PMID- 19772680 TI - Comparison of gut microbiota and allergic reactions in BALB/c mice fed different cultivars of rice. AB - Our preliminary clinical trial showed that consumption of cooked rice of a Japanese common cultivar Yukihikari improved atopic dermatitis associated with a suspected rice allergy, although the underlying mechanisms remain unclear. We hypothesised that the ameliorating effect of Yukihikari on atopic dermatitis is associated with the gut microbiota. BALB/c mice were fed a synthetic diet supplemented with uncooked and polished white rice powder prepared from one of four different cultivars: Yukihikari, rice A (common rice), rice B (brewery rice) and rice C (waxy rice). Denaturing gradient gel electrophoresis of PCR-amplified 16S rRNA gene fragments showed that the composition of faecal microbiota was different between mice fed Yukihikari and those fed rice A. Analysis of the 16S rRNA clone library and species-specific real-time PCR showed that the abundance of Akkermansia muciniphila, a mucin degrader, tended to be lower in mice fed Yukihikari. The incidence of allergic diarrhoea induced by oral administration of ovalbumin in systemically immunised mice was lower in mice fed Yukihikari, albeit with no difference in serum antibodies specific to ovalbumin. In a separate experiment, serum antibody levels specific to orally administered ovalbumin were lower in mice fed Yukihikari. Additionally, the translocation of horseradish peroxidase in isolated segments of ileum and colon tended to be lower in mice fed Yukihikari, suggesting a reduction in gut permeability in mice fed Yukihikari. These data indicate that changes in the gut microbiota of mice fed Yukihikari could be advantageous in the prevention of food allergy. PMID- 19772679 TI - Effect of rapeseed oil-derived plant sterol and stanol esters on atherosclerosis parameters in cholesterol-challenged heterozygous Watanabe heritable hyperlipidaemic rabbits. AB - Rapeseed oil (RSO) is a novel source of plant sterols, containing the unique brassicasterol in concentrations higher than allowed for plant sterol blends in food products in the European Union. Effects of RSO sterols and stanols on aortic atherosclerosis were studied in cholesterol-fed heterozygous Watanabe heritable hyperlipidaemic (Hh-WHHL) rabbits. Four groups (n 18 per group) received a cholesterol-added (2 g/kg) standard chow or this diet with added RSO stanol esters (17 g/kg), RSO stanol esters (34 g/kg) or RSO sterol esters (34 g/kg) for 18 weeks. Feeding RSO stanol esters increased plasma campestanol (P < 0.001) and sitostanol (P < 0.001) and aortic campestanol (P < 0.05) compared with controls. Feeding RSO sterol esters increased concentrations of plasma campesterol (P < 0.001), sitosterol (P < 0.001) and brassicasterol (P < 0.001) and aortic campesterol (P < 0.01). Significantly lower plasma cholesterol (P < 0.001) was recorded in the treated groups after 3 weeks and throughout the study. LDL cholesterol was reduced 50 % in the high-dose RSO sterol ester (P < 0.01) and high-dose RSO stanol ester (P < 0.001) groups compared with controls. Atherosclerotic lesions were found in three rabbits in each of the RSO stanol ester groups and in one in the RSO sterol ester group. Aortic cholesterol was decreased in the treated groups (P < 0.001) in response to lowering of plasma cholesterol induced by RSO sterol and stanol esters. In conclusion, RSO stanol and sterol esters with a high concentration of brassicasterol were well tolerated. They were hypocholesterolaemic and inhibited experimental atherosclerosis in cholesterol-fed Hh-WHHL rabbits. A significant uptake of plant sterols into the blood and incorporation of campesterol and campestanol into aortic tissue was recorded. PMID- 19772681 TI - Orally administered glucans from the edible mushroom Pleurotus pulmonarius reduce acute inflammation in dextran sulfate sodium-induced experimental colitis. AB - Polysaccharides are one of the most potent mushroom-derived substances exhibiting anti-inflammatory and immunomodulatory properties. The aims of the present study were to determine whether orally administered glucans from the edible mushroom Pleurotus pulmonarius could attenuate or prevent the development of experimental colitis in mice. Colonic inflammation was induced in mice by treatment with 3.5 % dextran sulfate sodium (DSS) for 18 d. Before or after DSS administration, mice were given hot water solubles (HWS) or mycelium extract (ME) (2 or 20 mg per mouse) daily in their food. Colonic damage was macroscopically and histologically evaluated. Inflammation was assessed by changes in colon length, TNF-alpha levels released by colonic samples in organ culture and myeloperoxidase (MPO) activity. mRNA levels of pro-inflammatory (IL-1beta) and anti-inflammatory (IL-10) cytokines in colonic samples were determined by quantitative real-time RT-PCR. P. pulmonarius glucans attenuated and prevented the development of symptoms associated with DSS-induced colitis. High doses of HWS and ME blocked colon shortening, suppressed MPO activity and improved macroscopic score in all treatment groups. In addition, histological damage from colitis was reduced by HWS and ME at all doses. The tissue levels of TNF-alpha protein were significantly decreased and correlated with degree of inflammation and macroscopic score. All treatments significantly attenuated the increased DSS mediated expression levels of IL-1beta. We conclude that the different glucan preparations (HWS or ME) harvested from P. pulmonarius when orally administered to DSS-treated mice attenuate the development of colonic inflammation, suggesting putative clinical utility for these extracts in the treatment of colitis. PMID- 19772682 TI - The relationship between birth weight and insulin resistance in childhood. AB - Chronic diseases that are typical of adulthood may originate in intra-uterine life through inadequate fetal development. The present epidemiological cohort study of 506 healthy children aged 5-8 years evaluated the relationship between birth weight and insulin resistance in an age group that has been assessed in few similar studies. Insulin concentration was determined by chemiluminescence and insulin resistance by the homeostasis model assessment (HOMA). Blood glucose, total cholesterol and fractions (LDL cholesterol and HDL cholesterol) and TAG concentrations were determined by automated enzymatic methods. Linear regression analysis investigated the relationship between birth weight (assessed as a continuous variable and in three categories: small for gestational age, SGA; adequate for gestational age and large for gestational age) and the HOMA index, using backward stepwise selection and biological models to explain the causal pathway of the relationship. There were negative associations between birth weight (P < 0.001), SGA (P = 0.027) and the HOMA index, and a positive association between waist circumference (P < 0.001) and the HOMA index. Considering the significant associations between birth weight and waist circumference (P < 0.001) and waist circumference and insulin resistance (P < 0.001), we can probably suspect that lower birth weight is a common cause of higher waist circumference and insulin resistance. In summary, the results of the present study showed increased insulin resistance in apparently healthy, young children, who had lower weight at birth and higher measurements of waist circumference. There is a need to develop public health policies that adopt preventive measures to promote adequate maternal-fetal and child development and enable early diagnosis of metabolic abnormalities. PMID- 19772683 TI - Maternal folic acid supplement use in early pregnancy and child behavioural problems: The Generation R Study. AB - Folate deficiency during embryogenesis is an established risk factor for neural tube defects in the fetus. An adequate folate nutritional status is also important for normal fetal growth and brain development. The aim of the present research was to study the association between folic acid use of the mother during pregnancy and child behavioural development. Within a population-based cohort, we prospectively assessed folic acid supplement use during the first trimester by questionnaire. Child behavioural and emotional problems were assessed with the Child Behaviour Checklist at the age of 18 months in 4214 toddlers. Results showed that children of mothers who did not use folic acid supplements in the first trimester had a higher risk of total problems (OR 1.44; 95 % CI 1.12, 1.86). Folic acid supplement use protected both from internalising (OR of no supplement use 1.65; 95 % CI 1.24, 2.19) and externalising problems (OR 1.45; 95 % CI 1.17, 1.80), even when adjusted for maternal characteristics. Birth weight and size of the fetal head did not mediate the association between folic acid use and child behaviour. In conclusion, inadequate use of folic acid supplements during early pregnancy may be associated with a higher risk of behavioural problems in the offspring. Folic acid supplementation in early pregnancy, aimed to prevent neural tube defects, may also reduce mental health problems in children. PMID- 19772684 TI - The impact of motivations and meanings on the wellbeing of caregivers of people with dementia: a systematic review. AB - BACKGROUND: The majority of people in the early and middle stages of dementia are cared for at home by non-paid caregivers, the majority of whom will be family members. Two factors which could have an impact on the quality of care provided to the care-recipient are the caregiver's motivations for providing care and the meaning s/he finds in caregiving. The aim of this review is to explore the potential impact of both meaning and motivation on the wellbeing of caregivers of people with dementia. The review also explores individual differences in motivations to provide care. METHODS: This was a systematic review of peer reviewed empirical studies exploring motivations and meanings in informal caregivers of people with dementia. Four studies were identified which examined the caregiver's motivations to provide care. Six studies were identified which examined the meaning that caregivers found in dementia caregiving. RESULTS: Caregivers' wellbeing could be influenced by the nature of their motivations to care. In addition, cultural norms and caregivers' kin-relationship to the care recipient impacted on motivations to provide care. Finding meaning had a positive impact on caregiver wellbeing. CONCLUSIONS: The limited evidence currently available indicates that both the caregiver's motivations to provide care and the meaning s/he finds in caregiving can have implications for the caregiver's wellbeing. More research is needed to explore the role of motivations and meaning in dementia caregiving. PMID- 19772685 TI - Top cited papers in International Psychogeriatrics: 6a. Quality of life for people with dementia living in residential and nursing home care: the impact of performance on activities of daily living, behavioral and psychological symptoms, language skills, and psychotropic drugs. PMID- 19772686 TI - Evaluating energy intake measurement in free-living subjects: when to record and for how long? AB - OBJECTIVE: To nutritionally analyse mean energy intake (EI) from different 3 d intervals within a 7 d recording period and to evaluate the seasonal effect on energy and nutrient intake. DESIGN: Cross-sectional study of dietary intake collected with 7 d food diaries. SETTING: Aberdeen, north-east Scotland, UK, between 2002 and 2004. SUBJECTS: Participants from two long-term trials were pooled. These trials, investigating genetic and environmental influences on body weight, were the Genotyping And Phenotyping (GAP) study and a cohort observational study, Rowett Assessment of Childhood Appetite and metaboLism (RASCAL). There were 260 Caucasian adults, BMI range 16.7-49.3 kg/m2, age range 21-64 years. RESULTS: Mean EI for Wednesday, Friday and Saturday had the closest approximation to the 7 d mean (0.1 % overestimate). A gender x season interaction (P = 0.019) with a different intake pattern for females and males was observed. For females, lower mean (se) EI was recorded in summer (8117 (610) kJ) and autumn (7941 (699) kJ) compared with spring (8929 (979) kJ) and winter (8132 (1041) kJ). For males, higher mean (se) EI was recorded in summer (10 420 (736) kJ) and autumn (10 490 (1041) kJ) compared with spring (9319 (1441) kJ) and winter (9103 (1505) kJ). CONCLUSIONS: The study results indicate that 3 d weighed intakes recorded from Wednesday, Friday and Saturday are most representative of 7 d habitual intake in free-living subjects. They also indicate that seasonality has a limited effect on EI and no effect on macronutrient intake. PMID- 19772687 TI - Trends in BMI of urban Australian adults, 1980-2000. AB - OBJECTIVE: To analyse changes in the distribution of BMI in Australia between 1980 and 2000. DESIGN: Data were from the 1980, 1983 and 1989 National Heart Foundation Risk Factor Prevalence Study, the 1995 National Nutrition Survey and the 1999/2000 Australian Diabetes, Obesity and Lifestyle Study. Survey participants were aged 25-64 years and resident in Australian capital cities. BMI was calculated as weight divided by height squared (kg/m2), where weight and height were measured using standard procedures. RESULTS: Mean BMI was higher in 2000 than 1980 in all sex and age groups. The age-adjusted increase was 1.4 kg/m2 in men and 2.1 kg/m2 in women. The BMI distribution shifted rightwards for all sex and age groups and became increasingly right-skewed. The change between 1980 and 2000 ranged from a decrease of 0.04 kg/m2 at the lower end of the distribution for men aged 25-34 years to an increase of 7.4 kg/m2 at the higher end for women aged 55-64 years. While the prevalence of obesity (BMI >or= 30 kg/m2) doubled, the prevalence of obesity class III (BMI >or= 40 kg/m2) increased fourfold. CONCLUSIONS: BMI in urban Australian adults has increased and its distribution has become increasingly right-skewed. This has resulted in a large increase in the prevalence of obesity, particularly the more severe levels of obesity. It will be important to monitor changes in the different classes of obesity and the extent to which obesity interventions both shift the BMI distribution leftwards and decrease the skew of the distribution. PMID- 19772688 TI - Television viewing, computer game play and book reading during meals are predictors of meal skipping in a cross-sectional sample of 12-, 14- and 16-year olds. AB - OBJECTIVE: To examine whether television viewing, computer game playing or book reading during meals predicts meal skipping with the aim of watching television, playing computer games or reading books (media meal skipping). DESIGN: A cross sectional study was conducted using a standardized self-administered questionnaire. Analyses were controlled for age, gender and BMI. SETTING: Data were obtained from a random sample of adolescents in Flanders, Belgium. SUBJECTS: Seven hundred and ten participants aged 12, 14 and 16 years. RESULTS: Of the participants, 11.8 % skipped meals to watch television, 10.5 % skipped meals to play computer games and 8.2 % skipped meals to read books. Compared with those who did not use these media during meals, the risk of skipping meals in order to watch television was significantly higher for those children who watched television during meals (2.9 times higher in those who watched television during at least one meal a day). The risk of skipping meals for computer game playing was 9.5 times higher in those who played computer games weekly or more while eating, and the risk of meal skipping in order to read books was 22.9 times higher in those who read books during meals less than weekly. The more meals the respondents ate with the entire family, the less likely they were to skip meals to watch television. CONCLUSIONS: The use of media during meals predicts meal skipping for using that same medium. Family meals appear to be inversely related to meal skipping for television viewing. PMID- 19772689 TI - Details and acceptability of a nutrition intervention programme designed to improve the contents of children's packed lunches. AB - OBJECTIVE: To describe the 'Smart Lunch Box' intervention and provide details on feedback from the participants on the acceptability and usability of the intervention materials. DESIGN: A cluster randomised controlled trial, randomised by school. English schools were stratified on percentage free-school-meals eligibility and attainment at Key Stage 2. A 'Smart Lunch Box' with supporting materials and activities on healthy eating was delivered to parents and children via schools in the intervention group. Feedback forms containing information on a total of fifteen intervention items were filled out by the parents and/or children participating in the intervention and were collected after each of the three phases of the intervention. SETTING: Eighty-nine primary schools in England, Scotland, Wales and Northern Ireland, randomly selected; forty-four schools in the intervention arm. SUBJECTS: A total of 1294 children, aged 9-10 years, took part in the trial. Of the 604 children in the intervention arm, 343 provided feedback after at least one of the three phases. RESULTS: A median of twelve items out of a total of fifteen were used by responders. The two intervention items most likely to be used were the individual food boxes and the cooler bags. Whether a participant liked an item significantly affected whether they used it for all items except the cooler bag, fruity face and individual food boxes. CONCLUSIONS: Practical intervention items aimed at parents are likely to be used in the longer term and therefore may be appropriate for use in an intervention strategy to improve packed lunches. PMID- 19772690 TI - Parental child-feeding strategies in relation to Dutch children's fruit and vegetable intake. AB - OBJECTIVE: To identify parental child-feeding strategies that may increase children's fruit or vegetable intake, since the relationship between these strategies and children's intake has never been investigated for fruit and vegetables as two separate food groups. DESIGN: A survey study, where parents provided information about their practices in relation to feeding their children and about their own and their children's fruit and vegetable intake. Children completed a preference questionnaire about fruit and vegetables. To find underlying parental child-feeding strategies, factor analysis was applied to parents' practices in relation to fruit and vegetables separately. Regression analysis was used to predict the effect of these strategies on children's fruit and vegetable intake. The impact of the strategies was further analysed by estimating children's intake based on the frequency of use of specific strategies. SETTING: The study was conducted at three primary schools in The Netherlands. SUBJECTS: A total of 259 children between 4 and 12 years old and their parents (n 242). RESULTS: Parents used different strategies for fruit as compared with vegetables. The vegetable-eating context was more negative than the fruit-eating context. Parental intake and presenting the children with choice were positive predictors of children's intake of both fruit and vegetables. The intake difference based on frequency of use of the strategy 'Choice' was 40 g/d for vegetables and 72 g/d for fruit (P < 0.001). CONCLUSIONS: Future interventions should focus on presenting children with choice during fruit- and vegetable-eating situations, since this is a powerful strategy to stimulate children's fruit and vegetable intake. PMID- 19772691 TI - Food group intake and central obesity among children and adolescents in the Third National Health and Nutrition Examination Survey (NHANES III). AB - OBJECTIVE: To explore mean food group intakes associated with central obesity anthropometry among children and adolescents enrolled in the Third National Health and Nutrition Examination Survey (NHANES III). DESIGN: Cross-sectional study. SETTING: Representative sampling of the US population (1998-2002). SUBJECTS: Subjects were 3761 children (5-11 years) and 1803 adolescents (12-16 years) with single 24 h dietary recalls and anthropometric measures of central body fat (waist circumference and sum of subscapular and suprailiac skinfold thicknesses). RESULTS: Results were controlled for confounding by age, height, race/ethnicity, Tanner stage, television viewing and parental education. In younger children, there was no relationship between central adiposity and mean intakes of dairy, fruit, vegetables or grains, while a positive association with meat intake was found among boys. In adolescent boys and girls, central body fat measures were inversely associated with mean dairy and grain intakes. Adolescent boys in the highest quartile of central adiposity consumed less fruit and fewer vegetables; those in the lowest central adiposity quartile consumed less meat. Finally, adolescents who met the criteria for central obesity (waist circumference >or=85th percentile for age and sex) reported consuming significantly less total dairy (as well as milk and cheese separately), total grains (whole and refined) and total fruit and vegetables. There was no association with meat consumption. To test the stability of these findings, the final analysis was replicated in 2541 same-aged adolescents from NHANES 1999 2002; the results were very similar. CONCLUSIONS: These cross-sectional analyses suggest that intakes of dairy, grains and total fruits and vegetables are inversely associated with central obesity among adolescents. PMID- 19772692 TI - Decrease in the prevalence of paediatric adiposity in Switzerland from 2002 to 2007. AB - OBJECTIVE: A national study in Switzerland in 2002 suggested nearly one in five schoolchildren was overweight. Since then, many programmes have been introduced in an attempt to control the problem. The aim of the present study was to determine the prevalence of childhood overweight in Switzerland five years later. DESIGN: In both studies a cross-sectional, three-stage, probability-proportional to-size cluster sampling of schools throughout Switzerland was used to obtain a representative sample of approximately 2500 children aged 6-13 years. Height and weight were measured and BMI calculated. The BMI references from the Centers for Disease Control and Prevention were used to determine the prevalences of underweight (<5th percentile), overweight (>or=85th and <95th percentile) and obesity (>or=95th percentile). RESULTS: In 2007 the prevalences of underweight, overweight and obesity in boys were 3.5 %, 11.3 % and 5.4 %, respectively; in girls they were 2.6 %, 9.9 % and 3.2 %. Compared with 2002, there was a significant decrease in the prevalence of overweight in girls and of obesity in both genders. In contrast to 2002, where there were no differences, in 2007 the prevalence of paediatric obesity was significantly higher in communities with a population >100 000 compared with smaller communities (P < 0.05). CONCLUSIONS: In summary, over the past 5 years, the prevalence of adiposity has decreased in Swiss children. These findings suggest that increased awareness combined with mainly school-based programmes aimed at physical activity and healthy nutrition may have helped to control this public health problem. Future monitoring in Switzerland will determine if these findings are sustained. PMID- 19772693 TI - Early growth and markers of cardiovascular risk in Keralan children in the Integrated Child Development Scheme. AB - OBJECTIVE: Low birth weight is associated with increased lifelong morbidity. Kerala has a renowned, low-cost, maternal-child health system in which is couched universal access to the Integrated Child Development Scheme (ICDS), central to which is community-based maternal-infant nutritional supplementation. We assessed whether children in this environment showed enhanced birth weight and postnatal growth and whether the evolution of early markers of CVD was attenuated in comparison to contemporaries from other states. DESIGN: A part retrospective, part prospective cohort study in which children (n 286) born in 1998-2000 in Calicut were identified from Anganwadi records. They were traced at 6 years and underwent full anthropometry and blood pressure measurements at 6 and 8 years. RESULTS: Mean birth weight (2.86 (SD 0.40) kg) was greater than in Indian contemporaries but consistently <-1 SD below the National Center for Health Statistics reference median throughout childhood. Birth weight significantly predicted body mass (BMI) at 8 years. Lower birth weight was strongly predictive of a higher waist:hip ratio (WHR) indicative of adverse central (coelomic) fat distribution (P < 0.01). Faster weight gain in infancy was weakly predictive of a lower WHR (P = 0.59), but faster late childhood growth at 6-8 years was non significantly predictive of adverse WHR. CONCLUSIONS: At 8 years of age, children in Calicut participating in the ICDS have greater birth weight and relative attenuation of the evolution of early CVD markers compared with children in apparently comparable states. The relative contributions of the ICDS and other factors inherent to Kerala cannot be inferred from the present study. PMID- 19772694 TI - Is the use of resveratrol in the treatment and prevention of obesity premature? AB - Obesity is a multi-faceted disease, predisposing sufferers to numerous co morbidities such as epithelial dysfunction and insulin resistance which ultimately result in CVD. Visceral adipose tissue in particular is associated with inflammation due to the release of pro-inflammatory cytokines by adipocytes. Inflammation seems to be rather central in causing damage to endothelial cells as well as exerting negative effects on glucose metabolism, ultimately leading to insulin resistance. Resveratrol is a naturally occurring phenolic substance which has been found to display anti-inflammatory, vasoprotective and insulin sensitising effects, among others. The popularity of resveratrol use is escalating in the treatment of various ailments including obesity in adults. The use of the substance in childhood obesity is, however, a worrying factor, as no studies have as yet been performed on adolescent animals and there is evidence of kidney toxicity of resveratrol and its metabolites at intake levels below those currently approved as safe. Another cause for concern is the uncertainty surrounding long-term, low-dose administration of the substance in humans. The supplement should thus not be recommended for use in the prevention and treatment of obesity until conclusive research is established on the safety of long-term usage of resveratrol in both children and adults. PMID- 19772695 TI - Bone abnormalities in constitutional thinness. PMID- 19772696 TI - Short-term effects of replacing milk with cola beverages on insulin-like growth factor-I and insulin-glucose metabolism: a 10 d interventional study in young men. AB - In the Western world, a trend towards increased consumption of carbonated soft drinks combined with a decreasing intake of milk is observed. This may affect circulating insulin-like growth factor I (IGF-I) and fasting insulin, as seen in pre-pubertal children. The present study was designed to reflect the trend of replacing milk with carbonated beverages in young men and to study the effects of this replacement on IGF-I, IGF-binding protein 3 (IGFBP-3), IGF-I:IGFBP-3 and glucose-insulin metabolism. A randomised, controlled crossover intervention study, in which eleven men aged 22-29 years were given a low-Ca diet in two 10 d periods with 10 d washout in between. In one period, they drank 2.5 litres of Coca Cola(R) per day and the other period 2.5 litres of semi-skimmed milk. Serum IGF-I, IGFBP-3 (RIA), insulin (fluoro immunoassay) and glucose (Cobas) were determined at baseline and end point of each intervention period. Insulin resistance and beta-cell function were calculated with the homeostasis model assessment. A decrease in serum IGF-I was observed in the cola period compared with the milk period (P < 0.05). No effects of treatment were observed on IGFBP 3, IGF-I:IGFBP-3, insulin, glucose, insulin resistance or beta-cell function. The present study demonstrates that high intake of cola over a 10 d period decreases total IGF-I compared with a high intake of milk, with no effect on glucose insulin metabolism in adult men. It is unknown whether this is a transient phenomenon or whether it has long-term consequences. PMID- 19772697 TI - A giant cord hemangioma diagnosed at 32 weeks' gestation. PMID- 19772699 TI - Butting out. PMID- 19772701 TI - Quitting smoking during early versus late pregnancy: the risk of preeclampsia and adverse birth outcomes. AB - OBJECTIVE: To examine the impact of women's quitting smoking during early and late pregnancy on their risk of preeclampsia and on birth outcomes. METHODS: We analyzed data from a case-control study of 86 preeclamptic women and 239 controls at three hospitals in Quebec between January 2003 and March 2006. RESULTS: Compared with never having smoked, early smoking cessation, i.e., quitting before 20 weeks' gestation, was not associated with a reduced risk of preeclampsia (adjusted OR 1.03; 95% CI 0.42-2.60). Both late smoking cessation (quitting after 20 weeks of gestation) and persistent smoking (smoking before and during pregnancy) were associated with a non-significant reduction in the risk of preeclampsia (aOR 0.78; 95% CI 0.12-5.02 for late quitting and aOR 0.62; 95% CI 0.16-2.37 for persistent smoking). However, persistent smoking was associated with an increased risk of other adverse pregnancy outcomes, such as low birth weight (aOR 10.2; 95% CI 2.49-41.8) and preterm birth (aOR 3.59; 95% CI 1.06 12.1). CONCLUSION: Although late quitting and persistent smoking may be associated with a decreased risk of preeclampsia, the benefit of early smoking cessation on pregnancy outcome is evident. PMID- 19772702 TI - Perinatal care for South Asian immigrant women and women born in Canada: telephone survey of users. AB - BACKGROUND: Previous research findings suggest that pregnant immigrant women receive less adequate perinatal care than pregnant non-immigrant women. This study was designed to assess the use of perinatal care services by newly immigrated South Asian women and Canadian-born women, and to determine any perceived barriers to receiving care. METHOD: We conducted a telephone survey of women who delivered at an academic community hospital in Calgary, Alberta. Two groups of women were interviewed at seven weeks postpartum: South Asian women who had immigrated within the last three years, and Canadian-born women of any ethnicity. Women who spoke Hindi, Punjabi, and/or English were eligible. Interviews consisted mainly of closed-ended questions. The main outcomes we sought were the proportion of women receiving perinatal care (such as attending prenatal classes or fetal monitoring), and any perceived barriers to care. RESULTS: Thirty South Asian and 30 Canadian-born women were interviewed. Most women in each group reported having pregnancy evaluations carried out. Fewer South Asian women than Canadian-born women understood the purpose of symphysis fundal height measurement (60% vs. 90%, P = 0.015) and tests for Group B streptococcus (33% vs. 73%, P = 0.004). Thirteen percent of South Asian and 23% of Canadian-born women attended prenatal classes. Most women (87-97%) believed they had received all necessary medical care. Language barriers were most commonly reported by South Asian women (33-43% vs. 0 for Canadian-born women). CONCLUSION: South Asian women considered language to be the most common barrier to receiving perinatal care. Such barriers may be overcome by wider availability of multilingual staff and educational materials in a variety of formats including illustrated books and videos. PMID- 19772703 TI - Pre-conception health awareness in infertility patients. AB - OBJECTIVE: Pre-conception counselling is important, as most pregnancies are unplanned. There are few published studies examining women's attitudes and knowledge in this area. As part of our ongoing education quality improvement program we evaluated the pre-conception knowledge and attitudes of women at an infertility clinic. METHODS: Women who presented for initial assessment to a university-affiliated infertility clinic completed a knowledge survey prior to the first physician consultation. RESULTS: Four hundred surveys were appropriately completed for data analysis. Patients were well informed about health optimization, folic acid consumption, infectious disease exposure, medication use, partner abuse, smoking, and recreational drug use. Patients were not well informed about the risks of daily alcohol consumption, advanced maternal age, exercise, cat litter exposure, and consumption of fish and certain other foods. They were uncertain about the importance of rubella immunization and family history. Nulliparous women were less knowledgeable about the significance of rubella immunization, exercise, recreational drug use, cat litter exposure, and fish consumption. Women who were more educated had more knowledge about the effects of the mother's age, exercise, alcohol exposure, and smoking on pregnancy. CONCLUSIONS: There are gaps in knowledge, even in the highly motivated population of infertile women who are planning to be pregnant. The results of this survey suggest that women need and want their physicians to educate them about optimal pre-pregnancy lifestyle. We will revise our education programs to account for these gaps. Larger population-based studies are needed to assess knowledge in the general population, so that appropriate health promotion and education programs can be implemented. PMID- 19772704 TI - Who are the providers of gynaecologic cancer surgical care in Ontario? AB - OBJECTIVE: To investigate the provision of surgical care for women with gynaecologic cancers in Ontario by examining the rate and distribution of procedures by hospital type, physician specialty, and region. METHODS: Women with an incident diagnosis of a gynaecologic malignancy were identified from April 1, 2003, to March 31, 2004, using the Ontario Cancer Registry. Records were linked to other provincial health databases, such as the Ontario Health Insurance Plan. RESULTS: The number of women with uterine cancer (UC) was 1436, with ovarian cancer (OC) 963, and cervical cancer (CC) 513. Surgery was a component of care for 94.7% of women with UC, for 72.7% of women with OC, and 57.1% of women with CC. Community hospitals were responsible for surgeries in 55.9% of UC, 38% of OC, and 37% of CC. The most common operation in the community hospital for UC was total abdominal hysterectomy and bilateral salpingo-oophorectomy (83.2%); for OC, it was unilateral or bilateral salpingo-oophorectomy (43%); and for CC it was total abdominal hysterectomy (46%) or cone biopsy (46%). The mean number of annual cases per community hospital was 14 for UC, three for OC, and three for CC. In academic centres, the acuity and volume was between four and 10 times higher. Gynaecologists performed 58.2% of all cancer surgeries: 68.2% of UC procedures, 41% of OC procedures, and 49.6% of CC procedures. The type of surgeries gynaecologists performed for each cancer are mirrored in the numbers seen in the community hospital. CONCLUSION: Gynaecologists perform over half of the operations for gynaecologic cancers in Ontario. The types of procedures reflect those seen in the community hospitals. Quality indicators must be defined to assess appropriateness. These data would be enhanced with further information about staging. The data reveal patterns which should influence planning for manpower and hospital resource requirements. PMID- 19772705 TI - Esophageal cancer associated with pregnancy. AB - BACKGROUND: Esophageal cancer concomitant with pregnancy is very rare and the prognosis is poor. The main concern in diagnosis is that the clinical presentations of esophageal cancer in pregnant woman are often not considered serious and are misinterpreted as pregnancy-related symptoms. CASE: A 29-year-old woman presented at 29 weeks' gestation with dysphagia, weight loss, and a single episode of hematemesis. Esophageal carcinoma was diagnosed on endoscopy, and local spread confirmed by MRI. A Caesarean section was performed at 32 weeks' gestation, and shortly afterwards the patient underwent thoracotomy, but resection of the tumour could not be performed. Palliative treatment was begun and she was discharged from hospital. CONCLUSION: Clinicians must be aware and include the probability of esophageal cancer in the differential diagnosis of gastrointestinal symptoms during pregnancy. PMID- 19772706 TI - Uterine peristalsis in women with repeated IVF failures: possible therapeutic effect of hyoscine bromide. AB - BACKGROUND: Uterine peristalsis, which is influenced by hormonal and cholinergic effects, may have a role in successful implantation and continuing pregnancy. CASES: We encountered abnormal uterine peristalsis in three women who had had repeated in vitro fertilization (IVF) treatment failures. They subsequently had successful pregnancies when hyoscine bromide was administered at the time of embryo transfer. CONCLUSION: It is possible that decreasing uterine peristalsis with use of an anticholinergic agent during IVF treatment facilitates retention of embryos and increases the probability of successful pregnancy. PMID- 19772707 TI - Postpartum depression and apical ballooning syndrome (takotsubo syndrome). AB - BACKGROUND: Acute cardiac complications occur occasionally during pregnancy and in the immediate postpartum period. Some of these cardiac scenarios are rare and provide a diagnostic challenge. We report a case of apical ballooning syndrome (ABS), also known as takotsubo cardiomyopathy or broken-heart syndrome, in a postpartum patient. CASE: A 32-year-old multigravid woman presented at 17 days after delivery with chest pain typical for cardiac ischemic pain. Her prior obstetrical history included two uncomplicated vaginal deliveries, and the current postpartum period had been uncomplicated until the time of presentation. Cardiac catheterization was performed and showed normal coronary blood vessels with no evidence of coronary artery occlusion. Left ventricular systolic function was moderately depressed, with an ejection fraction of 45%. The patient had full recovery of myocardial function in less than 40 days, with a subsequent echocardiogram during that time showing a normal ejection fraction of 65%. CONCLUSION: Apical ballooning syndrome is a rare reversible cardiac condition that should be differentiated from ischemic and peripartum cardiomyopathy, especially in the immediate postpartum period. PMID- 19772708 TI - Mallory-Weiss tear diagnosed in the immediate postpartum period: a case report. AB - BACKGROUND: Mallory-Weiss tears occur rarely during pregnancy, labour and delivery, and the puerperium, despite the increased frequency of retching and vomiting. CASE: We describe a Mallory-Weiss syndrome diagnosed during the immediate postpartum period in a 34-year-old primigravida. The syndrome initially manifested as lower gastrointestinal bleeding and melena. CONCLUSION: If unrecognized, this complication may lead to life-threatening internal bleeding. It is important to look for an occult bleeding source with such a presentation, and prompt intervention is essential. PMID- 19772709 TI - Nicotine replacement therapy during pregnancy: recommended or not recommended? AB - Smoking during pregnancy increases the risks of maternal and fetal complications and adverse neonatal outcomes, and it remains a significant health problem. Although pregnancy is often a strong motivator for smoking cessation, many pregnant women continue to smoke. Effective smoking cessation strategies for use during pregnancy are therefore clearly needed. Behavioural support provided by prenatal smoking cessation programs is safe and effective during pregnancy, but it generates a relatively modest reduction in smoking cessation rates. Nicotine replacement therapy (NRT), in conjunction with behavioural support, may offer an effective alternative to help pregnant women quit smoking. This suggestion is based on the convincing research evidence for the effectiveness of NRT in the general population. There is no consensus, however, on whether or not care providers should recommend NRT during pregnancy because of persistent concerns about its safety and effectiveness. We reviewed the data on the safety and effectiveness of NRT and on the possible physiological reasons for NRT's low effectiveness in pregnant women, and conclude that it is prudent to advise pregnant women who smoke 5 cigarettes or fewer per day to use behavioural support, and not NRT, to help them quit. Pregnant women with a moderate or high level of addiction may use NRT under the supervision of their physician. A combination of cognitive-behavioural therapy and counselling with NRT is the most effective strategy to achieve smoking cessation during pregnancy. PMID- 19772710 TI - Guidelines for the management of vasa previa. AB - OBJECTIVES: To describe the etiology of vasa previa and the risk factors and associated condition, to identify the various clinical presentations of vasa previa, to describe the ultrasound tools used in its diagnosis, and to describe the management of vasa previa. OUTCOMES: Reduction of perinatal mortality, short term neonatal morbidity, long-term infant morbidity, and short-term and long-term maternal morbidity and mortality. EVIDENCE: Published literature on randomized trials, prospective cohort studies, and selected retrospective cohort studies was retrieved through searches of PubMed or Medline, CINAHL, and the Cochrane Library, using appropriate controlled vocabulary (e.g., selected epidemiological studies comparing delivery by Caesarean section with vaginal delivery; studies comparing outcomes when vasa previa is diagnosed antenatally vs. intrapartum) and key words (e.g., vasa previa). Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Searches were updated on a regular basis and incorporated into the guideline to October 1, 2008. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment related agencies, clinical practice guideline collections, clinical trial registries, and from national and international medical specialty societies. VALUES: The evidence collected was reviewed by the Diagnostic Imaging Committee and the Maternal Fetal Medicine Committee of the Society of Obstetricians and Gynaecologists of Canada (SOGC) and quantified using the evaluation of evidence guidelines developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: The benefit expected from this guideline is facilitation of optimal and uniform care for pregnancies complicated by vasa previa. SPONSORS: The Society of Obstetricians and Gynaecologists of Canada. SUMMARY STATEMENT: A comparison of women who were diagnosed antenatally and those who were not shows respective neonatal survival rates of 97% and 44%, and neonatal blood transfusion rates of 3.4% and 58.5%, respectively. Vasa previa can be diagnosed antenatally, using combined abdominal and transvaginal ultrasound and colour flow mapping; however, many cases are not diagnosed, and not making such a diagnosis is still acceptable. Even under the best circumstances the false positive rate is extremely low. (II-2). RECOMMENDATIONS: 1. If the placenta is found to be low lying at the routine second trimester ultrasound examination, further evaluation for placental cord insertion should be performed. (II-2B) 2. Transvaginal ultrasound may be considered for all women at high risk for vasa previa, including those with low or velamentous insertion of the cord, bilobate or succenturiate placenta, or for those having vaginal bleeding, in order to evaluate the internal cervical os. (II-2B) 3. If vasa previa is suspected, transvaginal ultrasound colour Doppler may be used to facilitate the diagnosis. Even with the use of transvaginal ultrasound colour Doppler, vasa previa may be missed. (II-2B) 4. When vasa previa is diagnosed antenatally, an elective Caesarean section should be offered prior to the onset of labour. (II-1A) 5. In cases of vasa previa, premature delivery is most likely; therefore, consideration should be given to administration of corticosteroids at 28 to 32 weeks to promote fetal lung maturation and to hospitalization at about 30 to 32 weeks. (II-2B) 6. In a woman with an antenatal diagnosis of vasa previa, when there has been bleeding or premature rupture of membranes, the woman should be offered delivery in a birthing unit with continuous electronic fetal heart rate monitoring and, if time permits, a rapid biochemical test for fetal hemoglobin, to be done as soon as possible; if any of the above tests are abnormal, an urgent Caesarean section should be performed. (III-B) 7. Women admitted with diagnosed vasa previa should ideally be transferred for delivery in a tertiary facility where a pediatrician and blood for neonatal transfusion are immediately available in case aggressive resuscitation of the neonate is necessary. (II-3B) 8. Women admitted to a tertiary care unit with a diagnosis of vasa previa should have this diagnosis clearly identified on the chart, and all health care providers should be made aware of the potential need for immediate delivery by Caesarean section if vaginal bleeding occurs. (III-B). PMID- 19772712 TI - Preimplantation genetic testing. AB - OBJECTIVE: To review the techniques and indications of preimplantation genetic testing, including preimplantation genetic diagnosis and screening. OPTIONS: Limited to an introductory discussion about the genetic aspects of preimplantation reproductive techniques. OUTCOMES: This update does not discuss in detail the adverse outcomes that have been recorded in association with assisted reproductive technologies. EVIDENCE: The Cochrane Library and Medline were searched for articles relating to preimplantation testing that were published from 1990 to February 2008, using the following terms: preimplantation genetic diagnosis, preimplantation genetic screening, and in vitro fertilization. Results were restricted to systematic reviews, randomized control trials/controlled clinical trials, and observational studies. Additional publications were identified from the bibliographies of these articles. Randomized controlled trials were considered evidence of the highest quality, followed by cohort studies. Grey (unpublished) literature was identified through searching the websites of health technology assessment and health technology assessment-related agencies, clinical practice guideline collections, clinical trial registries, and from national and international medical specialty societies. VALUES: This update is a consensus of the Genetics Committee of the Society of Obstetricians and Gynaecologists of Canada. The recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. BENEFITS, HARMS, AND COSTS: This update educates readers about new genetic concepts, directions, and technology. The major harms and costs identified are those of assisted reproductive technologies. SPONSOR: The Society of Obstetricians and Gynaecologists of Canada. CONCLUSIONS: Preimplantation genetic diagnosis is an alternative to prenatal diagnosis for the detection of genetic disorders in couples at risk of transmitting a genetic condition to their offspring. Preimplantation genetic screening has been proposed to improve the effectiveness of in vitro fertilization in women of advanced maternal age or in couples with recurrent miscarriage or implantation failure, but the benefits of this approach are debated. RECOMMENDATIONS: The recommendations were made according to guidelines developed by the Canadian Task Force on Preventive Health Care. 1. Before preimplantation genetic diagnosis is performed, genetic counselling must be provided to ensure that patients fully understand the risk of having an affected child, the impact of the disease on an affected child, and the benefits and limitations of all available options for preimplantation and prenatal diagnosis. (III-A) 2. Couples should be informed that preimplantation genetic diagnosis can reduce the risk of conceiving a child with a genetic abnormality carried by one or both parents if that abnormality can be identified with tests performed on a single cell. (II-2B) 3. Invasive prenatal testing to confirm the results of preimplantation genetic diagnosis is encouraged because the methods used for preimplantation genetic diagnosis have technical limitations that include the possibility of a false negative result. (II-2B) 4. Before preimplantation genetic screening is performed, thorough education and counselling must be provided to ensure that patients fully understand the limitations of the technique, the risk of error, and the lack of evidence that preimplantation genetic screening improves live-birth rates. (III-A) 5. Available evidence does not support the use of preimplantation genetic screening as currently performed to improve live-birth rates in patients with advanced maternal age, recurrent implantation failure, or recurrent pregnancy loss. (I-D). PMID- 19772714 TI - Test selection, adaptation, and evaluation: a systematic approach to assess nutritional influences on child development in developing countries. AB - BACKGROUND: Evaluating the impact of nutrition interventions on developmental outcomes in developing countries can be challenging since most assessment tests have been produced in and for developed country settings. Such tests may not be valid measures of children's abilities when used in a new context. AIMS: We present several principles for the selection, adaptation, and evaluation of tests assessing the developmental outcomes of nutrition interventions in developing countries where standard assessment tests do not exist. We then report the application of these principles for a nutrition trial on the Indonesian island of Lombok. SAMPLE: Three hundred children age 22-55 months in Lombok participated in a series of pilot tests for the purpose of test adaptation and evaluation. Four hundred and eighty-seven 42-month-old children in Lombok were tested on the finalized test battery. METHODS: The developmental assessment tests were adapted to the local context and evaluated for a number of psychometric properties, including convergent and discriminant validity, which were measured based on multiple regression models with maternal education, depression, and age predicting each test score. RESULTS: The adapted tests demonstrated satisfactory psychometric properties and the expected pattern of relationships with the three maternal variables. Maternal education significantly predicted all scores but one, maternal depression predicted socio-emotional competence, socio-emotional problems, and vocabulary, while maternal age predicted socio-emotional competence only. CONCLUSION: Following the methodological principles we present resulted in tests that were appropriate for children in Lombok and informative for evaluating the developmental outcomes of nutritional supplementation in the research context. Following this approach in future studies will help to determine which interventions most effectively improve child development in developing countries. PMID- 19772715 TI - Post 9/11: high asthma rates among children in Chinatown, New York. AB - We reported increased rates of childhood asthma and worsening of preexisting asthma in Chinatown near the World Trade Center (WTC) after September 11, 2001. This conclusion was corroborated by the WTC Health Registry in 2003, which showed asthma prevalence in children <5 years old was higher than national estimates. In 2002, ethnic Chinese in New York City (NYC), based on 2000 U.S. Census addresses, were reported to have the lowest levels of asthma compared with other ethnic NYC neighborhoods. This study was designed to determine if Chinatown asthma rates are still higher than other ethnic neighborhoods and if rates decreased since 2003. We surveyed 353 parents of children at a Chinatown elementary school, conducted spirometry on 202 students, measured air pollution (PM2.5), and sampled dust from the floor of the school during 2008 for concentrations of dust-mite antigens, cat, rat, mouse, and cockroach. Asthma rates of 14.4% were reported in children who refused spirometry if they lived <1 mi from the WTC. The rate was 4.9% if they lived farther away. Twenty-nine percent of all students (4-12 years old) who had spirometry showed a forced expiratory volume at 1 second (FEV(1)) of <80% predicted normal. Among children who were alive in 2001, 17.4% had an FEV(1) of < or = 75% predicted. The concentration of PM2.5 reached a high level of 40 microg/m(3). Indoor aeroallergen concentrations were negligible. Chinatown asthma rates are still higher than among other groups (29% versus the NYC reference rate of 13%). High air pollution levels may account for increased asthma incidence. It is possible that exposure to toxins on September 11, 2001 accentuated the effect of subsequent exposure to air pollution. PMID- 19772716 TI - United States Environmental Protection Agency perchlorate method 332.0 via microbore and capillary chromatographic formats: statistical evaluation of the use of (18)O-perchlorate internal standard with deionized-water matrices. AB - A statistically sound evaluation is made of the United States Environmental Protection Agency's perchlorate Method 332.0 by tandem ion chromatography-mass spectrometry-mass spectrometry. Two microbore formats and one capillary format are used with a deionized-water matrix. The evaluation is made for raw peak-area data and for analyte responses scaled by the internal standard, over an analyte concentration range of 0.25 to 200 microg/L. Results indicate that: (i) the internal-standard signal is suppressed by the analyte in both microbore formats; (ii) the analyte signal is not affected by the internal standard; (iii) models for the calibration curves usually contain bias; (iv) the measurement uncertainty is similar in magnitude for both the peak-area- and ratio-based curves. PMID- 19772717 TI - Trace level haloacetic acids in drinking water by direct injection ion chromatography and single quadrupole mass spectrometry. AB - Chlorine has been widely used to kill disease-causing microbes in drinking water. During the disinfection process, organic and inorganic material in source waters can combine with chlorine and certain other chemical disinfectants to form disinfection by-products. The kind of disinfectant used can produce different types and levels of disinfectant byproducts in the drinking water, such as trihalomethanes and haloacetic acids (5HAAs). Currently, USEPA Method 552 utilizes a methyl tert-butyl ether extraction and diazomethane derivatization of HAAs and phenolic disinfectant by-products, and a gas chromatograph equipped with a capillary column to perform the separation of methyl-haloacetates and anisoles. To detect, gas chromatography and electron capture detector are used. This article demonstrates a simple method using direct injection ion chromatography hyphenated with mass spectrometry for the analysis of 5HAAs. PMID- 19772718 TI - Anion separation and preconcentration with cyclen and cyclen-resorcinarene derivatives. AB - N-undecyl cyclen and a resorcinarene bowl bearing four cyclen arms have been applied as anion exchangers in ion chromatography by strong adsorption to a reversed-phase column. The column loaded with the resorcinarene bowl cyclen tetramer exhibited significantly better performance in anion separation than that with N-undecyl cyclen monomer in isocratic elution mode. Both columns were tested for polarizable anion preconcentration or removal. By changing the eluent type from sodium bicarbonate to sodium hydroxide, the degree of protonation of the cyclen molecules could be modified, and the column capacity for anion retention adjusted thereby. Capacity gradient elution was successfully applied to removing sample matrix ions in the preconcentration of perchlorate and perrhenate ions as example analytes. PMID- 19772719 TI - Determination of low molecular weight monocarboxylic Acid gases in the atmosphere by parallel plate diffusion scrubber-ion chromatography. AB - A method has been developed for the determination of the concentration of low molecular weight monocarboxylic acid gases in the atmosphere. The method involves quantitative collection of analyte gases using a parallel plate diffusion scrubber and subsequent ion analysis by ion chromatography. Among the gases are formic acid, acetic acid, propionic acid, n-butyric acid, and n-valeric acid. Method detection limits are on the order of sub to low parts-per-trillion by volume. The method has been successfully applied to ambient air analysis. PMID- 19772720 TI - The determination of haloacetic acids in real world samples using IC-ESI-MS-MS. AB - This paper presents the determination of nine haloacetic acids (HAAs) in high ionic strength, treated effluent waters using an ion chromatography-electrospray ionization-tandem mass spectrometry (IC-ESI-MS-MS) method with internal standards and discussions of each of the method parameters. Data is also provided for these same samples using USEPA Method 552.2. The sample matrices contain up to 170 mg/L chloride and 243 mg/L sulfate. Matrix ions are separated from the analytes using a high capacity anion exchange analytical column and diverted to a waste stream during each analysis to avoid signal suppression and contamination of the detector. No derivatization, offline matrix elimination, or preconcentration is used. Four isotopically-labeled HAAs are used for quantification, and detection limits are in the range of 400-1000 microg/L with R(2) of at least 0.997 over two orders of magnitude for all analytes in matrix. A trichloroacetic acid (TCAA) internal standard with the label on the alpha carbon is found to be more stable than the TCAA-1-(13)C. Amounts found using IC-MS-MS are 65-130% of amounts found using Method 552.2 for all analytes in the real world treated effluent waters. Detection limits for all nine analytes in matrix are in the range of 100-700 ng/L. PMID- 19772721 TI - Matrix elimination ion chromatography method for trace level azide determination in irbesartan drug. AB - Ultra-trace analysis of azide in complicated Irbesartan sample matrix is achieved by the in-line sample preparation technique. Sodium azide is the precursor of Irbesartan, which is used as an anti-hypertensive drug. Due to the toxic nature of sodium azide, reliable determination of azide in Irbesartan is necessary. Irbesartan when analyzed for sodium azide, as per the USP 31-NF26 method, gets adsorbed to the analytical column, leading to reduction in column capacity and irreproducible retention time. The retained drug has to be removed with special rinsing solution, followed by re-equilibration with the mobile phase. This process takes at least 3 to 4 h for each sample analysis. The new method developed overcomes the limitations of the USP 31-NF26 method. This method is validated for specificity, linearity, accuracy, precision, sample solution stability, and robustness as per International Conference on Harmonization guidelines. The relationship between peak response and concentration is found to be linear between 5 to 80 ng/mL of sodium azide, with the correlation coefficient (r(2)) of 0.9995. The limits of detection and quantification for sodium azide are 0.532 and 1.61 microg/gm with respect to the sample weight. PMID- 19772722 TI - Evaluation of methods for the simultaneous analysis of cations and anions using HPLC with charged aerosol detection and a zwitterionic stationary phase. AB - This paper describes the development and qualification of a method capable of analyzing inorganic ions as salts and counter-ions of both active pharmaceutical ingredients and other compounds such as lysine. The use of a polymeric zwitterionic column with a binary high-performance liquid chromatography gradient enables the separation of several anions and cations in a single run. A generic gradient (method #1) was developed and validated with respect to specificity, correlation, intermediate precision, accuracy, and sensitivity (limits of quantitation and detection) for four anions and two cations. Furthermore, the ability to alter chromatographic selectivity by simple gradient manipulation (without altering the mobile phase composition or column type) is demonstrated for nine anions and three cations (method #2). The simultaneous measurement of cations and anions at the parts per billion level using the Corona charged aerosol detector with zwitterionic chromatography-polymeric hydrophilic interaction chromatography is a viable alternative to traditional techniques used for ion analysis. PMID- 19772723 TI - Ion chromatographic determination of residual phase transfer catalyst in active pharmaceutical ingredient. AB - A new ion chromatography method with non-suppressed conductivity detection has been developed for the quantification of residual phase transfer catalyst tetrabutylammonium bromide (TBAB) in an active pharmaceutical drug, Levetiracetam. Separation conditions are optimized to get a clear separation of TBAB from drug impurities using a Metrosep Cation C2-150 column. Conditions are also optimized to separate tetramethylammonium bromide, tetraethylammonium bromide, and tetrapropylammonium bromide, which are also used as phase transfer catalysts in several syntheses. Method performance was checked for selectivity, linearity, limit of quantification, limit of detection, accuracy, and precision. The method has superior performance with linearity r(2) > or = 0.9999, recovery from 94.7% to 96.5%, precision < or = 0.74%. In-line preconcentration is used to achieve limits of detection and quantification of 39 ng and 118 ng of TBAB, which corresponds to 1.56 and 4.72 microg/g of TBAB with respect to sample weight. The proposed method can be used for routine quality assurance analysis in the pharmaceutical industry. PMID- 19772724 TI - Separation of actinides using capillary extraction chromatography-inductively coupled plasma mass spectrometry. AB - Trace levels of actinides have been separated on capillary extraction chromatography columns. Detection of the actinides was achieved using an inductively coupled plasma mass spectrometer, which was coupled with the extraction chromatography system. In this study, we compare 30-cm long, 4.6 mm i.d. columns to capillary columns (750 microm i.d.) with lengths from 30 cm up to 150 cm. The columns that were tested were packed with TRU resin. We were able to separate a mixture of five actinides ((232)Th, (238)U, (237)Np, (239)Pu, and (241)Am). This work has application to rapid bioassay as well as automated separations of actinide materials. PMID- 19772725 TI - An improved ion chromatographic method for fast and sensitive determination of N methylpyrrolidine in cefepime hydrochloride. AB - An alternative ion chromatographic method to the existing USP method for the determination of N-methylpyrrolidine (NMP) in cefepime hydrochloride is developed. The cefepime in solution behaves as a strong cation and gets retained in the analytical column, leading to reduction in column capacity and irreproducible retention time. The retained drug has to be removed with a special rinsing solution, followed by re-equilibration with the mobile phase. This process takes at least 3 to 4 h time for sample analysis. We used a silica-based cation exchange column with poly-butadiene-maleic acid functional group attached with an optimized mobile phase composition. The characteristic feature of this method is the short analysis time with a clear separation of NMP and the cationic drug molecule within a run-time of 30 min. The developed method overcomes the limitations of the USP method. This method describes the matrix elimination by choosing appropriate column and eluent condition. The method is tested for selectivity, linearity, limits of detection and quantification, accuracy, and precision and is suitable for continuous sample analysis. PMID- 19772726 TI - Comparison of liquid/liquid and solid-phase extraction for alkaline drugs. AB - The extraction of drugs from biological matrices is an essential specimen preparation step in current forensic postmortem laboratories. Traditionally, liquid/liquid extractions (LLE) were developed and employed to screen for the general unknown. However, solid-phase extractions (SPE) are becoming more popular as the availability of columns with suitable stationary phases increased. The purpose of this work was to determine if switching from an existing LLE to SPE was feasible. The limits of detection (LOD) for 122 drugs and metabolites were determined in blood following SPE and compared to previously determined LOD's by LLE, if available. There were 41 drugs that had LOD's in blood established by both methods; LLE had a lower LOD for 8 drugs (19.5%), SPE had a lower LOD for 16 (39%), and the LOD's were comparable in the remaining drugs. Although SPE cartridges were more expensive than LLE, SPE was determined to be a faster technique and doubled the number of specimens that could be extracted by one analyst within a specific timeframe. The SPE method utilized enabled the detection of several drugs not detectable after LLE (most notably, morphine and benzoylecgonine) and allowed the extraction of weakly acidic and neutral drugs with only one extra step. PMID- 19772727 TI - Validated high-performance liquid chromatographic technique for determination of 5-fluorouracil: applications to stability studies and simulated colonic media. AB - A simple isocratic stability-indicating high-performance liquid chromatographic method with UV detection using thymine as an internal standard is developed. The method is validated and the degradation products are determined. The method is applied for the assessment of the stability of 5-fluorouracil in rat caecal content as a simulated colon medium under anaerobic conditions. The drug decomposes under acidic, alkaline, thermal, and oxidative stress. The drug is highly susceptible to acidic, alkaline, and oxidative hydrolysis as compared to alkaline conditions. Separation of the drug from major and minor degradation products is successfully achieved on a C(18) analytical, micro-bondapak column. The detection wavelength is 260 nm. The method is validated, and the response is found to be linear in the drug concentration range of 0.1-2.0 microg/mL. The high linearity of the standard calibration curve of 5-fluorouracil in the rat content is found to be R(2) = 0.998 in the concentration range from 0.5 to 5 microg/mL. No degradation occurred after incubation of 5-fluorouracil in the rat caecal contents. The standard deviation and coefficient of variation values for intra- and inter-day precision study exhibit acceptable accuracy and precision data throughout the concentration range investigated. PMID- 19772728 TI - Determination of gamma-aminobutyric acid in food matrices by isotope dilution hydrophilic interaction chromatography coupled to mass spectrometry. AB - The estimation of the dietary intake of gamma-aminobutyric acid (GABA) is dependent upon the knowledge of its concentration values in food matrices. To this end, an isotope dilution liquid chromatography-mass spectrometry method has been developed employing the hydrophilic interaction chromatography technique for analyte separation. This approach enabled accurate quantification of GABA in apple, potato, soybeans, and orange juice without the need of a pre- or post column derivatization reaction. A selective and precise analytical measurement has been obtained with a triple quadrupole mass spectrometer operating in multiple reaction monitoring using the method of standard additions and GABA-d(6) as an internal standard. The concentrations of GABA found in the matrices tested are 7 microg/g of apple, 342 microg/g of potatoes, 211 microg/g of soybeans, and 344 microg/mL of orange juice. PMID- 19772729 TI - Simple, quantitative headspace analysis by cryoadsorption on a short alumina PLOT column. AB - The use of purge and trap methods for sampling volatile organic compounds prior to chromatographic analysis is a mature technology. Application to low volatility compounds has been far less facile and sensitive. Especially problematic has been applications that require precise quantitative analysis and analyses as a function of sample temperature, especially for low volatility analytes. In this paper, we have applied short lengths of alumina-coated PLOT columns as purge traps and operate the traps at low temperature during the collection cycles to improve efficiency in a method called cryoadsorption. We have applied the method as a function of temperature to a medium volatility solid, coumarin, as a demonstration, with further application to the pure explosive compound 2,4,6 trinitrotoluene (TNT) and the practical explosive C-4. We estimate that by use of mass spectrometry, the sampling method discussed in this paper can provide a detection limit of 0.0019 microg TNT per gram of substrate (determined with a 60 min sweep with the sample held at 60 degrees C). Moreover, for quantitative results, we can achieve a percent standard deviation (coefficient of variation) of 10% with samples as low as 0.064 microg TNT per gram of substrate. PMID- 19772730 TI - Fingerprint of selected Salvia species by HS-GC-MS analysis of their volatile fraction. AB - Twenty species of Salvia, naturally grown or cultivated in Poland, are investigated by headspace gas chromatography-mass spectrometry analysis. The main components of the volatile fraction of Salvia species are identified as alpha pinene, camphene, beta-pinene, thujol, camphor, beta-chamigrene, and cadina-3,9 diene. There are also the compounds that can be considered as chemotaxonomic markers, namely beta-myrcene for Salvia lavadulifolia, beta-phelandrene for Salvia verticillata, tau-terpinene for Salvia stepposa, and isocaryophyllene and caryophyllene for Salvia officinalis. Certain compounds (such as o-cymene present in Salvia canariensis and Salvia stepposa; beta-trans-ocymene present in Salvia lavadulifolia, Salvia sclarea, and Salvia amplexicaulis; thujenone present in Salvia staminea, Salvia atropatana, Salvia jurisicii, and Salvia officinalis; and thujone present in Salvia azurea, Salvia lavandulifolia, Salvia hians, and Salvia triloba) can constitute chemotaxonomic advice for the aforementioned species. Also, the lack of certain compounds otherwise common in the individual sage species can be considered as chemotaxonomic advice (e.g., Salvia sclarea has no alpha-pinene and beta-pinene; Salvia lavadulifolia lacks camphene; Salvia triloba lacks beta-pinene and camphene; and Salvia officinalis lacks beta-chamigrene, thujol, and cadina-3,9-diene). PMID- 19772731 TI - High-performance liquid chromatographic method for the determination of cyromazine and melamine residues in milk and pork. AB - A high-performance liquid chromatography method is described in this paper. The method uses NH(2) column and 97% acetonitrile eluate to determine the insecticide cyromazine and metabolite melamine residues in milk and pork. Samples were treated with NaOH and extracted with acetonitrile containing 20% NH(4)OH. Target analytes of samples were cleaned up and concentrated by C(18) column solid-phase extraction. A separation for cyromazine and melamine was achieved, and respective retention times were 8 and 12 min. The calibration curves for cyromazine and melamine were linear in a concentration range of 0.01-1.0 microg/mL, with correlation coefficients of 0.9999 and 0.9997, respectively. The limit of detection of both compounds was 0.2 ng, and the limit of quantitation was 0.02 mg/kg. Recoveries of cyromazine and melamine at fortified levels of 0.02, 0.05, and 0.1 mg/kg ranged from 84.5-90.8%, and 83.6-91.3%, respectively, with coefficient of variation of 3.1-7.8%. PMID- 19772732 TI - A simple method for screening and quantification of ricinine in feed with HPLC and LC-MS. AB - A simple high-performance liquid chromatography (HPLC) and liquid chromatography mass spectrometry (LC-MS) method for screening and quantification of ricinine in feeds is established for use in feed quality control. Ricinine is extracted from the sample with methanol. The sample extract is directly used for screening with LC-MS and is cleaned up using solid-phase extraction for quantification with HPLC and LC-MS. A 9 min isocratic elution with 10% acetonitrile (v/v) at a flow rate of 0.2 mL/min is performed on an Atlantis dC(18) column (5 microm, 2.1 x 100 mm) at ambient temperature with UV detection at 310 nm and MS in positive selective ion recording mode. Good linearity (r(2) > or = 0.99) is found in the investigated concentration ranges from 0.054 to 55.4 microg/mL for HPLC and 5 to 1000 ng/mL for LC-MS. In the final extracts, the limits of detection (LOD) and quantification (LOQ) for HPLC are 75 pg and 150 pg, respectively; the LOD and LOQ for HPLC-MS are 6 pg and 15 pg, respectively. PMID- 19772733 TI - Stress degradation studies on duloxetine hydrochloride and development of an RP HPLC method for its determination in capsule formulation. AB - Duloxetine hydrochloride (HCl) is an antidepressant drug prescribed for major depressive disorders, pain related to diabetic peripheral neuropathy, and stress urinary incontinence. In the present study, degradation behavior of duloxetine HCl was studied by subjecting the drug to various International Conference on Harmonization-recommended stress conditions. Also, a stability-indicating high performance liquid chromatography method was established for analysis of the drug in the presence of various degradation products. An acceptable separation of the drug and its degradation products was achieved on a C-8 column at 40 degrees C using a mobile phase comprised of phosphate buffer (pH 2.5)-methanol tetrahydrofuran in the ratio of 50:40:10 at a flow rate of 1 mL/min. The detection wavelength was 232 nm. The method was validated for linearity, precision, accuracy, selectivity, specificity, and robustness. The method was found to be linear over a concentration range of 1-100 microg/mL (n = 6). The value of slope was found to be 85.735 mV/s ppm with correlation coefficient of 0.9994 and relative standard deviation (RSD) of 0.87%. RSD values ranged from 0.20% to 0.82% in the case of intra-day precision studies, whereas the values ranged from 0.63% to 1.57% in the case of inter-day precision. The drug was found to be stable on exposure of 30% H(2)O(2) for 48 h. It was found to be highly unstable in acidic conditions, as 41.35% degradation was observed in 0.01N HCl at 40 degrees C after 8 h. Degradation was also observed in alkaline and neutral conditions (2.83% and 42.75%, respectively) on refluxing the drug for 1 h. The drug was stable under photolytic and thermal stress on exposure in solid form but showed considerable degradation in solution form. PMID- 19772734 TI - Development and validation of a stability-indicating HPLC method for determination of voriconazole and its related substances. AB - An isocratic reversed-phase high performance liquid chromatographic (RP-HPLC) method has been developed and validated for the determination of voriconazole and its related substances. The drug substance was subjected to stress conditions of UV light, water hydrolysis, acid, base, oxidation, and deoxidization to observe the degradation products. The successful separation of voriconazole from its synthetic impurities and degradation products formed under stress conditions was achieved using an Agilent Zorbax SB-C18 (250mm x 4.6 mm i.d., 5 microm) column maintained at 25 degrees C with a mobile phase of a mixture of ammonium phosphate dibasic buffer (pH adjusted to 6.0 using diluted orthophosphoric acid; 50 mM) acetonitrile (52:48, v/v). The mobile phase flow rate was 1.0 mL/min, and the detection wavelength was 250 nm. The stress sample solutions were assayed against the qualified reference standard of voriconazole and the mass balance in each case was close to 99.7%, confirming its stability-indication capacity. The developed HPLC method was validated with respect to linearity, accuracy, precision, specificity, and robustness. The developed HPLC method to determine the related substances and assay determination of voriconazole can be used to evaluate the quality of regular production samples. It can be also used to test the stability samples of voriconazole. PMID- 19772735 TI - Development and validation of a stability-indicating method for the quantitation of Paclitaxel in pharmaceutical dosage forms. AB - A simple, rapid stability-indicating isocratic assay has been developed and validated for the determination of Paclitaxel (PTX) in commercial injection formulations. The assay is performed using a Nucleosil RP-18 (5 microm, 250 x 4.0 mm i.d) column protected by a Nucleosil C(18) precolumn (5 microm, 4.0 x 4.0 mm i.d.) with a mobile phase of methanol-water (80:20) and UV detection at 230 nm. The method was found to be specific for PTX in the presence of degradation products with an overall analytical run time of ~ 9 min. Accuracy reported as % bias was found to be 0.1-2.5% bias for all samples tested. Intra-assay precision (repeatability) was found to be 0.22-2.65% RSD, while inter-day precision (intermediate precision) was found to be 1.0-3.0% RSD for the samples studied. The calibration curve was found to be linear with the equation y = 29.78x + 7.65, and a linear regression coefficient of 0.9994 over the concentration range 0.05 20 microg/mL. The limits of quantitation and detection were 0.05 and 0.02 microg/mL, respectively. Taxol (30 mg/5 mL), a commercially available dosage form of PTX, was assayed and 100.6-103.6% of the label claim was recovered. PMID- 19772736 TI - Development of a stability-indicating HPLC method for simultaneous determination of olanzapine and fluoxetine in combined dosage forms. AB - A stability-indicating high-performance liquid chromatography method is developed for analysis of olanzapine and fluoxetine in the presence of their degradation products generated from forced decomposition studies as prescribed by the International Conference on Harmonization. Hydrolysis, oxidation, photolysis, and thermal degradation are evaluated by subjecting the drug substances to stress conditions. Successful separation of drugs from degradation products is achieved on a reversed-phase C(18) column using 75 mM potassium dihydrogen phosphate buffer (pH 4.0)-acetonitrile-methanol (55:40:5, v/v/v) as the mobile phase. The flow rate is 0.8 mL/min, and the detection wavelength is 227 nm. The method is validated with respect to linearity, precision, accuracy, system suitability, and robustness. The utility of the procedure is verified by its application to marketed formulations that are subjected to accelerated stability studies. Good separation of the drugs and their degradation products is observed using this method. The products formed in marketed tablet dosage forms are similar to those formed in standard drug solutions under similar stress conditions. PMID- 19772737 TI - On-line coupling of solid-phase extraction to liquid chromatography--a review. AB - Solid-phase extraction (SPE) is an effective sample preparation method for removal of interfering compound and enrichment of analyte. Liquid chromatography (LC) with various detectors is a main separation and detection technique used in the analytical field. This article reviews the literatures about the on-line coupling of SPE with LC. The advantages of on-line coupling are reduction of analysis time, sample contamination, and analyte losses, as well as improvement of precision and accuracy. The SPE sorbents including traditional materials, such as chemically bonded silica, ion-exchange and carbon-based materials, and some novel sorbents, such as restricted access material, molecularly imprinted polymer, immunosorbent, and monolithic material, used in the on-line analysis are discussed in detail. The on-line coupling of SPE-LC to other sample preparation techniques, such as supercritical fluid extraction, subcritical water extraction, microwave-assisted extraction, ultrasound-assisted extraction, and derivatization technique are also reviewed. PMID- 19772738 TI - On-line microdialysis coupled with liquid chromatography for biomedical analysis. AB - This work presents a review of the microdialysis (MD) sampling technique for on line coupling with high-performance liquid chromatography (HPLC) for biomedical analysis. MD-HPLC was first used in the field of brain metabolism to study neurotransmission, and this remains its common application in the biomedical field. On-line MD-HPLC hyphenated methods provide advantages over those with off line MD-based techniques, including simplified sample preparation, automated analyses, avoidance of contamination introduced during the analytical process, and in situ analysis of the extracellular fluid of living organisms. This review outlines the effectiveness of the continuous monitoring of unbound chemicals from tissues, organs, and body fluids by on-line MD-HPLC methods. In addition, a discussion is presented on the application of in vivo on-line MD-HPLC toward obtaining biochemical event information in the extracellular fluid of various tissues and in biological fluids for pharmacokinetic, pharmacodynamic, toxicological, and bioprocess monitoring. PMID- 19772739 TI - Flow injection and sequential injection on-line pre-column derivatization for liquid chromatography. AB - Approaches of on-line pre-column derivatization with flow injection (FI) and sequential injection (SI) for liquid chromatography (LC) are reviewed. Considerations in interfacing FI/SI to LC is discussed. Employing such on-line derivatization pre-column pretreatment approaches, applications to organic species (biomedical, food, pharmaceutical, environmental, and other types of samples) as well as metal ions are presented. Further developments in the approaches are recommended. PMID- 19772740 TI - Coupling of flow techniques with capillary electrophoresis: review of operation principles, challenges, potentials, and applications. AB - In this review, an overview is given of the up-to-date accomplished analytical systems combining flow techniques and capillary electrophoresis with the main focus on interfacing principles, challenges, potentials, and the resulting operation versatility as well as the incorporation of automated sample treatment prior to the electrophoretic separation. The up-to-date reported coupled systems are classified in tabular form in respect to interface types and analytical applications. An introduction into the different flow techniques and capillary electrophoresis is given further. In consequence, this review is aimed to complement former review articles, whose main focuses were analytical performance of the reviewed systems. PMID- 19772741 TI - Low pressure separations using automated flow and sequential injection analysis coupled to monolithic columns. AB - Automation is a key demand in modern analytical chemistry. Automated analytical schemes facilitate samples handling, and enable effective processes such as dilution, extraction, derivatization, and preconcentration to be carried out. Flow (FI) and sequential injection (SI) analysis are well-established and mature automated analytical techniques with more than 18,000 publications so far in all areas of analytical science. FI and SI offer significant advantages such as low instrumental and operational cost, widely available instrumentation, and effective automation of critical steps in the analytical process. Until recently, the main disadvantage of FI and SI was the inability of simultaneous determinations of more than two analytes in a single run. Due to the low pressure operation of these techniques, it was impossible for them to be coupled to conventional particulate-based separation columns that enable chromatographic separations. This drawback was overcome by the introduction of monolithic stationary phases. Monolithic columns are prepared from organic and silica monomers. Silica-based monoliths have small-sized skeletons and a bimodal pore size distribution with microm-sized throughpores and nm-sized mesopores. This gives silica-based monoliths favorable properties for high-efficiency fast separations, such as low-pressure drop across the column, fast mass transfer kinetics and a high binding capacity. They consist of a single rigid porous rod, enabling higher flow rates than particulate columns at reasonable back-pressures. These unique features of monolithic columns enabled their incorporation in low/moderate pressure setups, such as FI and SI, expanding dramatically their possibilities. PMID- 19772742 TI - Evaluation of automated stir bar sorptive extraction-thermal desorption-gas chromatography electron capture negative ion mass spectrometry for the analysis of PBDEs and PBBs in sheep and human serum. AB - Stir-bar sorptive extraction and automated thermal desorption/cryotrapping interfaced to capillary gas chromatography and electron capture negative ion mass spectrometry is shown to effectively isolate and recover polybrominated diphenyl ethers and polybrominated biphenyls from sheep and human serum. This paper describes the development of the method and demonstrates the feasibility of using Twister with spiked serum. Conditions for conducting stir-bar sorptive extraction and for automated thermal desorption that led to acceptable analyte recoveries were optimized. The approach to sample preparation introduced here significantly reduces tedious labor and solvent consumption associated with conventional liquid liquid extraction. PMID- 19772743 TI - Comparison of analytical techniques for detection of geosmin and 2 methylisoborneol in aqueous samples. AB - Geosmin and 2-methylisoborneol are secondary metabolites expressed by a variety of organisms that are responsible for off-flavors in public water supplies, aquaculture, and a host of other important products. Hence, there is continuing research into the causes for their expression and methods to mitigate it, which require sensitive and accurate detection methods. In recent years, several new techniques for collecting and concentrating volatile and semi-volatile compounds have been automated and commercialized, making them available for use in most laboratories. In this study, we compared solid-phase microextraction (SPME) and membrane-assisted solvent extraction (MASE) for the detection of 2 methylisoborneol and geosmin in aqueous samples. SPME is the most sensitive of these techniques with a limit of detection of 25 parts-per-trillion for 2 methylisoborneol and 10 parts-per-trillion for geosmin but with a large relative standard deviation. MASE is less sensitive, but provides a greater level of precision, as well as the ability for multiple injections from the same sample. PMID- 19772744 TI - Characterization of Jamaican agro-industrial wastes. Part I: characterization of amino acids using HPLC: pre-column derivatization with phenylisothiocyanate. AB - Jamaican agro-industries generate large quantities of wastes, which are either discarded or under-utilized. In order to evaluate the possible utilization of these wastes, it is necessary that the profiles of the major biochemical groups be developed. This paper describes the determination of the amino acid composition of coffee, citrus, and rum distillery wastes using a reversed-phase high-performance liquid chromatography method. Acid hydrolysates of the wastes are derivatized with phenylisothiocyanate. They are analyzed as their phenylthiocarbamyl derivatives and determined quantitatively using norleucine as the internal standard. The presence of all the 17 amino acids investigated, nine of which include those essential for animal nutrition, are observed in the samples investigated, suggesting a high quality of protein with implications in the formulation of animal feeds. PMID- 19772745 TI - Pressurized liquid extraction for the simultaneous analysis of polychlorinated biphenyls and polybrominated diphenyl ethers from soil by GC-TOF-MS detection. AB - Pressurized liquid extraction (PLE) system was optimized to simultaneously determine polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs) in soil samples by gas chromatography with time-of-flight mass spectrometry. PLE parameters (temperature, pressure, static time, and flush volume) and packing materials (activated copper and sorbents such as: Florisil, silica gel, and a combination of Florisil and silica gel) were studied to achieve a one-step extraction and cleanup that could be analytically rapid and reliable. Method detection limit was found to be in the range of 0.1-0.4 mg/kg for PCBs and 0.1-0.6 mg/kg for PBDEs with a relative standard deviation of 1.7-7.3% for PCBs and 2.6-6.3% for PBDEs. A standard reference material for PCBs, NIST-SRM 1939a, spiked with PBDEs standard, was analyzed to substantiate the validity of the optimized method. Experimental values agreed well with the certified values with recoveries of 71.6-117%, and the optimized PLE system has been proven to be useful for the simultaneous determination of PCBs and PBDEs with various congeners in soil samples. PMID- 19772746 TI - Optimization of a novel procedure for determination of VOCs in water and human urine samples based on SBSE coupled with TD-GC-HRMS. AB - In this study, stir-bar sorptive extraction and thermal desorption followed by gas chromatography coupled with high resolution mass spectrometry was applied for determination of halo-organic compounds (bromodichloromethane, dibromochloromethane, bromoform, and tetrachloroethylene) in water and human urine samples. Time of extraction and stirring speed were optimized. The results show that the optimum extraction time is 30 min with 600 rpm of stirring speed with Twister of 20 mm in length and 1.0-mm film thickness of PDMS (126 microL). The calibration curves, limits of detection and quantification for all compounds were calculated. This procedure is characterized by very low limits of detection and quantitation: lower than 0.0017 microg/L and good repeatability for all four volatile compounds. This new analytical procedure was identified to be easy, reliable, sensitive, and requires only small amounts of sample. It can constitute a good alternative to well-known procedures based on application of head space and gas chromatography coupled with electron capture detection. PMID- 19772747 TI - Comparison of HS-SDME with SPME and SPE for the determination of eight organochlorine and organophosphorus pesticide residues in food matrices. AB - A headspace single-drop microextraction (HS-SDME) procedure is optimized for the analysis of organochlorine and organophosphorous pesticide residues in food matrices, namely cucumbers and strawberries by gas chromatography with an electron capture detector. The parameters affecting the HS-SDME performance, such as selection of the extraction solvent, solvent drop volume, extraction time, temperature, stirring rate, and ionic strength, were studied and optimized. Extraction was achieved by exposing 1.5 microL toluene drop to the headspace of a 5 mL aqueous solution in a 15-mL vial and stirred at 800 rpm. The analytical parameters, such as linearity, correlation coefficients, precision, limits of detection (LOD), limits of quantification (LOQ), and recovery, were compared with those obtained from headspace solid-phase microextraction (HS-SPME) and solid phase extraction. The mean recoveries for all three methods were all above 70% and below 104%. HS-SPME was the best method with the lowest LOD and LOQ values. Overall, the proposed HS-SDME method is acceptable in the analysis of pesticide residues in food matrices. PMID- 19772748 TI - Stochastic resonance algorithm applied to quantitative analysis for weak chromatographic signals of alkyl halides and alkyl benzenes in water samples. AB - The stochastic resonance algorithm is applied to the trace analysis of alkyl halides and alkyl benzenes in water samples. Compared to encountering a single signal when applying the algorithm, the optimization of system parameters for a multicomponent is more complex. In this article, the resolution of adjacent chromatographic peaks is first involved in the optimization of parameters. With the optimized parameters, the algorithm gave an ideal output with good resolution as well as enhanced signal-to-noise ratio. Applying the enhanced signals, the method extended the limit of detection and exhibited good linearity, which ensures accurate determination of the multicomponent. PMID- 19772749 TI - RP-HPLC analysis of rhinacanthins in Rhinacanthus nasutus: validation and application for the preparation of rhinacanthin high-yielding extract. AB - A reversed-phase high-performance liquid chromatographic method is described for the simultaneous determination of rhinacanthin-C, rhinacanthin-D, and rhinacanthin-N in Rhinacanthus nasutus leaves. The method involved the use of a TSK-gel ODS-80Ts column (5 microm, 4.6 x 150 mm i.d.) with the mixture of methanol and 5% aqueous acetic acid (80:20, v/v) as the mobile phase. The parameters of linearity, repeatability, accuracy, and specificity of the method were evaluated. The recovery of the method was 94.3-100.9%, and good linearity (r(2) > or = 0.9999) was obtained for all rhinacanthins. A high degree of specificity as well as repeatability and reproducibility (relative standard deviation values less than 5%) were also achieved. The limit of detection and quantification of all rhinacanthins were 0.75 and 3.0 microg/mL, respectively. The solvents for extraction of rhinacanthins from R. nasutus leaves were examined in order to obtain the leaf extract with high rhinacanthin content. It was found that ethyl acetate was an appropriate solvent for rhinacanthin extraction. Fractionation of the ethyl acetate extract using a basic anion exchange resin (Amberlite IRA-67) eluted with 10% acetic acid in methanol afforded a rhinacanthin-rich extract (HRn). The total content of rhinacanthins was increased from 37.4% w/w to 77.5% w/w. The antifungal activities of HRn against Trichophyton rubrum, T. mentagrophytes, and Microsporum gypseum were also improved. PMID- 19772750 TI - Quantitative determination of five glucosyloxybenzyl 2-isobutylmalates in the tubers of Gymnadenia conopsea and Coeloglossum viride var. bracteatum by HPLC. AB - Glucosyloxybenzyl 2-isobutylmalates are one group of important active constituents in the tubers of Gymnadenia conopsea R. Br. and Coeloglossum viride (L.) Hartm. var. bracteatum (Willd.). For the purpose of quality evaluation of these two Chinese herbal medicines, it is necessary to use a rapid and reliable assay that is suitable for the determination of their active constituents. A high performance liquid chromatography method is firstly developed for the simultaneous quantification of five glucosyloxybenzyl 2-isobutylmalates in the tubers. The analytes including dactylorhin B, dactylorhin E, loroglossin, dactylorhin A, and militarine are isolated from the tubers of G. conopsea. The compounds are separated on an Agilent Hydrosphere C(18) (150 x 4.6 mm i.d., 5 microm) column using a mobile phase of acetonitrile-water including 0.3% acetic acid (adjusted with 36% acetic acid) with gradient elution at a flow rate of 1.0 mL/min. Detection is set at a UV wavelength of 221.5 nm. The recovery of the method is 97.7-101.0%, and linearity (r > 0.9998) is obtained for all the analytes. The assay is successfully applied to determine the contents of the analytes in the tubers of G. conopsea and C. viride var. bracteatum collected from different regions of China. PMID- 19772751 TI - Simultaneous determination of myricitrin, hyperin, quercitroside, and quercetin in Folium Rhododendri Micranthi by RP-HPLC. AB - A reversed-phase high-performance liquid chromatography method was established for the simultaneous determination of four major constituents, namely myricitrin, hyperin, quercitroside, and quercetin in Folium Rhododendri Micranthi. The optimal conditions of separation and detection were achieved on a C18 analytical column with a gradient mobile phase consisting of acetonitrile and 1% acetic acid at the flow rate of 1.0 mL/min, and detection wavelength was set at 355 nm. All calibration curves showed good linear regression (r > 0.9993) within test ranges. The reproducibility of relative standard deviations was less than 2.3%, and recovery of analytes was greater than 99.4%, respectively. The method was successfully applied to determine the contents of four compounds in Folium Rhododendri Micranthi. The results indicated that the contents of myricitrin, hyperin, quercitroside and quercetin in Folium Rhododendri Micranthi were 0.166%, 0.303%, 0.299%, and 0.053%, respectively. PMID- 19772752 TI - Study on determination of pentacyclic triterpenoids in Chaenomeles by HPLC-ELSD. AB - A new direct high-performance liquid chromatography analytical method using evaporative light scattering detection (ELSD) for the simultaneous determination of the major pentacyclic triterpenoids in Chaenomeles (Chinese medicinal herb) has been developed. The simultaneous separation of the seven pentacyclic triterpenoids was achieved on a Zorbax Stable Bound (4.6 mm x 100 mm i.d., 1.8 microm) C(18) column by gradient elution with acetonitrile-water as the mobile phase and detected with ELSD. This method provides good reproducibility and sensitivity for the quantification of seven major pentacyclic triterpenoids, namely erythodiol, betulin, acetyl ursolic acid, ursolic acid, oleanolic acid, betulinic acid, and pomolic acid, respectively. The relative standard deviation (RSD) of overall intra-day variations was less than 2.2%, and the RSD of inter day variations was less than 2.8%. The standard recoveries (three different concentrations of markers: 0.1, 0.5, and 2.0 mg) ranged from 96-104%. The results demonstrate that this method is simple, sensitive, selective, and suitable for the quality control of this commonly used Chinese medicinal herb. PMID- 19772753 TI - Simultaneous determination of seven components in Qibaomeiran pill by HPLC-DAD. AB - A high-performance liquid chromatography coupled with photo diode array detection method is developed for simultaneous determination of seven active components in Qibaomeiran pill, including rutin, 2,3,5,4'-tetrahydroxystilbene-2-O-beta-D glycoside, ferulic acid, psoralen, isopsoralen, emodin, and physcion. The analysis is performed on a C(18) column using a mobile phase composed of A (0.1% acetic acid) and B (acetonitrile) with linear gradient elution. Four wavelengths at 245, 290, 320, and 350 nm were chosen as the monitoring wavelength to determine seven active components, respectively. All the compounds show good linearity (r > 0.999). The developed method is fully validated in respect to precision, repeatability, and accuracy. The proposed method is successfully applied to quantify the seven active components in different Qibaomeiran pill samples. The results indicate that the developed assay could be considered as a suitable quality control method for the Qibaomeiran pill. PMID- 19772754 TI - A simple and rapid method for the determination of pennogenin diglycoside in rat plasma by HPLC-MS: application to the pharmacokinetics of the extract in Gongxuening capsules. AB - A sensitive, selective, and reproducible reversed-phase high-performance liquid chromatography method coupled with electrospray ionization-ion trap mass spectrometry (LC-ESI-ITMS) was developed for the simultaneous quantification of pennogenin diglycoside (PD) in a small volume (100 microL) of rat plasma. PD was extracted from rat plasma samples using liquid-liquid extraction with methanol, digoxin as internal standard. The chromatographic separation was performed on a reversed-phase Agilent C(18) (250 mm x 4.6 mm i.d., 5 mum particle size) analytical column using a mobile phase of 0.1% formic acid solution-acetonitrile (75:25, v/v) at a flow-rate of 1.0 mL/min. The mass spectrometer was operated in the negative ion mode at the deprotonated-molecular ions [M-H]- of parent drug. Calibration curve in spiked plasma was linear (correlation coefficient r = 0.999) from 0.5 to 50.0 mg/mL. For the different samples with concentration of 0.50, 5.00, and 50.0 microg/mL, recoveries of PD were (86.45 +/- 4.39)%, (91.40 +/- 4.40)%, and (93.79 +/- 3.29)%, respectively (n = 3). The intra-day assay relative standard deviation at 0.50, 5.00, and 50.0 mg/mL of PD were 4.29%, 5.66%, and 4.03% (n = 3), respectively. The inter-day assay %RSD at the previously mentioned concentrations were 5.53%, 4.99%, and 4.31% (n = 3), respectively. The method was successfully applied to the pharmacokinetic study of PD in rats following either intravenous administration of PD solution or oral administration of the extract in Gongxuening capsules, a famous patent Chinese botanic drug. PMID- 19772756 TI - Intranasal antihistamines for allergic rhinitis: mechanism of action. AB - Although antihistamines have been in common use for treatment of allergic diseases including rhinitis for >60 years and topical therapy of the respiratory tract has been common for centuries, it is only in the past few years that topical intranasal antihistamine therapy has been widely used for treatment of allergic rhinitis. Much research has been done over the past several years showing broad anti-inflammatory effects of these medications, involving many different pathways. Effects have been shown on mediators including histamine, leukotrienes, platelet-activating factor, and substance P, as well as on cytokines, adhesion molecules, and chemokines involved in chemotaxis. It is significant that these effects have been seen at clinically relevant concentrations of the topical drugs, as opposed to the situation with oral antihistamines where anti-inflammatory effects are generally found only at concentrations much higher than that achieved with routine dosing. Clinically, it appears that this delivery of high local concentrations allows for other pharmacologic activity to be expressed. These anti-inflammatory actions may be part of the reason why these drugs also are effective in relieving many symptoms of nonallergic rhinitis, where histamine has much less of a role and where oral antihistamines have traditionally been of minimal help. PMID- 19772757 TI - Intranasal antihistamines for allergic rhinitis: examining the clinical impact. AB - Allergic rhinitis is likely the most common medical complaint to a clinical allergist and immunologist affecting between 10 and 30% of all adults. This disease causes significant impact on quality of life as well as creating a financial burden on society with decreased work productivity and medication costs. Often, many allergy sufferers do not adhere to the medication recommendations provided by their physician most often because these therapies have not provided relief. Although in the past, the mainstay of treatment for allergic rhinitis has been environmental avoidance, immunotherapy, nasal corticosteroids, and oral antihistamines, the most recent rhinitis diagnosis parameters published by the American Academy of Allergy, Asthma and Immunology have also discussed the importance of other often overlooked therapies. More specifically, the new guidelines discuss a place for the use of intranasal antihistamines as first-line therapy as well as potentially providing superior relief to second-generation oral antihistamines. The guidelines also identify the biphasic nature of the allergic response with both phases consisting of nasal pruritus, sneezing, rhinorrhea, and congestion with the late phase predominated by nasal congestion. It is important to understand how intranasal antihistamines fit into these latest guidelines as first-line therapy and to understand how they may be beneficial to the symptoms associated with allergic rhinitis. It is equally important to identify the individuals who have had less success with their current therapies to determine if intranasal antihistamines would be an important adjunct in therapy. PMID- 19772758 TI - The impact of allergic rhinitis on sexual activity, sleep, and fatigue. AB - Allergic rhinitis (AR) has been found to impact the daily activities of allergic patients. This includes the effects on sleep and chronic fatigue. The effect of AR on sexual function has not been well studied. The purpose of this study was to assess the impact of AR on sexual function, sleep, and fatigue. The Rhinosinusitis Disability Index (RSDI) is a quality of life (QOL), validated outcomes tool that assesses how AR affects QOL. Specific questions address the adverse consequence on sexual function, sleep, and fatigue. Four subsets of patient with AR who completed the RSDI were evaluated for the specific questions as well as the physical, emotional, functional, and total scores. The scores were compared with a cohort of normal subjects, patients with a diffuse group of rhinologic disorders, and patients scheduled for septal surgery (non-AR patients). Patients with AR had significantly higher (worse) sexual and sleep RSDI scores than the non-AR patients and normal subjects. Although the AR subjects also had significantly higher fatigue RSDI scores than the normal subjects, there was no significant difference between the AR and non-AR patients' fatigue scores. Non-AR patients had significantly higher sexual, sleep, and fatigue RSDI scores than the normal subjects. AR has a significant negative impact on sexual function and can result in sleep disturbances and fatigue as measured by the RSDI. PMID- 19772759 TI - Low-cost interventions improve indoor air quality and children's health. AB - Intervention in the home environment to reduce asthma triggers theoretically improves health outcomes for asthmatic children. Practical benefit from application of these interventions has proven difficult. This single-blind study tested the effectiveness of simple low-cost home interventions in improving health scores of children with asthma. Families with at least one asthmatic child were recruited. Initial health examination, health, and home assessments were conducted and targeted interventions were implemented. Interventions included dehumidification, air filtration, furnace servicing, and high-efficiency furnace filters. When present, gross fungal contamination was remediated. Asthma education was provided along with education in healthy home practices. Follow-up assessments were conducted after 6 months. Health surveys were completed at enrollment and follow-up. This study enrolled 219 children with asthma. Home inspections and interventions were conducted in 181 homes and 83 families completed all phases. Reduction in asthma and allergy-related health scores was shown in follow-up health surveys. Health improvements were significant for cough when heating, ventilation, and air conditioning (HVAC) service and dehumidification were used. Breathing problems were significantly improved for dehumidification, HVAC service, and room air cleaners. Total dust allergen load was reduced for the dehumidification group (p < 0.05). Mold spore counts were reduced one order of magnitude in 25% of the homes. Indoor spore counts adjusted for outdoor spore levels were reduced overall (p < 0.01). Simple low-cost interventions directed to producing cleaner indoor air coupled with healthy home education improve the indoor air quality and health in asthmatic children. PMID- 19772760 TI - Comparison of serum-specific IgE (ImmunoCAP) and skin-prick test results for 53 inhalant allergens in patients with chronic rhinitis. AB - Prior studies comparing skin testing to serum-specific IgE testing for inhalant allergy focused on older technologies or small numbers of allergens. The purpose of this study was to compare ImmunoCAP (CAP) testing to skin prick testing (ST) for 53 inhalant allergens. Subjects > or =18 years old with chronic rhinitis and who had at least 1 positive ST to a 53 inhalant allergen panel underwent testing to an analogous CAP panel. ST was performed with the Quintip device. Using ST as a clinical gold standard, the sensitivity, specificity, positive, and negative predictive values (PPV, NPV) were calculated for CAP for each allergen. Percent agreement between testing methods was also evaluated, and the results were analyzed in association with the subjects' total IgE levels. Two-hundred fifty patients (96 male, 154 female, mean 37.1 years) were enrolled. Mean number of positive ST and CAP results were similar. The ST was more often positive for 69.8% of allergens, and 64% of patients had more positive ST than CAP. Overall, the specificity and NPV (generally 80-90%) of CAP were higher than the sensitivity and PPV. The overall agreement between tests was 80.6%, with 11.7% ST+CAP- results and 7.7% CAP+ST- results. In patients with a total IgE level > or = 200 IU/L, the percentage of positive CAP results for 52/53 allergens was significantly higher with more CAP+ST- results. The performance characteristics of CAP compared to ST vary among 53 inhalant allergens. CAP should be considered complementary, not equivalent, to ST. Total IgE levels should be obtained with serum-specific IgE testing. PMID- 19772761 TI - Effects of daily intake of Lactobacillus paracasei strain KW3110 on Japanese cedar pollinosis. AB - Japanese cedar pollinosis is an important contributor to allergic rhinitis in Japan. Lactobacillus may be useful as an immunomodulator and is used widely as a foodstuff. The purpose of the study was to examine the effects of daily intake of the Lactobacillus paracasei strain KW3110 in patients with cedar pollinosis. The effects of daily intake of KW3110 in patients with cedar pollinosis were investigated in 126 patients who received KW3110 or a placebo in a double-blind study. The study began 1 month before the start of the pollen season and lasted for 3 months. A significant reduction of nasal symptoms and the serum level of eosinophil cationic protein and improvement of quality of life scores occurred in the patients who received KW3110 when pollen scattering was low. However, the effects were limited during the peak period of pollen scattering. Intake of KW3110 may reduce allergic inflammation, but the effect is limited. PMID- 19772762 TI - Several interleukin-4 and interleukin-13 gene single nucleotide polymorphisms among Chinese asthmatic patients. AB - Asthma is a common respiratory disease associated with airway hyperactivity and high total serum immunoglobulin E (IgE) levels. The asthmatic phenotypes are widely considered to be caused by environmental effects on genetically predisposed individuals. Interleukin (IL)-4 and IL-13 act on B cells and regulate the IgE production, and the single nucleotide polymorphisms (SNPs) in the IL-4 and IL-13 genes are implicated in the pathogenesis of asthma. To study the association of IL-4 and IL-13 gene polymorphisms with asthma, we sequenced the promoter regions and exons of IL-4 and IL-13 genes in two groups: one (spouses group) consisted of 13 pairs of asthmatic patients (cases) and their unaffected spouses (controls); the other (parents group) consisted of 11 pairs of asthmatic children (cases) and their unaffected father/mother (controls). In total, seven polymorphisms were identified, one novel and six previously reported. However, according to the results of the statistical analysis we performed, no statistically significant association of these SNPs and asthma was observed (p > 0.05). Asthma is largely determined by the accumulation of several certain genetic variations other than one or two SNPs. Future function studies may be able to help us reveal the significance of genetic variants we identified in this study. PMID- 19772763 TI - Evaluation of airway hyperresponsiveness and exhaled nitric oxide as risk factors for airway remodeling in patients with stable asthma. AB - Chronic eosinophilic airway inflammation, airflow limitation, and airway hyperresponsiveness (AHR) are distinctive features of bronchial asthma. Exhaled nitric oxide (eNO) is a marker of eosinophilic airway inflammation. Airway remodeling due to chronic airway inflammation results in fixed airway obstruction. Asthmatic patients have been reported to have greater declines in forced expiratory volume in 1 second (FEV(1)) over time than nonasthmatic patients. This longitudinal observational study aimed to elucidate outcomes and risk factors for the decline in FEV(1) in patients with stable asthma. Postbronchodilator FEV(1) was measured in 30 outpatients with stable asthma every 6 months for 5 years. We calculated the rate of decline in postbronchodilator FEV(1) (deltaFEV(1)/year) in each subject and adjusted deltaFEV(1)/year with predictive FEV(1). Patients were examined while their asthma was well controlled. In the first observation period, we measured AHR to methacholine (the provocative concentration of methacholine causing a 20% fall in FEV(1) [PC(20)]). In the second observation period (defined as the period over 2 years from start of observation), we measured methacholine PC(20) and eNO. The mean deltaFEV(1)/year (SEM) was -36 +/- 4 mL/year and the adjusted deltaFEV(1)/year (SEM) was -0.015 +/ 0.001/year. Adjusted deltaFEV(1)/year did not correlate with eNO measured during the second observation period or methacholine PC(20) measured during the first observation period. On the other hand, methacholine PC(20) measured during the latter period was correlated significantly with adjusted deltaFEV(1)/year. Persistent AHR may be a risk factor for longitudinal decline in FEV(1) in asthma patients even if their asthma is stable and well controlled by inhaled corticosteroid. PMID- 19772764 TI - Comparative in vitro performance of valved holding chambers with a budesonide/formoterol pressurized metered-dose inhaler. AB - A combination of budesonide and formoterol in a single pressurized metered-dose inhaler (pMDI) is available in the United States and elsewhere. This study was designed to evaluate the delivered dose and fine particle dose (FPD; mass of particles <4.7-micrometer diameter) using the pMDI with two valved holding chambers (VHCs), using sampling methods reflecting different patient techniques. FPD was measured using an Andersen Cascade Impactor and delivered dose was measured using a disposable filter. Two VHCs, AeroChamber Plus and AeroChamber MAX (Trudell Medical International, London, Ontario, Canada), were evaluated using three sampling methods: (1) immediate collection; (2) collection after up to a 5-second delay; (3) using simulated adult, child, and infant tidal breathing patterns (delivered dose). Decreases in delivered dose were observed using a VHC compared with the pMDI alone. FPD with both VHCs was similar to that with the pMDI alone with minimal delay between actuation and collection. With delays, the antistatic AeroChamber MAX was more resistant than AeroChamber Plus to dose losses. Delivered doses from adult and child profiles were comparable with those after a 1-second delay. The infant profile produced lower delivered doses, probably because more breath cycles are required to empty the VHC. Budesonide/formoterol pMDI can be used effectively with AeroChamber Plus and the antistatic AeroChamber MAX. With minimal delay between actuation and collection, FPD with both VHCs was similar to that with the pMDI alone, giving physicians a choice of administration regimen and taking into account the needs and skills of the patient. PMID- 19772765 TI - Clinical reactivity to ingestion challenge with mixed mold extract may be enhanced in subjects sensitized to molds. AB - Manifestations of mold allergy are classically associated with inhalation of mold spores leading to symptoms of asthma and other respiratory illnesses. It is largely unknown, however, whether ingestion of aeroallergenic molds, mold spores, or other fungi found in food can also elicit hypersensitivity reactions in mold sensitive individuals. The aim of this study was to evaluate the association between exposure to molds by oral challenge and elicitation of symptoms in mold- versus nonmold-sensitive individuals. Thirty-four adult atopic subjects were randomized into mold-sensitive groups based on skin test reactivity by skin percutaneous testing (SPT) and/or intradermal (ID) testing to a mixed mold (MM) extract preparation. All subjects underwent a single-blinded, placebo-controlled food challenge to the MM preparation. A modified scoring system was used to grade the clinical severity of symptoms elicited by challenge. All subjects tolerated challenges to the maximal oral mold dose concentration. However, higher symptom scores after challenge were found in mold-sensitive subjects compared with nonmold-sensitive subjects (p = 0.01). When mold-sensitive subjects were compared based on SPT and/or ID reactivity, higher symptom scores and lower symptom eliciting concentrations of mold were associated with the SPT reactive subgroup compared with the subgroup with ID reactivity alone. In summary, based on our challenge results and scoring model, mold-sensitive subjects compared with nonmold-sensitive subjects experienced cumulatively higher symptom scores after oral challenge to an MM extract preparation. Future studies are warranted to confirm whether ingestion of aeroallergenic molds in food may be another contributor to symptoms in mold-sensitive individuals. PMID- 19772766 TI - Enhanced contact hypersensitivity by delayed T-helper 2 response in BALB/c mice. AB - T-helper (Th) 1/Th2 balance determines the direction of contact hypersensitivity (CHS). To clarify the immunopathogenesis of contact dermatitis, 2,4 dinitrofluorobenzene (DNFB)-induced CHS reaction was compared between the BALB/c and C57BL/6 mice. The two strains were sensitized with DNFB systemically and challenged with DNFB locally. The CHS reaction in BALB/c mice was intense compared with that in C57BL/6 mice at 24 and 48 hours post-DNFB challenge. The dermal lesions were characterized by infiltration of lymphocytes, eosinophils, neutrophils, and macrophages including CD4+ and CD8+ T cells, and interleukin (IL)-4-producing(+) and interferon (IFN)-gamma+ cells in BALB/c mice. In C57BL/6 mice, the composition of inflammatory cells was same as those in BALB/c mice except for eosinophils, CD4+ T cells, and IL-4+ cells. There was no increase in the number of mast cells in the two strains. Local and systemic productions of IL 4 and IFN-gamma in BALB/c mice were higher than those in C57BL/6 mice. Although blood IgE values increased in BALB/c mice, but not in C57BL/6 mice, at 48 hours postchallenge, its value was low. The delayed Th2-like response together with Th1 like response in BALB/c mice may induce strong CHS reaction compared with C57BL/6 mice, which may dominantly develop Th1-like reaction. Moreover, mast cell and IgE do not appear to be involved in delayed CHS. PMID- 19772767 TI - Hemophagocytic lymphohistiocytosis in a patient with x-linked lymphoproliferative disease. AB - X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency affecting approximately 1 to 3 per million live male births. Patients are generally healthy until facing a viral infection such as Epstein-Barr Virus and then may develop fulminant infectious mononucleosis and die. XLP patients are also at increased risk of hemophagocytic lymphohistiocytosis (HLH), which may be triggered by assorted viruses. Here we report a novel case of HLH in a patient with XLP. Significant to his presentation is a paradoxical increase in natural killer (NK) cell activity. We hypothesize that this indicates that Parvovirus B19 activates NK cells via a signaling lymphocytic activation molecule-associated protein (SAP)-independent mechanism. Our case demonstrates an important etiology to consider in the differential diagnosis of XLP patients with nonfocal findings and febrile illnesses. PMID- 19772768 TI - A review of the occurrence of hemoplasmas (hemotrophic mycoplasmas) in Brazil. AB - Recent studies have been conducted in Brazil using molecular techniques for the detection of hemotrophic mycoplasmas in several mammals. In domestic cats, Mycoplasma haemofelis, "Candidatus M. haemominutum", and "Candidatus M. turicensis" infections have been identified. These species have also been found in free-ranging and captive neotropical felid species. Two canine hemoplasmas, Mycoplasma haemocanis and "Candidatus Mycoplasma haematoparvum", have been identified in dogs. In commercial swine populations, Mycoplasma suis was found to be highly prevalent, especially in sows. Moreover, novel mycoplasma species have been identified in Brazilian commercial pigs and domestic dogs. A hemoplasma infection in a human patient infected with the human immunodeficiency virus (HIV) was also recently documented. In conclusion, hemoplasma species are common and important infectious agents in Brazil. Further studies should be conducted to better understand their impact on pets, production animals, and wildlife fauna, as well as their role as zoonotic agents, particularly in immunocompromised patients. PMID- 19772769 TI - Knockdown resistance in pyrethroid-resistant horn fy (Diptera: Muscidae) populations in Brazil. AB - To investigate the kdr (knockdown resistance) resistance-associated gene mutation and determine its frequency in pyrethroid-resistant horn fy (Haematobia irritans) populations, a total of 1,804 horn flies of 37 different populations from all Brazilian regions (North, Northeast, Central-West, Southeast, and South) were molecular screened through polymerase chain reaction (PCR). The kdr gene was not detected in 87.08% of the flies. However, the gene was amplified in 12.92% of the flies, of which 11.70% were resistant heterozygous and 1.22% were resistant homozygous. Deviation from Hardy-Weinberg equilibrium (HWE) was found only in 1 ranch with an excess of heterozygous. When populations were grouped by region, three metapopulations showed significant deviations of HWE (Central-West population, South population and Southeast population). Tis indicates that populations are isolated one from another and kdr occurrence seems to be an independent effect probably reflecting the insecticide strategy used by each ranch. Although resistance to pyrethroids is disseminated throughout Brazil, only 48% of resistant populations had kdr flies, and the frequency of kdr individuals in each of these resistant populations was quite low. But this study shows that, with the apparent exception of the Northeast region, the kdr mechanism associated with pyrethroid resistance occurs all over Brazil. PMID- 19772770 TI - Morphological description of Amblyomma brasiliense Aragao, 1908 (Acari: Ixodidae) larvae and nymphs. AB - The immature stages of Neotropical ticks are poorly known and in many cases have not been described. Tis work presents a morphological description of Amblyomma brasiliense larvae (F1) and a redescription of nymphs (F1). A. brasiliense is reported as one of the most aggressive ticks to humans in Brazil. Immature ticks obtained from a laboratory colony initiated from adult specimens collected in the Parque Estadual Intervales (24 degrees 18 degrees S and 48 degrees 24' W), Sao Paulo, Brazil, were analyzed under scanning electron microscope, and also under light and stereoscopic microscopes. A. brasiliense larvae present basis capituli rectangular; short palpi; rounded idiosoma; coxa I with two spurs, the external one being longer than the internal one; and coxae II and III each with one short spur. Nymphs present basis capituli rectangular with a sharp pointed cornua; oval idiosoma with scutum reaching coxa III; coxa I with two evident spurs, the external one being longer than the internal one; coxae II-III each with one short spur; and coxa IV with a very short spur and chitinous tubercles on internal surface of posterior border of idiosoma. These morphological features, in association with chaetotaxy and porotaxy, should make possible the identification of immature Amblyomma ticks. PMID- 19772771 TI - Ticks on domestic animals in Pernambuco, Northeastern Brazil. AB - The objective of this article was to discuss some aspects of ticks associated with domestic animals in the State of Pernambuco, northeastern Brazil, based on a literature review and present new data obtained from recent tick collections carried out in this northeastern Brazilian state. From August 2007 to June 2008, 1,405 ticks were collected and five species were identified: Amblyomma cajennense (Fabricius, 1787), Amblyomma ovale Koch, 1844, Dermacentor nitens Neumann, 1897, Rhipicephalus (Boophilus) microplus (Canestrini, 1887), and Rhipicephalus sanguineus (Latreille, 1806). Dogs from urban areas were found exclusively infested by R. sanguineus, whereas dogs from rural areas were found infested by A. cajennense, A. ovale, R. (B.) microplus, and R. sanguineus. The only tick species found on cattle and goats was R. (B.) microplus. Horses were found infested by D. nitens and at a lesser extent by A. cajennense and R. (B.) microplus. The only tick species found on donkeys was D. nitens. Tis study confirms the presence of A. cajennense in Pernambuco and describes for the first time the presence of A. ovale in this state. The medical and veterinary relevance and control of ticks associated with domestic animals in Pernambuco are also briefly discussed. PMID- 19772772 TI - Epidemiological profile of cutaneous leishmaniasis in an endemic region in the State of Rio de Janeiro, Brazil. AB - The objective of the present study was to investigate the dynamics and profile of American Cutaneous Leishmaniasis (ACL) in an old colonization area in the State of Rio de Janeiro. Health departments of municipalities in the Central-Southern region that had notified cases to the Ministry of Health's Notifable Diseases Information System between 1997 and 2002 were contacted to obtain data. Out of the 119 cases recorded, 51 patients were visited for an interview and inspection of the environment. The cases of ACL exhibited a profile similar to that observed in other Brazilian cities, affecting individuals of both genders, all age groups and different occupational categories, especially students. Risk activities were reported by 56.9% of the interviewees and 84.3% had never left their homeland. Water courses, chicken coops, bamboo plantations and different fruit trees including banana plants and mango trees were frequently observed in the surrounding environment. Most of the interviewees had not noted any environmental changes prior to becoming sick. Domestic animals were present in all homes, but only dogs presented lesions suggestive of the disease. These were on different occasions that rarely preceded or coincided with the human cases. The possible existence of distinct transmission cycles, i.e. one for canines and another for humans, was discussed. PMID- 19772773 TI - [Cattle helminthiasis: farmers perception in Minas Gerais, Brazil]. AB - This study aimed to characterize the cattle endoparasites control in Minas Gerais State. Questionnaires were applied in 1,304 farms and 1,289 were validated and used in this study. The farms were located at 555 municipalities inserted in 66 Minas Gerais micro-regions and were selected by random sampling. The interviewees were asked about socioeconomic profile, production characteristics and cattle sanitary management of each farm, and attitudes to control the endoparasites. Results showed that the parasites control practices recommended to cattle are unknown to most of the farmers. PMID- 19772774 TI - Comparison between a soluble antigen-based ELISA and IFAT in detecting antibodies against Babesia canis in dogs. AB - An available enzyme-linked immunosorbent assay (ELISA) was studied for the detection of anti-B. canis antibodies in the sera of dogs using, indirect fluorescent antibody test (IFAT) as a reference test. ELISA uses a soluble antigenic preparation of B. canis and the optimal dilutions of the antigen, serum and conjugate were determined by check board titration, using positive and negative reference serum. The soluble antigen preparation of B. canis merozoites was 10 microg x mL(-1), with reference sera from positive and negative in a single dilution of 1:100, and conjugated to 1:4.000. A total of 246 serum samples were collected from dogs during the rabies vaccination campaign in Jaboticabal, Sao Paulo, Brazil and examined for the presence of antibodies against B. canis by ELISA and IFAT. Under these conditions, the average absorbance of negative serum was 0.129 + or - 0.025, resulting in a cut-of value of 0.323 (ELISA level 3) and the average absorbance of positive reference serum was 2.156 + or - 1.187. The serological positive samples tested for B. canis by ELISA and IFAT were 67.89% (n = 167) and 59.35% (n = 146), respectively. These results suggest that ELISA described may prove to be an effective serological test to diagnose canine babesiosis. PMID- 19772775 TI - [Allochthonous cases of canine visceral leishmaniasis in Parana, Brazil: epidemiological implications]. AB - The south region is the only area in Brazil that does not present autochthonous cases of visceral leishmaniasis (VL), however, in the state of Parana, dogs and humans have been found showing a VL compatible clinical profile. In view of this problem, the present work aimed at isolating and identifying the parasite and determining the cases autochthony. All animals clinically suspect of VL were clinically evaluated, and had samples of their blood collected for hemoculture (NNN culture medium), serology, PCR and RAPD-PCR, hemogram, and biochemical assays. The dogs presenting VL clinical profile had their lymph nodes and/or bone marrow punctured and their content inoculated in NNN culture medium. The protozoan isolated was identified by PCR and PCR-RAPD. Strains of Leishmania were isolated in 19 out of the 24 studied animals. Fourteen isolates were identified as L. (Leishmania) infantum, and five were L. (Viannia) braziliensis. In the epidemiological analysis, it was possible to determine that all dogs with L. (L.) infantum being allochthonous cases. Leishmaniasis is a zoonose that has the domestic dog as reservoir, the migration of such animals can disseminate the parasite to other regions, provided the agent finds an adequate ecotope and a specific vector (Lutzomyia longipalpis). PMID- 19772776 TI - [Occurrence of antibodies and risk factors for infection for Toxoplasma gondii in dogs in the cities of Lages and Balneario Camboriu, Santa Catarina State, Brazil]. AB - The aim of this study was to identify the occurrence of antibodies and risk factors for infection for Toxoplasma gondii in dogs in the cities of Lages and Balneario Camboriu, Santa Catarina State, Brazil. Blood samples from 400 domiciliated dogs were processed for antibody detection against T. gondii by indirect immunofuorescence antibody test (IFAT). The following variables were obtained by questionnaire: breed, age, sex, diet, environment, presence of cats and street access. A Chi-Square test was performed to verify the association between the seroprevalence with the studied variables. From all evaluated dogs, 89 (22.3%) had antibodies against T. gondii. A total of 52 (26%) and 37 (18.5%) dogs were positive for T. gondii in Lages and Balneario Camboriu, respectively. No statistical differences were observed on the prevalences of T. gondii between both cities. Greater occurrences of seropositives for toxoplasmosis were observed in mixed-breed dogs (P = 0.002), who had access to the street (P = 0.003) and received homemade diet (P = 0.028). A strong trend for seropositivity against T. gondii was observed among adult dogs, indicating post-natal exposure, and among those that have previous contact with cats. PMID- 19772777 TI - [Ehrlichia canis in dogs attended in a veterinary hospital from Botucatu, Sao Paulo State, Brazil]. AB - This study investigated the etiology of canine ehrlichiosis and possible clinical and epidemiological data associated with the infection in 70 dogs suspect of ehrlichiosis attended at the Veterinary Hospital of the Sao Paulo State University in Botucatu city during 2001 and 2002. Dogs were evaluated by clinical epidemiological and hematological data and molecular analysis by partial amplification and DNA sequencing of the ehrlichial dsb gene. E. canis DNA was amplified and sequenced in 28 (40.0%) dogs. Dogs younger than 12 months old showed significantly higher infection rates (65.0%; P < 0.05). Diarrhea, apathy, and anorexia were the major clinical signs observed in 55.2% (P = 0.05), 47.0% (P > 0.05), and 42.4% (P > 0.05) of the PCR-positive dogs, respectively. Twenty-five anemic (<5.5 x 10(6) RBC x microL (-1)), and 8 leukopenic (<5.5 x 103 WBC x microL (-1)) dogs were PCR-positive (P > 0.05). All 28 PCR-positive dogs showed thrombocytopenia (< 175 x 103 platelets x microL (-1)) and revealed statistical significance (P < 0.05). E. canis was the only Ehrlichia species found in dogs in the studied region, with higher infection rates in younger dogs, and statistically associated with thrombocytopenia. PMID- 19772778 TI - [Ovicidal and larvicidal activity in vitro of Eucalyptus globulus essential oils on Haemonchus contortus]. AB - The objective of this work was to evaluate ovicidal and larvicidal effects of Eucalyptus globulus essential oil (EGEO) on Haemonchus contortus. The chemical composition determination of EGEO was through gas chromatography and mass spectrometry. Egg hatch test (EHT) was performed in concentrations 21.75; 17.4; 8.7; 5.43 e 2.71 mg x mL(-1). In larval development test (LDT) were used the concentrations 43.5; 21.75; 10.87; 5.43 e 2.71 mg x mL(-1). Each trial was conducted by negative control with Tween 80 (3%) and positive control, 0.02 mg x mL(-1) of thiabendazole in EHT and 0.008 mg x mL(-1) of ivermectin in LDT. The maximum effectiveness of EGEO on eggs was 99.3% in concentration of 21.75 mg x mL(-1) and on larvae was 98.7% in concentration 43.5 mg x mL(-1). The concentration of EGEO that inhibits 50% of the eggs and larvae was 8.3 and 6.92 mg x mL(-1), respectively. The oil chemical analysis identified as main component the monoterpen 1,8-cineol. EGEO presented ovicidal and larvicidal activities in vitro, revealing a good potential for use in the control of sheep and goat gastrointestinal nematodes. PMID- 19772779 TI - [Bilateral anomaly in the style of Sciopemyia sordellii (Shannon & Del Ponte) (Diptera, Psychodidae)]. AB - This paper presents a male specimen of Sciopemyia sordellii with a rare bilateral anomaly, consisting in eight spines in a style and five in the other. Tis species has four spines in each style as its normal number. The specimen was captured using a CDC light trap, in a forested area in the State Park "Floresta Estadual Edmundo Navarro de Andrade", in May 2004, located in the city of Rio Claro, Sao Paulo State, Brazil. Similar anomaly was once described but this is the first specimen found with a bilateral alteration. It may cause confusion in taxonomic identification and even lead to description of new species, increasing the number of synonymies. PMID- 19772780 TI - Paleoparasitology at "Place d'Armes", Namur, Belgium: a biostatistics analysis of trichurid eggs between the Old and New World. AB - Paleoparasitological findings about human occupation and their domestic animals, from Gallo-Roman period up to recent times, were described at the archaeological site of "Place d'Armes", Namur, Belgium, by preventive archaeological excavations. Organic sediment samples from cesspools, latrines and structures like were analyzed and revealed intestinal parasite eggs (helminthes) in all of the different archaeological contexts. The parasitic association Ascaris sp. and Trichuris sp. was found although it is not easy to determinate the specific parasite species. Trichurids were described in both New and Old Worlds since the prehistorical time. To elucidate the zoological origin of the organic remains, the parasites and the prior function of the sanitary structures Trichuris eggs were statistically analyzed for morphometric parameters, and suggest that it could be an important tool to help the whole paleoparasitological diagnosis. PMID- 19772781 TI - Ectoparasite infestation on rural dogs in the municipality of Sao Vicente Ferrer, Pernambuco, Northeastern Brazil. AB - This article presents the results of a study on ectoparasites infesting rural dogs in Pernambuco, northeastern Brazil. Forty-one dogs from a rural community of Pernambuco were examined and 70.7% were infested by ectoparasites. The prevalence rates of infestation by ticks, fleas, and lice were 58.5, 43.9 and 22%, respectively. Of 24 dogs parasitized by ticks, 15 were exclusively infested by Rhipicephalus sanguineus (Latreille) (32 females, 66 males, 9 nymphs; prevalence, 48.8%; mean intensity, 5.4), four by Amblyomma ovale Koch (33 females, 19 males; prevalence, 22%; mean intensity, 5.8), and five were coinfested by both species. Ctenocephalides felis felis (Bouche) (25 females, 8 males; prevalence, 43.9%; mean intensity, 1.9) and Heterodoxus spiniger (Enderlein) (16 females, 11 males, 10 nymphs; prevalence, 22%; mean intensity, 4.1) were the only species of flea and louse identified. Tick infestation was more frequent than flea or lice infestations (p < 0.05). No statistical difference was found by sex and age group of the dogs studied and prevalence of infestation. Overall, 48.8% (20/41) of the dogs were infested by more than one ectoparasite species. PMID- 19772782 TI - [Detection anti-Toxoplasma gondii antibodies in swines bred and abated in the Bahia State, Brazil]. AB - This study was performed to verify the occurrence of anti-Toxoplasma gondii antibodies in swine raised and slaughtered in the state of Bahia, Brazil. Four hundred sixty five swine blood samples from farms of different cities had been collected and examined. Anti-T. gondii antibodies was detected by the enzyme linked immunosorbent assay (ELISA) and considered positive all the animals with equal or bigger headings than 1:16. From these, 18.27% (85/465) of total sample were positive for T. gondii, 30.76% (24) in Ilheus, 18.10% (21/116) in Itabuna and 14.76% (40/271) in Simoes Filho. Significant differences were observed regarding animal sex (p = 0.0171), raising system (p = 0.0002) and origin of the animals (p = 0.0278) in the city of Itabuna. The occurrence of anti-T. gondii antibodies shows that swine can be a source of infection for the local human population. PMID- 19772783 TI - Ultrasound imaging for the rheumatologist. XXII. Achilles tendon involvement in spondyloarthritis. A multi-centre study using high frequency volumetric probe. AB - Three-dimensional (3D) US is a new sonographic modality which represents a promising tool in the assessment of joint and periarticular tissues abnormalities in rheumatic diseases. The available literature has recently underlined its advantages mainly related to the virtual operator independence due to image acquisition of infinite 3D data sets obtained by transducer automated sweeping. Shortening of the US examination time represents another notable advantage over conventional two-dimensional (2D) US. The aim of the present study was to investigate the validity of 3D US in assessing Achilles tendon enthesitis by comparing it with 2D US. US examinations were performed by using a Logiq 9 (General Electrics Medical Systems, Milwaukee, WI) equipment with a high frequency (8-15 MHz) volumetric probe. One hundred and eighty-six Achilles tendon enthesis of 93 SpA patients were examined. The analysis of each basic US finding demonstrated from good to excellent agreement rates between 3D and 2D US, both in dichotomous assessment of sonographic lesions and in the use of semi-quantitative grading. Excellent agreement between the two modalities was demonstrated in the assessment of both inflammatory changes and structural lesions. Our study for the first time demonstrated that 3D US is a valid imaging modality for the assessment of Achilles tendon enthesitis. PMID- 19772784 TI - Disease activity assessment of rheumatoid arthritis in daily practice: validity, internal consistency, reliability and congruency of the Disease Activity Score including 28 joints (DAS28) compared with the Clinical Disease Activity Index (CDAI). AB - OBJECTIVE: The Disease Activity Score including 28 joints (DAS28) and the Clinical Disease Activity Index (CDAI) were developed in order to provide a quantifiable measure of rheumatoid arthritis (RA) activity. The aim of this study was to evaluate the validity and internal consistency reliability for DAS28 and CDAI in patients with RA seen by rheumatologists in usual clinical care. We also compared proposed categories of high, moderate, and low activity and remission according to both scores. PATIENTS AND METHODS: A sample of 2864 RA patients (2267 female, 597 male; mean age 58.5 yr, range 18-88 yr) were enrolled in this cross-sectional community-based study. Disease activity was assessed in each patient based on DAS28 and CDAI. Patients completed the Health Assessment Questionnaire (HAQ). Statistical evaluation was carried out by applying the Cronbach's values and principal component analysis (internal consistency reliability), the Pearson's coefficients, ANOVA and kappa statistic (convergent validity) and receiver operating characteristic (ROC) curve analysis (discriminant validity). RESULTS: Internal consistency testing of both scores indicated a reasonable difference, with Cronbach's alpha slightly higher for the DAS28. Interestingly, factor analysis revealed that the DAS28 constitutes a monocomponent measure in RA. Linear regression analysis showed a significant correlation between DAS28 and CDAI (p<0.0001). In addition, the DAS28 and CDAI were well correlated with HAQ (both at p level of <0.0001). The discriminatory power of both indices was good, without significant difference, but our results showed wide differences in both moderate/high disease activity and remission percentages (k=0.418). CONCLUSIONS: DAS28 and CDAI are valid and simple acceptable ways to measure RA activity in the clinical practice, but disease activity categorized by these indices differ considerably. Further research is needed to resolve this issue. PMID- 19772785 TI - Prevalence of low hemoglobin levels and associations with other disease parameters in rheumatoid arthritis patients: evidence from the CORRONA registry. AB - OBJECTIVE: To estimate the prevalence of low hemoglobin (Hb) levels in a large US cohort of patients with rheumatoid arthritis (RA) and examine the relationship between Hb levels and RA severity, associated comorbidities, and quality-of-life parameters by cross-sectional analysis of data from the Consortium of Rheumatology Researchers of North America (CORRONA) registry. METHODS: The study population comprised patients with RA >18 years of age and clinical information recorded in the CORRONA registry between October 1, 2001 and February 1, 2007. Patients were separated into low (Hb <13 g/dl for men; <12 g/dl for women) and normal Hb groups (Hb >13 g/dl for men; >12 g/dl for women). Hb levels were calculated from recorded hematocrit values. RESULTS: Of the 10,397 study patients, 1734 (16.7%) had low Hb levels and 8663 (83.3%) had normal Hb levels. More patients in the low Hb group had a history of comorbid cardiovascular disease, diabetes, and gastrointestinal disease. The low Hb group exhibited greater disease severity and activity (p<0.05) as reported by patients and rheumatologists. In multivariate analyses, RA severity ([odds ratio] OR 1.24; 95% confidence interval [CI]: 1.07-1.44) and ESR (OR 1.04; 95% CI: 1.03-1.05), and comorbid bleeding ulcers (OR 2.04; 95% CI: 1.01-4.12) were predictive of low Hb levels. CONCLUSION: Despite changes in treatment paradigms, low Hb levels remain prevalent in RA patients. This analysis suggests that low Hb levels may be associated with RA disease severity and the presence of certain comorbidities. PMID- 19772786 TI - Effects of monthly intramuscular neridronate in rheumatic patients in chronic treatment with low-dose glucocorticoids. AB - OBJECTIVES: To assess the effects of intramuscular (im) neridronate (NE) on lumbar and femoral neck BMD and on markers of bone turnover in rheumatic patients under chronic low-dose glucocorticoids (GC) therapy. METHODS: Sixty-nine osteopoenic and osteoporotic patients, affected by rheumatic diseases and gastric or esophageal conditions which contraindicated treatment with oral bisphosphonates (BPs), were randomly assigned to: Group A (23 patients) administered with daily calcium 1 g and vitamin D 800 UI; Group B (46 patients) receiving daily calcium 1 g, vitamin D 800 UI and im NE 25 mg monthly. RESULTS: After 12 months of therapy (M12) lumbar BMD was reduced of 2.97% in Group A, and improved of 3.34% (p=0.001) in Group B; at M12, femoral neck BMD was reduced of 2.40% in Group A and improved of 1.78% in Group B (p=0.010). After 6 (M6) and 12 months of therapy, the bone resorption markers were significantly reduced in Group B: OHPr-41.64% at M6 (p<0.001) and -37.91% at M12 (p<0.001); DPD-33.4% at M6 (p<0.001) and -33.18% (p<0.001) at M12: NTX -57.08% (p<0.001) at M6 and 55.95% (p<0.001) at M12; OC-11.62% (p=0.05) at M6 and -12.62% at M12 (p=0.06); B ALP -13.95 % at M6 (p=0.04) and -0.85% at M12 (NS). CONCLUSION: A twelve-month intramuscular NE treatment in rheumatic patients under GCs therapy improves lumbar and femoral BMD and mainly reduces the markers of bone resorption. PMID- 19772787 TI - HLA-B27 homozygosity has no influence on clinical manifestations and functional disability in ankylosing spondylitis. AB - OBJECTIVE: There is an established association between the development of ankylosing spondylitis (AS) and the HLA-B27 allele, but whether or not homozygosity for HLA B27 has any additional effects on the clinical manifestations of AS is unclear. The aim of this study was to determine the influence of HLA-B27 homozygosity on the clinical manifestations of AS in Korea. METHODS: A total of 490 patients were enrolled in this study. Genotyping was carried out using polymerase chain reaction-sequence specific primers (PCR-SSP) to assess HLA-B27 homozygosity or heterozygosity. One PCR reaction was undertaken to determine the HLA-B27 carrier status, and 5 group-specific PCR reactions were carried out to determine all of the other HLA-B alleles. Clinical manifestations of AS and BASFI were also evaluated according to homozygosity or heterozygosity for HLA-B27. RESULTS: HLA-B27 positive patients had a significantly younger age at symptom onset, more uveitis, and a higher frequency of hip joint involvement than HLA-B27 negative patients. One hundred and forty-six (29.8%) patients were homozygous for HLA-B27. No significant association between HLA-B27 homozygosity or heterozygosity and a history of peripheral arthritis, acute anterior uveitis, age at onset, or the Bath Ankylosing Spondylitis Functional Index (BASFI) was found. CONCLUSIONS: Homozygosity for HLA-B27 does not affect the clinical manifestations of AS in Korean patients. PMID- 19772788 TI - Multimodal optical and Gd-based nanoparticles for imaging in inflammatory arthritis. AB - OBJECTIVES: This report documents a multimodal nanoparticle (MNP) contrast agent, containing embedded luminophores and surface-immobilized gadolinium chelates, as a contrast agent of inflamed synovium in a collagen induced arthritis (CIA) model. METHODS: DBA-1J mice were immunized for CIA and imaged after disease onset by two independent modalities. After intravenous administration of MNP contrast, optical and magnetic resonance images were obtained and clinical disease was scored, which was followed by processing of hindlimbs for immunofluorescence and confocal microscopy. RESULTS: We show a correlation between disease severity and MNP optical luminescence that is dose dependent. Immunofluorescence of hindlimb sections reveal that MNP-labeled cells are monocytes/macrophages within the inflamed synovium. Magnetic resonance (MR) relaxation time maps, which determine the quantitative measure of T1 and T2 values at each imaging voxel, demonstrated a decreasing T2 signal in actively inflamed joints that was more pronounced earlier rather than later during disease. CONCLUSIONS: MNPs containing surface immobilized gadolinium chelates and embedded luminophores are potential dual modality contrast agents in inflammatory arthritis and localize to monocytes/macrophages within inflamed synovium. PMID- 19772789 TI - Examination of in vivo gelatinolytic activity in rheumatoid arthritis synovial tissue using newly developed in situ zymography and image analyzer. AB - OBJECTIVE: The aim of this study was to examine in vivo gelatinolytic activity of rheumatoid arthritis (RA) synovium using a newly developed in situ zymography (ISZ) method and pathological image analyzer, and to evaluate the relationship between this activity and several features on RA. METHODS: A total of 8 samples of synovium were obtained from RA patients during surgery, and 8 samples from osteoarthritis (OA) patients were examined as controls. Furthermore, total 14 samples of syovium were obtained for comparison among radiographical classifications as Larsen grade (4 cases of grade III, 5 cases of grade IV and 5 cases of grade V). These specimens were frozen with OCT compound immediately after surgery. Frozen sections were applied to a newly developed gelatin-coated FIZ film (Fuji Film Co.Tokyo.Japan) designed for use ISZ, and incubated at 37 degrees C for 6 hours. Using an image analyzer (image processor for analytical pathology; IPAP), two variables were measured as indicators of in vivo gelatynolytic activity: optical density of gelatinolyzed area (ODG), and ratio of gelatinolyzed area (RGA). Also, we investigated the relationship between these indicators and the following variables: radiographic changes (Larsen grades), clinical data (C-reactive protein concentration), histological score of synovial tissue (modified Rooney's score), and expression of matrix metalloproteinase (MMP)-2, MMP-9, tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2 (assessed by immunohistochemistry). RESULTS: RA synovium had significantly higher RGA and lower ODG than OA, indicating higher gelatinolytic activity in RA. Synovium from cases with Larsen grade IV or V had significantly lower ODG than cases with grade III, but there was no significant difference in RGA between grades. There was no significant correlation between gelatinolytic activity (ODG or RGA) and either CRP or modified Rooney's Histological Score. The results of ISZ indicate that the gelatinolyzed areas were mainly localized in the lining area, with a small amount scattered throughout the stroma. The results of immunohistochemistry indicate that MMP-2, MMP-9, TIMP-1 and TIMP-2 were expressed in areas of gelatinolysis. CONCLUSIONS: The present results indicate that in vivo gelatinolytic activity of synovium is stronger in RA than in OA. They also indicate that gelatinolytic activity of RA synovial cells is stronger in cases with Larsen grade IV or V than in cases with grade III, although the gelatinolyzed area is similar. Gelatinolytic activity, as indicated by optical density and the gelatinolyzed area, differed between regions, even within the same specimen, suggesting an imbalance between production of proteinases and their inhibitors. We believe that the present zymography method can contribute to the elucidation of biological enzymatic activity of RA synovium. PMID- 19772790 TI - Rheumatoid arthritis, Klippel-Feil syndrome and Pott's disease in Cardinal Carlo de' Medici (1595-1666). AB - OBJECTIVE: A paleopathological study was carried out on the she skeletal remains of Cardinal Carlo de' Medici (1595-1666), son of the Grand Duke Ferdinando I (1549-1609) and Cristina from Lorraine (1565-1636), to investigate the articular pathology described in the archival sources. METHODS: The skeletal remains of Carlo, buried in the Basilica of San Lorenzo in Florence, have been exhumed and submitted to macroscopic and radiological examination. RESULTS: The skeleton of Carlo revealed a concentration of different severe pathologies. Ankylosis of the cervical column, associated with other facial and spine anomalies suggests a diagnosis of congenital disease: the Klippel-Feil syndrome. In addition, the cervical segment presents the results of the tuberculosis (Pott's disease) from which the Cardinal suffered in his infancy. The post-cranial skeleton shows an ankylosing disease, mainly symmetrical and extremely severe, involving the large as well as small articulations, and characterized by massive joint fusion, that totally disabled the Cardinal in his last years of life. CONCLUSIONS: The final diagnosis suggests an advanced, ankylosing stage of rheumatoid arthritis. PMID- 19772791 TI - IL10R1 loss-of-function alleles in rheumatoid arthritis and systemic lupus erythematosus. AB - OBJECTIVE: IL-10 is a pleiotropic cytokine involved in the regulation of innate and cell-mediated immunity and a key mediator within the disturbed SLE immune system. IL-10 binds to IL10R1, which is expressed on a variety of immune cells and activates the JAK-STAT pathway. Two (out of several known) genetic IL10R1 variants may alter IL-10 binding or signal transduction. Here we investigate the differential activity of these IL10R1 variants and their possible association with RA or SLE susceptibility. METHODS: IL10R1-wt, IL10R1-S138G, IL10R1-G330R, or IL10R1- S138G +G330R were cloned into pIRESpuro3 and transfected into HeLa cells. Single cell clones were tested for IL-10-induced SOCS3- and SLAM gene expression by real-time PCR. DNA from 182 RA patients, 222 SLE patients, and 250 healthy controls was genotyped by allele-specific PCR. RESULTS: A biphasic increase of SOCS3 mRNA was observed that peaked at 15 minutes and 4 hours after IL-10 stimulation. The presence of IL10R1 S138G and G330R showed a weaker induction of both SOCS3 and SLAM upon stimulation with IL-10. In RA a homozygous G330R genotype was more commonly present than in controls (15.4% vs. 7.6%; p<0.05). In SLE the G330R allele frequency was also increased (36.3% vs. 30.0%; p<0.05) without showing a gene-dose relationship at the genotype level. CONCLUSIONS: Based on these results, both variants of the IL10R1 gene are loss-of-function alleles. IL10R1 G330R may possibly contribute to RA or SLE disease susceptibility in Caucasian populations. PMID- 19772792 TI - Association between polymorphisms in the FCGRT gene and lupus nephritis in Chinese patients. AB - OBJECTIVE: Studies on mouse models have indicated that the neonatal Fc receptor (FcRn) plays important roles in a variety of autoimmune diseases. A variable number of tandem repeat (VNTR) polymorphisms within the FCGRT gene have been detected, and were found to affect the expression and functioning of FcRn. This study investigated the possible association of FCGRT VNTR polymorphisms with susceptibility and clinical manifestations in patients with lupus nephritis (LN). METHODS: A total of 404 Han Chinese subjects, comprising 200 patients with LN and 204 geographically-matched healthy controls, participated in the study. The FCGRT VNTR polymorphism was genotyped by DNA amplification using a touchdown polymerase chain reaction followed by polyacrylamide gel electrophoresis. RESULTS: The distribution of VNTR polymorphisms within the FCGRT gene in Chinese subjects was different to that in Caucasians. Analysis of allele and genotype frequencies revealed no significant difference between LN patients and controls. There was no significant difference in the clinical features or prognosis in LN patients when stratified by VNTR polymorphism. CONCLUSION: Our results suggest that VNTR polymorphisms within the FCGRT promoter are not associated with LN in the Chinese population. PMID- 19772793 TI - Association of rheumatoid arthritis with Mdm2 SNP309 and genetic evidence for an allele-specific interaction between MDM2 and p53 P72R variants: a case control study. AB - OBJECTIVE: This study examines two common, functional, single nucleotide polymorphisms (SNP) in the genes coding the human homolog of murine-double-minute 2 (MDM2) and p53 in patients with rheumatoid arthritis (RA) based on the hypothesis that p53 may be an important negative regulator of the pro inflammatory transcription factor nuclear factor kappa b (NFKappaB). METHODS: Genomic DNA was obtained from 221 patients with RA who fulfilled at least 4 ACR criteria and from 521 healthy controls. Mdm2 SNP309 and p53 P72R were genotyped by polymerase chain reaction and restriction enzyme analysis. RESULTS: In RA patients the frequencies of the mdm2 SNP309 G allele and both G-containing genotypes were significantly reduced (G allele: OR: 0.75, 95% CI: 0.59-0.95, p=0.016; genotype TG: OR: 0.71, 95% CI: 0.50-1.00; genotype GG: OR. 0.58, 95% CI: 0.34-0.99; both: p=0.049). Concerning p53 P72R, no differences in allele or genotype frequencies were detected. A combined analysis of both polymorphisms revealed a significant interaction between them (p=0.046). In individuals carrying >1 p53 72R allele, MDM2 had a protective effect, whereas in individuals homozygous for p53 72P, MDM2 had the opposite effect. CONCLUSION: The function of MDM2 depends on the p53 P72R genotype, resulting in either an increased or reduced risk for RA. We suggest that in most cases MDM2 stabilizes the conformation of p53, whereas in p53 PP-positive subjects MDM2 supports the degradation of p53. PMID- 19772794 TI - Receptor activator of nuclear factor kappa B ligand-mediated osteoclastogenesis is elevated in ankylosing spondylitis. AB - OBJECTIVE: Ankylosing spondylitis (AS) is an inflammatory arthritis involving the axial skeleton. Decreased bone mineral density has also been reported in AS patients. This study sought to determine whether osteoclastogenesis and osteoclast activity are increased in AS. METHODS: Twenty patients with AS were evaluated using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and other clinical parameters. Mononuclear cells were separated out from peripheral blood samples taken from AS patients and normal healthy controls and cultured with monocyte colony stimulating factor and receptor activator of the nuclear factor kappa B ligand (RANKL). Multi-nucleated, tartrate-resistant acid phosphatase stain-positive osteoclasts were counted after 9 days, and the areas of calcium absorption on calcium-coated plates were determined. RESULTS: Osteoclastogenesis was significantly greater in AS patients than in normal controls (number of osteoclasts/1106 mononuclear cells, median, 518.0 vs. 362.5, p=0.036). No differences were observed between AS patients and controls in terms of calcium absorption areas or the serum concentrations of tumor necrosis factor and RANKL. Osteoclastogenesis was greater in AS patients with sacroiliac joint ankylosis than in those without. Osteoclastogenesis and the calcium absorption area were not found to be correlated with BASDAI nor with other clinical parameters including age, erythrocyte sedimentation rate, and C-reactive protein levels. CONCLUSION: Osteoclastogenesis is elevated in AS patients, especially in those with sacroiliac joint ankylosis. Increased osteoclastogenesis may be related to osteopenia in AS patients. PMID- 19772795 TI - Antibodies against recombinant heat shock proteins of 60 kDa from enterobacteria in the sera and synovial fluid of HLA-B27 positive ankylosing spondylitis patients. AB - OBJECTIVE: To study the association of HLA-B27 with IgG antibodies to different enterobacterial HSP60s in patients with ankylosing spondylitis (AS). METHODS: IgG antibodies to 60 kDa enterobacterial HSPs were determined by ELISA in paired samples of sera and synovial fluid from 21 HLA-B27+ ankylosing spondylitis (AS) patients; and in sera from 32 HLA-B27+ AS patients, 35 HLA-B27+ healthy relatives of AS patients, and 60 HLA-B27- healthy individuals with no family members with AS. RESULTS: HLA-B27+ patients and healthy individuals showed significantly higher IgG antibody levels to recombinant enterobacterial HSP60s than HLA-B27- healthy controls. The levels of anti-HSP60Sf and anti-HSP60Ec antibodies correlated with disease activity and anti-HSP60Ec antibodies with male gender. No association between enterobacterial HSP60 antibody levels and disease duration was observed. All groups had lower levels of IgG antibodies to rHSP60 from Streptococcus pyogenes (rHSP60 Spy). In paired samples of sera and synovial fluid from B27+ patients, IgG antibodies to enterobacterial HSP60s were detected, but in significantly higher levels in sera than in synovial fluid. The anti-rHSPSpy IgG response in these samples was lower and similar in the three groups. CONCLUSIONS: A correlation was found between HLA-B27 and the response to recombinat enterobacterial HSP60s. This response could be associated with disease activitir and gender in some proteins and the presence eof IgG antibodies to these proteins in synovial fluid could be associated with the inflammatory process and initiation of AS. PMID- 19772796 TI - Poor to modest agreement between rheumatoid arthritis response measures in clinical practice. AB - OBJECTIVE: To evaluate the agreement among several rheumatoid arthritis (RA) response measures in a clinical setting. METHODS: 529 patients with RA were seen at 2 regular visits where the following response measures were determined: ACR 20, EULAR good or moderate (EULAR-GM), Simplified Disease Activity Index moderate (SDAI-M), Clinical DAI moderate (CDAI-M), and Patient Reported Outcomes Index-M 20 (PRO-IM-20). Each measure was modified to include a "worse" response, i.e. the inverse of the respective guidelines for a positive improvement response.Introduced for comparison was the Real-time Assessment of Disease Activity in Rheumatoid Arthritis (RADARA), a response measure that registers improvement if the patient's tender and swollen joint counts and HAQ score all improve and worsening if all three increase. Contingency tables comparing the three responses (worse, no change, and improvement) along with Cohen's kappa were calculated. RESULTS: The mean (SD) baseline characteristics of the patients included: age 66.5 (10.7) years, RA duration 12.9 (11.0) years, 91.3% male, 84.1% rheumatoid factor positive, and a Disease Activity Score-28 of 3.5 (1.3). The percentage of patients who improved/worsened were as follows: ACR-20 4.7/9.1, EULAR-GM 23.4/26.3, SDAI-M 16.1/20.6, CDAI-M 16.3/20.0, PRO-IM-20 22.5/34.4, and RADARA 7.0/11.5. Agreement (kappa) was poor to slight (G (TNFR1), 676T>G (TNFR2), -857C>T (TNF-alpha), -308G>A (TNF-alpha), and -238G>A (TNF-alpha) in AS susceptibility. METHODS: Forty-nine AS patients and 68 randomly chosen healthy volunteers were enrolled in the study. Polymerase chain reaction coupled with a restriction fragment length polymorphism assay was performed in the genotype analysis of each variant. RESULTS: The polymorphisms 36A>G (TNFR1) and -238G>A (TNF-alpha were not found to be in Hardy-Weinberg equilibrium in the patient group and therefore were excluded from the statistical analysis. A marginally statistically significant difference was observed in the distribution of 676T>G (TNFR2) genotypes between AS patients and controls (p=0.054) and was revealed to be more significant in the 676T>G allele distribution between the two groups (p=0.031). The complex genotype TNFR2 676TG/ TNF-alpha -857CC (p=0.041) was also differently distri-buted between AS patients and controls. CONCLUSIONS: The TNFR2 676T allele is reported here for first time to be differently distributed between AS patients and controls. The higher frequency of the wild type TNFR2 676T allele in AS patients suggests the functional ability of TNFR2 to support increased TNF alpha mediated immunoactivity. PMID- 19772799 TI - Methotrexate information booklet study 2008. AB - INTRODUCTION: I n order to assess the value of using the methotrexate information booklet, we conducted a single blind prospective controlled trial of the patients attending two rheumatology services. METHODS: The active-arm (n=40) used the MTX information booklet for the patients' education and the control-arm (n=38) did not. Patients' interviews were conducted over a 6-month period using an MTX questionnaire. RESULTS: The entire active-arm patients (100%) were taking folic acid and 32 (80%) knew the reason why they were taking folic-acid vs. [30 (79%) and 10 (26%) in the control-arm]. In the active-arm 35 (88%) knew the reason for their monthly blood tests vs. 18 (47%) in the control-arm. The entire active-arm was aware of the need for contraception use and MTX-side effects vs. 23 (60%) and 15 (40%) in the control-arm respectively. CONCLUSIONS: The use of the MTX information booklet in our cohort improved their understanding of the treatment. PMID- 19772800 TI - Quantitative and qualitative assessment of one rheumatology trainee's experience with a self-teaching programme in videocapillaroscopy. AB - OBJECTIVE: We have developed a self-taught course by which rheumatologists in training can learn how to conduct capillaroscopy examinations using a computerized videomicroscopy system. We assessed the effectiveness of this course by following the learning curve of one specialist trainee with no experience in capillaroscopy. METHODS: The student's training consisted of 10 practical sessions held on three consecutive days. The perceived difficulty in completing each session was graded from 0 (least difficult) to 10 (most difficult). All the images obtained were stored and the time spent by both the trainee and the tutor during the sessions was recorded. Each image was blindly judged by both the novice and the tutor for quality, assigning a score from 0 (lowest quality) to 10 (highest quality). The minimum acceptable score for standard clinical practice was considered to be >5. RESULTS: The student spent a total of approximately 5 non-consecutive hours engaged in 'direct' capillaroscopy and recorded a total of 172 images. The mean time required to produce each image varied from approximately 1.0 to 2.0 minutes. The perceived difficulty in completing a session decreased from the first to the last session. A quality score > 5 was assigned by the novice and tutor, respectively, to 16/49 images for the first group of sessions, 26/45 for the second group of sessions, and 56/78 for the third group of sessions. The overall agreement between the novice and tutor was good (K=0.617, SE=0.021). CONCLUSIONS: The monitoring of one rheumatologist in training indicates that novices can quickly learn, through an intensive self teaching programme under the supervision of an expert, how to use computerized videomicroscopy to conduct capillaroscopy studies. PMID- 19772801 TI - Spinal cord compression complicating aseptic spondylodiscitis in ankylosing spondylitis. AB - Aseptic spondylodiscitis is a well recognized complication of ankylosing spondylitis. Neurological complications of such discovertebral lesions are uncommon. We report a new case with a diagnosis of T12-L1 spondylodiscitis which developed ten years after a spinal cord compression. Such neurological complications of aseptic spondylodiscitis may be explained by proliferative epidural tissue without predominant inflammatory infiltrates and also the development of new bone reaction, suggesting the contribution of mechanical factors. PMID- 19772802 TI - Urate oxidase (rasburicase) for treatment of severe acute gout: a case report. AB - A 73-year-old female patient was referred to our department because of gouty arthritis in the right first toe. The patient suffered from progressive renal failure because of pauci-immune necrotising glomerulonephritis. As severe hyperuricaemia would further worsen progredient renal insufficiency and therapy with allopurinol was contraindicated because of renal insufficiency and previous pancytopenia, the patient was treated twice with intravenous rasburicase. This therapy was well tolerated by the patient and led to the decrease of serum uric acid below the detection limit within 24 hours. PMID- 19772803 TI - From ankylosis to pencil-in-cup deformity in psoriatic arthritis: a case report. AB - A 56-year-old woman with psoriatic arthritis is presented whose initially ankylosed digit was later found to develop pencil-in-cup change. The patient was treated over that period with etanercept and had no signs of active arthritis. The possible mechanisms for these changes are discussed. PMID- 19772804 TI - Experience with multiple stent implantations in primary antiphospholipid syndrome in childhood: a case report. AB - The antiphospholipid syndrome (APS) is an autoimmune condition characterized by the persisting presence of antiphospholipid antibodies in association with thrombosis and/or pregnancy morbidity. Primary APS is quite rare in childhood and exact prevalence is not known. However, substantial proportion of thrombotic events in children is being attributed to APS. We herein present a 9-year-old boy presented with impending pericardial tamponade and large pleural effusions likely secondary to transudation of fluid from his gradually developed collateral circulation which was resulted from almost completely occluded vena caval system due to primary APS. He was treated with multiple angioplasty-stenting which offered symptomatic relief and better quality of life. To our knowledge, this is the first reported paediatric case of primary APS presented with extensive occlusive lesions in both caval systems and treated with repeated endovascular stent placements. PMID- 19772805 TI - Antiphospholipid syndrome: a comprehensive review of a complex and multisystemic disease. AB - The antiphospholipid syndrome (APS) is an acquired thombophilia, which is characterized by one or more thrombotic episodes and obstetric complications in the presence of antiphospholipid (aPL) antibodies (Abs). APL Abs are detected by laboratory tests such as lupus anticoagulant (LAC), anticardiolipin (aCL) and anti-Beta2-glycoprotein I (Beta2GPI) Abs. This article reviews the most current aspects of APS with emphasis on the pathophysiology of the disease, clinical manifestations, laboratory tests, and current modalities of treatment. PMID- 19772806 TI - Systematic review on the safety of methotrexate in rheumatoid arthritis regarding the reproductive system (fertility, pregnancy, and breastfeeding). AB - OBJECTIVE: To analyze the safety of methotrexate (MTX) in rheumatoid arthritis (RA) regarding the reproductive system (fertility, pregnancy, and breastfeeding). METHODS: Systematic review of studies retrieved by a sensitive search strategy in Medline (1961 - October 2007), Embase (1961 - October 2007), Cochrane Library (up to October 2007), and from the abstracts of the ACR (2005, 2006) and EULAR (2005 2007) annual scientific meetings. SELECTION CRITERIA: a) population: studies had to include patients with RA; b) intervention and control: discontinuation of MTX or elective abortion versus continuation of MTX or continuing pregnancy; and c) outcomes: infertility, oligospermia, reversibility, miscarriages, malformations, premature babies, healthy newborn, percent of the dose of MTX that passes to human milk, adverse effects in the lactating child. There was no limitation regarding study design, except for case reports, or language. RESULTS: MTX and pregnancy: we selected 6 articles for detailed evaluation from 847 initial ones from the literature search. They were descriptions of cases obtained from searching retrospectively clinical databases of individual centers or from surveys. Patients had been exposed to MTX at doses used in rheumatology (5-25 mg/w), from conception to first trimester of pregnancy. Total number of MTX exposed pregnancies is 101, and the pooled outcomes (elective abortion not included): 19 miscarriages (23% of pregnancies); 55 live births (66% of pregnancies); and 5 of them had minor neonatal malformations (5% of pregnancies). The rate of induced abortions is 18%. MTX and lactation and fertility: no articles fulfilled the selection criteria. There is indirect evidence on the excretion of MTX in human milk and probably of reversible infertility from case reports. CONCLUSIONS: This review exposes the shortage of data on the safety and risks of MTX during conception, pregnancy and lactation at the doses commonly used in rheumatology. MTX and pregnancy: there is not sufficient evidence to support whether it is MTX or the disease what underlies miscarriage in these patients. Pooling the data from the studies included, the rates of miscarriages and of birth defects are similar to the rates observed in healthy population. MTX and lactation and fertility: there is absence of confirming evidence. PMID- 19772807 TI - Current educational status of paediatric rheumatology in Europe: the results of PReS survey. AB - OBJECTIVES: To understand the status of education and problems in paediatric rheumatology practice in Europe, through a survey. METHODS: A 26-item questionnaire was conducted during the 14th Congress of the Paediatric Rheumatology European Society in Istanbul, 2007. Physicians who were practicing or studying within the field of paediatric rheumatology for at least one year were included in the survey. RESULTS: One hundred and twenty eight physicians, 79 paediatric rheumatologists (including 5 paediatric immunologists and 10 paediatric nephrologists), 34 paediatric rheumatology fellows and 15 adult rheumatologists completed the survey. The physicians were from: Europe 95 (81.9%), South America 12 (10.4%), Middle East 5 (4.3%), Asia 2 (1.7%), Africa 2 (1.7%). The duration of training for paediatric rheumatology ranged between 1-5 years (mean: 3.12+/-1.11). Sixty physicians scored their education as unsatisfactory and among those, 48 physicians were from Europe. Physicians reported good skills in the following items; intraarticular injections (83.3%); soft tissue injections (47.6%); evaluation of radiographs (67.5%); whereas competence in the evaluation of computed tomography/magnetic resonance imaging (30.5%); and musculoskeletal sonography (16.7%) was much lower. A need for improved basic science and rotations among relevant fields were specifically expressed. CONCLUSION: Being a relatively new speciality in the realm of paediatrics, paediatric rheumatology education at the European level needs to be further discussed, revised and uniformed. PMID- 19772808 TI - Tarsitis as an initial manifestation of juvenile spondyloarthropathy. AB - OBJECTIVE: The aim of this study was to determine the frequency of tarsitis as one of the first symptoms of juvenile spondyloarthropathy (JSpA) and to analyze whether patients with tarsitis at onset differ from those without it. METHODS: A retrospective chart review was performed, from January 1996 to September 2007, at a paediatric rheumatology unit of a tertiary university hospital. RESULTS: Tarsitis was detected in one-third of the children diagnosed with JSpA. They had fever and received antibiotics due to a suspected infection more frequently than those without tarsitis. Inflammatory low back pain was extremely unusual among these patients. CONCLUSION: There were some differences between children diagnosed with JSpA initially affected with tarsitis and those without it. Patients with tarsitis as one of the first symptoms were often misdiagnosed as soft tissue infections. PMID- 19772809 TI - Recurrent pericarditis in hyper-IgD syndrome. PMID- 19772810 TI - Joint and tendineous involvement in ochronosis: clinical history and imaging of a case. PMID- 19772811 TI - Successful treatment of ankylosing spondylitis coexisting with pulmonary sarcoidosis by infliximab. PMID- 19772812 TI - Autoantibodies against U1RNP and monoclonal gammopathy of uncertain significance: an unusual association. PMID- 19772813 TI - Entero-insular axis in children with simple obesity. AB - INTRODUCTION: The entero-insular axis plays an important role in generation of satiety signal. Thus, disturbances in this axis can influence the path to a simple obesity. THE AIM OF THE STUDY was to assess the function of the hormonal part of the entero-insular axis in children with simple obesity. MATERIAL AND METHODS: Group of 13 girls with the simple obesity was analyzed and the results were compared with results taken in the control group of 10 healthy girls. Each girl was examined for the oral glucose tolerance and standard meal tests. Blood was collected before stimulation and after 15, 30, 60 and 120 min. Concentrations of insulin, glucagon, pancreatic polypeptide, cholecystokinin, gastric inhibitory peptide (GIP) and glucagon-like peptide 1 (GLP-1) were determined with radioimmunoassay. Fasted and postprandial levels of the peptides as well as their integrated outputs were measured. RESULTS: The results indicated that the disturbances in th entero-insular axis were limited to hyperinsulinaemia and changes in secretion of cholecystokinin (CCK) and GLP-1 in obese subjects. The integrated output of CCK in obese girls was significantly higher (p<0.001) than in control group but exclusively after the meal test. Mean values of the integrated output of GLP-1 in both tests were significantly higher in the control group than in the obese girls (oral glucose tolerance test- OGTT: p<0.001; meal: p<0.05). After OGTT and test meal, neither plasma concentrations of glucagon, pancreatic polypeptide nor GIP differed in the obese girl and control groups. CONCLUSIONS: Low postprandial level of GLP-1 in obese children seems to be responsible for excessive ingestion of food and a weaker inhibition of gastric emptying, both resulting in obesity. PMID- 19772814 TI - [Evaluation of the risk of diabetes in the offspring of patients with diagnosis of type 2 diabetes]. AB - INTRODUCTION: There are many commonly known risk factors of type 2 diabetes. One of them is the occurrence of the disease in 1st degree relatives. THE AIM OF THE STUDY was: a) to evaluate the threat of type 2 diabetes in adult children of patients with type 2 diabetes, b) to analyze the frequency of type 2 diabetes and other disorders in offspring of parents with type 2 diabetes, c) to detect metabolic disorders before clinical manifestation and the development of macro- and microangiopathy, d) to introduce early prevention and treatment in case of disorders, e) to evaluate the influence of sex and age on the metabolic disorders. MATERIAL AND METHODS: Included in the study were 197 declared as healthy probands, children from parents with type 2 diabetes, aged 18-71 years, 71 men and 126 women. In 74 of the probands the father has type 2 diabetes, mean age 42 years, in 121 the mother, mean age 43 years. In one case both the father and the mother has diabetes type 2. All the offspring's were divided in age groups. Group 1:18-44 years, group 2 over 44 years and in subgroups depending on sex. All the examined offspring's has had following examinations: BMJ, fasting glycaemia 2 times, OGTT, cholesterol, TG, HDL, LDL insulinaemia, peptide C, HbA1c, indirect insulin resistance index. RESULTS: Hyperglycemia was ascertained in 37%, including unknown diabetes type 2 in 25% in the group with a diabetic father. In the group with a diabetic mother unknown diabetes type 2 was shown in 23%. In the whole group 58% of the offspring's were overweight or obese, glycaemia disorders existed in 44%, especially in the age group over 44 years. More than half of the examined offspring's has an increased level of cholesterol and HbA1c, especially in sons of diabetic fathers, aged over 44 years. The increased level of insulin peptide C, HbA1c, BMI and blood pressure correlated with the age over 44 years and with the male sex. CONCLUSION: 1. Offspring of parents with type 2 diabetes is a group of high risk for the development of diabetes type 2. 2. Necessary is a complex examination and furthermore a close monitoring of the risk factors for diabetes, in offspring's of parents with type 2 diabetes. PMID- 19772815 TI - [Gonadal function in young men after the treatment for Hodgkin lymphoma]. AB - INTRODUCTION: The survival rate after the treatment for Hodgkin lymphoma improved in the last three decades and the late effects of anticancer therapy, particularly gonadal toxicity, became an important problem. THE AIM OF WORK: Assessment of the influence of chemo- and radiotherapy on gonadal function in young male survivors after the treatment for Hodgkin lymphoma (HL). MATERIAL AND METHODS: Levels of inhibin B, testosterone, FSH, LH and testicular volume were measured in 26 HL survivors aged from 15.6 to 25.2, who had been treated for HL in prepubertal (n=8) or pubertal (n=18) period. RESULTS: 1. In all groups, comparing to control one, we found higher FSH concentration (15.2+/-12.3 IU/l vs. 3.3+/-1.2 IU/l); p=0.0004, lower inhibin B (60.9+/-44.5 ng/l vs. 198.1+/-58.1 ng/l); p=0.0001, lower testicular volume (18.2+/-2.6ml vs. 21.3 +/-5.1ml) p=0.01 and normal LH as well as testosterone values. 2. Higher >+2SD FSH and LH were found in 62% and 23%, respectively, and lower <-2SD inhibin B - in 72% of survivors. 3. We did not observe the differences between the patients: a) treated before and during puberty and b) the patients in different stages of disease. 4. Persistently lowered inhibin B concentration and higher, but gradually normalized values of FSH were found >6 years after the end of therapy, 5. Azoospermia was observed in 4/10 patients, oligospermia - in 4/10 and normospermia - only in 2/10. CONCLUSIONS: Anticancer treatment for HL, independently of the age at diagnosis and clinical stage, leads to serious and persistent gonadal dysfunction. The patients should be informed about the problem of gonadal toxicity and possibility of fertility preservation at the moment of diagnosis. PMID- 19772816 TI - [Socio-demographic and healthy situation of children with Down syndrome based own observation]. AB - INTRODUCTION: Family creates the atmosphere and conditions for the development of a child with Down's syndrome, is a place where are the links, and course of personality development of its members. THE AIM OF THE WORKS IS the comparison of the socio-demographic situation, pregnancy period, birth and state of infant in children with Down syndrome born between 1981-2008, divided into 3 subgroups: A - 100 children born before 1990, B - 445 children born between 1991-2000, C - 85 children born between 2001-2008, in reference to control group of 50 healthy children. MATERIAL AND METHODS: Retrospective analysis consists of 630 children with Down syndrome treated in a subclinical specialist office. Documentation information grouped into 29 collective features (X1-X29) served for statistical analysis of results in Excel and Access programs of MS Office pack. RESULTS: Subgroups of examined children with Down syndrome did not differ according to the socio-demographic situation except in number of conducted cytogenetic examinations and the age of therapy onset. Distinction in reference to healthy children was noticed in the age and education level of parents, pregnancy period, birth and infant status, the amount of time spent in infant or pediatric ward. CONCLUSIONS: The examined group of Down syndrome children in reference to healthy children manifests statistically more presence of pathology in the pregnancy period (prematurity, miscarriage treat, intrauterus infections), birth and infant status which require longer stay at hospital ward. In the last 3 decades a positive change has been observed of Down syndrome child perception in the family, earlier diagnosis made based on cytogenetic examination, what consequently results in therapy onset in the first months of life. PMID- 19772817 TI - [Iodine prophylaxis in Poland in light of the WHO recommendation on reduction of the daily salt intake]. AB - Iodine prophylaxis started in Poland in 1935, was suspended in periods of time 1939-1945 and 1980-1988. In 1991 Polish Council for Control of Iodine Deficiency Disorders (PCCIDD) was established and epidemiological survey performed in 1992 1993, defined Poland as an area with moderated - at seaside part as light - severity of iodine deficiency. In 1996 the Minister of Health introduced disposition on obligatory iodization of household salt with 30+/-10 mg KJ/kg and neonates formula with 10 ug/100 ml. Additionally supplementation the pregnant and breast feeding women with daily dose of iodides 100-150 ug was recommended. This very effective model resulted with eradication of endemic goiter in schoolchildren 6-12-years-old, decrease of prevalence of goiter in adults and pregnant women decrease of frequency of the elevated TSH concentration in neonates blood and decrease of dynamic of increasing an incidence rate of differentiated thyroid cancer and its follicular fraction. Poland has been defined by WHO and ICCIDD as a country with sufficient iodine prophylaxis and WHO collaborating Centre for Nutrition has been established at the Department of Endocrinology CMUJ in Krakow. WHO in 2006 and 2007 formulated recommendation on reduction of daily salt intake and additional new carriers of iodine are recommended: milk and natural mineral water containing known concentration of iodide (100-200 ug/l). The coordinating organization for iodine prophylaxis in Poland is PCCIDD as executive body of the National Program for Elimination of Iodine Deficiency financed by the Ministry of Health. PMID- 19772818 TI - [Roles of PPARs in the origin of metabolic disturbances in children with low birth weight (below 2500 g)]. AB - Children, who are born with low birth weight (less than 2500 g) are known to have an increased risk of developing metabolic syndrome in later live. PPAR could play a regulatory role in the pathogenesis of hyperlipidemia disturbance and a modulatory role in the control of inflammatory response. Peroxisome proliferator activated receptors (PPARs) are members of the nuclear hormone receptor superfamily of lig and -dependent transcription factors with pleiotropic effects on lipid metabolism, glucose homeostasis, cell proliferation, control of inflammation and atherosclerosis. Three isoforms of PPAR, i.e. a, p, y have been identified and are differentially expressed in various tissues and play different metabolic functions. In this review, the roles of PPAR and their implications in the control of vascular inflammation and atherosclerosis are discussed, especially in the group of risk developing metabolic syndrome -children with low birth weight (below 2500 g). PMID- 19772819 TI - [The role of lymphocytes and secrete cytokines in autoimmune thyroid diseases]. AB - Grave's disease and autoimmune hypothyroidism represent the two main autoimmune thyroid diseases, where an immune response is directed against the thyroid gland. The essence of these diseases is loss of tolerance of own tissues caused by malfunction of the T lymphocytes, which effect the production of antibodies reacting with particular cell structures and tissues. Cytokines participate in the induction and effector phase of the immune and inflammatory response and therefore play a critical role in the development of autoimmune thyroid diseases. Regulatory T cells take part in regulation of immune response and play a leading role in developing immune tolerance through active suppression. PMID- 19772820 TI - [Insulin resistance in patients with type 1 diabetes]. AB - Insulin determines glucose transport to the most of cells. Decreased answer of target cells to insulin is called insulin resistance. This phenomenon depends on genetic and environmental factors. The most important risk factor of progression of insulin resistance is style of life created by civilizational progress. The coexistence of insulin resistance, obesity, diabetes mellitus, hypertension and dyslipidaemia is defined as metabolic syndrome. At the beginning decreased insulin sensitivity was linked only with obesity and diabetes type 2. However clinical features of insulin resistance are present also in many patients with type 1 diabetes. In pathogenesis of insulin resistance decreased number of insulin's binding places and postreceptor function's failure are mentioned. It was revealed that diminished glucose disposal in the organism is an effect of reduced glucose uptake in the skeletal muscle. There are different methods of insulin resistance's assessment, however in patients with type 1 diabetes not all of them can be used. The gold standard of determining insulin sensitivity is the euglycemic insulin clamp technique. Other methods of insulin resistance's evaluation which will be more available, easier and cheaper are searched. Thus, indirect parameters of insulin resistance such as: anthropometric data, features of metabolic syndrome or inflammatory markers, correlated with clamp technique results are suggested to be used. Insulin resistance in type 1 diabetes is an extremely important clinical aspect because it increases the risk of chronic complications' development. Identification of insulin resistant patient with type 1 diabetes is essential for better metabolic control and prevention of longterm complications in this group. PMID- 19772821 TI - Sex chromosome pentasomy 49,XXXXY connected with hypothyroidism. Case report. AB - 49,XXXXY syndrome is a very rare sex chromosomes polysomy, which is always connected with dysmorphic appearance, hypergonadothrophic hypogonadism and mental retardation. In this report we describe the clinical, biochemical, hormonal, radiological and developmental status of the patient with 49,XXXXY syndrome, referred to our department at the age of 12 months because of underdeveloped external genitalia. Subclinical hypothyroidism and severe scoliosis could further disturb his development. PMID- 19772822 TI - Methotrexate versus combination methotrexate and etanercept for rheumatoid arthritis. PMID- 19772823 TI - Certolizumab pegol in active rheumatoid arthritis. PMID- 19772824 TI - Tocilizumab versus methotrexate in moderate to severe rheumatoid arthritis. PMID- 19772825 TI - Clinical utility of ultrasonography in spondyloarthropathies. AB - Since the introduction of ultrasonography by Professor Ian Donald in Glasgow as a tool for imaging in medicine, it has become an important technology for imaging the musculoskeletal system. Musculoskeletal ultrasonography is a powerful adjunct to clinical examination that can detect subclinical abnormalities of soft tissues, tendons, and ligaments; it is also an important tool for the objective assessment of synovitis and bone erosion. Enthesitis, the hallmark of spondyloarthropathies, can be readily imaged using ultrasound. Furthermore, the characteristic soft tissue abnormalities and bone erosions seen in psoriatic arthritis, for example, are easily detected. The axial skeleton is a complex structure that currently is not very amenable to ultrasound imaging, but advances have been made in its use to image sacroiliac joints and semiquantify active sacroiliitis. Technological advances currently being made in ultrasonography will provide exciting new possibilities for the application of this imaging modality to the spondyloarthropathies. PMID- 19772826 TI - Diffuse idiopathic skeletal hyperostosis: differentiation from ankylosing spondylitis. AB - Diffuse idiopathic skeletal hyperostosis (DISH) and ankylosing spondylitis (AS) share involvement of the axial skeleton and peripheral entheses. Both diseases produce bone proliferations in the later phases of their course. Although the aspect of these bone proliferations is dissimilar, confusion of radiologic differential diagnosis between the two diseases exists mostly as a consequence of a lack of awareness of their characteristic clinical and radiographic features. The confusion may extend to the clinical field because both advanced DISH and advanced AS may cause the same limitations of spinal mobility and postural abnormalities. However, the radiologic spinal findings are so different that changes due to each disease can be recognized even in patients in whom both diseases occur. This article reviews the clinical and radiologic characteristics that should help clinicians differentiate between the two diseases without much difficulty. PMID- 19772827 TI - New insights into synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. AB - In 1987, synovitis, acne, pustulosis, hyperostosis and osteitis (SAPHO) syndrome was proposed as an umbrella term for a group of diseases with similar musculoskeletal manifestations, in particular hyperostosis of anterior chest wall, synovitis, and multifocal aseptic osteomyelitis, observed in association with dermatologic conditions such as palmoplantar pustulosis, severe acne, and hidradenitis suppurativa. Despite recent advances in our understanding of the epidemiologic, pathophysiologic, and immunogenetic mechanisms involved in SAPHO syndrome, etiopathogenesis remains poorly understood. Propionibacterium acnes, the microorganism associated with acne, has been recovered on bone biopsy in some patients, but the possible pathogenetic role of an infectious agent in a genetically predisposed individual, resulting in exaggerated inflammatory response as "reactive osteitis," is a largely unproven hypothesis. The newly available whole-body MRI will assist early diagnosis by detecting multifocal osteitis lesions, some of them asymptomatic, in axial (anterior chest wall, spine, and jaws) and nonaxial sites. Moreover, outcomes are vastly improved by treatment with bisphosphonates and tumor necrosis factor-alpha antagonists. PMID- 19772828 TI - Clinical assessment and outcome research in spondyloarthritis. AB - Spondyloarthritis (SpA; formerly called seronegative arthritis) generally follows a chronic course with an uncertain outcome and includes diseases, such as ankylosing spondylitis and psoriatic arthritis, that require regular medical care and monitoring to control for disease activity and maintain physical function. This article describes recent achievements in the field of clinical outcome assessment, imaging, and the classification of patients with SpA symptoms. Clinical instruments are addressed that measure function, disease activity, and pain through questionnaires, physical examination, and laboratory tests. Furthermore, the value of different imaging techniques for daily practice is described, and the new classification criteria for axial SpA are discussed. PMID- 19772829 TI - Recent studies on the genetic basis of ankylosing spondylitis. AB - Recent studies published on the genetic basis of ankylosing spondylitis (AS) reflect novel areas of investigation and extension of recent advances. As HLA-B27 subtypes have been extensively examined in other ethnic groups, novel insights into the relevance of HLA-B27 folding to disease susceptibility have led to questions regarding the influence of HLA-B27 on AS pathogenesis. The recent identification of IL23R, ERAP1, and interleukin-1 (IL1A) region genes in AS pathogenesis has led to a number of replication studies. Other genes with inconsistent AS associations (eg, KIR, TLR4, ANKH, and TNAP) have been further examined with inconsistent results. Potential candidate genes (TIRAP, COL1A6, and MEFV) have been examined with no associations found. Tremendous progress has been made with respect to understanding the genetic basis of AS. The identification of new genes-ARTS1, IL23R, and IL1A-substantiate that susceptibility to AS is also determined by genes outside the MHC. PMID- 19772830 TI - Rheumatoid arthritis genetics: 2009 update. AB - Recent human genetic discoveries have increased our understanding of rheumatoid arthritis (RA) susceptibility. Genome-wide association studies have expanded the number of validated RA risk loci beyond HLA-DRB1 "shared epitope" alleles to include additional major histocompatibility complex (MHC) risk alleles and more than 10 regions outside the MHC. The newly discovered risk alleles are common in the general population, have a modest effect on RA risk, and together explain less than 5% of the variance in disease risk. Whereas the actual causal mutation and causal gene for most loci remain to be determined, these studies are beginning to reveal general themes: many risk loci are associated with other autoimmune diseases; many genes fall within discrete biological pathways (eg, the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway); and human genetics can group diseases into clinically meaningful subset categories (eg, presence or absence of autoantibodies). This review discusses recent RA genetic discoveries in terms of their potential to improve patient care. PMID- 19772831 TI - The role of toll-like receptors in rheumatoid arthritis. AB - An increasing body of data supports the role of the innate immune system in the pathogenesis of rheumatoid arthritis (RA). Toll-like receptors (TLRs) are expressed by cells within the RA joint and various endogenous TLR ligands are present within the inflamed joints of patients with RA. Further, various animal models suggest that TLR signaling is important in the pathogenesis of disease. Overall, the data suggest that activation by endogenous TLR ligands may contribute to the persistent expression of proinflammatory cytokines by macrophages and the joint damage to cartilage and bone that occurs in RA. The data support a potential role for suppression of TLR signaling as a novel therapeutic approach in patients with RA. PMID- 19772832 TI - The role of interleukin-17 in the pathogenesis of rheumatoid arthritis. AB - Interleukin (IL)-17 (also known as IL-17A), the signature cytokine of the newly described T helper 17 (Th17) cell population, has been implicated in the pathogenesis of numerous autoimmune diseases including rheumatoid arthritis. IL 17 is the founding member of a new subclass of cytokines that have highly proinflammatory properties. Studies in rodents and mammalian cell culture systems, as well as clinical settings, support a role for IL-17 in promoting rheumatoid arthritis. This article discusses the history of the discovery of Th17 cells, the potential mechanisms of action of IL-17 in autoimmunity, and perspectives for IL-17-targeted cytokine therapy. PMID- 19772833 TI - The role of biomarkers in the management of patients with rheumatoid arthritis. AB - In recent years, patient outcomes have improved dramatically with the availability of effective treatments for the management of rheumatoid arthritis (RA). RA, however, is a heterogeneous disease with variable disease progression and treatment response. Whereas some patients respond to a single disease modifying antirheumatic drug, others require more intensive treatment strategies. Assessing disease severity at diagnosis and monitoring disease activity on an individual level would be a more accurate way of tailoring therapy, ensuring optimal treatment for those at greatest risk of disease progression, long-term disability, and joint damage without unnecessary overtreatment. Assessment of disease activity and severity is currently based on a combination of clinical and laboratory parameters that aid treatment decisions. Use of biomarkers may provide a more accurate means of objectively assessing the disease. This article reviews the role of biomarkers in the management of RA. PMID- 19772834 TI - Intracellular signal pathways: potential for therapies. AB - Drawbacks to current therapies for rheumatoid arthritis and the high cost of many of these drugs have lead to the investigation of novel approaches for treatment of this disease. One such tactic is the targeting of proteins involved in intracellular signal transduction. Inhibitors of p38 kinase have largely failed in clinical trials, due to both lack of efficacy and adverse events. The degree of adverse events may reflect off-target effects or, conversely, may be a mechanism-related event subsequent to successful inhibition of p38. Drugs targeting Janus kinases or spleen tyrosine kinase have shown greater success in clinical trials. A thorough analysis of specificity, as well as publication of both positive and negative results, must be the goal of continuing trials of these and other inhibitors of signal transduction molecules. The success of many clinical trials in this novel class of drugs provides optimism that more cost effective and improved therapies will soon be available. PMID- 19772835 TI - Inflammation, autoimmunity, and atherosclerosis. AB - Historically atherosclerosis has been viewed as a disease associated with dyslipidemia because many studies (e.g., Framingham study) have demonstrated that dyslipidemia is clearly a risk factor for the disease and lipid-lowering statin therapies have proven to be highly effective in reducing the cardiovascular events and improving the quality of life for patients with coronary heart disease all over the world. Over the last decade, both preclinical and clinical research has provided multiple lines of unequivocal evidence that inflammation and immune response are integral components of the pathogenesis for atherosclerosis. In this article, both clinical and preclinical evidence in support of atherosclerosis as an inflammatory disease will be reviewed. Evidence in support of atherosclerosis as an autoimmune disease will also be presented. Furthermore, opportunities for translating the newly gained knowledge of atherosclerosis as an inflammatory/autoimmune disease into novel diagnostic and therapeutic modalities will be discussed along with challenges in developing these modalities. PMID- 19772836 TI - The busy life of regulatory T cells in systemic lupus erythematosus. AB - CD4+CD25+Foxp3+ regulatory T (Treg) cells suppress the proliferation and release of cytokines in several subsets of immune cells. By doing so and by maintaining immune tolerance in peripheral tissues, Treg cells contribute to avert autoimmunity. Many studies have investigated how Treg cells operate in autoimmune diseases, and which cellular and molecular pathways are targeted by Treg cells. This review provides an update on the activities of Treg cells in systemic lupus erythematosus (SLE), an autoimmune disease characterized by the presence of hyperactive immune cells and aberrant antibody responses to multiple nuclear and cytoplasmic antigens. PMID- 19772837 TI - An emerging role for Ubiquilin 1 in regulating protein quality control system and in disease pathogenesis. AB - The process of refolding or degrading misfolded proteins is the most important function of protein quality control (PQC) system. An imbalance between the capacity of PQC system and the quantity and severity of misfolded proteins may result in protein aggregate accumulation, which can ultimately contribute to a class of diseases referred to as conformational disorders. Numerous lines of evidence suggest that Ubiquilin 1 is an important component in PQC. Ubiquilin 1 has been indicated to be involved in the pathophysiology of neurodegenerative diseases and cancer. Here we review the evidence that Ubiquilin 1 is an important component of the PQC system and also review the role of Ubiquilin 1 in human diseases. PMID- 19772838 TI - A new mechanism of blood vessel growth - hope for new treatment strategies. AB - Growth of new blood vessels (angiogenesis) is essential for embryo development as well as for wound healing and progression of a number of diseases such as cancer, inflammatory conditions, eye diseases, psoriasis, and rheumatoid arthritis in the adult. Current paradigms explain blood vessel growth entirely by sprouting angiogenesis or by vessel splitting through so called intussusceptive angiogenesis. However, these mechanisms are mainly derived from experiments on the developing embryo while less is known about angiogenesis in the adult during, e.g., wound healing, tumor growth, and inflammation. Recently we showed that blood vessel growth in the adult can be induced and directed by mechanical forces that naturally develop during healing or remodeling of tissues. In contrast to sprouting and intussusception, the new biomechanical hypothesis assumes that functional blood vessels are passively translocated which, if found generic, may drastically change the approach for developing anti- and pro-angiogenic therapies in the treatment of a variety of diseases. PMID- 19772839 TI - Green algae as a platform to express therapeutic proteins. AB - Proteins produced by DNA recombinant technology have been playing important roles in modern medicine ever since the first such protein drug was approved by the U.S. Food and Drug Administration about three decades ago. However the inherent high cost of producing recombinant proteins, particularly those produced from mammalian cells, has hampered their broad application. Other protein expression systems that can reduce the cost yet still maintain the high-level therapeutic activities of the recombinant proteins are a top R&D priority. Eukaryotic unicellular green algae cells may provide a good solution to this long-standing challenge. PMID- 19772840 TI - The neural correlates of altered consciousness during epileptic seizures. AB - Epileptic seizures are characterized by a multifaceted spectrum of alterations in the general level of awareness and/or the subjective contents of consciousness. Complete loss of consciousness occurs when epileptic activity involves both cortical and subcortical structures, as in generalized seizures. On the other hand, simple partial seizures can spare both the level and contents of consciousness. Finally, complex partial seizures associated with medial temporal lobe discharges can selectively impair the patient's subjective experiences with variable degrees of responsiveness. The differences in ictal semiology between patients with epilepsy offer unique avenues for understanding the relationship between pathological brain function and altered conscious states. PMID- 19772841 TI - Guidelines on the use of fluoride in children: an EAPD policy document. AB - The EAPD strongly endorses that the daily use of fluoride should be a major part of any comprehensive preventive program for the control of dental caries in children. Regardless of the type of program, community or individually based, the suggested use of fluoride must be balanced between the estimation of caries risks and the possible risks for toxic effects of the fluorides. Such a preventive program should be re-evaluated at regular intervals and adapted to a patient's needs and risks. For the majority of European communities, the EAPD recommends the use of appropriate fluoride toothpaste in conjunction with good oral hygiene to be the basic fluoride regimen. PMID- 19772842 TI - Fluoride and the caries lesion: interactions and mechanism of action. AB - AIM: To review the mechanisms of action of fluoride (F). METHODS: Narrative review of the literature. FINDINGS: Fluoride can reduce tooth mineral solubility by exchanging for hydroxyl groups and reducing carbonate content. Thus its presence in solution facilitates mineral precipitation or reprecipitation by lowering solubility products of precipitating calcium phosphates. While sound enamel tends to lose fluoride with age, it accumulates at stagnation sites where caries lesions develop indicating this as a site of action. Fluoride in the lesion will encourage remineralisation [Robinson et al., 2000] such that penetration of the lesion by fluoride is pivotal. Access from plaque, however, is limited due to restricted penetration. CONCLUSIONS: Maintaining a very thin plaque layer is thus important in delivering fluoride to the lesion. PMID- 19772843 TI - Water fluoridation. AB - AIM: This was to present a summary of the evidence from systematic reviews of the effectiveness and safety of water fluoridation. METHODS: A search for relevant systematic reviews was conducted using the terms Fluoridation [Mesh] OR "water fluoridation" OR fluoridation OR (water AND fluoride) and was run from 01/01/2000 to 17/10/2008 in Pubmed, Embase, the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects in the Cochrane Library. The quality of the systematic reviews was assessed using Scottish Intercollegiate Guideline Network (SIGN) methodology checklists for systematic reviews. Websites of guideline organisations were also searched for relevant evidence-based guidelines, which were appraised using the AGREE instrument. RESULTS: Of the 59 publications identified, 3 systematic reviews and 3 guidelines were included in this review. While the reviews themselves were of good methodological quality, the studies included in the reviews were generally of moderate to low quality. The results of the three reviews showed that water fluoridation is effective at reducing caries in children and adults. With the exception of dental fluorosis, no association between adverse effects and water fluoridation has been established. Water fluoridation reduces caries for all social classes, and there is some evidence that it may reduce the oral health gap between social classes. CONCLUSION: Water fluoridation, where technically feasible and culturally acceptable, remains a relevant and valid choice as a population measure for the prevention of dental caries. PMID- 19772844 TI - Caries preventive effect of fluoride in milk, salt and tablets: a literature review. AB - BACKGROUND: There are a number of studies in the literature about the effectiveness of fluoride in tablets, fluoride added to frequently-consumed food like milk, or to food additives like salt, in prevention of dental caries. This literature has been evaluated in different evidence based reviews. AIM: The scope of this paper was to identify the most recent evidence-based reviews on the effect in caries prevention from added fluoride in milk, salt and fluoride tablets/drops including newer RCT studies, and to synthesize the findings into practice guidelines. The key question was as follows: Does regular use of fluoride in milk, salt and fluoride tablets/ drops prevent dental caries among children and adolescents? METHODS: MEDLINE, EMBASE and EBM reviews (Cochrane database of systematic reviews) were searched using modified filters from a Cochrane review. One evidence-based report on fluoridated milk was identified. Salt fluoridation was covered by three HTA reviews. One Cochrane protocol on the caries preventive effect of fluoridated salt was identified. RESULTS: Very few studies of good quality were identified in general. Two studies on fluoridated milk were tabulated and seven studies dealing with fluoride tablets/ drops were analysed. One study showed a 78% reduction in caries in newly erupted permanent teeth among 8 year olds after 3 years with fluoridated milk. For primary teeth one study showed 31% caries reduction. The differences between fluoride-group and control were statistically significant. The reduction in caries prevalence in the fluoride tablet group compared with a negative control varied from 81% (carious surfaces in permanent teeth erupted in the study period) to 49% in DMFS for all permanent teeth. No RCT studies on fluoridated salt were identified. CONCLUSION: There is limited evidence that F tablets and drops are effective, and compliance is a key factor. There are good reasons to believe that fluoride in different applications and formulas does work as caries preventive agents under supervision. There is a need for new, well-designed studies within this field, but the use of negative controls without any fluoride exposure is difficult due to ethical reasons. In particular new research is needed concerning possible caries preventive effect of fluoridated milk and salt. PMID- 19772845 TI - Fluoride-containing gels, mouth rinses and varnishes: an update of evidence of efficacy. AB - AIM: This was to review and update knowledge from presently available systematic reviews of clinical trials on the effect of fluoride containing gels, mouth rinses and varnishes. METHODS: The review was based on an electronic search of three data bases (PubMed 2000 to 2008, EMBASE 2000- 2009, Cochrane 2000-2008) using a search profile similar to that used in previous Cochrane reviews on the caries-preventive effect of topical fluoride methods. Only randomized and semi randomized trials were included. RESULTS: Four new studies were identified on fluoride-containing gels, one on fluoride mouth rinses and four on fluoride containing varnishes. Prevented fractions obtained in the permanent dentition were consistent with the estimates found in previous reviews, while the effect obtained on caries in the primary dentition remains uncertain. The only study that compared the effect of different fluoride compounds, could not find any difference. CONCLUSIONS: The effect of the three methods on caries in the permanent dentition is well described, while the effect on caries in the primary dentition remains to be determined. The effect of choice of fluoride compound is also not known. PMID- 19772846 TI - Caries prevention with fluoride toothpaste in children: an update. AB - AIM: The aim was to examine recent literature and review the caries-preventive effect of fluoride toothpaste in children. METHODS: Based on three comprehensive systematic reviews published in 2003, a broad search of the PubMed and Cochrane library databases was conducted for papers published 2002-2008 using "fluoride toothpaste", "fluoride dentifrice" and "fluoride dental cream" as index terms. Relevant publications were identified after assessment of their abstracts. Papers were selected if they reported a prospective controlled design with caries data reported at baseline and at the end of the study. The targeted papers were critically assessed concerning design, methodology and performance according to a pre-determined checklist. RESULTS: The initial search revealed 179 papers of which 15 met the inclusion criteria. There was strong evidence that daily use of fluoride toothpaste has a significant caries-preventive effect in children compared with placebo (prevented fraction 24%). The effect was boosted by supervised tooth brushing, increased brushing frequency to twice daily, and use of a toothpaste concentration of 1,500 ppm fluoride. There were few studies of high quality reporting findings from the primary dentition. There were no studies available, and therefore insufficient evidence, on when to commence brushing with fluoride toothpaste as well as on the post-brushing behaviour. The use of "adult" toothpaste in very young children seemed to increase the risk for mild dental fluorosis in low-caries communities but not in socially deprived high-caries populations. CONCLUSIONS: The results reinforced the outstanding role of fluoride toothpaste as an effective caries preventive measure in children. PMID- 19772847 TI - How much toothpaste should a child under the age of 6 years use? AB - AIM: To discuss current concepts in the use of fluoride and to determine how much fluoride is sufficient for caries prevention but also how much is too much. Use of fluoride by young children is a balance between maximising caries efficacy and minimising the risk of fluorosis. METHODS: Review of the current literature. This review considers the importance of amount, concentration and dose of fluoride applied from toothpaste and the implications for risk and benefit. RESULTS: Dental fluorosis is dependent on local fluoride levels in the extra cellular fluid surrounding the tooth during its development. These fluoride levels are determined by the plasma concentration that in turn is a function of the daily intake of fluoride. Fluoride released from bone during remodelling may also contribute to fluoride levels in the tissue. There is evidence to suggest that the effects of fluoride resulting in fluorosis prior to eruption of the tooth are cumulative and dependent on the amount and duration of exposure rather than a specific window of vulnerability. In contrast to dilution of ingested fluoride in the large volume of plasma, dilution of toothpaste in oral fluids is relatively small. Hence, for a given dose of fluoride, higher fluoride levels can be achieved in the oral environment using small amounts of toothpaste with higher fluoride concentrations rather than larger amounts with lower fluoride concentrations. CONCLUSION: It is concluded that for young children fluoride ingestion needs to be carefully controlled during the first six years of life and the best balance between risk and efficacy might be achieved by using small amounts of high fluoride toothpaste under close supervision from parents. PMID- 19772848 TI - A review of slow-release fluoride devices. AB - BACKGROUND: Fluoride has been used to combat dental caries using a number of different clinical approaches. An exciting relatively new development is fluoride slow-releasing devices that consistently elevate intra-oral fluoride levels of plaque and saliva for prolonged periods of up to two years. METHODS: The literature on the use of slow-releasing fluoride devices in dentistry were reviewed. A Medline search on key words was carried out. All papers in English were individually reviewed. RESULTS: Slow-releasing fluoride devices have been shown to be effective in elevating salivary fluoride levels in both animals and human studies and to enhance the remineralisation of dental enamel. They have been demonstrated to be safe to use and without the risk of fluoride toxicity. A double blind randomised clinical trial demonstrated 76% fewer new carious surface increment in high caries-risk children after two years. CONCLUSIONS: These devices have a number of potential uses in dentistry and in particular have great potential for caries prevention of non-compliant high caries-risk groups. PMID- 19772849 TI - Cochrane reviews of randomized trials of fluoride therapies for preventing dental caries. AB - AIM: To present the evidence summarized in the Cochrane fluoride reviews. STUDY DESIGN: An overview of the results of selected systematic reviews. METHODS: Relevant systematic reviews published in the Cochrane Database of Systematic Reviews (CDSR) were identified by searching 'The Cochrane Library issue 4, 2008', using the terms 'Fluoride' and 'Caries'. Complete Cochrane reviews assessing the effectiveness of any fluoride-based intervention for preventing caries were selected, and their main features and findings were reviewed. RESULTS: 14 papers were identified of which 11 were relevant full-text reviews. The results were assessed of 7 reviews published from 2002 to 2004 concerning the relative effectiveness of 4 topical fluoride treatments (toothpastes, gels, varnishes and mouthrinses) in preventing caries in children and adolescents. Comparisons in these reviews were made against non-fluoride controls, against each other, and against different combinations. Findings from 4 reviews published between 2004 and 2006, assessing other fluoride modalities (slow release devices, milk), specific comparison/site (fluoride varnishes versus sealants in occlusal surfaces), and particular population and caries outcome (fluorides for white spot lesions in orthodontic patients) were also assessed. The 7 reviews confirm a clear and similar effectiveness of topical fluoride toothpastes, mouthrinses, gels and varnishes for preventing caries, and show that additional caries reduction can be expected when another topical fluoride is combined with fluoride toothpaste. Evidence is insufficient to confirm the effectiveness of slow release fluoride devices and fluoridated milk. The comparative effectiveness of other modes of delivering fluoride, such as to orthodontic patients is also as yet unclear. Fissure sealants appear more effective than fluoride varnish for preventing occlusal caries but the size of the difference is unclear. CONCLUSIONS: The benefits of topical fluorides are firmly established based on a sizeable body of evidence from randomized controlled trials. The size of the reductions in caries increment in both the permanent and the primary dentitions emphasizes the importance of including topical fluoride delivered through toothpastes, rinses, gels or varnishes in any caries preventive program. However, trials to discern potential adverse effects are required, and data on acceptability. Better quality research is needed to reach clearer conclusions on the effects of slow release fluoride devices, milk fluoridation, sealants in comparison with fluoride varnishes, and of different modes of delivering fluoride to orthodontic patients. PMID- 19772850 TI - DNA methyltransferase inhibitors increase baculovirus-mediated gene expression in mammalian cells when applied before infection. AB - The application of baculovirus as a gene delivery vector for mammalian cells is limited by gene silencing in host cells. Although histone deacetylation inhibitors were known to improve baculovirus-mediated gene expression in mammalian cells, another group of chemicals that induces epigenetic changes, DNA methyltransferase inhibitors (DNMTis), were reported to have no such effect. In the current work, we found that, when added prior to virus inoculation, DNMTis improved baculovirus-mediated gene expression by fourfold or more in all four mammalian cell lines tested. The presence of inhibitors during the period of virus inoculation was important for them to be effective. PMID- 19772851 TI - P-glycoprotein (ABCB1) modulates collateral sensitivity of a multidrug resistant cell line to verapamil. AB - P-glycoprotein (or P-gp1, ABCB1) expression in tumor cells is causative of multidrug resistance through the active efflux of drugs across the cell membrane. However, the over-expression of P-glycoprotein in some tumor cells has been associated with increased sensitivity, or "collateral sensitivity", of multidrug resistant cells to specific drugs, including the calcium channel blocker verapamil. We previously demonstrated that collateral sensitivity to verapamil correlates with the effect of this drug on P-gp1 ATPase, and is reversed by inhibitors of P-gp1 ATPase (e.g., PSC 833 and Ivermectin). In this report, we expand on our earlier study and demonstrate that P-gp1 expression in drug resistant cells modulates collateral sensitivity. Using P-gp1-specific siRNA, P gp1 expression in the multidrug resistant CH(R)C5 cells was significantly down regulated beginning on day 2 post-transfection of siRNA. Furthermore, down regulation of P-gp1 led to increased sensitivity of CH(R)C5 cells to paclitaxel and doxorubicin, but not to cis-platinum, due to inhibition of P-gp1 drug efflux pump. Down-regulation of P-gp1 expression completely reversed collateral sensitivity to verapamil. Moreover, known inhibitors of ETC, rotenone and antimycin A which cause an increase in reactive oxygen species, synergized with verapamil-induced collateral sensitivity leading to increased cell death as determined by MTT cell survival assay. Similarly, the addition of hydrogen peroxide also synergized with verapamil. Taken together, the results of this study demonstrate a direct link between P-gp1 expression and collateral sensitivity of drug-resistant cells, possibly due to an increase in reactive oxygen species. PMID- 19772852 TI - Binding-equilibrium and kinetic studies of anthocyanidin reductase from Vitis vinifera. AB - Anthocyanidin reductase from Vitis vinifera catalyzes an NADPH-dependent double reduction of anthocyanidins. At pH 7.5 and 30 degrees C, steady-state kinetics support a hyperbolic and rapid-equilibrium ordered mechanism, with NADPH binding first, K(M(cyan))=2.82+/-0.66microM and K(i(NADPH))=111+/-23microM. The chromatographic method of Hummel and Dreyer was used for binding-equilibrium studies of NADPH, NADP(+) and catechin, at pH 7. This confirmed hyperbolic binding of NADPH and NADP(+) to the free enzyme, with a single binding site each and with dissociation constants K(NADPH)=45.9+/-2microM and K(NADP+)=83+/ 5microM. There was no significant binding of catechin. We conclude (i) that the most likely mechanism is sequential ordered Bi Uni Uni Bi, with NADPH binding first and NADP(+) released last, and (ii) that internal conversion of the first ternary complex, i.e. that associated with the first hydride transfer, is rate limiting. PMID- 19772853 TI - Kinetic characterization and quaternary structure of glutamate racemase from the periodontal anaerobe Fusobacterium nucleatum. AB - Cofactor-independent glutamate racemases (GRs) that supply the d-glutamate required for biosynthesis of the peptidoglycan that encapsulates bacterial cells are attractive targets for the development of antibacterial drugs. Recombinant GR from Fusobacterium nucleatum (FnGR), a Gram-negative anaerobe involved in periodontal disease, was overproduced, purified, and characterized. Unlike most other GRs, FnGR is a pseudosymmetric enzyme, catalyzing the racemization of glutamate enantiomers with similar kinetic parameters (k(cat)(L-->D)=17.4+/-0.8s( 1), K(m)(L-->D)=1.04+/-0.07mM, k(cat)(D-->L)=26+/-1s(-1), and K(m)(D-->L)=1.7+/ 0.1mM; [corrected] pH optimum approximately 8.5). Mutational analysis of residue 151 (A151V) located at the entryway to the active site revealed that FnGR is very sensitive to increased steric bulk at this position. Blue native-polyacrylamide gel electrophoresis, Ferguson plot analyses, and cross-linking studies, indicated that FnGR existed predominately as dimers. Unlike Bacillus subtilis GR, the presence of glutamate did not significantly alter the position of the monomer dimer equilibrium of FnGR. PMID- 19772854 TI - Triacylglycerol-induced impairment in mitochondrial biogenesis and function in J774.2 and mouse peritoneal macrophage foam cells. AB - The aim of this study was to detect mitochondrial alterations in J774.2 macrophages and mouse peritoneal macrophages (MPM) foam cells. J774.2 and MPM cells were exposed to triacylglycerol (TG) emulsion (1 mg/ml) for induction of fat accumulation. Impairment of mitochondrial function was reflected by reduced cellular ATP production and decreased expression of subunits of mitochondrial complexes I and III. The expression of subunit IV of complex IV remained unchanged, however, the content of its precursor in cells increased. Inhibitors of mitochondrial complexes, rotenone (0.1 microM) and myxothiazol (25 nM), protected the viability in TG-loaded macrophages. The exposure to TG caused downregulation of PPARgamma coactivator (PGC)-1alpha and nuclear respiratory factor (NRF)-1. Activation of peroxisome proliferator-activated receptors attenuated reactive oxygen species production in the foam cells. Treatment with antioxidant N-acetylcysteine (NAC) prevented lipid-mediated mitochondrial and cellular damage. In conclusion, this study demonstrates the important role of mitochondrial biogenesis dysfunction in TG-induced lipotoxicity in macrophages. PMID- 19772855 TI - Quinolinol and peptide inhibitors of zinc protease in botulinum neurotoxin A: effects of zinc ion and peptides on inhibition. AB - Quinolinol derivatives were found to be effective inhibitors of botulinum neurotoxin serotype A (BoNT/A). Studies of the inhibition and binding of 7 (phenyl(8-quinolinylamino)methyl)-8-quinolinol (QAQ) to the light chain domain (BoNT/A LC) showed that QAQ is a non-competitive inhibitor for the zinc protease activity. Binding and molecular modeling studies reveal that QAQ binds to a hydrophobic pocket near the active site. Its inhibitor effect does not involve the removal of zinc ion from the light chain. A 24-mer SNAP-25 peptide containing E183 to G206 with Q197C mutation (Peptide C) binds to BoNT/A LC with an unusually slow second order binding rate constant of 76.7M(-1)s(-1). QAQ binds to Zn(2+) free BoNT/A LC with a K(D) of 0.67microM and to Peptide C-BoNT/A LC complex with a K(D) of 2.33microM. The insights of the interactions of quinolinols and peptides with the zinc protease of BoNT/A should aid in the development of inhibitors of metalloproteases. PMID- 19772856 TI - Hyper- and hypo-induction of cytochrome P450 activities with Aroclor 1254 and 3 methylcholanthrene in Cyp1a2(-/-) mice. AB - The response of hepatic mono-oxygenase activities to Aroclor 1254 or 3 methylcholanthrene was investigated in wild-type and Cyp1a2(-/-) mice. Cytochrome P450 concentrations were similar in naive Cyp1a2(-/-) and wild-type mice. There was no difference between naive wild-type and Cyp1a2(-/-) animals in 7 ethoxyresorufin and 7-ethoxy-4-trifluoromethylcoumarin dealkylase activities, nor was the induction response after 3-methylcholanthrene any different between the two genotypes. However, both activities were induced to a higher extent in Cyp1a2(-/-) mice after Aroclor 1254. In contrast, 7-pentoxyresorufin dealkylation activity was lower in Cyp1a2(-/-) mice and this differential was maintained during induction by both agents. 7-Methoxy- and 7-benzoxyresorufin dealkylation activities were also lower than wild-type in naive Cyp1a2(-/-) animals and during 3-methylcholanthrene induction, but showed accelerated induction in Cyp1a2(-/-) mice with Aroclor 1254. Bufuralol 1'- and testosterone 6beta-hydroxylation activities, and P450 characteristics were evaluated 48h after inducer administration. Bufuralol 1'-hydroxylation, a sexual dimorphic activity (female>male) showed no genotype differences in naive animals. Activity changes varied across gender and genotype, with 3-methylcholanthrene and Aroclor 1254 inducing in male Cyp1a2(-/-), and Aroclor 1254 inducing in female wild-type. Testosterone 6beta-hydroxylation activity was 16% higher in Cyp1a2(-/-) mice and neither 3-methylcholanthrene nor Aroclor 1254 elicited induction. After Aroclor 1254, a 24% increase in P450 concentration with a hypsochromic shift in the ferrous-CO maximum characteristic of CYP1A enzymes occurred in wild-type, compared to no change in either parameter in Cyp1a2(-/-) mice. Induction changes with 3-methylcholanthrene were greater in wild-type mice, a 60% increase in concentration and approximately 2 nm hypsochromic shift versus a 10% increase and approximately 1nm hypsochromic shift in Cyp1a2(-/-) mice. The study demonstrates that deletion of a single P450 can profoundly affect the induction response, as monitored with activities of other P450s, in a manner unrelated to the contribution of the deleted P450 to the activity. PMID- 19772857 TI - Effect of permethrin insecticide on rat polymorphonuclear neutrophils. AB - Polymorphonuclear neutrophils are professional phagocytes whose efficacy depends on a multicomponent NADPH oxidase for generating superoxide anions and bacterial killing. They can be primed and activated by different agents that can impair oxidative burst and phagocytosis with opposite effects: reduced capability to destroy bacteria or hyperactivation that induces the generation of large quantities of toxic reactive oxygen species, which can damage surrounding tissue and participate in inflammation. The present study was designed to evaluate the effect of sub-chronic (60 days) permethrin treatment (1/10 DL(50)) on rat polymorphonuclear neutrophils respiratory burst. The results show that permethrin treatment increases superoxide anion production (33 times) and the activity of hydrogen peroxide-myeloperoxidase system (67 times). In vitro experiments suggest that this effect can be related to permethrin priming and to physico-chemical changes at the plasma membrane level of neutrophils. The antioxidant supplementation with Vitamin E and coenzyme Q(10) can protect against the abnormal respiratory burst in rat treated with permethrin. The in vitro studies show that neutrophil apoptosis begins soon after 1h of incubation with permethrin (0.725% of total cells) or its metabolites (3-phenoxybenzyl alcohol, 3 phenoxybenzaldehyde and 3-phenoxybenzoic acid 1.36, 2.26 and 1.3 of total cells, respectively) and that the level of apoptotic cells is very low. In conclusion, immunotoxicity of permethrin measured in rats could prompt future studies on the consequences of chronic insecticide exposure. PMID- 19772858 TI - 3D morphometry of the human optic nerve head. AB - Human optic nerve head (ONH) anatomy is of interest in glaucoma. Our goal was to carry out a morphometric study of the human ONH based on 3D reconstructions from histologic sections. A set of 10 human ONHs (from four pairs of eyes plus two singles) were reconstructed in an iterative procedure that required the resulting geometries to satisfy a set of quality control criteria. Five models corresponded to eyes fixed at 5 mmHg and the other five models to eyes fixed at 50 mmHg. Several aspects of ONH morphology were measured based on surface and point landmarks: the thicknesses of the lamina cribrosa (LC), the peripapillary sclera and the pre-laminar neural tissue (peripapillary and within the cup); the minimum distance between the anterior surface of the LC and the subarachnoid space; the surface area of the anterior and posterior surfaces of the LC; and the diameter of the scleral canal opening. Our results showed that about one third of the anterior LC surface was obscured from view from the front by the sclera. In all eyes the LC inserted into the pia mater, and not only into the sclera. The variations in ONH morphology between eyes of a pair exceeded, or were of the same order as, changes in morphology due to acute changes in IOP. The reconstruction and morphometry techniques introduced are suitable for application to the ONH. Comparison of measurements in eyes fixed at different pressures suggested small effects on geometry of the increase in IOP. A large variability in ONH morphology, even between contralateral eyes of different IOP, was observed. We conclude that reconstruction of human ONH anatomy from 3D histology is possible, but that large inter-individual anatomic variations make morphometric analysis of the ONH very difficult in the absence of large sample numbers. The insertion of the pia mater into the LC may have biomechanical implications and should be further investigated. Emerging clinical imaging techniques such as deep-scanning OCT will be limited to investigation of the central and mid-peripheral regions of the LC due to optical "occluding" by the peripapillary sclera. PMID- 19772859 TI - Estimating the sensitivity and specificity of Kato-Katz stool examination technique for detection of hookworms, Ascaris lumbricoides and Trichuris trichiura infections in humans in the absence of a 'gold standard'. AB - The accuracy of the Kato-Katz technique in identifying individuals with soil transmitted helminth (STH) infections is limited by day-to-day variation in helminth egg excretion, confusion with other parasites and the laboratory technicians' experience. We aimed to estimate the sensitivity and specificity of the Kato-Katz technique to detect infection with Ascaris lumbricoides, hookworm and Trichuris trichiura using a Bayesian approach in the absence of a 'gold standard'. Data were obtained from a longitudinal study conducted between January 2004 and December 2005 in Samar Province, the Philippines. Each participant provided between one and three stool samples over consecutive days. Stool samples were examined using the Kato-Katz technique and reported as positive or negative for STHs. In the presence of measurement error, the true status of each individual is considered as latent data. Using a Bayesian method, we calculated marginal posterior densities of sensitivity and specificity parameters from the product of the likelihood function of observed and latent data. A uniform prior distribution was used (beta distribution: alpha=1, beta=1). A total of 5624 individuals provided at least one stool sample. One, two and three stool samples were provided by 1582, 1893 and 2149 individuals, respectively. All STHs showed variation in test results from day to day. Sensitivity estimates of the Kato-Katz technique for one stool sample were 96.9% (95% Bayesian Credible Interval [BCI]: 96.1%, 97.6%), 65.2% (60.0%, 69.8%) and 91.4% (90.5%, 92.3%), for A. lumbricoides, hookworm and T. trichiura, respectively. Specificity estimates for one stool sample were 96.1% (95.5%, 96.7%), 93.8% (92.4%, 95.4%) and 94.4% (93.2%, 95.5%), for A. lumbricoides, hookworm and T. trichiura, respectively. Our results show that the Kato-Katz technique can perform with reasonable accuracy with one day's stool collection for A. lumbricoides and T. trichiura. Low sensitivity of the Kato-Katz for detection of hookworm infection may be related to rapid degeneration of delicate hookworm eggs with time. PMID- 19772860 TI - Sterol limitation in a pollen-fed omnivorous lady beetle (Coleoptera: Coccinellidae). AB - Nutritional constraints of non-prey foods for entomophagous arthropods are seldom investigated, yet are crucial to understanding their nutritional ecology and function within natural and managed environments. We investigated whether pollen from five maize hybrids was of variable quality for the lady beetle, Coleomegilla maculata, whether suitability of these pollens was related with their sterol profiles, and how augmenting sterols (beta-sitosterol, cholesterol, or ergosterol) affected the fitness and performance of C. maculata. Preimaginal survival, development rates, the duration of the pre-oviposition period, post mortem adult dry weight, adult hind tibial length, sex ratio, fecundity, cohort generation time (T(c)), net replacement rate (R(0)) and intrinsic rate of increase (r) were measured. Individual sterols in the pollens were quantified using GC-MS. Pollens were of variable suitability for C. maculata; the development rate was positively correlated with the amount of 24-methylene cholesterol and r was positively correlated with episterol and 24-methylene lophenol found in the pollens. Performance of C. maculata was entirely unaffected by augmenting pollen meals with sterols. This research shows that pollens clearly vary in their sterol contents intraspecifically, which affects their suitability for omnivores that rely on pollen. However, sterols appear to be only one of the limiting nutrients in pollens. PMID- 19772861 TI - Steinernema brazilense n. sp. (Rhabditida: Steinernematidae), a new entomopathogenic nematode from Mato Grosso, Brazil. AB - A new entomopathogenic nematode, Steinernema brazilense n. sp., was isolated from a single soil sample collected from a natural forest in Mato Grosso do Sul state, Brazil. S. brazilense n. sp. is characterized morphologically by features of infective juveniles (IJ), males and females. For the IJ, body length averaging 1157 (1023-1284)microm, distance from anterior end to excretory pore 95 (87 102)microm, from anterior end to end of esophagus 148 (139-153)microm, tail length 85 (80-104)microm, D% and E% values 63 (58-70) and 106 (95-118.0), respectively. Lateral field pattern variable; the formula for the arrangement of ridges from head to tail is: 2, 4, 6, 8, 6, 2. For the male, the diagnostic characters include spicule averaging 83 (75-89)microm; D% about 65; the ratio SW% about 192. The length of spicule head is greater than width. Lateral field with one narrow ridge. First generation females are characterized by the presence of a ventral postanal swelling. S. brazilense n. sp. is morphologically close to Steinernema diaprepesi. It can be differentiated from S.diaprepesi by its longer IJ body length (1157 vs 1002microm), longer distance from anterior end to excretory pore (110 vs 75microm), a longer tail length (103 vs 83microm); males of the new species with longer spicule (83 vs 79microm). The new species can be distinguished further from other members of Steinernema glaseri group by characteristics of rDNA of ITS and D2D3 regions. PMID- 19772862 TI - Inhibitory effect of dehydroepiandrosterone on brain monoamine oxidase activity: in vivo and in vitro studies. AB - AIMS: To evaluate the acute effect of dehydroepiandrosterone (DHEA) on monoamine oxidase (MAO) activity in the corpus striatum (CS) and the nucleus accumbens (NAc) in vivo and in vitro. MAIN METHODS: Male Wistar rats received an i.p. injection of DHEA (30, 60 and 120mg/kg) and MAO activity was assayed by formation of 4-hydroxyquinoline 2h later. For in vitro studies, DHEA (100nM-1mM) was added to brain tissue homogenates to assay MAO activity. KEY FINDINGS: DHEA significantly reduced (-24%) total MAO activity in the NAc (F=8.5, p<0.001), but not in the CS, at 120mg/kg dose. No significant difference was observed when MAO A and MAO B activities were independently analyzed. When assayed in vitro, total MAO, MAO A and MAO B activities were reduced by DHEA to 55.7, 28.2 and 54.4% in the NAc and to 71.9, 44.2 and 61.2% in the CS, respectively (IC(50) 4.7 56.1microM). SIGNIFICANCE: An inhibitory effect of DHEA on MAO activity may be involved in the antidepressant and neuroprotective effects of the steroid. Since MAO inhibition reduces neurodegeneration in clinical trials for Parkinson's disease, our results suggest that DHEA may be useful to treat depression and to prevent neuronal death in this disorder. PMID- 19772863 TI - Pharmacokinetics and immunologic consequences of repeated administrations of purified heterologous and homologous butyrylcholinesterase in mice. AB - AIM: To assess the consequences of repeated administrations of purified human serum butyrylcholinesterase (Hu BChE) and mouse serum (Mo) BChE into mice. MAIN METHODS: Purified Hu BChE and Mo BChE isolated from the sera of CD-1 mice were administered into Balb/c or CD-1 mice. The enzymes were delivered by i.m. injections of approximately 100U (0.15mg) on day 1 and on day 28, respectively. The effects of two injections were monitored by following blood BChE and anti BChE IgG levels. KEY FINDINGS: Hu BChE displayed a mean residence time (MRT) of 50h, and an area under the curve (AUC) of 1220U/ml.h in Balb/c or CD-1 mice. Mo BChE exhibited an MRT of 78h and an AUC of 1815U/ml.h in Balb/c mice; the AUC increased to 2504U/ml.h in CD-1 mice. A second injection of Hu BChE in both strains exhibited a marked reduction in circulatory stability. The circulatory stability of the second injection of Mo BChE was reduced in Balb/c mice, but was almost identical to the first injection in CD-1 mice. Consistent with these observations, circulating anti-BChE IgGs were observed in mice injected with Hu BChE; low levels of anti-BChE IgGs were observed only in Balb/c mice injected with Mo BChE. No antibody response was detected in CD-1 mice following either injection of homologous Mo BChE. SIGNIFICANCE: The identical pharmacokinetic profiles and the absence of an immunologic response following a second administration of homologous BChE support the development of Hu BChE as a detoxifying drug in humans. PMID- 19772864 TI - Effect of administration of the nicotinic acetylcholine receptor antagonist BTMPS, during nicotine self-administration, on lever responding induced by context long after withdrawal. AB - The use-dependent, nicotinic acetylcholine receptor antagonist bis-(2,2,6,6 tetramethyl-4-piperidinyl) sebacate (BTMPS) was studied for its potential to reduce the self-administration of nicotine in rats, as well as to reduce context induced recidivistic-like behavior after a six-week period of cessation. Rats were allowed to self-administer nicotine (FR1 schedule) inside an operant chamber with a response lever active on a 24 h basis for 14 days. After the self administration phase, the rats were returned to standard maintenance cages for a period of six weeks. At the end of six weeks the rats were returned to the operant chambers for 7 days and lever responses were recorded under conditions identical to the original self-administration phase, except that lever responses were not rewarded. Daily administration (s.c.) of BTMPS produced a dose-dependent decrease in the self-administration of nicotine 55-80% compared to control animals, and significantly decreased context-induced lever responding initiated six weeks after cessation (35-78% reduction vs. controls). Decreasing the BTMPS regimen to administration once every 3 days was not effective in reducing nicotine self-administration, but lever responding induced during the return to the operant chambers 6 weeks later was significantly decreased (40% reduction vs. controls). Therefore BTMPS can selectively reduce both self-administration of nicotine and long-term recidivistic-like behavior depending upon the dose regimen. Since BTMPS does not evoke anti-nicotinic effects under normal physiological conditions, these data support a proof of concept for the safe use of such compounds in the treatment of tobacco abuse. PMID- 19772865 TI - An animal model of amnesia that uses Receiver Operating Characteristics (ROC) analysis to distinguish recollection from familiarity deficits in recognition memory. AB - Here we review our development of an animal model of episodic memory and amnesia that employs a signal detection analyses to characterize recognition memory performance in rats. This approach aims to distinguish episodic recollection of studied items from mere familiarity for recently experienced stimuli, and then to examine the neural basis of these memory processes. Our findings on intact animals indicate that it is possible to distinguish independent components of recognition that are associated with features of recollection and familiarity in humans. Furthermore, we have found that damage limited to the hippocampus results in a selective deficit in recollection and not familiarity. Also, aging and prefrontal damage result in a similar pattern of impaired recollection and spared familiarity. However, whereas the recollection deficit following hippocampal damage can be attributed to the forgetting of studied materials, the impairment following prefrontal damage is due to false alarms, likely reflecting a deficit in source monitoring. PMID- 19772866 TI - A revised Racine's scale for PTZ-induced seizures in rats. AB - Behavioral scoring is commonly used to access seizure intensity in different seizure models. Racine's scale, originally developed for the amygdala-kindling model, is also frequently used as an intensity measurement in other experimental seizure or epilepsy models. The aim of the present study is to assess the validity of Racine's scale as an adequate seizure intensity measurement for the Pentylenetetrazole (PTZ) model. Male adult Wistar rats received systemic injections of PTZ starting with an initial dose of 20 mg/kg added up by 10 mg/kg every 15 min until the occurrence of a 5minute lasting convulsive seizure. Simultaneous EEG and video recordings were made. The PTZ-induced seizures gradually increased in intensity. Eleven behavioral categories were identified and statistically analyzed. Six different seizure intensity categories were found to differ from each other based on differences in onset latencies, the pattern of occurrence during high or low doses of PTZ and the EEG pattern. These categories were quite different from those of Racine's scale. We suggest that Racine's scale is not adequate for the assessment of the seizure intensity of PTZ-induced seizures and that an alternative scale with the six proposed behavioral seizure categories is a more adequate description of PTZ-induced seizures. PMID- 19772867 TI - Hormone/brain relations serving the unity of the body. AB - Papers in this special issue of Physiology and Behavior illustrate some of the roles of steroid and thyroid hormones in achieving a modern version of what physiologists have described as 'the unity of the body'. Included are papers on stress physiology and on endocrine disruptors, studied at several levels. PMID- 19772868 TI - Inhibition of nitric oxide synthase desensitizes retinal ganglion cells to light by diminishing their excitatory synaptic currents under light adaptation. AB - The effect of inhibiting nitric oxide synthase (NOS) on the visual responses of mouse retinal ganglion cells (RGCs) was studied under light adaptation by using patch-clamp recordings. The results demonstrated that NOS inhibitor, l-NAME, reduced the sensitivity of RGCs to light under light adaptation at different ambient light conditions. These observations were seen in all cells that recordings were made from. l-NAME diminished the excitatory synaptic currents (EPSCs), rather than increasing the inhibitory synaptic currents, of RGCs to reduce the sensitivity of RGCs to light. Cones may be the sites that l-NAME acted to diminish the EPSCs of RGCs. PMID- 19772869 TI - A double-blind study of the influences of eszopiclone on dysgeusia and taste function. AB - Taste disturbance is a common, but poorly understood, side effect of a large number of medications. This double-blind study examined the frequency, intensity, and quality of taste disturbances related to the widely used hypnotic sleep aid eszopiclone (ESZ; Lunesta, as well as their associations with age, sex, body mass index (BMI), time of day, phenyl thiocarbamide (PTC) taste sensitivity, and ESZ saliva and blood levels. Sixty six percent of 24 female subjects and 53% of 15 male subjects reported dysgeusic sensations, mostly bitter/metallic, during the drug administration (respective placebo figures 17% and 7%). No meaningful relationships were found between the frequency or the intensity of the sensations and age, BMI, or PTC taste sensitivity. Dysgeusia was more intense and longer lasting in women than in men, stronger in the morning than in the evening, and positively correlated with drug plasma and saliva levels. In women, intensity ratings decreased across treatment days. Taste test measures were marginally, at best, influenced by ESZ. This study demonstrates, for the first time, that the dysgeusia associated with ESZ is systemically influenced by a number of factors, including sex, time since drug administration, and both blood and saliva levels of the drug. PMID- 19772870 TI - Effects of MDMA, methamphetamine and methylphenidate on repeated acquisition and performance in rats. AB - Repeated-acquisition procedures that include performance controls for effects not specific to acquisition permit the assessment of drug effects on learning on a within-subject, within-session basis. Despite the advantages of this methodology, few studies have examined effects of psychomotor stimulants on repeated acquisition in rodents. The purpose of the present study was to investigate the effects of methylenedioxymethamphetamine (MDMA, 0.3-10mg/kg), methamphetamine (MA, 0.1-3mg/kg) and methylphenidate (MPD,1-17 mg/kg) using repeated-acquisition procedures with performance controls in rats using a touch-screen apparatus. Rats were presented a 2x3 array of stimuli using a computer touch-screen and nose pokes to target locations within the array were reinforced. In the acquisition component, the correct location changed across sessions, whereas during the performance component, the correct location was constant across sessions. All three drugs reduced accuracy of responding to target locations in a dose dependent fashion. None of the compounds enhanced learning at any dose. MPD and MA produced significant disruptions of acquisition accuracy only at doses that also disrupted performance, but the 3mg/kg dose of MDMA impaired acquisition of target responding without affecting performance. The selective impairment of acquisition found in the present study adds to the evidence of learning and memory disruption produced by acute MDMA administration and raise questions about the mechanisms for these actions. PMID- 19772871 TI - A novel three-dimensional tubular scaffold prepared from silk fibroin by electrospinning. AB - Effects of electrospinning parameters (including voltage, collection distance, solution concentration and flow rate) on the morphology and diameter distribution of regenerated SF (silk fibroin) fiber were investigated. Afterward, SF tubular scaffold composed of homogenous fibers was fabricated at voltage of 18kV, collection distance of 18cm, concentration of 37%, and flow rate of 0.15mL/min. After methanol treatment, SF tubular scaffold showed tensile strength of 3.57MPa and porosity of 80.85%. It is satisfied that our work offers a simple method to fabricate seamless and porous tubular scaffold from SF without any additives and organic solvents. Furthermore, the results suggest that this tubular scaffold shows promising applications in small-diameter vascular graft. PMID- 19772873 TI - 'Weight of Evidence' analysis of neonatal sensory evoked potentials. AB - Abnormalities in neonatal sensory evoked potentials (EPs) may indicate a poor developmental prognosis, but such EPs are highly variable, changing with development, and requiring subjective analysis. 'Weight of Evidence' (W), the logarithm of the ratio of the probability that a response has occurred to the probability that it has not, and 'Response Entropy' (S), the spread of the response over time and frequency bands, might provide objective and quantitative measures of EP abnormalities and developmental changes, based on information processing characteristics. W and S were calculated from visual and somatosensory EPs recorded in 72 premature newborns over 2 sessions, separated by 6-9 weeks. Group 1 had normal brain ultrasound images at the time of recording, and a normal developmental outcome at age 2 years. Group 2 had abnormal brain ultrasound images but normal outcome. Group 3 had abnormal brain imaging and abnormal outcome.W values were lowest in Group 3 (visual p<0.001: somatosensory p<0.04). Entropy diminished between sessions (visual p<0.001: somatosensory p<0.015): it was highest in Group 2 (visual p<0.03). The low W in Group 3 implies a lower signal/noise ratio, reducing information capacity. Decreasing entropy suggests more efficient information encoding with maturation. PMID- 19772872 TI - The functional neuroanatomy of symptom dimensions in schizophrenia: a qualitative and quantitative review of a persistent question. AB - One of the fundamental goals in understanding schizophrenia is linking the observable symptoms to the underlying unobservable pathophysiology. Given recent advances in medical imaging, researchers are increasingly investigating brain behavior relationships to better understand the neural substrates of negative, positive, and disorganization symptoms in schizophrenia. This review focused on 25 task-related functional magnetic resonance imaging studies and found meaningful small to moderate associations between specific symptom dimensions and regional brain activity. Negative symptoms were related to the functioning of the ventrolateral prefrontal cortex and ventral striatum. Positive symptoms, particularly persecutory ideation, were related to functioning of the medial prefrontal cortex, amygdala, and hippocampus/parahippocampal region. Disorganization symptoms, although less frequently evaluated, were related to functioning of the dorsolateral prefrontal cortex. Surprisingly, no symptom domain had a consistent relationship with the middle or superior temporal regions. While a number of adaptations in experimental design and reporting standards can facilitate this work, current neuroimaging approaches appear to provide a number of consistent links between the manifest symptoms of schizophrenia and brain dysfunction. PMID- 19772874 TI - The consequences of stimulus intensity on sensory nerve action potentials. AB - Although clinical references recommend evoking sensory nerve action potentials (SNAPs) using supramaximal stimulation, many patients and research subjects report that the maximal and supramaximal stimulation is uncomfortable. The purpose of this study was to determine whether using stimulation intensities at maximal and submaximal levels results in differences in SNAP latency or amplitude outcomes relative to SNAPs recorded using supramaximal stimulation. Twenty healthy male and female subjects participated. Antidromic SNAPs were evoked at two separate sites along the course of the median nerve: (1) just proximal to the wrist and (2) just proximal to the antecubital fossa in each subject. All evoked potentials were recorded from the second digit. The stimulation current that resulted in a maximal amplitude SNAP was determined and 10 SNAPs were ensemble averaged using this stimulation level. Ten SNAPs were then evoked at each of four other stimulation intensities (20% and 10% both above and below that which generated a maximal amplitude SNAP) and were ensemble averaged. For each stimulation intensity and stimulation site, SNAP amplitude and latency determined for each ensemble average. SNAP amplitudes and latencies were compared among stimulus levels and between sexes using a repeated measures analyses of variance. The results of this study suggest that stimulus intensities used to generate SNAPs at the median nerve do not need to be supramaximal in order to generate valid and reliable SNAP data, with stimulation intensities as low as 20% below maximal proving to be sufficient, particularly for the measurement of SNAP latency. PMID- 19772875 TI - A rodent model of appetitive discrimination with concomitant evaluation of anxiety-like behavior. AB - The plus-maze discriminative avoidance paradigm has been used to study the relationship between aversive memory and anxiety. The present study aims to verify if the elevated plus-maze can provide information about appetitive memory and anxiety-like behavior, through a task motivated by food reward. Animals were allowed to explore an elevated plus-maze and received reinforcement in one of the enclosed arms. In a test session performed 24h later, in the absence of reward, rats showed preference for the previously rewarded enclosed arm over the neutral enclosed arm. The administration of diazepam and pentylenetetrazole before training induced, respectively, anxiolytic and anxiogenic effects (as evaluated by open-arm exploration). Both drugs induced amnestic effects, i.e., lack of preference for the rewarded arm in the test session. The results suggest that appetitive memory can be influenced by anxiety levels as well. The plus-maze appetitive discrimination task seems to be a useful model to investigate the relationship between memory and anxiety. PMID- 19772877 TI - Selection of high affine peptide ligands for detection of Clostridium Tyrobutyricum spores. AB - Clostridium tyrobutyricum is the main agent responsible for "late blowing" in cheese, which causes severe economic losses. Nowadays, the reference method for its detection is the Most-Probable-Number (MPN); however, it is time consuming and non-specific. Thus, in order to check milk contamination with spores of C. tyrobutyricum, a more specific and rapid method would be required. The objective of this work was to obtain a ligand to establish the basis to develop a biomagnetic separation method for detection of C. tyrobutyricum spores. This study describes the selection of thirteen highly affine peptides to C. tyrobutyricum spores from a phage-display peptide library. In order to test the ability of the peptides attached to a solid support to bind the spores, the most frequent peptide was synthesised and used to coat paramagnetic beads. PMID- 19772876 TI - Immunization by influenza virus-like particles protects aged mice against lethal influenza virus challenge. AB - Influenza virus-like particles (VLPs) were produced in Sf9 insect cells by co expressing the matrix protein M1 and the surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) using the recombinant baculovirus expression system. The VLPs were morphologically similar to influenza virions. Both HA and NA proteins were incorporated into VLPs and these proteins retained their functional activities. Further, influenza VLPs but not inactivated influenza viruses (IIV) stimulated secretion of inflammatory cytokines from mouse bone marrow-derived dendritic cells (BMDC). Immunogenicity of influenza VLPs and their protective efficacies against lethal influenza virus challenge were evaluated in young and aged mice. Immunization with influenza VLPs induced strong antibody responses against HA that inhibited hemagglutination by influenza virus, similar to IIV vaccines. Compared to young mice, antibody responses in aged mice immunized with a low dose of either influenza VLPs or IIV vaccines exhibited markedly reduced avidity for HA. However, immunization of aged mice with a high dose of influenza VLPs induced antibody responses with high avidity similar to those in young mice. Furthermore, all vaccinated animals survived a lethal challenge by a mouse adapted influenza virus (A/PR/8/34), indicating that influenza VLPs are highly efficacious for protection against influenza virus infection in both young and aged mice. PMID- 19772878 TI - Sustained release hGH microsphere formulation produced by a novel supercritical fluid technology: in vivo studies. AB - Novel sustained release formulations of hGH prepared by supercritical fluid processing of PLGA/PLA (the CriticalMix process) were produced in the form of microparticles for subcutaneous injection. The basis of the process is that PLGA/PLA polymers liquefy when exposed to supercritical CO(2), thereby allowing the hGH to be mixed efficiently into the polymers at an ambient temperature and in the absence of solvents. The CO(2) was removed from the mixture by depressurisation through a nozzle, resulting in the production of microparticles containing the hGH, which were collected in a cyclone. The best microparticle formulations showed an initial in vitro burst of around 35% and a sustained release over 14 days. When tested in the rat model, which displays a faster clearance rate of hGH than other animal models, two formulations showed prolonged release over 2-3 days with sustained plasma levels at 1-5 ng/ml whereas the soluble hGH formulation was cleared within 24h. Two selected sustained release formulations were tested in cynomolgus monkeys and compared to a single injection of soluble hGH. The burst release from the sustained release formulations was similar in magnitude to a daily dose of hGH and serum hGH levels were maintained for a seven day period. It is probable from the data that the sustained release would have continued for up to 14 days if sampling had been continued. The IGF-1 results showed there was no significant difference between the levels obtained for once daily injection of soluble hGH and the two sustained release formulations. PMID- 19772879 TI - Multifunctional role of VIP in prostate cancer progression in a xenograft model: suppression by curcumin and COX-2 inhibitor NS-398. AB - We used an in vivo model of human experimental prostate cancer in order to shed a new light on the effects of vasoactive intestinal peptide (VIP) on tumor growth as well as its pro-metastatic potential in this disease. We used nude mice subcutaneously injected with prostate cancer androgen-independent PC3 cells for 30 days. The regulatory role of VIP on cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) expression as well as on matrix metalloproteinase-2 and 9 (MMP-2 and 9) activities was examined. A selective COX 2 inhibitor, NS-398, and curcumin were used to block VIP effects. Xenografts of VIP-treated PC3 prostate cancer cells in nude mice gave tumors that grew significantly faster than those in the untreated group. It is conceivably a result of both the trophic effect of VIP on prostate cancer cells and the proangiogenic action of the neuropeptide in the growing tumor. We show the overexpression at mRNA and/or protein levels of VIP, its main receptor VPAC(1), the major angiogenic factor VEGF, and the pro-inflammatory enzyme COX-2 as well as the increased activity of MMP-2 and 9 in tumors derived from VIP-treated PC3 cells as compared with control group. The overexpression of the above biomarkers was suppressed in tumors derived from VIP-treated PC3 cells that had been previously incubated with curcumin or NS-398. Thus, the potential therapeutic role of curcumin and selective COX-2 inhibitors in combination with available VIP antagonists should be considered in prostate cancer therapy as supported by their inhibitory activities on tumor cell growth. PMID- 19772880 TI - Neurohormones implicated in the control of Malpighian tubule secretion in plant sucking heteropterans: The stink bugs Acrosternum hilare and Nezara viridula. AB - Plant sucking heteropteran bugs feed regularly on small amounts of K(+)-rich plant material, in contrast to their hematophagous relatives which imbibe large volumes of Na(+)-rich blood. It was anticipated that this would be reflected in the endocrine control of Malpighian tubule (MT) secretion. To explore this, neuroendocrine factors known to influence MT secretion were tested on MT of the pentatomid plant sucking stink bugs, Acrosternum hilare and Nezara viridula, and the results compared with previously published data from Rhodnius prolixus. Serotonin had no effect on N. viridula MT, although it stimulates secretion by R. prolixus MT >1000-fold, and initiates a rapid diuresis to remove excess salt and water from the blood meal. Kinins had no effect on stink bug MT, but secretion was increased by Zoone-DH, a CRF-like peptide, although the response was a modest 2-3-fold acceleration compared with 1000-fold in R. prolixus. Native CAPA peptides, which have diuretic activity in dipteran flies, had antidiuretic activity in MT of the stink bug (Acrhi/Nezvi-CAPA-1 and -2), as previously shown with Rhopr-CAPA-2 in R. prolixus. The antidiuretic activity of Rhopr-CAPA-2 has been linked with terminating the rapid diuresis, but results with stink bugs suggest it is a general feature of heteropteran MT. PMID- 19772881 TI - Peptide sequences identified by phage display are immunodominant functional motifs of Pet and Pic serine proteases secreted by Escherichia coli and Shigella flexneri. AB - Plasmid-encoded toxin (Pet) and protein involved in colonization (Pic), are serine protease autotransporters of Enterobacteriaceae (SPATEs) secreted by enteroaggregative Escherichia coli (EAEC), which display the GDSGSG sequence or the serine motif. Our research was directed to localize functional sites in both proteins using the phage display method. From a 12mer linear and a 7mer cysteine constrained (C7C) libraries displayed on the M13 phage pIII protein we selected different mimotopes using IgG purified from sera of children naturally infected with EAEC producing Pet and Pic proteins, and anti-Pet and anti-Pic IgG purified from rabbits immunized with each one of these proteins. Children IgG selected a homologous group of sequences forming the consensus sequence, motif, PQPxK, and the motifs PGxI/LN and CxPDDSSxC were selected by the rabbit anti-Pet and anti Pic IgGs, respectively. Analysis of the amino terminal region of a panel of SPATEs showed the presence in all of them of sequences matching the PGxI/LN or CxPDDSSxC motifs, and in a three-dimensional model (Modeller 9v2) designed for Pet, both these motifs were found in the globular portion of the protein, close to the protease active site GDSGSG. Antibodies induced in mice by mimotopes carrying the three aforementioned motifs were reactive with Pet, Pic, and with synthetic peptides carrying the immunogenic mimotope sequences TYPGYINHSKA and LLPQPPKLLLP, thus confirming that the peptide moiety of the selected phages induced the antibodies specific for the toxins. The antibodies induced in mice to the PGxI/LN and CxPDDSSxC mimotopes inhibited fodrin proteolysis and macrophage chemotaxis biological activities of Pet. Our results showed that we were able to generate, by a phage display procedure, mimotopes with sequence motifs PGxI/LN and CxPDDSSxC, and to identify them as functional motifs of the Pet, Pic and other SPATEs involved in their biological activities. PMID- 19772882 TI - Acute experimental autoimmune encephalomyelitis induces sex dimorphic changes in neuroactive steroid levels. AB - Incidence, progression and severity of the multiple sclerosis, an inflammatory, demyelinating disease of the central nervous system (CNS) are affected in a sex depending way. Physiological situations characterized by changes in sex steroid plasma levels, such as menstrual cycle, menopause or pregnancy, affect the disease course, suggesting that these molecules might exert a role in this disease. In order to understand better this possible relationship, we have here assessed the levels of neuroactive steroids present in different CNS regions of male and female rats affected by acute experimental autoimmune encephalomyelitis (EAE). In addition, we compared these levels with those present in plasma. Data obtained by liquid chromatography-tandem mass spectrometry indicate that the levels of neuroactive steroids show sex and regional differences in control and EAE nervous system and that a clear difference is also observed between CNS and plasma levels. In particular, among neuroactive steroids here considered, the levels of progesterone metabolites (i.e., dihydroprogesterone, tetrahydroprogesterone and isopregnanolone) and testosterone metabolites (i.e., dihydrotestosterone and 5alpha-androstane-3alpha17beta-diol), show sex dimorphic and region-specific changes in the CNS. Moreover, some changes observed in the CNS were not detected in plasma. These findings might represent an interesting background to design therapies and possibly sex-specific therapies for multiple sclerosis based on neuroactive steroids or synthetic ligands able to interact with classical and non-classical steroid receptors. PMID- 19772883 TI - Double-blind placebo-controlled trial of pentoxifylline added to risperidone: effects on aberrant behavior in children with autism. AB - BACKGROUND: There are several lines of evidence to indicate that the immune system plays an important role in the pathophysiology of autism. The objective of this study was to access the effects of pentoxifylline plus risperidone in the treatment of autistic disorder. METHODS: Forty children between the ages 4 and 12 years with a DSM IV-TR clinical diagnosis of autism were recruited. The children presented with a chief complaint of severely disruptive symptoms related to autistic disorder. Patients were randomly allocated to pentoxifylline+risperidone or placebo+risperidone for a 10-week, double-blind, placebo-controlled study. The dose of risperidone was titrated up to 3 mg/day, pentoxifylline was titrated to 600 mg/day. Patients were assessed at baseline and after 2, 4, 6, 8 and 10 weeks of starting medication. The measure of the outcome was the Aberrant Behavior Checklist-Community (ABC-C). RESULTS: The difference between the two protocols was significant as the group that received pentoxifylline had greater reduction in ABC-C subscale scores for Irritability, Lethargy/Social Withdrawal, Stereotypic Behavior, Hyperactivity/Noncompliance and Inappropriate Speech. CONCLUSION: The results suggest that combination of atypical antipsychotic medications and pentoxifylline might have synergistic effects in treatment of behavioral problems of children with autism. PMID- 19772884 TI - Modulation of the hepatic fatty acid pool in peroxisomal 3-ketoacyl-CoA thiolase B-null mice exposed to the selective PPARalpha agonist Wy14,643. AB - The peroxisomal 3-ketoacyl-CoA thiolase B (Thb) gene was previously identified as a direct target gene of PPARalpha, a nuclear hormone receptor activated by hypolipidemic fibrate drugs. To better understand the role of ThB in hepatic lipid metabolism in mice, Sv129 wild-type and Thb null mice were fed or not the selective PPARalpha agonist Wy14,643 (Wy). Here, it is shown that in contrast to some other mouse models deficient for peroxisomal enzymes, the hepatic PPARalpha signaling cascade in Thb null mice was normal under regular conditions. It is of interest that the hypotriglyceridemic action of Wy was reduced in Thb null mice underlining the conclusion that neither thiolase A nor SCPx/SCP2 thiolase can fully substitute for ThB in vivo. Moreover, a significant increased in the expression of lipogenic genes such as Stearoyl CoA Desaturase-1 (SCD1) was observed in Thb null mice fed Wy. Elevation of Scd1 mRNA and protein levels led to higher SCD1 activity, through a molecular mechanism that is probably SREBP1 independent. In agreement with higher SCD1, enrichment of liver mono-unsaturated fatty acids of the n-7 and n-9 series was found in Thb null mice fed Wy. Overall, we show that the reduced peroxisomal beta-oxidation of fat observed in Thb null mice fed Wy is associated with enhanced hepatic lipogenesis, through the combined elevation of microsomal SCD1 protein and activity. Ultimately, not only the amount but also the quality of the hepatic fatty acid pool is modulated upon the deletion of Thb. PMID- 19772885 TI - Structure and function of Plasmodium falciparum malate dehydrogenase: role of critical amino acids in co-substrate binding pocket. AB - The malaria parasite thrives on anaerobic fermentation of glucose for energy. Earlier studies from our laboratory have demonstrated that a cytosolic malate dehydrogenase (PfMDH) with striking similarity to lactate dehydrogenase (PfLDH) might complement PfLDH function in Plasmodium falciparum. The N-terminal glycine motif, which forms a characteristic Rossman dinucleotide-binding fold in the co substrate binding pocket, differentiates PfMDH (GlyXGlyXXGly) from other eukaryotic and prokaryotic malate dehydrogenases (GlyXXGlyXXGly). The amino acids lining the co-substrate binding pocket are completely conserved in MDHs from different species of human, primate and rodent malaria parasites. Based on this knowledge and conserved domains among prokaryotic and eukaryotic MDH, the role of critical amino acids lining the co-substrate binding pocket was analyzed in catalytic functions of PfMDH using site-directed mutagenesis. Insertion of Ala at the 9th or 10th position, which converts the N-terminal GlyXGlyXXGly motif (characteristic of malarial MDH and LDH) to GlyXXGlyXXGly (as in bacterial and eukaryotic MDH), uncoupled regulation of the enzyme through substrate inhibition. The dinucleotide fold GlyXGlyXXGly motif seems not to be responsible for the distinct affinity of PfMDH to 3-acetylpyridine-adenine dinucleotide (APAD, a synthetic analog of NAD), since Ala9 and Ala10 insertion mutants still utilized APADH. The Gln11Met mutation, which converts the signature glycine motif in PfMDH to that of PfLDH, did not change the enzyme function. However, the Gln11Gly mutant showed approximately a 5-fold increase in catalytic activity, and higher susceptibility to inhibition with gossypol. Asn119 and His174 participate in binding of both co-substrate and substrate. The Asn119Gly mutant exhibited approximately a 3-fold decrease in catalytic efficiency, while mutation of His174 to Asn or Ala resulted in an inactive enzyme. These studies provide critical insights into the co-substrate binding pocket of PfMDH, which may be important in design of selective PfMDH/PfLDH inhibitors as potential antimalarials. PMID- 19772886 TI - The role of lysosomal rupture in neuronal death. AB - Apoptosis research in the past two decades has provided an enormous insight into its role in regulating cell death. However, apoptosis is only part of the story, and inhibition of neuronal necrosis may have greater impact than apoptosis, on the treatment of stroke, traumatic brain injury, and neurodegenerative diseases. Since the "calpain-cathepsin hypothesis" was first formulated, the calpain- and cathepsin-mediated regulation of necrotic cascades observed in monkeys, has been demonstrated to be a common neuronal death mechanism occurring from simpler organisms to humans. However, the detailed mechanism inducing lysosomal destabilization still remains poorly understood. Heat-shock protein-70 (Hsp70) is known to stabilize lysosomal membrane and protect cells from oxidative stress and apoptotic stimuli in many cell death pathways. Recent proteomics approach comparing pre- and post-ischemic hippocampal CA1 neurons as well as normal and glaucoma-suffered retina of primates, suggested that the substrate protein upon which activated calpain acts at the lysosomal membrane of neurons might be Hsp70. Understanding the interaction between activated calpains and Hsp70 will help to unravel the mechanism that destabilizes the lysosomal membrane, and will provide new insights into clarifying the whole cascade of neuronal necrosis. Although available evidence is circumferential, it is hypothesized that activated calpain cleaves oxidative stress-induced carbonylated Hsp70.1 (a major human Hsp70) at the lysosomal membrane, which result in lysosomal rupture/permeabilization. This review aims at highlighting the possible mechanism of lysosomal rupture in neuronal death by a modified "calpain-cathepsin hypothesis". As the autophagy lysosomal degradation pathway is a target of oxidative stress, the implication of autophagy is also discussed. PMID- 19772887 TI - Inducible transgenes under the control of the hCD68 promoter identifies mouse macrophages with a distribution that differs from the F4/80 - and CSF-1R expressing populations. AB - OBJECTIVE: Macrophages are critical components of diverse microenvironments (ME) in adulthood, as well as during embryogenesis. Their role in development precludes the use of gene-targeting and knockout approaches for studying their function. Hence, we proposed to create a macrophage-specific inducible transgenic mouse where genes can be turned on or off at will. MATERIALS AND METHODS: A transgenic mouse in which the reverse tetracycline activator (rtTA-M2) is expressed under the hCD68 promoter for macrophage-specific gene induction was developed and crossed with a second transgenic reporter mouse strain in which the gene for green fluorescent protein (GFP) is under the control of tetracycline responsive element promoter. After doxycycline induction of the double transgenic animals (designated CD68-rtTA-tet-GFP), inducible expression of GFP was characterized by multicolor flow cytometric analysis of blood, marrow, and spleen cells and by demonstration of GFP expression in fresh-frozen sections in diverse tissues. RESULTS: In bone marrow, inducible GFP expression was not confined to, or inclusive of, all cells expressing the classical macrophage markers, such as F4/80. However, GFP-expressing cells in thioglycollate-elicited peritoneal macrophages were also positive for F4/80 and monocyte-macrophage-specific 2 antigen. Interestingly, flow analysis also indicated little overlap between the F4/80 and CSF-1R-positive populations. Fresh-frozen samples of tissues known to contain macrophages revealed GFP-expressing cells with variable morphologies. CONCLUSION: Our results show that the hCD68 promoter directs gene expression in a macrophage population distinct from that defined by classical monocyte-macrophage markers or promoters. Whether this population is functionally distinct remains to be established. PMID- 19772888 TI - A novel zebrafish jak2a(V581F) model shared features of human JAK2(V617F) polycythemia vera. AB - OBJECTIVE: The Janus kinase 2 (JAK2) is important for embryonic primitive hematopoiesis. A gain-of-function JAK2 (JAK2(V617F)) mutation in human is pathogenetically linked to polycythemia vera (PV). In this study, we generated a zebrafish ortholog of human JAK2(V617F) (referred herewith jak2a(V581F)) by site directed mutagenesis and examined its relevance as a model of human PV. MATERIALS AND METHODS: Zebrafish embryos at one-cell stage were injected with jak2a(V581F) mRNA (200pg/embryo). In some experiments, the embryos were treated with a specific JAK2 inhibitor, TG101209. The effects of jak2a stimulation on hematopoiesis, jak/stat signaling, and erythropoietin signaling were evaluated at 18-somites. RESULTS: Injection with jak2a(V581F) mRNA significantly increased erythropoiesis, as enumerated by flow cytometry based on gfp(+) population in dissociated Tg(gata1:gfp) embryos. The response was reduced by stat5.1 morpholino coinjection (control: 4.37% +/- 0.08%; jak2a(V581F) injected: 5.71% +/- 0.07%, coinjecting jak2a(V581F) mRNA and stat5.1 morpholino: 4.66% +/- 0.13%; p<0.01). jak2a(V581F) mRNA also upregulated gata1 (1.83 +/- 0.08 fold; p=0.005), embryonic alpha-hemoglobin (1.61 +/- 0.12 fold; p=0.049), and beta-hemoglobin gene expression (1.65 +/- 0.13-fold; p=0.026) and increased stat5 phosphorylation. These responses were also ameliorated by stat5.1 morpholino coinjection or treatment with a specific JAK2 inhibitor, TG101209. jak2a(V581F) mRNA significantly reduced erythropoietin gene (0.24 +/- 0.03 fold; p=0.006) and protein expression (control: 0.633+/-0.11; jak2a(V581F) mRNA: 0.222+/-0.07 mIU/mL; p=0.019). CONCLUSION: The zebrafish jak2a(V581F) model shared many features with human PV and might provide us with mechanistic insights of this disease. PMID- 19772889 TI - Downregulation of GATA-2 and overexpression of adipogenic gene-PPARgamma in mesenchymal stem cells from patients with aplastic anemia. AB - Aplastic anemia (AA) is characterized by a reduced number of hematopoietic stem cells and fatty replacement in the bone marrow. Transcriptional factor GATA-2 plays several important roles in both hematopoiesis and adipogenesis. Decreased levels of GATA-2 compromise the proliferation and survival of hematopoietic stem cells. GATA-2 suppresses adipocyte differentiation through direct inhibition of adipogenic factors, including peroxisome proliferator-activated receptor-gamma (PPARgamma). Previous studies have shown that expression of GATA-2 is decreased in marrow CD34-positive cells in AA. To elucidate the mechanisms of fatty marrow replacement, we evaluated the mRNA expression for GATA-2 and PPARgamma in mesenchymal stem cells (MSCs) from patients with AA by quantitative real-time polymerase chain reaction. GATA-2 expression by MSCs from AA patients was significantly lower than in normal subjects. Conversely, expression of PPARgamma was significantly higher in AA patients. Western blot analysis demonstrated that protein levels of GATA-2 were lower in AA patients than those in normal subjects. Moreover, incubation with interferon-gamma induced downregulation of GATA-2 levels in MSCs from normal subjects. These findings indicate that fatty marrow replacement in AA patients can be explained by downregulation of GATA-2 and overexpression of PPARgamma in MSCs. Decreased expression of GATA-2 might be responsible for the pathogenesis and development of the clinical features of the disease. PMID- 19772891 TI - Valproic acid restores ER alpha and antiestrogen sensitivity to ER alpha-negative breast cancer cells. AB - Histone deacetylase inhibitors (HDIs) are valuable drugs in breast cancer where estrogen receptor alpha (ER alpha) can be silenced by epigenetic modifications. We report the effect of the clinically available HDI, valproic acid (VPA), on ER alpha expression and function in ER-negative breast cancer cells, MDA-MB-231. VPA induced ER alpha mRNA and protein, while did not modify ER beta. In VPA-treated cells, we also observed: (1) a correct transcriptional response to estradiol after transfection with the luciferase gene under the control of an estrogen responsive minimal promoter (ERE-TKluc); (2) increased expression of the ER related transcription factor FoxA1; (3) estradiol-induced up-regulation of several estrogen-regulated genes (e.g. pS2, progesterone receptor); (4) inhibitory effect of tamoxifen on cell growth. In conclusion, the HDI VPA, inducing ER alpha and FoxA1, confers to MDA-MB 231 cells an estrogen-sensitive "phenotype", restoring their sensitivity to antiestrogen therapy. PMID- 19772890 TI - Mesenchymal stem cell-educated macrophages: a novel type of alternatively activated macrophages. AB - OBJECTIVE: Mesenchymal stem cells (MSCs) are capable of modulating the immune system through interaction with a wide range of immune cells. This study investigates the hypothesis that interaction of MSCs with macrophages could play a significant role in their antiinflammatory/immune modulatory effects. MATERIALS AND METHODS: MSCs were derived from bone marrow and monocytes were isolated from peripheral blood of healthy donors. We cultured human monocytes for 7 days without any added cytokines to generate macrophages, and then cocultured them for 3 more days with culture-expanded MSCs. We used cell surface antigen expression and intracellular cytokine expression patterns to study the immunophenotype of macrophages at the end of this coculture period, and phagocytic assays to investigate their functional activity in vitro. RESULTS: Macrophages cocultured with MSCs consistently showed high-level expression of CD206, a marker of alternatively activated macrophages. Furthermore, these macrophages expressed high levels of interleukin (IL)-10 and low levels of IL-12, as determined by intracellular staining, typical of alternatively activated macrophages. However, macrophages cocultured with MSCs also expressed high levels of IL-6 and low levels of tumor necrosis factor-alpha (TNF-alpha) compared to controls. Functionally, macrophages cocultured with MSCs showed a higher level of phagocytic activity. CONCLUSIONS: We describe a novel type of human macrophage generated in vitro after coculture with MSCs that assumes an immunophenotype defined as IL-10-high, IL-12-low, IL-6-high, and TNF-alpha-low secreting cells. These MSC-educated macrophages may be a unique and novel type of alternatively activated macrophage with a potentially significant role in tissue repair. PMID- 19772892 TI - Diversity and biological significance of sex hormone-binding globulin in fish, an evolutionary perspective. AB - In fish, two different genes, shbga and shbgb, exist that encode for very different proteins. Shbga is the ortholog of mammalian Shbg and was found in all investigated teleosts. In contrast, Shbgb is highly divergent and appears to be a salmonid-specific protein. Here, we review existing data on fish Shbga and Shbgb that have been obtained in chondrichthyes and osteichtyes. Even though other significant expression sites exist, existing data indicate that Shbga is mainly expressed in liver and subsequently secreted into the blood as a homodimer. In contrast, Shbgb is mainly expressed in the ovary, probably secreted as a monomer, and could contribute to the regulation of local steroid action. Binding studies indicate a specialization of circulating Shbg during evolution towards the preferential binding of estradiol and testosterone in teleosts. In contrast, specific fish steroids such as 11-oxo-androgens and oocyte maturation-inducing steroids that are crucial for reproduction are poorly bound by either form of Shbg. PMID- 19772893 TI - Molecular and Cellular Endocrinology. Foreward. PMID- 19772894 TI - PPARs and adipocyte function. AB - For long viewed as passive lipid storage depots, adipocytes are now recognised as key players in the pathogenesis of insulin resistance and metabolic disease. In parallel, the last two decades of research have seen the emergence of transcription factors of the peroxisome proliferator-activated receptor (PPAR) family as central regulators of lipid and glucose homeostasis and molecular targets for drugs to treat hyper-lipidaemia and type 2 diabetes mellitus. In this review we discuss the characteristics of PPARs and the role of the different isotypes in adipocyte biology. PMID- 19772896 TI - Subdiaphragmatic vagotomy promotes nociceptive sensitivity of deep tissue in rats. AB - To verify whether vagal dysfunction is associated with chronic pain, we evaluated the effects of subdiaphragmatic vagotomy (vgx) on the sensitivity toward noxious stimuli in rats. Vgx rats showed sustained hyperalgesia in the gastrocnemius muscle without tissue damage (no increase in vgx-induced plasma creatine phosphokinase or lactose dehydrogenase levels) accompanied by hypersensitivity to colonic distension. We found a dramatic increase in the levels of metabotropic glutamate receptor 5, protein kinase C (PKC) gamma and phosphorylated-PKCgamma within the spinal cord dorsal horn in vgx rats, which suggests that vgx may evoke sensory nerve plasticity. Morphine produced a dose-dependent increase in the withdrawal threshold in both vgx and sham-operated rats, but the effect of a lower dose in vgx rats was weaker than that in sham-operated rats. Muscle hyperalgesia in vgx rats was also attenuated by gabapentin and amitriptyline, but was not affected by diclofenac, dexamethasone or diazepam. These findings indicate that subdiaphragmatic vagal dysfunction caused chronic muscle hyperalgesia accompanied by visceral pain and both gabapentin and amitriptyline were effective for subdiaphragmatic vagotomy-induced pain, which are partially similar to fibromyalgia syndrome. Furthermore, this chronic muscle pain may result from nociceptive neuroplasticity of the spinal cord dorsal horn. PMID- 19772895 TI - Amyloid-beta expression in retrosplenial cortex of triple transgenic mice: relationship to cholinergic axonal afferents from medial septum. AB - Triple transgenic (3xTg-AD) mice harboring the presenilin 1, amyloid precursor protein, and tau transgenes (Oddo et al., 2003b) display prominent levels of amyloid-beta (Abeta) immunoreactivity in forebrain regions. The Abeta immunoreactivity is first seen intracellularly in neurons and later as extracellular plaque deposits. The present study examined Abeta immunoreactivity that occurs in layer III of the granular division of retrosplenial cortex (RSg). This pattern of Abeta immunoreactivity in layer III of RSg develops relatively late, and is seen in animals older than 14 months. The appearance of the Abeta immunoreactivity is similar to an axonal terminal field and thus may offer a unique opportunity to study the relationship between afferent projections and the formation of Abeta deposits. Axonal tract tracing techniques demonstrated that the pattern of axon terminal labeling in layer III of RSg, following placement of DiI in medial septum, is remarkably similar to the pattern of cholinergic axons in RSg, as detected by acetylcholinesterase histochemical staining, choline acetyltransferase immunoreactivity, or p75 receptor immunoreactivity; this pattern also is strikingly similar to the band of Abeta immunoreactivity. In animals sustaining early damage to the medial septal nucleus (prior to the advent of Abeta immunoreactivity), the band of Abeta in layer III of RSg does not develop; the corresponding band of cholinergic markers also is eliminated. In older animals (after the appearance of the Abeta immunoreactivity) damage to cholinergic afferents by electrolytic lesions, immunotoxin lesions, or cutting the cingulate bundle, result in a rapid loss of the cholinergic markers and a slower reduction of Abeta immunoreactivity. These results suggest that the septal cholinergic axonal projections transport Abeta or amyloid precursor protein (APP) to layer III of RSg. PMID- 19772897 TI - Neurodegeneration and prolonged immediate early gene expression throughout cortical areas of the rat brain following acute administration of dizocilpine. AB - N-methyl-d-aspartate receptor antagonist drugs (NMDA-A), such as dizocilpine (MK801), induce long-lasting behavioral disturbances reminiscent to psychotic disorders in humans. To identify cortical structures affected by NMDA-A, we used a single dose of MK801 (10 mg/kg) that caused low and high neurodegeneration in intact and orchiectomized male rats, respectively. Degenerating somas (neuronal death) and axonal/synaptic endings (terminal degeneration) were depicted by a silver technique, and functionally affected cortical neuronal subpopulations by Egr-1, c-Fos, and FosB/DeltaFosB-immunolabeling. In intact males, MK801 triggered a c-Fos induction that remained high for more than 24 h in selected layers of the retrosplenial, somatosensory and entorhinal cortices. MK801-induced neurodegeneration reached its peak at 72 h. Degenerating somas were restricted to layer IV of the granular subdivision of the retrosplenial cortex, and were accompanied by suppression of Egr-1 immunolabeling. Terminal degeneration extended to selected layers of the retrosplenial, somatosensory and parahippocampal cortices, which are target areas of retrosplenial cortex. Induction of FosB/DeltaFosB by MK801 also extended to the same cortical layers affected by terminal degeneration, likely reflecting the damage of synaptic connectivity. In orchiectomized males, the neurodegenerative and functional effects of MK801 were exacerbated. Degenerative somas in layer IV of the retrosplenial cortex significantly increased, with a parallel enhancement of terminal degeneration and FosB/DeltaFosB-expression in the mentioned cortical structures, but no additional areas were affected. These observations reveal that synaptic dysfunction/degeneration in the retrosplenial, somatosensory and parahippocampal cortices might underlie the long-lasting impairments induced by NMDA-A. PMID- 19772898 TI - Why "late equals large" does not work. AB - The concept of conservative scaling of mammalian brain subdivision size with respect to brain size is one of the more contentious issues in neuromorphological studies. What is generally less critically discussed is the widely-cited suggestion that a highly conserved neurogenetic sequence during brain development is the reason for this conservative scaling and other processes of mammalian brain evolution. Here I re-visit the data with which the influential notion of conserved neurogenesis and mechanistic relationship between neurogenesis and mammalian brain subdivision scaling was developed. I suggest that neurogenetic sequences in the species available are not particularly conserved, and that brain subdivision sizes do not correspond well with neurogenetic sequence timing. As an alternative, I propose favouring less generalized and more heterochrony-focused approaches of relating timing differences between species to adult morphology. PMID- 19772900 TI - Effects of beta-carboline harmine on behavioral and physiological parameters observed in the chronic mild stress model: further evidence of antidepressant properties. AB - The chronic mild stress (CMS) model has been used as an animal model of depression which induces anhedonic behavior in rodents. The present study was aimed to evaluate the behavioral and physiological effects of administration of beta-carboline harmine in rats exposed to CMS procedure. To this aim, after 40 days of exposure to CMS procedure, rats were treated with harmine (15 mg/kg/day) for 7 days. In this study, sweet food consumption, adrenal gland weight, adrenocorticotrophin hormone (ACTH) levels, and hippocampal brain-derived neurotrophic factor (BDNF) protein levels were assessed. Our findings demonstrated that chronic stressful situations induced anhedonia, hypertrophy of adrenal gland weight, increase ACTH circulating levels in rats and increase BDNF protein levels. Interestingly, treatment with harmine reversed anhedonia, the increase of adrenal gland weight, normalized ACTH circulating levels and BDNF protein levels. Finally, these findings further support the hypothesis that harmine could be a new pharmacological tool for the treatment of depression. PMID- 19772899 TI - 5-HT2 receptors modulate excitatory neurotransmission to cardiac vagal neurons within the nucleus ambiguus evoked during and after hypoxia. AB - To examine the role of 5-HT2 receptors in the central cardiorespiratory network, and in particular the respiratory modulation of parasympathetic activity to the heart, we used an in vitro medullary slice that allowed simultaneous examination of rhythmic inspiratory-related activity recorded from hypoglossal rootlet and excitatory inspiratory-related neurotransmission to cardioinhibitory vagal neurons (CVNs) within the nucleus ambiguus (NA). Focal application of ketanserin, a 5-HT2 receptor antagonist, did not significantly alter the frequency of spontaneous excitatory postsynaptic excitatory currents (EPSCs) in CVNs in control conditions. However, ketanserin diminished spontaneous excitatory neurotransmission to CVNs during hypoxia. The inhibitory action of ketanserin was on 5-HT3 mediated EPSCs during hypoxia since these responses were blocked by the 5-HT3 receptor antagonist ondansetron. In addition, a robust inspiratory-related excitatory neurotransmission was recruited during recovery from hypoxia. Focal application of ketanserin during this posthypoxia period evoked a significant augmentation of the frequency of inspiratory-related, but not spontaneous EPSCs in CVNs. This excitatory effect of ketanserin was prevented by application of the purinergic receptor blocker pyridoxal-phosphate-6-azophenyl-2',4'-disulfonic acid (PPADS). These results demonstrate 5-HT2 receptors differentially modulate excitatory neurotransmission to CVNs during and after hypoxia. Activation of 5 HT2 receptors acts to maintain excitatory neurotransmission to CVNs during hypoxia, likely via presynaptic facilitation of 5-HT3 receptor-mediated neurotransmission to CVNs. However, activation of 5HT2 receptors diminishes the subsequent inspiratory-related excitatory neurotransmission to CVNs that is recruited during the recovery from hypoxia likely exerting an inhibitory action on inspiratory-related purinergic signaling. PMID- 19772901 TI - Amitriptyline upregulates EAAT1 and EAAT2 in neuropathic pain rats. AB - Excitatory amino acid transporters (EAATs) appear to participate in the pathogenesis of neuropathic pain. The present study was performed to evaluate the effects of the tricyclic antidepressant amitriptyline on the expressions of EAATs in neuropathic pain rats. Using spared nerve injured (SNI) male Sprague Dawley rats, we found that SNI induced an initial EAATs upregulation on postoperative day 1 within the ipsilateral spinal cord dorsal horn, followed by a downregulation on postoperative days 3 and 5. Intraperitoneal administration of amitriptyline reversed the downregulation of EAATs in SNI rats on postoperative days 3-5 and attenuated the mechanical allodynia. We further demonstrated that administration of amitriptyline alone induced an upregulation of EAATs in sham operated rat but do not produce an antinociceptive effect. These results indicate that amitriptyline could increase the expression of EAATs which may be one of its mechanisms in the treatment of neuropathic pain. PMID- 19772902 TI - Brain creatine kinase activity is increased by chronic administration of paroxetine. AB - Major depression is a serious and recurrent disorder often manifested with symptoms at the psychological, behavioral, and physiological levels. In addition, several works also suggest brain metabolism impairment as a mechanism underlying depression. Creatine kinase (CK) plays a central role in the metabolism of high energy consuming tissues such as brain, where it functions as an effective buffering system of cellular ATP levels. Considering that CK plays an important role in brain energy homeostasis and that some antidepressants may modulate energy metabolism, we decided to investigate CK activity from rat brain after chronic administration of paroxetine (selective serotonin reuptake inhibitor), nortriptiline (tricyclic antidepressant) and venlafaxine (selective serotonin norepinephrine reuptake inhibitor). Adult male Wistar rats received daily injections of paroxetine (10 mg/kg), nortriptiline (15 mg/kg), venlafaxine (10 mg/kg) or saline in 1.0 mL/kg volume for 15 days. Twelve hours after the last administration, the rats were killed by decapitation, the hippocampus, striatum and prefrontal cortex were immediately removed, and activity of CK was measured. Our results demonstrated that chronic administration of paroxetine increased CK activity in the prefrontal cortex, hippocampus and striatum of adult rats. On the other hand, nortriptiline and venlafaxine chronic administration did not affect CK activity in these brain areas. In order to verify whether the effect of paroxetine on CK is direct or indirect, we also measured the in vitro effect of this drug on the activity of the enzyme. We verified that paroxetine did not affect CK activity in vitro. Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, an increase in CK activity by antidepressants may be an important mechanism of action of these drugs. PMID- 19772903 TI - The effects of acute stress and acute corticosterone administration on the immobility response in rats. AB - The immobility response is an innate antipredatory behavior in a broad variety of species. The immobility response varies in its postural components but in general is characterized by an absence of movement and a relative unresponsiveness to stimuli. Experimentally in rats, clamping the neck followed by body inversion and manual restrain elicits a response called "immobility by clamping the neck". Stress reactions protect animals against predators and are characterized by activation of the sympathetic and hypothalamic-pituitary-adrenal systems. However, in mammals, the role of acute stress as a modulator of immobility response has been less studied. The aim of our study was to assess the effects of acute stress and the injection of corticosterone (5mg/kg, ip) on immobility by clamping the neck in rats. We observed that either previous acute stress caused by forced exposure to elevated open platform or application of a heat-pain stimulus to the rat's tail during the immobility increased the duration of the immobility response caused by clamping the neck. Also, the corticosterone produced a rapid increase (15 min after injection) in the duration of this immobility response. Our results show that the acute stress, in rats, is a facilitator of the immobility response and suggest a possible nongenomic rapid action of corticosterone over brain structures that control this behavior. PMID- 19772904 TI - In vitro and in vivo genotoxicity tests on fullerene C60 nanoparticles. AB - There are several conflicting reports on the genotoxicity of fullerene C(60) in the literature. To determine the genotoxic potential of C(60) nanoparticles, we prepared stable nano-sized C(60) suspensions using 0.1% carboxymethylcellulose sodium (CMC-Na) or 0.1% Tween 80 aqueous solution. We conducted a bacterial reverse mutation test with Ames Salmonella typhimurium TA98, TA100, TA1535, and TA1537 strains and Escherichia coli strain and a chromosomal aberration test with cultured Chinese hamster CHL/IU cells in the presence and absence of metabolic activation under dark conditions and visible light irradiation using a stable C(60) nanoparticle suspension with CMC-Na. In addition, we performed a bone marrow micronucleus test using a stable C(60) nanoparticle suspension with Tween 80 on ICR mice. C(60) nanoparticles did not show a positive mutagenic response up to the maximum dose of 1000 microg/plate with any tester strain in the bacterial reverse mutation test regardless of metabolic activation and irradiation, although a slight but not significant increase in the number of revertants was observed in TA100 and WP2 uvrA/pKM101. No increase in the incidence of chromosomal aberrations was observed at any C(60) nanoparticle dose regardless of metabolic activation and irradiation in the chromosomal aberration test up to the maximum doses of 100 and 200 microg/mL. In addition, the micronucleus test showed that the in vivo clastogenic ability of the C(60) nanoparticles was negative up to the maximum dose of 88 mg/kg x 2. Therefore, we concluded that the stable and well-characterized C(60) nanoparticles did not have genotoxic ability in the bacterial reverse mutation assay, in vitro chromosome aberration assay, nor in vivo micronucleus assay. PMID- 19772905 TI - The effects of particle properties on nanoparticle drug retention and release in dynamic minoxidil foams. AB - Nanocarriers may act as useful tools to deliver therapeutic agents to the skin. However, balancing the drug-particle interactions; to ensure adequate drug loading, with the drug-vehicle interactions; to allow efficient drug release, presents a significant challenge using traditional semi-solid vehicles. The aim of this study was to determine how the physicochemical properties of nanoparticles influenced minoxidil release pre and post dose application when formulated as a simple aqueous suspension compared to dynamic hydrofluoroalkane (HFA) foams. Minoxidil loaded lipid nanoparticles (LN, 1.4 mg/ml, 50 nm) and polymeric nanoparticles with a lipid core (PN, 0.6 mg/ml, 260 nm) were produced and suspended in water to produce the aqueous suspensions. These aqueous suspensions were emulsified with HFA using pluronic surfactant to generate the foams. Approximately 60% of the minoxidil loaded into the PN and 80% of the minoxidil loaded into the LN was released into the external aqueous phase 24h after production. Drug permeation was superior from the PN, i.e. it was the particle that retained the most drugs, irrespective of the formulation method. Premature drug release, i.e. during storage, resulted in the performance of the topical formulation being dictated by the thermodynamic activity of the solubilised drug not the particle properties. PMID- 19772906 TI - Processing of broadband stimuli across A1 layers in young and aged rats. AB - Presbycusis can be considered a slow age-related peripheral and central deterioration of auditory function which manifests itself as deficits in speech comprehension, especially in noisy environments. The present study examined neural correlates of a simple broadband noise stimulus in primary auditory cortex (A1) of young and aged Fischer-Brown Norway (FBN) rats. Age-related changes in unit responses to broadband noise bursts and spontaneous activity were simultaneously recorded across A1 layers using a single shank, 16-channel electrode. Noise bursts were presented contralateral to the left A1 at 80 dB SPL. Aged A1 units displayed increased spontaneous (29%), peak (24%), and steady state response rates (38%) than did young A1 units. This was true across all A1 layers, although age-related differences were significantly greater for layers I-III (43% vs 18%) than lower layers. There was a significant age-related difference in the depth and duration of post-onset suppression between young and aged upper layer A1 units. The present functional differences across layers were consistent with studies showing greatest losses of gamma-aminobutyric acid (GABA) markers in superficial layers of A1 and with anatomic studies showing highest levels of inhibitory neurons located in superficial cortical layers. The present findings were also consistent with aging studies suggesting loss of functional inhibition in other cortical sensory systems. PMID- 19772908 TI - Clarin-1 protein expression in photoreceptors. PMID- 19772907 TI - Wideband acoustic-reflex test in a test battery to predict middle-ear dysfunction. AB - A wideband (WB) aural acoustical test battery of middle-ear status, including acoustic-reflex thresholds (ARTs) and acoustic-transfer functions (ATFs, i.e., absorbance and admittance) was hypothesized to be more accurate than 1-kHz tympanometry in classifying ears that pass or refer on a newborn hearing screening (NHS) protocol based on otoacoustic emissions. Assessment of middle-ear status may improve NHS programs by identifying conductive dysfunction and cases in which auditory neuropathy exists. Ipsilateral ARTs were assessed with a stimulus including four broadband-noise or tonal activator pulses alternating with five clicks presented before, between and after the pulses. The reflex shift was defined as the difference between final and initial click responses. ARTs were measured using maximum likelihood both at low frequencies (0.8-2.8 kHz) and high (2.8-8 kHz). The median low-frequency ART was elevated by 24 dB in NHS refers compared to passes. An optimal combination of ATF and ART tests performed better than either test alone in predicting NHS outcomes, and WB tests performed better than 1-kHz tympanometry. Medial olivocochlear efferent shifts in cochlear function may influence ARs, but their presence would also be consistent with normal conductive function. Baseline clinical and WB ARTs were also compared in ipsilateral and contralateral measurements in adults. PMID- 19772909 TI - A totally implantable hearing system--design and function characterization in 3D computational model and temporal bones. AB - Implantable middle ear hearing devices are emerging as an effective technology for patients with mild to moderately severe sensorineural hearing loss. Several devices with electromagnetic or piezoelectric transducers have been investigated or developed in the US and Europe since 1990. This paper reports a totally implantable hearing system (TIHS) currently under investigation in Oklahoma. The TIHS consists of implant transducer (magnet), implantable coil and microphone, DSP-audio signal processor, rechargeable battery, and remote control unit. The design of TIHS is based on a 3D finite element model of the human ear and the analysis of electromagnetic coupling of the transducer. Function of the TIHS is characterized over the auditory frequency range in three aspects: (1) mass loading effect on residual hearing with a passive implant, (2) efficiency of electromagnetic coupling between the implanted coil and magnet, and (3) functional gain of whole unit in response to acoustic input across the human skin. This paper focuses on mass loading effect and the efficiency of electromagnetic coupling of TIHS determined from the FE model of the human ear and the cadaver ears or temporal bones. Some preliminary data of whole unit function are also presented in the paper. PMID- 19772910 TI - Differential inductive profiles of hepatic cytochrome P450s by the extracts of Sophora flavescens in male and female C57BL/6JNarl mice. AB - AIM OF THE STUDY: Sophora flavescens has been used as an antipyretic and analgesic agent. To assess the possible herb-drug interaction, effects of S. flavescens extracts on hepatic cytochrome P450 (P450, CYP) enzymes were studied. MATERIALS AND METHODS: Effects of the extracts prepared by three different pharmaceutical companies on P450 enzymes were investigated in male and female C57BL/6JNarl mice. RESULTS: In male mice, extract 1 caused a dose- and time dependent increase of 7-ethoxyresorufin O-deethylation (EROD) activity. Three-day treatment with 3g/kg extracts 1-3 elevated EROD, 7-pentoxyresorufin O dealkylation (PROD), coumarin hydroxylation, and nifedipine oxidation (NFO) activities. In female mice, extracts 1 and 2 increased EROD and PROD activities without affecting coumarin hydroxylation and NFO activities. However, extract 3, which lacked prenylated flavonoids, caused an induction profile in females the same as in males. Treatment with extract 3 fortified with prenylated flavonoids restored the gender difference. An alkaloid, oxymatrine was present in all extracts and increased EROD and PROD activities. At a human equivalent dose (0.18 g/(kg day)), all extracts increased EROD activity. CONCLUSIONS: These results revealed that Cyp1a had a lower induction response threshold. Oxymatrine contributed at least partly to the P450 induction by S. flavescens. At a higher dose, Cyp2a, Cyp2b, and Cyp3a could be induced and the male-specific induction of Cyp2a and Cyp3a was associated with the presence of prenylated flavonoids. PMID- 19772911 TI - Subtractive hybridization identifies genes differentially expressed by olfactory ensheathing cells and neural stem cells. AB - The in vitro differentiation of embryonic stem cells into glia has received relatively limited attention to date when compared with the interest in the generation of neurons. We are interested in a particular glial phenotype, the aldynoglia, and their differentiation from multipotential neural precursors (MNP), since this type of glia can promote neuronal regeneration. We constructed cDNA libraries from cultures of purified olfactory ensheathing cells (OEC), an aldynoglia cell type, and MNP to perform subtractive hybridization. As a result, we isolated four genes from the OEC: one tenascin C (Tn-C) isoform, Insulin-like growth factor binding protein 5 (Igfbp-5), cytochrome oxidase subunit I (COX1) and a phosphodiesterase for cyclic nucleotides (CNPase). With the exception of CNPase, these genes are expressed more strongly in the OEC than in the MNP and moreover, the expression of all four is induced when MNP were exposed to OEC conditioned media. The data suggest a role for these genes in MNP differentiation, and their products appear to represent characteristic proteins of the aldynoglia phenotype. PMID- 19772912 TI - Involvement of mitochondria mediated pathways in hepatoprotection conferred by Fumaria parviflora Lam. extract against nimesulide induced apoptosis in vitro. AB - Nimesulide, a popular nonsteroidal anti-inflammatory drug, has been associated with serious hepatotoxicity. Reactive oxygen species (ROS) and mitochondrial perturbations have been implicated in drug induced hepatotoxicity, although their role in the pathway needs exploration. Study was undertaken to elucidate the effect of Fumaria parviflora Lam. (Fp) on nimesulide induced cell death in primary rat hepatocyte cultures. Fp extract treated cells showed increased viability as compared to nimesulide stressed cells as assessed by MTT assay. LDH leakage increased significantly at 500microM nimesulide, and the data suggested that apoptosis was the predominant mechanism responsible for cell death. Nimesulide induced apoptosis was further confirmed by DNA fragmentation and chromatin condensation. Nimesulide exposure increased intracellular ROS, translocation of Bax and Bcl2 followed by mitochondrial depolarization and cytochrome c (Cyt c) release along with caspase-9/-3 activity confirming involvement of mitochondria in nimesulide induced apoptosis. Events like membrane depolarization of mitochondria, expression of Bax, Bcl2, externalization of phosphatidyl serine are substantially reversed by the pre-treatment of Fp extract. Thus, the study indicates that Fp extract modulates critical events regulating pro and anti-apoptotic proteins in mitochondria dependent apoptosis induced by nimesulide. PMID- 19772913 TI - Titanium(IV) complexes: cytotoxicity and cellular uptake of titanium(IV) complexes on caco-2 cell line. AB - Replacement of the ancillary ligand in titanocene dichloride by amino acids provides titanocene species with high water solubility. As part of our research efforts in the area of titanium-based antitumor agents, we have investigated the cytotoxic activity of Cp(2)TiCl(2) and three water soluble titanocene-amino acid complexes - [Cp(2)Ti(aa)(2)]Cl(2) (aa=L-cysteine, L-methionine, and D penicillamine) and one water soluble coordination compound, [Ti(4)(maltolato)(8)(micro-O)(4)] on the human colon adenocarcinoma cell line, Caco-2. At pH of 7.4 all titanocene species decompose extensively while [Ti(4)(maltolato)(8)(micro-O)(4)] is stable for over seven days. In terms of cytotoxicity, the [Cp(2)Ti(aa)(2)]Cl(2) and [Ti(4)(maltolato)(8)(micro-O)(4)] complexes exhibited slightly higher toxicity than titanocene dichloride at 24h, but at 72h titanocene dichloride and [Ti(4)(maltolato)(8)(micro-O)(4)] have higher cytotoxic activity. Cellular titanium uptake was quantified at various time intervals to investigate the possible relationship between Ti uptake and cellular toxicity. Results indicated that there was not a clear relationship between Ti uptake and cytotoxicity. A structure-activity relationship is discussed. PMID- 19772914 TI - Differences in cytotoxicity versus pro-inflammatory potency of different PM fractions in human epithelial lung cells. AB - Air pollution in Milan causes health concern due to the high concentrations of particulate matter (PM10 and PM2.5). The aim of this study was to investigate possible seasonal differences in PM10 and PM2.5 chemical composition and their biological effects on pro-inflammatory cytokine release and cytotoxicity. The PM was sampled during winter and summer seasons. The winter PMs had higher levels of PAHs than the summer samples which contained a greater amount of mineral dust elements. The PM toxicity was tested in the human pulmonary epithelial cell lines BEAS-2B and A549. The winter PMs were more cytotoxic than summer samples, whereas the summer PM10 exhibited a higher pro-inflammatory potential, as measured by ELISA. This inflammatory potential seemed partly due to biological components such as bacterial lipopolysaccharides (LPS), as evaluated by the use of Polymixin B. Interestingly, in the BEAS-2B cells the winter PM2.5 reduced proliferation due to a mitotic delay/arrest, while no such effects were observed in the A549 cells. These results underline that the in vitro responsiveness to PM may be cell line dependent and suggest that the PM different properties may trigger different endpoints such as inflammation, perturbation of cell cycle and cell death. PMID- 19772916 TI - Involvement of aquaporin in thromboxane A2 receptor-mediated, G 12/13/RhoA/NHE sensitive cell swelling in 1321N1 human astrocytoma cells. AB - The physiological role of the thromboxane A(2) (TXA(2)) receptor expressed on glial cells remains unclear. We previously reported that 1321N1 human astrocytoma cells pretreated with dibutyryl cyclic AMP (dbcAMP) became swollen in response to U46619, a TXA(2) analogue. In the present study, we examined the detailed mechanisms of TXA(2) receptor-mediated cell swelling in 1321N1 cells. The cell swelling caused by U46619 was suppressed by expression of p115-RGS, an inhibitory peptide of G alpha(12/13) pathway and C3 toxin, an inhibitory protein for RhoA. The swelling was also inhibited by treatment with Y27632, a Rho kinase inhibitor and 5-(ethyl-N-isopropyl)amiloride (EIPA), a Na(+)/H(+)-exchanger inhibitor. Furthermore, cell swelling was suppressed by the pretreatment with aquaporin inhibitors mercury chloride or phloretin in a concentration-dependent manner, suggesting that aquaporins are involved in U46619-induced 1321N1 cell swelling. In fact, U46619 caused [(3)H]H(2)O influx into the cells, which was inhibited by p115-RGS, C3 toxin, EIPA, mercury chloride and phloretin. This is the first report that the TXA(2) receptor mediates water influx through aquaporins in astrocytoma cells via TXA(2) receptor-mediated activation of G alpha(12/13), Rho A, Rho kinase and Na(+)/H(+)-exchanger. PMID- 19772915 TI - Malt1 and cIAP2-Malt1 as effectors of NF-kappaB activation: kissing cousins or distant relatives? AB - Malt1 is a multi-domain cytosolic signaling molecule that was originally identified as the target of recurrent translocations in a large fraction of MALT lymphomas. The product of this translocation is a chimeric protein in which the N terminus is contributed by the apoptosis inhibitor, cIAP2, and the C-terminus is contributed by Malt1. Early studies suggested that Malt1 is an essential intermediate in antigen receptor activation of NF-kappaB, and that the juxtaposition of the cIAP2 N-terminus and the Malt1 C-terminus results in deregulation of Malt1 NF-kappaB stimulatory activity. Initial experimental data further suggested that the molecular mechanisms of Malt1- and cIAP-Malt1-mediated NF-kappaB activation were quite similar. However, a number of more recent studies of both Malt1 and cIAP2-Malt1 now reveal that these proteins influence NF-kappaB activation by multiple distinct mechanisms, several of which are non-overlapping. Currently available data suggest a revised model in which cIAP2-Malt1 induces NF kappaB activation via a mechanism that depends equally on domains contributed by cIAP2 and Malt1, which confer spontaneous oligomerization activity, polyubiquitin binding, proteolytic activity, and association with and activation of TRAF2 and TRAF6 at several independent binding sites. By contrast, emerging data suggest that the wild-type Malt1 protein uniquely contributes to NF-kappaB activation primarily through the control of two proteolytic cleavage mechanisms. Firstly, Malt1 directly cleaves and inactivates A20, a negative regulator of the antigen receptor-to-NF-kappaB pathway. Secondly, Malt1 interacts with caspase-8, inducing caspase-8 cleavage of c-FLIP(L), initiating a pathway that contributes to activation of the I kappaB kinase (IKK) complex. Furthermore, data suggest that Malt1 plays a more limited and focused role in antigen receptor activation of NF kappaB, serving to augment weak antigen signals and stimulate a defined subset of NF-kappaB dependent responses. Thus, the potent activation of NF-kappaB by cIAP2 Malt1 contrasts with the more subtle role of Malt1 in regulating specific NF kappaB responses downstream of antigen receptor ligation. PMID- 19772917 TI - New insights into the role of cAMP in the production and function of the incretin hormone glucagon-like peptide-1 (GLP-1). AB - The proglucagon gene (gcg) encodes both glucagon and glucagon-like peptide-1 (GLP 1), produced in pancreatic alpha cells and intestinal endocrine L cells, respectively. The incretin hormone GLP-1 stimulates insulin secretion and pro insulin gene transcription. GLP-1 also enhances pancreatic beta-cell proliferation, inhibits cell apoptosis, and has been utilized in the trans differentiation of insulin producing cells. A long-term effective GLP-1 receptor agonist, Byetta, has now been developed as the drug in treating type II diabetes and potentially other metabolic disorders. The expression of gcg and the production of GLP-1 can be activated by the elevation of the second messenger cyclic AMP (cAMP). Recent studies suggest that in addition to protein kinase A (PKA), exchange protein activated by cAMP (Epac), another effector of cAMP, and the crosstalk between PKA and the Wnt signaling pathway, are involved in cAMP stimulated gcg transcription and GLP-1 production as well. Finally, functions of GLP-1 in pancreatic beta cells are also mediated by PKA, Epac, as well as the effector of the Wnt signaling pathway. Together, these novel findings bring us a new insight into the role of cAMP in the production and function of the incretin hormone GLP-1. PMID- 19772918 TI - Regulation and quality control by Lon-dependent proteolysis. AB - After their first discovery in Escherichia coli, Lon homologues were found to be widely distributed among prokaryotes to eukaryotes. The ATP-dependent Lon protease belongs to the AAA(+) (ATPases associated with a variety of cellular activities) superfamily, and is involved in both general quality control by degrading abnormal proteins and in the specific control of several regulatory proteins. As such, this enzyme has a pivotal role in quality control and cellular physiology. This review focuses on mechanisms of degradation both from the protease and substrate points of view, and discusses the role of Lon in global regulation, stress response and virulence. PMID- 19772919 TI - Functional dissection of XDppa2/4 structural domains in Xenopus development. AB - The maintenance of pluripotency in mammalian embryonic stem cells depends upon the expression of regulatory genes like Oct3/4 and Sox2. While homologues of these genes are also characterized in non-mammalian vertebrates, like birds, amphibians and fish, existence and function of developmental pluripotency associated genes (Dppa) in lower vertebrates have not yet been reported. Here we describe a Dppa2/4-like gene, XDppa2/4, in Xenopus. The protein contains a SAP domain and a conserved C-terminal region. Overexpression of XDppa2/4, murine Dppa2 or Dppa4 produces similar phenotypes (defects in blastopore closure), while injection of XDppa2/4 morpholino generates a loss of blastopore closure and neural fold formation. Embryos die up to tailbud stage. mDppa2 (but not mDppa4) rescues blastopore closure and neurulation defects caused by XDppaMO, but does not prevent subsequent death of embryos. Although XDppa2/4 exhibits a Dppa-like expression pattern and is indispensable for embryogenesis, analyses of various marker genes make its role as a pluripotency factor rather unlikely. Both the gain and loss of function effects until the end of neurulation are caused by the conserved C-terminal region but not by the SAP domain. The SAP domain is required for association of XDppa2/4 to chromatin and for embryonic survival at later stages of development suggesting epigenetic programming events. PMID- 19772920 TI - Differential estrogen receptor subtype modulators: assessment of estrogen receptor subtype-binding selectivity and transcription-regulating properties of new cycloalkyl pyrazoles. AB - Several new cycloalkyl-fused diaryl pyrazoles were synthesized and their binding affinity for the estrogen receptor (ER) subtypes, ERalpha and ERbeta, and subtype specific agonist/antagonist properties were determined. Cyclopentane- and cyclohexane-fused pyrazoles with p-hydroxyphenyl rings at positions 1 and 3 displayed modest ERbeta-binding selectivity and variable agonism through ERalpha, while behaving as full estrogen antagonists through ERbeta in estrogen-responsive element (ERE)-dependent gene expression assays. By contrast, the 2,3-diphenolic derivatives were non-selective and considerably less effective ERbeta antagonists compared to 1,3-diphenolic ones. The cyclohexane-fused 1,3-diphenolic pyrazole 8, in particular, behaved as full ERalpha agonist/ERbeta antagonist in these assays. Molecular modelling revealed the structural determinants possibly accounting for the differential regulation of transcription through the two ERs exhibited by 8. The data also shows that the ER subtype-binding selectivity and agonist/antagonist efficacy of the 1,3-diphenolic pyrazoles is influenced by the cycloalkyl ring fused to the pyrazole core. Using 8 we show that, though the mutant androgen receptor (AR) of LNCaP cells is required for estrogen as well as androgen stimulation of cell growth, estrogen responsiveness of the cells depends on ERbeta and AR but not on ERalpha. PMID- 19772921 TI - Post-transplant increased levels of serum sCD30 is a marker for prediction of kidney allograft loss in a 5-year prospective study. AB - BACKGROUND: Levels of sCD30 represent a biomarker for early outcome in kidney transplantation. The purpose of this study was to determine the role of sCD30 levels for prediction of graft loss in the late post-transplant period. METHODS: Sera were collected immediately pre-transplant and yearly thereafter for up to 5 year post-transplant in 37 primary renal transplant recipients. Levels of serum sCD30 were tested using a fluorescent microsphere assay. RESULTS: Levels of sCD30 significantly decreased after transplantation and remained normal in 34 patients without graft loss up to 5-year post-transplant. Elevated levels of serum sCD30 preceded the increase of serum creatinine in patients with subsequent graft loss. CONCLUSIONS: Elevated levels of serum sCD30 post-transplant might be a marker for predicting subsequent graft loss in the post-transplant period. PMID- 19772922 TI - Vascular imaging in small rodents using micro-CT. AB - In vivo animal models of neoplasm, stroke, subarachnoid hemorrhage, and other diseases involving alterations in vessel anatomy and diameter, require a fast and easy-to-use imaging tool that captures anatomical structure and biologic function data. Micro-computed tomography angiography (muCTA) offers high spatial and temporal resolution and is suitable to perform this task. However, conducting muCTA in small rodents, especially in mice, requires a high degree of accuracy and precision. This article describes a setup for in vivo muCTA in mice using both a bolus technique with a conventional contrast agent, as well as, angiography with a blood-pool contrast agent. Our setup in mice is at isotropic resolutions up to 16 microm with scanning times less than 1 min. The described protocol also addresses some of the technical challenges associated with the imaging of vascular structures in mice models. PMID- 19772923 TI - A novel C1q family member with fucose-binding activity from surfperch, Neoditrema ransonnetii (Perciformes, Embiotocidae). AB - The C1q family is a growing group of proteins with a globular C1q domain in the C terminal region. We purified a new member of this family with L-fucose-binding activity from the plasma of surfperch, Neoditrema ransonnetii through L-fucose affinity chromatography and anion-exchange chromatography. N-terminal amino acid sequencing followed by cDNA sequencing revealed that the protein was composed of 212 amino acids including a signal peptide of 20 amino acids. The gene expression analysis by RT-PCR showed that the gene was transcribed in the liver, stomach and intestine. The hepatic gene expression was up-regulated within 3 h of an intraperitoneal injection of formalin-killed Edwardsiella tarda. A phylogenetic analysis of gC1q domains placed the 23 kDa protein in the same cluster as other fish non-complement C1q-like proteins including a precerebellin-like protein of rainbow trout and ovary-specific protein of crucian carp. Interestingly, sialic acid-binding lectins of mollusca were located on the neighboring branch. Though the lectin activity has yet to be ascribed to the gC1q domain, these findings, together with former findings on lectin activity of lamprey and human C1q, indicate that sugar-binding activity is relatively common among the C1q family. PMID- 19772924 TI - A putative endocrine factor SIBD (single insulin binding domain protein) involved in immune response of Chinese mitten crab Eriocheir sinensis. AB - Insulin growth factor binding proteins (IGFBPs), characterized by the conserved insulin binding (IB) domains, are important components of endocrine system and play key roles in metabolism and growth. In the present study, the full-length cDNA of a single IB domain protein (designated EsSIBD) was identified from Chinese mitten crab Eriocheir sinensis based on expressed sequence tag (EST) sequence. The 1187 bp EsSIBD cDNA contained a 321 bp open reading frame (ORF) encoding a putative protein of 106 amino acids, a 5'-untranslated region (UTR) of 189 bp, and a 3'-UTR of 677 bp. Multiple sequence alignment presented ten conserved cysteine residues critical for the fundamental structure and function of IB domain. BLAST analysis revealed that EsSIBD shared high similarity with previously known IB domains of IGFBPs with the identities ranging from 40% to 46%. The sequence similarity and domain conservation indicated that EsSIBD was a potential member of the IGFBP family. Phylogenic analysis presented that EsSIBD was closer to IGFBP7 than to the other IB domain containing proteins, suggesting its functional similarity with the endocrine factor IFGBP7. The mRNA expression of EsSIBD in different tissues including hepatopancreas, gill, gonad, muscle, heart and haemocytes, and the temporal expression in haemocytes challenged by Listonella anguillarum were measured by real-time RT-PCR. EsSIBD mRNA transcripts could be detected in all examined tissues with the highest expression level in gill. The EsSIBD mRNA expression in haemocytes was sensitive to L. anguillarum stimulation and it was up-regulated from 3 to 24 h after challenge. The structure conservation and functional similarity to IFGBPs, and its sensitivity to L. anguillarum stimulation collectively implied that EsSIBD was probably involved in endocrine and immune systems of Chinese mitten crab, and provided insight into the cross-talk between the invertebrate endocrine and immune system. PMID- 19772925 TI - Shall we chat? Evolutionary relationships in the genus Cercomela (Muscicapidae) and its relation to Oenanthe reveals extensive polyphyly among chats distributed in Africa, India and the Palearctic. AB - The genus Cercomela comprises nine arid-adapted terrestrial bird species distributed primarily across the African continent with one species occurring in India. Using mitochondrial genetic data, we reconstructed molecular evolutionary relationships within Cercomela and its relationship to other closely related genera. Included in our analysis were 24 individuals representing all nine Cercomela species and 23 individuals representing 17 of 21 Oenanthe species. In addition, we included representatives of the genera Myrmecocichla, Thamnolaea and Saxicola, with Phoenicurus, Tarsiger and Monticola as outgroup taxa. Results of our analyses suggest that the genus Cercomela is polyphyletic with species in three distinct clades. Five Cercomela species: C. dubia, C. scotocerca, C. familiaris, C. melanura and C. fusca are more closely affiliated with Oenanthe than with the remaining Cercomela species. Oenanthe is paraphyletic with regard to these five Cercomela species. The three southwest African Cercomela species; C. tractrac, C. schlegelii and C. sinuata, form their own distinct clade. Cercomelasordida (Pinarochroasordida, Sundevall) should remain Pinarochroasordida as this species is genetically highly distinct from all other chat genera/species. Based on our results, we make a number of taxonomic recommendations. PMID- 19772926 TI - Temporal speciation pattern in the western Mediterranean genus Tudorella P. Fischer, 1885 (Gastropoda, Pomatiidae) supports the Tyrrhenian vicariance hypothesis. AB - The land snail genus Tudorella shows a peculiar disjunct distribution around the western Mediterranean coasts. Despite high phenotypic plasticity, only two species with a disputed number of subspecific taxa are currently recognised. We delimited the species with mitochondrial (COI & 16S) and nuclear (ITS-1) markers based on the unified species concept and suggested that there are eight species in the genus, two of them currently undescribed. Applying Bayesian phylogenetic model selection, we tested four different biogeographic hypotheses that could be causal for the current distribution pattern of extant Tudorella species. A scenario involving vicariance events resulting from the repeated splits of the Tyrrhenian plate with subsequent dispersal events over land bridges during the Pliocene received greatest support in the data. PMID- 19772927 TI - Comparison of VIDAS CDAB and CDA immunoassay for the detection of Clostridium difficile in a tcdA- tcdB+ C. difficile prevalent area. AB - Enzyme immunoassays for TcdA and/or TcdB are widely used for diagnosis of C. difficile infection. This study compared the performance of the new VIDAS C. difficile Toxin A & B assay (CDAB) with that of the existing VIDAS C. difficile Toxin A II assay (CDA) in a tcdA(-)tcdB(+) prevalent area. A total of 555 fecal samples were cultured and tested using CDAB and CDA. C. difficile was isolated in 150 samples and the concordance rate was 81.8% (454/555) between CDAB and CDA. PCR assays for tcdA and/or tcdB were used as a confirmatory test on C. difficile strains recovered from culture positive cases (n=150) and on fecal specimens in culture negative/CDAB positive or equivocal cases (n=27). The number of tcdA(+)tcdB(+), tcdA(-)tcdB(+), and tcdA(-)tcdB(-) strains on culture positive isolates (n=150) were 75 (50.0%), 41 (27.3%), and 34 (22.7%), respectively. PCR assays for tcdB gene alone in stool specimens (n=27) showed positivity in five cases. The sensitivity of VIDAS CDAB was higher than that of VIDAS CDA (65.3% vs. 29.8%), by more than 2-fold. The specificity of CDAB was almost the same as CDA (93.8% vs. 94.5%). Toxigenic culture of C. difficile isolates in culture positive/VIDAS CDAB negative cases (n=62) additionally detected 22 VIDAS CDAB positive and 9 VIDAS CDAB equivocal cases. The VIDAS CDAB assay detects more tcdA(+)tcdB(+) strains (60% vs. 45.3%) and tcdA(-)tcdB(+) strains (70.7% vs. 0%) compared with VIDAS CDA. PMID- 19772928 TI - Ptk2 contributes to osmoadaptation in the filamentous fungus Neurospora crassa. AB - Hyphal tip-growing organisms often rely upon an internal hydrostatic pressure (turgor) to drive localized expansion of the cell. Regulation of the turgor in response to osmotic shock is mediated primarily by an osmotic MAP kinase cascade which activates osmolyte synthesis and ion uptake to effect turgor recovery. We characterized a Neurospora crassa homolog (PTK2) of ser/thr kinase regulators of ion transport in yeast to determine its role in turgor regulation in a filamentous fungi. The ptk2 mutant is osmosensitive, and has lower turgor poise than wildtype. The cause appears to be lower activity of the plasma membrane H+ ATPase. Its role in osmoadaptation is unrelated to the activity of the osmotic MAP kinase cascade. Instead, it acts in an alternative pathway that, like the osmotic MAP kinase cascade, also involves ion transport mediated osmoadaptation. PMID- 19772929 TI - New insights regarding the biology of Giardia lamblia. AB - Giardia lamblia is one of the most common causes of intestinal disease in humans. To adapt to environments both inside and outside of the host's small intestine, this protozoan parasite undergoes significant developmental changes during its life cycle. In this review, we analyze and discuss the most recent findings regarding the process of Giardia trophozoites differentiation into infective cysts as well as the mechanism of antigenic variation, which allows the parasite to cause chronic and recurrent infections in susceptible individuals. PMID- 19772930 TI - Divergence and genotyping of human alpha-herpesviruses: an overview. AB - Herpesviruses are large DNA viruses that are highly disseminated among animals. Of the eight herpesviruses identified in humans, three are classified into the alpha-herpesvirus subfamily: herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), which are typically associated with mucocutaneous lesions, and varicella-zoster virus (VZV), which is the cause of chicken pox and herpes zoster. All three viruses establish lifelong infections and may also induce more severe symptoms, such as neurological manifestations and fatal neonatal infections. Despite thorough investigation of the genetic variability among circulating strains of each virus in recent decades, little is known about possible associations between the genetic setups of the viruses and clinical manifestations in human hosts. This review focuses mainly on evolutionary studies of and genotyping strategies for these three human alpha-herpesviruses, emphasizing the ambiguities induced by a high frequency of circulating recombinant strains. It also aims to shed light on the challenges of establishing a uniform genotyping strategy for all three viruses. PMID- 19772931 TI - SM934, a water-soluble derivative of arteminisin, exerts immunosuppressive functions in vitro and in vivo. AB - In the present study, we investigated the immunosuppressive effects and underlying mechanisms of beta-aminoarteether maleate (SM934), a derivative of artemisinin, against T cell activation in vitro and in vivo. In vitro, SM934 significantly inhibited the proliferation of splenocytes induced by concanavalin A (Con A), lipopolysaccharide (LPS), mixed lymphocyte reaction (MLR), and anti CD3 plus anti-CD28 (anti-CD3/28). SM934 significantly inhibited interferon (IFN) gamma production and CD4(+) T cell division stimulated by anti-CD3/28. SM934 also promoted apoptosis of CD69(+) population in CD4(+) T cells stimulated by anti CD3/28. Furthermore, SM934 inhibited interleukin (IL)-2 mediated proliferation and survival through blocking Akt phosphorylation in activated T cells. In ovalbumin (OVA)-immunized mice, oral administration of SM934 suppressed OVA specific T cell proliferation and IFN-gamma production. SM934 treatment also significantly inhibited the sheep red blood cell (SRBC)-induced delayed type hypersensitivity (DTH) reactions in mice. Taken together, SM934 showed potent immunosuppressive activities in vitro and in vivo. Our results demonstrated that SM934 might be a potential therapeutic agent for immune-related diseases. PMID- 19772932 TI - Microstructure and magnetic susceptibility of as-cast Zr-Mo alloys. AB - The microstructures and magnetic susceptibilities of Zr-Mo alloys were investigated to develop a Zr alloy with a low magnetic susceptibility for magnetic resonance imaging (MRI). The microstructure was evaluated with an X-ray diffractometer (XRD), an optical microscope (OM) and a transmission electron microscope (TEM), and the magnetic susceptibility was measured with a magnetic susceptibility balance. The alpha' phase with acicular structure was dominant in Zr-1Mo alloys, while the omega and beta phases with the equiaxed and relatively flat (no acicular) microstructure was dominant in Zr-3Mo. The mixed microstructural features of Zr-1Mo and Zr-3Mo were observed in Zr-2Mo, which consists of the alpha', omega and beta phases. The beta phase is stabilized when the Mo content exceeds over 3 mass% Mo. As-cast Zr-Mo alloys showed a minimum value of magnetic susceptibility at 3 mass% Mo, and the value abruptly increased up to 10% Mo before remaining stable up to 15 mass% Mo. XRD, OM and TEM revealed that the minimum value of the susceptibility was closely related to the appearance of the athermal omega phase in the beta phase. As the Mo content decreases from 3 mass%, the alpha' phase appears with the omega and beta phases. On the other hand, as the Mo content increases from 3 mass%, the beta phase increases and the omega phase decreases. Thus the appearance of the alpha' and beta phase leads to an increase in magnetic susceptibility. The magnetic susceptibility of as-cast Zr-3Mo alloy was almost one-third that of Ti-6Al-4V, which is commonly used for medical implant devices. Zr-Mo alloys are useful for medical devices used under MRI. PMID- 19772933 TI - A novel 1.4 Mb de novo microdeletion of chromosome 1q21.3 in a child with microcephaly, dysmorphic features and mental retardation. AB - A 2.5 years old girl presented with moderate mental retardation, microcephaly, arching eyebrows, low set ears, long eyelashes, persistent fetal pads and clinodactyly. About 1 Mb deletion in the chromosomal region 1q21.3 was identified using BAC array CGH analysis. The parental follow up FISH analysis was normal. Further study of the deletion using a 244K oligo-array of Agilent Technologies Inc., Santa Clara, CA, USA defined the deleted region to span about 1.4 Mb with approximate genomic location chr1:152,511,593-153,993,103 (NCBI genome build 36). This is a novel deletion, not reported to-date. Larger proximal 1q deletions that were previously reported typically included microcephaly, mental retardation and multiple congenital anomalies. The deleted region reported here includes at least 30 coding genes. Among them of interest is a three-gene cluster of the ephrin gene family (EFNA1, EFNA3 and EFNA4). This is a group of receptor protein tyrosine kinase type genes with presumed, but not completely characterized function in nervous system development. PMID- 19772934 TI - 4.45 Mb microduplication in chromosome band 14q12 including FOXG1 in a girl with refractory epilepsy and intellectual impairment. AB - Microdeletions at 14q12 that include FOXG1, or loss of function mutations in FOXG1, are associated with the congenital variant of Rett syndrome. By SNP microarray analysis we identified a corresponding microduplication at 14q12 in a nine year old girl with symptomatic generalised epilepsy, severe intellectual impairment, and minor dysmorphisms, but without microcephaly. The 14q12 microduplication comprised 4.45 Mb of DNA and included FOXG1. This is the first report of duplication involving FOXG1 and suggests a dosage sensitive role for FOXG1 in brain development. PMID- 19772936 TI - Biotransformation of bromosesquiterpenes by marine fungi. AB - Biotransformation of bromosesquiterpenes was investigated with two types of fungi, Rhinocladiella atrovirens NRBC 32362 and also Rhinocladiella sp. K-001, isolated from the Okinawan brown alga Stypopodium zonale. R. atrovirens NRBC 32362 converted aplysistatin 1 into three compounds 5alpha-hydroxyaplysistatin 4, 5alpha-hydroxyisoaplysistatin 5 and 9beta-hydroxyaplysistatin 6. Transformation of 1, palisadin A 2 and 12-hydroxypalisadin B 3 by Rhinocladiella sp. K-001 gave two compounds, 3,4-dihydroaplysistatin 7 and 9,10-dehydrobromopalisadin A 8. PMID- 19772937 TI - Temporal and spatial trends of organotin contamination in the livers of finless porpoises (Neophocaena phocaenoides) and their association with parasitic infection status. AB - Organotins (OTs) are globally ubiquitous contaminants. Contamination of OTs, particularly butyltins (BTs), has been suspected to cause immunosuppressive effects leading to subsequent infectious diseases or opportunistic infection by pathogens in marine mammals. In the present study, we collected individuals from five different populations of finless porpoises (Neophocaena phocaenoides) from coastal areas of Japan (Seto Inland Sea, Ise Bay, Omura Bay, and Pacific coast) and Hong Kong, and measured OT concentrations in their livers. In addition, infection status of lung nematodes and liver trematodes was also observed to analyze the relationship between OT contamination and parasitic infection in finless porpoises. Hepatic OT concentrations were highest in the Hong Kong population, while levels in the Japanese populations were equivalent to those of other cetaceans from different locations. OT levels in Japan have been decreasing in the past few decades, while OT contamination has shown little improvement in Hong Kong. Observation of parasite infection in Seto Inland Sea porpoises revealed that 16 and 11 out of 22 individuals were infected by lung nematodes and liver trematodes, respectively. Additionally, a significant association between BT levels and parasitic infection status of lung nematodes was detected. Thus, the present study suggests that BTs could be a factor affecting parasitic infection, especially the presence or severity of lung nematodes in finless porpoises. Since chemical exposure may alter the susceptibility of organisms to infectious diseases, the interaction of chemical contamination with infectious diseases needs to be investigated in greater depth to understand the risk of population decline due to these factors in marine mammals. PMID- 19772938 TI - Application of temporal temperature gradient gel electrophoresis for characterisation of fungal endophyte communities of Salix caprea L. in a heavy metal polluted soil. AB - Fungal endophytes can affect the heavy metal uptake of their host plants and increase the tolerance of their host plants to heavy metal stress. Therefore, in the present study, a wide-range screening of the fungal endophyte communities was conducted to determine the fungal distribution and diversity on S. caprea roots on a metal polluted site. Fungal communities were screened using amplification with the 5.8S-ITS2-28S part of the rDNA operon, with the resulting amplicons analysed by temporal temperature gradient gel electrophoresis (TTGE) and sequencing. This technique is reproducible and shows good coverage of ascomycete and basidiomycete taxa, as 68% and 32% of all of the sequences, respectively. No clear shift in fungal ITS-TTGE profiles from S. caprea roots was seen along the secondary succession stages. Ascomycetes dominated the more polluted plots, while there was a greater diversity of basidiomycetes in the less polluted and control plots, suggesting greater tolerance of ascomycetes in comparison with basidiomycete fungi. The high diversity of DSEs was confirmed at the highly metal enriched locations, with species belonging to the genera Phialophora, Phialocephala and Leptodontidium. Furthermore, the DSE colonisation of S. caprea roots and the frequency of the sequences showing affinity towards DSE genus Phialophora, showed good correspondence with soil Pb, Cd and plant-available P concentrations, possibly indicating that DSEs improve metal tolerance of willows to high heavy metal contamination. PMID- 19772939 TI - Socioeconomic factors may contribute to neoadjuvant chemotherapy use in metastatic epithelial ovarian carcinoma. AB - OBJECTIVE.: To identify patient characteristics which predict receipt of neoadjuvant chemotherapy (NCT) versus standard therapy (ST) in metastatic ovarian cancer. METHODS.: A retrospective matched case control study was conducted of 52 women treated with NCT compared to 104 women who received standard treatment from 1996 to 2007. The t test was used for comparison of means between the groups, and the chi(2) test was used for categorical data. Multivariable analysis was performed with logistic regression models and only two-tailed analyses with a P value <0.05 were considered statistically significant. RESULTS.: Age, employment and marital status, and insurance alone did not affect treatment allocation (P=NS). However, non-Hispanic White (NHW) patients were more as likely to receive ST (P<0.05). When insurance was stratified by ethnicity, NHW patients were twice as likely to have private insurance (OR=2.29, CI=1.16-4.53). Furthermore, medically compromised (MC) patients who were NHW were almost three times more likely to receive ST (OR=2.72, CI=1.02-5.00). In multivariate analysis, only MC and publically funded women were more likely to receive NCT (OR 3.83 CI=1.35 11.11); P=0.01). During surgery, patients receiving NCT were found to have smaller tumors and less ascites, and were more likely to be optimally debulked with lower estimated blood loss and shorter hospital stays. The median survival for ST was 55.8 months versus 26 months for NCT (P<0.001). CONCLUSIONS.: Non clinical factors such as publically funded status and non-Hispanic White race may influence the allocation of NCT for women with metastatic ovarian cancer. PMID- 19772940 TI - History of suicide attempts among patients with depression in the GENDEP project. AB - BACKGROUND: It has been proposed that a history of suicide attempts could be a correlate of severe depressive disorder and that suicide attempters (SA) could represent a particular subtype of subjects suffering from major depressive disorder. We investigated clinical and demographic characteristics associated with SA and tested the hypothesis that a history of suicide attempts predicts poor response to antidepressants. METHODS: One-hundred-and-forty-one SA and 670 non-SA subjects with major depressive disorder (MDD) were treated for twelve weeks with escitalopram or nortriptyline in GENDEP, a part-randomized multi center clinical and pharmacogenetic study. Baseline characteristics were compared using linear and logistic regression. Linear mixed models were used to analyse continuous outcomes during the twelve weeks of follow-up. RESULTS: At baseline, SA subjects suffered from more severe depression (mean Montgomery-Asberg Depression Rating Scale: 30.29 (7.61) vs 28.43 (6.54), p=0.0002), reported higher level of suicidal ideation (1.21 (0.82) vs 0.73 (0.48), p<0.0001), had a younger age of onset and experienced more depressive episodes, had higher harm avoidance scores and poorer socio-demographic environment than non-SA individuals. However, during the twelve weeks of treatment and after adjustment for baseline severity of depression there was no difference in treatment response between SA and non SA. LIMITATIONS: Due to its retrospective design, it is possible that more severely depressed subjects might report more suicide attempts than less depressed individuals. CONCLUSIONS: While SA differed from non-SA in several clinical and demographic characteristics, the antidepressants were similarly effective in SA as in comparably severely depressed subjects without a history of suicide attempts. PMID- 19772942 TI - The novel adjuvant CoVaccineHT increases the immunogenicity of cell-culture derived influenza A/H5N1 vaccine and induces the maturation of murine and human dendritic cells in vitro. AB - A candidate influenza H5N1 vaccine based on cell-culture-derived whole inactivated virus and the novel adjuvant CoVaccineHT was evaluated in vitro and in vivo. To this end, mice were vaccinated with the whole inactivated influenza A/H5N1 virus vaccine with and without CoVaccineHT and virus-specific antibody and cellular immune responses were assessed. The addition of CoVaccineHT increased virus specific primary and secondary antibody responses against the homologous and an antigenically distinct heterologous influenza A/H5N1 strain. The superior antibody responses induced with the CoVaccineHT-adjuvanted vaccine correlated with the magnitude of the virus-specific CD4+ T helper cell responses. CoVaccineHT did not have an effect on the magnitude of the CD8+ T cell response. In vitro, CoVaccineHT upregulated the expression of co-stimulatory molecules both on mouse and human dendritic cells and induced the secretion of pro-inflammatory cytokines TNF-alpha, IL-6, IL-1beta and IL-12p70 in mouse- and IL-6 in human dendritic cells. Inhibition experiments indicated that the effect of CoVaccineHT is mediated through TLR4 signaling. These data suggest that CoVaccineHT also will increase the immunogenicity of an influenza A/H5N1 vaccine in humans. PMID- 19772941 TI - Prevalence of osteonecrosis of the jaw in patients with oral bisphosphonate exposure. AB - PURPOSE: Osteonecrosis of the jaw (ONJ) is a serious complication associated with bisphosphonate therapy, but its epidemiology in the setting of oral bisphosphonate therapy is poorly understood. The present study examined the prevalence of ONJ in patients receiving chronic oral bisphosphonate therapy. MATERIALS AND METHODS: We mailed a survey to 13,946 members who had received chronic oral bisphosphonate therapy as of 2006 within a large integrated health care delivery system in Northern California. Respondents who reported ONJ, exposed bone or gingival sores, moderate periodontal disease, persistent symptoms, or complications after dental procedures were invited for examination or to have their dental records reviewed. ONJ was defined as exposed bone (of >8 weeks' duration) in the maxillofacial region in the absence of previous radiotherapy. RESULTS: Of the 8,572 survey respondents (71 +/- 9 years, 93% women), 2,159 (25%) reported pertinent dental symptoms. Of these 2,159 patients, 1,005 were examined and an additional 536 provided dental records. Nine ONJ cases were identified, representing a prevalence of 0.10% (95% confidence interval 0.05% to 0.20%) among the survey respondents. Of the 9 cases, 5 had occurred spontaneously (3 in palatal tori) and 4 occurred in previous extraction sites. An additional 3 patients had mandibular osteomyelitis (2 after extraction and 1 with implant failure) but without exposed bone. Finally, 7 other patients had bone exposure that did not fulfill the criteria for ONJ. CONCLUSIONS: ONJ occurred in 1 of 952 survey respondents with oral bisphosphonate exposure (minimum prevalence of 1 in 1,537 of the entire mailed cohort). A similar number had select features concerning for ONJ that did not meet the criteria. The results of the present study provide important data on the spectrum of jaw complications among patients with oral bisphosphonate exposure. PMID- 19772943 TI - Oral chronic graft-versus-host disease scoring using the NIH consensus criteria. AB - The National Institutes of Health (NIH) Oral chronic Graft-versus-Host Disease (cGVHD) Activity Assessment Instrument is intended to be simple to use and to provide a reproducible objective measure of disease activity over time. The objective of this study was to assess inter- and intraobserver variability in the component and composite scores in patients evaluated with oral cGVHD. Twenty-four clinicians (bone marrow transplant [BMT] oncologists: BMTE, n = 16; BMT midlevel providers: BMT MLP; n = 4; and oral medicine experts [OME], n = 4), from 6 major transplant centers scored high-quality intraoral photographs of 12 patients. The same photographs were evaluated 1 week later by the same evaluators. An intraclass correlation coefficient (ICC) was used to calculate intrarater reliability and interrater agreement was analyzed using a weighted kappa statistic: 0 or=0.90) and highest for ulcers (0.97, 0.85, 0.94). Although 75% of OME were comfortable with their abilities to score the cases, approximately 50% of BMTE and BMT MLP were uncomfortable. The majority felt that their evaluations were accurate; however, 84% agreed that formal training is required. Interrater variability of the oral cGVHD instrument is unacceptable for the purposes of clinical trials. Greater concordance among OME, high intrarater reliability, and participant feedback suggests that formal training may significantly decrease variability. Parallel investigations must be completed using the other organ specific instruments prior to any revision and widespread prospective utilization of these tools as research endpoints. PMID- 19772944 TI - Interleukin 17 is not required for autoimmune-mediated pathologic damage during chronic graft-versus-host disease. AB - The transition from acute to chronic graft-versus-host disease (aGVHD, cGVHD) is characterized by the progressive loss of self-tolerance and the development of autoimmune manifestations. Interleukin 17 (IL-17) is a proinflammatory cytokine that has been shown to play a prominent role in autoimmune disorders in the nontransplant setting, but the extent to which IL-17 is necessary for the autoimmunity that occurs as a consequence of GVHD is not known. In this study, we demonstrate using a combination of antibody-based and genetic approaches that IL 17 is not required for the loss of self-tolerance and resulting CD4(+)T cell dependent pathologic damage that occurs during the evolution from aGVHD to cGVHD. Rather, T(H)1 cells and other proinflammatory cytokines are fully competent to promote autoimmune-mediated tissue damage. Thus, the selective targeting of IL-17 may not be a viable clinical strategy for preventing the autoimmune manifestations that develop during cGVHD. PMID- 19772945 TI - Critical situation of bone marrow transplantation: information distribution regarding the problem of a shortage of bone marrow filters. PMID- 19772946 TI - Transplantation of unrelated donor umbilical cord blood for nonmalignant diseases: a single institution's experience with 45 patients. AB - The potential benefits of unrelated donor bone marrow transplantation are offset by the immunologic complications of graft-versus-host disease (GVHD) and infection. We used cryopreserved umbilical cord blood (UCB) as a strategy to reduce the risks of GVHD and treatment-related mortality (TRM) and improved survival. Data on 45 patients with median age of 4.5 years who received transplants between October 2003 and February 2009 for the treatment of nonmalignant diseases were evaluated. As of May 15, 2009, the median follow-up was 25 months (range: 3-66). The majority (82%) of patients received an HLA mismatched graft. The median infused total nucleated cell dose was 7.6 x 10(7)/kg and CD34(+) count 4.0 x 10(5)/kg. Primary graft failure was encountered after 4 transplantations (8%). Log-rank tests and Cox regression analyses were used to determine the effects of various demographic, graft-related, and treatment factors on engraftment, GVHD, TRM, graft failure, and survival. Incidences of neutrophil and platelet engraftment were 88% and 82%, respectively. The incidence of severe grade III-IV acute GVHD (aGVHD) was 42%. Five-year overall survival (OS) and disease-free survival (DFS) were 88.1% and 77.1%, respectively. The cumulative incidence of TRM at 2 years was 12.0%. When cell dose and other factors are optimal, unrelated CBT is a promising approach for curative therapy of nonmalignant diseases. PMID- 19772947 TI - Stem cells: The root of all cells. AB - The plant basic body plan is laid down during embryogenesis. All post-embryonic development has its origin in the stem cells located in niches in the heart of the shoot and root meristems. Creating the root niche requires auxin dependent patterning cues that provide positional information in combination with parallel inputs to specify and maintain the root stem cell niche from embryogenesis onwards. Once established, the architecture of the root niche differs from that in the shoot but recent findings reveal a conserved module for stem cell control. Important for stem cell maintenance is the balance between cell division and differentiation. Dealing with the environment is the biggest challenge for plants and that includes complete regeneration of stem cell systems upon damage. Here we will address these issues as we follow the formation, function and maintenance of the root stem cell niche during development. PMID- 19772948 TI - CD4+CD25+ T regulatory cells limit effector T cells and favor the progression of brucellosis in BALB/c mice. AB - Brucellosis is one of the most common bacterial zoonoses worldwide. Infection is usually chronic and sometimes lifelong. Different mechanisms can be postulated as to the basis for the induction of the chronic status of brucellosis, but a comprehensive knowledge is still lacking. Here, we carried out a series of experiments in order to assess if the persistence of Brucella abortus could be ascribed to the effect of a down regulation of the immune response due to activity of regulatory T cells. We demonstrate that CD4+CD25+T regulatory cells are able to limit the effectiveness of CD4+T cells and are able to favor the maintenance and the progression of B. abortus infection. PMID- 19772949 TI - Chemoprevention in Barrett's esophagus: are we there yet, are we there yet...? PMID- 19772950 TI - Hepatitis C virus and nonalcoholic Fatty liver disease: similar risk factors for necroinflammation, fibrosis, and cirrhosis. PMID- 19772951 TI - Carvedilol protects against the renal mitochondrial toxicity induced by cisplatin in rats. AB - The clinical use of cisplatin is highly limited by its nephrotoxicity, which has been associated with mitochondrial dysfunction. We investigated the protective effect of carvedilol, an antihypertensive with strong antioxidant properties, against the nephrotoxicity induced by cisplatin in rats. Carvedilol was able to counteract the renal damage by preventing the mitochondrial dysfunction induced by cisplatin. The mitochondrial eletrochemical potential, calcium uptake, respiration and the phosphorylative capacity were preserved by the co administration of carvedilol. The mechanism of protection probably does not involve alterations in the cellular and sub-cellular distribution of cisplatin. The study suggests that carvedilol is a potential drug for the adjuvant nephroprotective therapy during cisplatin chemotherapy. PMID- 19772952 TI - Recent molecular biological progress in Marfan syndrome and Marfan-associated disorders. AB - Marfan syndrome (MFS) is a connective tissue disorder with autosomal dominant inheritance. Advances in medicine and surgery have increased the average lifespan of classically affected patients. Serious visual and/or musculoskeletal impairment often has detrimental effects on day-to-day activities and quality of life. MFS patients suffer from many problems at younger ages and with higher frequencies than the general population because of the degenerative nature of the genetic condition. In classical MFS, changes are caused by mutations in the fibrillin-1 gene (FBN1). Mutations in the fibrillin-2 gene were discovered in individuals with a phenotypically related disorder, congenital contractural arachnodactyly. Some of the clinical manifestations of MFS cannot be explained by mechanical properties alone. Recently, mutations in the genes required for transforming growth factor-beta signaling (TGFBR1 and TGFBR2) have been found in several disorders with varying degrees of overlap with classical MFS, including Loeys-Dietz syndrome and familial thoracic aortic aneurysms and dissections. MFS is a disorder that is variable in its phenotypic expression. Specific information about mutations in the large FBN1 gene will give rise to more information about the phenotype-genotype correlations. Possible molecular mechanisms for the pathogenesis of MFS will be discussed which may assist healthcare professionals to control environmental factors that provoke individual complications in MFS. PMID- 19772953 TI - Refining the locus of branchio-otic syndrome 2 (BOS2) to a 5.25 Mb locus on chromosome 1q31.3q32.1. AB - In 1991, a large family was described with an autosomal dominant inheritance of otological and branchial manifestations which was termed branchio-otic syndrome type 2 (BOS2). This trait was mapped by linkage analysis in this family to a region of 23-31 Mb on chromosome 1q25.1q32.1. In the present report we describe the clinical features of two patients with a deletion in this region: one patient has a deletion but no otological or branchial manifestations, the other patient manifests mild conductive hearing loss resulting from bilaterally malformed middle ear ossicles, as well as a preauricular pit. Mapping of the deletion breakpoints allowed to delineate the region involved in BOS2 to a 5.25 Mb region containing 27 protein-coding genes. A detailed medical history of both patients is provided and they are compared with the literature on other detected interstitial deletions of 1q25q32. These findings will aid in the identification of the genetic cause underlying BOS2. PMID- 19772954 TI - A characteristic syndrome associated with microduplication of 8q12, inclusive of CHD7. AB - This report describes a 4 year-old girl with history of hypotonia, developmental delay, and failure to thrive in infancy. She has cognitive impairment and multiple congenital anomalies, including Duane anomaly, Mondini malformation with associated deafness, external ear malformations, and atrial and ventricular septal defects. Array comparative genomic hybridization demonstrated a de novo tandem 6.9 Mb duplication of at least 15 genes in chromosome 8q12, inclusive of CHD7, with breakpoints at 58,388,614 bp and 65,306,097 bp (NCBI build 36.1). Loss of CHD7 by microdeletion or intragenic mutation causes CHARGE syndrome. There is one previous report of an individual with microduplication of 8q12 involving CHD7. He also had early hypotonia, cognitive impairment, Duane anomaly, sensorineural deafness and a congenital heart defect. This rather specific recurrent pattern of congenital anomalies associated with overlapping duplications of the genomic region containing CHD7 suggests that the phenotype in these two patients may be the result of abnormal CHD7 dosage. PMID- 19772955 TI - Isolation and characterization of a novel thermostable alpha-amylase from Korean pine seeds. AB - Amylases have significant importance in broad industrial application including bio-ethanol production. Although amylases are widely distributed in microbes, plants and animals, it has been sought for new amylases from various sources with special industrial potential. In this study we firstly isolated and characterized a novel thermostable alpha-amylase from Korean pine seed. Enzyme was purified to homogeneity level with purification fold of 1286.1 using several techniques such as self-precipitation, (NH(4))(2)SO(4) fractionation, DEAE anion exchange and starch affinity chromatography. The purified alpha-amylase showed two bands in SDS-PAGE with molecular weight of 44 and 45 kDa. The apparent molecular weight of native enzyme was calculated to be 46.7 kDa. Internal peptide sequencing confirmed that the purified alpha-amylase was a novel enzyme. The optimum pH and temperature for enzyme activity were pH 4.5 and 65 degrees C, respectively. This enzyme was fully stable for 48h at 50 degrees C and retained 80% activity up to 96h. The K(m) and V(max) were 0.84 mg/ml and 3.71 micromol/min, respectively. On the basis of high thermal stability and a broad range of pH stability, the pine seed alpha-amylase showed a good prospect of industrial application. PMID- 19772957 TI - High phosphorus diet induces vascular calcification, a related decrease in bone mass and changes in the aortic gene expression. AB - In chronic kidney disease, hyperphosphatemia has been associated to vascular calcifications. Moreover, the rate and progression of vascular calcification have been related with the reduction of bone mass and osteoporotic fractures, hereby suggesting a strong link between vascular calcification and bone loss. Our aim was to prospectively study the effects of high phosphorus diet on bone mass, vascular calcification and gene expression profile of the arterial wall. A rat model of 7/8 nephrectomy fed with normal (0.6%) and moderately high (0.9%) phosphorus diet was used. Biochemical parameters, bone mineral density and vascular calcifications were assessed. A microarray analysis of the aortic tissue was also performed to investigate the gene expression profile. After 20 weeks, the rats fed with a high phosphorus diet showed a significant increase in serum phosphorus, PTH, and creatinine, together with aortic calcification and a decrease in bone mass. The histological analysis of the vascular calcifications showed areas with calcified tissue and the gene expression profile of this calcified tissue showed repression of muscle-related genes and overexpression of bone-related genes, among them, the secreted frizzled related proteins, well known inhibitors of the Wnt pathway, involved in bone formation. The study demonstrated prospectively the inverse and direct relationship between vascular calcification and bone mass. In addition, the microarrays findings provide new information on the molecular mechanisms that may link this relationship. PMID- 19772956 TI - Direct bone formation during distraction osteogenesis does not require TNFalpha receptors and elevated serum TNFalpha fails to inhibit bone formation in TNFR1 deficient mice. AB - Distraction osteogenesis (DO) is a process which induces direct new bone formation as a result of mechanical distraction. Tumor necrosis factor-alpha (TNF) is a cytokine that can modulate osteoblastogenesis. The direct effects of TNF on direct bone formation in rodents are hypothetically mediated through TNF receptor 1 and/or 2 (TNFR1/2) signaling. We utilized a unique model of mouse DO to assess the effects of 1) TNFR homozygous null gene alterations on direct bone formation and 2) rmTNF on wild type (WT), TNFR1(-/-) (R1KO), and TNR2(-/-) (R2KO) mice. Radiological and histological analyses of direct bone formation in the distraction gaps demonstrated no significant differences between the WT, R1KO, R2KO, or TNFR1(-/-) and R2(-/-) (R1 and 2KO) mice. R1 and 2KO mice had elevated levels of serum TNF but demonstrated no inhibition of new bone formation. Systemic administration by osmotic pump of rmTNF during DO (10 microg/kg/day) resulted in significant inhibition of gap bone formation measures in WT and R2KO mice, but not in R1KO mice. We conclude that exogenous rmTNF and/or endogenous TNF act to inhibit new bone formation during DO by signaling primarily through TNFR1. PMID- 19772958 TI - Analysis of quantitative ultrasound graphic trace and derived variables assessed at proximal phalanges of the hand in healthy subjects and in patients with cerebral palsy or juvenile idiopathic arthritis. A pilot study. AB - Amplitude-dependent speed of sound (AD-SoS) and bone transmission time (BTT) are the quantitative ultrasound (QUS) variables usually assessed at proximal phalanges of the hand to estimate bone mineral status. The aim of the study was to provide a reference database for some additional QUS variables reflecting morphology of the ultrasound graphic trace according to gender, age, height, weight, and body mass index (BMI), and to assess their clinical usefulness. Fifty two patients (age 3.1-20.9 years) affected by cerebral palsy with spastic tetraplegia (CPST, n=38) or polyarticular active juvenile idiopathic arthritis (JIA, n=14) were examined. In addition to AD-SoS and BTT, two QUS variables derived from the morphological analysis of ultrasound graphic trace, such as energy, extrapolated from the area under the ultrasound signal received, and weighted-slope (W-slope), derived from the angular coefficient of the regression line fitting the top point of the peaks of the ultrasound signal, were measured by phalangeal QUS (DBM Sonic, IGEA). The values of all the QUS variables measured in the patients were compared with our own sex- and age-reference values (n=1083, 587 males and 496 females, aged 3-21 years). The mean values of AD-SoS, BTT, energy, and W-slope were reduced (P<0.0001) in patients as a whole compared with normative data (-2.4+/-1.2, -2.7+/-1.5, -2.5+/-1.1, -2.5+/-1.1 Z-score, respectively). Fractured patients showed lower (P<0.001-P<0.0001) values of the QUS variables than fracture-free patients (AD-SoS, -3.3+/-1.2 and -1.8+/-0.9; BTT, -3.9+/-1.7 and -1.8+/-1.1; energy, -3.2+/-1.2 and -2.2+/-0.7; W-slope, 3.4+/-1.4 and -2.2+/-0.9 Z-score, respectively). There was no difference (P=NS) between patients with CPST and those with JIA. Age and height were positively correlated with all the QUS variables (r=0.55-0.79, P<0.01-P<0.0001). QUS variables were positively correlated among them (r=0.74-0.94, P<0.0001). Age and number of fractures were independent predictors of the QUS variables (coefficients: AD-SoS, 11.466 and -17.642; BTT, 0.049 and -0.045; energy, 1.072 and -1.303; W-slope, 0.046 and -0.067; respectively). In conclusion, measurement of QUS variables derived from the morphological analysis of the ultrasound signal could give additional information in estimating bone mineral status in children and adolescents, probably reflecting some aspect related to bone structure. PMID- 19772959 TI - Biopolymer-protected CdSe nanoparticles. AB - A synthetic procedure for the encapsulation of cadmium selenide (CdSe) nanoparticles in a sago starch matrix is introduced. The nanocomposite was investigated using structural, spectroscopic, and thermal methods. TEM micrographs of the nanocomposite showed spherical CdSe particles of 4-5 nm in size coated with a biopolymer layer. The absorption edges of both the aqueous solution and the thin film of the CdSe-starch nanocomposite were shifted toward lower wavelengths in comparison to the value of the bulk semiconductor. Infrared measurements revealed that the interaction of CdSe nanoparticles and starch chains takes place via OH groups. Although the onset of the temperature of decomposition of CdSe-starch nanocomposite is lower than that of the pure matrix, thermogravimetric analysis also showed that introduction of CdSe nanoparticles significantly reduced starch degradation rate leading to high residual mass at the end of the degradation process. PMID- 19772960 TI - Involvement of FKHR (FOXO1) transcription factor in human uterus leiomyoma growth. AB - OBJECTIVE: To study the expression of FOXO1 and pSer256-FOXO1 parallel to Akt and pSer473-Akt in leiomyoma compared with adjacent myometrium from human uteri. DESIGN: Prospective study. SETTING: University departments. PATIENT(S): Thirty eight cyclic and 20 menopausal women who underwent hysterectomy for benign indications. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Western blot analyses were used for evaluation in leiomyoma and adjacent myometrium of Akt and pSer473-Akt, 14-3-3 gamma proteins and expression and subcellular distribution of FOXO1 and pSer256-FOXO1 during the menstrual cycle and at menopause. RESULT(S): The present study demonstrates the expression of FOXO1 and pSer256-FOXO1 at the tissue level in the human uterus leiomyoma and adjacent myometrium. The level of phosphorylated FOXO1 in leiomyoma was higher than in matched myometrium. The pSer256-FOXO1 in leiomyoma during menstrual phases was located mostly in the nuclear fraction comparison to that of the myometrium. The reason for this difference is presumably the simultaneously detected lower level of 14-3-3 protein. CONCLUSION(S): Abundant level of the phosphorylated FOXO1, its impaired nucleocytoplasmic shuttling, and the lowered expression of 14-3-3 protein in leiomyoma induces a shift in the cellular machinery toward a prosurvival execution program and thus presents a potential therapeutic target for treatment of leiomyoma. PMID- 19772961 TI - [Perineal recurrence of an aggressive angiomyxoma: Is an incomplete resection useful?]. AB - Angiomyxoma is a rare but aggressive mesenchymal tumor. It commonly develops in the pelvis, perineum and groin and is more common in females. Angiomyxoma characteristically has a high incidence of local recurrence. The only treatment of recurrence is surgical re-excision. We report a case of recurrent aggressive angiomyxoma, which was only incompletely resected. PMID- 19772962 TI - Pentraxin 3 and complement cascade activation in the failure of arteriovenous fistula. AB - OBJECTIVE: Pentraxin-3 (PTX3) has been suggested to play a role in the development of vascular pathology. Stenosis of arteriovenous fistula (AVF) leading to its failure is the major cause of morbidity in hemodialysis patients. To date, little is known on the pathogenesis of AVF stenosis. The aim of the present study was to investigate the potential role of PTX3 in this setting. METHODS AND RESULTS: A sample of venous wall was collected at the time of AVF formation in 44 patients with end stage renal disease. Ten patients developed AVF stenosis and from these patients a second portion of the venous wall was obtained during surgical revision of the AVF. Confocal laser scanning microscopy demonstrated that PTX3 immunostaining, hardly detectable in native AVF, was significantly increased in failed AVF, showing a specific co-localization with endothelial cell markers. Circulating mononuclear cells isolated at the time of AVF revision presented a significantly higher PTX3 mRNA expression than those collected during AVF creation. Interestingly, a significant deposition of C5b-9 on endothelial cells, co-localizing with PTX3, was observed in stenotic AVF. CONCLUSION: The present study demonstrates for the first time a close association between PTX3 deposition and complement activation at the endothelial cell level in failed AVF and suggests a role for PTX3 in modulating innate immunity in the pathogenesis of AVF stenosis. PMID- 19772963 TI - Physical activity, the Framingham risk score and risk of coronary heart disease in men and women of the EPIC-Norfolk study. AB - OBJECTIVE: Test the hypothesis that considering leisure-time and work-related physical activity habits in addition to the Framingham risk score (FRS) would result into better classification of coronary heart disease (CHD) risk than FRS alone. METHODS: Prospective, population-based study of 9564 men and 12165 women aged 45-79 years followed for an average of 11.4 years. A modified FRS which takes into account physical activity (evaluated using a validated lifestyle questionnaire taking into account leisure-time and work-related physical activity) was computed. RESULTS: During follow-up, 2191 CHD events occurred. Among 3369 men who were classified as intermediate risk (event rate of 12.4%) according to the FRS, 413 were reclassified into the low-risk category and 279 were reclassified into the high-risk category after modification of the FRS. After reclassification of these men, CHD event rate was of 5.3% and 18.6%, respectively for men classified at low and high CHD risk. Among 4766 women initially classified as intermediate risk (event rate of 8.4%), 1282 were reclassified into the low-risk category whereas 1071 women were reclassified into the high-risk category. After reclassification of these women, CHD event rate was of 6.8% and 12.2%, respectively for women classified at low and high CHD risk. CONCLUSIONS: Results of the present study suggest that asking simple questions about leisure-time and work-related physical activity which can be rapidly obtained by any physician at no cost could be helpful in the estimation of patients' CHD risk. PMID- 19772964 TI - Stress relaxation microscopy: imaging local stress in cells. AB - Biomechanics is gaining relevance as complementary discipline to structural and cellular biology. The response of cells to mechanical stimuli determines cell type and function, while the spatial distribution of mechanical forces within the cells is crucial to understand cell activity. The experimental methodologies to approach cell mechanics are diverse but either they are effective in few cases or they rule out the innate cell complexity. In this regard, we have developed a simple scanning probe-based methodology that overcomes the limitations of the available methods. Stress relaxation, the decay of the force exerted by the cell surface at constant deformation, has been used to extract relaxational responses at each cellular sublocalisation and generate maps. Surprisingly, decay curves exerted by test cells are fully described by a generalized viscoelastic model that accounts for more than one simultaneously occurring relaxations. Within the range of applied forces (0.5-4nN) a slow and a fast relaxation with characteristic times of 0.1 and 1s have been detected and assigned to rearrangements of cell membrane and cytoskeleton, respectively. Relaxation time mapping of entire cells is thus promising to simultaneously detect non uniformities in membrane and cytoskeleton and as identifying tool for cell type and disease. PMID- 19772965 TI - All leg joints contribute to quiet human stance: a mechanical analysis. AB - According to the state of the art model (single inverted pendulum) the regulation of quiet human stance seems to be dominated by ankle joint actions. Recent findings substantiated both in-phase and anti-phase fluctuations of ankle and hip joint kinematics can be identified in quiet human stance. Thus, we explored in an experimental study to what extent all three leg joints actually contribute to the balancing problem of quiet human stance. We also aimed at distinguishing kinematic from torque contributions. Thereto, we directly measured ankle, knee, and hip joint kinematics with high spatial resolution and ground reaction forces. Then, we calculated the six respective joint torques and, additionally, the centre of mass kinematics. We searched for high cross-correlations between all these mechanical variables. Beyond confirming correlated anti-phase kinematics of ankle and hip, the main results are: (i) ankle and knee joint fluctuate tightly (torque) coupled and (ii) the bi-articular muscles of the leg are well suited to fulfil the requirements of fluctuations around static equilibrium. Additionally, we (iii) identified high-frequency oscillations of the shank between about 4 and 8 Hz and (iv) discriminated potentially passive and active joint torque contributions. These results demonstrate that all leg joints contribute actively and concertedly to quiet human stance, even in the undisturbed case. Moreover, they substantiate the single inverted pendulum paradigm to be an invalid model for quiet human stance. PMID- 19772966 TI - Hollow PtCo nanospheres supported on multi-walled carbon nanotubes for methanol electrooxidation. AB - Hollow PtCo nanosphere electrocatalyst-supported multi-walled carbon nanotubes (MWCNTs) were prepared at room temperature in a homogeneous solution employing cobalt metal nanoparticles as sacrificial templates. The structure and elemental composition of the resulting hollow PtCo/MWCNT composites were characterized by transmission electron microscopy (TEM), X-ray diffraction (XRD), and energy dispersive X-ray spectroscopy (EDS). The hollow PtCo/MWCNT electrocatalysts demonstrated enhanced electrocatalytic activity toward methanol oxidation compared with carbon nanotube-supported solid PtCo nanoparticles and commercial E TEK Pt/C (20 wt.%Pt) catalysts. PMID- 19772967 TI - Competitive adsorption-driven separation of water/methanol mixtures using hydrogen as a third competitor. AB - In this study, we report competitive adsorption-driven separation of a water/methanol mixture in Pd-deposited silica membranes, which is induced by introducing hydrogen carrier gas as a third competitor. After replacing helium carrier gas by hydrogen carrier gas, water vapor permeance showed a slight decrease, whereas methanol vapor permeance significantly decreased. The water/methanol separation factor remarkably increased from 1.7-16.5 to 6.8-58.2 in the feed water content of 5.8-83.0 wt.%. From single vapor permeation tests in the presence of carrier gas (hydrogen or helium), it was confirmed that those permeation behavior was derived from stronger effect of the competitive adsorption between hydrogen and methanol vapor than that between hydrogen and water vapor. That is, hydrogen carrier gas dominantly inhibits adsorption of methanol vapor on the membrane surface, and the partial pressure of methanol on the membrane surface decreases, which leads to a decrease in methanol permeance with reduced driving force. In addition, temperature programmed desorption (TPD) results of water and methanol from Pd/silica particles also demonstrated that hydrogen carrier gas suppresses methanol adsorption on Pd/silica surface more dominantly than water adsorption. PMID- 19772968 TI - Categorizing neonatal deaths: a cross-cultural study in the United States, Canada, and The Netherlands. AB - OBJECTIVE: To clarify the process of end-of-life decision-making in culturally different neonatal intensive care units (NICUs). STUDY DESIGN: Review of medical files of newborns >22 weeks gestation who died in the delivery room (DR) or the NICU during 12 months in 4 NICUs (Chicago, Milwaukee, Montreal, and Groningen). We categorized deaths using a 2-by-2 matrix and determined whether mechanical ventilation was withdrawn/withheld and whether the child was dying despite ventilation or physiologically stable but extubated for neurological prognosis. RESULTS: Most unstable patients in all units died in their parents' arms after mechanical ventilation was withdrawn. In Milwaukee, Montreal, and Groningen, 4% to 12% of patients died while receiving cardiopulmonary resuscitation. This proportion was higher in Chicago (31%). Elective extubation for quality-of-life reasons never occurred in Chicago and occurred in 19% to 35% of deaths in the other units. The proportion of DR deaths in Milwaukee, Montreal, and Groningen was 16% to 22%. No DR deaths occurred in Chicago. CONCLUSIONS: Death in the NICU occurred differently within and between countries. Distinctive end-of-life decisions can be categorized separately by using a model with uniform definitions of withholding/withdrawing mechanical ventilation correlated with the patient's physiological condition. Cross-cultural comparison of end-of-life practice is feasible and important when comparing NICU outcomes. PMID- 19772969 TI - Pubertal metformin therapy to reduce total, visceral, and hepatic adiposity. AB - OBJECTIVE: Puberty is part of a critical window in which adiposity and its correlates can be fine-tuned toward reproduction, which implies that puberty provides an opportunity to reprogram a misprogramming that occurred in early life. We tested this hypothesis in low-birthweight (LBW) girls with precocious pubarche (PP), who are at risk for hyperinsulinemic body adiposity during and beyond puberty. STUDY DESIGN: LBW girls with PP (n = 38; mean age 8 years) were randomized to remain untreated or to receive metformin across puberty (425 mg/d for 2 years, then 850 mg/d for 2 years); subsequently, all girls were monitored for 1 year without intervention. Here we report on the latter year. RESULTS: The benefits of metformin were mostly maintained during the posttreatment year so that, after 5 years, metformin therapy was associated with more lean mass; with less total, visceral, and hepatic fat; with lower circulating levels of androgens and leptin; and with elevated levels of high-molecular-weight adiponectin and undercarboxylated osteocalcin. CONCLUSION: In LBW girls with PP, pubertal metformin therapy was followed by a favorable adipokine profile and by a reduction of total, visceral, and hepatic adiposity beyond puberty. PMID- 19772970 TI - Impact of sodium/proton exchanger 3 gene variants on sudden infant death syndrome. AB - OBJECTIVE: To determine the contribution of variations in the sodium/proton exchanger 3 (NHE3) gene in sudden infant death syndrome (SIDS). STUDY DESIGN: Variations in the exons and promoter of the NHE3 gene were analyzed with direct sequencing analysis and mini sequencing (SNaPshot analysis) in 251 cases of SIDS, plus 50 infant control subjects who had died of other causes, and 170 healthy adults. RESULTS: The C2405T variant (exon 16) and 2 polymorphisms in the promoter (G1131A and C1197T) were encountered significantly more frequently in cases of SIDS than in control subjects. At least 1 of these 3 variants was detected in 49% of SIDS cases, but only in 30% of control subjects. CONCLUSIONS: Our findings suggest the involvement of polymorphisms in the NHE3 gene and promoter in cases of SIDS, which may result in an overexpression of NHE3 in the medulla oblongata and which possibly leads to a disturbance in breathing control. Furthermore, our results underline the heterogeneous character of SIDS. PMID- 19772971 TI - Longevity in Rett syndrome: analysis of the North American Database. AB - OBJECTIVE: To determine longevity in Rett syndrome (RTT) from a large cohort. STUDY DESIGN: The North American RTT Database allows the examination of longevity in a large cohort of individuals with RTT from the United States and Canada. This database contains information on 1928 individuals, 85.5% with typical RTT, 13.4% with atypical RTT, and 1.1% with a mutation in the methyl-CpG-binding protein 2 gene (MECP2) but not RTT. Kaplan-Meier analyses were performed to assess longevity. RESULTS: Earlier decennial cohorts exhibited better survival than recent cohorts, with most participants surviving into middle age. Comparing overall survival in persons with typical RTT and atypical RTT revealed greater mortality in typical RTT across the observed lifespan (P < .0001). Comparing survival in persons with RTT and identified MECP2 mutations and persons with unknown MECP2 status demonstrated greater mortality in the latter group (P < .0001, log-rank test). CONCLUSIONS: This analysis provides strong evidence for significant longevity in RTT and indicates the need for careful planning for long term care of these women. The disproportionately greater survival seen in earlier time periods and in persons with atypical RTT may be attributed to more severely affected individuals dying before diagnosis in the former and to greater numbers with milder variants (ie, preserved speech and delayed onset) in the latter. PMID- 19772972 TI - Insular cortex morphometry in first-episode schizophrenia-spectrum patients: Diagnostic specificity and clinical correlations. AB - Evidence so far indicates that the consistent association between insular cortex abnormalities and schizophrenia is already present at early phases of the illness. In the present investigation we aimed to study the specificity of insular structural abnormalities in schizophrenia by using region-of-interest morphometry to assess insular cortex morphological characteristics in the same heterogeneous sample of schizophrenia-spectrum patients. The 225 subjects, comprising 82 schizophrenia patients, 36 schizophreniform disorder patients and 24 patients with nonschizophrenic non-affective psychoses, and 83 healthy individuals were investigated. Magnetic resonance imaging brain scans (1.5T) were obtained and images analysed to evaluate insular cortex morphometric variables. The main resulting measurements were for insular gray matter volume and cortical surface area. The contribution of sociodemographic and clinical characteristics was controlled. Patients with schizophrenia-spectrum disorders did not significantly differ from controls in the insular cortex morphometric variables evaluated (all P's>0.11). Clinical variables were not significantly related with insular morphological changes. Noteworthy is the fact that none of the group morphological measurements varied significantly by gender or hemisphere. Neither did we find significant differences when patients with schizophrenia and with other non-affective psychoses were compared. Contrary to our initial hypotheses, we were unable to demonstrate significant morphometric anomalies in a large and heterogeneous sample of patients with a first-episode of schizophrenia-spectrum disorders. PMID- 19772973 TI - Susceptibility-weighted imaging for differential diagnosis of cerebral vascular pathology: a pictorial review. AB - Susceptibility-weighted imaging (SWI) is a high-spatial resolution, three dimensional, gradient-echo (GRE) magnetic resonance (MR) technique. This fully velocity-compensated pulse sequence utilizes the magnetic susceptibility differences of various tissues or substances, such as blood products, iron, and calcification. By postprocessing the magnitude images using a phase mask, it emphasizes the magnetic properties of different susceptibility effects. Generated minimal intensity projection (minIP) images can further demonstrate tortuous vasculature and the continuity of vessels or abnormalities across slices. SWI has been used to improve the diagnosis of neurological trauma, brain neoplasm, neurodegenerative disorders, and cerebrovascular disease because of its ability to demonstrate microbleeds and conspicuity of the veins and other sources with susceptibility effects. We have used SWI to identify cerebrovascular lesions which may be obscured on other MR sequences to aid in the differential diagnosis. We present a review with selected cases to demonstrate the usefulness of this new neuroimaging technique in improving the diagnosis of cerebral vascular pathology. PMID- 19772974 TI - Clinical neuroprotection in Parkinson's disease - still waiting for the breakthrough. AB - Recent research in the pharmacotherapy of Parkinson's disease (PD) has been able to provide numerous agents for the symptomatic control of motor impairments, but has failed to identify substances capable to slow down or even halt the progression of the disease. In the absence of disease-modifying therapies, affected patients develop marked disability within some years after the onset of motor symptoms, which can be alleviated but eventually not prevented with currently available medical and surgical therapies. Despite promising results from preclinical studies, outcomes of clinical neuroprotection trials have been repeatedly disappointing, which calls for a review of our approach to this topic. This article attempts to explain the need for neuroprotective therapies in PD, discusses results and limitations of previous clinical trials and provides some food for thought for the future research of neuroprotection in PD. Previous experiences from neuroprotection studies may have been discouraging, but also teach us some important lessons for the next generation of preclinical and clinical trials. Firstly, our currently used animal models for PD need to be refined in order to more reliably predict the efficacy of putative neuroprotective agents in subsequent clinical studies. Furthermore, changes in the methodology and design of future neuroprotection trials are required in order to exclude an impact of confounding symptomatic effects on observations. Finally, coordination and concentration of future research on the most promising agents will be necessary in order to accelerate the search for neuroprotective therapies in PD. Just as the pathogenesis of the disease is manifold, it may be this multilateral approach that eventually leads us to a breakthrough in finding neuroprotective agents for PD, if they exist. PMID- 19772975 TI - Distribution of heterocyst glycolipids in cyanobacteria. AB - Thirty-four axenic strains of cyanobacteria were analysed for their glycolipid content using high performance liquid chromatography coupled to electrospray ionisation tandem mass spectrometry (HPLC/ESI-MS(2)). Species of the families Nostocaceae and Rivulariaceae, capable of biosynthesising heterocysts, contained a suite of glycolipids consisting of sugar moieties glycosidically bound to long chain diols, triols, keto-ols and keto-diols. The aglycone moiety consisted of C(26) or C(28) carbon-chains with hydroxyl groups at the C-3, omega-1 or omega-3 positions. Keto-ols and keto-diols contained their carbonyl functionalities likely at the C-3 position. These compounds were absent in all analysed unicellular and filamentous non-heterocystous cyanobacteria and in the heterocyst forming cyanobacterium Anabaena CCY9922 grown in the presence of combined nitrogen, supporting the idea that the long-chain glycolipids are an important and unique structural component of the heterocyst cell envelope. The glycolipids 1-(O-hexose)-3,25-hexacosanediol and 1-(O-hexose)-3-keto-25-hexacosanol were ubiquitously distributed in species of the family Nostocaceae. 1-(O-hexose) 3,25,27-octacosanetriol and 1-(O-hexose)-3-keto-25,27-octacosanediol were dominant in members of the Calothrix genus, while traces of those compounds were detected only in one species of the Nostocaceae family. Their distribution in heterocystous cyanobacteria suggests a chemotaxonomic relevance that might allow distinguishing between species of different genera. Culture experiments indicate that the amount of keto-ols and keto-diols decreases relatively to their corresponding diols and triols counterparts with increasing temperature. Possibly, this is an adaptation to optimise the cell wall gas permeability, preventing inactivation of the oxygen-sensitive nitrogenase while allowing the highest diffusion of atmospheric dinitrogen into the heterocyst. PMID- 19772976 TI - Cytotoxic, anti-proliferative and antimicrobial furanoditerpenoids from Stuhlmania moavi. AB - The furanoditerpenoids voucapane, voucapane-6alpha,7alpha-diol, voucapane-18,19 diol and 18-hydroxyvoucapan-19-al were isolated from the cytotoxic stem and root bark extracts of Stuhlmaniamoavi Verdc. (Ceasalpiniaceae) and their structures established based on analysis of spectroscopic data. The compounds exhibited anti proliferative, cytotoxic, antibacterial and antifungal activities, 18 hydroxyvoucapan-19-al showing the highest anti-proliferative and cytotoxic properties. Voucapane-18,19-diol was only mildly active but the activity was enhanced for its 18,19-di-(4-methyl)-benzenesulphonate. Some of these results thus corroborate the traditional medicinal uses of the crude extracts for the treatment of skin infections. PMID- 19772977 TI - Steroidal glycosides from the leaves of Ruscus colchicus: isolation and structural elucidation based on a preliminary liquid chromatography-electrospray ionization tandem mass spectrometry profiling. AB - An HPLC-ESIMS(n) method, based on high-performance liquid chromatography coupled to electrospray positive ionisation multistage ion trap mass spectrometry, has been used as an effective tool to rapidly identify and guide the isolation of target saponins from the ethanol extract of the leaves of Ruscus colchicus Y. Yeo. Twenty-two steroidal glycosides, including seventeen furostanol, four spirostanol and one cholestane glycosides, were online identified. Subsequently, compounds were isolated and their structures were established by the extensive use of 1D- and 2D-NMR experiments. The structures identified by MS were fully consistent with those elucidated by NMR data. Sixteen steroidal glycosides, including thirteen furostanol, two spirostanol and one cholestane glycosides, were identified along with four known furostanol and two spirostanol glycosides. The saponin profile shows that the furostanol glycosides are the main constituents of R. colchicus extract, unlike the other Ruscus species, for which the spirostanol derivatives generally are reported as the major compounds. Moreover, for the first time a cholestane glycoside has been isolated from R. colchicus. PMID- 19772978 TI - Picosecond time scale imaging of mechanical contacts. AB - By means of an ultrafast opto-acoustic technique we study the nanoindentation of thin chromium films on sapphire substrates using a ceramic ball bearing. Acoustic pulses at approximately 40 GHz returning from the film-indenter interface allow the film indentation profiles to be probed to sub-nanometer resolution over contact areas approximately 25 microm in radius. The deformation of the films during loading is thereby revealed. Furthermore, thermal wave imaging of the contact at megahertz frequencies is simultaneously achieved. PMID- 19772979 TI - Rapid determination of free and conjugated estrogen in different water matrices by liquid chromatography-tandem mass spectrometry. AB - This article describes the development of a short pre-treatment method that allows the simultaneous analysis of free estrogens (estrone, 17beta-estradiol, estriol and 17 alpha-ethynylestradiol) and their sulphate and glucuronide conjugated forms. For a range of matrices, from sewage effluent to river water, the developed methodology based on solid-phase extraction and fractionation technique with ultra-performance liquid chromatography system showed effective separation of the targeted estrogens. The detection limits of this method ranged from 0.2 to 0.8 ng L(-1) for river water. The recoveries for river water and sewage effluent varied from 63% to 127%. The problems of matrix effects and ion suppression or enhancement were allowed quantitatively for in the analysis using standard addition. The developed method was used successfully to detect estrogens and their conjugates in both raw and treated wastewater, and river water at a location in Japan. High concentrations of the free estrogens estrone, 17beta estradiol and estriol were found in the influent (22.6, 77.2, 64.6 ng L(-1), respectively) but only E1 was still present at a high concentration in the effluent which was reflected in the downstream river concentration. Estrone-3 sulphate was detected up to 18.0 ng L(-1) in influent water sample and 1.1 ng L( 1) in downstream water. For the sulphate conjugates, removal efficiencies varied from 35 to 88%. Glucuronide conjugates were detected only once in the sewage influent. PMID- 19772980 TI - 2-Hydroxypyridine photolytic degradation by 254 nm UV irradiation at different conditions. AB - The degradation and mineralisation of (400 mL, 3.15 mM) aqueous solutions of 2 hydroxypyridine (2-HPY), a primary intermediate formed during the photolytic degradation of 2-chloropyridine (2-CPY), 2-bromopyridine (2-BPY) and 2 iodopyridine (2-IPY), was studied at 50 degrees C, under 254 nm UV irradiation in a range of conditions. The rate of 2-HPY disappearance was found to heavily depend on agitation, dissolved oxygen, pH and hydroxyl radical scavenger presence. pH has a pronounced effect on the phototreatment of 2-HPY, i.e. 2-HPY removal is faster at lower pH, but except for their influence on the solution pH, Cl(-) or F(-) do not appear to affect 2-HPY rate of removal or mineralisation. 2 HPY removal rate increases with dissolved oxygen, thus indicating a prominent 2 HPY photooxidation pathway. Helium purging of the solution before and during the measurement reduced 2-HPY removal rate, thus supporting the existence of a photooxidation pathway. Pure photolytic 2-HPY removal, i.e. when photooxidation is limited, fits pseudo-first order kinetics, and a kinetic model was developed for 2-HPY formation and removal during 2-CPY, 2-BPY and 2-IPY photolytic degradation under laminar flow. The addition of radical scavenger (tert-butanol) had a detrimental effect on the photolytic degradation of 2-HPY. Complete total organic carbon removal was achieved. PMID- 19772981 TI - Biodegradation potential of wastewater micropollutants by ammonia-oxidizing bacteria. AB - This study examined the biodegradation potential of three wastewater micropollutants (triclosan, bisphenol A, and ibuprofen) by Nitrosomonas europaea and mixed ammonia-oxidizing bacteria in nitrifying activated sludge. N. europaea could degrade triclosan and bisphenol A, but not ibuprofen. The degradation was observed only in the absence of allylthiourea (an inhibitor for ammonia monooxygenase (AMO)), suggesting that AMO might be responsible for triclosan and bisphenol A degradation. Competitive inhibition among ammonia, triclosan, and bisphenol A was observed. Inactivation of N. europaea was observed after degrading a mixture of triclosan and bisphenol A. The inactivation might be due to product toxicity and/or antimicrobial effect of triclosan; however, the causes of the inactivation were not determined. Regardless of the presence of the AMO inhibitor, three micropollutants were degraded by two different nitrified activated sludge samples. The results suggested that both ammonia-oxidizing bacteria and heterotrophic microorganisms in the activated sludge can degrade triclosan and bisphenol A. On the other hand, ibuprofen was more likely degraded by heterotrophic microorganisms in the activated sludge. PMID- 19772982 TI - Persistent organochlorine pollutants and heavy metals in tissues of common bottlenose dolphin (Tursiops truncatus) from the Levantine Basin of the Eastern Mediterranean. AB - DDT's, PCBs and heavy metals (HM) were measured in tissues of common bottlenose dolphins, collected along the Israeli Mediterranean coast during 2004-2006. SigmaDDT and PCBs concentrations were highest in the blubber, with a wide concentration range of 0.92-142 and 0.05-7.9 mg kg(-1) wet weight, respectively. Blubber PCBs values were an order of magnitude lower than in tissues of this and other delphinid species in the Western Mediterranea. We found relatively high DDE/SigmaDDT percentage (85-96%); a common indicator of DDT degradation, which fitted the general trend of increase in the last 20 years in the Mediterranean Sea, indicating the progressive degradation of the remnant DDT and the absence of new inputs. Concentrations of HM ranged as follows: 0.01-123 mg kg(-1) wet weight for Hg, <0.04-1.3 for Cd, 1-30 for Cu, 0.3-4 for Mn, 19-517 for Fe, 4.3-68 for Zn and 2.4-48 for Ni. These concentrations were similar to those found in specimens collected during previous years in the region, suggesting stability over time in the HM levels of the basin's food-web. PMID- 19772983 TI - Organochlorine pesticides contamination in surface soils from two pesticide factories in Southeast China. AB - The present article attempts to investigate organochlorine pesticides' (OCPs) contamination in soils from polluted sites and to assess the soil quality in the study area. HCHs and eight other persistent organic pollutants (POPs) pesticides were studied in surface soil samples collected from a new (F) and an old (G) pesticide factory in Southeast China. According to the measured results, surface soils from F and G were contaminated with HCHs, DDTs, HCB, and chlordane, with beta-HCH and p,p'-DDT being the two dominant substances. The total OCPs concentrations of surface soils from F and G were 0.84 and 166mgkg(-1) respectively. Cluster analysis was performed to group the soil sites in terms of their total OCPs contamination levels. The ratios of alpha-HCH/gamma-HCH, o,p' DDT/p,p'-DDT, and trans-/cis- chlordane in some of the soil samples are similar to their technical products in the study area which indicates the lack of hazardous waste management practices of the pesticide production and transportation. According to GB 15618-1995, the HCHs could be classified as light pollution and little pollution for F and G, whereas DDTs levels of F and G could be defined as little pollution and heavy pollution, respectively. This study indicates that surface soils, especially residential area soils from F and G were facing varying degrees of pollutions. The situation is more hazardous due to the continuous exposure of the population that lives in the surroundings. Therefore, on-site remediation technologies and the best available techniques/best environmental practices (BAT/BEP) should be carried out on these factories with the national implementation of the Stockholm Convention. PMID- 19772993 TI - Federation of Pediatric Organizations Task Force on Women in Pediatrics II: survey of active members of the Society for Pediatric Research regarding part time and flexible work. PMID- 19772994 TI - Does swaddling decrease or increase the risk for sudden infant death syndrome? PMID- 19772995 TI - Keep your eyes on the prize. PMID- 19772996 TI - Patience is a virtue in the management of gastroesophageal reflux. PMID- 19772997 TI - What's new is old: maximizing the benefits of parental presence at bedside rounds through 100 years of insights from the literature. PMID- 19772998 TI - Pediatric nonalcoholic fatty liver disease in 2009. PMID- 19773003 TI - Adherence to guidelines for cardiovascular screening in current high school preparticipation evaluation forms. AB - We compared the content of the cardiac screening questions on US state high school athletic association preparticipation evaluation forms with current consensus recommendations. We reviewed the high school athletic association's approved, recommended, or required sports preparticipation form from each of the 50 US states and the District of Columbia, and compared the content of the personal and family history components with current recommendations for cardiac screening questions. We found that 85% of the preparticipation forms in current use contain all elements of the formerly recommended guidelines, but only 17% contain all elements of the new consensus guidelines. We conclude that although there appears to be some improvement in the content of the preparticipation forms in current use compared with previous studies, the vast majority of these forms are incomplete compared with current consensus guidelines. PMID- 19773004 TI - Deer sausage: a newly identified vehicle of transmission of Escherichia coli O157:H7. AB - Five Missouri patients infected with Escherichia coli O157:H7 were studied for an epidemiologically plausible association. Case isolates, case interviews, and pathogen and meat XbaI pulsed field electrophoresis patterns were consistent with the common source being contaminated, fermented deer sausage, a previously unrecognized mode of transmission for Escherichia coli O157:H7. PMID- 19773005 TI - School-based health promotion for mosquito-borne disease prevention in children. AB - We enrolled 345 fourth-grade students in a classroom-randomized, controlled trial to evaluate a school-based West Nile virus health education program's impact on knowledge, attitudes, and personal protective behavior use. Immediate and sustained improvements in West Nile virus knowledge and greater frequencies of reported personal protective behaviors resulted from the educational intervention. PMID- 19773006 TI - A novel presentation of diffuse lung disease caused by congenital hypothyroidism. AB - A term infant was born with respiratory distress, and subsequent imaging, histopathologic, and hormonal studies confirmed congenital hypothyroidism. This report is intended to alert pediatricians to the possibility of congenital hypothyroidism as a cause of respiratory symptoms of unknown cause in neonates with respiratory distress. PMID- 19773007 TI - Monitoring preterm infants' vision development with light-only melanopsin is functional. PMID- 19773008 TI - Successful treatment with hydrodistension in a boy with refractory overactive bladder with glomerulation. PMID- 19773009 TI - Multiple births and aplasia cutis. PMID- 19773012 TI - Obesity and gastrointestinal disorders. PMID- 19773013 TI - Relation between low-density lipoprotein particle size and insulin and diabetes mellitus. PMID- 19773015 TI - To GERD or not to GERD, this is the question. PMID- 19773016 TI - Background levels of polychlorinated biphenyls in the U.S. population. AB - BACKGROUND: Polychlorinated biphenyl (PCB) exposures are encountered by the general public by eating contaminated food or living near a previously operating PCB factory or hazardous waste site. PCBs affect the immune, reproductive, nervous, and endocrine systems and are carcinogens. PCBs were banned in the United States in 1977. For public health, it is important to be able to estimate individual risk, especially for vulnerable populations, to monitor the decline in risk over time and to alert the public health community if spikes occur in PCB exposures, by measuring serum PCB levels. The historical decline in PCB exposures cannot be documented within a repeatedly tested general population, since there is no such population. Therefore, our aim was to model serum PCB levels in the US general population over time using published data. METHODS: Models were developed based on 45 publications providing 16,914 background PCB levels in sera collected 1963-2003. Multiple linear regression and exponential decay were used to model the summary PCB levels. RESULTS: Background levels of higher-chlorinated PCBs (five or more chlorines) in sera increased before 1979 and decreased after 1979; a quadratic model was the best fit. However, the exponential decay model explained better the low PCB serum levels still seen in the general population. For lower-chlorinated serum PCBs, no increase or decrease was shown (1.7ppb for all years). CONCLUSIONS: Limitations for both models were lack of repeated measures, non-randomly selected study participants, selected years, concentration on geographic areas centered on PCB waste sites, lack of adjustment for BMI or for laboratory methods. Despite the limitations, this analysis shows that background PCB levels in the general population are still of concern. Future work should focus on uncertainties governing how to interpret the levels with respect to possible long term health effects. PMID- 19773017 TI - A study of metal concentrations and metallothionein binding capacity in liver, kidney and brain tissues of three Arctic seal species. AB - Arctic seals are known to accumulate relatively high concentrations of potential toxic heavy metals in their vital organs, such as livers and kidneys, as well as in their central nervous system. We therefore decided to determine whether mercury, copper, cadmium and zinc levels in liver, kidney and brain tissues of three Arctic seal species were associated with the intracellular metal-binding protein metallothionein (MT) as a sign of toxic exposure. Samples from four ringed (Phoca hispida), five harp (P.groenlandica) and five hooded (Cystophora cristata) seals taken during field trips to Central West Greenland (Godhavn) and the Barents Sea in the spring of 1999 were used for the present study. In all three seal species concentrations of mercury, zinc and copper were highest in the liver, except for cadmium which was highest in the kidneys. Metal concentrations increased significantly in the order: ringed seal or =60) was 22.2% in T1D patients and 7.6% in the controls (OR, 4.6; 95% CI, 1.7-12.8). TAS-20 scores were positively associated with diabetes duration and negatively with treatment intensification parameters. CONCLUSIONS: Alexithymia is higher in psychiatrically uncomplicated T1D patients than in healthy controls even after adjustment for confounding depressive symptoms; it is greater with longer diabetes duration and is associated with some reduced parameters of treatment intensification but not with worse outcome in terms of glycemic control or somatic complications. PMID- 19773025 TI - Screening for anxiety and depression after stroke: comparison of the hospital anxiety and depression scale and the Montgomery and Asberg depression rating scale. AB - OBJECTIVE: Anxiety and depression after stroke are frequent, but are often overlooked and not assessed. The aims of the study were to (1) assess the prevalence of anxiety and depression and (2) compare the performance of the Hospital Anxiety and Depression Scale (HADS) and Montgomery and Asberg Depression Rating Scale (MADRS) as screening instruments for anxiety and depression disorders 4 months after stroke. METHODS: Stroke patients, consecutively admitted to a stroke unit, were assessed with HADS and MADRS 4 months after stroke (n=104). Depression and anxiety disorders were diagnosed using the Structured Clinical Interview for DSM-IV (SCID). Measures were compared in terms of correlations, sensitivity, specificity, positive and negative predictive value, overall agreement, kappa, and ROC curves, using DSM-IV diagnoses of "at least one current significant anxiety disorder" (Anxiety) and "any current depression" (Depression), as the clinical criteria. RESULTS: Anxiety occurred in 23% of patients and Depression in 19% (13% major depression, 3% minor depression, 4% dysthymia). For Anxiety, the optimal screening cut-off was 4 for HADS-A and 6 for HADS-total; for Depression, optimal cut-offs were 4 for HADS-D, 11 for HADS total, and 8 for MADRS. At cut-offs commonly used in clinical practice for depression screening (HADS-D: 8, MADRS: 12), the MADRS performed marginally better than the HADS. CONCLUSION: Anxiety is as prevalent as depression 4 months after stroke. MADRS and HADS-D perform acceptably as screening instruments for depression, and HADS-A for anxiety after stroke. However, lower HADS cut-offs than recommended for the general population should be considered for stroke patients. PMID- 19773026 TI - Helplessness predicts the development of hypertension in older Mexican and European Americans. AB - OBJECTIVE: The mechanisms by which depression is associated with an elevated risk of cardiovascular disease remain unclear. It is possible that depressive symptoms could increase the risk of hypertension, which in turn could predispose to cardiovascular disease. The goal of this study was to explore whether individual depressive symptoms might predict the incidence of hypertension in a cohort of 240 initially normotensive Mexican-American and European-American elders. METHODS: Subjects were 65-78 years old on entering the San Antonio Longitudinal Study of Aging, an epidemiologic survey, at which time they completed the 30-item Geriatric Depression Scale in English or Spanish. Their blood pressure was reassessed a mean of 7.0 years later. Responses to six key scale items (depressed mood, decreased interest, worthlessness, hopelessness, helplessness, and fatigue) were evaluated for the ability to predict incident hypertension. RESULTS: In univariate analyses, only helplessness significantly predicted incident hypertension (chi-square 13.5, df=1, P=.0003). In a Cox proportional hazards model adjusted for sex, education, number of comorbid diseases, current drinking, social well-being, and marital status, helplessness remained a very strong predictor [hazard ratio (HR) 4.99, 95% confidence interval (CI) 1.90-13.12, P=.0011]. Total depression score also predicted incident hypertension, but less strongly (HR 1.08, CI 1.00-1.17, P=.0339). CONCLUSION: Helplessness may predict the development of hypertension in the elderly. Further research into this relationship might lead to interventions to reduce the risk of cardiovascular disease. PMID- 19773028 TI - Sensitivity and specificity of the Beck Depression Inventory in cardiologic inpatients: how useful is the conventional cut-off score? AB - OBJECTIVE: The Beck Depression Inventory (BDI) is widely used for depression screening in various patient populations. However, there are still insufficient data about its sensitivity and specificity in nonpsychiatric patients. Furthermore, some research suggests that somatic BDI items heighten its sum score artificially in physically ill patients. The aim of the present study was to validate the conventional BDI cut-off score by examination of its sensitivity and specificity in a mixed sample of cardiac inpatients and compare it to a modified "cognitive-emotional" BDI (BDI(c/e)) after exclusion of somatic items. METHODS: A total of 126 cardiologic inpatients were assessed. Receiver operating characteristic curves (ROC) were calculated for total BDI (BDI(t)) and BDI(c/e). Screening performance of cut-off scores was evaluated using the Youden Index (Y). RESULTS: With the application of the conventional BDI cut-off score, ROC analysis revealed a moderate overall screening performance with Y=52.6 and an area under the curve (AUC) of 0.83. In contrast, Y improved to 57.5 at a cut-off score of >9, but screening performance was still not optimal. BDI(c/e) showed also a moderate screening performance (AUC=.82); Y was maximized at a cut-off score of >8 (Y=0.53.5). Again, no cut-off score provided optimal screening performance. CONCLUSION: The BDI cannot be recommended as a formal screening instrument in cardiac inpatients since no cut-off score for either BDI(t) or BDI(c/e) combined both sufficiently high sensitivity and specificity. However, the shorter BDI(c/e) could be used as alternative to BDI(t) which may be confounded in physically ill patients. Generally, researchers should consider using alternative screening instruments (e.g., the Hospital Anxiety and Depression Scale) instead. PMID- 19773029 TI - Meaning in life, anxiety, depression, and general health among smoking cessation patients. AB - OBJECTIVE: Psychosocial factors play a widely recognized role in health and health care utilization. The present study investigated relations among meaning in life, depression, anxiety, and social support with self-reported general health. METHOD: Ninety-nine smoking cessation group patients were recruited to complete questionnaires during their third week of treatment. RESULTS: Depression was the strongest predictor of perceived general health. However, the interaction of people's experience of meaning in life and their propensity to seek deeper meaning in their lives predicted variance in perceived health above and beyond depression. Furthermore, propensity to seek meaning in life was the only psychosocial correlate of people's perceived social benefits of health care utilization. CONCLUSION: Psychosocial factors, particularly depression and the two primary dimensions of meaning in life (experiencing and seeking), were related to perceived health. Meaning in life thus emerges as a variable worth further scrutiny in the health of clinical populations. PMID- 19773030 TI - "Evidence based medicine in CL psychiatry and psychosomatics": an impression of the 12th annual conference of the EACLPP in Noordwijkerhout, the Netherlands, June 25-27, 2009. PMID- 19773027 TI - Coping styles in heart failure patients with depressive symptoms. AB - OBJECTIVE: Elevated depressive symptoms have been linked to poorer prognosis in heart failure (HF) patients. Our objective was to identify coping styles associated with depressive symptoms in HF patients. METHODS: A total of 222 stable HF patients (32.75% female, 45.4% non-Hispanic black) completed multiple questionnaires. Beck Depression Inventory (BDI) assessed depressive symptoms, Life Orientation Test (LOT-R) assessed optimism, ENRICHD Social Support Inventory (ESSI) and Perceived Social Support Scale (PSSS) assessed social support, and COPE assessed coping styles. Linear regression analyses were employed to assess the association of coping styles with continuous BDI scores. Logistic regression analyses were performed using BDI scores dichotomized into BDI<10 vs. BDI> or =10, to identify coping styles accompanying clinically significant depressive symptoms. RESULTS: In linear regression models, higher BDI scores were associated with lower scores on the acceptance (beta=-.14), humor (beta=-.15), planning (beta=-.15), and emotional support (beta=-.14) subscales of the COPE, and higher scores on the behavioral disengagement (beta=.41), denial (beta=.33), venting (beta=.25), and mental disengagement (beta=.22) subscales. Higher PSSS and ESSI scores were associated with lower BDI scores (beta=-.32 and -.25, respectively). Higher LOT-R scores were associated with higher BDI scores (beta=.39, P<.001). In logistical regression models, BDI> or =10 was associated with greater likelihood of behavioral disengagement (OR=1.3), denial (OR=1.2), mental disengagement (OR=1.3), venting (OR=1.2), and pessimism (OR=1.2), and lower perceived social support measured by PSSS (OR=.92) and ESSI (OR=.92). CONCLUSION: Depressive symptoms in HF patients are associated with avoidant coping, lower perceived social support, and pessimism. Results raise the possibility that interventions designed to improve coping may reduce depressive symptoms. PMID- 19773031 TI - Immunolocalisation of laminin-1 in keratocystic odontogenic tumors. AB - Keratocystic odontogenic tumors (KOTs) are distinct odontogenic lesions frequently affecting the jawbones. They may be associated with nevoid basal cell carcinoma syndrome (NBCCS), and may exhibit disorders involving the extracellular matrix. The aim of this study was to investigate the immunolocalisation of laminin-1 in 20 cases of KOTs in order to contribute to the characterization of this protein, which is little studied in odontogenic tumors. Our results showed laminin-1 in all 20 KOTs studied; its labelling intensity was weak in three cases (15%), moderate in five (25%) and strong in 12 cases (60%). Laminin-1 immunolocalisation was predominantly continuous in 18 (90%) KOTs, including areas of acanthosis, subepithelial split and epithelial buds. Weak immunolabelling was observed in regions exhibiting an inflammatory process, especially in the case of intense inflammation. These findings suggest that laminin-1 does not participate in biological processes such as cystic epithelium-cystic wall separation or the formation of epithelial islands in KOTs. Furthermore, the discontinuous and weak labelling of this protein in the basement membrane of these tumors is probably a consequence of the inflammatory process in the tumor stroma. PMID- 19773032 TI - Transabdominal micro-ultrasound imaging of bladder cancer in a mouse model: a validation study. AB - OBJECTIVES: To validate the use of transabdominal micro-ultrasound imaging (MUI) in an orthotopic murine bladder cancer model. The current in vivo imaging systems for murine bladder cancer include magnetic resonance imaging, bioluminescent and fluorescent imaging, and intravesical ultrasound. METHODS: We implanted murine bladder tumor-2 tumor cells into C3H/He female mice. Mice underwent MUI before, and every 3 days after instillation of tumor cells. Three mice were killed at every MUI session. Bladder tumors were measured and tumor volumes were calculated during MUI and gross stereomicroscopy. Bladders were harvested and examined under gross stereomicroscopy to confirm the presence, location, and size of bladder tumors, and were prepared for histology review. RESULTS: Overall, 15 of 33 (45%) mice were confirmed to have tumors, using MUI, gross stereomicroscopy, and histology. Measurements of tumor size by MUI and gross microscopy had a high correlation coefficient (r = 0.97). MUI identified all tumors that were present on final histology. The smallest confirmed tumor on MUI was detected at 0.52 mm(3), and mean tumor volume was 0.95 mm(3). No tumors that were not detected first using MUI were found on final histology. CONCLUSIONS: Transabdominal MUI is a valuable tool to use for translational studies involving orthotopic mouse bladder cancer models. MUI provides real-time, high resolution in vivo images of bladder tumors. Tumor presence can be confirmed with a high degree of accuracy pertaining to tumor volume before initiation of treatment. In addition, tumor growth or regression can be followed up in vivo longitudinally. PMID- 19773033 TI - Transurethral cystolithotripsy with holmium laser under local anesthesia in selected patients. AB - OBJECTIVES: To evaluate the feasibility and effectiveness of transurethral holmium:yttrium-aluminum-garnet (YAG) laser cystolithotripsy under local anesthesia in selected patients. METHODS: Thirteen consecutive male patients with large bladder calculi (3 cm or greater) caused by benign prostatic hyperplasia underwent transurethral cystolithotripsy using holmium:YAG laser under local anesthesia. The operation was performed with all the patients in the lithotomy position (except 3 with pelvic prosthesis). All patients underwent transurethral holmium laser cystolithotripsy (HLC) with a flexible cystoscope under local anesthesia by 1 surgeon. A urethral Foley catheter was placed postoperatively. RESULTS: Thirteen patients with a mean age of 58.2 years were managed with HLC. All patients were rendered stone-free, regardless of stone size. No patient underwent transurethral resection of the prostate at the completion of the procedure. The mean stone size was 3.6 cm (range 3-5) and the mean operative time was 51 minutes (range 45-65). The whole procedure was well tolerated and no significant differences were found in the mean pain score between the HLC group and a group of male patients who underwent flexible cystoscopy under local anesthesia (2.15 vs 1.86, respectively; P = .467). No major intraoperative complication occurred. The mean hospitalization was 2.3 days. After a mean follow up of 16.6 months, no recurrent stone, urinary retention, or urethral stricture developed. CONCLUSIONS: Transurethral holmium:YAG laser lithotripsy under local anesthesia appears to be a safe and effective technique for the large bladder calculi. Thus, it may be used as an alternative treatment option in selected patients. PMID- 19773034 TI - Effect of diabetes on cooling-induced detrusor muscle contraction: mediation via Rho-kinase activation. AB - OBJECTIVES: To investigate the possible involvement of Rho-kinase in cooling induced contraction of the detrusor muscle. The etiology of diabetic cystopathy is not clear. It may be due to various changes in bladder innervation and/or detrusor muscle dysfunction. Because cooling of urinary bladder smooth muscle normally is a potent stimulus to micturition due to increase in muscle tone, we studied the effects of cooling on normal and diabetic bladder specimens. METHODS: Urinary detrusor muscle strips isolated from rats were suspended in organ baths containing Krebs solution for isometric tension recording. Tissue responses to stepwise cooling were examined from normal and 12-week streptozocin-induced diabetic rats. We examined the effects of calcium-free, ethylene glycol bis (beta aminoethylether)-N,N,N,N,-tetraacetic acid (1 mm)-containing Krebs solution, and the Rho-kinase inhibitor Y-27632 on the cooling responses. RESULTS: Stepwise cooling from 37 degrees C to 5 degrees C induced a rapid and reproducible increase in basal tone, proportional to cooling temperature. This response was more pronounced in diabetic specimens. Cooling-induced contractions were significantly inhibited in calcium-free solutions in both control and diabetic bladders. Our investigation showed that the influx of extracellular calcium is important in inducing the cooling response. The Rho-kinase inhibitor Y-27632 (1 microm) inhibited cooling (20 degrees C)-induced contraction. It reduced the response by 52.1% +/- 10.0% in control and by 70.0% +/- 12.0% in diabetic rats. CONCLUSIONS: Cooling-induced contractions in control and diabetic detrusor muscle preparations are highly calcium dependant. It also involves activation of Rho kinase, which might be upregulated in the diabetic detrusor muscle. These results may help in the management of diabetes-induced incontinence due to involuntary detrusor muscle activity. PMID- 19773035 TI - Prostatic-specific antigen velocity after holmium laser enucleation of the prostate: possible predictor for the assessment of treatment effect durability for benign prostatic hyperplasia and detection of malignancy. AB - OBJECTIVES: To evaluate the prostate-specific antigen velocity (PSAV) as an indicator for effectiveness and durability of size reduction after holmium laser enucleation of the prostate (HoLEP). Additionally, PSAV monitoring in the detection of prostate cancer was also evaluated. METHODS: Between 1998 and 2006, we reviewed the prostate-specific antigen (PSA) data of 335 men who underwent HoLEP and had a complete PSA data including preoperative PSA, postoperative PSA (reset), and a minimum of 2 annual PSA readings after PSA reset. PSAV was calculated by 3 methods--simple arithmetic method, linear regression method, and rate method. RESULTS: In the benign group, the mean PSA dropped from 5.44 to 0.91 ng/mL (P <0.001). The prostate cancer patients who were newly discovered in the follow-up period had significantly higher baseline PSA (P = .032) and significantly lower PSA reduction than that of the benign group (75.39% vs 47.49%, P <.001). PSAV was calculated by 3 different methods and produced identical results; however, linear regression method produced significantly lower estimates at 7 years. In the malignant group, the mean PSAV at 1 and 3 years was higher than that of the benign group (1.28 vs 0.13 and 2.4 vs 0.09, P <0.022, 0.001, respectively). CONCLUSIONS: HoLEP results in a significant reduction in PSA that remained at lower levels during follow-up, suggesting that the glandular size reduction after HoLEP is durable. Monitoring of PSAV is important in long term follow-up of patients for prostatic carcinoma detection after prostatic surgery. PMID- 19773036 TI - Racial differences in vasectomy utilization in the United States: data from the national survey of family growth. AB - OBJECTIVES: To explore whether health care, socioeconomic, or personal characteristics account for disparities observed in the utilization of vasectomy. More than 500,000 vasectomies are performed annually in the United States. The safety and efficacy of vasectomy make it a good family planning option, yet the factors related to use of male surgical sterilization are not well understood. In this analysis, we examined differences in vasectomy rates according to factors such as race and socioeconomic status. METHODS: We analyzed data from the male sample of the 2002 National Survey of Family Growth to examine the use of vasectomy among the sample of men aged 30-45 (n = 2161). Demographic, socioeconomic, and reproductive characteristics were analyzed to assess associations with vasectomy. RESULTS: About 11.4% of men aged 30-45 years reported having a vasectomy, representing approximately 3.6 million American men. Although 14.1% of white men had a vasectomy, only 3.7% of black and 4.5% of Hispanic men reported undergoing vasectomy. On multivariate analysis, a significant difference in the odds of vasectomy by race/ethnicity remained, with black (odds ratio = 0.20, 0.09-0.45) and Hispanic men (odds ratio = 0.41, 0.18 0.95) having a significantly lower rate of vasectomy independent of demographic, partner, and socioeconomic factors. Having ever been married, fathering 2 or more children, older age, and higher income were the factors associated with vasectomy. CONCLUSIONS: After accounting for reproductive history, partner, and demographic characteristics, black and Hispanic men were less likely to rely on vasectomy for contraception. Further research is needed to identify the reasons for these race/ethnic differences and to identify factors that impede minority men's reliance on this means of fertility control. PMID- 19773037 TI - A comparative study evaluating the in vivo incorporation of biological sling materials. AB - OBJECTIVES: To comparatively investigate biological tissues that are clinical products currently used for implantation in urological reconstruction. Specifically, we examined biological materials in vivo and evidence regarding the tissue response observed. Biological tissues are widely used in urological surgeries to treat conditions such as pelvic organ prolapse and stress urinary incontinence. METHODS: Histologic data from 4 biological sling materials, that is, small intestinal submucosa (SIS), cadaveric fascia lata, cadaveric dermis, and porcine dermis, implanted within mice (n = 64) were evaluated at 2, 4, 8, and 12 weeks. Recovered tissue was assessed by several biocompatibility parameters such as capsule formation (collagen deposition), cellular number, cell morphology, and angiogenesis. RESULTS: Data provide a scientific depiction of the cellular response to these biomaterials through a 12-week evaluation. SIS had a significantly higher level of angiogenesis and cell infiltrate as compared with all other material tested. Collectively, the data suggest that SIS has improved biocompatibility over other tested materials. CONCLUSIONS: This study compared SIS with other biological tissues in an animal model and was found to have superior biocompatibility as seen in humans. This may be helpful for clinicians while selecting a particular biological material. The study provides evidence of the varying stages of remodeling each implant, with hopes to better understand the material response in vivo. PMID- 19773038 TI - Dynamic contrast-enhanced-magnetic resonance imaging evaluation of intraprostatic prostate cancer: correlation with radical prostatectomy specimens. AB - OBJECTIVES: To determine the diagnostic performance of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in the identification of intraprostatic cancer foci related to cancer volume at histopathology, in patients with clinically localized cancer treated by radical prostatectomy, with whole-mount histopathologic sections as the reference standard. METHODS: Eighty-three consecutive radical prostatectomy specimens from patients referred for a prostate specific antigen elevation were correlated with prebiopsy MRI. MRI results ranked on a 5-point scale were correlated with the findings of histopathology maps in 8 prostate sectors, including volume, largest surface area, and percentage of Gleason grade 4/5. The area under the receiver operating characteristic curve was used. RESULTS: Median prostate-specific antigen was 8.15 ng/mL. DCE-MRI was suspicious in 55 (66%) out of 83 patients. A separate cancer foci (mean 2.55 per patient) was present in 212 (34%) of 664 octants and DCE-MRI was suspicious in 68 of 212. Sensitivity and specificity of DCE-MRI at score 3.4 or 5 for identification of cancer foci at any volume was 32% and 95%, respectively. For identification of cancer foci > 0.5 mL, the sensitivity and specificity were 86% and 94%, respectively, with the under the receiver operating characteristic curve of 0.874. Mean volume of DCE-MRI detected and missed cancers were 2.44 mL (0.02 14.5) and 0.16 mL (0.005-2.4), respectively. Sensitivity and specificity of DCE MRI for identification of > 10% of Gleason grade 4/5 were 81% and 82%, respectively. CONCLUSIONS: DCE-MRI can accurately identify intraprostatic cancer foci. Possible applications are guidance for biopsies, selection of patients for watchful waiting, and focal treatment planning. PMID- 19773039 TI - Systemic absorption and pharmacokinetics of single-dose intravesical gemcitabine after transurethral resection of the bladder in non-muscle-invasive bladder cancer. AB - OBJECTIVES: To evaluate the systemic quantitative absorption, pharmacokinetics, and toxicities of gemcitabine administered intravesically at the recommended, high-concentration dose of 40 mg/mL, immediately after transurethral resection. METHODS: For a single intravesical instillation of gemcitabine after resection, 15 consecutive patients with recurrent, low-, or intermediate-risk non-muscle invasive bladder cancer candidates were selected. The extent of resection was defined as "small" if 6 excursions were needed to eliminate lesions. Eight and 7 patients, underwent a small and a large resection, respectively. Immediately after surgery 2000 mg of gemcitabine in 50 mL saline was instilled and held in the bladder for 1 hour. Pharmacokinetics of gemcitabine and its metabolite 2',2'-difluorodeoxyuridine were determined in plasma by high-performance liquid chromatography. Local and systemic toxicity were assessed. RESULTS: The highest mean gemcitabine concentrations were 1.38 microg/mL in small and 2.47 microg/mL in large resections. The difference was largest at 15 minutes after instillation (1.10 vs 2.47 microg/mL, P = .001). A significant difference was found between time and type of resection for gemcitabine plasma levels (P = .02) but not for 2',2' difluorodeoxyuridine. Toxicity never exceeded grade 2. At a mean follow-up of 2 years, 9 patients (60%) were found to be recurrence-free. CONCLUSIONS: The systemic absorption of a single postoperative intravesical instillation of high concentration gemcitabine is proportional to the extent of resection; peak plasma concentrations reached at 15 minutes are below the levels of intravenous administration. PMID- 19773040 TI - Pediatric transumbilical laparoendoscopic single-site nephroureterectomy: initial report. AB - OBJECTIVE: To present a case of laparoendoscopic single-site surgery (LESS) nephroureterectomy (NUx), a type of embroyonic natural orifice translumenal endoscopic surgery, which is one of the recent innovations in the era of laparoscopy, in a child. METHODS: A 10-year-old girl underwent left nephroureterectomy by LESS due to end-stage reflux nephropathy on December 25, 2008. The surgery is performed transperitoneally, through a 2-cm semicircular incision in the left inner curve of the umbilicus using three 5-mm trocars. NUx with LESS was performed duplicating standard laparoscopic steps with the help of flexible and straight laparoscopic instruments. RESULTS: Operation time was 140 minutes and the blood loss was minimal. There was no intraoperative or postoperative complication. The patient was discharged at the 24th postoperative hour. The postoperative cosmetic result was excellent as the incision scar was hidden inside the belly button. CONCLUSIONS: NUx with LESS is a feasible technique with the advantages of less pain, shortened convalescence, improved cosmesis, and absence of wound complications in children. However, clear indications of LESS in children remain to be clarified. PMID- 19773041 TI - Does the type of prostatic atrophy influence the association of extent of atrophy in needle biopsies and serum prostate-specific antigen levels? AB - OBJECTIVES: To consider the possibility that a positive and significant association between extent of atrophy and serum total or free prostate-specific antigen (PSA) elevation in patients with biopsies showing no cancer, high-grade prostatic intra-epithelial neoplasia or areas suspicious for cancer found in a previous study may be related to the type of atrophy. METHODS: The only diagnosis in 75 extended biopsies was focal prostatic atrophy. Both partial and complete atrophy were considered. Complete atrophy was subtyped into simple, hyperplastic, and sclerotic atrophy. The extent of each type of atrophy was measured in 2 ways: the linear extent in millimeters and the percentage of linear extent showing atrophy for each biopsy. On the basis of the median value of serum total PSA, the patients were divided into 2 groups: group A patients with PSA 8.2 ng/mL. RESULTS: There was a positive and statistically significant correlation of the linear atrophy extent as well as the percentage of linear extent with total and free serum PSA level. There was no statistically significant difference in the distribution of extent according to the type of atrophy between groups A and B. CONCLUSIONS: There is a positive and significant association between extent of atrophy and serum PSA elevation. This association is not related to the type of atrophy. We hypothesize that stress induced response by inflammation and/or ischemia may interfere in the physiological barrier that prevents any significant amount of PSA to gain the general circulation. PMID- 19773042 TI - Quality of life and body image for bladder cancer patients undergoing radical cystectomy and urinary diversion--a prospective cohort study with a systematic review of literature. AB - OBJECTIVES: To determine whether health and body image are important determinants of quality of life (QoL) for patients undergoing urinary diversion (UD). Patients with advanced bladder cancer who undergo cystectomy and UD face potential serious morbidity (25%-40%) and a small risk of mortality (0%-4%). The systematic review compares QoL and body image for different types of diversions. METHODS: One researcher trained in using schedule for evaluation of individual quality of life direct weighting interviewed 32 consecutive patients undergoing radical cystectomy. The European Organization for Research and Treatment of Cancer QLQ C30 and the Satisfaction With Life Scale questionnaire were also administered before cystectomy and 9-12 months postcystectomy. All QoL studies reporting on radical cystectomy and UD were reviewed between 1996 and March 2008. RESULTS: Family, relationships, health, and finance were the most important determinants of QoL, whereas body image was not mentioned by anyone. On using European Organization for Research and Treatment of Cancer QLQ-C30 and Satisfaction With Life Scale, it was found that there was no difference in QoL of patients pre- and postcystectomy. In our review of published data, 40 studies were identified reporting on 3645 patients. Only 2 studies reported a better QoL in favor of neobladders, whereas 2 other studies suggest a better body image perception in patients with neobladder. CONCLUSIONS: This prospective cohort study suggests that health and body image may not always be important to patients for their QoL. Our systematic review suggests an overall good QoL in most studies irrespective of the type of UD, with no significant differences among the different diversion types. PMID- 19773043 TI - Weekly combination of topotecan and gemcitabine in early recurrent ovarian cancer patients: a French multicenter phase II study. AB - OBJECTIVES: The aim of this phase II study was to assess the benefits of a weekly administration of topotecan and gemcitabine in patients with ovarian carcinoma having relapsed after platinum/taxane-based first-line chemotherapy. METHODS: Seventy-seven patients with progression of disease /=2 cycles administered). The only major severe toxicity was neutropenia grades 3 (17%) and 4 (6%). Approximately 60% of the patients received the complete schedule of treatment, dose interruptions/delays being mainly due to moderate thrombocytopenia or neutropenia. The objective response rate was 14%, the values for patients having relapsed within 6 (n=30) and 6-12 (n=36) months being 7% and 20%, respectively. Median durations of response were 4.9 and 6.4 months and clinical benefit rates including stabilizations reached 63% and 69% in patients having relapsed within 6 or 6-12 months, respectively. Corresponding median overall survival was 7.5 and 15.6 months. Symptoms and pain were reduced in 64% and 39% of the patients concerned, respectively. CONCLUSION: In early relapse ovarian cancer, weekly combination of gemcitabine and topotecan has a modest objective response rate. However, a high proportion of patients experienced stable disease and symptom control leading to acceptable quality of life. PMID- 19773045 TI - Accuracy of cervical specimens obtained for biomarker studies in women with CIN3. AB - OBJECTIVE: We developed a protocol to collect representative cervical specimens based on colposcopic evaluation from women treated with loop electrosurgical excision procedure (LEEP). METHODS: We analyzed the histology of biopsies targeting the worst and a normal area on the cervical surface in 74 women referred for LEEP because of cervical intraepithelial neoplasia grade 3 (CIN3) detected in a previous biopsy. Lesions and normal tissue were identified in colposcopy, marked, and removed after LEEP. Cervical cytology specimens collected at the same time were analyzed using Pap cytology and human papillomavirus (HPV) genotyping. RESULTS: All but two women had an abnormal colposcopic impression with 59 of 68 (87%) showing an impression of CIN2 or greater. In 19 of 58 (33%) women, the histology result of the frozen specimen targeting the worst lesion was < or =CIN1. In 18 of 46 (40%) women, the histology of the frozen specimen targeting normal tissue was CIN2+. A concordant histology result in specimens targeting the worst lesion was associated with a greater extension of the CIN3 in the LEEP (p trend=0.002) and a HSIL cytology result (p trend=0.02). CONCLUSION: It is challenging to sample representative cervical tissue. Even in women with confirmed CIN3, colposcopy performance to identify the worst lesion on the cervix was limited. Correctly identified CIN3s were more likely to be larger lesions that may have a higher risk of progression to cancer. PMID- 19773048 TI - Minimally invasive carpal tunnel release. AB - We prospectively compared the safety and effectiveness of mini-incision (group A) and a limited open technique (group B) for carpal tunnel release (CTR) in 185 consecutive patients operated between November 1999 and May 2001, with a 5-year minimum follow-up. Patients in Group A had a minimally invasive approach (<2 cm incision), performed using the KnifeLight (Stryker, Kalamazoo, Michigan) instrument. Patients in Group B had a limited longitudinal incision (3-4 cm). Patient status was evaluated with an Italian modified version of the Boston Carpal Tunnel questionnaire, administered preoperatively and at 19, 30, and 60 postoperative months. Mini-incision CTR showed advantages over standard technique in early recovery, pillar pain, and recurrence rate. The recovery period after mini-incision is shorter than after standard procedure. PMID- 19773049 TI - Percutaneous CT-guided vertebroplasty in the management of osteoporotic fractures and dorsolumbar metastases. AB - Percutaneous vertebroplasty (PVP) is a minimally invasive, image-guided procedure consisting of an injection of acrylic cement into a vertebral body to reinforce the compressed segment and achieve pain relief. The use of PVP is a minimally invasive option in the treatment of osteoporotic or metastatic vertebral collapses. Our personal experience, using a CT-guided technique, confirms the efficacy and safety of PVP with a lower risk for complications compared with conventional fluoroscopic approaches because of a precise placement of the instruments in the vertebral body and an early detection of small cement leakages. PMID- 19773050 TI - Thoracoscopy for minimally invasive thoracic spine surgery. AB - Thoracoscopy has been used worldwide for many years by thoracic surgeons. Despite a long learning curve and technical demands of the procedure, thoracoscopy has several advantages, including better cosmesis, adequate exposure to all levels of the thoracic spine from T2 to L 1, better illumination and magnification at the site of surgery, less damage to the tissue adjacent to the surgical field, less morbidity when compared with standard thoracotomy in terms of respiratory problems, pain, blood loss, muscle and chest wall damages, consequent shorter recovery time, less postoperative pulmonary function impairment, and shorter hospitalization. Good results at short- and medium-term follow-up need to be confirmed at long-term follow-up. PMID- 19773051 TI - Vertebroplasty and kyphoplasty: reasons for concern? AB - Two different minimally invasive percutaneous vertebral augmentation methods for cement application into the vertebral body for the management of symptomatic compression fractures without neurologic impairment have been developed, namely, vertebroplasty and kyphoplasty. In vertebroplasty, polymethylmethacrylate cement is injected percutaneously into a collapsed vertebral body. Kyphoplasty involves placing an inflatable bone tamp percutaneously into a vertebral body. The inflation of the bone tamp with fluid allows restoration of vertebral height and correction of the kyphosis. After deflation, the cavity that has been produced is filled by injection of polymethylmethacrylate. This article provides an overview of the state of the art in vertebroplasty and kyphoplasty, discussing the indications, techniques, results, and pitfalls. PMID- 19773052 TI - The anterolateral minimally invasive approach for total hip arthroplasty: technique, pitfalls, and way out. AB - Different approaches for the hip have been developed for minimally invasive surgery in total hip arthroplasty. The goal of minimally invasive surgery is to reduce invasiveness to skin, muscles, and bone and improve recovery time after total hip arthroplasty. This article describes the technique of a minimally invasive approach to the hip from the anterolateral direction step by step and includes preoperative settings and pitfalls. PMID- 19773053 TI - Minimally invasive total knee arthroplasty: a systematic review. AB - The concept of minimally invasive total knee arthroplasty surgery evolved to reduce quadriceps muscle strength loss and improve clinical outcome following total knee replacement. We performed a systematic review of the published literature on Minimally Invasive Total Knee Arthroplasty (MITKA) and analyzed the reported surgical outcomes. Twenty-eight studies published from January 2003 to June 2008 that met the inclusion criteria were evaluated using the modified Coleman Methodology Score (CMS). At a mean CMS of 60, most studies reporting on outcome of MITKA are of moderate scientific quality. Patients undergoing MITKA tend to have decreased postoperative pain, rapid recovery of quadriceps function, reduced blood loss, improved range of motion (mostly reported as a short-term gain) and shorter hospital stay compared with patients undergoing standard total knee arthroplasty. These benefits, however, need to be balanced against the incidence of increased tourniquet time and increased incidence of component malalignment in the MITKA group. So far, the evidence based knowledge regarding results of MITKA comes from prospective studies of moderate quality with short follow up periods. Multicenter studies with longer follow-ups are needed to justify the long-term advantages of MITKA over standard total knee arthroplasty. PMID- 19773054 TI - Minimally invasive surgery of the achilles tendon. AB - Minimally invasive surgical techniques for pathologies of the Achilles tendon (AT) hold the promise to decrease perioperative morbidity, allow faster recovery times, shorten hospital stays, and improve functional outcomes when compared with open procedures, which can lead to difficulty with wound healing because of the tenuous blood supply and increased chance of wound breakdown and infection. This article presents recent advances in the field of minimally invasive AT surgery for tendinopathy, acute ruptures, and chronic tears. All of the techniques described in this article are inexpensive and do not require highly specialized equipment and training. Future randomized controlled trials are required to address the issue of the comparison between open versus minimally invasive AT surgery. PMID- 19773055 TI - Minimally invasive osteosynthesis of distal tibial fractures using locking plates. AB - The management of distal tibia fractures can be challenging because of the scarcity of soft tissue, their subcutaneous nature, and poor vascularity. Classic open reduction and internal plate fixation require extensive soft tissue dissection and periosteal stripping, with high rates of complications. Minimally invasive plating techniques reduce iatrogenic soft tissue injury and damage to bone vascularity and preserve the osteogenic fracture hematoma. Locking plates (LPs) have the biomechanical properties of internal and external fixators, with superior holding power because of fixed angular stability through the head of locking screws, independent of friction fit. In this review, the rationale for the use of LPs and a description of the technique of minimally invasive LP osteosynthesis of distal tibia fractures are presented. PMID- 19773056 TI - Percutaneous hallux valgus surgery: a prospective multicenter study of 189 cases. AB - Distal first metatarsal osteotomies have been indicated for the correction of mild-to-moderate hallux valgus deformity. The aim of this study was to assess the clinical and radiographic results of the distal Reverdin-Isham first metatarsal osteotomy with use of a percutaneous procedure after a minimum 1-year followup. One hundred eighty-nine feet in 168 consecutive subjects were included in the present prospective multicenter study. A radiographic and clinical assessment using the American Orthopaedic Foot and Ankle Society's (AOFAS) hallux metatarsophalangeal-interphalangeal scale was performed for all the subjects with a minimum 1-year follow-up. One hundred fifty six subjects (87%) were satisfied or very satisfied with the outcome of the procedure. The median postoperative AOFAS score was 93 points. Subjects averaged a loss 17% of first metatarsophalangeal joint motion. The median hallux valgus angle and intermetatarsal angle improved from 28 degrees and 13 degrees preoperatively, to 14 degrees and 10 degrees postoperatively, respectively. Percutaneous correction of mild-to-moderate hallux valgus deformity with the Reverdin-Isham osteotomy of the first metatarsal enables us to achieve clinical and radiographic results comparable to other percutaneous or open distal metatarsal osteotomies after 1 year follow-up. PMID- 19773057 TI - Bosch osteotomy and scarf osteotomy for hallux valgus correction. AB - Minimally invasive distal metatarsal osteotomies are becoming broadly accepted for correction of hallux valgus. We compared the duration of surgery, the length of hospital stay, the American Orthopaedic Foot and Ankle Society (AOFAS) score, and the Foot and Ankle Outcome Score (FAOS) in 36 patients who underwent a minimal incision subcapital osteotomy of the first metatarsal with 36 matched patients who had hallux valgus corrected by a scarf technique. The minimum follow up was 2.1 years (mean, 2.5 years; range, 2.1-3.2 years). Patients having the osteotomy had similar AOFAS and FAOS scores with less operating time and earlier discharge. Less operative time may benefit the patients, and earlier discharge has financial implications for the hospital. PMID- 19773058 TI - Minimally invasive hallux valgus correction. AB - The most common complication following minimally invasive surgery (MIS) foot procedures is recurrence of the deformity, likely a direct consequence of incorrect selection of the procedure, incorrect surgical technique, or underestimated healing time of the osteotomy. This article describes our surgical MIS for hallux valgus correction, including the postoperative management, and reviews the literature on MIS for hallux valgus correction. The reports on such techniques are few, and mainly case series are reported. More adequately planned and executed randomized prospective clinical trials are needed. Historical attempts, indications, preferred surgical techniques, and complications are discussed. PMID- 19773059 TI - From mini-invasive to non-invasive treatment using monopolar radiofrequency: the next orthopaedic frontier. AB - Tendinopathy arises from a failed tendon healing process. Current non-invasive therapeutic alternatives are anti-inflammatory in nature, and outcomes are unpredictable. The benefit of invasive alternatives resides in the induction of the healing response. A new technology that uses non-invasive monopolar capacitive coupled radiofrequency has demonstrated the ability to raise temperatures in tendons and ligaments above 50 degrees C, the threshold for collagen modulation, tissue shrinkage and recruitment of macrophages, fibroblasts, and heat shock protein factors, without damaging the overlying structures, resulting in activation of the wound healing response. Monopolar capacitive-coupled radiofrequency offers a new non-invasive choice for tendinopathies and sprained ligaments. It does not interfere with subsequent surgical procedures should they become necessary. PMID- 19773060 TI - Minimally invasive computer-navigated total knee arthroplasty. AB - Modern computerized knee navigation systems aid surgeons both in the conventional and in the minimally invasive approach to optimize mechanical and rotational alignments of the components in all three planes to avoid any malrotation and/or any errors in coronal, sagittal, and axial alignments. The advantages of minimally invasive total knee arthroplasty can be achieved without loss of accuracy. There is increasing evidence of a positive correlation between accurate mechanical alignment after total knee arthroplasty and functional as well as quality-of-life patient outcomes. PMID- 19773061 TI - Induction of lactational estrus in organic piglet production. AB - The longer lactation period required in organic piglet producing herds reduces the potential number of produced litters per sow per year compared with that of conventional production. Induction and use of lactational estrus may be a way to increase the productivity in organic production. However, if lactational estrus is to be beneficial under practical husbandry conditions, it is crucial that the majority of sows are successfully mated within a few days to make batch farrowing procedures possible. The objective of this study was to investigate the occurrence and timing of lactational estrus in an organic outdoor system based on ad libitum feeding, individual housing until Day 35 in lactation, followed by grouping and introduction of a boar and weaning of piglets after 8 wk. Five groups with four sows ((Danish Yorkshire x Danish Landrace) x Danish Duroc) in each were observed, and rank was determined by a food competition test. All sows showed lactational estrus, and 84% of these sows showed estrus within 1 wk, on average 43.5 d and 7.3 d after farrowing and boar introduction, respectively. The number of days from boar introduction to estrus increased significantly with increasing feed competition rank (the lowest number being the top rank position). Eighty-four percent of all sows were diagnosed pregnant 5 wk after estrus. Behavioral observations revealed that the average total number of copulations per estrus sow was 2.3 with a range of 0 to 5 copulations. The findings of the current study indicate that it is possible to combine lactational estrus and batch farrowing procedures to increase the number of weaned piglets per year per sow in organic piglet production based on 8 wk of lactation or more. PMID- 19773062 TI - Freemartinism and FecXR allele determination in replacement ewes of the Rasa Aragonesa sheep breed by duplex PCR. AB - A new naturally occurring mutation in the fecundity gene BMP15 in the Rasa Aragonesa sheep breed (Ovis aries) has been found to affect prolificacy. This mutation (FecX(R) allele) is a deletion of 17 base pairs that leads to an altered amino acid sequence, and this alteration increases prolificacy in heterozygous ewes but causes sterility in homozygous ewes. Selection of repository lambs with the FecX(R) allele increases rates of twins and multiple lambing and thereby also increases the probability of lambing freemartins that will become sterile. In this sense, an accurate, reliable, and quick method was developed by duplex polymerase chain reaction (PCR) for sex, amplifying an ovine-specific Y chromosome repetitive fragment, and BMP15 genotype determination in replacement ewe lambs. The BMP15 fragment served as an internal control of the amplification and detected the FecX(R) allele, avoiding a false negative and then a mistake in freemartin detection. This assay uncovered 6 freemartin females among 195 replacement ewes from 7 different commercial flocks and 1 experimental flock. Furthermore, 1554 rams from 64 commercial flocks were also analyzed to identify FecX(R) rams. This analysis identified 103 rams hemizygous for the FecX(R) allele and 1 heterozygous ram. Because this gene is located on the X chromosome, this heterozygous animal is a freemartin ram that is co-amplifying the DNA from XX and XY lymphocytes. These results confirm the usefulness of this multiplex PCR assay for detecting phenotypically sexed females, freemartins, and the BMP15 genotype to detect highly prolific ewes in commercial flocks and to assist breeders in selection of repository lambs. PMID- 19773063 TI - Mycoplasma agalactiae detected in the semen of goat bucks. AB - Contagious agalactia (CA) is among the most significant diseases affecting small ruminant populations in Mediterranean countries. This study was designed to detect the excretion in semen of CA-causing mycoplasmas in goats (Capra hircus) reared in Spain, where the disease is considered endemic. Culture techniques and PCR were conducted on 147 semen samples collected from 113 goat bucks to detect mycoplasmas. No animal showed clinical symptoms of CA at the moment of the screening. M. agalactiae was identified using both diagnostic methods in three semen samples collected from three different bucks. These animals belonged to a group of animals in which semen had been analyzed twice and only the second sample proved positive, suggesting the possibility of intermittent excretion. This is the first report of the isolation of M. agalactiae from semen collected from naturally infected goats. Future studies should investigate whether semen could be a real source of CA infection by determining if the agent may be transmitted during natural service or when semen is used for artificial insemination. PMID- 19773064 TI - Parasitoids of Drosophila. Preface. PMID- 19773065 TI - Ecology and life history evolution of frugivorous Drosophila parasitoids. AB - Parasitoids and their hosts are linked by intimate and harmful interactions that make them well suited to analyze fundamental ecological and evolutionary processes with regard to life histories evolution of parasitic association. Drosophila aspects of what parasitoid Hymenoptera have become model organisms to study aspects that cannot be investigated with other associations. These include the genetic bases of fitness traits variations, physiology and genetics of resistance/virulence, and coevolutionary dynamics leading to local adaptation. Recent research on evolutionary ecology of Drosophila parasitoids were performed mainly on species that thrive in fermenting fruits (genera Leptopilina and Asobara). Here, we review information and add original data regarding community ecology of these parasitoids, including species distribution, pattern of abundance and diversity, host range and the nature and intensity of species interactions. Biology and the evolution of life histories in response to habitat heterogeneity and possible local adaptations leading to specialization of these wasps are reported with special emphasis on species living in southern Europe. We expose the diversity and intensity of selective constraints acting on parasitoid life history traits, which vary geographically and highlight the importance of considering both biotic and abiotic factors with their interactions to understand ecological and evolutionary dynamics of host-parasitoid associations. PMID- 19773066 TI - Decision-making dynamics in parasitoids of Drosophila. AB - Drosophilids and their associated parasitoids live in environments that vary in resource availability and quality within and between generations. The use of information to adapt behavior to the current environment is a key feature under such circumstances and Drosophila parasitic wasps are excellent model systems to study learning and information use. They are among the few parasitoid model species that have been tested in a wide array of situations. Moreover, several related species have been tested under similar conditions, allowing the analysis of within and between species variability, the effect of natural selection in a typical environment, the current physiological status, and previous experience of the individual. This holds for host habitat and host location as well as for host choice and search time allocation. Here, we review patterns of learning and memory, of information use and updating mechanisms, and we point out that information use itself is under strong selective pressure and thus, optimized by parasitic wasps. PMID- 19773067 TI - Dynamic use of fruit odours to locate host larvae: individual learning, physiological state and genetic variability as adaptive mechanisms. AB - This chapter presents a series of behavioral studies designed to document how Leptopilina spp. learn fruit odours in order to find and explore host-infested fruits. Experimental analyses of conditioned responses explored individual learning, physiological changes and genetic variability as adaptive mechanisms of the host searching behavior. Both oriented walking and substrate probing can be easily observed and quantified in laboratory devices. We studied walking in a four-arm olfactometer and probing in an agar substrate in response to olfactory stimulation by fruit odours. We analyzed the odour learning process and the dynamics of the memory. We next investigated how odour memory is influenced by motivation factors such as mating or egg-load, and how much variation is due to inheritance, using isofemale lines. Next, we addressed the adaptive significance of innate and conditioned responses to fruit odour by comparing and crossing populations originating from areas with contrasted levels of host availability. PMID- 19773068 TI - The role of melanization and cytotoxic by-products in the cellular immune responses of Drosophila against parasitic wasps. AB - The cellular innate immune response of several species of Drosophila terminates with the encasement of large foreign objects within melanotic capsules comprised of several layers of adhering blood cells or hemocytes. This reaction is manifested by various Drosophila hosts in response to infection by endoparasitic wasps (i.e., parasitoids). Creditable assessments of the factor(s) causing, or contributing to, parasite mortality have long been considered as cytotoxic elements certain molecules associated with enzyme-mediated melanogenesis. However, observations that warrant additional or alternative considerations are those documenting parasitoid survival despite melanotic encapsulation, and those where parasitoids are destroyed with no evidence of this host response. Recent studies of the production of some reactive intermediates of oxygen and nitrogen during infection provide a basis for proposing that these molecules constitute important components of the immune arsenal of Drosophila. Studies of the virulence factors injected by female wasps during oviposition that suppress the host response will likely facilitate identification of the cytotoxic molecules as well as the cell-signaling pathways that regulate their synthesis. PMID- 19773070 TI - Variation of Leptopilina boulardi success in Drosophila hosts: what is inside the black box? AB - Interactions between Drosophila hosts and parasitoid wasps are among the few examples in which occurrence of intraspecific variation of parasite success has been studied in natural populations. Such variations can originate from three categories of factors: environmental, host and parasitoid factors. Under controlled laboratory conditions, it is possible to focus on the two last categories, and, using specific reference lines, to analyze their respective importance. Parasitoid and host contributions to variations in parasite success have largely been studied in terms of evolutionary and mechanistic aspects in two Drosophila parasitoids, Asobara tabida and, in more details, in Leptopilina boulardi. This chapter focuses on the physiological and molecular aspects of L. boulardi interactions with two Drosophila host species, while most of the evolutionary hypotheses and models are presented in Chapter 11 of Dupas et al. PMID- 19773069 TI - Virulence factors and strategies of Leptopilina spp.: selective responses in Drosophila hosts. AB - To ensure survival, parasitic wasps of Drosophila have evolved strategies to optimize host development to their advantage. They also produce virulence factors that allow them to overcome or evade host defense. Wasp infection provokes cellular and humoral defense reactions, resulting in alteration in gene expression of the host. The activation of these reactions is controlled by conserved mechanisms shared by other invertebrate and vertebrate animals. Application of genomics and bioinformatics approaches is beginning to reveal comparative host gene expression changes after infection by different parasitic wasps. We analyze this comparison in the context of host physiology and immune cells, as well as the biology of the venom factors that wasps introduce into their hosts during oviposition. We compare virulence strategies of Leptopilina boulardi and L. heterotoma, in relation to genome-wide changes in gene expression in the fly hosts after infection. This analysis highlights fundamental differences in the changes that the host undergoes in its immune and general physiology in response to the two parasitic wasps. Such a comparative approach has the potential of revealing mechanisms governing the evolution of pathogenicity and how it impacts host range. PMID- 19773071 TI - Immune resistance of Drosophila hosts against Asobara parasitoids: cellular aspects. AB - The immunity of Drosophila relies on a variety of defenses cooperating to fight parasites and pathogens. The encapsulation reaction is the main hemocytic response neutralizing large parasites like endophagous parasitoids. The diversity of the mechanisms of immunoevasion evolved by Asobara parasitoids, together with the wide spectrum of Drosophila host species they can parasitize, make them ideal models to study and unravel the physiological and cellular aspects of host immunity. This chapter summarizes what could be learnt on the cellular features of the encapsulation process in various Drosophila spp., and also on the major role played by Drosophila hosts hemocytes subpopulations, both in a quantitative and qualitative manner, regarding the issue of the immune Asobara-Drosophila interactions. PMID- 19773072 TI - Components of Asobara venoms and their effects on hosts. AB - Hymenoptera of the Asobara genus are endophagous parasitoids of Drosophila larvae. In these apocrita insects whose venom gland is associated with the female reproductive tract, the wasp venom is injected into the host along with the parasitoid egg during oviposition. We conducted a comparative study of the venom apparatuses from three Asobara spp.: the European Asobara tabida, the Asiatic A. japonica and the African A. citri. Light and electron microscopy of venom glands, together with the biochemical analysis of their contents, revealed important differences between Asobara spp. In addition, the physiological effects of female wasp's venom injected into Drosophila larvae differed greatly between the tested Asobara spp. PMID- 19773073 TI - Strategies of avoidance of host immune defenses in Asobara species. AB - Eggs and larvae of endophagous parasitoids face the host's immunity reaction once they penetrate the insect host's hemocele. In order to overcome the host's immune barrier, endoparasitoids have developed various strategies. Conformer parasitoids hide and/or get protected from the attack by the host's immunity cells without interfering with the host's immune system. Differently, regulator parasitoids directly attack the host's hemocytes, therefore totally inhibiting the immunity reaction of encapsulation in the parasitized host. Female wasps may also discriminate immunoreactive hosts from nonreactive, permissive ones before laying an egg. These different strategies coexist within the same genus of the braconids Asobara, endoparasitoids of Drosophila larvae. The physiological mechanisms underlying the conformer and regulator strategies in Asobara are exposed. The factors which may contribute to the diversity of the means developed by Asobara parasitoids to overcome the hosts' immunity defenses are discussed. PMID- 19773074 TI - Evolution of host resistance and parasitoid counter-resistance. AB - By their nature, parasitoids will exert a selection pressure on their hosts to evolve a mechanism through which to resist parasitoid attack. In turn, such a resistance mechanism will lead to parasitoids evolving counter-resistance. In this chapter, we present an overview of the research on the (co)evolutionary interaction between Drosophila and their parasitoids, with the main focus on the cellular immune response of D. melanogaster, and the counter-resistance mechanism of one of its main parasitoids, Asobara tabida. A key aspect of this interaction is the existence of genetic variation: in the field, host resistance and parasitoid counter-resistance vary, both between and within populations. Host resistance and parasitoid counter-resistance are costly, and both these costs turn out to be density dependent. These tradeoffs can explain the existence of genetic variation. We briefly touch upon behavioral aspects of the interaction and the parasites and pathogens that the parasitoids themselves suffer from. We end this chapter by considering the data coming from gene chip experiments: early indications suggest that the genes involved in the actual immune response against parasitoids are mostly different from the genes involved in the evolution of resistance. PMID- 19773075 TI - Local, geographic and phylogenetic scales of coevolution in Drosophila-parasitoid interactions. AB - In this chapter, we describe the geographically widespread genetic fixation of traits involved in Drosophila-parasitoid immune interactions and the situations where such fixation is not observed. We then discuss how the three classes of coevolutionary dynamics that can occur at the local scale (coevolutionary escalation, coevolutionary alternation and coevolutionary polymorphism), the geographic mosaic of selection, and the phylogenetic constraints may explain such evolutionary patterns and drive diversification in the interactions. Most Drosophila parasitoid traits involved in virulence are host-species specific. Directional selection (coevolutionary escalation) on such traits can lead to their fixation or on the contrary maintain their polymorphism if these traits are associated with fitness costs. When hosts targeted by different host-specific virulence systems coexist, fluctuations in selective pressures on these systems, together with the ability of Drosophila parasitoids to select the most susceptible host for parasitization, can lead to coevolutionary alternation. Finally, we discuss the potential for parasitoid diversification in relation with the fact that most observed geographic situations, for different parasitoid clades, correspond to coevolutionary cold spots, due to fixation of virulence in parasitoid taxa. PMID- 19773076 TI - Drosophila-parasitoid communities as model systems for host-Wolbachia interactions. AB - Wolbachia bacteria are cytoplasmic endosymbionts that infect a wide range of arthropod and nematode hosts. They are transmitted from mother to offspring via the eggs (vertical transmission) and enhance their transmission to the next generation by manipulating the reproductive system of their hosts. These manipulations occur in many forms, such as the induction of cytoplasmic incompatibility, feminization, male killing and parthenogenesis induction. Wolbachia is estimated to occur in up to 66% of all insect species, but the greatest diversity of reproductive manipulations is found in the order of the Hymenoptera. Studies of Wolbachia in Drosophila-parasitoid communities have allowed for important insights into different aspects of Wolbachia biology. The extensive knowledge available on Drosophila parasitoids provides a solid base on which to test new hypotheses on host-Wolbachia interactions. The large range of Wolbachia phenotypes present in Drosophila parasitoids, combined with the recent acquisition of the bacteria from their Drosophilid hosts, make them an ideal model system to study the evolution and dynamics of Wolbachia infections, both in the laboratory as in the field. In this chapter, we aim to review the current knowledge on the associations between Wolbachia and Drosophila parasitoids, and identify open questions and specify new research directions. PMID- 19773077 TI - A virus-shaping reproductive strategy in a Drosophila parasitoid. AB - Insect parasitoids are often infected with heritable viruses. Some of them, such as polydnaviruses, have evolved toward an obligatory relationship with the parasitoid because they are necessary to protect the parasitoid egg from the host immune reaction. However, recent and past discoveries have revealed the presence of facultative inherited viruses in parasitoids for which no clear phenotypic effect was observed. In this chapter, we present how such an inherited virus was recently discovered in the Drosophila parasitoid, Leptopilina boulardi. We show that this virus is responsible for an increase in the superparasitism tendency of the infected females. This alteration is beneficial for the virus, since superparasitism conditions permit the horizontal transmission of the virus. We review theoretical developments suggesting that this leads to a conflict of interest between the parasitoid and the virus. The direct and indirect influence of the virus on several other fitness traits has also been studied both empirically and theoretically, in particular the egg load. Finally, because the frequency of horizontal transmission is a crucial parameter for the evolution of the superparasitism manipulation, we present an attempt to select the virus for high or low manipulation intensity. PMID- 19773078 TI - Temporal variability of benthic communities in an Alaskan glacial fjord, 1971 2007. AB - Temporal trends of deep-subtidal macrofauna in Port Valdez, Alaska, were assessed with respect to multiple environmental stressors. Effects from a magnitude 9.2 earthquake in Prince William Sound, Alaska, 1964, were reflected in recolonization of the basin of the fjord, increased abundance and number of taxa over time, and moderately increased variability in abundance through 1990, stabilizing 26years after the earthquake. Long-term climatic variability and local physical processes were important sources of spatial and temporal variability. Correlative evidence suggests that indirect effects of juvenile salmon from a shoreline salmon hatchery and deposition of adult salmon carcasses moderately enhanced deep-basin benthic communities. Effects on the deep benthos from a marine oil terminal were negligible. Overall, faunal trends deviated from the stability expected for benthic communities in other fjords. Physical characteristics of the fjord were important in mediating the effects of stressors and in delaying the readjustment process. PMID- 19773079 TI - Plutonium isotopes as tracers for ocean processes: a review. AB - Since the first nuclear weapons tests in the 1940s, pulsed inputs of plutonium isotopes have served as excellent tracers for understanding sources, pathways, dynamics and the fate of pollutants and particles in the marine environment. Due to the well-defined spatial and temporal inputs of Pu, the long half-lives of (240)Pu and (239)Pu and its unique chemical properties, Pu is a potential tracer for various physical and biogeochemical ocean processes, including circulation, sedimentation and biological productivity, and hence a means of assessing the impacts of global climate change. Due to the source dependency of the Pu isotopic signature, plutonium isotopes are beginning to be exploited as tools for the evaluation and improvement of regional and global ocean models that will enhance understanding of past and future changes in the oceans. This paper addresses the major sources of Pu and the physical and biogeochemical behaviour in the marine environment. Finally, the use of Pu isotopes as tracers for various oceanic processes (e.g. water mass transport, particle export, and sedimentation) is considered. PMID- 19773080 TI - Bortezomib in combination with dexamethasone and subsequent thalidomide for newly diagnosed multiple myeloma: a Chinese experience. AB - OBJECTIVE: Bortezomib-dexamethasone-thalidomide has been reported to be effective in newly-diagnosed multiple myeloma (MM) with an overall response rate of 92% and a CR rate of 18% (Alexanian et al, Hematology 2007;12(3):235-9), but this regimen has not been tested in the Chinese patients. We report here our results testing with this combination in the Chinese population and to investigate the efficacy and safety of bortezomib in combination of dexamethasone plus subsequent thalidomide as primary treatment for MM. METHODS: Between June 2006 and March 2008, 20 consecutive newly-diagnosed patients with symptomatic MM were treated with bortezomib at 1.3mg/m(2) IV on days 1, 4, 8 and 11 and dexamethasone at 20mg/m(2) IV daily on the day of bortezomib and the day after. All patients received daily oral thalidomide that was escalated from 100mg to 200mg. Fourteen patients were male and 6 were female. Median age was 59 years (range 43-86 years). 11 patients were stage 2 according to the International Staging System, 8 were stage 3, only 1 patient was stage 1. All patients received a median of two cycles of therapy (range 1-6). The EBMT criteria were used for response evaluation. Toxicities were evaluated according to the NCI Common Toxicity Criteria version 3. RESULTS: 16 out of 20 patients (80%) achieved PR and 3 (15%) achieved CR; therefore the overall response rate was 95%. With a median follow-up duration of 7.8 months (4-22 months), no patients died. Grade 3-4 toxicities included fatigue (3/20), thrombocytopenia (10/20) diarrhea (5/20) and orthostatic hypotension (3/20) Grade 2 neuropathy occurred in four out of 20 patients and herpes zoster occurred in four out of 20 patients. Routine anticoagulation or anti-thrombosis was not used. Only 1 patient suffered from DVT/PE. CONCLUSIONS: Our preliminary experience in Chinese patients indicated that bortezomib dexamethasone-thalidomide is highly effective in newly-diagnosed MM. Grade three and 4 toxicities are rare after median 2 cycles of therapy. The relative lower rates of neuropathy and DVT/PE in the Chinese patients with MM are being cautiously observed. PMID- 19773082 TI - Acute myeloid leukemia initially presenting as hemophagocytic lymphohistiocytosis -a case report and review of the literature. PMID- 19773081 TI - Triblock copolymer coated iron oxide nanoparticle conjugate for tumor integrin targeting. AB - A key challenge in developing nanoplatform-based molecular imaging is to achieve an optimal pharmacokinetic profile to allow sufficient targeting and to avoid rapid clearance by the reticuloendothelial system (RES). In the present study, iron oxide nanoparticles (IONPs) were coated with a PEGylated amphiphilic triblock copolymer, making them water soluble and function-extendable. These particles were then conjugated with a near-infrared fluorescent (NIRF) dye IRDye800 and cyclic Arginine-Glycine-Aspartic acid (RGD) containing peptide c(RGDyK) for integrin alpha(v)beta(3) targeting. In vitro binding assays confirmed the integrin-specific association between the RGD-particle adducts and U87MG glioblastoma cells. Successful tumor homing in vivo was perceived in a subcutaneous U87MG glioblastoma xenograft model by both magnetic resonance imaging (MRI) and NIRF imaging. Ex vivo histopathological studies also revealed low particle accumulation in the liver, which was attributed to their compact hydrodynamic size and PEGylated coating. In conclusion, we have developed a novel RGD-IONP conjugate with excellent tumor integrin targeting efficiency and specificity as well as limited RES uptake for molecular MRI. PMID- 19773083 TI - Imatinib achieved complete cytogenetic response in a CML patient received 32-year indirubin and its derivative treatment. PMID- 19773085 TI - Regulation of membrane progestin receptors in the zebrafish ovary by gonadotropin, activin, TGF-beta and BMP-15. AB - Progestin hormones are vital for inducing oocyte maturation in fish by binding to membrane progestin receptors (mPRs). The aim of this study was to examine the expression and regulation of mPRalpha and mPRbeta in zebrafish follicles. First, defolliculated fully grown oocytes were subjected to immunofluorescent staining using anti-mPRalpha and mPRbeta antibodies, and their expression on the oocyte membrane was confirmed. Second, total protein was collected from zebrafish follicles and Western blotting revealed that the level of mPRalpha and mPRbeta increased with follicle development. We have previously shown that several members of the transforming growth factor-beta (TGF-beta) superfamily, including TGF-beta1, activin-A, and bone morphogenetic protein (BMP)-15, regulate oocyte maturation in zebrafish. Therefore, the third major focus of this study was to test if these growth factors, as well as gonadotropins, regulate the expression of mPRs. Overexpression of BMP-15 significantly reduced, while knockdown of BMP 15 increased, mPRbeta levels. However, mPRalpha expression level remained unchanged with BMP-15 overexpression or knockdown. Treatment of follicles with human chorionic gonadotropin (hCG) resulted in an increased in mPRbeta, but not mPRalpha, expression levels. Activin-A induced the expression of mPRalpha and mPRbeta in a dose- and time-dependent manner. On the other hand, TGF-beta1 treatment suppressed the expression of mPRbeta, but not mPRalpha. Taken together, these findings further support the role of mPRs in oocyte maturation and suggest that gonadotropins, BMP-15, activin-A, and TGF-beta1 exert their regulatory effects on oocyte maturation in part by regulating mPR expression. PMID- 19773084 TI - Molecular mechanism underlying the suppression of lipid oxidation during endotoxemia. AB - Although both inflammatory and metabolic complications occur during sepsis and endotoxemia, relatively few studies have examined the molecular mechanism underlying LPS-modulated metabolic changes during sepsis. In this report, we have demonstrated that LPS suppresses free fatty acid (FFA) oxidation, and consequently contributes to elevated plasma levels of FFA and triglyceride (TG). Furthermore, this process depends upon the interleukin-1 receptor associated kinase 1 (IRAK-1), one of the key TLR4 intracellular signaling kinases. IRAK-1(-/ ) mice fail to exhibit the dramatic rise in plasma FFA and TG levels compared to wild-type (WT) mice following lethal LPS injection. Mechanistically, we demonstrated that LPS suppresses FFA oxidation through decreasing the expression levels of key FFA oxidative genes including CPT-1 and MCAD in both liver and kidney tissues of WT but not IRAK-1(-/-) mice. The expression of CPT-1 and MCAD is controlled by nuclear receptors and co-receptors including PPARalpha and PGC 1alpha. We observed that LPS selectively suppresses the levels of PPARalpha and PGC-1alpha in tissues from WT, but not IRAK-1(-/-) mice. Consequently, IRAK-1(-/ ) mice have a higher survival rate following a lethal dose of LPS. Our current study reveals a novel role for IRAK-1 in the metabolic alterations induced by LPS. PMID- 19773086 TI - Dysfunctional beliefs in bipolar disorder: hypomanic vs. depressive attitudes. AB - BACKGROUND: To date the effect of cognitive behavioural therapy modified for bipolar disorder has been inconsistent and sometimes disappointing. However studies exploring cognitive style in bipolar disorder have not identified the unique patterns of beliefs specific to bipolar disorder. The current study examines whether Mansell's hypomania-related dysfunctional belief scale specifically identifies bipolar disorder patients. METHOD: Forty remitted bipolar patients, twenty remitted unipolar patients and twenty healthy controls completed the Hypomanic Attitudes and Positive Prediction Inventory (HAPPI) and the Dysfunctional Attitude Scale (DAS). RESULTS: The remitted bipolar group scored higher than the unipolar and healthy control groups on the HAPPI scale overall score and on three subscales that measured self-catastrophic beliefs, beliefs related to negative responses from other people when in elevated mood and beliefs related the response style to activation and elevation. CONCLUSION: The study finds evidence of unique dysfunctional beliefs elevated only in remitted bipolar patients. Such findings could be used to inform the development of a specific cognitive behavioural therapy for bipolar disorder. PMID- 19773087 TI - Interferon-beta therapy for multiple sclerosis--is the injection site the relevant action site? AB - Multiple sclerosis (MS) has been characterized as a T cell-mediated autoimmune disease. Recent research on the immunopathology of MS has implicated dendritic cells, professional antigen-presenting cells essential for T cell differentiation and proliferation of self-reactive T cells. Interferon-beta therapy effectively reduces relapse rates in MS and can slow the progression of disability in patients with relapsing-remitting MS. The principal mechanism by which interferon beta drugs exert their effect is unclear; however, it is possible that an interaction with dendritic cells local to the site of injection may be critical. Most subcutaneously administered interferon-beta never leaves the injection site. This article reviews current concepts on the immunopathogenesis of MS and presents the hypothesis that the main effect of interferon-beta in MS is mediated by local effects on dendritic cells at the injection site. PMID- 19773088 TI - Simultaneous detection and quantitation of Chikungunya, dengue and West Nile viruses by multiplex RT-PCR assays and dengue virus typing using high resolution melting. AB - Chikungunya (CHIKV), Dengue (DENV) and West Nile (WNV) viruses are arthropod borne viruses that are able to emerge or re-emerge in many regions due to climatic changes and increase in travel. Since these viruses produce similar clinical signs it is important for physicians and epidemiologists to differentiate them rapidly. A molecular method was developed for their detection and quantitation in plasma samples and a DENV typing technique were developed. The method consisted in performing two multiplex real-time one-step RT-PCR assays, to detect and quantify the three viruses. Both assays were conducted in a single run, from a single RNA extract containing a unique coextracted and coamplified composite internal control. The quantitation results were close to the best detection thresholds obtained with simplex RT-PCR techniques. The differentiation of DENV types was performed using a High Resolution Melting technique. The assays enable the early diagnosis of the three arboviruses during viremia, including cases of coinfection. The method is rapid, specific and highly sensitive with a potential for clinical diagnosis and epidemiological surveillance. A DENV positive sample can be typed conveniently using the High Resolution Melting technique using the same apparatus. PMID- 19773089 TI - Genotoxicity of cigarette smoking in maternal and newborn lymphocytes. AB - Tobacco smoke contains a large number of substances known to induce DNA damage and to be hazardous to human health. Several reviews and meta-analyses have reported an association between maternal or paternal smoking habits and genetic related diseases, such as cancer, in children. The aim of the present study was to evaluate the level of DNA damage in lymphocytes of active- and passive-smoking mothers and in their newborns, using the comet assay. A total of 40 active smokers, 40 passive smokers, and 40 non-smokers, and their respective newborns, were evaluated. The active smokers presented a statistically significant increase of DNA damage when compared to the non-smokers and passive-smokers. No significant difference was observed between passive and non-smoking women. Similar results were detected in newborns. Those born to active-smoking mothers presented higher levels of DNA damage than those from passive- and non-smoking mothers. Additionally, no significant difference was detected between newborns from non-smoking and passive-smoking mothers. Also, no statistically significant difference in DNA damage was observed between mothers and their respective newborns, and a positive correlation in the level of DNA damage was detected between them. Logistic regression analyses showed positive associations between DNA damage, spontaneous abortion and smoking status. In conclusion, our data indicate that tobacco exposure during pregnancy has genotoxic effects for both mother and child, and it can be considered an important risk factor for childhood cancer or other genetic-related diseases. PMID- 19773090 TI - Setting priorities for safe motherhood interventions in resource-scarce settings. AB - OBJECTIVE: Guide policy-makers in prioritizing safe motherhood interventions. METHODS: Three models (LOW, MED, HIGH) were constructed based on 34 sub-Saharan African countries to assess the relative cost-effectiveness of available safe motherhood interventions. Cost and effectiveness data were compiled and inserted into the WHO Mother Baby Package Costing Spreadsheet. For each model we assessed the percentage in maternal mortality reduction after implementing all interventions, and optimal combinations of interventions given restricted budgets of US$ 0.50, US$ 1.00, US$ 1.50 per capital maternal health expenditures respectively for LOW, MED, and HIGH models. RESULTS: The most cost-effective interventions were family planning and safe abortion (fpsa), antenatal care including misoprostol distribution for postpartum hemorrhage prevention at home deliveries (anc-miso), followed by sepsis treatment (sepsis) and facility-based postpartum hemorrhage management (pph). CONCLUSIONS: The combination of interventions that avert the greatest number of maternal deaths should be prioritized and expanded to cover the greatest number of women at risk. Those which save the most number of lives in each model are 'fpsa, anc-miso' and 'fpsa, sepsis, safe delivery' for LOW; 'fpsa, anc-miso' and 'fpsa, sepsis, safe delivery' for MED; and 'fpsa, anc-miso, sepsis, eclampsia treatment, safe delivery' for HIGH settings. Safe motherhood interventions save a significant number of newborn lives. PMID- 19773091 TI - Protective effects of interleukin-6 in lipopolysaccharide (LPS)-induced experimental endotoxemia are linked to alteration in hepatic anti-oxidant enzymes and endogenous cytokines. AB - Endogenous interleukin-6 has been considered as an important anti-inflammatory cytokine controlling both local and systemic acute inflammatory responses; the usefulness of IL-6 in endotoxemia aiming to block the production of reactive oxygen species and the release of inflammatory cytokines is under discussion The aim of the study was to evaluate the protective effects of IL-6 in experimentally induced endotoxemia in mice correlating the changes in tissue anti-oxidant enzymes and circulating cytokines. Liver injury in low-dose bacterial lipopolysaccharide (5 microg/mouse)-induced endotoxemic mice receiving IL-6 (300 ng/mouse) treatment either before or after LPS injection was detected by the estimation of serum oxaloacetate transaminase and serum glutamate pyruvate transaminase. This finding supports that liver injury during experimental endotoxemia could be lowered by IL-6. Current data also demonstrate the critical role of IL-6 in inducing SOD in liver, whereas IL-6 prior and after LPS challenge group showed reduced PMN infiltration in the liver as evident by decreased hepatic MPO content in those mice. IL-6 treatment also showed higher IL-10 production in serum than endotoxic group as IL-10 is a potent and pleiotropic anti-inflammatory cytokine that inhibits the synthesis of pro-inflammatory cytokines and also has a suppressive effect on pro-inflammatory cytokine like TNF alpha, IFN-gamma and IL-12. It is also directly involved in the modulation of other aspects of inflammation, particularly cytokine responses and inflammatory cell infiltration. PMID- 19773093 TI - [Traveler with multiple skin lesions of six months' evolution]. PMID- 19773094 TI - [Salmonella typhi bacteremia after biliary stenting]. PMID- 19773092 TI - Cystatin C is released in association with exosomes: a new tool of neuronal communication which is unbalanced in Alzheimer's disease. AB - It has recently become clear that proteins associated with neurodegenerative disorders can be selectively incorporated into intraluminal vesicles of multivesicular bodies and subsequently released within exosomes. Multiple lines of research support a neuroprotective role for cystatin C in Alzheimer's disease (AD). Herein we demonstrate that cystatin C, a protein targeted to the classical secretory pathway by its signal peptide sequence, is also secreted by mouse primary neurons in association with exosomes. Immunoproteomic analysis using SELDI-TOF MS revealed the presence in exosomes of at least 9 different cystatin C glycoforms. Moreover, the over-expression of familial AD-associated presenilin 2 mutations (PS2 M239I and PS2 T122R) resulted in reduced levels of all cystatin C forms (native and glycosylated) and of amyloid-beta precursor protein (APP) metabolites within exosomes. A better understanding of the mechanisms involved in exosomal processing and release may have important implications for the fight against AD and other neurodegenerative diseases. PMID- 19773095 TI - [Evaluation of two immunochromatographic tests for the detection of anti Treponema pallidum antibodies]. PMID- 19773096 TI - Development of a sexual assault evidence collection kit - the need for standardization in Turkey. AB - Sexual offences are recognized to be one of the most critical of crimes throughout the world. In Turkey, forcible rapes show, in the sexual crime rates, an increase of approximately 3% every year. It becomes even more critical, when realizing that less than half of all rapes, which are believed to occur, are reported to law enforcement, and of those few assailants who are arrested even fewer are convicted of rape. Often, little or no knowledge of the correct methods of locating, recovering, packaging, and preserving evidence specimens are the causes for compromising the forensic examination in court. This problem occurs when medical personnel are not adequately trained or properly advised in the evidentiary aspects and medical features of treating a victim. The current survey is aimed to increase the awareness of the need of an initial and continuing education by health care policies to cope with increasing professional demands for forensic practice sexual assault cases, to take judicial and social precautions, and medico-legal evidence. To determine the likelihood of obtaining corroborating evidence this paper presents the results of a study referring to this problem. An updated questionnaire has been applied at random to medical personnel, a total of 543 participants, throughout Turkey. Taking certain criteria into consideration the findings revealed a significant deficiency of knowledge regarding medical-legal examination. In comparison, a one-semester course of basic forensic sciences proved to be sufficient to recognize the amount of knowledge required to work as a forensic professional. Based on the results, recommendations are presented in the form of a sexual assault evidence collection kit (SAECK). A kit, which takes into consideration the needs of crime laboratories, law enforcement agencies, medical personnel, and above all the victim. This is the first step in building a responsible and successful evidence collection program that will survive the rigors of courtroom challenge. PMID- 19773097 TI - Growth hormone and protein metabolism. AB - Growth hormone (GH) and intracellular STAT 5 signalling represents a very old regulatory system and, whereas insulin dominates periprandially, GH may be viewed as the primary anabolic hormone during stress and fasting. GH exerts metabolic effects both directly and through stimulation of IGF-I, insulin, and free fatty acids (FFA). When well nourished the GH-induced stimulation of IGF-I and insulin is important for tissue anabolism whereas during fasting and other catabolic states GH predominantly stimulates the release and oxidation of FFA which leads to decreased glucose and protein oxidation and preservation of LBM. The most prominent metabolic effect of GH is a marked increase in lipolysis and FFA levels. In the periprandial and postabsorptive states the effects of GH on protein metabolism are modest and include increased protein synthesis and decreased breakdown at the whole body level and in muscle together with decreased amino acid degradation/oxidation and decreased hepatic urea formation. During fasting and stress the effects of GH on protein metabolism become more pronounced; lack of GH during fasting increases protein loss and urea production rates by approximately 50% with a similar increase in muscle protein breakdown. The importance of GH is further substantiated by the observations that adult patients with GH-deficiency are obese and have reduced LBM, and impaired physical performance and acromegaly is characterised by increased LBM and decreased fat mass. PMID- 19773098 TI - Safety and immunogenicity of inactivated, Vero cell culture-derived whole virus influenza A/H5N1 vaccine given alone or with aluminum hydroxide adjuvant in healthy adults. AB - Dosage-sparing strategies, adjuvants and alternative substrates for vaccine production are being explored for influenza vaccine development. We assessed the safety and immunogenicity of a Vero cell culture-grown inactivated whole virus influenza A/H5N1 vaccine with or without aluminum hydroxide adjuvant [Al(OH)(3)] in healthy young adults. Vaccines were well tolerated, but injection site discomfort was more frequent in groups receiving Al(OH)(3). Dose-related increases in serum antibody levels were observed. Neutralizing antibody titers varied significantly when tested by two different laboratories. Al(OH)(3) did not enhance HAI or neutralizing antibody responses, and contributed to increased injection site pain. Because influenza antibody titers vary significantly between different laboratories, international standardization of assays is warranted. PMID- 19773099 TI - Birth after caesarean section: changes over a nine-year period in one Australian state. AB - OBJECTIVES: to describe the outcomes related to birth after a caesarean section (CS) in one Australian state, New South Wales (NSW), over a nine-year period. The objectives were to determine whether changes had occurred in the rates of attempted and successful vaginal birth after caesarean section (VBAC), induction of labour, place of birth, admission to special care or neonatal intensive care nursery and perinatal mortality. DESIGN AND SETTING: cross-sectional analytic study of hospital births in New South Wales using population-based data from 1998 2006. PARTICIPANTS: women experiencing the next birth after a CS where: the total number of previous CS was 1; the presentation at birth was vertex; it was a singleton pregnancy; and, the estimated gestational age was greater than or equal to 37 weeks. A total of 53,455 women met these criteria. MEASUREMENTS: data were obtained from NSW Health Department's Midwives Data Collection (MDC). The MDC includes all live births and stillbirths of at least 20 weeks gestation or 400g birth weight in the state. FINDINGS: over the nine-year period, the rate of vaginal birth after caesarean section declined significantly (31-19%). The proportion of women who 'attempted a vaginal birth' also declined (49-35%). Of those women who laboured, the vaginal birth rate declined from 64% to 53%. Babies whose mothers 'attempted' a VBAC were significantly less likely to require admission to a special care nursery (SCN) or neonatal intensive care (NICU). The perinatal mortality rate in babies whose mothers 'attempted' a VBAC was higher than those babies born after an elective caesarean section although the absolute numbers are very small. KEY CONCLUSIONS: rates of VBAC have declined over this nine-year period. Rates of neonatal mortality and proxy measures of morbidity (admission to a nursery) are generally in the low range for similar settings. IMPLICATIONS FOR PRACTICE: decisions around the next birth after CS are complex. Efforts to keep the first birth normal and support women who have had a CS to have a normal birth need to be made. More research to predict which women are likely to achieve a successful VBAC and the most effective ways to facilitate a VBAC is essential. Midwives have a critical role to play in these endeavours. PMID- 19773100 TI - Role of gender in sexual behaviours and response to education in sexually transmitted infections in 17-year-old adolescents. AB - OBJECTIVE: to investigate gender differences in high school students with respect to sexual risk behaviours, and their perceptions of the effect of an educational programme on sexually transmitted infections (STIs). In addition, this study aimed to investigate differences between students in programmes preparing for university compared with vocational programmes. PARTICIPANTS, SETTING AND DESIGN: second-year high school adolescents from two communities in south-west Sweden were invited to participate in the study, and completed a questionnaire on sexual experience, sexual risk behaviours and the impact of the educational programme on STIs. FINDINGS: males took less responsibility for STI prevention than females. Furthermore, males perceived themselves to be less influenced by the STI education than females. Females had more experience of same-sex sexuality than males. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: males take less responsibility for STI prevention than females. When planning STI education, it is important to consider gender, traditions and various learning styles. If STI education fails to reach males, the prevalence of these infections will continue to increase. PMID- 19773101 TI - Effects of unplanned pregnancy on maternal health in Turkey. AB - OBJECTIVE: to investigate the effects of unplanned pregnancy on maternal health in Turkey. DESIGN: a case-control study. SETTING: a government hospital in Aydin, Turkey. PARTICIPANTS: 314 women in the early postpartum period, selected with a non-probability method. FINDINGS: significantly more women with unplanned pregnancy had physical problems (76.4% vs. 63.7%; p<0.01) and lower haemoglobin levels (11.26+/-1.27g/dl vs. 11.62+/-1.27g/dl; p<0.01) compared with women with planned pregnancy. Also, significantly more women with unplanned pregnancy had lower scores for adaptive behaviour in pregnancy (14.78+/-3.08 vs. 19.19+/-3.11; p<0.001), felt negative feelings during labour (mean scores on Labour Agentry Scale: 81.03+/-19.07 vs. 98.64+/-16.94; p<0.001), felt more severe pain during labour (mean rank: 173.21 vs. 141.79, p<0.001), and were at high risk of depression in the early postpartum period (mean scores on Edinburgh Postpartum Depression Scale: 14.86+/-6.08 vs. 7.28+/-4.85; p<0.001) compared with women with planned pregnancy. KEY CONCLUSIONS: unplanned pregnancy has a negative impact on the development of positive behaviour concerning self-care, physical well-being, labour experience, pain in labour and psychological status in the early postpartum period. IMPLICATIONS FOR PRACTICE: midwives and nurses should identify women with unplanned pregnancy at an early stage, and try to decrease the negative effects of unplanned pregnancy on maternal health and to improve prenatal, perinatal and postnatal care. PMID- 19773102 TI - Crying babies, tired mothers: what do we know? A systematic review. AB - OBJECTIVE: to synthesise the evidence on the interconnectedness of infant crying and maternal tiredness in the postpartum period, both from quantitative as well as from qualitative studies. METHODS: a systematic review was conducted including studies in English, French and German published from 1980 to 2007. Studies were included in the systematic review if they had extractable data on infant crying as well as maternal tiredness in the period of 0-3 months post partum. Of 100 retrieved publications, 10 met these criteria. FINDINGS: evidence from this review indicated that the amount of infant crying during the first three months postpartum is associated with the experience of tiredness and fatigue in new mothers. Significant associations were found in five of six quantitative studies. The four identified qualitative studies describe how infant crying disrupts new mothers' circadian rhythms, reducing opportunities to rest and exacerbating tiredness. Incremental exhaustion diminished parents' ability to concentrate, raising the fear of harming their children, triggering depressive symptoms and burdening parent-child interaction. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: if healthcare professionals are to address the prominent concerns of parents caring for a neonate, it is essential to review current care practices and tailor them to maternal and infant needs. A care strategy alleviating the burden of infant crying and maternal fatigue has the potential to strengthen family health from the earliest stage. PMID- 19773103 TI - Migration of heavy metals in soil as influenced by compost amendments. AB - Soils contaminated with heavy metals can pose a major risk to freshwaters and food chains. In this study, the success of organic and inorganic intervention strategies to alleviate toxicity in a highly acidic soil heavily contaminated with As, Cu, Pb, and Zn was evaluated over 112 d in a mesocosm trial. Amelioration of metal toxicity was assessed by measuring changes in soil solution chemistry, metal leaching, plant growth, and foliar metal accumulation. Either green waste- or MSW-derived composts increased plant yield and rooting depth, reduced plant metal uptake, and raised the pH and nutrient status of the soil. We conclude that composts are well suited for promoting the re-vegetation of contaminated sites; however, care must be taken to ensure that very short-term leaching pulses of heavy metals induced by compost amendment are not of sufficient magnitude to cause contamination of the wider environment. PMID- 19773104 TI - Spatial soil zinc content distribution from terrain parameters: a GIS-based decision-tree model in Lebanon. AB - Heavy metal contamination has been and continues to be a worldwide phenomenon that has attracted a great deal of attention from governments and regulatory bodies. In this context, our study proposes a regression-tree model to predict the concentration level of zinc in the soils of northern Lebanon (as a case study of Mediterranean landscapes) under a GIS environment. The developed tree-model explained 88% of variance in zinc concentration using pH (100% in relative importance), surroundings of waste areas (90%), proximity to roads (80%), nearness to cities (50%), distance to drainage line (25%), lithology (24%), land cover/use (14%), slope gradient (10%), conductivity (7%), soil type (7%), organic matter (5%), and soil depth (5%). The overall accuracy of the quantitative zinc map produced (at 1:50.000 scale) was estimated to be 78%. The proposed tree model is relatively simple and may also be applied to other areas. PMID- 19773105 TI - Expression of alkane monooxygenase (alkB) genes by plant-associated bacteria in the rhizosphere and endosphere of Italian ryegrass (Lolium multiflorum L.) grown in diesel contaminated soil. AB - For phytoremediation of organic contaminants, plants have to host an efficiently degrading microflora. To assess the role of endophytes in alkane degradation, Italian ryegrass was grown in sterile soil with 0, 1 or 2% diesel and inoculated either with an alkane degrading bacterial strain originally derived from the rhizosphere of Italian ryegrass or with an endophyte. We studied plant colonization of these strains as well as the abundance and expression of alkane monooxygenase (alkB) genes in the rhizosphere, shoot and root interior. Results showed that the endophyte strain better colonized the plant, particularly the plant interior, and also showed higher expression of alkB genes suggesting a more efficient degradation of the pollutant. Furthermore, plants inoculated with the endophyte were better able to grow in the presence of diesel. The rhizosphere strain colonized primarily the rhizosphere and showed low alkB gene expression in the plant interior. PMID- 19773106 TI - Emissions of biogenic VOC from forest ecosystems in central Europe: estimation and comparison with anthropogenic emission inventory. AB - This paper describes a method of estimating emission fluxes of biogenic volatile organic compounds (BVOCs) based on the approach proposed by Guenther et al. (1995) and the high-resolution Corine land-cover 2000 database (1x1km resolution). The computed emission fluxes for the Czech Republic (selected for analysis as being representative of a heavily cultivated, central European country) are compared with anthropogenic emissions, both for the entire country and for individual administrative regions. In some regions, BVOC emissions are as high as anthropogenic emissions; however, in most regions the BVOC emissions are approximately 50% of the anthropogenic emissions. The yearly course of BVOC emissions (represented by monoterpenes and isoprene) is presented, along with the spatial distribution of annual mean values. Differences in emission distributions during winter (January) and summer (June) are also considered. PMID- 19773107 TI - Do birth cohorts matter? Age-period-cohort analyses of the obesity epidemic in the United States. AB - Many studies have cited the importance of secular changes or "period effects" as causes of the U.S. obesity epidemic. Unfortunately, relatively little attention has been devoted to the possible influence of cohort-related mechanisms. To address this current gap in the scientific literature, this investigation utilized the responses from 1.7 million participants in the 1976-2002 National Health Interview Surveys to determine how birth cohorts may have contributed to the rapid increase in the prevalence of obesity. Results from hierarchical age period-cohort (HAPC) models confirmed that period effects are principally responsible for the U.S. obesity epidemic. However, HAPC models also demonstrated that birth cohort membership is influential. Independent of age and period effects, the predicted probability of obesity at age 25 increased by 30% for cohorts born between 1955 and 1975. Our results also showed that age, period and cohort effects varied by race/gender and educational attainment. For instance, increases in the predicted probabilities of obesity were particularly sharp for recent cohorts of Black females. Our investigation successfully demonstrated that both secular change and birth cohort membership have independently contributed to elevated odds of obesity among recent generations of Americans, suggesting that cohort-specific strategies may be needed to combat disconcertingly high rates of obesity in the U.S. PMID- 19773108 TI - The influence of perceptual and semantic categorization on inhibitory processing as measured by the N2-P3 response. AB - In daily activities, humans must attend and respond to a range of important items and inhibit and not respond to unimportant distractions. Our current understanding of these processes is largely based on perceptually simple stimuli. This study investigates the interaction of conceptual-semantic categorization and inhibitory processing using Event Related Potentials (ERPs). Participants completed three Go-NoGo tasks that increased systematically in the degree of conceptual-semantic information necessary to respond correctly (from single items to categories of objects and animals). Findings indicate that the N2 response reflects inhibitory processing but does not change significantly with task difficulty. The P3 NoGo amplitude, on the other hand, is attenuated by task difficulty. Further, the latency of the peak of the P3 NoGo response elicited by the most difficult task is significantly later than are the peaks detected during performance of the other two tasks. Thus, the level of complexity of conceptual semantic representations influences inhibitory processing in a systematic way. This inhibition paradigm may be a key for investigating inhibitory dysfunction in patient populations. PMID- 19773109 TI - Contribution and limit of the model of perfused cotyledon to the study of placental transfer of drugs. Example of a protease inhibitor of HIV: nelfinavir. AB - OBJECTIVES: The perfused cotyledon model is a very useful method to study placental transfer of drugs. Here we studied placental transfer of the human immunodeficiency virus protease inhibitor nelfinavir using the non-recirculating dual human placental perfusion with a main goal to determining the clearance index of nelfinavir as related to maternal concentrations, and analyze the conditions under which ex vivo and in vivo data can be correlated. STUDY DESIGN: Thirteen human cotyledons, obtained after uneventful term pregnancies, were perfused in an open double circuit with nelfinavir (320-4436 microg/l) and a freely diffusing marker antipyrine 20 mg/l, in the presence of an albumin concentration of 2 g/l. Drug concentrations were determined by high-performance liquid chromatography. RESULTS: The mean clearance index of nelfinavir was very weak when maternal concentrations were under 500 microg/l (0.03+/-0.05). For maternal concentrations above 1200 microg/l, the mean fetal transfer rate was 14+/-3.4%, the mean clearance index was 0.39+/-0.10 and the fetal concentrations were between 133 and 671 microg/l. There was a good correlation between maternal and fetal concentrations (r=0.86; p<0.001). CONCLUSIONS: Our study with nelfinavir has achieved a good correlation between ex vivo and in vivo data. Our results also indicate that studies must be conducted under well defined conditions to obtain accurate and comparable data, underlining the fact that the ex vivo perfused cotyledon remains difficult to standardize as a model system. PMID- 19773110 TI - Advanced maternal age and adverse perinatal outcomes in an Asian population. AB - OBJECTIVE: To investigate (1) whether there is an increasing trend in the mean maternal age at the birth of the first child and in the group of women giving birth at age 35 or older, and (2) the association between advanced maternal age and adverse perinatal outcomes in an Asian population. STUDY DESIGN: We conducted a retrospective cohort study involving 39,763 Taiwanese women who delivered after 24 weeks of gestation between July 1990 and December 2003. Multivariable logistic regression was used to adjust for potential confounding variables. RESULTS: During the study period, the mean maternal age at the birth of the first child increased from 28.0 to 29.7 years, and the proportion of women giving birth at age 35 or older increased from 11.4% to 19.1%. Compared to women aged 20-34 years, women giving birth at age 35 or older carried a nearly 1.5-fold increased risk for pregnancy complications and a 1.6-2.6-fold increased risk for adverse perinatal outcomes. After adjusting for the confounding effects of maternal characteristics and coexisting pregnancy complications, women aged 35-39 years were at increased risk for operative vaginal delivery (adjusted odds ratio [OR] 1.5, 95% confidence interval [CI] 1.2-1.7) and cesarean delivery (adjusted OR 1.6, 95% CI 1.5-1.7), while women aged 40 years and older were at increased risk for preterm delivery (before 37 weeks of gestation) (adjusted OR 1.7, 95% CI 1.3 2.2), operative vaginal delivery (adjusted OR 3.1, 95% CI 2.0-4.6), and cesarean delivery (adjusted OR 2.6, 95% CI 2.2-3.1). In those women who had a completely uncomplicated pregnancy and a normal vaginal delivery, advanced maternal age was still significantly associated with early preterm delivery (before 34 weeks of gestation), a birth weight <1500 g, low Apgar scores, fetal demise, and neonatal death. CONCLUSION: In this population of Taiwanese women, there is an increasing trend in the mean maternal age at the birth of the first child. Furthermore, advanced maternal age is independently associated with specific adverse perinatal outcomes. PMID- 19773111 TI - Breast cancer during pregnancy. AB - Breast cancer in pregnancy is an uncommon situation but poses dilemmas for patients and their physicians. There is a paucity of prospective studies regarding diagnosis and treatment of breast cancer during pregnancy. Women diagnosed with breast cancer during pregnancy have similar disease characteristics to age-matched controls. Current evidence suggests that diagnosis may be carried out with limitations regarding staging. Surgical treatment may be performed as for non-pregnant women. Radiotherapy and endocrine or antibody treatment should be postponed until after delivery. Chemotherapy is allowed after the first trimester. Physicians should be aggressive in the workup of breast symptoms in the pregnant population to expedite diagnosis and allow multidisciplinary treatment without delay. PMID- 19773112 TI - Exploration of Shh and BMP paracrine signaling in a prostate cancer xenograft. AB - Stromal-epithelial signaling is a critical regulator of normal prostate development and has been speculated to play an equally important role in the development and progression of prostate cancer. Sonic hedgehog (Shh) and bone morphogenetic proteins (BMP-4, BMP-7), expressed by the urogenital sinus epithelium and mesenchyme, exert reciprocal and coordinate effects on outgrowth of nascent prostate ducts. Over-expression of Shh in the LNCaP xenograft was shown previously to accelerate tumor growth by a paracrine mechanism. A survey of BMP regulators expressed in the developing prostate revealed increased Noggin and BMP-7 mRNA in the stromal component of Shh over-expressing xenografts. In vitro studies demonstrated that treatment of LNCaP cells with BMP-4 and BMP-s7 induced Id-1 expression and inhibited tumor cell proliferation. The activity of BMP-4 was abrogated by co-addition of Noggin; the activity of BMP-7 was not. Quantitative analysis of BMP signaling revealed ambivalent results: decreased tumor cell expression of the BMP response gene Id-1 but increased staining for phospho-SMAD 1,5, 8. To directly test whether increased xenograft tumor growth could be explained by Noggin-mediated blockade of BMP-2/4 effects on tumor cell proliferation, we generated LNCaP xenografts containing stromal cells over expressing Noggin. Tumor cells in these xenografts exhibited decreased Id-1 and reduced SMAD phosphorylation, but tumor growth was not altered. We conclude that tumor cell Shh expression can induce significant changes in expression of BMP ligands and inhibitors in the stromal microenvironment but that acceleration of LNCaP xenograft tumor growth by Shh over-expression cannot be attributed solely to increased Noggin expression in the tumor stroma. PMID- 19773114 TI - Re: Alberto Briganti, Michael L. Blute, James H. Eastham, et al. Pelvic lymph node dissection in prostate cancer. Eur urol 2009;55:1251-65. PMID- 19773115 TI - Adsorption of Zn2+ ions onto NaA and NaX zeolites: kinetic, equilibrium and thermodynamic studies. AB - The adsorption of Zn(2+) onto NaA and NaX zeolites was investigated. The samples were synthesized according to a hydrothermal crystallization using aluminium isopropoxide (Al[OCH(CH(3))(2)](3)) as a new alumina source. The effects of pH, initial concentration, solid/liquid ratio and temperature were studied in batch experiments. The Freundlich and the Langmuir models were applied and the adsorption equilibrium followed Langmuir adsorption isotherm. The uptake distribution coefficient (K(d)) indicated that the Zn(2+) removal was the highest at minimum concentration. Thermodynamic parameters were calculated. The negative values of standard enthalpy of adsorption revealed the exothermic nature of the adsorption process whereas the negative activation entropies reflected that no significant change occurs in the internal structure of the zeolites solid matrix during the sorption of Zn(2+). The negative values of Gibbs free energy were indicative of the spontaneity of the adsorption process. Analysis of the kinetic and rate data revealed that the pseudo second-order sorption mechanism is predominant and the intra particle diffusion was the determining step for the sorption of zinc ions. The obtained optimal parameters have been applied to wastewater from the industrial zone (Algeria) in order to remove the contained zinc effluents. PMID- 19773116 TI - Effective degradation of C.I. Acid Red 73 by advanced Fenton process. AB - The degradation of C.I. Acid Red 73 (AR 73) was investigated by advanced Fenton process based on zero-valent iron and hydrogen peroxide. The effect of zero valent iron dosage, hydrogen peroxide concentration, initial pH, initial dye concentration, mixing rate and temperature on the degradation of AR 73 was studied. The results showed that AR 73 removal efficiency increased with the increase of zero-valent iron addition, hydrogen peroxide concentration, mixing rate and temperature, but decreased with the increase of initial pH value. The residual concentration of AR 73 was only 6.4 mg/L after 30 min treatment at optimum conditions for 200.0mg/L AR 73 initial concentration. And advanced Fenton process can partly remove COD values of AR 73. The activation energy of the degradation reaction is 31.98 kJ/mol. PMID- 19773117 TI - Speciation of Mn(II), Mn(VII) and total manganese in water and food samples by coprecipitation-atomic absorption spectrometry combination. AB - A speciation procedure based on the coprecipitation of manganese(II) with zirconium(IV) hydroxide has been developed for the investigation of levels of manganese species. The determination of manganese levels was performed by flame atomic absorption spectrometry (FAAS). Total manganese was determined after the reduction of Mn(VII) to Mn(II) by ascorbic acid. The analytical parameters including pH, amount of zirconium(IV), sample volume, etc., were investigated for the quantitative recoveries of manganese(II). The effects of matrix ions were also examined. The recoveries for manganese(II) were in the range of 95-98%. Preconcentration factor was calculated as 50. The detection limit for the analyte ions based on 3 sigma (n=21) was 0.75 microg L(-1) for Mn(II). The relative standard deviation was found to be lower than 7%. The validation of the presented procedure was performed by analysis of certified reference material having different matrices, NIST SRM 1515 (Apple Leaves) and NIST SRM 1568a (Rice Flour). The procedure was successfully applied to natural waters and food samples. PMID- 19773118 TI - Study of mercury in by-products from a Dutch co-combustion power station. AB - Fly ashes and gypsum are one of the main wastes produced in coal-fired power stations which may be sent to landfills for their disposal. In this work, leaching and speciation of mercury in fly ashes and gypsum from a modern co combustion power plant equipped with a selective catalytic reduction (SCR) unit in the Netherlands were studied. The mercury leachable contents were checked against different regulations, including Dutch, German and the Council Directive 2003/33/EC. The speciation of mercury in coal combustion products is essential not only to determine the risk when the wastes are finally disposed but also to understand the behaviour of mercury during combustion and therefore to select the appropriate mercury removal technology. A temperature-programmed decomposition technique was used in order to identify and quantify which mercury species are associated with coal combustion products. The main mercury species identified in fly ash samples was mercury sulphate, whereas in the gypsum sample the mercury present was mercury chloride. The quantitative mercury results carried out using the thermal desorption method may be considered accurate. The results obtained show that fly ash and gypsum samples from this power plant can be acceptable at landfills as a non-hazardous waste. PMID- 19773119 TI - Reactivity characteristics of poly(methyl methacrylate) coated nanoscale iron particles for trichloroethylene remediation. AB - The unstable characteristic of nanoscale zerovalent iron (NZVI) has been a drawback in practical application, despite the expectation of an enhanced reactivity. It has been ever-increasing interests to maintain the NZVI stability in air without significant reactivity sacrifice. This study demonstrated a novel method of coating NZVI particles with poly(methyl methacrylate) (PMMA), which protected the core iron nanoparticles from oxidation in air and enhanced their dispersion stability in organic solvents. The reactivity studies on trichloroethene (TCE) reduction showed that the PMMA coated nanoscale zerovalent iron (PNZVI) particles were capable of effectively reducing TCE. The main roles of PMMA on the dechlorination reactions were confirmed to be sorption enhancement, competitive sorption and corrosion inhibition. PMID- 19773120 TI - Degradation of amoxicillin, ampicillin and cloxacillin antibiotics in aqueous solution by the UV/ZnO photocatalytic process. AB - The study examined the effect of operating conditions (zinc oxide concentration, pH and irradiation time) of the UV/ZnO photocatalytic process on degradation of amoxicillin, ampicillin and cloxacillin in aqueous solution. pH has a great effect on amoxicillin, ampicillin and cloxacillin degradation. The optimum operating conditions for complete degradation of antibiotics in an aqueous solution containing 104, 105 and 103 mg/L amoxicillin, ampicillin and cloxacillin, respectively were: zinc oxide 0.5 g/L, irradiation time 180 min and pH 11. Under optimum operating conditions, complete degradation of amoxicillin, ampicillin and cloxacillin occurred and COD and DOC removal were 23.9 and 9.7%, respectively. The photocatalytic reactions under optimum conditions approximately followed a pseudo-first order kinetics with rate constant (k) 0.018, 0.015 and 0.029 min(-1) for amoxicillin, ampicillin and cloxacillin, respectively. UV/ZnO photocatalysis can be used for amoxicillin, ampicillin and cloxacillin degradation in aqueous solution. PMID- 19773121 TI - Risk assessment of the fatality due to explosion in land mass transport infrastructure by fast transient dynamic analysis. AB - Terrorist attacks in New York have shocked the world community showing clearly the vulnerability of air transport in such events. However, the terrorist attacks in Madrid and London showed that land mass transport infrastructure is equally vulnerable in case of similar attacks. The fact that there has not been substantial investment in the domain of risk analysis and evaluation of the possible effects due to such events in land mass transportation infrastructure leaves large room for new developments that could eventually fill this gap. In the present work using the finite element code EUROPLEXUS there has been a large effort to perform a complete study of the land mass infrastructure in case of explosion events. This study includes a train station, a metro station and a metro carriage providing thus valuable simulation data for a variety of different situations. For the analysis of these structures it has been necessary to apply a laser scanning method for the acquisition of geometrical data, to improve the simulation capabilities of EUROPLEXUS by adding failure capabilities for specific finite elements, to implement new material models (e.g. glass), and to add new modules that achieve data post-processing for the calculation of fatal and non fatal injuries risk. The aforementioned improvements are explained in the present work with emphasis in the newly developed risk analysis features of EUROPLEXUS. PMID- 19773122 TI - Effects of sulfate ions and slightly acidic pH conditions on Cr(VI) adsorption onto silica gelatin composite. AB - The feasibility of utilizing CTAB-silica gelatin composite (C-SGC) to remove hexavalent chromium from aqueous solutions under different conditions was investigated. Removal of chromate was assessed through evaluation of the adsorption kinetics of chromate ions on the composite under equilibrium conditions in the presence of sulfate ions and at a slightly acidic pH condition (pH 5.8). Adsorption competition tests in the presence of sulfate ions showed that Cr(VI) was still effectively adsorbed from aqueous solution regardless of the presence of the competing anions. In fact, the adsorption kinetics performed at different initial chromate concentrations were unaffected by the presence of 100 mg L(-1) sulfate ions (pH 7.5). The equilibrium adsorption data were fitted by Freundlich adsorption isotherms which confirmed that the adsorption efficiency of chromium on the CTAB-silica gelatin composite was unchanged in the presence of sulfate ions. Further, the adsorption process was shown to be pH dependent and more efficient at slightly acidic pH (5.8). These findings demonstrated a high specificity of the CTAB-silica gelatin composite for chromium, and highlight the possibility of using this matrix for efficient removal of chromium from industrial wastewater without the need to eliminate contaminant sulfate ions. PMID- 19773123 TI - Properties of sintered glass-ceramics prepared from plasma vitrified air pollution control residues. AB - Air pollution control (APC) residues, obtained from a major UK energy from waste (EfW) plant, processing municipal solid waste, have been blended with silica and alumina and melted using DC plasma arc technology. The glass produced was crushed, milled, uni-axially pressed and sintered at temperatures between 750 and 1150 degrees C, and the glass-ceramics formed were investigated by X-ray diffraction (XRD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Mechanical properties assessed included Vickers's hardness, flexural strength, Young's modulus and thermal shock resistance. The optimum sintering temperature was found to be 950 degrees C. This produced a glass ceramic with high density (approximately 2.58 g/cm(3)), minimum water absorption (approximately 2%) and relatively high mechanical strength (approximately 81+/-4 MPa). Thermal shock testing showed that 950 degrees C sintered samples could withstand a 700 degrees C quench in water without micro-cracking. The research demonstrates that glass-ceramics can be readily formed from DC plasma treated APC residues and that these have comparable properties to marble and porcelain. This novel approach represents a technically and commercially viable treatment option for APC residues that allow the beneficial reuse of this problematic waste. PMID- 19773124 TI - The effect of process conditions on the treatment of benzoquinone solution by electrocoagulation. AB - The present study provides an electrocoagulation (EC) process for the removal of p-benzoquinone (BQ) from aqueous solution using aluminium as anode and stainless steel as cathode materials. Experiments carried out to investigate the effects of solution pH and conductivity, current density, time, BQ concentration on the removal efficiency of the process and the adsorption capacity of aluminium hydroxide electrocoagulant flocs. The results show that pH 7.5 seems to be optimum for high removal of BQ near 90% at typical operating conditions such as 20 A/m(2) current density and 20 min operating time. The competing reduction of BQ to hydroquinone (HQ) accompanying the H(+) reduction at the cathode and low removal extent of HQ by electrocoagulant flocs decreases the performance of the EC process. PMID- 19773125 TI - Environmentally benign methanolysis of polycarbonate to recover bisphenol A and dimethyl carbonate in ionic liquids. AB - An environmentally friendly strategy for methanolysis of polycarbonate (PC) to recover bisphenol A (BPA) and dimethyl carbonate (DMC) was developed in which PC could be methanolyzed in an ionic liquid without any acid or base catalyst under moderate conditions. The effects of ionic liquid kinds, temperature, time, and methanol dosage on methanolysis results of PC were examined. It was showed that the methanolysis conversion of PC was almost 100% and the yields of both BPA and DMC were over 95% in presence of ionic liquid 1-n-butyl-3-methylimidazolium chloride ([Bmim][Cl]) and under the conditions of m(PC):m(CH(3)OH):m([Bmim][Cl])=2:3:2, reaction temperature 105 degrees C and time 2.5h. After easily separated from the product, the ionic liquid could be reused 8 times without obvious decrease in the conversion of PC and yields of BPA and DMC. PMID- 19773126 TI - Depressive symptoms and pain evaluations among persons with chronic pain: catastrophizing, but not pain acceptance, shows significant effects. AB - Cognitive factors such as catastrophic thoughts regarding pain, and conversely, one's acceptance of that pain, may affect emotional functioning among persons with chronic pain conditions. The aims of the present study were to examine the effects of both catastrophizing and acceptance on affective ratings of experimentally induced ischemic pain and also self-reports of depressive symptoms. Sixty-seven individuals with chronic back pain completed self-report measures of catastrophizing, acceptance, and depressive symptoms. In addition, participants underwent an ischemic pain induction procedure and were asked to rate the induced pain. Catastrophizing showed significant effects on sensory and intensity but not affective ratings of the induced pain. Acceptance did not show any significant associations, when catastrophizing was also in the model, with any form of ratings of the induced pain. Catastrophizing, but not acceptance, was also significantly associated with self-reported depressive symptoms when these two variables were both included in a regression model. Overall, results indicate negative thought patterns such as catastrophizing appear to be more closely related to outcomes of perceived pain severity and affect in persons with chronic pain exposed to an experimental laboratory pain stimulus than does more positive patterns as reflected in measures of acceptance. PMID- 19773128 TI - Mycobacterium marinum: current recommended pharmacologic therapy. PMID- 19773127 TI - PTSD contributes to teen and young adult cannabis use disorders. AB - BACKGROUND: Previous studies involving adults suggest that Post Traumatic Stress Disorder (PTSD) increases the prevalence of cannabis use disorders (CUD) (cannabis dependence and cannabis abuse). However, little work with PTSD and CUD has been conducted involving adolescents, despite the fact that CUD typically have their onset during adolescence. This study addresses the effect of PTSD on CUD among teenagers transitioning to young adulthood. METHOD: The subjects in this ongoing study were the offspring of adult men with a lifetime history of a substance use disorder (SUD) (SUD+probands, N=343) vs those with no lifetime history of a SUD (SUD-probands, N=350). The participants were initially recruited when the index sons of these fathers were 10-12 years of age, and subsequent assessments were conducted at age 12-14, 16, 19, 22, and 25. Other variables examined were an index of behavioral undercontrol associated with future risk for developing SUD, known as the Transmissible Liability Index, or TLI, and affiliation with deviant peers. Multivariate logistic regression and path analyses were conducted. RESULTS: Of these 693 subjects, 31 subjects were diagnosed with PTSD, and 161 were diagnosed with a CUD. The CUD subjects included 136 male participants and 25 female participants, including 103 (64%) Caucasian participants and 58 (36%) participants of other races. Logistic regression demonstrated that the development of a CUD was associated with deviance of peers (Wald=63.4, p=0.000), the TLI (Wald=28.8, p=0.000), African American race (Wald=14.2, p=0.000), PTSD (Wald=12.7, p=0.000), male gender (Wald=12.0, p=0.001), household SES (Wald=9.2, p=0.002), and being an offspring of a SUD+proband (Wald=6.9, p=0.009). Path analyses demonstrated that PTSD is directly associated with the presence of a CUD and with peer deviance, that higher peer deviance is associated with the presence of a CUD, and that PTSD mediated the association between peer deviance and CUD. CONCLUSIONS: These findings suggest that PTSD contributes to the etiology of CUD among teenagers making the transition to young adulthood beyond the effects of deviant peers, the TLI (Transmissible Liability Index, a measure of risk for SUD), and demographic factors. PMID- 19773129 TI - Thrombocytopenia absent radius syndrome: presence of brachiocarpalis muscle and its importance. AB - PURPOSE: Common clinical manifestations associated with thrombocytopenia absent radius (TAR) syndrome have been reported in the literature since its initial description in 1959. The purpose of this study was to report a clinical observation and describe the anatomic location of this brachiocarpalis muscle. METHODS: The radiographs of 20 patients (39 extremities) with TAR syndrome were reviewed and are the focus of this report. The presence or absence of an abnormal muscle crossing both the humero-ulnar and ulno-carpal joint, and its anatomic origin and insertion, were documented by radiographs, surgery, or both. A total of 12 patients underwent surgery on 19 extremities. Furthermore, we compared the radiographs of these 20 patients (39 extremities) with the radiographs of 20 arbitrarily selected patients with non-TAR type IV radial dysplasia, which were part of our database. RESULTS: An abnormal brachiocarpalis muscle was noted radiographically in all 39 of the extremities and was observed surgically in all 19 patients who underwent surgery. It was absent in all 40 extremities of the non TAR type IV radial dysplasia patients. One TAR patient had only unilateral radial dysplasia. This anomalous muscle has an abnormally high origin on the anterolateral aspect of the proximal humerus, and an insertion into the radial side of the carpus. As such, it has a deforming force at both the wrist and the elbow. CONCLUSIONS: We report the consistent finding of a brachiocarpalis muscle in patients with TAR syndrome. Because of its location, the presence of this muscle may influence the surgical treatment of these patients. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV. PMID- 19773130 TI - Spread of squamous cell carcinoma from the thumb to the small finger via the flexor tendon sheaths. AB - We report the development of metastatic squamous cell carcinoma at the tip of the small finger following the development of a thumb distal phalanx squamous cell carcinoma caused by chronic osteomyelitis. The spread of hand infections from the flexor tendons of the thumb to the small finger through a tendon sheath connection at the wrist is a well-described phenomenon. The evidence from this case suggests that the spread of the squamous cell carcinoma from the tip of the thumb to the tip of the small finger occurred in a similar fashion. This information is important in understanding how malignant tumors spread in the hand and wrist, and it might influence the management of such tumors. PMID- 19773131 TI - Mallet finger injuries. PMID- 19773132 TI - Airborne porcine circovirus in Canadian swine confinement buildings. AB - Porcine circovirus type 2 has been linked to many diseases, such as postweaning multisystemic wasting syndrome and can be found in most commercial swine confinement buildings around the world. Although the exact role of the virus in the appearance of disease in animals is not fully understood, the mechanisms responsible for the transmission of the virus are currently believed to happen mostly by contact. Nevertheless, the possibility of airborne transmission cannot be rejected. This study investigated the presence of the virus, total bacteria and total dusts in aerosols. Air samples were taken with gelatin filters in swine confinement buildings and were analyzed by quantitative polymerase chain reaction. Interestingly, concentrations of airborne PCV2 of up to 10(7) genomes per cubic meter of air were detected. Airborne dust concentrations were correlated to airborne concentrations of PCV2 and total bacteria. Although the infectivity potential of the airborne viral loads were not evaluated, it is clear that the virus can become airborne in detectable concentrations in commercial swine confinement building environments. The significance of this finding in an epidemiological point of view will need further investigation. PMID- 19773133 TI - Zoonotic aspects of infections with noroviruses and sapoviruses. AB - The close genetic relationship of noroviruses and sapoviruses found in animals and humans has raised the question whether these viruses have a zoonotic potential. Transmission from animals to humans and vice versa would have far reaching consequences for epidemiology and food safety. So far animal noro- and sapoviruses have not been found in humans. However detection of human noroviruses in animals as well as simultaneous presence of animal and human viruses in bivalve molluscs suggest a risk of transmission. Furthermore, antibodies against animal noroviruses were detected in humans as well as antibodies against human noroviruses in swine. Experimental infection of gnotobiotic calves and pigs with human noroviruses demonstrated that virus replication and seroconversion can occur. Accordingly the possible role of noro- and sapoviruses as zoonotic agents needs to be further investigated. PMID- 19773134 TI - Mycobacterium bovis at the animal-human interface: a problem, or not? AB - Mycobacterium bovis is a pathogen of significant importance in livestock and a wide range of wild animal species worldwide. It is also known to cause tuberculosis disease in humans, a fact which has raised renewed concerns regarding the zoonotic risk for humans, especially those living at the animal human interface. This review consolidates recent reports in the literature mainly on animal and zoonotic tuberculosis with an emphasis on evolution, epidemiology, treatment and diagnosis. The information presented reveals the fundamental differences in the complexity and level at which the disease affects the economy, ecosystem and human population of regions where animal tuberculosis control is achieved and regions where little or no control is implemented. In conclusion the review suggests that bovine tuberculosis has essentially been reduced to a disease of economic importance in the developed world, while low-income countries are facing a multifaceted impact which potentially affects the health of livestock, humans and ecosystems and which is likely to increase in the presence of debilitating diseases such as HIV/AIDS and other factors which negatively affect human livelihoods. PMID- 19773135 TI - Arm span increases predictive value of models for prevalent vertebral deformities: the Japanese Population-based Osteoporosis (JPOS) Study. AB - OBJECTIVE: We examined anthropometric indicators to improve predictive ability of asymptomatic vertebral fracture screening models. STUDY DESIGN AND SETTING: Data were obtained from the 1996 Japanese Population-based Osteoporosis (JPOS) Study. McCloskey-Kanis criteria diagnosed vertebral deformities on X-ray absorptiometric images in 693 women aged > or =50.The multiple logistic regression model included age, height, weight, postmenopausal status, total hip BMD, and arm span (AS) or sitting height as explanatory variables. Akaike's information criterion (AIC) evaluated model goodness-of-fit. RESULTS: Age-adjusted AS and sitting height in subjects with and without vertebral deformities were 147.2+/-0.6 cm and 148.5+/ 0.2 cm (P=0.055), 78.5+/-0.5 cm and 79.9+/-0.2 cm (P=0.007), respectively. Every 5-cm increase in AS indicated 1.5-fold increased risk of prevalent vertebral deformity in the model including age, height, weight, postmenopausal status, and BMD. Including the explanatory variable AS in models yielded better predictive accuracy than excluding AS (AIC, 441.7 vs 446.6, respectively). Sitting height did not significantly influence model predictive ability. CONCLUSION: Predictive accuracy of model for vertebral fracture including age, height, weight, postmenopausal status, and BMD improved when AS was added as an explanatory variable. Models to screen for asymptomatic vertebral fractures should include AS. PMID- 19773136 TI - Forensic anthropology population data: stature estimation from foot measurements- comparison of error in sex dependent and independent models. PMID- 19773137 TI - Effect of morphine on the growth rate of Calliphora stygia (Fabricius) (Diptera: Calliphoridae) and possible implications for forensic entomology. AB - Insect specimens collected from decomposing bodies enable forensic entomologists to estimate the minimum post-mortem interval (PMI). Drugs and toxins within a corpse may affect the development rate of insects that feed on them and it is vital to quantify these effects to accurately calculate minimum PMI. This study investigated the effects of morphine on growth rates of the native Australian blowfly, Calliphora stygia (Fabricius) (Diptera: Calliphoridae). Several morphine concentrations were incorporated into pet mince to simulate post-mortem concentrations in morphine, codeine and/or heroin-dosed corpses. There were four treatments for feeding larvae; T 1: control (no morphine); T 2: 2 microg/g morphine; T 3: 10 microg/g morphine; and T 4: 20 microg/g morphine. Ten replicates of 50 larvae were grown at 22 degrees C for each treatment and their development was compared at four comparison intervals; CI 1: 4-day-old larvae; CI 2: 7-day-old larvae; CI 3: pupae; and CI 4: adults. Length and width were measured for larvae and pupae, and costae and tibiae were measured for adults. Additionally, day of pupariation, day of adult eclosion, and survivorship were calculated for each replicate. The continued presence of morphine in meat was qualitatively verified using high-performance liquid chromatography with acidic potassium permanganate chemiluminescence detection. Growth rates of C. stygia fed on morphine-spiked mince did not differ significantly from those fed on control mince for any comparison interval or parameter measured. This suggests that C. stygia is a reliable model to use to accurately age a corpse containing morphine at any of the concentrations investigated. PMID- 19773138 TI - Measurement of ninhydrin reactive nitrogen influx into gravesoil during aboveground and belowground carcass (Sus domesticus) decomposition. AB - Carcass decomposition results in the release of nitrogenous compounds into associated soil. The current study investigated the release of ninhydrin reactive nitrogen (NRN) following burial (approximately 40 cm depth) and decomposition on the soil surface. Also investigated was the lateral extent of NRN in gravesoil. NRN concentration increased significantly in gravesoil collected from the center of graves (approximately 20 cm depth) during the initial two months of burial. A similar finding was also observed in the base of the grave during the initial six months of burial. However, no change in NRN concentration was observed 60 cm from buried carcasses. Carcasses decomposing on the soil surface were associated with higher NRN during the initial 97 days of decomposition. We conclude that the analysis of soil NRN can be a presumptive test for gravesoil within two months postmortem following burial and up to 97 days postmortem on the surface. PMID- 19773139 TI - [Giant fibroepithelial polyp of the anus]. PMID- 19773140 TI - Pancreatic cancer: incidence, treatment and survival trends--1175 cases in Calvados (France) from 1978 to 2002. AB - AIM: To assess the trends in incidence, therapeutic modalities and survival of pancreatic cancer between 1978 and 2002 in a well-defined population, as recorded in the Calvados digestive cancer registry database. PATIENTS AND METHODS: All patients living in Calvados with a diagnosis of pancreatic cancer were registered. Clinical data and treatment modalities were prospectively recorded. This 25-year database was divided into five 5-year periods. Data were compared using log-rank tests and the Cox model. RESULTS: A total of 1175 cases of pancreatic cancer (617 men, 558 women) were registered. Its incidence increased with an average annual coefficient of +2.8% in men and +5.1% in women. Therapeutic modalities changed over the five time periods: surgical resection increased from 6.8 to 13.4% (median survival 15 months) while radiation therapy and/or chemotherapy also increased from 5.5 to 13.2%. Palliative surgery decreased from 54.6 to 32.0% and favored interventional endoscopic techniques. Postoperative mortality decreased significantly. Survival increased significantly over the five time periods, although the median survival time remained stable (4 months). CONCLUSION: From 1978 to 2002, pancreatic cancer incidence increased in Calvados (France). Therapeutic modalities changed, with endoscopic treatments preferred over palliative surgery. The improvement in survival could be explained by the decrease in postoperative mortality. PMID- 19773141 TI - Breast ultrasound elastography--results of 193 breast lesions in a prospective study with histopathologic correlation. AB - PURPOSE: To evaluate the diagnostic performance of ultrasound elastography in breast masses. MATERIAL AND METHODS: 193 lesions (129 benign, 64 malignant) were analyzed with the EUB 8500 Logos-ultrasonic-unit (Hitachi Medical, Japan) and a linear-array-transducer of 7.5-13-MHz. Standard of reference was cytology (FNAfine needle aspiration) or histology (core biopsy). The elastic-score was classified according to a 6-point colour-scale (Ueno classification; 1-3 = benign, 4-5 = malignant). Conventional B-mode ultrasound (US) findings were classified according to the BI-RADS classification. Statistical analysis included sensitivity, specificity, ROC-analysis and kappa-values for intra-/interobserver reliability. RESULTS: The mean score for elasticity was 4.1 +/- 0.9 for malignant lesions, and 2.1 +/- 1.0 for benign lesions (p < 0.001). With a best cut-off point between elasticity scores 3 and 4, sensitivity was 96.9%, and specificity 76%. Setting a best cut-off point for conventional US between BI-RADS 4 and 5, sensitivity was 57.8%, and specificity 96.1%. Elastography provided higher sensitivity and lower specificity than conventional US, but two lesions with elasticity score 1 were false negative, whereas no lesion scored BI-RADS 1-3 were false negative. ROC-curve was 0.884 for elastography, and 0.820 for conventional US (p < 0.001). Weighted kappa-values for intra-/interobserver reliability were 0.784/0.634 for BI-RADS classification, and 0.720/0.561 for elasticity scores. CONCLUSION: In our study setting, elastography does not have the potential to replace conventional B-mode US for the detection of breast cancer, but may complement conventional US to improve the diagnostic performance. PMID- 19773142 TI - Characterization of metabolites of worenine in rat biological samples using liquid chromatography-tandem mass spectrometry. AB - The in vivo and in vitro metabolites of worenine in rat were identified or characterized using a specific and sensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. In vivo samples including rat urine, feces, and plasma samples were collected after ingestion of 25 mg/kg worenine to healthy rats. The in vivo and in vitro samples were cleaned up by a solid-phase extraction procedure (C18 cartridges) and a liquid-liquid extraction procedure, respectively. Then these pretreated samples were injected into a reversed-phase C18 column with mobile phase of methanol-ammonium acetate (2mM, adjusted to pH 3.5 with formic acid) (60:40, v/v) and detected by an on-line MS/MS system. As a result, at least twenty-seven metabolites and the parent medicine were found in rat urine after ingestion of worenine. Seven metabolites and the parent medicine were identified or characterized in rat feces. Three metabolites and the parent medicine were detected in rat plasma. One metabolite was found in the rat intestinal flora incubation mixture, and three metabolites were characterized in the homogenized liver incubation mixture. The main phase I metabolism of worenine in rat was dehydrogenization, hydrogenation, hydroxylation, and demethylene reactions, and that of phase II was sulfation and glucuronidation. PMID- 19773143 TI - Treatment of chronic fatigue syndrome: how to find a 'new equilibrium'? PMID- 19773144 TI - The association of health literacy and socio-demographic factors with medication knowledge. AB - OBJECTIVE: To compare patient demographics and Rapid Estimate of Adult Literacy in Medicine (REALM) scores with respect to their ability to predict medication comprehension. METHODS: A survey was conducted of 100 patients presenting for follow-up at an academic primary care clinic serving a low socio-economic status population. The Medication Knowledge Score (MKS) consisted of knowledge of drug name, dose, indication, and a potential side effect for each of their medications and then averaged. The REALM (Rapid Estimate of Adult Literacy in Medicine) was administered and socio-demographic characteristics were recorded. The association of REALM score and patient characteristics with MKS was evaluated by univariate and multivariable regression analysis. RESULTS: The subjects' mean age was 62 with an average of 9.8 years of schooling and 5.9 prescription medications. Participants identified a correct indication for 78.8% of their medications and correct dosage for 93.4%. However, they could provide the name for only 55.8% of medications and a known side effect for only 11.7%. On multivariate analysis without including REALM score, younger age (p=.01), highest grade completed (p=.001), and female sex (p=.004) remained positively associated with MKS. When the model included REALM, REALM (p<.0001), age (p=.001), and sex (p=.04) remained independently associated with MKS. CONCLUSION: REALM score predicts medication knowledge as assessed by the MKS. However, age, last grade completed, and sex were also independently associated with mean MKS with a similar strength of association to that of REALM. This suggests that simpler cues to screen for medication knowledge deficits may also be useful. Since the MKS incorporates knowledge of medication indications and side effects, it may also be useful for quality and safety purposes. PMID- 19773145 TI - Commentary on 'Elements of effective communication--rediscoveries from homeopathy'. PMID- 19773146 TI - [Comparison of three ventilatory modes during immediate postoperative transfer of cardiac surgical patients]. AB - OBJECTIVE: Compare three ventilatory strategies during the immediate postoperative transfer of cardiac surgical patient. STUDY DESIGN: Prospective, comparative and observational study. PATIENTS AND METHODS: After approval by our local ethical committee, 330 patients undergoing on-pump cardiac surgery were consecutively included. Patients suffering from chronic obstructive pulmonary disease, exhibiting intraoperative hypoxemia or requiring nitric oxide were excluded. The ventilatory mode was left at the discretion of the anesthesiologist and included: controlled mechanical ventilation (FiO(2)=1, N=124) or (FiO(2)=0.6, N=106), and manual ventilation using rebreathing bag (N=100). A blood gas analysis was performed immediately prior to connecting patient at ventilator at the arrival in ICU. RESULTS: The mean duration of transfer was 3.9+/-1.4 min. Invasive pressure monitoring was used in all patients. The pulse oxymetry and electrocardiogram were respectively used in 78% and 24% of patients. PaO(2) values less than 100 mmHg and those more than 300 mmHg were more frequently found in patients ventilated by rebreathing bag (42%) and mechanical ventilation FiO(2)1 (52%), respectively. No significant difference was found between groups regarding PaCO(2) values. CONCLUSION: When rebreathing bag is used for transfer in ICU, severe decrease in PaO(2) may be observed. In absence of intraoperative hypoxemia, a mechanical ventilation with FiO(2)0.6 seems to be the most suitable ventilatory strategy for such short immediate postoperative transfer. PMID- 19773147 TI - Image guidance for robotic minimally invasive coronary artery bypass. AB - A novel system for image guidance in totally endoscopic coronary artery bypass (TECAB) is presented. Key requirement is the availability of 2D-3D registration techniques that can deal with non-rigid motion and deformation. Image guidance for TECAB is mainly required before the mechanical stabilisation of the heart, when the most dominant source of misregistration is the deformation and non-rigid motion of the heart. To augment the images in the endoscope of the da Vinci robot, we have to find the transformation from the coordinate system of the preoperative imaging modality to the system of the endoscopic cameras. In a first step we build a 4D motion model of the beating heart. Intraoperatively we can use the ECG or video processing to determine the phase of the cardiac cycle, as well as the heart and respiratory frequencies. We then take the heart surface from the motion model and register it to the stereo endoscopic images of the da Vinci robot resp. of a validation system using photo-consistency. To take advantage of the fact that there is a whole image sequence available for registration, we use the different phases together to get the registration. We found the similarity function to be much smoother when using more phases. This also showed promising behaviour in convergence tests. Images of the vessels available in the preoperative coordinate system can then be transformed to the camera system and projected into the calibrated endoscope view using two video mixers with chroma keying. It is hoped that the augmented view can improve the efficiency of TECAB surgery and reduce the conversion rate to more conventional procedures. PMID- 19773148 TI - Characterization and flocculation mechanism of high efficiency microbial flocculant TJ-F1 from Proteus mirabilis. AB - The characterization and the flocculation mechanism of microbial flocculant TJ-F1 with high flocculating activity, produced by Proteus mirabilis from a mixed activated sludge, was investigated. Mainly consisting of protein and acid polysaccharide, TJ-F1 owns a molecular weight of 1.2 x 10(5)Da, which brings strong van der Waals forces and ample binding-sites. It contains carboxyl, hydroxyl, amino groups and hydrogen bonds preferred for the flocculation process. The key parameters influencing the flocculation behavior were investigated by analyzing both the Zeta potentials of the flocculation systems and the flocculating efficiencies of TJ-F1. An alkaline condition promotes its flocculating efficiency. CaCl(2) aids TJ-F1 by effectively decreasing the absolute value of Zeta potential. Appropriate dose of TJ-F1 is crucial to the flocculating efficiency. During the precipitating process, the growing flocs sweep the small flocs and the suspended particles to form big flocs, which also contribute to the excellent flocculating efficiency of TJ-F1. PMID- 19773149 TI - Interaction between phospholipids bilayer and chitosan in liposomes investigated by 31P NMR spectroscopy. AB - The interaction between chitosan and the polar head of phosphatidylcholine (PC) is discussed for a composite nanovesicle obtained by incorporating chitosan in the organic phase before PC self-assembling. Nanovesicles free of chitosan are studied in parallel to allow the comparison concerning modifications produced on the composite system. Zeta Potential increases in the presence of chitosan and with the increase in its concentration proving the localization of the polymer over the external surface of the vesicle as one interaction site. A (31)P resonance around 0 ppm, characteristic of the system, is reduced with addition of chitosan at 25 degrees C, indicating motional freedom reduction of the polar head phosphate group. The same resonance signal remains almost constant after increasing the temperature to 60 degrees C, suggesting that chitosan shields the phospholipids polar heads as a consequence of the electrostatic interactions leading to an increase in the thermodynamic stability of the composite. PMID- 19773150 TI - Cataracta ossea - Ultrastructural and specimen analysis. AB - BACKGROUND: Although intraocular osseous metaplasia is a well-known phenomenon, ossification of the lens is a rare phenomenon nowadays. MATERIAL AND METHODS: An enucleated phthisical eye showed a rock-hard intraocular particle. Lens status after a trauma 36 years ago had been unclear. Differential diagnosis included an intraocular foreign body or ossification of the lens. X-ray diffraction analysis showed microcrystalline apatite indicating a mineralized structure. Histologic specimens revealed a mineralized lens that underwent secondary osseous metaplasia. CONCLUSIONS: Due to the small number of cases, the mechanisms and preconditions of osseous metaplasia of the lens are not understood in detail, but injury to the lens capsule and availability of blood supply are being discussed. Both were present in this case, in which the luxated lens ended up in the ciliary body region. The mechanism resembled enchondral ossification rather than intramembranous ossification, which is seen in osseous metaplasia of other intraocular structures. PMID- 19773151 TI - Cell-to-cell contact and extracellular matrix. PMID- 19773152 TI - Ammonia volatilization, N(2)O and CO(2) emissions from landfill leachate irrigated soils. AB - Effects of leachate addition on ammonia volatilization and N(2)O and CO(2) emissions from two different soils were investigated using the 10-day laboratory incubation method at two levels of moisture content. Ammonia volatilization was dominated by soil pH and only occurred in alkaline clay soil, where 0.26-0.32% of soil ammonia could be lost. The N(2)O emission from the alkaline clay soil was one order of magnitude greater than that from the acidic sandy soil, when either water or leachate was irrigated. Increasing the moisture content from 46% water filled pore space (WFPS) to 70% WFPS in the alkaline clay soil or the acidic sandy soil by either water or leachate irrigation increased the N(2)O emission by over twofold. The CO(2) emission from each soil sample at the two WFPSs was almost the same. The CO(2) emission from the alkaline clay soil with leachate addition was 72% lower than that from the acidic sandy soil with leachate addition, and 6.7 times higher than that from the alkaline clay soil with distilled water addition. Ammonia volatilization and N(2)O emission under leachate irrigation could be minimized by avoiding the excessively wet condition and by selecting the acidic sandy soil with low organic carbon and total nitrogen content. PMID- 19773153 TI - Stereotactic body radiation therapy for liver metastases. AB - Although resection is the standard of care for liver metastasis, 80-90% of patients are not resectable at diagnosis. Advances in combination chemotherapy, particularly with targeted agents, have increased tumour response and survival in patients with unresectable metastatic colorectal cancer, but these techniques have limitations and may be associated with high recurrence rates. Some autopsy series have shown that as many as 40% of patients with metastatic colorectal cancer have disease confined to the liver; aggressive local therapy may improve overall survival in such patients. Local control of liver metastases can also ease hepatic capsular pain to improve quality of life. Stereotactic body radiation therapy (SBRT) offers an alternative, non-invasive approach to the treatment of liver metastasis through precisely targeted delivery of radiation to the tumours while minimising normal tissue toxicity. Early applications of SBRT to liver metastases have been promising with the reports of 2-year local control rates of 71-86% and other studies reporting 18-month local control rates of 71 93%. While these data establish the safety of SBRT for liver metastases, more rigorous phase II clinical studies are needed to fully evaluate long-term efficacy and toxicity results. In the interim, this review stresses that SBRT of liver must be performed cautiously given the challenges of organ motion and the low toxicity tolerance of the surrounding hepatic parenchyma. PMID- 19773154 TI - Competitive adsorption of Pb2+, Cd2+ and Zn2+ ions onto Eichhornia crassipes in binary and ternary systems. AB - A batch sorption technique was used to study the biosorption of Pb(2+), Cd(2+) and Zn(2+) ions onto the vastly abundant water hyacinth weed, Eichhornia crassipes biomass in binary and ternary systems at a temperature of 30 degrees C and pH 4.84. Mutual interference effects were probed using equilibrium adsorption capacity ratios, q(e)(')/q(e), where the prime indicates the presence of one or two other metal ions. The combined action of the metals was found to be antagonistic, and the metal sorption followed the order Pb(2+)>>Cd(2+)>>Zn(2+). The behaviour of competitive biosorption for Pb-Cd and Pb-Zn combinations were successfully described by the Langmuir Competitive Model (CLM), whilst the model showed poor fitting to the Cd-Zn data. In conclusion, Pb(2+) ions could still be effectively removed from aqueous solution in the presence of both Cd(2+) and Zn(2+) ions, but removal of the Cd(2+) and Zn(2+) ions would be suppressed in the presence of Pb(2+). PMID- 19773155 TI - Recovery of solanesol from tobacco as a value-added byproduct for alternative applications. AB - Solanesol in the waste streams of a bioprocess designed for alternative applications of low-alkaloid tobacco was recovered using three different extraction methods. Compared to the conventional heat-reflux extraction (HRE) and ultrasound-assisted extraction (UAE), microwave-assisted extraction (MAE) using 1:3 hexane:ethanol (v/v) as the solvent after saponification treatment of tobacco biomass was found the most effective in terms of solanesol yield, processing time, and volume of solvent consumed. Quantification of solanesol was achieved by optimizing the mobile phase at 60/40 acetonitrile-isopropanol and lowering the oven temperature to 22 degrees C using a standard reverse-phase high performance liquid chromatography (RP-HPLC). The total solanesol recovered from tobacco biomass and chloroplast accounted for 30% (w/w) of the total solanesol in the fresh leaves. Since solanesol is the precursor of metabolically active quinones such as coenzyme Q10 and vitamin K analogues, extraction of solanesol from tobacco bioprocess waste is a feasible operation and could leverage the overall profitability of biorefining tobacco for alternative, value-added uses. PMID- 19773156 TI - A glycerol-free process to produce biodiesel by supercritical methyl acetate technology: an optimization study via Response Surface Methodology. AB - In this study, fatty acid methyl esters (FAME) have been successfully produced from transesterification reaction between triglycerides and methyl acetate, instead of alcohol. In this non-catalytic supercritical methyl acetate (SCMA) technology, triacetin which is a valuable biodiesel additive is produced as side product rather than glycerol, which has lower commercial value. Besides, the properties of the biodiesel (FAME and triacetin) were found to be superior compared to those produced from conventional catalytic reactions (FAME only). In this study, the effects of various important parameters on the yield of biodiesel were optimized by utilizing Response Surface Methodology (RSM) analysis. The mathematical model developed was found to be adequate and statistically accurate to predict the optimum yield of biodiesel. The optimum conditions were found to be 399 degrees C for reaction temperature, 30 mol/mol of methyl acetate to oil molar ratio and reaction time of 59 min to achieve 97.6% biodiesel yield. PMID- 19773157 TI - Dilute-acid pretreatment of distillers' grains and corn fiber. AB - Distillers' grains and corn fiber are the coproducts of the dry grind and wet corn milling industries, respectively. Availability of distillers' grains and corn fiber at the ethanol plant and their high levels of lignocellulosic material make them attractive feedstock for conversion to ethanol. In this study, dilute sulfuric acid hydrolysis for the conversion of distillers' grains and corn fiber to monomeric sugars and the formation of furfural were investigated. The extent of solubilization of biomass beyond monomeric sugars was also monitored. Biomass loadings in the range of 5-20 wt.% at 5% intervals, acid concentrations in the range of 0.5-1.5 vol.% at 0.5% intervals, and temperatures of 120 and 140 degrees C were studied. The highest yields of monomeric sugars were observed when the least amount of biomass loading was pretreated with the highest concentration of sulfuric acid and when the temperature was 140 degrees C. For the majority of the cases under consideration, the most effective period of hydrolysis appeared to be during the initial 20-30 min of the reaction. Formation of furfural during the course of hydrolysis was significantly lower at 120 degrees C and also lower for the distillers' grains samples compared with the corn fiber samples. The total amount of the solubilized matter during the hydrolysis was significantly higher than the amount of the monomeric sugars. Analyses according to standard procedure were performed to quantify moisture, oil, carbohydrates, and ash in distillers' grains and corn fiber samples. The total carbohydrate content of distillers' grains and corn fiber were 57.7+/-2.0 and 77.0+/-1.0 wt.%, respectively. The presented results will provide a foundation for the suitability of the pretreated distillers' grains and corn fiber for enzymatic hydrolysis step. PMID- 19773158 TI - Fly-ash products from biomass co-combustion for VOC control. AB - Experiments were conducted in a continuous flow reactor at room temperature to evaluate the elimination of low-concentration toluene in the gas phase to verify if fly-ash products from biomass combustion in an ozonation system could be used in the removal of volatile organic compounds. The fly-ash products from pure biomass combustion (Ash(100)) demonstrated the highest ozonation activities upon the removal of low-concentration toluene (1.5 ppmv), followed by the fly-ash products from co-combustion (Ash(30)) and the coal combustion (Ash(0)). Kinetic experiments showed that the activation energy of the toluene elimination process was substantially reduced with the use of ozone and the reaction intermediates, such as formic acids, aldehydes, etc. Results also showed that the intermediates were reduced with increasing humidity level. The combined use of fly-ash products and zeolite 13X enhanced the removal of toluene to above 90% and suppressed the release of residual ozone and intermediates by holding them in the adsorbed phase. PMID- 19773159 TI - Effective bioremoval of reactive dye and heavy metals by Aspergillus versicolor. AB - In this study, bioaccumulation of heavy metal and dye by Aspergillus versicolor was investigated. Optimum pH values of the maximum heavy metal bioaccumulation was found as 6 for 50mg/L Cr(VI), Ni(II) and 5 for Cu(II) ions with the 99.89%, 30.05% and 29.06% removal yield, respectively. The bioremoval of the dye up to 800 mg/L at pH 5 and 6 was investigated and 27.15% and 28.95% removal rates were measured respectively. The presence of Cr(VI) with dye, decreased the uptake yield for both pollutants. In the medium with Cu(II) and dye, dye removal was not affected by Cu(II), but Cu(II) removal rate increased from 29.06% to 37.91% by the existence of the dye. When Ni(II) and dye were combined, neither pollutant affected the other's removal yield. These results indicate that the isolated A. versicolor strain deserves attention as a promising bioaccumulator of heavy metal ions and reactive dyes in wastewater effluents. PMID- 19773160 TI - A statistical experiment design approach for optimizing biodegradation of weathered crude oil in coastal sediments. AB - This work studied the bioremediation of weathered crude oil (WCO) in coastal sediment samples using central composite face centered design (CCFD) under response surface methodology (RSM). Initial oil concentration, biomass, nitrogen and phosphorus concentrations were used as independent variables (factors) and oil removal as dependent variable (response) in a 60 days trial. A statistically significant model for WCO removal was obtained. The coefficient of determination (R(2)=0.9732) and probability value (P<0.0001) demonstrated significance for the regression model. Numerical optimization based on desirability function were carried out for initial oil concentration of 2, 16 and 30 g per kg sediment and 83.13, 78.06 and 69.92 per cent removal were observed respectively, compare to 77.13, 74.17 and 69.87 per cent removal for un-optimized results. PMID- 19773161 TI - Effect of solvents and precipitant on the properties of chitosan nanoparticles in a water-in-oil microemulsion and its lipase immobilization performance. AB - When chitosan nanoparticles were prepared in a water-in-oil (W/O) microemulsion by using 2% (wt) acetic acid (HAc) and 30% (wt) tri-n-octylamine (TOA) as solvent and precipitant, respectively, particle diameters of 7 nm were observed and the particles formed ovoid shaped aggregates. Using 0.05% HCl and 5.0M NaOH as solvent and precipitant produced nanoparticles 10nm in size that aggregated in the form of snowflakes. These two types of nanoparticles were used to immobilize lipase, the lipase adsorption capacity using nanoparticles 7 nm in size reached 156 mg/g and activity retention compared to free enzyme was as high as 66.7%, and the residual activity of the immobilized lipase was 91% after 5 runs of reaction. In additional, the activity retention of nanoparticles 10nm in size also could reach 62.8%. This indicated that the chitosan nanoparticles prepared in a W/O microemulsion were suitable for lipase immobilization. PMID- 19773162 TI - Pyrimidine-based antagonists of h-MCH-R1 derived from ATC0175: in vitro profiling and in vivo evaluation. AB - A series of pyrimidine analogues derived from ATC0175 were potent antagonists of human MCH-R1 in vitro. Significantly improved receptor selectivity was achieved with several analogues from this series, but no improvement in brain partitioning was noted. One example from this series was shown to inhibit food intake and decrease body weight in a chronic study. However no clear correlation between the pharmacodynamic effect and the pharmacokinetic data with respect to brain concentration was discernible leading us to conclude that the observed effect was most likely not due to interaction with the MCH-R1. PMID- 19773163 TI - Inhibitor profiling of the Pseudomonas aeruginosa virulence factor LasB using N alpha mercaptoamide template-based inhibitors. AB - We report on the synthesis and biological evaluation of a focussed library of N alpha mercaptoamide containing dipeptides as inhibitors of the zinc metallopeptidase Pseudomonas aeruginosa elastase (LasB, EC 3.4.24.26). The aim of the study was to derive an inhibitor profile for LasB with regard to mapping the S'1 binding site of the enzyme. Consequently, a focussed library of 160 members has been synthesised, using standard Fmoc-solid phase methods (on a Rink-amide resin), in which a subset of amino acids including examples of those with basic (Lys, Arg), aromatic (Phe, Trp), large aliphatic (Val, Leu) and acidic (Asp, Glu) side-chains populated the P'2 position of the inhibitor sequence and all 20 natural amino acids were incorporated, in turn, at the P'1 position. The study has revealed a preference for aromatic and/or large aliphatic amino acids at P'1 and a distinct bias against acidic residues at P'2. Ten inhibitor sequences were discovered that exhibited sub to low micromolar Ki values. PMID- 19773165 TI - Pyrazole-based cathepsin S inhibitors with arylalkynes as P1 binding elements. AB - A crystal structure of 1 bound to a Cys25Ser mutant of cathepsin S helped to elucidate the binding mode of a previously disclosed series of pyrazole-based CatS inhibitors and facilitated the design of a new class of arylalkyne analogs. Optimization of the alkyne and tetrahydropyridine portions of the pharmacophore provided potent CatS inhibitors (IC50=40-300 nM), and an X-ray structure of 32 revealed that the arylalkyne moiety binds in the S1 pocket of the enzyme. PMID- 19773164 TI - Synthesis and structure-activity relationships of 2-(1,4'-bipiperidin-1' yl)thiazolopyridine as H3 receptor antagonists. AB - A series of 2-(1,4'-bipiperidine-1'-yl)thiazolopyridines was synthesized and evaluated as a new lead of non-imidazole histamine H(3) receptor antagonists. Introduction of diversity at the 6-position of the pyridine ring was designed to enhance in vitro potency and decrease hERG activity. The structure-activity relationships for these new thiazolopyridine antagonists are discussed. PMID- 19773166 TI - Efficient synthesis of nevirapine analogs to study its metabolic profile by click fishing. AB - Knowledge of the biotransformation and pharmacokinetics of the antiretroviral agent nevirapine is still insufficient. In order to trace rash inducing metabolites of nevirapine, we devised a short and efficient multi-gram synthesis of a nevirapine analog that can be coupled to azide containing compounds by click chemistry. PMID- 19773167 TI - Novel non-peptidic vinylsulfones targeting the S2 and S3 subsites of parasite cysteine proteases. AB - We describe here the identification of non-peptidic vinylsulfones that inhibit parasite cysteine proteases in vitro and inhibit the growth of Trypanosoma brucei brucei parasites in culture. A high resolution (1.75 A) co-crystal structure of 8a bound to cruzain reveals how the non-peptidic P2/P3 moiety in such analogs bind the S2 and S3 subsites of the protease, effectively recapitulating important binding interactions present in more traditional peptide-based protease inhibitors and natural substrates. PMID- 19773168 TI - Rippling muscle disease and cardiomyopathy associated with a mutation in the CAV3 gene. AB - Caveolin-3, the myocyte-specific isoform of caveolins, is preferentially expressed in skeletal, cardiac and smooth muscles. Mutations in the CAV3 gene cause clinically heterogeneous neuromuscular disorders, including rippling muscle disease, or cardiopathies. The same mutation may lead to different phenotypes, but cardiac and muscle involvement rarely coexists suggesting that the molecular network acting with caveolin-3 in skeletal muscle and heart may differ. Here we describe an Italian family (a father and his two sons) with clinical and neurophysiological features of rippling muscle disease and heart involvement characterized by atrio-ventricular conduction defects and dilated cardiomyopathy. Muscle biopsy showed loss of caveolin-3 immunosignal. Molecular studies identified the p.A46V mutation in CAV3 previously reported in a German family with autosomal dominant rippling muscle disease and sudden death in few individuals. We suggest that cardiac dysfunction in myopathic patients with CAV3 mutations may be underestimated and recommend a more thorough evaluation for the presence of cardiomyopathy and potentially lethal arrhythmias. PMID- 19773169 TI - Isolated inflammatory myopathy with rimmed vacuoles presenting with dropped head. AB - We describe an unusual case of inflammatory myopathy with rimmed vacuoles associated with dropped head syndrome. Muscle biopsy in our patient revealed variations in fiber size with fiber necrosis and regeneration, accompanied by many rimmed vacuoles and areas of endomysial cell infiltration. Electron microscopy demonstrated autophagic vacuoles and tubulofilamentous inclusions. This myopathy can cause dropped head syndrome in a subgroup of patients. PMID- 19773170 TI - Isolated cerebellopontine angle craniopharyngioma. AB - Primary cerebellopontine angle craniopharyngioma is rare; only 5 surgically treated patients have been reported. We report a 54-year-old female with craniopharyngioma occurring in isolation in the cerebellopontine angle and compare this patient with previously published reports. The origin of and surgical strategy for such tumors are discussed. PMID- 19773171 TI - Acute haematogenous infection of a closed vertebral fracture. AB - Acute haematogenous infection of a closed fractures is rare. A 68-year-old diabetic male sustained a burst fracture of a lumbar vertebra (L2) after a fall onto his back. After 5 days of conservative management, he developed a chest infection and amoxicillin was commenced empirically. However, after 6 days his previously moderate focal L2 back pain had become more severe. Pyrexia and systemic inflammatory markers continued to rise despite administration of antibiotics. Blood cultures and a CT-guided biopsy of L2 both revealed Staphylococcus aureus which was sensitive to flucloxacillin. The patient's symptoms and signs gradually normalised following administration of flucloxacillin for 6 weeks, and the use of a cast brace. We conclude that haematogenous infection can be successfully managed non-operatively. PMID- 19773172 TI - Darwin, natural selection and the biological essentiality of aluminium and silicon. AB - If one was asked to produce a set of 'Trump Cards' based upon 'Forces of Nature Defining Life on Earth' then which card would be 'Top Trump'? I was recently chastised on the Darwin Today website for suggesting Darwin and 'natural selection' rather than, for example, Newton and 'gravity'. Although there is no denying the significance of gravity, my argument in favour of natural selection is simply that gravity is just one factor that contributes towards an outcome which ultimately is defined by natural selection. Both the beauty and the brilliance of natural selection are reflected in its omnipotence to explain the myriad observations of life and, as I will affirm herein, its explanation of the biological essentiality of aluminium and silicon is no exception. PMID- 19773173 TI - Carbonic anhydrase inhibitors. Diazenylbenzenesulfonamides are potent and selective inhibitors of the tumor-associated isozymes IX and XII over the cytosolic isoforms I and II. AB - A series of diazenylbenzenesulfonamides, azo-dye derivatives of sulfanilamide or metanilamide incorporating phenol and amine moieties, were tested for inhibition of the tumor-associated isozymes of carbonic anhydrase (CA, EC 4.2.1.1), CA IX and XII. These compounds showed moderate-low inhibitory activities against the cytosolic isoforms CA I and II (offtargets) and excellent, low nanomolar inhibitory activity against the transmembrane CA IX and XII (K(I)s in the range of 3.5-63 nM against CA IX and 5.0-69.4 nM against CA XII, respectively). The selectivity ratio for inhibiting the tumor-associated CA IX over the offtarget CA II was in the range of 15-104 for these diazenylbenzenesulfonamides, making them among the most isoform-selective inhibitors targeting tumor-associated CAs (over the ubiquitous CA II). Since CA IX/XII were recently shown to be both therapeutic and diagnostic targets for hypoxic solid tumors overexpressing these proteins, such compounds held promise for the management of hypoxic tumors, which are largely non-responsible to classical chemo- and radio-therapy. PMID- 19773174 TI - Synthesis and discovery of pyrazole-5-carbohydrazide N-glycosides as inducer of autophagy in A549 lung cancer cells. AB - A series of novel 3-aryl-1-arylmethyl-1H-pyrazole-5-carbohydrazide N-beta glycoside derivatives was synthesized by the reaction of substituted 1H-pyrazole 5-carbohydrazide with d-sugar and the effects of all the compounds on A549 cell growth were investigated. The results showed that all compounds had inhibitory effects on the growth of A549 lung cancer cells and compound 3d possessed the highest growth inhibitory effect and induced autophagy of A549 lung cancer cells. PMID- 19773175 TI - 2,4-Diaminopyrimidines as histamine H4 receptor ligands--Scaffold optimization and pharmacological characterization. AB - The human histamine H(4) receptor (hH(4)R) is a promising new target in the therapy of inflammatory diseases and disorders of the immune system. For the development of new H(4)R antagonists a broad ligand-based virtual screening was performed resulting in two hits. The dissection of their common annelated aromatic core into its heteromonocyclic components showed that 2,4 diaminopyrimidine is a potent hH(4)R affinity scaffold, which was comprehensively investigated. Structure-activity relationship studies revealed that slight structural changes evoke extensive differences in functional activities and potencies: while o- and p-substituted benzyl amines mainly showed partial agonism, m-substituted and rigidified ones exhibited inverse agonist efficacy. PMID- 19773176 TI - 2-Benzoylpyridine-N(4)-tolyl thiosemicarbazones and their palladium(II) complexes: cytotoxicity against leukemia cells. AB - The palladium(II) complexes [Pd(2Bz4oT)Cl], [Pd(2Bz4mT)Cl], and [Pd(2Bz4pT)Cl] were prepared with N(4)-ortho- (H2Bz4oT) N(4)-meta- (H2Bz4mT) and N(4)-para- (H2Bz4pT) tolyl-thiosemicarbazones derived from 2-benzoylpyridine. The free thiosemicarbazones proved to be highly cytotoxic against Jurkat, HL60 and the resistant HL60.Bcl-X(L) leukemia cell lines at nanomolar concentrations, but were much less cytotoxic to HepG2human hepatoma cells. Upon coordination to palladium(II) the cytotoxic activity against all studied cell lines decreases. However, the high cytotoxicity of the free thiosemicarbazones against leukemia, together with their hepatotoxic profile similar to that of cisplatin suggest that N(4)-tolyl thiosemicarbazones have potential as chemotherapeutic drug candidates. PMID- 19773177 TI - Antibacterial activity of aminoderivatized chitosans against methicillin resistant Staphylococcus aureus (MRSA). AB - This work describes the anti-MRSA activity of aminoderivatized chitosans. Two kinds of aminoethyl-chitosans (AEC), AEC90 and AEC50, having degrees of deacetylation of 90% and 50%, respectively, exhibited the strongest anti-MRSA activities by presenting MICs of 16-64 microg/mL against two standard strains and twelve clinical isolates. The bactericidal activity, thermal and pH stability, and cell membrane integrity effects of AEC90 and AEC50 are also discussed. PMID- 19773178 TI - Primary aortic paraganglioma. PMID- 19773179 TI - Surgical removal of Kirschner wire from the right ventricle, migrated from the femur. PMID- 19773180 TI - Surgery for pulmonary tuberculosis - a 15-year experience. AB - BACKGROUND: Surgery for pulmonary tuberculosis (TB) has become rather limited. However, it is still required for some sequelae and complications. This is a 15 year retrospective study of cases operated upon for pulmonary TB at a centre. PATIENTS AND METHODS: A total of 2878 cases underwent surgical procedures for various complications of pulmonary TB over a 15-year-long period. After excluding those managed by tube thoracostomy, rib resection and open-window thoracostomy, 1297 cases out of this series were taken up for major thoracic surgical procedures. A total of 98 were operated for persistent sputum-positive status, 740 for recurrent massive haemoptysis or chest infections, 2024 for empyema and 18 for diagnostic reasons. Procedures were 830 lung resections, 12 primary thoracoplasties, 295 space-reducing thoracoplasties, 158 decortications, 744 open window thoracoplasties and 837 tube thoracotomies alone. RESULTS: There were 18 early deaths and 37 late deaths. The cause of death was haemorrhage in seven cases and respiratory failure in nine cases and septicaemia in two cases. Late deaths were mostly because of progressive tubercular disease. There was significant morbidity in terms of broncho-pleural fistula (BPF) in 95 cases and persistent sinus in 37 cases. Milder complications such as pneumonia, fever and wound sepsis were noticed in some cases but definite records were not available. BPF was managed by tube drainage followed by either window thoracostomy or thoracoplasty. In multi-drug-resistant (MDR) cases, persistent documented sputum negativity was achieved in 64 out of 86 cases. Results were better in haemoptysis and chest infection group where the desired result was achieved in 699 cases. CONCLUSIONS: Surgery in pulmonary TB is still relevant in many cases and yields a very gratifying result. It is a challenging surgery and this series is a very large one. PMID- 19773181 TI - Predictive accuracy of EuroSCORE: is end-diastolic dysfunction a missing variable? AB - OBJECTIVE: Left-ventricular function has been shown to be an important prognostic factor in estimating operative risk in cardiac surgery. As such, left-ventricular ejection fraction (LVEF) is included in the EuroSCORE. However, left-ventricular function is more comprehensively assessed by measures of both systolic and diastolic dysfunction. We hypothesised that end-diastolic dysfunction is an additional independent indicator for predicting outcome following coronary artery bypass grafting (CABG). METHODS: We retrospectively assessed all patients undergoing isolated off-pump CABG between October 2000 and September 2004 by two surgeons. Left-ventricular end-diastolic pressure (LVEDP), measured during cardiac catheterisation, was used as a measure of left-ventricular diastolic dysfunction. Logistic regression was used to assess the association between LVEDP (a continuous and dichotomous variable) and mortality, while adjusting for EuroSCORE. RESULTS: A total of 925 patients with complete LVEDP data were identified and stratified as follows: group 1 (LVEF >30% and LVEDP <20 mmHg), group 2 (LVEF <30% and LVEDP <20 mmHg), group 3 (LVEF >30% and LVEDP >20 mmHg) and group 4 (LVEF <30% and LVEDP >20 mmHg). Mortality increased progressively from group 2 (1.9%, odds ratio (OR) 1.22, RR 1.21, p 0.58) to group 3 (5.6%, OR 3.81, RR 3.66, p 0.07) and was highest in group 4 (7.4%, OR 5.18, RR 4.87, p 0.08). Receiver operating characteristic (ROC) curve c-characteristic improved from 0.7 to 0.78 when EuroSCORE was combined with LVEDP, identifying LVEDP as an independent predictor of mortality after adjusting for EuroSCORE. Logistic equation: odds of death = exp(-6.3283+[EuroSCORE x 0.1813]+[EDP x 0.0954]). CONCLUSIONS: LVEDP as a marker of diastolic dysfunction seems an important variable in predicting patient-specific risk and should be considered for incorporation in future risk models. PMID- 19773182 TI - Increased circulating IL-8 is associated with reduced IGF-1 and related to poor metabolic control in adolescents with type 1 diabetes mellitus. AB - BACKGROUND: A dysregulated growth hormone (GH)/insulin-like growth factor 1 (IGF 1) axis is well-recognized in children and adolescents with type 1 diabetes mellitus (T1DM). Decreased IGF-1 levels can also be found in chronic inflammatory diseases, while hyperglycemia promotes inflammatory cytokine production. Therefore, inflammatory cytokines may link poor metabolic control with GH/IGF-1 axis changes. This study examined the relationship between serum inflammatory cytokines and IGF-1 in adolescents (age 13-18) with TIDM in chronic poor (n=17) or favorable (n=19) glucose control. Poor control (PC) was defined as >or=3, consistent HbA1C>9% during the previous 2 years, while favorable control (FC) was consistent levels of HbA1C<9%. RESULTS: HbA1C (FC: 7.5+/-0.6%; PC: 10.5+/-0.9%, p<0.001) and interleukin (IL)-8 (FC: 3.7+/-4.0 pg/ml; PC: 7.4+/-4.3 pg/ml, p=0.01) were increased and IGF-1 (FC: 536.5+/-164.3 ng/ml; PC: 408.9+/-157.1 ng/ml, p=0.03) was decreased in patients with poor control compared to patients with favorable control. Moreover, IL-8 was inversely correlated with IGF-1 (r= 0.40, p=0.03) and positively correlated with HbA1C (r=0.36, p=0.03). CONCLUSIONS: In adolescents with T1DM and chronic, poor glucose control, increased serum IL-8 is associated with reduced IGF-1 suggesting a pro-inflammatory milieu that may contribute to alterations in the GH/IGF-1 axis. PMID- 19773184 TI - Stability of vaccines - bridging from stability data to continuous safety and efficacy throughout shelf life - an always reliable approach? AB - Stability studies are important tools to reliably ensure that efficacy and safety of medicinal products will remain unchanged from release of drug product until the end of shelf life. For complex medicinal products such as biological medicinal products, including vaccines, design and conduct of such studies requires particularly careful considerations in order to ensure that technical data resulting from stability studies are indeed indicative for unchanged clinical performance. Ideally, relevance of specifications controlled by stability studies as well as definition of shelf life should be justified by acceptable clinical data obtained with product at the end of the shelf life claimed. PMID- 19773183 TI - Precursor ion independent algorithm for top-down shotgun proteomics. AB - We present a precursor ion independent top-down algorithm (PIITA) for use in automated assignment of protein identifications from tandem mass spectra of whole proteins. To acquire the data, we utilize data-dependent acquisition to select protein precursor ions eluting from a C4-based HPLC column for collision induced dissociation in the linear ion trap of an LTQ-Orbitrap mass spectrometer. Gas phase fractionation is used to increase the number of acquired tandem mass spectra, all of which are recorded in the Orbitrap mass analyzer. To identify proteins, the PIITA algorithm compares deconvoluted, deisotoped, observed tandem mass spectra to all possible theoretical tandem mass spectra for each protein in a genomic sequence database without regard for measured parent ion mass. Only after a protein is identified, is any difference in measured and theoretical precursor mass used to identify and locate post-translation modifications. We demonstrate the application of PIITA to data generated via our wet-lab approach on a Salmonella typhimurium outer membrane extract and compare these results to bottom-up analysis. From these data, we identify 154 proteins by top-down analysis, 73 of which were not identified in a parallel bottom-up analysis. We also identify 201 unique isoforms of these 154 proteins at a false discovery rate (FDR) of <1%. PMID- 19773185 TI - 'Faultless' ignorance: strengths and limitations of epistemic definitions of confabulation. AB - There is no satisfactory account for the general phenomenon of confabulation, for the following reasons: (1) confabulation occurs in a number of pathological and non-pathological conditions; (2) impairments giving rise to confabulation are likely to have different neural bases; and (3) there is no unique theory explaining the aetiology of confabulations. An epistemic approach to defining confabulation could solve all of these issues, by focusing on the surface features of the phenomenon. However, existing epistemic accounts are unable to offer sufficient conditions for confabulation and tend to emphasise only its epistemic disadvantages. In this paper, we argue that a satisfactory epistemic account of confabulation should also acknowledge those features which are (potentially) epistemically advantageous. For example, confabulation may allow subjects to exercise some control over their own cognitive life which is instrumental to the construction or preservation of their sense of self. PMID- 19773186 TI - Amyloidosis: an unusual case of persistent oral ulceration. AB - We report a case of systemic amyloidosis, with an unusual oral presentation, in a 70-year-old patient suffering from light chain myeloma. The patient presented with extensive ulceration of the tongue and alveolar ridges, and a large swelling in the floor of mouth. Incisional biopsies of the tongue and floor of mouth confirmed amyloid deposition within the tissues with evidence of necrotic ulceration. Amyloid deposition in the oral cavity usually manifests as macroglossia, however it can present elsewhere in the mouth as nodular or plaquelike lesions. Ulceration is a rare finding. This case highlights the variable nature of this condition, and how it can present a challenge to clinicians in terms of diagnosis and treatment. PMID- 19773187 TI - Effects of tongue position on mandibular muscle activity and heart rate function. AB - OBJECTIVES: A primary goal of pain management for muscle-related pain is to reduce masticatory muscle activity. This study aimed to investigate masticatory muscle group activity and heart rate variability change when the tongue was placed on the palate or the floor of the mouth in a healthy pain-free sample. STUDY DESIGN: Participants were 23 females and 18 males with a mean age of 19.6 years (standard deviation = 1.5). Muscle activity was measured using surface electromyography and heart period were measured using electrocardiography. The experimental protocol consisted of 3 periods: baseline, tongue placement on the floor of mouth, and tongue placement on palate. RESULTS: Results indicated significantly more activity in the temporalis and suprahyoid muscle regions as well as a significant reduction in heart rate variability when the tongue was positioned on the palate compared with tongue position on the floor of the mouth. CONCLUSIONS: Instructions to place the tongue on the roof of the mouth are not instructions that will promote reduced physiological functioning (i.e., relaxation) but rather promote small, but potentially important increases in overall activity as indexed by muscle tone and cardiac function. PMID- 19773188 TI - Amphibian decline and mass mortality: the value of visualizing ranavirus in tissue sections. PMID- 19773189 TI - Japan Elaprase Treatment (JET) study: idursulfase enzyme replacement therapy in adult patients with attenuated Hunter syndrome (Mucopolysaccharidosis II, MPS II). AB - This open-label clinical study enrolled 10 adults with attenuated Mucopolysaccharidosis II and advanced disease under the direction of the Japan Society for Research on Mucopolysaccharidosis Disorders prior to regulatory approval of idursulfase in Japan. Ten male patients, ages 21-53 years, received weekly intravenous infusions of 0.5 mg/kg idursulfase for 12 months. Significant reductions in lysosomal storage and several clinical improvements were observed during the study (mean changes below). Urinary glycosaminoglycan excretion decreased rapidly within the first three months of treatment and normalized in all patients by study completion (-79.9%). Liver and spleen volumes also showed rapid reductions that were maintained in all patients through study completion ( 33.2% and -31.0%, respectively). Improvements were noted in the 6-Minute Walk Test (54.5 m), percent predicted forced vital capacity (3.8 percentage points), left ventricular mass index (-12.4%) and several joint range of motions (8.1-19.0 degrees). Ejection fraction and cardiac valve disease were stable. The sleep study oxygen desaturation index increased by 3.9 events/h, but was stable in 89% (8/9) of patients. Idursulfase was generally well-tolerated. Infusion-related reactions occurred in 50% of patients and were mostly mild with transient skin reactions that did not require medical intervention. Two infusion-related reactions were assessed as serious (urticaria and vasovagal syncope). One patient died of causes unrelated to idursulfase. Anti-idursulfase antibodies developed in 60% (6/10) of patients. In summary, idursulfase treatment appears to be safe and effective in adult Japanese patients with attenuated MPS II. These results are comparable to those of prior studies that enrolled predominantly pediatric, Caucasian, and less ill patients. No new safety risks were identified. PMID- 19773190 TI - Heterologous prime-boost strategy in non-human primates combining the infective dengue virus and a recombinant protein in a formulation suitable for human use. AB - OBJECTIVE: The aim of the present work was to test the concept of the heterologous prime-boost strategy combining an infective dengue virus with a recombinant chimeric protein carrying domain III of the envelope protein. METHODS: Two studies in monkeys, combining recombinant protein PD5 (domain III of the envelope protein from dengue-2 virus, fused to the protein carrier P64k) and the infective dengue virus in the same immunization schedules were carried out. Humoral and cell-mediated immunity were evaluated. RESULTS: In the first study, monkeys received four doses of the protein PD5 and were subsequently infected with one dose of dengue virus. Antibody response measured after virus inoculation was significantly higher compared to that in non-primed monkeys and comparable to that elicited after two doses of infective virus. In a second study, monkeys were infected with one dose of the virus and subsequently boosted with one dose of the recombinant protein, reaching high levels of neutralizing antibodies, which were still detectable 14 months after the last immunization. In addition, the cellular immune response was also recalled. CONCLUSIONS: The results obtained in the present work support the approach of heterologous prime-boosting, in either order prime or boost, combining the chimeric protein PD5 (formulated in alum-CPS-A) and an infective dengue virus. The latter could potentially be replaced by an attenuated vaccine candidate. PMID- 19773191 TI - Interferons and autoimmune disorders. AB - Interferons are ubiquitous cytokines produced by all mononuclear cell types in response to infection by a DNA or RNA virus. There are three major classes of interferons: type I or nonimmune interferons consist chiefly of interferons alpha produced by leukocytes and of interferon beta produced by fibroblasts, although there are several other less important variants; type II or immune interferon is interferon gamma, which is mainly produced by NK cells and T cells; and type III consists of the lambda interferons. Each type is characterized by a specific receptor and signal transduction pathway. Toll-like receptors (TLRs) on the cell membrane and endosomes recognize viruses and other microorganisms. Binding of DNA or RNA to endosomal TLRs generates a signal whose transduction pathways lead to molecules capable of binding to genes for various interferons, interleukin-1, and TNFalpha. Interferons can stimulate or inhibit up to 300 different genes encoding proteins involved in antiviral defense mechanisms, inflammation, adaptive immunity, angiogenesis, and other processes. The properties of interferons are used to treat a number of viral infections (e.g., hepatitis B and hepatitis C), inflammatory diseases (interferon beta for multiple sclerosis and interferon gamma for systemic sclerosis), and malignancies. Overactivation of the interferon pathways has been demonstrated in patients with systemic lupus erythematosus. The result is a characteristic pattern of mRNA expression known as the interferon signature. Interferon overactivation is related to inadequate clearance of apoptotic particles with accumulation of apoptosis products (DNA-CpG motifs and U RNA). Similar abnormalities have been found in patients with primary Sjogren's syndrome, systemic sclerosis, and polymyositis, as well as in some cases of rheumatoid arthritis. Immunomodulation strategies designed to decrease interferon overactivity are being evaluated in patients with systemic lupus erythematosus. PMID- 19773192 TI - Osteoporosis in men: other secondary causes. PMID- 19773193 TI - Advanced modeling strategy for the analysis of heart valve leaflet tissue mechanics using high-order finite element method. AB - Modeling soft tissue using the finite element method is one of the most challenging areas in the field of biomechanical engineering. To date, many models have been developed to describe heart valve leaflet tissue mechanics, which are accurate to some extent. Nevertheless, there is no comprehensive method to modeling soft tissue mechanics, This is because (1) the degree of anisotropy in the heart valve leaflet changes layer by layer due to a variety of collagen fiber densities and orientations that cannot be taken into account in the model and also (2) a constitutive material model fully describing the mechanical properties of the leaflet structure is not available in the literature. In this framework, we develop a new high-order element using p-type finite element formulation to create anisotropic material properties similar to those of the heart valve leaflet tissue in only one single element. This element also takes the nonlinearity of the leaflet tissue into consideration using a bilinear material model. This new element is composed a two-dimensional finite element in the principal directions of leaflet tissue and a p-type finite element in the direction of thickness. The proposed element is easy to implement, much more efficient than standard elements available in commercial finite element packages. This study is one step towards the modeling of soft tissue mechanics using a meshless finite element approach to be applied in real-time haptic feedback of soft-tissue models in virtual reality simulation. PMID- 19773194 TI - Histamine N-methyltransferase Thr105Ile is not associated with Parkinson's disease or essential tremor. AB - A functional variant in the Histamine N-Methyltransferase gene (HNMT - rs11558538) resulting in a threonine to isoleucine substitution (Thr105Ile) has been shown to impair histamine degradation. Two recent studies reported that the threonine allele of this polymorphism might be a risk factor for Parkinson disease (PD) and essential tremor (ET) development. Although PD and ET are considered different entities, they share some clinical and pathological features, suggesting a possible joint etiology. In this study we assess the role of the Thr105Ile variant in PD and ET development, genotyping the variant in a North American Caucasian PD and ET case-control series. Statistical analysis did not identify any significant association between this variant and PD or ET; therefore, our findings do not support the HNMT Thr105Ile variant as a factor in disease development or a genetic link between the disorders. PMID- 19773195 TI - Botanic gardens science for conservation and global change. AB - The contributions of botanic gardens to conservation biology and global-change research need to be understood within the context of the traditional strengths of such gardens in herbarium collections, living collections and interactions with the public. Here, I propose that research in conservation planning, modelling species responses to climate change, conservation of threatened species and experimental tests of global change build on the core strengths of botanic gardens. However, there are limits to what can be achieved through traditional gardens-based programs, and some botanic gardens have adapted their research to include studies of threatening processes and to monitor and verify global-change impacts. There is an opportunity for botanic gardens to use their living collections more effectively in global-change research and for them to have a role in linking biodiversity conservation with benefits derived from ecosystem services. PMID- 19773196 TI - Plants on the IUCN Red List: setting priorities to inform conservation. AB - The continuing decline of plant diversity will have a greater impact on human society than any other type of biodiversity loss. It is imperative, therefore, that efforts are increased to assess the conservation status of plants for the IUCN Red List of Threatened Species, the de facto baseline reference for many conservation decisions. As discussed here, a review of plants on the current Red List suggests that priorities for future Red Listing should serve multiple purposes: to inform national conservation policy, to contribute to global conservation analyses, to encompass the phylogenetic diversity of plants and to address the dependence of human societies on plants. Future progress in plant Red Listing requires greater participation by the world's herbaria and increased support for expert networks. PMID- 19773197 TI - Synthesis, growth and characterization of bis (glycine) lithium molybdate--a semi organic NLO material. AB - Single crystals of bis (glycine) lithium molybdate [BGLM] with dimensions 20mmx10mmx5mm were grown by slow evaporation technique. The grown crystals were subjected to powder X-ray diffraction studies. Functional groups of the crystallized molecules were confirmed by FTIR analyses. Transmission range of the crystal was determined by UV-vis-NIR spectra. Vickers microhardness test was performed on the prominent plane (011) of the grown crystal. The NLO property of the crystal was confirmed by Kurtz SHG test and compared with NLO efficiency of KDP crystal. PMID- 19773199 TI - The capsaicin cough reflex in patients with symptoms elicited by odorous chemicals. AB - Patients with multiple chemical sensitivity and eczema patients with airway symptoms elicited by odorous chemicals have enhanced cough reflex to capsaicin when applying the tidal breathing method. The aims of the present study were to test whether the capsaicin induced cough reflex was enhanced when applying the single breath inhalation method in similar groups of patients with symptoms related to odorous chemicals e.g. other persons wearing of perfume; and to investigate to what extent the reporting of lower airway symptoms influenced the cough reflex. Sixteen patients fulfilling Cullen's criteria for multiple chemical sensitivity and 15 eczema patients with airway symptoms elicited by odorous chemicals were compared with 29 age-matched, healthy controls. We measured C5- the capsaicin concentration causing five coughs or more--using the single breath inhalation test. No difference was found between groups in age, body mass index or pulmonary function. The median C5 were 129 micromol/L (control group), 48 micromol/L (multiple chemical sensitivity patients), 32 micromol/L (eczema patients). The reporting of lower airway symptoms from odorous chemicals was significantly (p<0.05) correlated to increased cough reflex sensitivity to capsaicin, independent of patient group or co-existence of asthma. The results suggest that the C5 is not reliable for diagnosing MCS but C5 can be used to verify presence of lower airway symptoms related to odorous chemicals. PMID- 19773200 TI - MicroRNAs in Barrett's esophagus and esophageal adenocarcinoma. AB - The molecular genetics of Barrett's esophagus (BE) and its evolution to esophageal adenocarcinoma (EAC) have been widely studied; however, the molecular mechanism of BE-EAC carcinogenesis has not been completely understood. MicroRNA (miRNA) is now essential to understand the molecular mechanism of cancer progression. Recent findings include the following: firstly, miRNA expression profiles can distinguish between BE and EAC; secondly, miR-196a is upregulated in EAC tissues targeting annexin A1, thereby exerting antiapoptotic effects and contributing to EAC cell survival; miR-196a may also constitute a good biomarker of progression during BE-EAC carcinogenesis; and thirdly, The miR-106b-25 polycistron is activated by genomic amplification and is involved in esophageal neoplastic progression and proliferation via the suppression of two target genes, p21 and Bim. PMID- 19773201 TI - Cutaneous T cell lymphoma and graft-versus-host disease: a comparison of in vivo effects of extracorporeal photochemotherapy on Foxp3+ regulatory T cells. AB - Extracorporeal photochemotherapy (ECP) is a well established treatment for both cutaneous T cell lymphoma (CTCL) and graft-versus-host disease (GVHD). However, the general effector mechanism is not fully settled. Twenty-four patients with CTCL and 14 patients with GVHD were included to assess the relative numbers of regulatory T cells (Treg) and any change in the serum cytokine profile during 6 months of ECP therapy. The relative amount of Treg cells was twice as high in CTCL compared to GVHD and healthy controls. TGF-beta was on average three times higher in GVHD than in CTCL. Both patient groups had a small but significant increase in TGF-beta after treatment. Our results indicate a strengthened Treg function as a result of ECP. Elevated TGF-beta may indicate high Treg activation in GVHD, whereas an increased number of Treg cells in CTCL could be interpreted as a response that is involved in down-regulating the lymphoma cells. PMID- 19773202 TI - The nucleus raphe magnus suppresses vomiting, and the solitary nucleus and 5-HT are not involved in this suppression. AB - In previous paper, we reported that stimulation of the nucleus raphe magnus (stim NRM) inhibits the induction of retching by afferent vagal fibers (VAs). We performed the present study to identity the transmitter of inhibition and then the site. The following results were obtained in decerebrated and paralyzed dogs. 1) The induction of fictive retching was suppressed by i.v. injection of 5-HT, and by 4th ventricular administration of 5-HT or a 5-HT3-receptor (R) agonist, 1 (m-chlorophenyl)-biguanade hydrochloride (m-CPBG). 2) Both forms of suppression were antagonized by i.v. injection of ondansetron, a 5-HT3-R antagonist. 3) Administration of the antagonist into the 4th ventricle did not affect the induction or its suppression by stim-NRM. These results suggest that the transmission from VAs to neurons in the nucleus solitarius (NTS) is suppressed by 5-HT via 5-HT3-R. However, these results also suggest that both the transmitter and receptor are not involved in the induction of retching by VAs or in its suppression by the NRM. Next, we examined the site of suppression. Unitary firings of NTS neurons in response to pulse-train stimulation of VAs were not inhibited by NRM stimulation. Moreover, the firing of NTS neurons during the induction of retching by vagal stimulation did not significantly decrease with the superimposition of stim-NRM, although the induction of retching was completely suppressed. These results suggest that suppression of the induction of retching by the descending inhibitory system of pain did not occur in the synapse between afferent vagal fibers and NTS neurons. The site of suppression is discussed. PMID- 19773203 TI - Simultaneous derivatization and extraction of free cyanide in biological samples with home-made hollow fiber-protected headspace liquid-phase microextraction followed by capillary electrophoresis with UV detection. AB - A new method is reported for the simultaneous derivatization and extraction of free cyanide in biological samples using home-made hollow fiber-protected headspace liquid-phase microextraction (HF-HS-LPME) followed by capillary electrophoresis (CE) determination. The acceptor phase containing Ni(II)-NH(3) (as derivatization agent), sodium carbonate and ammonium pyromellitate (as internal standard) is held within a hollow fiber membrane, affixed to a syringe needle and immersed in the headspace of sample container. The extracted cyanide from the neutral samples forms a stable Ni(CN)(4)(2-) complex which is determined by CE. Parameters affecting extraction efficiency were investigated and optimized. For optimum peak shapes, the capillary was coated with cetyltrimethylammonium bromide (CTAB). The calibration curve was linear for concentrations of CN(-) in the range from 0.1 to 20 micromol L(-1) (R(2)=0.9987). The LOD (S/N=3) was estimated to be 0.01 micromol L(-1) of CN(-) concentration. Such a detection sensitivity is high enough for free cyanide determination in common environmental and biological samples. Excellent repeatability of the extraction (RSD < or = 5.6%, n=5) was achieved. The feasibility of this method was demonstrated by analyzing human urine and saliva samples with spiked recoveries in the range of 92-103.4%. This work provided an efficient alternative to the present headspace microextraction techniques such as headspace solid-phase microextraction (HS-SPME) and headspace single-drop microextraction (HS-SDME). PMID- 19773204 TI - A novel and sensitive method for ethinylestradiol quantification in human plasma by high-performance liquid chromatography coupled to atmospheric pressure photoionization (APPI) tandem mass spectrometry: application to a comparative pharmacokinetics study. AB - In the present study, a novel, fast, sensitive and robust method to quantify ethinylestradiol in human plasma using 17alpha-ethinylestradiol-d4 as the internal standard (IS) is described. The analyte and the IS were extracted from acidified plasma by liquid-liquid extraction (LLE) using diethyl ether-hexane followed by online solid phase extraction (SPE) using online C18 cartridges. Extracted samples were analyzed by high-performance liquid chromatography coupled to atmospheric pressure photoionization tandem mass spectrometry (HPLC-APPI MS/MS). Chromatography was performed isocratically on a C18, 5 microm analytical column. The method had a chromatographic run time of 2.50 min and a linear calibration curve over the range 5-500 pg ml(-1) (r(2)>0.9992). The lowest concentration quantified was 5 pg ml(-1), demonstrating acceptable accuracy and precision. The intra-assay precisions ranged from 2.1 to 14.6%, while inter-assay precisions ranged from 4.4 to 11.4%. The intra-assay accuracies ranged from 94.6 to 103.8%, while the inter-assay accuracies ranged from 98.9 to 101.6%. The recovery of ethinylestradiol was determined as part of the assay validation process and was 73.1 and 79.0% for the concentrations 15 and 375 pg ml(-1), respectively. Short-term stability showed that ethinylestradiol was stable in plasma for at least 19 h at room temperature or for at least 385 days when stored at -20 degrees C. In the study of bioequivalence conducted in Brazil, healthy volunteers received two ethinylestradiol 0.035 mg tablet formulations using an open, randomized, two-period crossover design with a 2-week washout interval. Since the 90% confidence interval for C(max) and area under the curve ratios were all inside the 80-125% interval proposed by the US Food and Drug Administration, it was concluded that the two ethinylestradiol formulations are bioequivalent with respect to both the rate and the extent of absorption. PMID- 19773205 TI - Antimicrobial resistance and molecular epidemiology of Neisseria gonorrhoeae in Taiwan. PMID- 19773206 TI - Arsenic trioxide modulates the central snail neuron action potential. AB - BACKGROUND/PURPOSE: The electropharmacological effect of arsenic trioxide (As2O3) is unknown. The present study investigated the effects of As2O3 on spontaneous neuronal impulse activity. METHODS: Intracellular recordings and the two electrode voltage clamp method were used to study the effect of As2O3 on the RP4 neuron, the number 4 neuron in the right partial ganglion of the giant African snail (Achatina fulica Ferussac). RESULTS: The RP4 neuron generated spontaneous action potentials, which were affected by As2O3 in a concentration-dependent manner. Extracellular application of 1 or 3 mM As2O3 decreased the frequency of spontaneously generated action potentials. At 10 mM, As2O3 first depolarized and then elicited irreversible bursts of potential (BoPs) at 60 minutes after administration. At 30 mM, As2O3 depolarized the resting membrane potential and abolished the spontaneous action potentials. The BoPs elicited by 10mM As2O3 were blocked when neurons were pretreated with phospholipase C (PLC) inhibitors (10 microM U73122 or 3mM neomycin). The BoPs elicited by As2O3 remained unchanged in the presence of KT5720, verapamil, or calcium replacement solution. Voltage-clamp studies revealed that 10mM As2O3 decreased the fast inward current and had no effect on the steady-state outward current of the neuron. CONCLUSION: As2O3 at 10 mM elicits BoPs in central snail neurons and this effect may relate to the PLC activity of the neuron, rather than protein kinase A activity, or calcium influxes of the neuron. As2O3 at higher concentration irreversibly abolishes the spontaneous action potentials of the neuron. PMID- 19773207 TI - Timing of acute respiratory distress syndrome onset is related to patient outcome. AB - BACKGROUND/PURPOSE: Acute respiratory distress syndrome (ARDS) is a major cause of mortality and morbidity in adult intensive care units. The relationship between the timing of ARDS onset and outcome is not well known. The objective of this study was to investigate the outcome of patients with late-onset ARDS during hospitalization. METHODS: We prospectively enrolled patients who were intubated and fulfilled ARDS criteria in medical and surgical intensive care units in a tertiary referral medical center from December 1, 2004 to May 31, 2006. Those who developed ARDS more than 48 hours after hospital admission were categorized as late-onset ARDS; otherwise, they were defined as early-onset ARDS. We assessed the risk factors for hospital mortality using multivariate analysis and 90-day survival using Kaplan-Meier analysis between early- and late-onset ARDS, and between direct and indirect ARDS. RESULTS: A total of 172 patients were included in the study. Overall mortality rate was 70%. Late-onset ARDS [odds ratio (OR): 3.06; 95% confidence interval (CI): 1.41 to 6.63; p = 0.005] and initial shock (OR: 8.20; 95% CI: 3.39-19.79; p < 0.001) were the independent risk factors for hospital mortality. Patients with late-onset ARDS had higher hospital mortality rate (83% vs. 60%; p = 0.002), longer duration of mechanical ventilation (27.0 +/ 23.4 vs. 14.6 +/- 11.5 days; p < 0.001) and length of intensive care unit stay (25.5 +/- 20.6 vs. 15.6 +/- 13.6 days; p < 0.001) than patients with early-onset ARDS. The 90-day survival showed that both early-onset ARDS and direct ARDS were associated with better survival. CONCLUSION: Patients with late-onset ARDS are associated with poor prognosis and should be managed as high-risk patients. PMID- 19773208 TI - Alterations in respiratory mechanics in mechanically ventilated patients following bronchoalveolar lavage. AB - BACKGROUND/PURPOSE: Bronchoalveolar lavage (BAL) can be used for a variety of diagnostic purposes in mechanically ventilated patients. BAL can cause changes in respiratory mechanics. However, the risk factors associated with these changes remain unknown. The current study tried to identify the risk factors that contribute to changes in respiratory mechanics following BAL. METHODS: Changes in respiratory mechanics were assessed in 56 mechanically ventilated patients who received BAL using an interrupter method under constant flow. RESULTS: Intrinsic positive end-expiratory pressure (PEEPi) was correlated significantly with changes in respiratory system resistance and compliance following BAL in mechanically ventilated patients (p = 0.003). In 14 patients with PEEPi > 1 cmH2O, maximal resistance (Rmax) before BAL was 22.5 +/- 5.9 cmH2O/L/S, increasing to 31.6 +/- 8.5 cmH2O/L/S immediately after BAL, and remaining high (28.4 +/- 7.5 cmH2O/L/S) 30 minutes later (p < 0.001). Increase in minimal resistance (Rmin), delta resistance (DeltaR), and decrease in compliance followed the same time trend. In 42 patients with PEEPi < or = 1 cmH2O, Rmax before BAL was 15.5 +/- 3.5 cmH2O/L/S, increasing to 17.6 +/- 4.6 cmH2O/L/S immediately after BAL, and decreasing to 16.6 +/- 4.3 cmH2O/L/S (p < 0.001) 30 minutes later. Increase in Rmin, DeltaR and decrease in compliance were similar to those seen with Rmax. Increases in Rmax, Rmin and DeltaR, and decrease in compliance following BAL were significantly higher in patients with significant PEEPi than in those without throughout the recording period (p < 0.001). CONCLUSION: Patients with significant PEEPi experienced greater changes in respiratory mechanics than those without. Physicians should be cautious when performing BAL in such patients. PMID- 19773209 TI - Diagnostic value of finger-guided prostate nodule biopsy combined with systemic random biopsy. AB - BACKGROUND/PURPOSE: The purpose of this study was to compare prostate cancer detection rates and pathology results, using the Gleason grading system, of 12 core systemic random transrectal ultrasound-guided prostate biopsy (SB) and 3 core finger-guided prostate nodule biopsy (FGNB). METHODS: Between January 2002 and December 2006, 148 patients with digitally palpable prostate nodules received SB and additional FGNB. The prostate cancer detection rates and Gleason scores of positive cancer specimens were compared between SB and combination biopsy (SB + FGNB). The patients' characteristics, including age, prostate specific antigen (PSA), percentage of free PSA and prostate volume were also recorded. RESULTS: With simple SB, FGNB, and combination biopsy, the prostate cancer detection rates were 39.9%, 37.9%, and 44.6%, respectively. Of the 66 patients with prostate cancer, the Gleason sum was underestimated in three patients with simple SB only and in one patient with FGNB only. The false-negative rates for SB and FGNB were 10.6% and 15.2%, respectively. CONCLUSION: In patients with a palpable prostate nodule, combination biopsy with systemic and nodule biopsy could avoid some misdiagnoses of prostate cancer and provide more accurate information for pathology grading. PMID- 19773210 TI - Significant relationship between serum high-sensitivity C-reactive protein, high density lipoprotein cholesterol levels and children with Kawasaki disease and coronary artery lesions. AB - BACKGROUND/PURPOSE: The aim of this study was to understand the association between Kawasaki disease (KD) in children and serum high-sensitivity C-reactive protein (hs-CRP), which is a sensitive indicator of inflammation, lipid profiles and coronary artery lesions. METHODS: Between July 2005 and December 2007, 119 children with KD at least 1 year after diagnosis were recruited. The children were classified into one of two groups: Group I comprised 55 children with KD and coronary aneurysms; Group 2 comprised 64 children with KD and normal coronary arteries. The relationship between hs-CRP concentration and high-density lipoprotein cholesterol (HDL-C) and the size of arterial lesions was investigated in Group I 1 year after onset of KD. RESULTS: Serum hs-CRP levels in Group I (mean, 0.251 mg/dL) were significantly greater than those in Group II (mean, 0.162 mg/dL; p = 0.011). However, plasma HDL-C levels in Group I (mean 42.51 mg/dL) were significantly lower than those in Group II (mean, 44.34 mg/dL; p = 0.037). In Group I, there was a positive association between hs-CRP and the size of coronary artery lesions (r = 0.672, p = 0.035), but no association between lipid profiles, including HDL-C, and coronary artery lesions (all p > 0.05). CONCLUSION: Our results support the possibility of ongoing low-grade inflammation late after the acute phase of KD in children with coronary aneurysms. Serum hs CRP and HDL-C levels are associated with coronary artery lesions in children with KD. PMID- 19773211 TI - Clinicopathological study of oral giant cell fibromas. AB - BACKGROUND/PURPOSE: Oral giant cell fibromas (GCFs) are found predominantly in Caucasians and rarely in other races. This retrospective study evaluated the clinicopathological features of 24 GCFs in Taiwanese patients. METHODS: Twenty four consecutive cases of oral GCF were investigated from 1987 to 2008. Clinical data and microscopic features were reviewed and analyzed. RESULTS: The mean age of patients at the time of diagnosis was 29 years. Oral GCF occurred more commonly in patients between 11 and 40 years of age. There were 12 male and 12 female patients. The lesions were found more frequently on the tongue (8 cases) and gingiva (7 cases). The mean size of the lesion was 5.5mm (range, 2-10 mm) in greatest dimension. GCF is misdiagnosed frequently as fibroma (19 cases) or papilloma (5 cases). All tumors were treated by total surgical excision and no recurrence was found after treatment. Microscopically, the GCF was a sessile or pedunculated mass covered with a thin layer of parakeratinized or orthokeratinized stratified squamous epithelium. The tumor was composed mainly of loose or dense fibrous connective tissue with well-formed capillaries and no inflammation. The consistent and diagnostic feature was the presence of large stellate giant cells, usually with one or two nuclei. Multinucleated giant cells were seen occasionally. These giant cells were most numerous in the connective tissue just beneath the epithelium. CONCLUSION: Oral GCFs show no significant sex predilection and occur in patients in the second to fourth decades of life. Usually, the lesions are < 1 cm in diameter and are found more frequently on the tongue and gingiva. GCF resembles fibroma or papilloma and is difficult to diagnose correctly at the first glance. All GCFs can be treated by conservative surgical excision without subsequent recurrence. PMID- 19773212 TI - Amelioration of hypophosphatemic rickets and osteoporosis with pamidronate and growth hormone in Lowe syndrome. AB - The oculocerebrorenal syndrome of Lowe, an X-linked multisystem disorder, was diagnosed in a male patient who presented with typical abnormalities of the eyes, kidneys and nervous system. Besides congenital cataracts, renal tubular dysfunction and psychomotor retardation, the patient had also suffered from profound failure to thrive, growth hormone deficiency, severe osteoporosis with hypophosphatemic rickets, and progressive renal dysfunction since early childhood, which were attributed to the metabolic derangements following Fanconi syndrome. Direct sequencing of the OCRL1 gene (responsible for the oculocerebrorenal syndrome of Lowe) revealed a de novo c.2282_2283insT in exon 20, which resulted in premature termination of translation (D762X). After monthly intravenous administration of pamidronate since the age of 17.8 years, his urine creatinine clearance and tubular resorption of phosphate increased slightly and bone mineral density was much improved (Z score increased from -7.3 to -3.3) without deterioration of renal function. Simultaneous growth hormone therapy enhanced the positive response. The beneficial osseous and renal effects of the bisphosphonate, along with growth hormone treatment in Lowe syndrome with hypophosphatemia, may be related to reduced renal calcium and phosphate excretion. PMID- 19773213 TI - Lingual carcinoma metastases presenting as spontaneous pneumothorax. AB - Spontaneous pneumothorax is a rare manifestation of primary lung cancer or metastasis. We report a 39-year-old man with well-differentiated squamous cell carcinoma of the tongue and cervical lymph node metastases. He developed lung metastases and spontaneous pneumothorax 22 months later after intra-arterial infusion chemotherapy. The patient was managed with partial lung resection under thoracotomy. The pneumothorax resolved completely after the operation. Histological examination demonstrated metastatic squamous cell carcinoma, which had led to a bronchopleural fistula with subsequent induction of pneumothorax. The patient recovered uneventfully and continued to receive adjuvant chemotherapy in the oncology surgery outpatient department. Unfortunately, the tumors of the tongue and cervical lymph nodes progressively enlarged despite treatment. Eventually, the patient died of respiratory failure 5 months later. In most of the previously reported cases, pulmonary metastases associated with spontaneous pneumothorax usually originate from osteogenic or soft-tissue sarcomas. Although rare, pulmonary metastasis should be considered in the etiology of spontaneous pneumothorax. Despite advanced disease, surgical treatment may be feasible. PMID- 19773214 TI - Combined pancreatic endocrine tumor and serous cystadenoma. AB - Pancreatic serous cystadenomas account for 1-2% of all exocrine pancreatic tumors, and endocrine tumors account for 1-2% of all pancreatic neoplasms. The combination of pancreatic serous cystadenoma and endocrine tumor is even rarer. Here, we report two cases of combined pancreatic serous adenoma and endocrine tumor. One was a 64-year-old woman with serous cystadenoma and pancreatic endocrine tumor. The other case was a 28-year-old woman with von Hippel-Lindau disease with combined pancreatic serous oligocystic adenoma and well differentiated malignant endocrine carcinoma. Reviewing the literature, we found 15 similar cases that showed two different age distributions and clinical presentations. Careful examination of benign serous cystadenoma should be kept in mind during clinical practice, to rule out the possibility of combined malignant endocrine tumor. In addition, von Hippel-Lindau disease should also be suspected when a young adult presents with combination of pancreatic serous cystadenoma and endocrine tumor. PMID- 19773216 TI - ? PMID- 19773215 TI - Successful antiviral and antituberculosis treatment with pegylated interferon alfa and ribavirin in a chronic hepatitis C patient with pulmonary tuberculosis. AB - Pulmonary tuberculosis is a rare side effect of antiviral treatment for chronic hepatitis C. We present the case of 55-year-old woman with chronic hepatitis C, who developed pulmonary tuberculosis after receiving 8 weeks of peginterferon alfa-2a plus ribavirin therapy. Antituberculous treatment was started and antiviral agents were given continually at adjusted doses. Her symptoms of cough with blood-tinged sputum improved 1 month after antituberculous therapy. Treatment for hepatitis C and pulmonary tuberculosis were completed after 6 months. At 6 months after antiviral therapy, a sustained virological response was achieved and follow-up chest radiography showed a marked regressive change. This is believed to be the first case report of complete remission from hepatitis C and pulmonary tuberculosis treated concurrently with antiviral and antituberculous agents. PMID- 19773218 TI - Consequences of the Chicago consensus on disorders of sex development (DSD): current practices in Europe. AB - OBJECTIVE: To assess clinical management of disorders of sex development (DSD) subsequent to recommendations issued in the 2006 Consensus Statement. DESIGN: Online questionnaire and audit of DSD literature. SETTING: Invitation to complete a 28-item online questionnaire and a 12-item follow-up questionnaire, both assessing current clinic statistics and clinical management of DSD. PARTICIPANTS: Paediatric endocrinologists from 60 medical centres representing 23 European countries. MAIN OUTCOME MEASURES: Clinic activity, multidisciplinary team composition, provision of psychological support services, incidence of feminising clitoroplasty and use of diagnostic algorithms and newly proposed nomenclature. ANALYSES: Data are reported in terms of percentages with respect to implementation of recommendations outlined in the Consensus Statement. chi(2) was used to analyse changes in nomenclature reported in the literature. RESULTS: 60 centres reported on management of an average of 97.3 (range 8-374) patients per year, totalling approximately 6000. The mean number of new referrals in the previous year was 23.27 (range 8-100). 57% of centres regularly included the services of recommended paediatric subspecialists: paediatric endocrinologist, paediatric surgeon/urologist, plastic surgeon, paediatric psychiatrist/psychologist, gynaecologist, clinical geneticist, histopathologist and neonatologist; 35% reported providing these and additional services of endocrine and surgical nurses, a social worker and a medical ethicist. Additionally, 95% of centres reported offering primary psychological support services (either child psychiatrist or psychologist). 65% of centres reported using a diagnostic algorithm, and 83.3% supported the development of a standardised algorithm. 52% and 44.8% of centres reported having performed fewer or similar numbers, respectively, of clitoroplasties than in previous years and only 3.4% reported an increase. Finally, 100% of respondents reported using the newly proposed terminology. Likewise, an audit of the literature reflected a recent reduction in usage of the non-preferred historical terminology. CONCLUSIONS: There is evidence that the majority of European DSD centres have implemented policies and procedures in accordance with the recommendations issued by the 2006 Consensus Group. These findings represent a change in practice with the collaborative goal of improved patient care. PMID- 19773219 TI - Readmission in children's emergency care: an analysis of hospital episode statistics. AB - AIM: To compare rates of emergency readmission following discharge for common paediatric conditions from a range of hospital services. DESIGN: Retrospective analysis of hospital episode statistics (HES) and telephone survey of service provision. SETTING: Twelve hospitals serving a metropolitan area in the North West of England. OUTCOME MEASURES: Emergency admissions to hospital within 7 days of discharge for breathing difficulty, feverish illness and/or diarrhoea. RESULTS: HES were obtained for all children under 15 years of age discharged following emergency admission for breathing difficulty, feverish illness and/or diarrhoea during 2005/2006 (n=20,354) or 2006/2007 (n=23,018). The readmission rate for all hospitals in 2006/2007 was 5.5%. The percentage of same day discharges was associated with readmission (Kendall's tau(b) correlation=0.61, p=0.007). Readmissions were also associated with the proportion of same day discharges for breathing difficulty (Kendall's tau(b)=0.83, p<0.001) and feverish illness (Kendall's tau(b)=0.50, p=0.023) but not significantly so with diarrhoea (Kendall's tau(b)=0.37, p=0.098). The total number of admissions at a hospital in the year was associated with its readmission rate (Kendall's tau(b)=0.71, p=0.002). Most of the sample lived in the 40% most deprived areas in England, but there was no significant association between readmission and living in the 10% most deprived areas. CONCLUSIONS: Readmission rates are associated with higher numbers of annual admissions and higher proportions of children discharged on the day of admission. Variations between hospitals suggest that other factors can also affect readmission rates. Readmission rates calculated from HES can contribute to assessments of the outcome of emergency services. PMID- 19773220 TI - Ethics, governance and consent in the UK: implications for research into the longer-term outcomes of congenital heart defects. AB - OBJECTIVE: To explore the effect of research ethics, governance and consent requirements and recent reforms on UK-wide follow-up of children with congenital heart defects (CHD). DESIGN: Prospective cohort study. SETTING: UK National Health Service. PATIENTS: 3897 children with CHD requiring intervention, or resulting in death, before they were 1-year-old (1993-1995). MAIN OUTCOMES: Impact on study protocol, timeliness and findings of a multicentre study of survival and quality of life. RESULTS: The peer-reviewed study protocol was altered to accommodate ethics committee stipulations that researchers should not approach families directly with a request to participate and that the general practitioner's (GP) permission be sought before the local clinician could do so. Individual consent was required to confirm the vital status of participants and for future tracing of public death registrations. Local study registration took a median of 40 weeks (IQR 25-57). 180 (24%) of 739 surviving children (five centres) could not be contacted because their GP was untraceable (32), had changed (128) or considered contact inappropriate (20). Invitations could not be sent to 31% from the most deprived compared with 17% from the least deprived areas. CONCLUSIONS: Decision making concerning childhood interventions should be influenced by evidence on long-term outcomes. However, current UK research regulations hinder follow-up in multicentre studies. Stipulations preventing researchers contacting families directly with research invitations appear disproportionate to the risks, impede equitable access to research opportunities and introduce bias. The requirement for an individual's consent to confirm whether they are alive and monitor survival precludes effective long-term follow up. PMID- 19773221 TI - Arterial wall thickness and blood pressure in children who were born small for gestational age: correlation with umbilical cord high-sensitivity C-reactive protein. AB - BACKGROUND: Small for gestational age (SGA) infants have an increased risk of later cardiovascular disease. At birth, high sensitivity-C reactive protein (hs CRP), a prognostic marker of cardiovascular disease, is significantly higher in SGA than in appropriate for gestational age (AGA) infants. AIM: To measure aortic and carotid intima-media thickness (aIMT, cIMT) and blood pressure (BP) in children (aged 3-5 years) who were born SGA and AGA, and to assess the correlation between hs-CRP concentrations obtained at birth and these haemodynamic variables. METHODS: Umbilical cord hs-CRP concentrations were obtained in 38 neonates. In the same subjects aged 3-5 years, aIMT and cIMT were measured by high-resolution ultrasound scan, in the dorsal arterial wall. Anthropometric variables and BPs were obtained for each child. RESULTS: Maximum (median 0.700 mm, range 0.500-1.080 vs 0.650 mm, 0.400-0.860; p = 0.32) aIMTs were similar between children who were born SGA (n = 17) and AGA (n = 21), respectively. Concentrations of hs-CRP were not correlated with IMTs. In children who were born SGA, systolic BP was significantly correlated with umbilical cord hs-CRP concentrations (r = 0.60; p = 0.009). CONCLUSIONS: Children who were born SGA have a higher, although not significant, aortic thickening than those who were born AGA. Umbilical cord hs-CRP concentrations do not seem to be involved in this process. Instead, hs-CRP concentrations were significantly related to systolic BP values in children who were born SGA, suggesting that hs-CRP at birth could be associated with sympathetic system hyperactivity and with the stress response during childhood. PMID- 19773223 TI - Impact of cleavage-stage embryo biopsy in view of PGD on human blastocyst implantation: a prospective cohort of single embryo transfers. AB - BACKGROUND: Human embryo biopsy is performed for preimplantation genetic diagnosis (PGD). The impact of 1- or 2-cell removal at cleavage-stage on future embryo development and implantation capacity is highly debated. METHODS: In order to explore this issue further, a cohort of Day 5 single embryo transfers was analysed prospectively for embryological and clinical outcome. All transferred embryos resulted from 8-cell embryos on Day 3, from which subsequently either one cell (group I, n = 182) or two cells (group II, n = 259) were removed, or on which no invasion by means of embryo biopsy was performed (group III, control group, n = 702). RESULTS Blastocyst formation was significantly better in group III compared with group II, and similar to group I. Group I and group II did not differ in Day 3 nor in Day 5 embryo development. The overall live birth rate was significantly higher in group I (37.4%, CI 29.0-47.4%) than in group II (22.4%, CI 17.0-28.9%), and comparable to the reference ICSI population (35.0%, CI 30.8 39.7%). CONCLUSIONS: The clinical outcome of 1-cell biopsy was significantly better than that of 2-cell biopsy, even when adjusted for availability of genetically transferable embryos. PMID- 19773222 TI - Screening for child abuse at emergency departments: a systematic review. AB - INTRODUCTION: Child abuse is a serious problem worldwide and can be difficult to detect. Although children who experience the consequences of abuse will probably be treated at an emergency department, detection rates of child abuse at emergency departments remain low. OBJECTIVE: To identify effective interventions applied at emergency departments that significantly increase the detection rate of confirmed cases of child abuse. DESIGN: This review was carried out according to the Cochrane Handbook. Two reviewers individually searched PubMed, the Cochrane Library, EMBASE, Web of Science and CINAHL for papers that met the inclusion criteria. RESULTS: Fifteen papers describing interventions were selected and reviewed; four of these were finally included and assessed for quality. In these studies the intervention consisted of a checklist of indicators of risk for child abuse. After implementation, the rate of detected cases of suspected child abuse increased by 180% (weighted mean in three studies). The number of confirmed cases of child abuse, reported in two out of four studies, showed no significant increase. CONCLUSIONS: Interventions at emergency departments to increase the detection rate of cases of confirmed child abuse are scarce in the literature. Past study numbers and methodology have been inadequate to show conclusive evidence on effectiveness. PMID- 19773224 TI - MADIT-CRT (Multicenter Automatic Defibrillator Implantation Trial-Cardiac Resynchronization Therapy): cardiac resynchronization therapy towards early management of heart failure. PMID- 19773225 TI - Evidence for a role of sphingosine-1 phosphate in cardiovascular remodelling in Fabry disease. AB - AIMS: A hallmark of Fabry disease is the concomitant development of left ventricular hypertrophy and arterial intima-media thickening, the pathogenesis of which is thought to be related to the presence of a plasmatic circulating growth promoting factor. We therefore characterized the plasma of patients with Fabry disease in order to identify this factor. METHODS AND RESULTS: Using a classical biochemical strategy, we isolated and identified sphingosine-1 phosphate (S1P) as a proliferative factor present in the plasma of patients with Fabry disease. Plasma S1P levels were significantly higher in 17 patients with Fabry disease compared with 17 healthy controls (225 +/- 40 vs. 164 +/- 17 ng/mL; P = 0.005). There was a positive correlation between plasma S1P levels and both common carotid artery intima-media thickness and left-ventricular mass index (r(2) = 0.47; P = 0.006 and r(2) = 0.53; P = 0.0007, respectively). In an experimental model, mice treated with S1P developed cardiovascular remodelling similar to that observed in patients with Fabry disease. CONCLUSION: Sphingosine-1 phosphate participates in cardiovascular remodelling in Fabry disease. Our findings have implications for the treatment of cardiovascular involvement in Fabry disease. PMID- 19773226 TI - Intracoronary bone marrow cell transfer after myocardial infarction: 5-year follow-up from the randomized-controlled BOOST trial. AB - AIMS: We assessed whether a single intracoronary infusion of autologous bone marrow cells (BMCs) can have a sustained impact on left ventricular ejection fraction (LVEF) in patients after ST-elevation myocardial infarction (STEMI). In the BOne marrOw transfer to enhance ST-elevation infarct regeneration (BOOST) trial, 60 patients with STEMI and successful percutaneous coronary intervention were randomized to a control and a cell therapy group. As previously reported, BMC transfer led to an improvement of LVEF by 6.0% at 6 months (P = 0.003) and 2.8% at 18 months (P = 0.27). METHODS AND RESULTS: Left ventricular ejection fraction and clinical status were re-assessed in all surviving patients after 61 +/- 11 months. Major adverse cardiac events occurred with similar frequency in both groups. When compared with baseline, LVEF assessed by magnetic resonance imaging at 61 months decreased by 3.3 +/- 9.5% in the control group and by 2.5 +/ 11.9% in the BMC group (P = 0.30). Patients with an infarct transmurality > median appeared to benefit from BMC transfer throughout the 61-month study period (P = 0.040). CONCLUSION: A single intracoronary application of BMCs does not promote a sustained improvement of LVEF in STEMI patients with relatively preserved systolic function. It is conceivable that a subgroup of patients with more transmural infarcts may derive a sustained benefit from BMC therapy. However, this needs to be tested prospectively in a randomized trial. PMID- 19773227 TI - Severe right bivalvular carcinoid heart disease. PMID- 19773228 TI - Cardiac stunning in the clinic: the full picture. AB - Cardiac stunning refers to different dysfunctional levels occurring after an episode of acute ischemia, despite blood flow is near normal or normal. The phenomenon was initially identified in animal models, where it has been very well characterized. After being established in the experimental setting, it remained unclear, whether a similar syndrome occurs in humans. In addition, it remained controversial, whether stunning was of any clinical relevance as it is spontaneously reversible. Hence, many studies continue to focus on the properties and mechanisms of stunning, although therapies seem more relevant for attenuating and treating myocardial ischemia/reperfusion (I/R) injury, i.e. to bridge until recovery. This article reviews the different facets of cardiac stunning, i.e. myocardial, vascular/microvascular/endothelial, metabolic, neural/neuronal, and electrical stunning. This review also displays where these facets exist and which clinical relevance they might have. Particular attention is directed to the different therapeutic interventions that the various facets of this I/R-induced cardiac injury might require. A final outlook considers possible alternatives to further reduce the detrimental consequences of brief episodes of ischemia and reperfusion. PMID- 19773229 TI - Primary synovial sarcoma of the lung as an incidental finding. AB - Synovial sarcoma of the lung (SSL) is a very rare but aggressive primary lung tumor. Due to its unusual histological features, it can easily be misdiagnosed, if only small biopsies of the tumor are investigated. Here, we review two recent cases of SSL diagnosed and treated in our institution. The first case is a 37 year-old male with a round nodule in the right lower lobe; he underwent a lobectomy. Histologically, the nodule resembled a biphasic tumor. Cytogenetic analysis revealed a translocation t (X; 18), and the diagnosis of primary SSL could be established. The patient is alive and disease-free since 45 months following surgery. The second case is a 41-year-old male with a cystic lesion in the right lower lobe, removed by video-assisted thoracic surgery (VATS) segmentectomy. In the tumor tissue, spindle cell-rich and cystic structures could be found, together with epithelial elements. Because the tumor contained also a translocation t (X; 18), it could be diagnosed as monophasic SSL. The patient is alive and disease-free since 11 months. Since rare diseases of the lung may present as subtle and focal changes, complete removal of suspect pulmonary lesions is always advisable. PMID- 19773231 TI - Abstracts of the European Society of Cardiology Congress 2009. August 26 September 2, 2009. Barcelona, Spain. PMID- 19773230 TI - The hemiclamshell approach in thoracic surgery: indications and associated morbidity in 50 patients. AB - This retrospective study was carried out to evaluate the indications for and outcomes of the hemiclamshell (HCS) approach (longitudinal partial sternotomy with antero-lateral thoracotomy) in patients undergoing mass resection in thoracic surgery. All patients (50) who underwent a HCS procedure in our department, between July 1996 and July 2005, were studied retrospectively, analyzing the indications, morbidity and outcome (pain, neurological or shoulder defects, mortality) at one month and one year. The main indications were apical tumours (38%), tumours of the cervicothoracic junction (46%) and chest wall (10%), and 'bulky' tumours (6%). One-month mortality was 6%. Two patients suffered from a chylothorax and one from phrenic paralysis. The postoperative analgesic requirements were similar to those after other thoracic surgery approaches. Twelve percent of patients suffered pain at one month and 6% at one year. Shoulder dysfunction was observed in 10% of patients at one month and 6% at one year. In conclusion, the HCS surgical approach was associated with an uncomplicated postoperative course. This anterior approach is suitable for apical tumours, tumours of the cervicothoracic junction and 'bulky' lung tumours, providing good access for control of the large vessels and radical mediastinal clearance. PMID- 19773233 TI - eComment: Defective bronchial tissue homeostasis following neoadjuvant therapy for lung cancer. PMID- 19773234 TI - eComment: Mechanical valve replacement in the elderly: does anticoagulation have benefit? PMID- 19773235 TI - eComment: Re: Long-term follow-up of elderly patients subjected to aortic valve replacement with mechanical prostheses. PMID- 19773236 TI - eComment: Does EuroSCORE predict postoperative complications? PMID- 19773237 TI - eComment: Re: Is the aortic valve pathology type different for early and late mortality in concomitant aortic valve replacement and coronary artery bypass surgery? PMID- 19773238 TI - eComment: The role of lymph node dissection in pulmonary resection for metastases from colorectal cancer. PMID- 19773239 TI - eComment: Re: Brain natriuretic peptide a predictive marker in cardiac surgery. PMID- 19773240 TI - eComment: Re: Is reduction aortoplasty (with or without external wrap) an acceptable alternative to replacement of the dilated ascending aorta? PMID- 19773241 TI - eComment: Systemic thrombolysis with alteplase in impending paradoxical embolism. PMID- 19773242 TI - eComment: It could be an iatrogenic arteriovenous fistula. PMID- 19773243 TI - eComment: Routine preoperative evaluation of the internal mammary artery as conduit for coronary patients. Is it worth? PMID- 19773244 TI - eComment: How to reconstruct endarterectomized left anterior descending coronary artery. PMID- 19773245 TI - eComment: Re: Intra-diaphragmatic pacemaker implantation in very low weight premature neonate. PMID- 19773246 TI - eComment: Management options of tube thoracostomy-induced pulmonary artery injury. PMID- 19773247 TI - Analysis of regional wall motion during contrast-enhanced dobutamine stress echocardiography: effect of contrast imaging settings. AB - AIMS: Myocardial contrast perfusion echocardiography (MCE) allows simultaneous assessment of perfusion and function. However, low frame rate during MCE may reduce the viewer's ability to discern contractile dysfunction. This study sought to compare MCE and left ventricular opacification (LVO) settings with regard to wall motion abnormalities (WMA) at rest and during dobutamine stress echocardiography (DSE). METHODS AND RESULTS: In 50 patients scheduled for coronary angiography and with poor baseline image quality, MCE and LVO were performed during DSE. Regional wall motion was assessed and inter-observer agreement was determined for each imaging modality. The endocardial border score index was similar for both modalities. The wall motion score index (WMSCI) at peak stress using MCE was well correlated with WMSCI obtained with LVO (r(2) = 0.9, P < 0.001). However, WMSCI at peak stress was underestimated by MCE (1.66 +/ 0.58 with DSE-LVO vs. 1.535 +/- 0.50 with DSE-MCE; P < 0.001). Inter-observer agreement on the presence of WMA was 0.65 for MCE and 0.67 for LVO at peak stress. CONCLUSION: Myocardial contrast perfusion echocardiography provides equal endocardial border delineation compared with LVO modality. Although the inter observer agreement is slightly higher with LVO compared with MCE, it is not significantly different with MCE at peak stress. Despite the similar improvement in endocardial border delineation, LVO settings allow the detection of more WMA than MCE at peak stress, leading to a significantly higher accuracy for the detection of ischaemia in patients suspected of coronary artery disease when only wall motion is taken into account. PMID- 19773248 TI - Rapid progression of hormone receptor-negative breast cancer concomitant with ovarian stimulation--a paradoxon? PMID- 19773249 TI - Echinoside A, a new marine-derived anticancer saponin, targets topoisomerase2alpha by unique interference with its DNA binding and catalytic cycle. AB - BACKGROUND: Echinoside A was isolated from sea cucumber. This study demonstrates its anticancer effects and its mechanisms of action. MATERIALS AND METHODS: Anticancer effects of echinoside A were evaluated in vitro and in vivo. TUNEL and DNA fragmentation assays were applied to examine its ability to induce apoptosis. A series of biochemical assays were applied to investigate the inhibition of echinoside A on topoisomerase2alpha (Top2alpha). Molecular docking analyses were used to demonstrate the direct interaction between echinoside A and Top2alpha. RESULTS: Echinoside A inhibited the growth of tumors in mouse models and human prostate carcinoma xenografts in nude mouse models. Echinoside A shows the unique characteristics of inhibiting the noncovalent binding of Top2alpha to DNA by competing with DNA for the DNA-binding domain of the enzyme and of interfering predominantly with the Top2alpha-mediated prestrand passage cleavage/religation equilibrium over with the poststrand passage one. These features distinguish echinoside A from other known Top2alpha inhibitors. As a result, echinoside A induced DNA double-strand breaks in a Top2-dependent manner. CONCLUSION: Echinoside A targets Top2alpha by unique interference with the binding of Top2 to DNA and by imparing the Top2-mediated DNA cleavage and religation, exerting potent in vitro and in vivo antitumor activities. PMID- 19773250 TI - Natural history and clinical outcome of differentiated thyroid carcinoma: a retrospective analysis of 1503 patients treated at a single institution. AB - BACKGROUND: The study evaluates clinical presentation and outcome of differentiated thyroid cancer (DTC) on a large series of patients homogeneously managed. PATIENTS AND METHODS: A cohort of 1503 DTC followed according to a standardized protocol entered the study. Main outcome measures were clinical presentation at the diagnosis, survival, morbidity and prognostic risk factors. RESULTS: Median age at diagnosis was 46 years. Papillary cancer and low pathological tumor-node-metastasis stages represented >80% of cases. Cancer specific survival at 5, 10 and 15 years was 98.6%, 94.7% and 87.4%; 10-year disease-free and progression-free survivals were 96.8% and 17.1%, respectively. Cancer-specific mortality rate was 2.5% [95% confidence interval (CI) 1.7% to 3.4%], recurrence rate was 0.6 % while morbidity rate was 12.6% (95% CI 11% to 14%). Response to radioiodine treatment is the strongest predictor of a good outcome in multivariate analysis (hazard ratio 211, P < 0.0001). Other independent predictor variables are sex, age, histology and distant metastases for survival and metastases for morbidity. CONCLUSIONS: A rigorous initial therapeutic approach leads to a better survival and a very low morbidity. Patients who do not respond to radioiodine treatment have a worse prognosis. PMID- 19773251 TI - Aging and the management of cancer pain. PMID- 19773252 TI - The dangerous shortage of domestic violence services. AB - Domestic violence is a serious, preventable health problem affecting more than thirty million Americans annually, yet little is known about federally funded service provision. We used the National Census of Domestic Violence Services, an innovative victim-safety focused survey, to count services provided by more than 2,000 programs. During the twenty-four-hour survey period, 48,350 people used these services. The results show substantial unmet demand for services (10 percent of requests) because of resource constraints, particularly in rural, economically disadvantaged, and minority communities. Greater funding of domestic violence programs, particularly housing support, is likely to be a cost-effective public health investment. PMID- 19773253 TI - Dissemination of transposon Tn6001 in carbapenem-non-susceptible and extensively drug-resistant Pseudomonas aeruginosa in Taiwan. AB - OBJECTIVES: To investigate the prevalence of metallo-beta-lactamases (MBLs) and Tn6001 in carbapenem-non-susceptible Pseudomonas aeruginosa (CNSPA). The CNSPA included extensively drug-resistant P. aeruginosa (XDRPA) and non-XDRPA isolates in Taiwan. METHODS: A total of 308 CNSPA isolates collected at a medical centre from 2000 to 2005 and 26 XDRPA collected from six medical centres in different regions of Taiwan in 2003 were included. MBL genes and Tn6001 were detected by PCR. Clonal relatedness was determined by PFGE. RESULTS: Of the 308 CNSPA isolates, 30 (10%) were XDRPA, including 27 (9%) colistin-only-susceptible (COS) and 3 (1%) colistin-only-intermediate (COI) P. aeruginosa. bla(VIM-3) was found in 16 (53%) isolates of the XDRPA (n = 30), whereas only 72 (26%) of the non XDRPA (n = 278) carried the gene. In450 was higher in COS P. aeruginosa (12/27; 44%) than in non-XDRPA isolates (53/278; 19%). Tn6001 was highest in COS P. aeruginosa (11/27; 41%), followed by COI P. aeruginosa (1/3; 33%), and lowest in non-XDRPA (46/278; 17%). Of 26 XDRPA from six medical centres, higher prevalences of bla(VIM-3) (16/26; 62%), In450 (16/26; 62%) and Tn6001 (12/26; 46%) were found. Genotyping by PFGE revealed 60 pulsotypes. Hybridization of a bla(VIM-3) specific probe following PFGE suggested that the mobile element Tn6001 might have transferred horizontally. CONCLUSIONS: Tn6001 and In450 play an important role in the dissemination of CNSPA and XDRPA. The prevalence of these genetic constituents was higher in XDRPA than in non-XDRPA isolates, suggesting that the mobile element Tn6001 might have transferred horizontally. PMID- 19773254 TI - Novel genetic environment of qnrB2 associated with TEM-1 and SHV-12 on pB1004, an IncHI2 plasmid, in Salmonella Bredeney BB1047 from Spain. PMID- 19773255 TI - Flucloxacillin, still the empirical choice for putative Staphylococcus aureus infections in intensive care units in the Netherlands. AB - OBJECTIVES: To determine the usefulness of flucloxacillin as empirical therapy for putative Staphylococcus aureus infections in intensive care unit (ICU) patients in the Netherlands, the antibiotic resistance of S. aureus isolates from ICUs over a 13 year period was investigated. METHODS: From 1996 to 2008, 1146 consecutive S. aureus isolates from ICU patients in 14 large referral hospitals were collected. The susceptibility to relevant antibiotics was determined by microbroth dilution according to CLSI guidelines. RESULTS: Resistance to flucloxacillin was only found in 12 isolates (1%). The resistance to clarithromycin, ciprofloxacin and moxifloxacin showed a significant trend over time, from 4.2% to 10.3%, from 1.0% to approximately 10% and from 0.0% to approximately 5.0%, respectively (P < 0.05). The resistance to penicillin, clindamycin and doxycycline increased over time, from 74% to 75%, from approximately 3.0% in 1996 to 3.2% in 2008 and from 2.2% in 1996 to 8.2% in 2008, respectively (P > 0.05). Resistance to cephalosporins, carbapenems, rifampicin and gentamicin was sporadically observed. No resistance was found to vancomycin, teicoplanin and linezolid. CONCLUSIONS: The empirical choice of flucloxacillin in the case of putative S. aureus infections in patients admitted to ICUs in the Netherlands is still justified. PMID- 19773256 TI - Anti-CD20 monoclonal antibodies: historical and future perspectives. AB - Antibodies to CD20 have confirmed the hypothesis that monoclonal reagents can be given in vivo to alleviate human diseases. The targeting of CD20 on normal, malignant and auto-immune B-lymphocytes by rituximab has demonstrated substantial benefits for patients with a variety of B-cell lymphomas, as well as some with autoimmune disorders. There has been a notable increase in the survival rates from B-cell lymphoma in the decade since anti-CD20 therapy was introduced. PMID- 19773258 TI - Premature termination codon mutations in the von Willebrand factor gene are associated with allele-specific and position-dependent mRNA decay. PMID- 19773257 TI - Effect of lenalidomide therapy on hematopoiesis of patients with myelodysplastic syndrome associated with chromosome 5q deletion. AB - BACKGROUND: Lenalidomide improves erythropoiesis in patients with low/intermediate-1 risk myelodysplastic syndrome and interstitial deletion of the long arm of chromosome 5 [del(5q)]. The aim of this study was to explore the effect of lenalidomide treatment on the reserves and functional characteristics of bone marrow hematopoietic progenitor/precursor cells, bone marrow stromal cells and peripheral blood lymphocytes in patients with low/intermediate-1 risk myelodysplastic syndrome with del(5q). DESIGN AND METHODS: We evaluated the number and clonogenic potential of bone marrow erythroid/myeloid/megakaryocytic progenitor cells using clonogenic assays, the apoptotic characteristics and adhesion molecule expression of CD34(+) cells by flow cytometry, the hematopoiesis-supporting capacity of bone marrow stromal cells using long-term bone marrow cultures and the number and activation status of peripheral blood lymphocytes in ten patients with low/intermediate-1 risk myelodysplastic syndrome with del(5q) receiving lenalidomide. RESULTS: Compared to baseline, lenalidomide treatment significantly decreased the proportion of bone marrow CD34+ cells, increased the proportion of CD36(+)/GlycoA(+) and CD36(-)/GlycoA(+) erythroid cells and the percentage of apoptotic cells within these cell compartments. Treatment significantly improved the clonogenic potential of bone marrow erythroid, myeloid, megakaryocytic colony-forming cells and increased the proportion of CD34(+) cells expressing the adhesion molecules CD11a, CD49d, CD54, CXCR4 and the SLAM antigen CD48. The hematopoiesis-supporting capacity of bone marrow stroma improved significantly following treatment, as demonstrated by the number of colony-forming cells and the level of stromal-derived factor-1 alpha and intercellular adhesion molecule-1 in long-term bone marrow culture supernatants. Lenalidomide treatment also increased the proportion of activated peripheral blood T lymphocytes. CONCLUSIONS: The beneficial effect of lenalidomide in patients with lower risk myelodysplastic syndrome with del(5q) is associated with significant increases in the proportion of bone marrow erythroid precursor cells and in the frequency of clonogenic progenitor cells, a substantial improvement in the hematopoiesis-supporting potential of bone marrow stroma and significant alterations in the adhesion profile of bone marrow CD34(+) cells. PMID- 19773259 TI - Genome wide molecular analysis of minimally differentiated acute myeloid leukemia. AB - BACKGROUND: Minimally differentiated acute myeloid leukemia is heterogeneous in karyotype and is defined by immature morphological and molecular characteristics. This originally French-American-British classification is still used in the new World Health Organization classification when other criteria are not met. Apart from RUNX1 mutation, no characteristic molecular aberrations are recognized. DESIGN AND METHODS: We performed whole genome single nucleotide polymorphism analysis and extensive molecular analysis in a cohort of 52 patients with minimally differentiated acute myeloid leukemia. RESULTS: Many recurring and potentially relevant regions of loss of heterozygosity were revealed. These point towards a variety of candidate genes that could contribute to the pathogenesis of minimally differentiated acute myeloid leukemia, including the tumor suppressor genes TP53 and NF1, and reinforced the importance of RUNX1 in this leukemia. Furthermore, for the first time in this minimally differentiated form of leukemia we detected mutations in the transactivation domain of RUNX1. Mutations in other acute myeloid leukemia associated transcriptions factors were infrequent. In contrast, FLT3, RAS, PTPN11 and JAK2 were often mutated. Irrespective of the RUNX1 mutation status, our results show that RAS signaling is the most important pathway for proliferation in minimally differentiated acute myeloid leukemia. Importantly, we found that high terminal deoxynucleotidyl transferase expression is closely associated with RUNX1 mutation, which could allow an easier diagnosis of RUNX1 mutation in this hematologic malignancy. CONCLUSIONS: Our results suggest that in patients without RUNX1 mutation, several other molecular aberrations, separately or in combination, contribute to a common minimally differentiated phenotype. PMID- 19773261 TI - 5-azacitidine prolongs overall survival in patients with myelodysplastic syndrome -a systematic review and meta-analysis. AB - Hypomethylating agents have recently been shown to improve the outcome of patients with myelodysplastic syndrome. A meta-analysis and systematic review was carried out of randomized controlled trials comparing treatment with hypomethylating agents to conventional care, i.e., best supportive care or chemotherapy, in patients with myelodysplastic syndrome. The outcomes assessed were overall survival, time to transformation or death, overall response rate and toxicity. Hazard ratios with 95% confidence intervals were estimated and pooled for time-to-event data. For dichotomous data, relative risks were estimated and pooled. Four trials including 952 patients examined the effect of 5-azacitidine and decitabine. Treatment with hypomethylating agents significantly improved overall survival (hazard ratio 0.72, 95% confidence interval 0.60-0.85, three trials) and time to transformation or death (hazard ratio 0.69, 95% confidence interval 0.58-0.82, four trials). In a subgroup analysis per type of drug, these benefits could be shown for 5-azacitidine but not for decitabine. Both agents favorably influenced response rates. A higher rate of grade 3/4 adverse events was observed with their use. Since 5-azacitidine prolongs overall survival and time to transformation or death it should be highly considered in the treatment of patients with high-risk myelodysplastic syndrome. Further studies are needed to establish the exact role of decitabine compared to 5-azacitidine in these patients. PMID- 19773260 TI - GFI1B controls its own expression binding to multiple sites. AB - BACKGROUND: Transcription factors play essential roles in both normal and malignant hematopoiesis. This is the case for the growth factor independent 1b (GFI1B) transcription factor, which is required for erythroid and megakaryocytic differentiation and over-expressed in leukemic patients and cell lines. DESIGN AND METHODS: To investigate GFI1B regulation, we searched for multispecies conserved non-coding elements between GFI1B and neighboring genes. We used a formaldehyde-assisted isolation of regulatory elements (FAIRE) assay and DNase1 hypersensitivity to assess the chromatin conformation of these sites. Next, we analyzed transcription factor binding and histone modifications at the GFI1B locus including the conserved non-coding elements by a chromatin immunoprecipitation assay. Finally, we studied the interaction of the GFI1B promoter and the conserved non-coding elements with the chromatin conformation capture technique and used immunofluorescence to evaluate GFI1B levels in individual cells. RESULTS: We localized several conserved non-coding elements containing multiple erythroid specific transcription factor binding sites at the GFI1B locus. In GFI1B-expressing cells a subset of these conserved non-coding elements and the promoter adopt a close spatial conformation, localize with open chromatin sites, harbor chromatin modifications associated with gene activation and bind multiple transcription factors and co-repressors. Conclusions Our findings indicate that GFI1B regulatory elements behave as activators and repressors. Different protein levels within a cell population suggest that cells must activate and repress GFI1B continuously to control its final level. These data are consistent with a model of GFI1B regulation in which GFI1B binds to its own promoter and to the conserved non-coding elements as its levels rise. This would attract repressor complexes that progressively down-regulate the gene. GFI1B expression would decrease until a stage at which the activating complexes predominate and expression increases. PMID- 19773262 TI - Diamond-Blackfan anemia: genotype-phenotype correlations in Italian patients with RPL5 and RPL11 mutations. AB - BACKGROUND: Diamond-Blackfan anemia is a rare, pure red blood cell aplasia of childhood due to an intrinsic defect in erythropoietic progenitors. About 40% of patients display various malformations. Anemia is corrected by steroid treatment in more than 50% of cases; non-responders need chronic transfusions or stem cell transplantation. Defects in the RPS19 gene, encoding the ribosomal protein S19, are the main known cause of Diamond-Blackfan anemia and account for more than 25% of cases. Mutations in RPS24, RPS17, and RPL35A described in a minority of patients show that Diamond-Blackfan anemia is a disorder of ribosome biogenesis. Two new genes (RPL5, RPL11), encoding for ribosomal proteins of the large subunit, have been reported to be involved in a considerable percentage of patients. DESIGN AND METHODS: In this genotype-phenotype analysis we screened the coding sequence and intron-exon boundaries of RPS14, RPS16, RPS24, RPL5, RPL11, and RPL35A in 92 Italian patients with Diamond-Blackfan anemia who were negative for RPS19 mutations. RESULTS: About 20% of the patients screened had mutations in RPL5 or RPL11, and only 1.6% in RPS24. All but three mutations that we report here are new mutations. No mutations were found in RPS14, RPS16, or RPL35A. Remarkably, we observed a higher percentage of somatic malformations in patients with RPL5 and RPL11 mutations. A close association was evident between RPL5 mutations and craniofacial malformations, and between hand malformations and RPL11 mutations. CONCLUSIONS: Mutations in four ribosomal proteins account for around 50% of all cases of Diamond-Blackfan anemia in Italian patients. Genotype phenotype data suggest that mutation screening should begin with RPL5 and RPL11 in patients with Diamond-Blackfan anemia with malformations. PMID- 19773263 TI - Hepcidin targets ferroportin for degradation in hepatocytes. AB - Hepcidin, a circulating regulatory hormone peptide produced by hepatocytes, functions as the master regulator of cellular iron export by controlling the amount of ferroportin, an iron exporter present on the basolateral surface of intestinal enterocytes and macrophages. Hepcidin binding to ferroportin induces its internalization and degradation, resulting in cellular iron retention and decreased iron export. Whether hepatocytes express ferroportin that could be targeted by hepcidin has remained a subject of debate. Here, we describe a hepatocyte culture system expressing high levels of ferroportin, and demonstrate that both endogenously secreted and synthetic hepcidin are fully active in down regulating membrane-associated ferroportin. In agreement with this result, ferroportin is stabilized in liver hepatocytes of hepcidin-deficient mice and accumulates in periportal areas, supporting the centrolobular iron deposition observed in these mice. In conclusion, we show that hepcidin can trigger ferroportin degradation in hepatocytes, which must be taken into account when considering hepcidin therapeutics. PMID- 19773264 TI - Generation of mesenchymal stromal cells in the presence of platelet lysate: a phenotypic and functional comparison of umbilical cord blood- and bone marrow derived progenitors. AB - BACKGROUND: Mesenchymal stromal cells are employed in various different clinical settings in order to modulate immune response. However, relatively little is known about the mechanisms responsible for their immunomodulatory effects, which could be influenced by both the cell source and culture conditions. DESIGN AND METHODS: We tested the ability of a 5% platelet lysate-supplemented medium to support isolation and ex vivo expansion of mesenchymal stromal cells from full term umbilical-cord blood. We also investigated the biological/functional properties of umbilical cord blood mesenchymal stromal cells, in comparison with platelet lysate-expanded bone marrow mesenchymal stromal cells. RESULTS: The success rate of isolation of mesenchymal stromal cells from umbilical cord blood was in the order of 20%. These cells exhibited typical morphology, immunophenotype and differentiation capacity. Although they have a low clonogenic efficiency, umbilical cord blood mesenchymal stromal cells may possess high proliferative potential. The genetic stability of these cells from umbilical cord blood was demonstrated by a normal molecular karyotype; in addition, these cells do not express hTERT and telomerase activity, do express p16(ink4a) protein and do not show anchorage-independent cell growth. Concerning alloantigen-specific immune responses, umbilical cord blood mesenchymal stromal cells were able to: (i) suppress T- and NK-lymphocyte proliferation, (ii) decrease cytotoxic activity and (iii) only slightly increase interleukin-10, while decreasing interferon gamma secretion, in mixed lymphocyte culture supernatants. While an indoleamine 2,3-dioxygenase-specific inhibitor did not reverse mesenchymal stromal cell induced suppressive effects, a prostaglandin E(2)-specific inhibitor hampered the suppressive effect of both umbilical cord blood- and bone marrow-mesenchymal stromal cells on alloantigen-induced cytotoxic activity. Mesenchymal stromal cells from both sources expressed HLA-G. CONCLUSIONS: Umbilical cord blood- and bone marrow-mesenchymal stromal cells may differ in terms of clonogenic efficiency, proliferative capacity and immunomodulatory properties; these differences may be relevant for clinical applications. PMID- 19773265 TI - Autologous hematopoietic stem cell transplantation for autoimmune diseases: an observational study on 12 years' experience from the European Group for Blood and Marrow Transplantation Working Party on Autoimmune Diseases. AB - BACKGROUND: Autologous hematopoietic stem cell transplantation has been used since 1996 for the treatment of severe autoimmune diseases refractory to approved therapies. We evaluated the long-term outcomes of these transplants and aimed to identify potential prognostic factors. DESIGN AND METHODS: In this observational study we analyzed all first autologous hematopoietic stem cell transplants for autoimmune diseases reported to the European Group for Blood and Marrow Transplantation (EBMT) registry between 1996-2007. The primary end-points for analysis were overall survival, progression-free survival and transplant-related mortality at 100 days. RESULTS: Nine hundred patients with autoimmune diseases (64% female; median age, 35 years) who underwent a first autologous hematopoietic stem cell transplant were included. The main diseases were multiple sclerosis (n=345), systemic sclerosis (n=175), systemic lupus erythematosus (n=85), rheumatoid arthritis (n=89), juvenile arthritis (n=65), and hematologic immune cytopenia (n=37). Among all patients, the 5-year survival was 85% and the progression-free survival 43%, although the rates varied widely according to the type of autoimmune disease. By multivariate analysis, the 100-day transplant related mortality was associated with the transplant centers' experience (P=0.003) and type of autoimmune disease (P=0.03). No significant influence of transplant technique was identified. Age less than 35 years (P=0.004), transplantation after 2000 (P=0.0015) and diagnosis (P=0.0007) were associated with progression-free survival. CONCLUSIONS: This largest cohort studied worldwide shows that autologous hematopoietic stem cell transplantation can induce sustained remissions for more than 5 years in patients with severe autoimmune diseases refractory to conventional therapy. The type of autoimmune disease, rather than transplant technique, was the most relevant determinant of outcome. Results improved with time and were associated with the transplant centers' experience. These data support ongoing and planned phase III trials to evaluate the place of autologous hematopoietic stem cell transplantation in the treatment strategy for severe autoimmune diseases. PMID- 19773266 TI - Adverse prognostic significance of CD20 expression in adults with Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. AB - The prognostic significance of CD20 expression in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) has been mostly studied in children and yielded conflicting results. In 143 adults with Philadelphia chromosome-negative BCP-ALL treated in the multicentric GRAALL 2003 trial, CD20 positivity over 20% was observed in 32% of patients. While not influencing complete remission achievement, CD20 expression was associated with a higher cumulative incidence of relapse (CIR) at 42 months (P=0.04), independently of the ALL high-risk subset (P=0.025). Notably, the negative impact of CD20 expression on CIR was only observed in patients with a white blood cell count (WBC) over 30x10(9)/L (P=0.006), while not in those with a lower WBC. In the former subgroup, this impact translated into lower event-free survival (15% vs. 59% at 42 months, P=0.003). CD20 expression thus appears to be associated with a worse outcome, which reinforces the interest of evaluating rituximab combined to chemotherapy in CD20-positive adult BCP-ALL. ClinicalTrials.gov ID, NCT00222027. PMID- 19773267 TI - Double-staining chromogenic in situ hybridization as a useful alternative to split-signal fluorescence in situ hybridization in lymphoma diagnostics. AB - BACKGROUND: Malignant lymphomas are classified based on morphology, immunophenotype, genetics and clinical features. The pathological diagnosis is generally considered difficult and prone to mistakes. Since non-random chromosomal translocations are specifically involved in specific entities, their detection is an important adjunct for increasing the reliability of the diagnosis. Recently, split-signal fluorescence in situ hybridization has become available as a robust method to detect chromosomal breaks in paraffin-embedded formalin-fixed tissues. A bright field approach would bring this technology within the reach of every pathology laboratory. DESIGN AND METHODS: Our study was initiated to determine the consistency between chromogenic in situ hybridization and fluorescence in situ hybridization, both using split-signal probes developed for the detection of chromosomal breaks. Five hundred and forty cases of 11 lymphoma entities and reactive, benign lymphoid tissues, collected from eight different pathology laboratories, placed on 15 fluorescence in situ hybridization pre-stained tissue microarray slides, were double stained for the chromogenic hybridization. For each core morphology and actual signal were compared to the original fluorescence hybridization results. In addition, hematoxylin background staining intensity and signal intensity of the double-staining chromogenic in situ hybridization procedure were analyzed. RESULTS: With respect to the presence or absence of chromosomal breaks, 97% concordance was found between the results of the two techniques. Hematoxylin background staining intensity and signal intensity were found to correspond. The overall morphology after double-staining chromogenic in situ hybridization had decreased compared to the initial morphology scored after split-signal fluorescence in situ hybridization staining. CONCLUSIONS: We conclude that double-staining chromogenic in situ hybridization is equally reliable as fluorescence in situ hybridization in detecting chromosomal breaks in lymphoid tissue. Although differences in morphology, hematoxylin staining and chromogenic signal intensity vary between the tumor entities none of the entities appeared more easy or difficult to score. PMID- 19773268 TI - Long-term outcome of chemotherapy for advanced testicular and extragonadal germ cell tumors: a single-center 27-year experience. AB - OBJECTIVE: We retrospectively assessed long-term outcomes of chemotherapy for advanced germ cell tumors (GCTs) at our institution. METHODS: Ninety-five consecutive males with advanced GCTs of the testis or extragonadal origin who received chemotherapy between 1980 and 2006 were enrolled. All patients underwent induction chemotherapy including cisplatin. RESULTS: The median follow-up period was 36.1 months (0 - 288.5) for all patients and 52.6 months (2.2 - 288.5) for the 73 current survivors. Totally, 75 patients (78.9%) achieved complete remission (CR). CR was achieved in 61.1%, 37.9% and 75.0% of the patients after induction therapy, second-line therapy and third-line or more, respectively. As salvage therapy, high-dose chemotherapy was performed in 11 patients (11.7%) and regimens with novel anticancer agents such as paclitaxel and irinotecan were employed for 8 patients (8.5%) from 2003 and later. The era of the treatment, extrapulmonary metastasis and serum alpha-fetoprotein were independent prognostic factors for patients. The 5-year overall survival of patients after 1992 was 83.0%, which was significantly higher than that of those before 1992 (56.3%). CR was never achieved in 20 patients and most of them met the criteria of the poor prognosis group. Disease recurrence after CR was found in nine patients who were initially classified into the good- or intermediate-prognosis group. CONCLUSIONS: Improvement of medical management during chemotherapy and the development of several regimens for salvage chemotherapy seemed to contribute to improving outcomes of patients with advanced testicular cancer. Newly established chemotherapy regimens are needed for improvement of survival of patients in the poor-prognosis group. PMID- 19773269 TI - Biochemical and pathological response of prostate cancer in a patient with metastatic renal cell carcinoma on sunitinib treatment. AB - Sunitinib is a small molecular inhibitor of tyrosine kinases and is used to treat advanced renal cell carcinoma and gastrointestinal stromal tumour after disease progression or intolerance to imatinib therapy. Here, we describe biochemical and pathological response of prostate cancer in a patient with metastatic renal cell carcinoma during sunitinib treatment. A 62-year-old man was referred to our hospital because of a mass in the scalp. He was diagnosed with left renal cell carcinoma with right renal and scalp metastases. In addition, synchronous prostate cancer involving less than one-half of the right lobe was found with a prostate-specific antigen (PSA) value of 23.4 ng/ml. Treatment was begun with sunitinib (50 mg daily, 4 weeks on and 2 weeks off). Regarding the prostate cancer, active monitoring was planned considering the far advanced renal cell carcinoma. Surprisingly, the PSA level was 3.4 ng/ml at week 6 and 0.2 ng/ml at week 12, and it subsequently remained normal. At the time of writing (cycle 6 of sunitinib therapy), the prostate nodule significantly decreased in size. Furthermore, a 12-core re-biopsy revealed pathological evidence of regression with sunitinib treatment, with control of his renal cell carcinoma. PMID- 19773270 TI - A phase II study of irinotecan and capecitabine for patients with unresectable liver-only metastases from colorectal cancer. AB - OBJECTIVE: To assess the resectability rate of patients with initially unresectable liver-only metastases from colorectal cancer (CRC) after treatment with irinotecan/capecitabine. METHODS: Patients received irinotecan (240 mg/m(2)) as a 30 min intravenous infusion on day 1 and capecitabine (1000 mg/m(2)) orally bid for 14 days beginning on day 2. Treatment was repeated every 3 weeks. The protocol encouraged two to four cycles of irinotecan/capecitabine after recovery from surgery. RESULTS: Between May 2004 and February 2007, 48 patients entered in the study. Forty-seven (97.9%) of the 48 patients were assessable for response. The overall response rate before surgery was 56.3% (95% CI, 42.3-70.3%) in the treated population, including 2 non-confirmed complete response (CR), 18 partial responses (PR) and 7 non-confirmed PR. Twenty-three (47.9%) of 29 patients with tumor shrinkage proceeded to surgical intervention. Twenty of the 23 patients had a complete resection (S-CR). With a median follow-up time of 32 months (range, 24 38 months), the overall median time to progression and overall survival for all patients were 16.7 months (95% CI, 10.0-23.4 months) and 27.5 months (95% CI, 23.6-31.4 months) for all patients. The 1- 2- and 3-year overall survival estimates were 79.2% (95% CI, 67.7-90.7%), 60.4% (95% CI, 46.6-74.3%) and 29.2% (95% CI, 16.3-42.0%), respectively. Grade 3 diarrhea occurred in eight (17.0%) patients. The most common Grade 3/4 hematological adverse event was neutropenia in 8.5% of the patients. There were no treatment-related deaths during this study. CONCLUSIONS: Irinotecan/capecitabine appears to be a safe and very effective regimen in selected patients with unresectable liver metastases from CRC, but who are treated with a curative intent. PMID- 19773271 TI - Innovative trident fixation technique for allograft knee arthrodesis for high grade osteosarcoma around the knee. AB - OBJECTIVE: Reconstruction for osteosarcoma around the knee after wide resection faces the challenge of great bone defect and future limb length discrepancy in the skeletally immature patients. Modern prosthetic reconstruction may provide good results, but the longevity may be of concern and may not be affordable in certain communities. Allograft knee arthrodesis still has its role in light of bone stock preservation and cost-effectiveness. METHODS: We developed the innovative trident fixation technique utilizing three Steinmann pins to minimize limb length inequality without jeopardizing knee fusion stability. Twelve patients were enrolled. The mean age was 11.5 (10-13) years. Two had high-grade osteosarcoma in proximal tibia and others in distal femur. RESULTS: Two patients died of oncological disease. The median follow-up of the disease-free 10 patients was 47 (41-60) months. All allograft-host bone junctions healed uneventfully without major complications except one allograft fracture. The average limb length discrepancy was 1.45 (1.0-2.1) cm at latest follow-up. CONCLUSIONS: This straightforward technique was successful in knee arthrodesis with minimized limb length inequality. Accordingly, in light of bone stock preservation and longevity for the young children, it may be a surgical alternative for malignant bone tumors around the knee. PMID- 19773272 TI - How yield relates to ash content, Delta 13C and Delta 18O in maize grown under different water regimes. AB - BACKGROUND AND AIMS: Stable isotopes have proved a valuable phenotyping tool when breeding for yield potential and drought adaptation; however, the cost and technical skills involved in isotope analysis limit its large-scale application in breeding programmes. This is particularly so for Delta(18)O despite the potential relevance of this trait in C(4) crops. The accumulation of minerals (measured as ash content) has been proposed as an inexpensive way to evaluate drought adaptation and yield in C(3) cereals, but little is known of the usefulness of this measure in C(4) cereals such as maize (Zea mays). The present study investigates how yield relates to ash content, Delta(13)C and Delta(18)O, and evaluates the use of ash content as an alternative or complementary criterion to stable isotopes in assessing yield potential and drought resistance in maize. METHODS: A set of tropical maize hybrids developed by CIMMYT were subjected to different water availabilities, in order to induce water stress during the reproductive stages under field conditions. Ash content and Delta(13)C were determined in leaves and kernels. In addition, Delta(18)O was measured in kernels. KEY RESULTS: Water regime significantly affected yield, ash content and stable isotopes. The results revealed a close relationship between ash content in leaves and the traits informing about plant water status. Ash content in kernels appeared to reflect differences in sink-source balance. Genotypic variation in grain yield was mainly explained by the combination of ash content and Delta(18)O, whilst Delta(13)C did not explain a significant percentage of such variation. CONCLUSIONS: Ash content in leaves and kernels proved a useful alternative or complementary criterion to Delta(18)O in kernels for assessing yield performance in maize grown under drought conditions. PMID- 19773273 TI - Small effect of fragmentation on the genetic diversity of Dalbergia monticola, an endangered tree species of the eastern forest of Madagascar, detected by chloroplast and nuclear microsatellites. AB - BACKGROUND AND AIMS: The oriental forest ecosystem in Madagascar has been seriously impacted by fragmentation. The pattern of genetic diversity was analysed on a tree species, Dalbergia monticola, which plays an important economic role in Madagascar and is one of the many endangered tree species in the eastern forest. METHODS: Leaves from 546 individuals belonging to 18 small populations affected by different levels of fragmentation were genotyped using eight nuclear (nuc) and three chloroplast (cp) microsatellite markers. KEY RESULTS: For nuclear microsatellites, allelic richness (R) and heterozygosity (H(e,nuc)) differed between types of forest: R = 7.36 and R = 9.55, H(e,nuc) = 0.64 and H(e,nuc) = 0.80 in fragmented and non-fragmented forest, respectively, but the differences were not significant. Only the mean number of alleles (N(a,nuc)) and the fixation index F(IS) differed significantly: N(a,nuc) = 9.41 and N(a,nuc) = 13.18, F(IS) = 0.06 and F(IS) = 0.15 in fragmented and non fragmented forests, respectively. For chloroplast microsatellites, estimated genetic diversity was higher in non-fragmented forest, but the difference was not significant. No recent bottleneck effect was detected for either population. Overall differentiation was low for nuclear microsatellites (F(ST,nuc) = 0.08) and moderate for chloroplast microsatellites (F(ST,cp) = 0.49). A clear relationship was observed between genetic and geographic distance (r = 0.42 P < 0.01 and r = 0.42 P = 0.03 for nuclear and chloroplast microsatellites, respectively), suggesting a pattern of isolation by distance. Analysis of population structure using the neighbor-joining method or Bayesian models separated southern populations from central and northern populations with nuclear microsatellites, and grouped the population according to regions with chloroplast microsatellites, but did not separate the fragmented populations. CONCLUSIONS: Residual diversity and genetic structure of populations of D. monticola in Madagascar suggest a limited impact of fragmentation on molecular genetic parameters. PMID- 19773274 TI - Smoking habits and occupational disability: a cohort study of 14,483 construction workers. AB - OBJECTIVES: Although smoking causes a variety of diseases and both, a high smoking prevalence and permanent occupational disability are a great burden on the population level, data about the impact of smoking habits on occupational disability are sparse. The objective of this study was to examine the influence of smoking habits on occupational disability among construction workers, an occupational group with particularly high smoking prevalence. METHODS: The association between smoking and occupational disability was examined during a mean follow-up of 10.8 years in a cohort of 14,483 male construction workers in Wurttemberg, Germany. The cohort was linked to the regional pension register of the German pension fund to identify workers who were granted a disability pension during the follow-up. HRs (Hazard Ratios) were calculated with non-smokers as reference by the Cox proportional hazards model adjusting for potential confounding factors such as age, nationality, type of occupation, alcohol consumption and body mass index. RESULTS: Overall, 2643 cases of occupational disability were observed, with dorsopathy (21%) being the most common cause. Clear dose-response relationships were seen between smoking and occupational disability due to all causes, as well as occupational disability due to respiratory, cardiovascular and mental diseases, cancer and dorsopathy. Particularly strong associations were seen between heavy smoking (> or =20 cigarettes/day) and occupational disability due to mental and respiratory diseases (HR 3.25, 95% CI 1.93 to 5.46 and HR 3.26, 95% CI 1.69 to 6.27, respectively). CONCLUSION: Smoking is associated with increased risk of occupational disability among construction workers, in particular occupational disability due to respiratory, cardiovascular and mental diseases, cancer and dorsopathy. PMID- 19773275 TI - Pneumoconiosis among underground bituminous coal miners in the United States: is silicosis becoming more frequent? AB - OBJECTIVES: Epidemiological reports since 2000 have documented increased prevalence and rapid progression of pneumoconiosis among underground coal miners in the United States. To investigate a possible role of silica exposure in the increase, we examined chest x-rays (CXRs) for specific abnormalities (r-type small opacities) known to be associated with silicosis lung pathology. METHODS: Underground coal miners are offered CXRs every 5 years. Abnormalities consistent with pneumoconiosis are recorded by National Institute for Occupational Safety and Health (NIOSH) B Readers using the International Labour Organization Classification of Radiographs of Pneumoconioses. CXRs from 1980 to 2008 of 90 973 participating miners were studied, focussing on reporting of r-type opacities (small rounded opacities 3-10 mm in diameter). Log binomial regression was used to calculate prevalence ratios adjusted for miner age and profusion category. RESULTS: Among miners from Kentucky, Virginia and West Virginia, the proportion of radiographs showing r-type opacities increased during the 1990s (prevalence ratio (PR) 2.5; 95% CI 1.7 to 3.7) and after 1999 (PR 4.1; 95% CI 3.0 to 5.6), compared to the 1980s (adjusted for profusion category and miner age). The prevalence of progressive massive fibrosis in 2000-2008 was also elevated compared to the 1980s (PR 4.4; 95% CI 3.1 to 6.3) and 1990s (PR 3.8; 95% CI 2.1 to 6.8) in miners from Kentucky, Virginia and West Virginia. CONCLUSIONS: The increasing prevalence of pneumoconiosis over the past decade and the change in the epidemiology and disease profile documented in this and other recent studies imply that US coal miners are being exposed to excessive amounts of respirable crystalline silica. PMID- 19773276 TI - Occupational exposure to polycyclic aromatic hydrocarbons and lung cancer risk: a multicenter study in Europe. AB - BACKGROUND: Lung cancer incidence in Central and Eastern Europe (CEE) is among the highest in the world, and the role of occupational exposures has not been adequately studied in these countries. OBJECTIVES: To investigate the contribution of occupational exposure to polycyclic aromatic hydrocarbons (PAH) to lung cancer in CEE. METHODS: A case-control study was conducted in the Czech Republic, Hungary, Poland, Romania, Russia and Slovakia, as well as the United Kingdom (UK) between 1998 and 2002. Occupational and socio-demographic information was collected through interviews from 2861 newly diagnosed lung cancer cases and 2936 population or hospital controls. Industrial hygiene experts in each country evaluated exposure to 70 occupational agents, whereof 15 mixtures containing PAH. ORs of lung cancer were calculated after adjusting for other occupational exposures and tobacco smoking. RESULTS: The OR for ever exposure to PAH in the CEE countries was 0.93 (95% CI 0.77 to 1.14). The ORs for the highest category of cumulative exposure, duration of exposure and intensity of exposure were 1.13 (95% CI 0.80 to 1.58), 1.02 (95% CI 0.66 to 1.57) and 1.11 (95% CI 0.60 to 2.05), respectively. The OR for ever PAH exposure in the UK was 1.97 (95% CI 1.16 to 3.35). CONCLUSION: Occupational PAH exposure does not appear to substantially contribute to the burden of lung cancer in CEE. The apparently stronger effect observed in the UK may be due to high exposure levels and a joint effect with asbestos. PMID- 19773277 TI - Long-term exposure to traffic-related air pollution and mortality in Shizuoka, Japan. AB - OBJECTIVES: The number of studies investigating the health effects of long-term exposure to air pollution is increasing, however, most studies have been conducted in Western countries. The health status of Asian populations may be different to that of Western populations and may, therefore, respond differently to air pollution exposure. Therefore, we evaluated the health effects of long term exposure to traffic-related air pollution in Shizuoka, Japan. METHODS: Individual data were extracted from participants of an ongoing cohort study. A total of 14,001 older residents, who were randomly chosen from all 74 municipalities of Shizuoka, completed questionnaires and were followed from December 1999 to March 2006. Individual nitrogen dioxide exposure data, as an index for traffic-related exposure, were modelled using a land use regression model. We assigned participants an estimated concentration of nitrogen dioxide exposure during 2000-2006. We then estimated the adjusted HR and their CI for a 10 microg/m(3) increase in exposure to nitrogen dioxide for all-cause or cause specific mortality. RESULTS: The adjusted HR for all-cause mortality was 1.02 (95% CI 0.96 to 1.08). Regarding cause-specific mortality, the adjusted HR for cardiopulmonary mortality was 1.16 (95% CI 1.06 to 1.26); in particular the adjusted HR for ischaemic heart disease mortality was 1.27 (95% CI 1.02 to 1.58) and for pulmonary disease mortality it was 1.19 (95% CI 1.02 to 1.38). Furthermore, among non-smokers, a 10 microg/m(3) increase in nitrogen dioxide was associated with a higher risk for lung cancer mortality (HR 1.30, 95% CI 0.85 to 1.93). CONCLUSION: Long-term exposure to traffic-related air pollution, indexed by nitrogen dioxide concentration, increases the risk of cardiopulmonary mortality, even in a population with a relatively low body mass index and increases the risk of lung cancer mortality in non-smokers. PMID- 19773278 TI - Occupational coke oven emissions exposure and risk of abnormal liver function: modifications of body mass index and hepatitis virus infection. AB - OBJECTIVES: Occupational coke oven emissions (COEs) have been considered an important health issue. However, there are no conclusive data on human hepatic injury due to COE exposure. The association of COE exposure with liver function was explored and the effects of modification of potential non-occupational factors were assessed. METHODS: 705 coke oven workers and 247 referents were investigated. Individual cumulative COE exposure was quantitatively estimated. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase, alkaline phosphatase, hepatitis B surface antigen and anti hepatitis C antibody were measured. RESULTS: Among those with high COE exposure, the adjusted ORs of abnormal ALT and AST were 5.23 (95% CI 2.66 to 10.27) and 1.95 (95% CI 1.18 to 3.52), respectively. Overweight individuals (body mass index (BMI) > or =25 kg/m(2)) with high COE exposure had elevated risks of abnormal ALT (adjusted OR 23.93, 95% CI 8.73 to 65.62) and AST (adjusted OR 5.18, 95% CI 2.32 to 11.58). Risk of liver damage in hepatitis B virus- or hepatitis C virus positive individuals with COE exposure was also elevated. CONCLUSIONS: Long-term exposure to COE increases the risk of liver dysfunction, which is more prominent among those with higher BMI and hepatitis virus infection. The risk assessment of liver damage associated with COE exposure should take BMI and hepatitis virus infection into consideration. PMID- 19773279 TI - Association between genetic variants in VEGF, ERCC3 and occupational benzene haematotoxicity. AB - INTRODUCTION: Benzene is an established human haematotoxin, with substantial interindividual variation in benzene-induced toxicity. METHODS: To further examine if genetic variation contributes to benzene haematotoxicity, we analysed 1023 tagSNPs in 121 gene regions important for benzene metabolism, haematopoiesis, leukaemia and lymphoma among 250 workers exposed to benzene and 140 unexposed controls in a cross-sectional study carried out in China. Linear regression was used to analyse the relationship between genetic polymorphisms and total white blood cell (WBC) count and its subtypes, adjusting for potential confounders and occupational exposure to benzene and toluene among exposed workers. The minp test assessed the association on the gene region level. The false discovery rate method was used to control for multiple comparisons. RESULTS: VEGF (minp = 0.0030) and ERCC3 (minp = 0.0042) were the most significantly associated gene regions with altered WBC counts among benzene exposed workers, after accounting for multiple comparisons. Highly significant changes were also found for WBC subtype counts, including granulocytes, CD4+ T cells and lymphocytes for VEGF and granulocytes and NK cells for ERCC3. Further, in workers exposed to <1 ppm, a SNP in VEGF was associated with changes in WBC and granulocyte counts, and SNPs in ERCC3 were associated with changes in WBC, NK cell and granulocyte counts. DISCUSSION: Our findings suggest that genetic variation in VEGF, which plays an important role in blood vessel growth, and ERCC3, which is a member of the DNA repair pathway and is responsible for repairing bulky DNA adducts formed by chemicals, may contribute to individual susceptibility to benzene-induced haematotoxicity at relatively low levels of benzene exposure. PMID- 19773280 TI - Cross-validation and refinement of the Stoffenmanager as a first tier exposure assessment tool for REACH. AB - OBJECTIVES: For regulatory risk assessment under REACH a tiered approach is proposed in which the first tier models should provide a conservative exposure estimate that can discriminate between scenarios which are of concern and those which are not. The Stoffenmanager is mentioned as a first tier approach in the REACH guidance. In an attempt to investigate the validity of the Stoffenmanager algorithms, a cross-validation study was performed. METHODS: Exposure estimates using the Stoffenmanager algorithms were compared with exposure measurement results (n=254). Correlations between observed and predicted exposures, bias and precision were calculated. Stratified analyses were performed for the scenarios "handling of powders and granules" (n=82), "handling solids resulting in comminuting" (n=60), "handling of low-volatile liquids" (n=40) and "handling of volatile liquids" (n=72). RESULTS: The relative bias of the four algorithms ranged between -9% and -77% with a precision of approximately 1.7. The 90th percentile estimate of one out of four algorithms was not conservative enough. Based on these statistics and analyses of residual plots the underlying algorithm was adapted. Subsequently, the calibration and the cross-validation dataset were merged into one dataset (n=952) used for calibrating the adapted Stoffenmanager algorithms. This new calibration resulted in new exposure algorithms for the four scenarios. CONCLUSIONS: The Stoffenmanager is capable of discriminating among exposure levels mainly between scenarios in different companies. The 90th percentile estimates of the Stoffenmanager are verified to be sufficiently conservative. Therefore, the Stoffenmanager could be a useful tier 1 exposure assessment tool for REACH. PMID- 19773281 TI - Does deprivation index modify the acute effect of black smoke on cardiorespiratory mortality? AB - OBJECTIVES: To investigate whether deprivation index modifies the acute effect of black smoke on cardiorespiratory mortality. METHODS: Generalised linear Poisson regression models were used to investigate whether deprivation index (as measured by the Carstairs deprivation index) modified the acute effect of black smoke on mortality in two largest Scottish cities (Glasgow and Edinburgh) between January 1981 and December 2001. Lag periods of up to 1 month were assumed for the effects of black smoke. RESULTS: Deprivation index significantly modified the effect of black smoke on mortality, with black smoke effects generally increasing as level of deprivation increased. The interaction coefficient from a parametric model assuming a linear interaction between black smoke (microg/m(-3)) and deprivation in their effect on mortality--equivalent to a test of 'linear trend' across Carstairs categories--was significant for all mortality outcomes. In a model where black smoke effects were estimated independently for each deprivation category, the estimated increase in respiratory mortality over the ensuing 1 month period associated with a 10 microg/m(3) increase in the mean black smoke concentration was 8.0% (95% CI 5.1 to 10.9) for subjects residing in the 'most' deprived category (Carstairs category 7) compared to 3.7% (95% CI -0.7 to 8.4) for subjects residing in the 'least' deprived category (Carstairs category 1). CONCLUSIONS: The results suggest a stronger effect of black smoke on mortality among people living in more deprived areas. The effect was greatest for respiratory mortality, although significant trends were also seen for other groups. If corroborated, these findings could have important public health implications. PMID- 19773282 TI - Occupational exposure to silica and lung cancer risk in the Netherlands. AB - OBJECTIVES: The lung cancer carcinogenicity of crystalline silica dust remains the subject of discussion. Epidemiological evidence is based on occupational cohort studies and population-based case-control studies. The aim of this study was to assess associations between male lung cancer risk and silica exposure in a population-based cohort study. METHODS: The study was conducted among men aged 55 69 years (n=58 279) from the Netherlands Cohort Study, which included self reported, life-time job histories. Job titles were linked to the occupational groups of the external Finnish Job Exposure Matrix (FINJEM), including probability and level of silica exposure, each for specific time periods. 1667 incident lung cancer cases with known silica exposure status (210 exposed) were available after 11.3 years of follow-up. Risks were estimated based on a case cohort design, and using Cox proportional hazards models. RESULTS: Adjusted for smoking and other confounders, elevated risks were observed for exposure duration (RR 1.65, 95% CI 1.14 to 2.41 for 26-51 years vs no exposure) and cumulative exposure (RR 1.47, 95% CI 0.93 to 2.33 for >=3 vs <3 mg/m(3).year). Associations with average exposure levels were weaker. Associations were stronger for occupations with an exposure probability of >=90%. Adjustment for asbestos exposure slightly increased the risk. CONCLUSIONS: Results from this prospective population-based cohort study corroborate the classification of crystalline silica as a lung carcinogen. Associations could not be explained by smoking or by asbestos exposure. PMID- 19773283 TI - Respiratory health effects of ultrafine and fine particle exposure in cyclists. AB - OBJECTIVES: Monitoring studies have shown that commuters are exposed to high air pollution concentrations, but there is limited evidence of associated health effects. We carried out a study to investigate the acute respiratory health effects of air pollution related to commuting by bicycle. METHODS: Twelve healthy adults cycled a low- and a high-traffic intensity route during morning rush hour in Utrecht, The Netherlands. Exposure to traffic-related air pollution was characterised by measurements of PM(10), soot and particle number. Before, directly after and 6 h after cycling we measured lung function (FEV(1), FVC, PEF), exhaled NO (FE(NO)) and respiratory symptoms. The association between post- minus pre-exposure difference in health effects and exposure during cycling was evaluated with linear regression models. RESULTS: The average particle number concentration was 59% higher, while the average soot concentration was 39% higher on the high-traffic route than on the low-traffic route. There was no difference for PM(10). Contrary to our hypothesis, associations between air pollution during cycling and lung function changes immediately after cycling were mostly positive. Six hours after cycling, associations between air pollution exposure and health were mostly negative for lung function changes and positive for changes in exhaled NO, although non-significant. CONCLUSIONS: We found substantial differences in ultrafine particle number and soot exposure between two urban cycling routes. Exposure to ultrafine particles and soot during cycling was weakly associated with increased exhaled NO, indicative of airway inflammation, and decrements in lung function 6 h after exposure. A limitation of the study was the relatively small sample size. PMID- 19773284 TI - Prolonged time to pregnancy in residents exposed to ionising radiation in cobalt 60-contaminated buildings. AB - OBJECTIVES: Radiation-induced cytogenetic damage in somatic cells has raised concern that low-dose ionising radiation can also damage germ cells and influence gamete production and/or function, resulting in decreased fertility. Time to pregnancy (TTP) was used to investigate whether exposure to gamma-radiation affected fertility among the residents of cobalt-60-contaminated buildings in Taiwan. METHODS: This was a retrospective pregnancy-based study of 357 pregnancies born to 124 exposed couples. Both the cumulative dose and the dose rate for each pregnancy was estimated based on a physical dose reconstruction programme. The comparison population consisted of 612 pregnancies born to 225 couples randomly sampled from the Taiwan general population. Information on TTP was collected by personal interviews. Fecundability ratios (FRs) were calculated with a discrete proportional hazards model. RESULTS: For exposed mothers, fertility decreased significantly when unprotected intercourse began during the period of living in the radiation-contaminated buildings (FR 0.75, 95% CI 0.61 to 0.92). The effect was borderline significant for fathers (FR 0.83, 95% CI 0.68 to 1.02). There was evidence that prolonged TTP was associated with the rate of exposure for both mothers and fathers (tests for trend: female, p=0.0006; male, p=0.03), especially evident for dose rates > or =10 mSv/year (female, FR 0.60, 95% CI 0.43 to 0.84; male, FR 0.68, 95% CI 0.49 to 0.96). CONCLUSIONS: Our findings suggest that exposure to low-dose ionising radiation of cobalt-60 contaminated buildings may decrease fertility, especially in females. Fertility declined with increasing concurrent dose but not with cumulative dose. PMID- 19773285 TI - Organisational justice and markers of inflammation: the Whitehall II study. AB - OBJECTIVES: Low organisational justice has been shown to be associated with increased risk of various health problems, but the underlying mechanisms remain unclear. We tested whether organisational injustice contributes to chronic inflammation in a population of middle-aged men and women. METHODS: This prospective cohort study uses data from 3205 men and 1204 women aged 35-55 years at entry into the Whitehall II study (phase 1, 1985-1988). Organisational justice perceptions were assessed at phase 1 and phase 2 (1989-1990) and circulating inflammatory markers C-reactive protein (CRP) and interleukin (IL)-6 at phase 3 (1991-1993) and phase 7 (2003-2004). RESULTS: In men, low organisational justice was associated with increased CRP levels at both follow-ups (phase 3 and 7) and increased IL-6 at the second follow-up (phase 7). The long term (phase 7) associations were largely independent of covariates, such as age, employment grade, body mass index and depressive symptoms. In women, no relationship was found between organisational justice and CRP or IL-6. CONCLUSIONS: This study suggests that organisational injustice is associated with increased long-term levels of inflammatory markers among men. PMID- 19773286 TI - The role of microRNAs in endometriosis and associated reproductive conditions. AB - BACKGROUND: microRNAs (miRNAs) are short, single-stranded RNAs that regulate gene expression at the post-transcriptional level. Recent research has shown that miRNAs and their target mRNAs are differentially expressed in endometriosis and other disorders of the female reproductive system. Since miRNAs control a broad spectrum of normal and pathological cellular functions, they may play pivotal roles in the pathogenesis of these disorders. METHODS: A systematic review was undertaken of the published literature on; (i) the expression and functions of miRNAs in mammalian female reproductive tissues with a focus on endometriosis and the malignancies and fertility disorders related to this disease; and (ii) the potential roles played by validated mRNA targets of endometriosis-associated miRNAs. The current understanding of the biology of miRNAs is overviewed and the potential diagnostic and therapeutic potential of miRNAs in endometriosis is highlighted. RESULTS: The differential expression of miRNAs in endometriosis, and the putative molecular pathways constituted by their targets, suggests that miRNAs may play an important role in endometriotic lesion development. Models for miRNA regulatory functions in endometriosis are presented, including those associated with hypoxia, inflammation, tissue repair, TGFbeta-regulated pathways, cell growth, cell proliferation, apoptosis, extracellular matrix remodelling and angiogenesis. In addition, specific miRNAs which may be associated with malignant progression and subfertility in endometriosis are discussed. CONCLUSIONS: miRNAs appear to be potent regulators of gene expression in endometriosis and its associated reproductive disorders, raising the prospect of using miRNAs as biomarkers and therapeutic tools in endometriosis. PMID- 19773287 TI - The time has come to limit the placebo period in rheumatoid arthritis trials to 3 months: a systematic comparison of 3- and 6-month response rates in trials of biological agents. AB - BACKGROUND: Most registration trials in rheumatoid arthritis (RA) include a placebo arm in the setting of an incomplete response to disease-modifying antirheumatic treatment (DMARD-IR). A minimum duration of 6 months is required despite serious methodological and ethical shortcomings. OBJECTIVE: To study whether a 3-month placebo period is sufficient to prove efficacy. METHODS: Meta analysis of placebo- or active control trials of biological agents in DMARD-IR RA, comparing the contrast in ACR response between experimental and control groups at 3 and 6 months. RESULTS: Twenty trials yielded 15 placebo and 18 active control contrasts (>10,000 patients). At 3 months active treatment showed a highly significant contrast with placebo for ACR20 and ACR50 in every instance. As all groups improved further the mean contrast at 6 months was unchanged. For ACR70 the contrast was clearly greater at 6 months owing to further improvement only in the experimental groups. In active control trials contrasts were smaller, and for ACR50 and ACR70 these decreased somewhat owing to "catch-up" responses in the control groups. CONCLUSION: The placebo phase of registration trials for RA can be limited to 3 months. An accompanying viewpoint proposes that patients receiving placebo should then be switched to standard of care, allowing a more valid and comprehensive assessment, including safety. PMID- 19773288 TI - Tumour necrosis factor alpha blockade impairs dendritic cell survival and function in rheumatoid arthritis. AB - OBJECTIVES: Tumour necrosis factor alpha (TNFalpha) blockade is an effective therapy for rheumatoid arthritis (RA). The immunomodulatory effects of TNFalpha antagonists are thought to contribute to their therapeutic action. This study investigated whether anti-TNFalpha therapeutics exerted their immunoregulatory effects through modulation of dendritic cell (DC) function. METHODS: Two complementary approaches were taken: in the first 'in vitro' approach monocyte derived DC from healthy donors were matured with lipopolysaccharide and treated with TNFalpha antagonists in vitro for 48 h. In the second 'ex vivo' approach monocyte-derived DC were generated from RA patients before and 8-12 weeks into anti-TNFalpha treatment. DC were analysed for survival, phenotype, cytokine production and T-cell stimulatory capacity. RESULTS: TNFalpha blockade during DC maturation in vitro induced approximately 40% of DC to undergo apoptosis. Importantly, the surviving DC displayed a semimature phenotype with reduced levels of HLA-DR, CD80, CD83, CD86 and CCR7, and their production of IL-10 was enhanced compared with DC matured without TNFalpha antagonists. Furthermore, anti TNFalpha-treated DC were poor stimulators of T-cell proliferation and polarised T cell development towards a higher IL-10/lower IFNgamma cytokine profile. Similarly, DC derived from RA patients after anti-TNFalpha treatment showed impaired upregulation of CD80 and CD86 upon lipopolysaccharide activation and displayed poor T-cell stimulatory activity. CONCLUSIONS: The data show that TNFalpha blockade has profound effects on DC function with downstream, potentially immunoregulatory, effects on T cells. These data provide an interesting new insight into the potential mechanism by which anti-TNFalpha drugs contribute to the restoration of immunoregulation in RA patients. PMID- 19773289 TI - Ultrasonographic monitoring of response to therapy in polymyalgia rheumatica. AB - OBJECTIVE: To assess the responsiveness of ultrasound (US) inflammatory findings in the shoulder and hip of patients with polymyalgia rheumatica (PMR) who started treatment with corticosteroids. METHODS: Fifty-three patients with active PMR who started treatment with prednisone in six Spanish centres were prospectively studied. The patients underwent clinical, laboratory and US assessment at baseline, 4 and 12 weeks. The US investigation consisted of detection and quantification of inflammatory findings in the shoulder and hip. The responsiveness of clinical, laboratory and US parameters was tested by the standardised response mean. Intraobserver and interobserver reliability between US investigators was assessed. RESULTS: At baseline, 34 patients (69%) had inflammation in at least one bilateral site. During the follow-up period, clinical, laboratory and US variables showed a parallel decrease. A significant decrease in US inflammatory parameters was found at week 4 (p<0.001). After 4 and 12 weeks of treatment with corticosteroids, US inflammatory findings showed similar or better sensitivity to change than clinical and laboratory markers of PMR activity. Intraobserver and interobserver intraclass correlation coefficients were 0.96 and 0.99, respectively (p<0.05). CONCLUSION: US may be a responsive additional tool in monitoring the response to corticosteroids in patients with PMR in daily practice and multicentre trials. PMID- 19773290 TI - EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis. AB - OBJECTIVES: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR's "standardised operating procedures", the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. RESULTS: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk. CONCLUSIONS: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA. PMID- 19773291 TI - The effect of environmental parameters on the survival of airborne infectious agents. AB - The successful transmission of infection via the airborne route relies on several factors, including the survival of the airborne pathogen in the environment as it travels between susceptible hosts. This review summarizes the various environmental factors (particularly temperature and relative humidity) that may affect the airborne survival of viruses, bacteria and fungi, with the aim of highlighting specific aspects of environmental control that may eventually enhance the aerosol or airborne infection control of infectious disease transmission within hospitals. PMID- 19773293 TI - Infections as a stimulus for coronary occlusion, obstruction, or acute coronary syndromes. AB - BACKGROUND: Atherosclerosis is considered to be an inflammatory disease. Infections are a significant cause of inflammation. Acute infections might precipitate acute coronary syndromes (ACS) whereas chronic infections might be stimuli for the development of atherosclerosis. METHODS: Coronary angiograms were done on 211 of 335 patients with ACS and the percentage of coronary obstruction was determined. Serum antibody levels to Chlamydia pneumoniae, C. pneumoniae heat shock protein 60 (CpnHSP60), human heat shock protein 60 (hHSP60), enterovirus (EV), herpes simplex virus (HSV), cytomegalovirus (CMV), and two major periodontal pathogens, Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, were measured in healthy controls (n = 355) and all patients. RESULTS: Serum antibody levels to periodontal pathogens did not correlate with ACS. However, IgA-class antibody levels to Aggregatibacter actinomycetemcomitans (p = 0.021), CpnHSP60 (p = 0.048) an hHSP60 (p = 0.038) were higher in patients with coronary occlusion or obstruction compared to those without any obstruction. Odds ratios for coronary changes in the highest quartile as compared to the lower quartiles were for A. actinomycetemcomitans IgA 7.84 (95% CI 1.02-60.39, p = 0.048), for CpnHSP60 IgA 8.61 (1.12-65.89, p = 0.038), and for human HSP60 IgA 3.51 (0.79-15.69, p = 0.100). CONCLUSIONS: We have previously reported that EV and HSV titres correlated significantly to acute coronary events. They do not correlate to the degree of coronary obstruction as shown here. However, infection by A. actinomycetemcomitans or C. pneumoniae or host response against them associated with coronary obstruction. Clinical coronary events may arise by the effect of acute infections and obstructing lesions by a chronic inflammatory stimulus. PMID- 19773292 TI - Aerosol transmission of influenza A virus: a review of new studies. AB - Over the past few years, prompted by pandemic preparedness initiatives, the debate over the modes of transmission of influenza has been rekindled and several reviews have appeared. Arguments supporting an important role for aerosol transmission that were reviewed included prolonged survival of the virus in aerosol suspensions, demonstration of the low infectious dose required for aerosol transmission in human volunteers, and clinical and epidemiological observations were disentanglements of large droplets and aerosol transmission was possible. Since these reviews were published, several new studies have been done and generated new data. These include direct demonstration of the presence of influenza viruses in aerosolized droplets from the tidal breathing of infected persons and in the air of an emergency department; the establishment of the guinea pig model for influenza transmission, where it was shown that aerosol transmission is important and probably modulated by temperature and humidity; the demonstration of some genetic determinants of airborne transmission of influenza viruses as assessed using the ferret model; and mathematical modelling studies that strongly support the aerosol route. These recent results and their implication for infection control of influenza are discussed in this review. PMID- 19773294 TI - Platelet factor 4 (CXCL4) facilitates human macrophage infection with HIV-1 and potentiates virus replication. AB - Platelet factor 4 (CXCL4), a member of the CXC chemokine subfamily released in high amounts by activated platelets, has been identified as a monocyte survival factor that induces monocyte differentiation into macrophages. Although CXCL4 has been shown to have biological effects unique to chemokines, nothing is known about the role of CXCL4-derived human macrophages or CXCL4 in human immunodeficiency virus (HIV) disease. In this study, CXCL4-derived macrophages are compared with macrophage-colony stimulating factor (M-CSF)-derived macrophages for their ability to support HIV-1 replication. We show that CXCL4 derived macrophages can be infected with macrophage-tropic HIV-1 that uses either CC-chemokine receptor 5 (CCR5) or CXC-chemokine receptor 4 (CXCR4) as a co receptor for viral entry. We also find that M-CSF and the chemokines, monocyte chemoattractant protein 1 (MCP-1; CCL2) and macrophage-inflammatory-protein-1 alpha (MIP-1alpha; CCL3) are produced upon R5- and X4-tropic HIV-1 replication in both M-CSF- and CXCL4-derived human macrophages. In addition, CXCL4 added to M CSF-derived macrophages after virus adsorption and maintained throughout the infection enhances HIV-1 replication. We thus propose a novel role for CXCL4 in HIV disease. PMID- 19773295 TI - Knowledge transfer and the university system's functioning: need for change. PMID- 19773296 TI - Work life and mental well-being: single and coupled employed mothers in Southern Europe and Scandinavia. AB - Many European mothers, single and coupled, combine work outside the home and family life. The effects of this on their mental well-being may vary depending on the level of support available from the State's welfare system, since welfare may buffer working mothers from some of the stress that can arise from trying to manage significant responsibilities on the job and at home. Welfare may be especially important for single working mothers, for whom the burden of multiple roles may be even heavier. The present study assessed levels and predictors of well-being of single and coupled employed mothers in Greece, Portugal and Spain, where welfare support is relatively limited. Results were compared to a parallel study with data from Denmark, Norway and Sweden, where welfare support is relatively comprehensive. Coupled mothers in Scandinavia had significantly lower financial hardship, longer education, higher life satisfaction, more enriching jobs, practical support, financial support and social participation than coupled mothers in the Southern European sample. On the other hand, the Scandinavian coupled mothers had higher levels of work family conflict than coupled mothers in Southern Europe. Single mothers in Scandinavia, compared to single mothers in Southern Europe, had significantly longer education, higher life satisfaction and positive affect, more enriching jobs, confidant support, practical support, financial support and social participation. Level of job stress was the same for all mother groups. All groups differed significantly from each other in level of financial hardship, with Scandinavian coupled mothers being best off, followed by Scandinavian single mothers, Southern European coupled mothers, and Southern European single mothers. The regional differences suggest that single motherhood per se need not be a risk factor for poorer well-being, and that welfare policies may have a protective effect for the mental well-being of single mothers. PMID- 19773297 TI - The impact of an international health study abroad program on university students from the United States. AB - OBJECTIVE: International experience is paramount in society today. However, many US citizens have little understanding of the world beyond US borders. The purpose of this qualitative study was to (i) assess the impact of a study abroad program on students and (ii) the impact on the career goals of students who completed the program. PARTICIPANTS AND METHODS: Fall 2005 alumni (N = 68) of an international health study abroad program were sent a mail survey. RESULTS: Twenty-seven of the students who responded to the survey (61%) were currently in medical school, nursing school, or a master's program. CONCLUSIONS: All students indicated the program influenced their global view of the world. Participants indicated the experience continues to have an impact on how they critically think about the world, including US politics. PMID- 19773298 TI - Pedagogical competence and value clarification among health educators. AB - Individual and social values are increasingly important in health education. This article examines how health educators in Greenland and Denmark engage in value clarification as part of their educational practices. It presents the results of a study of health professionals in a variety of settings, focusing in particular on how development work and experimentation can strengthen their pedagogical competences. The study focuses on belief, reasoning, interpretation and reflection, rather than routines, skills, or ethical rules, and takes a participatory approach that oscillates between dialogical and qualitative empirical methodologies. It observes pedagogical practice in selected settings in Greenland and the municipality of Copenhagen. Within the framework provided by four discourses that appear to organize communication about health, it shows how values became important to the progress of two research-based development projects. On this basis, the article argues that health education can be effectively grounded in the values, perceptions, and experiences of a given population, while being guided by the health educators' biomedical knowledge and educational values. PMID- 19773299 TI - Development of a student health questionnaire: the necessity of a symbiosis of science and practice. AB - RATIONALE, AIMS AND OBJECTIVES: University students report more health complaints than their working peers, but do not appear to seek help for these problems. This stresses the importance of early detection. The aim of this study was to obtain information on indicators of health associated with academic functioning to develop a preliminary health surveillance questionnaire. In addition, we aimed to gain insight in the additional value of adding experience-based information from the priority population, and individuals in their direct environment, to the knowledge gained from the scientific literature. METHOD: First, a review of literature on indicators of health associated with academic functioning was conducted. Next, interviews were held with students (n = 11) and two groups of significant others with professional experience in student health care: general practitioners (n = 9) and practice assistants (n = 8). RESULTS AND CONCLUSIONS: A health surveillance questionnaire to detect students with health problems associated with academic functioning should consist of questions on social support, general health, physical health, psychological health, study-related issues and health, help-seeking behaviour and life events in the past. Experiences from practice should be integrated when developing a questionnaire. PMID- 19773300 TI - Exploring the effects of government funding on community-based organizations: 'top-down' or 'bottom-up' approaches to health promotion? AB - Community-based organizations hold an increasingly central role in the representation and advocacy of marginalized groups and individuals. In these capacities, such organizations make significant contributions to the areas of health and health services. In particular, they are considered well-positioned to operationalize 'bottom-up' approaches to health promotion. In this article we use a case study to illuminate unforeseen consequences of government funding of community-based organizations involved in health promotion and health service work. Previous research has found that many health promotion practitioners are engaged in a shift towards 'bottom-up' approaches to health promotion (1). In contrast, our findings suggest that due to government funding, those best positioned to promote community participation and empowerment may be experiencing a converse shift away from 'bottom-up' approaches. PMID- 19773301 TI - Reports from the field: engaging learners as interpreters for developing health messages -- designing the 'Familias Sin Plomo' English as a Second Language curriculum project. AB - California has a recently documented problem of trans-national environmental lead exposures in imported foods from Mexico but there is limited health information available in immigrant communities about this problem. This report highlights collaborative work with English as a Second Language (ESL) learners to critically review research data on lead exposures and reframe prevention messages about lead contamination of imported foods. These messages are now integrated into ESL curricula for dissemination to Spanish-speaking populations that are disproportionately affected by lead poisoning. This 'learners as interpreters' approach is a participatory method that can be applied across a wide range of public health activities. ESL learners emerged as ideal partners in developing curriculum for lead poisoning prevention for several reasons: the parents expressed strong interest in lead poisoning prevention, several have children under age 6 when lead screenings are recommended, and many have emigrated from regions in Mexico where lead hazards were identified. PMID- 19773302 TI - The contribution of social work in promoting rural health: a case from the grassroots. AB - Promotion of rural health has become a high priority of policy makers in many third world countries. Numerous NGOs are working to improve health quality in rural India. By describing a rural health promotion project in which a social worker played a key role, this article illustrates how social work practitioners can bring their many skills to bear in efforts to promote health. This commentary seeks to share the experience of an NGO in specific health promotion project in Rural Karnataka State (India). PMID- 19773303 TI - Flow and sense of coherence: two aspects of the same dynamic? AB - Antonovsky's sense of coherence (SOC) and Csikszentmihalyi's concept of flow appeared approximately 20 years ago and have received widespread recognition as resource-oriented approaches within the fields of health and psychology, respectively. Both focus on the dynamics of engagement with life, flow on one's level of engagement in the present and SOC on one's global orientation - one's self-perceived capacity for engagement over time. While the two constructs are very similar, even collinear, no attempt seems to have been made to integrate them. This article proposes that flow and sense of coherence are not only complementary but actually two aspects of the same dynamic: flow is sense of coherence made visible in the present, while sense of coherence is a product of flow over time. It is suggested that this hypothesis could be tested using existing or new empirical methods. If evidence is found to support the hypothesis, this could lead to a more useful, integrated model of the dynamics of engagement. PMID- 19773305 TI - [Equity and social determinants of health: the urgency to act]. PMID- 19773306 TI - [Accompany families to promote their participation in the medical care of their child]. PMID- 19773307 TI - [Proceedings of a French international meeting on social inequalities in health: states the situation, means, and framework for public health action aimed at reducing social inequalities in health]. PMID- 19773309 TI - [Evaluation of health promotion in schools in Spain]. PMID- 19773310 TI - Helicobacter pylori and ulcers. Against reductionism. PMID- 19773311 TI - Rosiglitazone and pioglitazone. Beware macular oedema. PMID- 19773312 TI - Promoting social mobility. Not just down to individuals. PMID- 19773313 TI - Has payment by results affected how care is recorded? PMID- 19773314 TI - Payment by results. Market failure. PMID- 19773315 TI - Contraception for women. Intrauterine devices and ectopic pregnancy. PMID- 19773316 TI - Contraception for women. Evidence based counselling. PMID- 19773317 TI - Noctors, doctors, and rules. PMID- 19773322 TI - Femtosecond laser fabricated spike structures for selective control of cellular behavior. AB - In this study we investigate the potential of femtosecond laser generated micrometer sized spike structures as functional surfaces for selective cell controlling. The spike dimensions as well as the average spike to spike distance can be easily tuned by varying the process parameters. Moreover, negative replications in soft materials such as silicone elastomer can be produced. This allows tailoring of wetting properties of the spike structures and their negative replicas representing a reduced surface contact area. Furthermore, we investigated material effects on cellular behavior. By comparing human fibroblasts and SH-SY5Y neuroblastoma cells we found that the influence of the material was cell specific. The cells not only changed their morphology, but also the cell growth was affected. Whereas, neuroblastoma cells proliferated at the same rate on the spike structures as on the control surfaces, the proliferation of fibroblasts was reduced by the spike structures. These effects can result from the cell specific adhesion patterns as shown in this work. These findings show a possibility to design defined surface microstructures, which could control cellular behavior in a cell specific manner. PMID- 19773324 TI - Appropriate requesting of serum tumour markers. PMID- 19773323 TI - Physical interventions to interrupt or reduce the spread of respiratory viruses: systematic review. AB - OBJECTIVE: To review systematically the evidence of effectiveness of physical interventions to interrupt or reduce the spread of respiratory viruses. DATA SOURCES: Cochrane Library, Medline, OldMedline, Embase, and CINAHL, without restrictions on language or publication. Data selection Studies of any intervention to prevent the transmission of respiratory viruses (isolation, quarantine, social distancing, barriers, personal protection, and hygiene). A search of study designs included randomised trials, cohort, case-control, crossover, before and after, and time series studies. After scanning of the titles, abstracts and full text articles as a first filter, a standardised form was used to assess the eligibility of the remainder. Risk of bias of randomised studies was assessed for generation of the allocation sequence, allocation concealment, blinding, and follow-up. Non-randomised studies were assessed for the presence of potential confounders and classified as being at low, medium, or high risk of bias. DATA SYNTHESIS: 58 papers of 59 studies were included. The quality of the studies was poor for all four randomised controlled trials and most cluster randomised controlled trials; the observational studies were of mixed quality. Meta-analysis of six case-control studies suggested that physical measures are highly effective in preventing the spread of severe acute respiratory syndrome: handwashing more than 10 times daily (odds ratio 0.45, 95% confidence interval 0.36 to 0.57; number needed to treat=4, 95% confidence interval 3.65 to 5.52), wearing masks (0.32, 0.25 to 0.40; NNT=6, 4.54 to 8.03), wearing N95 masks (0.09, 0.03 to 0.30; NNT=3, 2.37 to 4.06), wearing gloves (0.43, 0.29 to 0.65; NNT=5, 4.15 to 15.41), wearing gowns (0.23, 0.14 to 0.37; NNT=5, 3.37 to 7.12), and handwashing, masks, gloves, and gowns combined (0.09, 0.02 to 0.35; NNT=3, 2.66 to 4.97). The combination was also effective in interrupting the spread of influenza within households. The highest quality cluster randomised trials suggested that spread of respiratory viruses can be prevented by hygienic measures in younger children and within households. Evidence that the more uncomfortable and expensive N95 masks were superior to simple surgical masks was limited, but they caused skin irritation. The incremental effect of adding virucidals or antiseptics to normal handwashing to reduce respiratory disease remains uncertain. Global measures, such as screening at entry ports, were not properly evaluated. Evidence was limited for social distancing being effective, especially if related to risk of exposure-that is, the higher the risk the longer the distancing period. CONCLUSION: Routine long term implementation of some of the measures to interrupt or reduce the spread of respiratory viruses might be difficult. However, many simple and low cost interventions reduce the transmission of epidemic respiratory viruses. More resources should be invested into studying which physical interventions are the most effective, flexible, and cost effective means of minimising the impact of acute respiratory tract infections. PMID- 19773325 TI - Surgery for obesity in adulthood. PMID- 19773326 TI - Iterative diagnosis. PMID- 19773327 TI - Vertigo. PMID- 19773328 TI - Serum tumour markers: how to order and interpret them. PMID- 19773329 TI - Economic evaluation of arthritis self management in primary care. AB - OBJECTIVE: To assess the cost effectiveness of a self management programme plus education booklet for arthritis in primary care. DESIGN: Cost effectiveness and cost utility analysis from health and social care and societal perspectives alongside a randomised controlled trial. SETTING: 74 general practices in the United Kingdom. PARTICIPANTS: 812 patients aged 50 or more with osteoarthritis of the hips or knees, or both, and pain or disability, or both. INTERVENTIONS: Randomisation to either six sessions of an arthritis self management programme plus an education booklet (intervention group) or the education booklet alone (standard care control group). MAIN OUTCOME MEASURES: Total health and social care costs and total societal costs at 12 months; cost effectiveness (incremental cost effectiveness ratios and cost effectiveness acceptability curves) on basis of quality of life (SF-36, primary outcome measure), EuroQol visual analogue scale, and quality adjusted life years (QALYs). RESULTS: At 12 months health and social care costs in the intervention group were pound101 higher (95% confidence interval pound3 to pound176) than those in the control group because the additional costs of the arthritis self management programme did not seem to be fully offset by savings elsewhere. There were no significant differences in societal costs (which were up to 13 times the size of health and social care costs) or any of the outcomes. From the health and social care perspective the intervention was dominated by the control on the basis of QALYs (which were non significantly lower in the intervention group) and had incremental cost effectiveness ratios between pound279 and pound13 473 for the other outcomes. From the societal perspective the intervention seemed superior to the control owing to non-significantly lower costs and non-significantly better outcomes on all measures except QALYs. Probabilities of the arthritis self management programme's cost effectiveness ranged between 12% and 97% (for thresholds ranging pound0 to pound1000) based on one point improvements in SF-36 outcomes, but the clinical significance of this is debatable. Probabilities of cost effectiveness on the basis of the visual analogue scale and QALYs were low. CONCLUSIONS: Cost effectiveness of an arthritis self management programme is not suggested on the basis of current National Institute for Health and Clinical Excellence cost perspectives and QALY thresholds. The probability of cost effectiveness is greater when broader costs and other quality of life outcomes are considered. These results suggest that the cost effectiveness of the Department of Health's expert patients programme cannot be assumed across all clinical conditions and that further rigorous evaluations for other conditions may be needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN79115352. PMID- 19773334 TI - MOODS: fast search for position weight matrix matches in DNA sequences. AB - MOODS (MOtif Occurrence Detection Suite) is a software package for matching position weight matrices against DNA sequences. MOODS implements state-of-the-art online matching algorithms, achieving considerably faster scanning speed than with a simple brute-force search. MOODS is written in C++, with bindings for the popular BioPerl and Biopython toolkits. It can easily be adapted for different purposes and integrated into existing workflows. It can also be used as a C++ library. AVAILABILITY: The package with documentation and examples of usage is available at http://www.cs.helsinki.fi/group/pssmfind. The source code is also available under the terms of a GNU General Public License (GPL). PMID- 19773335 TI - HHsvm: fast and accurate classification of profile-profile matches identified by HHsearch. AB - MOTIVATION: Recently developed profile-profile methods rival structural comparisons in their ability to detect homology between distantly related proteins. Despite this tremendous progress, many genuine relationships between protein families cannot be recognized as comparisons of their profiles result in scores that are statistically insignificant. RESULTS: Using known evolutionary relationships among protein superfamilies in SCOP database, support vector machines were trained on four sets of discriminatory features derived from the output of HHsearch. Upon validation, it was shown that the automatic classification of all profile-profile matches was superior to fixed threshold based annotation in terms of sensitivity and specificity. The effectiveness of this approach was demonstrated by annotating several domains of unknown function from the Pfam database. AVAILABILITY: Programs and scripts implementing the methods described in this manuscript are freely available from http://hhsvm.dlakiclab.org/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 19773336 TI - Bayesian detection of non-sinusoidal periodic patterns in circadian expression data. AB - MOTIVATION: Cyclical biological processes such as cell division and circadian regulation produce coordinated periodic expression of thousands of genes. Identification of such genes and their expression patterns is a crucial step in discovering underlying regulatory mechanisms. Existing computational methods are biased toward discovering genes that follow sine-wave patterns. RESULTS: We present an analysis of variance (ANOVA) periodicity detector and its Bayesian extension that can be used to discover periodic transcripts of arbitrary shapes from replicated gene expression profiles. The models are applicable when the profiles are collected at comparable time points for at least two cycles. We provide an empirical Bayes procedure for estimating parameters of the prior distributions and derive closed-form expressions for the posterior probability of periodicity, enabling efficient computation. The model is applied to two datasets profiling circadian regulation in murine liver and skeletal muscle, revealing a substantial number of previously undetected non-sinusoidal periodic transcripts in each. We also apply quantitative real-time PCR to several highly ranked non sinusoidal transcripts in liver tissue found by the model, providing independent evidence of circadian regulation of these genes. AVAILABILITY: Matlab software for estimating prior distributions and performing inference is available for download from http://www.datalab.uci.edu/resources/periodicity/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 19773337 TI - Anatomy and morphology in developing vegetative buds on detached Norway spruce branches in controlled conditions before bud burst. AB - We studied the light and stereomicroscopic structure of developing vegetative buds from a 16-year-old Norway spruce [Picea abies (L.) Karst.] of southern Finnish origin in relation to temperature sum and to externally visible changes in the buds before and during bud burst in forcing conditions. Branches were collected on 17 January and transferred to the greenhouse where they were first subjected to preforcing conditions (darkness, +4 degrees C) for 7 days and then to the forcing conditions (day length 12 h, +20 degrees C). Buds were sampled 20 times between 17 January and 13 February. Air temperature was recorded hourly throughout the study period. The first microscopic change was a temporary increase in the size and number of lipid droplets before the onset of temperature sum (T > or = +5 degrees C) accumulation. From the 4th to the 9th day under the forcing conditions, tracheids started to develop from the base up to the top of the bud. This was closely synchronized with an observed morphological change in the shape of needle tip from rounded to pointed ones. Development from the first visible change in the bud scales on the 12th forcing day to bud burst took 9 days when the temperature sum was 313 d.d. The temperature sums in our experiment overestimated the requirements of temperature sum for bud development phases measured in the field. Bud development could be divided into four structural phases. The first two phases, i.e., morphological changes in the primary needles, occurred without any externally visible changes in the buds. Thus, these phases have a potential for testing and improving the phenological models, which, up to now, have mainly been based on the bud burst observation by the naked eye. PMID- 19773338 TI - Interpretation of stem CO2 efflux measurements. AB - It is known that stem CO2 efflux differs somewhat both temporally and spatially from actual stem respiration, but relations between these two are not fully understood. A physical model of CO2 diffusion and advection by xylem sap flow is developed to interpret the CO2 flux signal from the stem. Model predictions are compared against measured CO2 efflux data from a field-grown 16-m Pinus sylvestris L. tree. The ratio of CO2 efflux to CO2 production is predicted to be much larger in the upper part of the tree than in the lower part as the xylem sap carries the respired CO2 upwards. The model also predicts the temperature dependency of real respiration to be higher than that of the CO2 efflux due to the slowness of diffusion. The relation between stem respiration and CO2 efflux depends strongly on the sap flow rate, radial diffusion resistance and stem geometry and size. The model may be used to scale individual CO2 efflux measurements to evaluate the respiration rate of whole trees and forests. PMID- 19773339 TI - Leaf and canopy conductance in aspen and aspen-birch forests under free-air enrichment of carbon dioxide and ozone. AB - Increasing concentrations of atmospheric carbon dioxide (CO2) and tropospheric ozone (O3) have the potential to affect tree physiology and structure, and hence forest feedbacks on climate. Here, we investigated how elevated concentrations of CO2 (+45%) and O3 (+35%), alone and in combination, affected conductance for mass transfer at the leaf and canopy levels in pure aspen (Populus tremuloides Michx.) and in mixed aspen and birch (Betula papyrifera Marsh.) forests in the free-air CO2-O3 enrichment experiment near Rhinelander, Wisconsin (Aspen FACE). The study was conducted during two growing seasons, when steady-state leaf area index (L) had been reached after > 6 years of exposure to CO2- and O3-enrichment treatments. Canopy conductance (g(c)) was estimated from stand sap flux, while leaf-level conductance of sun leaves in the upper canopy was derived by three different and independent methods: sap flux and L in combination with vertical canopy modelling, leaf 13C discrimination methodology in combination with photosynthesis modelling and leaf-level gas exchange. Regardless of the method used, the mean values of leaf-level conductance were higher in trees growing under elevated CO2 and/or O3 than in trees growing in control plots, causing a CO2 x O3 interaction that was statistically significant (P < or = 0.10) for sap flux- and (for birch) 13C-derived leaf conductance. Canopy conductance was significantly increased by elevated CO2 but not significantly affected by elevated O3. Investigation of a short-term gap in CO2 enrichment demonstrated a +10% effect of transient exposure of elevated CO2-grown trees to ambient CO2 on g(c). All treatment effects were similar in pure aspen and mixed aspen-birch communities. These results demonstrate that short-term primary stomatal closure responses to elevated CO2 and O3 were completely offset by long-term cumulative effects of these trace gases on tree and stand structure in determining canopy- and leaf-level conductance in pure aspen and mixed aspen-birch forests. Our results, together with the findings from other long-term FACE experiments with trees, suggest that model assumptions of large reductions in stomatal conductance under rising atmospheric CO2 are very uncertain for forests. PMID- 19773340 TI - Productivity, water-use efficiency and tolerance to moderate water deficit correlate in 33 poplar genotypes from a Populus deltoides x Populus trichocarpa F1 progeny. AB - Genotypic variability for productivity, water-use efficiency and leaf traits in 33 genotypes selected from an F1 progeny of Populus deltoides Bartr. ex Marsh x Populus trichocarpa L. was explored under optimal and moderate water-deficit conditions. Saplings of the 33 genotypes were grown in a two-plot open field at INRA Orleans (France) and coppiced every year. A moderate water deficit was induced during two successive years on one plot by withholding irrigation, while the second one remained irrigated (control). Stem biomass and leaf structure (e.g., specific leaf area and leaf area) were measured in 2004 and 2005 and functional leaf traits (e.g., carbon isotope discrimination, Delta) were measured only in 2004. Tolerance to water deficit was estimated at genotype level as the ability to limit losses in biomass production in water deficit versus control trees. Stem biomass, leaf structure and Delta displayed a significant genotypic variability whatever the irrigation regime. For all traits, genotype ranks remained stable across years for similar irrigation conditions. Carbon isotope discrimination scaled negatively with productivity and leaf nitrogen content in controls. The most productive genotypes were the least tolerant to moderate water deficit. No relationship was evidenced between Delta and the level of tolerance to water deficit. The relationships between traits evidenced in this collection of P. deltoides x P. trichocarpa F1 genotypes contrast with the ones that were previously detected in a collection of P. deltoides x Populus nigra L. cultivars tested in the same field trial. PMID- 19773341 TI - Skeletal dysplasias due to filamin A mutations result from a gain-of-function mechanism distinct from allelic neurological disorders. AB - Filamin A (FLNA) crosslinks F-actin and binds proteins consistent with roles integrating cell signalling and the cytoskeleton. FLNA missense mutations are associated with the otopalatodigital syndrome (OPD) spectrum of skeletal disorders, clustering in discrete domains. One cluster is found in the second calponin homology domain of the FLNA actin-binding domain (ABD), implicating this region as essential for mediating correct function. Here we show that OPD (FLNA E254K) fibroblast lysates have equivalent concentrations of FLNA compared with controls and that recombinant FLNA E254K ABD has increased in vitro F-actin binding (K(d) 13 microm) compared with wild type (WT; K(d) 48 microm). These observations are consistent with a gain-of-function mechanism for OPD. We have determined the crystal structures of the WT and E254K FLNA ABDs at 2.3 A resolution, revealing that they adopt similar closed conformations. The E254K mutation removes a conserved salt bridge but does not disrupt the ABD structure. The solution structures are also equivalent as determined by circular dichroism spectroscopy, but differential scanning fluorimetry denaturation showed reduced stability (decreased T(m) of 5.6 degrees C) for E254K relative to WT. Ex vivo characterization of E254K OPD patient fibroblasts revealed they have similar motility and adhesion as control cells, implying that many core functions mediated by FLNA are unaffected, consistent with OPD only affecting specific tissues despite FLNA being widely expressed. These data provide the first biochemical evidence for a gain-of-function mechanism for the OPD disorders, and mechanistically distinguishes them from the loss-of-function phenotypes that manifest as disorders of neuronal migration. PMID- 19773350 TI - Role of kinesin light chain-2 of kinesin-1 in the traffic of Na,K-ATPase containing vesicles in alveolar epithelial cells. AB - Recruitment of the Na,K-ATPase to the plasma membrane of alveolar epithelial cells results in increased active Na(+) transport and fluid clearance in a process that requires an intact microtubule network. However, the microtubule motors involved in this process have not been identified. In the present report, we studied the role of kinesin-1, a plus-end microtubule molecular motor that has been implicated in the movement of organelles in the Na,K-ATPase traffic. We determined by confocal microscopy and biochemical assays that kinesin-1 and the Na,K-ATPase are present in the same membranous cellular compartment. Knockdown of kinesin-1 heavy chain (KHC) or the light chain-2 (KLC2), but not of the light chain-1 (KLC1), decreased the movement of Na,K-ATPase-containing vesicles when compared to sham siRNA-transfected cells (control group). Thus, a specific isoform of kinesin-1 is required for microtubule-dependent recruitment of Na,K ATPase to the plasma membrane, which is of physiological significance. PMID- 19773351 TI - The cyclin-dependent kinase inhibitor, p21(WAF1), promotes angiogenesis by repressing gene transcription of thioredoxin-binding protein 2 in cancer cells. AB - The cyclin-dependent kinase inhibitor, p21(WAF1), induces cell-cycle arrest and can act as a tumor suppressor. However, increasing evidence indicates that p21(WAF1) can also increase resistance to some anticancer therapies and thus promote tumor growth. The mechanisms explaining this paradox have not been explained. We found that conditioned media from MCF-7 breast cancer cells transfected with a p21(WAF1)-specific small interfering RNA (siRNA) significantly reduced endothelial cell migration, invasion and vascular sprouting. Liquid chromatography/mass spectrometry analysis of the conditioned media revealed that p21(WAF1) knockdown significantly reduced secretion of thioredoxin (Trx), a redox protein known to promote tumor angiogenesis. p21(WAF1) knockdown decreased Trx enzymatic activity in cancer cells, by effects on the expression levels of intracellular thioredoxin-binding protein 2 (TBP2), known to bind and inactivate Trx. Consistent with these findings, media from cancer cells transfected with TBP2 siRNA promoted endothelial cell invasion and blocked the anti-angiogenic effect of p21(WAF1) siRNA. Addition of Trx siRNA blocked the pro-angiogenic effects of TBP2 siRNA. Chromatin immunoprecipitation assays showed p21(WAF1) bound TBP2 gene promoter. Taken together, our data suggests that p21(WAF1) can induce Trx secretion and angiogenesis in cancer cells, by direct transcriptional repression of the TBP2 promoter. PMID- 19773352 TI - Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. AB - Several molecular subtypes of sporadic Creutzfeldt-Jakob disease have been identified and electroencephalogram and cerebrospinal fluid biomarkers have been reported to support clinical diagnosis but with variable utility according to subtype. In recent years, a series of publications have demonstrated a potentially important role for magnetic resonance imaging in the pre-mortem diagnosis of sporadic Creutzfeldt-Jakob disease. Magnetic resonance imaging signal alterations correlate with distinct sporadic Creutzfeldt-Jakob disease molecular subtypes and thus might contribute to the earlier identification of the whole spectrum of sporadic Creutzfeldt-Jakob disease cases. This multi-centre international study aimed to provide a rationale for the amendment of the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease. Patients with sporadic Creutzfeldt-Jakob disease and fluid attenuated inversion recovery or diffusion-weight imaging were recruited from 12 countries. Patients referred as 'suspected sporadic Creutzfeldt-Jakob disease' but with an alternative diagnosis after thorough follow up, were analysed as controls. All magnetic resonance imaging scans were assessed for signal changes according to a standard protocol encompassing seven cortical regions, basal ganglia, thalamus and cerebellum. Magnetic resonance imaging scans were evaluated in 436 sporadic Creutzfeldt-Jakob disease patients and 141 controls. The pattern of high signal intensity with the best sensitivity and specificity in the differential diagnosis of sporadic Creutzfeldt-Jakob disease was identified. The optimum diagnostic accuracy in the differential diagnosis of rapid progressive dementia was obtained when either at least two cortical regions (temporal, parietal or occipital) or both caudate nucleus and putamen displayed a high signal in fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging. Based on our analyses, magnetic resonance imaging was positive in 83% of cases. In all definite cases, the amended criteria would cover the vast majority of suspected cases, being positive in 98%. Cerebral cortical signal increase and high signal in caudate nucleus and putamen on fluid attenuated inversion recovery or diffusion-weight imaging magnetic resonance imaging are useful in the diagnosis of sporadic Creutzfeldt-Jakob disease. We propose an amendment to the clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease to include findings from magnetic resonance imaging scans. PMID- 19773353 TI - Increasing olfactory bulb volume due to treatment of chronic rhinosinusitis--a longitudinal study. AB - Differentiation of progenitor cells into neurons in the olfactory bulb depends on olfactory stimulation that can lead to an increase in olfactory bulb volume. In this study, we investigated whether the human olfactory bulb volume increases with increasing olfactory function due to treatment of chronic rhinosinusitis. Nineteen patients with chronic rhinosinusitis were investigated before and after treatment. For comparison, additional measurements were performed in 18 healthy volunteers. Volumetric measurements of the olfactory bulb were based on planimetric manual contouring of magnetic resonance scans. Olfactory function was evaluated separately for each nostril using tests for odour threshold, odour discrimination and odour identification. Measurements were performed on two occasions, 3 months apart. In healthy controls, the olfactory bulb volume did not change significantly between the two measurements. In contrast, the olfactory bulb volume in patients increased significantly from the initial 64.5 +/- 3.2 to 70.0 +/- 3.5 mm(3) on the left side (P = 0.02) and from 60.9 +/- 3.5 to 72.4 +/- 2.8 mm(3) on the right side (P < 0.001). The increase in olfactory bulb volume correlated significantly with an increase in odour thresholds (r = 0.60, P = 0.006, left side; r = 0.49, P = 0.03, right side), but not with changes in odour discrimination or odour identification. Results of this study support the idea that stimulation of olfactory receptor neurons impacts on the cell death in the olfactory bulb, not only in rodents but also in humans. To our knowledge, this is the first longitudinal study that describes an enlargement of the human olfactory bulb due to improvement of peripheral olfactory function. PMID- 19773355 TI - Neuronal correlates of functional magnetic resonance imaging in human temporal cortex. AB - The relationship between changes in functional magnetic resonance imaging and neuronal activity remains controversial. Data collected during awake neurosurgical procedures for the treatment of epilepsy provided a rare opportunity to examine this relationship in human temporal association cortex. We obtained functional magnetic resonance imaging blood oxygen dependent signals, single neuronal activity and local field potentials from 8 to 300 Hz at 13 temporal cortical sites, from nine subjects, during paired associate learning and control measures. The relation between the functional magnetic resonance imaging signal and the electrophysiologic parameters was assessed in two ways: colocalization between significant changes in these signals on the same paired associate-control comparisons and multiple linear regressions of the electrophysiologic measures on the functional magnetic resonance imaging signal, across all tasks. Significant colocalization was present between increased functional magnetic resonance imaging signals and increased local field potentials power in the 50-250 Hz range. Local field potentials power greater than 100 Hz was also a significant regressor for the functional magnetic resonance imaging signal, establishing this local field potentials frequency range as a neuronal correlate of the functional magnetic resonance imaging signal. There was a trend for a relation between power in some low frequency local field potentials frequencies and the functional magnetic resonance imaging signal, for 8-15 Hz increases in the colocalization analysis and 16-23 Hz in the multiple linear regression analysis. Neither analysis provided evidence for an independent relation to frequency of single neuron activity. PMID- 19773356 TI - Effects of pedunculopontine nucleus area stimulation on gait disorders in Parkinson's disease. AB - Gait disturbances are frequent and disabling in advanced Parkinson's disease. These symptoms respond poorly to usual medical and surgical treatments but were reported to be improved by stimulation of the pedunculopontine nucleus. We studied the effects of stimulating the pedunculopontine nucleus area in six patients with severe freezing of gait, unresponsive to levodopa and subthalamic nucleus stimulation. Electrodes were implanted bilaterally in the pedunculopontine nucleus area. Electrode placement was checked by postoperative magnetic resonance imaging. The primary outcome measures were a composite gait score, freezing of gait questionnaire score and duration of freezing episodes occurring during a walking protocol at baseline and one-year follow-up. A double blind cross-over study was carried out from months 4 to 6 after surgery with or without pedunculopontine nucleus area stimulation. At one-year follow-up, the duration of freezing episodes under off-drug condition improved, as well as falls related to freezing. The other primary outcome measures did not significantly change, nor did the results during the double-blind evaluation. Individual results showed major improvement of all gait measures in one patient, moderate improvement of some tests in four patients and global worsening in one patient. Stimulation frequency ranged between 15 and 25 Hz. Oscillopsia and limb myoclonus could hinder voltage increase. No serious adverse events occurred. Although freezing of gait can be improved by low-frequency electrical stimulation of the pedunculopontine nucleus area in some patients with Parkinson's disease our overall results are disappointing compared to the high levels of expectation raised by previous open label studies. Further controlled studies are needed to determine whether optimization of patient selection, targeting and setting of stimulation parameters might improve the outcome to a point that could transform this experimental approach to a treatment with a reasonable risk-benefit ratio. PMID- 19773354 TI - The subependymal zone neurogenic niche: a beating heart in the centre of the brain: how plastic is adult neurogenesis? Opportunities for therapy and questions to be addressed. AB - The mammalian brain is a remarkably complex organ comprising millions of neurons, glia and various other cell types. Its impressive cytoarchitecture led to the long standing belief that it is a structurally static organ and thus very sensitive to injury. However, an area of striking structural flexibility has been recently described at the centre of the brain. It is the subependymal zone of the lateral wall of the lateral ventricles. The subependymal zone--like a beating heart--continuously sends new cells to different areas of the brain: neurons to the olfactory bulbs and glial cells to the cortex and the corpus callosum. Interestingly, the generation and flow of cells changes in response to signals from anatomically remote areas of the brain or even from the external environment of the organism, therefore indicating that subependymal neurogenesis--as a system -is integrated in the overall homeostatic function of the brain. In this review, it will be attempted to describe the fundamental structural and functional characteristics of the subependymal neurogenic niche and to summarize the available evidence regarding its plasticity. Special focus is given on issues such as whether adult neural stem cells are activated after neurodegeneration, whether defects in neurogenesis contribute to neuropathological conditions and whether monitoring changes in neurogenic activity can have a diagnostic value. PMID- 19773357 TI - KCNE4 suppresses Kv1.3 currents by modulating trafficking, surface expression and channel gating. AB - Voltage-dependent potassium channels (Kv) play a crucial role in the activation and proliferation of leukocytes. Kv channels are either homo- or hetero oligomers. This composition modulates their surface expression and serves as a mechanism for regulating channel activity. Kv channel interaction with accessory subunits provides mechanisms for channels to respond to stimuli beyond changes in membrane potential. Here, we demonstrate that KCNE4 (potassium voltage-gated channel subfamily E member 4), but not KCNE2, functions as an inhibitory Kv1.3 partner in leukocytes. Kv1.3 trafficking, targeting and activity are altered by the presence of KCNE4. KCNE4 decreases current density, slows activation, accelerates inactivation, increases cumulative inactivation, retains Kv1.3 in the ER and impairs channel targeting to lipid raft microdomains. KCNE4 associates with Kv1.3 in the ER and decreases the number of Kv1.3 channels at the cell surface, which diminishes cell excitability. Kv1.3 and KCNE4 are differentially regulated upon activation or immunosuppression in macrophages. Thus, lipopolysaccharide-induced activation increases Kv1.3 and KCNE4 mRNA, whereas dexamethasone triggers a decrease in Kv1.3 with no changes in KCNE4. The channelosome composition determines the activity and affects surface expression and membrane localization. Therefore, KCNE4 association might play a crucial role in controlling immunological responses. Our results indicate that KCNE ancillary subunits could be new targets for immunomodulation. PMID- 19773358 TI - Targeting sequences of UBXD8 and AAM-B reveal that the ER has a direct role in the emergence and regression of lipid droplets. AB - Lipid droplets are sites of neutral lipid storage thought to be actively involved in lipid homeostasis. A popular model proposes that droplets are formed in the endoplasmic reticulum (ER) by a process that begins with the deposition of neutral lipids between the membrane bilayer. As the droplet grows, it becomes surrounded by a monolayer of phospholipid derived from the outer half of the ER membrane, which contains integral membrane proteins anchored by hydrophobic regions. This model predicts that for an integral droplet protein inserted into the outer half of the ER membrane to reach the forming droplet, it must migrate in the plane of the membrane to sites of lipid accumulation. Here, we report the results of experiments that directly test this hypothesis. Using two integral droplet proteins that contain unique hydrophobic targeting sequences (AAM-B and UBXD8), we present evidence that both proteins migrate from their site of insertion in the ER to droplets that are forming in response to fatty acid supplementation. Migration to droplets occurs even when further protein synthesis is inhibited or dominant-negative Sar1 blocks transport to the Golgi complex. Surprisingly, when droplets are induced to disappear from the cell, both proteins return to the ER as the level of neutral lipid declines. These data suggest that integral droplet proteins form from and regress to the ER as part of a cyclic process that does not involve traffic through the secretory pathway. PMID- 19773359 TI - The nuclear periphery of embryonic stem cells is a transcriptionally permissive and repressive compartment. AB - Chromatin adapts a distinct structure and epigenetic state in embryonic stem cells (ESCs), but how chromatin is three-dimensionally organized within the ESC nucleus is poorly understood. Because nuclear location can influence gene expression, we examined the nuclear distributions of chromatin with key epigenetic marks in ESC nuclei. We focused on chromatin at the nuclear periphery, a compartment that represses some but not all associated genes and accumulates facultative heterochromatin in differentiated cells. Using a quantitative, cytological approach, we measured the nuclear distributions of genes in undifferentiated mouse ESCs according to epigenetic state and transcriptional activity. We found that trimethyl histone H3 lysine 27 (H3K27-Me(3)), which marks repressed gene promoters, is enriched at the ESC nuclear periphery. In addition, this compartment contains 10-15% of chromatin with active epigenetic marks and hundreds of transcription sites. Surprisingly, comparisons with differentiated cell types revealed similar nuclear distributions of active chromatin. By contrast, H3K27-Me(3) was less concentrated at the nuclear peripheries of differentiated cells. These findings demonstrate that the nuclear periphery is an epigenetically dynamic compartment that might be distinctly marked in pluripotent ESCs. In addition, our data indicate that the nuclear peripheries of multiple cell types can contain a significant fraction of both active and repressed genes. PMID- 19773360 TI - Caenorhabditis elegans p97 controls germline-specific sex determination by controlling the TRA-1 level in a CUL-2-dependent manner. AB - p97 (CDC-48 in Caenorhabditis elegans) is a ubiquitin-selective AAA (ATPases associated with diverse cellular activities) chaperone and its key function is to disassemble protein complexes. p97 functions in diverse cellular processes including endoplasmic reticulum (ER)-associated degradation, membrane fusion, and meiotic and mitotic progression. However, its cellular functions in development have not yet been clarified. Here, we present data that p97 is involved in the switch from spermatogenesis to oogenesis in the germline of the C. elegans hermaphrodite. We found that the cdc-48.1 deletion mutant produced less sperm than the wild type and thus showed a decreased brood size. The cdc-48.1 mutation suppressed the sperm-overproducing phenotypes of fbf-1 and fem-3(gf) mutants. In addition, the p97/CDC-48-UFD-1-NPL-4 complex interacted with the E3 ubiquitin ligase CUL-2 complex via NPL-4 binding to Elongin C. Furthermore, TRA-1A, which is the terminal effector of the sex determination pathway and is regulated by CUL 2-mediated proteolysis, accumulated in the cdc-48.1 mutant. Proteasome activity was also required for the brood size determination and sperm-oocyte switch. Our results demonstrate that the C. elegans p97/CDC-48-UFD-1-NPL-4 complex controls the sperm-oocyte switch by regulating CUL-2-mediated TRA-1A proteasome degradation. PMID- 19773361 TI - Alternate raft pathways cooperate to mediate slow diffusion and efficient uptake of a sphingolipid tracer to degradative and recycling compartments. AB - Several cholesterol-dependent cellular uptake pathways involving microdomain resident sphingolipids have been characterized, but little is known about what controls the further intracellular trafficking routes of those domains. Here, we present evidence that the uptake and intracellular trafficking of a recently described sphingolipid-binding probe, the sphingolipid binding domain (SBD) peptide, is mediated by two parallel cooperating mechanisms requiring flotillin, dynamin and cdc42, which act in concert to direct a distinct surface behavior and trafficking itinerary. Diffusion measurements of SBD at the cell surface by fluorescence correlation spectroscopy suggest that cdc42- and flotillin associated uptake sites both correspond to domains of intermediate mobility, but that they can cooperate to form low-mobility, efficiently internalized domains. Interestingly, we find that the choice of uptake mechanism affects subsequent trafficking of SBD, as does cholesterol content. Interference with one or other uptake pathway acts as a toggle switch for the trafficking of SBD to recycling endosomes or endolysosomes, whereas both of these pathways are bypassed if cholesterol is reduced. The data are in accordance with a scenario in which SBD mirrors the trafficking response of raft-borne lipids towards a degradative or recycling target. In summary, we suggest that both the surface behavior of a cargo and its subsequent trafficking are determined by a combination of endocytic accessory proteins and the cholesterol content of different membrane compartments. PMID- 19773362 TI - A nonproteolytic proteasome activity controls organelle fission in yeast. AB - To understand the processes underlying organelle function, dynamics and inheritance, it is necessary to identify and characterize the regulatory components involved. Recently in yeast and mammals, proteins of the membrane fission machinery (Dnm1-Mdv1-Caf4-Fis1 in yeast and DLP1-FIS1 in human) have been shown to have a dual localization on mitochondria and peroxisomes, where they control mitochondrial fission and peroxisome division. Here, we show that whereas vacuole fusion is regulated by the proteasome degradation function, mitochondrial fission and peroxisomal division are not controlled by the proteasome activity but rather depend on a new function of the proteasomal lid subunit Rpn11. Rpn11 was found to regulate the Fis1-dependent fission machinery of both organelles. These findings indicate a unique role of the Rpn11 protein in mitochondrial fission and peroxisomal proliferation that is independent of its role in proteasome-associated deubiquitylation. PMID- 19773363 TI - Nuclear signaling by the APP intracellular domain occurs predominantly through the amyloidogenic processing pathway. AB - Proteolytic processing of the amyloid precursor protein (APP) occurs via two alternative pathways, localized to different subcellular compartments, which result in functionally distinct outcomes. Cleavage by a beta-gamma sequence generates the Abeta peptide that plays a central role in Alzheimer's disease. In the case of alpha-gamma cleavage, a secreted neurotrophic molecule is generated and the Abeta peptide cleaved and destroyed. In both cases, a cytosolic APP intracellular domain (AICD) is generated. We have previously shown that coexpression of APP with the APP-binding protein Fe65 and the histone acetyltransferase Tip60 results in the formation of nuclear complexes (termed AFT complexes), which localize to transcription sites. We now show that blocking endocytosis or the pharmacological or genetic inhibition of the endosomal beta cleavage pathway reduces translocation of AICD to these nuclear AFT complexes. AICD signaling further depends on active transport along microtubules and can be modulated by interference with both anterograde and retrograde transport systems. Nuclear signaling by endogenous AICD in primary neurons could similarly be blocked by inhibiting beta-cleavage but not by alpha-cleavage inhibition. This suggests that amyloidogenic cleavage, despite representing the minor cleavage pathway of APP, is predominantly responsible for AICD-mediated nuclear signaling. PMID- 19773364 TI - Dual modes of rabies P-protein association with microtubules: a novel strategy to suppress the antiviral response. AB - Conventional nuclear import is independent of the cytoskeleton, but recent data have shown that the import of specific proteins can be either facilitated or inhibited by microtubules (MTs). Nuclear import of the P-protein from rabies virus involves a MT-facilitated mechanism, but here, we show that P-protein is unique in that it also undergoes MT-inhibited import, with the mode of MT interaction being regulated by the oligomeric state of the P-protein. This is the first demonstration that a protein can utilise both MT-inhibited and MT facilitated import mechanisms, and can switch between these different modes of MT interaction to regulate its nuclear trafficking. Importantly, we show that the P protein exploits MT-dependent mechanisms to manipulate host cell processes by switching the import of the interferon-activated transcription factor STAT1 from a conventional to a MT-inhibited mechanism. This prevents STAT1 nuclear import and signalling in response to interferon, which is vital to the host innate antiviral response. This is the first report of MT involvement in the viral subversion of interferon signalling that is central to virus pathogenicity, and identifies novel targets for the development of antiviral drugs or attenuated viruses for vaccine applications. PMID- 19773365 TI - Molecular evolution within and between self-incompatibility specificities. AB - Genes under multiallelic balancing selection have sharply contrasted evolutionary dynamics across timescales, with much longer coalescence time among functionally distinct allelic lines but much shorter coalescence time among gene copies within allelic lines as compared with the genomic background. In this paper, we combine theoretical and empirical approaches to investigate patterns of molecular evolution within and between self-incompatibility (SI) specificities. We first use numerical simulations to investigate coalescence times within allelic lines in a subdivided population for a sporophytic SI system. We then report on a comprehensive analysis of nucleotide polymorphism among gene copies within five distinct allelic lines in the closely related Arabidopsis halleri and Arabidopsis lyrata. In line with our model predictions, we find that the observed level of polymorphism among gene copies was generally low but differed among allelic lines. The data provide compelling direct evidence for recombination and/or gene conversion not only within the two most recessive allelic lines but also between two closely related but distinct allelic lines, suggesting that recombination at the Arabidopsis SI locus is possible in the absence of large sequence divergence among haplotypes. We observed shared polymorphic sites between the two species in one allelic line and strikingly similar haplotypes in another allelic line. We discuss whether convergent evolution may have led to this pattern and suggest that these observations are consistent with ongoing or very recent introgression, as previously documented. PMID- 19773366 TI - The effect of body mass index on the diagnosis of GH deficiency in patients at risk due to a pituitary insult. AB - OBJECTIVES: Diminished GH response to stimulation has been demonstrated in obesity, leading to erroneous diagnosis of GH deficiency. The aim of this study was to evaluate the influence of body mass index (BMI) on GH responsiveness in patients at risk for pituitary function deficits. METHODS: A total of 59 healthy subjects and 75 patients with a pituitary insult underwent insulin tolerance test or pyridostigmine+GHRH test in order to assess GH secretory reserve. Normal subjects and patients were classified as normal weight (BMI <24.9 kg/m(2)), overweight (BMI 25-29.9 kg/m(2)), and obese (BMI >30 kg/m(2)). RESULTS: All normal individuals with BMI <24.9 kg/m(2) demonstrated adequate GH responses, while three of the 21 overweight (14.3%) and nine of the 28 obese subjects (32.1%) did not respond to GH stimulation. Among patients, four of 14 (28.6%) with BMI <24.9 kg/m(2), 18 of 22 (81.8%) who were overweight, and 28 of 39 (71.7%) who were obese did not respond to GH stimulation. Of the 46 nonresponder patients with increased BMI, nine (19.6%) had normal insulin-like growth factor 1 (IGF1) values and no other pituitary hormone deficits, raising questions about the accuracy of somatotroph function assessment, while all nonresponders with BMI <24.9 kg/m(2) had low IGF1 values and panhypopituitarism. CONCLUSIONS: Our results indicate that BMI >25 kg/m(2) has a negative effect on GH response not only in normal healthy subjects but also in patients at risk for pituitary function deficit as well. Parameters such as IGF1 levels and anterior pituitary deficits should be taken into account to accurately assess GH status in these patients. PMID- 19773367 TI - Vitamin D, parathyroid hormone and the metabolic syndrome in middle-aged and older European men. AB - OBJECTIVES: Low serum 25-hydroxyvitamin D (25(OH)D) and elevated parathyroid hormone (PTH) levels have been linked to insulin resistance, the metabolic syndrome (MetS) and its components. Data in healthy, community-dwelling Europeans are lacking, and previous studies have not excluded subjects receiving drug treatments that may distort the relationship between 25(OH)D/PTH and MetS. The aim of our analysis was to examine the association of 25(OH)D and PTH with Adult Treatment Panel III-defined MetS in middle-aged and older European men. DESIGN: This was a population-based, cross-sectional study of 3369 men aged 40-79 years enrolled in the European Male Ageing Study. RESULTS: After exclusion of subjects with missing data, 3069 men with a mean (+/-s.d.) age of 60+/-11 years were included in the analysis. Age-adjusted 25(OH)D levels were inversely associated with waist circumference, systolic blood pressure (BP), triglycerides, and glucose (all P<0.01). Age-adjusted PTH levels were only associated with waist and diastolic BP (both P<0.05). After adjusting for age, centre, season and lifestyle factors the odds for MetS decreased across increasing 25(OH)D quintiles (odds ratios 0.48 (95% confidence intervals 0.36-0.64) highest versus lowest quintile; P(trend)<0.001). This relationship was unchanged after adjustment for PTH, but was attenuated after additional adjustment for homoeostasis model assessment of insulin resistance (0.60 (0.47-0.78); P(trend)<0.001). There was no association between PTH and MetS. CONCLUSIONS: Our results demonstrate an inverse relationship between 25(OH)D levels and MetS, which is independent of several confounders and PTH. The relationship is partly explained by insulin resistance. The clinical significance of these observations warrants further study. PMID- 19773368 TI - Gamma knife radiosurgery: a safe and effective salvage treatment for pituitary tumours not controlled despite conventional radiotherapy. AB - OBJECTIVE: We report the use of 'gamma knife' (GK) radiosurgery in 25 patients with pituitary adenomas not cured despite conventional therapy, including external beam radiotherapy. PATIENTS AND METHODS: All patients had previously received conventional radiotherapy for a mean of 11.8 years prior to receiving GK; 23 out of 25 had also undergone pituitary surgery on at least one occasion. Seventeen had hyperfunctioning adenomas that still required medical therapy without an adequate biochemical control--ten somatotroph adenomas, six corticotroph adenomas and one prolactinoma, while eight patients had non functioning pituitary adenomas (NFPAs). RESULTS: Following GK, mean GH fell by 49% at 1 year in patients with somatotroph tumours. Serum IGF1 fell by 32% at 1 year and by 38% at 2 years. To date, 80% of the patients with acromegaly have achieved normalisation of IGF1, and 30% have also achieved a mean GH level of <1.8 ng/ml correlating with normalised mortality. A total of 75% NFPAs showed disease stabilisation or shrinkage post GK. The patient with a prolactinoma showed a dramatic response: 75% reduction in prolactin at 2 years, with a marked shrinkage on magnetic resonance imaging. The results in corticotroph adenomas were variable. Prior to GK, 72% of the patients were panhypopituitary, and 42% of the remainder have developed new anterior pituitary hormone deficiencies to date. No other adverse events have been detected at a mean follow-up of 36.4 months. CONCLUSIONS: These data indicate that GK is a safe and effective adjunctive treatment for patients with NFPAs and acromegaly not satisfactorily controlled with surgery and radiotherapy. PMID- 19773369 TI - Influence of disease control with pegvisomant on sleep apnoea and tongue volume in patients with active acromegaly. AB - OBJECTIVES: Sleep apnoea has been consistently reported to occur in acromegaly. In uncontrolled patients, the severity of sleep apnoea influences physical activity in the daytime. We investigated the influence of disease activity on tongue volume and sleep apnoea treated with the GH receptor antagonist pegvisomant in poorly controlled patients with acromegaly under octreotide. DESIGN AND METHODS: A total of 12 patients with active acromegaly (six females; six males; mean age 57+/-15 years; body mass index 29.4+/-4.2 kg/m(2); mean+/ S.D.) were treated with pegvisomant (13.5+/-5.0 mg/die) for 6 months. Tongue volume was examined by magnetic resonance imaging, and sleep apnoea was characterized by polysomnography before and after 6 months of treatment with pegvisomant. The mandibular length was determined by lateral X-ray films. RESULTS: IGF1 levels decreased after 6 months in all patients (407+/-114 to 199+/ 23 microg/l; P=0.0001). The tongue volume decreased (105+/-33 to 83+/-33 ml; P=0.007) as well as the apnoea-hypnoea index (23+/-22 to 18+/-18/h; P=0.0066). The mandibular length correlated with the initial tongue volume (r(2)=0.6072, P=0.0028). CONCLUSION: In conclusion, successful treatment with pegvisomant can decrease tongue volume, which has benefits for coexisting sleep disordered breathing. PMID- 19773370 TI - Narrow intra-individual variation of maternal thyroid function in pregnancy based on a longitudinal study on 132 women. AB - BACKGROUND: Adaptive alterations in maternal physiology cause changes in thyroid hormone levels throughout pregnancy, and precise biochemical evaluation is thus highly dependent on gestation-specific reference intervals and expected intra individual variation. OBJECTIVE: The aim of the study was the assessment of the intra-individual variation as well as the longitudinal course of thyroid hormones during normal pregnancy and factors that influence the normal reference range for thyroid function. For this purpose, a longitudinal statistical model was applied. DESIGN: In a cohort of 132 pregnant women, serial blood samples were obtained and ultrasound scans were performed throughout pregnancy. METHODS: Serum levels of TSH, free and total thyroxine (T(4)), free and total triiodothyronine (T(3)) as well as autoantibodies against thyroid peroxidase and thyroglobulin were measured in 979 serum samples. RESULTS: Intra-individual variations of thyroid hormone concentrations were smaller than inter-individual variations (individuality index range: 0.38-0.71). Maternal height was positively associated with free T(4) (FT(4)) (b=0.003; P=0.031) and pre-pregnancy body mass index with T(3) and free T(3) (b=0.017; <0.001 and b=0.007; P<0.001). Smoking was positively associated with T(4) and FT(4), but it was modulated by gestational age. Gestation-specific reference intervals for thyroid function variables from autoantibody-negative participants are presented. CONCLUSIONS: In accordance with the data from nonpregnant adults, intra-individual variations of thyroid hormones were smaller than inter-individual variations also during pregnancy. In the evaluation of thyroid function in pregnancy, the individual longitudinal course of thyroid hormones rather than absolute values should be considered. We present a longitudinal model for the prediction of maternal thyroid function tests in pregnant women. PMID- 19773371 TI - Beneficial effects of sorafenib on tumor progression, but not on radioiodine uptake, in patients with differentiated thyroid carcinoma. AB - OBJECTIVE: Treatment options for patients with radioactive iodine (RaI) refractory metastases of differentiated thyroid carcinoma (DTC) are limited. We studied the effects of the multitarget tyrosine kinase inhibitor sorafenib on the reinduction of RaI uptake and tumor progression. DESIGN: Open, single center, single arm 26-week prospective phase II study with open-ended extension. METHODS: We treated 31 patients with progressive metastatic or locally advanced RaI refractory DTC with sorafenib 400 mg b.i.d. The primary endpoint was reinduction of RaI uptake at 26 weeks. Additional endpoints were the radiological response and the influence of bone metastases. RESULTS: At 26 weeks of sorafenib therapy, no reinduction of RaI uptake at metastatic sites was observed, but 19 patients (59%) had a clinical beneficial response, eight of whom had a partial response (25%) and 11 had stable disease (34%). Seven patients had progressive disease (22%). Sorafenib was significantly less effective in patients with bone metastases. The estimated median progression free survival was 58 weeks (95% confidence interval, CI, 47-68). In general, thyroglobulin (Tg) response (both unstimulated and TSH stimulated) reflected radiological responses. The median time of the nadir of Tg levels was 3 months. Responses were not influenced by histological subtype, mutational status or other variables. No unusual side effects were observed. CONCLUSIONS: Sorafenib has a beneficial effect on tumor progression in patients with metastatic DTC, but was less effective in patients with bone metastases. Diagnostic whole body scintigraphy did not reveal an effect of sorafenib on the reinduction of RaI uptake. PMID- 19773372 TI - Acylated and nonacylated ghrelin levels and their associations with insulin resistance in obese and normal weight children with metabolic syndrome. AB - BACKGROUND: Ghrelin, a peptide mainly derived from the stomach, plays a pivotal role in the regulation of food intake, energy metabolism, and storage, as well as in insulin sensitivity. Ghrelin circulates in acylated (A-Ghr) and nonacylated (NA-Ghr) forms, and their potential differential associations with insulin resistance (IR) in childhood obesity remain undefined. OBJECTIVE: We investigated the associations of ghrelin forms with IR in normal weight and obese children and the impact of metabolic syndrome (MS) on their plasma values. DESIGN: A total of 210 children in four subgroups of normal weight/obese children with and without components of MS were studied. Fasting blood glucose, insulin, lipid profile, and acylated and total ghrelin were examined. IR was determined by a homeostasis model assessment (HOMA) of IR. RESULTS: In the entire population, plasma insulin and HOMA-IR were associated negatively with T-Ghr and NA-Ghr, but positively with the ratio of A/NA-Ghr after adjustment for age, gender, and Tanner stage. Obese metabolically abnormal children had lower T-Ghr and NA-Ghr, but comparable A-Ghr and a higher A/NA-Ghr ratio than obese metabolically normal subjects. Compared with lean healthy children, lean metabolically abnormal subjects had higher A-Ghr and the A/NA-Ghr ratio, but comparable T-Ghr and NA-Ghr. A multiple regression analysis showed that A-Ghr and the A/NA-Ghr ratios were positively associated with HOMA-IR, independent of age, gender, Tanner stage, and body mass index (or waist circumference) and other components of MS. CONCLUSIONS: A-Ghr excess may negatively modulate insulin action in obese and nonobese children, and may contribute to the association of IR and MS. PMID- 19773373 TI - Free leptin index and thyroid function in male highly trained athletes. AB - OBJECTIVE: Exercise training may cause changes in thyroid function. This thyroid response may be due to exercise-induced modulation of energy metabolism but also of the adipocytes endocrine function. In particular, the role of leptin and of circulating soluble leptin receptor (sOB-R) was unexplored. The aim of this study was to assess the relationships between thyroid function, whole body energy metabolism, and adipokines--mainly leptin and its receptor, sOB-R. METHODS: We measured serum TSH, free tri-iodothyronine (FT(3)), free thyroxine, leptin, and sOB-R and assessed energy homeostasis by means of indirect calorimetry, in 27 highly trained athletes and 27 sedentary, healthy men. RESULTS: TSH-FT(3) ratio was lower in athletes (P<0.03), either in sustained power or anaerobic power sprint athletes (n=13) or marathon runners (n=14). Whole body respiratory quotient was lower in athletes. Fasting serum sOB-R was higher and leptin lower in athletes than controls. Also serum adiponectin, resistin, and retinol binding protein-4 concentrations were different in athletes than in controls. The ratio between leptin and sOB-R, the free leptin index (FLI), was lower in athletes than in controls (0.025+/-0.014 vs 0.085+/-0.049; P<0.001). In multivariate analysis, FLI retained independent association with TSH-FT(3) ratio. CONCLUSION: Male, elite athletes had lower TSH-FT(3) ratio and FLI than controls while FLI was independently associated with TSH-FT(3) ratio supporting the hypothesis that the level of biologically active leptin is involved in the adaptive response of thyroid function in professional athletes. PMID- 19773374 TI - Interstitial fluid pressure as a prognostic factor in cervical cancer following radiation therapy. AB - PURPOSE: To investigate tumor interstitial fluid pressure as a prognostic factor for recurrence-free survival in patients with cervical cancer following radiation therapy. EXPERIMENTAL DESIGN: Tumor interstitial fluid pressure was measured in 55 cervical cancer patients who received radiation therapy between August 1998 and September 2002. Interstitial fluid pressure measurements were made before radiation therapy (pre-radiation therapy interstitial fluid pressure) and after a median of 28.8 Gy in 16 fractions (range, 25.2-30.6 Gy in 14-17 fractions) of radiation therapy (mid-radiation therapy interstitial fluid pressure), using a modified wick-in-needle technique. Median follow-up was 74 months (range, 2-118 months). The Kaplan-Meier method with the log-rank test and Cox's proportional hazard model were used in univariate and multivariate analyses, respectively, of prognostic factors for recurrence-free survival. RESULTS: Median pre-radiation therapy and mid-radiation therapy interstitial fluid pressure were 29.0 mm Hg (range, 4.0-93.9 mm Hg) and 20.0 mm Hg (range, -1.2 to 29.6 mm Hg), respectively (P = 0.001). Pre-radiation therapy interstitial fluid pressure was significantly higher in adenocarcinomas than squamous cell carcinomas (P = 0.028). Significant reduction of interstitial fluid pressure was noted only in patients with complete responses (P = 0.002), and mid-radiation therapy interstitial fluid pressure was significantly lower in patients with complete responses (P = 0.036). In the multivariate analysis including interstitial fluid pressures and clinical variables, pre-radiation therapy interstitial fluid pressure was an independent prognostic factor for local and distant recurrence-free survival (P = 0.001 and 0.027, respectively). CONCLUSIONS: Mid-radiation therapy interstitial fluid pressure measurement may be useful in predicting radiation therapy responses, and pre-radiation therapy interstitial fluid pressure was a significant prognostic factor for local and distant relapse-free survival in patients with cervical cancer after radiation therapy. PMID- 19773375 TI - A phase I study of sunitinib plus bevacizumab in advanced solid tumors. AB - PURPOSE: Bevacizumab is an antibody against vascular endothelial growth factor; sunitinib is an inhibitor of vascular endothelial growth factor and related receptors. The safety and maximum tolerated dose of sunitinib plus bevacizumab was assessed in this phase I trial. EXPERIMENTAL DESIGN: Patients with advanced solid tumors were treated on a 3+3 trial design. Patients received sunitinib daily (starting dose level, 25 mg) for 4 weeks on followed by 2 weeks off and bevacizumab (starting dose level, 5 mg/kg) on days 1, 15, and 29 of a 42-day cycle. Dose-limiting toxicities during the first 6-week cycle were used to determine the maximum tolerated dose. RESULTS: Thirty-eight patients were enrolled. Patients received a median of 3 cycles of treatment (range, 1-17(+)). There was one dose-limiting toxicity (grade 4 hypertension) at 37.5 mg sunitinib and 5 mg/kg bevacizumab. Grade 3 or greater toxicity was observed in 87% of patients including hypertension (47%), fatigue (24%), thrombocytopenia (18%), proteinuria (13%), and hand-foot syndrome (13%). Dose modifications and delays were common at higher dose levels. No clinical or laboratory evidence of microangiopathic hemolytic anemia was observed. Seven patients had a confirmed Response Evaluation Criteria in Solid Tumors-defined partial response (18%; 95% confidence interval, 8-34%). Nineteen of the 32 patients with a postbaseline scan (59%) had at least some reduction in overall tumor burden (median, 32%; range, 3 73%). CONCLUSIONS: The combination of sunitinib and bevacizumab in patients with advanced solid tumors is feasible, albeit with toxicity at higher dose levels and requiring dose modification with continued therapy. Antitumor activity was observed across multiple solid tumors. PMID- 19773377 TI - Synergistic effects of oncolytic reovirus and cisplatin chemotherapy in murine malignant melanoma. AB - PURPOSE: To test combination treatment schedules of reovirus and cisplatin chemotherapy in human and murine melanoma cell lines and murine models of melanoma and to investigate the possible mechanisms of synergistic antitumor effects. EXPERIMENTAL DESIGN: The effects of reovirus +/- chemotherapy on in vitro cytotoxicity and viral replication were assessed using 3-(4,5 dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assay and plaque assay. Interactions between agents were assessed by combination index analysis. Mode of cell death was assessed by Annexin V/propidium iodide fluorescence-activated cell sorting-based assays; gene expression profiling of single versus combination treatments was completed using the Agilent microarray system. Single agent and combination therapy effects were tested in vivo in two immunocompetent models of murine melanoma. RESULTS: Variable degrees of synergistic cytotoxicity between live reovirus and several chemotherapy agents were observed in B16.F10 mouse melanoma cells, most significantly with cisplatin (combination index of 0.42 +/- 0.03 at ED(50)). Combination of cisplatin and reovirus exposure led to increased late apoptotic/necrotic cell populations. Cisplatin almost completely abrogated the inflammatory cytokine gene up regulation induced by reovirus. Combination therapy led to significantly delayed tumor growth and improved survival in vivo (P < 0.0001 and P = 0.0003, respectively). Cisplatin had no effect on the humoral response to reovirus in mice. However, cisplatin treatment suppressed the cytokine and chemokine response to reovirus in vitro and in vivo. CONCLUSION: The combination of reovirus and several chemotherapeutic agents synergistically enhanced cytotoxicity in human and murine melanoma cell lines in vitro and murine tumors in vivo. The data support the current reovirus/chemotherapy combination phase I clinical studies currently ongoing in the clinic. PMID- 19773376 TI - Combined Bcl-2/mammalian target of rapamycin inhibition leads to enhanced radiosensitization via induction of apoptosis and autophagy in non-small cell lung tumor xenograft model. AB - PURPOSE: Radiotherapy has a central role in the treatment of non-small cell lung cancer. Effectiveness of this modality, however, is often limited as resistance results from defects in cell death. EXPERIMENTAL DESIGN: We investigated whether simultaneous up-regulation of apoptosis, via Bcl-2 inhibitor ABT-737, and autophagy, via mammalian target of rapamycin inhibitor rapamycin, can be used to enhance radiosensitivity of H460 cells in vitro and growth delay in a xenograft model. RESULTS: In vitro studies confirmed that ABT-737 and rapamycin induce apoptosis and autophagy, respectively. ABT-737 induced cleaved caspase-3, a marker of apoptosis, and rapamycin correlated with an increase in punctate localization of green fluorescent protein-LC3, characteristic of autophagy. The combination ABT-737/rapamycin markedly enhanced sensitivity of H460 cells to radiation (dose enhancement ratio = 2.47; P = 0.002) in clonogenic assay. In addition, the combination ABT-737/rapamycin/radiation showed a dramatic tumor growth delay in a mouse xenograft model. In vivo immunohistochemistry staining showed that combination therapy yielded over a 100% increase in caspase-3 activity (apoptosis) and a 6-fold decrease in p62 protein level (indicative of autophagic flux) compared with radiation alone control group. Moreover, cell proliferation (Ki-67 staining) was reduced by 77% (P = 0.001) and vascular density (von Willebrand factor staining) by 67.5% (P = 0.09) compared with radiation alone. Additional in vitro studies in human umbilical vein endothelial cells indicated that combined therapy also significantly decreases tubule formation. CONCLUSION: These results suggest that concurrent induction of apoptosis and autophagy enhances radiation therapy both in vitro and in lung cancer xenograft models. Further investigations are warranted to assess the clinical potential of such strategy in lung cancer patients. PMID- 19773378 TI - DeltaNp63 overexpression, alone and in combination with other biomarkers, predicts the development of oral cancer in patients with leukoplakia. AB - PURPOSE: The risk of malignant transformation of oral preneoplastic lesion (OPL) is difficult to assess. DeltaNp63 is an early oncoprotein associated with mucosal tumorigenesis. The purpose of this study was to assess DeltaNp63 expression in OPL and its role as a marker of oral cancer risk. EXPERIMENTAL DESIGN: DeltaNp63 expression was determined using immunohistochemistry in 152 OPL patients included in a clinical trial comparing retinyl palmitate alone or plus beta-carotene with low-dose 13-cis-retinoic acid. The associations between DeltaNp63 expression as well as DeltaNp63 expression with other potential risk factors for oral cancer development were analyzed. RESULTS: DeltaNp63 expression was positive in 41 (27%) patients, clusters of intraepithelial inflammatory cells (EIC) were noted in 37 (26%) patients, and podoplanin (previously reported) was positive in 56 (37%) patients. Significantly more patients whose lesions were DeltaNp63 positive or exhibited EIC developed oral cancers. In the multicovariate analysis including age, treatment, and histologic status as cofactors, positive DeltaNp63 expression was associated with an increased hazard ratio of 3.308 (95% confidence interval, 1.663-6.580; P = 0.0007). Patients whose lesions showed positive DeltaNp63, podoplanin, and EIC had the highest oral cancer risk with a hazard ratio of 4.372 (95% confidence interval, 1.912-9.992; P = 0.0005) and 61% oral cancer development rate at 5 years compared with 15% of other OPL patients (P < 0.0001). CONCLUSION: DeltaNp63 overepression in OPL is associated with increased oral cancer risk. Together, DeltaNp63, podoplanin, and EIC may be used as biomarkers to identify OPL patients with substantially high oral cancer risk. PMID- 19773379 TI - Ambulatory monitoring detects sorafenib-induced blood pressure elevations on the first day of treatment. AB - PURPOSE: Hypertension is a mechanism-based toxicity of sorafenib and other cancer therapeutics that inhibit the vascular endothelial growth factor (VEGF) signaling pathway. This prospective, single-center, cohort study characterized ambulatory blood pressure monitoring as an early pharmacodynamic biomarker of VEGF signaling pathway inhibition by sorafenib. EXPERIMENTAL DESIGN: Fifty-four normotensive advanced cancer patients underwent 24-hour ambulatory blood pressure monitoring before and between days 6 and 10 of sorafenib therapy. After blood pressure changes were detected among the first cohort within 10 days, ambulatory blood pressure monitoring was done during the first 24 hours of treatment for the second cohort. RESULTS: For the entire patient population, the blood pressure increase [mean systolic, +10.8 mm Hg; 95% confidence interval (95% CI), 8.6-13.0; range, -5.2 to +28.7 mm Hg; mean diastolic, +8.0 mm Hg; 95% CI, 6.3-9.7; range, 4.4 to +27.1 mm Hg] was detected between days 6 and 10 (P < 0.0001 for both) and plateaued thereafter. Variability in blood pressure change did not associate with: age, body size, sex, self-reported race, baseline blood pressure, or steady state sorafenib plasma concentrations. In the second cohort, the blood pressure elevation was detected during the first 24 hours (mean systolic, +8.2 mm Hg; 95% CI, 5.0-11.3; mean diastolic, +6.5 mm Hg; 95% CI, 4.7-8.3; P < 0.0001 for both). CONCLUSIONS: Ambulatory blood pressure monitoring detects the blood pressure response to VEGF signaling pathway inhibition by sorafenib during the first 24 hours of treatment. The magnitude of blood pressure elevation is highly variable and unpredictable but could be important in optimizing the therapeutic index of VEGF signaling pathway inhibitor therapy. PMID- 19773380 TI - Interaction of the multikinase inhibitors sorafenib and sunitinib with solute carriers and ATP-binding cassette transporters. AB - PURPOSE: To compare side-by-side the uptake of sorafenib and sunitinib in vitro by human uptake solute carriers of the SLC22A and SLCO families, the transport by and inhibition of efflux ATP-binding cassette (ABC) transporters, and the role of ABCB1 in the plasma pharmacokinetics and brain penetration of these agents. EXPERIMENTAL DESIGN: Uptake of [(3)H]sorafenib or [(3)H]sunitinib was assessed in Xenopus laevis oocytes or mammalian cells transfected with cDNAs coding for human OATP1A2, OATP1B1, OATP1B3, OCT1, OAT2, OAT3, OCTN1, or OCTN2. Efflux and inhibition experiments were conducted in cells transfected with human ABCB1, ABCG2, ABCC2, or ABCC4. In vivo pharmacokinetic studies were done in knockout mice lacking Abcb1-type transporters. RESULTS: Intracellular uptake was not appreciably affected by any of the studied solute carriers and was minute relative to the respective prototypical substrates. Sorafenib and sunitinib showed concentration-dependent (1 and 10 micromol/L), low to moderate affinity for ABCB1 but were not affected by the other ABC transporters. Both agents inhibited all tested ABC transporters. The absence of Abcb1 had no affect on plasma pharmacokinetics, but brain penetration was moderately increased by 1.9- and 2.9-fold for sorafenib and sunitinib, respectively, in knockout animals versus controls. CONCLUSIONS: Unlike other tyrosine kinase inhibitors, sorafenib and sunitinib do not appear to rely on active transport to enter the cell nor are they high-affinity substrates for ABC efflux transporters. Based on these characteristics, these two drugs may be less susceptible to transporter-mediated alterations in systemic exposure and transporter-related resistance mechanisms. PMID- 19773382 TI - CXCL13 and CXCL12 in central nervous system lymphoma patients. AB - PURPOSE: Homing of malignant lymphocytes to the central nervous system (CNS) may play a role in the pathogenesis of CNS lymphoma. In this study, we evaluated the chemokines CXCL12 and CXCL13 in the cerebrospinal fluid (CSF) and serum of patients with CNS lymphoma. EXPERIMENTAL DESIGN: Samples from 30 patients with CNS lymphoma (23 with primary and 7 with secondary CNS lymphoma; all B-cell lymphoma) and 40 controls (10 patients with other CNS malignancies and 30 without a malignant CNS disease) were examined. CXCL12 and CXCL13 concentrations were measured using enzyme-linked immunosorbent assays. The grade of blood-brain barrier disruption was estimated by the CSF/serum albumin ratio. RESULTS: CNS lymphoma patients and controls did not differ in CXCL12 serum and CSF levels. Serum levels of CXCL13 were generally low. CXCL13 CSF levels, however, were significantly higher in CNS lymphoma patients as compared with controls (P < 0.0001). Chemokine levels in CSF and serum did not correlate. In CNS lymphoma, CXCL13 concentration in CSF correlated with the degree of blood-brain barrier disruption (R = 0.66; P = 0.003). Elevated CSF levels of CXCL12 and CXCL13 measured in seven CNS lymphoma patients during therapy decreased in five patients who responded to chemotherapy and increased in two with lymphoma progression. CONCLUSIONS: Our results suggest a production of CXCL13 within the CNS of CNS lymphoma patients, which decreases with response to therapy. Thus, CXCL13 may represent a marker for further diagnostic and prognostic studies. PMID- 19773381 TI - Aberrant methylation of APC, MGMT, RASSF2A, and Wif-1 genes in plasma as a biomarker for early detection of colorectal cancer. AB - PURPOSE: To identify epigenetic molecular makers in plasma for the early detection of colorectal cancer. EXPERIMENTAL DESIGN: We retrospectively analyzed the methylation status of 10 genes in fresh-frozen tissues and corresponding plasma samples from 243 patients with stage I and II sporadic colorectal cancer, 276 healthy individuals, and plasma from 64 colorectal adenoma patients using methylation-specific PCR. The methylation score (Mscore) was used to find molecular markers with high sensitivity and specificity. RESULTS: Of the 243 colorectal cancer tissues, methylation was detected in 18% for p14, 34% for p16, 27% for APC, 34% for DAPK, 32% for HLTF, 21% for hMLH1, 39% for MGMT, 24% for RARbeta2, 58% for RASSF2A, and 74% for Wif-1. Receiver operator characteristic curve analysis in plasma from 243 patients with cancer and 276 healthy individuals showed that the M score of any single gene had a sensitivity of <40% after controlling for age, sex, and tumor location. The specificity of the M score was not different between multigene and single gene analyses, but the sensitivity of the M score was significantly increased by multigene analysis. For all patients, the M score in a model including APC, MGMT, RASSF2A, and Wif-1 genes had a sensitivity of 86.5% and a specificity of 92.1% when 1.6 was used as a cutoff. In this model, the M score had a positive predictive value of 90.6% and a negative predictive value of 88.8%. CONCLUSION: The present study suggests that tumor-specific methylation of APC, MGMT, RASSF2A, and Wif-1 genes might be a valuable biomarker in plasma for the early detection of colorectal cancer. PMID- 19773383 TI - Recent natural selection identifies a genetic variant in a regulatory subunit of protein phosphatase 2A that associates with altered cancer risk and survival. AB - PURPOSE: A regulated p53-dependent stress response is crucial in suppressing tumor formation and mediating the response to commonly used cancer therapeutics. However, little is known about the human, inherited genetics of this important signaling pathway. EXPERIMENTAL DESIGN: Studies of human genetic variants in the p53 tumor suppressor gene and MDM2 oncogene have shown that single nucleotide polymorphisms (SNP) can affect p53 signaling, confer cancer risk, and alter outcome, and also suggest that the pathway is under evolutionary selective pressure. Here, we attempt to accelerate the identification of functional p53 pathway SNPs by incorporating these characteristics into an analysis of 142 genes that are known to affect p53 signaling. RESULTS: We report that a genomic scan for recent natural selection denotes that of the 142 genes studied, the PPP2R5E gene that encodes a regulatory subunit of the tumor suppressing protein phosphatase 2A resides in a naturally selected genomic region. We go on to show that a selected SNP in PPP2R5E (epsilon-SNP2) associates with significant allelic differences in the onset (up to 19.2 years; P = 0.0002) and risk (odds ratio, up to 8.1; P = 0.0009) of soft tissue sarcoma development, as well as overall survival (relative risk, up to 3.04; P = 0.026). CONCLUSIONS: The PPP2R5E gene is identified as harboring genetic variants that can affect human cancer and are possibly under evolutionary selection pressure. PMID- 19773384 TI - The plasma membrane as first responder to heat stress. PMID- 19773385 TI - Autophagy negatively regulates cell death by controlling NPR1-dependent salicylic acid signaling during senescence and the innate immune response in Arabidopsis. AB - Autophagy is an evolutionarily conserved intracellular process for vacuolar degradation of cytoplasmic components. In higher plants, autophagy defects result in early senescence and excessive immunity-related programmed cell death (PCD) irrespective of nutrient conditions; however, the mechanisms by which cells die in the absence of autophagy have been unclear. Here, we demonstrate a conserved requirement for salicylic acid (SA) signaling for these phenomena in autophagy defective mutants (atg mutants). The atg mutant phenotypes of accelerated PCD in senescence and immunity are SA signaling dependent but do not require intact jasmonic acid or ethylene signaling pathways. Application of an SA agonist induces the senescence/cell death phenotype in SA-deficient atg mutants but not in atg npr1 plants, suggesting that the cell death phenotypes in the atg mutants are dependent on the SA signal transducer NONEXPRESSOR OF PATHOGENESIS-RELATED GENES1. We also show that autophagy is induced by the SA agonist. These findings imply that plant autophagy operates a novel negative feedback loop modulating SA signaling to negatively regulate senescence and immunity-related PCD. PMID- 19773386 TI - The heat shock response in moss plants is regulated by specific calcium-permeable channels in the plasma membrane. AB - Land plants are prone to strong thermal variations and must therefore sense early moderate temperature increments to induce appropriate cellular defenses, such as molecular chaperones, in anticipation of upcoming noxious temperatures. To investigate how plants perceive mild changes in ambient temperature, we monitored in recombinant lines of the moss Physcomitrella patens the activation of a heat inducible promoter, the integrity of a thermolabile enzyme, and the fluctuations of cytoplasmic calcium. Mild temperature increments, or isothermal treatments with membrane fluidizers or Hsp90 inhibitors, induced a heat shock response (HSR) that critically depended on a preceding Ca(2+) transient through the plasma membrane. Electrophysiological experiments revealed the presence of a Ca(2+) permeable channel in the plasma membrane that is transiently activated by mild temperature increments or chemical perturbations of membrane fluidity. The amplitude of the Ca(2+) influx during the first minutes of a temperature stress modulated the intensity of the HSR, and Ca(2+) channel blockers prevented HSR and the onset of thermotolerance. Our data suggest that early sensing of mild temperature increments occurs at the plasma membrane of plant cells independently from cytosolic protein unfolding. The heat signal is translated into an effective HSR by way of a specific membrane-regulated Ca(2+) influx, leading to thermotolerance. PMID- 19773387 TI - Chlorella saccharophila cytochrome f and its involvement in the heat shock response. AB - Cytochrome f is an essential component of the major redox complex of the thylakoid membrane. Cloning and characterization are presented here of a novel partial cDNA (ChspetA) encoding cytochrome f in the psychrophile unicellular green alga Chlorella saccharophila and its involvement in the heat shock (HS) response pathway has been analysed. Semi-quantitative reverse transcriptase PCR analysis showed that ChspetA expression is up-regulated in heat-shocked cells and the protein profile of cytochrome f highlighted a release of cytochrome f into the cytosol depending on the time lapse from the HS. Evans Blue assay, analysis of chromatin condensation, and chloroplast alterations showed the induction of cell death in cell suspensions treated with cytosolic extracts from heat-shocked cells. This study identifies cytochrome f in C. saccharophila that seems to be involved in the HS-induced programmed cell death process. The data suggest that cytochrome f fulfils its role through a modulation of its transcription and translation levels, together with its intracellular localization. This work focuses on a possible role of cytochrome f into the programmed cell death-like process in a unicellular chlorophyte and suggests the existence of chloroplast mediated programmed cell death machinery in an organism belonging to one of the primary lineages of photosynthetic eukaryotes. PMID- 19773388 TI - Arabidopsis L-type lectin receptor kinases: phylogeny, classification, and expression profiles. AB - In plants, lectin receptor kinases are considered to play crucial roles during development and in the adaptive response to various stimuli. Arabidopsis lectin receptor kinases can be divided into three type-classes based on sequence similarity of their extracellular lectin motifs. The current study focuses on the legume-like lectin receptor kinases (LecRKs), which are regarded as ideal candidates for monitoring cell wall integrity and are possibly functional in adaptive responses. An inventory of the Arabidopsis LecRK gene family is presented here. It consists of 45 members including three that were recently identified; two encode N-terminal truncated variants one of which has two in tandem kinase domains. Phylogenetic trees derived from full-length amino acid sequence alignments were highly concordant to phylograms that were purely based on lectin motifs or kinase domains. The phylograms allowed reclassification of the LecRK genes and hence a new proposal for gene nomenclature was suggested. In addition, a comprehensive expression analysis was executed by exploring public repositories. This revealed that several LecRK genes are differentially expressed during plant growth and development. Moreover, multiple LecRKs appear to be induced upon treatment with elicitors and pathogen infection. Variation in gene expression was also analysed in seedlings of diverse Arabidopsis accessions. Taken together, this study provides a genome-wide overview of the LecRK gene family and an up-to-date classification using a novel and systematic gene nomenclature. PMID- 19773389 TI - The use of intuition in homeopathic clinical decision making: an interpretative phenomenological study. AB - While intuition plays a role in clinical decision making within conventional medicine, little is understood about its use in complementary and alternative medicine (CAM). The aim of this qualitative study was to investigate intuition from the perspective of homeopathic practitioners; its' manifestation, how it was recognized, its origins and when it was used within daily clinical practice. Semi structured interviews were carried out with clinically experienced non-National Health Service (NHS) UK homeopathic practitioners. Interpretative phenomenological analysis was used to analyze the data. Homeopaths reported many similarities with conventional medical practitioner regarding the nature, perceived origin and manifestation of their intuitions in clinical practice. Intuition was used in two key aspects of the consultation: (i) to enhance the practitioner-patient relationship, these were generally trusted; and (ii) intuitions relating to the prescribing decision. Homeopaths were cautious about these latter intuitions, testing any intuitive thoughts through deductive reasoning before accepting them. Their reluctance is not surprising given the consequences for patient care, but we propose this also reflects homeopaths' sensitivity to the academic and medical mistrust of both homeopathy and intuition. This study is the first to explore the use of intuition in decision making in any form of complementary medicine. The similarities with conventional practitioners may provide confidence in validating intuition as a legitimate part of the decision making process for these specific practitioners. Further work is needed to elucidate if these findings reflect intuitive use in clinical practice of other CAM practitioners in both private and NHS (i.e., time limited) settings. PMID- 19773390 TI - Transcutaneous electrical stimulation of acupoints changes body composition and heart rate variability in postmenopausal women with obesity. AB - This study aimed to evaluate the effect of transcutaneous electric acupoint stimulations (TEAS) on body composition and heart rate variability (HRV) in postmenopausal women with obesity. In this prospective study, 49 postmenopausal women were recruited in Taiwan. Body composition was used as a screening test for obesity (percentage body fat > 30%, waist circumference > 80 cm). The experimental group (n = 24) received TEAS treatment 30 min twice per week for 12 weeks at the Zusanli (ST 36) and Sanyinjiao (SP 6) acupoints. The control group (n = 25) did not receive any intervention. The study of HRV was analyzed by time (standard deviation of the normal-to-normal (NN) intervals (SDNN) and square root of the mean squared differences of successive NN intervals (RMSSD) indices) and frequency domain methods. Power spectral components were obtained at low (LF) and high (HF) frequencies. Body composition and HRV values were measured at the 4th, 8th, and 12th weeks. A total of 40 subjects completed this study. Waist circumference and percentage body fat in the experimental group (n = 20) were significantly less than those of the control group (n = 20) at the 8th and 12th weeks (all P < .05). Additionally, at the same time points, percentage lean body mass in the experimental group was significantly greater than that in the control group (P < .05). SDNN values increased significantly at the 4th and 8th weeks when compared with the control group (all P < .05). At 12 weeks, SDNN value was not significantly different from that of the control group (P = .105). TEAS treatment improves body composition, and has a transient effect on the HRV in postmenopausal women with obesity. PMID- 19773391 TI - In Vitro Activity of 2-methoxy-1,4-naphthoquinone and Stigmasta-7,22-diene-3beta ol from Impatiens balsamina L. against Multiple Antibiotic-Resistant Helicobacter pylori. AB - Infection with Helicobacter pylori is strongly associated with gastric cancer and gastric adenocarcinoma. WHO classified H. pylori as a group 1 carcinogen in 1994. Impatiens balsamina L. has been used as indigenous medicine in Asia for the treatment of rheumatism, fractures and fingernail inflammation. In this study, we isolated anti-H. pylori compounds from this plant and investigated their anti- and bactericidal activity. Compounds of 2-methoxy-1,4-naphthoquinone (MeONQ) and stigmasta-7,22-diene-3beta-ol (spinasterol) were isolated from the pods and roots/stems/leaves of I. balsamina L., respectively. The minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations (MBCs) for MeONQ were in the ranges of 0.156-0.625 and 0.313-0.625 MUg mL(-1), respectively, and in the ranges of 20-80 MUg mL(-1) both of MICs and MBCs for spinasterol against antibiotic (clarithromycin, metronidazole and levofloxacin) resistant H. pylori. Notably, the activity of MeONQ was equivalent to that of amoxicillin (AMX). The bactericidal H. pylori action of MeONQ was dose-dependent. Furthermore, the activity of MeONQ was not influenced by the environmental pH values (4-8) and demonstrated good thermal (121 degrees C for 15 min) stability. MeONQ abounds in the I. balsamina L. pod at the level of 4.39% (w/w db). In conclusion, MeONQ exhibits strong potential to be developed as a candidate agent for the eradication of H. pylori infection. PMID- 19773392 TI - Sequence divergence of heat shock genes within and among 3 Oncorhynchids. AB - Heat shock proteins (Hsps) are induced in response to high temperatures and other stressors, and sequence variation plays a role in regulation of expression of these genes. In this study, we investigated the sequence variation in the 3 major classes of Hsps (Hsp90, Hsp70, and low-molecular weight Hsp) within and among 3 cold-water fish species of Oncorhynchus (Oncorhynchus clarki, Oncorhynchus mykiss, and Oncorhynchus tshawytscha) with variable life history and thermal tolerance characteristics. Sequences collectively totaled 4556 bp across 9 gene fragments and 198 single nucleotide polymorphisms and 43 indel sites were observed among species. Within species, sequence variation was much lower for O. clarki than the other 2 species. Sequence variation within and among species was high in cis-regulatory regions that are potentially involved in transcription of Hsps under variable stressors. Our results indicate that Hsp genes may be locally adapted in O. clarki, whereas higher Hsp polymorphism is necessary for O. mykiss and O. tshawytscha and variation at the sequence level may have important evolutionary consequences for these species. Further studies are needed to determine the association of observed sequence variation with the regulation of Hsps and performance of fish under stress. PMID- 19773393 TI - Recombinant thyrotropin use in children and adolescents with differentiated thyroid cancer: a multicenter retrospective study. AB - CONTEXT: Although recombinant human TSH (rhTSH) is widely used in differentiated thyroid cancer (DTC) to aid diagnostic follow-up procedures and radioiodine thyroid remnant ablation, almost all clinical investigation was in adults. OBJECTIVE: The aim of this study was to characterize rhTSH clinical safety and peak TSH response in DTC patients 18 yr old or younger. DESIGN AND SETTING: We conducted a retrospective study involving 23 tertiary referral centers in 12 European, Asian, and Oceanian countries. PATIENTS: One hundred DTC patients (69% female, 31% male, 84% papillary, 61% N1, 18% M1) ages 4.9-18 yr at first rhTSH administration were studied. INTERVENTIONS: A total of 181 rhTSH courses were administered (range, one to eight per patient; 42% of patients received two or more courses), 92% using the approved adult regimen (one 0.9 mg im injection daily on two consecutive days), 34% including thyroid hormone withdrawal for less than 7 d ("mini-THW"). MAIN OUTCOME MEASURES: Clinical adverse event (AE) incidence, type, and severity, and peak post-rhTSH serum TSH concentrations were assessed. RESULTS: No clinical AEs occurred in 88% of rhTSH courses. Most common clinical AEs were nausea (5% of courses) and vomiting (3%). Multiple or severe AEs were rare (0.6% and 2.8% of courses, respectively); serious AEs were absent. Peak TSH concentration post-rhTSH exceeded 25 mU/liter in approximately 98% of courses. In logistic regression analyses, the rhTSH regimen, "mini-THW," peak TSH concentration, body mass index (BMI), or peak TSH concentration/unit of BMI were not associated with clinical AE occurrence. In analyses of covariance, higher BMI was associated with lower peak TSH concentrations. CONCLUSIONS: rhTSH was clinically well tolerated in pediatric DTC patients although courses preponderantly comprised the adult regimen, and repeated courses were frequent. Both the adult and reduced-dose regimens almost always sufficiently elevate TSH in children and adolescents. PMID- 19773394 TI - Thyrotropin secretion profiles are not different in men and women. AB - CONTEXT: The hypothalamo-pituitary-thyroid axis in women may differ from that in men. Previous reports have shown an almost 2-fold increased response to TRH in females compared with males. OBJECTIVE: We analyzed TSH profiles in healthy men and women to delineate differences in the hypothalamo-pituitary-thyroid system. SUBJECTS AND INTERVENTION: The subjects, 24 men (mean age 44 +/- 3 yr) and 22 women (mean age 42 +/- 3 yr) underwent a 24-h study with blood sampling intervals of 10 min. Premenopausal women were investigated in the early follicular phase of the cycle. METHODS: Serum TSH concentration profiles were analyzed with a newly developed automated deconvolution program, approximate entropy, and cosinor regression. RESULTS: Basal and pulsatile TSH secretion, and also pulse frequency, hormone half-lives, and secretory mode were indistinguishable in the two genders. There were no differences in diurnal variation, and the times of maximal secretion coincided. Approximate entropy, reflecting secretory regularity, was not different between men and women. In women but not men, TSH secretion was dependent linearly on age. CONCLUSIONS: TSH secretion is gender invariant and depends on age in women only. PMID- 19773395 TI - A reappraisal of diagnosing GH deficiency in adults: role of gender, age, waist circumference, and body mass index. AB - OBJECTIVE: The objective of the study was to reevaluate the diagnostic accuracy of GH peak after GHRH plus arginine test (GHRH+ARG) according to patients' age, body mass index (BMI), and waist circumference to diagnose GH deficiency (GHD). OUTCOME MEASURES: GH peak after GHRH+ARG and IGF-I levels reported as sd score. SUBJECTS: Subjects included 408 controls (218 women, 190 men, aged 15-80 yr) and 374 patients with hypopituitarism (167 women, 207 men, aged 16-83 yr). RESULTS: In the (elderly) healthy subjects 15-25 yr old (young), 26-65 yr old (adults) and older than 65 yr, GH cutoffs were 15.6, 11.7, and 8.5 microg/liter, 11.8, 8.1, and 5.5 microg/liter, and 9.2, 6.1, and 4.0 microg/liter, respectively, in the lean, overweight, and obese subjects. Waist circumference was the best predictor of GH peak (t = -7.6, P < 0.0001) followed by BMI (t = -6.7, P < 0.0001) and age (t = -5.7, P < 0.0001). Based on the old (<9.1 microg/liter) and new GH cutoff, 286 (76.5%) and 276 (73.8%) of 374 hypopituitary patients had severe GHD. The receiving-operator characteristic analysis showed GH cutoffs in line with the third percentile or slightly higher results so that the prevalence of GHD increased to 90.1%. CONCLUSIONS: The results of the current study show that waist circumference and BMI are the strongest predictors of GH peak after GHRH+ARG followed by age. However, the old cutoff value of 9.0 microg/liter was in line with the new cutoffs in 95% of patients. PMID- 19773396 TI - Gender-specific prevalences of fatty liver in obese children and adolescents: roles of body fat distribution, sex steroids, and insulin resistance. AB - CONTEXT: Nonalcoholic fatty liver disease (NAFLD) is known to have a gender dimorphic prevalence in obese children. Less information is available on predictive factors for NAFLD in obese youths. OBJECTIVE: The aim of the study was to examine the prevalence pattern and to identify clinical and laboratory markers associated with the risk for NAFLD. DESIGN: This was a cross-sectional study. SETTING: The study setting was a rehabilitation clinic. STUDY PARTICIPANTS: A total of 532 obese subjects (291 girls) aged 8-19 yr participated in the study. MAIN MEASUREMENTS: Steatosis hepatis and visceral fat mass were determined by ultrasound. Laboratory tests included serum lipids, adiponectin, high-sensitivity C-reactive protein, sex steroids, and an oral glucose tolerance test. RESULTS: Prevalence of hepatic steatosis was significantly higher in boys (41.1%) than in girls (17.2%) and was highest in postpubertal boys (51.2%) and lowest in postpubertal girls (12.2%). Severity of steatosis was associated with increased visceral fat mass, insulin resistance, lower adiponectin levels, and higher blood pressure. Three factors were extracted from the panel of investigated parameters by principal component analysis. Logistic regression analysis revealed significant associations of simple steatosis with the "insulin resistance and visceral fat" factor and the "body fat distribution and inflammation" factor in both genders and additionally with the "steroid hormones" factor in girls. Risk for steatosis hepatis with concomitantly elevated ALT was associated only with "insulin resistance and visceral fat" in girls and with all three factors in boys. CONCLUSION: Our results suggest significant associations of NAFLD with markers of visceral obesity and insulin resistance in both genders and gender specific associations with parameters of body fat distribution and sex steroids. PMID- 19773397 TI - TSPY1 copy number variation influences spermatogenesis and shows differences among Y lineages. AB - CONTEXT: TSPY1 is a tandemly-repeated gene on the human Y chromosome forming an array of approximately 21-35 copies. The testicular expression pattern and the inferred function of the TSPY1 protein suggest possible involvement in spermatogenesis. However, data are scarce on TSPY1 copy number variation in different Y lineages and its role in spermatogenesis. OBJECTIVES: We sought to define: 1) the extent of TSPY1 copy number variation within and among Y chromosome haplogroups; and 2) the role of TSPY1 dosage in spermatogenic efficiency. MATERIALS AND METHODS: A total of 154 idiopathic infertile men and 130 normozoospermic controls from Central Italy were analyzed. We used a quantitative PCR assay to measure TSPY1 copy number and also defined Y haplogroups in all subjects. RESULTS: We provide evidence that TSPY1 copy number shows substantial variation among Y haplogroups and thus that population stratification does represent a potential bias in case-control association studies. We also found: 1) a significant positive correlation between TSPY1 copy number and sperm count (P < 0.001); 2) a significant difference in mean TSPY1 copy number between patients and controls (28.4 +/- 8.3 vs. 33.9 +/- 10.7; P < 0.001); and 3) a 1.5-fold increased risk of abnormal sperm parameters in men with less than 33 copies (P < 0.001). CONCLUSIONS: TSPY copy number variation significantly influences spermatogenic efficiency. Low TSPY1 copy number is a new risk factor for male infertility with potential clinical consequences. PMID- 19773398 TI - X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism caused by an inversion disrupting a conserved noncoding element upstream of the NR0B1 (DAX1) gene. AB - CONTEXT: X-linked congenital adrenal hypoplasia with hypogonadotropic hypogonadism (AHCH) is known to be caused by coding mutations in the nuclear receptor subfamily 0, group B, member 1 (NR0B1) gene, encoding the transcriptional repressor dosage-sensitive sex-reversal adrenal hypoplasia critical region on the X chromosome protein 1 (DAX1). OBJECTIVE/PATIENTS: Four males in a family were affected by AHCH. Our aim was to locate the genetic cause of their disease, knowing that they had no mutation in the obvious candidate gene, NR0B1. DESIGN: Linkage analysis of the X chromosome and mutational screening of conserved noncoding regions upstream of NR0B1 were performed. To functionally characterize the genetic defect, studies of transcription and expression of DAX1 and steroidogenic factor 1 (SF-1) were done. RESULTS: A 60 Mb inversion on the X chromosome with one of the inversion breakpoints located in a conserved noncoding region 4 kb upstream of NR0B1 was detected. The inversion causes relocation of a putative SF-1 binding site implicated in murine gonadal development. A reporter construct lacking this enhancer element upstream of NR0B1 was unresponsive to SF-1 transcriptional activation. Immunohistochemistry suggested that the inversion leads to SF-1 silencing in the patients' testes both in childhood and in adult life. CONCLUSION: We report a noncoding mutation causing AHCH, an inversion resulting in a phenotype similar to what is caused by intragenic NR0B1 null mutations. The inversion seems to disrupt and/or relocate regulatory sites crucial in DAX1 expression. PMID- 19773399 TI - 8-Cl-adenosine inhibits proliferation and causes apoptosis in B-lymphocytes via protein kinase A-dependent and independent effects: implications for treatment of Carney complex-associated tumors. AB - CONTEXT: Carney complex, a multiple neoplasia syndrome, characterized primarily by spotty skin pigmentation and a variety of endocrine and other tumors, is caused by mutations in PRKAR1A, the gene that codes for the RIalpha subunit of protein kinase A (PKA). PKA controls cell proliferation in many cell types. The cAMP analogue 8-Cl-adenosine (8-Cl-ADO) is thought to inhibit cancer cell proliferation. OBJECTIVE: The objective of the study was to study the antiproliferative effects of 8-Cl-ADO on growth and proliferation in B lymphocytes of Carney complex patients that have PKA defects and to determine whether 8-CL-ADO could be used as a therapeutic agent in the treatment of Carney complex-associated tumors. DESIGN: We used a multiparametric approach (i.e. growth and proliferation assays, PKA, and PKA subunit assays, cAMP and (3)H-cAMP binding assays, and apoptosis assays) to understand the growth and proliferative effects of 8-Cl-ADO on human B-lymphocytes. RESULTS: 8-Cl-ADO inhibited proliferation, mainly through its intracellular transport and metabolism, which induced apoptosis. PKA activity, cAMP levels, and (3)H-cAMP binding were increased or decreased, respectively, by 8-Cl-ADO, whereas PKA subunit levels were differentially affected. 8-Cl-ADO also inhibited proliferation induced by G protein-coupled receptors for isoproterenol and adenosine, as well as proliferation induced by tyrosine kinase receptors. CONCLUSIONS: 8-Cl-ADO in addition to unambiguously inhibiting proliferation and inducing apoptosis in a PKA-independent manner also has PKA-dependent effects that are unmasked by a mutant PRKAR1A. Thus, 8-Cl-ADO could serve as a therapeutic agent in patients with Carney complex-related tumors. PMID- 19773400 TI - A systematic review and meta-analysis of randomized placebo-controlled trials of DHEA treatment effects on quality of life in women with adrenal insufficiency. AB - CONTEXT: Women with primary or secondary adrenal insufficiency report a decreased health-related quality of life (HRQOL) despite traditional adrenal replacement therapy. Dehydroepiandrosterone (DHEA) has been studied as an agent to improve HRQOL in these patients. OBJECTIVE: We sought to conduct a systematic review and meta-analysis of randomized controlled trials of DHEA effects on HRQOL in women with adrenal insufficiency. DATA SOURCES: We searched electronic databases (MEDLINE, EMBASE, Cochrane CENTRAL, Web of Science, CINAHL, and PsycInfo) and reference lists of eligible studies through July 2008. STUDY SELECTION: Eligible trials randomly assigned women with primary or secondary adrenal insufficiency to either DHEA or control and measured the effect of treatment on HRQOL. DATA EXTRACTION: Reviewers working independently and in duplicate assessed the methodological quality of trials and collected data on patient characteristics, interventions, and outcomes. DATA SYNTHESIS: We found 10 eligible trials that measured HRQOL and depression, anxiety, and sexual function. Random-effects meta analysis showed a small improvement in HRQOL in women treated with DHEA compared with placebo [effect size of 0.21; 95% confidence interval, 0.08 to 0.33; inconsistency (I(2)) = 32%]. There was a small beneficial effect of DHEA on depression; effects on anxiety and sexual well-being were also small and not statistically significant. CONCLUSIONS: DHEA may improve, in a small and perhaps trivial manner, HRQOL and depression in women with adrenal insufficiency. There was no significant effect of DHEA on anxiety and sexual well-being. The evidence appears insufficient to support the routine use of DHEA in women with adrenal insufficiency. PMID- 19773401 TI - Noninvasive quantification of pancreatic fat in humans. AB - OBJECTIVE: To validate magnetic resonance spectroscopy (MRS) as a tool for non invasive quantification of pancreatic triglyceride (TG) content and to measure the pancreatic TG content in a diverse human population with a wide range of body mass index (BMI) and glucose control. METHODS: To validate the MRS method, we measured TG content in the pancreatic tissue of 12 lean and 12 fatty ZDF rats (ages 5-14 weeks) both by MRS and the gold standard biochemical assay. We used MRS to measure pancreatic TG content in vivo in 79 human volunteers. Additionally, to assess the reproducibility of the method, in 33 volunteers we obtained duplicate MRS measurements 1-2 weeks apart. RESULTS: MRS quantifies pancreatic TG content with high reproducibility and concordance to the biochemical measurement (Spearman's rank correlation coefficient = 0.91). In humans, median pancreatic TG content was as follows: (1) normal weight and normoglycemic group 0.46 f/w%, (2) overweight or obese but normoglycemic group 3.16 f/w%, (3) impaired fasting glucose or impaired glucose tolerance group (BMI matched with group 2) 5.64 f/w%, and (4) untreated type 2 diabetes group (BMI matched with group 2) 5.54 f/w% (Jonckheere-Terpstra trend test across groups p < 0.001). CONCLUSIONS: Human pancreatic steatosis, as measured by MRS, increases with BMI and with impaired glycemia. MRS is a quantitative and reproducible non invasive clinical research tool which will enable systematic studies of the relationship between ectopic fat accumulation in the pancreas and development of type 2 diabetes. PMID- 19773402 TI - Anthropometric and skeletal phenotype in men with idiopathic osteoporosis and their sons is consistent with deficient estrogen action during maturation. AB - CONTEXT: Pathophysiology of deficient bone mass acquisition in male idiopathic osteoporosis (IO) remains poorly understood. OBJECTIVE: Our objective was to investigate volumetric and geometric parameters of the appendicular skeleton, biochemical markers, and anthropometrics in men with IO. DESIGN, SETTING, AND PARTICIPANTS: Our cross-sectional study included 107 men diagnosed with idiopathic low bone mass, 23 of their adult sons, and 130 age-matched controls. MAIN OUTCOME MEASURES: Body composition and areal bone parameters (dual-energy x ray absorptiometry) and volumetric and geometric parameters of radius and tibia (peripheral quantitative computed tomography) were assessed. Serum levels of testosterone, estradiol (E(2)), and SHBG, and bone turnover markers were measured using immunoassays. Free hormone fractions were calculated. RESULTS: Men with idiopathic low bone mass had lower weight (-9.6%), truncal height (-3.3%), and upper/lower body segment ratio (-2.7%; all P < 0.001) and presented at the radius and tibia lower trabecular (-19.0 and -23.6%, respectively; both P < 0.001) and cortical volumetric bone mineral density (vBMD) (-2.4 and -1.7%; both P < 0.001) and smaller cortical areas (-9.7 and -13.6%; both P < 0.001) and thicknesses ( 13.5 and -14.5%, both P < 0.001) due to larger endosteal circumferences (+11.8 and +7.4%, both P < 0.001) than controls. Furthermore, (free) E(2) was lower and SHBG higher (both P < 0.01). Their sons had lower trabecular vBMD (-10.3%, P = 0.036) and a thinner cortex (-8.3%, P = 0.024) at the radius. CONCLUSION: Bone mass deficits in men with idiopathic low bone mass involve trabecular and cortical bone, resulting from lower vBMD and smaller cortical bone cross sectional areas and thicknesses. A similar bone phenotype is present in at least part of their sons. The lower E(2), together with characteristics as lower upper/lower body segment ratio, larger endosteal circumferences and lower vBMD, may indicate an estrogen-related factor in the pathogenesis of male IO. PMID- 19773403 TI - Duplications of the functional CYP21A2 gene are primarily restricted to Q318X alleles: evidence for a founder effect. AB - CONTEXT: Rare haplotypes with Q318X mutations and duplicated CYP21A2 genes have been reported to occur in different populations to a varying extent. Discrimination between a normal (Q318X mutation on one of the duplicated CYP21A2 genes) and a congenital adrenal hyperplasia (CAH, Q318X mutation without duplicated functional gene) allele is of importance, particularly for prenatal diagnosis and the respective genetic counseling. Although methods to differentiate between such alleles have been published only recently, it remains unclear with which frequency Q318X mutations are associated with duplicated CYP21A2 genes and whether these haplotypes have a common ancestry. SUBJECTS AND METHODS: Human leukocyte antigen (HLA) typing has been performed in 38 unrelated individuals and in 11 family members detected to carry a Q318X mutation in the course of CYP21 genotyping using sequence, multiplex ligation-dependent probe amplification, and Southern blot analyses. RESULTS: The majority (n = 32, 84.2%) of the 38 unrelated individuals carrying the Q318X mutation had the trimodular RCCX haplotype, carrying the Q318X mutation on a duplicated CYP21A2 gene. Twenty two individuals of these 32 (68.8%) were of the rare HLA-B*50-Cw*06 haplotype, suggesting a common ancestry of this haplotype. In five (13.2%) of the 38 subjects, the Q318X mutation was not associated with a duplicated CYP21A2 gene and thus represents a CAH allele. None of these five patients had the above mentioned HLA haplotype. CONCLUSION: The majority of individuals in whom Q318X mutations are detected carry a duplicated functional CYP21A2 gene and the rare HLA-B*50-Cw*06 haplotype. PMID- 19773404 TI - Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency. AB - CONTEXT: Familial glucocorticoid deficiency (FGD) is an autosomal recessive disorder resulting from resistance to the action of ACTH on the adrenal cortex. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia and/or overwhelming infection. Mutations of the ACTH receptor (MC2R) and the melanocortin 2 receptor accessory protein (MRAP), FGD types 1 and 2 respectively, account for approximately 45% of cases. OBJECTIVE: A locus on chromosome 8 has previously been linked to the disease in three families, but no underlying gene defect has to date been identified. DESIGN: The study design comprised single-nucleotide polymorphism genotyping and mutation detection. SETTING: The study was conducted at secondary and tertiary referral centers. PATIENTS: Eighty probands from families referred for investigation of the genetic cause of FGD participated in the study. INTERVENTIONS: There were no interventions. RESULTS: Analysis by single-nucleotide polymorphism array of the genotype of one individual with FGD previously linked to chromosome 8 revealed a large region of homozygosity encompassing the steroidogenic acute regulatory protein gene, STAR. We identified homozygous STAR mutations in this patient and his affected siblings. Screening of our total FGD patient cohort revealed homozygous STAR mutations in a further nine individuals from four other families. CONCLUSIONS: Mutations in STAR usually cause lipoid congenital adrenal hyperplasia, a disorder characterized by both gonadal and adrenal steroid deficiency. Our results demonstrate that certain mutations in STAR (R192C and the previously reported R188C) can present with a phenotype indistinguishable from that seen in FGD. PMID- 19773405 TI - Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development. AB - CONTEXT: IGF-I is essential for fetal and postnatal development. Only three IGF1 defects leading to dramatic loss of binding to its type 1 receptor, IGF-1R, have been reported. PATIENT: We describe a very lean boy who has intrauterine growth restriction and progressive postnatal growth failure associated with normal hearing, microcephaly, and mild intellectual impairment. He had markedly reduced concentrations of IGF-I, with IGFBP-3 and ALS serum levels in the upper normal range or above. IGF-I serum concentrations differed according to the immunoassay used. A higher than average GH dose was required for catch-up growth. Given the mismatch between IGF-I and IGFBP-3 levels, we sequenced his IGF1 gene. RESULT: We identified a homozygous missense IGF1 mutation. This causes the replacement of a highly conserved amino acid (arginine 36) by a glutamine (R36Q) in the C domain of the predicted peptide. We showed that the abnormal IGF-I peptide has reduced mitogenic activity and partial loss of binding to its receptor IGF-1R. The patient's IGF-I level was undetectable in a highly specific monoclonal assay but elevated in a polyclonal assay. CONCLUSION: This first report of mild deficiency of IGF-I activity demonstrates that the integrity of IGF-I signaling is important for normal growth and brain development. Molecular defects leading to partial loss of IGF-I activity may not be uncommon in patients born small for gestational age. The characterization of this complex phenotype and identification of such molecular defects have therapeutic implications, particularly now that, in addition to GH, recombinant IGF-I is available for clinical use. PMID- 19773406 TI - Fatigue is a reliable, sensitive and unique outcome measure in rheumatoid arthritis. AB - OBJECTIVE: Fatigue is an important symptom in patients with RA. Measurement of fatigue in clinical trials and in clinical practice requires scales that are reproducible, sensitive to change and practical. This study examined the reliability and sensitivity to change of fatigue and its relative independence as an outcome measure in RA. METHODS: Successive patients referred to the rheumatology clinic at St Vincent's University Hospital and Our Lady's Hospice were evaluated. Clinical assessments were undertaken at baseline and 3 months after commencing TNF-alpha blockade. Fatigue was measured using an 11-point numeric rating scale (NRS). Sensitivity to change when compared with current core set outcome measures was determined by calculation of the standardized response mean (SRM). Multiple regression analysis was employed to determine the independent variance of fatigue scores relative to the core set. RESULTS: Forty nine patients were evaluated. At baseline, mean (s.d.) fatigue scores were 6.7 +/ 2.1. At 3 months, fatigue scores had fallen to 4.3 +/- 2.6 (P < 0.001). Test retest intraclass correlation coefficient for the NRS was 0.79 (P < 0.008). Fatigue was ranked third for relative sensitivity to change as shown by SRM: pain, 1.37; tender joint count (TJC), 1.09; fatigue, 0.92; swollen joint count (SJC), 0.86; HAQ, 0.82; CRP, 0.69; and patient global health (GH), 0.25. The relative independent variance in fatigue of 22% was higher than that of the core set: TJC, 20%; pain, 19%; SJC, 16%; GH, 8%; HAQ, 7%; and CRP, 8%. CONCLUSIONS: This study demonstrates that measures of fatigue are reliable and sensitive to change, and should be considered for inclusion as a core outcome measure in RA. PMID- 19773407 TI - Bone erosions at the distal ulna detected by ultrasonography are associated with structural damage assessed by conventional radiography and MRI: a study of patients with recent onset rheumatoid arthritis. AB - OBJECTIVES: Ultrasonography (US) is a sensitive tool for detecting erosions in patients with RA. The wrist is usually involved in the RA process, where the distal ulna with its superficial localization is easily accessible for US examination. In this longitudinal study, we wanted to examine the presence, localization and development of erosions at the distal ulna by US in patients with recent onset RA, and to analyse whether erosions at this localization are associated with joint damage in hands assessed by conventional radiography (CR) and MRI. METHODS: Seventy patients with recent onset RA (median disease duration 106 days) were examined by US of the distal ulna, in addition to hand radiography [assessed by van der Heijde-modified Sharp score (vdHSS)] and MRI of the wrist [assessed by RA MRI scoring (RAMRIS) erosion score]. Twelve months later 58 patients were re-assessed. RESULTS: US detected erosions at the distal ulna in 11% of the patients at baseline and 24% at follow-up (the majority of erosions were at the ulnar side). Logistic regression analyses showed the presence of erosions at baseline to be associated with baseline RAMRIS erosion score (P < 0.001), and at follow-up to RAMRIS erosion score (P = 0.02) and vdHSS (P = 0.008). CONCLUSIONS: A significant number of patients had US erosions at the distal ulna at baseline, with increased prevalence after 1 year. The US-detected erosions were associated with structural joint damage in hands assessed by both MRI and CR. US of the distal ulna could thus give useful clinical information. PMID- 19773408 TI - The gene expression of type 17 T-helper cell-related cytokines in the urinary sediment of patients with systemic lupus erythematosus. AB - OBJECTIVE: We studied the role of type 17 Th cells (TH17) in the pathogenesis of SLE. METHODS: We quantified the mRNA expression of IL-17, -23, -27 and retinoic acid-related orphan receptor (ROR)-gamma, the regulator for the development and function of TH17, in the urinary sediment of 23 subjects with active lupus nephritis, 25 subjects with a history of lupus nephritis in remission, 30 SLE patients with no history of renal involvement and 8 healthy subjects. RESULTS: All three groups of lupus patients had a higher urinary expression of TH17 related cytokines than the controls. However, urinary expression of IL-17 and -27 was found to be inversely correlated with the SLEDAI score (r = -0.252 and 0.258, respectively; P < 0.05 for both). For patients with active lupus nephritis, the histological activity index of kidney biopsy was also found to be inversely correlated with the urinary expression of ROR-gamma (r = -0.447; P = 0.032), IL-17 (r = -0.454; P = 0.029) and IL-23 (r = -0.455; P = 0.029). Urinary expression of IL-17, -23, -27 and ROR was also found to be inversely correlated with the urinary expression of IFN-gamma and T-bet, the key transcription factor of type 1 Th cells. After 6 months of treatment, urinary IL-27 expression rose significantly in patients with complete response (from 2.07 +/- 1.62 to 3.70 +/- 1.69; P = 0.028) but remained unchanged in those with partial or no response (from 2.60 +/- 1.87 to 2.52 +/- 1.94; P = 0.9). CONCLUSIONS: The urinary expression of TH17-related genes is increased in SLE patients. The degree of up regulation, however, is inversely related to systemic and renal lupus activity, as well as urinary expression of TH1-related genes. Urinary expression of TH17 related genes increased again after successful immunosuppressive treatment of active disease. Our findings suggest a regulatory role of TH17-related cytokines in pathogenesis of lupus nephritis. PMID- 19773409 TI - Psychometric functions for ternary odor mixtures and their unmixed components. AB - People are often able to reliably detect a mixture of 2 or more odorants, even if they cannot reliably detect the individual mixture components when presented individually. This phenomenon has been called mixture agonism. However, for some mixtures, agonism among mixture components is greater in barely detectable mixtures than in more easily detectable mixtures (level dependence). Most studies that have used rigorous methods have focused on simple, 2-component (binary) mixtures. The current work takes the next logical step to study detection of 3 component (ternary) mixtures. Psychometric functions were measured for 5 unmixed compounds and for 3 ternary mixtures of these compounds (2 of 5, forced-choice method). Experimenters used air dilution olfactometry to precisely control the duration and concentration of stimuli and used gas chromatography/mass spectrometry to verify vapor-phase concentrations. For 2 of the 3 mixtures, agonism was approximately additive in general agreement with similar work on binary mixtures. A third mixture was no more detectable than the most detectable component, demonstrating a lack of agonism. None of the 3 mixtures showed evidence of level dependence. Agonism may be common in ternary mixtures, but general rules of mixture interaction have yet to emerge. For now, detection of any mixture must be measured empirically. PMID- 19773410 TI - A distorted yellowish kidney occupied by foamy macrophages. PMID- 19773411 TI - Commentary: Cornfield, epidemiology and causality. PMID- 19773412 TI - Commentary: 'Smoking and lung cancer'--the embryogenesis of modern epidemiology. PMID- 19773413 TI - Commentary: Smoking and lung cancer: reflections on a pioneering paper. PMID- 19773414 TI - Commentary: Cornfield on cigarette smoking and lung cancer and how to assess causality. PMID- 19773415 TI - Smoking and lung cancer: recent evidence and a discussion of some questions. 1959. PMID- 19773416 TI - A gene score of nine LDL and HDL regulating genes is associated with fluvastatin induced cholesterol changes in women. AB - While conventional pharmacogenetic studies have considered single gene effects, we tested if a genetic score of nine LDL- and HDL-associated single nucleotide polymorphisms, previously shown to predict cardiovascular disease, is related to fluvastatin-induced lipid change. In patients with asymptomatic plaque in the right carotid artery, thus candidates for statin therapy, we related score LDL [APOB(rs693), APOE(rs4420638), HMGCR(rs12654264), LDLR(rs1529729), and PCSK9(rs11591147)] and score HDL [ABCA1(rs3890182), CETP(rs1800775), LIPC(rs1800588), and LPL(rs328)] as well as the combined score LDL+HDL to fluvastatin-induced LDL reduction (+/- metoprolol) (n = 395) and HDL increase (n = 187) following 1 year of fluvastatin treatment. In women, an increasing number of unfavorable alleles (i.e., alleles conferring higher LDL and lower HDL) of score LDL+HDL (P = 0.037) and of score LDL (P = 0.023) was associated with less pronounced fluvastatin-induced LDL reduction. Furthermore, in women, both score LDL+HDL (P = 0.001) and score HDL (P = 0.022) were directly correlated with more pronounced fluvastatin-induced HDL increase, explaining 5.9-11.6% of the variance in treatment response in women. There were no such associations in men. This suggests that a gene score based on variation in nine different LDL- and HDL associated genes is of importance for the magnitude of fluvastatin HDL increase in women with asymptomatic plaque in the carotid artery. PMID- 19773417 TI - Impact of daclizumab, low-dose cyclosporine, mycophenolate mofetil and steroids on renal function after kidney transplantation. AB - BACKGROUND: Early and long-term use of cyclosporine A (CsA) leads to increased risks of renal toxicity. We hypothesized that administration of daclizumab in combination with mycophenolate mofetil (MMF) allows a relevant reduction in the dose of CsA. METHODS: We carried out a 3-year, prospective, randomized, controlled clinical multi-centre trial in 156 patients. The patients were randomized to standard treatment (CsA, MMF, steroids) or to high-dose daclizumab (first dose: 2 mg/kg), in combination with low-dose CsA, MMF and steroids. We maintained the mean CsA levels of daclizumab patients at 57% of standard patients (132 versus 216 ng/ml) on Day 7 post-transplant, and 84% by 6 months. RESULTS: Primary outcome, creatinine clearance (with imputation of informative dropouts) at 12 months, was significantly better in daclizumab-treated (34 +/- 17) than standard patients (29 +/- 17; P = 0.028, two sided). Only 5 cases of BPAR were recorded in the daclizumab compared to 22 in the standard group (P = 0.0016). Daclizumab patients had 91% event-free survival after 1 year compared to 66% in standard patients (P = 0.00017). CONCLUSION: We demonstrate here that high-dose daclizumab in combination with lower CsA levels in adult renal transplant recipients is as or more effective than standard regimen (CsA, MMF, steroids) and may result in better outcomes at 12 months post-transplant with no increase in adverse reactions. PMID- 19773418 TI - Rapamycin enhances lifespan: at last, an advantage for transplant recipients? PMID- 19773419 TI - Recurrence of nephrotic syndrome after transplantation in a mixed population of children and adults: course of glomerular lesions and value of the Columbia classification of histological variants of focal and segmental glomerulosclerosis (FSGS). AB - Introduction. Recurrence of nephrotic-range proteinuria in patients with idiopathic nephrotic syndrome (INS) and focal and segmental glomerulosclerosis (FSGS) on native kidneys is associated with poor graft survival. Identification of risk factors for recurrence is therefore an important issue. In 2004, Columbia University introduced a histological classification of FSGS that identifies five mutually exclusive variants. In non-transplant patients, the Columbia classification appears to predict the outcome and response to treatment better than clinical characteristics alone. However, the predictive value of this classification to assess the risk of recurrence after transplantation has not been addressed. METHODS: We retrospectively studied 77 patients with INS and FSGS on native kidneys who underwent renal transplantation. Of these, 42 recipients experienced recurrence of nephrotic range proteinuria. RESULTS: At time of recurrence, minimal-change disease (MCD) was the main histological feature. On serial biopsies, the incidence of MCD decreased over time, while the incidence of FSGS variants increased. The variant type observed in the native kidneys was not predictive of either recurrence or type of FSGS seen on the allograft. Patients with complete and sustained remission did not developed FSGS. CONCLUSION: In conclusion, the Columbia classification is of no help in predicting recurrence after renal transplantation or histological lesions in the case of recurrence of proteinuria. PMID- 19773420 TI - The Aspergillus Genome Database, a curated comparative genomics resource for gene, protein and sequence information for the Aspergillus research community. AB - The Aspergillus Genome Database (AspGD) is an online genomics resource for researchers studying the genetics and molecular biology of the Aspergilli. AspGD combines high-quality manual curation of the experimental scientific literature examining the genetics and molecular biology of Aspergilli, cutting-edge comparative genomics approaches to iteratively refine and improve structural gene annotations across multiple Aspergillus species, and web-based research tools for accessing and exploring the data. All of these data are freely available at http://www.aspgd.org. We welcome feedback from users and the research community at aspergillus-curator@genome.stanford.edu. PMID- 19773421 TI - Universal function-specificity of codon usage. AB - Synonymous codon usage has long been known as a factor that affects average expression level of proteins in fast-growing microorganisms, but neither its role in dynamic changes of expression in response to environmental changes nor selective factors shaping it in the genomes of higher eukaryotes have been fully understood. Here, we propose that codon usage is ubiquitously selected to synchronize the translation efficiency with the dynamic alteration of protein expression in response to environmental and physiological changes. Our analysis reveals that codon usage is universally correlated with gene function, suggesting its potential contribution to synchronized regulation of genes with similar functions. We directly show that coexpressed genes have similar synonymous codon usages within the genomes of human, yeast, Caenorhabditis elegans and Escherichia coli. We also demonstrate that perturbing the codon usage directly affects the level or even direction of changes in protein expression in response to environmental stimuli. Perturbing tRNA composition also has tangible phenotypic effects on the cell. By showing that codon usage is universally function specific, our results expand, to almost all organisms, the notion that cells may need to dynamically alter their intracellular tRNA composition in order to adapt to their new environment or physiological role. PMID- 19773422 TI - Phage T4 mobE promotes trans homing of the defunct homing endonuclease I-TevIII. AB - Homing endonucleases are site-specific DNA endonucleases that typically function as mobile genetic elements by introducing a double-strand break (DSB) in genomes that lack the endonuclease, resulting in a unidirectional gene conversion event that mobilizes the homing endonuclease gene and flanking DNA. Here, we characterize phage T4-encoded mobE, a predicted free-standing HNH family homing endonuclease. We show that mobE is promoterless and dependent on upstream transcription for expression, and that an internal intrinsic terminator regulates mobE transcript levels. Crucially, in vivo mapping experiments revealed a MobE dependent, strand-specific nick in the non-coding strand of the nrdB gene of phage T2. An internal deletion of the predicted HNH catalytic motif of MobE abolishes nicking, and reduces high-frequency inheritance of mobE. Sequence polymorphisms of progeny phage that inherit mobE are consistent with DSB repair pathways. Significantly, we found that mobility of the neighboring I-TevIII, a defunct homing endonuclease encoded within a group I intron interrupting the nrdB gene of phage T4, was dependent on an intact mobE gene. Thus, our data indicate that the stagnant nrdB intron and I-TevIII are mobilized in trans as a consequence of a MobE-dependent gene conversion event, facilitating persistence of genetic elements that have no inherent means of promoting their own mobility. PMID- 19773423 TI - The transcriptional co-activator PCAF regulates cdk2 activity. AB - Cyclin dependent kinases (cdks) regulate cell cycle progression and transcription. We report here that the transcriptional co-activator PCAF directly interacts with cdk2. This interaction is mainly produced during S and G(2)/M phases of the cell cycle. As a consequence of this association, PCAF inhibits the activity of cyclin/cdk2 complexes. This effect is specific for cdk2 because PCAF does not inhibit either cyclin D3/cdk6 or cyclin B/cdk1 activities. The inhibition is neither competitive with ATP, nor with the substrate histone H1 suggesting that somehow PCAF disturbs cyclin/cdk2 complexes. We also demonstrate that overexpression of PCAF in the cells inhibits cdk2 activity and arrests cell cycle progression at S and G(2)/M. This blockade is dependent on cdk2 because it is rescued by the simultaneous overexpression of this kinase. Moreover, we also observed that PCAF acetylates cdk2 at lysine 33. As this lysine is essential for the interaction with ATP, acetylation of this residue inhibits cdk2 activity. Thus, we report here that PCAF inhibits cyclin/cdk2 activity by two different mechanisms: (i) by somehow affecting cyclin/cdk2 interaction and (ii) by acetylating K33 at the catalytic pocket of cdk2. These findings identify a previously unknown mechanism that regulates cdk2 activity. PMID- 19773424 TI - HRTBLDb: an informative data resource for hormone receptors target binding loci. AB - Three hormone receptors, the estrogen receptor (ER), the androgen receptor (AR) and glucocorticoid receptor (GR) play an important role in regulating the cellular differentiation tissue development of skin, bone, the brain and the endocrine system; therefore, there is a strong scientific need to identify and characterize hormone receptor transcriptional regulation. Given that the vast amount of regulatory data for hormone being produced by ChIP-based high throughput experiments is widely scattered in disparate, poorly cross-indexed data stores, a flexible platform for organizing and relating these data would provide significant value. We created a data management system called the Hormone Receptor Target Binding Loci, HRTBLDb (http://motif.bmi.ohio-state.edu/hrtbldb), to address this problem. This database contains hormone receptor binding regions (binding loci) from in vivo ChIP-based high-throughput experiments as well as in silico, computationally predicted, binding motifs and cis-regulatory modules for the co-occurring transcription factor binding motifs, which are within a binding locus. It also contains individual binding sites whose regulatory action has been verified by in vitro experiments. The current version contains 44,673 binding elements with 114 hormone response elements which are verified by in vitro experiments; 75 binding motifs which occur with a hormone response element and whose co-regulatory action is verified by in vitro experiments; 18,472 binding loci from in vivo experiments; and 26,012 computationally predicted binding motifs. PMID- 19773425 TI - An Alu-derived intronic splicing enhancer facilitates intronic processing and modulates aberrant splicing in ATM. AB - We have previously reported a natural GTAA deletion within an intronic splicing processing element (ISPE) of the ataxia telangiectasia mutated (ATM) gene that disrupts a non-canonical U1 snRNP interaction and activates the excision of the upstream portion of the intron. The resulting pre-mRNA splicing intermediate is then processed to a cryptic exon, whose aberrant inclusion in the final mRNA is responsible for ataxia telangiectasia. We show here that the last 40 bases of a downstream intronic antisense Alu repeat are required for the activation of the cryptic exon by the ISPE deletion. Evaluation of the pre-mRNA splicing intermediate by a hybrid minigene assay indicates that the identified intronic splicing enhancer represents a novel class of enhancers that facilitates processing of splicing intermediates possibly by recruiting U1 snRNP to defective donor sites. In the absence of this element, the splicing intermediate accumulates and is not further processed to generate the cryptic exon. Our results indicate that Alu-derived sequences can provide intronic splicing regulatory elements that facilitate pre-mRNA processing and potentially affect the severity of disease-causing splicing mutations. PMID- 19773426 TI - A trimeric DNA polymerase complex increases the native replication processivity. AB - DNA polymerases are essential enzymes in all domains of life for both DNA replication and repair. The primary DNA replication polymerase from Sulfolobus solfataricus (SsoDpo1) has been shown previously to provide the necessary polymerization speed and exonuclease activity to replicate the genome accurately. We find that this polymerase is able to physically associate with itself to form a trimer and that this complex is stabilized in the presence of DNA. Analytical gel filtration and electrophoretic mobility shift assays establish that initially a single DNA polymerase binds to DNA followed by the cooperative binding of two additional molecules of the polymerase at higher concentrations of the enzyme. Protein chemical crosslinking experiments show that these are specific polymerase polymerase interactions and not just separate binding events along DNA. Isothermal titration calorimetry and fluorescence anisotropy experiments corroborate these findings and show a stoichiometry where three polymerases are bound to a single DNA substrate. The trimeric polymerase complex significantly increases both the DNA synthesis rate and the processivity of SsoDpo1. Taken together, these results suggest the presence of a trimeric DNA polymerase complex that is able to synthesize long DNA strands more efficiently than the monomeric form. PMID- 19773427 TI - A universal description for the experimental behavior of salt-(in)dependent oligocation-induced DNA condensation. AB - We report a systematic study of the condensation of plasmid DNA by oligocations with variation of the charge, Z, from +3 to +31. The oligocations include a series of synthetic linear epsilon-oligo(l-lysines), (denoted epsilonKn, n = 3 10, 31; n is the number of lysines equal to the ligand charge) and branched alpha substituted homologues of epsilonK10: epsilonYK10, epsilonLK10 (Z = +10); epsilonRK10, epsilonYRK10 and epsilonLYRK10 (Z = +20). Data were obtained by light scattering, UV absorption monitored precipitation assay and isothermal titration calorimetry in a wide range concentrations of DNA and monovalent salt (KCl, C(KCl)). The dependence of EC(50) (ligand concentration at the midpoint of DNA condensation) on C(KCl) shows the existence of a salt-independent regime at low C(KCl) and a salt-dependent regime with a steep rise of EC(50) with increase of C(KCl). Increase of the ligand charge shifts the transition from the salt independent to salt-dependent regime to higher C(KCl). A novel and simple relationship describing the EC(50) dependence on DNA concentration, charge of the ligand and the salt-dependent dissociation constant of the ligand-DNA complex is derived. For the epsilon-oligolysines epsilonK3-epsilonK10, the experimental dependencies of EC(50) on C(KCl) and Z are well-described by an equation with a common set of parameters. Implications from our findings for understanding DNA condensation in chromatin are discussed. PMID- 19773429 TI - Metastamir: the field of metastasis-regulatory microRNA is spreading. AB - Despite advancements in knowledge from more than a century of metastasis research, the genetic programs and molecular mechanisms required for cancer metastasis are still incompletely understood. Genes that specifically regulate the process of metastasis are useful tools to elucidate molecular mechanisms and may become markers and/or targets for antimetastatic therapy. Recently, several noncoding regulatory RNA genes, microRNA (miRNA), were identified, which play roles in various steps of metastasis, some without obvious roles in tumorigenesis. Understanding how these metastasis-associated miRNA, which we term metastamir, are involved in metastasis will help identify possible biomarkers or targets for the most lethal attribute of cancer: metastasis. PMID- 19773430 TI - Preclinical profile of a potent gamma-secretase inhibitor targeting notch signaling with in vivo efficacy and pharmacodynamic properties. AB - Notch signaling is an area of great interest in oncology. RO4929097 is a potent and selective inhibitor of gamma-secretase, producing inhibitory activity of Notch signaling in tumor cells. The RO4929097 IC50 in cell-free and cellular assays is in the low nanomolar range with >100-fold selectivity with respect to 75 other proteins of various types (receptors, ion channels, and enzymes). RO4929097 inhibits Notch processing in tumor cells as measured by the reduction of intracellular Notch expression by Western blot. This leads to reduced expression of the Notch transcriptional target gene Hes1. RO4929097 does not block tumor cell proliferation or induce apoptosis but instead produces a less transformed, flattened, slower-growing phenotype. RO4929097 is active following oral dosing. Antitumor activity was shown in 7 of 8 xenografts tested on an intermittent or daily schedule in the absence of body weight loss or Notch related toxicities. Importantly, efficacy is maintained after dosing is terminated. Angiogenesis reverse transcription-PCR array data show reduced expression of several key angiogenic genes. In addition, comparative microarray analysis suggests tumor cell differentiation as an additional mode of action. These preclinical results support evaluation of RO4929097 in clinical studies using an intermittent dosing schedule. A multicenter phase I dose escalation study in oncology is under way. PMID- 19773431 TI - Identification of a small molecule inhibitor of the human DNA repair enzyme polynucleotide kinase/phosphatase. AB - Human polynucleotide kinase/phosphatase (hPNKP) is a 57.1-kDa enzyme that phosphorylates DNA 5'-termini and dephosphorylates DNA 3'-termini. hPNKP is involved in both single- and double-strand break repair, and cells depleted of hPNKP show a marked sensitivity to ionizing radiation. Therefore, small molecule inhibitors of hPNKP should potentially increase the sensitivity of human tumors to gamma-radiation. To identify small molecule inhibitors of hPNKP, we modified a novel fluorescence-based assay to measure the phosphatase activity of the protein, and screened a diverse library of over 200 polysubstituted piperidines. We identified five compounds that significantly inhibited hPNKP phosphatase activity. Further analysis revealed that one of these compounds, 2-(1 hydroxyundecyl)-1-(4-nitrophenylamino)-6-phenyl-6,7a-dihydro-1H-pyrrolo[3,4 b]pyridine-5,7(2H,4aH)-dione (A12B4C3), was the most effective, with an IC50 of 0.06 micromol/L. When tested for its specificity, A12B4C3 displayed no inhibition of two well-known eukaryotic protein phosphatases, calcineurin and protein phosphatase-1, or APTX, another human DNA 3'-phosphatase, and only limited inhibition of the related PNKP from Schizosaccharomyces pombe. At a nontoxic dose (1 micromol/L), A12B4C3 enhanced the radiosensitivity of human A549 lung carcinoma and MDA-MB-231 breast adenocarcinoma cells by a factor of two, which was almost identical to the increased sensitivity resulting from shRNA-mediated depletion of hPNKP. Importantly, A12B4C3 failed to increase the radiosensitivity of the hPNKP-depleted cells, implicating hPNKP as the principal cellular target of A12B4C3 responsible for increasing the response to radiation. A12B4C3 is thus a useful reagent for probing hPNKP cellular function and will serve as the lead compound for further development of PNKP-targeting drugs. PMID- 19773432 TI - Down-regulation of c-FLIP Enhances death of cancer cells by smac mimetic compound. AB - Smac mimetic compounds (SMC) are novel small molecules being developed for cancer therapy. The mechanism of SMC-induced sensitivity in cancer cells depends on autocrine release of tumor necrosis factor alpha (TNFalpha); however, potential mechanisms of resistance remain unknown. Here, we investigated the molecular profile and cytotoxic responsiveness of a diverse panel of 51 cancer cell lines to combinations of a dimeric SMC (AEG40730), death ligand TNFalpha, and tumor necrosis factor-related apoptosis-inducing ligand. Synergy was seen in combination with death receptor agonists in some cells, although single-agent activity was limited to a fewsensitive lines. Unexpectedly, the majority of cell lines resistant to combinations of SMC-AEG40730 and death ligands expressed caspase-8, FADD, RIP1, and ligand receptors necessary for apoptosis execution. Furthermore, TNFalpha-mediated ubiquitination of RIP1 was repressed by SMC AEG40730 treatment, leading to the formation of the proapoptosis complex II. However, in resistant cancer cells, SMC-AEG40730 repressed TNFalpha-mediated c jun-NH(2)-kinase activation and the levels of caspase-8 inhibitor c-FLIP were persistently elevated, in contrast to SMC-responsive cancer cells. Importantly, the silencing of c-FLIP restored SMC sensitivity in previously resistant cancer cells by allowing ligand-mediated activation of caspase-8 and caspase-3 to proceed. Together, these results provide mechanistic insight into the action of SMCs, demonstrating that the deciphering of the relevant molecular signature in cancer cells leads to the prediction of cancer cell responsiveness to SMC treatment. Furthermore, a majority of resistant cancer cells were sensitized to SMC-AEG40730 and TNFalpha by down-regulating c-FLIP, suggesting novel approaches in the use of SMCs and c-FLIP antagonists in treating cancer. PMID- 19773433 TI - Overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-{beta}-induced cell death through impairing up-regulation of the NADPH oxidase NOX4. AB - Transforming growth factor-beta (TGF-beta) induces apoptosis in hepatocytes, being considered a liver tumor suppressor. However, many human hepatocellular carcinoma (HCC) cells escape from its proapoptotic effects, gaining response to this cytokine in terms of malignancy. We have recently reported that the apoptosis induced by TGF-beta in hepatocytes requires up-regulation of the NADPH oxidase NOX4, which mediates reactive oxygen species (ROS) production. TGF-beta induced NOX4 expression is inhibited by antiapoptotic signals, such as the phosphatydilinositol-3-phosphate kinase or the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathways. The aim of the present work was to analyze whether resistance to TGF-beta-induced apoptosis in HCC cells is related to the impairment of NOX4 up-regulation due to overactivation of survival signals. Results indicate that inhibition of the MAPK/ERK kinase (MEK)/ERK pathway in HepG2 cells, which are refractory to the proapoptotic effects of TGF-beta, sensitizes them to cell death through a mitochondrial-dependent mechanism, coincident with increased levels of BIM and BMF, decreased levels of BCL-XL and MCL1, and BAX/BAK activation. Regulation of BMF, BCL-XL, and MCL1 occurs at the mRNA level, whereas BIM regulation occurs post-transcriptionally. ROS production and glutathione depletion are only observed in cells treated with TGF-beta and PD98059, which correlates with NOX4 up-regulation. Targeting knockdown of NOX4 impairs ROS increase and all the mitochondrial-dependent apoptotic features by a mechanism that is upstream from the regulation of BIM, BMF, BCL-XL, and MCL1 levels. In conclusion, overactivation of the MEK/ERK pathway in liver tumor cells confers resistance to TGF-beta-induced cell death through impairing NOX4 up-regulation, which is required for an efficient mitochondrial-dependent apoptosis. PMID- 19773434 TI - Blockade of a chemokine, CCL2, reduces chronic colitis-associated carcinogenesis in mice. AB - Accumulating evidence indicates the crucial contribution of chronic inflammation to various types of carcinogenesis, including colon carcinoma associated with ulcerative colitis and asbestosis-induced malignant mesothelioma. Ulcerative colitis-associated colon carcinogenesis can be recapitulated in mice by azoxymethane administration followed by repetitive dextran sulfate sodium ingestion. In the course of this carcinogenesis process, the expression of a macrophage-tropic chemokine, CCL2, was enhanced together with intracolonic massive infiltration of macrophages, which were a major source of cyclooxygenase (COX)-2, a crucial mediator of colon carcinogenesis. Mice deficient in CCL2 specific receptor, CCR2, exhibited less macrophage infiltration and lower tumor numbers with attenuated COX-2 expression. Moreover, CCL2 antagonists decreased intracolonic macrophage infiltration and COX-2 expression, attenuated neovascularization, and eventually reduced the numbers and size of colon tumors, even when given after multiple colon tumors have developed. These observations identify CCL2 as a crucial mediator of the initiation and progression of chronic colitis-associated colon carcinogenesis and suggest that targeting CCL2 may be useful in treating colon cancers, particularly those associated with chronic inflammation. PMID- 19773435 TI - Rearrangements and amplification of IER3 (IEX-1) represent a novel and recurrent molecular abnormality in myelodysplastic syndromes. AB - IER3 (formerly IEX-1) encodes a 27-kDa glycoprotein that regulates death receptor induced apoptosis, interacts with NF-kappaB pathways, and increases expression rapidly in response to cellular stresses such as irradiation. Animal models, gene expression microarray experiments, and functional studies in cell lines have suggested a potential role for IER3 in oncogenesis, but, to date, no abnormalities of IER3 at the DNA level have been reported in patients with neoplasia. Here, we describe breakpoint cloning of a t(6;9)(p21;q34) translocation from a patient with a myelodysplastic syndrome (MDS), facilitated by conversion technology and array-based comparative genomic hybridization, which revealed a rearrangement translocating the IER3 coding region away from critical flanking/regulatory elements and to a transcript-poor chromosomal region, markedly decreasing expression. Using split-signal and locus-specific fluorescence in situ hybridization (FISH) probes, we analyzed 204 patients with diverse hematological malignancies accompanied by clonal chromosome 6p21 abnormalities, and found 8 additional patients with MDS with IER3 rearrangements (translocations or amplification). Although FISH studies on 157 additional samples from patients with MDS and a normal-karyotype were unrevealing, and sequencing the IER3 coding and proximal promoter regions of 74 MDS patients disclosed no point mutations, reverse transcription-PCR results suggested that dysregulated expression of IER3 is common in MDS (61% >4-fold increase or decrease in expression with decreased expression primarily in early MDS and increased expression primarily in later MDS progressing toward leukemia), consistent with findings in previous microarray experiments. These data support involvement of IER3 in the pathobiology of MDS. PMID- 19773436 TI - [18F]fluoromethyl-[1,2-2H4]-choline: a novel radiotracer for imaging choline metabolism in tumors by positron emission tomography. AB - Current radiotracers for positron emission tomography imaging of choline metabolism have poor systemic metabolic stability in vivo. We describe a novel radiotracer, [(18)F]fluoromethyl-[1,2-(2)H(4)]-choline (D4-FCH), that employs deuterium isotope effect to improve metabolic stability. D4-FCH proved more resistant to oxidation than its nondeuterated analogue, [(18)F]fluoromethylcholine, in plasma, kidneys, liver, and tumor, while retaining phosphorylation potential. Tumor radiotracer levels, a determinant of sensitivity in imaging studies, were improved by deuterium substitution; tumor uptake values expressed as percent injected dose per voxel at 60 min were 7.43 +/- 0.47 and 5.50 +/- 0.49 for D4-FCH and [(18)F]fluoromethylcholine, respectively (P = 0.04). D4-FCH was also found to be a useful response biomarker. Treatment with the mitogenic extracellular kinase inhibitor PD0325901 resulted in a reduction in tumor radiotracer uptake that occurred in parallel with reductions in choline kinase A expression. In conclusion, D4-FCH is a very promising metabolically stable radiotracer for imaging choline metabolism in tumors. PMID- 19773437 TI - Expression of IFN-beta enhances both efficacy and safety of oncolytic vesicular stomatitis virus for therapy of mesothelioma. AB - Our preclinical and clinical trials using a replication-defective adenoviral vector expressing IFN-beta have shown promising results for the treatment of malignant mesothelioma. Based on the hypotheses that a replication-competent vesicular stomatitis virus (VSV) oncolytic vector would transduce more tumor cells in vivo, that coexpression of the immunostimulatory IFN-beta gene would enhance the immune-based effector mechanisms associated both with regression of mesotheliomas and with VSV-mediated virotherapy, and that virus-derived IFN-beta would add further safety to the VSV platform, we tested the use of IFN-beta as a therapeutic transgene expressed from VSV as a novel treatment for mesothelioma. VSV-IFN-beta showed significant therapy against AB12 murine mesotheliomas in the context of both local and locoregional viral delivery. Biologically active IFN beta expressed from VSV added significantly to therapy compared with VSV alone, dependent in part on host CD8+ T-cell responses. Immune monitoring suggested that these antitumor T-cell responses may be due to a generalized T-cell activation rather than the priming of tumor antigen-specific T-cell responses. Finally, IFN beta also added considerable extra safety to the virus by providing protection from off-target viral replication in nontumor tissues and protected severe combined immunodeficient mice from developing lethal neurotoxicity. The enhanced therapeutic index provided by the addition of IFN-beta to VSV therefore provides a powerful justification for the development of this virus for future clinical trials. PMID- 19773438 TI - MYC activity mitigates response to rapamycin in prostate cancer through eukaryotic initiation factor 4E-binding protein 1-mediated inhibition of autophagy. AB - Loss of PTEN and activation of phosphoinositide 3-kinase are commonly observed in advanced prostate cancer. Inhibition of mammalian target of rapamycin (mTOR), a downstream target of phosphoinositide 3-kinase signaling, results in cell cycle arrest and apoptosis in multiple in vitro and in vivo models of prostate cancer. However, single-agent use of mTOR inhibition has limited clinical success, and the identification of molecular events mitigating tumor response to mTOR inhibition remains a critical question. Here, using genetically engineered human prostate epithelial cells (PrEC), we show that MYC, a frequent target of genetic gain in prostate cancers, abrogates sensitivity to rapamycin by decreasing rapamycin-induced cytostasis and autophagy. Analysis of MYC and the mTOR pathway in human prostate tumors and PrEC showed selective increased expression of eukaryotic initiation factor 4E-binding protein 1 (4EBP1) with gain in MYC copy number or forced MYC expression, respectively. We have also found that MYC binds to regulatory regions of the 4EBP1 gene. Suppression of 4EBP1 expression resulted in resensitization of MYC-expressing PrEC to rapamycin and increased autophagy. Taken together, our findings suggest that MYC expression abrogates sensitivity to rapamycin through increased expression of 4EBP1 and reduced autophagy. PMID- 19773439 TI - c-Myc and eIF4F constitute a feedforward loop that regulates cell growth: implications for anticancer therapy. AB - The Myc/Max/Mad family of transcription factors and the eukaryotic initiation factor 4F (4F) complex play fundamental roles in regulating cell growth, proliferation, differentiation, and oncogenic transformation. Recent findings indicate that the role of Myc during cell growth and proliferation is linked to an increase in eIF4F activity in a feedforward relationship, providing a possible molecular mechanism of cell transformation by Myc. Developing therapeutics to inhibit eIF4F and/or Myc could be a potential treatment for a wide range of human cancers. PMID- 19773440 TI - Adipocytes impair leukemia treatment in mice. AB - Obesity is associated with increased cancer incidence and mortality. We have previously found that obesity in children is associated with a 50% increased recurrence of acute lymphoblastic leukemia (ALL) in high-risk patients. We have therefore developed novel in vivo and in vitro preclinical models to study the mechanism(s) of this association. Obesity increased relapse after monotherapy with vincristine (P = 0.03) in obese mice injected with syngeneic ALL cells. This occurred although the drug was dosed proportionally to body weight, equalizing blood and tissue drug levels. In coculture, 3T3-L1 adipocytes significantly impaired the antileukemia efficacy of vincristine, as well as three other chemotherapies (P < 0.05). Interestingly, this protection was independent of cell cell contact, and it extended to human leukemia cell lines as well. Adipocytes prevented chemotherapy-induced apoptosis, and this was associated with increased expression of the two prosurvival signals Bcl-2 and Pim-2. These findings highlight the role of the adipocyte in fostering leukemia chemotherapy resistance, and may help explain the increased leukemia relapse rate in obese children and adults. Given the growing prevalence of obesity worldwide, these effects are likely to have increasing importance to cancer treatment. PMID- 19773441 TI - MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. AB - MicroRNA-34a (miR-34a) is a transcriptional target of p53 that is down-regulated in some cancer cell lines. We studied the expression, targets, and functional effects of miR-34a in brain tumor cells and human gliomas. Transfection of miR 34a down-regulated c-Met in human glioma and medulloblastoma cells and Notch-1, Notch-2, and CDK6 protein expressions in glioma cells. miR-34a expression inhibited c-Met reporter activities in glioma and medulloblastoma cells and Notch 1 and Notch-2 3'-untranslated region reporter activities in glioma cells and stem cells. Analysis of human specimens showed that miR-34a expression is down regulated in glioblastoma tissues as compared with normal brain and in mutant p53 gliomas as compared with wild-type p53 gliomas. miR-34a levels in human gliomas inversely correlated to c-Met levels measured in the same tumors. Transient transfection of miR-34a into glioma and medulloblastoma cell lines strongly inhibited cell proliferation, cell cycle progression, cell survival, and cell invasion, but transfection of miR-34a into human astrocytes did not affect cell survival and cell cycle status. Forced expression of c-Met or Notch-1/Notch-2 transcripts lacking the 3'-untranslated region sequences partially reversed the effects of miR-34a on cell cycle arrest and cell death in glioma cells and stem cells, respectively. Also, transient expression of miR-34a in glioblastoma cells strongly inhibited in vivo glioma xenograft growth. Together, these findings represent the first comprehensive analysis of the role of miR-34a in gliomas. They show that miR-34a suppresses brain tumor growth by targeting c-Met and Notch. The results also suggest that miR-34a could serve as a potential therapeutic agent for brain tumors. PMID- 19773442 TI - Nitrosative stress-induced s-glutathionylation of protein disulfide isomerase leads to activation of the unfolded protein response. AB - The rapid proliferation of cancer cells mandates a high protein turnover. The endoplasmic reticulum (ER) is intimately involved in protein processing. An accumulation of unfolded or misfolded proteins in the ER leads to a cascade of transcriptional and translational events collectively called the unfolded protein response (UPR). Protein disulfide isomerase (PDI) is one of the most abundant ER proteins and maintains a sentinel function in organizing accurate protein folding. Treatment of cells with O(2)-[2,4-dinitro-5-(N-methyl-N-4 carboxyphenylamino)phenyl]1-(N,N-dimethylamino)diazen-1-ium-1,2-diolate (PABA/NO) resulted in a dose-dependent increase in intracellular nitric oxide that caused S glutathionylation of various proteins. Within 4 h, PABA/NO activated the UPR and led to translational attenuation as measured by the phosphorylation and activation of the ER transmembrane kinase, pancreatic ER kinase, and its downstream effector eukaryotic initiation factor 2 in human leukemia (HL60) and ovarian cancer cells (SKOV3). Cleavage of the transcription factor X-box protein 1 and transcriptional activation of the ER resident proteins BiP, PDI, GRP94, and ERO1 (5- to 10-fold induction) also occurred. Immunoprecipitation of PDI showed that whereas nitrosylation was undetectable, PABA/NO treatment caused S glutathionylation of PDI. Mass spectroscopy analysis showed that single cysteine residues within each of the catalytic sites of PDI had a mass increase [+305.3 Da] consistent with S-glutathionylation. Circular dichroism confirmed that S glutathionylation of PDI results in alterations in the alpha-helix content of PDI and is concurrent with inhibition of its isomerase activity. Thus, it appears that S-glutathionylation of PDI is an upstream signaling event in the UPR and may be linked with the cytotoxic potential of PABA/NO. PMID- 19773443 TI - Molecular distinctions between stasis and telomere attrition senescence barriers shown by long-term culture of normal human mammary epithelial cells. AB - Normal human epithelial cells in culture have generally shown a limited proliferative potential of approximately 10 to 40 population doublings before encountering a stress-associated senescence barrier (stasis) associated with elevated levels of cyclin-dependent kinase inhibitors p16 and/or p21. We now show that simple changes in medium composition can expand the proliferative potential of human mammary epithelial cells (HMEC) initiated as primary cultures to 50 to 60 population doublings followed by p16-positive, senescence-associated beta galactosidase-positive stasis. We compared the properties of growing and senescent pre-stasis HMEC with growing and senescent post-selection HMEC, that is, cells grown in a serum-free medium that overcame stasis via silencing of p16 expression and that display senescence associated with telomere dysfunction. Cultured pre-stasis populations contained cells expressing markers associated with luminal and myoepithelial HMEC lineages in vivo in contrast to the basal like phenotype of the post-selection HMEC. Gene transcript and protein expression, DNA damage-associated markers, mean telomere restriction fragment length, and genomic stability differed significantly between HMEC populations at the stasis versus telomere dysfunction senescence barriers. Senescent isogenic fibroblasts showed greater similarity to HMEC at stasis than at telomere dysfunction, although their gene transcript profile was distinct from HMEC at both senescence barriers. These studies support our model of the senescence barriers encountered by cultured HMEC in which the first barrier, stasis, is retinoblastoma-mediated and independent of telomere length, whereas a second barrier (agonescence or crisis) results from telomere attrition leading to telomere dysfunction. Additionally, the ability to maintain long-term growth of genomically stable multilineage pre-stasis HMEC populations can greatly enhance experimentation with normal HMEC. PMID- 19773444 TI - Identification of candidate biomarkers of therapeutic response to docetaxel by proteomic profiling. AB - Docetaxel chemotherapy improves symptoms and survival in men with metastatic hormone-refractory prostate cancer (HRPC). However, approximately 50% of patients do not respond to Docetaxel and are exposed to significant toxicity without direct benefit. This study aimed to identify novel therapeutic targets and predictive biomarkers of Docetaxel resistance in HRPC. We used iTRAQ-mass spectrometry analysis to identify proteins associated with the development of Docetaxel resistance using Docetaxel-sensitive PC3 cells and Docetaxel-resistant PC3-Rx cells developed by Docetaxel dose escalation. Functional validation experiments were performed using recombinant protein treatment and siRNA knockdown experiments. Serum/plasma levels of the targets in patient samples were measured by ELISA. The IC(50) for Docetaxel in the PC3-Rx cells was 13-fold greater than the parent PC-3 cell line (P = 0.004). Protein profiling identified MIC-1 and AGR2 as respectively up-regulated and down-regulated in Docetaxel resistant cells. PC-3 cells treated with recombinant MIC-1 also became resistant to Docetaxel (P = 0.03). Conversely, treating PC3-Rx cells with MIC-1 siRNA restored sensitivity to Docetaxel (P = 0.02). Knockdown of AGR2 expression in PC3 cells resulted in Docetaxel resistance (P = 0.007). Furthermore, increased serum/plasma levels of MIC-1 after cycle one of chemotherapy were associated with progression of the cancer (P = 0.006) and shorter survival after treatment (P = 0.002). These results suggest that both AGR2 and MIC-1 play a role in Docetaxel resistance in HRPC. In addition, an increase in serum/plasma MIC-1 level after cycle one of Docetaxel may be an indication to abandon further treatment. Further investigation of MIC-1 as a biomarker and therapeutic target for Docetaxel resistance in HRPC is warranted. PMID- 19773445 TI - Acting locally and globally: Myc's ever-expanding roles on chromatin. AB - Myc regulates key cellular processes including cell cycle, differentiation, and apoptosis. It has long been thought to direct these functions by acting solely as a classic transcription factor regulating expression of a small number of key target genes through discrete chromatin events in their promoters. A recent wave of genomics studies together directly challenge the narrowness of this model. For example, Myc binds to tens of thousands of sites in the human genome. It also regulates histone acetylation at and transcription of a remarkable number of genes, far beyond that expected of a classical transcription factor. The influence of Myc on chromatin also surprisingly extends to both genic and expansive intergenic regions. These studies support an evolving model in which Myc activity on chromatin is far more complex than previously imagined. The ability of Myc to act both locally and globally on chromatin may be responsible for its wide-ranging effects on the biology of stem and tumor cells. PMID- 19773446 TI - Epidermal growth factor receptor variant III-induced glioma invasion is mediated through myristoylated alanine-rich protein kinase C substrate overexpression. AB - Glioblastoma multiforme (GBM) is the most common and most malignant adult brain tumor. A characteristic of GBM is their highly invasive nature, making complete surgical resection impossible. The most common gain-of-function alteration in GBM is amplification, overexpression, and mutations of the epidermal growth factor receptor (EGFR). The constitutively activated mutant EGFR variant III (EGFRvIII), found in approximately 20% of GBM, confers proliferative and invasive advantage. The signaling cascades downstream of aberrant EGFR activation contributing to the invasive phenotype are not completely understood. Here, we show myristoylated alanine-rich protein kinase C substrate (MARCKS), previously implicated in cell adhesion and motility, contributes to EGFR-mediated invasion of human GBM cells. EGFRvIII-expressing or EGF-stimulated human GBM cells increased expression, phosphorylation, and cytosolic translocation of MARCKS in a protein kinase C alpha-dependent manner. Down-regulation of MARCKS expression with small interfering RNA in GBM cells expressing EGFRvIII led to decreased cell adhesion, spreading, and invasion. Elucidation of mechanisms that promote EGFRvIII-mediated tumorigenesis in GBM, such as MARCKS, provides additional understanding and potential biological targets against this currently terminal human cancer. PMID- 19773447 TI - Pulmonary vascular destabilization in the premetastatic phase facilitates lung metastasis. AB - Before metastasis, certain organs have already been influenced by primary tumors. However, the exact alterations and regulatory mechanisms of the premetastatic organs remain poorly understood. Here, we report that, in the premetastatic stage, angiopoietin 2 (Angpt2), matrix metalloproteinase (MMP) 3, and MMP10 are up-regulated in the lung by primary B16/F10 tumor, which leads to the increased permeability of pulmonary vasculatures and extravasation of circulating tumor cells. Subsequent studies show that Angpt2, MMP3, and MMP10 have a synergistic effect on disrupting vascular integrity in both in vitro and in vivo models. Lentivirus-based in vivo RNA interference of Angpt2, MMP3, and MMP10 attenuates the pulmonary vascular permeability and suppresses the infiltration of myeloid cells in the premetastatic lung. Moreover, knocking down these factors significantly inhibits the spontaneous lung metastasis in the model by orthotopic implantation of MDA-MB-231-Luc-D3H1 cells in nude mice. Further investigations reveal that the malignancy of tumor cells is positively correlated with their capabilities to induce the expression of Angpt2, MMP3, and MMP10. Luciferase reporter assay and chromatin immunoprecipitation assay also suggest that transforming growth factor-beta1 and tumor necrosis factor-alpha signaling are involved in the regulation of these premetastatic factors. Our study shows that pulmonary vascular destabilization in the premetastatic phase promotes the extravasation of tumor cells and facilitates lung metastasis, which may provide potential targets for clinical prevention of metastasis. PMID- 19773448 TI - TrkBT1 induces liver metastasis of pancreatic cancer cells by sequestering Rho GDP dissociation inhibitor and promoting RhoA activation. AB - Many genetic and molecular alterations, such as K-ras mutation and NF-kappaB activation, have been identified in pancreatic cancer. However, the mechanisms by which pancreatic cancer metastasizes still remain to be determined. Although we previously showed that the tropomyosin-related kinase B (TrkB) was significantly correlated with the development of liver metastasis, its function in pancreatic cancer metastasis remained unresolved. In the present study, we showed that overexpressed TrkB is an alternatively spliced transcript variant of TrkB (TrkBT1) with a unique COOH-terminal 12-amino acid sequence and is mainly localized in the cytoplasm. Our results showed that overexpression of Flag-tagged TrkBT1 but not a Flag-tagged TrkBT1 COOH-terminal deletion mutant (Flag TrkBT1DeltaC) in nonmetastatic pancreatic cancer cells enhanced cell proliferation, promoted formation of colonies in soft agar, stimulated tumor cell invasion, and induced liver metastasis in an orthotopic xenograft mouse model of pancreatic cancer. TrkBT1 interacted with Rho GDP dissociation inhibitor (GDI) in vivo, but Flag-TrkBT1DeltaC did not. Furthermore, overexpression of Flag-TrkBT1 and knockdown of RhoGDI expression by RhoGDI short hairpin RNAs promoted RhoA activation, but Flag-TrkBT1DeltaC overexpression did not. Therefore, our results showed that TrkBT1 overexpression induces liver metastasis of pancreatic cancer and uncovered a unique signaling mechanism by which TrkBT1 sequesters GDI and activates RhoA signaling. PMID- 19773449 TI - Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer. AB - Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array comparative genomic hybridization (array CGH), gene expression arrays, and fluorescence in situ hybridization (FISH). Bycluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an overrepresentation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH, we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome 21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer. PMID- 19773450 TI - A small molecule polyamine oxidase inhibitor blocks androgen-induced oxidative stress and delays prostate cancer progression in the transgenic adenocarcinoma of the mouse prostate model. AB - High levels of reactive oxygen species (ROS) present in human prostate epithelia are an important etiologic factor in prostate cancer (CaP) occurrence, recurrence, and progression. Androgen induces ROS production in the prostate by a yet unknown mechanism. Here, to the best of our knowledge, we report for the first time that androgen induces an overexpression of spermidine/spermine N1 acetyltransferase, the rate-limiting enzyme in the polyamine oxidation pathway. As prostatic epithelia produce a large excess of polyamines, the androgen-induced polyamine oxidation that produces H2O2 could be a major reason for the high ROS levels in the prostate epithelia. A small molecule polyamine oxidase inhibitor N,N'-butanedienyl butanediamine (MDL 72,527 or CPC-200) effectively blocks androgen-induced ROS production in human CaP cells, as well as significantly delays CaP progression and death in animals developing spontaneous CaP. These data show that polyamine oxidation is not only a major pathway for ROS production in prostate, but inhibiting this pathway also successfully delays CaP progression. PMID- 19773451 TI - Role of inflammation gene polymorphisms on pain severity in lung cancer patients. AB - Many of the same inflammatory factors that promote tumor growth are also hypothesized to function as pain modulators. There is substantial interindividual variation in pain severity in cancer patients. Therefore, we evaluated 59 single nucleotide polymorphisms in 37 inflammation genes in newly diagnosed non-Hispanic Caucasian lung cancer patients (n = 667) and assessed their association with pain severity. Patients rated their pain "during the past week" on an 11-point numeric scale (0 = "no pain" and 10 = "pain as bad as you can imagine") at presentation before initiating cancer therapy. Reported analgesic use was abstracted from charts and converted to morphine equivalent daily dose. Results showed that 16% of the patients reported severe pain (score > or = 7). Advanced stage of disease [odds ratio (OR), 2.34; 95% confidence interval (95% CI), 1.50-3.65; P = 0.001], age < or = 50 years (OR, 2.10; 95% CI, 1.32-3.30; P = 0.002), reports of depressed mood (OR, 3.68; 95% CI, 1.96-6.93; P = 0.001), fatigue (OR, 3.72; 95% CI, 2.36-5.87; P = 0.001), and morphine equivalent daily dose (OR, 1.02; 95% CI, 1.01-1.03) were significantly correlated with severe pain. Controlling for these nongenetic covariates, we found that patients with CC genotypes for PTGS2 exon10+837T>C (rs5275) were at lower risk for severe pain (OR, 0.33; 95% CI, 0.11 0.97) and an additive model for TNFalpha -308GA (rs1800629; OR, 1.67; 95% CI, 1.08-2.58) and NFKBIA Ex6+50C>T (rs8904) was predictive of severe pain (OR, 0.64; 95% CI, 0.43-0.93). In a multigene analysis, we found a gene-dose effect, with each protective genotype reducing the risk for severe pain by as much as 38%. This study suggests the importance of inflammation gene polymorphisms in modulating pain severity. Additional studies are needed to validate our findings. PMID- 19773452 TI - A need for true GSTM1 and GSTT1 genotyping. PMID- 19773454 TI - Handing over the reins. PMID- 19773453 TI - Polymorphisms in telomere maintenance genes and risk of lung cancer. AB - This study was conducted to comprehensively evaluate the associations between polymorphisms in telomere maintenance genes (TERT, TRF1, TNKS1, TRF2, RAP1, and POT1) and lung cancer risk. We captured 35 polymorphisms in the genes and determined their frequencies in 27 healthy Koreans. Ten haplotype-tagging polymorphisms were examined in a case-control study that consisted of 720 lung cancer patients and 720 healthy controls. The TERT rs2735940 g.C > T and rs2736098 g.G > A, and TNKS1 rs6985140 g.A > G were significantly associated with the risk of lung cancer. In the haplotype analysis, the TERT rs2735940T/rs2736098A haplotype (ht4) was associated with a significantly increased risk of lung cancer compared with the rs2735940C/rs2736098G haplotype (adjusted odds ratio, 1.26; 95% confidence interval, 1.07-1.50; P = 0.008). When the TERT ht4 and TNKS1 rs6985140G as risk alleles, the risk of lung cancer increased in a dose-dependent manner as the number of risk alleles increased (P(trend) < 0.001). Subjects with two to four risk alleles were at a significantly increased risk of lung cancer (adjusted odds ratio, 1.67; 95% confidence interval, 1.23-2.27; P = 0.001) compared with subjects with zero risk allele. These findings suggest that genetic variants in the TERT and TNKS1 genes contribute to genetic susceptibility to lung cancer. PMID- 19773455 TI - HPV vaccine strategies: the cost of HPV and the choice of vaccine. PMID- 19773456 TI - HIV epidemics among men who have sex with men in central and eastern Europe. PMID- 19773457 TI - Concurrent sexual partnerships and racial disparities in HIV infection among men who have sex with men. AB - OBJECTIVES: To measure the level of sexual partner concurrency and assess its potential role in explaining disparities in HIV prevalence by race/ethnicity among men who have sex with men (MSM). METHODS: A cross-sectional, community based survey of MSM in San Francisco was conducted in 2008 using time-location sampling. Four different measures of sexual partner concurrency were assessed and compared across race/ethnicity groups: overlap in time with the most recent sexual partners, knowledge of the most recent sexual partner having other partners, any overlap with up to the last five partners and complete overlap with up to the last five partners. RESULTS: A total of 521 MSM was recruited; 10% self described their race/ethnicity as black, 62% as white, 25% as Latino and 9% as Asian (not mutually exclusive). Black MSM had fewer sexual partners overall, yet had three times the odds that all their partnerships were concurrent compared with non-black MSM (39% vs 17%, respectively, p = 0.034). None of the other measures of concurrency showed racial/ethnic differences. MSM whose partnerships were completely concurrent had a higher number of sexual episodes and unprotected sexual episodes per partnership compared with those whose partners were not completely concurrent. CONCLUSIONS: Findings support the hypothesis that the sexual networks of black MSM rather than individual behaviours account for their higher prevalence of HIV compared with non-black MSM. There remains the need specifically to validate different concurrency measures in larger samples and directly assess them as risk factors for acquiring HIV infection. PMID- 19773458 TI - Is phosphodiesterase type 5 inhibitor use associated with condom breakage? AB - We tested the hypothesis that phosphodiesterase type 5 inhibitor (PDE5i) use would be associated with increased likelihood of condom breakage using an event specific analysis. A convenience sample of 440 men completed an internet-based questionnaire that assessed variables pertaining to the last time they used condoms for penile-vaginal intercourse (PVI). A bivariate (screening) analysis was performed to identify covariates for a multivariate analysis using logistic regression. Altogether, 5.9% of the men reported breakage and 9.5% reported PDE5i use during the last time a condom was used for PVI. Among men who had used PDE5i during the last condom-protected occasion of PVI, 11.9% reported breakage compared with 5.3% of those not reporting PDE5i use. Adjusting for men's age, ethnic minority status, marital status, reported duration of PVI and alcohol use at last PVI, those using PDE5i were about four times more likely to also report condom breakage (AOR 4.02; 95% CI 1.20 to 13.48; p = 0.04). Of note, duration of PVI was independently associated with breakage (AOR 1.36; CI 1.02 to 1.83; p = 0.04). Findings suggest that PDE5i use may potentially be associated with increased odds of condom breakage among some men. PMID- 19773459 TI - Pathological evidence of vacuolar myelinopathy in a child following vigabatrin administration. AB - Vigabatrin, a gamma-aminobutyric acid (GABA) aminotransferase- inhibiting drug used for seizure control, has been associated with white matter vacuolation and intramyelinic edema in animal studies. Similar pathological lesions have never been described in the central nervous system of human participants treated with the drug. Described here is a child with quadriparetic cerebral palsy secondary to hypoxic-ischemic brain injury following premature birth, who received vigabatrin for the treatment of infantile spasms at 9 months of age. A severe deterioration of neurologic function immediately followed the initiation of vigabatrin, and the child died 3 weeks later. Neuropathological examination revealed white matter vacuolation and intramyelinic edema. This represents the first reported case of vigabatrin-induced intramyelinic edema in humans. It validates the concerns regarding vigabatrin safety in infants and individuals with preexisting abnormalities of myelin. PMID- 19773460 TI - Psychiatric comorbidity in pediatric patients with demyelinating disorders. AB - Little is known about psychiatric aspects of pediatric demyelinating conditions. A total of 23 youths (6-17 years) with demyelinating conditions underwent semistructured psychiatric interviews using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version. Adolescents and parents completed the Child Symptom Inventory-4 and the Youth's Inventory-4. Fears and conceptions of their neurological problems were elicited. In all, 48% (n = 11) met criteria for current psychiatric diagnoses, including 27% (n = 3) with depressive disorders and 64% (n = 7) with anxiety disorders. Fears and conceptions of the illness were severe and diverse. Depressive and anxiety disorders are common in pediatric demyelinating disease. Clinicians should therefore screen for psychiatric comorbidity symptoms as part of the routine evaluation of such patients. PMID- 19773461 TI - Fever plus mitochondrial disease could be risk factors for autistic regression. AB - Autistic spectrum disorders encompass etiologically heterogeneous persons, with many genetic causes. A subgroup of these individuals has mitochondrial disease. Because a variety of metabolic disorders, including mitochondrial disease show regression with fever, a retrospective chart review was performed and identified 28 patients who met diagnostic criteria for autistic spectrum disorders and mitochondrial disease. Autistic regression occurred in 60.7% (17 of 28), a statistically significant increase over the general autistic spectrum disorder population (P < .0001). Of the 17 individuals with autistic regression, 70.6% (12 of 17) regressed with fever and 29.4% (5 of 17) regressed without identifiable linkage to fever or vaccinations. None showed regression with vaccination unless a febrile response was present. Although the study is small, a subgroup of patients with mitochondrial disease may be at risk of autistic regression with fever. Although recommended vaccinations schedules are appropriate in mitochondrial disease, fever management appears important for decreasing regression risk. PMID- 19773462 TI - Congenital depression of the skull in neonate: a case of successful conservative management. AB - Congenital depression of the fetal skull unassociated with trauma is a rare event. In general, larger and deeper depressions are treated more aggressively either by neurosurgical correction or suction elevation with a breast pump. A case of right parietal skull depression noticed at birth in a term neonate born through cesarean section is reported here. Computed tomography scan revealed a bony depression without a fracture. The baby was managed conservatively, and the depression resolved completely at 6 months of age. This case highlights the potential role of spontaneous resolution in simple congenital skull depression. PMID- 19773463 TI - Cerebellum can be a possible generator of progressive myoclonus. AB - A 19-month-old girl presented with progressive myoclonic jerking of both proximal lower extremities. On her brain magnetic resonance imaging (MRI), the authors found an ill-defined mass involving cerebellar vermis and the right middle cerebellar peduncle. ( 11)C-methionine positron emission tomography (PET) showed no abnormalities, but (18)F-fluorodeoxyglucose ((18)F-FDG) PET revealed a well defined hypermetabolic focus. Depth electrodes were inserted deep into the mass, which recorded focal slow waves associated with the clinical myoclonus. Following the removal of the tumor, the myoclonus was completely resolved with no neurological deficit. Here, the authors present a case showing progressive myoclonus associated with a cerebellar ganglioglioma with the electrophysiological data, which provides strong supportive evidence that the cerebellum can be a myoclonus generator. PMID- 19773479 TI - At last: some insight. PMID- 19773480 TI - A blast from the present meets the MAST from the past: should the pneumatic anti shock garment ever be used? PMID- 19773481 TI - The use of atropine in a nerve agent response with specific reference to children: are current guidelines too cautious? AB - This review examines the potential use of nerve agents by a terrorist organisation against a civilian population, which has become an increasingly apparent threat in the UK. Present guidelines for the use of atropine, particularly in children, following such an event are unclear. No precise agreement exists on the most appropriate dose of atropine, or the frequency with which it should be administered. This uncertainty leaves children vulnerable as potentially life-saving treatment may be crucially delayed. Guidelines must be standardised to allow rapid antidotal delivery and maximise the potential for survivors. This review examines the issues currently surrounding the use of atropine in children following a nerve agent attack and propose strategies for treating exposed children. PMID- 19773482 TI - Routine pain scoring does not improve analgesia provision for children in the emergency department. AB - BACKGROUND: Scoring pain should lead to providing better analgesia for children attending the emergency department (ED). Our ED found that it offered analgesia to only 75% of children with painful injuries-36% of them receiving opiates, while scoring pain in 74%. This report describes what happened when we tried to ensure every child had their pain scored in an effort to improve analgesia provision. METHODS: We ensured mandatory pain scoring at triage during the introduction of our computerised notes system, backing this up with extra training of new staff and increased publicity of pain scoring tools. A retrospective audit was conducted after the intervention looking for completion of a pain score, provision of and type of analgesia. The study included children with long bone fractures or partial or full-thickness burns attending the ED. RESULTS: Following the intervention, we found that of 163 children, 97% had their pain scored on a zero-to-10 scale but only 66% received analgesia and only 10% were given opiates. CONCLUSIONS: The intervention was effective at achieving nearly universal early assessment and documentation of pain. This did not translate to an improvement in analgesic provision. Other means of changing behaviour need to be studied, possibly using the computerised record again to obligate analgesia provision. PMID- 19773484 TI - A simple intervention improves the recording of vital signs in children presenting to the emergency department. AB - OBJECTIVES: Vital signs are often not documented in paediatric patients at triage. This study was conducted to find out whether the use of a small, laminated aide memoire and a short teaching session might improve this situation. METHODS: A preliminary audit of the measurement of vital signs in 106 children aged less than 6 years was carried out in a district general hospital emergency department (ED). A small card illustrating normal values for these was then distributed-this could be attached to staff identity cards. At the same time doctors and nursing staff were given a teaching session on the importance of these measures. The audit was then repeated in a further 106 children. RESULTS: There was significant improvement in recording of all vital signs with the exception of blood pressure and temperature. CONCLUSION: A low-cost card together with a short period of training offers a useful strategy to improve the rate of documentation of vital signs in children presenting to the ED. PMID- 19773486 TI - The role of body mass index in acute exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND: Low body mass index (BMI) is a strong prognostic marker in stable chronic obstructive pulmonary disease (COPD); however, little is known about its role in acute exacerbations of COPD. OBJECTIVES: To determine the prevalence and determinants of low BMI in emergency department (ED) patients with acute exacerbations of COPD, and to examine whether low BMI was associated with more severe acute exacerbations, more intensive ED treatments and worse post-ED outcomes. METHODS: A secondary analysis was performed using data from a prospective multicentre cohort study involving 29 ED in the USA and Canada. Using a standard protocol, ED patients with acute exacerbations of COPD were interviewed and their charts reviewed. BMI was calculated using self-reported weight and height. Main outcome measures included hospital admission, post-ED relapse and ongoing exacerbation. RESULTS: 395 patients were enrolled. Their median age was 69 years (interquartile range 62-76); 52% were women. Thirteen per cent (95% CI 10% to 16%) were underweight, 37% normal weight, 27% overweight and 23% were obese. Current smoking was independently associated with underweight (OR 5.4, 95% CI 1.1 to 25.2). In the propensity-matched cohort, there were no significant differences in severity of exacerbation, treatments received in the ED, or short-term clinical outcomes, according to BMI. CONCLUSIONS: Low BMI is not uncommon in patients with acute exacerbations of COPD, and current smoking is associated with low BMI in these patients. Unlike its role in stable COPD, BMI appears to have little impact on exacerbation severity, treatments received in the ED, and short-term clinical outcomes in acute exacerbations of COPD. PMID- 19773487 TI - Perception of emergency medicine by consultants and specialist registrars from other hospital specialties. AB - BACKGROUND: This is the first study to consider feedback on the specialty of emergency medicine (EM) given by other hospital specialties. METHOD: A questionnaire was sent to 100 randomly selected consultants and specialist registrars from other specialties in a district general hospital in Northern England. The response rate was 67%. RESULTS: 80% of respondents felt that the official term for the specialty should be "accident and emergency medicine". Resuscitation and major trauma were given the highest importance scores (>9/10) when evaluating the purpose of EM and minor injuries were given an intermediate importance score (6.5/10). Respondents advocated "rapid rule out" of acute medical problems by the emergency department (75%) and "any trained individual" carrying out ultrasound (72%) or stroke thrombolysis (59%) in the emergency department. Rapid sequence induction of anaesthesia exclusively by emergency physicians was unpopular (3%). Respondents were least satisfied with the study department's documentation, availability of senior staff 24 h/day and the availability of equipment and drugs. Polyclinics and closure of smaller emergency department were unpopular future proposals, while 70% advocated a revival of traditional out-of-hours general practice services. CONCLUSION: The perceived purpose, strengths and weaknesses of EM provide a focus for training and development, while opinion on new practices indicates areas where resistance to change may be met. The results can contribute to decision-making for emergency departments and for EM as it strives to adapt to its role in the modern NHS. Further similar studies are planned on a wider scale. PMID- 19773488 TI - Atypical extravasation of contrast medium in massive extrapleural haematoma due to cardiac massage without rib fracture. PMID- 19773489 TI - Vulnerability to assault injury: an emergency department perspective. AB - OBJECTIVE: To evaluate risk and protective factors for violence-related injuries from an emergency department (ED) perspective. METHOD: Three study groups were recruited: (1) patients attending a major ED who had suffered an assault (n = 148), (2) patients attending a major ED who had not suffered an assault (n = 151) and (3) non-patients from public places in Cardiff (n = 171). Participants completed one of two proforma questionnaires: questions related to sociodemographic factors including their alcohol consumption and, for those in the assault group, the circumstances of the assault injury. RESULTS: The non assault groups consumed more alcohol units per annum but fewer alcohol units per drinking session than the assault group. The assault group visited entertainment venues more frequently than the non-assault groups. The relationship between alcohol units consumed per drinking session and the risk of assault injury was non-linear. The risk of assault injury increased for both genders with alcohol consumption (up to 5 units for women and 11 units for men), but at a slower rate for women. The model predicted that, at zero alcohol consumption, the risk of assault injury in men and women was similar. CONCLUSIONS: In the context of the number of alcohol units consumed in a drinking session, the risk of sustaining injury in assault for men and women is different. The risk of injury in assault for men and women is the same when no alcohol is consumed. Alcohol consumption may lead to different risk-taking behaviour in men and women. PMID- 19773490 TI - Matrix metalloproteinase levels in acute aortic dissection, acute pancreatitis and other abdominal pain. AB - BACKGROUND: Acute aortic dissection (AAD) is a life-threatening emergency. Patients with AAD who have abdominal pain are easily confused with patients with surgical acute abdomen. Matrix metalloproteinases (MMPs) play an important role in the pathophysiology of AAD. This study was undertaken to compare serum MMP-9 levels in patients with acute abdomen and those with AAD presenting as abdominal pain in the emergency department. METHODS: Blood samples were collected within 1 h and 24 h after admission to the emergency department. Serum levels of MMP-9, lipoprotein (a) (LP(a)) and high-sensitivity C-reactive protein (hsCRP) were measured in 20 healthy controls, 20 patients with acute pancreatitis, 20 with other acute abdomen and 20 patients with AAD with abdominal pain by enzyme-linked immunosorbent assay and immunoturbidimetric assay, respectively. RESULTS: Serum MMP-9, LP(a) and hsCRP levels were significantly higher in the three groups of patients than in the healthy controls, with no significant fluctuation within 24 h of admission in any group. Mean serum MMP-9 levels in patients with acute pancreatitis (768 (95% CI 651 to 885) ng/ml within 1 h; 708 (95% CI 677 to 740) ng/ml at 24 h) were significantly higher than in patients with other acute abdomen (244 (95% CI 182 to 266) ng/ml within 1 h; 259 (95% CI 219 to 299) ng/ml at 24 h) and lower than in patients with AAD (1052 (95% CI 921 to 1183) ng/ml at 1 h; 1107 (95% CI 973 to 1241) ng/ml at 24 h) (all p<0.05). No significant difference was detected in serum LP(a) and hsCRP levels among the three groups of patients. CONCLUSIONS: Patients with AAD who have abdominal pain have significantly higher serum MMP-9 levels than patients with surgical acute abdomen. PMID- 19773491 TI - 24-Hour observational ward management of diabetic patients presenting with hypoglycaemia: a prospective observational study. AB - BACKGROUND: A 24 h observational ward was set up in the study hospital emergency department (ED) in September 2005 to manage a group of patients with specific conditions including hypoglycaemia that require only short focused inpatient care. AIM: To evaluate the efficacy and safety of the management of hypoglycaemia in the observational ward via criteria of successful discharge of patients from the observational ward within 24 h and the recurrence of hypoglycaemia after discharge. METHODS: Hypoglycaemic patients admitted to the observational ward had their treatment and evaluation performed within 24 h. A protocol based on current available literature was formulated. Data were collected prospectively and included patient demographics, the duration and type of diabetes mellitus, current medications and treatment given. Patients were discharged only after a set of strict discharge criteria was fulfilled, and were followed up by telephone interviews at 7 and 28 days after discharge. RESULTS: A total of 203 patients were recruited. Of these, 170 (83.7%) patients were discharged and 33 (16.3%) were transferred to an inpatient team for a longer period of treatment. The median length of stay in the observational ward was 23.0 h. Of the 170 patients discharged, 151 (88.8%) were contacted at 7 and 28 days after discharge. Six patients had symptoms of recurrent hypoglycaemia, two of whom reattended the ED and had to be admitted. The remaining four patients had mild symptoms that were self-managed at home. Two other patients reattended for conditions not related to hypoglycaemia. Nineteen patients could not be contacted, but there was no record of any reattendances at the ED among this group of patients. CONCLUSION: There are currently no recommendations regarding the length of stay in hospital for patients with severe hypoglycaemia. This study shows that selected patients can be treated effectively and safely in a 24 hour observational ward. PMID- 19773492 TI - Retropharyngeal abscess secondary to a foreign body. PMID- 19773493 TI - Understanding target-driven action in emergency department performance using simulation. AB - Many computer simulation models of emergency departments have been developed to aid clinicians and managers to maintain and improve the performance of their departments. A model is presented that can also be used to understand changes in performance that may occur as a result of the 4-hour target regime in the English NHS. The model simulates the performance resulting from normal activity, and the differences between this and actual performance are revealing. The results from two departments are presented to demonstrate this mode of model use. These reveal the extent of special action taken in some emergency departments as patients approach the target time, and also show the true underlying performance of the departments. PMID- 19773494 TI - Trampolining injuries presenting to a children's emergency department. AB - BACKGROUND: There has been an unprecedented surge in the popularity of trampolines in the UK and in the number of children attending emergency departments with associated injuries. AIM: To record the incidence, injury type and risk factors for children attending the emergency department of a busy suburban hospital with trampolining injuries. METHODS: Between May and September 2008, all eligible patients had a proforma completed recording mechanism, time and type of injury, the number of children trampolining at the time of the injury and whether a supervising adult or safety net was present. Analgesia requirements, treatment and follow-up were recorded. RESULTS: 131 children presented with trampolining injuries (1.5% of paediatric attendances). The average age was 8.8 years (range 1-16). 77 (59%) had no net present and 87 (66%) no supervising adult. 89 (68%) sustained injuries without actually falling from the trampoline and, on average, 2.6 people (range 1-7) were on the trampoline at the time of the injury. 81 (62%) required a radiograph and 40 (31%) were diagnosed with fractures. 18 (14%) required surgery and 28 (21%) were discharged with clinic follow-up. 18 (14%) sustained lacerations that required closure in the department. CONCLUSION: The enormous increase in trampoline sales has brought with it a significant increase in the injuries presenting to UK emergency departments. Safety information is given by manufacturers, retailers and local government authorities, but many parents fail to heed this advice. A combination of inadequate adult supervision, several people using a trampoline simultaneously and insufficient safety equipment seems inextricably linked with injury. Greater parental and public awareness is required regarding the potential dangers of what is perhaps unwittingly considered a light-hearted pastime. PMID- 19773495 TI - Haemorrhage after Ru-Zhu. PMID- 19773496 TI - Pilot study of random finger prick glucose testing as a screening tool for type 2 diabetes mellitus in the emergency department. AB - BACKGROUND: A study was undertaken to determine the prevalence of undiagnosed hyperglycaemia among patients in the emergency department (ED) and to evaluate the usefulness of random fingerprick plasma glucose (RFPG) screening in the ED with GP follow-up. METHODS: A cross-sectional pilot study of 101 non-diabetic patients in the ED aged > or =45 years was performed. RESULTS: 31 (30.7%) had never had diabetic screening. 67 (66.3%) had plasma glucose levels > or =5.5 mmol/l and were advised to consult their GP; 38 (56.7%) did so and 23 (60.5%) of these had follow-up testing. Nine patients (8.9%) were ultimately diagnosed with impaired glucose metabolism. CONCLUSION: There is considerable potential for diabetic screening in the ED setting. PMID- 19773501 TI - Chest decompression during the resuscitation of patients in prehospital traumatic cardiac arrest. AB - BACKGROUND: Tension and bilateral pneumothorax can cause or contribute to death following trauma. A surgical incision (thoracostomy) or needle decompression through the chest wall rapidly treats these conditions. Resuscitation of patients in traumatic cardiac arrest focuses on treating common and reversible life threatening conditions. A study was undertaken to observe the practice, findings and outcome of chest decompression when performed as part of the resuscitation strategy of these patients by air ambulance crews. METHODS: Patients in prehospital traumatic cardiac arrest were identified over a 39-month period from an air ambulance database. The use of thoracostomy or needle decompression was identified together with indications, findings and outcome. Primary outcome was return of cardiac output by arrival at hospital. RESULTS: 18 of 37 cases underwent chest decompression (17 thoracostomy, 1 needle decompression). Four patients had a return of cardiac output (3 tension pneumothorax, 1 bilateral pneumothorax). Six further cases were positive for intrathoracic injury. In 2 cases the injuries identified were incompatible with life and resuscitation efforts were consequently ceased. CONCLUSIONS: Chest decompression in traumatic cardiac arrest identifies and treats a high proportion of potentially life-ending injuries and should be considered as part of the resuscitation effort of patients in traumatic cardiac arrest. In a proportion of patients, non-survivable injuries are identified which guide resuscitation efforts. PMID- 19773502 TI - "At the sharp end": does ambulance dispatch data from south Yorkshire support the picture of increased weapon-related violence in the UK? AB - OBJECTIVE: To assess whether ambulance responses in South Yorkshire to stabbing, gunshot, penetrating trauma cases have increased over the past few years, supporting the observed increase in media reporting. METHODS: A review was undertaken of the frequency with which the ambulance medical priority dispatch system card 27 (stab/gunshot/penetrating trauma) was used, grouped by financial year, and comparison made over time and by patient age group. RESULTS: There is a steady increase in the number of occurrences of these cases and also an increase in the percentage made up by the 10-29 year age group. CONCLUSIONS: Ambulance data from South Yorkshire support the media conclusion that there is an increase in stabbing, gunshot and penetrating trauma as well as an increase in the proportion of younger victims. This has wider implications for ambulance staff and the UK as a whole; however, these calls remain a low percentage of overall ambulance service activity. PMID- 19773503 TI - Level of training and experience in physicians performing interhospital transfers of adult patients in the internal medicine department. AB - AIM: To establish the level of training doctors who participate in interhospital transfers in Denmark. METHODS: A questionnaire was sent to every hospital department in Denmark with acute internal medicine admissions. RESULTS: Eighty nine internal medicine departments were contacted and 84 responded (response rate 94.4%). Of the 84 hospitals, 75 (89.3%) indicated that they perform interhospital transfers. Most transfers were performed by interns (61.3%) or senior house officers (10.7%) with only a few months' experience in their current speciality. Training in interhospital transfer was offered by 24.0% of departments. When presented with cases of interhospital transfers of critically ill patients, 77.3% of the responders stated that their department would not follow guidelines when performing the transfer. CONCLUSIONS: The gap between recommended professional standards and current practice shows a need to establish educational programmes in interhospital transfer. PMID- 19773504 TI - Luxatio erecta: a prehospital challenge in patient packaging. PMID- 19773505 TI - A penetrating trauma to the temple. PMID- 19773506 TI - A vanishing disease can still happen. AB - Lemierre's syndrome is a rare disease in the antibiotic era which is characterised by oropharyngitis, thrombophlebitis and septic metastases, but it can still occur and early recognition of its characteristic features and commencement of appropriate treatment can be life saving. The case history is described of a middle-aged man with Lemierre's syndrome who made an uneventful recovery following treatment with co-amoxiclav and metronidazole for 6 weeks. PMID- 19773507 TI - Wellens' syndrome: significance of ECG pattern recognition in the emergency department. AB - Wellens' syndrome describes a characteristic pattern of ECG T-wave changes in association with critical narrowing of the left anterior descending coronary artery. Failure to diagnose this condition, with subsequent inappropriate management, may have fatal consequences. A case of Wellens' syndrome is reported in a young man presenting with "atypical chest pain" and the significance of its prompt recognition is discussed. PMID- 19773508 TI - Small bowel intussusception following blunt abdominal trauma in an adult patient. AB - Blunt abdominal trauma is a rare cause of small bowel intussusception in adults. A patient is described who presented with signs and symptoms of intestinal obstruction following a fall from a ladder. A CT scan revealed evidence of ileo ileal intussusception. Exploratory laparotomy and resection of a necrotic bowel segment were performed. Rare occurrences like intussusception should be kept in mind in similar presentations with careful examination of the pathognomonic CT findings, as early detection and surgical intervention with manual reduction could preclude the need for small bowel resection and its untoward possible complications. PMID- 19773509 TI - Spontaneous rupture of kidney. PMID- 19773510 TI - Acute coronary syndrome triggered by honeybee sting: a case report. AB - A 56-year-old previously healthy man was admitted to our hospital with a severe chest pain that started shortly after being stung by a honeybee. He did not have any allergic symptoms and there was no cutaneous or respiratory evidence of allergy on physical examination. Electrocardiographic and biochemical markers were consistent with an acute coronary syndrome. Coronary angiography demonstrated a significant thrombotic lesion in the right coronary artery. Here, a rare and unexpected event is presented, the development of acute coronary syndrome after a bee sting. PMID- 19773511 TI - Inadvertent cannulation of the C6 transverse foramen during central venous catheterisation. PMID- 19773512 TI - Thrombolysis beyond 3 hours for acute ischaemic stroke. AB - Intravenous thrombolysis is an accepted form of treatment for acute ischaemic stroke when administered within 3 h of symptom onset. However, evidence for its benefit when given beyond this time continues to strengthen. The case history of a young woman is presented with an ischaemic stroke who was successfully thrombolysed with recombinant tissue-type plasminogen activator more than 3 h after presentation. Perfusion CT scanning was used to stratify the likelihood of benefit. Thrombolysis was administered through a combination of intravenous and intra-arterial routes. This case illustrates the advances being made both in the imaging techniques used and the forms of drug administration which can be applied to maximise benefit in this extended therapeutic window. These recent advances are reviewed and their possible impact on current and future practice assessed. While the drive remains the introduction of thrombolysis at a local level for ischaemic stroke within 3 h of symptom onset, it is necessary to consider treatment of subjects presenting beyond 3 h in tertiary centres with the appropriate facilities and expertise. PMID- 19773513 TI - Persistent idiopathic ventricular tachycardia in a 28-year-old woman. AB - The case history is presented of a normally fit and well 28-year-old woman with idiopathic right ventricular outflow tract ventricular tachycardia (RVOT VT). Presentation was with a broad complex tachycardia unresponsive to first-line anti arrhythmic drugs and DC cardioversion (immediate recurrence) but highly sensitive to flecainide and eventually successfully treated with catheter ablation. Assessment and management of broad complex tachycardia is challenging but requires a structured approach to the underlying differential diagnosis. Ventricular tachycardia may occur in structurally normal hearts and not cause haemodynamic compromise despite persistence over 48 h, as in this case. The clinical history, ECG morphology and response to adenosine were all instrumental in making the diagnosis and hence tailoring appropriate anti-arrhythmic therapy when DC cardioversion failed. PMID- 19773514 TI - "A head turning complication". PMID- 19773515 TI - Prehospital use of ketamine in mountain rescue. PMID- 19773516 TI - Management of cocaine-associated chest pain. PMID- 19773517 TI - The need for an educational DVD for procedural sedation using ketamine and propofol. PMID- 19773518 TI - Emergency physicians and police brutality. PMID- 19773520 TI - Emergency medicine in Uganda. PMID- 19773521 TI - Waiting times are they that important? A patient survey. PMID- 19773524 TI - Valproic acid plasma concentration decreases in a dose-independent manner following administration of meropenem: a retrospective study. AB - Several case reports indicate that carbapenem antibiotics, especially meropenem, may decrease the plasma concentrations of valproic acid (VPA), thus decreasing its therapeutic activity. To investigate the onset, severity, and dose dependency of the interaction between meropenem and VPA, the authors carried out a retrospective evaluation of data collected during 24 months from patients hospitalized in a tertiary medical center. The analysis included 36 patients. VPA mean +/- SEM plasma concentration decreased from of 50.8 +/- 4.5 microg/mL to 9.9 +/- 2.1 microg/mL (P < .001) following meropenem administration. After discontinuation of meropenem, VPA plasma concentrations remained low for 7 days and then gradually increased after 8 to 14 days, reaching values comparable to those before meropenem initiation. Different daily VPA doses showed a similar pattern of decreased VPA concentrations. The mean decrease in individual plasma VPA concentration was 82.1% +/- 2.7%. The mean VPA plasma concentration of patients in whom samples were drawn within 24 hours of meropenem initiation was 9.9 +/- 3.2 microg/mL. In conclusion, the interaction between meropenem and VPA causes a significant decrease in VPA plasma concentration, apparently within 24 hours. As the therapeutic effects of VPA are plasma concentration dependent, the data suggest that these drugs should not be administered concomitantly. PMID- 19773525 TI - Population pharmacokinetics of teduglutide following repeated subcutaneous administrations in healthy participants and in patients with short bowel syndrome and Crohn's disease. AB - Teduglutide is a GLP-2 analog currently evaluated for the treatment of short bowel syndrome, Crohn's disease, and other gastrointestinal disorders. The population pharmacokinetics (PK) of teduglutide were assessed following daily subcutaneous (SC) administrations of 2.5 to 80 mg doses in a total of 256 patients. A 1-compartment model with a site-specific rate constant of absorption in the abdomen, arm, and thigh was used to assess the PK of teduglutide. Apparent clearance (CL/F) of teduglutide in male participants was approximately 18% higher than that observed in female participants (12.4 vs 10.5 L/h, respectively). Body weight was detected as a significant covariate explaining the volume of distribution of teduglutide. The elimination half-life (t((1/2))) of teduglutide was also influenced by the body weight of participants. For a male patient weighing 50 and 90 kg, t((1/2)) of teduglutide was 0.897 and 2.99 hours, respectively. Renal and hepatic function of patients did not affect the PK of teduglutide. As a result, no dose adjustment was deemed necessary in patients with altered renal or liver function. The population PK model will help to support adequate drug labeling following SC administrations in patients and determine whether an individualized dosage is required. PMID- 19773526 TI - Review of type 2 diabetes management interventions for addressing emotional well being in Latinos. AB - PURPOSE: The purpose of this article is (1) to investigate if type 2 diabetes management programs with Latino participants address emotional well-being in addition to the standard diabetes self-care behaviors and (2) to describe the approaches taken to improve psychological and diabetes management outcomes. METHODS: Online article and research databases, Internet searches, and review of article citations were used to identify relevant articles published 1995-2008. Type 2 diabetes management interventions with a psychological (emotion or cognitive) component or outcome measure and Latino sample were selected. Articles were limited to randomized clinical/controlled trials and pre-post comparative studies. RESULTS: Thirteen interventions met the inclusion criteria for this review. Eight studies included emotion outcome measures, and 13 included at least one cognitive outcome measure. One study was specifically designed to improve emotional well-being. This study was not targeted for Latinos but did include Latino participants. A specialized depression case manager and collaborative care model showed significant improvements in depression and mental functioning. Psychological improvements were also found in those studies that assessed cognitive outcomes and were based on cognitive theories. The most frequent cognitive outcomes assessed were diabetes knowledge, problem solving, and self efficacy. CONCLUSIONS: Few type 2 diabetes interventions address emotional well being in Latinos. More attention has been directed toward designing culturally sensitive community-based programs for improving behavior and physical outcomes. Because some Latino groups believe that negative emotions cause diabetes and because depression and anxiety are associated with poor self-management, programs should address emotional well-being as an important aspect of diabetes management. PMID- 19773527 TI - Effect of rotator cuff muscle imbalance on forceful internal impingement and peel back of the superior labrum: a cadaveric study. AB - BACKGROUND: Throwing athletes with shoulder pain have been shown to have decreased rotator cuff muscle strength. Shoulder internal impingement and labral peel-back mechanism, as may occur during the late cocking phase of throwing motion, are thought to cause rotator cuff injury and type II superior labrum anterior and posterior lesions. Therefore, the objective of this study was to assess the effect of rotator cuff muscle force on internal impingement and the peel-back of the superior labrum by quantifying maximum external rotation, glenohumeral contact pressure, and position of the cuff insertion relative to the glenoid. HYPOTHESIS: A change in rotator cuff muscle force will lead to increased external rotation, glenohumeral contact pressure, and overlap of the cuff insertion relative to the glenoid. STUDY DESIGN: Controlled laboratory study. METHODS: Eight fresh-frozen cadaveric shoulders were tested at the simulated late cocking position. Glenohumeral contact pressure, location of the cuff insertion relative to the glenoid, and maximum humeral external rotation angle were measured. The forces of the supraspinatus, subscapularis, and infraspinatus muscles were determined based on published clinical electromyographic data. To assess the effect of cuff muscle imbalance, each muscle force was varied. Horizontal abduction positions of 20 degrees , 30 degrees , and 40 degrees with respect to the scapular plane were tested. RESULTS: Decreased subscapularis strength resulted in a significant increase in maximum external rotation (P <.001) and increased glenohumeral contact pressure (P <.01). The cuff insertion overlapped the edge of the glenoid at 30 degrees and 40 degrees of horizontal abduction for all muscle loading conditions. CONCLUSION: Decreased subscapularis muscle strength in the position simulating the late cocking phase of throwing motion results in increased maximum external rotation and also increased glenohumeral contact pressure. CLINICAL RELEVANCE: Athletes with decreased subscapularis muscle strength, such as fatigue with repetitive throwing, may be more susceptible to rotator cuff tears and type II superior labrum anterior and posterior lesions. Subscapularis muscle strengthening exercises may be beneficial for preventing these injuries. PMID- 19773528 TI - Efungumab: a novel agent in the treatment of invasive candidiasis. AB - OBJECTIVE: To review the use of efungumab as an adjunctive agent in the treatment of invasive candidiasis (IC) and to provide guidance on formulary placement. DATA SOURCES: Searches of MEDLINE (1966-June 2009) and EMBASE (1974-June 2009) were conducted using the terms efungumab, Mycograb, heat shock protein 90, and invasive candidiasis. Other resources included www.clinicaltrials.gov and article bibliographies. STUDY SELECTION AND DATA EXTRACTION: All studies and case reports evaluating efungumab use in IC were included. Literature review was limited to the English language. DATA SYNTHESIS: Efungumab is a monoclonal antibody targeted against heat shock protein 90 (HSP 90). It binds to HSP 90, preventing a conformational change needed for fungal viability. In vitro data show that HSP 90 inhibition may decrease resistance against antifungal agents and increase antifungal activity. Efungumab shows activity against Candida spp. when used alone and synergism when combined with fluconazole, caspofungin, and amphotericin B. A randomized controlled trial evaluated combination therapy of efungumab 1 mg/kg twice daily and liposomal amphotericin B versus amphotericin B therapy alone. At day 10, a favorable response was seen in 84% of patients in the efungumab group compared with 48% of patients in the placebo group (OR 5.76; 95% CI 2.4 to 13.8). Mortality at day 33 was also lower in the efungumab group, 4% versus 18%, respectively (OR 0.168; 95% CI 0.036 to 0.797). Although adverse effects were similar in this trial (10% vs 7%), case reports revealed an increased incidence of blood pressure fluctuations. Cytokine release syndrome has also been linked to efungumab use, warranting further exploration of its safety. CONCLUSIONS: Efungumab is a new antifungal agent with a novel mechanism of action. Available clinical data and synergy studies support the use of efungumab in combination with other antifungal agents for the treatment of IC. Further safety data are needed before formulary recommendations can be made. PMID- 19773529 TI - Comparison of the antinociceptive and antirewarding profiles of novel bifunctional nociceptin receptor/mu-opioid receptor ligands: implications for therapeutic applications. AB - The nociceptin receptor (NOPr), a member of the opioid receptor family, is a target for the treatment of pain and drug abuse. Nociceptin/orphanin FQ (N/OFQ), the endogenous peptide for NOPr, not only modulates opioid antinociception, but also blocks the rewarding effects of several abused drugs, such as morphine, cocaine, and amphetamine. We hypothesized that NOPr agonists, with bifunctional activity at the mu-opioid receptor (MOPr), may function as nonaddicting analgesics or as drug abuse medications. Bifunctional small-molecule NOPr agonists possessing different selectivities and efficacies at MOPr were evaluated in an acute thermal antinociception assay, and for their ability to induce conditioned place preference (CPP) and their effect on morphine-induced CPP. 1-(1 Cyclooctylpiperidin-4-yl)-indolin-2-one) (SR14150), a high-affinity NOPr partial agonist, with low MOPr affinity and efficacy, produced analgesia that was naloxone-reversible. SR14150 did not induce CPP alone, nor did it attenuate morphine-induced CPP. 3-Ethyl-1-(1-(4-isopropylcyclohexyl)piperidin-4-yl)-indolin 2-one (SR16507), which has high affinity for both NOPr and MOPr, full agonist activity at NOPr, and partial agonist activity at MOPr, was also a potent analgesic and produced CPP alone, but also modestly attenuated morphine CPP. 1-(1 (2,3,3a,4,5,6-hexahydro-1H-phenalen-1-yl)piperidinl-4-yl)-indolin-2-one (SR16835), a NOPr full agonist and low-affinity MOPr partial agonist, was not antinociceptive, did not produce CPP alone, but attenuated morphine CPP. Our results suggest that NOPr full-agonist activity is required to modulate opioid induced reward, whereas a bifunctional NOPr/MOPr partial agonist profile may be suitable as a nonaddicting analgesic. The opioid-modulating effects of the NOPr ligands may be used effectively to produce better medications for treatment of drug abuse and pain. PMID- 19773530 TI - Blockade of ethanol-induced potentiation of glycine receptors by a peptide that interferes with Gbetagamma binding. AB - The large intracellular loop (IL) of the glycine receptor (GlyR) interacts with various signaling proteins and plays a fundamental role in trafficking and regulation of several receptor properties, including a direct interaction with Gbetagamma. In the present study, we found that mutation of basic residues in the N-terminal region of the IL reduced the binding of Gbetagamma to 21 +/- 10% of control. Two basic residues in the C-terminal region, on the other hand, contributed to a smaller extent to Gbetagamma binding. Using docking analysis, we found that both basic regions of the IL bind in nearby regions to the Gbetagamma dimer, within an area of high density of amino acids having an electronegative character. Thereafter, we generated a 17-amino acid peptide with the N-terminal sequence of the wild-type IL (RQH) that was able to inhibit the in vitro binding of Gbetagamma to GlyRs to 57 +/- 5% of control in glutathione S-transferase pull down assays using purified proteins. More interestingly, when the peptide was intracellularly applied to human embryonic kidney 293 cells, it inhibited the Gbetagamma-mediated modulations of G protein-coupled inwardly rectifying potassium channel by baclofen (24 +/- 14% of control) and attenuated the GlyR potentiation by ethanol (51 +/- 10% versus 10 +/- 3%). PMID- 19773531 TI - Heme oxygenase-2 deletion causes endothelial cell activation marked by oxidative stress, inflammation, and angiogenesis. AB - In previous studies, we have shown that heme oxygenase (HO)-2 null [HO-2(-/-)] mice exhibit a faulty response to injury; chronic inflammation and massive neovascularization replaced resolution of inflammation and tissue repair. Endothelial cells play an active and essential role in the control of inflammation and the process of angiogenesis. We examined whether HO-2 deletion affects endothelial cell function. Under basal conditions, HO-2(-/-) aortic endothelial cells (mAEC) showed a 3-fold higher expression of vascular endothelial growth factor receptor 1 and a marked angiogenic response compared with wild-type (WT) cells. Compared with WT cells, HO-2(-/-) mAEC showed a 2-fold reduction in HO activity and marked increases in levels of gp91(phox)/NADPH oxidase isoform, superoxide, nuclear factor kappaB activation, and expression of inflammatory cytokines, including interleukin (IL)-1alpha and IL-6. HO-2 deletion transforms endothelial cells from a "normal" to an "activated" phenotype characterized by increases in inflammatory, oxidative, and angiogenic factors. This switch may be the result of reduced HO activity and the associated reduction in the cytoprotective HO products, carbon monoxide and biliverdin/bilirubin, because addition of biliverdin to HO-2(-/-) cells attenuated angiogenesis and reduced superoxide production. This transformation underscores the importance of HO-2 in the regulation of endothelial cell homeostasis. PMID- 19773532 TI - 17Beta-estradiol mediates the sex difference in capsaicin-induced nociception in rats. AB - We have previously shown that the male sex steroid testosterone inhibits slightly, but the female sex steroid 17beta-estradiol (E(2)) potentiates dramatically, the capsaicin receptor-mediated current in rat dorsal root ganglion (DRG) neurons. Here, we used pharmacological methods and the nociceptive behavioral test to determine whether there is a sex difference in capsaicin induced acute pain in rats in vivo and what mechanism underlies this sex difference. Results revealed that intradermal injection of capsaicin induced a dose-dependent nocifensive response in males and females, with the dose required to produce a comparable level of nociception being approximately 3- to 4-fold higher in males than in females. In addition, females during the proestrus stage exhibited significantly greater capsaicin-induced nocifensive responses compared with the estrus stage. Moreover, the female's enhanced sensitivity to the capsaicin-induced nocifensive response was completely reversed by ovariectomy 6 weeks before capsaicin injection. It is noteworthy that intradermal coinjection of E(2) but not progesterone with capsaicin potentiated the capsaicin-induced nocifensive response in ovariectomized rats. Likewise, intradermal E(2) injection dose-dependently potentiated the capsaicin-induced nocifensive response in male rats. Furthermore, potentiation by E(2) of the capsaicin-induced nocifensive response in male rats was not significantly reduced by a selective protein kinase C (PKC) inhibitor or by a selective protein kinase A (PKA) inhibitor, indicating that neither PKC nor PKA was involved in the effect of E(2). These data demonstrate that E(2) mediates the female's enhanced sensitivity to capsaicin induced acute pain, consistent with potentiation by E(2) of the capsaicin receptor-mediated current in rat DRG neurons. PMID- 19773535 TI - CYP2C8 activity recovers within 96 hours after gemfibrozil dosing: estimation of CYP2C8 half-life using repaglinide as an in vivo probe. AB - Gemfibrozil 1-O-beta-glucuronide is a mechanism-based inhibitor of cytochrome P450 2C8. We studied the recovery of CYP2C8 activity after discontinuation of gemfibrozil treatment using repaglinide as a probe drug, to estimate the in vivo turnover half-life of CYP2C8. In a randomized five-phase crossover study, nine healthy volunteers ingested 0.25 mg of repaglinide alone or after different time intervals after a 3-day treatment with 600 mg of gemfibrozil twice daily. The area under the plasma concentration-time curve (AUC) from time 0 to infinity of repaglinide was 7.6-, 2.9-, 1.4- and 1.0-fold compared with the control phase when it was administered 1, 24, 48, or 96 h after the last gemfibrozil dose, respectively (P < 0.001 versus control for 1, 24, and 48 h after gemfibrozil). Thus, a strong CYP2C8 inhibitory effect persisted even after gemfibrozil and gemfibrozil 1-O-beta-glucuronide concentrations had decreased to less than 1% of their maximum (24-h dosing interval). In addition, the metabolite to repaglinide AUC ratios indicated that significant (P < 0.05) inhibition of repaglinide metabolism continued up to 48 h after gemfibrozil administration. Based on the recovery of repaglinide oral clearance, the in vivo turnover half-life of CYP2C8 was estimated to average 22 +/- 6 h (mean +/- S.D.). In summary, CYP2C8 activity is recovered gradually during days 1 to 4 after gemfibrozil discontinuation, which should be considered when CYP2C8 substrate dosing is planned. The estimated CYP2C8 half-life will be useful for in vitro-in vivo extrapolations of drug-drug interactions involving induction or mechanism-based inhibition of CYP2C8. PMID- 19773536 TI - Vacuolar ATPase-mediated cellular concentration and retention of quinacrine: a model for the distribution of lipophilic cationic drugs to autophagic vacuoles. AB - The antiprotozoal agent quinacrine is a lipophilic cationic drug highly distributed to tissues. It has been used in the present experiments to examine whether the vacuolar and autophagic cytopathology induced by organic amines is independent from the therapeutic class. Furthermore, we tested the presence of the concentrated cationic drug itself in the enlarged vacuoles by exploiting the intense green fluorescence of quinacrine. Finally, the influence of lipophilicity on the apparent affinity of amine pseudotransport has been addressed by comparing quinacrine to another substituted triethylamine, procainamide. Quinacrine was concentration-dependently taken up by human smooth muscle cells (cytosolic granular-vacuolar morphology at and above 25 nM; in cell extracts, uptake nearly maximal in 2 h, apparent K(m) of 8.7 microM). The vacuolar (V)-ATPase inhibitor bafilomycin A1 prevented quinacrine uptake by cells or released the cell associated drug in preloaded cells. The lipidated (II) form of microtubule associated protein light chain 3 accumulated at and above a quinacrine concentration of 2.5 microM (4 h), indicating the conserved macroautophagic nature of the vacuolar cytopathology, although vacuole size was modest. The enlarged vacuoles containing quinacrine excluded cherry fluorescent protein; many vacuoles were lined with cherry fluorescent protein-conjugated Rab7, a GTPase associated with late endosomes/lysosomes. Taken together, these results are compatible with the transition of quinacrine-concentrating vacuoles toward an autophagolysosome identity. Quinacrine is concentrated in cells via V-ATPase mediated ion trapping with an apparent affinity approximately 500-fold higher than that of the less lipophilic drug procainamide, and, despite the small size of ensuing vacuoles, the macroautophagic signature of this cytopathology was observed. PMID- 19773537 TI - Glucuronidation and covalent protein binding of benoxaprofen and flunoxaprofen in sandwich-cultured rat and human hepatocytes. AB - Benoxaprofen (BNX), a nonsteroidal anti-inflammatory drug (NSAID) that was withdrawn because of hepatotoxicity, is more toxic than its structural analog flunoxaprofen (FLX) in humans and rats. Acyl glucuronides have been hypothesized to be reactive metabolites and may be associated with toxicity. Both time- and concentration-dependent glucuronidation and covalent binding of BNX, FLX, and ibuprofen (IBP) were determined by exposing sandwich-cultured rat hepatocytes to each NSAID. The levels of glucuronide and covalent protein adduct measured in cells followed the order BNX > FLX > IBP. These results indicate that 1) BNX glucuronide (G) is more reactive than FLX-G, and 2) IBP-G is the least reactive metabolite, which support previous in vivo studies in rats. The proportional increases of protein adduct formation for BNX, FLX, and IBP as acyl glucuronidation increased also support the hypothesis that part of the covalent binding of all three NSAIDs to hepatic proteins is acyl glucuronide-dependent. Moreover, theses studies confirmed the feasibility of using sandwich-cultured rat hepatocytes for studying glucuronidation and covalent binding to hepatocellular proteins. These studies also showed that these in vitro methods can be applied using human tissues for the study of acyl glucuronide reactivity. More BNX protein adduct was formed in sandwich-cultured human hepatocytes than FLX-protein adduct, which not only agreed with its relative toxicity in humans but also was consistent with the in vitro findings using rat hepatocyte cultures. These data support the use of sandwich-cultured human hepatocytes as an in vitro screening model of acyl glucuronide exposure and reactivity. PMID- 19773538 TI - Prediction of human drug-drug interactions from time-dependent inactivation of CYP3A4 in primary hepatocytes using a population-based simulator. AB - Time-dependent inactivation (TDI) of human cytochromes P450 3A4 (CYP3A4) is a major cause of clinical drug-drug interactions (DDIs). Human liver microsomes (HLM) are commonly used as an enzyme source for evaluating the inhibition of CYP3A4 by new chemical entities. The inhibition data can then be extrapolated to assess the risk of human DDIs. Using this approach, under- and overpredictions of in vivo DDIs have been observed. In the present study, human hepatocytes were used as an alternative to HLM. Hepatocytes incorporate the effects of other mechanisms of drug metabolism and disposition (i.e., phase II enzymes and transporters) that may modulate the effects of TDI on clinical DDIs. The in vitro potency (K(I) and k(inact)) of five known CYP3A4 TDI drugs (clarithromycin, diltiazem, erythromycin, verapamil, and troleandomycin) was determined in HLM (pooled, n = 20) and hepatocytes from two donors (D1 and D2), and the results were extrapolated to predict in vivo DDIs using a Simcyp population trial-based simulator. Compared with observed DDIs, the predictions derived from HLM appeared to be overestimated. The predictions based on TDI measured in hepatocytes were better correlated with the DDIs (n = 37) observed in vivo (R(2) = 0.601 for D1 and 0.740 for D2) than those from HLM (R(2) = 0.451). In addition, with the use of hepatocytes a greater proportion of the predictions were within a 2-fold range of the clinical DDIs compared with using HLM. These results suggest that DDI predictions from CYP3A4 TDI kinetics in hepatocytes could provide an alternative approach to balance HLM-based predictions that can sometimes substantially overestimate DDIs and possibly lead to erroneous conclusions about clinical risks. PMID- 19773539 TI - Metabolism of pyridalyl in rats. AB - Metabolism of pyridalyl [2,6-dichloro-4-(3,3-dichloroallyloxy)phenyl 3-[5 (trifluoromethyl)-2-pyridyloxy]propyl ether] was examined in male and female Sprague-Dawley rats. After a single oral administration of [dichlorophenyl (14)C]pyridalyl at 5 or 500 mg/kg, the (14)C concentration in blood reached maxima at 2 to 10 h and then decreased rapidly with a biological half-life of approximately 11 to 12 h. (14)C concentrations in liver, fat, adrenal gland, and spleen were relatively high at a low dose, reaching 2.3 to 2.7, 1.9 to 2.3, 1.1 to 1.9, and 1.4 ppm, respectively, in these tissues at 2 to 24 h after administration. Although (14)C elimination from fat and hair and skin was relatively slow compared with that from other tissues, the total residue on the 7th day was low, in the range of 1.3 to 2.3% of the dose. The (14)C distribution in tissues with a high dose, as examined by whole-body autoradiography, was similar to that observed for the low dose. Results revealed that more than 88% of the dosed radiocarbon was excreted within 1 day after administration, with cumulative (14)C excretion into urine and feces 7 days after administration of 1.7 to 2.6 and 98.7 to 101.7%, respectively. One urinary and fecal major metabolite (resulting from O-dealkylation) and two minor metabolites were identified by NMR and mass spectrometry. Residual (14)C in fat was extracted, and analysis by thin-layer chromatography showed it to be due to pyridalyl itself. No marked sex-related differences were observed in (14)C elimination, (14)C distribution, and metabolites. PMID- 19773540 TI - Enterohepatic disposition of rosuvastatin in pigs and the impact of concomitant dosing with cyclosporine and gemfibrozil. AB - The hepatobiliary transport and local disposition of rosuvastatin in pig were investigated, along with the impact of concomitant dosing with two known multiple transport inhibitors; cyclosporine and gemfibrozil. Rosuvastatin (80 mg) was administered as an intrajejunal bolus dose in treatments I, II, and III (TI, TII, and TIII, respectively; n = 6 per treatment). Cyclosporine (300 mg) and gemfibrozil (600 mg) were administered in addition to the rosuvastatin dose in TII and TIII, respectively. Cyclosporine was administered as a 2-h intravenous infusion and gemfibrozil as an intrajejunal bolus dose. In treatment IV (TIV, n = 4) 5.9 mg of rosuvastatin was administered as an intravenous bolus dose. The study was conducted using a pig model, which enabled plasma sampling from the portal (VP), hepatic (VH), and femoral veins and bile from the common hepatic duct. The biliary recoveries of the administered rosuvastatin dose were 9.0 +/- 3.5 and 35.7 +/- 15.6% in TI and TIV, respectively. Rosuvastatin was highly transported into bile as shown by the median AUC(bile)/AUC(VH) ratio in TI of 1770 (1640-11,300). Gemfibrozil did not have an effect on the plasma pharmacokinetics of rosuvastatin, most likely because the unbound inhibitor concentrations did not exceed the reported IC(50) values. However, cyclosporine significantly reduced the hepatic extraction of rosuvastatin (TI, 0.89 +/- 0.06; TII, 0.46 +/- 0.13) and increased the AUC(VP) and AUC(VH) by 1.6- and 9.1-fold, respectively. In addition, the biliary exposure and f(e, bile) were reduced by approximately 50%. The strong effect of cyclosporine was in accordance with inhibition of sinusoidal uptake transporters, such as members of the organic anion-transporting polypeptide family, rather than canalicular transporters. PMID- 19773541 TI - Identification of a novel CYP2C19-mediated metabolic pathway of S-citalopram in vitro. AB - Systemic exposure of the antidepressant S-citalopram (escitalopram, SCIT) differs several-fold according to variable cytochrome P450 2C19 activity, demonstrating the importance of this enzyme for the metabolic clearance of SCIT in vivo. However, previous studies have indicated that the involvement of CYP2C19 in formation of the metabolite N-desmethyl S-citalopram (SDCIT) is limited. Therefore, the purpose of the present in vitro study was to investigate to what extent the CYP2C19-mediated clearance of SCIT was due to a metabolic pathway different from N-desmethylation and to identify the product(s) of this possible alternative metabolic reaction. CYP2C19-mediated metabolism of SCIT was investigated using recombinant Supersomes expressing human CYP2C19. Initial experiments showed that approximately half of the CYP2C19-mediated clearance of SCIT was accounted for by the N-desmethylation pathway. Subsequent experiments identified that, in addition to SDCIT, the propionic acid metabolite of SCIT (SCIT PROP) was formed by CYP2C19 in vitro. Formation of SCIT PROP accounted for 35% of total CYP2C19-mediated clearance of SCIT (calculated as the ratio between metabolite formation rate and substrate concentration at low substrate concentration). Moreover, analysis of samples from six CYP2C19-genotyped patients treated with SCIT indicated that differences in serum concentrations of SCIT between CYP2C19 genotypes may be due to a combined effect on SCIT PROP and SDCIT formation. Identification of SCIT PROP as a metabolic pathway catalyzed by CYP2C19 might explain why impaired CYP2C19 activity has a substantially larger effect on SCIT exposure than estimated from in vitro data based solely on formation of SDCIT. PMID- 19773542 TI - Effect of rifampin and nelfinavir on the metabolism of methadone and buprenorphine in primary cultures of human hepatocytes. AB - We tested the hypothesis that primary cultures of human hepatocytes could predict potential drug interactions with methadone and buprenorphine. Hepatocytes (five donors) were preincubated with dimethyl sulfoxide (DMSO) (vehicle), rifampin, or nelfinavir before incubation with methadone or buprenorphine. Culture media (0-60 min) was analyzed by liquid chromatography-tandem mass spectrometry for R- and S methadone and R- and S-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP) or for buprenorphine, norbuprenorphine, and their glucuronides [buprenorphine-3 glucuronide (B-3-G) and norbuprenorphine-3-glucuronide (N-3-G)]. R- and S-EDDP were detected in three of five, four of five, and five of five media from cells pretreated with DMSO, nelfinavir, and rifampin. R-EDDP increased 3.1- and 26.5 fold, and S-EDDP increased 2.5- and 21.3-fold after nelfinavir and rifampin. The rifampin effect was significant. B-3-G production was detected in media of all cells incubated with buprenorphine and accounted for most of the buprenorphine loss from culture media; it was not significantly affected by either pretreatment. Norbuprenorphine and N-3-G together were detected in three of five, four of five, and five of five donors pretreated with DMSO, nelfinavir and rifampin, and norbuprenorphine in one of five, one of five, and two of five donors. Although there was a trend for norbuprenorphine (2.8- and 4.9-fold) and N 3-G (1.7- and 1.9-fold) to increase after nelfinavir and rifampin, none of the changes were significant. To investigate low norbuprenorphine production, buprenorphine was incubated with human liver and small intestine microsomes fortified to support both N-dealkylation and glucuronidation; N-dealkylation predominated in small intestine and glucuronidation in liver microsomes. These studies support the hypothesis that methadone metabolism and its potential for drug interactions can be predicted with cultured human hepatocytes, but for buprenorphine the combined effects of hepatic and small intestinal metabolism are probably involved. PMID- 19773543 TI - Class prediction models of thrombocytosis using genetic biomarkers. AB - Criteria for distinguishing among etiologies of thrombocytosis are limited in their capacity to delineate clonal (essential thrombocythemia [ET]) from nonclonal (reactive thrombocytosis [RT]) etiologies. We studied platelet transcript profiles of 126 subjects (48 controls, 38 RT, 40 ET [24 contained the JAK2V(617)F mutation]) to identify transcript subsets that segregated phenotypes. Cross-platform consistency was validated using quantitative real-time polymerase chain reaction (RT-PCR). Class prediction algorithms were developed to assign phenotypic class between the thrombocytosis cohorts, and by JAK2 genotype. Sex differences were rare in normal and ET cohorts (< 1% of genes) but were male skewed for approximately 3% of RT genes. An 11-biomarker gene subset using the microarray data discriminated among the 3 cohorts with 86.3% accuracy, with 93.6% accuracy in 2-way class prediction (ET vs RT). Subsequent quantitative RT-PCR analysis established that these biomarkers were 87.1% accurate in prospective classification of a new cohort. A 4-biomarker gene subset predicted JAK2 wild type ET in more than 85% patient samples using either microarray or RT-PCR profiling, with lower predictive capacity in JAK2V(617)F mutant ET patients. These results establish that distinct genetic biomarker subsets can predict thrombocytosis class using routine phlebotomy. PMID- 19773544 TI - A CD44v6 peptide reveals a role of CD44 in VEGFR-2 signaling and angiogenesis. AB - A specific splice variant of the CD44 cell- surface protein family, CD44v6, has been shown to act as a coreceptor for the receptor tyrosine kinase c-Met on epithelial cells. Here we show that also on endothelial cells (ECs), the activity of c-Met is dependent on CD44v6. Furthermore, another receptor tyrosine kinase, VEGFR-2, is also regulated by CD44v6. The CD44v6 ectodomain and a small peptide mimicking a specific extracellular motif of CD44v6 or a CD44v6-specific antibody prevent CD44v6-mediated receptor activation. This indicates that the extracellular part of CD44v6 is required for interaction with c-Met or VEGFR-2. In the cytoplasm, signaling by activated c-Met and VEGFR-2 requires association of the CD44 carboxy-terminus with ezrin that couples CD44v6 to the cytoskeleton. CD44v6 controls EC migration, sprouting, and tubule formation induced by hepatocyte growth factor (HGF) or VEGF-A. In vivo the development of blood vessels from grafted EC spheroids and angiogenesis in tumors is impaired by CD44v6 blocking reagents, suggesting that the coreceptor function of CD44v6 for c Met and VEGFR-2 is a promising target to block angiogenesis in pathologic conditions. PMID- 19773545 TI - Bone marrow as an alternative site for islet transplantation. AB - The liver is the current site for pancreatic islet transplantation, but has many drawbacks due to immunologic and nonimmunologic factors. We asked whether pancreatic islets could be engrafted in the bone marrow (BM), an easily accessible and widely distributed transplant site that may lack the limitations seen in the liver. Syngeneic islets engrafted efficiently in the BM of C57BL/6 mice rendered diabetic by streptozocin treatment. For more than 1 year after transplantation, these animals showed parameters of glucose metabolism that were similar to those of nondiabetic mice. Islets in BM had a higher probability to reach euglycemia than islets in liver (2.4-fold increase, P = .02), showed a compact morphology with a conserved ratio between alpha and beta cells, and affected bone structure only very marginally. Islets in BM did not compromise hematopoietic activity, even when it was strongly induced in response to a BM aplasia-inducing infection with lymphocytic choriomeningitis virus. In conclusion, BM is an attractive and safe alternative site for pancreatic islet transplantation. The results of our study open a research line with potentially significant clinical impact, not only for the treatment of diabetes, but also for other diseases amenable to treatment with cellular transplantation. PMID- 19773546 TI - The BH3-only protein Bim plays a critical role in leukemia cell death triggered by concomitant inhibition of the PI3K/Akt and MEK/ERK1/2 pathways. AB - Mechanisms underlying apoptosis induced by concomitant interruption of the mitogen-activated protein kinase kinase/extracellular signal-regulated kinase 1/2 (MEK/ERK1/2) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways were investigated in human leukemia cells. Inhibition of these pathways using the MEK inhibitor PD184352 or U0126 and the PI3K/Akt inhibitor perifosine strikingly induced apoptosis in multiple malignant human hematopoietic cells, and substantially reduced the colony-forming capacity of primary acute myeloblastic leukemia, but not normal CD34+ cells. These events were associated with pronounced Bim up-regulation, Mcl-1 down-regulation, marked Bak/Bax conformational change accompanied by Bax membrane translocation, and a pronounced increase in Bax/Bak association. Molecular studies using tet-inducible Akt, constitutively active MEK1, dominant-negative Akt, and MEK1 small interfering RNA revealed that inhibition of both MEK/ERK1/2 and Akt pathways plays a critical functional role in perifosine/PD184352-mediated lethality. Ectopic Mcl-1 expression potently inhibited perifosine/PD184352-induced apoptosis, as did Bak or Bax knockdown. Notably, knockdown of Bim, but not Bad, blocked Bak and Bax conformational change, inhibited Bax membrane translocation, diminished Bax/Bak binding, and sharply attenuated perifosine/PD184352-induced apoptosis. Finally, enforced expression of Bim significantly enhanced apoptosis induced by PI3K/Akt inhibitors, analogous to the effects of MEK1/2 inhibitors. Collectively, these findings suggest that Bim, and Mcl-1, but not Bad, integrate death signaling triggered by concomitant disruption of the PI3K/Akt and MEK1/2/ERK1/2 pathways in human leukemia cells. PMID- 19773547 TI - Cultural constraints on brain development: evidence from a developmental study of visual word processing in mandarin chinese. AB - Developmental differences in phonological and orthographic processing in Chinese were examined in 9 year olds, 11 year olds, and adults using functional magnetic resonance imaging. Rhyming and spelling judgments were made to 2-character words presented sequentially in the visual modality. The spelling task showed greater activation than the rhyming task in right superior parietal lobule and right inferior temporal gyrus, and there were developmental increases across tasks bilaterally in these regions in addition to bilateral occipital cortex, suggesting increased involvement over age on visuo-orthographic analysis. The rhyming task showed greater activation than the spelling task in left superior temporal gyrus and there were developmental decreases across tasks in this region, suggesting reduced involvement over age on phonological representations. The rhyming and spelling tasks included words with conflicting orthographic and phonological information (i.e., rhyming words spelled differently or nonrhyming words spelled similarly) or nonconflicting information. There was a developmental increase in the difference between conflicting and nonconflicting words in left inferior parietal lobule, suggesting greater engagement of systems for mapping between orthographic and phonological representations. Finally, there were developmental increases across tasks in an anterior (Broadman area [BA] 45, 46) and posterior (BA 9) left inferior frontal gyrus, suggesting greater reliance on controlled retrieval and selection of posterior lexical representations. PMID- 19773548 TI - Tyrosine phosphorylation of Kir3 following kappa-opioid receptor activation of p38 MAPK causes heterologous desensitization. AB - Prior studies showed that tyrosine 12 phosphorylation in the N-terminal, cytoplasmic domain of the G-protein-gated inwardly rectifying potassium channel, K(ir)3.1 facilitates channel deactivation by increasing intrinsic GTPase activity of the channel. Using a phosphoselective antibody directed against this residue (pY12), we now report that partial sciatic nerve ligation increased pY12-K(ir)3.1 immunoreactivity (ir) in the ipsilateral dorsal horn of wild-type mice, but not in mice lacking the kappa-opioid receptor (KOR) or lacking the G-protein receptor kinase 3 (GRK3) genes. Treatment of AtT-20 cells stably expressing KOR-GFP with the selective KOR agonist U50,488 increased both phospho-p38-ir and pY12-K(ir)3.1 ir. The U50,488-induced increase in pY12-K(ir)3.1-ir was blocked by the p38 inhibitor SB203580. Cells expressing KOR(S369A)-GFP did not increase either phospho-p38-ir or pY12-K(ir)3.1-ir following U50,488 treatment. Whole cell voltage clamp of AtT-20 cells expressing KOR-GFP demonstrated that p38 activation by U50,488 reduced somatostatin-evoked K(ir)3 currents. This heterologous desensitization was blocked by SB203580 and was not evident in cells expressing KOR(S369A)-GFP. Tyrosine phosphorylation of K(ir)3.1 was likely mediated by p38 MAPK activation of Src kinase. U50,488 also increased (pY418)Src-ir; this increase was blocked by SB203580 and not evident in KOR(S369A)-GFP expressing AtT20 cells; the Src inhibitor PP2 blocked the U50,488-induced increase in pY12 K(ir)3.1-ir; and the heterologous desensitization of K(ir)3 currents was blocked by PP2. These results suggest that KOR causes phosphorylation of Y12-K(ir)3.1 and channel inhibition through a GRK3-, p38 MAPK- and Src-dependent mechanism. Reduced inward potassium current following nerve ligation would increase dorsal horn neuronal excitability and may contribute to the neuropathic pain response. PMID- 19773549 TI - The fifth transmembrane domain of angiotensin II Type 1 receptor participates in the formation of the ligand-binding pocket and undergoes a counterclockwise rotation upon receptor activation. AB - The octapeptide hormone angiotensin II exerts a wide variety of cardiovascular effects through the activation of the angiotensin II Type 1 (AT(1)) receptor, which belongs to the G protein-coupled receptor superfamily. Like other G protein coupled receptors, the AT(1) receptor possesses seven transmembrane domains that provide structural support for the formation of the ligand-binding pocket. The role of the fifth transmembrane domain (TMD5) was investigated using the substituted cysteine accessibility method. All of the residues within Thr-190 to Leu-217 region were mutated one at a time to cysteine, and after expression in COS-7 cells, the mutant receptors were treated with the sulfhydryl-specific alkylating agent methanethiosulfonate-ethylammonium (MTSEA). MTSEA reacts selectively with water-accessible, free sulfhydryl groups of endogenous or introduced point mutation cysteines. If a cysteine is found in the binding pocket, the covalent modification will affect the binding kinetics of the ligand. MTSEA substantially decreased the binding affinity of L197C-AT(1), N200C-AT(1), I201C-AT(1), G203C-AT(1), and F204C-AT(1) mutant receptors, which suggests that these residues orient themselves within the water-accessible binding pocket of the AT(1) receptor. Interestingly, this pattern of acquired MTSEA sensitivity was altered for TMD5 reporter cysteines engineered in a constitutively active N111G AT(1) receptor background. Indeed, mutant I201C-N111G-AT(1) became more sensitive to MTSEA, whereas mutant G203C-N111G-AT(1) lost some sensitivity. Our results suggest that constitutive activation of AT(1) receptor causes an apparent counterclockwise rotation of TMD5 as viewed from the extracellular side. PMID- 19773550 TI - Alternative mRNA splicing produces a novel biologically active short isoform of PGC-1alpha. AB - The transcriptional co-activator PGC-1alpha regulates functional plasticity in adipose tissue by linking sympathetic input to the transcriptional program of adaptive thermogenesis. We report here a novel truncated form of PGC-1alpha (NT PGC-1alpha) produced by alternative 3' splicing that introduces an in-frame stop codon into PGC-1alpha mRNA. The expressed protein includes the first 267 amino acids of PGC-1alpha and 3 additional amino acids from the splicing insert. NT-PGC 1alpha contains the transactivation and nuclear receptor interaction domains but is missing key domains involved in nuclear localization, interaction with other transcription factors, and protein degradation. Expression and subcellular localization of NT-PGC-1alpha are dynamically regulated in the context of physiological signals that regulate full-length PGC-1alpha, but the truncated domain structure conveys unique properties with respect to protein-protein interactions, protein stability, and recruitment to target gene promoters. Therefore, NT-PGC-1alpha is a co-expressed, previously unrecognized form of PGC 1alpha with functions that are both unique from and complementary to PGC-1alpha. PMID- 19773551 TI - C-terminal domains of transmembrane alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptor regulatory proteins not only facilitate trafficking but are major modulators of AMPA receptor function. AB - Alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA)-type glutamate receptors are essential players in fast synaptic transmission in the vertebrate central nervous system. Their synaptic delivery and localization as well as their electrophysiological properties are regulated by transmembrane AMPA receptor regulatory proteins (TARPs). However, the exact mechanisms of how the four originally designated TARPs (gamma2, gamma3, gamma4, and gamma8) modulate AMPA receptor function remain largely unknown. Previous studies suggested the C terminal domain (CTD) of gamma2 to mediate increased trafficking and reduced desensitization of AMPA receptors. As it remained unclear whether these findings extend to other TARPs, we set out to investigate and compare the role of the CTDs of the four original TARPs in AMPA receptor modulation. To address this issue, we replaced the TARP CTDs with the CTD of the homologous subunit gamma1, a voltage dependent calcium channel subunit expressed in skeletal muscle that lacks TARP properties. We analyzed the impact of the resulting chimeras on GluR1 functional properties in Xenopus oocytes and HEK293 cells. Interestingly, the CTDs of all TARPs not only modulate the extent and kinetics of desensitization but also modulate agonist potencies of AMPA receptors. Furthermore, the CTDs are required for TARP-induced modulation of AMPA receptor gating, including conversion of antagonists to partial agonists and constitutive channel openings. Strikingly, we found a special role of the cytoplasmic tail of gamma4, suggesting that the underlying mechanisms of modulation of AMPA receptor function are different among the TARPs. We propose that the intracellularly located CTD is the origin of TARP specific functional modulation and not merely a facilitator of trafficking. PMID- 19773552 TI - Design of an insulin analog with enhanced receptor binding selectivity: rationale, structure, and therapeutic implications. AB - Insulin binds with high affinity to the insulin receptor (IR) and with low affinity to the type 1 insulin-like growth factor (IGF) receptor (IGFR). Such cross-binding, which reflects homologies within the insulin-IGF signaling system, is of clinical interest in relation to the association between hyperinsulinemia and colorectal cancer. Here, we employ nonstandard mutagenesis to design an insulin analog with enhanced affinity for the IR but reduced affinity for the IGFR. Unnatural amino acids were introduced by chemical synthesis at the N- and C capping positions of a recognition alpha-helix (residues A1 and A8). These sites adjoin the hormone-receptor interface as indicated by photocross-linking studies. Specificity is enhanced more than 3-fold on the following: (i) substitution of Gly(A1) by D-Ala or D-Leu, and (ii) substitution of Thr(A8) by diaminobutyric acid (Dab). The crystal structure of [D-Ala(A1),Dab(A8)]insulin, as determined within a T(6) zinc hexamer to a resolution of 1.35 A, is essentially identical to that of human insulin. The nonstandard side chains project into solvent at the edge of a conserved receptor-binding surface shared by insulin and IGF-I. Our results demonstrate that modifications at this edge discriminate between IR and IGFR. Because hyperinsulinemia is typically characterized by a 3-fold increase in integrated postprandial insulin concentrations, we envisage that such insulin analogs may facilitate studies of the initiation and progression of cancer in animal models. Future development of clinical analogs lacking significant IGFR cross-binding may enhance the safety of insulin replacement therapy in patients with type 2 diabetes mellitus at increased risk of colorectal cancer. PMID- 19773553 TI - Abeta42-to-Abeta40- and angiotensin-converting activities in different domains of angiotensin-converting enzyme. AB - Amyloid beta-protein 1-42 (Abeta42) is believed to play a causative role in the development of Alzheimer disease (AD), although it is a minor part of Abeta. In contrast, Abeta40 is the predominant secreted form of Abeta and recent studies have suggested that Abeta40 has neuroprotective effects and inhibits amyloid deposition. We have reported that angiotensin-converting enzyme (ACE) converts Abeta42 to Abeta40, and its inhibition enhances brain Abeta42 deposition (Zou, K., Yamaguchi, H., Akatsu, H., Sakamoto, T., Ko, M., Mizoguchi, K., Gong, J. S., Yu, W., Yamamoto, T., Kosaka, K., Yanagisawa, K., and Michikawa, M. (2007) J. Neurosci. 27, 8628-8635). ACE has two homologous domains, each having a functional active site. In the present study, we identified the domain of ACE, which is responsible for converting Abeta42 to Abeta40. Interestingly, Abeta42-to Abeta40-converting activity is solely found in the N-domain of ACE and the angiotensin-converting activity is found predominantly in the C-domain of ACE. We also found that the N-linked glycosylation is essential for both Abeta42-to Abeta40- and angiotensin-converting activities and that unglycosylated ACE rapidly degraded. The domain-specific converting activity of ACE suggests that ACE inhibitors could be designed to specifically target the angiotensin converting C-domain, without inhibiting the Abeta42-to-Abeta40-converting activity of ACE or increasing neurotoxic Abeta42. PMID- 19773554 TI - Identification of a novel family of laminin N-terminal alternate splice isoforms: structural and functional characterization. AB - The laminins are a family of heterotrimeric basement membrane proteins that play roles in cellular adhesion, migration, and tissue morphogenesis. Through in silico analysis of the laminin-encoding genes, we identified a novel family of alternate splice isoforms derived from the 5'-end of the LAMA3 and LAMA5 genes. These isoforms resemble the netrins in that they contain a laminin N-terminal domain followed by a short stretch of laminin-type epidermal growth factor-like repeats. We suggest the terms LaNt (laminin N terminus) alpha3 and LaNt alpha5, for the predicted protein products of these mRNAs. RT-PCR confirmed the presence of these transcripts at the mRNA level. Moreover, they exhibit differential, tissue-specific, expression profiles. To confirm the existence of LaNt alpha3 protein, we generated an antibody to a unique domain within the putative polypeptide. This antibody recognizes a protein at the predicted molecular mass of 64 kDa by immunoblotting. Furthermore, immunofluorescence analyses revealed a basement membrane staining in epithelial tissue for LaNt alpha3 and LaNt alpha3 localized along the substratum-associated surface of cultured keratinocytes. We have also tested the functionality LaNt alpha3 through RNAi-mediated knockdown. Keratinocytes exhibiting specific knockdown of LaNt alpha3 displayed impaired adhesion, stress resistance, and reduced ability to close scratch wounds in vitro. PMID- 19773555 TI - Induction of Th1/Th17 immune response by Mycobacterium tuberculosis: role of dectin-1, Mannose Receptor, and DC-SIGN. AB - Mtb influences DC activity and T cell-mediated immune responses. We show that the treatment of immature monocyte-derived DC with Mtb elicited the formation of mature DC, producing TNF-alpha, IL-1beta, IL-6, and IL-23 and instructing CD4(+) cells to secrete IFN-gamma and IL-17. Mtb-induced cytokine release by DC depended on dectin-1 receptor engagement, whereas MR or DC-SIGN stimulation inhibited this process. A selective dectin-1 binding by the receptor agonist glucan was sufficient to enable DC to generate Th1/Th17 lymphocytes, showing features comparable with those induced by Mtb-treated DC. Interestingly, DC-SIGN or MR engagement inhibited Th17 and increased Th1 generation by glucan- or Mtb-treated DC. Our results indicate that Mtb modulates the lymphocyte response by affecting DC maturation and cytokine release. Dectin-1 engagement by Mtb enables DC to promote a Th1/Th17 response, whereas DC-SIGN and MR costimulation limits dectin-1 dependent Th17 generation and favors a Th1 response, probably by interfering with release of cytokines. PMID- 19773556 TI - The cover. The physician Hua Tuo scraping the bone of Guan Yu to treat an arrow wound. PMID- 19773557 TI - A piece of my mind. Manipulation and the match. PMID- 19773558 TI - Professional behaviors of physicians and pursuing social justice. PMID- 19773559 TI - China's health system reform and medical education. PMID- 19773560 TI - Addressing physician specialty maldistribution. PMID- 19773561 TI - Postgraduate choices of graduates from medical scientist training programs, 2004 2008. PMID- 19773562 TI - Evaluating obstetrical residency programs using patient outcomes. AB - CONTEXT: Patient outcomes have been used to assess the performance of hospitals and physicians; in contrast, residency programs have been compared based on nonclinical measures. OBJECTIVE: To assess whether obstetrics and gynecology residency programs can be evaluated by the quality of care their alumni deliver. DESIGN, SETTING, AND PATIENTS: A retrospective analysis of all Florida and New York obstetrical hospital discharges between 1992 and 2007, representing 4 906 169 deliveries performed by 4124 obstetricians from 107 US residency programs. MAIN OUTCOME MEASURES: Nine measures of maternal complications from vaginal and cesarean births reflecting laceration, hemorrhage, and all other complications after vaginal delivery; hemorrhage, infection, and all other complications after cesarean delivery; and composites for vaginal and cesarean deliveries and for all deliveries regardless of mode. RESULTS: Obstetricians' residency program was associated with substantial variation in maternal complication rates. Women treated by obstetricians trained in residency programs in the bottom quintile for risk-standardized major maternal complication rates had an adjusted complication rate of 13.6%, approximately one-third higher than the 10.3% adjusted rate for women treated by obstetricians from programs in the top quintile (absolute difference, 3.3%; 95% confidence interval, 2.8%-3.8%). The rankings of residency programs based on each of the 9 measures were similar. Adjustment for medical licensure examination scores did not substantially alter the program ranking. CONCLUSIONS: Obstetrics and gynecology training programs can be ranked by the maternal complication rates of their graduates' patients. These rankings are stable across individual types of complications and are not associated with residents' licensing examination scores. PMID- 19773563 TI - Association of an educational program in mindful communication with burnout, empathy, and attitudes among primary care physicians. AB - CONTEXT: Primary care physicians report high levels of distress, which is linked to burnout, attrition, and poorer quality of care. Programs to reduce burnout before it results in impairment are rare; data on these programs are scarce. OBJECTIVE: To determine whether an intensive educational program in mindfulness, communication, and self-awareness is associated with improvement in primary care physicians' well-being, psychological distress, burnout, and capacity for relating to patients. DESIGN, SETTING, AND PARTICIPANTS: Before-and-after study of 70 primary care physicians in Rochester, New York, in a continuing medical education (CME) course in 2007-2008. The course included mindfulness meditation, self-awareness exercises, narratives about meaningful clinical experiences, appreciative interviews, didactic material, and discussion. An 8-week intensive phase (2.5 h/wk, 7-hour retreat) was followed by a 10-month maintenance phase (2.5 h/mo). MAIN OUTCOME MEASURES: Mindfulness (2 subscales), burnout (3 subscales), empathy (3 subscales), psychosocial orientation, personality (5 factors), and mood (6 subscales) measured at baseline and at 2, 12, and 15 months. RESULTS: Over the course of the program and follow-up, participants demonstrated improvements in mindfulness (raw score, 45.2 to 54.1; raw score change [Delta], 8.9; 95% confidence interval [CI], 7.0 to 10.8); burnout (emotional exhaustion, 26.8 to 20.0; Delta = -6.8; 95% CI, -4.8 to -8.8; depersonalization, 8.4 to 5.9; Delta = -2.5; 95% CI, -1.4 to -3.6; and personal accomplishment, 40.2 to 42.6; Delta = 2.4; 95% CI, 1.2 to 3.6); empathy (116.6 to 121.2; Delta = 4.6; 95% CI, 2.2 to 7.0); physician belief scale (76.7 to 72.6; Delta = -4.1; 95% CI, -1.8 to -6.4); total mood disturbance (33.2 to 16.1; Delta = -17.1; 95% CI, -11 to -23.2), and personality (conscientiousness, 6.5 to 6.8; Delta = 0.3; 95% CI, 0.1 to 5 and emotional stability, 6.1 to 6.6; Delta = 0.5; 95% CI, 0.3 to 0.7). Improvements in mindfulness were correlated with improvements in total mood disturbance (r = -0.39, P < .001), perspective taking subscale of physician empathy (r = 0.31, P < .001), burnout (emotional exhaustion and personal accomplishment subscales, r = -0.32 and 0.33, respectively; P < .001), and personality factors (conscientiousness and emotional stability, r = 0.29 and 0.25, respectively; P < .001). CONCLUSIONS: Participation in a mindful communication program was associated with short-term and sustained improvements in well-being and attitudes associated with patient-centered care. Because before and-after designs limit inferences about intervention effects, these findings warrant randomized trials involving a variety of practicing physicians. PMID- 19773564 TI - Association of resident fatigue and distress with perceived medical errors. AB - CONTEXT: Fatigue and distress have been separately shown to be associated with medical errors. The contribution of each factor when assessed simultaneously is unknown. OBJECTIVE: To determine the association of fatigue and distress with self-perceived major medical errors among resident physicians using validated metrics. DESIGN, SETTING, AND PARTICIPANTS: Prospective longitudinal cohort study of categorical and preliminary internal medicine residents at Mayo Clinic, Rochester, Minnesota. Data were provided by 380 of 430 eligible residents (88.3%). Participants began training from 2003 to 2008 and completed surveys quarterly through February 2009. Surveys included self-assessment of medical errors, linear analog self-assessment of overall quality of life (QOL) and fatigue, the Maslach Burnout Inventory, the PRIME-MD depression screening instrument, and the Epworth Sleepiness Scale. MAIN OUTCOME MEASURES: Frequency of self-perceived, self-defined major medical errors was recorded. Associations of fatigue, QOL, burnout, and symptoms of depression with a subsequently reported major medical error were determined using generalized estimating equations for repeated measures. RESULTS: The mean response rate to individual surveys was 67.5%. Of the 356 participants providing error data (93.7%), 139 (39%) reported making at least 1 major medical error during the study period. In univariate analyses, there was an association of subsequent self-reported error with the Epworth Sleepiness Scale score (odds ratio [OR], 1.10 per unit increase; 95% confidence interval [CI], 1.03-1.16; P = .002) and fatigue score (OR, 1.14 per unit increase; 95% CI, 1.08-1.21; P < .001). Subsequent error was also associated with burnout (ORs per 1-unit change: depersonalization OR, 1.09; 95% CI, 1.05 1.12; P < .001; emotional exhaustion OR, 1.06; 95% CI, 1.04-1.08; P < .001; lower personal accomplishment OR, 0.94; 95% CI, 0.92-0.97; P < .001), a positive depression screen (OR, 2.56; 95% CI, 1.76-3.72; P < .001), and overall QOL (OR, 0.84 per unit increase; 95% CI, 0.79-0.91; P < .001). Fatigue and distress variables remained statistically significant when modeled together with little change in the point estimates of effect. Sleepiness and distress, when modeled together, showed little change in point estimates of effect, but sleepiness no longer had a statistically significant association with errors when adjusted for burnout or depression. CONCLUSION: Among internal medicine residents, higher levels of fatigue and distress are independently associated with self-perceived medical errors. PMID- 19773565 TI - Attitudes, training experiences, and professional expectations of US general surgery residents: a national survey. AB - CONTEXT: General surgery residency programs are facing multiple pressures, including attracting and retaining residents. Despite the importance of resident perspectives in designing effective responses to these pressures, understanding of residents' views is limited. OBJECTIVE: To profile US general surgery residents; characterize resident attitudes, experiences, and expectations regarding training; and examine differences by sex and training year. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional study of all general surgery residents completing a survey in January 2008 following administration of the American Board of Surgery In-Training Examination. MAIN OUTCOME MEASURES: Resident satisfaction; perceived supports, strains and concern; career motivations; and professional expectations. RESULTS: Of 5345 categorical general surgery residents, 4402 (82.4%) responded, representing 248 of 249 surgical residency programs. Most respondents expressed satisfaction with training (3686 [85.2%]; 95% confidence interval [CI], 84.1%-86.3%) and supportive peer relationships (3433 [84.2%]; 95% CI, 83.1%-85.3%). However, residents also reported unmet needs and apprehensions about training and careers. Worry that they will not feel confident performing procedures independently was reported by 1185 (27.5%; 95% CI, 26.2%-28.8%), while 2681 (63.8%; 95% CI, 62.4%-65.3%) reported that they must complete specialty training to be competitive. Perceptions of program support differ, with men more likely than women to report that their program provides support (2188 [74.5%] vs 895 [65.6%]; P < .001), and that they can turn to faculty when having difficulties (2193 [74.5%] vs 901 [66.4%]; P < .001). Reports of having considered leaving training in the prior year differed significantly across years (P < .001), highest in postgraduate year 2 (19.2%) and lowest in postgraduate year 5 (7.2%). CONCLUSIONS: General surgery residents' attitudes, experiences, and expectations regarding training reflect both high levels of satisfaction and sources of strain. These factors vary by sex and training year. PMID- 19773566 TI - Online posting of unprofessional content by medical students. AB - CONTEXT: Web 2.0 applications, such as social networking sites, are creating new challenges for medical professionalism. The scope of this problem in undergraduate medical education is not well-defined. OBJECTIVE: To assess the experience of US medical schools with online posting of unprofessional content by students and existing medical school policies to address online posting. DESIGN, SETTING, AND PARTICIPANTS: An anonymous electronic survey was sent to deans of student affairs, their representatives, or counterparts from each institution in the Association of American Medical Colleges. Data were collected in March and April 2009. MAIN OUTCOME MEASURES: Percentage of schools reporting incidents of students posting unprofessional content online, type of professionalism infraction, disciplinary actions taken, existence of institution policies, and plans for policy development. RESULTS: Sixty percent of US medical schools responded (78/130). Of these schools, 60% (47/78) reported incidents of students posting unprofessional online content. Violations of patient confidentiality were reported by 13% (6/46). Student use of profanity (52%; 22/42), frankly discriminatory language (48%; 19/40), depiction of intoxication (39%; 17/44), and sexually suggestive material (38%; 16/42) were commonly reported. Of 45 schools that reported an incident and responded to the question about disciplinary actions, 30 gave informal warning (67%) and 3 reported student dismissal (7%). Policies that cover student-posted online content were reported by 38% (28/73) of deans. Of schools without such policies, 11% (5/46) were actively developing new policies to cover online content. Deans reporting incidents were significantly more likely to report having such a policy (51% vs 18%; P = .006), believing these issues could be effectively addressed (91% vs 63%; P = .003), and having higher levels of concern (P = .02). CONCLUSION: Many responding schools had incidents of unprofessional student online postings, but they may not have adequate policy in place. PMID- 19773567 TI - Tools for direct observation and assessment of clinical skills of medical trainees: a systematic review. AB - CONTEXT: Direct observation of medical trainees with actual patients is important for performance-based clinical skills assessment. Multiple tools for direct observation are available, but their characteristics and outcomes have not been compared systematically. OBJECTIVES: To identify observation tools used to assess medical trainees' clinical skills with actual patients and to summarize the evidence of their validity and outcomes. DATA SOURCES: Electronic literature search of PubMed, ERIC, CINAHL, and Web of Science for English-language articles published between 1965 and March 2009 and review of references from article bibliographies. STUDY SELECTION: Included studies described a tool designed for direct observation of medical trainees' clinical skills with actual patients by educational supervisors. Tools used only in simulated settings or assessing surgical/procedural skills were excluded. Of 10 672 citations, 199 articles were reviewed and 85 met inclusion criteria. DATA EXTRACTION: Two authors independently abstracted studies using a modified Best Evidence Medical Education coding form to inform judgment of key psychometric characteristics. Differences were reconciled by consensus. RESULTS: A total of 55 tools were identified. Twenty-one tools were studied with students and 32 with residents or fellows. Two were used across the educational continuum. Most (n = 32) were developed for formative assessment. Rater training was described for 26 tools. Only 11 tools had validity evidence based on internal structure and relationship to other variables. Trainee or observer attitudes about the tool were the most commonly measured outcomes. Self-assessed changes in trainee knowledge, skills, or attitudes (n = 9) or objectively measured change in knowledge or skills (n = 5) were infrequently reported. The strongest validity evidence has been established for the Mini Clinical Evaluation Exercise (Mini-CEX). CONCLUSION: Although many tools are available for the direct observation of clinical skills, validity evidence and description of educational outcomes are scarce. PMID- 19773568 TI - Academic year-end transfers of outpatients from outgoing to incoming residents: an unaddressed patient safety issue. PMID- 19773569 TI - Why medical educators may be failing at feedback. PMID- 19773570 TI - Clinical gist and medical education: connecting the dots. PMID- 19773571 TI - Educating health care professionals to care for patients with disabilities. PMID- 19773572 TI - Practice, rehearsal, and performance: an approach for simulation-based surgical and procedure training. PMID- 19773573 TI - Enhancing meaning in work: a prescription for preventing physician burnout and promoting patient-centered care. PMID- 19773574 TI - Medical schools in the United States, 2008-2009. PMID- 19773575 TI - Graduate medical education, 2008-2009. PMID- 19773576 TI - JAMA patient page. Continuing medical education. PMID- 19773577 TI - VLDL-TG kinetics: a dual isotope study for quantifying VLDL-TG pool size, production rates, and fractional oxidation in humans. AB - Very-low-density lipoproteins (VLDLs) are large, complex particles containing both surface proteins (e.g., ApoB100) and core lipids, e.g., cholesterol and triglycerides (TG). Whereas ApoB100 kinetics have been thoroughly studied, accurate measurement of VLDL-TG kinetics have proven difficult due to either complex mathematics or laborious procedures. The present study was therefore designed to measure VLDL-TG kinetics by dual isotope ex vivo labeled VLDL-TG tracers and well-established kinetics equations (bolus injection or the primed continuous infusion). Ten healthy Caucasian men [age, 23 +/- 3 yr old (mean +/- SD); body mass index, 24.7 +/- 1.3 kg/m(2)] were included in the study. VLDL-TG rate of appearance (Ra) was measured using a dual-tracer technique ([9,10-(3)H] labeled VLDL-TG and [1-(14)C]-labeled VLDL-TG) to allow comparison of various bolus decay curve fits with the Ra obtained by the primed continuous infusion (PCI; considered the gold standard). In addition, VLDL-TG fatty acid oxidation was measured as (14)CO(2) in exhaled breath, using the hyamine trapping technique. Following a bolus injection, tracer decay was better described by a biexponential than a monoexponential fit (r(2) = 0.99 +/- 0.01 vs. 0.97 +/- 0.04, respectively, P = 0.01). VLDL-TG Ra calculated using the PCI correlated significantly with the biexponential fit (rho = 0.62, P < 0.05), whereas this was not the case for the monoexponential fit (rho = -0.18, P = not significant). VLDL TG Ra using the best fit of the bolus injection method (biexponential) was less than values obtained by the constant infusion technique [biexponential, 34.3 (range, 27.1-69.6) vs. PCI, 44.4 (range, 33.0-72.7), P < 0.05]. Fractional oxidation of VLDL-TG was 37.2 +/- 8.8% at 240 min corresponding to 198.8 +/- 55.9 kcal/day or 10.6 +/- 3.3% of resting energy expenditure (REE). Our data demonstrate that VLDL-TG Ra measured by a biexponential fit to a bolus decay curve correlates well with VLDL-TG Ra measured by a primed continuous infusion, and therefore that a "second" peripheral VLDL-TG compartment with rapid exchange of TG exists. VLDL-TG volume of distribution is therefore greater than previously anticipated. Finally our data supports that VLDL-TG contributes quantitatively to REE. PMID- 19773578 TI - A regulatory role of LPCAT1 in the synthesis of inflammatory lipids, PAF and LPC, in the retina of diabetic mice. AB - Platelet-activating factor (PAF) and lysophosphatidylcholine (LPC) are potent inflammatory lipids. Elevated levels of PAF and LPC are associated with the onset of diabetic retinopathy and neurodegeneration. However, the molecular mechanisms underlying such defects remain elusive. LPCAT1 is a newly reported lysophospholipid acyltransferase implicated in the anti-inflammatory response by its role in conversion of LPC to PC. Intriguingly, the LPCAT1 enzyme also catalyzes the synthesis of PAF from lyso-PAF with use of acetyl-CoA as a substrate. The present studies investigated regulatory roles of LPCAT1 in the synthesis of inflammatory lipids during the onset of diabetes. Our work shows that LPCAT1 plays an important role in the inactivation of PAF by catalyzing the synthesis of alkyl-PC, an inactivated form of PAF with use of acyl-CoA and lyso PAF as substrates. In support of a role of LPCAT1 in anti-inflammatory responses in diabetic retinopathy, LPCAT1 is most abundantly expressed in the retina. Moreover, LPCAT1 mRNA levels and acyltransferase activity toward lyso-PAF and LPC were significantly downregulated in retina and brain tissues in response to the onset of diabetes in Ins2(Akita) and db/db mice, mouse models of type 1 and type 2 diabetes, respectively. Conversely, treatment of db/db mice with rosiglitazone, an antidiabetes compound, significantly upregulated LPCAT1 mRNA levels concurrently with increased acyltransferase activity in the retina and brain. Collectively, these findings identified a novel regulatory role of LPCAT1 in catalyzing the inactivation of inflammatory lipids in the retina of diabetic mice. PMID- 19773579 TI - USP19-deubiquitinating enzyme regulates levels of major myofibrillar proteins in L6 muscle cells. AB - The ubiquitin-proteasome system plays an important role in the degradation of myofibrillar proteins that occurs in muscle wasting. Many studies have demonstrated the importance of enzymes mediating conjugation of ubiquitin. However, little is known about the role of deubiquitinating enzymes. We previously showed that the USP19-deubiquitinating enzyme is induced in atrophying skeletal muscle (Combaret L, Adegoke OA, Bedard N, Baracos V, Attaix D, Wing SS. Am J Physiol Endocrinol Metab 288: E693-E700, 2005). To further explore the role of USP19, we used small interfering RNA (siRNA) in L6 muscle cells. Lowering USP19 by 70-90% in myotubes resulted in a 20% decrease in the rate of proteolysis and an 18% decrease in the rate of protein synthesis, with no net change in protein content. Despite the decrease in overall synthesis, there were approximately 1.5-fold increases in protein levels of myosin heavy chain (MHC), actin, and troponin T and a approximately 2.5-fold increase in tropomyosin. USP19 depletion also increased MHC and tropomyosin mRNA levels, suggesting that this effect is due to increased transcription. Consistent with this, USP19 depletion increased myogenin protein and mRNA levels approximately twofold. Lowering myogenin using siRNA prevented the increase in MHC and tropomyosin upon USP19 depletion, indicating that myogenin mediated the increase in myofibrillar proteins. Dexamethasone treatment lowered MHC and increased USP19. Depletion of USP19 reversed the dexamethasone suppression of MHC. These studies demonstrate that USP19 modulates transcription of major myofibrillar proteins and indicate that the ubiquitin system not only mediates the increased protein breakdown but is also involved in the decreased protein synthesis in atrophying skeletal muscle. PMID- 19773580 TI - Using the principles of randomized controlled trial design to guide test evaluation. AB - The decision to use a new test should be based on evidence that it will improve patient outcomes or produce other benefits without adversely affecting patients. In principle, long-term randomized controlled trials (RCTs) of test-plus treatment strategies offer ideal evidence of the benefits of introducing a new test relative to current best practice. However, long-term RCTs may not always be necessary. The authors advocate using the hypothetical RCT as a conceptual framework to identify what types of comparative evidence are needed for test evaluation. Evaluation begins by stating the major claims for the new test and determining whether it will be used as a replacement, add-on, or triage test to achieve these claims. A flow diagram of this hypothetical RCT is constructed to show the essential design elements, including population, prior tests, new test and existing test strategies, and primary and secondary outcomes. Critical steps in the pathway between testing and patient outcomes, such as differences in test accuracy, changes in treatment, or avoidance of other tests, are displayed for each test strategy. All differences between the tests at these critical steps are identified and prioritized to determine the most important questions for evaluation. Long-term RCTs will not be necessary if it is valid to use other sources of evidence to address these questions. Validity will depend on issues such as the spectrum of patients identified by the old and new test strategies. PMID- 19773581 TI - The German Coronary Artery Disease Risk Screening Model: development, validation, and application of a decision-analytic model for coronary artery disease prevention with statins. AB - BACKGROUND: Coronary artery disease (CAD) is a major cause of death in industrial countries, leading to high health-related costs and decreased quality of life. OBJECTIVE: To develop and validate a decision-analytic model for CAD risk screening in Germany (German Coronary Artery Disease Screening Model). DESIGN: Markov model. TARGET POPULATION: Age- and gender-specific cohorts of the German population. DATA SOURCES: Mortality rates posted by the German Federal Statistical Office, the German Health Survey, social health insurance institutions, the MONICA Augsburg study, and the literature. TIME HORIZON: Lifetime. INTERVENTIONS: CAD risk screening for high-risk individuals using Framingham risk equation and use of statins as the primary preventive measure, compared with a setting without screening. OUTCOME MEASURES: Life-years (LY) gained, quality-adjusted life-years (QALYs) gained. RESULTS: The model-based CAD incidence corresponds well with empirical data from the MONICA Augsburg study. Health outcomes depend on the screening threshold (cutoff value of Framingham 10 year risk) and on the age and gender of the cohort screened (0.03 to 0.26 LYs and 0.06 to 0.42 QALYs gained per person screened in cohorts of 50- and 60-year-old men and women, respectively). CONCLUSIONS: The model provides a valid tool for evaluating the long-term effectiveness of CAD risk screening in Germany. Using statins as a primary prevention intervention for CAD in high-risk individuals identified by screening could improve the long-term health of the German population. PMID- 19773582 TI - The adoption of cost-effectiveness acceptability curves in cost-utility analyses. AB - BACKGROUND: Cost-effectiveness acceptability curves (CEACs) plot the probability that one health intervention is more cost-effective than alternatives, as a function of societal willingness to pay for additional units of health (e.g., life-years or quality-adjusted life-years gained). OBJECTIVES: To quantify the adoption of CEACs in published cost-utility analyses (CUAs), and to identify factors associated with CEAC use. METHODS: Data from the Tufts Medical Center Cost-Effectiveness Analysis Registry (www.cearegistry.org), a database with detailed information on approximately 1,400 CUAs published in the peer reviewed literature through 2006, was analyzed. The registry includes data on study origin, study methodology, reporting of results, whether CEACs were presented, and a subjective quality score. Univariate and multivariate logistic regression analyses were used to identify factors predicting CEAC use, from their introduction in 1994 through 2006. RESULTS: Approximately 15% of CUAs published since 1994 present a CEAC. The use of CEACs has increased rapidly in recent years, from 2.1% of published CUAs in 2001 to 32.6% in 2006 (P < 0.0001). The most significant predictors of CEAC use were study quality (odds ratio [OR]: 2.26; 95% confidence interval [CI]: 1.80, 2.85), recent publication (OR: 1.99; 95% CI: 1.73, 2.29), and whether studies pertain to the UK (OR: 5.66; 95% CI: 3.67, 8.72) or Sweden (OR: 3.76; 95% CI: 1.67, 8.44). CONCLUSIONS: CEAC use is increasing in the published cost-effectiveness literature, especially in UK-based studies. PMID- 19773583 TI - A discrete event simulation model to evaluate operational performance of a colonoscopy suite. AB - BACKGROUND AND AIMS: Colorectal cancer, a leading cause of cancer death, is preventable with colonoscopic screening. Colonoscopy cost is high, and optimizing resource utilization for colonoscopy is important. This study's aim is to evaluate resource allocation for optimal use of facilities for colonoscopy screening. METHOD: The authors used data from a computerized colonoscopy database to develop a discrete event simulation model of a colonoscopy suite. Operational configurations were compared by varying the number of endoscopists, procedure rooms, the patient arrival times, and procedure room turnaround time. Performance measures included the number of patients served during the clinic day and utilization of key resources. Further analysis included considering patient waiting time tradeoffs as well as the sensitivity of the system to procedure room turnaround time. RESULTS: The maximum number of patients served is linearly related to the number of procedure rooms in the colonoscopy suite, with a fixed room to endoscopist ratio. Utilization of intake and recovery resources becomes more efficient as the number of procedure rooms increases, indicating the potential benefits of large colonoscopy suites. Procedure room turnaround time has a significant influence on patient throughput, procedure room utilization, and endoscopist utilization for varying ratios between 1:1 and 2:1 rooms per endoscopist. Finally, changes in the patient arrival schedule can reduce patient waiting time while not requiring a longer clinic day. CONCLUSIONS: Suite managers should keep a procedure room to endoscopist ratio between 1:1 and 2:1 while considering the utilization of related key resources as a decision factor as well. The sensitivity of the system to processes such as turnaround time should be evaluated before improvement efforts are made. PMID- 19773584 TI - Patient time requirements for anticoagulation therapy with warfarin. AB - BACKGROUND: Most patients receiving warfarin are managed in outpatient office settings or anticoagulation clinics that require frequent visits for monitoring. OBJECTIVE: To measure the amount and value of time required of patients for chronic anticoagulation therapy with warfarin. DESIGN: /Participants. Prospective observation of a cohort of adult patients treated at a university-based anticoagulation program. Measurements. Participants completed a questionnaire and a prospective diary of the time required for 1 visit to the anticoagulation clinic, including travel, waiting, and the clinic visit. The authors reviewed subjects' medical records to obtain additional information, including the frequency of visits to the anticoagulation clinic. They used the human capital method to estimate the value of time. RESULTS: Eighty-five subjects completed the study. The mean (median) total time per visit was 147 minutes (123). Subjects averaged 15 visits per year (14) and spent 39.0 hours (29.3) per year on their visits. Other anticoagulation-related activities, such as communication with providers, pharmacy trips, and extra time preparing food, added an average of 52.7 hours (19.0) per year. The mean annual value of patient time spent traveling, waiting, and attending anticoagulation visits was $707 (median $591). The mean annual value when also including other anticoagulation-related activities was $1799 (median $1132). CONCLUSIONS: The time required of patients for anticoagulation visits was considerable, averaging approximately 2.5 hours per visit and almost 40 hours per year. METHODS: for reducing patient time requirements, such as home-based testing, could reduce costs for patients, employers, and companions. PMID- 19773585 TI - A novel high-throughput screening assay for HCN channel blocker using membrane potential-sensitive dye and FLIPR. AB - Hyperpolarization-activated cation nonselective (HCN) channels represent an interesting group of targets for drug development. In this study, the authors report the development of a novel membrane potential-sensitive dye (MPSD) assay for HCN channel modulators that has been miniaturized into 384-well fluorescent imaging plate reader (FLIPR) high-throughput screening (HTS) format. When optimized (by cell plating density, plate type, cell recovery from cryopreservation), the well-to-well signal variability was low, with a Z' = 0.73 and coefficient of variation = 6.4%, whereas the MPSD fluorescence signal amplitude was -23,700 +/- 1500 FLIPR(3) relative fluorescence units (a linear relationship was found between HCN1 MPSD fluorescence signal and the cell plating density) and was completely blocked by 30 microM ZD7288. The assay tolerated up to 1% DMSO, inclusion of which did not significantly change the signal kinetics or amplitude. A single-concentration screening of an ion channel-focused library composed of 4855 compounds resulted in 89 HCN1 blocker hits, 51 of which were subsequently analyzed with an 8-point concentration-response analysis on the IonWorks HT electrophysiology platform. The correlation between MPSD and the electrophysiology assay was moderate, as shown by the linear regression analysis (r(2) = 0.56) between the respective IC(50)s obtained using these 2 assays. The reported HTS-compatible HCN channel blocker assay can serve as a tool in drug discovery in the pursuit of HCN channel isoform-selective small molecules that could be used in the development of clinically relevant compounds. PMID- 19773586 TI - Identification of upregulators of BMP2 expression via high-throughput screening of a synthetic and natural compound library. AB - Bone morphogenetic protein II (BMP2), a member of the transforming growth factor beta (TGF-beta) superfamily, is highly expressed in osteoblasts and is a crucial regulator of osteogenic differentiation. Many observations clearly indicate the high potency of BMP2 as an inducer of osteogenesis, and it may be a novel therapeutic target for diseases associated with bone loss, especially in menopausal and postmenopausal women. To discover new agents that enhance the expression of the mouse BMP2, the authors developed a high-throughput assay to screen a synthetic and natural compound library. The cell-based high-throughput screen was conducted in 96-well plates using the clonal murine calvarial MC3T3-E1 cells. These cells were stably transfected with mouse BMP2 promoter-luciferase and calibrated with the known antiosteoporosis compound genistein. Among 3192 compounds screened, 3 agents (daidzein, formononetin, and 2 Acetyldibenzothiophene) were picked up by the high-throughput screening assay, and those compounds were identified as upregulators of BMP2 expression by real time quantitative reverse transcription-polymerase chain reaction and flow cytometry. Thus, it is demonstrated that this screening model is useful for identifying lead compounds to treat osteoporosis and maintain bone metabolism balance. PMID- 19773587 TI - Optimizing a kinase assay for IKKbeta on an HTS station. AB - Using a commercially available time-resolved fluorescence resonance energy transfer (TR-FRET)-based assay for IKKbeta, the authors have automated the assay procedure on a high-throughput screening station to carry out screening campaigns on multiwell plates. They have determined the Z' factor and optimized volumes, times, and time-resolved fluorescence parameters. They have also compared 2 kinases with different fusion tags, the influence of different enzyme/substrate ratios and of DMSO presence at different concentration. The authors found that glutathione S-transferase (GST)-fused IKKbeta shows better signal-to-noise (S/N) ratios over the poly-histidine-tagged variant. The substrate can be used at 50 nM with optimal performances when the enzyme is used at 2 nM. DMSO at 0.2% and 1% only slightly affects the S/N ratio, whereas when used at 2%, the final concentration deriving from a 50-fold dilution from a 5-mM stock solution in pure solvent, S/N undergoes a decrease of about 15%. Under the optimized conditions, the assay Z' factor calculated over 192 data points has an optimized value of 0.881 and allows the testing of 94 molecules in quadruplicate in 140 min. PMID- 19773588 TI - Profiling bioactivity of the ToxCast chemical library using BioMAP primary human cell systems. AB - The complexity of human biology has made prediction of health effects as a consequence of exposure to environmental chemicals especially challenging. Complex cell systems, such as the Biologically Multiplexed Activity Profiling (BioMAP) primary, human, cell-based disease models, leverage cellular regulatory networks to detect and distinguish chemicals with a broad range of target mechanisms and biological processes relevant to human toxicity. Here the authors use the BioMAP human cell systems to characterize effects relevant to human tissue and inflammatory disease biology following exposure to the 320 environmental chemicals in the Environmental Protection Agency's (EPA's) ToxCast phase I library. The ToxCast chemicals were assayed at 4 concentrations in 8 BioMAP cell systems, with a total of 87 assay endpoints resulting in more than 100,000 data points. Within the context of the BioMAP database, ToxCast compounds could be classified based on their ability to cause overt cytotoxicity in primary human cell types or according to toxicity mechanism class derived from comparisons to activity profiles of BioMAP reference compounds. ToxCast chemicals with similarity to inducers of mitochondrial dysfunction, cAMP elevators, inhibitors of tubulin function, inducers of endoplasmic reticulum stress, or NFkappaB pathway inhibitors were identified based on this BioMAP analysis. This data set is being combined with additional ToxCast data sets for development of predictive toxicity models at the EPA. PMID- 19773589 TI - CXCR2 inverse agonism detected by arrestin redistribution. AB - To study CXCR2 modulated arrestin redistribution, the authors employed arrestin as a fusion protein containing either the Aequorea victoria-derived enhanced green fluorescent protein (EGFP) or a recently developed mutant of eqFP611, a red fluorescent protein derived from Entacmaea quadricolor. This mutant, referred to as RFP611, had earlier been found to assume a dimeric quarternary structure. It was therefore employed in this work as a "tandem" (td) construct for pseudo monomeric fusion protein labeling. Both arrestin fusion proteins, containing either td-RFP611 (Arr-td-RFP611) or enhanced green fluorescent protein (EGFP; Arr EGFP), were found to colocalize with internalized fluorescently labeled Gro-alpha a few minutes after Gro-alpha addition. Intriguingly, however, Arr-td-RFP611 and Arr-EGFP displayed distinct cellular distribution patterns in the absence of any CXCR2-activating ligand. Under these conditions, Arr-td-RFP611 showed a largely homogeneous cytosolic distribution, whereas Arr-EGFP segregated, to a large degree, into granular spots. These observations indicate a higher sensitivity of Arr EGFP to the constitutive activity of CXCR2 and, accordingly, an increased arrestin redistribution to coated pits and endocytic vesicles. In support of this interpretation, the authors found the known CXCR2 antagonist Sch527123 to act as an inverse agonist with respect to Arr-EGFP redistribution. The inverse agonistic properties of Sch527123 were confirmed in vitro in a guanine nucleotide binding assay, revealing an IC(50) value similar to that observed for Arr-EGFP redistribution. Thus, the redistribution assay, when based on Arr-EGFP, enables the profiling of antagonistic test compounds with respect to inverse agonism. When based on Arr-td-RFP611, the assay may be employed to study CXCR2 agonism or neutral antagonism. PMID- 19773590 TI - Mental health and family out-of-pocket expenditure burdens. AB - A growing literature finds that a significant fraction of American families experience high or "catastrophic" burdens of medical spending. Families facing mental health problems may be especially vulnerable to high burdens. This study uses data from the Medical Expenditure Panel Survey to determine the annual and within-year concentration of medical spending and the extent to which mental health treatment contributes to high out-of-pocket burdens among families with and without mental health problems. On average, families incurred 44% of non mental health and 37% of out-of-pocket mental health treatment expenditures in a single month. Families with one or more members experiencing mental health problems were more likely to have periods of high out-of-pocket spending burdens. However, this study found that mental health treatment itself contributes little to high out-of-pocket spending burdens. Most of the burden was due to other medical conditions and lower average incomes among families with mental health problems. PMID- 19773591 TI - Do standard risk assessment procedures adequately account for cumulative risks?: an exploration of the possibilities using California's Air Toxics Hot Spots guidelines. AB - Existing risk assessment data and procedures can be used to address the estimation of cumulative risk, but there are several uncertainties. These are explored in the context of the State of California's Air Toxic Hot Spots program. Hazard identification for single agents is an established procedure but is much more complex for incompletely characterized or variable mixtures. Hazards from exposure to multiple agents are often only identified by chance. Similar concerns affect dose-response assessment. Although additivity is assumed by default for similar effects at low doses, exceptions are known for specific mixtures and for higher dose rates. Exposure assessment is especially complex for multiple sources, multiple agents from different sources, and target populations or individuals who face cumulative, but not necessarily simultaneous, impacts. With these contributory uncertainties, providing an integrated analysis that can inform risk management and presenting this to a diverse and often already stressed community are challenging. PMID- 19773592 TI - The role of the toxicologic pathologist in risk management. PMID- 19773593 TI - Systemic inflammatory response syndrome in nonhuman primates culminating in multiple organ failure, acute lung injury, and disseminated intravascular coagulation. AB - The systemic inflammatory response syndrome (SIRS) is a clinicopathological manifestation of overexuberant acute-phase inflammation caused by infectious or noninfectious etiologies. The systemic release of pro-inflammatory cytokines, chemokines, and lipid and vasoactive mediators induces endothelial damage and microvascular thrombosis, potentially culminating in disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and multiple organ dysfunction (MOD) or failure (MOF). We present five cases in the pig-tailed macaque and olive baboon where SIRS resulted in MOF, ARDS, DIC, and the Waterhouse-Friderichsen syndrome; each with gross and histological elements manifested as edema, deposition of fibrin, hemorrhage, and thrombosis. In the described cases, SIRS was the end-common pathway for multiple risk factors that parallel those documented in humans: major surgery, obstetric complications, and infection. The diagnosis of SIRS should be considered when evaluating nonhuman primate (NHP) cases of MOF manifesting with histological evidence of vascular leakage. Experimental manipulation of NHP models may be complicated by SIRS and accompanying rapid clinical decompensation. Such adverse events may compromise toxicological studies and should be avoided when possible. PMID- 19773594 TI - Intralobar nephroblastematosis in a nine-week-old Wistar rat. AB - Intralobar nephroblastematosis (ILNB) is a precursor lesion to the development of nephroblastoma (NB) in rats. Unilateral ILNB was observed in the kidney of a nine week-old female Wistar rat (Crl:WI) from a short-term toxicity study. Clinical pathology and urinalysis did not reveal altered renal function. This microscopic, unencapsulated lesion consisted of basophilic sheets of blastemal cells that did not include a prominent mesenchymal component. These cells expanded in the interstitium, which trapped and compressed few normal renal tubules. The blastemal cells moderately differentiated to form rosettes, primitive tubules, and a glomeruloid body. Multifocally, the lumen of primitive tubules contained eosinophilic secretions with basophilic material in the center. The diagnostic criteria used were compared and differentiated with renal dysplasia, nephrogenic rest, NB in rats, and with that of the identical lesion in children. PMID- 19773596 TI - End-of-life communication: ethnic differences between Korean American and non Hispanic White older adults. AB - OBJECTIVE: This study examined ethnic differences in end-of-life communication between Korean American and non-Hispanic White older adults using the Health Belief Model as a conceptual framework. METHOD: A cross-sectional design was employed to survey 217 community-dwelling older adults (112 Korean Americans and 105 Non-Hispanic Whites). RESULTS: Half of the participants had never held end-of life discussions with significant others. Non-Hispanic Whites were more likely to engage in end-of-life communication than Korean Americans, but the ethnicity effect was not evident in a multivariate analysis. Only participants' knowledge, perceived barriers, perceived severity, and experience of illness significantly predicted the likelihood of the end-of-life communication. Higher knowledge, stronger beliefs about the perceived severity and barriers, and greater experience of illness were related to having end-of-life communication. DISCUSSION: Knowledge and health beliefs play an important role in end-of-life communication which differs by ethnicity. Culturally competent health care practitioners need to consider ethnic variation in advance care planning. PMID- 19773595 TI - Profiles of physical and psychological violence in childhood as a risk factor for poorer adult health: evidence from the 1995-2005 National Survey of Midlife in the United States. AB - OBJECTIVE: This study examined linkages between physical and psychological violence in childhood from parents and three dimensions of adult health (self rated health, functional limitations, chronic conditions). METHODS: Regression models were estimated using data from the 1995 and 2005 waves of the National Survey of Midlife in the U.S. Responses to an adapted version of the Conflict Tactics Scales in 1995 were used to code respondents into one of nine profiles of violence distinguished by types and frequency of violence. RESULTS: Reports of both frequent physical and frequent psychological violence were associated with poorer health at baseline across the three dimensions of health, as well as with more severe declines in health across all three dimensions over the 10-year study period. DISCUSSION: Results suggest that having experienced frequent physical and psychological violence in childhood is a risk factor for poorer adult health status and declining trajectories of health throughout adulthood. PMID- 19773597 TI - Determinants of adult day center attendance among older adults with functional limitations. AB - OBJECTIVE: To examine factors related to regularity of adult day center (ADC) attendance among seniors with functional limitations. METHODS: Using data collected as part of a larger study, we identified the proportion of scheduled days attended among 101 ADC users in Montreal and identified determinants of this attendance. RESULTS: More regular attendance was associated with previous profession of ADC participant or spouse in a sector other than health care, receiving formal help for activities of daily living or instrumental activities of daily living on days of expected ADC participation, participating for the whole day rather than half a day, lower participation in prevention and health promotion activities, and lower caregiver burden among persons with cognitive impairments and higher caregiver burden among persons without cognitive impairments. DISCUSSION: To enhance ADC intervention effects, levels of participation should be maximized. Study findings suggest ways to promote more regular attendance. PMID- 19773598 TI - Examining the social context in the caregiving experience: correlates of global self-esteem among adult daughter caregivers to an older parent with cancer. AB - OBJECTIVE: To examine the associations between various patient, disease, situation, and caregiver characteristics (organized by five conceptual domains) and global self-esteem among caregiver daughters to parents with cancer. METHOD: Dyads comprised of 237 cancer outpatients and their adult caregiving daughter completed structured telephone interviews. RESULTS: Two of the five domains of potential correlates significantly predicted caregiving daughters' global self esteem-daughters' sociodemographics and constraints on/facilitators of caregiving. Daughters' overall sense of self-worth was directly correlated with their household income and inversely correlated with greater depressive affect and the number of patient needs for which someone else provided assistance. It was also correlated with the daughters' other role obligations. A higher sense of self-worth was associated with either being employed or having to care for a child/grandchild; a lower sense of self-worth was associated with having a spouse/partner. DISCUSSION: The present analysis documents the complexity of social connectedness, demonstrating that various role obligations contribute to caregiving daughters' global self-esteem in different ways. In the context of assuming cancer careprovision, daughters' existing repertoire of social roles may possibly mediate the stress associated with their care involvement or serve as a buffer against the strain of the caregiving experience. PMID- 19773599 TI - Association between health education needs and stroke caregiver injury. AB - OBJECTIVE: Many stroke caregivers are inadequately informed about stroke and its sequelae and have little preparation for the physical demands of moving, lifting, and handling often required. Our objectives are to examine the association between health education needs and physical injury sustained as a result of activities related to the caregiving role. METHOD: A total of 276 caregivers of veterans who suffered an acute stroke event were surveyed about their information needs and injury status.We used multivariate logistic regression analysis to calculate adjusted and unadjusted odds ratios for injury status. RESULTS: Results indicate that in the adjusted model, caregivers who had increased educational needs were almost twice as likely (OR: 1.80; 95% CI: 1.74-1.94) to have incurred an injury related to caregiving activities. CONCLUSIONS: Health education interventions that provide stroke caregivers with educational materials may help reduce caregiver injuries. PMID- 19773600 TI - Potential impact of ADHD with stimulant medication label on teacher expectations. AB - OBJECTIVE: The present study investigated how teachers rated children's Behavior, IQ, and Personality contingent on the presence or absence of an Attention Deficit Hyperactivity Disorder (ADHD) label. METHOD: Teachers from K-12 read a hypothetical description of either a male or female child with no label, an ADHD label, or an ADHD with stimulant treatment label. Teachers responded to 30, 7 point Likert rating scales anchored with descriptors related to Behavior, IQ, and Personality. RESULTS: Teachers rated the child with an ADHD label and ADHD with stimulant treatment label significantly less favorably than the child with no label. Results partially supported that teachers rated the child with an ADHD label significantly less favorably than the child with an ADHD with stimulant treatment label. CONCLUSION: Teachers rated the children with ADHD and ADHD with stimulant treatment label less favorably than the child with no label. Implications for educators and future research are discussed. PMID- 19773602 TI - Short-term effects of playing computer games on attention. AB - OBJECTIVE: The main aim of the present study is to investigate the short-term cognitive effects of computer games in children with different psychiatric disorders and normal controls. METHOD: One hundred one children are recruited for the study (aged between 9 and 12 years). All participants played a motor-racing game on the computer for 1 hour. The TBAG form of the Stroop task was administered to all participants twice, before playing and immediately after playing the game. RESULTS: Participants with improved posttest scores, compared to their pretest scores, used the computer on average 0.67 +/- 1.1 hr/day, while the average administered was measured at 1.6 +/- 1.4 hr/day and 1.3 +/- 0.9 hr/day computer use for participants with worse or unaltered scores, respectively. According to the regression model, male gender, younger ages, duration of daily computer use, and ADHD inattention type were found to be independent risk factors for worsened posttest scores. CONCLUSION: Time spent playing computer games can exert a short-term effect on attention as measured by the Stroop test. PMID- 19773601 TI - Childhood attention deficit hyperactivity disorder, substance use, and adult functioning among incarcerated women. AB - OBJECTIVE: To estimate prevalence of childhood ADHD among incarcerated women and determine its association with substance use and adult functioning. METHOD: 192 female participants are recruited from the Department of Corrections in Rhode Island. Childhood ADHD is defined as scoring >46 on the Wender Utah Rating Scale. RESULTS: The findings reveal that 46% met criteria for childhood ADHD. Multivariate analysis reveal that women meeting WURS criteria were more likely to be inconsistently employed (OR = 0.23, 95% CI = 0.10-0.54), recently homeless (OR = 2.09, 95% CI = 1.02-4.30), lifetime incarceration of more than 90 days (OR = 3.00, 95% CI = 1.37-6.57), current smokers (OR = 2.99, 95% CI = 1.24-7.20), and ever used marijuana regularly (OR = 3.47, 95% CI = 1.61-7.45). CONCLUSION: Among incarcerated women, childhood ADHD is associated with negative social and health behaviors. PMID- 19773604 TI - Comparative analysis of rigidity across protein families. AB - We present a comparative study in which 'pebble game' rigidity analysis is applied to multiple protein crystal structures, for each of six different protein families. We find that the main-chain rigidity of a protein structure at a given hydrogen bond energy cutoff is quite sensitive to small structural variations, and conclude that the hydrogen bond constraints in rigidity analysis should be chosen so as to form and test specific hypotheses about the rigidity of a particular protein. Our comparative approach highlights two different characteristic patterns ('sudden' or 'gradual') for protein rigidity loss as constraints are removed, in line with recent results on the rigidity transitions of glassy networks. PMID- 19773605 TI - Flux networks in metabolic graphs. AB - A metabolic model can be represented as a bipartite graph comprising linked reaction and metabolite nodes. Here it is shown how a network of conserved fluxes can be assigned to the edges of such a graph by combining the reaction fluxes with a conserved metabolite property such as molecular weight. A similar flux network can be constructed by combining the primal and dual solutions to the linear programming problem that typically arises in constraint-based modelling. Such constructions may help with the visualization of flux distributions in complex metabolic networks. The analysis also explains the strong correlation observed between metabolite shadow prices (the dual linear programming variables) and conserved metabolite properties. The methods were applied to recent metabolic models for Escherichia coli, Saccharomyces cerevisiae and Methanosarcina barkeri. Detailed results are reported for E. coli; similar results were found for other organisms. PMID- 19773606 TI - Four-dimensional targeting error analysis in image-guided radiotherapy. AB - Image-guided therapy (IGT) involves acquisition and processing of biomedical images to actively guide medical interventions. The proliferation of IGT technologies has been particularly significant in image-guided radiotherapy (IGRT), as a way to increase the tumor targeting accuracy. When IGRT is applied to moving tumors, image guidance becomes challenging, as motion leads to increased uncertainty. Different strategies may be applied to mitigate the effects of motion: each technique is related to a different technological effort and complexity in treatment planning and delivery. The objective comparison of different motion mitigation strategies can be achieved by quantifying the residual uncertainties in tumor targeting, to be detected by means of IGRT technologies. Such quantification requires an extension of targeting error theory to a 4D space, where the 3D tumor trajectory as a function of time measured (4D Targeting Error, 4DTE). Accurate 4DTE analysis can be represented by a motion probability density function, describing the statistical fluctuations of tumor trajectory. We illustrate the application of 4DTE analysis through examples, including weekly variations in tumor trajectory as detected by 4DCT, respiratory gating via external surrogates and real-time tumor tracking. PMID- 19773607 TI - Absorbed fractions for alpha-particles in tissues of cortical bone. AB - Bone-seeking alpha-particle emitting radionuclides are common health physics hazards. Additionally, they are under consideration as an option for therapeutic molecular radiotherapy applications. Current dose models do not account for energy or bone-site dependence as shown by alpha-particle absorbed fractions given in ICRP Publication 30. Energy-dependent, yet bone-site independent, alpha particle absorbed fractions have been presented by the models of Stabin and Siegel (2003 Health Phys. 85 294-310). In this work, a chord-based computational model of alpha-particle transport in cortical bone has been developed that explicitly accounts for both the bone-site and particle-energy dependence of alpha-particle absorbed fractions in this region of the skeleton. The model accounts for energy deposition to three targets: cortical endosteum, haversian space tissues and cortical bone. Path length distributions for cortical bone given in Beddoe (1977 Phys. Med. Biol. 22 298-308) provided additional transport regions in the absorbed fraction calculation. Significant variations in absorbed fractions between different skeletal sites were observed. Differences were observed between this model and the absorbed fractions given in ICRP Publication 30, which varied by as much as a factor of 2.1 for a cortical bone surface source irradiating cortical endosteum. PMID- 19773603 TI - [New incidence and mortality data. 2003-2005]. AB - This is an update of incidence and mortality cancer data provided by the Italian Network of Cancer Registry (AIRTUM) relative to the period 2003-2005.AIRTUM is a network of general and specialized population-based cancer registries that covers about 1/3 of the Italian resident population (www.registri-tumori.it). Incidence and mortality data for the period 2003-2005 are based on 20 Registries. The five most frequently diagnosed cancers were: - prostate (18.5%), non melanoma skin (15.8%), lung (13.1%), colorectal (12.0%), bladder (5.7%) among males; - breast (24.9%), non melanoma skin (15.1%), colorectal (11.9%), lung (5.0%) and stomach (4.1%) among females. In the same period the most frequent causes of cancer death were: - cancer of the lung (27.6%), colorectal (10.7%), prostate (8.5%), stomach (7.3%) and liver (6.1%) among males; - breast cancer (16.3%), colorectal (11.9%), lung (10.3%), stomach (7.2%) and pancreas (6.5%) among females. According to the age-specific incidence rates one man and one woman every two will receive a cancer diagnosis during his/hers life (from birth to the age of 84 years). From 1993-1995 to 2003-2005, overall crude cancer incidence rate (males and females together) increased from 555.4 to 654.8 x 100,000. Standardization showed that 63% of this increase was due to ageing of the population. Moreover, most of the residual increase was among those cancer sites (breast, prostate, colorectal, thyroid and melanoma) for which early detection may have played a relevant role in anticipating (and therefore increasing) the number of diagnoses. Due to population ageing also overall cancer mortality did not show any decrease when crude rates were compared. On the contrary, standardized mortality rates (all cancers together) showed a strong decrease (311.4 vs. 266.5 x 100.000). The risk of receiving a diagnosis or dying because of cancer is still lower in residents in the regions of the South of Italy than in those of Central and Northern Italy, but they are becoming more and more similar. In Italy cancer incidence and mortality rates are similar to those in northern European countries and in USA among males, but they are still lower for women. PMID- 19773608 TI - Circulating biomarkers in cardiovascular disease. PMID- 19773609 TI - Evaluating the prognostic value of new cardiovascular biomarkers. AB - New predictors of cardiovascular outcomes are widely sought in research settings, and predictive tests are commonly recommended for routine use in cardiovascular clinical care. A number of multivariable scoring systems are in use around the world for assessment of a patient's risk. While such scoring systems are often recommended for clinical use in medical practice guidelines, their actual use in medical care falls short of recommendations. Limitations in the predictive capacity of existing predictive models are recognized, including lack of predictive accuracy, lack of ability to separate those who develop events from those who do not, and risks and costs of the testing modalities. Biomarker research is actively developing new testing strategies trying to improve upon current approaches, but it is often unclear how to assess the incremental prognostic information that a new test provides. In this report, we discuss the statistical approaches that can be used to evaluate additive predictive value of new tests. We also consider clinical research examples to put this information into a practical context. PMID- 19773610 TI - Lipid measures and cardiovascular disease prediction. AB - Traditional lipid measures are the cornerstone of risk assessment and treatment goals in cardiovascular prevention. Whereas the association between total, LDL-, HDL-cholesterol and cardiovascular disease risk has been generally acknowledged, the rather poor capacity to distinguish between patients who will and those who will not develop cardiovascular disease has prompted the search for further refinement of these traditional measures. A thorough understanding of lipid metabolism is mandatory to understand recent developments in this area. After a brief overview of lipid metabolism we will discuss the epidemiological data of total, LDL- and HDL-cholesterol and focus on recent advances in measurements of these lipoproteins. In addition we will discuss the role of triglycerides and the apolipoprotein B-A-I ratio on the incidence of cardiovascular disease. PMID- 19773611 TI - Markers of inflammation and risk of coronary heart disease. AB - Cardiovascular disease is the leading cause of global mortality, with coronary heart disease (CHD) its major manifestation. Although inflammation, the body's response to noxious stimuli, is implicated in several stages of CHD development, the relevance of circulating levels of markers of inflammation to CHD risk remains uncertain. This review summarizes available epidemiological evidence for four emerging inflammatory markers implicated in CHD (fibrinogen, C-reactive protein, lipoprotein-associated phospholipase A2 and interleukin-6); considers their likely utility in cardiovascular risk prediction; and outlines areas of outstanding uncertainty. PMID- 19773612 TI - Natriuretic peptides: prediction of cardiovascular disease in the general population and high risk populations. AB - The natriuretic peptides, especially the B-type peptide (BNP) and its inactive split-product N-terminal proBNP (Nt-proBNP) are increasingly used in screening for heart failure, primarily with reduced systolic function, in patients with symptoms suggestive of heart failure, as well in the stable (General Practitioner) setting as in the acute setting. Supporting this use is a very strong prognostic value of the natriuretic peptides. This has been shown in as well heart failure as acute coronary syndromes, but also in the general population and in high-risk groups as patients with diabetes, hypertension and coronary artery disease. This has of course raised interest for the use of the natriuretic peptides as a risk marker and for screening for heart failure with reduced systolic function in these populations. In symptomatic persons and in high risk populations, the natriuretic peptides have demonstrated a high sensitivity for ruling out the disease, if the right decision limits are choosen. Thus the number of normal echocardiographies can be reduced. More recently, the use in screening asymptomatic persons for left ventricular systolic dysfunction has gained more interest. In the unselected population, screening would probably not be cost-effective. In populations with a higher pre-test probability for heart failure, as patients with diabetes, hypertension and stable coronary artery disease, screening would presumably be more cost-effective, but evidence for the use in this setting is still lacking. PMID- 19773613 TI - Myocardial biomarkers for prediction of cardiovascular disease. AB - The identification of those persons in the population who have the highest risk of future cardiovascular events is important for targeting intensive preventive efforts. This can be reliably done using a handful of long since established risk factors. The unmet need for new molecular biomarkers for prediction of cardiovascular events in the general population is therefore low. In order for a new biomarker to be used clinically for risk prediction, a statistically significant association of levels of the biomarker to adverse outcome is not enough, but the biomarker should also be demonstrated to add discriminative capacity beyond established risk factors. In contrast to the limited value of new biomarkers for risk prediction, their usefulness for unraveling the pathophysiology of cardiovascular disease is large. The myocardium is the source of a vast number of interesting biomarkers, of which a few may be useful for risk prediction in the general population. Two of these, troponin-I and the N-terminal fragment of brain natriuretic peptide, have passed tests of added discriminatory value. Numerous other biomarkers produced by cardiomyocytes or non-cardiomyocytes in the myocardium are promising, and if they are not proven useful for risk prediction, they will unquestionably enhance our understanding of cardiovascular disease. PMID- 19773614 TI - Use of obesity biomarkers in cardiovascular epidemiology. AB - Obesity is an established risk factor for cardiovascular disease (CVD), yet, the underlying mechanisms are only poorly understood. The adipose tissue produces a variety of hormones and cytokines and thereby actively participates in a network of biomarkers that may be relevant for the development of CVD. Such obesity biomarkers have a great potential to better characterize the obesity phenotype that may be relevant for the risk of CVD beyond anthropometric parameters. They may be used to support mechanistic studies, to help identify individuals at risk for CVD, and to evaluate the effect of preventive measures. The present article discusses the role of some of the most promising obesity biomarkers in cardiovascular epidemiology, including inflammatory markers, adiponectin, resistin, and fetuin-A. Importantly, some of these markers have been related to cardiovascular risk even after accounting for anthropometric parameters. Further, the potential ability to manipulate blood levels of some of these biomarkers through medication, diet and lifestyle make them attractive markers for cardiovascular risk. However, many open questions remain--especially with regard to the causal role of the factors as well as with regard to the extent of improvement in CVD prediction by these markers--before measurement of these biomarkers may be recommended on a public health level. PMID- 19773615 TI - Prognostic biomarkers in individuals with prevalent coronary heart disease. AB - Coronary disease is the leading killer of individuals worldwide and a leading cause of healthcare expenditure. On a global scale, ischemic heart disease kills over 6 million individuals each year and is projected by the World Health Organization to be the greatest single-disease cause of death worldwide by an increasing margin into 2030. Nearly 17 million Americans (7.6% of the population) have prevalent coronary heart disease, 8 million of whom have had a prior myocardial infarction. It is estimated that in 2009, 550,000 will die from coronary heart disease in the United States and that the direct and indirect costs from treating coronary heart disease will exceed $165 billion. Although patients with known coronary artery disease are among the highest risk patients for future cardiac events, not all patients with coronary disease will have an ischemic event (first or recurrent). Determining which of these patients will have an ischemic event is critical to the concept of personalized cardiovascular care. Increasingly, biomarkers that can be readily assayed from blood or other body fluids will be critical to risk stratification and effective application of secondary prevention strategies, just as they have played an increasingly prominent role in risk stratification of acute coronary syndrome patients. PMID- 19773616 TI - Multimarker approach in cardiovascular risk prediction. AB - Various biomarkers express different pathways and pathophysiologic mechanisms of cardiovascular disease, such as inflammation, oxidative stress, myocardial injury, activation of the neurohormonal pathways, myocardial stress and renal function. Current thinking supports the notion that the combination of these biomarkers could increase their diagnostic and prognostic value. The multimarker approach offers benefits since it increases the diagnostic and prognostic information and may help in the design of a strategy for prevention or management of cardiovascular diseases. The purpose of the current review is to describe the characteristics of promising biomarkers which have shown an important additive value in the assessment of cardiovascular risk. Also, an extended reference is made regarding studies that address the prognostic value of multimarker models in the settings of primary prevention of cardiovascular disease and secondary prevention for patients with acute coronary syndromes, chronic coronary artery disease and heart failure. PMID- 19773617 TI - Cardiovascular magnetic resonance imaging for detection of myocardial viability in chronic ischemic left ventricular dysfunction. AB - Chronic ischemic left ventricular dysfunction is present in number of clinical syndromes in which myocardial revascularization results in an improvement of left ventricular function, patients' functional class, and their survival. Coronary arteriography is of limited value in diagnosis of viability. Noninvasive testing, traditionally nuclear imaging, stress echocardiography and (stress) electrocardiography have been the clinical mainstays for assessing myocardial viability as well as to detect myocardial ischemia. However, cardiovascular magnetic resonance is a rapidly emerging noninvasive imaging technique, providing high-resolution images of the heart in any desired plane and without radiation. Rather than a single technique, cardiovascular magnetic resonance consists of several techniques that can be performed separately or in various combinations during a patient examination. Whereas, no single cardiovascular magnetic resonance technique has a perfect, or near perfect, sensitivity and specificity, therefore, a combination of various cardiovascular magnetic resonance techniques are needed for the assessment of myocardial viability. The aim of this review article is to summarize our current understanding of the concept of myocardial viability, to discuss the clinical value of cardiovascular magnetic resonance (in particular the different cardiovascular magnetic resonance techniques to assess viability) for the evaluation of patients with coronary artery disease and chronic left ventricular dysfunction and to present the current place of cardiovascular magnetic resonance among other techniques for the assessment of viable myocardium. PMID- 19773618 TI - [Safety and efficacy study of the recombinant granulocyte colony-stimulating factor for prevention of neutropenia and neutropenia-related complications in women with metastatic breast cancer receiving docetaxel/doxorubicin]. AB - BACKGROUND: We evaluated efficacy and safety of recombinant granulocyte-colony stimulating factor (rGCSF) used as primary prophylaxis to prevent neutropenia and neutropenia-related complications induced by docetaxel and doxorubicin chemotherapy in patients with metastatic breast cancer. PATIENTS AND METHODS: Three centers in Lithuania enrolled 36 patients who received rGCSF (5 microg/kg/d) on day 2 of each 21-day chemotherapy with docetaxel 75 mg/m(2) and doxorubicin 50 mg/m(2) (AT) starting in the first cycle. Treatment regimen was repeated for up to six cycles. RESULTS: Leukocytosis, bone pain, and headache were the most frequent adverse events, with incidence rates of 22%, 19%, and 8%, respectively. Adverse events were typical for rGCSF in this patient population. Overall incidence rate of febrile neutropenia was 14%. The mean duration of febrile neutropenia episodes across cycles was 2.14 days. Incidence of chemotherapy delay was 2%. There was no reduction in chemotherapy dose due to expected toxicity or side effects. Intravenous antibiotics for the treatment of febrile neutropenia were needed in 19% of cases. Quality-of-life assessment shows a significant improvement in emotional functioning and a significant decrease in pain score. The efficacy profile of rGCSF observed in the present study was comparable with that of other rGCSF products previously described in the published scientific literature. CONCLUSIONS: The primary prophylaxis of neutropenia and its complications by rGCSF was safe and effective for women with metastatic breast cancer who received chemotherapy with docetaxel and doxorubicin. PMID- 19773619 TI - [Surgical treatment of humeral metastatic tumors]. AB - OBJECTIVE: To evaluate the functional outcome and pain control in patients after resection of humeral metastases. MATERIAL AND METHODS: A prospective randomized study of 24 cases of metastatic disease of the humerus with an associated pathologic fracture was carried out. The selected cases were divided into two groups based on the using methylmethacrylate cement for fracture fixation. Group 1 (n=12) included all cases in which the fracture was treated with bone cement augmentation. Group 2 (n=12) included all cases in which the fracture was treated without bone cement augmentation. Functional outcome was evaluated according to the American Musculoskeletal Tumor Society system. RESULTS: Good and excellent pain control was achieved in 95% of cases in both groups. Functional outcome after resection of humeral metastases and pathological fracture fixation was significantly better in Group 1. Total function in five patients (45%) accounted for 86% and in three patients (25%) for 83% of full normal upper extremity function, whereas in Group 2, total function in six patients (50%) accounted for 70% and in three patients (25%) for 83% of full normal upper extremity function. The rate of fixation failure was significantly greater in Group 2, where fixation instability was observed in 50% (n=6) of cases (P=0.03). There were no significant differences in complication rate (in 50% of cases, mechanical instability occurred after fixation with intramedullary nail and in 50% of cases after fixation with plates). CONCLUSIONS: The introduction of bone cement as an adjunct to fixation of pathologic fracture improved clinical results and reduced the rate of fixation failure. PMID- 19773620 TI - [Treatment results of Hodgkin's lymphoma]. AB - During last decades, there are strengthening attitudes to optimize the treatment of Hodgkin's lymphoma considering prognostic groups and risk factors. Based on the data of Vilnius University Clinics, a retrospective study was carried out, and treatment methods and outcomes of the patients treated during 1999-2004 were analyzed. Medical histories of 114 patients younger than 60 years were reviewed. Median age was 28 years. In 83% of cases, classic nodular sclerotic Hodgkin's lymphoma was diagnosed. Advanced-, intermediate-, and early-stage disease was diagnosed in 55%, 38%, and 7% of cases, respectively. The patients with early stage disease underwent four ABVD chemotherapy courses; 88% of them underwent radiotherapy afterwards. The patients with intermediate-stage disease underwent 4 6 courses of ABVD or in minor cases (12% of patients with intermediate-stage disease) - 4 standard BEACOPP chemotherapy courses. After this treatment, 88% of patients with intermediate-stage disease underwent radiotherapy. Patients with advanced-stage disease underwent 8 escalate (44%) or standard BEACOPP (29%) chemotherapy courses. More than half of these patients (71%) underwent radiotherapy after chemotherapy. Patient follow-up median was 65 months. One hundred seven patients (94%) after primary treatment achieved complete remission, in 7 patients (6%) primary progression was observed, 12 patients (11%) relapsed, and 8 patients died. Overall survival and event-free survival in patients with early-stage disease was 100%. Overall survival in patients with early/intermediate- and advanced-stage disease was 95.1% and 84.0%, respectively. Event-free survival in patients with early/intermediate- and advanced-stage disease was 91.7% and 76.2%, respectively. In the groups of intermediate- and advanced-stage disease, the results of treatment were worse in the subgroup, which underwent extended-field radiotherapy (P<0.05). Overall survival in the group of patients with advanced-stage disease was the best who underwent ABVD scheme, but the event-free survival (70.6%) and disease-free survival (81.3%) in ABVD subgroup were worse compared to BEACOPP subgroup. According to our results, there was no statistically significant difference in survival of patients with advanced-stage disease who underwent or did not radiotherapy (P>0.05). PMID- 19773621 TI - The accuracy of different imaging techniques in diagnosis of acute hematogenous osteomyelitis. AB - OBJECTIVE: The aim of this study was to establish and compare diagnostic accuracy (sensitivity, specificity, and diagnostic odds ratio) of plain x-ray, ultrasonography, bone scintigraphy, computed tomography (CT), and magnetic resonance imaging (MRI) in pediatric acute hematogenous osteomyelitis. MATERIAL AND METHODS: Analysis of patients' data, hospitalized at the Department of Pediatric Surgery with suspected acute hematogenous osteomyelitis in the period of 2002-2008, was carried out prospectively. Inclusion criteria were age of 1-18 years, pain in bone area, fever, functional disorder, and (or) signs of infection. Plain x-ray, ultrasonography, bone scintigraphy, computed tomography, and magnetic resonance imaging were performed. The recommendations of Standards for Reporting of Diagnostic Accuracy were used in study design. RESULTS: A total of 183 patients were included into the study. Acute hematogenous osteomyelitis was diagnosed in 156 (85%) patients, and 27 (15%) had other diseases. A total of 169 early plain x-rays (median on the first day of hospital stay), 142 late x rays (15th day of hospital stay), 82 ultrasonographies (second day), 76 bone scintigraphy (third day), 38 MRI scans (seventh day), and 17 CT (15th day) were performed. The sensitivity of ultrasonography was 0.55 (95% CI, 0.43-0.67); specificity, 0.47 (95% CI, 0.24-0.7); and diagnostic odds ratio, 1.08 (95% CI, 0.3-3.84). The sensitivity of CT was 0.67 (95% CI, 0.38-0.88); specificity, 0.5 (95% CI, 0.01-0.98); and diagnostic odds ratio, 2.0 (95% CI, 0.02-172.4). The sensitivity of early x-ray was 0.16 (95% CI 0.1-0.23); specificity, 0.96 (95% CI, 0.78-1.0); and diagnostic odds ratio, 4.34 (95% CI, 0.63-186.3). The sensitivity of MRI was 0.81 (95% CI, 0.64-0.93); specificity, 0.67 (95% CI, 0.22-0.96); and diagnostic odds ratio, 8.67 (95% CI, 0.91-108.5). The sensitivity of late x-ray was 0.82 (95% CI, 0.75-0.88); specificity, 0.92 (95% CI, 0.62-1.0); and diagnostic odds ratio, 51.17 (95% CI, 6.61-2222.0). The sensitivity of bone scintigraphy was 0.81 (95% CI, 0.68-0.90); specificity, 0.84 (95% CI, 0.60-0.97); and diagnostic odds ratio, 22.30 (95% CI, 4.9-132.7). CONCLUSIONS: Our analysis showed that late x-ray is the most valuable radiologic method in the diagnosis of acute hematogenous osteomyelitis, but bone scintigraphy and magnetic resonance imaging are the most valuable tests at the onset of the disease. PMID- 19773622 TI - Changes in electrophysiologic properties of the conductive system of the heart in children with atrioventricular nodal reentrant tachycardia after 2-8 years following radiofrequency catheter ablation of the slow pathway. AB - Radiofrequency ablation of the slow pathway is an effective method of treatment in children with atrioventricular nodal reentrant tachycardia. The aim of our study was to evaluate anterograde conduction properties in children before and after radiofrequency ablation of the slow pathway and to determine the efficacy and safety of this method. MATERIAL AND METHODS: Noninvasive transesophageal electrophysiological examination was performed in 30 patients at the follow-up period (mean duration, 3.24 years) after radiofrequency ablation of the slow pathway. RESULTS: The slow pathway function was observed in 13 patients one day after ablation, in 26 patients during the follow-up period, and in 28 patients after administration of atropine sulfate. Atrioventricular node conduction was significantly decreased the following day after ablation and at the follow-up versus the preablation (165.2 [30.2] bmp and 146.3 [28.5] bpm versus 190.9 [31.4] bpm; P<0.001). The atrioventricular node effective refractory period prolonged significantly the following day after ablation and at the follow-up versus the preablation (319.3 [55.3] ms and 351.0 [82.1] ms versus 248.3 [36.6] ms; P<0.001). Effective refractory period of the fast pathway prolonged significantly as compared with the preablation (from 408.0 [60.4] ms to 481.2 [132.9] ms; P=0.005). The prolongation of effective refractory period of the slow pathway was more significant than effective refractory period of the fast pathway at the follow-up (P<0.001). Two late recurrences occurred; one patient had atrial tachycardia. CONCLUSION: Children with atrioventricular nodal reentrant tachycardia can be effectively and safety cured by ablative therapy. The end point during slow pathway ablation should be the abolition of tachycardia with preservation of dual atrioventricular nodal physiology. PMID- 19773623 TI - Tension-free vaginal tape versus tension-free vaginal tape obturator (inside outside) in the surgical treatment of female stress urinary incontinence. AB - The objective of this study was to compare TVT (tension-free vaginal tape) and TVT-O (tension-free vaginal tape obturator from inside to outside) procedures for the female surgical treatment of stress urinary incontinence: results, complications, and effectiveness after 1 year. MATERIAL AND METHODS: A prospective randomized study was carried out. The patients were followed up for 12 months. A total of 114 patients were operated on using TVT procedure and 150 patients - TVT-O procedure. There was no significant difference in age, body mass index, parity, menopausal status, and prolapse (no patients had cystocele greater than stage II) comparing both groups. RESULTS: The mean time in surgery was significantly shorter in the TVT-O group (19+/-5.6 min) as compared with the TVT group (27+/-7.1 min). No differences in the effectiveness of both procedures were found: TVT - 94.6% and TVT-O - 94.6% after one year, respectively. Hospital stay was significantly shorter in the TVT-O group (1.5+/-0.5 days) than in the TVT group (4.0+/-1.6 days). Significantly fewer complications were observed in the TVT-O group. CONCLUSION: TVT and TVT-O operations are equally effective for the surgical treatment of female stress urinary incontinence. TVT-O group had shorter time in surgery and showed a lower rate of complications. PMID- 19773624 TI - Application of high-performance liquid chromatography for research of salicin in bark of different varieties of Salix. AB - Willow (Salix L.) species are widely spread in Lithuanian natural dendroflora. Willow bark contains active substances known for anti-inflammatory properties and is known as a phytotherapeutic precursor of aspirin. Bark extracts are components of analgesic and antirheumatic preparations. Therapeutic effectiveness is associated with salicin (2-(hydroxymethyl)phenyl-beta-D-glucopyranoside), which turns into salicylic acid. Increasing attention to natural preparations gives primary importance to research of plants. This study focused on 12 willow taxa and employed routine pharmacopoeia methods. High-performance liquid chromatography method was applied for the analysis of bark extractions. The investigation revealed that not all willow species accumulated a therapeutically sufficient amount of salicin. Bark samples were investigated after 1- and 2-year growth in autumn and spring. Salicin content ranged from 0.08 to 12.6%. Higher contents of active materials were determined in autumn and in 2-year-old willows. Certain willow taxa (Salix alba L., Salix mollissima L., Salix triandra L., Salix viminalis "Americana", Salix dasyclados L.) possessed extremely low salicin amounts. In the second year, analysis covered 32 willow species. Results indicated striking differences in salicin amounts (from 0.04% in Salix viminalis "Americana" to 12.06% in Salix acutifolia). Willow species, plant age, and season should be considered when collecting medicinal plant material. The amount of salicylates in 2-year-old willow bark collected in autumn exceeded by 25% that in 1-year-old willow bark collected in spring. Bark of some analyzed willow species contained the amount of salicylates too low for using as anti-inflammatory or antipyretic remedy. PMID- 19773625 TI - Do the quality of health care services provided at personal health care institutions of Kaunas city and access to it meet expectations of pregnant women. AB - OBJECTIVES: To evaluate if the quality of services provided by family physicians and obstetricians/gynecologists at primary personal health care institutions of Kaunas city and access to it meet the needs and expectations of pregnant women. MATERIAL AND METHODS: Pregnant women visiting the selected health care institutions at their third trimester of pregnancy were asked to fill in the anonymous questionnaire. The study was conducted at two randomly selected maternity centers of Kaunas city and two family practices of Kaunas city where antenatal care was provided by family physicians. The questionnaires were given to 106 patients visiting family physicians (response rate was 88.7%) and to 202 patients visiting obstetricians/gynecologists (response rate was 81.7%). RESULTS: Health services provided by family physicians and obstetricians/gynecologists met the expectations of pregnant women in respect of providing with information and communication. The patients of obstetricians/gynecologists significantly more often stated that they were very satisfied with patient-physician communication (P<0.05), they significantly more often understood explanations given by the physician (P<0.001) and claimed having sufficient knowledge about pregnancy (P<0.05), while the patients of family physicians significantly more often asserted that the physician helped them in preparation for childbirth (P<0.05). The patients of obstetricians/gynecologists significantly more often did not face any problems with access to services as compared to the patients of family physicians (z=3.0). Most of pregnant women stated that they were satisfied or very satisfied with the quality of health care at the health care facility providing them with antenatal care irrespective of the physician's specialty. CONCLUSIONS: The quality of antenatal health care provided by both family physicians and obstetricians/gynecologists and access to it satisfied the needs and expectations of the surveyed women. Correction of the limitations noticed, e.g., closer communication, more understandable explanations, more attention to preparation for childbirth, better work planning, could improve the quality of antenatal care provided by the family physicians. PMID- 19773626 TI - [Review on the effectiveness of prostate cancer brachytherapy]. AB - Ultrasound-guided transperineal prostate brachytherapy is now widely used modality in the treatment of prostate cancer. The overall prostate-specific antigen (PSA) progression-free survival at 10 years is 80-90% for low-risk patients. The results of long-term follow-up have showed better biochemical disease-free survival after I-125 and Pd-103 brachytherapy than after conventional external-beam radiotherapy and similar survival after radical prostatectomy. The most commonly reported dosimetric quantifiers include D90 (the dose that covers 90% of the prostate volume outlined on postimplant computed tomography images) and V100 (the fractional volume of the prostate that receives 100% of prescription dose). The biochemical disease-free survival correlates with the dose. In low-risk patients, achieving a D90 dose of 140-160 Gy might be adequate for prostate-specific antigen control. However, high-risk disease might require a D90 dose higher than 200 Gy. In the immediate posttreatment period, the most common complication is acute urinary retention. Urinary symptoms such as frequency, nocturia, and dysuria occur commonly and are documented in about 80% of patients complaining of symptoms 2-3 months after treatment. Late urinary complications of brachytherapy include urethral stricture and incontinence. Incontinence is rare and mainly occurs in patients who had transurethral resection of the prostate either prior or after brachytherapy. Rectal complications (proctitis, rectal bleeding) are rare after prostate brachytherapy. Brachytherapy like external-beam radiotherapy but unlike surgery preserves ejaculation; potency rates also appear to be relatively high after brachytherapy, at 50-85%, and most patients' sexual quality and function are preserved. Since July 2007, the real-time I-125 prostate brachytherapy has been started in Lithuania and Baltic countries at the Hospital of Kaunas University of Medicine. A total of 150 low-risk patients (< or =T2a, Gleason < or =6, PSA < or =10) were treated by this method. Permanent prostate brachytherapy is an appropriate method for standard treatment of localized prostate cancer. PMID- 19773627 TI - Evaluation of dental care and the prevalence of tooth decay among middle-aged and elderly population of Kaunas city. AB - The aim of the study was to evaluate the prevalence and the intensity of tooth decay among the middle-aged and elderly population of Kaunas, city, and to assess the need for prostheses as well as the possibilities for oral care. MATERIAL AND METHODS: During 2006-2008, we studied 1,141 inhabitants of Kaunas city; the subjects' age was 45-72 years. Oral evaluation technique proposed by the WHO was used in the investigation. We evaluated the prevalence of tooth decay, and its intensity was evaluated using the DMF-T index. We also evaluated dental prostheses, the need for prosthetics, and asked the subjects how they took care of their oral health. RESULTS: The prevalence of tooth decay among middle-aged and elderly population of Kaunas city was 99.9%. The DMF-T index was 21.01+/-0.3 in the age group of 45-54 years, 23.52+/-0.4 - in the age group of 55-64 years, and 25.63+/-0.3 - in the elderly subjects. Full removable dentures were found in 14.0% of the elderly subjects, while 1.0% of the middle-aged subjects and 1.2% of the elderly subjects required full dentures. 57.7% of the subjects aged 45-54 years, 53.1% of the subjects aged 55-64 years, and 43.4% of the elderly subjects brushed their teeth twice daily. CONCLUSIONS: The intensity of tooth decay in middle-aged and elderly population of Kaunas city significantly increased with age (21.01-25.63). A relationship was found between oral hygiene status and the DMF-T index. In the middle-aged and elderly population of Kaunas city, the intensity of tooth decay was significantly lower (DMF-T 23.04%) among those who brushed their teeth twice daily than among those who brushed their teeth once daily or less frequently (DMF-T 24.01%). Reduction of the prevalence of tooth decay among middle-aged and elderly population of Kaunas city necessitates alterations in people's attitudes towards dental care, implementation of suitable hygiene habits, and creation and implementation of the dental disease prevention program for adults and the elderly, based on the strategy proposed by the World Health Organization. PMID- 19773628 TI - Growth factors/cytokines/defensins and apoptosis in periodontal pathologies. AB - In the recent past there has been an increased emphasis on morphogenetic tissue research of periodontal tissues. The aim of this study was to find qualitative and quantitative correlations in distribution and appearance of growth factors/cytokines/defensins and apoptosis in periodontal pathologies. MATERIAL AND METHODS: Tissue was obtained from 5 controls and 6 chronical periodontitis patients 30-50 years of age referred to Latvian Institute of Stomatology. Histological investigations were performed at the Institute of Anatomy and Anthropology of Riga Stradins University. RESULTS: Epithelial cells abundantly expressed IL10 in patients. The expression of b-defensins was very variable in both sulcular and gingival epithelium. TUNEL positive cells were observed in patients and control specimens with dominance in control group. Gingival epithelium showed moderate expression of bFGF whereas few to moderate cells were positive for bFGF in sulcular epithelium. Fibroblast growth factor receptor (FGF 1R) was abundant in gingival epithelium and in connective tissue cells, but almost not detectable in sulcular epithelium. Insulin-like growth factor receptor was not expressed in gingival epithelium and was weakly seen in basal layer of sulcular epithelium. Basic nerve growth factor expresion in both types of epithelium was numerous to abundant. Staining for the NGFR in the gingival epithelium was variable, with prevalence to be moderate whereas sulcular epithelium was free from any factor immunoreactivity. CONCLUSION: 1. Finding of apoptotic cells are variable and seems to correlate with the expression of defensins in oral epithelium in patients with periodontitis. 2. FGFR was expressed more than the bFGF, but in case with NGFR and bNGF situation was opposite. Although IGFRI was found in sulcular epithelium with no expression in gingival one suggesting about stimulation in regeneration/adaptation in periodontitis affected tissue. 3. The expression of growth factors and their receptors in sulcular epithelium was lower than into the gingival epithelium and seems to be specific for periodontitis. PMID- 19773629 TI - Stress distribution of an internal connection implant prostheses set: a 3D finite element analysis. AB - OBJECTIVE: This study evaluated the stress distribution by loads, under a internal connection implant system with two sort of abutment screws and prosthetic crown models at ten observation points. MATERIALS AND METHOD: The analysis were made in two models with internal butt joint, and with gold and titanium screw, respectively. The load was 382N with 90 masculine to the occlusal surface and 15 masculine to the implant axis at 4 and 6 mm from the implant center. RESULTS: In both models, a large amount of stress was located around the implant neck and little stress was concentrated along the abutment screw. CONCLUSION: The simulations made suggest that the internal connection protects the abutment screw from the accumulated stresses; however, it exposes the implant walls to these stresses. PMID- 19773630 TI - Intra-articular injection of hyaluronic acid for temporomandibular joint osteoarthritis in elderly patients. AB - BACKGROUND: Preliminary findings gave encouraging results for the use of hyaluronic acid in temporomandibular joints with inflammatory/degenerative processes. This investigation aimed at evaluating retrospectively the efficacy of intra-articular injections of hyaluronic acid in elderly patients (aged >65 years) with osteoarthritis of the temporomandibular joint as compared with those of a group of adult non-elderly patients. MATERIALS AND METHODS: Two groups of patients with Research Diagnostic Criteria for Temporomandibular Disorders axis I group IIIb diagnosis of osteoarthritis, aged over (N=17)/under (N=33) 65 years respectively (elderly/non-elderly groups), underwent a cycle of five injections (one per week) of 1 ml low molecular weight hyaluronic acid and four follow-up assessments after the end of the treatment (at one week, at one month, at three months, at six months). RESULTS: At the end of the treatment period, improvements in the elderly group were significant with respect to baseline values in the minimum and maximum masticatory pain, maximum pain at rest values, and functional limitation scores. In the non-elderly group, significant improvements at the end of treatment were showed in all treatment outcome variables, except than minimum pain at rest values. All improvements were maintained over the six-month span of the follow-up period, and no significant differences were showed between groups for any of the outcome variables, except than functional limitation scores, which improved more in the elderly group. CONCLUSIONS: These findings are not supportive for a difference in efficacy between the elderly patients and the other subjects, even though further works on different age groups are needed before generalization of results. PMID- 19773631 TI - Evaluation of tensile strength of different configurations of orthodontic retraction loops for obtaining optimized forces. AB - The aim of this study was to analyze the mechanical behavior of different orthodontic retraction loops. Two designs of orthodontic loops for closing space were analyzed: teardrop-shaped (T) and circle-shaped loop (C), of two different heights (6 and 8 mm), and two types of orthodontic wires (stainless steel - 0.19' x 0.25'; TMA - titanium molybdenum alloy - 0.016' x 0.016'). The sample consisted of 80 loops, divided into 8 groups determined by the combination shape/height/type of wire, which were submitted to tensile testing at a speed of 2 mm/min., to measure the quantity of force generated when activated in the interval of 0.75 mm and 2.25 mm. The results were submitted to the ANOVA and Tukey statistical tests to compare the groups, and the Student's-t test to compare the means of two groups. Statistically higher values were observed for the size 6 mm, circle shape and stainless steel composition. The group "teardrop 8 mm-TMA" together with the group "circle-8 mm-TMA" presented the lowest mean value, differing statistically from all of the other groups. It was concluded that the alloy of the wire and the height of the loop would be more important than the loop design. PMID- 19773632 TI - Disease progression in HIV-1-infected patients heterozygous for the sickle hemoglobin gene. AB - The sickle cell trait-asymptomatic carriage is frequent in people originating from sub-Saharan Africa. Several host factors (including sickle cell anemia) have been previously reported to act upon the course of HIV disease. We studied the progression of infection in a cohort of African patients heterozygous for the sickle hemoglobin gene and harboring normal hemoglobin genes. No significant difference was evidenced between the two groups from this preliminary study. PMID- 19773634 TI - Efavirenz plasma concentrations did not predict cessation of therapy due to neuropsychiatric symptoms in a large randomized trial. AB - To assess whether trial participants who ceased efavirenz (EFV) because of neuropsychiatric events had elevated plasma concentrations, we performed a retrospective case-control study. EFV levels were measured by high-performance liquid chromatography in stored plasma from 35 cases and 75 matched controls. All had taken EFV for at least 4 weeks. Median EFV concentrations did not differ (P = 0.77). Measurement of EFV levels in plasma collected at variable times after the last dose did not predict central nervous system intolerance. PMID- 19773633 TI - Kupffer cells are depleted with HIV immunodeficiency and partially recovered with antiretroviral immune reconstitution. AB - OBJECTIVES: HIV-related enhancement of gut microbial translocation is associated with progression of hepatic fibrosis. Although hepatic macrophages (Kupffer cells) clear most microbial translocation products and can be infected by HIV, their fate in HIV progression has not been carefully investigated. METHODS: We studied Kupffer cell density (KCD) in 76 HIV-hepatitis C virus coinfected patients investigated at various stages of liver disease and CD4(+) lymphocyte depletion (and restoration). RESULTS: KCD averaged 23 cells per high-powered field (range 4.4-52.2) and was highest in portal and periportal regions as compared with centrilobular regions (P < 0.001). No differences were detected in KCD by age, liver fibrosis stage, or hepatic inflammatory score. Compared with individuals without apparent HIV-related immunosuppression, however, KCD was substantially lower in persons with lower peripheral blood CD4(+) lymphocyte counts (P = 0.027) and lowest among those with deepest CD4(+) lymphocyte nadir (P = 0.006). After the initial liver biopsy, eight patients began antiretroviral therapy and had immune restoration (> or = 2-fold increase in peripheral CD4(+) lymphocyte count) and a second histologic evaluation with a median of 36.8 months later (range 28.1-58.4 months); KCD increased in all (P = 0.007). CONCLUSION: Given the central role of Kupffer cells in controlling microbial translocation, these data suggest Kupffer cell loss needs to be considered in the pathogenesis of liver fibrosis in HIV-hepatitis C virus coinfected persons. The abundance of portal and periportal Kupffer cells is suggestive of their contribution to fibrosis in periportal regions in chronic viral hepatitis. PMID- 19773635 TI - GB virus type C infection modulates T-cell activation independently of HIV-1 viral load. AB - BACKGROUND: Many clinical studies have suggested a beneficial effect of GB virus type C (GBV-C) on the course of HIV-1 infection, but the mechanisms involved in such amelioration are not clear. As recent evidence has implicated cellular activation in HIV-1 pathogenesis, we investigated the effect of GBV-C viremia on T-cell activation in early HIV-1 infection. METHODS: Forty-eight recently infected HIV-1 patients (23 GBV-C viremic) were evaluated for T-cell counts, expanded immunophenotyping GBV-C RNA detection, and HIV-1 viral load. Nonparametric univariate and multivariate analyses were carried out to identify variables associated with cellular activation, including GBV-C status, HIV-1 viral load, T lymphocyte counts, and CD38 and chemokine (C-C motif) receptor 5 (CCR5) surface expression. FINDING: We not only confirmed the positive correlation between HIV-1 viral load and the percentage of T cells positive for CD38(+)CD8(+) but also observed that GBV-C viremic patients had a lower percentage of T cells positive for CD38(+)CD4(+), CD38(+)CD8(+), CCR5(+)CD4(+), and CCR5(+)CD8(+) compared with HIV-1-infected patients who were not GBV-C viremic. In regression models, GBV-C RNA(+) status was associated with a reduction in the CD38 on CD4(+) or CD8(+) T cells and CCR5(+) on CD8(+) T cells, independent of the HIV-1 viral load or CD4(+) and CD8(+) T-cell counts. These results were also supported by the lower expression of CD69 and CD25 in GBV-C viremic patients. INTERPRETATION: The association between GBV-C replication and lower T-cell activation may be a key mechanism involved in the protection conferred by this virus against HIV-1 disease progression to immunodeficiency in HIV-1-infected patients. PMID- 19773636 TI - Extrauterine epithelioid trophoblastic tumors presenting as primary lung carcinomas: morphologic and immunohistochemical features to resolve a diagnostic dilemma. AB - Our objective was to describe the clinicopathologic features of epithelioid trophoblastic tumors (ETTs) in a series of patients who presented with elevated beta-human chorionic gonadotrophin (hCG) levels and extrauterine lesions resembling primary lung carcinomas. Clinical and pathologic materials were reviewed and Shih and Kurman's diagnostic criteria were applied. Three parous women (38, 49, and 34 y of age) with elevated beta-hCG levels had nondiagnostic gynecologic evaluations, including negative dilation and curettage specimens. Imaging revealed isolated pulmonary lesions, 2 to 8.5 cm in size, resembling primary lung carcinomas. Two patients received multiagent chemotherapy consisting of etoposide, methotrexate, dactinomycin, alternating with cisplatin and etoposide, and all underwent pulmonary resection. Histologically, the cytologic features, epithelioid growth pattern, and hyaline-like material simulated the appearance of nonsmall cell lung carcinoma, but overall, the histologic features along with the immunophenotype supported classification as ETT. Follow-up hysterectomy specimens were histologically normal. All 3 patients are alive and well. The rarity of ETT and its resemblance to squamous and pleomorphic carcinomas of lung have led to diagnostic difficulties. When reproductive-age women present with elevated beta-hCG levels, a pulmonary lesion, and no apparent intrauterine disease, primary pulmonary ETT should be considered. Correlating clinical indices with specific morphologic and immunohistochemical features can ensure diagnostic accuracy and appropriate treatment for favorable outcomes. PMID- 19773637 TI - Pigmented epithelioid melanocytoma: favorable outcome after 5-year follow-up. AB - Pigmented epithelioid melanocytoma (PEM) is a recently described entity encompassing epithelioid blue nevus (of Carney complex) and most tumors earlier considered as so-called "animal-type melanoma". Loss of expression of a Carney complex gene, cyclic adenosine 3',5' monophosphate-dependent protein kinase regulatory subunit 1alpha, is observed in the majority of PEMs. Initial reports with short-term follow-up have suggested that although PEMs frequently metastasize to lymph nodes, they have a more favorable outcome than conventional melanomas. In this report, we present the results of long-term follow-up in 26 patients with PEMs from North America and Australia. There were 9 males and 17 females, with a median age of 20 years. The tumors involved the trunk (6 cases), extremities (12 cases), genitalia (1 case), and the head and neck region (7 cases) had a median Breslow thickness of 2.2 mm (range 0.80 to 10.0 mm) and a median Clark level of 4. Eight of the patients developed lymph node metastases. After a median follow-up period of 67 months (range 39 to 216 mo), all patients are alive and free of disease. These findings provide further evidence that PEM is a unique low-grade melanocytic tumor with limited metastatic potential (to lymph nodes), but a favorable long-term clinical course. PMID- 19773638 TI - Comprehensive histologic assessment helps to differentiate multiple lung primary nonsmall cell carcinomas from metastases. AB - The pathologic classification of nonsmall cell lung cancer (NSCLC) is evolving. Lung adenocarcinoma is morphologically heterogeneous, with mixtures of acinar, papillary, bronchioloalveolar, and solid patterns in more than 80% of cases. In case of synchronous or metachronous multiple NSCLC, the distinction of intrapulmonary metastases from independent primary tumors is of great clinical importance as it influences staging and potentially the therapeutic strategy. Here we took advantage of a cohort of 20 patients with 42 multiple NSCLC tumors (24 potential pair comparisons) that were annotated molecularly using genomic and mutational profiling to evaluate the value of comprehensive histologic assessment in this setting. Using the Martini-Melamed criteria, paired tumors were characterized as multiple primary NSCLCs in 21 cases and as intrapulmonary metastases in 3 cases. Genomic and mutational data led to a diagnosis of multiple primaries in 14 cases and of metastases in 8 cases; 2 cases could not be assessed. This molecular characterization contradicted the Martini-Melamed diagnosis in 7 (32%) of the 22 assessable comparisons. Adenocarcinoma was found in 32 (76%) of the 42 tumors. After review in a blinded fashion, semiquantitative comprehensive histologic assessment of paired tumors was different in 16 and similar in 8 paired tumors. We found that comparing adenocarcinomas is a complex issue that requires assessment not only of percentages of the histologic subtypes, but also the recording of additional histologic details such as cytologic features, patterns of stroma, necrosis, discrete nodularity versus miliary growth and variants such as clear cell, signet ring, mucinous, and fetal patterns. We also found that paired squamous cell carcinomas could be compared based on histologic subtyping in addition to cytologic and stromal characteristics. Considering histologically different tumors as multiple primaries, and similar tumors as metastases, comprehensive histologic subtyping was consistent with the molecular characterization in 20 (91%) of the 22 pairs comparisons. In summary, based on a well characterized cohort with detailed clinical, pathologic and molecular data, we found comprehensive histologic assessment is a powerful tool that seems to be a promising way to determine whether multiple lung adenocarcinomas or squamous cell carcinomas are metastatic or multiple primaries. This has great clinical implications for staging and therapeutic management of lung cancer patients with multiple tumors. Given its high correlation with molecular characterization of such tumors, it may provide a much cheaper and faster method to address this problem. PMID- 19773639 TI - Renal cell carcinoma in association with IgA nephropathy in the elderly. AB - IgA nephropathy can occur as a paraneoplastic syndrome of renal cell carcinoma. We report 3 cases of IgA nephropathy associated with renal cell carcinoma in the elderly patients and demonstrate that infiltrating lymphocytes and plasma cells around renal cell carcinoma produce IgA that likely contributed to mesangial IgA deposition. PMID- 19773640 TI - Pulmonary crystal-storing histiocytoma in a patient without a lymphoproliferative disorder. AB - Pulmonary crystal-storing histiocytoma is a very rare disorder and is characterized by infiltration of histiocytes with intracytoplasmic accumulation of crystallized immunoglobulins. It is usually associated with lymphoproliferative diseases or plasma cell dyscrasia. Here, we report a case of pulmonary crystal-storing histiocytoma in a 64-year-old man, presenting as a chronic pulmonary consolidation in the lung exposed to asbestos. Video-assisted thoracoscopic surgical biopsy displayed sheets of large, epithelioid histiocytes filled with a large number of needle-like crystals, showing the accumulation of crystallized polyclonal immunoglobulins. This lesion was consistent with crystal storing histiocytosis or crystal-storing histiocytoma. With extensive clinical work-up, the current case was not associated with lymphoproliferative diseases. Herein, we present this extremely rare entity of pulmonary pathology, a pulmonary crystal-storing histiocytoma arising in the lung exposed to asbestos, and demonstrate the clinical, radiologic, and pathologic features of the tumor. PMID- 19773641 TI - Activated protein C improves heatstroke outcomes through restoration of normal hypothalamic and thermoregulatory function. AB - BACKGROUND: Human recombinant activated protein C (APC) has been found to be beneficial in treating heatstroke in both humans and rats. Here, we further investigated the possible mechanism underlying the therapeutic action exerted by APC in experimental heatstroke. METHODS: Unanesthetized and unrestrained mice were exposed to an ambient temperature of 42.4 degrees C for 1 hour to induce heatstroke. They were given normal saline or APC (5 mg/kg of body weight, intravenously) 1 hour after the termination of heat stress. Their physiologic and biochemical parameters were continuously monitored for 4 hours after cessation of heat stress. Mice that survived on day 4 of heat treatment were considered survivors. RESULTS: When the vehicle-treated mice underwent heat treatment, the fraction survival and core temperature at 4 hours of body heating were found to be 0 of 12 and 33.8 +/- 0.6 degrees C, respectively. Administration of APC 1 hour after the cessation of heat stress rescued the mice from heat-induced death (fraction survival, 12 of 12) and reduced hypothermia (core temperature, 37.4 +/- 0.2 degrees C). Heat-induced apoptosis in the hypothalamus was significantly reduced by APC. The increased levels of cellular ischemia (eg, glutamate, lactate to-pyruvate ratio, nitrite, and dihydroxybenzoic acid) and damage (eg, glycerol) markers in the hypothalamus during heatstroke were also decreased significantly by APC therapy. The hypothalamic levels of tumor necrosis factor-alpha (a proinflammatory cytokine) that are upregulated in heat-stressed mice were significantly lower in APC-administered mice. CONCLUSIONS: Our results show that human recombinant APC improves heatstroke through restoration of normal hypothalamic and thermoregulatory function. PMID- 19773642 TI - A case of prekallikrein deficiency resulting in severe recurrent mucosal hemorrhage. AB - Although most cases of prekallikrein deficiency are asymptomatic, a few reports link severe prekallikrein deficiency with thrombotic phenomena and recurrent pregnancy loss. Here, we present a case of a Jamaican female patient with prekallikrein deficiency, associated with a severe bleeding diathesis. A low level of plasma prekallikrein activity, along with the presence of C529Y mutation, confirmed the diagnosis in our patient. Some animals with prekallikrein deficiency were shown to have moderate bleeding tendencies. Furthermore, the first patient with prekallikrein deficiency from the African continent was a young child who presented with severe, hemophilia-like bleeding, featuring recurrent hemarthrosis and subcutaneous hematomas. We find it intriguing that our patient is of African heritage and presented with a moderate nasal bleeding tendency in her youth, followed by severe recurrent mucosal bleeding later in life. PMID- 19773643 TI - Elevation of serum creatine phosphokinase in hospitalized patients. AB - BACKGROUND: The clinical characteristics and outcomes of patients with significant noncardiac and cardiac serum creatine phosphokinase (CPK) elevations are not well described. METHODS: One hundred fifty-eight inpatients who had CPK elevation of >1000 IU/L were identified. One hundred thirty-seven patients whose CPK elevations could be attributed to either noncardiac or cardiac etiologies were included and analyzed for clinical characteristics, 30-day, 3-month, and 1 year all-cause mortality rates. Twenty-one patients were excluded, in whom noncardiac and cardiac CPK (CCPK) elevations coexisted, or etiologies were unclear. RESULTS: Of the 137 patients, 43 (31%) patients had CCPK elevation and 94 (69%) patients had noncardiac CPK (NCCPK) elevation. One-year mortality rate was 26.6% (25 of 94 patients) in NCCPK elevation group. Decedents were older (P < 0.05), had higher blood urea nitrogen (P < 0.01) and creatinine (P < 0.05) levels, and had higher white blood cell counts (P < 0.05) compared with survivors. In CCPK elevation group, 37.2% (16 of 43 patients) died within 1 year after admission. Decedents were also older (P < 0.01) and had higher blood urea nitrogen (P < 0.01) and creatinine (P < 0.01) levels. CONCLUSION: The incidence of NCCPK elevation is greater than that of CCPK elevation in a veteran, mostly male, population. One-year mortality rate in patients with NCCPK elevation is comparable to that in patients with CCPK elevation (26.6% versus 37.2%, P = 0.290). Age and renal insufficiency are 2 major predictors for increased mortality in both groups. PMID- 19773644 TI - Cognitive effects of creatine ethyl ester supplementation. AB - Supplementation with creatine-based substances as a means of enhancing athletic performance has become widespread. Until recently, however, the effects of creatine supplementation on cognitive performance has been given little attention. This study used a new form of creatine--creatine ethyl ester--to investigate whether supplementation would improve performance in five cognitive tasks, using a double-blind, placebo-controlled study. Creatine dosing led to an improvement over the placebo condition on several measures. Although creatine seems to facilitate cognition on some tasks, these results require replication using objective measures of compliance. The improvement is discussed in the context of research examining the influence of brain energy capacity on cognitive performance. PMID- 19773645 TI - Ranolazine attenuates behavioral signs of neuropathic pain. AB - Ranolazine modulates the cardiac voltage-gated sodium channel (NaV 1.5) and is approved by the FDA in the treatment of ischemic heart disease. Ranolazine also targets neuronal (NaV 1.7, 1.8) isoforms that are implicated in neuropathic pain. Therefore, we determined the analgesic efficacy of ranolazine in a preclinical animal model of neuropathic pain. Both intraperitoneal and oral administration of ranolazine dose-dependently inhibited the mechanical and cold allodynia associated with spared nerve injury, without producing ataxia or other behavioral side effects. These data warrant clinical investigation of the potential use of ranolazine in the treatment of neuropathic pain. PMID- 19773646 TI - Clinical practice guideline: red blood cell transfusion in adult trauma and critical care. AB - OBJECTIVE: To develop a clinical practice guideline for red blood cell transfusion in adult trauma and critical care. DESIGN: Meetings, teleconferences and electronic-based communication to achieve grading of the published evidence, discussion and consensus among the entire committee members. METHODS: This practice management guideline was developed by a joint taskforce of EAST (Eastern Association for Surgery of Trauma) and the American College of Critical Care Medicine (ACCM) of the Society of Critical Care Medicine (SCCM). We performed a comprehensive literature review of the topic and graded the evidence using scientific assessment methods employed by the Canadian and U.S. Preventive Task Force (Grading of Evidence, Class I, II, III; Grading of Recommendations, Level I, II, III). A list of guideline recommendations was compiled by the members of the guidelines committees for the two societies. Following an extensive review process by external reviewers, the final guideline manuscript was reviewed and approved by the EAST Board of Directors, the Board of Regents of the ACCM and the Council of SCCM. RESULTS: Key recommendations are listed by category, including (A) Indications for RBC transfusion in the general critically ill patient; (B) RBC transfusion in sepsis; (C) RBC transfusion in patients at risk for or with acute lung injury and acute respiratory distress syndrome; (D) RBC transfusion in patients with neurologic injury and diseases; (E) RBC transfusion risks; (F) Alternatives to RBC transfusion; and (G) Strategies to reduce RBC transfusion. CONCLUSIONS: Evidence-based recommendations regarding the use of RBC transfusion in adult trauma and critical care will provide important information to critical care practitioners. PMID- 19773647 TI - Infection-induced lung injury is worsened after renal buffering of hypercapnic acidosis. AB - OBJECTIVE: Prolonged hypercapnia is commonly encountered during the treatment of acute respiratory distress syndrome and acute respiratory failure attributable to other causes with protective ventilation strategies. In these circumstances, compensatory renal buffering returns pH to normal establishing a condition of buffered hypercapnia. It is also common intensive care practice to correct the pH more rapidly using bicarbonate infusions. Although it is well-established that hypercapnic acidosis has potent anti-inflammatory and protective effects, the effect of buffered hypercapnia on acute lung injury and acute respiratory distress syndrome is unknown. We therefore wished to determine the effects of buffered hypercapnia on acute lung injury induced by endotoxin or Escherichia coli infection in vivo. DESIGN: Prospective, randomized animal study. SETTING: University research laboratory. SUBJECTS: Adult male Sprague-Dawley rats. INTERVENTIONS: We established buffered hypercapnia by exposing rats to a hypercapnic environment for 3 days before the induction of lung injury. Buffered hypercapnia rats (initial pH >7.35, FiCO2 = 0.05) and normocapnic controls (initial pH >7.35, FiCO2 = 0.00) were then anesthetized, mechanically ventilated, and lung injury induced by intra-tracheal inoculation of endotoxin (series I) or Escherichia coli (series II). MEASUREMENTS AND MAIN RESULTS: Buffered hypercapnia significantly increased both endotoxin and Escherichia coli-induced lung injury when compared to normocapnic controls, as assessed by arterial oxygenation, lung compliance, pro-inflammatory pulmonary cytokine concentrations, and measurements of structural lung damage. In additional in vitro experiments buffered hypercapnia did not alter neutrophil phagocytosis ability but did impaired epithelial wound healing. CONCLUSIONS: Our results demonstrate that infection induced injury in vivo is worsened after renal buffering of hypercapnic acidosis independently of any changes in tidal volume. These findings have important implications for our understanding of the pathogenesis of infection-induced lung injury during the use protective ventilation strategies that permits buffered hypercapnia and during infective exacerbations of chronic lung diseases associated with sustained hypercapnia. PMID- 19773648 TI - Cardiac output derived from arterial pressure waveform. AB - PURPOSE OF REVIEW: Cardiac output (CO) and other flow-based hemodynamic variables have become increasingly important to guide treatment of patients undergoing major surgery with expected fluid shifts in the operating room as well as critically ill ICU patients. Established techniques such as pulmonary artery thermodilution, however, might not be justified in all of these patients. As arterial access is commonly available, less-invasive arterial pressure waveform based CO devices are becoming more and more popular. RECENT FINDINGS: Many studies dealing with arterial pressure waveform-based CO have emerged in recent years providing additional information with regard to accuracy of the different commercially available devices. Furthermore, methods of comparative CO studies have been recently brought into question. SUMMARY: Although there are differences in invasiveness and the need for external calibration, all available devices provide parameters for enhanced hemodynamic monitoring. Initial validation studies of the more established techniques such as the pulse contour cardiac output (PiCCO) or LiDCO were recently met with less enthusiasm, whereas the initially disappointing validation studies of the FloTrac/Vigileo device had encouraging results after software updates. The pressure recording analytical method (PRAM) technique has not so far been sufficiently evaluated to be able to come to a conclusion. Further investigation is required with regard to the ability of the arterial pressure waveform-based methods to guide goal-directed therapy. PMID- 19773649 TI - Depth of anesthesia. AB - PURPOSE OF REVIEW: The present review article provides a summary of the recent literature evaluating the technology for monitoring depth of anesthesia and patient outcomes associated with its use. RECENT FINDINGS: The tentative and controversial findings of a 2006 study suggesting a correlation of mortality with lower intraoperative bispectral index scores were reproduced in a more recent study, but the correlation could be accounted for by controlling for patient comorbidities, particularly malignancy. In a large trial involving patients at high risk for awareness, general anesthesia with volatile agents guided by bispectral index monitoring was associated with a low incidence of awareness, but no more so than the use of alarms for limits on volatile agent concentration. Studies comparing both emerging and more established brain function monitors suggest that, in spite of their different algorithms for processing and filtering electromyographic signal, many monitors are affected by the use of neuromuscular blocking agents. Recent evidence is consistent with previous studies that describe a nonlinear model for the dose-response of EEG parameters to increasing concentration of anesthetic agents with a dosing plateau response over a clinically relevant dose range. SUMMARY: The goal of precisely dosed general anesthesia guided by brain monitoring remains elusive. PMID- 19773650 TI - Assessment of competence in anesthesiology. AB - PURPOSE OF REVIEW: This review is designed to evaluate various aspects of the teaching, demonstration and assessment of competence in anesthesiology. RECENT FINDINGS: The approach to evaluation of competence has evolved from global impressions to an understanding of the elements of performance that determine competence. This assessment of performance to measure competence has been applied to cognitive performance, technical skills, and behavior. There is increasing consensus that assessment of competence is more effective when more than one tool is used, and when the tool selected actually measures the element of competence it was selected to measure. SUMMARY: The traditional evaluation of clinical competence in anesthesiology has focused on written examinations and global evaluation of skill. Limits to this approach have become obvious. Assessment has evolved to specific competencies with performance and behavior-based standards and criteria for mastery of each competency. As standards for competency are better understood, multimedia tools, such as simulation and electronic portfolio, will further advance this evolution. PMID- 19773651 TI - Difficult mycoses of the skin: advances in the epidemiology and management of eumycetoma, phaeohyphomycosis and chromoblastomycosis. AB - PURPOSE OF REVIEW: Eumycetoma, phaeohyphomycosis and chromoblastomycosis are subcutaneous mycoses having in common the fact that they are acquired as a result of penetrating trauma to the skin and may be caused by a large variety of fungi. This article will review recent data regarding the epidemiology and treatment of these infections. RECENT FINDINGS: Recent epidemiologic observations in these mycoses include an increased incidence of phaeohyphomycosis in immunosuppressed patients, the association of polymorphisms in genes involved in innate immunity, the occurrence of eumycetoma caused by Madurella mycetomatis and the nosocomial acquisition of phaeohyphomycosis. The management of these infections continues to be challenging. An approach that involves early diagnosis, the use of systemic antifungal agents and local therapies, including surgical removal of lesions, is the basis of the treatment of these diseases. SUMMARY: It is crucial that the epidemiology and clinical presentation of these infections are understood if we are to improve their outcomes. PMID- 19773652 TI - Progress in the development of piperaquine combinations for the treatment of malaria. AB - PURPOSE OF REVIEW: Dihydroartemisinin-piperaquine is a new and extremely promising artemisinin-containing fixed-combination antimalarial, about to be registered with international regulatory authorities such as the European Medicines Agency. A formulation produced according to good manufacturing practices should be available soon. RECENT FINDINGS: Piperaquine is characterized by a slow absorption, long mean terminal elimination half-life and large mean volume distribution. However, children, compared to the population mean profile, tend to have a smaller central volume of distribution, a shorter distribution half-life and a more rapid fall in early piperaquine plasma concentrations, suggesting that an increase of the weight-adjusted dosage in children may be required. In addition, the oral bioavailability of piperaquine improves when given with a high-fat meal, though this does not necessarily translate into a higher efficacy. Several clinical trials have repeatedly shown that dihydroartemisinin-piperaquine is well tolerated and efficacious, with the only exception of one trial recently carried out in Papua New Guinea. Patients treated with dihydroartemisinin-piperaquine may have a higher rate of person-gametocyte weeks, though it is unclear whether this translates into a higher infectiousness to biting anophelines. SUMMARY: The dosage recommended for children may need to be reviewed and the usefulness of the coadministration with food should be determined. Establishing safety and efficacy of this treatment in pregnancy remains a priority. PMID- 19773653 TI - The unintended consequences of quality improvement. AB - PURPOSE OF REVIEW: The focus on quality improvement has led to several types of initiatives in pediatric care; however, these programs may lead to potential unintended consequences. RECENT FINDINGS: Unintended consequences of quality improvement programs that have been described are reviewed. Unintended effects on resource utilization include effects on costs, as well as the inability to apply programs across different populations and affect disparities in care. Unintended effects on provider behavior include measurement fixation behavior, as well as 'crowding out' behavior, in which gains in quality in one area may simply occur at the expense of quality of care in another. Patient preferences may not always match specific quality improvement measures. Unintended effects for patients may include decreased patient satisfaction, trust, or confidence in their provider. SUMMARY: Recognition and anticipation of the possible unintended consequences of guideline implementation is a critical step to harnessing all the benefits of quality improvement in practice. PMID- 19773654 TI - Familial hypobetalipoproteinemia: early neurological, hematological, and ocular manifestations in two affected twins responding to vitamin supplementation. AB - Familial hypobetalipoproteinemia is a disorder of lipid metabolism characterized by extremely low plasma levels of apolipoprotein B as well as low levels of total and low-density lipoprotein cholesterol. We report the case of impairment of retinal function and diffuse pain in both legs often related to physical activity, as well as the presence of acanthocytosis on peripheral blood smear. Neurophysiological studies suggested dysfunction of the thin myelinated (A) and unmyelinated (C) fibers, in spite of preserved A fiber function, which has not been previously described in this condition. All clinical symptoms and the neurophysiological abnormalities improved after high-dose vitamin E and A supplementation. These findings suggest that this syndrome may have a wide spectrum of manifestations and an early appearance of symptoms in the pediatric age group. PMID- 19773655 TI - International efforts to measure and improve the quality of mental healthcare. PMID- 19773656 TI - Mental health quality and outcome measurement and improvement in Scotland. AB - PURPOSE OF REVIEW: This review considers Scotland's approach to improving the quality of mental health services. FINDINGS: Scotland's mental health quality and outcomes framework focuses on improving both the effectiveness of care delivered and the experience of using services. It now has to deliver this within the context of an increased drive to improve efficiency. The framework supports improving both the skills of those delivering care and the design of the systems they work in. The use of information to drive improvement is key, and the Scottish Government is supporting this focus through the use of National Targets, the Scottish Benchmarking Programme and the Scottish Mental Health Collaborative. SUMMARY: Scotland's mental health quality and outcomes framework has a clear focus on the intelligent use of information and targets. Developing and refining our approach in partnership with key stakeholders has enabled a culture of trust over the use of information. The service is willing to collect it, analyse its meaning and redesign clinical practice and services to improve performance. PMID- 19773657 TI - Impact of visual cues on directional benefit and preference: Part II--field tests. AB - OBJECTIVES: The field tests performed in the current investigation examined how visual cues impact the benefit provided by directional (DIR) microphone hearing aids in the real world. Specifically, the study tested the hypotheses that (1) the provision of visual cues would reduce the preference for DIR processing (re: omnidirectional [OMNI] microphone) and (2) laboratory audiovisual (AV) testing would predict real-world outcomes better than auditory-only testing. DESIGN: The same 24 hearing-impaired adults enrolled in the laboratory testing of this study compared microphone modes (DIR versus OMNI processing) in their everyday activities three times a day for 4 wk using paper and pencil journals. In each comparison, the participants were asked to identify an environment that favored DIR processing (e.g., the talker standing in front of the user and noise at his or her back), listen to speech amid noise via both the DIR and OMNI microphone modes, and then record the preferred microphone mode in the journal. To further understand what the listeners based their preference on, the participants were also asked to provide the reasons for their preferences. Microphone modes were compared when the listeners' eyes were either open or closed. RESULTS: The field results first suggested that OMNI processing was more frequently preferred over DIR processing. Visual cues were not found to have a significant effect on preference for DIR processing. Furthermore, the analysis revealed that when listeners indicated "louder" or "less internal noise" as the reasons for their microphone preference, the likelihood of preferring the OMNI mode increased significantly, suggesting that OMNI processing was preferred for its louder output and lower internal circuit noise level. Finally, the preference score obtained by the laboratory preference judgment task under the AV condition was shown to be the best predictor of microphone preference in the real world. CONCLUSIONS: The field data did not reveal the effect of visual cues on preference for DIR processing because preference was not altered by the availability of visual cues. This negative result may be due to the unsuccessful control of visual cues during the field trial. However, the finding that AV laboratory testing predicted field outcomes more accurately than did auditory only testing demonstrates the role of visual cues in the real world and emphasizes the necessity of using AV testing in the laboratory to evaluate DIR microphone hearing aids. Furthermore, this study demonstrates the importance of factors other than DIR benefit-such as loudness and hearing aid internal noise-in determining preference for microphone mode in the real world. PMID- 19773658 TI - Performance-intensity functions for normal-hearing adults and children using computer-aided speech perception assessment. AB - OBJECTIVES: The Computer-Aided Speech Perception Assessment (CASPA) is a clinical measure of speech recognition that uses 10-item, isophonemic word lists to derive performance intensity (PI) functions for adult listeners. Because CASPA was developed for adults, the ability to obtain PI functions in children has not been evaluated directly. This study sought to evaluate PI functions for adults and four age groups of children with normal hearing to compare speech recognition as a function of age using CASPA. Comparisons between age groups for scoring by words and phonemes correct were made to determine the relative benefits of available scoring methods in CASPA. DESIGN: Speech recognition using CASPA was completed with 12 adults and four age groups of children (5- to 6-, 7- to 8-, 9- to 10-, and 11- to 12-yr olds), each with 12 participants. Results were scored by the percentage of words, phonemes, consonants, and vowels correct. All participants had normal hearing and age-appropriate speech production skills. RESULTS: Differences in speech recognition were significant across all age groups when responses were scored by the percentage of words correct. However, only differences between adults and the two youngest groups of children were significant when results were scored by the number of phonemes correct. Speech recognition scores decreased as a function of signal to noise ratio for both children and adults. However, the magnitude of degradation at poorer signal to noise ratios did not vary between adults and children, suggesting that mean differences could not be explained by interference from noise. CONCLUSIONS: Obtaining PI functions in noise using CASPA is feasible with children as young as 5 yrs. Statistically significant differences in speech recognition were observed between adults and the two youngest age groups of children when scored by the percentage of words correct. When results were scored by the percentage of phonemes correct, however, the only significant difference was between the youngest group of children and the adults. These results suggest that phoneme scoring may help to minimize differences between recognition scores of adults and children because children may be more likely to provide responses that are phonemic approximations when words are outside their lexicon. PMID- 19773659 TI - Transfer of auditory perceptual learning with spectrally reduced speech to speech and nonspeech tasks: implications for cochlear implants. AB - OBJECTIVE: The objective of this study was to assess whether training on speech processed with an eight-channel noise vocoder to simulate the output of a cochlear implant would produce transfer of auditory perceptual learning to the recognition of nonspeech environmental sounds, the identification of speaker gender, and the discrimination of talkers by voice. DESIGN: Twenty-four normal hearing subjects were trained to transcribe meaningful English sentences processed with a noise vocoder simulation of a cochlear implant. An additional 24 subjects served as an untrained control group and transcribed the same sentences in their unprocessed form. All subjects completed pre- and post-test sessions in which they transcribed vocoded sentences to provide an assessment of training efficacy. Transfer of perceptual learning was assessed using a series of closed set, nonlinguistic tasks: subjects identified talker gender, discriminated the identity of pairs of talkers, and identified ecologically significant environmental sounds from a closed set of alternatives. RESULTS: Although both groups of subjects showed significant pre- to post-test improvements, subjects who transcribed vocoded sentences during training performed significantly better at post-test than those in the control group. Both groups performed equally well on gender identification and talker discrimination. Subjects who received explicit training on the vocoded sentences, however, performed significantly better on environmental sound identification than the untrained subjects. Moreover, across both groups, pre-test speech performance and, to a higher degree, post-test speech performance, were significantly correlated with environmental sound identification. For both groups, environmental sounds that were characterized as having more salient temporal information were identified more often than environmental sounds that were characterized as having more salient spectral information. CONCLUSIONS: Listeners trained to identify noise vocoded sentences showed evidence of transfer of perceptual learning to the identification of environmental sounds. In addition, the correlation between environmental sound identification and sentence transcription indicates that subjects who were better able to use the degraded acoustic information to identify the environmental sounds were also better able to transcribe the linguistic content of novel sentences. Both trained and untrained groups performed equally well ( approximately 75% correct) on the gender-identification task, indicating that training did not have an effect on the ability to identify the gender of talkers. Although better than chance, performance on the talker discrimination task was poor overall ( approximately 55%), suggesting that either explicit training is required to discriminate talkers' voices reliably or that additional information (perhaps spectral in nature) not present in the vocoded speech is required to excel in such tasks. Taken together, the results suggest that although transfer of auditory perceptual learning with spectrally degraded speech does occur, explicit task-specific training may be necessary for tasks that cannot rely on temporal information alone. PMID- 19773661 TI - Intrauterine growth restriction: no unifying risk factor for the metabolic syndrome in young adults. AB - BACKGROUND: The validity and appropriateness of the metabolic syndrome as a cardiovascular risk factor are increasingly debated, partly because of the lack of a unifying underlying pathophysiological mechanism. Intrauterine growth retardation (low birth weight by sex and gestational length) has been associated with several cardiovascular problems and could be an important underlying risk factor for the metabolic syndrome. METHODS: The association between intrauterine growth retardation (from the Norwegian Medical Birth Registry) and the metabolic syndrome in 7435 men and women aged 20-30 years from the population-based HUNT 2 study was studied with logistic regression using fractional polynomial models. RESULTS: In men, there were significant associations with several of the separate components of the metabolic syndrome: central obesity (exponential, P<0.001), raised triglycerides (negative linear, P = 0.018), reduced HDL-cholesterol (U shaped, P = 0.086), raised blood pressure (negative linear, P = 0.036), and impaired glucose tolerance (negative linear, P = 0.036). In women, there were significant associations with central obesity (positive linear, P<0.001) and raised blood pressure (negative linear, P = 0.003) but not with the other components. When combining these components into the metabolic syndrome, an exponential association was found in men (P = 0.017), that is, increased risk in patients with high birth weight only. In women, there was no association at all (P = 0.959). CONCLUSION: Low birth weight was not associated with the metabolic syndrome at young adult age. Several associations between birth weight and the separate components of the syndrome were found, however, but these associations were partly in different directions. PMID- 19773660 TI - Re-evaluating the Rose approach: comparative benefits of the population and high risk preventive strategies. AB - BACKGROUND: Options for the prevention of cardiovascular disease, the greatest global cause of death, include population preventive measures (the Rose approach), or specifically seeking out and managing high-risk cases. However, the likely benefit of a population approach has been recently questioned. OBJECTIVE: To compare the estimated effects of population strategies at varying levels of population-wide risk factor reduction and high-risk strategies at varying rates of screening uptake on cardiovascular disease mortality. METHODS: Data (of 109 954 participants) were pooled from six European general population cohort studies [the high-risk cohorts from the SCORE (Systematic COronary Risk Evaluation) dataset]. The effects of various population and high-risk strategies for the reduction of risk factors were estimated by calculating the change in 10-year risk of cardiovascular disease mortality (SCORE risk) before and after the particular intervention. Risk factors studied were: total cholesterol, blood pressure and smoking. RESULTS: At population level, if a 10-year reduction of blood cholesterol level of 10%, a BP reduction of 10% and a 10% reduction in the prevalence of smoking is considered possible, then 9125 lives per million of the population would be saved over 10 years. In contrast, an approach that treats all high-risk individuals with a polypill containing statin, three half-dose antihypertensives and aspirin, with a 20-80% uptake, would save 1861-7452 lives per million. However, the high-risk estimates are very optimistic, as their achievement would require complete compliance. CONCLUSION: High-risk and population strategies are complementary. These estimates of the benefits of each may be useful to health planners, when combined with their local knowledge. Recently, benefits of population strategies have been underestimated. PMID- 19773662 TI - Identifying risk factors for an abnormal computed tomographic scan of the head among patients with altered mental status in the Emergency Department. AB - AIMS: The aims of our study are to evaluate the use of computed tomographic scan of the head (CT-head) in patients with altered mental status (AMS) presenting to the Emergency Department (ED) and to identify clinical features associated with an abnormal CT-head result. METHODS: In this prospective observational study, we recruited consecutive adult patients with undifferentiated AMS and no major trauma at a busy urban ED over 11 months. Demographical, clinical, radiological and laboratory data were collected prospectively. The primary outcome measure was an abnormal CT-head result. Secondary outcome measures were the distribution of aetiologies of AMS with age, mortality rate and length of hospital stay. Logistic regression was applied to identify variables associated with an abnormal CT-head result. RESULTS: Nine hundred and sixty-seven patients were recruited. The rate of CT-head use in the ED was 41%, with 45% of the scans being abnormal. We identified eight clinical factors associated with an abnormal CT-head result. Odds ratios (95% confidence intervals) for diastolic blood pressure greater than 80 mmHg, focal weakness, Glasgow Coma Score less than 15, antiplatelet use, upgoing plantar response, presence of headache, anticoagulant use and dilated pupils were 1.016 (1.003-1.029), 1.816 (1.063-3.103), 1.899 (1.113-3.242), 2.203 (1.146-4.234), 2.680 (1.623-4.427), 3.369 (1.449-7.830), 3.589 (1.253-10.283) and 5.212 (1.153-23.558), respectively. CONCLUSION: Our study identified important risk factors for an abnormal CT-head result which can be used in future research to establish a guideline for rational ordering of the test in AMS patients. PMID- 19773663 TI - Primary prevention of colorectal cancer: are we closer to reality? AB - Colorectal cancer is one of the leading causes of morbidity and mortality worldwide. An early detection of colorectal cancer determines therapeutic outcomes, while primary prevention remains a challenge. Our aim was to review the dietary, geographical and genetic factors in the causation and their possible role in the primary prevention of colorectal cancer. Data from experimental and clinical studies and population screening programmes were analysed to determine the factors responsible for causation of colorectal cancer. The role of dietary constituents, including the consumption of fat, red meat, fibre content, alcohol consumption, and other lifestyle issues, including obesity, lack of exercise and geographical variations in cancer prevalence were reviewed. The role of genetic and lifestyle factors in causation of colorectal cancer is evident from the experimental, clinical and population-based studies. Dietary factors, including the consumption of fat, fibre, red meat and alcohol, seem to have a significant influence in this regard. The role of micronutrients, vitamins, calcium may be relevant but remain largely unclear. In conclusion, there is ample evidence favouring the role of various dietary and lifestyle factors in the aetiology of colorectal cancer. Modification of these factors is an attractive option, which is likely to help in the primary prevention and reduced disease burden. PMID- 19773664 TI - Interobserver concordance in the assessment of liver fibrosis in HIV/HCV coinfected patients using transient elastometry. AB - OBJECTIVES: Although the reproducibility of transient elastometry (TE) in hepatitis C virus (HCV)-monoinfected patients seems to be high, this may not be the case in HIV/HCV-coinfected patients because of different degrees of steatosis and/or inflammation. This study was aimed to determine the interobserver concordance of TE measurements in HIV/HCV-coinfected patients. METHODS: A total of 188 patients were evaluated in a cross-sectional, prospective study in two hospitals. The interobserver variability of TE results and the rate of unequal classification of significant fibrosis (cutoff value = 7.2 kPa) and cirrhosis (cutoff value = 14.6 kPa) for two observers were evaluated. RESULTS: The values of liver stiffness (LS) for two observers highly correlated [intraclass correlation index = 0.976; 95% confidence interval (CI): 0.968-0.982]. The kappa indexes for the concordance of patient classification were 0.60 for significant fibrosis and 0.89 for cirrhosis. Using two cutoff points to diagnose or rule out significant fibrosis (LS >or=9 kPa or <6 kPa) yielded a kappa index of 0.96, but 46% of patients were not classified. Covariables that influenced the interobserver agreement were a high interquartile range in the determination (adjusted odd ratio: 0.189; 95% CI: 0.087-0.411; P = 0.001) and elevated levels of triglycerides (adjusted odd ratio: 1.004; 95% CI: 1.000-1.008; P = 0.031). CONCLUSION: TE measurement is an observer-independent method to evaluate LS in HIV/HCV coinfected patients. The concordance of the classification of mild-to severe fibrosis is good and for the diagnosis of cirrhosis is excellent. Lower interquartile ranges and triglyceride levels lead to a higher interobserver agreement. PMID- 19773665 TI - The effect of hepatectomy on coagulation: an evaluation by thromboelastography. AB - OBJECTIVES: Liver has a major role in coagulation. The hemostatic derangements measured by the mostly used coagulation parameters as prothrombin time, activated partial thromboplastin time, and thrombocyte count do not always correlate with the bleeding associated with liver diseases and these factors do not measure the thrombotic risks. So, thromboelastography is used in new clinical and laboratory research. The aim of this study is to study the effect of different levels of hepatectomy on coagulation. METHODS: Laparatomy, 40% hepatectomy, and 70% hepatectomy was performed in three different groups of rats. Prothrombin time, international normalized ratio, activated partial thromboplastin time, thrombocyte count, fibrinogen levels, and thromboelastography parameters were obtained at the 0, 6, and 24th hour of the study. RESULTS: Fibrinogen level at the 24th hour was greater than the early hours in both of the hepatectomy groups. Prothrombin time and international normalized ratio values were significantly higher in hepatectomy groups than in the sham group. There were no statistically significant difference in the clotting time, clot formation time, alpha-angle, and maximum clot firmness values in any of the thromboelastography channels, in any of the study times, in between the sham, 40% hepatectomy, and 70% hepatectomy groups. CONCLUSION: There is no difference between 40 and 70% hepatectomy when the coagulopathy is evaluated. The coagulation derangements as reflected by the increase in fibrinogen and prolongation of prothrombin time and activated partial thromboplastin time after hepatectomy were not supported by thromboelastography parameters in this study. PMID- 19773666 TI - Cost-effectiveness of the artificial liver support system MARS in patients with acute-on-chronic liver failure. AB - BACKGROUND: For patients with an acute exacerbation of chronic liver failure (ACLF), the molecular adsorbent recirculating system (MARS) can result in a prolongation of life, but data on costs and cost-effectiveness are lacking. METHODS: A health economic evaluation of a prospective controlled cohort trial in patients with ACLF not eligible for liver transplantation with 3 years follow-up and consecutive modelling of long-term costs, outcomes and cost-effectiveness was conducted. Costs were calculated from the perspective of the German health-care system. RESULTS: One hundred and forty-nine patients with ACLF were included of which 67 (44.9%) were treated with MARS and 82 (55.1%) assigned to the control group. Mean survival was 692 days in MARS-treated patients (33% survival after 3 years) and 453 days in control patients (15% after 3 years, logrank P = 0.022). MARS patients gained 0.66 [95% confidence interval (CI): -0.12 to 1.46] life years (LYs), determined by the bootstrap method. The mean cost difference was 19.835 euro (95% CI: 13.308-25.429) with 35639 euro for MARS-treated patients and 15804 euro for controls. Incremental costs per LY gained were 29.985 euro (95% CI: 9.441-321.761) and 43.040 euro (95% CI: 13.551-461.856) per quality-adjusted LY gained. CONCLUSION: There is an acceptable cost-effectiveness of MARS, compared with other medical technologies presently reimbursed. Randomized controlled trials with sufficient sample size are necessary before a final recommendation for MARS can be given. PMID- 19773667 TI - Hospitalization of hepatitis C-diagnosed individuals in Scotland for decompensated cirrhosis: a population-based record-linkage study. AB - OBJECTIVES: Although chronic infection with the hepatitis C virus (HCV) may lead to the development of cirrhosis and its complications, little data are available on progression to the decompensated stage in a hetereogeneous population. Our aims were to characterize the burden of HCV-related decompensated cirrhosis on the national health care system in Scotland in terms of hospital admissions and length of stay, and to estimate the associations between epidemiological variables and time to the first hospital admission/death with mention of decompensated cirrhosis. METHODS: We carried out a record-linkage study of 20 969 individuals diagnosed with hepatitis C through laboratory testing between 1991 and 30 June 2006, whose records were linked to the Scottish Morbidity Records hospital discharge database and to national HIV databases. RESULTS: Nine hundred and ninety-five individuals were admitted to hospital and 63 individuals died with first-time mention of decompensated cirrhosis during follow-up (median 5.2 years). The number of new cases increased over the period 1996-2005, with an average annual change of 11% [95% confidence interval (CI): 8-13]. The relative risk of developing decompensated cirrhosis was greater for men (hazard ratio = 1.4, 95% CI: 1.1-1.7), for those coinfected with HIV (hazard ratio = 2.1, 95% CI: 1.4-3.3), for those with a prior alcohol-related admission, fitted as a time dependent covariate (hazard ratio = 5.5, 95% CI: 4.6-6.6) and for those aged 30 years or older (30-39 years: hazard ratio = 3.7, 95% CI: 2.4-5.8; 40-49 years: hazard ratio = 10.0, 95% CI: 6.5-15.6; 50-59 years: hazard ratio = 20.6, 95% CI: 12.9-32.9, 60 years or older: hazard ratio = 37.4, 95% CI: 22.8-61.3). CONCLUSION: The burden from HCV-infected individuals developing cirrhotic complications is increasing because of the advancing age of this population. On account of the synergistic effect of HCV and excessive alcohol consumption on the development of liver disease, it is essential that policy-makers address alcohol intake when allocating resources for the management of HCV infection. PMID- 19773668 TI - Endothelial nitric oxide synthase gene polymorphisms and diabetic nephropathy: a HuGE review and meta-analysis. AB - Candidate-gene association studies that examined the association between polymorphisms of endothelial nitric oxide synthase (NOS3) gene (G894T, 4b/a, and T786C) and diabetic nephropathy or diabetes leading to severe nephropathy produced inconclusive results. Thus, a meta-analysis of all candidate-gene association studies with endothelial nitric oxide synthase genotyping (7401 cases and 8046 controls) was conducted. Other study designs, such as family-based association studies and genome-wide linkage and association studies were also reviewed for supportive evidence of implication of endothelial nitric oxide synthase gene in diabetic nephropathy. The meta-analysis showed that G894T is significantly associated with diabetic nephropathy and diabetes leading to severe nephropathy in type 2 diabetics and in East Asians, respectively. Concerning the 4b/a polymorphism and its relationship to diabetes leading to severe nephropathy, a significant association was shown for East Asians. Heterogeneity between studies was in general high. There was no differential magnitude of effect in large versus small studies. One genome-wide linkage scan provided evidence of linkage nearby the endothelial nitric oxide synthase locus. Studies exploring gene and environment interactions with endothelial nitric oxide synthase polymorphisms may help understand better the genetics of diabetic nephropathy. PMID- 19773669 TI - Factorial structure of the Pain Rehabilitation Expectations Scale: a preliminary study. AB - The aim of this study was to report the preliminary validation results for the Pain Rehabilitation Expectations Scale (PRES). The PRES is a clinical tool developed to measure the expectations about rehabilitation treatment and outcome for people with back pain. Fifty people with chronic back pain were recruited from 11 physiotherapy outpatient clinics in Hong Kong for this study. Multitrait scaling analysis indicated that the three subscales of the PRES (working alliance, proxy efficacy, and motivation/expectation) were internally consistent, with Cronbach's alpha reliability coefficients ranging from 0.93 to 0.96. Proxy efficacy was found to be related to working alliance, and working alliance was positively related to client motivation and expectations. The preliminary psychometric analysis results suggested that the PRES could potentially be used to measure chronic pain patients' expectations about pain rehabilitation treatments. However, this study is based on a very small sample size; psychometric validation of the PRES with a larger sample of chronic pain patients to confirm the measurement structure of the PRES using confirmatory factor analysis is warranted. PMID- 19773670 TI - Effects of 8 weeks of balance or weight training for the independently living elderly on the outcomes of induced slips. AB - The study was conducted to evaluate whether the balance or weight training could alter gait characteristics of elderly contributing to a reduction in the likelihood of slip-induced falls. A total of 18 elderly were evaluated for the study. The results indicated decreases in heel contact velocities and the friction demand characteristics after 8 weeks of training, although fundamental gait characteristics, such as walking velocity and step length, were not changed. The results also indicated an increase in transitional acceleration of the whole body center of mass. The number of falls after 8 weeks was reduced in training groups. These findings were found in conjunction with the improvements in knee flexor muscle and plantarflexor muscle strength. In conclusion, after training, elderly were less likely to initiate slips and more likely to recover from slips. PMID- 19773671 TI - Shoulder external rotator selective neurotomy in cerebral palsy: anatomical study and preliminary clinical results. AB - Shoulder external rotation posturing in patients with cerebral palsy can severely impair bimanual activities and lead to painful shoulder instability. We performed an anatomical study to describe the surgical approach to the shoulder external rotators nerves. Using this technique, we performed a selective neurotomy in five shoulders with external rotator shoulder spasticity. Ashworth scale dropped from 2 or 3 to 0 and active internal rotation increased from 0-10 to 60-70 degrees . This is a short series but preliminary results are encouraging and allow us to extend the study to a greater number of patients. PMID- 19773672 TI - Detection of colorectal cancer using 18F-FLT PET: comparison with 18F-FDG PET. AB - OBJECTIVE: We investigated the feasibility of 3'-deoxy-3'-18F-fluorothymidine (FLT) positron emission tomography (PET) for the detection of colorectal cancer, in comparison with 2-deoxy-2-18F-fluoro-D-glucose (FDG) PET, and investigated correlation of the two radiotracers used with proliferative activity as indicated by Ki-67 index. METHODS: A total of 26 patients with newly diagnosed colorectal cancer were examined with FLT PET and FDG PET. Tumor lesions were identified as areas of focally increased uptake, exceeding that of surrounding normal tissue. For semiquantitative analysis, the maximal standardized uptake value (SUV) was calculated. RESULTS: In all 26 patients, colorectal cancers were detected by both FLT PET and FDG PET. The mean (+/- SD) values of FLT SUV in colon cancer (5.4 +/- 2.4) and in rectal cancer (5.6 +/- 1.3) were significantly lower than the corresponding values of FDG SUV (12.4 +/- 6.3 and 12.5 +/- 4.7, respectively) (P < 0.003). There was no significant correlation between Ki-67 index and either FLT SUV or FDG SUV. CONCLUSION: Although uptake of FLT was found to be significantly lower than that of FDG, both FLT PET and FDG PET were able to detect colorectal cancers in all 26 patients. Neither of the two radiotracers used was correlated with proliferative activity. PMID- 19773673 TI - Cerebral blood flow changes during chanting meditation. AB - PURPOSE: To examine changes in brain physiology during a chanting meditation practice using cerebral blood flow single-photon emission computed tomography. METHODS: Single-photon emission computed tomography scans were acquired in 11 healthy individuals during either a resting state or meditation practice randomly performed on two separate days. Statistical parametric mapping analyses were conducted to identify significant changes in regional cerebral blood flow (rCBF) between the two conditions. RESULTS: When the meditation state was compared with the baseline condition, significant rCBF increases were observed in the right temporal lobe and posterior cingulate gyrus, and significant rCBF decreases were observed in the left parietotemporal and occipital gyri. CONCLUSION: The results offer evidence that this form of meditation practice is associated with changes in brain function in a way that is consistent with earlier studies of related types of meditation as well as with the positive clinical outcomes anecdotally reported by its users. PMID- 19773674 TI - Sporotrichoid-like tuberculosis. AB - Cutaneous tuberculosis (TB) is a rare presentation of tuberculosis infection in childhood, especially in developed countries. The commonest forms of cutaneous TB, in declining order, are scrofuloderma, lupus vulgaris, lichen scrofulosorum, and TB verrucosa cutis. We described 2 cases of sporotrichoid-like cutaneous tuberculosis infection, 1 localized to a limb and regional nodes and 1 associated with disseminated disease. PMID- 19773675 TI - Risk factors for infection-related outcomes during induction therapy for childhood acute lymphoblastic leukemia. AB - BACKGROUND: The primary objective was to describe microbiologically documented infections during induction therapy for acute lymphoblastic leukemia. The secondary objectives were to describe risk factors for microbiologically documented infections and for patients with a febrile episode, to identify risk factors for recurrence of fever or reinitiation of antibiotics. METHODS: This study was a retrospective review of children from 1 to 18 years of age who received induction chemotherapy between March 1997 and September 2006. Microbiologically documented infections were examined through the induction period. RESULTS: There were 425 children evaluated. The most common pre-existing risk factor for infection was Down syndrome in 11 children. Of the 425 children, 83 (19.5%) experienced at least one microbiologically documented infection. There were 85 infections consisting of 65 bacterial, 15 viral and 5 fungal infections.Variables significantly associated with a microbiologically documented infection were pre-existing risk factors (odds ratio [OR]: 3.63; P = 0.01) and neutropenia at initial infectious episode (OR: 1.86; P = 0.03). Factors associated with recurrence of fever and reinitiation of antibiotics after an initial infectious episode were receipt of a 4-drug induction, neutropenia at the initial infectious episode, initial fever documented in hospital, and lack of bone marrow recovery at the time of initial antibiotic cessation. CONCLUSIONS: About 20% of children with acute lymphoblastic leukemia have a microbiologically documented infection during induction. Those with pre-existing risk factors and neutropenia at the initial infectious episode were at higher risk of microbiologically documented infection. Continued efforts to refine risk groups may allow for risk-directed prophylactic or empiric strategies. PMID- 19773676 TI - Incidence of herpes zoster among children vaccinated with varicella vaccine in a prepaid health care plan in the United States, 2002-2008. AB - BACKGROUND: Herpes zoster (HZ), or shingles, is caused by reactivation of latent varicella-zoster virus after a primary infection with either wild-type or vaccine type varicella-zoster virus, the latter having been introduced in 1995 for children. Since then, few population-based data about the incidence of childhood HZ are available. METHODS: We identified children aged < or = 12 years who were vaccinated with 1 dose of varicella vaccine between 2002 and 2008 in a prepaid health plan and followed them through their electronic health records for a diagnosis of HZ. The medical records of these children were reviewed. Persistent and chronic conditions for these children before HZ were identified. RESULTS: There were 172,163 children vaccinated, with overall follow-up of 446,027 person years (Incidence rate = 27.4 per 100,000 person-years, 95% confidence interval: 22.7-32.7). Children vaccinated after age 5 years had a higher but not statistically significant different rate than children vaccinated between 12 and 18 months (34.3 vs. 28.5 per 100,000 person-years). Among children vaccinated between 12 and 18 months, incidence rates gradually increased each year in the first 4 years after vaccination (P < 0.001). Among the HZ cases, there were 1 (0.7%) case of lymphoid leukemia, 1 (0.7%) case of drug abuse, 16 (11.1%) cases of asthma with 3 or more acute exacerbations, 12 (8.3%) cases of developmental disorders, and 3 (2.1%) cases of psychological or mental disorders. CONCLUSIONS: These data demonstrate that diagnosed HZ is rare among children following varicella vaccine. Despite the small numbers, the roles of delayed vaccination, severe asthma, and development disorders warrant further investigation. In the future, analyses of HZ isolates will be needed to identify the virus strains causing reactivation. PMID- 19773677 TI - Gene polymorphism of IFNG +874 T/A and TLR4 +896 A/G and recurrent infections and wheezing in toddlers with history of bronchiolitis. AB - Cytokine and TLR4 polymorphisms and their association with the infection history of 129 children hospitalized for bronchiolitis during the first 6 months of life were analyzed. The carriers of IFNG +874 T/A allele A had fewer infections and use of inhaled corticosteroids and the carriers of TLR4+896 A/G allele G were more likely to need tympanostomy than noncarriers. PMID- 19773678 TI - Esthetic outcome of surgical excision versus antibiotic therapy for nontuberculous mycobacterial cervicofacial lymphadenitis in children. AB - One hundred children with microbiologically proven nontuberculous mycobacterial cervicofacial lymphadenitis were randomly assigned to excision of the involved lymph nodes, or antibiotic therapy consisting of clarithromycin and rifabutin. The esthetic outcome was rated using a revised and weighted Observer Scar Assessment Scale. The median weighted esthetic outcome in surgical patients was significantly better (30.6) than that for patients treated with antibiotics (42.2). PMID- 19773679 TI - The use of human papillomavirus seroepidemiology to inform vaccine policy. PMID- 19773680 TI - Eliminating congenital syphilis--if not now then when? PMID- 19773681 TI - One-stop service for antenatal syphilis screening and prevention of congenital syphilis in Ulaanbaatar, Mongolia: a cluster randomized trial. AB - BACKGROUND: This cluster randomized trial was performed to test whether one-stop service could better prevent congenital syphilis than the conventional antenatal screening service in Mongolia. METHODS: Out of 14 antenatal clinics in 6 districts of Ulaanbaatar, 7 were randomly selected for the one-stop service and the remaining for the conventional service. Intervention clinics provided on-site rapid syphilis testing and immediate treatment for positive cases and their partners. In control clinics, syphilis screening services with routine off-site rapid plasma regain testing and case management were followed. Analysis was intention to treat. RESULTS: Of 3850 antenatal women recruited in each group, the proportion of syphilis testing at the first visit and third trimester was over 99% in the intervention group and 79.6% and 61.5% in the control group, respectively (P <0.001 for both periods). Correspondingly, syphilis cases detected in the intervention group were 73 (1.9%) and 20 (0.5%) for the first visit and third trimester, respectively, and 27 (0.9%) and 2 (0.08%) in the control group; and 98.9% (92/93) of the detected cases in the intervention group and 89.6% (26/29) in the control group were adequately treated (P = 0.02). The corresponding treatment rates for sexual partners were 94.6% and 55.2% (P <0.001). One congenital syphilis case out of 3632 deliveries in the intervention group, compared to 15 of 3552 in the control group, was diagnosed, a reduction of 93.5% (95% confidence interval, 66.0%-98.6%). CONCLUSIONS: One-stop services increased the detection rate of syphilis, treated more positive women and their partners, and effectively reduced the rate of congenital syphilis. PMID- 19773683 TI - Damned if we do, damned if we don't. AB - Bad press is better than no press. I think the NHS will staunchly disagree. Across the Atlantic, right-wing healthcare pressure group, Conservatives for Patients' Rights, has launched a series of television adverts attacking the NHS, in a bid to undermine Barack Obama's healthcare reforms. It seems Americans are split over private and public health care. They agree that change needs to take place, but exact details on improvement are ubiquitous to say the least. PMID- 19773682 TI - Pre-treatment syphilis titers: distribution and evaluation of their use to distinguish early from late latent syphilis and to prioritize contact investigations. AB - BACKGROUND: Treatment, contact investigation, and reporting decisions for syphilis cases are based on the stage of disease. Because of limitations of current staging protocols, the rapid plasma reagin (RPR) titer has been proposed as an alternative priority marker for contact investigation. METHODS: We describe the RPR titers and stages for 10,021 syphilis cases reported between 1997 and 1999 in Columbia, South Carolina; Houston, Texas; and Jackson, Mississippi. We constructed receiver operating characteristic curves (ROC curves) to compare titer and stage. We calculated the number of infected contacts to evaluate the use of titer to prioritize contact investigation. RESULTS: RPR titers differed by stage, with 67% of primary, 95% of secondary, 78% of early latent, and 41% of late latent and unknown duration having titers >1:8; however, there was considerable overlap in titer distributions. The ROC curve based on titer values demonstrated good agreement between titer and latent stage. Prioritization by titer (> or =1:8) of latent cases would result in a similar number of cases interviewed and contacts located as stage prioritization, although different cases are prioritized. CONCLUSION: Titer distributions meaningfully but imperfectly distinguish populations with different stages. Recent analyses and anecdotal reports indicate the difficulty and inconsistency of staging latent syphilis. Over time, titer could provide a more objective and reliable historical record of syphilis trends. Titer may be a useful alternative or adjunct to stage in prioritizing latent syphilis cases for investigation. PMID- 19773684 TI - Exciting times for the Defence Medical Services. AB - The last dedicated military hospital in the UK, the Royal Hospital Haslar in Gosport, Hampshire, closed in May 2007. This was the final stage in a radical change in the delivery of health care for armed forces personnel. The change saw the opening of Ministry of Defence hospital units across the UK, which are fully integrated within the NHS (for example, the Royal Centre for Defence Medicine, located in Birmingham alongside the University Hospital Birmingham Foundation Trust). PMID- 19773685 TI - Preparing new graduate nurses. AB - As a requirement of pre-registration nurse education, student nurses must spend roughly 50% of their course, around 2300 hours, on clinical practice on hospital wards to become registered nurses. Lyn Karstadt discusses some of the international attitudes towards clinical placement, and asks whether placement time should be decreased in the UK. PMID- 19773686 TI - Infection control and IV therapy in patients with Clostridium difficile. AB - Clostridium difficile is a spore-forming anaerobe belonging to the family Clostridium, with the bacteria being found in low numbers in approximately 5% of the healthy adult population. Together with meticillin-resistant Staphylococcus aureus, it is a major healthcare-associated infection and is responsible for considerable morbidity and mortality. Antibiotics administered to patients can alter normal gut flora, allowing the proliferation of C. difficile and causing antibiotic-associated diarrhoea and colitis. Such diarrhoea, if severe, can lead to dangerous dehydration and even hypovolaemia, especially in the elderly. To limit the physiological impact of diarrhoea, it is sometimes necessary to administer intravenous therapy. Although good clinical practice demands that infection control should be considered in all clinical situations, specific infection control procedures need to be adhered to when administering intravenous therapy to patients with C. difficile. PMID- 19773687 TI - Current standards for infection control: audit assures compliance. AB - Having robust policies and procedures in place for infection control is fundamentally important. However, each organization has to go a step beyond this; evidence has to be provided that these policies and procedures are followed. As of 1 April 2009, with the introduction of the Care Quality Commission and The Health and Social Care Act 2008 Code of Practice for the NHS on the Prevention and Control of Healthcare-Associated Infections and Related Guidance, the assurance of robust infection control measures within any UK provider of health care became an even higher priority. Also, the commissioning of any service by the NHS must provide evidence that the provider has in place robust procedures for infection control. This article demonstrates how the clinical audit team at the Douglas Macmillan Hospice in North Staffordshire, UK, have used audit to assure high rates of compliance with the current national standards for infection control. Prior to the audit, hospice staff had assumed that the rates of compliance for infection control approached 100%. This article shows that a good quality audit tool can be used to identify areas of shortfall in infection control and the effectiveness of putting in place an action plan followed by re audit. PMID- 19773688 TI - Practical issues for emollient therapy in dry and itchy skin. AB - Managing atopic eczema and other dry and itchy skin conditions is a skill required in all nursing specialties. Nurses need to assess and address their patients' skin-care needs. Atopic eczema and all dry and itchy skin conditions require emollient therapy to restore the skin barrier. Nurses are ideally placed to educate patients in the importance of emollient therapy and provide practical information on the individual selection of bath additives, soap substitutes and moisturizers, as well as education on application and self-management. Nurse prescribers will benefit from understanding specific individual patient needs and individual emollient properties to enable them to make informed prescribing decisions and foster patient choice in selecting the best emollient therapy for the individual. This will restore the skin barrier function, reduce itch and suit the patient. PMID- 19773689 TI - Tomorrow's nurse graduate, today: the change in undergraduate education. AB - This article argues for a new kind of nurse graduate, equipped for the global challenges to health in the 21st century. The author points to the correlation between the public health role of a nurse in the 19th century and community health patterns of modern times to justify the shape of a recently installed undergraduate nursing studies programme at the University of Lincoln. The universal adoption of a public health philosophy by nurses is shown to be mutually advantageous to practitioners, to practice and to service users alike. In addition to research into the health inequalities and the patient experience, theoretical frameworks of learning and social policy are resourced to give direction to future nurse education and leadership among vulnerable individuals, communities and groups. PMID- 19773690 TI - Making rhetoric a reality: effective capacity building in mental health care provision. AB - Patients diagnosed with mental illness are statistically less likely to access physical healthcare services, resulting in increased mortality rates and diminished quality and decreased longevity of lifespan. This article identifies key aspects of the need for capacity building in, and between, all professional healthcare disciplines and utilizes a clinical case study to demonstrate the relevance of basic psychosocial interventions to all healthcare professionals. Alongside the practicalities of mental healthcare provision within the context of 21st-century society, discussion is extended to two basic theoretical models for understanding the relationship of mental illness to factors over which there can be no intraneous or conscious control. In this sense, the portrayal of patients with mental illness first and foremost as people whose somewhat transient demise from general wellbeing serves only to brand and stigmatize them from the point of diagnosis as fundamentally different to others. Mechanisms of how these stark rhetorical issues may be altered through building on the concept of therapeutic alliance with appropriately designed and insightful pathways of development for multidisciplinary healthcare teams aptly conclude the article. PMID- 19773692 TI - Patient confidentiality and mental health. Part 2: dilemmas of disclosure. AB - The article is the second in the series examining some of the issues relating to patient confidentiality and mental health. It explores the situations in which confidential patient information may be disclosed by nurses. First, disclosure with consent is considered. Second, disclosure where it is in 'the public interest' is explored. Third, those situations in which disclosure may be required by statute are discussed. The article concludes by suggesting that the whole area of confidentiality is ripe for reconsideration and perhaps statutory reform. PMID- 19773693 TI - Effectiveness of two opioid antagonists in treating opioid-induced constipation. AB - AIM: This literature review reports the effectiveness of two peripheral opioid antagonists to relieve constipation caused by prolonged use of opioids, primarily in patients with advanced cancer. BACKGROUND: Opioid-induced constipation can cause great discomfort to patients who use opioids for prolonged periods and on occasion decline pain-relief in an effort to help aid laxation. The use of peripheral opioid antagonists can help reverse the slowing of the gut caused by the opioids, but the correct one must be used in order not to reverse the important analgesic effects the opioids provide. DATA SOURCES: Information was obtained by searching the databases British Nursing Index, CINAHL and Medline. REVIEW METHODS: Selection criteria were as follows: original research in the form of randomized controlled trials; articles had to be written in English; articles had to focus on the effectiveness of naloxone and methylnaltrexone in the treatment of opioid-induced constipation; the search was limited to the period 1990-2008. RESULTS: Nineteen articles were included in the study. The results from the studies indicate that due to fewer withdrawal effects and less reversal of analgesia experienced, methylnaltrexone is more effective at relieving opioid induced constipation. CONCLUSION: The recent development of methylnaltrexone into a commercially-viable drug indicates its effectiveness. It may help patients suffering from the intense discomfort that constipation can cause. PMID- 19773694 TI - Principles of non-invasive ventilation: a critical review of practice issues. AB - This article is the second of a two-part review on mechanical ventilation, with particular emphasis on the practice of non-invasive ventilation. Part 1 explored the principles underpinning artificial ventilation. It went on to explain the difference between positive and negative pressure ventilation, and differentiated between invasive and non-invasive modes of ventilation. Finally, it examined the various operational features, flexibility in use and limitations that artificial ventilation therapy presents. In this second part, the article focuses on the practice of non-invasive ventilation. It addresses the indications and contraindications, patient selection, initiation, maintenance, weaning processes, and problems specifically associated with non-invasive ventilation. Practical remedies are explored and potential areas for research are indicated. PMID- 19773695 TI - The role of community nurses in providing a seamless patient pathway. AB - Every day, community nursing teams deliver evidence-based practice and use their expertise to oversee complex care pathways. However, much of the valuable work community nurses undertake remains invisible or tacit as practitioners concentrate on managing their patients' needs rather than raising the profile of the service they offer. This case study demonstrates the crucial role a community nursing team played in coordinating services, risk management and delivering evidence-based care. This enabled an individual to heal his problematic abdominal wound and quickly regain his former quality of life. When community nursing teams apply their experience and clinical expertise, they can facilitate dramatic improvements in patients' health and recovery times. Nursing teams need to highlight and promote the valuable role they play in care pathways to the commissioners of community services. Patients can then continue to be supported by professionals with the experience and skills to assist them in managing complex clinical situations. PMID- 19773696 TI - Lobbying for fitness. AB - When Lord Darzi of Denham, former health minister and architect of the new NHS reform agenda, said on leaving office in July that the health of the staff remained one of the most crucial areas of unfinished business, he was not far off the mark. Support for his view has now come from a recently published interim report by Dr Steve Boorman, a leading occupational health expert who has been examining the health and wellbeing of NHS staff. After 6 months of staff surveys, workshops, data reviews and responses from Trusts and experts in the field, Boorman sets out the key factors which are significant in producing an NHS workforce that is not caring enough about its own staff. PMID- 19773697 TI - Advocating palliative nursing. PMID- 19773698 TI - Extending knowledge of terror management theory to improve palliative nursing care. PMID- 19773699 TI - Advancing the use of 'Welam's sign' as a prognostic marker in patients with cancer. PMID- 19773700 TI - Evaluating the use of the Cleo 90 infusion set for patients on a palliative care unit. AB - Although the use of subcutaneous infusion is common in palliative care, problems can occur. Normally, butterfly needles are used; however, there are occasional issues with patients being able to walk around or with restless patients who suffer from delirium. In these cases, needles often dislocate; therefore, a small observational study was undertaken to evaluate the use of the Cleo 90 infusion set. The use of this needle system has been well established in diabetic patients who require continuous subcutaneous infusion of insulin, but has never been tested in a wider range of patients with other medications. In this 6-month study, 45 patients were identified for subcutaneous infusion and a total of 112 needles were used for this study, since we initially changed each site after 2 days to control the local site for adverse reactions. We have not observed any complications with drug combinations delivered via the attached tube and the needle, and have used up to five different drugs mixed together in a single syringe. Needles could be used for a mean time of 5 +/- 2 days (range 2-12 days). Local site reactions have been observed only with sodium chloride infusions, which were not delivered via a pump system. Reddening and induration of the skin occurred, but they were reversible after removing the needle. As this was a small study in only one unit, without standardization the results can only be observational. However, it has shown, for the first time, that the Cleo 90 needle can be safe and comfortable. PMID- 19773701 TI - A review of paediatric palliative care nursing education in Latin America. AB - Around the world, children suffering from catastrophic illnesses need quality palliative nursing care. However, unstable economic, social, and political structures in developing nations have delayed the advancement of paediatric palliative care programs in some regions. This systematic literature review primarily focuses on paediatric palliative care in Latin American countries. The aim is to identify existing support structures and possible barriers to paediatric palliative care nursing education. This review provides the background for a proposed collaborative paediatric palliative care nursing education initiative between a children's research hospital in the United States and a Chilean partner site. PMID- 19773702 TI - The implementation of an end-of-life integrated care pathway in a Chinese population. AB - The integrated care pathway is used in end-of-life care to improve quality of care; the Liverpool Care Pathway (LCP) has been used in Europe and North America. Tuen Mun Hospital is a regional hospital in Hong Kong, China. The End-of-life Care Pathway (ECP) based on the concepts used in the Liverpool Care Pathway, was developed, with modification to suit the local condition. Criteria for entry onto the ECP were that the multidisciplinary team agreed the patient was dying, and was at least two of the following: bedbound; semi-comatose; only able to take sips of fluid; no longer able to take tablets. The ECP template replaced all other inpatient documents. The ECP was implemented in the palliative care unit for terminal cancer patients. An audit was performed to review the result. Fifty one Chinese patients were included in the audit with mean age 64. The median duration of ECP use was 24 hours. All patients had current medication assessed and non-essential drugs were discontinued. The audit result suggested integrated care pathway in end-of-life care could be implemented successfully in an Oriental culture. The acceptance of using the ECP as a standard clinical practice takes time and education. Appropriate template design and supervision are the keys to success. PMID- 19773703 TI - Palliative respite services using nursing staff reduces hospitalization of patients and improves acceptance among carers. AB - People caring for palliative patients at home identify respite care as a key need. However, caregiver concern over the skill level of respite care providers has been cited as a common barrier to uptake and satisfaction with respite services. This study implemented and evaluated an at-home palliative care respite service delivered by enrolled nurses, known by various names in the UK. It was found that the program reduced hospitalizations of palliative patients by 80% and potentially increased the likelihood that they would die at home. PMID- 19773704 TI - Enteral tube feeding in older people with advanced dementia: findings from a Cochrane systematic review. AB - AIM: Enteral tube feeding for people with advanced dementia who have difficulty swallowing and poor nutritional intake is common. Potential benefits or harms of this practice are unclear and the authors aimed to evaluate the outcomes of this intervention. METHODS: A full literature review was undertaken in April 2008. Randomized controlled trials (RCTs), controlled clinical trials, controlled before and after studies, interrupted time series studies and controlled observational studies that evaluated the effectiveness of enteral feeding via a nasogastric tube or via a tube passed by percutaneous endoscopic gastrostomy were selected. The study population comprised adults aged 50 and over with a diagnosis of advanced primary degenerative dementia who had poor nutritional intake and/or developed problems with eating and swallowing. The primary outcomes were survival and quality of life (QOL). RESULTS: No RCTs were identified. Seven observational controlled studies were found; six assessed mortality. There was no evidence of increased survival in people with dementia receiving enteral tube feeding. The other study assessed nutritional outcomes. None of the studies examined the effect on QOL and there was no evidence of benefit in terms of nutritional status or the prevalence of pressure ulcers. CONCLUSIONS: There is insufficient evidence to suggest that enteral tube feeding is beneficial in people with advanced dementia. Data is lacking on the adverse effects of this intervention. PMID- 19773705 TI - Core attitudes of professionals in palliative care: a qualitative study. AB - INTRODUCTION: Self-awareness of one's own reactions towards patients and their relatives is of paramount importance for all professionals in palliative care. 'Core attitude' describes the way in which a person perceives himself and the world, and forms the basis for his actions and thoughts. OBJECTIVE: The aim of this study is to explore what core attitude means for palliative care professionals and whether there is a specific core attitude in palliative care. METHODS: Qualitative study with 10 face-to-face in-depth interviews with experts in palliative care (nurses, physicians, social workers, psychologists, chaplain) in Germany. RESULTS: Core attitude in palliative care can be best described with the following three domains: 1) personal characteristics; 2) experience of care; and 3) competence in care. Authenticity is the most important characteristic of professionals, along with honesty and mindfulness. Core attitude primarily becomes apparent in the relationship with the patient. Perception and listening are key competences. The experts emphasized the universality of the core attitude in the care of ill people. They stressed the importance and relevance of teaching core attitudes in palliative care education. CONCLUSION: In the field of palliative care, core attitude consists predominately of authenticity, manifests itself in relationships, and requires a high degree of perceptiveness. PMID- 19773708 TI - Distress: to treat or not to treat? PMID- 19773709 TI - Varenicline-induced mixed mood and psychotic episode in a patient with Schizoaffective Disorder. PMID- 19773710 TI - Borderline personality disorder: toward integration. AB - Several psychiatric disorders, including borderline personality disorder (BPD), are characterized by emotional dysregulation and impulse dyscontrol. More specifically, symptoms in patients with BPD often occur within the context of disruptions in attachment and related distortions in cognitive-affective processing of the self and others. From a neurocircuitry perspective, findings include prefrontal hypoactivity, amygdala hyperreactivity, and alterations in prefrontal-limbic interaction. Molecular pathways relevant to these circuits include the serotonergic, noradrenergic, and dopaminergic systems, and there is some evidence that pharmacotherapy with agents that act on these systems may be useful. Given the disruptions in attachment and schemas of the self and others in BPD, establishing a therapeutic alliance is crucial while psychotherapy remains the cornerstone of an integrated approach to management. PMID- 19773711 TI - Nail-biting stuff? The effect of N-acetyl cysteine on nail-biting. AB - N-acetyl cysteine (NAC) is a widely available nutraceutical with a variety of actions. As a precursor of cysteine and glutathione, it has antioxidant properties that may impact on mood and contribute to an effect on impulsivity and obsessive behaviour. Via its additional effect on glutamate via the cystine glutamate exchange system, NAC has been shown to mediate impulsivity in preclinical models of addiction, reduce craving, and cue extinction. Further, by boosting glutathione, NAC acts as a potent antioxidant and has been shown in two positive, large-scale randomized placebo-controlled trials to affect negative symptoms in schizophrenia and depression in bipolar disorder. We describe three cases in which its actions specifically on nail-biting and associated anxiety may offer a potential treatment. The spontaneous findings are reported as part of an ongoing treatment trial examining the utility of NAC in bipolar disorder. Its actions, if robustly replicated, also point to potential treatment targets in glutathione or glutamate pathways in the brain. PMID- 19773712 TI - Early onset obsessive-compulsive disorder with and without tics. AB - INTRODUCTION: Research suggests that obsessive-compulsive disorder (OCD) is not a unitary entity, but rather a highly heterogeneous condition, with complex and variable clinical manifestations. OBJECTIVE: The aims of this study were to compare clinical and demographic characteristics of OCD patients with early and late age of onset of obsessive-compulsive symptoms (OCS); and to compare the same features in early onset OCD with and without tics. The independent impact of age at onset and presence of tics on comorbidity patterns was investigated. METHODS: Three hundred and thirty consecutive outpatients meeting Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for OCD were evaluated: 160 patients belonged to the "early onset" group (EOG): before 11 years of age, 75 patients had an "intermediate onset" (IOG), and 95 patients were from the "late onset" group (LOG): after 18 years of age. From the 160 EOG, 60 had comorbidity with tic disorders. The diagnostic instruments used were: the Yale-Brown Obsessive Compulsive Scale and the Dimensional Yale-Brown Obsessive Compulsive Scale (DY-BOCS), Yale Global Tics Severity Scale, and Structured Clinical Interview for DSM-IV Axis I Disorders-patient edition. Statistical tests used were: Mann-Whitney, full Bayesian significance test, and logistic regression. RESULTS: The EOG had a predominance of males, higher frequency of family history of OCS, higher mean scores on the "aggression/violence" and "miscellaneous" dimensions, and higher mean global DY-BOCS scores. Patients with EOG without tic disorders presented higher mean global DY-BOCS scores and higher mean scores in the "contamination/cleaning" dimension. CONCLUSION: The current results disentangle some of the clinical overlap between early onset OCD with and without tics. PMID- 19773713 TI - Gender differences in the association between body mass index and psychopathology. AB - INTRODUCTION: The objective of the study was to examine gender differences in the relationship between weight group (under-weight to severely obese), and Axis I and Axis II psychopathology. METHODS: Data from the National Epidemiologic Survey of Alcohol and Related Conditions (NESARC) were analyzed. Logistic regression models examined the past-year likelihood for meeting diagnostic criteria for psychiatric disorders. Interactions between weight group and gender were utilized to determine whether associations were significantly different in men and women after adjusting for demographic characteristics. RESULTS: First, consistent with previous NESARC analyses, the prevalence estimates of psychiatric disorders were higher among people of higher body mass index groups, regardless of gender. However, these patterns differed across genders. Both severely obese women and men, in comparison to normal weight respondents, were much more likely to meet criteria for affective and anxiety disorders, but these associations were significantly (1.5-2 times) stronger among women. For Axis II disorders, while there were very few associations between personality disorders and weight in men, among women increases in weight group were associated with increases in the likelihood of meeting criteria for a personality disorder. CONCLUSION: Weight and psychopathology appear more strongly associated in women than in men. While these data do not allow for identification of underlying mechanisms, they highlight the importance of assessing for psychopathology in overweight and obese patients, and suggest that weight management may be an important consideration in the treatment of psychiatric disorders. PMID- 19773714 TI - A case of alcohol withdrawal requiring 1,600 mg of lorazepam in 24 hours. AB - Alcohol withdrawal continues to present significant morbidity and mortality in hospitalized medical/surgical patients. The authors present a case of a patient with delirium tremens requiring up to 1,600 mg/day of lorazepam and discuss alternative treatments for alcohol withdrawal. PMID- 19773716 TI - Adult ADHD and comorbid depressive disorders: diagnostic challenges and treatment options. AB - Attention-deficit/hyperactivity disorder (ADHD) and major depressive disorder (MDD) are separately common mental health conditions that can have an adverse effect on a patient's quality of life if left untreated. These disorders frequently co-occur with one another, which can lead to increased patient suffering and diagnostic challenges for the treating clinician. In the United States adult population, epidemiological data show that the prevalence rate for MDD is 6.7%, while the ADHD prevalence rate in US adults is 4.4%. This epidemiological data represents the general population and likely underestimates the prevalence rates in clinic or practice patients. Examining the concurrent comorbid rate, if a patient has MDD, the likelihood of that patient also having ADHD is 18.6%; if the patient has ADHD, the likelihood of that patient having comorbid MDD is 9.4%. If the patient has dysthymia, the comorbid rate of ADHD is 12.8%, while those adults with ADHD have a comorbid rate of dysthymia of 22.6%. PMID- 19773717 TI - Bipolar disorder and ADHD: Clinical concerns. AB - During the past decade, a similar composite has emerged for both bipolar disorder and adult attention-deficit/hyperactive disorder (ADHD). First, both conditions have a relatively high prevalence, a low case detection, a protracted illness course, a high rate of comorbidity, multifactorial ideology, substantial heritable liability, and tremendous burden of illness in economic cost as well as interpersonal and vocational maladjustments. What has also been interesting along with these reports is that there has been emerging scientific studies implicating common brain regions and neural circuits subserving essential features of both conditions. PMID- 19773719 TI - Preconditioning: from experimental findings to novel therapies in acute kidney injury. AB - Improving the ability of the kidney to tolerate injury through preconditioning is likely to have important clinical implications. Although a number of preconditioning strategies have been studied, ischemic preconditioning (IP) has been studied the most experimentally. The information gathered has helped us shed more light into the mechanisms responsible for this tissue adaptation that confers to tissues a more resistant status. IP is effective within minutes, suggesting that preformed mediators are involved. This is followed by delayed preconditioning, a phenomenon that is less potent but longer acting. Remote preconditioning occurs also in non-affected tissues and can be transferable. A number of mediators and transcription factors have been implicated including kinases, heat shock proteins, nitric oxide and neurogenic pathways, all of which help change the cell into a more resistant phenotype. There is evidence that IP also occurs in the human environment with lessons learned from myocardial ischemia, hepatic resection and cerebral ischemia. Because of the ethical impediment with intentionally applying organ ischemia, there has been an interest in pharmacological preconditioning lately. Exogenously administered erythropoietin was shown to benefit kidneys subjected to different insults. In addition, mesenchymal stem cells-based approaches for the prevention and treatment of acute kidney injury (AKI) are being studied. Calcineurin inhibitors may represent a viable way to reduce ischemia reperfusion injury in transplantation. Translating the experimental findings to the clinical arena remains a challenge. The discovery of new biomarkers for AKI should help initiate therapy early, when therapy could make a difference. PMID- 19773720 TI - Acute kidney injury as a risk and progression factor for chronic kidney injury. AB - Acute kidney injury is common in hospitalized patients and is associated with significant in-hospital morbidity and mortality. However, hospital-acquired acute kidney injury is neither a harmless complication of severe underlying diseases nor a life threatening short-term illness. Posthospital discharge follow-up of patients highlights that survivors of acute kidney injury may develop serious long-term sequelae. Long-term mortality is greater in those patients who survived acute kidney injury when compared with critically or non-critically ill patients without acute kidney injury. Among survivors of acute kidney injury at long-term follow-up approximately 12.5% may be dialysis dependent and 19-31% may have chronic kidney disease. The incidence of end-stage renal disease secondary to acute kidney injury will likely continue to increase with more elderly patients treated in Intensive Care Units, with a higher burden of extra renal and renal comorbid diseases. Nephrologists should recognize acute kidney injury as an underestimated cause of chronic kidney disease and patients who survive with incomplete recovery should be followed closely for new chronic kidney disease or progression of pre-existing chronic kidney disease. Non-recovery or re-need for dialysis are not only important determinants of long-term health status, quality of life and mortality of these patients, but add also a burden to health resources. PMID- 19773721 TI - Acute kidney injury and multiple organ dysfunction syndrome. AB - Acute kidney injury occurs in approximately 30% patients admitted to the intensive care unit and is commonly associated with multiple organ dysfunction syndrome. A decade ago, acute kidney injury was thought to be a benign entity that could be managed easily with supportive care and dialysis. It is now known that acute kidney injury has a tremendous negative impact on patient morbidity and mortality. Although epidemiologic data clearly demonstrate that acute kidney injury is independently associated with increased mortality, the mechanisms by which acute kidney injury causes death remain unclear. One explanation for the increased mortality is that acute kidney injury causes deleterious systemic effects including injury to other organs. In this review, clinical and experimental data demonstrating the role of acute kidney injury in affecting inflammation and distant organ dysfunction will be discussed with the view that acute kidney injury is a critical factor in the development and maintenance of multiple organ dysfunction syndrome. Current recommendations regarding management of AKI in light of these data and recent clinical trials will also be discussed. PMID- 19773722 TI - Renal replacement therapy for acute renal failure. AB - Renal replacement therapy became a common clinical tool to treat patients with severe acute kidney injury (AKI) since the 1960s. During this time dialytic options have expanded considerably; biocompatible membranes, bicarbonate dialysate and dialysis machines with volumetric ultrafiltration control have improved the treatment for acute kidney injury. Along with advances in methods of intermittent hemodialysis, continuous renal replacement therapies have gained widespread acceptance in the treatment of dialysis-requiring AKI. However, many of the fundamental aspects of the renal replacement treatment such as indication, timing of dialytic intervention, and choice of dialysis modality are still controversial and may influence AKI patient's outcomes. This review outlines current concepts in the use of dialysis techniques for AKI and suggests an approach for selecting the optimal method of renal replacement therapy. PMID- 19773723 TI - Stem cells in acute kidney injury repair. AB - New discoveries and developments in the biology and propagation of stem cells have fueled a whole new field of Medicine that has sparked great interest in the scientific community as well as in the general media and public. Stem cells are a very prominent and debated topic and have given ground to a new field of therapy in Medicine, which is called Regenerative Medicine. The kidney is a highly sophisticated and complicated organ, yet stem cell therapies have become of interest to Nephrologists and promising animal data are available showing the use of different stem cell populations in Nephrology. Acute kidney injury (AKI) is a clinical entity caused by a variety of factors resulting in renal damage and loss of function. Although it is reversible up to a point, it contributes tremendously to hospital morbidity and mortality. At the current time there are only supportive treatments available. Stem cell based therapies have the potential to become a broader and diverse treatment approach that is tailored to the pathophysiology of the disease and is therefore potentially more effective than traditional pharmacological approaches. The current article gives an overview about the field in general as well as potential treatment approaches and mechanisms. PMID- 19773724 TI - Radiocontrast-induced nephropathy: an update. AB - Both diagnostic and therapeutic studies frequently utilize radiocontrast media to enhance images. As a result, use of these agents has increased markedly over the past decade with more than 10 million studies performed on a yearly basis in the United States. Development of acute kidney injury (AKI) is a common complication of radiocontrast exposure in patients who possess underlying risk factors. Impor tantly, radiocontrast-induce nephropathy (RCIN) is associated with increased short- and long-term mortality. Thus, at risk patients should be identified prior to administration of radiocontrast to allow choice of other potential imaging options or employment of prophylactic interventions. Currently, use of isotonic intravenous fluids is the only proven beneficial preventive therapy. Use of low volumes of radiocontrast and avoidance of nephrotoxic medications are also accepted as nephroprotective. Mixed results exist on the utility of N acetylcysteine (NAC) therapy and low versus iso-osmolar radiocontrast agents in preventing RCIN. While hemodialysis appears to have no beneficial role, a single center's experience with hemofiltration is associated with a reduction in RCIN and other clinical endpoints. Several therapies have no role in the prevention of RCIN and should be avoided. This review will provide an up to date examination of the current status of these issues as they relate to RCIN. PMID- 19773725 TI - Proteinuria in the prognosis of IgA nephropathy. AB - IgA Nephropathy (IgAN) is the most common lesion causing primary glomerulonephritis in the world. The main clinical predictors of progression are: elevated blood pressure, high histological score and proteinuria. Although elevated serum creatinine concentration at diagnosis, increased excretion of cytochines, age at onset, obesity and genetic factors may all influence clinical outcome, it is quite clear that proteinuria is the hallmark of renal damage in IgAN. Patients with IgAN and little or no proteinuria (<500 mg/day) have low risk of progression in the short term, while the rate of decline in renal function is 25-fold faster in those with sustained proteinuria >3 g/day. The product of duration (years) and urinary protein excretion (g/day) at the time of renal biopsy is more significantly correlated with progression. So, this so called proteinuria index may be a useful predictor for glomerular and interstitial histopathological changes and the fate of renal function in IgAN. The progression of IgAN may be slowed by antihypertensive and antiproteinuric therapy, such as angiotensin converting enzyme inhibitors and/or angiotensin II receptor blockers, that can minimize secondary glomerular injury. Proteinuria has been shown to be an adverse prognostic factor in IgAN, with a strong relationship between proteinuria and prognosis and established importance of remission. Consequently, targeting proteinuria may be a valid surrogate for individualized kidney protective therapy. PMID- 19773726 TI - Gemcitabine, paclitaxel, and cisplatin as combined adjuvant approach in transitional cell carcinoma of the urothelium. AB - AIM: The objective of this study was to evaluate the adjuvant chemotherapy with gemcitabine, paclitaxel, and cisplatin for urothelial carcinoma. METHODS: Twenty seven patients with invasive transitional cell carcinoma of the urothelium were treated between 2001 and 2007. All patients received chemotherapy with intravenous gemcitabine at a dose of 1000 mg/mC on Days 1 and 8, intravenous paclitaxel at a dose of 80 mg/mC on Days 1 and 8, and intravenous cisplatin at a dose of 50 mg/mC on Day 2. Treatment courses were repeated every 21 days. RESULTS: Median follow-up period was 32.5 months. Six patients came to progressive disease. The median overall survival was not reached, and the actuarial 1-year and 2-year survival rates were 89% and 67% respectively. The median progression-free survival was 10.0 months. Median survival time for patients with ECOG status 0, and 1 was 52.0, and 22.0 months respectively. Grade 4 neutropenia occurred in 18.5% of patients, but there was no treatment related mortality. CONCLUSIONS: The combination of gemcitabine, paclitaxel, and cisplatin is a highly effective and tolerable regimen for patients with invasive transitional cell carcinoma of the urothelium. This treatment should be considered as a suitable option that deserves further prospective evaluation. ECOG performance status is an important predictive factors for survival. PMID- 19773727 TI - Update in minimal invasive therapy in benign prostatic hyperplasia. AB - Last decade several new treatment modalities for minimal invasive therapy of benign prostatic hyperplasia have been developed, both ablative and non-ablative. In this review the authors describe the different techniques and clinical studies of bipolar transurethral resection of the prostate (TURP), transurethral resection in saline (TURis), the different laser therapies for the prostate, transurethral microwave thermotherapy (TUMT), high intensity focused ultrasound (HIFU), transurethral needle ablation (TUNA), hot water induced thermotherapy (WIT), prostatic stents, intraprostatic ethanol injections and botulinum toxin A injections. The different bipolar systems and photoselective vaporisation might replace the ''gold standard'', monopolar TURP, in the near future. The holmium laser enucleation of the prostate is also a real challenger of the ''gold standard'', but the technique is difficult to learn. The TUMT definitively found its place as alternative to TURP, especially because it can be performed in an outpatient setting without the need of anaesthesia. Therefore it is also suitable in patients at high risk. The long-term data on TUNA and HIFU is disappointing and therefore these treatment modalities did not stand the test of time. WIT seemed to be a promising therapy, but durability is questionable. Intraprostatic ethanol injections are safe and effective in small series, but larger series are needed to confirm its efficacy. Intraprostatic botulinum toxin A injections are the first treatment of BPH to target both the increase in smooth muscle tone (dynamic component) and the excessive growth (static component) of BPH. This approach of BPH is very promising but more studies with long-term follow up are needed. PMID- 19773728 TI - Minimally invasive surgery in the management of benign prostatic hyperplasia. AB - Benign prostatic hyperplasia (BPH) is a chronic and often progressive condition, affecting the majority of men by the seventh decade of life. The historical gold standard has been transurethral resection of prostate (TURP), an effective procedure still associated with risk of bleeding, TUR syndrome, and need for general anesthetic and hospitalization. Minimally Invasive Surgical Techniques aim to address these limitations by offering lower morbidity, reducing hospitalization, and increasing convenience. These therapies include transurethral microwave therapy (TUMT), transurethral needle ablation (TUNA), laser resection/ablation therapies, transurethral ethanel ablation of prostate (TEAP), and high intensity frequency ultrasound (HIFU). A PubMed search was conducted using the keywords ''benign prostatic hyperplasia'' and ''minimally invasive surgery''. Additionally, searches involving the specific procedures (e.g. ''transurethral microwave thermotherapy'' or ''TUMT'') were performed. Relevant English articles were reviewed and synthesized. Randomized, comparative trials between TUMT versus TURP show symptom scores to be comparable, though flow rates were clearly superior for TURP. Similar findings were seen in studies between TUNA and TURP, though the follow-ups times were shorter. Laser therapies vary by characteristic wave-lengths, delivery systems, and techniques used. They all possess excellent safety and hemostatic profile, with the use of Holmium laser well studied in anticoagulated patients. The levels of efficacy vary, with Holmium the most established at providing comparable results to TURP in IPSS and flow rates, while having lowing complication rates. Fewer randomized trials with KTP versus TURP exist, and show divergent results and more trials with longer follow-up are needed. TEAP shows promising results, though several severe morbities have been reported. HIFU remains mostly experimental though feasible, with very few studies conducted. The MISTs offer certain advantages over traditional TURP, including improved hemostasis and the convenience/savings of shorter hospitalization or availability of office procedures. This must be tempered with the various shortcomings of the MISTs, including higher rates of reoperations for the office based procedures of TUMT and TUNA, lower flow rates, and less established RESULTS: Despite these various limitations, their general convenience, safety, and clinical efficacy make the MISTs compelling alternatives to TURP for the surgical management of BPH. PMID- 19773729 TI - Transurethral resection of the prostate: defending its leading position in the management of benign prostatic enlargement. AB - Although challenged by medical therapy and numerous minimal-invasive treatment modalities, transurethral resection of the prostate (TURP) is still considered as the gold standard of interventional treatment of benign prostatic enlargement (BPE). It is characterized by an immediate improvement in symptoms and voiding parameters and achieves long lasting RESULTS: While its efficacy is out of question, the associated peri- and postoperative morbidity remains a major point of criticism and has let to the introduction of numerous less invasive treatment options. On the other hand, this also brought various improvements in the technique of TURP aiming to improve treatment results and reduce perioperative morbidity. This review article gives an overview over the historical development, treatment results, associated complications and recent technical developments in TURP, highlighting especially the role of bipolar TURP. PMID- 19773730 TI - Open prostatectomy and the evolution of HoLEP in the management of benign prostatic hyperplasia. AB - Trans-urethral resection of the prostate (TURP) and other minimally invasive therapies are the most common surgical procedures used to treat benign prostatic hyperplasia today. However, many patients with a markedly enlarged prostate are often not amenable to these treatment options. In these patients open prostatectomy has been representing a viable and preferred treatment. Despite the morbidity of open enucleation is substantial, until recently no other options were available when the size of the prostate approached 100 g and beyond. The use of holmium laser for the treatment of benign prostatic hyperplasia was first reported in 1996. Holmium laser enucleation of the prostate (HoLEP) has been proposed as an alternative to TURP and to open prostatectomy for patients with lower urinary tract symptoms (LUTS) due to large benign prostatic enlargement. In this manuscript, the development of HoLEP from the initial reports to the long term follow-up data which demonstrate the effectiveness of the technique in treating patients affected by LUTS secondary to large adenomas has been reviewed. HoLEP seems to represent a valid alternative to both TURP and OP, with valid long term functional results, a low rate of short-term and long-term complications, and very low rates of reintervention. In conclusion, HoLEP can be offered as the size-independent gold standard treatment of patients with LUTS due to benign prostatic enlargement. PMID- 19773731 TI - Laser treatments of the prostate vs TURP/ open prostatectomy: systematic review of urodynamic data. AB - Bladder outlet obstruction (BOO) is believed to be the major component of benign prostatic hyperplasia (BPH) that harms the urinary tract. Therefore, BOO relief is the primary treatment objective in patients with obstructive BPH. This systematic review aims to analyze urodynamic data of laser treatment modalities of the prostate in direct comparison with standard treatment (TURP or open prostatectomy). We systematically searched the literature for randomized controlled trials (RCTs) of prostate laser treatments in which urodynamic results were compared to TURP or open prostatectomy. The literature search included articles that were published between January 1995 and January 2009. Thirty five RCTs were identified encompassing in total 3669 patients. Of all available laser treatments, only one RCT used pressure-flow data to compare the laser treatment of the prostate (holmium laser enucleation, HoLEP) with standard treatment. Improvement of maximum urinary flow rate (Q(max)) of free uroflowmetry was similar for contact laser ablation (CLAP) with Nd:YAG, interstitial laser coagulation with Nd:YAG, potassium potassium-titanyl-phosphate (KTP)/Nd: YAG hybrid treatment, and HoLEP. Qmax improvement was also similar for holmium laser ablation (HoLAP) with 60-80 Watts, holmium laser resection, and thulium laser resection but limited to only one study each. The laser hybrid therapy with CLAP/visual laser ablation of the prostate (VLAP)/Nd:YAG was inferior to TURP. VLAP and KTP showed inhomogeneous RESULTS: Most contemporary laser treatments modalities provide similar Qmax improvement compared to standard treatment. However, precise differences can only be determined by comparative computer urodynamic investigations. Therefore, new laser techniques (such as thulium laser vapoenucleation of the prostate) should be investigated by urodynamic studies in the future. PMID- 19773732 TI - Patients' pretreatment beliefs about recovery influence outcome of a pain rehabilitation program. AB - AIM: The aim of this study was to monitor the outcome of a five-week cognitive behavioral interdisciplinary rehabilitation program for patients disabled by chronic pain, utilizing data collected for a national quality registry. METHODS: The study included 255 consecutive patients from a university hospital setting. Demographic data and patient beliefs about recovery recorded on a five-category scale were collected before the program. Pain intensity (VAS), Disability Rating Index (DRI) and life satisfaction (LiSat-11) were collected before, immediately after and one year after the program. Partial respondents and non-respondents were excluded;168 patients remained. RESULTS: Pain intensity decreased (''pain now''; Friedman's test, P<0.0001) by 13 mm (median) after the program, (Dunn's test; P<0.001) and by 5 mm after one year (P<0.05). Only one of twelve DRI items (activity), ''participating in exercise/sports'' improved significantly after rehabilitation (Wilcoxon's test; P=0.0009), and remained improved one year later (P=0.0144). Life satisfaction in the physical and psychological domains increased after the program. A clinically meaningful reduction in pain intensity (10 mm) was reported by 43% of patients at the one-year follow-up. This group had significant increases in life satisfaction. Only patients with positive beliefs about recovery before rehabilitation showed a decrease in pain intensity at the one-year follow-up (P<0.028). CONCLUSIONS: The program influenced the pain, life satisfaction and, to a small extent, activity. A clinically relevant pain reduction and an increase in life satisfaction were related. Patients' pretreatment beliefs about recovery influenced the long-term decrease of pain intensity, indicating that more attention should be focused on patients' pretreatment beliefs. PMID- 19773733 TI - Association of hemoglobin levels, acute hemoglobin decrease and age with Rehabilitation outcomes after total hip and knee replacement. AB - AIM: A previous retrospective study suggested that an anemia prevention may shorten hospitalization and improve recovery, stating the usefulness of a proper therapy for preventing anemization, in order to get a better functional recovery and reduce hospitalization length. The present study analyzed the association of preoperative and postoperative hemoglobin levels with rehabilitation outcomes to check these results in the Rehabilitation Unit. METHODS: The study enrolled 104 patients, 94 underwent hip replacement surgery and 10 knee replacement. Patients were functionally studied through the six-meter walking test (6MWT) at admittance and at discharge from the Rehabilitation Unit. RESULTS: Preoperative hemoglobin has no correlation either with the results of WT executed at discharge nor with the improvement of it compared to the WT executed at admittance, while there is a significant relationship with the results of the WT executed at admittance. Age impacts on the result of 6MWT at admittance, on the one at discharge and on the improvement as well. CONCLUSIONS: Despite movement weakening by anemization due to surgery, patients transferred to the Rehabilitation Unit after total hip- and knee replacement, are able to get a better movement performance independently on hemoglobin loss. PMID- 19773734 TI - Preparation and culture of rat lens epithelial explants for studying terminal differentiation. AB - The anterior surface of the ocular lens is covered by a monolayer of epithelial cells, which proliferate in an annular zone underlying the ciliary body. Following division, these cells migrate posteriorly, where FGF diffusing from the retina induces them to differentiate into a posterior array of elongated lens fiber cells, which compose the bulk of the lens. Differentiation of lens epithelial cells into lens fibers can be induced in vitro by culturing explants of the central region of the anterior epithelium in the presence of FGF-2. Explants are prepared from lenses of neonatal rats by removing the lens from the eye and grasping the lens capsule on the posterior side with dissecting tweezers. The posterior capsule is then gently torn open and pressed down into the plastic bottom of a tissue culture dish. The peripheral regions of the explant are removed with a scalpel and the central area is then cultured in the presence of 100 ng/ml FGF-2 for as long as 2-3 weeks, depending on the parameters to be studied. Since epithelial cells in cultured explants differentiate in approximate synchrony over a period of days to weeks, the time course of signaling and gene expression can be determined using molecular, biochemical, and pharmacological techniques. Immunofluorescence microscopy is a powerful adjunct to these methods as it demonstrates the subcellular localization of proteins of interest and can reveal the physiological consequences of experimental manipulations of signaling pathways. PMID- 19773735 TI - Measures of adiposity: the inappropriate use of the fat mass index. PMID- 19773736 TI - Associations between weight change since 20 years of age and sleep-disordered breathing among male truck drivers. AB - BACKGROUND: Limited evidence for association of weight gain with sleep-disordered breathing (SDB) has been produced for Asian populations whose body mass index (BMI) levels are lower than in western countries. OBJECTIVE: The aim of this study was to examine weight change since 20 years of age and risk of SDB among Japanese. DESIGN: Retrospective cohort study. SUBJECTS: This study includes a large sample of 5320 male Japanese truck drivers aged 30-69 years. MEASUREMENTS: The respiratory disturbance index (RDI) was selected as an indicator of SDB, and it was estimated with a one-night sleep test using an airflow monitor, and the Epworth Sleepiness Scale (ESS) was used to estimate excessive daytime sleepiness. RESULTS: Respiratory disturbance and sleepiness were more prevalent among men with BMI of 25.0-29.9 and > or =30.0 kg/m(2) than among those with BMI of 18.5 24.9; multivariable odds ratios (ORs) were 1.8(1.5-2.0), P<0.001 and 4.4(3.5 5.5), P<0.001 for RDI > or =10, and 1.2(0.9-1.4), P=0.18 and 1.5(1.1-2.1), P=0.02 for ESS > or =11, respectively. Compared with men showing BMI changes within +/ 1.0, the respective multivariable ORs for those with BMI changes of 3.0-4.9 and > or =5.0 were 1.4(1.2-1.6), P<0.001 and 2.4(2.0-2.9), P<0.001 for RDI > or =10, and 1.2(0.9-1.6), P=0.22 and 2.0(1.5-2.6), P<0.001 for ESS > or =11. The corresponding ORs for weight gain of > or =10.0 kg compared with weight change less than +/-5.0 kg were 2.0(1.7-2.4), P<0.001 for RDI > or =10 and 1.5(1.2-2.0), P=0.002 for ESS > or =11. Similar trends were observed for RDI > or =20. CONCLUSION: Our results suggest that an increase in BMI of > or =5 kg/m(2) or weight gain of > or =10 kg is a risk factor for SDB and excessive daytime sleepiness among Japanese truck drivers. PMID- 19773737 TI - Telomere length and adiposity in a racially diverse sample. AB - OBJECTIVE: To evaluate the cross-sectional relationship of anthropometric measures (body mass index (BMI) and visceral fat and the adipokines leptin and adiponectin) with telomere length in a racially diverse sample. DESIGN: Cross sectional study of participants recruited from a health science university. SUBJECTS: Participants include 317 men and women aged 40-64 years without diagnosed diabetes, cardiovascular disease (defined as coronary heart disease or stroke/transient ischemic attack) or cancer. RESULTS: Study participants were 54.9% female, 58% non-Hispanic white (NHW) and 42% non-Hispanic Black (NHB). Of the sample, 76% were either overweight or obese. Linear regressions showed no association between the anthropometric measures (BMI (kg m(-2)), visceral fat (cm(2)), adiponectin (microg ml(-1)), leptin (ng ml(-1)) or adiponectin to leptin ratio (microg ng(-1))) assessed in a continuous manner and telomere length assay ratio, either for the whole sample or when stratified by race or by gender. CONCLUSION: This study finds no linear associations between telomere length and several measures of obesity in a sample of NHB and NHW men and women. Further studies are needed to identify factors that influence telomere length in diverse populations. PMID- 19773738 TI - Chronic increase of circulating galanin levels induces obesity and marked alterations in lipid metabolism similar to metabolic syndrome. AB - OBJECTIVE: Galanin (GAL) has a role in the regulation of food intake by way of acting on the central nervous system in rodents. High serum GAL levels have been observed in obese human subjects, suggesting that peripheral GAL has a role in the regulation of energy balance and that elevated circulating GAL levels contribute to the development of obesity and obesity-associated metabolic impairments. Currently, it is not known how chronically increased levels of circulating GAL affect energy balance. The purpose of this study is to clarify the importance of chronically increased levels of circulating GAL on energy balance in a transgenic mouse model. RESEARCH DESIGN AND METHODS: Male wild-type and homozygous galanin transgenic (GAL-Tg) mice were used to study the peripheral effects of a 10-fold increase in circulating GAL on food intake, body weight, lipid metabolism, hepatic steatosis, glucose homeostasis and energy expenditure. RESULTS: In the absence of an orexigenic effect, GAL-Tg mice had increased body weight, visceral adiposity, total serum cholesterol, total serum triglycerides and hyperinsulinemia, as well as impaired glucose tolerance. Compared with wild type mice, the obese phenotype observed in the GAL-Tg mice was attributed to decreased oxygen consumption and carbon dioxide production, and this effect was independent of any changes in food intake or horizontal activity. In this obese model, GAL contributed to the development of fatty liver disease, which was associated with impaired glucose tolerance, as well as a reduction in heat production and metabolic rate. CONCLUSIONS: Chronically elevated GAL may regulate body weight, metabolic rate, and lipid and carbohydrate metabolism through a mechanism that is independent of feeding regulation. The obese phenotype in the GAL-Tg mice is related to the reduced energy expenditure and insulin resistance. These findings support the hypothesis that increased circulating GAL levels contribute to the development of metabolic syndrome. PMID- 19773739 TI - Body mass index as a phenotypic expression of adiposity: quantitative contribution of muscularity in a population-based sample. AB - OBJECTIVE: Although widely applied as a phenotypic expression of adiposity in population and gene-search studies, body mass index (BMI) is also acknowledged to reflect muscularity even though relevant studies directly measuring skeletal muscle (SM) mass are lacking. The current study aimed to fill this important gap by applying advanced imaging methods to test the hypothesis that, after controlling first for adiposity, SM mass is also a significant determinant of BMI in a population-based sample. DESIGN: Whole-body magnetic resonance imaging scans were completed in Coronary Artery Risk Development in Young Adults study subjects aged 33-45 years. Physical activity (PA) levels, alcohol intake and adequacy of food intake were assessed by standardized questionnaires. SUBJECTS: The study included 58 African-American (AA) and 78 Caucasian (C) men; and 63 AA and 64 C women. MEASUREMENTS: Whole-body adipose tissue (AT) and SM volumes. RESULTS: AT was significantly predicted by not only BMI, but also PA and alcohol intake with total model R (2)'s of 0.68 (P<0.0001) for men and 0.89 (P<0.0001) for women. Men had more SM than AT at all levels of BMI whereas SM predominated in women at lower BMIs (C<26 kg/m(2); AA<28 kg/m(2)). In men, both AT and SM contributed a similar proportion of between-subject variation in BMI. In contrast, in women AT contributed approximately 30% more than SM to the variation in BMI. Developed allometric models indicated SM associations with AT, PA and race after adjusting for height. There was little association of age, lifestyle factors or race with BMI after controlling for both AT and SM. CONCLUSION: Variation in muscularity provides a mechanistic basis for the previously observed nonspecificity of BMI as a phenotypic expression of adiposity. These quantitative observations have important implications when choosing adiposity measures in population and gene search studies. PMID- 19773740 TI - Capsiate administration results in an uncoupling protein-3 downregulation, an enhanced muscle oxidative capacity and a decreased abdominal fat content in vivo. AB - OBJECTIVES: The involvement of skeletal muscle mitochondrial uncoupling protein-3 (UCP3) in the control of energy expenditure in skeletal muscle and at the whole body level is still a matter of debate. We previously reported that UCP3 downregulation is linked to an enhanced mitochondrial energy metabolism in rat skeletal muscle as a result of acute capsiate treatment. Here, we aimed at investigating noninvasively the effects of chronic capsiate ingestion on metabolic changes occurring in exercising gastrocnemius muscle and at the whole body level. METHODS: We used an original experimental setup allowing a complete noninvasive investigation of gastrocnemius muscle function in situ using 31 phosphorus magnetic resonance spectroscopy. Whole-body fat composition was determined using magnetic resonance imaging and UCP3 gene expression was measured by quantitative real-time RT-PCR analysis. RESULTS: We found that a 14-day daily administration of capsiate (100 mg kg(-1) body weight) reduced UCP3 gene expression and increased phosphocreatine level at baseline and during the stimulation period in gastrocnemius muscle. During muscle stimulation, pH(i) showed a larger alkalosis in the capsiate group suggesting a lower glycolysis and a compensatory higher aerobic contribution to ATP production. Although the capsiate-treated rats were hyperphagic as compared to control animals, they showed a lower weight gain coupled to a decreased abdominal fat content. CONCLUSION: Overall, our data indicated that capsiate administration contributes to the enhancement of aerobic ATP production and the reduction of body fat content coupled to a UCP3 gene downregulation. PMID- 19773741 TI - Accepting risk in clinical research: is the gene therapy field becoming too risk averse? AB - Risk is an inescapable aspect of clinical research and is increasingly pertinent to the gene therapy field as the imperative for clinical trial activity grows. In recent years, the widely reported occurrence of serious adverse events (SAEs) in gene therapy studies, including trials for ornithine transcarbamylase (OTC) deficiency, X-linked severe combined immunodeficiency (SCID-X1), and rheumatoid arthritis, has heightened fear in public perceptions of gene therapy. Although it is essential to be cognizant of the risks involved in gene therapy research, there is a danger that gene therapy may become too risk-averse. If the field is to make progress, it is necessary to understand how risk is defined in gene therapy research, how understandings of risk differ, how risk is assessed, how decisions about risk are made, and how gene therapy risks are communicated to subjects and research participants during the informed consent process. In addition to minimizing the risks of clinical research through extensive preclinical safety studies, attention should be given to how decisions about risk and risk acceptability are made by researchers and subjects, and to the methods used to communicate risks to patients. Critical attention to risk will help ensure that the safety of subjects is protected, while also enabling research to develop better treatments for patients. PMID- 19773742 TI - The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. AB - Fabry disease is an X-linked lysosomal storage disorder caused by a deficiency in alpha-galactosidase A (alpha-Gal A) activity and subsequent accumulation of the substrate globotriaosylceramide (GL-3), which contributes to disease pathology. The pharmacological chaperone (PC) DGJ (1-deoxygalactonojirimycin) binds and stabilizes alpha-Gal A, increasing enzyme levels in cultured cells and in vivo. The ability of DGJ to reduce GL-3 in vivo was investigated using transgenic (Tg) mice that express a mutant form of human alpha-Gal A (R301Q) on a knockout background (Tg/KO), which leads to GL-3 accumulation in disease-relevant tissues. Four-week daily oral administration of DGJ to Tg/KO mice resulted in significant and dose-dependent increases in alpha-Gal A activity, with concomitant GL-3 reduction in skin, heart, kidney, brain, and plasma; 24-week administration resulted in even greater reductions. Compared to daily administration, less frequent DGJ administration, including repeated cycles of 4 days with DGJ followed by 3 days without or every other day with DGJ, resulted in even greater GL-3 reductions that were comparable to those obtained with Fabrazyme. Collectively, these data indicate that oral administration of DGJ increases mutant alpha-Gal A activity and reduces GL-3 in disease-relevant tissues in Tg/KO mice, and thus merits further evaluation as a treatment for Fabry disease. PMID- 19773743 TI - Abrogation of local cancer recurrence after radiofrequency ablation by dendritic cell-based hyperthermic tumor vaccine. AB - Local recurrence is a therapeutic challenge for radiofrequency ablation (RFA) in treatment of small solid focal malignancies. Here we show that RFA induced heat shock proteins (HSPs) expression and high mobility group box-1 (HMGB1) translocation in xenografted melanoma, which might create a proinflammatory microenvironment that favors tumor antigen presentation and activation of the effector T cells. On this basis, we investigate whether a prime-boost strategy combining a prime with heat-shocked tumor cell lysate-pulsed dendritic cell (HT DC) followed by an in situ boost with radiofrequency thermal ablation can prevent local tumor recurrence. The combination treatment with HT-DC and RFA showed potent antitumor effects, with >or=90% of tumor recurrence abrogated following RFA treatment. By contrast, prevaccination with unheated tumor lysate-pulsed DC had little effect on tumor relapse. Analysis of the underlying mechanism revealed that splenocytes from mice treated with HT-DC plus RFA contained significantly more tumor-specific, IFN-gamma-secreting T cells compared with control groups. Moreover, adoptive transfer of splenocytes from successfully treated tumor-free mice protected naive animals from tumor recurrence following RFA, and this was mediated mainly by CD8(+) T cells. Therefore, the optimal priming for the DC vaccination before RFA is important for boosting antigen-specific T cell responses and prevention of cancer recurrence. PMID- 19773744 TI - Noninvasive imaging and radiovirotherapy of prostate cancer using an oncolytic measles virus expressing the sodium iodide symporter. AB - Prostate cancer cells overexpress the measles virus (MV) receptor CD46. Herein, we evaluated the antitumor activity of an oncolytic derivative of the MV Edmonston (MV-Edm) vaccine strain engineered to express the human sodium iodide symporter (NIS; MV-NIS virus). MV-NIS showed significant cytopathic effect (CPE) against prostate cancer cell lines in vitro. Infected cells effectively concentrated radioiodide isotopes as measured in vitro by Iodide-125 ((125)I) uptake assays. Virus localization and spread in vivo could be effectively followed by imaging of (123)I uptake. In vivo administration of MV-NIS either locally or systemically (total dose of 9 x 10(6) TCID(50)) resulted in significant tumor regression (P < 0.05) and prolongation of survival (P < 0.01). Administration of (131)I further enhanced the antitumor effect of MV-NIS virotherapy (P < 0.05). In conclusion, MV-NIS is an oncolytic vector with significant antitumor activity against prostate cancer, which can be further enhanced by (131)I administration. The NIS transgene allows viral localization and monitoring by noninvasive imaging which can facilitate dose optimization in a clinical setting. PMID- 19773746 TI - Differential transduction following basal ganglia administration of distinct pseudotyped AAV capsid serotypes in nonhuman primates. AB - We examined the transduction efficiency of different adeno-associated virus (AAV) capsid serotypes encoding for green fluorescent protein (GFP) flanked by AAV2 inverted terminal repeats in the nonhuman primate basal ganglia as a prelude to translational studies, as well as clinical trials in patients with Parkinson's disease (PD). Six intact young adult cynomolgus monkeys received a single 10 microl injection of AAV2/1-GFP, AAV2/5-GFP, or AAV2/8-GFP pseudotyped vectors into the caudate nucleus and putamen bilaterally in a pattern that resulted in each capsid serotype being injected into at least four striatal sites. GFP immunohistochemistry revealed excellent transduction rates for each AAV pseudotype. Stereological estimates of GFP+ cells within the striatum revealed that AAV2/5-GFP transduces significantly higher number of cells than AAV2/8-GFP (P < 0.05) and there was no significant difference between AAV2/5-GFP and AAV2/1 GFP (P = 0.348). Consistent with this result, Cavalieri estimates revealed that AAV2/5-GFP resulted in a significantly larger transduction volume than AAV2/8-GFP (P < 0.05). Each pseudotype transduced striatal neurons effectively [>95% GFP+ cells colocalized neuron-specific nuclear protein (NeuN)]. The current data suggest that AAV2/5 and AAV2/1 are superior to AAV2/8 for gene delivery to the nonhuman primate striatum and therefore better candidates for therapeutic applications targeting this structure. PMID- 19773745 TI - Chimeric antigen receptors combining 4-1BB and CD28 signaling domains augment PI3kinase/AKT/Bcl-XL activation and CD8+ T cell-mediated tumor eradication. AB - To enhance the strength of activation afforded by tumor antigen-specific receptors, we investigated the effect of adding combined CD28 and 4-1BB costimulatory signaling domains to a chimeric antigen receptor (CAR) specific for prostate-specific membrane antigen (PSMA). Having transferred receptors encompassing the CD28, 4-1BB, and/or CD3zeta cytoplasmic domains in primary human CD8(+) T cells, we find that the P28BBz receptor, which includes all three signaling domains, is superior to receptors that only include one or two of these domains in promoting cytokine release, in vivo T-cell survival and tumor elimination following intravenous T-cell administration to tumor-bearing severe combined immunodeficient (SCID)/beige mice. Upon in vitro exposure to PSMA, the P28BBZ receptor-induced the strongest PI(3)Kinase/Akt activation and Bcl-X(L) expression, and the least apoptosis in transduced peripheral blood CD8(+) T cells. These findings further support the concept of integrating optimized costimulatory properties into recombinant antigen receptors to augment the survival and function of genetically targeted T cells within the tumor microenvironment. PMID- 19773747 TI - Germline bone morphogenesis protein receptor 1A mutation causes colorectal tumorigenesis in hereditary mixed polyposis syndrome. AB - OBJECTIVES: Hereditary mixed polyposis syndrome (HMPS) is characterized by polyps of mixed adenomatous/hyperplastic/atypical juvenile histology that are autosomal dominantly inherited and that eventually lead to colorectal cancer (CRC). Although CRC with adenomatous polyps is initiated by inactivating adenomatous polyposis coli (APC), the initiating event of CRC with mixed polyps remains unclear. We aimed to identify the underlying germline defect in HMPS. METHODS: We screened for bone morphogenesis protein receptor 1A (BMPR1A) mutation by exonic sequencing, reverse-transcriptase polymerase chain reaction (PCR) followed by cDNA sequencing, and multiplex ligation-dependent probe amplification (MLPA) analysis in eight Singapore Chinese HMPS families. RESULTS: Germline BMPR1A defects were found in four (50%) families. In two families, it is shown to co segregate with the disease phenotype in all affected members over three generations, indicating that it is the disease-causing mutation. CRC incidence is 75%. The most defining characteristic is the presence of mixed hyperplastic adenomatous polyps. Juvenile polyps are rarely reported, and if present, are usually of mixed components. Detailed histology of the polyps from one patient over 11 years distinguishes HMPS from juvenile polyposis syndrome (JPS). We report further the first cases of Wilms' tumor and papillary thyroid carcinoma associated with BMPR1A germline defect. CONCLUSIONS: Germline BMPR1A defect is the disease-causing mutation in 50% of the HMPS families. If patients present with mixed morphology polyps in the large bowel that are autosomal dominantly inherited and corresponding absence of upper gastrointestinal abnormalities, the gene to begin mutation screening should be BMPR1A rather than APC. PMID- 19773748 TI - Assessment of need for repeat ERCP during biliary stent removal after clinical resolution of postcholecystectomy bile leak. AB - OBJECTIVES: In patients who have undergone endoscopic retrograde cholangiopancreatography (ERCP) with biliary stent placement for postcholecystectomy bile leak there is limited evidence to support the repeat ERCP at the time of stent removal. Esophagogastroduodenoscopy (EGD) with biliary stent removal may suffice. The aim of this study was to describe the clinical course of patients who underwent biliary stent placement for a postcholecystectomy bile leak and determine whether repeat ERCP is necessary. METHODS: We identified all adult patients who underwent biliary stent placement for postcholecystectomy bile leak from 1 January 1996 to 31 October 2008. Demographic data, cholecystectomy details, and procedural data were collected, specifically focusing on closure of the bile leak. Time to resolution of leak was calculated, up to either the date of the first repeat ERCP that demonstrated no persistent leak or the date of removal of any radiologically placed percutaneous drain, whichever came first. RESULTS: Sixty-four patients underwent repeat ERCP with biliary stent removal. The median time to repeat ERCP was 36 days (interquartile range (IQR) 26-48). Fifty-seven (89%) patients had resolved the leak by time of repeat ERCP. Of those in whom the leak had not resolved, 6 had a repeat exam within 14 days of stent placement; 4 of these resolved the leak by day 39. There were no procedure-related complications in the ERCP group. Thirteen patients underwent EGD with stent removal after a median of 29 days (IQR 23-38). None had adverse events, with a median follow-up of 38 months. Overall, the median time to resolution of biliary leak was 33 days (IQR 22-44). Importantly, repeat ERCP altered the management in only one patient in whom bile duct stones were found. CONCLUSIONS: Patients with uncomplicated postcholecystectomy bile leak who have clinically resolved their leak do not require cholangiography at the time of stent removal. In these patients, EGD with stent removal at 4-6 weeks seems to be sufficient and significantly less expensive. PMID- 19773749 TI - Efficacy of an endo-knife with a water-jet function (Flushknife) for endoscopic submucosal dissection of superficial colorectal neoplasms. AB - OBJECTIVES: Endoscopic submucosal dissection (ESD) is currently not a common treatment for colorectal neoplasms because it is time consuming and technically difficult. Flushknife--an electrosurgical endo-knife with a water-jet function- is expected to reduce the difficulty of colorectal ESD. The objective of this study was to investigate the efficacy of a water-jet function for colorectal ESD. METHODS: This study was a prospective randomized controlled trial, which was conducted at a cancer referral center. A total of 49 patients, with a total of 51 superficial colorectal neoplasms (median tumor size of 30 mm), were enrolled and randomly assigned to undergo ESD using either the Flexknife (electrosurgical endo knife without a water-jet function) or the Flushknife. Tumors were resected by ESD using each endo-knife. The procedures were conducted by two endoscopists. Operation time was defined as the main outcome measure. RESULTS: En bloc resection was achieved in 23 out of 26 (88%) lesions in the Flexknife group and in 24 out of 24 (100%) lesions in the Flushknife group. The mean operation time (95% confidence interval) was 87.3 (71.3-103.4) min in the Flexknife group and 61.0 (49.3-72.7) min in the Flushknife group (P=0.02). The Flushknife reduced the number of endoscopic device changes (P=0.001), the number of submucosal injections (P=0.001), and the mean amount of injected hyaluronate sodium (P=0.001) compared with the Flexknife. No severe adverse events were observed in either group. CONCLUSIONS: Without increasing adverse events, the endo-knife with a water-jet function efficiently reduced the operation time of colorectal ESD in patients with large superficial colorectal neoplasms. (University hospital Medical Information Network Clinical Trials Registry number UMIN000001302). PMID- 19773750 TI - Melatonin inhibits aromatase promoter expression by regulating cyclooxygenases expression and activity in breast cancer cells. AB - BACKGROUND: Melatonin reduces the development of breast cancer interfering with oestrogen-signalling pathways, and also inhibits aromatase activity and expression. Our objective was to study the promoters through which melatonin modifies aromatase expression, evaluate the ability of melatonin to regulate cyclooxygenases and assess whether the effects of melatonin are related to its effects on intracellular cAMP, in MCF-7 cells. METHODS: Total aromatase mRNA, aromatase mRNA promoter regions and cyclooxygenases mRNA expression were determined by real-time RT-PCR. PGE(2) and cAMP were measured by kits. RESULTS: Melatonin downregulated the gene expression of the two major specific aromatase promoter regions, pII and pI.3, and also that of the aromatase promoter region pI.4. Melatonin 1 nM was able to counteract the stimulatory effect of tetradecanoyl phorbol acetate on PGE(2) production and inhibit COX-2 and COX-1 mRNA expression. Melatonin 1 nM elicited a parallel time-dependent decrease in both cyclic AMP formation and aromatase mRNA expression. CONCLUSIONS: This study shows that melatonin inhibits aromatase activity and expression by regulating the gene expression of specific aromatase promoter regions. A possible mechanism for these effects would be the regulation by melatonin of intracellular cAMP levels, mediated by an inhibition of cyclooxygenase activity and expression. PMID- 19773751 TI - Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis. AB - BACKGROUND: Enhancer of zeste homologue 2 (EZH2) is a member of the Polycomb group of genes that is involved in epigenetic silencing and cell cycle regulation. METHODS: We studied EZH2 expression in 409 patients with colorectal cancer stages II and III. The patients were included in a randomised study, and treated with surgery alone or surgery followed by adjuvant chemotherapy. RESULTS: EZH2 expression was significantly related to increased tumour cell proliferation, as assessed by Ki-67 expression. In colon cancer, strong EZH2 expression (P=0.041) and high proliferation (>or=40%; P=0.001) were both associated with better relapse-free survival (RFS). In contrast, no such associations were found among rectal cancers. High Ki-67 staining was associated with improved RFS in colon cancer patients who received adjuvant chemotherapy (P=0.001), but not among those who were treated by surgery alone (P=0.087). In colon cancers stage III, a significant association between RFS and randomisation group was found in patients with high proliferation (P=0.046), but not in patients with low proliferation (P=0.26). Multivariate analyses of colon cancers showed that stage III (hazard ratio (HR) 4.00) and high histological grade (HR 1.80) were independent predictors of reduced RFS, whereas high proliferation indicated improved RFS (HR 0.55). CONCLUSION: Strong EZH2 expression and high proliferation are associated features and both indicate improved RFS in colon cancer, but not so in rectal cancer. PMID- 19773752 TI - Down-regulation of frizzled-7 expression decreases survival, invasion and metastatic capabilities of colon cancer cells. AB - BACKGROUND: The canonical Wnt signalling pathway is activated in most sporadic colorectal cancers (CRCs). We previously reported that FZD7 functions as a receptor for the canonical Wnt signalling pathway in colon cancer cells. METHODS AND RESULTS: In this study, we examined the function of FZD7 in survival, invasion and metastatic capabilities of colon cancer cells. FZD7_siRNA transfection decreased cell viability of HT-29 and HCT-116 colon cancer cells. Expression of c-Jun, phosphorylation of JNK and c-Jun, and activation of RhoA were suppressed after FZD7_siRNA transfection into HCT-116 cells. In vitro invasion activity and Wnt target gene expression were also reduced in HCT-116 cells transfected with FZD7_siRNA. Liver metastasis of stable FZD7_siRNA HCT-116 cell transfectants in scid mice was decreased to 40-50% compared to controls. The mRNA levels of FZD7 in 135 primary CRC tissues were examined by real-time PCR. FZD7 mRNA levels were significantly higher in stage II, III or IV tumours than in non-tumour tissues (P<0.005), and overall survival was shorter in those patients with higher FZD7 expression (P<0.001). CONCLUSION: These data suggest that FZD7 may be involved in enhancement of survival, invasion and metastatic capabilities of colon cancer cells through non-canonical Wnt signalling pathways as well as the canonical pathway. PMID- 19773753 TI - Weekly administration of sagopilone (ZK-EPO), a fully synthetic epothilone, in patients with refractory solid tumours: results of a phase I trial. AB - BACKGROUND: Epothilones are a novel class of microtubule-stabilising agents, and sagopilone is a fully synthetic epothilone that has shown marked in vivo and in vitro preclinical activity. METHODS: This phase I, open-label study investigated the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of weekly sagopilone. Twenty-three patients with malignancy resistant or refractory to standard treatment were enrolled into this study evaluating sagopilone doses from 0.6 to 7.0 mg m(-2). RESULTS: The incidence of drug-related haematological adverse events (AEs) was low, with two grade 3 events observed. Nonhaematological AEs were generally mild and reversible; increased gamma-GT was the only grade 4 event and grade 3 events comprised peripheral neuropathy (n=2), diarrhoea (n=1) and fatigue (n=1). Two grade 3 events were DLTs (diarrhoea and peripheral neuropathy at 7.0 mg m(-2)). The MTD of weekly sagopilone was therefore established as 5.3 mg m(-2). Stable disease was the best overall response (n=3). Microtubule bundle formation in peripheral blood mononuclear cells increased post treatment, peaking after 1 h. Sagopilone disposition was similar across treatment courses and showed rapidly decreasing serum concentrations after infusion end and a long terminal disposition phase with no obvious accumulation in the serum, probably reflecting a fast uptake into tissues followed by a slow release. CONCLUSION: Weekly administration of sagopilone could represent an alternative to the 3-weekly administration currently evaluated in phase II trials. PMID- 19773754 TI - Inflammation and tissue repair markers distinguish the nodular sclerosis and mixed cellularity subtypes of classical Hodgkin's lymphoma. AB - BACKGROUND: Classical Hodgkin's lymphoma (cHL), although a malignant disease, has many features in common with an inflammatory condition. The aim of this study was to establish the molecular characteristics of the two most common cHL subtypes, nodular sclerosis (NS) and mixed cellularity (MC), based on molecular profiling and immunohistochemistry, with special reference to the inflammatory microenvironment. METHODS: We analysed 44 gene expression profiles of cHL whole tumour tissues, 25 cases of NS and 19 cases of MC, using Affymetrix chip technology and immunohistochemistry. RESULTS: In the NS subtype, 152 genes showed a significantly higher expression, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing. Among these were SPARC, CTSK and COLI. Immunohistochemistry revealed that the NS-related genes were mainly expressed by macrophages and fibroblasts. Fifty-three genes had a higher expression in the MC subtype, including several inflammation-related genes, such as C1Qalpha, C1Qbeta and CXCL9. In MC tissues, the C1Q subunits were mainly expressed by infiltrating macrophages. CONCLUSIONS AND INTERPRETATIONS: We suggest that the identified subtype-specific genes could reflect different phases of wound healing. Our study underlines the potential function of infiltrating macrophages in shaping the cHL tumour microenvironment. PMID- 19773755 TI - Mutant p53 mediates survival of breast cancer cells. AB - BACKGROUND: p53 is the most commonly mutated tumour-suppressor gene in human cancers. Unlike other tumour-suppressor genes, most p53 cancer mutations are missense mutations within the core domain, leading to the expression of a full length mutant p53 protein. Accumulating evidence has indicated that p53 cancer mutants not only lose tumour suppression activity but also gain new oncogenic activities to promote tumourigenesis. METHODS: The endogenous mutant p53 function in human breast cancer cells was studied using RNA interference (RNAi). Gene knockdown was confirmed by quantitative PCR and western blotting. Apoptosis was evaluated by morphological changes of cells, their PARP cleavage and annexin V staining. RESULTS: We show that cancer-associated p53 missense mutants are required for the survival of breast cancer cells. Inhibition of endogenous mutant p53 by RNAi led to massive apoptosis in two mutant p53-expressing cell lines, T47D and MDA-MB-468, but not in the wild-type p53-expressing cells, MCF-7 and MCF 10A. Reconstitution of an RNAi-insensitive mutant p53 in MDA-MB-468 cells completely abolished the apoptotic effects after silencing of endogenous mutant p53, suggesting the specific survival effects of mutant p53. The apoptotic effect induced by mutant p53 ablation, however, is independent of p63 or p73 function. CONCLUSION: These findings provide clear evidence of a pro-survival 'gain-of function' property of a subset of p53 cancer mutants in breast cancer cells. PMID- 19773757 TI - Synergistic anti-cancer effects of immunotoxin and cyclosporin in vitro and in vivo. AB - BACKGROUND: The clinical use of immunotoxins (ITs) has been hampered by hepatotoxicity, and the induction of a strong human-anti-IT response. The human anti-IT response results in neutralisation of the immunoconjugates, rendering repetitive treatment inefficacious. METHODS: We evaluated the combination of cyclosporin A (CsA) with various Pseudomonas exotoxin A-based ITs in human breast, cervical, and prostate cancer cell lines measured by protein synthesis, cell viability, and TUNEL assay. Furthermore, expression of essential proteins were analysed by western blot. We used cervical cancer model in nude rats to evaluate the anti-metastatic effect of the combination. The anti-immunogenic response by the CsA treatment was investigated in immunocompetent rats. RESULTS: The combination of CsA with ITs caused remarkable synergistic cytotoxicity, in several cancer cell lines, characterised by protein synthesis inhibition, decreased cell viability, and an increased apoptotic index. Furthermore, the combination strongly inhibited formation of metastases in a cervical cancer model in nude rats with a statistically significant increase in median survival time of the combination-treated animals, as compared with those receiving a suboptimal dose of IT alone. Notably, we found in immunocompetent rats that the anti-IT immunoresponse elicited by repeated administration of IT was efficiently abrogated by CsA; notably the antibody responds towards the highly immunogenic PE was shown to be prevented. CONCLUSION: The combination of ITs and CsA might constitute a significant improvement in the clinical potential of systemic IT treatment of cancer patients. PMID- 19773756 TI - Molecular characteristics of screen-detected vs symptomatic breast cancers and their impact on survival. AB - BACKGROUND: Several recent studies have shown that screen detection remains an independent prognostic factor after adjusting for disease stage at presentation. This study compares the molecular characteristics of screen-detected with symptomatic breast cancers to identify if differences in tumour biology may explain some of the survival benefit conferred by screen detection. METHODS: A total of 1379 women (aged 50-70 years) with invasive breast cancer from a large population-based case-control study were included in the analysis. Individual patient data included tumour size, grade, lymph node status, adjuvant therapy, mammographic screening status and mortality. Immunohistochemistry was performed on tumour samples using 11 primary antibodies to define five molecular subtypes. The effect of screen detection compared with symptomatic diagnosis on survival was estimated after adjustment for grade, nodal status, Nottingham Prognostic Index (NPI) and the molecular markers. RESULTS: Fifty-six per cent of the survival benefit associated with screen-detected breast cancer was accounted for by a shift in the NPI, a further 3-10% was explained by the biological variables and more than 30% of the effect remained unexplained. CONCLUSION: Currently known biomarkers remain limited in their ability to explain the heterogeneity of breast cancer fully. A more complete understanding of the biological profile of breast tumours will be necessary to assess the true impact of tumour biology on the improvement in survival seen with screen detection. PMID- 19773758 TI - Evaluation of bowel cancer registration data in England, 1996-2004. AB - BACKGROUND: The National Health Service (NHS) bowel cancer screening programme (BCSP) was initiated across England in April 2006. To determine the feasibility of using national cancer registration data to assess the impact of the BCSP on stage-specific incidence, we studied trends in the incidence rates of colon (ICD10 C18) and rectosigmoid junction and rectum (ICD10 C19-C20) cancers and the completeness of data on Dukes stage in England. METHODS: Data were obtained from all nine cancer registries for the period 1996-2004, before the introduction of the BCSP, in men and women aged 50-79 years. RESULTS: Overall, incidence rates declined by 1% per year in the 9 years before the introduction of the BCSP (P<0.001). Dukes stage was recorded for 60% of all registrations but this varied between regions and over time. Only four registries had completeness of 74% or more. Registrations with unknown Dukes stage decreased from 1996 to 2000, and then increased during 2001-2004 affecting trends in stage-specific incidence. CONCLUSION: To study the impact of the BCSP on stage-specific incidence, regional variations in data completeness need to be addressed. PMID- 19773759 TI - Direct cancer-stromal interaction increases fibroblast proliferation and enhances invasive properties of scirrhous-type gastric carcinoma cells. AB - BACKGROUND: Scirrhous-type gastric carcinoma (SGC) exhibits an extensive submucosal fibrosis and extremely poor patient prognosis. We investigated the importance of the cancer-stromal interaction in the histogenesis of SGC. METHODS: Gastric fibroblasts NF-25 and intestinal fibroblasts NF-j2 were co-cultured with SGC-derived (HSC-39) or non-SGC-derived (HSC-57 and HSC-64) cells. To identify genes that are up- or downregulated in NF-25, complementary DNA (cDNA) microarray analysis was performed. The antibody against vascular-cell adhesion molecule-1 (VCAM-1) was used for cell growth test and immunohistochemistry. Moreover, the impact of interaction with NF-25 fibroblasts on HSC-39 cells was investigated using western blot and reverse transcription-polymerase chain reaction. RESULTS: HSC-39 cells stimulated growth of NF-25 but not NF-j2 when co-cultured. Induction of VCAM-1 in NF-25 fibroblasts was identified, which was specific when co cultured with HSC-39 but not with non-SGC-derived HSC-57 and HSC-64 cells. Neutralising antibody to VCAM-1 suppressed NF-25 growth in dose-dependent manners. In tissue samples, positive immunoreactivity of VCAM-1 in SGC-derived fibroblasts was significantly higher than that in non-SGC-derived fibroblasts. Furthermore, interaction with NF-25 fibroblasts not only induced the epithelial mesenchymal transition-like change, but also expressions of matrix metalloproteinase- related genes in HSC-39 cells. CONCLUSION: Direct interaction between SGC cells and gastric fibroblasts establishes the tumour microenvironment and reinforces the aggressiveness of SGC. PMID- 19773760 TI - Phase II study of cetuximab in combination with cisplatin and docetaxel in patients with untreated advanced gastric or gastro-oesophageal junction adenocarcinoma (DOCETUX study). AB - BACKGROUND: The conventional treatment options for advanced gastric patients remain unsatisfactory in terms of response rate, response duration, toxicity, and overall survival benefit. The purpose of this phase II study was to evaluate the activity and safety of cetuximab combined with cisplatin and docetaxel as a first line treatment for advanced gastric or gastro-oesophageal junction adenocarcinoma. METHODS: Untreated patients with histologically confirmed advanced gastric or gastro-oesophageal adenocarcinoma received cetuximab at an initial dose of 400 mg m(-2) i.v. followed by weekly doses of 250 mg m(-2), cisplatin 75 mg m(-2) i.v. on day 1, docetaxel 75 mg m(-2) i.v. on day 1, every 3 weeks, for a maximum of 6 cycles, and then cetuximab maintenance treatment was allowed in patients with a complete response, partial response, or stable disease. RESULTS: Seventy-two patients (stomach 81.9% and gastro-oesophageal junction 18.1%; locally advanced disease 4.2%; and metastatic disease 95.8%) were enrolled. The ORR was 41.2% (95% CI, 29.5-52.9). Median time to progression was 5 months (95% CI, 3.7-5.4). Median survival time was 9 months (95% CI, 7-11). The most frequent grades 3-4 toxicity was neutropenia (44.4%). No toxic death was observed. CONCLUSIONS: The addition of cetuximab to the cisplatin/docetaxel regimen improved the ORR of the cisplatin/docetaxel doublet in the first-line treatment of advanced gastric and gastro-oesophageal junction adenocarcinoma, but this combination did not improve the TTP and OS. The toxicity of cisplatin/docetaxel chemotherapy was not affected by the addition of cetuximab. PMID- 19773761 TI - Loss of Coxsackie and adenovirus receptor downregulates alpha-catenin expression. AB - BACKGROUND: The Coxsackie and adenovirus receptor (CAR) has been shown to inhibit cancer cell proliferation, migration, and invasion. The underlying mechanisms, however, are poorly understood. METHODS: The differential gene expression in the human colon cancer cell line DLD1 on RNAi-mediated functional CAR knockdown was analysed using oligo-array technology. Expression of alpha-catenin was determined by quantitative RT-PCR and western blotting. Proliferation, migration, and invasion after CAR knockdown were assessed by in vitro assays, and cell morphology in a three-dimensional context was evaluated using matrigel. RESULTS: Oligo-array technology identified alpha-catenin as the strongest downregulated gene after CAR knockdown. Western blotting and quantitative RT-PCR confirmed a reduced alpha-catenin expression after CAR knockdown in DLD1 cells and in the rat intestinal cell line IEC-6. Functionally, both cell lines showed a marked increase in proliferation, migration, and invasion on CAR knockdown. In matrigel, both cell lines formed amorphous cell clusters in contrast to well-organised three-dimensional structures of CAR-expressing vector controls. Ectopic 're' expression of alpha-catenin in DLD1 and IEC-6 CAR knockdown cells reversed these functional and morphological effects. CONCLUSION: These data suggest that an interaction of CAR and alpha-catenin mediates the impact of CAR on cell proliferation, migration, invasion, and morphology. PMID- 19773762 TI - Koilocytes indicate a role for human papilloma virus in breast cancer. AB - BACKGROUND: High-risk human papilloma viruses (HPVs) are candidates as causal viruses in breast cancer. The scientific challenge is to determine whether HPVs are causal and not merely passengers or parasites. Studies of HPV-related koilocytes in breast cancer offer an opportunity to address this crucial issue. Koilocytes are epithelial cells characterised by perinuclear haloes surrounding condensed nuclei and are commonly present in cervical intraepithelial neoplasia. Koilocytosis is accepted as pathognomonic (characteristic of a particular disease) of HPV infection. The aim of this investigation is to determine whether putative koilocytes in normal and malignant breast tissues are because of HPV infection. METHODS: Archival formalin-fixed normal and malignant breast specimens were investigated by histology, in situ PCR with confirmation of the findings by standard PCR and sequencing of the products, plus immunohistochemistry to identify HPV E6 oncoproteins. RESULTS: human papilloma virus-associated koilocytes were present in normal breast skin and lobules and in the breast skin and cancer tissue of patients with ductal carcinoma in situ (DCIS) and invasive ductal carcinomas (IDCs). INTERPRETATION: As koilocytes are known to be the precursors of some HPV-associated cervical cancer, it follows that HPVs may be causally associated with breast cancer. PMID- 19773765 TI - Cunning parasite manipulates immune system. PMID- 19773763 TI - Glucocorticoid therapy and risk of bladder cancer. AB - BACKGROUND: Use of immunosuppressive drugs post organ transplantation, and prolonged use of glucorticoids for other conditions have been associated with subsequent risk of certain malignancies, that is, skin cancers and lymphoma. There is evidence that the incidence of bladder cancer is also elevated among organ transplant recipients, however, it is unknown whether other groups of patients, that is, those taking oral glucocorticoids, likewise are at an increased risk. METHODS: In a population-based case-control study in New Hampshire, USA, we compared the use of glucocorticoids in 786 bladder cancer cases and in 1083 controls. We used unconditional logistic regression analysis to compute adjusted odds ratios (ORs) associated with oral glucocorticoid use. RESULTS: In our analysis, the risk of bladder cancer was related to a history of prolonged oral glucocorticoid use (OR=1.85, 95% CI=1.24-2.76, adjusted for age, gender and smoking). Associations with oral glucocorticoid use were stronger for invasive tumours (OR=2.12, 95% CI=1.17-3.85) and tumours with high (3+) p53 staining intensity (OR=2.35, 95% CI=1.26-4.36). CONCLUSION: Our results raise the possibility of an increased risk of bladder cancer from systemic use of glucocorticoids, and a potential role of immune surveillance in bladder cancer aetiology. PMID- 19773766 TI - Bee toxin takes the sting out of cancer. PMID- 19773769 TI - Use of animals on expiring protocols. Transferring animals responsibly. PMID- 19773770 TI - Use of animals on expiring protocols. PMID- 19773771 TI - Use of animals on expiring protocols. No 'ongoing' work. PMID- 19773772 TI - Use of animals on expiring protocols. Plan ahead. PMID- 19773773 TI - Cutaneous lesions in a pig. Diagnosis: Porcine juvenile pustular psoriaform dermatitis. PMID- 19773775 TI - Diagnostic contrast radiography in fish. AB - Despite the abundance of fish as research models, diagnostic techniques for fish diseases are relatively scarce. With some accommodations for handling fish, the same diagnostic tools that are frequently used for other animals can be applied in fish. This column describes indications, preparation and techniques for contrast radiography in fish. PMID- 19773776 TI - Regulatory issues regarding the use of food and water restriction in laboratory animals. AB - While investigating certain aspects of animal physiology, neurology or behavior, research scientists sometimes must limit the amount of food or water provided to animals used in a study. Such limitations can negatively impact the health and welfare of laboratory animals by, for example, causing them to experience distress or pain. The author discusses the veterinary and regulatory concerns that laboratory personnel should consider when limiting food or water given to research animals. He concludes that by adequately addressing the needs of animals receiving less food or water than required by regulation, researchers will improve both animal care and scientific study results. PMID- 19773777 TI - A novel system for individually housing bullfrogs. AB - A researcher at the authors' institution needed to house adult bullfrogs (Rana catesbeiana) individually. The authors responded to this need by modifying 5 gallon plastic buckets to use for individual housing of bullfrogs. These buckets provided a simple, inexpensive housing system that successfully maintained healthy and behaviorally normal frogs. The authors describe the housing and husbandry of the bullfrogs in this individual housing situation and recommend it for use by others. PMID- 19773778 TI - The cost of animal research. AB - The US biomedical research community has long debated how to bill different types of animal research costs. Specifically, which aspects of animal research should be charged as direct costs, and which should be charged as indirect (or facilities and administrative) costs? In this paper, the author describes why the community has yet to clearly define what constitutes indirect costs. He then suggests how researchers, administrators and government officials can categorize different aspects of animal research as direct or indirect costs. PMID- 19773781 TI - Modes and regulation of glial migration in vertebrates and invertebrates. AB - Neurons and glial cells show mutual interdependence in many developmental and functional aspects of their biology. To establish their intricate relationships with neurons, glial cells must migrate over what are often long distances. In the CNS glial cells generally migrate as single cells, whereas PNS glial cells tend to migrate as cohorts of cells. How are their journeys initiated and directed, and what stops the migratory phase once glial cells are aligned with their neuronal counterparts? A deeper understanding of glial migration and the underlying neuron-glia interactions may contribute to the development of therapeutics for demyelinating diseases or glial tumours. PMID- 19773782 TI - Anniversary of a myth. AB - Richard Feynman's talk anticipating nanotechnology was inspirational, but no blueprint. PMID- 19773779 TI - Ubiquitin-binding domains - from structures to functions. AB - Ubiquitin-binding domains (UBDs) are modular elements that bind non-covalently to the protein modifier ubiquitin. Recent atomic-level resolution structures of ubiquitin-UBD complexes have revealed some of the mechanisms that underlie the versatile functions of ubiquitin in vivo. The preferences of UBDs for ubiquitin chains of specific length and linkage are central to these functions. These preferences originate from multimeric interactions, whereby UBDs synergistically bind multiple ubiquitin molecules, and from contacts with regions that link ubiquitin molecules into a polymer. The sequence context of UBDs and the conformational changes that follow their binding to ubiquitin also contribute to ubiquitin signalling. These new structure-based insights provide strategies for controlling cellular processes by targeting ubiquitin-UBD interfaces. PMID- 19773784 TI - Soft matter: Spots and stripes. PMID- 19773780 TI - Kinesin superfamily motor proteins and intracellular transport. AB - Intracellular transport is fundamental for cellular function, survival and morphogenesis. Kinesin superfamily proteins (also known as KIFs) are important molecular motors that directionally transport various cargos, including membranous organelles, protein complexes and mRNAs. The mechanisms by which different kinesins recognize and bind to specific cargos, as well as how kinesins unload cargo and determine the direction of transport, have now been identified. Furthermore, recent molecular genetic experiments have uncovered important and unexpected roles for kinesins in the regulation of such physiological processes as higher brain function, tumour suppression and developmental patterning. These findings open exciting new areas of kinesin research. PMID- 19773785 TI - Material witness: Older and madder. PMID- 19773786 TI - Quantum dots: Long life in zero dimensions. PMID- 19773787 TI - Scanning electron microscopy: Second best no more. PMID- 19773788 TI - Magnetism: A flood of spin current. PMID- 19773789 TI - Lipid lowering: education is key. PMID- 19773790 TI - Stem cells: bone marrow cell therapy for MI-goal achieved? PMID- 19773791 TI - Vascular disease: is AAA screening worth the cost? PMID- 19773792 TI - Valvular disease: transcatheter aortic valve implantation-time for wider use? PMID- 19773793 TI - Acute coronary syndromes: oral factor Xa inhibitors in acute coronary syndromes. PMID- 19773794 TI - Intra-bone marrow bone marrow transplantation rejuvenates the B-cell lineage in aged mice. AB - Age-related reductions in the frequency and absolute number of early B lineage precursors in the bone marrow of aged mice have been reported. Reversal of B-cell lineage senescence has not been achieved. Age-related impairment of the B-cell lineage is caused by the decreasing functionality of hematopoietic and B lineage precursors, and reduced efficacy of bone marrow stromal cells that constitute the bone marrow microenvironment. To induce rejuvenation of aged B cells, we injected whole bone marrow from young donors to irradiated aged recipients through the tibia and analyzed B-cell development and immune responsiveness. In aged mice, we found significant reductions in the frequencies and absolute numbers of pro-B cells (B220(+)CD43(+)CD24(+)BP-1(-) and B220(+)CD43(+)CD24(int)BP-1(+)) and pre-B cells (B220(+)CD43(+)CD24(high)BP-1(+) and B220(+)CD43(-)IgM(-)IgD(-)). Intra bone marrow bone marrow transplantation (IBM-BMT) of young marrow cells including both hematopoietic stem cells and bone marrow stromal cells reversed the reduction of pro-B cells and pre-B cells. In the periphery, the frequency and absolute number of marginal zone-B cell were not significantly different between young, old and IBM-BMT group. The frequency of follicular-B cells in the IBM-BMT group was significantly increased compared to old group. The frequency of B1a B cells in the peritoneal cavity was significantly decreased in the IBM-BMT group. Antibody production against T-independent antigens was not different among the young, the aged and IBM-BMT groups. PMID- 19773796 TI - Congenital absence of the internal carotid artery in a patient with spinal cord injury: case report. AB - STUDY DESIGN: Case report. OBJECTIVE: To describe a rare case of congenital absence of the internal carotid artery (ICA) in the setting of acute spinal cord injury and review the existing literature. SETTING: Regional Spinal Cord Injury Center of the Delaware Valley, Philadelphia, PA, USA. CLINICAL PRESENTATION: We report on a 47-year-old male who presented as a T2 ASIA A spinal cord injury with a T2-T3 fracture dislocation injury after a 25-feet fall from a tree. Magnetic resonance angiography imaging of the neck carried out as per routine spinal trauma protocol suggested an acute traumatic injury to the carotid artery. Therefore, computed tomographic angiography imaging of the neck was performed, which revealed absence of the left ICA and a diminutive left carotid canal at the skull base, suggesting congenital absence. Follow-up magnetic resonance imaging of the brain to evaluate for acute infarct showed no diffusion restriction contributing to the evidence that this was a congenital anomaly and not traumatic occlusion of the artery. CONCLUSION: Congenital absence or hypoplasia of the ICA is a rare anomaly. It should be considered in the differential in patients who have absent or diminished carotid arteries on radiologic imaging in the setting of trauma. PMID- 19773797 TI - Standing balance assessment in ASIA D paraplegic and tetraplegic participants: concurrent validity of the Berg Balance Scale. AB - STUDY DESIGNS: Longitudinal and correlational study with repeated measures. OBJECTIVES: The aim of this study was to test the concurrent validity of the Berg Balance Scale (BBS) for a spinal cord injury (SCI) population. PARTICIPANTS: A total of 32 individuals with an ASIA D SCI walking 10 m independently, with or without walking assistive devices. SETTING: An intensive rehabilitation center in Montreal, Canada. METHODS: Subjects were evaluated on the BBS, the Walking Index for Spinal Cord Injury (WISCI II), the Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI), the 10-m walk test (10MWT) and the Timed Up and Go (TUG). Individuals were reassessed during rehabilitation when progressing to a device providing less support or to unassisted gait. RESULTS: All walking tests were highly correlated with the BBS (0.714 1 and n < 1. In addition, the remote infrared sensing capability of the hollow waveguides was demonstrated by the detection of CO(2) in N(2) by utilizing hollow sapphire fibers capped with ZnSe windows. PMID- 19773827 TI - Methods of analyzing planar optical waveguides. AB - We present a new approximate solution of the scalar-wave equation for planar optical waveguides with arbitrary refractive-index profiles. Test calculations are done for an index profile with a known solution. The comparison demonstrates the accuracy of our method. The method may also be applied to circularly symmetric optical fibers. PMID- 19773828 TI - Injection-seeded titanium-doped-sapphire laser. AB - We demonstrate injection seeding of a pulsed, laser-pumped, titanium-doped sapphire ring laser by both continuous-wave dye and diode lasers. As little as 100 microW of seed light is required to produce 4 mJ of 30-nsec TEM(00) output having a bandwidth of less than 25 MHz FWHM. Using an atomic resonance filter we find that more than 99.9% of the energy is at the 780-nm seed wavelength. We discuss the spatial and longitudinal mode-matching requirements for successful seeding. PMID- 19773829 TI - Photonic ring counter using batch-fabricated symmetric self-electro-optic-effect devices. AB - We describe a photonic ring counter that demonstrates cascadability of batch fabricated symmetric self-electrooptic-effect devices at a bit rate of 12.5 Mbits/sec for conventional operation and at a bit rate of 50 Mbits/sec when the devices are operated as optical signal sense amplifiers. In each of these experiments the average laser power incident upon each device was less than 1 mW. The system switching speeds agree well with speeds calculated by using the measured switching energies of the devices. PMID- 19773830 TI - Direct determination of the amplitude and the phase of femtosecond light pulses. AB - A direct measurement of the amplitude and the phase of a femtosecond light pulse is performed for the first time to our knowledge. The measurement is made in the frequency domain, and the time dependence of the field can be easily obtained by a Fourier transform. The technique relies on a pulse synthesis scheme to unravel the frequency dependence of the phase. A mask filters the spectrum, which gives rise to a pulse with a measurable temporal profile related to the frequency dependence of the phase. In particular, with a rectangular slit the time delay of the synthesized pulse is the first derivative of the phase with respect to the frequency of the original pulse at the central frequency of the filter. The amplitude of the spectrum is obtained from the power spectrum. PMID- 19773831 TI - 60-fsec pulse generation from a self-mode-locked Ti:sapphire laser. AB - Pulses having durations as short as 60 fsec have been directly generated by a self-mode-locked, dispersion-compensated Ti:sapphire laser. By using an extracavity fiber-prism pulse compressor, pulse durations as short as 45 fsec have been obtained. PMID- 19773832 TI - Optical implementation of a second-order neural network. AB - An optical implementation of a single-layer, second-order neural network is presented. The quadratic products are obtained by passing the optical beam twice through the input ferroelectric liquid-crystal (FLC) spatial light modulator (SLM), with the interconnection weights being implemented by a further two dimensional 128 x 128 FLC SLM. The machine successfully associates eight randomly chosen pattern-target pairs (dimensions 16 and 4, respectively) and can learn the parity association. Translation invariance is also demonstrated. Results from a computer model indicate that input SLM contrast ratios of 4:1 and electronic noise of 10% of the maximum output can be tolerated. PMID- 19773834 TI - Observation of the cesium clock transition using laser-cooled atoms in a vapor cell. PMID- 19773833 TI - Picosecond pump and probe spectroscopy utilizing freely propagating terahertz radiation. AB - We demonstrate the feasibility of scaling up a terahertz-pulse generation scheme for use with a 10-Hz amplified femtosecond laser system. Visible pulsed excitation combined with a far-infrared probe should prove to be a powerful picosecond time-resolved technique. PMID- 19773835 TI - Holographic interferometry using anisotropic self-diffraction in Bi(12)SiO(20). AB - Anisotropic self-diffraction in photorefractive Bi(12)SiO(20) crystals is applied to the investigation of dynamic holographic recording through the diffusion process. Specific attention is paid to optimization of experimental parameters for real-time holographic interferometry. The resultant interferometer is applied to obtain both timeaverage and double-exposure interferograms of vibrating and displaced structures. PMID- 19773836 TI - Stabilized dual-wavelength fiber-optic interferometer for vibration measurement. AB - A stabilized fiber-optic interferometer was developed for vibration measurement by using two laser diodes of different wavelengths and one polarization maintaining fiber. Passive signal processing of two signals in quadrature is used to obtain the vibration amplitude with a resolution of approximately 0.1 nm. An extension of the signalprocessing scheme is proposed that provides compensation for bending or temperature-induced transmission losses of the two propagation modes of the fiber. PMID- 19773837 TI - Focused-beam interaction with a phase step. AB - The interaction of a tightly focused laser beam with a step function is encountered in optical storage media, scanning microscopy, positioning and aligning systems, and various other applications. A theoretical and experimental investigation provides an improved description of the physical process and indicates the possibility of achieving extreme superresolution suitable for certain applications. PMID- 19773838 TI - Evidence of a chaotic attractor in star-wander data. AB - The observed motion of stellar-image centroids is shown to have a chaotic attractor with a correlation dimension of ~6. The existence of a chaotic attractor in star wander, or equivalently in wave-front tilts, indicates that the atmospheric processes that cause image degradation may be more accurately described as chaotic, not so random as is usually assumed. This new result has important implications for the accurate modeling of atmospheric processes, the operation of adaptive optics systems, and the processing of stellar images. PMID- 19773839 TI - Parametric solitons: nonlinear propagation of coherently coupled pulses generated through four-photon mixing processes. AB - We discuss the nonlinear propagation of three coherently coupled pulses interacting through the parametric four-photon mixing process in a single-mode fiber. An intense pump pulse whose wavelength lies near the zero-group-velocity dispersion wavelength gives rise to a pair of Stokes and anti-Stokes pulses. A compressed solitonlike pulse at the Stokes wavelength is generated, while the anti-Stokes wave propagates as a dark pulse. The propagation equations also describe modulational instability in the presence of pump depletion. PMID- 19773840 TI - Group velocity and dispersion in nonlinear-optical fibers. AB - Many of the nonlinear effects being studied in optical fibers depend critically on the dispersion characteristics of the fiber. We generalize the scalar form of Brown's identity for group velocity in a linear waveguide to deal with arbitrary nonlinearity and use this generalization to show that the dispersion characteristics of a step-index fiber at the high powers required for many nonlinear processes may be significantly different from their linear values. PMID- 19773841 TI - Passive mode locking with a nonlinear external coupled cavity at high pulse repetition rates. AB - A general consideration is presented for obtaining high repetition rates in passively mode-locked lasers with a nonlinear external coupled cavity. Without modification of the main cavity, as much as a sixfold increase over the original repetition rate of 76 MHz has been obtained in a coupled-cavity passively mode locked Nd:YLF laser. At a constant average output power, the pulse width increases linearly, while the detuning range decreases with increasing repetition rates. PMID- 19773842 TI - Spatial coherence of laboratory soft-x-ray lasers. AB - Employing a time-dependent model with counterpropagating beams and saturable gain, we calculate the degree of coherence for a range of x-ray lasers. From these results we infer a scaling law that can be used to estimate the degree of coherence of a general class of x-ray lasers. PMID- 19773843 TI - Frequency stabilization of a diode-laser-pumped microchip Nd:YAG laser at 1.3 microm. AB - We report the active frequency stabilization of a diode-pumped microchip Nd:YAG laser using a frequency-modulation sideband locking technique. The novel aspect of this scheme is that the piezo-mounted output coupler acts as both the frequency modulator and the frequency-correcting element. When the laser is locked to a reference cavity of 300-MHz free spectral range and 5-MHz linewidth, the laser frequency stability is found to be 88 kHz relative to the cavity. PMID- 19773844 TI - Effects of birefringence on the interaction between adjacent nonlinear pulses. AB - We investigate the effects of the birefringence that is latent in ordinary single mode fibers on the interaction between two adjacent soliton pulses. Such birefringence could be induced by distortions of the core cross section along the propagation axis owing to structural imperfections or external disturbances. As the incident angle of pulses into a fiber deviates from the slow axis, the behavior of two pulses undergoes a complete change because of the combined effect of the birefringence and the cross-phase modulation. Through numerical results we conclude that the birefringence corresponding to the ordinary single-mode fiber is large enough to affect the interaction between adjacent nonlinear pulses. PMID- 19773845 TI - Characteristics of an actively mode-locked 2-psec Ti:sapphire laser operating in the 1-microm wavelength regime. AB - We examine the performance of an actively mode-locked Ti:sapphire laser operating in the 1-microm wavelength regime. Pulse durations of 1.7 psec are produced with an average output power of 400 mW. With the use of external dispersion compensation this pulse width has been further reduced to 850 fsec. PMID- 19773846 TI - Self-starting mode-locked laser with a nonlinear ring resonator. AB - A laser with a ring resonator that incorporates a nonlinear antiresonant loop is proposed and analyzed. With computer simulation it is shown that the mode-locking process is self-starting and that, when the laser is properly designed, gain bandwidth-limited pulses can be obtained. Passive mode-locked, bistable, and chaotic solutions are found to depend on the design parameters of the model. PMID- 19773847 TI - Fast optical binary multiplication using a sign/logarithm number system. AB - A new fast binary multiplication scheme based on a nonholographic optical content addressable memory (CAM) is presented. By using a sign/logarithm number (SLN) system, the multiplication operation is performed through a binary logarithmic addition. A three-stage CAM-based multiplication scheme is proposed in which the first CAM converts input binary numbers to SLN's, the second CAM performs a fixed point binary addition, and the third CAM converts this SLN result back to the binary number system. The design and experimental demonstration of a 7-bit nonholographic optoelectronic CAM-based multiplier are presented. PMID- 19773848 TI - Gain and phase-conjugation fidelity of a four-wave Brillouin mirror based on methane. AB - We report measurements of the gain and phase-conjugation fidelity of a nondegenerate four-wave Brillouin mirror (FWBM) based on high-pressure methane. In the experiments we used a Nd:YAG laser that produced single-mode pulses of 13 nsec duration. Depending on the energy of the pump we measured signal reflectivities between 10 and 10(3), constant over six orders of magnitude of signal energy. We also determined the conjugation fidelity of the FWBM by measuring the Strehl ratio of the conjugated return as a function of the energy of the input signal. We show that the Strehl ratio reduces to 0.5 for an input energy of 1.5 x 10(-13) J/mode of the FWBM. This noise-equivalent signal energy constitutes the limiting sensitivity of the FWBM. Our experiments show that a gas filled FWBM could be used as a phase conjugator and high-repetition-rate optical image intensifier. PMID- 19773849 TI - Enhanced scattering of higher-order anti-Stokes waves by polarization switching. AB - The polarization-switching technique has been successfully applied to the enhancement of scattered anti-Stokes powers in the ultraviolet region. Anti Stokes waves up to the fifth order were observed in stimulated rotational scattering of hydrogen, and their pulse widths were approximately 300 psec (FWHM), which is shorter than the dephasing time of the medium and the switching time. PMID- 19773850 TI - Optical associative memory using an orthogonalized hologram. AB - A two-dimensional orthogonal model of optical associative memory for storage of nonnegative patterns using a single hologram is presented. Two sets of patterns after prior orthogonal processing are composed and used for hologram recording, which permits the sequential holographic recordings to be carried on spatially separated regions of the recording material. High diffraction efficiency of the hologram is achieved. Computer simulations and optical demonstrations are also given. PMID- 19773851 TI - Use of phase-noisy laser fields in the storage of optical pulse shapes in inhomogeneously broadened absorbers. AB - It has been demonstrated [see, e.g., W.R. Babbitt and T. W. Mossberg, Opt. Commun. 65, 185 (1988)] that coherent optical processes can be employed to store and reproduce temporal sequences of optical data, thereby providing a mechanism for advanced optical memories. We find that excitation pulse phase noise can be used to extend the range of experimental conditions under which the storage process is effective and discuss the use of phase noise to achieve secure data storage. PMID- 19773852 TI - Planar temperature measurement in compressible flows using laser-induced iodine fluorescence. AB - A laser-induced iodine fluorescence technique that is suitable for the planar measurement of temperature in cold nonreacting compressible air flows is investigated analytically and demonstrated in a known flow field. The technique is based on the temperature dependence of the broadband fluorescence from iodine excited by the 514-nm line of an argon-ion laser. Temperatures ranging from 165 to 245 K were measured in the calibration flow field. This technique makes complete, spatially resolved surveys of temperature practical in highly three dimensional, low-temperature compressible flows. PMID- 19773853 TI - Development of a Schwarzschild-type x-ray microscope. AB - A Schwarzschild-type x-ray microscope has been designed, constructed, and tested. Ni/C multilayers were used as the x-ray mirrors, with a thickness (2d) of 7 nm and 30 layer pairs. The microscope has attained a spatial resolution of 0.5 microm at a magnification of 15. By using bright laser-produced plasmas as an x ray source [R. Kodama, K. Okada, N. Ikeda, M. Mineo, K. A. Tanaka, T. Mochizuki, and C. Yamanaka, J. Appl. Phys. 59, 3050 (1986)], images could be recorded during the 400-psec laser pulse. PMID- 19773854 TI - Pressure sensor that uses bent biconically tapered single-mode fibers. AB - A novel sensor that uses tapere single-mode fibers is discussed. The tapered single-mode fiber is bent in a simple fixture to increase its sensitivity. Pressure sensors have been fabricated utilizing the bend-sensitive property of the biconically tapered single-mode fibers. PMID- 19773855 TI - Fine structures in the angular distribution of stimulated Raman scattering from single droplets. AB - The angular distribution of the stimulated Raman scattering (SRS) from ethanol droplets is observed to be sinusoidal with n peaks, which are consistent with the mode number n of the morphology-dependent resonances (MDR's). Two distinct values of n depend on the illumination geometry and the linewidth of the input laser radiation. Angular fine structures of the SRS can be used to identify the n of the MDR. PMID- 19773856 TI - Birefringence and scattering in highly oriented artificial Kerr media. AB - We have measured both electric birefringence and polarization-resolved static light scattering at visible wave-lengths in highly oriented aqueous suspensions of shaped microparticles. In these experiments the microparticles were oriented by a high-frequency electric field, and saturation effects were clearly observed in both the Kerr effect and light scattering. The transient dynamics of the Kerr effect was studied and a field-dependent medium response time measured. PMID- 19773857 TI - Laser-induced stimulated Raman scattering in the forward direction of a droplet: comparison of Mie theory with geometrical optics. AB - Comparison of Mie theory calculations of the internal electromagnetic source function for a 120-microm-diameter water droplet with geometrical optics suggests that the field enhancement located at the critical ring region encircling the axis in the forward direction of the droplet can support stimulated Raman scattering as found experimentally. PMID- 19773858 TI - Contradirectional nonlinear-optical Bragg scattering in Kerr media. AB - Contradirectional nonlinear-optical Bragg scattering in Kerr media is considered, and analytical solutions are derived and discussed. The scattering exhibits nonlinearity and nonreciprocity. The nonlinear response provides a model for stimulated Brillouin scattering. PMID- 19773859 TI - Modal evolution of induced second-harmonic light in an optical fiber. AB - We show how the mode of the photoinduced second-harmonic light in an optical fiber changes with preparation time. We also discuss what type of nonlinear interaction can be causing the induced second-harmonic light and give experimental evidence that the initial second-harmonic light is a core-cladding interface effect. PMID- 19773860 TI - Direct numerical analysis of dual-mode elliptical-core optical fibers. AB - A direct solution of the scalar wave equation (SWE) for an elliptical-core weakly guiding fiber is considered. We decompose the SWE into two ordinary differential equations by using the method of separation of variables, demand the periodicity of the solution in terms of the angular coordinate, and, by matching the boundary conditions numerically, obtain the characteristic propagation curves for the two modes. A simple computer program permits the acquisition of two-mode fiber device parameters as functions of the core ellipticity, the core dimensions, and the refractive-index difference. PMID- 19773861 TI - Demonstration of optical switching by means of solitary wave collisions in a fiber ring reflector. AB - We have demonstrated the use of solitary wave collisions in optical pulse switching. Our apparatus consisted of a fiber ring with 11 sections of polarization-maintaining fiber, with successive sections fusion spliced with the axes rotated 90 deg. The configuration yielded enhanced transmission (autocorrelation contrast ratio 2.82:1), in agreement with expectation for this number of sections and the unoptimized fiber coupler that was used. Design criteria for complete switching are presented. PMID- 19773862 TI - Correlation of defect centers with a wavelength-dependent photosensitive response in germania-doped silica optical fibers. AB - We demonstrate a similar wavelength-dependent response for both the generation of Ge E' centers and the formation of photosensitive gratings in germania-doped silica fibers. This supports a model for the grating formation whereby two-photon absorption of laser radiation into the UV bleachable absorption band of an oxygendeficient germania site creates hole traps, modeled as Ge E' centers, which are detectable with electron spin reasonance spectroscopy. PMID- 19773863 TI - High-efficiency multipass Ti:sapphire amplifiers for a continuous-wave single mode laser. AB - We present the amplification of a continuous-wave single-mode ring dye laser in Ti:sapphire. A peak gain of 2 x 10(6) has been obtained in a passive multipass amplifier, which yielded 20-nsec pulses of 0.7-mJ energy at 780 nm. We discuss the advantages of this passive multipass amplifier in comparison with a regenerative amplifier that we have also developed. By second-harmonic generation we obtained high-peak-power UV pulses from the amplified single-mode laser. PMID- 19773864 TI - Mode locking of a diode-laser-pumped Nd:glass laser by frequency modulation. AB - We report frequency-modulation mode locking of a diode-laser-pumped Nd:glass laser. We have obtained pulses of 9-psec duration using a lithium niobate phase modulator operating at a repetition rate of 235 MHz. The average output power is 14 mW, for pumping with a 500-mW laser-diode array, and the pulses are approximately 1.4 times transform limited. PMID- 19773865 TI - Frequency stabilization of a tunable erbium-doped fiber laser. AB - A single-frequency Er-doped fiber laser that is tunable from 1.52 to 1.58 ,microm has been constructed. The laser linewidth was determined to be less than 1.6 MHz FWHM by observing the spectrum of the beat between the fiber laser and a 1.523 microm He-Ne laser. The frequency of the fiber laser was locked to several absorption lines of acetylene near 1.53 microm. This research demonstrates the inherent stability of fiber lasers and their potential for use in a wavelength standard for optical communications. PMID- 19773866 TI - Generation of 50-fsec pulses from a pulse-compressed, cw, passively mode-locked Ti:sapphire laser. AB - Stable pulses of less than 150 fsec are generated directly from a tunable cw passively mode-locked Ti:sapphire laser, through a balance of self-phase modulation in the Ti:sapphire rod and negative group-velocity dispersion produced by a prism pair. After external fiber compression, 50-fsec pulses are obtained at approximately 750 nm. PMID- 19773867 TI - Observation of fundamental dark spatial solitons in semiconductors using picosecond pulses. AB - We report what is to our knowledge the first observation of fundamental dark spatial solitons. The solitons are launched in bulk semiconductors using an initial condition with odd symmetry. In order to form the initial condition, a glass platelet is positioned in one half of an incident 30-psec pulse, creating a pi phase shift in the spatial profile. Several propagation parameters for the solitons are measured experimentally, and good agreement with theory is obtained. PMID- 19773868 TI - Picosecond separation and measurement of coexisting photorefractive, bound electronic, and free-carrier grating dynamics in GaAs. AB - A novel transient-grating geometry, which is nondegenerate, copropagating, phase matched, and polarization sensitive, is used to isolate and measure independently the ultrafast dynamics of multiple coexisting gratings in GaAs:EL2 with a temporal resolution of <5 psec. This technique permits the measurement of the evolution of the photorefractive grating in materials with zinc blende symmetry, where the photorefractive grating is usually obscured by the stronger free carrier and instantaneous bound-electronic gratings. PMID- 19773869 TI - Design of a general optical interconnection system with phase-only masks. AB - A general optical interconnection system with phase-only masks is proposed; it is a high-efficiency system. The optical general transform theory is modified for the design. Results show that an arbitrary one-to-one interconnection pattern between an array of N sources and N detectors can be achieved by two phase-only masks in which the number of sampling points is N(2). PMID- 19773870 TI - Switchable optical image adder/subtractor. AB - We demonstrate a switchable, parallel optical image adder/subtractor, using a Michelson interferometer configured with a phase-conjugating mirror. With the path difference of the interferometer legs within the coherence length of the laser, coherent image subtraction is obtained. By electronically switching the beam in one of the legs in the interferometer into an extra length, beyond the coherence length of the laser, incoherent image addition is performed. Two simple experiments showing the switching characteristics and the arithmetic operations are described. This kind of device should find applications in image processing and optical computing. PMID- 19773871 TI - Optimization of the weighted median filter by learning. AB - The weighted median filter (WMF) is a generalization of the median filter. The WMF is more effective for image processing than the conventional median filter. However, the design of the parameters of the WMF is a difficult problem. A novel method of optimizing the WMF is proposed that utilizes the close relation between the nonrecursive WMF and the feed-forward neural network with shift-invariant weight coefficients. The optimization problem of the WMF results in the learning of the interconnection weights of the network. PMID- 19773872 TI - Quantum-noise reduction in a phase-sensitive interferometer using nonclassical light produced through Kerr media. AB - A phase-sensitive interferometer system is proposed. Quantum noise in this system is reduced by using nonclassical light that is produced by a simple squeezer with Kerr media. The noise in a balanced detector can be less than the noise attained by using an ordinary squeezed vacuum. PMID- 19773873 TI - Role of stimulated four-photon mixing and efficient Stokes generation of stimulated Raman scattering in excimer-laser-pumped UV multimode fibers. AB - Efficient frequency downconversion by stimulated Raman scattering (SRS) was obtained in a XeF excimer-laser-pumped fused-silica multimode fiber at 351 nm. Twenty orders of Stokes generation were observed covering a spectral range of ~8800 cm(-1), a number we were able to predict numerically using a model for SRS only but incuding a finite gain width. Gains from stimulated four-photon mixing were found to be not important in SRS Stokes generation. Only occasionally did we observe new frequency lines in addition to the normal Raman lines, which are attributed to phase-matched wave mixing processes. PMID- 19773874 TI - Picosecond time-resolved four-wave mixing experiments in sodium-seeded flames. AB - Picosecond four-wave mixing experiments have been used to study collisions in a Na-seeded, premixed, methane-air flame. Population gratings are used to measure Na excited-state quenching collision rates, while polarization gratings are used to measure Na ground-state hyperfine coherence randomizing collision rates and overall Na diffusion rates, even though these processes are slower than the excited-state quenching rate. PMID- 19773875 TI - Diffraction efficiency of volume holograms written by coupled beams. AB - We describe volume holograms written in photorefractive crystals in which the writing beams experience two-beam coupling. We obtain analytic expressions for the diffraction efficiency of a weak reading beam that has a different polarization from the writing beams. Good agreement is obtained between experimental and theoretical results. PMID- 19773876 TI - Highly parallel single-mode multiplanar holographic interconnects. AB - We present theoretical and experimental results of a novel highly parallel multiplanar holographic interconnect design. It combines single-mode integrated optics with highly efficient volume holography and holographic waveguide couplers. A multiple-plane optical bus was fabricated. The interconnect density and power budget of the system are presented. This new type of very-large-scale integrated interconnect can provide performance benefits for local area networks and highly parallel supercomputing systems. PMID- 19773877 TI - Formulation for the design of birefringent phased-array Bragg cells in uniaxial crystals. AB - Tangential phase matching is generally used as an enhancement technique in the design of wideband acousto-optic deflectors operating in birefringent media. We present an exact formulation that describes the behavior of birefringent phased array Bragg cells in uniaxial crystals. It is demonstrated that wideband deflection around a desired center frequency can be obtained while one has freedom of choice regarding the acoustic mode and interaction plane. Furthermore it is shown that some major disadvantages of the optically rotated and acoustically rotated tangential phase-matching configurations can be eliminated. PMID- 19773878 TI - Fiber-optic gyroscopes based on polarization scrambling. AB - A novel fiber-optic gyroscope with a single-mode diode laser as the light source and two polarization scramblers as time-varying depolarizers is demonstrated. This arrangement reduces the nonreciprocal phase noise induced by the cross coupling between polarization modes in single-mode fibers. The experimental results show that a phase-noise reduction factor of 18 can be achieved. PMID- 19773879 TI - Diffraction efficiency of reflection gratings with a parabolic section profile. AB - Diffraction properties of reflection gratings with a parabolic groove profile are analyzed. It is shown that these structures produce a large number of diffracted waves with similar intensities. Theoretical and experimental results at the wavelength of 780 nm are shown. These gratings are made from holographic diffraction gratings recorded in a photoresist. PMID- 19773880 TI - Beam propagation and the ABCD ray matrices. AB - We have generalized the ABCD propagation law, Q(2) = (AQ(1) + B)/(CQ(1) + D), for an optical system by introducing a generalized complex radius of curvature Q for a general optical beam. The real part of 1/Q is related to the mean radius of curvature of the wave front, while the imaginary part is related to the second moment of the amplitude of the beam. PMID- 19773881 TI - Saturation of second-harmonic generation in GaAs-AlGaAs asymmetric quantum wells. AB - The saturation of second-harmonic generation is observed for the first time to our knowledge in GaAs-GaAlAs asymmetric quantum wells. The sample, which consists of 200 periods of a 30-nm Ga(0.6)Al(0.4)As barrier, a 4.5-nm Ga(0.4)Al(0.09)As step barrier, and a 6-nm GaAs well, is pumped by a CO(2) TEA laser. The saturation of second-harmonic conversion is found to occur near 16 MW/cm(2). The power conversion efficiency is measured to be of the order of 3.4 x 10(-4). These results are in good agreement with theoretical predictions from a density matrix treatment. PMID- 19773882 TI - Polarization instability in a waveguide geometry. AB - We show theoretically that polarization instability can be observed in planar optical waveguides. Such instability would lead to energy exchange between the spatial solitons associated with the TE(0) and TM(0) waveguide modes as well as to amplitude-modulation gain, which was recently observed in an optical-fiber geometry. PMID- 19773883 TI - Blue parametric generation from temperature-tuned LiB(3)O(5). AB - We have demonstrated optical parametric generation from 470 to 487 mn with LiB(3)O(5), using a 355-nm pump in a noncritical phase-matched orientation by temperature tuning. A Conversion efficiency of 9% at 480 nm was achieved at room temperature. PMID- 19773884 TI - Effects of initial overlap on the propagation of optical solitons at different wavelengths. AB - Effects of initial overlap between two solitons at different carrier wavelengths are studied theoretically and numerically as a function of the degree of overlap and the frequency separation of the two carriers. When the two solitons are fully overlapped, the carrier frequencies of the emerging two solitons are shifted toward each other by an amount proportional to the initial power and inversely proportional to the initial frequency separation with little effect on their amplitudes provided that the frequency separation is sufficiently larger than the spectral width of the solitons. PMID- 19773885 TI - Seeded second-harmonic generation in optical fibers: the effect of phase fluctuations. AB - Phase fluctuations between the infrared and green beams during seeding of second harmonic generation (SHG) in optical fibers lead to a drastic reduction of the initial SHG intensity and to a strong time dependence of the SHG after seeding. Experiments using mode-locked lasers with a stable phase relation between the infrared and green writing beams lead to reliable, reproducible results. Under these conditions we do not observe a significant difference in SH efficiency between fibers with Ge concentrations of 3 and 14 mol. %. PMID- 19773886 TI - Chirp mechanisms in soliton-dragging logic gates. AB - We theoretically and experimentally study the chirping mechanism responsible for the time shifts in soliton-dragging logic gates. Cross-phase modulation during the first one or two walk-off lengths in a birefringent optical fiber causes most of the frequency shift that translates into a time shift after propagation in a soliton dispersive delay line. Introducing gain or loss during the pulse interaction asymmetrizes the pulse walk-off and, consequently, increases the temporal window over which soliton dragging can result in a time shift. Analytic formulas for the time shift provide the scaling laws as a function of various fiber parameters. PMID- 19773887 TI - Grating-assisted couplers. AB - A simple closed-form description of grating-assisted coupling between twin cores is presented. It is exact in the limit of weakly coupled cores and weak grating perturbations. PMID- 19773888 TI - Ultrafast all-optical logic operations in a nonlinear Sagnac interferometer with two control beams. AB - Ultrafast highly stable all-optical logic operations, including inversion, AND, XOR, and XOR, in a two-wavelength nonlinear Sagnac interferometer with two control beams have been reported. The interferometer consists of a dichroic polarization-maintaining fiber coupler and a 200-m-long dispersion-shifted polarization-maintaining fiber Sagnac loop. The logic operations were successfully demonstrated at multigigabit operation per second, and the required signal power was 1.8 W for a 200-m fiber. PMID- 19773890 TI - Effect of gain dispersion and stimulated Raman scattering on soliton amplification in fiber amplifiers. AB - Amplification of ultrashort solitons in fiber amplifiers is discussed by considering a general model that includes gain saturation, gain dispersion, and intrapulse stimulated Raman scattering. The numerical results show that an interplay between gain dispersion and intrapulse Raman scattering can lead to novel temporal and spectral features. Under high-gain conditions the input pulse is found to split into several subpulses propagating at different speeds. Each subpulse evolves toward a chirped soliton whose width is governed by the gain bandwidth and is ~50 fsec for erbium-doped fiber amplifiers. PMID- 19773889 TI - Observation of a topological phase in a noncyclic case by use of a half-sturn optical fiber. AB - We describe direct observation of a geometrical phase in a noncyclic case as the rotation of the plane of polarization of a linearly polarized beam of light. The beam travels down uniformly wound half-turn single-mode optical fibers with various pitch angles. PMID- 19773891 TI - Stimulated Brillouin fiber-optic laser gyroscope. AB - We achieved simultaneous bidirectional lasing in an all-fiber ring laser, using stimulated Brillouin scattering as the gain medium. The Brillouin lasing threshold was 60 microW for a He-Ne pump at 1.15 microm. The operation of this device as a ring-laser gyroscope was demonstrated. PMID- 19773893 TI - Self-starting passive mode locking. AB - We investigate the evolution of continuous-wave laser oscillation from free running to mode-locked operation assuming a nonlinear device with an intensity dependent transmittivity or reflectivity to be the mode-locking element. An intensity threshold for self-starting passive mode locking is predicted and related to the linewidth of the first beat note of the power spectrum of the free running laser output. Experimental results confirm the predictions of the theory. PMID- 19773892 TI - Continuous-wave 1.50-microm thulium cascade laser. AB - A cascade laser scheme is used to obtain continuous-wave 1.50-microm laser emission at room temperature on the normally self-terminating Tm(3+)(3)H(4) ? (3)F(4) transition in YLiF(4). The long-lived (3)F(4) state is quenched through energy transfer to the Ho(3+)(5)I(7) state, which is depopulated through the Ho(3+)(5)I(7) ? (5)I(8) 2.06-microm laser transition. PMID- 19773894 TI - Generation of 20-TW pulses of picosecond duration using chirped-pulse amplification in a Nd:glass power chain. AB - Pulses of 20-TW peak power have been generated at 1064 nm using the chirped-pulse amplification technique with a 90-mm output-aperture Nd:silicate glass amplification line. This system delivers 60 J of energy in a chirped pulse of 600 psec duration, with a capacity to maintain a 3.5-nm output bandwidth. These chirped pulses are compressed to 1.2 psec with an energy of 24 J by using large holographic gold-coated 1740-lines/mm diffraction gratings. PMID- 19773895 TI - Mode locking using a type II multiple-quantum-well structure as a fast saturable absorber. AB - We demonstrate the application of a type II Al(x)Ga((1-x))As/AlAs multiple quantum well as a fast saturable absorber in a hybridly mode-locked dye laser. Type II multiple quantum wells are promising for this application because of the fast recovery of the saturated absorption with picosecond or even subpicosecond time constants. We obtain almost transform-limited pulses as short as 0.9 psec for a type II sample with a recovery time of 2.3 psec. PMID- 19773896 TI - Additive-pulse-compression mode locking of a neodymium fiber laser. AB - The generation of bandwidth-limited shoulder-free 125-fsec pulses by additive pulse-compression mode locking of a neodymium glass laser is described. An all fiber nonlinear amplifying loop mirror is employed as a fast saturable absorber and permits stable pulse generation under the condition of large pulse shaping in the cavity. PMID- 19773897 TI - Space-time-sharing optical neural network. AB - A space-time-sharing optical neural network for implementing a large-scale operation is presented. If the interconnection weight matrix is partitioned into an array of submatrices, a large space-bandwidth pattern can be processed with a smaller neural network. We show that the processing time increases as a square function of the space-bandwidth product of the pattern. To illustrate the space time-sharing operation, experimental and simulated results are provided. PMID- 19773898 TI - Photorefractive flip-flop. AB - We demonstrate an optical flip-flop that consists of two unidirectional ring resonators that are coupled competitively through two-beam interactions in a photorefractive BaTiO(3) crystal. This crystal provides an active loss for each ring that depends on the oscillation intensity of the other. The coupled rings exhibit flip-flop bistability when the net gain, given by the product of the passive cavity losses and the gain, is greater than unity but is less than the small-signal active loss. The state of the system can be switched with an injected signal. PMID- 19773899 TI - Comparison between the peak-to-sidelobe ratio of the matched and phase-only filters. AB - It is shown that for any given bandpass, the phase-only filter always gives a better peak-to-correlation energy than the matched filter. An example is given that shows that this result does not carry over when one uses a more general measure of the peak-to-sidelobe ratio. PMID- 19773900 TI - Two-dimensional optical architecture for time-delay beam forming in a phased array antenna. AB - We propose and experimentally demonstrate a new two-dimensional optical architecture based on polarization switching by N spatial light modulators that provides 2(N) time delays to a phased-array antenna of p x p radiating elements. Moreover the 0 to 2pi phase of the microwave signals is optically controlled by a liquid-crystal spatial light modulator that operates in the birefringent mode. The microwave signal originates from the coherent detection of a dual-frequency laser beam obtained with an acousto-optic frequency shifter. Preliminary experimental results obtained at a microwave frequency f = 1.85 GHz are presented. PMID- 19773901 TI - General procedure for the analysis of Er(3+) cross sections. AB - We have applied the theory of McCumber to the (4)4I(13/2) ? (4)I(15/2) transition of Er(3+) -doped glasses and confirmed its ability to provide both spectra and accurate values of cross sections. For an Al/P-silica fiber, the exact McCumber treatment is within 3% of the measured emission cross section, whereas an Einstein analysis is off by >50%. An approximate treatment that eliminates the McCumber theory's requirement of detailed electronic structure has been developed and found to usually provide more accurate values than an Einstein analysis. PMID- 19773902 TI - Second-harmonic generation at Lyman-alpha in atomic hydrogen. AB - Second-harmonic generation in atomic hydrogen is investigated with and without an applied electric field, by tuning laser radiation at 243.1 nm through the 2 (2)S((1/2))-1(2)S((1/2)) two-photon resonance. Even at zero applied field, secondharmonic radiation at 121.6 nm was observed. The measured intensity is shown to arise from a charge-separation field caused by ions produced in three photon ionization. calculated value based on the measured ion density. PMID- 19773903 TI - Spectrally programmed stimulated photon echo. AB - A stimulated photon echo has been observed from the artificially modulated inhomogeneous distribution of a medium. A cryogenic Eu (3+):YAlO(3) sample with a quasi-persistent hole lifetime is exposed to a frequency-scanned and intensity modulated cw laser for multiple hole burning. A coherent burst equivalent to the stimulated photon echo is obtained by triggering this sample by a pulsed laser. We demonstrate further that any desired transient pulse shape can, in principle, be obtained by appropriate frequency-domain programming, which opens the way to a novel type of optical memory. PMID- 19773904 TI - Autoionizing decay rates measured by optical nutation. AB - Using a single-mode pulsed laser we have measured autoionizing lifetimes for the 3p' (3)D states of atomic oxygen by measuring the dependence of ionization on the fluence of light driving the 3s' (3)D-3p' (3)D transition. From the frequency of the Rabi oscillations we deduce transition strengths, and from the modulation depth we calculate ionization lifetimes. These are to our knowledge the first measurements of these quantities for these transitions. PMID- 19773905 TI - Moving grating for enhanced holographic recording in cerium-doped Sr(0.6)Ba(0.4)Nb(2)O(6). AB - We demonstrate that holographic recording in photorefractive materials can be improved by using a moving grating to reduce energy coupling. In cerium-doped Sr(0.6)Ba(0.4)Nb(2)O(6) under an applied dc electric field, experimental and theoretical results show that the proper grating velocity can maximize the modulus and the real part of the spacecharge field while reducing the imaginary component of the space-charge field (and energy coupling) to zero. Avoiding energy transfer between the recording beams allows us to maintain maximum contrast throughout the crystal, producing a uniform, high-index-modulation grating with enhanced diffraction efficiency and superposition properties. PMID- 19773906 TI - Quadrature phase-shifted, extrinsic Fabry-Perot optical fiber sensors. AB - We demonstrate the operation of a quadrature phase-shifted extrinsic Fabry-Perot fiber-optic sensor for the detection of the amplitude and the relative polarity of dynamically varying strain. Two laterally displaced single-mode fibers inserted within a hollow silica tube form the 90 degrees phase-shifted sensing system. A multimode fiber, placed in the tube facing the two fibers, acts as a reflector, thereby creating an air gap that acts as a Fabry-Perot cavity. A theoretical description of the sensor is given, and its operation as a dynamically varying strain sensor is described. Strain sensitivities of 5.54 degrees phase shift/microstrain cm(-1) are obtained. PMID- 19773907 TI - Optical interconnect for a ring array of single-instruction-multiple-data processors. AB - A novel optical interconnect scheme for a ring of single-instruction-multiple data processing elements is proposed. This unexplored optical interconnect topology promises several important advantages over the conventional rectangular array topology, such as the use of space-invariant elements and identical interconnect latency for implementation. PMID- 19773908 TI - Optical trapping of small particles using a 1.3-microm compact InGaAsP diode laser. AB - We describe the noncontact optical trapping of small particles by a single-beam gradient force using a near-infrared InGaAsP diode laser operating at 1.33 microm. The feasibility and reliability of diode-laser trapping was confirmed with polystyrene latex and glass spheres as well as with yeast cells. By moving small particles vertically to the laser beam axis, we measured the horizontal component of the trapping force based on the Stokes law. Thus a linear relationship between the trapping laser power and the horizontal trapping force is demonstrated and compared quantitatively with that for the Ar laser. PMID- 19773909 TI - Decay of dark solitons due to the stimulated Raman effect. AB - It is demonstrated analytically and numerically that dark solitons always disappear owing to the stimulated Raman effect. Instead of dark solitons, the stable propagation of optical kinks on the cw background in the region of the normal group-velocity dispersion is possible. PMID- 19773910 TI - Stationary states of two coupled double phase-conjugate mirrors. AB - Stationary states of the system of two coupled double phase-conjugate mirrors are considered by taking into account small but finite seed values of the scattered waves at the entry into a nonlinear medium. Seed values are shown to determine both the possibility of self-starting oscillation for a given level of nonlinearity and the position and width of the bistability region. PMID- 19773911 TI - Spatial ring emission and filament formation in an optical fiber with a saturable nonlinear cladding. AB - We present numerical simulations of Gaussian beam propagation in an optical fiber with a linear core and a saturable self-focusing cladding. Cylindrical nonlinear waves are emitted from the core into the cladding and are initially localized only in the radial direction, forming rings. These rings can break their cylindrical symmetry through a transverse instability, which yields filaments localized both azimuthally and radially, most of which stay close to the core for long propagation distances. PMID- 19773912 TI - Nonlinear switching in multiple-core couplers. AB - Power-controlled switching between any output ports of different multiple-core nonlinear directional couplers is predicted. The input-output characteristic is calculated both at the half-beat length and the beat length. A second conservation law has been found in addition to the power conservation law. PMID- 19773913 TI - Polarization-resolved nondegenerate two-wave mixing in shaped microparticle suspensions. AB - We observe polarization-resolved coherent beam combination through nondegenerate two-wave mixing in water-glycerol suspensions of shaped polytetrafluoroethylene microparticles. Coherent energy transfer that arises from translational and orientational moving index gratings was observed. A theory for beam combination through nondegenerate two-wave mixing is presented and found to be in excellent agreement with these measurements. PMID- 19773914 TI - Mode multiplexing and holographic demultiplexing communication channels on a multimode fiber. AB - Spatial mode multiplexing is used to transmit several communication channels on a single multimode optical fiber. Each channel is encoded by an orthogonal pattern produced by a spatial light modulator. A photorefractive medium holographically decodes the output speckle pattern at a receiver station. We demonstrate ring and star architectures for interconnection networks. Typical cross-talk-to-signal ratios, for fully interconnected three-processor networks, are -24 and -26 dB for the ring and star, respectively. PMID- 19773916 TI - Two-dimensional control of mode size in optical channel waveguides by lateral channel tapering. AB - We propose optical channel waveguide structures in which two-dimensional mode size transformation is achieved by lateral tapering only. The layer structure of the waveguide is designed such that tapering the lateral channel width results in a tapering of the vertical size of the mode as well. This is accomplished by providing two waveguide cores in a single-mode system. When the rib is wide, the mode resides in the upper core, tightly confined by the rib. As the rib narrows, the field migrates to the lower core and spreads out in both dimensions, permitting a better match to large-mode structures such as optical fibers. Our calculations show that such waveguide tapers can significantly reduce the losses for coupling single-mode optical fibers to semiconductor channel waveguides. PMID- 19773915 TI - All-fiber filter for efficient dispersion compensation. AB - A dispersive filter is proposed that is based on the coupling, with a chirped periodic perturbation, of two copropagating waveguide modes that have different group velocities. Numerical calculations show that a nearly constant dispersion can be obtained over the filter bandwidth. Pulse recompression by a factor of 10 or more is possible. The filter could be made with photoinduced refractive-index gratings in optical filters. PMID- 19773917 TI - Low-loss coherent-coupling Y branches. AB - We propose the design of low-loss waveguide Y branches with coherently coupled bends. According to results of beam-propagation simulations, the excess loss of a complete Ti:LiNbO(3) Y branch with a nominal half-branching angle of 1 degree can be as low as -0.18 dB. Similar to the case of other cascaded Y branches, when two coherently coupled Y branches are cascaded, the power distribution at the output varies with the length of the straight connecting waveguide. Details of the Y branch design that gives low loss and equal power splitting are presented. PMID- 19773918 TI - Nonlinear wave propagation along a bent nonlinear dielectric interface. AB - The transmission properties of abruptly and uniformly bent nonlinear interfaces are investigated by using the beam-propagation method. An approximate analytical solution of the threshold power for the straight interface is also derived. It is found that the incident surface wave can propagate along the interface bent toward a nonlinear medium, whereas it cannot propagate along that bent toward a linear medium. The bent interface can be used as a lower-threshold device and for an experimental verification of the nonlinear surface wave along a single interface. Moreover the results given here are useful for the design of all optical waveguide devices that contain bends and tapers, since the nonlinear surface wave can propagate in many nonlinear waveguides. PMID- 19773919 TI - Frequency-modulated cavity-dumped Nd-doped fiber laser. AB - A cw-pumped Nd-doped single-mode double-clad fiber laser coiled around a resonant piezoelectric ceramic ring and coupled to an empty external cavity with strong feedback is described. Intensity laser pulses with durations in the 1-2-micros range are observed as the pump power or the ring drive voltage is increased, yielding peak powers as much as 25 times greater than average powers. The effect is attributed to strong phase modulation of the fiber laser by the piezoelectric ring, which induces FM laser oscillation. The external cavity acts as a frequency dependent reflector, thus effectively cavity dumping the fiber laser as the oscillation frequency is swept through the narrow transparent windows of the external cavity. PMID- 19773920 TI - High-power Nd:YAG laser end pumped by a cw, 10 mm x 1 microm aperture, 10-W laser diode bar. AB - A Nd:YAG laser is end pumped with a 10-W laser-diode bar to produce 1.9 W of TEM(00)-mode power at 1.064 microm. The 10 mm x 1 microm bar is imaged into a 1.8 mm x 390 microm elliptical laser mode. Q-switched operation results in pulse energies of 160 microJ at a 10-kHz repetition rate, which rises to 250 microJ at 5 kHz. Frequency doubling in KTP produces 75-microJ pulses at 10 kHz, corresponding to 750 mW of average power at 532 nm and a nonlinear conversion efficiency of 47%. PMID- 19773921 TI - Resonant frequency doubling of a self-starting, coupled-cavity, mode-locked Ti:A12O3 laser. AB - We report the efficient frequency doubling of a self-starting, coupled-cavity, mode-locked Ti:sapphire laser (Ti:A1(2)O(3)). The laser produced pulses of 2.5 3.4 ps at a 122-MHz repetition rate that were tunable from 740 to 820 nm. These pulses were frequency doubled in an external ring enhancement cavity. Using a l mm-long, Brewstercut LiIO(3) crystal, we obtained conversion efficiencies of as much as 34% in the form of picosecond pulses tunable from 370 to 410 nm. The maximum generated power in the blue was 48 mW at 384 nm. PMID- 19773922 TI - 100-fs pulse generation and amplification in Ti:AI2O3. AB - We have constructed a self-mode-locked Ti:Al(2)O(3) laser that produces 100-fs pulses at 750 nm. These pulses are then amplified in a Ti:Al(2)O(3) regenerative amplifier to the millijoule energy level. 105-fs, 10-GW pulses have been produced. PMID- 19773923 TI - Optical associative memory based on an echo correlator. AB - A physical principle of the associative-memory optical implementation by using the photon-echo effect is proposed. The properties inherent in this phenomenon permit an optical scheme similar to the nonlinear holographic associative memory [Appl. Opt. 26, 1900 (1987)] to be considered. The associative-memory system based on the photon-echo effect uses a temporal selectivity instead of a spatial one. PMID- 19773924 TI - Iterative generation of complex reference functions in a joint-transform correlator. AB - Iterative learning procedures on hybrid electro-optic systems are employed to generate complex discriminant reference functions. The procedures are implemented experimentally on a joint-transform correlator by using a single inexpensive spatial light modulator. High-quality class discrimination is demonstrated even in the presence of noise. PMID- 19773925 TI - Photorefractive time-integrating correlator. AB - We propose and demonstrate a new configuration of a photorefractive time integrating correlator system using acousto-optic devices to process rf signals. In our system, two rf signals are transferred onto two laser beams by two acousto optic devices, and the beams interact inside a photorefractive crystal to form a grating for time integration and correlation. The novelty of our scheme is that the direction of the rf signal in the beams is orthogonal to the resulting grating wave vector inside the crystal. This new geometry eliminates any resolution-limiting cross talk that arises from undesirable beam interactions. It also permits a longer crystal interaction length, which reduces constraints on the photorefractive material. PMID- 19773926 TI - Passive Fraunhofer-wavelength atomic filter at 422.7 nm. AB - We have demonstrated 25% internal photon conversion efficiency of a new passive atomic filter. The signal wavelength matches an intense Fraunhofer line at 422.7 nm, thereby offering enhanced sunlight rejection. A quasimolecular interaction promotes rapid energy transfer between the 4p (1)P(1) level and the 4p (3)P(J) level of neutral calcium for wavelength shifting of 422.7-nm light into 657.3-nm emission. We discuss augmentation of the photon conversion efficiency by radiation trapping. PMID- 19773927 TI - Four-beam laser trap of neutral atoms. AB - An efficient spontaneous-force laser trap of neutral atoms without standing waves is demonstrated by using the Ne 1s(5) metastable state. The metastable Ne beam is decelerated by a laser by using Zeeman tuning and is trapped in a trap consisting of a quadrupole magnetic field and four laserbeams in a tetrahedral configuration. The dynamics of atomic motion from the deceleration stage to the trap is discussed. PMID- 19773928 TI - Quasi-distributed pressure sensor using intensity-type optical coherence domain polarimetry. AB - We investigate a quasi-distributed optical fiber sensor that locates the positions of sensing units along a high-birefringence fiber by using white-light interferometry and measures the physical parameters by directly detecting the measured-induced cross coupling between two polarization modes. Important factors that affect the performance of the system, such as cross-term spurious signals and thermostability, are analyzed. Preliminary experimental results of such a system with 10 pressure sensors are presented. PMID- 19773929 TI - Wavelength demultiplexer that uses an interference filter and achromatic quarter wave plates. AB - A new two-channel demultiplexer structure for closely spaced wavelength-division multiplexing systems is proposed. The demultiplexer is constructed with an interference filter and achromatic quarter-wave plates. Its feature is that wavelength-multiplexed light falls normally upon the filter. Two demultiplexers coupled with single-mode fibers are fabricated. Their measured insertion losses are 1.8 and 2.8 dB. PMID- 19773930 TI - Speed of the coherent component of femtosecond laser pulses propagating through random scattering media. AB - The pulse profile and the speed of the coherent component of 85-fs laser pulses propagating through a slab of a random scattering medium were measured. The pulse profile was found to remain essentially the same, while the speed was reduced proportionally to the thickness of the slab and the concentration of the scatterers. The reduction in speed can be accounted for by an effective index of refraction that is described either by the volume fractional combination of the indices of refraction of the scatterers and the water or by the coherent interference between the scattered waves and the primary wave. PMID- 19773931 TI - Generalized propagation techniques. AB - We introduce a new identity that relates the exponential of the sum of two noncommuting operators to the exponentials of the individual operators. This formula generates rapid fourth-order split-step fast-Fourier-transform, split operator finite-difference, split-operator finite-element, and real-space propagation algorithms. To illustrate the procedure, we model the focusing of a light beam by a spherical integrated-optic microlens. PMID- 19773932 TI - Interferometric laser profilometer for rough surfaces. AB - A simple synthetic-wavelength interferometer is reported that uses two wavelengths of a multimode laser diode. The difference in interferometric phase measurements at the two wavelengths provides absolute range information to an accuracy of 0.75 microm over an ambiguity interval of 310 microm. The instrument can be used to profile surfaces too rough to be measured by conventional interferometry. PMID- 19773934 TI - High-fidelity image amplification and phase conjugation in photorefractive Bi(12)SiO(20) crystals. AB - Wide-angle, large space-bandwidth-product coherent image amplification with a flat spatial frequency response is demonstrated in photorefractive Bi(12)SiO(20) crystals under nonstationary grating recording conditions. By utilizing large divergence, mutually phase-conjugate pump beams provided by a self-pumped BaTiO(3) crystal, high-fidelity phase conjugation with high reflectivity in Bi(12)SiO(20) is demonstrated. PMID- 19773933 TI - Threshold degenerate wave mixing in dye-doped polymer-dispersed liquid crystals. AB - We report what is to our knowledge the first observation of nonlinear light diffraction in polymer-dispersed liquid crystals. The superposition with the self transparency effect produces a threshold in the observed wave-mixing phenomenon. PMID- 19773935 TI - Stimulated rotational Raman scattering in air with a high-power broadband laser. AB - We study the growth of stimulated rotational Raman scattering (SRRS) from noise by propagating one beam of the OMEGA fusion laser over a 35-m path in air. The spectrum at the end of the path is measured and calibrated to give the energy scattered into all the Stokes lines. Pure phase-modulated bandwidth as well as the bandwidth known as smoothing by spectral dispersion (SSD) are installed on the laser. The experimental results show that the threshold for SRRS is unchanged when one uses a pure phase-modulated bandwidth and increases when one uses a SSD bandwidth. PMID- 19773936 TI - Stimulated Brillouin scattering phase-conjugation fidelity fluctuations. AB - We observe shot-to-shot fluctuations in the far-field fidelity of stimulated Brillouin scattering phase-conjugate mirrors in the saturated reflectivity regime under various experimental conditions. The fluctuations, which are not seen in the reflectivity, reflect a partial breakdown in the discrimination mechanism that selectively amplifies the conjugate mode above the stimulated Brillouin scattering noise seed. PMID- 19773937 TI - Dynamical equation for polarization dispersion. AB - Polarization dispersion in single-mode fiber that contains arbitrary birefringence is described through a vector differential equation. Monte-Carlo simulations using this equation show good agreement with experimental measurements in a randomly birefringent fiber and with a previously reported analytic expression for the length dependence of the dispersion. We also correct an error made in earlier research and show that the probability density function for the magnitude of the dispersion at long lengths is Maxwellian rather than Gaussian as previously reported. PMID- 19773938 TI - LiNbO(3) waveguide second-harmonic-generation device phase matched with a fan-out domain-inverted grating. AB - A LiNbO(3) waveguide optical second-harmonic-generation (SHG) device, consisting of a channel waveguide array and a ferroelectric domain-inverted grating in a fan pattern for quasi-phase matching, is proposed. The structure has redundancy to absorb the residual phase mismatch caused by design uncertainties and fabrication errors. A SHG device of 3-mm interaction length was fabricated by domain inversion by Ti indiffusion and channel waveguide formation by annealed proton exchanging and reactive ion etching. A normalized SHG efficiency of 17%/W was experimentally obtained for pumping by a cw Nd:YAG laser. PMID- 19773939 TI - Single-frequency Q-switched operation of a diode-laser-pumped Nd:YAG ring laser using an acousto-optic modulator. AB - Single-frequency Q-switched operation of a diode-laser-pumped Nd:YAG ring laser has been achieved by using an acousto-optic modulator both to enforce unidirectional operation and to provide Q switching. Pulses with energies of 13 microJ and 36-ns duration have been obtained, corresponding to a peak power of 400 W, at a repetition rate of 1 kHz. PMID- 19773940 TI - Depolarized source for fiber-optic applications. AB - Two diode-pumped Nd:YAG lasers are combined with their polarization vectors at 90 degrees to each other to create a depolarized source suitable for propagation over long lengths of ordinary, low-birefringence single-mode fiber without a change in the polarization state. The source is demonstrated with an integrated optical Mach-Zehnder interferometer and provides a constant -3.dB intensity input to the required linear input polarization state. PMID- 19773941 TI - Passive coupled-cavity mode-locked color-center lasers. AB - Stable, self-starting operation of a coupled-cavity mode-locked KCl:T1(0)(1) color-center laser has been achieved by incorporating a semiconductor diode optical amplifier into the control cavity. By adjustment of the amplifier drive current, nonlinearity in the regimes of either saturable gain or saturable absorption has been exploited to generate subpicosecond pulses. Under conditions of saturable gain, pulse durations as short as 280 fs were obtained. Self starting has also been demonstrated for a coupled-cavity mode-locked NaCl:OH(-) color-center laser by using the same technique. PMID- 19773942 TI - Acoustically tuned erbium-doped fiber ring laser. AB - We report what is to our knowledge the first narrow-linewidth, continuously tunable laser that uses an acousto-optic filter to achieve a broad tuning range. The unidirectional ring-laser configuration incorporates an erbium-doped fiber amplifier as the gain medium and an integrated, frequency-shift-compensated acousto-optic filter as the tuning element. Using a 980-nm optical pump with 60 mW of launched power, we obtained nearly 2 mW of laser output with 10% output coupling. A tuning range of 40 nm was achieved, centered about 1545 nm. Single longitudinal-mode operation with a 10-kHz linewidth was demonstrated, although the laser wavelength hopped between nearby longitudinal modes because of path length fluctuations. Wavelength switching at rates up to 100 kHz was examined. PMID- 19773943 TI - Coupled-cavity resonant passive mode-locked Nd:yttrium lithium fluoride laser. AB - We report coupled-cavity resonant passive mode locking of a Nd:YLF laser. This technique has produced 4-ps pulses at a wavelength of 1.047 microm with 390-mW average power at a 250-MHz repetition rate, corresponding to a 1.6-nJ pulse energy. The Nd:YLF rod was pumped with 1.5 W of power at 798 nm from a Ti:sapphire laser. The nonlinear reflector used in the coupled cavity was an InGaAs/GaAs strained layer multiple-quantum-well sample. PMID- 19773944 TI - Narrow-linewidth stimulated Brillouin fiber laser and applications. AB - A stimulated Brillouin fiber ring laser with a spectral width of 2 kHz and an intrinsic linewidth of less than 30 Hz has been demonstrated. Applications of such a laser include laser linewidth narrowing, microwave frequency generation, high-rate amplitude modulation, and optical inertial rotation sensing. PMID- 19773945 TI - Pump-resonant excitation of the 946-nm Nd:YAG laser. AB - Pump-resonant excitation, in which a weakly absorbing gain medium is placed inside an optical cavity that is resonant at both the pump and laser wavelengths, is shown to reduce significantly the losses due to saturable absorption in a quasi-three-level, diode-pumped laser. Initial experiments, in which this technique is applied to the 946-nm Nd:YAG laser, have yielded incident threshold power levels below 1.3 mW and optical slope efficiencies exceeding 25%. PMID- 19773946 TI - Broadly tunable high-power operation of an all-solid-state titanium-doped sapphire laser system. AB - Broadly tunable and high-power operation of a titanium-doped sapphire laser is obtained with a diode-laser-pumped frequency-doubled Nd:YAG laser as the pump source. A maximum broadband (FWHM = 25 nm) output pulse energy of 720 microJ at 795 nm in a TEM(00) mode is obtained for 1850 microJ of energy of 532-nm pump light. A minimum pulse duration of 7 ns is obtained from a 40-mm-long cavity. With the use of an intracavity prism, the Ti:sapphire laser is tunable continuously over the 696-1000-nm spectral range (with three different mirror sets). PMID- 19773947 TI - Single-shot autocorrelator for KrF subpicosecond pulses based on two-photon fluorescence of cadmium vapor at lambda = 508 nm. AB - By excitation of cadmium vapor with a high-peak-power KrF excimer laser pulse, fluorescence of an atomic transition at lambda = 508 nm is induced by a two photon ionization process followed by fast recombination. The nonlinear response of the medium is used to develop a simple single-shot autocorrelator for subpicosecond KrF excimer laser pulses operating down to intensities of less than 10(9)W/cm.(2) We have measured 360-fs (FWHM) pulses at lambda = 248 nm with a time resolution of 15 fs. PMID- 19773948 TI - Passive stabilization of a synchronously pumped mode-locked dye laser with the use of a modified outcoupling mirror. AB - Recently a new passive stabilization technique for synchronously pumped dye lasers was reported that allows one to generate nearly transform-limited pulses. The idea of this technique is to split off an extremely small fraction of the laser pulse and to superimpose it back on itself slightly advanced in time. In these experiments the seeding pulse was provided by an external cavity, which led to an undesirable frequency hopping. Here we present a simple modification of an outcoupling mirror that integrates the generation of the seeding pulse into the main laser cavity. In this way frequency-stable, nearly transform-limited pulses are generated. PMID- 19773950 TI - Femtosecond pulses in the mid-infrared generated by downconversion of a traveling wave dye laser. AB - Amplified pulses from a colliding-pulse mode-locked dye laser at 620 nm and the output of a femtosecond traveling-wave dye cell are mixed in a LiIO(3) crystal to generate femtosecond pulses in the wavelength range near 5 microm. As much as 10% of the photons from the traveling-wave laser are converted to stable infrared pulses of less than 400-fs duration, 10-nJ energy, and 8-kHz repetition rate. PMID- 19773949 TI - All-optical switching in a 200-m twin-core fiber nonlinear Mach-Zehnder interferometer. AB - All-optical switching is demonstrated in a 200-m-long fiber nonlinear Mach Zehnder interferometer. The only stabilization mechanism used is passive enclosure of the interferometer. Stable operation is obtained by using a twin core fiber. The experiment demonstrates the feasibility of use of fiber nonlinear Mach-Zehnder interferometers for ultrafast switching and pipeline logic. PMID- 19773951 TI - Nondegenerate two-wave interaction in a photorefractive crystal in an external detecting field. AB - A hologram recording mechanism in photorefractive Bi(12)TiO(20) crystal by different-frequency laser beams in an ac field is studied. The frequency difference between the beams is essentially more than the reverse of the response time of the hologram. PMID- 19773952 TI - Fan-in issues in a holographic grating interconnect system. AB - Coherent holographic grating interconnect systems exhibit deleterious interference effects when multiple optical beams are fanned into a single beam with the use of multiplexed gratings. Elimination of such effects is possible with the use of arrays of incoherent sources for readout, temporal sequencing, random phase modulation of the readout beams, or allocated volume configurations. The merits and drawbacks of each alternative are analyzed. PMID- 19773953 TI - Room-temperature microparticle-based persistent spectral hole burning memory. AB - We show both theoretically and experimentally that a random distribution of spherical microparticles may be used as a spectral hole burning memory. This microparticle hole burning memory, which can be both written and read at room temperature, is a direct consequence of the properties of morphology-dependent resonances of microparticles. PMID- 19773954 TI - Efficient multilevel phase holograms for CO(2) lasers. AB - Multilevel phase holograms for monochromatic radiation at a wavelength of 10.6 microm are recorded as surface relief gratings with multilevel discrete binary steps. Our experiments show that diffraction efficiencies close to 90% can be achieved both for transmissive and reflective elements. The reduction of efficiency due to errors in the depth and the width of the step levels is considered. PMID- 19773955 TI - Scale-factor-stabilized fiber-optic gyroscope based on a spectrum-broadened laser diode source. AB - A spectrum-broadened laser-diode source that uses the optical feedback and current-modulation effects has been adopted as the light source of a fiber-optic gyroscope to reduce the inherent phase noise. The scale factor of the gyroscope has also been stabilized. PMID- 19773956 TI - Accurate design of a noncollinear acousto-optic tunable filter. AB - The analysis of a noncollinear acousto-optic tunable filter commonly found in the literature is based on an approximation for the birefringence of the interaction material. It is demonstrated that this approximation leads to a significant error in calculating the optimum incident angle for a device, which can seriously degrade its performance if a fixed output beam angle is required. An alternative, exact analysis is presented and compared with experimental results. PMID- 19773957 TI - Thermal noise spectrum of a fiber-optic magnetostrictive transducer. AB - We report the observation of the thermal equilibrium strain fluctuation spectrum in a transducer using a fiber interferometer. The thermal noise power spectrum in the range of 20-30 kHz of the metallic glass cylinder in this experiment is determined by the dynamic elastic susceptibility and has peak value corresponding to approximately 0.8 microrad/ radicalHZ at 25.5 kHz. The data are analyzed by using the fluctuation-dissipation theorem and a coupled-mode model for dynamic response in metallic glass. PMID- 19773958 TI - All-fiber optical frequency shifter. AB - A new type of all-fiber frequency shifter is demonstrated. It is capable of operation at lower frequencies than traditional approaches based on surface acoustic waves and is believed to be unique in not requiring the removal of the fiber buffer coat. For 2.3-W electrical drive the prototype achieved a 2.5% conversion efficiency and greater than 20-dB unwanted sideband suppression. PMID- 19773959 TI - Ultrafast all-optical deflection based on an induced area modulation in nonlinear materials. AB - A novel all-optical area-modulation scheme is suggested and experimentally demonstrated. In a mutually perpendicular interaction geometry inside a nonlinear material, the signal beam, which passes through an induced temporal prism formed by an area-modulated optical pump beam, undergoes a spatial phase modulation that leads to a beam deflection. Advantages and potential applications of the new all optical modulation are addressed. PMID- 19773960 TI - Preparation of optical fibers for effective second-harmonic generation by the poling technique. AB - A new model of the process of preparing optical fibers for effective second harmonic generation by the poling technique is presented. The model is based on the idea that the formation of a second-order susceptibility [X((2))] structure is a consequence of a nonlinear anisotropic optoelectric hysteresis of doped fibers. Strings of interconnected dopant defects are assumed to be oriented along the fiber, which necessitates the formation of a X((2)) structure with periodically alternating sign. PMID- 19773961 TI - Nonlinear wave propagation in optically active and birefringent media. AB - It is shown that nonlinear wave propagation in optically active and birefringent media can be described by means of an extended version of the so-called massive Thirring model, which is known to exhibit solitary-wave solutions. PMID- 19773963 TI - Nondegenerate two-wave mixing in GdAIO(3):Cr(3+). AB - We have measured the nearly degenerate two-wave mixing in GdAlO(3):Cr(3+) crystals. In contrast to that in other chromium-doped materials, the signal in this sample arises from a mixed phase absorption grating where the absorption contribution is intensity dependent. The real (n(2)') and the imaginary (n(2)'') parts of the nonlinear index of refraction, the saturation intensity, and the excited-state lifetime are determined. The ratio r = n(2)''/n(2)' changes linearly with the intensity. Owing to saturation, the grating presents anharmonicities that give rise to self-diffracted beams (forward four-wave mixing). For comparison, results are also presented for ruby and alexandrite. PMID- 19773962 TI - Generation of continuous-wave ultraviolet light by sum-frequency mixing of diode laser and argon-ion-laser radiation in beta-BaB(2)O(4). AB - More than 1 microW of tunable continuous-wave radiation at 369 nm has been generated by sum-frequency mixing of the radiation from a 1310-nm diode laser with the radiation from a 515-nm argon-ion laser in a beta-BaB(2)O(4) crystal. The phase-mismatching tolerance for nearly optimum focusing of input beams was found to be several times as large as that for no focusing or the calculated value. This effect was caused by relatively large double refraction of beta BaB(2)O(4). PMID- 19773964 TI - Reciprocity in photorefractive wave mixing. AB - We consider the validity of the reciprocity theorem as applied to steady-state photorefractive wave mixing. constants of integration in four-wave mixing are physically interpreted as results of reciprocity. PMID- 19773965 TI - Large nonresonant light-induced refractive-index changes in thin films of amorphous arsenic sulfide. AB - We have measured a light-intensity-dependent change in the refractive index of thin films of the amorphous semiconductor arsenic sulfide. In a novel type of nonlinearity, strongly absorbed light produces a relatively large change in the optical properties of the material at wavelengths where the absorption is weak. This represents a compromise between the large resonant nonlinearities found in crystalline semiconductors, which have the disadvantage of large signal attenuation, and the nonresonant nonlinearities, which occur at wavelengths with low absorption but are small. PMID- 19773966 TI - Dispersion-related amplification in a nonlinear fiber pumped by counterpropagating waves. AB - We investigate the dispersion-related amplification induced by two counterpropagating waves in a nonlinear fiber and demonstrate that this system can provide broadband (of the order of terahertz) and large (>10(5)) amplification even in the presence of absorption, with the pumping significantly below the threshold of instability. PMID- 19773967 TI - Polarimetric analysis of two-mode, elliptical-core optical fibers. AB - We show that linearly polarized light launched at different angles with respect to the major axis of a two-mode, elliptical-core fiber results in an amplitude modulated beat-length pattern in the far field. The variation of the output pattern is explained theoretically and confirmed experimentally. A polarizer placed at the output of the fiber is shown to eliminate the amplitude modulation in the output signal. A simple theoretical model, based on the weakly guiding assumption, is shown to be helpful in determining few-mode fiber sensor parameters in practical systems. PMID- 19773968 TI - Evolution of the bandwidth of the principal states of polarization in single-mode fibers. AB - The bandwidth in which the first-order approximation of the principal states of polarization of a single-mode fiber can be assumed valid is examined. The principal states of polarization and their bandwidth are found for a fiber with both constant coupling and birefringence, and the relationship with the fiber's eigenmodes is examined. On the basis of these results, a fiber cascade is analyzed, and a Monte Carlo simulation provides theoretical values of the bandwidth that have been experimentally verified on a 2-km-long concatenation of single-mode dispersion-shifted fibers. PMID- 19773969 TI - Optical power transfer in vertically integrated impedance-matched waveguide/photodetectors: physics and implications for diode-length reduction. AB - We identify the physical basis of the irregular absorption (spatial transients) observed in vertically integrated and impedance-matched waveguide/photodiodes using numerical simulations. We then show how the mechanism underlying these transients can be exploited to design diodes 500% shorter than conventional evanescently coupled waveguide/photodiodes, in order to achieve low capacitance and high-speed operation. PMID- 19773970 TI - Four-channel Ti:LiNbO(3) wavelength division multiplexer for 1.3-microm wavelength operation. AB - A four-channel Ti:LiNbO(3) wavelength division multiplexer (WDM) that uses cascaded two-mode-interference dual-channel WDM waveguide structures was demonstrated. Its implementation in integrated-optic form affords ease of fabrication, voltage tunability, and the potential for combining other devices for different functions on the same chip. The device was operated in the wavelength region of 1.3 microm. The channel spacings ranged from 12 to 15 nm. The channel wavelengths can be electro-optically tuned at the rate of 1 nm/V. The cross talk was measured to be less than -20 dB. PMID- 19773971 TI - M modes in a diode side-pumped Nd:glass slab laser. AB - We have operated a pulsed Nd:glass slab laser in a hemiconfocal cavity with beam stops to produce a multibounce beam in the shape of the letter M. This configuration permits the extraction of diffraction-limited beams from a large volume of the slab. The output of the slab was in four beams, and the optical slope efficiency was 14%. PMID- 19773972 TI - High-power single-mode diode-pumped Nd:YAG laser using a monolithic nonplanar ring resonator. AB - A 0.91-W single-frequency diode-pumped Nd:YAG laser at 1.06 microm is demonstrated with a TEM(00) output. We also report a 60% slope efficiency from another nonplanar monolithic ring laser with diffraction-limited, single frequency, 1.06-microm output. Injection locking of two 0.17-W monolithic nonplanar ring resonators gave 0.34 W of single-mode power. Actively controlled injection locking of two lasers was demonstrated for indefinite periods. PMID- 19773973 TI - Ion-implanted Nd:MgO:LiNbO(3) planar waveguide laser. AB - Laser oscillation in an ion-implanted planar Nd:MgO:LiNbO(3) waveguide is demonstrated for the first time to our knowledge. Details of the waveguide structure, spectroscopic properties, photorefractive effects, and laser performance are given. A simple calculation of the absorbed power threshold gives ~8 mW, in fair agreement with the experimental value of ~17 mW. PMID- 19773974 TI - All-optical time-domain chirp switches. AB - We describe a novel architecture for an all-optical time-domain chirp switch in which digital logic is based on timeshift keying. This architecture is a generalization of fiber soliton-dragging logic gates that have a switching energy approaching 1 pJ. By using solitons we separate the nonlinear chirping from the time shifting and, consequently, reduce the required phase shift during the nonlinear interaction. We discuss the scaling laws for energy and latency versus pulse width and show that the chirp switches have low switching energies for high bit-rate applications. PMID- 19773975 TI - Two-dimensional imaging through diffusing media using 150-fs gated electronic holography techniques. AB - We combine 150-fs holographic gating with specifically adapted electronic holography techniques to produce transmission images of objects embedded in diffusing material. The technique captures, without the use of scanning procedures, complete two-dimensional images with 150-fs temporal resolution, thereby yielding submillimeter spatial resolution through diffusing objects several centimeters thick. PMID- 19773976 TI - Prepulse energy suppression for high-energy ultrashort pulses using self-induced plasma shuttering. AB - We demonstrate the technique of self-induced plasma shuttering as a means of suppressing prepulse energy that accompanies high-energy, ultrashort laser pulses. This technique makes possible the generation of clean, high-intensity subpicosecond laser pulses even in the presence of high levels of amplified spontaneous emission from the laser system. Low prepulse energy is important in applications such as the generation of solid-density subpico-second plasmas. PMID- 19773977 TI - Antiresonant-ring transient spectroscopy. AB - We show theoretically and experimentally that the antiresonant ring is a versatile detection arrangement in ultrafast spectroscopy that permits accurate optical subtraction of probe-laser background light, independent measurement of absorption and refractive-index transients through optical heterodyning, and improvement of signal-to-noise ratios. In addition, because the sample medium is placed off center in the ring, it also permits tunable high-pass filter operation: signals from effects with time scales longer than twice the light travel time from the sample to the ring center can be suppressed. PMID- 19773978 TI - Effect of degenerate four-wave mixing on pulse amplification and compression in the degenerate cross-phase-modulation process. AB - The results of pulse compression using degenerate cross-phase modulation with and without degenerate four-wave mixing are compared. We show that the weak pulse can be amplified by the strong pump pulses through degenerate four-wave mixing, which improves the compression effect with the use of group-velocity dispersion. PMID- 19773979 TI - Two-photon absorption in diamond and its application to ultraviolet femtosecond pulse-width measurement. AB - Intensity-dependent transmission measurements of 310-nm femtosecond pulses show that diamond has a twophoton absorption coefficient of 0.75 +/- 0.15 cm/GW, in approximate agreement with universal scaling formulas for two-photon absorption in diamond-structure materials. We then demonstrate that two-photon absorption is strong enough to permit simple measurements of ultraviolet femtosecond pulse widths in single-crystal diamond plates that are thin enough (250 microm) to be both inexpensive and dispersion free. Autocorrelation measurements of 10-50-nJ, 0.18-1.4-ps pulses are presented. The method requires no phase matching and can be applied to pulses in the wavelength range of 220-550 nm. PMID- 19773980 TI - Mode locking with cross-phase and self-phase modulation. AB - Cross-phase and self-phase modulation are used for self-sustained mode locking of a high-power neodymium glass fiber laser. Stable pulses with a FWHM as short as 70 fs and pulse energies of as much as 1 nJ are generated at a wavelength of 1.064 microm. PMID- 19773981 TI - Mode locking of a Nd:YAlO(3) laser at the 1.34-microm transition by a second harmonic nonlinear mirror. AB - A second-harmonic nonlinear mirror formed by a LiIO(3) frequency doubler and a dichroic output mirror is employed to mode lock the 1.34-microm transition of a pulsed Nd:YAlO(3) laser. Pulses of 15-ps duration are reliably generated simultaneously at 1.34 and 0.67 microm. PMID- 19773982 TI - Design of optimal binary phase and amplitude filters for maximization of correlation peak sharpness. AB - Current binary phase filters used for optical correlation are usually assumed to have uniform amplitude transmission. Here a new type of filter is studied, the binary phase and amplitude filter. If binary phase values of 0 and pi are assumed, the amplitude transmittance values of this type of filter may be optimized to maximize the peak sharpness. For a polarization-encoded binary phase filter this can be translated into optimization of the rotation angle of the output polarizer following the filter spatial light modulator. An analytic expression is presented for the optimum polarizer angle and thus for the optimum binary phase and amplitude filter design. PMID- 19773983 TI - Simultaneous measurement of absorption lines for right and left circularly polarized fields using saturation spectroscopy. AB - By employing a Doppler-free saturation spectroscopic method, absorption lines for the left and the right circular polarizations have been measured simultaneously at the sodium D(1) line that was pumped by a circularly polarized beam. These experimental results are compared with theoretical results obtained with the velocity-selective optical pumping effect in a four-level atomic system. The effects of the pump-beam intensity on the signal spectra are also investigated. PMID- 19773984 TI - Laser detection of the rare isotope (3)He at concentrations as low as 10(-9). AB - The method of collinear laser photoionization of atoms in a modulated fast beam is used to detect the rare isotope (3)He, with high-repetition-rate lasers being applied to improve the detection sensitivity. The method has made it possible to detect (3)He at relative abundances as low as 10(-9). PMID- 19773985 TI - Frequency-chirped copropagating multiple-bit stimulated-echo storage and retrieval in Pr(3+):YAlO(3). AB - Using a frequency-chirped ring dye laser, we have stored and recalled as much as 48 bits of information with the copropagating stimulated-echo geometry on the (3)H(4)-(1)D(2) transition in Pr(3+):YAlO(3). Since the copropagating excitation scheme has all the excitation pulses spatially overlapping, this technique will be useful to the practical implementation of stimulated-echo memory because there is no need for alignment of beams. Our experiments also demonstrate that frequency chirping of the excitation pulses dramatically improves not only pulse shape reproduction by the echo pulse but also the shot-to-shot stability of the amplitude of the recalled data. PMID- 19773986 TI - Improvement in high-speed, large-area, multiple-exposure holography. AB - The method of encoding more than one large-area hologram on a single recording medium by changing the angle between the object beam and the reference beam between successive exposures is well established. We report an extension of this technique to record over 16 individual large-area holograms on a single emulsion plate by taking advantage of the characteristics inherent in a solution physical developer. The tests were carried out on 8E75-HD holographic plates with a short pulse ruby laser for high-speed recording. Multiple-image-plane doubled-exposure holographic interferograms were also obtained, and the results are presented. PMID- 19773987 TI - Holographic axilens: high resolution and long focal depth. AB - We report a novel aspheric holographic optical element, the holographic axilens, for achieving extended focal depth while keeping high lateral resolution. The element is designed according to special optimization techniques and recorded as a computer-generated hologram. The results for a specific element, which has a depth of focus of 30 mm, a lateral resolution of 80 microm, a focal length of 1250 mm, and a diameter of 12.5 mm at a wavelength of 633 nm, are presented. PMID- 19773988 TI - Near-resonant holography. AB - Experimental results of a new technique for measuring species concentration by using two-wavelength holography are described. The refractive-index difference between two pulsed dye-laser wavelengths tuned to the nearresonant region of atomic sodium is recorded on a hologram. For small wavelength differences, the nonresonance aberrations are subtracted out. PMID- 19773989 TI - Femtosecond ring dye laser: a potential new laser gyro. AB - Measurements on a passively mode-locked dye laser demonstrate a sensitive gyro type response, when Fresnel drag in air is used to simulate rotation. Such a response is unexpected for a homogeneously broadened ring laser. PMID- 19773990 TI - Electrically controlled polarization-independent liquid-crystal Fresnel lens arrays. AB - We describe the properties and construction of a polarization-independent Fresnel lens array using nematic liquid crystals in which the diffraction efficiency of lenses can be electrically controlled. A novel structure is used such that the principal axis of the liquid crystals in two adjacent zones of each Fresnel lens are orthogonal. This makes the device polarization independent. We have characterized these lenses at different applied fields and input polarizations by diffracting an argon-ion beam into focus. PMID- 19773991 TI - All-fiber ring soliton laser mode locked with a nonlinear mirror. AB - An amplifying nonlinear-optical fiber loop mirror is used as the gain element in an all-fiber ring laser. The resulting double-loop structure resembles a figure eight. The output of the amplifying nonlinear-optical fiber loop mirror is fed back to the input through an optical isolator to ensure unidirectional operation. The laser produces 2-ps transform-limited pulses. The pulse energy corresponds to that of the fundamental soliton in the fiber used. PMID- 19773992 TI - Optical instability in noncollinear second-harmonic generation. AB - An analysis is made of second-harmonic generation in the scheme of noncollinear (vectorial) synchronism, where the second pump beam is built up from the first pump beam after it passes through the crystal. We find the threshold of self pulsations with this scheme. PMID- 19773993 TI - Double phase-conjugate mirror is not an oscillator. AB - The double phase-conjugate mirror is an oscillator in the framework of the one dimensional theoretical model previously used for its description. Results of a more consistent two-dimensional approach qualitatively differ from those of a one dimensional analysis, indicating that the double phase-conjugate mirror is a convective amplifier. The correct physical picture of the scattering development is revealed, and the transverse profiles of scattered beams and the dynamics of nonlinear reflectivity are calculated. PMID- 19773994 TI - Measurements for the nonlinear refractive index of a new kind of polymer material doped with chlorophyll using nanosecond laser pulses. AB - A new kind of organic polymer doped with natural active chlorophyll is made, and self-focusing and saturable absorption are observed on it under the excited laser light at 532 nm with a pulse width of 20 ns. The nonlinear refractive indices n(2), estimated to be ~10(-7) cm(2)/W, measured by two methods were consistent with each other. By analyzing the experimental data based on the glassy polymer dye model, it can be confirmed that the nonlinearity is induced by the transition of excited on-site pi electrons. PMID- 19773995 TI - Intensity-dependent thresholding and switching in the photorefractive bridge mutually pumped phase conjugator. AB - Beam-intensity-ratio-dependent effects have previously been observed in several photorefractive mixing configurations. Here we report the observation of total input-intensity-dependent effects in the bridge mutually pumped phase conjugator, which results in optical thresholding and switching behavior. The cause of these effects is attributed to competition between bridge conjugation and self-pumped phase conjugation that results from different exponents in their measured intensity-dependent response times (10-90%), namely, tau(bridge) alpha I(-0.79) and tau(SPPC) alpha I(-0.38). PMID- 19773996 TI - Fixing of a photorefractive grating in KTa(1-x)Nb(x)O(3) by cooling through the ferroelectric phase transition. AB - We report the fixing of a photorefractive grating in KTa(1-x)Nb(x)O(3). The procedure involves the writing of a photorefractive grating in the cubic phase and the cooling of the sample under an applied field into the rhombohedral phase. We discuss possible mechanisms responsible for the effect. PMID- 19773997 TI - Multiple four-wave mixing process in an optical fiber. AB - We report the results of a theoretical and experimental investigation of multiple four-wave mixing processes in the simultaneous propagation of two pump waves through an optical fiber. The pump waves at frequencies omega(1) and omega(2) are observed to generate sidebands at 2omega(2) - omega(1) and 2omega(1) - omega(2) owing to four-wave mixing in the fiber. The power in the sidebands is studied as a function of pump power and detuning. The experimental observations provide a direct verification of the theoretical formalism. PMID- 19773998 TI - Quasi-phase-matched multiwave mixing in a periodically poled ferroelectric crystal. AB - A method for realizing quasi-phase-matched multiwave mixing through second-order nonlinear susceptibilities of a periodically poled ferroelectric crystal is proposed. With an appropriate combination of light polarizations and the order of the quasi-phase-matching, all the nonlinear interactions involved are simultaneously phase matchable. Sample results predicted are shown for five-wave mixing in a periodically poled lithium niobate crystal. PMID- 19773999 TI - Induced superspike in an enhanced induced-phase-modulation two-dimensional nonlinear medium. AB - I show that a probe pulse that is copropagating in an enhanced induced-phase modulation nonlinear two-dimensional medium in the presence of a pump may be transformed into an induced superspike in time and space. The conditions of this induced collapse are that the ratio of the probe and pump initial transverse dimension to the duration be equal to 1/[beta((2))k(probe)]((1/2)), that their group velocities be equal, that the pump energy be larger than a waveguiding critical value, and that the probe central frequency be in the group-velocity dispersion anomalous region. PMID- 19774000 TI - Raman effect in birefringent optical fibers. AB - Equations governing the Raman effect in birefringent optical fibers are derived. Both the parallel and perpendicular Raman effects are taken into account. The evolution of solitons is discussed. PMID- 19774001 TI - Nd:YAG laser with a phase-conjugating mirror based on stimulated Brillouin scattering in SF(6) gas. AB - A Nd:YAG laser setup that uses SF(6) gas as a stimulated Brillouin scattering phase-conjugating mirror is described. Stable emission with 100-mJ output energy and a 15-ns pulse width in the TEM(00) mode has been obtained. PMID- 19774002 TI - Dynamics of circularly polarized eigenstates in lasers with nonweak atomic coupling. AB - It is shown theoretically and experimentally that the two circularly polarized eigenstates of a laser oscillating on a nonweak atomic coupling transition exhibit two types of vectorial bistability. A rotation and an inhibition mechanism are isolated, depending on the eigenfrequency difference of the two eigenstates. For both mechanisms, the evolution of the hysteresis loop with this frequency difference shows good agreement with a phenomenological Landau's potential model. PMID- 19774003 TI - Q-switched operation of microchip lasers. PMID- 19774004 TI - Frequency-modulated Nd:YAG laser. AB - A frequency-modulated, single-mode Nd:YAG laser has been constructed that tunes up to 12 GHz. The laser incorporates a LiTaO(3) electro-optic phase modulator with acoustic damping to provide a tuning sensitivity of 12 MHz/V and linear voltage-to-frequency conversion. A frequency excursion of 1.2 GHz has been generated with a rise time of 0.6 ns. PMID- 19774005 TI - Low-threshold, cw, all-solid-state Ti:Al(2)O(3) laser. AB - A cw Ti:A1(2)O(3) ring laser with a threshold power of 119 mW is demonstrated. It provides a tunable source of single-frequency, diffraction-limited radiation that is suitable for injection seeding. The Ti:A1(2)O(3) laser is operated with a diode-laser-pumped, frequency-doubled, Nd:YAG laser as the sole pump source. PMID- 19774006 TI - Efficient, 15-W output power, diode-end-pumped Nd:YAG laser. AB - The design and performance of a 15-W output-power, diode-pumped cw Nd:YAG laser is described. With the use of geometrically multiplexed end pumping, the combined power of four 10-W diode-laser bars is deposited in the active-medium mode volume with an efficiency of 80%. While operating on several transverse modes the laser has a threshold of 3 W, an optical slope efficiency of 60%, and an overall electrical efficiency of 10.5%. Thermally induced higher-order spherical aberration of 1.2 waves limits the output power in the TEM(00) mode to approximately 6 W. PMID- 19774007 TI - Induced waveguiding effects in a two-dimensional nonlinear medium. AB - I compute the invariant spatial configurations and their spatial Fourier transforms for a weak probe propagating in a two-dimensional X((3)) medium in the presence of a spatial optical soliton pump. The number of these configurations increases in an enhanced induced-phase-modulation medium. PMID- 19774008 TI - Ultrafast gain quenching in laser amplifiers. AB - A versatile and simple passive optical technique for quenching gain in laser amplifiers on picosecond and subpicosecond time scales is described. The scheme can be used to eliminate undesirable postpulses or to reduce laser pulse widths. A 30-fold suppression of satellite pulses from a synchronously pumped amplified dye laser is demonstrated. PMID- 19774009 TI - Prechirper to relax the timing restrictions for soliton-dragging logic gates. AB - The timing restrictions for soliton-dragging logic gates can be relaxed by asymmetrizing the interaction between the orthogonally polarized control and signal pulses. In particular, by prechirping the signal pulse in a normal group velocity dispersion fiber, we find experimentally that the timing restriction can be loosened from less than 2 pulse widths to over 3.3 pulse widths. For this passive prechirper arrangement the timing restrictions are loosened at the expense of increased minimum switching energy. Soliton-dragging logic gates with a signal prechirper can provide timing restoration as well as logic-level restoration, so that two inverter gates can be cascaded to implement an ultrafast, all-optical pulse regenerator. PMID- 19774010 TI - Effects of laser coherence on coupling efficiency for the double phase-conjugate mirror. AB - We present the results of an experimental study of the effects of laser coherence on the operation of the double phase-conjugate mirror using barium titanate as the nonlinear medium. In our experiment the two input beams that drive the interaction originate from a single helium-neon laser, and the degree of coherence between the input beams at the crystal is varied through the use of a time-dependent phase delay in one of the beam paths. As the two input beams make the transition from being mutually incoherent to mutually coherent, the phase conjugate reflectivity decreases dramatically and becomes unstable. These results are significant to laser phase-locking applications where changes in the coupling intensity can affect the quality of phase locking. PMID- 19774011 TI - Discrete correlators using multiple imaging for digital optical computing. AB - New optical discrete correlators based on multiple-imaging systems with a simple structure and good stability are proposed. The systems are composed of lenses for image duplication and optical shutters for kernel specification. As a result, large throughput can be attained with an incoherent configuration. The throughput of the system is estimated, and several logic operations are demonstrated to verify the usefulness of the proposed systems for digital optical computing. The proposed system will be especially useful for constructing a compact and stable optical computing system. PMID- 19774012 TI - Continuous-wave stimulated Raman scattering. AB - We report what is to our knowledge the first observation of continuous-wave stimulated Raman scattering (SRS). Both forward and enhanced backward SRS were observed in liquids, and the large spectral frequency shift between pump and probe makes signal detection easy. No separate collection optics are necessary for the backscattered SRS, whose signal-to-noise ratio is much improved compared with that measured by forward or side scatter. This is attributed to the existence of a phase-conjugate beam. Higher orders of Stokes scattering are also observed in return. Contrary to theoretical expectation, both forward-scattered and backscattered signals have identical gains owing to saturation effects in a number of the high-gain liquids studied. PMID- 19774013 TI - Storage of 500 high-resolution holograms in a LiNbO(3) crystal. AB - We have recorded (at room temperature) as many as 500 high-resolution, uniformly diffracting volume holograms in a single Fe-doped LiNbO(3) crystal. The holograms were stored by angularly multiplexing a plane-wave reference beam. The graphical procedure that we used to compute exposure schedules is described. Experimental results are also presented. PMID- 19774014 TI - Surface absorption measurements of thin films by cavity-enhanced photothermal spectroscopy. AB - Cavity-enhanced photothermal spectroscopy has been applied to perform ultrasensitive absorption measurements on thin metallic and high-reflectivity dielectric films. The novel method can be employed to determine minute surface specific absorbances of alpha in the range of a few parts in 10(6) and has high sensitivity since the sample is placed inside a resonant optical cavity. Spatial , spectral-, and time-resolved measurements were carried out. Laser surface heating calculations have been performed and can be evaluated to yield the thermal diffusivity of the thin films with a resolution at the level of a few micrometers. PMID- 19774015 TI - Variable-sensitivity photodetector that uses a metal-semiconductor-metal structure for optical neural networks. AB - A novel type of photodetector called a variable-sensitivity photodetector has been developed for optical implementation of neural networks. It utilizes a metal semiconductor-metal structure whose quantum efficiency can be modulated by an applied bias voltage. A linear dependence of the sensitivity on the bias voltage was obtained with the bipolar current flow. This device operated as a multiplier of the incident light intensity and the bias voltage. It is shown that this device is suitable for achieving dynamic synaptic interconnections. A 4 x 4 array device was fabricated and demonstrated. PMID- 19774016 TI - Hybrid fiber-optic sensor using true heterodyne measurement techniques. AB - We describe a hybrid, coherent, fiber-optic sensor for the measurement of phenomena that lead to birefringence, polarization rotation, or differential phase shifts in a remote-sensing element. By utilizing a single fiber that carries two orthogonally linearly polarized laser beams of different frequencies to the sensor and true heterodyne detection, we obtain high common-mode rejection of any unwanted intrinsic sensitivity of the fiber itself. The sensor is resistant to fading and has a high dynamic range. For demodulation we use high frequency phase-locked loop detection that is insensitive to slowly varying phase shifts. PMID- 19774017 TI - Construction and test of phase zone plates for x-ray microscopy. AB - We report the construction and test of an x-ray phase zone plate with 0.1-microm imaging resolution and >14% diffraction efficiency. The zone plate served as the focusing optic in a scanning microscope that operated in the water window, 2.5 nm < lambda < 4.5 nm, and therefore is optimally suited for imaging wet biological specimens. We enhanced the efficiency of the zone plate by using germanium for the absorbing zones, so that some of the incident radiation is transmitted with the correct phase shift to interfere constructively at the focal spot. The zone plate was supported on a relatively transparent membrane, giving the microscope a high absolute throughput. PMID- 19774018 TI - Transparent boundary condition for beam propagation. AB - A new boundary condition algorithm is presented that passes outgoing radiation freely with a minimum reflection coefficient (typically 10(-5)) while inhibiting the flux of incoming radiation. In contrast to the commonly used absorber method, this algorithm contains no adjustable parameters and is thus problem independent. It adapts naturally to a standard Crank-Nicholson difference scheme and is shown to be accurate and robust for both two-and three-dimensional problems. PMID- 19774019 TI - Design of an anamorphic gradient-index lens to correct astigmatism of Gaussian laser beams. AB - Diode lasers are often used as light sources for transmitting information through optical fibers. One of the inherent properties of this kind of laser is the astigmatism. Therefore, in applications that require focusing, an anamorphic system is needed. We present a theoretical study for the design of an anamorphic gradient-index lens to correct the astigmatism of the elliptical Gaussian beams emitted by diode lasers. PMID- 19774020 TI - Method to determine the phase dispersion of the third-order susceptibility. AB - A new method for measuring the phase of the third-order susceptibility chi((3)) that is based on the phenomenon of polarization beats is proposed and demonstrated. As a first application, the method was employed to study the phase dispersion of chi((3)) in Cd(S, Se)-doped glasses. PMID- 19774021 TI - Extraordinary-polarized light does not always yield the highest reflectivity in self-pumped BaTiO(3). AB - For certain input geometries it is possible to double the phase-conjugate reflectivity of the self-pumped (cat) phase conjugator in BaTiO(3) by the inclusion of an ordinary-polarized component in the input beam. It is also shown that it is possible to control the power in the phase-conjugate output with an overall gain. The observed enhancement is attributed to erasure of competing parasitic gratings by the ordinary-polarized component. PMID- 19774022 TI - Normalized parameters for Y-branch optical waveguides. AB - Y-branch optical waveguides are analyzed in terms of normalized parameters by means of the usual modal analysis. With these parameters the number of variables of the problem is reduced, and universal plots for the mode conversion are obtained. Our results show that the normalized parameters are useful for the design of branching waveguides more tolerant of fabrication errors. PMID- 19774023 TI - Frequency-domain analysis of the mode-locking process in a laser with a second harmonic nonlinear mirror. AB - We present a computer simulation of the mode-locking process in a pulsed Nd:YAG laser with a nonlinear mirror based on second-harmonic generation. For the first time to our knowledge, a frequency-domain description of the passive mode-locking process is presented, which provides complete information for the amplitude and phase evolution of the individual modes. The mode locking is described as being due to the interaction of the longitudinal modes in the nonlinear mirror through second-harmonic and sum- and difference-frequency generation. PMID- 19774025 TI - Remote image classification through multimode optical fiber using a neural network. PMID- 19774024 TI - Q-switched Nd:YAG laser with super-Gaussian resonators. AB - An unstable resonator that uses radially variable-reflectivity mirrors of super Gaussian profile has been used in a Nd:YAG laser in the Q-switching regime. Three reflectivity profiles, corresponding to different super-Gaussian orders, have been tested. The output energy increases with the super-Gaussian order and can be higher than that of a traditional stable multimode resonator. The output beams are diffraction limited, showing only moderate spreading of energy out of the central lobe in the far field. PMID- 19774026 TI - Genetic algorithm for optical pattern recognition. AB - A genetic algorithm is used to generate binary reference functions for optical pattern recognition and classification. Procedures based on the properties of convex functions can be implemented directly on hybrid electro-optical systems. Computer simulations demonstrate the efficiency of this novel approach. PMID- 19774027 TI - Bacteriorhodopsin films as spatial light modulators for nonlinear-optical filtering. AB - The application of dry purple membrane films for nonlinear-optical filtering is described. The biological photochrome bacteriorhodopsin (BR) is contained in the purple membrane (PM) from Halobacterium halobium. BR has two dominant photoactive states, B and M, which have well-separated absorption bands with maxima at 570 nm (B) and 412 nm (M). Since the local transmission of a PM film depends on the ratio between the forward (B ? M) and the backward (M ? B) photoreactions, PM films can be used as light-controlled absorptive spatial light modulators. A model describing the nonlinear transmission of PM films containing the wild-type form of BR or one of its mutated variants, e.g., BR(D96N), and examples of their application in spatial filtering, e.g., edge enhancement, are presented. PMID- 19774028 TI - Effective hybrid processor to compute image moments for pattern recognition. AB - A hybrid optical-digital processor is presented for computing the invariant moments of images in real time, which consists of a holographic mask, two lenses, a charge-coupled-device detector, and a microcomputer. The processor is tested by inputting some roman letters, and the produced results show that the invariant moments of a letter are approximately independent of shift and rotation and that the moments are distinct with different letters. PMID- 19774029 TI - Saturation splitting of line shapes in noncollinear four-wave mixing in SF(6). AB - Phase-conjugate emission by resonant degenerate four-wave mixing with two counterpropagating weak pump beams and a noncollinear strong object beam was calculated for a Doppler-broadened two-level system. Singlepeak Doppler-free lines with small saturation broadening at a collinear configuration became split for a wide angle. The effect is demonstrated with the use of a CO(2) laser and SF(6). Conversely, calculated line shapes with Stark splitting in a collinear arrangement became single peaked for a wide angle. PMID- 19774031 TI - Squeezing in fibers with optical pulses. AB - A novel method of squeezing with optical pulses in a fiber ring reflector is demonstrated experimentally. Squeezing of greater than 5 +/- 0.3 dB has been observed. The pump is separated from the squeezed radiation with a fiber ring reflector and can be reused, in principle fully, as the local oscillator. The detection is at low frequencies (35-85 kHz) and is unaffected by guided-acoustic wave Brillouin scattering. PMID- 19774030 TI - Two-dimensional imaging of molecular hydrogen in H(2)-air diffusion flames using two-photon laser-induced fluorescence. AB - We report the use of a tunable ArF laser at 193.26 nm to record simultaneous single-laser-shot, planar images of molecular hydrogen and hot oxygen in a turbulent H(2)-air diffusion flame. Excitation spectra of fuel and oxidantrich flame zones confirm a partial overlap of the two-photon H(2) (6,0) Q(1) E, F ? X and single-photon O(2) (10,2) R(17) B ? X (Schumann-Runge) absorption bands. UV Rayleigh scattering images of flame structure and estimated detection limits for the H(2) two-photon imaging are also presented. PMID- 19774032 TI - Lase-induced grating measurements of energy migration in Tm,Ho:YAG. AB - We report what is to our knowledge the first direct measurement of spatial energy migration among the Tm(3+) ions in a Tm,Ho:YAG crystal at room temperature. Four wave mixing techniques were used to establish and probe transient laser-induced population gratings in the Tm(3+) ions. The grating decay rate was measured as a function of the grating spacing. The results show the presence of spatial energy migration among the Tm(3+) ions, and the diffusion coefficient of this process was measured to be 4 x 10(-7) cm(2) s(-1) for a sample containing 8.3 x 10(20) cm(-3) Tm(3+) ions. PMID- 19774033 TI - Application of fiber holography to associative memory. AB - An application of two photorefractive crystal fibers connected in cascade to heteroassociative memory is experimentally demonstrated. The crystal is iron doped lithium niobate. The crystal fiber parameters are 1 mm x 1 mm in cross section and 5 mm in length. An angular multiple-recording technique is used to record Fourier-transformed images. It is shown experimentally that this fiber holography can be used as an alternative to bulk photorefractive crystals in optical memory devices. PMID- 19774034 TI - Photorefractive hologram writing with modulation 1. AB - The photorefractive recording process as described by Kukhtarev's material equations is investigated for large modulation depths. We find that for modulation 1 the density N(+)(D) of ionized traps at the dark sites is zero in the steady state if dark conductivity can be neglected. Therefore, in this case, it is essential to take the depletion of ionized traps into account. PMID- 19774035 TI - Optical interconnection method for neural networks using self-pumped phase conjugate mirrors. AB - We describe an optical interconnection method based on self-pumped phase conjugate mirrors in which each connection weight is distributed among many angularly and spatially multiplexed gratings. This approach greatly reduces cross talk caused by the conical Bragg degeneracy associated with a single grating and permits the entire input plane to be used. Applications to optical neural networks are described. PMID- 19774036 TI - High-dynamic-range heterodyne measurement of optical spectra. AB - The dynamic range of a conventional heterodyne spectroscope is limited by the intensity noise and the shot noise of the optical spectrum under test. We propose to improve the dynamic range by several orders of magnitude by using phase sensitive detection. We demonstrate the feasibility of our method by measuring the tails of a distributedfeedback laser line 60 dB below maximum, which gave an improvement of 35 dB compared with that of the conventional technique: 15 dB by using a balanced receiver and another 20 dB by the phase-sensitive detection. PMID- 19774037 TI - Efficient optical parametric oscillator at 1.6 microm. AB - We extend the operating regime of diode-pumped Nd:YAG lasers into the eye-safe region at 1.61 microm by using an efficient optical parametric oscillator in KTP. Total energy conversion efficiencies of the 1.06-microm pump to 1.61-microm signal and 3.1-microm idler approach 40%, with 25% converson to 1.61microm alone. This device has a wallplug efficiency of 0.8%, producing 2.5-mJ output energies at an eye-safe wavelength, and is readily scalable to higher energies. PMID- 19774038 TI - Design of multilevel thin-film phase gratings with optimized diffraction efficiency. AB - An analytical discussion of the thin-film design optimization for high-efficiency multilevel phase gratings is presented. The results permit the determination of the thin-film optimum thickness and refraction index in order to obtain high efficiency in phase-only diffractive optical elements. PMID- 19774039 TI - Geometrical separation between the birefringence components in Faraday-rotation fiber-optic current sensors. AB - A novel optical fiber current sensor for low-current measurements is proposed and tested. By winding a commonly used low-birefringence single-mode optical fiber in a special geometry, one can circumvent the bend-induced birefringence problem. Smaller sensors can now be built with a sensitivity that linearly increases with the number of fiber windings. PMID- 19774040 TI - Variable attenuator for intense unpolarized laser beams. AB - Utilization of polarizing optics for dynamic attenuation of intense unpolarized laser beams is reported. The new family of variable attenuator is composed of a retardation plate mounted between two identical polarization splitters placed in tandem. By varying the retardation, or by rotating the plate, the transmission is varied. These attenuators are characterized by a high transmission and a high optical damage threshold. A transmission dynamic range as large as 1 to 10(-5) is achievable with polarization splitters made of crystals such as sapphire. These attenuators are applicable in laser material processing and in Q switching of unpolarized lasers. PMID- 19774041 TI - Coherent effects in the scattering of light from random surfaces with symmetry: erratum. PMID- 19774042 TI - Organic quarter-wave stack filter fabricated by Langmuir-Blodgett deposition. AB - The fabrication and characterization of an optical interference filter formed using organic materials deposited by the Langmuir-Blodgett technique are described. The measured filter response is in good agreement with the calculated response. PMID- 19774043 TI - Phase-matched second-harmonic generation in a four-layer 2-methyl-4-nitroaniline waveguide with grating couplers. AB - A four-layer 2-methyl-4-nitroaniline (MNA) crystal waveguide device with grating couplers is fabricated. Second-harmonic generation is observed under phase matching conditions using the mode dispersion curves of the optical waveguide. A second-harmonic generation conversion efficiency in the waveguide of 0.71% is obtained with a grating coupling efficiency of 11.4% and a decoupling efficiency of 43.2%. The MNA single crystal is never damaged mechanically, and it has been kept stable for nine months. PMID- 19774044 TI - Near-diffraction-limited single-lobe emission from a high-power diode-laser array coupled to a photorefractive self-pumped phase-conjugate mirror. AB - Details of a 20-stripe, 1-W diode-laser array coupled to a photorefractive self pumped phase-conjugate mirror in a self-injection-locking geometry are discussed. Single-lobe emission is observed, with 75% of the array output in an ~2.2 times diffraction-limited beam, for array output powers of as much as 450 mW. PMID- 19774045 TI - Photorefractive two-beam coupling with white light. AB - We demonstrate, for the first time to our knowledge, two-beam coupling in BaTiO(3) using white light. An achromatic grating arrangement in conjunction with a high-pressure mercury-arc lamp is used to produce the white-light fringes. The sensitivity of the coupling to source coherence, crystal orientation, and grating spacing is determined, and a comparison with two-beam coupling with monochromatic light at the same intensity is made. PMID- 19774046 TI - Polarization noise suppression in retracing optical fiber circuits. AB - A novel scheme is proposed in which the presence of a Faraday rotator in a retracing fiber-optic circuit allows the complete, passive, and universal compensation of any birefringence (reciprocal) change occurring in the fiber. The action of the scheme was experimentally tested by inducing thermal and mechanical perturbations on a fiber coil. The results confirm the theoretical expectations and compensating for unwanted birefringence effects. PMID- 19774047 TI - Performance of the effective-index method for the analysis of dielectric waveguides. AB - An asymptotic study of the effective-index method for the analysis of rectangular core dielectric waveguides is given. Two ways of applying the effective-index method, depending on how the effective index is calculated, are considered, and expressions for the errors in the calculation of the propagation constant are derived. These expressions show explicitly how the accuracy of the method varies with the normalized frequency, the mode orders, the dimensions of the waveguide, and the relative refractive indices of the core and the surrounding media. Many novel properties of the method are revealed by these expressions. For example, it can be shown that the effective-index method can underestimate the propagation constant for a strip waveguide. PMID- 19774048 TI - Waveguide polarizers with hydrogenated amorphous silicon claddings. AB - We have fabricated TE- and TM-pass waveguide polarizers with polarization isolations of 42 and 35 dB, respectively. The devices were fabricated by the growth of hydrogenated amorphous silicon claddings on K(+)-Na(+) ionexchanged channel waveguides in glass. Cladding thicknesses were accurately tuned to permit optimum coupling of either a TE or a TM mode to the cladding. We have also demonstrated that a waveguide polarizer attenuation as high as 760 dB/cm can be measured by using a photothermal deflection technique. PMID- 19774049 TI - Surface plasmon-polariton waves guided by thin metal films. AB - Surface plasmon-polariton modes supported by thin metal films surrounded by dissimilar semi-infinite dielectrics are studied. The dispersion of the modes is evaluated, and their characteristics are investigated when the metal film thickness and the superstrate refractive index are varied. Long-range surface plasmon-polaritons are shown to be supported even by highly asymmetric configurations. PMID- 19774050 TI - Surface waves in chiral layers. AB - We analyze the surface-wave propagation in homogeneous layers of chiral or optically active materials. Two cases of chiral slab are considered: a symmetric chiral slab waveguide and a grounded chiral slab waveguide. The dispersion relation and the electric-field components for surface waves guided in a symmetric chiral slab are analyzed and discussed in detail. The plots of dispersion diagrams and normalized intensities of electric-field components of surface waves are given for both symmetric and grounded chiral slabs, and their novel features are pointed out. The effects of chirality on these diagrams and field components are discussed. Physical insights and potential applications of the results are addressed. PMID- 19774051 TI - Theory of mode-locked intracavity second-harmonic generation in a ring laser. AB - We model the dynamics of a Q-switched mode-locked intracavity second-harmonic generation (SHG) ring laser. Numerical studies show that a long train of constant pulse-duration short pulses at the second-harmonic and fundamental frequencies result. The efficiency of the mode-locked intracavity SHG laser is comparable with that of the mode-locked fundamental-frequency laser not containing SHG. PMID- 19774052 TI - Twin-guide Y-junction laser amplifier switches. AB - A simple analysis is presented of twin-stripe semiconductor Y-junction laser amplifier switches that operate through simultaneous changes in gain and refractive index due to free carrier injection. This shows that (in contrast to four-port directional coupler devices based on the same mechnism) good cross-talk performance may be obtained for a wide range of operating conditions. PMID- 19774054 TI - Effect of temperature on the performance of a bipolar transistor carrier-injected optical waveguide modulator/switch. AB - The effect of ambient temperature on the performance of a GaAs/AlGaAs heterojunction bipolar transistor waveguide structure carrier-injected optical intensity modulator/switch is discussed. An increase in the temperature increases the achievable optical modulation ratio at the expense of increased absorption loss, and vice versa. Analysis also shows that for practical use a tolerable temperature change should be no more than approximately 10 degrees C. PMID- 19774053 TI - Electronically tunable single-mode external-cavity diode laser. AB - A six-stage birefringent filter placed in an external cavity of an AlGaAs diode laser is used to scan the laser electronically over 10.3 nm, hopping single modes of the external cavity. Continuous electronic tuning of the single mode over the free spectral range of the external cavity, 182 MHz, is also demonstrated by using a variable-phase plate. All tuning mechanisms use nematic liquid-crystal electro-optic effects operating at <2 V. PMID- 19774055 TI - 50-fs pulse generation directly from a colliding-pulse mode-locked Ti:sapphire laser using an antiresonant ring mirror. AB - 50-fs pulses were directly generated from a colliding-pulse mode-locked Ti:sapphire laser. To achieve the collidingpulse mode locking, a miniature antiresonant ring containing an organic saturable dye jet was employed as the end mirror for the linear cavity laser. Based on measured dispersion of intracavity elements, a prism pair was implemented to control the cavity dispersion. The generated pulses have no linear chirp but do exhibit parabolic instantaneous frequency owing to third-order dispersion introduced by the prism pair. PMID- 19774056 TI - Detection of multipath effect using a self-pumped optical phase-conjugate filter. AB - A new optical Fourier domain filtering scheme that combines the conventional optical space-invariant linear filtering with a self-pumped nonlinear-optical phase-conjugation technique is proposed. The new method is used for a real-time detection and channel evaluation of the multipath information needed in radar, sonar, and communication signal-processing applications. Preliminary experimental demonstrations are included. PMID- 19774057 TI - Dynamic optical neurochip using variable-sensitivity photodiodes. AB - A novel type of a dynamic optical neurochip that uses sensitivity-variable photodiodes (VSPD's) as variable interconnection weight elements is proposed and analyzed. The chip consists of the line-shaped light-emitting diode array and the VSPD matrix array. A monolithic integration of these arrays is presented. This dynamic chip has advantages such as less optical cross talk, higher processing speed, and realization of analog synaptic weights. Also, experimental results of the VSPD array using metal-semiconductor-metal structure are shown. The results of the computer simulation using this chip as a learning element show that the unwanted effect of the optical cross talk on the recognition rate can be alleviated by the learning capability of the chip. It is also found that the theoretical maximum density is ~2000 neurons/cm(2) for the backpropagation model. PMID- 19774058 TI - Noise reduction using adaptive spatial filtering in photorefractive two-beam coupling. AB - We present an optical signal-processing technique for additive noise reduction that uses the noisy signal and a Gaussian reference beam to produce an adaptive Wiener filter. We experimentally demonstrate an improvement from 1 to 8 in the signal-to-noise ratio by using nonlinear gain in two-beam coupling in barium titanate to transmit 50% of the signal and 6% of the noise. PMID- 19774059 TI - Image subtraction using fixed holograms in photorefractive Bi(12)TiO(20) crystals. AB - A simple method for image subtraction by two-wave mixing in photorefractive cubic Bi(12)TiO(20) crystals is proposed and demonstrated. Intensity inversion and edge enhancement are also achieved. PMID- 19774060 TI - Application of the projection-onto-constraint-sets algorithm for optical pattern recognition. AB - Projection-onto-constraint sets is an efficient algorithm for constructing synthetic discriminant functions to be employed in pattern-recognition systems. The algorithm is implemented by a digital procedure based on a simulated joint transform correlator. PMID- 19774061 TI - Tunable squeezed-light generation from twin beams using an optical-phase feed forward scheme. AB - We analyze an optical-phase feed-forward scheme to produce a squeezed-light beam from intensity-correlated twin beams generated by nondegenerate parametric amplification. The quadrature measurement of the idler beam at the output of the parametric amplifier is linearly fed forward onto the output signal beam with an electro-optic phase modulator. The minimum available squeezing factor is shown to be 1/(2g - 1), where g is the parametric amplifier gain, and is equal to the nonclassical intensity-noise reduction factor of the original twin beams at the output of the parametric amplifier. By changing the frequency of the input signal beam, one can generate tunable squeezed light with this scheme for application in precision spectroscopy. PMID- 19774062 TI - Sign of chi((3)) in polysilane polymers. AB - The signs of the third-order optical nonlinear susceptibility chi((3)) of polysilane have been determined to be negative at 532 nm and positive at 1064 nm from single-beam Z-scan measurements. The small and positive chi((3)) at 1064 nm arises from the bound-electronic process. The negative chi((3)) at 532 nm is attributed to two-photon absorption resonance transition. PMID- 19774063 TI - Electronically scanned optical-fiber Young's white-light interferometer. AB - An optical-fiber version of Young's interferometer that uses a low-coherent-light source and a linear chargecoupled-device detector is described. With its unique, simple structure, this interferometer greatly reduces the spatial coherence mismatch from which other electronically scanned white-light interferometers suffer. Experimental results are presented for the use of this interferometer as a strain or temperature sensor with a large dynamic range. PMID- 19774064 TI - Spatial light modulators with super twisted nematic liquid crystals. PMID- 19774066 TI - Diffractive ferroelectric liquid-crystal shutters for unpolarized light. AB - Electro-optic modulators using ferroelectric liquid-crystal technology have generally been limited to use with polarized light. It is possible, however, to construct a diffractive array of ferroelectric liquid-crystal phase modulators that can act as a shutter for unpolarized light. We have built two types of polarization-independent diffractive shutter based on this principle. We describe their principles of operation and performance. PMID- 19774065 TI - Efficient ultraviolet LiB(3)O(5) optical parametric oscillator. AB - We report what is to our knowledge the first optical parametric oscillator (OPO) generating coherent laser radiation with high optical-to-optical conversion efficiency in the near ultraviolet. The OPO, pumped at 307.8 nm by a pulsed injection-seeded XeCl excimer laser, employs a crystal of LiB(3)O(5) in a noncritical phase-matching geometry to generate tunable output over the range 381 387 nm in the near ultraviolet and 1.5-1.6 microm in the near infrared. We report internal energy conversion efficiencies as high as 28% for the signal wave at 385.5 nm and 7% for the idler wave at 1.53 microm, leading to a total internal conversion efficiency of 35%. Studies of oscillation threshold, external and internal conversion efficiency, spectral linewidth, and temporal variation of output pulses are also reported. Temperature tuning of the LiB(3)O(5) OPO under the noncritical phase-matching condition is demonstrated for the first time to our knowledge. PMID- 19774067 TI - Eye-safe coherent laser radar system at 2.1 microm using Tm,Ho:YAG lasers. AB - An eye-safe pulsed coherent laser radar has been developed by using single frequency Tm,Ho:YAG lasers and heterodyne detection. Returns from a mountainside located 145 km from the laser radar system and the measurement of wind velocity to ranges exceeding 20 km have been demonstrated with transmitted pulse energies of 22 mJ. PMID- 19774068 TI - Population genetic analysis infers migration pathways of Phytophthora ramorum in US nurseries. AB - Recently introduced, exotic plant pathogens may exhibit low genetic diversity and be limited to clonal reproduction. However, rapidly mutating molecular markers such as microsatellites can reveal genetic variation within these populations and be used to model putative migration patterns. Phytophthora ramorum is the exotic pathogen, discovered in the late 1990s, that is responsible for sudden oak death in California forests and ramorum blight of common ornamentals. The nursery trade has moved this pathogen from source populations on the West Coast to locations across the United States, thus risking introduction to other native forests. We examined the genetic diversity of P. ramorum in United States nurseries by microsatellite genotyping 279 isolates collected from 19 states between 2004 and 2007. Of the three known P. ramorum clonal lineages, the most common and genetically diverse lineage in the sample was NA1. Two eastward migration pathways were revealed in the clustering of NA1 isolates into two groups, one containing isolates from Connecticut, Oregon, and Washington and the other isolates from California and the remaining states. This finding is consistent with trace forward analyses conducted by the US Department of Agriculture's Animal and Plant Health Inspection Service. At the same time, genetic diversities in several states equaled those observed in California, Oregon, and Washington and two-thirds of multilocus genotypes exhibited limited geographic distributions, indicating that mutation was common during or subsequent to migration. Together, these data suggest that migration, rapid mutation, and genetic drift all play a role in structuring the genetic diversity of P. ramorum in US nurseries. This work demonstrates that fast-evolving genetic markers can be used to examine the evolutionary processes acting on recently introduced pathogens and to infer their putative migration patterns, thus showing promise for the application of forensics to plant pathogens. PMID- 19774069 TI - Relationships of Cetacea (Artiodactyla) among mammals: increased taxon sampling alters interpretations of key fossils and character evolution. AB - BACKGROUND: Integration of diverse data (molecules, fossils) provides the most robust test of the phylogeny of cetaceans. Positioning key fossils is critical for reconstructing the character change from life on land to life in the water. METHODOLOGY/PRINCIPAL FINDINGS: We reexamine relationships of critical extinct taxa that impact our understanding of the origin of Cetacea. We do this in the context of the largest total evidence analysis of morphological and molecular information for Artiodactyla (661 phenotypic characters and 46,587 molecular characters, coded for 33 extant and 48 extinct taxa). We score morphological data for Carnivoramorpha, Creodonta, Lipotyphla, and the raoellid artiodactylan Indohyus and concentrate on determining which fossils are positioned along stem lineages to major artiodactylan crown clades. Shortest trees place Cetacea within Artiodactyla and close to Indohyus, with Mesonychia outside of Artiodactyla. The relationships of Mesonychia and Indohyus are highly unstable, however--in trees only two steps longer than minimum length, Mesonychia falls inside Artiodactyla and displaces Indohyus from a position close to Cetacea. Trees based only on data that fossilize continue to show the classic arrangement of relationships within Artiodactyla with Cetacea grouping outside the clade, a signal incongruent with the molecular data that dominate the total evidence result. CONCLUSIONS/SIGNIFICANCE: Integration of new fossil material of Indohyus impacts placement of another extinct clade Mesonychia, pushing it much farther down the tree. The phylogenetic position of Indohyus suggests that the cetacean stem lineage included herbivorous and carnivorous aquatic species. We also conclude that extinct members of Cetancodonta (whales+hippopotamids) shared a derived ability to hear underwater sounds, even though several cetancodontans lack a pachyostotic auditory bulla. We revise the taxonomy of living and extinct artiodactylans and propose explicit node and stem-based definitions for the ingroup. PMID- 19774070 TI - How are 'Barack Obama' and 'President Elect' differentially stored in the brain? An ERP investigation on the processing of proper and common noun pairs. AB - BACKGROUND: One of the most debated issues in the cognitive neuroscience of language is whether distinct semantic domains are differentially represented in the brain. Clinical studies described several anomic dissociations with no clear neuroanatomical correlate. Neuroimaging studies have shown that memory retrieval is more demanding for proper than common nouns in that the former are purely arbitrary referential expressions. In this study a semantic relatedness paradigm was devised to investigate neural processing of proper and common nouns. METHODOLOGY/PRINCIPAL FINDINGS: 780 words (arranged in pairs of Italian nouns/adjectives and the first/last names of well known persons) were presented. Half pairs were semantically related ("Woody Allen" or "social security"), while the others were not ("Sigmund Parodi" or "judicial cream"). All items were balanced for length, frequency, familiarity and semantic relatedness. Participants were to decide about the semantic relatedness of the two items in a pair. RTs and N400 data suggest that the task was more demanding for common nouns. The LORETA neural generators for the related-unrelated contrast (for proper names) included the left fusiform gyrus, right medial temporal gyrus, limbic and parahippocampal regions, inferior parietal and inferior frontal areas, which are thought to be involved in the conjoined processing a familiar face with the relevant episodic information. Person name was more emotional and sensory vivid than common noun semantic access. CONCLUSIONS/SIGNIFICANCE: When memory retrieval is not required, proper name access (conspecifics knowledge) is not more demanding. The neural generators of N400 to unrelated items (unknown persons and things) did not differ as a function of lexical class, thus suggesting that proper and common nouns are not treated differently as belonging to different grammatical classes. PMID- 19774071 TI - Sonic hedgehog is a chemoattractant for midbrain dopaminergic axons. AB - Midbrain dopaminergic axons project from the substantia nigra (SN) and the ventral tegmental area (VTA) to rostral target tissues, including the striatum, pallidum, and hypothalamus. The axons from the medially located VTA project primarily to more medial target tissues in the forebrain, whereas the more lateral SN axons project to lateral targets including the dorsolateral striatum. This structural diversity underlies the distinct functions of these pathways. Although a number of guidance cues have been implicated in the formation of the distinct axonal projections of the SN and VTA, the molecular basis of their diversity remains unclear. Here we investigate the molecular basis of structural diversity in mDN axonal projections. We find that Sonic Hedgehog (Shh) is expressed at a choice point in the course of the rostral dopaminergic projections. Furthermore, in midbrain explants, dopaminergic projections are attracted to a Shh source. Finally, in mice in which Shh signaling is inactivated during late neuronal development, the most medial dopaminergic projections are deficient. In addition to the role of Shh in the induction of mDN precursors, Shh plays an important role in dopaminergic axon pathfinding to rostral target tissues. Furthermore, Shh signaling is involved in determining the structural diversity of these dopaminergic projections. PMID- 19774072 TI - Genomic analysis of the function of the transcription factor gata3 during development of the mammalian inner ear. AB - We have studied the function of the zinc finger transcription factor gata3 in auditory system development by analysing temporal profiles of gene expression during differentiation of conditionally immortal cell lines derived to model specific auditory cell types and developmental stages. We tested and applied a novel probabilistic method called the gamma Model for Oligonucleotide Signals to analyse hybridization signals from Affymetrix oligonucleotide arrays. Expression levels estimated by this method correlated closely (p<0.0001) across a 10-fold range with those measured by quantitative RT-PCR for a sample of 61 different genes. In an unbiased list of 26 genes whose temporal profiles clustered most closely with that of gata3 in all cell lines, 10 were linked to Insulin-like Growth Factor signalling, including the serine/threonine kinase Akt/PKB. Knock down of gata3 in vitro was associated with a decrease in expression of genes linked to IGF-signalling, including IGF1, IGF2 and several IGF-binding proteins. It also led to a small decrease in protein levels of the serine-threonine kinase Akt2/PKBbeta, a dramatic increase in Akt1/PKBalpha protein and relocation of Akt1/PKBalpha from the nucleus to the cytoplasm. The cyclin-dependent kinase inhibitor p27(kip1), a known target of PKB/Akt, simultaneously decreased. In heterozygous gata3 null mice the expression of gata3 correlated with high levels of activated Akt/PKB. This functional relationship could explain the diverse function of gata3 during development, the hearing loss associated with gata3 heterozygous null mice and the broader symptoms of human patients with Hearing Deafness-Renal anomaly syndrome. PMID- 19774073 TI - Genetic epidemiology of glioblastoma multiforme: confirmatory and new findings from analyses of human leukocyte antigen alleles and motifs. AB - BACKGROUND: Human leukocyte antigen (HLA) class I genes mediate cytotoxic T lymphocyte responses and natural killer cell function. In a previous study, several HLA-B and HLA-C alleles and haplotypes were positively or negatively associated with the occurrence and prognosis of glioblastoma multiforme (GBM). METHODOLOGY/PRINCIPAL FINDINGS: As an extension of the Upper Midwest Health Study, we have performed HLA genotyping for 149 GBM patients and 149 healthy control subjects from a non-metropolitan population consisting almost exclusively of European Americans. Conditional logistic regression models did not reproduce the association of HLA-B*07 or the B*07-Cw*07 haplotype with GBM. Nonetheless, HLA-A*32, which has previously been shown to predispose GBM patients to a favorable prognosis, was negatively associated with occurrence of GBM (odds ratio=0.41, p=0.04 by univariate analysis). Other alleles (A*29, A*30, A*31 and A*33) within the A19 serology group to which A*32 belongs showed inconsistent trends. Sequencing-based HLA-A genotyping established that A*3201 was the single A*32 allele underlying the observed association. Additional evaluation of HLA-A promoter and exon 1 sequences did not detect any unexpected single nucleotide polymorphisms that could suggest differential allelic expression. Further analyses restricted to female GBM cases and controls revealed a second association with a specific HLA-B sequence motif corresponding to Bw4-80Ile (odds ratio=2.71, p=0.02). CONCLUSIONS/SIGNIFICANCE: HLA-A allelic product encoded by A*3201 is likely to be functionally important to GBM. The novel, sex-specific association will require further confirmation in other representative study populations. PMID- 19774074 TI - Monitoring bacterial community of human gut microbiota reveals an increase in Lactobacillus in obese patients and Methanogens in anorexic patients. AB - BACKGROUND: Studies of the bacterial communities of the gut microbiota have revealed a shift in the ratio of Firmicutes and Bacteroidetes in obese patients. Determining the variations of microbial communities in feces may be beneficial for the identification of specific profiles in patients with abnormal weights. The roles of the archaeon Methanobrevibacter smithii and Lactobacillus species have not been described in these studies. METHODS AND FINDINGS: We developed an efficient and robust real-time PCR tool that includes a plasmid-based internal control and allows for quantification of the bacterial divisions Bacteroidetes, Firmicutes, and Lactobacillus as well as the methanogen M. smithii. We applied this technique to the feces of 20 obese subjects, 9 patients with anorexia nervosa, and 20 normal-weight healthy controls. Our results confirmed a reduction in the Bacteroidetes community in obese patients (p<0.01). We found a significantly higher Lactobacillus species concentration in obese patients than in lean controls (p=0.0197) or anorexic patients (p=0.0332). The M. smithii concentration was much higher in anorexic patients than in the lean population (p=0.0171). CONCLUSIONS: Lactobacillus species are widely used as growth promoters in the farm industry and are now linked to obesity in humans. The study of the bacterial flora in anorexic patients revealed an increase in M. smithii. This increase might represent an adaptive use of nutrients in this population. PMID- 19774075 TI - Identification by automated screening of a small molecule that selectively eliminates neural stem cells derived from hESCs but not dopamine neurons. AB - BACKGROUND: We have previously described fundamental differences in the biology of stem cells as compared to other dividing cell populations. We reasoned therefore that a differential screen using US Food and Drug Administration (FDA) approved compounds may identify either selective survival factors or specific toxins and may be useful for the therapeutically-driven manufacturing of cells in vitro and possibly in vivo. METHODOLOGY/PRINCIPAL FINDINGS: In this study we report on optimized methods for feeder-free culture of hESCs and hESC-derived neural stem cells (NSCs) to facilitate automated screening. We show that we are able to measure ATP as an indicator of metabolic activity in an automated screening assay. With this optimized platform we screened a collection of FDA approved drugs to identify compounds that have differential toxicity to hESCs and their neural derivatives. Nine compounds were identified to be specifically toxic for NSCs to a greater extent than for hESCs. Six of these initial hits were retested and verified by large-scale cell culture to determine dose-responsive NSC toxicity. One of the compounds retested, amiodarone HCL, was further tested for possible effects on postmitotic neurons, a likely target for transplant therapy. Amiodarone HCL was found to be selectively toxic to NSCs but not to differentiated neurons or glial cells. Treated and untreated NSCs and neurons were then interrogated with global gene expression analysis to explore the mechanisms of action of amiodarone HCl. The gene expression analysis suggests that activation of cell-type specific cationic channels may underlie the toxicity of the drug. CONCLUSIONS/SIGNIFICANCE: In conclusion, we have developed a screening strategy that allows us to rapidly identify clinically approved drugs for use in a Chemistry, Manufacture and Control protocol that can be safely used to deplete unwanted contaminating precursor cells from a differentiated cell product. Our results also suggest that such a strategy is rich in the potential of identifying lineage specific reagents and provides additional evidence for the utility of stem cells in screening and discovery paradigms. PMID- 19774076 TI - Inducible bronchus-associated lymphoid tissue elicited by a protein cage nanoparticle enhances protection in mice against diverse respiratory viruses. AB - BACKGROUND: Destruction of the architectural and subsequently the functional integrity of the lung following pulmonary viral infections is attributable to both the extent of pathogen replication and to the host-generated inflammation associated with the recruitment of immune responses. The presence of antigenically disparate pulmonary viruses and the emergence of novel viruses assures the recurrence of lung damage with infection and resolution of each primary viral infection. Thus, there is a need to develop safe broad spectrum immunoprophylactic strategies capable of enhancing protective immune responses in the lung but which limits immune-mediated lung damage. The immunoprophylactic strategy described here utilizes a protein cage nanoparticle (PCN) to significantly accelerate clearance of diverse respiratory viruses after primary infection and also results in a host immune response that causes less lung damage. METHODOLOGY/PRINCIPAL FINDINGS: Mice pre-treated with PCN, independent of any specific viral antigens, were protected against both sub-lethal and lethal doses of two different influenza viruses, a mouse-adapted SARS-coronavirus, or mouse pneumovirus. Treatment with PCN significantly increased survival and was marked by enhanced viral clearance, accelerated induction of viral-specific antibody production, and significant decreases in morbidity and lung damage. The enhanced protection appears to be dependent upon the prior development of inducible bronchus-associated lymphoid tissue (iBALT) in the lung in response to the PCN treatment and to be mediated through CD4+ T cell and B cell dependent mechanisms. CONCLUSIONS/SIGNIFICANCE: The immunoprophylactic strategy described utilizes an infection-independent induction of naturally occurring iBALT prior to infection by a pulmonary viral pathogen. This strategy non-specifically enhances primary immunity to respiratory viruses and is not restricted by the antigen specificities inherent in typical vaccination strategies. PCN treatment is asymptomatic in its application and importantly, ameliorates the damaging inflammation normally associated with the recruitment of immune responses into the lung. PMID- 19774077 TI - MyosinVIIa interacts with Twinfilin-2 at the tips of mechanosensory stereocilia in the inner ear. AB - In vertebrates hearing is dependent upon the microvilli-like mechanosensory stereocilia and their length gradation. The staircase-like organization of the stereocilia bundle is dynamically maintained by variable actin turnover rates. Two unconventional myosins were previously implicated in stereocilia length regulation but the mechanisms of their action remain unknown. MyosinXVa is expressed in stereocilia tips at levels proportional to stereocilia length and its absence produces staircase-like bundles of very short stereocilia. MyosinVIIa localizes to the tips of the shorter stereocilia within bundles, and when absent, the stereocilia are abnormally long. We show here that myosinVIIa interacts with twinfilin-2, an actin binding protein, which inhibits actin polymerization at the barbed end of the filament, and that twinfilin localization in stereocilia overlaps with myosinVIIa. Exogenous expression of myosinVIIa in fibroblasts results in a reduced number of filopodia and promotes accumulation of twinfilin-2 at the filopodia tips. We hypothesize that the newly described interaction between myosinVIIa and twinfilin-2 is responsible for the establishment and maintenance of slower rates of actin turnover in shorter stereocilia, and that interplay between complexes of myosinVIIa/twinfilin-2 and myosinXVa/whirlin is responsible for stereocilia length gradation within the bundle staircase. PMID- 19774078 TI - Early in-hospital mortality following trainee doctors' first day at work. AB - BACKGROUND: There is a commonly held assumption that early August is an unsafe period to be admitted to hospital in England, as newly qualified doctors start work in NHS hospitals on the first Wednesday of August. We investigate whether in hospital mortality is higher in the week following the first Wednesday in August than in the previous week. METHODOLOGY: A retrospective study in England using administrative hospital admissions data. Two retrospective cohorts of all emergency patients admitted on the last Wednesday in July and the first Wednesday in August for 2000 to 2008, each followed up for one week. PRINCIPAL FINDINGS: The odds of death for patients admitted on the first Wednesday in August was 6% higher (OR 1.06, 95% CI 1.00 to 1.15, p=0.05) after controlling for year, gender, age, socio-economic deprivation and co-morbidity. When subdivided into medical, surgical and neoplasm admissions, medical admissions admitted on the first Wednesday in August had an 8% (OR 1.08, 95% CI 1.01 to 1.16, p=0.03) higher odds of death. In 2007 and 2008, when the system for junior doctors' job applications changed, patients admitted on Wednesday August 1(st) had 8% higher adjusted odds of death than those admitted the previous Wednesday, but this was not statistically significant (OR 1.08, 95% CI 0.95 to 1.23, p=0.24). CONCLUSIONS: We found evidence that patients admitted on the first Wednesday in August have a higher early death rate in English hospitals compared with patients admitted on the previous Wednesday. This was higher for patients admitted with a medical primary diagnosis. PMID- 19774079 TI - Parallel routes of human carcinoma development: implications of the age-specific incidence data. AB - BACKGROUND: The multi-stage hypothesis suggests that cancers develop through a single defined series of genetic alterations. This hypothesis was first suggested over 50 years ago based upon age-specific incidence data. However, recent molecular studies of tumors indicate that multiple routes exist to the formation of cancer, not a single route. This parallel route hypothesis has not been tested with age-specific incidence data. METHODOLOGY/PRINCIPAL FINDINGS: To test the parallel route hypothesis, I formulated it in terms of a mathematical equation and then tested whether this equation was consistent with age-specific incidence data compiled by the Surveillance Epidemiology and End Results (SEER) cancer registries since 1973. I used the chi-squared goodness of fit test to measure consistency. The age-specific incidence data from most human carcinomas, including those of the colon, lung, prostate, and breast were consistent with the parallel route hypothesis. However, this hypothesis is only consistent if an immune sub-population exists, one that will never develop carcinoma. Furthermore, breast carcinoma has two distinct forms of the disease, and one of these occurs at significantly different rates in different racial groups. CONCLUSIONS/SIGNIFICANCE: I conclude that the parallel route hypothesis is consistent with the age-specific incidence data only if carcinoma occurs in a distinct sub population, while the multi-stage hypothesis is inconsistent with this data. PMID- 19774080 TI - A novel mouse model reveals that polycystin-1 deficiency in ependyma and choroid plexus results in dysfunctional cilia and hydrocephalus. AB - Polycystin-1 (PC-1), the product of the PKD1 gene, mutated in the majority of cases of Autosomal Dominant Polycystic Kidney Disease (ADPKD), is a very large (approximately 520 kDa) plasma membrane receptor localized in several subcellular compartments including cell-cell/matrix junctions as well as cilia. While heterologous over-expression systems have allowed identification of several of the potential biological roles of this receptor, its precise function remains largely elusive. Studying PC-1 in vivo has been a challenging task due to its complexity and low expression levels. To overcome these limitations and facilitate the study of endogenous PC-1, we have inserted HA- or Myc-tag sequences into the Pkd1 locus by homologous recombination. Here, we show that our approach was successful in generating a fully functional and easily detectable endogenous PC-1. Characterization of PC-1 distribution in vivo showed that it is expressed ubiquitously and is developmentally-regulated in most tissues. Furthermore, our novel tool allowed us to investigate the role of PC-1 in brain, where the protein is abundantly expressed. Subcellular localization of PC-1 revealed strong and specific staining in ciliated ependymal and choroid plexus cells. Consistent with this distribution, we observed hydrocephalus formation both in the ubiquitous knock-out embryos and in newborn mice with conditional inactivation of the Pkd1 gene in the brain. Both choroid plexus and ependymal cilia were morphologically normal in these mice, suggesting a role for PC-1 in ciliary function or signalling in this compartment, rather than in ciliogenesis. We propose that the role of PC-1 in the brain cilia might be to prevent hydrocephalus, a previously unrecognized role for this receptor and one that might have important implications for other genetic or sporadic diseases. PMID- 19774081 TI - Participation of actin on Giardia lamblia growth and encystation. AB - BACKGROUND: Microfilaments play a determinant role in different cell processes such as: motility, cell division, phagocytosis and intracellular transport; however, these structures are poorly understood in the parasite Giardia lamblia. METHODOLOGY AND PRINCIPAL FINDINGS: By confocal microscopy using TRITC phalloidin, we found structured actin distributed in the entire trophozoite, the label stand out at the ventral disc, median body, flagella and around the nuclei. During Giardia encystation, a sequence of morphological changes concurrent to modifications on the distribution of structured actin and in the expression of actin mRNA were observed. To elucidate whether actin participates actively on growth and encystation, cells were treated with Cytochalasin D, Latrunculin A and Jasplakinolide and analyzed by confocal and scanning electron microscopy. All drugs caused a growth reduction (27 to 45%) and changes on the distribution of actin. Besides, 60 to 80% of trophozoites treated with the drugs, exhibited damage at the caudal region, alterations in the flagella and wrinkles-like on the plasma membrane. The drugs also altered the cyst-yield and the morphology, scanning electron microscopy revealed diminished cytokinesis, cysts with damages in the wall and alterations in the size and on the intermembranal space. Furthermore, the drugs caused a significant reduction of the intensity of fluorescence-labeled CWP1 on ESV and on cyst wall, this was coincident with a reduction of CWP1 gene expression (34%). CONCLUSIONS AND SIGNIFICANCE: All our results, indicated an important role of actin in the morphology, growth and encystation and indirectly suggested an actin role in gene expression. PMID- 19774082 TI - Enhanced generation of induced pluripotent stem cells from a subpopulation of human fibroblasts. AB - BACKGROUND: The derivation of induced pluripotent stem cells (iPSCs) provides new possibilities for basic research and novel cell-based therapies. Limitations, however, include our current lack of understanding regarding the underlying mechanisms and the inefficiency of reprogramming. METHODOLOGY/PRINCIPAL FINDINGS: Here, we report identification and isolation of a subpopulation of human dermal fibroblasts that express the pluripotency marker stage specific embryonic antigen 3 (SSEA3). Fibroblasts that expressed SSEA3 demonstrated an enhanced iPSC generation efficiency, while no iPSC derivation was obtained from the fibroblasts that did not express SSEA3. Transcriptional analysis revealed NANOG expression was significantly increased in the SSEA3 expressing fibroblasts, suggesting a possible mechanistic explanation for the differential reprogramming. CONCLUSIONS/SIGNIFICANCE: To our knowledge, this study is the first to identify a pluripotency marker in a heterogeneous population of human dermal fibroblasts, to isolate a subpopulation of cells that have a significantly increased propensity to reprogram to pluripotency and to identify a possible mechanism to explain this differential reprogramming. This discovery provides a method to significantly increase the efficiency of reprogramming, enhancing the feasibility of the potential applications based on this technology, and a tool for basic research studies to understand the underlying reprogramming mechanisms. PMID- 19774083 TI - Loss of ATRX in chondrocytes has minimal effects on skeletal development. AB - BACKGROUND: Mutations in the human ATRX gene cause developmental defects, including skeletal deformities and dwarfism. ATRX encodes a chromatin remodeling protein, however the role of ATRX in skeletal development is currently unknown. METHODOLOGY/PRINCIPAL FINDINGS: We induced Atrx deletion in mouse cartilage using the Cre-loxP system, with Cre expression driven by the collagen II (Col2a1) promoter. Growth rate, body size and weight, and long bone length did not differ in Atrx(Col2cre) mice compared to control littermates. Histological analyses of the growth plate did not reveal any differences between control and mutant mice. Expression patterns of Sox9, a transcription factor required for cartilage morphogenesis, and p57, a marker of cell cycle arrest and hypertrophic chondrocyte differentiation, was unaffected. However, loss of ATRX in cartilage led to a delay in the ossification of the hips in some mice. We also observed hindlimb polydactily in one out of 61 mutants. CONCLUSIONS/SIGNIFICANCE: These findings indicate that ATRX is not directly required for development or growth of cartilage in the mouse, suggesting that the short stature in ATR-X patients is caused by defects in cartilage-extrinsic mechanisms. PMID- 19774084 TI - Altered immune responses in rhesus macaques co-infected with SIV and Plasmodium cynomolgi: an animal model for coincident AIDS and relapsing malaria. AB - BACKGROUND: Dual epidemics of the malaria parasite Plasmodium and HIV-1 in sub Saharan Africa and Asia present a significant risk for co-infection in these overlapping endemic regions. Recent studies of HIV/Plasmodium falciparum co infection have reported significant interactions of these pathogens, including more rapid CD4+ T cell loss, increased viral load, increased immunosuppression, and increased episodes of clinical malaria. Here, we describe a novel rhesus macaque model for co-infection that supports and expands upon findings in human co-infection studies and can be used to identify interactions between these two pathogens. METHODOLOGY/PRINCIPAL FINDINGS: Five rhesus macaques were infected with P. cynomolgi and, following three parasite relapses, with SIV. Compared to macaques infected with SIV alone, co-infected animals had, as a group, decreased survival time and more rapid declines in markers for SIV progression, including peripheral CD4+ T cells and CD4+/CD8+ T cell ratios. The naive CD4+ T cell pool of the co-infected animals was depleted more rapidly than animals infected with SIV alone. The co-infected animals also failed to generate proliferative responses to parasitemia by CD4+ and CD8+ T cells as well as B cells while also having a less robust anti-parasite and altered anti-SIV antibody response. CONCLUSIONS/SIGNIFICANCE: These data suggest that infection with both SIV and Plasmodium enhances SIV-induced disease progression and impairs the anti Plasmodium immune response. These data support findings in HIV/Plasmodium co infection studies. This animal model can be used to further define impacts of lentivirus and Plasmodium co-infection and guide public health and therapeutic interventions. PMID- 19774085 TI - An integrated approach to rapid diagnosis of tuberculosis and multidrug resistance using liquid culture and molecular methods in Russia. AB - OBJECTIVE: To analyse the feasibility, cost and performance of rapid tuberculosis (TB) molecular and culture systems, in a high multidrug-resistant TB (MDR TB) middle-income region (Samara, Russia) and provide evidence for WHO policy change. METHODS: Performance and cost evaluation was conducted to compare the BACTEC MGIT 960 system for culture and drug susceptibility testing (DST) and molecular systems for TB diagnosis, resistance to isoniazid and rifampin, and MDR TB identification compared to conventional Lowenstein-Jensen culture assays. FINDINGS: 698 consecutive patients (2487 sputum samples) with risk factors for drug-resistant tuberculosis were recruited. Overall M. tuberculosis complex culture positivity rates were 31.6% (787/2487) in MGIT and 27.1% (675/2487) in LJ (90.5% and 83.2% for smear-positive specimens). In total, 809 cultures of M. tuberculosis complex were isolated by any method. Median time to detection was 14 days for MGIT and 36 days for LJ (10 and 33 days for smear positive specimens) and indirect DST in MGIT took 9 days compared to 21 days on LJ. There was good concordance between DST on LJ and MGIT (96.8% for rifampin and 95.6% for isoniazid). Both molecular hybridization assay results correlated well with MGIT DST results, although molecular assays generally yielded higher rates of resistance (by approximately 3% for both isoniazid and rifampin). CONCLUSION: With effective planning and logistics, the MGIT 960 and molecular based methodologies can be successfully introduced into a reference laboratory setting in a middle incidence country. High rates of MDR TB in the Russian Federation make the introduction of such assays particularly useful. PMID- 19774086 TI - LKR/SDH plays important roles throughout the tick life cycle including a long starvation period. AB - BACKGROUND: Lysine-ketoglutarate reductase/saccharopine dehydrogenase (LKR/SDH) is a bifunctional enzyme catalyzing the first two steps of lysine catabolism in plants and mammals. However, to date, the properties of the lysine degradation pathway and biological functions of LKR/SDH have been very little described in arthropods such as ticks. METHODOLOGY/PRINCIPAL FINDINGS: We isolated and characterized the gene encoding lysine-ketoglutarate reductase (LKR, EC 1.5.1.8) and saccharopine dehydrogenase (SDH, EC 1.5.1.9) from a tick, Haemaphysalis longicornis, cDNA library that encodes a bifunctional polypeptide bearing domains similar to the plant and mammalian LKR/SDH enzymes. Expression of LKR/SDH was detected in all developmental stages, indicating an important role throughout the tick life cycle, including a long period of starvation after detachment from the host. The LKR/SDH mRNA transcripts were more abundant in unfed and starved ticks than in fed and engorged ticks, suggesting that tick LKR/SDH are important for the starved tick. Gene silencing of LKR/SDH by RNAi indicated that the tick LKR/SDH plays an integral role in the osmotic regulation of water balance and development of eggs in ovary of engorged females. CONCLUSIONS/SIGNIFICANCE: Transcription analysis and gene silencing of LKR/SDH indicated that tick LKR/SDH enzyme plays not only important roles in egg production, reproduction and development of the tick, but also in carbon, nitrogen and water balance, crucial physiological processes for the survival of ticks. This is the first report on the role of LKR/SDH in osmotic regulation in animals including vertebrate and arthropods. PMID- 19774087 TI - How to achieve fast entrainment? The timescale to synchronization. AB - Entrainment, where oscillators synchronize to an external signal, is ubiquitous in nature. The transient time leading to entrainment plays a major role in many biological processes. Our goal is to unveil the specific dynamics that leads to fast entrainment. By studying a generic model, we characterize the transient time to entrainment and show how it is governed by two basic properties of an oscillator: the radial relaxation time and the phase velocity distribution around the limit cycle. Those two basic properties are inherent in every oscillator. This concept can be applied to many biological systems to predict the average transient time to entrainment or to infer properties of the underlying oscillator from the observed transients. We found that both a sinusoidal oscillator with fast radial relaxation and a spike-like oscillator with slow radial relaxation give rise to fast entrainment. As an example, we discuss the jet-lag experiments in the mammalian circadian pacemaker. PMID- 19774088 TI - Identification of an unusual pattern of global gene expression in group B Streptococcus grown in human blood. AB - Because passage of the bacterium to blood is a crucial step in the pathogenesis of many group B Streptococcus (GBS) invasive infections, we recently conducted a whole-genome transcriptome analysis during GBS incubation ex vivo with human blood. In the current work, we sought to analyze in detail the difference in GBS gene expression that occurred in one blood sample (donor A) relative to other blood samples. We incubated GBS strain NEM316 with fresh heparinized human blood obtained from healthy volunteers, and analyzed GBS genome expression and cytokine production. Principal component analysis identified extensive clustering of the transcriptome data among all samples at time 0. In striking contrast, the whole bacterial gene expression in the donor A blood sample was significantly different from the gene expression in all other blood samples studied, both after 30 and 90 min of incubation. More genes were up-regulated in donor A blood relative to the other samples, at 30 min and 90 min. Furthermore, there was significant variation in transcript levels between donor A blood and other blood samples. Notably, genes with the highest transcript levels in donor A blood were those involved in carbohydrate metabolism. We also discovered an unusual production of proinflammatory and immunomodulatory cytokines: MIF, tPAI-1 and IL-1beta were produced at higher levels in donor A blood relative to the other blood samples, whereas GM-CSF, TNF-alpha, IFN-gamma, IL-7 and IL-10 remained at lower levels in donor A blood. Potential reasons for our observations are that the immune response of donor A significantly influenced the bacterial transcriptome, or both GBS gene expression and immune response were influenced by the metabolic status of donor A. PMID- 19774089 TI - A mammalian lost world in southwest Europe during the late Pliocene. AB - BACKGROUND: Over the last decades, there has been an increasing interest on the chronology, distribution and mammal taxonomy (including hominins) related with the faunal turnovers that took place around the Pliocene-Pleistocene transition [ca. 1.8 mega-annum (Ma)] in Europe. However, these turnovers are not fully understood due to: the precarious nature of the period's fossil record; the "non coexistence" in this record of many of the species involved; and the enormous geographical area encompassed. This palaeontological information gap can now be in part bridged with data from the Fonelas P-1 site (Granada, Spain), whose faunal composition and late Upper Pliocene date shed light on some of the problems concerning the timing and geography of the dispersals. METHODOLOGY/PRINCIPAL FINDINGS: This rich fossil site yielded 32 species of mammals, among which autochthonous species of the European Upper Villafranchian coexist with canids (Canis), ovibovines (Praeovibos) and giraffids (Mitilanotherium) from Asia. Typical African species, such as the brown hyena (Hyaena brunnea) and the bush pig (Potamochoerus) are also present. CONCLUSIONS/SIGNIFICANCE: This assemblage is taxonomically and palaeobiogeographically unique, and suggests that fewer dispersal events than was previously thought (possibly only one close to 2.0 Ma) are responsible for the changes seen around 1.9-1.7 Ma ago in the fauna of the two continents. PMID- 19774090 TI - Beyond element-wise interactions: identifying complex interactions in biological processes. AB - BACKGROUND: Biological processes typically involve the interactions of a number of elements (genes, cells) acting on each others. Such processes are often modelled as networks whose nodes are the elements in question and edges pairwise relations between them (transcription, inhibition). But more often than not, elements actually work cooperatively or competitively to achieve a task. Or an element can act on the interaction between two others, as in the case of an enzyme controlling a reaction rate. We call "complex" these types of interaction and propose ways to identify them from time-series observations. METHODOLOGY: We use Granger Causality, a measure of the interaction between two signals, to characterize the influence of an enzyme on a reaction rate. We extend its traditional formulation to the case of multi-dimensional signals in order to capture group interactions, and not only element interactions. Our method is extensively tested on simulated data and applied to three biological datasets: microarray data of the Saccharomyces cerevisiae yeast, local field potential recordings of two brain areas and a metabolic reaction. CONCLUSIONS: Our results demonstrate that complex Granger causality can reveal new types of relation between signals and is particularly suited to biological data. Our approach raises some fundamental issues of the systems biology approach since finding all complex causalities (interactions) is an NP hard problem. PMID- 19774091 TI - How Marginal Deviations Sometimes Grow Into Serious Aggression. AB - We offer a theory of marginal deviations that articulates the processes through which initial behavior that is only slightly deviant from the norm gets transformed into more serious antisocial outcomes. We present evidence that, of the one third of the population that is marginally deviant, about one fourth (or 8% of the total population) becomes seriously deviant over time. Hypothesized factors in this transformation involve the child actor, peer observer-judges, and social transactions between them in processes that derive from self-fulfilling prophecies and dynamic systems theory. Hypotheses and studies are proposed to address the circumstances and processes that determine whether a marginal deviation will be bought back to the norm (through assimilation and attenuation) or accelerated to severe deviance (through accommodation and amplification). PMID- 19774092 TI - Medfly populations differ in diel and age patterns of sexual signalling. AB - Insect populations may differ in several life history traits, including behavioural ones such as sexual signalling. We tested whether male Mediterranean fruit fly (medlfy), Ceratitis capitata (Wiedemann) (Diptera: Tephritidae), populations obtained from geographically isolated areas exhibit differences in quantitative and qualitative aspects of male sexual signalling. Male sexual signalling was studied in four medfly populations (originating from Brazil, Portugal, Kenya, and Greece) under identical laboratory conditions (25 degrees C, 60% r.h., and L14:D10). The four populations had been reared for one generation in the laboratory. Sexual signalling was studied in the F(1) progeny that were fed one of two diets (yeast hydrolysate plus sugar or sugar only). On both diets, the four populations differed significantly in the progress of maturity (indicated by the average number of males exhibiting sexual signalling) and in the quantity of signalling after attaining maturity. Yeast availability significantly increased sexual signalling; however, it had a different impact on the quantity of signalling in the different populations. A bimodal pattern of sexual signalling, with one peak at approximately 08:00-09:00 hours and the second at approximately 13:00-14:00 hours, was recorded for all populations and diets. However, quantitative differences among the populations within the 'sexually active' period of the day resulted in significant differences in the daily pattern of sexual signalling. The significance of these findings for understanding adaptations of geographically-isolated medfly populations to different ecosystems, as well as its practical importance for the application of the Sterile Insect Technique (SIT) against C. capitata, is discussed. PMID- 19774093 TI - Adult diet affects lifespan and reproduction of the fruit-feeding butterfly Charaxes fulvescens. AB - Fruit-feeding butterflies are among the longest lived Lepidoptera. While the use of pollen-derived amino acids by Heliconius butterflies has been interpreted as important for the evolution of extended lifespans, very little is known about the life-history consequences of frugivory. This issue is addressed by investigating effects of four adult diets (sugar, sugar with amino acids, banana, and moistened banana) on lifespan and reproduction in the fruit-feeding butterfly Charaxes fulvescens Aurivillius (Lepidoptera: Nymphalidae). Female butterflies were collected from Kibale National Park, Uganda, and kept individually in cages near their natural habitat and data were collected on lifespan, oviposition, and hatching of eggs. Lifespan in captivity was longer for the sugar and the amino acid cohort, than for the banana cohorts. The longitudinal pattern of oviposition was erratic, with many days without oviposition and few periods with high numbers of eggs laid. Butterflies typically did not lay eggs during their 1st week in captivity and the length of the period between capture and first reproduction was significantly shorter for butterflies fed moistened banana. The length of the reproduction period (first reproduction-last reproduction in captivity) and the reproduction rate (total number of eggs/length of the reproduction period) did not differ significantly between the diet treatments. Those fed with amino acid and moistened banana had significantly higher egg hatchability than those fed with sugar and banana. We found no evidence for a lifespan cost of reproduction. Our results show that (1) female C. fulvescens can use amino acids in their diet for laying fertile eggs, (2) more wing-wear does correlate with lower survival in captivity (indicating aging in the wild), but not with intensity of reproduction (providing no evidence for reproductive aging), and (3) fruit-feeding butterflies may be dietary restricted in the field. PMID- 19774094 TI - Using zebrafish to assess the impact of drugs on neural development and function. AB - BACKGROUND: Zebrafish is becoming an increasingly attractive model organism for understanding biology and developing therapeutics, because as a vertebrate, it shares considerable similarity with mammals in both genetic compositions and tissue/organ structures, and yet remains accessible to high throughput phenotype based genetic and small molecule compound screening. OBJECTIVE/METHOD: The focus of this review is on the nervous system, which is arguably the most complex organ and known to be afflicted by more than six hundred disorders in humans. I discuss the past, present, and future of using zebrafish to assess the impact of small molecule drugs on neural development and function, in light of understanding and treating neurodevelopmental disorders such as autism, neurodegenerative disorders including Alzheimer's, Parkinson's, and Hungtington's disease, and neural system dysfunctions such as anxiety/depression and addiction. CONCLUSION: These studies hold promise to reveal fundamental mechanisms governing nervous system development and function, and to facilitate small molecule drug discovery for the many types of neurological disorders. PMID- 19774095 TI - Developing neuroprotective strategies for treatment of HIV-associated neurocognitive dysfunction. AB - Important advances have been made in recent years in identifying the molecular mechanisms of HIV neuropathogenesis. Defining the pathways leading to HIV dementia has created an opportunity to therapeutically target many steps in the pathogenic process. HIV itself rarely infects neurons, but significant neuronal damage is caused both by viral proteins and by inflammatory mediators produced by the host in response to infection. Highly active antiretroviral therapy (HAART) does not target these mediators of neuronal damage, and the prevalence of HIV associated neurocognitive dysfunction has actually been rising in the post-HAART era. This review will briefly summarize our current understanding of the mechanisms of HIV-induced neurological disease, and emphasize translation of this basic research into potential clinical applications. PMID- 19774096 TI - A deformable model for tracking tumors across consecutive imaging studies. AB - OBJECTIVE: A deformable registration technique was developed and evaluated to track and quantify tumor response to radiofrequency ablation for patients with liver malignancies. MATERIALS AND METHODS: The method uses the combined power of global and local alignment of pre- and post-treatment computed tomography image data sets. The strategy of the algorithm is to infer volumetric deformation based upon surface displacements using a linearly elastic finite element model (FEM). Using this framework, the major challenge for tracking tumor location is not the tissue mechanical properties for FEM modeling but rather the evaluation of boundary conditions. Three different methods were systematically investigated to automatically determine the boundary conditions defined by the correspondences on liver surfaces. RESULTS: Using both 2D synthetic phantoms and imaged 3D beef liver data we performed gold standard registration while measuring the accuracy of non-rigid deformation. The fact that the algorithms could support mean displacement error of tumor deformation up to 2 mm indicates that this technique may serve as a useful tool for surgical interventions. The method was further demonstrated and evaluated using consecutive imaging studies for three liver cancer patients. CONCLUSION: The FEM-based surface registration technique provides accurate tracking and monitoring of tumor and surrounding tissue during the course of treatment and follow-up. PMID- 19774097 TI - Cytoskeletal basis of ion channel function in cardiac muscle. AB - The heart is a force-generating organ that responds to self-generated electrical stimuli from specialized cardiomyocytes. This function is modulated by sympathetic and parasympathetic activity. In order to contract and accommodate the repetitive morphological changes induced by the cardiac cycle, cardiomyocytes depend on their highly evolved and specialized cytoskeletal apparatus. Defects in components of the cytoskeleton affect the ability of the cell to compensate at both functional and structural levels in the long term. In addition to structural remodeling, the myocardium becomes increasingly susceptible to altered electrical activity, leading to arrhythmogenesis. The development of arrhythmias secondary to structural remodeling defects has been noted, although the detailed molecular mechanisms are still elusive. Here, the author reviews the current knowledge of the molecular and functional relationships between the cytoskeleton and ion channels, and discusses the future impact of new data on molecular cardiology research and clinical practice. PMID- 19774098 TI - Who Stays in Treatment? Child and Family Predictors of Youth Client Retention in a Public Mental Health Agency. AB - The present study examined possible predictors of youth client retention in therapy in a large community-based sample. We used several conceptualizations of retention, including (a) "intake retention" (i.e., returned to treatment after intake session); (b) "mutual termination" (i.e., termination agreed upon by family and therapist), (c) "mean treatment duration" (i.e., completing the mean number of sessions in the agency), and (d) "total treatment duration" (i.e., total number of sessions). Archival data from over 400 children and adolescents who sought treatment at a large public mental health clinic were analyzed using regression analyses. Although different predictors were identified across the various conceptualizations, a few robust predictors emerged including ethnicity and client symptom severity. Clinical implications and future research directions are discussed. PMID- 19774099 TI - Effect of Electromechanical Stimulation on the Maturation of Myotubes on Aligned Electrospun Fibers. AB - Tissue engineering may provide an alternative to cell injection as a therapeutic solution for myocardial infarction. A tissue-engineered muscle patch may offer better host integration and higher functional performance. This study examined the differentiation of skeletal myoblasts on aligned electrospun polyurethane (PU) fibers and in the presence of electromechanical stimulation. Skeletal myoblasts cultured on aligned PU fibers showed more pronounced elongation, better alignment, higher level of transient receptor potential cation channel-1 (TRPC-1) expression, upregulation of contractile proteins and higher percentage of striated myotubes compared to those cultured on random PU fibers and film. The resulting tissue constructs generated tetanus forces of 1.1 mN with a 10-ms time to tetanus. Additional mechanical, electrical, or synchronized electromechanical stimuli applied to myoblasts cultured on PU fibers increased the percentage of striated myotubes from 70 to 85% under optimal stimulation conditions, which was accompanied by an upregulation of contractile proteins such as alpha-actinin and myosin heavy chain. In describing how electromechanical cues can be combined with topographical cue, this study helped move towards the goal of generating a biomimetic microenvironment for engineering of functional skeletal muscle. PMID- 19774100 TI - ILLUMINATING THE ROLE OF AGGLOMERATES ON CRITICAL PHYSICOCHEMICAL PROPERTIES OF AMORPHOUS CALCIUM PHOSPHATE COMPOSITES. AB - Water sorption (WS), mechanical strength, and ion release of polymeric composites formulated with 40 % as-made or milled amorphous calcium phosphate (ACP) are compared after 1, 2 and 3 months of aqueous exposure. Ethoxylated bisphenol A dimethacrylate, triethylene glycol dimethacrylate, 2-hydroxyethyl methacrylate and methacryloxyethyl phthalate comprised the resin. The WS (mass %) peaked at 3 months. WS of as-made ACP composites was significantly higher than WS of milled ACP composites and copolymers. Both composite groups experienced decreases in biaxial flexural strength (BFS) with water aging, with milled ACP composites retaining a significantly higher BFS throughout immersion. Ion release was moderately reduced in milled ACP composites, though they remained superior to as made ACP composites due to significantly lower WS and higher BFS after prolonged aqueous exposure. PMID- 19774102 TI - Training the next generation of research mentors: the University of California, San Francisco, Clinical & Translational Science Institute Mentor Development Program. AB - Mentoring is a critical component of career development and success for clinical translational science research faculty. Yet few programs train faculty in mentoring skills. We describe outcomes from the first two faculty cohorts who completed a Mentor Development Program (MDP) at UCSF. Eligibility includes having dedicated research time, expertise in a scientific area and a desire to be a lead research mentor. A post-MDP survey measured the program's impact on enhancement of five key mentoring skills, change in the Mentors-in-Training (MIT) self-rated importance of being a mentor to their career satisfaction, and overall confidence in their mentoring skills. Since 2007, 29 MITs participated in and 26 completed the MDP. Only 15% of the MITs reported any previous mentor training. Overall, 96% of MITs felt that participation in the MDP helped them to become better mentors. A majority reported a significant increase in confidence in mentoring skills and most reported an increased understanding of important mentoring issues at UCSF. MITs reported increased confidence in overall and specific mentoring skills after completion of the MDP. The MDP can serve as a model for other institutions to develop the next generation of clinical-translational research mentors. PMID- 19774101 TI - Leptin signaling: A key pathway in immune responses. AB - Leptin is a hormone whose central role is to regulate endocrine functions and to control energy expenditure. After the discovery that leptin can also have pro inflammatory effects, several studies have tried to address - at the molecular level - the pathways involved in leptin-induced modulation of the immune functions in normal and pathologic conditions. The signaling events influenced by leptin after its binding to the leptin receptor have been under scrutiny in the past few years, and considerable experimental work has elucidated the consequences of leptin effects on immune cells. This review examines the biochemistry, function and regulation of leptin signaling in view of possible intervention on this molecule for a better management and therapy of immune mediated diseases. PMID- 19774104 TI - Examining the economic costs related to lifestyle and pharmacological interventions in youth with Type 2 diabetes. AB - The best treatment option for children with Type 2 diabetes has not yet been established. The Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) study is currently testing the efficacy of three therapies: metformin, metformin plus rosiglitazone and metformin plus an intensive lifestyle intervention. The relative cost-effectiveness of these therapies is also being examined. This review discusses the rationale for the design and methods applied in the economic analysis. The design of the economic analysis in the TODAY study was influenced by the existing literature and two primary study parameters: the nature of the interventions and the participants' age. The lifestyle intervention is an intensive behavioral intervention comprising diet and physical activity. Since economic factors influence both diet and physical activity, the analytical plan includes measurement of food and exercise-related purchases. Due to the young age of the participants, the impact of the intervention on adult caregivers is also included in the analysis. This analysis focuses on the time spent by the caregivers in both medical treatment and nutrition- and activity-related activities, and the value of this time relative to usual activities. Important methodological questions include how and when to collect information, not only on medical costs, but also on the impact of caregiver time, travel, food and equipment purchases. In the TODAY study, these latter resources are being measured by regularly administered surveys completed by the caregivers. The approach to the cost-effectiveness assessment undertaken by the TODAY study is one of the first in diabetes research to focus on youth and to include a societal perspective, regular and prospective assessment of clinician and caregiver time, and a comprehensive assessment of the costs associated with lifestyle behaviors. It can serve as a model for future studies of diabetes treatments. PMID- 19774103 TI - Statistical issues in the analysis of DNA Copy Number Variations. AB - Approaches to assess copy number variation have advanced rapidly and are being incorporated into genetic studies. While the technology exists for CNV genotyping, a further understanding and discussion of how to use the CNV data for association analyses is warranted. We present the options available for processing and analysing CNV data. We break these steps down into choice of genotyping platform, normalisation of the array data, calling algorithm, and statistical analysis. PMID- 19774106 TI - Personality and Career Success: Concurrent and Longitudinal Relations. AB - The present research addresses the dynamic transaction between extrinsic (occupational prestige, income) and intrinsic (job satisfaction) career success and the Five-Factor Model of personality. Participants (N = 731) completed a comprehensive measure of personality and reported their job title, annual income, and job satisfaction; a subset of these participants (n = 302) provided the same information approximately 10 years later. Measured concurrently, emotionally stable and conscientious participants reported higher incomes and job satisfaction. Longitudinal analyses revealed that, among younger participants, higher income at baseline predicted decreases in Neuroticism and baseline Extraversion predicted increases in income across the 10 years. Results suggest that the mutual influence of career success and personality is limited to income and occurs early in the career. PMID- 19774105 TI - Aberrant regulation of choline metabolism by mitochondrial electron transport system inhibition in neuroblastoma cells. AB - Anomalous choline metabolic patterns have been consistently observed in vivo using Magnetic Resonance Spectroscopy (MRS) analysis of patients with neurodegenerative diseases and tissues from cancer patient. It remains unclear; however, what signaling events may have triggered these choline metabolic aberrancies. This study investigates how changes in choline and phospholipid metabolism are regulated by distinct changes in the mitochondrial electron transport system (ETS). We used specific inhibitors to down regulate the function of individual protein complexes in the ETS of SH-SY5Y neuroblastoma cells. Interestingly, we found that dramatic elevation in the levels of phosphatidylcholine metabolites could be induced by the inhibition of individual ETS complexes, similar to in vivo observations. Such interferences produced divergent metabolic patterns, which were distinguishable via principal component analysis of the cellular metabolomes. Functional impairments in ETS components have been reported in several central nervous system (CNS) diseases, including Alzheimer's disease (AD) and Parkinson's disease (PD); however, it remains largely unknown how the suppression of individual ETS complex function could lead to specific dysfunction in different cell types, resulting in distinct disease phenotypes. Our results suggest that the inhibition of each of the five ETS complexes might differentially regulate phospholipase activities within choline metabolic pathways in neuronal cells, which could contribute to the overall understanding of mitochondrial diseases. PMID- 19774108 TI - Can English-learning toddlers acquire and generalize a novel spatial word? AB - English-learning toddlers of 21 and 22 months were taught a novel spatial word for four actions resulting in a tight-fit spatial relation, a relation that is lexically marked in Korean but not English (Choi & Bowerman, 1991). Toddlers in a control condition viewed the same tight-fit action events without the novel word. Toddlers' comprehension of the novel word was tested in a preferential-looking paradigm. Across four videotaped pairs of action events, a tight-fit event was paired with a loose-fit event. Only toddlers who were taught the novel spatial word looked significantly longer at the tight-fit events during the test trials that presented the novel word than during control trials that presented neutral linguistic stimuli. The results indicate that toddlers can map and generalize a novel word onto actions resulting in a tight-fit relation, given limited experience with the novel word. The results provide insight into how young word learners begin to form language-specific semantic spatial categories. PMID- 19774107 TI - Development and Validation of Instruments to Assess Potential Religion-Health Mechanisms in an African American Population. AB - The health disparities that negatively affect African Americans are well documented; however, there are also many sociocultural factors that may play a protective role in health outcomes. Religious involvement is noted to be important in the African American community and to have a positive association with health outcomes. However, few studies have explained why this relationship exists. This article reports on the development and validation of instruments to assess two proposed mediators of the relationship between religiosity and health for an African American population; perceived religious influence on health behaviors and illness as punishment from a higher power. We used a systematic iterative process, including interviews and questionnaire data from African Americans who provided feedback on item wording. We also solicited input from African American pastors. In a sample of 55 African Americans, the instruments appeared to have strong internal reliability (alpha = .74 and .91, respectively) as well as test-retest reliability (r = .65, .84, respectively, p < .001). Evidence far construct validity is also discussed, as are recommendations for health disparities research using these instruments. PMID- 19774109 TI - Who Dislikes Whom, and For Whom Does It Matter: Predicting Aggression in Middle Childhood. AB - This study investigated the role of mutual dislike dyads (MDDs) in the development of aggressive behavior across the middle childhood years. Of particular interest was whether involvement in MDDs predicted later aggression, and whether the magnitude of the association between MDDs and later aggression varied based on characteristics of target children and 'others' involved in their MDDs. Data were collected on a community sample of 453 children participating in an ongoing longitudinal study. Classroom peer nomination and rating-scale measures were collected in kindergarten through third grade; aggressive behavior problems were assessed via teacher ratings in the early elementary years (kindergarten and first grade) and late elementary years (fourth and fifth grade). MDD involvement in the middle elementary years (second and third grade) was associated with higher levels of aggression in the late elementary years among boys (but not girls), and these predictions held after controlling for group-level peer disliking in the middle elementary years, aggression in the early elementary years, and demographic variables. The association between MDD involvement and subsequent aggression was also qualified by the aggressiveness of others in children's MDDs: Having more MDDs predicted later aggression only among boys whose MDDs involved mostly non-aggressive others. PMID- 19774111 TI - Bioinformatics analysis of the complete sequences of cytochrome b of Takydromus sylvaticus and modeling the tertiary structure of encoded protein. AB - Cytochrome b (cyt b) gene complete sequences (1143bp) of Takydromus sylvaticus were sequenced. In order to clarify the phylogenetic position of the Takydromus sylvaticus, we investigated the phylogeny of 15 Takydromus spp. distributed in East-Asia by Maximum Parsimony (MP), Bayesian Inference (BI), and Maximum Likelihood (ML) methods using DNA fragments of cyt b genes. The results supported that the Platyplacopus merged into Takydromus and negated the validity of Platyplacopus. Furthermore, the prediction of tertiary structures of cyt b exhibited the CD loop region contain two short helices forming a hairpin arrangement, namely cd1 and cd2. Thermostability analysis shows that the CD-loop region is unstable thermodynamically and may provide mobility to amino acids located at the heme, and might provide high flexibility to the top of ISP (iron sulfur protein) and the cavity region of Qo binding site. It suggested that the two short helices of CD loop region of cyt b was a dominating portion for ISP binding site. PMID- 19774110 TI - Fungal bioconversion of lignocellulosic residues; opportunities & perspectives. AB - The development of alternative energy technology is critically important because of the rising prices of crude oil, security issues regarding the oil supply, and environmental issues such as global warming and air pollution. Bioconversion of biomass has significant advantages over other alternative energy strategies because biomass is the most abundant and also the most renewable biomaterial on our planet. Bioconversion of lignocellulosic residues is initiated primarily by microorganisms such as fungi and bacteria which are capable of degrading lignocellulolytic materials. Fungi such as Trichoderma reesei and Aspergillus niger produce large amounts of extracellular cellulolytic enzymes, whereas bacterial and a few anaerobic fungal strains mostly produce cellulolytic enzymes in a complex called cellulosome, which is associated with the cell wall. In filamentous fungi, cellulolytic enzymes including endoglucanases, cellobiohydrolases (exoglucanases) and beta-glucosidases work efficiently on cellulolytic residues in a synergistic manner. In addition to cellulolytic/hemicellulolytic activities, higher fungi such as basidiomycetes (e.g. Phanerochaete chrysosporium) have unique oxidative systems which together with ligninolytic enzymes are responsible for lignocellulose degradation. This review gives an overview of different fungal lignocellulolytic enzymatic systems including extracellular and cellulosome-associated in aerobic and anaerobic fungi, respectively. In addition, oxidative lignocellulose-degradation mechanisms of higher fungi are discussed. Moreover, this paper reviews the current status of the technology for bioconversion of biomass by fungi, with focus on mutagenesis, co-culturing and heterologous gene expression attempts to improve fungal lignocellulolytic activities to create robust fungal strains. PMID- 19774112 TI - Synergistic role of hydroxyapatite nanoparticles and pulsed electromagnetic field therapy to prevent bone loss in rats following exposure to simulated microgravity. AB - The purpose of the present study was to use capacitive coupling of pulsed electromagnetic field (CC-PEMF) and hydroxyapatite nanoparticles (HAp) as a countermeasure to prevent osteoporosis induced by simulated microgravity. We used the hind-limb suspension (HLS) rat model to simulate microgravity-induced bone losses for 45 days. In order to compare the resulting changes, mineralogical (bone mineral density [BMD], calcium [Ca], and phosphorus [P]), biochemical (osteocalcin, alkaline phosphatase [ALP], and type I collagen), and histological (scanning electron microscopy) parameters were adopted. As a countermeasure to the above, the effect of PEMF and HAp application were examined. Three-month-old female Wistar rats were randomly divided into control (n = 8), HLS (n = 8), HLS with PEMF (n = 8), HLS with HAp nanoparticles (n = 8), and HLS with HAp and PEMF (n = 8). We observed: 1) significant decrease (p < 0.01) in BMD, Ca, P, type I collagen, and ALP activity in femur and tibia in hind-limb bone and serum osteocalcin in HLS rats as compared with the ground control. 2) Nonsignificant increase in BMD (p < 0.1), Ca (p < 0.1), P (p < 0.5), type I collagen (p < 0.1), and ALP activity (p < 0.5) in femur and tibia in hind-limb bone and serum osteocalcin (p < 0.5) in HLS + PEMF rats compared with HLS rats. 3) Significant increase in BMD (p < 0.02), Ca (p < 0.05), P (p < 0.05), type I collagen (p < 0.02), and ALP activity (p > 0.02) in femur and tibia in hind-limb bone with a nonsignificant increase in serum osteocalcin (p > 0.1) in HLS + HAp rats compared to HLS rats. 4) Significant increase in BMD (p > 0.01). Ca (p > 0.01). P (p > 0.01). type I collagen (p > 0.01). and ALP activity (p > 0.01) in femur and tibia in hind-limb bone and serum osteocalcin (p > 0.02) were also observed. Results suggest that a combination of low level PEMF and Hap nanoparticles has potential to control bone loss induced by simulated microgravity. PMID- 19774113 TI - The use of superparamagnetic nanoparticles for prosthetic biofilm prevention. AB - As with all surgical procedures, implantation comes with the added risk of infection. The goal of this in vitro study was to explore the use of superparamagnetic iron oxide nanoparticles (SPION) as a multifunctional platform to prevent biofilm formation. Results showed for the first time decreased Staphylococcus epidermidis numbers when exposed to 100 microg/ml of SPION for 12 hours and this trend continued for up to 48 hours. Prevention of colony assembly, a prerequisite to biofilm formation, was also observed at lower SPION dosages of 10 microg/ml after 12 hours. Coupled with previous studies demonstrating enhanced bone cell functions in the presence of the same concentration of SPION, the present results provided much promise for the use of SPION for numerous anti infection orthopedic applications. PMID- 19774114 TI - Characterization of complexation of poly (N-isopropylacrylamide-co-2 (dimethylamino) ethyl methacrylate) thermoresponsive cationic nanogels with salmon sperm DNA. AB - Thermoresponsive cationic nanogel (TCNG) networks based on N-isopropylacrylamide (NIPAM), 2-(dimethylamino)ethyl methacrylate (DMAEMA), and quaternary alkyl ammonium halide salts of DMAEMA (DMAEMAQ) were synthesized by dispersion polymerization technique. The thermoresponsive properties of TCNGs and TCNG salmon sperm DNA (sasDNA) polyplexes were characterized in aqueous media of various pH and ionic strength. P[NIPAM] and P[NIPAM/DMAEMA] TCNGs exhibited sharp volume phase transition (VPT) in water at critical temperatures (T(c)) of 32 degrees C and 36 degrees C, respectively. Quaternized P[NIPAM/DMAEMAQ] TCNGs did not undergo sharp VPT up to 50 degrees C. The VPT of uncomplexed TCNGs were sensitive to the ionic composition and ionic strength of salts in solution, but were insensitive to pH in the range 5.0 to 7.4. The VPT of P[NIPAM/DMAEMAQ]/sasDNA diminished in magnitude with increasing W(p)/W(d) suggesting greater compaction of the polyplexes. The distinct phase-transition properties of P[NIPAM/DMAEMA]/sasDNA and P[NIPAM/DMAEMAQ]/sasDNA polyplexes were attributed to the condensing capability of polycations and to differences in the spatial distribution of structural charges in quaternized and nonquaternized networks. The findings demonstrate that stable TCNGs can be prepared with controllable responsive properties determined by the nature of the cationic charge incorporated and may have potential as vehicles for DNA delivery. PMID- 19774115 TI - Irradiation stability and cytotoxicity of gold nanoparticles for radiotherapy. AB - Gold nanoparticles are promising as a kind of novel radiosensitizer in radiotherapy. If gold nanoparticles are shown to have good irradiation stability and biocompatibility, they would play an important role in radiotherapy. In this work, we investigated irradiation effects of gold nanoparticles under 2-10 kR gamma irradiation and cytotoxicity of gold nanoparticles with human K562 cells by using Cell Titre-Glo luminescent cell viability assay. The results revealed that gamma irradiation had not induced any obvious instability and size variations in gold nanoparticles. We found that gold nanoparticles showed excellent radiation hardness with an absorbed dose conversation factor of 9.491 rad/R. Meanwhile, the surface plasmon resonance of gold nanoparticles was enhanced obviously after 2-10 kR gamma irradiation. Subsequently, cytotoxicity tests indicated that the extremely high concentration of gold nanoparticles could cause a sharp decrease in K562 cell viability, while the low concentration of gold nanoparticles had no obvious influence on the cell viability. Our results revealed that gold nanoparticles were stable under high-energy ray irradiation and showed concentration-dependent cytotoxicity. PMID- 19774116 TI - Pharmacokinetics and tolerance study of intravitreal injection of dexamethasone loaded nanoparticles in rabbits. AB - The aim of the study was to investigate the tolerance and pharmacokinetics of dexamethasone (DEX)-loaded poly(lactic acid-co-glycolic acid) nanoparticles (DEX NPs) in rabbits after intravitreal injection. The DEX-NPs were prepared and characterized in terms of morphology, particle size and size distribution, encapsulation efficiency, and in vitro release. Ophthalmic investigations were performed, including fundus observation and photography, intraocular pressure measurement, and B-scan ocular ultrasonography. There were no abnormalities up to 50 days after administration of DEX-NPs in rabbits. The DEX concentrations in plasma and the ocular tissues such as the cornea, aqueous humor, lens, iris, vitreous humor, and chorioretina were determined by high-pressure liquid chromatography. The DEX-NPs maintained a sustained release of DEX for about 50 days in vitreous and provided relatively constant DEX levels for more than 30 days with a mean concentration of 3.85 mg/L(-1). Based on the areas under the curve, the bioavailability of DEX in the experimental group was significantly higher than that in the control group injected with regular DEX. These results suggest that intravitreal injection of DEX-NPs lead to a sustained release of DEX with a high bioavailability, providing a basis for a novel approach to the treatment of posterior segment diseases. PMID- 19774117 TI - Food effect on the bioavailability of two distinct formulations of megestrol acetate oral suspension. AB - OBJECTIVE: Megestrol acetate oral suspension (MAOS) is an appetite stimulant indicated for cachexia in patients with AIDS. It is available in its original formulation, Megace (MAOS), and as a nanocrystal dispersion, Megace ES (MA-ES). Three studies were conducted to evaluate the pharmacokinetic properties of these formulations under fed and fasting conditions. METHODS: An open-label, crossover trial was conducted in 24 healthy males randomized to MA-ES 625 mg/5 mL given with a high-calorie, high-fat meal, or after an overnight fast. Blood samples were drawn at multiple time points and pharmacokinetic parameters were determined. Two separate, open-label reference studies evaluated MAOS 800 mg/20 mL in 40 fed or 40 fasting healthy male volunteers. RESULTS: In fasting MA-ES subjects, the average maximum concentration (C(max)) was 30% less than the fed C(max) value. For MAOS, fasting C(max) was 86% less than fed C(max). In fasting subjects, the area under the curve was 12,095 ng.h/mL for MA-ES, and 8,942 ng.h/mL for MAOS. In fed subjects, the absorption of the two formulations was comparable. CONCLUSION: Bioavailability and absorption are greater for MA-ES than MAOS in fasting subjects. MA-ES may be a preferred formulation of megestrol acetate when managing cachectic patients whose caloric intake is reduced. PMID- 19774119 TI - Connecticut's continuing role in advancing stem cell research. PMID- 19774120 TI - Embryonic stem cell research: a decade of debate from Bush to Obama. PMID- 19774118 TI - Binding fullerenol C(60)(OH)(24) to dsDNA. AB - The first C(60)(OH)(24)-DNA complex and its fluorescence enhancement is reported. The enhanced fluorescence intensity of fullerenol C(60)(OH)(24) is in proportion to the concentration of DNA in the range of 1 x 10(-9) to 8 x 10(-5) molL(-1) and the detection limit was 1.3 ng mL(-1). Fullerenol C(60)(OH)(24) binds significantly to the phosphate backbone of native dsDNA and to base-pairs within the major groove of sodium salt of dsDNA. PMID- 19774121 TI - Understanding the mysteries of iPS cells. PMID- 19774122 TI - Anticipating a next-generation census of stem-cell small RNA. PMID- 19774123 TI - Stem cell-based drug therapies: a discussion on emerging technologies and future developments. PMID- 19774124 TI - Stem cell research policies around the world. AB - The proliferation of stem cell research, conflated with its ethical and moral implications, has led governments to attempt regulation of both the science and funding of stem cells. Due to a diversity of opinions and cultural viewpoints, no single policy or set of rules exist to govern stem cell research. Instead, each country has developed its own policy. The following map catalogs the general legal and political milleu regarding stem cell research by country. PMID- 19774125 TI - Regeneration of a heart cell. PMID- 19774126 TI - PIWI, piRNAs, and germline stem cells: what's the link? PMID- 19774127 TI - We are like that only. PMID- 19774128 TI - Presidential address. PMID- 19774129 TI - Leading by learning: A lifelong commitment to leadership programme. PMID- 19774130 TI - Three-dimensional imaging for hepatobiliary and pancreatic diseases: Emphasis on clinical utility. AB - Three-dimensional (3D) imaging allows disease processes and anatomy to be better understood, both by radiologists as well as physicians and surgeons. 3D imaging can be performed with USG, CT scan and MRI, using different modes or rendering that include surface-shaded display, volume-based rendering, multiplanar imaging, etc. All these techniques are used variably depending on the indications. PMID- 19774131 TI - Teleradiology: The Indian perspective. PMID- 19774132 TI - Commentary: teleradiology: the Indian perspective. PMID- 19774133 TI - Consent in radiology practice. PMID- 19774134 TI - Signature on consent form when the patient's right/left hand is impaired. PMID- 19774135 TI - Monitor displays in radiology: Part 1. AB - Monitor displays are an integral part of today's radiology work environment, attached to workstations, USG, CT/MRI consoles and PACS terminals. For each modality and method of use, the correct display monitor needs to be deployed. It helps to have a basic understanding of how monitors work and what are the issues involved in their selection. PMID- 19774136 TI - Image-guided lumbar facet joint infiltration in nonradicular low back pain. AB - OBJECTIVE: To assess the efficacy of facet joint infiltrations for pain relief in 44 selected patients with chronic nonradicular low back pain (LBP). MATERIALS AND METHODS: Forty-four patients with chronic LBP of more than 3 months' duration were selected for facet joint infiltration. The majority (n = 24) had facetal pain with no evidence of significant facetal arthropathy on imaging. Fifteen patients had radiological evidence of facetal arthropathy, one had a facet joint synovial cyst, three were post-lumbar surgery patients, and two patients had spondylolysis. Facet joint injections were carried out under fluoroscopic guidance in 39 patients and under CT guidance in 5 cases. Pain relief was assessed using the visual analog scale at 1 h post-procedure and, thereafter, at 1, 4, 12, and 24 weeks. RESULTS: A total of 141 facet joints were infiltrated in 44 patients over a 2-year period. There was significant pain relief in 81.8% patients 1 h after the procedure, in 86.3% after 1 week, in 93.3% after 4 weeks, in 85.7% after 12 weeks, and in 62.5% after 24 weeks. No major complications were encountered. CONCLUSIONS: Facet nerve block was found to be a simple, minimally invasive, and safe procedure. With meticulous patient selection, we achieved long term success rates of over 60%. We conclude that this method represents an important alternative treatment for nonradicular back pain. PMID- 19774137 TI - Commentary: Facet joint infiltration for chronic low back pain: Is it worthwhile? PMID- 19774138 TI - Percutaneous radiofrequency ablation for osteoid osteoma: How we do it. AB - AIMS AND OBJECTIVES: To describe our technique for performing radiofrequency ablation (RFA) in osteoid osteoma and to evaluate the results of treatment. MATERIALS AND METHODS: We evaluated 40 patients in whom RFA was performed for osteoid osteomas between October 2005 and February 2008. The lesions were located in the femur (n = 22), tibia (n = 10), humerus (n = 2), acetabulum (n = 2), radius (n = 1), fibula (n = 1), patella (n = 1), and calcaneum (n = 1). The procedure was performed using a standard technique. RESULTS: Technical success was achieved in all patients, with intranidal localization of the needle and complete ablation. All patients were fully weight bearing 2-3 h after the procedure. Successful pain relief was achieved in all patients within 48 h. Immediate complications included a case of minor thermal skin burn and a small cortical chip fracture, which healed on its own. There were no delayed complications. The average follow-up period was 12 months. Two patients (5% of cases) had recurrence of pain after intervals of 5 and 8 months, respectively, following the ablation; this was due to recurrence of the lesion. Complete pain relief was however achieved after a second ablation in both cases. Thus, our primary and secondary clinical success rates were 95 and 100%, respectively. CONCLUSION: RFA is a safe, quick, minimally invasive, and extremely effective method for the management of osteoid osteomas. PMID- 19774139 TI - Intracranial dural arteriovenous fistulas: A Review. AB - Dural arteriovenous fistulas are fistulas connecting the branches of dural arteries to dural veins or a venous sinus. Digital subtraction angiography remains the gold standard for diagnosing these fistulas. Endovascular treatment is one of the first line options available for their management. This review article reviews the etiopathogenesis, natural history, common classification systems and various available treatment options. PMID- 19774140 TI - Pictorial essay: Coronary artery variants and anomalies. AB - CT coronary angiography has helped radiologists understand the variations and anomalies of the anatomy of the coronary arteries and, thus, to alert the cardiologist whenever such an anomaly is present. This can be of immense help to the clinician planning interventional procedures such as stenting, balloon dilatation, or graft surgery, particularly when there are secondary changes of calcification, plaque formation and stenosis. PMID- 19774141 TI - 64-slice CT imaging in a case of total anomalous pulmonary venous circulation. AB - For long, catheter angiography has been the investigation of choice for the diagnosis of congenital anomalies of the heart such as total anomalous pulmonary venous circulation (TAPVC). In the last few years, MRI and multislice CT scan have also been introduced for this purpose. We report a case where 64-slice CT scan was found very useful in the evaluation of TAPVC. PMID- 19774142 TI - Case report: Myocardial tuberculosis-MRI. PMID- 19774143 TI - Fetal echocardiography. AB - USG performed with a high-end machine, using a good cine-loop facility is extremely helpful in the diagnosis of fetal cardiac anomalies. In fetal echocardiography, the four-chamber view and the outflow-tract view are used to diagnose cardiac anomalies. The most important objective during a targeted anomaly scan is to identify those cases that need a dedicated fetal echocardiogram. Associated truncal and chromosomal anomalies need to be identified. This review shows how fetal echocardiography, apart from identifying structural defects in the fetal heart, can be used to look at rhythm abnormalities and other functional aspects of the fetal heart. PMID- 19774145 TI - Case report: Antenatal MRI diagnosis of esophageal duplication cyst. AB - Esophageal duplication cysts are classified as a subgroup of foregut duplication cysts. They are very rare and are predominantly detected in children. Antenatal detection is very rare. We report a case of an esophageal duplication cyst that was accurately identified antenatally by USG and MRI. PMID- 19774144 TI - Pictorial essay: MRI of the fetal brain. AB - MRI is a useful supplement to USG for the assessment of fetal brain malformations. Superior soft tissue contrast and the ability to depict sulcation and myelination are the strengths of MRI. Subtle or inconclusive USG abnormalities can be confirmed or ruled out by MRI. In some cases, additional findings detected with MRI often help in arriving at a definitive diagnosis, which is necessary for parental counseling and for guiding management. Fast T2W sequences form the basis of fetal MRI. There have been no reports of deleterious effects of MRI on the fetus. A few case examples are presented to illustrate the advantages of MRI. PMID- 19774146 TI - Fetal diastematomyelia: MR imaging: A case report. AB - MRI is increasingly being used in the diagnosis of fetal anomalies suspected on USG. The USG evaluation of fetal spinal anomalies is limited by acoustic shadowing, fetal position and the amount of liquor. Fetal MRI is able to show spinal anomalies well, as in our case of fetal diastematomyelia with a dorsal dermal sinus, suspected on USG at 28 weeks gestation. PMID- 19774147 TI - Case series: TRAP sequence. AB - TRAP (twin reversed arterial perfusion) sequence / acardiac twinning is a rare anomaly that occurs in monozygotic monochorionic twins with an incidence of 1% and in 1 in 35,000 pregnancies overall. The anomalous twin appears as a heterogeneous mass, simulating a teratoma or intrauterine fetal demise. As the normal twin faces increased morbidity and mortality, antenatal diagnosis with gray-scale examination, and Doppler confirmation of the diagnosis of TRAP sequence in twin pregnancies, aids in proper prenatal management. We report two cases of TRAP sequence that we encountered over a single month, with the two cases having different outcomes. PMID- 19774148 TI - Prenatal diagnosis of left ventricular aneurysm. AB - Fetal cardiac anomalies involving the ventricular and atrial septa, outflow tracts, chambers, and valves are often encountered in routine screening. However, the prenatal detection of a fetal left ventricular aneurysm is rare. This report describes the case of a left ventricular aneurysm that was diagnosed at 24 weeks of gestation; the diagnosis was later confirmed by postnatal echocardiography. This case is reported because of its rarity and the characteristic echocardiographic findings. An early specific antenatal USG diagnosis helps in prognostication and in counseling of the parents. PMID- 19774149 TI - Chest. PMID- 19774150 TI - Pediatric imaging. PMID- 19774151 TI - The 'why' of radiology and related issues. PMID- 19774153 TI - Commentary - radiology in India: the next decade. PMID- 19774152 TI - Commentary - radiology in India: the next decade. PMID- 19774154 TI - Commentary - radiology in India: the next decade. PMID- 19774155 TI - Law and the radiologist, socio-legal perspectives in radiology practice, lex radiologica: Fundamental commandments of radiology practice in the times that be. PMID- 19774156 TI - Liberalizing consent - Supreme Court's preference for 'real consent' over 'informed consent'. PMID- 19774157 TI - Roentgenological diagnosis of alimentary tract emergencies in the new born. PMID- 19774158 TI - Impact of computers in radiography: The advent of digital radiography, Part-2. PMID- 19774159 TI - Clinical applications of functional MRI in epilepsy. AB - The role of functional MRI (fMRI) in the presurgical evaluation of patients with intractable epilepsy is being increasingly recognized. Real-time fMRI is an easily performable diagnostic technique in the clinical setting. It has become a noninvasive alternative to intraoperative cortical stimulation and the Wada test for eloquent cortex mapping and language lateralization, respectively. Its role in predicting postsurgical memory outcome and in localizing the ictal activity is being recognized. This review article describes the biophysical basis of blood oxygen-level-dependent (BOLD) fMRI and the methodology adopted, including the design, paradigms, the fMRI setup, and data analysis. Illustrative cases have been discussed, wherein the fMRI results influenced the seizure team's decisions with regard to diagnosis and therapy. Finally, the special issues involved in fMRI of epilepsy patients and the various challenges of clinical fMRI are detailed. PMID- 19774160 TI - Case series: Nocardiosis of the brain and lungs. AB - Localized and multisystem nocardiosis is an opportunistic disease that occurs commonly in immunocompromised patients. Rarely, it is also seen in immunocompetent individuals. The lungs and brain are commonly involved. Typical, but nonspecific, findings are often seen on imaging and the presence of concomitant lesions in these two systems often suggests this diagnosis. We report two cases of cerebral and pulmonary involvement by nocardiosis. PMID- 19774161 TI - Case report: Middle cranial fossa arachnoid cyst in association with subdural hygroma. PMID- 19774162 TI - Case series: MRI features in cerebral malaria. PMID- 19774163 TI - Case report: Reversible restricted diffusion and cytotoxic edema in the perilesional zone following continuous partial seizures. PMID- 19774164 TI - Case report: Fat-containing liver metastases from retroperitoneal liposarcoma. PMID- 19774165 TI - Case report: Retroperitoneal biliary fluid collections secondary to common bile duct rupture - an unusual complication of choledocholithiasis in a child. AB - Rupture of the common bile duct (CBD) in a child secondary to choledocholithiasis is a rare event. In this article, the authors describe a child who presented with an acute abdomen due to CBD rupture, with subsequent acute retroperitoneal fluid collections, all diagnosed preoperatively on CT scan. The aim of this article is to show the pathways that such collections can take in the retroperitoneum. PMID- 19774166 TI - Case report: Cholangiocarcinoma in a choledochal cyst. AB - Cholangiocarcinoma is a dreaded complication of unresected choledochal cysts, with an incidence approaching 20-30% in early adulthood. The risk of cholangiocarcinoma remains high where an internal drainage procedure has been performed and the cyst has been partially resected or left unresected. We report a case of cholangiocarcinoma occurring in an unresected choledochal cyst following a drainage procedure in infancy and highlight the role of PET/CT in its diagnosis. PMID- 19774167 TI - Case report: MRI diagnosis of multifocal epithelioid hemangioendothelioma of the liver. PMID- 19774168 TI - Case report: Anomalous systemic drainage of ileocolic veins (veins of Retzius) causing pelviureteric junction obstruction. PMID- 19774169 TI - Transjugular liver biopsy: What to do and what not to do. PMID- 19774170 TI - Interventional radiology in the management of portal hypertension. AB - From being a mere (though important) diagnostic tool, radiology has evolved to become an integral part of therapy in portal hypertension today. Various procedures are currently available, the choice depending on the etiology and location of disease, the pathoanatomy, and the symptomatology. The main aim of any procedure is to reduce the portal pressure by either direct or indirect methods. This can be achieved with transjugular intrahepatic portosystemic shunt (TIPS), recanalization of the hepatic vein outflow, recanalization of the portal vein and its tributaries, recanalization of dysfunctional portosystemic shunts, partial splenic embolization, and embolization of arterioportal shunts. When any of these procedures cannot be performed due to anatomical or physiological reasons, the symptoms can often be controlled effectively with embolization of varices or balloon-occluded retrograde transvenous obliteration of varices (BRTO). This article briefly describes the procedures, their results, and their current status in the treatment of portal hypertension. PMID- 19774171 TI - Current trends in endovascular management of intracranial aneurysms (including posterior fossa aneurysms and multiple aneurysms). PMID- 19774172 TI - Webgroups: A way of facilitating web-based professional interaction - Initial experience at the IRIA, Delhi state branch. PMID- 19774173 TI - Tuberculosis - The spoil sport. PMID- 19774174 TI - Anterior abdominal wall cysticercosis-the role of high-resolution USG. PMID- 19774175 TI - Radiology websites: Fetal imaging. PMID- 19774176 TI - We have a problem! PMID- 19774177 TI - Evolutionary trends in radiology assessment: The importance of the learning cycle and its assessment in radiology. PMID- 19774178 TI - Radiologist's liability for an erroneous report due to wrong labeling by juniors/para medics. PMID- 19774179 TI - Radiology curriculum. PMID- 19774180 TI - Editorial, the practice of radiology, ethical considerations. PMID- 19774181 TI - CT perfusion in acute stroke. AB - Stroke is a heterogeneous syndrome caused by multiple mechanisms, all of which result in disruption of normal cerebral blood flow and thereby cause cerebral dysfunction. Its early diagnosis is important as its treatment is dependent on the time elapsed since ictus. Delay in diagnosis and treatment translates into increase neuronal loss and thereby increased morbidity. CT scan, and in particular perfusion CT, has helped greatly in the early diagnosis of stroke. This article is an endeavor to explain the pathophysiology of cerebral ischemia and the role of CT perfusion in detecting it. PMID- 19774182 TI - Storage media for computers in radiology. AB - The introduction and wide acceptance of digital technology in medical imaging has resulted in an exponential increase in the amount of data produced by the radiology department. There is an insatiable need for storage space to archive this ever-growing volume of image data. Healthcare facilities should plan the type and size of the storage media that they needed, based not just on the volume of data but also on considerations such as the speed and ease of access, redundancy, security, costs, as well as the longevity of the archival technology. This article reviews the various digital storage media and compares their merits and demerits. PMID- 19774183 TI - PET/CT: Current status in India. AB - PET/CT is a new modality with integration of PET and CT systems. In India, since December 2004 there has been a steady increase in the number of imaging systems. From stand-alone PET/CT systems with on-site cyclotrons, mostly in the government sector, the modality has matured to such an extent that, today, the majority of the PET/CT scanners and cyclotrons are in the private setup; also, scanners situated in different locations (and even different cities) share the isotope produced from one cyclotron. This shows how much this field has developed and reflects the confidence of the end users. The current status of PET/CT in India is indeed healthy and heartening and the future certainly looks promising. PMID- 19774184 TI - Case report: Subutaneous hemangiomatosis causing Kasabach-Merritt syndrome - MRI features. AB - Hemangiomatosis is an uncommon entity in which there is diffuse infiltration of soft tissue or bone by hemangioma. Kasabach-Merritt syndrome is an uncommon complication of large hemangiomas, in which there is thrombocytopenia and coagulopathy. Plain radiographs, in addition to showing a soft tissue mass, also show a variety of findings in the bones. MRI is the investigation of choice. A case of a 2-year-old child suffering from hemangiomatosis and a resultant Kasabach-Merritt syndrome is presented. PMID- 19774185 TI - Case Report: Macrodystrophia lipomatosa - Illustration of two cases. AB - Macrodystrophia lipomatosa is a rare cause of congenital macrodactyly, characterized by progressive proliferation of all mesenchymal elements, with a disproportionate increase in fibroadipose tissue. This developmental anomaly is reportedly more common in the foot than in the hand, with a predilection for the plantar and median nerve distribution. We present two cases of MDL of the hand, one of which had an unusual nerve territory distribution, making clinical diagnosis difficult. Preoperative diagnosis was however made on the basis of radiography and MRI and was later confirmed on surgery. PMID- 19774186 TI - Role of cervical ultrasonography in primary hyperparathyroidism. AB - AIM: To evaluate the role of USG in the preoperative localization of parathyroid adenomas in patients with symptomatic hyperparathyroidism and to compare its usefulness with that of scintigraphy scan and postoperative findings. MATERIAL AND METHODS: Twenty-five patients with symptomatic primary hyperparathyroidism were subjected to USG of the neck and nuclear scintigraphy, followed by surgery. The results were independently analyzed and compared with per-operative findings. RESULTS: The 25 patients had a total of 28 abnormal glands: 22 solitary adenomas, and 6 multiple adenomas (two each in three patients). USG detected 20 out of 22 solitary adenomas and three out of six multiple adenomas. USG missed five abnormal glands, two of which were in the neck and three in the mediastinum. Scintigraphy was positive in 26 abnormal glands, out of which 22 were single and four were multiple. Two abnormal glands were missed: one in the neck and one in the mediastinum. CONCLUSION: As limited neck dissection for primary hyperparathyroidism becomes increasingly popular, USG has been found to be a sensitive, specific, and easily available noninvasive investigation for parathyroid localization. It can be easily offered to patients as a method for preoperative localization prior to limited parathyroid surgery outside tertiary care settings. PMID- 19774187 TI - Case Report: Congenital infiltrating lipomatosis of face. AB - Congenital infiltrating lipomatosis of the face is a rare condition characterized by diffuse fatty infiltration of the facial soft tissues. There may be muscle involvement along with associated bony hyperplasia. It is a type of lipomatous tumor that is congenital in origin; it is rare and seen usually in childhood. We recently saw an 11-year-old girl with this condition. She presented with a swelling of the right side of the face that had been present since birth; there were typical findings on plain radiographs, CT, and MRI. The patient underwent cosmetic surgery. Histopathological examination showed mature adipocytes without any capsule. PMID- 19774188 TI - Extraconal cavernous hemangioma of orbit: A case report. AB - Cavernous hemangioma is the most common benign noninfiltrative neoplasm of the orbit. Most cavernous hemangiomas are intraconal and lateral in location. We present a case of a cavernous hemangioma with an unusual extraconal and superomedial location. PMID- 19774189 TI - Right-sided hemiagenesis of the thyroid lobe and isthmus: A case report. AB - Unilateral or bilateral hypoplasia or agenesis of one or both thyroid lobes, with or without isthmic agenesis, is a rare developmental anomaly. Hemiagenesis of the left lobe is far commoner than of the right. Clinically, these patients may be euthyroid, hyperthyroid, or hypothyroid. Ultrasonography is usually able to diagnose this condition easily, as we demonstrate in this case report of a 37 year-old lady with an incidentally detected thyroid nodule who was found to have hemiagenesis of the right lobe and isthmus. PMID- 19774190 TI - Case report: Mounier-Kuhn syndrome. AB - Tracheobronchomegaly or Mounier-Kuhn syndrome is a rare disorder characterized by marked dilatation of the trachea and main bronchi, bronchiectasis, and recurrent respiratory tract infections. The etiology of this disorder is uncertain and the clinical presentation is variable. The diagnosis is usually made on the basis of the characteristic CT scan findings. We report a case in a 21-year-old man presenting with recurrent lower respiratory tract infections. PMID- 19774191 TI - Case report: Epidermoid cyst misdiagnosed as a loculated pericardial effusion. AB - A 25-year old man presented with a mediastinal lesion which was initially diagnosed as a loculated pericardial collection on echocardiography. Subsequent imaging showed it to be a cystic mediastinal mass, and following surgery and histopathology, it turned out to be an epidermoid cyst. PMID- 19774192 TI - Case Report: Spontaneous aneurysm of ductus arteriosus: A rare cause of hoarseness of voice in adults. AB - Ortner's syndrome (left recurrent laryngeal nerve palsy caused by cardiovascular pathology) is described in literature as occurring secondary to a variety of conditions. Spontaneous aneurysm of ductus arteriosus is a rare cause of this condition. We present a case where an adult patient with an aneurysm of the ductus arteriosus presented for the first time at the age of 62 years with hoarseness of voice secondary to left recurrent laryngeal nerve palsy. PMID- 19774193 TI - Editorial: Mini symposium on obstetric imaging. PMID- 19774195 TI - Prenatal diagnosis of fetal syndromes. AB - A syndrome is a pattern of multiple anomalies arising due to a single known causative factor. Ultrasonography has enabled us to recognize many fetal anomalies and dysmorphic features. Recognition of the anomaly pattern leads to the diagnosis of a particular syndrome. This enables us to counsel prospective parents and aids in management. We present a selection of fetal syndromes in the form of a pictorial essay. PMID- 19774194 TI - Fetal environment. AB - The intrauterine environment has a strong influence on pregnancy outcome. The placenta and the umbilical cord together form the main supply line of the fetus. Amniotic fluid also serves important functions. These three main components decide whether there will be an uneventful pregnancy and the successful birth of a healthy baby. An insult to the intrauterine environment has an impact on the programming of the fetus, which can become evident in later life, mainly in the form of cardiovascular diseases, diabetes, and certain learning disabilities. The past two decades have witnessed major contributions from researchers in this field, who have included ultrasonologists, epidemiologists, neonatologists, and pediatricians. Besides being responsible for these delayed postnatal effects, abnormalities of the placenta, umbilical cord, and amniotic fluid also have associations with structural and chromosomal disorders. Population and race also influence pregnancy outcomes to some extent in certain situations. USG is the most sensitive imaging tool currently available for evaluation of these factors and can offer considerable information in this area. This article aims at reviewing the USG-related developments in this area and the anatomy, physiology, and various pathologies of the placenta, umbilical cord, and the amniotic fluid. PMID- 19774196 TI - Case report: Antenatal diagnosis of congenital high airway obstruction syndrome - laryngeal atresia. AB - Congenital high airway obstruction syndrome (CHAOS) is a near fatal condition of multifactorial inheritence, in which the fetus has a dilated trachea, enlarged echogenic lungs, an inverted or flattened diaphagram, and ascites. A case of CHAOS, diagnosed antenatally on USG at 28 weeks of gestation, is being reported here. PMID- 19774197 TI - Absent pulmonary valve syndrome with tetralogy of Fallot and associated dextrocardia detected at an early gestational age of 26 weeks. AB - Absent pulmonary valve syndrome is a rare congenital anomaly, usually seen in association with a ventricular septal defect. It has been reported to occur in 3 6% of cases of tetralogy of Fallot. Absence of the pulmonary valve results in a dilated main pulmonary artery, which can be seen as a cystic, pulsatile, paracardiac lesion on antenatal USG. Such a lesion, though rare, can easily be detected. We report a case of this rare anomaly which was present in association with a ventricular septal defect, tetralogy of Fallot, and dextrocardia. The case was detected at 26 weeks of gestation. PMID- 19774198 TI - Radiology websites: Conventional radiology. PMID- 19774199 TI - Differentiation of convulsive syncope from epilepsy with an implantable loop recorder. AB - INTRODUCTION: Not all convulsive episodes are due to epilepsy and a number of these have a cardiovascular cause. Failure to identify these patients delays the provision of adequate therapy while at the same time exposes the individual to the risk of injury or death. METHODS: We report on three patients who suffered from recurrent convulsive episodes, thought to be epileptic in origin, who were refractory to antiseizure therapy. Although each patient had undergone extensive evaluation, no other potential cause of his or her seizure like episodes had been uncovered. In each patient placement of an implantable loop recorder (ILR) demonstrated that their convulsive episodes were due to prolonged periods of cardiac asystole and/or complete heart block. In all patients their convulsive episodes were eliminated by permanent pacemaker implantation. CONCLUSION: In patients with refractory "seizure' like episodes of convulsive activity of unknown etiology a potential cardiac rhythm disturbance should be considered and can be easily evaluated by ILR placement. PMID- 19774200 TI - A k2A-positive Klebsiella pneumoniae causes liver and brain abscess in a Saint Kitt's man. AB - Klebsiella pneumoniae isolated in community-acquired pneumonia is increasingly found in primary pyogenic liver abscesses. The presence of magA in K. pneumoniae has been implicated in hypermucoviscosity and virulence of liver abscess isolates. The K2 serotype has also been strongly associated with hypervirulence. We report the isolation of non-magA, K2 K. pneumoniae strain from a liver abscess of a Saint Kitt's man who survived the invasive syndrome. PMID- 19774202 TI - Segmentation of heterogeneous blob objects through voting and level set formulation. AB - Blob-like structures occur often in nature, where they aid in cueing and the pre attentive process. These structures often overlap, form perceptual boundaries, and are heterogeneous in shape, size, and intensity. In this paper, voting, Voronoi tessellation, and level set methods are combined to delineate blob-like structures. Voting and subsequent Voronoi tessellation provide the initial condition and the boundary constraints for each blob, while curve evolution through level set formulation provides refined segmentation of each blob within the Voronoi region. The paper concludes with the application of the proposed method to a dataset produced from cell based fluorescence assays and stellar data. PMID- 19774201 TI - Anti-angiogenesis approach to genitourinary cancer treatment. AB - Angiogenesis plays a crucial role in the survival, proliferation, and metastatic potential of several tumors, including genitourinary (GU) cancers. Over the last decade, increasing basic science and clinical research have led to the approval of several angiogenesis inhibitors. GU tumors are unique in its pathogenesis whereby specific pathways, such as involvement of the Von Hippel-Lindau gene in clear cell renal cell cancer and aberrant overexpression of vascular endothelial growth factor in prostatic cancers and transitional cell bladder cancers, allow for potential targeting using angiogenesis inhibitors. This review discusses the biologic pathways as well as the rationale for using angiogenesis inhibitors in renal cell, prostate, and transitional cell bladder cancers. This review also focuses on pivotal trials and emerging data on the use of these inhibitors. PMID- 19774203 TI - Parenting Efficacy and the Early School Adjustment of Poor and Near-Poor Black Children. AB - This short-term longitudinal study investigated whether maternal educational attainment, maternal employment status, and family income affect African-American children's behavioral and cognitive functioning over time through their impacts on mothers' psychological functioning and parenting efficacy in a sample of 100 poor and near-poor single black mothers and their 3- and 4-year-old focal children. Results indicate that education, working status, and earnings display statistically significant, negative, indirect relations with behavior problems and, with the exception of earnings, statistically significant, positive, indirect relationships with teacher-rated adaptive language skills over time. Findings suggest further that parenting efficacy may mediate the link between poor and near-poor single black mothers' depressive symptoms and their preschoolers' subsequent school adjustment. Implications of these findings for policy and program interventions are discussed. PMID- 19774204 TI - Volume-based Feature Analysis of Mucosa for Automatic Initial Polyp Detection in Virtual Colonoscopy. AB - In this paper, we present a volume-based mucosa-based polyp candidate determination scheme for automatic polyp detection in computed colonography. Different from most of the existing computer-aided detection (CAD) methods where mucosa layer is a one-layer surface, a thick mucosa of 3-5 voxels wide fully reflecting partial volume effect is intentionally extracted, which excludes the direct applications of the traditional geometrical features. In order to address this dilemma, fast marching-based adaptive gradient/curvature and weighted integral curvature along normal directions (WICND) are developed for volume-based mucosa. In doing so, polyp candidates are optimally determined by computing and clustering these fast marching-based adaptive geometrical features. By testing on 52 patients datasets in which 26 patients were found with polyps of size 4-22 mm, both the locations and number of polyp candidates detected by WICND and previously developed linear integral curvature (LIC) were compared. The results were promising that WICND outperformed LIC mainly in two aspects: (1) the number of detected false positives was reduced from 706 to 132 on average, which significantly released our burden of machine learning in the feature space, and (2) both the sensitivity and accuracy of polyp detection have been slightly improved, especially for those polyps smaller than 5mm. PMID- 19774206 TI - Safety and efficacy of pegylated liposomal doxorubicin in HIV-associated Kaposi's sarcoma. AB - Kaposi's sarcoma is a vascular tumor linked to the presence of Kaposi's sarcoma associated herpesvirus (human herpesvirus-8) and the incidence of which has increased considerably the world over after the onset of the human immunodeficiency virus (HIV) pandemic. Antiretroviral therapy combined with cytotoxic agents has been established as the treatment of choice in the past 10 years. Among chemotherapeutic agents, pegylated liposomal doxorubicin has become the preferred one for patients with HIV-associated Kaposi's sarcoma in Western countries. The drug in this formulation localizes better to the tumor and has higher efficacy. Skin toxicity, mucositis, and leukopenia/neutropenia are the main side effects. Hepatotoxicity and mild cardiotoxicity are observed less frequently. Pegylated liposomal doxorubicin impacts favorably on quality of life. Although cost effective in Western countries, the drug is less so in developing countries. PMID- 19774205 TI - Finding a new drug and vaccine for emerging swine flu: what is the concept? AB - Influenza is a well known infection of the respiratory system. The main clinical manifestations of influenza include fever, sore throat, headache, cough, coryza, and malaise. Apart from the well known classical influenza, there are also groups of influenza virus infections that are called "atypical infection". These infections are usually due to a novel influenza virus infection. In early 2009, an emerging novel influenza originating from Mexico called swine flu was reported. The World Health Organization noted a level VI precaution, the highest level precaution possible, for this newest influenza virus infection. As of June 2009, it is not known if this disease will be successfully controlled. Finding new drugs and vaccine for the emerging swine flu is still required to cope with this emerging worldwide problem. PMID- 19774207 TI - Growing insights into the potential benefits and risks of activated protein C administration in sepsis: a review of preclinical and clinical studies. AB - Recombinant human activated protein C (rhAPC) was developed to reduce excessive coagulant and inflammatory activity during sepsis. Basic and clinical research has suggested these pathways contribute to the pathogenesis of this lethal syndrome and are inhibited by rhAPC. Based in large part on the results of a single multicenter randomized controlled trial, rhAPC was first approved in 2001 by the US Food and Drug Administration (FDA) as adjunctive therapy in septic patients with a high risk of death. This was followed closely by approval in Europe, Australia, and New Zealand. At the original FDA review of rhAPC, concerns were raised as to whether a confirmatory trial should be done before final regulatory approval because of concerns that rhAPCs bleeding risk might outweigh its potential benefit during clinical use. Since 2001, continuing basic and clinical research has further elucidated the complex role activated protein C may have in both adaptive and maladaptive responses during sepsis. Moreover, subsequent controlled trials in other types of septic patients and observational studies appear to support earlier concerns that the benefit-to-risk ratio of rhAPC may not support its clinical use. This experience has prompted additional trials presently underway, to define whether treatment with rhAPC as it was originally indicated in septic patients with persistent shock, is safe and effective. Until such trials are complete, physicians employing this agent must carefully consider which patients may be appropriate candidates for rhAPC administration. PMID- 19774208 TI - Review of the safety and efficacy of imiglucerase treatment of Gaucher disease. AB - Most patients who suffer from symptomatic Gaucher disease will benefit from enzyme replacement therapy (ERT) with imiglucerase. The safety profile is excellent, only a small percentage of those exposed developing antibodies; similarly, very few patients require pre-medication for allergic reactions. Within 3 to 5 years of imiglucerase therapy, best documented at doses of 30 to 60 units/kg/infusion, hepatosplenomegaly can be expected to be reduced so that the liver volume will be maintained at 1 to 1.5 times normal (30% to 40% reduction from advent of ERT) and spleen volume to /= 11 g/dL for women and children and >/= 12 g/dL for men; and platelet counts in patients with an intact spleen, depending on the baseline value, should approximately be doubled. Bone crises and bone pain but not irreversible skeletal damage will improve in most patients. Nonetheless, some features and some symptomatic patients apparently do not respond equally well and/or perhaps inadequately. The benefit for patients with the neuronopathic forms is primarily in improved visceral and hematological signs and symptoms. There are still several unresolved issues, the high per-unit cost being an important one, which have spurred the development of biosimilar enzymes as well as chaperone therapies currently in clinical trials. PMID- 19774209 TI - Treatment of pancreatic cancer with epidermal growth factor receptor-targeted therapy. AB - Pancreatic adenocarcinoma is a common malignancy that remains refractory to available therapies. Gemcitabine has long been the standard, first-line agent in advanced disease. The epidermal growth factor receptor (EGFR) is a commonly expressed target in pancreatic cancer that is involved in tumor proliferation, metastasis, and induction of angiogenesis. The addition of the EGFR inhibitor erlotinib to gemcitabine has recently been demonstrated to provide a small, yet statistically significant, survival benefit in advanced disease. This has prompted further research into the applications of EGFR-targeted therapy in pancreatic cancer, albeit with disappointing results. Resistance to these therapies seems highly prevalent and has been implicated in their limited efficacy. The development of rash is associated with treatment efficacy and suggests that predictive factors may one day be identified to guide appropriate patient selection for these agents. Preclinical research has shown promise that resistance to EGFR-targeted therapies can be overcome through a variety of approaches. Application of this research in clinical trials may ultimately yield an unquestioned role for EGFR-targeted therapy in the management of this disease. PMID- 19774211 TI - Role of everolimus in the treatment of renal cell carcinoma. AB - The therapeutic options in metastatic renal cell carcinoma have been recently expanded by the discovery of the VHL gene, the mutation of which is associated with development of clear cell carcinoma, and overexpression of the angiogenesis pathway, resulting in a very vascular tumor. This breakthrough in science led to the development of a variety of small molecules inhibiting the VEGF-dependent angiogenic pathway, such as sunitinib and sorafenib. These agents prolong overall and progression-free survival, respectively. The result was the development of robust front-line therapies which ultimately fail and are associated with disease progression. In this setting, there existed an unmet need for developing second line therapies for patients with refractory metastatic renal cell carcinoma (MRCC). Everolimus (RAD 001) is an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway. The double-blind, randomized, placebo-controlled phase III trial of everolimus (RECORD-1) conducted in MRCC patients after progression on sunitinib or sorafenib, or both, demonstrated a progression-free survival benefit favoring the study drug (4.9 months vs 1.9 months, HR 0.33, 95% CI 0.25 to 0.43, P 1 mus) parent molecular anions are detected at zero eV and near 1 eV. The close similarity of the electron transmission spectrum with the derivatives with respect to energy of the anion currents suggests strongly that shape resonances produced by electron capture into empty pi* orbitals are the initial step in formation of the long lived molecular anions. This appears to rule out mechanisms in which direct formation of core-excited anion states are invoked. However, according to DFT calculations, conversion of the shape resonances around 1 eV to longer-lived sigma-pi* core-excited doublet anion states is possible on energetic grounds. PMID- 19774276 TI - Resonant UV-fs-TCFWM spectroscopy on formaldehyde. AB - The first electronically excited singlet A 1A2 state of formaldehyde (H2CO) is the origin of different competing dissociation channels. An all-ultraviolet (UV) electronically resonant variant of time-resolved fs-two-colour four-wave mixing (fs-TCFWM) spectroscopy has been applied to monitor the dynamics of rovibrational manifolds in this state. The method provides a variety of options to probe molecular dynamics according to the temporal sequence of dipole transitions involved. Signal contributions arising from different molecular states can partially be distinguished by specific sequences of the applied laser pulses. A dispersed signal detection method reveals additional information that is often inaccessible using spectrally integrated detection. We discuss UV-fs-TCFWM experiments which involve resonant transitions to the rovibrational manifolds of the C-O stretch and out-of-plane combination bands in the first electronically excited singlet state of H2CO at energies close to the HCO production threshold. The experimental results are compared to simulations. PMID- 19774277 TI - Role of solvation dynamics in the kinetics of solvolysis reactions in microreactors. AB - In this contribution we attempt to correlate the dynamical states of water molecules in reverse micelles with a solvolysis reaction in accordance with the activation energy barrier crossing model at the micellar interface. Precise measurement of the different dynamical states of water molecules at the reverse micellar interface with various degrees of hydration is achieved through temperature-dependent solvation dynamics of coumarin 523. The rotational anisotropy studies along with a wobbling-in-cone analysis show that the probe residing at the micellar interface pointing towards the core water experiences less microviscosity at elevated temperature. The consequences of the dynamical freedom of the water at elevated temperature in the solvolysis reaction of benzoyl chloride have also been explored. The accelerated rate of solvolysis has been correlated with the increased solvation dynamics, both of which are associated with a temperature-induced transition of bound to free type water molecules at the micellar interface. PMID- 19774278 TI - A theoretical analysis of the reaction between CN radicals and NH3. AB - The reaction between CN radicals and NH3 molecules has been studied experimentally over an unusually wide range of temperature (25-716 K). Below 295 K, the rate constant exhibits a strong negative dependence on temperature; that is, it increases sharply as the temperature is lowered. The present work analyses the kinetics of this reaction theoretically, both to explain this unusual temperature-dependence and to identify the major products of the reaction--which have not been well established by experiment. Quantum chemical calculations at the CCSD(T) theoretical level show that the minimum energy path for reaction proceeds: (a) first, via a potential well, which is 39.3 kJ mol(-1) below the energy of the separated reactants, when allowance is made for zero-point energies, corresponding to a quite strongly bound NC-NH3 complex, and (ii) then over a 'submerged' barrier with a crest 10.9 kJ mol(-1) below the energy of the reactants to the products HCN + NH2. These ab initio calculations also demonstrate that there is no low energy path to the products NCNH2 + H. The dynamics of the main reaction have been further investigated using the two transition state model of Klippenstein and co-workers, in which transition state theory is applied at the selected E, J microcanonical level. The rate constants calculated for temperatures between 25 and 200 K are in excellent agreement with the experimental values. PMID- 19774279 TI - Equilibrium and mid-infrared driven vibrational dynamics of artificial hydrogen bonded networks. AB - Stereo-selectively synthesized 1,3-poly-alcohols are introduced as low dimensional spectroscopic model systems for molecular dynamics in hydrogen-bonded networks. The molecular and vibrational structures of the artificial networks are studied by means of density functional theory. The flexibility of the networks and the time scales associated with hydrogen-bond breakage and formation are investigated through Langevin dynamics simulations. Experimentally, the dynamics of the polyols are explored by femtosecond mid-infrared spectroscopy in the OH stretching spectral region. Polyols with their hydroxyl groups distributed along the hydrocarbon backbone in an all-syn configuration are highly rigid and form an extended quasi 1-dimensional hydrogen-bond wire that is stable for tens of picoseconds. The mid-infrared pump-probe data on these rigid networks exhibit biexponential kinetics. This finding supports a mechanism for vibrational energy relaxation in all-syn polyols that is mediated by hydrogen-bond dissociation within 850 fs. The hydrogen-bond wire is subsequently re-established on a time scale of about 14 ps. In contrast, poly-alcohols with their OH groups in an all anti configuration are highly flexible and display hydrogen-bond breakage formation on a 100 fs time scale already at thermal equilibrium. As a result the pump-probe data are mono-exponential and can be understood in terms of pure intramolecular vibrational relaxation occurring with a time constant of 1.3 ps. PMID- 19774280 TI - Quantitative analysis of 2H NMR T1Q, T1Z and T2 relaxation times in the SmA phase of a liquid crystal dendrimer. AB - In this work the 2H NMR spin-lattice relaxation times, T1Z and T1Q, and the spin spin relaxation times measured by means of the quadrupolar echo sequence, T2, have been analyzed in order to study the dynamic processes of a liquid crystalline dendrimer labelled on the aromatic core of the lateral mesogenic units in the SmA phase. Several theoretical models describing both internal and overall molecular diffusion motions have been used to reproduce the temperature dependence of the spectral densities J(0)(0), J1(omega0) and J2(2omega0) experimentally determined at the Larmor frequency omega0 of 61.3 MHz. This analysis identifies in the internal rotation of the deuterated phenyl ring around its para axis the main contribution to the longitudinal relaxation. Moreover, the best fitting of the minimum in the trend of both T1Z and T1Q was obtained by introducing a distribution of activation energies for such internal motion, thus confirming previous hypothesis of dynamic heterogeneity. A much slower motion, affecting the sole transverse relaxation and ascribable to the reorientation of the whole macromolecular dendrimers, was modelled through the so called "slowly relaxing local structure" approach. PMID- 19774281 TI - Vibrational relaxation of NO (v = 1-16) with NO, N2O, NO2, He and Ar studied by time-resolved Fourier transform infrared emission. AB - Rates of vibrational quenching of NO (v = 1-16) in collisions with a series of quenching species NO, NO2, N2O, He and Ar have been measured at 295 K. NO (v) was formed both by the O(1D) + N2O reaction and the 193 nm photolysis of NO(2), and time-resolved FTIR emission was used to follow the behaviour of the vibrationally excited species. The trends in quenching rate constants can be explained in terms of V-T transfer, V-V transfer and by the effects of competing processes. He and Ar show trends expected from SSH theory, but with relaxation rates that are considerably higher than those expected from previous studies with closed shell molecules, and the influence of non-adiabatic pathways in the relaxation of the NO 2Pi state is discussed. Relaxation with NO2 shows the influence of resonant energy transfer to the nu3 mode, with rate constants peaking at v = 10. For N2O, relaxation rates show essentially a linear increase with v. A linear increase is expected for the change of the transition moment with v for the harmonic oscillator approximation, and when this is taken into account the "reduced probabilities" (defined as P/v, where P is probability of a gas kinetic collision changing the vibrational level from v to v-1) are approximately independent of the energy lost in the NO molecule. The influence of complex formation far from resonance is invoked in both this and for quenching of low vibrational levels by NO2. Finally, self-quenching shows rates which initially decrease with increasing v, but then show a marked increase, with a minimum value at v = 9. Both V-V and V T processes are believed to occur. Where previously published data are available, general agreement is observed in this study. PMID- 19774282 TI - Pure multistep oriented attachment growth kinetics of surfactant-free SnO2 nanocrystals. AB - In this work, crystal growth kinetics of surfactant-free nanocrystalline SnO2 in distilled water at 175-250 degrees C were investigated. The growth rate followed the type of asymptotic curve in hundreds of hours, which could be fitted by the multistep oriented attachment (OA) kinetic model. High-resolution transmission electron microscope (HRTEM) data also indicated crystal growth occurring via the multistep OA mechanism. During the growth of SnO2, the concentration of Sn ions in the aqueous solution was examined. It reveals that the unsaturated situation of SnO2 results in crystal growth via the pure OA mechanism. A growth model of self-integration of conjugated nanocrystals was discussed for understanding the OA behavior. PMID- 19774284 TI - CdS thin-film electrodeposition from a phosphonium ionic liquid. AB - Thin, adherent films of CdS were electrodeposited on FTO coated glass by reduction of a thiosulfate precursor in the presence of Cd(II) ions in methyltributylphosphonium (P(1,4,4,4)) tosylate ionic liquid at 130-150 degrees C. The structural properties of the deposits have been characterized by profilometry, scanning electron microscopy (SEM) and optical microscopy. Energy dispersive X-ray spectroscopy (EDX) was used to evaluate the chemical composition, which was found to be close to stoichiometric. Semiconductor properties including the band gap and flat band potential were calculated from UV Vis and impedance spectroscopy measurements. The crystal structure was analyzed by X-ray diffraction (XRD). The data obtained from XRD and band gap measurements suggest the presence of hexagonal CdS crystals. The possible growth mechanism of the films is also addressed. PMID- 19774283 TI - Acetone photolysis at 248 nm revisited: pressure dependence of the CO and CO2 quantum yields. AB - Pressure dependent CO and CO2 quantum yields in the laser pulse photolysis of acetone at 248 nm and T = 298 K have been measured directly using quantitative infrared diode laser absorption. The experiments cover the pressure range from 50 to 900 mbar. It is found that the quantum yields show a significant dependence on total pressure, with Phi(CO) decreasing from around 0.5 at 20 mbar to approximately 0.3 at 900 mbar. The corresponding CO2 yields as observed when O2 exists in the reaction mixture, exhibit exactly the opposite behaviour. For the sum of both a value of 1.05(-0.05)(+0.02) independent of pressure is obtained, showing that the sum of (Phi(CO) + Phi(CO2)) is a measure for the primary quantum yield in the photolysis of acetone. In addition, CO quantum yields and corresponding pressure dependences were measured in experiments using different bath gases including He, Ar, Kr, SF6, and O2 as third body colliders. The theoretical framework in which we discuss these data is based on our previous findings that the pressure dependence of the CO yield is a consequence of a stepwise fragmentation mechanism during which acetone decomposes initially into methyl and a vibrationally 'hot' acetyl radical, with the latter being able to decompose promptly into methyl plus CO. The pressure dependence of the CO yield then originates from the second step and is modelled quantitatively via statistical dynamical calculations using a combination of RRKM theory with a time dependent master equation (ME) approach. From a comparison of experiment with theory the amount of excess energy in the vibrationally hot acetyl radicals (E* approximately 65 kJ mol(-1)) as well as the characteristic collision parameters for interaction of acetyl with the different bath gases were derived. Values of 90, 280, 310, 545, 550 and 1800 cm(-1) for the average energy transferred per downward collision for the bath gases He, Ar, Kr, O2, N2, and SF6, respectively, are obtained. The calculations also considered different models for the energy transfer kernel P(E,E') and best fits were obtained with a rho-weighted exponential down model. PMID- 19774285 TI - Thermodynamic and FTIR studies of supercooled water confined to exterior and interior of mesoporous MCM-41. AB - The thermal properties of water confined to both exterior and interior of cylindrical mesoporous MCM-41 (pore diameter d = 1.8-3.6 nm) were analysed by differential scanning calorimetry and FTIR spectroscopy. A three-step freezing of the exterior water was observed just above 233 K, the homogeneous nucleation temperature of bulk water, before the interior water was frozen. The first freezing of water was ascribed to the outermost bulk water, the second one to water between bulk and water bound to the exterior wall, and the third one to the bound exterior water. With decreasing pore size, the second freezing water decreased in magnitude. This stepwise freezing of the exterior water has been found in porous zeolite materials. The exothermic peak of the interior water confined in MCM-41 was observed at 227.5 K before freezing, ascribed probably to a high-density liquid-low-density liquid phase change. FTIR data of the interior water confirmed this finding. The present results substantiate the static and dynamic crossover of supercooled water in MCM-41 reported from previous neutron scattering and NMR data. PMID- 19774286 TI - Measuring and predicting Delta(vap)H298 values of ionic liquids. AB - We report the enthalpies of vaporisation (measured using temperature programmed desorption by mass spectrometry) of twelve ionic liquids (ILs), covering four imidazolium, [C(m)C(n)Im]+, five pyrrolidinium, [C(n)C(m)Pyrr]+, two pyridinium, [C(n)Py]+, and a dication, [C3(C1Im)2]2+ based IL. These cations were paired with a range of anions: [BF4]-, [FeCl4]-, [N(CN)2]-, [PF3(C2F5)3]- ([FAP]-), [(CF3SO2)2N]- ([Tf2N]-) and [SCN]-. Using these results, plus those for a further eight imidazolium based ILs published earlier (which include the anions [CF3SO3]- ([TfO]-), [PF6]- and [EtSO4]-), we show that the enthalpies of vaporisation can be decomposed into three components. The first component is the Coulombic interaction between the ions, DeltaU(Cou,R), which is a function of the IL molar volume, V(m), and a parameter R(r) which quantifies the relative change in anion cation distance on evaporation from the liquid phase to the ion pair in the gas phase. The second and third components are the van der Waals contributions from the anion, DeltaH(vdw,A), and the cation, DeltaH(vdw,C). We derive a universal value for R(r), and individual values of DeltaH(vdw,A) and DeltaH(vdw,C) for each of the anions and cations considered in this study. Given the molar volume, it is possible to estimate the enthalpies of vaporisation of ILs composed of any combination of the ions considered here; values for fourteen ILs which have not yet been studied experimentally are given. PMID- 19774287 TI - Carbon dioxide capture at the molecular level. AB - Carbon dioxide is recognized as a typical greenhouse gas and drastic reduction of CO2 emissions from industrial process is becoming more and more important in relation to global warming. In fact, the reaction between monoethanolamine (MEA) and CO2 in aqueous solution has been widely used for the removal from flue gases. In this study, the role of the interplay between solvent water and nitrogen (MEA) carbon (CO2) bond formation is discussed based on the molecular theory using RISM SCF-SEDD, which is the hybrid method of quantum chemistry of solute and statistical mechanics of solvent. PMID- 19774288 TI - From the molecular behaviors of fullerene derivatives C50X2 (X = H, F, Cl, Br, OH) to the general parallels among isostructural derivatives of fullerenes and carbon nanotubes. AB - A systematic investigation of all possible isomers of fullerene derivatives C50X2 (X = H, F, Cl, Br, OH) has been performed using the semiempirical AM1 method. The equilibrium geometrical structures, heats of formation, HOMO-LUMO energy gaps, ionization potentials, electronic affinities, strain and aromaticity have been studied. The results indicate that the selection rule for two groups adding to fullerene C50 is independent of the type of functional group. The isomer-78, which corresponds to a 1,4-addition at the six-membered ring located on the equator, is the most stable isomer for C50X2 (X = H, F, Cl, Br, OH). The driving force governing the stabilities of the presently studied C50X2 isomers is the strain inherent in the C50 cage. The contribution of the conjugation effect to the stabilization is not able to compete with that of the strain. The more stable C50X2 isomers have larger ionization potentials and smaller electronic affinities compared with C50, which suggests that it is more difficult to oxidize and reduce C50X2 than to oxidize and reduce C50. Energies as well as HOMO-LUMO gaps of isostructural C50X2 (X = H, F, Cl, Br, OH) isomers are almost parallel, i.e., energy differences between isostructural isomers of any two kinds of C50X2 derivatives are constant. This phenomenon can be called H/F/Cl/Br/OH parallels, which may result from the same degree of perturbation for addition of different functional groups to the structure of the parent carbon cage. H/F parallels are generalized characteristics among not only isostructural isomers of fullerenes but also isostructural isomers of carbon nanotubes. Furthermore, it is predictable that general H/F/Cl/Br/OH... parallels may exist among various derivatives of other fullerenes and carbon nanotubes. PMID- 19774289 TI - Thiadiazole-containing expanded heteroazaporphyrinoids: a gas-phase electron diffraction and computational structural study. AB - The gas-phase molecular structure of a thiadiazole-containing expanded heteroazaporphyrinoid (C42H39N15S3) has been studied by a synchronous gas electron diffraction and mass spectrometric experiment and density functional theory calculations using the B3LYP hybrid method and cc-pVTZ basis sets. The molecule has an equilibrium structure of C3h symmetry with a planar macrocycle and the thiadiazole rings oriented in such a way that the sulfur atoms point outwards from the inner cavity. The unsubstituted macrocycle (C30H15N15S3) has been studied by DFT computations. An algorithm for building a complete set of internal coordinates, used in the computation of vibrational corrections, is also described. PMID- 19774290 TI - A correlation between the ionic conductivities and the formation enthalpies of trivalent-doped ceria at relatively low temperatures. AB - We report a correlation between oxygen ionic conductivity and the enthalpy of formation of trivalent-doped ceria from the component binary oxides observed at relatively low temperatures (150-275 degrees C). The bulk conductivities of La doped ceria samples identical to those previously examined by thermochemical studies were measured as a function of La content for a direct comparison. The conductivity showed a maximum at a La concentration of 5 mol%, implying that the number of freely mobile oxygen vacancies reaches a maximum near that doping level in the temperature range of interest. The formation enthalpies previously reported by Chen and Navrotsky also show a maximum, indicating destabilization near that composition. Additional measurements show that this maximum is very pronounced and sharply peaked near that composition. These enthalpies suggest that the energetically favorable long-range interactions between the charged defects that trap the oxygen vacancies become dominant above 5 mol% doping in the CeO2-LaO1.5 solid solution. In addition, the conductivities measured from independently prepared Gd-doped ceria samples show a maximum at around 10 mol% doping below 450 degrees C as anticipated from a pronounced maximum in the formation enthalpies of the CeO2-GdO1.5 solid solution. These empirical findings confirm that the ionic conductivity of trivalent-doped ceria is strongly enough correlated with its formation enthalpy at relatively low temperatures so that information about the critical dopant concentration associated with the conductivity maximum may be gained from the formation enthalpies of the solid solutions, and vice versa. We have no direct information about this correlation at higher temperatures; both thermodynamics and conductivity maximum might change if the defect clusters dissociate to any significant extent. PMID- 19774291 TI - Solvent-induced configuration mixing and triplet excited-state inversion: insights from transient absorption and transient dc photoconductivity measurements. AB - Solvent-induced excited-state configuration mixing in a Pt(II) diimine chromophore with phenylene ethynylene containing acetylide ligands, [Pt((t)Bu2bpy)(PE3)2] (1), was characterized by nanosecond transient absorption spectroscopy and transient dc photoconductivity (TDCP). The mixing is a result of closely spaced triplet charge transfer (3CT) and intraligand-localized (3IL) triplet energy levels that are finely tuned with solvent polarity as ascertained by their parent model chromophores [Pt((t)Bu2bpy)(PE1)2] (2) and [Pt(P2)(PE3)2] (3), respectively. The absorption difference spectrum of the mixed triplet state is dramatically different from those of the 3CT and 3IL state model chromophores. The 3CT, 3IL and configuration-mixed triplet states led to distinct TDCP signals. The TDCP response is of negative polarity for 3CT excited states but of positive polarity for 3IL excited states. TDCP transients for 1 in mixed solvents are a combination of signals from the 3IL and 3CT states, with the signal magnitude depending on the polarity of solvent composition. The fraction of 3CT state character in the configurationally mixed excited state was quantified by TDCP to be approximately 0.24 in pure benzene, while it decreased to approximately 0.05 in 20 : 80 (v : v) benzene-CH2Cl2. The charge transfer fraction appears to increase slightly to approximately 0.11 in the lower polarity 20 : 80 n-hexane CH2Cl2 medium. TDCP is shown to be a useful tool for the identification of the lowest excited state in electrically neutral metal-organic chromophores. PMID- 19774292 TI - NMR and DFT study on media effects on proton transfer in hydrogen bonding: concept of molecular probe with an application to ionic and super-polar liquids. AB - Media effects of ionic and super-polar liquids on the state of H-bonding were studied by NMR and DFT methods. The proton sharing (positioning) in the H-bond was monitored following the chemical shifts of picolinic acid N-oxide (PANO) used as the molecular probe. The relationships between PANO 1H and 13C chemical shifts and proton position in the O-H...O bridge were calibrated using traditional organic solvents and other H-bond complexes of pyridine N-oxide with acids to increase the H-bond strength. A reliable parameter for H-bond monitoring was proposed. The state of the H-bond in ionic liquid media is largely governed by the dielectric properties of the bulk media. A drastic fall-out of PANO/[BuMePyr][TfO] from the general dielectric scheme built using solvents with increasing dielectric constant (from chloroform to water and culminating with formamide) was observed. On a molecular level this effect indicates that the ionic liquid [BuMePyr][TfO] can act on H-bonded systems as a stimulant of proton transfer. In 'super-polar' media (formamide) the intramolecular H-bond system converts into an intermolecular one forming a neutral H-bond complex of PANO with the formamide molecule. PMID- 19774293 TI - Cis-trans conversion of the CH3S-Au-SCH3 complex on Au(111). AB - The RS-Au-SR complex (RS- being an alkylthiolate group) has been determined to be an important structural motif at the interface of self-assembled monolayers (SAMs) of thiolate on gold. We investigate the conversion between two stable configurations (cis and trans) of the CH3S-Au-SCH3 complex on Au(111) by applying density functional theory. We show that this cis-trans conversion has a barrier of only 0.5 eV, indicating that the two geometrical isomers can easily interchange on Au(111) to facilitate packing of the CH3S-Au-SCH3 complexes on Au(111). We further examine how this conversion connects two stable structural models recently predicted for the well known c(4 x 2) superstructure of SAMs on Au(111). PMID- 19774294 TI - Determination of the charge profile in the KcsA selectivity filter using ab initio calculations and molecular dynamics simulations. AB - The charge profile of K+ and Na+ ions moving in a single file across the filter of the KcsA channel is determined using both molecular dynamics simulations and ab initio calculations. We show a strong correlation between the charge variation and the ion location resulting in a saw-tooth profile, which provides additional information on the influence of charge transfer on the permeation and selectivity of the channel. PMID- 19774295 TI - Effect of induced electric field on single-file reverse osmosis. AB - We investigated the effect of the electric field on single-file reverse osmosis (RO) water flux using molecular dynamics simulations. The electric field is generated by introducing oppositely charged biomolecules to the salt solution and pure water chambers attached to the nanopore. Simulation results indicate that an electric field in the direction of RO enhances the water flux while in the direction opposite to RO it suppresses the water flux. When the RO water flux is enhanced, the single-file water dipoles are aligned in the direction of the electric field. The addition of an electric field in the direction of RO led to a flux of 3 water molecules ns(-1) by constantly maintaining water dipole vectors in the direction of the electric field, and this water flux is superimposed on the pressure driven water flux. PMID- 19774296 TI - Operando X-ray absorption spectroscopy studies on Pd-SnO2 based sensors. AB - SnO2 gas sensors with palladium as additive in the range of 0.2 wt% and 3 wt% were studied by in situ X-ray absorption spectroscopy under idealized and real operating conditions. Simultaneously to the structural studies, measurements of the sensing properties were undertaken allowing for the determination of structure-function relationships. For this purpose a new in situ spectroscopic cell was designed which permitted on the one hand sensing on conventional screen printed 50 microm thick sensing layers and on the other hand structural analysis with X-rays provided by an insertion device at a 3rd generation synchrotron facility in fluorescence mode. Pd K-edge XANES and EXAFS results on gas sensors showed that palladium, present in an oxidized state, is finely dispersed if it is added in small quantities (0.2 wt%) while it forms clusters at higher concentrations (3 wt%). This is also reflected by the much easier reduction of palladium in the latter, higher concentrated ones. Under realistic sensing conditions (30-200 ppm H2; 10-50 ppm CO in dry and humid air at 200 and 300 degrees C) for the low additive concentration samples, no change in oxidation state was observed, i.e. palladium remained in its oxidized state. This has important consequences on the understanding and modeling of the gas sensing mechanism. PMID- 19774297 TI - Photophysical comparative study of amylose and polyvinyle pyrrolidone/single walled carbon nanotubes complex. AB - Progressive addition of hydroxypropylated amylose (AmH), from 0.05 wt% to 4.5 wt%, to single-walled carbon nanotubes (SWNTs) in aqueous surfactant suspensions quenches the intrinsic near Infra-Red fluorescence of semiconducting SWNTs while dispersions obtained with a same amount of polyvinylpyrrolidone (PVP) remain luminescent. Near Infra-Red emission spectroscopy (fluorescence and Raman scattering) of the samples is used to characterize the supramolecular organization of these polymer/SWNT complexes. The SWNTs are found to be wrapped by the PVP chains and not by the AmH chains which rather form AmH/surfactant/SWNTs complexes. In PVP/SWNTs dispersion, the fluorescence line position and intensity are affected by dielectric screening. In the case of AmH/surfactant/SWNTs complex, dielectric screening plays also a role but quenching occurs above about 3 wt% of AmH. We attribute the quenching to the formation of a "composite like" microstructure by opposition to stabilized dispersion. PMID- 19774298 TI - Importance of the support material in thin palladium composite membranes for steady hydrogen permeation at elevated temperatures. AB - Hydrogen permeation performance of palladium membranes supported on porous alpha alumina and yttria-stabilized zirconia (YSZ) was studied at 300-850 degrees C. The hydrogen permeation flux across the palladium-alpha-alumina membrane decreased markedly during permeation tests conducted at >600 degrees C. The SEM and XPS studies of the post-test membrane revealed the presence of aluminium in the palladium layer. Such migration of aluminium was not observed by heating the palladium-alpha-alumina membrane under an argon atmosphere, indicating that hydrogen is responsible for this phenomenon. Hydrogen-induced strong metal support interaction might be related to this considerable loss of the hydrogen flux. Reduction of alumina to Al(0) by active hydrogen at the membrane-support interface and subsequent migration of Al(0) into the palladium layer represents the most plausible mechanism for the aluminium diffusion. Actually, Al(0) that migrated into the palladium membrane layer generated less hydrogen-permeable palladium-aluminium alloy or inter-metallic compound phase. In contrast, no such strong interaction was found between the YSZ support and the palladium membrane. This composite membrane exhibited a steady permeation of hydrogen at 650 degrees C for 336 h. Having a remarkably high reduction potential, Y(III) is unlikely to be reduced to Y(0), although Zr(IV) has a comparable reduction potential to that of Al(III). A binary phase diagram shows a liquid alloy phase present for the Pd/Al couple at temperatures greater than 615 degrees C (eutectic point), while an inter-metallic compound or liquid alloy phase in the Pd-Zr binary system is not apparent at temperatures less than 750 degrees C. Consequently, inter diffusion of zirconium with palladium did not occur during operations at 650 degrees C. PMID- 19774300 TI - Rehabilitating torture survivors. AB - Refugees have often been exposed to torture in their countries of origin. A core issue is the resulting multifaceted presentation of somatic, psychological and social problems in the same individual, leading to severe activity limitations and participation restrictions. An international conference, "Rehabilitating Torture Survivors", was organized by the Rehabilitation and Research Centre for Torture Victims (a rehabilitation clinic and global knowledge and research centre with government support) in collaboration with the Centre for Transcultural Psychiatry at Rigshospitalet in Copenhagen, Denmark, in December 2008. The main topics were: the context of torture; mental problems including psychotherapy; internet-based therapy and pharmaco-therapy; chronic pain; social integration and family; and functioning and rehabilitation. Available evidence highlights the importance of an interdisciplinary approach to rehabilitation, but scientifically rigorous studies of comprehensive rehabilitation programmes for torture survivors are lacking. Therefore, effect studies are urgently warranted. Nevertheless, by combining expertise from different scientific and professional areas, important elements in the problems of torture survivors can be addressed from an evidence base generated both from traumatized and non-traumatized patient populations. Thus, trauma-focused cognitive behavioural therapy and/or eye movement desensitization and reprocessing, as well as interdisciplinary pain rehabilitation, should be components of a successful rehabilitation process, and great attention should be paid to contextual components. PMID- 19774301 TI - Mobility devices to promote activity and participation: a systematic review. AB - OBJECTIVE: To determine the effectiveness of mobility device interventions in terms of activity and participation for people with mobility limitations. DESIGN: Systematic review. Search of 7 databases during the period 1996 to 2008. METHODS: Controlled studies and non-controlled follow-up studies were included if they covered both baseline and follow-up data and focused on activity and participation. Study participants had to be aged over 18 years with mobility limitations. Mobility device interventions encompassed crutches, walking frames, rollators, manual wheelchairs and powered wheelchairs (including scooter types). Two reviewers independently selected the studies, performed the data extraction, and 4 reviewers assessed the studies' methodological quality. Disagreements were resolved by consensus. RESULTS: Eight studies were included: one randomized controlled trial, 4 controlled studies, and 3 follow-up studies that included before and after data. Two studies dealt with the effects of powered wheelchair interventions and the other studies with various other types of mobility device. Two studies were of high, internal and external methodological quality. Interventions were found to be clinically effective in terms of activity and participation in 6 studies. The results did not, however, give a unanimous verdict on the effectiveness of mobility devices in enhancing the activity and participation of mobility impaired people. CONCLUSION: Interventions and outcome measurement methods varied between the studies; consequently, it was not possible to draw any general conclusions about the effectiveness of mobility device interventions. However, evidence was found that mobility devices improve users' activity and participation and increase mobility. A lack of high-quality research hampers conclusions about effectiveness. More original, well-designed research is required. PMID- 19774302 TI - A review of the relationship between dysphagia and malnutrition following stroke. AB - OBJECTIVE: To clarify the relationship between malnutrition and dysphagia following stroke. DESIGN: Systematic review. METHODS: All published trials that had examined both the swallowing ability and nutritional status of subjects following stroke were identified. Pooled analyses were performed to establish whether the odds of being malnourished were increased given the presence of dysphagia. RESULTS: Eight studies were identified. The presence of malnutrition and dysphagia ranged from 8.2% to 49.0% and 24.3% to 52.6%, respectively. Five of the included trials were conducted within the first 7 days following stroke, while 3 were conducted during the rehabilitation phase. The overall odds of being malnourished were higher among subjects who were dysphagic compared with subjects with intact swallowing (odds ratio: 2.425; 95% confidence interval: 1.264-4.649, p < 0.008). In subgroup analysis, the odds of malnutrition were significantly increased during the rehabilitation stage (odds ratio: 2.445; 95% confidence interval: 1.009-5.925, p < 0.048), but not during the first 7 days of hospital admission (odds ratio: 2.401; 95% confidence interval: 0.918-6.277, p < 0.074). CONCLUSION: In a systematic review including the results from 8 studies, the odds of being malnourished were increased given the presence of dysphagia following stroke. PMID- 19774303 TI - Positive attitudes and preserved high level of motor performance are important factors for return to work in younger persons after stroke: a national survey. AB - OBJECTIVE: Significant numbers of younger persons with stroke should be given the opportunity to return to work. The aim of this study was to investigate factors of importance for return to work among persons after first ever stroke, in the age range 18-55 years. METHODS: A questionnaire was sent to all persons who had experienced a first ever stroke, 18-55 years of age, registered in the Swedish national quality register for stroke care, Riks-Stroke. Of the 1068 who answered the questionnaire, 855 (539 men and 316 women) were in paid employment before their stroke, and were included in this study. RESULTS: Sixty-five percent returned to work and, of these, an equal proportion were men and women. Significant factors associated with return to work were the perceived importance of work (odds ratio (OR) 5.10), not perceiving themselves as a burden on others (OR 3.33), support from others for return to work (OR 3.66), retaining the ability to run a short distance (OR 2.77), and higher socioeconomic codes (OR 2.12). A negative association was found between those rehabilitated in wards intended for younger persons and return to work (OR 0.37). CONCLUSION: External support from others, and positive attitudes towards return to work, were factors associated with successful return to work after stroke. Contrary to what was expected, independence in personal activities of daily living and cognitive factors were not associated with return to work to the same extent as persistent higher level of physical functions, such as ability to run a short distance. PMID- 19774304 TI - Effect of seat height and turning direction on the timed up and go test scores of people after stroke. AB - OBJECTIVE: To identify the effect of chair seat height and turning direction on the Timed Up and Go scores of patients after stroke. DESIGN: A cross-sectional study. SETTING: A geriatric day hospital in Hong Kong. SUBJECTS: Twenty-five patients with sub-acute stroke. METHODS: The time taken to complete the Timed Up and Go test with various chair seat heights (65%, 90% and 115% of each subject's leg length - distance from lateral knee joint line to ground in sitting) and turning directions (toward the affected and unaffected side) was recorded using a stopwatch with randomized test order. RESULTS: There were significant differences in Timed Up and Go scores between the 3 levels of chair seat height (p < 0.001), with the lowest Timed Up and Go scores recorded when the seat height was 115% of the subject's leg length and the highest at a seat height of 65% of the subject's leg length. Turning toward the affected side was found to be significantly quicker than turning toward the unaffected side (p < 0.001). CONCLUSION: Chair seat height and turning direction significantly influence the Timed Up and Go scores of patients after sub-acute stroke. Optimizing chair seat height with reference to subject's leg length and turning direction is essential when using the Timed Up and Go test as an outcome measure in stroke rehabilitation. PMID- 19774305 TI - Spinal Cord Independence Measure, version III: applicability to the UK spinal cord injured population. AB - OBJECTIVE: To examine the validity, reliability and usefulness of the Spinal Cord Independence Measure for the UK spinal cord injury population. DESIGN: Multi centre cohort study. SETTING: Four UK regional spinal cord injury centres. SUBJECTS: Eighty-six people with spinal cord injury. INTERVENTIONS: Spinal Cord Independence Measure and Functional Independence Measure on admission analysed using inferential statistics, and Rasch analysis of Spinal Cord Independence Measure. MAIN OUTCOME MEASURES: Internal consistency, inter-rater reliability, discriminant validity; Spinal Cord Independence Measure subscale match between distribution of item difficulty and patient ability measurements; reliability of patient ability measures; fit of data to Rasch model; unidimensionality of subscales; hierarchical ordering of categories within items; differential item functioning across patient groups. RESULTS: Scale reliability (kappa coefficients range 0.491-0.835; (p < 0.001)), internal consistency (Cronbach's alpha 0.770 and 0.780 for raters), and validity (Pearson correlation; p < 0.01) were all significant. Spinal Cord Independence Measure subscales compatible with stringent Rasch requirements; mean infit indices high; distinct strata of abilities identified; most thresholds ordered; item hierarchy stable across clinical groups and centres. Misfit and differences in item hierarchy identified. Difficulties assessing central cord injuries highlighted. CONCLUSION: Conventional statistical and Rasch analyses justify the use of the Spinal Cord Independence Measure in clinical practice and research in the UK. Cross-cultural validity may be further improved. PMID- 19774307 TI - Improved walking ability and reduced therapeutic stress with an electromechanical gait device. AB - OBJECTIVE: To evaluate the effectiveness of repetitive locomotor training using a newly developed electromechanical gait device compared with treadmill training/gait training with respect to patient's ambulatory motor outcome, necessary personnel resources, and discomfort experienced by therapists and patients. METHODS: Randomized, controlled, cross-over trial. Sixteen non ambulatory patients after stroke, severe brain or spinal cord injury sequentially received 2 kinds of gait training. Study intervention A: 20 treatments of locomotor training with an electromechanical gait device; control intervention B: 20 treatments of locomotor training with treadmill or task-oriented gait training. The primary variable was walking ability (Functional Ambulation Category). Secondary variables included gait velocity, Motricity-Index, Rivermead Mobility-Index, number of therapists needed, and discomfort and effort of patients and therapists during training. RESULTS: Gait ability and the other motor outcome related parameters improved for all patients, but without significant difference between intervention types. However, during intervention A, significantly fewer therapists were needed, and they reported less discomfort and a lower level of effort during training sessions. CONCLUSION: Locomotor training with or without an electromechanical gait trainer leads to improved gait ability; however, using the electromechanical gait trainer requires less therapeutic assistance, and therapist discomfort is reduced. PMID- 19774306 TI - Predicting respiratory infection one year after inpatient rehabilitation with pulmonary function measured at discharge in persons with spinal cord injury. AB - OBJECTIVE: To determine whether pulmonary function at discharge from inpatient rehabilitation can predict respiratory infection in spinal cord injury in the first year after discharge, and to determine which pulmonary function parameter predicts best. DESIGN: Multicentre prospective cohort study. SUBJECTS: A total of 140 persons with spinal cord injury. METHODS: Pulmonary function was tested at discharge from inpatient rehabilitation. Pulmonary function parameters (expressed in absolute and percentage predicted values) were: forced vital capacity, forced expiratory volume in 1 sec, and peak expiratory flow. Respiratory infection was determined one year after discharge by a physician. Differences between the respiratory infection and non-respiratory infection groups were tested; and receiver operating characteristic curves were used to determine how accurately pulmonary function parameters could predict respiratory infection. RESULTS: Of the 140 participants, 14 (10%) experienced respiratory infection in the first year after discharge. All pulmonary function parameters were significantly lower in persons who experienced respiratory infection than in those who did not. All pulmonary function parameters were almost equally accurate in predicting respiratory infection; only percentage predicted forced vital capacity was less accurate. CONCLUSION: Pulmonary function at discharge from inpatient rehabilitation can be used as a predictor of respiratory infection in the first year after discharge in spinal cord injury. No single pulmonary function parameter was a clearly superior predictor of respiratory infection. PMID- 19774308 TI - Effects of different dilutions of botulinum toxin type A treatment for children with cerebral palsy with spastic ankle plantarflexor: a randomized controlled trial. AB - OBJECTIVE: The aim of this study was to investigate the influence of different volumes of saline vehicle on the effects of botulinum toxin type A in reducing ankle plantarflexor spasticity and improving gait pattern in children with cerebral palsy. DESIGN: Children with cerebral palsy having ankle plantarflexor spasticity were recruited. They were divided randomly into 2 groups. Botulinum toxin type A mixed with 2 ml or 8 ml saline was injected into the gastrocnemius in each group. Passive range of movement of ankle joint, Modified Ashworth Scale, and results of 3-dimensional motion analysis obtained at pre-treatment, 4, 12, and 24 weeks after treatment were compared. RESULTS: Ankle dorsiflexion was increased and ankle plantarflexor spasticity was decreased significantly after botulinum toxin type A treatment. Linear parameters were generally improved, and these improvements persisted until 12-24 weeks. The ankle dorsiflexion angle in the stance phase was also increased, and this increase was maintained until 24 weeks, as revealed by 3-dimensional gait analysis. However, no significantly different effect of varying the amount of saline vehicle was detected. CONCLUSION: Botulinum toxin type A improved physical findings and gait pattern in patients with cerebral palsy. The volume of saline mixed with botulinum toxin type A did not result in significant differences in physical evaluation or gait analysis. However, the large-volume group revealed side-effects more frequently and showed no clinical benefits compared with the small-volume group. We conclude that 2 ml of dilution is preferable for botulinum toxin type A treatment in children. PMID- 19774309 TI - Limited upper limb functioning has impact on restrictions in participation and autonomy of patients with hereditary motor and sensory neuropathy 1a. AB - OBJECTIVE: To evaluate upper limb functioning, restrictions on participation and the independent contribution of upper and lower limb disability to participation in hereditary motor and sensory neuropathy 1a. DESIGN: Descriptive cross sectional study. SUBJECTS: Forty-nine patients with hereditary motor and sensory neuropathy 1a. METHODS: Perceived upper limb functioning was evaluated using the Michigan Hand Outcomes Questionnaire and participation restrictions with the Impact on Participation and Autonomy Questionnaire. Upper and lower limb domains of Guy's Neurological Disability Scale were used to determine their impact on participation restrictions. RESULTS: Limitations in upper limb functioning were perceived by 98% of the patients. Median scores ranged between 70 points for overall hand function and 100 points for aesthetics (scale 0-100). Patients were least satisfied with dominant hand performance. Most patients (46-78%) reported their participation to be sufficient. Restrictions were reported in the domains work, family roles, and autonomy outdoors. Minor problems with restricted participation were indicated by 22-55%, severe problems by 2-12%. Upper limb functioning correlated significantly with all participation subscales. Upper limb disability was independently associated with participation restrictions, whereas lower limb disability was not. CONCLUSION: Limitations in upper limb functioning were perceived by the majority of patients with hereditary motor and sensory neuropathy 1a and strongly related to restricted participation. PMID- 19774310 TI - Pool exercise for patients with fibromyalgia or chronic widespread pain: a randomized controlled trial and subgroup analyses. AB - OBJECTIVE: To evaluate the effects of pool exercise in patients with fibromyalgia and chronic widespread pain and to determine characteristics influencing the effects of treatment. METHODS: A total of 134 women with fibromyalgia and 32 with chronic widespread pain were randomized to a 20-session pool exercise and a 6 session education programme or to a control group undertaking the same education programme. The primary outcomes were the Fibromyalgia Impact Questionnaire (FIQ) total score and the 6-minute walk test (6MWT). FIQ Pain and other health variables were included. RESULTS: The FIQ total (p = 0.04) improved in the intervention group, with an effect size of 0.32. Patients who had participated in at least 60% of the exercise sessions improved in the FIQ total (effect size 0.44), the 6MWT (effect size 0.43) and FIQ Pain (effect size 0.69) compared with controls (p < 0.05). Long-term follow-up revealed lasting, but small, improvement (effect size < 0.29) in the 6MWT among the active participants (p < 0.05). Analyses within the subgroups showed that patients with milder stress, pain or depression improved most by treatment on the FIQ total (effect size > 0.50, p < 0.05) compared with controls. CONCLUSION: The exercise-education programme showed significant, but small, improvement in health status in patients with fibromyalgia and chronic widespread pain, compared with education only. Patients with milder symptoms improved most with this treatment. PMID- 19774311 TI - Effects of Qigong in patients with burnout: a randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy of Qigong in rehabilitation for patients with burnout. DESIGN: Prospective, randomized controlled trial. SUBJECTS: Eighty-two patients (68 women and 14 men, mean age 44.3 (standard deviation 9.1) years) diagnosed with burnout. METHODS: Basic care was offered to both the intervention and the control group. Patients in the intervention group received basic care and, in addition, performed Qigong twice a week for 12 weeks. Psychological variables, health-related quality of life, perceived relaxation and physical measurements were assessed at baseline and after the intervention period. RESULTS: No significant difference in treatment efficacy between the groups was found by either intention-to-treat or per-protocol analyses. Both groups improved significantly over time, with reduced levels of burnout, fatigue, anxiety and depression, and increased dynamic balance and physical capacity. CONCLUSION: In this study, a Qigong intervention twice a week for 12 weeks had no additional effect beyond basic care for patients with burnout. PMID- 19774312 TI - Striving to master variable pain: an interview study in primary care patients with non-specific long-term neck/shoulder pain. AB - OBJECTIVE: The aim of this study was to explore and analyse the experience of living with long-term neck/shoulder pain and its effect on daily life. DESIGN: A thematic interview study with emergent design. SUBJECTS: Twelve patients in primary care (6 women and 6 men) with long-term neck/shoulder pain. METHODS: Thematic interviews analysed using grounded theory. RESULTS: A conceptual model emerged. The core category "striving to master variable pain" comprises how the informants are constantly aiming at not letting it become too much of a hindrance. The 3 sub-categories "space for health", "strategies for pain control" and "disruptions in daily life" interact with each other. Giving oneself adequate time and prioritizing one's health-promoting behaviour in relation to pain were important when adopting strategies for pain control. Men and women differed when describing consequences for domestic life and prioritizing their own health in relation to pain. CONCLUSION: Living with long-term variable neck/shoulder pain involves a struggle not to let the pain become too much of a physical obstacle to daily life. Individuals learn to respond to the pain in different ways. Allowing oneself adequate time and prioritizing health in relation to pain appear to be important for controlling pain. PMID- 19774313 TI - Recovery from neurological sequelae secondary to oncological brain surgery in an adult growth hormone-deficient patient after growth hormone treatment. AB - OBJECTIVE: To report an unusual case of significant neurological recovery in a 26 year-old growth hormone-deficient female patient with significant neurological sequelae resulting from brain surgery at 11 years of age. DESIGN: Case report. RESULTS: Most of the neurological sequelae present at admission recovered after 8 months of combined growth hormone administration and kinesitherapy/speech therapy. These include an increase in tongue size and mobility and in the amount and quality of saliva, improvement in vocal cords function, recovery of oesophageal peristalsis and disappearance of sleep apnoea. CONCLUSION: Since the patient had undergone intensive physical rehabilitation for a 15-year period with no significant improvement, it is tempting to speculate that the correction of growth hormone deficiency improved her rehabilitation. Therefore, we propose that growth hormone treatment, combined with the adequate kinesitherapy, may be a useful therapy for effective recovery from some neurological deficits in patients with growth hormone deficiency. PMID- 19774314 TI - About the hypothesis of overwork weakness in Charcot-Marie-Tooth disease. PMID- 19774315 TI - Functional status after intensive care. PMID- 19774316 TI - Developing the International Society of Physical and Rehabilitation Medicine (ISPM). Foreword. PMID- 19774317 TI - Chapter 1: Achievements and challenges of ISPRM. AB - This paper describes the history of the International Society of Physical and Rehabilitation Medicine (ISPRM). Past achievements and current challenges are outlined. ISPRM has been successful in setting up a central office, attracting individual and national members, holding international congresses, and establishing relations with the Journal of Rehabilitation Medicine (JRM) as the organization's official journal. ISPRM is currently in official relations with the World Health Organization (WHO) and collaborates closely with WHO's Disability and Rehabilitation team. ISPRM, however, also faces challenges with regard to its growth and the realization of its goals. These include boundaries of voluntary leadership, limited economic resources, the need for enhancing the central office, variations in membership, limits of the current congress bidding system and structure, relations with regional societies, and the need to further develop policies within the field of Physical and Rehabilitation Medicine (PRM) and in relation to WHO and the United Nations system. It is concluded that ISPRM must evolve from an organization, of which the main activities are to hold a biennial congress hosted by a member nation and to provide input to WHO on request, into a professional non-governmental organization (NGO). ISPRM should embark on assuming a leadership role in the further development of PRM within the broader area of human functioning and rehabilitation. PMID- 19774318 TI - Chapter 2: ISPRM's way forward. AB - This paper outlines approaches to developing the International Society of Physical and Rehabilitation Medicine (ISPRM) and addresses many current challenges. Most importantly, these approaches provide the basis for ISPRM to develop its leadership role within the field of Physical and Rehabilitation Medicine (PRM) and in relation to the World Health Organization (WHO) and the United Nations (UN) system at large. They also address a number of specific critiques of the current situation. A positioning of ISPRM within the world architecture of the UN and WHO systems, as well as the consideration and fostering of respective emerging regional PRM societies, is central to establishing networking connections at different levels of the world society. Yearly congresses, possibly in co-operation with a regional society, based on a defined regional rotation, are suggested. Thus, frustration with the current bidding system for a biennial congress and an intermediate meeting could be overcome. Yearly congresses are also an important step towards increasing the organization's funding base, and hence the possibility to expand the functions of ISPRM's Central Office. ISPRM's envisioned leadership role in the context of an international web of PRM journals complementing the formally defined official journal of ISPRM, regional societies, and so forth, is an inclusive rather than exclusive approach that contributes to the development of PRM journals worldwide. An important prerequisite for the further development of ISPRM is the expansion and bureaucratization of its Central Office, adding professionalism and systematic allocation of resources to the strengths of the voluntary engagement of individual PRM doctors. PMID- 19774319 TI - Chapter 3: International non-governmental organizations in the emerging world society: the example of ISPRM. AB - Using the International Society of Physical and Rehabilitation Medicine (ISPRM) as a case in point, the paper describes the complex world societal situation within which non-governmental organizations that address health issues have to operate.This paper describes the complex world societal situation within which non-governmental organizations (NGOs), that are addressing health issues have to operate. In particular, as an international organization in official relation with the World Health Organization (WHO), ISPRM is confronted with a variety of responsibilities and a true world health political mandate. The accompanying rights need to be played out in relation to its own internal member organization and external allies. The theory of the world society and the current situation are briefly reviewed. The role of international NGOs within the world health polity, rehabilitation and Physical and Rehabilitation Medicine (PRM) is highlighted, whilst special emphasis is placed on NGOs in official relation with WHO. Functions, dysfunctions and challenges of international NGOs operating in the health sector are discussed. Against this background, key approaches to enhance ISPRM's political role are analysed. These include transparent and accountable development of the organization, the differentiation between internal and external policy relations, the harmonization of organizational structures and procedures, the consequential use of political structures available to influence WHO's agenda, and the identification of other policy players of major relevance to PRM in order to build strategic alliances with external partners and to enhance ISPRM's membership base. PMID- 19774320 TI - Chapter 4: A policy process and tools for international non-governmental organizations in the health sector using ISPRM as a case in point. AB - The politics of international non-governmental organizations (NGOs) such as the International Society of Physical and Rehabilitation Medicine (ISPRM) serve the function of selecting and attaining particular socially valued goals. The selection and attainment of goals as the primary function of political action can be structured along a policy process or cycle comprising the stages of strategic goal setting and planning of strategic pathways, agenda setting, resource mobilization, implementation, evaluation and innovation. At the various stages of this policy process different policy tools or instruments, which can be used to influence citizen and organizational behaviour in the light of defined goals, can be applied. The objective of this paper is to introduce and describe policy tools of potential relevance to ISPRM with regard to different policy functions and stages of the policy process. PMID- 19774321 TI - Chapter 5: Organizational structures suited to ISPRM's evolving role as an international non-governmental organization in official relation with the world health organization. AB - International non-governmental organizations (NGOs) in official relation with the World Health Organization (WHO) face organizational challenges against the background of legitimate representation of their membership and accountable procedures within the organization. Moreover, challenges arise in the light of such an international NGO's civil societal mandate to help reach the "health-for all" goals as defined by WHO and to facilitate the implementation of the United Nations (UN) Convention on the Rights of Persons with Disabilities. The objective of this paper is to examine how such an international NGO using the International Society of Physical and Rehabilitation Medicine (ISPRM) as a case in point can address these challenges. The specific aims are to analyse ISPRM's structures and procedures of internal organs and external relations and to develop solutions. These possible solutions will be presented as internal organizational scenarios and a yearly schedule of meetings closely aligned to that of WHO to facilitate an efficient internal and external interaction. PMID- 19774322 TI - Chapter 6: The policy agenda of ISPRM. AB - This paper suggests a comprehensive policy agenda and first steps to be undertaken by the International Society of Physical and Rehabilitation Medicine (ISPRM) in order to realize its humanitarian, professional and scientific mandates. The general aims of ISPRM, as formulated in its guiding documents, the relations with the World Health Organization (WHO) and the United Nations system, and demands of ISPRM's constituency herein form the basis of this policy agenda. Agenda items encompass contributions to the establishment of rehabilitation services worldwide and the development of rapid rehabilitation disaster response, the enhancement of research capacity in Physical and Rehabilitation Medicine (PRM), and the development of PRM societies. ISPRM's possible input in general curricula in disability and rehabilitation, and in fighting discrimination against people experiencing disability are discussed. Moreover, the implementation of the International Classification of Functioning, Disability and Health (ICF) in medicine, contributions to WHO guidelines relevant to disability and rehabilitation, the provision of a conceptual description of the rehabilitation strategy and the outline of a rehabilitation services matrix are seen as important agenda items of ISPRM's external policy. With regard to its constituency and internal policy, a definition of the field of competence and a conceptual description of PRM, as well as the development of a consistent and comprehensive congress topic list and congress structure appear to be crucial items. The proposed agenda items serve as a basis for future discussions. PMID- 19774323 TI - Low-energy distal radius fractures in middle-aged and elderly women-seasonal variations, prevalence of osteoporosis, and associates with fractures. AB - There is a lack of data on the prevalence of osteoporosis in patients with distal radius fractures occurring at the various seasons. The prevalence of osteoporosis is high, both in patients with indoor and outdoor fractures and higher than in controls. All female distal radius fracture patients >or=50 years should be referred for osteoporosis assessment. INTRODUCTION: The objectives of this study in female distal radius fracture patients were to investigate seasonal differences, estimate the prevalence of osteoporosis, and identify factors associated with distal radius fractures compared with controls. METHODS: In a 2 year period, 263 women >/=50 years suffered a low-energy distal radius fracture in the geographic catchment area. The 214 women who met for osteoporosis assessment were age-matched with 191 controls. Bone mineral density was assessed by dual energy X-ray absorptiometry at femoral neck, total hip, and lumbar spine. Demographic and clinical data were collected. RESULTS: The prevalence of indoor fractures showed no seasonal variance. For outdoor fractures, the prevalence was highest in the winter months. The prevalence of osteoporosis among patients with indoor fractures was higher (58.5%) than outdoor fractures without (38.6%) and with snow/ice (36.0%; p < 0.001). The prevalence of osteoporosis was higher in fracture patients (42.5%) than controls (24.1%; p < 0.001), this was also found in the youngest age group 50-59 years (22.2% vs 1.8%; p < 0.001). In conditional logistic regression analyses osteoporosis, current use of glucocorticoids, and living alone were independently associated with distal radius fractures. CONCLUSIONS: Our study highlights that environmental factor, as well as osteoporosis are associated with distal radius fractures in middle-aged and elderly women. Osteoporosis is also frequently found in outdoor patients, thus, all female distal radius fracture patients >or=50 years should be referred for osteoporosis assessment. PMID- 19774324 TI - Polycyclic aromatic hydrocarbon contamination of recent sediments and marine organisms from Xiamen Bay, China. AB - Surface marine sediments from 12 sites within Xiamen Bay (XMB) and marine organisms (clam, crab, and fish) from a heavily polycyclic aromatic hydrocarbon (PAH)-contaminated site at Yuandang Lagoon were sampled and analyzed for 16 priority PAH content by gas chromatography/mass spectrometry. The total PAH concentrations in sediments ranged from 203.7 to 1590.5 ng/g, with an average value of 670.0 ng/g. Overall, the total PAH concentrations were relatively lower in the east coastal zone and significantly higher in Yuandang Lagoon. These concentrations were intermediate in comparison with those observed in other estuaries in China. The sources of PAH inputs to sediments in XMB were quantitatively determined by principal components analysis with multiple linear regression. The results showed that, on average, vehicle emissions, petroleum spills, and coal combustion contributed to 41, 36, and 23% of the total PAHs, respectively. Analysis of the PAH composition pattern in marine organisms showed that the total PAHs levels of fishes were lower than those of the clam and crab. The PAH burden of the crab and calm was characterized by the non-negligible occurrence of high-molecular-weight compounds, whereas the fish PAH pattern was dominated by the lower-molecular-weight compounds. In addition, the carcinogenic PAH benzo[a]pyrene was detected in all samples. Molecular indices based on isomeric PAH ratios differentiated the uptake pathway among organisms. The water soluble matter and the petroleum seemed to be the most favorable uptake pathway in fish from Yuandang Lagoon, whereas the crab and clam shared a mix uptake by the water-soluble and the particulate matter. PMID- 19774325 TI - Forecasting the effects of land-use change on forest rodents in Indiana. AB - Forest cover in the upper Wabash River basin in Indiana was fragmented due to agricultural conversion beginning more than 175 years ago. Currently, urban expansion is an important driver of land-use change in the basin. A land transformation model was applied to the basin to forecast land use from 2000 to 2020. We assessed the effect of this projected land-use change scenario on five forest rodent species at three scales: using occupancy models at the patch level, proportional occupancy models at the landscape level, and ecologically scaled landscape indices to assess the change in connectivity at the watershed level. At the patch and landscape scales, occupancy models had low predictability but suggest that gray squirrels are most susceptible to land-use change. At the watershed scale, declines in connectivity did not correspond with the decline of forest. This study highlights the importance of map resolution and consideration of matrix elements in constructing forecast models. Unforeseen drivers of land use, such as changing economic incentives, may also have important ramifications. PMID- 19774326 TI - Water consumption in the production of ethanol and petroleum gasoline. AB - We assessed current water consumption during liquid fuel production, evaluating major steps of fuel lifecycle for five fuel pathways: bioethanol from corn, bioethanol from cellulosic feedstocks, gasoline from U.S. conventional crude obtained from onshore wells, gasoline from Saudi Arabian crude, and gasoline from Canadian oil sands. Our analysis revealed that the amount of irrigation water used to grow biofuel feedstocks varies significantly from one region to another and that water consumption for biofuel production varies with processing technology. In oil exploration and production, water consumption depends on the source and location of crude, the recovery technology, and the amount of produced water re-injected for oil recovery. Our results also indicate that crop irrigation is the most important factor determining water consumption in the production of corn ethanol. Nearly 70% of U.S. corn used for ethanol is produced in regions where 10-17 liters of water are consumed to produce one liter of ethanol. Ethanol production plants are less water intensive and there is a downward trend in water consumption. Water requirements for switchgrass ethanol production vary from 1.9 to 9.8 liters for each liter of ethanol produced. We found that water is consumed at a rate of 2.8-6.6 liters for each liter of gasoline produced for more than 90% of crude oil obtained from conventional onshore sources in the U.S. and more than half of crude oil imported from Saudi Arabia. For more than 55% of crude oil from Canadian oil sands, about 5.2 liters of water are consumed for each liter of gasoline produced. Our analysis highlighted the vital importance of water management during the feedstock production and conversion stage of the fuel lifecycle. PMID- 19774327 TI - Hotlines and clinical trial updates presented at the European Society of Cardiology Meeting 2009: data from RE-LY, PLATO, MADIT-CRT, PROTECT, SYNTAX, TRITON and more. AB - This summary article provides an update on novel clinical trials in the field of cardiovascular (CV) medicine which were presented at the annual meeting of the European Cardiac Society, held in Barcelona, Spain, in August-September 2009. The data were presented by leading experts in the field with relevant positions in the trials and registries. Unpublished reports should be considered as preliminary data as the analysis may change in the final publications. This article provides the reader with comprehensive summaries of the most recent diagnostic and therapeutic developments in CV medicine as previously reported (Kindermann et al. in Clin Res Cardiol 96:767-786, 2007; Muller et al. in Clin Res Cardiol 97:851-864, 2008). PMID- 19774328 TI - Reduction in ECG abnormalities and improvement of regional left ventricular function in a patient with Fabry's disease during enzyme-replacement therapy. PMID- 19774329 TI - Recurrent syncope associated with a distinct ECG pattern consisting of short QT interval, early repolarization and atrioventricular block. PMID- 19774330 TI - Complete reversal of paraplegia after thoracic endovascular aortic repair in a patient with complicated acute aortic dissection using immediate cerebrospinal fluid drainage. PMID- 19774331 TI - Incidence and clinical significance of mitral regurgitation in Takotsubo cardiomyopathy. AB - BACKGROUND: In a previous report, acute mitral regurgitation (MR) was found to indicate the more severe end of the spectrum of Takotsubo cardiomyopathy (TC). The aim of this study was to determine the incidence and clinical significance of acute MR in TC. METHODS: Early (<24 h of presentation) left ventricular (LV) angiograms of 47 patients with TC were reviewed by two blinded reviewers. MR severity was graded on a four graded scale. MR > or = grade 2 was considered significant. RESULTS: Significant MR was present in nine (19%) patients. MR was severe (grade 3 or 4) in four and moderate (grade 2) in five. LV outflow tract gradients were not observed in any of these patients. Patients with and without significant MR did not differ with regard to various clinical parameters, including age, gender, type of TC, cardiovascular risk factors, presenting ECG, level of troponin I, triggering factors, ejection fraction (EF), vasopressor therapy, pulmonary edema, and survival to discharge. When patients were grouped according to the presence or absence of pulmonary edema, the only significant difference between the two groups was EF which was significantly lower in patients with pulmonary edema (40 +/- 12% vs. 50 +/- 12%, P = 0.011). CONCLUSIONS: Acute MR is a noteworthy finding in TC, but it is not associated with the severity of TC. Dysfunction of mid-ventricular myocardium seems to be a conditio sine qua non, whereas LVOT obstruction does not seem to play an important role. PMID- 19774332 TI - Are measures of height and leg length related to incident diabetes mellitus? The ARIC (Atherosclerosis Risk in Communities) study. AB - This study was designed to estimate the risk of developing diabetes in relation to adult height components, namely leg length and leg length/height ratio. Data on 12,800 individuals without diabetes were obtained at the baseline examination from the ARIC cohort. Cox proportional hazard models were used to estimate hazard rate ratios of diabetes for each 5-cm difference in leg length and 1 SD difference in the leg length/height ratio. During a mean follow-up period of 7.6 years, the age-adjusted incidence per 1,000 person years of follow-up was 25.8, 24.2, 10.4, and 16.2 in African American (AA) women, AA men, white women, and white men, respectively. The hazard ratio for diabetes (95% CI) per 5-cm difference in leg length was 0.85 (0.75-0.95) in white men, 0.79 (0.69-0.90) in white women, 0.90 (0.75-1.07) in AA women, and 0.99 (0.77-1.27) in AA men, after adjusting for age, parental history of diabetes, parental socioeconomic status, and weight at age 25. The hazard ratio for diabetes per 1 SD difference in leg length/height ratio followed the same trend. Leg length is inversely and independently related to an increased risk of diabetes in middle-age white men and women but not in African-Americans. This sex-race heterogeneity suggests that nutritional and environmental factors in childhood may modify this risk through different pathways. PMID- 19774333 TI - Middle age is not associated with altered fibrinogen concentration and production in males. AB - Whether ageing is associated with increased fibrinogen concentration and production remains unclear. We measured fibrinogen fractional (FSR) and absolute synthesis (ASR) rates in male volunteers, of either young (mean age: 28 years, range: 22-34) or middle age (mean age: 57 years, range: 38-72), using a leucine tracer isotope dilution technique. In the middle-age group, neither fibrinogen FSR (20.8 +/- 1.6%/day) nor ASR (1.8 +/- 0.1 g/day), or concentration (274 +/- 15 mg/dl), were different from those of the younger group (FSR: 20.2 +/- 1.4; ASR: 1.7 +/- 0.2; concentration: 265 +/- 8, respectively). Leucine Ra, an index of endogenous proteolysis, was approximately 20% lower in the older than in the younger group (P < 0.02). Thus, middle age in males is not associated with increased fibrinogen concentration and turnover, whereas endogenous protein breakdown in decreased. Factor(s) different from age per se are likely to be involved in the dysfibrinogenemia possibly occurring with ageing. Protein turnover is already reduced in middle-age males. PMID- 19774334 TI - Paragangliomas of head and neck: a treatment option with CyberKnife radiosurgery. AB - Paragangliomas are highly vascular and predominantly benign neoplasms that have traditionally been treated by surgery, embolization and/or external beam radiotherapy (EBRT). The aim of this study is to evaluate the short-term local tumor control and safety of CyberKnife radiosurgery for these lesions. Nine patients, eight with jugular glomus paragangliomas and one with a carotid body paraganglioma, were treated. The target contouring was performed on merged CT and MR images. Eight patients were treated with doses ranging from 11 to 13 Gy (mean 12.5 Gy) in a single fraction and one with 24 Gy in three fractions prescribed to 72-83% isodose line. The mean follow-up was 20 months. One patient died from unrelated causes. There were no local recurrences. All eight patients also demonstrated neurological stability or improvement. Neither cranial nerve palsies have arisen, nor has deterioration beyond baseline been observed. In conclusion, CyberKnife radiosurgery appears to be both safe and effective in the treatment of skull base paragangliomas. Determining whether long-term complications will arise will require further investigation. PMID- 19774335 TI - Complete genome sequence of turnip ringspot virus. AB - Here we present the complete genome sequences of two TuRSV isolates. They are 90 100% identical in distinct genes, but reasonably less identical with RaMV isolates. Regarding the CPs, TuRSV and RaMV have an aa sequence identity of 72 74% among all isolates and the proposed cut-off level is 75%. For the proteinase polymerase region, the average value between the two isolates of TuRSV and three isolates of RaMV is 79.8% and the cut-off level is 80%. At the moment, TuRSV and RaMV are the two identified species most closely related within the genus Comovirus. PMID- 19774336 TI - Complete nucleotide sequence of an isolate of Euphorbia mosaic virus that infects Euphorbia heterophylla and Wissadula amplissima in Jamaica. PMID- 19774337 TI - Anti-influenza-virus activity of total alkaloids from Commelina communis L. AB - The antiviral activity of total alkaloids from Commelina communis L. (TAC) against influenza virus A/PR/8/34 (H1N1) was investigated in vitro and in vivo. TAC exhibited an inhibitory action on the growth of influenza virus in Madin Darby canine kidney cells when added before or after viral infection. In mice infected with influenza virus, orally administered TAC at 8, 16 or 32 mg/kg per day for 6 days significantly increased the survival rate, prolonged the mean survival time and reduced the viral titers in the lung and the lung index, compared with that of the untreated virus control. The results obtained suggest that TAC has a pronounced protective effect against infection by influenza A virus. PMID- 19774338 TI - Prevalence of human metapneumovirus in hospitalized children with respiratory tract infections in Tianjin, China. AB - Human metapneumovirus (hMPV) has recently been recognized as an important respiratory pathogen, especially in children. At present, our understanding of the characteristics of hMPV from China is very limited. Nasopharyngeal aspirates were taken from 310 hospitalized pediatric patients. Twenty (6.5%) of them were infected with hMPV, and they all developed pneumonia. Sixty five percent (13/20) of the cases were under 12 months. Phylogenetic analysis of F gene fragments indicated that three sub-genotypes of hMPV(A2a/A2b, B1,B2) circulated in Tianjin and A2b was the predominant subtype. The Vero-E6 cell line was better than LLC MK2 for hMPV isolation. Three hMPV strains were successfully isolated using the Vero-E6 cell line. PMID- 19774339 TI - Support for smoke-free policies in a pro-smoking culture: findings from the European survey on tobacco control attitudes and knowledge. AB - OBJECTIVES: To assess support for tobacco control policies between smokers and non-smokers, and the effects of nicotine dependence on smokers' policy support in a country with high smoking rates and pro-smoking norms. METHODS: Population based, cross-sectional telephone survey of a random sample of 700 Greek adults (mean age = 40.2, SD = 10.9) assessing smoking status and attitudes towards tobacco control policies. RESULTS: Almost half of the respondents were current smokers, and smoking prevalence was significantly higher in males than females. Compared to non-smokers and former smokers, current smokers were less supportive of smoke-free public places and taxation policies. All groups appeared equally supportive for policies against sales of tobacco products to minors. Daily smokers with higher nicotine dependence were less supportive for smoke-free public places and taxation policies compared to smokers with lower dependence scores. CONCLUSIONS: Smoking status and nicotine dependence differentiate the level of support for smoke-free policies. However, both smokers and non-smokers seem to be supportive for policies aiming to prevent youth from smoking, even in a country with pro-smoking social norms and high smoking rates. PMID- 19774340 TI - US local action on heat and health: are we prepared for climate change? AB - OBJECTIVES: Global climate change is increasing the frequency of heat waves, hot weather, and temperature variability, which contribute to mortality and illness. Baseline information on local efforts to reduce heat vulnerability, including public advisories; minimizing greenhouse gas emissions; and mitigating urban heat islands, is lacking. METHODS: We designed a survey about local government programs to prevent health problems and reduce heat exposure during heatwaves and administered it to 285 US communities. RESULTS: Of 70 respondents, 26 indicated that excessive heat events are a significant issue for the local government; 30 had established preventive programs. Local government leadership and public health impacts of heat were cited most frequently as extremely important determinants of preventive programs, followed by implementation costs, economic impacts of hot weather, and greenhouse gas emissions mitigation. Cool paving materials and vegetated roofs were common heat mitigation strategies. Fact sheets and case studies were desired guidance for protecting communities during hot weather. CONCLUSIONS: New partnerships and financial resources are needed to support more widespread local action to prevent adverse health consequences of climate change and promote environmental sustainability. PMID- 19774341 TI - Poor social relations and adverse health behaviour: stronger associations in low socioeconomic groups? AB - OBJECTIVE: Poor social relations are supposed to contribute to adverse health behaviour. We examined this association and the role of low socio-economic position. METHODS: We regressed health behaviour on composite variables of the two exposures of social relations and socio-economic position (SEP). Social relations included networks and support; health behaviour was analysed in terms of smoking, poor nutrition and physical inactivity; socio-economic position comprised of income and education. Cross sectional data from a population based epidemiological study in German (4,814 men and women aged 45-75) was analysed. RESULTS: Among the indicators for social relations, social isolation was consistently associated with adverse health behaviour; social support showed modest effect. A combination of poor social relations and low SEP displayed stronger (additive) associations with adverse health behaviour than each factor alone. However, superadditivity was excluded. CONCLUSION: Given the important role of health adverse behaviour in chronic disease development, results underline the relevance of social environment and socio-economic structure in Public Health interventions. PMID- 19774342 TI - A phase I study of rebeccamycin analog in combination with oxaliplatin in patients with refractory solid tumors. AB - Rebeccamycin analog (RA) is an antitumor antibiotic with both topoisomerase I and II inhibiting activity. Topoisomerase inhibitors have demonstrated synergy with platinum agents. We performed a phase I trial of combination RA with oxaliplatin in patients with refractory solid tumors. RA was administered as a 1-hour infusion daily on days 1-5 with oxaliplatin administered on day 5. Cycles were repeated every 21 days. A total of 17 patients were enrolled. The MTD for RA was 80 mg/m(2)/d for five days along with oxaliplatin 130 mg/m(2) on day 5. Myelosuppression was a common occurrence but was mild except in one instance. Dose limiting toxicities included atrial fibrillation and hypophosphatemia. There was evidence of antitumor activity including 3 partial responses in patients with esophageal, gallbladder and hepato-cellular carcinoma; 5 additional patients had stable disease. Thus, the combination of RA and oxaliplatin is both tolerable and has evidence of clinical activity, but given the lack of significant activity for single agent RA across a variety of disease sites, it is unlikely to proceed to phase II development. PMID- 19774343 TI - "ChilDrive": a technique of combining regional cutaneous hypothermia with iontophoresis for the delivery of drugs to synovial fluid. AB - PURPOSE: Bioavailability of drugs in the synovial fluid when administered via transdermal route is highly limited due to the dermal clearance. The purpose of this project was to assess the efficiency of ChilDrive (CD) technique to improve the drug targeting to the synovial fluid. CD is a technique of transdermal delivery of drugs combining regional hypothermia and iontophoresis. METHODS: Diclofenac sodium and Prednisolone sodium phosphate were administered by transdermal route (Passive, Iontophoresis, Chil-Passive and ChilDrive) at the knee-joint region of hind limb in sprague dawley rats for 6 h. Intraarticular microdialysis was carried out to determine the time course of drug concentration in the synovial fluid. Drug levels in synovial fluid after intravenous and intraarticular administration were also determined. RESULTS: Iontophoretic delivery increased the AUC(0-t) (area under the curve) of drugs in the synovial fluid by 3-fold over passive delivery (0.86 +/- 0.04 and 2.0 +/- 0.06 microg.h/ml for diclofenac sodium and prednisolone sodium phosphate, respectively). CD resulted in an AUC(0-t) of 5.2 +/- 0.69 and 24.6 +/- 1.97 microg.h/ml for diclofenac sodium and prednisolone sodium phosphate which was approximately 6-12 fold higher than the passive and 2-4-fold higher than iontophoresis. CONCLUSIONS: The results support our hypothesis that CD improves bioavailability of drugs to the synovial joints. CD could be developed as a potential noninvasive technique for treatment of arthritis. PMID- 19774345 TI - Thymidine production by overexpressing NAD+ kinase in an Escherichia coli recombinant strain. AB - Abstract Intracellular NADPH/NADP+ ratio in cells grown on various production media with different carbon and nitrogen sources had a positive correlation with the thymidine production. To improve thymidine production in a previously engineered E. coli strain, NAD+ kinase was overexpressed in it resulting in the NADPH/NADP+ ratio shifting from 0.184 to 0.267. The [NADH + NADP+]/[NAD+ + NADPH] ratio was, however, not significantly altered. In jar fermentation, 740 mg thymidine l-1 was produced in parental strain, while 940 mg l-1 of thymidine was produced in NAD+ kinase-expressing strain. PMID- 19774344 TI - Uptake of ANG1005, a novel paclitaxel derivative, through the blood-brain barrier into brain and experimental brain metastases of breast cancer. AB - PURPOSE: We evaluated the uptake of angiopep-2 paclitaxel conjugate, ANG1005, into brain and brain metastases of breast cancer in rodents. Most anticancer drugs show poor delivery to brain tumors due to limited transport across the blood-brain barrier (BBB). To overcome this, a 19-amino acid peptide (angiopep-2) was developed that binds to low density lipoprotein receptor-related protein (LRP) receptors at the BBB and has the potential to deliver drugs to brain by receptor-mediated transport. METHODS: The transfer coefficient (K(in)) for brain influx was measured by in situ rat brain perfusion. Drug distribution was determined at 30 min after i.v. injection in mice bearing intracerebral MDA-MB 231BR metastases of breast cancer. RESULTS: The BBB K(in) for (125)I-ANG1005 uptake (7.3 +/- 0.2 x 10(-3) mL/s/g) exceeded that for (3)H-paclitaxel (8.5 +/- 0.5 x 10(-5)) by 86-fold. Over 70% of (125)I-ANG1005 tracer stayed in brain after capillary depletion or vascular washout. Brain (125)I-ANG1005 uptake was reduced by unlabeled angiopep-2 vector and by LRP ligands, consistent with receptor transport. In vivo uptake of (125)I-ANG1005 into vascularly corrected brain and brain metastases exceeded that of (14)C-paclitaxel by 4-54-fold. CONCLUSIONS: The results demonstrate that ANG1005 shows significantly improved delivery to brain and brain metastases of breast cancer compared to free paclitaxel. PMID- 19774346 TI - The intrabody targeting of hTERT attenuates the immortality of cancer cells. AB - hTERT (human telomerase reverse transcriptase) plays a key role in the process of cell immortalization. Overexpression of hTERT has been implicated in 85% of malignant tumors and offers a specific target for cancer therapy. In this paper, we describe an effective approach using a single-chain variable fragment (scFv) intrabody derived from monoclonal hybridoma directed against hTERT to attenuate the immortalization of human uterine cervix and hepatoma cells. The scFv we constructed had a high affinity to hTERT, and specifically neutralized over 70% of telomere synthesis activity, thereby inhibiting the viability and proliferation of the cancer cells. Our results indicate that this anti-hTERT intrabody is a promising tool to target hTERT and intervene in the immortalization process of cancer cells. PMID- 19774347 TI - Hypocalcemia in pregnant women. AB - The objective of this study is to estimate the prevalence of hypocalcemia and its correlation with dietary intake of calcium (DICa) and urinary calcium excretion (UCaE) in pregnant women. Healthy pregnant women (n = 543) were enrolled consecutively. DICa was calculated form dietary history. Serum calcium (SCa) and 24-h UCaE was measured. Student t test and Chi-square tests were used to compare the continuous and categorical data in women with and without hypocalcemia (SCa 3 months. PMID- 19774381 TI - A confusing patient's history: small or large vessel vasculitis? PMID- 19774382 TI - Mucosal lesions may be a minor complication of SAPHO syndrome: a study of 11 Japanese patients with SAPHO syndrome. AB - Since the term synovitis-acne-pustulosis-hyperostosis-osteitis (SAPHO) syndrome was proposed by Chamot et al. (Rev Rhum Mal Osteoartic 54:187-196, 1987), clinical reviews concerning this syndrome have been mainly reported from Europe. We carried out a retrospective analysis of 11 Japanese patients with SAPHO syndrome, and reviewed the clinical features of our series in comparison with those in a European large case study. In this study the major features of SAPHO syndrome were chronic osteitis of the anterior chest wall and pustulotic arthro ostitis with middle age onset, and mucosal lesions seemed to be a minor complication of SAPHO syndrome. The non-erosive peripheral large joints arthritis and the particular HLA types (HLA-B51, B52, or A26), which had been reported to be increased in Behcet's disease, were frequently seen in SAPHO syndrome with mucosal lesions. This study also suggests that SAPHO syndrome with mucosal lesions may be part of a broader disease spectrum including Behcet's disease. PMID- 19774383 TI - TNF-alpha gene polymorphisms in Iranian Azeri Turkish patients with Behcet's Disease. AB - Genetic factors that predispose individuals to Behcet's disease (BD) are considered to play an important role in the development of the disease. The serum level of tumor necrosis factor (TNF) is elevated in patients with BD, and a dramatic response to anti-TNF-alpha antibody treatment further supports the role of TNF in BD. We investigated the distribution of TNF-alpha promoter -1031T/C and -308G/A polymorphisms in 53 BD patients of Iranian Azeri Turks and 79 matched healthy controls, via the PCR-RFLP technique. The frequency of the TNF-alpha 1031C allele was significantly higher in Behcet's patients than in healthy controls (p < 0.0001, OR = 3.08; 95% CI = 1.73-5.47), whereas the frequency of the TNF-alpha -308A allele was similar in the two compared groups. The frequency of CG haplotype was significantly higher (p < 0.0001, OR = 3.42; 95% CI = 1.89 6.18), and that of the TA haplotype was significantly lower in BD patients than in healthy controls. These results suggest that TNF-alpha is a susceptibility gene for BD in patients from Iranian Azeri Turk ethnic group. PMID- 19774385 TI - Retraction. Transgenic ramie [Boehmeria nivea (L.) Gaud.]: factors affecting the efficiency of Agrobacterium tumefaciens-mediated transformation and regeneration. PMID- 19774384 TI - Microscopic polyangiitis initiated with liver dysfunction, calf pain and fever of unknown origin. AB - We report herein a case of microscopic polyangiitis (MPA), presenting onset with a spiking fever, liver/biliary dysfunction without jaundice and calf pain without elevation of serum creatine phosphokinase. During 1 month of careful examinations for initial diagnosis, the patient developed renal dysfunction and pulmonary hemorrhage. Based on the results of positive MPO-ANCA, renal and pulmonary involvements, the patient was diagnosed with MPA and treated with high-dose prednisolone and oral cyclophosphamide. Soon after initiation of the treatment, symptoms such as fever, calf pain, liver/biliary dysfunction and renal dysfunction disappeared with decrease of MPO-ANCA titer to the normal level. PMID- 19774386 TI - A potential role for ribosomal protein S2 in the gene network regulating reproductive diapause in the mosquito Culex pipiens. AB - We propose that a shut-down in expression of ribosomal protein S2 (rpS2) contributes to regulation of diapause in adult females of Culex pipiens. While this gene is expressed continuously in nondiapausing females reared under long day conditions, it is strongly down-regulated 5-18 days after adult eclosion in females reared under the short-day conditions that induce diapause. The possibility that this shut-down in expression of rpS2 contributes to the arrest in ovarian development characteristic of diapause is bolstered by the diapause like arrest in follicle growth observed when nondiapausing females are injected with dsrpS2. A control gene encoding another ribosomal protein, L19, is expressed equally in nondiapausing and diapausing females, and RNA interference directed against rpL19 did not arrest follicle growth, thus indicating that the response we observed in knocking down expression of rpS2 is not common to all ribosomal proteins. Diapause in C. pipiens is readily terminated with juvenile hormone (JH), and in this study we demonstrated that an exogenous application of JHIII can rescue the arrest in follicle growth caused by dsrpS2. Together, these results suggest that rpS2 plays a critical role in arresting the ovarian development associated with diapause in this mosquito. PMID- 19774388 TI - Morgagni hydatids: a new factor in infertility? AB - PURPOSE: To evaluate the effect of Morgagni hydatid (MH) on infertility by comparing women known to be fertile and infertile with respect to MH frequency. METHODS: The study was conducted in Gaziantep University Faculty of Medicine with the precipitation of total 455 patients. The 240 of them were pregnant to whom planned cesarean section (C/S) and the other 215 were infertile one who have undergone diagnostic laparoscopy. Fertile Group (Group 1) consisted of women whom have become spontaneously pregnant without any kind of infertility management. These are planned to undergo C/S with different indications. Infertile group (Group 2) consisted of women diagnosed as unexplained infertility and planned to undergo diagnostic laparoscopy according to ASRM 2006 guidelines. The frequency, number, and the bilaterality of the MH were evaluated during the C/S in fertile group and diagnostic laparoscopy in infertile group. SPSS was used for statistical analyses. RESULTS: The MH frequency was higher in Group 2 than Group 1 (P < 0.05). The bilaterality of MHs were significantly higher in Group 2 than Group 1 (P < 0.05).The number of the MHs were significantly higher in Group 2 than Group 1 (P < 0.05). CONCLUSIONS: These findings suggest a possible effect of MH on fertility. The theory of MH disturbing tubal motility with respect to the pick-up and transport of ovum appears logical in this aspect. PMID- 19774387 TI - High expression of cathepsin B and plasminogen activator inhibitor type-1 are strong predictors of survival in glioblastomas. AB - In contrast to pilocytic astrocytomas (WHO grade I gliomas) that are circumscribed and cured by surgical resection, invasion is a hallmark of grades II-IV gliomas. Proteases play a major role in the invasion process and correlations between glioma grading, survival and protease expression have been demonstrated. In this study, we have chosen to study using different technical approaches (Q-RT-PCR, in situ hybridization and immunohistochemistry) the expression of five molecules involved in extracellular matrix degradation (cathepsin B, MMP2, MMP9, uPA and PAI-1) in glioblastomas in order to determine their prognostic impact among grade IV gliomas. Pilocytic astrocytomas were used as controls. Q-RT-PCR showed that transcripts of uPA, PAI-1, cathepsin B and MMP9 were significantly more expressed in glioblastomas (n = 52), in comparison to pilocytic astrocytomas (n = 17) (P = 0.049, P < 0.0001, P = 0.03 and P < 0.0001, respectively). On both univariate and multivariate analyses, cathepsin B and PAI 1 were strong predictors of overall survival among the group of glioblastomas (P < 0.0001 and P = 0.01, respectively). Immunohistochemical expression of cathepsin B further confirmed its prognostic value in an independent cohort of patients with glioblastoma. In situ hybridization showed that uPA is detected at the invasive edge of glioblastomas, whereas PAI-1 is more abundant in microvascular proliferation and pseudo-palisading cells than at the infiltrative edges. These results suggest that cathepsin B and PAI-1 are important biomarkers for the stratification of glioblastoma patients with respect to survival. PMID- 19774389 TI - Histologic and colposcopic correlation of cervical cytology showing "? glandular neoplasia". AB - OBJECTIVE: To evaluate the role of cervical cytology and colposcopy in the management of patients with cervical smear reported "? glandular neoplasia". STUDY DESIGN: A retrospective study of 116 patients referred to the colposcopy clinic with cytology samples showing "? glandular neoplasia". RESULTS: Histological results were available for 114 patients; of those, 103 had cervical biopsy, 52 had endometrial biopsy and 41 patients had both. 17 (15.5%) had invasive disease, 12 cervical carcinoma (11 adenocarcinoma and one squamous cell carcinoma) and 5 endometrial adenocarcinoma. 12 (10.5%) had high-grade cervical glandular intra-epithelial neoplasia (HG CGIN). 23 (20.2%) had high-grade cervical intra-epithelial neoplasia (HG CIN). None of the patients in whom colposcopy was normal were found to have invasive cervical disease. All the patients with endometrial carcinoma were above the age of 50 years, and none of the patients with cervical carcinoma was above this age. CONCLUSIONS: Cytology samples with "? glandular neoplasia" are associated with significant pathology. Colposcopy is important in the assessment of this group of patients. Endometrial assessment should be offered to all patients above the age of 50 years or postmenopausal presenting with such cytology. PMID- 19774390 TI - Use of uterine fundal pressure maneuver at vaginal delivery and risk of severe perineal laceration. PMID- 19774391 TI - Can venous occlusion plethysmography be used to measure high rates of arterial inflow? AB - To investigate whether venous occlusion plethysmography (VOP) may be used to measure high rates of arterial inflow associated with exercise, venous occlusions were performed at rest, and following dynamic handgrip exercise at 15, 30, 45, and 60% of maximum voluntary contraction (MVC) in seven healthy males. The effect of including more than one cardiac cycle in the calculation of blood flow was assessed by comparing the cumulative blood flow over one, two, three, or four cardiac cycles. The inclusion of more than one cardiac cycle at 30 and 60% MVC, and more than two cardiac cycles at 15 and 45% MVC resulted in a lower blood flow compared to using only the first cardiac cycle (P < 0.05). Despite the small time interval over which arterial inflow was measured (~1 s), this did not affect the reproducibility of the technique. Reproducibility (coefficient of variation for arterial inflow over three trials) tended to be poorer at the higher workloads, although this was not significant (12.7 +/- 6.6, 16.2 +/- 7.3, and 22.9 +/- 9.9% for the 15, 30, and 45% MVC workloads; P = 0.102). There was also a tendency for greater reproducibility with the inclusion of more cardiac cycles at the highest workload, but this did not reach significance (P = 0.070). In conclusion, when calculated over the first cardiac cycle only during venous occlusion, high rates of forearm blood flow can be measured using VOP, and this can be achieved without a significant decrease in the reproducibility of the measurement. PMID- 19774392 TI - Dehydration rate and time of desiccation affect recovery of the lichen alga [corrected] Trebouxia erici: alternative and classical protective mechanisms. AB - The mechanisms involved in desiccation tolerance of lichens and their photobionts are still poorly understood. To better understand these mechanisms we have studied dehydration rate and desiccation time in Trebouxia, the most abundant chlorophytic photobiont in lichen. Our findings indicate that the drying rate has a profound effect on the recovery of photosynthetic activity of algae after rehydration, greater than the effects of desiccation duration. The basal fluorescence (F'(o)) values in desiccated algae were significantly higher after rapid dehydration, than after slow dehydration, suggesting higher levels of light energy dissipation in slow-dried algae. Higher values of PSII electron transport were recovered after rehydration of slow-dried Trebouxia erici compared to rapid dried algae. The main component of non-photochemical quenching after slow dehydration was energy dependent (q (E)), whereas after fast dehydration it was photoinhibition (q (I)). Although q (E) seems to play a role during desiccation recovery, no significant variations were detected in the xanthophyll cycle components. Desiccation did not affect PSI functionality. Classical antioxidant activities like superoxide dismutase or peroxidase decreased during desiccation and early recovery. Dehydrins were detected in the lichen-forming algae T. erici and were constitutively expressed. There is probably a minimal period required to develop strategies which will facilitate transition to the desiccated state in this algae. In this process, the xanthophyll cycle and classical antioxidant mechanisms play a very limited role, if any. However, our results indicate that there is an alternative mechanism of light energy dissipation during desiccation, where activation is dependent on a sufficiently slow dehydration rate. PMID- 19774393 TI - Pediatricians' working conditions in German hospitals: a real-time task analysis. AB - Surveys of pediatricians in Germany report low levels of job satisfaction. Preferably, such subjective reports should be corroborated by objective data regarding physicians' working conditions. However, such data in the field of pediatrics could not be found in the scientific literature. The aim of the present observational field study was to collect exact data about pediatricians' workflow in different pediatric hospital departments to evaluate and to optimize work routines. Data of 697 working hours were collected by using Tablet PCs during weekday shifts at three urban German hospitals. Twenty-five pediatricians were observed separately. A pediatrician's workday lasted on average 9 h and 18 min (SD = 0:53:44 h). The following amount of time was spent on various job tasks within this period: 29.80% (SD = 8.25 %) on meetings, 17.54% (SD = 6.51%) on documentation duties, 12.65% (SD = 3.73%) on indirect patient care, 9.22 % (SD = 5.74%) on hospital admissions and ward rounds and 4.03% (SD = 2.49%) on direct patient care. This is the first objective task analysis of physicians' workflow in pediatric hospital wards. Some of the physicians' self-reported problems were verified. Improvements in work organization and a new allocation of responsibilities among the medical staff may prove helpful in improving the quality of patient care by reducing the burden on pediatricians. PMID- 19774394 TI - Mycoplasma pneumoniae associated opsoclonus-myoclonus syndrome in three cases. AB - Opsoclonus-myoclonus syndrome (OMS) is a rare acquired movement disorder occurring in all age groups, predominantly in infants. Although the exact pathogenesis is still undefined, there is strong evidence for a paraneoplastic or parainfectious immune process resulting in central nervous system dysfunction. Mycoplasma pneumoniae has been implicated in a number of immune-mediated neurologic diseases [28]. However, the association of M. pneumoniae and opsoclonus-myoclonus-ataxia syndrome is not well established so far. We present three cases with opsoclonus-myoclonus-ataxia syndrome in adolescents following an infection with M. pneumoniae. Monophasic disease course and full recovery correspond to the favorable prognosis known from parainfectious cases in young adults. This should affect therapeutic consideration. OMS should be added to the spectrum of M. pneumoniae-associated neurologic complications. Nevertheless, neuroblastoma has to be ruled out in all cases of OMS. PMID- 19774395 TI - The clinical significance of ascitic fluid CEA in advanced gastric cancer with ascites. AB - BACKGROUND: This study was carried out to evaluate the clinical significance of ascitic fluid carcinoembryonic antigen (CEA) in advanced gastric cancer patients with ascites. PATIENTS AND METHODS: From November 2001 to February 2008, 119 gastric cancer patients with concurrent ascites who were clinically diagnosed with carcinomatosis, were retrospectively reviewed with regard to ascitic fluid cytology and clinicopathological parameters. Serum CEA (sCEA) and ascitic fluid CEA (aCEA) were measured using a chemiluminescent enzyme immunoassay. RESULTS: The patients' median age was 50 years (range 23-80 years). The median value of aCEA was significantly higher than sCEA [130.5 ng/ml (range 0.2-12.211 ng/ml) vs. 2.1 ng/ml (range 0.02-8.152 ng/ml), p < 0.001]. Sixty-five patients (54.6%) had positive ascitic fluid cytology. The median overall survival of all patients was 3.0 months (95% CI 2.0-4.0 months). The patients with low aCEA (<5 ng/ml) had a significantly longer overall survival compared to patients with high aCEA (>or=5 ng/ml) (7.4 months vs. 2.3 months, p = 0.003). However, we found no difference in overall survival according to ascitic fluid cytology (median, 3.0 months vs. 2.5 months, p = 0.530). Multivariate analysis also demonstrated that aCEA levels of more than 5 ng/ml were associated with poor prognosis (HR = 2.88; 95% CI 1.45 5.74; p = 0.003), while sCEA levels were not associated with poor prognosis (HR = 1.15; 95% CI 0.67-2.03; p = 0.622). CONCLUSION: These results suggest that aCEA levels can be used as a prognostic marker for advanced gastric cancer patients with ascites. PMID- 19774396 TI - Modified apical dissection of the prostate improves early continence in laparoscopic radical prostatectomy: technique and initial results. AB - OBJECTIVES: Incontinence after radical retropubic prostatectomy (RRP) is one of the greatest worries for all patients. One of the possible reasons for this urinary incontinence is a postoperative deficiency of the external striated urethral sphincter (EUS) complex and continence nerves. This study evaluated the application of a modified simple technique to dissection of the apical prostate in laparoscopic radical prostatectomy (LRP) and assessed the rate of urinary continence. METHODS: A total of 104 patients were randomly selected using envelopes and enrolled in this study. A standard LRP was performed in 52 patients (standard LRP group) and a modified technique for simple dissection of the apical prostate in LRP was performed in another 52 patients (modified LRP group). The urethra was dissected and transected at the apex of the prostate, proximal to the nerve-distributing rhabdosphincter using sharp scissors to avoid damage to the EUS complex and continence nerves. In all patients, a pad test was performed on 3, 30 and 90 days postoperatively and correlated with urinary continence. Continence was defined as zero pads or a liner used for security reasons only. RESULTS: After catheter removal, the continence rates were regained in 66, 85 and 96% of patients in the modified LRP group compared with 28, 55 and 91% of the patients in the standard LRP group at 3, 30 and 90 days, respectively. A statistically significant difference was present at 3 and 30 days (p < 0.01, respectively). At 90 days, the difference, although still present, was not statistically significant (p > 0.05). CONCLUSIONS: In this preliminary study, the technique of simplified apical dissection of the prostate in LRP appears to be an easy and feasible technique in early recovery of urinary continence. Further long term and larger sample studies are necessary to elucidate the modified technique in LRP on early restoration of urinary continence. PMID- 19774397 TI - Nature helps: from research to products against blood-sucking arthropods. AB - Today, there is a trend in research to return to plant extracts as remedies against endo- and ectoparasites. Many daily appearing papers describe the efficacy of different plant extracts. However, the second step, to develop a product for the market (that could settle obvious needs), is in general not done. Thus, many results will be forgotten soon and the work was done in vain. The present review shows in examples that very efficacious biocidal and repellent products were developed from extracts of the plants Vitex agnus castus, Azadirachta indica, and from others which produce etheric oils. Of course, it is needed that the extracts have to be tested seriously for their activity, non toxicity, tolerability, and user compliance. However, the selected examples show that it is worthwhile to consider plants in the fight against endo- and ectoparasites. PMID- 19774398 TI - The effect of temperature on the viability of Demodex folliculorum and Demodex brevis. AB - Demodex folliculorum and Demodex brevis are obligatory parasites of the pilosebaceous unit in humans and are cosmopolitan in terms of their distribution. This study was conducted to explore the effect of temperature on the viability of D. folliculorum and D. brevis. Both types of parasites were collected with the cellophane tape method, then randomly grouped and placed into separate moist cabinets. They were divided into 15 groups and exposed to experimental temperatures ranging from -15 degrees C to 60 degrees C. Curve diagrams and scatter plots on the relationship between temperature and the corresponding survival time were drawn and analyzed. It is demonstrated that temperature has a tremendous influence on the viability of D. folliculorum and D. brevis. Survival time and temperature are inversely correlated in the temperature range of 5-37 degrees C. Both D. folliculorum and D. brevis can survive better at low temperatures than at high temperatures. The most suitable maintenance temperature is 5 degrees C, and the optimal temperature for D. folliculorum and D. brevis to develop in vitro is 16-20 degrees C. Temperatures below 0 degrees C and above 37 degrees C are harmful to the mites. The lethal temperature is 54 degrees C, and the effective temperature that kills Demodex mites is 58 degrees C. PMID- 19774399 TI - Characterizing the transcriptional regulation of let-721, a Caenorhabditis elegans homolog of human electron flavoprotein dehydrogenase. AB - LET-721 is the Caenorhabditis elegans ortholog of electron-transferring flavoprotein dehydrogenase (ETFDH). We are studying this protein in C. elegans in order to establish a tractable model system for further exploration of ETFDH structure and function. ETFDH is an inner mitochondrial membrane localized enzyme that plays a key role in the beta-oxidation of fatty acids and catabolism of amino acids and choline. ETFDH accepts electrons from at least twelve mitochondrial matrix flavoprotein dehydrogenases via an intermediate dimer protein and transfers the electrons to ubiquinone. In humans, ETFDH mutations result in the autosomal recessive metabolic disorder, multiple acyl-CoA dehydrogenase deficiency. Mutants of let-721 in C. elegans are either maternal effect lethals or semi-sterile. let-721 is transcribed in the pharynx, body wall muscle, hypoderm, intestine and somatic gonad. In addition, the subcellular localization of LET-721 agrees with predictions that it is localized to mitochondria. We identified and confirmed three cis-regulatory sequences (pha site, rep-site, and act-site). Phylogenetic footprinting of each site indicates that they are conserved between four Caenorhabditis species. The pha-site mapped roughly 1,300 bp upstream of let-721's translational start site and is necessary for expression in pharyngeal tissues. The rep-site mapped roughly 830 bp upstream of the translational start site and represses expression of LET-721 within pharyngeal tissues. The act-site mapped roughly 800 bp upstream of the translational start site and is required for expression within spermatheca, body wall muscle, pharynx, and intestine. Taken together, we find that LET-721 is a mitochondrially expressed protein that is under complex transcriptional controls. PMID- 19774400 TI - Physical properties of DNA components affecting the transposition efficiency of the mariner Mos1 element. AB - Previous studies have shown that the transposase and the inverted terminal repeat (ITR) of the Mos1 mariner elements are suboptimal for transposition; and that hyperactive transposases and transposon with more efficient ITR configurations can be obtained by rational molecular engineering. In an attempt to determine the extent to which this element is suboptimal for transposition, we investigate here the impact of the three main DNA components on its transposition efficiency in bacteria and in vitro. We found that combinations of natural and synthetic ITRs obtained by systematic evolution of ligands by exponential enrichment did increase the transposition rate. We observed that when untranslated terminal regions were associated with their respective natural ITRs, they acted as transposition enhancers, probably via the early transposition steps. Finally, we demonstrated that the integrity of the Mos1 inner region was essential for transposition. These findings allowed us to propose prototypes of optimized Mos1 vectors, and to define the best sequence features of their associated marker cassettes. These vector prototypes were assayed in HeLa cells, in which Mos1 vectors had so far been found to be inactive. The results obtained revealed that using these prototypes does not circumvent this problem. However, such vectors can be expected to provide new tools for the use in genome engineering in systems such as Caenorhabditis elegans in which Mos1 is very active. PMID- 19774403 TI - Nitroborazines as potential high energy materials: density functional theoretical calculations. AB - As part of a search for new high energy density materials, we used density functional theoretical calculations to determine the thermochemical properties of various nitro-substituted borazine molecules. Optimized geometries, vibrational frequencies and spectra, and enthalpies of formation and combustion were determined for nitroborazine, dinitroborazine, trinitroborazine, and methyltrinitroborazine with substituents on either the boron atoms or the nitrogen atoms of the parent borazine ring. Our results indicate that the specific enthalpy of combustion ranged from 4 to 11 kJ g(-1), with increasing substitution of nitro groups lowering the energy of combustion per unit mass. PMID- 19774402 TI - Bone resorption and complications in alveolar distraction osteogenesis. AB - Distraction osteogenesis presents an alternative procedure for augmentation of atrophic alveolar bone prior to inserting dental implants. The aim of this retrospective study was to evaluate complications of this method with specific focus on bone resorption during the consolidation period and the follow-up period after dental implant insertion into distracted bone. Thirty partially edentulous patients underwent a total of 36 vertical alveolar distractions with an extraosseous distraction system. Eleven devices were placed in the maxilla and 25 in the mandible. Eighty-two dental implants were inserted after a mean consolidation period of 4.5 months. Treatment results were evaluated by means of panoramic radiographs for distraction follow-up and periapical radiographs for implant follow-up. The mean length of the transport segment was 19 mm. The average alveolar height achieved was 6.4 mm with a mean resorption of 1.8 mm (21.1%) at the time of dental implant insertion. Main problems comprised oral displacement of the transport segment (n = 15) and inadequate soft tissue extension (n = 13). Eighty-two dental implants were inserted with an overall survival rate of 95.1% after 45.8 months. For periimplant marginal bone, an average resorption of 3.5 mm was recorded 50.4 months after implant insertion. Although alveolar distraction osteogenesis seems to be an effective tool to treat vertical defects of the alveolar ridge, it is not an uncomplicated procedure. A combination with vestibular augmentation of autogenous bone grafts should be considered. Overcorrection of 20% may compensate bone relapse during the consolidation period of the distracted alveolar bone. Further bone resorption after dental implantation is common. PMID- 19774401 TI - Response of gram-positive bacteria to copper stress. AB - The Gram-positive bacteria Enterococcus hirae, Lactococcus lactis, and Bacillus subtilis have received wide attention in the study of copper homeostasis. Consequently, copper extrusion by ATPases, gene regulation by copper, and intracellular copper chaperoning are understood in some detail. This has provided profound insight into basic principles of how organisms handle copper. It also emerged that many bacterial species may not require copper for life, making copper homeostatic systems pure defense mechanisms. Structural work on copper homeostatic proteins has given insight into copper coordination and bonding and has started to give molecular insight into copper handling in biological systems. Finally, recent biochemical work has shed new light on the mechanism of copper toxicity, which may not primarily be mediated by reactive oxygen radicals. PMID- 19774404 TI - Expenditures of the German statutory health insurance system for patients suffering from acute coronary syndrome and treated with percutaneous coronary intervention. AB - Patients with acute coronary syndrome (ACS) are in need of cost-intensive treatment involving different aspects of the German Health System. Percutaneous coronary intervention (PCI) is the treatment of choice for a large proportion of cases. In the present study, an analysis of the cost impact of ACS with focus on PCI therapy was conducted across-the-board for the German Health System. Results indicated that 85% of all costs arising from treatment of ACS with a trial of PCI are due to in-patient care. Projection of results onto the entire insurant collective of the statutory health system estimated a total of Euro 954,995,603-a proportional 0.7% of all expenditure by statutory health insurance in 2005. PMID- 19774405 TI - A digital receiver with fast frequency- and gain-switching capabilities for MRI systems. AB - OBJECT: In this article, two issues pertaining to MRI digital receivers are addressed. One is the maintenance of phase coherence between the transmitter and the receiver-an effective solution is proposed, in which the receiver frequency is switched synchronously with the transmitter frequency. The other is the dynamic range of the receiver-gain-switching technique is utilized to improve the dynamic range. To meet the hardware requirements of these solutions, a digital receiver with fast frequency- and gain-switching capabilities was implemented. MATERIALS AND METHODS: The primary components of the proposed digital receiver are a variable gain amplifier, a high-speed analog-to-digital converter and a single-chip digital receiver core. The radio-frequency magnetic resonance signal is directly sampled by the analog-to-digital converter and processed in the digital receiver core. By pre-storing the receiver waveform in the on-board SDRAM, the frequency and gain of the receiver may be switched very quickly. RESULTS: The performance of the proposed digital receiver is verified by embedding it in an imaging spectrometer. It is then demonstrated by conducting experiments on a home-built 0.3-T magnetic resonance imaging system. CONCLUSION: The results show that the phase coherence between the transmitter and the receiver and the dynamic range of the receiver are greatly improved. Consequently, the proposed digital receiver may be useful for obtaining multiple slice two-dimensional magnetic resonance images with very high resolution. PMID- 19774406 TI - Circadian preference in bipolar disorder. AB - PURPOSE: A role for circadian rhythm abnormalities in the pathogenesis of bipolar disorder (BD) has been suggested. The present study assessed circadian preference, a subjective preference for activities in the morning or evening related to chronotype. METHODS: The sample was comprised of 81 outpatients with BD in remission and 79 control subjects. Circadian preference was derived from an interview evaluating biological rhythms and sleep pattern from the Pittsburgh Sleep Quality Index. RESULTS: Patients were significantly more likely to have an evening preference than control subjects. Circadian preference was also associated with sleep latency. CONCLUSIONS: The association of evening preference and longer sleep latency may be related to the frequent clinical observation of a sleep/wake cycle reversal in bipolar disorder. PMID- 19774407 TI - Bioremediation of acidic oily sludge-contaminated soil by the novel yeast strain Candida digboiensis TERI ASN6. AB - BACKGROUND, AIM, AND SCOPE: Primitive wax refining techniques had resulted in almost 50,000 tonnes of acidic oily sludge (pH 1-3) being accumulated inside the Digboi refinery premises in Assam state, northeast India. A novel yeast species Candida digboiensis TERI ASN6 was obtained that could degrade the acidic petroleum hydrocarbons at pH 3 under laboratory conditions. The aim of this study was to evaluate the degradation potential of this strain under laboratory and field conditions. MATERIALS AND METHODS: The ability of TERI ASN6 to degrade the hydrocarbons found in the acidic oily sludge was established by gravimetry and gas chromatography-mass spectroscopy. Following this, a feasibility study was done, on site, to study various treatments for the remediation of the acidic sludge. Among the treatments, the application of C. digboiensis TERI ASN6 with nutrients showed the highest degradation of the acidic oily sludge. This treatment was then selected for the full-scale bioremediation study conducted on site, inside the refinery premises. RESULTS: The novel yeast strain TERI ASN6 could degrade 40 mg of eicosane in 50 ml of minimal salts medium in 10 days and 72% of heneicosane in 192 h at pH 3. The degradation of alkanes yielded monocarboxylic acid intermediates while the polycyclic aromatic hydrocarbon pyrene found in the acidic oily sludge yielded the oxygenated intermediate pyrenol. In the feasibility study, the application of TERI ASN6 with nutrients showed a reduction of solvent extractable total petroleum hydrocarbon (TPH) from 160 to 28.81 g kg(-1) soil as compared to a TPH reduction from 183.85 to 151.10 g kg(-1) soil in the untreated control in 135 days. The full-scale bioremediation study in a 3,280-m(2) area in the refinery showed a reduction of TPH from 184.06 to 7.96 g kg(-1) soil in 175 days. DISCUSSION: Degradation of petroleum hydrocarbons by microbes is a well-known phenomenon, but most microbes are unable to withstand the low pH conditions found in Digboi refinery. The strain C. digboiensis could efficiently degrade the acidic oily sludge on site because of its robust nature, probably acquired by prolonged exposure to the contaminants. CONCLUSIONS: This study establishes the potential of novel yeast strain to bioremediate hydrocarbons at low pH under field conditions. RECOMMENDATIONS AND PERSPECTIVES: Acidic oily sludge is a potential environmental hazard. The components of the oily sludge are toxic and carcinogenic, and the acidity of the sludge further increases this problem. These results establish that the novel yeast strain C. digboiensis was able to degrade hydrocarbons at low pH and can therefore be used for bioremediating soils that have been contaminated by acidic hydrocarbon wastes generated by other methods as well. PMID- 19774408 TI - Anti-IL-1 treatment for secondary amyloidosis in an adolescent with FMF and Behcet's disease. AB - Familial Mediterranean fever (FMF) is associated with mutations in the gene coding for pyrin which lead to accentuated innate immune responses resulting in increased production of IL-1. We present a teenager who had severe FMF and Behcet's disease and developed moderate proteinuria. Renal biopsy showed secondary amyloidosis. Anakinra was started at 1 mg/kg/day subcutaneously along with colchicine treatment. The clinical response was excellent. Acute phase reactants decreased. The level of proteinuria and renal functions remained stable and the hypoalbuminemia returned to normal. Her clinical and laboratory symptoms returned when anakinra had to be stopped at 6 months. Thus, the drug was restarted and she is now clinically in excellent condition a year after the start of therapy. She has normal renal functions, normal serum proteins, and normal acute-phase reactants. However, recently, after 18 months of anakinra treatment, her proteinuria gradually increased and albumin levels decreased. We suggest that anti-IL-1 treatment is beneficial for the suppression of inflammation; however, long-term studies are needed to understand whether progressive renal disease will be prevented. PMID- 19774409 TI - Effectiveness of a 5-day external stenting protocol on urological complications after renal transplantation. AB - BACKGROUND: Ureteral stents are successful in reducing urological complications after renal transplantation. However, the optimal duration and method of stenting have not yet been clarified. The objective of the present study was to investigate the frequency of urological complications when a 5-day external stented ureterocystostomy protocol was followed. METHODS: A single-center nonrandomized analysis of 392 kidney transplantations between June 2003 and June 2007 was conducted. From July 2005 all 196 renal transplant recipients received a 5-day external stented ureterocystostomy. A urological complication was defined as any cause leading to the placement of a percutaneous nephrostomy catheter and/or surgical revision of the ureterocystostomy. RESULTS: In the non-stented group, 21 of the 196 patients (10.7%) developed a urological complication compared to 13 patients (6.6%) in the stented group (p = 0.151). In the stented group, 2 of the 66 recipients of a living donor transplant (3.0%) developed a urological complication compared to 8 of the 59 recipients (13.6%) in the non stented group (P = 0.030). Eleven of 130 recipients of a deceased donor transplant (8.5%) in the stented group developed a urological complication, compared to 13 of the 137 recipients (9.5%) in the non-stented group (P = 0.769). The surgical revision rate of the stented and the non-stented group was 5/13 39% and 6/21 29%, respectively. CONCLUSIONS: A 5-day routine external stent protocol is efficacious in living donor renal transplantation in preventing early postoperative ureter obstruction, but this stenting period seems inadequate for deceased donor renal transplantation. PMID- 19774410 TI - How do we predict the clinically relevant pancreatic fistula after pancreaticoduodenectomy?--an analysis in 244 consecutive patients. AB - BACKGROUND: The most important problem in pancreatic fistula is whether one can distinguish clinical pancreatic fistula, grade B + C fistula by the International Study Group on Pancreatic Fistula (ISGPF), from transient pancreatic fistula (grade A), in the early period after pancreaticoduodenectomy (PD). It remains unclear what predictive risk factors can precisely predict which clinical relevant or transient pancreatic fistula when diagnosed pancreatic fistula on POD3 by ISGPF criteria. METHODS: We analyzed the predictive factors of clinical pancreatic fistula by logistic regression analysis in 244 consecutive patients who underwent PD. Pancreatic fistula was classified into three categories by ISGPF. RESULTS: The rate of pancreatic fistula was 69 of 244 consecutive patients (28%) who underwent PD. Of these, 47 (19%) had grade A by ISGPF criteria, 17 patients (7.0%) had grade B, and five patients (2.0%) had grade C. The independent risk factor of incidence of pancreatic fistula is soft pancreatic parenchyma. However, soft pancreatic parenchyma did not predict underlying clinically relevant pancreatic fistula. The independent predictive factors of clinically relevant pancreatic fistula were serum albumin level 9,800 mm(-3) on POD 4. Positive predictive value of the combination of two predictive factors for clinical relevant pancreatic fistula was 88%. CONCLUSIONS: The combination of two factors on POD4, serum albumin level 9,800 mm(-3), is predictive of clinical relevant pancreatic fistula when diagnosed pancreatic fistula on POD 3 by ISGPF criteria. PMID- 19774411 TI - One-stage percutaneous treatment in a patient with pelvic and vertebral compression fractures. AB - An active 38-year-old patient presenting a vertebral compression fracture associated with a pelvic fracture was treated in one stage with CT-guided fixation of the sacrum and kyphoplasty. This treatment decreased the pain, restored the vertebral height, and enabled the patient to be ambulatory. The main advantage of this double approach was to shorten the hospital stay and the nonworking period. PMID- 19774412 TI - A model of incomplete adaptation to a severely shifted frequency-to-electrode mapping by cochlear implant users. AB - In the present study, a computational model of phoneme identification was applied to data from a previous study, wherein cochlear implant (CI) users' adaption to a severely shifted frequency allocation map was assessed regularly over 3 months of continual use. This map provided more input filters below 1 kHz, but at the expense of introducing a downwards frequency shift of up to one octave in relation to the CI subjects' clinical maps. At the end of the 3-month study period, it was unclear whether subjects' asymptotic speech recognition performance represented a complete or partial adaptation. To clarify the matter, the computational model was applied to the CI subjects' vowel identification data in order to estimate the degree of adaptation, and to predict performance levels with complete adaptation to the frequency shift. Two model parameters were used to quantify this adaptation; one representing the listener's ability to shift their internal representation of how vowels should sound, and the other representing the listener's uncertainty in consistently recalling these representations. Two of the three CI users could shift their internal representations towards the new stimulation pattern within 1 week, whereas one could not do so completely even after 3 months. Subjects' uncertainty for recalling these representations increased substantially with the frequency shifted map. Although this uncertainty decreased after 3 months, it remained much larger than subjects' uncertainty with their clinically assigned maps. This result suggests that subjects could not completely remap their phoneme labels, stored in long-term memory, towards the frequency-shifted vowels. The model also predicted that even with complete adaptation, the frequency-shifted map would not have resulted in improved speech understanding. Hence, the model presented here can be used to assess adaptation, and the anticipated gains in speech perception expected from changing a given CI device parameter. PMID- 19774413 TI - The effects of insect extracts and some insect-derived compounds on the settling behavior of Liposcelis bostrychophila. AB - Extracts of whole booklice (Liposcelis bostrychophila)-sequentially extracted in hexane and aqueous 80% methanol (80%MeOH)-repel conspecifics. A methanol-soluble fraction (MFr) of the 80% methanol extract was more repellent than either its corresponding water fraction (WFr) or the hexane extract. The repellent effect of the MFr was repeatable across extracts prepared on different occasions over a 1 month period. Gas chromatography, mass-spectrometry (GC-MS) analyses showed that saturated (C(16); C(18)) monoenoic (C(16:1); C(18:1)) and a dienoic fatty acid (C(18:2)) and the corresponding methyl esters of all but C(16:1) and C(18) constituted approximately 95% and 30%, of the detected compounds in the methanol fractions and the hexane extract, respectively. Qualitative thin layer chromatography showed that cholesterol was present in methanol fractions and the hexane extract, and also enabled tentative identification of triacylglycerols and phospholipids in the methanol fractions. Extracts of wheatgerm, dried skimmed milk powder, active yeast, and wholemeal flour-L. bostrychophila dietary components-were analyzed by GC-MS, and C(16), C(18:1) and C(18:2) were detected, indicating that C(18) and the methyl esters were not directly extractable and/or that they were products of booklice metabolism. A fatty acid amide (stearamide) previously identified in cuticular extracts of L. bostrychophila was not detected, and therefore was not responsible for the observed biological activity. Pure fatty acids and fatty acid methyl esters repelled settling of L. bostrychophila at 10 mM, with the exception of palmitic and stearic acids, indicating, among other things, a difference between the efficacy of saturated and unsaturated fatty acids. The effect of concentrations <10 mM was less significant, although palmiteoleic acid appeared to be attractive to L. bostrychophila at 0.1 mM. Fatty acids and fatty acid methyl esters were at a much lower concentration than 10 mM in the repellent methanol fractions, indicating that an interaction between known and as yet unidentified compounds is likely. The significance of fatty acids in relation to the biology and behavior of L. bostrychophila and their potential for use in traps and monitoring are discussed. PMID- 19774414 TI - Effect of light conditions on the resistance of current-year Fagus Crenata seedlings against fungal pathogens causing damping-off in a natural beech forest: fungus isolation and histological and chemical resistance. AB - Forest gap dynamics affects light intensity on the forest floor, which in turn may influence defense and survival of tree seedlings. Current-year Fagus crenata seedlings show high mortality under the canopy caused by damping-off. In contrast, they survive pathogen attacks in gaps. However, defense mechanisms against damping-off have not been fully understood. In order to determine the resistance factors that affect mortality in current-year seedlings, we compared seedling survival and chemical and histological characteristics of the hypocotyls of seedlings from closed-stand and forest-edge plots. Damping-off occurred in the current-year seedlings mainly from the end of June to July; survival rate of the seedlings was higher in the forest-edge plot than in the closed-stand plot. By performing an inoculation test on the seedling hypocotyls, we identified Colletotrichum dematium and Cylindrocarpon sp. as the causative pathogens under low illumination only. In the beginning of July, only seedling hypocotyls from the forest-edge plot exhibited periderm formation. From mid-June to July, seedling hypocotyls from the forest-edge plot accumulated approximately twice the amount of total phenols as those accumulated by seedling hypocotyls from the closed-stand plot. The ethyl acetate phase of methanol extracts of hypocotyls showed antifungal activity. We conclude that seedlings from the forest-edge plot may resist pathogenic attack via periderm formation and increased phenol synthesis. Plant defense mechanisms that are controlled by light intensity may be important for promoting seedling regeneration in forest gap dynamics. PMID- 19774415 TI - Feasibility of a lateral region sentinel node biopsy of lower rectal cancer guided by indocyanine green using a near-infrared camera system. AB - BACKGROUND: A lateral pelvic lymph node dissection (LPLD) for lower rectal cancer may be beneficial for a limited number of patients. If sentinel node (SN) navigation surgery could be applied to lower rectal cancer, then unnecessary LPLDs could be avoided. The aim of this study was to investigate the feasibility of lateral region SN biopsy by means of indocyanine green (ICG) visualized with a near-infrared camera system (Photodynamic Eye, PDE). METHODS: This study investigated the existence of a lateral region SN in 25 patients with lower rectal cancer. ICG was injected around the tumor, and the lateral pelvic region was observed with PDE. RESULTS: With PDE, the lymph nodes and lymph vessels that received ICG appeared as shining fluorescent spots and streams in the fluorescence image. This allowed the detection of not only tumor-negative SNs but also tumor-positive SNs as shining spots. The lateral SNs were detected in 6 of 6 T1 and T2 diseases and 17 of 19 T3 diseases. The lateral SNs were successfully identified in 23 (92%) of the 25 patients. The mean number of lateral SNs per patients was 2.1. Of the 23 patients, 6 patients underwent LPLD. Of the 3 patients who had a tumor-negative SN, all dissected lateral non-SNs were negative in all 3 cases. CONCLUSIONS: We could detect the lateral SNs, not only in T1 and T2 disease, but also in T3 disease. Although this is only a preliminary study, the detection of lateral SNs in lower rectal cancer by means of the ICG fluorescence imaging system is considered to be a promising technique that may be used for determining the indications for performing LPLD. PMID- 19774417 TI - Practice patterns and outcomes for anorectal melanoma in the USA, reviewing three decades of treatment: is more extensive surgical resection beneficial in all patients? AB - INTRODUCTION: Historically, the treatment of anorectal melanoma has been abdominoperineal resection (APR), but more recently local resection alone. Although treatment at melanoma centers has become less aggressive, the adoption of this approach and related outcomes across the USA is unknown. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was queried to identify patients treated for anorectal melanoma (1973-2003). Treatment patterns and survival were studied. Frequency of treatment was compared using the chi square test; survival was calculated using the Kaplan-Meier method. RESULTS: The 183 patients identified from the SEER database had a median age of 68 years. Of the 143 patients whose data were included, 51 underwent APR and 92 underwent transanal excision (TAE). Despite similar pathologic characteristics, median survival was similar in the two groups: 16 months for APR and 18 months for TAE (P = ns). Five-year survival also was similar in the two groups: 16.8% for APR and 19.3% for TAE (P = ns). The rate of APR was 27.0% between 1973 and 1996, as compared with 43.2% between 1997 and 2003 (P = ns). CONCLUSION: This study, the largest series to analyze widespread practice patterns and outcomes for anorectal melanoma in the USA, did not reveal a survival difference comparing TAE with APR. Moreover, the study did not reveal a trend toward less aggressive surgical resection. Since the extent of surgical intervention did not correlate with survival or extent of primary tumor, APR should be reserved for selected patients in whom TAE is not technically feasible. PMID- 19774416 TI - High expression of atypical protein kinase C lambda/iota in gastric cancer as a prognostic factor for recurrence. AB - BACKGROUND: The atypical protein kinase C lambda/iota (aPKClambda/iota) is involved in several signal transduction pathways that influence cell growth, apoptosis, and the establishment and maintenance of epithelial cell polarity. Overexpression of aPKClambda/iota has been reported in several cancers and been shown to be associated with oncogenesis. However, the expression and role of aPKClambda/iota in gastric cancer, one of the commonest cancers in Asia, have not so far been investigated. This study aimed to clarify the relationship between aPKClambda/iota expression and the clinicopathological features of gastric cancer. PATIENTS AND METHODS: Gastric adenocarcinoma samples were obtained from 177 patients who underwent gastrectomy at the Yokohama City University Hospital between 1999 and 2004. Expression of aPKClambda/iota and E: -cadherin was examined immunohistochemically and compared with clinicopathological features of the tumors. Univariate and multivariate analyses were performed for both disease specific and relapse-free survival. RESULTS: Overexpression of aPKClambda/iota protein was detected in 126 of the 177 (71.2%) gastric cancers. Immunohistological staining for aPKClambda/iota was stronger in gastric adenocarcinoma of intestinal type than diffuse type (p = 0.036), but was not correlated with E: -cadherin expression. A multivariate analysis suggested that nodal metastasis and aPKClambda/iota overexpression were prognostic factors for disease recurrence. CONCLUSIONS: Our results suggested that aPKClambda/iota overexpression was a strong prognostic factor for gastric adenocarcinoma recurrence. As well as being a new prognostic indicator, aPKClambda/iota is also likely to be a novel therapeutic target for gastric cancer. PMID- 19774419 TI - Detection of Pulmonary Embolism in the Postoperative Orthopedic Patient Using Spiral CT Scans. AB - Orthopedic surgery is associated with a significant risk of postoperative pulmonary embolism (PE) and/or deep vein thrombosis (DVT). This study was performed to compare the clinical presentations of a suspected versus a documented PE/DVT and to determine the actual incidence of PE/DVT in the post operative orthopedic patient in whom CT was ordered. All 695 patients at our institution who had a postoperative spiral CT to rule out PE/DVT from March 2004 to February 2006 were evaluated and information regarding their surgical procedure, risk factors, presenting symptoms, location of PE/DVT, and anticoagulation were assessed. Statistical analysis was performed using an independent samples t test with a two-tailed p value to examine significant associations between the patient variables and CT scans positive for PE. Logistic regression models were used to determine which variables appeared to be significant predictors of a positive chest CT. Of 32,854 patients admitted for same day surgery across all services, 695 (2.1%) had a postoperative spiral CT based on specific clinical guidelines. The incidence of a positive scan was 27.8% (193/695). Of these, 155 (22.3%) scans were positive for PE only, 24 (3.5%) for PE and DVT, and 14 (2.0%) for DVT only. The most common presenting symptoms were tachycardia (56%, 393/695), low oxygen saturation (48%, 336/695), and shortness of breath (19.6%, 136/695). Symptoms significantly associated with DVT were syncope and chest pain. A past medical history of PE/DVT was the only significant predictor of a positive scan. Patients who have a history of thromboembolic disease should be carefully monitored in the postoperative setting. PMID- 19774418 TI - Initial presentation and management of hilar and peripheral cholangiocarcinoma: is a node-positive status or potential margin-positive result a contraindication to resection? AB - BACKGROUND: Cholangiocarcinoma (CC) frequently presents at an advanced stage and the majority of patients are unresectable at diagnosis. We sought to examine our recent experience with surgical resection for hilar and peripheral CC. METHODS: A review of all CC patients who presented to our multidisciplinary liver cancer center for evaluation of their CC between January 2000 and August 2008 was performed. Demographics, therapeutic management, pathologic characteristics, and overall survival were analyzed. RESULTS: A total of 280 patients were evaluated over the 8-year period, and 222 patients (79%) were unresectable at presentation. Fifty-eight out of 280 patients were candidates for resection, of whom, 51 patients underwent resection. Hilar CC was identified in 27 patients (53%) and peripheral CC was present in 24 patients (47%). Morbidity and 90-day mortality were 61 and 9.8%, respectively. Overall, negative margin (R0) resection was achieved in 26 patients (51%). Using multivariate Cox regression analysis, only margin status was found to be a significant predictor of survival (p = 0.009). Compared with peripheral CC, hilar CC was associated with shorter overall survival (p = 0.001) and higher rates of positive margins (p = 0.001) and perineural invasion (p = 0.02), and no difference in angiolymphatic, portal vein, and lymph node involvement. CONCLUSIONS: Survival benefits can be achieved with resection for cholangiocarcinoma. Given the lack of effective alternative therapy, when confronted with the potential risk of positive margins or isolated nodal disease, we continue to advocate aggressive surgical resection for both hilar and peripheral CC with the ultimate goal of negative margin resection. PMID- 19774420 TI - Scratch Collapse Test Localizes Osborne's Band as the Point of Maximal Nerve Compression in Cubital Tunnel Syndrome. AB - The objective of this study is to demonstrate the utility of the scratch collapse test (SCT) in localizing the point of maximal compression in cubital tunnel syndrome. From January 1, 2004 to December 1, 2005, 64 adult patients with cubital tunnel syndrome were evaluated by a single surgeon. Cubital tunnel syndrome was diagnosed based upon symptoms of numbness, tingling, and/or pain in the ulnar nerve distribution or by the presence of weakness or wasting of the ulnar-innervated intrinsic hand muscles. All diagnoses were confirmed with electrodiagnostic studies. As part of the physical examination, the SCT was performed along three subdivided segments in the region of the cubital tunnel. Results of the SCT were recorded and correlated with intraoperative findings. Of the 64 patients evaluated, 44 had a positive SCT that was either more profound or solely present a few centimeters distal to the medial epicondyle in the region of Osborne's band. All of these patients subsequently underwent anterior submuscular transposition and were found to have a tight compression point at Osborne's band corresponding to their preoperative SCT. This study suggests that the scratch collapse test may be a reliable physical examination technique for localizing the point of maximal nerve compression in patients with cubital tunnel syndrome. That point, in this series, corresponded with Osborne's band. PMID- 19774421 TI - Palmar xanthoma-an indicator of a more sinister problem. AB - Multiple palmar xanthomas may often be seen first by the hand surgeon. One such case presented to us in the hand clinic. Further investigations revealed the presence of a more sinister metabolic problem of type III hyperlipoproteinemia. We discuss the details of this case and review relevant literature on the subject. PMID- 19774422 TI - Basic science right, not basic science lite: medical education at a crossroad. AB - This perspective is a counterpoint to Dr. Brass' article, Basic biomedical sciences and the future of medical education: implications for internal medicine. The authors review development of the US medical education system as an introduction to a discussion of Dr. Brass' perspectives. The authors agree that sound scientific foundations and skill in critical thinking are important and that effective educational strategies to improve foundational science education should be implemented. Unfortunately, many students do not perceive the relevance of basic science education to clinical practice.The authors cite areas of disagreement. They believe it is unlikely that the importance of basic sciences will be diminished by contemporary directions in medical education and planned modifications of USMLE. Graduates' diminished interest in internal medicine is unlikely from changes in basic science education.Thoughtful changes in education provide the opportunity to improve understanding of fundamental sciences, the process of scientific inquiry, and translation of that knowledge to clinical practice. PMID- 19774423 TI - Improving fecal occult blood testing compliance using a mailed educational reminder. AB - BACKGROUND: Colorectal cancer (CRC) is one of the leading causes of cancer related deaths in the United States. Randomized controlled trials have shown that annual screening fecal occult blood testing (FOBT) reduces CRC mortality and incidence. However, patient compliance with FOBT is low. OBJECTIVE: To determine whether a mailed educational reminder increases FOBT card return rates and to examine predictors of FOBT compliance. DESIGN: Blinded, randomized, controlled trial at the Veteran Affairs Medical Center, San Diego, California. PATIENTS: Seven hundred and seventy-five consecutive patients > or =50 years of age referred by their primary care physicians for FOBT. INTERVENTION: Patients were randomly assigned to the usual care group or the intervention group. Ten days after picking up the FOBT cards, a 1-page reminder with information related to CRC screening was mailed to the intervention group only. MEASUREMENTS: The primary outcome was proportion of returned FOBT cards after 6 months. Patient demographic, clinical characteristics and prior FOBT completed were collected for multivariate regression analysis. RESULTS: At 6 months after card distribution, 64.6% of patients in the intervention group returned cards compared with 48.4% in the control group (P < 0.001). Patients who received a mailed reminder (OR 2.02; 95% CI: 1.48-2.74) or have a prior history of returning the FOBT cards (OR 1.87; 95% CI: 1.29-2.70) were more likely to return the FOBT cards. Patients with current or recent illicit drug use were less likely to return the FOBT cards (OR 0.26; 95% CI: 0.13-0.50). CONCLUSION: A simple mailed educational reminder significantly increases compliance with FOBT for CRC screening. PMID- 19774424 TI - A matched case-control study of preoperative biliary drainage in patients with pancreatic adenocarcinoma: routine drainage is not justified. AB - BACKGROUND: Preoperative biliary drainage (PBD) prior to pancreaticoduodenectomy (PD) continues to be routine in many centers despite retrospective and randomized data showing that PBD increases perioperative infectious complications. METHODS: Review of a prospectively maintained database identified 340 consecutive patients with pancreatic adenocarcinoma who underwent PD between 2000 and 2005. From this cohort, 94 PBD and 94 nonstented (no-PBD) patients were matched for age, gender, preoperative albumin, and bilirubin levels (PBD group: prestent bilirubin; no-PBD group: preoperative bilirubin). RESULTS: The majority of PBD patients (89%) underwent internal endoscopic biliary drainage. Stent-related complications occurred in 46 patients (23%) and resulted in a significant delay in time to resection. In the matched-pair comparison, there was more operative blood loss in PBD patients, but similar operative times, transfusions, and hospital stay. Bile cultures were positive in 82% of PBD patients versus 7% no PBD. There was a statistically significant increase in infectious complications including wound infections and intra-abdominal abscess in PBD patients, but equal incidence of anastomotic leak. CONCLUSIONS: In this case-matched control study, PBD was associated with a stent-related complication rate of 23% and resulted in a twofold increase in postpancreatectomy infectious complications. The routine use of PBD remains unjustified. PMID- 19774425 TI - Murine functional liver mass is reduced following partial small bowel resection. AB - INTRODUCTION: Liver mass is regulated in precise proportion to body mass in health and is restored by regeneration following acute injury. Despite extensive experimental analyses, the mechanisms involved in this regulation have not been fully elucidated. Previous investigations suggest that signals from the bowel may play an important role. The purpose of the studies reported here was to determine the effect of proximal partial small bowel resection on liver mass in a murine model. METHODS: Mice were subjected to a 50% proximal small bowel resection or sham surgery followed by primary anastomosis, then sacrificed at serial times for determination of liver:body mass ratio and analyses of liver tissue. RESULTS: Liver:body weight ratio was significantly decreased 72 h after small bowel resection, and this decrease correlated with reduced functional liver mass as assessed by determination of total hepatic tissue protein and alanine transaminase (ALT) activity. Liver from bowel-resected animals demonstrated increased expression of LC3-II, a marker of autophagy, and also of pro-apoptotic Bax compared to anti-apoptotic Bcl-2. CONCLUSION: These data support a role for signals from the intestine in liver mass regulation, and they have potential implications regarding the pathogenesis of liver injury following small bowel resection. PMID- 19774426 TI - Evolution of surgical treatment of amebiasis-associated colon perforation. AB - BACKGROUND: Amebiasis is a worldwide health problem that mainly affects developing countries. Invasive amebiasis tends to develop complications, and among these, perforation of the colon, although infrequent (1.9-9.1%), is the most lethal. Surgical treatment in these cases should be carried out in a timely fashion prior to the presentation of systemic repercussions or death. In the present study, we analyzed a total of 122 cases of invasive amebiasis-associated colon perforation. METHODS AND STUDY DESIGN: We conducted a clinical, retrospective, and observational study and presented cases of colonic perforation observed over the past 30 years at the Medical-Surgical Emergency Service of the Mexico City-based Hospital General de Mexico OD during the 1970-1999 period. RESULTS: During this time, a total of 19,916 emergency abdominal surgeries were performed. One hundred twenty-two of these procedures corresponded to cases of colon perforation by ameba, which represents 0.6%; 80 patients were men (65.6%) and 42 were women (34.4%), with an average age of 48 years. Multiple colon perforation was 74%, with right colon the most affected (90.5%). Depending on the perforation's extension and localization, right hemicolectomy with ileostomy were performed in 53 patients (43.45%), subtotal colectomy with ileostomy in 43 (35.25%), left hemicolectomy with transverse colostomy in 12 (9.83%), exteriorization of perforated left colon (stoma) in 13 (10.65%), and primary closure with exteriorization in one patient (0.8%). Post-operative complications were present in 48 patients (39.3%), and 20 cases were related with the creation of a stoma. Eighteen of these cases were due to persistent abdominal sepsis and ten due to toxic colon; the latter correspond solely to patients with initial nonresective treatment. General mortality was 40%, with 32% (17 of 53 cases) of mortality in those submitted to right hemicolestomy, 16.7% (two of 12) of left hemicolestomy, 44.2% (19 of 43) in those in whom a subtotal colectomy was performed, with 76.9% (ten of 13) patients with exteriorization of the perforated right colon, and with 100% (one of one patient) mortality with primary closure. CONCLUSIONS: Perforation is the most frequent surgical complication of invasive amebiasis of the colon, occurring principally in masculine gender and in the fourth decade of life. Resection and stoma creation is the procedure of choice that can resolve the septic focus from the first surgical procedure, depending on the general status of the patient. However, morbidity and mortality are high, and there is a tendency for these to be lower on comparing initial cases with those with recently conducted surgical procedures. PMID- 19774427 TI - Esophagectomy without mortality: what can surgeons do? AB - INTRODUCTION: Surgical resection remains the mainstay treatment for patients with localized esophageal cancer. It is, however, a complex procedure. Mortality rate used to be high, but in recent years, death rate has been reduced to below 5% in specialized centers. METHODS: Outcome of esophagectomy can be improved by paying attention to (1) appropriate patient section, (2) choice of surgical techniques and their execution, and (3) optimizing perioperative care. A volume-outcome relationship is also evident. Surgeons can perform esophagectomy without mortality, but a multi-disciplinary team management is essential to achieve this goal. PMID- 19774428 TI - Bile in the esophagus-model for a bile acid biosensor. AB - Acid and bile acids form important constituents of the refluxed substances in patients who suffer from gastroesophageal reflux disease. Whilst 24h ambulatory pH monitoring using antimony or glass pH electrodes measures acid levels 5 cm above the gastroesophageal junction, there are no reliable methods of measuring other constituents of duodenal juices such as bile acids. Past studies in detection of bile acids have included esophageal aspiration studies with detection of bile acids with HPLC or indirect methods using fiber-optic bile sensor "Bilitec" to detect bilirubin in the bile. These methods have either been impracticable or unreliable for routine and accurate measurement of bile acid. More recently, impedance technology has been used to define "weakly" acid or alkaline reflux. There are many potential applications of biosensors of various types, and it is envisaged that a biosensor specific for bile acid would be a more practical tool for routine measurement. This paper looks at a model for development of a biosensor for bile acid based on molecular imprinted polymers. PMID- 19774429 TI - Proton pump inhibitors in the management of GERD. AB - INTRODUCTION: Management of gastroesophageal reflux disease (GERD) is based on the concept that gastric contents, principally acid and pepsin, are responsible for symptoms of reflux and esophageal injury. Pharmacologic treatment is based on the principle that controlling intragastric pH will affect esophageal healing and subsequently symptom relief. RESULTS AND DISCUSSION: Control of pH can be accomplished with antisecretory agents, principally proton pump inhibitors (PPIs). The majority of patients respond to a single daily dose of a PPI; however, some will require higher doses, and a small percentage are "refractory" to twice daily dosing of these drugs. The success of these agents, and in fact the reasons for "failure," is elucidated by understanding the mechanism of action of PPIs and the effect of dose timing and meals on their efficacy. CONCLUSION: Awareness of new concerns regarding potential side effects of PPIs when used long term require careful thought as GERD is a chronic disease with most needing some form of medical treatment over time. This article reviews the pharmacologic properties of PPIs and the impact on the treatment of GERD. PMID- 19774431 TI - Postoperative complications in patients with obstructive sleep apnea: a retrospective matched cohort study. AB - PURPOSE: Obstructive sleep apnea (OSA) is presumed to be a risk factor for postoperative morbidity and mortality, but the current evidence is incomplete. This retrospective matched cohort study tested the hypothesis that OSA is a risk factor for the development of postoperative complications. METHODS: Hospital ethics approval was obtained for the conduct of this study. The patients who were selected for the study were >18 yr of age, diagnosed preoperatively with OSA, and scheduled to undergo elective surgery. A cohort of surgical patients without OSA was used as a comparator group based on a one-to-one match. Matching criteria included gender, age difference <5 yr, type of surgery, and a <5 yr difference between two surgery dates. Summary data are presented and conditional logistic regression was used to identify risk factors for postoperative complications. RESULTS: The 240 pairs of study subjects aged 57 +/- 13 yr included 184 (77%) males and 56 (23%) females. The OSA patients had a higher mean body mass index relative to their non-OSA counterparts (35 +/- 9 vs 28 +/- 6 kg . m-2, respectively) and a higher frequency of co-morbidities, including hypertension (48% vs 36%, respectively) and obesity (61% vs 23%, respectively). Also, the incidence of postoperative complications in the OSA patients was significantly greater (44% OSA group vs 28% non-OSA group; P < 0.05). The most commonly observed between-group difference was oxygen desaturation < 90% (17% OSA group vs 8% non-OSA group). The OSA patients who did not use home continuous positive airway pressure (CPAP) devices prior to surgery but required the use of a CPAP device after surgery had the highest rate of complications. Conditional logistic regression was used to diagnose OSA and pre-existing stroke as significant risk factors for developing postoperative complications. The hazard ratio for OSA was 2.0 (1.25-3.19). CONCLUSION: Patients with diagnosed OSA have an increased incidence of postoperative complications, the most frequent being oxygen desaturation. PMID- 19774432 TI - Two-operator approach to improve eye-hand coordination using the GlideScope videolaryngoscope. PMID- 19774433 TI - Hemodynamic instability in septic shock. PMID- 19774434 TI - A new tacrine-melatonin hybrid reduces amyloid burden and behavioral deficits in a mouse model of Alzheimer's disease. AB - Alzheimer's disease (AD) is a progressive degenerative disorder characterized by the presence of amyloid deposits, neurofibrillary tangles and neuron loss. Emerging evidence indicates that antioxidants could be useful either for the prevention or treatment of AD. Tacrine and melatonin are well-known drugs which act as an acetylcholinesterase inhibitor and a free radical scavenger, respectively. In this study, we evaluated the effects of a new tacrine-melatonin hybrid on behavior and the biochemical and neuropathologic changes observed in amyloid precursor protein/presenilin 1 (APP/Ps1) transgenic mice. Our findings showed that direct intracerebral administration of this hybrid decreased amyloid beta peptide (Abeta)-induced cell death and amyloid burden in the brain parenchyma of APP/Ps1 mice. This reduction in Abeta pathology was accompanied by a recovery in cognitive function. Since this tacrine-melatonin hybrid apparently reduces brain Abeta and behavioral deficits, we believe this drug has remarkable and significant neuroprotective effects and might be considered a potential therapeutic strategy in AD. PMID- 19774436 TI - Very high plant stanol intake and serum plant stanols and non-cholesterol sterols. AB - BACKGROUND: Today, consumers meet abundant supply of functional foods with plant stanol increments for serum cholesterol lowering purposes. However, efficacy and safety of plant stanols intake beyond 4 g/day have remained unexplored. AIM OF THE STUDY: We evaluated the effects of very high daily intake of plant stanols (8.8 g/day) as esters on cholesterol metabolism, and serum levels of plant sterols and stanols. METHODS: In a randomized, double-blind, parallel study of 49 hypercholesterolemic subjects (mean age 62 years, range 41-73) consumed a test diet without (control, n = 24), and with added plant stanol esters (staest, n = 25) over 10 weeks followed by 4 weeks on home diet. Serum lipids, lipoprotein lipids, and non-cholesterol sterols were determined at baseline, during intervention, and 4 weeks afterwards. Cholesterol precursor sterol lathosterol reflected cholesterol synthesis, and serum plant sterols and cholestanol mirrored cholesterol absorption. RESULTS: When compared with controls, 8.8 g/day of plant stanols reduced serum and LDL cholesterol by 12 and 17% (P < 0.01 for both). Synthesis marker lathosterol was increased by 30%, while absorption markers decreased up to 62% when compared with controls (P < 0.001 for both). Serum plant stanols increased slightly, but significantly compared with controls (serum sitostanol during intervention, controls: 16 +/- 1 microg/dL, staest: 37 +/- 2 microg/dL, serum campestanol during intervention, controls: 0.5 +/- 0 microg/dL, staest: 9 +/- 1 microg/dL, P < 0.001 for both). Changes in serum cholesterol, non cholesterol sterols, and plant stanols were normalized during post-treatment weeks. CONCLUSIONS: Serum plant stanol levels remained at comparable low levels as in studies with daily intake of 2-3 g, and were normalized in 4 weeks suggesting that daily intake of 8.8 g of plant stanols might not increase systemic availability of plant stanols, but reduces effectively serum cholesterol and plant sterol levels. PMID- 19774437 TI - SPECT and PET analysis of subthalamic stimulation in Parkinson's disease: analysis using a manual segmentation. AB - The subthalamic nucleus (STN) has become an effective target of deep-brain stimulation (DBS) in severely disabled patients with advanced Parkinson's disease (PD). Clinical studies have reported DBS-induced adverse effects on cognitive functions, mood, emotion and behavior. STN DBS seems to interfere with the limbic functions of the basal ganglia, but the limbic effects of STN DBS are controversial. We measured prospectively resting regional cerebral metabolism (rCMb) with 18-fluorodeoxyglucose and PET, and resting regional cerebral blood flow (rCBF) with HMPAO and SPECT in six patients with Parkinson's disease. We compared PET and SPECT 1 month before and 3 months after STN DBS. On cerebral MRI, 13 regions of interest (ROI) were manually delineated slice by slice in frontal and limbic lobes. We obtained mean rCBF and rCMb values for each ROI and the whole brain. We normalized rCBF and rCMB values to ones for the whole brain volume, which we compared before and following STN DBS. No significant difference emerged in the SPECT analysis. PET analysis revealed a significant decrease in rCMb following STN DBS in the superior frontal gyri and left and right dorsolateral prefrontal cortex (p < 0.05). A non-significant decrease in rCMb in the left anterior cingulate gyrus appeared following STN DBS (p = 0.075). Our prospective SPECT and PET study revealed significantly decreased glucose metabolism of the two superior frontal gyri without any attendant perfusion changes following STN DBS. These results suggest that STN DBS may change medial prefrontal function and therefore the integration of limbic information, either by disrupting emotional processes within the STN, or by hampering the normal function of a limbic circuit. PMID- 19774438 TI - Immunomodulation does not alter histology in resected Crohn's disease. AB - BACKGROUND: The use of immunomodulators (Azathioprine, 6-Mercaptopurine and Methotrexate) and biological agents (Infliximab and adalimumab) for the treatment of Crohn's disease (CD) has increased in the recent years with the aim of treating the inflammatory component of the disease and hoping to change the natural history of the disease. The aim of this study was to determine if the use of immunomodulators or biological agents in the 2 years prior to resection affects the histopathological characteristics of the patient's disease. METHODS: A retrospective review was conducted over a 10-year period (1996-2005) of patients who underwent resection for CD. Clinical case notes and histology specimens were reviewed. Patients treated with Azathioprine, 6-Mercaptopurine, Methotrexate or Infliximab for more than 3 months within the 2 years preceding surgery were deemed to have been immunomodulated. The results were also analysed by Montreal phenotype. RESULTS: A total of 165 patients were identified. 52 patients had been treated with either immunomodulator or biological agent. Of 20 histological features examined, only muscular hypertrophy approached significance (P = 0.05), Montreal A and Montreal L phenotypes were the same regardless on immunomodulators, however, there was a significant difference (P = 0.03) with regard to Montreal B in patients with stricturing disease being more likely to have received an immunomodulator. CONCLUSIONS: In this cohort of patients requiring resection for CD, those with stricturing disease were more likely to receive immunomodulators or biologics than those without stricturing disease. However, there were no significant histological differences in the resected specimens between those who did and those who did not receive these drugs. PMID- 19774439 TI - Comparison between 64-row CT angiography and digital subtraction angiography in the study of lower extremities: personal experience. AB - PURPOSE: This study was undertaken to evaluate the potential of 64-row multislice computed tomography (CT) versus digital subtraction angiography (DSA) in detecting significant lesions of lower-extremity inflow and runoff arteries. MATERIALS AND METHODS: Fifty-three patients underwent 64-row multislice CT and DSA over a mean of 36 days. The vascular tree was divided into 33 segments. Three readers independently reviewed the axial CT scans and multiplanar oblique and two and three-dimensional reconstructions (maximum intensity projection and volume rendering) images to assess degree of stenosis according to four categories: 1 (0%-49% stenosis); 2 (50%-99% stenosis); 3 (occluded); 4 (not evaluable). In all cases, DSA was performed by arterial catheterisation. RESULTS: In 53 patients, 1,440 segments were evaluated (infrarenal aorta and 16 arterial segments for each leg; 42 bilateral studies, 11 unilateral studies). Compared with DSA, CT angiography yielded 97.2% sensitivity, 97% specificity, 92.5% positive predictive value, 98.9% negative predictive value, 97.1% diagnostic accuracy and 95.4% concordance on the degree of stenosis. CONCLUSIONS: Sixty-four-row multislice CT proved to be helpful in detecting haemodynamically significant lesions in peripheral arterial occlusive disease and improved the results obtained with 4- and 16-slice multidetector CT. In addition, owing to the high spatial resolution and rigorous technique, no variations in the data obtained below the knee were detected, overcoming a limitation of earlier generations of CT scanners. PMID- 19774440 TI - Diagnostic performance of 64-MDCT and 1.5-T MRI with high-resolution sequences in the T staging of gastric cancer: a comparative analysis with histopathology. AB - PURPOSE: This study was undertaken to compare the accuracy of magnetic resonance (MR) imaging and 64-slice multidetector computed tomography (64-MDCT) in the T staging of gastric carcinoma in comparison with histopathology. MATERIALS AND METHODS: Forty patients with an endoscopic diagnosis of gastric carcinoma underwent preoperative MR imaging and 64-MDCT, both of which were performed after i.v. injection of scopolamine and water distension of the stomach. In the MR imaging protocol, we acquired T2-weighted turbo spin-echo (TSE) sequences, true fast imaging steady-state free precession (true-FISP) and gadolinium-enhanced T1 weighted volumetric interpolated breath-hold examination (VIBE) 3D sequences. Contrastenhanced CT scans were obtained in the arterial and venous phases. Two groups of radiologists independently reviewed the MR and 64-MDCT images. The results were compared with pathology findings. RESULTS: In the evaluation of T stage, 64-MDCT had 82.5% and MR imaging had 80% sensitivity. Accuracy of MR imaging was slightly higher than that of 64-MDCT in identifying T1 lesions (50% vs 37.5%), whereas the accuracy of 64-MDCT was higher in differentiating T2 lesions (81.2% vs 68.7%). The accuracy of MR imaging and 64-MDCT did not differ significantly in the evaluation of T3-T4 lesions (p>0.05). Understaging was observed in 20% of cases with MR imaging and in 17.5% with 64-MDCT. CONCLUSIONS: MR imaging and 64-MDCT accuracy levels did not differ in advanced stages of disease, whereas MR imaging was superior in identifying early stages of gastric cancer and can be considered a valid alternative to MDCT in clinical practice. PMID- 19774441 TI - Fischer's score criteria correlating with histopathological prognostic factors in invasive breast cancer. AB - PURPOSE: This study aimed to evaluate whether the Fischer score criteria on contrast-enhanced magnetic resonance (CE-MR) imaging could correlate with histopathological prognostic factors in invasive breast cancer. MATERIALS AND METHODS: Seventy-two women with histologically proven invasive breast cancer underwent preoperative CE-MR imaging. Images were assessed for the following parameters, according to the scoring system described by Fischer in 1999: tumour shape, margins, internal enhancement, signal intensity increase, signal intensity course and overall Fischer score. Evaluated histopathological prognostic factors included histological type, associated extensive intraductal component, diameter, lymph node metastasis, tumour grade, and oestrogen receptor (ER), progesterone receptor (PgR), Ki67 proliferation, oncogene c-erbB-2 (HER2/neu) expression. Fisher's exact test was used to correlate the CE-MR imaging parameters and histopathological findings (with significance set a p < 0.05). RESULTS: Fischer's score was 0-4 in 14/72 (19%) cases, >4 in 58/72 (81%) and 3 in 5/72 (7%; false negative), with a sensitivity of 93%. A significant correlation (p=0.02) was found between stellate-dendritic shape and the presence of an associated extensive intraductal component (EIC), which was found in 78% of stellate tumours vs. 49% of round-oval tumours. A significant correlation (p=0.039) was found between Ki67 expression and signal intensity course (Ki67 overexpression was present in 81% of tumours with washout course vs. 21% with plateau course). CONCLUSIONS: The CE-MR imaging findings that correlate with prognostic factors are shape and signal intensity curve. Fischer's multifactorial analysis was helpful in the interpretation of CE-MR images, showing a sensitivity of 93% for invasive breast cancer. PMID- 19774442 TI - Atypical appendicitis: diagnostic value of volume-rendered reconstructions obtained with 16-slice multidetector-row CT. AB - PURPOSE: This study was done to assess the possible clinical value of volume rendered (VR) and curved volume-rendered (cVR) reconstructions obtained from isotropic data in the diagnosis of atypical appendicitis. MATERIALS AND METHODS: Forty-five patients with suspected acute appendicitis were examined with 16-slice multidetector computed tomography (MDCT) before and after contrast material injection. A diagnosis of atypical appendicitis was made in 33 cases. Two independent blinded radiologists with 2 and 9 years of CT experience assessed the axial scans and 2 months later the VR and cVR reconstructions. The following parameters were considered: presence, location, and wall thickness of the appendix; wall enhancement; distension; periappendiceal fat attenuation; presence of appendicolith; and free air and/or periappendiceal fluid collections. Sensitivity, specificity, and diagnostic accuracy values were calculated for each reader. The concordance between the two radiologists was analysed by using Cohen's kappa statistic. RESULTS: Mean sensitivity, specificity and accuracy for the less experienced radiologist were, respectively, 82%, 91% and 84% for the axial scans and 94%, 91% and 93% for the VR and cVR images, whereas the values for the more experienced reader were 94%, 100% and 95% for axial scans, and 97%, 100% and 98% for VR and cVR images. CONCLUSIONS: In patients with atypical appendicitis, VR and cVR reconstructions increase the accuracy of MDCT in relation to the reader's experience and reduce the number of false negative results. PMID- 19774444 TI - Primary hyperparathyroidism: can ultrasonography be the only preoperative diagnostic procedure? AB - PURPOSE: The purpose of our study was to assess the role of ultrasonography (US) before surgical treatment of primary hyperparathyroidism. MATERIALS AND METHODS: We retrospectively evaluated 77 patients (60 women, 17 men; mean age 59 years) with primary hyperparathyroidism who underwent parathyroid US prior to surgery. Sixty-five of 77 (84%) patients had undergone (99m)Tc- sestamibi (MIBI) scintigraphy. The results were correlated with the surgical and histopathological findings. RESULTS: Surgery revealed 85 abnormal parathyroid glands in 77 patients (70 adenomas, 15 hyperplasias). The locations of the parathyroid glands were typical cervical (n=77), thyrothymic ligament (n=3), carotid sheath (n=2), and mediastinum (n=3). In two patients, intrathyroid microadenoma was diagnosed by histopathology. Seventy-four enlarged glands in 64 patients were correctly identified at US. Per-patient sensitivity and positive predictive values, respectively, were 84% (64/76) and 99% (64/65) for US, 68% (44/65) and 100% (44/44) for scintigraphy and 91% (59/65) and 98% (59/60) for both techniques combined. We weighed 63 out of 85 glands, obtaining a value of 1,004+/-1,564 mg; 460 mg (mean+/-standard deviation; median). CONCLUSIONS: Preoperative detection and localisation of enlarged parathyroid glands can be based on US, an inexpensive and widely available method, limiting the use of scintigraphy to those cases with negative and/or doubtful findings on US. PMID- 19774443 TI - Percutaneous vertebroplasty: optimizing the procedure after treatment of 250 vertebral levels under fluoroscopic guidance. AB - PURPOSE: Percutaneous vertebroplasty (PVP) is a minimally invasive treatment for symptomatic vertebral compression fractures (VCFs). The aim of this study was to assess the effectiveness, complications and progress of results of PVP optimized in terms of technique, costs, time and strategic protocol after 3 years of procedures performed under fluoroscopic guidance alone. MATERIALS AND METHODS: We treated 250 VCFs in 120 consecutive patients after assessing clinical and radiological indications. The effectiveness of the procedure was determined by statistical analysis of numerical scores for pain, mobility and drug consumption before and after treatment. RESULTS: No major complications and only three minor complications occurred. Clinically relevant improved mobility and reduction of pain and analgesics were observed, with overall significant results (p<0.0001) in all patients at 24 h after PVP and in 83 available patients at 6 months. A total of five asymptomatic refractures of cemented vertebrae and 14 new symptomatic vertebral fractures at different levels were observed between 1 and 10 months after the procedure. CONCLUSIONS: PVP is a safe, rapid, effective and costeffective therapy for VCFs, requiring only brief hospital admission and with long-lasting clinical results, when performed under good-quality radiological guidance, when correct indications are respected and when it is associated with rehabilitation therapy in the follow-up. It is a valid alternative to conservative therapy, which is burdened by high healthcare costs and often requires long-term immobilisation of frail and elderly patients at risk of clinical complications. PMID- 19774446 TI - Hybrid treatment of isolated aortic arch aneurysms. AB - PURPOSE: This study sought to assess the feasibility and effectiveness of hybrid treatment of isolated aortic arch aneurysms. MATERIALS AND METHODS: Between December 2000 and December 2006, we selected 14 patients affected by 14 isolated aortic arch aneurysms. All patients had involvement of the left subclavian artery, four of the innominate artery and four of the left carotid artery. All patients underwent intentional exclusion of the left subclavian artery and placement of a straight graft; four patients underwent supra-aortic vessel transposition and four underwent carotid-carotid bypass in one case combined with carotid-subclavian bypass. The procedures were planned with multislice computed tomography (MSCT), in some cases associated with virtual endoscopy. The follow-up was performed with MSCT angiography at 1, 3, 6 and 12 months and yearly thereafter. RESULTS: Immediate technical success was achieved in 100% of cases. There were four ischaemic attacks (three transient ischaemic attacks and one stroke). During follow-up (range 12-48, average 21 months), we observed two type I endoleaks that were treated by endograft extension, in one case associated with supra-aortic vessel transposition, and two type-II endoleaks that were treated with embolisation. CONCLUSIONS: Hybrid treatment for aortic arch aneurysms is feasible and provides good short-term results, although it requires accurate planning. Further studies are needed to verify the long-term results. PMID- 19774445 TI - Contrast-enhanced ultrasonography in blunt abdominal trauma: considerations after 5 years of experience. AB - PURPOSE: The aim of the study was to evaluate the diagnostic capability of contrast-enhanced ultrasonography (CEUS) in a large series of patients with blunt abdominal trauma. MATERIALS AND METHODS: We studied 133 haemodynamically stable patients with blunt abdominal trauma. Patients were assessed by ultrasonography (US), CEUS and multislice computed tomography (MSCT) with and without administration of a contrast agent. The study was approved by our hospital ethics committee (clinical study no. 1/2004/O). RESULTS: In the 133 selected patients, CT identified 84 lesions; namely, 48 splenic, 21 hepatic, 13 renal or adrenal and two pancreatic. US identified free fluid or parenchymal alterations in 59/84 patients with positive CT and free fluid in 20/49 patients with negative CT. CEUS detected 81/84 traumatic lesions identified on CT and ruled out traumatic lesions in 48/49 patients with negative CT. The sensitivity, specificity and positive and negative predictive values of US were 70.2%, 59.2%, 74.7% and 53.7%, respectively, whereas those of CEUS were 96.4%, 98%, 98.8% and 94.1%, respectively. CONCLUSIONS: Our study showed that CEUS is an accurate technique for evaluating traumatic lesions of solid abdominal organs. The technique is able to detect active bleeding and vascular lesions, avoids exposure to ionising radiation and is useful for monitoring patients undergoing conservative treatment. PMID- 19774447 TI - MR imaging findings of elastofibroma dorsi in correlation with pathological features: our experience. AB - PURPOSE: This paper describes the role of magnetic resonance (MR) imaging for characterising elastofibroma dorsi in correlation with pathological findings. MATERIALS AND METHODS: Over a period of 9 years, 1,233 MR examinations of the periscapular region assessed for the presence of elastofibroma dorsi with superconductive 1.5-T MR scanners at three different radiology institutes were retrospectively reviewed. RESULTS: Our study population included 15 patients (12 women, three men; mean age 58 years, range 28-82 years) presenting with 17 lesions. Two patients had bilateral elastofibroma dorsi. Thirteen of 15 patients underwent MR examination for clinical suspicion of a lesion located in the periscapular region, whereas in 2/15 cases it was an incidental finding during MR examination performed for other diseases. Diagnosis of elastofibroma dorsi was confirmed by histopathology in 11/17 cases. The remaining lesions were considered benign, as their size and morphology did not change over a mean follow-up period of 1.5 years. CONCLUSIONS: MR imaging with its multiplanar capabilities and high contrast resolution has a high level of accuracy in characterising elastofibroma dorsi and may avoid the need for biopsy or surgical operation. PMID- 19774448 TI - Fucoidan increases TNF-alpha-induced MMP-9 secretion in monocytic cell line U937. AB - OBJECTIVE: To investigate the effect of fucoidan on the expression of matrix metalloproteinase-9 (MMP-9) from monocytes. METHODS: Human monocytic cell line U937 was purchased from ATCC. During the experiment, FBS-free 1640 was used and U937 was cultivated with 20 ng/ml TNF-alpha and/or different concentrations of fucoidan for 24 h. RT-PCR experiments were used to determine the MMP-9 mRNA expression. ELISA and gelatin zymography detected MMP-9 amounts and activity in the supernatant. The intracellular level of MMP-9 was assayed by Western blot, and the level of CD44 on the surface was assayed by FACS. RESULTS: In this study, we showed that pro-inflammatory cytokine TNF-alpha up-regulated U937 MMP-9 mRNA and protein levels (P < 0.05). Fucoidan can increase the TNF-alpha-induced MMP-9 secretion from U937 (P < 0.05), but no significant difference was observed in MMP 9 mRNA. The intracellular level of MMP-9 treated with TNF-alpha and fucoidan was lower (P < 0.05) than that treated with TNF-alpha alone. In addition, we demonstrated that fucoidan downregulated the surface level of CD44, the main molecule to which MMP-9 attaches. CONCLUSIONS: We demonstrated that fucoidan post translationally regulated MMP-9 secretion from U937. Reduced intracellular level and decreased membrane attachment may contribute to the increase in MMP-9 secretion. PMID- 19774449 TI - Immunomodulation by atorvastatin upregulates expression of gap junction proteins in coxsackievirus B3 (CVB3)-induced myocarditis. AB - OBJECTIVE: To investigate the effect of atorvastatin on myocardial expression of gap junction proteins, connexins (Cxs), during coxsackievirus B3 (CVB3)-induced myocarditis. METHODS: Viral myocarditis was induced in mice by inoculation with CVB3. Atorvastatin (5 or 10 mg kg(-1) day(-1)) or saline was administered by daily oral gavage from the day of induction of viral myocarditis to the day of sacrifice. Fourteen days after injection of CVB3, animals were sacrificed. Alterations in myocardial Cxs expression were examined by RT-PCR, immunoblot, and immunohistochemistry. Plasma levels of TNF-alpha and IFN-gamma were measured by ELISA. RESULTS: Fourteen days after inoculation with CVB3, myocardial expression of Cx43 and Cx45 was significantly downregulated. Treatment with atorvastatin not only reduced the overproduction of TNF-alpha and IFN-gamma, but also enhanced the expression of Cx43 and Cx45, therefore attenuating myocardial injury and improving the survival rate of viral myocarditis. CONCLUSION: This study shows for the first time that myocardial expression of Cxs is downregulated during CVB3 induced myocarditis and that immunomodulation by atorvastatin could restore the impaired gap junction channels and improve the outcome of viral myocarditis. PMID- 19774450 TI - Reliability, validity and classification accuracy of the South Oaks Gambling Screen in a Brazilian sample. AB - The purpose of this study was to examine the reliability, validity and classification accuracy of the South Oaks Gambling Screen (SOGS) in a sample of the Brazilian population. Participants in this study were drawn from three sources: 71 men and women from the general population interviewed at a metropolitan train station; 116 men and women encountered at a bingo venue; and 54 men and women undergoing treatment for gambling. The SOGS and a DSM-IV-based instrument were applied by trained researchers. The internal consistency of the SOGS was 0.75 according to the Cronbach's alpha model, and construct validity was good. A significant difference among groups was demonstrated by ANOVA (F2.238 = 221.3, P < 0.001). The SOGS items and DSM-IV symptoms were highly correlated (r = 0.854, P < 0.01). The SOGS also presented satisfactory psychometric properties: sensitivity (100), specificity (74.7), positive predictive rate (60.7), negative predictive rate (100) and misclassification rate (0.18). However, a cut-off score of eight improved classification accuracy and reduced the rate of false positives: sensitivity (95.4), specificity (89.8), positive predictive rate (78.5), negative predictive rate (98) and misclassification rate (0.09). Thus, the SOGS was found to be reliable and valid in the Brazilian population. PMID- 19774451 TI - Synthesis and fluorescence properties of lanthanide (III) perchlorate complexes with naphthyl-naphthalinesulphonylpropyl sulfoxide. AB - A ligand with double sulfinyl groups, naphthyl-naphthalinesulphonylpropyl sulfoxide(dinaphthyl disulfoxide, L), was synthesized by a new method and its several lanthanide (III) complexes were synthesized and characterized by element analysis, molar conductivity, coordination titration analysis, IR, TG-DTA, (1)HNMR and UV spectra. The composition of these complexes, were RE(2)(ClO(4))(6).(L)(5).nH(2)O (RE = La, Nd, Eu, Tb, Yb, n = 2 approximately 6, L = C(10)H(7)SOC(3)H(6)SOC(10)H(7)). The fluorescent spectra illustrated that the Eu (III) complex had an excellent luminescence. It was supposed that the ligand was benefited for transferring the energy from ligand to the excitation state energy level ((5)D(0)) of Eu (III). The Tb (III) complex displayed weak luminescence, which attributed to low energy transferring efficiency between the average triplet state energy level of ligand and the excited state ((5)D(4)) of Tb (III). So the Eu (III) complex displayed a good antenna effect for luminescence. The phosphorescence spectra and the relationship between fluorescence lifetime and fluorescence intensity were also discussed. PMID- 19774452 TI - Characterization of coupled ground state and excited state equilibria by fluorescence spectral deconvolution. AB - Fluorescence probes with multiparametric response based on the relative variation in the intensities of several emission bands are of great general utility. An accurate interpretation of the system requires the determination of the number, positions and intensities of the spectral components. We have developed a new algorithm for spectral deconvolution that is applicable to fluorescence probes exhibiting a two-state ground-state equilibrium and a two-state excited-state reaction. Three distinct fluorescence emission bands are resolved, with a distribution of intensities that is excitation-wavelength-dependent. The deconvolution of the spectrum into individual components is based on their representation as asymmetric Siano-Metzler log-normal functions. The application of the algorithm to the solvation response of a 3-hydroxychromone (3HC) derivative that exhibits an H-bonding-dependent excited-state intramolecular proton transfer (ESIPT) reaction allowed the separation of the spectral signatures characteristic of polarity and hydrogen bonding. This example demonstrates the ability of the method to characterize two potentially uncorrelated parameters characterizing dye environment and interactions. PMID- 19774453 TI - Elevated production of B cell chemokine CXCL13 is correlated with systemic lupus erythematosus disease activity. AB - INTRODUCTION: B lymphocyte chemoattractant (BLC/CXCL13), a CXC chemokine, is involved in B1 and B2 cell trafficking for the activation of autoreactive T helper (Th) cells and autoantibody production in target organs during the development of lupus. CXCL13 can induce the trafficking of CXCR5+ T lymphocyte subset designated as follicular helper T lymphocytes (T(FH)) which are specifically involved in autoantibody production. MATERIALS AND METHODS: We herein measured the plasma concentrations of CXCL13, B-cell-activating factor of the TNF family (BAFF), and T(FH)-cells-related cytokine IL-21 and cell surface expression of T(FH)-related receptor CXCR5 and IL-21R on CD4+Th and CD19+B cells in 35 systemic lupus erythematosus (SLE) patients and 23 sex- and age-matched control subjects (NC) using enzyme-linked immunosorbent assay and flow cytometry, respectively. RESULTS AND DISCUSSION: Plasma CXCL13, BAFF, and IL-21 concentrations were significantly higher in SLE patients than NC group (all p < 0.0001). Increase in CXCL13 concentration correlated positively and significantly with SLEDAI score in SLE patients (r = 0.399, p = 0.032). Cell surface expression of CXCR5 on Th and B cells and IL-21R on B cells was however significantly lower in SLE patients than controls (both p < 0.01). It may indicate that most differentiated T(FH) cells migrate out from circulation into lymphoid organ upon activation during the disease development of SLE. CONCLUSIONS: The above results suggest that the elevated production of CXCL13, BAFF, and IL-21 may be associated with the function of T(FH) for the immunopathogenesis in SLE, and CXCL13 may serve as a potential disease marker of SLE. PMID- 19774454 TI - Comments on adolescent peer crowd affiliation: a response to Cross and Fletcher (2009). PMID- 19774455 TI - Resistin up-regulates COX-2 expression via TAK1-IKK-NF-kappaB signaling pathway. AB - The hormone resistin, which was originally shown to induce insulin resistance, has been implicated in the regulation of inflammatory processes, but the molecular mechanism underlying such regulation has not been clearly defined. The goal of our study was to determine whether the expression of COX-2 can be induced by resistin and what the potential signaling pathway involved in this process is. Compared with controls, resistin significantly upregulated COX-2 expression in RAW264.7 macrophage cells. Administration of anti-resistin antibody could significantly reduce this effect. Induction of COX-2 by resistin was also markedly reduced in the presence of either dominant negative mutant IkappaBalpha or PDTC, a pharmacological inhibitor of NF-kappaB. On the other hand, NF-kappaB subunit p65 was upregulated by resistin. Moreover, we found that transforming growth factor-beta-activated kinase 1 (TAK1), a mitogen-activated protein kinase kinase kinase (MAPKKK), could be activated in response to resistin. These results suggest that resistin enhances COX-2 expression in mouse macrophage cells in a TAK1-IKK-NF-kappaB-dependent manner and therefore plays a critical role in inflammatory processes. PMID- 19774456 TI - Experimental evidence that phenylalanine provokes oxidative stress in hippocampus and cerebral cortex of developing rats. AB - High levels of phenylalanine (Phe) are the biochemical hallmark of phenylketonuria (PKU), a neurometabolic disorder clinically characterized by severe mental retardation and other brain abnormalities, including cortical atrophy and microcephaly. Considering that the pathomechanisms leading to brain damage and particularly the marked cognitive impairment in this disease are poorly understood, in the present study we investigated the in vitro effect of Phe, at similar concentrations as to those found in brain of PKU patients, on important parameters of oxidative stress in the hippocampus and cerebral cortex of developing rats. We found that Phe induced in vitro lipid peroxidation (increase of TBA-RS values) and protein oxidative damage (sulfhydryl oxidation) in both cerebral structures. Furthermore, these effects were probably mediated by reactive oxygen species, since the lipid oxidative damage was totally prevented by the free radical scavengers alpha-tocopherol and melatonin, but not by L-NAME, a potent inhibitor of nitric oxide synthase. Accordingly, Phe did not induce nitric oxide synthesis, but significantly decreased the levels of reduced glutathione (GSH), the major brain antioxidant defense, in hippocampus and cerebral cortex supernatants. Phe also reduced the thiol groups of a commercial GSH solution in a cell-free medium. We also found that the major metabolites of Phe catabolism, phenylpyruvate, phenyllactate and phenylacetate also increased TBA-RS levels in cerebral cortex, but to a lesser degree. The data indicate that Phe elicits oxidative stress in the hippocampus, a structure mainly involved with learning/memory, and also in the cerebral cortex, which is severely damaged in PKU patients. It is therefore presumed that this pathomechanism may be involved at least in part in the severe cognitive deficit and in the characteristic cortical atrophy associated with dysmyelination and leukodystrophy observed in this disorder. PMID- 19774458 TI - Conclusion: QEEG-guided neurofeedback in context and in practice. PMID- 19774457 TI - Understanding and determining the etiology of autism. AB - Worldwide, the rate of autism has been steadily rising. There are several environmental factors in concert with genetic susceptibilities that are contributing to this rise. Impaired methylation and mutations of mecp2 have been associated with autistic spectrum disorders, and related Rett syndrome. Genetic polymorphisms of cytochrome P450 enzymes have also been linked to autism, specifically CYP27B1 that is essential for proper vitamin D metabolism. Vitamin D is important for neuronal growth and neurodevelopment, and defects in metabolism or deficiency have been implicated in autistic individuals. Other factors that have been considered include: maternally derived antibodies, maternal infection, heavy metal exposure, folic acid supplementation, epigenetics, measles, mumps, rubella vaccination, and even electromagnetic radiation. In each case, the consequences, whether direct or indirect, negatively affect the nervous system, neurodevelopment, and environmental responsive genes. The etiology of autism is a topic of controversial debate, while researchers strive to achieve a common objective. The goal is to identify the cause(s) of autism to understand the complex interplay between environment and gene regulation. There is optimism that specific causes and risk factors will be identified. The results of future investigations will facilitate enhanced screening, prevention, and therapy for "at risk" and autistic patients. PMID- 19774459 TI - Ki67: a time-varying biomarker of risk of breast cancer in atypical hyperplasia. AB - Uncontrolled proliferation is a defining feature of the malignant phenotype. Ki67 is a marker for proliferating cells and is overexpressed in many breast cancers. Atypical hyperplasia is a premalignant lesion of the breast (relative risk approximately 4.0). Here, we asked if Ki67 expression could stratify risk in women with atypia. Ki67 expression was assessed immunohistochemically by digital image analysis in archival sections from 192 women with atypia diagnosed at the Mayo Clinic 1/1/67-12/31/91. Risk factor and follow-up data were obtained via study questionnaire and medical records. Observed breast cancer events were compared to population expected rates (Iowa SEER) using standardized incidence ratios (SIRs). We examined two endpoints: risk of breast cancer within 10 years and after 10 years of atypia biopsy. Thirty-two (16.7%) of the 192 women developed breast cancer over a median of 14.6 years. Thirty percent (58) of the atypias had >or=2% cells staining for Ki67. In these women, the risk of breast cancer within 10 years after atypia was increased (SIR 4.42 [2.21-8.84]) but not in those with <2% staining. Specifically, the cumulative incidence for breast cancer at 10 years was 14% in the high Ki67 vs. 3% in the low Ki67 group. Conversely, after 10 years, risk in the low Ki67 group rose significantly (SIR 5.69 [3.63-8.92]) vs. no further increased risk in the high Ki67 group (SIR 0.78 [0.11-5.55]). Ki67 appears to be a time-varying biomarker of risk of breast cancer in women with atypical hyperplasia. PMID- 19774460 TI - Effect of treadmill exercise on serotonin immunoreactivity in medullary raphe nuclei and spinal cord following sciatic nerve transection in rats. AB - The serotoninergic system modulates nociceptive and locomotor spinal cord circuits. Exercise improves motor function and changes dopaminergic, noradrenergic, and serotonergic central systems. However, the direct relationship between serotonin, peripheral nerve lesion and aerobic treadmill exercise has not been studied. Using immunohistochemistry and optic densitometry, this study showed that the sciatic nerve transection increased the serotoninergic immunoreactivity in neuronal cytoplasm of the magnus raphe nuclei of trained and sedentary rats. In the dorsal raphe nucleus the increase only occurred in sedentary-sham-operated rats. In the spinal cord of trained, transected rats, the ventral horn showed significant changes, while the change in dorsal horn was insignificant. Von Frey's test indicated analgesia in all exercise-trained rats. The sciatic nerve functional index indicated recovery in the trained group. Thus, both the aerobic treadmill exercise training and the nervous lesion appear to contribute to changes in serotonin immunoreactivity. PMID- 19774461 TI - Curcumin improves outcomes and attenuates focal cerebral ischemic injury via antiapoptotic mechanisms in rats. AB - Curcumin, a member of the curcuminoid family of compounds, is a yellow colored phenolic pigment obtained from the powdered rhizome of C. longa Linn. Recent studies have demonstrated that curcumin has protective effects against cerebral ischemia/reperfusion injury. However, little is known about its mechanism. In the present study, we tested the effects of curcumin in focal cerebral ischemia in rats and the possible mechanisms. Adult male Sprague-Dawley rats were treated with curcumin (100, 300 and 500 mg/kg) administered intraperitoneally after 60 min of occlusion (beginning of reperfusion). Neurological score and infarct volume were assessed at 24 and 72 h. Oxidative stress was evaluated by malondialdehyde assay and the apoptotic mechanisms were studied by Western blotting. Curcumin treatment significantly reduced infarct volume and improved neurological scores at different time points compared with the vehicle-treated group. Curcumin treatment decreased malondialdehyde levels, cytochrome c, and cleaved caspase 3 expression and increased mitochondrial Bcl-2 expression. Inhibition of oxidative stress with curcumin treatment improves outcomes after focal cerebral ischemia. This neuroprotective effect is likely exerted by antiapoptotic mechanisms. PMID- 19774462 TI - Three-year trajectory of teachers' fidelity to a drug prevention curriculum. AB - Little is known about the trajectories over time of classroom teachers' fidelity to drug prevention curricula. Using the "Concerns-Based Adoption Model" (C-BAM) as a theoretical framework, we hypothesized that teachers' fidelity would improve with repetition. Participants comprised 23 middle school teachers who videotaped their administration of three entire iterations of the All Stars curriculum. Investigators coded two key curriculum lessons, specifically assessing the proportion of activities of each lesson teachers attempted and whether they omitted, added, or changed prescribed content, or delivered it using new methods. Study findings provided only partial support for the C-BAM model. Considerable variability in teachers' performance over time was noted, suggesting that their progression over time may be nonlinear and dynamic, and quite possibly a function of their classroom and school contexts. There was also evidence that, by their third iteration of All Stars, teachers tended to regress toward the baseline mean. That is, the implementation quality of those that started out with high levels of fidelity tended to degrade, while those that started out with very low fidelity to the curriculum tended to improve. Study findings suggest the need for ongoing training and technical assistance, as well as "just in time" messages delivered electronically; but it is also possible that some prevention curricula may impose unrealistic expectations or burdens on teachers' abilities and classroom time. PMID- 19774463 TI - Characterization of gastric electrical activity using magnetic field measurements: a simulation study. AB - Gastric disorders are often associated with abnormal propagation of gastric electrical activity (GEA). The identification of clinically relevant parameters of GEA using noninvasive measures would therefore be highly beneficial for clinical diagnosis. While magnetogastrograms (MGG) are known to provide a noninvasive representation of GEA, standard methods for their analysis are limited. It has previously been shown in simplistic conditions that the surface current density (SCD) calculated from multichannel MGG measurements provides an estimate of the gastric source location and propagation velocity. We examine the accuracy of this technique using more realistic source models and an anatomically realistic volume conductor model. The results showed that the SCD method was able to resolve the GEA parameters more reliably when the dipole source was located within 100 mm of the sensor. Therefore, the theoretical accuracy of SCD method would be relatively diminished for patients with a larger body habitus, and particularly in those patients with significant truncal obesity. However, many patients with gastric motility disorders are relatively thin due to food intolerance, meaning that the majority of the population of gastric motility patients could benefit from the methods developed here. Large errors resulted when the source was located deep within the body due to the distorting effects of the secondary sources on the magnetic fields. Larger errors also resulted when the dipole was oriented normal to the sensor plane. This was believed to be due to the relatively small contribution of the dipole source when compared to the field produced by the volume conductor. The use of three orthogonal magnetic field components rather than just one component to calculate the SCD yielded marginally more accurate results when using a realistic dipole source. However, this slight increase in accuracy may not warrant the use of more complex vector channels in future superconducting quantum interference device designs. When multiple slow waves were present in the stomach, the SCD map contained only one maximum point corresponding to the more dominant source located in the distal stomach. Parameters corresponding to the slow wave in the proximal stomach were obtained once the dominant slow terminated at the antrum. Additional validation studies are warranted to address the utility of the SCD method to resolve parameters related to gastric slow waves in a clinical setting. PMID- 19774464 TI - Parallelism effects and verb activation: the sustained reactivation hypothesis. AB - This study investigated the processes underlying parallelism by evaluating the activation of a parallel element (i.e., a verb) throughout and-coordinated sentences. Four points were tested: (1) approximately 1,600 ms after the verb in the first conjunct (PP1), (2) immediately following the conjunction (PP2), (3) approximately 1,100 ms after the conjunction (PP3), (4) at the end of the second conjunct (PP4). The results revealed no activation at PP1, suggesting activation related to the initial presentation had decayed by this point; however, activation was observed at PP2, PP3, and PP4, suggesting the conjunction elicits reactivation that is sustained throughout the second conjunct. These findings support a specific hypothesis about parallelism, the sustained reactivation hypothesis. This hypothesis claims that, in conjoined structures, a cue that is associated with parallelism elicits the reactivation of material from the first conjunct and that this activation is sustained until integration with the second conjunct can be completed. PMID- 19774465 TI - Computational modelling of protein interactions: energy minimization for the refinement and scoring of association decoys. AB - The prediction of protein-protein interactions based on independently obtained structural information for each interacting partner remains an important challenge in computational chemistry. Procedures where hypothetical interaction models (or decoys) are generated, then ranked using a biochemically relevant scoring function have been garnering interest as an avenue for addressing such challenges. The program PatchDock has been shown to produce reasonable decoys for modeling the association between pig alpha-amylase and the VH-domains of camelide antibody raised against it. We designed a biochemically relevant method by which PatchDock decoys could be ranked in order to separate near-native structures from false positives. Several thousand steps of energy minimization were used to simulate induced fit within the otherwise rigid decoys and to rank them. We applied a partial free energy function to rank each of the binding modes, improving discrimination between near-native structures and false positives. Sorting decoys according to strain energy increased the proportion of near-native decoys near the bottom of the ranked list. Additionally, we propose a novel method which utilizes regression analysis for the selection of minimization convergence criteria and provides approximation of the partial free energy function as the number of algorithmic steps approaches infinity. PMID- 19774466 TI - Unparalleled GC content in the plastid DNA of Selaginella. AB - One of the more conspicuous features of plastid DNA (ptDNA) is its low guanine and cytosine (GC) content. As of February 2009, all completely-sequenced plastid genomes have a GC content below 43% except for the ptDNA of the lycophyte Selaginella uncinata, which is 55% GC. The forces driving the S. uncinata ptDNA towards G and C are undetermined, and it is unknown if other Selaginella species have GC-biased plastid genomes. This study presents the complete ptDNA sequence of Selaginella moellendorffii and compares it with the previously reported S. uncinata plastid genome. Partial ptDNA sequences from 103 different Selaginella species are also described as well as a significant proportion of the S. moellendorffii mitochondrial genome. Moreover, S. moellendorffii express sequence tags are data-mined to estimate levels of plastid and mitochondrial RNA editing. Overall, these data are used to show that: (1) there is a genus-wide GC bias in Selaginella ptDNA, which is most pronounced in South American articulate species; (2) within the Lycopsida class (and among plants in general), GC-biased ptDNA is restricted to the Selaginella genus; (3) the cause of this GC bias is arguably a combination of reduced AT-mutation pressure relative to other plastid genomes and a large number of C-to-U RNA editing sites; and (4) the mitochondrial DNA (mtDNA) of S. moellendorffii is also GC biased (even more so than the ptDNA) and is arguably the most GC-rich organelle genome observed to date-the high GC content of the mtDNA also appears to be influenced by RNA editing. Ultimately, these findings provide convincing support for the earlier proposed theory that the GC content of land-plant organelle DNA is positively correlated and directly connected to levels of organelle RNA editing. PMID- 19774467 TI - Decolorization and detoxification of Congo red and textile industry effluent by an isolated bacterium Pseudomonas sp. SU-EBT. AB - The 16S rRNA sequence and biochemical characteristics revealed the isolated organism as Pseudomonas sp. SU-EBT. This strain showed 97 and 90% decolorization of a recalcitrant dye, Congo red (100 mg l(-1)) and textile industry effluent with 50% reduction in COD within 12 and 60 h, respectively. The optimum pH and temperature for the decolorization was 8.0 and 40 degrees C, respectively. Pseudomonas sp. SU-EBT was found to tolerate the dye concentration up to 1.0 g l( 1). Significant induction in the activity of intracellular laccase suggested its involvement in the decolorization of Congo red. The metabolites formed after decolorization of Congo red, such as p-dihydroxy biphenyl, 8-amino naphthol 3 sulfonic acid and 3-hydroperoxy 8-nitrosonaphthol were characterized using FTIR and GC-MS. Phytotoxicity study revealed nontoxic nature of the degradation metabolites to Sorghum bicolor, Vigna radiata, Lens culinaris and Oryza sativa plants as compared to Congo red and textile industry effluent. Pseudomonas sp. SU EBT decolorized several individual textile dyes, dye mixtures and textile industry effluent, thus it is a useful strain for the development of effluent treatment methods in textile processing industries. PMID- 19774468 TI - Molecular dissimilarities of Rhipicephalus sanguineus (Acari: Ixodidae) in Brazil and its relation with samples throughout the world: is there a geographical pattern? AB - In this study the genetic variability of Rhipicephalus sanguineus within Brazil and its relation with ticks of the same group from different continents was evaluated. Mitochondrial 12S and 16S rDNA fragments of R. sanguineus from seven Brazilian States were sequenced and compared to GenBank sequences of R. sanguineus and R. turanicus ticks from Africa, Asia, Europe, South America and USA. Results indicate a relatively high intra-specific variability between Brazilian samples but also a global latitude linked distribution pattern of at least two major R. sanguineus groups; one group distributed from latitude 25 degrees N to 22 degrees S including R. sanguineus from Brazil, Taiwan and Thailand and R. turanicus from Zambia and Zimbabwe, and the other group found closer to the poles, roughly above 29 degrees N and below 30 degrees S with ticks from Argentina, Uruguay, France, Oklahoma (USA), Israel and Egypt. PMID- 19774469 TI - Diet-dependent life history, feeding preference and thermal requirements of the predatory mite Neoseiulus baraki (Acari: Phytoseiidae). AB - Neoseiulus baraki Athias-Henriot (Acari: Phytoseiidae) has been reported from the Americas, Africa and Asia, often in association with Aceria guerreronis Keifer (Acari: Eriophyidae), one of the most important pests of coconut (Cocos nucifera L.) in different parts of the world. That phytoseiid has been considered one of the most common predators associated with A. guerreronis in Brazil. The objective of this study was to evaluate the feeding preference and the effect of food items commonly present on coconut fruits and several temperature regimes on the life history of a Brazilian population of N. baraki. Completion of immature development was possible when N. baraki was fed A. guerreronis, Steneotarsonemus concavuscutum Lofego and Gondim Jr., and Tyrophagus putrescentiae (Schrank). Fecundity was highest on T. putrescentiae (39.4 eggs), followed by A. guerreronis (24.8 eggs). In choice tests, irrespective of the food on which N. baraki was reared, a larger number of adults of this predator chose leaf discs containing A. guerreronis than discs containing other food items, demonstrating a preference of the former for the latter as food. Egg to adult thermal developmental time was calculated as 84.2 degree-days, above a threshold of 15.8 degrees C. This lower developmental threshold is higher than previously published for phytoseiid species from higher latitudes. Neoseiulus baraki was shown to have higher biotic potential at 30 degrees C (r (m) 0.29). The results suggest N. baraki to be a promising biological control agent of A. guerreronis, well adapted to survive and develop in areas with relatively high temperatures, where that pest prevails. PMID- 19774470 TI - The role of eriophyoids in fungal pathogen epidemiology, mere association or true interaction? AB - A considerable number of plant feeding mites representing different families such as Acaridae, Siteroptidae, Tydeidae, and Tarsonemidae interact with plant pathogenic fungi. While species within the Eriophyoidea appear to be the most common phytophagous mites vectoring virus diseases, little is known of their role in fungal pathogen epidemiology. In the present article, we present two studies on eriophyoid-fungal relationships. The first focusing on the association between Aceria mangiferae and the fungal pathogen Fusarium mangiferae in mango is presented as a case study. The second, as the research is still in a preliminary phase, reports on quantitative and descriptive associations between the cereal rust mite Abacarus hystrix and rusts caused by Puccinia spp. Mango bud tissue colonized with F. mangiferae, and wheat and quackgrass leaves colonized with Puccinia spp., supported significantly higher populations of eriophyoid mites. Both mite species were observed bearing the spores of the respective pathogens on their body integument. Aceria mangiferae vectored the pathogen's spores into the bud, the sole port of entry for the fungal pathogen and the frequency and severity of fungal infection increased in the presence of A. mangiferae. While it appears that eriophyoids are playing a role in fungal epidemiology, clearly further research is needed to enhance our understanding of direct and indirect (plant mediated) interactions between plant pathogens and eriophyoid mites in different plant-pathogen systems. PMID- 19774471 TI - Metabolic syndrome components and colorectal adenoma in the CLUE II cohort. AB - BACKGROUND: Metabolic syndrome components have been associated with colorectal cancer in several studies; however, evidence for colorectal adenomas is limited. Thus, we evaluated the association between markers of the metabolic syndrome with colorectal adenoma development in a nested case-control study. METHODS: Colorectal adenoma cases (n = 132) and matched controls, who had a negative sigmoidoscopy or a colonoscopy (n = 260), were identified between baseline in 1989 and 2000 among participants in the CLUE II cohort of Washington County, Maryland. Concentrations of C-peptide, insulin-like growth factor binding protein 1, glycosylated hemoglobin, total cholesterol, high-density lipoprotein cholesterol, and triglycerides were measured in baseline blood specimens. Body mass index was calculated using baseline height and weight. Use of medications to treat diabetes mellitus was self-reported at baseline. Blood pressure was measured at baseline. Distributional cutpoints of the latter markers were used to define the metabolic syndrome components (hyperinsulinemia, hyperglycemia, obesity, dyslipidemia, and hypertension) present at baseline. RESULTS: No statistically significant associations with adenomas were observed for the markers of the metabolic syndrome, with the exception of a strong positive association for use of diabetes medications (OR, 8.00; 95% CI, 1.70-37.67), albeit based on small numbers. CONCLUSION: Our findings do not support that components of the metabolic syndrome influence risk of colorectal adenomas, except possibly for severe diabetes mellitus warranting medical treatment. PMID- 19774472 TI - Assignment of genetic linkage maps to diploid Solanum tuberosum pachytene chromosomes by BAC-FISH technology. AB - A cytogenetic map has been developed for diploid potato (Solanum tuberosum), in which the arms of the 12 potato bivalents can be identified in pachytene complements using multicolor fluorescence in situ hybridization (FISH) with a set of 60 genetically anchored bacterial artificial chromosome (BAC) clones from the RHPOTKEY BAC library. This diagnostic set of selected BACs (five per chromosome) hybridizes to euchromatic regions and corresponds to well-defined loci in the ultradense genetic map, and with these probes a new detailed and reliable pachytene karyotype could be established. Chromosome size has been estimated both from microscopic length measurements and from 4',6-diamidino-2-phenylindole fluorescence-based DNA content measurements. In both approaches, chromosome 1 is the largest (100-115 Mb) and chromosome 11 the smallest (49-53 Mb). Detailed measurements of mega-base-pair to micrometer ratios have been obtained for chromosome 5, with average values of 1.07 Mb/mum for euchromatin and 3.67 Mb/mum for heterochromatin. In addition, our FISH results helped to solve two discrepancies in the potato genetic map related to chromosomes 8 and 12. Finally, we discuss the significance of the potato cytogenetic map for extended FISH studies in potato and related Solanaceae, which will be especially beneficial for the potato genome-sequencing project. PMID- 19774473 TI - Effect of fixed-fraction subsampling on macroinvertebrate bioassessment of rivers. AB - We investigated the effect of different subsample fractions on the variability of benthic invertebrate metrics. The results of six fractions 1/12, 1/6, 1/4, 1/3, 5/12 and 1/2 were compared to the results of the whole samples. Over 120 metrics were tested using five datasets: ecoregion Alps and four river types. In general, variability of metrics decreased with increasing subsample size, but variability varied greatly with the selected metric group and river type. Independent of river type, the highest variation was observed for the composition/abundance group metrics and the richness metrics, whereas it was low for the diversity indices and for the metrics of the sensitivity/tolerance group and intermediate for the functional metric group. For all metric groups independent of river type, the main decrease in variability occurs up to 1/4 subsample. We suggest that the effect of subsample size on variability of metrics should be tested prior to selecting potential assessment metrics. PMID- 19774474 TI - Weekly variation of atmospheric particle micromorphology and chemistry in Brussels urban environment. AB - The purpose of this study was to measure the impact of urban activities on airborne particle dynamics during weekend periods in Brussels urban area. Differences in the granulometry and micromorphology between particles sampled on working days and weekends were studied. We quantified the area, size, number, and the chemistry parameters of the airborne particles and compared between Saturday, Sunday, and Monday. We report and analyze data on airborne particles up to PM10, measured in the Brussels region from October 2002 to September 2003. Our investigation reveals detailed information regarding chemical composition of the airborne particles over the weekend period in the Brussels urban area. Furthermore, the majority of the airborne particles in the Brussels region may belong to sources geographically outside the (in situ) Brussels area. PMID- 19774475 TI - Significant increase in factual knowledge with web-assisted problem-based learning as part of an undergraduate cardio-respiratory curriculum. AB - In recent years, increasing attention has been paid to web-based learning although the advantages of computer-aided instruction over traditional teaching formats still need to be confirmed. This study examined whether participation in an online module on the differential diagnosis of dyspnoea impacts on student performance in a multiple choice examination of factual knowledge in cardiology and pneumology. A virtual problem-based learning environment for medical students supervised by postgraduate teachers was created. Seventy-four out of 183 fourth year medical students volunteered to use the online module while attending a 6 week cardio-respiratory curriculum in summer 2007. Of these, 40 were randomly selected to be included (intervention group); the remaining 34 served as an internal control group. Analysis of all written exams taken during the preceding term showed that both groups were comparable (86.4 +/- 1.1 vs. 85.9 +/- 1.1%; p = 0.751). Students in the intervention group scored significantly higher in the final course assessment than students allocated to the control group (84.8 +/- 1.3 vs. 79.5 +/- 1.4%; p = 0.006; effect size 0.67). Thus, additional problem based learning with an online module as part of an undergraduate cardio respiratory curriculum lead to higher students' scores in an exam testing factual knowledge. Whether using this teaching format increases overall student motivation to engage in the learning process needs to be further investigated. PMID- 19774476 TI - Effects of age, gender and educational background on strength of motivation for medical school. AB - The aim of this study was to determine the effects of selection, educational background, age and gender on strength of motivation to attend and pursue medical school. Graduate entry (GE) medical students (having Bachelor's degree in Life Sciences or related field) and Non-Graduate Entry (NGE) medical students (having only completed high school), were asked to fill out the Strength of Motivation for Medical School (SMMS) questionnaire at the start of medical school. The questionnaire measures the willingness of the medical students to pursue medical education even in the face of difficulty and sacrifice. GE students (59.64 +/- 7.30) had higher strength of motivation as compared to NGE students (55.26 +/- 8.33), so did females (57.05 +/- 8.28) as compared to males (54.30 +/- 8.08). 7.9% of the variance in the SMMS scores could be explained with the help of a linear regression model with age, gender and educational background/selection as predictor variables. Age was the single largest predictor. Maturity, taking developmental differences between sexes into account, was used as a predictor to correct for differences in the maturation of males and females. Still, the gender differences prevailed, though they were reduced. Pre-entrance educational background and selection also predicted the strength of motivation, but the effect of the two was confounded. Strength of motivation appears to be a dynamic entity, changing primarily with age and maturity and to a small extent with gender and experience. PMID- 19774477 TI - Effects of an educational intervention on female biomedical scientists' research self-efficacy. AB - Women and people of color continue to be underrepresented among biomedical researchers to an alarming degree. Research interest and subsequent productivity have been shown to be affected by the research training environment through the mediating effects of research self-efficacy. This article presents the findings of a study to determine whether a short-term research training program coupled with an efficacy enhancing intervention for novice female biomedical scientists of diverse racial backgrounds would increase their research self-efficacy beliefs. Forty-three female biomedical scientists were randomized into a control or intervention group and 15 men participated as a control group. Research self efficacy significantly increased for women who participated in the self-efficacy intervention workshop. Research self-efficacy within each group also significantly increased following the short-term research training program, but cross-group comparisons were not significant. These findings suggest that educational interventions that target sources of self-efficacy and provide domain specific learning experiences are effective at increasing research self-efficacy for women and men. Further studies are needed to determine the longitudinal outcomes of this effort. PMID- 19774478 TI - Preparation and evaluation of danofloxacin mesylate microspheres and its pharmacokinetics in pigs. AB - Danofloxacin mesylate gelatin microspheres (DFM-GMS) were prepared by an emulsion chemical crosslinking technique. Distribution of particle size, morphologic characteristics, drug content, and drug stability were evaluated. In-vitro study showed that the release of danofloxacin mesylate (DFM) from microspheres was much slower than from the raw material (DFM) in the release medium. Pharmacokinetic characteristics were evaluated following intramuscular injection of DFM-GMS or DFM in pigs at dosage of 2.5 mg/kg body weight. Elimination half-life (t(1/2beta)) of the drug was 24.32 h for DFM-GMS, and 6.61 h for DFM (P < 0.01). Overall, DFM-GMS could be applied as a long-acting and lung targeting dosage form of DFM for clinical application. PMID- 19774479 TI - Soil-plant-animal continuum in relation to macro and micro mineral status of dairy cattle in subtropical hill agro ecosystem. AB - The purpose of the present study was to study the soil-plant-animal continuum in subtropical hilly areas. Soil (n = 96), fodder (n = 96), and blood serum samples from dairy cattle (n = 120) were collected from eight districts of Mizoram, a hilly state in India. The samples were digested using diacid mixture (HNO(3):HClO(4); 10:4) and analyzed for macro (Ca, P, Mg, Na, and K) and micro (Cu, Co, Mn, Fe, and Zn) mineral concentrations. The macro and micro mineral concentrations varied among the different districts. The correlation values between fodder and cattle were significant for all the minerals studied except for P and K. The correlation value between fodder and cattle was highly significant (P < 0.01) for Ca (0.878), Mg (0.88), Cu (0.885), and Zn (0.928). However, such correlations were not observed between the mineral levels in cattle and mineral levels in soil except for Ca (0.782). Equations developed in the present study for prediction of Ca (R(2) = 0.797), Mg (R(2) = 0.777), Zn (R(2) = 0.937), Fe (R(2) = 0.861), and Cu (R(2) = 0.794) had significant R(2) values. Further, it is inferred that dairy cattle reared under smallholder production system were deficient in most of the minerals and supplementation of required minerals is essential for optimum production. PMID- 19774480 TI - Gonadal dysfunction and infertility in kidney transplant patients receiving sirolimus. AB - Sirolimus is an immunosupressor of the mammalian target of rapamycin inhibitors (mTOR-I) group. Recent studies have emphasized a potential impact of sirolimus on male gonadal function. We report our clinical experience with sirolimus-induced gonadal dysfunction and infertility in both male and female kidney transplant patients. Of the 170 kidney transplant patients, nine (5.3%) patients (six males and three females) were receiving sirolimus. Follow-up data for two male patients were not available. The one unmarried female patient developed amenorrhea post transplantation and had resumption of her menstrual cycles after discontinuation of sirolimus. The remaining six married patients (four males and two females), who all had fathered or conceived children in the pre-transplantation period, developed gonadal dysfunction and infertility on average 5-12 months after transplantation. Sirolimus was discontinued in all four male patients with full recovery of the oligo/azospermia and restoration of fertility. Both married female patients developed amenorrhea post-transplantation. Sirolimus was discontinued in one female patient with resumption of her menstrual cycles. In this small population of patients treated with sirolimus, the prevalence rate of reversible gonadal dysfunction and infertility was significant in both males and females. Infertility secondary to sirolimus is under-diagnosed and should be studied further. PMID- 19774481 TI - Effect of melatonin on age induced changes in daily serotonin rhythms in suprachiasmatic nucleus of male Wistar rat. AB - The decline in physiological functions with aging may affect the ability of the SCN, the biological clock, circadian pacemaker to transmit rhythmic information to other neural target sites, and thereby modify the expression of biological rhythms resulting in circadian disorders. Neurotransmitter serotonin plays important role in the photic and non-photic regulation of circadian rhythms and is a precursor of neurohormone melatonin, an internal zeitgeber. To assess effects of aging on the functional integrity of circadian system, we studied daily serotonin rhythms in the SCN by measuring serotonin levels at variable time points in wide range of age groups such as 15 days, 1, 2, 3 (adult), 4, 6, 9, 12, 18 and 24 months old male wistar rats. Animals were maintained in light-dark conditions (LD; 12:12) two weeks prior to experiment. We report here that in 15 days, 1 and 2 months old rat SCN the mean serotonin level is low and daily serotonin rhythm is just beginning; at 3, 4 and 6 months, serotonin levels and rhythms are robust and at 9, 12, 18 and 24 months mean serotonin levels are low again and rhythm is becoming more disrupted. Previous studies have shown the 5-HT rhythmicity was established by 3 month in rat brain but disintegrated by 6 months of age. As melatonin, an endogenous synchronizer and an antiaging agent, declines with aging, the effects of exogenous melatonin administration on serotonin rhythmicity in SCN in 3, 6, 9 and 24 months old rats were studied to assess effects of aging on responsiveness to melatonin. Our studies indicated an age related loss of sensitivity to melatonin in the restoration of age induced changes in SCN serotonin amplitude and rhythmicity. PMID- 19774482 TI - Virgibacillus zhanjiangensis sp. nov., a marine bacterium isolated from sea water. AB - A Gram-positive, endospore-forming, catalase- and oxidase-positive, motile, rod shaped, aerobic bacterium, designated strain JSM 079157(T), was isolated from surface seawater off the coastline of Naozhou Island in South China Sea. The organism was able to grow with 1-15% (w/v) total salts (optimum, 4-7%), and at pH 6.0-10.0 (optimum, pH 7.5) and 10-45 degrees C (optimum, 30 degrees C). meso Diaminopimelic acid was present in the cell-wall peptidoglycan. The predominant menaquinone was MK-7, and the polar lipids were diphosphatidylglycerol and phosphatidylglycerol. The major cellular fatty acids were anteiso-C(15:0) (45.1%) and anteiso-C(17:0) (16.2%), and the DNA G + C content was 39.5 mol%. A phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that strain JSM 079157(T) should be assigned to the genus Virgibacillus, being related most closely to the type strains of Virgibacillus litoralis (97.4% sequence similarity), Virgibacillus necropolis (97.3%) and Virgibacillus carmonensis (97.1%). These four strains formed a distinct subcluster in the phylogenetic tree. The levels of DNA-DNA relatedness between the new isolate and the type strains of V. litoralis, V. necropolis and V. carmonensis were 30.4, 19.3 and 12.6%, respectively. The results of the phylogenetic analysis, combined with DNA DNA relatedness data, phenotypic characteristics and chemotaxonomic information, support the suggestion that strain JSM 079157(T) represents a new species of the genus Virgibacillus, for which the name Virgibacillus zhanjiangensis sp. nov. is proposed. The type strain is JSM 079157(T) (=DSM 21084(T) = KCTC 13227(T)). PMID- 19774483 TI - Survival mechanisms and culturability of Campylobacter jejuni under stress conditions. AB - Culture-based isolation and enumeration of bacterial human pathogens from environmental and human food samples has significant limitations.Many pathogens enter a viable but non-culturable(VBNC) state in response to stress, and cannot be detected via culturing methods. Favourable growth conditions with a source of energy and an ideal stoichiometric ratio of carbon to inorganic elements can reverse this VBNC state. This review will focus on the bacterium Campylobacter jejuni which is a leading cause of food borne illness in the developed world. C. jejuni can enter a VBNC state in response to extremes in: pH, moisture content, temperature,nutrient content and salinity. Once in a VBNC state,the organism must maintain an energy balance from substrate oxidation through respiration to grow,divide and remain viable. The goal of this review isa greater understanding of how abiotic stress and thermodynamics influence the viability of C. jejuni. PMID- 19774484 TI - Constriction infection. AB - Chronic constrictive pericarditis (CCP) is a clinical syndrome caused by compression of the heart due to a thickened or rigid pericardium. In the affluent West, the majority of cases of CCP are neither tuberculous nor calcific. In an American cohort undergoing pericardectomy for the condition, only 27% had calcification and under 10% had TB [1]. As a result, pericardial calcification (PC) as a marker of CCP has become neglected. We present a 48-year-old male admitted with atrial flutter, acute chest infection and signs of right heart congestion. PC was documented one year previously on a non-contrast CT chest. On this occasion, cardiac catheterisation confirmed hemodynamically significant CCP and cardiac magnetic resonance (cMR) study showed contiguous mass lesions in the pericardium, compression of the right ventricle, enlargement of the right atrium, hepatic enlargement and a pneumonic process in the left lung. He was commenced on antibiotics and anti-tuberculous therapy with a diagnosis of bacterial super infection of tuberculous CCP. This was confirmed at pericardectomy along with an infected fistula into the left lung. Any finding of PC should be followed up with a thorough haemodynamic and anatomical assessment using any of a wide range of non-invasive imaging modalities. PMID- 19774485 TI - Quantitative image analysis for the detection of motion artefacts in coronary artery computed tomography. AB - Multi detector-row CT (MDCT), the current preferred method for coronary artery disease assessment, is still affected by motion artefacts. To rule out motion artefacts, qualitative image analysis is usually performed. Our study aimed to develop a quantitative image analysis for motion artefacts detection as an added value to the qualitative analysis. An anthropomorphic moving heart phantom with adjustable heart-rate was scanned on 64-MDCT and dual-source-CT. A new software technique was developed which detected motion artefacts in the coronaries and also in the myocardium, where motion artefacts are more apparent; with direct association to the qualitative analysis. The new quantitative analysis managed to detect motion artefacts in phantom scans and relate them to artefact-induced vessel stenoses. Quantifying these artefacts at corresponding locations in the myocardium, artefact-induced vessel stenosis findings could be avoided. In conclusion, the quantitative analysis together with the qualitative analysis rules out artefact-induced stenosis. PMID- 19774486 TI - Inhibition of Candida albicans biofilm formation by antimycotics released from modified polydimethyl siloxane. AB - Unlike various disinfectants, antifungals have not been commonly incorporated so far in medical devices, such as catheters or prostheses, to prevent biofilm formation by Candida spp. In the present study, five antimycotics were added to polydimethyl siloxane (PDMS) disks via admixture (nystatin) or impregnation (trimethylsilyl-nystatin (TMS-nystatin), miconazole, tea tree oil (TTO), zinc pyrithione). Nystatin-medicated PDMS disks exhibited a concentration-dependent inhibitory effect on biofilm formation in a microtiter plate (MTP) but not in a Modified Robbins Device (MRD). This observation, together with HPLC data and agar diffusion tests, indicates that a small fraction of free nystatin is released, which kills Candida albicans cells in the limited volume of a MTP well. In contrast, biofilm inhibition amounted to more than one log unit in the MRD on disks impregnated with miconazole, TTO, and zinc pyrithione. It is hypothesized that the reduction in biofilm formation by these compounds in a flow system occurs through a contact-dependent effect. PMID- 19774487 TI - Toothbrush contamination by Candida spp. and efficacy of mouthrinse spray for their disinfection. AB - The aim of the study was to evaluate toothbrush contamination in vivo by Candida spp. and the efficacy of Periogard and Neem Sattiva, in spray, in the disinfection of these toothbrushes. This study was performed in three phases in which mouthrinses and sterile distilled water (control group) were sprayed six times on toothbrush bristles used by 61 university students. Toothbrushes were then submitted to microbiological processing for the isolation and identification of Candida species. Fifty-nine students completed the three phases of this study, and 22 (37.3%) control group toothbrushes presented growth of Candida species. Periogard and Neem Sattiva eliminated growth of Candida spp. in 48.1 and 7.4% of toothbrushes, respectively. Contamination by Candida spp. was observed on various toothbrushes of the control group. Periogard was more efficacious than Neem Sattiva in eliminating growth of Candida spp. on the toothbrush bristles. PMID- 19774488 TI - Polymorphism of chicken myocyte-specific enhancer-binding factor 2A gene and its association with chicken carcass traits. AB - Myocyte-specific enhancer-binding factor 2A (MEF2A) gene is a member of the myocyte-specific enhancer-binding factor 2 (MEF2) protein family which involved in vertebrate skeletal muscle development and differentiation. The aim of the current study is to investigate the potential associations between MEF2A gene SNPs (single nucleotide polymorphisms) and the carcass traits in 471 chicken samples from four populations. Three new SNPs (T46023C, A72626G, and T89232G) were detected in the chicken MEF2A gene. The T46023C genotypes were associated with live body weight (BW), carcass weight (CW), eviscerated weight, semi eviscerated weight (SEW), and leg muscle weight (LMW) (P < 0.05); the A72626G genotypes were associated with BW, CW, LMW (P < 0.01) and breast muscle weight (BMW), leg muscle percentage (LMP) (P < 0.05); whereas the T89232G genotypes were associated with carcass percentage (CP) and semi-eviscerated percentage (SEP) (P < 0.05). The haplotypes constructed on the three SNPs were associated with BW, CW, LMW (P < 0.01), SEW, BMW, CP (P < 0.05). Significantly and suggestive dominant effects of diplotype H1H2 were observed for BW, CW, SEW, BMW and CP, whereas diplotype H5H5 had a negative effect on BW, CW, SEW, BMW and LMW. Our results suggest that the MEF2A gene may be a potential marker affecting the muscle trait of chickens. PMID- 19774489 TI - Modified low density lipoproteins binding requires a lysine cluster region in the murine macrophage scavenger receptor class A type II. AB - Atherosclerosis is a consequence of lipid deposition and foam cell formation in the arterial wall. Macrophage scavenger receptor A II is involved in the uptake of modified low density lipoproteins. It contains an extracellular conserved lysine cluster which has been proposed to form a positively charged groove that interacts with acetylated low density lipoproteins (AcLDL). This study evaluated the role of the murine SRA-II and a lysine mutated SRA-II on AcLDL uptake. Fluorescence labeled AcLDL uptake was quantified using a Laser Scan Cytometer. A significant increase in fluorescence uptake was found in the cells transfected with SRA-II versus those with empty vector. Cells expressing the lysine mutated SRA-II also demonstrated a significant decrease in their uptake of AcLDL. This data supports the concept that the conserved lysine cluster in murine SRA-II is the binding region for AcLDL or contributes to the trimeric structure of SRA-II necessary for AcLDL binding. PMID- 19774490 TI - Tissue-specific expression of the chicken adipose differentiation-related protein (ADP) gene. AB - Adipose differentiation-related protein gene (ADP) plays an important role in controlling lipid accumulation in mammals. It may also affect lipid deposition in birds. However, the molecular mechanism of its actions in birds remains unknown. In the present study, the coding sequence of ADP cDNA for Chinese native breed Sichuan Mountainous Black-bone chicken (MB) was first cloned from abdominal fat using reverse transcription-PCR (RT-PCR). This putative MB ADP cDNA (1,881 bp) encodes an open reading frame of 438 amino acids (AA) and shares high AA sequence identity with that of red jungle fowl (99%), duck (92%), house mouse (70%), human (70%), chimpanzee (70%), pig (70%), domestic cow (69%) and domestic sheep (68%). Further analysis using bioinformatics shows the deduced MB ADP protein has the typical characters of PAT (Perilipin, Adipophilin and Tip47) family. Quantitative real-time PCR (qRT-PCR) analysis revealed that ADP expresses in chicken leg muscle, whole brain, heart, liver, pectoralis muscle, abdominal fat and subcutaneous fat. Ontogenetic expression studies shows ADP expression levels in abdominal fat, subcutaneous fat and pectoralis muscle were prior to that in leg muscles at posthatch day (P) 84. But, its levels in abdominal fat and subcutaneous fat were less than that in leg muscles at P28, 42, 56 and 70, respectively. The ADP expression levels in subcutaneous fat and abdominal fat were stable from P28 to P70 and both were less than their counterparts at P84. However, it changed greatly in pectoralis muscle, liver, brain, heart and leg muscle at all points. Patterns of ADP expression suggest that ADP plays an important role in fat development, but further study is needed to reconfirm its function in a large population and in other breeds with different genetic backgrounds. PMID- 19774491 TI - Isolation and expression analysis of tuberous root development related genes in Rehmannia glutinosa. AB - As one kind of important modified storage organs, tuberous roots are attractive for their economic and biological values. Although considerable progresses have been made in the past, molecular information regarding the tuberous root development is still limited. In this study, we focused on the molecular profiling of the tuberous root development of Rehmannia glutinosa. Suppression subtractive hybridization technology was employed to compare gene expression between adventitious root and developing tuberous root. As a result, a tuberous root subtractive library was constructed and 199 development-related unique expressed sequence tags were identified, which represent different groups of genes involved in metabolism, protein synthesis, protein fate, cell fate, signaling, transcription and development, etc. In order to further validate the obtained result, 18 genes were selected for expression analysis and the genes most likely being involved in tuberous root development were discussed. Our present study provided the first molecular profiling of tuberous root development related genes in Rehmannia glutinosa, which will establish the basis for future deciphering the tuberous root development mechanism. PMID- 19774492 TI - A single-nucleotide polymorphism of the TNFAIP3 gene is associated with systemic lupus erythematosus in Chinese Han population. AB - Systemic lupus erythematosus (SLE) is a complex systemic disease influenced by genetic and environmental factors. The exact pathogenesis of SLE is still unknown. Recently, several genome-wide association studies (GWA) in European population have found many novel susceptibility genes for SLE including TNFAIP3. In order to examine whether TNFAIP3 is associated with SLE in Chinese Han population, we genotyped one of its non-synonymous mutation SNP rs2230926, showing significant association evidence with SLE in European population, with 1,420 cases and 4,461 controls of Chinese Han by using Sequenom MassArray system. Highly significant association between SNP rs2230926 and SLE of Chinese Han was detected [OR = 1.65, 95% confidence interval (CI): 1.392-1.986, P = 2.03 x 10( 8)]. Interestingly, rs2230926 of TNFAIP3 was also associated with arthritis, ANA and some other subphenotypes of the disease. Our findings suggest that SNP rs2230926 in the TNFAIP3 might be a common genetic factor for SLE within different populations in terms of Chinese Han and European population. PMID- 19774494 TI - NMR assignments of the FK506-binding domain of FK506-binding protein 35 from Plasmodium vivax. AB - PvFKBP35 is a member of the FK506 binding protein family (FKBP) from Plasmodium vivax. The FK506-binding domain of PvFKBP35 shows a canonical peptidylprolyl cis trans isomerase (PPIase) activity. To understand the role of PvFKBP35 in the parasite, we have performed NMR studies. Here, we report the assignment of the FK506-binding domain of PvFKBP35. PMID- 19774493 TI - Age and gender differences in health-related quality of life of children and adolescents in Europe: a multilevel analysis. AB - OBJECTIVES: To determine age and gender differences in health-related quality of life (HRQOL) in children and adolescents across 12 European countries using a newly developed HRQOL measure (KIDSCREEN). METHODS: The KIDSCREEN-52 questionnaire was filled in by 21,590 children and adolescents aged 8-18 from 12 countries. We used multilevel regression analyses to model the hierarchical structure of the data. In addition, effect sizes were computed to test for gender differences within each age group. RESULTS: Children generally showed better HRQOL than adolescents (P < 0.001). While boys and girls had similar HRQOL at young age, girls' HRQOL declined more than boys' (P < 0.001) with increasing age, depending on the HRQOL scale. There was significant variation between countries both at the youngest age and for age trajectories. CONCLUSIONS: For the first time, gender and age differences in children's and adolescents' HRQOL across Europe were assessed using a comprehensive and standardised instrument. Gender and age differences exist for most HRQOL scales. Differences in HRQOL across Europe point to the importance of national contexts for youth's well-being. PMID- 19774496 TI - Interleukin-1 mediates long-term hippocampal dentate granule cell loss following postnatal viral infection. AB - Viral infections of the developing CNS can cause long-term neuropathological sequela through undefined mechanisms. Proinflammatory cytokines such as IL-1beta have gained attention in mediating neurodegeneration in corticohippocampal structures due to a variety of insults in adults, though there is less information on the developing brain. Little is known concerning the spatial temporal pattern of IL-1beta induction in the developing hippocampus following live virus infection, and there are few studies addressing the long-term consequences of this cytokine induction. We report that infection of rats with lymphocytic choriomeningitis virus on postnatal day 4 induces IL-1beta protein in select regions of the hippocampus on 6, 15, 21, and 45 days after infection. This infection resulted in a 71% reduction of dentate granule cell neurons by the time the rats reached mid-adulthood. We further investigated the causative role of IL 1 in this dentate granule cell loss by blocking IL-1 activity using an IL-1ra expressing adenoviral vector administered at the time of infection. Blockade of IL-1 abrogated the infection-associated neuron loss in this vivo model. Considering that IL-1 can be triggered by multiple perinatal insults, our findings suggest that early therapy with anti-inflammatory agents that block IL-1 may be effective for reducing adulthood neuropathology. PMID- 19774498 TI - Polyneuropathy associated with cholesterol crystal embolism. AB - INTRODUCTION: Cholesterol crystal embolism complicating arterial catheterization usually presents as a multiorgan disease with renal failure, abdominal problems, and skin manifestations. METHODS: We present a patient with hypertension and generalized arteriosclerosis who presented with muscle weakness, diffuse pain in the extremities, and renal failure 3 weeks after coronary catheterization and angioplasty of the right coronary artery. Muscle weakness progressed during the following months. RESULTS: Nerve conduction studies and nerve biopsy showed severe axonal nerve injury. Biopsy of the kidney revealed the diagnosis of cholesterol crystal embolism. CONCLUSION: The clinical presentation indicates a direct association of cholesterol crystal embolism and polyneuropathy. Although cholesterol crystal embolism represents a rare cause of polyneuropathy, it should be considered in patients with acute onset polyneuropathy and sudden onset multiorgan disease after arterial catheterization. PMID- 19774499 TI - Clinicopathological characterization of TSH-producing adenomas: special reference to TSH-immunoreactive but clinically non-functioning adenomas. AB - Thyrotropin (thyroid-stimulating hormone (TSH))-producing pituitary adenomas have been known to be quite variable in clinical features covering from typical functioning TSH-producing adenomas (FTSHomas) associated with hyperthyroidism to clinically silent TSH cell adenomas (STAs) that are apparently unassociated with hyperthyroidism. It is important to distinguish STAs from other types of clinically non-functioning adenomas for adequate postoperative managements. However, because of rareness of TSH-producing adenomas, their histopathological features linking to the clinical manifestations have not been well characterized. Herein, we investigated clinical and histopathological findings to characterize 29 TSH-producing adenomas including 20 FTSHomas and nine STAs. Clinical symptoms of the patients with STAs included headache, visual defect, vertigo, and nausea. All STAs and 19 FTSHomas were macroadenoma. The average tumor size of STAs was significantly larger than that of FTSHomas (P < 0.05). The invasiveness was detected in 33% STAs and in 20% FTSHomas. Both STAs and FTSHomas showed a variety of morphological features and immunohistochemical profiles. Chromophobic polygonal or short-spindled tumor cells usually proliferated in a diffuse pattern, while they exhibited globoid or whorl-like appearance with intertwined cytoplasmic processes in both subgroups. Stromal fibrosis and calcification were often noted. Their nuclei were somehow pleomorphic. Ultrastructural features of all four STAs examined were similar to those of normal thyrotrophs. Thus, STAs and FTSHomas were indistinguishable by histology alone. Immunohistochemically, the number of TSH-positive cells in individual FTSHomas was highly various. Six tumors showed only a few TSH-positive cells (1-5%), and three were negative for TSH by conventional method without antigen retrieval. After proteinase K treatment, these tumors turned out TSH positive. As defined, STAs were TSH positive in more than 20% of tumor cells and three of them in more than 50%. Growth hormone- and/or prolactin-positive cells were detected in 55% STAs and 63% FTSHomas. Both pituitary-specific transcription factor 1 and GATA-binding protein 2 were expressed in all STAs and 20 FTSHomas. Membranous somatostatin receptor (SSTR)-2A immunoreactivity was found in 89% STAs and 94% FTSHomas, whereas SSTR5 was positive in 78% of both STAs and FTSHomas. MIB-1 labeling index was related to tumor invasiveness and tumor size (P < 0.05, P = 0.09, respectively). Thus, although both STAs and FTSHomas showed unique histopathological features distinct from other type adenomas, these two subgroups were indistinguishable by histopathology. Immunohistochemistry for TSH by use of antigen retrieval, transcription factors, and SSTRs may be useful to confirm STAs and to determine the postoperative therapy among various kinds of clinically non-functioning adenomas. PMID- 19774497 TI - Immunomodulatory therapies in neurologic critical care. AB - INTRODUCTION: Neurologic disorders with autoimmune dysregulation are commonly encountered in the critical care setting. Frequently encountered diseases include Guillain-Barre syndrome (GBS), myasthenia gravis, multiple sclerosis, acute demyelinating encephalomyelitis, and encephalitides. Immunomodulatory therapies, including high-dose corticosteroids, plasmapheresis, and intravenous immunoglobulins, are the cornerstone of the treatment of these diseases. Here we review the efficacy and side effects of immunomodulatory therapies commonly utilized in critically ill neurologic patients in the intensive care setting. METHODS: Search of Medline, Cochrane databases, and manual review of article bibliographies. RESULTS: The efficacy of high-dose corticosteroids, plasmapheresis, and intravenous immunoglobulins have been studied extensively in GBS, myasthenia gravis, and demyelinating disorders such as multiple sclerosis and acute demyelinating encephalomyelitis. For these diseases, however, the duration of treatment, dosing regimens, and choices among different therapeutic modalities remain controversial. For many of the other diseases (e.g., encephalitis and status epilepticus of autoimmune etiology) discussed in this review, evidence is limited to small case series. CONCLUSIONS: There is good evidence for the efficacy and tolerability of immunomodulatory therapies in GBS, myasthenia gravis, and acute central nervous system demyelination, though data to establish superiority of one therapeutic regimen over another remains lacking. For most other conditions, the data for immunomodulatory therapies are limited, and further research is required. PMID- 19774500 TI - Serum levels of CEA and CA 15-3 in triple-negative breast cancer at the time of diagnosis. PMID- 19774501 TI - Interaction between fatness and fitness on CVD risk factors in Asian youth. AB - The purpose of this study was to investigate the effects of fatness and fitness on insulin resistance (IR) and cardiovascular disease (CVD) risk factors among Korean adolescents. A total of 322 male high school students participated Departme nt of Sport and Leisure Studies, Yonsei University, Seoup, Republic of Korea Department of Sport and Leisure Studies, Yonsei University, Seoup, Republic of Korea in the cross-sectional part of the study. To determine the interaction of fatness and fitness levels on IR and CVD risk factors, subjects were stratified into four groups based on their body mass index (BMI) and cardio respiratory fitness. Subjects who were in the high-fat category had significantly higher IR and CVD risk score than subjects in the low-fat category regardless of their fitness level. Subjects who were in high-fat-high-fit group showed significantly lower IR and CVD risk score than high-fat-low-fit group. Twenty nine obese and unfit subjects participated in the intervention study. Twelve weeks of exercise training significantly reduced body weight (4.11+/-0.75 kg) and improved VO(2max) which resulted in a significant improvement in IR and CVD risk score (2.16+/-0.62 vs. 0.20+/-0.75). Interestingly, improvement in cardio respiratory fitness and small reduction in body weight in relatively short-term significantly reduced the CVD risk score to the level of low-fat-low-fit subjects. Our results show the importance of fitness in determining IR and CVD risk factors among obese adolescents. PMID- 19774502 TI - The effect of ischemic preconditioning on secondary ischemia in myocutaneous flaps. AB - We sought to determine the effect of ischemic preconditioning (IPC) on secondary ischemia in myocutaneous flaps in a rat model. Forty rectus abdominis myocutaneous flaps were elevated in 40 rats, and the animals were randomized into control or IPC groups (20 flaps each group). All flaps were then subject to primary ischemia for 2 hours via pedicle clamping. Twenty-four hours later, the control and IPC flaps were randomized to two groups each of 1 or 2 hours of secondary ischemia (4 groups, 10 flaps per group). Flap survival was evaluated on postoperative day 5 by measuring the percentage area of flap survival by a blinded observer. Mean flap survival area and total necrosis rates were compared between the groups. In the 1-hour secondary ischemia groups, IPC improved mean flap survival area from 11 +/- 7% to 36 +/- 22%, and the total necrosis rates from 40 to 0%. These differences were statistically significant (p < 0.006, p < 0.05, respectively). In the 2-hour secondary ischemia groups, differences were not statistically significant (p = 0.2, p = 0.4, respectively). IPC improves the survival of myocutaneous flaps subjected to secondary ischemia of 1 hour in this rat free flap model. PMID- 19774503 TI - Cost analysis of 109 microsurgical reconstructions and flap monitoring with microdialysis. AB - Few studies have examined the cost-effectiveness of microsurgery, and little is known about the cost-effectiveness of flap monitoring. We studied the costs related to microsurgery during 2004 to 2006 in Kuopio University Hospital. A total of 99 patients were reconstructed with 109 flaps. Primary success was achieved in 64% of cases. Reoperation for anastomosis was conducted in 25% and for other surgical complications in 27%. The intended result was achieved in 94% of cases. The mean total cost of hospital care was 20,000 euro in head and neck cancer surgery, 15,500 euro in defects of the lower extremities, and 9200 euro in breast reconstruction. The costs were greatly influenced by surgical complications (i.e., if the primary reconstruction failed, then the secondary microvascular flap almost doubled the expense involved; mean expenses per case 27,900 euro). Microdialysis was used in flap monitoring with an additional cost of 535 euro per patient. We found that microdialysis provided an early diagnosis of perfusion failure and helped to save the flap. It was estimated that if one or two flaps per year are saved due to more effective monitoring, then the extra costs of using microdialysis are covered. PMID- 19774504 TI - Herb-drug interactions: in vivo and in vitro effect of Shenmai injection, a herbal preparation, on the metabolic activities of hepatic cytochrome P450 3A1/2, 2C6, 1A2, and 2E1 in rats. AB - Shenmai injection (SMI), a mixture of Radix Ginseng and Radix Ophiopogonis, is one of the most popular herbal medicinal products and is widely used for the treatment of coronary atherosclerotic cardiopathy and viral myocarditis. The purpose of this study was to investigate the effect of SMI, in vivo and in vitro, on the metabolic activities of hepatic cytochrome CYP450 3A1/2, 2C6, 2E1, and 1A2 in rats. After a single or multiple pretreatment with SMI, the rats were administrated intravenously a cocktail containing midazolam (1 mg/kg), diclofenac (0.5 mg/kg), theophylline (1 mg/kg), and chlorzoxazone (0.5 mg/kg) as probe substrates of rat CYP450 3A1/2, 2C6, 1A2, and 2E1, respectively. Single and multiple SMI pretreatment to rats resulted in a rise of 33.8 % (p < 0.01) and 25.6 % (p < 0.01) in AUC for midazolam, and an increase in AUC for diclofenac by 14.7 % (p < 0.05) and 31.2 % (p < 0.01), respectively. However, the pharmacokinetics of chlorzoxazone and theophylline in rats was not altered markedly. In rat liver microsomes, linear mixed-type inhibition of SMI against the enzyme activities of CYP3A1/2, CYP2C6, and CYP1A2 was shown with IC(50) values of 3.3 %, 2.0 %, and 3.1 % and K(i) values of 3.8 %, 1.5 %. and 1.9 %, respectively. These in vivo and in vitro results demonstrated that SMI had the potential to inhibit the activities of hepatic CYP3A1/2 and CYP2C6, but might not significantly affect CYP1A2 and CYP2E1-mediated metabolism in rats. PMID- 19774505 TI - Cryptotanshinone, an acetylcholinesterase inhibitor from Salvia miltiorrhiza, ameliorates scopolamine-induced amnesia in Morris water maze task. AB - Alzheimer's disease (AD) is a common form of dementia which is characterized by the deposition of amyloids in affected neurons and a cholinergic neurotransmission deficit in the brain. The current therapeutic intervention for AD is primarily based on the inhibition of brain acetylcholinesterase (AChE) to restore the brain acetylcholine level. Cryptotanshinone (CT) is a diterpene extracted from the root of Salvia miltiorrhiza, a herb that is commonly prescribed in Chinese medicine to treat cardiovascular disease. In the present study, we demonstrated that CT is an inhibitor of both human acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) with IC(50) values of 4.09 and 6.38 microM, respectively. The IC(50) ratio of CT for BuChE:AChE was 1.56. CT inhibited human AChE in a reversible manner, and the inhibition showed the characteristics of mixed-type as both the KM and V(max) were affected by CT. The effect of CT on learning impairment in scopolamine-treated rats was also evaluated by the acquisition protocol of the Morris water maze. The task learning ability of scopolamine-treated rats was significantly reversed by CT (5 mg/kg), and the CT-fed rats were able to develop a spatial searching strategy comparable to that of the control animals. In addition, chronic CT treatment did not cause hepatotoxicity as measured by blood alanine transferase (ALT) level. Our findings demonstrate the ability of CT to improve task learning in rats with scopolamine induced cognitive impairment. These results suggest that CT has the potential as a therapeutic drug for treating AD. PMID- 19774506 TI - Anti-inflammatory effects of madecassic acid via the suppression of NF-kappaB pathway in LPS-induced RAW 264.7 macrophage cells. AB - We have investigated the anti-inflammatory effects of madecassic acid and madecassoside isolated from Centella asiatica (Umbelliferae) on lipopolysaccharide (LPS)-stimulated RAW 264.7 murine macrophage cells. Both madecassic acid and madecassoside inhibited the production of nitric oxide (NO), prostaglandin E(2) (PGE(2)), tumor necrosis factor-alpha (TNF-alpha), interleukin 1 beta (IL-1beta), and IL-6. However, madecassic acid more potently suppressed these inflammatory mediators than did madecassoside. Consistent with these observations, madecassic acid inhibited the LPS-induced expression of iNOS and COX-2 at the protein level and of iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6 at the mRNA level in RAW 264.7 macrophage cells, as determined by Western blotting and RT-PCR, respectively. Furthermore, madecassic acid suppressed the LPS-induced activation of nuclear factor-kappaB (NF-kappaB), and this was associated with the abrogation of inhibitory kappa B-alpha (IkappaB-alpha) degradation and with the subsequent blocking of p65 protein translocation to the nucleus. These results suggest that the anti-inflammatory properties of madecassic acid are caused by iNOS, COX-2, TNF-alpha, IL-1beta, and IL-6 inhibition via the downregulation of NF-kappaB activation in RAW 264.7 macrophage cells. PMID- 19774507 TI - Screening of five essential oils for identification of potential inhibitors of IL 1-induced Nf-kappaB activation and NO production in human chondrocytes: characterization of the inhibitory activity of alpha-pinene. AB - Nuclear factor-kappaB is a key transcription factor activated by pro-inflammatory signals, like interleukin-1beta (IL-1), being required for the expression of many inflammatory and catabolic mediators, such as nitric oxide (NO), that play an important role in arthritic diseases. This work aimed at screening and identifying natural inhibitors of IL-induced NF-kappaB activation and NO production in human articular chondrocytes. Five essential oils obtained from four plants of the Iberian flora, Mentha x piperita L. (Lamiaceae), Origanum virens L. (Lamiaceae), Lavandula luiseri L. (Lamiaceae), and Juniperus oxycedrus L. subsp. oxycedrus (Cupressaceae), were screened for their ability to prevent IL 1-induced NO production. The oil showing higher inhibitory activity was fractionated, concentrated, analyzed for composition elucidation and prepared for further assays. For this purpose, the human chondrocytic cell line C-28/I2 was used to evaluate NF-kappaB activation by determining the cytoplasmic levels of the total and phosphorylated forms of the inhibitory protein, I kappaB-alpha, and the NF-kappaB-DNA binding activity. The essential oil from the leaves of J. oxycedrus in a concentration of 0.02 % (v/v) achieved the greatest inhibition (80 +/- 8%) of IL-1-induced NO production. Chemical analysis showed that this essential oil is predominantly composed of monoterpene hydrocabons, being alpha pinene [2,6,6-trimethyl-bicyclo(3.1.1)hept-3-ene] the major constituent (76 %). Similarly to the effect of the whole oil, a fraction containing 93% alpha-pinene reduced significantly IL-1-induced I kappaB-alpha degradation. Moreover, alpha pinene also decreased I kappaB-alpha phosphorylation, NF-kappaB-DNA binding activity, and NO production. Another fraction containing oxygenated mono- and sesquiterpenes was nearly as effective as alpha-pinene. The ability of the alpha pinene-containing fraction to reduce IL-1-induced NF-kappaB activation and NO production warrants further studies to demonstrate the usefulness of alpha-pinene in the treatment of arthritic diseases and other conditions in which NF-kappaB and NO play pathological roles. PMID- 19774508 TI - Sesquiterpene lactone parthenolide markedly enhances sensitivity of human A549 cells to low-dose oxaliplatin via inhibition of NF-kappaB activation and induction of apoptosis. AB - Aberrant activation of NF-kappaB has been proposed as the major cause of chemoresistance in lung cancer. Low-dose chemotherapeutic agents with limited toxicity and achieving profoundly enhanced efficacy by blocking NF-kappaB activation may be a useful strategy in cancer therapy. Thus, this study was performed to explore the effect of parthenolide, a natural NF-kappaB inhibitor, on human lung cancer A549 cells treated with low-dose oxaliplatin, as well as to determine the potential mechanisms involved. We incubated A549 cells with different concentrations of parthenolide in the absence or presence of a low-dose of oxaliplatin for 48 h. Then, cell proliferation was determined by MTT assay, and flow cytometry was used to study apoptosis. PGE(2) production in culture supernatants was detected by competitive ELISA, while expression of NF kappaB/p65, COX-2, caspase-3 and caspase-9 proteins were analyzed by Western blot. Finally, compared to parthenolide or oxaliplatin alone, significant improvements in cell apoptosis and growth inhibition indexes were observed in the combined treatment. NF-kappaB/p65, COX-2, and PGE(2) expression were suppressed by the co-application; meanwhile, caspase-3 and caspase-9 proteins were obviously activated. These findings indicate that parthenolide could markedly enhance sensitivity of A549 cells to low-dose oxaliplatin by inhibiting NF-kappaB activation and inducing apoptosis. Parthenolide in combination with a low dose of oxaliplatin may be a beneficial chemotherapeutic strategy for patients who cannot tolerate the severe side effects of the drug at therapeutic concentrations. PMID- 19774509 TI - Evaluation of the antiangiogenic, anti-inflammatory, and antinociceptive activities of morin. AB - Morin displayed significant inhibition of chick chorioallantoic membrane (CAM) angiogenesis and was able to increase the endostatin level in human umbilical vein endothelial cells (HUVECs). Morin was shown to contain an in vivo anti inflammatory activity using a carrageenan-induced air pouch model in mice. Antinociceptive activity of morin was also assessed using an acetic acid-induced writhing test in mice. Collectively, morin possesses antiangiogenic, in vivo anti inflammatory, and antinociceptive activities. PMID- 19774510 TI - [Weight loss]. PMID- 19774511 TI - [What is your diagnosis? Reversible hydronephrosis due to impacted feces]. PMID- 19774512 TI - [Comment on rule of thumb 5 in PRAXIS no. 13]. PMID- 19774513 TI - [Diagnosis of coronary artery disease--part 1: general approach]. AB - Tests for the diagnosis of coronary artery disease (CAD) rely on two main diagnostic principles, that is direct visualisation of coronary anatomy or detection of stress-induced myocardial ischaemia. Whether a given test is useful for the patient's management critically depends on the clinical context, that is pre-test probability for significant CAD. Not every test is suitable for every patient. Non-invasive tests have the highest diagnostic yield in patients with chest pain and intermediate pre-test probability. In these patients, tests typically confirm the presence of CAD or make it highly unlikely. In patients with low or high pre-test probability, non-invasive tests provide hardly any added diagnostic information. However, in patients with high pre-test probability of CAD, non-invasive tests are helpful for risk stratification. In asymptomatic patients, there is no established indication for any tests apart from calculation of a global cardiovascular risk based on traditional risk factors and initiation of primary preventive measures if appropriate. PMID- 19774514 TI - [Diagnosis of coronary artery disease - part 2: Exercise electrocardiogram and myocardial perfusion scintigraphy]. AB - The principle of exercise stress test and myocardial perfusions scintigraphy (MPS) is based on the detection of exercise-induced myocardial ischaemia by ECG and non-invasive assessment of myocardial perfusion respectively, MPS being the more sensitive method. The exercise stress test is the method of choice in patients with a normal resting ECG and good exercise tolerance, whereas MPS is a suitable test for patients with abnormal resting ECG and/or exercise intolerance. Stressors for MPS included exercise, pharmacological stress, or a combination. Both exercise stress test and MPS are suitable for the evaluation of patients with chest pain and intermediate pre-test probability of significant coronary artery disease. For patients with high pre-test probability, both tests are helpful for risk stratification. Neither test makes sense for the evaluation of patients with chest pain and low pre-test probability of significant coronary artery disease or unselected asymptomatic patients. PMID- 19774515 TI - [Diagnosis of coronary artery disease - part 3: Stress echocardiography and cardiac magnetic resonance imaging]. AB - The diagnostic principle of stress echocardiography and cardiac magnetic resonance imaging (CMR) for the diagnosis of coronary artery disease is based on the visualisation of ischaemia-induced wall motion abnormalities. From a logistic point of view, stress echocardiography is the easiest test given that it can be performed at bedside. Both stress echocardiography and stress CMR also permit direct visualisation of myocardial perfusion at rest and during pharmacological stress (typically adenosine) using contrast administration (microbubbles for stress echocardiography, gadolinium for stress CMR). These novel methods for the visualisation of myocardial perfusion seem to provide information similar to that obtained using myocardial perfusion imaging but these techniques (particularly myocardial perfusion echocardiography) are not broadly established in daily practice yet. Similar to other non-invasive tests stress echocardiography and stress CMR have the highest diagnostic yield in patients with intermediate probability of significant coronary artery disease. PMID- 19774516 TI - [Diagnosis of coronary artery disease - part 4: Computed tomography and coronary angiography]. AB - Invasive coronary angiography and computed tomography (CT) coronary angiography directly visualise coronary anatomy but do not provide information about the presence of inducible myocardial ischaemia. Due to its excellent negative predictive value CT coronary angiography is a suitable test to exclude significant coronary artery disease. However, given its high rate of false positive results particularly in the presence of significant coronary calcification CT coronary angiography only rarely is a real alternative to invasive coronary angiography in clinical practice. The coronary artery calcium score (CACS) is a surrogate for the extent of coronary atherosclerosis and a possible marker of biological age but does not provide any anatomical or pathophysiological information. In asymptomatic patients a CACS of zero is associated with a very low likelihood of a significant coronary stenosis and a good prognosis. However, this is not the case in symptomatic patients, and thus, CACS does not play a significant role in the diagnostic work-up in symptomatic patients in daily routine. PMID- 19774517 TI - [Transient ischemic attacks]. PMID- 19774518 TI - [Odynophagia of a young mother]. AB - We report the case of a 34-year old mother presenting in the emergency unit because of fever and odynophagia. Herpetic esophagitis with Herpes simplex virus primoinfection in a immunocompetent patient was diagnosed. The virus was transmitted by her own child which came to be hospitalised because of herpetic stomatitis. In the blood chemistry pancreas enzymes were elevated which we interpreted as herpetic pancreatitis because of coincidence with herpetic esophagitis. PMID- 19774519 TI - [Solitary pulmonary nodule]. AB - Primary pulmonary amyloidosis is rare. Three patterns of involvement have been described: tracheobronchial, nodular and diffuse parenchymal. The nodular parenchymal amyloid deposits are often multiple, much less common focal. We hereby present a case of a 70 year old patient, a former smoker, with coincidentally diagnosed solitary, pulmonary nodule, a rather common finding in CT. The list of differential diagnosis is long, as shown above, the amyloidosis is a quite uncommon cause, but it should be kept in mind. PMID- 19774523 TI - [CME ultrasound diagnosis 30. Mature teratoma]. PMID- 19774524 TI - [Medical sculpture mystery. Images from travel II. An ideal physician. Guy de Chauliac, Francois Rabelais and others]. PMID- 19774525 TI - [Medical art column. Dream-like metamorphosis]. PMID- 19774526 TI - [Quality of life in Alzheimer's disease]. AB - INTRODUCTION: Quality of life is a concept that is receiving increasing amounts of attention; its assessment complements the traditional clinical evaluation, which is of special interest in areas related with healthcare organisation. Here, we present a study on quality of life in Alzheimer's disease and its relationship with cognitive and functional measures. PATIENTS AND METHODS: Quality of life was evaluated by means of the EQ-5D scale in a sample of cases of Alzheimer's disease (diagnosed according to criteria established by the National Institute of Neurologic, Communicative Disorders and Stroke-Alzheimer's Disease and Related Disorders Association) that donated blood samples for the National DNA Bank. The status of the global deterioration scale was determined and a verbal fluency test and the Folstein minimental test were also carried out. A classic analysis, variable contrast by means of chi-square for proportions and Student's t test for measurements were conducted, as well as estimation of r for the regression models in the quantitative variables. The social rate was determined using the software application SPSS v. 11. RESULTS: Altogether 141 cases were analysed, with a male to female ratio of 2:1, and a mean age of 76.2 years. Aspects such as personal hygiene, activity and, to a lesser extent, motility are affected in Alzheimer's disease, but pain and anxiety aspects do not seem to be affected. There is a relationship between quality of life, functional scales and cognitive scales. Functional aspects correlate with quality of life better than cognitive ones. CONCLUSIONS: Quality of life is evaluated in Alzheimer's disease using general scales, such as EQ-5D. Cognitive aspects do not appear to provide relevant information about quality of life that is not already provided by the functional aspects. PMID- 19774527 TI - [Neuropsychology of primary progressive multiple sclerosis]. AB - INTRODUCTION: Cognitive impairment is a symptom of multiple sclerosis (MS); however, in the primary progressive form of the disease (PPMS), data on the prevalence and type of cognitive impairment are controversial. AIM: To evaluate the frequency of cognitive impairment, according to the diagnostic criteria defined by Thompson, in Brazilian patients with PPMS attending a referral center for the treatment of MS in Rio de Janeiro, Brazil. SUBJECTS AND METHODS: A battery of neuropsychological tests was used to evaluate the following cognitive functions: screening for dementia, attention/concentration, speed of information processing, verbal fluency, memory and abstract/conceptual thought. The Beck scale was used to evaluate mood disorders. Twenty-six patients with PPMS and 26 controls paired for gender, age and education level were evaluated. Statistical analysis was based on the study performed by Rao. RESULTS: The frequency of cognitive impairment in the PPMS patients in the present study was 50%. The cognitive functions most affected were: recent memory (60%), verbal fluency (40%) and speed of information processing (40%). Depression was more common in the PPMS patients compared to the control group; however, no association was found between cognitive impairment and depression. CONCLUSION: These results confirm the presence of cognitive impairment in PPMS and emphasize the need for further studies with larger sample sizes. PMID- 19774528 TI - [Aetiology of epileptic seizures in a rehabilitation centre]. AB - INTRODUCTION: Epileptic seizures are a common complication among patients who are admitted to rehabilitation hospitals. This work examines aspects related to their aetiology and progress. PATIENTS AND METHODS: The study involved all the patients with a history of epileptic seizures who had been consecutively admitted for rehabilitation during the second semester of 2008. The protocol for data collection included sociodemographic variables, the aetiology, type, frequency and complications of the seizures, and their treatment and side effects. RESULTS: An analysis was performed on 160 patients (62.5% males; mean age: 43.6 years). The main aetiologies were the following: stroke (41.2%), traumatic brain injury (35%), meningitis/encephalitis (5%), primary brain tumour (3.8%), anoxia (3.8%), static encephalopathy (3.8%) and others (7.6%). 7.6% had a history of epilepsy before suffering the brain injury. 16.3% had had a single epileptic seizure. 6.2% presented treatment failure with two antiepileptic drugs, and 12.5% suffered from more than one seizure per month. 17.5% of the patients had suffered from an epileptic status. In semiological terms, the most common seizures were focal seizures (54.5%), generalised seizures (44.4%) and focal seizures with secondary generalisation (31.9%). 76% of the subjects took antiepileptic drugs on a regular basis, but the caregiver was responsible for medication in 70% of cases. Carbamazepine and valproate were the two most frequently used drugs. CONCLUSIONS: Epilepsy can limit rehabilitation therapy in patients with stroke or traumatic injury, due to the risk of developing difficult-to-treat epilepsy. Caregivers often have to take responsibility for the pharmacological treatment in disabled patients with brain damage. PMID- 19774529 TI - [Surgical treatment of the stroke in the middle cerebral artery]. AB - INTRODUCTION: Decompressive craniectomy increases the survival rate in cases of malignant middle cerebral artery (MCA) stroke. The imaging and clinical signs that predict a malignant progression of stroke of the MCA are analysed, together with factors associated with a poorer prognosis. PATIENTS AND METHODS: The study involved 30 patients, who were divided into three groups: patients who had undergone surgery, and patients who had not undergone surgery but were admitted to intensive care or to neurology wards. The surgical procedure consisted in creating a bone window with a diameter of at least 10 cm and a dural opening. The initial evaluation of the patient was performed using the Glasgow scale and the National Institute of Health stroke scale; follow-up was carried out using the modified Rankin scale, the Barthel index and the Glasgow Outcome Scale at six months. RESULTS: Younger patients have a better functional prognosis than those over 60 years of age. A deviation of more than 10 mm from the mean line is associated with a poorer prognosis, as are volumes of infarcted tissue above 350 cm3. Lower scores on the Glasgow scale on admission are associated with a poorer prognosis for survival and a higher number of sequelae, as well as their reduction during hospitalisation. CONCLUSIONS: Age conditions the presence of sequelae in these patients. The presence of clinical signs of herniation (anisocoria, lower initial score or important drop on the Glasgow scale) and imaging signs (displacement of the mean line, volume of infarcted tissue) imply a poorer prognosis. Early surgery in those patients in whom it is indicated reduces the number of sequelae and increases the rate of survival. PMID- 19774530 TI - [Sub-acute encephalopathy that responds to steroids without any evidence of autoimmune thyroid disease: a case of non-vasculitic autoimmune meningoencephalitis]. AB - AIM: To report a case of sub-acute encephalopathy with all the extension study negative and with response to steroid therapy. CASE REPORT: The study involves a 22-year-old female with no relevant past history who presented symptoms of sub acute encephalopathy consisting in behavioural disorders, generalised seizures and bradypsychia, which gradually progressed to a state of low-level consciousness. While she was in hospital all kinds of diagnostic tests were conducted, the results of which were either normal or negative; the electroencephalogram was repeatedly abnormal and detection of protein 14-3-3 in cerebrospinal fluid was positive. Empirical corticoid therapy was begun with clinical and electrophysiological improvements and the patient recovered completely without any sequelae. CONCLUSIONS: With no evidence of autoimmune thyroid disease, although non-specific autoimmunity was present, the patient was diagnosed as having non-vasculitic autoimmune meningoencephalitis. PMID- 19774531 TI - [Sense of smell, physiological ageing and neurodegenerative diseases: II. Ageing and neurodegenerative diseases]. AB - INTRODUCTION: The sense of smell, which was once studied because of its biological and evolutionary significance, is today one of the centres of interest in research on normal and pathological ageing. The latest scientific developments point to an inversely proportional relationship between age and olfactory sensitivity. In certain neurodegenerative diseases this sensory decline is one of the first symptoms of the disorder and is correlated with the progression of the disease. DEVELOPMENT: In this work we are going to review the scientific knowledge on loss of sense of smell in ageing and in neurodegenerative diseases, with special attention given to Alzheimer's and Parkinson's diseases. CONCLUSIONS: A survey of studies that have examined the olfactory deficits in ageing and in some neurodegenerative diseases offers conclusive results about the presence of these impairments in the early stages of these disorders and even among healthy elderly persons. Although a number of causes contribute to these sensory losses in physiological ageing, a common neurological foundation has been proposed for Alzheimer's and Parkinson's diseases. Nevertheless, despite certain initial similarities, the olfactory deficits shown in these disorders seem to be qualitatively different. PMID- 19774532 TI - [Duchenne muscular dystrophy: current aspects and perspectives on treatment]. AB - INTRODUCTION AND DEVELOPMENT: Duchenne muscular dystrophy (DMD) is a severe neuromuscular disease of genetic origin that affects male children. It is characterized by progressive muscle deterioration which results in the patient becoming wheelchair-dependent until death from cardio-respiratory complications. A few years ago, DMD patients' life quality and expectancy were poor and treatment options limited; valuable recommendations that significantly delay the progress of the disease and improve the patient's life quality have been brought about recently. Numerous therapeutic approaches are now in development in order to correct the DMD genetic defect at molecular level. In the mean time, a comprehensive system to maintain patients in their best possible physical condition is needed. CONCLUSIONS: Accurate detection of complications enables caregivers to determine which patients are at higher risk and to provide treatment accordingly. Nevertheless, all of these efforts are dependent on early clinical and molecular diagnosis, careful record of clinical changes and long term follow-up of DMD patients. Furthermore, the involvement of multidisciplinary groups and the patient's family is essential in said interventions. PMID- 19774533 TI - [Sleep and women]. AB - INTRODUCTION: There is a strong link between female sex hormones and sleep. This implies the existence of sex differences both in the structure of sleep as in the incidence of various sleep disorders. AIM: To review the changes in the pattern of sleep experienced by women along different stages of their life cycle (fertile period, menstruation, pregnancy, menopause and postmenopause), as well as the most frequent sleeping pathologies in which there exist more gender differences (insomnia, obstructive sleep apnea syndrome, restless legs syndrome and narcolepsy). DEVELOPMENT: About normal sleeping has been reported a higher quality of it, in women compared with men (increased sleeping time, reduced sleep onset latency, and a greater efficiency of sleeping), but they frequently complain of sleep problems. Moreover, different stages in the life of women are associated with significant physiological and hormonal changes that favour the disruption of normal sleep pattern and by this way, possibly, increase risk to suffer sleep disorders. CONCLUSIONS: The reasons that underlie in gender differences in sleeping disorders are attributed to differences in normal sleep pattern, in the clinical manifestations and risk factors for sleep disorders, and in the results and optimal dose of treatments. PMID- 19774534 TI - [Central neurocytoma: findings from magnetic resonance imaging and computerised tomography]. PMID- 19774536 TI - [Relationship between motor function and cognitive performance]. PMID- 19774537 TI - [Paraneoplastic bilateral proptosis in a case of lung adenocarcinoma]. PMID- 19774538 TI - [Spinal cord hemorrhage complicating diagnostic lumbar puncture]. PMID- 19774539 TI - [Spinal cord hemorrhage complicating diagnostic lumbar puncture]. PMID- 19774541 TI - Cytohistological and phytochemical study of madder root extracts obtained by ultrasonic and classical extractions. AB - INTRODUCTION: Madder (Rubia tinctorum) has been used since ancient times as a source of pigments for dyeing and painting. Madder dyes are localised in roots and the native chemical population is composed of glycosiled and aglycone compounds. The aim of this study is to elaborate an efficient extraction process without any chemical denaturation of dyes. OBJECTIVE: To compare an optimised ultrasonic process, using for madder dye extraction, with two conventional procedures and to determine the efficiency of ultrasound on these vegetable matrix. METHODOLOGY: Madder roots were extract in a methanol-water mixture in 37 : 63 (v/v) for ultrasound and 80 : 20 (v/v) for reflux and agitation. HPLC-PAD analyses showed the anthraquinone proportion for each extraction process and their denaturing effects. Finally, cytohistological observations were made to show the consequence of each process on the cell organisation in madder roots. RESULTS: The results showed that the amount of extracted dyes was higher with UAE than with agitation and reflux. HPLC-PAD analysis revealed that the anthraquinone composition differed according to the extraction procedure. The UAE extracts presented an important richness in terms of anthraquinonic compounds that suggests a preserving effect. Cytohistological observations showed that the main alterations concerned the cell walls of phloem. After UAE the walls exhibited numerous pitted areas reflecting an ultrasound-induced cavitation that enhances the extraction effectiveness of this method. CONCLUSION: The study has shown the improvement of madder roots extraction both quantitatively and qualitatively using the efficiency of ultrasound-assisted extraction in comparison with magnetic agitation and reflux techniques. PMID- 19774542 TI - Metabolic profiling of bioactive Pancratium canariense extracts by GC-MS. AB - INTRODUCTION: Pancratium canariense Ker Gawler is a plant species belonging to family Amaryllidaceae. Plants from this family are known to synthesise a particular type of bioactive compounds, named Amaryllidaceae alkaloids, which have shown AChE inhibitory activity. OBJECTIVE: To perform the metabolite profiling of methanolic extracts from P. canariense in order to identify bioactive compounds. METHODOLOGY: Methanolic extracts from bulbs, leaves and fruits were separated into alkaloid-free apolar and polar fractions, as well as alkaloid fractions, and subjected to AChE assay. Metabolite profiling of extracts and fractions of P. canariense was carried out by GC-EI-MS and LC-ESI-TOF-MS. RESULTS: AChE inhibitory activities of the alkaloid fractions at a concentration of 10 microg/mL were 29.80 +/- 0.91, 40.93 +/- 4.60 and 58.06 +/- 1.18% for the bulbs, leaves and fruits, respectively. Seventy-six metabolites-mono-, di- and trisaccharides, fatty acids, amino acids, sterols as well as several Amaryllidaceae alkaloids-were detected. Further purification of the alkaloids from the methanolic extracts resulted in the detection of 31 compounds including several potent AChE inhibitors such as habranthine and galanthamine, and the structural elucidation of 3-O-acetylhabranthine, a new natural compound with potential AChE inhibitory activity. CONCLUSION: The described method resulted in effective integration of both GC-EI-MS and LC-ESI-TOF-MS strategies, which permitted the identification of many metabolites, as well as the structural elucidation of new compounds with potential AChE inhibitory activity. PMID- 19774543 TI - A TLC bioautographic method for the detection of alpha- and beta-glucosidase inhibitors in plant extracts. AB - INTRODUCTION: Bioautographic assays using TLC play an important role in the search for active compounds from plants. A TLC assay has previously been established for the detection of beta-glucosidase inhibitors but not for alpha glucosidase. Nonetheless, alpha-glucosidase inhibition is an important target for therapeutic agents against of type 2 diabetes and anti-viral infections. OBJECTIVE: To develop a TLC bioautographic method to detect alpha- and beta glucosidase inhibitors in plant extracts. METHODOLOGY: The enzymes alpha- and beta-d-glucosidase were dissolved in sodium acetate buffer. After migration of the samples, the TLC plate was sprayed with enzyme solution and incubated at room temperature for 60 min in the case of alpha-d-glucosidase, and 37 degrees C for 20 min in the case of beta-d-glucosidase. For detection of the active enzyme, solutions of 2-naphthyl-alpha-D-glucopyranoside or 2-naphthyl-beta-D glucopyranoside and Fast Blue Salt were mixed at a ratio of 1 : 1 (for alpha-d glucosidase) or 1 : 4 (for beta-d-glucosidase) and sprayed onto the plate to give a purple background colouration after 2-5 min. RESULTS: Enzyme inhibitors were visualised as white spots on the TLC plates. Conduritol B epoxide inhibited alpha d-glucosidase and beta-d-glucosidase down to 0.1 microg. Methanol extracts of Tussilago farfara and Urtica dioica after migration on TLC gave enzymatic inhibition when applied in amounts of 100 microg for alpha-glucosidase and 50 microg for beta-glucosidase. CONCLUSION: The screening test was able to detect inhibition of alpha- and beta-glucosidases by pure reference substances and by compounds present in complex matrices, such as plant extracts. PMID- 19774544 TI - The effect of electrostatic shielding on H tunneling in R67 dihydrofolate reductase. PMID- 19774545 TI - Vesicle budding and the origin of cellular life. AB - This Minireview provides an appropriate opportunity to demonstrate the connection between the results of some early experimental and theoretical investigations of vesicle budding and the more recent application of the concepts developed there to the process of vesicle self-reproduction. Herein, we also explain why vesicle budding could have preceded the establishment of cellular life. PMID- 19774546 TI - Ifosfamide metabolite chloroacetaldehyde inhibits cell proliferation and glucose metabolism without decreasing cellular ATP content in human breast cancer cells MCF-7. AB - Chloroacetaldehyde (CAA), a product of hepatic metabolism of the widely used anticancer drug ifosfamide (IFO), has been reported to decrease cancer cell proliferation. The basis of this effect is not completely known but has been attributed to a drop of cellular ATP content. Given the importance of glucose metabolism and of the 'Warburg effect' in cancer cells, we examined in the present study the ability of CAA to inhibit cancer cell proliferation by altering the glycolytic pathway. Cell proliferation, ATP content, glucose transport and metabolism as well as the activities of the main enzymes of glycolysis were determined in human breast cancer cells MCF-7 in the presence of various CAA concentrations (5-50 microm). Our results show that low CAA concentrations inhibited cell proliferation in a concentration-dependent manner. This inhibition was explained by a decrease in glucose utilization. Cellular ATP content was not reduced but even increased with 25 microm CAA. The inhibition of glucose metabolism was mainly explained by the decrease in glucose transport and hexokinase activity. The activity of glyceraldehyde-3-phosphate dehydrogenase, but not that of phosphofructokinase, was also inhibited. Glycolysis inhibition by CAA was effective in decreasing the proliferation of MCF-7 cells. Interestingly, this decrease was not due to ATP depletion; rather, it was linked to a drop of biosynthetic precursors from glycolytic intermediates. This CAA-induced inhibition of cell proliferation suggests that it might play a role in the antitumor activity of IFO. PMID- 19774547 TI - RRD1, a component of the TORC1 signalling pathway, affects anaesthetic response in Saccharomyces cerevisiae. AB - The molecular mechanisms of action of volatile anaesthetics remain unknown despite clinical use for over 150 years. While many effects of these agents have been characterized, clear insight into how these effects relate to the physiological state of anaesthesia has not been established. Volatile anaesthetics arrest cell division in Saccharomyces cerevisiae in a manner that parallels the anaesthetic actions of these drugs in mammals. To gain additional insight into the cellular activities of these drugs, we isolated genes that, when present on multi-copy plasmids, render S. cerevisiae resistant to the volatile anaesthetic isoflurane. One of these genes, RRD1, encodes a subunit of the Tap42p Sit4p-Rrd1p phosphatase complex that functions in the target of rapamycin complex 1 (TORC1) signalling pathway. In addition, we show that mutations in two other genes encoding components of the TORC1 pathway, GLN3 and URE2, also affect yeast anaesthetic response. These findings suggest that TORC1-mediated signalling is involved in cellular response to volatile anaesthetics in S. cerevisiae. PMID- 19774548 TI - Yap4 PKA- and GSK3-dependent phosphorylation affects its stability but not its nuclear localization. AB - Yap4 is a nuclear-resident transcription factor induced in Saccharomyces cerevisiae when exposed to several stress conditions, which include mild hyperosmotic and oxidative stress, temperature shift or metal exposure. This protein is also phosphorylated. Here we report that this modification is driven by PKA and GSK3. In order to ascertain whether Yap4 is directly or indirectly phosphorylated by PKA, we searched for stress and PKA-related kinases that could phosphorylate Yap4. We show that phosphorylation is independent of the kinases Rim15, Yak1, Sch9, Slt2, Ste20 and Ptk2. In addition, we showed that Yap4 phosphorylation is also abrogated in the triple GSK3 mutant mck1 rim11 yol128c. Furthermore, our data reveal that Yap4 nuclear localization is independent of its phosphorylation state. This protein has several putative phosphorylation sites, but only the mutation of residues T192 and S196 impairs its phosphorylation under different stress conditions. The ability of the non-phosphorylated forms of Yap4 to partially rescue the hog1 severe sensitivity phenotype is not affected, suggesting that Yap4 activity is maintained in the absence of phosphorylation. However, this modification seems to be required for stability of the protein, as the non-phosphorylated form has a shorter half-life than the phosphorylated one. PMID- 19774549 TI - Prion-associated proteins in yeast: comparative analysis of isogenic [PSI(+)] and [psi(-)] strains. AB - A large group of prion-associated proteins was identified in yeast cells using a new approach, comparative analysis of pellet proteins of crude cell lysates in isogenic strains of Saccharomyces cerevisiae differing by their prion composition. Two-dimensional (2D) electrophoresis followed by MALDI analysis of the pellet proteins of [PSI(+)] and [psi(-)] strains after prion elimination by GuHCl and prion transmission by cytoduction permitted identification of ca. 40 proteins whose aggregation state correlated with the change of prion(s) content. Approximately half of these proteins belonged to chaperones and to enzymes of glucose metabolism. Chaperones are known to be involved in prion metabolism and are expected to be present in prion-containing aggregates, but glucose metabolism enzymes are not predicted to be present. Nevertheless, several recent data suggest that their presence is not incidental. We detected six proteins involved in oxidative stress response and eight in translation. Also notable is a protease. Most of the identified proteins seem to be prion-associated, but we cannot exclude the possibility that several proteins may propagate as prions. PMID- 19774550 TI - Assessment of CASP8 structure predictions for template free targets. AB - The biennial CASP experiment is a crucial way to evaluate, in an unbiased way, the progress in predicting novel 3D protein structures. In this article, we assess the quality of prediction of template free models, that is, ab initio prediction of 3D structures of proteins based solely on the amino acid sequences, that is, proteins that did not have significant sequence identity to any protein in the Protein Data Bank. There were 13 targets in this category and 102 groups submitted predictions. Analysis was based on the GDT_TS analysis, which has been used in previous CASP experiments, together with a newly developed method, the OK_Rank, as well as by visual inspection. There is no doubt that in recent years many obstacles have been removed on the long and elusive way to deciphering the protein-folding problem. Out of the 13 targets, six were predicted well by a number of groups. On the other hand, it must be stressed that for four targets, none of the models were judged to be satisfactory. Thus, for template free model prediction, as evaluated in this CASP, successes have been achieved for most targets; however, a great deal of research is still required, both in improving the existing methods and in development of new approaches. PMID- 19774552 TI - Selected bioactive plant compounds in human nutrition. PMID- 19774551 TI - Stressors, resources, and well-being among Latino and White warehouse workers in the United States. AB - BACKGROUND: Social forces and cultural factors may contribute to Latino and White workers experiencing similar jobs differently. This study examines the psychosocial stressors and resources experienced by Latino and White workers in manual material handling jobs in the US and the effects of these stressors and resources on worker well-being. METHODS: Fifty-nine Latino warehouse workers were matched with White workers by job title, job tenure, and warehouse facility. Matched sample t tests and linear regression analyses models were conducted. RESULTS: Results reveal similar psychosocial stressors and resources for both groups. However, Latino workers reported better well-being. For Latino workers, social resources at work such as management fairness and supervisor support have a stronger relationship with well-being. For White workers wage fairness is the most significant predictor for well-being. CONCLUSIONS: These differential results challenge us to consider how cultural factors, expectations and the prior work history of Latino workers may influence their experience of work and the effect of work on health. PMID- 19774553 TI - Impact of new technologies on the health benefits and safety of bioactive plant compounds. PMID- 19774554 TI - Vocal and locomotor responses of piglets to social isolation and reunion. AB - Potentiation of infant isolation calls following a brief reunion with the mother is considered an index of filial bonding in altricial rodents. We investigated potentiation of isolation and reunion responses in 15-day-old unweaned domestic piglets (Sus scrofa domesticus). When piglets were re-isolated following a brief, comforting reunion with their mother and littermates in their home pen, they displayed a persistence (relative potentiation) of calling and jumping. In contrast, when re-isolated following a brief interaction with their mother or an unfamiliar sow in a familiar or unfamiliar location, or with littermates alone, calling rate and locomotion dropped. Subsequently, piglets spent more time near their mother's face if they had previously interacted with an unfamiliar sow rather than their mother, consistent with maternal recognition. Although we did not detect maternal potentiation as described in altricial rodents, filial attachment bonding was clearly evident in piglet responses, especially during reunions. PMID- 19774555 TI - Analytical and compositional aspects of isoflavones in food and their biological effects. AB - This paper provides an overview of analytical techniques used to determine isoflavones (IFs) in foods and biological fluids with main emphasis on sample preparation methods. Factors influencing the content of IFs in food including processing and natural variability are summarized and an insight into IF databases is given. Comparisons of dietary intake of IFs in Asian and Western populations, in special subgroups like vegetarians, vegans, and infants are made and our knowledge on their absorption, distribution, metabolism, and excretion by the human body is presented. The influences of the gut microflora, age, gender, background diet, food matrix, and the chemical nature of the IFs on the metabolism of IFs are described. Potential mechanisms by which IFs may exert their actions are reviewed, and genetic polymorphism as determinants of biological response to soy IFs is discussed. The effects of IFs on a range of health outcomes including atherosclerosis, breast, intestinal, and prostate cancers, menopausal symptoms, bone health, and cognition are reviewed on the basis of the available in vitro, in vivo animal and human data. PMID- 19774556 TI - Phytate in foods and significance for humans: food sources, intake, processing, bioavailability, protective role and analysis. AB - The article gives an overview of phytic acid in food and of its significance for human nutrition. It summarises phytate sources in foods and discusses problems of phytic acid/phytate contents of food tables. Data on phytic acid intake are evaluated and daily phytic acid intake depending on food habits is assessed. Degradation of phytate during gastro-intestinal passage is summarised, the mechanism of phytate interacting with minerals and trace elements in the gastro intestinal chyme described and the pathway of inositol phosphate hydrolysis in the gut presented. The present knowledge of phytate absorption is summarised and discussed. Effects of phytate on mineral and trace element bioavailability are reported and phytate degradation during processing and storage is described. Beneficial activities of dietary phytate such as its effects on calcification and kidney stone formation and on lowering blood glucose and lipids are reported. The antioxidative property of phytic acid and its potentional anticancerogenic activities are briefly surveyed. Development of the analysis of phytic acid and other inositol phosphates is described, problems of inositol phosphate determination and detection discussed and the need for standardisation of phytic acid analysis in foods argued. PMID- 19774557 TI - Heterogeneity of non-cycling and cycling synchronized murine hematopoietic stem/progenitor cells. AB - Purified long-term multilineage repopulating marrow stem cells have been considered to be homogenous, but functionally these cells are heterogeneous. Many investigators urge clonal studies to define stem cells but, if stem cells are truly heterogeneous, clonal studies can only define heterogeneity. We have determined the colony growth and differentiation of individual lineage negative, rhodamine low, Hoechst low (LRH) stem cells at various times in cytokine culture, corresponding to specific cell cycle stages. These highly purified and cycle synchronized (98% in S phase at 40 h of culture) stem cells were exposed to two cytokine cocktails for 0, 18, 32, or 40 h and clonal differentiation assessed 14 days later. Total heterogeneity as to gross colony morphology and differentiation stage was demonstrated. This heterogeneity showed patterns of differentiation at different cycle times. These data hearken to previous suggestions that stem cells might be similar to radioactive isotopes; decay rate of a population of radioisotopes being highly predictable, while the decay of individual nuclei is heterogeneous and unpredictable (Till et al., 1964). Marrow stem cells may be most adequately defined on a population basis; stem cells existing in a continuum of reversible change rather than a hierarchy. PMID- 19774558 TI - p38 MAPK activity is stimulated by vascular endothelial growth factor receptor 2 activation and is essential for shear stress-induced angiogenesis. AB - Increased capillary shear stress induces angiogenesis in skeletal muscle, but the signaling mechanisms underlying this response are not known. We hypothesize that shear stress-dependent activation of vascular endothelial growth factor receptor 2 (VEGFR2) causes p38 and ERK1/2 phosphorylation, which contribute to shear stress-induced angiogenesis. Skeletal muscle microvascular endothelial cells were sheared (12 dynes/cm(2), 0.5-24 h). VEGFR2-Y1214 phosphorylation increased in response to elevated shear stress and VEGF stimulation. p38 and ERK1/2 phosphorylation increased at 2 h of shear stress but only p38 remained phosphorylated at 6 and 24 h of shear stress. VEGFR2 inhibition abrogated p38, but not ERK1/2 phosphorylation. VEGF production was increased in response to shear stress at 6 h, and this increased production was abolished by p38 inhibition. Male Sprague-Dawley rats were administered prazosin (50 mg/L drinking water, 1, 2, 4, or 7 days) to induce chronically elevated capillary shear stress in skeletal muscle. In some experiments, mini-osmotic pumps were used to dispense p38 inhibitor SB203580 or its inactive analog SB202474, to the extensor digitorum longus (EDL) of control and prazosin-treated rats. Immunostaining and Western blotting showed increases in p38 phosphorylation in capillaries from rats treated with prazosin for 2 days but returned to basal levels at 4 and 7 days. p38 inhibition abolished the increase in capillary to muscle fiber ratio seen after 7 days of prazosin treatment. Our data suggest that p38 activation is necessary for shear stress-dependent angiogenesis. PMID- 19774560 TI - Orthogonally self-assembled multifunctional block copolymers. AB - We report the synthesis of telechelic poly(norbornene) and poly(cyclooctene) homopolymers by ring-opening metathesis polymerization (ROMP) and their subsequent functionalization and block copolymer formation based on noncovalent interactions. Whereas all the poly(norbornene)s contain either a metal complex or a hydrogen-bonding moiety along the polymer side-chains, together with a single hydrogen-bonding-based molecular recognition moiety at one terminal end of the polymer chain. These homopolymers allow for the formation of side-chain functionalized AB and ABA block copolymers through self-assembly. The orthogonal natures of all side- and main-chain self-assembly events were demonstrated by (1)H NMR spectroscopy and isothermal titration calorimetry. The resulting fully functionalized block copolymers are the first copolymers combining both side- and main-chain self-assembly, thereby providing a high degree of control over copolymer functionalization and architecture and bringing synthetic materials one step closer to the dynamic self-assembly structures found in nature. PMID- 19774559 TI - Human embryonic stem cells are pre-mitotically committed to self-renewal and acquire a lengthened G1 phase upon lineage programming. AB - Self-renewal of human embryonic stem (hES) cells proceeds by a unique abbreviated cell cycle with a shortened G1 phase and distinctions in molecular cell cycle regulatory parameters. In this study, we show that early lineage-commitment of pluripotent hES cells modifies cell cycle kinetics. Human ES cells acquire a lengthened G1 within 72 h after lineage-programming is initiated, as reflected by loss of the pluripotency factor Oct4 and alterations in nuclear morphology. In hES cells that maintain the pristine pluripotent state, we find that autocrine mechanisms contribute to sustaining the abbreviated cell cycle. Our data show that naive and mitotically synchronized pluripotent hES cells are competent to initiate two consecutive S phases in the absence of external growth factors. We conclude that short-term self-renewal of pluripotent hES cells occurs autonomously, in part due to secreted factors, and that pluripotency is functionally linked to the abbreviated hES cell cycle. PMID- 19774561 TI - Hybrid organic-inorganic silica gel carriers with controlled drug-delivery properties. AB - Pure and modified silica materials were synthesised by a sol-gel process and used as carrier for the controlled release of ibuprofen, selected as model drug. A one step synthesis was optimised for the preparation of various silica-drug composites by using tetraethoxysilane and 3-aminopropyltriethoxysilane as precursors at different molar ratios. The presence of aminopropyl groups on the silica surface influences the drug-delivery rate leading to a high degree the desorption process controlled. PMID- 19774562 TI - A panel of cytochrome P450 BM3 variants to produce drug metabolites and diversify lead compounds. AB - Herein we demonstrate that a small panel of variants of cytochrome P450 BM3 from Bacillus megaterium covers the breadth of reactivity of human P450s by producing 12 of 13 mammalian metabolites for two marketed drugs, verapamil and astemizole, and one research compound. The most active enzymes support preparation of individual metabolites for preclinical bioactivity and toxicology evaluations. Underscoring their potential utility in drug lead diversification, engineered P450 BM3 variants also produce novel metabolites by catalyzing reactions at carbon centers beyond those targeted by animal and human P450s. Production of a specific metabolite can be improved by directed evolution of the enzyme catalyst. Some variants are more active on the more hydrophobic parent drug than on its metabolites, which limits production of multiply-hydroxylated species, a preference that appears to depend on the evolutionary history of the P450 variant. PMID- 19774563 TI - The ambident reactivity of 2,4,6-tris(trifluoromethanesulfonyl)anisole in methanol: using the SO2CF3 group as a tool to reach the superelectrophilic dimension in sigma-complexation processes. AB - The kinetics of sigma complexation of 2,4,6-tris(trifluoromethanesulfonyl)anisole (7 d) have been investigated over a large pH range of 2-13.70 at T = 20 degrees C in methanol. Two competitive processes associated with the initial addition of MeO(-) at the unsubstituted 3-position of 7 d to give a 1,3-dimethoxy adduct (9 d Me) and a subsequent and slow conversion of this species into a 1,1-dimethoxy isomer (8 d-Me) have been identified. Both adducts 8 d-Me and 9 d-Me are 10(5) 10(6) times more stable than the related adducts 8 a-Me and 9 a-Me of 2,4,6 trinitroanisole (7 a), a conventional reference aromatic electrophile in Meisenheimer complex chemistry. The high stability of 8 d-Me and 9 d-Me is shown to derive from greater rates of formation and lower rates of decomposition than previously determined for 8 a-Me and 9 a-Me, thereby emphasising the especially high activation of a benzene ring by SO(2)CF(3) group(s). Analysis of the collected rate and equilibrium data for sigma complexation in the anisole series 2,4,6-tris(SO(2)CF(3))-, 2,6-bis(SO(2)CF(3))-4-nitro-, 4-SO(2)CF(3)-2,6-dinitro- and 2,4,6-trinitro- supports the idea that the especially high capacity of resonance stabilisation of the negative charge of the adducts through an F(pi) type (as defined in ref. 49) polarisation effect is a major factor that accounts for the strong activation provided by SO(2)CF(3) groups. A most significant result is the finding that the 1,1-dimethoxy adduct 8 d-Me is by far the most stable benzene sigma adduct so far reported. With a pK(a)(MeOH) value of 7.32, this adduct is formed exclusively through methanol addition up to pH approximately 10. This is consistent with the location of 7 d in the superelectrophilic region defined by pK(a)(MeOH) < or = 9.5-10.5. For comparison, the solvent contribution is negligible in the formation of the 1,3-isomer 9 d-Me, the pK(a)(MeOH) (10.59) of which is situated on the upper limit of the boundary. Taking advantage of the simple relationship linking pK(a) values for sigma complexation in methanol and water, a ranking of the triflone 7 d on the general thermodynamic scale constructed for Meisenheimer electrophiles in water is informative. An approximate calibration on the electrophilicity scale kinetically derived by Mayr et al. has also been made. PMID- 19774564 TI - Asymmetric synthesis of 1,1-diarylalkyl units by a copper hydride catalyzed reduction: differentiation between two similar aryl substituents. AB - An efficient method for the preparation of enantiomerically enriched 1,1 diarylalkyl units has been developed. The use of copper hydride complexed by the (R)-1-[(S)-2-diphenylphosphino)ferrocenyl]ethyldicyclohexylphosphine (Josiphos) ligand effects a highly enantioselective conjugate reduction of beta,beta-diaryl substituted alpha,beta-unsaturated nitriles with aryl groups of similar steric demand and no secondary coordination site. A range of substrates with meta and para substituents on the aryl group were reduced with good to excellent enantioselectivities (up to 97 % enantiomeric excess (ee)) and this methodology was applied to the formal synthesis of indatraline. PMID- 19774565 TI - Structural variations and molecular dynamics of rare-earth metal complexes with the N,N-bis(2-{pyrid-2-yl}ethyl)hydroxylaminato ligand. AB - The reaction of the donor-functionalised N,N-bis(2-{pyrid-2 yl}ethyl)hydroxylamine and [LnCp3] (Cp=cyclopentadiene) resulted in the formation of bis(cyclopentadienyl) hydroxylaminato rare-earth metal complexes of the general constitution [Ln(C5H5)2{ON(C2H4-o-Py)2}] (Py=pyridyl) with Ln=Lu (1), Y (2), Ho (3), Sm (4), Nd (5), Pr (6), La (7). These compounds were characterised by elemental analysis, mass spectrometry, NMR spectroscopy (for compounds 1, 2, 4 and 7) and single-crystal X-ray diffraction experiments. The complexes exhibit three different aggregation modes and binding motifs in the solid state. The late rare-earth metal atoms (Lu, Y, Ho and Sm) form monomeric complexes of the formula [Ln(C5H5)2{eta2-ON(C2H4-eta1-o-Py)(C2H4-o-Py)}] (1-4, respectively), in which one of the pyridyl nitrogen donor atoms is bonded to the metal atom in addition to the side-on coordinating hydroxylaminato unit. The larger Nd3+ and Pr3+ ions in 5 and 6 make the hydroxylaminato unit capable of dimerising through the oxygen atoms. This leads to the dimeric complexes [(Ln(C5H5)2{mu-eta1:eta2-ON(C2H4-o Py)2})2] without metal-pyridine bonds. Compound 7 exhibits a dimeric coordination mode similar to the complexes 5 and 6, but, in addition, two pyridyl functions coordinate to the lanthanum atoms leading to the [(La(C5H5)2{ON(C2H4-o-Py)}{mu eta1:eta2-ON(C2H4-eta1-o-Py)})2] complex. The aggregation trend is directly related to the size of the metal ions. The complexes with coordinative pyridine metal bonds show highly dynamic behaviour in solution. The two pyridine nitrogen atoms rapidly change their coordination to the metal atom at ambient temperature. Variable-temperature (VT) NMR experiments showed that this dynamic exchange can be frozen on the NMR timescale. PMID- 19774566 TI - Asymmetric cyanation of aldehydes, ketones, aldimines, and ketimines catalyzed by a versatile catalyst generated from cinchona alkaloid, achiral substituted 2,2' biphenol and tetraisopropyl titanate. AB - Full investigation of cyanation of aldehydes, ketones, aldimines and ketimines with trimethylsilyl cyanide (TMSCN) or ethyl cyanoformate (CNCOOEt) as the cyanide source has been accomplished by employing an in situ generated catalyst from cinchona alkaloid, tetraisopropyl titanate [Ti(OiPr)(4)] and an achiral modified biphenol. With TMSCN as the cyanide source, good to excellent results have been achieved for the Strecker reaction of N-Ts (Ts=p-toluenesulfonyl) aldimines and ketimines (up to >99% yield and >99% ee) as well as for the cyanation of ketones (up to 99% yield and 98% ee). By using CNCOOEt as the alternative cyanide source, cyanation of aldehyde was accomplished and various enantioenriched cyanohydrin carbonates were prepared in up to 99% yield and 96% ee. Noteworthy, CNCOOEt was successfully employed for the first time in the asymmetric Strecker reaction of aldimines and ketimines, affording various alpha amino nitriles with excellent yields and ee values (up to >99% yield and >99% ee). The merits of current protocol involved facile availability of ligand components, operational simplicity and mild reaction conditions, which made it convenient to prepare synthetically important chiral cyanohydrins and alpha-amino nitriles. Furthermore, control experiments and NMR analyses were performed to shed light on the catalyst structure. It is indicated that all the hydroxyl groups in cinchona alkaloid and biphenol complex with Ti(IV), forming the catalyst with the structure of (biphenoxide)Ti(OR*)(OiPr). The absolute configuration adopted by biphenol 4 m in the catalyst was identified as S configuration according to the evidence from control experiments and NMR analyses. Moreover, the roles of the protonic additive (iPrOH) and the tertiary amine in the cinchona alkaloid were studied in detail, and the real cyanide reagent in the catalytic cycle was found to be hydrogen cyanide (HCN). Finally, two plausible catalytic cycles were proposed to elucidate the reaction mechanisms. PMID- 19774567 TI - Unstable Supramolecular Structure of [Bmim][BF4 ] in Aqueous Solution. AB - To unravel the exact composition and structure of aggregates in an aqueous solution of 1-butyl-3-methylimidazolium tetrafluoroborate ([Bmim][BF4 ]), we performed static and dynamic light-scattering measurements, as well as transmission electron microscopy (TEM). Results from this work show that the aggregates are vesicles and unstable; herein, we discuss the driving force behind the self-assembly. Apart from the van der Waals forces and repulsive electrostatic interactions between adjacent cation clusters, the hydrogen-bonding forces as well as counterion effects might also contribute to this driving force. The information obtained here is useful for a better understanding of the vital role that aggregation behavior plays in the field of ionic liquid recovery, and its potential use in controlled release, drug delivery, and petroleum recovery. PMID- 19774568 TI - Fluorene-based pi-conjugated oligomers for efficient three-photon excited photoluminescence and lasing. AB - A novel series of diphenylamino- and 1,2,4-triazole-end-capped, fluorene-based, pi-conjugated oligomers that includes extended oligofluorenes and oligothienylfluorenes has been synthesized by means of the palladium-catalyzed Suzuki cross-coupling of 9,9-dibutyl-7-(diphenylamino)-2-fluorenylboronic acid and the corresponding 1,2,4,-triazole-based aryl halide as a key step. It was demonstrated that efficient two- and three-photon excited photoluminescence and lasing in the blue region are obtained by pumping near-infrared femtosecond lasers on these materials. Although the absorption and emission maxima of the highly fluorescent and extended oligofluorenes reach a saturation limit, there exists an effective conjugation length for an optimum three-photon absorption cross section in the homologous oligofluorene series. On the other hand, the multiphoton excited emission spectrum and lasing wavelength can easily be modified or tuned by an incorporation of thienyl unit(s) into the fluorene-based pi-conjugated core with which exceptionally large three-photon absorption cross sections up to 3.59 x 10(-77) cm6 s2 in the femtosecond regime have been obtained, thereby highlighting the potential of this series of photonic materials. The optimized full width at half-maximum of the cavityless three photon upconverted blue lasing spectra are sharply narrowed to approximately 6 nm with an efficiency of up to 0.013%. PMID- 19774569 TI - Cucurbit[7]uril complexation drives thermal trans-cis-azobenzene isomerization and enables colorimetric amine detection. AB - Complexation of yellow diaminoazobenzenes 1 and 3 inside cucurbit[7]uril (CB[7]) results in the formation of purple-colored CB[7].cis-1.2H+ and CB[7].cis-3.2H+ complexes, respectively. The high binding affinity and selectivity displayed by CB[7] toward 1 and 3 pays the >10 kcal mol(-1) thermodynamic cost for this isomerization. We investigated the behavior of these complexes as a function of pH and observed large pK(a) shifts and high pH responsiveness, which are characteristic of cucurbit[n]uril molecular containers. The remarkable yellow to purple color change was utilized in the construction of an indicator displacement assay for biologically active amines 4-10. This indicator displacement assay is capable of quantifying the pseudoephedrine (5) content in Sudafed tablets over the 5-350 microM range. PMID- 19774570 TI - Metal-organic perovskites: synthesis, structures, and magnetic properties of [C(NH2)3][M(II)(HCOO)3] (M = Mn, Fe, Co, Ni, Cu, and Zn; C(NH2)3 = guanidinium). AB - We report the synthesis, crystal structures, and spectral, thermal, and magnetic properties of a family of metal-organic perovskite ABX(3), [C(NH(2))(3)][M(II)(HCOO)(3)], in which A = C(NH(2))(3) is guanidinium, B = M is a divalent metal ion (Mn, Fe, Co, Ni, Cu, or Zn), and X is the formate HCOO(-). The compounds could be synthesized by either diffusion or hydrothermal methods from water or water-rich solutions depending on the metal. The five members (Mn, Fe, Co, Ni, and Zn) are isostructural and crystallize in the orthorhombic space group Pnna, while the Cu member in Pna2(1). In the perovskite structures, the octahedrally coordinated metal ions are connected by the anti-anti formate bridges, thus forming the anionic NaCl-type [M(HCOO)(3)](-) frameworks, with the guanidinium in the nearly cubic cavities of the frameworks. The Jahn-Teller effect of Cu(2+) results in a distorted anionic Cu-formate framework that can be regarded as Cu-formate chains through short basal Cu-O bonds linked by the long axial Cu-O bonds. These materials show higher thermal stability than other metal organic perovskite series of [AmineH][M(HCOO)(3)] templated by the organic monoammonium cations (AmineH(+)) as a result of the stronger hydrogen bonding between guanidinium and the formate of the framework. A magnetic study revealed that the five magnetic members (except Zn) display spin-canted antiferromagnetism, with a Neel temperature of 8.8 (Mn), 10.0 (Fe), 14.2 (Co), 34.2 (Ni), and 4.6 K (Cu). In addition to the general spin-canted antiferromagnetism, the Fe compound shows two isothermal transformations (a spin flop and a spin-flip to the paramagnetic phase) within 50 kOe. The Co member possesses quite a large canting angle. The Cu member is a magnetic system with low dimensional character and shows slow magnetic relaxation that probably results from the domain dynamics. PMID- 19774571 TI - Cooperative self-assembly-assisted formation of monodisperse optically active spherical and anisotropic nanoparticles. AB - We report a new method in which spontaneous self-assembly is employed to synthesize monodisperse polymer nanoparticles with controlled size (<50 nm), shape, tunable functionality, and enhanced solvent and thermal stability. Cooperative noncovalent interactions, such as hydrogen bonding and aromatic pi-pi stacking, assist self-assembly of amphiphilic macromolecules (polystyrene-block polyvinylpyridine, PS--PVP) and structure directing agents (SDAs) to form both spherical and anisotropic solid polymer nanoparticles with SDAs residing in the particle core surrounded by the polymers. Through detailed investigations by scanning electron microscopy and transmission electron microscopy (TEM), we have rationalized nanoparticle morphology evolution and dependence on factors such as SDA concentration and PVP size. By keeping the PS chain size constant, the particle morphology progresses from continuous films to spherical particles, and on to cylindrical nanowires or rods with increasing the PVP chain size. The final nanoparticles are very stable and can be redispersed in common solvents to form homogenous solutions and thin films of ordered nanoparticle arrays through solvent evaporation processes. These nanoparticles exhibit tunable fluorescent colors (or emissions) depending on the choices of the central SDAs. Our method is simple and general without requiring complicated synthetic chemistry, stabilizing surfactants, or annealing procedures (e.g., temperature or solvent annealing), making scalable synthesis feasible. PMID- 19774572 TI - A DFT-based analysis of the grossly varying reactivity pattern in room temperature activation and dehydrogenation of CH4 by main-group atomic M+ (M=Ga, Ge, As, and Se). AB - Insight into the mechanism(s) of the recently reported thermal reactions of methane with the main-group atomic cations Ga+, Ge+, As+ and Se+ (A. Shayesteh et al. J. Phys. Chem. A 2009, 113, 5602) has been obtained from DFT-based calculations including relativistic effects. Excellent agreement with the experimental findings has been achieved, and a coherent description of the reactivity is provided. For example, the chemical inertness of the Ga+/CH4 couple is due to an endergonic formation of an encounter complex as well as a high endothermicity for the dehydrogenation of methane (DeltaG298=84.7 kcal mol(-1)). For Ge+/CH4, formation of an encounter complex is slightly exergonic (DeltaG298= 8.9 kcal mol(-1)) and thus is observed with low efficiency; the dehydrogenation path, however, is not accessible (DeltaG298=13.6 kcal mol(-1)). For the Se+/CH4 couple, the significantly enhanced rate of adduct formation is suggested to result from a spin-orbit-mediated quartet-doublet spin flip that generates the insertion product [(H)Se(CH3)]+, 2Se-3, in its doublet state rather than forming a simple encounter complex. For the dehydrogenation of 2Se-3 to generate 2[Se(CH2)]+, various mechanistic variants have been explored, all of which, however, involve transition structures that are located energetically above the entrance channel, thus preventing the reaction from occurring. In contrast, facile and efficient dehydrogenation of CH4 by ground-state As+ (3P0) takes place, and this reaction constitutes a textbook example of the operation of a two state reactivity scenario. Here, a triplet-singlet conversion occurs along the oxidative insertion of As+ into the C-H bond of CH4 to generate [(H)As(CH3)]+ in its singlet state. From this intermediate, which constitutes the global minimum on the As+/CH4 potential energy surface, dehydrogenation is brought about by a sequence of alpha-hydrogen migration and reductive elimination of molecular hydrogen from the hydride carbene complex 1As-5. The potential energy surfaces for the As+/CH4 couple are remarkably similar irrespective of including or ignoring relativistic effects in the calculations. PMID- 19774573 TI - Microwave-assisted cross-coupling and hydrogenation chemistry by using heterogeneous transition-metal catalysts: an evaluation of the role of selective catalyst heating. AB - The concept of specific microwave effects in solid/liquid catalytic processes resulting from the selective heating of a microwave-absorbing heterogeneous transition-metal catalyst by using 2.45 GHz microwave irradiation was evaluated. As model transformations Ni/C-, Cu/C-, Pd/C-, and Pd/Al2O3-catalyzed carbon carbon/carbon-heteroatom cross-couplings and hydrogenation reactions were investigated. To probe the existence of specific microwave effects by means of selective catalyst heating in these transformations, control experiments comparing microwave dielectric heating and conventional thermal heating at the same reaction temperature were performed. Although the supported metal catalysts were experimentally found to be strongly microwave absorbing, for all chemistry examples investigated herein no differences in reaction rate or selectivity between microwave and conventional heating experiments under carefully controlled conditions were observed. This was true also for reactions that use low-absorbing or microwave transparent solvents, and was independent of the microwave absorbtivity of the catalyst support material. In the case of hydrogenation reactions, the stirring speed was found to be a critical factor on the mass transfer between gas and liquid phase, influencing the rate of the hydrogenation in both microwave and conventionally heated experiments. PMID- 19774574 TI - Versatile photophysical properties of meso-aryl-substituted subporphyrins: dipolar and octupolar charge-transfer interactions. AB - Donor-acceptor systems based on subporphyrins with nitro and amino substituents at meta and para positions of the meso-phenyl groups were synthesized and their photophysical properties have been systematically investigated. These molecules show two types of charge-transfer interactions, that is, from center to periphery and periphery to center depending on the peripheral substitution, in which the subporphyrin moiety plays a dual role as both donor and acceptor. Based on the solvent-polarity-dependent photophysical properties, we have shown that the fluorescence emission of para isomers originates from the solvatochromic, dipolar, symmetry-broken, and relaxed excited states, whereas the non solvatochromic fluorescence of meta isomers is of the octupolar type with false symmetry breaking. The restricted meso-(4-aminophenyl) rotation at low temperature prevents the intramolecular charge-transfer (ICT)-forming process. The two-photon absorption (TPA) cross-section values were determined by photoexcitation at 800 nm in nonpolar toluene and polar acetonitrile solvents to see the effect of ICT on the TPA processes. The large enhancement in the TPA cross-section value of approximately 3200 GM (1 GM = 10(-50) cm(4) s photon(-1)) with donor-acceptor substitution has been attributed to the octupolar effect and ICT interactions. A correlation was found between the electron-donating/ withdrawing abilities of the peripheral groups and the TPA cross-section values, that is, p-aminophenyl > m-aminophenyl > nitrophenyl. The increased stability of octupolar ICT interactions in highly polar solvents enhances the TPA cross section value by a factor of approximately 2 and 4, respectively, for p-amino- and m-nitrophenyl-substituted subporphyrins. On the other hand, the stabilization of the symmetry-broken, dipolar ICT state gives rise to a negligible impact on the TPA processes. PMID- 19774575 TI - Copper-catalyzed C-C bond formation through C-H functionalization: synthesis of multisubstituted indoles from N-aryl enaminones. PMID- 19774576 TI - Use of relaxation enhancements in a paramagnetic environment for the structure determination of proteins using NMR spectroscopy. PMID- 19774577 TI - High-yield synthesis of ultrathin metal nanowires in carbon nanotubes. PMID- 19774578 TI - Unmasking a third polymorph of a benchmark crystal-structure-prediction compound. PMID- 19774579 TI - DNA-templated homo- and heterodimerization of peptide nucleic acid encoded oligosaccharides that mimick the carbohydrate epitope of HIV. PMID- 19774580 TI - Protein scaffold engineering towards tunable surface attachment. PMID- 19774581 TI - Copper(I)-catalyzed cycloaddition of organic azides and 1-iodoalkynes. PMID- 19774582 TI - Supramolecular catalyst for aldehyde hydrogenation and tandem hydroformylation hydrogenation. PMID- 19774583 TI - A spherical 24 butyrate aggregate with a hydrophobic cavity in a capsule with flexible pores: confinement effects and uptake-release equilibria at elevated temperatures. PMID- 19774584 TI - Synthesis of phenol, aromatic ether, and benzofuran derivatives by copper catalyzed hydroxylation of aryl halides. PMID- 19774585 TI - Synthesis of chiral tetrasubstituted alkenes by an asymmetric cascade reaction catalyzed cooperatively by cationic rhodium(I) and silver(I) complexes. PMID- 19774586 TI - Isolation, structural characterization, and synthetic application of oxycyclopentadienyl dianions. PMID- 19774587 TI - Cationic-oxazaborolidine-catalyzed enantioselective Diels-Alder reaction of alpha,beta-unsaturated acetylenic ketones. PMID- 19774589 TI - Bisubstrate inhibitors of protein kinases: from principle to practical applications. AB - Bisubstrate inhibitors consist of two conjugated fragments, each targeted to a different binding site of a bisubstrate enzyme. The design of bisubstrate inhibitors presupposes the formation of the ternary complex in the course of the catalyzed reaction. The principle advantage of bisubstrate inhibitors is their ability to generate more interactions with the target enzyme that could result in improved affinity and selectivity of the conjugates, when compared with single site inhibitors. Among phosphotransferases, the approach was first successfully used for adenylate kinase in 1973. Since then, several types of bisubstrate inhibitors have been developed for protein kinases, including conjugates of peptides with nucleotides, adenosine derivatives and potent ATP-competitive inhibitors. Earlier bisubstrate inhibitors had pharmacokinetic qualities that were unsuitable for cellular experiments and hence were mostly used for in vitro studies. The recently constructed conjugates of adenosine derivatives and D arginine-rich peptides (ARCs) possess high kinase affinity, high biological and chemical stability and good cell plasma membrane penetrative properties that enable their application in the regulation of cellular protein phosphorylation balances in cell and tissue experiments. PMID- 19774590 TI - Synthesis of modified 4H-1,2,4-benzothiadiazine-1,1-dioxides and determination of their affinity and selectivity for different types of K(ATP) channels. AB - 4H-1,2,4-Benzothiadiazine-1,1-dioxides with various substituents in positions 3, 5, and 7 were synthesized and tested as K(ATP) channel agonists in artificial cell systems (CHO cells transfected with SUR1/Kir6.2, and HEK 293 transfected with SUR2B/Kir6.1) as model systems for insulin-secreting pancreatic beta-cells and for smooth muscle cells, respectively. The effects of agonists were tested in intact cells using DiBAC4(3) [bis-(1,3-dibarbituric acid)trimethine oxanol] as a membrane potential dye, and the results compared with their binding affinity for the SUR2B-type K(ATP) channels using the radioligand [(3)H]P1075. Compounds with cycloalkyl and (cycloalkyl)methyl side chains in position 3 had higher affinities towards the SUR2B/Kir6.1 receptor compared with the parent compound diazoxide (1 a). Compounds with bulky, nonpolar residues in position 3 exhibited remarkable selectivity for SUR2B-type K(ATP) channels. The compound substituted with a bulky (1-adamantyl)methyl residue exhibited micromolar affinity and activity on SUR2B type K(ATP) channels without being able to activate the SUR1-type K(ATP) channels. PMID- 19774591 TI - Classification of organic molecules by molecular quantum numbers. PMID- 19774593 TI - Thermal wet decomposition of Prussian Blue: implications for prebiotic chemistry. AB - The complex salt named Prussian Blue, Fe4[Fe(CN)6]3 x 15 H2O, can release cyanide at pH > 10. From the point of view of the origin of life, this fact is of interest, since the oligomers of HCN, formed in the presence of ammonium or amines, leads to a variety of biomolecules. In this work, for the first time, the thermal wet decomposition of Prussian Blue was studied. To establish the influence of temperature and reaction time on the ability of Prussian Blue to release cyanide and to subsequently generate other compounds, suspensions of Prussian Blue were heated at temperatures from room temperature to 150 degrees at pH 12 in NH3 environment for several days. The NH3 wet decomposition of Prussian Blue generated hematite, alpha-Fe2O3, the soluble complex salt (NH4)4[Fe(CN6)] x 1.5 H2O, and several organic compounds, the nature and yield of which depend on the experimental conditions. Urea, lactic acid, 5,5-dimethylhydantoin, and several amino acids and carboxylic acids were identified by their trimethylsilyl (TMS) derivatives. HCN, cyanogen (C2N2), and formamide (HCONH2) were detected in the gas phase by GC/MS analysis. PMID- 19774592 TI - Chemical constituents of plants from the genus Xylocarpus. PMID- 19774594 TI - Interaction of isoquinoline alkaloids with polymorphic DNA structures. AB - The interaction of berberine, palmatine, and coralyne with the B, Z, and H(L) form of poly[d(G-C)] was studied. Berberine and palmatine showed moderate binding to the B form, while coralyne showed higher binding, as revealed from spectroscopic and thermodynamic data. Berberine and coralyne binding to the B form was exothermic and enthalpy-driven, while palmatine showed exothermic binding which was favored by both negative enthalpy and negative entropy changes. Berberine and palmatine neither bind nor converted the Z-form structure to B form. Coralyne, on the other hand, exhibited a strong binding affinity to Z DNA structure that was enthalpy-driven. Berberine binding to the H(L) form was cooperative, exothermic, and favored by both negative enthalpy and negative entropy changes with the formation of an induced CD band. Palmatine showed weak binding, while coralyne showed a strong binding with the H(L) form. The structural differences in the isoquinoline alkaloids appear to influence the affinity and mode of interactions with these polymorphic DNA structures. PMID- 19774595 TI - Syntheses, characterizations, and biological activities of tetradeca-4,8-dien-1 yl acetates as sex attractants of leaf-mining moth of the genus Phyllonorycter (Lepidoptera: Gracillariidae). AB - The four possible isomers of tetradeca-4,8-dien-1-yl acetate and corresponding alcohols were synthesized stereoselectively by synthetic routes employing Wittig coupling reaction for the preparation of (Z,E)- and (Z,Z)-isomers, and alkylation of terminal alkynes for the preparation of (E,E)- and (E,Z)-isomers as the key steps. Synthetic products were characterized by 13C- and 1H-NMR spectroscopy as well as mass-spectrometric methods. All four isomers gave distinctive mass spectra where m/z 81 fragments clearly dominated. Elution order, followed by retention index presented in parenthesis, of tetradeca-4,8-dien-1-ols was determined as (Z,Z) (2082.1), (Z,E) (2082.8), (E,E) (2083.1), and (E,Z) (2083.2) from unpolar SPB-1 column, and as (E,E) (2210.2), (Z,E) (2222.1), (E,Z) (2223.4), and (Z,Z) (2224.7) from polar DB-WAX column. The isomers of tetradeca-4,8-dien-1 yl acetates eluted in the order of (Z,Z) (2176.1), (Z,E) (2178.4), (E,Z) (2185.9), and (E,E) (2186.4) from SPB-1, and (Z,E) (2124.3), (E,E) (2157.7), (Z,Z) (2128.9), and (E,Z) (2135.9) from DB-WAX columns. Field-screening tests for attractiveness of tetradeca-4,8-dien-1-yl acetates revealed that (4Z,8E) tetradeca-4,8-dien-1-yl acetate significantly attracted Phyllonorycter coryli and Chrysoesthia drurella males. (4E,8E)-Tetradeca-4,8-dien-1-yl acetate was the most efficient attractant for Ph. esperella and Ph. saportella males, and (4E,8Z) tetradeca-4,8-dien-1-yl acetate was attractive to Ph. cerasicolella males. PMID- 19774596 TI - Rediocides A and G as potential antitoxins against cobra venom. AB - Rediocides A and G, the principle components of Trigonostemon reidioides (Kurz) Craib, which is known as Lotthanong in Thai, were investigated for a detoxification mechanism against Naja kaouthia venom by in silico, in vitro, and in vivo methods. Molecular dockings of alpha-cobratoxin with rediocides A and G were performed, and the binding energies were found to be -14.17 and -14.14 kcal/mol, respectively. Rediocides bind to alpha-cobratoxin at the same location as alpha-cobratoxin binds to the nicotinic acetylcholine receptor (nAChR), i.e., at the Asp27, Phe29, Arg33, Gly34, Lys35, and Val37 residues. alpha-Cobratoxin cannot bind to nAChR, because some of its binding sites are occupied with rediocides. From in vitro SDS-PAGE, it was found that rediocides can diminish the bands of alpha-cobratoxin. In the presence of acetylcholine-binding protein (AChBP), it was apparent that rediocides can bind both alpha-cobratoxin and AChBP. From an in vivo test, it was found that injection of rediocides at 0.5 mg/kg immediately after an alpha-cobratoxin dose of three times LD(50) cannot prolong the survival time of mice. However, rediocide can prolong the survival time, if it is injected 30 min before the injection of alpha-cobratoxin. The in vitro SDS-PAGE and the in vivo results support the in silico detoxification mechanism of rediocides against cobra venom at a molecular level. PMID- 19774597 TI - Adsorption of the Pt(II) anticancer drug carboplatin by mesoporous silica. AB - MCM-41, a mesoporous silica nanomaterial with a high surface area for adsorption of small molecules, is a potential new type of delivery vehicle for therapeutic and diagnostic agents. In this report, we show that MCM-41 adsorbs the front-line anticancer drug carboplatin, [Pt(CBDCA-O,O')(NH3)2] (CBDCA=cyclobutane-1,1 dicarboxylate; 1), which is used to treat ovarian, lung, and other types of cancer. UV/Visible difference absorption spectroscopy shows that MCM-41 adsorbs 1.8+/-0.2% of its own weight of carboplatin after a 24 h exposure to 26.9 mM drug in H2O. The pseudo-first-order rate constant for adsorption of carboplatin by MCM 41, measured using [1H,15N] heteronuclear single quantum coherence (HSQC) NMR, and 15N-labeled carboplatin is k(1)=2.92+/-2.17 x 10(-6) s(-1) at ca. 25 degrees. PMID- 19774598 TI - Removal of anionic surfactants from wastewater using a constructed wetland. AB - Removal of anionic surfactants from municipal wastewater using a constructed wetland with a horizontal subsurface flow was studied in 2007 and 2008. Extraction spectrophotometry with methylene blue served to determine the analyte concentrations in individual samples. The anionic surfactant-removal efficiency depended on actual conditions, mostly the treated water flow intensity, its temperature, and a redox-potential gradient in the longitudinal profile of the wetland bed. It increased with decreasing inflow and increasing temperature. The average efficiency was 83.7% in 2007 and 81.7% in 2008; however, values higher than 85% were often determined during the summer period. On the other hand, the efficiencies were usually lower than 80% in winter, especially in periods with intensive precipitation and inflows. The average concentration of anionic surfactants in water taken at the outflow was lower than 0.65 mg/l (expressed as sodium dodecyl sulfate). The most significant fraction of anionic surfactants (almost 50%) was degraded at the beginning (1 m from the inflow zone) of the wetland bed. The rhizosphere aeration via the vegetation roots strongly supported the anionic-surfactant removal. PMID- 19774599 TI - Terpenoid diversity in the leaf essential oils of Himalayan Lauraceae species. AB - The leaf terpenoid compositions of nine Lauraceae species, viz., Neolitsea pallens, Lindera pulcherrima, Dodecadenia grandiflora, Persea duthiei, Persea odoratissima, Persea gamblei, Phoebe lanceolata, Cinnamomum tamala, and Cinnamomum camphora, collected from the Himalayan region (India) were examined by GC, GC/MS, and NMR analyses in order to determine the similarities and differences among their volatile constituents. Furano-sesquiterpenoids were the principal constituents of N. pallens, L. pulcherrima, and D. grandiflora. (E) Nerolidol, limonene, beta-pinene, and alpha-pinene were the major constituents of P. duthiei; alpha-pinene, sabinene, and beta-caryophyllene were predominant in P. odoratissima, while the oils of P. gamblei and P. lanceolata possessed beta caryophyllene as common major constituent. C. camphora and C. tamala were marked by the presence of camphor and cinnamaldehyde, respectively. Cluster analysis of the oil composition was carried out in order to discern the differences and similarities within nine species of six genera of Lauraceae. PMID- 19774600 TI - A new antimicrobial fatty acid from the calcareous sponge Paragrantia cf. waguensis. AB - A new acetylenic fatty acid, 1, has been isolated from the title sponge. The structure of the molecule was elucidated to contain an enyne and a thiophene by spectroscopic methods. Compound 1 showed a weak cytotoxic effect against NBT-T2 rat bladder epithelial cells (IC(50) > 20 microg/ml), and antimicrobial activity with minimal-inhibitory concentrations (MIC) of 64 and 128 microg/ml against Staphylococcus aureus and Escherichia coli, respectively. PMID- 19774601 TI - Seasonal and geographical influences on the chemical composition of Juniperus phoenicea L. essential oil leaves from the Northern Tunisia. AB - The essential-oil composition of 60 individual trees of Juniperus phoenicea L. from four Tunisian populations in three different periods were investigated by GC and GC/MS analyses. 59 Compounds were identified in the oils, and a relatively high variation in their contents was found. All the oils were dominated by the terpenic hydrocarbon fraction, and the main component was alpha-pinene (20.28 40.86%). The results of the oil compositions were processed by hierarchical clustering and principal component analysis (PCA) allowing establishing four groups of essential-oils differentiated by one compound or more. Pattern of geographic variation in essential-oil composition indicated that individuals from the continental site (Makthar) were clearly distinguished from those from littoral localities (Tabarka, Hawaria, and Rimel). PMID- 19774602 TI - Cashmirols A and B, new lipoxygenase inhibiting triterpenes from Sorbus cashmiriana. AB - Two new triterpenes, cashmirols A and B, along with three known compounds have been isolated from the AcOEt-soluble fraction of Sorbus cashmiriana, and their structures were elucidated by spectroscopic techniques including two-dimensional NMR. Both compounds displayed lipoxygenase enzyme inhibitory potential. PMID- 19774603 TI - Immunosuppressive withanolides from Withania coagulans. AB - Six new withanolides, withacoagulins A-F (1-6, resp.), together with ten known withanolides, 7-16, were isolated from the aerial parts of Withania coagulans. Their structures were determined by spectroscopic techniques including 1D- and 2D NMR (1H, 13C, HMQC, and HMBC) and MS experiments. These compounds, including the crude extracts of this herb, exhibited strong inhibitory activities on the T- and B-cell proliferation. PMID- 19774604 TI - Chemical variation in Piper aduncum and biological properties of its dillapiole rich essential oil. AB - The essential oils of the specimens of Piper aduncum that occur in deforested areas of Brazilian Amazon, North Brazil, are rich in dillapiole (35-90%), a derivative of phenylpropene, to which are attributed biological properties. On the other hand, the oils of the specimens with occurrence in the Atlantic Forest, and Northeastern and Southeastern Brazil, do not contain dillapiole, but only terpene compounds such as (E)-nerolidol and linalool. One specimen existing in the Amazon was hydrodistilled. The obtained oil was fractioned on a silica chromatographic column, resulting in fractions rich in dillapiole (95.0-98.9%) utilized for analyses by GC and GC/MS, structural characterization by NMR, confirmation of their biological properties, and to obtain the isomer isodillapiole. Dillapiole showed a fungicide action against the fungus Clinipellis perniciosa (witches' broom) by inhibition of its basidiospores, in concentrations ranging from 0.6 to 1.0 ppm. The larvicide and insecticide actions of dillapiole were tested against the larvae and the adult insects of Anopheles marajoara and Aedes aegypti (malaria and dengue mosquitoes), resulting in mortality of the larvae (48 h, 100%) at a concentration of 100 ppm, and mortality of the insects (30 min, 100%) at a concentration of 600 ppm. The isomeric isodillapiole showed no significant activity in the same biological tests. PMID- 19774605 TI - Cytotoxic grifolin derivatives isolated from the wild mushroom Boletus pseudocalopus (Basidiomycetes). AB - Activity-guided purification of a MeOH extract of the Korean wild mushroom Boletus pseudocalopus afforded three new grifolin derivatives, 1-3, along with four known phenolic compounds 4-7. Their structures were established by a combination of 1H- and 13C-NMR, NOESY, and extensive two-dimensional NMR spectroscopic experiments such as gCOSY, gHSQC, gHMBC, and ROESY. The major metabolites 4 and 5 were subjected to reduction to provide the side chain-reduced compounds 8 and 9 for biological testing. All of the compounds except compound 6 showed anticancer activities in the range of IC(50) 3.5-11.0 microg/ml against human lung carcinoma A549 and mouse melanoma B16F1 cell lines. In addition, all compounds showed moderate radical-scavenging activities determined by DPPH assay. PMID- 19774606 TI - Two new triterpenoid saponins cytotoxic to human glioblastoma U251MG cells from Ardisia pusilla. AB - Two new triterpenoid saponins, ardipusillosides IV and V (1 and 2, resp.), together with one known saponin, ardisiacrispin B(3), were isolated from the whole plants of Ardisia pusilla A. DC. Their structures were deduced by extensive spectral analysis and chemical evidences. Compound 1 contains a glycosylated glycerol residue which is a very rare structural feature among triterpenoid glycosides and has been so far found only in the genus Ardisia. All the saponins exhibited significant cytotoxicity against human glioblastoma U251MG cells, but did not affect the growth of primary cultured human astrocytes. PMID- 19774607 TI - Microbial reactions on 7alpha-hydroxyfrullanolide and evaluation of biotransformed products for antibacterial activity. AB - 7alpha-Hydroxyfrullanolide (1), a known sesquiterpenoid, was isolated from Sphaeranthus indicus using an antibacterial-activity-directed fractionation method. This compound had exhibited a significant antibacterial activity against Gram-positive bacteria. Chemical and microbial reactions were performed to prepare eight different analogues of compound 1 in order to evaluate these newly synthesized compounds for antibacterial activity. These compounds were 1beta,7alpha-dihydroxyfrullanolide (2), 7alpha-hydroxy-1-oxofrullanolide (3), 4,5 dihydro-7alpha-hydroxyfrullanolide (4), 11,13-dihydro-7alpha-hydroxyfrullanolide (5), 13-acetyl-7alpha-hydroxyfrullanolide (6), 2alpha,7alpha dihydroxysphaerantholide (7), 4alpha,5alpha-epoxy-7alpha-hydroxyfrullanolide (8), and 4beta,5beta-epoxy-7alpha-hydroxyfrullanolide (9). Microbial reactions on 1 using whole-cell cultures of Cunninghamella echinulata and Curvularia lunata yielded compounds 2-4. Incubation of compound 1 with the liquid cultures of Apsergillus niger and Rhizopus circinans yielded metabolites 5-7, while 8 and 9 were prepared by carrying out an epoxidation reaction on 1 using meta chloroperbenzoic acid (mCPBA). Structures of compounds 2-9 were elucidated with the aid of extensive NMR spectral studies. Compounds 2-4 were found to be new metabolites. Compounds 1-9 were evaluated for antibacterial activity and found to exhibit a wide range of bioactivities. Antibacterial-activity data of 1-9 suggested that the bioactivity of 1 is largely due to the presence of C4=C5, C11=C13, and a gamma-lactone moiety. PMID- 19774608 TI - New (9betaH)-lanostanes and lanostanes from Mikania aff. jeffreyi (Asteraceae). AB - Four new (9betaH)-lanostanes, i.e., (9betaH)-3beta-acetoxylanosta-7,24-diene, (9betaH)-3-oxolanosta-7,24-diene, (9betaH,24R)-3beta-acetoxy-24-hydroxylanosta 7,25-diene, and (9betaH,24S)-3beta-acetoxy-24-hydroxylanosta-7,25-diene, two new lanostanes, i.e., (24R)-3beta-acetoxy-24-hydroxylanosta-8,25-diene and (24S) 3beta-acetoxy-24-hydroxylanosta-8,25-diene, and two known lanostanes, i.e., 3beta acetoxylanosta-8,24-diene and 3-oxolanosta-8,24-diene, were obtained from a new Mikania species (Asteraceae) besides pentacyclic triterpenes, steroids, and diterpenes. The structures of the compounds were determined by spectroscopic methods. This is the second study about acetyl-lanosterols from higher plants. Moreover, (9betaH)-lanostanes are very rare metabolites from dicotyledone angiosperms. The occurrence of these terpenes together in the same plant makes the species a good source for lanostane- and (9betaH)-lanostane-biosynthesis studies. PMID- 19774609 TI - Centrosome structure and function under normal and pathological conditions. PMID- 19774610 TI - Aurora A, centrosome structure, and the centrosome cycle. AB - The centrosome, also known as the microtubule organizing center of the cell, is a membrane-less organelle composed of a pair of barrel-shaped centrioles surrounded by electron-dense pericentriolar material. The centrosome progresses through the centrosome cycle in step with the cell cycle such that centrosomes are duplicated in time to serve as the spindle poles during mitosis and that each resultant daughter cell contains a single centrosome. Regulation of the centrosome cycle with relation to the cell cycle is an essential process to maintain the ratio of one centrosome per new daughter cell. Numerous mitosis-specific kinases have been implicated in this regulation, and phosphorlyation plays an important role in coordinating the centrosome and cell cycles. Centrosome amplification can occur when the cycles are uncoupled, and this amplification is associated with cancer and with an increase in the levels of chromosomal instability. The aurora kinases A, B, and C are serine/threonine kinases that are active during mitosis. Aurora A is associated with centrosomes, being localized at the centrosome just prior to the onset of mitosis and for the duration of mitosis. Overexpression of aurora A leads to centrosome amplification and cellular transformation. The activity of aurora A is regulated by phosphorlyation and proteasomal degradation. PMID- 19774611 TI - Induction of aneuploidy by single-walled carbon nanotubes. AB - Engineered carbon nanotubes are newly emerging manufactured particles with potential applications in electronics, computers, aerospace, and medicine. The low density and small size of these biologically persistent particles makes respiratory exposures to workers likely during the production or use of commercial products. The narrow diameter and great length of single-walled carbon nanotubes (SWCNT) suggest the potential to interact with critical biological structures. To examine the potential of nanotubes to induce genetic damage in normal lung cells, cultured primary and immortalized human airway epithelial cells were exposed to SWCNT or a positive control, vanadium pentoxide. After 24 hr of exposure to either SWCNT or vanadium pentoxide, fragmented centrosomes, multiple mitotic spindle poles, anaphase bridges, and aneuploid chromosome number were observed. Confocal microscopy demonstrated nanotubes within the nucleus that were in association with cellular and mitotic tubulin as well as the chromatin. Our results are the first to report disruption of the mitotic spindle by SWCNT. The nanotube bundles are similar to the size of microtubules that form the mitotic spindle and may be incorporated into the mitotic spindle apparatus. PMID- 19774612 TI - Anteromedial thigh flaps: an anatomical study to localize and classify anteromedial thigh perforators. AB - Until now, research on flaps in the anteromedial thigh region has focused on flaps in specific regions. To elucidate the complete pattern of suitable anteromedial thigh perforators, an anatomical study was performed by dissecting nine thighs from different cadavers. The ideal perforator has maximum length and diameter and runs through a septum. According to the data found in our study, these perforators can predominantly be found in the middle third of the anteromedial thigh region. All of the three main thigh vessels supply perforators which can be used for flaps. Pertaining to length and diameter the most suitable perforators originate from the deep femoral artery, which can be found in the proximal and middle third of the anteromedial thigh. Musculocutaneous perforators are found to be longer than septocutaneous perforators. Because of their position, the proximal and distal third perforators should preferentially be used for local pedicled flaps. Defects in the pelvic area and around the knee can be closed with perforator flaps from the proximal and distal anteromedial thigh, respectively. Because of their diameter, length, and number, the middle third perforators should be the first choice for harvesting free flaps. Skin closure is easily achieved in the anteromedial thigh region even when larger flaps are used. PMID- 19774613 TI - Pulmonary non-Hodgkin's lymphoma (NHL) of diffuse large B-cell type with simultaneous humeral involvement in a young lady: an uncommon presentation with cytologic implications. AB - A bronchogenic carcinoma, almost invariably, presents as a lung mass. Primary pulmonary lymphomas are rare. We report an unusual case of a pulmonary non Hodgkin's lymphoma (NHL) with simultaneous involvement of the right humerus in a 37 year old lady. Bronchial lavage smears showed atypical cells with irregular nuclear membranes raising a suspicion of a hematolymphoid tumor, over a small cell carcinoma that was the closest differential diagnosis. Biopsy from the lung mass and from the lesion in the humerus showed an identical malignant round cell tumor with prominent apoptosis. On immunohistochemistry (IHC), tumor cells were diffusely positive for leukocyte common antigen (LCA), CD20 and MIB1 (70%), while negative for cytokeratin (CK), epithelial membrane antigen (EMA) synaptophysin, chromogranin, neuron specific enolase (NSE), CD3, and CD10. Diagnosis of a pulmonary NHL of diffuse large B-cell type with involvement of the humerus was formed. The case is presented to create an index of suspicion for the possibility of a NHL on respiratory samples, while dealing with small round cells with irregular nuclear membranes. IHC is necessary to confirm he diagnosis. A simultaneous association in the humerus in our case makes it unusual. PMID- 19774614 TI - Fine needle aspiration cytology of ALK1(-), CD30+ anaplastic large cell lymphoma post renal transplantation: a case report and literature review. AB - Post transplant lymphoproliferative disorders (PTLD) complicates the course of 0.3 to 3% of renal transplant patients receiving immunosuppression. Epstein-Barr virus (EBV) related non-Hodgkin's lymphomas of B-cell type is more common than those of T-cell origin. CD30 positive Anaplastic Large Cell Lymphoma (ALCL) is a Non-Hodgkin's lymphoma (B or T cell type) that accounts for a small percentage of PTLD's. ALCL of T-cell type are a spectrum of disease ranging from primary cutaneous to systemic nodal ALCL. The systemic nodal ALCL is further subdivided into anaplastic lymphoma kinase-1 (ALK-1) positive or negative. ALK-1 protein is a gene fusion product of translocation (2;5) and carries prognostic implications. We present an unusual manifestation of ALK-1 negative CD30 positive ALCL in a post renal transplant patient in FNA cytology with all supportive adjuvant studies and differential diagnoses and review the cytology literature on this topic. PMID- 19774615 TI - A critical role of TRAIL expressed on cotransplanted hepatic stellate cells in prevention of islet allograft rejection. AB - Hepatic stellate cells (HSCs) have demonstrated a strong T-cell inhibitory activity. In a mouse islet transplantation model, cotransplanted HSCs can protect islet allografts from rejection. The involved mechanism is not fully understood. We showed in this study that expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), an important apoptosis-inducing ligand, on HSCs was crucial in protection of islet allografts, since HSCs derived from TRAIL knockout mice demonstrated less inhibitory activity towards T-cell proliferative responses, and substantially lost their capacity in protecting cotransplanted islet allografts from rejection, suggesting that TRAIL-mediated T cell apoptotic death is important in HSC-delivered immune regulation activity. PMID- 19774616 TI - Fine needle aspiration of pleomorphic lipoma of the neck: report of two cases. AB - Pleomorphic lipoma is a rare lipocytic neoplasm that most commonly occurs in the head and neck region in middle-aged to elderly men. Clinically, it presents as a slow-growing, well-circumscribed subcutaneous mass. Histopathologically and cytogenetically, it has some features overlapping with other benign and malignant tumors, such as benign spindle cell lipoma, atypical lipomatous tumor, liposarcoma, and malignant fibrous histiocytoma. However, cure rates are high when pleomorphic lipoma is treated with complete surgical excision with clear margins. Therefore, an accurate preoperative diagnosis is very important for proper treatment. Due to the rarity of this tumor, few cases diagnosed by cytology have been reported in the English literature. Here, we report two cases of pleomorphic lipoma, the diagnoses of which were suggested on fine needle aspiration biopsies and subsequently confirmed by surgical excisions. PMID- 19774617 TI - Primary tibial adamantinoma diagnosed by fine needle aspiration. AB - Adamantinoma is one of the rarest primary bone tumors and is almost exclusively found in the tibia. Because of its scarcity, there are only a handful of reported cases of adamantinoma diagnosed by fine needle aspiration (FNA). We report a case of a 30-year-old woman seen at The Johns Hopkins Hospital for a 2.5-cm lytic lesion in the distal diaphysis of the tibia. A computed tomography-guided FNA of the lesion revealed a moderately cellular lesion consisting of a biphasic admixture of epithelioid cells seen singly and in fragments. These cells had round to oval nuclei with pale chromatin and well-formed nuclear grooves. The other population had more elongated nuclei and spindled appearance. An immunostain for cytokeratin was positive, supporting the diagnosis of adamantinoma. Due primarily to its rarity, the diagnosis of adamantinoma on FNA can be challenging and must be made in the context of its characteristic clinical and radiographic setting. PMID- 19774618 TI - Sequence fingerprint and structural analysis of the SCOR enzyme A3DFK9 from Clostridium thermocellum. AB - We have identified a highly conserved fingerprint of 40 residues in the TGYK subfamily of the short-chain oxidoreductase enzymes. The TGYK subfamily is defined by the presence of an N-terminal TGxxxGxG motif and a catalytic YxxxK motif. This subfamily contains more than 12,000 members, with individual members displaying unique substrate specificities. The 40 fingerprint residues are critical to catalysis, cofactor binding, protein folding, and oligomerization but are substrate independent. Their conservation provides critical insight into evolution of the folding and function of TGYK enzymes. Substrate specificity is determined by distinct combinations of residues in three flexible loops that make up the substrate-binding pocket. Here, we report the structure determinations of the TGYK enzyme A3DFK9 from Clostridium thermocellum in its apo form and with bound NAD(+) cofactor. The function of this protein is unknown, but our analysis of the substrate-binding loops putatively identifies A3DFK9 as a carbohydrate or polyalcohol metabolizing enzyme. C. thermocellum has potential commercial applications because of its ability to convert biomaterial into ethanol. A3DFK9 contains 31 of the 40 TGYK subfamily fingerprint residues. The most significant variations are the substitution of a cysteine (Cys84) for a highly conserved glycine within a characteristic VNNAG motif, and the substitution of a glycine (Gly106) for a highly conserved asparagine residue at a helical kink. Both of these variations occur at positions typically participating in the formation of a catalytically important proton transfer network. An alternate means of stabilizing this proton wire was observed in the A3DFK9 crystal structures. PMID- 19774619 TI - Assessment of disorder predictions in CASP8. AB - The interest in intrinsically disordered proteins has greatly increased, as it has become clear that they are very widespread, especially in eukaryotic organisms. Functionally, they appear to play a significant role in the control of many cellular processes and signalling pathways and have been, also, associated with a number of diseases ranging from cancer to Alzheimer's. Thus, there is enormous interest in attempts to predict disordered regions in proteins solely from knowledge of their amino acid sequences. In this study, we assess the quality of predictions for 25 groups on predicting disordered regions in 122 target proteins. In addition, we suggest the need of a "knowledge-independent" measure that would enable one to normalize the results of the different CASP experiments and to determine whether the disorder prediction field had improved across the years. PMID- 19774620 TI - Critical assessment of methods of protein structure prediction - Round VIII. AB - This article is an introduction to the special issue of the journal Proteins, dedicated to the eighth CASP experiment to assess the state of the art in protein structure prediction. The article describes the conduct of the experiment, the categories of prediction included, and outlines the evaluation and assessment procedures. Highlights are the first blind assessment of model refinement methods showing that under some circumstances substantial model improvements are possible; improvements in the performance of methods for determining the accuracy of a model; and some progress in the accuracy of comparative models in regions not present in a principal template. Against these advances must be stacked the fact that there is no detectable progress in model quality compared with CASP7 in either template-based or template free modeling, using the established CASP measures. PMID- 19774621 TI - Clinical and molecular characterization of S1118F-CFTR. AB - BACKGROUND: Cystic fibrosis is a lethal autosomal recessive disorder usually associated with lung disease, pancreatic insufficiency and high sweat chloride levels. CLINICAL CASE: A patient admitted to Le Bonheur Children's Medical Center (LBCMC, Memphis, TN) showed symptoms of meconium ileus which required exploratory laparotomy, bowel resection and ileostomy. Genotyping showed DeltaF508/I1027T on one chromosome and S1118F on the other. Sweat testing on three different occasions gave negative and intermediate results (22.7, 24.6 mmol/L; 55.1, 58.6 mmol/L and 55.1, 58 mmol/L) and pancreatic elastase testing showed normal levels. OBJECTIVE: To characterize S1118F-CFTR mutation at a molecular level to help understand the associated CF-phenotype. METHODS: Molecular characterization of S1118F-CFTR mutant was studied in HEK-293 cells at 37 degrees C. Various biochemical methods such as Western blotting, real-time PCR, Pulse chase labeling and iodide efflux assay were employed. RESULTS: S1118F-CFTR makes less than 10 15% of mature CFTR (band C) compared to WT-CFTR. The mRNA levels of S1118F-CFTR and WT-CFTR are comparable. S1118F-CFTR is functional but shows about 10-15% of WT-CFTR activity. S1118F-CFTR shows impaired maturation and CF-correctors can increase the amount of mature and functional CFTR by three- to fourfold. CONCLUSION: S1118F-CFTR shows impaired maturation and an individual with S1118F CFTR paired with DeltaF508-CFTR exhibits atypical CF symptoms with intermediate sweat chloride level and meconium ileus despite documented pancreatic sufficiency. PMID- 19774622 TI - Extended exhaled nitric oxide analysis in field surveys of schoolchildren: a pilot test. AB - Extended exhaled nitric oxide (eNO) analysis can distinguish proximal and distal airway contributions to FeNO. Thus, it has the potential to detect effects of different environmental influences, allergic phenotypes, and genetic variants on proximal and distal airways. However, its feasibility in field surveys has not been demonstrated, and models for estimating compartmental NO contributions have not been standardized. In this study we verified that extended NO tests can be performed by children in schools, and assessed different analytical models to estimate bronchial flux and alveolar NO concentration. We tested students at a middle school, using EcoMedics NO analyzers with ambient NO scrubbers, at flows of 50 (conventional), 30, 100, and 300 ml/sec, with 2-3 trials at each flow. Data from 65 children were analyzed by two linear and four nonlinear published models, plus a new empirical nonlinear model. Bronchial NO flux estimates from different models differed in magnitude but were strongly correlated (r >or= 0.95), and increased in subjects with allergic asthma. Alveolar concentration estimates differed among models and did not consistently show the same effects of allergy or asthma. A novel index of nonlinear behavior of NO output versus flow was significantly related to asthma status, and not strongly correlated with bronchial flux or alveolar concentration. Field-based extended NO testing of children can yield useful information about NO in different regions of the respiratory tract that is not obtainable from conventional FeNO. Extended NO analysis holds promise for investigating environmental and genetic determinants of regional airway inflammatory states. PMID- 19774623 TI - Evaluation of DPC immulite 2000 Toxoplasma quantitative IgG/IgM kits for automated toxoplasmosis serology with immulite 2000. AB - In this study, we evaluated a new immunoassay for the automated detection of anti toxoplasma IgG and IgM with Immulite 2000 (DPC-Siemens, La Garenne-Colombes, France). We tested 280 sera from 112 patients with past infection (PI), 40 PI with residual IgM, 75 seronegatives, 16 infants (31 sera) monitored for neonatal screening of congenital toxoplasmosis, and 13 patients with recent seroconversion (SC) (22 sequential sera). Detection sensitivity and specificity for IgG were 99 and 100%, respectively. IgG titers obtained with Immulite 2000 were higher than with Vidas (BioMerieux, Marcy I'Etoile, France) and Access (Beckman-Coulter, Villepinte, France) (paired Wilcoxon test z=4.44 and z=3.67, respectively, P<0.001). IgM specificity was 100%. Detection sensitivity for IgM was 100% in the SC group, 86% in congenitally infected infants, and 75% in PI with persistent IgM. IgM detection seemed less prolonged in time than with the IgM Access and ISAGA IgM techniques. PMID- 19774624 TI - Comparison of the influence of thyroglobulin antibodies on serum thyroglobulin values from two different immunoassays in post surgical differentiated thyroid carcinoma patients. AB - Measurement of serum thyroglobulin (Tg) is a highly specific test in the management of patients with differentiated thyroid cancer (DTC) after surgical treatment. The aim of our study was to evaluate and compare Tg levels in these patients found by radioimmunoassay (RIA) and immunoradiometric assay (IRMA) and to assess the influence of Tg antibodies (TgAbs) on the values obtained for Tg concentration. Both Tg and TgAb were determined postoperatively in the serum of 71 DTC patients using RIA Tg-PEG (INEP) and Tg IRMA (CIS) for Tg, together with TgAb (CIS) for circulating endogenous anti-TgAbs. The obtained concentrations were evaluated statistically. We found a significant difference of Tg concentrations between paired samples from the IRMA and RIA, although the intermethod comparison yielded satisfactory concordance of the two assays (Spearman correlation coefficient -0.792). Positive TgAb was found in 28.2% of the serum samples analyzed. Spearman rank correlation analysis revealed a significant negative relationship between serum TgAb and Tg level measured by IRMA (P=0.02), but not by RIA (P=0.417). On the other hand, our clinical data revealed that 1/18 and 3/18 patients with proven lymph node metastasis had Tg values below the detection limit by RIA and IRMA assay, respectively. Their sera were TgAb positive. We concluded that RIA was less prone to influence of TgAb than IRMA. As the presence of TgAbs may interfere in Tg measurement irrespective of the method selected for determination, this should be considered during the clinical management of these patients. PMID- 19774625 TI - Oxidative status in iron-deficiency anemia. AB - Oxidative stress is an imbalance between free radicals and antioxidant molecules that can play an important role in the pathogenesis of iron-deficiency anemia (IDA). The aim of this study was to investigate oxidative status in patients with IDA and alteration of oxidative status after iron treatment. Thirty-three female patients with IDA and 25 healthy controls were included in this study. Oxidant and total antioxidant capacity were determined using free oxygen radicals test and free oxygen radicals defence (Form CR 3000, Callegari, Parma, Italy). Catalase activity was measured by spectrophotometer using a commercially available kit (Bioxytech Catalase-520, OxisResearch, Portland, OR). Oxidant activity in patients with IDA was significantly higher than controls (P<0.05), while total antioxidant and catalase activity were significantly lower (P<0.05). After treatment, oxidant, antioxidant, and catalase activity reached the levels of the control group, and no significant differences were observed among groups (P>0.05). In conclusion, our data indicate that blood reactive oxygen species was lower and total antioxidant and catalase activity were higher after rather than before treatment in patients with IDA. The results of our study support the higher oxidative stress hypothesis in IDA; however, due to the limited number of cases included, more studies may be required to confirm the results. PMID- 19774626 TI - The utility of serum human epididymis protein 4 (HE4) in patients with a pelvic mass. AB - AIM: Although CA125 is the most widely used cancer marker in the diagnostic approach of pelvic masses in women, its clinical usefulness is limited because it lacks expression of the antigen in the early stages of disease. The human epididymis protein 4 (HE4) is frequently over-expressed in ovarian cancer, whereas its expression in normal tissues, including the ovary, is low. The aim of this study was to assess the concentration of both HE4 and CA125 in patients with different forms of benign and malign pelvic masses. METHODS: The study population included 99 patients with gynecological cancer (46 ovarian, 39 endometrial, 14 cervical) and 40 affected by benign disease (22 endometriosis and 18 benign ovarian mass). Twelve control subjects were also included in the study. In all the patients, serum samples were collected on the day before scheduled surgery. RESULTS: The median CA125 and HE4 serum levels were significantly higher among ovarian cancer patients as compared with healthy subjects and with those with benign mass, cervical, and endometrial tumors. The receiver operating characteristics curve analysis on healthy controls and patients with ovarian cancers revealed that HE4 had a significantly higher area under the curve when compared with CA125 (0.99 vs. 0.91), with a sensibility and specificity of 98 and 100%, respectively. CONCLUSIONS: HE4 seems to be a promising ovarian cancer marker, and its measurement might improve the diagnostic approach to patients with pelvic masses. PMID- 19774627 TI - Free flap options for reconstruction of complicated scalp and calvarial defects: report of a series of cases and literature review. AB - OBJECTIVE: The advent of free tissue transfer has offered several options that allow the restoration of both the structural and functional defects of the scalp and calvaria caused by malignant tumors or sequelae after trauma. This study aims to investigate the free flap options for complicated scalp and calvarial reconstructions. METHODS: There were 12 free tissue transfers used to reconstruct scalp and calvarial defects in this study, with nine acute or subacute wounds resulting from trauma or cranietomy, two congenital hydrocephalus post ventriculo peritoneal shunting and one primary cancer. They consisted of five fasciocutaneous flaps (four anterolateral thigh fasciocutaneous flaps and one deep inferior epigastric perforator flap) and seven myocutaenosu flaps (five anterolateral thigh myocutaneous flaps and two rectus abdominis myocutaneous flaps). RESULTS: The overall flap success rate was 100%. There were no major complications except for one where wound dehiscence was caused by hematoma accumulation and was healed by local debridement. All donor sites underwent primary closure except for three receiving split-thickness skin grafting after bulky anterolateral thigh flap harvest. No major donor-site morbidity was observed except for one patient with some graft loss. CONCLUSIONS: With its evident structural and functional advantages, fasciocutaneous flaps were suitable for larger scalp defect only and myocutaneous flaps can be considered as an excellent reconstructive option for complicated scalp and calvarial defects, especially where dead space coexists. PMID- 19774628 TI - Comparison of free anterolateral thigh flaps and free muscle-musculocutaneous flaps in soft tissue reconstruction of lower extremity. AB - BACKGROUND: The objective of this study was to compare the free muscle musculocutaneous flaps and free perforator skin flaps used for soft tissue reconstruction of the lower extremities. METHODS: Fifty-three patients whose skin and soft tissue of the lower extremities had been reconstructed were divided into two groups: a perforator flap group, reconstructed using anterolateral thigh (ALT) free flap (23 cases), and a muscle-musculocutaneous flap group, in whom latissimus dorsi and rectus abdominus muscle-musculocutaneous free flaps were used (30 cases). Postoperative complications, long-term results, and donor site morbidities were studied in the two groups. RESULTS: Complete flap survival was 78.3% with four total and one partial flap loss in the ALT group and 90.0% with one total and two partial failure in the muscle-musculocutaneous flap group. Muscle-musculocutaneous flaps were the flaps of choice in Gustillo grade IIIB-C injuries and for reconstruction of more proximal localizations. ALT was preferred in relatively younger patients and was typically used for coverage of the distally localized defects. Flap complication rate was significantly higher in the ALT group, but the overall complication rate was similar between the groups. CONCLUSION: ALT perforator flap is a precious option for lower extremity soft tissue reconstruction with minimal donor site morbidity. Nevertheless, the beginners should be attentive to an increased rate of flap complications with the ALT flap and free axial muscle-musculocutaneous flaps would still be the tissue of choice for coverage of leg defects for a surgeon before gaining enough experience with perforator flap dissection. PMID- 19774629 TI - Use of the descending branch of lateral circumflex femoral artery as a recipient pedicle for coverage of a knee defect with free flap: anatomical and clinical study. AB - BACKGROUND: With recent advances in free tissue transfer, soft tissue defects involving the knee can be covered perfectly utilizing various free flaps. Yet the success of this operation depends on a secure nontraumatic recipient pedicle around the knee area. The purpose of this study is to introduce the descending branch (DB) of the lateral circumflex femoral artery (LCFA) as a new recipient pedicle for knee defect coverage. METHODS: Through autopsies of eight cadavers and a total of 11 extremities involving the area 10- and 15-cm above the upper margin of the patella, the number and sizes of the artery and vein of the descending branch of the lateral circumflex femoral artery were investigated. In a clinical setting, two cases of soft tissue defects in the area of the knee were reconstructed utilizing the DB of the LCFA with an anterolateral thigh perforator (ALTP) free flap on the ipsilateral side. RESULTS: Anatomical: The descending branches of the lateral circumflex femoral vessels measuring 10- and 15-cm above the lateral aspect of the patella numbered 1 artery and about 1.5 veins. The diameters of these vessels ranged from 1.0 to 2.0 mm (1.4 +/- 0.4 mm) for the artery at 10-cm site and 1.0 to 3.0 mm (1.9 +/- 0.5 mm) at the 15-cm site and 0.8 to 2.0 mm (1.2 +/- 0.4 mm) for the vein at the 10-cm site and 1.0 to 3.0 mm (1.9 +/- 0.5 mm) at the 15-cm site. Under clinical conditions, the two case flaps survived well without major complications. The clinical follow-up period was from 12 to 14 months (mean: 13 months). CONCLUSIONS: The advantage in using this recipient pedicle lies not only in its superficial aspect but also in the protection offered by the surrounding muscle. Thus the defect could be reconstructed efficiently without stress upon the surgeon; if the ALTP flap of the ipsilateral side was used, the defect could be reconstructed efficiently within the same surgical field. PMID- 19774631 TI - Bone marrow aspirate and biopsy: a pathologist's perspective. II. interpretation of the bone marrow aspirate and biopsy. AB - Bone marrow examination has become increasingly important for the diagnosis and treatment of hematologic and other illnesses. Morphologic evaluation of the bone marrow aspirate and biopsy has recently been supplemented by increasingly sophisticated ancillary assays, including immunocytochemistry, cytogenetic analysis, flow cytometry, and molecular assays. With our rapidly expanding knowledge of the clinical and biologic diversity of leukemia and other hematologic neoplasms, and an increasing variety of therapeutic options, the bone marrow examination has became more critical for therapeutic monitoring and planning optimal therapy. Sensitive molecular techniques, in vitro drug sensitivity testing, and a number of other special assays are available to provide valuable data to assist these endeavors. Fortunately, improvements in bone marrow aspirate and needle technology has made the procurement of adequate specimens more reliable and efficient, while the use of conscious sedation has improved patient comfort. The procurement of bone marrow specimens was reviewed in the first part of this series. This paper specifically addresses the diagnostic interpretation of bone marrow specimens and the use of ancillary techniques. PMID- 19774630 TI - An improved microalbumin method (microALB_2) with extended analytical measurement range evaluated on the ADVIA chemistry systems. AB - Quantitative determination of albumin (ALB) in human urine is important to assess kidney functions in a variety of diseases. Recently, Siemens released an improved Microalbumin assay (microALB_2) to measure urinary ALB on the automated, random access ADVIA 1650/1800, ADVIA 2400, and ADVIA 1200 Chemistry Systems. We evaluated analytical performances of this new method. All ADVIA Chemistry Systems use the same microalbumin reagent packs, microALB_2 calibrators, and commercial controls. The within-run and total CVs of the improved method with two-level BioRad Liquichek Urine Chemistry controls (approximately 2 and 9 mg/dl ALB) and a urine pool (approximately 29 mg/dl ALB) on all ADVIA Chemistry systems were <4.1 and <6.1%, respectively (40 replicates per sample). The analytical range/linearity of the method (all ADVIA systems) was from 0.3 mg/dl to theALB concentration in the highest level of calibrator (approximately 38-42 mg/dl). The improved method (microALB_2) on the ADVIA 1650/1800 (y) correlated well with both the Beckman DXC 800 Microalbumin and the old microalbumin method on the ADVIA 1650/1800 analyzers. The improved method showed <10% interference with 16 chemicals from acetaminophen to uric acid that may be present in urine. The improved method has a minimum of 60 days' on-system stability on all systems with the calibration frequencies of (with/without a Reagent Container insert) 20/30 days (ADVIA1200), 50/60 days (ADVIA1650/1800), and 20/60 days (ADVIA2400). No prozone was observed with the method on any platform up to the highest ALB concentration tested in a sample (4,000 mg/dl). PMID- 19774632 TI - Systematic analysis of interference due to stutter in estimating chimerism following hematopoietic cell transplantation. AB - Stutter formed during amplification of short tandem repeats (STRs) interfere with accurate engraftment monitoring following hematopoietic cell transplantation (HCT). We describe a mathematical approach to minimize the contribution of stutter when estimating chimerism following HCT. Pretransplant DNA samples from 409 donors and recipients were used to define marker-specific stutter cut-off values for all makers used in the AMPFlSTR Profiler Plus amplification kit. Mock chimerism samples (5, 20, and 50%) were used to evaluate the contribution of stutter in estimating chimerism. Three markers, vWA, D13S317, and D18S51, had overlapping stutter in the mock chimerism samples. Only D18S51 had stutter from a shared allele, whereas the other two markers had stutter from nonshared alleles. Without adjustment for stutter, D18S51 showed a 8, 6, and 4% difference from expected chimerism values (5, 20, and 50%) and after adjusting for laboratory defined marker-specific stutter cut-offs the corresponding difference from expected chimerism values was 1, 0, and 0%. Difference from expected chimerism values in the vWa and D13S317 markers were similar before and after adjustment of stutter. Adjustment for stutter from shared alleles may improve accuracy of estimated chimerism. PMID- 19774634 TI - Ocular late effects in childhood and adolescent cancer survivors: a report from the childhood cancer survivor study. AB - INTRODUCTION: Approximately 80% of children currently survive 5 years following diagnosis of their cancer. Studies based on limited data have implicated certain cancer therapies in the development of ocular sequelae in these survivors. PROCEDURE: The Childhood Cancer Survivor Study (CCSS) is a retrospective cohort study investigating health outcomes of 5+ year survivors diagnosed and treated between 1970 and 1986 compared to a sibling cohort. The baseline questionnaire included questions about the first occurrence of six ocular conditions. Relative risks (RR) and 95% confidence intervals (CI) were calculated from responses of 14,362 survivors and 3,901 siblings. RESULTS: Five or more years from the diagnosis, survivors were at increased risk of cataracts (RR: 10.8; 95% CI: 6.2 18.9), glaucoma (RR: 2.5; 95% CI: 1.1-5.7), legal blindness (RR: 2.6; 95% CI: 1.7 4.0), double vision (RR: 4.1; 95% CI: 2.7-6.1), and dry eyes (RR: 1.9; 95% CI: 1.6-2.4), when compared to siblings. Dose of radiation to the eye was significantly associated with risk of cataracts, legal blindness, double vision, and dry eyes, in a dose-dependent manner. Risk of cataracts were also associated with radiation 3,000+ cGy to the posterior fossa (RR: 8.4; 95% CI: 5.0-14.3), temporal lobe (RR: 9.4; 95% CI: 5.6-15.6), and exposure to prednisone (RR: 2.3; 95% CI: 1.6-3.4). CONCLUSIONS: Childhood cancer survivors are at risk of developing late occurring ocular complications, with exposure to glucocorticoids and cranial radiation being important determinants of increased risk. Long-term follow-up is needed to evaluate potential progression of ocular deficits and impact on quality of life. PMID- 19774635 TI - Long-term population-based divorce rates among adult survivors of childhood cancer in Britain. AB - BACKGROUND: Previously from the British Childhood Cancer Survivor Study (BCCSS) it was seen that adult survivors of childhood cancer were less likely to marry than the general population. The objectives of this study were to assess the number of childhood cancer survivors from the BCCSS who were currently divorced or separated, examine factors associated with marriage dissolution and compare survivor divorce rates to population rates. PROCEDURE: The BCCSS is a population based cohort of 18,119 individuals diagnosed with cancer aged 0-14 years between 1940 and 1991, and survived at least 5 years. 14,539 were alive, aged 16 years or over and eligible to receive a questionnaire, which ascertained marital status. RESULTS: From 8,155 survivors, who were aged at least 20 years at questionnaire completion, the proportions currently divorced and divorced or separated were 13.5% and 18.1%, respectively. Only current age, educational attainment and age at marriage were associated with divorce, and for divorce and separation status only age at marriage (P < 0.05). Overall the survivors were no different to the general population for being currently divorced (odds ratio (OR) (95% confidence intervals (95% CI)): 0.94 (0.81-1.10)). However, the survivors overall (OR (95% CI): 0.82 (0.72-0.94)), and separately for those diagnosed with non-Hodgkin lymphoma (OR (95% CI): 0.55 (0.34-0.89)) and leukaemia (OR (95% CI): 0.70 (0.52 0.95)), were less likely to be currently divorced or separated than the general population. CONCLUSIONS: It is reassuring that survivors do not experience more divorce than the general population, and that no cancer or treatment factors were shown to be associated with marriage dissolution. PMID- 19774637 TI - Cystatin C and parenchymal thickness/kidney length ratio in Wilms tumor survivors. AB - BACKGROUND: This study presents a clinical, biochemical, and sonographic evaluation of single kidneys in Wilms tumor survivors. PROCEDURE: The function of single kidneys in 26 Wilms tumor survivors (mean age, 11.17 years; mean follow up, 7.09 years) was evaluated using cystatin C (CysC) levels and compared to serum creatinine concentration and glomerular filtration rate (eGFR), the latter of which was estimated by the Schwartz formula. The length of the kidney, the resistance index (RI) of the renal vessels, and the parenchymal thickness/kidney length ratio (PT/KL) were evaluated by sonographic examination. RESULTS: Group A (n = 15) consisted of children with normal CysC levels, and group B (n = 11) consisted of children with CysC over 0.95 mg/L. No differences were observed between the groups in creatinine concentration, age, follow-up evaluation, age at the time of diagnosis, or kidney size. Children with elevated CysC had statistically lower eGFR (P = 0.02) and PT/KL (P = 0.0065). The correlation rate between CysC and PT/KL in all children was -0.38. Kidney hypertrophy was observed in 23 children and was correlated with CysC (group A, R = 0.46; group B, R = 0.4; P < 0.05). RI was normal in all individuals. CONCLUSIONS: CysC levels may be elevated in people with normal GFR. Hypertrophy of a single kidney increases with deteriorating kidney function. PT/KL should be verified in future studies as a sonographic marker of kidney impairment. PMID- 19774638 TI - Pharmacogenomic variations in treatment protocols for childhood acute lymphoblastic leukemia. AB - OBJECTIVES: This retrospective study evaluates the role of pharmacogenomic determinants in the treatment of childhood acute lymphoblastic leukemia (ALL) in the Taiwanese population. METHODS: A total of 105 childhood ALL patients received combined chemotherapy of different intensities based on risk-directed Taiwan Pediatric Oncology Group (TPOG)-ALL-93 protocols. Seventeen genetic polymorphisms in 13 pharmacogenomic targets were analyzed by PCR-based restriction fragment length polymorphism (RFLP) and sequence-specific oligonucleotide (SSO) probe hybridization. Pharmacogenomic polymorphisms were correlated with event-free survival (EFS) of patients, with confounding effects adjusted by multivariate regression. RESULTS: Three polymorphic alleles in the multi-drug resistance 1 (MDR1) ABCB1 gene, and homozygotic MDR1 2677GG, 3435CC, and 2677G-3435C genotypes were highly associated with a significant reduction in EFS in those patients treated by the standard risk (SR) protocol (TPOG-ALL-93-SR). The hazard ratios were 6.8 (p = 0.01), 21.7 (p = 0.009), and 6.8 (p = 0.01), respectively. CONCLUSIONS: Independent pharmacogenomic determinants associated with treatment outcome were identified in subsets of Taiwanese ALL patients. PMID- 19774639 TI - Autism in children and adolescents with cancer. AB - BACKGROUND: The causes of autistic disorders (AD) are not known. Abnormalities of tumor suppressor genes have suggested that these genes may be important to the development of autism in some cases, and result in an increased risk of developing cancer or other neoplasms. We explore possible associations between AD and childhood cancer. PROCEDURE: We reviewed our institutional pediatric cancer database for all new cancer diagnoses 1997-2007. Medical records from patients older than 2 years at last visit were reviewed for a diagnosis of AD. The prevalence of AD was estimated for neoplasms overall and for specific tumor types, and compared with that in the general pediatric population. RESULTS: Of 702 eligible patients, 7 (1%; 95% CI: (0.4%, 2.04%)) were labeled as AD, not different than the prevalence of AD in North Carolina's general population (0.65%, P = 0.35). Cancer diagnoses for these 7 children were acute lymphoblastic leukemia (n = 1), acute nonlymphocytic leukemia (n = 2), non-Hodgkin lymphoma (n = 1), Hodgkin Disease (n = 1), brain tumor (n = 1), osteogenic sarcoma (n = 1). CONCLUSIONS: These data do not suggest that there is a high concordance between AD and childhood cancer. However, studies of large rigorously characterized AD cohorts will be needed to definitively address this issue. PMID- 19774640 TI - Bacteremia in febrile nonneutropenic pediatric oncology patients. AB - BACKGROUND: We sought to determine the risk of bacteremia in a cohort of outpatient febrile nonneutropenic pediatric oncology patients and to assess clinical characteristics that may influence decisions regarding empiric antibiotic therapy. PROCEDURE: A single institution retrospective cohort study was performed of outpatient pediatric oncology patients presenting with fever, a central venous catheter, and an absolute neutrophil count (ANC) of >/=500/microl over a 6-year period. We also collected data regarding the presence of clinically evident infections, antibiotics prescribed, and the sensitivity of bacteria to specific antibiotics. RESULTS: There were 29 cases of bacteremia in 459 (6.3%) febrile outpatient visits by 167 patients. Bacteremia was documented in 4.4% of patients with ports and in 16.2% of patients with external catheters. Patients with external catheters had a relative risk of bacteremia of 3.7 (95% CI: 1.8 7.4) times the risk of those with internal catheters (P < 0.0001). A documented source for fever on exam was noted in 21% of patients but in none of the patients with bacteremia (P = 0.004). Empiric treatment with ceftriaxone was administered to 92% of the patients. Of the high-risk bacteremic infections (Gram-negative organisms, Streptococcus pneumoniae, viridans group streptococcus, and Staphylococcus aureus) 94% had at least an intermediate sensitivity to ceftriaxone. CONCLUSIONS: Bacteremia is an important issue in febrile nonneutropenic pediatric oncology patients occurring in 6% of the patient visits in this study. The overall sensitivity of high-risk bacteremia to ceftriaxone provides justification for its empiric use in outpatient febrile nonneutropenic pediatric oncology patients. PMID- 19774641 TI - Functional independence score in hemophilia: a cross-sectional study assessment of Mexican children. AB - BACKGROUND: The Functional Independence Score in Hemophilia (FISH) is a performance-based assessment tool used to measure the patients functional ability so far only used in patients with severe hemophilia. Its aim is to determine if FISH is useful in patients with mild and moderate disease. PROCEDURE: In a cross sectional study 90 children 60 hemophilic and 30 sex-, race-, and age-matched healthy males were assessed. Patients between 5 and 16 years of age were selected each patient was evaluated in seven activities under three categories: self-care (grooming and eating, bathing, and dressing), transfers (chair and squat), and locomotion (walking and step climbing). Each activity was graded from 1 to 4 according to the amount of assistance required to perform the activity with total scores ranging from 7 to 28. RESULTS: As a whole, the mean age of the patients was 10.0 +/- 3.4 years with a mean FISH of 25.8 +/- 3.6 (range 15-28). There were no differences in the FISH between healthy males and patients with mild hemophilia; however, the score was significantly higher in patients with mild hemophilia (28 +/- 0) than patients with moderate (26.2 +/- 2.5; P = 0.004) or severe hemophilia (24.0 +/- 4.7; P = 0.0006). The most affected activities were squatting, walking, and step climbing. CONCLUSIONS: A significant decrease in functional ability was demonstrated according to the severity of hemophilia, especially for those activities involving weight-bearing demands like locomotion and step climbing. Of seven activities evaluated, changes were observed in the group with moderate and severe hemophilia, but no changes detected in patients with mild disease. PMID- 19774642 TI - Does psychological counseling alter the natural history of inflammatory bowel disease? AB - BACKGROUND: There is increasing evidence that psychological stress can increase mucosal inflammation and worsen the course of inflammatory bowel disease (IBD). We have now assessed whether psychotherapy by a counselor specially trained in the management of IBD can influence the course of disease. METHODS: Using retrospective case note review, we compared the course of IBD in 24 patients (13 ulcerative colitis; 11 Crohn's disease), during the year before (year 1) and the year after referral (year 2) for supportive outpatient psychotherapy to an IBD counselor, to that of 24 IBD controls who were matched to individual cases for age, sex, disease, duration of disease, medication at baseline, and for relapse rate in year 1. Counselor assessments were made using a visual analog scale 0-6 (0 denotes poor, 6 excellent response to counseling). The results are shown as median (range). RESULTS: Patients were referred for counseling because of disease related stress (14 patients), work problems (3), concerns about surgery (5), and bereavement (2); they received 6 (1-13) 1-hour sessions in year 2. In the year after starting counseling (year 2), patients had fewer relapses (0 [0-2]) and outpatient attendances (3.5 [1-10]) than in the year before referral (year 1) (2 [0-5], P = 0.0008; and 6.5 [1-17], P = 0.0006, respectively; furthermore, steroid usage (1 course [0-4] before, 0 [0-2] after, P = 0.005) and relapse-related use of other IBD medications declined during psychotherapy (1 drug [0-5] before, 0 [0 2] after, P = 0.002). There were no differences in any of these measures between years 1 and 2 in the control group. Numbers of hospital admissions did not change between year 1 and 2 in either group. In the 20 patients who attended >1 session counseling helped solve stress-related difficulties (counselor's score 4 [3-5]), the counselor scored them 4 (3-6) overall in psychological well-being after the counseling sessions. CONCLUSIONS: IBD-focused counseling may improve not only psychological well-being, but also the course of IBD in individuals with psychosocial stress. PMID- 19774643 TI - Butyrate utilization by the colonic mucosa in inflammatory bowel diseases: a transport deficiency. AB - The short-chain fatty acid butyrate, which is mainly produced in the lumen of the large intestine by the fermentation of dietary fibers, plays a major role in the physiology of the colonic mucosa. It is also the major energy source for the colonocyte. Numerous studies have reported that butyrate metabolism is impaired in intestinal inflamed mucosa of patients with inflammatory bowel disease (IBD). The data of butyrate oxidation in normal and inflamed colonic tissues depend on several factors, such as the methodology or the models used or the intensity of inflammation. The putative mechanisms involved in butyrate oxidation impairment may include a defect in beta oxidation, luminal compounds interfering with butyrate metabolism, changes in luminal butyrate concentrations or pH, and a defect in butyrate transport. Recent data show that butyrate deficiency results from the reduction of butyrate uptake by the inflamed mucosa through downregulation of the monocarboxylate transporter MCT1. The concomitant induction of the glucose transporter GLUT1 suggests that inflammation could induce a metabolic switch from butyrate to glucose oxidation. Butyrate transport deficiency is expected to have clinical consequences. Particularly, the reduction of the intracellular availability of butyrate in colonocytes may decrease its protective effects toward cancer in IBD patients. PMID- 19774644 TI - Spray drying technique. I: Hardware and process parameters. AB - Spray drying is a transformation of feed from a fluid state into a dried particulate form by spraying the feed into a hot drying medium. The main aim of drying by this method in pharmaceutical technology is to obtain dry particles with desired properties. This review presents the hardware and process parameters that affect the properties of the dried product. The atomization devices, drying chambers, air-droplet contact systems, the collection of dried product, auxiliary devices, the conduct of the spray drying process, and the significance of the individual parameters in the drying process, as well as the obtained product, are described and discussed. PMID- 19774645 TI - CXCL12 is a constitutive and inflammatory chemokine in the intestinal immune system. AB - BACKGROUND: Inflammatory bowel disease (IBD) is characterized by increased lymphocytic infiltrate to the lamina propria (LP) and upregulation of inflammatory chemokines and receptors. CXCL12 is a constitutive chemokine involved in lung, brain, and joint inflammation. We hypothesized that CXCL12 and its receptor, CXCR4, would have a constitutive and inflammatory role in the gut. METHODS: Intestinal epithelial cells (IECs) and T lymphocytes were isolated from intestinal mucosa of IBD and control patients undergoing bowel resection. Autologous T cells were isolated from peripheral blood (PB). CXCL12 and CXCR4 expression by IECs was assessed by polymerase chain reaction and immunohistochemistry, lymphocyte phenotype by flow cytometry, and migration by Transwells. RESULTS: IECs expressed CXCL12 and expression was increased and more diffuse in IBD compared to normal crypts (ulcerative colitis [UC] > Crohn's disease [CD], inflamed > noninflamed). CXCR4 was expressed by IECs, LP T cells (LPTs), and PB T cells (PBTs), and CXCR4+ cells were increased in IBD LP in situ. PBTs and LPTs from all patients had a high and comparable migration toward CXCL12 (P < 0.0001 and P < 0.05 vs. medium, respectively). Migration toward IBD-IEC derived supernatant was significantly higher compared to normal. Antibodies against CXCR4 and CXCL12 blocked migration. CONCLUSIONS: CXCL12 is expressed by normal IECs and upregulated and differentially distributed in IBD IECs. CXCR4 is expressed by IECs and LPTs, and CXCR4+ cells are significantly increased in IBD LP. CXCL12 is chemotactic for both PBTs and LPTs. Thus, CXCL12 and CXCR4 have a constitutive and inflammatory role in the intestinal mucosa and their selective therapeutic manipulation may be considered in IBD management. PMID- 19774646 TI - TLR5 is not required for flagellin-mediated exacerbation of DSS colitis. AB - BACKGROUND: The two forms of human inflammatory bowel disease, Crohn's disease (CD) and ulcerative colitis (UC), are both associated with loss of tolerance to gut microbial antigens. The dominant antigen recognized by antibody and T-cell responses in patients with CD is bacterial flagellin. Flagellin is also the only known ligand for Toll-like receptor 5 (TLR5), a key protein in innate immunity. Although flagellin activates TLR5 to produce inflammatory responses in many cell types in the gut, there is conflicting evidence as to whether TLR5 is harmful or protective in CD and murine colitis models. A recent study found that administration of flagellin enemas to mice along with dextran sodium sulfate (DSS) made their colitis worse. METHODS: We sought to determine whether this exacerbation was due to TLR5 ligation, or to TLR5-independent adaptive immune responses to flagellin as an antigen, by using a transposon insertional mutant of the Escherichia coli H18 flagellin, 2H3, which lacks TLR5 stimulatory activity. RESULTS: We found that flagellin enemas produced only a mild exacerbation of DSS colitis, and that 2H3 was equivalent to or worse than wildtype flagellin. Moreover, we found that DSS colitis was more severe in TLR5(-/-) mice than wildtype C57BL/6 mice. CONCLUSIONS: Together, these results suggest that flagellin-mediated exacerbation of colitis is independent of TLR5. PMID- 19774647 TI - Mapping of inflammatory bowel disease in northern France: spatial variations and relation to affluence. AB - BACKGROUND: Geographic variations in the incidence of inflammatory bowel disease (IBD) may reflect variations in the distribution of environmental etiologic factors. We assessed spatial variation in the incidence of IBD in northern France and analyzed its association with a deprivation index. METHODS: All cases of IBD included in the EPIMAD registry between 1990 and 2003 were extracted. The standardized incidence ratio (SIR) was calculated for each canton in the region. The association between incidence and deprivation was assessed using the Townsend deprivation index. RESULTS: The mean annual incidence rates of Crohn's disease (CD) and ulcerative colitis (UC) were 6.2 x 10(-5) and 3.8 x 10(-5), respectively. The mean cumulative numbers of cases by canton were 18.4 (1-183) for CD and 11.3 (0-148) for UC. For both CD and UC, mapping depicted spatial heterogeneity in the SIR with spatial autocorrelation. A high relative risk (RR) of CD was observed in mainly rural and periurban cantons of the region. For UC, a high RR was found in cantons of the south and the center of Pas-de-Calais. No significant correlation was observed between spatial variations in IBD and deprivation. CONCLUSIONS: The incidence of IBD is associated with spatial heterogeneity in northern France. The noteworthy predominance of CD in agricultural areas warrants further investigations. PMID- 19774648 TI - Transmission ratio distortion of DLG5 R30Q: evidence for prenatal selection? PMID- 19774649 TI - 5-aminosalicylic acid interferes in the cell cycle of colorectal cancer cells and induces cell death modes. AB - INTRODUCTION: Epidemiological data suggests that 5-aminosalicylic acid (5-ASA), a nonsteroidal antiinflammatory drug used in the treatment of inflammatory bowel diseases, prevents colorectal cancer development in these patients, although the mechanisms remain incompletely understood. METHODS AND RESULTS: Here we report that 5-ASA prevents growth of several colorectal cancer cell lines by interfering in the cell cycle, i.e., an S-phase and G2/M phase arrest, dependent on 5-ASA dosage and concentration, together with an increased mitotic index. In addition, prolonged cell cycle arrest by repeated 5-ASA treatment induced apoptosis and caused abnormal spindle organization leading to mitotic catastrophe, another form of cell death. CONCLUSION: These observations illustrate that 5-ASA has chemopreventive and chemotherapeutic properties. PMID- 19774650 TI - Interaction of antithyroid drugs with bovine serum albumin: electrophoretic and fluorimetric study. AB - The pre-equilibrium capillary zone electrophoretic (pre-eq CZE) method to determine association constants of active anionic forms of antithyroid drugs: 6-n propyl-2-thiouracil (PTU), 6-methyl-2-thiouracil (MTU), 2-thiouracil (TU) with bovine serum albumin (BSA) under physiological pH 7.4 has been developed for the first time. Using the decrease of the selective electrochromatographic peak area of a drug anionic form due to binding with BSA the association constants K of the binary BSA complexes were calculated. It has been found that the binding constants (log K) of BSA with TU, MTU, and PTU are equal to 2.99, 1.85, and 2.11, respectively. The interaction of PTU, MTU, TU, 2-mercapto-1-methylimidazole (MMI), and ethyl-3-methyl-2-thionoimidazoline-1-carboxylate (Carb), which is considered to be a prodrug for MMI, with BSA has been investigated under physiological conditions by means of fluorescence spectroscopy. Fluorescence emission spectra of BSA in the presence of thioamides recorded at 295 nm excitation wavelength clearly show that the studied drugs act as quenchers, except MMI, which acts as quencher when being excited at 280 nm. The 295 nm light excites tryptophan residues, while the 280 nm light excites both tryptophan and tyrosine residues. The binding constants (log K) of BSA with PTU, MTU, TU, MMI, and Carb have been found to be 4.51, 4.30, 4.30, 2.64, and 4.32, respectively. PMID- 19774651 TI - Inhibition of agitation-induced aggregation of an IgG-antibody by hydroxypropyl beta-cyclodextrin. AB - In order to provide an alternative to nonionic surfactants as excipients for protein formulations, cyclodextrin-derivatives (CDs) were examined for their potential to inhibit agitation-induced aggregation of an IgG in aqueous solution. Loss of monomeric protein and protein aggregation were monitored throughout the agitation experiments by size exclusion chromatography. Hydroxypropyl-beta cyclodextrin (HPbetaCD) completely suppressed IgG-aggregation at a remarkably low concentration (2.5 mM) and in contrast to other CDs it also did not negatively affect IgG-stability during storage in nonagitated solution. Further agitation experiments demonstrated the superiority of HPbetaCD to other common excipients in protein formulation, such as sugars and sugar alcohols or polysorbate 80 in low concentrations. Spectroscopic (fluorescence spectroscopy and Fourier transform infrared spectroscopy), thermodynamic (microcalorimetry), and physical investigations (surface tension measurements) were carried out to elucidate the mechanism of stabilization of the IgG. In contrast to other studies with HPbetaCD, protein stabilization could not be attributed to direct interaction between hydrophobic amino acids on the IgG and this excipient. Competition with the protein for the air-water interface appears to be the dominating mechanism of stabilization. PMID- 19774652 TI - Manufacture of pharmaceutical co-crystals using twin screw extrusion: a solvent less and scalable process. PMID- 19774653 TI - Prediction of solubility of drugs and other compounds in organic solvents. AB - We have set out a procedure for the prediction of solubilities of drugs and other compounds in a wide range of solvents, based on the Abraham solvation equations. The method requires a knowledge of solubilities of a given compound in a few solvents, as shown by our own experimental data on apocynin, diapocynin, dehydrodivanillin, and dehydrodi(methyl vanillate). The procedure is especially useful for very hydrophobic compounds such as cholesteryl acetate and cholesterol that we give as examples. Other examples include vanillin and 3,4-dichlorobenzoic acid. If the solubility in water is available, then this alone is sufficient to predict solubilities in organic solvents, provided that the Abraham descriptors are available for the compound. Predictions can be made for solubilities in some 85 solvents. PMID- 19774654 TI - Quality-by-Design (QbD): an integrated process analytical technology (PAT) approach for real-time monitoring and mapping the state of a pharmaceutical coprecipitation process. AB - In this work, an integrated PAT approach was developed for monitoring a pharmaceutical (naproxen) and a polymer (eudragit) coprecipitation process: real time in-line near-infrared (NIR) absorbance monitoring, real-time on-line turbidity monitoring, and in situ crystal size monitoring. The data and information obtained through these three monitoring techniques confirmed the observation of the onsets of three distinct stages: incubation, nucleation, and crystal growth. The process trajectory constructed based on results of applying principal component analysis (PCA) to either process NIR spectra data or process turbidity profile, clearly demonstrated that various distinguishable process events, including incubation, nucleation, and crystal growth, could be accurately tracked and differentiated. These findings were further supported by process knowledge and information, such as process design, process sequence, thermodynamic and mass-transfer analysis. Therefore, this work provides a case study that illustrated a rational approach to develop a science-based and knowledge-based process monitoring strategy, which is essential for establishing both a suitable process control strategy and an operational process space for a pharmaceutical unit operation. PMID- 19774655 TI - Limitations of amorphous content quantification by isothermal calorimetry using saturated salt solutions to control relative humidity: alternative methods. AB - Despite the high sensitivity of isothermal calorimetry (IC), reported measurements of amorphous content by this technique show significant variability even for the same compound. An investigation into the reasons behind such variability is presented using amorphous lactose and salbutamol sulfate as model compounds. An analysis was carried out on the heat evolved as a result of the exchange of water vapor between the solid sample during crystallization and the saline solution reservoir. The use of saturated salt solutions as means of control of the vapor pressure of water within sealed ampoules bears inherent limitations that lead in turn to the variability associated with the IC technique. We present an alternative IC method, based on an open cell configuration that effectively addresses the limitations encountered with the sealed ampoule system. The proposed approach yields an integral whose value is proportional to the amorphous content in the sample, thus enabling reliable and consistent quantifications. PMID- 19774656 TI - Preparation and physicochemical characterization of a novel water-soluble prodrug of carbamazepine. AB - N-acyl-urea derivatives of carbamazepine (CBZ) were synthesized through the reactions of iminostilbene with acyl-isocyanates to form N-glycyl-carbamazepine (N-Gly-CBZ, after a deprotection step) or N-acetyl-carbamazepine (N-acetyl-CBZ). N-Gly-CBZ was isolated as its water-soluble HCl salt and was designed to act as a prodrug and convert to CBZ and glycine in vivo by enzymatic cleavage of the acyl urea bond. The stability pH-rate profiles for N-Gly-CBZ and N-acetyl-CBZ were determined. The stability of N-Gly-CBZ was found to range over four orders of magnitude with its greatest stability at pH 3-4 and a t(90) value of 5.9 day at pH 4 at 25 degrees C. From the fit of the pH rate profile two pK(a) values were estimated to be 7.2 (terminal amine) and 10.0 (imide), which were independently verified using UV-visible spectroscopic analysis. The solubility of N-Gly-CBZ in aqueous solution was determined in the range of pH 5.5-7.5. The intrinsic solubility of the neutral form of the prodrug was found to be 4.4 mg/mL, and the solubility of the prodrug increased exponentially (log linear) as pH was decreased below its pK(a1) value. N-Gly-CBZ was found to have an aqueous solubility in excess of 50 mg/mL at pH 4. The presence of N-Gly-CBZ was found to increase the aqueous solubility of CBZ, a degradation product. CBZ showed an 8.6 fold greater solubility in an aqueous solution containing 23 mg/mL of N-Gly-CBZ than in water alone. The solubilization of CBZ by N-Gly-CBZ was investigated by examining the diffusion coefficients of the predominant species in D(2)O and was found to be more consistent with stacking complex formation than micelle formation. The stability of N-Gly-CBZ makes a ready-to-use parenteral formulation impractical, but a freeze-dried preparation for reconstitution appears to be feasible. PMID- 19774657 TI - Physiologically based pharmacokinetic model for T84.66: a monoclonal anti-CEA antibody. AB - Antibodies directed against tumor associated antigens are being increasingly used for detection and treatment of cancers; however, there is an incomplete understanding of the physiological determinants of antibody pharmacokinetics and tumor distribution. The purpose of this study is to (a) compare the plasma pharmacokinetics of T84.66, a monoclonal anti-CEA antibody directed against tumor associated carcinoembryonic antigen (CEA), in control and CEA expressing LS174T xenograft bearing mice, and (b) to develop a physiologically based pharmacokinetic (PBPK) model capable of integrating the influence of CEA and the IgG salvage receptor, FcRn, on T84.66 disposition. T84.66 pharmacokinetics were studied following i.v. administration (1, 10, 25 mg/kg) in control and xenograft bearing mice. In control mice, no significant differences in clearance were observed across the dose range studied. In mice bearing xenograft tumors, clearance was increased by four- to sevenfold, suggesting the presence of a "target mediated" elimination pathway. T84.66 plasma disposition was characterized with a PBPK model, and the model was applied to successfully predict antibody concentrations in tumor tissue. The PBPK model will be used to assist in the development of antibody-based targeting strategies for CEA-positive tumors. PMID- 19774658 TI - Spectral and spatial characterization of protein loaded PLGA nanoparticles. AB - The objective of this study was to evaluate near infrared (NIR) spectroscopy and imaging as approaches to assess drug contents in poly(dl-lactide-co-glycolide) (PLGA) based nanoparticles of a model protein, cyclosporine A (CyA). A 6-factors 12-runs designed set of experiments with Plackett-Burman (PB) screening was applied in order to examine the effects of drug loading (X(1)), polymer loading (X(2)), emulsifier concentration (X(3)), stirring rate (X(4)), type of organic solvent (X(5)), and ratio of organic to aqueous phases' volumes (X(6)), on drug entrapment efficiency (EFF). After omitting the factors with nonsignificant influences on EFF, a reduced mathematical relationship, EFF = 48.34 + 7.3X(1) - 29.95X(3), was obtained to explain the effect of the significant factors on EFF. Using two different sets for calibration and validation, the developed NIR calibration model was able to assess CyA contents within the 12 PB formulations. NIR spectral imaging was capable of clearly distinguishing the 12 formulations, both qualitatively and quantitatively. A good correlation with a coefficient of 0.9727 was obtained for constructing a quantile-quantile plot for the actual drug loading percentage and the % standard deviation obtained for the drug loading prediction using the hyperspectral images. PMID- 19774659 TI - Methyl trypsin loaded poly(D,L-lactide-coglycolide) nanoparticles for contact lens care. AB - The need of an enzymatic cleaner for soft contact lens care with an improved ocular safety and stability profile led us to evaluate the use of nanoparticles (NPs) of poly(D,L-lactide-coglycolide) (PLGA) and methyl trypsin (MT). NPs were prepared by double emulsion-solvent evaporation technique. A factorial design was performed to select the lactic acid proportion in the copolymer and conditions of the second sonication. The increment in proportion of lactic acid provided higher particle size results. When the time of second sonication was decreased, the entrapment efficiency (EE) increased. PLGA 50:50 NPs were chosen for further development since PLGA 50:50H NPs settled fast with different particle size in the sediment and PLGA 75:25 NPs led to form aggregates. The addition of glycerol to the NPs provided the highest EE of MT (>90%) while the addition of Tetronic 1304 promoted the fast release of enzyme initially and decreased the zeta potential (zeta) up to neutral values after gamma irradiation. NPs are expected to be effective as a lens care cleaner after 3 days or even longer with a very low quantity of enzyme released. Formulations showed an acceptable irritation ocular tolerance after in vitro HET-CAM test and in vivo Draize test. PMID- 19774660 TI - Brain delivery of proteins by the intranasal route of administration: a comparison of cationic liposomes versus aqueous solution formulations. AB - The goal of this research was to evaluate the effectiveness of cationic liposomes for intranasal administration of proteins to the brain. Cationic liposomes were loaded with a model protein, ovalbumin (OVAL), and a 50 microg dose was administered intranasally to rats. In qualitative studies, liposomes were loaded with Alexa 488-OVAL and delivery was assessed by fluorescence microscopy. By 6 and 24 h after administration, Alexa 488-OVAL deposits were widely distributed throughout brain, with apparent cellular uptake in midbrain by 6 h after administration. In quantitative studies, liposomes were loaded with (111)In-OVAL, and distribution to brain and peripheral tissues was monitored by gamma counting at 1, 4, 6, and 24 h after administration. The highest brain concentrations were achieved at the shortest time point, 1 h, for both liposomal and aqueous OVAL. However, the liposomes yielded higher (111)In-OVAL concentrations in brain than (111)In-OVAL in PBS. Moreover, a 2 microg/microL form of liposomal OVAL yielded a higher percentage of dose in brain, and a lower percentage in stomach and intestines, than twice the volume of a 1 microg/microL preparation. Cationic liposomes may provide a novel, noninvasive strategy for delivery of neuroactive proteins to the brain for treatment of central nervous system disorders. PMID- 19774661 TI - Development of patch and spray formulations for enhancing topical delivery of sinomenine hydrochloride. AB - The purpose of this work was to investigate feasibility of a promising topical drug delivery system (TDDS) for sinomenine hydrochloride (SMH), extracted from the Chinese medicinal plant sinomenine acutum and currently used for the treatment of rheumatoid arthritis. It was found that SMH was a weak base (pK(a), 7.98 +/- 0.04) with pH-dependent solubility and partition coefficient. The result of in vitro permeation studies demonstrated that the permeation enhancer azone was the most effective. In contrast, spray had higher accumulative permeated amounts of SMH than patch, but permeated duration of spray was shorter than that of patch. The efficacy on Freund's complete adjuvant-induced arthritis suggested that there was near arthritis index for SMH spray with medium dose (i.e., 15 mg/rat) and oral solution at a dose of 12 mg/rat, indicating that topical SMH delivery system could achieve the similar anti-inflammatory efficacy with oral administration. Pharmacokinetic parameters including C(max) and AUC for both topical preparations were lower than those for oral preparation, which hinted that systemic side effect could be ignored. Therefore, the spray and patch were promising formulations for successful topical delivery of SMH through the skin instead of oral administration with side effects. PMID- 19774662 TI - A novel route for immobilization of proteins to silica particles incorporating silaffin domains. AB - In the diatom Cylindrotheca fusiformis, modified peptides called silaffin polypeptides are responsible for silica deposition in vivo at ambient conditions. Recently, it was discovered that the synthetic R5 peptide, the repeat unit of silaffin polypeptide without post-translational modification, was capable of precipitating silica in vitro and at ambient conditions. Herein, chimeric proteins were generated by incorporating synthetic silaffin R5 peptides and related unmodified silaffin domains (R1-R7) from Cylindrotheca fusiformis onto green fluorescent protein (GFP) by recombinant DNA technology and their ability to cause silicification was also examined. GFP chimeric proteins showed silicification at very low concentrations (600-700 microg/mL) when compared with adding excess amounts of R5 peptides (10 mg/mL) as previously reported. Sensitive to pH conditions, only the GFP-R1 chimera showed silicification activity at pH 8.0. The protein immobilization efficiencies of these chimeras were unexpectedly high ranging from 75 to 85%, with the R1 silaffin-protein construct showing excellent immobilization efficiency and a constant molar ratio of silica to protein ranging from 250 to 350 over a wide pH range. The average silica particle sizes had a tendency to decrease as pH increased to basic conditions. This study demonstrated the production of nanoscale immobilized protein, fabricated via silaffin-fused proteins. PMID- 19774663 TI - Metabolic engineering of the anaerobic central metabolic pathway in Escherichia coli for the simultaneous anaerobic production of isoamyl acetate and succinic acid. AB - An in vivo method of producing isoamyl acetate and succinate simultaneously has been developed in Escherichia coli to maximize yields of both high value compounds as well as maintain the proper redox balance between NADH and NAD(+). Previous attempts at producing the ester isoamyl acetate anaerobically did not produce the compound in high concentrations because of competing pathways and the need for NAD(+) regeneration. The objective of this study is to produce succinate as an example of a reduced coproduct to balance the ratio of NADH/NAD(+) as a way of maximizing isoamyl acetate production. Because the volatility of the two compounds differs greatly, the two could be easily separated in an industrial setting. An ldhA, adhE double mutant strain (SBS110MG) served as the control strain to test the effect of an additional ackA-pta mutation as found in SBS990MG. Both strains overexpressed the two heterologous genes pyruvate carboxylase and alcohol acetyltransferase (for ester production). The triple mutant SBS990MG was found to produce higher levels of both isoamyl acetate and succinate. At the optimal condition of 25 degrees C, the culture produced 9.4 mM isoamyl acetate and 45.5 mM succinate. SBS990MG produced 36% more ester and over 700% more succinate than SBS110MG. In addition, this study demonstrated that a significantly higher isoamyl acetate concentration can be attained by simultaneously balancing the carbon and cofactor flow; the isoamyl acetate concentration of 9.4 mM is more than seven times higher than an earlier report of about 1.2 mM. PMID- 19774664 TI - Indispensable structure of solution additives to prevent inactivation of lysozyme for heating and refolding. AB - This article investigates solution additives that prevent misfolding of lysozyme from heating treatment and during refolding processes. Comparison of heat treatment of native lysozyme and oxidative refolding from the reduced and denatured state of lysozyme in the presence of 44 different additives revealed an indispensable chemical structure for the additives to be effective against heat induced misfolding and for refolding. The additives effective against heat treatment of native lysozyme possessed a main chain of the amino acid moiety. Amino acids that have esterificated and amidated carboxy groups prevented heat induced misfoldings more effectively than amino acids themselves. On the other hand, the additives effective against oxidative refolding possessed a guanidium or ureido group. The former additives prevented hydrophobic interaction between the main chains of the unfolded polypeptide, while the latter additives increased the solubility of the aromatic and aliphatic side-chains. These data also support the fact that arginine (Arg) and Arg derivatives are versatile additives for both misfolding processes. PMID- 19774665 TI - Posttraumatic stress disorder: anxiety or traumatic stress disorder? AB - The authors examine the question of whether posttraumatic stress disorder (PTSD) should continue to be classified with the anxiety disorders in the upcoming revision of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V; American Psychiatric Association) classification system. They examine four areas of research that challenge the placement of PTSD among the anxiety disorders: research on peritraumatic emotions and their association with later PTSD symptoms, the role of emotions over the course of PTSD, physiological reactivity and emotional responses, and comorbidity patterns. The authors conclude with the recommendation that PTSD be included among a new category of traumatic stress disorders in DSM-V. PMID- 19774666 TI - Roles of astrocytes and microglia in seizure-induced aberrant neurogenesis in the hippocampus of adult rats. AB - Recent evidence showed that epileptic seizures increase hippocampal neurogenesis in the adult rat, but prolonged seizures result in the aberrant hippocampal neurogenesis that often leads to a recurrent excitatory circuitry and thus contributes to epileptogenesis. However, the mechanism underlying the aberrant neurogenesis after prolonged seizures remains largely unclear. In this study, we examined the role of activated astrocytes and microglia in the aberrant hippocampal neurogenesis induced by status epilepticus. Using a lithium pilocarpine model to mimic human temporal lobe epilepsy, we found that status epilepticus induced a prominent activation of astrocytes and microglia in the dentate gyrus 3, 7, 14, and 20 days after the initial seizures. Then, we injected fluorocitrate stereotaxicly into the dentate hilus to inhibit astrocytic metabolism and found that fluorocitrate failed to prevent the seizure-induced formation of ectopic hilar basal dendrites but instead promoted the degeneration of dentate granule cells after seizures. In contrast, a selective inhibitor of microglia activation, minocycline, inhibited the aberrant migration of newborn neurons at 14 days after status epilepticus. Furthermore, with stereotaxic injection of lipopolysaccharide into the intact dentate hilus to activate local microglia, we found that lipopolysaccharide promoted the development of ectopic hilar basal dendrites in the hippocampus. These results indicate that the activated microglia in the epileptic hilus may guide the aberrant migration of newborn neurons and that minocycline could be a potential drug to impede seizure induced aberrant migration of newborn neurons. PMID- 19774667 TI - Matrigel supports survival and neuronal differentiation of grafted embryonic stem cell-derived neural precursor cells. AB - Cell replacement therapy holds great promise as a means of treating neurological disorders, including Parkinson's disease. However, one of the major obstacles to the success of this treatment is the low survival rate of grafted cells, which probably results from mechanical damage, acute inflammation, and immunological rejection. To overcome this problem, we investigated the effect of different types of extracellular matrix (ECM) on the survival and differentiation of embryonic stem (ES) cell-derived neural precursor cells (NPCs). We tested materials from natural sources, including collagen, ornithine/laminin, and growth factor-reduced Matrigel (gfrMG), as well as the synthetic biomaterial PuraMatrix, which consists of self-assembling polypeptides. GfrMG efficiently supported cell survival, migration, and neurite outgrowth in vitro and promoted proliferation of grafted cells in vivo, resulting in larger graft volume and an increase in the number of TH-positive dopaminergic neurons in the graft. GfrMG did not induce dopaminergic differentiation directly; rather, it reduced the invasion of pan leukocytic CD45-positive cells into the graft. Insofar as the inflammatory or immune response in the host brain inhibits neuronal differentiation of grafted NPCs, gfrMG may increase the number of TH-positive cells by suppressing this effect. Thus, gfrMG appears to provide a suitable scaffold that supports survival and differentiation of NPCs. However, because it is derived from mouse sarcomas, a human-derived matrix or synthetic biomaterial must be developed for clinical applications. PMID- 19774668 TI - Subcellular distribution of low-voltage activated T-type Ca2+ channel subunits (Ca(v)3.1 and Ca(v)3.3) in reticular thalamic neurons of the cat. AB - Low-voltage-activated (LVA) Ca(2+) channels play a critical role in the generation of burst firing in the thalamus. Recently, three LVA Ca(2+) channel isoforms (Ca(v)3.1, Ca(v)3.2, Ca(v)3.3) have been identified in the reticular thalamic nucleus (RE). Previous electrophysiological and modelling studies have suggested that kinetically different T-type channels might be expressed in a compartmentalized manner in RE cells. However, their precise subcellular distribution has not been fully elucidated. Using light and electron microscopic (EM) immunocytochemistry, we investigated the subcellular expression pattern of Ca(v)3.1 and Ca(v)3.3 channel subunits in RE neurons of the cat. Fluorescent and peroxidase labelling demonstrated the presence of Ca(v)3.1 channel predominantly on the somata and proximal dendrites and Ca(v)3.3 channels on cell bodies. Quantitative immunogold localization disclosed that Ca(v)3.1 and Ca(v)3.3 isoforms showed 5.8- and 8.7-fold higher density, respectively, in the cytoplasm compared with somatic plasma membrane. Density of Ca(v)3.1 isoform in the somatic plasma membrane was 2.21-fold higher compared with Ca(v)3.3 subunit. In the dendritic plasma membrane, Ca(v)3.1 channel isoform was expressed throughout the entire dendritic tree. In contrast, Ca(v)3.3 isoform was absent from large caliber, presumably proximal dendritic segments. Quantitative comparison showed that the relative density of immunogold particles compared with dendritic surface was 8.9- and 14.8-fold higher for Ca(v)3.1 and Ca(v)3.3, respectively, in small diameter dendrites than in large proximal dendritic segments or somata. Our results demonstrate a higher density of low-threshold Ca(2+) channels in distal dendrites and provide further evidence of the role of RE neuron dendrites in the generation of prolonged, low-threshold spike bursts. PMID- 19774669 TI - Early continuous white noise exposure alters l-alpha-amino-3-hydroxy-5-methyl-4 isoxazole propionic acid receptor subunit glutamate receptor 2 and gamma aminobutyric acid type a receptor subunit beta3 protein expression in rat auditory cortex. AB - Auditory experience during the postnatal critical period is essential for the normal maturation of auditory function. Previous studies have shown that rearing infant rat pups under conditions of continuous moderate-level noise delayed the emergence of adult-like topographic representational order and the refinement of response selectivity in the primary auditory cortex (A1) beyond normal developmental benchmarks and indefinitely blocked the closure of a brief, critical-period window. To gain insight into the molecular mechanisms of these physiological changes after noise rearing, we studied expression of the AMPA receptor subunit GluR2 and GABA(A) receptor subunit beta3 in the auditory cortex after noise rearing. Our results show that continuous moderate-level noise rearing during the early stages of development decreases the expression levels of GluR2 and GABA(A)beta3. Furthermore, noise rearing also induced a significant decrease in the level of GABA(A) receptors relative to AMPA receptors. However, in adult rats, noise rearing did not have significant effects on GluR2 and GABA(A)beta3 expression or the ratio between the two units. These changes could have a role in the cellular mechanisms involved in the delayed maturation of auditory receptive field structure and topographic organization of A1 after noise rearing. PMID- 19774671 TI - Achyranthes bidentata polypeptides confer neuroprotection through inhibition of reactive oxygen species production, Bax expression, and mitochondrial dysfunction induced by overstimulation of N-methyl-D-aspartate receptors. AB - Achyranthes bidentata polypeptides (ABPP), the important constituents separated from the aqueous extract of Achyranthes bidentata, have been shown to attenuate N methyl-D-aspartate (NMDA)-induced cell apoptosis in cultured hippocampal neurons through differential modulation of NR2A- and NR2B-containing NMDA receptors. The present study sought to investigate the possible mechanism underlying the neuroprotective effect of ABPP on NMDA-induced cell death. Western blot analysis and colorimetric enzymatic assay demonstrated that ABPP pretreatment inhibited NMDA-induced increase of Bax protein expression or caspase-3 activity in cultured hippocampal neurons. Fluorescence measurements after staining with 2,7 dichlorofluorescin diacetate and rhodamine 123 showed that ABPP treatment also reversed NMDA-induced intracellular radical oxygen species (ROS) elevation and mitochondrial membrane potential depression in cultured hippocampal neurons. Furthermore, the in vivo effects of ABPP on cerebral neuronal damage during focal ischemia-reperfusion were also investigated. In rat middle cerebral artery occlusion (MCAO) model, ABPP attenuated the increase in the neurological deficit and cerebral infarction induced by focal ischemia-reperfusion, showing in vivo neuroprotective effects. The results collectively suggest that ABPP might exert neuroprotective actions through inhibiting Bax protein expression, caspase-3 activity, ROS production, and mitochondrial dysfunction that are all caused by overstimulation of NMDA receptors. PMID- 19774670 TI - p38 mitogen-activated protein kinase and calcium channels mediate signaling in depolarization-induced activation of peroxisome proliferator-activated receptor gamma coactivator-1alpha in neurons. AB - Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) coactivates a number of transcription factors critical for mitochondrial biogenesis. Previously, we found that the expression of PGC-1alpha is governed by neuronal activity, but the signaling mechanism is poorly understood. The present study aimed at testing our hypothesis that depolarizing activation of PGC-1alpha in neurons is mediated by p38 mitogen-activated protein kinase (MAPK) and calcium channels. Cultured primary neurons and N2a cells were depolarized with 20 mM KCl for varying times, and increases in PGC-1alpha mRNA and protein levels were found after 0.5 and 1 hr of stimulation, respectively. These levels returned to those of controls after the withdrawal of KCl. Significantly, 15 min of KCl stimulation induced an up-regulation of both p38 MAPK and phosphorylated p38 MAPK that were suppressed by 30 min of pretreatment with SB203580, a blocker of p38 MAPK that also blocked the up-regulation of PGC-1alpha by KCl. Likewise, 30 min of pretreatment with nifedipine, a calcium channel blocker, also prevented the up regulation of PGC-1alpha mRNA and proteins by KCl. Furthermore, a knockdown of p38 MAPK with small interference hairpin RNA significantly suppressed PGC-1alpha mRNA and protein levels. Our results indicate that both p38 MAPK and calcium play important roles in mediating signaling in depolarization-induced activation of PGC-1alpha at the protein and message levels in neurons. PMID- 19774672 TI - Alterations in calcium signaling and a decrease in Bcl-2 expression: possible correlation with apoptosis in aged striatum. AB - Aging is a multifaceted process associated with various functional and structural deficits that might be evolved in degenerative diseases. It has been shown that neurodegenerative disorders are associated with alterations in Ca(2+) homeostasis. Thus, in the present work, we have investigated Ca(2+) signaling and apoptosis in aged striatum. Our results show that glutamate and NMDA evoke a greater Ca(2+) rise in striatum slices from aged animals. However, this difference is not present when glutamate is tested in the absence of external Ca(2+). Immunostaining of glutamate receptors shows that only NMDA receptors (NR1) are increased in the striatum of aged rats. Increases in mitochondrial Ca(2+) content and in the reactive oxygen species levels were also observed in aged animals, which could be associated with tissue vulnerability. In addition, a decrease in the Bcl-2 protein expression and an enhancement in apoptosis were also present in aged striatum. Together the results indicate that, in aged animals, alterations in Ca(2+) handling coupled to an increase in ROS accumulation and a decrease in the prosurvival protein Bcl-2 may contribute to apoptosis induction and cell death in rat striatum. PMID- 19774673 TI - Different antipsychotics elicit different effects on magnocellular oxytocinergic and vasopressinergic neurons as revealed by Fos immunohistochemistry. AB - Acute administration of antipsychotics elicits regionally distinct patterns of Fos expression in the rat brain. Stimulation of oxytocin (OXY) and vasopressin (AVP) release in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei indicates that antipsychotics may play a role in autonomic, neuroendocrine, and behavioral processes. This study was focused to reveal the responsiveness of hypothalamic OXY- and AVP- producing magnocellular neurons, in terms of quantitative and topographical distinctions, to antipsychotics displaying different pharmacological profiles. Naive male Wistar rats were injected intraperitoneally with haloperidol (1 mg/kg), clozapine (30 mg/kg), olanzapine (30 mg/kg), risperidone (2mg/kg), and vehicle (5% chremophor) and were sacrificed 60 min later by a fixative. Fos, Fos/OXY, and Fos/AVP labelings were visualized by immunohistochemistry in the SON, 5 accessory (ACS) cell groups, and 4 distinct PVN subdivisions using a computerized light microscope. Most apparent activation of single Fos, Fos/OXY, and Fos/AVP cells was induced by clozapine and olanzapine; effects of risperidone and haloperidol were substantially lower; no colocalizations were revealed in naive or vehicle treated control rats. The data indicate the existence of a substantial diversity in the stimulatory effect of the selected antipsychotics on quantity of Fos, Fos/OXY, and Fos/AVP immunostainings with the preferential action of the atypicals clozapine over olanzapine and little effects of risperidone and haloperidol. Variabilities in Fos distribution in the PVN, SON, and ACS induced by antipsychotics may be helpful to understand more precisely the extent of their extra-forebrain actions with possible presumption of their functional impact and side effect consequences. PMID- 19774674 TI - Protective effects of peroxisome proliferator-activated receptors gamma coactivator-1alpha against neuronal cell death in the hippocampal CA1 subfield after transient global ischemia. AB - Peroxisome proliferator-activated receptors gamma coactivator-1alpha (PGC-1alpha) may regulate the mitochondrial antioxidant defense system under many neuropathological settings. However, the exact role of PGC-1alpha in ischemic brain damage is still under debate. Based on an experimental model of transient global ischemia (TGI), this study evaluated the hypothesis that the activation of PGC-1alpha signaling pathway protects hippocampal CA1 neurons against delayed neuronal death after TGI. In Sprague-Dawley rats, significantly increased content of oxidized proteins in the hippocampal CA1 tissue was observed as early as 30 min after TGI, followed by augmentation of PGC-1alpha expression at 1 hr. Expression of uncoupling protein 2 (UCP2) and superoxide dismutases 2 (SOD2) in the hippocampal CA1 neurons was upregulated 4-48 hr after TGI. In addition, knock down of PGC-1alpha expression by pretreatment with a specific antisense oligodeoxynucleotide in the hippocampal CA1 subfield downregulated the expression of UCP2 and SOD2 with resultant exacerbation of oxidative stress and augmentation of delayed neuronal cell death in the hippocampus after TGI. Overall, our results indicate that PGC-1alpha is induced by cerebral ischemia leading to upregulation of UCP2 and SOD2, thereby providing a neuroprotective effect against ischemic brain injury in the hippocampus by ameliorating oxidative stress. PMID- 19774675 TI - Overexpression of aldehyde dehydrogenase 1A1 reduces oxidation-induced toxicity in SH-SY5Y neuroblastoma cells. AB - Oxidative stress leading to lipid peroxidation is a problem in neurodegenerative diseases, because the brain is rich in polyunsaturated fatty acids and low in endogenous antioxidants. One of the most toxic byproducts of lipid peroxidation, 4-hydroxynonenal (HNE), is implicated in oxidative stress-induced damage in neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), and amyotrophic lateral sclerosis (ALS). In this study, the human neuroblastoma cell line SH-SY5Y was used to test the protective effects of increasing the detoxification of HNE by overexpressing the HNE-detoxifying enzyme aldehyde dehydrogenase 1A1 (ALDH1). Overexpression of ALDH1 in the SH-SY5Y cells acts to reduce production of protein-HNE adducts and activation of caspase-3. Our data suggest that detoxification of HNE could be therapeutic in preventing some of the toxic disruptions of the brain's redox systems found in many neurodegenerative diseases. PMID- 19774676 TI - Decreased level and defective function of circulating endothelial progenitor cells in children with moyamoya disease. AB - Circulating endothelial progenitor cells (EPCs) play an important role in physiological and pathological neovascularization and may be involved in attenuating ischemic diseases. This study aimed to characterize circulating EPCs in moyamoya disease (MMD), one of the most common pediatric cerebrovascular diseases. Twenty-eight children with MMD prior to any surgical treatment and 12 healthy volunteers were recruited. Peripheral blood mononuclear cells (PBMNCs) were isolated and cultured in endothelial cell growth medium. Temporal change of phenotype of cells was analyzed on days 0 and 7. The formation of EPC clusters was evaluated on day 7. The CD34(+), CD133(+), and KDR(+) cells, and the number of EPC clusters was significantly reduced in children with MMD. In controls, CD34(+) cells were significantly decreased on day 7 compared with day 0, but in MMD they were only slightly decreased. The change in KDR(+) cells on day 7 compared with day 0 was the reverse of that for CD34(+) cells. Functional assay of EPC demonstrated less tube formation and increased senescent-like phenotype in children with MMD. Analysis of the circulating EPCs of MMD children reveals decreased level and defective function. This study suggests that circulating EPCs may be associated with MMD pathogenesis. PMID- 19774678 TI - Just like SARS. PMID- 19774677 TI - Decreased levels of PSD95 and two associated proteins and increased levels of BCl2 and caspase 3 in hippocampus from subjects with amnestic mild cognitive impairment: Insights into their potential roles for loss of synapses and memory, accumulation of Abeta, and neurodegeneration in a prodromal stage of Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia and is pathologically characterized by senile plaques, neurofibrillary tangles, synaptic disruption and loss, and progressive neuronal deficits. The exact mechanism(s) of AD pathogenesis largely remain unknown. With advances in technology diagnosis of a pre-AD stage referred to as amnestic mild cognitive impairment (MCI) has become possible. Amnestic MCI is characterized clinically by memory deficit, but normal activities of daily living and no dementia. In the present study, compared to controls, we observed in hippocampus from subjects with MCI a significantly decreased level of PSD95, a key synaptic protein, and also decreased levels of two proteins associated with PSD95, the N-methyl-D-aspartate receptor, subunit 2A (NR2A) and the low-density lipoprotein receptor-1 (LRP1). PSD95 and NR2A are involved in long-term potentiation, a key component of memory formation, and LRP1 is involved in efflux of amyloid beta-peptide (1-42). Abeta (1-42) conceivably is critical to the pathogenesis of MCI and AD, including the oxidative stress under which brain in both conditions exist. The data obtained from the current study suggest a possible involvement of these proteins in synaptic alterations, apoptosis and consequent decrements in learning and memory associated with the progression of MCI to AD. PMID- 19774679 TI - Improved detection of JC virus in AIDS patients with progressive multifocal leukoencephalopathy by T-antigen specific fluorescence resonance energy transfer hybridization probe real-time PCR: evidence of diverse JC virus genotypes associated with progressive multifocal leukoencephalopathy in Southern Africa. AB - JC virus (JCV) causes progressive multifocal leukoencephalopathy under conditions of immunosuppression, especially associated with HIV. Despite the high prevalence of HIV-1 infection, few cases of progressive multifocal leukoencephalopathy have been reported and only a small number of JCV strains have been characterized in AIDS patients in Southern Africa. Diagnosis of progressive multifocal leukoencephalopathy through PCR detection of JCV DNA in CSF may result in false negative results if variable regions of the genome are targeted. Characterization of circulating JCV genotypes in Southern Africa may assist with designing appropriate diagnostic assays and characterizing the molecular epidemiology of JCV in African AIDS patients. In this study, a new real-time PCR using fluorescence resonance energy transfer hybridization probes targeting the conserved large T-antigen was developed and compared to a conventional nested PCR targeting the variable VP1 region. Validation against known JCV positive specimens confirmed its specificity while amplification of a serial dilution of JCV control DNA suggests that the new real-time PCR can detect lower concentrations of JCV than the VP1 nested PCR. Investigation of CSF specimens from 44 suspected progressive multifocal leukoencephalopathy patients suggest that the new assay is more sensitive being able to detect JCV in 12 specimens versus 5 specimens with the VP1 nested PCR. Sequence analysis confirmed that the T-antigen region is completely conserved while phylogenetic analysis of the five VP1 products identified two genotype 3, one genotype 1 and two genotype 4 strains, the latter two identified for the first time in South African AIDS patients. PMID- 19774680 TI - Molecular characterization of the env gene of two CCR5/CXCR4-independent human immunodeficiency 2 primary isolates. AB - Human immunodeficiency virus 2 (HIV-2) infection is characterized by a slower disease progression and lower transmission rates. The molecular features that could be assigned as directly involved in this in vivo phenotype remain essentially unknown, and the importance of HIV-2 as a model to understand pathogenicity of HIV infection has been frequently underestimated. The early events of the HIV replication cycle involve the interaction between viral envelope glycoproteins and cellular receptors: the CD4 molecule and a chemokine receptor, usually CCR5 or CXCR4. Despite the importance of these two chemokine receptors in human immunodeficiency virus 1 (HIV-1) entry into cells, we have previously shown that in some HIV-2 asymptomatic individuals, a viral population exists that is unable to use both CCR5 and CXCR4. The goal of the present study was to investigate whether possible regions in the env gene of these viruses might account for this phenotype. From the molecular characterization of these env genes we could not detect any correlation between V3 loop sequence and viral phenotype. In contrast, it reveals the existence of remarkable differences in the V1/V2 and C5 regions of the surface glycoprotein, including the loss of a putative glycosilation site. Moreover, in the transmembrane glycoprotein some unique sequence signatures could be detected in the central ectodomain and second heptad repeat (HR2). Some of the mutations affect well-conserved residues, and may affect the conformation and/or the dynamics of envelope glycoproteins complex, including the SU-TM association and the modulation of viral entry function. PMID- 19774681 TI - Relationship of Th1/Th2 cell balance with the immune response to influenza vaccine during pregnancy. AB - To determine the optimal timing for influenza vaccination in pregnant women, we measured alterations in the types 1 and 2 T helper cell (Th1/Th2) balance during pregnancy, monitored specific immunity to inoculated antigens after vaccination with inactivated influenza vaccine, evaluated the relevance of the Th1/Th2 ratio and immune responses to the vaccination, monitored the maintenance of high antibody titers until delivery and measured the transplacental antibody transfer rate. No significant alterations of the Th1/Th2 balance were noted in the 65% of pregnant women among whom the Th1/Th2 ratio was lower than 9.9% in the first trimester. In those groups with a ratio higher than 10% in the first trimester, there was a tendency for the ratio to decrease as gestation advanced. The efficiency of immunization was not influenced by the Th1/Th2 status or by the stage of gestation. The antibody titer decreased steadily with time from 1 month after vaccination to the time of delivery. Conversely, the transfer rate of antibodies from maternal to fetal blood at the time of delivery increased with the duration of gestation after vaccination. Nevertheless, the antibody titers in both maternal and fetal blood were sufficient to afford protection against infection. Thus, efficient influenza vaccination can be undertaken at any stage of pregnancy. PMID- 19774682 TI - Investigation of the occurrence of torque tenovirus in malignant and potentially malignant disorders associated with human papillomavirus. AB - In a previous pilot study, a significantly poorer outcome of laryngeal cancer was found in patients co-infected with human papillomavirus (HPV) and genogroup 1 torque tenovirus (TTV). The present study aimed to collect data on the overall prevalence of TTVs on the prevalence of genogroup 1 TTV in two other malignancies associated with HPV, oral squamous cell cancer and cervical cancer, and in oral and cervical premalignant lesions (oral lichen planus, oral leukoplakia, cervical atypia). Oral samples from all patients were accompanied with a sample from the healthy mucosa. The overall prevalence of TTV was significantly higher both in oral squamous cell cancer and cervical cancer compared with other patient groups or with the respective controls. The prevalence of genogroup 1 TTV was significantly higher in lesions of oral squamous cell cancer and oral lichen planus, but not in lesions of oral leukoplakia (24.6%, 10.1%, and 4.5%, respectively), compared with the prevalence in the oral cavity of controls (1.4%). Co-infection rates with genogroup 1 TTV and HPV were significantly higher in oral squamous cell cancer than in controls, oral lichen planus or oral leukoplakia patients (12.3%, 0.0%, 6.7%, and 4.5%, respectively). The prevalence of genogroup 1 TTV in all cervical samples were comparable. These data suggest that genogroup 1 TTV may be associated specifically with some head and neck mucosal disorders, but disproves a (co)carcinogenic role in oral cancer or cervical cancer as well as an association with HPV or with malignancies associated with HPV. PMID- 19774683 TI - Detection of Merkel cell polyomavirus in Merkel cell carcinoma and Kaposi's sarcoma. AB - Merkel cell carcinoma is a rare malignancy that sometimes occurs in the skin of elderly people. Recently, a new human polyomavirus, Merkel cell polyomavirus (MCPyV) was identified in Merkel cell carcinoma. In the present study, MCPyV-DNA was detected in 6 of 11 (55%) cases of Merkel cell carcinoma by nested PCR and real-time PCR. Histologically, MCPyV-positive cases showed round and vesicular nuclei with a fine granular chromatin and small nucleoli, whereas MCPyV-negative cases showed polygonal nuclei with diffusely distributed chromatin. Real-time PCR analysis to detect the MCPyV gene revealed that viral copy numbers ranged 0.04 0.43 per cell in cases of Merkel cell carcinoma. MCPyV was also detected in 3 of 49 (6.1%) cases of Kaposi's sarcoma (KS), but not in 192 DNA samples of other diseases including 142 autopsy samples from 20 immunodeficient patients. The MCPyV copy number in KS was lower than that in Merkel cell carcinoma. PCR successfully amplified a full-length MCPyV genome from a case of KS. Sequence analysis revealed that the MCPyV isolated from KS had 98% homology to the previously reported MCPyV genomes. These data suggest that the prevalence of MCPyV is low in Japan, and is at least partly associated with the pathogenesis of Merkel cell carcinoma. PMID- 19774684 TI - Detection of group B rotavirus in an adult with acute gastroenteritis in Yangon, Myanmar. AB - In Yangon, Myanmar, a human group B rotavirus was first detected in 2007 in a stool specimen from a sporadic case of acute gastroenteritis in an adult. The strain was designated as MMR-B1. The full-length sequences of the MMR-B1 genes encoding VP7, VP4 (VP5* and VP8*), VP6, and NSP4 were determined for genetic characterization. These four MMR-B1 genes showed considerable higher sequence identities (97.2-98.4%) to those of group B rotaviruses detected in India (CAL-1 in 1998) and Bangladesh (Bang373 and Bang544 in 2000 and 2001, respectively) than to those of Chinese strains (90.7-93.6%) (ADRV and WH-1 in 1982 and 2002, respectively). Phylogenetically, the four genes of MMR-B1 were clustered into the Indian-Bangladeshi lineage. Although the deduced amino acid sequences of MMR-B1 were similar to those of strains CAL-1 and Bang373, several amino acids in VP8* were found to be different from those of the group B rotaviruses described previously. The first detection in Myanmar of a human group B rotavirus suggested endemic distribution or expansion of the group B rotavirus of the Indian Bangladeshi lineage in Southeast Asia. PMID- 19774685 TI - Emergence and diversity of different HIV-1 subtypes in South Africa, 2000-2001. AB - HIV-1 is a major health problem in South Africa with an average prevalence rate of 29.1% in pregnant women and between 4.9 and 6.1 million people infected. Using env gp120 V3 serotyping and genotyping techniques 410 patient samples were investigated. Most of the samples were obtained from different clinics in the greater Cape Town area of the Western Cape Province in South Africa. These included an academic hospital, state and private clinics, an informal settlement, sex worker cohorts, and the blood transfusion services. RNA was extracted from plasma samples followed by RT-PCR and sequencing of the env gp120 V3 region. Sequence fragments were assembled using Sequencher V4.7 and subsequently codon aligned. Distance calculation, tree construction methods, and bootstrap analysis were implemented using MEGA version 4.0. Viral load measurements indicated that HIV-1 RNA levels from 74 samples were below the assay detection limit. Three hundred thirty-six samples were used for env PCR and sequencing and 320 were assigned to subtypes. The majority of the sequences were subtyped as C (n = 285, 89.0%). Other subtypes detected were subtype A (n = 10, 3.1%); subtype B (n = 22, 6.8%); one each of subtypes F1, G, U, and a CH recombinant. Whether this diversity will have major implications for HIV-1 evolution and vaccine development in this region remains undetermined. PMID- 19774686 TI - Prevalence of diarrhea viruses in hospitalized children in Hong Kong in 2008. AB - A total of 209 stool samples were collected from pediatric patients admitted for acute gastroenteritis in a hospital in Hong Kong, during an 8-month period from January to August 2008, and were tested for the presence of rotavirus, norovirus, sapovirus, adenovirus, and astrovirus using a multiplex RT-PCR assay. The most common virus was rotavirus group A (59 of 209, 28%, mainly serotypes G1, G2, G3, and G9), followed by norovirus group II (48 of 209, 23%), adenovirus (7 of 209, 3%, serotypes 2, 3, and 41), and sapovirus (2 of 209, 1%). Interestingly, none of the specimens in this study were positive for astrovirus. One sample was found to have a dual infection with both norovirus group II and adenovirus. The results support the importance of norovirus as a causative agent of diarrhea in children, which may be underestimated by the current routine diagnostic testing. PMID- 19774687 TI - Prevalence of persistent and latent viruses in untreated patients infected with HIV-1 from Ghana, West Africa. AB - Only limited epidemiological data, pertaining to the prevalence of common persistent viruses has been reported in Ghana. This study was conducted to determine the prevalence of persistent viruses in individuals with untreated HIV 1 infection and uninfected blood donors. Paired plasma and cellular samples from HIV-negative blood donors, asymptomatic HIV and symptomatic/AIDS cohorts were screened by multiplex PCR then qPCR for parvovirus B19 (B19V), hepatitis B virus (HBV), GB virus-C (GBV-C), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus-8 (HHV-8) and varicella-zoster virus (VZV). IgG antibodies specific to each target virus were tested to determine exposure rates. No evidence of viraemia was found for B19V and VZV in any group. Prevalence of GBV-C plasma viraemia was significantly higher in asymptomatic and symptomatic HIV infection (16.7%) and (16.2%) than in blood donors (4%) P < 0.005. Occult HBV infection was significantly more frequent in symptomatic HIV infection (10.9%) compared to asymptomatic HIV (3.6%) and blood donors (1.6%) P < 0.005. Although there was a high background of EBV viraemia in cellular fractions of blood donors (8.3%), it was significantly higher in asymptomatic (44.6%) and symptomatic HIV (14.6%) P < 0.0001. For CMV, the significantly increased prevalence of viraemia was only observed in the plasma fraction of the symptomatic HIV-1/AIDS patients (7.6%) compared to asymptomatic individuals (1.8%) and blood donors (0.8%) P < or = 0.001. The background seroprevalence in blood donors was high for B19V (> or =64%), HBV (> or =70%), CMV and EBV (> or =90%) and was significantly increased in HIV infections for HBV, CMV, VZV (symptomatic HIV), and HHV-8 (asymptomatic and symptomatic HIV). PMID- 19774688 TI - Epstein-Barr virus BZLF1 gene promoter variants in pediatric patients with acute infectious mononucleosis: its comparison with pediatric lymphomas. AB - Epstein-Barr virus genotypes can be distinguished by polymorphic variations in the genes encoding EBNA2, 3A, 3B, and 3C. The immediate early gene BZLF1 plays a key role in modulating the switch from latency to lytic replication and therefore enabling viral propagation. The aim of this study was to investigate and compare BZLF1 promoter sequence (Zp) variation in pediatric infectious mononucleosis (IM) and in pediatric EBV positive lymphoma biopsies. Zp was sequenced from peripheral blood mononuclear cells (PBMC) and throat swabs from 10 patients with IM at the time of diagnosis (D0) and during convalescence; and from 13 lymphoma biopsies. Zp - P and Zp - V3 variants were found in eight and one IM patients, as well as in five and six tumor biopsies, respectively. A correlation between viral genotype and Zp variant was found significant for Zp - V3 and EBV2 (P = 0.0002). One IM patient harbored two concomitant Zp variants. Regardless of anatomical compartment or stage of disease all IM patients displayed the same Zp variant along the course of the study. No new infections or adaptative selection of different variants was evidenced. A new Zp variant (Zp - V3 + 49) was described in two Hodgkin lymphomas, but not in IM. This is the first study to describe Zp variants compartmentalization in children with acute EBV infection and convalescence in a developing country; and comparing them with Zp variants in pediatric lymphomas from the same geographic area. PMID- 19774689 TI - Functional analysis of polyomavirus BK non-coding control region quasispecies from kidney transplant recipients. AB - Replication of the human polyomavirus BK (BKV) in renal tubular epithelial cells causes viruria and BKV-nephropathy in kidney transplant recipients. Following prolonged high-level BKV replication, rearrangement of the archetype non-coding control region (NCCR) leads to a mixture of BKV variants. The aim of this study was to compare potential functional differences of 12 rearranged (rr)-NCCR variants with the archetype (ww)-NCCR (WWT) found in allograft biopsies or urine from three kidney transplant recipients including two with BKV-nephropathy. Twelve different rr-NCCRs and one archetype ww-NCCR were inserted between the early and late protein coding region of BKV(Dunlop) to make recombinant BKV genomes for transfection into Vero cells. Immunoblotting, immunofluorescence staining, and quantitative PCR demonstrated that viral protein expression and extracellular BKV loads of 10 rr-NCCR variants were similar or higher than observed for the ww-NCCR BKV. Two rr-NCCR variants (RH-2 and RH-19) were non functional. The functional rr-NCCRs produced infectious progeny successfully infecting primary renal proximal tubular epithelial cells. The number of infected cells and extracellular BKV loads corresponded to the activity seen in Vero cells. Three rr-NCCR variants (RH-1, RH-10, RH-13) only gave rise to a few infected cells similar to ww-NCCR, whereas seven variants had intermediate activity (RH-5, RH-6, RH-8, RH-9, RH-11) or high replication activity (RH-7 and RH-18) with several hundred infected cells per well. The results indicate that both functional and non-functional BKV rr-NCCR variants arise during BKV replication in kidney transplant recipients and that most functional rr-NCCR variants confer a higher replication capacity than archetype ww-NCCR. PMID- 19774690 TI - Diversity of hepatitis B and C viruses in Chile. AB - Although there is a low prevalence rate (around 1% of the population) of infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) in Chile, little is known about the diversity and molecular characteristics of the circulating viruses. In the present study, 40 HBV and 57 HCV samples from Santiago City, Chile, were examined. The phylogenetic analysis of HBV samples showed the autochthonous genotype F as the most represented genotype in the study (67.5%), while genotypes A, B, C, and D were less frequent (7.5%, 5%, 7.5%, and 12.5%, respectively). The frequency of circulation of HBV genotypes observed is in accordance with the genetic background of the Chilean population. Most of the HCV samples tested belonged to subtype 1b (82%). The coalescent analysis conducted for both the NS5A and NS5B regions of the HCV strains showed similar population growth rates, with a most recent common ancestor estimated to date between 1893 and 1901. This result may indicate that genotype 1b strains circulating in Chile have epidemiological features similar to those described for HCV genotype 1b in Brazil and the United States. However, the most recent common ancestor for Chile is older than that reported recently for genotype 1b in Argentina. PMID- 19774691 TI - Correlation between HIV-1 seropositivity and prevalence of a gamma-secretase polymorphism in two distinct ethnic populations. AB - Susceptibility for human immunodeficiency virus type 1 (HIV-1) infection may be influenced by host genetics. Recent findings with a Wistar rat model raised the possibility that the gamma-secretase pathway may be associated with an individual's susceptibility to infection. A functional single-nucleotide polymorphism (SNP) in the gamma-secretase component APH1B (Phe217Leu; rs1047552) was therefore analyzed for association with HIV-1 infection. The SNP showed a tendency for association with HIV-1 infection in a Xhosa indigenous South African Bantu study (P = 0.087), and associated significantly in a Caucasian Dutch study (P = 0.049). Together, the results suggest a role for the gamma-secretase pathway in susceptibility to HIV-1 infection. PMID- 19774692 TI - Development of a consensus microarray method for identification of some highly pathogenic viruses. AB - Some highly pathogenic viruses, such as Chikungunya virus, Japanese encephalitis virus, Yellow fever virus, Dengue virus, Hanta virus, SARS-CoV, and H5N1 avian influenza virus can cause severe infectious diseases. However, the consensus method for detecting these viruses has not been well established. A rapid and sensitive microarray approach for detection of these viruses and a panel of specific probes covering nine genera and 16 virus species were designed. 70-mer oligonucleotides were used at the genus level and 50-mer oligonucleotides were at the species level, respectively. To decrease the interference of the host genome in hybridization, the consensus genus primers were designed and used to reverse transcribe only virus genome. The synthesis of the second strand was carried out with a random primer sequence (5'-GTTTCCCAGTAGGTCTCNNNNNNNN-3'). The amplified products were labeled and processed for microarray analyses. This microarray based method used the highly conserved consensus primers to synthesize specifically the virus cDNA and could identify effectively Chikungunya virus, Japanese encephalitis virus, Yellow fever virus, Dengue virus, Tick borne encephalitis virus, and H5N1 avian influenza virus. Using this method, one unknown virus isolated from pig brain in Shanxi Province, China was identified. This method may have an important potential application for the diagnosis of virus infection. PMID- 19774693 TI - Evaluation of twenty rapid antigen tests for the detection of human influenza A H5N1, H3N2, H1N1, and B viruses. AB - Twenty rapid antigen assays were compared for their ability to detect influenza using dilutions of virus culture supernatants from human isolates of influenza A H5N1 (clade 1 and 2 strains), H3N2 and H1N1 viruses, and influenza B. There was variation amongst the rapid antigen assays in their ability to detect different influenza viruses. Six of the 12 assays labeled as distinguishing between influenza A and B had comparable analytical sensitivities for detecting both influenza A H5N1 strains, although their ability to detect influenza A H3N2 and H1N1 strains varied. The two assays claiming H5 specificity did not detect either influenza A H5N1 strains, and the two avian influenza-specific assays detected influenza A H5N1, but missed some influenza A H3N2 virus supernatants. Clinical trials of rapid antigen tests for influenza A H5N1 are limited. For use in a pandemic where novel influenza strains are circulating (such as the current novel influenza A H1N1 09 virus), rapid antigen tests should ideally have comparable sensitivity and specificity for the new strains as for co-circulating seasonal influenza strains. PMID- 19774694 TI - Clinical and virological survey of patients with hepatitis B surface antigen in an Italian region: clinical considerations and disease burden. AB - The aim of this study was to determine the prevalence of hepatitis B virus (HBV) infection in an Italian region, Liguria (1,572,000 inhabitants), by means of a network of 12 referral centers for liver diseases. All patients with HBV surface antigen followed throughout 2006 were included. Personal data, infectious status with risk factors, other non-infectious risk factors for liver disease, clinical status, and treatment were the questionnaire. Four hundred forty-five patients (71% male) were evaluated. Their median age was 48 years (range 5-84), and 83.4% were of Italian origin. Community-acquired infection was the principal mode of HBV transmission (82.5%), followed by previous intravenous drug use (9.4%), perinatal transmission (6.3%), and transfusion-associated transmission (1.8%). Hepatitis B e-antigen was present in 20.4% of the patients, while co-infections with hepatitis D virus and/or hepatitis C virus and/or human immunodeficiency virus (HIV) were observed in 18.7% of the patients. Chronic active hepatitis was present in 62.5% of the patients, cirrhosis in 13.5%, hepatocellular carcinoma in 2.2%, and 21.8% of the patients were inactive carriers of HBV. In all, 42.5% of the patients were treated with interferon or lamivudine and/or adefovir dipivoxil. Forty-nine patients were co-infected with HIV (86% on highly active antiviral therapy). Nevertheless, this study identified only 2.2% of the expected patients with HBV. Hence, it has to be reasoned that few potential infectious or treatable patients are referred to liver disease centers. HBV infection is still an underestimated health problem, and few potential infectious or treatable patients are referred to tertiary centers. PMID- 19774696 TI - In vitro, high-resolution 1H and 31P NMR based analysis of the lipid components in the tissue, serum, and CSF of the patients with primary brain tumors: one possible diagnostic view. AB - In vitro, high-resolution (1)H and (31)P NMR based qualitative and quantitative analyses of the lipid components of the tissue, serum, and CSF of patients with primary brain tumors were performed. Proton NMR spectra of the lipid extract of serum (blood specimen collected before the surgical procedure) and surgically discarded tissue showed that the total cholesterol (T.CHOL) and choline containing phospholipids (PL) were significantly higher in quantity in medulloblastoma and glioblastoma multiforme as compared to normal subjects. Serum lipid extracts of grade II/ III gliomas showed a higher quantity of PL than normal subjects. Cholesterol esters (CHOLest) were detectable in the tissue lipid extract of the patients with tumors and absent in normal tissue. There was a reduction in the quantity of CHOLest in the serum lipid extract of the tumor patients as compared to normal subjects. Ratio of PL to T.CHOL in serum lipid extract showed a significant difference between different grades of tumors versus normal subjects, while, a significant difference was observed only in medulloblastoma versus normal subjects in tissue lipid extract. Ratio of CHOL to CHOLest distinguishes the different grades of tumors versus normal subjects as well as between different grades of tumors (except medulloblastoma versus glioblastoma). The ratio of the Ph (total phospholipids except phosphatidylcholine) to PC (phosphatidylcholine) in (31)P NMR based study showed a significant difference in all grades of tumors (except medulloblastoma) in normal subjects in tissue lipid extract as well as between different grades of tumors. Medulloblastoma could be differentiated from glioblastoma as well as from normal subjects in serum lipid extract by the ratio of the Ph to PC. Proton NMR spectra of the lipid extract of CSF showed that the CHOL, CHOLest, and PL were present in the patients with tumors, although these were absent in the patients with meningitis, motor neuron disease, and mitochondrial myopathies as well as in normal subjects. PL and T.CHOL provided discrimination between different grades of tumors (except glioblastoma versus medulloblastoma) in the lipid extract of the CSF. This study suggests the role of lipid estimation in CSF and serum as a complementary diagnostic tool for the evaluation of brain tumors preoperatively. NMR-based lipid estimation of post-surgical tumor tissue may also contribute to differentiating the tumor types. PMID- 19774695 TI - Molecular epidemiology of human astrovirus and adenovirus serotypes 40/41 strains related to acute diarrhea in Tunisian children. AB - Human astrovirus (AstV) and adenovirus types 40 and 41 (AdV 40/41) are responsible for epidemic and endemic acute gastroenteritis in children and adults. The present study was designed to evaluate the prevalence and genetic diversity of enteric viruses in children in Tunisia. A total of 788 fecal samples were collected during a 4-year period in the region of Monastir, from children under 12 years old, hospitalized or presenting in dispensaries with symptoms of acute gastroenteritis. AstV and AdV40/41 were detected by immunoenzymatic methods and confirmed by PCR/RT-PCR and sequence analysis. Phylogenetic analyses were performed for nucleotide homology with reference strains. AstV and AdV40/41 were characterized as a causative agent in 28 (3.6%) and 18 (2.3%) of the fecal samples, respectively. Phylogenetic analysis showed that the AstVs belonged to the serotypes 3 (n = 4; 14.3%) and 1 (n = 24; 85.7%), and the enteric AdVs to the serotypes 40 (n = 1; 5.6%) and 41 (n = 17; 94.4%). This is the first report that describes the molecular epidemiology of AstV and AdV40/41 in Tunisian children. Their respective detection rate was very low, far below that of rotavirus and norovirus. The genetic diversity among these two viruses is relatively limited and varies depending on the area. PMID- 19774697 TI - [Euthanasia]. PMID- 19774698 TI - Inflammation induced by Bothrops asper venom. AB - Inflammation is a major characteristic of envenomation by snakes from viperine and crotaline species. Bothrops asper snake venom elicits, among other alterations, a pronounced inflammatory response at the site of injection both in humans and experimental animals. This review describes the current status of our understanding of the inflammatory reaction, including pain, triggered by B. asper venom. The experimental studies on the action of this venom as well as the complex network of chemical mediators involved are summarized. Moreover, aspects of the molecular mechanisms orchestrating this important response to envenomation by B. asper are presented. Considering that isolated toxins are relevant tools for understanding the actions of the whole venom, studies dealing with the mechanisms of inflammatory and nociceptive properties of phospholipases A2, a metalloproteinase and serine proteinases isolated from B. asper venom are also described. PMID- 19774699 TI - [Helped by a physician]. PMID- 19774701 TI - Proceedings of the 21st International Conference on Information Processing in Medical Imaging. July 5-10, 2009. Williamsburg, Virginia, USA. PMID- 19774702 TI - [Proceedings of PHUp2Date. February 11-12, 2009. Munich, Germany]. PMID- 19774703 TI - Abstracts of the American Peptides Symposium, June 7-12, 2009, Indiana, USA. PMID- 19774704 TI - Australia considers string of preventive health measures. PMID- 19774705 TI - Questions remain over validity of EUROCARE data. PMID- 19774700 TI - Fanconi anemia proteins and endogenous stresses. AB - Each of the thirteen identified Fanconi anemia (FA) genes is required for resistance to DNA interstrand crosslinking agents, such as mitomycin C, cisplatin, and melphalan. While these agents are excellent tools for understanding the function of FA proteins in DNA repair, it is uncertain whether a defect in the removal of DNA interstrand crosslinks (ICLs) is the basis for the pathophysiology of FA. For example, DNA interstrand crosslinking agents induce other types of DNA damage, in addition to ICLs. Further, other DNA-damaging agents, such as ionizing or ultraviolet radiation, activate the FA pathway, leading to monoubiquitination of FANCD2 and FANCI. Also, FA patients display congenital abnormalities, hematologic deficiencies, and a predisposition to cancer in the absence of an environmental source of ICLs that is external to cells. Here we consider potential sources of endogenous DNA damage, or endogenous stresses, to which FA proteins may respond. These include ICLs formed by products of lipid peroxidation, and other forms of oxidative DNA damage. FA proteins may also potentially respond to telomere shortening or replication stress. Defining these endogenous sources of DNA damage or stresses is critical for understanding the pathogenesis of deficiencies for FA proteins.We propose that FA proteins are centrally involved in the response to replication stress, including replication stress arising from oxidative DNA damage. PMID- 19774706 TI - Concerns grow over Cambodia's "AIDS colony". PMID- 19774707 TI - Bioengineered bodies and the moral imagination. PMID- 19774708 TI - Demographic stability metrics for conservation prioritization of isolated populations. AB - Systems of geographically isolated habitat patches house species that occur naturally as small, disjunct populations. Many of these species are of conservation concern, particularly under the interacting influences of isolation and rapid global change. One potential conservation strategy is to prioritize the populations most likely to persist through change and act as sources for future recolonization of less stable localities. We propose an approach to classify long term population stability (and, presumably, future persistence potential) with composite demographic metrics derived from standard population-genetic data. Stability metrics can be related to simple habitat measures for a straightforward method of classifying localities to inform conservation management. We tested these ideas in a system of isolated desert headwater streams with mitochondrial sequence data from 16 populations of a flightless aquatic insect. Populations exhibited a wide range of stability scores, which were significantly predicted by dry-season aquatic habitat size. This preliminary test suggests strong potential for our proposed method of classifying isolated populations according to persistence potential. The approach is complementary to existing methods for prioritizing local habitats according to diversity patterns and should be tested further in other systems and with additional loci to inform composite demographic stability scores. PMID- 19774709 TI - Impact and dynamics of disease in species threatened by the amphibian chytrid fungus, Batrachochytrium dendrobatidis. AB - Estimating disease-associated mortality and transmission processes is difficult in free-ranging wildlife but important for understanding disease impacts and dynamics and for informing management decisions. In a capture-mark-recapture study, we used a PCR-based diagnostic test in combination with multistate models to provide the first estimates of disease-associated mortality and detection, infection, and recovery rates for frogs endemically infected with the chytrid fungus Batrachochytrium dendrobatidis (Bd), which causes the pandemic amphibian disease chytridiomycosis. We found that endemic chytridiomycosis was associated with a substantial reduction (approximately 38%) in apparent monthly survival of the threatened rainforest treefrog Litoria pearsoniana despite a long period of coexistence (approximately 30 years); detection rate was not influenced by disease status; improved recovery and reduced infection rates correlated with decreased prevalence, which occurred when temperatures increased; and incorporating changes in individuals' infection status through time with multistate models increased effect size and support (98.6% vs. 71% of total support) for the presence of disease-associated mortality when compared with a Cormack-Jolly-Seber model in which infection status was restricted to the time of first capture. Our results indicate that amphibian populations can face significant ongoing pressure from chytridiomycosis long after epidemics associated with initial Bd invasions subside, an important consideration for the long-term conservation of many amphibian species worldwide. Our findings also improve confidence in estimates of disease prevalence in wild amphibians and provide a general framework for estimating parameters in epidemiological models for chytridiomycosis, an important step toward better understanding and management of this disease. PMID- 19774710 TI - Real shunts-unproven effect on gas exchange. PMID- 19774711 TI - Pathophysiological insight into shunted bubbles. PMID- 19774712 TI - Let's find out the size of these "shunts". PMID- 19774714 TI - ["New reference to development of the reflexive attitude of the nurse"]. PMID- 19774713 TI - A potential role for intrapulmonary shunt pathways in pathology. PMID- 19774715 TI - Preparing for internship. PMID- 19774716 TI - Rewards of acupuncture. PMID- 19774718 TI - Clearing up a misunderstanding. PMID- 19774719 TI - Time consuming portfolio preparation. PMID- 19774720 TI - Formula can never replace breast milk. PMID- 19774721 TI - Formula ad 'inappropriate'. PMID- 19774722 TI - Board decision on fees 'paternalistic'. PMID- 19774723 TI - 'Red faces' to the fore in Hamilton. PMID- 19774724 TI - Inappropriately explicit. PMID- 19774725 TI - On-call hours. PMID- 19774726 TI - BBVI. PMID- 19774727 TI - Rubin Bressler 1928-2009. PMID- 19774728 TI - Biosynthesis of mannophosphoinositides by Mycobacterium phlei. The family of dimannophosphoinositides. 1967. Biosynthesis of mannophosphoinositides by Mycobacterium phlei. Enzymatic acylation of the dimannophosphoinositides. 1968. PMID- 19774729 TI - Applying Toyota Production System principles to a psychiatric hospital: making transfers safer and more timely. AB - BACKGROUND: Health care organizations have increasingly embraced industrial methods, such as the Toyota Production System (TPS), to improve quality, safety, timeliness, and efficiency. However, the use of such methods in psychiatric hospitals has been limited. METHODS: A psychiatric hospital applied TPS principles to patient transfers to the outpatient medication management clinics (MMCs) from all other inpatient and outpatient services within the hospital's system. Sources of error and delay were identified, and a new process was designed to improve timely access (measured by elapsed time from request for transfer to scheduling of an appointment and to the actual visit) and patient safety by decreasing communication errors (measured by number of failed transfers). Complexity was substantially reduced, with one streamlined pathway replacing five distinct and more complicated pathways. To assess sustainability, the postintervention period was divided into Period 1 (first 12 months) and Period 2 (next 24 months). RESULTS: Time required to process the transfer and schedule the first appointment was reduced by 74.1% in Period 1 (p < .001) and by an additional 52.7% in Period 2 (p < .0001) for an overall reduction of 87% (p < .0001). Similarly, time to the actual appointment was reduced 31.2% in Period 1 (p < .0001), but was stable in Period 2 (p = .48). The number of transfers per month successfully processed and scheduled increased 95% in the postintervention period compared with the pre-implementation period (p = .015). Finally, data for failed transfers were only available for the postintervention period, and the rate decreased 89% in Period 2 compared with Period 1 (p = .017). DISCUSSION: The application of TPS principles enhanced access and safety through marked and sustained improvements in the transfer process's timeliness and reliability. Almost all transfer processes have now been standardized. PMID- 19774730 TI - Treating patients with type 2 diabetes: what is after lifestyle management and metformin? A focus on the glucagon-like peptide-1 receptor agonists. PMID- 19774731 TI - Michael Servetus (1511-1553) and the discovery of pulmonary circulation. AB - Michael Servetus was the first doctor ever to challenge and scientifically argue against the theories of Galen, which predominated for 14 centuries in medical schools worldwide. Even though he was relatively correct in scientific terms, Servetus was punished because of his boldness in challenging Galen's theories and was condemned to death by the Holy Inquisition. Yet, by publicly challenging Galen's and Hippocrates' predominant and unquestionable lessons on medicine for the first time, Servetus opened the door for other doctors to challenge and correct those theories and subsequently to bring about a new view of human anatomy and physiology. This article underlines the contribution of Servetus to the description of the pulmonary circulation. PMID- 19774732 TI - The emerging risk factors for cardiovascular disease: a review of the epidemiologic evidence for lipoprotein(a), homocysteine, and fibrinogen. AB - Appropriate correction of cardiovascular risk factors is a mainstay of the treatment of patients that have developed or might develop cardiovascular disease. In addition to classical risk factors, such as hypertension, smoking, dyslipidemia, diabetes, obesity, and sedentary life, epidemiological research has identified a number of additional conditions that are associated with a greater risk of cardiovascular disease. In fact, a substantial percentage of patients who develop cardiovascular events do not have any of the classical risk factors. Over the past thirty years, effective intervention in the treatment of hypertension, dyslipidemia, and diabetes has reduced remarkably cardiovascular morbidity and mortality, but the incidence of coronary artery disease and stroke remains unacceptably high and cardiovascular diseases are still the leading cause of death in the Western world. New cardiovascular risk factors are likely to give substantial contribution to this scenario and it could be easily anticipated that this contribution will become more evident in the upcoming years. This is why physicians who operate in the field of cardiovascular medicine and deal with problems related to cardiovascular prevention should be aware of these emergent risk factors, evaluate them accurately in their patients, and treat them appropriately. This review will summarize the literature supporting the role of lipoprotein(a), homocysteine, and fibrinogen as cardiovascular risk factors. PMID- 19774733 TI - The mast cell: a multifunctional effector cell. AB - Mast cells (MC) are recognized key cells of type I hypersensitivity reactions. Several lines of evidence, however, indicate that MC not only express critical effector functions in classic IgE-associated allergic disorders, but also play important roles in host defence against parasites, bacteria and perhaps even viruses. Indeed, it is now clear that MC can contribute to host defence in the context of either acquired or innate immune responses through the release of a myriad of pro-inflammatory and immunoregulatory molecules and the expression of a wide spectrum of surface receptors for cytokines and chemokines. Moreover, there is growing evidence that MC exert distinct nonimmunological functions, playing a relevant role in tissue homeostasis, remodeling and fibrosis as well as in the processes of tissue angiogenesis. In this review, we provide a small insight into the biology of mast cells and their potential implications in human pathology. PMID- 19774734 TI - Tubular differentiation in African breast cancer. AB - In an effort to determine numerical thresholds for histological breast cancer grading, we evaluated the fraction of fields with tubular differentiation (FTD) in Nigerian breast cancers (n=300). Analyses were based on Kaplan-Meier survival curves, and univariate and multivariate analyses by Cox's regression. The mean (SD) value of FTD in Nigeria, 16.7 (19.3)%, was much lower than reported in European breast cancer. Decreasing FTD was associated with increasing histological grades (p < 0.0001) and clinical stage (p = 0.0190). The most significant cut-point for FTD in predicting outcome was 15.0%. In univariate analysis, FTD 15% was a significant prognosticator in the whole material, in larger than 5cm tumours, among postmenopausal and premenopausal patients, and LN+ patients. After multivariate analysis with mitotic count, FTD was an independent prognosticator among tumours larger than 5cm, but not in other groups. We conclude that the rational grading of breast cancers need be optimised according to diagnostic and therapeutic environment. We propose FTD 15% as a cut-point to grade breast cancer in Nigerian material. PMID- 19774735 TI - Vascular expression of adhesion molecules in acute and chronic rejection of kidney allografts. AB - AIMS: It has been shown that adhesion molecules are upregulated on different structures in kidney during allograft rejection. Although vascular endothelium is one of the major targets in rejection, little is known about the expression of adhesion molecules in kidney vasculature. METHODS: Expression of adhesion molecules ICAM-1, VCAM-1 and E-selectin, and activation markers HLA-DR and IL2R was investigated in different vascular segments of nephrectomy specimens in 8 kidney allografts with acute and 5 with chronic rejection. RESULTS: In acute rejection, ICAM-1, VCAM-1 and HLA-DR were strongly upregulated on the endothelium and IL2R on inflammatory cells of all vessels. In chronic rejection, ICAM-1, VCAM 1 and HLA-DR were less intensive and focal, with the exception of peritubular capillaries and small veins in which VCAM-1 and HLA-DR were significantly upregulated. CONCLUSION: Upregulation of adhesion molecules in acute rejection is probably important in inflammatory infiltration of tubulointerstitium and vessels, as a part of cellular immune mechanisms. Cellular immunity is also supported by finding of IL2R positive activated lymphocytes. In chronic rejection, upregulation of VCAM-1 and HLA-DR on capillaries and small veins may be one of the important etiological factors, explaining the characteristic interstitial and perivascular inflammation. Inflammatory cell infiltration of fibrosed vessel walls in chronic rejection was, as well as the expression of adhesion molecules, low-grade and focal. These findings are in accordance with the general opinion that the pathogenesis of chronic rejection is more complex than in acute rejection, and that, in addition to cellular response, probably include other mechanisms. PMID- 19774736 TI - Spontaneous rupture of spleen: histological, immunohistochemical and ultrastructural study. AB - Pathological examination in the spleen of an 81-year old female with hemoperitoneum, hypovolemic shock, anemia, thrombocytopenia and hyperglicemia revealed the presence of an angiosarcoma. On histological examination, characteristically the neoplasm was formed by vascular lumina and cystic spaces into which papillary fronds projected and solid nests. Neoplastic cells had scant cytoplasm, hyperchromatic, oval or reniform nuclei, with prominent nucleoli. The necrosis was evident and mitoses were frequent. Immunohistochemical analysis revealed positivity for endothelial (CD31, CD34) and histiocytic markers (CD68 and lysozyme) and negativity for CD21. Ultrastructural examination also disclosed a biphasic differentiation, showing the presence of organelles associated with histiocytic and endothelial differentiation. These findings suggest that this lesion can be considered a conventional splenic angiosarcoma with focal histocytic differentiation. PMID- 19774737 TI - Chronic myelogenous leukemia: the new paradigm. PMID- 19774738 TI - Myelodysplastic syndromes. Clinical practice guidelines in oncology. AB - These suggested practice guidelines extensively evaluate reviewed risk-based data and indicate useful current approaches for managing MDS. Given the limited number of studies comparing different therapies in MDS, most of the therapeutic drugs used to treat this disease should be assessed in the context of clinical trials. A number of clinical trials are ongoing assessing the efficacy of novel biospecific agents in MDS (see related article in this issue, page 473). The role of thrombopoietic cytokines for management of thrombocytopenia in MDS needs further evaluation. In addition, determination of the effects of these therapeutic interventions on the patient's quality of life is important. Further progress toward improving management of MDS is anticipated using these guidelines as a framework for coordination of suggested comparative clinical trials. PMID- 19774739 TI - Novel biospecific agents for the treatment of myelodysplastic syndromes. AB - Levels of treatment for patients with myelodysplastic syndromes (MDS) fall within 3 broad categories: supportive care, low- and high-intensity therapy. Most approaches remain experimental, and supportive care remains the standard of treatment in MDS. In parallel with the growing knowledge of the multiple pathobiologic abnormalities in MDS, increasing numbers of low-intensity, biospecific agents that target these pathogenetic lesions have entered clinical trial testing. Although the term "biospecific" has been applied to many of these investigational drugs, they often exert pleiotropic effects, many of which remain to be identified. An ongoing challenge will be to more fully characterize the mechanisms of action of these drugs and to characterize biologic correlates of response. With these data in hand, it will be increasingly feasible to treat patients with combinations of biospecific drugs with non-overlapping actions and toxicities, a therapeutic approach that is likely required to effectively overcome the barriers posed by the biologic heterogeneity of MDS. This review focuses on recent therapeutic approaches using such biologic response modifiers to treat MDS. PMID- 19774740 TI - Chronic myelogenous leukemia. Clinical practice guidelines in oncology. PMID- 19774741 TI - New agents in chronic myelogenous leukemia. AB - Multiple new agents are currently being developed in chronic myelogenous leukemia (CML). Most of these agents are now being investigated in patients who have developed resistance to imatinib. Their mechanisms of action are diverse and many may be synergistic with imatinib. These agents will be used soon in different combinations, most likely including imatinib, with the hope of obtaining a complete blockade of the intracellular pathways that are triggered by Bcr-Abl. If this is successful, complete eradication of disease may become a reality for the majority of patients with CML. PMID- 19774742 TI - How to monitor patients with chronic myelogenous leukemia. AB - The introduction of imatinib has radically altered the treatment options and, perhaps, prognosis for patients with newly diagnosed chronic myelogenous leukemia (CML). However, although the majority of patients appear to benefit from this agent, it is important to recognize as early as possible the patients who experience a suboptimal response and those who may be at risk of disease progression. This article reviews current available methods of monitoring and provides recommendations for appropriate follow up of imatinib-treated patients. PMID- 19774743 TI - Acute myeloid leukemia. Clinical practice guidelines in oncology. PMID- 19774744 TI - The downside of Viagra: women's experiences and concerns. AB - While much is known about the efficacy and safety of sexuopharmaceuticals used by men for the treatment of erectile difficulties, there remains a dearth of knowledge on the perspectives and experiences of their sexual partners. In particular, few studies have focused on the possible detrimental effects for women of Viagra use within a heterosexual relationship. In this paper we report on a qualitative study based in New Zealand, which involved in-depth interviews with 27 women whose partners used Viagra. A number of key dimensions were identified, three of which revealed issues and concerns for women regarding the use of Viagra by their male partners: the neglect of women by those producing and prescribing Viagra; the embodied relationship (which encompasses physical and psychosocial effects of Viagra use); and broader socio-cultural implications (e.g the impact of 'the culture of Viagra' on understandings about sexuality in older age, and on ideas about male and female sexuality). We argue that while previous medically-oriented research in this area has generally assumed an unproblematic link between Viagra use and the resumption of penetrative sex within heterosexual relationships, more attention needs to be paid to partners' perspectives and desires, and to the specific dynamics of any given relationship. Moreover, while the publicity surrounding Viagra may potentially facilitate more positive attitudes to sexuality in older age, it may also produce a societal expectation that 'healthy' and 'normal' life for older people requires the continuation of 'youthful' (energetic) sex lives focused on penetrative intercourse. PMID- 19774745 TI - The body and doing gender: the relations between doctors and nurses in hospital work. AB - This article attempts to show how the concept of the body - as it has been applied in feminist thought - can be utilised in trying to understand the changing and at times problematic working relations between doctors and nurses in Sweden. Three approaches are applied with respect to the body: (1) Doctors and nurses belong to two different collective bodies which embody historical constructions of masculinity and femininity - which in turn have influenced how members of each corps have seen and worked with the other and how they approach each other even in the present day. (2) Gender is inscribed on the body. It is contended that in social encounters we never interact with each other as genderless beings, although we may very well take gender for granted and its importance may possibly be most salient in initial encounters. A nurse, then, never just interacts with a doctor--it is a female doctor or a male doctor and this makes a difference. 'Doing gender' is accomplished in these practices. (3) There is the question of situatedness--where (hospital staff) bodies find themselves on the ward and in the hospital in the daily run of things. Space and place are not neutral but are linked to relations of power and gender and class. How doing dominance and doing deference are accomplished--but also changed--in hospital work is addressed. PMID- 19774746 TI - Blurring, moving and broken boundaries: men's encounters with the pregnant body. AB - This paper draws on the findings of a longitudinal ethnographic study of men's transition to fatherhood, conducted in the United Kingdom (UK). It is concerned with their encounters with the pregnant and labouring body. Until relatively recently there has been surprisingly little work, either theoretical or empirical, on the experience of pregnant embodiment. Work in the last decade has indicated that women's experience of 'being-with-child', their experience of living in and being a pregnant body, can be an ambivalent affair, as some find disconcerting the experience of simultaneously being self and yet Other. If women, who possess the embodied and therefore privileged knowledge of pregnancy, can feel ambivalence, perhaps the case for expectant men is more so. This paper draws on interviews with men making the transition to fatherhood and analyses their experiences of and relation to the pregnant and labouring body. The theoretical analysis of their empirical accounts explores in particular the blurring, moving and broken boundaries of the pregnant and labouring body and how these changing body boundaries can challenge the taken-for-granted assumption that bodies should always be contained, strong and firm. The implications of men's encounters with this 'differently bounded' body are examined. PMID- 19774747 TI - Envisaging the embryo in stem cell research: rhetorical strategies and media reporting of the ethical debates. AB - How is the embryo defined, envisaged, imagined? Who speaks on its behalf, and how? Based on a study of UK press and TV news reporting, this paper identifies the rhetorical strategies used to assert competing ethical positions around embryonic stem cell research. We show how both sides in the dispute mobilise metaphors and use personification to recruit support; and how they promote different ideas about the embryo's significance, size, and social embeddedness and present competing narratives about its origins, destiny and 'death'. The role of visual representation is key here. It does not follow the usual pattern whereby, in the abortion debate, those 'on the side' of the fetus display its image while those who are 'pro-choice' shy away from this. In the stem cell debate the pattern is inverted, highlighting the role of technologies of visualisation in defining what counts as human. Our analysis also shows how the media coverage marginalises women's perspectives, disregards more fundamental challenges to science, side-lines concerns about effectiveness or safety and curtails discussion of broader issues. We reflect on the media processes restricting debate in this way and conclude by identifying opportunities for a more inclusive discussion of science ethics. PMID- 19774748 TI - Understanding women's sleep management: beyond medicalization-healthicization? AB - This paper addresses sleep, which to date has been a neglected area within the sociology of health and illness. We explore the extent to which the concepts of medicalization and healthicization provide appropriate models for understanding the management of women's sleep disruption. The prescription of sleeping pills remains as an indicator of the medicalization of sleep, while the trend towards the healthicization of sleep as part of healthy lifestyle practice is reflected in the increased focus of the media, pharmaceutical and complementary health care industries on sleep. The paper analyses qualitative data on women aged 40 and over to argue that the medicalization-healthicization framework fails to encapsulate a complete understanding of how women manage sleep disruption within the social context of their lives. It suggests that by looking inside the world of women's sleep we uncover a hidden dimension of self-directed personalized activity which plays a key role in women's response to sleep disruption. We propose an alternative model for the management of women's sleep which incorporates a core of personalised activity, linked to strategies associated with healthicization and medicalization. PMID- 19774749 TI - Family stories and the use of heuristics: women from suspected hereditary breast and ovarian cancer (HBOC) families. AB - The practice of medicine will increasingly be medicine of the family rather than the traditional physician/patient dyad, especially where a genetic condition is involved. This study explores how clients from suspected hereditary breast and ovarian cancer (HBOC) families seeking cancer genetics risk counselling are influenced by family stories and the use of heuristics (inferential shortcuts used to make sense of complicated information) in interpreting and applying genetic information they receive, and suggests ways in which genetic counsellors can integrate family context into their traditional counselling practices. We conducted an exploratory, qualitative study at a major clinical and research cancer centre in the United Kingdom from January to June 2000 which was reviewed by the hospital clinical research and ethics committees. Twenty-one semi structured, in-depth interviews were conducted using a purposive sample of women coming to the cancer genetics clinic for the first time, supplemented by five months of clinical observation at weekly clinics. In addition to many family stories based on the number and outcomes of the cancers in their families, we noted: (1) fragments of stories, (2) secret stories, (3) emerging explanations and (4) misconceptions, We did not find widespread intergenerational family myths, The women used three main heuristics in interpreting their breast/ ovarian cancer risk: (1) representativeness, (2) availability and (3) illusion of control, as well as what Kahneman refers to as the Peak and End rule. Recent psychological research indicates that illusions of control may have positive affects on both physical and mental health. This may pose a future ethical issue for genetic counsellors in determining how to balance the benefit of positive illusions with the delivery of statistical probabilities of risk. PMID- 19774750 TI - Changes in mental health status amongst children of migrants to Australia: a longitudinal study. AB - This paper examines the mental wellbeing of children of Australian migrants. Migration can be viewed as a natural experiment in which persons of one culture have their beliefs, values and behaviours challenged by the host culture. Such a process could be expected to lead to impaired mental health amongst migrants and their children. This paper investigates the relationship between migrants' region of origin, length of stay in Australia and indicators of impaired mental health. The data were taken from the Mater-University of Queensland Study of Pregnancy (MUSP), a longitudinal study of mothers and children which started in Brisbane, Australia, in 1981. The study comprises a cohort of over 5,000 women interviewed at their first ante-natal clinic visit and followed up at 3-5 days, six months, 5 and 14 years after the baby was born. Results showed no significant differences between the mental health of 'second generation' children and their Australian counterparts. Length of stay in Australia was not associated with internalising symptoms (anxiety and depression). There was a positive association, however, between the length of stay in Australia and increased externalising problems (aggression and delinquency) amongst the children at both 5- and 14-years follow up. We conclude that children of migrants do not differ from comparable children of Australian-born parents in their mental health. Children of migrant parents have fewer symptoms of some behaviour problems in the years after their arrival in Australia, but these rates increase to the Australian level over time. PMID- 19774751 TI - The challenge of implementing dietary advice. PMID- 19774752 TI - Comparison of dietary fat and fatty acid intake estimated by the duplicate diet collection technique and estimated dietary records. AB - INTRODUCTION: A high saturated fatty acid intake is a well recognized risk factor for coronary heart disease development. More recently a high intake of n-6 polyunsaturated fatty acids (PUFA) in combination with a low intake of the long chain n-3 PUFA, eicosapentaenoic acid and docosahexaenoic acid has also been implicated as an important risk factor. AIM: To compare total dietary fat and fatty acid intake measured by chemical analysis of duplicate diets with nutritional database analysis of estimated dietary records, collected over the same 3-day study period. METHODS: Total fat was analysed using soxhlet extraction and subsequently the individual fatty acid content of the diet was determined by gas chromatography. Estimated dietary records were analysed using a nutrient database which was supplemented with a selection of dishes commonly consumed by study participants. RESULTS: Bland & Altman statistical analysis demonstrated a lack of agreement between the two dietary assessment techniques for determining dietary fat and fatty acid intake. CONCLUSION: The lack of agreement observed between dietary evaluation techniques may be attributed to inadequacies in either or both assessment techniques. This study highlights the difficulties that may be encountered when attempting to accurately evaluate dietary fat intake among the population. PMID- 19774753 TI - A measurement and comparison of the fluid intake in people with and without back pain. AB - BACKGROUND: The aim of this study was to investigate and compare fluid intake of people with and without chronic back pain (BP). The research hypothesis was that fluid intake is lower in people with chronic BP. METHOD: A diary to record fluid intake in the general public was piloted. Seventy-seven people with chronic BP and 88 without BP were recruited from outpatient clinics and asked to record their fluid intake using this diary for nine consecutive days. Data were analysed to compare the intake of fluid in the two groups. RESULTS: T-tests showed that there is a higher fluid intake among the cohort with BP for the total daily fluid intake 2344 +/- 669 mL (P = 0.008), and daily fluid intake excluding alcohol 2065 +/- 658 mL (P = 0.039). CONCLUSIONS: This study found that a sample of people with BP drank more fluid than a similar group with no BP. PMID- 19774755 TI - The dietitians challenge: the implementation of nutritional advice for people with diabetes. AB - The evidence base for current nutritional recommendations has been extensively reviewed on behalf of the European Association for the Study of Diabetes (EASD) 1998 and the American Diabetes Association (ADA) 2002. The nutrition Sub Committee of Diabetes UK is in general agreement with those recommendations. This paper provides consensus-based recommendations that emphasize the practical implementation of nutritional advice for people with diabetes, and describe the provision of dietetic services required to provide the information. Important changes from previous Diabetes UK (previously British Diabetic Association Diabet. Med. 9, 189) recommendations include greater flexibility in the proportions of energy derived from carbohydrate and monounsaturated fat, further liberalization in the consumption of sucrose, more active promotion of foods with a low glycaemic index, and greater emphasis on the provision of nutritional advice in the context of wider lifestyle changes, particularly physical activity. Monounsaturated fats are now promoted as the main source of dietary fat because of their lower susceptibility to lipid peroxidation--and consequent lower atherogenic potential. Consumption of sucrose for patients who are not overweight can be increased up to 10% of daily energy derived from carbohydrate provided that this is eaten in the context of a healthy diet and distributed throughout the day. The role of the dietitian is outlined in facilitating lifestyle changes and evidence is presented for the effectiveness of advice provided by trained dietitians. The increasing evidence for the importance of good metabolic control and the growing requirement for measures to prevent Type 2 diabetes in an increasingly obese population will require major expansion of dietetic services if the standards in National Service Frameworks are to be successfully implemented at local level. PMID- 19774754 TI - Caffeine ingestion and fluid balance: a review. AB - BACKGROUND: Caffeine and related methylxanthine compounds are recognized as having a diuretic action, and consumers are often advised to avoid beverages containing these compounds in situations where fluid balance may be compromised. The aim of this review is to evaluate the available literature concerning the effect of caffeine ingestion on fluid balance and to formulate targeted and evidence-based advice on caffeinated beverages in the context of optimum hydration. METHOD: A literature search was performed using the Medline database of articles published in the medical and scientific literature for the period of January 1966-March 2002. Subject headings and key words used in this search were: tea, coffee, caffeine, diuresis, fluid balance and water-electrolyte balance. A secondary search was performed using the bibliographies of publications identified in the initial search. RESULTS: The available literature suggests that acute ingestion of caffeine in large doses (at least 250-300 mg, equivalent to the amount found in 2-3 cups of coffee or 5-8 cups of tea) results in a short term stimulation of urine output in individuals who have been deprived of caffeine for a period of days or weeks. A profound tolerance to the diuretic and other effects of caffeine develops, however, and the actions are much diminished in individuals who regularly consume tea or coffee. Doses of caffeine equivalent to the amount normally found in standard servings of tea, coffee and carbonated soft drinks appear to have no diuretic action. CONCLUSION: The most ecologically valid of the published studies offers no support for the suggestion that consumption of caffeine-containing beverages as part of a normal lifestyle leads to fluid loss in excess of the volume ingested or is associated with poor hydration status. Therefore, there would appear to be no clear basis for refraining from caffeine containing drinks in situations where fluid balance might be compromised. PMID- 19774756 TI - Lay conception of hypertension and its significance to clients and professionals in nutrition and health. AB - BACKGROUND: In line with the Philippines' National Cardiovascular Disease Prevention and Control Programme, a study was conducted among young adults to determine their concepts and conceptualization of hypertension: its causation, prevention and consequences. METHOD: Focus group discussions, conducted in the region with the highest prevalence of hypertension in the Philippines, 73 males and females were participated in the age group of 20-39 years, without medical history of the disease and with no training or employment in a health-related field. RESULTS: Hypertension was perceived not as a discrete disease but interrelated with diseases having 'blood-origin' and common signs and symptoms. It was conceptualized as having multiple causes, acting singly or in combination, with too little or too much food and physical activity as among the causal factors. Perceived pathways in its development were systematic and included both traditional and scientific biomedical concepts. Hypertension was considered a problem not only in the affected individual but also the family. CONCLUSION: The concepts of hypertension of young adults are multidimensional, interconnected and linked to their day-to-day living. In thus conceptualizing the disease, they are able to make sense of it and, when respected by dietetic practitioners, provide guidance for improved communication. The introduction of scientific concepts of hypertension by nutrition and health professionals should draw from, inform and build on, existing lay perceptions. PMID- 19774757 TI - Serum osteocalcin in donkeys as evaluated with an equine-specific radioimmunoassay. AB - The purpose of this study was to validate an equine-specific osteocalcin (OC) radioimmunoassay (RIA) for use in donkeys and to establish age-related changes in serum OC concentrations in healthy donkeys. Serial dilutions of donkey serum showed parallelism with standard curves obtained with the equine-specific OC RIA. There was a tight linear regression between donkey serum OC values obtained with the equine specific OC RIA and a commercially available bovine-specific OC RIA. Serum OC levels of 27 healthy donkeys, analysed with the equine-specific OC RIA, showed a tight negative logarithmic regression with age. Least square means and standard error of serum OC values were 67 +/- 10 microg/l in 0.6-4-year-old donkeys (group 1), 32 +/- 9 microg/l in 5-9-year-old donkeys (group 2) and 15 +/- 11 microg/l in > 9-year-old donkeys (group 3). Serum OC values were significantly (p < 0.01) higher in group 1 than in groups 2 and 3. The equine-specific OC RIA may be a useful and practical tool to assess bone metabolism and skeletal diseases in donkeys. PMID- 19774758 TI - Effects of hay intake and feeding sequence on variables in faeces and faecal water (dry matter, pH value, organic acids, ammonia, buffering capacity) of horses. AB - To investigate effects of hay intake and feeding sequence on indicators of the microbial activity within the hindgut, six horses were fed 1.00 kg oats plus 0.50, 0.67, 0.83 or 1.00 kg hay/100 kg body weight (BW) x day, each for 14 days. Oats was offered either 30 min prior to hay (OA) or in the reversed sequence (HA) in a 2 x 8-week crossover design. Because typically exercised horses should be subjected to the study, faeces was used as substrate. Faecal dry matter (DM), the faecal waters' short-chain fatty acids (SCFA, in mmol/1) and molar percentages (mol%) of propionate and iso-butyrate were highest with OA (p < 0.01). Acetate mol%, acetate-propionate quotient (A/P) and buffering capacities 1 and 2 (BC1: current pH to pH 6; BC2: pH 6 to 5) of the faecal water were highest with HA (p < 0.01). While the hay intake rose, faecal pH, acetate mol%, A/P, BC1 and BC2 (the latter with HA only) increased (p < 0.05), but DM, SCFA and propionate mol% declined (p < 0.05). The hay-induced rise in A/P and BC1 was much higher with HA than with OA. L-Lactate and ammonia were unaffected by the feeding sequence and hay intake. In conclusion, hay intake and feeding sequence influence the microbial activity within the hindgut, although the concentrate level remains consistent. In horse rations with 1.00 kg oats/100 kg BW x day amounts of at least 0.83 kg hay/100 kg BW x day and offering the hay first seem to have the potency to protect the hindgut content from acidification. Behavioural abnormality was not observed any longer first with 1.00 kg hay/100 kg BW x day. PMID- 19774759 TI - [An extended evaluation of a neuroleptanesthesia for the guinea pig with analysis of mixed expiratory gases during spontaneous breathing. Effects of fasting on the cardiorespiratory system and metabolism]. AB - The artificially ventilated guinea pig was frequently used for neurophysiological and respiratory studies. This species is also preferable for an evaluation of hemoglobin based artificial oxygen carriers, because its oxygen hemoglobin binding is very similar to that of man. But the narcosis of this animal-species is very difficult, because of cardiorespiratory depression induced by conventional procedures. The following intraperitoneal administered neuroleptanesthesia was proved in guinea pigs: 0.2 mg Fentanyl (Janssen/D), 10 mg Droperidol (Janssen/D) and 400 mg Urethan in 10 ml isotonic sodium chloride solution per kg body weight. Our new animal model with a special valve system enables to assess the gas exchange under spontaneous breathing, cardiovascular and the acid-base parameters. The vital parameters of animals were stable over 6 hours and very close to those of awake animals, especially the arterial average blood pressure. For that reason, this established neuroleptanesthesia of guinea pigs is preferable for research purpose. The fasted animals show significantly decreased values of arterial blood pH (7,345 vs. 7401), of heart frequency (244 vs. 277 min(-1)), and of ventilation value (167 vs. 205 ml/min) compared to non fasted animals. PMID- 19774760 TI - Comparative nutritive value of cassava leaf meal, soya beans, fish meal and casein in diets for growing pigs. AB - A trial was conducted to investigate energy and nutrient digestibility of cassava leaf meal (CLM), casein (CAS), fish meal (FM), full-fat soya bean (FFSB) and extracted soya bean meal (SBM). The basal diet containing cassava root meal (CRM) and FFSB meal and the other five dietary treatments were evaluated with 12 crossbred castrated male pigs in a metabolism study covering three successive experimental periods between 40 and 60 kg body weight (BW). Total tract digestibility of dry matter (DM), organic matter (OM) and gross energy (GE) of diets, generally increased significantly (p < 0.05) from CLM diet to FFSB and FM diets and finally to CAS and SBM diets, corresponding to a decrease in fibre content in the diets. Except for CAS diets, the pattern of acid detergent fibre (ADF) digestibility followed a similar trend. Significantly higher ADF digestibility was recorded for soya bean diets while ADF digestibility value obtained for CLM diet was significantly lower. The digestible energy values obtained for CAS, FM, FFSB, SBM and CLM were 22.2, 16.3, 17.5, 17.0 and 8.0 MJ/kg DM, respectively. Corresponding metabolizable energy values were 22.1, 15.6, 17.1, 16.3 and 7.6 MJ/kg DM, respectively, PMID- 19774761 TI - Effects of the level of dietary valine supply on amino acids and urea concentration in milk and blood plasma of lactating sows. AB - In order to determine the valine (Val) requirement, suckling sows with 10-12 piglets were supplied with feed mixtures, which contained various levels of Val derived by adding crystalline L-Val to the native diet (0.45% = native, 0.55, 0.65, 0.85, 1.05 and 1.45%) during a total of 72 lactations. Milk and blood plasma, taken after 3 weeks of lactation, was examined on the concentration of amino acids (total amino acids in milk, free amino acids in plasma) and urea by ion exchange chromatography or autoanalyzer, respectively. The contents of almost all amino acids in milk were significantly higher compared with the native diet, when Val was supplemented, reflecting increasing milk protein concentrations. Highest amino acid concentrations were observed with 0.85% dietary Val. Amino acid pattern in milk was not affected by the Val supply. In blood plasma the concentration of free Val rose with the dietary Val from 9 mg/l (0.45% dietary Val) to 132 mg/l (1.45% dietary Val). Several other amino acid contents were also higher when Val was added to the native diet, but there was no dose-response. Urea concentrations in milk and blood plasma were lowest with 0.65% and 0.85% dietary Val, respectively. Conclusively, for sows nursing litters with 10-12 piglets a dietary valine supply of 0.85% (0.75% apparent ileal digestible Val) can be recommended with a minimum requirement of 0.65% (0.55% apparent ileal digestible Val). PMID- 19774762 TI - Influences of stage of lactation, teat position and sequential milk sampling on the composition of domestic cat milk (Felis catus). AB - Milk from 11 domestic shorthair cats (Felis catus; n=7 fed dry low-fat diet, n=4 fed dry high-fat diet) was collected weekly for 6 weeks following parturition, and analysed for total solids (TS), crude protein (CP), fat, lactose and ash. Samples were collected in 1-ml sequential fractions to determine whether within sampling changes in composition existed Samples of extracted milk fat were also analysed for fatty acid content. Two commercia kitten milk replacers were analysed according to the same procedures utilized for mil samples. In statistical analyses individual cat, diet, stage of lactation, litter size, and teat position influenced concentrations of milk components; parity and sequential sampling had no effect. Averaged cat milk was 27.9% TS, and 8.7% CP, 12.7% fat, 4.2% lactose and 1.3% ash (on a wet basis). Milk protein percentage increased over lactation for both diet groups, but fat percentage increased only for queens fed the high-fat diet. Milk replacers were lower in fat and protein content than milk from queens, and had considerably lower levels of arachidonic acid. Data from this study contribute to the limited information available regarding the composition of domestic cat milk, and give possible reasons for poor growth occasionally observed in kittens fed unsupplemented commercial milk replacers. PMID- 19774763 TI - The effect of dietary oxidized fats on the antioxidant status of erythrocytes and their susceptibility to haemolysis in rats and guinea pigs. AB - Three experiments were carried out with rats (experiments 1 and 2) and guinea pigs (experiment 3) to study the effect of oxidized fats, in interaction with dietary concentrations of vitamins E and C, on the antioxidant status of erythrocytes and the rate of haemolysis. In experiment 1, diets with fresh or thermoxidized fats, containing either 25 or 250 mg alpha-tocopherol equivalents/kg were used; experiment 2 included diets with fresh or thermoxidized fats, containing 25 mg alpha-tocopherol equivalents/kg; in experiment 3, besides a control diet with a fresh fat, diets containing thermoxidized fats with various concentrations of Vitamin E (35 vs. 175 mg alpha-tocopherol equivalent/kg) and Vitamin C (300 vs. 1000 mg/kg) were used. Rats and guinea pigs fed diets with oxidized fats had reduced concentrations of glutathione in erythrocytes as compared with animals fed the fresh fat diets. In rats fed oxidized fats, the activity of catalase and in guinea pigs fed oxidized fats, the activity of glutathione peroxidase plus the concentration of alpha-tocopherol was reduced in erythrocytes as compared with animals fed the equivalent fresh fat diets. The concentrations of alpha-tocopherol in erythrocytes were increased by both, Vitamin E and Vitamin C while the concentrations of glutathione were independent of the concentrations of those vitamins in the diets. Erythrocytes of guinea pigs fed oxidized fats also showed an increased susceptibility to haemolysis during incubation in hypotonic salt solutions; this effect could be improved by increasing the concentrations of both, Vitamin E and Vitamin C. Parameters of in vivo haemolysis (activities of lactate dehydrogenase and acidic phosphatase and concentrations of potassium and free haemoglobin in plasma) were not adversely affected in rats and guinea pigs fed the oxidized fats as compared with animals fed the fresh fats. The study shows that dietary oxidized fats reduce the antioxidant status of erythrocytes and increase their susceptibility against haemolysis but do not increase the rate of haemolysis in vivo. PMID- 19774764 TI - Intimate terrorism and common couple violence. A test of Johnson's predictions in four British samples. AB - This study sought to both replicate and considerably extend the findings of Johnson (1999) that there are two distinct subgroups of physical aggression within relationships: intimate terrorism and common couple violence. The present sample consisted of women residing at Women's Aid shelters and their partners (N=86), male and female students (N=208), men attending male treatment programs for domestic violence and their partners (N=8), and male prisoners and their partners (N=192). Respondents completed measures on physical aggression, injuries sustained, escalation of physical aggression, and controlling behaviors. Cluster analysis was employed to categorize relationships as either intimate terrorism or common couple violence. Frequency analysis showed broad support for Johnson's findings. PMID- 19774765 TI - Predicting the psychosocial effects of interpersonal partner violence (IPV). How much does a woman's history of IPV matter? AB - Women's (N=205) IPV experiences were assessed during their pregnancies, in the year before their pregnancies, and with their previous partners. The study explored whether psychosocial indicators and severity of violence could be predicted from a woman's continuity and history of IPV. Two 4-group classifications-partner (IPV experiences across partners) and time (history of IPV experiences)-and one 2-group classification (IPV or no IPV in the past 6 months) were compared. Both four-group classifications accounted for more variance than did the two-group. Within the four-group classifications, most of the significant differences on psychosocial outcomes and severity of IPV were between the no IPV and chronic IPV groups (IPV experiences with two partners and across three different time periods). However the groups that also fared poorly were those who experienced recent IPV and continuity of IPV across time with their current partners. PMID- 19774766 TI - Sex crime recidivism. Evaluation of a sexual offender treatment program. AB - Evaluations of programs for sex offenders report mixed results, are costly, and require validation. This study examines recidivism following a sexual offender treatment program in an Australian male offender population over an average at risk period of 5 years and 1 month in the community. The group format, cognitive behavioral program was offered to a subgroup of adult male prisoners. Subsequent reoffense types and rates for program completers, dropouts, and controls were compared. No statistically significant recidivism reduction was observed following participation in this sexual offender treatment program, whereas recidivism appears to be related to a history of violent or sexual offenses. The initial promise of sexual offender treatment programs must be further examined by individual and meta-analytic studies. Limited follow-up, missing data, and fidelity of the program may have contributed to the null result. Monitoring treatment programs to ensure inclusion of proven interventions may enhance future program effectiveness. PMID- 19774767 TI - Addressing the service linkage problem. Increasing substance abuse treatment engagement using personalized feedback interventions in heavy-using female domestic violence shelter residents. AB - Two personalized substance abuse assessment and feedback interventions were tested for effectiveness in engaging female domestic violence shelter residents in substance abuse treatment. One hundred forty-seven residents were assessed for quantity andfrequency of substance use, negative consequences due to use, motivation to change substance use behavior, and psychopathological symptoms related to substance abuse. Assessment identified (33) 22% of participants as heavy substance users. Twenty of the 33 heavy-using residents received one of two personalized substance use feedback interventions:face-to-face feedback or writtenfeedbackplaced in shelter mailboxes. Treatment engagement was defined as attending at least one substance abuse treatment session within 30 days after the intervention. Results showed a significant difference in treatment engagement rates in favor of the face-to-face feedback group (60% vs. 0%). The results provide preliminary data suggesting that substance abuse assessment can be effectively accomplished in the shelter environment and that the face-to-face feedback procedure may be an effective intervention to bridge the service linkage problem between domestic violence services and substance abuse treatment. PMID- 19774768 TI - Cross-validation of the Self-Appraisal Questionnaire with a maximum-security psychiatric population. AB - The Self-Appraisal Questionnaire (SAQ) is a 72-item, self-report measure designed to predict recidivism, supervision violations, and related behaviors among nonmentally disordered Canadian federal offenders. In the present article, the authors demonstrate that the SAQ maintains satisfactory predictive validity on cross-validation with a high-risk correctional psychiatric sample. PMID- 19774769 TI - The toll of domestic violence. PTSD among battered women in an Israeli sample. AB - The study examines the prevalence of posttraumatic stress disorder (PTSD) among battered women in Israel and the associated psychological distress. This study inquires into the psychological reactions of battered women in comparison to women who experienced other types of traumas by examining PTSD rates and intensity of psychiatric symptoms and suicide risk. The research sample was comprised of 91 battered women, and the control group was comprised of 82 women who underwent other traumas excluding interpersonal traumas. The participants were administered questionnaires relating to type and intensity of domestic violence, PTSD symptoms, intensity of psychiatric symptoms, and suicide risk. The results showed that 51.6% of the battered women had full PTSD. Battered women exhibited significantly higher levels of psychiatric symptoms than the control group. Battered women who were diagnosed with PTSD scored significantly higher than battered women without PTSD on the same indicator. The findings emphasize the toll and severity of domestic trauma. PMID- 19774770 TI - The Expect Respect Project. Creating a positive elementary school climate. AB - The Expect Respect Project, a violence prevention program, was developed to reduce the incidence of bullying and sexual harassment by creating a positive school climate in which inappropriate behaviors are not tolerated and staff members respond consistently to incidents. The project implemented an educational intervention for students, parents, and staff members on expecting respect in student relationships and strategies for responding to inappropriate student behaviors. This article describes the educational intervention and evaluation of the project. Findings from the project showed a significant increase in awareness of bullying following the educational intervention. Bullying was reported to have occurred in areas with less adult supervision such as the playground, cafeteria, hallway, and buses. Students thought staff would respond to inappropriate behaviors by telling students to ignore verbal bullying or sexual harassment. In contrast, staff at the elementary schools thought adults would respond to inappropriate behaviors by telling the bully to stop, calling his or her parents, or giving a specific punishment. PMID- 19774771 TI - Performance-enhancing mouth wear and craniofacial neurometabolic physiology. PMID- 19774772 TI - Performance enhancement and oral appliances. AB - The use of some type of oral appliance to enhance human performance, decrease stress or improve strength, has occurred throughout human history, from ancient soldiers to modern athletes. To date, the science describing this phenomenon has been poorly understood, and the research has been limited. The goal of this paper is to review the efforts to improve human performance with oral appliances, and the research exploring the science behind these efforts. PMID- 19774773 TI - Effects of mouthpiece use on airway openings and lactate levels in healthy college males. AB - Research has described the use of mouthpieces not only in preventing oral-facial injuries, but linking use to improvements in muscular strength and endurance. However, the mechanisms by which these improvements occur have not been elucidated. The purpose of this study was to understand possible physiological explanations for improvements in exercise performance with the use of a mouthpiece. Specifically, this study focused on differences in lactate levels after 30 minutes of endurance exercise with and without a mouthpiece. In addition, computed tomography (CT) scans were taken of the cross-sectional area of the oropharynx in each participant (N = 10) with and without a mouthpiece. CT scans showed a significant difference in mean width (28.27 mm with the mouthpiece vs 25.93 mm without the mouthpiece, P = .029) and an increase in mean diameter with a mouthpiece (12.17 mm vs 11.21 mm, P = .096). Lactate levels were lowered with the mouthpiece at 1.86 mmol/L vs 2.72 mmol/L without mouthpiece. This research suggests that there is an improvement in endurance performance that may be linked to improved airway openings resulting from the use of a mouthpiece. Future studies should continue to clarify the possible mechanisms for these exercise outcomes as well as to understand the optimal mandibular advancement to elicit these exercise improvements. PMID- 19774774 TI - Effects of mouthpiece use on auditory and visual reaction time in college males and females. AB - Studies in exercise science have suggested that the use of a mouthpiece can improve performance, and these improvements may be linked to an enhancement in temporomandibular joint (TMJ) positioning. Studies have suggested that by improving TMJ positioning, there is improved blood flow in the area of the TMJ. Changes in TMJ positioning may be improved with an oral device. The purpose of this study was to determine if there were improvements in auditory and visual reaction time with the use of a boil and bite mouthpiece. Using a BIOPAC system, study participants (N = 34) were asked to respond to an auditory signal during 40 trials. In the visual reaction time test, participants (N = 13) were assessed on how quickly they responded to a computer cue for a total of 30 trials. Auditory results showed a significant improvement with the use of a mouthpiece (241.44 ms) vs without a mouthpiece (249.94 ms). Visual results showed that participants performed slightly better with the mouthpiece (285.55 ms) vs without the mouthpiece (287.55 ms). These findings suggest that the use of mouthpiece positively affects visual and auditory reaction time, which is a vital aspect to optimal sport and exercise performance. Future studies should continue to shed light on possible reasons for the improvements in auditory and visual reaction time with the use of a mouthpeice. In addition, future studies should further illuminate what, if any, connection these improvements have with enhanced TMJ positioning. PMID- 19774775 TI - The role of intraoral protective appliances in the reduction of mild traumatic brain injury. AB - Intraoral appliances (mouthguards) have long been used and mandated for several sports, with good results on the reduction of dentition injury. Recently claims have arisen that mouthguards prevent brain injury. This article reviews the data on such claims, the basic science that has been conducted, and how an intraoral appliance may in the future become part of an engineered system to reduce transfer of energy from impacts to specific locations on the head, in an effort to mitigate some types of mild traumatic brain injury. PMID- 19774776 TI - Would an increased proportion of male nurses benefit the profession? PMID- 19774777 TI - No sweat. AB - When nurse Julie Halford discovered what misery hyperhidrosis causes, she was determined to help. PMID- 19774778 TI - Front line trauma care. AB - Military and civilian nurses rise to the challenge of treating wounded service personnel. PMID- 19774779 TI - Valued to the end. PMID- 19774780 TI - Implementing end of life care for patients with renal failure. AB - Traditional palliative care services have focused on individuals with cancer. The NHS National End of Life Care Programme, launched in December 2003, has been working to address this anomaly and to try to enhance end of life care provision for other patient groups. This article reports on work in the area of renal failure at Westmorland General Hospital, Cumbria, where the Preferred Priorities for Care tool has been introduced to support patients nearing the end of life. PMID- 19774781 TI - Retaining central venous catheters in paediatric parenteral nutrition. AB - This article aims to discuss problems with central venous catheters (CVCs) and offer strategies to assist in preventing their replacement. The article focuses on the most frequent complications of infection and obstruction. Traditional treatment options are presented and endoluminal brushing is introduced as an innovative treatment for retaining CVCs. The expert opinion that follows focuses on CVCs that are used for parenteral nutrition in paediatrics, but the evidence described can also be applied to larger adult catheters. PMID- 19774782 TI - Obesity: prevalence, causes and clinical consequences. AB - Obesity is a growing problem affecting the health of the nation and requiring long-term management. This article aims to explore the prevalence and multifactoral causes of obesity, focusing on the biopsychosocial aspects of the disease. The health risks associated with obesity are discussed, in particular type 2 diabetes and cardiovascular disease. PMID- 19774783 TI - Oxygen therapy. PMID- 19774784 TI - Reading the signs. PMID- 19774786 TI - The sky's the limit. PMID- 19774785 TI - Volunteer to share your skills. PMID- 19774787 TI - Slowly progressive dopamine cell loss--a model on which to test neuroprotective strategies for Parkinson's disease? AB - Making animal models of human disease is a very flawed process. Aspects of the disease can be imitated but models do not necessarily give reliable leads for treatment strategies. When Ungerstedt in Sweden first described the 6 hydroxydopamine (6-OHDA) treated rat model of Parkinson's disease /89/ we knew that the symptoms would not map readily to those of the human disease--rats have four legs after all. On the other hand, the neuropathology looked exactly like end-stage Parkinsonian pathology. That remained true even as we explored other types of neuropathology in the rats /24,43-46,80/. Many of today's treatments for Parkinsonism are developed from pharmacological studies on that model of rats with a chemically induced lesion. However, the 6-OHDA model does not address the important issue of a cure for the disease. The triggers and the time-course of dopamine (DA) cell death in rats are known for nearly every disease model - but for the human disease there is no equivalent knowledge. In the human, the neurons have been dying for a considerable time before the symptoms become obvious and they go on dying even with adequate symptomatic relief /94/, but after intracerebral administration of 6-OHDA to an animal the cells die quickly; all cells are destroyed in less than 5 days /42,88,89/. Thus, we were interested in developing an animal model of DA cell death with a slower time-course. After ibotenic acid injections into rat globus pallidus (GP), DA cells are lost from the ipsilateral substantia nigra over the slower time scale of about six weeks. This time scale has allowed us to test some interventions to prevent the cells from dying. Although some attempts have succeeded, cell death is prevented only for three weeks -beyond that treatments fail and DA cells die. At the moment, this model has at least opened a window into causes of neuronal death in a slower time scale /94/ than previous rodent models. PMID- 19774788 TI - Crosstalk between calcium, amyloid beta and the receptor for advanced glycation endproducts in Alzheimer's disease. AB - Hallmarks of Alzheimer's disease (AD) include the accumulation of amyloid beta peptide (Abeta), hyperphosphorylation of tau protein, and increased inflammatory activity in the hippocampus and cerebral cortex. The receptor for advanced glycation endproducts (RAGE) has been shown to interact with Abeta and to modulate Abeta transport across the blood-brain barrier. Furthermore, RAGE is upregulated at sites of inflammation and its activation results in distinct intracellular signaling cascades in respect to Abeta conformers. Besides Abeta, RAGE interacts with several members of the calcium binding S100 protein family, amphoterin and advanced glycation endproducts. Mounting evidence suggests that RAGE is a key player in the signaling pathways triggered by Abeta and S100 proteins in AD. In this review, we discuss recent discoveries about the crosstalk between RAGE, Abeta and S100 proteins in the pathophysiology of AD. PMID- 19774789 TI - Autistic spectrum disorders as functional disconnection syndrome. AB - We outline the basis of how functional disconnection with reduced activity and coherence in the right hemisphere would explain all of the symptoms of autistic spectrum disorder as well as the observed increases in sympathetic activation. If the problem of autistic spectrum disorder is primarily one of desynchronization and ineffective interhemispheric communication, then the best way to address the symptoms is to improve coordination between areas of the brain. To do that the best approach would include multimodal therapeusis that would include a combination of somatosensory, cognitive, behavioral, and biochemical interventions all directed at improving overall health, reducing inflammation and increasing right hemisphere activity to the level that it becomes temporally coherent with the left hemisphere. We hypothesize that the unilateral increased hemispheric stimulation has the effect of increasing the temporal oscillations within the thalamocortical pathways bringing it closer to the oscillation rate of the adequately functioning hemisphere. We propose that increasing the baseline oscillation speed of one entire hemisphere will enhance the coordination and coherence between the two hemispheres allowing for enhanced motor and cognitive binding. PMID- 19774790 TI - Nerve growth factor as a signaling molecule for nerve cells and also for the neuroendocrine-immune systems. AB - Nerve growth factor (NGF) is a signaling molecule, originally discovered for its role on differentiation and survival of peripheral sensory and sympathetic neurons. It has also been associated with functional activities of cells of the immune and endocrine systems. NGF biological activity is mediated by two classes of receptors: (i) p75 neurotrophin receptor (p75(NTR)), a 75 kDa glycoprotein, belonging to a superfamily of cytokine receptors including TNF receptors, and (ii) TrkA, a transmembrane tyrosine kinase of 140 kDa. Both TrkA and p75(NTR) are known to play a marked action in neurodegenerative disorders, immune-related deficits, and neuroendocrine (including adipoendocrine) mechanisms. This review focuses on these cellular events and presents a working model which attempts to explain the close interrelationships of the neuro-endocrine-immune triad via a modulatory action of NGF. PMID- 19774791 TI - Home sweet home. PMID- 19774792 TI - To screen or not to screen: part 1--the thyroid gland in pregnancy. PMID- 19774793 TI - Hip fracture management and outcomes at a regional South Dakota hospital. AB - The annual number of hip fractures is expected to increase dramatically in coming decades. It is, therefore, in the best interest of the health care community to maximize its efficiency in treatment of such fractures. This study examines the outcomes for elderly patients admitted to a Midwest regional hospital with the diagnosis of hip fracture in 2007. It found that the hospital tended to keep auxiliary cardiac testing at a minimum, treat as many patients as possible, get patients into surgery as quickly as possible and minimize both lengths of stays and mortality. However, our study found there was room for improvement in decreasing the wait time to surgery for the patient by improving physician communication and laboratory turnaround. PMID- 19774794 TI - The impact of secondhand smoke during pregnancy. AB - No one disputes the adverse effects of smoking. Pregnant women should not smoke, as study after study proves the serious damage done by exposure to tobacco. Understanding the deadly effects of secondhand smoke has led to legislation by countries and individual states in the United States. Around the world, countries including England, Ireland, Italy, France and Uruguay have banned smoking from all public places. In the United States, 26 states to date have adopted comprehensive clean air acts, including Nebraska, Iowa and Minnesota. At the time this article went to print, South Dakota's smoke-free legislation, which will ban smoking in all indoor public places except smoke shops, existing cigar bars and lodging rooms, was to take effect July 1, 2009. PMID- 19774795 TI - Vancomycin: new dosing and monitoring recommendations for adults. PMID- 19774796 TI - Hospital quality information from the consumer perspective. PMID- 19774798 TI - Pharmacy benefit manager switch--why the change? PMID- 19774799 TI - Wedding cake and funerals. PMID- 19774800 TI - Systemic, prophylactic and local applications of antimicrobials in endodontics: an update review. AB - Antibiotics were first discovered in the late 1920s but were not routinely used clinically until the early 1940s during the Second World War. They can be used as an adjunct to endodontic treatment in a number of ways-systemically, prophylactically and locally. There are few real indications for the systemic use of antibiotics in conjunction with endodontic treatment. They are only needed when the body's efforts at fighting bacteria are failing. Use of antibiotics to prevent infection (antibiotic prophylaxis) may prevent some case of bacterial endocarditis. Therefore, prophylaxis is recommended for individuals in high-risk and moderate-risk categories. Another mode of application of antibiotics is local application as intracanal medicaments and root canal irrigants. PMID- 19774801 TI - Oral manifestations among people living with HIV/AIDS in Tanzania. AB - BACKGROUND: This study aimed to determine the prevalence of various oral and peri oral manifestations in people living with HIV/AIDS in Tanzania. METHODS: A cross sectional study. A total of 187 persons with HIV infection were recruited from non-governmental organisations serving people living with HIV/AIDS, 16.6% were males and females 83.4%. Information on weight and height, as well as extra oral and intra oral examinations for different manifestations were gathered. Treatment and referral for special care were offered. RESULTS: At least one oral lesion was present in 45% of the participants. Candidiasis (28.9%) and non-tender lymphadenopathy (11.8%) were the most common lesions. Candidiasis occurred most frequently on lips/mucosa, and the tongue, and pseudomembranous candidiasis was the most frequent type. Candidiasis occurred with several other conditions and was statistically significantly associated with low body mass index (BMI). CONCLUSION: This community survey carried out in an African sub-Saharan country showed that oral lesions are frequent among people living with HIV/AIDS. As emphasised by the World Health Organization Global Oral Health Programme, national HIV/AIDS programmes should incorporate oral health components. PMID- 19774802 TI - Replacement of missing teeth in a southern region of Vietnam--a descriptive dental laboratory study. AB - AIM: To explore whether tooth replacement in a southern region of Vietnam is in line with the primary health care approach, aiming at health services for all people at affordable costs. METHODS: Tooth replacement was investigated by means of prostheses as delivered by four dental laboratories of which the output was considered representative. Information was based on dental casts related to the prostheses. RESULTS: Prostheses replaced almost all missing teeth, irrespective of the types (interrupted or shortened dental arches) and numbers of missing teeth in the dental arch they were made for. Acrylic removable partial dentures were the most common prostheses delivered (65% of removable partial dentures). CONCLUSION: It cannot be stated that dental arch conditions in this study were representative for the southern Vietnamese population. However, it is concluded that dental practitioners tend to provide complete dental arches by tooth replacements. This morphologically based approach might introduce over treatment. In line with primary oral health care, a functionally oriented treatment management, including the shortened dental arch concept, should be implemented. PMID- 19774803 TI - Periodontal diseases and cardiovascular events: meta-analysis of observational studies. AB - OBJECTIVE: Many studies have investigated the relationship between periodontal and cardiovascular diseases but their results are heterogeneous. Meta-analyses were conducted to examine the association between exposure to periodontitis and cardiovascular diseases. MATERIAL AND METHODS: Studies published between 1989 and 2007 were retrieved from seven databases. The included articles reported the results from observational studies (cohort, cross-sectional and case-control studies) and assessed the link between periodontal exposure and cardiovascular diseases as confirmed by one of the following criteria: diagnosed coronary artery disease, angina pectoris, acute myocardial infarction, mortality caused by cardiac pathology. The study characteristics were abstracted by independent researchers following a standardised protocol. The MOOSE guidelines for meta analysis of observational studies were followed. RESULTS: From 215 epidemiological studies, 47 were observational, of which 29 articles could be combined by the meta-analysis methodology. The pooled odds ratio calculated from the 22 case-control and cross-sectional studies was 2.35 (95% CI [1.87; 2.96], p < 0.0001). The risk of developing cardiovascular disease was found to be significantly (34%) higher in subjects with periodontal disease compared to those without periodontal disease (pooled relative risk from the 7 cohort studies was 1.34 (95% CI [1.27; 1.42], p < 0.0001). CONCLUSIONS: It seems from observational studies that subjects with periodontal diseases have higher odds and higher risks of developing cardiovascular diseases but the reduction in the risk of cardiovascular events associated with the treatment of periodontitis remains to be investigated. PMID- 19774804 TI - Dental research in Iran: a bibliometric analysis of electronically available literature. AB - PURPOSE: To carry out a bibliometric analysis of all electronically available dental literature in Iran from 1983 to 2006, in order to study availability and examine trends. MATERIALS AND METHODS: Accessing all electronically available Iranian dental articles published in domestic journals, and comparing the results with Iranian dental articles published in Pubmed. The following data were collected from each article: name of journal, year of publication, number of authors, gender of corresponding author, academic levels of authors, main language of article, language of abstract, study environment, population studied, field of dentistry, type of article, design strategy, design of study, and analysis design. RESULTS: In terms of publications in domestic journals, a total of 1,994 dental articles were electronically available, published in six different dental journals in Iran. Majority of articles, 84.5%, were original studies. In terms of design strategy, 49.7% of studies were cross-sectional, 35.5% were prospective, and 14.8% were retrospective studies. The main language of 99.3% of articles was Farsi, and 0.7% was English. Majority of articles, 38.7%, were written by two authors. Gender of corresponding author in 66.7% of articles was male, and in 33.3% of articles was female. There was an increasing trend in percentage of original studies, clinical trials and female corresponding authors. In terms of publications in Pubmed, a total of 75 dental articles from Iran were electronically available. Significant differences were revealed in terms of number of authors, study types and design strategies when compared to publications in domestic journals. CONCLUSION: A number of encouraging trends were identified, which is a reflection of improvements in quality of domestic electronic dental literature. However, as the majority of articles are written in Farsi, availability of research evidence to the international community is limited. Overall, results of this study indicate the need for future bibliometric analyses which can be used to construct a comprehensive database that will assist in evidence-based clinical decision making. PMID- 19774805 TI - Long-term follow-up of the effects of a school-based caries preventive programme involving fluoride mouth rinse and targeted fissure sealant: evaluation at 20 years old. AB - AIMS: The evaluation of long-term effects five years after the completion of a school-based caries prevention programme combined with fluoride mouth rinse (FMR) and targeted sealant application (TS). PARTICIPANTS: 46 subjects in the FMR+TS group and 55 subjects in the FMR group, who were 20 -21 years old, were analysed. They had participated in each 11-year programme, underwent a dental examination at the age of 20 years and answered a self-administered questionnaire. METHODS: The caries prevalence and mean DMFT were calculated, and differences between the two groups were analysed by the chi2 test and Mann-Whitney test, respectively. Logistic and multiple regression analyses were performed using sex, group, and five questionnaire items as independent variables. RESULTS: The caries prevalence and mean DMFT (SD) was 28.3%, 1.56 (3.00) in the FMR+TS group and 60.0%, 2.20 (2.44) in the FMR group, and the difference was significant respectively. In the logistic regression analysis the odds ratio of the FMR+TS group to the FMR group was 0.28 (p < 0.05). CONCLUSIONS: The caries-preventive effects of a school-based combined programme with FMR and TS continued for more than five years after the programme until the age of 20 years. PMID- 19774806 TI - The challenges and effects of globalisation on forensic dentistry. AB - This paper deals with the challenges faced by forensic dentists in a world in which globalisation has become a reality. People travelling across the globe on a daily basis become victims of violent crime, terrorist attacks, human displacement, natural and man made disasters. This has forced colleagues in the profession to participate in joint operations exposing inadequacies which need urgent attention. Forensic dentists practise in isolation creating their own rules and regulations oblivious to the greater global community. No international protocols exist for the many procedures practised by the profession. Possible solutions to the complex problems are offered. These include co-operation with colleagues around the globe while striving for the highest levels of quality control, standardisation, reliability, impartiality, reproducibility and ethical accountability. PMID- 19774807 TI - Addressing underperformance in the United Kingdom NHS dental system and its possible implications for other care systems. AB - OBJECTIVE: To outline the rationale for, background to and role of the National Clinical Assessment Service (NCAS) in helping improve the quality of care provided through the NHS dental care system and identify possible lessons for international dental care delivery systems. DESCRIPTION: Due to shortcomings in the provision of healthcare and changes in societal attitudes towards healthcare professionals new arrangements for ensuring the quality of care are evolving. The performance of individual practitioners is increasingly being challenged as new regulatory mechanisms for the delivery of care evolve. Historically, regulatory bodies have had few options to handle poor performance and this will need to change: one such approach is the development of an agency to help identify the rationale for poor performance and, most importantly, develop solutions to address them. SUMMARY: The creation of NCAS has provided a mechanism through which shortcomings in dental practitioners' performance can be addressed in a systematic and more appropriate manner than has previously existed. The approach used has applicability for helping improve the quality of care within all oral health care systems. PMID- 19774808 TI - Modalities in prevention of flexor tendon adhesion in the hand: what have we achieved so far? AB - Several modifications in surgical techniques and various pharmacological and non pharmacological modalities have been introduced to prevent adhesions formation in surgery on flexor tendons of the hand. However, most studies have been carried out in animals with very few human trials. Only early postoperative rehabilitation is supported by clinical evidence, while the optimal rehabilitation protocol remains controversial. Innovations in surgical techniques and other modalities need to be tested with adequately powered human trials, before their potential benefit in clinical practice is accepted. PMID- 19774809 TI - Outcome of shoulder hemiarthroplasty in acute proximal humeral fractures: a frustrating meta-analysis experience. AB - Limited evidence is available on the optimal treatment of complex fractures of the proximal humerus. No randomized prospective studies have compared hemiarthroplasty, open reduction internal fixation and/or conservative treatment. Two systematic reviews are available but they do not include angle-stable plate osteosynthesis or third-generation prosthetic designs. We conducted a systematic review of studies published in the last 10 years. The MOOSE guidelines were followed and we focused on functional outcome and its relation to age, gender and tuberosity healing after hemiarthroplasty. Sixteen studies met the inclusion criteria. We found a correlation between increasing age and decreasing Constant score (r = -0.60, p = 0.0142). Tuberosity healing has influenced functional outcome in all series mentioning this parameter. Hemiarthroplasty remains a valuable option for the treatment of proximal humerus fractures in elderly patients. However the quality of the available reports is poor. Large-scale, structured, prospective studies are needed to determine the current place of hemiarthroplasty of the shoulder in treatment of fractures of the proximal humerus. PMID- 19774810 TI - High- versus low-energy extracorporeal shock wave therapy of rotator cuff tendinopathy: a prospective, randomised, controlled study. AB - A prospective, controlled, randomised trial was performed to compare the effect of high-energy extracorporeal shock wave therapy (ESWT) versus low-energy ESWT in treatment of rotator cuff tendinopathy. Forty adult patients were included in the study. Patients in the intervention group received 6000 impulses of high-energy (ED+ 0.78 mJ/mm2) in 3 sessions under local anaesthesia. Patients in the control group received 6000 impulses of a low-energy ESWT (ED+ 0.33 mJ/mm2) under local anaesthesia. Follow-up examinations were performed 12 weeks and one year after treatment by an independent observer. An increase in function and a reduction of pain were found in both groups (p < 0.001). Although the improvement in Constant score was greater in the high-energy group compared to the low-energy group, statistical analyses showed no significant difference between the groups with respect to all parameters studied (Constant score/pain/subjective improvement) after 12 weeks and one year follow-up. No statistically significant differences were found between the results of high-energy and low-energy ESWT of rotator cuff tendinopathy. PMID- 19774811 TI - Percutaneous Kirschner-wire fixation for displaced distal forearm fractures in children. AB - A prospective study was conducted to evaluate the efficacy of percutaneous Kirschner-wire fixation for the management of high-risk distal forearm fractures in children. Thirty two children (22 boys & 10 girls) with displaced fractures of the distal third of the radius with or without ulnar fractures were managed by closed reduction and percutaneous Kirschner-wire fixation. Their average age was 10.1 years (4-16 years). The fracture was open (Grade 1) in two cases (6.3%). Antegrade intramedullary Kirschner-wire fixation was done for distal radial fractures in 71.9% of cases. Patients were evaluated clinically and radiologically after an average duration of follow-up of 28.6 months. Patients with residual angulation more than 15 degrees, limitation of forearm or wrist movement more than 20 degrees, persistent pain or clinical deformity were considered to have unsatisfactory results. Satisfactory results were obtained in 87.5% of all cases. The residual radioulnar and dorsovolar angulations were significantly related to the decrease in forearm rotation and the unsatisfactory results. High-risk distal forearm fractures in children should be treated by primary percutaneous Kirschner-wire fixation supplemented by cast immobilisation. PMID- 19774812 TI - The role of the transverse carpal ligament in carpal stability: an in vitro study. AB - A biomechanical in vitro study was performed on 16 fresh frozen cadaver forearms to investigate the role of the transverse carpal ligament (TCL) in carpal stability. The distance between the scaphoid and hamate was measured, as a reference for the length of the TCL. Distances were recorded in both loaded and unloaded conditions after gradual sectioning of the transverse carpal ligament, the palmar scapholunate, long radiolunate ligament and radioscapholunate ligament. The largest increase in spread of the carpal bones (55.3% of total spread) was noted after loading with the ligament intact. Thereafter, sectioning of the TCL resulted in a further 32.9% increase in the distance between the scaphoid and the hamate. We conclude that the intact carpal bones-ligament complex displays some elasticity. Progressive sectioning of the TCL ligament under loading further opens the palmar arch. Nevertheless it appears that the carpal arch will still retain reasonable intrinsic stability even without an intact TCL. PMID- 19774813 TI - Is the tip of the greater trochanter a reliable reference for the rotation centre of the femoral head in total hip arthroplasty? AB - A variety of techniques have been used to determine intra-operative leg length during total hip arthroplasty. One method often described is using the tip of greater trochanter as the reference for the rotation centre of the femoral head to align the femoral component. There is little in the literature to support this method of leg length restoration. We analysed standard anterior-posterior pelvic radiographs of 225 patients with osteoarthritis of the hip who were about to undergo total hip arthroplasty. The distance between the tip of the greater trochanter and the rotation centre of the femoral head was measured for the affected hip. The average location of the tip of greater trochanter is 3.4 mm proximal to the centre of the femoral head, with a range from 20 mm proximal to 10 mm distal to the femoral head centre. There is considerable variation in the anatomy of the proximal femur; however, with adequate preoperative templating, the greater trochanter can be a helpful guide to determine the rotation centre of the femoral head of the femoral component and should be used with other conventional techniques to determine leg length intra-operatively. PMID- 19774814 TI - Pseudotumours associated with metal-on-metal hip resurfacing: 10-year Newcastle experience. AB - We report the incidence of pseudotumours in a single-surgeon consecutive series of 670 metal-on-metal hip resurfacings performed in the last ten years, with a minimum follow-up of one year. Two cases of pseudotumours have been found and are discussed in detail including metrology and wear analyses of the explanted components. The first was a painless, large synovial cyst in the thigh, secondary to aseptic femoral cup loosening 8 years following hip resurfacing. The second was a painful collection of wear debris in the psoas region at one year post surgery caused by impingement, resulting in eccentric edge wearing. In the first case it was decided to retain the bearing surface; in the second case, conversion to a metal-on-polyethylene hip replacement was performed. In our experience the risk of pseudotumours is low (0.15%) and can be fully explained. In selected cases the bearing surface can be retained. PMID- 19774815 TI - Quality of life in patients following percutaneous PMMA acetabuloplasty for acetabular metastasis due to carcinoma. AB - Pain is the main symptom of acetabular osteolysis from metastatic carcinoma, and it is frequently associated with pathologic fractures. Radiotherapy alone usually is not effective for pain control, and it does not allow weight bearing. Surgical procedures requiring an aggressive approach and consequently high morbidity are rarely indicated in patients with multiple metastases. Polymethylmethacrylate (PMMA) has been widely used in oncologic and spinal surgery as a bone filler. We evaluated the functional results of percutaneous injection of PMMA in 20 patients (24 acetabula) with acetabular osteolysis from metastatic carcinoma. Patients were assessed before and after percutaneous acetabuloplasty, evaluating pain, mobility of the hip joint, general condition, use of analgesics, using the SF-36, QLQ-C30, Eastern Cooperative Oncology Group (ECOG) Performance Scale and Harris Hip Score. There was a marked clinical improvement in all patients during the first six post-operative months, with gradual worsening thereafter from deterioration of their general condition over the 12-month follow-up period. Percutaneous acetabuloplasty is reliable and effective in the short term, with a statistically significant reduction of pain and improvement in quality of daily life. PMID- 19774816 TI - Treatment of reduced femoral antetorsion by subtrochanteric rotational osteotomy. AB - The purpose of this study was to assess bone healing and complication rate following subtrochanteric rotational osteotomy fixed with a 4.5/5.0 Locking Compression Plate (LCP, Synthes) for reduced femoral antetorsion with early full weight bearing. The effects of the osteotomy on the range of internal rotation of the hip and complaints due to reduced antetorsion were also recorded. Between July 2004 and October 2007, 25 children (39 hips) with a mean age of 13 years (range, 9-18 years) were treated for reduced internal rotation of the hip by a subtrochanteric rotational osteotomy. Four patients (six hips) were excluded from this study due to concomitant surgeries prohibiting full weight bearing. Of the 21 patients who were allowed full weight bearing, nine had a unilateral and twelve a single-stage bilateral correction. We investigated time to union, implant failure, and complication rate as well as improvement in the range of internal rotation. All osteotomies healed without secondary displacement or angulation. Internal rotation improved from a mean of 8.6 degrees (-5 degrees to 20 degrees) preoperatively to 37.3 degrees (25 degrees to 60 degrees) postoperatively. We noted no complication related with the femoral osteotomy. Subtrochanteric rotational osteotomy appeared as a reliable procedure to improve internal rotation of the hip. Fixation with 4.5/5.0 LCP allows simultaneous bilateral correction and immediate full weightbearing with crutches, with a minimal risk of implant failure. PMID- 19774817 TI - Biological plate fixation of comminuted subtrochanteric fractures with the Dynamic Condylar Screw: a clinical study. AB - Subtrochanteric fractures are fraught with anatomical, biological and biomechanical challenges which account for an increased incidence of nonunion and malunion. We retrospectively assessed the results achieved in 40 patients with a mean age of 36 years who were treated with biological plating using a Dynamic Condylar Screw for comminuted subtrochanteric femoral fractures between January 2004 to May 2007. Union was achieved in all cases at a mean of 15.6 weeks, with one major and 3 minor technical difficulties. There was limb length discrepancy (mean: 1 cm) in 5 cases and rotational deformity in 4 cases. Results were excellent in 45% of cases, good in 50% and fair in 5% according to Sanders' criteria. There was no statistically significant difference between the healthy and fractured sides with respect to femoral neck-shaft angles. Use of fracture table, adequate two plane fluoroscopy and adherence to technical details give predictable results with this implant available at an affordable cost, even in countries with low socio-economic status. PMID- 19774818 TI - Isometric reconstruction of the posterolateral corner of the knee. AB - To date, there is no consensus on the best technique to repair injured posterolateral structures of the knee. We evaluated the effects of a fibular head based isometric reconstruction of the posterolateral knee corner with a double bundle semitendinosus tendon. From February 2001 to February 2005, 18 isometric reconstructions of a chronic posterolateral corner (PLC) injury of the knee were performed using the semitendinosus tendon. The average age of the patients was 39 years, ranging from 19 to 52 years. Twelve were male and 6 female. The time interval between injury and treatment ranged from 1.5 to 14 months. Three patients had simple PLC injuries, 10 had combined PLC-posterior cruciate ligament (PCL) injuries and two of them had undergone a PCL reconstruction elsewhere 6.5 months prior to referral. Three other patients had an associated anterior cruciate ligament (ACL) injury and two had a combination of PLC with ACL and PCL injury. A doubled semitendinosus tendon was threaded through bony tunnels in the fibular head running from the insertion of the lateral collateral ligament (LCL) to the fibular insertion of the popliteo-fibular ligament and both ends were fixed proximally into bony tunnels of the lateral femoral condyle at their respective isometric point. The varus stress test and the posterolateral rotation test were used to evaluate stability of the posterolateral structures. Isometry was optimal between the femoral attachment site of the popliteal tendon to the anatomical insertion of the popliteofibular ligament at the fibular head. The fibular insertion of the LCL is isometric to the anterior or antero-inferior 8-10 mm of the femoral insertion of the LCL. The average follow-up period was 32 months (30-42 months). There was no varus knee instability in full extension. At 30 degrees of flexion two cases demonstrated a grade I varus instability. A fibular head based isometric reconstruction is a reproducible and reliable technique for reconstruction of the posterolateral corner of the knee. PMID- 19774819 TI - Titanium elastic nail fixation for paediatric femoral and tibial fractures. AB - The aim of this prospective study was to evaluate the results of treatment of paediatric femoral and/or tibial diaphyseal fractures with titanium elastic nails (TENs). Sixty six patients with 48 femoral and 25 tibial fractures were followed up for 15 to 24 months. The outcome rating system proposed by Flynn et al was used to evaluate the final results. Most patients (56.1%) were operated between 2 to 4 days after injury; a traction table was used in 54.8% of cases. The average operative time was 28 minutes, and the average hospital stay was 5.7 days. Postoperative immobilisation was used in 30% of cases, mostly with femoral fractures. The fractures united in an average time period of 85 days; 89% had united within 3 months. The nails were removed in 87.8% of cases after an average of 5.9 months. The following complications were noted: soft tissue and skin problem (9.1%) in relation to nail ends at the entry points, limb-length discrepancy (9.1%), malunion (4.5%). Based on Flynn et al's outcome rating system, 75.8% of the results were excellent, 24.2% were satisfactory and there were no poor results. With good knowledge of the technique of TEN fixation for paediatric femoral and tibial fractures, excellent and satisfactory results were achieved in all cases, with few minor complications. TENs can give stable fixation allowing early mobilisation and shorter hospitalisation with less disruption of patient and family life. PMID- 19774820 TI - A family with cleidocranial dysplasia and crossed ectopic kidney in one child. AB - Cleidocranial dysplasia or dysostosis (CCD) is a condition characterised by failure of membranous ossification resulting in absence or pseudarthrosis of the clavicle, open fontanelles, wormian bones and supernumerary teeth. The aetiology though not completely known is thought to be due to a CBFA1 (core binding factor activity 1) gene defect on the short arm of chromosome 6p21. CBFA1 is essential for differentiation of stem cells into osteoblasts, so any defect in this gene will cause defects in membranous and endochondral bone formation. Since the first description, over 700 cases have been reported in literature. The authors report a family with mother and her four sons affected with CCD and Crossed Renal Ectopia (CRE) in one child, which has not been reported in CCD before. PMID- 19774821 TI - Renal profile in patients with orthopaedic trauma: a prospective study. AB - This prospective study was undertaken to determine the incidence of acute renal failure (ARF) and to identify factors contributing to development of ARF in orthopaedic trauma patients. A total of 55 patients who presented over a period of one year with trauma to upper and lower limbs were studied. Patients with renal injury, chest or abdominal injury, isolated fractures of the hands, feet and axial skeleton involvement were excluded. Out of these, five developed acute renal failure, three recovered and two died. The overall incidence of ARF in this study was 9.1%. Patients with lower limb injuries are at higher risk of developing ARF. Mangled Extremity Severity Score (MESS) > or = 7, higher age, patient presenting with shock, increased myoglobin levels in urine and serum have been correlated with a greater risk of patients developing ARF and a higher mortality. This study attempts to determine the magnitude of crush injury causing renal failure and the incidence of renal failure in patients with injuries affecting the appendicular skeleton exclusively. PMID- 19774822 TI - Lipoblastoma--an unfamiliar but important diagnosis. A case series and literature review. AB - Lipoblastoma and its infiltrative variant lipoblastomatosis are rare adipose tissue tumours seen in infants and children. Many surgeons are unfamiliar with these uncommon lesions and hence they are suboptimally treated. We report a case series of six patients in our tertiary paediatric hospital. Cases were reviewed retrospectively with reference to demographics, investigations, diagnosis and their management. Lipoblastomas are easily misdiagnosed and excision before proper investigations may result in incomplete resection, recurrence and further potentially mutilating surgery. PMID- 19774823 TI - Elution of ciprofloxacin from acrylic bone cement and fibrin clot: an in vitro study. AB - The purpose of this study was to investigate the release of ciprofloxacin from acrylic bone cement and fibrin clot. Under sterile conditions, bone cement and fibrin clot were individually mixed with ciprofloxacin. Ten specimens of each complex were placed in 1 ml of nutrient broth and incubated at 37 degrees C. The nutrient broth was changed daily, and the removed samples were stored at -70 degrees C until the antibiotic concentration in each sample was determined by a microbiological method. The maximum level in bone cement specimens was obtained at the second day (80.80 microg/ml) and its diffusion was rapid at first, decreasing gradually over a period of 365 days. Fibrin clot biodegradable specimens released high concentrations of ciprofloxacin (1.52-49.91 microg/ml) in vitro for the period of time needed to treat bone infections (i.e. 65 days). We conclude that the high release of ciprofloxacin in vitro from acrylic bone cement and fibrin clot is very promising since the obtained levels are much higher than the required minimal inhibitory concentration (MIC) against the implicated pathogens in soft tissue and bone infections. The in vivo relevance of the obtained results requires carefully performed studies in animal models. PMID- 19774824 TI - Negative pressure suction technique for bone cement introduction into the delivery syringe. A technical note. AB - The authors present in this brief note a technique to facilitate the introduction of high viscosity bone cement into a cement syringe for retrograde high pressure cementing during total hip or revision knee arthroplasty. The nozzle part of the syringe is connected to the suction device used intra-operatively, to achieve a negative pressure in the syringe. Introduction of the cement into the syringe is thus greatly facilitated, which saves time during the curing process. PMID- 19774825 TI - Hemi resurfacing of the humeral head for an osteochondral lesion affecting the entire head surface. AB - An osteochondral lesion of the entire articular surface of the humeral head has not previously been reported. We report the case of a 73-year-old woman with a huge osteochrondal lesion which affected virtually the whole articular surface of the humeral head, caused by an unusal mechanism of injury. Clinical examination revealed a stiff, weak, painful shoulder. Radiographs were unremarkable and an ultrasound scan suggested a supraspinatus tear with retraction. At arthroscopy the lesion was identified but the lesion was to large for arthroscopic removal. A humeral head hemi-resurfacing as a treatment for this lesion produced excellent results, the patient returned to her pre-injury level of function with no pain. PMID- 19774826 TI - Angiosarcoma around a knee arthroplasty. Report of a case and literature review. AB - The development of periprosthetic malignancy in proximity to an arthroplasty has been a matter of debate since it was first reported in 1978. We report a case of tibial angiosarcoma, an extremely rare malignancy, which developed in proximity to a primary knee arthroplasty performed ten years before. To our knowledge this is the second case ever described around a knee arthroplasty. While implantation of orthopaedic material can induce the development of malignant tumours in experimental animals, the overall incidence of malignancy recorded following arthroplasty in clinical studies does not appear to be increased compared to the control population. Each case of periprosthetic malignancy following arthroplasty must receive attention in order to better understand the underlying pathology and to measure the possibility for an increased risk of development of specific cancer types. PMID- 19774827 TI - Haematogenous osteomyelitis of the patella in a child. AB - Osteomyelitis of the patella is rare; it essentially occurs in child age. The diagnosis is difficult because of its variable presentation; it should always be considered in patients with persistent peripatellar pain and swelling. This paper reports one case of haematogenous osteomyelitis of the patella not associated with septic knee arthritis. The identification of the organism was performed by the injection-aspiration fluid technique. Treatment is identical to the treatment of osteomyelitis at other locations. The literature is also reviewed and discussed. PMID- 19774828 TI - Unusual mode of mechanical failure of an AO cannulated self drilling screw. A case report. AB - Cannulated AO screws are commonly used for fracture fixation. Mechanical failure of screws has been well reported but this was mainly breakage of the screw head during removal. We report an unusual mode of failure of an AO self drilling cannulated screw which we have not previously experienced, where the screw threads were found to be unravelled during insertion. We also suggest the way to recognise this complication early and how to prevent or deal with it. PMID- 19774829 TI - Intraosseous leiomyoma in a rib. A case report. AB - Intraosseous leiomyomas are very rare. To the best of our knowledge, this is the first published case of primary intraosseous leiomyoma in a rib. This rare benign tumour should be included in the differential diagnosis of any relatively small intraosseous lesion with benign imaging findings, but with gradually worsening, long-standing pain. PMID- 19774830 TI - Management of a post-operative multi-resistant infectious spondylitis associated with a kyphotic deformity. AB - Anterior spinal infection (prevertebral abscess and/or discitis) after posterior instrumentation for vertebral fractures is a challenging complication, since a new implant may become necessary anteriorly, in a septic environment. Generally accepted management guidelines are yet to be established. The authors present a case of posterior instrumentation for fractures of T12 and L1, complicated after 9 months with an anterior infection (prevertebral abscess and discitis) with extended-spectrum beta-lactamase (ESBL) producing Escherichia coli (E. coli). This case is unique in that the multi-resistant organism was isolated only after the second stage of infection treatment, which consisted of anterior debridement and anterior implantation of titanium cages and rods. In this particular case, infection was controlled despite implantation of multiple cages, screws and rods, and fusion was achieved, by means of intravenous antibiotic treatment for 12 months. At the latest follow-up, 24 months post surgery, there was no evidence of infection. This problem case may be helpful for surgeons confronted with spinal deformities secondary to infections with multi-resistant organisms. PMID- 19774831 TI - Unemployment, mortality and the problem of health-related selection: evidence from the Scottish and England & Wales (ONS) longitudinal studies. AB - Testing whether unemployment causes health deterioration is complicated because failing health may increase the probability of unemployment. In some previous studies of unemployment and mortality a 'wear-off' period is used to exclude any deaths occurring in the first few years after employment status was observed. It is assumed that selection effects will wear-off during this period. In this article the effectiveness of using wear-off periods is tested. Using data from the Scottish Longitudinal Study and the England and Wales Longitudinal Study, logistic regression models were used for estimating the odds of death in a given time period after the 1991 Census for those aged 35-64 in 1991. The odds ratios for the different economic positions (in work, unemployed, retired, permanently sick and other inactive) were compared, as well as the changes in risk associated with cumulatively increasing the length of wear-off prior to follow-up. No evidence was found of health-related selection for the unemployed in 1991. This observation was consistent across both studies. This suggests that the use of the five year wear-off period in many studies of mortality and unemployment may be an ineffective and unnecessary technique for mitigating the effects of health related selection. PMID- 19774832 TI - Deaths involving MRSA: England and Wales, 2008. PMID- 19774833 TI - Deaths involving Clostridium difficile: England and Wales, 2008. PMID- 19774834 TI - Deaths related to drug poisoning in England and Wales, 2008. PMID- 19774835 TI - Cancer incidence and mortality in the United Kingdom and constituent countries, 2004-06. PMID- 19774836 TI - Unexplained deaths in infancy, England and Wales, 2007. PMID- 19774837 TI - Death registrations in England and Wales, 2008, causes. PMID- 19774838 TI - Vitamins and trace elements are important for the integrity of the endocrine system. PMID- 19774839 TI - Pleiotropic genetic syndromes with developmental abnormalities associated with obesity. AB - Childhood obesity is a common and complex problem that may persist in adulthood. It may present as a component of genetic syndromes associated with dysmorphic features, developmental abnormalities, mental retardation and/or learning disabilities and often neuroendocrine dysfunction. Although the chromosomal abnormalities of these rare syndromes are already known, the specific genetic and pathophysiological mechanisms leading to the distinct phenotypes and obesity still remain unclarified. New exciting genetic pathways contributing to syndrome phenotype and leading to obesity have recently been identified. Prader-Willi syndrome is caused by loss of expression of the C/D box HBII-84 cluster of snoRNAs. Dysfunction of the primary cilium, thought to have important signalling functions, may contribute to disease phenotype and obesity in Bardet-Biedl, Alstrom and Carpenter syndromes. In this mini-review current knowledge of clinical and genetic characteristics is summarized as well as the pathogenesis of these syndromes with special emphasis on the pathogenesis of obesity. PMID- 19774840 TI - Short child with interesting hand radiograph. PMID- 19774841 TI - A randomized controlled trial of Kung Fu training for metabolic health in overweight/obese adolescents: the "martial fitness" study. AB - Twenty overweight/obese adolescents underwent six months of Kung Fu or placebo (Tai Chi) training, 3x.wk(-1). Outcomes included fasting insulin and insulin resistance, lipids, glucose and HbA(1c), and C-reactive protein (CRP). CRP decreased significantly (p = 0.03) in both groups over time at six months. Although insulin sensitivity did not change, HbA(1c) tended to decrease over time (p = 0.09), again with no group difference (p = 0.60). Reduced CRP was related to increased upper body strength (p = 0.01). Increased lean body mass was related to reductions in HbA(1c), insulin resistance, triglycerides, and total cholesterol. Improvements in lean body mass appear to have a potential role in favorable metabolic outcomes, independent of changes in fat mass. Further research in this area is warranted before definite conclusions can be drawn about the efficacy of martial arts training for metabolic outcomes in this cohort. PMID- 19774843 TI - A stepwise increase in recombinant human growth hormone dosing during puberty achieves improved pubertal growth: a National Cooperative Growth Study report. AB - The magnitude of the pubertal growth spurt contributes to adult height. Children treated with increased doses of recombinant human growth hormone (rhGH) during puberty have shown improved near adult height (NAH) outcomes that varied by treatment duration. METHODS: Males, in a single clinic, treated with a prepubertal dose of rhGH (0.3 mg/kg/wk) received 0.1 mg/kg/wk dose increases with successive Tanner stages up to 0.6 mg/kg/wk. Changes in height and height SDS from pubertal onset to NAH were assessed in patients attaining NAH after > or =3 years (n = 23) and > or =4 years (n = 16). Using ANCOVA, outcomes were compared to closely matched patients (n = 758) from the National Cooperative Growth Study treated with a fixed dose (0.3 mg/kg/wk) throughout puberty. RESULTS: Compared to matched patients, a 3.6 cm greater increase in mean height gain and a 0.49 greater increase in mean height SDS (p <0.0001) during puberty was observed in patients attaining NAH after > or =3 years. Corresponding values were 3.9 cm and 0.54 (p <0.0001) in patients attaining NAH after > or =4 years. CONCLUSION: Stepwise increases in rhGH improved pubertal height gain when compared to a fixed dose and may represent an alternate approach to managing the patient during puberty. PMID- 19774842 TI - Accuracy of self-assessed Tanner staging against hormonal assessment of sexual maturation in overweight African-American children. AB - AIM: To evaluate the accuracy of self-reported Tanner (SRT) staging against a proxy method of physician's assessment of sexual maturation, using pubertal hormones in overweight African-American (AA) children. METHODS: Cross-sectional data from 196 children (113 girls, 83 boys) aged 9-11 years, who were 'overweight' (>85th and <95th percentile for age- and gender-matched BMI; n = 43) or 'obese' (>95th percentile; n = 153) were used. Children assessed their breast or genital and pubic hair development using standardized Tanner drawings representing different stages of sexual maturity. SRT data were compared to pubertal stage assessed by measuring fasting serum concentrations of luteinizing hormone (LH) in boys, and LH and estradiol (E2) in girls, which were used to stage children into pubertal stages 1-5. RESULTS: SRT stages of genital and pubic hair assessments in boys, and breast and pubic hair assessments in girls, yielded 15-20% concordance (kappa statistic = 0.02-0.12) compared to their hormone derived pubertal stages. CONCLUSIONS: Among overweight AA 9-11 year-old children, self-assessment of Tanner staging did not accurately assess their pubertal development when compared to a hormone-derived pubertal assessment method. PMID- 19774844 TI - Importance of leuprolide acetate variable dosing for precocious puberty: a range of acceptable suppression. AB - AIM: The effect of the variation in hormonal suppression on bone maturation, growth velocity, and adult height prediction was examined during treatment with leuprolide acetate for central precocious puberty (CPP). METHODS: Ten girls on variable doses of Lupron were studied for one year. Height, weight, body mass index, luteinizing hormone (LH), estradiol, and growth velocity were measured every 3 months. Bone age and predicted height were assessed every 6 months. RESULTS: LH range changed from 0.5-1.4 IU/I to 0.1-2.8 IU/I. The average Lupron dose decreased from 0.33 +/- 0.11 to 0.26 +/- 0.08 mg/kg. Predicted adult height averaged 158.33 +/- 9.5cm at the start of the study and increased to 161.45 +/- 6.26 cm (p <0.01). LH and estradiol did not correlate with the rate of bone maturation, growth velocity, predicted height, or with leuprolide dose. CONCLUSION: Variable dosing of leuprolide acetate is needed to achieve similar amounts of hormonal suppression, yet small changes in dose did not significantly change LH or estradiol levels or predicted height. PMID- 19774845 TI - Glycation and lipid peroxidation in children and adolescents with type 1 diabetes mellitus with and without diabetic complications. AB - Glycation and oxidative stress lead to formation of compounds that have several biological effects and contribute to the development of the complications of diabetes mellitus. All steps of glycoxidation generate oxygen free radicals, some of them in common with lipid peroxidation pathways. Some oxidation or lipid peroxidation products may bind to proteins and amplify glycoxidation-generated lesions. The aim of this study was to measure glycation and lipid peroxidation parameters and examine the relationship between them in patients with type 1 diabetes mellitus (DM1) with (+DC) and without (-DC) diabetic complications. Fifty patients with DM1 aged from 7-19 years and with duration of DM1 (DD) at least 5 years were included. Twenty-four patients were -DC and 26 were +DC. Twelve healthy children formed a control group. There were significantly higher values of fructosamine (FAM), HbA(1c), serum advanced glycation endproducts (s AGEs) and lipid peroxides (LPO) in the +DC group compared with -DC, and significantly higher values of HbA(1c), FAM and LPO in both diabetic groups than in controls. The s-AGEs level in the -DC group was similar to that in controls. In the total diabetic group, regardless of DC, there was a significant negative correlation between LPO and HDL-C (r = -0.379; p <0.05), and a positive correlation between LPO and triacylglycerol (TAG) (r = 0.852; p <<0.05), FAM (r = 0.414; p <0.05) and s-AGEs (r = 0.454; p <0.05). In the +DC group LPO correlated negatively with HDL-C (r = -0.392, p <0.05) and positively with TAG (r = 0.848; p <<0.05), FAM (r = 0.457; p = 0.02), and s-AGEs (r = 0.516, p = 0.02), whereas in the -DC group LPO correlated only with HDL-C (r = -0.441; p = 0.03) and TAG (r = 0.769; p <<0.05). We demonstrated a linkage between enhanced formation of AGEs and lipid peroxidation products and the presence of diabetic complications. Thus, the overproduction of glycation and lipid peroxidation products may take part in DC development as early as in childhood and adolescence. PMID- 19774846 TI - Hepatocyte growth factor is elevated in obese adolescents. AB - Hepatocyte growth factor (HGF) is a pleiotropic factor with angiogenic and mitogenic effects and has been linked to vascular diseases. It is elevated in obese adults. AIM: To investigate whether HGF levels are altered in obese adolescents and whether they correlate with anthropometric measurements of obesity. METHODS: Seventy-nine male adolescents were enrolled. Forty-eight percent were overweight. Various parameters were recorded at one visit, including BMI and waist circumference, and blood samples were taken. HGF was determined by ELISA. RESULTS: Overweight adolescents have higher plasma levels of HGF (1,099.8 +/- 416.7 pg/ml) than controls (883.2 +/- 218.7 pg/ml) (p = 0.008). HGF levels correlated with BMI and waist circumference. HGF correlated closely with high sensitive C-reactive protein. CONCLUSIONS: We demonstrated elevated HGF levels in obese adolescents. We speculate that HGF is a possible link between obesity in early life and related comorbidities. PMID- 19774847 TI - Pituitary enlargement in patients with PROP1 gene inactivating mutation represents cystic hyperplasia of the intermediate pituitary lobe. Histopathology and over 10 years follow-up of two patients. AB - Patients with a PROP1 inactivating mutation present combined pituitary hormone deficiency (CPHD) and pituitary maldevelopment. A retrospective analysis of 31 CPHD patients with a PROP1 mutation revealed two individuals, aged 18 and 4.5 years, who had undergone subtotal surgery to remove pituitary tumors, 16.8 x 12 mm and 9 x 10 x 12 mm in size. Histological reassessment of tissue samples revealed epithelial cells, partially oxyphilic, forming gland-like microcystic structures, most of them filled with eosinophilic colloid. These structures were directly linked with fragments of the posterior lobe. Neither atypia nor any traces of proliferation activity (Ki-67 LI=0%) were noted. Immunohistochemistry showed the presence of all hormonal phenotypes of cells. These findings corresponded to the intermediate lobe of the pituitary gland. For this type of pathology we propose the term 'cystic hyperplasia of the intermediate pituitary lobe' and suggest PROP1 gene assessment in patients with CPHD in order to avoid unnecessary neurosurgical interventions. PMID- 19774848 TI - Improved diabetic control during oral sulfonylurea treatment in two children with permanent neonatal diabetes mellitus. AB - Permanent neonatal diabetes mellitus (PND), defined as diabetes diagnosed in the first 6 months of age and requiring life-long insulin therapy, is a rare disorder of unknown etiology. Activating mutations of the KCNJ11 gene, which encodes the Kir6.2 subunit of the ATP-dependent potassium channel in beta-cells, have been found to cause 30-58% of cases of PND. Sulfonylurea treatment in theses patients reduces or eliminates the need for exogenous insulin. We report two Taiwanese boys who were diagnosed with PND at 1 and 4.5 months of age. They had been treated with exogenous insulin for 6 and 15 years, respectively. In September 2006, they were both found to have a KCNJ11 mutation (valine-to-methionine at codon 59; V59M). Glibenclamide successfully increased the basal C-peptide level, lowered HbA(1c), and reduced blood sugar excursions. In one patient, the insulin dose was reduced to 0.2 U/kg/day, and the other was able to discontinue insulin altogether. These two cases from Taiwan add to the experience with similar mutations reported in Caucasians. PMID- 19774849 TI - Donohue syndrome in a neonate with homozygous deletion of exon 3 of the insulin receptor gene. AB - Donohue syndrome describes the clinical consequences of the most severe genetic loss of insulin receptor function. The cardinal features are severe linear growth impairment pre- and postnatally with abnormal glucose metabolism and a characteristic pattern of soft tissue overgrowth. We report a 5 day old neonate with refractory hyperglycemia and paradoxical hypoglycemia, severe intrauterine growth retardation, typical 'elfin' facies (hypertrichosis, large and low-set ears, broad nasal tip, flared nares, thick lips), reduced subcutaneous fat, distended abdomen, and enlarged external genitalia and nipples. Fasting serum insulin and C-peptide were severely elevated at >2,100 pmol/l and >2,331 pmol/l, respectively. In addition, hepatic, ovarian and renal enlargement was demonstrated by ultrasonography. The neonate died within two months secondary to hypoglycemia. Diplex PCR analysis of the insulin receptor gene revealed the neonate to be homozygous for deletion of exon 3. Both parents were heterozygous for this deletion but were metabolically healthy. As such a deletion has previously been reported in Israel, we suggest that it may show a founder effect in the Middle East. PMID- 19774850 TI - Special focus on WEFTEC 2008: biological treatment. PMID- 19774851 TI - Biological application of micro-electro mechanical systems microelectrode array sensors for direct measurement of phosphate in the enhanced biological phosphorous removal process. AB - The determination of phosphate has been of great importance in the fields of clinical, environmental, and horticultural analysis for over three decades. New cobalt-based micro-electro mechanical systems (MEMS) microelectrode array (MEA) sensors for direct measurement of phosphate in small environmental samples, such as microbial aggregates, has been introduced and applied here for in situ measurement of phosphate within activated sludge flocs in the enhanced biological phosphorus removal process. The MEMS technologies offer the advantages of accurate fabrication methods, reduced complexity of the fabrication process, mass production, low cost, and increased reliability. Well-defined phosphate profiles across the flocs were observed under anaerobic conditions, during which, phosphate was released from the flocs, using the MEMS MEA sensor. The microprofiles were compared with the microprofiles measured using conventional phosphate microelectrodes. The developed MEMS MEA sensors were useful tools for the in situ measurement of phosphate in small aggregates. PMID- 19774852 TI - Characterization of lectins and bacterial adhesins in activated sludge flocs. AB - Bacterial lectins are carbohydrate-binding proteins that are involved in bacterial adhesion and aggregation. To investigate whether lectins are involved in floc formation of activated sludge, hemaaggultination (HA) and HA inhibition assays were conducted on extracellular polymeric substances (EPS) extracted from activated sludges. Six sludges from both full-scale and synthetic chemical-fed laboratory activated sludge systems were subjected to EPS extraction and lectin assay. Activated sludge EPS resulted in strong agglutination with trypsin-treated human red blood cells. While simple monosaccharides failed to exhibit inhibition of agglutination, several glycoproteins clearly reversed agglutination, indicating that glycoprotein (oligosaccharide)-specific lectins are present in activated sludge. This inhibitory pattern was the same for both the field and laboratory-grown activated sludges, indicating that these lectins are indigenously generated by activated sludge microorganisms. The major lectin activities were found to be present in a hydrophobic region of EPS. The activities remained unaffected after heat and urea treatment of EPS, but were significantly reduced by the ethylenediaminetetraacetic acid (EDTA) treatment. These results share similar properties with previously studied pure culture bacterial lectins and support the conclusion that lectin-mediated bacterial aggregation is one of the mechanisms responsible for activated sludge bioflocculation. PMID- 19774853 TI - Predicting the degradability of waste activated sludge. AB - The objective of this study was to identify methods for estimating anaerobic digestibility of waste activated sludge (WAS). The WAS streams were generated in three sequencing batch reactors (SBRs) treating municipal wastewater. The wastewater and WAS properties were initially determined through simulation of SBR operation with BioWin (EnviroSim Associates Ltd., Flamborough, Ontario, Canada). Samples of WAS from the SBRs were subsequently characterized through respirometry and batch anaerobic digestion. Respirometry was an effective tool for characterizing the active fraction of WAS and could be a suitable technique for determining sludge composition for input to anaerobic models. Anaerobic digestion of the WAS revealed decreasing methane production and lower chemical oxygen demand removals as the SRT of the sludge increased. BioWin was capable of accurately describing the digestion of the WAS samples for typical digester SRTs. For extended digestion times (i.e., greater than 30 days), some degradation of the endogenous decay products was assumed to achieve accurate simulations for all sludge SRTs. PMID- 19774854 TI - Estrogen nitration kinetics and implications for wastewater treatment. AB - Understanding estrogen-removal mechanisms in wastewater treatment is imperative, as estrogens have environmental effects at trace concentrations. Previous research investigating co-metabolic degradation of 17alpha-ethinylestradiol (EE2) by ammonia-oxidizing bacteria (AOB) revealed that, in batch tests where high nitrite-nitrogen (NO2-N) concentrations occurred as a result of ammonia-nitrogen (NH4-N) oxidation by AOB, an abiotic estrogen nitration reaction actually was occurring--not co-metabolic degradation. This paper addresses nitration kinetics. A first-order abiotic nitration model was developed that predicts nitration of EE2, 17beta-estradiol (E2), and estrone (El) as a function of temperature, pH, estrogen (EE2, E2, and E1), and NO2-N concentration. A contact time of 3.6 to 4.1 days is required for 90% estrogen nitration at 500 mg/L NO2-N and pH 6.4. At 20 degrees C and pH 6.4, the threshold NO2-N concentration for nitration to occur is 9 mg/L; therefore, estrogen nitration is not likely in activated sludge treatment of domestic wastewater, but has potential for high-NH4-N-strength wastewaters. PMID- 19774855 TI - Method development for measuring biodegradable dissolved organic nitrogen in treated wastewater. AB - A method for determining biodegradable dissolved organic nitrogen (BDON) in treated wastewater was developed. The method adopts the approaches used in the biochemical oxygen demand and biodegradable dissolved organic carbon tests to make it usable as a routine procedure at wastewater treatment plants (WWTPs). The development focused on various aspects of the procedure, including inoculum type and concentration, incubation period, and the need for sample filtration after incubation. The method was tested with filtered effluent samples from two nutrient removal WWTPs and standard organic nitrogen solutions. Accurate and precise BDON results were obtained with 2 mL of acclimated mixed-liquor suspended solids diluted to a concentration of 240 mg/L as an inoculum and an incubation period of 20 days. Sample filtration after incubation was not required. PMID- 19774856 TI - Implication of using different carbon sources for denitrification in wastewater treatments. AB - Application of external carbon sources for denitrification becomes necessary for wastewater treatment plants that have to meet very stringent effluent nitrogen limits (e.g., 3 to 5 mgTN/L). In this study, we evaluated and compared three carbon sources--MicroC (Environmental Operating Solutions, Bourne, Massachusetts), methanol, and acetate-in terms of their denitrification rates and kinetics, effect on overall nitrogen removal performance, and microbial community structure of carbon-specific denitrifying enrichments. Denitrification rates and kinetics were determined with both acclimated and non-acclimated biomass, obtained from laboratory-scale sequencing batch reactor systems or full-scale plants. The results demonstrate the feasibility of the use of MicroC for denitrification processes, with maximum denitrification rates (k(dmax)) of 6.4 mgN/gVSSh and an observed yield of 0.36 mgVSS/mgCOD. Comparable maximum nitrate uptake rates were found with methanol, while acetate showed a maximum denitrification rate nearly twice as high as the others. The maximum growth rates measured at 20 degrees C for MicroC and methanol were 3.7 and 1.2 day(-1), respectively. The implications resulting from the differences in the denitrification rates and kinetics of different carbon sources on the full-scale nitrogen removal performance, under various configurations and operational conditions, were assessed using Biowin (EnviroSim Associates, Ltd., Flamborough, Ontario, Canada) simulations for both pre- and post-denitrification systems. Examination of microbial population structures using Automated Ribosomal Intergenic Spacer Analysis (ARISA) throughout the study period showed dynamic temporal changes and distinct microbial community structures of different carbon specific denitrifying cultures. The ability of a specific carbon-acclimated denitrifying population to instantly use other carbon source also was investigated, and the chemical-structure-associated behavior patterns observed suggested that the complex biochemical pathways/enzymes involved in the denitrification process depended on the carbon sources used. PMID- 19774857 TI - Variation in biofilm structure and activity along the length of a rising main sewer. AB - Sewers systems are dynamic in nature, with periodic variation of hydraulic flow and wastewater substrate concentrations. While various models are currently available for predicting hydrogen sulfide (H2S) production in rising mains, they assume constant biofilm activities along the length and ignore the effect of substrate availability on biofilm development. To investigate variation in rising main biofilm structure and activity, detailed studies were carried out on a Robbins device setup, which was established in parallel to a real rising main that it simulated. The changes in wastewater characteristics, as wastewater traveled through both the experimental setup and the real sewer system, were monitored. The study revealed that the biofilm activities varied significantly with locations, with biofilm corresponding to the start of the rising main capable of greater sulfide and volatile fatty acid production than biofilm downstream. Analysis of microbial community composition of these biofilms showed a difference in diversity and abundance, both with regard to general bacterial populations and sulfate reducers. These differences were hypothesized to be a consequence of varying substrate types and availability along the sewer line. The results suggest that the biofilm structure and activity may vary considerably along the length of rising mains and should be taken into consideration for improved sewer modeling and when considering the overall effect of different hydrogen sulfide management options. PMID- 19774858 TI - Evolving urban water and residuals management paradigms: water reclamation and reuse, decentralization, and resource recovery. AB - Population growth and improving standards of living, coupled with dramatically increased urbanization, are placing increased pressures on available water resources, necessitating new approaches to urban water management. The tradition linear "take, make, waste" approach to managing water increasingly is proving to be unsustainable, as it is leading to water stress (insufficient water supplies), unsustainable resource (energy and chemicals) consumption, the dispersion of nutrients into the aquatic environment (especially phosphorus), and financially unstable utilities. Different approaches are needed to achieve economic, environmental, and social sustainability. Fortunately, a toolkit consisting of stormwater management/rainwater harvesting, water conservation, water reclamation and reuse, energy management, nutrient recovery, and source separation is available to allow more closed-loop urban water and resource management systems to be developed and implemented. Water conservation and water reclamation and reuse (multiple uses) are becoming commonplace in numerous water-short locations. Decentralization, enabled by new, high-performance treatment technologies and distributed stormwater management/rainwater harvesting, is furthering this transition. Likewise, traditional approaches to residuals management are evolving, as higher levels of energy recovery are desired, and nutrient recovery and reuse is to be enhanced. A variety of factors affect selection of the optimum approach for a particular urban area, including local hydrology, available water supplies, water demands, local energy and nutrient-management situations, existing infrastructure, and utility governance structure. A proper approach to economic analysis is critical to determine the most sustainable solutions. Stove piping (i.e., separate management of drinking, storm, and waste water) within the urban water and resource management profession must be eliminated. Adoption of these new approaches to urban water and resource management can lead to more sustainable solutions, defined as financially stable, using locally sustainable water supplies, energy-neutral, providing responsible nutrient management, and with access to clean water and appropriate sanitation for all. PMID- 19774859 TI - Freezing inactivation of Escherichia coli and Enterococcus faecalis in water: response of different strains. AB - The effect of freezing temperature (-7, -15, -30 and -80 degrees C), number of freeze/thaw cycles (1 to 5 cycles) and sample volume (100 mL and 100 microL) on the viability of a pathogenic and an opportunistically pathogenic Escherichia coli, a vancomycin-resistant and a vancomycin-sensitive Enterococcus faecalis were examined. About 3.3 to 4.3 and 1.5 to 2.4 log reduction in cell density were observed in E. coli and E. faecalis, respectively, in the 100 mL samples frozen at -30 degrees C or warmer. Freezing at -80 degrees C was the least effective in killing the microbes, on average the log reduction at -80 degrees C was approximately 1.0 to 1.5 units less than those achieved at the three warmer temperatures. Based on statistical analysis, cell inactivation levels achieved at -7, -15, or -30 degrees C were not significantly different (P-value = 0.1648). There were no statistical difference in terms of log reduction obtained under all experimental conditions for the two E. coli strains (P-value = 0.46) and the two E. faecalis strains (P-value = 0.10). The number of freezing/thaw cycles and sample volume, however, profoundly affected inactivation capacity of freezing. Freezing could be an effective method for further reduction of E. coli and Enterococcus in municipal wastewater/sludge. PMID- 19774860 TI - Using a pulsed electric field as a pretreatment for improved biosolids digestion and methanogenesis. AB - Researchers tested using pulsed electric field (PEF) technology to enhance conversion of organic solids material in waste activated sludge (WAS) and pig manure to soluble and colloidal forms, which are more bioavailable for methane production during subsequent anaerobic digestion. Operating parameters were varied from 1.1 to 19.8 kWhr/m3 to show the influence amount of treatment has on soluble chemical oxygen demand (SCOD), small colloidal solids, and methane production via the biochemical methane potential test. When PEF treatment exceeded a threshold, which was approximately 10 kWhr/m3, focused pulsed treatment solubilized approximately 10% of the total COD, increasing SCOD from as low as 20 mg/L to more than 1000 mg/L. The process also disrupted a larger portion of the volatile suspended solids (VSS) to form small colloids not measured by the VSS assay (between 0.2 and 1.2 microm). The effects increased the biological methane potential of the samples significantly: by 80% for pig manure and 100% for WAS after 25 to 30 days. These results support the conclusion that PEF pretreatment before anaerobic digestion has the potential to significantly improve digester performance, resulting in added methane production and decreased residual biosolids. PMID- 19774861 TI - Leveling the playing field. PMID- 19774862 TI - What you don't know can hurt you. PMID- 19774863 TI - Consumer-directed health care--the future of health care? PMID- 19774864 TI - Adults with special needs and proper dental care. AB - The Special Olympics was founded by Eunice Kennedy Shriver in 1968 and has grown into a global movement involving 2.5 million athletes, in addition to millions of volunteers, family members, and friends. The international organization provides year-round sports training and athletic competition in a variety of Olympic-style sports for children and adults with intellectual disabilities. The year-round programs provide opportunities for participants to develop physical fitness, demonstrate courage, experience joy and participate in the sharing of gifts, skills, and friendship with their families, other Special Olympics athletes, and the community. Most important has been the opportunity to demonstrate what people with intellectual disabilities can do, rather than what they can't do. PMID- 19774865 TI - Anesthesia morbidity and mortality experience among Massachusetts oral and maxillofacial surgeons. AB - Anesthesia-related morbidity is a serious risk to oral and maxillofacial surgery patients receiving outpatient surgery. Unfortunately, there is little data to track the risks of outpatient anesthesia to offer as an appeasement for these concerns. The most recent and comprehensive review is the American Association of Oral and Maxillofacial Surgeons (AAOMS) anesthesia study published in 2003. In an insurance claims analysis, Deegan presented data that the mortality risk in the oral surgery office was 19 deaths in 14,206,923 anesthetics administered. PMID- 19774866 TI - Transient lingual papillitis: case reports. AB - The term transient lingual papillitis (TLP) was suggested by Whitaker et al. in 1996. It describes a condition of the tongue that is relatively common but with few documented cases. It is seen more in young women as a painful enlargement of one or more fungiform papillae that resolve quickly within a day or several days. Trauma may be a likely cause but the exact cause is elusive. The following brief reports are presented to augment the clinical documentation of this condition. PMID- 19774867 TI - Pierre Fauchard: the father of modern dentistry. AB - Throughout the history of modern dentisty, there have been many luminaries in the profession. All have made tremendous contributions to various aspects of dentistry and the betterment of oral care in general. However, only one can be known as "the Father of Modern Dentistry." This title is bestowed upon Pierre Fauchard (1678-1761). Fauchard truly metamorphosed the primitive "practice" of dentistry at the time into a new vocation now fully deserving of the term "profession". PMID- 19774868 TI - The toothbrush plant. AB - The toothbrush plant is a low-growing shrub that is found throughout Africa and the Middle East. It is used by the native peoples as a chew stick for cleaning their teeth. When the end of the wood is chewed, it becomes frayed and can be used as a natural brush that delivers therapeutic minerals and chemicals, present in the wood fiber to the teeth and gingiva. The use of this wood for oral care could be a great benefit to people in industrialized nations. PMID- 19774870 TI - Incidental findings on dental radiographs: dentigerous cyst. AB - Dentigerous cysts are the second-most-common cysts occurring in the jaws. A dentigerous cyst is formed as a result of fluid accumulation in the reduced enamel epithelium surrounding an unerupted tooth. These cysts typically present as well-defined pericoronal radiolucencies either superior or lateral to the unerupted tooth. Dentigerous cysts involving the posterior maxillary teeth tend to grow into and fill the maxillary sinus and, hence, are discovered late. Posterior mandibular dentigerous cysts commonly extend well into the ramus. There are often no clinical symptoms, with the exception of swelling once the cyst reaches a considerable size. PMID- 19774869 TI - A clinico-pathologic correlation: primary Ewing's sarcoma of the mandibular body ramus. AB - A 15-year-old Asian male was referred to the department of oral and maxillofacial surgery at Tufts University School of Dental Medicine (TUSDM) for evaluation of a radiolucent lesion on the posterior left mandible. The patient was initially evaluated by his primary dentist for pain of two months' duration associated with teeth #17 and 18. Radiographic examination was performed and the panoramic radiograph revealed a radiolucent lesion involving the left mandibular body and ascending ramus, along with resorption of the roots of the predetermined teeth. Considering odontogenic infection, the patient was placed on antibiotics and referred to TUSDM for further evaluation and treatment. PMID- 19774871 TI - Cemento-osseous dysplasia. PMID- 19774873 TI - Splitting hairs. PMID- 19774872 TI - Root coverage in the esthetic zone using the supraperiosteal envelope procedure. PMID- 19774874 TI - Innovation in dental education in Texas: technology putting patients and students first. PMID- 19774875 TI - Innovation in dental education in Texas: Texas A&M Health Science Center Baylor College of Dentistry. PMID- 19774876 TI - Innovation in dental education in Texas: The University of Texas Dental Branch at Houston. AB - Innovation has been an integral part of The University of Texas Dental Branch at Houston and its approach to educating dentists since the school's origin in 1905. Its history is rich with examples, such as a modular, self-directed curriculum and a general practice-based patient care delivery system. Moving into the 21st century, the school has embraced new models for patient care and research upon which to build innovative programs for teaching and learning. Combined with a technological explosion across the world and in education, UTDB has been a leader on many fronts, such as electronic patient records, clinical simulation and research in informatics. As the school looks ahead to a new building by 2012, additional advances and innovations are planned to follow. This article takes a look at the past, present, and future contributions by UTDB to innovation in dental education. PMID- 19774877 TI - Innovation in dental education in Texas: The University of Texas Health Science Center at San Antonio School of Dentistry. PMID- 19774878 TI - Differential diagnosis of oral lesions in geriatric patients. PMID- 19774879 TI - Protecting your most valuable practice asset: your data. Understanding the technology of internet offsite data backup. PMID- 19774880 TI - Oral and maxillofacial pathology case of the month. Nasopalatine duct cyst. PMID- 19774881 TI - [Prevalence of Tritrichomonas foetus among Dutch cats]. AB - Prevalence of Tritrichomonas foetus among Dutch cats The aim of this study was to determine the prevalence of and risk factors for, Tritrichomonas foetus among cats in the Netherlands. A total of 154 faecal samples were collected from three groups of cats: cats with diarrhoea (n=53), cattery cats (n=47), and healthy pet cats (n=54). Faecal samples were examined with a T. foetus specific real-time PCR. All PCR-positive samples were run on gel electrophoresis for definitive diagnosis. The prevalence of T. foetus was 2% among cats with diarrhoea and 4% among cattery cats; T. foetus was not prevalent among pet cats (none of the samples tested positive). Questionnaires had been distributed to cat and cattery owners to determine risk factors for T. foetus, but the low prevalence precluded statistical analysis of the questionnaire results. PMID- 19774882 TI - [Pine cone poisoning in young calves]. PMID- 19774883 TI - [Cattle feed: improvement characteristics of cell wall carbohydrates]. PMID- 19774884 TI - [Convenia un-easy]. PMID- 19774885 TI - [Swine flu and Mexican flu: the role of the pig]. PMID- 19774886 TI - [Taking your own profession seriously, that is the key. Interviewed by M.M. Sloet van Oldruitenborgh-Oosterbaan]. PMID- 19774889 TI - [Reaction to case report ethics]. PMID- 19774890 TI - [Evidence based veterinary medicine, the translational reality to the individual patient]. PMID- 19774891 TI - Arousing passions among sister organisations. PMID- 19774895 TI - Meeting the needs of grieving relatives. PMID- 19774896 TI - Coping with Cyclone Heta. PMID- 19774897 TI - Fronting up to a civil emergency. PMID- 19774898 TI - Four Auckland hospitals become one. PMID- 19774899 TI - Accountability and fair pay. PMID- 19774900 TI - Preparing nurses for change. PMID- 19774901 TI - Health Sector Code of Good Faith developed. PMID- 19774902 TI - New research funding provides opportunities for nursing. PMID- 19774907 TI - Forums familiarise nurses with the HPCA Act. PMID- 19774908 TI - A snapshot of Maori nurses' health and safety issues. PMID- 19774909 TI - Multi-disciplinary care plans--a key to reclaiming nursing passion. PMID- 19774910 TI - To vaccinate or not to vaccinate. PMID- 19774911 TI - Nursing in prison--a primary health care role to be proud of. Interview by Anne Manchester. PMID- 19774912 TI - The end of exemplars? PMID- 19774913 TI - Are care and communication lost arts? PMID- 19774914 TI - Highlighting NZNO midwives' concerns. PMID- 19774915 TI - Survey highlights caregivers' low pay and exploitation. PMID- 19774916 TI - Leading primary health care. PMID- 19774921 TI - Professional development in primary care--who is responsible? PMID- 19774922 TI - How much can nurses handle? PMID- 19774923 TI - Practice nurses as providers--creating a future. PMID- 19774924 TI - Nurses' skills add value to boards. PMID- 19774925 TI - Accountability in primary health care nursing. PMID- 19774926 TI - Structural changes threaten NSU's future. PMID- 19774927 TI - Nursing education--time for a re-think? PMID- 19774932 TI - New nurses face endemic violence. PMID- 19774933 TI - Why on earth would you want to go nursing? PMID- 19774934 TI - What's happening to our emergency departments? PMID- 19774935 TI - Prescribing practicums--getting the balance right. PMID- 19774936 TI - The practice of euthanasia: more than a debate. PMID- 19774937 TI - 'You speak such good Norwegian'. PMID- 19774938 TI - Revisiting cultural safety. PMID- 19774939 TI - All nurses must value enrolled nurses. PMID- 19774940 TI - Special day for enrolled nurses launched. PMID- 19774941 TI - Enrolled nurse courses meeting a demand. PMID- 19774942 TI - The general surgery residency at Gundersen Lutheran Medical Foundation: a tradition of training the complete general surgeon. PMID- 19774943 TI - Rural surgery rotation during surgical residency. AB - General surgery in the rural hospital is threatened by declining resident interest in pursuing a career in the rural setting. We found that by initiating a rural rotation of 3 months in the senior resident years, a case mix that more approximated that of the rural surgeons was experienced. Also, by experiencing a rural rotation, more residents chose to practice in a rural setting when compared with residents before the initiation of the rotation. PMID- 19774944 TI - Effects on health of volunteers deployed during a disaster. AB - Little is known about the risks, hazards, and health outcomes for health care personnel and volunteers working in disaster relief. We sought to characterize risks and outcomes in volunteers deployed to provide relief for victims of Hurricane Katrina. We performed a longitudinal e-mail survey that assessed preventive measures taken before and during deployment, exposures to hazards while deployed, and health outcomes at 1, 3, and 6 months postdeployment. Overall response rate was 36.1 per cent and one-third of those who responded did so for all three surveys. Exposures to different types of hazards changed over time with exposures to contaminated water being common. Despite predeployment and on-site education, use of preventive measures such as vaccination, appropriate clothing, hydration, sunscreen, and insect repellant was variable. Few injuries were sustained. Insect bites were common despite the use of insect repellants. Skin lesions, diarrhea, and other gastrointestinal complaints occurred most commonly early on during or after deployment. Psychological complaints were common at 3 and 6 months. In conclusion, identification of at risk volunteer cohorts with longitudinal surveillance is critical for future disaster planning to provide training for volunteers and workers and to allow for deployment of appropriate resources pre, during, and postdeployment. PMID- 19774945 TI - Important prognostic factors in adenocarcinoma of the ampulla of Vater. AB - Ampullary adenocarcinoma (AmpCA) carries a better overall survival (OS) rate than other periampullary cancers. We examined clinicopathologic features in AmpCA for impact on OS. Records of patients undergoing pancreaticoduodenectomy from 2000 to 2007 for AmpCA were reviewed and histological specimens were reanalyzed. Of 302 patients undergoing pancreaticoduodenectomy for malignancy, 45 (14.9%) had AmpCA. Mean age was 61.3 +/- 12.2 years, mean tumor size was 2.6 +/- 1.3 cm, 57 per cent were > or = T3 tumors, 42 per cent were N1 stage, 13 (49%) had perineural invasion (PNI), and 29 (64%) had lymphovascular invasion (LVI). Thirteen were intestinal (29%), 14 were pancreaticobiliary (31%), and 18 were mixed (40%). Median OS was 42 months (range 4-80 mos). On log rank testing, > or = T3 (24 vs 65 mos, P < 0.01), N1 (25 vs 61 mos, P < 0.01), poor differentiation (24 vs 44 mos, P = 0.01), pancreaticobiliary subtype (23 vs 44 mos, P = 0.01), and PNI (23 vs 44 mos, P < 0.01) were significant for worse survival. By multivariate analysis, N1 disease (hazard ratio [HR] 4.50, 95% confidence interval [CI] 1.16 17.40) and PNI (HR 4.62, CI 1.11-19.21) maintained associations with worse survival, whereas histological subtype did not. N1 disease and presence of PNI demonstrated independent associations with worse survival. Given high percentage of mixed histology, PNI may be more informative than the subtype in predicting outcome for patients with AmpCA. PMID- 19774946 TI - Infection risk of open placement of intraperitoneal composite mesh. AB - Mesh contamination is the most feared postoperative complication after ventral herniorrhaphy. The morbidity is significant requiring additional operative procedures for debridement or complete removal of the prosthesis. From July 1998 to December 2007, a retrospective review was performed to evaluate the incidence of mesh infection in patients undergoing an elective, open intra-abdominal sublay technique of repair using a composite mesh of polypropylene and expanded polytetrafluoroethylene (Composix, Davol, Inc., Cranston, RI). There were 206 procedures involving open, intraperitoneal placement of Composix mesh resulting in 21 mesh infections (10.2%). The majority of infections were secondary to Staphylococcus aureus contamination (76%), and over half were infected with MRSA. All patients, except two, required mesh removal. Reoperation for repair of the recurrent defect after mesh removal was necessary in 67 per cent. Two patients with MRSA infection subsequently reinfected their recurrent repair. Overall, the infected group required 44 additional procedures (mean of 2.1 procedures/patient). The infection risk was reduced with the lighter density, newer generation composite mesh (7.3% vs 14.5%). Mesh infection after ventral herniorrhaphy conveys significant morbidity. An open intraabdominal underlay of a composite mesh of polypropylene and ePTFE carries a real risk of contamination and should be reconsidered. PMID- 19774947 TI - Odontogenic ameloblast associated protein as a novel biomarker for human breast cancer. AB - Odontogenic Ameloblast Associated Protein (ODAM) is a protein isolated in ameloblasts during odontogenesis. ODAM expression was identified in breast cancer, but its significance remains unknown. The purpose of this study is to determine if ODAM expression can serve as a prognostic marker and provide information regarding treatment in human breast cancer. Breast cancer patients were identified from our tumor registry from 1993 to 2003. Archived breast cancer tissue from 243 patients (stage 0 = 53, stage I = 51, stage II = 53, stage III = 47, stage IV = 39) was stained using monoclonal antibody for ODAM. Presence or absence of immunostaining was correlated with stage, histologic grade, response to chemotherapy, and survival using chi2 and logistic regression analyses. Tumor nuclear staining for ODAM increased with increasing group stage (P < 0.001). Staining for ODAM did not correlate with histologic grade or chemotherapy (P = 0.558, P = 0.093). Improved outcomes within each stage were noted with ODAM staining, statistically significant for stages 0, I, and II (P < 0.001, P = 0.003, P = 0.003) and underpowered for stages III and IV (P = 0.724, P = 0.059). Survival benefit associated with tumor nuclear staining increased with advancing stage (P < 0.001). These results show that ODAM predicts survival in breast cancer. Research is ongoing to determine ODAM's clinical utility and role in carcinogenesis. PMID- 19774948 TI - Clinical significance of p53 and bcl-2 protein coexpression phenotypes in molecular breast cancer subtypes of pre-menopausal and post-menopausal African American women. AB - With the current classification of breast carcinoma into molecular subtypes with distinct prognosis and response to therapy, we sort to assess the clinical significance of p53 and bcl-2 coexpression phenotypes in invasive breast tumors and correlate this to the different molecular breast cancer subtypes in African American women. We performed a retrospective analysis of data on p53 and bcl-2 expression. Results were correlated to molecular breast cancer subtypes, and clinicopathologic variables of prognostic significance. Our study sample included all African-American women diagnosed with breast cancer from 1998 to 2005. Twenty seven (27.6%) per cent of cases in our study sample over-expressed p53, whereas 69.3 per cent over-expressed bcl-2 protein. A significant inverse correlation was observed between expression of p53 and bcl-2. Combined analysis of p53 and bcl-2 showed that 53.2 per cent of the tumors displayed p53(-)bcl-2(+) phenotype which was significantly associated with the luminal A subtype, whereas 11.6 per cent displayed the p53(+)bcl-2(-) phenotype which was significantly associated with the basal cell-like and Her-2/neu. Neither p53 expression nor bcl-2 expression individually or in combination were of independent prognostic significance. p53(+)bcl-2(-) phenotype is significantly correlated with the basal cell-like subtype and may be associated with the biologic aggressiveness of this cohort of molecular breast cancer. PMID- 19774949 TI - Expression of estrogen receptor, progesterone receptor, and vascular endothelial growth factor-A in thyroid cancer. AB - Thyroid cancer is three times more prevalent in females but the role of sex hormones in its pathogenesis is unknown. Vascular endothelial growth factor (VEGF) is crucial for angiogenesis. Its expression correlates with tumor aggressiveness and metastatic potential. We determined the expression of estrogen receptor (ER), progesterone receptor (PR), and VEGF-A in thyroid neoplasms to see if expression correlated with age and sex, histological type, cancer stage, and clinical outcome. Pathological samples of thyroid cancer diagnosed from 2002 to 2007 were stained immunohistochemically for ER, PR, and VEGF-A. Grading was done qualitatively in intensity and quantitatively in percentage. Both grades were multiplied to assign a final score. One hundred and four patients were studied, of which 82 per cent were female with a mean age of 53 years (range 23-86 years). Most tumors were papillary in origin. Overall, final scores were significantly higher for ER (1.41) and PR (1.0) in tumors compared with the ER (1.07) and PR (0.42) in normal tissue (P = 0.005 and < 0.001, respectively). Conversely, VEGF-A had lower expression in tumor tissues (7.2) than in normal tissue (8.2) (P = 0.024). No predilection was found for specific age group, gender, histological subtype, or stage of the cancer. Thus, compared with normal tissue, ER and PR expression is higher and VEGF-A expression is lower in tumor thyroid tissue. The overexpression of sex hormone receptors in thyroid tumor suggests their role in thyroid cancer pathogenesis and needs further investigation. PMID- 19774950 TI - Elective surgery in patients with end stage renal disease: what's the risk? AB - Little research has been performed in regards to the morbidity and outcomes associated with elective general surgery performed on patients with end stage renal disease (ESRD). With minimal data about the severity of disease in these patients, we sought to quantify the differences in the ESRD patient undergoing elective surgical procedures compared with matched controls. A review of all ESRD patients undergoing elective surgical procedures at a University Medical Center between 2001 and 2005 was performed. Outcomes included length of hospital stay, 1 year morbidity, and mortality. These patients were then compared with a control group with normal renal function matched 2:1. Fifty-two consecutive ESRD patients undergoing elective general surgery procedures were compared with 104 matched controls. The ESRD group experienced more complications (25 vs 16, P = 0.05) and had a larger number of overall complications compared with the controls (33 vs 19, P < 0.05). Length of stay was significantly longer in the ESRD group as well (8 vs 2.65 days, P < 0.0001). Incidence of death (4%) in the ESRD group was increased as well. Patients with ESRD require longer hospital stays and have an increased overall incidence and frequency of complications than patients with normal renal function undergoing elective general surgery procedures. The significantly increased morbidity should be considered when evaluating expected outcomes. PMID- 19774951 TI - Wasted hospital days impair the value of length-of-stay variables in the quality assessment of trauma care. AB - Hospital length of stay (LOS) is frequently used to evaluate the quality of trauma care but LOS may be impacted by nonmedical factors as well. We reviewed our experience with delays in patient discharge to determine its financial consequences and its impact on LOS. We performed an analysis of linked trauma registry and "delayed discharge" databases. Actual LOS (A-LOS) values were compared with calculated ideal LOS (I-LOS) values, and the per cent increase in LOS was calculated. Linear regression analysis was used to identify significant predictors of prolonged LOS. One thousand, five hundred and seventeen patients were studied, with an A-LOS of 6.54 days. Seven per cent of patients experienced discharge delays, resulting in 580 excess hospital days. Calculated I-LOS was 6.15 days, 6.34 per cent lower than A-LOS. Other I-LOS estimates were as much as 25 per cent lower than A-LOS. Estimated excess patient charges associated with delayed discharges were $4,000,000 to $15,000,000. Discharge delays are an infrequent, although costly, occurrence that has a significant impact on LOS. LOS therefore may not be an appropriate metric for assessing the quality of trauma care, and should only be used if it has been corrected for discharge delays. Concerted efforts should be directed towards identifying and correcting the factors responsible for delayed discharge in trauma patients. PMID- 19774952 TI - Resection of portovenous structures to obtain microscopically negative margins during pancreaticoduodenectomy for pancreatic adenocarcinoma is worthwhile. AB - Locally advanced pancreatic adenocarcinoma may require resections of the portal vein and/or its major tributaries to achieve tumor extirpation, albeit with the potential for increased morbidity and mortality. However, major venous resections can impart complete tumor extirpation and thereby a survival advantage compared with resections with residual microscopic disease. This study was undertaken to determine if resection of the portal vein and/or its splenic or superior mesenteric venous (SMV) tributaries is a worthwhile endeavor. Since 1995, patients undergoing pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma have been prospectively followed. The impact of portovenous resections (portal vein, SMV, and/or splenic vein) on survival was evaluated using survival curve analysis (Mantel-Cox test). Margins were codified as R0 or R1 and data are presented as median, mean +/- SD where appropriate. For 220 patients undergoing PD for pancreatic adenocarcinoma, survival was 17 months. Patients undergoing R0 resections had improved survival relative to patients undergoing R1 resections (20 vs 13 months, P < 0.03). Concomitant portovenous resections were undertaken in 48 patients. There was no difference in survival after PD without portovenous resection (17 months) versus PD with portovenous resection (18 months). Resections with complete tumor extirpation (i.e., R0 resections) provide superior long-term survival; all efforts to obtain R0 resections should be undertaken. Portovenous resections during pancreaticoduodenectomy can be undertaken safely and are worthwhile when complete tumor extirpation is attainable. PMID- 19774953 TI - Mesenteric cavernous hemangioma involving small bowel and appendix: a rare presentation of a vascular tumor. AB - We report on a case of cavernous hemangioma of the small bowel mesentery. Fewer than five cases of large mesenteric cavernous hemangioma have been reported in the English literature. Cavernous hemangioma of the small bowel mesentery is extremely rare. A 32-year-old black male presented with 1 week of abdominal pain, nausea, vomiting, and anorexia. He had recently undergone computed tomographic guided biopsy of a pelvic mass at another facility. Repeat CT guided biopsy was nondiagnostic, mesenteric angiography was inconclusive, and magnetic resonance imaging was performed as well. Complete workup was performed to localize primary source of abdominal mass and eventual open biopsy was planned resulting in en bloc resection of the mass, which had invaded the terminal ileum and appendix. Final pathologic diagnosis was cavernous mesenteric hemangioma. The patient experienced a prolonged postoperative ileus and was eventually discharged in stable condition, tolerating a regular diet with adequate bowel and urinary function. Diagnosis of cavernous mesenteric hemangioma is difficult and multiple imaging modalities can prove inconclusive. Adequate biopsy can be difficult to obtain even in patients with small body habitus. Standard of care is resection of entire mass en bloc. PMID- 19774954 TI - Benefits of mock oral examinations in a multi-institutional consortium for board certification in general surgery training. AB - The Southeast Michigan Center for Medical Education (SEMCME) is a consortium of teaching hospitals in the Greater Detroit metropolitan area. SEMCME pools its resources for several educational means, including mock oral board examinations. The educational and cost benefits to mock oral examinations on a multi institutional basis in preparation for the American Board of Surgery (ABS) certifying examination were analyzed. Ten-year multi-institution data from the mock oral examinations were correlated with ABS certifying examination pass rates. Mock oral examination scores were available for 107 of 147 graduates, which included 12 candidates who failed their certifying examination on the first attempt (pass rate = 89%). Four of 31 examinees who had a low score (4.9 or less) in their mock oral exams failed their certifying examination in their first attempt. The cost of running the mock examination was low (approximately $35/resident for 50 residents). When graduates from the last 10 years were surveyed, the majority of respondents believed that the mock oral examination helped in their success and with their preparation for the certifying examination. Thus, the many benefits of administering the examination with the resources of a consortium of hospitals result in the accurate reproduction of real-life testing conditions with reasonable overall costs per resident. PMID- 19774955 TI - Clinical implications of the seat belt sign in blunt trauma. AB - Patients with the seat belt sign (SBS) from motor vehicle crashes (MVCs) are prone to specific regional injury patterns. Investigators at a Level 1 trauma center analyzed the incidence, clinical implications, and spectrum of regional injuries in patients injured in MVC over 2 years. SBS was seen in 11.3 per cent of patients injured in MVCs and 20.5 per cent of patients with known restraint use. Restrained patients were less severely injured with lower injury severity scores (7.62 vs 11.33) and mortality (1.1 vs 5.7%). Patients with SBS had lower mortality rates than patients without SBS (1.4 vs 3.7%). Thoraco-abdominal injuries were present in 47 per cent (34 of 72) of patients with SBS. Compared with patients without SBS, patients had a higher incidence of hollow viscous injuries (HVI) and solid organ trauma (8 and 17% vs 1 and 3%, P < 0.05); splenic trauma was 24-fold higher (9.7 vs 0.4%), liver injuries 3.1-fold higher (6 vs 3%), and rib fractures 2.4-fold higher (P < 0.05). Children had 2.8-fold higher rates of HVI (18 vs 9%, P < 0.05). SBS is associated with underlying regional injuries in nearly half of patients with a higher prevalence of HVI and solid organ trauma. PMID- 19774956 TI - Incidence of anastomotic leak in patients undergoing elective colon resection without mechanical bowel preparation: our updated experience and two-year review. AB - Mechanical bowel preparation before elective colon resection has recently been questioned in the literature. We report a prospective study evaluating the anastomotic leak rate in patients undergoing elective colorectal surgery without preoperative mechanical bowel preparation. One hundred fifty-three patients undergoing elective colon resection from July 2006 to June 2008 were enrolled into this Institutional Review Board-approved study. All patients were operated on by a single surgeon at a single institution. No patients received mechanical bowel preparation. Of the 153 patients enrolled, 51.6 per cent had a colorectostomy, 32 per cent had an ileocolostomy, 10.4 per cent had a colocolostomy, 5.2 per cent had an ileoanal anastomosis, and 0.6 per cent had an ileorectostomy performed. A total of eight patients (5.2%) developed an anastomotic leak. Of these patients, four required reoperation, three were managed with percutaneous drainage, and one was managed with antibiotics alone. Five of the eight patients who developed an anastomotic leak had significant preoperative comorbidities, including neoadjuvant radiation therapy, diabetes mellitus, end-stage renal disease, prior anastomotic leak, and tobacco use. Elective colon resection can be performed safely without preoperative mechanical bowel preparation. Vigilance for anastomotic leak must be maintained at all times, especially in patients with comorbidities that predispose to anastomotic leak. PMID- 19774957 TI - Unplanned intubation after surgery: risk factors, prognosis, and medical emergency team effects. AB - Unplanned intubation after surgery is a marker for severe adverse events. We investigated the incidence, risk factors, and prognosis of unplanned intubation after general and vascular surgery and sought to determine whether the deployment of a hospital-wide medical emergency team (MET) had a preventive effect. We included all patients undergoing general and vascular surgical procedures between April 1, 2006, and June 30, 2008, from our American College of Surgeons National Surgical Quality Improvement Program data. Risk factors and incidence rates of unplanned intubation were compared before (preMET) and after (postMET) June 7, 2007. Chart review identified case details and fatality rates. There were 2426 patients included (1815 preMET, 611 postMET). The overall incidence of unplanned intubation was 2.6 per cent; significant risk factors included chronic obstructive pulmonary disease, dependent functional status, and emergent operation. Most (84%) unplanned intubations occurred in a critical care setting and the most common underlying reason was sepsis (40%). The overall case fatality rate was 43 per cent but varied significantly depending on the underlying reason for unplanned intubation. Incidence rates of unplanned intubation did not change significantly after MET deployment, suggesting that other strategies are needed to prevent this rare but highly morbid and mortal event. PMID- 19774958 TI - Omental reinforcement for intraoperative leak repairs during laparoscopic Roux-en Y gastric bypass. AB - Leaks from the gastrojejunostomy after laparoscopic Roux-en-Y gastric bypass (LRYGB) have the potential for significant morbidity and mortality. When intraoperative leaks are discovered, we choose to perform omental reinforcement around the gastrojejunostomy and pouch after suture repair of the leaks. This study examined the hypothesis that omental reinforcement would be useful after intraoperative leaks during LRYGB. Omental reinforcement was performed on gastrojejunostomies, in which leaks were seen, created using a circular stapler during LRYGB. Data were reviewed retrospectively on these patients. There were a total of 387 patients with 32 (8.26%) patients who had a staple line dehiscence or evidence of gastric pouch or gastrojejunostomy leak intraoperatively. Leaks/dehiscences were repaired with sutures and then reinforced with omentum. None of these patient developed anastomotic leak postoperatively. Of the other 365 patients, there were four (1.1%) leaks from the gastrojejunostomy and/or gastric pouch. Omental reinforcement may be useful in decreasing the incidence of postoperative leaks when an intraoperative leak is encountered during LRYGB. However, omental reinforcement does not completely prevent a postoperative leak. Consideration of reinforcement with omentum may be given for patients in whom an intraoperative leak is noted. PMID- 19774959 TI - Postoperative hypocalcemia after parathyroidectomy for renal hyperparathyroidism in the era of cinacalcet. AB - Chronic kidney disease is often accompanied by hyperparathyroidism. Cinacalcet, a recent addition to the medical armamentarium, has proven efficacious. It is unclear whether cinacalcet use has any impact on the postoperative course in patients progressing to surgery. The records of 77 patients operated on for renal hyperparathyroidism were reviewed. Sixty-three were treated before the use of cinacalcet and 14 after. Ten subtotal and 67 total parathyroidectomies were performed. Mean nadir serum calcium was similar (6.6 +/- 1.3 vs 6.2 +/- 1.4 mg/dL). More patients taking cinacalcet preoperatively required intravenous calcium postoperatively (62%) than those treated before its use (41%), although this did not reach statistical significance (P = 0.09). In those undergoing total parathyroidectomy, cinacalcet use preoperatively (n = 11) led to a lower postoperative nadir calcium (5.8 +/- 1.7 vs 6.6 +/- 1.3 mg/dL) as compared with those who did not receive it (n = 56) (P = 0.05). This translated to a greater need for intravenous calcium infusion postoperatively (72 vs 38%) (P = 0.03). These data suggest a somewhat more aggressive postoperative course in patients who fail calcimimetic and require surgery. This may be useful to inform physicians and patients of expectations postoperatively, although it is not likely to alter management. PMID- 19774960 TI - Arterial revascularization for upper extremity ischemia in patients with chronic kidney disease. AB - Surgical revascularization of the upper extremity is uncommon, comprising only 4 to 18 per cent of all vascular surgical interventions. Patients with renal failure have higher rates of atherosclerotic cardiovascular and peripheral arterial disease resulting from chronic inflammation, endothelial damage associated with hemodialysis, and vascular trauma. Upper extremity arterial disease with chronic ischemia may be underrecognized in these patients. We reviewed our experience with upper extremity revascularization in patients with renal failure presenting with chronic ischemia. Four patients with longstanding chronic kidney disease developed chronic severe ischemia affecting the forearm or hand. All had previous dialysis access in the symptomatic arm, although none had a functional ipsilateral access at the time of presentation. All patients had successful revascularization with resolution of symptoms and patent bypass grafts at follow up. There was one death 4 months postoperatively and one patient has not returned for follow up. Patients with renal failure with symptomatic upper extremity arterial occlusion should be considered for revascularization of the infrabrachial arteries. PMID- 19774961 TI - Proteus syndrome: a case report. AB - Proteus syndrome is a rare, sporadically occurring hamartomatous disorder with complex multisystem involvement and wide clinical variability. Clinical characteristics include craniofacial abnormalities; asymmetrical overgrowth of the trunk, limbs, and digits; lipomas; and vascular malformations. Cystic lung disease is noted in approximately 10 per cent of patients. These cystic malformations may lead to cystic pulmonary emphysema, which may cause significant morbidity for the patient. We describe the case of a 27-year-old woman with known Proteus syndrome who developed acute on chronic respiratory failure. Subsequent CT scan of the chest was significant for extensive bullous disease with nearly complete replacement of the right lung tissue. Our operative management and the patient's clinical course are described. PMID- 19774962 TI - Track configuration determines risk of driver injury in open wheel motor racing. PMID- 19774963 TI - Fulminant Clostridium difficile colitis isolated to the ascending colon by a diverting transverse loop colostomy. PMID- 19774964 TI - Cystic sarcoma of the psoas muscle masquerading as appendicitis. PMID- 19774965 TI - Recurrent intramuscular psoas myxoma. PMID- 19774966 TI - Stage IV small bowel carcinoma mimicking advanced ovarian cancer. PMID- 19774967 TI - Hemosuccus pancreaticus. PMID- 19774968 TI - Strategies to prepare for electronic discovery in healthcare. AB - While many healthcare risk managers have not yet received interrogatories requesting electronic information during discovery, all should nevertheless be prepared to face such requests. It is increasingly important to become knowledgeable of the legal exposure, due in part to recent amendments to the rules of civil procedure and case law that support the rules. This article provides healthcare risk managers with the basic knowledge necessary to prepare for electronic discovery. PMID- 19774969 TI - Vaginal birth after cesarean checklist: an evidence-based approach to improving care during VBAC trials. AB - Several medical organizations and specialty societies, as part of their approach to patient safety, have recommended that checklists be introduced and followed in certain high-risk healthcare situations. There is now evidence that following these kinds of checklists leads to improved outcomes. This article recommends a checklist that can be completed for each patient when she is admitted for a trial of labor after a previous cesarean delivery (VBAC). The elements of the checklist will help confirm the preparedness of the organization, compliance with national standards, and the consent of the patient for the VBAC trial. PMID- 19774970 TI - "Ticket to ride": how useful is this new handoff tool? AB - Patient handoffs come in many forms, some of which are permanent (the provider will not get the patient back) and some of which are temporary (the provider will get the patient back). The danger inherent in temporary handoffs is that the temporary provider will not have sufficient information, or will not have time to gather the necessary information, to provide care for the patient safely. The "ticket-to-ride" tool, in addition to the verbal handoff communication, can be used to provide temporary providers of care with a salient synopsis of the patient's condition to protect the patient during an absence from the floor or unit. This article gives guidance on the development of a ticket-to-ride form. PMID- 19774971 TI - The risk management professional and medication safety. AB - ASHRM is committed to the future development of the healthcare risk management profession. A key contribution to this commitment is the creation of a student version of ASHRM's best-selling Risk Management Handbook for Healthcare Organizations. The Student Edition was released this spring. It is now being made available to universities and colleges to incorporate into their degree programs. PMID- 19774972 TI - Case law update: corporate negligence, peer review information, medical malpractice, Good Samaritan statute, emergency medicine. PMID- 19774978 TI - [Regional PM pollution in Beijing and surrounding area during summertime]. AB - The air quality in Beijing and surrounding area is influenced by local emission and regional transport. To study the characteristics of regional pollution, PM (particulate matter) samples were collected simultaneously at 4 sites including Tsinghua University (TH) and Miyun reservoir (MY) in Beijing, Renqiu (RQ, Hebei Province), and Shangdu (SD, Inner Mongolia) during August, 2007, and temporal/spatial distributions of PM2.5 mass concentrations along with 22 elements in TSP were characterized. PM2.5 mass concentrations were quite different at 4 sites, following the sequence as RQ > TH > MY > SD. The highest concentrations of pollution-derived elements S, Zn, Pb, Cu, As, Sb, Ni, Cd, In, Se were found in RQ, showing the most intensive anthropogenic influence around this region, and their lowest variation indicated that the pollution mostly came from local sources. Controlled by the meteorological factors, highest daily variations of these elements were found at SD with relative lower concentrations. The correlation coefficients of S, Pb, Cd, In, As, Zn concentrations between TH and MY were all higher than 0.70, which implies similar sources for these elements at the 2 sites in Beijing. At the beginning and the end of the Sawtooth pollution episode in Beijing, concentrations of most elements in Miyun were comparable with the lowest concentrations at Shangdu observed during the sampling period, which means Miyun could well represent the regional characteristics of clean air mass from the northwest. Uniform spatial distribution of high sulfate was found (about 10 microg/m3) at the peaks of Sawtooth episode, which implies the important contribution from secondary aerosol during the regional pollution. Variable sources of PM at each site and their regional influence were discussed based on the different characteristics of elemental enrichment factors. PMID- 19774979 TI - [Current status and future prospects of anthropogenic particulate matter emissions in China]. AB - The emission inventory of particulate matter (PM) in 2000 and 2005 were established based on the activity data and emission factors of power, industrial, residential and transportation sectors in China. Future emissions from 2010 to 2030 were projected under different scenarios of energy consumption and PM emission control policies. The emissions of TSP, PM10 and PM2.5 in 2005 were 29.98 Mt, 15.30 Mt and 9.79 Mt respectively, and the annual increasing rates were 3.4%, 4.7% and 5.4% during 2000 to 2005. By 2030, the emissions of TSP and PM2.5 would be 23.06 Mt and 10.59 Mt under reference scenario, of which industrial boilers are the largest contributor. With improvement of energy efficiency, the emissions of TSP and PM2.5 would be reduced by 15% and 16% respectively in 2030 compared with that under reference scenario. By intensifying the enforcement of legislation, 25% of TSP and 10% of PM2.5 can be further reduced in 2015. By tightening the emission standard and promoting high-efficiency dust collector after 2015, 21% of TSP and 19% of PM2.5 can be further reduced in 2030 and the emissions can become 13.81 Mt and 6.88 Mt separately. The control of particulate matter shall cover power, industrial and residential sectors. Actions shall include improving energy efficiency, enforcing legislation and tightening control policies. PMID- 19774980 TI - [Study on the types and water pollution driving forces of the typical and medium small-sized cities in the southern China based on the analysis of water environment]. AB - According to the major pollution sources of urban water environment, 10 indexes such as industrial sewage quantity were closen to establish evaluation indexes system about the types and influencing factors of the typical and medium-small sized cities in the southern China. Case studies of 16 typical and medium-small sized cities were taken in Jiangsu, Zhejiang, Hubei and Anhui provinces. Combined with SPSS 11.0 cluster analysis results, city types were divided in reference to the values of water resources comprehensive pollution indexes and economical development indexes. The driving forces about city water environment pollution were studied by principal component analysis method. The result indicates that the 16 cities belong to two categories and four sub-categories, which are rich economy as well as light pollution of water environment and poor economy as well as heavy pollution of water environment. The influencing factors of water environment pollution are in sequence of industrial water pollution, agricultural no-point source pollution and urban domestic water pollution. The main factors of water environment pollution influenced I category cities, II as well as IV category cities and III category cities are industrial water pollution, urban domestic pollution and agricultural no-point source pollution respectively. PMID- 19774981 TI - [Hydrology and water quality of rainfall-runoff in combined sewerage system along Suzhou Creek in central Shanghai]. AB - In order to obtain the processes of hydrology and water quality of urban combined sewerage system (CSS) in highly urbanized region, the precipitation, discharge and pollutant concentration of four different intensity rainfall (light rain, moderate rain, heavy rain and storm) were measured from Jul. to Sep. 2007 in the Chendulu CSS along Suzhou Creek in Shanghai. The results show that the shapes of runoff graph are similar to rainfall graph, with a weaker fluctuation range and a 15-25 min delay between rainfall and runoff graph. Runoff coefficients of the four different rainfall are 0.33, 0.62, 0.67 and 0.73, respectively. The 30/30 first flush phenomenon is found in Chendulu CSS. The peak of pollutant concentration graph lags rainfall peak about 30-40 min. The pH and event mean concentration (EMC) of Cu, Zn, Cr, Cd, Pb and Ni totally measure up to environmental quality standards V for surface water of China besides COD, BOD5, NH4(+) -N and TP, and the EMC of COD, BOD5, NH4(+) -N and TP are 225.0-544.1, 31.5-98.9, 8.9-44.2 and 1.98-3.52 mg x L(-1), respectively. The rainfall-runoff pollutant concentration in Chendulu CSS is close to those of other foreign cites. At the confidence level of p < 0.01, good relationships exist between SS and COD, BOD5, NH4(+) -N and TP, respectively, and the average proportion of particulate organic pollutant and nutrient is 70.21%. PMID- 19774982 TI - [Study on the growth characteristics and root exudates of three wetlands plants at different culture conditions]. AB - Wetland plants are the important component of constructed wetlands and their root exudates provide the interior hydrocarbon for denitrification. In this study, the growth characteristics and root exudates of Canna indica, Zizania caduciflora and Lythrum salicari in different culture conditions were researched. The results showed that the average biomass initial/biomass in 120 days growth of Canna indica, Zizania caduciflora and Lythrum salicari were 9.1, 3.7, and 4.7, respectively. There was a positive correlation between the root exudates and the biomass of plants, but the release rate of root exudates decreased with the biomass increase. The root exudates release rates of unit biomass were 0.92, 0.47, 0.43 mg x (g x d)(-1) for Lythrum salicari, Canna indica and Zizania caduciflora, respectively. And the root exudates of those three plants are mainly organic acids and arylprotein based on the three-dimensional fluorescence spectrum analysis. The results ofthis study also indicate that Canna indiea and Lythrum salicari are befitting wetlands plants. PMID- 19774983 TI - [Marine inorganic carbon system responses to macro-DIN supply coupled with Ulva pertusa in simulated experiments]. AB - Effects of macronutrient (NO3(-) -N and NH4(+) -N) on inorganic carbon system of water with Ulva pertusa existed were studied in laboratory simulation experiments. The results demonstrated that nutrient enrichment induced DIC, HCO3- and p(CO2) decreased while pH and CO3(2-) increased. The seawater changed from carbon source to carbon sink. During the experiments, the concentration of DIC, HCO3- and p(CO2) decreased with increasing concentration of nutrient when the NO3(-) -N and N4(+) -N were less than critical concentration. The concentration of DIC changed most at the NO3(-3) and NH4(-)3 groups, which decreased 151 micromol x L(-1) and 232 micromol x L(-1) compared with the control groups in the end of experiment. The increased dry weight of Ulva pertusa (deltam) of nutrient addition groups showed a significant negative correlation with deltaDIC (r = - 0.91, p < 0.0001, n = 11). The main controlling factor to inorganic carbon variation is the adaptation of Ulva pertusa to different DIN. When the concentration of DIN facilitates the growth of Ulva pertusa, the concentration of DIC decreased and dry weight of Ulva pertusa increased. NH(4) -N has more influence on inorganic carbon system than NO(3-) -N. PMID- 19774984 TI - [Algae removal of high algae raw water by coagulation enhanced by ozonation]. AB - Apparent molecular weight distribution (AMWD) and resin fractionation were used to characterize organic matters of the raw water. Removal of algae, change and removal of dissolved organic carbon (DOC), disinfection by products (DBPs) control during the preozonation enhanced coagulation treatments in the jar-scale and pilot-scale experiment were studied. Algae activity (AA) was measured and used to elucidate the mechanisms of algae removal by above treatments. Results show that algae removal can be improved distinctively by proper preozonation, as the ozone dose 1.0 mg x L(-1), for instance. Algae removal could be increased from 55%-85% by traditional coagulation to 95% by enhanced coagulation after preozonation; and the best removal achieved 99.3% with ozone 1.0 mg x L(-1) and PACl 3.0 mg x L(-1); the residual THMFP (Trihalomethanes formation potential) was lowered from 117 microg x L(-1) by traditional coagulation to 46 microg x L(-1). But higher dose of ozone (as > or = 2.0 mg x L(-1)) impairs organic matter removal, although it decreases algae activity further. Significant differences were found in algae removal by AA detection between ozonation and traditional coagulation. Traditional coagulation had little effect on AA no matter the different PAC1 doses; while AA decreased clearly after ozonation. AA was lowered below 12 under 0.5-2.0 mg x L(-1) ozonation; and it kept decreasing with increase of ozone dosage. During the following coagulation, coagulant or some of its hydrolysised components enhanced the AA decrease by ozonation. Compared to the method of normal microscopy counting, AA test expresses the influence of algae living state by water treatment processes more clearly; which would provide treatment process designer with more distinct information about algae removal mechanisms and how to arrange the treatment processes to improve algae removal. PMID- 19774985 TI - [Anoxic bioremediation of urban polluted river water with biofilm]. AB - Reactor like oxidation ditch was used for anaerobic bioremediation of urban river water, in which biofilm formed on ceramic honeycomb carrier was used instated of activated sludge. The dissolved oxygen in the wastewater was controlled under 0.5 mg/L for anoxic oxidation, and ammonia nitrogen was removed 40 to 60 percent, and total nitrogen removed 40 to 45 percent, that is ammonia nitrogen and total nitrogen were removed at the same time, also, nitrite was not any accumulated during the process. The biofilm was taken into flask to culture under anoxic oxidation condition in order to prove if anaerobic ammonium oxidation (ANAMMOX) occurred in the process, and ammonia and nitrite nitrogen were also removed at the same time in the experiment, which suggested that nitrification denitrification and ANAMMOX occurred in bioremediation of urban surface water with low ratio of carbon and nitrogen at the same time. The anammox bacteria were existed in the biofilm according to molecular biological analysis. The experiment will be significant for bioremediation of eutrophication water body. PMID- 19774986 TI - [Research on synergy of combining electrochemical oxidation and catalytic wet oxidation]. AB - A new catalytic wet oxidation fixed-bed reactor combined with three-dimensional electric-field was developed to investigate catalytic wet oxidation, electrochemical oxidation and electroassisted catalytic wet oxidation of the solution containing phenol in the presence of a catalyst Mn-Sn-Sb-3/gamma-Al2O3. Good electroassisted catalytic wet oxidation efficiency was obtained in the setup for the combination system even at mild conditions (T = 130 degrees C, po2 = 1.0 MPa) that the phenol conversion and TOC reduction were up to 94.0% and 88.4% after 27 min treatment, respectively. The result also shows that the rate constants of electroassisted catalytic wet oxidation are much higher than that of not only both catalytic wet oxidation and electrochemical oxidation process alone but also additive efficiencies of catalytic wet oxidation and electrochemical oxidation processes, which indicates an apparent synergetic effect between CWO and ECO processes. PMID- 19774987 TI - [Bio-electrochemical effect on hydrogenotrophic sulfate reduction stimulated by electrical field in the presence of H2 under atmospheric pressure]. AB - Microbial sulfate reduction rate is limited with H2 as electron donor. In order to improve hydrogenotrophic sulfate reduction under normal atmospheric H2 pressure, a bio-electrochemical system with direct current was designed and performed in this study. Results indicates that sulfate reduction rate (SRR) increases with the augment of current intensity under lower current intensity (I < or = 1.50 mA). When optimum current intensity of 1.50 mA is applied, the SRR is 1.7 to 2.1 times higher than that of the control reactor. The synergistic effect of electrochemistry and microbiology on sulfate reduction varies at different current intensity. Under the condition of I < or = 1.50 mA, the most probable mechanism of SRR increase is that electric or magnetic field stimulates the proliferation of sulfate-reducing bacteria (SRB) and the activity of the enzymes. When I is higher than 1.50 mA, the activity of SRB is inhibited, resulting in lower reduction rate compared with that at lower current. If controlling the cathode potential lower than -0.69 V and H2 partial pressure 1.01 x 10(5) Pa, electro-catalytic sulfate reduction process takes place with H2 as reductant in this bio-electrochemical system. However, the overall reduction rate is still lower than that when I = 1.50 mA is applied, and additionally the energy consumption is much higher. Therefore, electric field of low intensity can enhance hydrogenotrophic sulfate reduction in the presence of H2 under atmospheric pressure. PMID- 19774988 TI - [Reduction of nitrobenzene by iron oxides bound Fe(II) system at different pH values]. AB - Batch tests were conducted to investigate the reductive transformation of nitrobenzene by goethite, hematite, magnetite and steel converter slag bound Fe(II) system. And the reduction mechanism was explored at different pH values. Experimental results showed that hematite, magnetite and steel converter slag could adsorb Fe(II) on surfaces and form iron oxides bound Fe(II) system at pH from 6.5 to 7.0. The systems had strong reductive capacity and could reduce nitrobenzene to aniline. The reduction efficiency of nitrobenzene in surface bound Fe(II) system followed the sequence of magnetite, hematite and steel converter slag from high to low. The reduction efficiency of hematite and magnetite system increased with pH increasing. While it was almost pH independent in steel converter slag system. Although goethite adsorbed most of Fe(II) in solution, the adsorbed Fe(II) had no reductive activity for nitrobenzene. At pH 6.0, small amount of Fe(II) was adsorbed on magnetite and hematite and the systems did not show reductive activity for nitrobenzene. However, steel converter slag could adsorb Fe(II) at pH 6.0 and reduction efficiency almost equaled to the value at pH 7.0. When pH was above 7.5, dissolved Fe(II) could be converted to Fe(OH)2 and the newly formed Fe(OH)2 became the main redactor in the system. Under alkali condition, the presence of iron oxides inhibited the reduction capacity of system. PMID- 19774989 TI - [Fly ash-catalyzed oxidation of p-nitro phenol with H2O2]. AB - Fly ash was investigated as a catalyst in the oxidation of p-nitro phenol (PNP) with H2O2 at ambient temperature and pressure. The physical and chemical properties of fly ash were analyzed. The effects of fly ash composition, pretreatment methods and other parameters (such as dosage, pH, reaction time and oxidant concentration) on PNP removal rate were studied. It was found that fly ash with larger specific surface area and higher carbon content demonstrated higher catalytic activity. Heat treatment (350 degrees C) on fly ash could effectively improve the PNP removal rate. With an initial H2O2 concentration of 200 mg/L, 60 g/L heat-treated fly ash could remove 62.38% PNP at 25 degrees C, pH = 2. Specific surface area, carbon and metal oxide contents of fly ash play an important role in the catalysis process. The adsorption control experiment showed that adsorption was the main effect (65.97%) in the catalysis process. The activity of the catalyst gradually increased during its reuse. The PNP removal rate could reach 82.47% and 98.72% in the second and third rounds of reuse, respectively. The removal rate remained at about 99% in the rest 9 rounds of reuse. And the catalytic properties decreased after 12 times uses. PMID- 19774990 TI - [Electrochemical oxidation of dual electrodes with iron promoting used for the treatment of wastewater from acrylonitrile production]. AB - Effects and laws of electrochemical oxidation of dual electrodes with iron promoting for the treatment of wastewater from acrylonitrile production were investigated using Ti/SnO2 + Fe as combined anodes and graphite as cathode. Compared with traditional electrochemical oxidation, the higher removal of organic pollutants and current efficiency were obtained via oxidation of dual electrodes. Through the process COD removal efficiency and current efficiency were enhanced by 11.0%-13.8% and 8.0%-15.0% respectively, referred to the results from traditional electrochemical oxidation under conditions of the same voltage and no hydrogen peroxide added. With 2 200 mg x L(-1) hydrogen peroxide and voltage of 4.0 V, COD and TOC removal efficiencies increased to 74.6% and 67.9% respectively, and with the increase of hydrogen peroxide, both were enhanced obviously. During the initial reaction period, the higher hydrogen peroxide concentration and the lower Fe2+ concentration were detected, and with reaction time increased, hydrogen peroxide concentration decreased rapidly and Fe2+ concentration increased gradually. The voltage value had great effect on the concentrations of hydrogen peroxide and Fe2+, and the current efficiency was affected obviously by the time of current passed through iron anode under certain initial dosage of hydrogen peroxide. The better color removal was also obtained from electrochemical oxidation of dual electrodes. The electrochemical oxidation of dual electrodes with iron promoting presents a new alternative for the treatment of organic wastewater. PMID- 19774991 TI - [Enhanced decomposition of 1, 4-benzoquinone ring by DSA electrode under ultraviolet irradiation]. AB - Commercial DSA electrode was employed for photoelectrochemical degradation of a model pollutant 1,4-benzoquinone. The effect of electrolyte, electrical field intensity and solution pH conditions were investigated. The results proved that the TOC removal by photoelectrochemical oxidation was 1.25 times that of photocatalytic oxidation and electrocatalytic oxidation alone, indicating a synergetic effect. Addition of electrolyte and application of external electrical field have effectively enhanced the photoelectrochemical oxidation efficiency within a certain range of concentration and intensity. Acidic and neutral pH conditions are favorable for ring opening of 1,4-Benzoquinone.The photoelectrochemical oxidation mechanism is also discussed. It suggests that the efficiency of electrochemically assisted photoelectrochemical oxidation process can be manipulated, accompanied by the generation of hydroxyl radicals, which will be more adaptable for water and wastewater treatment. PMID- 19774992 TI - [Efficiency and mechanism on reduction of U(VI) by sulfate reducing bacteria]. AB - Under anaerobic conditions, the characteristics of sulfate reducing bacteria (SRB) were applied to reduce U(VI) under different temperature, pH values, U(VI) concentrations and coexisting ions. The results showed that the optimum reduction condition was the temperature 35 degrees C, pH 7.0 and U(VI) concentration 25 mg x L(-1). The maximum reduction capacity of SRB was 179.1 mg x g(-1). Mo(VI) or Ca2+ did not affect SRB on the reduction process of U(VI) under the concentration less than 5 g x L(-1), but they strongly inhibited the process under the concentration more than 20 g x L(-1). The main inhibition of Mo (VI) was physiological inhibition and the inhibition of Ca2+ was competitive inhibition through the stable complex formation, Ca-UO2-CO3. The results also showed that lag phase did not appear on the concentration of Ca2+ less than 5 g x L(-1), but the lag phase of 24 hours appeared on the concentration of Ca2+ more than 20 g x L(-1). PMID- 19774993 TI - [Enhanced visible-light absorbance of nanosized AgI/TiO2 by using calcination combined with light irradiation]. AB - With the aim to enhance visible-light absorbance, calcination combined with light irradiation was used to modify nanosized AgI/TiO2. UV-Vis spectrum curves indicated that the modified sample exhibited an intense absorption in the whole visible light range and a spectrum shifted from 465 nm to 800 nm, and that absorbance at 500 nm was improved three times as much as that of the reported pertinent material. XRD analytic results demonstrated that calcined AgI/TiO2 possessed more rutile phase with reduced band gap from 2.89 eV to 2.81 eV, and that the following xenon-light irradiation further enhanced the relative contents of anatase TiO2, rutile TiO2 and AgI accompanied with produced AgCl phase, leading to the decrease in band gap to 1.55 eV. Formation of AgCl and increases in the relative contents of rutile TiO2 and AgI should take the main responsibilities for the decrease in the band gap and enlargement of visible light absorbance. Additionally, it was confirmed that only the spectrum absorption of the calcined AgI/TiO2 could be improved by light irradiation, and that ultraviolet light played more role than visible part during the light irradiation. Moreover, it was proposed here that two or more silver halides supported on TiO2 could show more capabilities to stimulate visible-light activation of TiO2. PMID- 19774994 TI - [Effects of pH and Cu2+ on the detection of the Microcystin-LR based on fluorescence immunoassay and their elimination]. AB - The effects of pH and Cu2+ on the detection of the Microcystin-LR based on evanescent wave all-fiber immunosensor (EWAI) and their elimination were studied. The experimental results indicated that both low pH and high pH greatly affected the immunoassay results of MC-LR. When pH was less than 6 or higher than 8, the fluorescence signals detected by immunosensor system obviously reduced with the decrease or increase of pH. While pH ranged from 6 to 8, IC50 and the linear working range of MC-LR calculated from the calibration curve were 1.01-1.04 microg/L and 0.12-10.5 microg/L, respectively, which was favourable for MC-LR immunoassay. Low concentration Cu2+ rarely affected the detection performance of MC-LR. When the concentration of CuSO4 was higher than 5 mg/L, the fluorescence signal detected by EWAI clearly decreased. Furthermore, when the concentration of CuSO4 equalled to 10 mg/L, the fluorescence signal detected reduced 70%. The influence of Cu2+ on the immunoassay could effectively be compromised when 1% EDTA was added to the pre-reaction mixture. PMID- 19774995 TI - [Membrane fouling alleviation characteristics of sludge/water pre-separation MBR]. AB - A long-term operation was conducted to investigate the alleviation of membrane fouling by sludge/water pre-separation membrane bioreactor (S/W-MBR). The variation of trans-membrane pressure (TMP), concentration of sludge and extracellular polymeric substances (EPS) on S/W-MBR and submerged membrane bioreactor (SMBR) was also studied. The results showed that the sludge concentration in S/W-MBR was basically identical with that of SMBR's biotic area, while the sludge concentration was significantly decreased in S/W-MBR's membrane area than that of SMBR's. The concentration of EPS was increased with operation time in both two MBRs' biotic area, but it was lower and basically maintained at the level of 15 mg/g in S/W-MBR's membrane area. The S/W-MBR was more capable of alleviating membrane fouling, and it had been cleaned only 2 times while the SMBR who had been cleaned 5 times during the period of about 90 days laboratory performance. PMID- 19774996 TI - [Preparation and characterization of polyvinyl alcohol microsphere pre-coated dynamic membranes]. AB - To alleviate membrane fouling and reduce the price of membrane module, polyvinyl alcohol microsphere pre-coated dynamic membranes (PVA-MS/PCDMs) were investigated detailedly. It was prepared when the polyvinyl alcohol microsphere of the pre coated reagent deposited on the surface and entered the pores of porous substrate common filter cloth which was low-cost by means of circulatory filtration. The morphology and structure of PVA-MS/PCDMs were examined using scanning electron microscope (SEM), and approximate maximal separated aperture, water contact angle, pure water permeation resistance and relative Zeta potential of the membrance surface were also determined. The results showed that pure water permeation resistance of PVA-MS/PCDMs was between 0.64 x 10(10) m(-1) and 3.84 x 10(10) m(-1) and the approximate maximal separated aperture reached microfiltration level. The hydrophilicity of PVA-MS/PCDMs increased with increasing PVA-MS pre-coated mass. The relative Zeta potential of the PVA MS/PCDMs, which were measured using 0.01 mol x L(-1) KCl solution, pH 8.0 +/- 0.2 and at 20 degrees C, reached a peak value of -36.4 mV with pre-coated mass of 15.7 g x m(-2) PVA-MS on the membrance surface. In addition, evolutions of PVA MS/PCDMs flux versus time were investigated using a 4 hours short-term filtration experiment at 9.5 kPa in an SMBR and the permeability coefficient of PVA-MS/PCDMs were measured by the extracellular polymeric substances (EPS) diffusion experiments. Results indicated that the PVA-MS/PCDMs presented dramatically high anti-fouling characteristics when the pre-coated mass of PVA-MS was 23.9-61.9 g x m(-2). PMID- 19774997 TI - [Influence of carbon source on EBPR metabolism and microorganism communities]. AB - A SBR was used in this study for investigating the influence of carbon source on EBPR metabolism and microorganism communities when feeding with acetate and propionate. The SBR was operated with a cycle time of 8 h and each cycle consisted of 4 min feeding, 2 h anaerobic period, 5 h aerobic period, 35 min setting, 15 min decanting and 6 min waiting. The COD of influent was kept at 300 mg/L during the experiment. Acetate and propionate were used as the sole carbon source for operation of 60 days, respectively. The phosphorus release/ COD consumption in the end of anaerobic phase were 0.35 and 0.27 when acetate and propionate were used as the carbon source, respectively. The PHA composition was different when different carbon source was dosed. PHB accounted for 92.6% in the end of anaerobic phase but the value for PHV was only 7.4% when acetate was selected as the carbon source. No PH2MV was detected during this process. The compositions of PHA were PHB (10.2%), PHV (35.8%) and PH2MV (54.0%) in the end of anaerobic cycle when propionate was used as the sole carbon source. There was variation of microorganism communities during this process for the results of DGGE combined with SEM micrographs and PHA staining. Coccus morphotype PAOs were accumulated in acetate-fed phase and rod morphotype PAOs were accumulated in propionate-fed stage. Different PAOs were accumulated and the metabolic pathways were different when different carbon sources were used, but good EBPR could be achieved during all these conditions. PMID- 19774998 TI - [Denitrifying phosphorus removal in MUCT-MBR]. AB - The self-designed MUCT-MBR simplifies the MUCT process with reducing reactors from 5 to 2, which greatly reduces land occupied by equipment. Instead of secondary sedimentation tank, the membrane effluent quality is quite safe, and the operation is simple. In the investigation about simultaneous phosphorus and nitrogen removal of MUCT-MBR, the results showed that: when the proportions of C, N and P in the influent were 33.3/5/1-25/5.5/1, the average removal rate of COD, TN and TP in the whole experimental process were 89.3%, 75.4% and 79.2%, respectively. And the sludge settling capacity had no influence on the membrane effluent quality. The key factor of N and P removal rates is denitrifying phosphorus removal in anoxic condition. The proportion of denitrifying phosphate accumulating organisms (DPAOs) and the rate of denitrifying phosphorous removal were 84.2% and 67.07% on the 58th day, respectively. PMID- 19774999 TI - [Research on CANON process for municipal sewage in room temperature]. AB - In the room temperature 14.7-24.7 degrees C, simultaneous nitrification-ANAMMOX (CANON) process for municipal sewage was tested by SBR while the DO was controlled between 0.05 and 0.30 mg/L. As a result, the research shows that CANON process can be applied to the nitrogen treatment of municipal wastewater in room temperature by SBR. DO can be regarded as the indication parameter of reaction terminal, and 1 mg/L has been confirmed in the experiment. In the exploring SBR experiments, the consumption velocity of NH4(+) -N was 0.164-0.218 kg/(m3 x d), the production velocity of NO3(-) -N was 0.026-0.036 kg/(m3 x d), the removal velocity and efficiency of TN were 0.124-0.194 kg/(m3 x d) and 65%-75% respectively. Additionally, in the improving SBR experiments, there were three methods for avoiding nitrite accumulation and increasing the nitrogen removal efficiency. They were improving temperature, adding non-aeration period of time and increasing the quantity of ANAMMOX bacteria. Therefore, the removal efficiency of TN was increased to 77%-88% through the three ways above. However, in view of the nitrogen removal velocity and the fact of engineering application condition, the third approach was the best to advance the general ability of ANAMMOX. PMID- 19775000 TI - [Effect of C/N ratio on nitrous oxide production during denitrification with different electron acceptors]. AB - The experiment investigated the nitrous oxide production under different C/N ratios during denitrification, taking nitrate and nitrite as electron acceptor respectively. Ethanol was selected as carbon source. The C/N ratios were 0, 1.2, 2.4, 3.5, 5.0 and 20 when nitrate was taken as electron acceptor and C/N ratios 0, 1.8, 2.4, 3.0, 4.3, 5.2, 6.6, 20.6 when electron acceptor was nitrite. The results indicated that: the optimum C/N ratio was 3.0 taking nitrite as electron acceptor and the N2O production was 0.044 mg x L(-1); the optimum C/N ratio was 5.0 taking nitrate as electron acceptor and the N2O production was 0.135 mg x L( 1) which was 3 times higher than that of nitrite as electron acceptor. Though the electron acceptor changed, the trend of N2O production was similar: when carbon source was badly insufficient, the production of N2O and denitrification rate were both quite small; the N2O production increased with the increasing of the quantity of carbon source; when the carbon source was excessive, the N2O production sharply raised. Consequently, compared to complete nitrification and denitrification, short-cut nitrification and denitrification could save 40% carbon source. Moreover, controlling C/N = 3 could reduce the production of N2O in short-cut nitrification. PMID- 19775001 TI - [Fractal structure and physicochemical characteristics analysis of aerobic sludge floc in A2/O process]. AB - Image analysis method, free settling test were performed to determine the morphology, particle size distribution, free setting velocity, effective density, porosity and fractal dimensions in different topological spaces of aerobic sludge flocs in A2/O process. Then the physicochemical indices, corresponding to the sludge properties such as: settleability, compressibility, dewaterability and stability, were measured. Besides these, the extra-cellular polymeric substances (EPS) were extracted from sludge and classified as different components. The results showed that the sludge floc with irregular morphology was high porous. The effective densities of these sludge flocs generally increased with the increase of their size, but the porosities within the flocs and their free settling velocities decreased accordingly. The median diameters of the sludge flocs at two different sampling times were 248.81 microm, 332.86 microm, respectively. Their corresponding average effective densities were 0.0040, 0.0072 g x cm(-3), and average free settling velocities were 2.67 mm x s(-1), 4.79 mm x s(-1), and giving the average porosities of0.94, 0.89. The dimensional analysis methods, based on power law correlations between floc perimeter, projected area and maximum length, were used to determine the one- and two-dimensional fractal dimensions (D1 and D2 ) of sludge flocs, giving D1 = 1.03 or 1.19, D2 = 1.64 or 1.84. The mass fractal dimensions (D(f)) of these sludge flocs were determined by the bi-logarithm relations of effective density (based on Logan empirical equation)-maximum diameter which equaled to 1.74 or 2.29. The above results demonstrated that the second sample of sludge flocs was larger and more compact, but smoother than the first sample. Moreover, the results also showed that the sludge flocs in A2/O process with high flocculating ability or high negative surface charge had high values of sludge volume index (SVI) and zone setting velocity (ZSV), and low values of fractal dimensions in 2-D or 3-D spaces of sludge flocs correlated to high shear sensitivity and low floc strength, indicating low sludge stability. The high quantity of extra-cellular substances (EPS) in the sludge was related to poor dewaterability. As same as the conclusion of literature, the protein component in EPS could improve the negative surface charge of sludge flocs. PMID- 19775002 TI - [Impact of hydraulic retention time (HRT) in ABR on its operation performance and granular sludge characteristics when treating low-strength wastewater]. AB - The impact of hydraulic retention time (HRT) in an anaerobic baffled reactor (ABR) on its operation performance and granular sludge characteristics was investigated through both testing its operation and analyzing the particle size distribution (PSD) and fractal dimensions of these sludge granules when treating low-strength wastewater. As HRT was gradually reduced from 24 h to 5 h, ABR had good performance on the organics removal and could reach about 90% for the COD removal, the VFA contents in ABR effluent and their pH values showed opposite trends. Most COD in wastewater was removed in the first two compartments of ABR during the running period of HRT from 24 h to 12 h, after that, the middle three compartments in ABR performed the most removal work. The MISS in latter compartments of ABR increased and the tendency of MLVSS/MISS ratios in the former three compartments were higher than that in the latter two ones appeared more and more remarkable along with the decrease of HRT. At HRT 24 h and 18 h, the granules grew bigger than before start-up,whose one-dimensional fractal dimension (D) decreased and two-dimensional fractal dimension (D2) increased, implying the smoother surface and more compact structure. As the HRT changed to 12 h and 8 h, the increasing D1 and decreasing D2 of granular sludge indicated its rougher surface and looser structure, and the bigger granules were formed with holes in their center. At HRT 5 h, smoother and more compact granules formed with smaller number median diameters of 0.72-0.82 mm than that at HRT 8 h. The looser granules were broken-up and some granules were discharged from ABR under the hydraulic disturbance and screening effect, at the same time, the growth of microorganism and their EPS (extracellular polymer substance) secretion could smooth the surface of the fragmentized granules. The fractal dimensions of granular sludge in the one-dimensional and two-dimensional topological spaces behaved inversely in each compartment of ABR at the same HRT, that is to say, the granular sludge along the ABR sequences became smoother on the surface meanwhile more compact structurally. PMID- 19775003 TI - [Effect of ammonia concentration on the characteristic of aerobic granular sludge]. AB - The effect of ammonia concentration in influent on the characteristic of granular sludge was investigated in the granular SBR. Results indicated that the increase of ammonia concentration could induce filamentous growth. When the loading rate of ammonia was as high as 0.80 kg/(m3 x d), obvious disintegration of granules and washout of sludge were observed. However, in absent of ammonia, aerobic granules could not form either. Moreover, it was found that the increase of ammonia concentration could result in disperse structure, diameter increase, settleability and MLSS reduce of aerobic granular sludge system. The average removals of COD and TP by granular SBR could keep 90% and 70% respectively, and were not influenced by the increase of ammonia. But the activities of nitrification bacteria and denitrification bacteria were restricted seriously by the ammonia concentration increase. When loading rate of ammonia was increased from 0.48 kg/(m3 x d) to 0.80 kg/(m3 x d), the average removal rates of NH4(+) -N and TN reduced to 70% and 50%. PMID- 19775004 TI - [Community structure and kinetics characterization of enriched nitrifiers cultivated with reject water]. AB - The community of nitrifiers cultivated with reject water were investigated by fluorescent in situ hybridization (FISH) performed with 16S rRNA-targeted oligonucleotide probes, and the kinetic properties such as temperature correction factor tauN and the half saturation coefficient K(N) were also investigated. The results showed that the percentage of ammonia oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) in the activated sludge was 15.7% +/- 3.7% and 12.9% +/- 3.2%, Nitrosomonas europaea-Nitrosococcus mobilis lineage were the dominant AOB, Nitrobacter spp. were the dominant NOB. The temperature correction factors of ammonium utilized rate (AUR) and nitrite utilized rate (NUR) were 1.092 and 1.061 respectively; the K(N) of AOB and NOB were (1.60 +/- 0.29) mg/L (NH4(+) -N), (2.78 +/- 0.30) mg/L (NO2(-) -N) respectively. PMID- 19775005 TI - [Aluminum mobilization models of forest yellow earth in South China]. AB - For the application of acidification models in predicting effects of acid deposition and formulating control strategy in China, it is important selecting regionally applicable models of soil aluminum mobilization and determining their parameters. Based on the long-term monitoring results of soil water chemistry from four forested watersheds in South China, the applicability of a range of equilibriums describing aluminum mobilization was evaluated. The tested equilibriums included those for gibbsite, jurbanite, kaolinite, imogolite, and SOM-Al: Results show that the gibbsite equilibrium commonly used in several acidification models is not suitable for the typical forest soil in South China, while the modified empirical gibbsite equation is applicable with pK = - 2.40, a = 1.65 (for upper layer) and pK = - 2.82, a = 1.66 (for lower layers) at only pH > or = 4. Comparing with the empirical gibbsite equation, the other equilibriums do not perform better. It can also be seen that pAl varies slightly with pH decreases at pH < 4, which is unexplainable by any of these suggested equilibriums. PMID- 19775006 TI - [Content and density characteristics of soil organic carbon in typical landscapes of subtropical region]. AB - The contrasts of the content and density characteristics of surface soil organic carbon among four typical landscapes of subtropical region in China were investigated. The results show that the area-weighted mean content of SOC varies widely with landscapes and the highest mean content is present in the lacustrine plain landscape (25.10 g x kg(-1)), followed by the karst landscape (20.84 g x kg(-1)) and mountainous landscape (17.75 g x kg(-1)), whereas the lowest occurs in the hilly red soil landscape (12.07 g x kg(-1)). The coefficient of variation of SOC content ranges from 24.06% to 43.76%, being moderate variation. The main distribution ranges of SOC content are higher than 20 g x kg(-1) in the lacustrine plain landscape and lower than 20 g x kg(-1) in the other three landscapes. The sequence of SOC density in the four landscapes is highly consistent with the sequence of SOC content, and the sequence is as follows: lacustrine plain landscape (6.12 kg x m(-2) > karst landscape (4.30 kg x m(-2)) > mountainous landscape (4.25 kg x m(-2)) > hilly red soil landscape (3.04 kg x m( 2)). The results reveal that the difference of soil parent material, cultivation strength, topography and proportion of land use may be the main reasons caused the variation of SOC content among the four landscapes. Surface soils in typical landscapes of subtropical region are important carbon pool in China. PMID- 19775007 TI - [Changes in bio-availability of immobilized Cu and Zn bound to phosphate in contaminated soils with different nutrient addition]. AB - Bio-availability of Cu and Zn fixed by phosphate in contaminated soils with application of nutrients were measured by pot experiment. It was simulated for the third national standardization of copper and zinc polluted soils by adding copper and zinc nitrate into red and paddy soils, respectively and together. Phosphate amendment was added to the soils to fix Cu and Zn, then added KCl and NH4Cl or K2SO4 and (NH4)2SO4 fertilizers following to plant Ryegrass, which was harvested after 40 d. Available Cu/Zn content in soils and biomass, Cu/Zn content in the shoot of Ryegrass were determined. Results showed that, compared with no nutrient application, adding KCl and NH4 Cl/K2SO4 and (NH4)2SO4 to polluted red and paddy soils increased the available Cu and Zn content in red soil significantly. The increasing order was KCl and NH4 Cl > K2SO4 and (NH4)2SO4. Especially in single Zn polluted red soil, the available Zn content increased by 133.4% in maximum. Although adding K2SO4 and (NH4)2SO4 could promote the growth of Ryegrass on red soil, and the largest increasing was up to 22.2%, it increased Cu and Zn content in the shoot of Ryegrass for 21.5%-112.6% remarkably. These nutrient effects on available Cu and Zn were not significantly in paddy soil. It was suggested that application of nitrogen and potassium fertilizers to soils could change the bioavailability of Cu/Zn. So it is necessary to take full account of the nutrient influence to the heavy metal stability which fixed by phosphate in contaminated soils when consider contaminated soils remediation by fertilization. PMID- 19775008 TI - [Spatiotemporal distribution characteristics of soil iron in the annular wetland under different water regime]. AB - The effect of water regime on the spatial distribution of total iron and the seasonal variation of dissolved iron in a typical annular wetland of Sanjiang Plain, Northeast China, was analyzed through in situ sampling of soils and soil solutions. The results showed that the average level of total iron of the wetland soil (0-60 cm) was (2.54 +/- 0.73) x 10(4) mg x kg(-1), which decreased gradually from the Calamagrostis angustifolia community in the edge of the annular wetland [(2.91 +/- 0.51) x 10(4) mg x kg(-1)], to the C. meyeriana community [(2.60 +/- 0.35) x 10(4) mg x kg(-1)], the C. lasiocarpa community [(2.48 +/- 0.31) x 10(4) mg x kg(-1)], and the of C. pseudocuraica community [(2.17 +/- 0.31) x 10(4) mg x kg(-1)] in the centre of the annular wetland. The iron solubility of perennial flooding soil was higher than seasonal flooding soil. The gross dissolved iron increased from soil thawing in the late spring [(0.35 +/- 0.086) mg x L(-1)] to freezing in the late autumn [(12.67 +/- 2.92) mg x L(-1)], because the soil iron was activated by continuous submergence. The reduced degree as shown by Fe3+/Fe2+ increased with the increment of water depth or flooding duration. Significant and extremely significant correlations were observed between dissolved Fe3+ or Fe2+ and pH, TOC, TN and PO4(3-), which suggested that the distribution of iron was influenced by the soil physical and chemical properties, and coupled with the transfer and transformation of C, N, and P elements. PMID- 19775009 TI - [Environmental concerns on geochemical mobility of lead, zinc and cadmium from zinc smelting areas: western Guizhou, China]. AB - Indigenous zinc smelting activity, widely spread in western Guizhou, China, had caused serious pollution of heavy metals of lead (Pb), zinc (Zn) and cadmium (Cd) in soil and water and posed risk to the local ecosystem. Geochemical distribution and mobility of Pb, Zn and Cd in soil, waste residue and waters were investigated in a small watershed in order to provide scientific base for the approach to pollution control and remediation. Concentrations of Pb, Zn and Cd in smelting residues averaged at 4 632 mg/kg, 8 968 mg/kg, and 58 mg/kg, respectively; whereas Pb 234 mg/kg, Zn 400 mg/kg and Cd 9.6 mg/kg in average in the soils around the smelting areas were measured. The sequential geochemical extraction test showed that Pb, Zn and Cd in the contaminated soils had high mobility and bioavailability for the metals, whereas smelting waste residues had lower mobility and bioavailability because their concentrations presented small percentages (all less than 0.2%) in the exchangeable fraction. Concentrations of Pb, Zn and Cd were high in the local stream water but low in groundwater. In the surface water, Pb, Zn and Cd were significantly concentrated in the suspended sediment. The results indicated that metal-rich erosion process of smelting residue and contaminated soil contributed to mobility of the metals into stream water. PMID- 19775010 TI - [Spatial variation of heavy metals contamination in the soil and vegetables of Huludao City]. AB - Hg, Pb, Cd, Zn, and Cu concentrations in the soil, vegetables and crop of Huludao city were investigated. The Hg, Pb, Cd, Zn, and Cu concentrations in soils of the smelting areas are 1.422, 443.1, 60.94, 4084, and 247.8 mg x kg(-1), thus 6.092, 3195, 341.7, 35 157, and 1 557 mg x kg(-1) for the maximal concentrations, respectively. Spatial distribution maps of heavy metals concentrations in top soils in Huludao City were separately laid out by using Kriging. Heavy metals spatial distribution patterns in soils show that Ph, Cd, Zn, Cu emissions from Huludao Zinc Plant are the main pollution sources of heavy metals to the top soils in Huludao City, but Hg emission from Huludao Zinc Plant and chlor-alkali industry is the main pollution source of mercury to the top soils. Heavy metals concentrations in top soils decrease exponentially with distance from the zinc smelting area. Except Hg, the exponential equation could be better to fit the variety forother heavy metals. Heavy metals in vegetable and crop cultivated around Huludao Zinc Plant are higher than from markets, suggests that heavy metals affect the local soil and crops seriously. PMID- 19775011 TI - [Heavy metal contents in insects collected from the Huludao City suffering pollution by zinc smelting and cholor-alkai production]. AB - 14 insect species, which were classified to three groups: the herbivorous, the polyphagous and the carnivorous, and earthworms were collected from the grasslands in Huludao City, Liaoning Province, China. Mercury, cadmium and lead contents in biota were determined to discuss the heavy metal pollution in organisms. Mercury, cadmium and lead contents were 0.168, 9.19 and 12.58 mg x kg( 1) in the herbivorous insects, respectively; 0.375, 24.43 and 17.71 mg x kg(-1) in the polyphagous insects, respectively; 0.928, 29.78 and 18.39 mg x kg(-1) in the carnivorous insects, respectively. It showed that heavy metal pollution in biota in Huludao City was heavy. Bioaccumulation abilities to heavy metals significantly differed with insect species. Snails and dragonflies could accumulate more mercury than the other insects and spiders could accumulate the most cadmium and lead in all insect species. These three metals investigated in insects were all sorted as the herbivorous < the polyphagous < the carnivorous. Cadmium and lead contents between the polyphagous and the carnivorous varied slightly. Correlation analysis showed that cadmium and lead contents were significantly related, but mercury and cadmium or mercury and lead were not. It indicated that cadmium and lead in insects were from the same pollution sources while mercury was more complex. PMID- 19775012 TI - [Anolyte enhanced electrokinetic remediation of fluorine-contaminated soils]. AB - An experimental study was carried out in order to determine the characteristics of migration and its influencing factor of soil fluorine in the electrokinetic process under different applied voltage and concentration of anolyte. The feasibility of anolyte enhanced on electrokinetic remediation of fluorine contaminated soil was analyzed. The results show that when deionized water is used as anolyte with the 1.0 V/cm voltage gradient, the cumulative mass of fluorine in catholyte and anolyte are 8.2 mg and 47.7 mg respectively and the removal rate of fluorine is only 8.8%. Anolyte enhanced electrokinetic process can promote effectively the migration of fluoride in soil. When 0.02 mol/L NaOH solutionis employed as the anolyte, the removal rates are 25.9%, 31.2% and 47.3% with 1.0, 1.5 and 2.0 V/cm voltage gradient respectively. As the concentration of anolyte increased to 0.1 mol/L, the removal rates are 55.4%, 61.1% and 73.0%. The electromigration is the main transport mechanism and the electroosmotic flow has an effect on the migration of fluorine in soil. The voltage gradient and the concentration of anolyte are the main factors influencing the removal rate of fluorine in soil. Appropriate anolyte enhanced electrokinetic method can be applied to remediate fluorine from contaminated soil. PMID- 19775013 TI - [Sorption behavior of phenanthrene to natural carbonaceous sediments]. AB - Natural sediments impacted by previous coal mining activities were collected and separated according to grain size and density. Sorption experiments were performed with original sediments and different sub-fractions. Abundant coal and other coal-derived particles were identified using organic spectrographic analysis. Both Freundlich and partitioning and pore-filling model were applied to fit the experimental data. All sorption isotherms showed non-linear sorption properties, with n in the range of 0.72-0.76. The light fraction had the highest sorption capacity (lgK(Fr) = 4.03), which is comparable to that of raw coal. In addition, partitioning and pore-filling model yields the better fitting than Freundlich model, indicating that at low c(w), "pore-filling" dominants the whole sorption; while with the increase of c(w), partition takes place of adsorption and dominants the sorption. In addition, in spite of the very low mass weight, the light fraction dominated by carbonaceous materials contributed more than 60% of the sorption for the whole sediments. PMID- 19775014 TI - [Formation mechanism of by-product PCBs in the p-DCB production]. AB - A typical p-DCB production process was selected in this study. A series of p-DCB product samples, 1 Japanese sample and 1 chlorobenzene sample were collected and analyzed for by-product polychlorinated biphenyls (PCBs). It is a common phenomenon that byproduct PCBs exists in the p-DCB production process. The PCBs levels in the p-DCB samples were 62-781 ng/g and the highest WHO-TEQ in the process was 0.24 ng/g, while the PCBs level in the Japanese sample reached 881 ng/g. PCB31 was the dominate PCB congener in all the p-DCB samples with the maximum 98.5% of the total PCBs. Maximum content of PCBs was TrCBs in the p-DCB samples with the next TeCBs, DiCBs and PeCBs, while MoCBs were the highest in the chlorobenzene sample. Furthermore, a formation mechanism of PCBs in the production process was proposed and proved by the analysis result. It suggested that the formation of PCBs form the condensation of polychlorobenzenes had a relation with the concentration of polychlorobenzenes and the chlorine position in the benzene ring. PMID- 19775015 TI - [Plasmid pJP4 mediated gene-augmentation in different systems and its effect on 2,4-D biodegradation]. AB - With pJP4 plasmid carrying genetic engineering bacteria Pseudomonas putida SM1443 :: gfp2x (pJP4 :: dsRed) as the donor, horizontal gene transfer of pJP4 plasmid in 4 isolated pure strains was investigated, and effects of the donor bacteria inoculation on the removal of the target pollutant 2,4-dichlorophenoxyacetic acid (2,4-D) was studied through conducting gene augmentation in activated sludge, biofilm, aerobic granular sludge and river sediment system, respectively. Results showed that plasmid pJP4 could transfer from Pseudomonas putida SM1443 to a broad spectrum of bacteria. Inoculation of pJP4 plasmid carrying donor bacterium apparently promoted the degradation of 2,4-D for all the above four systems. For the activated sludge system (2,4-D initial concentration at 450 mg/L), 66% and 54% removal of 2,4-D was achieved after 143.5 h reaction for the gene augmented and control system, respectively. For the biofilm system with 2,4-D initial concentration at 180 mg/L, 2,4-D removal percentage at 113 h was 99% and 61%, respectively. For aerobic granular sludge system (2,4-D initial concentration at 160 mg/L), 2,4-D was nearly completely removed by 62 h in the gene-augmented system, while the control system only degraded 26% at 66 h. For the system with sediment (2,4-D initial concentration at 2 mg/L), 93% and 69% removal of 2,4-D was obtained at 344 h reaction for the gene augmented and control system, respectively. Confocal laser scanning microscopy (CLSM) analysis revealed the formation and presence of transconjugants in different gene augmentation systems. PMID- 19775016 TI - [Isolation of heterotrophic nitrifiers/aerobic denitrifiers and their roles in N2O production for different incubations]. AB - Soil microorganisms are important sources of N2O for the atmosphere. Peak emissions of N2O are often observed after wetting of soil. The simultaneous heterotrophic nitrifying and aerobic denitrifying bacteria with respect to N2O emission were studied to obtain more information about the microbiologcal aspects of peak emissions. Using acetamide as the C and N source, two strains of nitrifying and denitrifying bacteria were isolated, coded as XM1 and HX2,respectively. XM1 strain was Gram-negative chain-like bacilli, and the HX2 was Gram-negative cocci. In enrichment culture, N2O production of HX2 was 76 times more than XM1. Two strains could grow with glucose, mannitol or sodium tartrate as sole carbon source, respectively. They could nitrify with sodium nitrate or denitrify with ammonium sulfate as unique nitrogen source, and produce intermediate product nitrite. XM1 strain growth velocity and nitrite formation were obviously higher than HX2. The phylogentic analysis based on partial 16S rDNA showed that two isolated strains were the closest relative of Pseudomonas sp.99% sequence similarity. Under different WFPS (water-filled-pore-space) conditions, the aerobic autoclaved soil incubation trial showed that, HX2 strain was suitable for growing in 30% WFPS, and N2O production was (36.01 +/- 2.48) ng/g which was 1.9 times than that in 60% WFPS. But XM1 was suitable for growing in 60% WFPS and almost had no N2O production. To investigate the nitrifying and denitrifying mechanisms of heterotrophic nitrifiers/aerobic denitrifiers should be useful for mastering the mitigation way of soil N2O emission in future. PMID- 19775017 TI - [Composition diversity of the multifunctional bacterium community NSC-7]. AB - The NSC-7 microbial community could decompose cellulose and lindan with high efficiency. In order to determine the bacterial composition of the community, 11 isolate strains were detected by plate isolation, while a community reset by the 11 isolate strains lost the capacity of degrading cellulose. The capacity of degrading of the filter paper in double deck plate and monolayer plate were determined, only the filter paper in double deck plate were degraded, that means the main or key microbe are anaerobic. The denaturing gradient gel electrophoresis (DGGE) and construction of 16S rDNA clone library were used to identify the composition diversity of NSC-7 community. 195 clones and 25 strains were detected in clone library, and about 60% closest relative among them was known the detailed information which were belonged to Clostridium, Petrobacter, Bacteria, Paenibacillus, Proteobacterium. Furthermore, there were 40% closest relative belonged to uncultured bacterium clone. PMID- 19775018 TI - [Isolation and characterization of electrochemical active bacterial Pseudomonas aeruginosa strain RE7]. AB - Microbial components of the microbial fuel cells (MFCs), including species constitution and metabolic mechanism of the anodic microorganisms, are critical to the optimization of electricity generation. An electrogenesis baterium strain (designated as RE7) was isolated from an MFC that had been running in a fed batch mode for over one year. The isolate was identified as a strain of Pseudomonas aeruginosa based on its physiological, morphological characteristics and 16S rRNA sequence analysis. Direct electron transfer from RE7 to an electrode was examined using cyclic voltammetry and MFC. Results of both methods showed the electrochemical activity of the bacterium without any electrochemical mediator. The P. aeruginosa strain RE7 was inoculated into the anode chamber of a packing type MFC and the maximal voltage output was 352 mV with 1 500 mg/L glucose as the fuel. Correspondingly, the maximal area and volumetric power densities were 69.2 mW/m2 and 6.2 W/m3, respectively. Bacteria-producing soluble redox mediators, such as phenazine derivatives, are possible mechanism to facilitate the direct electron transfer to the electrode from the bacterial cells. PMID- 19775019 TI - [Analysis of dynamic characteristics for fermentative hydrogen-producing bacteria community and hydrogen producing capability in CSTR]. AB - The start into the types of fermentation was carried out by pH adjustment from 4.2 to 6.0 in CSTR system. The process of transforming of hydrogen production and dynamic community of bacteria were studied. The results showed that with the organic load maintained at (33 +/- 1) kg/(m3 x d), there was no change in 10 d for the type of fermentation, the amount of hydrogen does not reduce in 8 d. After 15 d, the system was transformed from the ethanol-based type into butyric acid type and water alkalinity was from 250 mg/L to 2450 mg/L. The use of fluorescence in situ hybridization (FISH) system was in response to the 3 groups of micro-organisms. It was found that in the process of transforming, Clostridium cluster XI increases and Clostridium cluster I and II decreases. Enterobacteriaceae always existed with no change. The microbial growth must be considered with hydrogen production capability. The average hydrogen production rate reached to 23.6 mol/(kg x d) with Clostridium cluster I and II dominated in fermentation reactor. PMID- 19775020 TI - [Effect of cow feces on anaerobic digestion process of Spartina alterniflora]. AB - Effects of cow feces on anaerobic digestion process of Spartina alterniflora was studied by batch model at 35 degrees C. When Spartina alterniflora was digested alone, the biogas yield was 222.61 mL/g, and it was acidified from 10 d to 15 d. When cow feces was added, the environment where microorganisms lived in was meliorated, pH value was stabilized and biogas production was improved by 38.83%. Volatile fatty acids production was not affected significantly, but the peak was advanced. FTIR and XRD analysis of solid residue substances further proved that co-digestion promoted the removal of carbohydrates and resulted in higher content of lignin than Spartina alterniflora straw digested alone, and promoted the destruction of crystalline of cellulose. The crystallinity index (C(x)I) of Spartina alterniflora, digested Spartina alterniflora and co-digested Spartina alterniflora were 0.617 6, 0.6200 and 0.615 4, respectively. Therefore, adding cow feces was beneficial for the decomposition and increasing the biotransformation rate of Spartina alterniflora straw. PMID- 19775021 TI - [Kinetics and mechanism of 4-aminobenzenesulphonate biodegradation]. AB - Kinetics of 4-aminobensenesulphonate (4-ABS) degradation by Pannonibacter sp. W1 under aerobic condition was studied. At medium and low initial concentration (50 1000 mg/L), the 4-ABS could be degraded almost completely in 14 h,and the degradation reaction conformed to one order kinetics. At high initial concentration (1 200-2500 mg/L), up to 90% degradation rate could be achieved in 32 h, and it conformed to zero order kinetics in earlier period of degradation and one order kinetics in later period of degradation. Haldane inhibition model was used to fit the special degradation rate at different initial concentration, and the parameters micro(max), K(s) and K(i) were determined to be 227.977 mg/(g x h), 84.306 mg/L and 1270.675 mg/L, respectively. UV spectrum and HPLC detection indicated that no other aromatic intermediates were accumulated during the 4-ABS degradation. The degradation of other substituted benzenes by strain W1 were detected, and the metabolic pathway of 4-ABS degradation was proposed. PMID- 19775022 TI - [Sustainable electricity generation in microbial fuel cells using Fe(III)-EDTA as cathodic electron shuttle]. AB - The rate of oxygen reduction reaction (ORR) at the cathode is a major factor affecting the performance of the microbial fuel cells (MFC). Results showed that when using Fe(III)-EDTA solution as catholyte, the ORR rate was significantly increased and the internal resistance was reduced, consequently leading to an increase in power output. With a concentration of Fe(III )-EDTA at 20.0 mmol/L in the catholyte, the MFC produced the voltage and power density at approximate 200.1 mV and 16.0 mW/m2, respectively, which was increased by 73.2% and 70.1% contrary to the MFC without the presence of Fe(III)-EDTA. The further experiment suggested that Fe(III)-EDTA functioned as electron shuttle to accelerate electron transfer. Fe(III)-EDTA received electron and got reduced to Fe(III)-EDTA, which further provided electrons to oxygen and got reoxidized at the same time. Therefore Fe(III)-EDTA can act as recyclable electron shuttles between cathode electrode and oxygen. The optimum condition in the case of using Fe(III)-EDTA as cathode electron shuttles was tested to be Fe(III)-EDTA concentration at 20.0 mmol/L and pH at 5.0, which allowed MFC produced the maximum power density of 100.9 mW/m2. PMID- 19775023 TI - [Influence of environmental factors on electricity production by microbial fuel cell inoculation Shewanella baltica]. AB - The influences of the anodic substance, concentration, pH and temperature on the electricity production by MFCs were discussed. The lactic sodium was better than acetic sodium or glucose. The power density of MFC and the concentration of lactic sodium were well filled with Monod model. The power density was 1236 mW/m2 when the pH of anodic chamber was 8. The power density of MFC increased with the pH increasing from 6 to 8, which was due to the anodic internal resistance. The power density was 1 197 mW/m2 when the temperature was 50 degrees C. The power density of MFC changed with temperature because the anodic resistance decreased with the temperature increasing. While the temperature changed from 20 degrees C to 50 degrees C, the current density and the temperature were well filled in Arrhenius equation. PMID- 19775024 TI - [Removal mechanism of light non-aqueous phase liquid from soil and groundwater by surfactant]. AB - Surfactant increases solubilization of n-hexadecane and reduces interfacial tension between surfactant and n-hexadecane, which are very important for the removal of residual LNAPLs in porous media. After the solubilization of n hexadecane and interfacial tension between Triton X-100 solution and n-hexadecane were studied through experiments, the forming rule of different states of n hexadecane were analyzed through equilibrium washing experiment and sand pillar leaching experiment. The experimental results show that: the dissolving ability was proportional to the concentration of Triton X-100 solution, and MSR = 1.680 4 and lgk(mc) = 1.715 8 calculated by solubilization of n-hexadecane when Triton X 100 solution concentration was large than CMC. The interfacial tension was inversely proportional to Triton X-100 solution concentration, and the variation was in accord with Gauss model (R2 = 0.996 4). Dissolved state and free state n hexadecane had very good corresponding relation with solubilization and reducing interfacial tension respectively. Both solubilization and reducing interfacial tension could remove n-hexadecane from porous media. Reducing interfacial tension increased the flow ability of n-hexadecane effectively, and it removed most of residual n-hexadecane in soil and groundwater remediation. PMID- 19775025 TI - [Characteristics of bacteria variation and pollutants behavior in landfill leachate polluted site]. AB - Static and dynamic simulated experiments were conducted to investigate the characteristics of bacterial variation in landfill leachate polluted site, and relations between attenuation, species-distribution, bioavailability of pollutants and bacterial activity. Results indicated that bacterial activity in soil and fine sand showed a trend of increase first and then decreased with time; the increase rate was up to 0.081 d(-1) and 0.022 d(-1) at the increasing stage,and the decrease rate reached 0.0095 d(-1) and 0.005 1 d(-1) at the decreasing stage, respectively. A clear correlation between attenuation of COD and variation of bacterial activity with time was shown; the removal efficiency of COD in soil was about 30% higher than that in fine sand, and the attenuation rate of COD was 500 mg/d in fine sand approximately. There was no clear correlation between ammonium-nitrogen attenuation and bacterial activity in short term with time. Variation of heavy metals species and bioavailability was related to their properties, redox environment, and other factors. PMID- 19775026 TI - [Application of struvite crystallization on co-composting of swine manure and cornstalk]. AB - Aimed at controlling the nitrogen loss caused by the ammonia gas emission during composting, the mixtures of magnesium hydroxide [Mg(OH)2] and phosphoric acid (H3PO4) were added into composting materials of swine manure and cornstalk. After 26 d composting, ammonical nitrogen and total nitrogen were improved obviously,which were 10.7 g x kg(-1) and 36.9 g x kg(-1) respectively in amended treatment (B), while they were 7.7 g x kg(-1) and 26.8 g x kg(-1) in un-amended trial. By analysis of the total organic carbon, t suggested that amendments accelerated the degradation of organic matter, germination index test showed the maturity of trial B(96%) was better than trial A(82%) in final compost. The scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) analysis confirmed the existence of struvite (MgNH4PO4 x 6H2O). These results indicated that Mg (OH)2 and H3PO4 could accelerate the degradation of organic matter, and reduce the ammonia emission by struvite crystallization reaction. PMID- 19775027 TI - [Effects of adsorbents on partitioning of Cd and Pb in MSW incineration]. AB - An incineration experiment using simulated municipal solid waste (MSW) in the tubular furnace was performed to study the effects of SiO2, Al2o3 and CaO on the partitioning of Cd and Pb under different operating conditions which included adsorbents percentage, furnace temperature and residence time. The results indicated that the increasing of SiO2, AL2O3, CaO concentration were favorable for Cd to partition in the bottom ash. And for Pb, SiO2 and Al2O3 had the same effects. However, the condition with CaO showed an opposite tendency of increasing Pb distribution in fly ash. While all of these adsorbents increasing, the effects were also enhanced. When the temperature of the tubular furnace was 850 degrees C, the adsorption efficiencies of these adsorbents for Cd were in the sequence of CaO > Al, O3 > SiO2, and for Pb, Al2O3 > SiO2 > CaO. In addition,with increasing of tubular furnace temperature and residence time, there would be more Cd and Pb compounds moving to the fly ash. PMID- 19775028 TI - [Utilizing fly ash to prepare polysilicon acid and compounded PFS and the study of its properties]. AB - Fly ash which is a kind of solid waste of power station in Dalian was prepared as polysilicon acid, and compound polymerized ferric sulphate and its properties was studied. Fly ash was dipped in NaOH solution. The effects of temperature, concentration of NaOH solution and reactive time were examined respectively on the conversion efficiencies of silicon. Then the solution which was rich in silicon was used to compound polymerized ferric sulfate (PFS) and got compounded polymerized ferric sulphate (F-PFS), and evaluated the effects of slaking time and Fe3+/Si molar ratio on conversion efficiencies of silicon. Then used Na2SiO3 to prepare polysilicon acid compounded polymerized ferric sulphate (N-PFS) with the same silicon concentration at the best condition. The best ratio of dissolved silicon 0.207 9 g x g(-1) was attained at the condition of 4 mol x L(-1) NaOH solution, 120 degrees C for 4 h. The coagulant was attained at the condition of Fe3+/Si molar ratio of 1:0.2 and slaking time of 2 h. The reducing turbidity by F PFS is the same as N-PFS, but F-PFS is better than N-PFS and PFS is in the stabilization, sedimentation,and the property of treating with urban sewage. PMID- 19775029 TI - Central venous pressure monitoring. PMID- 19775030 TI - Preoperative screening for obstructive sleep apnoea--are we losing sleep over nothing? PMID- 19775031 TI - The microcirculation, regional blood flow and tissue oxygenation: will new technologies drive new resuscitation goals? PMID- 19775032 TI - The new College of Intensive Care Medicine--update. PMID- 19775033 TI - Diagnosis of postoperative arrhythmias following paediatric cardiac surgery. AB - Arrhythmias are commonly encountered in the paediatric intensive care unit setting, most frequently in the setting of postoperative congenital heart disease. Postoperative arrhythmias are an important cause of morbidity in children in the postoperative period following cardiac surgery for congenital cardiac lesions. It is important for all paediatric critical care physicians involved in the care of these children to understand the potential mechanisms involved and how to make an accurate diagnosis. The existing literature has focused on small groups and specific arrhythmias. There is a paucity of literature to guide the clinician in approaching arrhythmias in the paediatric intensive care unit setting. Our objective was to review the recognition and diagnosis of paediatric arrhythmias in the postoperative period following congenital cardiac surgery. Timely and accurate identification of the rhythm disturbance is mandatory and allows for the institution of effective, rhythm specific management strategies. PMID- 19775034 TI - Postoperative analgesia and respiratory events in patients with symptoms of obstructive sleep apnoea. AB - Symptoms of obstructive sleep apnoea are common in patients presenting for surgery and are associated with increased morbidity. Analgesia contributes significantly to postoperative respiratory depression and obstruction, so we compared standard morphine patient-controlled analgesia with an opioid-sparing protocol (tramadol patient-controlled analgesia, parecoxib and rescue-only morphine) in these patients. Sixty-two patients presenting for elective surgery with body mass index > or = 28 and signs or symptoms suggesting obstructive sleep apnoea were randomised to receive either the opioid or opioid-sparing postoperative analgesia protocol, with continuous respiratory monitoring for 12 hours on the first postoperative night. The number of respiratory events (apnoeas and hypopnoeas) and oxygen desaturations were compared. There was no difference between treatment groups in the number of obstructive apnoeas, hypopnoeas or central apnoeas. However, central apnoeas and a rate of respiratory events > 15 per hour were related to postoperative morphine dose (P = 0.005 and P = 0.002). In patients at risk of obstructed breathing, intention to treat with an opioid sparing analgesia protocol did not decrease the rate of respiratory events, although the rate was still related to the total morphine dose. PMID- 19775035 TI - Hypercapnia test and weaning outcome from mechanical ventilation in COPD patients. AB - We evaluated the hypercapnia response test as a weaning outcome predictor from mechanical ventilation in patients with chronic obstructive pulmonary disease (COPD). We studied 44 COPD intubated patients considered ready for a weaning trial. The hypercapnia test was based on the modified method of re-inhalation of expired air Through the hypercapnic test we calculated the ratio of the change in minute volume (V(E)) to the change in PaCO2 (deltaV(E)/deltaPaCO2), the change in airway occlusion pressure at 0.1 second of inspiration (P0.1) to change in PaCO2 (deltaP0.1/deltaPACO2), the ratio of the change in P0.1 to baseline PaCO2 (deltaP0.1/PaCO2) and the ratio of the change in V(E) to baseline PaCO2 (deltaV(E)/PaCO2). Nineteen patients were successfully weaned and 25 patients failed. No differences in baseline clinical characteristics were found between the two groups. Weaning failure COPD patients had lower deltaP0.1/deltaPaCO2 (0.19 +/- 0.11 and 0.34 +/- 0.20 cm H2O/mmHg respectively, P = 0.006) and lower deltaV(E)/deltaPaCO2 (0.21 +/- 0.15 and 0.40 +/- 0.22 l/min/mmHg respectively, P = 0.002) than successfully weaned patients. The area under the receiver operating characteristic curve to discriminate weaning outcome was for the baseline PaCO2 0.81 (95% confidence interval: 0.66 to 0.91), hypercapnic PaCO2 0.76 (0.61 to 0.88), hypercapnic drive response 0.74 (0.59 to 0.86), hypercapnic ventilatory response 0.76 (0.60 to 0.87), deltaP0.1/PaCO2 0.76 (0.60 to 0.87) and for the deltaV(E)/PaCO2 0.81 (0.67 to 0.91). COPD patients with weaning failure have a significantly more blunted response to the hypercapnia response test than weaning success patients. This test could be useful to predict weaning failure patients if the combined values of the hypercapnic drive and hypercapnic ventilatory response were below the threshold values. PMID- 19775036 TI - Non-invasive assessment of the microcirculation in critically ill patients. AB - Sepsis is associated with abnormalities of muscle tissue oxygenation and of microvascular function. We investigated whether the technique of near-infrared spectroscopy can evaluate such abnormalities in critically ill patients and compared near-infrared spectroscopy-derived indices of critically ill patients with those of healthy volunteers. We studied 41 patients (mean age 58 +/- 22 years) and 15 healthy volunteers (mean age 49 +/- 13 years). Patients were classified into one of three groups: systemic inflammatory response syndrome (SIRS) (n = 21), severe sepsis (n = 8) and septic shock (n = 12). Near-infrared spectroscopy was used to continuously measure thenar muscle oxygen saturation before, during and after a three-minute occlusion of the brachial artery via pneumatic cuff. Oxygen saturation was significantly lower in patients with SIRS, severe sepsis or septic shock than in healthy volunteers. Oxygen consumption rate during stagnant ischaemia was significantly lower in patients with SIRS (23.9 +/- 7.7%/minute, P < 0.001), severe sepsis (16.9 +/- 3.4%/minute, P < 0.001) or septic shock (14.8 +/- 6%/minute, P < 0.001) than in healthy volunteers (35.5 +/- 10.6%/minute). Furthermore, oxygen consumption rate was significantly lower in patients with septic shock than patients with SIRS. Reperfusion rate was significantly lower in patients with SIRS (336 +/- 141%/minute, P < 0.001), severe sepsis (257 +/- 150%/minute, P < 0.001) or septic shock (146 +/- 101%/minute, P < 0.001) than in healthy volunteers (713 +/- 223%/minute) and significantly lower in the septic shock than in the SIRS group. Near-infrared spectroscopy can detect tissue oxygenation deficits and impaired microvascular reactivity in critically ill patients, as well as discriminate among groups with different disease severity. PMID- 19775037 TI - Inflammation, vitamin deficiencies and organ failure in critically ill patients. AB - It is unknown whether biochemical vitamin deficiencies in critical illness are associated with severity of illness, organ dysfunction, inflammation or mortality. This nested cohort study recruited 98 patients admitted as emergencies to the intensive care unit, who had a stay of greater than 48 hours. Patient data were prospectively collected. Within the first 48 hours of admission, concentrations of C-reactive protein, vitamins A, E, B1, B12 and folate were measured on arterial blood. These measures were then repeated at least once during the later (> 48 hours) period of their stay. Seventy patients (71%) had completed vitamin studies eligible for inclusion in the analysis. Ten patients died (14.3%) during their hospital stay and mortality was associated with age, admission source and severity of illness scores. Vitamin B12 concentration was weakly associated with C-reactive protein concentrations on admission to the intensive care unit (r on days one and two = 0.4 [P = 0.002], 0.36 [P = 0.04], respectively) and with the Sequential Organ Failure Assessment score between days two and four (Spearman's r = 0.361 [P = 0.04], 0.42 [P = 0.02] and 0.48 [P = 0.02], respectively). Vitamin A concentration was weakly associated with the C reactive protein concentrations on days one and five (Spearman's r = -0.5 [P = 0.001], -0.4 [P = 0.03], respectively). Change in deficiency status of any of the vitamins over time in the first week of intensive care admission did not appear to influence mortality. We conclude that while weak correlations were identified between vitamins A and B12 and C-reactive protein and Sequential Organ Failure Assessment scores, the importance of these associations and their relationship to hospital mortality remain to be determined. PMID- 19775038 TI - Incidence and risk factors for chronic pain after caesarean section under spinal anaesthesia. AB - This study investigated the incidence and risk factors associated with chronic pain after elective caesarean section under spinal anaesthesia in an Asian population. A prospective cohort study was conducted among subjects who underwent elective caesarean section under spinal anaesthesia, with morphine patient controlled analgesia administered for 24 hours postoperatively. Perioperative, surgical and obstetric factors were investigated prospectively. Phone surveys were conducted to identify risk factors associated with chronic pain. A total of 857 subjects completed both the perioperative study and phone survey. The incidence of wound scar pain for three months after surgery was 9.2% (79). Of the 51 subjects with persistent pain at the time of subsequent survey, 9.8% (n = 5) had constant pain, 9.8% (n = 5) had daily pain and 23.5% (n = 12) had pain intermittently, at an interval of days. The independent risk factors for development of chronic pain were higher pain scores recalled in the immediate postoperative period (odds ratio [OR, 95% confidence interval] 1.348 [1.219 to 1.490], P = 0.0001), pain present elsewhere (OR 2.471 [1.485 to 4.112], P = 0.001) and non-private insurance status (OR 1.679 [1.034 to 2.727], P = 0.036). The two most common sites of pain other than wound pain were back pain (n = 316) and migraine (n = 87). PMID- 19775039 TI - An intraoperative pre-incision single dose of intravenous ketamine does not have an effect on postoperative analgesic requirements under clinical conditions. AB - Evidence about the effectiveness of the N-methyl-D-aspartate antagonist ketamine to reduce postoperative acute and long-lasting pain is inconclusive. The aim of this study was to investigate effects of adding an intraoperative, pre-incision single intravenous dose of ketamine to a routine anaesthesia regimen on postoperative analgesic requirements, side-effects and persisting pain up to three months. After obtaining Ethical Committee approval and written informed patient consent, 120 patients were included in this prospective, randomised, double-blinded, placebo-controlled study. Patients were randomised into three groups, receiving 0.15 mg/kg ketamine intravenously, 0.5 mg/kg ketamine intravenously or normal saline in groups low-dose ketamine, moderate-dose ketamine and placebo, respectively. Anaesthesia maintenance, intraoperative pain management and postoperative pain therapy were standardised. The primary study endpoint was consumption of morphine during the first 24 hours after surgery. Three months after surgery, pain scores were assessed. Data were compared by t test and Kruskall-Wallis test with alpha = 0.05. There was no difference between the groups in the assessed variables. These findings indicate that with the anaesthesia regimen described, and in the doses used, a single intravenous dose of ketamine does not reduce postoperative analgesic requirement or postoperative pain at three months. PMID- 19775040 TI - Ambulatory continuous femoral analgesia for major knee surgery: a randomised study of ultrasound-guided femoral catheter placement. AB - Needle-nerve stimulation has a false negative motor response rate, which may increase needle passes. This prospective, randomised study tested the hypothesis that femoral nerve catheters placed with ultrasound-only guidance could provide comparable postoperative analgesia to those placed using a conventional nerve stimulation endpoint. Patients presenting for major knee surgery to the lead investigator were recruited. Needles introduced for femoral nerve catheter placement were initially guided with 'oblique' out-of-plane ultrasound imaging but were then prospectively randomised to either an ultrasound (n = 21) or nerve stimulation (n = 24) endpoint. An elastomeric infusion of ropivacaine 0.2% 2 ml/hour with as required hourly 5 ml boluses was continued for > 48 hours in hospital and/or in the home. Needle time under the skin and numerical rating pain score during insertion were recorded. Patients were questioned for worst numerical rating pain score, the need for supplementary ropivacaine boluses and tramadol on postoperative days one and two. There was no difference in the worst numerical rating pain score at rest and on movement and the requirement for supplementary ropivacaine boluses or tramadol during the first 48 postoperative hours. The median (quartiles) needle time under the skin was 58 seconds (51 to 76) in the ultrasound group and 120 seconds (95 to 178) in the nerve stimulation group (P = 0.001). The median (quartiles) insertion numerical rating pain score was 2 (0 to 2) in the ultrasound group and 4 (2 to 6) in the nerve stimulation group (P = 0.014). Femoral nerve catheters placed for major knee surgery using an ultrasound endpoint provided postoperative analgesia comparable to that obtained when using a nerve stimulation endpoint and were associated with a reduction in both needle manipulations and procedure-related pain. PMID- 19775041 TI - Effect of pump prime on acidosis, strong-ion-difference and unmeasured ions during cardiopulmonary bypass. AB - We tested the hypothesis that a cardiopulmonary bypass prime with lactate would be associated with less acidosis than a prime with only chloride anions because of differences in the measured strong-ion-difference. We randomised 20 patients to a 1500 ml bypass prime with either a chloride-only solution (Ringer's Injection; anions: chloride 152 mmol/l) or a lactated solution (Hartmann's solution; anions: chloride 109 mmol/l, lactate 29 mmol/l). Arterial blood was sampled before bypass and then two, five, 15 and 30 minutes after initiating bypass. We used repeated measures analysis of variance to compare groups. In both groups, the base-excess and measured strong-ion-difference decreased markedly from baseline after two minutes of bypass. The chloride-only group had greater acidosis with lower base-excess and pH (P < 0.05), greatest after five minutes of bypass (C5). Contrary to our hypothesis, however, the difference between the groups was not due to a difference in the measured strong-ion-difference, P = 0.88. At C5 when the difference in standard base-excess between the groups was greatest, 1.9 mmol/l (95% confidence interval: 0.1 to 3.6 mmol/l, P < 0.05), the difference in the measured strong-ion-difference was only 0.2 mmol/l (95% confidence interval: -2.4 to 2.7 mmol/l, P > 0.05). There was, however a difference in the net-unmeasured-ions (strong-ion-gap). We conclude that acid base changes with cardiopulmonary bypass may differ with the prime but that the early differences between chloride-only and lactated primes appear not to be due to differences in the measured strong-ion-difference. We suggest future studies examine other possible mechanisms including unmeasured ions. PMID- 19775042 TI - Mortality and cost outcomes of elderly trauma patients admitted to intensive care and the general wards of an Australian tertiary referral hospital. AB - Mortality and cost outcomes of elderly intensive care unit (ICU) trauma patients were characterised in a retrospective cohort study from an Australian tertiary ICU Trauma patients admitted between January 2000 and December 2005 were grouped into three major age categories: aged > or =65 years admitted into ICU (n = 272); aged -65 years admitted into general ward (n = 610) and aged < 65 years admitted into ICU (n = 1617). Hospital mortality predictors were characterised as odds ratios (OR) using logistic regression. The impact of predictor variables on (log) total hospital-stay costs was determined using least squares regression. An alternate treatment-effects regression model estimated the mortality cost-effect as an endogenous variable. Mortality predictors (P < or = 0.0001, comparator: ICU > or = 65 years, ventilated) were: ICU < 65 not-ventilated (OR 0.014); ICU < 65 ventilated (OR 0.090); ICU age > or = 65 not-ventilated (OR 0.061) and ward > or = 65 (OR 0.086); increasing injury severity score and increased Charlson comorbidity index of 1 and 2, compared with zero (OR 2.21 [1.40 to 3.48] and OR 2.57 [1.45 to 4.55]). The raw mean daily ICU and hospital costs in A$ 2005 (US$) for age < 65 and > or = 65 to ICU, and > or = 65 to the ward were; for year 2000: ICU, $2717 (1462) and $2777 (1494); hospital, $1837 (988) and $1590 (855); ward $933 (502); for year 2005: ICU, $3202 (2393) and $3086 (2307); hospital, $1938 (1449) and $1914 (1431); ward $1180 (882). Cost increments were predicted by age < or = 65 and ICU admission, increasing injury severity score, mechanical ventilation, Charlson comorbidity index increments and hospital survival. Mortality cost-effect was estimated at -63% by least squares regression and -82% by treatment-effects regression model. Patient demographic factors, injury severity and its consequences predict both cost and survival in trauma. The cost mortality effect was biased upwards by conventional least squares regression estimation. PMID- 19775043 TI - The performance of customised APACHE II and SAPS II in predicting mortality of mixed critically ill patients in a Thai medical intensive care unit. AB - The aim of this study was to evaluate and compare the performance of customised Acute Physiology and Chronic Health Evaluation HII (APACHE II) and Simplified Acute Physiology Score HII (SAPS II) in predicting hospital mortality of mixed critically ill Thai patients in a medical intensive care unit. A prospective cohort study was conducted over a four-year period. The subjects were randomly divided into calibration and validation groups. Logistic regression analysis was used for customisation. The performance of the scores was evaluated by the discrimination, calibration and overall fit in the overall group and across subgroups in the validation group. Two thousand and forty consecutive intensive care unit admissions during the study period were split into two groups. Both customised models showed excellent discrimination. The area under the receiver operating characteristic curve of the customised APACHE II was greater than the customised SAPS II (0.925 and 0.892, P < 0.001). Hosmer-Lemeshow goodness-of-fit showed good calibration for the customised APACHE II in overall populations and various subgroups but insufficient calibration for the customised SAPS II. The customised SAPS II showed good calibration in only the younger, postoperative and sepsis patients subgroups. The overall performance of the customised APACHE II was better than the customised SAPS II (Brier score 0.089 and 0.109, respectively). Our results indicate that the customised APACHE II shows better performance than the customised SAPS II in predicting hospital mortality and could be used to predict mortality and quality assessment in our unit or other intensive care units with a similar case mix. PMID- 19775044 TI - The influence of gender and experience on intubation ability and technique: a manikin study. AB - Female anaesthetists in early training commonly question whether their strength is adequate for tracheal intubation. This study investigated the influence of gender and experience on intubation ability and laryngoscopic technique. A manikin model and purpose-designed force-transducing laryngoscope was used to test three cohorts at different levels of experience (novice, intermediate and experienced males and females, n = 65) for the axial force and torque exerted, best laryngoscopic view obtained, success with and time for intubation and laryngoscopic technique. There were no significant differences between novice or experienced female and male intubators in markers of their ability to intubate or in the forces generated. For novice females compared with novice males, mean success rate was 90% (80.2 to 99.9) versus 97% (91.1 to 100, P = 0.29); and mean time to intubate 24 seconds (19 to 29 seconds) versus 18 seconds (14 to 21 seconds, P = 0.057). With experience, the forces generated during intubation reduced and ability improved. Proximal laryngoscope grips (close to the blade) generated lower forces than distal grips. Female and male intubators did not differ in ability to intubate or in the forces they exerted during direct laryngoscopy. PMID- 19775045 TI - The functional outcome and recovery of patients admitted to an intensive care unit following drug overdose: a follow-up study. AB - Patients who have overdosed on drugs commonly present to emergency departments, with only the most severe cases requiring intensive care unit (ICU) admission. Such patients typically survive hospitalisation. We studied their longer term functional outcomes and recovery patterns which have not been well described. All patients admitted to the 18-bed ICU of a university-affiliated teaching hospital following drug overdoses between 1 January 2004 and 31 December 2006 were identified. With ethical approval, we evaluated the functional outcome and recovery patterns of the surviving patients 31 months after presentation, by telephone or personal interview. These were recorded as Glasgow outcome score, Karnofsky performance index and present work status. During the three years studied, 43 patients were identified as being admitted to our ICU because of an overdose. The average age was 34 years, 72% were male and the mean APACHE II score was 16.7. Of these, 32 were discharged from hospital alive. Follow-up data was attained on all of them. At a median of 31 months follow-up, a further eight had died. Of the 24 surviving there were 13 unemployed, seven employed and four in custody. The median Glasgow outcome score of survivors was 4.5, their Karnofsky score 80. Admission to ICU for treatment of overdose is associated with a very high risk of death in both the short- and long-term. While excellent functional recovery is achievable, 16% of survivors were held in custody and 54% unemployed. PMID- 19775046 TI - Comparison between the effects of propofol and etomidate on motor and electroencephalogram seizure duration during electroconvulsive therapy. AB - An ideal anaesthetic for electroconvulsive therapy (ECT) should have rapid onset and offset with no effect on seizure duration, and provide cardiovascular stability during the procedure. Propofol is commonly used, even though it has been shown to shorten seizure duration which might affect the efficacy of ECT Etomidate has been advocated as an alternative. This prospective, randomised, single-blind, crossover study was conducted to compare the effects of etomidate (Etomidate-Lipuro, B. Braun Ltd, Melsungen, Germany) and propofol (Diprivan, AstraZeneca, UK) on seizure duration as well as haemodynamic parameters in patients undergoing ECT Twenty patients aged between 18 and 70 years were recruited. Group I received etomidate 0.3 mg/kg for the first course of ECT (Group IA) and propofol 1.5 mg/kg for the second ECT (Group IB), while Group II received propofol for the first ECT (Group IIA) and etomidate for the second ECT (Group IIB). There was a washout period of two to three days in between procedures. Parameters recorded included motor seizure duration, electroencephalogram seizure duration, blood pressure and heart rate. Analysis demonstrated neither period effect nor treatment period interaction. Etomidate was associated with a significantly longer motor and electroencephalogram seizure duration compared with propofol (P < 0.01). Neither drug demonstrated consistent effects in suppressing the rise in heart rate or blood pressure during ECT Myoclonus and pain on injection were the most common adverse effects in etomidate group and propofol group respectively. Etomidate is a useful anaesthetic agent for ECT and should be considered in patients with inadequate seizure duration with propofol. PMID- 19775047 TI - Comparison of the single-use LMA supreme with the reusable ProSeal LMA for anaesthesia in gynaecological laparoscopic surgery. AB - The Laryngeal Mask Airway Supreme (LMAS) is a new, single-use laryngeal mask airway with gastric access. We conducted a randomised controlled study comparing the LMAS with the reusable ProSeal Laryngeal Mask Airway (PLMA) in 70 patients undergoing general anaesthesia with paralysis for gynaecological laparoscopic surgery. Our primary outcome measure was the oropharynegal leak pressure. We also compared the two devices for ease of insertion, adequacy of ventilation and incidence of complications. Both devices had similar rates of successful insertion at the first attempt (LMAS 94% vs PLMA 91%). There was no difference in the time to establish an effective airway (LMAS 25 +/- 22 vs PLMA 24 +/- 9 seconds), although gastric tube insertion was faster for the LMAS (5 +/- 1 vs 7 +/- 3 seconds, P < 0.001). The mean oropharyngeal leak pressure in the LMAS was significantly lower than in the PLMA (27.9 +/- 4.7 vs 31.7 +/- 6.3 cmH2O, P = 0.007). This was consistent with a lower maximum tidal volume achieved with the LMAS (481 +/- 76 vs 515 +/- 63 ml, P = 0.044). We found that after 60 minutes the cuff pressure was significantly higher in the PLMA (110 +/- 21 vs 57 +/- 8 cmH2O, P < 0.001). There was no difference in the ability to provide adequate ventilation and oxygenation during anaesthesia. Complication rates were similar We conclude that the oropharyngeal leak pressure and the maximum achievable tidal volume are lower with the LMAS than with the PLMA. PMID- 19775048 TI - An audit of potentially recyclable waste from anaesthetic practice. AB - Little is known about the amount of anaesthesia waste that is recyclable. We tested the hypotheses: 1) that anaesthetists produce a small proportion (< 10%) of total operating suite waste, 2) that much of this waste (> 30%) is recyclable and 3) that there is little (< 10%) cross-contamination of infectious and non infectious waste. For five weekdays in a metropolitan hospital with six operating theatres, we weighed waste and determined the proportion of anaesthesia waste that was recyclable. Waste was routinely divided into general and infectious streams. For safety reasons the infectious waste was considered unavailable for recycling, leaving the general waste as potentially recyclable. Anaesthesia waste (90 kg) was 25% (95% confidence interval: 22 to 29%) of the total 357 kg of operating suite waste. Of 66 kg of general anaesthesia waste, 38 kg was recyclable (58%; 95% confidence interval: 47 to 67%). Most cardboard waste, however was included in the operating suite waste; therefore we under-estimated the total amount of recyclable anaesthesia waste. Of 24 kg of anaesthesia infectious waste, 2 kg (8%) was recyclable. The general waste contained 4 kg (7%; 95% confidence interval: 3 to 13%) of infectious items. No sharps were found. Anaesthesia waste was a quarter of total operating suite waste. Almost 60% of anaesthesia general waste could be recycled. Failure to eliminate infectious waste from general waste could be a barrier to recycling. PMID- 19775049 TI - The ethics of anaesthesia learning curves. AB - While the concept of the 'learning curve' is widely accepted and understood in medical education, the ethical appreciation of what this involves for patients has been under-represented in medical journals. Advances in medical technology have produced an armoury of diagnostic and therapeutic invasive procedures, which must be perfected by anaesthetists for the benefit of patients. Anaesthetic training involves practice using patients, which potentially exposes patients to excess procedural risk. However, such risk can be minimised through close supervision of trainees and the development of non-patient training aids. Most importantly, for training to be ethical, it must involve the patient: it is for patients to decide whether they consent to taking part in training and their consent should always be sought where possible. PMID- 19775050 TI - Continuous venovenous haemodiafiltration for metformin-induced lactic acidosis. AB - A 74-year-old man with cardiac failure and renal impairment was admitted to the cardiothoracic intensive care unit with metformin-induced lactic acidosis and shock. He was successfully treated with high-dose (80 ml/kg/hour) continuous venovenous haemodiafiltration. Lactic acidosis is a known complication of metformin and is associated with a high mortality. The use of high-dose continuous venovenous haemodiafiltration for this condition has not previously been reported. PMID- 19775051 TI - In vivo evaluation of tissue microflow under combined therapy with extracorporeal life support and intra-aortic balloon counterpulsation. AB - Treatment with percutaneous extracorporeal mechanical assist devices provides the ultimate therapeutic option to improve the macrocirculation in patients suffering from refractory cardiac arrest, severe cardiogenic shock or during high-risk interventions. However, the flow in the smallest vessels in these critical periods is poorly understood but prognostically of high importance. Using sidestream darkfield intravitalmicroscopy, we visualised the sublingual microflow in a patient suffering from severe cardiogenic shock supported by extracorporeal membrane oxygenation and intra-aortic balloon pump. Our results show that intra aortic balloon counterpulsation applied in addition to extracorporeal membrane oxygenation further improves the microflow. This in vivo finding supports pilot studies favouring the application of devices supporting cardiac output (extracorporeal membrane oxygenation) together with devices aimed at pulsatility (intra-aortic balloon pump). PMID- 19775052 TI - Takotsubo cardiomyopathy during emergence from general anaesthesia. AB - Takotsubo cardiomyopathy, or stress-induced cardiomyopathy, is a clinical syndrome mimicking acute myocardial infarction. We report a case of a 55-year-old man who developed Takotsubo cardiomyopathy during emergence from general anaesthesia for an elective procedure to remove a spinal cord stimulator The perioperative state is known to induce stress, but there are few cases describing the onset of Takotsubo syndrome during this period. The case presented demonstrates that Takotsubo cardiomyopathy may occur on emergence from anaesthesia and that the pattern of left ventricular dysfunction produced may not be typical. PMID- 19775053 TI - Ruptured hydatid cyst masquerading as tension pneumothorax. AB - We report a 35-year-old man who presented to us with features suggestive of a tension pneumothorax. However insertion of a chest tube did not result in any signs of improvement. Further investigation demonstrated that he had a ruptured hydatid cyst. He underwent an emergency thoractomy and excision of the cyst. Ruptured hydatid cyst should be considered as a possibility in patients who present with sudden onset respiratory distress and hypoxia in geographical areas where the disease may be prevalent. PMID- 19775054 TI - Arytenoid subluxation after a difficult intubation treated successfully with voice therapy. AB - Arytenoid subluxation is a rare laryngeal injury that may follow instrumentation of the airway and present as hoarseness, vocal fatigue, stridor, dysphagia, odynophagia and sore throat. We report the case of an 88-year-old man with type 2 diabetes mellitus who developed this complication during a difficult intubation where a Macintosh laryngoscope and gum elastic bougie were used to facilitate intubation. Previously considered to play a minor role in treatment, voice therapy was used successfully in this patient to correct subluxation of the arytenoid, with prompt resolution of his symptoms. PMID- 19775055 TI - Communication failure in the intensive care unit--learning from a near miss. AB - A 51-year-old female patient with Guillain-Barre syndrome was given three times the intended dose of intravenous human immunoglobulin while admitted to a tertiary intensive care unit. The error went unnoticed for seven hours and appears to have been the result of several successive breakdowns in communication between key staff The patient, fortunately, made a full recovery. This report analyses the communication failure and explores possible ways of avoiding similar occurrences in the future. PMID- 19775056 TI - Fibreoptic intubation under general anaesthesia--a simple method using an endotracheal tube as a conduit. PMID- 19775058 TI - Eternal vigilance "the T-Bag". PMID- 19775057 TI - Analysing day-of-surgery cancellation rates. PMID- 19775059 TI - The use of a bougie to assist the passage of a tracheal tube over a paediatric fibrescope. PMID- 19775060 TI - Mydriasis in a critically ill patient. PMID- 19775061 TI - Transoesophageal ultrasound monitoring of subcapsular splenic haematoma in the intensive care unit. PMID- 19775062 TI - Conscious sedation for difficult intubation in children. PMID- 19775063 TI - Hypoxaemia and persistently increased extravascular lung water in a diffuse bronchioloalveolar carcinoma. PMID- 19775064 TI - Anaphylactic bronchospasm due to propofol. PMID- 19775065 TI - Should serum calcium levels be measured preoperatively in all multiparous, lactating females? PMID- 19775066 TI - Massive pulmonary embolism leading to cardiac arrest after tourniquet deflation following lower limb surgery. PMID- 19775067 TI - Lifestyle factors in deteriorating male reproductive health. AB - Many health problems are related to lifestyle and dietary factors. Increasing trend in reproductive disorders observed in recent years may be associated at least in part with these factors, which are compounded by some of the new emergent life styles. The data available suggests that lifestyle factors such as obesity, tobacco smoking or chewing, alcohol and some of the illicit drugs like cocaine, cannabis etc and exposure to extreme heat, have adverse effects on male reproduction. The data on other factors such as use of mobile phone and stress on reproductive health are inadequate and need detailed study. Lifestyle related diseases could be lowered with modification in diet, living and working environment etc. Sub-fertile and/or normal subjects have some control over their reproductive function by adopting healthy lifestyles to avoid additional complications. PMID- 19775068 TI - Role of different cytokines and seizure susceptibility: a new dimension towards epilepsy research. AB - Epilepsy is a common health problem. Although variety of factors influence the incidence and prevalence of seizures, cytokines are considered to play an important role in seizures. Cytokines are also known to be involved in other neurodegenerative disorders. Proinflammatory cytokines like IL-1, IL-6, TNF-alpha and growth factor vascular endothelial growth factor (VEGF) as well as anti inflammatory cytokine IL-10 and related molecules have been described in CNS and plasma of experimental models of seizures and clinical cases of epilepsy. There are reports suggesting more predispositions to seizures during inflammatory conditions like colitis, pneumonia and rheumatoid arthritis. These inflammatory cytokines and growth factors are also known to have dual roles in affecting seizure susceptibility. It remains to be seen if cytokine modulators can be therapeutically exploited for patients with inflammatory disorder and suffering from epilepsy. PMID- 19775070 TI - Molluscicidal activity of Piper cubeba Linn., Piper longum Linn. and Tribulus terrestris Linn. and their combinations against snail Indoplanorbis exustus Desh. AB - The toxic effect of dried berries powder of P. cubeba, dried fruit powder of P. longum and T. terrestris singly as well as in combination [binary (1:1) and tertiary (1:1:1)] were studied against snail L. exustus. Toxicity of these plant products were time and concentration dependent. Ethanol extracts of these plants were more effective than that of other organic solvents. 96 h LC50 value of column purified fraction of T. terrestris against I. exustus was 9.57 mg/l, where as 96 h LC50 values of column purified fractions of P. longum and P. cubeba were 11.57 mg/l and 10.93 mg/l, respectively. Binary (1:1) combination of P. cubeba (PC) + P. longum (PL) (41.78 mg/l) was more effective than P. cubeba (PC) + T. terrestris (TT) (42.17 mg/l) and P. longum (PL) + T. terrestris (TT) (55.84 mg/l) respectively; while tertiary (1:1:1) combinations of P. cubeba (PC) + T. terrestris (TT) + T. foenum-graecum (TF) (10.67 mg/l) was more effective than rest of the combinations. These plants can be used as potent source of molluscicides against the snail I. exustus. PMID- 19775069 TI - Stem cell-like outgrowths from in vitro fertilized goat blastocysts. AB - With an aim to isolate, culture and characterize goat embryonic stem cell-like cells derived from in vitro fertilized goat blastocysts, slaughterhouse derived goat oocytes were in vitro matured in maturation medium in 5% CO2 air at 38.5 degrees C. Matured oocytes were fertilized in vitro with fresh capacitated spermatozoa. Total 636 (36.5%) cleaved embryos were obtained which were further co-cultured with goat oviductal epithelial cells (GOEC) for 7-10 days. GOEC culture system was better for formation of morula (150; 44.3%) and hatched blastocyst (13; 3.8%) than embryo development medium culture system, [morula (69; 23.1%) and hatched blastocyst (5; 1.6%)]. Out of total blastocysts (48) the primary colonies were formed in 23.3% (7/30) blastocysts, and 66.6% (12/18) of hatched blastocysts. The cells of the inner cell mass (ICM) derived primary colonies were small, aggregated and tightly packed in nature forming embryoid bodies on further subculture. The colonies were stained to see the expression of alkaline phosphatase and positive result was obtained. Goat embryonic stem cell like outgrowths were also characterized for Oct-4 expression and positive result was found. It could be concluded that ICM cells were isolated from in vitro fertilized goat blastocysts and cultured for embryonic stem cell-like cells and expression of alkaline phosphatase and Oct-4 in these cells were positive. PMID- 19775071 TI - Effect of methanolic extract of Pongamia pinnata Linn seed on gastro-duodenal ulceration and mucosal offensive and defensive factors in rats. AB - Pongamia pinnata has been advocated in Ayurveda for the treatment of various inflammatory conditions and dyspepsia. The present work includes initial phytochemical screening and study of ulcer protective and healing effects of methanolic extract of seeds of P. pinnata (PPSM) in rats. Phytochemical tests indicated the presence of flavonoids in PPSM. PPSM when administered orally (po) showed dose-dependent (12.5-50 mg/kg for 5 days) ulcer protective effects against gastric ulcer induced by 2 h cold restraint stress. Optimal effective dose of PPSM (25 mg/kg) showed antiulcerogenic activity against acute gastric ulcers (GU) induced by pylorus ligation and aspirin and duodenal ulcer induced by cysteamine but not against ethanol-induced GU. It healed chronic gastric ulcer induced by acetic acid when given for 5 and 10 days. Further, its effects were studied on various parameters of gastric offensive acid-pepsin secretion, lipid peroxidation (LPO) and nitric oxide (NO) and defensive mucosal factors like mucin secretion and mucosal cell shedding, glycoproteins, proliferation and antioxidants; catalase (CAT), superoxide dismutase (SOD) and glutathione (GSH) levels. PPSM tended to decrease acid output and increased mucin secretion and mucosal glycoproteins, while it decreased gastric mucosal cell shedding without any effect on cell proliferation. PPSM significantly reversed the increase in gastric mucosal LPO, NO and SOD levels caused by CRS near to the normal level while it tended to increase CAT and GSH level decreased by CRS and ethanol respectively. Thus, the ulcer protective effects of PPSM may be attributed to the presence of flavonoids and the actions may be due to its effects both on mucosal offensive and defensive factors. PMID- 19775072 TI - Hepatoprotective effect of Carissa carandas Linn root extract against CCl4 and paracetamol induced hepatic oxidative stress. AB - Oral pre-treatment with ethanolic extract of the roots of C. carandas (ERCC; 100, 200 and 400 mg/kg, po) showed significant hepatoprotective activity against CCl4 and paracetamol induced hepatotoxicity by decreasing the activities of serum marker enzymes, bilirubin and lipid peroxidation, and significant increase in the levels of uric acid, glutathione, super oxide dismutase, catalase and protein in a dose dependent manner, which was confirmed by the decrease in the total weight of the liver and histopathological examination. Data also showed that ERCC possessed strong antioxidant activity, which may probably lead to the promising hepatoprotective activities of C. carandas root extract. These findings therefore supported the traditional belief on hepatoprotective effect of the roots of C. carandas. PMID- 19775073 TI - Immunomodulatory activity of aqueous extract of Achillea wilhelmsii C. Koch in mice. AB - Immunomodulatory activity of aqueous extract of Achillea wilhelmsii (25, 50 and 100 mg/kg body weight for 5 days) was evaluated on body weight, relative organ weight, delayed type of hypersensitivity (DTH) response and haemagglutination titre (HT) in female Swiss albino mice. No significant body weight gain differences were recorded in various groups of animals. Significant increase in relative organ weight of spleen at 100 mg/kg was observed. No elevation in the levels of liver function test (LFT) enzymes and kidney relative weight was observed in tested doses of the plant. The extract of A. wilhelmsii elicited a significant increase in the DTH response at the dose of 100 mg/kg. In the HT test, plant extract showed stimulatory effect in all doses, however this changes were significant at 50 mg/kg. No mortality was occurred in tested doses. Overall, A. wilhelmsii showed a stimulatory effect on both humoral and cellular immune functions in mice. PMID- 19775074 TI - Sequence information, ontogeny and tissue-specific expression of complement component C3 in Indian major carp, Labeo rohita (Hamilton). AB - The complement system is one of the first line of immune defence mechanisms as well as a modifier of acquired immunity. C3 is the central complement component primarily synthesized in liver. The local synthesis of C3 in tissues other than liver may play an important role in local inflammatory processes. The present study aims at looking into ontogeny of C3 in Labeo rohita and its tissue-specific expression that is yet to be explored for Indian carps. Unfertilised eggs, and eggs after 0, 1, 3, 6, 12 h post-fertilization and hatchlings at 24 h, and 3 and 7 days post-fertilization were collected from three brood fish of L. rohita (rohu). Total RNA was extracted from approximately 50 mg of tissue and subjected to RT-PCR using heterologous carp primers to amplify C3 fragment. A product of 155 bp size of rohu C3 was amplified, the deduced amino acid sequence of which had 91.1% similarity to that of Cyprinus carpio C3. C3 mRNA was not detected in unfertilized and 6 h post-fertilised eggs. C3 transcripts were detected 12 h post fertilisation. Similarly, tissues from liver, spleen, kidney, muscle, brain, gonads, intestine, blood, heart and gills collected from juveniles of rohu were subjected to detection of C3 transcripts by RT-PCR and C3 mRNA was detected in all the tissues. Thus, it is concluded that there is extra-hepatic synthesis of complement (C3) in L. rohita and the synthesis of this component occurs only 6 h post-fertilisation. PMID- 19775075 TI - Hybridization between threatened freshwater catfish Mystus gulio (Hamilton & buchanan) and Mystus montanus (Jerdon) by artificial fertilization. AB - Inter-specific hybrids were produced between the threatened catfish species Mystus gulio x Mystus montanus. The differences in percentage of fertilization and hatching between control and interspecies were significant. The survival of hybrid was significantly lower (24.80 +/- 4.3%) when compared to control (95.1 +/ 3.5%). Time difference in yolk absorption by hybrid (73.30 h) was higher than that of control (72 h). When compared to interspecific fertilized egg the hatching time (24-25 h) and viability of larvae of the control were significantly better. In hybrids more deformed hatchlings (52.7 +/- 4.2 %) were noticed than the control (24.80 +/- 4.3%). PMID- 19775076 TI - Carborundum-dependent entrance of EcoRI restriction enzyme into plant cells and specific cleavage of genomic DNA. AB - In a basic research to determine the morpho-molecular interactions of plant tissues with EcoRI DNA restriction enzyme, it was demonstrated that this protein is capable of entering the sunflower and maize leaf cells using a plant tissue abrading material and cleaving the genomic DNA at specific sites. This was inferred from the analysis of morphological patterns of EcoRI-treated leaf areas as well as using some molecular tests, including the cleavage pattern analysis of genomic DNA isolated from treated locations followed by ligation of cleaved fragments into EcoRI site of a DNA cloning vector system. The overall results indicated that the specific restriction of genomic DNA may happen following the entrance of EcoRI protein most likely into the nucleus of plant cells. PMID- 19775077 TI - Comparative biosorption of Pb2+ by live algal consortium and immobilized dead biomass from aqueous solution. AB - The percent removal and uptake of Pb2+ by algal-consortium (CP1) developed from wastewater of biological oxidation pond (Wazirabad, New Delhi, India) was studied under batch conditions with live biomass compared with continuous system using dried biomass immobilized on silica under laboratory conditions. In batch study, algal consortium (CP1) consisting of a mixed culture of Chlorella > Chlamydomonas > Lyngbya sp. was found to remove 17% of Pb2+ after 15 days of incubation from culture media containing 10 mg/L Pb2+, which decreased by increasing metal concentration from 20-50 mg/L. This reduction in removal efficiency was co related with direct toxic effect of Pb2+ on live consortium as indicated by drastic inhibition in growth. A maximum lead uptake capacity (q(max)) of 33.31 mg/g showed good accumulation potential of live consortium. Bioresin derived from the biomass of dried algal consortium immobilized on silica gel and packed in column exhibited 92.5% removal of Pb2+ with inlet Pb2+ concentration of 33.90 mg/L was brought down to minimum 0.375 mg/L of Pb2+ in outlet stream. The plot of outlet concentration to volume exhibited the typical 'S' shape curve with Pb2+ uptake capacity of 15.95 mg/g. Efficient recovery of 86.16% of Pb2+ was achieved by elution with dilute HCl which indicated multiple usability of immobilized biomass. PMID- 19775078 TI - Translation initiation from two in-frame AUGs generates mitochondrial and cytoplasmic forms of the p43 component of the multisynthetase complex. AB - In humans, nine aminoacyl-tRNA synthetases form a stable multiprotein complex with the three auxiliary proteins p18, p38, and p43. The N-terminal moiety of p43 is involved in its anchoring to the complex, and its C-terminal moiety has a potent tRNA binding capacity. The p43 component of the complex is also the precursor of p43(ARF), an apoptosis-released factor, and of p43(EMAPII), the endothelial-monocyte activating polypeptide II. Here we identified a new translation product of the gene of p43, which contains nine additional N-terminal amino acid residues. This gene product is targeted to the mitochondria and accounts for 2% of p43 expressed in human cells. The cytoplasmic and mitochondrial species of p43 are produced from the same mRNA by a mechanism of leaky scanning of the AUG codon at position -27, which is in an unfavorable sequence context for translation initiation. The finding that a mitochondrial species of p43 exists in human cells further exemplifies the multifaceted implications of p43 and opens new perspectives for the understanding of the role of p43 in the apoptotic cell. PMID- 19775079 TI - Molecularly imprinted microgels as enzyme inhibitors. AB - We demonstrate, on the example of trypsin, the use of water-soluble molecularly imprinted polymer microgels as specific enzyme inhibitors. Using a strong anchoring monomer, methacryloylaminobenzamidine, the growing polymer chains are confined to close proximity of the substrate recognition site of our model enzyme. The microgels bind selectively trypsin over other proteins of similar size and molecular weight, and show competitive inhibition of trypsin with an inhibition constant K(i) of 79 nM, making them more potent inhibitors than the low molecular-weight competitive inhibitor benzamidine by almost 3 orders of magnitude. We believe that these tailor-made materials with biological activity have potential for future drug development that extends beyond enzyme inhibition. PMID- 19775080 TI - Group-4 transition-metal boryl complexes: syntheses, structures, boron-metal bonding properties, and application as a polymerization catalyst. AB - Two group-4 boryl complexes, boryltitanium 2 and borylhafnium 3, were synthesized via nucleophilic borylation using boryllithium 1. Complexes 2 and 3 are the first examples of group-4 borylmetals. Theoretical calculations on model molecules 5 and 6 indicated that the boron-metal bond in both complexes has a covalent character. Complex 3 has activity for polymerization of ethylene or hex-1-ene. PMID- 19775082 TI - Conductance enhancement in nanographene-gold junctions by molecular pi-stacking. AB - First-principles calculations on gold-pentacene-gold and several gold-circumacene gold nanojunctions indicate that their low-bias conductance is due to the onset of a HOMO-derived resonance, thus being quite sensitive to the detailed interaction between the molecule and the gold leads. It is also found that such interaction is dominated by the electrophilic binding of Au to the (circum)acene, in agreement with previous theoretical and experimental results on pentacene. Therefore, the alignment of the HOMO resonance with the Fermi level, and thus the conductance, increases as the ionization potential and the HOMO-LUMO gap of the molecular arrangement diminish. It is shown here that both quantities are inversely proportional to the molecular length and the number of molecules present on a pi stack. It is also found that the conductance depends dramatically on the amount of pi overlap between the molecules in the stack, as well as on the particular disposition of the metallic tips with respect to the molecule. The conclusions reached point toward pi-stacked arrangements of large circumacenes as potential candidates to build useful nanodevices for molecular electronics made out of nanographene-based materials. PMID- 19775083 TI - Mass sensing based on deterministic and stochastic responses of elastically coupled nanocantilevers. AB - Coupled nanomechanical systems and their entangled eigenstates offer unique opportunities for the detection of ultrasmall masses. In this paper we show theoretically and experimentally that the stochastic and deterministic responses of a pair of coupled nanocantilevers provide different and complementary information about the added mass of an analyte and its location. This method allows the sensitive detection of minute quantities of mass even in the presence of large initial differences in the active masses of the two cantilevers. Finally, we show the fundamental limits in mass detection of this sensing paradigm. PMID- 19775081 TI - Chemistry of personalized solar energy. AB - Personalized energy (PE) is a transformative idea that provides a new modality for the planet's energy future. By providing solar energy to the individual, an energy supply becomes secure and available to people of both legacy and nonlegacy worlds and minimally contributes to an increase in the anthropogenic level of carbon dioxide. Because PE will be possible only if solar energy is available 24 h a day, 7 days a week, the key enabler for solar PE is an inexpensive storage mechanism. HY (Y = halide or OH(-)) splitting is a fuel-forming reaction of sufficient energy density for large-scale solar storage, but the reaction relies on chemical transformations that are not understood at the most basic science level. Critical among these are multielectron transfers that are proton-coupled and involve the activation of bonds in energy-poor substrates. The chemistry of these three italicized areas is developed, and from this platform, discovery paths leading to new hydrohalic acid- and water-splitting catalysts are delineated. The latter water-splitting catalyst captures many of the functional elements of photosynthesis. In doing so, a highly manufacturable and inexpensive method for solar PE storage has been discovered. PMID- 19775084 TI - Ordered mesoporous metallic MoO2 materials with highly reversible lithium storage capacity. AB - Highly ordered mesoporous crystalline MoO(2) materials with bicontinuous Ia3d mesostructure were synthesized by using phosphomolybdic acid as a precursor and mesoporous silica KIT-6 as a hard template in a 10% H(2) atmosphere via nanocasting strategy. The prepared mesoporous MoO(2) material shows a typical metallic conductivity with a low resistivity ( approximately 0.01Omega cm at 300 K), which makes it different from all previously reported mesoporous metal oxides materials. Primary test found that mesoporous MoO(2) material exhibits a reversible electrochemical lithium storage capacity as high as 750 mA h g(-1) at C/20 after 30 cycles, rendering it as a promising anode material for lithium ion batteries. PMID- 19775085 TI - Electrospray ion beam deposition: soft-landing and fragmentation of functional molecules at solid surfaces. AB - The ion beam deposition (IBD) of rhodamine dye molecules on solid surfaces in high vacuum is explored in order to characterize the possibility of fabricating molecular coatings or nanostructures from nonvolatile molecules. Molecular ion beams with a well-defined composition are deposited on silicon oxide surfaces with a controlled kinetic energy. Photoluminescence spectroscopy and time-of flight secondary ion mass spectrometry (TOF-SIMS) are employed in order to characterize the sample with respect to coverage, homogeneity, and the fraction of intact landed ions (soft-landing ratio). We find that homogeneous rhodamine films of defined composition can be produced at energies of 2-100 eV. The coverage is found to be proportional to the ion dose. Soft-landing is observed for energies up to 35 eV. PMID- 19775086 TI - Organic reactions in water: a distinct novel approach for an efficient synthesis of alpha-amino phosphonates starting directly from nitro compounds. AB - A distinct approach for high-yielding synthesis of alpha-amino phosphonates has been discovered through three-component reaction of nitro compounds, aldehydes, or ketones and dialkyl or trialkyl phosphites using indium in dilute aqueous HCl at room temperature. This one-pot conversion consists of the following steps: (i) reduction of nitro compounds to amines, (ii) formation of imines from amines and carbonyl compounds, and (iii) hydrophosphonylation of imines. PMID- 19775087 TI - Intramolecular electron arrangement with a rotative trigger. AB - We have constructed a single molecule system, consisting of a ferrocene-tethered copper complex, in which electron transfer between redox centers is triggered by molecular rotational motion. In the compound, an asymmetric methyl-substituted 2,2'-pyridylpyrimidine ligand, tethered to the ferrocene moiety, has two isomeric ring-inversion coordination conformations around the copper center. Both isomeric structures were characterized by X-ray crystallography. (1)H NMR and electrochemical measurements revealed that these isomers interconvert through rotation of the pyrimidine at room temperature, but the process is frozen below 233 K in the solution state. The two isomers undergo different redox processes, and the identity of the first oxidation center alternates between the copper center and ferrocene, as confirmed by chemical oxidation monitored by EPR and UV vis absorption spectroscopy. Oxidation of the compound causes spontaneous isomerization of the pyrimidine due to the different relative stabilities of the isomers in the monovalent and divalent states. Oxidation in the motionless state at low temperatures extracts the first electron from the ferrocene center. When molecular motion is released by warming, the electron moves from the copper center to the ferrocene, leading to an enhancement of the copper(II) signal in the EPR spectrum. The synchronized motion/electron migration process was observed as a one-step UV-vis absorption spectral conversion. PMID- 19775088 TI - Assembly of substituted 1H-benzimidazoles and 1,3-dihydrobenzimidazol-2-ones via CuI/L-proline catalyzed coupling of aqueous ammonia with 2-iodoacetanilides and 2 iodophenylcarbamates. AB - CuI/l-proline catalyzed coupling of aqueous ammonia with 2-iodoacetanilides and 2 iodophenylcarbamates affords the aryl amination products at room temperature, which undergo in situ additive cyclization under acidic conditions or heating to give substituted 1H-benzimidazoles and 1,3-dihydrobenzimidazol-2-ones, respectively. A wide range of functional groups including ketone, nitro, iodo, bromo, and ester are tolerated under these reaction conditions, providing these heterocycles with great diversity. PMID- 19775089 TI - Functionalization of unactivated alkenes through iridium-catalyzed borylation of carbon-hydrogen bonds. Mechanism and synthetic applications. AB - This paper describes an efficient carbon-carbon bond formation reaction, which is based on carbon-hydrogen bond functionalization of unactivated alkenes. This process is based on in situ generation of allylic and vinylic boronates by iridium-catalyzed borylation of alkenes followed by carbon-carbon bond formation reactions. The selectivity of the carbon-hydrogen bond functionalization can be efficiently controlled for cyclic alkenes. By using additives, such as methylimidazole and DBU, the iridium-catalyzed borylation led to formation of allyl boronates, which reacted with aldehydes in a one-pot sequence affording stereodefined homoallylic alcohols. Cycloalkenes without additives as well as acyclic substrates gave vinylic boronates, which were coupled with organohalides in a Suzuki-Miyaura sequence. By this process allylic and vinylic silabutadiene derivatives can be prepared from allylsilanes with excellent regio- and stereoselectivity. The mechanism of the carbon-hydrogen bond functionalization based on the borylation reaction was explored by isotope labeling experiments, measuring the kinetic isotope effect and study of the effects of the additives on the selectivity of the process. It was concluded that the reactions proceed via a dehydrogenative borylation mechanism, which shows analogous features with the palladium-catalyzed Heck coupling reaction. PMID- 19775090 TI - Rhodium and iridium amido complexes supported by silyl pincer ligation: ammonia N H bond activation by a [PSiP]Ir complex. AB - Ir silyl pincer complexes insert into the N-H bonds of anilines and ammonia under mild conditions to form isolable [Cy-PSiP]Ir(H)(NHR) complexes that are resistant to N-H bond reductive elimination at room temperature, even in the presence of arenes, alkenes, and phosphines. PMID- 19775091 TI - Human liver microsomal metabolism of (+)-discodermolide. AB - The polyketide natural product (+)-discodermolide is a potent microtubule stabilizer that has generated considerable interest in its synthetic, medicinal, and biological chemistry. It progressed to early clinical oncology trials, where it showed some efficacy in terms of disease stabilization but also some indications of causing pneumotoxicity. Remarkably, there are no reports of its metabolism. Here, we examined its fate in mixed human liver microsomes. Due to limited availability of the agent, we chose a nanoflow liquid chromatography electrospray ionization-mass spectrometry analytical approach employing quadrupolar ion trap and quadrupole-quadrupole-time-of-flight instruments for these studies. (+)-Discodermolide was rapidly converted to eight metabolites, with the left-side lactone (net oxidation) and the right-side diene (epoxidation followed by hydrolysis, along with an oxygen insertion product) being the most metabolically labile sites. Other sites of metabolism were the allylic and pendant methyl moieties in the C12-C14 region of the molecule. The results provide information on the metabolic soft spots of the molecule and can be used in further medicinal chemistry efforts to optimize discodermolide analogues. PMID- 19775092 TI - Monoterpenoid indole alkaloids from Alstonia yunnanensis. AB - Eight new monoterpenoid indole alkaloids, alstoyunines A-H (1-8), along with 17 known analogues, were isolated from Alstonia yunnanensis. The structures of the new alkaloids were established by means of extensive spectroscopic methods. Alstoyunines C (3), E (5), and F (6) showed selective inhibition of Cox-2 (>75%). Alstoyunine F (6) showed weak cytotoxicity against the human myeloid leukemia HL 60 (IC50 = 3.89 microM) and hepatocellular carcinoma SMMC-7721 (IC50 = 21.73 microM) cell lines. PMID- 19775094 TI - Interfacial tension oscillations without surfactant transfer. AB - The dynamic interfacial tension oscillations of different frequency and amplitude were observed by using a pendant drop method for tetraoctyl-, tetradodecyl-, tetrahexadecyl-, and tetraoctadecylammonium bromides at a nitrobenzene/water interface. Despite surfactant mass transfer from the nitrobenzene to the aqueous phase being negligible for these lipophilic derivatives, the oscillations were often accompanied by clouding of the organic phase in the vicinity of the interface. A possible mechanism of the observed phenomena is discussed in relation to spontaneous emulsification at the liquid-liquid interface. PMID- 19775093 TI - Total synthesis and stereochemical assignment of (-)-ushikulide A. AB - We report the determination of the full stereostructure of (-)-ushikulide A (1), a spiroketal containing macrolide by total synthesis. Ushikulide A (1) was isolated from a culture broth of Streptomyces sp. IUK-102 and exhibits potent immunosuppressant activity (IC(50) = 70 nM). To embark upon an ushikulide A synthesis, a tentative assignment was made based on analogy to cytovaricin (2), a related macrolide isolated from a culture of Streptomyces diastatochromogenes whose full structure was previously established via synthesis and X-ray crystallography. This report delineates studies on several key steps, namely a direct aldol reaction catalyzed by the dinuclear zinc ProPhenol complex, a metal catalyzed spiroketalization, as well as application of an unprecedented asymmetric alkynylation of a simple saturated aldehyde with methyl propiolate to prepare the nucleophilic partner for a Marshall-Tamaru propargylation. These studies culminated in the first total synthesis and stereochemical assignment of (-)-ushikulide A and significantly extended the scope of the above-mentioned methodologies. PMID- 19775095 TI - Seeing through macromolecules: T2-filtered NMR for the purity assay of functionalized nanosystems and the screening of biofluids. AB - For samples whose NMR spectra are dominated by the broad signals of macromolecules or functionalized nanoparticles, transverse relaxation (T(2)) spectral editing lends itself to a precise identification and determination of small molecules such as metabolites or contaminants. In order to retain the most sensitivity, we propose a method for efficiently removing the interference of spin-spin couplings that typically lead to signal losses in standard pulse schemes designed for T(2) editing. PMID- 19775096 TI - Coarse-grained molecular dynamics simulation of the aggregation properties of multiheaded cationic surfactants in water. AB - The aggregation property of multiheaded surfactants has been investigated by constant pressure molecular dynamics (MD) simulation in aqueous medium. The model multiheaded surfactants contain more than one headgroup (x = 2, 3, and 4) for a single tail group. This increases the hydrophilic charge progressively over the hydrophobic tail which has dramatic consequences in the aggregation behavior. In particular, we have looked at the change in the aggregation property such as critical micellar concentration (cmc), aggregation number, and size of the micelles for the multiheaded surfactants in water. We find with increasing number of headgroups of the multiheaded surfactants that the cmc values increase and the aggregation numbers as well as the size of the micelles decrease. These trends are in agreement with the experimental findings as reported earlier with x = 1, 2, and 3. We also predict the aggregation properties of multiheaded surfactant with four headgroups (x = 4) for which no experimental studies exist yet. PMID- 19775097 TI - A highly active catalyst for Huisgen 1,3-dipolar cycloadditions based on the tris(triazolyl)methanol-Cu(I) structure. AB - A new tris(1-benzyl-1H-1,2,3-triazol-4-yl)methanol ligand 3 has been prepared by a triple Cu(I)-catalyzed alkyne-azide 1,3-dipolar cycloaddition (CuAAC). Ligand 3 forms a stable complex with CuCl, which catalyzes the Huisgen 1,3-dipolar cycloaddition on water or under neat conditions. Low catalyst loadings, short reaction times at room temperature, and compatibility with free amino groups make 3.CuCl an outstanding catalyst for CuAAC. PMID- 19775098 TI - Two-port transmission line technique for dielectric property characterization of polymer electrolyte membranes. AB - Performance improvements of perfluorosulfonic acid membranes, such as Nafion and Flemion, underline a need for dielectric characterization of these materials toward a quantitative understanding of the dynamics of water molecules and protons within the membranes. In this Article, a two-port transmission line technique for measuring the complex permittivity spectra of polymeric electrolytes in the microwave region is described, and the algorithms for permittivity determination are presented. The technique is experimentally validated with liquid water and polytertrafluoroethylene film, whose dielectric properties are well-known. Further, the permittivity spectra of dry and hydrated Flemion SH150 membranes are measured and compared to those of Nafion 117. Two water relaxation modes are observed in the microwave region (0.045-26 GHz) at 25 degrees C. The higher-frequency process observed is identified as the cooperative relaxation of bulk-like water, whose amount was found to increase linearly with water content in the polymer. The lower-frequency process, characterized by longer relaxation times in the range of 20-70 ps, is attributed to water molecules that are loosely bound to sulfonate groups. The loosely bound water amount was found to increase with hydration level at low water content and levels off at higher water contents. Flemion SH150, which has an equivalent weight of 909 g/equiv, displays higher dielectric strengths for both of these water modes as compared to Nafion 117 (equivalent weight of 1100 g/equiv), which probably reflects the effect of equivalent weight on the polymers' hydrated structure, and in particular its effect on the extended ionic cluster domains. PMID- 19775099 TI - Design, synthesis, biological evaluation, and NMR studies of a new series of arylsulfones as selective and potent matrix metalloproteinase-12 inhibitors. AB - Overexpression of macrophage elastase (MMP-12), a member of the matrix metalloproteinases family, can be linked to tissue remodeling and degradation in some inflammatory processes, such as chronic obstructive pulmonary disease (COPD), emphysema, rheumatoid arthritis (RA), and atherosclerosis. On this basis, MMP-12 can be considered an attractive target for studying selective inhibitors that are useful in the development of new therapies for COPD and other inflammatory diseases. We report herein the design, synthesis, and in vitro evaluation of a new series of compounds, possessing an arylsulfonyl scaffold, for their potential as selective inhibitors of MMP-12. The best compound in the series showed an IC50 value of 0.2 nM, with good selectivity over MMP-1 and MMP 14. A docking study was carried out on this compound in order to investigate its binding interactions with MMP-12, and NMR studies on the complex with the MMP-12 catalytic domain were able to validate the proposed binding mode. PMID- 19775100 TI - Amino acid catalyzed bulk-phase gelation of organoalkoxysilanes via a transient co-operative self-assembly. AB - We report acceleration in the rate of bulk phase gelation of an organoalkoxysilane, 3-methacryloxypropyltrimethoxysilane (MAPTMS), in the presence of an amphiphilic additive, N-phenyl glycine (NPG). The MAPTMS gelation occurs within 30 min in the presence of 0.5 wt % NPG, which took several months in the absence of NPG. Using a combination of ATR-FT IR, (29)Si NMR, (1)H NMR, viscosity analysis, SEM, UV-vis, and pi-A isotherm measurements, we elucidate the molecular-level details of the structural changes during NPG-catalyzed MPTMS gelation rate. On the basis of these results, we propose a gelation mechanism in which a transient cooperative self-assembly process fosters hydrolysis and retards early condensation thereby promoting the formation of extended three dimensionally cross-linked gels. Specifically, the amphiphilic character of the hydrolysis product of MAPTMS, consisting of a hydrophobic tail R = CH(2)CH(2)CH(2)O(CO)C(CH(3)) horizontal lineCH(2) and a hydrophilic Si-OH headgroup, promotes micelle formation at high MAPTMS/water ratio. NPG readily inserts within these micelles thus retarding the topotactic condensation of silanols at the micellar surface. This in turn allows for a more complete hydrolysis of Si-OCH(3) groups prior to condensation in MAPTMS. With increased silanol concentration at the micellar periphery, a delayed condensation phase initiates. This formation of a covalently bonded Si-O-Si framework (and possibly also the formation of the methanol byproduct) likely destabilizes the micellar motif thus promoting its transformation into condensed mesophases (e.g., lamellar microstructure) upon gelation. Because of the generality of this transient and co operative organic-inorganic self-assembly between hydrolyzed amphiphilic organoalkoxysilanes and surfactant-like amino acid additives, we envisage applications in controlling bulk phase gelation of many chain-substituted organoalkoxysilanes. PMID- 19775101 TI - General theoretical/computational tool for interpreting NMR spin relaxation in proteins. AB - We developed in recent years the slowly relaxing local structure (SRLS) approach for analyzing NMR spin relaxation in proteins. SRLS is a two-body coupled rotator model which accounts rigorously for mode-coupling between the global motion of the protein and the local motion of the spin-bearing probe and allows for general properties of the second rank tensors involved. We showed that a general tool of data analysis requires both capabilities. Several important functionalities were missing in our previous implementations of SRLS in data fitting schemes, and in some important cases, the calculations were tedious. Here we present a general implementation which allows for asymmetric local and global diffusion tensors, distinct local ordering and local diffusion frames, and features a rhombic local potential which includes Wigner matrix element terms of ranks 2 and 4. A recently developed hydrodynamics-based approach for calculating global diffusion tensors has been incorporated into the data-fitting scheme. The computational efficiency of the latter has been increased significantly through object-oriented programming within the scope of the C++ programming language, and code parallelization. A convenient graphical user interface is provided. Currently autocorrelated (15)N spin relaxation data can be analyzed effectively. Adaptation to any autocorrelated and cross-correlated relaxation analysis is straightforward. New physical insight is gleaned on largely preserved local structure in solution, even in chain segments which experience slow local motion. Prospects associated with improved dynamic models, and new applications made possible by the current implementation of SRLS, are delineated. PMID- 19775103 TI - 2-Norbornyl ion-pair leakage in electrophilic addition of HCl to nortricyclene and norbornene. AB - Ion pair "leakage" pathways, located computationally by means of multidimensional potential energy surface scans, rationalize the unsymmetrical D-label scrambling observed experimentally in the DCl addition products of nortricyclene and norbornene. "Classical" addition transition structures can interconvert ("leak") to symmetrical nonclassical 2-norbornyl ion pair species, either TS's or a minimum, before products form. PMID- 19775105 TI - A modular rearrangement approach toward medicinally relevant phosphinic structures. AB - An unprecedented coupling of a P-C and a C-C bond-forming event in a practical operation was developed to access medicinally relevant phosphinic structures. The strategy relies on an Ireland-Claisen rearrangement triggered by the phospha Michael addition of silyl phosphonites to allyl acrylates. This protocol was extended to a more versatile three-component variant that utilizes phosphinic acids, acryloyl chlorides, and allylic alcohols as starting materials. PMID- 19775104 TI - Self-assembly and cellular uptake of degradable and water-soluble polyperoxides. AB - Water-soluble polyperoxides (PPs) as a new type of degradable and polymeric material were synthesized by the radical alternating copolymerization of sorbic derivatives containing a tetra(ethylene oxide) unit in the ester group using molecular oxygen. The obtained PPs showed a lower critical solution temperature (LCST)-type phase separation, and the transition temperature decreased according to the content of the hydrophobic ester group in the PPs. The PPs formed nanoaggregates with a diameter of 250-370 nm in water under the LCST. These PP aggregates were revealed to include 1-anilinonaphthalene-8-sulfonic acid as the fluorescence probe and epirubicin as the anticancer drug in their hydrophobic compartment. We evaluated the cytotoxicity and cellular uptake of the PPs in order to test their ability as a carrier used for the delivery of anticancer drugs. The cell viability in the presence of the PPs was comparable to those for the other biodegradable polymers, and epirubicin was taken up into the A549 efficiently with the PPs via an endocytosis mechanism. PMID- 19775102 TI - Peptide targeting of platinum anti-cancer drugs. AB - Besides various side effects caused by platinum anticancer drugs, they are not efficiently absorbed by the tumor cells. Two Pt-peptide conjugates; cyclic mPeg CNGRC-Pt (7) and cyclic mPeg-CNGRC-Pten (8) bearing the Asn-Gly-Arg (NGR) targeting sequence, a malonoyl linker, and low molecular weight miniPEG groups have been synthesized. The platinum ligand was attached to the peptide via the carboxylic end of the malonate group at the end of the peptide. The pegylated peptide is nontoxic and highly soluble in water. Platinum conjugates synthesized using the pegylated peptides are also water-soluble with reduced or eliminated peptide immunogenicity. The choice of carboplatin as our untargeted platinum complex was due to the fact that the malonate linker chelates platinum in a manner similar to that of carboplatin. Cell toxicity assay and competition assay on the PC-3 cells (CD13 positive receptors) revealed selective delivery and destruction of PC-3 cells using targeted Pt-peptide conjugates 7 and 8 significantly more than untargeted carboplatin. Platinum uptake on PC-3 cells was 12-fold more for conjugate 7 and 3-fold more for conjugate 8 compared to that of the untargeted carboplatin, indicating selective activation of the CD13 receptors and delivery of the conjugates to CD13 positive cells. Further analysis on effects of conjugates 7 and 8 on PC-3 cells using caspase-3/7, fluorescence microscopy, and DNA fragmentation confirmed that the cells were dying by apoptosis. PMID- 19775106 TI - Total synthesis of the antiproliferative macrolide (+)-neopeltolide. AB - A concise total synthesis of the very promising antiproliferative macrolide (+) neopeltolide (1) has been performed in 16 steps. The main steps of this approach are a Ru(II)-catalyzed alkyne-enal coupling, a Pd0-catalyzed desulfurative cross coupling, and a stereoselective In(III)-catalyzed propargylation. Four stereogenic centers out of six have been set thanks to substrate-controlled diastereoselective reactions with minimal reliance on protecting groups. PMID- 19775107 TI - Pearling of lipid vesicles induced by nanoparticles. AB - We show that cationic nanoparticles encapsulated within vesicles of phosphocholine lipid can induce pearling. The dynamic process occurs as two stages: formation of tubular protrusions followed by pearling instability. The breakup into individual vesicles can be controlled by nanoparticle concentration. PMID- 19775108 TI - Preparation of the [(DippNP)2(P4)2]2+-dication by the reaction of [DippNPCl]2 and a Lewis acid with P4. AB - The controlled activation of white phosphorus, P(4), provides a key entry point into many aspects of phosphorus chemistry. The activation and functionalization of P(4) by N-heterocyclic carbenes and carbene-like main group element fragments is of considerable current interest. In this communication, we report on the first use of a disguised bifunctional Lewis acid [DippNP](2)(2+) obtained from the cyclo-1,3-diphospha-2,4-diazane [DippNPCl](2) for P(4) functionalization. This has enabled the targeted preparation of novel mono- and dicationic phosphorus-rich clusters [(DippNP)(2)(P(4))Cl](+) and [(DippNP)(2)(P(4))(2)](+). The utilization of such a bifunctional phosphenium cation represents a rational and potentially versatile synthetic method for the assembly of large clusters using P(4) as a building block. PMID- 19775109 TI - Liquid-liquid phase separation in mixed organic/inorganic aerosol particles. AB - Currently, the physical state of mixed organic/inorganic aerosol particles is not well characterized, largely because of the still unclear chemical composition of the organic fraction and of its properties with respect to mixing with the inorganic fraction. To obtain insight in the possible phases and phase transitions of such aerosol particles, we investigated the ternary poly(ethylene glycol)-400/ammonium sulfate/water system as a representative model system with partially immiscible constituents. For this purpose, we used optical microscopy and micro-Raman spectroscopy on micrometer-sized particles deposited on a hydrophobically coated substrate. The particles show liquid-liquid phase separations both upon decreasing (approximately 90-85%) and increasing (during ammonium sulfate deliquescence) relative humidities. In dependence upon the organic-to-inorganic ratio, OIR (i.e., poly(ethylene glycol)-400 to ammonium sulfate dry mass), phase separation is observed to occur by fundamentally different mechanisms, namely, nucleation-and-growth (OIR = 8:1 to 2:1), spinodal decomposition (OIR = 1.5:1 to 1:1.5) and growth of a second phase at the surface of the particle (OIR = 1:2 to 1:8). For each of these mechanisms, after completion of the phase separation, the resulting morphology of the particles is an aqueous ammonium sulfate inner phase surrounded by a mainly poly(ethylene glycol)-400 containing outer phase. We depict the various physical states of the ternary system in the relative humidity/composition phase diagram, constructed from bulk data and single particle measurements. Given the complex chemical composition of the organic fraction in tropospheric aerosols, it is expected that repulsive forces between the organic and inorganic aerosol constituents exist and that liquid-liquid phase separations commonly occur. The presence of liquid liquid phase separations may change the partitioning of semivolatile species between the gas and the condensed phase, whereas the predominantly organic shell is likely to influence heterogeneous chemical reactions, such as N(2)O(5) hydrolysis. PMID- 19775110 TI - High-level ab initio predictions for the ionization energy, bond dissociation energies, and heats of formations of iron carbide (FeC) and its cation (FeC+). AB - The ionization energy (IE) of FeC and the 0 K bond dissociation energies (D(0)) and the heats of formation at 0 K (DeltaH(o)(f0)) and 298 K (DeltaH(o)(f298)) for FeC and FeC(+) are predicted by the single-reference wave function based CCSDTQ(Full)/CBS approach, which involves the approximation to the complete basis set (CBS) limit at the coupled cluster level up to full quadruple excitations. The zero-point vibrational energy (ZPVE) correction, the core-valence electronic corrections (up to CCSDT level), spin-orbit couplings, and relativistic effects (up to CCSDTQ level) are included in the calculations. The present calculations provide the correct symmetry predictions for the ground states of FeC and FeC(+) to be (3)Delta and (2)Delta, respectively. We have also examined the theoretical harmonic vibrational frequencies of FeC/FeC(+) at the ROHF-UCCSD(T) and UHF UCCSD(T) levels. While the UHF-UCCSD(T) harmonic frequencies are in good agreement with the experimental measurements, the ROHF-UCCSD(T) yields significantly higher harmonic frequency predictions for FeC/FeC(+). The CCSDTQ(Full)/CBS IE(FeC) = 7.565 eV is found to compare favorably with the experimental IE value of 7.59318 +/- 0.00006 eV, suggesting that the single reference-based coupled cluster theory is capable of providing reliable IE prediction for FeC, despite its multireference character. The CCSDTQ(Full)/CBS D(0)(Fe(+)-C) and D(0)(Fe-C) give the prediction of D(0)(Fe(+)-C) - D(0)(Fe-C) = 0.334 eV, which is consistent with the experimental determination of 0.3094 +/- 0.0001 eV. The D(0) calculations also support the experimental D(0)(Fe(+)-C) = 4.1 +/- 0.3 eV and D(0)(Fe-C) = 3.8 +/- 0.3 eV determined by the previous ion photodissociation study. The present calculations also provide the DeltaH(o)(f0)(DeltaH(o)(f298)) predictions for FeC/FeC(+). The analysis of the correction terms in these calculations shows that the core-valence and valence valence electronic correlations beyond CCSD(T) wave function and the relativistic effects make significant contributions to the calculated thermochemical properties of FeC/FeC(+). For the experimental D(0) and DeltaH(o)(f0) values of FeC/FeC(+), which are not known to high precision, we recommend the CCSDTQ(Full)/CBS predictions [D(0)(Fe-C) = 3.778 eV, D(0)(Fe(+)-C) = 4.112 eV, DeltaH(o)(f0)(FeC) = 760.8 kJ/mol and DeltaH(o)(f0)(FeC(+)) = 1490.6 kJ/mol] based on the ZPVE corrections using the experimental vibrational frequencies of FeC and FeC(+). PMID- 19775111 TI - Does tetrahydrofuran ring open upon ionization and dissociation? A TPES and TPEPICO investigation. AB - The threshold photoelectron spectrum (TPES) of tetrahydrofuran (THF) is compared to that of the unsaturated furan molecule. In general, there is a similarity in the orbital ionization profile for the two species, though unlike furan, THF exhibits (modest) vibrational detail only in the (9b)(-1) X (2)B band. An adiabatic ionization energy of 9.445 +/- 0.010 eV has been derived from the onset of the TPES spectrum. Threshold photoelectron photoion coincidence spectroscopy was used to explore the loss of a hydrogen atom from ionized THF over the photon energy range of 9.9-10.4 eV. RRKM fitting of the resulting breakdown curves yields an E(0) of 0.85 +/- 0.03 eV (82 +/- 3 kJ mol(-1)) (AE = 10.30 +/- 0.04 eV). If the G3 IE of 9.48 eV is used to convert the experimental data from photon energy to THF ion internal energy, E(0) = 0.81 +/- 0.01 eV (78 +/- 1 kJ mol(-1)). The latter value is closer to the G3 E(0) of 72 kJ mol(-1) for the formation of the cyclic ion 1. A variety of ring-opening reactions were also probed at the B3 LYP/6-31+G(d) and G3 levels of theory. The distonic isomer (*)CH(2)CH(2)CH(2)OCH(2)(+) lies 70 kJ mol(-1) higher than ionized THF, which places it within 1 kJ mol(-1) of the threshold for the dissociation to 1. All of the probed H-loss products from the distonic isomer (which includes singlet and triplet species) lie significantly higher in energy than ion 1, eliminating the possibility that ionized THF dissociates to m/z 71 via a ring-opening reaction in the present experiment. The derived Delta(double dagger)S value for the dissociation, 8 +/- 5 J K(-1) mol(-1), is also consistent with the formation of 1. The experimentally derived E(0) values can be used to derive the Delta(f)H(o)(0) for ion 1. Together with the Delta(f)H(o)(0) values for the THF ion (752.0 +/- 2 kJ mol(-1), derived from the neutral Delta(f)H(o)(0) of -154.9 +/- 0.7 kJ mol(-1) and experimental IE of 9.445 +/- 0.010 eV) and H atom (218.5 kJ mol(-1)) our E(0) of 82 +/- 3 kJ mol(-1) yields a Delta(f)H(o)(0) for ion 1 of 620 +/- 4 kJ mol(-1) (Delta(f)H(o)(298) = 594 +/- 4 kJ mol(-1)), in good agreement with the G3 Delta(f)H(o)(0) of 621 kJ mol(-1). Appearance energies for all fragment ions up to photon energies of 34 eV are also reported and discussed in comparison with the available literature. PMID- 19775112 TI - How measurements of rate coefficients at low temperature increase the predictivity of photochemical models of Titan's atmosphere. AB - The predictivity of photochemical models of Titan's atmosphere depends strongly on the precision and accuracy of reaction rates. For many reactions, large uncertainty results from the extrapolation of rate laws to low temperatures. A few reactions have been measured directly at temperatures relevant to Titan's atmosphere. In the present study, we observed the consequences of the reduced uncertainty attributed to these reactions. The global predictivity of the model was improved, i.e., most species are predicted with lower uncertainty factors. Nevertheless, high uncertainty factors are still observed, and a new list of key reactions has been established. PMID- 19775113 TI - Alpha shapes applied to molecular shape characterization exhibit novel properties compared to established shape descriptors. AB - Despite considerable efforts, description of molecular shape is still largely an unresolved problem. Given the importance of molecular shape in the description of spatial interactions in crystals or ligand-target complexes, this is not a satisfying state. In the current work, we propose a novel application of alpha shapes to the description of the shapes of small molecules. Alpha shapes are parametrized generalizations of the convex hull. For a specific value of alpha, the alpha shape is the geometric dual of the space-filling model of a molecule, with the parameter alpha allowing description of shape in varying degrees of detail. To date, alpha shapes have been used to find macromolecular cavities and to estimate molecular surface areas and volumes. We developed a novel methodology for computing molecular shape characteristics from the alpha shape. In this work, we show that alpha-shape descriptors reveal aspects of molecular shape that are complementary to other shape descriptors and that accord well with chemists' intuition about shape. While our implementation of alpha-shape descriptors is not computationally trivial, we suggest that the additional shape characteristics they provide can be used to improve and complement shape-analysis methods in domains such as crystallography and ligand-target interactions. In this communication, we present a unique methodology for computing molecular shape characteristics from the alpha shape. We first describe details of the alpha shape calculation, an outline of validation experiments performed, and a discussion of the advantages and challenges we found while implementing this approach. The results show that, relative to known shape calculations, this method provides a high degree of shape resolution with even small changes in atomic coordinates. PMID- 19775114 TI - On-tissue N-terminal peptide derivatizations for enhancing protein identification in MALDI mass spectrometric imaging strategies. AB - Matrix-assisted laser desorption/ionization (MALDI) is a new tool that can acquire the localization of various compounds, including peptides and proteins, directly from tissue sections. Despite the important developments recently performed in the field of MALDI imaging in tissue, the precise identification of compounds still needs improvement. We have developed N-terminal chemical derivatization strategies to improve tissue identification of proteins, including de novo sequencing performance. We have first focused on sulfonation agents, such as 4-SPITC and 3-SBASE. These two derivatizations were optimized to be performed directly on tissue sections. By adding a negative charge at the N-terminus of a tryptic digest peptide, we were able to generate a complete y fragment series directly from the tissue. Of these derivatizations, 3-SBASE has shown to be more efficient, as loss of the derivative group is one of the major fragmentation pathways for 4-SPITC. 3-SBASE was optimized so that the derivatization reaction could be automatically performed using an automatic microspotting device. It was then included in an automatic process that included automated trypsin digestion and matrix deposition. Derivatizations allowed the acquisition to be easily interpretable by MS(2) spectra, leading to very precise identification as well as easy manual reading of sequences for de novo sequencing. It was observed that only arginine-terminated peptides were observed after derivatization, likely due to the high gas-phase basicity of such peptides compared to those that are lysine terminated. We also observed a stop in the y fragmentation series for peptides presenting a miscleavage. We have now begun to study a different derivatization using N-succinimidyloxycarbonylmethyl)tris(2,4,6-trimethoxyphenyl)phosphonium bromide (TMPP). This derivatization allows the orientating of a fragmentation toward a series of fragment ions, and thus it is independent of the presence of basic residues in the sequence. This derivatization can be performed at room temperature, which greatly facilitates the automation of the process. The TMPP derivatization therefore yields an advantageous new generation of derivatives suited for use in tissue. PMID- 19775115 TI - A novel cis-selective cyclohexanone annulation as the key step of a total synthesis of the sesquiterpene isoacanthodoral. AB - Isoacanthodoral (1) is a structurally unique sesquiterpene in that it is a bicyclo[4.4.0]dec-1-ene with a cis- rather than the common trans-junction between the constituting rings. An efficient construction of this motif has been accomplished by a novel cis-selective cyclohexanone annulation, combining the lithium enolate of ester 8, the alpha,beta-unsaturated ester 6, and vinylmagnesium bromide in a single synthetic operation. For completing the total synthesis of 1, a Shapiro-olefination/hydrogenation sequence and a reductive cyanation were employed. PMID- 19775116 TI - Multiorifice flow fractionation: continuous size-based separation of microspheres using a series of contraction/expansion microchannels. AB - We designed a new microfluidic method, multiorifice flow fractionation (MOFF), for continuous size-based separation of spherical microparticles. This method utilizes inertial lift force and momentum-change-induced inertial force generated in a series of contraction/expansion microchannels. The particles were concentrated gradually along the walls of microchannels by those inertial forces as they passed through the channels. The particle trajectory was deflected from the carrier fluid by means of numerous sudden turns formed in a multiorifice channel. The inertial force was induced by this trajectory mismatching between fluid and particle that resulted from the momentum change. The trajectory mismatching induces the lateral drift of the equilibrium position of particle distribution, and its extent is variable according to particle size and flow rate. In the case of polydispersion, the size-based particle separation could be achieved in the specific range of the channel Reynolds number (Re(c)). It was found that, at Re(c) of 63-91, large polymer particles (approximately 15 microm) were aligned along the centerline of outlet channel, whereas small particles (approximately 7 microm) remained near both sidewalls. This method has potential in continuous separation without using a sheath flow. PMID- 19775117 TI - Chemical and thermal unfolding of glypican-1: protective effect of heparan sulfate against heat-induced irreversible aggregation. AB - Glypicans are cell-surface heparan sulfate proteoglycans that influence Wnt, hedgehog, decapentaplegic, and fibroblast growth factor activity via their heparan sulfate chains. However, recent studies have shown that glypican core proteins also have a role in growth factor signaling. Here, we expressed secreted recombinant human glypican-1 in eukaryotic cells. Recombinant glypican-1 was expressed as two glycoforms, one as proteoglycan substituted with heparan sulfate chains and one as the core protein devoid of glycosaminoglycans. Far-UV circular dichroism (CD) analysis of glypican-1 isolated under native conditions showed that the glypican-1 core protein is predominantly alpha-helical in structure, with identical spectra for the core protein and the proteoglycan form. The conformational stability of glypican-1 core protein to urea and guanidine hydrochloride denaturation was monitored by CD and fluorescence spectroscopy and showed a single unfolding transition at high concentrations of the denaturant (5.8 and 2.6 M, respectively). Renaturation from guanidine hydrochloride gave far UV CD and fluorescence spectra identical to the spectra of native glypican-1. Thermal denaturation monitored by CD and differential scanning calorimetry (DSC) showed a single structural transition at a temperature of approximately 70 degrees C. Refolding of the heat-denatured glypican-1 core protein was dependent on protein concentration, suggesting that intermolecular interactions are involved in irreversible denaturation. However, refolding was concentration independent for the proteoglycan form, suggesting that O-glycosylation protects the protein from irreversible aggregation. In summary, we have shown that the glypican-1 core protein is a stable alpha-helical protein and that the proteoglycan form of glypican-1 is protected from heat-induced aggregation. PMID- 19775118 TI - Upconversion luminescence of monodisperse CaF2:Yb(3+)/Er(3+) nanocrystals. AB - Monodispersed CaF(2):Yb(3+)/Er(3+) nanocrystals have been prepared via a facile wet chemical technology. The upconversion luminescence properties of CaF(2):Yb(3+)/Er(3+) nanocrystals were compared with those of NaYF(4):Yb(3+)/Er(3+) nanocrystals with different phases and particle sizes. The results indicated that CaF(2) is a promising host material for producing desirable upconversion luminescence. PMID- 19775119 TI - Utilization of a protein "shuttle" to load vault nanocapsules with gold probes and proteins. AB - Vaults are large protein nanocapsules that may be useful as drug delivery vehicles due to their normal presence in humans, their large interior volume, their simple structural composition consisting of multiple copies of one protein, and a recombinant production system that also provides a means to tailor their structure. However, for vaults to be effective in such applications, efficient means to load the interiors of the capsules must be demonstrated. Here we describe the use of a domain derived from a vault lumen-associated protein as a carrier to target both gold nanoclusters and heterologous His-tagged proteins to specific binding sites on the vault interior wall. PMID- 19775120 TI - PAMAM-RGD conjugates enhance siRNA delivery through a multicellular spheroid model of malignant glioma. AB - Generation 5 poly(amidoamine) (PAMAM) dendrimers were modified by the addition of cyclic RGD targeting peptides and were evaluated for their ability to associate with siRNA and mediate siRNA delivery to U87 malignant glioma cells. PAMAM-RGD conjugates were able to complex with siRNA to form complexes of approximately 200 nm in size. Modest siRNA delivery was observed in U87 cells using either PAMAM or PAMAM-RGD conjugates. PAMAM-RGD conjugates prevented the adhesion of U87 cells to fibrinogen-coated plates, in a manner that depends on the number of RGD ligands per dendrimer. The delivery of siRNA through three-dimensional multicellular spheroids of U87 cells was enhanced using PAMAM-RGD conjugates compared to the native PAMAM dendrimers, presumably by interfering with integrin-ECM contacts present in a three-dimensional tumor model. PMID- 19775121 TI - Amperometric nitric oxide microsensor based on nanopore-platinized platinum: the application for imaging NO concentrations. AB - This paper reports an amperometric nitric oxide (NO) microsensor based on a cone shaped nanopore-platinized Pt working electrode. The senor was fabricated using the following procedure: (1) a parent nanodisk electrode was prepared by polishing an etched Pt wire (radius = 12.5 microm; dimension of etched tip end point <10 nm) embedded in a glass capillary, (2) the nanodisk Pt was further etched to produce a nanopore (pore opening radius <1 microm; pore depth approximately 30 microm), (3) the Pt base surface in the nanopore electrode was platinized electrochemically to improve the sensor sensitivity, and (4) silanization and further modification with the electropolymerized polymeric film [poly(5-amino-1-naphthol)] on the nanopore-platinized Pt electrode were carried out to obtain the sensor selectivity to NO. The analytical performance of the sensor was characterized. For example, a sensor with a pore opening radius of 797 nm exhibited a decent linear dynamic range (at least for 0.2-1.8 microM), detection limit of < approximately 32 nM, response time (t(90%)) of < approximately 5 s, and sensitivity of 6.5 +/- 0.02 pA/nM. This sensor was used successfully as a NO-selective probe tip in scanning electrochemical microscopy (SECM) to obtain a two-dimensional image of the local NO concentrations for an inlaid NO-emitting microdisk film (radius = 12.5 microm) on a glass substrate. PMID- 19775122 TI - Asymmetric syntheses of (-)-enterolactone and (7'R)-7'-hydroxyenterolactone via organocatalyzed aldol reaction. AB - Short syntheses of (-)-enterolactone (1a) and (7'R)-7'-hydroxyenterolactone (1b) have been achieved utilizing organocatalyzed asymmetric cross-aldol reaction of aldehydes 2 and 3 and base-mediated alkylation of lactones 5 and 4. PMID- 19775124 TI - Directed single molecule diffusion triggered by surface energy gradients. AB - We demonstrate the diffusion of single poly(ethylene glycol) molecules on surfaces which change from hydrophilic to hydrophobic over a few micrometers. These gradients in surface energy are shown to drive the molecular diffusion in the direction of the hydrophilic component. The polymer diffusion coefficients on these surfaces are measured by fluorescence correlation spectroscopy and are shown to be elevated by more than an order of magnitude compared to surfaces without the surface energy gradient. Along the gradient, the diffusion is asymmetric, with diffusion coefficients approximately 100 times greater in the direction of the gradient than orthogonal to it. This diffusion can be explained by a Stokes-Einstein treatment of the surface-adsorbed polymer. PMID- 19775123 TI - Spectral tuning of organic nanocolloids by controlled molecular interactions. AB - The controlled self-assembly of molecules and interactions between them remain a challenge in creating tunable and functional organic nanostructures. One class of molecular systems that has proven useful for incorporating tunable functionality at different length scales is liquid crystals (LCs) due to its ability to inherently self-organize. Here we present a novel approach to utilize the self assembly of polymerizable liquid crystals to control the molecular aggregation of stable fluorescent chromophores and create a unique class of organic fluorescent nanocolloids. By adjusting the ratio between the dye and LC molecules inside the nanocolloids, we demonstrate the ability to control the molecular interactions and tune the fluorescent emission spectra of nanocolloid populations under single wavelength excitation. The single absorption spectrum and multiple emission spectra are highly desirable and reminiscent of the spectroscopic signature of quantum dots. These novel fluorescent nanocolloids have broad potential applications in fluorescent imaging and biological labeling. PMID- 19775126 TI - Electrical connectivity in single-walled carbon nanotube networks. AB - Transport in single-walled carbon nanotubes (SWCNTs) networks is shown to be dominated by resistance at network junctions which scale with the size of the interconnecting bundles. Acid treatment, known to dope individual tubes, actually produces a dramatic reduction in junction resistances, whereas annealing significantly increases this resistance. Measured junction resistances for pristine, acid-treated and annealed SWCNT bundles correlate with conductivities of the corresponding films, in excellent agreement with a model in which junctions control the overall network performance. PMID- 19775125 TI - Real-time chemical imaging of bacterial activity in biofilms using open-channel microfluidics and synchrotron FTIR spectromicroscopy. AB - Real-time chemical imaging of bacterial activities can facilitate a comprehensive understanding of the dynamics of biofilm structures and functions. Synchrotron radiation-based Fourier transform infrared (SR-FTIR) spectromicroscopy can yield high spatial resolution and label-free vibrational signatures of chemical bonds in biomolecules, but the abundance of water in biofilms has hindered SR-FTIR's sensitivity in investigating bacterial activity. We developed a simple open channel microfluidic system that can circumvent the water-absorption barrier for chemical imaging of the developmental dynamics of bacterial biofilms with a spatial resolution of several micrometers. This system maintains a 10 microm thick laminar-flow-through biofilm system that minimizes both the imaging volume in liquid and the signal interference from geometry-induced fringing. Here we demonstrate the ability of the open-channel microfluidic platform to maintain the functionality of living cells while enabling high-quality SR-FTIR measurements. We include several applications that show how microbes in biofilms adapt to their immediate environments. The ability to directly monitor and map bacterial changes in biofilms can yield significant insight into a wide range of microbial systems, especially when coupled to more sophisticated microfluidic platforms. PMID- 19775127 TI - Visible to near-infrared light harvesting in TiO2 nanotube array-P3HT based heterojunction solar cells. AB - The development of high-efficiency solid-state excitonic photovoltaic solar cells compatible with solution processing techniques is a research area of intense interest, with the poor optical harvesting in the red and near-IR (NIR) portion of the solar spectrum a significant limitation to device performance. Herein we present a solid-state solar cell design, consisting of TiO(2) nanotube arrays vertically oriented from the FTO-coated glass substrate, sensitized with unsymmetrical squaraine dye (SQ-1) that absorbs in the red and NIR portion of solar spectrum, and which are uniformly infiltrated with p-type regioregular poly(3-hexylthiophene-2,5-diyl) (P3HT) that absorbs higher energy photons. Our solid-state solar cells exhibit broad, near-UV to NIR, spectral response with external quantum yields of up to 65%. Under UV filtered AM 1.5G of 90 mW/cm(2) intensity we achieve typical device photoconversion efficiencies of 3.2%, with champion device efficiencies of 3.8%. PMID- 19775128 TI - Direct compressive measurements of individual titanium dioxide nanotubes. AB - The mechanical compressive properties of individual thin-wall and thick-wall TiO(2) nanotubes were directly measured for the first time. Nanotubes with outside diameters of 75 and 110 nm and wall thicknesses of 5 and 15 nm, respectively, were axially compressed inside a 400 keV high-resolution transmission electron microscope (TEM) using a new fully integrated TEM-atomic force microscope (AFM) piezo-driven fixture for continuous recording of the force displacement curves. Individual nanotubes were directly subjected to compressive loading. We found that the Young's modulus of titanium dioxide nanotubes depended on the diameter and wall thickness of the nanotube and is in the range of 23-44 GPa. The thin-wall nanotubes collapsed at approximately 1.0 to 1.2 microN during axial compression. PMID- 19775129 TI - Invertible enantioselectivity in 6'-deoxy-6'-acylamino-beta-isocupreidine catalyzed asymmetric aza-Morita-Baylis-Hillman reaction: key role of achiral additive. AB - The beta-ICD (1a) or beta-ICD-amide (1e)-catalyzed aza-Morita-Baylis-Hillman reaction between N-sulfonylimines 3 and alkyl vinyl ketones 4 produced the (R) enriched adducts 5. By adding a catalytic amount of beta-naphthol (2a), the enantioselectivity of the same reaction was inversed leading to (S)-5 in excellent yields and enantioselectivities. Both aromatic and aliphatic imines are accepted as substrates for this reaction. PMID- 19775130 TI - Facile organization of colloidal particles into large, perfect one- and two dimensional arrays by dry manual assembly on patterned substrates. AB - The ability to rapidly and reproducibly assemble colloidal particles into large (>mm) one- (1D) and two-dimensional (2D) single crystals with perfect control of the particle networking pattern would open a new world rich with high quality novel materials, technologies, and sciences. However, current methods rely on self-assembly of colloidal particles in solution (wet self-assembly), which intrinsically makes the assembly of the colloidal particles into defect-free large 1D and 2D single crystals difficult. We now demonstrate a new paradigm of colloidal particle organization into 1D and 2D single crystals, a process we call 'dry manual assembly on nanolithographically patterned substrates', which enables facile and rapid organization of colloidal particles in dry states into 1D and 2D single crystals in the centimeter or larger scales with a well-defined particle networking pattern. We believe that this novel methodology will serve as a key to open a new era of particle organization. PMID- 19775131 TI - Nucleation kinetics vs chemical kinetics in the initial formation of semiconductor nanocrystals. AB - The initial formation of semiconductor nanocrystals/nanoclusters, that is, nucleation in the classic literature, was examined both theoretically and experimentally. An experimental method based on determining the initial reaction rate for the formation of nanocrystals/nanoclusters with fixed size and size distribution was developed using InP and CdS nanocrystals/nanoclusters systems, especially the InP one. This experimental strategy relies on the size-dependent absorption spectra of these semiconductor nanoparticles as quantitative probes. The experimental results along with theoretical analysis indicate that the classic nucleation model was unlikely relevant for such crystallization systems, whose bulk crystal solubility in a solution is extremely low. Instead, the formation process was found to match a reaction-controlled kinetics model. The results further imply that understanding of crystallization and development of controlled synthesis of high quality colloidal nanocrystals are both closely related to identifying the molecular mechanism and chemical kinetics. PMID- 19775132 TI - A highly delocalized triplet carbene, 5-Methylhexa-1,2,4-triene-1,3-diyl: matrix IR identification, structure, and reactions. AB - The first representative of highly delocalized triplet carbenes bearing both vinyl and ethynyl groups at the formal carbene center, 5-methylhexa-1,2,4-triene 1,3-diyl, has been generated in a low-temperature Ar matrix upon UV photolysis of 5-ethynyl-3,3-dimethyl-3H-pyrazole and detected by FTIR spectroscopy. The transformation of 3H-pyrazole into the carbene proceeds in two stages via intermediate 3-diazo-5-methylhex-4-en-1-yne. According to DFT PBE/TZ2P calculations, 5-methylhexa-1,2,4-triene-1,3-diyl possesses an effective conjugation along the five-carbon chain and shows the same type of the bond length alternation as the HC(4m+1)H-type polyacetylenic carbenes. The carbene readily reacts with molecular oxygen, producing carbonyl oxides, which undergo further transformations typical of this type of compound upon irradiation in the UV-visible region. Two major photolytic rearrangements of 5-methylhexa-1,2,4 triene-1,3-diyl represent reactions characteristic of vinyl carbenes and resulting in the formation of 1-ethynyl-3,3-dimethylcyclopropene and 3E-2 methylhexa-1,3-dien-5-yne. A minor reaction is that typical of ethynylcarbenes; this leads to the formation of singlet 2-(2-methylpropenyl)cyclopropenylidene. Fragments of singlet and triplet potential energy surfaces of the C(7)H(8) system have been explored in DFT PBE/TZ2P calculations. PMID- 19775133 TI - Interfacial effects of in situ-synthesized Ag nanoparticles on breath figures. AB - In the present study, we introduced Ag nanoparticles into polymer and found for the first time that Ag nanoparticles can induce the formation of breath figure (BF) arrays on polymer surfaces. The effect of Ag nanoparticles has a balance with the BF process, which is influenced by humidity levels and polymers. These nanoparticle-induced BF process involves an interesting interaction between two self-assembly processes on different length scales. The aggregation of Ag nanoparticles on the water/polymer interface might be the key to their inducing ability. Hence, the interfacial-active Ag nanoparticles can be utilized to widen the applications of the BF method and to fabricate a wide variety of novel functionalized porous polymer films. PMID- 19775135 TI - From hydrophilic to superhydrophobic: fabrication of micrometer-sized nail-head shaped pillars in diamond. AB - The hydrophobicity of microtextured diamond surfaces was investigated. Pillarlike structures were fabricated in both nanocrystalline diamond and microcrystalline diamond. By changing the surface termination of the textured diamond surface, we could switch between superhydrophobic surfaces and hydrophilic surfaces. Examined terminations were hydrogen, fluorine, and oxygen. To evaluate the wetting properties, advancing and receding contact angles were measured. By designing pillars with a wide diamond top on a narrower silicon stem, superhydrophobicity was achieved even when the advancing contact angle on the unstructured diamond surface was below 70 degrees. The possibility to manipulate the hydrophobicity and the Fresnel reflection simultaneously at an infrared wavelength is also demonstrated. PMID- 19775134 TI - Preparation and characterization of Fe3O4/CdTe magnetic/fluorescent nanocomposites and their applications in immuno-labeling and fluorescent imaging of cancer cells. AB - The synthesis of a new kind of magnetic, fluorescent multifunctional nanoparticles (approximately 30 nm in diameter) was demonstrated, where multiple fluorescent CdTe quantum dots (QDs) are covalently linked to and assembled around individual silica-coated superparamagnetic Fe(3)O(4) nanoparticles and active carboxylic groups are presented on the surface for easy bioconjugation with biomolecules. The Fe(3)O(4) nanoparticles were first functionalized with thiol groups, followed by chemical conjugation with multiple thioglycolic acid modified CdTe QDs to form water-soluble Fe(3)O(4)/CdTe magnetic/fluorescent nanocomposites. X-ray diffraction, infrared spectroscopy, transmission electron microscopy, absorption and fluorescence spectroscopy, and magnetometry were applied to fully characterize the multifunctional nanocomposites. The nanocomposites were found to exhibit magnetic and fluorescent properties favorable for their applications in magnetic separation and guiding as well as fluorescent imaging. The carboxyl groups on the nanocomposite surface were proved to be chemically active and readily available for further bioconjugation with biomolecules such as bovine serum albumin and antibodies, enabling the applications of the nanocomposites for specific recognition of biological targets. The Fe(3)O(4)/CdTe magnetic/fluorescent nanocomposites conjugated with anti-CEACAM8 antibody were successfully employed for immuno-labeling and fluorescent imaging of HeLa cells. PMID- 19775136 TI - Fabrication of high-capacity biomolecular carriers from dispersible single-walled carbon nanotube-polymer composites. AB - One of the most interesting applications for carbon nanotubes is as a support material for bioanalytical devices. In this work, we successfully used an ultraviolet light initiated "graft from" polymerization method to fabricate polymer functionalized carbon nanotubes (PFCNTs) with pendant chains of various functionalities, including poly(ethylene glycol) chains to boost dispersibility and pendant epoxy groups for protein conjugate sites. A model enzyme, alkaline phosphatase, was used to study biomolecule loading efficiency as well as the retention of enzyme activity. Samples with various ratios of the two monomers were fabricated to optimize their use in aqueous environments, and an optimal composition was determined. This method allows the enhancement of enzyme loading amount while retaining high enzyme activity. The morphology of the carbon nanotubes were characterized by STEM and AFM before and after functionalization. In addition, the resulting PFCNTs were analyzed by FT-IR, TGA, and XPS. PMID- 19775137 TI - Studies on the adsorption property and structure of polyamine-ended poly(ethylene glycol) derivatives on a gold surface by surface plasmon resonance and angle resolved X-ray photoelectron spectroscopy. AB - The adsorption properties and structure of polyamine-ended poly(ethylene glycol) (PEG) derivatives on a flat gold surface were studied by means of surface plasmon resonance (SPR) and X-ray photoelectron spectroscopy (XPS) using PEG(5k)-block poly[2-(N,N-dimethylamino)ethyl methacrylate](7.5k) [PEG-b-PAMA(5k/7.5k)] and pentaethylenhexamine-ended PEG(5k) [N6-PEG(5k)], which had 48 and 6 amino groups at the omega-end, respectively. The SPR analysis showed that the amount of PEG-b PAMA(5k/7.5k) adsorbed onto the gold surface was not affected by the change in pH, and the desorption of this copolymer from the surface was not observed upon the addition of a solution at high salt concentration. The angle-resolved XPS (ARXPS) analysis revealed the structure of the PEG-b-PAMA polymer layer constructed on the gold surface: the PAMA segments were concentrated and located at the interface between the PEG layer and the gold surface. On the other hand, in the case of the PEG-graft-PAMA copolymer (PAMA-g-PEG)-modified gold surface, both the PAMA and the PEG segments homogeneously migrated to all regions of the constructed copolymer layer. The adsorbed amounts of N6-PEG(5k) under different pH conditions were constant and 2-3 times higher than those caused by the adsorption of single amino group-terminated PEG(5k) [PEG-NH(2)(5k)] and hydroxyl group-terminated PEG(5k) [PEG-OH(5k)]. The N6-PEG(5k)-modified gold surface showed a higher nonfouling property toward the adsorption of bovine serum albumin compared with the bare and the N6-modified gold surface. These results indicate that polyamine-ended PEGs were strongly immobilized onto the gold surface by polyamine anchors, even though electrostatic interaction between the polyamine and the gold substrate was not the dominant factor in this adsorption event. Furthermore, the formation of an almost complete phase-separated PEG/polyamine layer on the gold surface by polyamine-ended PEGs was strongly suggested. PMID- 19775138 TI - Roaming dynamics in formaldehyde-d2 dissociation. AB - State-resolved photodissociation dynamics of formaldehyde-d(2), i.e., D(2)CO, at energies slightly above the deuterium atom elimination channel have been studied both experimentally and theoretically. The results showed a clear bimodal distribution of energy into molecular photofragments. Substantial translational excitation of products at high rotational levels of CO was observed together with the D(2) cofragment in moderately excited vibrational levels, whereas rather small translational energy release of CO in low rotational levels was matched by a large degree of vibrational excitation in the D(2) molecule. An analogous distribution of energy in two distinct channels has been recently observed under similar conditions in H(2)CO photolysis and attributed to two different dissociation pathways, namely, a pathway via the conventional transition state geometry and the previously unobserved pathway, deemed "roaming". Our experimental and theoretical data indicated that the same two dissociation pathways were responsible for the bimodal energy distribution into the molecular fragments resulting from the photolysis of D(2)CO. Energy partitioning into molecular products was compared between photolysis of H(2)CO and D(2)CO at energies slightly above the H/D atom abstraction threshold. PMID- 19775139 TI - Dissecting competitive mechanisms: thionation vs. cycloaddition in the reaction of thioisomunchnones with isothiocyanates under microwave irradiation. AB - This paper documents in detail the reaction of 1,3-thiazolium-4-olates (thioisomunchnones) with aryl isothiocyanates. Having demonstrated with a chiral model that thionation occurs under these conditions to provide 1,3-thiazolium-4 thiolates and that this process is actually a stepwise domino reaction (J. Org. Chem. 2009, 74, 3698-3705), we extend this study to monocyclic thioisomunchnones. Herein, competition between thionation and 1,3-dipolar cycloaddition takes place. The process is synthetically disappointing at room temperature requiring prolonged reaction times for completion. The protocol has been subsequently investigated by using both microwave dielectric heating and conventional thermal heating (oil bath) in DMF at 100 degrees C with an accurate internal reaction temperature measurement. Although a slight acceleration was observed for reactions conducted under microwave irradiation, for most cases the observed yields and chemoselectivities were quite similar. Thus one can conclude that, within experimental errors, the reactivity is not related to nonthermal effects in agreement with recent reassessments on this subject, particularly by Kappe and associates (J. Org. Chem. 2008, 73, 36; J. Org. Chem. 2009, 74, 6157). The whole reaction system, which includes numerous heavy atoms, can be computationally modeled with a hybrid ONIOM[B3LYP/6-31G(d):PM3] level. This reproduces well experimental results and suggests a sequential mechanism. To further corroborate the nonconcertedness, the potential energy surface (PES) has been constructed for simplified models, locating the corresponding stationary points. In doing so, we introduce for the first time a useful and convenient mathematical protocol to locate the stationary points along a reaction path. The protocol is quite simple and should convince many organic chemists that certain daunting theoretical treatments can be made easy. PMID- 19775140 TI - Uptake of NO2 to deliquesced dihydroxybenzoate aerosol particles. AB - The uptake of nitrogen dioxide (NO2), a major trace gas in the atmosphere, to deliquesced particles containing the sodium salts of hydroquinone (1,4 dihydroxybenzene) or gentisic (2,5-dihydroxybenzoic) acid was investigated at 40% relative humidity and 23 degrees C in an aerosol flow tube. The experiments were performed using the short-lived radioactive tracer 13N and a denuder technique. The observed uptake coefficient for NO2 was up to approximately 6 x 10(-3) for the hydroquinone disodium salt aerosol, which exceeds previously reported data in the range 10(-4) to 10(-3). The measured time dependence of NO2 uptake was fitted using a kinetic model taking into account reactant consumption in the particle phase, and keeping the bulk accommodation coefficient, alpha(b), and the rate constants for the reaction of dissolved NO2 with the deprotonated forms of the mentioned phenolic compounds as variables. We obtained alpha(b) = 0.024( 0.003)(+0.018) as a best estimate. For gentisic acid, the second-order rate constant was k2 = (2.9 +/- 0.1) x 10(8) L mol(-1) s(-1) and is reported for the first time. The data are consistent with bulk reaction limited uptake, without indications for a surface component in the kinetics. PMID- 19775141 TI - A systematic investigation of factors influencing the decarboxylation of imidazolium carboxylates. AB - A series of 1,3-disubstituted-2-imidazolium carboxylates, an adduct of CO(2) and N-heterocyclic carbenes, were synthesized and characterized using single crystal X-ray, thermogravimetric, IR, and NMR analysis. The TGA analysis of the NHC CO(2)'s shows that as steric bulk on the N-substituent increases, the ability of the NHC-CO(2) to decarboxylate increases. The comparison of NHC-CO(2)'s with and without methyls at the 4,5-position indicate that extra electron density in the imidazolium ring enhances the stability of an NHC-CO(2) thereby making it less prone to decarboxylation. Single crystal X-ray analysis shows that the torsional angle of the carboxylate group and the C-CO(2) bond length with respect to the imidazolium ring is dependent on the steric bulk of the N-substituent. Rotamers in the unit cell of a single crystal of I(t)BuPrCO(2) (2f) indicate that the C CO(2) bond length increases as the N-substituents rotate toward the carboxylate moiety, which suggests that rotation of the N-substituents through the plane of the C-CO(2) bond may be involved in the bond breaking event to release CO(2). PMID- 19775142 TI - Structure versus solvent effects on nonlinear optical properties of push-pull systems: a quantum-mechanical study based on a polarizable continuum model. AB - A quantum mechanical investigation on the effects of the solvent and the structure on nonlinear optical activity of a class of merocyanine compounds has been conducted. The interplay of the two effects on the first hyperpolarizability, computed at density functional theory and second-order Moller-Plesset level, has been analyzed in combination with ground state properties and geometries and excited state energies and dipoles. A critical analysis of the simplified two-level model has also been presented. PMID- 19775143 TI - Influence of salts and natural organic matter on the stability of bacteriophage MS2. AB - The stability of functionalized nanoparticles generally results from both steric and electrostatic interactions. Viruses like bacteriophage MS2 have adopted similar strategies for stability against aggregation, including a net negative charge under natural water conditions and using polypeptides that form loops extending from the surface of the protein capsid for stabilization. In natural systems, dissolved organic matter can adsorb to and effectively functionalize nanoparticle surfaces, affecting the fate and transport of these nanoparticles. We used time-resolved dynamic light scattering to measure the aggregation kinetics of a model virus, bacteriophage MS2, across a range of solution chemistries to determine what factors might destabilize viruses in aquatic systems. In monovalent electrolytes (LiCl, NaCl, and KCl), aggregation of MS2 could not be induced within a reasonable kinetic time frame, and MS2 was stable even at salt concentrations greater than 1.0 M. Aggregation of MS2 could be induced in divalent electrolytes when we employed Ca(2+). This trend was also observed in solutions containing 10 mg/L Suwannee River organic matter (SROM) reference material. Even at Ca(2+) concentrations as high 200 mM, diffusion controlled aggregation was never achieved, demonstrating an additional barrier to aggregation. These results were confirmed by small-angle X-ray scattering experiments, which indicate a transition from repulsive to attractive interactions between MS2 virus particles as monovalent salts are replaced by divalent salts. PMID- 19775144 TI - On the nature of the adsorbed hydrogen phase in microporous metal-organic frameworks at supercritical temperatures. AB - Hydrogen adsorption measurements on different metal-organic frameworks (MOFs) over the 0-60 bar range at 50 and 77 K are presented. The results are discussed with respect to the materials' surface area and thermodynamic properties of the adsorbed phase. A nearly linear correlation between the maximum hydrogen excess amount adsorbed and the Brunauer-Emmett-Teller (BET) surface area was evidenced at both temperatures. Such a trend suggests that the adsorbed phase on the different materials is similar in nature. This interpretation is supported by measurements of the adsorbed hydrogen phase properties near saturation at 50 K. In particular it was found that the adsorbed hydrogen consistently exhibits liquid state properties despite significant structural and chemical differences between the tested adsorbents. This behavior is viewed as a consequence of molecular confinement in nanoscale pores. The variability in the trend relating the surface area and the amount of hydrogen adsorbed could be explained by differences in the adsorbed phase densities. Importantly, the latter were found to lie in the known range of bulk liquid hydrogen densities. The chemical composition and structure (e.g., pore size) were found to influence mainly how adsorption isotherms increase as a function of pressure. Finally, the absolute isotherms were calculated on the basis of measured adsorbed phase volumes, allowing for an estimation of the total amounts of hydrogen that can be stored in the microporous volumes at 50 K. These amounts were found to reach values up to 25% higher than their excess counterparts, and to correlate with the BET surface areas. The measurements and analysis in this study provide new insights on supercritical adsorption, as well as on possible limitations and optimization paths for MOFs as hydrogen storage materials. PMID- 19775145 TI - Experimental investigation of evaporation from low-contact-angle sessile droplets. AB - Evaporating sessile drops remain pinned at the contact line during much of the evaporation process, and leave a ring of residue on the surface upon dryout. The intensive mass loss near the contact line causes solute particles to flow to the edge of the droplet and deposit at the contact line. The high vapor diffusion gradient and the low thermal resistance of the film near the contact line are responsible for very efficient mass transfer in this region. Although heat and mass transfer at the contact line have been extensively studied, well characterized experiments remain scarce. The local mass transport in a 100-400 microm region near the contact line of a water droplet of radius 1810 microm on a glass substrate is experimentally quantified in the present work. Microparticle image velocimetry measurements of the three-dimensional flow field near the contact line are conducted to map the velocity field. Combined with high resolution transient liquid profile shapes, the measured velocity field yields transient local evaporative mass fluxes near the contact line. The spatial and temporal distribution of the local evaporative flux is also documented. The temperature distribution in the droplet near the contact line is deduced from the local evaporative fluxes and interface mass transport theory. PMID- 19775146 TI - Engineering surfaces for substrate-mediated gene delivery using recombinant proteins. AB - Immobilized fibronectin and other natural proteins have been utilized to enhance substrate-mediated gene delivery, with apparent contributions from the intrinsic bioactivity and also physical properties of the immobilized proteins. In this report, we investigated the use of recombinant proteins, compared to the full length fibronectin protein, as surface coatings for gene delivery to investigate the mechanisms by which fibronectin enhances gene transfer. The recombinant fibronectin fragment FNIII(7-10) (FNIII) contains the alpha(5)beta(1) binding domain of fibronectin and supports cell adhesion, whereas the recombinant protein polymer PP-12 is also negatively charged and has a molecular weight similar to FNIII, but lacks cell binding domains. Transfection was compared on surfaces modified with FNIII, full-length fibronectin, or PP-12. The full-length fibronectin provided the greatest extent of transgene expression relative to FNIII or PP-12, which was consistent with the amount of DNA that associated with cells. FNIII had 4.2-fold or 4.7-fold lower expression levels relative to fibronectin for polyplexes and lipoplexes, respectively. PP-12 produced expression levels that were 317-fold and 12.0-fold less than fibronectin for polyplexes and lipoplexes, respectively. Although expression was greater on FNIII relative to PP-12, the levels of DNA associated per cell with FNIII were similar to or less than those with PP-12, suggesting that the bioactive sequences may contribute to an enhanced intracellular trafficking. For lipoplexes delivered on FNIII, the efficiency of intracellular trafficking and levels of caveolar DNA were greater than that observed with either the full-length fibronectin or PP-12. For polyplexes, fibronectin fragment resulted in greater intracellular trafficking efficiency compared to PP-12 protein polymer. Recombinant proteins can be employed in place of full-length extracellular matrix proteins for substrate-mediated gene delivery, and bioactive sequences can influence one or more steps in the gene delivery process to maximize transfection. PMID- 19775147 TI - Consequences of polylactide stereochemistry on the properties of polylactide polymenthide-polylactide thermoplastic elastomers. AB - A series of polylactide-polymenthide-polylactide triblock copolymers containing either amorphous poly(D,L-lactide) or semicrystalline, enantiopure poly(L lactide) or poly(D-lactide) end segments were synthesized. Small-angle X-ray scattering and differential scanning calorimetry data were consistent with microphase separation of these materials. The Young's moduli and ultimate tensile strengths of the semicrystalline triblock copolymers were 2- and 3-fold greater, respectively, than their amorphous analogs. Symmetric (50:50) and asymmetric (95:5) blends of the triblock copolymers containing two different enantomeric forms of the polylactide segments formed stereocomplex crystallites, as revealed by wide-angle X-ray scattering and differential scanning calorimetry. Compared to the enantiopure analogs, these blends exhibited similar ultimate elongations and tensile strengths, but significantly increased Young's moduli. Collectively, these results demonstrate that the properties of these new biorenewable thermoplastic elastomers can be systematically modulated by changing the stereochemistry of the polylactide end blocks. PMID- 19775148 TI - Effects of wheat storage proteins on the functional properties of rice dough. AB - The objective of this work was to develop a rice flour based procedure for in vitro structure-function studies of wheat proteins. Rice flour has an advantage over wheat flour, because the signal/noise ratio should be higher after the incorporation of the wheat prolamins into the protein matrix of the dough. A reduction/oxidation procedure has been developed to incorporate glutenin subunits into the polymeric structure of rice dough protein. The results indicated that incorporation of bulk fractions of HMW and LMW glutenin subunits increased the mixing requirements of the dough, whereas simple addition resulted in weaker dough. The incorporation studies of individual HMW subunits (Bx6, Bx7, and By8) demonstrated that rice flour can be used to study and compare the functional properties of different glutenin subunits. PMID- 19775149 TI - Synthesis and solution conformation of homo-beta-peptides consisting of N mannofuranosyl-3-ulosonic acids. AB - The synthesis and solution conformation of homo-oligomers of beta-aminoacids, beta-N-mannofuranosyl-3-ulosonic acids, have been studied by NMR, MD simulation, and circular dichroism. These oligomers feature a spirocyclic disubstitution and a N,O-acetal functionality at the beta-carbon of the backbone, an unprecedented situation in the realm of beta-peptides. Our study shows that tetramer 10 and hexamer 11 adopt a characteristic secondary structure. In the hexamer 11, NMR investigations coupled with MD simulations suggest the preference for a double C(8) turn forming conformation. PMID- 19775150 TI - Spectroscopic investigation of peridinin analogues having different pi-electron conjugated chain lengths: exploring the nature of the intramolecular charge transfer state. AB - The lifetime of the lowest excited singlet (S(1)) state of peridinin and many other carbonyl-containing carotenoids and polyenes has been reported to depend on the polarity of the solvent. This effect has been attributed to the presence of an intramolecular charge transfer (ICT) state in the manifold of excited states for these molecules. The nature of this ICT state has yet to be elucidated. In the present work, steady-state and ultrafast time-resolved optical spectroscopy have been performed on peridinin and three synthetic analogues, C(33)-peridinin, C(35)-peridinin, and C(39)-peridinin, which have different numbers of conjugated carbon-carbon double bonds. Otherwise, the molecules are structurally similar in that they possess the same functional groups. The trends in the positions of the steady-state and transient spectral profiles for this systematic series of molecules allow an assignment of the spectral features to transitions involving the S(0), S(1), S(2), and ICT states. A kinetics analysis reveals the lifetimes of the excited states and the dynamics of their excited state deactivation pathways. The most striking observation in the data is that the lifetime of the ICT state converges to the same value of 10.0 +/- 2.0 ps in the polar solvent, methanol, for all the peridinin analogues, regardless of the extent of pi electron conjugation. This suggests that the ICT state is highly localized on the lactone ring, which is a common structural feature in all the molecules. The data further suggest that the S(1) and ICT states behave independently and that the ICT state is populated from both S(1) and S(2), the rate and efficiency from S(1) being dependent on the length of the pi-electron chain of the carotenoid and the solvent polarity. PMID- 19775151 TI - Multiple decomposition pathways for the oxenium ion precursor O-(4-(4' methylphenyl)phenyl)-N-methanesulfonylhydroxylamine. AB - Although O-arylhydroxylamine derivatives have been claimed to be sources of oxenium ions in a large number of studies, it is not clear that the products of these reactions are due to oxenium ions. Previously, we had shown through azide trapping studies that the quinol ester 2a and the title compound 3a generate the oxenium ion 1a. The ester 2a exclusively generates 1a in water and is also a photoprecursor of 1a in water. This is not true of 3a. The oxenium ion pathway accounts for a significant fraction of the reaction of 3a under neutral and acidic pH conditions, but there are three other pathways that account for hydrolysis of 3a. Both 3a and its conjugate base 3a(-) are present in aqueous solution under mild pH conditions. In addition to the oxenium ion product 4a, two other significant products are generated: the phenol 6a and the rearrangement product 8a. Both 4a and 8a are generated exclusively from 3a, whereas 6a is generated from both 3a and 3a(-). Azide trapping studies show that 6a and 8a are not generated from the oxenium ion. The phenol 6a is generated by two paths, one involving an apparent radical intermediate 7a and the other through a stepwise alpha-elimination pathway through 3a(-). The rearrangement product 8a is generated either through a concerted rearrangement or via an ion-pair rearrangement. Photolysis of 3a does not generate 1a. The only products of photolysis of 3a in water are 6a (major) and 8a (minor). The weak O-N bond of 3a is susceptible to homolysis under photolysis conditions, and the radical 7a is observed after laser flash photolysis of 3a. The cation 1a that is observed during laser flash photolysis experiments on 2a cannot be detected during similar experiments on 3a. These results suggest that the previous attribution of oxenium ions as the source of the decomposition products of other O-arylhydroxylamine derivatives in aromatic solvents via thermolysis or acid-catalyzed decomposition may not be correct. PMID- 19775152 TI - PTMSearchPlus: software tool for automated protein identification and post translational modification characterization by integrating accurate intact protein mass and bottom-up mass spectrometric data searches. AB - PTMSearchPlus is a software tool for the automated integration of accurate intact protein mass (AIPM) and bottom-up (BU) mass spectra searches/data in order to both confidently identify the intact proteins and to characterize their post translational modifications (PTMs). The development of PTMSearchPlus was motivated by the desire to effectively integrate high-resolution intact protein molecular masses with bottom-up peptide MS/MS data. PTMSearchPlus requires as input both intact protein and proteolytic peptide mass spectra collected from the same protein mixture, a FASTA protein database, and a selection of possible PTMs, the types and ranges of which can be specified. The output of PTMSearchPlus is a list of intact and modified proteins matching the AIPM data concomitant with their respective peptides found by the BU search. This list also contains protein and peptide sequence coverage information, scores, etc. that can be used for further evaluation or refiltering of the results. Corresponding and annotated AIPM and BU mass spectra are also displayed for visual inspection when a listed protein or a peptide is selected. These and other controls ensure that the user can manually evaluate, modify (e.g., remove obvious false positives, low quality spectra etc.), and save the results of the automated search if necessary. Driven by the exponential growth in the number of possible peptide candidates in a BU search when multiple PTMs are probed, the advantages on search speed by limiting the total number of possible PTMs on a peptide in the BU search or by performing an "AIPM predicted" BU search are also discussed in addition to the integration approach. The features of PTMSearchPlus are demonstrated using both a protein standard mixture and a complex protein mixture from Escherichia coli. Experimental data revealed a unique advantage of coupling AIPM and the BU data sets that is mutually beneficial for both approaches. Namely, AIPM data can confirm that no PTM peptides were missed in a BU search, while the BU search determines the location of the PTM. This information is not available using an AIPM search alone. PMID- 19775153 TI - Activated-electron photodetachment dissociation for the structural characterization of protein polyanions. AB - Multiply deprotonated anions [M - nH](n-) of large peptide mellitin, ubiquitin, and beta-casein proteins were subjected to laser irradiation at 260 nm in a quadrupole ion trap. For all compounds, the predominant event consecutive to laser irradiation was the detachment of an electron. The subsequent isolation and collisional activation of the oxidized [M - nH]((n-1)-*) resulted in extensive fragmentation of the peptide backbone. For mellitin peptide, nearly a complete series of c(*), z, and a(*), x product ions were observed. Applied to proteins, this technique, coined as activated-electron photodetachment dissociation (activated-EPD), achieved much more extensive sequence coverage than regular collision activated dissociation (CAD) on the even-electron components. Furthermore, the activated-EPD spectrum of beta-casein displayed phosphorylated fragment ions which suggest that the method is able to preserve part of the labile bonds of post-translational modifications. Activated-EPD is, therefore, a promising complementary technique to other dissociation techniques governed by radicals, i.e., electron capture dissociation (ECD), electron transfer dissociation (ETD), and electron detachment dissociation (EDD), for the structural characterization of large peptides and small proteins. PMID- 19775154 TI - Single-wall carbon nanotube forest arrays for immunoelectrochemical measurement of four protein biomarkers for prostate cancer. AB - Protein arrays that measure multiple protein cancer biomarkers in clinical samples hold great promise for reliable early cancer detection. Herein, we report a prototype 4-unit electrochemical immunoarray based on single-wall carbon nanotube forests for the simultaneous detection of multiple protein biomarkers for prostate cancer. Immunoarray procedures were designed to measure prostate specific antigen (PSA), prostate specific membrane antigen (PSMA), platelet factor-4 (PF-4), and interleukin-6 (IL-6) simultaneously in a single serum sample. All of these proteins are elevated in serum of patients with prostate cancer, but they have widely different relative levels of serum concentration. Horseradish peroxidase (HRP) was used as label on detection (secondary) antibodies in a sandwich immunoassay scheme. Biotinylated secondary antibodies (Ab(2)) that bind specifically to streptavidin-HRP conjugates provided 14-16 labels per antibody and gave the necessary higher sensitivity required for PF-4 and IL-6 detection at physiological levels. Conventional singly labeled Ab(2)-HRP conjugates were sufficient for PSA and PSMA detection. Immunoarrays were used to measure four biomarkers in clinical human serum samples of prostate cancer patients and controls with excellent correlation to referee enzyme-linked immunosorbent (ELISA) assays. PMID- 19775155 TI - Thermodynamics and kinetics of the pressure unfolding of phosphoglycerate kinase. AB - Due to the relationship between compressibility and volume fluctuations, high pressure studies provide vital insight into protein dynamics and function. Most high-pressure experiments were performed on small and fast folding proteins or model peptides. Here we show that a detailed kinetic study is necessary to extract reliable information from the high-pressure-induced structural conversion of large, slowly folding proteins. The pressure-jump unfolding kinetics of yeast phosphoglycerate kinase was recorded at pressures between 50 and 150 MPa. The time dependence of the conformational state of the protein was followed by tryptophan fluorescence measurements from 30 s to 2 h. The observed changes were described by a three-state model, and the volume change and the activation volume as well as the midpoint pressure of the transitions between the folded, intermediate, and unfolded states were determined. An interesting feature of the pressure unfolding of phosphoglycerate kinase was that the unfolding process speeds up with increasing pressure, which is the consequence of negative activation volumes for the folded --> intermediate, intermediate --> unfolded, and unfolded --> intermediate transitions. PMID- 19775156 TI - Oxidation of methionine to dehydromethionine by reactive halogen species generated by neutrophils. AB - During infection and inflammation, neutrophils and eosinophils produce hypochlorous acid, hypobromous acid, chloramines, and bromamines. These reactive halogen species preferentially oxidize methionine and thiols. It is commonly assumed that they convert methionine to methionine sulfoxide. However, iodine and organic chloramines are known to convert methionine to dehydromethionine, which is a cyclic azasulfonium salt. The potential for this reaction to occur in biologically relevant situations has so far been neglected. Therefore, we investigated the oxidation of methionine and N-terminal methionine residues by biologically relevant reactive halogen species and neutrophils. When hypochlorous acid reacted with methionine, two major products in addition to methionine sulfoxide were formed. They both had molecular masses two mass units lower than that of methionine and were identified as the diastereomers of dehydromethionine. Hypochlorous acid and chloramines converted methionine to a mixture of approximately 25% dehydromethionine and 75% methionine sulfoxide. Hypobromous acid and bromamines produced upward of 50% dehydromethionine. When methionine was present on the N-termini of peptides, reactive halogen species oxidized them to dehydromethionine with yields as high as 80%. Formylated N-terminal methionines and non-N-terminal methionine residues gave stoichiometric production of the corresponding sulfoxides only. Purified myeloperoxidase used hydrogen peroxide and chloride to catalyze the oxidation of N-terminal methionines to dehydromethionine. Neutrophils oxidized extracellular methionine to 30% dehydromethionine and 70% methionine sulfoxide. They also oxidized their intracellular methionine to dehydromethionine as well as methionine sulfoxide. We propose that reactive halogen species will produce dehydromethionine and form azasulfonium cations on the N-termini of peptides and proteins during inflammatory events. PMID- 19775157 TI - Catalytic hydrogenation of carbon dioxide using Ir(III)-pincer complexes. AB - Catalytic hydrogenation of carbon dioxide in aqueous potassium hydroxide was performed using a newly synthesized isopropyl-substituted PNP-pincer iridium trihydride complex as a catalyst. Potassium formate was obtained with turnover numbers up to 3,500,000 and a turnover frequency of 150,000 h(-1), both of which are the highest values reported to date. PMID- 19775158 TI - Dynamic properties of a psychrophilic alpha-amylase in comparison with a mesophilic homologue. AB - The cold-active, chloride-dependent alpha-amylase from Pseudoalteromonas haloplanktis (AHA) is one of the best characterized psychrophilic enzymes, and shares high sequence and structural similarity with its mesophilic porcine counterpart (PPA). An atomic detail comparative analysis was carried out by performing more than 60 ns of multiple-replica explicit-solvent molecular dynamics simulations on the two enzymes in order to characterize the differences in ensemble properties and dynamics in solution between the two homologues. We find in both enzymes high flexibility clusters in the surroundings of the substrate-binding groove, primarily involving the long loops that protrude from the main domain's barrel structure. These loops are longer in PPA and extend further away from the core of the barrel, where the active site is located: essential fluctuations in PPA mainly affect the highly solvent-accessible portions of these loops, whereas AHA is characterized by greater flexibility in the immediate surroundings of the active site. Furthermore, detailed analysis of active-site dynamics has revealed that elements previously identified through X ray crystallography as involved in substrate binding in both enzymes undergo concerted motions that may be linked to catalysis. PMID- 19775159 TI - Stereoselective synthesis of gamma-substituted (Z)-allylic boranes via kinetically controlled hydroboration of allenes with 10-TMS-9 borabicyclo[3.3.2]decane. AB - Kinetically controlled hydroboration of allenes 8 and 14a-d with the readily accessible Soderquist borane 7, which is generated in situ from borohydride 6, constitutes a convenient and preparatively useful method for synthesis of (Z) gamma-(substituted)allylboranes 9 and 15a-d. These allylboranes undergo highly diastereo- (> or = 90: 10) and enantioselective (typically 89-96% e.e.) allylboration reactions with representative aldehydes to give syn-beta functionalized homoallylic alcohols. PMID- 19775160 TI - 2-{3-[4-(Alkylsulfinyl)phenyl]-1-benzofuran-5-yl}-5-methyl-1,3,4-oxadiazole derivatives as novel inhibitors of glycogen synthase kinase-3beta with good brain permeability. AB - Glycogen synthase kinase 3beta (GSK-3beta) inhibition is expected to be a promising therapeutic approach for treating Alzheimer's disease. Previously we reported a series of 1,3,4-oxadiazole derivatives as potent and highly selective GSK-3beta inhibitors, however, the representative compounds 1a,b showed poor pharmacokinetic profiles. Efforts were made to address this issue by reducing molecular weight and lipophilicity, leading to the identification of oxadiazole derivatives containing a sulfinyl group, (S)-9b and (S)-9c. These compounds exhibited not only highly selective and potent inhibitory activity against GSK 3beta but also showed good pharmacokinetic profiles including favorable BBB penetration. In addition, (S)-9b and (S)-9c given orally to mice significantly inhibited cold water stress-induced tau hyperphosphorylation in mouse brain. PMID- 19775161 TI - Crystallographic study of a novel subnanomolar inhibitor provides insight on the binding interactions of alkenyldiarylmethanes with human immunodeficiency virus-1 reverse transcriptase. AB - Two crystal structures have been solved for separate complexes of alkenyldiarylmethane (ADAM) nonnucleoside reverse transcriptase inhibitors (NNRTI) 3 and 4 with HIV-1 reverse transcriptase (RT). The structures reveal inhibitor binding is exclusively hydrophobic in nature and the shape of the inhibitor-bound NNRTI binding pocket is unique among other reported inhibitor-RT crystal structures. Primarily, ADAMs 3 and 4 protrude from a large gap in the back side of the binding pocket, placing portions of the inhibitors unusually close to the polymerase active site and allowing 3 to form a weak hydrogen bond with Lys223. The lack of additional stabilizing interactions, beyond the observed hydrophobic surface contacts, between 4 and RT is quite perplexing given the extreme potency of the compound (IC(50) C(wedge)NN (or C(wedge)N(wedge)N or N(wedge)C(wedge)N) transitions are found within the absorption bands centered at ca. 400 nm. The properties of a series of compounds furnished with carboxylic acid anchoring groups at various positions are also examined for applications involving the sensitization of metal-oxide semiconductors. It is determined that the thermodynamic potentials of many of these compounds are appropriate for conventional photoelectrochemical cells (e.g., dye-sensitized solar cells) that utilize a titania electrode and iodide-based electrolyte. PMID- 19775164 TI - Direct correlation between structural and optical properties of III-V nitride nanowire heterostructures with nanoscale resolution. AB - Direct correlation of structural and optical properties on the nanoscale is essential for rational synthesis of nanomaterials with predefined structure and functionality. We study optical properties of single III-V nitride nanowire radial heterostructures with measured spatial resolution of <20 nm using cathodoluminescence (CL) technique coupled with scanning transmission electron microscopy (STEM). Enhanced carrier recombination in nanowire quantum wells and reduced light emission from regions containing structural defects were directly observed. Using newly developed parallel-detection-mode CL-STEM, we show that optical properties can vary within a single nanowire heterostructure as a function of nanowire morphology. PMID- 19775165 TI - Assignment of the C5' relative stereochemistry in (+)-lepadin F and (+)-lepadin G and absolute configuration of (+)-lepadin G. AB - Concise assignments of the C5' stereochemistry in (+)-lepadin F and (+)-lepadin G and the absolute configuration of (+)-lepadin G via the first total syntheses of (+)-5'-epi-lepadin F, (+)-lepadin G, and (+)-5'-epi-lepadin G are described. This work represents an illustrative example in which a diastereomeric pair can possess sufficient spectroscopic difference for clear assignment despite differing only at a highly insulated acyclic stereocenter. PMID- 19775166 TI - Simultaneous evaluation of ligand binding properties and protein size by electrophoresis and Taylor dispersion in capillaries. AB - The interplay between biophysical characteristics such as protein size and shape and protein function is difficult to ascertain using simple methods. Here, we present an approach for characterizing both protein-ligand binding as well as protein hydrodynamic radius in one operation combining electrophoresis and size measurement by dispersion using capillaries. The methodology is based on the integration of Taylor dispersion analysis and capillary electrophoresis and is here demonstrated using commercially available capillary electrophoresis instrumentation modified with a pixel sensor UV area imager, allowing two detection points along the capillary. Analytes are the human serum proteins alpha(1)-acid glycoprotein and albumin interacting with the drug propranolol in a frontal analysis mode. Upon introduction of the propranolol-protein sample, voltage is initially applied to facilitate electrophoretically mediated separation of ligand and protein and frontal analysis. Then a pressure mobilization step is used whereby Taylor dispersion can be characterized online based on the signal from the UV area imager. Estimates of ligand binding and values for hydrodynamic radii agree with values obtained by independent methods. PMID- 19775167 TI - High carrier densities achieved at low voltages in Ambipolar PbSe nanocrystal thin-film transistors. AB - Efficient transport of both electrons and holes with high carrier densities is a requirement for obtaining light-emitting transistors from films of colloidal semiconductor nanocrystals. Such devices offer an approach to efficient electrically pumped nanocrystal lasers with tunable emission. Here, we report a low-voltage ambipolar thin-film transistor that features high carrier mobility and high induced carrier density by combining a PbSe nanocrystal film with a high capacitance ion-gel gate dielectric layer ( approximately 22 and approximately 9 microF/cm2 for electron and hole accumulation, respectively). At operation voltages below 2.5 V, electron and hole densities higher than approximately 10(14) carriers/cm2 could be achieved in the PbSe nanocrystal film, which corresponds to approximately 3 electrons or holes per particle. Carrier mobilities were also dependent on charge density and were as high as 0.4 and 0.02 cm2/(V s) for electrons and holes, respectively. PMID- 19775168 TI - Discovery of azetidinyl ketolides for the treatment of susceptible and multidrug resistant community-acquired respiratory tract infections. AB - Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1. PMID- 19775169 TI - New 2-aryloxy-3-phenyl-propanoic acids as peroxisome proliferator-activated receptors alpha/gamma dual agonists with improved potency and reduced adverse effects on skeletal muscle function. AB - The preparation of a new series of 2-aryloxy-3-phenyl-propanoic acids, resulting from the introduction of a linker into the diphenyl system of the previously reported PPARalpha/gamma dual agonist 1, allowed the identification of new ligands with improved potency on PPARalpha and unchanged activity on PPARgamma. For the most interesting stereoisomers S-2 and S-4, X-ray studies in PPARgamma and docking experiments in PPARalpha provided a molecular explanation for their different behavior as full and partial agonists of PPARalpha and PPARgamma, respectively. Due to the adverse effects provoked by hypolipidemic drugs on skeletal muscle function, we also investigated the blocking activity of S-2 and S 4 on skeletal muscle membrane chloride channel conductance and found that these ligands have a pharmacological profile more beneficial compared to fibrates currently used in therapy. PMID- 19775171 TI - A benchmark study of different methods for calculating one- and two-dimensional optical spectra. AB - The accuracy and robustness of several approximate methods for computing linear and nonlinear optical spectra are considered. The analysis is performed in the context of a benchmark model that consists of a two-state chromophore with shifted harmonic potential surfaces that differ in frequency. The exact one- and two-dimensional spectra for this system are calculated and compared to spectra calculated via the following approximate methods: (1) The semiclassical forward backward initial-value representation (FB-IVR) method; (2) the linearized semiclassical (LSC) method; (3) the standard second-order cumulant approximation which is based on the ground-state equilibrium frequency-frequency correlation function (2OC); (4) an alternative second-order cumulant approximation which is able to account for nonequilibrium dynamics on the excited-state potential surface (2OCa). All four approximate methods can be shown to reproduce the exact results when the frequencies of the ground and excited harmonic surfaces are identical. However, allowing for the ground and excited surfaces to differ in frequency leads to a more meaningful benchmark model for which none of the four approximate methods is exact. We present a comparison of one- and two-dimensional spectra calculated via the above-mentioned approximate methods to the corresponding exact spectra, as a function of the following parameters: (1) The ratio of excited state to ground-state frequencies; (2) Temperature; (3) The horizontal displacement of the excited-state potential relative to the ground state potential; (4) The waiting time between the coherence periods in the case of two-dimensional spectra. The FB-IVR method is found to predict spectra which are practically indistinguishable from the exact ones over a wide region of parameter space. The LSC method is found to predict spectra which are in good agreement with the exact ones over the same region of parameter space. The 2OC and 2OCa are found to be highly inaccurate unless the frequencies of the ground and excited states are very similar. These observations give credence to the use of the LSC method for modeling spectra in complex systems, where exact or even FB IVR-based calculations are prohibitively expensive. PMID- 19775170 TI - Surface plasmon resonance binding kinetics of Alzheimer's disease amyloid beta peptide-capturing and plaque-binding monoclonal antibodies. AB - Several different monoclonal antibodies (mAbs) have been actively developed in the field of Alzheimer's disease (AD) for basic science and clinical applications; however, the binding kinetics of many of the mAbs with the beta amyloid peptides (Abeta) are poorly understood. A panel of mAbs with different Abeta recognition sites, including our plaque-binding antibody (IgG4.1), a peptide-capturing antibody (11A50), and two classical mAbs (6E10 and 4G8) used for immunohistochemistry, were chosen for characterization of their kinetics of binding to monomeric and fibrillar forms of Abeta40 using surface plasmon resonance and their amyloid plaque binding ability in AD mouse brain sections using immunohistochemistry. The plaque-binding antibody (IgG4.1) with epitope specificity of Abeta(2-10) showed a weaker affinity (512 nM) for monomeric Abeta40 but a higher affinity (1.5 nM) for Abeta40 fibrils and labeled dense core plaques better than 6E10 as determined by immunohistochemistry. The peptide capturing antibody (11A50) showed preferential affinity (32.5 nM) for monomeric Abeta40 but did not bind to Abeta40 fibrils, whereas antibodies 6E10 and 4G8 had moderate affinity for monomeric Abeta40 (22.3 and 30.1 nM, respectively). 4G8, which labels diffuse plaques better than 6E10, had a higher association rate constant than 6E10 but showed similar association and dissociation kinetics compared to those of 11A50. Enzymatic digestion of IgG4.1 to the F(ab')(2)4.1 fragments or their polyamine-modified derivatives that enhance blood-brain barrier permeability did not affect the kinetic properties of the antigen binding site. These differences in kinetic binding to monomeric and fibrillar Abeta among various antibodies could be utilized to distinguish mAbs that might be useful for immunotherapy or amyloid plaque imaging versus those that could be utilized for bioanalytical techniques. PMID- 19775172 TI - Accurately reproducing ab initio electrostatic potentials with multipoles and fragmentation. AB - In this work, we show that our energy based fragmentation method (Bettens, R. P. A.; Lee, A. M. J. Phys. Chem. A 2006, 110, 8777) accurately reproduces the electrostatic potential for a selection of peptides, both charged and uncharged, and other molecules of biological interest at the solvent accessible surface and beyond when compared with the full ab initio or density functional theory electrostatic potential. We also consider the ability of various point charge models to reproduce the full electrostatic potential and compare the results to our fragmentation electrostatic potentials with the latter being significantly superior. We demonstrate that our fragmentation approach can be readily applied to very large systems and provide the fragmentation electrostatic potential for the neuraminidase tetramer (ca. 24,000 atom system) at the MP2/6-311(+)G(2d,p) level. We also show that by using at least distributed monopoles, dipoles, and quadrupoles at atomic sites in the fragment molecules an essentially identical electrostatic potential to that given by the fragmentation electrostatic potential at and beyond the solvent accessible surface can be obtained. PMID- 19775173 TI - Theoretical investigation on triagonal symmetry copper trimers: magneto structural correlation and spin frustration. AB - The mechanisms of the magnetic coupling interactions for two trigonal-bipyramid trinuclear Cu(II) complexes Cu3(mu3-X)2(mu-pz)3X3 (X = Cl and Br, respectively) and three trigonal trinuclear Cu(II) complexes Cu3(mu3-X)(mu-pz)3Cl3 (X = Cl, Br, and O) are investigated by the calculations based on density functional theory combined with broken-symmetry approach (DFT-BS). The research on the magneto structural correlation reveals that the magnetic coupling interaction is sensitive to the Cu-(mu3-X)-Cu angle. With the Cu-(mu3-X)-Cu angle changing from 76 to 120 degrees, the magnetic coupling interaction is switched from ferromagnetic to antiferromagnetic. According to the analysis of the molecular orbitals and the variation of the spin-state energies versus the ratio of the magnetic coupling constants, it is found that there exists spin frustration phenomenon in these complexes. PMID- 19775175 TI - Chain end distribution of block copolymer in two-dimensional microphase-separated structure studied by scanning near-field optical microscopy. AB - The chain end distribution of a block copolymer in a two-dimensional microphase separated structure was studied by scanning near-field optical microscopy (SNOM). In the monolayer of poly(octadecyl methacrylate)-block-poly(isobutyl methacrylate) (PODMA-b-PiBMA), the free end of the PiBMA subchain was directly observed by SNOM, and the spatial distributions of the whole block and the chain end are examined and compared with the convolution of the point spread function of the microscope and distribution function of the model structures. It was found that the chain end distribution of the block copolymer confined in two dimensions has a peak near the domain center, being concentrated in the narrower region, as compared with three-dimensional systems. PMID- 19775174 TI - Color hues in red fluorescent proteins are due to internal quadratic Stark effect. AB - Intrinsically fluorescent proteins (FPs) exhibit broad variations of absorption and emission colors and are available for different imaging applications. The physical cause of the absorption wavelength change from 540 to 590 nm in the Fruits series of red FPs has been puzzling because the mutations that cause the shifts do not disturb the pi-conjugation pathway of the chromophore. Here, we use two-photon absorption measurements to show that the different colors can be explained by quadratic Stark effect due to variations of the strong electric field within the beta barrel. This model brings simplicity to a bewildering diversity of fluorescent protein properties, and it suggests a new way to sense electrical fields in biological systems. PMID- 19775176 TI - Effect of elongation of alternating sequences on swelling behavior and large deformation properties of natural alginate gels. AB - The physical properties of alginate gels correlate with alginate composition. Blocks of guluronic acid (G) strongly contribute to gel formation. Recently, the role of alternating sequences in calcium-alginate gels has been elucidated. The present contribution aimed at extending the analysis already reported (Donati, I.; Holtan, S.; Morch, Y. A.; Borgogna, M.; Dentini, M.; Skjak-Braek, G. Biomacromolecules 2005, 6, 1031) and at explaining some apparent mismatch of experimental data. In the present work, calcium hydrogels from different alginate samples have been analyzed by means of uniaxial compression and puncture tests to evaluate their Young's modulus and work at break. The role of long MG blocks in mechanical deformations (small and large domains) as well as in swelling experiments was investigated with natural and MG-enriched (AlgE4 epimerized) alginate samples. Alginates with elongated alternating sequences displayed, upon treatment with saline solution, a notable increase in swelling behavior, which was not paralleled by increased mechanical properties (Young's modulus). This behavior was traced back to the disentanglement of MG/MG junctions, which increased the local charge density, reducing the osmotic contribution to hydrogel swelling. The analyses of the large deformation curves for natural and epimerized alginates revealed an increase in the energy to breakage in the latter case caused by the dissipation effect of "sliding" MG/MG junctions. PMID- 19775177 TI - Insights into the interactions between dendrimers and bioactive surfactants: 3. Size-dependent and hydrophobic property-dependent encapsulation of bile salts. AB - The supramolecular structures of dendrimer-bile salt complexes have been investigated by multidimensional and multinuclear NMR techniques, such as (1)H NMR, COSY, TOCSY, NOESY, and DOSY. 2D-NOESY analysis indicated the localization of bile salt in the interior pockets of dendrimers. The orientation of the guest in the pockets was predicted by the NOE cross-peaks based on NOESY spectrum. (1)H NMR experiments suggested that no electrostatic interactions between the amine groups of dendrimers and the negatively charged group of bile salts occur in the complexes. DOSY studies further confirmed the inclusion structures based on the diffusion coefficient information. The supramolecular structures of dendrimer bile salt complexes were mainly formed by hydrophobic interactions/hydrogen-bond interactions in the interior pockets of dendrimers. In addition, size- and hydrophobic property-dependent encapsulation of bile salts and bile derivates in the cavities was observed. These results suggest a new interaction model of dendrimer-surfactant aggregates and provide new insight into the interactions between dendrimers and bioactive surfactants. PMID- 19775178 TI - Phenolic resin surface restructuring upon exposure to humid air: a sum frequency generation vibrational spectroscopic study. AB - Epoxy and phenolic resins are extensively used for modern microelectronics, for example, as packaging materials. Humidity may greatly alter or degrade their function and application, leading to failure of the device. A nonlinear optical laser technique, sum frequency generation (SFG) vibrational spectroscopy, was used to investigate the molecular surface structures of the epoxy and phenolic resins after exposure to humid air. It was found that the adsorbed water molecules at the phenolic resin surface can induce substantial surface restructuring. The surface phenyl groups were reoriented closer to a perpendicular position to the surface after exposure to humid air from a more parallel position in air. Epoxide group surface restructuring was not observed. PMID- 19775179 TI - Effect of cation driven loading of dibenzo-18-crown-6 in Nafion-117 membrane on the diffusion and transport behavior of alkali metal ions. AB - The possibility of enhancing the selectivity to separate the alkali metal ions was studied by loading dibenzo-18-crown-6 (DB18C6) in Li(+), Na(+), K(+), and Cs(+) form of cation exchange membrane, Nafion-117 (M-Naf-Cr where M = Li, Na, K, and Cs). DB18C6 was incorporated in Nafion-117 in corresponding ionic forms. Presence of DB18C6 in Nafion-117 was confirmed by FTIR. Self-diffusion and ion exchange kinetics of the alkali metal ions were studied in these membranes. It was observed that the diffusion in the membrane slowed down drastically from Li(+) to all other monovalent alkali metal ions. Two compartment cell experiments were done with DB18C6 loaded Cs(+)- form of Nafion-117 (Cs-Naf-Cr) membrane to study the transport of Na(+) and Cs(+) ions. No transport of ions was observed. When the same experiment were performed by replacing Li(+) of Li-Naf-Cr with Cs(+) (Cs-Li-Naf-Cr), transport of Cs(+) and H(+) were observed at much faster time scale compared to Cs-Naf-Cr. The selectivity of Cs(+) over Li(+) was enhanced by a factor of about 6 when Li-Naf-Cr was used in place Li(+) form of Nafion-117 for the transport experiments. PMID- 19775180 TI - A concise approach to the synthesis of opp-dibenzoporphyrins through the Heck reaction. AB - A concise approach to the synthesis of functionalized opp-dibenzoporphyrins is described. In this method, introduction of alkenyl groups to the porphyrin periphery through the vicinal 2-fold Heck reaction, 6-pi electrocyclization, and subsequent aromatization occur in one pot. PMID- 19775181 TI - Preparation of polyfunctional indazoles and heteroarylazo compounds using highly functionalized zinc reagents. AB - Readily available 2-chloromethylarylzinc reagents react with functionalized aryldiazonium tetrafluoroborates providing polyfunctional indazoles. Selective metalations of these 2-aryl-2H-indazoles afford new polycyclic aromatics. The performance of a chemoselective addition of diheteroarylzincs to aryldiazonium salts allows an efficient preparation of new heterocyclic azo compounds. PMID- 19775182 TI - Air-stable secondary phosphine oxide as preligand for palladium-catalyzed intramolecular alpha-arylations with chloroarenes. AB - A palladium catalyst derived from air-stable secondary phosphine oxide (1 Ad)(2)P(O)H enabled efficient intramolecular alpha-arylations of amides with aryl chlorides, which allowed for the synthesis of diversely substituted (aza)oxindoles. PMID- 19775183 TI - Nonbonding interactions and stereoselection in the Corey-Bakshi-Shibata reduction. AB - Deuterium kinetic isotope effect measurements upon enantiotopic methyl groups for the Corey-Bakshi-Shibata reduction of 2',5'-dimethylphenyl isopropyl ketone suggest a complex role for nonbonding interactions in the mediation of stereoselection. PMID- 19775184 TI - Synthesis of enantioenriched homopropargylic sulfonamides by a three component reaction of aldehydes, sulfonamides, and chiral allenylsilanes. AB - Enantioenriched allenylsilanes are used as carbon nucleophiles in three-component reactions with in situ generated N-sulfonylimines to selectively form syn homopropargylic sulfonamides. The reactions proceed with a variety of aldehyde and sulfonamide reaction partners. These novel reaction products are obtained with useful levels of diastereoselectivity, and the axial chirality of the allenylsilane is fully transferred to point chirality, forming products with >97% ee. PMID- 19775185 TI - Novel synthesis of amphiphilic dendrons by the double-stage convergent method. AB - A series of amphiphilic dendrons (G1-G4) have been designed and synthesized, which have a highly branched aliphatic hydrocarbon skeleton and a hydrophilic hydroxyl functionality to enable conjugation with other substrates. The higher generation dendrons (G3 and G4) were synthesized by a double-stage convergent method, which shortened the synthetic route significantly and provided the products in an efficient manner. The key branching step involved a double alkyl metal addition to an ester functionality followed by deoxygenation of a resulting tertiary alcohol by triethylsilane. PMID- 19775186 TI - Cu2+-selective ratiometric and "off-on" sensor based on the rhodamine derivative bearing pyrene group. AB - A new rhodamine-based derivative bearing a pyrene group (PRC) was synthesized as a ratiometric and "off-on" chemosensor for Cu(2+). PRC displayed a selective and chelation enhanced ratiometric fluorescence change and colorimetric change with Cu(2+) among the metal ions examined. PMID- 19775187 TI - Synthesis of ketene N,N-acetals by copper-catalyzed double-amidation of 1,1 dibromo-1-alkenes. AB - An efficient procedure for the preparation of ketene N,N-acetals by copper catalyzed double amidation of 1,1-dibromo-1-alkenes is reported. The reaction was found to be general, and ketene aminals could be obtained in good yields when potassium phosphate in toluene was used at 80 degrees C. The reaction was found to proceed through a regioselective monocoupling reaction followed by dehydrobromination and hydroamidation. PMID- 19775188 TI - Solid-state melt reaction for the domino process: highly efficient synthesis of fused tetracyclic chromenopyran pyrimidinediones using Baylis-Hillman derivatives. AB - A solid-state melt reaction (SSMR) has been demonstrated via a domino process for the synthesis of tetracyclic chromenopyran pyrimidinedione frameworks using Baylis-Hillman derivatives through in situ formation of an olefin followed by an intramolecular [4 + 2] cycloaddition reaction sequence. The tetracyclic frameworks were obtained without using catalyst and solvent in a highly stereoselective and stereospecific fashion. The isolated yield is excellent and does not require column chromatography purification to obtain the pure product. PMID- 19775190 TI - Retrofitting the bridges between science, economics, and policy. PMID- 19775189 TI - Reduced expression of lamin A/C results in modified cell signaling and metabolism coupled with changes in expression of structural proteins. AB - Nuclear lamins are intermediate filament proteins that define the shape and stability of nuclei in mammalian cells. In addition to this dominant structural role, recent studies have suggested that the lamin proteins also regulate fundamental aspects of nuclear function. In order to understand different roles played by lamin proteins, we used RNA interference to generate a series of HeLa cell lines to study loss-of-function phenotypes associated with depletion of lamin protein expression. In this study, we used genome-wide proteomic approaches to monitor global changes in protein expression in cells with <10% of normal lamin A/C expression. Of approximately 2000 protein spots analyzed by two dimensional electrophoresis, only 38 showed significantly altered expression in lamin A/C depleted cells. Of these, 4 protein spots were up-regulated, and 34 were down-regulated. Significant changes were seen to involve the general reduction in expression of cytoskeletal proteins, consistent with altered functionality of the structural cellular networks. At the same time, alterations in expression of proteins involved in cellular metabolism correlated with altered patterns of metabolic activity. In order to link these two features, we used antibody microarrays to perform a focused analysis of expression of cell cycle regulatory proteins. This confirmed a general reduction in expression of proteins regulating cell cycle progression and alteration in signaling pathways that regulate the metabolic activity of cells. The cross-talk between signal transduction and the cytoskeleton emphasizes how structural and kinase-based networks are integrated in mammalian cells to fine-tune metabolic responses. PMID- 19775192 TI - Bioaccumulation assessment using predictive approaches. AB - Mandated efforts to assess chemicals for their potential to bioaccumulate within the environment are increasingly moving into the realm of data inadequacy. Consequently, there is an increasing reliance on predictive tools to complete regulatory requirements in a timely and cost-effective manner. The kinetic processes of absorption, distribution, metabolism, and elimination (ADME) determine the extent to which chemicals accumulate in fish and other biota. Current mathematical models of bioaccumulation implicitly or explicitly consider these ADME processes, but there is a lack of data needed to specify critical model input parameters. This is particularly true for compounds that are metabolized, exhibit restricted diffusion across biological membranes, or do not partition simply to tissue lipid. Here we discuss the potential of in vitro test systems to provide needed data for bioaccumulation modeling efforts. Recent studies demonstrate the utility of these systems and provide a "proof of concept" for the prediction models. Computational methods that predict ADME processes from an evaluation of chemical structure are also described. Most regulatory agencies perform bioaccumulation assessments using a weight-of-evidence approach. A strategy is presented for incorporating predictive methods into this approach. To implement this strategy it is important to understand the "domain of applicability" of both in vitro and structure-based approaches, and the context in which they are applied. PMID- 19775193 TI - Indicators for monitoring soil biodiversity. PMID- 19775194 TI - Undertreatment of menopausal symptoms and novel options for comprehensive management. AB - OBJECTIVE: There is currently a gap in treatment options for menopausal symptoms and a need for comprehensive therapies that are safe and effective for postmenopausal women. This review discusses challenges in the management of menopausal symptoms and the effect of the Women's Health Initiative (WHI) study findings on current treatment patterns. It also examines present and future therapies. RESEARCH DESIGN AND METHODS: A literature search was conducted using Medline, the Cochrane Database, and the National Heart Lung and Blood Institute WHI website with the following search terms: primary care, menopause, vasomotor symptoms, hormone therapy, osteoporosis, and vaginal atrophy. Searches were limited to articles published between 1995 and 2009. RESULTS: Comprehensive therapies that target several aspects of menopause, such as vasomotor symptoms and chronic disease prevention, are currently hormone based. These hormone-based approaches are considered more effective than currently available nonhormonal therapies for the relief of menopausal symptoms. However, hormone therapy is not recommended for women at high risk for venous thromboembolic events, cardiovascular disease, and/or breast cancer. A need exists for novel therapies that mitigate menopausal symptoms, provide protection from osteoporosis, and encourage patient compliance without promoting cancer, heart disease, or stroke. Emerging modalities and strategies, such as the tissue selective estrogen complex (TSEC), Org 50081, MF101, and desvenlafaxine, may provide improved options for postmenopausal women. CONCLUSIONS: Several new menopausal therapies that may help to address the ongoing unmet need for safe and effective therapies for postmenopausal women are currently in development. In particular, the TSEC, which provides the benefits of both a selective estrogen receptor modulator and conjugated estrogens with an improved tolerability profile, may offer advantages over currently available treatment options. Limitations of this review include the narrow search criteria and limited search period. PMID- 19775195 TI - Healthcare costs of GERD and acid-related conditions in pediatric patients, with comparison between histamine-2 receptor antagonists and proton pump inhibitors. AB - BACKGROUND: Gastroesophageal reflux disease and acid-related conditions (GERD/ARC) are common in pediatric practice but their costs have not been well characterized. AIM: To compare healthcare costs (HCC) and healthcare utilization (HCU) of pediatric GERD/ARC between groups of GERD/ARC patients initiated on histamine-2 receptor antagonists (H(2)RAs) or proton pump inhibitors (PPIs) and matched controls. PATIENTS AND METHODS: Children (age < 18 years) diagnosed with GERD or ARC (exploratory category) were identified from a large US claims database (1999-2005) using ICD-9 codes. Costs of pediatric GERD/ARC were estimated by comparing 6-month post-diagnosis HCC between cases and matched controls. GERD/ARC-related HCC and HCU for the year 2005 were further compared between GERD/ARC patients initiated with PPIs vs. H(2)RAs in terms of the cost differences relative to pre-initiation (difference-in-difference) and using multivariate regression to adjust for demographics, pre-treatment health status and pre-treatment costs. RESULTS: A total of 27 865 matched pairs were identified. GERD/ARC patients incurred on average more 6-month total HCC than controls ($2386). In 2005, 1010 pediatric patients were initiated on H(2)RAs or PPIs. About 61% were initiated on PPIs and incurred 1.8 times higher 6-month post initiation GERD/ARC-related HCC than H(2)RA-initiated patients ($661 vs. $372, p < 0.001). Although total 6-month GERD/ARC-related HCC increased for both PPI- and H(2)RA-treated patients, the increase was 30% less for PPI-treated patients ($173 vs. $246, p = 0.521) in the difference-in-difference analysis and 69% less in the multivariate analysis ($109 vs. $347, p = 0.040). LIMITATIONS: The use of an exploratory definition for GERD/ARC, administrative claims data and potential coding errors in diagnosis codes used in selection process may limit the generalizability of the results. CONCLUSION: Pediatric GERD/ARC patients incurred significantly higher healthcare costs compared to similar children without GERD/ARC. Compared to patients initiated with H(2)RAs, patients initiated with PPIs had more baseline comorbidities, and lower GERD/ARC-related HCC after beginning treatment. PMID- 19775196 TI - Effect of X-ray radiation exposure on lyophilized recombinant activated factor VII (formulated for storage at room temperature). AB - OBJECTIVE: To investigate effects of air transport and X-ray radiation exposure through airport security of a new room temperature-stable rFVIIa formulation (NovoSeven/NovoSeven RT, Novo Nordisk A/S, Bagsvaerd, Denmark) lyophilized using in vitro study methodology, thus evaluating possible effects of exposure through airport security and airplane travel. RESEARCH DESIGN AND METHODS: The effect of X-ray radiation exposure of rFVIIa and the solvent histidine at two different doses (400 microSv and 2000 microSv) was examined immediately after exposure, and post-exposure after storage at 30 degrees C for 1 month. References samples, not exposed to X-ray radiation, were used for comparison. MAIN OUTCOME MEASURE: Stability of rFVIIa after X-ray radiation exposure. RESULTS: All product parameters analyzed were within the acceptance criteria as well as within shelf life specification limits for the selected parameters for each product. CONCLUSION: The product rFVIIa and solvent histidine are therefore not expected to be affected as a consequence of airplane traveling and X-ray exposure during airport security check using hand luggage scanners. PMID- 19775197 TI - Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via an NFkappaB-mediated increase in interleukin-6 production. AB - Mesenchymal stromal cell (MSC) therapy has shown promise for the treatment of traumatic brain injury (TBI). Although the mechanism(s) by which MSCs offer protection is unclear, initial in vivo work has suggested that modulation of the locoregional inflammatory response could explain the observed benefit. We hypothesize that the direct implantation of MSCs into the injured brain activates resident neuronal stem cell (NSC) niches altering the intracerebral milieu. To test our hypothesis, we conducted initial in vivo studies, followed by a sequence of in vitro studies. In vivo: Sprague-Dawley rats received a controlled cortical impact (CCI) injury with implantation of 1 million MSCs 6 h after injury. Brain tissue supernatant was harvested for analysis of the proinflammatory cytokine profile. In vitro: NSCs were transfected with a firefly luciferase reporter for NFkappaB and placed in contact culture and transwell culture. Additionally, multiplex, quantitative PCR, caspase 3, and EDU assays were completed to evaluate NSC cytokine production, apoptosis, and proliferation, respectively. In vivo: Brain supernatant analysis showed an increase in the proinflammatory cytokines IL 1alpha, IL-1beta, and IL-6. In vitro: NSC NFkappaB activity increased only when in contact culture with MSCs. When in contact with MSCs, NSCs show an increase in IL-6 production as well as a decrease in apoptosis. Direct implantation of MSCs enhances neuroprotection via activation of resident NSC NFkappaB activity (independent of PI3 kinase/AKT pathway) leading to an increase in IL-6 production and decrease in apoptosis. In addition, the observed NFkappaB activity depends on direct cell contact. PMID- 19775198 TI - Reduced differentiation efficiency of murine embryonic stem cells in stirred suspension bioreactors. AB - The use of embryonic stem cells (ESCs) for regenerative medicine has generated increased attention due to the favorable attributes of these cells; namely, they are pluripotent and possess long-term self-renewal capacity. The initial aims of the present study were: (i) to use stirred suspension bioreactors to expand and differentiate ESCs into osteogenic and chondrogenic cell types and (ii) to explore if these ESC-derived cells influenced skeletal healing in an in vivo fracture model. We show that differentiation protocols used in static culture are insufficient when applied directly to suspension culture bioreactors. Moreover, when bioreactor-differentiated cells are transplanted into a burr-hole defect in bone, severe disruption of the bone architecture was noted at the fracture site, as determined by microcomputed tomography (microCT) imaging and histopathology. Further characterization of the bioreactor-differentiated cultures revealed that a subpopulation of cells in the resulting aggregates expressed the pluripotency marker Oct-4 in the nucleus. Nuclear Oct-4 expression persisted even after 30 days of culture in the absence of leukemia inhibitory factor (LIF). Remarkably, and unlike ESCs differentiated into skeletal cell types in static cultures, bioreactor-differentiated aggregates implanted subcutaneously into SCID mice formed teratomas. The development of effective ESC differentiation protocols for suspension bioreactors will require a more complete understanding of the environmental conditions within these culture systems and the influence that these conditions have on the regulation of pluripotency and differentiation in ESCs. PMID- 19775200 TI - Public willingness to take a vaccine or drug under Emergency Use Authorization during the 2009 H1N1 pandemic. AB - On April 26, 2009, the United States declared a public health emergency in response to a growing but uncertain threat from H1N1 influenza, or swine flu. In June, the World Health Organization declared a pandemic. In the U.S., hospitalizations due to swine flu numbered 6,506 on August 6, 2009, with 436 deaths; all 50 states have reported cases. The declaration of a public health emergency, followed by the approval of multiple Emergency Use Authorizations (EUAs) by the Food and Drug Administration, allowed the distribution of unapproved drugs or the off-label use of approved drugs to the public. Thus far, there are 2 antiviral medications available to the public as EUA drugs. It is possible that an H1N1 vaccine will be initially released as an EUA in the fall in the first large-scale use of the EUA mechanism. This study explores the public's willingness to use a drug or vaccine under the conditions stipulated in the FDA's nonbinding guidance regarding EUAs. Using Knowledge Networks' panel, we conducted an internet survey with 1,543 adults from a representative sample of the U.S. population with 2 over samples of African Americans and Spanish-speaking Hispanics. Our completion rate was 62%. We examined willingness to accept an EUA drug or an H1N1 vaccine, the extent of worry associated with taking either, the conditions under which respondents would accept an EUA drug or vaccine, and the impact of language from the EUA fact sheets on people's willingness to accept a drug for themselves or their children. We also examined the association among these variables and race/ethnicity, education level, trust in government, previous vaccine acceptance, and perceived personal consequences from H1N1 influenza. These results provide critical insights into the challenges of communicating about EUA drugs and vaccine in our current pandemic. PMID- 19775199 TI - High-resolution peripheral quantitative computed tomography can assess microstructural and mechanical properties of human distal tibial bone. AB - High-resolution peripheral quantitative computed tomography (HR-pQCT) is a newly developed in vivo clinical imaging modality. It can assess the 3D microstructure of cortical and trabecular bone at the distal radius and tibia and is suitable as an input for microstructural finite element (microFE) analysis to evaluate bone's mechanical competence. In order for microstructural and image-based microFE analyses to become standard clinical tools, validation with a current gold standard, namely, high-resolution micro-computed tomography (microCT), is required. Microstructural measurements of 19 human cadaveric distal tibiae were performed for the registered HR-pQCT and microCT images, respectively. Next, whole bone stiffness, trabecular bone stiffness, and elastic moduli of cubic subvolumes of trabecular bone in both HR-pQCT and microCT images were determined by microFE analysis. The standard HR-pQCT patient protocol measurements, derived bone volume fraction (BV/TV(d)), trabecular number (Tb.N*), trabecular thickness (Tb.Th), trabecular spacing (Tb.Sp), and cortical thickness (Ct.Th), as well as the voxel-based direct measurements, BV/TV, Tb.N*, Tb.Th*, Tb.Sp*, Ct.Th, bone surface-to-volume ratio (BS/BV), structure model index (SMI), and connectivity density (Conn.D), correlated well with their respective gold standards, and both contributed to microFE-predicted mechanical properties in either single or multiple linear regressions. The mechanical measurements, although overestimated by HR-pQCT, correlated highly with their gold standards. Moreover, elastic moduli of cubic subvolumes of trabecular bone predicted whole bone or trabecular bone stiffness in distal tibia. We conclude that microstructural measurements and mechanical parameters of distal tibia can be efficiently derived from HR-pQCT images and provide additional information regarding bone fragility. PMID- 19775201 TI - Serum 25-hydroxyvitamin D and the risk of hip and nonspine fractures in older men. AB - The association between vitamin D levels and incident fractures in older men is uncertain. To test the hypothesis that low serum 25-hydroxyvitamin D [(25(OH)D] levels are associated with an increased risk of fracture, we performed a case cohort study of 436 men with incident nonspine fractures, including 81 hip fractures, and a random subcohort of 1608 men; average follow-up time 5.3 years. Serum vitamin D(2) and vitamin D(3) were measured on baseline sera using mass spectrometry and summed for total vitamin D. Modified Cox proportional hazards models were used to estimate the hazard ratio (HR) of fracture with 95% confidence intervals (CIs). Multivariable models included age, clinic, season, race, height, weight, and physical activity. The mean (SD) total 25(OH)D was 24.6 (7.8) ng/mL in nonspine fracture subjects, 21.5 (7.9) ng/mL in hip fracture subjects, and 25.2 (7.8) ng/mL in controls (nonspine fracture subjects versus nonpatients, p = .14; hip fracture subjects versus controls, p < .0001). 25(OH)D levels were unrelated to nonspine fractures. One SD decrease in total 25(OH)D was associated with an increased risk of hip fracture (multivariate HR = 1.60; 95% CI 1.18-2.17). Compared with men in the top quartile of total 25(OH)D (> or =28), the HR of hip fracture was 2.36 (95% CI 1.08-5.15) for men in the lowest quartile (<20) (p = .009 for trend). Adjusting for hip bone mineral density attenuated the association by more than 50% (p = .065 for trend). Low serum 25(OH)D concentrations are associated with a higher risk of hip fracture in older men. Measurement of 25(OH)D may be useful in identifying men at high risk of hip fracture. PMID- 19775202 TI - Genome-wide expression analyses establish dendritic cells as a new osteoclast precursor able to generate bone-resorbing cells more efficiently than monocytes. AB - Dendritic cells (DCs), mononuclear cells that initiate immune responses, and osteoclasts (OCs), multinucleated bone-resorbing cells, are hematopoietic cells derived from monocytic precursor cells. Using in vitro generated dendritic cells, we previously showed that human and murine DCs could transdifferentiate into resorbing osteoclasts in the presence of macrophage colony-stimulating factor (M CSF) and receptor activator of NF-kappaB ligand (RANKL). In this study we globally compared by transcriptomic profiling this new osteoclast differentiation pathway from DCs with the canonical differentiation pathway from monocytes. DNA chip data revealed that starting from two very distinct cell types, treatment with M-CSF and RANKL generated two highly similar types of osteoclast. In particular, DC-derived osteoclasts expressed all the characteristic marker genes of monocyte-derived osteoclasts. Two major molecular events could be observed during osteoclastogenesis: downregulation of a large set of monocyte or DC specific markers, together with upregulation of characteristic osteoclast marker genes. Most interestingly, our transcriptomic data showed a closer molecular profile between DCs and OCs than between monocytes and OCs. Our data establish DCs as a new osteoclast precursor able to generate OCs more efficiently than monocytes. PMID- 19775203 TI - Effects of the Src kinase inhibitor saracatinib (AZD0530) on bone turnover in healthy men: a randomized, double-blind, placebo-controlled, multiple-ascending dose phase I trial. AB - Src is a nonreceptor tyrosine kinase thought to be essential for osteoclast function and bone resorption. We investigated the effect of the orally available Src inhibitor saracatinib (AZD0530) on bone turnover in healthy men. The study was part of a randomized, double-blind, placebo-controlled multiple-ascending dose phase I trial of saracatinib. Fifty-nine healthy men (mean age 34.6 years) were divided into five cohorts; four with 12 subjects and one with 11 subjects, and randomized within each cohort in the ratio 3:1 to receive a single dose of saracatinib or placebo, respectively, followed 7 to 10 days later with daily doses for a further 10 to 14 days. Dosing levels of saracatinib ascended by cohort (60 to 250 mg). Markers of bone turnover were measured predose and 24 and 48 hours after the initial single dose and immediately before and 24 and 48 hours and 10 to 14 days after the final dose. Data from 44 subjects were included in the analysis. There was a dose-dependent decrease in bone resorption markers [serum cross-linked C-telopeptide of type I collagen (sCTX) and urinary cross linked N-telopeptide of type I collagen normalized to creatinine (uNTX/Cr)]. At a dose of 250 mg (maximum tolerated dose), sCTX decreased by 88% [95% confidence interval (CI) 84-91%] and uNTX/Cr decreased by 67% (95% CI 53-77%) from baseline 24 hours after the final dose. There was no significant effect on bone formation markers. There were no significant adverse events. We conclude that inhibition of Src reduces osteoclastic bone resorption in humans. Saracatinib is a potentially useful treatment for diseases characterized by increased bone resorption, such as metastatic bone disease and osteoporosis. PMID- 19775204 TI - Early impairment of trabecular microarchitecture assessed with HR-pQCT in patients with stage II-IV chronic kidney disease. AB - Bone fragility is a complication of chronic kidney disease (CKD). The aim of this study was to assess whether volumetric bone mineral density (vBMD) and microarchitecture could be impaired early in the course of CKD. Bone microarchitecture was examined with a noninvasive 3D imaging technique [high resolution peripheral quantitative computed tomography (HR-pQCT)] at the tibia and radius in 70 stage II-IV CKD patients older than 50 years of age; controls belonged to two cohorts of healthy subjects comparable for age and gender (OFELY cohort in women and STRAMBO cohort in men). We examined 46 men and 24 women; 19 patients were diabetic. Mean age was 70.8 +/- 8.5 years, mean glomerular filtration rate (GFR) was 34 +/- 12 mL/min per 1.73 m(2), and mean serum parathyroid hormone (PTH) level was 87 +/- 59 pg/mL. Both CKD men and women experienced a moderate but significant trabecular (Tb) impairment, positioning CKD patient values between those of normal and osteopenic controls (e.g., CKD men versus healthy controls: Tb vBMD 172 +/- 35 versus 188 +/- 34 mg HA/cm(3); Tb number 1.75 +/- 0.27 versus 1.86 +/- 0.26 mm(-1), and Tb separation 503 +/- 94 versus 465 +/- 78 microm; p < .05). Cortical thickness (Ct.Th) in men also was significantly decreased compared with healthy controls (e.g., CKD men versus healthy controls: tibial Ct.Th 1171 +/- 331 versus 1288 +/- 283 microm; p < .05). In conclusion, this study, using a noninvasive bone-imaging device, shows for the first time an early impairment of trabecular microarchitecture in stage II-IV CKD patients. Further longitudinal studies should be performed to validate HR-pQCT as a tool for predicting the fracture risk in CKD. PMID- 19775206 TI - Tolerance to hypoxia. PMID- 19775205 TI - Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. AB - The SIBLING family (small integrin-binding ligand N-linked glycoproteins) of mineral-regulating proteins, which includes matrix extracellular phosphoglycoprotein (MEPE) and osteopontin (OPN), contains an acidic serine- and aspartate-rich motif (ASARM). X-linked hypophosphatemia caused by inactivating mutations of the PHEX gene results in elevated mineralization-inhibiting MEPE derived ASARM peptides. Although the OPN ASARM motif shares 60% homology with MEPE ASARM, it is still unknown whether OPN ASARM similarly inhibits mineralization. In this study we have examined the role of OPN ASARM and its interaction with PHEX enzyme using an osteoblast cell culture model, mass spectrometry, mineral-binding assays, and computational modeling. MC3T3-E1 osteoblast cultures were treated with differently phosphorylated OPN ASARM peptides [with 5 phosphoserines (OpnAs5) or 3 phosphoserines (OpnAs3)] or with control nonphosphorylated peptide (OpnAs0). Phosphorylated peptides dose dependently inhibited mineralization, and binding of phosphorylated peptides to mineral was confirmed by a hydroxyapatite-binding assay. OpnAs0 showed no binding to hydroxyapatite and did not inhibit culture mineralization. Computational modeling of peptide-mineral interactions indicated a favorable change in binding energy with increasing phosphorylation consistent with hydroxyapatite-binding experiments and inhibition of culture mineralization. Addition of PHEX rescued inhibition of mineralization by OpnAs3. Mass spectrometry of cleaved peptides after ASARM-PHEX incubations identified OpnAs3 as a PHEX substrate. We conclude that OPN ASARM inhibits mineralization by binding to hydroxyapatite in a phosphorylation-dependent manner and that this inhibitor can be cleaved by PHEX, thus providing a mechanistic explanation for how loss of PHEX activity in X linked hyposphosphatemia can lead to extracellular matrix accumulation of ASARM resulting in the osteomalacia. PMID- 19775210 TI - Can patients with pulmonary hypertension travel to high altitude? AB - With the increasing popularity of adventure travel and mountain activities, it is likely that many high altitude travelers will have underlying medical problems and approach clinicians for advice about ensuring a safe sojourn. Patients with underlying pulmonary hypertension are one group who warrants significant concern during high altitude travel, because ambient hypoxia at high altitude will trigger hypoxic pulmonary vasoconstriction and cause further increases in pulmonary artery (PA) pressure, which may worsen hemodynamics and also predispose to acute altitude illness. After addressing basic information about pulmonary hypertension and pulmonary vascular responses to acute hypoxia, this review discusses the evidence supporting an increased risk for high altitude pulmonary edema in these patients, concerns regarding worsening oxygenation and right-heart function, the degree of underlying pulmonary hypertension necessary to increase risk, and the altitude at which such problems may occur. These patients may be able to travel to high altitude, but they require careful pre-trip assessment, including echocardiography and, when feasible, high altitude simulation testing with echocardiography to assess changes in PA pressure and oxygenation under hypoxic conditions. Those with mean PA pressure > or =35 mm Hg or systolic PA pressure > or =50 mm Hg at baseline should avoid travel to >2000 m; but if such travel is necessary or strongly desired, they should use supplemental oxygen during the sojourn. Patients with milder degrees of pulmonary hypertension may travel to altitudes <3000 m, but should consider prophylactic measures, including pulmonary vasodilators or supplemental oxygen. PMID- 19775211 TI - Reduced incidence and severity of acute mountain sickness in Qinghai-Tibet railroad construction workers after repeated 7-month exposures despite 5-month low altitude periods. AB - The construction of the Qinghai-Tibet railroad provided a unique opportunity to study the relation between intermittent altitude exposure and acute mountain sickness (AMS). For 5 yr, workers spent 7-month periods at altitude interspaced with 5-month periods at sea level; the incidence, severity, and risk factors of AMS were prospectively investigated. Six hundred lowlanders commuted for 5 yr between near sea level and approximately 4500 m and were compared to 600 other lowland workers, recruited each year upon their first ascent to high altitude as newcomers, and to 200 Tibetan workers native to approximately 4500 m. AMS was assessed with the Lake Louise Scoring System. The incidence and severity of AMS in commuters were lower upon each subsequent exposure, whereas they remained similar in newcomers each year. AMS susceptibility was thus lowered by repeated exposure to altitude. Repeated exposure increased resting Sao(2) and decreased resting heart rate. Tibetans had no AMS, higher Sao(2), and lower heart rates. In conclusion, repetitive 7-month exposures increasingly protect lowlanders against AMS, even when interspaced with 5-month periods spent at low altitude, but do not allow attaining the level of adaptation of altitude natives. PMID- 19775212 TI - The hypoxic profile during trekking to the Pyramid Laboratory. AB - The oxygen saturation values reported in the high altitude literature are usually taken during a few minutes of measurement either at rest or during exercise. We aimed to investigate the daily hypoxic profile by monitoring oxygen saturation for 24 h in 8 lowlanders (4 females, ages 26 to 59) during trekking from Lukla (2850 m) to the Pyramid Laboratory (5050 m). Oxygen saturation was measured (1) daily at each altitude (sm), (2) for 24-h during ascent to 3500 m, 4200 m, and on day 1 at 5050 m (lm), and (3) during a standardized exercise (em). RESULTS: (1) the sm and lm values were 90.9% (+/-0.5) and 86.4% (+/-1.1) at 3500 m; 85.2%(+/ 1.1), and 80% (+/-1.9) at 4200 m; 83.8%(+/-1) and 77% (+/-1.7) at 5050 m (p < or = 0.05); (2) the daily time spent with oxygen saturation < or =90% was 56.5% at 3500 m, 81% at 4200 m, and 95.5% at 5050 m; (3) during exercise, oxygen saturation decreased by 10.58%, 13.43%, and 11.24% at 3500, 4200, and 5050 m, respectively. In conclusion, our data show that the level of hypoxemia during trekking at altitude is more severe than expected on the basis of a short evaluation at rest and should be taken into account. PMID- 19775213 TI - Prevalence of acute mountain sickness in the Eastern Alps. AB - Little information is available on the prevalence of acute mountain sickness (AMS) in the Eastern Alps compared with the Western Alps. Because of differences regarding the populations of mountaineers, we hypothesized that the prevalence differs between the Eastern and Western Alps. Thus, we determined the prevalence and risk factors of AMS at four different altitudes in the Eastern Alps of Austria. Four hundred and thirty-one recreational hikers were studied using questionnaires on the morning of their first night at high altitude. A diagnosis of AMS was based on a Lake Louise Score > or =4, the presence of headache, and at least one additional symptom. Overall 16.2% of the subjects met the criteria for AMS, and the prevalence of AMS increased significantly with altitude (2200 m: 6.9%; 2500 m: 9.1%; 2800 m: 17.4%; 3500 m: 38.0%). Heavy perceived exertion, a history of migraine, the absolute altitude reached, little mountaineering experience, and inadequate water intake (< or =2 L) were independent AMS risk factors. The reported altitude-related AMS prevalence in the Western Alps is 4% to 8% lower compared with that found in this study for the Eastern Alps. In conclusion, the prevalence of AMS is higher in the tourist population of the Eastern Alps compared to the more experienced mountaineers of the Western Alps. Consideration of easily modifiable risk factors such as individual exertion and water intake could markedly reduce AMS and contribute to the enjoyment of mountaineering. PMID- 19775214 TI - Changes of cardiac structure and function in pediatric patients with high altitude pulmonary hypertension in Tibet. AB - This study was performed to evaluate the structural and functional cardiac changes in pediatric high altitude pulmonary hypertension (HAPH) using magnetic resonance imaging (MRI) and Doppler echocardiography (Echo). Ten patients with infantile HAPH (aged 12 to 24 months) and eight healthy age-matched children (control group) underwent MRI and Echo studies. All participants were born and living in the Qinghai-Tibetan Plateau (3600 to 4600 m). The studies were performed at the Children's Hospital located in Xining, Qinghai (2260 m). The right and left ventricular end-systolic (RVEST and LVEST, respectively) and end diastolic (RVEDT and LVEDT, respectively) wall thicknesses were calculated directly from the MRI scans. The mean pulmonary arterial pressure (mPAP) was measured using Echo. RVEST was significantly higher in the HAPH group than in the control group (6.8 +/- 0.6 and 3.7 +/- 0.5 mm, respectively; p < 0.001). RVEDT was significantly higher in the HAPH patients when compared with the control group (4.9 +/- 1.1 and 2.1 +/- 0.3 mm, respectively; p < 0.05). Mean PAP in the HAPH group was significantly higher than in the control group (66.8 +/- 6.7 and 33.8 +/- 3.6 mmHg, respectively; p < 0.001) and was positively correlated with RVEDT (r(2) = 0.562, p < 0.001). Right ventricular ejection fraction was significantly lower in the HAPH group when compared with the control group (29.8 +/- 11.8 and 55.5 +/- 9.9%, respectively; p < 0.001); however, left ventricular ejection fraction was similar in both groups. These results indicate that hypoxia induced infantile HAPH leads to right ventricular hypertrophy in these patients. These structural cardiac changes may lead to right ventricular dysfunction and right heart failure; however, left ventricular function is preserved. PMID- 19775215 TI - Effect of six days of staging on physiologic adjustments and acute mountain sickness during ascent to 4300 meters. AB - This study determined the effectiveness of 6 days (d) of staging at 2200 m on physiologic adjustments and acute mountain sickness (AMS) during rapid, high-risk ascent to 4300 m. Eleven sea-level (SL) resident men (means +/- SD; 21 +/- 3 yr; 78 +/- 13 kg) completed resting measures of end-tidal CO(2) (Petco(2)), arterial oxygen saturation (Sao(2)), heart rate (HR), and mean arterial pressure (MAP) at SL and within 1 h of exposure to 4300 m in a hypobaric chamber prior to 6 d of staging at 2200 m (preSTG) and on the summit of Pikes Peak following 6 d of staging at 2200 m (postSTG). Immediately following resting ventilation measures, all performed submaximal exercise ( approximately 55% of altitude-specific maximal oxygen uptake) for approximately 2 h on a bicycle ergometer to induce higher levels of AMS. AMS-C, calculated from the Environmental Symptoms Questionnaire, was measured following 4 h and 8 h of exposure at preSTG and postSTG, and the mean was calculated. Resting Petco(2) (mmHg) was unchanged from SL (39.8 +/- 2.6) to preSTG (39.3 +/- 3.0), but decreased (p < 0.05) from preSTG to postSTG (32.8 +/- 2.6). Resting Sao(2) (%) decreased (p < 0.05) from SL (97 +/ 2) to preSTG (80 +/- 4) and increased (p < 0.05) from preSTG to postSTG (83 +/- 3). Resting HR (bpm) and MAP (mmHg) did not change in any of the test conditions. The incidence and severity of AMS-C decreased (p < 0.05) from preSTG (91 +/- 30%; 1.05 +/- 0.56) to postSTG (45 +/- 53%; 0.59 +/- 0.43), respectively. These results suggest that modest physiologic adjustments induced by staging for 6 d at 2200 m reduced the incidence and severity of AMS during rapid, high-risk ascent to 4300 m. PMID- 19775216 TI - Genotype at the missense G894T polymorphism (Glu298Asp) in the NOS3 gene is associated with susceptibility to acute mountain sickness. AB - Acute mountain sickness (AMS) is a potentially serious affliction that frequently occurs in travelers to altitudes above 2500 m. The probability of developing AMS depends on environmental factors such as rate of ascent and altitude attained; however, familial clustering and recurrence rates suggest that there may be a genetic contribution to the etiology of the condition. The underlying pathophysiology of AMS is unknown, but it may involve vasogenic edema secondary to hypoxia-induced sympathetic response and endothelial dysfunction. Nitric oxide is a potent vasomodulator, and variants in the gene that encodes endothelial nitric oxide synthase (NOS3) have been shown to affect blood pressure. We tested the hypothesis that haplotypes, as determined by tagSNPs, in NOS3 would be differentially represented in individuals with and without AMS sampled at the Janai Purnima Festival at Lake Gosain Kunda, Nepal, at 4380 m. Seven SNPs were tested, and a highly significant association (p = 0.004) was found for genotypes of the commonly studied missense polymorphism Glu298Asp (rs 1799983; G/T transversion at base 894). The T allele, which previously has been associated with hypertension, was overrepresented in individuals with AMS (0.30 vs. 0.10), but not significantly when the data were corrected for multiple testing (p = 0.024). These data suggest that a variant in a gene involved in nitric oxide synthesis is a risk factor for developing AMS. PMID- 19775217 TI - Total antioxidant status at high altitude in lowlanders and native highlanders: role of uric acid. AB - Hypobaric hypoxia causes oxidative stress and the antioxidant system of the body plays a vital role in controlling it. Urate contributes up to two-thirds of the antioxidant capacity of human blood. The urate production is catalyzed by xanthine oxidase with a concomitant release of free radicals. This study was designed to appraise the role of urate as an antioxidant at high altitude. The study was conducted on 92 male lowlanders and 66 highlanders after ascent to high altitude at 4560 m. Blood was collected at sea level and after 4 weeks of high altitude exposure. In lowlanders, a significant increase in levels of hydroperoxide (551.4 +/- 4.2 micromol/mL vs. 582.0 +/- 3.55, p < 0.001], protein carbonyl (2.4 +/- 0.11 micromol/mL/mg protein vs. 3.03 +/- 0.11, p < 0.001), TAS (1.02 +/- 0.01 mmol/L vs. 1.19 +/- 0.02, p < 0.001), and UA (298.0 +/- 6.68 micromol/L vs. 383.0 +/- 6.55, p < 0.001) was observed at high altitude. These measurements were significantly lower in highlanders than in lowlanders at high altitude. Total antioxidant status (TAS) and uric acid (UA) showed a positive correlation in lowlanders at sea level and in highlanders at high altitude. Hydroperoxide and TAS also showed a positive correlation in both groups at high altitude. This indicates increased oxidative stress at high altitude despite an increase in antioxidant capacity in lowlanders. To conclude, a hypoxia-induced increase in UA contributes an appreciable portion of plasma total antioxidant capacity, but may not be effective in preventing oxidative stress at high altitude. PMID- 19775218 TI - Blood rheology adjustments in rats after a program of intermittent exposure to hypobaric hypoxia. AB - Intermittent hypobaric hypoxia (IHH) exposure induces a rise in hemoglobin concentration and an increase in erythrocyte mass in both rats and humans. Although this response increases blood oxygen transport capacity, paradoxically, it could impair blood flow and gas exchange because of the blood viscosity alterations associated with the rising hematocrit. In the present study, male rats were subjected to an IHH program consisting of a daily 4-h session for 5 days/week until they had completed 22 days of hypoxia exposure in a hypobaric chamber at a simulated altitude of 5000 m. Blood samples were taken at the end of the exposure period (H) and at 20 (P20) and 40 (P40) days after the end of the program and were compared to control (C) maintained at sea- level pressure. Apparent blood viscosity (eta(a)) and plasma viscosity (eta(p)) were measured in a cone-plate microviscometer. Although the hematocrit significantly increased in the H group, blood apparent viscosity did not differ among groups, ranging from 7.67 to 6.57 mPa*sec at a shear rate of 90 sec(-1). Relative blood viscosity showed a clear increase (about 27%) in H rats, mainly due to the significant decrease in plasma viscosity. This finding could be interpreted as a compensatory response, which reduced the effect of increased erythrocyte mass volume on whole blood viscosity. Oxygen delivery index and blood oxygen potential transport capacity remained unchanged in all groups. These data indicate that the IHH program has a deep but transitory effect on red cell parameters and a moderate effect on blood rheological behavior. PMID- 19775219 TI - Hyperoxygenated solution: effects on acute hypobaric hypoxia-induced oxidative damage in rabbits. AB - High altitude (HA) exposure disrupts the efficiency of the antioxidant system and can lead to oxidative damage in various organs and tissues. The present study investigated the effect of hyperoxygenated solution (HOS) intravenous infusion therapy on oxidative damage induced by acute hypobaric hypoxia. Experimental rabbits were exposed to a simulated high altitude (HA), equivalent to 8500 m, in an animal decompression chamber for 3 h. HOS infusion attenuated the rise in malondialdehyde (MDA) levels and the decrease of the reduced oxidized glutathione (GSH/GSSG) ratio. HOS also increased the activity of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GSH-Px); the arterial partial pressure of oxygen (Pao(2)); and arterial blood oxygen saturation (Sao(2)) levels. Animals treated with HOS had higher Pao(2) compared with those subjected to airway oxygen therapy (p < 0.01) during HA exposure. These observations suggest that HOS intravenous infusion exerts protective effects against acute hypobaric hypoxia-induced oxidative damage. PMID- 19775220 TI - Secondary prevention of HAPE in a Mount Everest summiteer. AB - Climbers who have suffered a previous episode of high altitude pulmonary edema (HAPE) are at significantly increased risk of developing it again on return to high altitude. In spite of the high mortality associated with HAPE, some climbers are willing to take this risk in order to summit the tallest mountains in the world. This is a case report of a climber who suffered an episode of HAPE partway up Mount Everest. He was determined to complete his summit attempt that same climbing season, which would involve a return to extreme altitude less than 3 weeks following recovery. Based on experimental evidence suggesting that sildenafil, salmeterol, and acetazolamide may have therapeutic value for both the prevention and treatment of HAPE, he used these medications for secondary prevention. He was able to successfully reach the summit of Mount Everest and return to base camp without any evidence of recurrence of pulmonary edema. This provides clinical evidence that medication can be used to increase the safety margin for HAPE-susceptible individuals traveling to extremely high altitudes. PMID- 19775221 TI - 16th International Hypoxia Symposium at Chateau Lake Louise, March 10-14, 2009, Alberta, Canada. PMID- 19775222 TI - Is there a safer and more successful way to climb Kilimanjaro? PMID- 19775224 TI - Should travelers with hypertension adjust their medications when traveling to high altitude? PMID- 19775227 TI - Different effects of species diversity on temporal stability in single-trophic and multitrophic communities. AB - The question of how species diversity affects ecological stability has long interested ecologists and yet remains largely unresolved. Historically, attempts to answer this question have been hampered by the presence of multiple potentially confounding stability concepts, confusion over responses at different levels of ecological organization, discrepancy between theoretical predictions, and, particularly, the paucity of empirical studies. Here we used meta-analyses to synthesize results of empirical studies published primarily in the past 2 decades on the relationship between species diversity and temporal stability. We show that the overall effect of increasing diversity was positive for community level temporal stability but neutral for population-level temporal stability. There were, however, striking differences in the diversity-stability relationship between single- and multitrophic systems, with diversity stabilizing both population and community dynamics in multitrophic but not single-trophic communities. These patterns were broadly equivalent across experimental and observational studies as well as across terrestrial and aquatic studies. We discuss possible mechanisms for population stability to increase with diversity in multitrophic systems and for diversity to influence community-level stability in general. Overall, our results indicate that diversity can affect temporal stability, but the effects may critically depend on trophic complexity. PMID- 19775232 TI - Abstracts of the 80th Annual Meeting of the American Thyroid Association. Palm Beach, Florida, USA. September 23-27, 2009. PMID- 19775228 TI - Expression of angiopoietin-like 4 and tenascin C but not cathepsin C mRNA predicts prognosis of oral tongue squamous cell carcinoma. AB - Analysis of gene expression using RNA from the paraffin-embedded tissues is becoming an important way to study cancer pathogenesis. In this article, total RNA was extracted from tissue of 158 cases of paraffin-embedded tongue cancer, and expression of angiopoietin-like 4, tenascin-C and cathepsin-C were detected by real-time reverse transcriptase-polymerase chain reaction (RT-PCR). Our results demonstrated that high expression level of angiopoietin-like 4 or tenascin-C was predictive of poor prognosis of tongue cancer patients (p = 0.024 and p = 0.011, respectively), especially when expression levels of both genes were concomitantly high (p = 0.001). Additionally, high expression of angiopoietin-like 4 and tenascin-C, or concomitant high expression of angiopoietin-like 4 and tenascin-C were independent prognostic factors of poor survival in patients with tongue cancer. These results suggest that the improved method of RNA extraction is suitable for analysing gene expression of paraffin embedded solid tumours. Angiopoietin-like and tenascin-C, especially the combination of angiopoietin-like 4 and tenascin-C, are useful for predicting the prognosis of the patients with tongue cancer, independent of lymph node metastasis status. PMID- 19775234 TI - Clinical veterinarian's perspective of non-human primate (NHP) use in drug safety studies. AB - Owing to their size, cost, and availability, the cynomolgus macaque (Macaca fascicularis) has surpassed the rhesus macaque in its use as a non-human primate preclinical model for drug safety studies. There are three major regions where cynomolgus macaques are bred: China, Southeast Asia, and the island of Mauritius. Country of origin of the macaque is important, as disease status and background disease incidence in non-human primates from each of these sites can differ. Once a source of macaque has been decided, careful monitoring of the animal during breeding and by the importing vendor while the animals are in quarantine is important. During vendor quarantine, the animals should be monitored and evaluated for disease, response to tuberculosis testing, retroviral status, and both ecto- and endoparasites. After animals arrive at the test facility, additional quarantine and acclimation are important to ascertain health status further and to reduce stress on the animals, thereby providing a better research model. The type of caging, food, water, and enrichment should be carefully selected to best suit the needs of the study while working within Federal Regulations (i.e., Animal Welfare Act and Good Laboratory Practices). Careful prescreening by performing tests (such as physical, neurologic, and ophthalmologic examinations), complete blood count, biochemical profile, urinanalysis, electrocardiograms, and pulse oximetry is important when selecting the most appropriate animals for the study. After the in-life portion of the study begins, animals that present with clinical signs should be examined and an appropriate treatment course begun while maintaining study objectives. As many commonly used medications have immunomodulatory effects, having an understanding of the mechanism of action of test articles will aid in the appropriate choice of treatment of study animals. A tiered approach to the treatment of these animals is a conservative and usually acceptable approach. PMID- 19775236 TI - Preparation and evaluation of solid lipid nanoparticles with JSH18 for skin whitening efficacy. AB - A new molecule having the structure of 6-methyl-3-phenethyl-3,4-dihydro-1H quinazoline-2-thione (JSH18) was synthesized and it was possibly presupposed to show depigmentation through the inhibition of tyrosinase which is involved in the formation of melanin. Therefore, we are going to develop JSH18 as an inhibitor of melanin synthesis with topical formulations to show its optimal efficiency for skin whitening. Solid lipid nanoparticles (SLNs) play an important role as drug delivery systems for intravenous, peroral, parenteral, or ocular administration and for topical delivery. The particle size of prepared SLNs of JSH18 was variable from 59.8-919.6 nm. When the optimal SLNs cream (PU3) including 4 uM of JSH18 was applied to the backs of hairless rats for four days after the backs were irradiated by UV ray for seven days and the skin color was checked by reflectance spectrophotometer, the rat skin applied with PU3 cream quickly recovered to normal compared to SLNs cream without JSH18. Taken together, this study suggests topical formulations such as creams including SLNs with JSH18 might be an appropriate carrier for skin-whitening agents. PMID- 19775238 TI - Evaluation of an electronic device for real-time measurement of alcohol-based hand rub use. AB - BACKGROUND: Observational surveys of hand hygiene compliance are time consuming. Measuring the use of a hand hygiene product is a less time-consuming method of monitoring the frequency of hand hygiene performance. OBJECTIVE: To evaluate the usefulness of electronic devices for monitoring alcohol-based hand rub use. DESIGN: Prospective observational trial. SETTING: A university-affiliated teaching hospital. METHODS: Prototypes of an electronic device designed to record each time a dispenser is used (hereafter referred to as a hand hygiene event) were placed in alcohol-based hand rub dispensers on the general medical ward and in the surgical intensive care unit. Data were downloaded wirelessly to a data logger and then uploaded to a dedicated Web site for analysis. Alcohol-based hand rub dispensers were located in patient rooms and in corridors. RESULTS: During a 6-month trial, 105,462 hand hygiene events occurred in the surgical intensive care unit, and 44,845 events occurred on the general medical ward. The dispensers located in patient rooms accounted for 47% of the hand hygiene events performed in the surgical intensive care unit but for only 36% of events on the general medical ward (P < .001). The dispensers most often used were located in corridors. Hand hygiene events were most common on Tuesdays, Wednesdays, and Thursdays, between 7:00 am and 11:00 am. CONCLUSIONS: The use of these electronic devices provided an efficient and accurate method of monitoring the frequency of alcohol-based hand rub performance on the general medical ward and in the surgical intensive care unit, and yielded more detailed information on usage patterns than did expressing use as liters per 1,000 patient-days. The wireless downloading of data from dispensers required a limited amount of time, and the dedicated Web site facilitated data analysis. Such devices should prove useful in monitoring the impact of various interventions on the frequency of hand hygiene performance. PMID- 19775239 TI - Regulation of midgut growth, development, and metamorphosis. AB - The insect midgut is an important site of entry for pathogens and insect control agents. This review focuses on recent information related to midgut epithelial growth, metamorphosis, and repair as a defense against pathogens. The roles of stem cell mitogens and differentiation factors are described. Included is a discussion of apoptosis and autophagy in the yellow body. Sloughing, also described, protects the midgut from virus infections and bacterial toxins through death and replacement of affected cells. The mechanisms by which the repair process reduces the effectiveness of pest control strategies are discussed. Primary tissue culture methods also are described, and their value in understanding the mechanisms by which biologically based insecticides work is discussed. PMID- 19775240 TI - Cost of reproduction, resource quality, and terminal investment in a burying beetle. AB - We evaluate the cost-of-reproduction hypothesis in the burying beetle Nicrophorus orbicollis and examine how the importance of this trade-off changes as females age (i.e., the terminal-investment hypothesis). These beetles breed on small vertebrate carcasses, which serve as a food resource for them and their offspring. Consistent with the cost-of-reproduction hypothesis, females manipulated to overproduce offspring suffered a reduction in fecundity and life span when compared to controls, although all reproducing females had reduced life spans compared to nonbreeding females. Older females produced larger broods and allocated less of the carcass to their own body mass and a greater proportion to offspring than did younger females. Resource allocation to offspring increased with age. Females given larger carcasses invested more in current reproduction and less in future reproduction than did females given smaller carcasses. Our results provide unconfounded support for both the cost-of-reproduction hypothesis (i.e., current reproduction constrains future reproductive output) and the terminal-investment hypothesis (i.e., the importance of the trade-off between current and future reproduction declines with age such that allocation to current reproduction should increase as females age). PMID- 19775241 TI - How different types of natal experience affect habitat preference. AB - In many animals, exposure to cues in a natal habitat increases disperser preferences for those cues (natal habitat preference induction [NHPI]), but the proximate and ultimate bases for this phenomenon are obscure. We developed a Bayesian model to study how different types of experience in the natal habitat and survival to the age/stage of dispersal interact to affect a disperser's estimate of the quality of new natal-type habitats. The model predicts that the types of experience a disperser had before leaving its natal habitat will affect the attractiveness of cues from new natal-type habitats and that favorable experiences will increase the level of preference for natal-type habitats more than unfavorable experiences will decrease it. An experimental study of NHPI in Drosophila melanogaster provided with "good" and "bad" experiences in their natal habitats supports these predictions while also indicating that the effects of different types of natal experience on NHPI vary across genotypes. If habitat preferences are modulated by an individual's experience before dispersal as described in this study, then NHPI may have stronger effects on sympatric speciation, metapopulation dynamics, conservation biology, and pest management than previously supposed. PMID- 19775242 TI - Post-translational modifications of connexin26 revealed by mass spectrometry. AB - Gap junctions play important roles in auditory function and skin biology; mutations in the Cx26 (connexin26) gene are the predominant cause of inherited non-syndromic deafness and cause disfiguring skin disorders. Mass spectrometry (MS) was used to identify PTMs (post-translational modifications) of Cx26 and to determine whether they occur at sites of disease-causing mutations. Cx26 was isolated from transfected HeLa cells by sequential immunoaffinity and metal chelate chromatography using a tandem C-terminal haemagglutinin epitope and a (His-Asn)6 sequence. In-gel and in-solution enzymatic digestions were carried out in parallel with trypsin, chymotrypsin and endoproteinase GluC. Peptides were fractionated using a reversed-phase matrix by stepwise elution with increasing concentrations of organic solvent. To improve detection of low-abundance peptides and to maximize sequence coverage, MALDI-TOF-MS (matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry; MS) and MALDI-TOF/TOF MS/MS (matrix-assisted laser desorption/ionization-time-of-flight/time-of-flight tandem mass spectrometry; MS/MS) spectra were acquired from each elution step using an Applied Biosystems 4800 tandem mass spectrometer. Acquisition, processing and interpretation parameters were optimized to improve ionization and fragmentation of hydrophobic peptides. MS and MS/MS coverage of Cx26 was significantly above that reported for other membrane proteins: 71.3% by MS, with 29.9% by MS/MS. MS coverage was 92.6% if peptides resulting from in-source collisions and/or partial enzymatic cleavages were considered. A variety of putative PTMs of Cx26 were identified, including acetylation, hydroxylation, gamma-carboxyglutamation, methylation and phosphorylation, some of which are at sites of deafness-causing mutations. Knowledge of the PTMs of Cx26 will be instrumental in understanding how alterations in the cellular mechanisms of Cx26 channel biogenesis and function lead to losses in auditory function and disfiguring skin disorders. PMID- 19775243 TI - Targeted gene inactivation in Clostridium phytofermentans shows that cellulose degradation requires the family 9 hydrolase Cphy3367. AB - Summary Microbial cellulose degradation is a central part of the global carbon cycle and has great potential for the development of inexpensive, carbon-neutral biofuels from non-food crops. Clostridium phytofermentans has a repertoire of 108 putative glycoside hydrolases to break down cellulose and hemicellulose into sugars, which this organism then ferments primarily to ethanol. An understanding of cellulose degradation at the molecular level requires learning the different roles of these hydrolases. In this study, we show that interspecific conjugation with Escherichia coli can be used to transfer a plasmid into C. phytofermentans that has a resistance marker, an origin of replication that can be selectively lost, and a designed group II intron for efficient, targeted chromosomal insertions without selection. We applied these methods to disrupt the cphy3367 gene, which encodes the sole family 9 glycoside hydrolase (GH9) in the C. phytofermentans genome. The GH9-deficient strain grew normally on some carbon sources such as glucose, but had lost the ability to degrade cellulose. Although C. phytofermentans upregulates the expression of numerous enzymes to break down cellulose, this process thus relies upon a single, key hydrolase, Cphy3367. PMID- 19775245 TI - Analysis of the Yersinia enterocolitica PspBC proteins defines functional domains, essential amino acids and new roles within the phage-shock-protein response. AB - The Yersinia enterocolitica phage-shock-protein (Psp) stress response system is activated by mislocalized outer-membrane secretin components of protein export systems and is essential for virulence. The cytoplasmic membrane proteins PspB and PspC were proposed to be dual function components of the system, acting both as positive regulators of psp gene expression and to support survival during secretin-induced stress. In this study we have uncoupled the regulatory and physiological functions of PspBC and discovered unexpected new roles, functional domains and essential amino acids. First, we showed that PspB controls PspC concentration by both pre- and post-transcriptional mechanisms. We then screened for PspBC mutants with altered transcriptional regulatory function. Unexpectedly, we identified PspB and PspC mutants that activated psp gene expression in the absence of secretin-induced stress. Together with a subsequent truncation analysis, this revealed that the PspC cytoplasmic domain plays an unforeseen role in negatively regulating psp gene expression. Conversely, mutations within the PspC periplasmic domain abolished its ability to activate psp gene expression. Significantly, PspC mutants unable to activate psp gene expression retained their ability to support survival during secretin-induced stress. These data provide compelling support for the proposal that these two functions are independent. PMID- 19775246 TI - Hybrid Ptr2-like activators of archaeal transcription. AB - Methanocaldococcus jannaschii Ptr2, a member of the Lrp/AsnC family of bacterial DNA-binding proteins, is an activator of its eukaryal-type core transcription apparatus. In Lrp-family proteins, an N-terminal helix-turn-helix DNA-binding and dimerizing domain is joined to a C-terminal effector and multimerizing domain. A cysteine-scanning surface mutagenesis shows that the C-terminal domain of Ptr2 is responsible for transcriptional activation; two types of DNA binding-positive but activation-defective mutants are found: those unable to recruit the TBP and TFB initiation factors to the promoter, and those failing at a post-recruitment step. Transcriptional activation through the C-terminal Ptr2 effector domain is exploited in a screen of other Lrp effector domains for activation capability by constructing hybrid proteins with the N-terminal DNA-binding domain of Ptr2. Two hybrid proteins are effective activators: Ptr-H10, fusing the effector domain of Pyrococcus furiosus LrpA, and Ptr-H16, fusing the P. furiosus ORF1231 effector domain. Both new activators exhibit distinguishing characteristics: unlike octameric Ptr2, Ptr-H10 is a dimer; unlike Ptr2, the octameric Ptr-H16 poorly recruits TBP to the promoter, but more effectively co-recruits TFB with TBP. In contrast, the effector domain of Ptr1, the M. jannaschii Ptr2 paralogue, yields only very weak activation. PMID- 19775244 TI - The coat morphogenetic protein SpoVID is necessary for spore encasement in Bacillus subtilis. AB - Endospores formed by Bacillus subtilis are encased in a tough protein shell known as the coat, which consists of at least 70 different proteins. We investigated the process of spore coat morphogenesis using a library of 40 coat proteins fused to green fluorescent protein and demonstrate that two successive steps can be distinguished in coat assembly. The first step, initial localization of proteins to the spore surface, is dependent on the coat morphogenetic proteins SpoIVA and SpoVM. The second step, spore encasement, requires a third protein, SpoVID. We show that in spoVID mutant cells, most coat proteins assembled into a cap at one side of the developing spore but failed to migrate around and encase it. We also found that SpoIVA directly interacts with SpoVID. A domain analysis revealed that the N-terminus of SpoVID is required for encasement and is a structural homologue of a virion protein, whereas the C-terminus is necessary for the interaction with SpoIVA. Thus, SpoVM, SpoIVA and SpoVID are recruited to the spore surface in a concerted manner and form a tripartite machine that drives coat formation and spore encasement. PMID- 19775247 TI - Cannibalism enhances biofilm development in Bacillus subtilis. AB - Cannibalism is a mechanism to delay sporulation in Bacillus subtilis. Cannibal cells express the skf and sdp toxin systems to lyse a fraction of their sensitive siblings. The lysed cells release nutrients that serve to feed the community, effectively delaying spore formation. Here we provide evidence that the subpopulation of cells that differentiates into cannibals is the same subpopulation that produces the extracellular matrix that holds cells together in biofilms. Cannibalism and matrix formation are both triggered in response to the signalling molecule surfactin. Nutrients released by the cannibalized cells are preferentially used by matrix-producing cells, as they are the only cells expressing resistance to the Skf and Sdp toxins. As a result this subpopulation increases in number and matrix production is enhanced when cannibalism toxins are produced. The cannibal/matrix-producing subpopulation is also generated in response to antimicrobials produced by other microorganisms and may thus constitute a defense mechanism to protect B. subtilis from the action of antibiotics in natural settings. PMID- 19775249 TI - Functions and regulation of the Nox family in the filamentous fungus Podospora anserina: a new role in cellulose degradation. AB - NADPH oxidases are enzymes that produce reactive oxygen species. Studies in mammals, plants and fungi have shown that they play important roles in differentiation, defence, host/pathogen interaction and mutualistic symbiosis. In this paper, we have identified a Podospora anserina mutant strain impaired for processes controlled by PaNox1 and PaNox2, the two Nox isoforms characterized in this model ascomycete. We show that the gene mutated is PaNoxR, the homologue of the gene encoding the regulatory subunit p67(phox), conserved in mammals and fungi, and that PaNoxR regulates both PaNox1 and PaNox2. Genome sequence analysis of P. anserina reveals that this fungus posses a third Nox isoform, PaNox3, related to human Nox5/Duox and plant Rboh. We have generated a knock-out mutant of PaNox3 and report that PaNox3 plays a minor role in P. anserina, if any. We show that PaNox1 and PaNox2 play antagonist roles in cellulose degradation. Finally, we report for the first time that a saprobic fungus, P. anserina, develops special cell structures dedicated to breach and to exploit a solid cellulosic substrate, cellophane. Importantly, as for similar structures present in some plant pathogens, their proper differentiation requires PaNox1, PaNox2, PaNoxR and the tetraspanin PaPls1. PMID- 19775248 TI - Molecular characterization of staphyloferrin B biosynthesis in Staphylococcus aureus. AB - Siderophores are iron-scavenging molecules produced by many microbes. In general, they are synthesized using either non-ribosomal peptide synthetase (NRPS) or NRPS independent siderophore (NIS) pathways. Staphylococcus aureus produces siderophores, of which the structures of staphyloferrin A and staphyloferrin B are known. Recently, the NIS biosynthetic pathway for staphyloferrin A was characterized. Here we show that, in S. aureus, the previously identified sbn (siderophore biosynthesis) locus encodes enzymes required for the synthesis of staphyloferrin B, an alpha-hydroxycarboxylate siderophore comprised of l-2,3 diaminopropionic acid, citric acid, 1,2-diaminoethane and alpha-ketoglutaric acid. Staphyloferrin B NIS biosynthesis was recapitulated in vitro, using purified recombinant Sbn enzymes and the component substrates. In vitro synthesized staphyloferrin B readily promoted the growth of iron-starved S. aureus, via the ABC transporter SirABC. The SbnCEF synthetases and a decarboxylase, SbnH, were necessary and sufficient to produce staphyloferrin B in reactions containing component substrates l-2,3-diaminopropionic acid, citric acid and alpha-ketoglutaric acid. Since 1,2-diaminoethane was not required, this component of the siderophore arises from the SbnH-dependent decarboxylation of a 2,3-diaminoproprionic acid-containing intermediate. Liquid chromatography electrospray ionization-mass spectrometry (LC-ESI-MS) analyses of a series of enzyme reactions identified mass ions corresponding to biosynthetic intermediates, allowing for the first proposed biosynthetic pathway for staphyloferrin B. PMID- 19775251 TI - Effects of tissue age, presence of neurones and endothelin-3 on the ability of enteric neurone precursors to colonize recipient gut: implications for cell-based therapies. AB - BACKGROUND Most enteric neurones arise from neural crest cells that originate in the post-otic hindbrain, and migrate into and along the developing gastrointestinal tract. There is currently great interest in the possibility of cell therapy to replace diseased or absent enteric neurones in patients with enteric neuropathies, such as Hirschsprung's disease. However, it is unclear whether neural crest stem/progenitor cells will be able to colonize colon (i) in which the mesenchyme has differentiated into distinct layers, (ii) that already contains enteric neurones or (iii) that lacks a gene expressed by the gut mesenchyme, such as endothelin-3 (Et-3). METHODS Co-cultures were used to examine the ability of enteric neural crest-derived cells (ENCCs) from E11.5 mouse gut to colonize a variety of recipient hindguts. KEY RESULTS Enteric neural crest derived cells migrated and gave rise to neurones in E14.5 and E16.5 aneural colon in which the external muscle layers had differentiated, but they did not migrate as far as in younger colon. There was no evidence of altered ENCC proliferation, cell death or neuronal differentiation in older recipient explants. Enteric neural crest-derived cells failed to enter most recipient E14.5 and E16.5 colon explants already containing enteric neurones, and the few that did showed very limited migration. Finally, ENCCs migrated a shorter distance and a higher proportion expressed the pan-neuronal marker, Hu, in recipient E11.5 Et-3(-/-) colon compared to wild-type recipient colon. CONCLUSIONS & INFERENCES Age and an absence of Et-3 from the recipient gut both significantly reduced but did not prevent ENCC migration, but the presence of neurones almost totally prevented ENCC migration. PMID- 19775250 TI - Regulation of the type IV pili molecular machine by dynamic localization of two motor proteins. AB - Type IV pili (T4P) are surface structures that undergo extension/retraction oscillations to generate cell motility. In Myxococcus xanthus, T4P are unipolarly localized and undergo pole-to-pole oscillations synchronously with cellular reversals. We investigated the mechanisms underlying these oscillations. We show that several T4P proteins localize symmetrically in clusters at both cell poles between reversals, and these clusters remain stationary during reversals. Conversely, the PilB and PilT motor ATPases that energize extension and retraction, respectively, localize to opposite poles with PilB predominantly at the piliated and PilT predominantly at the non-piliated pole, and these proteins oscillate between the poles during reversals. Therefore, T4P pole-to-pole oscillations involve the disassembly of T4P machinery at one pole and reassembly of this machinery at the opposite pole. Fluorescence recovery after photobleaching experiments showed rapid turnover of YFP-PilT in the polar clusters between reversals. Moreover, PilT displays bursts of accumulation at the piliated pole between reversals. These observations suggest that the spatial separation of PilB and PilT in combination with the noisy PilT accumulation at the piliated pole allow the temporal separation of extension and retraction. This is the first demonstration that the function of a molecular machine depends on disassembly and reassembly of its individual parts. PMID- 19775252 TI - Luminex-based virtual crossmatching facilitates combined third-time cardiac and de novo renal transplantation in a sensitized patient with sustained antibody mediated cardiac allograft rejection. AB - Allosensitization represents a major obstacle to successful re-transplantation since circulating antibodies can elicit antibody-mediated rejection episodes with subsequent graft failure. Since sensitization is primarily considered a contraindication to transplantation the duration for patients waiting for a suitable donor organ to become available is considerably prolonged. Herein, we report on the successful application of a Luminex-based virtual crossmatch approach to facilitate combined third-time cardiac and de novo renal transplantation in a sensitized patient with sustained antibody-mediated cardiac allograft rejection. PMID- 19775253 TI - Clinical effects of sulphite additives. AB - Sulphites are widely used as preservative and antioxidant additives in the food and pharmaceutical industries. Topical, oral or parenteral exposure to sulphites has been reported to induce a range of adverse clinical effects in sensitive individuals, ranging from dermatitis, urticaria, flushing, hypotension, abdominal pain and diarrhoea to life-threatening anaphylactic and asthmatic reactions. Exposure to the sulphites arises mainly from the consumption of foods and drinks that contain these additives; however, exposure may also occur through the use of pharmaceutical products, as well as in occupational settings. While contact sensitivity to sulphite additives in topical medications is increasingly being recognized, skin reactions also occur after ingestion of or parenteral exposure to sulphites. Most studies report a 3-10% prevalence of sulphite sensitivity among asthmatic subjects following ingestion of these additives. However, the severity of these reactions varies, and steroid-dependent asthmatics, those with marked airway hyperresponsiveness, and children with chronic asthma, appear to be at greater risk. In addition to episodic and acute symptoms, sulphites may also contribute to chronic skin and respiratory symptoms. To date, the mechanisms underlying sulphite sensitivity remain unclear, although a number of potential mechanisms have been proposed. Physicians should be aware of the range of clinical manifestations of sulphite sensitivity, as well as the potential sources of exposure. Minor modifications to diet or behaviour lead to excellent clinical outcomes for sulphite-sensitive individuals. PMID- 19775254 TI - Salmonella--the ultimate insider. Salmonella virulence factors that modulate intracellular survival. AB - Salmonella enterica serovar Typhimurium is a common facultative intracellular pathogen that causes food-borne gastroenteritis in millions of people worldwide. Intracellular survival and replication are important virulence determinants and the bacteria can be found in a variety of phagocytic and non-phagocytic cells in vivo. Invasion of host cells and intracellular survival are dependent on two type III secretion systems, T3SS1 and T3SS2, each of which translocates a distinct set of effector proteins. However, other virulence factors including ion transporters, superoxide dismutase, flagella and fimbriae are also involved in accessing and utilizing the intracellular niche. PMID- 19775255 TI - Zaire Ebola virus entry into human dendritic cells is insensitive to cathepsin L inhibition. AB - Cathepsins B and L contribute to Ebola virus (EBOV) entry into Vero cells and mouse embryonic fibroblasts. However, the role of cathepsins in EBOV-infection of human dendritic cells (DCs), important targets of infection in vivo, remains undefined. Here, EBOV-like particles containing a beta-lactamase-VP40 fusion reporter and Ebola virus were used to demonstrate the cathepsin dependence of EBOV entry into human monocyte-derived DCs. However, while DC infection is blocked by cathepsin B inhibitor, it is insensitive to cathepsin L inhibitor. Furthermore, DCs pre-treated for 48 h with TNFalpha were generally less susceptible to entry and infection by EBOV. This decrease in infection was associated with a decrease in cathepsin B activity. Thus, cathepsin L plays a minimal, if any, role in EBOV infection in human DCs. The inflammatory cytokine TNFalpha modulates cathepsin B activity and affects EBOV entry into and infection of human DCs. PMID- 19775257 TI - From Appalachia to the world. PMID- 19775258 TI - Tribute to Dr. Michael E. DeBakey and his spirit of pioneering: perspective from the international community. PMID- 19775259 TI - Lifelong contributions of Dr. Michael E. DeBakey and the 16th Congress of the International Society for Rotary Blood Pumps. PMID- 19775260 TI - Usability and safety of ventricular assist devices: human factors and design aspects. AB - The purpose of this study was the investigation of the usability and ergonomics of ventricular assist devices (VADs) in everyday usage. Patients with four different VAD types were observed. After implantation, instruction, and discharge from the hospital, the patients returned on a regular basis to the outpatient clinic, where the investigation took place. Data collection took place in two phases. In phase I home-released VAD patients were asked about perceived problems with the system at home. Additionally health-care professionals were interviewed to gather information on frequent VAD inconveniences and shortcomings. This inquiry resulted in a standardized self-assessment questionnaire and a manual skill test, which were performed in phase II by the whole collective (16 patients and ongoing). As a result, 38% of the patients disconnected parts of their system unintentionally at least once. All of them ascribed this problem to their own carelessness. Thirty-eight percent had to replace a cable. Seventy-five percent desired an additional cable strain relief. Thirty-eight percent suffered from rubbing of parts on the body. Sixty-three percent used a separate repository aside from the factory-provided transportation systems. The overall noise emission (pump, ventilators, and alarms) annoyed 56%; however, for 32% the alarm signals were too quiet to wake them up. No correlation between the assessed manual skills and the number of adverse events was found. To conclude, this preliminary study revealed considerable potential for improvements in the usability of ventricular assist systems. PMID- 19775261 TI - Emergency use of extracorporeal membrane oxygenation in cardiopulmonary failure. AB - Severe pulmonary and cardiopulmonary failure resistant to critical care treatment leads to hypoxemia and hypoxia-dependent organ failure. New treatment options for cardiopulmonary failure are necessary even for patients in outlying medical facilities. If these patients are in need of specialized center treatment, additional emergency medical service has to be carried out quick and safely. We describe our experiences with a pumpless extracorporeal lung assist (PECLA/iLA) for out-of-center emergency treatment of hypercapnic respiratory failure and the use of a newly developed hand-held extracorporeal membrane oxygenation (ECMO) system in cardiac, pulmonary, and cardiopulmonary failure (EMERGENCY-LIFE Support System, ELS System, MAQUET Cardiopulmonary AG, Hechingen, Germany). Between March 2000 and April 2009, we used the PECLA System (n = 20) and the ELS System (n = 33) in adult patients. Cannulation was employed using percutaneous vessel access. The new hand-held ELS System consists of a centrifugal pump and a membrane oxygenator, both mounted on a special holder system for storing on a standard patient gurney for air or ground ambulance transfer. Bedside cannulation processes were uneventful. The PECLA System resulted in sufficient CO(2) removal. In all ECMO patients, oxygen delivery and systemic blood flow could be restored and vasopressor support was markedly down. Hospital survival rate in the PECLA group was 50%, and 61% in the ECMO group. Out-of-center emergency treatment of hypercapnic pulmonary failure with pumpless extracorporeal gas exchange and treatment of cardiac, pulmonary, and cardiopulmonary failure with this new hand held ECMO device is safe and highlyeffective. Patient outcome in cardiopulmonary organ failure could be improved. PMID- 19775262 TI - Development of a disposable maglev centrifugal blood pump intended for one-month support in bridge-to-bridge applications: in vitro and initial in vivo evaluation. AB - MedTech Dispo, a disposable maglev centrifugal blood pump with two degrees of freedom magnetic suspension and radial magnetic coupling rotation, has been developed for 1-month extracorporeal circulatory support. As the first stage of a two-stage in vivo evaluation, 2-week evaluation of a prototype MedTech Dispo was conducted. In in vitro study, the pump could produce 5 L/min against 800 mm Hg and the normalized index of hemolysis was 0.0054 +/- 0.0008 g/100 L. In in vivo study, the pump, with its blood-contacting surface coated with biocompatible 2 methacryloyloxyethyl phosphorylcholine polymer, was implanted in seven calves in left heart bypass. Pump performance was stable with a mean flow of 4.49 +/- 0.38 L/min at a mean speed of 2072.1 +/- 64.5 rpm. The maglev control revealed its stability in rotor position during normal activity by the calves. During 2 weeks of operation in two calves which survived the intended study period, no thrombus formation was seen inside the pump and levels of plasma free hemoglobin were maintained below 4 mg/dL. Although further experiments are required, the pump demonstrated the potential for sufficient and reliable performance and biocompatibility in meeting the requirements for cardiopulmonary bypass and 1 week circulatory support. PMID- 19775263 TI - Design of a small centrifugal blood pump with magnetic bearings. AB - Design of a blood pump with a magnetically levitated rotor requires rigorous evaluation of the magnetic bearing and motor requirements and analysis of rotor dynamics and hydraulic performance with attention to hemolysis and thrombosis potential. Given the desired geometric dimensions, the required operating speed, flow in both the main and wash flow regions, and magnetic bearing performance, one of several design approaches was selected for a new prototype. Based on the estimated operating speed and clearance between the rotor and stator, the motor characteristics and dimensions were estimated. The motor stiffness values were calculated and used along with the hydraulic loading due to the fluid motion to determine the best design for the axial and radial magnetic bearings. Radial and axial stability of the left ventricular assist device prototype was verified using finite element rotor dynamic analysis. The analysis indicated that the rotor could be completely levitated and spun to the desired operating speed with low power loss and no mechanical contact. In vitro experiments with a mock loop test setup were performed to evaluate the performance of the new blood pump prototype. PMID- 19775264 TI - The impact of aortic/subclavian outflow cannulation for cardiopulmonary bypass and cardiac support: a computational fluid dynamics study. AB - Approximately 100 000 cases of oxygen deficiency in the brain occur during cardiopulmonary bypass (CPB) procedures each year. In particular, perfusion of the carotid and vertebral arteries is affected. The position of the outflow cannula influences the blood flow to the cardiovascular system and thus end organ perfusion. Traditionally, the cannula returns blood into the ascending aorta. But some surgeons prefer cannulation to the right subclavian artery. A computational fluid dynamics study was initially undertaken for both approaches. The vessel model was created from real computed tomography/magnetic resonance imaging data of young healthy patients. The simulations were run with usual CPB conditions. The flow distribution for different cannula positions in the aorta was studied, as well as the impact of the cannula tip distance to vertebral artery for the subclavian position. The study presents a fast method of analyzing the flow distribution in the cardiovascular system, and can be adapted for other applications such as ventricular assist device support. It revealed that two effects cause the loss of perfusion seen clinically: a vortex under the brachiocephalic trunk and low pressure regions near the cannula jet. The results suggest that cannulation to the subclavian artery is preferred if the cannula tip is sufficiently far away from the branch of the vertebral artery. For the aortic positions, however, the cannula should be injected from the left body side. PMID- 19775265 TI - Glucose depletion enhances sensitivity to shear stress-induced mechanical damage in red blood cells by rotary blood pumps. AB - The metabolic process in red blood cells (RBCs) is anaerobic. The life-dependent adenosine triphosphate (ATP) for survival of cells is produced through glycolytic process. The aim of the study was to evaluate the effects of the glucose level on the mean corpuscular volume, mean corpuscular hemoglobin concentration, and hemolysis rate during hemolysis study by rotary blood pumps. The shear stress generated by rotary blood pumps may enhance glucose utilization by RBCs with depletion of glucose affecting ATP production and, consequently, cell size, shape, and morphology. The shear stress increases metabolism of RBCs consuming more energy ATP which is produced anaerobically from glycolytic process. Hence, in the closed circuit testing of rotary blood pumps, depletion of glucose might occur after prolonged pumping, which in turn affects metabolic process of RBCs by changing their size, shape, and morphology. It is thus suggested to monitor and control the glucose level of the fluid that suspends RBCs depending on the study duration. PMID- 19775266 TI - Impact of hyperthermal rotary blood pump surfaces on blood clotting behavior: an approach. AB - The influence of heat dissipating systems, such as rotary blood pumps, was investigated. Titanium cylinders as rotary blood pump housing dummies were immersed in porcine blood and constantly tempered at specific temperatures (37-60 degrees C) over a defined period of time. The porcine blood was anticoagulated either by low heparin dosage or citrate. At frequent intervals, samples were taken for blood analysis and the determination of the plasmatic coagulation cascade. Blood parameters do not alter at surface temperatures below 50 degrees C. Hyperthermia-induced hemolysis could be confirmed. The plasmatic coagulation cascade is terminated at surface temperatures exceeding 55 degrees C. The adhesion of blood constituents on surfaces is temperature and time dependent, and structural changes of adhesions and blood itself were detected. PMID- 19775267 TI - Improvement of the accuracy in the optical hematocrit measurement by optimizing mean optical path length. AB - Optical techniques have been developed to acquire blood information (e.g., hematocrit [Hct], saturation of oxygen, thrombus) noninvasively and continuously in an artificial heart. For the practical use of an optical Hct measurement, Twersky's theory has been shown to be useful and have a good agreement in forward scattered measurements. However, it was not applied to backward-scattered measurements, which can provide the measurement with a less demanding spatial requirement. Additionally, optimal measurement for accuracy is not well examined. Therefore, we developed an accurate Hct measurement in an artificial heart using current optical devices. To this end, we focused on optimizing an emitter detector distance to provide a maximum optical path length. We attached optical emitter and detector fibers on Tygon tubing at various distances to measure forward- and backward-scattered light. Fresh bovine blood (Hct: 30-50%) was circulated in the tubing by a nonpulsatile artificial heart. We calculated the optical path length at various emitter-detector distances by fitting the measured optical outputs and the reference Hcts to Twersky's theory. Then, we performed Hct measurements. As a result, Twersky's theory is applicable not only to forward but also to backward-scattered measurements in the physiogical Hct range. In both forward- and backward-scattered measurements, calculated optical path lengths become maximum at the same emitter-detector distance. The accuracy of Hct measurement is improved two to three times with the emitter-detector distance compared with other distances. The mean error is less than 1 Hct%. This result shows that an accurate Hct measurement is realized by selecting the optimal emitter-detector distance, which provides maximum optical path length defined by Twersky's theory. Our study provides a framework for the practical and less restrictive application of the optical Hct measurement to patients with an artificial heart. PMID- 19775268 TI - The importance of dQ/dt on the flow field in a turbodynamic pump with pulsatile flow. AB - Fluid dynamic analysis of turbodynamic blood pumps (TBPs) is often conducted under steady flow conditions. However, the preponderance of clinical applications for ventricular assistance involves unsteady, pulsatile flow-due to the residual contractility of the native heart. This study was undertaken to demonstrate the importance of pulsatility and the associated time derivative of the flow rate (dQ/dt) on hemodynamics within a clinical-scale TBP. This was accomplished by performing flow visualization studies on a transparent model of a centrifugal TBP interposed within a cardiovascular simulator with controllable heart rate and stroke volume. Particle image velocimetry triggered to both the rotation angle of the impeller and phase of the cardiac cycle was used to quantify the velocity field in the outlet volute and in between the impeller blades for 16 phases of the cardiac cycle. Comparison of the unsteady flow fields to corresponding steady conditions at the same (instantaneous) flow rates revealed marked differences. In particular, deceleration of flow was found to promote separation within the outlet diffuser, while acceleration served to stabilize the velocity field. The notable differences between the acceleration and deceleration phases illustrated the prominence of inertial fluid forces. These studies emphasize the importance of dQ/dt as an independent variable for thorough preclinical validation of TBPs intended for use as a ventricular assist device. PMID- 19775269 TI - First clinical application of the DuraHeart centrifugal ventricular assist device for a Japanese patient. AB - The DuraHeart ventricular assist device (VAD) is a third-generation implantable centrifugal pump with a magnetically levitated impeller. Since February 2007, the device has been clinically applied with excellent results as a bridge to heart transplantation in Europe. As of this writing, however, the device has yet to be approved by the Ministry of Health, Labour and Welfare for clinical use in Japan. We herein report the first clinical application of this device for a Japanese patient. A 31-year-old man with dilated cardiomyopathy was transferred to the Heart and Diabetes Center NRW (HDZ-NRW) in Bad Oeynhausen, Germany, where he was to await heart transplantation. The transfer was safely completed under management with low-dose dopamine. His condition gradually deteriorated at HDZ NRW, and the DuraHeart left ventricular assist device was implanted for the left ventricle at 7 weeks after admission. Shortly thereafter, however, on POD 7, a Thoratec VAD had to be inserted on the right side due to refractory right heart failure. The right ventricular assist device could be explanted after a 3-month assist, and the patient is now waiting for heart transplantation at home in Germany. PMID- 19775270 TI - Baroreflex sensitivity of an arterial wall during rotary blood pump assistance. AB - It is well known that the baroreflex system is one of the most important indicators of the pathophysiology in hypertensive patients. We can check the sensitivity of the baroreflex by observing heart rate (HR) responses; however, there is no simple diagnostic method to measure the arterial behavior in the baroreflex system. Presently, we report the development of a method and associated hardware that enables the diagnosis of baroreflex sensitivity by measuring the responses of both the heart and the artery. In this system, the measurements are obtained by monitoring an electrocardiogram and a pulse wave recorded from the radial artery or fingertip. The arterial responses were measured in terms of the pulse wave velocity (PWV) calculated from the pulse wave transmission time (PTT) from the heart to the artery. In this system, the HR change corresponding to the blood pressure change in time series sequence was observed. Slope of the changes in blood pressure and HR indicated the sensitivity of the baroreflex system of the heart. This system could also measure the sensitivity of the baroreflex system of an artery. Changes in the PWV in response to the blood pressure changes were observed. Significant correlation was observed in the time sequence between blood pressure change and PWV change after calculating the delay time by cross-correlation. The slope of these parameter changes was easily obtained and it demonstrated the sensitivity of the baroreflex system of an artery. We evaluated this method in animal experiments using rotary blood pump (RBP) with undulation pump ventricular assist device, and PTT elongation was observed in response to increased blood pressure with RBP assistance. Furthermore, when tested clinically, decreased sensitivity of the baroreflex system in hypertensive patients was observed. This system may be useful when we consider the ideal treatment and follow-up of patients with hypertension. PMID- 19775271 TI - Sealing performance of a magnetic fluid seal for rotary blood pumps. AB - A magnetic fluid (MF) for a rotary blood pump seal enables mechanical contact free rotation of the shaft and, hence, has excellent durability. The performance of a MF seal, however, has been reported to decrease in liquids. We have developed a MF seal that has a "shield" mechanism and a new MF with a higher magnetization of 47.9 kA/m. The sealing performance of the MF seal installed in a rotary blood pump was studied. Under the condition of continuous flow, the MF seal remained in perfect condition against a pressure of 298 mm Hg (pump flow rate: 3.96 L/min). The seal was also perfect against a pressure of 170 mm Hg in a continuous flow of 3.9 L/min for 275 days. We have developed a MF seal that works in liquid against clinically used pressures. The MF seal is promising as a shaft seal for rotary blood pumps. PMID- 19775273 TI - Estimating the density of honeybee colonies across their natural range to fill the gap in pollinator decline censuses. AB - Although pollinator declines are a global biodiversity threat, the demography of the western honeybee (Apis mellifera) has not been considered by conservationists because it is biased by the activity of beekeepers. To fill this gap in pollinator decline censuses and to provide a broad picture of the current status of honeybees across their natural range, we used microsatellite genetic markers to estimate colony densities and genetic diversity at different locations in Europe, Africa, and central Asia that had different patterns of land use. Genetic diversity and colony densities were highest in South Africa and lowest in Northern Europe and were correlated with mean annual temperature. Confounding factors not related to climate, however, are also likely to influence genetic diversity and colony densities in honeybee populations. Land use showed a significantly negative influence over genetic diversity and the density of honeybee colonies over all sampling locations. In Europe honeybees sampled in nature reserves had genetic diversity and colony densities similar to those sampled in agricultural landscapes, which suggests that the former are not wild but may have come from managed hives. Other results also support this idea: putative wild bees were rare in our European samples, and the mean estimated density of honeybee colonies on the continent closely resembled the reported mean number of managed hives. Current densities of European honeybee populations are in the same range as those found in the adverse climatic conditions of the Kalahari and Saharan deserts, which suggests that beekeeping activities do not compensate for the loss of wild colonies. Our findings highlight the importance of reconsidering the conservation status of honeybees in Europe and of regarding beekeeping not only as a profitable business for producing honey, but also as an essential component of biodiversity conservation. PMID- 19775274 TI - The value of rehabilitating logged rainforest for birds. AB - The recent advent of carbon crediting has led to a rapid rise in biosequestration projects that seek to remove carbon from the atmosphere through afforestation and forest rehabilitation. Such projects also present an important potential opportunity to reverse biodiversity losses resulting from deforestation and forest degradation, but the biodiversity benefits of different forms of biosequestration have not been considered adequately. We captured birds in mist nets to examine the effects of rehabilitation of logged forest on birds in Sabah, Borneo, and to test the hypothesis that rehabilitation restores avian assemblages within regenerating forest to a condition closer to that seen in unlogged forest. Species richness and diversity were similar in unlogged and rehabilitated forest, but significantly lower in naturally regenerating forest. Rehabilitation resulted in a relatively rapid recovery of populations of insectivores within logged forest, especially those species that forage by sallying, but had a marked adverse effect on frugivores and possibly reduced the overall abundance of birds within regenerating forest. In view of these results, we advocate increased management for heterogeneity within rehabilitated forests, but we strongly urge an increased role for forest rehabilitation in the design and implementation of a biodiversity-friendly carbon-offsetting market. PMID- 19775275 TI - Efficacy of a voluntary area to be avoided to reduce risk of lethal vessel strikes to endangered whales. AB - Ocean-going vessels pose a threat to large whales worldwide and are responsible for the majority of reported deaths diagnosed among endangered North Atlantic right whales (Eubalaena glacialis). Various conservation policies have been implemented to reduce vessel-strike mortality in this species. The International Maritime Organization adopted the Roseway Basin Area to be avoided on the Scotian Shelf as a voluntary conservation initiative to reduce the risk of lethal vessel strikes to right whales. We initiated the Vessel Avoidance & Conservation Area Transit Experiment to evaluate the efficacy of this initiative because the effectiveness of the avoidance scheme in reducing risk without the imposition of vessel-speed restrictions depends entirely on vessel-operator compliance. Using a network of automatic identification system receivers, we collected static, dynamic, and voyage-related vessel data in near real time from the Roseway Basin region for 12 months before and 6 months after the implementation of the area to be avoided. Using pre- and post-implementation vessel navigation and speed data, along with right whale sightings per unit effort data, all resolved at 3'N latitude by 3'W longitude, we estimated the post-implementation change in risk of lethal vessel strikes. Estimates of vessel-operator voluntary compliance ranged from 57% to 87% and stabilized at 71% within the first 5 months of implementation. Our estimates showed an 82% reduction in the risk of lethal vessel strikes to right whales due to vessel-operator compliance. We conclude that the high level of compliance achieved with this voluntary conservation initiative occurred because the area to be avoided was adopted by the International Maritime Organization. Our results demonstrate that international shipping interests are able and willing to voluntarily alter course to protect endangered whales. PMID- 19775276 TI - Motivations for conserving urban biodiversity. AB - In a time of increasing urbanization, the fundamental value of conserving urban biodiversity remains controversial. How much of a fixed budget should be spent on conservation in urban versus nonurban landscapes? The answer should depend on the goals that drive our conservation actions, yet proponents of urban conservation often fail to specify the motivation for protecting urban biodiversity. This is an important shortcoming on several fronts, including a missed opportunity to make a stronger appeal to those who believe conservation biology should focus exclusively on more natural, wilder landscapes. We argue that urban areas do offer an important venue for conservation biology, but that we must become better at choosing and articulating our goals. We explored seven possible motivations for urban biodiversity conservation: preserving local biodiversity, creating stepping stones to nonurban habitat, understanding and facilitating responses to environmental change, conducting environmental education, providing ecosystem services, fulfilling ethical responsibilities, and improving human well-being. To attain all these goals, challenges must be faced that are common to the urban environment, such as localized pollution, disruption of ecosystem structure, and limited availability of land. There are, however, also challenges specific only to particular goals, meaning that different goals will require different approaches and actions. This highlights the importance of specifying the motivations behind urban biodiversity conservation. If the goals are unknown, progress cannot be assessed. PMID- 19775277 TI - The silent mass extinction of insect herbivores in biodiversity hotspots. AB - Habitat loss is silently leading numerous insects to extinction. Conservation efforts, however, have not been designed specifically to protect these organisms, despite their ecological and evolutionary significance. On the basis of species host area equations, parameterized with data from the literature and interviews with botanical experts, I estimated the number of specialized plant-feeding insects (i.e., monophages) that live in 34 biodiversity hotspots and the number committed to extinction because of habitat loss. I estimated that 795,971 1,602,423 monophagous insect species live in biodiversity hotspots on 150,371 endemic plant species, which is 5.3-10.6 monophages per plant species. I calculated that 213,830-547,500 monophagous species are committed to extinction in biodiversity hotspots because of reduction of the geographic range size of their endemic hosts. I provided rankings of biodiversity hotspots on the basis of estimated richness of monophagous insects and on estimated number of extinctions of monophagous species. Extinction rates were predicted to be higher in biodiversity hotspots located along strong environmental gradients and on archipelagos, where high spatial turnover of monophagous species along the geographic distribution of their endemic plants is likely. The results strongly support the overall strategy of selecting priority conservation areas worldwide primarily on the basis of richness of endemic plants. To face the global decline of insect herbivores, one must expand the coverage of the network of protected areas and improve the richness of native plants on private lands. PMID- 19775278 TI - Joint effects of inbreeding and local adaptation on the evolution of genetic load after fragmentation. AB - Disruption of gene flow among demes after landscape fragmentation can facilitate local adaptation but increase the effect of genetic drift and inbreeding. The joint effects of these conflicting forces on the mean fitness of individuals in a population are unknown. Through simulations, we explored the effect of increased isolation on the evolution of genetic load over the short and long term when fitness depends in part on local adaptation. We ignored genetic effects on demography. We modeled complex genomes, where a subset of the loci were under divergent selection in different localities. When a fraction of the loci were under heterogeneous selection, isolation increased mean fitness in larger demes made up of hundreds of individuals because of improved local adaptation. In smaller demes of tens of individuals, increased isolation improved local adaptation very little and reduced overall fitness. Short-term improvement of mean fitness after fragmentation may not be indicative of the long-term evolution of fitness. Whatever the deme size and potential for local adaptation, migration of one or two individuals per generation minimized the genetic load in general. The slow dynamics of mean fitness following fragmentation suggests that conservation measures should be implemented before the consequences of isolation on the genetic load become of concern. PMID- 19775279 TI - Update on the evaluation of a new drug for effects on cardiac repolarization in humans: issues in early drug development. AB - Following reports of death from cardiac arrhythmias with drugs like terfenadine and cisapride, the International Conference for Harmonization formulated a guidance (E14) document. This specifies that all new drugs must undergo a 'thorough QT/QTc' (TQT) study to detect drug-induced QT prolongation, a surrogate marker of ventricular tachycardia, especially torsades de pointes (TdPs). With better understanding of data from several completed TQT studies, regulatory requirements have undergone some changes since the E14 guidance was implemented in October 2005. This article reviews the implications of the E14 guidance and the changes in its interpretation including choice of baseline QT, demonstration of assay sensitivity, statistical analysis of the effect of new drug and positive control, and PK-PD modelling. Some issues like use of automated QT measurements remain unresolved. Pharmaceutical companies too are modifying Phase 1 studies to detect QTc liability early in order to save time and resources. After the E14 guidance, development of several drugs that prolong QTc by >5 ms is being abandoned by sponsors. However, all drugs that prolong the QT interval do not increase risk of TdP. Researchers in regulatory agencies, academia and industry are working to find better biomarkers of drug-induced TdP which could prevent many useful drugs from being prematurely abandoned. Drug-induced TdP is a rare occurrence. With fewer drugs that prolong QT interval reaching the licensing stage, knowing which of these drugs are torsadogenic is proving to be elusive. Thus, paradoxically, the effectiveness of the E14 guidance itself has made prospective validation of new biomarkers difficult. PMID- 19775281 TI - Cyclin-dependent kinase inhibitor drugs as potential novel anti-inflammatory and pro-resolution agents. AB - The cyclin-dependent kinase inhibitor (CDKi) drugs such as R-roscovitine have emerged as potential anti-inflammatory, pharmacological agents that can influence the resolution of inflammation. Usually, once an inciting inflammatory stimulus has been eliminated, resolution proceeds by prompt, safe removal of dominant inflammatory cells. This is accomplished by programmed cell death (apoptosis) of prominent effector, inflammatory cells typified by the neutrophil. Apoptosis of neutrophils ensures that toxic neutrophil granule contents are securely packaged in apoptotic bodies and expedites phagocytosis by professional phagocytes such as macrophages. A panel of CDKi drugs have been shown to promote neutrophil apoptosis in a concentration- and time-dependent manner and the archetypal CDKi drug, R-roscovitine, overrides the anti-apoptotic effects of powerful survival factors [including lipopolysaccharide (LPS) and granulocyte macrophage-colony stimulating factor (GM-CSF)]. Inflammatory cell longevity and survival signalling is integral to the inflammatory process and any putative anti-inflammatory agent must unravel a complex web of redundancy in order to be effective. CDKi drugs have also been demonstrated to have significant effects on other cell types including lymphocytes and fibroblasts indicating that they may have pleiotropic anti-inflammatory, pro-resolution activity. In keeping with this, CDKi drugs like R-roscovitine have been reported to be efficacious in resolving established animal models of neutrophil-dominant and lymphocyte-driven inflammation. However, the mechanism of action behind these powerful effects has not yet been fully elucidated. CDKs play an integral role in the regulation of the cell cycle but are also recognized as participants in processes such as apoptosis and transcriptional regulation. Neutrophils have functional CDKs, are transcriptionally active and demonstrate augmented apoptosis in response to CDKi drugs, while lymphocyte proliferation and secretory function are inhibited. This review will discuss current understanding of the processes of inflammation and resolution but will focus on CDKis and their potential mechanisms of action. PMID- 19775280 TI - DNA mismatch repair (MMR)-dependent 5-fluorouracil cytotoxicity and the potential for new therapeutic targets. AB - The metabolism and efficacy of 5-fluorouracil (FUra) and other fluorinated pyrimidine (FP) derivatives have been intensively investigated for over fifty years. FUra and its antimetabolites can be incorporated at RNA- and DNA-levels, with RNA level incorporation provoking toxic responses in human normal tissue, and DNA-level antimetabolite formation and incorporation believed primarily responsible for tumour-selective responses. Attempts to direct FUra into DNA level antimetabolites, based on mechanism-of-action studies, have led to gradual improvements in tumour therapy. These include the use of leukovorin to stabilize the inhibitory thymidylate synthase-5-fluoro-2'-deoxyuridine 5' monophoshate (FdUMP)-5,10-methylene tetrahydrofolate (5,10-CH(2)FH(4)) trimeric complex. FUra incorporated into DNA also contributes to antitumour activity in preclinical and clinical studies. This review examines our current state of knowledge regarding the mechanistic aspects of FUra:Gua lesion detection by DNA mismatch repair (MMR) machinery that ultimately results in lethality. MMR-dependent direct cell death signalling or futile cycle responses will be discussed. As 10-30% of sporadic colon and endometrial tumours display MMR defects as a result of human MutL homologue-1 (hMLH1) promoter hypermethylation, we discuss the use and manipulation of the hypomethylating agent, 5-fluorodeoxycytidine (FdCyd), and our ability to manipulate its metabolism using the cytidine or deoxycytidylate (dCMP) deaminase inhibitors, tetrahydrouridine or deoxytetrahydrouridine, respectively, as a method for re-expression of hMLH1 and re-sensitization of tumours to FP therapy. PMID- 19775282 TI - Down-regulation of the Notch pathway mediated by a gamma-secretase inhibitor induces anti-tumour effects in mouse models of T-cell leukaemia. AB - BACKGROUND AND PURPOSE: gamma-Secretase inhibitors (GSIs) block NOTCH receptor cleavage and pathway activation and have been under clinical evaluation for the treatment of malignancies such as T-cell acute lymphoblastic leukaemia (T-ALL). The ability of GSIs to decrease T-ALL cell viability in vitro is a slow process requiring >8 days, however, such treatment durations are not well tolerated in vivo. Here we study GSI's effect on tumour and normal cellular processes to optimize dosing regimens for anti-tumour efficacy. EXPERIMENTAL APPROACH: Inhibition of the Notch pathway in mouse intestinal epithelium was used to evaluate the effect of GSIs and guide the design of dosing regimens for xenograft models. Serum Abeta(40) and Notch target gene modulation in tumours were used to evaluate the degree and duration of target inhibition. Pharmacokinetic and pharmacodynamic correlations with biochemical, immunohistochemical and profiling data were used to demonstrate GSI mechanism of action in xenograft tumours. KEY RESULTS: Three days of >70% Notch pathway inhibition was sufficient to provide an anti-tumour effect and was well tolerated. GSI-induced conversion of mouse epithelial cells to a secretory lineage was time- and dose-dependent. Anti-tumour efficacy was associated with cell cycle arrest and apoptosis that was in part due to Notch-dependent regulation of mitochondrial homeostasis. CONCLUSIONS AND IMPLICATIONS: Intermittent but potent inhibition of Notch signalling is sufficient for anti-tumour efficacy in these T-ALL models. These findings provide support for the use of GSI in Notch-dependent malignancies and that clinical benefits may be derived from transient but potent inhibition of Notch. PMID- 19775283 TI - Tanshinone I enhances learning and memory, and ameliorates memory impairment in mice via the extracellular signal-regulated kinase signalling pathway. AB - BACKGROUND AND PURPOSE: The intracellular signalling kinase, extracellular signal regulated kinase 1/2 (ERK1/2) is required for new memory formation, suggesting that control of ERK signalling might be a target for the treatment of cognitive dysfunction. Previously, we reported that tanshinone congeners have ameliorating effects on drug-induced memory impairment in mice. Here, we have investigated possible modes of action of tanshinone I on learning and memory, associated with ERK phosphorylation. EXPERIMENTAL APPROACH: Using immunohistochemical, Western blot techniques, and behavioural testing, we studied the effect of tanshinone I on memory impairment induced by diazepam or dizocilpine (MK-801) in mice. KEY RESULTS: Tanshinone I (2 or 4 mg.kg(-1), p.o.) increased latency times versus vehicle-treated control group in the passive avoidance task. Western blot analysis and immunohistochemical data showed that tanshinone I (4 mg.kg(-1)) increased levels of phosphorylated cAMP response element binding protein (pCREB) and phosphorylated ERK (pERK) in the hippocampus. These increases in pCREB and pERK were blocked by U0126 (inhibitor of ERK1/2), which also prevented the increase in passive avoidance task latency time after tanshinone I. In models of learning and memory impairment induced by diazepam and MK-801, tanshinone I (4 mg.kg(-1)) reversed learning and memory impairments detected by the passive avoidance test. Western blot analysis showed that tanshinone I reversed the diazepam- and MK-801-induced inhibitions of ERK and CREB activation in hippocampal tissues. These effects were also blocked by U0126. CONCLUSIONS AND IMPLICATIONS: Tanshinone I ameliorates the learning and memory impairments induced by diazepam and MK-801 through activation of ERK signalling. PMID- 19775285 TI - Insulin-independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice. AB - Diabetes mellitus has been proposed as an epidemiological risk factor for human liver cancer development. One reasonable possibility is that this is attributable to hyperinsulinemia compensatory for obesity-related insulin resistance. However, diabetes mellitus is a complex disease with multiple abnormal conditions essentially caused by hyperglycemia. Therefore, it is not evident whether hyperinsulinemia is prerequisite for the elevated cancer risk. To gain a clue to answer this question, we characterized chemically induced hepatocarcinogenesis in diabetic model mice genetically deficient for insulin. Akita inbred mice originating from the C57BL/6 strain carry a heterozygous germline mutation of the insulin II gene and suffer from inherited insulin deficiency and diabetes in an autosomal dominant manner. They were mated with normal C3H/HeJ mice with high sensitivity to liver carcinogenesis and the resultant F(1) littermates, which were either normal or insulin deficient, were exposed to diethylnitrosamine and induced hepatocellular tumors were evaluated for number, size, proliferative activity, and apoptosis. Unexpectedly, both mean and total volumes of hepatocellular tumors in the insulin-deficient animals were more than twofold larger than those in the normal controls, with no significant difference in tumor number. The tumors in insulin-deficient mice showed a significantly lower frequency of apoptosis but no alteration in cell proliferation. In conclusion, our results indicate that insulin-independent liver tumor promotion occurred in diabetic mice. Clearly, insulin-independent mechanisms for the human case also deserve consideration. PMID- 19775286 TI - Dual antitumor mechanisms of Notch signaling inhibitor in a T-cell acute lymphoblastic leukemia xenograft model. AB - Constitutive activation of Notch signaling is required for the proliferation of a subgroup of human T-cell acute lymphoblastic leukemias (T-ALL). Previous in vitro studies have demonstrated the therapeutic potential of Notch signaling inhibitors for treating T-ALL. To further examine this possibility, we applied a gamma secretase inhibitor (GSI) to T-ALL xenograft models. Treatment of established subcutaneous tumors with GSI resulted in partial or complete regression of tumors arising from four T-ALL cell lines that were also sensitive to GSI in vitro. To elucidate the mechanism of action, we transduced DND-41 cells with the active form of Notch1 (aN1), which conferred resistance to in vitro GSI treatment. Nevertheless, in vivo treatment with GSI induced a partial but significant regression of subcutaneous tumors that developed from aN1-transduced DND-41 cells, whereas it induced complete regression of tumors that developed from mock transduced DND-41 cells. These findings indicate that the remarkable efficacy of GSI might be attributable to dual mechanisms, directly via apoptosis of DND-41 cells through the inhibition of cell-autonomous Notch signaling, and indirectly via disturbance of tumor angiogenesis through the inhibition of non-cell autonomous Notch signaling. PMID- 19775287 TI - 15-Lipoxygenase-1 expression suppresses the invasive properties of colorectal carcinoma cell lines HCT-116 and HT-29. AB - Colorectal carcinoma (CRC) is often lethal when invasion and/or metastasis occur. 15-Lipoxygenase-1 (15-LO-1), a member of the inflammatory eicosanoid pathway, oxidatively metabolizes linoleic acid and its expression is repressed in CRC. In this study, we investigated the hypothesis that the lack of 15-LO-1 expression in CRC cells might contribute to tumorigenesis. Therefore we introduced 15-LO-1 into HCT-116 and HT-29 cells that do not have detectable levels of 15-LO-1. Our data indicate that expression of 15-LO-1 significantly decreased cell proliferation and increased apoptosis. In addition, we observed a reduction in adhesion to fibronectin, anchorage-independent growth on soft agar, cellular motility and ability to heal a scratch wound, and migratory and invasive capacity across Matrigel. 15-LO-1 expression also reduced the expression of metastasis associated protein-1, a part of the nucleosome remodeling and histone deacetylase silencing complex. We propose that 15-LO-1 expression in CRC might contribute to the inhibition of metastatic capacity in vitro and can be exploited for therapeutic purposes. PMID- 19775284 TI - Tanshinone IIA protects against sudden cardiac death induced by lethal arrhythmias via repression of microRNA-1. AB - BACKGROUND AND PURPOSE: Tanshinone IIA is an active component of a traditional Chinese medicine based on Salvia miltiorrhiza, which reduces sudden cardiac death by suppressing ischaemic arrhythmias. However, the mechanisms underlying the anti arrhythmic effects remain unclear. EXPERIMENTAL APPROACH: A model of myocardial infarction (MI) in rats by ligating the left anterior descending coronary artery was used. Tanshinone IIA or quinidine was given daily, before (7 days) and after (3 months) MI; cardiac electrical activity was monitored by ECG recording. Whole cell patch-clamp techniques were used to measure the inward rectifying K(+) current (I(K1)) in rat isolated ventricular myocytes. Kir2.1 and serum response factor (SRF) levels were analysed by Western blot and microRNA-1 (miR-1) level was determined by real-time RT-PCR. KEY RESULTS: Tanshinone IIA decreased the incidence of arrhythmias induced by acute cardiac ischaemia and mortality in rats 3 months after MI. Tanshinone IIA restored the diminished I(K1) current density and Kir2.1 protein after MI in rat ventricular myocytes, while quinidine further inhibited I(K1)/Kir2.1. MiR-1 was up-regulated in MI, possibly due to the concomitant increase in SRF, a transcriptional activator of the miR-1 gene, accounting for decreased Kir2.1. Treatment with tanshinone IIA prevented increased SRF and hence increased miR-1 post-MI, whereas quinidine did not. CONCLUSIONS AND IMPLICATIONS: Down-regulation of miR-1 and consequent recovery of Kir2.1 may account partially for the efficacy of tanshinone IIA in suppressing ischaemic arrhythmias and cardiac mortality. These finding support the proposal that miR-1 could be a potential therapeutic target for the prevention of ischaemic arrhythmias. PMID- 19775289 TI - Genome-wide DNA methylation profiles in urothelial carcinomas and urothelia at the precancerous stage. AB - To clarify genome-wide DNA methylation profiles during multistage urothelial carcinogenesis, bacterial artificial chromosome (BAC) array-based methylated CpG island amplification (BAMCA) was performed in 18 normal urothelia obtained from patients without urothelial carcinomas (UCs) (C), 17 noncancerous urothelia obtained from patients with UCs (N), and 40 UCs. DNA hypo- and hypermethylation on multiple BAC clones was observed even in N compared to C. Principal component analysis revealed progressive DNA methylation alterations from C to N, and to UCs. DNA methylation profiles in N obtained from patients with invasive UCs were inherited by the invasive UCs themselves, that is DNA methylation alterations in N were correlated with the development of more malignant UCs. The combination of DNA methylation status on 83 BAC clones selected by Wilcoxon test was able to completely discriminate N from C, and diagnose N as having a high risk of carcinogenesis, with 100% sensitivity and specificity. The combination of DNA methylation status on 20 BAC clones selected by Wilcoxon test was able to completely discriminate patients who suffered from recurrence after surgery from patients who did not. The combination of DNA methylation status for 11 BAC clones selected by Wilcoxon test was able to completely discriminate patients with UCs of the renal pelvis or ureter who suffered from intravesical metachronous UC development from patients who did not. Genome-wide alterations of DNA methylation may participate in urothelial carcinogenesis from the precancerous stage to UC, and DNA methylation profiling may provide optimal indicators for carcinogenetic risk estimation and prognostication. PMID- 19775288 TI - SIAH1 induced apoptosis by activation of the JNK pathway and inhibited invasion by inactivation of the ERK pathway in breast cancer cells. AB - Seven in absentia homolog 1 (SIAH1), a homologue of Drosophila seven in absentia (Sina), has emerged as a tumor suppressor and plays an important role in regulating cell apoptosis. To investigate the role and possible mechanism of SIAH1 in breast cancer cells, we up-regulated the expression of SIAH1 using pcDNA3-myc-SIAH1 and knocked down SIAH1 using SIAH1 siRNA. We found that the overexpression of SIAH1 induced cell apoptosis by up-regulating the level of Bim through the activation of the JNK signaling pathway, and the suppression of SIAH1 expression increased cell invasion via the activation of the ERK signaling pathway in breast cancer cells. All these results indicate that the JNK and ERK signaling pathways may play an important role in the SIAH1-dependent biological behavior of breast cancer, and it may be a good molecular therapeutic target to increase the expression level of SIAH1 through promoting cell apoptosis and inhibiting cell invasion in human breast cancer. PMID- 19775290 TI - Identification of serum biomarkers for pancreatic adenocarcinoma by proteomic analysis. AB - Diagnosis of pancreatic adenocarcinoma (PaCa) at an early stage is important for successful treatment and improving the prognosis of patients. Serum samples were applied to strong anionic exchange chromatography (SAX) protein chips for protein profiling by surface enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) to distinguish PaCa from noncancer. The Wilcoxon rank sum test, decision tree algorithm, and logistic regression were used to statistically analyze the multiple protein peaks. Sixty-one protein peaks between 2000 and 30,000 m/z ratios were detected to establish multiple decision classification trees for differentiating the known disease states. A sensitivity of 0.833 and a specificity of 1.000 were obtained in distinguishing PaCa from healthy controls and benign pancreatic diseases. Six protein biomarkers related to different PaCa TNM stages were detected (P < 0.01). One protein biomarker (m/z 4016) rich in PaCa had a down-regulated trend when preoperative and postoperative samples (P < 0.05) were compared. Three protein biomarkers (m/z 4155, 4791, and 28,068) were detected in the differential diagnosis of the three test groups (P < 0.05). A peak m/z 28 068 was identified as C14orf16 using ProteinChip immunoassay. C14orf166 levels were significantly higher in the serum of patients with PaCa compared with the control group using a sandwich immunoenzymatic system. Immunolabeling of tissue sections revealed that the C14orf166 protein was strongly expressed in tumor cells. The results suggest that SELDI-TOF-MS serum profiling is helpful for the diagnostic, prognostic or therapeutic effects of PaCa, which is superior to CA 19-9. The identified protein biomarker C14orf166 is a potential biomarker of PaCa. PMID- 19775291 TI - Leptin and its receptor are overexpressed in brain tumors and correlate with the degree of malignancy. AB - Although leptin and its receptor (ObR) have emerged as important cancer biomarkers, the role of the leptin system in brain tumor development remains unknown. We screened 87 human brain tumor biopsies using immunohistochemistry and detected leptin and ObR in 55.2% and 60.9% cases, respectively. In contrast, leptin and ObR were absent in 14 samples of normal brain tissue. The presence of leptin correlated with ObR with overall concordance 80.5%. The leptin/ObR system was highly expressed in glioblastomas and anaplastic astrocytomas, while lower expression of both markers was noted in low-grade astrocytomas and gangliogliomas. The association between leptin/ObR and the degree of tumor malignancy was highly significant (P < 0.001). Using double immunofluorescence of glioblastoma tissues, we found co-expression of leptin with ObR and with the proliferation marker Ki-67 in 87% and 64% of cells, respectively. The leptin/ObR positive tissues also expressed activated forms of STAT3 and Akt. In line with this finding, ObR-positive glioblastoma cells responded to leptin with cell growth and induction of the STAT3 and Akt pathways as well as inactivation of the cell cycle suppressor Rb. In summary, our data demonstrate that the leptin/ObR system is expressed in malignant brain tumors and might be involved in tumor progression. PMID- 19775292 TI - Axonal pathology and loss precede demyelination and accompany chronic lesions in a spontaneously occurring animal model of multiple sclerosis. AB - Axonal damage has been highlighted recently as a cause of neurological disability in various demyelinating diseases, including multiple sclerosis, either as a primary pathological change or secondary due to myelin loss. To characterize and quantify axonal damage and loss in canine distemper demyelinating leukoencephalomyelitis (DL), formalin-fixed paraffin-embedded cerebella were investigated histochemically and immunohistochemically using the modified Bielschowsky's silver stain as well as antibodies against nonphosphorylated (n NF), phosphorylated neurofilament (p-NF) and beta-amyloid precursor protein (beta APP). Injured axons characterized by immunoreactivity against n-NF and beta-APP were detected in early distemper lesions without demyelination. In subacute and chronic demyelinating lesions the number of injured axons increased. Moreover, a significant decrease in axonal density was observed within lesions and in the normal appearing white matter in DL as determined by morphometric analyses using Bielschowsky's silver stain and p-NF immunohistochemistry. Summarized, the observed findings indicate that axonal damage (i) occurs early in DL; (ii) can be detected before myelin loss; and (iii) represents a pivotal feature in advanced lesions. It must be postulated that axonal damage plays an important role in the initial phase as a primary event and during progression of nervous distemper as a result of demyelination. PMID- 19775293 TI - Identification and functional characterization of microRNAs involved in the malignant progression of gliomas. AB - Diffuse astrocytoma of World Health Organization (WHO) grade II has an inherent tendency to spontaneously progress to anaplastic astrocytoma WHO grade III or secondary glioblastoma WHO grade IV. We explored the role of microRNAs (miRNAs) in glioma progression by investigating the expression profiles of 157 miRNAs in four patients with primary WHO grade II gliomas that spontaneously progressed to WHO grade IV secondary glioblastomas. Thereby, we identified 12 miRNAs (miR-9, miR-15a, miR-16, miR-17, miR-19a, miR-20a, miR-21, miR-25, miR-28, miR-130b, miR 140 and miR-210) showing increased expression, and two miRNAs (miR-184 and miR 328) showing reduced expression upon progression. Validation experiments on independent series of primary low-grade and secondary high-grade astrocytomas confirmed miR-17 and miR-184 as promising candidates, which were selected for functional analyses. These studies revealed miRNA-specific influences on the viability, proliferation, apoptosis and invasive growth properties of A172 and T98G glioma cells in vitro. Using mRNA and protein expression profiling, we identified distinct sets of transcripts and proteins that were differentially expressed after inhibition of miR-17 or overexpression of miR-184 in glioma cells. Taken together, our results support an important role of altered miRNA expression in gliomas, and suggest miR-17 and miR-184 as interesting candidates contributing to glioma progression. PMID- 19775294 TI - Loss of inhibitor of growth (ING-4) is implicated in the pathogenesis and progression of human astrocytomas. AB - Inhibitor of growth 4 (ING-4) is a tumor suppressor gene that interacts with nuclear factor-kappaB (NF-kappaB) and represses its transcriptional activity. Several lines of evidence suggest that the tumor suppressor gene ING-4, the transcription factor NF-kappaB and its target genes matrix metalloproteases MMP 2, MMP-9 and urokinase plasminogen activator (u-PA) are critically involved in tumor invasion. The aim of the present study was to investigate immunohistochemically the expression pattern of ING-4, NF-kappaB and the NF kappaB downstream targets MMP-2, MMP-9 and u-PA in human astrocytomas from 101 patients. We found that ING-4 expression was significantly decreased in astrocytomas, and ING-4 loss was associated with tumor grade progression. Expression of p65, a NF-kappaB subunit, was significantly higher in grade IV than in grade III and grade I/II tumors, and a statistical significant negative correlation between expression of ING-4 and expression of nuclear p65 was noticed. MMP-9, MMP-2 and u-PA were overexpressed in human astrocytomas. Of note, astrocytomas of advanced histologic grades (grade III, IV) displayed significantly higher expression levels of these proteins compared to tumors of lower grades (grade I, II). Collectively, our data suggest an essential role for ING-4 in human astrocytoma development and progression possibly through regulation of the NF-kappaB-dependent expression of genes involved in tumor invasion. PMID- 19775295 TI - Prevalence of mutations in ELANE, GFI1, HAX1, SBDS, WAS and G6PC3 in patients with severe congenital neutropenia. AB - Severe congenital neutropenia (SCN) is a genetically heterogeneous syndrome associated with mutations of ELANE (ELA2), HAX1, GFI1, WAS, CSF3R or G6PC3. We investigated the prevalence of mutations of ELANE in a cohort of 162 SCN patients for whom blood or bone marrow samples were submitted to the North American Severe Chronic Neutropenia Tissue Repository. Mutations of ELANE were found in 90 of 162 patients (55.6%). Subsequently, we conducted an analysis of a subset of 73 of these cases utilising a high throughput sequencing approach to determine the prevalence of other mutations associated with SCN. Among the 73 patients, mutations of ELANE were detected in 28. In the remaining 45 patients with wild type ELANE alleles, five patients had mutations: GFI1 (1), SBDS (1), WAS (1) and G6PC3 (2); no mutations of HAX1 were detected. In approximately 40% of our cases, the genetic basis of SCN remains unknown. These data suggest that for genetic diagnosis of SCN, ELANE genotyping should first be performed. In patients without ELANE mutations, other known SCN-associated gene mutations will be found rarely and genotyping can be guided by the clinical features of each patient. PMID- 19775296 TI - Comparison of miRNA profiles of microdissected Hodgkin/Reed-Sternberg cells and Hodgkin cell lines versus CD77+ B-cells reveals a distinct subset of differentially expressed miRNAs. AB - Classical Hodgkin lymphoma (cHL) is characterized by the presence of malignant Hodgkin and Reed Sternberg (HRS) cells. The scarcity of tumour cells in lymphoma biopsies has hampered genetic analyses of HRS cells, including microRNA (miRNA) expression profiling. We determined the expression of 360 miRNAs in microdissected HRS cells from nine cHL patients. These miRNA profiles were compared to those from four cHL cell lines and CD77+ B-cells, yielding a distinct cHL signature of 12 over- and three underexpressed miRNAs. Our data suggest that miRNAs are implicated in the pathogenesis of Hodgkin lymphoma and prompt further investigations concerning their role in cHL. PMID- 19775297 TI - Expression of histone deacetylases in lymphoma: implication for the development of selective inhibitors. AB - Unselective histone deacetylase (HDAC) inhibitors are a promising novel therapy for lymphoid malignancies. However, these treatments remain empiric as the pattern of HDAC enzymes in different types of cancer, including lymphoid malignancies, remains unknown. We examined the expression of class I and class II HDACs in a panel of cell lines and tissue sections from primary lymphoid tumours. Class I enzymes were highly expressed in all cell lines and primary tumours studied, including the non-malignant reactive cells in the Hodgkin lymphoma (HL) microenvironment. The most frequently altered HDAC expression was HDAC6, as it was either weakly expressed or undetected in 9/14 (64%) of lymphoid cell lines and in 83/89 (93%) of primary lymphoma tissue specimens, including 50/52 (96%) cases of diffuse large B-cell lymphoma, and 18/22 (82%) cases of classical HL. Cell lines that had low expression level of HDAC6 demonstrated aberrant expression of hyper-acetylated tubulin, and were found to be more sensitive to the growth inhibitory effects of the class I HDAC inhibitor MGCD0103. Collectively, our data demonstrate that HDAC6 is rarely expressed in primary lymphoma cases, suggesting that it may not be an important therapeutic target in these lymphoid malignancies. PMID- 19775298 TI - Germ-line mutation of the NRAS gene may be responsible for the development of juvenile myelomonocytic leukaemia. AB - We report the case of a child with clinical and haematological features indicative of juvenile myelomonocytic leukaemia (JMML). The patient showed dysmorphic features: high forehead, bilateral epicanthal folds, long eyebrows, low nasal bridge and slightly low-set ears. A 38G>A (G13D) mutation in exon 1 of the NRAS gene was first demonstrated on peripheral blood cells, and then confirmed on granulocyte-macrophage colony-forming units. The same mutation was also found in buccal swab, hair bulbs, endothelial cells, skin fibroblasts. This case suggests for the first time that constitutional mutations of NRAS may be responsible for development of a myeloproliferative/myelodysplastic disorder in children. PMID- 19775300 TI - FLT3-ITD expression levels and their effect on STAT5 in AML with and without NPM mutations. AB - FLT3-internal tandem duplication (ITD) mutations are heterogeneous with regards to length and proportion of DNA harbouring the mutation and the expression level of FLT3 also varies widely, however very little is known about the biological effects of these variables. We studied FLT3-associated biological parameters in 322 acute myeloid leukaemia samples to establish their importance. Expression of total FLT3 transcripts was shown to be significantly higher in the FLT3-ITD cohort (n = 121) compared to the wild-type cohort (P = 0.004). Whilst phosphorylated signal transducer and activator of transcription 5 (phospho-STAT5) was not confined to FLT3-ITD samples, within the FLT3-ITD group phosphorylation correlated with adjusted FLT3-ITD levels assessed by determining the total transcripts and proportion of FLT3-ITD within a sample. Expression of the STAT5 downstream target Bcl-xl (an isoform of BCL2L1) was strongly correlated with FLT3 total and adjusted FLT3-ITD levels in FLT3-ITD samples (P < 0.001), however there was no association between Bcl-xl and phospho-STAT5 levels suggesting that STAT5 is not the sole regulator of Bcl-xl in FLT3-ITD cells. We further stratified our cohort by the presence/absence of a cytoplasmic nucleophosmin NPMc+ mutation. Samples co-expressing NPMc+ had longer FLT3-ITD mutations (P = 0.01) and there was a high occurrence of NPMc+ in samples that had >1 FLT3-ITD mutation. Phospho STAT5 levels were reduced in the FLT3-ITD/NPMc+ group (P = 0.04) suggesting that NPMc+ may oppose the FLT3-ITD-dependent activation of STAT5. PMID- 19775299 TI - Endothelin receptor antagonists for pulmonary hypertension in adult patients with sickle cell disease. AB - Pulmonary Hypertension is a serious complication of sickle cell disease (SCD), with high morbidity and mortality. Endothelin (ET)-1, a potent vasoconstrictor elevated in SCD, acts through the ET receptors (ETR), ETR-A and ETR-B. Bosentan and ambrisentan are ETR blockers used in primary pulmonary hypertension. We report on the use of ETR blocking agents in a cohort of 14 high-risk SCD adult patients with pulmonary hypertension. Patients underwent right heart catheterization, 6-min walk test, echocardiogram, physical examination and blood work-up before starting ETR blockers. Eight patients received ETR blockers as initial therapy; six patients were already taking sildenafil. Over more than 6 months of therapy, sequential measurements of 6-min walk distance increased significantly (baseline 357 +/- 22 to 398 +/- 18 m at 5-6 months, P < 0.05). Downward trends were observed for amino-terminal brain natriuretic peptide and tricuspid regurgitant velocity. Pulmonary artery mean pressures decreased in three patients that had repeat right heart catheterization (44-38 mmHg). Adverse events were: increased serum alanine aminotransferase (2), peripheral oedema (4), rash (1), headache (3), decreased haemoglobin (2). Therapy was stopped in two patients who were switched then to the other ETR blocker agent. These data suggest preliminary evidence for the benefit of bosentan and ambrisentan in pulmonary hypertension in SCD. PMID- 19775301 TI - The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals. AB - Neuraxial anaesthesia is increasingly performed in thrombocytopenic patients at the time of delivery of pregnancy. There is a lack of data regarding the optimum platelet count at which spinal procedures can be safely performed. Reports are often confounded by the presence of other risk factors for spinal haematomata, such as anticoagulants, antiplatelet agents and other acquired or congenital coagulopathies/platelet function defects or rapidly falling platelet counts. In the absence of these additional risk factors, a platelet count of 80 x 10(9)/l is a 'safe' count for placing an epidural or spinal anaesthetic and 40 x 10(9)/l is a 'safe' count for lumbar puncture. It is likely that lower platelet counts may also be safe but there is insufficient published evidence to make recommendations for lower levels at this stage. For patients with platelet counts of 50-80 x 10(9)/l requiring epidural or spinal anaesthesia and patients with a platelet count 20-40 x 10(9)/l requiring a lumbar puncture, an individual decision based on assessment of risks and benefits should be made. PMID- 19775302 TI - Folate related gene polymorphisms and susceptibility to develop childhood acute lymphoblastic leukaemia. AB - Acute lymphoblastic leukaemia (ALL) is the most common paediatric cancer, accounting for nearly 30% of all paediatric cancers and 80% of childhood leukaemias. Polymorphisms in folate-related genes may influence the susceptibility to childhood ALL. This review summarizes the results of 14 studies that focussed on the relationship between folate-related gene polymorphisms and the susceptibility to ALL and that fulfilled certain quality criteria. The total group consisted of 729 children and 1821 adults or non age-defined patients. The results of different studies sometimes contradict each other, for which there are several possible explanations. This includes an influence of the type of population studied, because there was a difference between Asian and European study results. Based on several studies, it is plausible that polymorphisms in the MTHFR gene, 677C>T and 1298A>C, are associated with a decreased susceptibility to childhood ALL in non-Asian populations. Polymorphisms in other folate related genes (MTRR, MTR [MS], TYMS [TS], SLC19A1 [RFC1], NNMT, and SHMT1) are less clearly associated with susceptibility to ALL, and the number of included studies on this subject in this review is limited. Further investigations on the relevance of these polymorphisms need to be performed. In general, it is clear that susceptibility to (childhood) ALL is partly related to constitutional differences in folate gene polymorphisms. PMID- 19775303 TI - Diagnosis of mild platelet function disorders. Reliability and usefulness of light transmission platelet aggregation and serotonin secretion assays. AB - Light transmission platelet aggregation (PA), adapted to measure platelet secretion (PS), is the reference test for diagnosing platelet functional disorders (PFD). Problems with these assays include lack of standardisation, unknown reproducibility and lack of universally accepted diagnostic criteria. We addressed these issues in patients with inherited mucocutaneous bleeding (MCB). Normal and abnormal PA tests in 213 patients were reproducible in 93.3% and 90.4% of the cases, respectively. Mean intra-subject coefficient of variation for PA with strong agonists were <9% and mean intra-class correlation coefficient for weak agonists were >0.86 (P < 0.0001). Concomitant impaired PA with 10 micromol/l adrenaline and 4 micromol/l-ADP was observed in 13.7% of the controls. This combination was not considered per se a criterion for PFD. PA with adrenaline > or = 42% or irreversible aggregation with 4 micromol/l ADP had 93% and 95% Negative Predictive Value for diagnosing PFD, respectively. PA defects were consistently associated with abnormal PS. In contrast, 14.3% of patients with MCB had isolated PS. Thus, standardized PA/PS assays are highly reproducible and concordant in normal and patient populations. Normal PA with adrenaline and low ADP concentration robustly predict a normal PA. Simultaneous PA/PS assays enable the diagnosis of isolated PS defects. This study confirmed that hereditary PA-PS defects are highly prevalent. PMID- 19775304 TI - A simple tool to measure patient perceptions of operative birth. AB - OBJECTIVE: To assess the feasibility and validity of a maternal satisfaction measurement tool, the SaFE study Patient Perception Score (PPS), after operative delivery. DESIGN: Cross-sectional survey. SETTING: A large maternity unit in England. SAMPLE: 150 women who had had an operative birth. METHODS: We recruited women within 24 hours of birth and quantified their satisfaction with two questionnaires: PPS, and the Mackey Childbirth Satisfaction Rating Scale (CSRS; modified). MAIN OUTCOME MEASURES: Participation rate to determine feasibility; Cronbach's alpha as measure of internal consistency; PPS satisfaction scores for groups of accoucheurs of different seniority to assess construct validity; correlation coefficient of PPS scores with total scores from the CSRS questionnaire to establish criterion validity. RESULTS: Participation rate approached 85%. We observed high scores for most births except a few outliers. Internal consistency of the PPS was high (Cronbach's alpha=0.83). Total PPS scores correlated strongly with total CSRS scores (Spearman's r=0.64, P<0.001). CONCLUSIONS: The PPS is a simple and valid tool for patient-centred assessments. High scores were observed for most births but there were a small minority of accoucheurs who consistently scored poorly and these data could be used during appraisal and training. PMID- 19775305 TI - A qualitative study of pharmacists' views on offering chlamydia screening to women requesting Emergency Hormonal Contraception. AB - This was a qualitative study to understand why pharmacists, asked to offer free chlamydia postal screening to Emergency Hormonal Contraception clients, had not offered screening to all eligible women. Twenty-six pharmacists completed exit interviews and 12 agreed to semi-structured in-depth interviews. Although pharmacists were keen to expand their services, they were reluctant to offer chlamydia screening to women who were married or in a long term relationship. To avoid offence they selected women based on age, education and ethnicity. The rationale for chlamydia screening in pharmacy-based EHC schemes is compromised if pharmacists do not offer screening comprehensively. PMID- 19775306 TI - Serum insulin patterns and the relationship between insulin sensitivity and glycaemic profile in women with polycystic ovary syndrome. AB - OBJECTIVE: To evaluate serum insulin levels and insulin sensitivity in women with polycystic ovary syndrome (PCOS) in relation to their glycaemic status. DESIGN: An observational study. SETTING: A tertiary-level reproductive health centre in Sri Lanka. SAMPLE: Infertile women diagnosed as having PCOS (n=168) on the basis of the Rotterdam criteria were included in the study. METHODS: Glycaemic status and serum insulin values were assessed at fasting and at 2 hours after a 75-g oral glucose load and stratified as diabetes mellitus (DM) (10.12%), impaired glucose tolerance (IGT) (23.21%) and normoglycaemia (66.67%). The normoglycaemic group was restratified as groups A (10.7%), B (79.5%) and C (9.8%) on the basis of serum insulin levels, with group A having the lowest and group C the highest values. The Quantitative Insulin Sensitivity Check Index (QUICKI) scores of women with DM and IGT and those in groups A, B and C in the normoglycaemic category were compared. MAIN OUTCOME MEASURES: Insulin sensitivity in these groups of women. RESULTS: Body mass index (BMI) exceeded 23 kg/m(2) in 77.38% of the women. In normoglycaemic women with PCOS, insulin sensitivity was highest in group A. In groups B and C, insulin sensitivities corresponded to those found for women with IGT and DM respectively. This pattern was also reflected in the BMI. CONCLUSIONS: Normoglycaemic women with PCOS are heterogeneous regarding insulin sensitivity. The treatment offered to those with DM and IGT could be extended to subgroups B and C of normoglycaemic subjects. Normoglycaemic women with PCOS with high insulin sensitivity (group A) would not qualify for this treatment. PMID- 19775307 TI - Soy intake and risk of endocrine-related gynaecological cancer: a meta-analysis. AB - BACKGROUND: Epidemiology studies have reported associations between soy intake and the risk of endocrine-related gynaecological cancers. However, to date there have been no quantitative meta-analyses reported regarding this topic. OBJECTIVES: We investigated the quantitative associations between soy food intake and the risk of endometrial cancer and ovarian cancer by a meta-analysis of case control studies and cohort studies. SEARCH STRATEGY: We searched MEDLINE (PubMed), EMBASE and the Cochrane Library during October 2008 using common keywords related to soy intake and endometrial or ovarian cancer. Two evaluators independently reviewed and selected articles, based on predetermined selection criteria. SELECTION CRITERIA: Included studies met all of the following criteria: (1) a case-control study or cohort study (to date, no randomized controlled trials have been reported); (2) investigated the associations between 'soy or soy product intake' and 'endometrial cancer' or 'ovarian cancer'; (3) reported outcome measures with adjusted odds ratios (OR) or relative risks (RR) and 95% confidence intervals (CI). DATA COLLECTION AND ANALYSIS: We investigated the associations between the overall soy intake (highest versus lowest intake) and the risk of endocrine-related gynaecological cancers (endometrial or ovarian cancer) as the main analysis. We also performed subgroup analyses by type of cancer (endometrial or ovarian), type of study design (case-control or cohort) and type of soy intake (soy foods or soy constituents). MAIN RESULTS: Out of 477 articles that met our initial criteria, a total of seven epidemiology studies consisting of five case-control studies and two cohort studies were included in the final analyses. Compared with the lowest soy intake, the OR for the highest soy intake was 0.61 (95% CI, 0.53-0.72) of all endocrine-related cancers among seven studies; 0.70 for endometrial cancer (95% CI, 0.57-0.86) and 0.52 for ovarian cancer (95% CI, 0.42-0.66) in the fixed-effects meta-analyses. The subgroup analyses by study design showed similar findings among the case-control studies (OR, 0.62; 95% CI, 0.53-0.73) and the cohort studies (OR, 0.57; 95% CI, 0.36-0.90). AUTHOR'S CONCLUSIONS: The results of the current study showed protective effects of soy intake on the risk for endocrine-related gynaecological cancers. Additional larger prospective studies are now needed. PMID- 19775308 TI - Aicardi-Goutieres syndrome presenting with haematemesis in infancy. AB - Aicardi-Goutieres syndrome is a genetic childhood encephalopathy characterized by basal ganglia calcification, chronic cerebrospinal lymphocytosis and elevated cerebrospinal fluid interferon-alpha, mimicking acquired congenital viral infections. As more is discovered about the pathogenesis of Aicardi-Goutieres, it is becoming evident that a dysfunction of the immune system is likely to be responsible for the disease phenotype. We describe a previously healthy 2-month old female infant who presented with haematemesis and seizures and was subsequently diagnosed with Aicardi-Goutieres syndrome. To our knowledge, this is the first documented case of Aicardi-Goutieres syndrome presenting with haematemesis. The gastrointestinal tract is an area of high cell loss, revealing early signs of systemic inflammation and we postulate that a systemic proinflammatory milieu occurs in Aicardi-Goutieres syndrome. CONCLUSION: Aicardi Goutieres syndrome can present with haematemesis, adding to the growing evidence that the Aicardi-Goutieres syndrome spectrum encompasses an immune-mediated multisystem involvement. Gastrointestinal inflammation should also be considered in these patients and treated appropriately. PMID- 19775309 TI - Beneficial effects of preoperative intravitreal bevacizumab on trabeculectomy outcomes in neovascular glaucoma. AB - PURPOSE: This study aimed to investigate the effects of preoperative intravitreal bevacizumab (IVB) on outcomes in trabeculectomy for neovascular glaucoma (NVG). METHODS: Charts for 52 NVG eyes of 52 consecutive patients who received primary trabeculectomy with mitomycin C (MMC) were reviewed. Postoperative follow-up periods for all patients were > or = 4 months. Thirty-two consecutive eyes were treated without IVB (control group) and 20 consecutive eyes received IVB (1.25 mg) 10 +/- 11 days before trabeculectomy (IVB group). The main outcome measures were postoperative intraocular pressure (IOP) and incidence of postoperative complications. Surgical success was defined as IOP< 21 mmHg with or without medication (qualified or complete success, respectively). Failure was defined as IOP exceeding these criteria, phthisis bulbi, loss of light perception or additional glaucoma surgeries. Kaplan-Meier survival analysis with the log-rank test was performed to compare surgical success rates between the two groups. RESULTS: Complete and qualified success rates at 6 months were 95% versus 50% and 95% versus 75% in the IVB and control groups, respectively. The IVB group achieved significantly better surgical success rates than the control group (complete success, p < 0.001; qualified success, p = 0.026). Postoperative hyphaema on day 1 or hyphaema with a duration of > 1 week occurred significantly less frequently in the IVB group than in the control group (p = 0.009, p = 0.014, respectively). The incidence of serious complications such as endophthalmitis, phthisis bulbi and a marked decrease in visual acuity did not increase in the IVB group. CONCLUSIONS: This retrospective study showed that preoperative IVB decreased postoperative hyphaema and increased surgical success rates, and thus may be an effective adjunct to trabeculectomy in NVG. PMID- 19775311 TI - Improved survival after liver transplantation in patients with hepatopulmonary syndrome. AB - Hepatopulmonary syndrome (HPS) is present in 10-32% of chronic liver disease patients, carries a poor prognosis and is treatable by liver transplantation (LT). Previous reports have shown high LT mortality in HPS and severe HPS (arterial oxygen (PaO(2)) < or =50 mmHg). We reviewed outcomes in HPS patients who received LT between 2002 and 2008 at two transplant centers supported by a dedicated HPS clinic. We assessed mortality, complications and gas exchange in 21 HPS patients (mean age 51 years, MELD score 14), including 11/21 (52%) with severe HPS and 5/21 (24%) with living donor LT (median follow-up 20.2 months after LT). Overall mortality was 1/21 (5%); mortality in severe HPS was 1/11 (9%). Peritransplant hypoxemic respiratory failure occurred in 5/21 (24%), biliary complications in 8/21 (38%) and bleeding or vascular complications in 6/21 (29%). Oxygenation improved in all 19 patients in whom PaO(2) or SaO(2) were recorded. PaO(2) increased from 52.2 +/- 13.2 to 90.3 +/- 11.5 mmHg (room air) (p < 0.0001) (12 patients); a higher baseline macroaggregated albumin shunt fraction predicted a lower rate of postoperative improvement (p = 0.045) (7 patients). Liver transplant survival in HPS and severe HPS was higher than previously demonstrated. Severity of HPS should not be the basis for transplant refusal. PMID- 19775310 TI - The effect of deep sclerectomy on intraocular pressure of normal-tension glaucoma patients: 1-year results. AB - PURPOSE: To study the intraocular pressure (IOP)-reducing effect of deep sclerectomy on normal-tension glaucoma (NTG) patients. METHODS: We retrospectively analysed 21 eyes of 18 consecutive NTG patients who had undergone deep sclerectomy with mitomycin-C and a collagen implant. RESULTS: Median (range) preoperative IOP was 15.1 mmHg (9.3-20.8) and median follow-up time 13 months (12 18). At the 1-year follow-up visit, median IOP was significantly (P < 0.001) reduced to 10.5 mmHg (4-15) with median IOP reduction from preoperative values of 37% (12-78). Laser goniopuncture was performed in 10 eyes (48%) 1-16 months postoperatively. After 13 months' follow-up, a complete success at 20%, 25% and 30% IOP reduction levels was achieved in 67%, 62% and 52% of eyes, respectively. Few complications were encountered, but these included reduced visual acuity, problems with conjunctiva, microperforation, hyphaema, Dellen formation and encapsulated bleb. We encountered no complications related to postoperative hypotony. CONCLUSION: Deep sclerectomy with a collagen implant and mitomycin-C was a safe and effective method for reducing IOP in NTG patients during 1-year follow-up. PMID- 19775312 TI - Recurrence-free long-term survival after liver transplantation in patients with 18F-FDG non-avid hilar cholangiocarcinoma on PET. AB - The aim of this retrospective study was to assess the value of (18)F fluorodeoxyglucose positron emission tomography ((18)F-FDG-PET) for predicting biological tumor behavior and outcome after liver transplantation (LT) in patients with otherwise unresectable hilar cholangiocarcinoma (HC). Preoperative (18)F-FDG-PET scanning was performed in 13 patients with type IV Klatskin tumor before LT. PET+ status indicated patients with an increased pretransplant (18)F FDG uptake, whereas PET- recipients had no increased preoperative (18)F-FDG uptake on PET. Pretransplant PET findings were correlated with histopathological tumor characteristics and patient outcome after LT. Eight patients demonstrated positive preoperative PET findings (61.5%), whereas five patients had no increased preoperative (18)F-FDG tumor uptake (38.5%) on PET. One PET+ patient died after 1 month due to liver allograft dysfunction. Seven PET+ liver recipients developed tumor recurrence, whereas five PET- patients were tumor-free alive after a median of 76 months post-LT (p = 0.001). The 2-year recurrence-free survival rate after LT was 100% in PET- patients and 28.6% in the PET+ population (log-rank = 0.008). Our results suggest that patients with (18)F-FDG non-avid HC on PET may achieve recurrence-free long-term survival after LT. PMID- 19775313 TI - Memory T-cell predominance following T-cell depletional therapy derives from homeostatic expansion of naive T cells. AB - T-cell depletion reportedly leads to alterations in the T-cell compartment with predominant survival of memory phenotype CD4 T cells. Here, we asked whether the prevalence of memory T cells postdepletion results from their inherent resistance to depletion and/or to the homeostatic expansion of naive T cells and their phenotypic conversion to memory, which is known to occur in lymphopenic conditions. Using a 'mosaic memory' mouse model with trackable populations of alloreactive memory T cells, we found that treatment with murine antithymocyte globulin (mATG) or antilymphocyte serum (ALS) effectively depleted alloreactive memory CD4 T cells, followed by rapid homeostatic proliferation of endogenous CD4 T cells peaking at 4 days postdepletion, with no homeostatic advantage to the antigen-specific memory population. Interestingly, naive (CD44lo) CD4 T cells exhibited the greatest increase in homeostatic proliferation following mATG treatment, divided more extensively compared to memory (CD44hi) CD4 T cells and converted to a memory phenotype. Our results provide novel evidence that memory CD4 T cells are susceptible to lymphodepletion and that the postdepletional T cell compartment is repopulated to a significant extent by homeostatically expanded naive T cells in a mouse model, with important important implications for immune alterations triggered by induction therapy. PMID- 19775314 TI - Effect of antibodies on endothelium. AB - Patients developing posttransplant antibodies against HLA and non-HLA antigens expressed by the endothelium of the graft undergo more frequent episodes of rejection and have decreased long-term graft survival. Antibodies against the endothelium can alter/damage the cells of the graft through several mechanisms. Historically, antibodies were thought to elicit endothelial cell injury via complement-dependent mechanisms. New research has shown that antibodies can also contribute to the process of transplant rejection by stimulating proinflammatory and proproliferation signals. Antibody ligation leads to several functional alterations in EC including Weibel Palade body exocytosis, leukocyte recruitment, growth factor expression and cell proliferation. In contrast, under certain circumstances, antibodies may induce prosurvival signals and graft accommodation. The signaling events regulating accommodation vs. rejection appear to be influenced by the specificity and concentration of the anti-HLA antibody and the degree of molecular aggregation. Knowledge of the HLA and non-HLA antibody mediated signaling pathways has the potential to identify new therapeutic targets to promote accommodation and prevent acute and chronic antibody-mediated rejection. PMID- 19775315 TI - Reduced size liver transplantation from a donor supported by a Berlin Heart. AB - Patients on cardiac assist devices are often considered to be high-risk solid organ donors. We report the first case of a reduced size liver transplant performed using the left lateral segment of a pediatric donor whose cardiac function was supported by a Berlin Heart. The recipient was a 22-day-old boy with neonatal hemochromatosis who developed fulminant liver failure shortly after birth. The transplant was complicated by mild delayed graft function, which required delayed biliary reconstruction and abdominal wall closure, as well as a bile leak. However, the graft function improved quickly over the first week and the patient was discharged home with normal liver function 8 weeks after transplant. The presence of a cardiac assist device should not be considered an absolute contraindication for abdominal organ donation. Normal organ procurement procedures may require alteration due to the unusual technical obstacles that are encountered when the donor has a cardiac assist device. PMID- 19775316 TI - Safety and long-term efficacy of eculizumab in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome. PMID- 19775317 TI - The impact of preexisting or acquired Kaposi sarcoma herpesvirus infection in kidney transplant recipients on morbidity and survival. AB - The impact of preexisting or acquired Kaposi sarcoma herpesvirus (KSHV) infection in kidney transplant recipients was evaluated in a prospective study. Serum collected from kidney donors and recipients before transplantation were tested for antibodies against KSHV latent nuclear antigen. Three groups of recipients were defined: group A (KSHV+), group B (KSHV-, KSHV+ donor) and group C (donor and recipient KSHV-). Blood was collected from recipients, every 3 months for 3 years, for KSHV viremia (groups A and B), quantitative (group A) and qualitative serology (group B). Data of group C recipients were extracted from a French database. The prevalence of KSHV antibodies was 1.1% in donors and 3.2% in recipients. There were respectively 161, 64 and 4744 recipients in groups A, B and C. In group A, 13% developed Kaposi's sarcoma (KS). Age >53.5 years (p = 0.025) and black skin (p = 0.0054) were associated with KS development. In group B, three recipients developed clinical manifestations related to KSHV infection. There was no difference in terms of survival and graft loss between the three groups. In conclusion, although kidney recipients should be aware of the additional risk of KSHV morbidity, KSHV+ recipients should not be systematically excluded from kidney transplantation. PMID- 19775318 TI - Endoscopic gastric submucosal transplantation of islets (ENDO-STI): technique and initial results in diabetic pigs. AB - The results of transplantation of human donor islets into the portal vein (PV) in patients with diabetes are encouraging. However, there are complications, for example, hemorrhage, thrombosis and an immediate loss of islets through the 'instant blood-mediated inflammatory reaction' (IBMIR). The gastric submucosal space (GSMS) offers potential advantages. Islets were isolated from adult pigs. Recipient pigs were made diabetic by streptozotocin. Donor islets were injected into the GSMS through a laparotomy (Group 1A, n = 4) or endoscopically (Group 1B, n = 8) or into the PV through a laparotomy (Group 2, n = 3). The pigs were followed for a maximum of 28 days. Monitoring of C-peptide in Group 1 indicated that there was minimal immediate loss of islets whereas in Group 2 there was considerable loss from IBMIR. In Group 1, there were significant reductions in mean blood glucose and mean exogenous insulin requirement between pretransplantation and 20 days posttransplantation. In Group 2, there was no significant reduction in either parameter. Insulin-positive cells were seen in the GSMS in Group 1, but not in the liver in Group 2. Endoscopic gastric submucosal transplantation of islets (ENDO-STI) offers a minimally invasive and quick approach to islet transplantation, avoids IBMIR and warrants further exploration. PMID- 19775319 TI - Evolution of coronary artery calcifications following kidney transplantation: relationship with osteoprotegerin levels. AB - We prospectively assessed the evolution of coronary artery calcification (CAC) and osteoprotegerin (OPG) levels after renal transplantation (RT). Eighty-three recipients were followed-up prospectively during 1 year. Blood was collected before (baseline) and after RT for determination of mineral metabolism parameters including OPG. CAC was measured by multidetector computed tomography at transplantation (baseline) and 1 year later. Progression of CAC was defined as a difference between the follow-up square-root transformed volume (SRV) and the baseline SRV >or= 2.5. By multivariate analysis, baseline OPG level, age and low LDL levels were significantly associated with baseline CAC. RT was accompanied by mineral metabolism improvement with a decrease of OPG from 955 [395-5652] to 527 [217-1818] pg/mL and parathyroid hormone from 94 [1-550] to 62 [16-410] pg/mL. Thirty-one percent of patients did not exhibit CAC at baseline. CAC diminished in 14.5%, stabilized in 59.2% and progressed in 26.3% of patients. Baseline CAC was associated with progression (OR 2.92 [1.02-8.36]). No significant association was found between OPG and CAC progression despite a higher baseline OPG level in progressors (1046 [456-3285]) vs. non-progressors (899 [396-5952] pg/mL). CAC at baseline, but not 1 year after RT, is independently associated with baseline OPG; posttransplant CAC progression is predicted by baseline CAC score. PMID- 19775320 TI - Outcome of subclinical antibody-mediated rejection in kidney transplant recipients with preformed donor-specific antibodies. AB - This study describes clinical relevance of subclinical antibody-mediated rejection (SAMR) in a cohort of 54 DSA-positive kidney transplant recipients receiving a deceased donor. In 3 months screening biopsies, 31.1% of patients met the criteria of SAMR. A total of 48.9% had an incomplete form of SAMR (g+/ptc+/C4d-negative) whereas 20% had no humoral lesions. Patients with SAMR at 3 months had at 1 year: a higher C4d score, ptc score, and arteriosclerosis score, higher rate of IFTA (100% vs. 33.3%, p < 0.01) and a higher rate of transplant glomerulopathy (43% vs. 0%, p = 0.02) compared to patients without 3 month SAMR. Patients with SAMR at 3 months exhibited at 1 year a higher class II MFImax-DSA and a lower mGFR compared to patients without SAMR (39.2 +/- 13.9 vs. 61.9 +/- 19.2 mL/min/1.73 m(2) respectively, p < 0.01). The group of patients with C4d-negative SAMR at 3 months developed more ptc and IFTA lesions, and lower GFR at 1 year in comparison to biopsies without humoral lesions. SAMR is a frequent entity in KTR with preexisting DSAs and promotes subsequent GFR impairment and development of chronic AMR. C4d-negative SAMR patients displayed an intermediate course between the no-SAMR group and the C4d+ SAMR group. Screening biopsies may be useful to recognize patients more likely to develop SAMR. PMID- 19775321 TI - Mycophenolate mofetil and calcineurin-inhibitor reduction: recent progress. AB - Mycophenolate mofetil (MMF) in combination with calcineurin inhibitors (CNIs) has greatly contributed to acute rejection rate reduction. Because of its immunosuppressive potency it was initially thought that MMF would help in reducing/avoiding CNI-related nephrotoxicity. Elective avoidance of CNI in induction and maintenance MMF-based immunosuppression has resulted in an increased risk for acute and chronic rejection. A recent meta-analysis suggests that CNI elimination in patients on MMF with progressive renal dysfunction is associated with a better outcome, although more data are needed to support any recommendation. So far, the more conservative approach involving CNI minimization with MMF has been associated with amelioration of renal function and low risk for rejection, providing an adequate risk/benefit balance. However, MMF with belatacept might pave the way for CNI-free induction and maintenance immunosuppression. Meanwhile, the assessment of immunological risk by new monitoring tools could be a prerequisite to further implement such CNI sparing strategies. PMID- 19775323 TI - Breast cancer risk assessment and follow-up management: is there a magic marker to identify high risk individuals? PMID- 19775322 TI - Long-term effects of minimum drinking age laws on past-year alcohol and drug use disorders. AB - BACKGROUND: Many studies have found that earlier drinking initiation predicts higher risk of later alcohol and substance use problems, but the causal relationship between age of initiation and later risk of substance use disorder remains unknown. METHOD: We use a "natural experiment" study design to compare the 12-month prevalence of Diagnostic and Statistical Manual, Fourth Edition, alcohol and substance use disorders among adult subjects exposed to different minimum legal drinking age laws minimum legal drinking age in the 1970s and 1980s. The sample pools 33,869 respondents born in the United States 1948 to 1970, drawn from 2 nationally representative cross-sectional surveys: the 1991 National Longitudinal Alcohol Epidemiological Survey (NLAES) and the 2001 National Epidemiological Study of Alcohol and Related Conditions. Analyses control for state and birth year fixed effects, age at assessment, alcohol taxes, and other demographic and social background factors. RESULTS: Adults who had been legally allowed to purchase alcohol before age 21 were more likely to meet criteria for an alcohol use disorder [odds ratio (OR) 1.31, 95% confidence intervals (95% CI) 1.15 to 1.46, p < 0.0001] or another drug use disorder (OR 1.70, 95% CI 1.19 to 2.44, p = 0.003) within the past-year, even among subjects in their 40s and 50s. There were no significant differences in effect estimates by respondent gender, black or Hispanic ethnicity, age, birth cohort, or self reported age of initiation of regular drinking; furthermore, the effect estimates were little changed by inclusion of age of initiation as a potential mediating variable in the multiple regression models. CONCLUSION: Exposure to a lower minimum legal purchase age was associated with a significantly higher risk of a past-year alcohol or other substance use disorder, even among respondents in their 40s or 50s. However, this association does not seem to be explained by age of initiation of drinking, per se. Instead, it seems plausible that frequency or intensity of drinking in late adolescence may have long-term effects on adult substance use patterns. PMID- 19775324 TI - Genetic counseling and the advanced practice oncology nursing role in a hereditary cancer prevention clinic: hereditary breast cancer focus (part II). AB - Hereditary breast cancer (BC) is heterogeneous to the extent that no two high risk patients can be considered as being the same. These individual differences are magnified further when patients' emotional response to all facets of hereditary BC are considered, particularly issues surrounding gene testing. A series of case histories have been provided that illustrate the wide range of attitudes, feelings, and emotional responses explained by patients when learning of their hereditary cancer risk status. The role of the oncology nurse-genetic counselor has been described in each of these family reports. PMID- 19775325 TI - Genetic counseling and the advanced practice oncology nursing role in a hereditary cancer prevention clinic: hereditary breast cancer focus (part I). AB - Interest in hereditary breast cancer has increased rapidly among all health care providers as well as the laity. A major problem for health care providers, however, is the time and skill required for gathering family history, interpreting the pedigree, and providing genetic counseling for the high-risk patient so that BRCA testing, when indicated, can be pursued and screening and prevention strategies employed by the patient. The fields of hereditary cancer and molecular biology have developed at a rate that makes it difficult for physicians to keep up with this explosive knowledge. Therefore, "Who is going to take care of all of these crucial matters for patient benefit?" is a germane question. Our experience has confirmed that the advanced practice oncology nurse who is interested in cancer genetics can become skilled at providing this service to the patient and his/her family. This study portrays the role of such an oncology nurse in meeting this important public health challenge, with special attention devoted to the logistics of this role in the rapidly emerging field of hereditary breast cancer. PMID- 19775327 TI - Controversies in communication of genetic risk for hereditary breast cancer. AB - Increased availability and heightened consumer awareness of "cancer genes" has increased consumer interest in, and demand for breast cancer risk assessment, and thus a pressing need for providers to identify effective, efficient methods of communicating complicated genetic information to consumers and their potentially at-risk relatives. With increasing direct-to-consumer and -physician marketing of predictive genetic tests, there has been considerable growth in web- and telephone-based genetic services. There is urgent need to further evaluate the psychosocial and behavioral outcomes (i.e., risks and benefits) of telephone and web-based methods of delivery before they become fully incorporated into clinical care models. Given the implications of genetic test results for family members, and the inherent conflicts in health care providers' dual responsibilities to protect patient privacy and to "warn" those at-risk, new models for communicating risk to at-risk relatives are emerging. Additional controversies arise when the at-risk relative is a minor. Research evaluating the impact of communicating genetic risk to offspring is necessary to inform optimal communication of genetic risk for breast cancer across the lifespan. Better understanding the risks and benefits associated with each of these controversial areas in cancer risk communication are crucial to optimizing adherence to recommended breast cancer risk management strategies and ensuring psycho-social well-being in the clinical delivery of genetic services for breast cancer susceptibility. PMID- 19775328 TI - Establishing a family risk assessment clinic for breast cancer. AB - Breast cancer is the most common cancer affecting European women and the leading cause of cancer-related death. A total of 15-20% of women who develop breast cancer have a family history and 5-10% a true genetic predisposition. The identification and screening of women at increased risk may allow early detection of breast cancer and improve prognosis. We established a family risk assessment clinic in May 2005 to assess and counsel women with a family history of breast cancer, to initiate surveillance, and to offer risk-reducing strategies for selected high-risk patients. Patients at medium or high risk of developing breast cancer according to NICE guidelines were accepted. Family history was determined by structured questionnaire and interview. Lifetime risk of developing breast cancer was calculated using Claus and Tyrer-Cuzick scoring. Risk of carrying a breast cancer-related gene mutation was calculated using the Manchester system. One thousand two hundred and forty-three patients have been referred. Ninety-two percent were at medium or high risk of developing breast cancer. Formal assessment of risk has been performed in 368 patients, 73% have a high lifetime risk of developing breast cancer, and 72% a Manchester score >or=16. BRCA1/2 mutations have been identified in 14 patients and breast cancer diagnosed in two. Our initial experience of family risk assessment has shown there to be a significant demand for this service. Identification of patients at increased risk of developing breast cancer allows us to provide individuals with accurate risk profiles, and enables patients to make informed choices regarding their follow-up and management. PMID- 19775326 TI - Family information service participation increases the rates of mutation testing among members of families with BRCA1/2 mutations. AB - Some members of hereditary breast-ovarian cancer (HBOC) families may not participate in BRCA testing to determine their mutation status in part because they are unaware of their cancer risk and the availability of BRCA testing. Participation in a family information service (FIS), of which we have provided more than 100 sessions during the past 30 years, has been seen to effectively allow family members to be educated regarding their cancer genetic risk and potential benefits from cancer control measures such as mutation testing. However, the effect of the FIS on the rate of mutation testing has not been studied. One thousand five hundred seventy-four eligible (>18-year old, at a 25% or higher pedigree risk) members from 60 extended HBOC families with BRCA1/2 mutations were invited to attend a FIS to learn about their risk and undergo genetic testing. The rates of mutation testing were compared between those who had attended an FIS, and those who had not with chi-squared test and logistic regression analysis. Seventy five percent (334/444) of FIS attendees had undergone mutation testing following or during an FIS which was significantly higher than the 33.8% (382/1130) rate among nonattendees (p < 0.0001). Logistic regression analysis showed that FIS attendance, breast-ovarian cancer history, gender, and age were significant variables for undertaking a mutation test. FIS attendance significantly increased the rate of mutation testing among high-risk family members. PMID- 19775329 TI - Assessing breast cancer risk and providing treatment recommendations: immediate impact of an educational session. AB - The widespread availability of information regarding advancements in breast cancer care has heightened public awareness about risk and prevention, but there is limited knowledge as to the translation of these evolving advancements into physician practice patterns. The purpose of this study was to: (a) determine current practice patterns/treatment recommendations for evaluating patients at high-risk for breast cancer and (b) measure the immediate effect of an educational session on new knowledge acquired for high-risk patients. Five thousand and one health care provider surveys were sent to physicians in the greater Chicago area. The survey inquired about practice patterns and offered an opportunity to attend an educational session utilizing our "Spectrum of Care Options" framework. To evaluate session effectiveness, pre and post-tests were administered to participants. Of 767 survey respondents, 78 attended an educational session, 64 completed a pre and post-test, and 65 completed program evaluations. Pretest scores averaged 67.1% correct (range = 29-100%, SD = 15.8%) while post-test scores averaged 80.3% correct (range = 59-100%, SD = 11.0%), p < 0.0001. Participants rated the following on a 1-5 (poor to excellent) Likert scale (average scores): presentations 4.74, instructional materials 4.58, usefulness to practice 4.60, new knowledge gained 4.71, and likelihood of changing practice 4.49. Primary care physicians and surgeons are interested in identifying and treating high-risk patients, but may lack sufficient state-of-the art knowledge to do so. An educational session providing information on this subject, based on Spectrum of Care Options, significantly improved their knowledge and may influence their future practices. PMID- 19775330 TI - Electronic health records and the management of women at high risk of hereditary breast and ovarian cancer. AB - Currently, management strategies exist that can decrease the morbidity and mortality associated with having a BRCA1 or BRCA2 mutation. Unfortunately, the task of identifying these patients at high risk is a daunting challenge. This problem is intensified because Electronic Health Records (EHRs) today lack the functionality needed to identify these women and to manage those women once they have been identified. Numerous niche software programs have been developed to fill this gap. Unfortunately, these extremely valuable niche programs are prevented from being interoperable with the EHRs, on the premise that each EHR vendor will build their own programs. Effectively, in our efforts to adopt EHRs, we have lost sight of the fact that they can only have a major impact on quality of care if they contain structured data and if they interact with robust Clinical Decision Support (CDS) tools. We are at a cross roads in the development of the health care Information Technology infrastructure. We can choose a path where each EHR vendor develops each CDS module independently. Alternatively, we can choose a path where experts in each field develop external niche software modules that are interoperable with any EHR vendor. We believe that the modular approach to development of niche software programs that are interoperable with current EHRs will markedly increase the speed at which useful and functional EHRs that improve quality of care become a reality. Thus, in order to realize the benefits of CDS, we suggest vendors develop means to become interoperable with external modular niche programs. PMID- 19775331 TI - Influence of race/ethnicity on genetic counseling and testing for hereditary breast and ovarian cancer. AB - Risk assessment coupled with genetic counseling and testing for the cancer predisposition genes BRCA1 and BRCA2 (BRCA1/2) has become an integral element of comprehensive patient evaluation and cancer risk management in the United States for individuals meeting high-risk criteria for hereditary breast and ovarian cancer (HBOC). For mutation carriers, several options for risk modification have achieved substantial reductions in future cancer risk. However, several recent studies have shown lower rates of BRCA1/2 counseling and testing among minority populations. Here, we explore the role of race/ethnicity in cancer risk assessment, genetic counseling and genetic testing for HBOC and the BRCA1/2 cancer predisposition genes. Barriers to genetic services related to race/ethnicity and underserved populations, including socioeconomic barriers (e.g., time, access, geographic, language/cultural, awareness, cost) and psychosocial barriers (e.g., medical mistrust, perceived disadvantages to genetic services), as well as additional barriers to care once mutation carriers are identified, will be reviewed. PMID- 19775332 TI - Risk of breast cancer among French-Canadian women, noncarriers of more frequent BRCA1/2 mutations and consumption of total energy, coffee, and alcohol. AB - Although the connection between diet, lifestyle and hormones suggests that nutritional and lifestyle factors may exert an influence in the etiology of breast cancer, it is not clear whether these factors operate in the same way in women without BRCA gene mutations. A nested case-control study was conducted in a cohort of French-Canadian women, with 560 members involving 280 nongene carriers of mutated BRCA gene affected by breast cancer and 280 nonaffected and nongene carriers of mutated BRCA gene. A validated semi-quantitative food frequency questionnaire was used to ascertain dietary intake, and a core questionnaire, to gather information on lifestyle risk factors. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated in logistic regression models. It was found that energy intake >2,057 Kcal/day was significantly and positively related to breast cancer risk (OR = 2.54; 95% CI: 1.67-3.84; p = 0.01). Women who drank more than eight cups of coffee per day had an increased risk of breast cancer: OR = 1.40 (95% CI: 1.09-2.24; p = 0.03). Subjects who drank >9 g of alcohol (ethanol) per day had an increased risk of breast cancer: OR = 1.55 (95% CI: 1.02 2.37; p = 0.04). In addition, a positive and significant association was noted between the consumption of beer, wine and spirits, and breast cancer risk. The ORs were 1.34 (95% CI: 1.28-2.11; p = 0.04) for more than two bottles of beer per week, OR = 1.16 (95% CI: 1.08-2.58; p = 0.05) for >10 oz of wine per week and OR = 1.09 (95% CI: 1.02-2.08; p = 0.05) for >6 oz of spirit per week, respectively. Intakes of other nutrients and dietary components were not significantly associated with nongene carrier breast cancer risk. This study provides evidence that total energy intake, coffee, and alcohol consumption may play a role in breast cancer risk. PMID- 19775334 TI - Targeted tailored management of the breast cancer patient at risk for harboring a germline mutation-current trends affecting the selection of patients considering surgical prophylaxis for breast cancer. AB - Recent reports have documented the increasing use of mastectomy in women with breast cancer otherwise amenable to breast conservation. Similarly, other reports document an increase in the number of women undergoing contra-lateral prophylactic mastectomy for a single unilateral breast cancer. These trends are abetted by increasing use of MRI, inadequate risk counseling, and patient fear. Adequate and reliable risk assessment and genetic counseling are indispensable for the appropriate and personalized treatment of these individuals. In all of these instances, such counseling should be instituted well before the patients are submitted to any surgical intervention. An algorithm is presented which permits the orderly selection of patients who may benefit from such aggressive surgical intervention. PMID- 19775333 TI - Breast cancer risk assessments comparing Gail and CARE models in African-American women. AB - The Gail model has been used to predict invasive breast cancer risk in women using risk factors of age, age at menarche, age at first live birth, number of first-degree relatives with breast cancer, and number of previous benign breast biopsies. However, this model underestimates breast cancer risk in African American women. The Contraceptive and Reproductive Experience (CARE) model has been developed to replace the Gail model in predicting breast cancer risk in African-American women. In a sample of 883 women who participated in the breast cancer screening program at Howard University Cancer Center, we compared the breast cancer risk estimates from the Gail model and the CARE model. The mean 5 year breast cancer risk was 0.88% (Range: 0.18-6.60%) for the Gail model and 1.29% (Range: 0.20-4.50%) for the CARE model. Using the usual cutoff-point of 1.67% or above for elevated risk, there is a significant difference in the proportion of women with elevated breast cancer risk between the Gail and the CARE models (McNemar's test, p < 0.0001). For both models, there was a significant mean risk difference between those with and without a family history of breast cancer (Wilcoxon rank-sum test, p < 0.0001). Our results confirm the need for validation of the Gail model in African-Americans and diversity in research. Although these findings are not perfect and perhaps not definitive, they are additive in the discussions during counseling and risk assessment in African-Americans. Furthermore, these findings will be complemented by new technologies such as genomics in refining our ability to assess risk. PMID- 19775335 TI - Breast reconstruction after bilateral prophylactic mastectomy in women at high risk for breast cancer. AB - Several studies have shown the effectiveness of bilateral prophylactic mastectomies (BPM) at reducing the risk of developing breast cancer in women by more than 90%. A growing number of women at high risk for breast cancer are electing to undergo prophylactic mastectomy as part of a risk reduction strategy. This unique group of women frequently chooses to undergo reconstructive surgery as a part of their immediate treatment plan. Breast reconstruction after BPM has profound physiological and emotional impact on body image, sexuality, and quality of life. These factors should be taken into consideration and addressed when consulting the patient prior to BPM and reconstructive surgery. The timing of reconstructive surgery, the type of mastectomy performed, the reconstructive modalities available, and the possibility to preserve the nipple-areola complex, should all be discussed with the patient prior to surgery. In this article, we review our experience and the current existing literature on breast reconstruction for high-risk women after BPM. PMID- 19775336 TI - Breast ductoscopy and the evolution of the intra-ductal approach to breast cancer. AB - Interest in breast endoscopy came from Oriental investigators in the early 1990s where bloody nipple discharge is a more common presentation of breast cancer. The early techniques using a single microfiber scope without ductal distension was successful in navigating only the first 1-3 cm of the ducts and fraught with technical problems such as scope breakage and poor image quality. In spite of these barriers there has been increasing use of this technology in Japan and more widespread acceptance as the technology of scope design improved. Dooley and others tested a new method of obtaining a rich cytologic specimen from the ducts of high-risk women known as ductal lavage recently. The success of this procedure was that it detected severe cytologic and malignant atypia in clinically and radiographically normal breasts. Reproducibly, the same breast duct could be cannulated and severely atypical cytology obtained. The problem arose in identifying the lesion within the breast, which was the source for the atypia. New American multi-fiber microendoscopes were applied to solve this problem in an initial series of patients with abnormal cytology to identify the lesions. Success of that series lead to wider application of the imaging technology and eventual adoption of this imaging modality help to guide during all non mastectomy breast surgery where fluid could be elicited from the nipple to identify the duct connecting to the lesion for which surgery was being performed. Initial reports have demonstrated the types of operative findings in certain sub populations early in the use of this technology. PMID- 19775337 TI - Biologic markers in endometrial cancer treatment. AB - With a lifetime risk among women of 2-3%, endometrial cancer is the most common pelvic gynecologic malignancy in industrialized countries. Approximately 75% of cases are diagnosed at an early stage with a tumor confined to the uterine corpus. Although most patients are cured by surgery alone, about 15-20% with no signs of locally advanced or metastatic disease at primary treatment recurs, with limited responsiveness to systemic therapy. The most common basis for determining the risk of recurrent disease has been classification of endometrial cancers into two subtypes. Type I, associated with a good prognosis, accounts for the majority of cases and is associated with a low-stage, low-grade and endometrioid histology. In contrast, type II, associated with a poor prognosis, is characterized by a high-stage, high-grade and non-endometrioid histology. However, the prognostic value of this distinction is limited, as up to 20% of type I endometrial cancers recur, while half of type II cancers do not. We review the current literature on epidemiology, etiology, pathology, molecular alterations, staging, treatment and prognostic factors in endometrial cancer. Ongoing molecular-based clinical trials and newly reported molecular alterations with a potential for development of new targeted therapy are discussed. PMID- 19775338 TI - Comparison of human papillomavirus genotyping using commercial assays based on PCR and reverse hybridization methods. AB - Different tests for human papillomavirus (HPV) screening are commercially available, detecting high-risk oncogenic HPV types with a pool of genotype specific probes. However, it is necessary to establish reliable methods for the identification of individual genotypes. The purpose of this study was to compare three different commercial methods for HPV genotyping: INNO-LiPA HPV Genotyping v2 (LiPA), Linear Arrays HPV Genotyping Test (LA) and Clinical Arrays Human Papillomavirus (CA). A total of 83 HPV DNA-positive samples by hybrid capture method were genotyped (82, 78 and 81 by LiPA, LA and CA, respectively). Comparison analysis was limited to the HPV genotypes common to the three assays. There were concordant results (absolute agreement between assays) in 31 samples (39.7%) and compatible results (correspondence for some but not all genotypes) were found in 44 samples (56.4%). Only three samples (3.8%) were considered as discordant (did not show any similarity between the tests). Analyzing kappa values we have a very good agreement (>0.8) for HPV16 and HPV31 and good agreement (0.6-0.8) for HPV types 6, 18, 53 and 66 when all methods are compared. We conclude that all genotyping methods tested are highly comparable and suitable for clinical and epidemiological studies. PMID- 19775339 TI - Anti-angiogenic factor endostatin in osteosarcoma. AB - Neoplastic neovascularization is regulated not only by stimulators, but also by inhibitors of angiogenesis and might be the result of a net balance between the positive and negative regulators. Endostatin (ES) is a potent inhibitor of angiogenesis. The expression of ES has not been investigated in patients with osteosarcomas (OSAs). The aim of this study was to determine whether there is a correlation between the expression of ES and clinicopathologic parameters and/or outcomes in patients with OSAs. We made tissue microarrays from 46 cases of OSA and analyzed the expression of ES using immunohistochemistry. Staining was assessed in a semi-quantitative manner by scoring the proportion of positive tumor cells over the total number of tumor cells. A sample was defined as ES positive when 10% or more of the tumor cells were stained positively throughout the tumor core. ES was localized to the cytoplasm of the tumor cells. 32.6% (15/46) of the patients were ES-positive. The expression of ES was positively correlated with tumor size (p = 0.011), histologic grade (p = 0.034), stage (p = 0.025), and distant metastasis (p = 0.036). Our results suggest that the expression of ES is increased in OSA, and ES may be used as a prognostic marker in patients with OSAs. PMID- 19775340 TI - Symptoms and signs in culture-proven acute maxillary sinusitis in a general practice population. AB - The objective of this study was to assess symptoms and signs in patients with maxillary sinusitis and a bacteriological diagnosis obtained by sinus aspiration or lavage. Designed as a prospective cohort study in general practice, the study included 174 patients, aged 18-65 years, suspected of having acute maxillary sinusitis by their general practitioner. The main outcome measures were the independent association of symptoms, signs, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) concentration and confirmed infection with the predominant bacterial pathogens Streptococcus pneumoniae and Haemophilus influenzae. The predominant organisms found in patients with acute maxillary sinusitis were S. pneumoniae and H. influenzae. Body temperature >38 degrees C and maxillary toothache were significantly associated with the presence of S. pneumoniae and H. influenzae. Positive bacteriological culture results were significantly associated with increasing ESR and CRP values. None of the symptoms and signs, with the exception of body temperature >38 degrees C and maxillary toothache, were particularly sensitive indicators of the specific aetiology in patients with acute maxillary sinusitis. Elevated ESR and CRP values were significantly associated with positive bacteriological culture results. On the other hand, absence of these symptoms and signs did not exclude the presence of acute maxillary sinusitis. PMID- 19775341 TI - Large-scale genomic instability in colon adenocarcinomas and correlation with patient outcome. AB - The purpose of this study was to evaluate the association between DNA content in colon adenocarcinomas using high-resolution image cytometry and patient outcome. Tumours from 219 patients operated for colon adenocarcinoma were analysed using high-resolution image cytometry. Proteins involved in cell cycle propulsion (cyclins A, D1, D3 and E) and cell proliferation (c-Myc and non-membranous beta catenin) have previously been reported in the same cohort and were included in this study. The results were related to disease-free survival and to cancer specific death. Patients with aneuploid tumours showed shorter relapse-free survival than patients with euploid tumours (univariate log-rank test, p = 0.004 and multivariate Cox regression model p = 0.009, HR 0.51, 95% CI 0.31-0.84). Also the risk of death from cancer was greater in patients with aneuploid tumours (log rank test, p = 0.006 multivariate Cox regression model p = 0.014, HR 0.47, 95% CI 0.26-0.86). When analysing patients with Dukes stages A and B, nuclear expression of beta-catenin was highly significantly associated with both shorter relapse free survival (p < 0.005, HR 5.0, 95% CI 1.6-15.5) and cancer-specific death (p = 0.036, HR 6.9, 95% CI 1.1-42.1). DNA content in colon adenocarcinomas measured by image cytometry is an independent predictor of prognosis in our patients operated for colon adenocarcinoma. PMID- 19775342 TI - HER2/neu (c-erbB-2) gene amplification and protein expression are rare in uterine cervical neoplasia: a tissue microarray study of 814 archival specimens. AB - Published studies have reported widely variable incidence of HER2/neu (c-erbB-2) protein expression and HER2/neu (c-erbB-2) gene amplification in cervical carcinoma. We examined tissue microarrays (TMAs) constructed from 814 formaldehyde-fixed paraffin-embedded archival specimens of cervical intraepithelial neoplasia (CIN)1 (n = 262), CIN2 (n = 230), CIN3 (n = 186) and invasive carcinoma (n = 136), for HER2/neu protein expression by immunohistochemistry (IHC) and for HER2/neu gene amplification by chromogenic in situ hybridization (CISH). We found moderate or strong immunohistochemical positivity for HER2/neu in 64 of 814 specimens (7.9%). Using CISH, polysomy of the HER2/neu gene was detected in 87 cases (10.7%), low/borderline amplification in five cases (0.6%) and true amplification in four cases (0.5%). The correlation between IHC and CISH was statistically significant in CIN2, CIN3 and invasive cervical carcinoma specimens. When present, Her-2/neu positivity is more commonly seen in higher grades of cervical dysplasia and in carcinoma. However, this large TMA study shows that HER2/neu oncoprotein expression and HER2/neu gene amplification overall are uncommon events in cervical neoplasia. This provides compelling evidence that HER2/neu plays no major role in the development and progression of cervical neoplasia. PMID- 19775343 TI - Influence of lipopolysaccharide and interleukin-6 on RANKL and OPG expression and release in human periodontal ligament cells. AB - Recent research into periodontal disease pathology focuses on the role of receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) in periodontal bone destruction processes. RANKL regulates the differentiation of osteoclast by binding to its specific receptor RANK, while OPG inhibits the differentiation of osteoclasts by binding RANKL and therefore preventing RANKL to bind RANK. The aim of the present study was to investigate the influence of Porphyromonas gingivalis lipopolysaccharide (LPS) and interleukin-6 (IL-6) on RANKL and OPG expression and release in periodontal ligament (PDL) cells. Human PDL cells were stimulated for 48 h with purified P. gingivalis LPS and IL-6. OPG and sRANKL release were assessed by using enzyme linked immunosorbent assay technique. OPG and RANKL expression was quantitatively measured by using the real-time PCR technique. Whereas P. gingivalis LPS induced sRANKL release, expression was only slightly increased, IL-6 did not show an effect on RANKL expression or release. In conclusion the data demonstrate that stimulation of PDL cells with P. gingivalis LPS leads to an increased release of sRANKL, rather than increased RANKL expression. Through this action, P. gingivalis LPS may exert its biological effect on osteoclast formation and bone resorption. PMID- 19775344 TI - Prognostic significance of urokinase plasminogen activator receptor and its cleaved forms in blood from patients with non-small cell lung cancer. AB - Urokinase plasminogen activator (uPA) cleaves its three-domain cell surface receptor, uPAR, liberating domain I [uPAR(I)] and leaving the cleaved uPAR(II III) on the cell surface. Both intact and cleaved uPAR can be shed from the cell surface. uPAR(I) was previously shown to be a prognostic factor in lung tumour extracts. Here we analyse uPAR forms in blood from patients with non-small cell lung cancer (NSCLC). Preoperatively sampled plasma/serum from 32 patients with NSCLC was analysed. Three time-resolved fluoroimmunoassays (TR-FIAs) measuring intact uPAR(I-III) (TR-FIA 1), uPAR(I-III) + uPAR(II-III) (TR-FIA 2) and uPAR(I) (TR-FIA 3) were applied. The Spearman rank correlations between plasma and serum levels of uPAR(I-III), uPAR(I-III) + uPAR(II-III), and uPAR(I) were 0.89, 0.94 and 0.68 respectively. Survival analysis demonstrated that high levels of all uPAR forms were associated with shorter survival. Adjusted for histological subtype high plasma uPAR(I-III) and uPAR(I) levels as well as serum uPAR(I) levels were significantly associated with shorter OS (hazards ratios = 4.3, 2.8 and 3.8 respectively). High blood levels of intact uPAR and its cleaved forms are associated with poor prognosis in NSCLC. PMID- 19775345 TI - Secondary breast cancer: a 5-year population-based study with review of the literature. AB - Secondary tumours in the breast are rare. Based on literature, an incidence of 0.4-2% is reported. In this population-based study, secondary breast tumours from a 5-year period (2001-2005), not including metastasis from contralateral breast carcinoma, were reviewed (Vestfold County, Norway). A total of 722 patients with breast malignancies were found in this population (89.3% from Vestfold County Hospital). Ten of these, approximately 1.4%, were metastatic tumours, representing four cutaneous melanomas, three pulmonary carcinomas and three malignant lymphomas. The tumours were often solitary, palpable and close to the skin. Radiologically, the lesions mostly resembled primary carcinomas by mammography and ultrasound, which differs from other studies. Comparison with a known primary tumour and use of immunohistochemical profiling is of crucial importance. Melanoma markers (Melan-A, HMB-45, S-100 protein), lung cancer markers (Cytokeratins, TTF1, Chromogranin, Synapthophysin) and lymphoid markers (CD3, CD20) usually help to confirm a secondary breast tumour diagnosis. This approach is especially indicated in diffusely growing tumours with lack of glandular structure and high-grade cytological features, and staining for ER and GCDFP15 may be helpful. Thus, the diagnosis of a breast metastasis may be suspected by careful mammography and ultrasound imaging, although some cases have atypical radiological features, and histological examination might be necessary to ensure a correct diagnosis and appropriate treatment. PMID- 19775346 TI - Antibody-negative neuromyelitis optica with heavy B-cell infiltration. AB - There are several distinct clinical phenotypes of inflammatory demyelinating diseases of the central nervous system. In classical multiple sclerosis (MS) there are varied pathological patterns, possibly with differences in pathogenesis. Neuromyelitis optica (NMO) is often associated with a specific antibody, suggesting a distinct pathogenesis. We report a case of a young Caucasian male who presented with right hemiparesis secondary to a left fronto parietal inflammatory brain lesion, which improved over years leaving minimal deficit. Seventeen years later he re-presented with a progressive tetraparesis secondary to cervical myelitis that did not respond to treatment. The NMO antibody was not detected and neuropathological examination was unusual with evidence of a persistent B-cell inflammatory response in the cord. Although having some of the clinical features of NMO, this case presented novel clinico pathological features that do not easily fit into current MS subtypes. PMID- 19775347 TI - Fulminant parvovirus B19-associated pancarditis with haemophagocytic lympho histiocytosis in an immunocompetent adult. AB - Myocarditis is a common cardiac disease that is identified on routine postmortem examinations. Initially, coxsackie viruses, other enteroviruses and adenoviruses were thought to be more common causes of myocarditis; however, recently, parvovirus B19 (PVB19) as well as human herpesvirus 6 (HHV6) have entered the arena. We describe autopsy findings of a patient who had a lethal myocarditis with haemophagocytic lympho-histiocytosis in a course of systemic PVB19 infection. The present case illustrates the unusually severe and rapid course of PVB19 myocarditis with associated haemophagocytic lympho-histiocytosis leading to death. PMID- 19775349 TI - Advances in the management of UVR-induced skin cancer. PMID- 19775350 TI - The European Skin Cancer Foundation. PMID- 19775351 TI - Certification of sun protection practices in a German child day-care centre improves children's sun protection--the 'SunPass' pilot study. AB - BACKGROUND: Nonmelanoma skin cancer (NMSC) and malignant melanoma (CMM) are among the most common malignancies in the white population. The major risk factor for those malignancies is ultraviolet radiation (UV) causing directly DNA damage and promoting the development of skin cancer. It is suggested that the exposure to UV during childhood elevates an individual's lifetime risk of developing skin cancer more than exposure in adulthood. Since an increasing number of children spend the time of the most intense UV in a day-care centre, it seems an excellent place for establishing primary skin cancer prevention. Important targets are staff members and parents of the day-care centre, since sun protection of children depends directly on their knowledge and their attitude towards sun protection practices. OBJECTIVES: To establish a feasible certification program for sun protection in a German child day-care centre, for a better sun protection of the children and the reduction of skin cancer incidence in the long term. METHODS: Initially sun protection practices of the centre at baseline were assessed. A written sun protection policy was developed in consultation with all members of the day-care centre as basis for certification. It was followed by training sessions for staff members (n=12) and parents (n=46). After a fixed period of time the final assessment of the child day-care centre was conducted and the centre then was certified for improved sun protection practices and better protection of the children. The primary assessed outcomes were the gain in knowledge of staff members and parents after the training sessions, the number of children wearing a hat when playing outside, the use of sunscreen and the percentage of shaded areas on the playground. RESULTS: Sun protection was an issue more discussed during the time of intervention than before. Staff members (n=12) and parents (n=27) had a significant gain in knowledge (staff members: P=0.002; parents: P=0.001) concerning sun related issues. The number of children wearing a hat increased from 13.2% to 73%. The sunscreen use increased, 58.8% of staff members reported a more regular application of sunscreen to the children. There was a higher percentage of shaded area on the playground (70-80% before intervention, 90% after intervention). The intervention failed in keeping the children inside during the most intense UV and in educating the staff members to be a convincing example of sun protection by wearing appropriate clothes. CONCLUSIONS: The intervention showed that the introduction of a simple certification program including a written sun protection policy and training sessions for staff members and parents helps to improve children's sun protection. We suggest that a certificate for adequate sun protection acts as a motivating factor. It seems important to refresh sun protection practices each year by repeating training sessions and reviewing the sun protection policy. PMID- 19775352 TI - Sun protection factors: world wide confusion. AB - The Sun Protection Factor (SPF) is a very popular instrument in the marketing of sunscreens. Unfortunately it is often not understood how sunscreens work and where the limitations of the SPF are. A lot of aspects of the SPF are confusing, e.g. the race for higher and higher numbers, the effect on SPF when less sunscreen is applied and if sunscreen should be used at all because they may block the Vitamin D synthesis. All this has a negative impact on compliance by the consumer or patient which is the most important influence factor in sun protection. This paper explains how sunscreens work, how the SPF is determined and where the limitations of the current methods exist. The dynamic view of 'UV radiation applied' and the 'UV dose transmitted' through the sunscreen onto the skin as well as onto a substrate in vitro help in the understanding and are also promising approaches in the in vitro assessment. A variation of the in vitro assessment of a sunscreen is the in silico calculation based on the absorption spectrum of the UV filters and an assumption about the irregular sunscreen film on the skin. The sunscreen simulator program can be used to determine how the SPF is affected by applying smaller amounts of sunscreen. Besides the SPF, UVA protection is also discussed. The degree of UVA protection determines the quality of the overall UV protection, whereas the SPF is an indication of the quantity of protection. Furthermore other protection factors such as IPF, iSPF, RSF and p53, and the inhibition of the Vitamin D3 synthesis by sunscreens are also discussed. In conclusion it is shown that the accuracy and robustness of the SPF and other Protection Factors will improve significantly with the availability of true broad spectrum sunscreens rather than conventional UVB-biased sunscreens, because uniform protection profiles lead to protection independent of the action spectrum of the endpoint and the UV-radiation source. PMID- 19775353 TI - Sunscreens as a preventative measure in melanoma: an evidence-based approach or the precautionary principle? AB - BACKGROUND: Meta-analyses of observational case-control studies have demonstrated no association between sunscreen use and the development of malignant melanoma. OBJECTIVES: To postulate whether modern sunscreens are likely to be effective as a preventative agent in melanoma and, if so, how many cases might be avoided by their use. METHODS: The potential number of melanomas prevented by encouraging the use of modern, high SPF, broad spectrum sunscreens during recreational summer exposure was estimated by combining the prevalence of their use with the relative risk of melanoma in nonusers compared with those people who regularly use these products. RESULTS: Notwithstanding the inherent uncertainties and assumptions that this approach involves, it is shown that significant numbers of melanomas might be avoided by regular sunscreen use during recreational summer sun exposure, and with them appreciable financial, social and emotional costs, even for very modest estimates of the benefit of broad-spectrum sunscreens. CONCLUSIONS: Despite the lack of evidence demonstrating the efficacy of modern sunscreens in preventing melanoma, it is argued that it would be irresponsible not to encourage their use, along with other sun protection strategies, as a means of combating the year-on-year rise in melanoma incidence. PMID- 19775354 TI - Assessment of sunscreen knowledge: a pilot survey. AB - BACKGROUND: Topical sunscreens are designed to block and absorb UV radiation from the sun and have the potential to decrease the risk of skin cancer and delay the photoaging. Many studies have examined the behavior patterns of the public on sunscreen use, but little is known regarding the level of knowledge the public has regarding sunscreen. OBJECTIVE: To assess general sunscreen knowledge of the public and to determine factors associated with sunscreen purchasing decisions. METHODS: Individuals attending health seminars in New Jersey were asked to complete a 22-question survey regarding sunscreen. The questions assessed the respondent's familiarity and comprehension of sunscreen terminology, sunscreen application and sunscreen efficacy claims. Descriptive frequencies, Chi-square analyses and t-tests were used to characterize the responses. RESULTS: Four hundred and twenty-three individuals completed the survey. Approximately 86% of the subjects knew that sunscreen use could prevent sunburn, and 70% reported that sunscreen could prevent skin cancer. However, only 32.1% of respondents knew that sunscreen should be applied 30 min before going outside, and only 30% knew the appropriate reapplication recommendation. Merely 18% of respondents knew that approximately 1 ounce of sunscreen is required to cover the entire body. The overall mean composite sunscreen knowledge score for the respondents was 4.9 out of a possible 12 points. SPF and UVA are the most important factors that effect purchase decision. CONCLUSIONS: The study indicates that a majority of the subjects understand the benefits associated with sunscreen use, but their knowledge base is somewhat superficial. More education is needed on the appropriate application of the sunscreen. More importantly, the majority did not understand the subtle, but crucial difference between a UVA claim for a product and the SPF value listed on the product. PMID- 19775355 TI - Children and sun protection. AB - Sun protection is a central measure to avoid the development of skin cancer and premature aging of the skin. In this context skin protection of children is of particular relevance since children spend a lot of time outdoors and they cannot provide themselves with sun protection measures as adults can. In addition to this sunburn reactions in childhood are particularly important in the development of melanoma skin cancer. This special situation of children with regards to sun protection has not only become aware to dermatologists but also to politicians, which is why a recent recommendation of the European Union explicitly points out the necessity of stringent sun protection of children. This review summarizes the current knowledge about sun protection of children. Underlying mechanisms of skin carcinogenesis in children, available sun protection measures as well as practical advice on daily sun protection of children are discussed. PMID- 19775356 TI - Sunscreen abuse for intentional sun exposure. AB - Skin cancer is caused by exposure to ultraviolet radiation (UV) and the sun is the main source of this radiation. Sunscreens were initially formulated to prevent sunburns; laboratory studies later revealed that in rodents they could reduce UV-induced skin cancer which resembles human squamous cell carcinoma. Three randomized trials in older adults showed the ability of sunscreens to moderately reduce the occurrence of solar keratoses and of squamous cell carcinoma. However, no effect was observed for basal cell carcinoma. There is no animal model for human melanoma and observational studies often found sunscreen use associated with a higher risk of nevus, melanoma and basal cell carcinoma. These higher risks were found when sun exposure appeared to be intentional, that is, with the desire to acquire a tan, a healthy look or simply to spend as long as possible in the sun with as much skin exposed as possible. Three randomized trials showed that sunscreen use by sun sensitive subjects engaging in intentional sun exposure could increase the duration of exposure without decreasing sunburn occurrence. This increased duration could be the reason why melanoma risk is increased when sunscreen is used. Hence, sunscreen abuse may extend sun exposure duration thus allowing sun exposure behaviours that would not be possible otherwise. Advertising for sunscreens and labeling of sunscreen bottles should inform consumers of the carcinogenic hazards associated with sunscreen abuse. It would be good to use a personal UV dosimeter which would give an alert when one's individual sunburn threshold in the absence of sunscreen use is nearing. The combination of sunscreen and a UV dosimeter may be an option for reducing the melanoma risk among sun worshippers. PMID- 19775357 TI - Comparison of UV-induced skin changes in sun-exposed vs. sun-protected skin- preliminary evaluation by reflectance confocal microscopy. AB - BACKGROUND: UV radiation (UVR) represents the main risk factor for skin cancer. Sunscreens are commonly used to prevent acute and chronic effects of UVR. The efficacy of sunscreens is currently determined by measurement of minimal erythema dose. Reflectance confocal microscopy represents a non-invasive imaging technique that allows the in- vivo characterization of the skin at near histological resolution. OBJECTIVE: The aim of this study was to compare standardized clinical and histological features of UV-exposure with morphological changes detected by RCM. RESULTS: RCM allowed the detection of morphological changes induced by UV including spongiosis, sunburn cells, micro-vesicles and blood vessel dilatation. The appearance of sunburn cells and micro-vesicles was depending on the dose of UV-B and on the individual susceptibility of the study participants. CONCLUSION: RCM seems to be beneficial for the non-invasive evaluation of dynamic changes following acute UV exposure. Similar to histopathology RCM allows the characterization of sunburn cells and micro-vesicle formation as a sign for acute photo damage. RCM may therefore be used for classification of sunburn reaction and to test the efficacy of sunscreens on a cellular level. PMID- 19775358 TI - Skin cancer prevention and UV-protection: how to avoid vitamin D-deficiency? AB - Because solar UV-radiation represents the most important environmental risk factor for the development of non-melanoma skin cancer, UV protection is important to prevent these malignancies. Consequently, public health campaigns were developed to improve the knowledge of the general population regarding the role of UV-radiation for the development of skin cancer. However, it has to be noted that vitamin D-mediated positive effects of UV light were not adequately considered in most of these campaigns, that often propose a strict 'no sun policy' without giving recommendations how to prevent vitamin D-deficiency. Under our living conditions, approximately 90% of all vitamin D needed by the human body has to be formed in the skin through the action of UV-B-radiation and it has been shown that strict sun protection causes vitamin D-deficiency. This dilemma represents a serious problem, for an association of vitamin D-deficiency and multiple independent diseases including various types of cancer, bone diseases, autoimmune diseases, infectious diseases, cardiovascular diseases and hypertension has now been reported in a large number of laboratory and epidemiologic investigations. Although further work is necessary to define an adequate vitamin D-status and adequate guidelines for UV-exposure, it is at present mandatory that guidelines for UV-exposure (e.g. in skin cancer prevention campaigns) consider these facts and give recommendations how to prevent vitamin D deficiency. At present, most experts in the field agree that the evidence to date suggests that daily intake of 1000-2000 IU vitamin D could reduce the incidence of vitamin D-deficiency-related diseases with minimal risk in Europe, the US, and other countries. In this review, we analyze the present literature to help developing well-balanced guidelines on UV-protection that ensure an adequate vitamin D-status. These recommendations will hopefully protect us against vitamin D-deficiency without increasing the risk to develop UV-induced skin cancer. PMID- 19775359 TI - Photodermatoses: classification, evaluation and management. AB - Photodermatoses are skin disorders induced or exacerbated by light. They can be broadly classified into four groups: (i) immunologically mediated photodermatoses (idioapathic); (ii) drug- and chemical-induced photosensitivity; (iii) defective DNA repair disorders; and (iv) photoaggravated dermatoses. The exact pathomechanism of those diverse skin reactions to light radiation remains unclear. Immunologically mediated photodermatoses are the most common dermatoses among all photosesnsitive disorders. The management of photodermatoses starts with clinical recognition of characteristic lesions localized predominantly in light exposed skin. Detailed history-taking, phototesting and photopatch testing are required to establish a correct diagnosis, especially if patients present in disease-free intervals. Classification and short description of distinctive clinical features of most common photodermatoses, several practical aspects of evaluation and management of the patient with photosensitivity will be outlined. PMID- 19775360 TI - Photodermatoses with onset in the elderly. AB - Photodermatoses are a group of skin disorders induced by ultraviolet radiation (UVR) and, in some cases, visible light. To establish a diagnosis it is important to carefully take a history, physical examination and perform phototesting as well as other testing when appropriate (patch and photopatch tests, antinuclear antibodies, porphyrin profile). This article focuses on the photodermatoses that affect the elderly, which with the ageing of population, particularly in the industrialized societies, are becoming an increasingly important group for the healthcare systems. The most common photodermatoses with onset in the elderly are chronic actinic dermatitis and drug induced photosensitivity. PMID- 19775361 TI - Prevention of non-melanoma skin cancer in organ transplant patients by regular use of a sunscreen: a 24 months, prospective, case-control study. AB - BACKGROUND: Skin cancers represent a major challenge within the ever growing group of long time surviving organ transplant recipients (OTR) world wide. Especially UV-induced non-melanoma skin cancers (NMSC) like invasive squamous cell carcinomas (SCC) and actinic keratoses (AK), and basal cell carcinoma (BCC), outnumber every other form of cancer in organ transplant recipients. Despite encouraging reports of protective effects of broad-spectrum sunscreens in immunocompetent patients, evidence for the prevention of NMSC in immunocompromised patients is still missing. OBJECTIVES: To assess preventive effects of regular sun-screen use on AK, SCC and BCC in chronically immunocompromised organ transplant recipients. METHODS: Hundred and twenty matched (age, sex, skin type, graft, transplant duration, previous post transplant skin malignancies) organ transplant recipients (40 heart, 40 kidney, 40 liver grafted) were recruited for this prospective, single-center study. Both groups received equally written and oral information on sun protection measures. Sixty patients were provided with a free broad spectrum study-sunscreen (SPF>50, high-UVA absorption) for daily application of 2 mg cm(-2) to the head, neck, forearms, and hands. RESULTS: All 120 patients completed the 24 months study. Within this 24 month study interval 42 of the 120 patients developed 82 new AK ( 102 sunscreen group vs. +82 control; P<0.01), 8 new invasive SCC (0 vs. 8; P<0.01) and 11 BCC (2 vs. 9; ns). In spite of equal numbers of AK at baseline, a marked difference in favor of the intent-to-treat sunscreen group was recorded after 24 months (89 vs. 273; P<0.01, mean difference 3.07 [1.76-4.36]) and the lesion count was significantly lower as compared to the initial visit (89 vs. 191; P<0.01, mean difference 1.7 [0.68-2.72]). With an average of 5.6 applications per week throughout the 24 months the study sunscreen was generally well tolerated. Serum 25-hydroxy vitamin D levels as marker for vitamin D status were decreased in all patients without adequate substitution and 25(OH)D was found to be lower in the sunscreen-group as compared to the control group (mean value 53 ng mL(-1) vs. 60 ng mL(-1)). INTERPRETATION: Regular use of sunscreens, as part of a consequent UV-protection strategy, may prevent the development of further AK and invasive SCC and, to a lesser degree, BCC in immune-compromised organ transplant recipients. PMID- 19775362 TI - Organ transplant recipients and skin cancer: assessment of risk factors with focus on sun exposure. AB - BACKGROUND: Organ transplant recipients (OTRs) have an increased risk of developing skin cancer, especially epithelial tumours. A number of factors such as immunosuppression, age, ultraviolet radiation and skin type are considered as important in aetiology. OBJECTIVES: The purpose of this study was to further evaluate the risk factors for OTRs regarding skin cancer after transplantation. A detailed investigation of the specific compounds of sun exposure was realised. METHODS: A questionnaire-based study was performed in a specialist OTR dermatology clinic from January to April 2009. The subjects were 70 organ transplanted patients who had developed some form of skin cancer after transplantation. As controls served 69 organ transplanted patients who had no history of skin cancer. The controls were matched concerning age, transplanted organ and gender. Photo protection, sun exposure and transplantation data were part of the questionnaire. Statistical analysis was performed with Mann-Whitney-U test, chi-square test or Fisher's exact test. RESULTS: The total sun burden (TSB) and the recreational sun exposure in particular attained higher scores in the skin cancer group (TSB-score: mean 11.8 vs. 10.0, P<0.05; recreational sun exposure: mean 6.3 vs. 5.1, P<0.05). The skin cancer group had fairer skin types than the control group (median skin type 2 vs. 3, P<0.05). The OTRs who developed skin cancer have been more likely to have a history or present intake of azathioprine (mean 42% vs. 21%, P<0.05). Also, the skin cancer group has been transplanted for a longer time (mean 12.3 vs. 7.2 years, P<0.001), analogously had a younger age at transplantation (mean 49.5 vs. 52.7 years, P<0.001). CONCLUSIONS: Recreational sun exposure is of central importance for OTRs. A long period of transplantation and thus immunosuppression presents a main risk factor for the development of skin cancer in OTRs. A multi disciplinary management with the best medication and a focus on sun protection is needed to prevent skin cancer in OTRs. PMID- 19775363 TI - Ultraviolet radiation and immunosuppression. AB - Ultraviolet (UV) radiation is a complete carcinogen. The effects of UV radiation are mediated via direct damage to cellular DNA in the skin and suppression of image surveillance mechanisms. In the context of organ transplantation, addiction of drugs which suppress the immune system add greatly to the carcinogenicity of UV radiation. This review considers the mechanisms of such effects. PMID- 19775364 TI - Advances in the management of UVR-associated skin cancers: autoimmune diseases and UV protection. AB - Ultra violet radiation (UVR) is an important feature for the development or aggravation of several dermatologic diseases. In autoimmune skin diseases it has been suggested as an important cofactor in autoimmune bullous skin diseases and more importantly cutaneous lupus erythematosus (CLE). The pathophysiological role of UVR in CLE is a result of several effects which are triggered by UVR. In detail UVR induces apoptosis of keratinocytes and an abnormal local immune response which triggers inflammation in the skin. These findings result in the clinical approach of a stringent UVR protection in affected patients. Currently UVR protection is advised to patients as a supportive measure but cannot be prescribed to patients as these products are not licensed. Well-defined prospective placebo controlled studies regarding UVR protection are missing. PMID- 19775365 TI - Inpatient management of patients with skin cancer in Germany: an analysis of the nationwide DRG-statistic 2005-2006. AB - BACKGROUND: In 2004, Germany introduced a nationwide DRG (Diagnosis Related Groups) based recompensation system for hospitals. The aim of this study was to provide nationwide quantitative information about the in-hospital management of skin cancer patients in Germany based on the DRG statistic of the years 2005 through 2006. METHODS: We analysed the DRG statistic of the years 2005 and 2006. For each hospitalisation, diagnoses and procedures codes were analysed. The unit of analysis was the hospital admission with a diagnosis of skin melanoma (MEL) or nonmelanoma skin cancer (NMSC) including 151.144 hospitalisations. RESULTS: In 60% and 28% of all MEL- and NMSC-related hospitalisations respectively, skin cancers were surgically excised. Local therapies other than surgical excision were more prevalent among hospitalisations for NMSC than for MEL (9% vs. 4%). 22% and 1% of all MEL-related and NMSC-related hospitalisations respectively included a systemic chemotherapy. Plastic surgery was more common among NMSC-related hospitalisations (56%) than among MEL-related hospitalisations (30%). Native CT or MRI scans were coded in 11% and 2% of all MEL- and NMSC-related hospitalisations respectively. Age-standardized hospitalisation rates for MEL and NMSC varied considerably across the 16 Federal States of Germany. However, these rates were neither associated with the number of dermatology hospital beds or number of registered dermatologists. DISCUSSION: We provide for the first time nationwide quantitative data on the in-hospital management of skin cancer patients. The observed differences in the management of MEL and NMSC most likely reflect differences of the biology, epidemiology and therapeutic modalities of these cancers. PMID- 19775366 TI - UV-induced squamous cell carcinoma--a role for antiapoptotic signalling pathways. AB - The incidence of nonmelanoma skin cancer including squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) has dramatically increased in the last decades, and chronic sun exposure was identified as a main etiologic agent. UV radiation may produce DNA damage either directly or through reactive oxygen species (ROS). As mutations caused by UV may lead to skin cancer due to oncogene activation and tumor suppressor gene inactivation, efficient safeguard mechanisms have been developed during evolution. These enclose induction of apoptosis and formation sunburn cells aiming at the removal of premalignant cells. The keratinocyte apoptotic machinery in response to UV consists of both intrinsic/mitochondrial and extrinsic/death receptor-mediated cell-death pathways, which are particularly regulated by mitogen-activated protein kinases (MAPKs, JNK and p38) and the tumor suppressor protein p53. For development of skin cancer, it appears that critical steps in apoptosis control are dysregulated leading to resistance both to death ligand-mediated and intrinsic proapoptotic pathways. These particularly include inactivation of p53, as well as activation of EGFR, COX-2 and MAPKs, which result in specific regulation of Bcl-2 proteins, death ligands and death receptors. The final unravelling of apoptosis regulation in epithelial skin cancer may allow the development of new targeted therapeutic strategies. PMID- 19775367 TI - Skin cancer prevention in Australia. AB - Australia has one of the highest skin cancer incidence and mortality rates in the world. The reason for these high rates is due in part to the high ambient UV radiation levels, combined with a predominantly susceptible fair-skinned population. To address this problem, since 1980 Australians have been exposed to social marketing campaigns to raise awareness of skin cancer prevention. These campaigns have used mass media alongside interventions in schools, workplaces, and in community and leisure settings to motivate sun protective behaviour. As a result of these interventions it can be demonstrated that social marketing campaigns can be a very effective method to not only motivate behaviour change, reduce sunburn, and increase awareness but more importantly, reduce melanoma rates and bring positive economic returns to government. However long term investment in this area is required otherwise any population gains in behaviour are very likely to be quickly eroded. PMID- 19775368 TI - Adoptive immunotherapy for cancer: the next generation of gene-engineered immune cells. AB - Adoptive cellular immunotherapy involving transfer of tumor-reactive T cells has shown some notable antitumor responses in a minority of cancer patients. In particular, transfer of tumor-infiltrating lymphocytes has resulted in long-term objective responses in patients with advanced melanoma. However, the inability to isolate sufficient numbers of tumor-specific T cells from most malignancies has restricted the broad utility of this approach. An emerging approach to circumvent this limitation involves the genetic modification of effector cells with T cell receptor (TCR) transgenes or chimeric single-chain variable fragment (scFv) receptors that can specifically redirect T cells to tumor. There has been much progress in the design of TCR and scFv receptors to enhance the antigen-specific activation of effector cells and their trafficking and persistence in vivo. Considerable effort has been directed toward improving the safety of this approach and reducing the immunogenicity of the receptor. This review discusses the latest developments in the field of adoptive immunotherapy using genetically modified immune cells that have been transduced with either TCR or scFv receptor transgenes and used in preclinical and clinical settings as anticancer agents. PMID- 19775369 TI - Genetic and structural analysis of MBL2 and MASP2 polymorphisms in south-eastern African children. AB - The mannose-binding lectin (MBL) pathway of complement system is activated when carbohydrate-bound MBL forms complexes with different serine proteases (MASP-1, MASP-2 and MASP-3), among which MASP-2 has a predominant functional role. Polymorphisms impairing the quantity and/or the functional activity of proteins encoded by the MBL2 and MASP2 genes have been reported in all human populations showing different allelic frequency and distribution. This likely reflects the existence of environmental influences on MBL2 and MASP2 genetic evolution. Herewith, we conducted a study in a children population from Mozambique to analyse the genetic diversity of sequences corresponding to the promoter and collagen-like region (exon 1) of MBL2 and to the CUB-1 and epidermal growth factor domain (exon 3) of MASP2, which are critical regions for the formation of functional MBL/MASP-2 complexes. Our results show a high prevalence of MBL intermediate/low genotypes (43.5%); the description of new alleles and a high level of sequence polymorphism at both MBL2 and MASP2, with no statistical evidence for positive or balancing selection. Furthermore, Biacore analyses performed to explore the functional relevance of the MASP2 variants found [T73M (2.9%), R84Q (12.7%) and P111L (25.4%)] were compared with those of two previously reported variants (R103C and D105G). None of the analysed MASP2 variants, with the exception of D105G, interfered with interactions with either MBL or ficolins (H and L). PMID- 19775370 TI - HLA-G polymorphism influences the susceptibility to HCV infection in sickle cell disease patients. AB - Despite its well known monogenic etiopathogenesis, sickle cell disease (SCD) is characterized by a striking variability of clinical presentation. There is growing evidence that genetic factors may be involved in this variability. Human leukocyte antigen (HLA)-G is a non-classical HLA molecule which was shown to be expressed at sites of inflammation and in inflammatory diseases. Besides its large and highly polymorphic promoter region, the 3' UTR region seems also to play an important role on regulating HLA-G expression. We investigated the influence of the 14 pb (rs1704) and the +3142 (rs1063320) HLA-G polymorphisms in 93 SCD patients in order to evaluate its potential role on clinical parameters. Twenty-one patients presented an HCV infection. Among all SCD patients 16 (22.2%) were homozygous for the +3142C genotype, none of them hepatitis C (HCV) positive. Controlling for blood transfusions in the last year, the C allele represented a dose dependent protection effect for HCV infection (PR = 0.41; 95% CI: 0.24 0.71). The +3142C allele was also underrepresented among patients with history of respiratory-tract infections. Our results support a role of the +3142 polymorphism in the susceptibility to infections, in particular to HCV infection, and suggest a possible interference of the HLA-G molecule in the response to infections, among SCD patients. PMID- 19775371 TI - A single-nucleotide polymorphism marker within the FCRL5 gene and HLA-B27 positive Han Chinese ankylosing spondylitis patients. AB - The aim of this study was to determine whether FCRL5 genes in concert with human leukocyte antigen-B27 (HLA-B27) genotypes are associated with susceptibility to ankylosing spondylitis (AS) in Chinese population. One hundred and sixty-nine HLA B27-positive AS patients (107 males and 62 females) and 184 HLA-B27-positive matched controls (112 males and 72 females) were analyzed from Han Chinese populations by case-control design, and their samples were genotyped using a panel of two single-nucleotide polymorphism (SNP) markers (rs6427384, rs12036228) within the FCRL5 gene by ligase detection reactions (LDRs) and the HLA-B27 subtypes were determined by polymerase chain reaction (PCR) using sequence specific primer (SSP) methods. Our results show that in addition to B27, the SNPs rs6427384 and rs12036228 were associated with AS, and the C-T haplotype was higher in cases with AS than in the control population [74.8% vs 63.6%, Fisher's P = 0.003, odds ratio (OR) = 1.660,95% confidence interval (CI) = 1.184-- 2.326]. Our results suggest that, in addition to HLA-B27, a novel polymorphism within the FCRL5 gene confers susceptibility to AS in Han Chinese population. PMID- 19775372 TI - DQB1 intron 3 sequences provide an insight into the evolution of DQB1 alleles and form the basis for intron-based sequencing. AB - The goal of this project was to obtain sequences of intron 3 of DQB1 in order to develop a sequencing-based typing protocol that provides a complete DQB1 exon 3 sequence. Current protocols do not provide complete sequences of exon 3, thus not allowing to differentiate common and well-documented alleles DQB1*0301 and *0319 and resolve some common trans-ambiguities with group-specific sequencing primer (GSSP) sequencing using positions 641 and 650. Samples homozygous for the most common DQB1 alleles were used to obtain intron 3 sequences, which were used to design intron-based primers for exon 3 amplification. The protocol was extensively validated; no allele dropouts were observed. The presented protocol allows differential typing of DQB1*0301 and *0319 and resolves some common trans ambiguities. PMID- 19775373 TI - A novel HLA-B*37 allele, B*370105, was identified in a Chinese Han individual. AB - We report here the sequence of a novel human leukocyte antigen B*37 allele, B*370105, which is identical to B*370101 except for a single nucleotide substitution in exon 3 at nucleotide 558 where C>A, codon 162 GGC>GGA, no coding change. PMID- 19775374 TI - Identification of a novel HLA-C allele, Cw*021602, by sequence-based typing in a family of German descent. AB - The novel allele HLA-Cw*021602 differs from HLA-Cw*021601 by a nuecleotide substitution at condon 162 (ACG to ACA). PMID- 19775375 TI - A novel HLA-DRB1 allele, DRB1*112802, was identified in a Chinese individual. AB - We report here a novel human leukocyte antigen-DRB1 allele, DRB1*112802, which was identified from a Chinese individual during sequence-based typing. The new allele is identical to DRB1*112801 except for one nucleotide change at nucleotide 189 (A --> G ), codon 34 Q (CAA) --> Q (CAG), no coding change. PMID- 19775376 TI - In a study for acne vulgaris, sequence-based HLA typing showed a novel DPB1 allele, DPB1*2402. AB - In this paper, we characterize the novel human leucocyte antigen (HLA)-DPB1*2402 allele that we found in a patient suffering from acne vulgaris. In comparison to the closest related allele DPB1*0401, HLA-DPB1*2402 has a single nucleotide exchange at position 115 (202), T replaces G. In consequence, codon 39 (68) TAC encodes for tyrosine in the novel allele instead of aspartic acid 39 (68) GAC in DPB1*0401. PMID- 19775377 TI - New CD3zeta allele showing a 9-bp deletion in the 3'-UT region of the gene. AB - We report here a non-previously described 9-bp deletion in the 3'-UT region of the CD3zeta gene, located in between two AREs. PMID- 19775378 TI - Nomenclature for factors of the HLA system, update June 2009. PMID- 19775380 TI - Disparities in the prevalence of cognitive delay: how early do they appear? AB - Cognitively delayed children are at risk for poor mental and physical health throughout their lives. The economically disadvantaged and some race/ethnic groups are more likely to experience cognitive delay, but the age at which delays first emerge and the underlying mechanisms responsible for disparities are not well understood. The objective of this study was to determine when sociodemographic disparities in cognitive functioning emerge, and identify predictors of low cognitive functioning in early childhood. Data were from 7308 singleton and 1463 multiple births in the Early Childhood Longitudinal Study Birth Cohort (ECLS-B), a nationally representative cohort of children born in the USA in 2001. Multiple logistic regression analyses examined associations between sociodemographic characteristics and low cognitive functioning at 9 and 24 months, and tested whether gestational and birth-related factors mediate these associations. Sociodemographic characteristics were statistically significant predictors of low cognitive functioning among singletons at 24 months, including the three lowest quintiles of socio-economic status [lowest quintile, odds ratio (OR) = 2.7, 95% confidence interval [CI][1.7, 4.1]], non-white race/ethnicity (African American OR = 1.8 [95% CI 1.3, 2.5], Hispanic OR = 2.3 [95% CI 1.6, 3.2]), and gender (male OR = 2.1, [95% CI 1.7, 2.5]). Gestational and birth characteristics associated with low cognitive function at 9 months included very low and moderately low birthweight (OR = 55.0 [95% CI 28.3, 107.9] and OR = 3.6 [95% CI 2.6, 5.1]), respectively, and very preterm and moderately preterm delivery (OR = 3.6 [95% CI 2.0, 6.7] and OR = 2.4 [95% CI 1.7, 3.5]), respectively, but they had weaker effects by 24 months (ORs for birthweight: 3.7 [95% CI 2.3, 5.9] and 1.8 [95% CI 1.4, 2.3]; ORs for preterm: 1.8 [95% CI 1.1, 2.9] and 0.9 [95% CI 0.7, 1.3]). Results for multiple births were similar. Sociodemographic disparities in poor cognitive functioning emerged by 24 months of age, but were not mediated by gestational or birth characteristics. Further investigation of processes whereby social disadvantage adversely affects development prior to 24 months is needed. PMID- 19775381 TI - Maternal use of folic acid supplements during pregnancy and four-year-old neurodevelopment in a population-based birth cohort. AB - The use of folic acid supplements during very early pregnancy is recommended in order to reduce the incidence of neural tube defects. Little is known about the possible benefits of folic acid on child neurodevelopment. A total of 420 children (87% of those eligible) from a birth cohort had complete data for final analyses at age 4 years. Information about folic acid and other over-the-counter dietary supplements was obtained prospectively using interviewer-administered questionnaires at the end of the first trimester of pregnancy. Psychological outcomes were assessed by two psychologists and teachers 4 years later. Low maternal socio-economic status, smoking, high parity and short duration of breast feeding were associated with lower prevalence of folic acid supplement use. Verbal (b = 3.98, SE = 1.69), motor (b = 4.54, SE = 1.66) and verbal-executive function (b = 3.97, SE = 1.68) scores, social competence (b = 3.97, SE = 1.61) and inattention symptom [OR = 0.46; 95% CI 0.22, 0.95] scores were associated with reported folic acid use. Reported folic acid supplement use during pregnancy was associated with improved neurodevelopment in children after adjusting for a number of sociodemographic and behavioural factors. PMID- 19775382 TI - Pre-pregnancy body mass index change between pregnancies and preterm birth in the following pregnancy. AB - Maternal pre-pregnancy body mass index (BMI) may affect the risk of preterm birth. However, it is unclear how changes in BMI between pregnancies modify the risk of preterm birth in the following pregnancy. We studied this effect in the Collaborative Perinatal Project, when obesity was uncommon and the prevalence of induction of labour was low. This analysis included 1892 primiparae whose first enrolled (index) pregnancy was a singleton livebirth and the second enrolled (outcome) pregnancy was a consecutive singleton pregnancy (both pregnancies within 20-51 weeks of gestation). We used the Cox regression model to calculate the hazard ratio (HR) of preterm birth at the outcome pregnancy as a function of reduced BMI (<25(th) percentile of change) and increased BMI (>75(th) percentile), compared with stable BMI (25(th)-75(th) percentile), adjusted for pre-pregnancy BMI at the index pregnancy and other covariates. Body mass index reduction was associated with a non-significant increased risk of preterm birth, adjusted HR 1.17 [95% confidence interval 0.90, 1.53]; BMI increase had effects close to null (adjusted HR 1.08 [0.83, 1.41]). In the model with linear BMI change, each 1 kg/m(2) increase was associated with an HR of 0.96 [0.89, 1.03]. The estimates associated with a BMI reduction were higher in women whose index pregnancy ended preterm (HR 1.49 [0.90, 2.44]) and in those with BMI < 25 kg/m(2) at the index pregnancy (HR 1.30 [0.98, 1.71]). This study involved mainly low-to normal weight women with spontaneous deliveries, and might suffer from type II error owing to small sample size. The effect of BMI change in overweight and obese women needs to be studied using contemporary data. PMID- 19775383 TI - Explaining educational inequalities in birthweight: the Generation R Study. AB - Although low socio-economic status has consistently been associated with lower birthweight, little is known about the factors whereby socio-economic disadvantage influences birthweight. We therefore examined explanatory mechanisms that may underlie the association between the educational level of pregnant women, as an indicator of socio-economic status, and birthweight. The study was embedded within a population-based cohort study in the Netherlands. Information on maternal education, offspring's birthweight and several determinants of birthweight was available for 3546 pregnant women of Dutch origin. Infants of the lowest educated women had a statistically significantly lower birthweight than infants of the highest educated women [difference adjusted for gender and gestational age: -123 g (95% CI -167, -79)]. Parity, age of the pregnant women, hypertension, parental height and parental birthweight, marital status, pregnancy planning, financial concerns, number of people in household, weight gain and smoking habits individually explained part of the differences in birthweight, while adjustment for working hours and body mass index resulted in increases in birthweight differences between the educational levels. After full adjustment, the difference in birthweight between lowest and highest education was reduced by 66%. Our study confirmed remarkable educational inequalities in birthweight, a large part of which was explained by pregnancy characteristics, anthropometrics, the psychosocial and material situation, and lifestyle-related factors. Altering smoking habits may be an option to reduce educational differences in birthweight, as many lower-educated women tend to continue smoking during pregnancy. In order to tackle inequalities in birthweight, it is important that interventions are accessible for pregnant women in lower socio-economic strata. PMID- 19775384 TI - Incidence and pattern of unintentional injuries and resulting disability among children under 5 years of age: results of the National Health Survey of Pakistan. AB - National estimates of injuries for children under 5 years based on population representative surveys are not readily available globally and have not been reported for developing countries. This study estimated the annual incidence, pattern and distribution of unintentional injuries according to age, gender, socio-economic status, urban/rural residence and disability caused among children aged under 5 years in Pakistan. The National Health Survey of Pakistan (NHSP 1990 94) is a nationally representative survey of households to assess the health profile of the country. A two-stage stratified design was used to select 3223 children under 5 years of age for interview and examination. Data were used for boys and girls in urban and rural areas over the preceding year. A community development index was developed to assess the relationship between socio-economic status and injuries. Weighted estimates were computed adjusting for complex survey design using surveyfreq and surveylogistic option of SAS 9.1 software. Post hoc power calculations were made for each variable keeping the design effect at 3.0. The overall annual incidence of unintentional injuries was 47.8 [95% CI 36.6, 59.0] per 1000 per year; 50.2 [95% CI 37.0, 63.4] and 45.2 [95% CI 29.4, 61.0] per 1000 per year among boys and girls under 5 years of age respectively. An estimated 1.1 million unintentional injuries occur in Pakistan annually among these children. Injury rates increase with age among the under-5s. Urban and rural injuries were 56.1 [95% CI 33.5, 78.7] and 44.1 [95% CI 31.1, 57.1] per 1000 per year respectively. The children living in least developed communities had almost 3 times higher risks of injuries than most developed communities. The annual incidence of types of injuries were: falls 28.7 [95% CI 19.5, 37.9], cuts/bruises 9.7 [95% CI 5.3, 14.1] and burns 6.6 [95% CI 3.0, 10.2] per 1000 per year. Falls were the most common type of injury (60%) followed by cuts/bruises (21%) and burns (14%). The majority of injuries occur at home (85%), with just 10% due to road traffic. Road traffic injuries and injuries to the female child were more likely to result in disability. There is a high burden of unintentional injuries and disability among children under 5 in Pakistan. These results are useful for planning further research and for prioritising prevention programmes nationally and in other developing countries with similar situation. PMID- 19775385 TI - A population-based study of repeat hospital admissions due to interpersonal violence for children aged 0-9 years. AB - To assess the magnitude and nature of interpersonal violence resulting in hospitalisation of children and to identify subgroups at risk of repeat hospital admissions, a population-based, retrospective study of all violence hospitalisations in Western Australia for children aged 9 years or less was undertaken, using the 1990-2004 linked data retrieved from the Western Australian Mortality Database and the Hospital Morbidity Data System. Of the 747 patients aged <10 years incurring 834 hospitalisations for the consequences of violence during the study period, 570 (76%) were less than 4 years of age. A total of 43 deaths from violence were recorded and 74 (9%) patients were admitted for more than one episode of violence. Victims aged 0-4 years from rural (hazard ratio [HR] = 2.72; 95% confidence interval [CI] 1.35, 5.43) and remote parts (HR = 2.79; 95% CI 1.25, 6.25) of the state were at increased risk of a subsequent admission for violence compared with those residing within the metropolitan area. Indigenous children aged 5-9 years were significantly more likely (HR = 3.57; 95% CI 1.14, 11.13) to incur a second hospitalisation for violence than their non Indigenous counterparts. The identification of young victim subgroups at high risk of repeat hospitalisations is important for developing intervention strategies to reduce the burden of interpersonal violence. Young children aged 0 4 years living in rural and remote locations and Indigenous children aged 5-9 years should be specifically targeted for attention. PMID- 19775386 TI - Associations between birthweight and weight change during infancy and later childhood, and systolic blood pressure at age 15 years: the COMPASS study. AB - Inconsistent findings have been reported on associations between postnatal weight change with later blood pressure. This study analysed the impact of weight change during fetal life, infancy and later childhood on systolic blood pressure (SBP) in adolescence. A longitudinal population-based study was conducted in Stockholm, Sweden. Weight, length at birth and gestational age were extracted from the Medical Birth Register, weight and height in childhood was collected from child health records, and body size and SBP were measured during a health examination at 15 years of age. Complete data on 2438 individuals were analysed using linear regression. In fully adjusted models SBP increased 0.99 mmHg [95% confidence interval (CI), 0.27, 1.71] in girls and 1.02 mmHg [0.31, 1.73] in boys per 1 SD increase in weight during the first year of life. The effect on SBP of weight change from 10 to 15 years among boys was 3.70 mmHg [2.67, 4.73] and among girls 1.30 mmHg [0.38, 2.22] per 1 SD increase in weight. Weight gain in infancy and later childhood was positively associated with SBP at age 15 years, while birthweight showed a weaker inverse association with SBP. No apparent effect of weight gain from 1 to 10 years of age was seen. Degree of weight change in infancy was equally important for SBP in both boys and girls, while growth during puberty showed a stronger association with SBP among boys than among girls. PMID- 19775387 TI - Modelling the association of blood pressure during pregnancy with gestational age and body mass index. AB - Improved understanding of the determinants of blood pressure (BP) changes during pregnancy is essential for decreasing the morbidity and mortality borne by women and their families worldwide. While most epidemiological studies consider associations based on categorical risk factor classifications, using measurements on a continuous scale has been advocated as a means of gaining richer insights into biological processes. We modelled the relationship during pregnancy of continuous systolic (S) and diastolic (D) BP distributions with gestational age and pre-pregnancy body mass index (BMI) using fractional polynomials. We used information, including antenatal BP values abstracted from medical records, from a prospective cohort of 1733 women recruited before 20 weeks' gestation. The percentiles for SBP and DBP changed over pregnancy, with DBP percentiles decreasing initially, followed by an increase starting about mid-second trimester. Modelling the joint impact of BMI and gestational age on mean BP indicated an increase in mean BP with increasing BMI that was attenuated at higher BMI levels, later in pregnancy. This attenuation persisted in a variety of sub-analyses which explored the possibility that it was caused by confounding or by influential groupings of subjects. Estimated longitudinal percentiles that characterise the BP distribution across gestation may facilitate evaluation of BP during pregnancy. BP patterns observed over pregnancy and, in particular, the attenuation of BP increases at high BMI, late in pregnancy, can provide insights towards elucidating the mechanisms that drive BP changes during pregnancy. PMID- 19775388 TI - Anonymous non-response analysis in the ABCD cohort study enabled by probabilistic record linkage. AB - Selective non-response is an important threat to study validity as it can lead to selection bias. The Amsterdam Born Children and their Development study (ABCD study) is a large cohort study addressing the relationship between life style, psychological conditions, nutrition and sociodemographic background of pregnant women and their children's health. Possible selective non-response and selection bias in the ABCD-study were analysed using national perinatal registry data. ABCD study data were linked with national perinatal registry data by probabilistic medical record linkage techniques. Differences in the prevalence of relevant risk factors (sociodemographic and care-related factors) and birth outcomes between respondents and non-respondents were tested using Pearson chi-squared tests. Selection bias (i.e. bias in the association between risk factors and specific outcomes) was analysed by regression analysis with and without adjustment for participation status. The ABCD non-respondents were significantly younger, more often non-western, and more often multiparae. Non-respondents entered antenatal care later, were more often under supervision of an obstetrician and had a spontaneous delivery more often. Non-response however, was not significantly associated with preterm birth (odds ratio 1.10; 95% CI 0.93, 1.29) or low birthweight (odds ratio 1.16; 95% CI 0.98, 1.37) after adjustment for sociodemographic risk factors. The associations found between risk factors and adverse pregnancy outcomes were similar for respondents and non-respondents. Anonymised record linkage of cohort study data with national registry data indicated that selective non-response was present in the ABCD-study, but selection bias was acceptably low and did not influence the main study questions. PMID- 19775389 TI - Gender-specific selection in utero among contemporary human birth cohorts. AB - Much literature argues that natural selection has conserved mechanisms by which stressed females cull frail males in utero. This argument implies that males from low sex ratio birth cohorts should, on average, live longer than those from high sex ratio cohorts. Research reports such associations but these tests use completed lifespan as the outcome and, therefore, must end with cohorts born in 1913 because too many males survive from more contemporary cohorts to determine average lifespan. The empirical literature does not, therefore, address whether selection affects male mortality in contemporary cohorts. We apply time-series methods to monthly cohorts born in California between 1989 and 2003 to measure the association between the ratio of male to female live births and infant mortality, controlling for all forms of autocorrelation that induce spurious correlations. Consistent with theories of selection in utero, we find a positive correlation between cohort sex ratio and male infant mortality. The results suggest that natural selection conserved the stress mechanism in females to end the gestation of relatively less fit males and that this mechanism manifests itself in contemporary human societies. PMID- 19775390 TI - Ulcerated dermatofibroma with osteoclast-like giant cells. AB - BACKGROUND: Ulceration and osteoclast-like giant cells are two pathological features uncommonly seen in dermatofibromas. To our knowledge, the presence of these features has not been previously described within the same lesion. METHODS: We report the clinical, histopathological and immunohistochemical findings of a 38-year-old man with an ulcerated dermatofibroma (DF) on the sole containing OLGC. COMMENTS: DF, or cutaneous fibrous histiocytoma, is a frequent dermatological lesion with many clinicopathological variants. Therefore, a correct diagnosis is not always straightforward, especially when two rare features co-exist in the same lesion. Differential diagnosis was performed with cutaneous and even non-cutaneous lesions. An explanation for the clinicopathological findings is also described. PMID- 19775391 TI - Cutaneous involvement in the lymphoepithelioid variant of peripheral T-cell lymphoma, unspecified (Lennert lymphoma). Report of a case and review of the literature. AB - Lennert lymphoma (LL), or the lymphoepithelioid variant of peripheral T-cell lymphoma, is an uncommon entity with rarely seen or reported presentations in the skin. Cutaneous involvement of LL has been characterized by asymptomatic, non ulcerated, red to violet papules, nodules and small plaques (less than 5 cm) on the trunk and extremities. Histologically, there are localized cellular lymphoid infiltrates in the dermis that tend to localize around blood vessels or skin appendages. Key to the diagnosis of LL is the presence of epithelioid histiocytes and atypical small lymphoid cells without increased vascularity or epidermotropism. Immunophenotyping shows a dense monoclonal T-cell population commonly associated with aberrant loss of T-cell-associated antigens. T-cell receptor gene rearrangements are also identified. Patients typically present with advanced stage and have a low 5-year survival. Herein, we present a case of cutaneous involvement by LL at the time of initial presentation that persisted after initiation of chemotherapy and was finally verified as secondary cutaneous involvement of LL 1 year later histologically, immunophenotypically and by T-cell receptor gene rearrangement studies. PMID- 19775392 TI - Light and electron microscopy of eruptive collagenoma. AB - Connective tissue nevi may be multiple or solitary, sporadic or familial. Eruptive collagenoma is a variant of the acquired collagenomas characterized by multiple sclerotic papules with an acute onset. A 13-year-old girl reported that in the past year, small asymptomatic lesions began to appear in her skin, 30 lesions were seen in the trunk, 5 in the cervical region and 1 in the face. Light microscopy with hematoxylin and eosin staining showed sparse collagen fibers, with Weigert staining diminished elastic tissue was observed. Scanning electron microscopy of the dermis showed individualized collagen fibers forming waved compact masses and not bundles. Transmission electron microscopy also showed sparse and loose collagen fibers with different diameters in cross sections. PMID- 19775393 TI - Scedosporium apiospermum: an emerging opportunistic pathogen that must be distinguished from Aspergillus and other hyalohyphomycetes. AB - We report a case of cutaneous Scedosporium apiospermum infection in an immunocompromised host. S.apiospermum is an emerging opportunistic pathogen, especially in organ transplant recipients. Prompt identification is critical because of its resistance to most antifungal drugs. Its histopathologic features are indistinct and overlap with those of more commonly recognized hyalohyphomycetes such as Aspergillus species. Cultures from infected tissue are generally required for correct identification. Clinicians and pathologists must be familiar with this organism and recognize the need for culture studies in addition to histopathology in the evaluation of specimens from immunocompromised patients with suspected fungal infection. PMID- 19775394 TI - Cutaneous myoepithelioma with a plexiform pattern of growth: a case report. AB - Cutaneous myoepithelioma, a recently recognized, rare but well-characterized entity, is comprised solely of myoepithelial cells. In this report, we describe a cutaneous myoepithelioma with a plexiform pattern of growth in the scapular region of a 58-year-old woman. PMID- 19775395 TI - Atypical apocrine proliferation involving anogenital mammary-like glands of the perianal region. AB - Anogenital mammary-like glands (MLGs) are a normal constituent of the anogenital area showing similarities to breast glands. MLGs are recognized to be the possible origin for various neoplastic and reactive conditions that show homology to their mammary counterparts. We report the case of an 85-year-old woman presenting with 10 cm polypoid mass of the perianal region. Histopathological examination of the excised lesion showed atypical apocrine proliferation arising in a complex lesion with features of fibroadenoma, adenosis and hyperplastic and cystic change. Normal MLGs were observed at the tumor periphery. There was no recurrence after 3 years of follow up. This report represents an illustration of the complexity of lesions developed from MLG. PMID- 19775396 TI - Solitary plaque on the scalp as a primary manifestation of Hodgkin lymphoma: a case report and review of the literature. AB - Cutaneous Hodgkin lymphoma is infrequent and typically occurs after extensive involvement of the lymph nodes. The condition decreased significantly in incidence in the past two decades, likely owing to the new treatment protocols composed of chemotherapy, radiotherapy and stem cell transplantation. Nevertheless, recognition of this uncommon but significant disease manifestation is important from a prognostic and therapeutic perspective. We are sharing a recent case of Hodgkin lymphoma where the primary presentation appeared as a solitary plaque on the left side of the occipital scalp, clinically suspected to represent a ruptured follicular cyst. The patient underwent excisional biopsy. Histological assessment revealed Hodgkin lymphoma affecting the skin. Radiological studies showed no regional lymphadenopathy. However, two enlarged lymph nodes were identified in the mediastinum and were positron emission tomography avid. The patient underwent systemic treatment without further histopathological examination of these two lymph nodes. Not being clear if these enlarged two lymph nodes were related to his cutaneous disease or not, we cannot be sure if the patient was afflicted either by primary cutaneous Hodgkin lymphoma or by secondary cutaneous involvement because of hematogenous spread. In either case, primary or secondary cutaneous Hodgkin disease is an extreme rarity. The literature is critically reviewed. PMID- 19775397 TI - Iatrogenic osteoporosis in dermatology. PMID- 19775398 TI - Epidemiology of desquamative gingivitis: evaluation of 125 patients and review of the literature. AB - BACKGROUND: Desquamative gingivitis (DG) is a descriptive term used to indicate epithelial desquamation, erythema, erosions, and/or vesiculobullous lesions of the gingiva. DG is commonly associated with several mucocutaneous disorders and systemic conditions that may carry a poor prognosis and high morbidity; however, there are no clear data concerning the frequency of these disease associations. METHODS: We investigated the epidemiologic features of DG in 125 patients and compared our findings with information from a literature review. RESULTS: In our series, 88% of patients with DG had one of the following three disorders: oral lichen planus (OLP), mucous membrane pemphigoid (MMP), or pemphigus vulgaris. The most common cause of DG was OLP (75% of patients). 22% of patients had isolated gingival involvement, and there were diffuse gingival lesions in 57% of patients. Symptoms ranged from none (1%) to severe pain (10%). There was extra-oral involvement of skin in 14% of patients, conjunctiva in 7%, genital mucosa in 26%, and internal organs in 3%. Our study showed MMP to be associated with DG in only a small percentage of patients (9%); this finding may be related to the patient population, epidemiology of the specific disease, and referral and/or past diagnostic bias. CONCLUSION: Based on our series and recent reports, OLP seems to be the most common cause of DG. PMID- 19775399 TI - Factors leading to the biopsy of 1547 pigmented lesions at Mayo Clinic, Scottsdale, Arizona, in 2005. AB - BACKGROUND: Both physician-driven and patient-driven factors influence biopsy decisions. We sought to determine the ratio of benign to malignant melanocytic biopsy findings in our general dermatology practice and to characterize the reasons for biopsy. METHODS: A retrospective review of institutional records (1 January to 31 December 2005) was undertaken. RESULTS: We identified 1398 nevi, 147 invasive and in situ melanomas, and two lesions interpreted as atypical melanocytic proliferations. Prior histories of melanoma, atypical nevi, or nonmelanoma skin cancer were common. Patient concerns about changes or symptoms drove about one-third of the biopsies. Physician concerns more commonly drove biopsies in men and older patients (> 60 years). Physician-directed biopsies more commonly yielded atypical nevi, but there was no difference in the likelihood of melanoma. The ratio of removed nevi to melanomas was 9.2 : 1. CONCLUSIONS: Both patient-driven and physician-driven indications lead to skin biopsies. We found no standard method of documentation of dermoscopic evaluation, which prevented us from making definitive conclusions about the role of dermoscopy in this cohort. PMID- 19775400 TI - Role of vascular endothelial growth factor in keloids: a clinicopathologic study. AB - BACKGROUND: Despite their benign nature, keloids are usually associated with considerable cosmetic effects and may lead to functional problems. Recently, it has been reported that vascular endothelial growth factor (VEGF), a potent angiogenic factor, is overexpressed in keloid tissue and may have a potential role in its evolution. METHODS: Twenty patients with keloids were included in this study and classified into two groups according to the treatment received: intralesional triamcinolone acetonide 20 mg/mL (group 1) and cryotherapy spray technique (group 2). Treatment was continued until clearance or for a maximum of six sessions, and the follow-up period was 1 year. Skin biopsies were taken from patients before and after treatment to evaluate keloid pathology and from patients and 10 healthy controls to detect the immunohistochemical expression of VEGF. RESULTS: Histopathologic examination revealed a remarkable resolution of the nodular arrangement of collagen after therapy, particularly in group 1. A statistically significant difference in VEGF expression was found between patients before therapy and controls, and between patients before and after therapy in each group. There was no significant difference in the treatment outcome between intralesional steroids and cryotherapy. No significant correlation was observed between the clinical variables of keloids and both VEGF expression and clinical response to therapy. CONCLUSION: VEGF seems to play an important role in the pathogenesis of keloids and may be a useful guide in the evaluation of keloid therapeutics. Modulation of its production may provide a valuable treatment for keloids. PMID- 19775401 TI - Dermatitis cruris pustulosa et atrophicans revisited: our experience with 37 patients in south India. AB - BACKGROUND: Dermatitis cruris pustulosa et atrophicans (DCPA) is a distinctive type of chronic superficial folliculitis, with a number of unique features such as its peculiar symmetric localization to legs, extreme chronicity, resistance to therapy, and inevitable alopecia and atrophy. METHODS: All patients with DCPA, attending the Dermatology Outpatient Department at Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER) Hospital, Pondicherry, from December 2006 to June 2008 were included. Parameters recorded were detailed history and examination, hemogram, erythrocyte sedimentation rate, random blood sugar, skin biopsy and cultures from pus and carrier sites (nares, axillae and gluteal fold). RESULTS: 37 patients were studied (35 males and 2 females). Sixteen patients (43.24%) belonged to the 21-30 year-old age group. The disease most commonly began on the legs (81.1%). Majority (78.38%) had a disease duration of less than 5 years. Itching was the most common symptom (89.19%), followed by bleeding and scaling, with no significant systemic symptoms. The lower limbs were involved in all patients. Eleven patients (29.73%) had involvement of other sites -beard, axillae, chest, moustache, abdomen, and eyebrows. Pustules, papules, and scaling were seen in all patients, followed by wiry roughness, atrophy, alopecia, and pigmentation. Aggravating factors included use of full-length synthetic trousers, occupational exposure to potential irritants, and season (summer). Pus culture from the folliculitic lesions grew Staphylococcus aureus in 32 (86.49%) patients. Twenty one patients (56.75%) were carriers of S. aureus in one or more sites. CONCLUSION: DCPA is a chronic folliculitis of the legs, with a multifactorial etiopathogenesis, in which staphylococcal carrier status may be a new potential pathogenetic factor. PMID- 19775402 TI - Immunohistochemistry and polymerase chain reaction on paraffin-embedded material improve the diagnosis of cutaneous leishmaniasis in the Amazon region. AB - BACKGROUND: Recently, there has been an increase in the incidence of cutaneous leishmaniasis (CL), which represents an important health problem. This increase may be related to the epidemiologic expansion of the infective agent and the increase in tourism in tropical areas. The difficulty in clinical diagnosis, mainly in areas in which CL is not the first consideration of local physicians, has intensified efforts to describe diagnostic tests, which should be specific, sensitive, and practical. Amongst the new tests described are those including nucleic acid amplification (polymerase chain reaction, PCR) and immunohistochemistry (IHC). METHODS: In this study, we evaluated the sensitivity of a PCR based on small subunit (SSU) ribosomal DNA, in comparison with IHC using Leishmania spp. antibodies, in biopsies embedded in paraffin. RESULT: The results indicated a total sensitivity of 96% (90.9% with PCR and 68.8% with IHC), showing the possibility of using paraffin-embedded biopsies to diagnose CL. CONCLUSION: We propose the use of the two tests together as a routine protocol for diagnosis. This would require the provision of local medical services to perform molecular biology techniques and adequate Leishmania antibodies. PMID- 19775404 TI - Leprosy presenting as nodular eruptions in a segmental distribution. PMID- 19775403 TI - Necrolytic acral erythema seronegative for hepatitis C virus--two cases from India treated with oral zinc. AB - BACKGROUND: Necrolytic acral erythema (NAE) is a distinct skin entity and is strongly associated with chronic hepatitis C virus (HCV) infection. It is distinguished by its acral location, typical clinical and histopathologic features, and positive serum antibodies against HCV. Most cases have been treated with variable success using oral zinc, amino acids, and interferon with or without ribavirin therapy. METHODS: We report two patients with the clinical and histopathologic features of NAE; however, both tested seronegative for HCV. Both patients were treated with oral zinc acetate with good response, with one showing a partial relapse after stopping oral zinc. The clinical features, histopathologic findings, association of HCV, and treatment of NAE in different case reports were reviewed. CONCLUSION: NAE has a strong association with HCV, particularly in prevalent countries such as Egypt. Nevertheless, it may occur independently without HCV association, and oral zinc may prove to be a less toxic therapeutic option for such cases. PMID- 19775405 TI - Phacomatosis cesiomarmorata in an 8-month-old infant. PMID- 19775406 TI - Lipodystrophia centrifugalis abdominalis infantilis manifesting as recurrent skin ulcerations. PMID- 19775407 TI - Goltz syndrome in a moderately affected newborn boy. PMID- 19775408 TI - An urban outbreak of red mite dermatitis in Italy. PMID- 19775409 TI - Combination therapy of intravenous immunoglobulin and corticosteroid in the treatment of toxic epidermal necrolysis and Stevens-Johnson syndrome: a retrospective comparative study in China. AB - BACKGROUND: Toxic epidermal necrolysis (TEN) and Stevens-Johnson Syndrome (SJS) are drug-induced diseases with no well-established treatments. The application of corticosteroid therapy is controversial. Intravenous immunoglobulin (IVIG) therapy is emerging as a promising new method for the treatment of these two diseases. The efficacy of combination therapy of IVIG and corticosteroid in the treatment of TEN/SJS has seldom been reported. METHODS: Sixty-five consecutive patients with either TEN or SJS, admitted over a 14-year period from January 1993 to October 2007, were treated with corticosteroid and analyzed retrospectively using SCORTEN, a severity-of-illness scoring system for TEN/SJS prognosis, to evaluate efficacy. For patients admitted after January 2001, additional therapy with a dose of 0.4 g/kg/day of IVIG for 5 days was applied. RESULTS: In the 45 patients with TEN treated without IVIG, 8.63 patients were expected to die based on the SCORTEN system, but 10 deaths were observed. Standardized mortality ratio (SMR) analysis [(Sigmaobserved deaths/Sigmaexpected deaths) x 100] suggested that patients with TEN treated with systemic corticosteroid were 16% more likely to die than those treated with routine therapy (SMR = 1.16; 95% confidence interval, 0.56-2.13). In the further study of combination therapy, 12 patients with TEN and eight patients with SJS were admitted. There were two deaths in the TEN group and one death in the SJS group, with 3.51 deaths expected on the basis of the SCORTEN system. SMR analysis showed that combination therapy had a tendency to reduce the mortality rate of TEN (SMR = 0.85; 95% confidence interval, 0.18-2.50). Nevertheless, in both the TEN and SJS groups, the difference in mortality rate between the two therapies was not statistically significant (P = 0.651 and P = 1, respectively). In patients with TEN, combination therapy also reduced significantly the time of arrested progression (P = 0.019) and the total hospitalization time (P = 0.043), but could not reduce the time to the tapering of corticosteroid (P = 0.96). In SJS patients, the times of arrested progression and hospitalization were also reduced significantly (P = 0.019 and P = 0.0475, respectively). Likewise, the time to the tapering of corticosteroid was not reduced (P = 0.122). CONCLUSION: Combination therapy with corticosteroid and IVIG exhibited a tendency to reduce the mortality rate in comparison with the solo administration of corticosteroid. The decrease in the mortality rate, however, was not statistically significant. Combination therapy also arrested progression earlier and decreased the hospitalization time, meaning that the total dose of corticosteroid may be reduced. Combination therapy, however, did not lead to earlier tapering of corticosteroid. No severe adverse effects of IVIG were found during treatment. PMID- 19775410 TI - Purpura annularis telangiectodes of Majocchi: case report and review of the literature. AB - BACKGROUND: Purpura annularis telangiectodes of Majocchi is an uncommon form of pigmented purpuric dermatosis which may present a therapeutic challenge. Given the rare nature of this condition, there is limited anecdotal information available regarding optimal therapy. Although pigmented purpuric dermatoses are generally innocuous, in some cases they may cause patients significant distress, and there is a need to exclude cutaneous T-cell lymphoma. METHODS: We reviewed the literature on the treatment of pigmented purpuric dermatoses and managed a 69 year-old woman who presented with purpuric annular patches on the legs. RESULTS: Three separate biopsies demonstrated an interstitial to perivascular lymphocytic infiltrate with erythrocyte extravasation, consistent with pigmented purpuric dermatosis. The patient's condition proved refractory to many of the previously reported modes of management, but markedly improved with methotrexate. Treatment alternatives for pigmented purpuric dermatosis are reviewed, and a treatment algorithm is proposed. CONCLUSION: This is the first reported case regarding the successful use of methotrexate for pigmented purpuric dermatosis. Methotrexate may offer a therapeutic alternative to patients with highly symptomatic pigmented purpuric dermatosis refractory to other, more conservative, treatment modalities. PMID- 19775411 TI - A pedunculated hyalinizing Spitz nevus on the penile shaft. PMID- 19775412 TI - Penile and scrotal edema as a manifestation of Crohn's disease. PMID- 19775413 TI - Scedosporium apiospermum septicemia following a wedge excision of an ingrown toenail. PMID- 19775414 TI - Treatment of hypertrophic thyroidectomy scar using 532-nm potassium-titanyl phosphate (KTP) laser. PMID- 19775415 TI - Photoinduced acute exanthematous pustulosis caused by ciprofloxacin and sunlight exposure. PMID- 19775417 TI - Hemodialysis International. Preface. PMID- 19775418 TI - Can dialyzer membrane selection affect outcomes in patients with acute kidney injury requiring dialysis? AB - The choice of dialyzer membrane may potentially affect not only solute clearances but also blood-dialyzer interactions. Although on one hand alteration of the dialyzer surface or pore size to increase inflammatory mediator loss may potentially be beneficial for patients with acute kidney injury (AKI), dialyzer membrane interactions, which precipitate intradialytic hypotension, may worsen AKI. Several years ago cellulosic membrane dialyzers were shown to reduce both patient survival and renal recovery in patients with AKI. This review looks at the earlier studies of dialyzer membrane choice and outcomes in AKI, besides discussing the newer developments in membrane technology for patients with AKI. PMID- 19775419 TI - Intracardiac access for hemodialysis: a case series. PMID- 19775420 TI - Effect of packing density of hollow fibers on solute removal performances of dialyzers. AB - Solute removal performances of dialyzers are dependent not only on the solute permeabilities of the membrane but also on the module design. We have investigated how the packing density of hollow fiber (PDF) affects the solute removal performances. A series of 4 polyester polymer alloy membrane test dialyzers were assembled with varying PDFs of 29.6%, 35.3%, 44.1%, and 53.1%. Clearances (C(L)) were measured in vitro for creatinine (MW113), vitamin B(12) (MW1355), and chymotrypsin (MW25300) with various Q(B)=100 to 400 and Q(D)=350 to 650 mL/min in the absence of net ultrafiltration. When Q(B) was 44.1%, which was also considered to be due to the internal filtration. Packing density of hollow fiber can be optimized in terms of solute removal performances when the target solute and therapeutic conditions are specified. PMID- 19775421 TI - Does concurrent renin-angiotensin-aldosterone blockade in (older) chronic kidney disease patients play a role in the acute renal failure epidemic in US hospitalized patients?--Three cases of severe acute renal failure encountered in a northwestern Wisconsin Nephrology practice. AB - Following the publication of several large multicenter randomized placebo controlled trials showing reno-protection with renin-angiotensin-aldosterone (RAAS) blockade, the last 2 decades have witnessed an escalating use of the angiotensin-converting enzyme inhibitors and the angiotensin receptor blockers. Simultaneously, we continue to experience an increasing epidemic of acute renal failure (ARF) both in community-based and in hospital-based studies. Even though other factors would be contributing to this ARF epidemic, recent published data have raised concerns of a plausible connection between increased use of the RAAS blocking agents and this ARF epidemic. In our 4-nephrologist northwestern practice, we have, in recent years, anecdotally encountered an increasing number and severity of ARF, often with hyperkalemia, sometimes requiring dialysis intervention, in patients concurrently on these agents. Over the 3-day Christmas weekend in 2007, we treated 3 cases of severe ARF (peak serum creatinine of 7.0 (3.3-9.2) mg/dL), all on RAAS blockade. Renin-angiotensin-aldosterone blockade was promptly discontinued. All patients received intravenous fluid repletion. Kidney function rapidly normalized in 2 within 1 week. One patient required hemodialysis for 14 days before his serum creatinine returned to normal after 5 weeks. All 3 patients have continued to maintain baseline serum creatinine several months later, still off RAAS blockade. The mean baseline eGFR for the 3 patients was 46 (41-51) mL/min/1.73 m(2) body surface area. This phenomenon of ARF exacerbation, which may have implications for chronic kidney disease progression to ESRD especially in the elderly, merits further study. We support the recommendation that (older, >65 years old) chronic kidney disease patients on RAAS blocking agents should have the medications temporarily suspended during any acute illness, before major surgical procedures, and before iodinated contrast or oral phosphate sodium administration. PMID- 19775422 TI - Spontaneous erythrocytosis in a patient on chronic hemodialysis. AB - While anemia is common in patients on chronic hemodialysis (HD), spontaneous erythrocytosis is rare and can be caused by either the same conditions causing erythrocytosis in the general population or any condition specific to chronic renal failure. We present a patient illustrating this latter circumstance. A 53 year-old man with diabetic nephropathy, with no known disease causing hypoxemia started HD in April 2001. Blood hemoglobin (Hgb) level was 13.7 +/- 2.8 g/dL while his kidney function was normal (1993-1996) and after 1997, with the development of chronic kidney disease, decreased progressively to a low of 10.2 g/dL in March 2001 when erythropoietin (EPO) injections were started. Erythropoietin requirements progressively decreased because of rising Hgb. Erythropoietin was discontinued in mid-2005. Blood hemoglobin continued to rise, however, to a high value of 17.6 g/dL in February 2006. At the same time, endogenous blood EPO level was 3.6 mIU/mL, a value consistent with primary polycythemia. White blood cell and platelet counts were normal. Several small renal cysts, including 1 complex cyst, were detected by ultrasonography and computer tomography in April 2006. He refused surgical treatment. He was treated with small phlebotomies (not returning the blood in the dialyzer at the end of dialysis) and monitoring of Hgb, which decreased toward the desired range. Repeated computer tomographic scans showed a slow increase in the size of the complex cyst and several other cysts. In late 2007 Hgb started rising again, and in February 2008, while the Hgb level was 16.4 g/dL, the endogenous serum EPO level was 726 mIU/mL (upper normal limit 31.5 mIU/mL). Intermittent phlebotomies were reinstituted. He subsequently developed multiple vascular catastrophes and expired from ischemic bowel disease in September 2008. Acquired cystic disease of the kidneys should be considered in HD patients who develop spontaneous erythrocytosis. The risks of acquired cystic disease include, in addition to the development of malignancy, vascular events from elevated Hgb. PMID- 19775423 TI - Genetic and environmental effects and characteristics of Japanese end-stage renal disease patients. AB - Few studies of end-stage renal disease (ESRD) investigate genetic and environmental effects simultaneously in one racial/ethnic group. United States Renal Data System data show racial differences in primary causes of ESRD, survival rates, and causes of death. Comparing these with Japanese Society for Dialysis Therapy data, survival rates appear better for Japanese than for US patients. To explore genetic and environmental differences, we investigated incident and prevalent ESRD patient characteristics. The United States Renal Data System and Japanese Society for Dialysis Therapy databases were analyzed between 1983 and 2002 for the following patient subsets: Americans excluding Asian Americans (n=1,153,974); Asian Americans excluding Japanese Americans (n=35,983); Hawaiian and non-Hawaiian Japanese Americans by state, race, and Japanese surname (n=3932); native Japanese living in Japan (n=450,593). Japanese Americans tended to be older, male, have more diabetes and hypertension and less glomerulonephritis, and to die more often of heart failure than the other US groups. Adjusted mortality hazard ratios were 0.70 for non-Japanese Asian Americans and 0.75 for Japanese Americans vs. non-Asian Americans (1.00). Hawaiian Japanese patients tended to be older, with more diabetes and hypertension and less glomerulonephritis than the other Japanese groups; their survival rates improved after adjustment for rate of diabetes. Japanese American ESRD patients differ from Asian and non-Asian Americans, and from native Japanese, despite similar genetic make-ups. Both genetic and environmental factors may affect patient outcomes. PMID- 19775424 TI - The economics of treating stroke as an acute brain attack. AB - Currently, treatments for ischemic stroke focus on restoring or improving perfusion to the ischemic area using thrombolytics. The increased hospitalization costs related to thrombolysis are offset by a decrease in rehabilitation costs, for a net cost savings to the healthcare system. However, early treatment is essential. The benefit of thrombolysis is time-dependent but only a very small proportion of patients, 2%, are presently being treated with tPA. In the United States, if the proportion of all ischemic stroke patients that receive tPA were increased to 4, 6, 8, 10, 15, or 20%, the realized cost saving would be approximately $ 15, 22, 30, 37, 55, and 74 million, respectively. Being so, efforts should be made to educate the public and paramedics regarding early stroke signs. Furthermore, additional acute stroke therapy training programs need to be established for emergency departments. Finally, hospital systems need to be re-engineered to treat patients as quickly as possible in order to optimize thrombolytic benefit as well as maximize cost-effectiveness. PMID- 19775425 TI - Can ill-structured problems reveal beliefs about medical knowledge and knowing? A focus-group approach. AB - BACKGROUND: Epistemological beliefs (EB) are an individual's cognitions about knowledge and knowing. In several non-medical domains, EB have been found to contribute to the way individuals reason when faced with ill-structured problems (i.e. problems with no clear-cut, right or wrong solutions). Such problems are very common in medical practice. Determining whether EB are also influential in reasoning processes with regard to medical issues to which there is no straightforward answer, could have implications for medical education. This study focused on 2 research questions: 1. Can ill-structured problems be used to elicit general practice trainees' and trainers' EB? and 2. What are the views of general practice trainees and trainers about knowledge and how do they justify knowing? METHODS: 2 focus groups of trainees (n = 18) were convened on 3 occasions during their 1st year of postgraduate GP training. 2 groups of GP trainers (n = 11) met on one occasion. Based on the methodology of the Reflective Judgement Interview (RJI), participants were asked to comment on 11 ill-structured problems. The sessions were audio taped and transcribed and an adapted version of the RJI scoring rules was used to assess the trainees' reasoning about ill-structured problems. RESULTS: Participants made a number of statements illustrating their EB and their importance in clinical reasoning. The level of EB varied widely form one meeting to another and depending on the problem addressed. Overall, the EB expressed by trainees did not differ from those of trainers except on a particular ill-structured problem regarding shoulder pain. CONCLUSION: The use of focus groups has entailed some difficulties in the interpretation of the results, but a number of preliminary conclusions can be drawn. Ill-structured medical problems can be used to elicit EB. Most trainees and trainers displayed pre reflective and quasi-reflective EB. The way trainees and doctors view and justify knowledge are likely to be involved in medical reasoning processes. PMID- 19775426 TI - KSRP-PMR1-exosome association determines parathyroid hormone mRNA levels and stability in transfected cells. AB - BACKGROUND: Parathyroid hormone (PTH) gene expression is regulated post transcriptionally through the binding of the trans-acting proteins AU rich binding factor 1 (AUF1), Upstream of N-ras (Unr) and KH-type splicing regulatory protein (KSRP) to an AU rich element (ARE) in PTH mRNA 3'-UTR. AUF1 and Unr stabilize PTH mRNA while KSRP, recruiting the exoribonucleolytic complex exosome, promotes PTH mRNA decay. RESULTS: PTH mRNA is cleaved by the endoribonuclease polysomal ribonuclease 1 (PMR1) in an ARE-dependent manner. Moreover, PMR1 co immunoprecipitates with PTH mRNA, the exosome and KSRP. Knock-down of either exosome components or KSRP by siRNAs prevents PMR1-mediated cleavage of PTH mRNA. CONCLUSION: PTH mRNA is a target for the endonuclease PMR1. The PMR1 mediated decrease in PTH mRNA levels involves the PTH mRNA 3'-UTR ARE, KSRP and the exosome. This represents an unanticipated mechanism by which the decay of an ARE containing mRNA is facilitated by KSRP and is dependent on both the exosome and an endoribonuclease. PMID- 19775427 TI - Trauma-related psychological disorders among Palestinian children and adults in Gaza and West Bank, 2005-2008. AB - BACKGROUND: Trauma from war and violence has led to psychological disorders in individuals living in the Gaza strip and West Bank. Few reports are available on the psychiatric disorders seen in children and adolescents or the treatment of affected populations. This study was conducted in order to describe the occurrence and treatment of psychiatric disorders in the Palestinian populations of the Gaza strip and Nablus district in the West Bank. METHODS: From 2005 to 2008, 1369 patients aged more than 1 year were identified through a local mental health and counseling health network. All were clinically assessed using a semi structured interview based on the DSM-IV-TR criteria. RESULTS: Among 1254 patients, 23.2% reported post-traumatic stress disorder [PTSD], 17.3% anxiety disorder (other than PTSD or acute stress disorder), and 15.3% depression. PTSD was more frequently identified in children < or = 15 years old, while depression was the main symptom observed in adults. Among children < or = 15 years old, factors significantly associated with PTSD included being witness to murder or physical abuse, receiving threats, and property destruction or loss (p < 0.03). Psychological care, primarily in the form of individual, short-term psychotherapy, was provided to 65.1% of patients, with about 30.6% required psychotropic medication. Duration of therapy sessions was higher for children < or = 15 years old compared with adults (p = 0.05). Following psychotherapy, 79.0% had improved symptoms, and this improvement was significantly higher in children < or = 15 years old (82.8%) compared with adults (75.3%; p = 0.001). CONCLUSION: These observations suggest that short-term psychotherapy could be an effective treatment for specific psychiatric disorders occurring in vulnerable populations, including children, living in violent conflict zones, such as in Gaza strip and the West Bank. PMID- 19775428 TI - Infarct evolution in man studied in patients with first-time coronary occlusion in comparison to different species - implications for assessment of myocardial salvage. AB - BACKGROUND: The time course of infarct evolution, i.e. how fast myocardial infarction (MI) develops during coronary artery occlusion, is well known for several species, whereas no direct evidence exists on the evolution of MI size normalized to myocardium at risk (MaR) in man. Despite the lack of direct evidence, current literature often refers to the "golden hour" as the time during which myocardial salvage can be accomplished by reperfusion therapy. Therefore, the aim of the present study was to investigate how duration of myocardial ischemia affects infarct evolution in man in relation to previous animal data. Consecutive patients with clinical signs of acute myocardial ischemia were screened and considered for enrollment. Particular care was taken to assure uniformity of the patients enrolled with regard to old MI, success of revascularization, collateral flow, release of biochemical markers prior to intervention etc. Sixteen patients were ultimately included in the study. Myocardium at risk was assessed acutely by acute myocardial perfusion single photon emission computed tomography (MPS) and by T2 imaging (T2-STIR) cardiovascular magnetic resonance (CMR) after one week in 10 of the 16 patients. Infarct size was measured by late gadolinium enhancement (LGE) at one week. RESULTS: The time to reach 50% MI of the MaR (T50) was significantly shorter in pigs (37 min), rats (41 min) and dogs (181 min) compared to humans (288 min). There was no significant difference in T50 when using MPS compared to T2-STIR (p = 0.53) for assessment of MaR (288 +/- 23 min vs 310 +/- 22 min, T50 +/- standard error). The transmural extent of MI increased progressively as the duration of ischemia increased (R2 = 0.56, p < 0.001). CONCLUSION: This is the first study to provide direct evidence of the time course of acute myocardial infarct evolution in relation to MaR in man with first-time MI. Infarct evolution in man is significantly slower than in pigs, rats and dogs. Furthermore, infarct evolution assessments in man are similar when using MPS acutely and T2-STIR one week later for determination of MaR, which significantly facilitates future clinical trials of cardioprotective therapies in acute coronary syndrome by the use of CMR. PMID- 19775429 TI - External validation suggests Integrin beta 3 as prognostic biomarker in serous ovarian adenocarcinomas. AB - BACKGROUND: The majority of women with ovarian cancer are diagnosed in late stages, and the mortality rate is high. The use of biomarkers as prognostic factors may improve the treatment and clinical outcome of these patients. We performed an external validation of the potential biomarkers CLU, ITGB3, CAPG, and PRAME to determine if the expression levels are relevant to use as prognostic factors. METHODS: We analysed the gene expression of CLU, ITGB3, CAPG, and PRAME in 30 advanced staged serous adenocarcinomas with quantitative real-time polymerase chain reaction (QPCR) and the protein levels were analysed in 98 serous adenocarcinomas with western blot for semiquantitative analysis. Statistical differences in mRNA and protein expressions between tumours from survivors and tumours from deceased patients were evaluated using the Mann Whitney U test. RESULTS: The gene and protein ITGB3 (Integrin beta 3) were significantly more expressed in tumours from survivors compared to tumours from deceased patients, which is in concordance with our previous results. However, no significant differences were detected for the other three genes or proteins CLU, CAPG, and PRAME. CONCLUSION: The loss of ITGB3 expression in tumours from deceased patients and high expression in tumours from survivors could be used as a biomarker for patients with advanced serous tumours. PMID- 19775430 TI - Vestibular effects on cerebral blood flow. AB - BACKGROUND: Humans demonstrate a number of unique adaptations that allow for the maintenance of blood pressure and brain blood flow when upright. While several physiological systems, including cerebral autoregulation, are involved in this adaptation the unique role the vestibular system plays in helping to maintain brain blood flow is just beginning to be elucidated. In this study, we tested the hypothesis that stimulation of the vestibular system, specifically the otoliths organs, would result in changes in cerebral blood flow. RESULTS: To test our hypothesis, we stimulated the vestibular organs of 25 healthy subjects by pitch tilt (stimulates both canals and otoliths) and by translation on a centrifuge (stimulates otoliths and not the canals) at five frequencies: 0.5, 0.25, 0.125 and 0.0625 Hz for 80 sec and 0.03125 Hz for 160 sec. Changes in cerebral flow velocity (by transcranial Doppler) and blood pressure (by Finapres) were similar during both stimuli and dependent on frequency of stimulation (P < 0.01). However, changes in cerebral blood flow were in opposition to changes in blood pressure and not fully dependent on changes in end tidal CO2. CONCLUSION: The experimental results support our hypothesis and provide evidence that activation of the vestibular apparatus, specifically the otolith organs, directly affects cerebral blood flow regulation, independent of blood pressure and end tidal CO2 changes. PMID- 19775432 TI - Temporal patterns of inflammatory gene expression in local tissues after banding or burdizzo castration in cattle. AB - BACKGROUND: Castration of male cattle has been shown to elicit inflammatory reactions and acute inflammation is initiated and sustained by the participation of cytokines. METHODS: Sixty continental x beef bulls (Mean age 12 +/- (s.e.) 0.2 months; Mean weight 341 +/- (s.e.) 3.0 kg) were blocked by weight and randomly assigned to one of three treatments (n = 20 animals per treatment): 1) untreated control (Con); 2) banding castration at 0 min (Band); 3) Burdizzo castration at 0 min (Burd). Samples of the testis, epididymis and scrotal skin were collected surgically from 5 animals from each group at 12 h, 24 h, 7 d, and 14 d post treatment, and analysed using real-time PCR. A repeated measurement analysis (Proc GLM) was performed using SAS. If there was no treatment and time interaction, main effects of treatment by time were tested by ANOVA. RESULTS: Electrophoresis data showed that by 7 d post-castration RNA isolated from all the testicle samples of the Burd castrated animals, the epididymis and middle scrotum samples from Band castrates were degraded. Transitory effects were observed in the gene expression of IFN-gamma, IL-6, IL-8 and TNF-alpha at 12 h and 24 h post treatment. Burd castrates had greater (P < 0.05) testicular IFN-gamma mRNA levels compared with Band and Con animals, but lower (P < 0.05) testicular TNF-alpha mRNA levels compared with Con animals. Band castrates had greater (P < 0.05) testicular IL-6 mRNA levels than Burd castrates at 12 h post-castration. Burd castrates had greater (P < 0.05) testicular IL-8 mRNA levels than Band and Con animals at 24 h post-castration. In the epididymis, Burd castrates had greater (P < 0.05) IL-6 mRNA (both at 12 h and 24 h post treatment) and IL-8 mRNA (12 h post treatment) levels compared with Band and Con animals; Burd castrates had greater (P = 0.049) IL-10 mRNA levels than Band castrates at 12 h post-castration. CONCLUSION: Banding castration caused more inflammatory associated gene expression changes to the epididymis and scrotum than burdizzo. Burdizzo caused more severe acute inflammatory responses, in terms of pro-inflammatory cytokine gene expression, in the testis and epididymis than banding. PMID- 19775431 TI - Complete genome sequence of the sugarcane nitrogen-fixing endophyte Gluconacetobacter diazotrophicus Pal5. AB - BACKGROUND: Gluconacetobacter diazotrophicus Pal5 is an endophytic diazotrophic bacterium that lives in association with sugarcane plants. It has important biotechnological features such as nitrogen fixation, plant growth promotion, sugar metabolism pathways, secretion of organic acids, synthesis of auxin and the occurrence of bacteriocins. RESULTS: Gluconacetobacter diazotrophicus Pal5 is the third diazotrophic endophytic bacterium to be completely sequenced. Its genome is composed of a 3.9 Mb chromosome and 2 plasmids of 16.6 and 38.8 kb, respectively. We annotated 3,938 coding sequences which reveal several characteristics related to the endophytic lifestyle such as nitrogen fixation, plant growth promotion, sugar metabolism, transport systems, synthesis of auxin and the occurrence of bacteriocins. Genomic analysis identified a core component of 894 genes shared with phylogenetically related bacteria. Gene clusters for gum-like polysaccharide biosynthesis, tad pilus, quorum sensing, for modulation of plant growth by indole acetic acid and mechanisms involved in tolerance to acidic conditions were identified and may be related to the sugarcane endophytic and plant-growth promoting traits of G. diazotrophicus. An accessory component of at least 851 genes distributed in genome islands was identified, and was most likely acquired by horizontal gene transfer. This portion of the genome has likely contributed to adaptation to the plant habitat. CONCLUSION: The genome data offer an important resource of information that can be used to manipulate plant/bacterium interactions with the aim of improving sugarcane crop production and other biotechnological applications. PMID- 19775433 TI - A secretory phospholipase A2-mediated neuroprotection and anti-apoptosis. AB - BACKGROUND: Phospholipase A2 liberates free fatty acids and lysophospholipids upon hydrolysis of phospholipids and these products are often associated with detrimental effects such as inflammation and cerebral ischemia. The neuroprotective effect of neutral phospholipase from snake venom has been investigated. RESULTS: A neutral anticoagulant secretory phospholipase A2 (nPLA) from the venom of Naja sputatrix (Malayan spitting cobra) has been found to reduce infarct volume in rats subjected to focal transient cerebral ischemia and to alleviate the neuronal damage in organotypic hippocampal slices subjected to oxygen-glucose deprivation (OGD). Real-time PCR based gene expression analysis showed that anti-apoptotic and pro-survival genes have been up-regulated in both in vivo and in vitro models. Staurosporine or OGD mediated apoptotic cell death in astrocytoma cells has also been found to be reduced by nPLA with a corresponding reduction in caspase 3 activity. CONCLUSION: We have found that a secretory phospholipase (nPLA) purified from snake venom could reduce infarct volume in rodent stroke model. nPLA, has also been found to reduce neuronal cell death, apoptosis and promote cell survival in vitro ischemic conditions. In all conditions, the protective effects could be seen at sub-lethal concentrations of the protein. PMID- 19775434 TI - Preliminary results, methodological considerations and recruitment difficulties of a randomised clinical trial comparing two treatment regimens for patients with headache and neck pain. AB - BACKGROUND: Headache is a highly prevalent disorder. Irrespective of the headache diagnosis it is often accompanied with neck pain and -stiffness. Due to this common combination of headache and neck pain, physical treatments of the cervical spine are often considered. The additional value of these treatments to standard medical care or usual care (UC) is insufficiently documented.We therefore wanted to compare the treatment effects of UC alone and in combination with manual therapy (MT) in patients with a combination of headache and neck pain. UC consisted of a stepped treatment approach according to the Dutch General Practitioners Guideline for headache, the additional MT consisted of articular mobilisations and low load exercises.Due to insufficient enrolment the study was terminated prematurely. We aim to report not only our preliminary clinical findings but also to discuss the encountered difficulties and to formulate recommendations for future research. METHODS: A randomised clinical trial was conducted. Thirty-seven patients were included and randomly allocated to one of both treatment groups. The treatment period was 6 weeks, with follow-up measurements at weeks 7, 12 and 26. Primary outcome measures were global perceived effect (GPE) and the impact of the headache using the Headache Impact Test (HIT-6). Reduction in headache frequency, pain intensity, medication intake, absenteeism and the use of additional professional help were secondary outcome measures RESULTS: Significant improvements on primary and secondary outcome measures were recorded in both treatment groups. No significant differences between both treatment groups were found. The number of recruited patients remained low despite various strategies. CONCLUSION: It appears that both treatment strategies can have equivalent positive influences on headache complaints. Additional studies with larger study populations are needed to draw firm conclusions. Recommendations to increase patient inflow in primary care trials, such as the use of an extended network of participating physicians and of clinical alert software applications, are discussed. TRIAL REGISTRATION NUMBER: NCT00298142. PMID- 19775435 TI - MLVA distribution characteristics of Yersinia pestis in China and the correlation analysis. AB - BACKGROUND: Yersinia pestis, the aetiological agent of plague, has been well defined genotypically on local and worldwide scales. In November 2005, five cases of severe pneumonia of unknown causes, resulting in two deaths, were reported in Yulong, Yunnan province. In this study, we compared Y. pestis isolated from the Yulong focus to strains from other areas. RESULTS: Two hundred and thirteen Y. pestis strains collected from different plague foci in China and a live attenuated vaccine strain of Y. pestis (EV76) were genotyped using multiple-locus variable-number tandem repeat analysis (MLVA) on 14 loci. A total of 214 Y. pestis strains were divided into 85 MLVA types, and Nei's genetic diversity indices of the various loci ranged between 0.02 - 0.76. Minimum spanning tree analysis showed that Y. pestis in China could be divided into six complexes. It was observed that Microtus strains were different from the other three biovar strains. Each plague focus had its own unique MLVA types. CONCLUSION: The strains isolated from Yulong, Yunnan province had a unique MLVA type, indicating a new clone group. Our results suggest that Yulong strains may have a close relationship with strains from the Qinghai-Tibet Plateau plague focus. PMID- 19775436 TI - Parkinson's disease brain mitochondria have impaired respirasome assembly, age related increases in distribution of oxidative damage to mtDNA and no differences in heteroplasmic mtDNA mutation abundance. AB - BACKGROUND: Sporadic Parkinson's disease (sPD) is a nervous system-wide disease that presents with a bradykinetic movement disorder and is frequently complicated by depression and cognitive impairment. sPD likely has multiple interacting causes that include increased oxidative stress damage to mitochondrial components and reduced mitochondrial bioenergetic capacity. We analyzed mitochondria from postmortem sPD and CTL brains for evidence of oxidative damage to mitochondrial DNA (mtDNA), heteroplasmic mtDNA point mutations and levels of electron transport chain proteins. We sought to determine if sPD brains possess any mtDNA genotype respiratory phenotype relationships. RESULTS: Treatment of sPD brain mtDNA with the mitochondrial base-excision repair enzyme 8-oxyguanosine glycosylase-1 (hOGG1) inhibited, in an age-dependent manner, qPCR amplification of overlapping ~2 kbase products; amplification of CTL brain mtDNA showed moderate sensitivity to hOGG1 not dependent on donor age. hOGG1 mRNA expression was not different between sPD and CTL brains. Heteroplasmy analysis of brain mtDNA using Surveyor nuclease(R) showed asymmetric distributions and levels of heteroplasmic mutations across mtDNA but no patterns that statistically distinguished sPD from CTL. sPD brain mitochondria displayed reductions of nine respirasome proteins (respiratory complexes I-V). Reduced levels of sPD brain mitochondrial complex II, III and V, but not complex I or IV proteins, correlated closely with rates of NADH-driven electron flow. mtDNA levels and PGC-1alpha expression did not differ between sPD and CTL brains. CONCLUSION: PD brain mitochondria have reduced mitochondrial respiratory protein levels in complexes I-V, implying a generalized defect in respirasome assembly. These deficiencies do not appear to arise from altered point mutational burden in mtDNA or reduction of nuclear signaling for mitochondrial biogenesis, implying downstream etiologies. The origin of age related increases in distribution of oxidative mtDNA damage in sPD but not CTL brains is not clear, tracks with but does not determine the sPD phenotype, and may indicate a unique consequence of aging present in sPD that could contribute to mtDNA deletion generation in addition to mtDNA replication, transcription and sequencing errors. sPD frontal cortex experiences a generalized bioenergetic deficiency above and beyond aging that could contribute to mood disorders and cognitive impairments. PMID- 19775437 TI - Lifetime intimate partner violence exposure, attitudes and comfort among Canadian health professions students. AB - BACKGROUND: Intimate partner violence (IPV) is a widespread public health problem and training of health professions students has become common. Understanding students' prior knowledge, attitudes and personal exposure to IPV will aid educators in designing more effective curriculum. As interprofessional educational efforts proliferate, understanding differences across disciplines will be critical. FINDINGS: Students in the schools of Medicine, Nursing and Rehabilitation at a university in Ontario attend an annual daylong interprofessional IPV training. To measure perceived role and comfort with IPV and prior personal exposure, we administered a brief Likert scale survey to a convenience sample of students over three years. 552 students completed the survey; the overall response rate was 73%. The majority (82%) agreed that it was their role to intervene in cases of IPV; however Rehabilitation students expressed lower overall comfort levels than did their peers in other schools (p < .0001). Gender, age and prior training on the subject were not significant predictors of comfort. Seven percent reported lifetime IPV and one-fifth had witnessed IPV, but these exposures did not predict comfort in adjusted logistic regression models. CONCLUSION: While the majority of professional students believe it is their role to address IPV in clinical practice, comfort level varied significantly by field of study. More than one fifth of the students reported some personal exposure to IPV. However this did not impact their level of comfort in addressing this issue. Educators need to take students' preexisting attitudes and personal exposure into account when planning curriculum initiatives in this area. PMID- 19775438 TI - Commentary: childhood cancer near nuclear power stations. AB - In 2008, the KiKK study in Germany reported a 1.6-fold increase in solid cancers and a 2.2-fold increase in leukemias among children living within 5 km of all German nuclear power stations. The study has triggered debates as to the cause(s) of these increased cancers. This article reports on the findings of the KiKK study; discusses past and more recent epidemiological studies of leukemias near nuclear installations around the world, and outlines a possible biological mechanism to explain the increased cancers. This suggests that the observed high rates of infant leukemias may be a teratogenic effect from incorporated radionuclides. Doses from environmental emissions from nuclear reactors to embryos and fetuses in pregnant women near nuclear power stations may be larger than suspected. Hematopoietic tissues appear to be considerably more radiosensitive in embryos/fetuses than in newborn babies. Recommendations for advice to local residents and for further research are made. PMID- 19775439 TI - A randomized controlled trial evaluating the impact of knowledge translation and exchange strategies. AB - CONTEXT: Significant resources and time are invested in the production of research knowledge. The primary objective of this randomized controlled trial was to evaluate the effectiveness of three knowledge translation and exchange strategies in the incorporation of research evidence into public health policies and programs. METHODS: This trial was conducted with a national sample of public health departments in Canada from 2004 to 2006. The three interventions, implemented over one year in 2005, included access to an online registry of research evidence; tailored messaging; and a knowledge broker. The primary outcome assessed the extent to which research evidence was used in a recent program decision, and the secondary outcome measured the change in the sum of evidence-informed healthy body weight promotion policies or programs being delivered at health departments. Mixed-effects models were used to test the hypotheses. FINDINGS: One hundred and eight of 141 (77%) health departments participated in this study. No significant effect of the intervention was observed for primary outcome (p < 0.45). However, for public health policies and programs (HPPs), a significant effect of the intervention was observed only for tailored, targeted messages (p < 0.01). The treatment effect was moderated by organizational research culture (e.g., value placed on research evidence in decision making). CONCLUSION: The results of this study suggest that under certain conditions tailored, targeted messages are more effective than knowledge brokering and access to an online registry of research evidence. Greater emphasis on the identification of organizational factors is needed in order to implement strategies that best meet the needs of individual organizations. TRIAL REGISTRATION: The trial registration number and title are as follows: ISRCTN35240937 -- Is a knowledge broker more effective than other strategies in promoting evidence-based physical activity and healthy body weight programming? PMID- 19775440 TI - Transcriptome analysis of the central nervous system of the mollusc Lymnaea stagnalis. AB - BACKGROUND: The freshwater snail Lymnaea stagnalis (L. stagnalis) has served as a successful model for studies in the field of Neuroscience. However, a serious drawback in the molecular analysis of the nervous system of L. stagnalis has been the lack of large-scale genomic or neuronal transcriptome information, thereby limiting the use of this unique model. RESULTS: In this study, we report 7,712 distinct EST sequences (median length: 847 nucleotides) of a normalized L. stagnalis central nervous system (CNS) cDNA library, resulting in the largest collection of L. stagnalis neuronal transcriptome data currently available. Approximately 42% of the cDNAs can be translated into more than 100 consecutive amino acids, indicating the high quality of the library. The annotated sequences contribute 12% of the predicted transcriptome size of 20,000. Surprisingly, approximately 37% of the L. stagnalis sequences only have a tBLASTx hit in the EST library of another snail species Aplysia californica (A. californica) even using a low stringency e-value cutoff at 0.01. Using the same cutoff, approximately 67% of the cDNAs have a BLAST hit in the NCBI non-redundant protein and nucleotide sequence databases (nr and nt), suggesting that one third of the sequences may be unique to L. stagnalis. Finally, using the same cutoff (0.01), more than half of the cDNA sequences (54%) do not have a hit in nematode, fruitfly or human genome data, suggesting that the L. stagnalis transcriptome is significantly different from these species as well. The cDNA sequences are enriched in the following gene ontology functional categories: protein binding, hydrolase, transferase, and catalytic enzymes. CONCLUSION: This study provides novel molecular insights into the transcriptome of an important molluscan model organism. Our findings will contribute to functional analyses in neurobiology, and comparative evolutionary biology. The L. stagnalis CNS EST database is available at http://www.Lymnaea.org/. PMID- 19775441 TI - Association between subjective memory complaints and health care utilisation: a three-year follow up. AB - BACKGROUND: Subjective memory complaints (SMC) are common among elderly patients and little is know about the association between SMC and health care utilisation. Thus, the aim of this study was to investigate health care utilisation during a three-year follow-up among elderly patients consulting their general practitioner and reporting subjective memory complaints (SMC). METHODS: This study was conducted as a prospective cohort survey in general practice with three-year follow-up. Selected health care utilisation or costs relative to SMC adjusted for potential confounders were analyzed in a two-part model where the incidence of use of a selected health care service were analyzed separately from the quantity of use for those that use the service. The former analyzed in a Poisson regression approach, the latter in a generalized linear regression model. RESULTS: A total 758 non-nursing home residents aged 65 years and older consulted their GP in October and November 2002 and participated in the present study. The adjusted probability of nursing home placement was significantly increased in subjects with SMC relative to subjects without SMC (RR = 2.3). More generally, SMC was associated with an increase in the cost of selected health care utilisation of 60% over three years (p = 0.003). CONCLUSION: The data of this study indicated that in an elderly primary care population the presence of SMC increased the cost of health care utilisation by 60% over three years. Thus, inquiry into SMC may contribute to a risk profile assessment of elderly patients and may identify patients with an increased use of health care services. PMID- 19775442 TI - Alcohol consumption and carotid artery structure in Korean adults aged 50 years and older. AB - BACKGROUND: Epidemiologic studies of the association between alcohol consumption and carotid artery structure have reported conflicting results. We investigated the association between alcohol consumption and carotid atherosclerosis by evaluating the effects of alcohol intake on carotid artery enlargement. METHODS: The study population consisted of 4302 community-dwelling Koreans (1577 men and 2725 women) aged 50 years and over. All the subjects had participated in the baseline survey of the Dong-gu Study conducted between 2007 and 2008. Daily alcohol consumption was determined by the number and frequency of alcoholic beverages consumed. We measured common carotid artery intima-media thickness (CCA IMT), common carotid and bulb IMT (CB-IMT), carotid plaques, and the diameter of the common carotid artery (CCA-diameter) using high-resolution B-mode ultrasonography. We used analysis of covariance and multiple logistic regressions to determine the relationship between alcohol consumption and carotid artery parameters. RESULTS: CCA-IMT and CB-IMT were negatively correlated with alcohol consumption after controlling for cardiovascular risk factors in men (p for linear trend = 0.009 and = 0.038, respectively). The multivariate-adjusted odds ratio (OR) for carotid plaques was significantly higher in men who consumed >40.0 g/d (OR = 1.81, 95% CI = 1.13-2.91), although a significant positive correlation was observed between alcohol consumption and carotid plaques (p for linear trend = 0.027). Neither carotid IMT nor carotid plaques were correlated with alcohol intake in women. Alcohol intake was positively correlated with CCA-diameter adjusted for carotid IMT and plaques in the multivariate-adjusted model in both sexes (p for linear trend <0.001 for men and 0.020 for women). CONCLUSION: The results of our study indicate that alcohol consumption is inversely related to carotid IMT and positively related to carotid plaques in men, but not women. However, alcohol intake is positively associated with CCA-diameter in both men and women. Additional large population-based prospective studies are needed to confirm the effects of alcohol consumption on carotid artery structure. PMID- 19775443 TI - Robust extraction of functional signals from gene set analysis using a generalized threshold free scoring function. AB - BACKGROUND: A central task in contemporary biosciences is the identification of biological processes showing response in genome-wide differential gene expression experiments. Two types of analysis are common. Either, one generates an ordered list based on the differential expression values of the probed genes and examines the tail areas of the list for over-representation of various functional classes. Alternatively, one monitors the average differential expression level of genes belonging to a given functional class. So far these two types of method have not been combined. RESULTS: We introduce a scoring function, Gene Set Z-score (GSZ), for the analysis of functional class over-representation that combines two previous analysis methods. GSZ encompasses popular functions such as correlation, hypergeometric test, Max-Mean and Random Sets as limiting cases. GSZ is stable against changes in class size as well as across different positions of the analysed gene list in tests with randomized data. GSZ shows the best overall performance in a detailed comparison to popular functions using artificial data. Likewise, GSZ stands out in a cross-validation of methods using split real data. A comparison of empirical p-values further shows a strong difference in favour of GSZ, which clearly reports better p-values for top classes than the other methods. Furthermore, GSZ detects relevant biological themes that are missed by the other methods. These observations also hold when comparing GSZ with popular program packages. CONCLUSION: GSZ and improved versions of earlier methods are a useful contribution to the analysis of differential gene expression. The methods and supplementary material are available from the website http://ekhidna.biocenter.helsinki.fi/users/petri/public/GSZ/GSZscore.html. PMID- 19775444 TI - Detection of recurrent copy number alterations in the genome: taking among subject heterogeneity seriously. AB - BACKGROUND: Alterations in the number of copies of genomic DNA that are common or recurrent among diseased individuals are likely to contain disease-critical genes. Unfortunately, defining common or recurrent copy number alteration (CNA) regions remains a challenge. Moreover, the heterogeneous nature of many diseases requires that we search for common or recurrent CNA regions that affect only some subsets of the samples (without knowledge of the regions and subsets affected), but this is neglected by most methods. RESULTS: We have developed two methods to define recurrent CNA regions from aCGH data. Our methods are unique and qualitatively different from existing approaches: they detect regions over both the complete set of arrays and alterations that are common only to some subsets of the samples (i.e., alterations that might characterize previously unknown groups); they use probabilities of alteration as input and return probabilities of being a common region, thus allowing researchers to modify thresholds as needed; the two parameters of the methods have an immediate, straightforward, biological interpretation. Using data from previous studies, we show that we can detect patterns that other methods miss and that researchers can modify, as needed, thresholds of immediate interpretability and develop custom statistics to answer specific research questions. CONCLUSION: These methods represent a qualitative advance in the location of recurrent CNA regions, highlight the relevance of population heterogeneity for definitions of recurrence, and can facilitate the clustering of samples with respect to patterns of CNA. Ultimately, the methods developed can become important tools in the search for genomic regions harboring disease-critical genes. PMID- 19775445 TI - Inhibition of the NMDA receptor/Nitric Oxide pathway in the dorsolateral periaqueductal gray causes anxiolytic-like effects in rats submitted to the Vogel conflict test. AB - BACKGROUND: Several studies had demonstrated the involvement of the dorsolateral portion of periaqueductal grey matter (dlPAG) in defensive responses. This region contains a significant number of neurons containing the enzyme nitric oxide synthase (NOS) and previous studies showed that non-selective NOS inhibition or glutamate NMDA-receptor antagonism in the dlPAG caused anxiolytic-like effects in the elevated plus maze. METHODS: In the present study we verified if the NMDA/NO pathway in the dlPAG would also involve in the behavioral suppression observed in rats submitted to the Vogel conflict test. In addition, the involvement of this pathway was investigated by using a selective nNOS inhibitor, Nomega-propyl-L arginine (N-Propyl, 0.08 nmol/200 nL), a NO scavenger, carboxy-PTIO (c-PTIO, 2 nmol/200 nL) and a specific NMDA receptor antagonist, LY235959 (4 nmol/200 nL). RESULTS: Intra-dlPAG microinjection of these drugs increased the number of punished licks without changing the number of unpunished licks or nociceptive threshold, as measure by the tail flick test. CONCLUSION: The results indicate that activation of NMDA receptors and increased production of NO in the dlPAG are involved in the anxiety behavior displayed by rats in the VCT. PMID- 19775446 TI - The expression of PLK-1 in cervical carcinoma: a possible target for enhancing chemosensitivity. AB - BACKGROUND: Polo-like kinase-1 (PLK-1) is reported to be upregulated in a variety of human tumors and is implicated in cell proliferation and survival. However, its importance in cervical carcinoma has not yet been fully elucidated. METHODS: We examined PLK-1 expression in cervical carcinoma tissues using immunohistochemical staining. Furthermore, we blocked PLK-1 expression in HeLa cells using specific siRNA and detected the cell cycle, cell proliferation and chemosensitivity using western blotting, MTT and flow cytometry. RESULTS: We provide evidence that expression of PLK-1 exists in human cervical carcinoma tissues and establish an association with tumor size. Furthermore, we show that PLK-1 knockdown by transfection of siRNA induces accumulation of HeLa cells in the G2/M cell cycle phase and enhances cisplatin-induced apoptosis. CONCLUSION: Our results indicate that PLK-1 production in HeLa cells might be critical in determining whether cells survive or undergo apoptosis. Therefore, targeting PLK 1 might be a promising strategy for enhancing sensitivity to chemotherapeutic reagents in cervical carcinoma. PMID- 19775447 TI - Effects of dielectric permittivities on skin heating due to millimeter wave exposure. AB - BACKGROUND: Because the possibility of millimeter wave (MMW) exposure has increased, public concern about the health issues due to electromagnetic radiation has also increased. While many studies have been conducted for MMW exposure, the effect of dielectric permittivities on skin heating in multilayer/heterogeneous human-body models have not been adequately investigated. This is partly due to the fact that a detailed investigation of skin heating in a multilayer model by computational methods is difficult since many parameters are involved. In the present study, therefore, theoretical analyses were conducted to investigate the relationship between dielectric permittivities and MMW-induced skin heating in a one-dimensional three-layer model (skin, fat, and muscle). METHODS: Approximate expressions were derived for the temperature elevation and temperature difference in the skin due to MMW exposure from analytical solutions for the temperature distribution. First, the power absorption distribution was approximated from the analytical solution for a one-layer model (skin only). Then, the analytical expression of the temperature in the three-layer model was simplified on the basis of the proposal in our previous study. By examining the approximate expressions, the dominant term influencing skin heating was clarified to identify the effects of the dielectric permittivities. Finally, the effects of dielectric permittivities were clarified by applying partial differentiation to the derived dominant term. RESULTS: Skin heating can be characterized by the parameters associated with the dielectric permittivities, independently of morphological and thermal parameters. With the derived expressions, it was first clarified that skin heating correlates with the total power absorbed in the skin rather than the specific absorption rate (SAR) at the skin surface or the incident power density. Using Debye-type expression we next investigated the effect of frequency dispersion on the complex relative permittivity of tissue. The parametric study on the total power absorbed in the skin showed that skin heating increases as the static permittivity and static conductivity decrease. In addition, the maximum temperature elevation on the body surface was approximately 1.6 times that of the minimum case. This difference is smaller than the difference caused by the thermal and morphological parameters reported in our previous study. CONCLUSION: This paper analytically clarified the effects of dielectric permittivities on the thermally steady state temperature elevation and the temperature difference in the skin of a one-dimensional three-layer model due to MMW exposure. PMID- 19775448 TI - Development and validation of the accommodation and enabling scale for eating disorders (AESED) for caregivers in eating disorders. AB - BACKGROUND: Families of people with eating disorders are often caught up in rule bound eating and safety behaviours that characterise the illness. The main aim of this study was to develop a valid and specific scale to measure family accommodation in the context of having a relative with an eating disorder. METHODS: A new scale, the Accommodation and Enabling Scale for Eating Disorders (AESED), was jointly generated by professionals and expert carers through qualitative analysis. In the first stage, this instrument was given to 201 family members of relatives diagnosed with an eating disorder, with additional self report measures including the Experience of Caregiving Inventory (ECI), the Hospital Anxiety and Depression Scale (HADS) and the Family Questionnaire (FQ). In the second stage, the sensitivity of the AESED to change was tested in a pre and-post design study with a new sample of 116 caregivers, using a DVDs-distance skills training for caregivers. RESULTS: A 33 item instrument was derived consisting of five factors: Avoidance and Modifying Routine, Reassurance Seeking, Meal Ritual, Control of Family and Turning a Blind Eye, which together explained 60.1% of the variance. This scale had good psychometric properties in terms of Cronbach's alpha which ranged from 0.77 to 0.92. Regarding the convergent validity, most of the AESED subscales was moderately supported by correlations with anxiety (HADS; r = 0.24 to 0.48) and depression levels (HADS; r = 0.17 to 0.47), negative caregiving (ECI; r = 0.18 to 0.45), and expressed emotion levels (FQ; r = 0.17 to 0.51). Pre-post intervention assessments showed that the overall AESED scale (d = 0.38) and the avoidance and modifying routine (d = 0.52), meal ritual (d = 0.27) and control of the family (d = 0.49) subscales were sensitive to change. CONCLUSION: Internal consistency was good and initial validity of the scale was adequate, it was able to discriminate differences between clinical variables, however, further work is needed to confirm the factor structure and validity of the AESED. Nevertheless, this scale may be of value in exploring and helping to improve carers' coping strategies and in examining the effectiveness of family based interventions. PMID- 19775449 TI - Intensity modulated radiotherapy (IMRT) in the treatment of children and adolescents--a single institution's experience and a review of the literature. AB - BACKGROUND: While IMRT is widely used in treating complex oncological cases in adults, it is not commonly used in pediatric radiation oncology for a variety of reasons. This report evaluates our 9 year experience using stereotactic-guided, inverse planned intensity-modulated radiotherapy (IMRT) in children and adolescents in the context of the current literature. METHODS: Between 1999 and 2008 thirty-one children and adolescents with a mean age of 14.2 years (1.5 - 20.5) were treated with IMRT in our department. This heterogeneous group of patients consisted of 20 different tumor entities, with Ewing's sarcoma being the largest (5 patients), followed by juvenile nasopharyngeal fibroma, esthesioneuroblastoma and rhabdomyosarcoma (3 patients each). In addition a review of the available literature reporting on technology, quality, toxicity, outcome and concerns of IMRT was performed. RESULTS: With IMRT individualized dose distributions and excellent sparing of organs at risk were obtained in the most challenging cases. This was achieved at the cost of an increased volume of normal tissue receiving low radiation doses. Local control was achieved in 21 patients. 5 patients died due to progressive distant metastases. No severe acute or chronic toxicity was observed. CONCLUSION: IMRT in the treatment of children and adolescents is feasible and was applied safely within the last 9 years at our institution. Several reports in literature show the excellent possibilities of IMRT in selective sparing of organs at risk and achieving local control. In selected cases the quality of IMRT plans increases the therapeutic ratio and outweighs the risk of potentially increased rates of secondary malignancies by the augmented low dose exposure. PMID- 19775451 TI - Portuguese students' knowledge of antibiotics: a cross-sectional study of secondary school and university students in Braga. AB - BACKGROUND: Recent surveys show that the knowledge of the general public about the correct use of antibiotics is limited. This contributes to the problem of inappropriate antibiotic use, leading to a progressive loss of bacterial sensitivity to these drugs and the spreading of resistant strains of bacteria. METHODS: In this cross-sectional study, a questionnaire about antibiotic use was given to a sample of students in the 9(th) and 12(th) grades of secondary school and in the first year of university in the north of Portugal. RESULTS: 349 students returned completed questionnaires. Deficits were found in the students' knowledge of antibiotics and their correct use. Only 4% of 9(th) grade students were aware that antibiotics are used to treat bacteria only, while 14% of 12(th) grade students and 29% of first-year university students were aware of this. Fewer students were aware that antibiotics are used to treat tuberculosis. There were deficiencies in the knowledge of timing and duration of therapy. However close to 70% of these students are aware that inappropriate use of antibiotics can contribute to resistance to these drugs. CONCLUSION: This study has observed a lack of general knowledge on correct antibiotic use in Portugal, as has been found in other countries. Since this may be due to a lack of formal education on this subject, we believe that a teaching unit on infectious diseases should be included in the 9(th) and 12(th) grades, in all curricular areas, with emphasis on bacterial and viral pathogens and correct antibiotic use. In addition, education on the correct use of medications may need to begin at much earlier ages. PMID- 19775450 TI - Clinical research of Olanzapine for prevention of chemotherapy-induced nausea and vomiting. AB - BACKGROUND: This study was designed to mainly evaluate the activity and safety of olanzapine compared with 5-hydroxytryptamine 3(5-HT3) receptor antagonists for prevention of chemotherapy-induced nausea and vomiting(CINV) in patients receiving highly or moderately emetogenic chemotherapy (HEC or MEC). The second goal was to evaluate the impact of olanzapine on quality of life (QoL) of cancer patients during the period of chemotherapy. METHODS: 229 patients receiving highly or moderately emetogenic chemotherapy were randomly assigned to the test group [olanzapine(O) 10 mg p.o. plus azasetron (A) 10 mg i.v. and dexamethasone (D) 10 mg i.v. on day 1; O 10 mg once a day on days 2-5] or the control group (A 10 mg i.v. and D 10 mg i.v. on day 1; D 10 mg i.v. once a day on days 2-5). All the patients filled the observation table of CINV once a day on days 1-5, patients were instructed to fill the EORTC QLQ-C30 QoL observation table on day 0 and day 6. The primary endpoint was the complete response (CR) (without nausea and vomiting, no rescue therapy) for the acute period (24 h postchemotherapy), delayed period (days 2-5 postchemotherapy), the whole period (days 1-5 postchemotherapy). The second endpoint was QoL during chemotherapy administration, drug safety and toxicity. RESULTS: 229 patients were evaluable for efficacy. Compared with control group, complete response for acute nausea and vomiting in test group had no difference (p > 0.05), complete response for delayed nausea and vomiting in patients with highly emetogenic chemotherapy respectively improved 39.21% (69.64% versus 30.43%, p < 0.05), 22.05% (78.57% versus 56.52%, p < 0.05), complete response for delayed nausea and vomiting in patients with moderately emetogenic chemotherapy respectively improved 25.01% (83.07% versus 58.06%, p < 0.05), 13.43% (89.23% versus 75.80%, p < 0.05), complete response for the whole period of nausea and vomiting in patients with highly emetogenic chemotherapy respectively improved 41.38% (69.64% versus 28.26%, p < 0.05), 22.05% (78.57% versus 56.52%, p < 0.05), complete response for the whole period of nausea and vomiting in patients with moderately emetogenic chemotherapy respectively improved 26.62% (83.07% versus 56.45%, p < 0.05), 13.43% (89.23% versus 75.80%, p < 0.05). 214 of 299 patients were evaluable for QoL. Comparing test group with control group in QoL evolution, significant differences were seen in global health status, emotional functioning, social functioning, fatigue, nausea and vomiting, insomnia and appetite loss evolution in favour of the test group (p < 0.01). Both treatments were well tolerated. CONCLUSION: Olanzapine can improve the complete response of delayed nausea and vomiting in patients receiving the highly or moderately emetogenic chemotherapy comparing with the standard therapy of antiemesis, as well as improve the QoL of the cancer patients during chemotherapy administration. Olanzapine is a safe and efficient drug for prevention of CINV. PMID- 19775452 TI - Do genetic predictors of pain sensitivity associate with persistent widespread pain? AB - Genetic risk factors for pain sensitivity may also play a role in susceptibility to chronic pain disorders, in which subjects have low pain thresholds. The aim of this study was to determine if proposed functional single nucleotide polymorphisms (SNPs) in the GTP cyclohydrolase (GCH1) and mu opioid receptor (OPRM1) genes previously associated with pain sensitivity affect susceptibility to chronic widespread pain (CWP). Pain data was collected using body manikins via questionnaire at three time-points over a four year period from subjects aged 25 65 in the North-West of England as part of a population based cohort study, EPIFUND. CWP was defined at each time point using standard criteria. Three SNPs forming a proposed "pain-protective" haplotype in GCH1 (rs10483639, rs3783641 and rs8007267) and two SNPs in OPRM1 (rs1777971 (A118G) and rs563649) were genotyped in cases with persistent CWP (CWP present at >or=2 time-points) and controls who were pain-free at all time-points. The expectation-maximisation algorithm was used to estimate haplotype frequencies. The frequency of the "pain-protective" (CAT - C allele of rs10483639, A allele of rs3783641 and T allele of rs8007267) haplotype was compared to the frequency of the other haplotypes between cases and controls using the chi2 test. Allele frequencies and carriage of the minor allele was compared between cases and controls using chi2 tests for the OPRM1 SNPs. The frequency of the proposed GCH1 "pain-protective" haplotype (CAT) did not significantly differ between cases and controls and no significant associations were observed between the OPRM1 SNPs and CWP. In conclusion, there was no evidence of association between proposed functional SNPs, previously reported to influence pain sensitivity, in GCH1 and OPRM1 with CWP. Further evidence of null association in large independent cohorts is required to truly exclude these SNPs as genetic risk factors for CWP. PMID- 19775454 TI - Reliable enumeration of malaria parasites in thick blood films using digital image analysis. AB - BACKGROUND: Quantitation of malaria parasite density is an important component of laboratory diagnosis of malaria. Microscopy of Giemsa-stained thick blood films is the conventional method for parasite enumeration. Accurate and reproducible parasite counts are difficult to achieve, because of inherent technical limitations and human inconsistency. Inaccurate parasite density estimation may have adverse clinical and therapeutic implications for patients, and for endpoints of clinical trials of anti-malarial vaccines or drugs. Digital image analysis provides an opportunity to improve performance of parasite density quantitation. METHODS: Accurate manual parasite counts were done on 497 images of a range of thick blood films with varying densities of malaria parasites, to establish a uniformly reliable standard against which to assess the digital technique. By utilizing descriptive statistical parameters of parasite size frequency distributions, particle counting algorithms of the digital image analysis programme were semi-automatically adapted to variations in parasite size, shape and staining characteristics, to produce optimum signal/noise ratios. RESULTS: A reliable counting process was developed that requires no operator decisions that might bias the outcome. Digital counts were highly correlated with manual counts for medium to high parasite densities, and slightly less well correlated with conventional counts. At low densities (fewer than 6 parasites per analysed image) signal/noise ratios were compromised and correlation between digital and manual counts was poor. Conventional counts were consistently lower than both digital and manual counts. CONCLUSION: Using open-access software and avoiding custom programming or any special operator intervention, accurate digital counts were obtained, particularly at high parasite densities that are difficult to count conventionally. The technique is potentially useful for laboratories that routinely perform malaria parasite enumeration. The requirements of a digital microscope camera, personal computer and good quality staining of slides are potentially reasonably easy to meet. PMID- 19775453 TI - The interaction of HAb18G/CD147 with integrin alpha6beta1 and its implications for the invasion potential of human hepatoma cells. AB - BACKGROUND: HAb18G/CD147 plays pivotal roles in invasion by hepatoma cells, but the underlying mechanism remains unclear. Our previous study demonstrated that overexpression of HAb18G/CD147 promotes invasion by interacting with integrin alpha3beta1. However, it has never been investigated whether alpha3beta1 is solely responsible for this process or if other integrin family members also interact with HAb18G/CD147 in human hepatoma cells. METHODS: Human SMMC-7721 and FHCC98 cells were cultured and transfected with siRNA fragments against HAb18G/CD147. The expression levels of HAb18G/CD147 and integrin alpha6beta1 were determined by immunofluorescent double-staining and confocal imaging analysis. Co immunoprecipitation and Western blot analyses were performed to examine the native conformations of HAb18G/CD147 and integrin alpha6beta1. Invasion potential was evaluated with an invasion assay and gelatin zymography. RESULTS: We found that integrin alpha6beta1 co-localizes and interacts with HAb18G/CD147 in human hepatoma cells. The enhancing effects of HAb18G/CD147 on invasion capacity and secretion of matrix metalloproteinases (MMPs) were partially blocked by integrin alpha6beta1 antibodies (P < 0.01). Wortmannin, a specific phosphatidylinositol kinase (PI3K) inhibitor that reverses the effect of HAb18G/CD147 on the regulation of intracellular Ca2+ mobilization, significantly reduced cell invasion potential and secretion of MMPs in human hepatoma cells (P < 0.05). Importantly, no additive effect between Wortmannin and alpha6beta1 antibodies was observed, indicating that alpha6beta1 and PI3K transmit the signal in an upstream downstream relationship. CONCLUSION: These results suggest that alpha6beta1 interacts with HAb18G/CD147 to mediate tumor invasion and metastatic processes through the PI3K pathway. PMID- 19775455 TI - Measuring the costs of outreach motivational interviewing for smoking cessation and relapse prevention among low-income pregnant women. AB - BACKGROUND: Economic theory provides the philosophical foundation for valuing costs in judging medical and public health interventions. When evaluating smoking cessation interventions, accurate data on costs are essential for understanding resource consumption. Smoking cessation interventions, for which prior data on resource costs are typically not available, present special challenges. We develop a micro-costing methodology for estimating the real resource costs of outreach motivational interviewing (MI) for smoking cessation and relapse prevention among low-income pregnant women and report results from a randomized controlled trial (RCT) employing the methodology. Methodological standards in cost analysis are necessary for comparison and uniformity in analysis across interventions. Estimating the costs of outreach programs is critical for understanding the economics of reaching underserved and hard-to-reach populations. METHODS: Randomized controlled trial (1997-2000) collecting primary cost data for intervention. A sample of 302 low-income pregnant women was recruited from multiple obstetrical sites in the Boston metropolitan area. MI delivered by outreach health nurses vs. usual care (UC), with economic costs as the main outcome measures. RESULTS: The total cost of the MI intervention for 156 participants was $48,672 or $312 per participant. The total cost of $311.8 per participant for the MI intervention compared with a cost of $4.82 per participant for usual care, a difference of $307 ([CI], $289.2 to $322.8). The total fixed costs of the MI were $3,930 and the total variable costs of the MI were $44,710. The total expected program costs for delivering MI to 500 participants would be 147,430, assuming no economies of scale in program delivery. The main cost components of outreach MI were intervention delivery, travel time, scheduling, and training. CONCLUSION: Grounded in economic theory, this methodology systematically identifies and measures resource utilization, using a process tracking system and calculates both component-specific and total costs of outreach MI. The methodology could help improve collection of accurate data on costs and estimates of the real resource costs of interventions alongside clinical trials and improve the validity and reliability of estimates of resource costs for interventions targeted at underserved and hard-to-reach populations. PMID- 19775456 TI - Anti-inflammatory properties of Salograviolide A purified from Lebanese plant Centaurea ainetensis. AB - BACKGROUND: Anti-inflammatory activities of medicinal plants have largely been attributed to their content of sesquiterpene lactones (SLs). SLs are predominantly found in the sunflower family Asteraceae and have been isolated from many plants of this family, particularly Centaurea. The anti-inflammatory activities of extract of Centaurea ainetensis, a Lebanese endemic plant, and the isolated active molecule were assessed for their potential ant-inflammatory activities. METHODS: Plant extract from Centaurea ainetensis, and the isolated active ingredient Salograviolide A (SA), a sesquiterpene lactones guaianolide, were used for the study. Western blotting and electrophoretic mobility shift assays were used to test the effects of the plant extract and SA on interleukin-1 (IL-1) induced increase in cyclooxygenase-2 (COX-2) levels and in nuclear factor kappaB (NF-kappaB) translocation in an intestinal epithelial cell (IEC) of inflammation. Their effects on inflammation score and cytokine levels were also studied in an iodoacetoamide-induced rat model of inflammation. RESULTS: Plant extract and SA were shown to reverse the effects observed by IL-1 on COX-2 levels and NF-kappaB translocation in IEC. SA decreased the level of inflammatory cytokines and the level of inflammation in the animal model. CONCLUSION: These findings suggest that SA may be useful in the development of natural therapies for inflammatory diseases. PMID- 19775457 TI - Genetic variation in the pleiotropic association between physical activity and body weight in mice. AB - BACKGROUND: A sedentary lifestyle is often assumed to lead to increases in body weight and potentially obesity and related diseases but in fact little is known about the genetic association between physical activity and body weight. We tested for such an association between body weight and the distance, duration, and speed voluntarily run by 310 mice from the F2 generation produced from an intercross of two inbred lines that differed dramatically in their physical activity levels. METHODS: We used a conventional interval mapping approach with SNP markers to search for QTLs that affected both body weight and activity traits. We also conducted a genome scan to search for relationship QTLs (relQTLs), or chromosomal regions that affected an activity trait variably depending on the phenotypic value of body weight. RESULTS: We uncovered seven quantitative trait loci (QTLs) affecting body weight, but only one co-localized with another QTL previously found for activity traits. We discovered 19 relQTLs that provided evidence for a genetic (pleiotropic) association of physical activity and body weight. The three genotypes at each of these loci typically exhibited a combination of negative, zero, and positive regressions of the activity traits on body weight, the net effect of which was to produce overall independence of body weight from physical activity. We also demonstrated that the relQTLs produced these varying associations through differential epistatic interactions with a number of other epistatic QTLs throughout the genome. CONCLUSION: It was concluded that individuals with specific combinations of genotypes at the relQTLs and epiQTLs might account for some of the variation typically seen in plots of the association of physical activity with body weight. PMID- 19775459 TI - Seroprevalence of hepatitis B virus and hepatitis C virus among blood donors in Nyala, South Dar Fur, Sudan. AB - The objective of this study was to determine the seroprevalence of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections and the possible risk factors among blood donors in Nyala, South Dar Fur State of western Sudan, which has never been studied before. A total of 400 male blood donors were tested for the detection of HBsAg and anti-HCV antibodies, (6.25%) were found reactive for HBsAg and (0.65%) were reactive for anti-HCV antibodies. The highest seroprevalence (30.8%) was found in those between 19-24 and 37-42 years for HBsAg, whereas it was (50%) in those between 31-36 years for anti-HCV antibodies. Unprotected sexual activities (20%) was the most apparent predisposing risk factor for both HBV and HCV seroreactors, followed by razor sharing (13.3%), parenteral drug injections (10%), history of migration to Egypt and alcoholism (6.6%) for each, tattooing and surgical procedures (3.3%) for each and (36.6%) were not aware for their condition. Serum alanine aminotansferase (ALT) was elevated in (30.7%) of HBV seroreactors and in (50%) of HCV seroreactors. Serum albumin was reduced in (23.1%) HBV and in (50%) HCV seroreactors. The study concluded that the seroprevalence of HBV and HCV was in an intermediate and low rates respectively and unprotected sexual activities was the major risk factor for infection in the population studied. PMID- 19775458 TI - Thrombelastography and tromboelastometry in assessing coagulopathy in trauma. AB - Death due to trauma is the leading cause of lost life years worldwide, with haemorrhage being responsible for 30-40% of trauma mortality and accounting for almost 50% of the deaths the initial 24 h. On admission, 25-35% of trauma patients present with coagulopathy, which is associated with a several-fold increase in morbidity and mortality. The recent introduction of haemostatic control resuscitation along with emerging understanding of acute post-traumatic coagulability, are important means to improve therapy and outcome in exsanguinating trauma patients. This change in therapy has emphasized the urgent need for adequate haemostatic assays to monitor traumatic coagulopathy and guide therapy. Based on the cell-based model of haemostasis, there is emerging consensus that plasma-based routine coagulation tests (RCoT), like prothrombin time (PT) and activated partial thromboplastin time (APTT), are inappropriate for monitoring coagulopathy and guide therapy in trauma. The necessity to analyze whole blood to accurately identify relevant coagulopathies, has led to a revival of the interest in viscoelastic haemostatic assays (VHA) such as Thromboelastography (TEG) and Rotation Thromboelastometry (ROTEM). Clinical studies including about 5000 surgical and/or trauma patients have reported on the benefit of using the VHA as compared to plasma-based assays, to identify coagulopathy and guide therapy. This article reviews the basic principles of VHA, the correlation between the VHA whole blood clot formation in accordance with the cell-based model of haemostasis, the current use of VHA-guided therapy in trauma and massive transfusion (haemostatic control resuscitation), limitations of VHA and future perspectives of this assay in trauma. PMID- 19775460 TI - SSWAP: A Simple Semantic Web Architecture and Protocol for semantic web services. AB - BACKGROUND: SSWAP (Simple Semantic Web Architecture and Protocol; pronounced "swap") is an architecture, protocol, and platform for using reasoning to semantically integrate heterogeneous disparate data and services on the web. SSWAP was developed as a hybrid semantic web services technology to overcome limitations found in both pure web service technologies and pure semantic web technologies. RESULTS: There are currently over 2400 resources published in SSWAP. Approximately two dozen are custom-written services for QTL (Quantitative Trait Loci) and mapping data for legumes and grasses (grains). The remaining are wrappers to Nucleic Acids Research Database and Web Server entries. As an architecture, SSWAP establishes how clients (users of data, services, and ontologies), providers (suppliers of data, services, and ontologies), and discovery servers (semantic search engines) interact to allow for the description, querying, discovery, invocation, and response of semantic web services. As a protocol, SSWAP provides the vocabulary and semantics to allow clients, providers, and discovery servers to engage in semantic web services. The protocol is based on the W3C-sanctioned first-order description logic language OWL DL. As an open source platform, a discovery server running at http://sswap.info (as in to "swap info") uses the description logic reasoner Pellet to integrate semantic resources. The platform hosts an interactive guide to the protocol at http://sswap.info/protocol.jsp, developer tools at http://sswap.info/developer.jsp, and a portal to third-party ontologies at http://sswapmeet.sswap.info (a "swap meet"). CONCLUSION: SSWAP addresses the three basic requirements of a semantic web services architecture (i.e., a common syntax, shared semantic, and semantic discovery) while addressing three technology limitations common in distributed service systems: i.e., i) the fatal mutability of traditional interfaces, ii) the rigidity and fragility of static subsumption hierarchies, and iii) the confounding of content, structure, and presentation. SSWAP is novel by establishing the concept of a canonical yet mutable OWL DL graph that allows data and service providers to describe their resources, to allow discovery servers to offer semantically rich search engines, to allow clients to discover and invoke those resources, and to allow providers to respond with semantically tagged data. SSWAP allows for a mix-and-match of terms from both new and legacy third-party ontologies in these graphs. PMID- 19775461 TI - Between-day reliability of electromechanical delay of selected neck muscles during performance of maximal isometric efforts. AB - BACKGROUND: The purpose of this study was to assess the between-day reliability of the electromechanical delay (EMD) of selected neck muscles during the performance of maximal isometric contractions in five different directions. METHODS: Twenty-one physically active males participated in two testing sessions separated by seven to eight days. Using a custom-made fixed frame dynamometer, cervical force and surface electromyography (EMG) were recorded bilaterally from the splenius capitis, upper trapezius and sternocleidomastoid muscles during the performance of efforts in extension, flexion, left and right lateral bending, and protraction. The EMD was extracted using the Teager-Kaiser Energy Operator. Reliability indices calculated for each muscle in each testing direction were: the difference in scores between the two testing sessions and corresponding 95% confidence intervals, the standard error of measurement (SEM) and intra-class correlation coefficients (ICC). RESULTS: EMD values showed no evidence of systematic difference between the two testing sessions across all muscles and testing directions. The SEM for extension, flexion and lateral bending efforts ranged between 2.5 ms to 4.8 ms, indicating a good level of measurement precision. For protraction, SEM values were higher and considered to be imprecise for research and clinical purposes. ICC values for all muscles across all testing directions ranged from 0.23 to 0.79. CONCLUSION: EMD of selected neck muscles can be measured with sufficient precision for the assessment of neck muscle function in an athletic population in the majority of directions tested. PMID- 19775462 TI - Basic properties and information theory of Audic-Claverie statistic for analyzing cDNA arrays. AB - BACKGROUND: The Audic-Claverie method 1 has been and still continues to be a popular approach for detection of differentially expressed genes in the SAGE framework. The method is based on the assumption that under the null hypothesis tag counts of the same gene in two libraries come from the same but unknown Poisson distribution. The problem is that each SAGE library represents only a single measurement. We ask: Given that the tag count samples from SAGE libraries are extremely limited, how useful actually is the Audic-Claverie methodology? We rigorously analyze the A-C statistic that forms a backbone of the methodology and represents our knowledge of the underlying tag generating process based on one observation. RESULTS: We show that the A-C statistic and the underlying Poisson distribution of the tag counts share the same mode structure. Moreover, the K-L divergence from the true unknown Poisson distribution to the A-C statistic is minimized when the A-C statistic is conditioned on the mode of the Poisson distribution. Most importantly, the expectation of this K-L divergence never exceeds 1/2 bit. CONCLUSION: A rigorous underpinning of the Audic-Claverie methodology has been missing. Our results constitute a rigorous argument supporting the use of Audic-Claverie method even though the SAGE libraries represent very sparse samples. PMID- 19775463 TI - Evidence for calcium-mediated perception of plant symbiotic signals in aequorin expressing Mesorhizobium loti. AB - BACKGROUND: During the interaction between rhizobia and leguminous plants the two partners engage in a molecular conversation that leads to reciprocal recognition and ensures the beginning of a successful symbiotic integration. In host plants, intracellular Ca(2+) changes are an integral part of the signalling mechanism. In rhizobia it is not yet known whether Ca(2+) can act as a transducer of symbiotic signals. RESULTS: A plasmid encoding the bioluminescent Ca(2+) probe aequorin was introduced into Mesorhizobium loti USDA 3147(T) strain to investigate whether a Ca(2+) response is activated in rhizobia upon perception of plant root exudates. We find that M. loti cells respond to environmental and symbiotic cues through transient elevations in intracellular free Ca(2+) concentration. Only root exudates from the homologous host Lotus japonicus induce Ca(2+) signalling and downstream activation of nodulation genes. The extracellular Ca(2+) chelator EGTA inhibits both transient intracellular Ca(2+) increase and inducible nod gene expression, while not affecting the expression of other genes, either constitutively expressed or inducible. CONCLUSION: These findings indicate a newly described early event in the molecular dialogue between plants and rhizobia and highlight the use of aequorin-expressing bacterial strains as a promising novel approach for research in legume symbiosis. PMID- 19775464 TI - A long-term follow-up of a girl with dilated cardiomyopathy after mitral valve replacement and septal anterior ventricular exclusion. AB - We treated a 10 year 11 month old girl with severe mitral valve regurgitation, stenosis and dilated cardiomyopathy, presented with New York Heart Association (NYHA) functional classification IV. She acutely developed cardiogenic shock with a dyskinetic anterior-septal left ventricle and entered a shock state during our consultation about heart transplantation. Septal-anterior ventricular exclusion and mitral valve replacement were performed emergently. She successfully recovered from cardiogenic shock. Left ventricular end-diastolic diameter and fractional shortening improved from 71.5 mm (188.0% of normal) to 62.5 mm (144.2% of normal) and 7.6% to 18.3% respectively. Furthermore, her serum BNP decreased from 2217.5 pg/ml to 112.0 pg/ml. Her cardiac function has remained stable for 7 years since the procedures were performed. PMID- 19775466 TI - Salvage therapy of pretreated advanced breast cancer with bevacizumab and paclitaxel every two weeks: a retrospective case review study. AB - BACKGROUND: Targeting angiogenesis is nowadays one of the most promising approaches for breast cancer. Bevacizumab (BEV), a VEGF-trap monoclonal antibody, was recently approved in combination with paclitaxel (PAC) for the first line treatment of advanced breast cancer (ABC). The activity of this combination in pretreated patients is not known. METHODS: Patients with pretreated ABC and progressive disease received BEV 10 mg/kg with PAC 135 mg/m(2) every two weeks for six months and then maintenance with BEV 15 mg/kg every three weeks until progression. This regimen was chosen for better patient convenience, while maintaining the same dose intensity for both drugs. RESULTS: 42 patients were reviewed retrospectively (41 f, 1 m, mean age 57 years). Overall response rate was 35.7%. Stable disease was observed in 45.2% of patients, whereas 14.3% of patients progressed. The median overall survival was greater than 20 months, with a one year rate of 83.4%. The median progression free survival was 12.1 months, with a one year rate of 51.8%. Toxicity was in general acceptable. CONCLUSION: This biweekly BEV/PAC combination seems to be active with acceptable toxicity in pretreated ABC with an advantage over the weekly regimen regarding quality of life and preservation of resources. PMID- 19775465 TI - The Irish DAFNE study protocol: a cluster randomised trial of group versus individual follow-up after structured education for type 1 diabetes. AB - BACKGROUND: Structured education programmes for individuals with Type 1 diabetes have become a recognised means of delivering the knowledge and skills necessary for optimal self-management of the condition. The Dose Adjustment for Normal Eating (DAFNE) programme has been shown to improve biomedical (HbA(1c) and rates of severe hypoglycaemia) and psychosocial outcomes for up to 12 months following course delivery. The optimal way to support DAFNE graduates and maintain the benefits of the programme has not been established. We aimed to compare 2 different methods of follow-up of DAFNE graduates in a pragmatic clinical trial delivered in busy diabetes clinics on the island of Ireland. METHODS: Six participating centres were cluster randomised to deliver either group follow-up or a return to traditional one-to-one clinic visits. In the intervention arm group follow-up was delivered at 6 and 12 months post DAFNE training according to a curriculum developed for the study. In the control arm patients were seen individually in diabetes clinics as part of routine care. Study outcomes included HbA(1c) levels, self-reported rates of severe hypoglycaemia, body weight and measures of diabetes wellbeing and quality of life. These were measured at 6, 12 and 18 months after recruitment. Generalisability (external validity) was maximised by recruiting study participants from existing DAFNE waiting lists in each centre, by using broad inclusion criteria (including HbA(1c) values less than 13 percent with no lower limit) and by using existing clinic staff to deliver the training and follow-up. Internal validity and treatment fidelity were maximised by quality assuring the training of all DAFNE educators, by external peer review of the group follow-up sessions and by striving for full attendance at follow-up visits. Assays of HbA(1c) were undertaken in a central laboratory. DISCUSSION: This pragmatic clinical trial evaluating group follow-up after a structured education programme has been designed to have broad generalisability. The results should inform how best to manage the well educated patient with Type 1 diabetes in the real world of clinical practice TRIAL REGISTRATION: Current Controlled Trials ISRCTN79759174. PMID- 19775467 TI - Education and support needs during recovery in acute respiratory distress syndrome survivors. AB - INTRODUCTION: There is a limited understanding of the long-term needs of survivors of the acute respiratory distress syndrome (ARDS) as they recover from their episode of critical illness. The Timing it Right (TIR) framework, which emphasizes ARDS survivors' journey from the ICU through to community re integration, may provide a valuable construct to explore the support needs of ARDS survivors during their recovery. METHODS: Twenty-five ARDS survivors participated in qualitative interviews examining their needs for educational, emotional and tangible support for each phase of the TIR framework. Transcripts were analyzed using framework methodology. RESULTS: ARDS survivors' support needs varied across the illness trajectory. During the ICU stay, survivors were generally too ill to require information. The transfer to the general ward was characterized by anxiety surrounding decreased surveillance and concern for future health and treatment. Information needs focused on the events surrounding the acute illness, while physical and emotional needs revolved around physical therapy and psychological support for depression and anxiety. As patients were preparing for hospital discharge, they expressed a desire for specific information about the recovery and rehabilitation process following an episode of ARDS (e.g., outpatient physiotherapy, long-term sequela of the illness). Once in the community, survivors wanted guidance on home care, secondary prevention, and ARDS support groups. CONCLUSIONS: Our findings support the need for future educational and support interventions to meet the changing needs of ARDS survivors during their recovery. PMID- 19775469 TI - Study protocol: the development of a randomised controlled trial testing a postcard intervention designed to reduce suicide risk among young help-seekers. AB - BACKGROUND: Suicidal behaviour and deliberate self harm are common among adolescents. Limited evidence exists regarding interventions that can reduce risk; however research indicates that maintaining contact either via letter or postcard with at-risk adults following discharge from services can reduce risk. The aim of the study is to test a postcard intervention among people aged 15-24 who presented to mental health services but are not accepted, yet are at risk of suicide. METHODS/DESIGN: The study is a 3-year randomised controlled trial conducted at Orygen Youth Health Research Centre in Melbourne Australia. Participants are young help-seekers aged 15-24 who are at risk of suicide. Participants will be recruited over a 12 month period. The intervention comprises a regular postcard to be sent monthly for 12 months. The postcard enquires after their well being and includes information regarding individual sources of help and evidence-based self help strategies. Participants are assessed at baseline, 12 and 18 months. DISCUSSION: This paper describes the development of a study which aims to reduce suicide risk in a sample of young help-seekers. If effective, this intervention could have significant clinical and research implications for a population who can be hard to treat and difficult to research. TRIAL REGISTRATION: The study was registered with the Australian Clinical Trials Registry; number: ACTRN012606000274572. PMID- 19775470 TI - Prevalence of HIV-associated ophthalmic disease among patients enrolling for antiretroviral treatment in India: a cross-sectional study. AB - BACKGROUND: The ocular manifestations of HIV may lead to visual impairment or blindness. In India, patients typically initiate antiretroviral treatment (ART) with low CD4 cell counts when the risk of ocular complications may be high. The objective of this study was to determine the prevalence and types of HIV associated ocular conditions in patients referred for ART in India. METHODS: This cross-sectional study was undertaken at a large public sector ART centre in Mumbai, India. Data collection including a standardised symptom screen, and an ophthalmic examination were performed on all consecutive patients satisfying the criteria for enrollment into the ART clinic irrespective of the presence or absence of ophthalmic/visual symptoms. RESULTS: Enrolled patients (n = 149) had a median CD4 cell count of 180 cell/microL (inter-quartile range [IQR], 106-253 cells/microL). The prevalence of HIV-associated ocular disease was 17.5% (95% CI, 11.2-23.6%) in all participants and 23.8% (95% CI: 14.5-33.1) in those with CD4 cell counts <200 cells/microL (n = 84). Only 7.7% of patients with HIV-associated ocular disease reported any eye symptoms in the standardised symptom screen. Objective visual impairment was detected in 20% of those with HIV-associated ocular disease compared to 6% in those without ocular manifestations (p = 0.02). Vitreoretinal disease was the most common manifestation, of which cytomegalovirus retinitis (CMVR) was the most frequent retinal infection (overall prevalence 8.7%, 95% CI: 4.1-13.3%). In a multivariable analysis, HIV-associated ocular disease was independently associated with a CD4 count <100 cells/microL (odds ratio [OR], 6.3, 95% CI: 1.5-25.9) and WHO clinical stages 3 and 4 (OR 9.4, 95% CI: 2.4-37.2). However, symptoms were not independently predictive of ocular disease. Sensitivity of ocular symptom screening was 7.7%, with a positive predictive value of 18% in this population. CONCLUSION: Over a fifth of unselected patients who are eligible for ART in this setting have HIV-related ocular disease of which CMVR is the most common form. Such patients may be at risk of developing ocular immune reconstitution phenomena during ART. Screening for ocular symptoms is not a reliable method to identify those with ocular morbidity and this highlights the need for routine ophthalmic screening prior to commencement of ART. PMID- 19775468 TI - Regulation of peripheral blood flow in complex regional pain syndrome: clinical implication for symptomatic relief and pain management. AB - BACKGROUND: During the chronic stage of Complex Regional Pain Syndrome (CRPS), impaired microcirculation is related to increased vasoconstriction, tissue hypoxia, and metabolic tissue acidosis in the affected limb. Several mechanisms may be responsible for the ischemia and pain in chronic cold CPRS. DISCUSSION: The diminished blood flow may be caused by either sympathetic dysfunction, hypersensitivity to circulating catecholamines, or endothelial dysfunction. The pain may be of neuropathic, inflammatory, nociceptive, or functional nature, or of mixed origin. SUMMARY: The origin of the pain should be the basis of the symptomatic therapy. Since the difference in temperature between both hands fluctuates over time in cold CRPS, when in doubt, the clinician should prioritize the patient's report of a persistent cold extremity over clinical tests that show no difference. Future research should focus on developing easily applied methods for clinical use to differentiate between central and peripheral blood flow regulation disorders in individual patients. PMID- 19775471 TI - Analysis of TACI mutations in CVID & RESPI patients who have inherited HLA B*44 or HLA*B8. AB - BACKGROUND: Recent reports have suggested that Common Variable Immunodeficieny (CVID) can present as an autosomal dominant trait dependent on the inheritance of a set of uncommon mutations/alleles of TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) involving exons 3 or 4. Penetrance, however, appears to be incomplete. Among our clinic population, the greatest genetic linkage for CVID is to the major histocompatibility complex (MHC) on chromosome 6. The majority of our patients have inherited HLA *DQ2, *DR7, *DR3(17), *B8, and/or *B44. Of these, HLA*B44 was present in almost half of the patients and was thus the most common susceptibility allele. HLA *B44 was also found to be over-represented among patients who presented to our clinic with adult-onset recurrent sinopulmonary infections (RESPI) and normal serum immunoglobulin levels, a cohort that included first and second degree relatives of patients with CVID. One of the two original reports of the association between TACI and CVID also reported Human Leukocyte Antigen (HLA) haplotypes. Of 13 affected subjects, nine had inherited HLA *B8 and six had inherited HLA B44. This raised the possibility that TACI mutations might synergize with MHC class I alleles to enhance susceptibility to humoral immune deficiency. METHODS: We identified 63 CVID patients irrespective of HLA status and 13 RESPI patients who had inherited HLA*B44. To evaluate for mutations in the gene for TACI, we PCR amplified and sequenced TACI exons 3 and 4 from these patients. RESULTS: Of the 76 patients, eleven proved heterozygous for a previously reported, silent T->G polymorphism [rs35062843] at proline 97 in exon 3. However, none of the 13 RESPI patients and only one of the 63 CVID patients inherited a TACI allele previously associated with CVID. This patient was heterozygous for the TACI A181E allele (exon 4). She did not carry *DQ2, *DR7, *DR3(17), *B8, or *B44. CONCLUSION: These findings suggest that TACI mutations are unlikely to play a critical role in creating susceptibility to CVID among patients with previously recognized MHC class I and class II susceptibility alleles. Supported by NIH/USIDNET N01 AI30070, NIH R21 AI079741 and NIH M01-RR00032. PMID- 19775472 TI - Comparative SNP diversity among four Eucalyptus species for genes from secondary metabolite biosynthetic pathways. AB - BACKGROUND: There is little information about the DNA sequence variation within and between closely related plant species. The combination of re-sequencing technologies, large-scale DNA pools and availability of reference gene sequences allowed the extensive characterisation of single nucleotide polymorphisms (SNPs) in genes of four biosynthetic pathways leading to the formation of ecologically relevant secondary metabolites in Eucalyptus. With this approach the occurrence and patterns of SNP variation for a set of genes can be compared across different species from the same genus. RESULTS: In a single GS-FLX run, we sequenced over 103 Mbp and assembled them to approximately 50 kbp of reference sequences. An average sequencing depth of 315 reads per nucleotide site was achieved for all four eucalypt species, Eucalyptus globulus, E. nitens, E. camaldulensis and E. loxophleba. We sequenced 23 genes from 1,764 individuals and discovered 8,631 SNPs across the species, with about 1.5 times as many SNPs per kbp in the introns compared to exons. The exons of the two closely related species (E. globulus and E. nitens) had similar numbers of SNPs at synonymous and non-synonymous sites. These species also had similar levels of SNP diversity, whereas E. camaldulensis and E. loxophleba had much higher SNP diversity. Neither the pathway nor the position in the pathway influenced gene diversity. The four species share between 20 and 43% of the SNPs in these genes. CONCLUSION: By using conservative statistical detection methods, we were confident about the validity of each SNP. With numerous individuals sampled over the geographical range of each species, we discovered one SNP in every 33 bp for E. nitens and one in every 31 bp in E. globulus. In contrast, the more distantly related species contained more SNPs: one in every 16 bp for E. camaldulensis and one in 17 bp for E. loxophleba, which is, to the best of our knowledge, the highest frequency of SNPs described in woody plant species. PMID- 19775473 TI - The control of hookworm infection in China. AB - BACKGROUND: Hookworm is still one of the three main soil-transmitted helminths prevalent in China, and 39 million cases infected with hookworm were estimated in China in 2006. RESULTS: The main approach to the control of hookworm infections in China consists of large-scale deworming, rebuilding sanitation systems in rural areas and health education. The availability of low-cost, safe and single dose albendazole make large-scale deworming programs possible in China. Currently, sanitary latrines with three-cells are recommended by government for the control of soil-transmitted helminths, since 35% of helminth infections and 83% of worm eggs could be reduced after using this kind of sanitary latrine. In addition, economic prosperity contributes greatly to the reduction of hookworm prevalence, but the inequity of economic and social development among different regions of China provides a scenario that the worst threat of hookworm infection is located in the poorest areas of southern and central China. Therefore, it is necessary to put more investments into prophylaxis and treatment of hookworm in these poor regions. CONCLUSION: Although the prevalence of hookworm infection has fallen significantly in the last 15 years in China, the current strategy for controlling hookworm infections still needs to be strengthened along with the three-pronged approach, e.g. distributing anthelmintic drugs in schools and undertaking large-scale of hookworm deworming, improving water supplies and sanitation, and proper health education. PMID- 19775475 TI - Australian Aboriginal Birth Cohort study: follow-up processes at 20 years. AB - BACKGROUND: In 1987, a prospective study of an Australian Aboriginal Birth Cohort was established focusing on the relationships of fetal and childhood growth with the risk of chronic adult disease. However as the study is being conducted in a highly marginalized population it is also an important resource for cross sectional descriptive and analytical studies. The aim of this paper is to describe the processes of the third follow up which was conducted 20 years after recruitment at birth. METHODS: Progressive steps in a multiphase protocol were used for tracing, with modifications for the expected rural or urban location of the participants. RESULTS: Of the original 686 cohort participants recruited 68 were untraced and 27 were known to have died. Of the 591 available for examination 122 were not examined; 11 of these were refusals and the remainder were not seen for logistical reasons relating to inclement weather, mobility of participants and single participants living in very remote locations. CONCLUSION: The high retention rate of this follow-up 20 years after birth recruitment is a testament to the development of successful multiphase protocols aimed at overcoming the challenges of tracing a cohort over a widespread remote area and also to the perseverance of the study personnel. We also interpret the high retention rate as a reflection of the good will of the wider Aboriginal community towards this study and that researchers interactions with the community were positive. The continued follow-up of this life course study now seems feasible and there are plans to trace and reexamine the cohort at age 25 years. PMID- 19775474 TI - A novel variant of ER-alpha, ER-alpha36 mediates testosterone-stimulated ERK and Akt activation in endometrial cancer Hec1A cells. AB - BACKGROUND: Endometrial cancer is one of the most common gynecologic malignancies and its incidence has recently increased. Experimental and epidemiological data support that testosterone plays an important role in the pathogenesis of endometrial cancer, but the underlying mechanism has not been fully understood. Recently, we identified and cloned a variant of estrogen receptor (ER) alpha, ER alpha36. The aim of the present study was to investigate the role of ER-alpha36 in testosterone carcinogenesis. METHODS: The cellular localization of ER-alpha36 was determined by immunofluorescence. Hec1A endometrial cancer cells (Hec1A/V) and Hec1A cells with siRNA knockdown of ER-alpha36 (Hec1A/RNAi) were treated with testosterone, ERK and Akt phosphorylation was assessed by Western blot analysis. Furthermore, the kinase inhibitors U0126 and LY294002 and the aromatase inhibitor letrozole were used to elucidate the pathway underlying testosterone-induced activities. RESULTS: Immunofluorescence shows that ER-alpha36 was localized on the plasma membrane of the both ER-alpha- and androgen receptor-negative endometrial cancer Hec1A cells. Testosterone induced ERK and Akt phosphorylation, which could be abrogated by ER-alpha 36 shRNA knockdown or the kinase inhibitors, U0126 and LY294002, and the aromatase inhibitor letrozole. CONCLUSION: Testosterone induces ERK and Akt phosphorylation via the membrane-initiated signaling pathways mediated by ER-alpha36, suggesting a possible involvement of ER-alpha 36 in testosterone carcinogenesis. PMID- 19775476 TI - Long-term care cost drivers and expenditure projection to 2036 in Hong Kong. AB - BACKGROUND: Hong Kong's rapidly ageing population, characterised by one of the longest life expectancies and the lowest fertility rate in the world, is likely to drive long-term care (LTC) expenditure higher. This study aims to identify key cost drivers and derive quantitative estimates of Hong Kong's LTC expenditure to 2036. METHODS: We parameterised a macro actuarial simulation with data from official demographic projections, Thematic Household Survey 2004, Hong Kong's Domestic Health Accounts and other routine data from relevant government departments, Hospital Authority and other LTC service providers. Base case results were tested against a wide range of sensitivity assumptions. RESULTS: Total projected LTC expenditure as a proportion of GDP reflected secular trends in the elderly dependency ratio, showing a shallow dip between 2004 and 2011, but thereafter yielding a monotonic rise to reach 3.0% by 2036. Demographic changes would have a larger impact than changes in unit costs on overall spending. Different sensitivity scenarios resulted in a wide range of spending estimates from 2.2% to 4.9% of GDP. The availability of informal care and the setting of formal care as well as associated unit costs were important drivers of expenditure. CONCLUSION: The "demographic window" between the present and 2011 is critical in developing policies to cope with the anticipated burgeoning LTC burden, in concert with the related issues of health care financing and retirement planning. PMID- 19775477 TI - Upper limbs dysmetria caused by cervical spinal cord injury: a case report. AB - BACKGROUND: Upper limbs dysmetria caused by spinal cord injury is very rare. We will discuss the associated mechanism in our articles. CASE PRESENTATION: A 51 year-old male had sudden onset of weakness, dysmetria over bilateral upper limbs and ataxia after he fell accidentally. Brain magnetic resonance imaging (MRI) revealed no specific findings. C-spine MRI revealed C1 myelopathy and C4-6 spinal cord compression by bulged disc. The symptoms subsided after surgical intervention. CONCLUSION: Sudden onset of upper limbs dysmetria is a sign of dysfunction in cerebellum and its associated pathway. However, lesion in spinal cord can also cause cerebellar signs such as dysmetria. PMID- 19775478 TI - Right-sided "trapdoor" incision provides necessary exposure of complex cervicothoracic vascular injury: a case report. AB - Combined cervicothoracical vascular traumas are very uncommon, mostly resulting from penetrating injuries. These injuries are accompanied with very high morbidity and mortality rates. In this manuscript we present a case of hemodinamycally unstable trauma patient whose major injury was penetrating trauma of both cervical and mediastinal major vessels. The standard surgical approach of median sternotomy and neck incision was insufficient, and the patient's instability forced the authors to improvise previously not described right-sided trap-door thoracomy. Incorporation of such incision in the surgical arsenal may be very effective in selective cases. PMID- 19775479 TI - The effect of on-line position correction on the dose distribution in focal radiotherapy for bladder cancer. AB - BACKGROUND: The purpose of this study was to determine the dosimetric effect of on-line position correction for bladder tumor irradiation and to find methods to predict and handle this effect. METHODS: For 25 patients with unifocal bladder cancer intensity modulated radiotherapy (IMRT) with 5 beams was planned. The requirement for each plan was that 99% of the target volume received 95% of the prescribed dose. Tumor displacements from -2.0 cm to 2.0 cm in each dimension were simulated, using 0.5 cm increments, resulting in 729 simulations per patient. We assumed that on-line correction for the tumor was applied perfectly. We determined the correlation between the change in D99% and the change in path length, which is defined here as the distance from the skin to the isocenter for each beam. In addition the margin needed to avoid underdosage was determined and the probability that an underdosage occurs in a real treatment was calculated. RESULTS: Adjustments for tumor displacement with perfect on-line position correction resulted in an altered dose distribution. The altered fraction dose to the target varied from 91.9% to 100.4% of the prescribed dose. The mean D99% (+/- SD) was 95.8% +/- 1.0%. There was a modest linear correlation between the difference in D99% and the change in path length of the beams after correction (R2 = 0.590). The median probability that a systematic underdosage occurs in a real treatment was 0.23% (range: 0-24.5%). A margin of 2 mm reduced that probability to < 0.001% in all patients. CONCLUSION: On-line position correction does result in an altered target coverage, due to changes in average path length after position correction. An extra margin can be added to prevent underdosage. PMID- 19775480 TI - Topoisomerase I but not thymidylate synthase is associated with improved outcome in patients with resected colorectal cancer treated with irinotecan containing adjuvant chemotherapy. AB - BACKGROUND: Thymidylate synthase (TS) and Topoisomerase I (Topo I) are significant biomarkers in colorectal cancer (CRC). We aimed to study the expression of TS and Topo I in patients with resected CRC who received adjuvant chemotherapy and correlated it with clinical outcome. METHODS: All patients diagnosed with CRC between 1989 and 2007 and treated with adjuvant chemotherapy within Hellenic Cooperative Oncology Group's (HeCOG) protocols, were identified. Archival paraffin-embedded tumor tissues were used for immunohistochemical detection of TS and Topo I. Immunohistochemistry was performed on tissue microarray slides using monoclonal antibodies against TS and Topo I. The results were correlated with survival (OS) and disease free survival (DFS). RESULTS: A cohort of 498 patients with a median age of 61 years and Dukes' stage B (49%) and C (51%) fulfilled the criteria of the study. All patients received adjuvant 5-FU based chemotherapy, 38% irinotecan-containing. Positive TS and Topo I expression was found in 43% and 48% of cases, respectively. Five-year OS was 74% and DFS was 68%. In univariate analysis no association of TS and Topo I expression with OS and DFS was identified. In multivariate analysis however, Topo I expression was associated with a reduced risk of death (HR = 0.61, 95% CI 0.42-0.88, p = 0.009). In the irinotecan-treated subgroup, those patients who expressed Topo I had a better OS (HR = 0.47, 95% CI 0.23-0.94, p = 0.033). CONCLUSION: Patients with resected CRC expressing Topo I seem to benefit from irinotecan-containing adjuvant chemotherapy. However randomised prospective trials are needed to confirm these results. PMID- 19775481 TI - Explanation and relations. How do general practitioners deal with patients with persistent medically unexplained symptoms: a focus group study. AB - BACKGROUND: Persistent presentation of medically unexplained symptoms (MUS) is troublesome for general practitioners (GPs) and causes pressure on the doctor patient relationship. As a consequence, GPs face the problem of establishing an ongoing, preferably effective relationship with these patients. This study aims at exploring GPs' perceptions about explaining MUS to patients and about how relationships with these patients evolve over time in daily practice. METHODS: A qualitative approach, interviewing a purposive sample of twenty-two Dutch GPs within five focus groups. Data were analyzed according to the principles of constant comparative analysis. RESULTS: GPs recognise the importance of an adequate explanation of the diagnosis of MUS but often feel incapable of being able to explain it clearly to their patients. GPs therefore indicate that they try to reassure patients in non-specific ways, for example by telling patients that there is no disease, by using metaphors and by normalizing the symptoms. When patients keep returning with MUS, GPs report the importance of maintaining the doctor-patient relationship. GPs describe three different models to do this; mutual alliance characterized by ritual care (e.g. regular physical examination, regular doctor visits) with approval of the patient and the doctor, ambivalent alliance characterized by ritual care without approval of the doctor and non alliance characterized by cutting off all reasons for encounter in which symptoms are not of somatic origin. CONCLUSION: GPs feel difficulties in explaining the symptoms. GPs report that, when patients keep presenting with MUS, they focus on maintaining the doctor-patient relationship by using ritual care. In this care they meticulously balance between maintaining a good doctor-patient relationship and the prevention of unintended consequences of unnecessary interventions. PMID- 19775482 TI - An ethnobotanical study of medicinal plants used by local people in the lowlands of Konta Special Woreda, southern nations, nationalities and peoples regional state, Ethiopia. AB - BACKGROUND: Research was carried out in Konta Special Woreda (District); it is a remote area with lack of infrastructure like road to make any research activities in the area. Therefore, this research was conducted to investigate medicinal plants of the Konta people and to document the local knowledge before environmental and cultural changes deplete the resources. METHODS: The information was collected between October 2006 and February 2007. Interview-based field study constituted the main data collection method in which the gathering, preparation, use, previous and current status and cultivation practices were systematically investigated. The abundance, taxonomic diversity and distribution of medicinal plants were studied using ecological approach. RESULTS: A total of 120 species, grouped within 100 genera and 47 families that are used in traditional medical practices were identified and studied. The Fabaceae and Lamiaceae were the most commonly reported medicinal plants with 16 (13.3%) and 14 (12%) species, respectively. 25.4% of the total medicinal plants are collected from homegardens and the rest (74.6%) are collected from wild habitats. Of the total number of medicinal plants, 108 species (90%) were used to treat human ailments, 6 (5%) for livestock diseases and the remaining 6 (5%) were used to treat both human and livestock health problems. The major threats to medicinal plants reported include harvesting medicinal plants for firewood (24.8%) followed by fire (22.3%) and construction (19%). Of the four plant communities identified in the wild, more medicinal plant species (34) were found in community type-4 (Hyparrhenia cymbaria-Erythrina abyssinica community), which accounted for 61.8%. CONCLUSION: Konta Special Woreda is an important area for medicinal plants and associated local knowledge; the natural vegetation being the most important reservoir for the majority of the medicinal plants. Environmental and cultural changes are in the process of threatening the resources and this signals the need for serious efforts to create public awareness so that measures are taken to conserve the medicinal plants in the natural ecosystems and other suitable environments. PMID- 19775483 TI - Comparison of rates of suicide methods used by the elderly in England and Wales. PMID- 19775484 TI - Elderly suicides by drug poisoning in England and Wales: time trends within two elderly age-bands. PMID- 19775485 TI - Are nasal decongestants safer than rhinitis? A case of oxymetazoline-induced syncope. AB - Derivatives of Imidazoline usually act to stimulate peripheral alpha2 receptors causing vasoconstriction. In young children, however, they can also stimulate alpha2receptors in the cardiovascular and central nervous systems, possibly causing cardiovascular, neurological, and respiratory depression. These medications do not require medical prescriptions, so often parents use them, bypassing paediatricians. We report here a case of cardiovascular and neurological depression induced by oxymetalzoline in a toddler. PMID- 19775486 TI - A 15-year follow-up study on schistosomiasis in a low-endemic area in Rio de Janeiro State, Brazil. AB - Fifteen years after our first investigation, a follow-up study was carried out with the purpose of assessing the evolution of schistosomiasis in the locality of Sabugo, Paracambi, state of Rio de Janeiro, Brazil, an area with low prevalence of the disease. The coprological techniques adopted were spontaneous sedimentation and Kato-Katz. Out of the 1356 individuals assessed, 13 (1%) were infected with Schistosoma mansoni. From those, 10 were males, 12 were over 15 years old, and at least 11 had been infected in Sabugo. All patients presented either the intestinal or the hepato-intestinal form of the disease, and 8 (61.5%) harboured light parasitic loads. In 1990, there were 27 (2.7%) infected individuals; less than half harboured light parasitic loads, with the predominance of moderate and heavy forms. Although our results indicate an improvement in the epidemiological situation of schistosomiasis in Sabugo, transmission of the disease in the locality is still active, especially among young males, and tends to be acquired during leisure activities. PMID- 19775487 TI - Effects of septal perforation on nasal airflow: computer simulation study. AB - BACKGROUND: Nasal septal perforation is a structural or anatomical defect in the septum. The present study focused on the effects of septal perforation on nasal airflow and nasal patency, investigated using a computer simulation model. METHODS: The effect of nasal septal perforation size on nasal airflow pattern was analysed using computer-generated, three-dimensional nasal models reconstructed using data from magnetic resonance imaging scans of a healthy human subject. Computer-based simulations using computational fluid dynamics were then conducted to determine nasal airflow patterns. RESULTS: The maximum velocity and wall shear stress were found always to occur in the downstream region of the septal perforation, and could potentially cause bleeding in that region, as previously reported. During the breathing process, there was flow exchange and flow reversal through the septal perforation, from the higher flow rate to the lower flow rate nostril side, especially for moderate and larger sized perforations. CONCLUSION: In the breathing process of patients with septal perforations, there is airflow exchange from the higher flow rate to the lower flow rate nostril side, especially for moderate and large sized perforations. For relatively small septal perforations, the amount of cross-flow is negligible. This cross-flow may cause the whistling sound typically experienced by patients. PMID- 19775488 TI - Recurrent vestibulopathy: natural course and prognostic factors. AB - OBJECTIVE: To evaluate the natural course of recurrent vestibulopathy. STUDY DESIGN: Retrospective analysis. PATIENTS: One hundred and five adult patients with attacks of vertigo without auditory or neurological symptoms. METHODS: A structured interview was conducted over the telephone, 12 to 62 months after the patient's first visit to the out-patient department. RESULTS: Two-thirds of patients experienced spontaneous resolution of vertigo, while one-third continued to have symptoms. The diagnosis was subsequently changed to migraine in 2 per cent of patients and to Meniere's disease in 1 per cent. CONCLUSION: The prognosis for patients with recurrent vestibulopathy is good. In a few cases, the diagnosis is provisional and will be subsequently changed to migraine or Meniere's disease. PMID- 19775489 TI - Ventilation and clearance of the middle ear. AB - OBJECTIVE: To investigate the ventilation and drainage mechanism of the middle ear. STUDY DESIGN: Prospective. SETTING: We observed 304 (of 337) middle ears with tympanic membrane perforation or myringotomy (102 normal, 90 with otitis media with effusion and 112 with chronic otitis media); 912 observations were recorded overall. Perforations were covered with solution, creating a fluid film, and inspected for gas bubbling at rest, and for outward and inward movement of the fluid film during swallowing. We also noted the inflammatory condition of the ear (i.e. dry, wet or purulent) and the perforation size. RESULTS: Ears sometimes reacted differently in various sessions. Due to these differences, reactions were classified as 'types' of reactions rather than 'ears'. We refer to 449 'types' of 304 ears. Spontaneous gas bubbling at rest (indicating gas production) was observed in 98 per cent of normal types, 68 per cent of otitis media with effusion types and 65 per cent of chronic otitis media types. Evacuation towards the eustachian tube was observed in 47 per cent, no movement in 46 per cent and outward movement in 9 per cent. During swallowing, inward movement of the fluid film was observed in 74 per cent of normal types, 41 per cent of otitis media with effusion types and 32 per cent of chronic otitis media types. CONCLUSIONS: We found no support for the theory that the eustachian tube supplies air to the middle ear during swallowing. The normal middle ear produces gas which is evacuated by the Eustachian tube. In ears with otitis media, this mechanism appears to be impaired. PMID- 19775490 TI - Role of magnetic resonance imaging in evaluating sphenoid sinus and internal carotid artery. AB - OBJECTIVE: This study aimed to determine whether magnetic resonance imaging has a role in the evaluation of the sphenoid sinus and internal carotid artery. In addition, we aimed to establish reference measurements for the minimal distance between the internal carotid arteries. METHOD: The sphenoid sinuses and neighbouring internal carotid arteries of 90 patients were evaluated using sagittal T1-weighted and axial and coronal T2-weighted magnetic resonance images. RESULTS: Sphenoid sinus pneumatisation was categorised as occipitosphenoidal (0 per cent), conchal (3.3 per cent), presellar (14.4 per cent) or sellar (82.2 per cent). The internal carotid artery protruded into the sphenoid sinus in 32.8 per cent, with a septum in 9.4 per cent. The incidence of sellar-type sphenoid sinus pneumatisation was higher in patients with protrusion of the internal carotid artery into the sphenoid sinus (p < 0.001). The incidence of presellar pneumatisation was higher in patients without internal carotid artery protrusion (p < 0.001). The minimal distance between the internal carotid arteries varied between 9.04 and 24.26 mm (mean, 15.94 mm). CONCLUSION: Magnetic resonance imaging can provide useful information about the sphenoid sinus and internal carotid artery, prior to endoscopic sphenoidotomy and trans-sphenoidal hypophysectomy. PMID- 19775491 TI - Long-term follow up after bony mastoid and epitympanic obliteration: radiological findings. AB - OBJECTIVE: The canal wall up bony obliteration technique lowers the incidence of recurrent cholesteatoma, but carries the potential risk of obliterating residual cholesteatoma. The objective of this study was to report long-term follow-up radiological findings after performing a canal wall up bony obliteration technique procedure, in order to detect residual and/or recurrent cholesteatoma. PATIENTS: Fifty-one patients presenting with a cholesteatoma or a troublesome cavity were operated upon using the canal wall up bony obliteration technique, and were evaluated by follow-up imaging a mean of 76.4 months post-operatively (range, 53.8-113.6 months). INTERVENTION: All patients were evaluated with high resolution computed tomography and magnetic resonance imaging (including delayed contrast, T1-weighted imaging and non-echo-planar, diffusion-weighted imaging). RESULTS: Imaging revealed the presence of one residual, one recurrent and one congenital petrosal apex cholesteatoma. On high resolution computed tomography, completely obliterated mastoid filled with bone was observed in 74.5 per cent (38/51) of patients, and an aerated middle-ear cavity in 64.7 per cent (33/51). High resolution computed tomography clearly detected any associated soft tissue present in the middle-ear cavity (18/51) and in the obliterated mastoids (13/51), but could not characterise this tissue. Non-echo-planar, diffusion-weighted magnetic resonance imaging clearly identified all three cholesteatomas, and differentiated them from other associated soft tissues. No cholesteatoma was found within the obliterated mastoids. CONCLUSION: Long-term follow up indicated that the canal wall up bony obliteration technique is a safe method with which to treat primary and recurrent cholesteatoma and to reconstruct unstable cavities. Soft tissue was found quite often in the middle ear and obliterated mastoids. High resolution computed tomography identified its presence but could not further characterise it. However, non-echo-planar, diffusion-weighted magnetic resonance imaging succeeded in differentiating soft tissues, enabling detection of residual or recurrent cholesteatoma after a canal wall up bony obliteration technique procedure. PMID- 19775492 TI - Cochlear implantation at King Abdulaziz University Hospital, Riyadh, Saudi Arabia: a 12-year experience. AB - OBJECTIVE: This paper aims to report our experience with different multichannel cochlear implant devices, and to discuss the outcomes of our cochlear implant programme, together with the problems encountered. SETTING: Cochlear implantation was undertaken in 117 patients (35 post-lingual and 82 pre-lingual cases; 70 males and 47 females) over a 12-year period. Three cochlear implant systems were used: Nucleus (22 and 24), Med-El and Advanced Bionics Clarion. An extended endaural incision was used in 78 cases and a minimally invasive approach in 39 cases. RESULTS: Complications occurred in 16.2 per cent of patients. All patients showed a significant post-implantation improvement in their perception and discrimination of sound and speech. Better results were noted in pre-lingual patients under the age of six years. The cause of hearing loss was unknown in 81 per cent of patients. CONCLUSION: The outcomes of our cochlear implantation series are comparable to previous reports. The possibility of an abnormally rotated cochlea should be borne in mind when difficulty is encountered during cochleostomy. PMID- 19775493 TI - Metastatic cutaneous squamous cell carcinoma of the external ear: a high-risk cutaneous subsite. AB - INTRODUCTION: Patients with cutaneous squamous cell carcinoma of the external ear may develop metastatic spread to the nearby ipsilateral parotid and/or upper cervical lymph nodes. The literature suggests that the external ear is a high risk subsite for such tumours, due to nodal metastasis and its associated morbidity and mortality. METHODS: Between 1980 and 2007, 43 patients with a diagnosis of metastatic cutaneous squamous cell carcinoma of the external ear were treated with surgery alone, surgery plus adjuvant radiotherapy, or radiotherapy alone. RESULTS: Patients comprised 39 men and four women. Their median age at diagnosis was 72 years, with a median follow up of 35 months. The median size of the primary lesion was 21 mm, with a median thickness of 7 mm. Fifteen patients presented concurrently with nodal metastases. Thirty patients developed parotid metastases (with positive cervical nodes in six patients), while 13 developed cervical metastases only. Eight patients underwent surgery alone, 32 underwent surgery plus adjuvant radiotherapy, and three received radiotherapy alone. At the last follow up, 15 patients had relapsed and nine had died of their disease, with a median survival after relapse of 5.5 months. CONCLUSION: Patients with metastatic cutaneous squamous cell carcinoma of the external ear have a relatively poor outcome, with a significant number of patients experiencing nodal relapse and death after treatment. PMID- 19775494 TI - Thermogenesis challenges the adipostat hypothesis for body-weight control. AB - According to the adipostat hypothesis for body-weight control, alterations in body weight should always be compensated by adequate alterations in food intake and thermogenesis. Thus, increased thermogenesis should not be able to counteract obesity because food intake would be increased. However evidence is presented here that thermogenesis in different forms (through artificial uncouplers, exercise, cold exposure) may counteract obesity and is not always fully compensated by increased food intake. Correspondingly, a decreased capacity for metaboloregulatory thermogenesis (i.e. non-functional brown adipose tissue) may in itself lead to obesity. This is evident in mice and may be valid for human subjects, as a substantial proportion of adults possess brown adipose tissue, and those with less or without brown adipose tissue would seem to be more prone to obesity. Thus, increased thermogenesis may counteract obesity, without dietary intervention. PMID- 19775495 TI - Using the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess the cognitive impact of electroconvulsive therapy on visual and visuospatial memory. AB - BACKGROUND: The cognitive impact of electroconvulsive therapy (ECT) is rarely measured systematically in everyday clinical practice even though patient and clinician acceptance is limited by its adverse affect on memory. If patients are tested it is often with simple paper and pencil tests of visual or verbal memory. There are no reported studies of computerized neuropsychological testing to assess the cognitive impact of ECT on visuospatial memory. METHOD: Twenty-four patients with severe depression were treated with a course of bilateral ECT and assessed with a battery of visual memory tests within the Cambridge Neuropsychological Test Automated Battery (CANTAB). These included spatial and pattern recognition memory, pattern-location associative learning and a delayed matching to sample test. Testing was carried out before ECT, during ECT, within the week after ECT and 1 month after ECT. RESULTS: Patients showed significant impairments in visual and visuospatial memory both during and within the week after ECT. Most impairments resolved 1 month following ECT; however, significant impairment in spatial recognition memory remained. This is one of only a few studies that have detected anterograde memory deficits more than 2 weeks after treatment. CONCLUSIONS: Patients receiving ECT displayed a range of visual and visuospatial deficits over the course of their treatment. These deficits were most prominent for tasks dependent on the use of the right medial temporal lobe; frontal lobe function may also be implicated. The CANTAB appears to be a useful instrument for measuring the adverse cognitive effects of ECT on aspects of visual and visuospatial memory. PMID- 19775496 TI - Facial emotion processing in schizophrenia: a non-specific neuropsychological deficit? AB - BACKGROUND: Identification of facial emotions has been found to be impaired in schizophrenia but there are uncertainties about the neuropsychological specificity of the finding. METHOD: Twenty-two patients with schizophrenia and 20 healthy controls were given tests requiring identification of facial emotion, judgement of the intensity of emotional expressions without identification, familiar face recognition and the Benton Facial Recognition Test (BFRT). The schizophrenia patients were selected to be relatively intellectually preserved. RESULTS: The patients with schizophrenia showed no deficit in identifying facial emotion, although they were slower than the controls. They were, however, impaired on judging the intensity of emotional expression without identification. They showed impairment in recognizing familiar faces but not on the BFRT. CONCLUSIONS: When steps are taken to reduce the effects of general intellectual impairment, there is no deficit in identifying facial emotions in schizophrenia. There may, however, be a deficit in judging emotional intensity. The impairment found in naming familiar faces is consistent with other evidence of semantic memory impairment in the disorder. PMID- 19775497 TI - Early intervention in psychosis: keeping faith with evidence-based health care. PMID- 19775498 TI - Replacement of the aortic valve in a patient with mucolipidosis III. AB - We report replacement of the aortic valve in a patient aged 9 years with mucolipidosis III and severe aortic insufficiency. Histopathology demonstrated abnormalities of the matrix and lysosomal inclusion bodies. As life expectancy increases for patients with lysosomal storage disorders, approaches to intervention for valvar disease become increasingly important. PMID- 19775499 TI - Behavioural and neuroplastic effects of the new-generation antidepressant agomelatine compared to fluoxetine in glucocorticoid receptor-impaired mice. AB - Major depression is associated with reduced hippocampal volume linked to stress and high glucocorticoid secretion. Glucocorticoid receptor-impaired (GR-i) mice, a transgenic model for affective disorders with hypothalamic-pituitary-adrenal (HPA) axis feedback control deficit, were used to assess the antidepressant-like effects of the mixed melatonin receptor agonist/5-HT(2C) receptor antagonist, agomelatine, compared to the selective 5-HT reuptake inhibitor (SSRI), fluoxetine, on hippocampal neurogenesis, GR and BDNF expression and antidepressant-responsive behaviour (tail suspension test, TST). GR-i and paired wild-type (WT) mice were given acute or chronic (21 d) treatment with these drugs. Both hippocampal cell proliferation and BDNF mRNA expression were down regulated in GR-i mice, and these alterations were reversed by chronic agomelatine and fluoxetine treatments, whereas GR mRNA down-regulation was reversed only by agomelatine. Furthermore, chronic agomelatine, but not fluoxetine, increased survival of newly formed cells in the ventral part of the hippocampus without changing their phenotypic differentiation into neurons. In the TST, the enhanced immobility of GR-i mice was reduced to WT level by acute (but not chronic) fluoxetine and chronic (but not acute) agomelatine. These results indicate that agomelatine reversed the neuroplastic changes and helpless behaviour associated with HPA axis alterations in GR-i mice, suggesting neurobiological and behavioural effects mostly similar to those typically seen with classical antidepressants such as fluoxetine, but through clearly distinct mechanisms. PMID- 19775500 TI - Modulation of effective connectivity during emotional processing by Delta 9 tetrahydrocannabinol and cannabidiol. AB - Cannabis sativa, the most widely used illicit drug, has profound effects on levels of anxiety in animals and humans. Although recent studies have helped provide a better understanding of the neurofunctional correlates of these effects, indicating the involvement of the amygdala and cingulate cortex, their reciprocal influence is still mostly unknown. In this study dynamic causal modelling (DCM) and Bayesian model selection (BMS) were used to explore the effects of pure compounds of C. sativa [600 mg of cannabidiol (CBD) and 10 mg Delta 9-tetrahydrocannabinol (Delta 9-THC)] on prefrontal-subcortical effective connectivity in 15 healthy subjects who underwent a double-blind randomized, placebo-controlled fMRI paradigm while viewing faces which elicited different levels of anxiety. In the placebo condition, BMS identified a model with driving inputs entering via the anterior cingulate and forward intrinsic connectivity between the amygdala and the anterior cingulate as the best fit. CBD but not Delta 9-THC disrupted forward connectivity between these regions during the neural response to fearful faces. This is the first study to show that the disruption of prefrontal-subocritical connectivity by CBD may represent neurophysiological correlates of its anxiolytic properties. PMID- 19775502 TI - Review and meta-analysis of usage of ginkgo as an adjunct therapy in chronic schizophrenia. AB - This study aimed to review the roles of antioxidants in the pathophysiology of schizophrenia, whether the properties of ginkgo can ameliorate symptoms of this illness, and evaluate available literature to test this assumption. This review is based upon published works on antioxidants and ginkgo. A primary electronic search for meta-analysis on the usage of ginkgo or its derived products in schizophrenia was conducted using Pubmed, Cochrane Library, EMBASE, CINAHL, PsycINFO and AMED. Inclusion criteria were: criteria-based diagnosis of schizophrenia, randomized case assignment, use of ginkgo as an add-on therapy, and assessment using standardized rating scales to measure the state of psychopathology for negative and total symptoms of schizophrenia. Additionally, a detailed review was undertaken to investigate if antioxidants are involved in development of psychotic symptoms in schizophrenia. The six studies that fulfilled the selection criteria were constituted of 466 cases on ginkgo and 362 cases on placebo. They all used the Scale for the Assessment of Negative Symptoms (SANS) to measure negative symptoms, and the Scale for the Assessment of Positive Symptoms (SAPS) or the Brief Psychiatric Rating Scale (BPRS) to measure total symptoms. Difference between ginkgo and control groups from their pre- and post trial scores and its pooled standard deviation were used to compute standardized mean difference (SMD). Ginkgo as an add-on therapy to antipsychotic medication produced statistically significant moderate improvement (SMD=-0.50) in total and negative symptoms of chronic schizophrenia. Ginkgo as add-on therapy ameliorates the symptoms of chronic schizophrenia. The role of antioxidants in pathogenesis of schizophrenia has also been explored. PMID- 19775501 TI - Eszopiclone and fluoxetine enhance the survival of newborn neurons in the adult rat hippocampus. AB - Clinical research has shown that co-administration of eszopiclone, a sedative hypnotic sleeping agent, and fluoxetine, a serotonin uptake inhibitor, exerts an additive antidepressant action in treating patients with both depression and insomnia. Preclinical studies demonstrate that the behavioural actions of antidepressants are linked to neurogenesis in the adult hippocampus. To test the hypothesis that the additive effects of eszopiclone and fluoxetine could act via such a mechanism, the influence of combined administration of these agents on the proliferation and survival of bromodeoxyuridine (BrdU)-labelled newborn cells in the hippocampus of adult rats was determined. Chronic eszopiclone+fluoxetine co administration significantly increased the survival, but not proliferation, of newborn neurons in dorsal hippocampus by approximately 50%, an effect greater than either drug alone. These findings are consistent with the hypothesis that eszopiclone enhances the antidepressant action of fluoxetine, in part via a novel mechanism that increases the survival of newborn neurons. PMID- 19775503 TI - Discrimination between cocaine-associated context and cue in a modified conditioned place preference paradigm: role of the nNOS gene in cue conditioning. AB - The conditioned place preference (CPP) paradigm entails appetitive learning and is utilized to investigate the motivational effects of drug and natural reward in rodents. However, a typical CPP design does not allow dissociation between cue- and context-dependent appetitive learning. In humans, context and cues that had been associated with drug reward can elicit conditioned response and drug craving. Therefore, we investigated (a) methods by which to discriminate between cue- and context-dependent appetitive learning, and (b) the role of the neuronal nitric oxide synthase (nNOS) gene in appetitive learning. Wild-type (WT) and nNOS knockout (KO) mice were trained by cocaine (20 mg/kg) in a discrete context paired with a light cue (a compound context-cue stimulus). In test 1, approach behaviour to either the training context or to the cue in a novel context was determined. WT mice showed robust preference for both cocaine-associated context and cue. nNOS KO mice acquired approach behaviour for the cocaine-associated context but not cue. This finding suggests that the nNOS gene is required for cue dependent appetitive learning. On the following day (test 2), mice were tested for approach behaviour to the compound context-cue stimulus. Context but not cue exposure in test 1 reduced approach behaviour to the compound context-cue stimulus in test 2, suggesting that repeated context but not cue exposures diminished the conditioned response. Hence, this modified CPP paradigm is useful for the investigation of approach behaviour for both drug-associated context and cue, and allows further investigation of mechanisms underlying cue- and context dependent appetitive learning. PMID- 19775504 TI - Alterations of excitatory transmission in the lateral amygdala during expression and extinction of fear memory. AB - Understanding the neurophysiology of fear extinction has important implications for the treatment of post-traumatic stress disorders. Here we report that fear conditioning resulted in an increase in AMPA/NMDA ratio as well as depression of paired-pulse facilitation (PPF) in neurons of the lateral nucleus of amygdala. These conditioning-induced changes in synaptic transmission were not affected by extinction training. D-cycloserine (DCS), a partial agonist at the glycine binding site of the NMDA receptor, facilitated extinction and reversed the increase in AMPA/NMDA ratio without altering the depression of PPF when administered before extinction training. Extinction training, however, significantly increased the frequency and amplitude of miniature inhibitory post synaptic currents and these effects were unaffected by the DCS treatment. Disruption of AMPA receptor endocytosis with a synthetic peptide containing a short C-terminal sequence of GluR2 (869YKEGYNVYG877, GluR23Y) specifically blocked DCS-induced reversal of AMPA/NMDA ratio and the facilitation of extinction. These results suggest that extinction training mainly increases inhibitory transmission leaving conditioning-induced excitatory association unaltered. DCS does not affect inhibitory transmission but reverses the conditioning-induced post-synaptic memory trace when administered before extinction training. PMID- 19775506 TI - Anatomic variations of sphenopalatine artery and minimally invasive surgical cauterization procedure. AB - BACKGROUND: Sphenopalatine artery (SPA) ligation or cauterization stands to be one of the most common management options of refractory epistaxis. Ramification pattern of SPA as it passes through sphenopalatine foramen (SPF) has not been clearly established. The aim of this study is to investigate situations in which middle meatal approach may fail due to anatomic variations of SPA and to define a minimally invasive surgical cauterization procedure. Anatomic variations of SPA were determined by microdissection of 20 adult sagittally cross-sectioned head specimens. METHODS: Branching characteristics of SPA and its anatomic relations were evaluated and anatomic variations were noted. RESULTS: SPA was generally (80%) forming branches within SPF before entering into the nasal cavity. In 20% of the specimens, SPF was located superior to the horizontal lamella of the middle turbinate, and accessory foramen was present in 10%. In 10% of the cases, the posterior lateral nasal branch was situated as two branches in a deep sulcus in the middle meatus. CONCLUSION: The ramification pattern of SPA can not be fully exposed without resection of the posterior part of the middle turbinate via the middle meatal approach. Two-step procedures are advocated in reducing failure rates. Previously defined two-step procedures are relatively invasive. A less invasive procedure is defined based on the variations of SPA and SPF. PMID- 19775507 TI - Spreading the wings of organ biology further. PMID- 19775508 TI - Regenerative medicine for diabetes mellitus. AB - In diabetes, a loss of pancreatic beta-cells causes insulin dependency. When insulin dependency is caused by type 1 diabetes or pancreatic diabetes, for example, pancreatic beta-cells need to be regenerated for definitive treatment. The methods for generating pancreatic beta-cells include a method of creating pancreatic beta-cells in vitro and implanting them into the body and a method of regenerating pancreatic beta-cells in the body via gene introduction or the administration of differential proliferation factors to the body. Moreover, the number of pancreatic beta-cells is also low in type 2 diabetes, caused by the compounding factors of insulin secretory failure and insulin resistance; therefore, if pancreatic beta-cells can be regenerated in a living body, then a further amelioration of the pathology can be expected. The development of pancreatic beta-cell-targeting regenerative medicine can lead to the next generation of diabetes treatment. PMID- 19775509 TI - Pancreas preservation by the two-layer method: does it have a beneficial effect compared with simple preservation in University of Wisconsin solution? AB - A large number of reports have shown that the two-layer method (TLM), which employs oxygenated perfluorochemical (PFC) and University of Wisconsin (UW) solution, is superior to simple cold storage in UW in islet transplantation. However, two recent large-scale studies showed no beneficial effect of TLM compared with UW storage in human islet transplantation. We reevaluated the effect of TLM by following three groups: group 1: UW simple storage; group 2: TLM performed by multiorgan procurement teams (not specialists of islet isolation); and group 3: TLM performed by specialists of islet isolation (Noguchi and Matsumoto). There were no significant differences between groups 1 and 2, whereas islet yields were significantly higher in group 3 compared with either group 1 or 2. Our data suggest that exact, complete performance of TLM could improve the outcome of islet isolation and transplantation. In this review, we describe the mechanisms of the TLM, the procedure of preoxygenated TLM, and the several possibilities for the reasons of the discrepancy. PMID- 19775510 TI - Beneficial storage effects of epigallocatechin-3-o-gallate on the articular cartilage of rabbit osteochondral allografts. AB - A fresh osteochondral allograft is one of the most effective treatments for cartilage defects of the knee. Despite the clinical success, fresh osteochondral allografts have great limitations in relation to the short storage time that cartilage tissues can be well-preserved. Fresh osteochondral grafts are generally stored in culture medium at 4 degrees C. While the viability of articular cartilage stored in culture medium is significantly diminished within 1 week, appropriate serology testing to minimize the chances for the disease transmission requires a minimum of 2 weeks. (-)-Epigallocatechin-3-O-gallate (EGCG) has differential effects on the proliferation of cancer and normal cells, thus a cytotoxic effect on various cancer cells, but a cytopreservative effect on normal cells. Therefore, a storage solution containing EGCG might extend the storage duration of articular cartilages. Rabbit osteochondral allografts were performed with osteochondral grafts stored at 4 degrees C in culture medium containing EGCG for 2 weeks and then the clinical effects were examined with macroscopic and histological assessment after 4 weeks. The cartilaginous structure of an osteochondral graft stored with EGCG was well-preserved with high cell viability and glycosaminoglycan (GAG) content of the extracellular matrix (ECM). After an osteochondral allograft, the implanted osteochondral grafts stored with EGCG also provided a significantly better retention of the articular cartilage with viability and metabolic activity. These data suggest that EGCG can be an effective storage agent that allows long-term preservation of articular cartilage under cold storage conditions. PMID- 19775511 TI - Long-term preservation of rat skin tissue by epigallocatechin-3-o-gallate. AB - Skin grafts can be preserved by cryopreservation and refrigerated storage at 4 degrees C. Epigallocatechin-3-O-gallate (EGCG) enhances the viability of stored skin grafts and also extends the storage time up to 7 weeks at 4 degrees C. EGCG, the major polyphenolic constituent present in green tea, has potent antioxidant, antimicrobial, antiproliferative, and free radical scavenging effects. This study examined the effects of EGCG on skin cryopreservation. Skin sample biopsy specimens from GFP rats were previously treated with/without EGCG then moved to 196 degrees C. Skin samples were transplanted to nude mice after 2, 8, and 24 weeks of preservation. Glucose consumption was measured after thawing to assess the metabolic activity. Two weeks later the transplanted skin grafts were excised and histologically analyzed. Histological examinations revealed the degeneration of the epidermal and dermal layers in all groups. In the EGCG groups, the grafts showed higher integrity in the epidermal layer and dermal matrix. The present findings suggest the future clinical usefulness of EGCG for skin preservation; however, the mechanism by which EGCG promotes skin preservation still remains unclear. PMID- 19775512 TI - Preservation of platelets by adding epigallocatechin-3-o-gallate to platelet concentrates. AB - The effect of epigallocatechin-3-O-gallate (EGCG), a major component of green tea, on platelet preservation was evaluated. Single donor platelets (N = 10) were collected and preserved by the standard method. EGCG was added to the platelet concentrates before preservation and then the functional and biochemical parameters were monitored throughout the storage period. After 6 days of preservation, the aggregability of the platelets was significantly maintained by addition of 50 and 100 microg/ml of EGCG. Platelet prothrombinase activity was also significantly retained by the addition of EGCG. The accumulation of P selectin and RANTES in the plasma preserved with EGCG was less than those preserved without EGCG, which indicated that EGCG might inhibit platelet activation. Furthermore, EGCG reduced the increase of LDH in plasma during preservation and inhibited the activation of caspase-3 and cleavage of gelsolin, thereby showing that EGCG could inhibit the apoptosis of platelets. These results suggest that EGCG may play an effective role in preserving platelets by inhibiting the activation and apoptosis of platelets. PMID- 19775513 TI - A study on the perfusion preservation, resuscitation, and transplantation of a rat heart isolated for 96 hours. AB - Krebs-Henseleit (KH) solution was used to fill the heart chamber of an isolated rat heart before it was immersed in perfluorocarbon (PFC), which is an inert fluid. A gas mixture (PCO(2) = 150 hPa and PO(2) = 850 hPa) was then aerated at a constant rate into the PFC solution, and the isolated heart was thereafter preserved for 96 h with KH solution perfused continuously at a rate of 0.1 ml/h from the aorta of the isolated heart through a cannula. After preservation, the preserved heart was heterotopically transplanted into the neck of a recipient rat and then it was resuscitated. Using this method for preserving mammalian organs, we attained reproducibility after perfusion preservation for 96 h. PMID- 19775514 TI - Study on the preservation with CO (PCO = 200-2,000 hPa), resuscitation, and heterotopic transplantation of an isolated rat heart. AB - In this experiment, CO was used as a gas mixture in a reversible relationship with O(2). CO was added in a gas form mixed with O(2). An isolated donor rat heart was obtained, exposed to a gas mixture such as PO(2) = 1,800 hPa and PCO = 200 hPa, and PO(2) = 1,000 hPa and PCO = 1,000 hPa in a 2 ATA high-pressure chamber and preserved in a refrigerator at 4 degrees C. This report demonstrates that significant reproducibility has been verified. The heart was removed from the refrigerator 24 h later and heterotopic heart transplantation was performed in the right neck of a recipient rat and the pulsating of the transplanted heart was detected by an electrocardiogram. PMID- 19775515 TI - Comparison of trypsin inhibitors in preservation solution for islet isolation. AB - Islet transplantation has recently emerged as an effective therapy and potential cure for type 1 diabetes mellitus. Recent reports show that the two-layer method (TLM), which employs oxygenated perfluorochemical (PFC) and University of Wisconsin (UW) solution, is superior to simple cold storage in UW for pancreas preservation in islet transplantation. Moreover, we recently reported that islet yield was significantly higher in the ET-Kyoto solution with ulinastatin (MK)/PFC preservation solution compared with the UW/PFC preservation solution in the porcine model and that the advantages of MK solution are trypsin inhibition and less collagenase inhibition. In this study, we compared ulinastatin with another trypsin inhibitor, Pefabloc, in preservation solution for islet isolation. Islet yield before purification was higher in the MK/PFC group compared with the ET Kyoto with Pefabloc (PK)/PFC group. The stimulation index was higher for the MK/PFC group than for the PK/PFC group. These data suggest that ET-Kyoto with ulinastatin was the better combination for pancreas preservation than ET-Kyoto with Pefabloc. Based on these data, we now use ET-Kyoto solution with ulinastatin for clinical islet transplantation. PMID- 19775516 TI - Estimation of donor usability for islet transplantation in the United States with the kyoto islet isolation method. AB - The quality of donor pancreata is important for successful islet isolation. However, in some countries like Japan, the number of donor pancreata is very low; therefore, marginal donors have been used with less restrictive donor criteria. In order to use marginal donor pancreata, we established the Kyoto islet isolation method (KIIM). According to United Network for Organ Sharing (UNOS) in 2005, more than 6,000 pancreata were not clinically used in the US. In this study, we applied the KIIM for brain-dead donors and reevaluated donor usability based on the Japanese islet donor criteria. Islets were isolated with the Ricordi method using pancreata stored in University of Wisconsin (UW) solution (UW group) or by the two-layer method (TLM group) or the TLM combined with ductal injection (DI group). We implemented the KIIM (KIIM group) to confirm the effect of the KIIM on brain-dead donors. Donor charts in Texas from 2005 to 2006 were reviewed. If pancreata were not used clinically, the reason was reviewed and donors were reevaluated based on Japanese criteria. There were no significant differences of islet yield, viability, and purity between the UW and TLM groups. The DI group significantly improved islet yields and isolations were further improved in the KIIM group [UW: 251,663 +/- 60,217 islet equivalent (IE); TLM: 243,738 +/- 54,170 IE; DI: 498,639 +/- 28,853 IE; KIIM: 678,286 +/- 55,853]. The KIIM provided high quality islets in high numbers from islet isolations from brain-dead donors. A total of 236 donor charts were reviewed and 194 pancreata (82%) were not used. Of these, 185 cases identified the reasons that the pancreata were not used. When we applied the Japanese criteria, an additional 82 cases out of 185 (44%) seem to be suitable for islet isolations. With the KIIM, more than 2,500 additional donor pancreata can be used for islet isolation in the US every year when the Japanese criteria are applied. PMID- 19775517 TI - SUITO index for evaluation of efficacy of single donor islet transplantation. AB - Evaluation of engrafted islets mass is important for clinical care of patients after islet transplantation. Recently, we developed the secretory unit of islet transplant objects (SUITO) index, which reflected engrafted islet mass. In this study, we evaluated the SUITO index for the prediction of clinical outcome after single islet transplantation. Single islet transplantations were performed into six type 1 diabetic patients. Isolated islets were quantitatively assessed at the time of transplantation. The SUITO index was calculated as follows: fasting C peptide (ng/dl)/[fasting blood glucose (mg/dl) - 63] x 1500. Islet yield/recipient's body weight and SUITO index were evaluated, along with HbA(1C), relative insulin dose (insulin dose posttransplant/pretransplant), and M-values. HbA(1C) improved in all cases, irrespective of the SUITO index score or islet yield/body weight. The average SUITO index from postoperative days 3 to 30 (R(2) = 0.728, p < 0.04), but not islet yield/body weight (R(2) = 0.259, p = 0.303), correlated with relative insulin dose. The daily SUITO index strongly correlated with the daily relative insulin dose (R(2) = 0.558, p < 0.0001) and weakly correlated with the daily M-values (R(2) = 0.207, p < 0.02). A SUITO index score of less than 10 was associated with increasing insulin dose even after islet transplantation. The SUITO index seems to be a better predictor of success of islet transplantations than islet yield/body weight. SUITO index is recommended to assess clinical outcome of islet transplantation. PMID- 19775518 TI - Establishment of mouse pancreatic stem cell line. AB - beta-Cell replacement therapy via islet transplantation is a promising possibility for the optimal treatment of type 1 diabetes. However, such an approach is severely limited by the shortage of donor organs. Pancreatic stem/progenitor cells could become a useful target for beta-cell replacement therapy in diabetic patients because the cells are abundantly available in the pancreas of these patients and in donor organs. In this study, we established a mouse pancreatic stem cell line without genetic manipulation. The duct-rich population after islet isolation was inoculated into 96-well plates in limiting dilution. From over 200 clones, 15 clones were able to be cultured for over 3 months. The HN#13 cells, which had the highest expression of insulin mRNA after induction, expressed PDX-1 transcription factor, glucagon-like peptide-1 (GLP-1) receptor, and cytokeratin-19 (duct-like cells). These cells continue to divide actively beyond the population doubling level (PDL) of 300. Exendin-4 treatment and transduction of PDX-1 and NeuroD proteins by protein transduction technology in HN#13 cells induced insulin and pancreas-related gene expression. This cell line could be useful for analyzing pancreatic stem cell differentiation. Moreover, the isolation technique might be useful for identification and isolation of human pancreatic stem/progenitor cells. PMID- 19775519 TI - Recombinant sendai virus-mediated gene transfer to mouse pancreatic stem cells. AB - Efficient gene transfer into stem cells is essential for the basic research and for therapeutic applications in gene-modified regenerative medicine. Adenovirus (AdV) vectors, one of the most commonly used types of vectors, can mediate high, albeit transient, levels of expression of the transgene in pancreatic stem/progenitor cells. However, high multiplicity of infection (MOI) with AdV vectors can result in cellular toxicity. Therefore, AdV vectors have been of limited usefulness in clinical applications. In this study, we investigated the in vitro gene transfer efficiency of Sendai virus (SeV) vectors, a paramyxovirus vector that can efficiently introduce foreign genes without toxicity into several cell types, including pancreatic stem cells. The dose-dependent GFP expression of pancreatic stem cells transfected with SeV vectors after 48 h of culture at 37 degrees C was observed. The transfection of pancreatic stem cells with SeV vectors and AdV vectors results in equal expression of the transgene (GFP expression) in the cells after 48 h of culture at 37 degrees C. Although the transfection of pancreatic stem cells with AdV vectors at high MOIs was cytotoxic, transfection with SeV vectors at high MOIs was rarely cytotoxic. In addition, pancreatic stem cells transfected with SeV maintained their differentiation ability. These data suggest that SeV could provide advantages with respect to safety issues in gene-modified regenerative medicine. PMID- 19775520 TI - Differential ability of somatic stem cells. AB - Somatic stem cells can be isolated from a variety of sources. Although some studies have suggested that somatic stem cells may represent a cell population that is very similar to embryonic stem (ES) cells, it remains unclear whether somatic stem cells retain the potential to differentiate into any cell type derived from the three germ layers. In this study, we investigated the transdifferentiation potential of somatic stem cells using adipose tissue-derived stem/progenitor cells (ASCs; mesodermal stem cells) and pancreatic stem cells (endodermal stem cells). Previous reports from other groups describe the protocol that has been used to differentiate ASCs or mesenchymal stem cells (MSCs) in bone marrow into insulin-producing cells. Induction 1: ASCs were cultured for 3 days in ultra-low attachment plates under serum-free conditions. Induction 2: ASCs were cultured for 24 h with L-DMEM, and reinduced with serum-free H-DMEM for another 10 h. Unlike previous reports, we did not get ASCs to express any pancreas-specific genes, including insulin-1 or insulin-2. Pancreatic stem cells were induced to differentiate into adipo/osteogenic by the following protocols. Induction protocol 1: ACSs were cultured for 7 days with medium containing indometacin, dexamethasone, hydrocortisone, and insulin for adipogenic differentiation. Induction protocol 2: The cells were cultured for 7 days with medium containing dexamethasone, ascorbate-2-phosphate, and beta-glycerophosphate for osteogenic differentiation. Although these approaches have been widely used for adipo/osteogenic differentiation from MSCs, adipo/osteogenic differentiation from pancreatic stem cells was not observed. These data suggest that it is not easy for somatic stem cells to transdifferentiate into other germ cell types, at least, under these conditions. PMID- 19775521 TI - Quantum dots for labeling adipose tissue-derived stem cells. AB - Adipose tissue-derived stem cells (ASCs) have a self-renewing ability and can be induced to differentiate into various types of mesenchymal tissue. Because of their potential for clinical application, it has become desirable to label the cells for tracing transplanted cells and for in vivo imaging. Quantum dots (QDs) are novel inorganic probes that consist of CdSe/ZnS-core/shell semiconductor nanocrystals and have recently been explored as fluorescent probes for stem cell labeling. In this study, negatively charged QDs655 were applied for ASCs labeling, with the cationic liposome, Lipofectamine. The cytotoxicity of QDs655 Lipofectamine was assessed for ASCs. Although some cytotoxicity was observed in ASCs transfected with more than 2.0 nM of QDs655, none was observed with less than 0.8 nM. To evaluate the time dependency, the fluorescent intensity with QDs655 was observed until 24 h after transfection. The fluorescent intensity gradually increased until 2 h at the concentrations of 0.2 and 0.4 nM, while the intensity increased until 4 h at 0.8 nM. The ASCs were differentiated into both adipogenic and osteogenic cells with red fluorescence after transfection with QDs655, thus suggesting that the cells retain their potential for differentiation even after transfected with QDs655. These data suggest that QDs could be utilized for the labeling of ASCs. PMID- 19775522 TI - Comparison of sendai virus-mediated gene transfer efficiency to adhesive and floating adipose tissue-derived stem cells. AB - Sendai virus (SeV) vectors have potential clinical applications because they can efficiently introduce foreign genes without toxicity into various organs. A recent study reported the green fluorescent protein (GFP) gene transfer to adipose tissue-derived stem cells (ASCs) with SeV vectors results in more efficient expression of GFP than AdV and identified the preservation of the multilineage potential of ASCs transfected with SeV vectors. This study assessed the gene transfer efficiency to floating ASCs with SeV vectors. Although a slight cytotoxicity was observed, the efficiency of gene transfer to cells in the floating state was much higher at all times and all concentrations at MOIs of 2, 10, and 20 than in the adhesion state. Moreover, ASCs transfected with SeV vectors in floating state have the same potential for their differentiation into specific tissues, such as adipocytes and osteocytes, as untransfected ASCs. These data suggest that SeV transfection to ASCs in the floating state could therefore be useful for gene transfer technology. PMID- 19775523 TI - Cell transplantation of adipose tissue-derived stem cells in combination with heparin attenuated acute liver failure in mice. AB - The effect of adipose tissue-derived stem cells (ASCs) in combination with heparin transplantation on acute liver failure mice with carbon tetrachloride (CCl(4)) injection was investigated. CCl(4) is a well-known hepatotoxin and induces hepatic necrosis. Heparin did not affect the viability of ASCs for at least 24 h. The injection of heparin into the caudal tail vein decreased slightly the activities of the alanine aminotransferase (ALT), asparate aminotransferase (AST), and lactate dehydrogenase (LDH) in plasma. In the transplantation of ASCs (1 x 10(6) cells) group, there was a trend toward decreased activities of all markers. However, four out of six mice died of the lung infarction. In the transplantation of ASCs in combination with heparin group, there was also a trend toward decreased activities of all markers. In addition, all mice survived for at least the duration of the study period. In conclusion, the transplantation of ASCs in combination with heparin was thus found to effectively treat acute liver failure. PMID- 19775524 TI - Cryopreservation in situ of cell monolayers on collagen vitrigel membrane culture substrata: ready-to-use preparation of primary hepatocytes and ES cells. AB - Cryopreservation is generally performed on cells in suspension. In the case of adherent cells such as hepatocytes, a loss of their ability to attach is a more serious problem than a decreased viability after cryopreservation. We herein report a novel technology of direct in situ cryopreservation of cells cultured on collagen vitrigel membranes, which have excellent mechanical strength and can be easily handled by tweezers even when coated with cultured cells. Rat primary hepatocytes, mitomycin C-treated mouse fibroblasts (feeder cells for ES cells), and mouse ES cells on the feeder cells were cultured on collagen vitrigel membranes for 1 day. The membranes with cells attached were then plucked up from the dish, soaked in cryopreservation medium containing 10% dimethyl sulfoxide, frozen using a controlled-rate freezer, and transferred to liquid nitrogen. The cells cultured on plastic cell culture dishes were also frozen as controls. After storage in liquid nitrogen for periods from 1 week to 3 months, the cryopreserved membranes with the cells still attached were thawed by adding warmed culture medium. Cell viability estimated by morphology and functional staining with calcein showed significant improvement in comparison to cells cryopreserved without the collagen vitrigel membrane. The recoveries of living cells after cryopreservation were 26.7%, 76.2%, and 58.6% for rat hepatocytes, mitomycin C treated mouse fibroblasts, and mouse ES cells on collagen vitrigel membranes, respectively. In contrast, essentially no cells at all remained on the plastic cell culture dishes after thawing. Because adherent cell storage under these conditions is very convenient, the use of this technique employing collagen vitrigel membranes should be generally applicable to the cryopreservation of adherent cells that are otherwise problematic to store as frozen stocks. PMID- 19775525 TI - Superagonist CD28 antibody preferentially expanded Foxp3-expressing nTreg cells and prevented graft-versus-host diseases. AB - Regulatory lymphocytes play a pivotal role in preventing organ-specific autoimmune disease and in induction and maintenance of tolerance in various experimental transplantation models. The enhancement of the number and activity of peripheral CD4(+)CD25(+) Treg cells is an obvious goal for the treatment of autoimmunity and for the suppression of alloreactions. The present study demonstrates that naturally occurring CD4(+)CD25(+) Treg (nTreg) cells preferentially proliferate to a fourfold increase within 3 days in response to the administration of a single superagonistic CD28-specific monoclonal antibody (supCD28 mAb). The appearance of increased Foxp3 molecules was accompanied with polarization toward a Th2 cytokine profile with decreased production of IFN-gamma and increased production of IL-4 and IL-10 in the expanded Treg subset. Adoptive transfer of supCD28 mAb-expanded cells in a graft-versus-host disease (GvHD) model induced a potent inhibition of lethality. These results suggest that this therapeutic effect is mediated by the in vivo expansion of nTreg cells. Taken together, these data demonstrate that supCD28-mAb may target nTreg cells in vivo and maintain and enhance their potent regulatory functions for the treatment GvHD. PMID- 19775526 TI - Comparative study of the cellular pharmacodynamics of calcineurin inhibitors between patients with chronic renal failure awaiting renal transplantation and cirrhosis patients awaiting liver transplantation. AB - The in vitro response of peripheral blood mononuclear cells (PBMCs) to the suppressive effects of calcineurin inhibitors is known to correlate with the clinical efficacy of drugs used in renal transplantations. The present study was conducted to examine the differences of PBMC responses to calcineurin inhibitors between chronic renal failure (CRF) patients awaiting renal transplantation and cirrhosis patients awaiting liver transplantation. The study included 99 CRF patients awaiting renal transplantation and 27 cirrhosis patients awaiting liver transplantation. Twenty milliliters of venous blood was taken 1-7 days before transplantation. The in vitro drug concentrations giving 50% inhibition of PBMC blastogenesis stimulated with concanavalin A (IC(50)s) were calculated. The suppressive effects of tacrolimus against PBMC blastogenesis were more than 10 100 times stronger than those of cyclosporine. The median IC(50) value for cyclosporine against the CRF PBMCs was not significantly different from the median IC(50) value against the cirrhosis PBMCs. In contrast, tacrolimus sensitivity in cirrhosis PBMCs is approximately seven times higher than that in CRF PBMCs. The median IC(50) value for tacrolimus against cirrhosis PBMCs was significantly lower and therefore the effect was stronger in comparison to the CRF PBMCs (p < 0.001). These data suggest that the PBMCs of cirrhosis patients, in comparison to those of CRF patients, are highly sensitive to the suppressive effect of tacrolimus. However, PBMC sensitivity to cyclosporine was not significantly different between the CRF and cirrhosis patients. These observations raise the possibility that treatment with tacrolimus, rather than cyclosporine, may therefore be a better choice to reduce the risks of allograft rejection in liver transplantation. PMID- 19775527 TI - Global expression profiles in 1-hour biopsy specimens of human kidney transplantation from donors after cardiac death. AB - Because of the worldwide shortage of renal grafts, kidney transplantation (KTx) from donors after cardiac death (DCD) is an alternative way to obtain KTx from brain-dead donors. Although the prognosis of DCD KTx is gradually improving, the graft often undergoes delayed graft function (DGF), rendering the control of DGF essential for post-KTx patient care. In an attempt to characterize etiology of DGF, genome-wide gene expression profiling was performed using renal biopsy samples performed at 1 h after KTx from DCD and the data were compared with those of KTx from living donors (LD). A total of 526 genes were differentially expressed between them. Genes involved in acute inflammation were activated, while metabolic pathways were consistently downregulated in DCD. These findings imply the inferior performance of the DCD grafts relative to LD grafts. Several genes were identified where the expression levels were correlated well with parameters indicating short- and long-term prognosis of the DCD patients. In addition, several genes encoding secretory proteins were identified that might reflect the performance of the graft and be potential noninvasive biomarkers. These data provide a good source for candidates of biomarkers that are potentially useful for the control of DGF. PMID- 19775528 TI - Clinical significance of the cellular pharmacodynamics of tacrolimus in living donor liver transplantation. AB - Successful immunosuppressive therapy is critical for liver transplantation; however, a considerable number of patients experience fatal rejection or alternatively exhibit serious infection resulting from excessive immunosuppression. The in vitro tacrolimus response of peripheral blood mononuclear cells (PBMCs) before transplantation was compared to the clinical outcome up to 4 weeks after operation in 28 living-donor liver transplant recipients treated with tacrolimus. The tacrolimus IC(50) values against concanavalin A-induced PBMC blastogenesis in vitro were calculated. These recipients were classified into two groups with the mean tacrolimus IC(50) (0.18 ng/ml) as the cutoff point, after which the clinical outcome between the patient groups was compared. The allograft rejection incidence in the low-sensitivity group (IC(50) < 0.18 ng/ml; n = 16) was 6/12 (50.0%), which was significantly higher than the incidence of 2/16 (12.5%) in the high-sensitivity group (IC(50) > 0.18 ng/ml; n = 12) (p = 0.0297). In contrast, the infection incidence in the high-sensitivity group was 6/16 (37.5%), which was significantly higher than that of the low-sensitivity group (1/12; 8.3%) (p = 0.0401). These data suggest that patients exhibiting a low PBMC sensitivity to tacrolimus have a risk of rejection, whereas highly sensitive patients have a risk of infection in living donor liver transplantations under tacrolimus therapy. PMID- 19775529 TI - Hepatocytes from fibrotic liver possess high growth potential in vivo. AB - Hepatocyte transplantation is effective for treating liver failure, but healthy donors as a source of hepatocytes are quite limited. The livers of patients with hepatic fibrosis could be an alternative source; however, few reports have examined the nature of hepatocytes from fibrotic livers (f-hepatocytes). In this study, we compared the growth of f-hepatocytes and hepatocytes from normal livers (n-hepatocytes). Hepatocytes were isolated from normal and CCl(4)-treated wild type Fischer rats that express dipeptidyl dipeptidase IV (DPPIV) gene (DPPIV(+)). The n- and f-hepatocytes proliferated in culture at similar rates. Both types of hepatocytes were transplanted into DPPIV(-) mutant Fischer rats that had been treated with retrorsine to injure the liver and were partially hepatectomized (PHx) before transplantation. Both n- and f-DPPIV(+)-hepatocytes proliferated and formed colonies. The colony sizes of f-hepatocytes 21 days posttransplantation were approximately three times those of n-hepatocytes. The hepatocytes were analyzed using a fluorescence activated cell sorter (FACS). The FACS profile differed between f- and n-hepatocytes: f-hepatocytes were less granular, less autofluorescent, and smaller than n-hepatocytes. These characteristics of f hepatocytes resembled those reported for small-sized n-hepatocytes (SHs), which are highly proliferative and preferentially express a unique set of 10 SH genes. However, f-hepatocytes preferentially expressed only five of the SH genes. The expression profile of f-hepatocytes was rather similar to that of proliferating n hepatocytes in the regenerating liver after PHx. The f-hepatocytes were morphologically normal and did not show any preneoplastic phenotype. These normal and proliferative natures of f-hepatocytes in vivo suggest the fibrotic liver as a source of hepatocytes for transplantation. PMID- 19775530 TI - Preconditioned cell array optimized for a three-dimensional culture of hepatocytes. AB - Three-dimensional culture procedures have attracted attention in various fields of cell biology. A newly developed cell array assisted in the formation of hepatocyte spheroids by two innovations: 1) micropatterning by a hydrophilic polymer, and 2) the use of bovine carotid artery-derived HH cells as feeder cells. The former contributes to the standardization of the spheroid size and the latter to the maintenance of the spheroids. We created a way to provide a ready to-use cell array by cryopreservation of an HH feeder cell cultured array. After inoculation of HH cells on the cell array, the culture medium was replaced by freezing medium containing dimethyl sulfoxide. Thereafter, the array was frozen and stored in a -80 degrees C deep freezer. At the start of the hepatocyte culture, the cryopreserved HH cell array was thawed by adding warmed (37 degrees C) culture medium. The morphology and biological activities of the cryopreserved HH cells were intact, as confirmed by phase contrast microscopy and functional staining with calcein and formazan. The rat hepatocytes formed perfect spheroids on the cryopreserved HH cell array without any differences from those on the freshly prepared HH cell array. The CYP3A drug metabolism activities of the hepatocytes were well maintained on the cryopreserved and fresh cell arrays. The present protocol greatly shortened the time and labor required to prepare a cell array for culturing hepatocytes. PMID- 19775531 TI - Neovascularization induced around an artificial device implanted in the abdomen by the use of gelatinized fibroblast growth factor 2. AB - The development of a bioartificial pancreas (BAP) with immunoisolating fashion has been gaining attention as a new method for treating diabetes. We have been proceeding with the development of a bag-type BAP that can be easily implanted and that allows for the optional injection or rejection of cells at any time. If fibrosis develops around a BAP device, then the permeability of substances transmitted through a semipermeable membrane will decrease, thereby reducing the reactivity with glucose, so it is necessary for the material of the device to have an excellent histocompatibility. Furthermore, in order to improve the efficacy of BAP treatment, it is important to maintain an environment of ample blood flow around the device. We have created a bag-type device for BAP that is 20 x 20 mm in size and comprises two layers of membranes. We have used an EVAL membrane for the outer membrane of the two layers. The EVAL membrane is a semipermeable membrane with good insulin permeability, which functions as an immunoisolation membrane. The inner membrane consists of PAU-coated HD-PE (nonwoven material processed with polyaminourethan) and it is designed to function as a scaffold for cells. We used Lewis rats to determine whether the effectiveness of fibroblast growth factor 2 (bFGF) can be improved by concomitantly using bFGF with a capacity for blood vessel regeneration as well as bFGF immersed in a sheet of gelatin. We placed the BAP in the abdominal cavity and covered it with the greater omentum. We were able to significantly increase the blood flow and the number of new blood vessels in the tissue surrounding the BAP device by using gelatinized bFGF. There were only a few instances of fibrosis as a biological reaction to the EVAL membrane, and the infiltration of inflammatory cells was mild. There were no adverse effects related to implantation of the device. We confirmed in this study that the use of an implantable BAP device and bFGF allowed for a better blood flow around the BAP device. There were only minor instances of fibrosis and inflammation reaction around the BAP, thus indicating the BAP that we are currently developing to have an excellent histocompatibility. PMID- 19775532 TI - Splitting the technology: functional imaging between open and high-field magnetic resonance. PMID- 19775533 TI - Psychosexual well-being in women using oral contraceptives containing drospirenone. AB - Considerable advances have been made in hormonal contraception in recent years, geared at maximizing compliance and minimizing discontinuation. In oral contraceptive (OC) formulations, the estrogenic component, generally ethinyl estradiol (EE), has been reduced significantly and newer progestins like dienogest and drospirenone (DRSP), compounds with different molecular structures, have been introduced; in addition, new regimens (extended, flexible, 24/4 formats instead of the standard 21/7 format) and innovative delivery systems (vaginal rings, transdermal patches, subcutaneous implants and intrauterine devices) are available. The multitude of choices allows hormonal contraception to be tailored to the individual woman in order to obtain non-contraceptive benefits, without significant side effects, and also a favorable risk/benefit profile for her general and reproductive health. Over the past few years, new OC formulations combining DRSP (3 mg), a unique progestin with both antimineralocorticoid and antiandrogenic activities, with estrogen (30 mcg or 20 mcg EE), in two regimens (24/4 and 21/7) of active pills in a 28-day cycle, have shown positive effects on water retention-related weight gain and physical, emotional and psychosexual well being. It seems likely that the use of a low-dose, well-balanced OC and the shorter 4-day hormone-free interval may minimize the side effects that can impair quality of life and thus increase women's compliance with hormonal contraception therapy. PMID- 19775534 TI - Women, alcohol and the environment: an update and perspectives in neuroscience. AB - This paper highlights gender peculiarities in the neuroscience of alcohol effects and draws attention to emerging problems due to simultaneous exposure to alcohol and environmental factors. All the available gender studies on alcohol show greater severity of alcohol-related damage, including brain damage, in females compared with males. The differences are due to physiological peculiarities that make women more vulnerable to the effects of alcohol. Today the trend to start consuming alcohol at a younger age, together with the growing number of women drinking excessively, is increasing the alcohol-related risks to women's health and justifying the need for better, gender-based studies of alcohol use and abuse. A further aspect to consider in this context is the risk of the occurrence of foetal alcohol spectrum disorders and foetal alcohol syndrome in the offspring of women who drink during pregnancy. Several lines of evidence indicate that prenatal ethanol exposure can influence cell proliferation and differentiation in the central nervous system, causing severe neurotoxicity and permanent birth defects. PMID- 19775535 TI - Depression in women with epilepsy: clinical and neurobiological aspects. AB - Patients affected by epilepsy show a considerably higher incidence of depression compared with the general population. Since women are twice as likely as men to suffer from depression, female gender could be considered a major risk factor for developing this condition. Converging lines of evidence suggest that sex hormones, which are known to contribute to remodelling the hippocampus, play a pivotal role in both epilepsy and depression. In women, the role of sex hormone levels may be more important because of their physiological cyclic fluctuations. Oestrogens, more than other ovarian hormones, show an effect similar to antidepressant drugs by stimulating hippocampal synaptogenesis, thus exerting a protective role against seizures as well. This paper reviews the current knowledge on the neurobiological basis of depression in women with epilepsy. The emerging picture informs therapeutic strategies to improve the clinical management of this common comorbidity. PMID- 19775536 TI - Gender differences in the occurrence of Alzheimer's disease. AB - Prevalence studies on dementia generally show a higher risk in women than in men. American studies reported equal rates whereas European ones showed higher rates in women. Observational studies on hormone replacement therapy showed that treated women had a lower risk than untreated ones. Two large clinical trials in menopausal women did not find any protective effect of therapy with oestrogens or oestrogens plus progestinic hormones. However, as regards a potential protective role of female gonadal hormones on brain neurodegenerative diseases, this result cannot be considered conclusive since a large cohort study showed an increased risk of Alzheimer's disease (AD) in women who underwent early oophorectomy. A possible gender difference in the risk of AD is further supported by recent evidence suggesting that the brain's so-called cognitive reserve is reduced in women. The area of gender differences in AD and in neurodegenerative processes generally, although still largely unexplored, appears to offer great promise for the future development of better strategies of intervention for patients. PMID- 19775537 TI - Added diagnostic utility of CT perfusion and CT angiography in acute ischemic stroke. Evaluation of three different patient categories. AB - Patients with a clinical picture of acute ischemic stroke are a heterogeneous group. The aim of this study was to evaluate the added utility of CT perfusion (CTP) and CT angiography (CTA) in the workup of three different categories of acute ischemic stroke patients. Fifty patients (61+/-15 years old) were included in this retrospective analysis. Twenty-nine patients had transient ischemic attacks (TIAs) (Group I), 15 were not eligible for treatment with thrombolysis (Group II) and six showed no improvement after thrombolysis (Group III). CTP and CTA provided additional information, not revealed by plain CT, in all the Group II patients and in one third of the patients belonging to the other groups. The final diagnoses were TIA (n=23), thromboembolic cerebral infarctions (n=22), carotid artery dissection (n=4) and metastases (n=1). Of the 29 patients admitted with TIA, only 22 patients still had this diagnosis on discharge from the stroke unit. Given the risk of impending stroke, it would be important to include these modalities in the initial workup of TIA. PMID- 19775538 TI - Localisation of cervical spinal cord compression by TMS and MRI. AB - The authors set out to study the role of transcranial magnetic stimulation (TMS) in the pre-surgical assessment of patients with cervical spondylotic myelopathy. Central motor conduction time (CMCT) was calculated in 50 patients and 50 controls by recording muscle evoked potentials from upper limb muscles. The level of spinal cord compression was determined according to the pattern of CMCT prolongation and compared with the level disclosed by MRI. Direct comparison of the TMS and MRI results was possible in 42 cases and agreement was noted in 25 (59.5%). In the 23 patients in whom the two methods did not give convergent findings, post-operative data were used in order to determine the actual level of compression. This level was correctly indicated by TMS in 87.5% of cases and by MRI in 12.5%. TMS is a neurophysiological tool that can complement existing methods for determining the level of cervical spinal cord compression. PMID- 19775539 TI - Effects of systemic administration of the essential oil of bergamot (BEO) on gross behaviour and EEG power spectra recorded from the rat hippocampus and cerebral cortex. AB - Bergamot (Citrus bergamia Risso et Poiteau) is a citrus fruit growing almost exclusively in the South of Italy. Its essential oil is obtained by cold pressing of the epicarp and, partly, of the mesocarp of the fresh fruit. Although this phytocomplex has been used for centuries, reputedly effectively, as a traditional medicine, there is very little verified scientific evidence to support this use. This paper reports original data on the systemic effects of the essential oil of bergamot (BEO) on gross behaviour and EEG activity recorded from the hippocampus and cerebral cortex of the rat. The Fast Fourier Transformation (FFT) was used to analyse and quantify the energy in single frequency bands of the EEG spectrum. The results obtained indicate that systemic administration of increasing volumes of BEO produces dose-dependent increases in locomotor and exploratory activity that correlate with a predominant increase in the energy in the faster frequency bands of the EEG spectrum. These data contribute to our understanding of the neurobiological profile of BEO. PMID- 19775540 TI - ["Amarcord". Memories and anecdotes from my presidency of the AEDV (1977-1982) from the 50th anniversary of our academy (1959)]. PMID- 19775541 TI - [Actas Dermo-Sifiliograficas 1909-2009. The Legacy]. PMID- 19775542 TI - [Cutaneous adverse reactions to tattoos and piercings]. AB - Piercings and tattoos have become very popular in western society in recent decades, particularly among younger generations. Reports of medical complications associated with these decorative techniques have increased in parallel with the rise in their popularity. Due to their high frequency, adverse cutaneous reactions are particularly important among these potential complications. Tattoo related complications include a number of cutaneous and systemic infections secondary to breach of the epidermal barrier, acute and delayed inflammatory reactions with different histopathological patterns, the appearance of benign and malignant tumors on tattooed areas of skin, and certain dermatoses triggered by isomorphic phenomena. Piercing-related complications are similar, though some, such as pyogenic skin infections, are much more common due to the delayed wound healing after piercing in certain sites. We must differentiate between complications that are independent of the site of piercing, and specific complications, which are closely related to the body area pierced. The rate of complications after performing piercings or tattoos depends on the experience of the artist, the hygiene techniques applied, and the postprocedural care by the customer. However, some of these complications are unpredictable and depend on factors intrinsic to the patient. In this article, we review the most common decorative techniques of body art, with particular focus on the potential cutaneous complications and their management. PMID- 19775543 TI - [Dermatitis artefacta 100 years ago]. AB - In 1909, the Spanish dermatologist Juan de Azua published a study of the main features of skin lesions in dermatitis artefacta. In the article, he paid particular attention to the psychological state of these patients, their family situation, and what they were hoping to gain with pathomimicry. Azua directly confronted the patients with the diagnosis, which he demonstrated by applying an occlusive dressing. Written in a literary style typical of the times, the article includes the subjective impressions of Azua, through which he manages to transmit a much more realistic image of these patients than that portrayed with the sterile language we tend to use in current medical literature. PMID- 19775544 TI - [Complications in dermatologic surgery]. AB - Surgical complications are any deviation from the expected course of the surgical procedure. They occur as a consequence of one or more unexpected events, which can be avoided in the majority of cases through careful planning, a precise surgical technique, and correct postoperative care. Some complications, such as cardiac arrhythmias, anaphylaxis, and cardiorespiratory arrest, are life threatening whereas others, occurring as a direct result of surgery, can affect the healing process and the final cosmetic appearance of the scar. We must therefore have not only the relevant training in dermatologic surgery, but also in basic and advanced cardiopulmonary resuscitation. In this review we discuss the perioperative measures necessary to avoid the onset of complications in dermatologic surgery and we define the various complications that can develop. PMID- 19775545 TI - [Oral leukoplakia: clinical, histopathologic, and molecular features and therapeutic approach]. AB - Dermatology departments are currently seeing an increase in the number of cases of oral diseases. Of note among the range of lesions covered by this broad area of knowledge is oral leukoplakia-the most common precancerous lesion and the most problematic in terms of both diagnosis and therapeutic management. In addition to defining leukoplakia, this review also establishes a differential diagnosis with the other most important oral diseases and analyzes the different clinical, histologic, and molecular features that can provide an indication of the risk of malignant transformation. Finally, a therapeutic algorithm is presented to help us optimize clinical management of the disease. PMID- 19775546 TI - [Occupational dermatoses. Cross-cultural adaptation of the Nordic Occupational Skin Questionnaire (NOSQ-2002) from English to Spanish and Catalan]. AB - BACKGROUND: Eczema of the hands and urticaria are very common occupational dermatoses. The Nordic Occupational Skin Questionnaire (NOSQ-2002), developed in English, is an essential tool for the study of occupational skin diseases. The short version of the questionnaire is useful for screening and the long version is used to study risk factors. OBJECTIVE. The aim of this study was to culturally adapt the long version of the NOSQ to Spanish and Catalan and to ensure comprehension, semantic validity, and equivalence with the original. METHODS: The principles of the International Society for Pharmacoeconomics and Outcomes Research for good research practices were applied. A 4-phase method was used, with direct, revised translation, back translation, and cognitive interviews. RESULTS: After direct translation, a first version was issued by the Spanish Working Group. This version was evaluated in cognitive interviews. Modifications were made to 39 questions (68 %) in the Spanish version and 27 questions (47 %) in the Catalan version. Changes included addition of examples to improve understanding, reformulation of instructions, change to use of a direct question format, and addition of certain definitions. The back translation was evaluated by the original authors, leading to a further 7 changes in the Spanish version and 2 in the Catalan version. The third consensus version underwent a second round of cognitive interviews, after which the definitive version in each language was issued. CONCLUSION. Spanish and Catalan versions of the NOSQ-2002 questionnaire are available at www.ami.dk/NOSQ and www.arbejdsmiljoforskning.dk. PMID- 19775547 TI - [Microcystic adnexal carcinoma: Mohs micrographic surgery as the treatment of choice]. AB - INTRODUCTION AND OBJECTIVES: Microcystic adnexal carcinoma is a rare and aggressive tumor that manifests clinically as a subcutaneous nodule located on the head or neck. The tumor can be confused clinically and histologically with other benign and malignant skin lesions, often leading to inappropriate initial treatment. The chief concern with microcystic adnexal carcinoma is the elevated morbidity and the high rate of recurrence after wide local excision. Recent preliminary studies point to higher cure rates with Mohs micrographic surgery. MATERIAL AND METHODS: We reviewed the medical histories of 6 consecutive patients with microcystic adnexal carcinoma who underwent Mohs micrographic surgery in our dermatology department between 1995 and 2007. RESULTS: In all cases, lesions were located on the head and were primary tumors. Seventy percent of the tumors were wrongly diagnosed initially as basal cell carcinoma. Perineural invasion was not detected in any patient, and all were free of recurrence after between 1 and 12 years of postoperative follow-up. CONCLUSIONS: The absence of perineural involvement and substantial cell atypia can be attributed to the lesions being primary tumors. This would provide a rationale for definitive radical treatment of the primary tumor from the outset to avoid the complications associated with recurrence. The site and the absence of recurrence in all our patients who underwent Mohs micrographic surgery support the use of this technique as the treatment of choice in microcystic adnexal carcinoma. PMID- 19775548 TI - [CD1a+ Langerhans cells in the peritumoral epidermis of basal cell carcinoma]. AB - BACKGROUND: Basal cell carcinoma (BCC) is a common malignant tumor and its incidence has risen in recent decades. Research has shown the relationship between ultraviolet (UV) radiation, the skin immune system, and BCC. The role of Langerhans cells (LC) in the immune response to tumors has prompted research into LC density and morphology in response to UV radiation and BCC. However, the data are inconsistent due to differences in research methodology. OBJECTIVE. To study the density and morphology of LCs in the peritumoral epidermis of BCC using immunohistochemistry and image processing software and compare the results with those from the epidermis overlying the tumor. MATERIAL AND METHODS: Twelve samples from patients with BCC were prepared with a CD1a stain. Areas of epidermis overlying and adjacent to the tumor were defined using light microscopy and the Image J image processing software. The LCs in each area were counted and the cell densities were calculated and compared. Morphological features of LCs were also evaluated in each epidermal areas. RESULTS: The results showed a lower density of LCs in the epidermis overlying the tumor than in the peritumoral epidermis (p < 0.05). There were also differences in the size, shape, and dendritic pattern of the LCs between the epidermal areas. CONCLUSIONS: The lower density and fewer morphological changes of LCs in the epidermis overlying BCC may give rise to alterations in the immune response to BCC. Digital image analysis is a reliable method for the morphometric evaluation of LCs. PMID- 19775549 TI - [Acute postinfectious pityriasis rubra pilaris: a superantigen-mediated dermatosis]. AB - Acute postinfectious pityriasis rubra pilaris (PRP) is a variant of juvenile PRP (Griffiths type III) characterized by no family history, an acute course associated with a prior fever, and good prognosis. Clinical features may resemble other superantigen-mediated diseases, such as scarlatiniform rash or staphylococcal scalded skin syndrome, but its histology and treatment are different. We present 4 cases of acute postinfectious PRP that illustrate the clinical features of this uncommon disease and we review possible underlying pathogenic mechanisms. PMID- 19775550 TI - [Amicrobial pustulosis of the folds: report of a new case and review of literature]. AB - Amicrobial pustulosis of the folds is a rare disorder characterized by a recurrent sterile pustular rash mainly affecting the skinfolds, scalp, and periorificial regions such as around the external auditory meatus. Few cases have been reported in the literature, most of them occurring women and all of them associated with some immunological disorder, the most common being lupus erythematosus. We present a new case of amicrobial pustulosis of the folds in a woman; the only immunologic abnormality detected was an elevation of immunoglobulin E. We have also reviewed the 35 cases reported in the literature. PMID- 19775551 TI - [Skin and bone lesions in an adolescent boy]. PMID- 19775552 TI - [Perianal papules in a child]. PMID- 19775553 TI - [Syringomas and lichen amyloidosus as a presentation of reactive dermatosis]. PMID- 19775554 TI - [Tattoo-induced pigmentation in a sentinel node in a patient with melanoma]. PMID- 19775555 TI - [Fistula with foreign body granulomatous reaction caused by electrodes left in place after pacemaker removal]. PMID- 19775556 TI - [Diltiazem-induced acute generalized exanthemic pustulosis: a case and review of the literature]. PMID- 19775557 TI - [Chronic painless dactylitis as the initial finding in disseminated lung adenocarcinoma]. PMID- 19775558 TI - [Proliferating pilomatricoma treated using a bilateral advancement flap]. PMID- 19775559 TI - [Patients with malformations of the face, mouth, and fingers: type I orofaciodigital or Papillon-Leage Psaume syndrome]. PMID- 19775560 TI - [Refractory subacute cutaneous lupus erythematosus with a response to efalizumab]. PMID- 19775561 TI - [Palmoplantar cutaneous reaction to sorafenib]. PMID- 19775562 TI - [Utility of immunohistochemical analysis of CD34 expression in the diagnosis of lesions with trichilemmal differentiation]. PMID- 19775563 TI - [XXXV national congress of SEEIUC, Valladolid 2009]. PMID- 19775565 TI - [Analysis of 4 sedation rating scales in the critical patient]. AB - BACKGROUND: This study aimed to verify the relationship between different Sedation Rating Scales (SRSs) for critical patients on mechanical ventilation and to know the relationship between the SRSs, clinical information and the dose of sedative and analgesia drugs (SAD). MATERIAL AND METHODS: A longitudinal, prospective analytic pilot study conducted in a Medical-Surgical Intensive Care Unit of a tertiary hospital from October-December 2006. The sample included patients who required administration of SAP and mechanical ventilation. The following biological parameters and scales were evaluated: patient's demographics, RAMSAY, Sedation Agitation Scale (SAS), Richmond Agitation Sedation Scale (RASS), Motor Activity Assessment Scale (MASS), SAD dose, mean blood pressure, cardiac rate, pupil diameter and respiratory frequency. Spearman coefficient of interrelation was used to compare the relationship between the different scales. RESULTS: A total of 2.412 measurements were made for each variable: SRS, clinical information and SAD dose in 30 patients with different diseases, 63 % males, age 52 +/- 19 years, APACHEII 24 +/- 8, SAPSII 44 +/- 16, with an ICU mortality UCI 34 %. Median and IQ range of stay in ICU 15.5 and 20 days, of mechanical ventilation 9 and 14 days, of SAD 6 and 5.5 days and of paralyzing drugs (PD) 2 and 5 days, respectively. Interrelation was detected between all the SRSs, with p < 0.0001. The relationship between SAS, RASS and MASS was direct, whereas these were related inversely to RAMSAY. No evidence of interrelation was found between the SRSs, the clinical information and the SAD doses. CONCLUSION: The RAMSAY scale that has not been validated in ICU patients has a strong interrelation with the other already validated SRSs. SRSs are subjective and do not correlate with the clinical information and the SAD doses, probably due to the sample's small size and heterogeneity. PMID- 19775566 TI - [Apache III score: a prognostic factor in pressure ulcer development in an intensive care unit]. AB - OBJECTIVE. To analyze total APACHE III score association to pressure ulcers development in patients hospitalized in an intensive care unit (ICU). MATERIAL AND METHODS: Prospective cohort study conducted in an intensive care unit of the Hospital General de VIC. All the patients hospitalized between January 2001 to December 2001 were enrolled. Age, gender, length of stay, total Norton and APACHE III score and pressure sore development were collected. RESULTS: Pressure sore incidence was 12.5% of the patients. The factors were significantly associated with the appearance of pressure sores in those patients with a length of stay in the intensive care unit, total Norton and severity of the disease measured by the APACHE III score. Patients having the greatest risk of pressure ulcers development were those whose Norton score was less than or equal to 14, and an APACHE III score higher than or equal to 50 (Odds Ratio: 37.9, 95% CI 11.16 128.47) CONCLUSION: The severity of the diseases measured with the APACHE III scale showed a relationship with the appearance of in-hospital pressure ulcers. The joint use of the APACHE III and Norton scale could be a good strategy to detect patients with very high risk of suffering pressure sores. PMID- 19775567 TI - [The nursing profession regarding limitation of life support treatment in the intensive care units. Technical and practical features]. AB - The scientific and technical developments in medicine in the recent decades have greatly helped to increase life expectancy and quality of life of many patients. In hospitals, this technological scenario has clearly influenced patient care, for example, in the Intensive Medicine Departments, leading to new clinical perspectives and has made the growing complexity of giving treatment and making decisions more evident. In some cases, it is difficult to predict how beneficial intensive medical care can be when there is no reasonable prospect of improving the patient's health, prolonging their life in situations with poor prognosis or dramatically reducing their quality of life. The clinical diagnosis of irreversibility, through indicators of severity and principles of beneficence, autonomy and justice in the professional conduct are the elements that give rise to the consideration of withholding and withdrawing treatment in the critical patient. However, there are other factors that need to be taken into consideration and that are analyzed by professional ethics and bioethics. It is from this approach that any decision involving withholding and withdrawing treatment should be taken so that these decisions can be considered estimable form an ethical point of view. The nursing professional in intensive care units is expected to actively participate in decision making by contributing with their humanizing vision and care ethics. They should be aware of their contribution in the medical team behaving, representing and encouraging the requirements of bioethics. PMID- 19775568 TI - [Patient-noninvasive mechanical ventilation interaction]. AB - Noninvasive mechanical ventilation is one more step in the treatment of patients with acute respiratory failure. In addition to gas exchange disorders, its primary indication to initiate it is the presence of signs of respiratory muscles fatigue. To assure successful mechanical ventilation, the ventilator and patient must be synchronized, that is, the effort the patient makes to start inspiration is recognized by the ventilator and it quickly delivers gas flow, that the flow provided by the ventilator adapts to the flow need of the patient during delivery of gas phase and that the ventilator recognizes the cessation of inspiratory activity by the patient, ends the delivery of gas and opens the expiratory valve to allow the patient expiration. This sequence of events, which seem so logical, is almost never achieved in the clinical practice, commonly observing some asynchrony in ventilated patients. The presence of patient-ventilator asynchrony leads to increased breathing work, which would lead to the failure of the main objective of ventilatory support, that is none other than decline in the patient's respiratory work. PMID- 19775569 TI - [Review of knowledge on prophylaxis of the infection in the critical patient]. PMID- 19775570 TI - [Review of knowledge of nursing care in organ and tissue transplantation (Test answer Vol. 20-number 2)]. PMID- 19775571 TI - [Perception of the hospital nursing staff on intensive cares]. PMID- 19775572 TI - [The challenge of reducing costs for the treatment of renal anemia with erythropoietic factors]. PMID- 19775573 TI - [Position of the hospital pharmacist regarding the use of medication in non authorised conditions]. PMID- 19775574 TI - [Cost-reduction analysis for oral versus intravenous fludarabine (Beneflur) in Spain]. AB - INTRODUCTION: Various international studies have shown that fludarabine is effective, safe, and efficient for treating B-cell chronic lymphocytic leukemia (B-CLL). The purpose of the present study was to carry out a cost-minimization analysis for two alternative forms of fludarabine (oral and intravenous) used to treat B-CLL in Spain. METHODS: The presence of clinical evidence about the treatment equivalence of the two options being compared (oral fludarabine vs. intravenous fludarabine) led us to carry out a cost-minimization analysis. A pharmacoeconomic model was constructed to compile data from the literature and experts' opinions in order to determine the use of health resources associated with the treatment; unit costs were obtained from Spanish databases. The analysis contemplated two perspectives: that of the national health service, which includes only direct health costs, and the social perspective, which also includes the indirect costs that result from loss of productivity. RESULTS: Although fludarabine in its oral form has a higher purchase price than generic intravenous fludarabine does, increased administration costs for the latter, which is used in hospitals, mean that oral fludarabine use produces total savings of euro1,908 and euro1,292 for single-drug therapy and combined therapy with cyclophosphamide, respectively. Including indirect costs increased the savings associated with the oral form of the drug. CONCLUSIONS: In B-CLL patients, treatment with oral fludarabine has a lower cost than treatment with intravenous fludarabine, in both single-drug therapy and combined therapy. Various sensitivity analyses confirmed these results and showed that oral fludarabine should be the treatment of choice for B-CLL in Spain, unless contrain. PMID- 19775575 TI - [Budget impact of a set-dose combination of efavirenz-emtricitabine-tenofovir in the treatment of patients infected with HIV-1]. AB - OBJECTIVE: Estimate the budgetary impact of using a set-dose combination of efavirenz-emtricitabine-tenofovir for the Spanish health care system's treatment of patients infected with HIV-1, while evaluating repercussions for each autonomous community in 2008. METHODS: We developed a budgetary impact model with pharmacological costs for the different currently available treatment options, based on GeSida's recommended guidelines for treating HIV-positive patients. The model defines five possible scenarios in which various possibilities for substituting different drug cocktails with the efavirenz-emtricitabine-enofovir combination are contemplated. RESULTS: The investment per patient on a national level amounts to euro7,989 in the base scenario (without considering the availability of the efavirenz-emtricitabine-tenofovir combination) and to euro7,997, euro8,424, euro7,830, euro8,375 and euro8,527 for scenario 1 (substitution of recommended drugs with efavirenz, emtricitabine and tenofovir or efavirenz, lamivudine and tenofovir); scenario 2 (substitution of recommended drugs with efavirenz); scenario 3 (substitution of recommended drugs with tenofovir); scenario 4 (substitution of recommended drugs with tenoforvir or zidovudine) and scenario 5 (total substitution), respectively. Compared with the base scenario this means increments of 0.11 %, 5.45 %, -1.99 %, 4.83 % and 6.73 % for scenarios 1, 2, 3, 4 and 5. CONCLUSION: Use of a set combination of efavirenz, emtricitabine and tenofovir to treat adult patients with the HIV-1 virus would lead to slight surpluses or even budgetary savings by decreasing the number of daily doses, which could increase patients' quality of life and help them stay on the treatment properly. PMID- 19775576 TI - [Incident study of medication errors in drug use processes: prescription, transcription, validation, preparation, dispensing and administering in the hospital environment]. AB - OBJECTIVE: To determine both the global Incident, and the Incident for stages of medication errors in six Catalonian hospitals, the types of error and the consequences. METHOD: A prospective design, with the global variable of the medication error. Potential errors have been excluded. The patients admitted to each hospital were studied in 2 groups of up to 300 patients and 1,500 administrations were observed. The NCCMERP taxonomy was applied. The prescription error was detected through the review of prescriptions, checking the patient, medication, adherence to protocols, interactions, contraindications, omission, duplicated therapy, doses, frequency, method, and lack of follow-up. During the transcription/validation, it was verified that the prescription matched the original order. In the dispensing process, the content of the drawers was checked, comparing it to the computer generated list, before sending out the single dose trolley. The transcription, preparation and administration were observed on the wards. The information for all the procedures was registered in a specific data sheet. There was moderate concordance amongst the inspectors (kappa = 0.525). RESULTS: 16.94 errors were detected per 100 patients-day and 0.98 errors per patient: 16 % in prescription, 27 % in transcription/validation, 48 % in dispensing, and 9 % in administration. 84.47 % were category B errors (they did not reach the patient), and < 0.5 % of the errors were harmful. The population, with an average age of 65, had a male/female ratio of 60/40. The principal therapeutic groups were: agents against peptic ulcer and GERD, antithrombotic agents, and other analgesics and antipyretics, principally in a solid oral drug form (58 %). The medications per patient-day were 5.5 and the units of medication were on average 11.21, varying greatly among the institutions. The adjustment of 10 units made the results more uniform. In all the stages, omission was the most frequent error. DISCUSSION: The different methods used and different areas of the investigations make comparisons difficult. This is evident in the harmful errors, the proportion of which is affected by the detection procedure. The number of mistakes avoided during the execution of this project demonstrates the need to improve the planning of the work systems and to establish safety measures. PMID- 19775577 TI - [Quality of the pharmacotherapeutic recommendations for the integrated care procedures in Andalusia]. AB - OBJECTIVES: To evaluate the quality of the pharmacotherapeutic recommendations included in the Integrated Care Procedures (PAIs regarding its initials in Spanish) of the Andalusian Ministry of Health, published up to March 2008, through the design and validation of a tool. METHODS: The assessment tool was designed based on similar instruments, specifically the AGREE. Other criteria included were taken from various literature sources or were devised by ourselves. The tool was validated prior to being used. After applying it to all the PAIs, we examined the degree of compliance with these pharmacotherapeutic criteria, both as a whole and by PAIs subgroups. RESULTS: The developed tool is a questionnaire of 20 items, divided into 4 sections. The first section consists of the essential criteria, and the rest make reference to more specific, non essential criteria: definition of the level of evidence, thoroughness of information and definition of indicators. It was found that 4 of the 60 PAIs do not contain any type of therapeutic recommendation. No PAI fulfils all the items listed in the tool, however, 70 % of them fulfil the essential quality criteria established. CONCLUSIONS: There is a great variability in the content of pharmacotherapeutic recommendations for each PAI. Once the validity of the tool has been proved, it could be used to assess the quality of the therapeutic recommendations in clinical practice guidelines. PMID- 19775578 TI - [Review of legislation regarding clinical research in the Spanish health care system and hospital pharmacy services]. AB - The call for public funding for the Spanish Health Care System clinical research with drugs for human use projects Subprogramme highlights the need for hospital pharmacy services to include the manufacture of investigational drugs which are the subject of a clinical trial, developed by either a researcher or a group of researchers, within its activities. This article discusses the legislation concerning the manufacture of investigational drugs and the requirements that the pharmacy services must meet in order to develop, distribute, or conceal an investigational drug in a clinical trial sponsored by a professional from the SHS. PMID- 19775579 TI - [Bivalirudine in heparin-induced thrombocytopenia]. PMID- 19775580 TI - [Generalised clonic seizure associated with vincristine in a pediatric case]. PMID- 19775581 TI - [Sorafenib: effectiveness versus safety. Prevention of hand-foot syndrome]. PMID- 19775582 TI - [Hepatitis associated with aqueous green tea infusions: a case study]. PMID- 19775583 TI - [Decline of clinical art and growth of high-tech medicine]. PMID- 19775584 TI - [Post-hospital mortality in patients re-admitted due to COPD. Utility of BODE index]. AB - BACKGROUND: The BODE index can accurately predict mortality in ambulatory patients with COPD, although its utility in hospitalized patients is unknown. MATERIAL AND METHODS: We prospectively evaluated all patients hospitalized during one year for acute exacerbation of COPD with one or more admissions in the previous year. On discharge, previous functional dependence, comorbidity, depression and quality of life, among other variables, were evaluated. Body mass index, 6-minute walking test, dyspnea scale and spirometry with a post bronchodilator test were performed on the last day of hospitalization and the BODE index was calculated using these data. RESULTS: A total of 66 patients were included, with a mean age of 71.6 +/- 8.9 years. Of these patients, 42 (63.6%) died before the end of the study (median follow-up 1,490 days). A higher mortality was observed among the oldest patients (p < 0.004), those with more comorbidities (p < 0.05), worse score on the BODE index (p < 0.006; OR 1.3; CI 95%: 1.07-1.54) and the dyspnea scale (p < 0.008). Functional dependence (p < 0.02), and pCO2 > 45 mmHg at discharge (p < 0.001) were also significant predictors of mortality. In the multivariate analysis, only hypercapnia (p < 0.004; OR 3.48; CI 95% 1.49-8.14) and the BODE index (p < 0.0005; OR 1.47; CI 95%: 1.18-1.82) were independent predictors of mortality. CONCLUSIONS: The BODE index measured at hospital discharge is an accurate and reliable predictor of mortality in patients who require several admissions for acute exacerbations of COPD. PMID- 19775585 TI - [Restless legs syndrome: detection, diagnosis, impact on health and utilization of health care resources]. AB - INTRODUCTION: Despite the high prevalence of Restless Legs Syndrome (RLS) reported, little information is available about this disorder in Spain. The present study was conducted to obtain information on this condition from patients identified by a simple screening questionnaire and subsequent diagnostic confirmation by the Primary Care Practitioner (PCP). MATERIALS AND METHODS: Three stage, cross-sectional and retrospective (resource utilization), observational study in a sample of adult patients (2,047 subject) attending 10 outpatient Primary Care centers in Madrid, Barcelona and Valencia. A screening questionnaire containing the 4 RLS diagnostic criteria was used. Clinical assessment and RLS diagnosis confirmation was performed using a structured questionnaire. Other variables assessed were quality of life by SF-36 questionnaire scoring; sleep by the MOS sleep scale; symptom severity of RLS symptoms by the IRLS scales; health care resource utilization in the previous 12 months by completion of questionnaire following patient chart review. The diagnosis made by the PCP was confirmed in a small sample of patients by a neurologist expert in Movement Disorders. RESULTS: A total of 19.7% (404 out of 2,047) subjects positively answered the 4 diagnostic questions of the RLS screening questionnaire. Of these, 185 (9.0%) reported moderate to severe symptoms at least twice weekly. The PCP made a diagnosis of RLS in 79 of 154 patients completing the diagnostic interview. Thus, prevalence of RLS estimated in this adult population was 4.6%. The predictive value of the screening RLS questionnaire was 51.3%. Average age of symptom onset was 42 years (range: 20 - over 80 years). RLS symptoms were moderately (50.6%) or extremely (38%) distressing and 73.4% of RLS patients slept poorly at least two nights a week. This diagnosis represents 9.4% of all patients presenting to PCP and experiencing poor sleep. Mean score in the IRLS scale (0 - 40) was 19.4. Average score of SF-36 questionnaire (0-100) was 54.6, lower than the Spanish general reference population (61.4). About one third of the RLS patients had seen a physician because of RLS symptoms. However, a diagnosis was made in only 48% of these and only 5% the diagnosis was RLS. CONCLUSIONS: The DECODE RLS - Spain study shows that many patients with classical RLS symptoms frequently see their PCP without being adequately diagnosed and treated. Screening tools such as that used in this study may contribute to the detection of these patients. PMID- 19775586 TI - [Characteristics of acute pyelonephritis at a short-stay medical unit]. AB - OBJECTIVES: To analyze the epidemiological characteristics of the population admitted to a short-stay medical unit (SSMU) during 2005 due to acute pyelonephritis. To describe and analyze microbiological aspects recorded in these infections and their clinical implication. MATERIAL AND METHOD. A retrospective study was carried out in a cohort of 208 patients admitted in the SSMU during 2005 because of acute pyelonephritis. Epidemiological, clinical and microbiological data were collected. The statistical analysis was done with the SPSS v. 14.0. RESULTS: 208 patients were included, 74% of whom were females. Average age was 43.6 (16-87). Mean length of stay was 4.7+/-1.2 days and 96.6% of patients were discharged successfully from SSMU. Urine culture was valid in 173 patients, 51.4% of which were positive. Escherichia coli was isolated in 93.2% of urine cultures. Blood cultures were valid in 178 cases and in 37 of which were positive. E. coli was isolated in 64.8% of these. In E. coli urine samples, resistance rate to ampicillin was 68.7%, to cotrimoxazole 22.9%, to ciprofloxacin 18.1%; to amoxicillin/clavulanic acid 16.9% and to fosfomycin 2.4. Seven patients were transferred to hospital home care, there being no deaths. CONCLUSIONS: Acute pyelonephritis with admission criteria can be managed successfully in the SSMU with the applicable therapeutics guidelines with regard to the most common microbiological aspects registered and the low incidence of complications. PMID- 19775587 TI - [Patient with bilateral lung nodes like metastasis. Late silicosis]. AB - We present a 72-year-old patient that he has admitted to analize a large amount and bilateral lung nodes in a incidentally thorax x-ray. It is carried out a lung node biopsy, with a result of silicoanthacosis. PMID- 19775588 TI - [An intervention program to improve the quality of the medical records in an Internal Medicine Department]. AB - INTRODUCTION: The medical records are key documents for the patient's diagnosis, treatment and follow-up. Thus, the clinical histories must be made with high technical quality. Although some studies relate the quality of the clinical history with better control of a disease, as far as we know, there are few that evaluate the quality of the medical record itself. This study aims to analyze the quality of the clinical histories of our Internal Medicine Department and then evaluate the improvement achieved. MATERIAL AND METHODS: A descriptive and intervention study with a before and after design was conducted. It included 186 medical records elaborated by the physicians of our Internal Medicine Department. A 16-item Likert-like scale was designed for the evaluation. The items were analyzed item by item and a score combining them was elaborated. A baseline analysis and a second analysis 3 months after making several interventions were made. RESULTS: Weak points were detected in the baseline analysis (described) and after the interventions. There was an improvement in almost all the items, this being very significant in the recording of allergies and habits. The global score also improved significantly. CONCLUSION. The study has allowed us to learn our weak points in the elaboration of the medical records. We have improved their quality with the interventions. We estimate that this intervention has also been useful for the training of internal medicine physicians, residents and students. PMID- 19775589 TI - [47-year old patient with pericardial effusion]. PMID- 19775590 TI - [Male with acute left iliac fossa pain]. PMID- 19775591 TI - [Patient with respiratory insufficiency and stridor]. PMID- 19775592 TI - [Spontaneous bacterial peritonitis and Listeria monocytogenes]. PMID- 19775593 TI - [Immunologic therapy in severe psoriasis pustulosa]. PMID- 19775594 TI - [Utility of magnetic resonance spectroscopy for the non-invasive diagnosis of cerebral tuberculomas]. PMID- 19775596 TI - Ethanol induces apoptosis in human mast cells. AB - AIMS: Alcohol abuse is associated with increased frequency of infections attributed to ethanol-induced immune suppression. The precise mechanism of immune suppression is however not known. Mast cells (MC) belong to the innate immune system and they have been implicated in the first line of immune defence against bacteria and parasites. Therefore we studied the effects of ethanol and its first metabolite acetaldehyde on mast cell viability, proliferation and apoptosis. MAIN METHODS: Human mast cell line (HMC)-1 cells, mouse bone marrow derived mast cells (mBMMC) and human peripheral blood derived mast cells (HuMC) were used. Effects of ethanol and acetaldehyde on mast cell proliferation were determined by assessing incorporation of [(3)H]thymidine into cellular DNA and by trypan blue exclusion. Apoptosis was assessed by measuring apoptotic nucleosomes and caspase 3, -8 and -9 activities using ELISA and by using Tunel assay. The expression of anti- and proapoptotic proteins Bcl-2 and Bax was analyzed by RT-PCR and western blot, respectively. KEY FINDINGS: Ethanol, but not acetaldehyde inhibited dose dependently the proliferation and viability HMC-1 and mBMMC cells. The decreased viability was caused by apoptotic cell death of the MC. Significant apoptosis of HMC-1 cells was observed in the presence of 43mM (2.5 per thousand) ethanol. Induction of apoptosis was associated with clearly increased caspase-3 activity and moderately increased caspase-8 and 9 activities. Ethanol also shifted the Bcl 2/Bax balance towards apoptosis. SIGNIFICANCE: The ethanol-induced reduction of MC viability could contribute to immunosuppression associated with ethanol abuse. PMID- 19775595 TI - Mutations in the Salmonella enterica serovar Choleraesuis cAMP-receptor protein gene lead to functional defects in the SPI-1 Type III secretion system. AB - Salmonella enterica serovar Choleraesuis (Salmonella Choleraesuis) causes a lethal systemic infection (salmonellosis) in swine. Live attenuated Salmonella Choleraesuis vaccines are effective in preventing the disease, and isolates of Salmonella Choleraesuis with mutations in the cAMP-receptor protein (CRP) gene (Salmonella Choleraesuis Deltacrp) are the most widely used, although the basis of the attenuation remains unclear. The objective of this study was to determine if the attenuated phenotype of Salmonella Choleraesuis Deltacrp was due to alterations in susceptibility to gastrointestinal factors such as pH and bile salts, ability to colonize or invade the intestine, or cytotoxicity for macrophages. Compared with the parental strain, the survival rate of Salmonella Choleraesuis Deltacrp at low pH or in the presence of bile salts was higher, while the ability of the mutant to invade intestinal epithelia was significantly decreased. In examining the role of CRP on the secretory function of the Salmonella pathogenicity island 1 (SPI-1) encoded type III secretion system (T3SS), it was shown that Salmonella Choleraesuis Deltacrp was unable to secrete the SPI-1 T3SS effector proteins, SopB and SipB, which play a role in Salmonella intestinal invasiveness and macrophage cytotoxicity, respectively. In addition, caspase-1 dependent cytotoxicity for macrophages was significantly reduced in Salmonella Choleraesuis Deltacrp. Collectively, this study demonstrates that the CRP affects the secretory function of SPI-1 T3SS and the resulting ability to invade the host intestinal epithelium, which is a critical element in the pathogenesis of Salmonella Choleraesuis. PMID- 19775597 TI - Bioactive flavones and biflavones from Selaginella moellendorffii Hieron. AB - Three new flavones named 5-carboxymethyl-4',7-dihydroxyflavone (1), its ethyl ester (2) and butyl ester (3) were isolated from the herb Selaginella moellendorffii Hieron., together with ten known compounds. Their structures were elucidated on the basis of spectroscopic and chemical analysis. Selected compounds were evaluated for their anti-HBV and cytotoxic activity. Among them, compounds 2 and 3 displayed inhibitory activity in vitro on hepatitis B virus (HBV) surface antigen (HBsAg) secretion of the Hep G2.2.15 cell line with IC(50) values of 0.17 mg/ml and 0.46 mg/ml, and on HBV e antigen (HBeAg) secretion with IC(50) values of 0.42 mg/ml and 0.42 mg/ml, respectively. Compounds 7, 8, 10 and 12 exhibited selective cytotoxicity against the three human cancer cell lines tested. PMID- 19775598 TI - Proteome analysis of Citrus sinensis L. (Osbeck) flesh at ripening time. AB - A combination of 2-DE and LC-MSMS approaches was used to identify the differentially expressed proteome of a pigmented sweet orange (Citrus sinensis, cv. Moro) in comparison with a common cultivar (Cadenera) at ripening time. The comparison of the protein patterns of Moro and Cadenera showed 64 differential expressed protein spots. Fifty-five differentially expressed proteins were identified. Proteins were classified according to their putative function and known biosynthetic pathways. Most of the proteins related to sugar metabolism were overexpressed in Moro, while those related to stress responses were overexpressed in Cadenera. The abundance of proteins belonging to Unknown/Unnamed and Hypothetical classes could be associated to the incomplete data available on the Citrus genome. The relative abundance of Secondary metabolism and Oxidative process proteins substantiated the key role of the anthocyanin pathway in Moro, which is characterized by a strong pigmentation at ripening time. The potential role of protein differential expression between Moro and Cadenera fruits was discussed, and proteomic results were compared with the known variations of transcripts of the same fruits. The latter analyses highlighted many discrepancies, confirming the necessity to associate both proteomic and transcriptomic approaches in order to achieve a more complete characterization of the biological system. PMID- 19775599 TI - Low temperature restoring effect on F508del-CFTR misprocessing: A proteomic approach. AB - To gain insight into the proteins potentially involved in the low temperature induced F508del-CFTR rescue process, we have explored by two-dimensional electrophoresis (2DE) the proteome of BHK cell lines expressing wt or F508del CFTR, grown at 37 degrees C or 26 degrees C/24h or 26 degrees C/48h followed by 3h of metabolic labelling with [(35)S]-methionine. A set of 139 protein spots (yielding 125 mass spectrometry identifications) was identified as differentially expressed (p ANOVA<0.05) among the six phenotypic groups analysed. The data analysis suggests that the unfolded protein response (UPR) induction and some cell-metabolism repression are the major cold-shock responses that may generate a favourable cellular environment to promote F508del-CFTR rescue. Down-regulation of proteasome regulatory PA28 and/or COP9 signalosome subunit, both involved in CFTR degradation, could also be a relevant cold-shock-induced condition for F508de-CFTR rescue. Moreover, cold-shock may promote the reestablishment of some proteostasis imbalance associated with over-expression of F508del-CFTR. In BHK F508del cells, the deregulation of RACK1, a protein described to be important for stable expression of CFTR in the plasma membrane, is partially repaired after low temperature treatment. Together these findings give new insights about F508del CFTR rescue by low temperature treatment and the proteins involved could ultimately constitute potential therapeutic targets in CF disease. PMID- 19775600 TI - Pathological definition of triple negative breast cancer. PMID- 19775601 TI - Clinical relevance of the triple-negative breast cancer concept: genetic basis and clinical utility of the concept. AB - The beginning of microarray technology in the 1990s and the sequencing of the human genome in 2000 paved the way for the seminal paper of the Stanford group on the molecular portraits of human breast tumours in the same year. They described four distinct breast cancer subtypes, which they called 'luminal', 'basal', 'HER2 positive', and 'normal breast-like', based on unique gene expression patterns. This paper caused a paradigm shift. Breast cancer was no longer hormone receptor positive or -negative, but rather luminal, basal or HER2-positive. Since then, numerous papers have appeared, trying to further characterise these subtypes on the DNA, RNA and protein level. Other groups have focussed on the epidemiology, prognosis and outcome after therapy of breast cancer patients according to these molecular subtypes. A promising prognostic marker within the subgroup of basal like breast cancer is an up-regulated immune response, which is associated with favourable outcome. In addition, the majority of basal-like breast cancers harbour traits of a DNA damage repair defect. This feature can be exploited by the use of DNA damaging agents, and first exciting clinical results of the combination of carboplatin, gemcitabine and a poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor have recently been reported. In this review, the molecular characterisation of triple-negative breast cancer, a proxy for basal-like breast cancer, is described and findings have been put into clinical context. PMID- 19775602 TI - Triple negative breast cancers: clinical and prognostic implications. AB - Triple negative breast cancers are defined by the absence of oestrogen, progesterone and HER2 expression. Most triple negative cancers display distinct clinical and pathological characteristics with a high proportion of these tumours occurring at a younger age of onset and in African-American women. Triple negative tumours typically demonstrate high histological grade and are the most common breast cancer subtype in BRCA1 carriers. In addition, many of the features of triple negative cancers are similar to those identified in the basal-like molecular subtype which has recently been characterised by gene expression profiling. Although the two groups overlap, they are not synonymous. Triple negative breast cancers are of pivotal clinical importance given the lack of therapeutic options. The prognostic significance of triple negative tumours remains unclear since the group is heterogeneous and worst prognosis seems to be mostly confined to those that express basal cytokeratins or epidermal growth factor receptor (EGFR). This review focuses on outlining the pathological, molecular, and clinical features of triple negative breast cancers, discusses its prognostic value and summarises current therapeutic approaches and future directions of research. PMID- 19775603 TI - Clinical predictive factors. PMID- 19775604 TI - Chemotherapy, which drugs and when. PMID- 19775605 TI - How to integrate biologicals in the continuum of care. PMID- 19775606 TI - Impact of molecular markers on treatment selection in advanced colorectal cancer. PMID- 19775607 TI - New approaches and targets in advanced colorectal cancer. PMID- 19775608 TI - The multidisciplinarity of stage III non-small cell lung cancer. PMID- 19775609 TI - Surgical treatment of stage III non-small cell lung cancer. PMID- 19775610 TI - Radiotherapy for locally advanced non-small cell lung cancer. PMID- 19775611 TI - Chemotherapy in stage III non-small cell lung cancer. PMID- 19775612 TI - Treatment of local progression following radiotherapy. PMID- 19775613 TI - Salvage radiotherapy in patients with persisting/rising PSA after radical prostatectomy for prostate cancer. PMID- 19775614 TI - Hormonal treatment for progression. PMID- 19775615 TI - Chemotherapy in patients with castration-resistant prostate cancer. PMID- 19775616 TI - Stem cells and cancer in the aerodigestive tract. AB - Recently, there have been significant advances in our knowledge of stem cells found in epithelial tissues. In particular, novel stem cell markers have been identified that for the first time identify multipotential cells; a required characteristic of a stem cell. The scarcity of cancer stem cells has been questioned. Current dogma states that they are rare, but novel research has suggested that this may not be the case. Here I review the latest literature on stem cells, particularly so-called cancer stem cells present in tumours of the respiratory tract and colorectum. I discuss current thinking on how stem cells develop into cancer stem cells, how they protect themselves from doing so, and whether cancer stem cells express unique markers that can be used to detect them. Finally, I attempt to put into perspective these latest advances in cancer stem cell biology from the viewpoint of perhaps more effective cancer therapies. PMID- 19775617 TI - Mammary epithelial and breast cancer stem cells. PMID- 19775618 TI - Cancer stem cells and the cellular hierarchy in haematological malignancies. AB - Malignancies in the haematopoietic system seem to depend on a small subset of so called cancer stem cells (CSC) for their continued growth and progression - this was first described as the "sleeper-feeder theory" for leukaemia. The leukaemia stem cell was the first of such subsets to be described although the origins of these cells have been difficult to dissect. Consequently, their biology is not fully elucidated, which also holds true for the normal-tissue counterparts. The stem cell concept describes stem cells to be of low frequency, self renewing and with multilineage potential based on phenomenology - a definition which may not hold strictly true for CSCs when studied in animals and humans in vivo and in vitro. Several studies have analysed the cellular hierarchy of the haematopoietic system by cell sorting of few and even single cells, tracking acquired genetic changes and performing transplantation model studies to document subsets within the differentiating hierarchy as potential CSC compartments. In leukaemia the CSC has been described in the bone marrow compartment of haematopoietic stem cells (HSC); however, in other bone marrow disorders like multiple myeloma it is likely that the cell of origin is a more differentiated cell, like post-germinal memory B cells or plasmablasts. Studies performed so far have even indicated that the genetic events may occur in different B cell subsets in accordance with the stepwise oncogenesis of the disease. Although our understanding of the nature and biology of these initiating cells remains unknown, the obvious existence of such cells has implications for understanding initial malignant transformation and disease metastasis or progression and, most important, the selection of individualised therapeutic strategies targeting the subsets harbouring the CSC function. In the present review on stem cells in haematological malignancies we have focused on two topics, first, describing the stem cell concept in health and disease, and its "phenomenology", and second, describing the CSC compartments in leukaemia and multiple myeloma. PMID- 19775619 TI - The epidermal growth factor system of ligands and receptors in cancer. PMID- 19775620 TI - RAS in cellular transformation and senescence. PMID- 19775621 TI - p53: balancing tumour suppression and implications for the clinic. AB - It is well accepted today that cancer develops through a multi-step process that involves normal cells being led by well-defined phases into cancer cells. Along this process cells lose their natural cancer defence system that is mediated by tumour suppressor genes and accumulate genetic instabilities that permit the expression of the specific oncogenic networks. Remarkable is the p53 tumour suppressor which is mutated in more than 50% of human cancers. In turn, various mutant p53 proteins with an oncogenic activity are accumulated in the cells and contribute to malignancy. This chapter overviews the p53 field with respect to the history behind the discovery of the p53 tumour suppressor, the structure and function of p53, the oncogenic activities of the various p53 mutants and the clinical significance of a tailor-made p53-based gene therapy. PMID- 19775622 TI - Surgical aspects of neuroendocrine tumours. PMID- 19775623 TI - Lung tumours with neuroendocrine differentiation. PMID- 19775624 TI - Multiple endocrine neoplasia type 2 (MEN 2). PMID- 19775625 TI - Role of radiopharmaceuticals in the diagnosis and treatment of neuroendocrine tumours. PMID- 19775626 TI - Skin toxicities of targeted therapies. PMID- 19775627 TI - Management and interpretation of novel toxicities of molecular targeted therapies: renal toxicities. PMID- 19775628 TI - Cardiovascular toxicity of molecularly targeted agents. PMID- 19775629 TI - Gastrointestinal toxicities of novel agents in cancer therapy. PMID- 19775631 TI - The rationale and potential of cancer chemoprevention with special emphasis on breast cancer. PMID- 19775632 TI - Prostate cancer--chemoprevention. PMID- 19775633 TI - Colorectal cancer chemoprevention: ready for practice? PMID- 19775634 TI - Neoadjuvant chemotherapy for breast cancers: current recommendations and future directions. PMID- 19775635 TI - Genomic profiling of colorectal cancer. PMID- 19775636 TI - Lung cancer screening with low dose computed tomography: where do we stand today? PMID- 19775637 TI - Current challenges in lung cancer early detection biomarkers. PMID- 19775638 TI - New agents in metastatic prostate cancer. PMID- 19775639 TI - Particle therapy--physical, technical and clinical aspects. PMID- 19775640 TI - HPV and prognosis for patients with oropharynx cancer. PMID- 19775641 TI - Therapy of diffuse large B-cell lymphomas. PMID- 19775642 TI - MicroRNAs and their antagonists as novel therapeutics. PMID- 19775643 TI - Whole body optical imaging in small animals and its translation to the clinic: intra-operative optical imaging guided surgery. AB - Whole body optical imaging using bioluminescence or fluorescence is one of the most rapidly emerging technologies to non-invasively follow all kinds of molecular and cellular processes in small animals. Using tomographic approaches it is now also possible to get better quantitative data. Due to its sensitivity and simplicity it is now also widely used in drug development and drug screening. Finally, using near infrared fluorescent probes that have much deeper penetration also opens up new exciting applications such as intra-operative image guided surgery for sentinel lymph node mapping and radical resection of tumours. Recent advances in imaging strategies that reveal cellular and molecular biological events in real-time facilitate our understanding of biological processes occurring in living animals. The development of molecular tags, such as green fluorescent protein (GFP) from the jellyfish Aequorea victoria, red fluorescent proteins (RFP) from the Discosoma species (dsRed2) and luciferase (Luc) from the firefly Photinus pyralis (fLuc) and the sea pansy Renilla (rLuc), has revolutionised research over the past decade, allowing complex biochemical processes to be associated with the functioning of proteins in living cells. Optical technologies, both microscopic and macroscopic, are developing fast. Recent technical advances for imaging weak visible light sources using cooled charged coupled device (CCCD) cameras, peltier cooled detectors and micro-plate channel intensifiers allow detection of photon emission from inside the tissues of small animals. Whole body fluorescent imaging (FLI) and bioluminescent imaging (BLI) are now applied to study cell- and tissue-specific gene promoter activity and also to follow trafficking, differentiation and fate of i.e. GFP or RFP and/or luciferase expressing cells, or biological processes like apoptosis, protein-protein interaction, angiogenesis, proteolysis and gene-transfer. Optical imaging (OI) and optical reporter systems are also very cost-effective and time efficient and they are particularly well suited for small animal imaging and for in vitro assays to validate different reporter systems. PMID- 19775644 TI - Bisphosphonates for care and cure. PMID- 19775646 TI - Rare tumours of the chest. PMID- 19775645 TI - Beyond the KRAS test. PMID- 19775647 TI - PSA screening--a review of recent studies. PMID- 19775648 TI - The value of new imaging technology for target volume delineation. PMID- 19775649 TI - Cancer and nutrition: key determinants of quality of life. PMID- 19775650 TI - Re-irradiation of brain tumours--evidence, indications and limitations. PMID- 19775651 TI - Allogeneic blood stem cell transplantation. PMID- 19775652 TI - Biology of cancer and ageing. PMID- 19775653 TI - Minichromosome maintenance proteins in cancer screening. PMID- 19775654 TI - Advances in fertility preservation for children and adolescents with cancer. PMID- 19775655 TI - Cardiac disease and second lung cancer after radiotherapy for breast cancer. PMID- 19775656 TI - Screening for colorectal cancer, where are we now? AB - The most important disadvantage of the currently available colonoscopes is the need for bowel preparation. Preparation less virtual would be an attractive option. The cost of the new endoscopic methods for colorectal cancer screening is another issue, and needs to be reduced to less than US$200 if large-scale use is intended. Proof of concept for the new endoscopes has been achieved, although significant improvements are still required before colonoscopy can be replaced. PMID- 19775657 TI - Treatment of limited disease small cell lung cancer. PMID- 19775658 TI - Subclassification of ovarian cancer based on pathology and genetics. PMID- 19775659 TI - IMRT and molecular biological approaches in radiotherapy for prostate cancer. PMID- 19775660 TI - Value of quality indicators for cancer services. PMID- 19775661 TI - Current treatment of high risk testis cancer. PMID- 19775662 TI - Pharmacokinetics and pharmacodynamic biomarkers in early oncology drug development. PMID- 19775663 TI - Antiemetics: state of the art. PMID- 19775664 TI - Epigenetic information in chromatin and cancer. AB - It is now widely recognised that epigenetic changes are implicated in human cancer. Epigenetic information in chromatin (known as the 'histone code') has been proposed to extend and modulate the genetic (DNA) code in the regulation of key cellular processes. Histone modifications and histone modifying complexes have been traditionally associated with transcriptional regulation; however, recent studies indicated that the mechanisms involving the histone code play important roles in DNA replication, DNA damage detection and DNA repair. The histone code is believed to be 'read' by cellular machineries to regulate accessibility to, and functions of, chromatin DNA and the disruption of this code may lead to diseases, notably cancer. PMID- 19775665 TI - The challenge of interacting with patients in oncology. PMID- 19775666 TI - An update of sentinel node biopsy in breast cancer. PMID- 19775667 TI - Portrait of invasive lobular carcinoma of the breast. PMID- 19775668 TI - Current standards and options in the treatment of squamous cell oesophageal carcinoma. PMID- 19775669 TI - Psycho-science: where do we go from here? PMID- 19775670 TI - Cervical cancer and vaccination--an overview. PMID- 19775671 TI - Functional image-guided intensity modulated radiation therapy: integration of the tumour microenvironment in treatment planning. PMID- 19775672 TI - How to use functional imaging information for radiotherapy planning. PMID- 19775673 TI - Developments in early rectal cancer treatment. PMID- 19775674 TI - Desmoid-type fibromatosis: what works best? PMID- 19775675 TI - Evidence-based medicine: development and implementation of guidelines in oncology. PMID- 19775676 TI - Functional alterations in mechanical loading of condylar cartilage induces changes in the bony subcondylar region. AB - Bone remodeling is orchestrated by cells of the osteoblast lineage and involves an intricate network of cell-cell and cell-matrix interactions. This dynamic process engages systemic hormones, locally produced cytokines and growth factors, as well as the mechanical environment of the cells. In growing subjects, the mandibular condyle consists of both articular and growth components and the presence of progenitor cells is verified by their anabolic responses to growth hormones. The pathways of chondrocyte and osteoblast differentiation during endochondral bone formation are interconnected and controlled by key transcription factors. The present study was undertaken to explore the possibility and the extent by which the mechano-transduction events in chondrocytes are 'sensed' in the subchondral bony area under altered functional loading. To this end, the involvement of the JNK/ERK-AP-1/Runx2 signaling axe was investigated by immunohistochemistry in temporomandibular joints of young rats subjected to different functional mastication loads. Our results showed that mechanical load triggers differentiation phenomena through the induction of master tissue regulators, namely the expression and/or activation of the JNK-c Jun signaling pathway components and c-Fos in subchondral osteoblasts, as well as the activation of ERK/MAPK and the cellular expression of the transcription factor Runx2 in subchondral osteoblasts. PMID- 19775678 TI - The role of sugar configuration in the acetolysis of 6-deoxyhexose methyl glycosides. AB - The acetolysis of several perbenzylated 6-deoxyhexose methyl glycosides under two mild conditions (10 equiv ZnCl(2) in 2:1 v/v Ac(2)O-AcOH at 5 degrees C; 10:10:1 v/v/v Ac(2)O-AcOH-TFA at 70 degrees C) was studied. We focused on the effect of sugar configuration on the competition between mechanisms with activation at exocyclic or endocyclic oxygen site. No effect was detected in acetolysis using the TFA protocol promoting an exo-activation mechanism, which affords 1-O-Ac pyranosides regardless of sugar configuration. On the contrary, it has a primary role in determining the endo- versus exo-product distribution on ZnCl(2)-promoted acetolysis. PMID- 19775677 TI - Social problem-solving among adolescents treated for depression. AB - Studies suggest that deficits in social problem-solving may be associated with increased risk of depression and suicidality in children and adolescents. It is unclear, however, which specific dimensions of social problem-solving are related to depression and suicidality among youth. Moreover, rational problem-solving strategies and problem-solving motivation may moderate or predict change in depression and suicidality among children and adolescents receiving treatment. The effect of social problem-solving on acute treatment outcomes were explored in a randomized controlled trial of 439 clinically depressed adolescents enrolled in the Treatment for Adolescents with Depression Study (TADS). Measures included the Children's Depression Rating Scale-Revised (CDRS-R), the Suicidal Ideation Questionnaire--Grades 7-9 (SIQ-Jr), and the Social Problem-Solving Inventory Revised (SPSI-R). A random coefficients regression model was conducted to examine main and interaction effects of treatment and SPSI-R subscale scores on outcomes during the 12-week acute treatment stage. Negative problem orientation, positive problem orientation, and avoidant problem-solving style were non-specific predictors of depression severity. In terms of suicidality, avoidant problem solving style and impulsiveness/carelessness style were predictors, whereas negative problem orientation and positive problem orientation were moderators of treatment outcome. Implications of these findings, limitations, and directions for future research are discussed. PMID- 19775679 TI - [Giant leiomyoma in the Retzius space]. PMID- 19775680 TI - [Gastrointestinal stromal tumour in the rectovaginal septum]. PMID- 19775681 TI - [Extrapulmonary small cell carcinoma located in the oesophagus]. PMID- 19775682 TI - [Massive haemothorax associated with essential thrombocytopenia after a minor thoracic trauma]. PMID- 19775683 TI - Gray-scale edge detection for gastric tumor pathologic cell images by morphological analysis. AB - For the purpose of analyzing gastric tumor pathologic cell images, a novel method is developed with gray-scale edge detection of mathematical morphology in this study. In combination with texture features of the image under investigation, this paper works on edge detection with various structuring elements (SEs) and gray-scale values. The results of the experiment are presented, and we found several advantages by using the morphological edge detection scheme for the analysis of gastric tumor pathologic cell images. Meanwhile, the results of the binary morphological edge detection are given for comparison. PMID- 19775684 TI - Anatomic dissection of the inferior fronto-occipital fasciculus revisited in the lights of brain stimulation data. AB - Despite electrostimulation studies of the white matter pathways, supporting the role of the inferior fronto-occipital fasciculus (IFOF) in semantic processing, little is known about the precise anatomical course of this fascicle, especially regarding its exact cortical terminations. Here, in the lights of these new functional data, we dissected 14 post-mortem human hemispheres using the Klingler fiber dissection technique, to study the IFOF fibers and to identify their actual cortical terminations in the parietal, occipital and temporal lobes. We identified two different components of the IFOF: (i) a superficial and dorsal subcomponent, which connects the frontal lobe with the superior parietal lobe and the posterior portion of the superior and middle occipital gyri, (ii) a deep and ventral subcomponent, which connects the frontal lobe with the posterior portion of the inferior occipital gyrus and the posterior temporo-basal area. Thus, our results are in line with the hypothesis of the functional role of the IFOF in the semantic system, by showing that it is mainly connected with two areas involved in semantics: the occipital associative extrastriate cortex and the temporo-basal region. Further combined anatomical (dissection and Diffusion Tensor Imaging) and functional (intraoperative subcortical stimulation) studies are needed, to clarify the exact participation of each IFOF subcomponent in semantic processing. PMID- 19775685 TI - Determination of ten perfluorinated compounds in bluegill sunfish (Lepomis macrochirus) fillets. AB - A rigorous solid phase extraction/liquid chromatography/tandem mass spectrometry method for the measurement of 10 perfluorinated compounds (PFCs) in fish fillets is described and applied to fillets of bluegill sunfish (Lepomis macrochirus) collected from selected areas of Minnesota and North Carolina. The 4 PFC analytes routinely detected in bluegill fillets were perfluorooctane sulfonate (PFOS), perfluorodecanoic acid (C10), perfluoroundecanoic acid (C11), and perflurododecanoic acid (C12). Measures of method accuracy and precision for these compounds showed that calculated concentrations of PFCs in spiked samples differed by less than 20% from their theoretical values and that the %RSD for repeated measurements was less than 20%. Minnesota samples were collected from areas of the Mississippi River near historical PFC sources, from the St. Croix River as a background site, and from Lake Calhoun, which has no documented PFC sources. PFOS was the most prevalent PFC found in the Minnesota samples, with median concentrations of 47.0-102 ng/g at locations along the Mississippi River, 2.08 ng/g in the St. Croix River, and 275 ng/g in Lake Calhoun. North Carolina samples were collected from two rivers with no known historical PFC sources. PFOS was the predominant analyte in fish taken from the Haw and Deep Rivers, with median concentrations of 30.3 and 62.2 ng/g, respectively. Concentrations of C10, C11, and C12 in NC samples were among the highest reported in the literature, with respective median values of 9.08, 23.9, and 6.60 ng/g in fish from the Haw River and 2.90, 9.15, and 3.46 ng/g in fish from the Deep River. These results suggest that PFC contamination in freshwater fish may not be limited to areas with known historical PFC inputs. PMID- 19775686 TI - Comparison of the effect of tamoxifen on endometrial thickness in women with thin endometrium (<7mm) undergoing ovulation induction with clomiphene citrate. AB - Infertile women undergoing ovulation induction (OI) with clomiphene citrate (CC) who have adequate follicular recruitment and an endometrial thickness of <7 mm as determined by transvaginal sonography in the late follicular phase were switched to tamoxifen for OI in a subsequent cycle. A comparison between the endometrial thickness on CC and tamoxifen was made with by paired analysis. For women undergoing OI with CC who have adequate follicular recruitment and thin endometrium (<7 mm), switching to tamoxifen in subsequent cycles improves endometrial thickness. PMID- 19775687 TI - Characteristics and outcomes of injury patients in an Aboriginal and Torres Strait Islander population--Queensland Trauma Registry, Australia. AB - INTRODUCTION: There are few published data for the magnitude of injury-related health problems in indigenous people such as Aboriginal and Torres Strait Islanders. The objective of our study was to compare the characteristics and outcomes of injury in the indigenous population to the non-indigenous population, who are living in Queensland, Australia. METHODS: Participants were injured patients who presented to the emergency department for treatment and admitted to 15 public hospitals participating in the Queensland Trauma Registry (QTR) during 2003-2005. RESULTS: Amongst 38,036 injured patients, 1847 patients were identified as indigenous and 35,530 as non-indigenous. Compared to the non indigenous group, the indigenous group was significantly younger with no difference by gender. The injury severity score (ISS) and percentage of major injury (ISS > or = 16) were lower in the indigenous group. Indigenous patients had a significantly higher percentage of penetrating type injuries compared to non-indigenous (19.5% vs. 12.5%). The age- and injury severity-adjusted mortality rate was also significantly higher in indigenous. In age-stratified logistic regression analysis, the injury severity-adjusted odds for mortality was 3.0 times higher [95% confidence interval (95% CI): 1.6-5.5] in the indigenous, compared to the non-indigenous group, in 40-64-year olds, whilst increased odds in other age groups were not statistically significant. CONCLUSION: Our results indicate that middle-aged indigenous patients are more likely to die due to injury compared to non-indigenous patients. This suggests that strategies are required to improve outcomes particularly in the most affected injury patient group. PMID- 19775688 TI - Bilateral femoral fractures: does intramedullary nailing increase systemic complications and mortality rates? AB - In order to evaluate the impact of simultaneous intramedullary nailing in patients with bilateral femoral fractures on systemic complications a comprehensive review of the literature was performed. Four studies reporting the results of 197 patients following trauma were analysed. The mean Injury Severity Score was 20.6 (range, 9-75). According to the data available, reamed intramedullary nailing was performed in 96% of the cases. The incidence of fat embolism was 4.1%, ARDS 14.6% and pulmonary embolism 6.9%. The overall mortality was 6%. The mean hospital stay was 17.9 days (range, 4-108). Bilateral femoral fractures have a high risk of complications and mortality. Damage control surgery should be considered in these cases where the clinician anticipates the development of systemic complications. PMID- 19775689 TI - [Searching for evidence-based data]. AB - The foundation of evidence-based medicine is critical analysis and synthesis of the best data available concerning a given health problem. These factual data are accessible because of the availability on the Internet of web tools specialized in research for scientific publications. A bibliographic database is a collection of bibliographic references describing the documents indexed. Such a reference includes at least the title, summary (or abstract), a set of keywords, and the type of publication. To conduct a strategically effective search, it is necessary to formulate the question - clinical, diagnostic, prognostic, or related to treatment or prevention - in a form understandable by the research engine. Moreover, it is necessary to choose the specific database or databases, which may have particular specificity, and to analyze the results rapidly to refine the strategy. The search for information is facilitated by the knowledge of the standardized terms commonly used to describe the desired information. These come from a specific thesaurus devoted to document indexing. The most frequently used is MeSH (Medical Subject Heading). The principal bibliographic database whose references include a set of describers from the MeSH thesaurus is Medical Literature Analysis and Retrieval System Online (Medline), which has in turn become a subpart of a still more vast bibliography called PubMed, which indexes an additional 1.4 million references. Numerous other databases are maintained by national or international entities. These include the Cochrane Library, Embase, and the PASCAL and FRANCIS databases. PMID- 19775690 TI - The haptoglobin 2-2 genotype is associated with increased redox active hemoglobin derived iron in the atherosclerotic plaque. PMID- 19775691 TI - Cathepsin K gene disruption does not affect murine aneurysm formation. AB - Cathepsin K (catK), a lysosomal cysteine protease, exerts strong elastinolytic and collagenolytic activity and is implicated in a range of pathological disorders including cardiovascular disease. CatK expression was found to be elevated in human aortic aneurysm pointing to a role in this vasculopathy. In the angiotensin II (Ang II)-induced mouse model for aneurysm formation, catK, S and C expression was strongly upregulated. Therefore, we investigated the effect of catK deficiency on Ang II-induced aneurysm formation in the abdominal aorta of apoE-/- mice. Contrary to our expectations, catK deficiency did not protect against aneurysm formation, nor did it affect medial elastin breaks. Proteolytic activity in abdominal aortic lysates were comparable between apoE-/- and catK-// apoE-/- mice. Adventitial presence of catS- and catC-expressing cells was significantly increased in catK-/-//apoE-/- versus apoE-/- mice, which might have compensated for the deficiency of catK-derived proteolysis in the aneurysm tissue of catK deficient apoE-/- mice. Circulating granulocytes and activated T cell numbers were significantly increased in Ang II-infused catK-/-//apoE-/- mice, which is consistent with the borderline significant increase in adventitial leukocyte content in catK-/-//apoE-/- compared to apoE-/- mice. Strikingly, despite unchanged proteolytic activity in AAA lesions, collagen content in the aneurysm was significantly increased in catK-//-apoE-/- mice. In conclusion, while catK deficiency has major impact on various vasculopathies, it did not affect murine aneurysm formation. PMID- 19775692 TI - Ex vivo gene transferring of human dimethylarginine dimethylaminohydrolase-2 improved endothelial dysfunction in diabetic rat aortas and high glucose-treated endothelial cells. AB - OBJECTIVES: Elevated level of asymmetric dimethylarginine (ADMA) is an independent risk factor for endothelial dysfunction. Dimethylarginine dimethylaminohydrolase (DDAH) is the key enzyme responsible for the degradation of endogenous ADMA. The purposes of this study were to determine whether suppressed DDAH2 expression would implicate in endothelial dysfunction associated with diabetes mellitus and further to investigate whether adenovirus-mediated DDAH2 gene overexpression could improve the hyperglycemia-induced endothelial dysfunction. METHODS: Diabetic model was induced by intraperitoneal injection of streptozotocin to male Sprague-Dawley rats. Recombinant adenoviral vector encoding human DDAH2 gene driven by a cytomegalovirus promoter was constructed to overexpress hDDAH2 gene in isolated rat aortas and endothelial cells. Changes in DDHA/ADMA/nitric oxide (NO) pathway in diabetic rats and high glucose-treated endothelial cells were examined. RESULTS: DDAH2 expression was distinctly suppressed, which was accompanied by inhibited DDAH activity and impaired endothelium-dependent relaxation in aortas, and elevated ADMA concentrations in serum of diabetic rats compared to control rats. Suppressions of DDAH2 expression and DDAH activity, accumulation of ADMA, and inhibition of NO synthesis were observed in high glucose-treated endothelial cells. DDAH2 overexpression not only improved endothelial dysfunction in diabetic aortas but also attenuated hyperglycemia-induced changes in DDAH/ADMA//NO pathway in endothelial cells. CONCLUSION: These results indicate that suppression of DDAH2 expression contributes to hyperglycemia-induced endothelial dysfunction, which can be improved by DDAH2 overexpression. This study suggests that targeted modulation of DDAH2 gene in vascular endothelium may be a novel approach for the treatment of endothelial dysfunction in diabetes mellitus. PMID- 19775693 TI - Biomechanical characteristics of the eccentric Achilles tendon exercise. AB - BACKGROUND: Eccentric exercise has been shown to provide good short-term clinical results in the treatment of painful mid-portion chronic Achilles tendinopathies. However, the mechanisms behind the positive effects of eccentric rehabilitation regimes are not known, and research into the biomechanics of the exercise may improve our understanding. METHODS: Sixteen healthy subjects performed one-legged full weight bearing ankle plantar and dorsiflexion exercises during which three dimensional ground reaction forces (GRF), ankle joint kinematics and surface electromyography (EMG) of the lower leg muscles were recorded. Joint kinematics, GRF frequency contents, average EMG amplitudes, and Achilles tendon loads were calculated. FINDINGS: The eccentric movement phase was characterized by a higher GRF frequency content in the 8-12 Hz range, and reduced EMG activity in the lower leg muscles. No differences in Achilles tendon loads were found. INTERPRETATION: This descriptive study demonstrates differences in the movement biomechanics between the eccentric and concentric phases of one-legged full weight bearing ankle dorsal and plantar flexion exercises. In particular, the findings imply that although the tendon loads are similar, the tendon is vibrated at higher frequencies during the eccentric phase than during the concentric phases. This study provides data that may explain the mechanisms behind the effectiveness of eccentric exercises used in the treatment of Achilles tendinopathies. PMID- 19775694 TI - Specifications for machining the bovine cortical bone in relation to its microstructure. AB - Until date, many devices have been developed for cutting human bones during orthopedic surgeries. However, bones are anisotropic material, and their machining characteristics depend on the tool feed direction. In this study, microcutting of the bovine cortical bone is performed and its structure observed under a microscope. Furthermore, the formation of cutting chips and measurement of the cutting force during bone machining are dynamically observed while considering the anisotropy of bone tissue. In particular, the fracture of secondary osteons and crack propagation in bones are observed and analyzed. The results indicate that when the cut depth exceeds 20mum and is greater than the interval of concentric lamellae, cracks are formed together with chips. A new method for bone machining is proposed. This method is based on the characteristics of crack propagation in bones and is expected to produce low mechanical stress and realize highly efficient and precise machining of living tissues such as bones. PMID- 19775695 TI - Influence of coronary collateral flow on coronary diagnostic parameters: an in vitro study. AB - Functional severity of coronary stenosis is often assessed using diagnostic parameters. These parameters are evaluated from the combined pressure and/or flow measurements taken at the site of the stenosis. However, when there are functional collaterals operating downstream to the stenosis, the coronary flow rate increases, and the pressure in the stenosed artery is altered. This effect of downstream collaterals on different diagnostic parameters is studied using a physiological representative in vitro coronary flow-loop. The three diagnostic parameters tested are fractional flow reserve (FFR), lesion flow coefficient (LFC), and pressure drop coefficient (CDP). The latter two were discussed in recent publications by our group (Banerjee et al., 2007, 2008, 2009). They are evaluated for three different severities of stenosis and tested for possible misinterpretation in the presence of variable collateral flows. Pressure and flow are measured with and without downstream collaterals. The diagnostic parameters are then calculated from these readings. In the case of intermediate stenosis (80% area blockage), FFR and LFC increased from 0.74 to 0.77 and 0.58 to 0.62, respectively, for no collateral to fully developed collateral flow. Also, CDP decreased from 47 to 42 for no collateral to fully developed collateral flow. These changes in diagnostic parameters might lead to erroneous postponement of coronary intervention. Thus, variability in diagnostic parameters for the same stenosis might lead to misinterpretation of stenosis severity in the presence of operating downstream collaterals. PMID- 19775696 TI - Study of a new chiral selector: Sodium arsenyl-(l)-(+) tartrate for capillary electrophoresis. AB - Sodium arsenyl-(l)-(+) tartrate (Na(2)[As(2)(+)-tart(2)].3H(2)O) was examined and evaluated as a chiral selector using capillary electrophoresis. This chiral selector showed enantioselective associations with many cationic analytes, including primary, secondary, and tertiary amines. Also, baseline separations of ruthenium(II) polypyridyl complexes were achieved within 10min. The effect of buffer type, chiral selector concentration, voltage applied, buffer concentration, buffer pH and organic modifier concentration were examined and optimized. PMID- 19775697 TI - Architecture of polymer particles composed of brush structure at surfaces and construction of colloidal crystals. AB - The synthesis of polymer particles is reported, which are composed of (1) a spherical colloidal core particle, (2) encapsulation of such seed particles with the inimer 4-vinylbenzyl N,N-diethyldithiocarbamate (VBDC) providing the formation of a hyperbranched structure by a living radical mechanism, and followed by (3) a grafted polymer brush prepared by photo-induced atom transfer radical polymerization (ATRP). The particle sizes (number-average particle diameter Dn=190-300 nm) were controlled by varying the temperature and size distributions were extremely narrow (Dw/Dn=ca. 1.0001). By variation of the particle size, the brilliant color could be varied throughout the visible spectrum. The morphology of the core-shell particles and the properties of corresponding film were characterized by Fourier transform infrared (FT-IR), dynamic light scattering (DLS), reflection spectrum measurements, and scanning electron microscopy (SEM). PMID- 19775698 TI - Fabrication and superhydrophobicity of fluorinated titanium dioxide nanocoatings. AB - This study demonstrates the fabrication of a stable superhydrophobic surface with low contact angle hysteresis (CAH) using an arrangement of nanoscale TiO(2) spheres. The control of precursor quantity is selected as the key factor in determining surface roughness that significantly intensifies water contact angle (CA) of TiO(2) films. After surface fluorination treatment, the anatase-type crystalline surfaces exhibit good water repellency (CA approximately 166.1 degrees ), low CAH ( approximately 6 degrees ), and superhydrophobic stability (>60min). Enhanced water repellency is attributed to the fact that the higher density of TiO(2) spheres results in more tortuous three-phase contact line, leading to the self-cleaning effect. Such a unique textured surface imparts many promising potentials for engineering and the development of optics devices with robust superhydrophobic materials. PMID- 19775699 TI - Twice-daily cysteamine bitartrate therapy for children with cystinosis. AB - OBJECTIVE: Cystinosis causes renal and other organ failure. Regular 6-hourly cysteamine bitartrate (Cystagon; Mylan, Morgantown, West Virginia) reduces intracellular cystine and the rate of organ deterioration. A formulation of cysteamine requiring less frequent dosing may improve compliance and possibly patient outcome. METHODS: Enteric-release cysteamine was prepared. For a period of 1 month, patients received their regular cysteamine dose every 6 hours (stage I). The patients then underwent pharmacokinetic and pharmacodynamic studies following washout periods using single-doses of cysteamine and enteric-release cysteamine (stage II). Finally, the patients commenced regular enteric-release cysteamine therapy (stage III). Weekly trough white blood cell (WBC) cystine levels were recorded. RESULTS: Seven children with cystinosis (mean age, 11.8 years; range, 8-17 years) who received cysteamine and enteric-release cysteamine (mean dose, 45 and 28.8 mg/kg body weight/day, respectively) had mean WBC cystine levels of 0.7+/-0.3 and 0.41+/-0.22 nmol half-cystine/mg protein in study stages I and III, respectively. Study stage II showed that the mean time (T(max)) to reach the maximum plasma cysteamine level (C(max)) was longer for enteric-release cysteamine than for cysteamine (176 minutes vs 60 minutes; P=.001), but the mean C(max) at the same dose was similar. Mean serum gastrin levels were similar after ingestion of cysteamine and enteric-release cysteamine. CONCLUSIONS: Twelve-hour enteric-release cysteamine, given at approximately 60% of the previous daily dose of cysteamine, was effective in maintaining trough WBC cystine levels within a satisfactory range. PMID- 19775701 TI - Modified Paul-Mikulicz ileostomy in a Swine model of isolated small bowel transplantation. AB - BACKGROUND: Intestinal transplantation (ITx) is a life-saving procedure for patients with intestinal failure. The poorer outcome of ITx than of other organ transplantation, however, warrants more clinical and basic research on ITx. Herein, we developed a modified Paul-Mikulicz ileostomy procedure in a swine model of ITx, and investigated its feasibility for obtaining intestinal samples of both the graft and the recipient. MATERIALS AND METHODS: We performed ITx in 10 pairs of piglets, each weighing 15-20 kg. Procurement included an isolated segment of the small bowel, constituting a model of a living, related donor surgery. The recipient procedures included end-to-end anastomosis of vascular stumps, a proximal jejuno-jejunal anastomosis, and a distal modified Paul Mikulicz ileostomy. The procedure differed from the classic Paul-Mikulicz ileostomy in that a common channel was created in a side-to-side fashion. RESULTS: Vascular thrombosis occurred in three pigs, resulting in immediate loss of the graft. All other pigs underwent ITx successfully and survived for at least 1 wk (7-180 d). No pig experienced anastomotic leaks, ileus, or stoma-related complications. Moreover, this technique enabled us to obtain tissue samples of both the graft and the native ileum without disturbing the natural bowel conduit. CONCLUSIONS: The modified Paul-Mikulicz ileostomy was feasible in a swine model of ITx. It facilitated the collection of intestinal samples of both the graft and the recipient. PMID- 19775700 TI - Baseline BMI is a strong predictor of nadir BMI after adolescent gastric bypass. AB - OBJECTIVE: Surgical treatment of extreme obesity may be appropriate for some adolescents. We hypothesized that surgical weight loss outcomes may differ by preoperative level of extreme obesity (body mass index [BMI] > or=99th percentile). STUDY DESIGN: A longitudinal assessment of clinical characteristics from 61 adolescents who underwent laparoscopic Roux-en-Y gastric bypass at a single pediatric center from 2002 until 2007 was performed. Patients were categorized into 1 of 3 preoperative BMI groups: group 1, BMI = 40.0 to 54.9 (n = 23); group 2, BMI = 55.0 to 64.9 (n = 21); group 3, BMI = 65.0 to 95.0 (n = 17). Changes in BMI and cardiovascular risk factors between baseline and year 1 were evaluated using repeated-measures mixed linear modeling. RESULTS: BMI in the overall cohort at baseline (60.2 +/- 11 kg/m(2)) decreased by 37.4% at 1 year after surgery (P < .001). Percent BMI change varied little by preoperative BMI groups (-37.2%, -36.8%, and -37.7% for groups 1, 2, and 3 respectively; P = .8762). The rate of change in absolute BMI units significantly varied by preoperative BMI class (group x time interaction, P < .0001), with 1-year nadir BMI values for groups 1, 2, and 3 falling to 31 +/- 4 kg/m(2), 38 +/- 5 kg/m(2), and 47 +/- 9 kg/m(2), respectively. One year after surgery, only 17% of patients achieved a nonobese BMI (<30 kg/m(2)). Significant improvements in systolic and diastolic blood pressure (P < .0001), fasting insulin (P < .0001), total cholesterol (P = .0007), and triglyceride levels (P < .0001) were seen after surgery irrespective of baseline BMI class. Mean albumin levels remained normal despite significant caloric restriction and weight loss. CONCLUSIONS: Laparoscopic gastric bypass resulted in improvement or reversal of cardiovascular risk factors and resulted in a decrease in BMI of approximately 37% in all patients, regardless of starting BMI, 1 year after surgery. The timing of surgery for adolescent extreme obesity is an important consideration, because "late" referral for bariatric surgery at the highest of BMI values may preclude reversal of obesity. PMID- 19775702 TI - Anomalous medial origin of the anterior choroidal artery with associated aneurysm. AB - Injury to the anterior choroidal artery (AchA) can be devastating owing to the importance of the territory it supplies. The AchA is a known site of aneurysm formation, and is often exposed during various surgical and endovascular procedures. We report a patient with an aneurysm at the origin of the AchA, and an anomalous medial take off of the artery from the internal carotid artery, then a sharp lateral turn followed by a normal course toward the choroidal fissure, unreported to date to our knowledge. The aneurysm was treated successfully by endovascular therapy. The typical anatomy of the AchA, and reported variations in its origin are discussed. Thorough knowledge of the normal cerebrovascular anatomy and attention to variations play an important role in the successful management of patients with neurological vascular conditions. PMID- 19775703 TI - Immunohistochemical, volumetric, and functional neuroimaging studies in patients with idiopathic Parkinson's disease. AB - Idiopathic Parkinson's disease (PD) is closely associated with olfactory loss. Deficits in the sense of smell may precede clinical motor symptoms by years. Although there is more and more evidence from recent studies to support this view, it remains unclear which substrates would cause the olfactory deficit. Studies based on biopsies from the olfactory epithelium did not reveal specific changes in the nasal mucosa of PD patients compared to patients who were hyposmic for other reasons. Thus, PD-related olfactory impairment seems not to be directly associated with specific changes in the olfactory epithelium. With regard to volumetrics of the olfactory bulb (OB) results indicated that there is little or no difference between PD patients and healthy controls in terms of OB volume. Again, these data support the idea that olfactory loss in PD is not a consequence of damage to the olfactory epithelium but rather results from central-nervous changes. Finally, studies based on functional MRI suggested that neuronal activity in the amygdala and hippocampus is reduced in PD patients compared to controls which may specifically impact on olfactory function. In addition, neuronal activity in components of cortico-striatal loops appears to be up regulated indicating compensatory processes involving the dopaminergic system. Thus, it seems that cerebral changes, and not changes at the level of the olfactory epithelium, are the basis of the olfactory loss observed in PD patients. PMID- 19775704 TI - Management and long-term outcome of neonatal Ebstein anomaly. AB - OBJECTIVE: The objective of this study was to review the long-term results of symptomatic patients with Ebstein anomaly in the neonatal period. METHODS: The medical records of 40 neonates with a diagnosis of Ebstein anomaly who were admitted to our institution between January 1988 and June 2008 were retrospectively reviewed. Primary outcomes studied included patient survival and need for reintervention. RESULTS: No early intervention was required in 16 of the 40 patients with a hospital survival of 94% (15/16) and no late mortality. The remaining 24 patients underwent surgical intervention in the neonatal period. A shunt alone was performed in 9 patients with an actuarial survival of 88.9% at 1 year and 76.2% at 5 and 10 years. For the patients undergoing intervention on the tricuspid valve, survival estimates for the 11 patients with a right ventricular exclusion procedure were 63.6% at 1, 5, and 10 years and 47.7% at 15 years compared with 25.0% at 1, 5, and 10 years for the 4 patients with tricuspid valve repair. All long-term survivors were in New York Heart Association class I or II, and only 1 patient required antiarrhythmic medication. CONCLUSION: Symptomatic neonates with Ebstein anomaly requiring no intervention or shunting alone have good long-term survival. For patients needing intervention on the tricuspid valve, overall survival is lower. For these patients, right ventricular exclusion may be superior to tricuspid valve repair. PMID- 19775705 TI - Skeletonized internal thoracic artery harvesting reduces chest wall dysesthesia after coronary bypass surgery. AB - OBJECTIVE: A pain syndrome related to intercostal nerve injury during internal thoracic artery harvesting causes significant morbidity after coronary bypass surgery. We hypothesized that its incidence and severity might be reduced by using skeletonized internal thoracic artery harvesting rather than pedicled harvesting. METHODS: In a prospective double-blind clinical trial, 41 patients undergoing coronary bypass were randomized to receive either unilateral pedicled or skeletonized internal thoracic artery harvesting. Patients were assessed 7 (early) and 21 (late) weeks postoperatively with reproducible sensory stimuli used to detect chest wall sensory deficits (dysesthesia) and with a pain questionnaire used to assess neuropathic pain. RESULTS: At 7 weeks postoperatively, the area of harvest dysesthesia (percentage of the chest) in the skeletonized group (n = 21) was less (median, 0%; interquartile range, 0-0) than in the pedicled group (n = 20) (2.8% [0-13], P = .005). The incidence of harvest dysesthesia at 7 weeks was 14% in the skeletonized group versus 50% in the pedicled group (P = .02). These differences were not sustained at 21 weeks, as the median area of harvest dysesthesia in both groups was 0% (P = .89) and the incidence was 24% and 25% in the skeletonized and pedicled groups, respectively (P = 1.0). The incidence of neuropathic pain in the skeletonized group compared with the pedicled group was 5% versus 10% (P = .6) at 7 weeks and 0% versus 0% (P = 1.0) at 21 weeks. CONCLUSIONS: Compared with pedicled harvesting, skeletonized harvesting of the internal thoracic artery provides a short-term reduction in the extent and incidence of chest wall dysesthesia after coronary bypass, consistent with reduced intercostal nerve injury and therefore the reduced potential for neuropathic chest pain. PMID- 19775706 TI - Outcome of coronary artery bypass grafting performed in young children. AB - OBJECTIVES: The long-term patency rate of coronary artery bypass grafting for which arterial grafts are used is known to be high in the pediatric population. However, this issue remains uncertain in children under 3 years of age. Here, we report the outcome in this specific population. METHODS: From July 1988 to July 2007, 18 children less than 3 years of age (age at operation, 0.1-35 months; median, 4 months) underwent 20 coronary artery bypass graft operations using an arterial graft. Indications for bypass grafting were coronary artery complications related to the arterial switch operation for transposition of the great arteries in 12 patients (coronary obstruction in 8 patients, peroperative coronary anomalies precluding coronary transfer in 4 patients), congenital anomalies of the coronary arteries in 4 patients, and Kawasaki disease in 2 patients. RESULTS: After a mean follow-up of 55 months (range, 1-176 months; median, 41 months), patency of 19 bypass grafts was assessed. One was occluded and 2 have necessitated a percutaneous procedure. Two patients died suddenly (1 with an occluded graft and 1 with a patent graft and hypertrophic myocardiopathy) 3.5 and 4.6 months, respectively, after bypass grafting. CONCLUSIONS: Coronary artery bypass grafting should be considered as a possible alternative for coronary revascularization in young children. Although our series shows quite a good patency rate, this procedure remains a technical challenge and requires careful follow-up. PMID- 19775707 TI - The influence of postoperative mitral valve function on the late recurrence of atrial fibrillation after the maze procedure combined with mitral valvuloplasty. AB - OBJECTIVES: Although a number of reports have identified risk factors for postoperative recurrence of atrial fibrillation after the maze procedure, no studies have investigated the influence of postoperative mitral valve disease on atrial fibrillation recurrence after mitral valvuloplasty combined with the maze procedure. METHODS: Between January 1999 and October 2006, 228 patients underwent the maze procedure and concomitant mitral valve repair. There were 4 early deaths. Of the early survivors, 206 patients with restored sinus rhythm were chosen for analysis. During a median follow-up of 50.8 months (range, 0.6-122.8 months), there were 35 patients who had mitral regurgitation (n = 26) or mitral stenosis (n = 9). Patients who had postoperative mitral valve disease (disease group, n = 35) were compared with those who did not (control group, n = 171) for late recurrence of atrial fibrillation. RESULTS: Twenty-eight patients experienced late recurrence of atrial fibrillation. The disease group had a higher atrial fibrillation recurrence rate than the control group (5-year atrial fibrillation-free rates were 65.2% +/- 10.3% and 85.8% +/- 3.4%, respectively; P = .014). Univariate and multivariate analyses of a range of variables revealed that a larger preoperative left atrial size (hazard ratio, 2.61; P = .041), the use of microwave ablation rather than cryoablation (hazard ratio, 2.33; P = .041), the presence of early (<3 months) postoperative atrial fibrillation events (hazard ratio, 3.75; P = .001), and the presence of postoperative mitral valve disease (hazard ratio, 3.67; P = .005) were independent predictors for late atrial fibrillation recurrence. CONCLUSIONS: Maze procedure outcomes were negatively affected by postoperative mitral valve disease after mitral valvuloplasty, as evidenced by greater atrial fibrillation recurrence. PMID- 19775708 TI - Miniaturized cardiopulmonary bypass improves short-term outcome in cardiac surgery: a meta-analysis of randomized controlled studies. AB - OBJECTIVE: To investigate whether the use of miniaturized cardiopulmonary bypass translates into decreased morbidity and mortality in patients having cardiac surgery. METHODS: We independently conducted a systematic review and meta analysis of data pooled from existing trials listed in PubMed and conference proceedings. Sixteen studies were identified, including 1619 patients having cardiac surgery. Inclusion criteria were random allocation to treatment and comparison of a miniaturized cardiopulmonary bypass system versus conventional cardiac surgery. Exclusion criteria were duplicate publications, nonhuman experimental studies, and no outcome data. The end points were the rate of neurologic and myocardial damage and the number of patients transfused. RESULTS: Miniaturized cardiopulmonary bypass was associated with significant reductions of neurologic damage (4/548 [0.7%] vs 19/555 [3.4%], odds ratio = 0.30 [0.12-0.73], P = .008), reduction in peak cardiac troponin (weighted mean difference = -0.15 ng/dL [-0.18, -0.11], P < .001), and in the number of transfused patients (55/552 [9.9%] vs 101/563 [17.9%], odds ratio = 0.42 [0.28-0.63], P < .001). No difference in mortality was noted (8/758 [1.0%] vs 14/771 [1.8%], odds ratio = 0.60 [0.26-1.39]). CONCLUSIONS: Miniaturized cardiopulmonary bypass has beneficial effects resulting in decreased transfusion rate and cardiac and neurologic damage. PMID- 19775709 TI - On the SAR derived alert in the detection of oil spills according to the analysis of the EGEMP. AB - Satellite services that deliver information about possible oil spills at sea currently use different labels of "confidence" to describe the detections based on radar image processing. A common approach is to use a classification differentiating between low, medium and high levels of confidence. There is an ongoing discussion on the suitability of the existing classification systems of possible oil spills detected by radar satellite images with regard to the relevant significance and correspondence to user requirements. This paper contains a basic analysis of user requirements, current technical possibilities of satellite services as well as proposals for a redesign of the classification system as an evolution towards a more structured alert system. This research work offers a first review of implemented methodologies for the categorisation of detected oil spills, together with the proposal of explorative ideas evaluated by the European Group of Experts on satellite Monitoring of sea-based oil Pollution (EGEMP). PMID- 19775710 TI - [Analysis of asthma control and quality of life in severe allergic asthmatics under treatment with anti-IgE, omalizumab]. AB - BACKGROUND AND OBJECTIVES: To evaluate anti-IgE (ie, omalizumab) efficacy on severe allergic asthma in order to achieve the efficacy of this treatment on severe allergic asthma progress by means of asthma control questionnaire (ACQ), asthma quality of life questionnaire (AQLQ) as well as pulmonary function (FEV1) and physician overall assessment. PATIENTS AND METHODS: Fourteen patients were studied who suffered from severe allergic asthma for several years; average 20.7yr. A positive skin prick test or specific IgE antibodies to a common aeroallergen were observed in all patients who were under treatment with high doses of inhaled corticosteroids (eight of them also with oral corticosteroids). Omalizumab 150-600 mg were administrated once or twice monthly and each patient was monthly evaluated until sixteen weeks, deciding at this time which patient was or not responder in order to follow up or not omalizumab treatment. RESULTS: Physician overall assessment improved in 11 out of every 14 patients. A marked improvement was observed at two months in ACQ and AQLQ (p<0.05) and at 3 and 4 moths only in AQLQ and AQLQ-symptoms respectively (p<0.05). The FEV1 improved by 9.4% average (p=0.24). Oral corticosteroids were reduced in 4 of 8 patients and in another one there was a definitive suspension. Two patients suffered adverse reactions which suspension of treatment despite the fact that they presented improvement in questionnaires of quality of life and control of asthma. CONCLUSIONS: Omalizumab showed a marked global efficacy in more than 3 out of 4 patients suffering severe allergic asthma as revealed by physician overall assessment. Moreover significant improvements were observed in ACQ; AQLQ; AQLQ symptoms at 2, 3 and 4 months of treatment, without significant changes in FEV1 probably due to chronic irreversible changes in airways. PMID- 19775711 TI - [Laughter medicine and therapy: a complementary/alternative approach in health and patient care]. PMID- 19775712 TI - Postprandial effects of a lipid-rich meal in the rat are modulated by the degree of unsaturation of 18C fatty acids. AB - The fatty acid composition of high-fat diets is known to influence the magnitude of postprandial events that increase the risk of metabolic syndrome. These variations in magnitude may be directly ascribed to differences in the channeling of lipids toward oxidation or storage. A study was designed to compare the effects of 4 dietary fats on postprandial energy expenditure and on some risk factors of the metabolic syndrome. To avoid usual confounding factors due to simultaneous variations in chain length and double-bounds number of fatty acids, dietary fats were chosen to provide mainly 18-carbon fatty acids with 0 (stearic acid [SA]), 1 (oleic acid [OA]), 2 (linoleic acid [LA]), or 3 (alpha-linolenic acid [ALA]) double bounds. They were given as single high-fat test meals to 4 different groups of male rats. The resting metabolic rate and the lipid and carbohydrate oxidation were measured from oxygen consumption and carbon dioxide production using indirect calorimetry 2 hours before and 6.5 hours after the test meal. Plasma glucose, triglyceride, and chylomicron concentrations were determined at 0, 1.5, and 4 hours after the test meal. Postprandial concentration of glucose and triglyceride did not vary with the nature of the test meals, whereas that of chylomicrons was the highest after the LA test meal and the lowest after the SA test meal. Postprandial increase in resting metabolic rate was the highest after the LA and OA test meals, and the lowest after the SA and ALA test meals. Compared with the 3 other diets, the ALA test meal enhanced lipid oxidation and decreased glucose oxidation during the early postprandial period (0.25-3.25 hours). This suggests that stearic acid may not induce all the adverse effects classically described for other saturated fatty acids and that alpha linolenic acid may beneficially influence energy partitioning, especially during the early postprandial state. PMID- 19775713 TI - [Dual-source computed tomography in inpatients with atypical chest pain]. AB - OBJECTIVE: To evaluate the potential usefulness of dual-source CT (DSCT) in the diagnostic work-up of inpatients with atypical chest pain of unknown etiology. MATERIAL AND METHODS: Forty-one consecutive inpatients (25 male, 16 female; mean age 55.6+/-17.39 years) with atypical chest pain underwent DSCT to determine the cause of pain. Images were acquired with retrospective ECG gating after the administration of 120ml of iodinated contrast medium at 4ml/s using the bolus tracking technique. Two readers analyzed the images in consensus. RESULTS: DSCT was diagnostic in all patients. We detected pulmonary embolisms in five patients and aortic disease in two (one aortic ulcer and one sacular aneurysm). Anomalies of the coronary arteries were depicted in 15 patients, two of whom presented luminal stenosis >50%. Extracardiovascular findings at DSCT included pneumonia in eleven patients, sarcoidosis in one, and non-small cell lung carcinoma in one. Pleural effusion was detected in four patients and pericardial effusion in another four. No pathological findings were observed in 22% of subjects. Evolution was favorable in all patients. No patients were readmitted for persistent pain or new onset of acute chest pain during the follow-up period. CONCLUSION: DSCT can rule out most life-threatening clinical conditions that cause chest pain and is useful in determining the cause of chest pain in inpatients. PMID- 19775714 TI - Comprehensive primary health care, a viable strategy for the elimination of schistosomiasis. AB - Large-scale chemotherapy has proved to be an affordable, feasible and effective strategy for the control of schistosomiasis in most endemic countries. However, it is becoming increasingly evident that chemotherapy alone has failed to break the cycle of transmission in high-risk communities, and data from Egypt confirm this. To accelerate the elimination of schistosomiasis will require more complex and integrated control strategies aimed at a permanent improvement in sanitation and living conditions in those few endemic foci where transmission is still occurring. An innovative strategy for the elimination of this disease, endemic in Egypt since the time of the pharaohs, is presented. PMID- 19775715 TI - Intestinal helminths and protozoa in children in pre-schools in Kafue district, Zambia. AB - Intestinal parasitic infections are among the most widespread of human infections in developing countries, and children are the most vulnerable. The aim of this study was to determine the prevalence of the protozoa Cryptosporidium and Giardia, as well as prevalence and intensity of intestinal helminths in children attending pre-school or day-care centres in Kafue District, Zambia. Single stool samples were collected from 403 children from 10 pre-schools and were subjected to duplicate Kato-Katz thick smears to identify and quantify helminths. A commercial immunofluorescence kit was used to identify Cryptosporidium- and Giardia-positive samples. The overall prevalence of helminth infection was 17.9%. Ascarislumbricoides was found in 12.0%, hookworm in 8.3%, Taenia spp. in 0.9%, Hymenolepisnana in 0.6% and Schistosomamansoni in 0.3%. The overall prevalence of Cryptosporidium and Giardia was 28.0 and 29.0%, respectively, with more girls infected with Giardia (33.8%) than boys (22.7%) (P=0.02). Significant differences in infections with A. lumbricoides and Cryptosporidium were observed between the various pre-schools (P < 0.001). These findings indicate that intestinal parasites are prevalent in children enrolled in pre-schools in Zambia. Future studies should explore local factors associated with transmission of these infections, and consequently provide the necessary health education to parents and teachers. PMID- 19775716 TI - Non-destructive imaging using the time domain topological energy method. AB - The time domain topological gradient has recently been presented as a promising technique for imaging of complex structures [N. Dominguez, et al., Wave Motion 42 (1) (2005) 31-52], showing results obtained on simulated data. The method relies on the adequate combination of two computed ultrasonic fields, one forward and one adjoint. The adjoint field, that carries the information about the defects, is analogous to a time reversal operation. The forward field plays the role of a "photographic developer". The great interest of the method is that the time reversal operation is not done experimentally but numerically, allowing implementation of low cost systems. The expected low sensitivity of the method to the presence of measurement or structure noise had been discussed in a former work. This paper shows results obtained on experimental data in the context of non-destructive testing, showing the efficiency of the method even in complex configuration such that composite material testing. PMID- 19775717 TI - Importance of the major splice donor and redefinition of cis-acting sequences of gutless feline foamy virus vectors. AB - Foamy virus vectors are potent alternatives to lenti- and gamma-retroviral vectors for gene therapy. To construct and optimize gutless feline foamy virus (FFV) replication-deficient (RD) vectors, viral elements essential for optimal efficient marker gene transduction were characterized and fine-mapped and packaging clones constructed. For these purposes, new Gag and Pol expression clones which allow efficient expression of packaging proteins and vectors carrying deletions in coding and non-coding regions of the genome were constructed and functionally evaluated. These studies demonstrate that the 5' major splice donor (5' SD) is indispensable for RD vectors while defined mutations introduced to inactivate the gag start codon improve transgene delivery efficiency. Based on these findings, new gutless FFV vectors were generated yielding un-concentrated vector titers above 10(5) transducing units (TU)/ml. By minimizing the second cis-acting sequence in the pol gene, only 3.8 kb viral sequences are maintained in the novel gutless FFV RD vectors. PMID- 19775718 TI - Fate and impact of organics in an immersed membrane bioreactor applied to brine denitrification and ion exchange regeneration. AB - The application of membrane bioreactors (MBRs) to brine denitrification for ion exchange regeneration has been studied. The developed culture was capable of complete brine denitrification at 50 gNaCl.l(-1). Denitrification reduced to c.60% and c.70% when salinity was respectively increased to 75 and 100g.l(-1), presumed to be due to reduced growth rate and the low imposed solids retention time (10 days). Polysaccharide secretion was not induced by stressed cells following salt shocking, implying that cell lysis did not occur. Fouling propensity, monitored by critical flux, was steady at 12-15l.m(-2).h(-1) during salinity shocking and after brine recirculation, indicating that the system was stable following perturbation. Low molecular weight polysaccharide physically adsorbed onto the nitrate selective anion exchange resin during regeneration reducing exchange capacity by c.6.5% when operating up to complete exhaustion. However, based on a breakthrough threshold of 10 mgNO(3)(-)-N.l(-1) the exchange capacity was comparative to that determined when using freshly produced brine for regeneration. It was concluded that a denitrification MBR was an appropriate technology for IEX spent brine recovery and reuse. PMID- 19775719 TI - Modeling water flow and bacterial transport in undisturbed lysimeters under irrigations of dairy shed effluent and water using HYDRUS-1D. AB - HYDRUS-1D was used to simulate water flow and leaching of fecal coliforms and bromide (Br) through six undisturbed soil lysimeters (70 cm depth by 50 cm diameter) under field conditions. Dairy shed effluent (DSE) spiked with Br was applied to the lysimeters, which contained fine sandy loam layers. This application was followed by fortnightly spray or flood water irrigation. Soil water contents were measured at four soil depths over 171 days, and leachate was collected from the bottom. The post-DSE period simulations yielded a generally decreased saturated water content compared to the pre-DSE period, and an increased saturated hydraulic conductivity and air-entry index, suggesting that changes in soil hydraulic properties (e.g. via changes in structure) can be induced by irrigation and seasonal effects. The single-porosity flow model was successful in simulating water flow under natural climatic conditions and spray irrigation. However, for lysimeters under flood irrigation, when the effect of preferential flow paths becomes more significant, the good agreement between predicted and observed water contents could only be achieved by using a dual porosity flow model. Results derived from a mobile-immobile transport model suggest that compared to Br, bacteria were transported through a narrower pore network with less mass exchange between mobile and immobile water zones. Our study suggests that soils with higher topsoil clay content and soils under flood irrigation are at a high risk of bacteria leaching through preferential flow paths. Irrigation management strategies must minimize the effect of preferential flow to reduce bacterial leaching from land applications of effluent. PMID- 19775720 TI - Water and phosphorus content affect PAH dissipation in spiked soil planted with mycorrhizal alfalfa and tall fescue. AB - Polycyclic aromatic hydrocarbon (PAH) dissipation efficiency can be increased in the plant rhizosphere, but may be affected by various environmental factors. We investigated the effects of the watering regime and phosphorus concentration on PAH dissipation in the rhizosphere of mycorrhizal plants in a pot experiment. Two plant species, alfalfa (Medicago sativa) and tall fescue (Festuca arundinacea), were co-cultured and inoculated with an arbuscular mycorrhizal (AM) fungus (Glomus intraradices) in PAH (phenanthrene (PHE)=500 mg kg(-1), pyrene (PYR)=500 mg kg(-1), dibenzo(a,h)anthracene (DBA)=65 mg kg(-1)) spiked agricultural soil for 6 weeks. Treatments with different phosphorus concentrations and watering regimes were compared. The PHE dissipation reached 90% in all treatments and was not affected by the treatments. The major finding was the significant positive impact of mycorrhizal plants on the dissipation of high molecular weight PAH (DBA) in high-water low-phosphorus treatment. Such an effect was not observed in high-water high-phosphorus and low-water low-phosphorus treatments, where AM colonization was very low. A positive linear relationship was detected between PYR dissipation and the percentage of Gram-positive PAH-ring hydroxylating dioxygenase genes in high-water high-phosphorus treatments, but not in the other two treatments with lower phosphorus concentrations and water contents. Such results indicated that the phosphorus and water regime were important parameters for the dissipation of HMW-PAH. PMID- 19775721 TI - Stockholm Convention organochlorine pesticides and polycyclic aromatic hydrocarbons in Hong Kong air. AB - Organochlorine pesticides (OCPs) including eight of the original nine pesticides listed in the Stockholm Convention on Persistent Organic Pollutants, and polycyclic aromatic hydrocarbons (PAHs) were measured in 90 air samples collected from January 2004 to March 2005, and in 304 air samples collected from January 1998 to December 2005 in Hong Kong, respectively. The annual average OCP concentrations at Tap Mun, Yuen Long and Tsuen Wan were 135+/-140 (ND-482), 186+/ 183 (ND-656), and 190+/-239 fg m(-3) (ND-966), respectively, while annual (January 1998 to December 2005) average concentrations of total PAHs at Tsuen Wan, and Central/Western were 578+/-261 (117-938) and 588+/-248ngm(-3) (103-874), respectively. No seasonal and spatial variations in OCP concentrations were observed due to trace levels, and estimation of carcinogenic risks of OC pesticides was low. Naphthalene (>70%) was the dominant PAH in terms of concentrations measured. The sum of three-ring PAHs, including acenaphthene, acenaphthylene, anthracene, fluorene and phenanthrene, contributed to around 20% of the total PAH concentration while the contribution of heavier PAHs (sum of four-, five- and six-rings) was less than 5%. t-Values of the paired samples T test for the individual PAHs showed that the concentrations of benzo(a)pyrene, the relative high cancer risk PAH, and most of the PAHs detected at Tsuen Wan and Central/Western were significantly different (p<0.01), with higher concentrations detected at Tsuen Wan. Several PAHs exhibited strong seasonality with higher concentrations in winter. Sources of PAHs were determined by investigating PAH isomer ratios which suggested petrogenic sources as primary sources of PAHs in Hong Kong air. PMID- 19775722 TI - PFOS and PFOA in environmental and tap water in China. AB - There is a great concern about global contamination with persistent fluoroorganic compounds including perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA), however, few data are available on the environmental levels of these chemicals in China. In the present study, therefore, environmental or tap water samples collected from various regions of China were assayed for PFOS and PFOA by solid phase extraction and liquid chromatography-mass spectrometry technique. Median concentrations (maximum concentration) of PFOS and PFOA in environmental water were 0.4 (2.4) and 0.1 (1.3) ngL(-1) for the remote area (n=13), 4.0 (14.1) and 3.9 (30.8) ngL(-1) for the urban area (n=22), respectively. Systematic survey was also conducted in the Hun River (n=11) and the Yangtze River (n=34). In the Hun River, the median of PFOS concentration was 4.9ngL(-1), while PFOA was below the limit of quantitation (0.1ngL(-1)) at many of the sampling sites. The Yangtze River was moderately contaminated with both chemicals: median concentration was 4.2ngL(-1) for PFOS and 5.4ngL(-1) for PFOA. Remarkably high concentration of PFOA was found at 2 sampling sites of the Yangtze River (110.6 and 297.5ngL(-1)), but the concentration had declined to the average level at the next sampling site in both cases. Many cities provided tap water with low levels of PFOS and PFOA, however, tap water in Guangzhou and Shenzhen exceeded 10ngL(-1) for both chemicals. This study revealed obvious presence of perfluorinated compounds spread out the entire territory of China, and the levels in urban area of China were almost comparable to those in the US, Europe and Japan. PMID- 19775723 TI - Application of a peroxymonosulfate/cobalt (PMS/Co(II)) system to treat diesel contaminated soil. AB - We investigated the feasibility of using peroxymonosulfate (PMS) with transition metals (PMS/M(+) system) for remediation of diesel-contaminated soils. To the best of our knowledge, this is the first attempt to apply a PMS/M(+) system for the treatment of diesel-contaminated soils. Two well-known transition metals, Fe(II) and Co(II), used to activate PMS including the effect of co-existence of counter anions (Cl(-) and SO(4)(2-)) were tested and it revealed that the most effective degradation of diesel was achieved with cobalt chloride. The effect of PMS (i.e. 0-500 mM) indicated that the increasing the molar ratio of PMS/diesel increased degradation of diesel on soils. The effect of Co(II) (i.e. 0-4mM) showed that at least 2mM of Co(II) was needed to degrade above 30% of diesel. Moreover, a maximum diesel degradation of 47% was achieved at a single injection of PMS/Co(II) (i.e. 500 mM/2mM). Assessments of system pH showed that diesel degradation was higher under acidic conditions (pH 3) possibly due to the dissolution of metal ions from soils that are not possible at other pHs (pH 6 and 9). Sequential injections of both PMS and Co(II) were employed to improve the level of remediation (approximately 90% degradation). The degradation of diesel increased as much as 88% when PMS/Co(II) was sequentially injected. This indicates that PMS/Co(II) systems are applicable for remediation of soil contaminated with diesel fuel as an aspect of in situ chemical oxidation. PMID- 19775724 TI - A combined recovery process of metals in spent lithium-ion batteries. AB - This work proposes a new process of recovering Co from spent Li-ion batteries (LIBs) by a combination of crushing, ultrasonic washing, acid leaching and precipitation, in which ultrasonic washing was used for the first time as an alternative process to improve the recovery efficiency of Co and reduce energy consumption and pollution. Spent LIBs were crushed with a 12 mm aperture screen, and the undersize products were put into an ultrasonic washing container to separate electrode materials from their support substrate. The washed materials were filtered through a 2mm aperture screen to get underflow products, namely recovered electrodes. Ninety two percent of the Co was transferred to the recovered electrodes where Co accounted for 28% of the mass and impurities, including Al, Fe, and Cu, accounted for 2%. The valuable materials left in 2-12 mm products, including Cu, Al, and Fe, were presented as thin sheets, and could be easily separated. The recovered electrodes were leached with 4.0M HCl for 2.0 h, at 80 degrees C, along with concurrent agitation. Ninety seven percent of the Li and 99% of the Co in recovered electrodes could be dissolved. The impurities could be removed at pH 4.5-6.0 with little loss of Co by chemical precipitation. This process is feasible for recycling spent LIBs in scale-up. PMID- 19775725 TI - Electrochemical degradation of gallic acid on a BDD anode. AB - The electrochemical oxidation of gallic acid (3,4,5-trihydroxybenzoic acid) has been studied on a boron-doped diamond anode (BDD). Cyclic voltammetries, chronoamperometries and bulk electrolyses were performed to characterise the electrochemical behaviour of gallic acid on diamond-type anode and to study the kinetics of gallic acid degradation. UV spectroscopy, HPLC analysis, COD and TOC measurements were conducted to study the reaction pathway for gallic acid mineralisation. The results showed that both direct and mediated electrochemical processes were involved in the oxidation of gallic acid. The degradation of gallic acid evidenced a pseudo first-order kinetics and the rate constant increased with applied current. Aliphatic acids were the main intermediates formed during the electrolyses and they were finally mineralised to CO(2) and water. The degradation rate on boron-doped diamond was under mass-transport control and was favoured by the increase of the flow rate of the solution into the electrochemical reactor. PMID- 19775726 TI - Trichlorfon-induced apoptosis in hepatocyte primary cultures of Carassius auratus gibelio. AB - Trichlorfon, an organophosphorus pesticide, can disrupt metabolism, reproduction and immune functions of some aquatic animals. In the present study, the effect of trichlorfon on apoptosis and the underlying apoptotic mechanism were investigated in primary cultures of Carassius auratus gibelio hepatocytes. Analyses of cultures exposed to 0, 0.01, 0.1, and 1.0 mg L(-1) trichlorfon concentrations for 24h indicated that trichlorfon induced apoptosis and caused nuclear shrinkage, cell membrane rupture, cytoskeletal collapse, loss of cytoplasm, mitochondria vacuolization, and apoptotic body formation, as well as lipid droplet accumulation. Trichlorfon increased intracellular reactive oxygen species and malondialdehyde concentrations and caused cytochrome c release from mitochondria into the cytoplasm, leading to caspase-3 activation. These findings contributed to a better understanding of the mechanisms underlying trichlorfon-induced apoptosis via activation of mitochondrial pathways while clearly indicating that trichlorfon-induced cell death was via apoptosis accompanied by mitochondrial cytochrome c release and consequent caspase-3 activation. PMID- 19775727 TI - Fluorescence in situ hybridization analysis of extraskeletal myxoid chondrosarcomas using EWSR1 and NR4A3 probes. AB - Extraskeletal myxoid chondrosarcomas (EMCs) are characterized histologically by a cord-like or lace-like arrangement of small round cells or short spindle cells with eosinophilic cytoplasm distributed in a rich myxoid matrix. Atypical cases of EMC have also been described, with areas of poor mucus production and high cellularity and a transition to typical EMC. Most cases of EMC harbor the chromosomal reciprocal translocation t(9;22) (q22;q12) and the resultant fused gene, Ewing sarcoma region 1-nuclear receptor subfamily 4, group A, member 3 (EWSR1-NR4A3). Other translocations, such as those involving the NR4A3 gene, have also been noted, although these occur at a lower frequency. On this basis, we conducted a fluorescence in situ hybridization (FISH) analysis of 18 cases of EMC in which patients presented with typical or atypical (areas of high cellularity) histologic features of EMC. We used an EWSR1 probe and a newly prepared NR4A3 probe to evaluate the usefulness of FISH in the pathologic diagnosis of EMC. FISH analysis using the EWSR1 or NR4A3 probe showed split signals in 83% (15/18) of the cases, regardless of the presence of typical/atypical histologic features. Gene rearrangement of EWSR1 was noted in 72% (13/18) of the cases, and rearrangement of NR4A3 was noted in 61% (11/18) of the cases. The NR4A3 rearrangement was detected in 2 cases not carrying any EWSR1 rearrangement, as determined by reverse transcription-polymerase chain reaction. These results suggest that FISH analysis of formalin-fixed, paraffin-embedded specimens using EWSR1 and NR4A3 probes is useful and convenient and may provide an ancillary method for the diagnosis of EMC. PMID- 19775728 TI - An ecological study of physical environmental risk factors for elderly falls in an urban setting of Hong Kong. AB - Elderly fall has become an issue of great public health concern and typically important to the aging population in Hong Kong because it carries a great burden to the individuals and the society. More accurate information about environmental risk factors to falls among the elderly could alleviate if not overcome the situation. Conventional approaches to elderly falls were mainly conducted using statistical methods and clinical tests on falls. This study employs ecological and associative analysis using the geographic information systems (GIS) technology to visualize spatial association of falls and environmental factors. The study identified eleven hot spots of elderly falls with unique environmental characteristics. Amongst various environmental attributes, busy streets and junctions, outdoor markets, and refuse collection points, exhibit a strong spatial relationship with the hot spots. The results have demonstrated that GIS can offer an excellent synergic platform to explore the role of space and pattern in fall occurrences. PMID- 19775729 TI - Natural attenuation processes applying to antimony: a study in the abandoned antimony mine in Goesdorf, Luxembourg. AB - The processes leading to the attenuation of the antimony concentration in the water draining from the abandoned antimony mine in Goesdorf, Luxembourg, have been studied. Antimony has been mined in Goesdorf since Roman times from a stibnite-rich mesothermal vein system hosted in metasedimentary schist. The draining waters have pH values between 7 and 8 because the mineralization itself contains calcite and dolomite. This study combines the identification of minerals in the supergene zone with the application of bulk techniques (e.g., measurement of antimony in the waters of the adit and the creek draining the mine, sediment sequential extractions) over a period of five years. Antimony concentrations in the water that leaves the supergene zone are controlled by the dissolution of stibnite and the subsequent formation of Sb(III) oxides and sulphates. The relative proportions of the main secondary minerals can be qualitatively estimated as follows: 70% valentinite, 15% senarmontite and 12% sulphates (coquandite, klebelsbergite and peretaite). Further antimony attenuation along the adit and the creek that drain the mine waters is due partly to dilution, through mixing with waters that have not been in contact with the ore, and partly to sorption onto amorphous iron and manganese oxides present in the colluvial sediments. PMID- 19775730 TI - Comparision of biocompatibility and cytotoxicity of two new root canal sealers. AB - The aim of this study was to investigate the remote organ toxicity and connective tissue reaction of two new root canal sealers ("GuttaFlow((r))" and "EndoREZ((r))") and to compare them with zinc oxide eugenol sealer using biochemical and histopathological parameters. A total of 60 white albino Wistar rats were used in the study. 0.1ml of GuttaFlow((r)), EndoREZ((r)) or Kerr Pulp Canal Sealer((r)) were administered subcutaneously into the mid-dorsal thoracic region of rats (15 in each group). Control rats were given saline only. Rats were decapitated after 24h, on day 7 and on day 30 of the experiment and tissue samples from lung, liver, kidney and skin were removed for the determination of malondialdehyde (MDA) and glutathione (GSH) levels. In parallel, tissues were also examined histologically. Serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) levels, and creatinine and blood urea nitrogen (BUN), concentrations (BUN) were measured to assess liver and kidney functions, respectively. Tumor necrosis factor (TNF) and lactate dehydrogenase (LDH) were also assayed in serum samples. No statistical differences were found among the control and EndoREZ((r)), GuttaFlow((r)) and Kerr Pulp Canal sealers regarding tissue MDA, GSH levels or serum parameters (p>0.05) at all time points examined. Both of the new root canal sealers showed good compatibility and acceptable tissue toxicity. PMID- 19775731 TI - Multiple immunoenzyme labeling using heat treatment combined with the polymer method: an analysis of the appropriate inactivation conditions of primary antibodies. AB - Multiple immunoenzyme labeling is of considerable value to detect several antigens in the same specimen, although this technique is limited when the primary antibodies have been raised in the same animal species. Multiple immunoenzyme labeling using heat treatment is a simple, reliable and straightforward technique wherein the heat treatment prevents mixed labeling and cross-reaction. The present study determined the inactivation time for primary antibodies by heat treatment in order to apply this procedure to routine histopathological diagnosis and research, and found that the inactivation time differed among the primary antibodies. The secondary antibodies and the labeling enzyme were completely inactivated by heating for 10 min. Therefore, the inactivation of the primary antibodies is crucial to perform multiple immunoenzyme labeling using heat treatment. The sequential combination of the primary antibodies is also important; in the study presented here, an anti thyroid transcription factor-1 (TTF-1) antibody should be used first and anti cytokeratin AE1/AE3 antibody second, but not in the opposite sequence, to avoid a mixed-colour-labeling reaction. The present data provided the optimum combination of primary antibodies for multiple immunoenzyme labeling using heat treatment. PMID- 19775732 TI - Methimazole-induced hypothyroidism causes cellular damage in the spleen, heart, liver, lung and kidney. AB - It is known that a hypothyroidism-induced hypometabolic state protects against oxidative damage caused by toxins. However, some workers demonstrated that antithyroid drug-induced hypothyroidism can cause cellular damage. Our objective was to determine if methimazole (an antithyroid drug) or hypothyroidism causes cellular damage in the liver, kidney, lung, spleen and heart. Twenty-five male Wistar rats were divided into 5 groups: euthyroid, false thyroidectomy, thyroidectomy-induced hypothyroidism, methimazole-induced hypothyroidism (60 mg/kg), and treatment with methimazole (60 mg/kg) and a T4 injection (20 MUg/kg/d sc). At the end of the treatments (4 weeks for the pharmacological groups and 8 weeks for the surgical groups), the animals were anesthetized with sodium pentobarbital and they were transcardially perfused with 10% formaldehyde. The spleen, heart, liver, lung and kidney were removed and were processed for embedding in paraffin wax. Coronal sections were stained with hematoxylin-eosin. At the end of treatment, animals with both the methimazole- and thyroidectomy induced hypothyroidism had a significant reduction of serum concentration of thyroid hormones. Only methimazole-induced hypothyroidism causes cellular damage in the kidney, lung, liver, heart, kidney and spleen. In addition, animals treated with methimazole and T4 showed cellular damage in the lung, spleen and renal medulla with lesser damage in the liver, renal cortex and heart. The thyroidectomy only altered the lung structure. The alterations were prevented by T4 completely in the heart and partially in the kidney cortex. These results indicate that tissue damage found in hypothyroidism is caused by methimazole. PMID- 19775733 TI - Immunolocalization of androgen receptor and steroidogenic enzymes in cumuli oophori of pre- and post-ovulatory rats. AB - Immunolocalization of 3beta-hydroxysteroid dehydrogense (3beta-HSD), cytochrome P450c17 (P450c17) and androgen receptor (AR) were investigated in rat cumuli oophori (COCs) of late pre-ovulatory follicles and in post-ovulatory COCs bearing fertilized oocytes. A gradient of intensity of 3beta-HSD immunolabelling was observed in the granulosa layer of pre-ovulatory follicles, with almost negative immunolabelling in COCs and with the strongest immunoreaction in the mural granulosa cells. Post-ovulatory COCs showed strong 3beta-HSD immunolabelling in the peripheral regions and weak labelling near the oocyte, suggestive of responsiveness of cumulus cells to an anti-luteinizing effect exerted by the fertilized oocyte. In pre-ovulatory follicles, a weak P450c17 immunopositivity was limited to expanded cumulus granulosa cells and the positive labelling persisted in post-ovulatory COCs. P450c17 immunopositivity was also found in ampullary epithelial cells. A strong AR immunopositivity was confined mainly to the COCs in pre-ovulatory follicles and a similar immunoreaction was present in the granulosa cells of ovulated COCs. Simultaneous AR and cytochrome P450c17 immunolabelling in the pre- and post-ovulatory COCs is suggestive of an intra- and paracrine androgen regulation of the cumulus granulosa cell function. PMID- 19775734 TI - Peripheral blood mononuclear cell gene array profiles in patients with overactive bladder. AB - OBJECTIVES: To investigate the utility of using peripheral blood mononuclear cells (PBMC) as a marker for patients with overactive bladder (OAB). Patients with OAB may suffer from varying degrees of symptoms such as frequency, urgency, nocturia, and incontinence; however, there is no definitive test for OAB at this time. Questionnaires may provide useful tools for screening patients for OAB but often clinicians may need to rely on more invasive procedures to confirm the diagnosis. We have previously demonstrated that PBMC can provide a reporter function in solid organ retroperitoneal disease. METHODS: Twenty-one patients were assessed for OAB. PBMC was obtained from whole blood of the patients, and RNA was subjected to microarray gene chip analysis. RESULTS: Microarray analysis revealed that 16 genes were differentially regulated (8 upregulated and 8 downregulated) in all patients with OAB in comparison with healthy controls. A sex-based analysis demonstrated 74 genes that were differentially regulated in males (25 upregulated and 49 downregulated), and 30 in females (13 upregulated and 17 downregulated). Of these platelet-derived growth factors, microfibrillar associated protein and tropomyosin were downregulated in all sets that were analyzed. CONCLUSIONS: Microarray analysis revealed many genes that were differentially regulated in PBMC from OAB patients, including regulatory elements and genes encoding structural proteins, which may be important in regulating structural integrity of the bladder and supporting tissues. These data suggest that PBMC can provide a reporter function for patients with OAB and may serve as a diagnostic marker and elucidate genes involved in this condition. PMID- 19775735 TI - Reflectance confocal microscopy in early diagnosis of cutaneous metastases of breast cancer. PMID- 19775736 TI - Tumor platinum concentration following intraperitoneal administration of cisplatin versus carboplatin in an ovarian cancer model. AB - OBJECTIVE: Current intraperitoneal (IP) regimens for the treatment of ovarian cancer rely on cisplatin (DDP) whereas intravenous regimens rely on carboplatin (CBDCA). A major question in the field is whether CBDCA can replace DDP for IP treatment. We compared the uptake of IP administered DDP and CBDCA into human ovarian carcinoma nodules of various sizes growing on the peritoneal surface of nu/nu mice. METHODS: Human 2008 cells expressing GFP were inoculated IP in nu/nu mice. When small tumor nodules became visible by external imaging, a maximum tolerated dose of DDP, or either an equimolar or equitoxic dose of CBDCA, was injected IP. Platinum (Pt) concentration in tumor nodules was measured by inductively coupled plasma mass spectrometry. RESULTS: A total of 749 tumors harvested from 33 mice were analyzed for Pt concentration. DDP produced a 3.4 fold higher level of Pt in tumor nodules when compared to an equimolar dose of CBDCA (p=0.02). However, when DDP and CBDCA were injected at doses that were equitoxic to the mice, tumor Pt levels were equivalent (p=0.63). Although Pt concentrations of equal-sized nodules were highly variable, tumor Pt content (ng Pt/mg tumor) decreased with increasing nodule size following IP DDP, an effect not seen with IP administration of equitoxic doses of CBDCA (p<0.001). CONCLUSIONS: These results suggest that IP CBDCA has comparable or better drug penetration when compared to DDP given at equitoxic doses, and thus provide support for replacing DDP with CBDCA in the IP treatment of patients with ovarian cancer. PMID- 19775737 TI - Effects of exogenous progesterone and cloprostenol on ovarian follicular development and first ovulation in prepubertal heifers. AB - The objective of this study was to determine the effects of progesterone and cloprostenol (a PGF(2alpha) analogue) on ovarian follicular development and ovulation in prepubertal heifers. In Experiment 1, crossbred Hereford heifers (Bos taurus; 10 to 12 mo old, 255 to 320 kg) were assigned randomly to three groups and given (1) an intravaginal progesterone-releasing insert (CIDR; P group, n=13); (2) a CIDR plus 500 microg cloprostenol im (PGF(2alpha) analogue) at CIDR removal (PPG group, n=11); or (3) no treatment (control group, n=14). The CIDR inserts were removed 5 d after follicular wave emergence. Progesterone treated heifers (P and PPG groups) had a larger dominant follicle than that of the control group (P=0.01). The percentage ovulating was highest in the PPG group (8 of 11, 73%), intermediate in the P group (4 of 13, 31%), and lowest in the control group (1 of 14, 7%; P<0.02). In Experiment 2, 16 heifers (14 to 16 mo old, 300 to 330 kg) were designated to have follicular wave emergence synchronized with either a CIDR and 1mg estradiol benzoate im (EP group, n=8) on Day 0 (beginning of experiment) or by transvaginal ultrasound-guided ablation of all follicles >or=5mm on Day 3 (FA group, n=8). On Day 7, CIDRs were removed in the EP group, and all heifers received 500 microg cloprostenol im. Ovulation was detected in 6 of 8 heifers (75%) in both groups. In summary, the use of PGF(2alpha) with or without exogenous progesterone treatment increased the percentage ovulating in heifers close to spontaneous puberty. PMID- 19775738 TI - Sexual behavior and ejaculate characteristics in Pega donkeys (Equus asinus) mounting estrous horse mares (Equus caballus). AB - The objectives were to (i) characterize sexual behavior of donkey stallions (jacks; Equus asinus) during on-farm semen collection using estrous horse mares (mares; Equus caballus); (ii) compare behavior of young (less experienced) versus older (more experienced) jacks; (iii) determine whether semen suitable for artificial insemination (AI) could be collected using mares; and (iv) determine the suitability of using mares in field collection of semen from jacks. Six Pega jacks (3.5 to 16 yr old), previously conditioned to breed mares, were used. Mount mares were confirmed in estrus by a teaser horse stallion (stallion) and a jack. Semen was collected with an artificial vagina, at intervals of 48 to 72h (180 collections). The mean+/-SD (young [3.5 yr] vs. old [14 to 16 yr]) were Flehmen response frequency, 7.4+/-5.8 (8.1+/-3.0 vs. 7.0+/-2.0); number of mounts without erection, 1.1+/-1.3 (2.1+/-1.4 vs. 1.2+/-0.4, P<0.05); latency from first exposure to mare to full erection on the ejaculatory mount, 18.3+/-17.7min (25.3+/-21.3 vs. 12.2+/-6.2, P<0.05); latency from erection to insertion, 5.1+/ 3.5sec (5.3+/-3.8 vs. 4.8+/-3.2); and duration of copulation from insertion to dismount after ejaculation, 25.4+/-7.8sec (22.1+/-2.9 vs. 28.1+/-9.3). In all jacks, sexual behavior was generally normal, with the notable absence of open mouth behavior. Mare estrous behavior was markedly less intense than that in the presence of a stallion and usually absent. Semen characteristics were gel free volume, 47.3+/-28.7mL; gel volume, 71.8+/-54.8mL; total motility, 84.3+/-6.0%; progressive motility, 74.3+/-74.5%; sperm vigor, 3.9+/-0.5 (scale 1 to 5); sperm concentration, 253x10(6) cells/mL; and total number of sperm, 10.3x10(9) cells. Copulation duration was significantly correlated with gel free volume (r=0.9) and gel volume (r=0.7). We concluded that (i) the sexual behavior of jacks during semen collection using mares was similar to that reported for natural mating to jennies, (ii) precopulatory and copulatory behavior for the young (less experienced) jacks and older (more experienced) jacks were generally similar (except number of mounts without erection and latency to full erection); (iii) semen obtained using mares as stimulus and mount females was similar to that reported with estrous jennies; and (iv) semen collection from previously conditioned jacks, using estrous mares, was appropriate for field collection of semen. PMID- 19775739 TI - Follicle population, cumulus mucification, and oocyte chromatin configuration during the periovulatory period in the female dog. AB - This study was designed to describe the follicular population present on the canine ovary (Canis familiaris) during the preovulatory period and essentially the changes in oocyte size, mucification, and chromatin configuration occurring from before the luteinizing hormone (LH) surge up to postovulation. In a first experiment, ovaries of beagle bitches were collected before (n=21) or after LH surge but before ovulation (post-LH surge/preovulation stage, n=24) as determined using hormone (LH, estradiol, progesterone) assays and ultrasonography. All large (>2mm) follicles were measured and punctured. The numbers of oocytes collected per follicle and the degree of cumulus mucification were recorded. In a second experiment, ovaries were similarly collected before (n=13) and after the LH surge but before ovulation (n=11) as well as after ovulation as determined by ultrasonography (n=9). Chromatin configuration of the oocytes was observed by DNA staining and confocal microscopy. In Experiment 1, before the LH peak, an average of 13.5+/-0.7 follicles per bitch (total 284 follicles) were detected, and the maximal follicle diameter reached 6.5mm. Large follicles were observed already in this period of the cycle and as early as when progesterone was still below 0.5 ng/mL. After the LH peak but before ovulation, 11.0+/-0.7 follicles were present (total 264 follicles). Fully mucified cumulus cells were observed only in follicles larger than 4mm. Multi-oocytic follicles represented 7% (before LH peak) and 4% (after LH peak) of the follicular population. In Experiment 2, all the oocytes were at the germinal vesicle (GV) stage, but three chromatin configurations could be distinguished: diffuse, partly grouped, and fully grouped chromatin. The proportion of oocytes with fully grouped chromatin increased with the follicular diameter and the time in estrus, the maximum being observed after the LH peak. These results suggest that (1) before LH peak, follicles are already of large diameter, similar to the ones at ovulation; (2) the ability for cumulus mucification is acquired during the late steps of follicular growth; (3) three GV patterns may be observed during the periovulatory period. PMID- 19775740 TI - Effect of storage of domestic cat (Felis catus) epididymides at 5 degrees C on sperm quality and cryopreservation. AB - Postmortem sperm recovery from the epididymides may constitute a powerful tool for the conservation of valuable genetic material. The domestic cat (Felis catus) is a good model for wild felids and, using this model, we have explored the effect of epididymides storage time on sperm motility and percentage of intact acrosomes upon sperm recovery and after cryopreservation. We also examined the effect of time of sperm equilibration with glycerol before freezing on sperm motility and the percentage of intact acrosomes. Motility varied between sperm recovered from epididymides that were stored for different times. Significant differences were seen in the sperm motility index (SMI) before freezing (55.91+/ 2.02, 48.21+/-1.47, and 43.03+/-1.32) and after thawing (51.81+/-3.02, 41.90+/ 2.14, and 42.35+/-1.95) of sperm recovered from epididymides stored for 0, 48, or 72 h, respectively. The percentage of intact acrosomes did not vary significantly with storage time (average 60.33+/-1.38% before and 52.50+/-1.91% after freezing, respectively). The percentage of normal sperm after different storage times did not differ (average 19.22+/-1.25% normal sperm after recovery). When epididymides were stored for 72 h, time of sperm equilibration with glycerol (30 vs. 120 min) resulted in significant differences in both motility (SMI=39.17+/-2.76 and 45.00+/-2.65, respectively) and the percentage of intact acrosomes (45.76+/-4.91% and 60.67+/-3.64%, respectively) after thawing. In conclusion, best results are achieved when sperm are recovered from epididymides within 24h of cool storage and when they are equilibrated with glycerol during 120 min before freezing. The current results should be useful in the further development of techniques for the rescue and cryostorage of epididymal spermatozoa of endangered felids. PMID- 19775741 TI - Comparison of accuracy of ultrasonography, progesterone, and pregnancy-associated glycoprotein tests for pregnancy diagnosis in semidomesticated reindeer. AB - The aim of the study was to compare transrectal ultrasound with progesterone (P4) and pregnancy-associated glycoproteins (PAGs) as pregnancy detection methods for semidomesticated reindeer (Rangifer tarandus tarandus) in field conditions. Female reindeer (n=195) were scanned transrectally by a 7.5-MHz linear array transducer, and blood was sampled either in December 2005 (n=33), December 2006 (n=92), or January 2007 (n=70) during early or mid gestation. Plasma levels of P4 and PAGs were assessed by radioimmunoassay (RIA). Based on calving records, the sensitivity, specificity, predictive values, and the overall accuracy of the three tests were calculated. The overall calving rate calculated from the calving records was 86.2%. The overall accuracy of transrectal ultrasound was 99.5%. The sensitivity and specificity of transrectal ultrasound were 99.4% and 100%, respectively. In the plasma P4 test, the threshold level of 5.0 nmol/L gave the highest overall accuracy (94.9%). The sensitivity of the P4 test decreased from 96.4% to 81.5%, when the threshold level increased from 5.0 nmol/L to 8.0 nmol/L, while the specificity remained at 85.2% over the range of these cutoff values. The overall accuracy of the plasma PAG test decreased from 96.4% to 64.1% when the plasma PAG threshold level increased from 0.5 ng/mL to 3.5 ng/mL, whereas sensitivity decreased from 99.4% to 58.3%. Specificity increased from 77.8% to 100% when the plasma PAG threshold level reached 3.0 ng/mL. Transrectal ultrasound showed higher diagnostic values than those of plasma P4-RIA and PAG RIA in diagnosing pregnancy of reindeer, with the advantage that diagnoses can be made in real time in field conditions. PMID- 19775742 TI - The reliable targeting of specific drug release profiles by integrating arrays of different albumin-encapsulated microsphere types. AB - Biodegradable polymer microspheres have been successfully utilized as a medium for controlled protein or peptide-based drug release. Because the release kinetics has been typically controlled by modulating physical or chemical properties of the medium, these parameters must be optimized to obtain a specific release profile. However, due to the complexity of the release mechanism and the complicated interplay between various design parameters of the release medium, detailed prediction of the resulting release profile is a challenge. Herein we suggest a simple method to target specific release profiles more efficiently by integrating release profiles for an array of different microsphere types. This scheme is based on our observation that the resulting release profile from a mixture of different samples can be predicted as the linear summation of the individually measured release profiles of each sample. Hence, by employing a linear equation at each time point and formulating them as a matrix equation, we could determine how much of each microsphere type to include in a mixture in order to have a specific release profile. In accordance with this method, several targeted release profiles were successfully obtained. We expect that the proposed method will allow us to overcome limitations in controlling complicated release mechanisms so that drug delivery systems can be reliably designed to satisfy clinical demands. PMID- 19775743 TI - Perlecan domain I-conjugated, hyaluronic acid-based hydrogel particles for enhanced chondrogenic differentiation via BMP-2 release. AB - We have developed a biomimetic growth factor delivery system that effectively stimulates the chondrogenic differentiation of the cultured mesenchymal stem cells via the controlled presentation of bone morphogenetic protein-2 (BMP-2). Hyaluronic acid (HA)-based, microscopic hydrogel particles (HGPs) with inherent nanopores and defined functional groups were synthesized by an inverse emulsion polymerization technique. Recombinantly produced, heparan sulfate (HS)-bearing perlecan domain I (PlnDI) was covalently immobilized to HA HGPs (HGP-P(1)) via a flexible poly(ethylene glycol) (PEG) linker through the lysine amines in the core protein of PlnDI employing reductive amination. Compared to HGP without PlnDI, HGP-P(1) exhibited significantly (p<0.05) higher BMP-2 binding capacity and distinctly different BMP-2 release kinetics. Heparitinase treatment increased the amount of BMP-2 released from HGP-P(1), confirming the HS-dependent BMP-2 binding. While BMP-2 was released from HGPs with a distinct burst release followed by a minimal cumulative release, its release from HGP-P(1) exhibited a minimal burst release followed by linear release kinetics over 15 days. The bioactivity of the hydrogel particles was evaluated using micromass culture of multipotent mesenchymal stem cells (MSCs), and the chondrogenic differentiation was assessed by the production of glycosaminoglycan, aggrecan and collagen type II. Our results revealed that BMP-2 loaded HGP-P(1) stimulates more robust cartilage specific ECM production as compared to BMP-2 loaded HGP, due to the ability of HGP-P(1) to potentiate BMP-2 and modulate its release with a near zero order release kinetics. The PlnDI-conjugated, HA HGPs provide an improved BMP-2 delivery system for stimulating chondrogenic differentiation in vitro, with potential therapeutic application for cartilage repair and regeneration. PMID- 19775744 TI - The use of progenitor cell/biodegradable MMP2-PLGA polymer constructs to enhance cellular integration and retinal repopulation. AB - The inability of the adult mammalian retina to regenerate can be partly attributed to the expression of injury-induced inhibitory extracellular matrix (ECM) and cell adhesion molecules. In particular, photoreceptor degeneration stimulates deposition of the inhibitory ECM proteins neurocan and CD44 at the outer limits of the dystrophic retina, where they act as a barrier against cellular migration and axonal extension. We have previously shown that degradation of these molecules, via induction of MMP2, promotes host-donor integration and retinal repopulation following transplantation. Here we present a biodegradable/biocompatible polymer scaffold that has the ability to deliver MMP2, in conjunction with retinal progenitor cells, directly to the site of retinal injury in an attempt to enhance cellular integration and promote retinal repopulation. Pre-activated MMP2, loaded into a PLGA polymer, maintained its activity throughout polymer fabrication and hydrolysis. Following delivery, significant degradation of CD44 and neurocan from the outer limits of the dystrophic retina, without further disruption of retinal architecture, was observed. As a result, the number of retinal progenitor cells that migrated beyond the glial barrier into the degenerating host increased significantly. These cells took up residence in the retinal outer nuclear layer, adopted appropriate photoreceptor morphology and expressed the mature photoreceptor markers recoverin and rhodopsin. Thus, we have created a cell delivery platform that upon transplantation provides controlled release of active-MMP2 directly to the site of retinal injury, stimulating inhibitory ECM barrier removal and enhancement of stem cell integration and retinal repopulation. PMID- 19775745 TI - The characteristics and transfection efficiency of cationic poly (ester-co urethane) - short chain PEI conjugates self-assembled with DNA. AB - To improve the transfection efficiency of polycations with DNA, we synthesized poly(ester-co-urethane)(PEU-g-PEI800) with short chain PEI800 in the side chain, and poly(ester-co-urethane)(PEU) without short chain PEI800. Both PEU-g-PEI800 and PEU, readily self-assembled with plasmid DNA (pCMV-betagal) in a HEPES buffer, were characterized by dynamic light scattering and zeta-potential. The results reveal that PEU-g-PEI800 and PEU were able to self-assemble particles with DNA and yield nano-sized complexes (<200nm) with positive charge at N/P ratios of 20/1 and 120/1, respectively. The degradation studies indicate that the half-life of PEU-g-PEI800 and PEU in the HEPES buffer were 14 and 35h at pH 7.4, respectively. Titration studies were performed to determine the buffering capacities of the polymers. The COS-7 cell viabilities in the presence of PEU-g PEI800/DNA, PEU/DNA, and PEI25k/DNA were studied. In addition, The PEU-g PEI800/DNA complexes were able to transfect COS-7 cells in vitro with a high efficiency comparable to a well-known gene carrier PEI25k. The results indicate that PEU-g-PEI800 is an attractive cationic poly (ester-co-urethane) for gene delivery and an interesting candidate for further study. PMID- 19775746 TI - Modulation of the resorption and osteoconductivity of alpha-calcium sulfate by histone deacetylase inhibitors. AB - Calcium sulfate (CS) is an osteoconductive material with a long history of clinical use. However, its resorptive properties are not optimal for bone regeneration. Recently, histone deacetylase inhibitors (HDIs) have been suggested as bone regeneration tools. In this study, we investigated the effects of the HDIs sodium butyrate and trichostatin A on alpha-form CS (alphaCS) performance. MC3T3-E1 pre-osteoblasts cultured on alphaCS containing either HDI (alphaCS/HDI) showed higher levels of alkaline phosphatase activity than those cultured on alphaCS alone. The expression of genes characteristic of the osteoblast phenotype, including Runx2, osteocalcin, and bone sialoprotein, was strongly promoted by alphaCS/HDI. When cultured on alphaCS/HDIs, the osteoclastic differentiation of RAW264.7 monocytes was substantially suppressed, as measured by tartrate-resistant acid phosphatase (TRAP) activity and the expression levels of calcitonin receptor and TRAP. Neither HDI affected the CS setting time, compressive strength, or dissolution in a simulated body fluid. In a rat calvarial model of critical size bone defects, alphaCS/HDIs enhanced osteoblast differentiation, led to new bone formation, and delayed resorption, as confirmed by micro-computed tomography and histological analyses. PMID- 19775747 TI - The influence of synthetic peptides derived from the laminin alpha1 chain on hepatocyte adhesion and gene expression. AB - Laminin-111, a heterotrimer composed of the laminin alpha1, beta1, and gamma1 chains, has been used as a biomaterial for primary cell culture to maintain cellular functions. Our previous studies have reported that synthetic peptides derived from laminin alpha1 exhibit biological functions such as influencing cell adhesion, migration, angiogenesis, and tumor metastasis. In this study we screened hepatocyte attachment peptides using twenty-five biologically active peptides from laminin alpha1 and examined the maintenance of hepatic function on the peptides using primary rat hepatocytes. Peptide A13 (RQVFQVAYIIIKA), mouse laminin alpha1 chain residues 121-133, exhibited the strongest activity. Furthermore, primary hepatocytes on A13 peptide maintained expression of hepatic differentiation markers such as tyrosine aminotransferase, tryptophan-2,3 dioxygenase, and cytochrome P450. We also determined the active core sequence of A13 using systematically truncated N- and C-terminal peptides. The results indicated that the nine-amino acid sequence RQVFQVAYI was critical for A13's hepatocyte adhesion activity. However, the truncated peptides could not interact with beta1-intgerin and maintain expression of hepatic differentiation markers. The amino acid sequence of A13 peptide was required for regulating hepatocyte behavior. The hepatocyte adhesive peptides can be utilized in tailoring synthetic biomaterials in order to achieve a specific cellular response. PMID- 19775748 TI - Hydrogel blends of chitin/chitosan, fucoidan and alginate as healing-impaired wound dressings. AB - In order to create a moist environment for rapid wound healing, a hydrogel sheet composed of a blended powder of alginate, chitin/chitosan and fucoidan (ACF-HS; 60:20:2:4 w/w) has been developed as a functional wound dressing. ACF-HS gradually absorbed DMEM without any maceration, and fluid absorption became constant within 18 h. On application, ACF-HS was expected to effectively interact with and protect the wound in rats, providing a good moist healing environment with exudates. In addition, the wound dressing has properties such as ease of application and removal and good adherence. Full-thickness skin defects were made on the backs of rats and mitomycin C solution (1 mg/ml in saline) was applied onto the wound for 10 min in order to prepare healing-impaired wounds. After thoroughly washing out the mitomycin C, ACF-HS was applied to the healing impaired wounds. Although normal rat wound repair was not stimulated by the application of ACF-HS, healing-impaired wound repair was significantly stimulated. Histological examination demonstrated significantly advanced granulation tissue and capillary formation in the healing-impaired wounds treated with ACF-HS on day 7, as compared to those treated with calcium alginate fiber (Kaltostat; Convatec Ltd., Tokyo, Japan) and those left untreated. PMID- 19775749 TI - The effect of substrate stiffness on adult neural stem cell behavior. AB - Adult stem cells reside in unique niches that provide vital cues for their survival, self-renewal and differentiation. In order to better understand the contribution of substrate stiffness to neural stem/progenitor cell (NSPC) differentiation and proliferation, a photopolymerizable methacrylamide chitosan (MAC) biomaterial was developed. Photopolymerizable MAC is particularly compelling for the study of the central nervous system stem cell niche because Young's elastic modulus (E(Y)) can be tuned from less than 1 kPa to greater than 30 kPa. Additionally, the numerous free amine functional groups enable inclusion of biochemical signaling molecules that, together with the mechanical environment, influence cell behavior. Herein, NSPCs proliferated on MAC substrates with Young's elastic moduli below 10 kPa and exhibited maximal proliferation on 3.5 kPa surfaces. Neuronal differentiation was favored on the soft est surfaces with E(Y) < 1 kPa as confirmed by both immunohistochemistry and qRT-PCR. Oligodendrocyte differentiation was favored on stiffer scaffolds (> 7 kPa); however, myelin oligodendrocyte glycoprotein (MOG) gene expression suggested that oligodendrocyte maturation and myelination was best on < 1 kPa scaffolds where more mature neurons were present. Astrocyte differentiation was only observed on < 1 and 3.5 kPa surfaces and represented less than 2% of the total cell population. This work demonstrates the importance of substrate stiffness to the proliferation and differentiation of adult NSPCs and highlights the importance of mechanical properties to the success of scaffolds designed to engineer central nervous system tissue. PMID- 19775750 TI - Gene delivery via DNA incorporation within a biomimetic apatite coating. AB - Integrating inductivity with conductivity in a material may advance tissue engineering. An organic/inorganic hybrid was developed by incorporating plasmid DNA encoding for the beta-gal gene complexed with Lipofectamine 2000 (DNA Lipoplex) within apatite via coprecipitation. It was hypothesized that this system will result in enhanced transfection efficiency compared to DNA-Lipoplexes adsorbed to the mineral surface and DNA coprecipitated without Lipofectamine 2000. PLGA films were cast onto glass slips and apatite and DNA were coprecipitated in modified simulated body fluid (mSBF). DNA-Lipoplex presence in mineral, DNA-Lipoplex stability (vs. coprecipitation time), and transfection efficiency (determined with C3H10T1/2 cells) as a function of coprecipitation time, DNA-Lipoplex concentration, and DNA incorporation method were studied. DNA Lipoplex presence and spatial distribution on apatite were confirmed through fluorescence. Transfection efficiency was highest for 6h of DNA-Lipoplex coprecipitation. Differences in transfection efficiency were found between the DNA concentrations, with the highest efficiency for coprecipitation being 40 microg/ml (p < or = 0.009 relative to other coprecipitation concentrations). Significant differences in transfection efficiency existed between incorporation methods (p < 0.05) with the highest efficiency for DNA-Lipoplex coprecipitation. This hybrid material system not only integrates inductivity provided by the DNA and conductivity provided by the apatite, but it also has significant implications in non-viral gene delivery due to its ability to increase transfection efficiency. PMID- 19775751 TI - The remodeling of cardiovascular bioprostheses under influence of stem cell homing signal pathways. AB - Optimizing current heart valve replacement strategies by creating living prostheses is a necessity to alleviate complications with current bioprosthetic devices such as calcification and degeneration. Regenerative medicine, mostly in vitro tissue engineering, is the forerunner of this optimization search, yet here we show the functionality of an in vivo alternative making use of 2 homing axes for stem cells. In rats we studied the signaling pathways of stem cells on implanted bioprosthetic tissue (photooxidized bovine pericardium (POP)), by gene and protein expression analysis. We found that SDF-1alpha/CXCR4 and FN/VLA4 homing axes play a role. When we implanted vascular grafts impregnated with SDF 1alpha and/or FN as carotid artery interpositions, primitive cells were attracted from the circulation. Next, bioprosthetic heart valves, constructed from POP impregnated with SDF-1alpha and/or FN, were implanted in pulmonary position. As shown by CD90, CD34 and CD117 immunofluorescent staining they became completely recellularized after 5 months, had a normal function and biomechanical properties and specifically the combination of SDF-1alpha and FN had an optimal valve-cell phenotype. PMID- 19775752 TI - Changes in the metabolic footprint of placental explant-conditioned culture medium identifies metabolic disturbances related to hypoxia and pre-eclampsia. AB - Pre-eclampsia (PE) is a multi-system disorder thought to be mediated by circulating factors released from damaged placental villous trophoblast. There is extensive evidence of changes in the villous tissue in PE, some of which may be replicated by culturing villous tissue in hypoxic conditions. Metabolic footprinting offers a hypothesis-generating strategy to investigate factors released from this tissue in vitro. This study investigated differences in the factors released from villous trophoblast from uncomplicated pregnancies (n=6) and those with PE (n=6). In both cases, explanted placental villous fragments were cultured for 96 h in 1% O(2) (hypoxia) or 6% O(2) (placental normoxia). Metabolites consumed from and released into serum-conditioned culture medium were analysed by Ultra Performance Liquid Chromatography-Mass Spectrometry (UPLC-MS). The relative concentration of 154 features of the metabolic footprint were observed to change in culture medium from uncomplicated pregnancies cultured in normoxic and hypoxic conditions (p<0.00005). 21 and 80 features were also different in culture medium from PE versus uncomplicated pregnancies cultured in hypoxic and normoxic conditions, respectively (p<0.00005). When comparing all 4 groups, 47 metabolic features showed a similar relative concentration in PE derived media cultured in normoxic conditions to conditioned media from normal villous tissue cultured in hypoxic conditions. These data suggest that hypoxia may have a role in the placental pathogenesis of PE. Three areas of metabolism were highlighted for systems biology investigation; glutamate and glutamine, tryptophan metabolism and leukotriene or prostaglandin metabolism. PMID- 19775753 TI - Methodologic issues in the study of the relationship between histologic indicators of intraamniotic infection and clinical outcomes. AB - GOAL: To determine the structure of the relationships of the histology scores for acute intraamniotic infection collected in the Collaborative Perinatal Project (CPP). MATERIALS AND METHODS: 44,427 subjects of the CPP had complete histology scores available for the 9 measures that related to acute intraamniotic infection (i.e., neutrophil infiltrates in umbilical cord, amnion of extraplacental membranes and chorionic plate, decidua, chorionic plate and fetal chorionic vessels). Confirmatory factor analysis was used to determine the relationships among the different markers of maternal inflammatory responses (in amnion, chorion and decidua) and fetal inflammatory responses (in umbilical cord and fetal chorionic vessels). RESULTS: A single CFA model could not be developed across all CPP sites. A well-fit model was developed from the Boston site (N=10,803) and the factor loadings applied to the histology scores from the other CPP sites. The resultant scores for the latent variables (maternal and fetal inflammatory responses) were compared across sites. There was not only considerable variability in factor loadings, and the signs of factor loadings were also inconsistent across sites. CONCLUSION: Histopathology scores of neutrophil infiltrates performed by different observers do not have the same interrelationships and, by extension, the latent variables they are supposed to reflect may not be equivalent. The lack of measurement invariance renders their use as indicators of the underlying processes of maternal and fetal inflammatory responses problematic in analysis with any clinical outcome. PMID- 19775754 TI - NDRG1/2 expression is inhibited in primary acute myeloid leukemia. AB - Expression of N-myc downregulated gene 1 (NDRG1) is associated with growth arrest and differentiation of tumor cells. In hematopoietic cells, NDRG1 was identified in a screen for differentiation-related genes in human myelomonocytic leukemic U937 cells. In the present study, we found significantly higher NDRG1 mRNA levels in granulocytes of healthy donors than in primary acute myeloid leukemia (AML) cells. Another NDRG family member, NDRG2, was significantly higher expressed in normal macrophages compared to primary AML cells. Moreover, NDRG1 mRNA levels increased in two acute promyelocytic leukemia (APL) patients as well as in NB4 and HT93 APL cells upon all-trans retinoic acid (ATRA) therapy. In line with these observations, silencing of NDRG1 diminished neutrophil differentiation of leukemic cell lines. In conclusion, we found an association of low NDRG1 levels with an immature cell phenotype and provide evidence that NDRG1 is functionally involved in neutrophil maturation. PMID- 19775755 TI - Using face validity to recognize empirical community observations. AB - There is a growing interest among international planning scholars to explore community participation in the plan making process from a qualitative research approach. In this paper the research assessment tool "face validity" is discussed as one way to help planners decipher when the community is sharing empirically grounded observations that can advance the applicability of the plan making process. Face validity provides a common sense assessment of research conclusions. It allows the assessor to look at an entire research project and ask: "on the face of things, does this research make sense?" With planners listening to citizen comments with an ear for face validity observations, holds open the opportunity for government to empirically learn from the community to see if they "got it right." And if not, to chart out a course on how they can get it right. PMID- 19775756 TI - Expressed gene sequences of the equine cytokines interleukin-17 and interleukin 23. AB - This report describes the initial cloning and characterization of the equine interleukin-17 (IL-17) expressed gene sequence from mRNA obtained from equine intestinal tissue and interleukin-23 (IL-23) expressed gene sequence from mRNA obtained from equine peripheral blood mononuclear cells. Equine IL-17 has 462 nucleotides in the translated region, determined by homology with known human and mouse sequences, and shares 84% and 75% identity, respectively. For the deduced amino acid sequences, the identity with human and mouse is 76% and 70%. Equine IL 23 has 579 nucleotides in the translated region. Homology with known human and mouse sequences was determined to be 89% and 77%. Deduced amino acid identities are 89% with the human sequence and 70% with the mouse sequence. The gene sequences were identified as part of the U.S. Veterinary Immune Reagent Network with a goal of developing reagents in order to aid veterinary researchers in the investigation of diseases in livestock species. PMID- 19775757 TI - Cochlear abnormalities associated with enlarged vestibular aqueduct anomaly. AB - OBJECTIVES: The objective of this study is to examine the correlation between enlarged vestibular aqueduct (EVA) anomaly and other inner ear anomalies such as cochlear dysplasia, vestibulocochlear dysplasia and modiolar hypoplasia. METHODS: Retrospective chart review, with institutional review board approval, of patients with EVA who received treatment at Primary Children's Medical Center or University Hospital at the University of Utah, between 1997 and 2006. Review of radiographs was done to evaluate for the presence of EVA and other inner ear anomalies. RESULTS: Twenty patients (40 ears) were included in the study, 17 patients had bilateral EVA and three patients had unilateral EVA. There were 10 females and 10 males. The average age of all patients at the time of initial diagnosis was 1.7 years (0-6 years). Thirty-seven ears were shown to have EVA (92.5%). Of those ears with EVA, 29 (78.4%) had one or more inner ear anomalies. Twenty-three (62.2%) ears had cochlear dysplasia, six (16.2%) had vestibulocochlear dysplasia, and 18 (48.7%) had modiolar hypoplasia. CONCLUSIONS: Using small field of view, thin section CT and/or MR imaging, cochleovestibular abnormalities are commonly identified in association with EVA. PMID- 19775758 TI - The prelexical development in children implanted by 16 months compared with normal hearing children. AB - OBJECTIVE: Few studies exist which document the early speech development of German-speaking children or German-speaking children who are deaf and using cochlear implants. The current study aims to: (1) document the pre-canonical and canonical speech development of German-speaking children who are deaf and receive cochlear implants by the age of 16 months and (2) compare these children's results with those of children with normal hearing. DESIGN: This longitudinal study included 5 German-speaking children with normal hearing and 5 with sensorineural deafness. All children from the deaf group received hearing amplification before cochlear implantation, received their first implant by 16 months of age, and became bilateral implant users by 31 months of age. The pre canonical and canonical vocalisations of each child were recorded on video- and audiotapes in a semi-standardised playing situation every 4 weeks over a span of 1 year. In the cochlear implant group, the recording started 4-5 days postoperatively (first implant); in the normal hearing group it began between the ages of 4 and 5 months. The video and audio recordings were analysed using EUDICO Linguistic Annotator version 2.4 (Nijmegen, The Netherlands) and International Phonetic Alphabet transcription. RESULTS: Both groups showed individual patterns of babbling acquisition, though the groups' patterns of acquisition were similar when analysed for consonant manner and place. Some children started with plosives and others, with nasals, but all acquired fricatives and laterals next. Onset of canonical babbling for children in the cochlear implant group began 0-4 months after first fitting of the first device, while children from the normal hearing group demonstrated an onset of canonical babbling between 4 and 9 months of age. CONCLUSION: Our results show that deaf children who receive cochlear implants at an early age are capable of reaching the canonical babbling milestone in a shorter time than children with normal hearing typically do and that their consonant phoneme acquisition follows a similar sequence to normal hearing peers'. These results are consistent with the literature indicating that early identification and intervention are important for allowing children with cochlear implants the opportunity to catch up to hearing peers. PMID- 19775760 TI - The effects of parafunctional habit control and topical lubricant on discomforts associated with burning mouth syndrome (BMS). AB - The BMS is a common chronic pain condition which mainly affects old women. The high prevalence of oral parafunctional habits and dry mouth symptoms in patients with BMS suggests that inflammation at the subclinical level due to repetitive microtrauma may cause burning mouth sensations. In this study, using a comprehensive questionnaire, we have investigated the efficacy of oral habit control and use of topical lubricant or corticosteroid on oral complaints associated with BMS. Twenty-five patients with BMS (1 man and 24 women, mean age 59.4+/-8.3 years) were included to investigate the effects of habit control and topical lubricant on discomforts associated with BMS. Another 29 patients (2 men and 27 women, mean age 55.0+/-10.6 years) were included to investigate the effects of habit control and topical dexamethasone (DXM). The burning and aching qualities of discomfort, and the effect of oral complaints on daily life were significantly decreased by both types of treatments. However, there were no significant differences between the different treatment groups. The salivary flow rate did not affect the treatment outcome. We concluded that the concomitant prescription of topical lubricants with oral habit control is an effective initial approach for patients with BMS. PMID- 19775761 TI - The relationship between functional capacity (FC) and cardiovascular risk factors (CVRFs) in senile patients after noncardiac surgery. AB - The aim of the present study was to investigate the relationship between the number of cardiovascular risk factors (CVRFs) and functional capacity (FC) in the senile patients undergone noncardiac surgery. One hundred and eighty-two senile patients scheduled for elective noncardiac surgery were selected. According to the Duke activity status index (DASI), the FC of each patient was evaluated, and also their CVRFs were recorded. According to the number of CVRFs, the patients were ranked into different groups. The significant differences in FC between the groups(') were identified using the analysis of variance. The examination showed that FC decreased with the increasing number of CVRFs. As a conclusion, we emphasize that with the increasing number of CVRFs, the FC of senile patients, i.e., their metabolic equivalents (METs) decrease. The occurrence of low FC and higher CVRFs is a common phenomenon in senile patients. PMID- 19775759 TI - Multiple roles of HDAC inhibition in neurodegenerative conditions. AB - Histone deacetylases (HDACs) play a key role in homeostasis of protein acetylation in histones and other proteins and in regulating fundamental cellular activities such as transcription. A wide range of brain disorders are associated with imbalances in protein acetylation levels and transcriptional dysfunctions. Treatment with various HDAC inhibitors can correct these deficiencies and has emerged as a promising new strategy for therapeutic intervention in neurodegenerative disease. Here, we review and discuss intriguing recent developments in the use of HDAC inhibitors to combat neurodegenerative conditions in cellular and disease models. HDAC inhibitors have neuroprotective, neurotrophic and anti-inflammatory properties; improvements in neurological performance, learning/memory and other disease phenotypes are frequently seen in these models. We discuss the targets and mechanisms underlying these effects of HDAC inhibition and comment on the potential for some HDAC inhibitors to prove clinically effective in the treatment of neurodegenerative disorders. PMID- 19775762 TI - Attitudes and knowledge of medical and nursing staff toward elder abuse. AB - Although physicians and nurses are best positioned to recognize and diagnose cases of elder abuse, the level of reporting these cases is much lower than its true incidence. Our aim was to assess and compare knowledge and attitudes of physicians and nurses toward this phenomenon. Two hundred and thirty-five nurses and physicians were asked to participate in the study. One hundred nurses and 57 physicians ultimately completed the questionnaires. The main finding was that participants had a low level of knowledge of elder abuse issues and the relevant laws and regulations (mean correct answers 5.36+/-1.45 of 10 and 4.67+/-1.34 of 8, respectively). No significant differences were found in the physicians' knowledge according to medical specialty, hospital type, years in the profession and geriatric experience. Licensed practical nurses knew less than registered and academic nurses relating to the abuse issue and state reporting laws (p=0.003 and 0.02, respectively). No significant differences relating to the knowledge of elder abuse were found between nurses and physicians nor between general and geriatric hospital employees. Both physicians and nurses tended to have neutral attitudes regarding this issue. However, employees of geriatric hospitals had better attitudes than general hospital workers (p=0.008). Most responders believed that the unwillingness to get legally involved had been the main reason of not reporting suspected cases. This study emphasizes the need to take more efficient measures to improve the knowledge of the medical and nursing staff concerning elder abuse and to encourage medical personnel to be more concerned and involved in the safeguarding of the elderly. PMID- 19775763 TI - The prognostic impact of allopurinol in patients with acute myocardial infarction undergoing primary percutaneous coronary intervention. AB - Oxidative stress has been shown to increase after acute myocardial infarction and during coronary reperfusion. Allopurinol inhibits xanthine oxidase, an enzyme involved in reperfusion injury. In this study, 40 patients with ST elevation myocardial infarction and symptoms' onset 3-12 h, who underwent primary coronary intervention, were administered either allopurinol (loading dose 400 mg followed by 100 mg for 1 month--group A, 21 patients), or placebo (group B). Allopurinol resulted in a more effective ST-E recovery (P<0.05 for all comparisons) and lower peak values of troponin I (P=0.04), CPK (P=0.01) and CK-MB (P=0.03). After 1 month follow-up period, 13% lower incidence of major adverse cardiac events (P=0.002) was also observed in group A, whereas no significant differences in the EF were detected between the groups studied. In our study population, allopurinol administration was beneficial concerning tissue reperfusion, myocardial injury and clinical outcomes. PMID- 19775765 TI - Network analysis of Italian cattle trade patterns and evaluation of risks for potential disease spread. AB - Livestock movement data represent a valuable source of information to understand the pattern of contacts between premises which may determine the spread of diseases. Social network analysis techniques have been used to analyse the movement patterns of cattle in Italy in 2007. A description of the structure of the Italian cattle industry is presented and the main trade flows and the relations between premises in relation to the potential spread of cattle diseases are investigated. Epidemic simulations have been carried out on the network build out of movement data using a network-based meta-population model. The simulations show the influence of the network structure on the dynamics and size of a hypothetic epidemic and give useful indications on the effects of targeted removal of nodes based on the centrality of premises within the network of animal movements. PMID- 19775766 TI - Factors affecting persistence of high Salmonella serology in Danish pig herds. AB - In 1995, Denmark implemented a National Surveillance-and-Control Programme for Salmonella in finisher pigs. It was based on serological surveillance that enabled assignment of pig herds into three prevalence levels. Herds in levels 2 and 3 (corresponding to moderate and high Salmonella seroprevalence) were subjected to control measures, compulsory pen faecal sampling for bacteriological examination and serotyping. The initial dataset contained all herds that had mandatory bacteriological samples taken (N=3691 samples), out of which 44.4% were negative. Data from January 2005 to November 2007 obtained from the Danish programme were used to investigate the persistence of high serology (Salmonella index > or =40, corresponding to levels 2 or 3) for herds infected with one of the four most common Salmonella serotypes found in pig herds, S. Typhimurium, S. Derby, S. Infantis or S. Livingstone, using survival analysis. The effects of other potential factors, such as season, year, herd size and herd health status were also evaluated. An event was defined as return to low serology measured by a Salmonella index <40, for at least 6 consecutive months. A total of 1242 pig herds positive for one of the four serotypes of interest and 1433 events were included in the preliminary analysis using the Kaplan-Meyer method. The median high serology time (survival time) was 8 months and all explanatory variables were found to be significant (p<0.05), except the herd health status (p=0.49). Cox proportional hazards regression was used for herds infected with S. Typhimurium (N=1066) or S. Derby (N=314). Herds infected with S. Typhimurium presented a lower probability for returning to low serology (HR=0.69, p<0.001), compared to S. Derby, indicating longer high serology periods. Herds that started having high seroprevalence in Summer and Fall had a higher probability of returning to low serology compared to those starting in Winter and Spring (p<0.001). Compared to 2005, periods with high Salmonella serology were fewer and shorter in 2006 and 2007 (p<0.001). A positive impact of herd size was found, with larger herds being associated with shorter high serology periods, compared to smaller herds (p=0.012). This might indicate effective implementation of biosecurity measures in large herds. The health status of the herds was not found to be a significant factor (p=0.87), which might reflect that biosecurity measures in place in SPF herds are not effective for clearing Salmonella infections. PMID- 19775767 TI - Gut health promoting activity of new putative probiotic/protective Lactobacillus spp. strains: a functional study in the small intestinal cell model. AB - In interaction studies with the host intestine, the use of the appropriate gut functional cell model is essential. Therefore, we examined the protective properties of selected lactobacilli in a newly established intestinal cell model. Bacteria were cocultured with the pig small intestinal epithelial cells (PSIc1) and pig blood monocytes (PoM2) in a functional intestinal cell model. Intercellular intestinal integrity was measured by transepithelial electrical resistance (TER), before and after coculture with selected bacterial strains. All selected bacterial strains showed important gut health promoting activity by: enhancing the intestinal integrity and increasing metabolic activity of intestinal cells. Stimulation of immune response was strain specific. The best stimulants were unidentified lactobacillus strains obtained from fermented food in Africa (PCK87 and 66), followed by Lactobacillus plantarum (PCS26). Their activity was significantly higher (p<0.05) than that of the commercial Lactobacillus casei Shirota strain. PMID- 19775764 TI - Differentiation induction of mouse embryonic stem cells into sinus node-like cells by suramin. AB - BACKGROUND: Embryonic stem (ES) cells differentiate into cardiac phenotypes representing early pacemaker-, atrial-, ventricular-, and sinus node-like cells, however, ES-derived specification into sinus nodal cells is not yet known. By using the naphthylamine derivative of urea, suramin, we were able to follow the process of cardiac specialization into sinus node-like cells. METHODS: Differentiating mouse ES cells were treated with suramin (500 uM) from day 5 to 7 of embryoid body formation, and cells were analysed for their differentiation potential via morphological analysis, flow cytometry, RT-PCR, immunohistochemistry and patch clamp analysis. RESULTS: Application of suramin resulted in an increased number of cardiac cells, but inhibition of neuronal, skeletal muscle and definitive endoderm differentiation. Immediately after suramin treatment, a decreased mesendoderm differentiation was found. Brachyury, FGF10, Wnt8 and Wnt3a transcript levels were significantly down-regulated, followed by a decrease in mesoderm- and cardiac progenitor-specific markers BMP2, GATA4/5, Wnt11, Isl1, Nkx2.5 and Tbx5 immediately after removal of the substance. With continued differentiation, a significant up-regulation of Brachyury, FGF10 and GATA5 transcript levels was observed, whereas Nkx2.5, Isl1, Tbx5, BMP2 and Wnt11 levels were normalized to control levels. At advanced differentiation stages, sinus node-specific HCN4, Tbx2 and Tbx3 transcript levels were significantly up-regulated. Immunofluorescence and patch-clamp analysis confirmed the increased number of sinus node-like cells, and electrophysiological analysis revealed a lower number of atrial- and ventricular-like cardiomyocytes following suramin treatment. CONCLUSION: We conclude that the interference of suramin with the cardiac differentiation process modified mesoderm- and cardiac-specific gene expression resulting in enhanced formation of sinus node-like cells. PMID- 19775768 TI - Inhibition of Salmonella Enteritidis by cerein 8A, EDTA and sodium lactate. AB - The ability of the bacteriocin cerein 8A to inhibit Salmonella Enteritidis in combination with EDTA and sodium lactate was investigated. Salmonella Enteritidis was incubated with combinations of cerein 8A (3200AU/mL) and EDTA (20, 50, 100 mmol/L) or sodium lactate (200 mmol/L). All treatments caused a significant reduction in the OD(600) values of Salmonella Enteritidis cultures. The addition of cerein 8A plus EDTA resulted in higher inhibition in comparison with the bacteriocin alone; the greater the concentration of EDTA, the greater the inhibitory effect. The combination of cerein 8A plus 100 mmol/L EDTA results in a more efficient treatment to reduce the number of viable cells of Salmonella Enteritidis. The combination of cerein 8A plus sodium lactate also showed significant inhibition of the indicator organism. Transmission electron microscopy showed damaged cell walls and loss of protoplasmic material in treated cells. The cells of Salmonella Enteritidis treated with cerein 8A plus EDTA appeared more injured. The bacteriocin cerein 8A may be useful to inhibit Gram negative bacteria, with enhanced effect in combination with chelating agents. Control of Salmonella Enteritidis, a Gram-negative bacterium constantly linked to food outbreaks, addresses an important aspect of food safety. PMID- 19775769 TI - Study on the antibiotic activity of microcapsule curcumin against foodborne pathogens. AB - Curcumin as an edible natural pigment has several biological activities but its use as a food colorant and preservative is restricted due to low stability and insolubility in water. Stabilizing it with microencapsulation to obtain microcapsule curcumin can improve its stability and solubility. The microcapsule curcumin was studied for their antibacterial and antifungal activities against some foodborne pathogens and spoilage microbe such as Escherichia coli, Yersinia enterocolitica, Staphylococcus aureus, Bacillus subtilis, Bacillus cereus, Aspergillus niger, Penicllium notatum, and Saccharomyces cerevisiae. It exhibited broad spectrum inhibitory effect against all organisms by Oxford cup methods, and its minimum inhibitory concentrations (MIC) were determined by agar dilution method and ranged from 15.7 to 250 microg/mL. For the selected microorganisms, its antibacterial activity was more pronounced against Gram-positive bacteria than Gram-negative bacteria. Furthermore, its antifungal activity is much better than antibacterial activity. Microcapsule curcumin remains in antibacterial and antifungal activities after microencapsulation, which can be potential colorant and preservative in food industry. PMID- 19775770 TI - HCV genotype 3: an independent predictor of fibrosis progression in chronic hepatitis C. PMID- 19775772 TI - Difference in lifetime medical expenditures between male smokers and non-smokers. AB - OBJECTIVES: It is controversial whether smokers have higher lifetime medical expenditures than non-smokers, because smokers have high annual medical expenditures but comparatively short lives. We examined differences in lifetime medical expenditures between them. METHODS: We constructed life tables for male smokers and non-smokers from 40 years of age. We calculated average annual medical expenditures of them categorized by survivors and deceased, which were used to examine differences in lifetime medical expenditures between them and perform sensitivity analyses. RESULTS: Smokers had a higher mortality rate, shorter life expectancy, and generally higher annual medical expenditures than non-smokers. We also observed tendencies for smokers to have higher inpatient expenditures, but non-smokers to have higher outpatient expenditures. Although non-smokers had lower long-term cumulative medical expenditures between 64 and 81 years of age, their lifetime medical expenditures were higher by a minimal amount. Sensitivity analyses did not change this result. CONCLUSIONS: Smoking may not cause increases in lifetime medical expenditures because smokers had lower lifetime medical expenditures than non-smokers. However, it was clear that smokers, especially survivors, often had higher annual medical expenditures than non-smokers. The importance of tobacco control is still relevant. PMID- 19775771 TI - A review of quality of life instruments used in liver transplantation. AB - With improvements in patient and graft survival after liver transplantation, recipient quality of life (QOL) has become an important focus of patient care and clinical outcomes research. To provide a better understanding of the instruments used to assess QOL in the adult liver transplant population, we conducted a systematic review of the MEDLINE database and Cochrane library. Our review identified 128 relevant articles utilizing more than 50 different QOL instruments. Generic health status instruments are the most commonly used, and among them the Medical Outcomes Study Short Form-36 (SF-36), the Hospital Anxiety and Depression Scale (HADS), and the Beck Depression Inventory (BDI) are the most prevalent. Few studies (16%) included targeted, disease-specific instruments. The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Quality of Life questionnaire, the Liver Disease Quality of Life questionnaire, and the Chronic Liver Disease questionnaire are the most frequently employed targeted instruments; however, these instruments have been designed to assess QOL in patients with chronic liver disease rather than patients after liver transplantation. The present review focuses on the psychometric properties of the existing QOL instruments and discusses their individual strengths and limitations in evaluating liver transplantation recipients. The lack of a gold-standard QOL instrument for liver transplant recipients is an impediment to cross-study comparisons. We conclude that the development of a QOL instrument specifically for liver transplant recipients will improve QOL assessment in this population leading to a more nuanced understanding of the factors that influence transplant recipients' well-being. PMID- 19775773 TI - Noroviruses in healthcare settings: a challenging problem. AB - Current knowledge about noroviruses in relation to healthcare-associated infections (HCAIs) merely scratches the surface. Most data come from outbreak based studies, which represent only a small piece of the puzzle. Nevertheless, the data available show that the clinical impact of noroviruses is particularly severe in outbreaks in healthcare settings, and that it may be increasing. Coupled with the projected increases of the population aged >65 years, especially those needing healthcare, it is timely to consider noroviruses in discussions around HCAIs. In particular, broadening the scope from a field mostly discussing bacteriological problems and a more holistic approach to dealing with HCAIs may be needed to avoid introducing new risks when trying to deal with the antimicrobial resistance problem. PMID- 19775774 TI - Compliance with hand hygiene on surgical, medical, and neurologic intensive care units: direct observation versus calculated disinfectant usage. AB - BACKGROUND: Hand hygiene (HH) is considered the single most effective measure to prevent and control health care-associated infections (HAIs). Although there have been several reports on compliance rates (CRs) to HH recommendations, data for intensive care units (ICUs) in general and for shift- and indication-specific opportunities in particular are scarce. METHODS: The aim of this study was to collect data on ICU-, shift-, and indication-specific opportunities, activities and CRs at a surgical ICU (SICU), a medical ICU (MICU), and a neurologic ICU (NICU) at the University Hospital Aachen based on direct observation (DO) and calculated disinfectant usage (DU). RESULTS: Opportunities for HH recorded over a 24-hour period were significantly higher for the SICU (188 per patient day [PD]) and MICU (163 per PD) than for the NICU (124 per PD). Directly observed CRs were 39% (73/188) in the SICU, 72% (117/163) in the MICU, and 73% (90/124) in the NICU. However, CRs calculated as a measure of DU were considerably lower: 16% (29/188) in the SICU, 21% (34/163) in the MICU, and 25% (31/124) in the NICU. Notably, CRs calculated from DO were lowest before aseptic tasks and before patient contact. CONCLUSIONS: To the best of our knowledge, this study provides the first data picturing a complete day, including shift- and indication-specific analyses, and comparing directly observed CRs with those calculated based on DU, the latter of which revealed a 2.75-fold difference. Worrisomely, CRs were very low, especially concerning indications of greatest impact in preventing HAIs, such as before aseptic task. Thus, the gathering of additional data on CRs and the reasons for noncompliance is warranted. PMID- 19775775 TI - Expression of the HFE allelic variant H63D in SH-SY5Y cells affects tau phosphorylation at serine residues. AB - A number of genetic association studies have appeared that address HFE gene variants in neurodegenerative disorders. However, the cellular impact of HFE in the nervous system has received little attention. To begin to address the role of the HFE allelic variants on cellular events associated with neurodegeneration, we examined the hypothesis that HFE polymorphisms are associated with alterations in tau phosphorylation in a human neuroblastoma cell line (SH-SY5Y). The results show that in a cell culture model, the H63D allele is associated with increased tau phosphorylation. The mechanisms responsible for these changes appear related to increased glycogen synthase kinase (GSK)-3beta activity. GSK-3beta activity is up-regulated in the cells expressing H63D HFE and can be modified by the addition of iron or treatment with an iron chelator in SH-SY5Y cells expressing wild-type HFE. Oxidative stress, also associated with elevated cellular iron, is associated with increased tau phosphorylation at the same sites as seen in H63D cells and treatment with Trolox, an anti-oxidant, lowered tau phosphorylation. These results suggest H63D HFE increases tau phosphorylation via GSK-3beta activity and iron-mediated oxidative stress. PMID- 19775777 TI - [Coffee and cardiovascular diseases]. PMID- 19775778 TI - [Utility of an immunochromatographic test for Chagas disease screening in primary healthcare]. AB - INTRODUCTION: Chagas disease is a common condition among Latin American immigrants living in Spain. MATERIAL AND METHODS: An immunochromatographic test was used for Chagas disease screening in 148 patients from Latin America and the results were compared with those of 2 ELISA techniques. RESULTS: The test had a sensitivity of 92.5%, a specificity of 96.8%, and a coefficient of agreement with the 2 ELISA techniques of 0.9. CONCLUSIONS: The specificity of the test assayed suffices for Chagas disease screening, but the sensitivity needs to be improved before it can be used for this purpose. PMID- 19775779 TI - [Psoas and paravesical abscess formation due to Achromobacter xylosoxidans: a case report]. PMID- 19775780 TI - Activity and molecular modeling of a new small molecule active against NNRTI resistant HIV-1 mutants. AB - In this preliminary study we report the antiviral screening of triazolo[4,5 g]quinoline derivatives (compounds 1-6). 4,9-Dihydrotriazolo[4,5-g]quinoline-1 oxide (1) stood out as a new, small molecule endowed with a selective, promising activity in cell-based assays against HIV-1wt and clinically relevant NNRTI resistant mutants. In order to identify the molecular target, compound 1 was assayed in enzyme assay against the HIV-1wt RT. The molecular modeling strategy adopted yielded a rationale, in terms of molecular interactions and free energy of binding, for the possible reasons of the activity of this compound against NNRTI-resistant HIV-1 mutants with the RT isoforms K103N and Y181C. PMID- 19775781 TI - A qualitative study of the Australian midwives' approaches to Listeria education as a food-related risk during pregnancy. AB - OBJECTIVE: to explore midwives' perceptions of food-related risks and their approaches to Listeria education during pregnancy. DESIGN: an exploratory design within a qualitative framework. SETTING: one private and two public hospitals in New South Wales, Australia. PARTICIPANTS: 10 midwives providing antenatal care in the selected hospitals. FINDINGS: midwives had a range of approaches, from active to passive, to Listeria education. The main education provided was focused only on some of the high Listeria-risk foods with little education on safe food handling practices. Midwives' perception of food-related risks was a function of their limited scientific knowledge and their reliance on their experiential knowledge and their common sense. System constraints such as temporal pressure, limited availability of educational materials and low adherence to Listeria recommendations within the health system were also identified to influence midwives' practice. KEY CONCLUSIONS: professional practice guidelines regarding food safety and Listeria education are needed, together with relevant professional training and review of hospital practices in relation to this important health issue. PMID- 19775782 TI - A diet and physical activity intervention for preventing weight retention among Taiwanese childbearing women: a randomised controlled trial. AB - OBJECTIVE: to examine the effect of individual counselling on diet and physical activity from pregnancy to six months post partum, or from birth to six months post partum, on weight retention among Taiwanese women. DESIGN: a randomised controlled trial assigned participants to two experimental groups [from pregnancy to six months post partum (EP) and from birth to six months post partum (EPP)] and one comparison group. SETTING: a 3900-bed medical centre in northern Taiwan with around 3000 births annually. PARTICIPANTS: a sample of 189 women who had regular check-ups during pregnancy and gave birth at the medical centre. INTERVENTIONS: the comparison group received the routine outpatient department obstetric educational programme. The EP group attended regularly scheduled clinic visits with individualised dietary and physical activity education plans from 16 gestational weeks to six months post partum, and received on brochure. The EPP group received the same educational intervention as the EP group from 24-48 hours after birth to six months post partum. MEASUREMENTS: body weight, body mass index, health-promoting behaviour and psycho-social variables (self-efficacy, body image, depression and social support). FINDINGS: average gestational weight gain was 14.02, 15.27 and 16.22 kg in the three EP, EPP and comparison groups respectively, and average weight retention at six months post partum was 2.34, 4.06 and 5.08 kg in the three groups, respectively. KEY CONCLUSIONS: a diet and physical activity intervention from pregnancy is effective for reducing post pregnancy weight retention. IMPLICATIONS FOR PRACTICE: the findings of the present study should be taken into consideration when incorporating significant others and weight-loss maintenance strategies with interventions for a healthier family lifestyle. PMID- 19775783 TI - Kurdish pregnant women's feelings: a qualitative study. AB - OBJECTIVE: to gain a deeper understanding of how Kurdish pregnant women feel about their pregnancy. DESIGN: a qualitative study analysed by a grounded theory approach. SETTING: the study was conducted among women in the third trimester of their pregnancy in either their homes or the health-care centres in Sanandaj in the western part of Iran. PARTICIPANTS: 22 pregnant women were recruited and interviewed. FINDINGS: during pregnancy, women experienced a variety of feelings: 'satisfied and happy', 'unpleasant' and 'ambivalent'. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: it is important for midwives to ask pregnant women about their feelings concerning their current pregnancy, childbirth and future motherhood. If they express negative or ambivalent feelings, these should be discussed in greater detail and their causes identified. Special consideration should be given to primiparous women and multiparous women with negative experiences of previous pregnancies. PMID- 19775784 TI - Menarche among Brazilian women: memories of experiences. AB - OBJECTIVE: to present women's experiences of menarche and related memories. DESIGN: qualitative study using focus groups for data collection. SETTING: the city of Campinas, Sao Paulo state, Brazil. PARTICIPANTS: 64 women aged 21-51 years, experiencing menstrual periods, with former or current sexual activity and no perceived infertility. METHODS: eight focus groups were carried out using a semi-structured guideline. Discussions were recorded with participants' consent, and transcribed and revised. Thematic content analysis was carried out using gender relations as the theoretical framework. FINDINGS: menarche was experienced as a passage from childhood to womanhood, associated with belonging to a new group and acquiring a new status in the family. The experiences of menarche were not always welcomed or expected, but were recalled as associated with body changes and awareness of sexual issues. The mother's behaviour and attitudes towards menarche were clearly seen as generators of strong and everlasting impressions, either in a positive or negative way. Memories related to the experience of menarche extended through their life, interfering with their relation with their own body, including their reproductive health. KEY CONCLUSIONS: the way in which menarche is experienced may exert an impact on women's reproductive health, sexuality and lifestyle behaviours. IMPLICATIONS FOR PRACTICE: the acknowledgement of menarche experiences can be useful to guide health-care providers towards more effective education of girls on sexual and reproductive health issues and better attention to women's needs. PMID- 19775776 TI - Alzheimer's disease as homeostatic responses to age-related myelin breakdown. AB - The amyloid hypothesis (AH) of Alzheimer's disease (AD) posits that the fundamental cause of AD is the accumulation of the peptide amyloid beta (Abeta) in the brain. This hypothesis has been supported by observations that genetic defects in amyloid precursor protein (APP) and presenilin increase Abeta production and cause familial AD (FAD). The AH is widely accepted but does not account for important phenomena including recent failures of clinical trials to impact dementia in humans even after successfully reducing Abeta deposits. Herein, the AH is viewed from the broader overarching perspective of the myelin model of the human brain that focuses on functioning brain circuits and encompasses white matter and myelin in addition to neurons and synapses. The model proposes that the recently evolved and extensive myelination of the human brain underlies both our unique abilities and susceptibility to highly prevalent age-related neuropsychiatric disorders such as late onset AD (LOAD). It regards oligodendrocytes and the myelin they produce as being both critical for circuit function and uniquely vulnerable to damage. This perspective reframes key observations such as axonal transport disruptions, formation of axonal swellings/sphenoids and neuritic plaques, and proteinaceous deposits such as Abeta and tau as by-products of homeostatic myelin repair processes. It delineates empirically testable mechanisms of action for genes underlying FAD and LOAD and provides "upstream" treatment targets. Such interventions could potentially treat multiple degenerative brain disorders by mitigating the effects of aging and associated changes in iron, cholesterol, and free radicals on oligodendrocytes and their myelin. PMID- 19775785 TI - 'Shedding light' on the challenges faced by Palestinian maternal health-care providers. AB - OBJECTIVE: to explore the challenges and barriers faced by Palestinian maternal health-care providers (HCPs) to the provision of quality maternal health-care services through a case study of a Palestinian public referral hospital in the Occupied Palestinian Territory. DESIGN AND METHOD: descriptive qualitative study. The data are from a broader study, conducted in 2005 at the same hospital as part of a baseline assessment of maternal health services. PARTICIPANTS: 31 maternal HCPs; nine midwives and 14 nurses and eight doctors. FINDINGS: the quality of care provided for women and infants at this Palestinian public hospital is substandard. The maternal HCPs work within a difficult and resource-constrained environment. ISSUES INCLUDE: high workload, poor compensation, humiliation in the workplace, suboptimal supervision and the absence of professional support and guidance. Midwives are perceived to be at the bottom of the health professional hierarchy. CONCLUSIONS: there is a need for managers and policy makers to enable maternal HCPs to provide better quality care for women and infants during childbirth, through facilitating the roles of midwives and nurses and creating a more positive and resourceful environment. IMPLICATIONS FOR PRACTICE: Palestinian midwives need to increase their knowledge and use evidence-based practices during childbirth. They need to unite and create their own circle of professional support in the form of a Palestinian midwifery professional body. PMID- 19775786 TI - Prophylactic therapy in haemophilia. AB - Clinical experience since decades and numerous retro- and, recently, also prospective studies clearly demonstrate that prophylactic treatment, albeit much more expensive, is superior to on-demand treatment regardless if outcome focus on number of joint- or life-threatening bleeds or arthropathy, evaluated by X-ray or MRI, or quality of life measured by general or hemophilia specific instruments. Optimal prophylactic treatment should be started early (primary prophylaxis) but various opinions exist on the dose and dose interval, depending on the objective of treatment in the individual patient which in turn is usually dependent on the resources in the health care system. Secondary prophylaxis, started later in childhood or in adults is beneficial but less cost-effective. This review covers proof of concept of primary prophylaxis in children and secondary prophylaxis in adults, comparisons between prophylaxis and on demand treatment as well as outcome measurers, health economics and future trends of prophylactic treatment of hemophilia. PMID- 19775787 TI - Impact of climate fluctuations on deposition of DDT and hexachlorocyclohexane in mountain glaciers: evidence from ice core records. AB - How do climate fluctuations affect DDT and hexachlorocyclohexane (HCH) distribution in the global scale? In this study, the interactions between climate variations and depositions of DDT and HCH in ice cores from Mt. Everest (the Tibetan Plateau), Mt. Muztagata (the eastern Pamirs) and the Rocky Mountains were investigated. All data regarding DDT/HCH deposition were obtained from the published results. Concentrations of DDT and HCH in an ice core from Mt. Everest were associated with the El Nino-Southern Oscillation. Concentrations of DDT in an ice core from Mt. Muztagata were significantly correlated with the Siberia High pattern. Concentrations of HCH in an ice core from Snow Dome of the Rocky Mountains responded to the North Atlantic Oscillation. These associations suggested that there are some linkages between climate variations and the global distribution of persistent organic pollutants. PMID- 19775788 TI - Bioavailability of residual polycyclic aromatic hydrocarbons following enhanced natural attenuation of creosote-contaminated soil. AB - The impact of residual PAHs (2250 +/- 71 microg total PAHs g(-1)) following enhanced natural attenuation (ENA) of creosote-contaminated soil (7767 +/- 1286 microg total PAHs g(-1)) was assessed using a variety of ecological assays. Microtox results for aqueous soil extracts indicated that there was no significant difference in EC(50) values for uncontaminated, pre- and post remediated soil. However, in studies conducted with Eisenia fetida, PAH bioaccumulation was reduced by up to 6.5-fold as a result of ENA. Similarly, Beta vulgaris L. biomass yields were increased 2.1-fold following ENA of creosote contaminated soil. While earthworm and plant assays indicated that PAH bioavailability was reduced following ENA, the residual PAH fraction still exerted toxicological impacts on both receptors. Results from this study highlight that residual PAHs following ENA (presumably non-bioavailable to bioremediation) may still be bioavailable to important receptor organisms such as earthworms and plants. PMID- 19775789 TI - Trends in vehicular emissions in China's mega cities from 1995 to 2005. AB - Multiyear inventories of vehicular emissions in Beijing, Shanghai and Guangzhou from 1995 through 2005 have been developed in this paper to study the vehicle emissions trends in China's mega cities during the past decade. The results show that the vehicular emissions of CO, HC, NO(x) and PM(10) have begun to slow their growth rates and perhaps even to decline in recent years due to the implementation of measures to control vehicular emissions in these cities. However, vehicular CO(2) emissions have substantially increased and still continue to grow due to little fuel economy improvement. Passenger cars and large vehicles (including heavy duty trucks and buses) are the major sources of vehicular CO(2) and CO emissions while large vehicles were responsible for nearly 70% and 80% of the vehicular NO(x) and PM(10) emissions in these mega cities. Motorcycles are also important contributors to vehicular emissions in Guangzhou and Shanghai. PMID- 19775790 TI - Temporal variations of concentrations of currently used pesticides in the atmosphere of Strasbourg, France. AB - Atmospheric samples have been collected in Strasbourg between April 18 and May 29, 2007 and were analyzed for 71 current-use pesticides, of which 38 were detected. Average concentrations ranged from 0.09 ng m(-3) for Fenarimol to 110.42 ng m(-3) for Dimethachlor, which was slightly higher than the concentrations reported from other, comparable agricultural regions. Significant temporal variations were observed for 30 pesticides, and for most of them it could be shown that these were linked to time, temperature or atmospheric pressure. In several cases this helped to identify pesticide application just before or at the beginning of the sampling period, or ongoing treatment. Humidity, in contrast to previous reports, could not be linked to these variations. For the other 8 pesticides, only very little temporal variations were observed. Generally, these concentrations were low (less than 1 ng m(-3)), and it was assumed that they are not in use in Alsace at present. PMID- 19775791 TI - Factors influencing concentrations of dissolved gaseous mercury (DGM) and total mercury (TM) in an artificial reservoir. AB - The effects of various factors including turbidity, pH, DOC, temperature, and solar radiation on the concentrations of total mercury (TM) and dissolved gaseous mercury (DGM) were investigated in an artificial reservoir in Korea. Episodic total mercury accumulation events occurred during the rainy season as turbidity increased, indicating that the TM concentration was not controlled by direct atmospheric deposition. The DGM concentration in surface water ranged from 3.6 to 160 pg/L, having a maximum in summer and minimum in winter. While in most previous studies DGM was controlled primarily by a photo-reduction process, DGM concentrations tracked the amount of solar radiation only in winter when the water temperature was fairly low in this study. During the other seasons microbial transformation seemed to play an important role in reducing Hg(II) to Hg(0). DGM increased as dissolved organic carbon (DOC) concentration increased (p value < 0.01) while it increased with a decrease of pH (p-value < 0.01). PMID- 19775792 TI - Psychological treatment of panic disorder with or without agoraphobia: a meta analysis. AB - Although the efficacy of psychological treatment for panic disorder (PD) with or without agoraphobia has been the subject of a great deal of research, the specific contribution of techniques such as exposure, cognitive therapy, relaxation training and breathing retraining has not yet been clearly established. This paper presents a meta-analysis applying random- and mixed effects models to a total of 65 comparisons between a treated and a control group, obtained from 42 studies published between 1980 and 2006. The results showed that, after controlling for the methodological quality of the studies and the type of control group, the combination of exposure, relaxation training, and breathing retraining gives the most consistent evidence for treating PD. Other factors that improve the effectiveness of treatments are the inclusion of homework during the intervention and a follow-up program after it has finished. Furthermore, the treatment is more effective when the patients have no comorbid disorders and the shorter the time they have been suffering from the illness. Publication bias and several methodological factors were discarded as a threat against the validity of our results. Finally the implications of the results for clinical practice and for future research are discussed. PMID- 19775793 TI - Policy-related determinants of child nutritional status in China: the effect of only-child status and access to healthcare. AB - This paper examines the determinants of child nutritional status in China, focusing specifically on those determinants related to health system reform and only-child status. Data are drawn from four waves of the China Health and Nutrition Survey (1991-2000). The empirical relationship between nutritional status, on the one hand, and income, access to quality healthcare and being an only-child, on the other hand, is investigated using ordinary least squares (OLS), random effects (RE), fixed effects (FE) and instrumental variables (IV) models. In the preferred model - a fixed effects model where income is instrumented - we find that being an only-child increases height-for-age z-scores by 0.12 of a standard deviation. By contrast, measures of access to quality healthcare are not found to be significantly associated with improved nutritional status. PMID- 19775794 TI - Dynamics of adolescent friendship networks and smoking behavior: social network analyses in six European countries. AB - The co-evolution of adolescents' friendship networks and their smoking behavior is examined in a large sample across six European countries. Selection and influence processes are disentangled using new methods of social network analysis that enable alternative selection mechanisms to be controlled for. The sample consisted of 7704 adolescents participating in the control group of the ESFA (European Smoking prevention Framework Approach) study. The design was longitudinal with four observations. The main measurements were friendship ties, adolescents smoking behavior, parental smoking behavior, and sibling smoking behavior. Results indicated that in each country adolescents preferred selecting friends based on similar smoking behavior. Support for the influence of friends was found in only two countries. A similarity in smoking behavior between friends was explained more strongly by smoking-based selection processes than by the influence of friends in each of the six countries. Prevention programs need to address aspects that drive peer selection, and reinforce non-smoking attitudes in adolescents. PMID- 19775795 TI - Gray matter density negatively correlates with duration of heroin use in young lifetime heroin-dependent individuals. AB - Numerous studies have documented cognitive impairments and hypoactivity in the prefrontal and anterior cingulate cortices in drug users. However, the relationships between opiate dependence and brain structure changes in heroin users are largely unknown. In the present study, we measured the density of gray matter (DGM) with voxel-based morphometry in 30 lifetime heroin-dependent individuals who had abstained from drug use for 5 months, and 34 healthy participants. The DGM of the prefrontal, temporal and cingulate cortices significantly decreased in heroin addicts relative to the healthy group. Critically, partial correlation analysis, which controlled for age, education and gender factors as well as nicotine use and heroin abstinence duration, showed that the duration of heroin use negatively correlated with the DGM in heroin dependent individuals. These results provide compelling evidence for structural abnormality in heroin-dependent individuals and further suggest that duration of heroin use is a critical factor leading to brain damage. PMID- 19775796 TI - The frequency of self-reported allergic diseases in patients with crimean-congo haemorrhagic fever. AB - BACKGROUND: Crimean-Congo haemorrhagic fever (CCHF) is an acute, tick-borne viral disease. In temperate areas, CCHF cases occur between spring and early autumn when tick activity is high. This period is also the pollen season during which symptoms of allergic diseases are exacerbated. Viruses induce inflammatory and antiviral responses by binding to specific receptors on the surface of airway epithelial cells, resulting in activation of innate immune responses; release of mediators such as cytokines and chemokines; and recruitment of neutrophils and mononuclear cells to the area. AIM: We aimed to evaluate the frequency of self reported allergic diseases and the effect on CCHF severity. METHOD: Between June and August 2008, a questionnaire was applied to 114 CCHF (+) patients and 122 healthy control subjects, 16 to 88 years old who attended the Infectious Diseases clinic and were hospitalised with CCHF suspected, by face to face interview including history of allergic rhinitis (AR), asthma symptoms and nonspecific bronchial reactivity, doctor diagnosed AR and/or asthma, and familial allergic diseases history. RESULTS: According to PCR and/or enzyme-linked immunoassay (ELISA) results, 51.7% of patients (n=114) had CCHF. There was no significant relation between CCHF and history of AR, asthma symptoms and nonspecific bronchial reactivity, doctor diagnosed AR and/or asthma, and familial allergic diseases history. The severity of CCHF has not affected these parameters (p>.05). Of patients with positive CCHF test, 2.6% (n=3) and 3.5% (n=4) had doctor diagnosed AR and asthma, respectively. CONCLUSION: Self-reported allergic diseases and CCHF are not related with each other. PMID- 19775797 TI - Work up of patients with history of beta-lactam hypersensitivity. AB - INTRODUCTION: Beta-lactam antibiotics are the most frequent cause of antibiotic hypersensitivity reactions. The study of all cases of suspected beta-lactam hypersensitivity is highly important, to avoid the use of less efficient or more expensive alternatives, for fear of a reaction. MATERIALS AND METHODS: Sixty seven consecutive patients with suspected beta-lactam hypersensitivity reactions were studied. Skin prick tests (SPT), intradermal tests (IDT) and specific IgE determination were performed. In non-immediate reactions, epicutaneous testing was also done. If all were negative, a drug challenge was performed. RESULTS: Sixty-seven patients (54 female symbol), with a mean age + or - SD of 36.6 + or 19.3 years (4-78 years) were studied. The self-reported antibiotics were amoxicillin and amoxicillin/clavulanic acid in 30 (45%), penicillin in 24 (36%), cephalosporins in 11 (16%) and flucloxacillin in 2 (3%). SPT and IDT were positive in 6 patients (9%) and specific IgE in 11 (16%). Only one patient had both positive specific IgE and skin tests. Of the remaining 51 cases, 33 underwent a drug challenge with the culprit antibiotic, with a positive reaction in 2 (6%). In all positive cases and when a drug challenge with the suspected antibiotic was not indicated, a challenge with an alternative drug was done, all with negative results. CONCLUSIONS: Of the 67 studied cases with history of beta lactam hypersensitivity reactions, 18 (27%) were confirmed after testing. A combination of skin testing, specific IgE determination and drug challenge is necessary since none has sufficient sensitivity to be used alone. PMID- 19775798 TI - Why can patients with baker's asthma tolerate wheat flour ingestion? Is wheat pollen allergy relevant? AB - Diagnosis in patients sensitised to multiple pollens is difficult due to the relationship between pollen and food allergens. Misdiagnosis is often a cause for unsuccessful specific immunotherapy. Wheat is a potent allergen source and is one of the causes of baker's asthma, food and pollen allergy. Recently, we have performed a study on pollen sensitisation in our area, where cereal crops are very important. The clinical data from 19718 patients reviewed showed that grass pollen was the main source of clinical symptoms (6369 patients, 32.30% of asthmatics). However, wheat and cereal crop pollen showed very low prevalence. On the other hand, patients with wheat flour allergy after ingestion and/or with baker's asthma were not sensitised to wheat pollen, despite it containing some common allergens. In the same way, all our asthmatic bakers (135 patients) tolerated the ingestion of bread. Here we try to explain the reason for these surprising observations. PMID- 19775799 TI - Medical audit on children with asthma in an Emergency Department. AB - OBJECTIVE: To carry out a medical audit or evaluation and improvement procedure on the management of children with asthmatic crises in our Emergency Department (ED). MATERIAL AND METHODS: We carried out a retrospective audit between January and March 2007, analysing the medical records of a random sample of 50 patients aged 2-14 years consulting our ED for asthmatic crises. Following the international guides, we first selected 17 explicit indicators divided into four domains: "evaluation", "examination", "diagnostic resources", and "treatment and conditions at discharge". RESULTS: Indicators' compliance proved unequal; it was scarce for cause of asthma crisis (32%); degree of severity (18%); and supportive treatment (24%). Auscultation was registered in 100%, but respiratory frequency only in 49%, and peak flow in 0%. A total of 78% of the patients were treated in the ED, in all cases with beta-mimetic agents, and with systemic corticosteroids in 12%. The result of treatment was registered in only 69% of cases. The medical documentation of resident doctors was not signed by the staff. CONCLUSIONS: We identified the following weak points: failure to determine the degree of severity; lack of specification of the details of the crisis (prior duration, treatment at home, supportive treatment); scant asthma background history; and deficient recording of respiratory frequency and peak flow. We propose improving the anamnesis, recording respiratory frequency, with the introduction of tools to measure peak flow, specification of treatment response, and the development of a simpler and more practical protocol, with the performance of a re-audit. PMID- 19775800 TI - Concordance between the Piko - 1 portable device and pneumotachography in measuring PEF and FEV(1) in asthmatic children. AB - OBJECTIVE: To assess concordance in the measurement of peak expiratory flow (PEF) and forced expiratory volume ino ne second (FEV(1)) between the portable device Piko-1 (Ferraris) and a pneumotachograph. PATIENTS AND METHODS: Forced spirometry (Master Screen Jaeger) was performed according to ATS/ERS norms, selecting the best value of three curves, and three measurements with the Piko-1 were recorded the recommendations of the manufacturer. RESULTS: Eighty patients between 5-18 years of age were studied. Based on the Bland-Altman method, the mean differences obtained were 9.82 (95%Cl: 2.43-17.21) for PEF and 0.17 (95%CL: 0.12-0.21 for FEV(1). The intraclass correlation coefficient was 0.96 (p <0,001; 95%Cl: 0.93 0.97) for PEV(1) and 0.93 (p<0,0001; 95%Cl: 0.89-0.95) for PEF. CONCLUSIONS: Piko 1 offers FEV(1) measurements close to those obtained with forced spirometry, thus allowing more exact patient assessment in home-based follow-up emergency services, or hospital wards. PMID- 19775801 TI - A retrospective study of allergic diseases in children with food hypersensitivity. PMID- 19775802 TI - Response to medical or surgical therapy in chronic rhinosinusitis: A one year prospective analysis. AB - INTRODUCTION: Chronic rhinosinusitis (CRS) is treated with both surgical and medication options. However, long term data on patient outcomes is rare. In a real world clinical environment, our objective was to identify CRS patients, gather patient characteristics, and follow symptoms over one year. PATIENTS AND METHODS: This observational study enrolled patients with CRS, primary clinical makers included atopy testing, serum lgE, and complete blood counts. A sinus computerized tomography (CT) scan was performed serially. Patients were enrolled into medical treatment Arm A and into surgical treatment Arm B. Symptom scores were calculated using the chronic sinusitis survey (CSS). RESULTS: Atopy testing was positive in 67%. lgE levels or atopy did not correlate with CSS scores A 23% decrease in total CSS scores was noted in Arm A at one year (p =.01). Arm B demonstrated a 38% reduction in total CSS scores at 3 months (p =.02) only. CT evidence of CRS was found in 74% of patients. However, CT scores did not change significantly over 12 months. CONCLUSIONS: No correlation was found between serum lgE levels or atopy versus CSS scores. CT scan scores did not change significantly over 12 months in either treatment group. A reduction of CSS scores was seen in both treatment groups: however a rebound effect was suggest in the surgical arm. Our study demonstrates the disconnection common clinical setting. It exemplifies the need for controlled studies with years of chronic rhinosinusitis outcome analysis. PMID- 19775803 TI - Relationship between the characteristics of hospitalised acute asthma patients and the severity of their asthma. A case-control study. AB - BACKGROUND: The EAGLE project database was analysed to assess the characteristics of patients with severe (SA) who required hospitalisation as a result of an acute episode during the period 1994-2004, and the relationship with asthma severity. METHODS: A total od 2593 clinical records corresponding to an equal number of patients hospitalised for acute asthma (15-69 years), with sufficient information to characterize their asthma severity in agreement with GNA criteria were identified (727 patients with SA compared with 1866 patients with non-severe asthma). RESULTS: Patients with SA were older, displayed a greater predominance of female asthmatics, lower antecedents of atopy, and a higher frequency of previous hospitalisations compared with non-severe asthmatics (86.1% vs. 50.5%, p< or = 0.01). Additionally, SA patients showed more severe exacerbations characterized by acidosis, significant spirometric deterioration, greater length of hospital stay (9.4 days vs. 7.0 days), as well as a higher frequency of intubation (16.8% vs. 2.1%), intensive care unit admission (11.3% vs.4.9%), cardiopulmonary arrest (5.5% vs. 1.3%), and asthma deaths (2.1% vs. 0.4%) (all < or = 0.01) compared wit non-severe patients. CONCLUSIONS: This study suggests that SA patients have greater morbidity and a disproportionate need for health care as a result of more severe exacerbations. However, non-severe asthmatics can also still present acute severe episodes (although with a lower frequency) with risk of life. PMID- 19775804 TI - Review of fluoride removal from drinking water. AB - Fluoride in drinking water has a profound effect on teeth and bones. Up to a small level (1-1.5mg/L) this strengthens the enamel. Concentrations in the range of 1.5-4 mg/L result in dental fluorosis whereas with prolonged exposure at still higher fluoride concentrations (4-10mg/L) dental fluorosis progresses to skeletal fluorosis. High fluoride concentrations in groundwater, up to more than 30 mg/L, occur widely, in many parts of the world. This review article is aimed at providing precise information on efforts made by various researchers in the field of fluoride removal for drinking water. The fluoride removal has been broadly divided in two sections dealing with membrane and adsorption techniques. Under the membrane techniques reverse osmosis, nanofiltration, dialysis and electro dialysis have been discussed. Adsorption, which is a conventional technique, deals with adsorbents such as: alumina/aluminium based materials, clays and soils, calcium based minerals, synthetic compounds and carbon based materials. Studies on fluoride removal from aqueous solutions using various reversed zeolites, modified zeolites and ion exchange resins based on cross-linked polystyrene are reviewed. During the last few years, layered double oxides have been of interest as adsorbents for fluoride removal. Such recent developments have been briefly discussed. PMID- 19775805 TI - Evidence-based medicine: the supporting pillar of trial registration. PMID- 19775806 TI - Feasibility of transvaginal NOTES-assisted laparoscopic nephrectomy. AB - BACKGROUND: Recently, the feasibility of a transvaginal hybrid natural orifice transluminal endoscopic surgery (NOTES) nephrectomy was demonstrated in a 23-yr old woman with a nonfunctional atrophic kidney. OBJECTIVE: To evaluate the feasibility and reproducibility of transvaginal NOTES-assisted laparoscopic nephrectomy in female patients with and without renal cancer. DESIGN, SETTING, AND PARTICIPANTS: Between March 2008 and June 2009, 14 female patients were submitted to transvaginal NOTES-assisted laparoscopic nephrectomy for T1-T3a N0M0 renal cancer (n=10), lithiasis (n=2), or renal atrophy (n=2) at the Hospital Clinic of Barcelona, Spain. SURGICAL PROCEDURE: Under general anaesthesia, female patients underwent laparoscopic nephrectomy by transvaginal NOTES using a deflectable camera by vaginal access and two additional 5- and 10-mm trocars in the abdomen. The renal artery and vein were dissected and taken separately between clips. The dissected kidney was removed via the vagina after enlarging the vaginal trocar incision. MEASUREMENTS: All data referring to patient demographics, surgery, pathology, and perioperative outcomes were recorded. RESULTS AND LIMITATIONS: The procedure was completed in all patients. The mean age of the women was 59.1 yr. The mean operative time was 132.9 min and the mean estimated blood loss was 111.2 ml. None of the patients required a blood transfusion and the use of analgesics was low. The mean hospital stay was 4 d. In one case, a major complication (a colon injury) occurred. The patient underwent surgery and a temporary colostomy was performed. The patient has already undergone reconstruction. CONCLUSIONS: Transvaginal NOTES-assisted laparoscopic nephrectomy is feasible and reproducible and may be an alternative technique for treatment of women with renal cancer. Proper selection of patients is warranted for success of this new approach. However, longer follow-up in an increasing number of patients is needed to establish its role in the treatment of renal cancer. PMID- 19775807 TI - Oncologic outcome after extraperitoneal laparoscopic radical prostatectomy: midterm follow-up of 1115 procedures. AB - BACKGROUND: Although the first laparoscopic radical prostatectomy was performed in 1997, few midterm oncologic data have been published for the extraperitoneal procedure. OBJECTIVE: To determine the oncologic outcome of extraperitoneal laparoscopic radical prostatectomy (ELRP). DESIGN, SETTING, AND PARTICIPANTS: From 2000 to 2007, 1115 consecutive patients underwent ELRP for a localized prostate cancer at our department. Follow-up was scheduled and standardized for all patients and recorded into a prospective database. Median postoperative follow-up was 35.6 mo. INTERVENTION: All ELRP were performed by three surgeons at the Department of Urology, Hospital Henri Mondor, Creteil, France. MEASUREMENTS: Biochemical recurrence was defined by prostate-specific antigen level > or =0.2 ng/ml. RESULTS AND LIMITATIONS: In pN0/pNx cancers, postoperative stage was pT2 in 664 patients (59.5%), pT3 in 350 patients (31.4%), and pT4 in 77 patients (6.9%). Positive lymph nodes were reported in 24 patients (2.2%). Margins were positive in 16.1% and 34.6% of pT2 and pT3 cancers, respectively. Final Gleason score was <7 in 288 men (25.8%), =7 in 701 men (62.9%), and >7 in 126 men (11.3%). Overall prostate-specific antigen (PSA) recurrence-free survival was 83% at 5 yr. The 5-yr progression-free survival rates were 93.4% for pT2, 74.5% for pT3a, and 55.0% for pT3b tumors, respectively. Multivariate Cox model showed that PSA, Gleason score, pT category, nodal status, and surgical margins were significant independent predictors of biochemical recurrence-free survival. CONCLUSIONS: This assessment of oncologic results demonstrates that ELRP is a safe and effective procedure. On the basis of midterm follow-up data, the prognostic factors of PSA after ELRP failure are the same as those described previously in transperitoneal or open retropubic approaches. The oncologic results of ELRP also are in line with those reported with the use of the retropubic or the transperitoneal laparoscopic approaches. PMID- 19775808 TI - Editorial comment on: oncologic outcome after extraperitoneal laparoscopic radical prostatectomy: midterm follow-up of 1115 procedures. PMID- 19775809 TI - Isolated trochlear palsy due to midbrain stroke. AB - Trochlear palsy from intra-axial lesions usually accompanies other neurological deficits, and isolated trochlear palsy due to midbrain stroke is extremely rare. We report two patients with isolated trochlear nerve palsy due to circumscribed dorsal midbrain strokes, one from infarction and the other from hemorrhage, which are located in the region of the trochlear nucleus or adjacent fascicle. Focal brain stem stroke should be considered as a rare cause of trochlear palsy even though there are no associated neurological deficits. PMID- 19775810 TI - Phytotoxicity of biosolids and screening of selected plant species with potential for mercury phytoextraction. AB - Mercury contaminated stockpiles of biosolids (3.5-8.4 mg kg(-1) Hg) from Melbourne Water's Western Treatment Plant (MW-WTP) were investigated to evaluate the possibility for their phytoremediation. Nine plant species (Atriplex codonocarpa, Atriplex semibaccata, Austrodanthonia caespitosa, Brassica juncea, Brassica napus, Gypsophila paniculata, Sorghum bicolor, Themeda triandra and Trifolium subterraneum) were screened for phytoextraction potential in Hg contaminated biosolids from MW-WTP. In addition, the same plant species were germinated and grown in two other substrates (i.e. potting mix and potting mix spiked with mercury(II)). Growth measurements and the mercury uptake for all three substrates were compared. Some plant species grown in potting mix spiked with mercury(II) grew more vigorously than in the other two substrates and showed higher levels of sulphur in their tissues. These results suggested that the mercury stress activated defence mechanisms and it was hypothesised that this was the likely reason for the enhanced production of sulphur compounds in the plant species studied which stimulated their growth. Some species did not grow in biosolids because of the combined effect of high mercury toxicity and high salt content. Atriplex conodocarpa and Australodanthonia caespitose proved to be the most suitable candidates for mercury phytoextraction because of their ability to translocate mercury from roots to the above-ground tissues. PMID- 19775811 TI - Variations in cadmium accumulation among Chinese cabbage cultivars and screening for Cd-safe cultivars. AB - Variations in cadmium accumulation and translocation among 40 Chinese cabbage cultivars were studied to identify and screen out Cd-safe cultivars (CSCs), i.e. cultivars with low enough accumulation of Cd in their edible parts even when grown in contaminated soils. It was observed in the pot-culture experiment that there was a significant difference (p<0.05) in shoot Cd concentrations under three Cd treatments (1.0, 2.5 and 5.0mg/kg), with corresponding average values 0.88, 4.45 and 7.76 mg/kg, respectively. Shoot Cd concentrations in 16 cabbage cultivars were lower than 0.50mg/kg. The translocation factors (TFs) and the extraction factors (EFs) in five cabbage cultivars were lower than 1.0 in the pot culture experiment. The field-culture experiment further validated that New Beijing 3 and Fengyuanxin 3 could be considered as CSCs. In particular, the two cultivars can be cultivated in low to moderate Cd-contaminated soils (Cd concentration <1.25mg/kg) to minimize the Cd accumulation in the food. PMID- 19775812 TI - Preparation of sintered foam materials by alkali-activated coal fly ash. AB - Coal fly ash from coal fired power stations is a potential raw material for the production of ceramic tiles, bricks and blocks. Previous works have demonstrated that coal fly ash consists mainly of glassy spheres that are relatively resistant to reaction. An objective of this research was to investigate the effect of alkali on the preparation process of the foam material. Moreover, the influence of foam dosage on the water absorption, apparent density and compressive strength was evaluated. The experimental results showed that homogenous microstructures of interconnected pores could be obtained by adding 13 wt.% foaming agent at 1050 degrees C, leading to foams presenting water absorption, apparent density and compressive strength values of about 126.5%, 0.414 g/cm(3), 6.76 MPa, respectively. PMID- 19775813 TI - Improvement in soil and sorghum health following the application of polyacrylate polymers to a Cd-contaminated soil. AB - Contamination of soils with cadmium (Cd) is a serious global issue due to its high mobility and toxicity. We investigated the application of insoluble polyacrylate polymers to improve soil and plant health. Sorghum was grown in a Cd contaminated sandy soil. Polyacrylate polymers at 0.2% (w/w) were added to half of the soil. Control soil without plants was also included in the experiment. Growth of sorghum was stimulated in the polymer-amended soil. The concentration of Cd in the shoots, and the activities of catalase and ascorbate peroxidase decreased in plants from polymer-amended soil compared with unamended control. The amount of CaCl(2)-extractable Cd in the polymer-amended soil was 55% of that in the unamended soil. The Cd extracted in sorghum shoots was 0.19 mg per plant grown on soil without polymer and 0.41 mg per plant grown on polymer-amended soil. The total amount of Cd removed from each pot corresponded to 1.5 and more than 6% of soil CaCl(2)-extractable Cd in unamended and polymer-amended soil, respectively. The activities of soil acid phosphatase, beta-glucosidase, urease, protease and cellulase were greatest in polymer-amended soil with sorghum. In conclusion, the application of polyacrylate polymers to reduce the bioavailable Cd pool seems a promising method to enhance productivity and health of plants grown on Cd-contaminated soils. PMID- 19775814 TI - The fear-avoidance model of pain: We are not there yet. Comment on Wideman et al. "A prospective sequential analysis of the fear-avoidance model of pain" [Pain, 2009] and Nicholas "First things first: reduction in catastrophizing before fear of movement" [Pain, 2009]. PMID- 19775815 TI - Dopant distributions in n-MOSFET structure observed by atom probe tomography. AB - The dopant distributions in an n-type metal-oxide-semiconductor field effect transistor (MOSFET) structure were analyzed by atom probe tomography. The dopant distributions of As, P, and B atoms in a MOSFET structure (gate, gate oxide, channel, source/drain extension, and halo) were obtained. P atoms were segregated at the interface between the poly-Si gate and the gate oxide, and on the grain boundaries of the poly-Si gate, which had an elongated grain structure along the gate height direction. The concentration of B atoms was enriched near the edge of the source/drain extension where the As atoms were implanted. PMID- 19775816 TI - Validation of the FAMACHA(c) eye colour chart using sensitivity/specificity analysis on two South African sheep farms. AB - A validation study of the FAMACHA((c)) system for clinical evaluation of anaemia due to Haemonchus contortus was conducted on two commercial sheep farms in the summer rainfall region of South Africa. In this region, the Haemonchus season lasts from October to April. On Farm 1 the system was tested over a period of five successive years in consecutive sets of young stud Merino replacement rams and ewes examined at intervals of 3-5 weeks over each Haemonchus season, under routine farming conditions. When FAMACHA((c)) scores of 3, 4, and 5 and haematocrit values of <= 22%, <= 19%, and <= 15% were separately considered to be anaemic, sensitivity on Farm 1 ranged from a maximum of 83% for a haematocrit cut off of <= 15%, to 40% for a haematocrit cut-off of <= 22%. Sensitivity increased to 93% when FAMACHA((c)) scores of 2, 3, 4, and 5 were considered anaemic at a cut-off value of <= 19%, but the positive predictive value decreased to 0.43, indicating that many non-anaemic animals would be treated. The analysis indicated a high level of classification bias on Farm 1, with the animals consistently being classified one FAMACHA((c)) category lower (i.e. less anaemic) than reality. On Farm 2 the test was conducted over two successive years in yearling rams evaluated at weekly to fortnightly intervals during each worm season. Every ram judged to be in FAMACHA((c)) category 4 or 5 was bled for haematocrit determination, and it was only dewormed with effective anthelmintics if the haematocrit was 15% or lower. When FAMACHA((c)) scores of 3, 4, and 5 and haematocrit values of <= 22% and <= 19% were separately considered to be anaemic on Farm 2, sensitivity ranged from 64% for a haematocrit cut-off of <= 22%, to 80% for a cut-off of <= 19%. For identical haematocrit cut-off values and proportions of the sampled flock considered to be diseased as for Farm 1, sensitivity was always higher for Farm 2. On the other hand, further analysis of the data indicated that the magnitude of the error on Farm 1 was very consistent on average over the entire trial period. The results of this study indicate that (i) persons introduced to the system should not only be trained, but also be evaluated for accuracy of application; (ii) the sensitivity of the FAMACHA((c)) diagnostic system should ideally be evaluated at shorter intervals to avoid production losses due to failure to detect anaemic animals which may be at risk of death; (iii) that calibration of the FAMACHA((c)) scoring is essential per individual evaluator, and (iv) that animals should be examined at weekly intervals during periods of the highest worm challenge. PMID- 19775817 TI - The periparturient relaxation of immunity in Merino ewes infected with Trichostrongylus colubriformis: parasitological and immunological responses. AB - The temporal association between the periparturient rise (PPR) in worm egg count (WEC) of grazing Merino ewes to infection with Trichostrongylus colubriformis and the underlying causal mechanisms was investigated in an experiment that incorporated two levels of pregnancy (pregnant or unmated), two levels of infection (infected with 6000 T. colubriformis L(3)/week or uninfected) and, following lambing, three levels of lactation (non-lactating/"dry", early-weaned 2 days after parturition, or suckled). The 128 ewes in the experiment were monitored for a range of parasitological and host systemic and local immune responses from days -50 to 42, relative to the midpoint of lambing (day 0). Unmated/non-lactating (dry) ewes remained largely resistant to T. colubriformis infection with WEC remaining below 200 eggs per gram (epg) throughout the experiment. For infected ewes, the PPR in WEC commenced during late pregnancy and peaked at 1552epg on day 42. There was evidence of a relaxation of immunity that preceded the rise, as demonstrated by a reduction in circulating eosinophils and plasma total antibody (Tab) and lower titres of Tab and IgG(1) in the small intestine in pregnant ewes. Circulating eosinophils and plasma Tab remained low in suckled ewes, and at the local level, lactating ewes also had lower titres of Tab, IgG(1), IgM, IgA and IgE as well as fewer mast cells (MC), globule leucocytes (GL) and goblet cells (GC) in intestinal tissue. These effects were associated with higher worm burdens. Weaning at 2 days after lambing resulted in a rapid amelioration of immunological responsiveness and a reduction in WEC, worm burden and parasite establishment rate. A rapid increase in circulating eosinophils and Tab titre followed by an improvement in components of the local immune response was also observed. Over the 6-week period following lambing, weaned ewes exhibited higher titres of Tab, IgG(1), IgM, IgA and IgE as well as higher numbers of MC, GL and GC present in the small intestinal tissue, compared to lactating ewes. The results provide a detailed characterisation of the periparturient relaxation of immunity to T. colubriformis, and highlight possible causative factors that deserve further investigation. PMID- 19775818 TI - Alterations in neonatal neurosteroids affect exploration during adolescence and prepulse inhibition in adulthood. AB - Allopregnanolone (AlloP) is a neurosteroid that plays an important role during neural development. Alterations of endogenous neonatal allopregnanolone levels alter the localisation and function of GABA neurons in the adult brain and affect behaviour in adulthood. We have carried out research into the effects of an increase (AlloP administration) or a decrease (administration of finasteride, inhibitor of the AlloP synthesis) of neonatal AlloP levels during the fifth to ninth postnatal days in male Wistar rats on the novelty exploration (Boissier test) at adolescent ages (40 and 60 days old), and on the prepulse inhibition achievement in adulthood (85 days). We also investigated the role of a GABA(A) modulator (midazolam, 1, 1.75 or 2.5mg/kg body weight) in the long-lasting behavioural changes in adulthood (85 days). Results indicate that neonatal finasteride decreases both novelty-exploration (head-dipping and locomotion) and anxiety-relevant scores (the distance travelled in and the number of entries into the central zone) at adolescent age, along with a reduction in body weight and general locomotion. Also, neonatal AlloP administration decreases prepulse inhibition in adulthood. Prepulse inhibition disruption was only partially reproduced decreasing the neonatal AlloP levels by means of finasteride administration. Although there was no interaction between neonatal neurosteroid manipulation and adult benzodiazepine treatments, the effects of midazolam were dose-dependent: the lowest dose of midazolam increased whereas the highest disrupted the expected progressive reduction of the startle response (and the consequent improvement of the PPI percentage) after the gradual increase in prepulse intensity. Reduced prepulse inhibition of startle provides evidence of deficient sensorimotor gating in several disorders, including schizophrenia. Alterations of AlloP levels during maturation could partly explain the inter individual differences shown by adult subjects in response to novelty (exploration) and in the sensorimotor gating and prepulse inhibition. Also, abrupt changes in neonatal levels of AlloP could be related to a susceptibility to neurodevelopmental disorders. PMID- 19775819 TI - The self-perceived symptom distress and health-related conditions associated with morning to evening diurnal cortisol patterns in outpatients with major depressive disorder. AB - OBJECTIVE: This study was an examination of 126 major depressive disorder (MDD) outpatients' morning to evening diurnal cortisol patterns to determine their association with family histories of mental illness, self-perceived depressive and anxiety distress, self-perceived health-related conditions, and healthy behaviors. METHODS: 126 MDD outpatients and 106 healthy subjects were recruited. Self-reports of symptom distress, health-related conditions, and healthy behaviors and objective measures of salivary cortisol upon awakening, 45min after awakening, and at 1200, 1700, and 2100h were collected at subjects' homes. The individual growth curve model was used to manage data and to analyze repeated observations of self-report data associated with diurnal cortisol patterns. RESULTS: For MDD outpatients, flatter diurnal cortisol patterns were more likely found in subjects with family histories of mental illness than in those without. Patient-reported shorter total sleep hours, more severe levels of depression and higher suffering levels were positively associated with flatter diurnal cortisol patterns. Less than 5 sleep hours was more likely associated with flatter diurnal cortisol patterns than above 7 sleep hours. Severe levels of depression were more likely related to flatter diurnal cortisol patterns than moderate and mild levels of depression. Higher anxiety levels, better sleep quality and higher levels of physical activity reported by patients were positively associated with steeper diurnal cortisol patterns. Unlike the MDD outpatients, the only trait associated with diurnal cortisol patterns in healthy subjects was total sleep hours. CONCLUSIONS: These results suggested that self-perceived good sleep quality, total hours slept of 7 or greater, and self-perceived higher levels of physical activity in the home environment could be positively related to positive stress endocrine outcomes seen as steep diurnal cortisol patterns in outpatients with major depressive disorder. PMID- 19775820 TI - Childhood trauma and health outcomes in adults with comorbid substance abuse and mental health disorders. AB - This study describes the prevalence of childhood traumatic events (CTEs) among adults with comorbid substance use disorders (SUDs) and mental health problems (MHPs) and assesses the relation between cumulative CTEs and adult health outcomes. Adults with SUDs/MHPs (N=402) were recruited from residential treatment programs and interviewed at treatment admission. Exposures to 9 types of adverse childhood experiences were summed and categorized into 6 ordinal levels of exposure. Descriptive analyses were conducted to assess the prevalence and range of exposure to CTEs in comparison with a sample from primary health care. Logistic regression analyses were conducted to examine the association between the cumulative exposure to CTEs and adverse health outcomes. Most of the sample reported exposure to CTEs, with higher exposure rates among the study sample compared with the primary health care sample. Greater exposure to CTEs significantly increased the odds of several adverse adult outcomes, including PTSD, alcohol dependence, injection drug use, tobacco use, sex work, medical problems, and poor quality of life. Study findings support the importance of early prevention and intervention and provision of trauma treatment for individuals with SUDs/MHPs. PMID- 19775821 TI - Drinking motives, drinking restraint and drinking behaviour among young adults. AB - Motives to drink alcohol are widely thought to be the proximal cognitive factors involved in the decision to consume alcohol beverages. However it has also been argued that the ability to restrain drinking may be a more proximal predictor of drinking behaviour. The current study aimed to examine the relationships between drinking motives, drinking restraint and both alcohol consumption and alcohol related problems in a sample of young adults. A sample of 221 young adults (aged 17-34 years) completed self-report measures assessing drinking behaviour, motives for drinking and drinking restraint. Multiple regression analyses revealed that coping, enhancement and social motives were related to alcohol consumption and alcohol-related problems, while Cognitive and Emotional Preoccupation with drinking was related to all criterion variables. Further, the relationship between coping motives and drinking behaviour was mediated by preoccupation with drinking. The results are discussed in light of the roles of drinking motives and drinking restraint in risky drinking among young people, and implications for prevention and early intervention are presented. PMID- 19775822 TI - Non-invasive brain stimulation for the management of arterial hypertension. AB - The neural control of the cardiovascular system is a complex process that involves many structures at different levels of nervous system. Several cortical areas are involved in the control of systemic blood pressure, such as the sensorimotor cortex, the medial prefrontal cortex and the insular cortex. Non invasive brain stimulation techniques - repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) - induce sustained and prolonged functional changes of the human cerebral cortex. rTMS and tDCS has led to positive results in the treatment of some neurological and psychiatric disorders. Because experiments in animals show that cortical modulation can be an effective method to regulate the cardiovascular system, non invasive brain stimulation might be a novel tool in the therapeutics of human arterial hypertension. We here review the experimental evidence that non-invasive brain stimulation can influence the autonomic nervous system and discuss the hypothesis that focal modulation of cortical excitability by rTMS or tDCS can influence sympathetic outflow and, eventually, blood pressure, thus providing a novel therapeutic tool for human arterial hypertension. PMID- 19775823 TI - Inexpensive health care reform: the mathematics of medicine. AB - There is data to support the hypothesis that US healthcare reform will require systemic changes in their delivery system rather than a segment-by-segment approach to improving individual components such as administrative or pharmaceutical costs or illness-by-illness programs such as comparative effectiveness or disease management. Mathematically, personnel costs provide the largest potential for savings. These costs are reflected in utilization rates. However, when governments or insurers try to control utilization, shortages or dissatisfaction ensue. Therefore, reform should be structured to encourage individually initiated reductions in utilization. This can be facilitated by changing from employer-paid comprehensive group policies of variable coverage to a three-part, standardized, individually purchased, group policy with a targeted deductible and co-pays that provide disincentives to over-utilization and incentives (refunds on unused contributions) to reduce utilization. There will be a public health policy (maternal, infant, and immunizations) that will be very inexpensive and not subject to any disincentives, a catastrophic policy with a deductible and enhanced but diminishing co-pays, and a Health Savings Account that pre-positions funds to cover the deductible and co-pays. These changes will lead to a reduction in administrative costs. The excess capacity created will provide care for the currently uninsured. Savings will be refunded to individuals thereby generating taxes that can pay for needed subsidies. Reform can be inexpensive if it puts the mathematics before the politics. PMID- 19775824 TI - Longitudinal changes in tumor perfusion pattern during the radiation therapy course and its clinical impact in cervical cancer. AB - PURPOSE: To study the temporal changes of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) perfusion patterns during the radiation therapy (RT) course and their influence on local control and survival in cervical cancer. METHODS AND MATERIALS: DCE-MRI was performed in 98 patients with Stage IB(2)-IVA cervical cancer before RT (pre-RT) and during early RT (20-25 Gy) and mid-RT (45 50 Gy). Signal intensity (SI) from the DCE-MRI time-SI curve was derived for each tumor voxel. The poorly perfused low-DCE tumor subregions were quantified as lower 10th percentiles of SI (SI10). Local control, disease-specific survival, and overall survival were correlated with DCE parameters at pre-RT, early RT, and mid-RT. Median follow-up was 4.9 (range, 0.2-9.0) years. RESULTS: Patients (16/98) with initial pre-RT high DCE (SI10 >or=2.1) had 100% 5-year local control, 81% disease-specific survival, and 81% overall survival, compared with only 79%, 61%, and 55%, respectively, in patients with pre-RT low DCE. Conversion from pre-RT low DCE to high DCE in early RT (28/82 patients) was associated with higher local control, disease-specific survival, and overall survival (93%, 74%, and 67%, respectively). In comparison with all other groups, outcome was worst in patients with persistently low DCE from pre-RT throughout the mid-RT phase (66%, 44%, and 43%; p = 0.003, 0.003, and 0.020; respectively). CONCLUSION: Longitudinal tumor perfusion changes during RT correlate with treatment outcome. Persistently low perfusion in pre-RT, early RT, and mid-RT indicates a high risk of treatment failure, whereas outcome is favorable in patients with initially high perfusion or subsequent improvements of initially low perfusion. These findings likely reflect reoxygenation and may have potential for noninvasive monitoring of intra-treatment radio-responsiveness and for guiding adaptive therapy. PMID- 19775825 TI - Outcome with neck dissection after chemoradiation for N3 head-and-neck squamous cell carcinoma. AB - PURPOSE: To evaluate the role of neck dissection (ND) after chemoradiation therapy (CRT) for head and neck squamous cell carcinoma (HNSCC) with N3 disease. METHODS AND MATERIALS: From March 1998 to September 2006, 70 patients with HNSCC and N3 neck disease were treated with concomitant CRT as primary therapy. Response to treatment was assessed using clinical examination and computed tomography 6 to 8 weeks posttreatment. Neck dissection was not routinely performed and considered for those with less than complete response. Of the patients, 26 (37.1%) achieved clinical complete response (cCR) after CRT. A total of 31 (44.3%) underwent ND after partial response (cPR-ND). Thirteen patients (29.5%) did not achieve cCR and did not undergo ND for the following reasons: incomplete response/progression at primary site, refusal/contraindication to surgery, metastatic progression, or death. These patients were excluded from the analysis. Outcomes were computed using Kaplan-Meier curves and were compared with log rank tests. RESULTS: Comparing the cCR and cPR-ND groups at 2 years, the disease-free survival was respectively 62.7% and 84.9% (p = 0.048); overall survival was 63.0% and 79.4% (p = 0.26), regional relapse-free survival was 87.8% and 96.0% (p = 0.21); and distant disease-free survival was 67.1% and 92.6% (p = 0.059). In the cPR-ND group, 71.0% had no pathologic evidence of disease (PPV of 29.0%). CONCLUSIONS: Patients with N3 disease achieving regional cPR and primary cCR who underwent ND seemed to have better outcomes than patients achieving global cCR without ND. Clinical assessment with computed tomography is not adequate for evaluating response to treatment. Because of the inherent limitations of our study, further confirmatory studies are warranted. PMID- 19775826 TI - Electromagnetic tracking of intrafraction prostate displacement in patients externally immobilized in the prone position. AB - PURPOSE: To evaluate intrafraction prostate displacement among patients immobilized in the prone position using real-time monitoring of implanted radiofrequency transponders. METHODS AND MATERIALS: The Calypso localization system was used to track prostate motion in patients receiving external beam radiation therapy (XRT) for prostate cancer. All patients were treated in the prone position and immobilized with a thermoplastic immobilization device. Real time measurement of prostate displacement was recorded for each treatment fraction. These measurements were used to determine the duration and magnitude of displacement along the three directional axes. RESULTS: The calculated centroid of the implanted transponders was offset from the treatment isocenter by >or=2 mm, >or=3 mm, and >or=4 mm for 38.0%, 13.9%, and 4.5% of the time. In the lateral dimension, the centroid was offset from the treatment isocenter by >or=2 mm, >or=3 mm, and >or=4 mm for 2.7%, 0.4%, and 0.06% of the time. In the superior inferior dimension, the centroid was offset from the treatment isocenter by >or=2 mm, >or=3 mm, and >or=4 mm for 16.1%, 4.7%, and 1.5% of the time, respectively. In the anterior-posterior dimension, the centroid was offset from the treatment isocenter by >or=2 mm, >or=3 mm, and >or=4 mm for 13.4%, 3.0%, and 0.5% of the time. CONCLUSIONS: Intrafraction prostate displacement in the prone position is comparable to that in the supine position. For patients with large girth, in whom the supine position may preclude accurate detection of implanted radiofrequency transponders, treatment in the prone position is a suitable alternative. PMID- 19775827 TI - Impact of incidental irradiation on clinically uninvolved nodal regions in patients with advanced non-small-cell lung cancer treated with involved-field radiation therapy: does incidental irradiation contribute to the low incidence of elective nodal failure? AB - PURPOSE: To evaluate the incidental irradiation dose to elective nodal regions in the treatment of advanced non-small-cell lung cancer with involved-field radiation therapy (IF-RT) and the pattern of elective nodal failure (ENF). METHODS AND MATERIALS: Fifty patients with advanced non-small-cell lung cancer, who received IF-RT at Kagawa University were enrolled. To evaluate the dose of incidental irradiation, we delineated nodal regions with a Japanese map and the American Thoracic Society map (levels 1-11) in each patient retrospectively and calculated the dose parameters such as mean dose, D95, and V95 (40 Gy as the prescribed dose of elective nodal irradiation). RESULTS: Using the Japanese map, the median mean dose was more than 40 Gy in most of the nodal regions, except at levels 1, 3, and 7. In particular, each dosimetric parameter of level 1 was significantly lower than those at other levels, and each dosimetric parameter of levels 10 to 11 ipsilateral (11I) was significantly higher than those in other nodal regions. Using the American Thoracic Society map, basically, the results were similar to those of the Japanese map. ENF was observed in 4 patients (8%), five nodal regions, and no mean dose to the nodal region exceeded 40 Gy. On the Japanese map, each parameter of these five nodal region was significantly lower than those of the other nodal regions. CONCLUSIONS: These results show that a high dose of incidental irradiation may contribute to the low incidence of ENF in patients who have received IF-RT. PMID- 19775828 TI - Cone beam computed tomography-derived adaptive radiotherapy for radical treatment of esophageal cancer. AB - PURPOSE: To investigate the potential for reduction in normal tissue irradiation by creating a patient specific planning target volume (PTV) using cone beam computed tomography (CBCT) imaging acquired in the first week of radiotherapy for patients receiving radical radiotherapy. METHODS AND MATERIALS: Patients receiving radical RT for carcinoma of the esophagus were investigated. The PTV is defined as CTV(tumor, nodes) plus esophagus outlined 3 to 5 cm cranio-caudally and a 1.5-cm circumferential margin is added (clinical plan). Prefraction CBCT are acquired on Days 1 to 4, then weekly. No correction for setup error made. The images are imported into the planning system. The tumor and esophagus for the length of the PTV are contoured on each CBCT and 5 mm margin is added. A composite volume (PTV1) is created using Week 1 composite CBCT volumes. The same process is repeated using CBCT Week 2 to 6 (PTV2). A new plan is created using PTV1 (adaptive plan). The coverage of the 95% isodose of PTV1 is evaluated on PTV2. Dose-volume histograms (DVH) for lungs, heart, and cord for two plans are compared. RESULTS: A total of 139 CBCT for 14 cases were analyzed. For the adaptive plan the coverage of the 95% prescription isodose for PTV1 = 95.6% +/- 4% and the PTV2 = 96.8% +/- 4.1% (t test, 0.19). Lungs V20 (15.6 Gy vs. 10.2 Gy) and heart mean dose (26.9 Gy vs. 20.7 Gy) were significantly smaller for the adaptive plan. CONCLUSIONS: A reduced planning volume can be constructed within the first week of treatment using CBCT. A single plan modification can be performed within the second week of treatment with considerable reduction in organ at risk dose. PMID- 19775829 TI - A multicenter retrospective analysis of survival outcome following postoperative chemoradiotherapy in non-small-cell lung cancer patients with N2 nodal disease. AB - PURPOSE: To retrospectively evaluate the role of postoperative chemoradiotherapy (POCRT) in patients with completely resected non-small-cell lung cancer (NSCLC) with N2 lymph node involvement. METHODS AND MATERIALS: This study included 183 patients from four centers in southwest China who underwent radical section of Stage III-N2 NSCLC without any preoperative therapy. One hundred and four were treated with POCRT and 79 with postoperative chemotherapy (POCT) alone. The median radiation dose to clinical target volume (CTV) was 50 Gy (varying between 48 and 54 Gy), whereas the cycles of platinum-based chemotherapy ranged from two to six with a median of four. RESULTS: The median duration of follow-up was 72 months. The 5-year overall survival rate (OS) was 30.5% in the POCRT group, and 14.4% in the POCT group (p = 0.007). The 5-year disease-free survival rate (DFS) was 22.2% in POCRT group and 9.3% in POCT group (p = 0.003). In a multivariate analysis, N1 nodal involvement (N1+/N2+) was associated with significantly worse OS (HR = 1.454, 95% CI, 1.012-2.087, p = 0.043) and DFS (HR = 1.685, 95% CI, 1.196-2.372, p = 0.003). Absence of radiotherapy and treatment with fewer than three cycles of chemotherapy both were poor prognostic factors for both OS and DFS. CONCLUSIONS: As compared with chemotherapy alone, adjuvant treatment with both radiotherapy and chemotherapy improves survival in patients with completely resected Stage III-N2 nodal disease in NSCLC. Future study of treatment modality with radiotherapy and chemotherapy is warranted, especially focusing on both N1 and N2 nodal status. PMID- 19775830 TI - Phase I/II study evaluating early tolerance in breast cancer patients undergoing accelerated partial breast irradiation treated with the mammosite balloon breast brachytherapy catheter using a 2-day dose schedule. AB - PURPOSE: Initial Phase I/II results using balloon brachytherapy to deliver accelerated partial breast irradiation (APBI) in 2 days in patients with early stage breast cancer are presented. MATERIALS AND METHODS: Between March 2004 and August 2007, 45 patients received adjuvant radiation therapy after lumpectomy with balloon brachytherapy in a Phase I/II trial delivering 2800 cGy in four fractions of 700 cGy. Toxicities were evaluated using the National Cancer Institute Common Toxicity Criteria for Adverse Events v3.0 scale and cosmesis was documented at >or=6 months. RESULTS: The median age was 66 years (range, 48-83) and median skin spacing was 12 mm (range, 8-24). The median follow-up was 11.4 months (5.4-48 months) with 21 patients (47%) followed >or=1 year, 11 (24%) >or=2 years, and 7 (16%) >or=3 years. At <6 months (n = 45), Grade II toxicity rates were 9% radiation dermatitis, 13% breast pain, 2% edema, and 2% hyperpigmentation. Grade III breast pain was reported in 13% (n = 6). At >or=6 months (n = 43), Grade II toxicity rates were: 2% radiation dermatitis, 2% induration, and 2% hypopigmentation. Grade III breast pain was reported in 2%. Infection was 13% (n = 6) at <6 months and 5% (n = 2) at >or=6 months. Persistent seroma >or=6 months was 30% (n = 13). Fat necrosis developed in 4 cases (2 symptomatic). Rib fractures were seen in 4% (n = 2). Cosmesis was good/excellent in 96% of cases. CONCLUSIONS: Treatment with balloon brachytherapy using a 2-day dose schedule resulted acceptable rates of Grade II/III chronic toxicity rates and similar cosmetic results observed with a standard 5-day accelerated partial breast irradiation schedule. PMID- 19775832 TI - Volumetric modulated arc therapy improves dosimetry and reduces treatment time compared to conventional intensity-modulated radiotherapy for locoregional radiotherapy of left-sided breast cancer and internal mammary nodes. AB - PURPOSE: Volumetric modulated arc therapy (VMAT) is a novel extension of conventional intensity-modulated radiotherapy (cIMRT), in which an optimized three-dimensional dose distribution may be delivered in a single gantry rotation. VMAT is the predecessor to RapidArc (Varian Medical System). This study compared VMAT with cIMRT and with conventional modified wide-tangent (MWT) techniques for locoregional radiotherapy for left-sided breast cancer, including internal mammary nodes. METHODS AND MATERIALS: Therapy for 5 patients previously treated with 50 Gy/25 fractions using nine-field cIMRT was replanned with VMAT and MWT. Comparative endpoints were planning target volume (PTV) dose homogeneity, doses to surrounding structures, number of monitor units, and treatment delivery time. RESULTS: For VMAT, two 190 degrees arcs with 2-cm overlapping jaws were required to optimize over the large treatment volumes. Treatment plans generated using VMAT optimization resulted in PTV homogeneity similar to that of cIMRT and MWT. The average heart volumes receiving >30 Gy for VMAT, cIMRT, and MWT were 2.6% +/- 0.7%, 3.5% +/- 0.8%, and 16.4% +/- 4.3%, respectively, and the average ipsilateral lung volumes receiving >20 Gy were 16.9% +/- 1.1%, 17.3% +/- 0.9%, and 37.3% +/- 7.2%, respectively. The average mean dose to the contralateral medial breast was 3.2 +/- 0.6 Gy for VMAT, 4.3 +/- 0.4 Gy for cIMRT, and 4.4 +/- 4.7 Gy for MWT. The healthy tissue volume percentages receiving 5 Gy were significantly larger with VMAT (33.1% +/- 2.1%) and IMRT (45.3% +/- 3.1%) than with MWT (19.4% +/- 3.7%). VMAT reduced the number of monitor units by 30% and the treatment time by 55% compared with cIMRT. CONCLUSIONS: VMAT achieved similar PTV coverage and sparing of organs at risk, with fewer monitor units and shorter delivery time than cIMRT. PMID- 19775831 TI - A retrospective, multicenter study of the tolerance of induction chemotherapy with docetaxel, Cisplatin, and 5-Fluorouracil followed by radiotherapy with concomitant cetuximab in 46 cases of squamous cell carcinoma of the head and neck. AB - PURPOSE: To investigate, in a multicenter study, the tolerance of induction chemotherapy (ICT) and external radiotherapy (ERT) with concomitant cetuximab in the treatment of patients with squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: Clinical data from 46 patients with Stage III or IV nonmetastatic SCCHN who received docetaxel, cisplatin, and 5-fluorouracil as ICT, followed by ERT with concomitant cetuximab, were retrospectively analyzed. Clinical safety (weight, allergy, mucositis, and dermatitis) and paraclinical safety (levels of hemoglobin, polynuclear neutrophils, and creatinine clearance) were studied. The primary objective was the proportion of patients who completed the protocol. RESULTS: The percentage of patients completing ICT was 73.9%, ERT 93.5%, and cetuximab 69.6%. Induction chemotherapy was better tolerated than that previously reported. The rates of temporary suspensions of radiation (39.1%, mean duration of 13 days) and hospitalization (26.1%) during ERT with concomitant cetuximab were high. Weight loss during treatment (21.4% of patients lost >10% of their body weight), radiodermatitis, and radiomucositis were the main causes of temporary suspension of treatment, although Grade 4 dermatitis was not experienced. There were no allergic reactions to cetuximab. CONCLUSION: The completed protocol rate for SCCHN patients receiving ICT and ERT with concomitant cetuximab is high and the toxicity acceptable. Future improvements to protocol will be possible through early action and systematic implementation of nutritional support coupled with antibiotic treatment upon the first signs of radiodermatitis. These data could be useful for prospective studies on the safety and efficacy of this protocol. PMID- 19775833 TI - Dosimetric comparison of high-dose-rate brachytherapy and intensity-modulated radiation therapy as a boost to the prostate. AB - PURPOSE: We compared the dose conformity of two radiation modalities: high-dose rate brachytherapy (HDR BT) and intensity-modulated radiation therapy (IMRT) to deliver a boost to the prostate after external beam radiotherapy (EBRT). METHODS AND MATERIALS: Ten successive patients with prostate adenocarcinoma treated with a single 10-Gy HDR BT boost after EBRT were investigated. Four theoretical IMRT plans were computed: (a) 32.85 Gy IMRT and (b) 26 Gy IMRT with CTV-PTV expansions, doses corresponding to the equivalent dose in 2-Gy fractions (EQD2) of one 10-Gy fraction calculated with a prostate alpha/beta ratio of respectively 1.5 and 3 Gy; and (c) 32.85 Gy IMRT and (d) 26 Gy IMRT without CTV-PTV expansions. The dose-volume histogram values converted in EQD2 with an alpha/beta ratio of 3 Gy for the organs at risk were compared. RESULTS: The HDR BT plan delivered higher mean doses to the PTV compared with IMRT plans. In all, 33% of the rectal volume received a mean dose of 5.32 +/- 0.65 Gy and 20% of bladder volume received 4.61 +/- 1.24 Gy with HDR BT. In comparison, doses delivered with IMRT were respectively 13.4 +/- 1.49 Gy and 10.81 +/- 4 Gy, even if only 26 Gy was prescribed to the PTV with no CTV-PTV expansion (p < 0.0001). The hot spots inside the urethra were greater with HDR BT but acceptable. CONCLUSIONS: Use of HDR BT produced a more conformal plan for the boost to the prostate than IMRT even without CTV-PTV expansions. PMID- 19775834 TI - Three-year outcomes of breast intensity-modulated radiation therapy with simultaneous integrated boost. AB - PURPOSE: To report our clinical experience using breast intensity-modulated radiation therapy with simultaneous integrated boost (SIB-IMRT). METHODS AND MATERIALS: Retrospective review identified 354 Stage 0 to III breast cancer patients treated with SIB-IMRT after conservative surgery between 2003 and 2006. The most common fractionation (89%) simultaneously delivered 1.8 Gy to the ipsilateral breast tissue and 2.14 Gy to the resection cavity, yielding a breast dose of 45 Gy (25 fractions) and cavity dose 59.92 Gy (28 fractions), biologically equivalent for tumor control to 45 Gy to the breast with sequential 16-Gy boost (33 fractions). RESULTS: A total of 356 breasts in 354 patients were treated: 282 with invasive breast cancer, and 74 with ductal carcinoma in situ (DCIS). For left breast radiation, median cardiac V(15) was 2.9% and left ventricular V(15) 1.7%. Median follow-up was 33 months (range, 4-73 months). Acute toxicity was Grade 1 in 57% of cases, Grade 2 in 43%, and Grade 3 in <1%. For invasive breast cancer, the 3-year overall survival was 97.6% and risk of any locoregional recurrence was 2.8%. For ductal carcinoma in situ, 3-year overall survival was 98% and risk of locoregional recurrence 1.4%. In 142 cases at a minimum of 3 years follow-up, global breast cosmesis was judged by physicians as good or excellent in 96.5% and fair in 3.5%. CONCLUSIONS: Breast SIB-IMRT reduced treatment duration by five fractions with a favorable acute toxicity profile and low cardiac dose for left breast treatment. At 3 years, locoregional control was excellent, and initial assessment suggested good or excellent cosmesis in a high percentage of evaluable patients. PMID- 19775835 TI - Effects of sleep deprivation on sleep homeostasis and restoration during methadone-maintenance: a [31]P MRS brain imaging study. AB - Insomnia afflicts many individuals, but particularly those in chronic methadone treatment. Studies examining sleep deprivation (SD) have begun to identify sleep restoration processes involving brain bioenergetics. The technique ([31])P magnetic resonance spectroscopy (MRS) can measure brain changes in the high energy phosphates: alpha-, beta-, and gamma-nucleoside triphosphate (NTP). In the present study, 21 methadone-maintained (MM) and 16 control participants underwent baseline (BL), SD (40 wakeful hours), recovery1 (RE1), and recovery2 (RE2) study nights. Polysomnographic sleep was recorded each night and ([31])P MRS brain scanning conducted each morning using a 4T MR scanner (dual-tuned proton/phosphorus head-coil). Interestingly, increases in total sleep time (TST) and sleep efficiency index (SEI) commonly associated with RE sleep were not apparent in MM participants. Analysis of methadone treatment duration revealed that the lack of RE sleep increases in TST and SEI was primarily exhibited by short-term MM participants (methadone <12 months), while RE sleep in long-term MM (methadone >12 months) participants was more comparable to control participants. Slow wave sleep increased during RE1, but there was no difference between MM and control participants. Spectral power analysis revealed that compared to control participants; MM participants had greater delta, theta, and alpha spectral power during BL and RE sleep. ([31])P MRS revealed that elevations in brain beta-NTP (a direct measure of ATP) following RE sleep were greater in MM compared to control participants. Results suggest that differences in sleep and brain chemistry during RE in MM participants may be reflective of a disruption in homeostatic sleep function. PMID- 19775837 TI - Neurophysiological evaluation in children with Friedreich's ataxia. AB - INTRODUCTION: In children with Friedreich's ataxia (FRDA children), clinical ataxia outcomes are hardly substantiated by underlying neurophysiological parameters. In young FRDA children, some reports (based upon International Cooperative Ataxia Rating Scale scores (ICARS)) mention transient neurological improvement upon idebenone treatment. However, these outcomes are obtained with adult instead of pediatric reference values. It is unknown whether age-related neurophysiological parameters can really substantiate neurologic improvement. AIM: In young FRDA children, we aimed to determine longitudinal neurophysiological parameters during idebenone treatment. METHODS: During a two year study period, 6 genetically proven FRDA children with cardiomyopathy (6 18years) were longitudinally assessed for neurophysiological parameters [sensory evoked potentials (SEPs), F response, peripheral nerve conduction and dynamometry] in association with age-matched ICARS-scores. RESULTS: In all FRDA children, SEPs remained absent during the two-year study period. Peroneal nerve conduction velocity declined (from -1SD to -2SD; p<.05), whereas F responses remained essentially unaltered. Total muscle force and leg muscle force decreased (from -2 to -3SD and -2.5 to -3.5SD; both p<.05) and age-related ICARS-scores deteriorated (median increase +41%; p<.05). CONCLUSION: In FRDA children, age related neurophysiological and ataxia parameters deteriorate during idebenone treatment. Although we cannot exclude some (subjective) disease stabilization, age-related neurophysiological parameters do not substantiate neurologic improvement. PMID- 19775836 TI - Encephalitic alphaviruses. AB - This review will cover zoonotic, encephalitic alphaviruses in the family Togaviridae. Encephalitic alphaviruses, i.e. Western- (WEEV), Eastern- (EEEV), Venezuelan equine encephalitis virus (VEEV) and, more rarely, Ross River virus, Chikungunya virus and Highlands J virus (HJV), are neuroinvasive and may cause neurological symptoms ranging from mild (e.g., febrile illness) to severe (e.g., encephalitis) in humans and equines. Among the naturally occurring alphaviruses, WEEV, EEEV and VEEV have widespread distributions in North, Central and South America. WEEV has found spanning the U.S. from the mid-West (Michigan and Illinois) to the West coast and extending to Canada with human cases reported in 21 states. EEEV is found along the Gulf (Texas to Florida) and Atlantic Coast (Georgia to New Hampshire), as well as in the mid-West (Wisconsin, Illinois and Michigan) and in Canada, with human cases reported in 19 states. In contrast, transmission of VEEV occurs predominantly in Central and South America. As with their geographical distribution, equine encephalitis viruses differ in their main mosquito vector species and their zoonotic potential. PMID- 19775838 TI - Vaccines and preterm neonates: why, when, and with what. AB - This review analyses what is known concerning the immune response of preterm (PTIs) and low birth weight infants (LBWIs) to widely used vaccines, the protection they receive from routine immunisation, and the safety and tolerability of the vaccines themselves. It shows why PTIs and LBWIs should be vaccinated using the same schedules as those usually recommended for full-term infants (FTIs), except in the case of hepatitis B vaccine, whose schedule should be repeated in infants who received the first dose during the first days of life when they weighed less than 2000 g because of their reduced immune response. Vaccines are immunogenic, safe and well tolerated in PTIs and LBWIs, in whom early active immunisation is particularly important because they are among the most vulnerable subjects for pediatric infectious diseases. It is therefore essential to make every effort to convince pediatricians and parents that compliance with these recommendations will not cause any clinical problems. PMID- 19775839 TI - Ethical and safety aspects of clinical trials in neonates. AB - Clinical trials in neonates are essential in order to provide scientific evidence in relation to the efficacy and safety of medicines. European legislation has recently been passed in order to stimulate clinical research in this area. This should hopefully result in more licensed medicines in the neonatal period. It is essential that the clinical trials are performed safely and ethically and one therefore needs to be aware of predisposing factors for drug toxicity in the neonatal period. PMID- 19775840 TI - Transorbital intracranial impalement injuries by wooden foreign bodies: clinical, radiological and forensic aspects. AB - Facial impalement injuries involve the danger of diagnostic pitfalls. Even if the penetrating object extends into the cranial cavity, the clinical symptoms and the radiological signs may be uncharacteristic. In order to illustrate the diagnostic problems, two cases of accidental impalement are reported. In both of them, a wooden foreign body penetrated via the orbita into the cranium and remained undetected at first. Imaging by CT and MRI is presented and compared with regard to the respective diagnostic validity of these methods. Due to its specific anatomic configuration, the orbita constitutes a predilective pathway for low velocity foreign bodies entering the skull. Based on the clinical data and the radiological findings, transorbital impalement wounds inflicted by wooden objects are discussed under neurosurgical and medicolegal aspects. PMID- 19775841 TI - Application of time of flight secondary ion mass spectrometry to the in situ analysis of ballpoint pen inks on paper. AB - Results presented in this paper demonstrate that time of flight secondary ion mass spectrometry (TOF-SIMS) can be used for the analysis of ballpoint pen inks producing mass spectra that were highly characteristic of the constituent dyes and inorganic substances used in their formulations. Analysis was performed directly off the substrate (typically document paper) containing the ink with no interference from the background matrix. The resultant spectra were highly characteristic of the ink formulation and could be used to confidently discriminate between different inks. No extraction or complicated sample preparation was necessary which ensures the integrity of the document under examination. This is not only important in forensic applications but also indicates the potential for the application of this technique to the analysis of inks on documents of historical or archaeological significance. TOF-SIMS was also shown to be capable of analysing ink containing a mixture of dyes, initially separated by thin-layer chromatography, directly on the chromatographic material. PMID- 19775842 TI - Fragmentary femora: evaluation of the accuracy of the direct and indirect methods in stature reconstruction. AB - Selected measurements of the femur have been used in the derivation of regression equations for stature estimation in several populations. Various studies have indicated that stature can be estimated from fragmentary bones by either the direct or the indirect method. The direct method allows for the estimation of stature directly from individual or combination of measurements of fragments of the femur. However, the indirect method consists of two steps. An initial step which involves the estimation of maximum length of the femur from measurements of its fragments is followed by stature estimation from the estimated maximum length of the femur. While Steele noted that the indirect method provides a relatively more precise estimate of stature, none of the subsequent studies on stature reconstruction has addressed the issue of accuracy of the two methods. The current study utilized 120 complete skeletons obtained from the Raymond A. Dart Collection of Human Skeletons. Total skeletal height for each of the skeletons (TSH(Fully)) was calculated using the Fully's method. Measurements of fragments of the femur acquired from the current study were substituted into each of the previously derived equations for Indigenous South Africans (ISA) and South Africans of European Descent (SAED) in order to obtain an estimate of the skeletal height (TSH(Est)). Analyses were carried out separately for each group. An assessment of the differences between the estimated skeletal height (TSH(Est)) and the obtained skeletal height using the Fully's method (TSH(Fully)) was performed using the paired t test. While no significant difference was observed between TSH(Fully) and TSH(Est) for all equations (except one) used in the direct estimation of skeletal height, a number of indirect equations significantly overestimated TSH(Fully). These observations indicate that the direct method is more accurate than the indirect method. Since it is also less complicated, it is therefore the preferred of the two methods contrary to earlier recommendation made by Steele. PMID- 19775843 TI - Splenic volume measurements on computed tomography utilizing automatically contouring software and its relationship with age, gender, and anthropometric parameters. AB - OBJECTIVE: The present research was conducted to establish the normal splenic volume in adults using a novel and fast technique. The relationship between splenic volume and age, gender, and anthropometric parameters was also examined. MATERIALS AND METHODS: The splenic volume was measured in 230 consecutive patients who underwent computed tomography (CT) scans for various indications. Patients with conditions that have known effect on the spleen size were not included in this study. A new technique using volumetric software to automatically contour the spleen in each CT slice and quickly calculate splenic volume was employed. Inter- and intra-observer variability were also examined. RESULTS: The average splenic volume of all the subjects was 127.4+/-62.9 cm(3), ranging from 22 to 417 cm(3). The splenic volume (S) correlated with age (A) (r= 0.33, p<0.0001), body weight (W) (r=0.35, p<0.0001), body mass index (r=0.24, p<0.0001) and body surface area (BSA) (r=0.31, p<0.0001). The age-adjusted splenic volume index correlated with gender (p=0.0089). The formulae S=W[6.47A( 0.31)] and S=BSA[278A(-0.36)] were derived and can be used to estimate the splenic volume. Inter- and intra-observer variability were 6.4+/-9.8% and 2.8+/ 3.5% respectively. CONCLUSION: Of the anthropometric parameters, the splenic volume was most closely linked to body weight. The automatically contouring software as well as formulae can be used to obtain the volume of the spleen in regular practice. PMID- 19775844 TI - Abdominal aspergillosis: CT findings. AB - OBJECTIVE: In order to retrospectively evaluate the CT findings of abdominal aspergillosis in immunocompromised patients. MATERIALS AND METHODS: CT scans were reviewed with regard to the sites, number, morphologic appearance, attenuation, and the contrast enhancement patterns of the lesions in six patients (5 women, 1 man; mean age, 43.4 years; range, 23-59 years) with pathologically proved abdominal aspergillosis by two gastrointestinal radiologists in consensus. Medical records were also reviewed to determine each patient's clinical status and outcome. RESULTS: All patients were immunocompromised state: 4 patients received immunosuppressive therapy for solid organ transplantation and 2 patients received chemotherapy for acute myeloid leukemia. Aspergillosis involved blood vessels (n = 3), liver (n = 2), spleen (n = 2), gastrointestinal tract (n = 2), native kidney (n = 1), transplanted kidney (n = 1), peritoneum (n = 1), and retroperitoneum (n = 1). CT demonstrated solid organ or bowel infarction or perforation secondary to vascular thrombosis or pseudoaneurysm, multiple low attenuating lesions of solid organs presenting as abscesses, concentric bowel wall thickening mimicking typhlitis, or diffuse or nodular infiltration of the peritoneum and retroperitoneum. CONCLUSION: Familiarity with findings commonly presenting as angioinvasive features or abscesses on CT, may facilitate the diagnosis of rare and fatal abdominal aspergillosis. PMID- 19775845 TI - Imipenem-resistant Pseudomonas aeruginosa gastrointestinal carriage among hospitalized patients: risk factors and resistance mechanisms. AB - Risk factors for imipenem (IMP)-resistant Pseudomonas aeruginosa (IRPA) digestive carriage were analyzed, and genetic events contributing to select resistant isolates in patients exposed to IMP were investigated. Among the 150 patients with hospital-acquired P. aeruginosa digestive carriage, 38 isolates were IRPA. DNA pulsotypes revealed 16 distinct clones. In 4 patients, a second P. aeruginosa isolate showed resistance to IMP compared with the initial susceptible isolate. By comparing the different oprD sequences between IMP-susceptible P. aeruginosa and IRPA strains, a genetic event was systematically found for each resistant isolate, leading to either the absence of OprD or a truncated porin. The multivariate analysis demonstrated that prior IMP exposure was associated with IRPA carriage. In summary, we confirmed that IMP use selects for IRPA in the gut flora. Cross-transmission, however, was frequently observed in intensive care units. Combining epidemiologic approach and molecular analysis is a powerful tool to delineate mechanisms of emerging resistance. PMID- 19775846 TI - Characterization of plasmids encoding CMY-2 AmpC beta-lactamases from Escherichia coli in Canadian intensive care units. AB - The dissemination of CMY-2 AmpC beta-lactamases among Escherichia coli in Canadian intensive care units occurs through a combination of clonal spread of virulent strains and the horizontal transfer of genetically similar IncI1, IncA/C, and IncK/B plasmids. PMID- 19775847 TI - High prevalence of tcdC deletion-carrying Clostridium difficile and lack of association with disease severity. AB - We assessed the prevalence of tcdC deletion-carrying Clostridium difficile using a stool polymerase chain reaction (PCR) assay that detects previously described 18- and 39-bp deletions (J. Clin. Microbiol. 2008;46:1996). We divided inpatients into 2 groups, those for whom the assay detected a deletion in tcdC and those for whom no deletion was detected. We compared risk factors (antibiotic use, hospitalization, nursing home stay, immunocompromise, age >65 years), complications (pseudomembranous colitis, toxic megacolon, colonic perforation, colectomy, and intensive care unit admission), duration of antibiotic treatment, and 30-day mortality between the groups. Forty-two of 141 patients had deletion positive C. difficile. Prior nursing home stay and age >65 years were significantly more common in the deletion-positive group. Other risk factors, complications, antibiotic duration, and mortality did not differ significantly. Deletion-carrying C. difficile was commonly present but not associated with more severe disease and not markedly different in terms of risk factor profile. Severity of disease was relatively low, regardless of the presence or absence of a deletion. PMID- 19775848 TI - High-dose statins prior to percutaneous coronary intervention: a paradigm shift to influence clinical outcomes in the cardiac catheterization laboratory. PMID- 19775849 TI - Disclosure of diagnosis and treatment among early stage prostate cancer survivors. AB - OBJECTIVE: Increased long-term survival rates have led to a greater focus on the health-related quality of life (HRQL) of prostate cancer survivors. This study assessed the motivations of prostate cancer survivors for disclosing their diagnosis and treatment to close others, and their perceptions of their own and others' responses to the disclosure. METHODS: Prostate cancer survivors (N=35) who were 24-36 months post-treatment for localized disease completed a semi structured telephone interview. Open-ended questions concerning disclosure of men's diagnosis and treatment and their perceptions of their own and others' reactions to the disclosure were included. RESULTS: Regarding men's motivations for disclosing their diagnosis and treatment, men reported that they were seeking social support (SS) and that others had a 'right to know.' Further, the receipt of emotional support and feeling a sense of positive emotions were common following disclosure about their diagnosis and treatment. Participants reported continuing to discuss their treatment side effects 2-3 years post-treatment. CONCLUSION: Prostate cancer survivors reported an overall positive and supportive response following the disclosure of their diagnosis and treatment. Further examination of the relationship between SS and HRQL will be necessary to identify interventions to enhance the well-being of this growing population of survivors. PRACTICE IMPLICATIONS: Providers need to be aware of the extent and long-term nature of the side effects following treatment for prostate cancer. If providers encourage men to talk about their diagnosis, treatment, and side effects, providers may better understand men's experience with the disease, and men may be more likely to accept these commonly experienced changes, as well as seek treatment for them. These efforts may result in improved quality of life for survivors of prostate cancer. PMID- 19775850 TI - Anastomotic leakage after colon cancer surgery: a predictor of significant morbidity and hospital mortality, and diminished tumour-free survival. AB - AIM: The objective of this study was to find out the effects of anastomotic leakage (AL) following resection of colon cancer upon perioperative outcome and long-term oncological result. PATIENTS AND METHODS: Using the database of a country-wide quality assurance study "Quality Assurance in Primary Colorectal Carcinoma" we analysed the data from the complete sub-population of 844 patients who had AL after resection of colon cancer. These were compared with corresponding data from 27 427 similar patients without AL. Hospital mortality, AL-associated post-operative morbidity and long-term outcome were investigated. RESULTS: Hospital mortality after AL was 18.6%, compared with 2.6% for patients without AI. AL-related secondary complications occurred in 62.7% cases, while patients without AL had a corresponding rate of 19.9%. Those with AL had a poorer long-term oncological result, with a five-year survival rate of 51.0% (p<0.001) and a five-year tumour-free survival rate of 63.0% (compare 74.6% without AL; p<0.001). CONCLUSIONS: Post-operative AL after resection of colon cancer is associated with significant morbidity and hospital mortality rates and with a greater risk of a poor oncological outcome. PMID- 19775851 TI - Preoperative staging of liver metastases from uveal melanoma by magnetic resonance imaging (MRI) and fluorodeoxyglucose-positron emission tomography (FDG PET). AB - BACKGROUND: Microscopically complete (R0) resection of metastases from uveal melanoma prolongs median overall survival compared to incomplete surgery. The aim of this study was to compare the sensitivity of dynamic-enhanced magnetic resonance imaging (MRI) with fluorodeoxyglucose-positron emission tomography (FDG PET) in the preoperative diagnosis of liver metastases from uveal melanoma. PATIENTS AND METHODS: Fifteen consecutive patients (mean age: 56 years) underwent FDG-PET and liver MRI. Extrahepatic metastatic disease was excluded by whole body computed tomography and bone scintigraphy. MRI and FDG-PET were performed with a mean of 19 days (range: 1-30) before surgery. Imaging findings were compared with surgical (including intraoperative ultrasonography) and histological findings on a lesion by lesion analysis. RESULTS: R0 resection was performed in 12 patients. A total of 28 lesions were resected with 27 histologically proven metastases. Nine lesions were smaller than 5mm, 7 measured 5-10mm and 11 were larger than 10mm. Sensitivity and positive predictive value were 67% and 95% for MRI compared to 41% and 100% for FDG-PET. The difference between the two modalities was statistically significant (p=0.01; McNemar test). In remaining 3 patients, diffuse miliary disease (>10 capsular lesions) was discovered intraoperatively, and was suspected on preoperative MRI in 2 cases. Only one extrahepatic lesion identified by FDG-PET was falsely positive. CONCLUSIONS: In this preliminary study, MRI was superior to FDG-PET for staging of liver metastases from uveal melanoma. Although miliary disease was suggested by MRI in some cases, preoperative confirmation remains imperfect. PMID- 19775852 TI - Comparison of autograft vs allograft in opening-wedge high tibial osteotomy. AB - Opening-wedge high tibial osteotomy (HTO) is used to treat isolated medial knee joint arthritis. A benefit of using allograft instead of autograft is avoiding a second surgical site, thereby decreasing operative time, blood loss, and pain. Our study objective was to evaluate allograft vs autograft in the failure and complication rates of HTO using the same technique and implant system (Arthrex HTO plate system, Arthrex, Inc, Naples, Fla). Seventy knees in 65 patients were evaluated. There was a 6-fold higher failure rate for the allograft group. When there was no lateral cortical breach, construct failure did not occur in 87.8% of the knees (P = .0006); with lateral cortical breach, construct failure occurred 53% of the time (P = .0006). Seventy-six and a half percent of breached cortices and 75% of failures were associated with large wedge sizes (>or=11 mm); this may suggest a role for closing-wedge osteotomy or alternative osteotomies when larger alignment corrections are needed. PMID- 19775853 TI - Restoration of the center of rotation in revision total hip arthroplasty. AB - We measured the change of the center of hip rotation after the revision of acetabular loosening using an acetabular reconstruction ring and an impaction allogenic bone grafting. Thirty-five revision total hip arthroplasties were performed. The average follow-up was 3.8 years. Horizontal distance was changed from 34.01+/-10 mm preoperatively to 41.07+/-6 mm at the latest follow-up. Vertical distance was changed from 32.06+/-9 mm preoperatively to 20.21+/-7 mm at the latest follow-up. The Harris hip score was improved from an average of 47 in the preoperative period to 86 at the final follow-up. The restoration of the anatomical hip center has shown to be favorable in terms of functional and radiologic evaluation in total hip revision. PMID- 19775854 TI - Distribution of periacetabular osteolytic lesions varies according to component design. AB - Using computed tomography, the volume, location, and number of osteolytic lesions were determined adjacent to 38 Harris-Galante 1 (HG-1) acetabular components fixed with screws and 19 porous-coated anatomic (PCA) acetabular components press fitted without screws. The median implantation times were 16 and 15 years, respectively. The mean total lesion volumes were similar: 11.1 cm(3) (range, 0.7 49 cm(3)) and 9.8 cm(3) (range, 0.4-52 cm(3)), respectively, for hips with HG-1 and PCA components (P = .32). There was a significant difference in the proportion of rim-related, screw or screw hole-related, and combined lesions between the 2 component designs (P < .0001). HG-1 components had more screw and screw hole-related lesions, and PCA components had more rim-related lesions. Although there are concerns regarding screw and screw hole-associated osteolysis, these findings suggest that peripheral fixation may be well maintained in the long term with the use of multiple-hole acetabular components with screw fixation. PMID- 19775855 TI - Nailed cementoplasty: a salvage technique for rorabeck type II periprosthetic fractures in octogenarians. AB - Periprosthetic femoral fractures around a total knee arthroplasty present a surgical challenge in octogenarians with advanced osteoporosis. We describe a salvage technique combining retrograde intramedullary nailing augmented with polymethylmethacrylate cement in 5 patients followed up for a median time of 12 months. The nail/cement construct bridges the femoral canal tightly and simulates a stemmed cemented revision component. All patients had an uncomplicated recovery and returned to their preinjury functional status within 4 months. This procedure does not disrupt the soft tissue envelope around the fracture site, is easy to perform and permits immediate full range of movement. When standard retrograde nailing or plating alone is inadequate in maintaining severely osteoporotic fracture reduction, nailed cementoplasty is proposed as a salvage procedure in octogenarians unfit for lengthy interventions. PMID- 19775856 TI - Mobile-bearing total knee arthroplasty improves patellar tracking and patellofemoral contact stress: in vivo measurements in the same patients. AB - Controversies exist in clinical study concerning the effect of rotating platform on patellar tracking. The aim of this in vivo study was to compare tibial rotation, patellar tracking, and patellofemoral contact stress in mobile and fixed-bearing platform intraoperatively in the same knee. Sixty-six knees of posterior-stabilized total knee prostheses were evaluated using a computed tomography-guided navigation system. Medial shift and lateral tilt of patella were significantly smaller in mobile knee. Averaged maximum contact stress was significantly smaller in mobile knee than fixed knee. However, tibial rotation during flexion has no significant difference. This study showed that mobile platform total knee arthroplasty significantly improved patellar tracking and decreased patellofemoral contact stress. PMID- 19775857 TI - RE: Unrecognized acetabular component rotation with formation of a pseudoarticulation after total hip arthroplasty. PMID- 19775858 TI - Mobile-bearing total knee arthroplasty: better than a fixed-bearing? AB - The purported advantages of mobile-bearing knee include increased survivorship and restoration of more natural knee kinematics compared to a standard fixed bearing design. To evaluate these claims, an extensive review of the available literature was undertaken. We compared survivorship and clinical function, including patient preference. We found no difference in survivorship at 12 to 23 years. Kinematic profiles of both designs did not differ significantly: rotation, flexion, and extension were comparable. Studies evaluating both designs in the same patient showed no difference in range of motion, knee preference, knee scores, and survivorship at midterm follow-up. Both designs were capable of producing excellent long-term results and clinical outcomes if properly implanted. The available evidence does not point to the superiority of one design over another in survivorship and clinical function. PMID- 19775860 TI - A framework for assessing quality indicators for cancer care at the end of life. AB - Patients with advanced cancer often do not receive high-quality pain and symptom management or support with coordination of care, communication, and decision making. Implementing quality indicators that are reflective of the scope of care, feasible to implement, and supported by evidence might help to identify areas and settings most in need of improvement. However, recent reviews and policy initiatives identified only a few indicators that met these criteria. To help advance quality indicator development and implementation in this area, we developed a conceptual framework based on previous related initiatives, updated reviews of end-of-life cancer quality indicators and relevant data sources, and expert input. The framework describes five steps for developing and assessing a quality indicator for end-of-life care, defining the 1) population of focus, 2) broad quality domains, 3) specific target areas, 4) steps of the care process, and 5) evaluation criteria for quality indicators. The defined population includes seriously or terminally ill cancer patients, who are unlikely to recover or stabilize, and their families. Domains include the structure and processes of care; the physical, psychiatric, psychosocial, spiritual, and cultural aspects of care; as well as the care of the imminently dying, ethical and legal issues, and the delivery of care. Evaluation criteria include importance; scientific acceptability, including validity, evidence to improve outcomes, reliability, responsiveness, and variability; usability; and feasibility, including ready data sources. By using this conceptual framework, indicator developers, researchers, and policymakers can refine and implement indicator sets to effectively evaluate and improve care at the end of life. PMID- 19775859 TI - Wear and range of motion of different femoral head sizes. AB - Femoral head sizes greater than 32 mm are more prevalent with current total hip arthroplasty. We hypothesized that linear wear rates of Durasul highly cross linked polyethylene would not differ with different head sizes. We also compared the range of motion of the hip. Ninety-four consecutive arthroplasties in 84 patients were studied for a mean 3.6 +/- 0.7 years. There was no statistical difference in linear wear rates and annual or total penetration rates when 28-mm and 32-mm heads were compared to 38-mm and 44-mm heads. Volumetric wear was 12.4 mm(3)/y higher with bigger heads. Range of motion did not differ. Larger femoral head sizes show no evidence of an accelerated wear pattern when used with Durasul. PMID- 19775861 TI - State of consciousness during the last days of life in patients receiving palliative care. PMID- 19775862 TI - Differences in the use of pain coping strategies between oncology inpatients with mild vs. moderate to severe pain. AB - The purposes of this study were to determine a clinically significant cutpoint for worst pain and to evaluate for differences in the use of pain coping strategies between oncology inpatients with mild (i.e., worst pain intensity scores of 4) pain based on results of the cutpoint analysis. Oncology inpatients in pain (n=224) completed the Coping Strategies Questionnaire (CSQ), the Brief Pain Inventory, and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). Fifty-six percent had moderate to severe pain. Patients in the moderate to severe pain group had significantly poorer Karnofsky Performance Status scores (P=0.04) and significantly lower ratings of overall health (P<0.0001). No differences were found between the two pain groups on any of the subscales of the CSQ, except catastrophizing (P<0.0001). Compared with the mild pain group, patients in the moderate to severe group scored significantly higher on this subscale. In addition, patients in the moderate to severe group used more passive coping strategies (P=0.02). Except for catastrophizing, the number and types of pain coping strategies used by this sample of hospitalized patients do not appear to be influenced by their pain intensity scores. Finally, when the CSQ scores of these hospitalized oncology patients were compared with those found in previous studies of oncology outpatients and patients with chronic noncancer pain, the scores were similar. PMID- 19775863 TI - A meta-analysis of the relationship between response expectancies and cancer treatment-related side effects. AB - Response expectancies, defined as expectations for nonvolitional responses, have been proposed to contribute to the experience of side effects of cancer and its treatment. To statistically evaluate this association, a systematic search of the published literature was conducted, resulting in 14 studies appropriate for meta analysis. Results revealed a significant (Z=6.58, P<0.001) medium-sized (r=0.36) association between patients' response expectancies for cancer treatment-related side effects and the experience of these side effects. Assessment of response expectancies with reference to the time the treatment-related side effect would occur resulted in larger effect sizes than when such temporal specificity in assessment was not included, Q(1)=10.27, P<0.01. Effect sizes were also moderated by patients' prior experience with cancer treatment, Q(1)=18.91, P=0.001, such that prior experience led to stronger associations between response expectancies and side effects than no prior experience. Relationships between response expectancies and pain, fatigue, nausea, and vomiting were explored. Effect sizes did not differ between side effects, with the exception that the relationship was significantly stronger for pain than for vomiting (P<0.05). Overall, these results support the contribution of response expectancies to cancer treatment related side effects. Additionally, the results support the conduct of research on interventions to alter response expectancies, with the goal of reducing side effects and improving patient quality of life. PMID- 19775864 TI - Associations between physical activity and quality of life in cancer patients receiving palliative care: a pilot survey. AB - The primary aim of this study was to examine the association between physical activity and quality of life (QoL) in cancer patients receiving palliative care. Fifty advanced cancer patients aged 18 years or older with clinician-estimated life expectancy of 3-12 months and Palliative Performance Status Scale scores greater than 30% were recruited from an outpatient palliative care clinic and palliative home care. Participants completed a cross-sectional survey by means of face-to-face interview assessing self-reported QoL (McGill Quality of Life Questionnaire [MQOL]), self-reported physical function (Late-Life Function and Disability Instrument), symptoms (Edmonton Symptom Assessment System), and physical activity behavior. Seventy-six percent (38 of 50) of the participants were deceased at the time of data analysis, with a median survival of 104 days from time of survey to time of death. Walking was the most common reported physical activity. Analyses of variance indicated that participants who reported walking more than 30 minutes per day also reported higher existential subscores (+/-0.8 [95% CI, 0.0-1.5]; P=0.045), support subscores (+/-0.7 [95% CI, 0.1-1.4]; P=0.027), and total scores (+/-0.5 [95% CI, 0.0-0.9]; P=0.046) on the MQOL. There were no significant differences for self-reported physical function or symptoms. Our findings show a significant positive association between physical activity and QoL scores in this sample of patients with advanced cancer. A pilot intervention trial testing the causal effects of physical activity on QoL in cancer patients receiving palliative care is warranted. PMID- 19775865 TI - Predictors of social anxiety in an opioid dependent sample and a control sample. AB - Compared to other mental health problems, social anxiety is under-acknowledged amongst opioid dependent populations. This study aimed to assess levels of social anxiety and identify its predictors in an opioid dependent sample and a matched control group. Opioid dependent participants (n=1385) and controls (n=417) completed the Social Interaction Anxiety Scale (SIAS), the Social Phobia Scale (SPS) and a diagnostic interview. Regression analyses were used to test a range of predictors of social anxiety. Opioid dependent cases had higher mean scores on both scales compared to controls. Predictors of social anxiety centred on emotional rejection in childhood, either by parents or peers. For opioid dependent cases, but not controls, lifetime non-opioid substance dependence (cannabis, sedatives, and tobacco) was associated with higher levels of social anxiety. However, much of the variance in social anxiety remains unexplained for this population. PMID- 19775867 TI - The relationship between the glottic configuration after frontolateral laryngectomy and the acoustic voice analysis. AB - The relative measurement of the anterior commissure synechia (S) is a crucial factor worsening voice quality and the perceptual analysis score has a strong correlation to the synechia's impact. The aim of this study is to correlate the laryngeal configuration regarding the anterior commissure synechia and its relationship with the acoustic vocal parameters. Fifteen male patients underwent frontolateral partial vertical laryngectomy and reconstruction with bipedicle sternohyoid muscle flap for the treatment of T1b/T2 glottic cancer. The patients were free of disease, and the evaluation was performed after a minimum postoperative period of 12 months. Measurements of the anterior commissure synechia and the free border of both the preserved and the reconstructed vocal folds were simultaneously performed with the acoustic analysis of the voice. We calculated the mathematical proportion between the midsagital dimension of the synechia of the anterior commissure and the measurement of the free border of the intermembranous region of each vocal fold-the preserved one and that reconstructed with the bipedicle sternohyoid muscle flap. The acoustic evaluation showed an important increase in the fundamental frequency, and the values of all parameters were changed regardless of the anterior commissure synechia findings. These results suggest that the acoustic voice parameters are always changed because of the aperiodic pattern regardless of the anterior commissure synechia findings. PMID- 19775866 TI - Patient perceptions of voice therapy adherence. AB - Patient perspectives of behavioral voice therapy, including perspectives of treatment adherence, have not been formally documented. Because treatment adherence is, to a large extent, determined by patient beliefs, assessment of patient perspectives is integral to the study of adherence. Fifteen patients who had undergone at least two sessions of direct voice therapy for a variety of voice disorders/complaints were interviewed about their perspectives on voice therapy, with a particular focus on adherence. Interviews were transcribed and analyzed for content according to qualitative methods. Three common content themes emerged from the transcripts: Voice Therapy is Hard, Make it Happen, and The Match Matters. Findings were compared with reports of patient experiences in other behavioral interventions, such as diet and exercise, and related to existing theoretical models of behavior change and therapeutic process. This study yields information toward the development of scales to measure adherence related constructs and strategies to improve treatment adherence in voice therapy. PMID- 19775868 TI - Introduction to the special issue of image-guided surgical planning and therapy. PMID- 19775869 TI - Determinants of everyday outcomes in schizophrenia: the influences of cognitive impairment, functional capacity, and symptoms. AB - Deficits in everyday living skills and social skills are associated with the pervasive disability seen in schizophrenia. Cognitive impairments are determinants of these skills deficits and it is known that positive and negative symptoms add to the influence of cognitive impairments for prediction of real world outcomes. This study examined the relative importance of cognitive impairments measured with a neuropsychological battery, performance-based measures of social and everyday living skills, and positive and negative symptoms for the prediction of real-world outcomes in social and residential domains. In contrast to most previous studies, we examined the importance of individual symptoms, as well as total subscale scores, for predicting clinician rated outcomes in 194 older outpatients with schizophrenia. Symptoms were rated with the Positive and Negative Syndrome Scale; everyday living skills were measured by the UCSD Performance-based Skills Assessment; and social skills were measured with the Social Skills Performance Assessment. For prediction of real-world social outcomes, blunted affect and passive-apathetic social withdrawal accounted for all of the predicted variance, while social competence and cognitive impairments did not enter the final equation. For residential functioning, everyday living skills were the most important predictor, followed by lack of spontaneity. The positive symptoms of hallucinatory behavior and suspiciousness also predicted real-world residential outcomes. These results suggest that real world disability is the product of a complex array of ability deficits and symptoms, indicating interventions will need to be carefully targeted. For social and everyday living outcomes, variance accounted for by the entire array of predictive variables was less than 40%, suggesting that other factors, such as social and cultural influences, are involved as well. PMID- 19775870 TI - The impact of developmental instability on Voxel-Based Morphometry analyses of neuroanatomical abnormalities in schizophrenia. AB - The etiologic factors underlying schizophrenia have been conceptualized as reflecting two largely genetic components - those unique to schizophrenia and those representing vulnerability to neurodevelopmental deviation in general. The Developmental Instability (DI) approach suggests that the latter can be indexed by minor physical anomalies (MPAs), which assess early prenatal growth abnormalities, and fluctuating anatomic asymmetries (FA), which reflects later deviations. Individuals with schizophrenia (N=19) had elevated scores on both measures as compared to healthy controls (N=23). Further, MPAs and FA were very highly correlated in the sample of individuals with schizophrenia but not in controls. In order to identify neuroanatomic variation linked with the unique factor, we conducted gray matter Voxel Based Morphometry analyses of group membership, with and without treating a composite measure of DI (based on FA, and MPAs) as a covariate. When DI was treated as a covariate, many more gray matter regions were found to statistically differ as a function of diagnosis. These results support the DI approach and suggest that the unique etiologic factors associated with schizophrenia lead to widespread gray matter volume reductions. PMID- 19775871 TI - Characterisation of the de-agglomeration effects of bovine serum albumin on nanoparticles in aqueous suspension. AB - This paper describes the use of nanoparticle characterisation tools to evaluate the interaction between bovine serum albumin (BSA) and dispersed nanoparticles in aqueous media. Dynamic light scattering, zeta-potential measurements and scanning electron microscopy were used to probe the state of zinc oxide (ZnO) and titanium dioxide (TiO(2)) nanoparticles in the presence of various concentrations of BSA, throughout a three-day period. BSA was shown to adhere to ZnO but not to TiO(2). The adsorption of BSA led to subsequent de-agglomeration of the sub-micron ZnO clusters into smaller fragments, even breaking them up into individual isolated nanoparticles. We propose that certain factors, such as adsorption kinetics of BSA on to the surface of ZnO, as well as the initial agglomerated state of the ZnO, prior to BSA addition, are responsible for promoting the de-agglomeration process. Hence, in the case of TiO(2) we see no de-agglomeration because: (a) the nanoparticles are more highly agglomerated to begin with and (b) BSA does not adsorb effectively on the surface of the nanoparticles. The zeta-potential results show that, for either ZnO or TiO(2), the presence of BSA resulted in enhanced stability. In the case of ZnO, the enhanced stability is limited to BSA concentrations below 0.5 wt.%. Steric and electrostatic repulsion are thought to be responsible for improved stability of the dispersion. PMID- 19775872 TI - Preparation and characterization of a polymeric (PLGA) nanoparticulate drug delivery system with simultaneous incorporation of chemotherapeutic and thermo optical agents. AB - The objective of this study was to develop biodegradable poly(DL-lactide-co glycolic acid) (PLGA) nanoparticles simultaneously loaded with indocyanine green (ICG) and doxorubicin (DOX). The modified oil in water single emulsion solvent evaporation method was used. To enhance the incorporation of both agents and control particle size, four independent processing parameters including amount of polymer, initial ICG content, initial DOX content, and concentration of poly vinyl alcohol (PVA) were investigated. The ICG and DOX entrapment in nanoparticles as well as the nanoparticle size were determined. The nanoparticles produced by standardized formulation were in the range of 171+/-2 nm (n=3) with low polydispersity index (0.040+/-0.014, n=3). The entrapment efficiency was determined by spectrofluorometer measurements. The efficiency was 44.4+/-1.6% for ICG and 74.3+/-1.9% for DOX. Drug loading was 0.015+/-0.001%, w/w, for ICG and 0.022+/-0.001%, w/w, for DOX (n=3). The release pattern was biphasic. ICG and DOX loaded-nanoparticle preparation was standardized based on the following parameters: PLGA concentration, PVA concentration and initial drug content. PMID- 19775873 TI - Thermal stability of bioactive enzymatic papers. AB - The thermal stability of two enzymes adsorbed on paper, alkaline phosphatase (ALP) and horseradish peroxidase (HRP), was measured using a colorimetric technique quantifying the intensity of the product complex. The enzymes adsorbed on paper retained their functionality and selectivity. Adsorption on paper increased the enzyme thermal stability by 2-3 orders of magnitude compared to the same enzyme in solution. ALP and HRP enzymatic papers had half-lives of 533 h and 239 h at 23 degrees C, respectively. The thermal degradation of adsorbed enzyme was found to follow two sequential first-order reactions, indication of a reaction system. A complex pattern of enzyme was printed on paper using a thermal inkjet printer. Paper and inkjet printing are ideal material and process to manufacture low-cost-high volume bioactive surfaces. PMID- 19775874 TI - Impact of RGD micro-patterns on cell adhesion. AB - In order to avoid the problems related to biomaterial use (inflammation, infections, aseptic loosening, etc.), a new approach consisting of associating the material and autologous cells before implantation is being developed, thus requiring a perfect cooperation between the material's surface and the cell. To improve cell adhesion to biomaterials, a suitable method is to functionalize their surface by pro-adhesive ligand grafting. The aim of this study was to covalently graft RGD containing peptides onto a poly-(ethylene terephthalate) surface in well-defined microstructures in order to control MC3T3 cell adhesion. We followed two different routes for obtaining micro-patterned materials: (1) a photoablation technique using an excimer laser and (2) a photolithography process. The resulting patterns were characterized by optical microscopy, scanning electron microscopy, optical profilometry and high resolution mu-imager. The biological evaluation of cell adhesion onto the micro-patterned surfaces was carried out using optical microscopy, scanning electron microscopy and fluorescence microscopy. Cells seeded onto photolithographical or photoablated micro-patterned PET exhibited an alignment with the RGD domains and appear to be connecting through pseudopods extending towards each other. Whatever the technique used to create micro-patterns, a cell alignment occurs once the thickness of the RGD line reaches approximately 100 microm. These results prove the importance of microstructured surfaces for the elaboration of tissue engineered biomaterials. PMID- 19775875 TI - Morphology, morphogenesis and gene sequence of a freshwater ciliate, Pseudourostyla cristata (Ciliophora, Urostyloidea) from the ancient Lake Biwa, Japan. AB - The urostyloid freshwater ciliate Pseudourostyla cristata was recorded for the first time from Lake Biwa, a 4-million-year-old lake located in Shiga Prefecture, Japan. Its morphology and morphogenesis were investigated using live observation and protargol impregnation, and the SSU ribosomal RNA gene was sequenced. Based on the current observations and previous descriptions, this species is readily recognized mainly by the following characters: body slender or broadly oval to elliptical, and dark grey in color; size in vivo about 170-400 x 40-150 microm; pellicle flexible and contractile, with extrusomes forming a hyaline seam underneath; ciliature comprising about 60-130 adoral membranelles, usually 1 buccal cirrus, 20-24 frontal, 2 frontoterminal, 17-26 pairs of midventral, and 5 16 transverse cirri, 4-6 left and 4-5 right marginal rows, and 8-10 dorsal kineties; 15-83 macronuclear nodules and 2-9 micronuclei; freshwater habitat. The main morphogenetic developments are: (1) the oral primordium for the proter originates de novo on the dorsal wall of the buccal cavity, and the dedifferentiated undulating membranes and some parental proximal membranelles join in the primordial development; the old adoral zone will be partly replaced by new structures; (2) the oral primordium for the opisthe occurs epiapokinetally left of the midventral complex between the adoral zone and the transverse cirri; (3) the fronto-midventral transverse cirral (FVT) anlagen develop separately in both dividers by dedifferentiation of most of the midventral cirri; (4) the single buccal cirrus is generated from the posterior end of FVT anlage II; (5) the leftmost frontal cirrus is derived from the anterior end of the undulating membranes anlage (FVT anlage I); (6) the marginal rows of each side are formed from a single anlage which arises within the rightmost row; (7) the dorsal kineties develop by intrakinetal basal body proliferation; and (8) the most posterior FVT anlage contributes the two fronto-terminal cirri at its anterior end. The present observations indicate that P. cristata has a wide geographic distribution, and possesses constant morphological and morphogenetic traits. Phylogenetic trees inferred from SSU rRNA gene sequences suggest paraphyly of the genus Pseudourostyla. PMID- 19775876 TI - Management of stage I seminomatous testicular cancer: a systematic review. AB - The treatment options available for the management of stage I seminoma consist of either a surveillance strategy or adjuvant therapy after orchidectomy. A systematic review was undertaken to identify the optimal management strategy. The MEDLINE and EMBASE databases, in addition to the American Society of Clinical Oncology Meeting Proceedings, were searched for the period 1981 to May 2007. Studies were eligible for inclusion if they discussed at least one of survival, recurrence, second malignancy, cardiac toxicity, or quality of life for patients with stage I seminoma. A search update was carried out in June 2009. Fifty-four reports satisfied the eligibility criteria, including seven clinical practice guidelines, one systematic review, three randomised controlled trials focused on treatment options, 26 non-randomised studies of treatment options, and 15 non randomised long-term toxicity studies. The existing data suggest that virtually all patients with stage I testicular seminoma are cured regardless of the post orchidectomy management. The 5-year survival reported in all the studies identified in this systematic review was over 95%, regardless of the management strategy, including surveillance alone with no adjuvant therapy. In conclusion, to date, the optimal management of stage I seminoma remains to be defined. Surveillance seems to be the preferable option, as this strategy minimises the toxicity that might be associated with adjuvant treatment, while preserving high long-term cure rates. The currently available evidence should be presented to patients in order to select the most appropriate option for the individual. PMID- 19775877 TI - Rosiglitazone (peroxisome proliferator-activated receptor-gamma) counters hypertension and adverse cardiac and vascular remodeling in 2K1C hypertensive rats. AB - Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonists have been shown controlling blood pressure (BP) in spontaneously hypertensive rats and salt sensitive hypertensive rats. The present study aims to test the hypothesis that PPAR-gamma agonist rosiglitazone has beneficial effects on cardiac and vascular adverse remodeling in a model of renovascular hypertension (two-kidneys-one-clip, 2K1C model). Wistar rats were divided into four groups (n=6): SHAM group, 2K1C, 2K1C+HYD (treated with hydralazine for 5 weeks) and 2K1C+ROSI (treated with rosiglitazone for 5 weeks). The left ventricle (LV), thoracic aorta (Ao) and common carotid artery (CCA) were analyzed. The BP did not show significant difference at the end of the experiment in groups 2K1C+ROSI, 2K1C+HYD and SHAM. The LV mass was smaller in 2K1C+ROSI compared with the other groups. The intima media thickness was smaller in 2K1C+ROSI compared with untreated 2K1C ones, but not in 2K1C+HYD; 2K1C and 2K1C+HYD showed smaller Ao and CCA density of smooth muscle cell nuclei, and smaller surface density of the elastic lamellae than SHAM. The Ao and CCA circumferential wall tension and tensile stress were greater in 2K1C than in SHAM. Hypertrophied cardiomyocytes were seen in 2K1C, but not in 2K1C+ROSI and SHAM; 2K1C+ROSI had enhanced volume and length densities of intramyocardial arteries than 2K1C. The volume density of cardiac interstitium was greater in 2K1C and 2K1C+HYD than in SHAM. In conclusion, PPAR-gamma agonist rosiglitazone has beneficial effects controlling BP, reducing vascular adverse remodeling, and preserving intramyocardial vascularization in renovascular hypertensive rats (2K1C model). PMID- 19775878 TI - Myocardial infarction does not affect fatty-acid profiles in rats. AB - Plasma and red blood cell fatty-acid (RBC FA) composition have both been proposed as biomarkers for cardiovascular (CV) risk. Since case/control studies using samples obtained after a CV constitute a source of supporting evidence, demonstrating that FA profiles are not affected by a myocardial infarction (MI) would improve our understanding of the usefulness of such studies. The primary goal of the present study was to determine the impact of an MI on RBC and whole plasma eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) levels and to do so with sufficient power to conclude that there was no effect. FA profiles were obtained from rats 24h after an MI or a sham-MI and compared to control animals by tests for differences and equivalence. In RBCs, neither DHA nor EPA was changed and were statistically equivalent in control and MI rats, as were a majority of other FAs and FA composite indices; only shingolipid-associated fatty acids had abundances that were changed in either MI or sham-MI animals. In whole plasma 8 of 22 FAs were changed in MI or sham-MI rats, including EPA which was reduced from 2.53 (2.3, 2.8)% to 1.71 (1.4, 2)%; mean (95% CI). In conclusion, the levels of EPA, DHA, and most other FAs in RBCs are unaffected by an MI or by sham surgery, whereas the same cannot be said of plasma. This finding suggests that differences between cases and controls have prognostic implications. PMID- 19775880 TI - Daidzein and the daidzein metabolite, equol, enhance adipocyte differentiation and PPARgamma transcriptional activity. AB - Dietary soy isoflavones have been shown to favorably alter the metabolic phenotypes associated with Type 2 diabetes. However, the identification of direct targets and the underlying molecular mechanisms by which soy isoflaovones exert antidiabetic effects remain elusive. Since the insulin-sensitizing effects of thiazolidinediones, antidiabetic drugs, are mediated through activation of peroxisome proliferators-activated receptor gamma (PPARgamma), we examined the effects of daidzein and the daidzein metabolite, equol, on adipocyte differentiation and PPARgamma activation. In 3T3-L1 cells, daidzein enhanced adipocyte differentiation and PPARgamma expression in a dose-dependent manner. Daidzein also dose-dependently increased insulin-stimulated glucose uptake and the relative abundance of insulin-responsive glucose transporter 4 (GLUT4) and insulin receptor substrate 1 (IRS-1) mRNA. In C3H10T1/2 cells, both daidzein and equol at 1 micromol/L and higher significantly increased adipocyte differentiation and insulin-stimulated glucose uptake. Furthermore, daidzein and equol up-regulated PPARgamma-mediated transcriptional activity, and daidzein restored the PPARgamma antagonist-induced inhibition of aP2 and GLUT4 mRNA levels. Our results indicate that daidzein enhances insulin-stimulated glucose uptake in adipocytes by increasing the expression of GLUT4 and IRS-1 via the activation of PPARgamma. These data further support the recent findings that favorable effects of dietary soy isoflavones may be attributable to daidzein and its metabolite equol. PMID- 19775879 TI - Control of cell growth by the SCF and APC/C ubiquitin ligases. AB - The ubiquitin-proteasome system plays key roles in the control of cell growth. The cell cycle, in particular, is highly regulated by the functions of the SCF and APC/C ubiquitin ligases, and perturbation of their function can result in tumorigenesis. Although the SCF and APC/C complexes are well established in growth control pathways, many aspects of their function remain unknown. Recent studies have shed light on the mechanism of SCF-mediated ubiquitination and new functions for the SCF complex and APC/C. Our expanding understanding of the roles of the SCF and APC/C complexes highlight the potential for targeted molecular therapies. PMID- 19775881 TI - Electrochemical single-cell gene-expression assay combining dielectrophoretic manipulation with secreted alkaline phosphatase reporter system. AB - Scanning electrochemical microscopy (SECM) was used for the analysis of single cell gene-expression signals on the basis of a reporter system. We microfabricated a single-cell array on an Indium tin oxide (ITO) electrode comprising 4 x 4 SU-8 microwells with a diameter of 30microm and a depth of 25microm. HeLa cells transfected with plasmid vectors encoding the secreted alkaline phosphatase (SEAP) were seeded in the microwell at a concentration of 1 cell per well by positive-dielectrophoresis (pDEP). A pDEP pulse of 3.0Vpp and 1MHz was applied between the microwell array/ITO electrode and an ITO counter electrode located on the top of the flow-cell assembly of the microdevice. The electrochemical responses of the individual HeLa cells transfected with SEAP were significantly larger than those of the wild-type HeLa cells. The electrochemical response of the transfected single cells was statistically distinguishable from that of wild-type HeLa cells. The size of the wells and the material of the single-cell array were optimized in order to evaluate the tumor necrosis factor alpha (TNF-alpha)-induced activation process of nuclear factor kappa B (NFkappaB) that was used as the model for on-chip monitoring of cellular signal transduction. PMID- 19775882 TI - Rapid homogenous detection of the Ibaraki virus NS3 cDNA at picomolar concentrations by magnetic modulation. AB - Magnetic modulation biosensing (MMB) system is experimentally demonstrated for rapid and homogeneous detection of the Ibaraki virus NS3 cDNA. A novel fluorescent resonance energy transfer (FRET)-based probe discriminates the target DNA from the control. When detection is made, the FRET-based probe is cleaved using Taq-polymerase activity and fluorescent light is produced. The biotinylated probes are attached to streptavidin-coupled superparamagnetic beads and are maneuvered into oscillatory motion by applying an alternating magnetic field gradient through two electromagnetic poles. The beads are condensed into the detection area and their movement in and out the orthogonal laser beam produces a periodic fluorescent signal that is demodulated using synchronous detection. 1.9pM of the Ibaraki virus NS3 cDNA was detected in homogeneous solution within 18min without separation or washing steps. PMID- 19775883 TI - Wireless powering for a self-propelled and steerable endoscopic capsule for stomach inspection. AB - This paper describes the integration of an active locomotion module in a wirelessly powered endoscopic capsule. The device is a submersible capsule optimized to operate in a fluid environment in a liquid-distended stomach. A 3D inductive link is used to supply up to 400mW to the embedded electronics and a set of 4 radio-controlled motor propellers. The design takes advantage of a ferrite-core in the receiving coil-set. This approach significantly improves the coupling with the external field source with respect to earlier work by the group. It doubles the power that can be received with a coreless coil-set under identical external conditions. The upper limit of the received power was achieved complying with the strict regulations for safe exposure of biological tissue to variable magnetic fields. The wireless transferred power was proven to be sufficient to achieve the speed of 7cm/s in any directions. An optimized locomotion strategy was defined which limits the power consumption by running only 2 motors at a time. A user interface and a joystick controller allow to fully drive the capsule in an intuitive manner. The device functionalities were successfully tested in a dry and a wet environment in a laboratory set-up. PMID- 19775884 TI - Fiber optic SPR biosensing of DNA hybridization and DNA-protein interactions. AB - In this paper we present a fiber optic surface plasmon resonance (SPR) sensor as a reusable, cost-effective and label free biosensor for measuring DNA hybridization and DNA-protein interactions. This is the first paper that combines the concept of a fiber-based SPR system with DNA aptamer bioreceptors. The fibers were sputtered with a 50nm gold layer which was then covered with a protein repulsive self-assembled monolayer of mixed polyethylene glycol (PEG). Streptavidin was attached to the PEG's carboxyl groups to serve as a versatile binding element for biotinylated ssDNA. The ssDNA coated SPR fibers were first evaluated as a nucleic acid biosensor through a DNA-DNA hybridization assay for a random 37-mer ssDNA. This single stranded DNA showed a 15 nucleotides overlap with the receptor ssDNA on the SPR fiber. A linear calibration curve was observed in 0.5-5 microM range. A negative control test did not reveal any significant non specific binding, and the biosensor was easily regenerated. In a second assay the fiber optic SPR biosensor was functionalized with ssDNA aptamers against human immunoglobulin E. Limits of detection (2nM) and quantification (6nM) in the low nanomolar range were observed. The presented biosensor was not only useful for DNA and protein quantification purposes, but also to reveal the binding kinetics occurring at the sensor surface. The dissociation constant between aptamer and hIgE was equal to 30.9+/-2.9nM. The observed kinetics fully comply with most data from the literature and were also confirmed by own control measurements. PMID- 19775885 TI - A novel interdigitated capacitor based biosensor for detection of cardiovascular risk marker. AB - C-reactive protein (CRP) is a potential biomarker whose elevated levels in humans determine cardiovascular disease risk and inflammation. In this study, we have developed a novel capacitive biosensor for detection of CRP-antigen using capacitor with interdigitated gold (GID) electrodes on nanocrystalline diamond (NCD) surface. The NCD surface served as a dielectric layer between the gold electrodes. GID-surface was functionalized by antibodies and the immobilization was confirmed by Fourier transform spectroscopy (FT-IR) and contact angle measurements. The CRP-antigen detection was performed by capacitive/dielectric constant measurements. The relaxation time and polarizability constants were estimated using Cole-Cole model. Our results showed that the relaxation time constant (tau) of only CRP-antibody was within 10(-16)-10(-13)s, which was increased to 10(-11)s after the incubation with CRP-antigen, suggesting that the CRP-antigen was captured by the antibodies on GID-surface. In addition, polarizability constant (m) of CRP was also increased upon incubation with increasing concentration of CRP-antigen. Our results showed that the response of GID-NCD-based capacitive biosensor for CRP-antigen was dependent on both concentration (25-800ng/ml) as well as frequency (50-350MHz). Furthermore, using optimized conditions, the GID-NCD based capacitive biosensor developed in this study can potentially be used for detection of elevated levels of protein risk markers in suspected subjects for early diagnosis of disease. PMID- 19775886 TI - Thermogravimetric analysis and emission characteristics of two energy crops in air atmosphere: Arundo donax and Miscanthus giganthus. AB - The aim of this work was to study the thermal behavior of two herbaceous crops (Miscanthus giganthus, Arundo donax) obtained from energy plantations. Thermogravimetric analyses were performed at 5 degrees C min(-1) under air atmosphere. The thermal degradation rates in devolatilization and combustion steps, the initial degradation temperature, and the residual weight were determined. The gas emissions and Particle Matter (PM) were also quantified. The thermal behavior of energy crops depends on the chemical composition. In fact, the initial degradation temperature for A. donax under air atmosphere was lower than for M. giganthus. However, the thermal degradation rate was higher for M. giganthus. Kinetic expressions for the degradation rate in devolatilization and combustion steps have been obtained for both energy crops. The comparison of the gas and PM emissions showed the same order of magnitude for both energy crops. In fact, 26.8 mmol/g of CO, CO(2), VOC and 1.8 x 10(13) particles/g were mainly emitted. PMID- 19775887 TI - Cellulase production by continuous culture of Trichoderma reesei Rut C30 using acid hydrolysate prepared to retain more oligosaccharides for induction. AB - An acid hydrolysate was prepared by a procedure chosen for retaining more oligosaccharides to improve the cellulase-inducing capability when used as substrate in the fungal fermentation for cellulase production. The effect was evaluated with continuous culture of Trichoderma reesei Rut C30 at the dilution rates of 0.03-0.08 h(-1). The specific cellulase production rates were found to be relatively constant at 8.9+/-0.3 (FPU/g dry cells-h), except for the lower rate, i.e., 7.2 (FPU/g-h), at the lowest dilution rate investigated (0.03 h(-1)). The former value was slightly higher than the rate obtained with a lactose-based medium, i.e., 8.2 (FPU/g-h). The maximum specific cell growth rate supported by the hydrolysate-based medium was 0.096 (h(-1)) and the apparent cell yield increased from 0.44 to 0.57 (g dry cells)/(g consumed reducing sugars) with increasing dilution rates. The best-fit maximum/ideal cell yield (without endogenous metabolism) was 0.68 (g/g), the endogenous substrate consumption rate was 0.023 (g reducing sugars)/(g dry cells-h), and the specific cell death rate was 0.016 h(-1). PMID- 19775888 TI - Bulk density determination as a simple and complementary tool in composting process control. AB - Ten composting facilities (CF) treating source-sorted organic fraction of municipal solid waste (OF) were sampled to study the relationship between the bulk density and the composting process (CP) development. Hundred and fourteen samples from different stages of the CP were considered (organic fraction, initial mixture, final decomposition, final maturation and compost), including the reject materials coming from the densimetric table at postprocessing. Total organic matter (TOM), moisture content (MC), wet bulk density and dry basis (BDd) were determined. Significant differences were detected for MC, TOM and BDd between some stages of the CP. The BDd increased along the CP while TOM decreased. Correlation studies showed a significant negative relationship between TOM and bulk density, especially BDd, during the CP, as a result of the biological activity. Moreover, a clear relationship was also found between TOM and BDd in samples related to reject materials. The results indicate that bulk density could be a simple and useful tool to evaluate the CP, in addition to the others parameters commonly used. At the same time, BDd could be an easy way to infer TOM lost within rejects. PMID- 19775889 TI - Pretreatment of spruce and oak by N-methylmorpholine-N-oxide (NMMO) for efficient conversion of their cellulose to ethanol. AB - Pretreatment of softwood spruce and hardwood oak with an industrial cellulose solvent, N-methylmorpholine-N-oxide (NMMO), was investigated prior to enzymatic hydrolysis and fermentation to ethanol. The pretreatments were carried out at 90, 110 and 130 degrees C for 1-3 h with 85% NMMO solution, followed by non isothermal simultaneous saccharification and fermentation (NSSF). This NSSF included hydrolysis with cellulase and beta-glucosidase for 24 h at 45 degrees C, followed by continuous saccharification and fermentation with Saccharomyces cerevisiae at 37 degrees C for 3 days. The NSSF of untreated oak and spruce resulted in 18.6% and 6.8% ethanol compared to the maximum theoretical yield. However, the pretreatment of oak and spruce at 130 degrees C resulted in almost total conversion of cellulose to ethanol and improved ethanol yield up to 85.4% and 89%, respectively. These numbers are comparable with ethanol from pure glucose with the same strain, which yielded between 84% and 90% of the theoretical ethanol yield. PMID- 19775891 TI - 2-Oxoglutarate analogue inhibitors of prolyl hydroxylase domain 2. AB - Analogues of the 2-oxoglutarate cosubstrate of the human oxygen sensing enzyme prolyl hydroxylase domain 2 (PHD2) with variations in the potential iron chelating group were screened as inhibitors and for binding (using non-denaturing electrospray ionization mass spectrometry) to PHD2. PMID- 19775890 TI - A naturally occurring brominated furanone covalently modifies and inactivates LuxS. AB - Halogenated furanones, a group of natural products initially isolated from marine red algae, are known to inhibit bacterial biofilm formation, swarming, and quorum sensing. However, their molecular targets and the precise mode of action remain elusive. Herein, we show that a naturally occurring brominated furanone covalently modifies and inactivates LuxS (S-ribosylhomocysteine lyase, EC 4.4.1.21), the enzyme which produces autoinducer-2 (AI-2). PMID- 19775892 TI - Visual contribution to postural stability: Interaction between target fixation or tracking and static or dynamic large-field stimulus. AB - Stationary visual information has a stabilizing effect on posture, whereas moving visual information is destabilizing. We compared the influence of a stationary or moving fixation point to the influence of stationary or moving large-field stimulation, as well as the interaction between a fixation point and a large field stimulus. We recorded body sway in 20 healthy subjects who were fixating a stationary or oscillating dot (vertical or horizontal motion, 1/3 Hz, +/-12 degrees amplitude, distance 96 cm). In addition, a large-field random dot pattern (extension: approximately 80 x 70 degrees) was stationary, moving or absent. Visual fixation of a stationary dot in darkness did not reduce antero-posterior (AP) sway compared to the situation in total darkness, but slightly reduced lateral sway at frequencies below 0.5 Hz. In contrast, fixating a stationary dot on a stationary large-field pattern reduced both AP and lateral body sway at all frequencies (0.1-2 Hz). Ocular tracking of the oscillating dot caused a peak in body sway at 1/3 Hz, i.e. the stimulus frequency, but there was no influence of large-field stimulus at this frequency. A stationary large-field pattern, however, reduced AP and lateral sway at frequencies between 0.1 and 2 Hz when subjects tracked a moving dot, compared to tracking in darkness. Our results demonstrate that a stationary large-field pattern has a stabilizing effect in all conditions, independent of whether the eyes are fixing on a stationary target or tracking a moving target. PMID- 19775893 TI - Reproducibility of fascicle length and pennation angle of gastrocnemius medialis in human gait in vivo. AB - The purpose of the current study was to examine the reproducibility of fascicle length and pennation angle of gastrocnemius medialis while human walking. To the best of our knowledge, this is the first study of the reproducibility of fascicle length and pennation angle of gastrocnemius medialis in vivo during human gait. Twelve males performed 10 gait trials on a treadmill, in 2 separate days. B-mode ultrasonography, with the ultrasound probe firmly adjusted in the transverse and frontal planes using a special cast, was used to measure the fascicle length and the pennation angle of the gastrocnemius medialis (GM). A Vicon 624 system with three cameras operating at 120 Hz was also used to record the ankle and knee joint angles. The results showed that measurements of fascicle length and pennation angle showed high reproducibility during the gait cycle, both within the same day and between different days. Moreover, the root mean square differences between the repeated waveforms of both variables were very small, compared with their ranges (fascicle length: RMS= approximately 3mm, range: 38-63 mm; pennation angle: RMS= approximately 1.5 degrees, range: 22-32 degrees). However, their reproducibility was lower compared to the joint angles. It was found that representative data have to be derived by a wide number of gait trials (fascicle length approximately six trials, pennation angle more than 10 trials), to assure the reliability of the fascicle length and pennation angle in human gait. PMID- 19775894 TI - Repeatability and sources of variability in multi-center assessment of segmental foot kinematics in normal adults. AB - Multi-site application of biomechanical models can be a powerful tool as quantitative methods are employed to improve clinical care and to assess larger populations for research purposes. However, the use of such models depends on adequate validation to assure reliability in inter-site measures. We assessed repeatability and sources of variability associated with the assessment of segmental foot kinematics using the Milwaukee Foot Model during multiple testing sessions at two sites. Six healthy ambulators were instrumented and tested during comfortable ambulation; data were analyzed with variance components analysis using a mixed effects linear model. Results indicated that the largest source of variability was inter-subject; measurement error associated with Site and Session fell below 3.5 degrees in over 80% of position measurements and below 2.5 degrees in over 80% of ROM measurements. These findings support the continued use of the segmental foot model at multiple sites for clinical and research purposes. PMID- 19775895 TI - Hepatoprotective amide constituents from the fruit of Piper chaba: Structural requirements, mode of action, and new amides. AB - The 80% aqueous acetone extract from the fruit of Piper chaba (Piperaceae) was found to have hepatoprotective effects on D-galactosamine (D GalN)/lipopolysaccharide-induced liver injury in mice. From the ethyl acetate soluble fraction, three new amides, piperchabamides E, G, and H, 33 amides, and four aromatic constituents were isolated. Among the isolates, several amide constituents inhibited D-GalN/tumor necrosis factor-alpha (TNF-alpha)-induced death of hepatocytes, and the following structural requirements were suggested: (i) the amide moiety is essential for potent activity; and (ii) the 1,9-decadiene structure between the benzene ring and the amide moiety tended to enhance the activity. Moreover, a principal constituent, piperine, exhibited strong in vivo hepatoprotective effects at doses of 5 and 10 mg/kg, po and its mode of action was suggested to depend on the reduced sensitivity of hepatocytes to TNF-alpha. PMID- 19775896 TI - Pochonicine, a polyhydroxylated pyrrolizidine alkaloid from fungus Pochonia suchlasporia var. suchlasporia TAMA 87 as a potent beta-N-acetylglucosaminidase inhibitor. AB - A new polyhydroxylated pyrrolizidine alkaloid designated as pochonicine (1) was isolated from a solid fermentation culture of the fungal strain Pochonia suchlasporia var. suchlasporia TAMA 87. The structure of 1 was determined using NMR and MS techniques as (1R*, 3S*, 5S*, 6S*, 7R*, 7a S*)-5-acetamidomethyl-3 hydroxymethyl-1,6,7-trihydroxypyrrolizidine. Pochonicine (1) showed potent inhibition against beta-N-acetylglucosaminidases (GlcNAcases) of various organisms including insects, fungi, mammals, and a plant but no inhibition against beta-glucosidase of almond, alpha-glucosidase of yeast, or chitinase of Bacillus sp. The GlcNAcase inhibitory activity of pochonicine (1) was comparable to nagstatin, a potent GlcNAcase inhibitor of natural origin. PMID- 19775897 TI - Production of the therapeutic radioisotope (114m)In through the (116)Cd(p,3n)(114m)In reaction. AB - Excitation curves for reactions induced by proton beams up to 36MeV on highly enriched (116)Cd targets were assessed. The standard stacked foil method, with monitoring of beam parameters over the whole energy region, and high resolution gamma spectrometry were used. We report cross sections for reactions leading to (113m)(,114m,115m,116m1)In and (115)Cd. A comparison with some earlier experimental data and with results of theoretical model codes ALICE-IPPE and EMPIRE are presented. Our previous estimation of use of the (116)Cd(p,3n) reaction for production of (114m)In is confirmed. PMID- 19775898 TI - Long term comparison of methods to sustain energy calibration in low level gamma ray spectroscopy and investigation of possible sources for drift. AB - Two methods to compensate the gain drift of low level gamma-ray spectrometers are compared. For a period of 4 years, source injection and pulser method have been applied in parallel. The long term stability of a reference peak, injected by a precision pulser, has been validated by periodical source injection to sustain the energy calibration. The pros and cons of both methods and the advantage of active vs. passive energy calibration are discussed. The main cause for gain drift and the critical components have been identified. PMID- 19775899 TI - Characteristics of a new polymer gel for high-dose gradient dosimetry using a micro optical CT scanner. AB - The properties of a new polymer gel with two sensitivities, made specifically for high-dose-gradient dosimetry, were investigated. The measurements were performed at NIST using a 1cmx1cm calibrated (60)Co field, and a 1cm active diameter (90)Sr/(90)Y beta particle source. A high-resolution laser CT scanner was used to quantify the response. The results show that the high-sensitivity gel responds linearly to the absorbed dose for doses from 0.5 up to 15Gy, while the low sensitivity one is linear up to 225Gy. For both radiation types, the gel response remains stable in time up to a month after the irradiation. The response of the gel was found to have no dose rate dependence for dose rates ranging from 3.7 to 15mGy/s. Within the measurement uncertainty, the gel response is more sensitive for beta particles than high energy photons. PMID- 19775900 TI - Proteomic evaluation of coffee zygotic embryos in two different stages of seed development. AB - Coffee seed development is accompanied by severe modifications in water soluble proteins, several of these being associated to a specific developmental stage. For this reason, a proteomic approach has been used to describe spatial-temporal proteome modifications in zygotic embryos at different stages of seed development. Embryos from Coffea arabica seeds were harvested in two different developmental stages: stage 1 at 210 days after anthesis and stage 2 at 255 days. Total proteins were extracted and submitted to 2-DE. From these gels, several spots were identified by mass spectrometry including kinases, MYB transcription factor and enzymes involved in metabolic pathways. All proteins identified seem to affect coffee development in different ways, being directly involved in plant growth or used as an intermediate in some metabolic pathway that, indirectly, will influence coffee development. This is the first work using two-dimensional electrophoresis followed by mass spectrometry analyses that evaluates the expression of proteins during coffee zygotic embryos development. Data here reported supply some light over coffee development and could be used in a near future to improve coffee plants' growth and development by molecular strategies. PMID- 19775901 TI - Impact of neo-adjuvant radiochemotherapy on bronchial tissue viability. AB - OBJECTIVE: In the treatment of advanced stages of lung cancer, increasingly more multimodality approaches applying radiotherapy and/or chemotherapy in a neo adjuvant setting are being introduced. The impact of induction therapy, especially radiotherapy, on bronchial tissue viability has not been investigated so far. METHODS: In 2008, we determined the tissue viability of bronchial segments obtained during surgery in 45 consecutive patients, including patients after neo-adjuvant radiochemotherapy (RCTX). Bronchial tissue viability was analysed by histology, life-dead assay and cell proliferation in tissue-specific culture media. Biomedical findings were compared with the clinical course of the patients. RESULTS: Tissue samples of 44 patients were included into this study. Fourteen patients (32%) had undergone neo-adjuvant RCTX. Histology and life-dead assay of the bronchial segments did not show significant differences. While patient age, sex, tumour entity and site of resection had no influence on cell proliferation in vitro, previous RCTX resulted in a 46% decrease of bronchial tissue viability (P=0.01). However, this effect was not reflected by the clinical course of the operated patients. CONCLUSIONS: Neo-adjuvant RCTX reduces bronchial tissue viability substantially. However, this impairment does not necessarily translate into an increased rate of postoperative bronchial insufficiencies. Standard histological work-up is not sensitive enough to characterise changes in bronchial tissue viability following RCTX. PMID- 19775902 TI - Prescribing statins in aortic stenosis: little to lose, much to gain. PMID- 19775903 TI - The EuroSCORE - 10 years later. Time to change? PMID- 19775904 TI - Transcatheter aortic valve prosthesis surgically replaced 4 months after implantation. AB - Transcatheter aortic valve implantation is a new and rapidly evolving treatment option for high-risk surgical patients with degenerative aortic valve stenosis. Long-term results with these new valve prostheses are lacking, and potential valve dysfunction and failure would require valve replacement. We report the first case of surgical valve replacement in a patient with a dysfunctional transcatheter-implanted aortic valve prosthesis 4 months after implantation. PMID- 19775905 TI - Results of a simple exercise test performed routinely to predict postoperative morbidity after anatomical lung resection. AB - BACKGROUND AND OBJECTIVE: Exercise tests are considered the most reliable ones for the preoperative workup of lung resection candidates but frequently are indicated only in cases with low predicted postoperative forced expiratory volume in 1s (FEV1) and carbon monoxide diffusing capacity (DLCO). The aim of this investigation is to evaluate if a simple, standardised incremental bicycle exercise test routinely performed in patients considered operable is predictive of postoperative cardio-respiratory complication and if its performance is comparable to a logistic regression model including frequently cited clinical predictive variables. METHODS: A series of 103 lung resection candidates were included in a prospective observational study. All patients underwent a standardised, incremental exercise test on a bicycle up to exhaustion. The analysed outcome was the occurrence of postoperative cardio-respiratory complications prospectively recorded and codified. The correlation of distance reached at the end of the test and the outcome was estimated by non-parametric tests. A logistic regression model including age, BMI, predicted postoperative (ppoFEV1%) and predicted postoperative DLCO (ppoDLCO) was adjusted and the individual probability of complication calculated and set as a new variable. Finally, two receiver operating characteristic (ROC) curves were constructed and compared: one with distance at the exercise test and the other with logistic regression probability of complication. RESULTS: Mortality of the series was nil. Outcome prevalence was 14%. Distance reached at the end of the exercise test was lower in cases with a positive outcome (3498.6m vs 4543.5m, p=0.001). On logistic regression analysis, age of the patient (p=0.016) and ppoDLCO (p=0.000) were predictive for the outcome. On ROC analysis, C-indices were 0.77 (distance) and 0.78 (logistic model, p=0.95). CONCLUSION: Reached distance in a simple standardised exercise test is related to postoperative morbidity after lung resection; and the accuracy of prediction using this variable alone is comparable to a logistic regression model including age and ppoDLCO. PMID- 19775906 TI - Recurrent sternal infection following treatment with negative pressure wound therapy and titanium transverse plate fixation. AB - OBJECTIVE: To provide a definition for recurrent sternal infection (RSI), analyse the risk factors and describe the management of this complication following treatment of deep sternal wound infection (DSWI) with horizontal titanium sternal osteosynthesis and coverage with pectoralis major myocutaneous flaps. METHODS: Between 2002 and 2007, 10665 patients were submitted to open-heart surgery (OHS) in our institution, of whom 149 (1.4%) developed a DSWI. Negative pressure wound therapy (NPWT) followed by sternal osteosynthesis with musculocutaneous coverage was used in 92 (61.7%) patients. A retrospective review was done using a prospectively maintained database to identify risk factors for recurrent infection in this group of patients. RESULTS: Of the 92 patients who underwent sternal osteosynthesis, nine (9.8%) developed recurrent sternal infection requiring hardware removal. Univariate analysis showed that preoperative methicillin-resistant Staphylococcus aureus (MRSA) status (33.3% vs 6.1%; p=0.03) and prolonged intubation time in ICU (44.4% vs 14.6%; p<0.05) were significant risk factors. Two-thirds of these patients were also found to be infected with the same germ as the one responsible for their initial DSWI. No death was reported and sternal integrity was preserved in all patients despite plate removal. CONCLUSIONS: To lower the rate of RSI in patients treated with transverse sternal ostheosynthesis along with myocutaneous coverage for DSWI, surgeons must consider the MRSA preoperative status as a significant predictor of RSI and/or persistent infection. Chest-wall integrity in patients with RSI can be maintained after hardware removal, even after only a few weeks following initial plating. PMID- 19775908 TI - Reduction of chemical noise in electrospray ionization mass spectrometry by supplemental IR activation. AB - Supplemental infrared (IR) activation was applied to reduce background chemical noise and increase analyte ion signal in a linear ion trap mass spectrometer. Peptides, proteins, and small molecules were all introduced by electrospray ionization, and when regions of chemical noise were isolated and subjected to IR irradiation, protonated analyte molecules were observed in the product ion mass spectra. By isolating the entire mass range (e.g., m/z 400-2000) and then irradiating all ions in the trap, supplemental IR activation increased the signal of singly protonated peptides by almost 70% and by 40%-55% for the lower charge states of cytochrome c. This increase in analyte ion signal was less dramatic for the higher charge states of peptides and proteins. The chemical noise present in the mass spectra is attributed to incomplete desolvation of the electrospray, as the abundance of the protonated peptides observed upon supplemental IR activation of the chemical noise decreased with higher inlet capillary temperatures. Collision activation was not as effective for desolvating the ions present in the chemical noise. PMID- 19775909 TI - Synchronized dual-polarity electrospray ionization mass spectrometry. AB - This work describes the synchronized dual-polarity (DP) electrospray ionization (ESI) method and demonstrates the first DP ESI mass spectra obtained using two mass spectrometers. Stable double Taylor cones were produced by applying two counter electric voltages with opposite polarities to one electrosprayer. The development of double Taylor cones required higher extraction voltages than conventional ESI, but DP ESI worked effectively at liquid flow rate range three times wider than conventional ESI. Using pure methanol, the emission currents of the two cones were neutralized and no current was drawn from the sprayer. Synchronized DP mass spectra were obtained using electrospray calibrants dissolved in methanol solution of low water content. For bovine insulin with conventional electrospray solution, the gas-assisted electrospray delivered satisfactory sensitivity and stability for routine mass analyses. PMID- 19775907 TI - Toll-like receptor signaling in cell proliferation and survival. AB - Toll-like receptors (TLRs) are important sensors of foreign microbial components as well as products of damaged or inflamed self tissues. Upon sensing these molecules, TLRs initiate a series of downstream signaling events that drive cellular responses including the production of cytokines, chemokines, and other inflammatory mediators. This outcome results from the intracellular assembly of protein complexes that drive phosphorylation and other signaling cascades ultimately leading to chromatin remodeling and transcription factor activation. In addition to driving inflammatory responses, TLRs also regulate cell proliferation and survival which serves to expand useful immune cells and integrate inflammatory responses and tissue repair processes. In this context, central TLR signaling molecules, such as the mitogen-activated protein kinases (MAPK) and phosphoinositide 3-kinase (PI3K), play key roles. In addition, four major groups of transcription factors which are targets of TLR activation also control cell fate. This review focuses on the role of TLR signaling as it relates to cell proliferation and survival. This topic not only has important implications for understanding host defense and tissue repair, but also cancer which is often associated with conditions of chronic inflammation. PMID- 19775910 TI - Genetics and pathogenesis of multiple sclerosis. AB - Multiple sclerosis (MS) is an idiopathic autoimmune neurodegenerative disease. Like many common diseases, MS has a genetic component; however, as with most complex diseases, the genetic architecture may be influenced by heterogeneity, incomplete penetrance, polygenic inheritance, and environmental factors. This clinically complex disease has provided great challenges for geneticists over the years. Although the first consistent genetic association to MS (with HLA-DR*1501) was discovered more than 30 years ago, lack of consistently replicated genetic results has plagued the scientific community. New study design methods (particularly genome-wide associations studies [GWAS]) along with genome project data and larger datasets have allowed several additional MS genes to be identified and consistently replicated. Thus, after many years of frustration, the strong genetic component associated with MS is finally beginning to be characterized. PMID- 19775911 TI - Goals of stability evaluation throughout the vaccine life cycle. AB - Stability studies play a critical role in assuring product quality at all points in the vaccine life cycle. At and after licensure, stability studies on quality attributes (including potency) provide a critical link between marketed and clinically evaluated vaccine product, addressing important regulatory concerns by assuring that product quality is maintained throughout the dating period. During development, stability studies are done to assure product quality and to obtain the data needed to support licensure. Stability studies may also be performed after licensure to assure that product continues to perform as it did pre licensure, as well as to evaluate the effect on product quality of deliberately introduced manufacturing changes. At each phase in the product life cycle, it is important to consider the goals of stability evaluation and to perform appropriate statistical analyses in order to assure and reach appropriate conclusions about product quality. PMID- 19775913 TI - Approach run increases preactivation and eccentric phases muscle activity during drop jumps from different drop heights. AB - The purpose of this study was to investigate the effects of a horizontal approach run and drop height on the activation of lower extremity muscles during drop jumps. Ten participants performed drop jumps from drop heights of 15, 30, 45 and 60cm with zero (standing), one, two, and three approach run steps. The EMG activities of the Gluteus Maximus (GM), Rectus Femoris (RF), Biceps Femoris (BF), Vastus Lateralis (VL), Tibialis Anterior (TA), Gastrocnemius (GA) and Soleus (SO) were recorded, full-wave rectified, and averaged (aEMG) during the preactivation (50ms before touchdown), downward, and push-off phases. Increasing drop height did not enhance the muscle activation level of any examined muscles except GA. During the preactivation phase, the aEMG of all muscles except TA increased with the number of approach run steps. The aEMG of RF, BF, VL, and SO also increased with the number of approach run steps during the downward phase, while no aEMG changes were observed during the push-off phase. These results suggest that a horizontal approach run preceding the drop jump is an effective strategy for increasing the muscle preactivation level, which contributes to a higher level of muscle activity during the eccentric contraction phase and could potentially contribute to the reported higher power output during the concentric contraction phase. PMID- 19775912 TI - Repeat mammography screening among unmarried women with and without a disability. AB - OBJECTIVES: Unmarried women with disabilities may be a particularly vulnerable group for underutilization of repeat mammography screening. Our goal was to compare the breast cancer screening experiences of unmarried women with disabilities (WWD) versus women with no disabilities (WND), and determine whether these experiences are associated with adherence to repeat screening. METHODS: We conducted a matched cohort study of 93 WWD and 93 WND to compare mammography experiences by disability status, examine rates of repeat mammography by disability status, and identify factors that are associated with repeat mammography. RESULTS: WWD were less likely to be on-schedule than WND in univariable (54.8% vs. 71.0%; relative risk, 0.77; 95% confidence limits, 0.61, 0.97), but not multivariable, analyses. In multivariable analyses, there was a significant interaction between disability status and positive experiences as the reasons for returning to the same mammography facility. Among WND, repeat screening ranged from 59% to 86%, depending on the number of positive experiences endorsed (range, 1-5). In contrast, among WWD, screening rates were only 37% among those who did not report any positive experiences and increased to a maximum of 60% regardless of whether women endorsed one to four or all five positive experiences. Severity and type of disability were not associated with repeat screening. CONCLUSION: WWD may be less likely than WND to remain on schedule for mammography. WWD who do not report any positive experiences as reasons for returning to a mammography facility may be at particularly high risk of underutilization of screening. PMID- 19775914 TI - Intracranial EEG power spectra and phase synchrony during consciousness and unconsciousness. AB - Power density spectra and phase synchrony measurements were taken from intracranial electrode grids implanted in epileptic subjects. Comparisons were made between data from the waking state and from the period of unconsciousness immediately following a generalised tonic-clonic seizure. Power spectra in the waking state resembled coloured noise. Power spectra in the unconscious state resembled coloured noise from 1 to about 5 Hz, but at higher frequencies changed in two out of three subjects to resemble white noise. This boosted unconscious gamma power to a higher level than conscious gamma power. For both gamma and beta passbands, synchrony measurements showed more widespread phase synchrony in the unconscious than the conscious state. We conclude that neither gamma activity per se nor phase synchrony per se are neural correlates of consciousness. PMID- 19775915 TI - The metamorphosis of myocardial infarction following coronary recanalization. AB - The "metamorphosis" of acute myocardial infarction (AMI) in terms of pathological features and complications in the reperfusion era is herein discussed. Typically, the AMI following coronary artery recanalization is characterized by frequent subendocardial location, since a prompt coronary lumen recanalization is able to prevent the transmural progression of myocardial necrosis from the endocardium towards the epicardium. Transmural AMI may develop when recanalization occurs late (>6 hours) or is not effective (persistent coronary occlusion). Moreover, reperfused AMI frequently appears reddish because of interstitial haemorrhage, which is thought to be caused by vascular cell damage with leakage of blood out of the injured vessels. Hemorrhage occurs always within the area of necrosis and it is significantly related to the infarct size and to the coronary occlusion time. At histology, typical features of reperfused AMI consist of contraction band necrosis and interstitial hemorrhage. Moreover, a more pronounced inflammatory cellular response is visible within the necrotic area when comparing reperfused with non-reperfused AMI. Reperfusion after prolonged coronary occlusion is also associated with secondary impairment of microcirculatory flow ("no-reflow" phenomenon), that is due to endothelial swelling, luminal obstruction and external compression but may also be aggravated by distal embolization. Finally, the reperfused AMI with its typical subendocardial, non transmural location, is characterized by a lower incidence of expansive remodelling and related complications, in terms of cardiogenic shock, myocardial rupture, aneurysm and pseudoaneurysm formation and thromboembolism. Moreover, pericardial involvement is a rare occurrence. Unfavorable mechanical consequences of intramyocardial haemorrhage could consist in increased myocardial stiffness, propensity to wall rupture and delayed healing process. However, prospective in vivo large-scale studies in patients with reperfused AMI are needed to assess the prognostic value of hemorrhagic AMI in terms of morbidity and mortality. The knowledge and correct interpretation of these findings at post-mortem by the general and forensic pathologists is of great importance, to provide useful information to the clinicians. PMID- 19775916 TI - Myocardial infarction: a paradigm of success in modern medicine. AB - Hospital mortality for acute myocardial infarction declined from 30% to 10% in the last 30 years, thanks to coronary care units and early revascularization with thrombolysis, angioplasty, and stent implantation. Pathologists played a major role by establishing plaque rupture and coronary thrombosis as the major cause of acute myocardial infarction and by discovering that ischemic myocardium necrosis progresses from endocardium to epicardium as a "wave front" phenomenon, with potential reversible injury if the reperfusion is accomplished within 3 h. Long term mortality following myocardial infarction is mostly due to sudden electrical death, which may be prevented by pharmacologic (antiarrhythmic drugs) and nonpharmacologic (implantable cardioverter defibrillator, pacemaker) therapy. Ventricular assist devices may support the left ventricle as a bridge to transplantation. Long-term mortality at distance from acute myocardial infarction declined from 10% to 2% per year. Despite these indisputable achievements, there are still pending questions: in vivo identification of vulnerable plaque, mechanisms of thrombosis by plaque erosion, prompt treatment on the spot of instantaneous cardiac arrest by external defibrillation, adverse effect of myocardial reperfusion, fate of bare- and drug-eluting coronary stents. With these limitations and challenges well in mind, nowadays myocardial infarction does not represent a nightmare as it was in the past. The achievements in its prevention, diagnosis, and treatment should be considered as a pride of cardiovascular medicine. PMID- 19775917 TI - Exercise in patients with intermittent claudication elicits signs of inflammation and angiogenesis. AB - OBJECTIVES: Previous studies have demonstrated elevation of systemic levels of inflammatory cytokines after treadmill exercise in patients with intermittent claudication (IC), but it is unknown if growth factor expression also is stimulated. The aim of this study was to assess whether physical exercise-induced ischemia elicits an inflammatory response and increase in local and systemic vascular growth factor expression in patients with IC. METHODS: Nineteen patients with IC had plasma concentrations of inflammatory markers (IL-6, TNF-alpha, hs CRP) and vascular growth factors (VEGF and FGF-2) measured before and at four time points after a treadmill exercise test. In 10 patients a gastrocnemius muscle biopsy was obtained to measure VEGF and FGF-2 mRNA. Plasma concentrations of vWF were also measured. Five patients who underwent the treadmill test without experiencing calf pain were enrolled as controls. RESULTS: Plasma concentrations of IL-6 increased after exercise (p=0.004), while TNF-alpha and hs-CRP were unchanged (p=0.191 and p=0.709, respectively). Plasma concentrations of VEGF were similar (p=0.151) at the different time points after exercise but FGF-2 levels decreased (p=0.013). In biopsies after treadmill testing VEGF-A mRNA was increased (p=0.043), but no change was observed for FGF-2 (p=0.456). CONCLUSION: Exercise in IC triggers an inflammatory response as exemplified by elevated concentrations of IL-6. After exercise-induced pain, VEGF mRNA in calf muscle is increased. Therefore, it is plausible that angiogenesis is stimulated by exercise in IC. PMID- 19775918 TI - The Anaconda AAA stent graft system: 2-year clinical and technical results of a multicentre clinical evaluation. AB - INTRODUCTION: This study reports the technical and mid-term clinical results of the second-generation Anaconda AAA Stent Graft System endovascular device for treatment of abdominal aortic aneurysm (AAA). The design of the Anaconda AAA Stent Graft System is characterised by a three-piece system consisting of two proximal independent saddle-shaped nitinol self-expandable rings with hooks fixation, zero body support and vacuum-cleaner tube leg design. METHODS: From July 2002 to April 2005, a total of 61 patients with AAA were enrolled in a multicentre, prospective, non-randomised controlled design study. All patients received a second-generation Anaconda AAA Stent Graft System. They entered a standard follow-up protocol at discharge for 3, 6, 12 and 24 months. Follow-up data included survival; rupture-free survival; incidence of aneurysm rupture, death from aneurysm rupture, aneurysm-related death; freedom from aneurysm expansion; freedom from Types I and III endoleaks; endograft patency and technical and clinical success rates. RESULTS: Successful access to the arterial system was achieved in all patients. The primary technical success was 59 out of 61 and the primary assisted technical success was 60 out of 61. All endovascular grafts were patent without significant twists, kinks or obstructions. Migration was not observed in any of the grafts. During the first 30-day period, two serious adverse events (3%), both not related to the procedure, were observed. Nine patients (15%) needed a secondary intervention; two of these interventions were related to stent graft (3%). The mean aneurysm sac diameter decreased significantly from 57 mm pre-operative to 45mm after 24 months, without aneurysm growth. There was one Type I endoleak at initial implantation, which was corrected using a proximal extension cuff. In total, three Type II endoleaks were still present after 24 months without any signs of aneurysm growth. CONCLUSION: The design features of the second-generation Anaconda AAA Stent Graft System are effective in the treatment of AAAs on mid-term evaluation. PMID- 19775919 TI - Patient preference for surgical method of abdominal aortic aneurysm repair: postal survey. AB - OBJECTIVES: To determine whether men with small abdominal aortic aneurysm have a preference between either endovascular or open aneurysm repair for future treatment. DESIGN: Prospective study of self-declared treatment preference following receipt of a validated patient information pack. PARTICIPANTS: Men aged 65-84 years (n=237) with asymptomatic aneurysm (4.0-5.4 cm) detected by population-based screening. METHODS: An unbiased, validated patient information pack and questionnaire were developed to conduct a postal survey. RESULTS: One hundred sixty seven participants (70%) returned a completed questionnaire; 24 (10%) did not respond at all. Initially, only 38 (23%) declared a treatment preference. After reading the information pack, 130 participants (80%) declared a treatment preference: 30 preferred open repair (18%), 77 endovascular repair (46%), 23 were happy with either option (14%) and only 34 remained without any preference (20%). Nearly all (92%) thought that the information pack had prepared them well for future discussions with clinicians and with no single feature identified as influencing the preference-making process, 66 respondents (40%) still opted to 'take the advice of the doctor'. CONCLUSION: The patient information pack facilitated the development of treatment preferences with endovascular repair being preferred to open repair. Nevertheless for patient centred care, vascular centres must continue to safely provide both open and endovascular repair. PMID- 19775920 TI - Dual-energy X-ray absorptiometry and evaluation of the osteoporosis self assessment tool in men with rheumatoid arthritis. AB - Males with rheumatoid arthritis (RA) are at risk for osteoporosis but infrequently undergo dual-energy X-ray absorptiometry (DXA). We examined the frequency of DXA in males enrolled in the Veterans Affairs Rheumatoid Arthritis Registry. The Osteoporosis Self-Assessment Tool (OST) index, a formula using age and weight, was calculated for all subjects. DXA was performed on 282 (35.5%) of the males who were younger (p < 0.01), had lower mean OST index score (p < 0.05), and were more likely to have been prescribed prednisone (p < 0.01) than subjects without DXA. Low bone mass (T-score < -1) was present in 73% of subjects with DXA; 37% of subjects with low-risk OST index scores had normal bone mineral density (BMD) compared with 5.6% of those with high-risk OST index scores (p < 0.01). There was a significant but modest correlation between BMD and the OST index (r = 0.17, p < 0.01). No OST score had a sensitivity and specificity of more than 80%. Association between OST index and BMD was strongest in non Hispanic whites, subjects older than 60 yr, and smokers. DXA was underutilized in males with RA. The OST index correlated with low bone mass but could not reliably predict osteoporosis in this population. PMID- 19775922 TI - [Influence of management models on the quality of professional life of the personal carer in old people's homes in Albacete (Spain)]. AB - OBJECTIVE: Determine if there is any relationship between different management models (public, private, mixed and English) and the quality of professional life (QPL) of the nursing staff. METHOD: A cross-sectional descriptive among the geriatric nursing staff (n=389) from the 7 geriatric homes in the city of Albacete. Using a questionnaire which included sociodemographic variables, along with a validated scale (QPL -35.), which measures quality of professional life using 35 questions (1 to 10 scale, from lower to higher degree). RESULTS: With a response rate of 66.33%, the QPL average value was 4.98 (standard deviation [SD]=2.32). Perception of "workload" achieved 5.89 (SD=1.59), "intrinsic motivation" 8.07 (SD=1.46) and "management support" 4.55 (SD=1.70.). The QPL is positively related to variables such as "management support" and "intrinsic motivation" and negatively with "workload". There are no statistically significant differences, with the work and social variables. Comparing management models, there were slightly significant differences between workload in private models than mixed ones (6.95/8.37), intrinsic motivation has lower results in private than mixed (6.95/8.37) and English (6.95/8.56). Management support is lower in mixed than English (4,20/5,03) and private (4,20/5,11). CONCLUSIONS: The QPL of our professionals is low-medium. Our data could show the need of a cultural management change based on participation and motivation, being necessary to increase the level of management support to reinforce intrinsic motivation, in order to help resolve conflicts. PMID- 19775923 TI - OARSI recommendations on knee and hip osteoarthritis: use with discernment. PMID- 19775921 TI - Cross-reactive immunologic material status affects treatment outcomes in Pompe disease infants. AB - Deficiency of acid alpha glucosidase (GAA) causes Pompe disease, which is usually fatal if onset occurs in infancy. Patients synthesize a non-functional form of GAA or are unable to form native enzyme. Enzyme replacement therapy with recombinant human GAA (rhGAA) prolongs survival in infantile Pompe patients but may be less effective in cross-reactive immunologic material (CRIM)-negative patients. We retrospectively analyzed the influence of CRIM status on outcome in 21 CRIM-positive and 11 CRIM-negative infantile Pompe patients receiving rhGAA. Patients were from the clinical setting and from clinical trials of rhGAA, were 6 months of age, were not invasively ventilated, and were treated with IV rhGAA at a cumulative or total dose of 20 or 40 mg/kg/2 weeks. Outcome measures included survival, invasive ventilator-free survival, cardiac status, gross motor development, development of antibodies to rhGAA, and levels of urinary Glc(4). Following 52 weeks of treatment, 6/11 (54.5%) CRIM-negative and 1/21 (4.8%) CRIM positive patients were deceased or invasively ventilated (p<0.0001). By age 27.1 months, all CRIM-negative patients and 4/21 (19.0%) CRIM-positive patients were deceased or invasively ventilated. Cardiac function and gross motor development improved significantly more in the CRIM-positive group. IgG antibodies to rhGAA developed earlier and serotiters were higher and more sustained in the CRIM negative group. CRIM-negative status predicted reduced overall survival and invasive ventilator-free survival and poorer clinical outcomes in infants with Pompe disease treated with rhGAA. The effect of CRIM status on outcome appears to be mediated by antibody responses to the exogenous protein. PMID- 19775924 TI - Long-term effects of therapeutic education for patients with rheumatoid arthritis. AB - INTRODUCTION: The objective of this study was to assess the effects of an educational program on the course of rheumatoid arthritis (RA) after 3 years. METHODS: From December 2002 to December 2003, 39 RA patients participated in a 3 day education program delivered to groups of four or five patients. Effects of the program were evaluated after 3 years in 33 patients, comparatively to baseline, based on the following variables: knowledge of RA (self-questionnaire), disease activity (DAS 28), functional impairment (health assessment questionnaire [HAQ]) and quality of life (arthritis impact measurement scale 2 [AIMS2], short form). We also compared patient knowledge in the educational program participants and in 38 controls with RA. Direct questions were used to evaluate the program after 3 years. RESULTS: Patient knowledge 3 years after the education program was significantly improved compared to baseline (P<0.0001) and was significantly better than in the controls (P<0.0001). Disease activity was significantly lower in the education group after 3 years than at baseline (DAS28, 3.1 vs. 3.8, P<0.005). Neither the HAQ nor the AIMS2 scores changed significantly after 3 years compared to baseline. The replies to the direct questions indicated a very high level of overall satisfaction with the educational program. CONCLUSION: An educational program tailored to patient needs can produce lasting improvements in knowledge of the disease and may help to control the activity of RA. These results warrant the development of education programs for patients with chronic inflammatory joint disease. PMID- 19775925 TI - Ultrasonic degradation of poly(methyl methacrylate-co-alkyl acrylate) copolymers. AB - The copolymers, poly(methyl methacrylate-co-methyl acrylate) (PMMAMA), poly(methyl methacrylate-co-ethyl acrylate) (PMMAEA) and poly(methyl methacrylate co-butyl acrylate) (PMMABA), of different compositions were synthesized and characterized. The effect of alkyl acrylate content, alkyl group substituents and solvents on the ultrasonic degradation of these copolymers was studied. A model based on continuous distribution kinetics was used to study the kinetics of degradation. The rate coefficients were obtained by fitting the experimental data with the model. The linear dependence of the rate coefficients on the logarithm of the vapor pressure of the solvent indicated that vapor pressure is the crucial parameter that controls the degradation process. The rate of degradation increases with an increase in the alkyl acrylate content. At any particular copolymer composition, the rate of degradation follows the order: PMMAMA>PMMAEA>PMMABA. It was observed that the degradation rate coefficient varies linearly with the mole percentage of the alkyl acrylate in the copolymer. PMID- 19775926 TI - Neuropsychological changes 1-year after subthalamic DBS in PD patients: A prospective controlled study. AB - OBJECTIVE: This study aimed at investigating the neuropsychological effect of DBS of the Subthalamic Nucleus in patients with advanced Parkinson's disease (PD). METHODS: A standardized neuropsychological test battery, assessing reasoning, memory and executive functions, was administered to 27 PD patients who underwent DBS-STN (DBS group) and to a matched control group of 31 PD patients under optimal medical treatment (MED group). Patients were evaluated at baseline and at the end of 1 year. RESULTS: Change score analysis (T1 minus T0 scores) demonstrated a significant decline in phonemic verbal fluency in the DBS group compared with the MED group (p < 0.005), while there were no significant changes between the two groups for the other cognitive tests. Single cases analysis by means of multivariate normative comparisons revealed that 4 out of 27 DBS patients (15%) showed cognitive deterioration one year post surgery. These patients were significantly more compromised from a motor standpoint (UPDRS, section III) than the 23 DBS PD patients who had no cognitive decline post surgery. CONCLUSION: Results of this prospective controlled-study showed that phonemic verbal fluency declined one year after DBS-STN, while the other cognitive domains did not change significantly. Nevertheless, single case analysis highlighted the fact that a subgroup comprising 15% of DBS-STN patients (4/27) showed significant cognitive decline 1 year after surgery. PMID- 19775927 TI - The socio-spatial distribution of alcohol outlets in Glasgow city. AB - AIMS: The aim of this study was to examine the distribution of alcohol outlets by area deprivation across Glasgow, Scotland. METHODS: All alcohol outlets were mapped and density per 1000 residents and proximity to nearest outlet calculated across quintiles of area deprivation. RESULTS: The socio-spatial distribution of alcohol outlets varies by deprivation across Glasgow but not systematically. Some deprived areas contain the highest concentration while others in similar deprivation quintiles contain very few. CONCLUSIONS: Considerations of the local context are important in examining access to alcohol but more research is also required on purchasing behaviour. PMID- 19775928 TI - Leisure home ownership and early death: a longitudinal study in Sweden. AB - People who perform paid work may benefit from psychological restoration afforded by a leisure home and its natural surroundings. This may hinder the development of some forms of life-threatening illness. Using longitudinal register data for 108,114 employed Swedes, we assessed the prospective association between leisure home ownership and death before age 65. Among men, but not among women, leisure home owners had lower odds of early death, after adjustment for sociodemographic and residential characteristics (OR=0.875, 95% CI=0.702-0.980). The results bear on natural environments as health resources, inform debate on urban densification, and broaden the discussion of residence and health. PMID- 19775930 TI - Directed mass spectrometry: towards hypothesis-driven proteomics. AB - To date, the vast majority of the proteomic data sets collected by mass spectrometry (MS) have been generated by nondirected methods, whereby the identified precursor ions are stochastically selected for sequencing from complex sample mixtures. Recently, new MS approaches have been developed in which the mass spectrometer is directed to select and fragment sets of precursor ions that represent the most informative peptides in a sample mixture. These directed MS methods have shown superior performance for the fast, sensitive, and highly reproducible generation of consistent data sets at low redundancy. In this manuscript we summarize recent technical advances in directed MS and discuss important applications to quantitative proteomics. PMID- 19775929 TI - Glycomics and disease markers. AB - Glycomics is the comprehensive study of all glycans expressed in biological systems. The biosynthesis of glycan relies on a number of highly competitive processes involving glycosyl transferases. Glycosylation is therefore highly sensitive to the biochemical environment and has been implicated in many diseases including cancer. Recently, interest in profiling the glycome has increased owing to the potential of glycans for disease markers. In this regard, mass spectrometry is emerging as a powerful technique for profiling the glycome. Global glycan profiling of human serum based on mass spectrometry has already led to several potentially promising markers for several types of cancer and diseases. PMID- 19775931 TI - Characterization of the interaction between 8-bromoadenosine with human serum albumin and its analytical application. AB - This study was designed to examine the interaction of 8-bromoadenosine with human serum albumin (HSA) by fluorescence spectroscopy in combination with molecular modeling under simulative physiological conditions. The results of fluorescence measurements indicate that 8-bromoadenosine has a strong ability to quench the intrinsic fluorescence of HSA through static quenching procedure. The binding constants (K) at different temperatures and thermodynamic parameters, enthalpy changes (DeltaH) and entropy changes (DeltaS) were calculated according to the fluorescence data. The results showed that the hydrophobic force played the major role in the binding of 8-bromoadenosine to HSA. The fluorescence experimental results were in agreement with the results obtained by molecular modeling study. The effects of some normal positive and negative ions on the binding constants were also discussed. Moreover, the synchronous fluorescence technique was used to characterize the interaction of 8-bromoadenosine to HSA and successfully applied to determine the total proteins in human serum, urine and saliva samples at room temperature under the optimum conditions with a wide linear range and satisfactory results. PMID- 19775932 TI - Solute-solvent interactions of acid-1,4-dioxane mixtures-By dielectric, FTIR, UV vis and 13C NMR spectrometric methods. AB - Results of the dielectric studies carried out on the binary mixture of n-butyric and caprylic acids with 1,4-dioxane over the entire composition range and at temperatures 303K, 308K, 313K and 318K, and FTIR, UV-vis and 13C NMR spectral studies are presented in this paper. The excess permittivity and excess free energy were fitted with the Redlich-Kister polynomial. The variation of Kirkwood correlation factors, excess permittivity and excess free energy of mixing with the concentration and temperature has been investigated in view of understanding the ordering of dipoles of solute and solvent molecules. The FTIR, UV-vis and 13C NMR spectral analysis reveals the formation of complex between solute and solvent molecules. The parallel alignment of electric dipoles of the complex predicted by dielectric studies is well supported by UV-vis spectral analysis. The structure of the complex molecule present in the clusters has been deduced. PMID- 19775933 TI - Using a web-based system for the continuous distance education in cytopathology. AB - BACKGROUND: The evolution of information technologies and telecommunications has made the World Wide Web a low cost and easily accessible tool for the dissemination of information and knowledge. Continuous Medical Education (CME) sites dedicated in cytopathology field are rather poor, they do not succeed in following the constant changes and lack the ability of providing cytopathologists with a dynamic learning environment, adaptable to the development of cytopathology. Learning methods including skills such as decision making, reasoning and problem solving are critical in the development of such a learning environment. OBJECTIVES: The objectives of this study are (1) to demonstrate on the basis of a web-based training system the successful application of traditional learning theories and methods and (2) to effectively evaluate users' perception towards the educational program, using a combination of observers, theories and methods. IMPLEMENTATION: Trainees are given the opportunity to browse through the educational material, collaborate in synchronous and asynchronous mode, practice their skills through problems and tasks and test their knowledge using the self-evaluation tool. On the other hand, the trainers are responsible for editing learning material, attending students' progress and organizing the problem-based and task-based scenarios. The implementation of the web-based training system is based on the three-tier architecture and uses an Apache Tomcat web server and a MySQL database server. METHODS: By December 2008, CytoTrainer's learning environment contains two courses in cytopathology: Gynaecological Cytology and Thyroid Cytology offering about 2000 digital images and 20 case sessions. Our evaluation method is a combination of both qualitative and quantitative approaches to explore how the various parts of the system and students' attitudes work together. RESULTS: Trainees approved of the course's content, methodology and learning activities. The triangulation of evaluation methods revealed that the training program is suitable for the continuous distance education in cytopathology and that it has improved the trainees' skills in diagnostic cytopathology. CONCLUSIONS: The web-based training system can be successfully involved in the continuous distance education in cytopathology. It provides the opportunity to access learning material from any place at any time and supports the acquisition of diagnostic knowledge. PMID- 19775934 TI - Zoonotic bovine rotavirus strain in a diarrheic child, Nicaragua. PMID- 19775935 TI - Determinants of double discharges in amyotrophic lateral sclerosis and Kennedy disease. AB - OBJECTIVE: Double discharges (DDs) of the motor unit are frequent in amyotrophic lateral sclerosis (ALS) and Kennedy's disease (KD). This likely reflects changes in the intrinsic properties of motor neurons but in ALS changes in corticomotoneuronal inputs may also contribute. We determined the corticomotoneuronal contribution to DDs. METHODS: DD prevalence, intra-doublet interval (IDI) of DDs and their timing with respect to transcranial magnetic stimulation (TMS)-induced primary peaks (PPs) in the peristimulus time histogram (PSTH) were measured in 23 ALS patients (96 motor units), 11 patients with KD (45 motor units) and 13 control subjects (60 motor units). RESULTS: In patients with KD more motor units (82%) fired DDs than in ALS patients (51%) and control subjects (63%); (p=0.013). DDs occurred before (pre-peak), during (peak), and after (post-suppression) the peristimulus time histogram (PSTH) primary peak. The prevalence of pre-peak DD in KD was 4.06-fold higher (95% CI 0.53-2.81; p=0.0014) than in controls. In contrast the prevalence of ALS peak DDs was 4.79-fold higher (95% CI 1.09-21.10; p=0.041) than in controls. Both pre-peak and peak IDIs were significantly prolonged in ALS compared with controls (p<0.003). Motor unit action potential (MUAP) amplitude, size of the excitatory postsynaptic potential (EPSP) and interspike interval (ISI) all correlated significantly with pre-peak, but not peak DD prevalence. CONCLUSIONS: A high peak DD prevalence with prolonged IDIs in ALS are consistent with complex, multiple descending corticomotoneuronal volleys, indicating that the upper motor neuron contributes to the generation of DDs in ALS. SIGNIFICANCE: Although double discharges are a manifestation of reinnervating motor neurons in ALS the corticomotoneuronal descending input is also influential and probably accounts for some of the distinguishing features of DDs in ALS. PMID- 19775936 TI - Nutritional supplementation habits and perceptions of elite athletes within a state-based sporting institute. AB - The purpose of this investigation was to examine the nutritional supplement intake of athletes from a state-based sports institute. Athletes (n=72) from seven sports (kayaking, field hockey, rowing, waterpolo, swimming, athletics and netball) completed a questionnaire detailing their daily usage and rationale therefore. The large majority (63/72; 87.5+/-12.5%) of surveyed athletes reported using nutritional supplements, with no difference between female (31/36; 86.1+/ 13.9%) and male (32/36; 88.9+/-11.1%) athletes. Kayakers (6.0+/-2.9) consumed a higher number of nutritional supplements than swimmers (4+/-2.2), field hockey (1.5+/-1.0), rowing (2.4+/-1.4), waterpolo (2.3+/-2.4), athletics (2.5+/-1.9) and netball (1.7+/-1.0) athletes. The athletes believed that nutritional supplements are related to performance enhancements (47/72; 65.3%), positive doping results (45/72; 62.5%), and that heavy training increases supplement requirements (47/72; 65.3%). The cohort was equivocal as to their health risks (40/72; 55.6%) or their need with a balanced diet (38/72; 52.8%). The most popular supplements were minerals (33/72; 45.8%), vitamins (31/72; 43.1%), other (23/72; 31.9%), iron (22/72; 30.6%), caffeine (16/72; 22.2%), protein (12/72; 16.7%), protein carbohydrate mix (10/72; 13.9%), creatine (9/72; 12.5%) and glucosamine (3/72; 4.2%). The majority of supplementing athletes (n=63) did not know their supplements active ingredient (39/63; 61.9%), side effects (36/63; 57.1%) or mechanism of action (34/63; 54.0%) and admitted to wanting additional information (36/63; 57.0%). Only half of the athletes knew the recommended supplement dosages (33/63; 52.4%). The performance enhancing perception may explain the large proportion of athletes that reported using nutritional supplements, despite over half of the athletes believing that supplements are not required with a balanced diet and can cause positive doping violations. PMID- 19775937 TI - Novel trends in high-throughput screening. AB - High-throughput screening (HTS) is a well-established process for lead discovery in Pharma and Biotech companies and is now also being used for basic and applied research in academia. It comprises the screening of large chemical libraries for activity against biological targets via the use of automation, miniaturized assays and large-scale data analysis. Since its first advent in the early to mid 1990s, the field of HTS has seen not only a continuous change in technology and processes, but also an adaptation to various needs in lead discovery. HTS has now evolved into a mature discipline that is a crucial source of chemical starting points for drug discovery. Whereas in previous years much emphasis has been put on a steady increase in screening capacity ('quantitative increase') via automation and miniaturization, the past years have seen a much greater emphasis on content and quality ('qualitative increase'). Today, many experts in the field see HTS at a crossroad with the need to decide on either higher throughput/more experimentation or a greater focus on assays of greater physiological relevance, both of which may lead to higher productivity in pharmaceutical R&D. In this paper, we describe the development of HTS over the past decade and point out our own ideas for future directions of HTS in biomedical research. We predict that the trend toward further miniaturization will slow down with the balanced implementation of 384 well, 1536 well, and 384 low volume well plates. Furthermore, we envisage that there will be much more emphasis on rigorous assay and chemical characterization, particularly considering that novel and more difficult target classes will be pursued. In recent years we have witnessed a clear trend in the drug discovery community toward rigorous hit validation by the use of orthogonal readout technologies, label free and biophysical methodologies. We also see a trend toward a more flexible use of the various screening approaches in lead discovery, that is, the use of both full deck compound screening as well as the use of focused screening and iterative screening approaches. Moreover, we expect greater usage of target identification strategies downstream of phenotypic screening and the more effective implementation of affinity selection technologies as a result of advances in chemical diversity methodologies. We predict that, ultimately, each hit finding strategy will be much more project-related, tailor-made, and better integrated into the broader drug discovery efforts. PMID- 19775938 TI - Polymorphonuclear neutrophils and T lymphocytes: strange bedfellows or brothers in arms? AB - Polymorphonuclear neutrophils (PMN) are linked invariably to the innate immune response, particularly to the defence against bacterial infection. T lymphocytes are studied mainly in virus infections, the defence against tumours, the development and progression of chronic inflammatory processes, in autoimmune phenomena and in materno-fetal tolerance. There is, however, increasing evidence for communication and interactions between PMN and T cells that we discuss here in the context of different physiological and pathological conditions, including acute and chronic inflammatory disease, defence against tumours, and maintenance of pregnancy. PMID- 19775940 TI - Driving the lane: a clearer view of facet joint cyst intervention. PMID- 19775939 TI - Decreasing presentations of seizures to emergency departments in a large Australian population. AB - This study was designed (1) to compare the prevalence of emergency department (ED) presentations in Western Zone Sydney South West Area Health Service (WZS) between 1998-2002 and 2003-2007 for epilepsy (including status epilepticus (SE) and convulsions), hospital admission rates, and proportion of first seizure presentations; and (2) to compare these data with those for New South Wales (NSW) and Australia-wide figures. Using health department data sets, we found 19,834 presentations to WZS EDs between 1998 and 2007 (24.85/10,000 population/year). When the periods 2003-2007 and 1998-2002 in WZS are compared, ED presentations fell by 3% (P=0.03) and hospital admissions fell by 6% (P=0.001). The prevalence of ED presentations for seizures in NSW did not change (P=0.92), but hospital admissions fell by 3% (P<0.0001). When 1999/2000-2002/2003 was compared with 2003/2004-2006/2007, the prevalence of hospital admissions in Australia fell by 1% (P=0.0002). Rates of presentation for epilepsy in WZS have fallen over the last decade. Most presentations were first seizures rather than recurrences. The reason for this is speculative, but may reflect improved levels of education and health care delivery. PMID- 19775942 TI - Screening ionisation and chromatography conditions for quantitative LC/MS methods. AB - To develop an optimal quantitative LC/MS method with high sensitivity, high selectivity and robustness in a limited time period can be very challenging, especially for methods in which many analytes are to be quantified. In this study the relevant options are reviewed and a simple screening strategy of mass spectrometric and chromatographic conditions is presented. The strategy is divided into two stages, mass spectrometric ionisation screening and reversed phase LC column screening. The objective of the first stage is to find out how sensitivity is affected by ionisation technique, ionisation polarity and buffer. The compounds are dissolved in different buffers covering a broad pH range. Thereafter they are injected using flow injection analysis without LC column, evaluating both electrospray and atmospheric pressure chemical ionisation (APCI). In the second stage the buffers yielding the best sensitivity and selectivity in the ionisation screening stage are used as mobile phase buffers to LC column screening with different stationary phases applying a shallow gradient. The aim is to find the combinations of column(s) and buffer(s) that give symmetric peaks, adequate retention and selectivity. Finally the retention is adjusted using isocratic or gradient elution. The strategy provides a simple and practical experimental design that allows fast screening a large range of ionisation and chromatographic conditions especially for multiple compounds. The examples included in this study demonstrate that optimal buffer, ionisation technique, ionisation polarity and column cannot be predicted from compound properties such as structure and pK(a). PMID- 19775941 TI - An exploratory study investigating factors associated with adherence to chest physiotherapy and exercise in adults with cystic fibrosis. AB - This study explored the relationship between psychological and demographic variables relating to chest physiotherapy (CP) and exercise in adults with cystic fibrosis. The main results were that adherence to both treatments was low and analysis of variance indicated that severity and gender were associated with exercise adherence, importance and burden. These results suggest potential areas for interventions to improve exercise adherence. PMID- 19775943 TI - Simultaneous determination of epothilone D and its hydrolytic metabolite in human plasma by high performance liquid chromatography-tandem mass spectrometry for pharmacokinetic studies. AB - A sensitive, simple and rapid high performance liquid chromatographic-tandem mass spectrometric (HPLC-MS/MS) method was developed for simultaneous quantitation of epothilone D and its major metabolite, the hydrolytic metabolite, epothilone C as internal standard in human plasma. Plasma samples were precipitated with acetonitrile, the analysis used a Venusil ASB C(18) analytical column. A tandem mass spectrometer equipped with electrospray ionization source was used as detector and operated in the positive-ion mode. Selected reaction monitoring (SRM) using the precursor to product ion pairs of m/z 492.3-->304.1 (epothilone D), m/z 510.3-->492.3 (metabolite), m/z 478.3-->290.1 (internal standard) was used for quantification. The analytical method was validated in terms of specificity, precision, accuracy, extraction recovery, stability, matrix effect and dilution effect. The linear calibration curves of epothilone D and metabolite were obtained over the concentration range of 0.2-1000 ng/ml and 5.0-1000 ng/ml, respectively. Lower limits of quantification (LLOQ) of epothilone D and metabolite were 0.2 ng/ml and 5.0 ng/ml, respectively. Due to its high sensitivity, specificity and simplicity, the method could be used for pharmacokinetic studies of both epothilone D and its hydrolytic metabolite. PMID- 19775944 TI - Electrospun polyethersulfone affinity membrane: membrane preparation and performance evaluation. AB - Non-woven polyethersulfone (PES) membranes were prepared by electrospinning. After heat treatment and surface activation, the membranes were covalently functionalized with ligands to be used as affinity membranes. The membranes were characterized in terms of fiber diameter, porosity, specific area, pore size, ligand density and binding capacities. To evaluate the binding efficiency of the membrane, dynamic adsorption of bovine serum albumin (BSA) on the Cibacron blue F3GA (CB) functionalized PES membrane was studied. Experimental breakthrough curves were fitted with the theoretical curves based on the plate model to estimate plate height (H(p)) of the affinity membrane. The high value of H(p) (1.6-8 cm) of the affinity membrane implied a poor dynamic binding efficiency, which can be explained by the intrinsic microstructures of the material. Although the electrospun membrane might not be an ideal candidate for the preparative affinity membrane chromatography for large-scale production, it still can be used for fast small-scale protein purification in which a highly efficient binding is not required. Spin columns packed with protein A/G immobilized PES membranes were demonstrated to be capable of binding IgG specifically. SDS-PAGE results demonstrated that the PES affinity membrane had high specific binding selectivity for IgG molecules and low non-specific protein adsorption. Compared with other reported affinity membranes, the PES affinity membrane had a comparable IgG binding capacity of 4.5 mg/ml, and had a lower flow through pressure drop due to its larger pore size. In conclusion, the novel PES affinity membrane is an ideal spin column packing material for fast protein purification. PMID- 19775945 TI - [13C] GC-C-IRMS analysis of methylboronic acid derivatives of glucose from liver glycogen after the ingestion of [13C] labeled tracers in rats. AB - We developed a complete method to measure low [(13)C] enrichments in glycogen. Fourteen rats were fed a control diet. Six of them also ingested either [U-(13)C] glucose (n=2) or a mixture of 20 [U-(13)C] amino acids (n=4). Hepatic glycogen was extracted, digested to glucose and purified on anion-cation exchange resins. After the optimization of methylboronic acid derivatization using GC-MS, [(13)C] enrichment of extracted glucose was measured by GC-C-IRMS. The accuracy was addressed by measuring the enrichment excess of a calibration curve, which observed values were in good agreement with the expected values (R=0.9979). Corrected delta values were -15.6+/-1.6 delta(13)C (per thousand) for control rats (n=8) and increased to -5 to 8 delta(13)C (per thousand) per thousand and 12 14 delta(13)C (per thousand) per thousand after the ingestion of [U-(13)C] amino acids or [U-(13)C] glucose as oral tracers, respectively. The method enabled the determination of dietary substrate transfer into glycogen. The sequestration of dietary glucose in liver glycogen 4 h after the meal was 35% of the ingested dose whereas the transfer of carbon skeletons from amino acids was only 0.25 to 1%. PMID- 19775946 TI - [Fatal poisoning by accidental inhalation of aluminium phosphide]. AB - The cases of two 6 and 9-year-old sisters with lethal poisoning by inhalation of aluminium phosphide, after its inadequate use in a rural environment, are described. The clinical symptoms consisted of sudden vomiting, cardiac arrhythmias, shock, dyspnea, pulmonary edema/acute respiratory distress, metabolic acidosis and hepatic dysfunction, and the patients died in spite of advanced life support. Although an early diagnosis might theoretically improve the poisoning outcome, its high lethality rate and the absence of a specific antidote, efforts must be directed towards prevention and restricting its use as pesticide and being aware of its toxicity. PMID- 19775947 TI - [Diagnosis of hemoglobinopathies in newborns in Venezuela hospitals]. AB - OBJECTIVES: Hemoglobinopathies are the most common hereditary disorders in humans representing a public health problem in Venezuela. In this study the prevalence of hemoglobinopathies was evaluated in newborns from different areas of Venezuela, in cooperation with the neonatal screening system of the Study Unit of Inborn Errors of Metabolism (IDEA). MATERIALS AND METHODS: The heel blood samples of 101,301 newborns were analysed by high performance liquid chromatography (HPLC CE) technique using Variant* Bio Rad System with the Sickle Cell Short program for the filter paper samples in and the Beta Tal Short program for the family studies. RESULTS: We found a high prevalence of newborns heterozygous for hemoglobin S and C (Hb S and Hb C). It was observed that 1.96% (1989) of the newborns were carriers, with Hb FAS (67.92) being the most frequent phenotype, followed by Hb FAC (23.18%), Hb FAD (7.49%), Hb FSC (0.96%),) and Hb FSD (0.20%). All the neonatal positives cases were confirmed at 3 months of age. CONCLUSIONS: The frequencies of the variants found in this study confirms that the hemoglobin disorders are a public health problem in Venezuela, emphasizing the importance of instituting a national program of screening for hemoglobinopathies throughout the country, comprising not only an early treatment, but also an educational program and genetic counseling for the family group. PMID- 19775948 TI - [Laryngotracheal separation as treatment for severe bronchopulmonary aspiration]. AB - We present the case of a patient with brain stem tumour and severe chronic aspiration. The bilateral dysfunction of lower cranial nerves and the severe gastroesophageal reflux contributed to the aspirations. Despite medical treatment and cuffed tracheotomy tube, she required almost constant hospitalization for a year and a half due to respiratory infections. Laryngotracheal separation dramatically reduced the infections and improved her quality of life. PMID- 19775949 TI - Cosmetic surgery in the NHS: Applying local and national guidelines. AB - There is no worldwide consensus, as to how healthcare should be funded, in a modern society. Limited resources in the UK, have led to restrictions on cosmetic surgery in the NHS. Guidelines governing access to cosmetic surgery have been formulated. A retrospective audit has been undertaken, to assess adherence to local and national guidelines, in an NHS trust. Ninety-nine casenotes were reviewed over 1 year. Data on complications were collected. Compliance to local guidelines was 44% and to national guidelines was 22%. Complication rate was 23% in guideline compliant patients and 55% in non-compliant patients (P<0.005). Guidelines are difficult to follow in practice. Total adherence to guidelines would reduce waiting lists and complications, but some needy patients could be denied treatment. In practice, rigid adherence to guidelines is not possible. PMID- 19775950 TI - Alkyl isothiocyanates suppress epidermal growth factor receptor kinase activity but augment tyrosine kinase activity. AB - AIM: We have reported the in vitro and in vivo anticancer activities of 6 (methylsulfinyl)hexyl isothiocyanate (6-MITC) derived from a Japanese spice, wasabi. In order to obtain some clues about the mechanism of the anticancer activity, we have studied the effect of alkyl isothiocyanates (MITCs) on protein kinase activities. METHODS: The anti-autophosphorylation activity of MITCs with respect to the epidermal growth factor (EGF)-stimulated receptor kinase of A431 epidermoid carcinoma cells was examined by incorporation of radioactive ATP into an acid-insoluble fraction. Their anti-phosphorylation activity with respect to the non-receptor protein kinase was analyzed by a standard SDS-PAGE method. RESULTS: All the tested MITCs interfered with the EGF-stimulated receptor kinase activity in a dose-dependent manner, although their effects were less than 1/10 of that of erbstatin in microg/ml. On the other hand, the MITCs did not interfere with non-receptor kinases (kinase A, kinase C, tyrosine kinase and calmodulin dependent kinase III), but enhanced non-receptor tyrosine kinase. DISCUSSION: A possible anticancer mechanism of MITCs may involve the suppression of EGF receptor kinase activity and augmentation of non-receptor PTK. PMID- 19775951 TI - Introducing wavelets and time--frequency analysis. PMID- 19775952 TI - Time--frequency analysis of biosignals. PMID- 19775953 TI - Predictability analysis of voice signals. PMID- 19775954 TI - Pressure-detection algorithms. PMID- 19775955 TI - Microcalcification border characterization. PMID- 19775956 TI - Normal versus pathological voice signals. PMID- 19775957 TI - Signal from noise? PMID- 19775958 TI - BMEplanet. PMID- 19775959 TI - Where do ideas come from? PMID- 19775960 TI - Nonorthogonal approximate joint diagonalization with well-conditioned diagonalizers. AB - To make the results reasonable, existing joint diagonalization algorithms have imposed a variety of constraints on diagonalizers. Actually, those constraints can be imposed uniformly by minimizing the condition number of diagonalizers. Motivated by this, the approximate joint diagonalization problem is reviewed as a multiobjective optimization problem for the first time. Based on this, a new algorithm for nonorthogonal joint diagonalization is developed. The new algorithm yields diagonalizers which not only minimize the diagonalization error but also have as small condition numbers as possible. Meanwhile, degenerate solutions are avoided strictly. Besides, the new algorithm imposes few restrictions on the target set of matrices to be diagonalized, which makes it widely applicable. Primary results on convergence are presented and we also show that, for exactly jointly diagonalizable sets, no local minima exist and the solutions are unique under mild conditions. Extensive numerical simulations illustrate the performance of the algorithm and provide comparison with other leading diagonalization methods. The practical use of our algorithm is shown for blind source separation (BSS) problems, especially when ill-conditioned mixing matrices are involved. PMID- 19775961 TI - Real-time robot path planning based on a modified pulse-coupled neural network model. AB - This paper presents a modified pulse-coupled neural network (MPCNN) model for real-time collision-free path planning of mobile robots in nonstationary environments. The proposed neural network for robots is topologically organized with only local lateral connections among neurons. It works in dynamic environments and requires no prior knowledge of target or barrier movements. The target neuron fires first, and then the firing event spreads out, through the lateral connections among the neurons, like the propagation of a wave. Obstacles have no connections to their neighbors. Each neuron records its parent, that is, the neighbor that caused it to fire. The real-time optimal path is then the sequence of parents from the robot to the target. In a static case where the barriers and targets are stationary, this paper proves that the generated wave in the network spreads outward with travel times proportional to the linking strength among neurons. Thus, the generated path is always the global shortest path from the robot to the target. In addition, each neuron in the proposed model can propagate a firing event to its neighboring neuron without any comparing computations. The proposed model is applied to generate collision-free paths for a mobile robot to solve a maze-type problem, to circumvent concave U-shaped obstacles, and to track a moving target in an environment with varying obstacles. The effectiveness and efficiency of the proposed approach is demonstrated through simulation and comparison studies. PMID- 19775962 TI - Bounded influence support vector regression for robust single-model estimation. AB - Support vector regression (SVR) is now a well-established method for estimating real-valued functions. However, the standard SVR is not effective to deal with severe outlier contamination of both response and predictor variables commonly encountered in numerous real applications. In this paper, we present a bounded influence SVR, which downweights the influence of outliers in all the regression variables. The proposed approach adopts an adaptive weighting strategy, which is based on both a robust adaptive scale estimator for large regression residuals and the statistic of a "kernelized" hat matrix for leverage point removal. Thus, our algorithm has the ability to accurately extract the dominant subset in corrupted data sets. Simulated linear and nonlinear data sets show the robustness of our algorithm against outliers. Last, chemical and astronomical data sets that exhibit severe outlier contamination are used to demonstrate the performance of the proposed approach in real situations. PMID- 19775963 TI - The hybrid screen--improving the breed. AB - The hybrid screen is a halftoning method that generates stochastic dispersed dot textures in highlights and periodic clustered dot textures in midtones. Each tone level is sequentially designed from highlight to midtone by applying an iterative halftoning algorithm such as direct binary search (DBS). By allowing random seeding followed by swap-only DBS in a predefined core region within each microcell, each level can be designed while satisfying the stacking constraint and guaranteeing a smooth transition between levels. This paper describes a complete design process for the hybrid screen, introduces a number of enhancements to the original hybrid screen, and evaluates their impact on print quality. These enhancements include a multilevel screen design based on either extending a bilevel screen or directly generating a multilevel screen on a high resolution grid, and extending the hybrid screen design procedure to color by jointly optimizing the color screens using color DBS. For the multilevel screen, we show that the best choice for the core size critically depends on the bit depth and screen frequency. For the color hybrid screen, we demonstrate a significant improvement in the highlights over halftones generated by independently designed screens. PMID- 19775964 TI - Effective level set image segmentation with a kernel induced data term. AB - This study investigates level set multiphase image segmentation by kernel mapping and piecewise constant modeling of the image data thereof. A kernel function maps implicitly the original data into data of a higher dimension so that the piecewise constant model becomes applicable. This leads to a flexible and effective alternative to complex modeling of the image data. The method uses an active curve objective functional with two terms: an original term which evaluates the deviation of the mapped image data within each segmentation region from the piecewise constant model and a classic length regularization term for smooth region boundaries. Functional minimization is carried out by iterations of two consecutive steps: 1) minimization with respect to the segmentation by curve evolution via Euler-Lagrange descent equations and 2) minimization with respect to the regions parameters via fixed point iterations. Using a common kernel function, this step amounts to a mean shift parameter update. We verified the effectiveness of the method by a quantitative and comparative performance evaluation over a large number of experiments on synthetic images, as well as experiments with a variety of real images such as medical, satellite, and natural images, as well as motion maps. PMID- 19775965 TI - Optimizing motion compensated prediction for error resilient video coding. AB - This paper is concerned with optimization of the motion compensated prediction framework to improve the error resilience of video coding for transmission over lossy networks. First, accurate end-to-end distortion estimation is employed to optimize both motion estimation and prediction within an overall rate-distortion framework. Low complexity practical variants are proposed: a method to approximate the optimal motion via simple distortion and source coding rate models, and a source-channel prediction method that uses the expected decoder reference frame for prediction. Second, reference frame generation is revisited as a problem of filter design to optimize the error resilience versus coding efficiency tradeoff. The special cases of leaky prediction and weighted prediction (i.e., finite impulse response filtering), are analyzed. A novel reference frame generation approach, called "generalized source-channel prediction", is proposed, which involves infinite impulse response filtering. Experimental results show significant performance gains and substantiate the effectiveness of the proposed encoder optimization approaches. PMID- 19775966 TI - Bayesian compressive sensing using laplace priors. AB - In this paper, we model the components of the compressive sensing (CS) problem, i.e., the signal acquisition process, the unknown signal coefficients and the model parameters for the signal and noise using the Bayesian framework. We utilize a hierarchical form of the Laplace prior to model the sparsity of the unknown signal. We describe the relationship among a number of sparsity priors proposed in the literature, and show the advantages of the proposed model including its high degree of sparsity. Moreover, we show that some of the existing models are special cases of the proposed model. Using our model, we develop a constructive (greedy) algorithm designed for fast reconstruction useful in practical settings. Unlike most existing CS reconstruction methods, the proposed algorithm is fully automated, i.e., the unknown signal coefficients and all necessary parameters are estimated solely from the observation, and, therefore, no user-intervention is needed. Additionally, the proposed algorithm provides estimates of the uncertainty of the reconstructions. We provide experimental results with synthetic 1-D signals and images, and compare with the state-of-the-art CS reconstruction algorithms demonstrating the superior performance of the proposed approach. PMID- 19775967 TI - Reconstruction from limited-angle projections based on delta-u spectrum analysis. AB - This paper proposes a sparse representation of an image using discrete delta-u functions. A delta-u function is defined as the product of a Kronecker delta function and a step function. Based on the sparse representation, we have developed a novel and effective method for reconstructing an image from limited angle projections. The method first estimates the parameters of the sparse representation from the incomplete projection data, and then directly calculates the image to be reconstructed. Experiments have shown that the proposed method can effectively recover the missing data and reconstruct images more accurately than the total-variation (TV) regularized reconstruction method. PMID- 19775968 TI - ISAR imaging of maneuvering targets based on the range centroid Doppler technique. AB - A new inverse synthetic aperture radar (ISAR) imaging approach is presented for application in situations where the maneuverability of noncooperative target is not too severe and the Doppler variation of subechoes from scatterers can be approximated as a first-order polynomial. The proposed algorithm is referred to as the range centroid Doppler (RCD) ISAR imaging technique and is based on the stretch Keystone-Wigner transform (SKWT). The SKWT introduces a stretch weight factor containing a range of chirp rate into the autocorrelation function of each cross-range profile and uses a 1-D interpolation of the phase history which we call stretch keystone formatting. The processing simultaneously eliminates the effects of linear frequency migration for all signal components regardless of their unknown chirp rate in time-frequency plane, but not for the noise or for the cross terms. By utilizing this novel technique, clear ISAR imaging can be achieved for maneuvering targets without an exhaustive search procedure for the motion parameters. Performance comparison is carried out to evaluate the improvement of the RCD technique versus other methods such as the conventional range Doppler (RD) technique, the range instantaneous Doppler (RID) technique, and adaptive joint time-frequency (AJTF) technique. Examples provided demonstrate the effectiveness of the RCD technique with both simulated and experimental ISAR data. PMID- 19775969 TI - Active contouring based on gradient vector interaction and constrained level set diffusion. AB - This paper presents an extension of our recently introduced MAC model to deal with the initialization dependency problem that commonly appears in edge-based approaches. Its dynamic force field, unique bidirectionality, and constrained diffusion-based level set evolution provide great freedom in contour initialization and show significant improvements in initialization independency compared to other edge-based techniques. It can handle more sophisticated topological changes than splitting and merging. It provides new potentials for edge-based active contour methods, particularly when detecting and localizing objects with unknown location, geometry, and topology. PMID- 19775970 TI - A zernike moment phase-based descriptor for local image representation and matching. AB - A local image descriptor robust to the common photometric transformations (blur, illumination, noise, and JPEG compression) and geometric transformations (rotation, scaling, translation, and viewpoint) is crucial to many image understanding and computer vision applications. In this paper, the representation and matching power of region descriptors are to be evaluated. A common set of elliptical interest regions is used to evaluate the performance. The elliptical regions are further normalized to be circular with a fixed size. The normalized circular regions will become affine invariant up to a rotational ambiguity. Here, a new distinctive image descriptor to represent the normalized region is proposed, which primarily comprises the Zernike moment (ZM) phase information. An accurate and robust estimation of the rotation angle between a pair of normalized regions is then described and used to measure the similarity between two matching regions. The discriminative power of the new ZM phase descriptor is compared with five major existing region descriptors (SIFT, GLOH, PCA-SIFT, complex moments, and steerable filters) based on the precision-recall criterion. The experimental results, involving more than 15 million region pairs, indicate the proposed ZM phase descriptor has, generally speaking, the best performance under the common photometric and geometric transformations. Both quantitative and qualitative analyses on the descriptor performances are given to account for the performance discrepancy. First, the key factor for its striking performance is due to the fact that the ZM phase has accurate estimation accuracy of the rotation angle between two matching regions. Second, the feature dimensionality and feature orthogonality also affect the descriptor performance. Third, the ZM phase is more robust under the nonuniform image intensity fluctuation. Finally, a time complexity analysis is provided. PMID- 19775971 TI - Variable density compressed image sampling. AB - Compressed sensing (CS) provides an efficient way to acquire and reconstruct natural images from a limited number of linear projection measurements leading to sub-Nyquist sampling rates. A key to the success of CS is the design of the measurement ensemble. This correspondence focuses on the design of a novel variable density sampling strategy, where the a priori information of the statistical distributions that natural images exhibit in the wavelet domain is exploited. The proposed variable density sampling has the following advantages: 1) the generation of the measurement ensemble is computationally efficient and requires less memory; 2) the necessary number of measurements for image reconstruction is reduced; 3) the proposed sampling method can be applied to several transform domains and leads to simple implementations. Extensive simulations show the effectiveness of the proposed sampling method. PMID- 19775972 TI - Adaptive inferential sensors based on evolving fuzzy models. AB - A new technique to the design and use of inferential sensors in the process industry is proposed in this paper, which is based on the recently introduced concept of evolving fuzzy models (EFMs). They address the challenge that the modern process industry faces today, namely, to develop such adaptive and self calibrating online inferential sensors that reduce the maintenance costs while keeping the high precision and interpretability/transparency. The proposed new methodology makes possible inferential sensors to recalibrate automatically, which reduces significantly the life-cycle efforts for their maintenance. This is achieved by the adaptive and flexible open-structure EFM used. The novelty of this paper lies in the following: (1) the overall concept of inferential sensors with evolving and self-developing structure from the data streams; (2) the new methodology for online automatic selection of input variables that are most relevant for the prediction; (3) the technique to detect automatically a shift in the data pattern using the age of the clusters (and fuzzy rules); (4) the online standardization technique used by the learning procedure of the evolving model; and (5) the application of this innovative approach to several real-life industrial processes from the chemical industry (evolving inferential sensors, namely, eSensors, were used for predicting the chemical properties of different products in The Dow Chemical Company, Freeport, TX). It should be noted, however, that the methodology and conclusions of this paper are valid for the broader area of chemical and process industries in general. The results demonstrate that well interpretable and with-simple-structure inferential sensors can automatically be designed from the data stream in real time, which predict various process variables of interest. The proposed approach can be used as a basis for the development of a new generation of adaptive and evolving inferential sensors that can address the challenges of the modern advanced process industry. PMID- 19775973 TI - Diagnostic models based on personalized analysis of trends (PAT). AB - Many changes have taken place in medicine over the last century. In the first half of the 20th century physicians were faced with the challenge of making diagnoses with too little information, often resorting to exploratory surgery to confirm the presence or absence of a condition. Due to rapid technological advances during the second-half of the 20th century, and continuing to this day, the position of the physician has now shifted from an information-poor environment to an environment with too much information, often exceeding the limits of human decision-making capabilities. To take full advantage of all available information, a new approach based on refined automated decision support methods is needed to assist the physician in the decision-making process. Medical decision support systems need to evolve from stand-alone systems to cooperative systems in which the physician becomes the decision maker, but relies on the decision support system to sift through information to determine relevant trends. In this paper, a decision support system that combines a number of methodologies for trend analysis is described, along with examples in cardiology. The methods have also been used in applications in neurology as well as cancer diagnosis and prognosis. PMID- 19775974 TI - Automated scoring of obstructive sleep apnea and hypopnea events using short-term electrocardiogram recordings. AB - Obstructive sleep apnea or hypopnea causes a pause or reduction in airflow with continuous breathing effort. The aim of this study is to identify individual apnea and hypopnea events from normal breathing events using wavelet-based features of 5-s ECG signals (sampling rate = 250 Hz) and estimate the surrogate apnea index (AI)/hypopnea index (HI) (AHI). Total 82,535 ECG epochs (each of 5-s duration) from normal breathing during sleep, 1638 ECG epochs from 689 hypopnea events, and 3151 ECG epochs from 1862 apnea events were collected from 17 patients in the training set. Two-staged feedforward neural network model was trained using features from ECG signals with leave-one-patient-out cross validation technique. At the first stage of classification, events (apnea and hypopnea) were classified from normal breathing events, and at the second stage, hypopneas were identified from apnea. Independent test was performed on 16 subjects' ECGs containing 483 hypopnea and 1352 apnea events. The cross validation and independent test accuracies of apnea and hypopnea detection were found to be 94.84% and 76.82%, respectively, for training set, and 94.72% and 79.77%, respectively, for test set. The Bland-Altman plots showed unbiased estimations with standard deviations of +/- 2.19, +/- 2.16, and +/- 3.64 events/h for AI, HI, and AHI, respectively. Results indicate the possibility of recognizing apnea/hypopnea events based on shorter segments of ECG signals. PMID- 19775975 TI - ECG signal compression and classification algorithm with quad level vector for ECG holter system. AB - An ECG signal processing method with quad level vector (QLV) is proposed for the ECG holter system. The ECG processing consists of the compression flow and the classification flow, and the QLV is proposed for both flows to achieve better performance with low-computation complexity. The compression algorithm is performed by using ECG skeleton and the Huffman coding. Unit block size optimization, adaptive threshold adjustment, and 4-bit-wise Huffman coding methods are applied to reduce the processing cost while maintaining the signal quality. The heartbeat segmentation and the R-peak detection methods are employed for the classification algorithm. The performance is evaluated by using the Massachusetts Institute of Technology-Boston's Beth Israel Hospital Arrhythmia Database, and the noise robust test is also performed for the reliability of the algorithm. Its average compression ratio is 16.9:1 with 0.641% percentage root mean square difference value and the encoding rate is 6.4 kbps. The accuracy performance of the R-peak detection is 100% without noise and 95.63% at the worst case with -10-dB SNR noise. The overall processing cost is reduced by 45.3% with the proposed compression techniques. PMID- 19775976 TI - A service-oriented medical framework for fast and adaptive information delivery in mobile environment. AB - The need for fast treatment of patients in critical conditions motivates the use of mobile devices to provide prompt and consistent communication between hospitals and physicians. We propose a framework that supports ubiquitous access to medical systems using personalized mobile services and integrated medical systems. The proposed service-oriented medical framework provides dynamically composed services that are adapted to contextual variables such as the user's role, the network bandwidth, and resources available at mobile devices while supporting task allocation in distributed servers for massive resource-consuming services. It also manages accurate patient data by integrating local medical systems using medical information standards such as Digital Imaging and Communications in Medicine and Health Level 7. We have demonstrated the effectiveness of our framework by building a prototype of context-based adaptation of computerized tomography image retrieval for acute stroke treatments, which allows images to be viewed on mobile devices with WiMax wireless network. The proposed medical framework reduces hospital delays of patients and facilitates treatments in the absence of medical specialists. PMID- 19775977 TI - Design and implementation of a distributed fall detection system--personal server. AB - In this paper, the main results related to a fall detection system are shown by means of a personal server for the control and processing of the data acquired from multiple intelligent biomedical sensors. This server is designed in the context of a telehealthcare system for the elderly, to whom falls represent a high-risk cause of serious injuries, and its architecture can be extended to patients suffering from chronic diseases. The main design issues and developments in terms of the server hardware and software are presented with the aim of providing a real-time analysis of the processed biosignals. As a result, the evaluation study of the implemented algorithm for fall detection through a set of laboratory experiments is presented, together with some important issues in terms of the device's consumption. The proposed algorithm exhibits excellent outcomes in fall detection. PMID- 19775978 TI - Automatic detection of respiration rate from ambulatory single-lead ECG. AB - Ambulatory electrocardiography is increasingly being used in clinical practice to detect abnormal electrical behavior of the heart during ordinary daily activities. The utility of this monitoring can be improved by deriving respiration, which previously has been based on overnight apnea studies where patients are stationary, or the use of multilead ECG systems for stress testing. We compared six respiratory measures derived from a single-lead portable ECG monitor with simultaneously measured respiration air flow obtained from an ambulatory nasal cannula respiratory monitor. Ten controlled 1-h recordings were performed covering activities of daily living (lying, sitting, standing, walking, jogging, running, and stair climbing) and six overnight studies. The best method was an average of a 0.2-0.8 Hz bandpass filter and RR technique based on lengthening and shortening of the RR interval. Mean error rates with the reference gold standard were +/-4 breaths per minute (bpm) (all activities), +/-2 bpm (lying and sitting), and +/-1 breath per minute (overnight studies). Statistically similar results were obtained using heart rate information alone (RR technique) compared to the best technique derived from the full ECG waveform that simplifies data collection procedures. The study shows that respiration can be derived under dynamic activities from a single-lead ECG without significant differences from traditional methods. PMID- 19775979 TI - Photoplethysmogram measurement without direct skin-to-sensor contact using an adaptive light source intensity control. AB - We developed a chair-attached, nonintrusive photoplethysmogram (PPG) measuring system for everyday life, unconstrained monitoring using nonskin-contacting sensor-amplifier circuits capable of emitting suitable light intensity adaptable to clothing characteristics. Comparison between proposed and conventional systems showed reasonable correlation and root-mean-squared error levels, indicating its feasibility for unconstrained PPG monitoring. PMID- 19775980 TI - Dynamic voltage and frequency scaling for on-demand performance and availability of biomedical embedded systems. AB - The goal of the study presented in this paper is to develop an embedded biomedical system capable of delivering maximum performance on demand, while maintaining the optimal energy efficiency whenever possible. Several hardware and software solutions are presented allowing the system to intelligently change the power supply voltage and frequency in runtime. The resulting system allows use of more energy-efficient components, operates most of the time in its most battery efficient mode, and provides means to quickly change the operation mode while maintaining reliable performance. While all of these techniques extend battery life, the main benefit is on-demand availability of computational performance using a system that is not excessive. Biomedical applications, perhaps more than any other application, require battery operation, favor infrequent battery replacements, and can benefit from increased performance under certain conditions (e.g., when anomaly is detected) that makes them ideal candidates for this approach. In addition, if the system is a part of a body area network, it needs to be light, inexpensive, and adaptable enough to satisfy changing requirements of the other nodes in the network. PMID- 19775981 TI - Effects of dielectric values of human body on specific absorption rate following 430, 800, and 1200 MHz RF exposure to ingestible wireless device. AB - In order to assess the compliance of ingestible wireless device (IWD) within safety guidelines, the SAR, and near fields of IWD in two realistic human body models, whose dielectric values are increased from the original by +/-10% and +/- 20% are studied using the finite-difference time-domain method. The radiation characteristics of the IWD in the human body models with changed and unchanged dielectric values are compared. Simulations are carried out at 13 scenarios where the IWD is placed at center positions of abdomens in the two models at the operation frequency of 430, 800, and 1200 MHz, respectively. Results show that variation of radiation intensity near the surface of abdomen is around 2.5, 2.6, and 3.5 dB within 20% variation of dielectric values corresponding to the frequency of 430, 800, and 1200 MHz, respectively. Electric fields in the anterior of the human body models are higher than those in the posterior for all scenarios. SAR values increase with the increase of conductivities of human body tissues, and usually decrease with the increase of relative permittivities of human body tissues. The effect of the dielectric values of human body on SAR is orientation-, human-body-, and frequency-dependent. A variation up to 20% in conductivities and relative permittivities alone or simultaneously always causes a SAR variation less than 10%, 20%, and 30% at the frequency of 430, 800, and 1200 MHz, respectively. As far as the compliance of safety was concerned, the IWD was safe to be used at the input power less than 12.6, 9.3, and 8.4 mW, according to the IEEE safety standards at the frequency of 430, 800, and 1200 MHz, respectively. PMID- 19775983 TI - Examination of force discrimination in human upper limb amputees with reinnervated limb sensation following peripheral nerve transfer. AB - Artificial limbs allow amputees to manipulate objects, but the loss of a limb severs the sensory link between a subject and objects they touch. A novel surgical technique we term targeted reinnervation (TR) allows severed cutaneous nerves to reinnervate skin on a different portion of the body. This technique provides a physiologically appropriate portal to the sensory pathways of the missing limb through the reinnervated skin. This study quantified the ability of three amputee subjects who had undergone TR surgery on the chest (two subjects) and upper arm (one subject) to discriminate changes in graded force on their reinnervated skin over a range of 1-4 N using a stochastic staircase approach. These values were compared to those from sites on their intact contralateral skin and index fingers, and from the chests and index fingers of a control population (n = 10) . Weber's ratio (WR) was used to examine the subjects' abilities to discriminate between a baseline force and subsequent forces of different magnitudes. WRs of 0.22, 0.25, and 0.12 were measured on the reinnervated skin of the three TR subjects, whereas WRs of 0.25, 0.23, and 0.12 were measured on their contralateral skin. TR subjects did not have substantially different WRs on their reinnervated versus their contralateral normal side and did not appear to exhibit a trend towards impaired sensation. No significant difference was found between the WR of the chest and index finger of the control subjects, which ranged between 0.09 and 0.21. WR of reinnervated skin for TR subjects were within the 95% confidence interval of the control group. These data suggest that subjects with targeted reinnervation have unimpaired ability to discriminate gradations in force. PMID- 19775984 TI - The application of machine learning algorithms to the analysis of electromyographic patterns from arthritic patients. AB - The main aim of our study was to investigate the possibility of applying machine learning techniques to the analysis of electromyographic patterns (EMG) collected from arthritic patients during gait. The EMG recordings were collected from the lower limbs of patients with arthritis and compared with those of healthy subjects (CO) with no musculoskeletal disorder. The study involved subjects suffering from two forms of arthritis, viz, rheumatoid arthritis (RA) and hip osteoarthritis (OA). The analysis of the data was plagued by two problems which frequently render the analysis of this type of data extremely difficult. One was the small number of human subjects that could be included in the investigation based on the terms specified in the inclusion and exclusion criteria for the study. The other was the high intra- and inter-subject variability present in EMG data. We identified some of the muscles differently employed by the arthritic patients by using machine learning techniques to classify the two groups and then identified the muscles that were critical for the classification. For the classification we employed least-squares kernel (LSK) algorithms, neural network algorithms like the Kohonen self organizing map, learning vector quantification and the multilayer perceptron. Finally we also tested the more classical technique of linear discriminant analysis (LDA). The performance of the different algorithms was compared. The LSK algorithm showed the highest capacity for classification. Our study demonstrates that the newly developed LSK algorithm is adept for the treatment of biological data. The muscles that were most important for distinguishing the RA from the CO subjects were the soleus and biceps femoris. For separating the OA and CO subjects however, it was the gluteus medialis muscle. Our study demonstrates how classification with EMG data can be used in the clinical setting. While such procedures are unnecessary for the diagnosis of the type of arthritis present, an understanding of the muscles which are responsible for the classification can help to better identify targets for rehabilitative measures. PMID- 19775985 TI - Phase stability analysis of chirp evoked auditory brainstem responses by Gabor frame operators. AB - We have recently shown that click evoked auditory brainstem responses (ABRs) can be efficiently processed using a novelty detection paradigm. Here, ABRs as a large-scale reflection of a stimulus locked neuronal group synchronization at the brainstem level are detected as novel instance-novel as compared to the spontaneous activity which does not exhibit a regular stimulus locked synchronization. In this paper we propose for the first time Gabor frame operators as an efficient feature extraction technique for ABR single sweep sequences that is in line with this paradigm. In particular, we use this decomposition technique to derive the Gabor frame phase stability (GFPS) of sweep sequences of click and chirp evoked ABRs. We show that the GFPS of chirp evoked ABRs provides a stable discrimination of the spontaneous activity from stimulations above the hearing threshold with a small number of sweeps, even at low stimulation intensities. It is concluded that the GFPS analysis represents a robust feature extraction method for ABR single sweep sequences. Further studies are necessary to evaluate the value of the presented approach for clinical applications. PMID- 19775986 TI - Estimation of 2-D center of mass movement during trunk flexion-extension movements using body accelerations. AB - Motions of the center of body mass (COM) and body segment acceleration signals are commonly used to indicate movement performance and stability during standing activities. The COM trajectory is usually calculated by video motion analysis, which has a time consuming setup and also is not readily available in all clinical settings. In this paper, we present a novel method to estimate the COM trajectory from the upper and lower limb accelerations, based on experimental data. We have modeled the relationships that exist between the 2-D hip and trunk acceleration data with the 2-D COM trajectory in the sagittal plane, during four trunk flexion-extension movement tasks and estimated the COM trajectory based on that model. The model accounted for between 93 +/- 9% to 97 +/- 3% of the resultant COM trajectory's variability, depending on the task. This corresponded to a range of absolute error between the true and estimated COM trajectories of 0.65 +/- 0.62 to 1.07 +/- 1.13 cm. The advantage of this model compared to our previous work on COM trajectory estimation is that it does not require any calibration and provides a reasonably accurate estimation of the COM trajectory, which can be used to study human balance performance in any clinical setting. PMID- 19775987 TI - Stimulation stability and selectivity of chronically implanted multicontact nerve cuff electrodes in the human upper extremity. AB - Nine spiral nerve cuff electrodes were implanted in two human subjects for up to three years with no adverse functional effects. The objective of this study was to look at the long term nerve and muscle response to stimulation through nerve cuff electrodes. The nerve conduction velocity remained within the clinically accepted range for the entire testing period. The stimulation thresholds stabilized after approximately 20 weeks. The variability in the activation over time was not different from muscle-based electrodes used in implanted functional electrical stimulation systems. Three electrodes had multiple, independent contacts to evaluate selective recruitment of muscles. A single muscle could be selectively activated from each electrode using single-contact stimulation and the selectivity was increased with the use of field steering techniques. The selectivity after three years was consistent with selectivity measured during the implant surgery. Nerve cuff electrodes are effective for chronic muscle activation and multichannel functional electrical stimulation in humans. PMID- 19775988 TI - Interpretation of muscle spindle afferent nerve response to passive muscle stretch recorded with thin-film longitudinal intrafascicular electrodes. AB - In this study, we explored the feasibility of estimating muscle length in passive conditions by interpreting nerve responses from muscle spindle afferents recorded with thin-film longitudinal intrafascicular electrodes. Afferent muscle spindle response to passive stretch was recorded in ten acute rabbit experiments. A newly proposed first-order model of muscle spindle response to passive sinusoidal muscle stretch manages to capture the relationship between afferent neural firing rate and muscle length. We demonstrate that the model can be used to track random motion trajectories with bandwidth from 0.1 to 1 Hz over a range of 4 mm with a muscle length estimation error of 0.3 mm (1.4 degrees of joint angle). When estimation is performed using four-channel ENG there is a 50% reduction in estimate variation, compared to using single-channel recordings. PMID- 19775989 TI - Concept mapping for virtual rehabilitation and training of the blind. AB - Concept mapping is a technique that allows for the strengthening of the learning process, based on graphic representations of the learner's mental schemes. However, due to its graphic nature, it cannot be utilized by learners with visual disabilities. In response to this limitation we implemented a study that involves the design of AudiodMC, an audio-based, virtual environment for concept mapping designed for use by blind users and aimed at virtual training and rehabilitation. We analyzed the stages involved in the design of AudiodMC from a user-centered design perspective, considering user involvement and usability testing. These include an observation stage to learn how blind learners construct conceptual maps using concrete materials, a design stage to design of a software tool that aids blind users in creating concept maps, and a cognitive evaluation stage using AudiodMC. We also present the results of a study implemented in order to determine the impact of the use of this software on the development of essential skills for concept mapping (association, classification, categorization, sorting and summarizing). The results point to a high level of user acceptance, having identified key sound characteristics that help blind learners to learn concept codification and selection skills. The use of AudiodMC also allowed for the effective development of the skills under review in our research, thus facilitating meaningful learning. PMID- 19775990 TI - Functional hemispherectomy in adults with intractable epilepsy syndromes: a report of 4 cases. AB - BACKGROUND: Functional hemispherectomy (FH) is mainly performed in children with catastrophic epilepsies and pre-existing severe hemiparesis. It is accepted that mainly patients at young ages with more or less complete loss of their hand function are suitable candidates for FH. However, we feel that FH should be considered also in some adults with devastating unilateral epilepsy syndromes. PATIENTS AND METHODS: We report four cases of adults who underwent FH because of their intractable epilepsy syndromes. Three of the four patients had reduced but not complete loss of hand function. Careful weighing-up of the risk-benefit ratio still led to the decision to perform FH in order to achieve complete seizure relief. RESULTS: All patients had a surgical outcome of Engel class I; one of them suffered from post-operative psychogenic non-epileptic seizures which were treated successfully by psychotherapy. No clinically relevant complications occurred. CONCLUSION: We wish to point out that FH is a possible surgical option in cases with catastrophic epilepsies in adulthood. Patients and relatives should strongly consider that the likelihood of at least partially, impaired hand function or other surgery-related additional handicaps may be outweighed by the chance of freedom of seizures in a limited number of patients. In all of our cases, patients and relatives agreed that the surgical outcome led to a marked improvement of quality of life and that it had been the right decision to proceed with FH in spite of the expected negative impacts of the operation. Video examples of the pre- and post-surgical hand function of one sample patient are enclosed. PMID- 19775991 TI - Huh? Hemispherectomy in adults?: an exercise in risk-benefit analysis. PMID- 19775992 TI - Immune diagnosis of pure ocular mucous membrane pemphigoid: indirect immunofluorescence versus immunoblot. AB - Diagnosis of pure ocular mucous membrane pemphigoid (OMMP) is based on the demonstration of linear depositions of IgG, IgA, C3 or combinations thereof alongside the epithelial basal membrane zone with direct immunofluorescence (DIF) or immunoperoxidase (DIP) analysis of a freeze biopsy of the conjunctiva in patients with cicatrizing kerato-conjunctivitis. The aims of this study were: 1) to investigate whether the direct immunoperoxidase method is more sensitive than direct immunofluorescence; 2) to analyse whether circulating antibodies against basement membrane autoantigens can be detected in DIF positive and DIF negative patients and which method is the most sensitive for this. In 11 patients with exclusively cicatrizing keratoconjunctivitis, biopsies were evaluated with DIF and DIP. Serum was investigated with indirect immunofluorescence and immunoblot. Immunofluorescence analysis revealed linear IgG and/or IgA depositions in five out of 11 conjunctival biopsies. These depositions were less intense with immunoperoxidase analysis. Serum immunofluorescence analysis was positive in only one case (20%); immunoblot analysis for circulating antibodies was positive in 4 of 5 patients (80%) with pure OMMP. With the methods used in this study: a) the immunoperoxidase analysis was no more sensitive than direct immunofluorescence, and b) the immunoblot was more sensitive in demonstrating circulating antibodies than indirect immunofluorescence. PMID- 19775993 TI - Anti-angiogenic therapy in ovarian cancer: a great expectation to be confirmed. PMID- 19775994 TI - Fantastic voyage. PMID- 19775995 TI - Angiogenesis and ovarian cancer. AB - Ovarian carcinoma is the most important cause of gynaecological cancer-related mortality in Western societies. The age at diagnosis, extent of disease (as expressed by FIGO state), success of primary surgery and the histopathological features of the tumour are important prognostic markers. The majority of patients with ovarian cancer present with advanced disease (FIGO stage III/IV) and in this group of patients the median survival is only three years. New treatment approaches are therefore required to improve outcome in this disease. Angiogenesis, the development of a neovascular blood supply, is a critical step in the propagation of malignant tumour growth and metastasis and represents a promising target. This review will focus on angiogenesis, VEGF biology and the potential value of angiogenic factors with prognostic value in ovarian cancer. PMID- 19775996 TI - Inhibiting PI3K as a therapeutic strategy against cancer. AB - Class I PI3K is composed of heterodimeric lipid kinases regulating essential cellular functions including proliferation, apoptosis and metabolism. Class I PI3K isoforms are commonly amplified in different cancer types and the PI3Kalpha catalytic subunit, PIK3CA, has been found mutated in a variable proportion of tumours of different origin. Furthermore, PI3K has been shown to mediate oncogenic signalling induced by several oncogenes such as HER2 or Ras. These facts suggest that PI3K might be a good target for anticancer drug discovery. Today, the rise of PI3K inhibitors and their first in vivo results have cleared much of the path for the development of PI3K inhibitors for anticancer therapy. Here we will review the PI3K pathway and the pharmacological results of PI3K inhibition. PMID- 19775998 TI - Current status of anti-angiogenic agents in the treatment of ovarian carcinoma. AB - During the last decade we have assisted in the development of new therapeutic strategies for the treatment of ovarian cancer, based on the best knowledge of molecular biology. One of the most promising strategies under investigation is antiangiogenic therapy. Bevacizumab is a monoclonal humanised antibody targeting vascular endothelial growth factor (VEGF), which has shown antitumour activity in ovarian cancer in preclinical models as well as in clinical trials, both in monotherapy and in combination with other therapies. Currently, ongoing phase III trials are testing bevacizumab as a front-line therapy with carboplatin and paclitaxel. Bevacizumab has been generally well tolerated with mild frequent toxicities (proteinuria, hypertension and bleeding). However, the drug may result in other uncommon, but potentially life-threatening side effects, such as arterial thromboembolism, wound healing complications, and gastrointestinal perforation or fistulae, which should be considered when the drug is administered. Other new therapeutic antiangiogenic strategies that include small molecule tyrosine kinase inhibitors, antibodies neutralising the VEGF receptor (VEGFR) and soluble VEGFR hybrids (VEGF Trap) are being investigated with promising early results. PMID- 19775997 TI - Translational research in phase I trials. AB - "Translational research" (TR) has the main aim of transferring the results of preclinical research into clinical practice and includes the study of the biology of the disease to provide solid rationales for the development or improvement of new drugs, the evaluation of the biological effects of the drugs in animals to define how to best use those drugs in humans and the study of the biological effects of those drugs in humans. To facilitate the development of new cancer targeted therapies, TR focuses its efforts on the discovery and validation of biomarkers, defined as "a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacologic responses to a therapeutic intervention". Biomarkers could allow a rational development of targeted agents, based on the mechanistic assessment of their effects. This knowledge can then be used during the subsequent steps of drug discovery, screening, preclinical and clinical testing. This review will focus on the contributions provided by biomarkers to facilitate the development of new targeted therapies. PMID- 19775999 TI - Radiation therapy for early breast cancer. AB - In women with early-stage breast cancer treated with surgery alone, microscopic residual disease may not be eliminated and can eventually cause life-threatening metastatic recurrence. Radiation therapy has been widely recommended for local control after breast-conserving surgery (BCS) and after a complete mastectomy in women at high risk of recurrence. However, even with widespread support for these recommendations within the medical community, they are not always heeded. Because local recurrence, when detected early, can often be treated with additional surgery alone, some physicians and patients still elect to avoid radiation therapy. It was felt, based upon individual trial data, that radiation therapy did not affect overall survival, but just decreased local relapse. The meta analysis, published in the December 17/2005 Lancet, analysed individual data from 42,000 women, collected during 78 different randomised trials conducted since 1985. The availability of extensive 15-year survival data allowed the investigators to quantify the relationship between successful local control and long-term survivorship. Moreover, individual trials all show a benefit in local control and some trends toward survival advantages. The pooled meta-analysis of breast conservative surgery with or without radiation therapy Vinh Hung (2004) demonstrates a significant impact on local relapse and a small but significant impact on survival. It is considered that after BCS and in certain cases after mastectomy, radiation therapy is the standard treatment for improved local control and longterm survival. PMID- 19776000 TI - Clinical experience with biweekly CHOP plus rituximab chemoimmunotherapy for the treatment of aggressive B-cell non-Hodgkin lymphoma. AB - BACKGROUND: The results of CHOP-21 (cyclophosphamide, doxorubicin, vincristine and prednisone given every 21 days) for the treatment of aggressive B-cell lymphoma have recently been improved by the addition of rituximab and by increasing the dose density. R-CHOP-14 combines these two approaches. PATIENTS AND METHODS: We present our experience with R-CHOP-14 in a retrospective single centre review of 50 patients consecutively treated for aggressive B-cell lymphoma. RESULTS: The median age was 59 years and 48% of patients were >60 years. Stage III-IV was present in 62% of the patients and international prognostic index was high-to-intermediate risk or high risk in 32% of the patients. Toxicity was mainly haematological, with grade 3-4 neutropenia observed in 32% and febrile neutropenia in 18%. Other relevant toxicities were peripheral neuropathy in 45% (grade 3 in 4%) and cardiac dysfunction grade 3 in 7.5%. After therapy, 82% of the patients achieved complete response or unproved complete response. With a median follow-up of 30 months, 3-year event-free survival and overall survival were 67% and 82% respectively. CONCLUSIONS: In our experience the combination of RCHOP- 14 is highly effective in patients with aggressive B cell lymphoma. However special attention must be paid to the control of early and late toxicities. PMID- 19776001 TI - Treatment of anal carcinoma in immune-compromised patients. AB - BACKGROUND: Immune-compromised populations show an increased incidence of anogenital tract neoplasms. This study was undertaken to evaluate local control (LC), overall survival (OS) and toxicity in immune-compromised patients with anal carcinoma treated with radiotherapy with or without chemotherapy. METHODS: We identified 25 patients with anal carcinoma and human immunodeficiency virus (HIV) infection or history of solid-organ transplant on chronic medical immune suppression. Median age and follow-up were 44 years and 26 months respectively. AJCC T-stages were Tis (4%), T1 (8%), T2 (58%) and T3 (29%). N-stages were N0 (79%), N1 (4%), N2 (13%) and N3 (4%). One patient had metastatic disease at diagnosis. Seventy-five percent received concurrent chemoradiotherapy. Median radiation dose to the primary tumour was 50 Gy. RESULTS: One-, 3- and 5-year LC without salvage therapy was 87%, 87% and 70% respectively. One-, 3- and 5-year actuarial OS was 96%, 73% and 61% respectively. One-, 3- and 5-year OS was 100% for treatment time (TT) <50 days and 57%, 38% and 0% for TT > or =50 days (p=0.0009). All patients had acute grade 2-3 skin toxicity. Acute grade 3-4 gastrointestinal (GI), genitourinary (GU) and haematological toxicity occurred in 8%, 0% and 38%. Late grade 3-4 skin, GI and GU toxicity occurred in 8%, 4% and 0%. CONCLUSIONS: Most HIV-positive and organ transplant patients receiving radiotherapy with or without chemotherapy experience acute toxicity but few have chronic complications. T-stage and CD4 level in HIV-positive patients predict for LC. T-stage and TT predict for OS. PMID- 19776002 TI - CTV to PTV margins for prostate irradiation. Three-dimensional quantitative assessment of interfraction uncertainties using portal imaging and serial CT scans. AB - PURPOSE: To determine the magnitude of setup and organ motion errors from a subset of prostate cancer patients treated with conventional conformal radiotherapy, and to estimate the CTV-PTV margin according to published margin recipes. METHODS AND MATERIALS: Twenty prostate cancer patients were treated with external radiotherapy using electronic portal images (EPIs). Weekly treatment EPIs and pelvic CT scans were obtained. These data allowed interfractional analysis of prostate centre of mass motion and setup error. The margins needed to compensate these uncertainties were calculated. RESULTS: Tattoo localisation requires a margin of 9-10.5 mm (LR), 15.2-17.8 mm (anterior-posterior (AP)) and 10.6-12.4 mm (superior-inferior (S-I)). Systematic displacements due to prostatic motion, with standard deviations of 2.4 mm (LR), 4.2 mm (AP) and 3.1 mm (S-I) were found to be larger than setup errors (1.8, 3.0 and 1.7 mm respectively). CONCLUSIONS: Customised PTV margin definition has been possible through in-house measurements of geometrical clinical uncertainties involved in the conventional conformal radiotherapy process. Uncertainty measurements in our department have proved to be larger than those used in common practice. Additional margin reduction procedures are needed in order to accomplish conformal radiotherapy goals. PMID- 19776003 TI - Gamma Knife radiosurgery for occipital condyle metastasis. AB - We present a 45 year old female with right occipital condylar metastases who was treated at William Beaumont Hospital in the Gamma Knife Unit. Clinical results at 17 months follow-up and MRI are exposed. PMID- 19776004 TI - Skull metastasis from rectal gastrointestinal stromal tumours. AB - Gastrointestinal stromal tumours (GIST) are the most common mesenchymal neoplasm of the gastrointestinal tract. Rectum localisation is infrequent for these neoplasms, accounting for about 5% of all cases. Distant metastases of GIST are also rare. We present a patient with special features: the tumour is localised in rectum and it has an uncommon metastatic site, the skull, implying a complex differential diagnosis approach. PMID- 19776005 TI - Phosphorylation of myocardin by extracellular signal-regulated kinase. AB - The contractile phenotype of smooth muscle (SM) cells is controlled by serum response factor (SRF), which drives the expression of SM-specific genes including SM alpha-actin, SM22, and others. Myocardin is a cardiac and SM-restricted coactivator of SRF that is necessary for SM gene transcription. Growth factors inducing proliferation of SM cells inhibit SM gene transcription, in a manner dependent on the activation of extracellular signal-regulated kinases ERK1/2. In this study, we found that ERK1/2 phosphorylates mouse myocardin (isoform B) at four sites (Ser(812), Ser(859), Ser(866), and Thr(893)), all of which are located within the transactivation domain of myocardin. The single mutation of each site either to alanine or to aspartate has no effect on the ability of myocardin to activate SRF. However, the phosphomimetic mutation of all four sites to aspartate (4xD) significantly impairs activation of SRF by myocardin, whereas the phosphodeficient mutation of all four sites to alanine (4xA) has no effect. This translates to a reduced ability of the 4xD (but not of 4xA) mutant of myocardin to stimulate expression of SM alpha-actin and SM22, as assessed by corresponding promoter, mRNA, or protein assays. Furthermore, we found that phosphorylation of myocardin at these sites impairs its interaction with acetyltransferase, cAMP response element-binding protein-binding protein, which is known to promote the transcriptional activity of myocardin. In conclusion, we describe a novel mode of modulation of SM gene transcription by ERK1/2 through a direct phosphorylation of myocardin. PMID- 19776006 TI - Ribosomal protein S12 and aminoglycoside antibiotics modulate A-site mRNA cleavage and transfer-messenger RNA activity in Escherichia coli. AB - Translational pausing in Escherichia coli can lead to mRNA cleavage within the ribosomal A-site. A-site mRNA cleavage is thought to facilitate transfer messenger RNA (tmRNA).SmpB- mediated recycling of stalled ribosome complexes. Here, we demonstrate that the aminoglycosides paromomycin and streptomycin inhibit A-site cleavage of stop codons during inefficient translation termination. Aminoglycosides also induced stop codon read-through, suggesting that these antibiotics alleviate ribosome pausing during termination. Streptomycin did not inhibit A-site cleavage in rpsL mutants, which express streptomycin-resistant variants of ribosomal protein S12. However, rpsL strains exhibited reduced A-site mRNA cleavage compared with rpsL(+) cells. Additionally, tmRNA.SmpB-mediated SsrA peptide tagging was significantly reduced in several rpsL strains but could be fully restored in a subset of mutants when treated with streptomycin. The streptomycin-dependent rpsL(P90K) mutant also showed significantly lower levels of A-site cleavage and tmRNA.SmpB activity. Mutations in rpsD (encoding ribosomal protein S4), which suppressed streptomycin dependence, were able to partially restore A-site cleavage to rpsL(P90K) cells but failed to increase tmRNA.SmpB activity. Taken together, these results show that perturbations to A-site structure and function modulate A-site mRNA cleavage and tmRNA.SmpB activity. We propose that tmRNA.SmpB binds to streptomycin resistant rpsL ribosomes less efficiently, leading to a partial loss of ribosome rescue function in these mutants. PMID- 19776007 TI - Galectin-9 is a high affinity IgE-binding lectin with anti-allergic effect by blocking IgE-antigen complex formation. AB - Galectin (Gal)-9 was first described as an eosinophil chemoattractant. With the progress in research, Gal-9 has come to be known as a versatile immunomodulator that is involved in various aspects of immune regulations, and the entire picture of the function still remains elusive. To uncover as-yet unknown activity of Gal 9, we have been examining the effect of the protein in various disease animal models. Here we show that Gal-9 attenuated asthmatic reaction in guinea pigs and suppressed passive-cutaneous anaphylaxis in mice. These results indicate the mast cell stabilizing effect of Gal-9. In vitro studies of mast cell degranulation involving RBL-2H3 cells demonstrated that Gal-9 suppressed degranulation from the cells stimulated by IgE plus antigen and that the inhibitory effect was completely abrogated in the presence of lactose, indicating lectin activity of Gal-9 is critical. We found that Gal-9 strongly and specifically bound IgE, which is a heavily glycosylated immunoglobulin, and that the interaction prevented IgE antigen complex formation, clarifying the mode of action of the anti degranulation effect. Gal-9 is expressed by several mast cells including mouse mast cell line MC/9. The fact that immunological stimuli of MC/9 cells augmented Gal-9 secretion from the cells implies that Gal-9 is an autocrine regulator of mast cell function to suppress excessive degranulation. Collectively, these findings shed light on a novel function of Gal-9 in mast cells and suggest a beneficial utility of Gal-9 for the treatment of allergic disorders including asthma. PMID- 19776008 TI - Geranylgeranyl pyrophosphate is a potent regulator of HRD-dependent 3-Hydroxy-3 methylglutaryl-CoA reductase degradation in yeast. AB - 3-Hydroxy-3-methylglutaryl (HMG)-CoA reductase (HMGR), the rate-limiting enzymes of sterol synthesis, undergoes feedback-regulated endoplasmic reticulum degradation in both mammals and yeast. The yeast Hmg2p isozyme is subject to ubiquitin-mediated endoplasmic reticulum degradation by the HRD pathway. We had previously shown that alterations in cellular levels of the 15-carbon sterol pathway intermediate farnesyl pyrophosphate (FPP) cause increased Hmg2p ubiquitination and degradation. We now present evidence that the FPP-derived, 20 carbon molecule geranylgeranyl pyrophosphate (GGPP) is a potent endogenous regulator of Hmg2p degradation. This work was launched by the unexpected observation that GGPP addition directly to living yeast cultures caused high potency and specific stimulation of Hmg2p degradation. This effect of GGPP was not recapitulated by FPP, GGOH, or related isoprenoids. GGPP-caused Hmg2p degradation met all the criteria for the previously characterized endogenous signal. The action of added GGPP did not require production of endogenous sterol molecules, indicating that it did not act by causing the build-up of an endogenous pathway signal. Manipulation of endogenous GGPP by several means showed that naturally made GGPP controls Hmg2p stability. Analysis of the action of GGPP indicated that the molecule works upstream of retrotranslocation and can directly alter the structure of Hmg2p. We propose that GGPP is the FPP-derived regulator of Hmg2p ubiquitination. Intriguingly, the sterol-dependent degradation of mammalian HMGR is similarly stimulated by the addition of GGOH to intact cells, implying that a dependence on 20-carbon geranylgeranyl signals may be a common conserved feature of HMGR regulation that may lead to highly specific therapeutic approaches for modulation of HMGR. PMID- 19776009 TI - Autophosphorylation-independent and -dependent functions of focal adhesion kinase during development. AB - Focal adhesion kinase (FAK) regulates numerous cellular functions and is critical for processes ranging from embryo development to cancer progression. Although autophosphorylation on Tyr-397 appears required for FAK functions in vitro, its role in vivo has not been established. We addressed this question using a mutant mouse (fakDelta) deleted of exon 15, which encodes Tyr-397. The resulting mutant protein FAKDelta is an active kinase expressed at normal levels. Our results demonstrate that the requirement for FAK autophosphorylation varies during development. FAK(Delta/Delta) embryos developed normally up to embryonic day (E) 12.5, contrasting with the lethality at E8.5 of FAK-null embryos. Thus, autophosphorylation on Tyr-397 is not required for FAK to achieve its functions until late mid-gestation. However, FAK(Delta/Delta) embryos displayed hemorrhages, edema, delayed artery formation, vascular remodeling defects, multiple organ abnormalities, and overall developmental retardation at E13.5 14.5, and died thereafter demonstrating that FAK autophosphorylation is also necessary for normal development. Fibroblasts derived from mutant embryos had a normal stellate morphology and expression of focal adhesion proteins, Src family members, p53, and Pyk2. In contrast, in FAK(Delta/Delta) fibroblasts and endothelial cells, spreading and lamellipodia formation were altered with an increased size and number of focal adhesions, enriched in FAKDelta. FAK mutation also decreased fibroblast proliferation. These results show that the physiological functions of FAK in vivo are achieved through both autophosphorylation-independent and autophosphorylation-dependent mechanisms. PMID- 19776011 TI - Role of Bacillus subtilis BacB in the synthesis of bacilysin. AB - Bacilysin is a non-ribosomally synthesized dipeptide antibiotic that is active against a wide range of bacteria and some fungi. Synthesis of bacilysin (l alanine-[2,3-epoxycyclohexano-4]-l-alanine) is achieved by proteins in the bac operon, also referred to as the bacABCDE (ywfBCDEF) gene cluster in B. subtilis. Extensive genetic analysis from several strains of B. subtilis suggests that the bacABC gene cluster encodes all the proteins that synthesize the epoxyhexanone ring of l-anticapsin. These data, however, were not consistent with the putative functional annotation for these proteins whereby BacA, a prephenate dehydratase along with a potential isomerase/guanylyl transferase, BacB and an oxidoreductase, BacC, could synthesize l-anticapsin. Here we demonstrate that BacA is a decarboxylase that acts on prephenate. Further, based on the biochemical characterization and the crystal structure of BacB, we show that BacB is an oxidase that catalyzes the synthesis of 2-oxo-3-(4-oxocyclohexa-2,5 dienyl)propanoic acid, a precursor to l-anticapsin. This protein is a bi-cupin, with two putative active sites each containing a bound metal ion. Additional electron density at the active site of the C-terminal domain of BacB could be interpreted as a bound phenylpyruvic acid. A significant decrease in the catalytic activity of a point variant of BacB with a mutation at the N-terminal domain suggests that the N-terminal cupin domain is involved in catalysis. PMID- 19776010 TI - Interferon gamma attenuates insulin signaling, lipid storage, and differentiation in human adipocytes via activation of the JAK/STAT pathway. AB - Recent reports demonstrate T-cell infiltration of adipose tissue in early obesity. We hypothesized that interferon (IFN) gamma, a major T-cell inflammatory cytokine, would attenuate human adipocyte functions and sought to establish signaling mechanisms. Differentiated human adipocytes were treated with IFNgamma +/- pharmacological inhibitors prior to insulin stimulation. [(3)H]Glucose uptake and AKT phosphorylation were assessed as markers of insulin sensitivity. IFNgamma induced sustained loss of insulin-stimulated glucose uptake in human adipocytes, coincident with reduced Akt phosphorylation and down-regulation of the insulin receptor, insulin receptor substrate-1, and GLUT4. Loss of adipocyte triglyceride storage was observed with IFNgamma co-incident with reduced expression of peroxisome proliferator-activated receptor gamma, adiponectin, perilipin, fatty acid synthase, and lipoprotein lipase. Treatment with IFNgamma also blocked differentiation of pre-adipocytes to the mature phenotype. IFNgamma-induced robust STAT1 phosphorylation and SOCS1 mRNA expression, with modest, transient STAT3 phosphorylation and SOCS3 induction. Preincubation with a non-selective JAK inhibitor restored glucose uptake and Akt phosphorylation while completely reversing IFNgamma suppression of adipogenic mRNAs and adipocyte differentiation. Specific inhibition of JAK2 or JAK3 failed to block IFNgamma effects suggesting a predominant role for JAK1-STAT1. We demonstrate that IFNgamma attenuates insulin sensitivity and suppresses differentiation in human adipocytes, an effect most likely mediated via sustained JAK-STAT1 pathway activation. PMID- 19776012 TI - Improved binding of raf to Ras.GDP is correlated with biological activity. AB - The GTP-binding protein Ras plays a central role in the regulation of various cellular processes, acting as a molecular switch that triggers signaling cascades. Only Ras bound to GTP is able to interact strongly with effector proteins like Raf kinase, phosphatidylinositol 3-kinase, and RalGDS, whereas in the GDP-bound state, the stability of the complex is strongly decreased, and signaling is interrupted. To determine whether this process is only controlled by the stability of the complex, we used computer-aided protein design to improve the interaction between Ras and effector. We challenged the Ras.Raf complex in this study because Raf among all effectors shows the highest Ras affinity and the fastest association kinetics. The proposed mutations were characterized as to their changes in dynamics and binding strength. We demonstrate that Ras-Raf interaction can only be improved at the cost of a loss in specificity of Ras.GTP versus Ras.GDP. As shown by NMR spectroscopy, the Raf mutation A85K leads to a shift of Ras switch I in the GTP-bound as well as in the GDP-bound state, thereby increasing the complex stability. In a luciferase-based reporter gene assay, Raf A85K is associated with higher signaling activity, which appears to be a mere matter of Ras-Raf affinity. PMID- 19776013 TI - Control of respiration by cytochrome c oxidase in intact cells: role of the membrane potential. AB - Metabolic control analysis was applied to intact HepG2 cells. The effect on the control coefficient of cytochrome c oxidase (CcOX) over cell respiration of both the electrical (Delta psi) and chemical (Delta pH) component of the mitochondrial transmembrane proton electrochemical gradient (Delta mu(H(+))) was investigated. The overall O(2) consumption and specific CcOX activity of actively phosphorylating cells were titrated with cyanide under conditions in which Delta psi and Delta pH were selectively modulated by addition of ionophores. In the absence of ionophores, CcOX displayed a high control coefficient (C(IV) = 0.73), thus representing an important site of regulation of mitochondrial oxidative phosphorylation. A high control coefficient value (C(IV) = 0.85) was also measured in the presence of nigericin, i.e. when Delta psi is maximal, and in the presence of nigericin and valinomycin (C(IV) = 0.77), when Delta mu(H(+)) is abolished. In contrast, CcOX displayed a markedly lower control coefficient (C(IV) = 0.30) upon addition of valinomycin, when Delta psi is converted into Delta pH. These results show that Delta psi is responsible for the tight control of CcOX over respiration in actively phosphorylating cells. PMID- 19776014 TI - Glucocorticoid-mediated inhibition of Lck modulates the pattern of T cell receptor-induced calcium signals by down-regulating inositol 1,4,5-trisphosphate receptors. AB - Glucocorticoids are potent immunosuppressive agents that block upstream signaling events required for T cell receptor (TCR) activation. However, the mechanism by which glucocorticoids inhibit downstream responses, such as inositol 1,4,5 trisphosphate (IP(3))-induced calcium signals, is not completely understood. Here we demonstrate that low concentrations of dexamethasone rapidly convert transient calcium elevations to oscillations after strong TCR stimulation. Dexamethasone converted the pattern of calcium signaling by inhibiting the Src family kinase Lck, which was shown to interact with and positively regulate Type I IP(3) receptor. In addition, low concentrations of dexamethasone were sufficient to inhibit calcium oscillations and interleukin-2 mRNA after weak TCR stimulation. Together, these findings indicate that by inhibiting Lck and subsequently down regulating IP(3) receptors, glucocorticoids suppress immune responses by weakening the strength of the TCR signal. PMID- 19776015 TI - Phosphorylation of Williams syndrome transcription factor by MAPK induces a switching between two distinct chromatin remodeling complexes. AB - Changes in the environment of a cell precipitate extracellular signals and sequential cascades of protein modification and elicit nuclear transcriptional responses. However, the functional links between intracellular signaling dependent gene regulation and epigenetic regulation by chromatin-modifying proteins within the nucleus are largely unknown. Here, we describe novel epigenetic regulation by MAPK cascades that modulate formation of an ATP dependent chromatin remodeling complex, WINAC (WSTF Including Nucleosome Assembly Complex), an SWI/SNF-type complex containing Williams syndrome transcription factor (WSTF). WSTF, a specific component of two chromatin remodeling complexes (SWI/SNF-type WINAC and ISWI-type WICH), was phosphorylated by the stimulation of MAPK cascades in vitro and in vivo. Ser-158 residue in the WAC (WSTF/Acf1/cbpq46) domain, located close to the N terminus of WSTF, was identified as a major phosphorylation target. Using biochemical analysis of a WSTF mutant (WSTF-S158A) stably expressing cell line, the phosphorylation of this residue (Ser-158) was found to be essential for maintaining the association between WSTF and core BAF complex components, thereby maintaining the ATPase activity of WINAC. WINAC dependent transcriptional regulation of vitamin D receptor was consequently impaired by this WSTF mutation, but the recovery from DNA damage mediated by WICH was not impaired. Our results suggest that WSTF serves as a nuclear sensor of the extracellular signals to fine-tune the chromatin remodeling activity of WINAC. WINAC mediates a previously unknown MAPK-dependent step in epigenetic regulation, and this MAPK-dependent switching mechanism between the two functionally distinct WSTF-containing complexes might underlie the diverse functions of WSTF in various nuclear events. PMID- 19776016 TI - Employing a recombinant HLA-DR3 expression system to dissect major histocompatibility complex II-thyroglobulin peptide dynamism: a genetic, biochemical, and reverse immunological perspective. AB - Previously, we have shown that statistical synergism between amino acid variants in thyroglobulin (Tg) and specific HLA-DR3 pocket sequence signatures conferred a high risk for autoimmune thyroid disease (AITD). Therefore, we hypothesized that this statistical synergism mirrors a biochemical interaction between Tg peptides and HLA-DR3, which is key to the pathoetiology of AITD. To test this hypothesis, we designed a recombinant HLA-DR3 expression system that was used to express HLA DR molecules harboring either AITD susceptibility or resistance DR pocket sequences. Next, we biochemically generated the potential Tg peptidic repertoire available to HLA-DR3 by separately treating 20 purified human thyroglobulin samples with cathepsins B, D, or L, lysosomal proteases that are involved in antigen processing and thyroid biology. Sequences of the cathepsin-generated peptides were then determined by matrix-assisted laser desorption ionization time of-flight-mass spectroscopy, and algorithmic means were employed to identify putative AITD-susceptible HLA-DR3 binders. From four predicted peptides, we identified two novel peptides that bound strongly and specifically to both recombinant AITD-susceptible HLA-DR3 protein and HLA-DR3 molecules expressed on stably transfected cells. Intriguingly, the HLA-DR3-binding peptides we identified had a marked preference for the AITD-susceptibility DR signatures and not to those signatures that were AITD-protective. Structural analyses demonstrated the profound influence that the pocket signatures have on the interaction of HLA-DR molecules with Tg peptides. Our study suggests that interactions between Tg and discrete HLA-DR pocket signatures contribute to the initiation of AITD. PMID- 19776017 TI - Interleukin-25 expressed by brain capillary endothelial cells maintains blood brain barrier function in a protein kinase Cepsilon-dependent manner. AB - Interleukin (IL)-25, a member of the IL-17 family of cytokines, is expressed in the brains of normal mice. However, the cellular source of IL-25 and its function in the brain remain to be elucidated. Here, we show that IL-25 plays an important role in preventing infiltration of the inflammatory cells into the central nervous system. Brain capillary endothelial cells (BCECs) express IL-25. However, it is down-regulated by inflammatory cytokines, including tumor necrosis factor (TNF)-alpha, IL-17, interferon-gamma, IL-1beta, and IL-6 in vitro, and is also reduced in active multiple sclerosis (MS) lesions and in the inflamed spinal cord of experimental autoimmune encephalomyelitis, an animal model of MS. Furthermore, IL-25 restores the reduced expression of tight junction proteins, occludin, junction adhesion molecule, and claudin-5, induced by TNF-alpha in BCECs and consequently repairs TNF-alpha-induced blood-brain barrier (BBB) permeability. IL 25 induces protein kinase Cepsilon (PKCepsilon) phosphorylation, and up regulation of claudin-5 is suppressed by PKCepsilon inhibitor peptide in the IL 25-stimulated BCECs. These results suggest that IL-25 is produced by BCECs and protects against inflammatory cytokine-induced excessive BBB collapse through a PKCepsilon-dependent pathway. These novel functions of IL-25 in maintaining BBB integrity may help us understand the pathophysiology of inflammatory brain diseases such as MS. PMID- 19776018 TI - High resolution NMR-based model for the structure of a scFv-IL-1beta complex: potential for NMR as a key tool in therapeutic antibody design and development. AB - Monoclonal antibodies have recently started to deliver on their promise as highly specific and active drugs; however, a more effective, knowledge-based approach to the selection, design, and optimization of potential therapeutic antibodies is currently limited by the surprising lack of detailed structural information for complexes formed with target proteins. Here we show that complexes formed with minimal antigen binding single chain variable fragments (scFv) reliably reflect all the features of the binding interface present in larger Fab fragments, which are commonly used as therapeutics, and report the development of a robust, reliable, and relatively rapid approach to the determination of high resolution models for scFv-target protein complexes. This NMR spectroscopy-based approach combines experimental determination of the interaction surfaces and relative orientations of the scFv and target protein, with NMR restraint-driven, semiflexible docking of the proteins to produce a reliable and highly informative model of the complex. Experience with scFvs and Fabs targeted at a number of secreted regulatory proteins suggests that the approach will be applicable to many therapeutic antibodies targeted at proteins, and its application is illustrated for a potential therapeutic antibody targeted at the cytokine IL 1beta. The detailed structural information that can be obtained by this approach has the potential to have a major impact on the rational design and development of an increasingly important class of biological pharmaceuticals. PMID- 19776019 TI - Direct modification of the proinflammatory cytokine macrophage migration inhibitory factor by dietary isothiocyanates. AB - Isothiocyanates are a class of phytochemicals with widely reported anti-cancer and anti-inflammatory activity. However, knowledge of their activity at a molecular level is limited. The objective of this study was to identify biological targets of phenethyl isothiocyanate (PEITC) using an affinity purification approach. An analogue of PEITC was synthesized to enable conjugation to a solid-phase resin. The pleiotropic cytokine macrophage migration inhibitory factor (MIF) was the major protein captured from cell lysates. Site-directed mutagenesis and mass spectrometry showed that PEITC covalently modified the N terminal proline residue of MIF. This resulted in complete loss of catalytic tautomerase activity and disruption of protein conformation, as determined by impaired recognition by a monoclonal antibody directed to the region that receptors and interacting proteins bind to MIF. The conformational change was supported by in silico modeling. Monoclonal antibody binding to plasma MIF was disrupted in humans consuming watercress, a major dietary source of PEITC. The isothiocyanates have significant potential for development as MIF inhibitors, and this activity may contribute to the biological properties of these phytochemicals. PMID- 19776020 TI - Interleukin-10 facilitates both cholesterol uptake and efflux in macrophages. AB - Foam cell formation is a hallmark event during atherosclerosis. The current paradigm is that lipid uptake by scavenger receptor in macrophages initiates the chronic proinflammatory cascade and necrosis core formation that characterize atherosclerosis. We report here that a cytokine considered to be anti atherogenic, interleukin-10 (IL10), promotes cholesterol uptake from modified lipoproteins in macrophages and its transformation into foam cells by increasing the expression of scavenger receptor CD36 and scavenger receptor A. Although uptake of modified lipoproteins is considered proatherogenic, we found that IL10 also increases cholesterol efflux from macrophages to protect against toxicity of free cholesterol accumulation in the cell. This process was PPARgamma-dependent and was mediated through up-regulation of ABCA1 (ATP-binding cassette transporter A1) protein expression. Importantly, expression of inflammatory molecules, such as tumor necrosis factor-alpha, intercellular adhesion molecule-1, and MMP9 as well as apoptosis were dramatically suppressed in lipid-laden foam cells treated with IL10. The notion that IL10 can mediate both the uptake of cholesterol from modified lipoproteins and the efflux of stored cholesterol suggests that the process of foam cell formation is not necessarily detrimental as long as mechanisms of cholesterol efflux and transfer to an exogenous acceptor are functioning robustly. Our results present a comprehensive antiatherogenic role of IL10 in macrophages, including enhanced disposal of harmful lipoproteins, inhibition of inflammatory molecules, and reduced apoptosis. PMID- 19776021 TI - Crystal structure and functional analysis of homocitrate synthase, an essential enzyme in lysine biosynthesis. AB - Homocitrate synthase (HCS) catalyzes the first and committed step in lysine biosynthesis in many fungi and certain Archaea and is a potential target for antifungal drugs. Here we report the crystal structure of the HCS apoenzyme from Schizosaccharomyces pombe and two distinct structures of the enzyme in complex with the substrate 2-oxoglutarate (2-OG). The structures reveal that HCS forms an intertwined homodimer stabilized by domain-swapping between the N- and C-terminal domains of each monomer. The N-terminal catalytic domain is composed of a TIM barrel fold in which 2-OG binds via hydrogen bonds and coordination to the active site divalent metal ion, whereas the C-terminal domain is composed of mixed alpha/beta topology. In the structures of the HCS apoenzyme and one of the 2-OG binary complexes, a lid motif from the C-terminal domain occludes the entrance to the active site of the neighboring monomer, whereas in the second 2-OG complex the lid is disordered, suggesting that it regulates substrate access to the active site through its apparent flexibility. Mutations of the active site residues involved in 2-OG binding or implicated in acid-base catalysis impair or abolish activity in vitro and in vivo. Together, these results yield new insights into the structure and catalytic mechanism of HCSs and furnish a platform for developing HCS-selective inhibitors. PMID- 19776022 TI - Phase II study of gemcitabine monotherapy as a salvage treatment for Japanese metastatic breast cancer patients after anthracycline and taxane treatment. AB - OBJECTIVE: This Phase II study was conducted to evaluate efficacy and safety of gemcitabine monotherapy in anthracycline and taxane pre-treated Japanese metastatic breast cancer patients. METHODS: At Step 1, twelve patients were divided into two groups of six patients each and the dose-limiting toxicity was evaluated at gemcitabine 1000 and 1250 mg/m(2) to determine the dose for Step 2. At Step 2, an additional 56 patients were assessed for efficacy and safety of gemcitabine monotherapy. Patients were treated with gemcitabine on days 1 and 8 of a 21-day cycle and explored incidence of adverse events graded by Common Terminology Criteria for Adverse Events (CTCAE) version 3.0, overall response rate (RR), time to progression disease and overall survival time. RESULTS: Gemcitabine 1250 mg/m(2) was determined as the dose for Step 2. Adverse events reported in this study were similar in type, frequency and toxicity grades as seen in other tumor types. Of the 62 patients at 1250 mg/m(2), 1 complete response (1.6%), 4 partial response (6.5%) and 20 stable disease (32.3%) were achieved, yielding an RR of 8.1% (95% CI: 2.7%, 17.8%). Median time to progression was 92.0 days (range: 29-651 days). The median survival time was 17.8 months (95% CI: 14.9 months to incalculable). CONCLUSION: Gemcitabine at 1250 mg/m(2) on days 1 and 8 of a 21-day cycle was tolerable and can be a salvage treatment option for Japanese metastatic breast cancer patients previously treated with anthracyclines and taxanes. PMID- 19776023 TI - Respiratory monitoring of neonatal resuscitation. AB - Video observations and recordings of respiratory signals from mannequin studies and delivery room (DR) resuscitations are described. This article discusses the uses of a respiratory function monitor (RFM) during training and resuscitations along with potential pitfalls and limitations. It adds objectivity to the clinical assessment. A respiratory function monitor provides real-time quantitative information including tidal volume and leak. It may be used to teach correct mask hold and positioning techniques during simulation-based mannequin. Examples demonstrating its potential usefulness during resuscitations are provided. However, further studies are needed to investigate whether it can help improve short-term and long-term outcomes. PMID- 19776027 TI - A novel method of measuring the mental workload of anaesthetists during simulated practice. AB - BACKGROUND: Cognitive overload has been recognized as a significant cause of error in industries such as aviation, and measuring mental workload has become a key method of improving safety. The aim of this study was to pilot the use of a new method of measuring mental workload using a previously published study design. METHODS: Ten trainee anaesthetists were exposed to a simulated crisis, similar to that used in a previous study. The mental workload of the trainees was assessed by measuring their response times to a wireless vibrotactile device. RESULTS: Although all subjects treated the 'patient' adequately, response times increased significantly during the crisis (P=0.005). These findings are consistent with increased mental workload and with the findings of other studies using similar techniques. CONCLUSIONS: These findings confirm the importance of mental workload to the performance of anaesthetists, and suggest that raised mental workload is likely to be a common problem. Although further studies are required, the method described may provide a useful method for the measurement of the mental workload of anaesthetists. PMID- 19776024 TI - Programmed health surveillance and detection of emerging diseases in occupational health: contribution of the French national occupational disease surveillance and prevention network (RNV3P). AB - OBJECTIVE: The French national occupational disease surveillance and prevention network (RNV3P) includes the 30 occupational disease consultation centres in university hospitals to which patients are referred for potentially work-related diseases, and an occupational health service. The aim of this work is to demonstrate the contribution of RNV3P to national health surveillance. METHODS: Data from consultations are recorded in standardised occupational health reports and coded using international or national classifications. Programmed health surveillance is carried out through annual follow-up of annual referrals to experts for pre-selected disease-exposure associations, as well as incidence estimations for the well characterised working population followed by the occupational health service. Hypotheses on new emerging diseases are generated using statistical methods employed in pharmacosurveillance and by modelling as an exposome to analyse multiple exposures. RESULTS: 58,777 occupational health reports were collected and analysed from 2001 to 2007. Referrals to the 30 university hospital centres increased significantly for asbestos-related diseases, mood disorders and adjustment disorders related to psychological and organisational demands, and for elbow and shoulder disorders related to manual handling. Referrals significantly decreased for asthma and for rhinitis related to exposure to organic dusts (vegetable or animal) or chemicals, except for cosmetics and cleaning products. Estimation of incidences by the occupational health services showed different patterns in different sectors of activity. The methods for detecting emerging diseases are presented and illustrated using the example of systemic sclerosis, identifying new exposures and new sectors of activity to be investigated. CONCLUSION: The RNV3P collects data from two complementary samples: 30 university hospital centres (workers or former workers) and an occupational health service (current workers). This dual approach is useful for surveillance and for hypothesis generation on new emerging disease exposure associations. PMID- 19776028 TI - Effect of anaesthetic technique on oestrogen receptor-negative breast cancer cell function in vitro. AB - BACKGROUND: Metastatic recurrence is the main cause of breast cancer-related deaths. Tumour cell proliferation and migration are crucial steps in the metastatic process. Several perioperative factors, including general anaesthesia and opioid analgesia, adversely affect immune function, potentially increasing metastatic recurrence. Regional anaesthesia-analgesia has been consistently shown to attenuate the stress response to surgery, and also reduce opioid and general anaesthesia requirements, thereby attenuating this perioperative immunosuppression. We investigated the effect of serum from breast cancer surgery patients who received different anaesthetic techniques on breast cancer cell function in vitro. METHODS: Patients were randomized to receive propofol/paravertebral anaesthesia-analgesia (propofol/paravertebral, n=11) or sevoflurane general anaesthesia with opioid analgesia (sevoflurane/opioid, n=11). The ER-negative MDA-MB-231 cell line was treated with patient serum from both groups. The effects on proliferation and migration were measured. RESULTS: Treatment groups were well balanced for age, weight, surgical procedure, and cancer pathology. Pain scores were lower at 1 and 2 h in the propofol/paravertebral analgesia group. Compared with preoperative values, proliferation of MDA-MB-231 cells treated with postoperative patient serum at 10% concentration from the propofol/paravertebral group was significantly reduced compared with the sevoflurane/opioid group (-24% vs 73%, P=0.01). There was no significant change in MDA-MB-231 cell migration after treatment with patient serum between the two groups. CONCLUSIONS: Serum from patients receiving propofol/paravertebral anaesthesia for breast cancer surgery inhibited proliferation, but not migration, of ER-MDA-MB-231 cells in vitro, to a greater extent than that from patients receiving sevoflurane/opioid anaesthesia analgesia. This implies that anaesthetic technique alters the serum molecular milieu in ways that may affect breast cancer cell function, possibly by altering anaesthetic and opioid drug administration and resultant pain scores. PMID- 19776029 TI - GPCR-GIA: a web-server for identifying G-protein coupled receptors and their families with grey incidence analysis. AB - G-protein-coupled receptors (GPCRs) play fundamental roles in regulating various physiological processes as well as the activity of virtually all cells. Different GPCR families are responsible for different functions. With the avalanche of protein sequences generated in the postgenomic age, it is highly desired to develop an automated method to address the two problems: given the sequence of a query protein, can we identify whether it is a GPCR? If it is, what family class does it belong to? Here, a two-layer ensemble classifier called GPCR-GIA was proposed by introducing a novel scale called 'grey incident degree'. The overall success rate by GPCR-GIA in identifying GPCR and non-GPCR was about 95%, and that in identifying the GPCRs among their nine family classes was about 80%. These rates were obtained by the jackknife cross-validation tests on the stringent benchmark data sets where none of the proteins has > or = 50% pairwise sequence identity to any other in a same class. Moreover, a user-friendly web-server was established at http://218.65.61.89:8080/bioinfo/GPCR-GIA. For user's convenience, a step-by-step guide on how to use the GPCR-GIA web server is provided. Generally speaking, one can get the desired two-level results in around 10 s for a query protein sequence of 300-400 amino acids; the longer the sequence is, the more time that is needed. PMID- 19776030 TI - Identification of a microRNA signature associated with progression of leukoplakia to oral carcinoma. AB - MicroRNAs (miRs) are non-coding RNA molecules involved in cancer initiation and progression. Deregulated miR expression has been implicated in cancer; however, there are no studies implicating an miR signature associated with progression in oral squamous cell carcinoma (OSCC). Although OSCC may develop from oral leukoplakia, clinical and histological assessments have limited prognostic value in predicting which leukoplakic lesions will progress. Our aim was to quantify miR expression changes in leukoplakia and same-site OSCC and to identify an miR signature associated with progression. We examined miR expression changes in 43 sequential progressive samples from 12 patients and four non-progressive leukoplakias from four different patients, using TaqMan Low Density Arrays. The findings were validated using quantitative RT-PCR in an independent cohort of 52 progressive dysplasias and OSCCs, and five non-progressive dysplasias. Global miR expression profiles distinguished progressive leukoplakia/OSCC from non progressive leukoplakias/normal tissues. One hundred and nine miRs were highly expressed exclusively in progressive leukoplakia and invasive OSCC. miR-21, miR 181b and miR-345 expressions were consistently increased and associated with increases in lesion severity during progression. Over-expression of miR-21, miR 181b and miR-345 may play an important role in malignant transformation. Our study provides the first evidence of an miR signature potentially useful for identifying leukoplakias at risk of malignant transformation. PMID- 19776031 TI - Adenosine deamination in human transcripts generates novel microRNA binding sites. AB - Animals regulate gene expression at multiple levels, contributing to the complexity of the proteome. Among these regulatory events are post transcriptional gene silencing, mediated by small non-coding RNAs (e.g. microRNAs), and adenosine-to-inosine (A-to-I) editing, generated by adenosine deaminases that act on double-stranded RNA (ADAR). Recent data suggest that these regulatory processes are connected at a fundamental level. A-to-I editing can affect Drosha processing or directly alter the microRNA (miRNA) sequences responsible for mRNA targeting. Here, we analyzed the previously reported adenosine deaminations occurring in human cDNAs, and asked if there was a relationship between A-to-I editing events in the mRNA 3' untranslated regions (UTRs) and mRNA:miRNA binding. We find significant correlations between A-to-I editing and changes in miRNA complementarities. In all, over 3000 of the 12 723 distinct adenosine deaminations assessed were found to form 7-mer complementarities (known as seed matches) to a subset of human miRNAs. In 200 of the ESTs, we also noted editing within a specific 13 nucleotide motif. Strikingly, deamination of this motif simultaneously creates seed matches to three (otherwise unrelated) miRNAs. Our results suggest the creation of miRNA regulatory sites as a novel function for ADAR activity. Consequently, many miRNA target sites may only be identifiable through examining expressed sequences. PMID- 19776032 TI - Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns. AB - DNA methylation is known to be associated with cell differentiation, aging, disease and cancer. There exists an expanding base of knowledge regarding tissue specific DNA methylation, but we have little information about person-specific DNA methylation. Here, we analyze the DNA methylation patterns of multiple tissues from multiple individuals using a high-throughput quantitative assay of genome-wide DNA methylation, namely the Illumina GoldenGate BeadArray. DNA methylation patterns were largely conserved across 11 different tissues (r = 0.852) and across six individuals (r = 0.829), and we found that DNA was highly methylated in non-CpG islands and/or CpG sites that are not occupied by either H3K4me3 or H3K27me3 (P < 0.05). Finally, we found that the Illumina GoldenGate assay features a large number of probes (265/1505 probes, 17.6%) that contain single-nucleotide polymorphisms, which may interfere with DNA methylation analyses in genome-wide studies. PMID- 19776033 TI - A mouse model for Meckel syndrome reveals Mks1 is required for ciliogenesis and Hedgehog signaling. AB - Meckel syndrome (MKS) is a rare autosomal recessive disease causing perinatal lethality associated with a complex syndrome that includes occipital meningoencephalocele, hepatic biliary ductal plate malformation, postaxial polydactyly and polycystic kidneys. The gene mutated in type 1 MKS encodes a protein associated with the base of the cilium in vertebrates and nematodes. However, shRNA knockdown studies in cell culture have reported conflicting results on the role of Mks1 in ciliogenesis. Here we show that loss of function of mouse Mks1 results in an accurate model of human MKS, with structural abnormalities in the neural tube, biliary duct, limb patterning, bone development and the kidney that mirror the human syndrome. In contrast to cell culture studies, loss of Mks1 in vivo does not interfere with apical localization of epithelial basal bodies but rather leads to defective cilia formation in most, but not all, tissues. Analysis of patterning in the neural tube and the limb demonstrates altered Hedgehog (Hh) pathway signaling underlies some MKS defects, although both tissues show an expansion of the domain of response to Shh signaling, unlike the phenotypes seen in other mutants with cilia loss. Other defects in the skull, lung, rib cage and long bones are likely to be the result of the disruption of Hh signaling, and the basis of defects in the liver and kidney require further analysis. Thus the disruption of Hh signaling can explain many, but not all, of the defects caused by loss of Mks1. PMID- 19776034 TI - Global and regional causes of death. AB - BACKGROUND: Assessing the causes of death across all regions of the world requires a framework for integrating, and analysing, the fragmentary information that is available on numbers of deaths and their cause distributions. This paper provides an overview of the met and methods used by the World Health Organization to develop global-, regional- and country-level estimates of mortality for a comprehensive set of causes, and provides an overview of global and regional levels and patterns of causes of death for the year 2004. The paper also examines some of the data gaps, uncertainties and limitations in the resulting mortality estimates. SOURCES OF DATA: Deaths for 136 disease and injury causes were estimated from available death registration data (111 countries), sample death registration data (India and China), and for the remaining countries from census and survey information, and cause-of-death models. Population-based epidemiological studies and notifications systems also contributed to estimating mortality for 21 of these causes (representing 28% of deaths globally, 58% in Africa). AREAS OF AGREEMENT: Ischaemic heart disease and cerebrovascular disease are the leading causes of death, followed by lower respiratory infections, chronic obstructive pulmonary disease and diarrhoeal diseases. AIDS and TB are the sixth and seventh most common causes of death, respectively, lower than in previous estimates. One-half of all child deaths are from four preventable and treatable communicable diseases. Globally, around 6 in 10 deaths are from non communicable diseases, 3 from communicable diseases and 1 from injuries. Injury mortality is highest in South-East Asia, Latin America and the Eastern Mediterranean region. These results illustrate continuing huge disparities in risks and causes of death across the world. AREAS OF CONTROVERSY: Global mortality analyses of the type reported here have been criticized for making estimates of mortality for regions with limited, incomplete and uncertain data. Estimates presented here use a range of techniques depending on the type and quality of evidence. Better evidence on levels of adult mortality is needed for African countries. GROWING POINTS: Considerable gaps and deficiencies remain in the information available on causes of death. Nine of 10 deaths in 2004 occurred in low- and middle-income countries, reinforcing the fundamental importance of improving mortality statistics as a measure of health status in the developing world. Acknowledging the controversies around use of incomplete and uncertain data, systematic assessments and synthesis of the available evidence will continue to provide important inputs for global health planning. AREAS TIMELY FOR DEVELOPING RESEARCH: Innovative methods involving sample registration, and the use of verbal autopsy questionnaires in surveys, are needed to address these gaps. Research on strategies to improve comparability of cause-of-death certification and coding practices across countries is also a high priority. PMID- 19776035 TI - Age-associated cognitive decline. AB - INTRODUCTION: Age-associated cognitive decline-or normal (non-pathological, normative, usual) cognitive ageing-is an important human experience which differs in extent between individuals. The determinants of the differences in age-related cognitive decline are not fully understood. Progress in the field is taking place across many areas of biomedical and psychosocial sciences. AREAS OF AGREEMENT AND CONTROVERSY: The phenotype of normal cognitive ageing is well described. Some mental capabilities are well maintained into old age. From early adulthood, there are declines in mental domains such as processing speed, reasoning, memory and executive functions, some of which is underpinned by a decline in a general cognitive factor. There are contributions to understanding individual differences in normal cognitive ageing from genetics, general health and medical disorders such as atherosclerotic disease, biological processes such as inflammation, neurobiological changes, diet and lifestyle. Many of these effect sizes are small; some are poorly replicated; and in some cases, there is the possibility of reverse causation, with prior cognitive ability causing the supposed 'cause' of cognitive ability in old age. EMERGING AREAS FOR DEVELOPING RESEARCH: Genome-wide scans are a likely source to establish genetic contributions. The role of vascular factors in cognitive ageing is increasingly studied and understood. The same applies to diet, biomarkers such as inflammation and lifestyle factors such as exercise. There are marked advances in brain imaging, affording better in vivo studies of brain correlates of cognitive changes. There is growing appreciation that factors affecting general bodily ageing also influence cognitive functions in old age. PMID- 19776036 TI - Dried blood spots can expand access to virological monitoring of HIV treatment in resource-limited settings. AB - The global scale-up of antiretroviral treatment in past years has, unfortunately, not been accompanied by adequate strengthening of laboratory capacity. Monitoring of treatment with HIV viral load and resistance testing, as recommended in industrialized countries, is rarely available in resource-limited settings due to high costs and stringent requirements for storage and transport of plasma. Consequently, treatment failure usually passes unnoticed until severe symptoms occur, when resistance mutations have accumulated and second-line drug options are restricted. Dried blood spots (DBS) are easy to collect and store, and can be a convenient alternative to plasma. Recently, a number of studies have demonstrated the feasibility and reliability of using DBS to monitor viral load and genotypic resistance. Moreover, several African countries have already started to use DBS for paediatric HIV screening. In the absence of point-of-care assays, the WHO should encourage virological monitoring on DBS in antiretroviral treatment programmes in resource-limited settings. PMID- 19776037 TI - Once-daily treatment with saquinavir mesylate (2000 mg) and ritonavir (100 mg) together with a fixed-dose combination of abacavir/lamivudine (600/300 mg) or tenofovir/emtricitabine (245/200 mg) in HIV-1-infected patients. AB - OBJECTIVES: To investigate the feasibility and pharmacokinetics of a once-daily regimen of 2000 mg saquinavir mesylate boosted with 100 mg ritonavir. PATIENTS AND METHODS: Patients successfully treated with 1000 mg saquinavir boosted with 100 mg ritonavir twice daily together with two nucleoside or nucleotide reverse transcriptase inhibitors [N(t)RTIs] who were switched to 2000 mg saquinavir with 100 mg ritonavir once daily with unchanged N(t)RTI therapy were analysed. CD4 cells, HIV-RNA PCR and metabolic parameters were compared between baseline and 3, 6, 9 and 12 months after the switch. Saquinavir and ritonavir drug levels were measured before and a median of 3 weeks after switching from twice to once daily at 0, 1, 2, 4, 6, 9, 12 and 24 h after intake of the medication. The area under the serum concentration-time curve from 0 to 24 h (AUC(0-24)) was calculated using the trapezoidal rule. RESULTS: Eighteen patients (16 males, median age of 41 years) with a median CD4 cell count of 464 cells/mm(3) were analysed. HIV-RNA PCR remained <500 copies/mL for all patients. After switching from 100 mg twice daily to 100 mg once daily, the AUC(0-24) for ritonavir decreased significantly [21 874 to 10 267 ng.h/mL, geometric mean ratio (GMR) = 0.47; P < 0.001], whereas the AUC(0-24) for saquinavir decreased only marginally from 35 000 to 34 490 ng.h/mL (GMR = 0.99; P = 0.426). The CD4 cell count and the fasting metabolic parameters remained unchanged. CONCLUSIONS: Once-daily treatment with ritonavir boosted saquinavir was well tolerated and resulted in similar saquinavir drug exposure despite much lower ritonavir concentrations when compared with a twice daily dosing schedule. PMID- 19776038 TI - Hypothesis: gender and encapsulating peritoneal sclerosis. PMID- 19776039 TI - Peritoneal dialysis in Brazil: twenty-five years of experience in a single center. AB - OBJECTIVES: To evaluate patient and technique survival and to provide an analysis of peritoneal dialysis (PD)-related peritonitis in 25 years of experience in a single center. STUDY DESIGN: Retrospective study of incident patients on PD from July 1980 to July 2005. SETTING: Single, university based, Brazilian dialysis program. PATIENTS: 680 patients were analyzed in our study from July 1980 to July 2005, with a cumulative experience of 15 303 patient-months. All patients over 15 years of age entering the dialysis program were included in the study. Patients with less than 30 days of follow-up were excluded. Biochemical and demographic variables, peritonitis episodes, and patient and technique survival were analyzed. RESULTS: Mean age at start of PD was 53 +/- 16 years; diabetic nephropathy was the main cause of chronic kidney disease. Cardiovascular disease was the main cause of death (44%); peritonitis was responsible for 16% of fatal events. The predictors of death in our study were diabetes [relative risk (RR) 1.23, p < 0.01], advanced age (RR 1.58, p < 0.001), low serum albumin level (RR 1.25, p < 0.01), and low serum phosphate level (RR 1.39, p < 0.001) upon starting PD. There were 1048 cases of peritonitis over the 25-year period, with a significant reduction in incidence after the introduction of the double-bag system. The number of incident PD patients originating from hemodialysis increased threefold over the observation period (p < 0.001), with a similar increase in comorbidities over time. CONCLUSION: In the largest single-center report of PD experience in Latin America, we describe the overall rate and trends over time of peritonitis as well as patient and technique survival, which are similar to previous reports. Significant changes in peritonitis rates and causative organisms as well as a significant time-dependent increase in high-risk patients starting PD were observed. PMID- 19776040 TI - Encapsulating peritoneal sclerosis -- have we found the perpetrator? PMID- 19776041 TI - Computed tomographic scanning and diagnosis of encapsulating peritoneal sclerosis. PMID- 19776042 TI - Free nitric oxide in spent CAPD fluid: a leap of faith? PMID- 19776043 TI - Prolonged peritoneal gene expression using a helper-dependent adenovirus. AB - BACKGROUND: Encapsulating peritoneal sclerosis (EPS) is a rare complication of peritoneal dialysis. The causes of EPS are not well defined and are likely multifactorial. A suitable animal model would facilitate research into the pathophysiology and treatment of EPS. METHODS: We developed a helper-dependent adenovirus that expresses both green fluorescent protein (GFP) and active transforming growth factor-beta (TGF-beta1; HDAdTGF-beta1). Mice were administered HDAdTGF-beta1 via intraperitoneal injection and the response was compared with mice administered either first-generation adenovirus expressing TGF beta1 (AdTGF-beta1) or control adenovirus (AdGFP). RESULTS: HDAdTGF-beta1-treated mice continued to express the GFP reporter transgene to day 74, the end of the observation period. Transgene expression lasted less than 28 days in the animals treated with first-generation adenoviruses. Animals treated with first-generation AdTGF-beta1 demonstrated submesothelial thickening and angiogenesis at day 7, with almost complete resolution by day 28. The HDAdTGF-beta1-treated mice demonstrated progressive peritoneal fibrosis with adhesion formation and encapsulation of bowels. Weight gain was significantly reduced in animals treated with HDAdTGF-beta1 compared to both the control-treated animals and the AdTGF beta1-treated animals. Inflammation was not a major component of the fibroproliferative response. CONCLUSIONS: Peritoneal administration of a first generation AdTGF-beta1 leads to transient gene expression, resulting in a resolving fibrotic response and histology similar to that seen in simple peritoneal sclerosis. Prolonged TGF-beta1 expression induced by the helper dependent HDAdTGF-beta1 led to changes in peritoneal morphology resembling EPS. This suggests that TGF-beta1 may be a contributing factor in both simple peritoneal sclerosis and EPS. This model will be useful for elucidation of the mechanism of EPS and evaluation of potential treatment. PMID- 19776044 TI - Computed tomographic findings characteristic for encapsulating peritoneal sclerosis: a case-control study. AB - BACKGROUND: Computed tomography (CT) is often used to confirm the diagnosis of encapsulating peritoneal sclerosis (EPS) but there is no consensus on specific CT abnormalities. To establish CT findings characteristic for EPS, we compared CT findings between EPS patients and long-term peritoneal dialysis (PD) patients without EPS. METHODS: We included as cases all EPS patients in our center from 1996 to 2008 that underwent a CT scan at the time of diagnosis. Controls were all other long-term PD patients (PD duration > or = 4 years) without EPS that had a CT scan for different reasons. The CT scans were blindly and independently reviewed by 3 radiologists: 2 abdominal radiologists with PD knowledge (Observers 1 and 2) and 1 radiologist without PD experience (Observer 3). RESULTS: We included 15 EPS patients and 16 controls. Observer 1 found 6 CT findings that were significantly more often present in EPS than in controls (p < or = 0.05): peritoneal enhancement, thickening, and calcifications; adhesions of bowel loops; signs of obstruction; and fluid loculation/septation. Observer 2 scored almost identically but Observer 3 scored differently. The sensitivity and specificity of a combination of specific CT findings were, respectively, 100% and 94% for Observers 1 and 2, and 79% and 88% for Observer 3. CONCLUSION: CT scans showed characteristic abnormalities that were significantly more often present in EPS patients compared to long-term PD control patients. CT can be used to confirm the diagnosis of EPS when experienced radiologists apply a combination of specific CT findings. PMID- 19776045 TI - Quantification of free water transport during the peritoneal equilibration test. AB - OBJECTIVE: Free water transport (FWT) can be calculated after a dwell of 1 hour with a 3.86% glucose solution using sodium kinetics (mini-PET, as developed by LaMilia et al.). This requires measurement of the intraperitoneal volume after drainage of the abdomen. Since valuable information of a 4-hour peritoneal equilibration test (PET) may be lost, the aim of the present study was to investigate whether temporary drainage of the peritoneal cavity after 1 hour and re-instillation thereafter would influence the results of the 4-hour PET. METHODS AND PATIENTS: Two PETs were performed in 10 stable peritoneal dialysis (PD) patients (mean age 59 +/- 13 years, mean duration on PD 33 +/- 15 months) within a mean period of 54 (range 13 - 104) days: one standardized 4-hour PET using 3.86% glucose (PET A) and one with drainage after 1 hour followed by re instillation (PET B). RESULTS: Mean total ultrafiltration (UF) of PETs A and B was 667 +/- 210 mL and 621 +/- 206 mL (NS). Mean FWT at 60 minutes was 164 +/- 74 mL and mean UF through the small pores was 204 +/- 181 mL; FWT correlated well with total UF (r = 0.720, p = 0.019). Classification of transport categories was identical for 9 of the 10 patients. Comparison of 1-hour and 4-hour results in test B showed a good correlation between dialysate-to-plasma ratios (D/P) of creatinine and urea and D(t)/D(0) ratios of glucose. CONCLUSION: A 4-hour 3.86% glucose PET, including temporary drainage after 1 hour for assessment of free water transport, does not influence the results of D/P creatinine or D(t)/D(0) glucose and gives essential additional information on aquaporin function. PMID- 19776046 TI - Novel low Na peritoneal dialysis solutions designed to optimize Na gap of effluent: kinetics of Na and water removal. AB - BACKGROUND: An imbalance between sodium intake to and excretion from the body contributes to overhydration in peritoneal dialysis (PD) patients. Novel low Na solutions were developed based on the concept of optimizing the Na gap of effluent to achieve better Na balance. The present study investigated Na and water removal by those solutions. METHODS: Compositions of low Na (LS) and standard Na (SS) solutions were as follows: Na 133, 126, and 118 mEq/L with respective corresponding glucose concentrations of 0.9%, 1.6%, and 2.5% in LS(90), LS(160), and LS(250) solutions; Na 135 mEq/L with glucose 1.35% and 2.5% in SS(135) and SS(250) solutions respectively. Based on the status of their daily PD prescriptions, respective LS solutions were assigned to 41 patients as follows: LS(90) or LS(160) for SS(135) solution, and LS(160) or LS(250) for SS(250) solution. RESULTS: In the 4-hour dwell, no differences were found in Na removal between LS(90) and SS(135), whereas Na removal by LS(160) and LS(250) was significantly increased compared to SS(135) and SS(250) (p < 0.05 respectively). The Na gaps of the 3 respective LS solutions were significantly less than those of controls (p < 0.05 respectively). With 1-day full-time use of LS solutions, no significant changes were found in daily water removal compared to controls, while Na removal was significantly increased in LS solutions (p < 0.05), with conversion to a negative Na gap in total daily effluent. CONCLUSION: The low Na solutions used in the present study facilitated Na removal by reducing the Na gap. This characteristic is expected to achieve better Na balance in PD patients with excess body fluid retention. PMID- 19776047 TI - Calcium and magnesium flux in automated peritoneal dialysis. AB - BACKGROUND: Calcium and magnesium balance in continuous ambulatory peritoneal dialysis (CAPD) has been extensively studied with several of the different formulations of fluid available. Calcium and magnesium balance in automated PD (APD) is less well studied and the effect on Ca and Mg flux is unknown. Data on glucose polymer solutions are also lacking. This prospective observational study was undertaken to examine mass transfer of Ca and Mg in APD patients. METHODS: 12 patients on APD were studied for two 24-hour periods using, alternately, 1.75 mmol/L and 1.25 mmol/L Ca (Dianeal PD1 and Dianeal PD4; Baxter Healthcare, Newbury, UK) 1.36% glucose-based dialysis fluid for the 9-hour overnight dialysis, followed by a 15-hour daytime dwell of glucose polymer-based fluid (icodextrin). Serum ionized Ca, serum Mg, and dialysate Ca and Mg concentrations were measured at the beginning and end of each period. Mass transfer was calculated as millimoles per exchange. RESULTS: During rapid overnight exchanges with Dianeal PD1 and PD4, mass transfer of Mg and Ca did not show significant correlations with serum levels when using PD1 fluid; however, mass transfer of Mg, but not Ca, was significantly correlated to serum levels when using PD4 fluid. During the long dwell with icodextrin, dialysate drain volume was the most significant factor determining the flux of both Ca and Mg. CONCLUSION: Mass transfer of Ca and Mg in APD patients using conventional dialysis fluid was not related to drain volume in this study, which differs to studies in CAPD. Flux of Ca and Mg during icodextrin use was found to be dependent on ultrafiltration rate and not dialysate or serum concentration. PMID- 19776048 TI - Retroperitoneal leakage as a cause of acute ultrafiltration failure: its associated risk factors in peritoneal dialysis. AB - BACKGROUND: Ultrafiltration failure is an important clinical problem in patients on maintenance peritoneal dialysis (PD) and is associated with high morbidity and mortality. Acute ultrafiltration failure (AUFF) is usually secondary to mechanical problems with the peritoneal catheter or peritoneal leakage. Retroperitoneal leakage (RPL) is an important cause of AUFF and often poses diagnostic difficulty. Herein we analyze the incidence of AUFF secondary to RPL in our centers and study its associated risk factors. METHODS: After excluding causes due to mechanical problems with the peritoneal catheter, patients complicated by AUFF underwent computerized tomographic peritoneography (CTP) or magnetic resonance imaging of the peritoneal cavity (MRP) to determine any RPL. Other patients on maintenance PD without RPL served as controls for comparison of risk factors. Demographic and peritoneal membrane characteristics, including history of hernia and pleuroperitoneal leakage, were analyzed. RESULTS: During the 5-year study period, 36 patients in a cohort of 743 patients on maintenance PD developed AUFF. 23 of these 36 patients were found to have RPL, which was confirmed by either CTP (n = 16) or MRP (n = 7). The duration of PD at the time of RPL and the dialysate-to-plasma ratio of creatinine at 4 hours were 49.3 +/- 24.5 (range 0.5 - 87.9) months and 0.70 +/- 0.09 respectively. Incidences of hernia (52.2%) and pleuroperitoneal communication (34.8%) were significantly higher than in PD patients without RPL (13% and 7% respectively, p = 0.001). Logistic regression analysis identified hernia and pleuroperitoneal communication as the risk factors for RPL. The odds ratios for RPL with hernia and pleuroperitoneal communication were 6.62 [95% confidence interval (CI) 2.35 - 18.69, p < 0.001] and 6.23 (95% CI 1.83 - 21.19, p = 0.003) respectively. CONCLUSION: RPL was not uncommon in patients with AUFF. A high index of suspicion for RPL is needed in the management of patients with history of hernia or pleuroperitoneal communication presenting with AUFF. PMID- 19776049 TI - Intraperitoneal urokinase and oral rifampicin for persisting asymptomatic dialysate infection following acute coagulase-negative staphylococcus peritonitis. AB - BACKGROUND: Coagulase-negative staphylococcus (CoNS) is responsible for cases of refractory and relapsing peritonitis in peritoneal dialysis (PD) patients, probably by biofilm formation on the catheter. The ISPD recommends catheter removal in such cases. Urokinase has been used to dissolve the biofilm lining the PD catheter, thus favoring antibiotic efficacy. Rifampicin has shown its efficacy in penetrating CoNS biofilm. METHODS: We defined persisting asymptomatic CoNS dialysate infection as a peritonitis episode with clinical improvement within 48 hours and dialysate clearing, but with persisting positive dialysate cultures. We retrospectively analyzed the outcome of such cases observed between 1/1998 and 12/2007. In all cases, intraperitoneal (IP) urokinase (100 000 units) and oral rifampicin (600 mg every day for 3 weeks) were added to intravenous vancomycin. RESULTS: 33 cases of CoNS peritonitis were recorded and 11 of them (33.3%) met the criteria of persisting asymptomatic CoNS dialysate infection. All were initially treated with intravenous vancomycin and oral ciprofloxacin, according to our protocol. Dialysate clearing, defined by a white blood cell count <100/microL, was noted at day 8 (range 4 - 17 days) on average, while dialysate cultures were still positive a mean of 6 (range 0 - 16) days later [i.e., 13.9 (range 5 - 24) days after peritonitis onset]. IP urokinase instillation was performed an average of 18.9 (range 11 - 30) days after peritonitis onset. Treatment success, defined by peritonitis resolution with sterilization of the dialysate, without catheter removal and relapse peritonitis within 6 weeks of treatment completion, was observed in 7 of 11 (64%) cases. No side effects following IP urokinase instillation were noted. One case of rifampicin-induced toxidermia was recorded. CONCLUSION: IP urokinase and oral rifampicin in addition to conventional antibiotics resulted in a catheter salvage rate of 64% in persisting asymptomatic dialysate infection following a CoNS peritonitis. Larger studies are needed to confirm these results. In CoNS peritonitis, dialysate cultures should be repeated, even after clearing of the dialysate, to avoid missing persisting asymptomatic infection. PMID- 19776050 TI - Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in peritoneal dialysis: systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are widely used in clinical practice. The safety and efficacy of these agents in peritoneal dialysis (PD) patients are unclear. OBJECTIVES: We conducted a systematic review to study the safety and efficacy of ACEI and ARB use in PD patients. Primary outcome measures were mortality and cardiovascular (CV) events; secondary outcome measures were renal function, proteinuria, hyperkalemia, and erythropoietin requirement at 3 months. METHODS: We searched Medline, EMBASE, Cochrane Central Register of Controlled Trials, trial registry Web sites, reference lists of eligible and review articles, as well as abstracts from the American Society of Nephrology and Canadian Society of Nephrology meetings. To be eligible, studies had to be randomized controlled trials that allocated PD patients to ACEI and ARB use or to placebo or other antihypertensive medications, included adult patients, and reported on at least one of the outcome measures. RESULTS: 418 citations were identified. Four met the eligibility criteria. Three examined CV events and mortality, of which two studies did not have any events. The third showed no statistically significant difference between control and treatment groups in either CV events or mortality: odds ratio 1.56 [95% confidence interval (CI) 0.24 - 10.05] for mortality and odds ratio 1.00 (95% CI 0.19 - 5.40) for CV events. Two studies reported renal function at 12 months and the weighted mean difference was 0.91 mL/minute/1.73 m(2) (95% CI 0.14 - 1.68), favoring ACEI and ARB use. CONCLUSIONS: In PD patients, evidence for the use of ACEIs and ARBs for reduction of mortality and CV events is lacking. Limited data suggest that they slow the loss of residual renal function. PMID- 19776051 TI - The effect of oral niacinamide on plasma phosphorus levels in peritoneal dialysis patients. AB - BACKGROUND: Hyperphosphatemia remains a significant problem for patients requiring dialysis and is associated with increased mortality. Current treatment options include dietary restriction, dialysis, and phosphate binders. Treatment using the latter is frequently limited by cost, tolerability, and calcium loading. One open-label trial found niacinamide to be effective at decreasing serum phosphorus values in hemodialysis patients. Niacinamide may effectively reduce phosphorus levels in peritoneal dialysis (PD) patients already receiving standard phosphorus-lowering therapies. METHODS: An 8 week, randomized, double blind, placebo-controlled trial to evaluate the effectiveness of niacinamide to reduce plasma phosphorus levels in PD patients. Patients had to demonstrate a baseline phosphorus value > 4.9 mg/dL. Patients were randomized to niacinamide or placebo and prescribed 250 mg twice daily, with titration to 750 mg twice daily, as long as safety parameters were not violated. Phosphate binders, active vitamin D, and cinacalcet were kept constant during the study. The primary end point was change in plasma phosphorus. Secondary end points included changes in lipid parameters. RESULTS: 15 patients started on the study drug (8 niacinamide, 7 placebo) and 7 in each arm had at least one on-study phosphorus measurement. The niacinamide treatment group experienced an average 0.7 +/- 0.9 mg/dL decrease in plasma phosphorus and the placebo-treated group experienced an average 0.4 +/- 0.8 mg/dL increase. The treatment effect difference (1.1 mg/dL) was significant (p = 0.037). No significant changes in high- or low-density lipoproteins or triglycerides were demonstrated. Two of the 8 patients randomized to the niacinamide treatment arm had to withdraw from the study due to drug-related adverse effects. Adverse effects may limit the use of niacinamide in PD patients. CONCLUSION: Niacinamide, when added to standard phosphorus-lowering therapies, resulted in a modest yet statistically significant reduction in plasma phosphorus levels at 8 weeks. [ClinicalTrials.gov number NCT00508885]. PMID- 19776052 TI - Identification of inflamed atherosclerotic plaque using 123 I-labeled interleukin 2 scintigraphy in high-risk peritoneal dialysis patients: a pilot study. AB - BACKGROUND: Patients with end-stage renal disease (ESRD) suffer from markedly increased cardiovascular morbidity and mortality. Common carotid artery (CCA) intima-media thickness (IMT) assessment and CCA plaque identification using ultrasound are well-recognized tools for identification and monitoring of atherosclerosis. A new method for monitoring the inflammatory status of plaque, namely radiolabeled interleukin-2 (IL-2) scintigraphy, was proposed recently. The aim of this pilot study was to perform (123)I-labeled-IL-2 carotid plaque scintigraphy in ESRD patients treated with peritoneal dialysis and to correlate obtained results with ultrasound assessment of CCA and selected inflammatory markers. METHODS: CCA-IMT was measured and CCA plaques were identified by ultrasound in 10 patients (5 women, 5 men; mean age 62.4 +/- 10.4 years; median peritoneal dialysis duration 32.5 months, range 12 - 55 months) with advanced cardiovascular comorbidity. Following CCA ultrasound, (123)I-labeled IL-2 carotid plaque scintigraphy was performed. Several biomarkers of inflammation and atherosclerosis were also measured in all patients. RESULTS: Mean target/non target ratio for focal (123)I-IL-2 uptake within the plaque was 3.15 +/- 0.54, and mean IMT from the site of the scintigraphy analysis was 0.975 +/- 0.337 mm. Highly significant correlation was found between CCA-IMT and a target/non-target ratio for focal (123)I-IL-2 uptake in a corresponding artery (R = 0.92, p = 0.01). However, no significant correlations were found between target/non-target ratio for focal (123)I-IL-2 uptake and levels of measured biomarkers. CONCLUSIONS: Our preliminary results suggest potential for identification of an inflamed (vulnerable) plaque using IL-2 scintigraphy in ESRD patients with cardiovascular comorbidities. PMID- 19776053 TI - Pharmacokinetics of moxifloxacin in patients undergoing continuous ambulatory peritoneal dialysis. AB - OBJECTIVE: To investigate the effect of continuous ambulatory peritoneal dialysis (CAPD) on plasma and peritoneal fluid concentration and pharmacokinetics of moxifloxacin after administration of one 400 mg dose orally to end-stage renal failure patients undergoing CAPD. PATIENTS AND METHODS: Blood and peritoneal samples were collected from 8 patients at standard time intervals and concentrations of moxifloxacin were estimated by HPLC analysis with fluorometric and ultraviolet detection. Pharmacokinetic parameters were estimated using standard noncompartmental methods. RESULTS: Median maximum plasma moxifloxacin concentration was 5.86 mg/L at a median time of 1.25 hours. In serum, median area under the concentration-time curve (AUC(0-->inf)) was 157.95 +/- 100.34 mg.hour/L, median t(1/2) 25.00 hours, median clearance 2.54 L/hour, and median distribution volume 94.90 L. Median peritoneal fluid-to-plasma ratio of moxifloxacin ranged between 0.84 and 1.00, denoting adequate penetration and lack of considerable moxifloxacin removal during CAPD. Maximum moxifloxacin concentration/minimum inhibitory concentration (MIC) and AUC(0-->24)/MIC ratios were above the cutoff points that indicate clinical success. CONCLUSION: A single 400 mg oral dose of moxifloxacin is safe, presents rapid peritoneal fluid penetration, has similar plasma and peritoneal fluid pharmacokinetics, and should therefore be efficacious in the treatment of CAPD-induced peritonitis. PMID- 19776054 TI - Peritoneoscopic reinsertion of a peritoneal dialysis catheter after fungal peritonitis: the advantage of visual information. PMID- 19776055 TI - CAPD-related peritonitis caused by Rhodotorula mucilaginosa. PMID- 19776056 TI - Chyloperitoneum: is secondary amyloidosis a possible cause? PMID- 19776057 TI - Recurrence of severe hemoperitoneum in a patient on peritoneal dialysis. PMID- 19776058 TI - Rapid adaptive evolution of northeastern coyotes via hybridization with wolves. AB - The dramatic expansion of the geographical range of coyotes over the last 90 years is partly explained by changes to the landscape and local extinctions of wolves, but hybridization may also have facilitated their movement. We present mtDNA sequence data from 686 eastern coyotes and measurements of 196 skulls related to their two-front colonization pattern. We find evidence for hybridization with Great Lakes wolves only along the northern front, which is correlated with larger skull size, increased sexual dimorphism and a five times faster colonization rate than the southern front. Northeastern haplotype diversity is low, suggesting that this population was founded by very few females moving across the Saint Lawrence River. This northern front then spread south and west, eventually coming in contact with an expanding front of non-hybrid coyotes in western New York and Pennsylvania. We suggest that hybridization with wolves in Canada introduced adaptive variation that contributed to larger size, which in turn allowed eastern coyotes to better hunt deer, allowing a more rapid colonization of new areas than coyotes without introgressed wolf genes. Thus, hybridization is a conduit by which genetic variation from an extirpated species has been reintroduced into northeastern USA, enabling northeastern coyotes to occupy a portion of the niche left vacant by wolves. PMID- 19776059 TI - Exposure to seismic survey alters blue whale acoustic communication. AB - The ability to perceive biologically important sounds is critical to marine mammals, and acoustic disturbance through human-generated noise can interfere with their natural functions. Sounds from seismic surveys are intense and have peak frequency bands overlapping those used by baleen whales, but evidence of interference with baleen whale acoustic communication is sparse. Here we investigated whether blue whales (Balaenoptera musculus) changed their vocal behaviour during a seismic survey that deployed a low-medium power technology (sparker). We found that blue whales called consistently more on seismic exploration days than on non-exploration days as well as during periods within a seismic survey day when the sparker was operating. This increase was observed for the discrete, audible calls that are emitted during social encounters and feeding. This response presumably represents a compensatory behaviour to the elevated ambient noise from seismic survey operations. PMID- 19776060 TI - Sometimes the obvious answer is the right one: a response to 'missing the rarest: is the positive interspecific abundance-distribution relationship a truly general macroecological pattern?'. Author reply 779-80. PMID- 19776061 TI - DNA from a 100-year-old holotype confirms the validity of a potentially extinct hummingbird species. AB - We used mtDNA sequence data to confirm that the controversial 100-year-old holotype of the Bogota sunangel (Heliangelus zusii) represents a valid species. We demonstrate that H. zusii is genetically well differentiated from taxa previously hypothesized to have given rise to the specimen via hybridization. Phylogenetic analyses place H. zusii as sister to a clade of mid- to high elevation Andean species currently placed in the genera Taphrolesbia and Aglaiocercus. Heliangelus zusii, presumed extinct, has never been observed in nature by biologists. We infer that the species occupied a restricted distribution between the upper tropical and temperate zones of the northern Andes and that it was most probably driven to extinction by deforestation that accompanied human population growth during the nineteenth and early twentieth centuries. We demonstrate the feasibility of obtaining DNA from nearly microscopic tissue samples from old hummingbird specimens and suggest that these methods could be used to resolve the taxonomy of dozens of avian taxa known only from type specimens. PMID- 19776062 TI - Are female monarch butterflies declining in eastern North America? Evidence of a 30-year change in sex ratios at Mexican overwintering sites. AB - Every autumn the entire eastern North American population of monarch butterflies (Danaus plexippus) undergoes a spectacular migration to overwintering sites in the mountains of central Mexico, where they form massive clusters and can number in the millions. Since their discovery, these sites have been extensively studied, and in many of these studies, monarchs were captured and sexes recorded. In a recent effort to compile the sex ratio data from these published records, a surprising trend was found, which appears to show a gradual decline in proportion of females over time. Sex ratio data from 14 collections of monarchs, all spanning 30 years and totaling 69 113 individuals, showed a significant negative correlation between proportion of females and year (r = -0.69, p = 0.007). Between 1976 and 1985, 53 per cent of overwintering monarchs were female, whereas in the last decade, 43 per cent were female. The relationship was significant with and without weighting the analyses by sampling effort. Moreover, analysis of a recent three-year dataset of sex ratios revealed no variation among nine separate colonies, so differences in sampling location did not influence the trend. Additional evidence from autumn migration collections appears to confirm that proportions of females are declining, and also suggests the sex ratio is shifting on breeding grounds. While breeding monarchs face a number of threats, one possibility is an increase in prevalence of the protozoan parasite, Ophryocystis elektroscirrha, which recent evidence shows affects females more so than males. Further study will be needed to determine the exact cause of this trend, but for now it should be monitored closely. PMID- 19776063 TI - Environmental modulation of metabolic allometry in ornate rainbowfish Rhadinocentrus ornatus. AB - The nature of the relationship between the metabolic rate (MR) and body mass (M) of animals has been the source of controversy for over seven decades, with much of the focus on the value of the scaling exponent b, where MR is proportional to M(b). While it is well known that MR does not generally scale isometrically (i.e. b is seldom equal to 1), the value of b remains the subject of heated debate. In the present study, we examine the influence of an ecologically relevant abiotic variable, pH, on the metabolic allometry of an Australian freshwater fish, Rhadinocentrus ornatus. We show that the value of b is lower for rainbowfish acclimated to acidic (pH 5.0) conditions compared to rainbowfish acclimated to alkaline conditions (pH 8.5), but that acute exposure to altered pH does not alter the value of b. This significant effect of an abiotic variable on metabolic allometry supports a growing body of evidence that there is no universal value of b and demonstrates that experimental manipulations of metabolic allometry represent powerful, and as yet underused, tools to understand the factors that constrain and influence the allometry of metabolic rate. PMID- 19776064 TI - Meta-analysis in applied ecology. AB - This overview examines research synthesis in applied ecology and conservation. Vote counting and pooling unweighted averages are widespread despite the superiority of syntheses based on weighted combination of effects. Such analyses allow exploration of methodological uncertainty in addition to consistency of effects across species, space and time, but exploring heterogeneity remains controversial. Meta-analyses are required to generalize in ecology, and to inform evidence-based decision-making, but the more sophisticated statistical techniques and registers of research used in other disciplines must be employed in ecology to fully realize their benefits. PMID- 19776065 TI - Group-foraging is not associated with longevity in North American birds. AB - Group-foraging is common in many animal taxa and is thought to offer protection against predators and greater foraging efficiency. Such benefits may have driven evolutionary transitions from solitary to group-foraging. Greater protection against predators and greater access to resources should reduce extrinsic sources of mortality and thus select for higher longevity according to life-history theory. I assessed the association between group-foraging and longevity in a sample of 421 North American birds. Taking into account known correlates of longevity, such as age at first reproduction and body mass, foraging group size was not correlated with maximum longevity, with and without phylogenetic correction. However, longevity increased with body mass in non-passerine birds. The results suggest that the hypothesized changes in predation risk with group size may not correlate with mortality rate in foraging birds. PMID- 19776066 TI - A strain of the bacterial symbiont Regiella insecticola protects aphids against parasitoids. AB - Aphids commonly harbour facultative bacterial endosymbionts and may benefit from their presence through increased resistance to parasitoids. This has been demonstrated for Hamiltonella defensa and Serratia symbiotica, while a third common endosymbiont, Regiella insecticola, did not provide such protection. However, this symbiont was recently detected in a highly resistant clone of the peach-potato aphid, Myzus persicae, from Australia. To test if resistance was indeed conferred by the endosymbiont, we eliminated it from this clone with antibiotics, and we transferred it to two other clones of the same and one clone of a different aphid species (Aphis fabae). Exposing these lines to the parasitoid Aphidius colemani showed clearly that unlike other strains of this bacterium, this specific isolate of R. insecticola provides strong protection against parasitic wasps, suggesting that the ability to protect their host against natural enemies may evolve readily in multiple species of endosymbiotic bacteria. PMID- 19776067 TI - Life history, sexual dimorphism and 'ornamental' feathers in the mesozoic bird Confuciusornis sanctus. AB - The life history of Confuciusornis sanctus is controversial. Recently, the species' body size spectrum was claimed to contradict osteohistological evidence for a rapid, bird-like development. Moreover, sexual size dimorphism was rejected as an explanation for the observed bimodal size distribution since the presence of elongated rectrices, an assumed 'male' trait, was uncorrelated with size. However, this interpretation (i) fails to explain the size spectrum of C. sanctus which is trimodal rather than bimodal, (ii) requires implausible neonate masses and (iii) is not supported by analogy with sexual dimorphisms in modern birds, in which elongated central rectrices are mostly sex-independent. Available information on C. sanctus is readily reconciled if we assume a bird-like life history, as well as a pronounced sexual size dimorphism and sexually isomorphic extravagant feathers as frequently observed in extant species. PMID- 19776068 TI - Evicting cuckoo nestlings from the nest: a new anti-parasitism behaviour. AB - As avian brood parasitism usually reduces hosts' reproductive success, hosts often exhibit strong defence mechanisms. While such host defences at the egg stage (especially egg rejection) have been extensively studied, defence mechanisms at the nestling stage have been reported only recently. We found a previously unknown anti-parasitism behaviour in the large-billed Gerygone, which is a host species of the little bronze-cuckoo, a host-evicting brood parasite. The hosts forcibly pulled resisting nestlings out of their nests and dumped them. Although it has been suggested that defence mechanisms at the nestling stage may evolve when host defence at the egg stage is evaded by the parasite, the studied host seems to lack an anti-parasitism strategy at the egg stage. This suggests that the evolutionary pathway may be quite different from those of previously studied cuckoo-host systems. Future research on this unique system may give us new insights into the evolution of avian brood parasitism. PMID- 19776070 TI - High stimulus specificity characterizes anti-predator habituation under natural conditions. AB - Habituation is one of the most fundamental learning processes that allow animals to adapt to dynamic environments. It is ubiquitous and often thought of as a simple form of non-associative learning. Very little is known, though, about the rules that govern habituation and their significance under natural conditions. Questions about how animals incorporate habituation into their daily behaviour and how they can assure only to habituate to non-relevant stimuli are still unanswered. Animals under threat of predation should be particularly selective about which stimuli they habituate to, since ignoring a real threat could be fatal. In this study, we tested the response of fiddler crabs, Uca vomeris, to repeatedly approaching dummy predators to find out whether these animals habituate to potential predators and to test the selectivity of the habituation process. The crabs habituated to model predators, even though they were confronted with real predators during the same habituation process. They showed remarkable selectivity towards the stimulus: a simple change in the approach distance of the stimulus led to a recovery in their responses. The results strongly indicate that in the context of predator avoidance, habituation under natural conditions is highly selective and a stimulus is not defined just by its current sensory signature, but also its spatio-temporal history. PMID- 19776069 TI - No evidence for competition between cytotoxic T-lymphocyte responses in HIV-1 infection. AB - Strong competition between cytotoxic T-lymphocytes (CTLs) specific for different epitopes in human immunodeficiency virus (HIV) infection would have important implications for the design of an HIV vaccine. To investigate evidence for this type of competition, we analysed CTL response data from 97 patients with chronic HIV infection who were frequently sampled for up to 96 weeks. For each sample, CTL responses directed against a range of known epitopes in gag, pol and nef were measured using an enzyme-linked immunospot assay. The Lotka-Volterra model of competition was used to predict patterns that would be expected from these data if competitive interactions materially affect CTL numbers. In this application, the model predicts that when hosts make responses to a larger number of epitopes, they would have diminished responses to each epitope and that if one epitope specific response becomes dramatically smaller, others would increase in size to compensate; conversely if one response grows, others would shrink. Analysis of the experimental data reveals results that are wholly inconsistent with these predictions. In hosts who respond to more epitopes, the average epitope-specific response tends to be larger, not smaller. Furthermore, responses to different epitopes almost always increase in unison or decrease in unison. Our findings are therefore inconsistent with the hypothesis that there is competition between CTL responses directed against different epitopes in HIV infection. This suggests that vaccines that elicit broad responses would be favourable because they would direct a larger total response against the virus, in addition to being more robust to the effects of CTL escape. PMID- 19776071 TI - Environment, but not migration rate, influences extinction risk in experimental metapopulations. AB - Ecological theory suggests that several demographic factors influence metapopulation extinction risk, including synchrony in population size between subpopulations, metapopulation size and the magnitude of fluctuations in population size. Theoretically, each of these is influenced by the rate of migration between subpopulations. Here we report on an experiment where we manipulated migration rate within metapopulations of the freshwater zooplankton Daphnia magna to examine how migration influenced each of these demographic variables, and subsequent effects on metapopulation extinction. In addition, our experimental procedures introduced unplanned but controlled differences between metapopulations in light intensity, enabling us to examine the relative influences of environmental and demographic factors. We found that increasing migration rate increased subpopulation synchrony. We failed to detect effects of migration on population size and fluctuations in population size at the metapopulation or subpopulation level, however. In contrast, light intensity did not influence synchrony, but was positively correlated with population size and negatively correlated with population fluctuation. Finally, synchrony did not influence time to extinction, while population size and the magnitude of fluctuations did. We conclude that environmental factors had a greater influence on extinction risk than demographic factors, and that metapopulation size and fluctuation were more important to extinction risk than metapopulation synchrony. PMID- 19776072 TI - Flexible task allocation and the organization of work in ants. AB - Flexibility in task performance is essential for a robust system of division of labour. We investigated what factors determine which social insect workers respond to colony-level changes in task demand. We used radio-frequency identification technology to compare the roles of corpulence, age, spatial location and previous activity (intra-nest/extra-nest) in determining whether worker ants (Temnothorax albipennis) respond to an increase in demand for foraging or brood care. The less corpulent ants took on the extra foraging, irrespective of their age, previous activity or location in the nest, supporting a physiological threshold model. We found no relationship between ants that tended the extra brood and corpulence, age, spatial location or previous activity, but ants that transported the extra brood to the main brood pile were less corpulent and had high previous intra-nest activity. This supports spatial task-encounter and physiological threshold models for brood transport. Our data suggest a flexible task-allocation system allowing the colony to respond rapidly to changing needs, using a simple task-encounter system for generalized tasks, combined with physiologically based response thresholds for more specialized tasks. This could provide a social insect colony with a robust division of labour, flexibly allocating the workforce in response to current needs. PMID- 19776073 TI - Noise improves collective decision-making by ants in dynamic environments. AB - Recruitment via pheromone trails by ants is arguably one of the best-studied examples of self-organization in animal societies. Yet it is still unclear if and how trail recruitment allows a colony to adapt to changes in its foraging environment. We study foraging decisions by colonies of the ant Pheidole megacephala under dynamic conditions. Our experiments show that P. megacephala, unlike many other mass recruiting species, can make a collective decision for the better of two food sources even when the environment changes dynamically. We developed a stochastic differential equation model that explains our data qualitatively and quantitatively. Analysing this model reveals that both deterministic and stochastic effects (noise) work together to allow colonies to efficiently track changes in the environment. Our study thus suggests that a certain level of noise is not a disturbance in self-organized decision-making but rather serves an important functional role. PMID- 19776074 TI - No post-Cretaceous ecosystem depression in European forests? Rich insect-feeding damage on diverse middle Palaeocene plants, Menat, France. AB - Insect herbivores are considered vulnerable to extinctions of their plant hosts. Previous studies of insect-damaged fossil leaves in the US Western Interior showed major plant and insect herbivore extinction at the Cretaceous-Palaeogene (K-T) boundary. Further, the regional plant-insect system remained depressed or ecologically unbalanced throughout the Palaeocene. Whereas Cretaceous floras had high plant and insect-feeding diversity, all Palaeocene assemblages to date had low richness of plants, insect feeding or both. Here, we use leaf fossils from the middle Palaeocene Menat site, France, which has the oldest well-preserved leaf assemblage from the Palaeocene of Europe, to test the generality of the observed Palaeocene US pattern. Surprisingly, Menat combines high floral diversity with high insect activity, making it the first observation of a 'healthy' Palaeocene plant-insect system. Furthermore, rich and abundant leaf mines across plant species indicate well-developed host specialization. The diversity and complexity of plant-insect interactions at Menat suggest that the net effects of the K-T extinction were less at this greater distance from the Chicxulub, Mexico, impact site. Along with the available data from other regions, our results show that the end-Cretaceous event did not cause a uniform, long lasting depression of global terrestrial ecosystems. Rather, it gave rise to varying regional patterns of ecological collapse and recovery that appear to have been strongly influenced by distance from the Chicxulub structure. PMID- 19776075 TI - Predicting the direction of ornament evolution in Trinidadian guppies (Poecilia reticulata). AB - Sexual selection is thought to be opposed by natural selection such that ornamental traits express a balance between these two antagonistic influences. Phenotypic variation among populations may indicate local shifts in this balance, or that different stable 'solutions' are possible, but testing these alternatives presents a major challenge. In the guppy (Poecilia reticulata), a small freshwater fish with male-limited ornamental coloration, these issues can be addressed by transplanting fish among sites of varying predation pressure, thus effectively manipulating the strength and nature of natural selection. Here, we contrast the evolutionary outcome of two such introductions conducted in the Trinidadian El Cedro and Aripo Rivers. We use sophisticated colour appraisal methods that account for full spectrum colour variation and which incorporate the very latest visual sensitivity data for guppies and their predators. Our data indicate that ornamentation evolved along different trajectories: whereas Aripo males evolved more numerous and/or larger orange, black and iridescent markings, El Cedro males only evolved more extensive and brighter iridescence. Examination of the El Cedro experiment also revealed little or no ornamental evolution at the control site over 29 years, which contrasts markedly with the rapid (approx. 2-3 years) changes reported for introduction populations. Finally, whole colour pattern analysis suggested that the greatest visual difference between El Cedro introduction and control fish would be perceived by the two most salient viewers: guppies and the putatively dangerous predator Crenicichla alta. We discuss whether and how these evolutionary trajectories may result from founder effects, population-specific mate preferences and/or sensory drive. PMID- 19776076 TI - Life history influences rates of climatic niche evolution in flowering plants. AB - Across angiosperms, variable rates of molecular substitution are linked with life history attributes associated with woody and herbaceous growth forms. As the number of generations per unit time is correlated with molecular substitution rates, it is expected that rates of phenotypic evolution would also be influenced by differences in generation times. Here, we make the first broad-scale comparison of growth-form-dependent rates of niche evolution. We examined the climatic niches of species on large time-calibrated phylogenies of five angiosperm clades and found that woody lineages have accumulated fewer changes per million years in climatic niche space than related herbaceous lineages. Also, climate space explored by woody lineages is consistently smaller than sister lineages composed mainly of herbaceous taxa. This pattern is probably linked to differences in the rate of climatic niche evolution. These results have implications for niche conservatism; in particular, the role of niche conservatism in the distribution of plant biodiversity. The consistent differences in the rate of climatic niche evolution also emphasize the need to incorporate models of phenotypic evolution that allow for rate heterogeneity when examining large datasets. PMID- 19776077 TI - Characterization of GD3 ganglioside as a novel biomarker of mouse neural stem cells. AB - Neural stem cells (NSCs) are undifferentiated neural cells characterized by their high proliferative potential and the capacity for self-renewal with retention of multipotency. Over the past two decades, there has been a huge effort to identify NSCs morphologically, genetically, and molecular biologically. It is still controversial, however, what bona fide NSCs are. To define and characterize NSCs more systematically, it is crucial to explore novel cell-surface marker molecules of NSCs. In this study, we focused on GD3, a b-series ganglioside that is enriched in the immature brain and the subventricular zone (SVZ) of the postnatal and adult brain, and evaluated the usefulness of GD3 as a cell-surface biomarker for identifying NSCs. We demonstrated that GD3 was expressed in more than 80% of NSCs prepared from embryonic, postnatal, and adult mouse brain tissue by the neurosphere culture method. The percentage of GD3-expressing NSCs in neurospheres was nearly the same as it was in neurospheres derived from embryonic, postnatal, and adult brains but decreased drastically to about 40% after differentiation. GD3(+) cells isolated from embryonic mouse striata, postnatal, and adult mouse SVZs by fluorescence-activated cell sorting with an R24 anti-GD3 monoclonal antibody efficiently generated neurospheres compared with GD3(-) cells. These cells possessed multipotency to differentiate into neurons, astrocytes, and oligodendrocytes. These data indicate that GD3 is a unique and powerful cell surface biomarker to identify and isolate NSCs. PMID- 19776078 TI - Protective effect of N-glycan bisecting GlcNAc residues on beta-amyloid production in Alzheimer's disease. AB - Alteration of glycoprotein glycans often changes various properties of the target glycoprotein and contributes to a wide variety of diseases. Here, we focused on the N-glycans of amyloid precursor protein whose cleaved fragment, beta-amyloid, is thought to cause much of the pathology of Alzheimer's disease (AD). We previously determined the N-glycan structures of normal and mutant amyloid precursor proteins (the Swedish type and the London type). In comparison with normal amyloid precursor protein, mutant amyloid precursor proteins had higher contents of bisecting GlcNAc residues. Because N-acetylglucosaminyltransferase III (GnT-III) is the glycosyltransferase responsible for synthesizing a bisecting GlcNAc residue, the current report measured GnT-III mRNA expression levels in the brains of AD patients. Interestingly, GnT-III mRNA expression was increased in AD brains. Furthermore, beta-amyloid treatment increased GnT-III mRNA expression in Neuro2a mouse neuroblastoma cells. We then examined the influence of bisecting GlcNAc on the production of beta-amyloid. Both beta-amyloid 40 and beta-amyloid 42 were significantly decreased in GnT-III-transfected cells. When secretase activities were analyzed in GnT-III transfectant cells, alpha-secretase activity was increased. Taken together, these results suggest that upregulation of GnT-III in AD brains may represent an adaptive response to protect them from additional beta-amyloid production. PMID- 19776080 TI - Controlled antegrade single lung reperfusion during double lung transplant. AB - Prompt controlled reperfusion of a pulmonary allograft in a sequential double lung transplant may correct cellular ischemia prior to exposure to full hydrostatic pressures and minimize organ dysfunction. We reviewed the process of a sequential double lung transplant and describe the technique of controlled antegrade graft reperfusion of the initial implant as performed at our institution. PMID- 19776079 TI - Inability to access addiction treatment and risk of HIV infection among injection drug users recruited from a supervised injection facility. AB - BACKGROUND: Treatment for drug addiction is effective in reducing the harms of injection drug use, including infection with HIV and/or hepatitis C. We sought to examine the prevalence and correlates of being unable to access addiction treatment in a representative sample of injection drug users randomly recruited from a supervised injection facility. METHODS: Using generalized estimating equations, we determined the prevalence and factors associated with being unable to access addiction treatment. RESULTS: Between 1 July 2004 and 30 June 2006, 889 individuals completed at least one interview and were included in this analysis. At each interview, approximately 20% of respondents reported trying but being unable to access any type of drug or alcohol treatment in the previous 6 months. Being unable to access treatment was independently associated with recent incarceration, daily use of heroin and borrowing used syringes. In a secondary question, the majority of individuals reported waiting lists were the reason for being unable to access treatment. CONCLUSION: Given the independent association between inability to access addiction treatment and elevated HIV risk behavior, these results suggest expanding addiction treatment may contribute significantly to HIV prevention efforts in this population. PMID- 19776081 TI - Myocyte injury along myofibers in left ventricular remodeling after myocardial infarction. AB - Left ventricular (LV) remodeling following myocardial infarction (MI) is considered to contribute to cardiac dysfunction. Though myofiber organization is a key component of cardiac structure, functional and anatomical features of injured myofiber during LV remodeling have not been fully defined. We investigated myocyte injury after acute MI in a mouse model. Mice were subjected to surgical coronary occlusion/reperfusion by left anterior descending coronary artery (LAD) ligation and examined at 1 week and 4 weeks post-MI. Magnetic resonance imaging (MRI) analysis demonstrated a significant decrease in systolic regional wall thickening (WT) in the border and remote zones at 4 weeks post-MI compared to that at 1 week post-MI (-86% in border zone, P<0.05, and -77% in remote zone, P<0.05). Histological assays demonstrated that a broad fibrotic scar extended from the initial infarct zone to the remote zone along mid circumferential myofibers. Of particular note was the fact that no fibrosis was found in longitudinal myofibers in the epi- and endo-myocardium. This pattern of the scar formation coincided with the helical ventricular myocardial band (HVMB) model, introduced by Torrent-Guasp. MRI analysis demonstrated that the extension of the fibrotic scar along the band might account for the progression in cardiac dysfunction during LV remodeling. PMID- 19776082 TI - Air-leak management after upper lobectomy in patients with fused fissure and chronic obstructive pulmonary disease: a pilot trial comparing sealant and standard treatment. AB - A pilot trial to compare the efficacy of two different procedures to prevent postoperative air-leak in chronic obstructive pulmonary disease (COPD) patients submitted to upper lobectomy for non-small cell lung cancer. Sixty patients with COPD and lung cancer at the upper pulmonary lobes eligible for lobectomy were enrolled and randomly assigned either to standard treatment (ST) with stapling device or to electrocautery dissection and application of a collagen patch coated with human fibrinogen and thrombin (TachoSil) (experimental treatment [ET]) for the intra-operative completion of their fused fissures. Thirty patients were enrolled in each group during a three-year period. Preoperative characteristics were similar between the two groups. Statistically significant reduction of air leak was registered in the ET group when overall incidence of postoperative air leak (55% vs. 96%; P=0.03), postoperative air-leak (mean 1.63+/-1.96 vs. 4.33+/ 4.12 days; P=0.0018), chest-drain (mean 3.53+/-1.59 vs. 5.90+/-3.72 days; P=0.0021) and hospital stay duration (mean 5.87+/-1.07 vs. 7.50+/-3.20 days; P=0.01) were considered. The use of TachoSil to prevent postoperative air-leak after interlobar fissure completion in patients with COPD submitted to upper lobectomy seems to be safe and more effective than the ST based on stapling device application. PMID- 19776083 TI - The emergence of basophils as antigen-presenting cells in Th2 inflammatory responses. AB - Basophils gain prominence in Th2 inflammatory responses with the discovery that they function as antigen-presenting cells and are sufficient to drive Th2 cell differentiation. PMID- 19776084 TI - Violence and women's mental health: the pain unequalled. PMID- 19776085 TI - When crises collide: how intimate partner violence and poverty intersect to shape women's mental health and coping? AB - Until recently, the connection between intimate partner violence (IPV) and persistent poverty had been largely ignored. Recent research indicates, however, that the two phenomena cooccur at high rates; produce parallel effects; and, in each other's presence, constrain coping options. Therefore, both external situational, and internal psychological difficulties are missed when women contending with both poverty and IPV are viewed through the lens of just one or just the other. This article describes mental health consequences for women who contend with both partner violence and poverty. It proposes that the stress, powerlessness, and social isolation at the heart of both phenomena combine to produce posttraumatic stress disorder, depression, and other emotional difficulties. The article also introduces the term ''survival-focused coping'' to describe women's methods of coping with IPV in the context of poverty and highlights the role that domestic violence advocates, mental health providers, and researchers can play in addressing these tightly intertwined phenomena. PMID- 19776086 TI - Childhood maltreatment, intervening variables, and adult psychological difficulties in women: an overview. AB - This article reviews the complex relationship between child maltreatment and later psychosocial difficulties among adult women. Specifically addressed are (a) the various forms of childhood maltreatment, (b) the range of potential long-term psychological outcomes, and (c) important contextual variables that mediate or add to these maltreatment-symptom relationships. Among the latter are characteristics of the abuse and/or neglect; effects of impaired parental functioning; premaltreatment and postmaltreatment psychobiology; qualities of the parent-child attachment; abuse and/or neglect-related affect dysregulation that may lead to further symptomatology; the extent to which the child responds with significant emotional or behavioral avoidance; and whether later traumas are also present. Also relevant are sociocultural contributors to both child maltreatment and maltreatment effects, especially poverty and marginalization. Clinical and research implications are considered. PMID- 19776087 TI - Cytogenetic aberrations in soft tissue tumors harvested from fresh tissue submitted for surgical pathology: a single institutional experience. AB - AIMS: Recurrent cytogenetic abnormalities have been reported in many types of soft tissue neoplasms, and the detection of these aberrations imparts diagnostic utility. The aim of this study is to demonstrate that classical karyotyping may be performed with minimal effort as an adjunct to surgical pathology on fresh tissue submitted for histopathological examination. To the authors' knowledge, there are no recently published reviews in the literature in English of cytogenetic abnormalities in soft tissue tumors from a single institution. METHODS: Conventional metaphase cytogenetics was performed in the authors' cytogenetics laboratory on fresh tissue from mesenchymal tumors from their surgical pathology laboratory over a period of 4 years. Cytogenetics reports, clinical history, and histopathology were reviewed for 48 soft tissue tumors. Recurrent cytogenetic abnormalities were identified using the Mitelman Database of Chromosome Aberrations in Cancer and a review of the literature. RESULTS: The authors reviewed 48 cases of benign and malignant soft tissue tumors, which included 28 distinct morphologies. Cytogenetic abnormalities were observed in 23 (48%) cases, a normal chromosome profile was found in 20 (42%) cases, and 5 (10%) cases had no karyotype reported because of specimen contamination or inadequacy. Of the 23 cases with an aberrant karyotype, 15 (65%) tumors had cytogenetic abnormalities present in 2 or more cases in the literature. CONCLUSIONS: Cytogenetic analysis demonstrated abnormal karyotypes in nearly half of this series of mesenchymal neoplasms, the majority of which consisted of recognized aberrations reported in the literature. PMID- 19776088 TI - Small-cell plasmacytoma with prominent myxoid stroma mimicking a soft-tissue neoplasm. PMID- 19776089 TI - Topical chemotherapy for ocular surface squamous neoplasia: current status. AB - Although there are no randomised trials directly comparing topical chemotherapeutic agents mitomycin-C, 5-fluorouracil, and interferon-alpha2b, published studies indicate equal efficacy of these agents for treatment of non invasive ocular surface squamous neoplasia (80%-88%). 5-Fluorouracil may be preferred, given low incidence of serious side effects and low cost to the patient. PMID- 19776090 TI - Natural history and predictors for progression of mild childhood obstructive sleep apnoea. AB - AIMS: The natural history of mild childhood obstructive sleep apnoea (OSA) was examined and factors associated with disease progression were identified. METHODS: Subjects were recruited from an epidemiological study which examined the prevalence of OSA in Chinese children aged 6-13 years. The first 56 consecutive children identified with mild OSA (apnoea-hypopnoea index 1-5) were invited for a repeat assessment 2 years after the diagnosis. RESULTS: 45 children participated in the follow-up study, in 13 of whom (29%) the OSA was found to have worsened. Compared with those in whom OSA had not worsened, the worsened OSA group had a greater increase in waist circumference, a higher prevalence of large tonsils (occupying > or =50% of the airway) at both baseline and follow-up, and a higher prevalence of habitual snoring at both baseline and follow-up. The presence of large tonsils had a positive predictive value of 53% and a negative predictive value of 83% for worsening OSA over a 2-year period. Multivariate linear regression analysis showed that the change in obstructive apnoea-hypopnoea index was associated with age at baseline (beta (SE) = -0.92 (0.34), p = 0.009), gender (male = 1; female = 0) (beta (SE) = 4.69 (1.29), p<0.001), presence of large tonsils at baseline (beta (SE) = 4.36 (1.24), p = 0.001), change in waist circumference (beta (SE) = 0.30 (0.09), p = 0.002) and persistently large tonsils (beta (SE) = 5.69 (1.36), p<0.001) over the 2-year period. CONCLUSIONS: Mild OSA in the majority of children does not resolve spontaneously. Subjects with tonsillar hypertrophy, especially boys, should be closely monitored to allow early detection of worsening OSA. Weight control should be stressed in the management of childhood OSA. PMID- 19776091 TI - Hepatic artery aneurysm: an unusual case of biliary obstruction. PMID- 19776092 TI - Glatiramer acetate in combination with minocycline in patients with relapsing- remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, placebo-controlled trial. AB - Minocycline is proposed as an add-on therapy to improve the efficacy of glatiramer acetate in relapsing-remitting multiple sclerosis. The effect of minocycline plus glatiramer acetate was evaluated in this double-blind, placebo controlled study by determining the total number of T1 gadolinium-enhanced lesions at months 8 and 9 in patients who were starting glatiramer acetate and had at least one T1 gadolinium-enhanced lesion on screening magnetic resonance imaging. Forty-four participants were randomized to either minocycline 100 mg twice daily or matching placebo for 9 months as add-on therapy. They were assessed at screening and months 1, 3, 6, 8 and 9. Forty participants completed the study. Compared with glatiramer acetate/placebo, glatiramer acetate/minocycline reduced the total number of T1 gadolinium-enhanced lesions by 63% (mean 1.47 versus 2.95; p = 0.08), the total number of new and enlarging T2 lesions by 65% (mean 1.84 versus 5.14; p = 0.06), and the total T2 disease burden (p = 0.10). A higher number of gadolinium-enhanced lesions were present in the glatiramer acetate/minocycline group at baseline; this was incorporated into the analysis of the primary endpoint but makes interpretation of the data more challenging. The risk of relapse tended to be lower in the combination group (0.19 versus 0.41; p = NS). Treatment was safe and well tolerated. We conclude that efficacy endpoints showed a consistent trend favoring combination treatment. As minocycline is a relatively safe oral therapy, further study of this combination is warranted in relapsing-remitting multiple sclerosis. PMID- 19776093 TI - Treatment with the phosphodiesterase type-4 inhibitor rolipram fails to inhibit blood--brain barrier disruption in multiple sclerosis. AB - Rolipram, a prototypic phosphodiesterase-4 inhibitor, is highly effective in suppressing Th1 autoimmunity in multiple animal models, including experimental autoimmune encephalomyelitis. In addition, rolipram has been extensively studied as a potential neuroprotective agent. Based on its anti-inflammatory activity, we tested the efficacy of rolipram in suppressing inflammatory disease activity in multiple sclerosis in a proof-of-principle phase I/II open-label clinical trial. Enrolled MS patients were evaluated by monthly MRI and clinical examinations during 3 months (four MRIs) of pretreatment baseline and 8 months of rolipram therapy. The primary outcome was a change in contrast-enhanced lesions between baseline and the last 4 months of rolipram therapy. Previously defined biomarkers of rolipram-mediated immunomodulation were evaluated during the study. The trial was stopped prematurely because the drug was poorly tolerated and because of safety concerns: we observed an increase, rather than decrease, in the brain inflammatory activity measured by contrast-enhanced lesions on brain MRI. At the administered doses rolipram was active in vivo as documented by immunological assays. We conclude that the reasons underlying the discrepancy between the therapeutic efficacy of rolipram in experimental autoimmune encephalomyelitis versus multiple sclerosis are at present not clear. PMID- 19776094 TI - Prognostic factors in metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy. AB - BACKGROUND: With no U.S. Food and Drug Administration-approved standard therapy other than high-dose interleukin-2 and dacarbazine for metastatic melanoma, biochemotherapy has shown promise, with long-term survival in selected patients. We felt that the study of prognostic factors would determine which patients might benefit from this intensive therapy. METHODS: One hundred thirty-five consecutive patients with metastatic melanoma treated with decrescendo biochemotherapy followed by maintenance immunotherapy over 5 years were retrospectively studied to determine the most important prognostic factors for both overall survival and progression-free survival. RESULTS: The median overall survival (OS) time was 16.6 months, with 1-year and 5-year survival rates of 70% and 28%, respectively. The median progression-free survival (PFS) time was 7.6 months, with 15% of patients progression free at 5 years. PFS curves showed no relapses after 30 months, so remissions were durable. For OS, a performance status score of zero, normal lactate dehydrogenase (LDH) level, stage M1a, and nonvisceral sites of metastasis were favorable factors. The group with normal LDH levels and skin or nodes as one of their metastatic sites had a relatively good prognosis, with median survival time of 44 months and an estimated 5-year survival rate of 38%. Conversely, patients with an elevated LDH level without any skin or nodal metastases had a poor prognosis, with no long-term survivors. CONCLUSIONS: Metastatic melanoma patients treated with biochemotherapy and maintenance immunotherapy who have either a normal LDH level or skin or nodes as one of their metastatic sites may have durable remissions of their disease, and this therapy should be studied further in these groups. PMID- 19776095 TI - Plasma fibrinogen levels and prognosis in patients with ovarian cancer: a multicenter study. AB - INTRODUCTION: To evaluate pretherapeutic plasma fibrinogen levels as a prognostic parameter in patients with epithelial ovarian cancer (EOC). Materials and Methods. In the present multicenter study, pretherapeutic plasma fibrinogen levels were evaluated in 422 patients with EOC. Plasma fibrinogen levels were correlated with clinicopathological parameters and patient survival. RESULTS: The mean (standard deviation) pretherapeutic plasma fibrinogen level was 450.0 (150.1) mg/dl. Elevated plasma fibrinogen levels were associated with advanced tumor stage (p = .01) and the presence of a postoperative residual tumor mass (p < .001), but not with histological grade (p = .1) and histological type (p = .8). In a multivariate Cox regression model, tumor stage (p < .001 and p < .001), postoperative residual tumor mass (p = .001 and p = .008), and plasma fibrinogen level (p < .001 and p = .002), but not histological type (p = .8 and p = .2), patient age (p = .9 and p = .9), and serum cancer antigen 125 (p = 0.2 and p = 0.3) and C-reactive protein (p = .2 and p = .3) levels, were associated with disease-free and overall survival, respectively. Histological grade was associated with overall but not with disease-free survival (p = .01 and p = .8), respectively. CONCLUSIONS: Pretherapeutic plasma fibrinogen levels can be used as an independent prognostic parameter in patients with EOC. PMID- 19776096 TI - Planning ahead: waste management as a cornerstone in a world with limited resources. PMID- 19776097 TI - Unravelling the genetics of spermatogenic failure. AB - Subfertility, defined as the inability to conceive within 1 year of unprotected intercourse, affects 10-15% of couples. In up to 55% of couples, the male partner is diagnosed with spermatogenic failure, i.e. one or more semen parameters fall below the WHO criteria for normozoospermia. In these cases, assisted reproductive technology is usually used to achieve pregnancy. Both genetic and environmental factors are thought to underlie spermatogenic failure. Despite years of research, only few genetic factors have clearly been shown to cause spermatogenic failure, and the identification of additional genetic causes or risk factors has proven to be extremely difficult. In this review, we will present an overview of established genetic causes of spermatogenic failure, describe pitfalls in searching for novel genetic factors and discuss research opportunities for the future. PMID- 19776098 TI - Mechanical stretch regulates hypertrophic phenotype of the myometrium during pregnancy. AB - The adaptive growth of the uterus is a critical event that involves changes in cellular phenotypes throughout pregnancy. In early pregnancy, uterine growth is due to hyperplasia of uterine smooth muscle cells (SMCs) within the myometrium; however, the major component of myometrial growth occurs after mid-gestation. This study sought to test the hypothesis that increase in myometrial growth seen during late pregnancy is due to SMC hypertrophy caused by mechanical stretch of uterine tissue by a growing fetus(es) by providing direct measurements of individual SMC size. We employed a stereological approach to calculate the average cell volumes of uterine myocytes through diameter measurements using the Stereoinvestigator statistical software. Uterine tissues were collected from nonpregnant Wistar rats, as well as from gravid and nongravid horns of unilaterally pregnant animals on gestational days (d) 8 (early gestation), 14 (mid-gestation), 19 (late gestation), 22 (term), and 4 days post partum. Anti caveolin-1 immunostaining was used to clearly delineate SMC boundaries. The stereological analysis revealed that the dramatic increase in myometrial growth seen during late gestation (d19-22) is due to a threefold increase in the size of uterine myocytes. A significant increase in SMC volumes was detected in the gravid uterine horn as compared with the corresponding empty horn of unilateral term pregnant animals (day 22, mean cell volume 1114 vs 361 microm(3), P<0.05), indicating the effect of uterine occupancy. The restriction of the hypertrophy to cells within the gravid horn suggests that it may be a response to the biological mechanical stretch of uterine walls by the growing fetus(es) and placenta(s). PMID- 19776100 TI - The reversible developmental unipotency of germ cells in chicken. AB - We recently developed bimodal germline chimera production approaches by transfer of primordial germ cells (PGCs) or embryonic germ cells (EGCs) into embryos and by transplantation of spermatogonial stem cells (SSCs) or germline stem cells (GSCs) into adult testes. This study was undertaken to investigate the reversible developmental unipotency of chicken germ cells using our established germline chimera production systems. First, we transferred freshly isolated SSCs from adult testis or in vitro cultured GSCs into stage X and stage 14-16 embryos, and we found that these transferred SSCs/GSCs could migrate to the recipient embryonic gonads. Of the 527 embryos that received SSCs or GSCs, 135 yielded hatchlings. Of 17 sexually mature males (35.3%), six were confirmed as germline chimeras through testcross analysis resulting in an average germline transmission efficiency of 1.3%. Second, PGCs/EGCs, germ cells isolated from embryonic gonads were transplanted into adult testes. The EGC transplantation induced germline transmission, whereas the PGC transplantation did not. The germline transmission efficiency was 12.5 fold higher (16.3 vs 1.3%) in EGC transplantation into testis (EGCs to adult testis) than that in SSC/GSC transfer into embryos (testicular germ cells to embryo stage). In conclusion, chicken germ cells from different developmental stages can (de)differentiate into gametes even after the germ cell developmental clock is set back or ahead. Use of germ cell reversible unipotency might improve the efficiency of germ cell-mediated germline transmission. PMID- 19776099 TI - The reverse cholesterol transport system as a potential mediator of luteolysis in the primate corpus luteum. AB - The cessation of progesterone (P(4)) production (i.e. functional regression), arguably the key event in luteolysis of the primate corpus luteum (CL), is poorly understood. Previously, we found that genes encoding proteins involved in cholesterol uptake decreased, while those involved in cholesterol efflux (reverse cholesterol transport, RCT) increased in expression during spontaneous functional regression of the rhesus macaque CL, thereby potentially depleting the cholesterol reserves needed for steroidogenesis. Therefore, a comprehensive analysis of the components necessary for RCT was performed. RCT components were expressed (mRNA and/or protein) in the macaque CL including cholesterol sensors (liver X receptors alpha or NR1H3; and beta or NR1H2), efflux proteins (ATP binding cassette subfamilies A1 (ABCA1) and G1), acceptors (apolipoproteins A1 or APOA1; and E or APOE), and plasma proteins facilitating high-density lipoprotein formation (lecithin:cholesterol acyltransferase or LCAT; phospholipid transfer protein or PLTP). ABCA1, APOE, PLTP, and NR1H3 increased, while lipoprotein receptors decreased, in expression (mRNA and/or protein) through the period of functional regression. The expression of APOA1 and APOE, as well as NR1H3, was greatest in the CL and tissues involved in regulating cholesterol homeostasis. Immunolocalization studies revealed that RCT proteins and lipoprotein receptors were expressed in large luteal cells, which possess intracellular cholesterol reserves during periods of P(4) synthesis. Lipid staining revealed changes in luteal cholesterol ester/lipid distribution that occurred following functional regression. These results indicate that decreased cholesterol uptake and increased RCT may be critical for the initiation of primate luteolysis by limiting intracellular cholesterol pools required for steroidogenesis. PMID- 19776101 TI - Development of strips of ovine testes after xenografting under the skin of mice and co-transplantation of exogenous spermatogonia with grafts. AB - Xenografting of testicular tissue is an attractive new strategy for studying postnatal development of spermatogenesis and to preserve male genetics in large mammals. Typically, small cubes of immature testis (1 mm(3)) are grafted under the dorsal skin of immune-deficient mice. We attempted to increase the total number of seminiferous tubules in each xenograft with spermatogenesis by grafting flat strips of testis (approximately 9 x 5 x 1 mm) from ram lambs in immune deficient mice. The percentage of grafts that survived and percentage of seminiferous tubules that developed spermatogenesis were the same as those reported after xenografting small cubes of lamb testis. Partially purified sheep spermatogonia were labeled with the fluorescent dye carboxy fluorescein diacetate succinyl diester and transplanted into the seminiferous tubules of one of the donor testis just before engraftment. The temporary label in the donor cells was detected for 4 weeks after xenografting, suggesting that co-engraftment of spermatogonia with testicular tissue may be a way to rapidly determine the effect of a specific gene on spermatogenesis. Finally, Sertoli cell lesions in xenografts of lamb testes were quantified, and their number and severity were found to increase, especially after grafts had been in place for 4 weeks. Although this coincided with the development of spermatogenesis, the extent of germ cell differentiation negatively correlated with severity of the lesions. PMID- 19776102 TI - Selective serotonin reuptake inhibitors and congenital malformations. PMID- 19776103 TI - Selective serotonin reuptake inhibitors in pregnancy and congenital malformations: population based cohort study. AB - OBJECTIVE: To investigate any association between selective serotonin reuptake inhibitors (SSRIs) taken during pregnancy and congenital major malformations. DESIGN: Population based cohort study. PARTICIPANTS: 493 113 children born in Denmark, 1996-2003. MAIN OUTCOME MEASURE: Major malformations categorised according to Eurocat (European Surveillance of Congenital Anomalies) with additional diagnostic grouping of heart defects. Nationwide registers on medical redemptions (filled prescriptions), delivery, and hospital diagnosis provided information on mothers and newborns. Follow-up data available to December 2005. RESULTS: Redemptions for SSRIs were not associated with major malformations overall but were associated with septal heart defects (odds ratio 1.99, 95% confidence interval 1.13 to 3.53). For individual SSRIs, the odds ratio for septal heart defects was 3.25 (1.21 to 8.75) for sertraline, 2.52 (1.04 to 6.10) for citalopram, and 1.34 (0.33 to 5.41) for fluoxetine. Redemptions for more than one type of SSRI were associated with septal heart defects (4.70, 1.74 to 12.7)). The absolute increase in the prevalence of malformations was low-for example, the prevalence of septal heart defects was 0.5% (2315/493 113) among unexposed children, 0.9% (12/1370) among children whose mothers were prescribed any SSRI, and 2.1% (4/193) among children whose mothers were prescribed more than one type of SSRI. CONCLUSION: There is an increased prevalence of septal heart defects among children whose mothers were prescribed an SSRI in early pregnancy, particularly sertraline and citalopram. The largest association was found for children of women who redeemed prescriptions for more than one type of SSRI. PMID- 19776104 TI - An elderly woman with obstruction. PMID- 19776108 TI - Improving patient safety through training in non-technical skills. PMID- 19776110 TI - Europe's knowledge broker. PMID- 19776111 TI - UN expert calls for greater care and assistance for victims of child pornography. PMID- 19776112 TI - Health effects of toxic waste dumped in Cote d'Ivoire need urgent examination, UN expert says. PMID- 19776115 TI - Human cytomegalovirus IE1-72 protein interacts with p53 and inhibits p53 dependent transactivation by a mechanism different from that of IE2-86 protein. AB - Infection of host cells with human cytomegalovirus (HCMV) induces cell cycle dysregulation. Two HCMV immediate-early (IE) proteins, IE1-72 and IE2-86, are promiscuous transactivators that have been implicated in the dysregulatory events. Cellular p53 protein is accumulated to high levels in HCMV-infected cells, but the indicative marker of p53 transcriptional activity, p21, is markedly decreased. Both IE1-72 and IE2-86 were able to transactivate the p53 promoter and interact with p53 protein in DNA-transfected or HCMV-infected cells. HCMV UL84, a multiregulatory protein expressed in early periods of HCMV infection, also interacted with p53. HCMV IE1-72 prevented or disrupted p53 binding to p53-specific DNA sequences, while IE2-86 and/or UL84 enhanced p53 binding and induced supershift of this DNA-protein complex. Both HCMV IE1-72 and IE2-86 were able to inhibit p53-dependent transcriptional activation in plasmid transfected cells. IE1-72, rather than IE2-86, was found to be responsible for p21 downregulation in HCMV-infected HEL cells. DNA transfection analysis using IE1-72 mutants revealed that exon 2/3 and the zinc finger region of IE1-72 are essential for IE1-72's effect on the repression of p53-dependent transcriptional activation. These data suggest that HCMV IE1-72 and/or IE2-86 transactivates the p53 promoter and induces p53 accumulation, but HCMV IE1-72 represses the p53 transactivation activity by a unique binding hindrance mechanism different from that of IE2-86. Thus, various modes of viral IE proteins and p53 interactions might result in multiple outcomes, such as stimulation of cellular DNA synthesis, cell cycle progression and cell cycle arrest, and prevention of program cell death. PMID- 19776116 TI - Bacteriophage-mediated toxin gene regulation in Clostridium difficile. AB - Clostridium difficile has been identified as the most important single identifiable cause of nosocomial antibiotic-associated diarrhea and colitis. Virulent strains of C. difficile produce two large protein toxins, toxin A and toxin B, which are involved in pathogenesis. In this study, we examined the effect of lysogeny by PhiCD119 on C. difficile toxin production. Transcriptional analysis demonstrated a decrease in the expression of pathogenicity locus (PaLoc) genes tcdA, tcdB, tcdR, tcdE, and tcdC in PhiCD119 lysogens. During this study we found that repR, a putative repressor gene of PhiCD119, was expressed in C. difficile lysogens and that its product, RepR, could downregulate tcdA::gusA and tcdR::gusA reporter fusions in Escherichia coli. We cloned and purified a recombinant RepR containing a C-terminal six-His tag and documented its binding to the upstream regions of tcdR in C. difficile PaLoc and in repR upstream region in PhiCD119 by gel shift assays. DNA footprinting experiments revealed similarities between the RepR binding sites in tcdR and repR upstream regions. These findings suggest that presence of a CD119-like temperate phage can influence toxin gene regulation in this nosocomially important pathogen. PMID- 19776117 TI - Replication mode and landscape topology differentially affect RNA virus mutational load and robustness. AB - Regardless of genome polarity, intermediaries of complementary sense must be synthesized and used as templates for the production of new genomic strands. Depending on whether these new genomic strands become themselves templates for producing extra antigenomic ones, thus giving rise to geometric growth, or only the firstly synthesized antigenomic strands can be used to this end, thus following Luria's stamping machine model, the abundances and distributions of mutant genomes will be different. Here we propose mathematical and bit string models that allow distinguishing between stamping machine and geometric replication. We have observed that, regardless the topology of the fitness landscape, the critical mutation rate at which the master sequence disappears increases as the mechanism of replication switches from purely geometric to stamping machine. We also found that, for a wide range of mutation rates, large effect mutations do not accumulate regardless the scheme of replication. However, mild mutations accumulate more in the geometric model. Furthermore, at high mutation rates, geometric growth leads to a population collapse for intermediate values of mutational effects at which the stamping machine still produces master genomes. We observed that the critical mutation rate was weakly dependent on the strength of antagonistic epistasis but strongly dependent on synergistic epistasis. In conclusion, we have shown that RNA viruses may increase their robustness against the accumulation of deleterious mutations by replicating as stamping machines and that the magnitude of this benefit depends on the topology of the fitness landscape assumed. PMID- 19776118 TI - Analysis of human immunodeficiency virus type 1 matrix binding to membranes and nucleic acids. AB - The human immunodeficiency virus type 1 (HIV-1) matrix (MA) protein targets HIV-1 precursor Gag (PrGag) proteins to assembly sites at plasma membrane (PM) sites that are enriched in cholesterol and phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P(2)]. MA is myristoylated, which enhances membrane binding, and specifically binds PI(4,5)P(2) through headgroup and 2' acyl chain contacts. MA also binds nucleic acids, although the significance of this association with regard to the viral life cycle is unclear. We have devised a novel MA binding assay and used it to examine MA interactions with membranes and nucleic acids. Our results indicate that cholesterol increases the selectivity of MA for PI(4,5)P(2)-containing membranes, that PI(4,5)P(2) binding tolerates 2' acyl chain variation, and that the MA myristate enhances membrane binding efficiency but not selectivity. We also observed that soluble PI(4,5)P(2) analogues do not compete effectively with PI(4,5)P(2)-containing liposomes for MA binding but surprisingly do increase nonspecific binding to liposomes. Finally, we have demonstrated that PI(4,5)P(2)-containing liposomes successfully outcompete nucleic acids for MA binding, whereas other liposomes do not. These results support a model in which RNA binding protects MA from associating with inappropriate cellular membranes prior to PrGag delivery to PM assembly sites. PMID- 19776119 TI - Glycoprotein-dependent acidification of vesicular stomatitis virus enhances release of matrix protein. AB - To study vesicular stomatitis virus (VSV) entry and uncoating, we generated a recombinant VSV encoding a matrix (M) protein containing a C-terminal tetracysteine Lumio tag (rVSV-ML) that could be fluorescently labeled using biarsenical compounds. Quantitative confocal microscopy showed that there is a transient loss of fluorescence at early times after the initiation of endocytosis of rVSV-ML-Green (rVSV-MLG) virions, which did not occur when cells were treated with bafilomycin A1. The reduction in fluorescence occurred 5 to 10 min postentry, followed by a steady increase in fluorescence intensity from 15 to 60 min postentry. A similar loss of fluorescence was observed in vitro when virions were exposed to acidic pH. The reduction in fluorescence required G protein since "bald" DeltaG-MLG particles did not show a similar loss of fluorescence at low pH. Based on the pH-dependent fluorescence properties of Lumio Green, we hypothesize that the loss of fluorescence of rVSV-MLG virions during virus entry is due to a G ectodomain-dependent acidification of the virion interior. Biochemical analysis indicated that low pH also resulted in an enhancement of M protein dissociation from partially permeabilized, but otherwise intact, wild type virions. From these data we propose that low-pH conformational changes in G protein promote acidification of the virus interior, which facilitates the release of M from ribonucleoprotein particles during uncoating. PMID- 19776120 TI - The myxoma virus m-t5 ankyrin repeat host range protein is a novel adaptor that coordinately links the cellular signaling pathways mediated by Akt and Skp1 in virus-infected cells. AB - Most poxviruses express multiple proteins containing ankyrin (ANK) repeats accounting for a large superfamily of related but unique determinants of poxviral tropism. Recently, select members of this novel family of poxvirus proteins have drawn considerable attention for their potential roles in modulating intracellular signaling networks during viral infection. The rabbit-specific poxvirus, myxoma virus (MYXV), encodes four unique ANK repeat proteins, termed M T5, M148, M149, and M150, all of which include a carboxy-terminal PRANC domain which closely resembles a cellular protein motif called the F-box domain. Here, we show that each MYXV-encoded ANK repeat protein, including M-T5, interacts directly with the Skp1 component of the host SCF ubiquitin ligase complex, and that the binding of M-T5 to cullin 1 is indirect via binding to Skp1 in the host SCF complex. To understand the significance of these virus-host protein interactions, the various binding domains of M-T5 were mapped. The N-terminal ANK repeats I and II were identified as being important for interaction with Akt, whereas the C-terminal PRANC/F-box-like domain was essential for binding to Skp1. We also report that M-T5 can bind Akt and the host SCF complex (via Skp1) simultaneously in MYXV-infected cells. Finally, we report that M-T5 specifically mediates the relocalization of Akt from the nucleus to the cytoplasm during infection with the wild-type MYXV, but not the M-T5 knockout version of the virus. These results indicate that ANK/PRANC proteins play a critical role in reprogramming disparate cellular signaling cascades to establish a new cellular environment more favorable for virus replication. PMID- 19776121 TI - A single point mutation in nonstructural protein NS2 of bovine viral diarrhea virus results in temperature-sensitive attenuation of viral cytopathogenicity. AB - For Bovine viral diarrhea virus (BVDV), the type species of the genus Pestivirus in the family Flaviviridae, cytopathogenic (cp) and noncytopathogenic (ncp) viruses are distinguished according to their effect on cultured cells. It has been established that cytopathogenicity of BVDV correlates with efficient production of viral nonstructural protein NS3 and with enhanced viral RNA synthesis. Here, we describe generation and characterization of a temperature sensitive (ts) mutant of cp BVDV strain CP7, termed TS2.7. Infection of bovine cells with TS2.7 and the parent CP7 at 33 degrees C resulted in efficient viral replication and a cytopathic effect. In contrast, the ability of TS2.7 to cause cytopathogenicity at 39.5 degrees C was drastically reduced despite production of high titers of infectious virus. Further experiments, including nucleotide sequencing of the TS2.7 genome and reverse genetics, showed that a Y1338H substitution at residue 193 of NS2 resulted in the temperature-dependent attenuation of cytopathogenicity despite high levels of infectious virus production. Interestingly, TS2.7 and the reconstructed mutant CP7-Y1338H produced NS3 in addition to NS2-3 throughout infection. Compared to the parent CP7, NS2-3 processing was slightly decreased at both temperatures. Quantification of viral RNAs that were accumulated at 10 h postinfection demonstrated that attenuation of the cytopathogenicity of the ts mutants at 39.5 degrees C correlated with reduced amounts of viral RNA, while the efficiency of viral RNA synthesis at 33 degrees C was not affected. Taken together, the results of this study show that a mutation in BVDV NS2 attenuates viral RNA replication and suppresses viral cytopathogenicity at high temperature without altering NS3 expression and infectious virus production in a temperature-dependent manner. PMID- 19776122 TI - Incorporation of eukaryotic translation initiation factor eIF4E into viral nucleocapsids via interaction with hepatitis B virus polymerase. AB - The DNA genome of hepatitis B virus (HBV) replicates via reverse transcription within capsids following the encapsidation of an RNA template, the pregenomic RNA (pgRNA). We previously demonstrated that the 5' cap proximity of the stem-loop structure (epsilon or epsilon), an encapsidation signal, is critically important for the encapsidation of the pgRNA (J. K. Jeong, G. S. Yoon, and W. S. Ryu, J. Virol. 74:5502-5508, 2000). Therefore, we speculated that the viral polymerase (Pol), while bound to the 5' epsilon stem-loop structure, could recognize the cap via its interaction with eIF4E, a eukaryotic translation initiation factor. Our data showed the direct interaction between HBV Pol and eIF4E, as measured by coimmunoprecipitation. Further, we demonstrated that eIF4E interacts with the Pol epsilon ribonucleoprotein complex (RNP) rather than Pol alone, resulting in eIF4E Pol-epsilon RNP complex formation. In addition, we asked whether eIF4E remains engaged to the Pol-epsilon RNP complex during nucleocapsid assembly. Density gradient analysis revealed that eIF4E indeed was incorporated into nucleocapsids. It is of great importance to uncover whether the incorporated eIF4E contributes to viral reverse transcription or other steps in the HBV life cycle. PMID- 19776123 TI - Protective efficacy and immunogenicity of an adenoviral vector vaccine encoding the codon-optimized F protein of respiratory syncytial virus. AB - Adenoviral vectors (AdV) have received considerable attention for vaccine development because of their high immunogenicity and efficacy. In previous studies, it was shown that DNA immunization of mice with codon-optimized expression plasmids encoding the fusion protein of respiratory syncytial virus (RSV F) resulted in enhanced protection against RSV challenge compared to immunization with plasmids carrying the wild-type cDNA sequence of RSV F. In this study, we constructed AdV carrying the codon-optimized full-length RSV F gene (AdV-F) or the soluble form of the RSV F gene (AdV-Fsol). BALB/c mice were immunized twice with AdV-F or AdV-Fsol and challenged with RSV intranasally. Substantial levels of antibody to RSV F were induced by both AdV vaccines, with peak neutralizing-antibody titers of 1:900. Consistently, the viral loads in lung homogenates and bronchoalveolar lavage fluids were significantly reduced by a factor of more than 60,000. The protection against viral challenge could be measured even 8 months after the booster immunization. AdV-F and AdV-Fsol induced similar levels of immunogenicity and protective efficacy. Therefore, these results encourage further development of AdV vaccines against RSV infection in humans. PMID- 19776124 TI - Jaagsiekte sheep retrovirus encodes a regulatory factor, Rej, required for synthesis of Gag protein. AB - Retroviruses express Gag and Pol proteins by translation of unspliced genome length viral RNA. For some retroviruses, transport of unspliced viral RNA to the cytoplasm is mediated by small regulatory proteins such as human immunodeficiency virus Rev, while other retroviruses contain constitutive transport elements in their RNAs that allow transport without splicing. In this study, we found that the betaretrovirus Jaagsiekte sheep retrovirus (JSRV) encodes within the env gene a trans-acting factor (Rej) necessary for the synthesis of Gag protein from unspliced viral RNA. Deletion of env sequences from a JSRV proviral expression plasmid (pTN3) abolished its ability to produce Gag polyprotein in transfected 293T cells, and Gag synthesis could be restored by cotransfection of an env expression plasmid (DeltaGP). Deletion analysis localized the complementing activity (Rej) to the putative Env signal peptide, and a signal peptide expression construct showed Rej activity. Two other betaretroviruses, mouse mammary tumor virus (MMTV) and human endogenous retrovirus type K, encode analogous factors (Rem and Rec, respectively) that are encoded from doubly spliced env mRNAs. Reverse transcriptase-PCR cloning and sequencing identified alternate internal splicing events in the 5' end of JSRV env that could signify analogous doubly spliced Rej mRNAs, and cDNA clones expressing two of them also showed Rej activity. The predicted Rej proteins contain motifs similar to those found in MMTV Rem and other analogous retroviral regulatory proteins. Interestingly, in most cell lines, JSRV expression plasmids with Rej deleted showed normal transport of unspliced JSRV RNA to the cytoplasm; however, in 293T cells Rej modestly enhanced export of unspliced viral RNA (2.8-fold). Metabolic labeling experiments with [(35)S]methionine indicated that JSRV Rej is required for the synthesis of viral Gag polyprotein. Thus, in most cell lines, the predominant function of Rej is to facilitate translation of unspliced viral mRNA. PMID- 19776125 TI - Herpes simplex virus requires VP11/12 to induce phosphorylation of the activation loop tyrosine (Y394) of the Src family kinase Lck in T lymphocytes. AB - Herpes simplex virus (HSV) tegument proteins are released into the cytoplasm during viral entry and hence are among the first viral proteins encountered by an infected cell. Despite the implied importance of these proteins in the evasion of host defenses, the function of some, like virion protein 11/12 (VP11/12), have not been clearly defined. Previously, we reported that VP11/12 is strongly tyrosine phosphorylated during the infection of lymphocytes but not in fibroblasts or an epithelial cell line (G. Zahariadis, M. J. Wagner, R. C. Doepker, J. M. Maciejko, C. M. Crider, K. R. Jerome, and J. R. Smiley, J. Virol. 82:6098-6108, 2008). We also showed that tyrosine phosphorylation depends in part on the activity of the lymphocyte-specific Src family kinase (SFK) Lck in Jurkat T cells. These data suggested that VP11/12 is a substrate of Lck and that Lck is activated during HSV infection. Here, we show that HSV infection markedly increases the fraction of Lck phosphorylated on its activation loop tyrosine (Y394), a feature characteristic of activated Lck. A previous report implicated the immediate-early protein ICP0 and the viral serine/threonine kinases US3 and UL13 in the induction of a similar activated phenotype of SFKs other than Lck in fibroblasts and suggested that ICP0 interacts directly with SFKs through their SH3 domain. However, we were unable to detect an interaction between ICP0 and Lck in T lymphocytes, and we show that ICP0, US3, and UL13 are not strictly required for Lck activation. In contrast, VP11/12 interacted with Lck or Lck signaling complexes and was strictly required for Lck activation during HSV infection. Thus, VP11/12 likely modulates host cell signaling pathways for the benefit of the virus. PMID- 19776126 TI - Epstein-Barr virus nuclear protein 3C domains necessary for lymphoblastoid cell growth: interaction with RBP-Jkappa regulates TCL1. AB - B lymphocytes converted into lymphoblastoid cell lines (LCLs) by an Epstein-Barr virus that expresses a conditional EBNA3C require complementation with EBNA3C for growth under nonpermissive conditions. Complementation with relatively large EBNA3C deletion mutants identified amino acids (aa) 1 to 506 (which includes the RBP-Jkappa/CSL [RBP-Jkappa] binding domain) and 733 to 909 to be essential for LCL growth, aa 728 to 732 and 910 to 992 to be important for full wild-type (wt) growth, and only aa 507 to 727 to be unimportant (S. Maruo, Y. Wu, T. Ito, T. Kanda, E. D. Kieff, and K. Takada, Proc. Natl. Acad. Sci. USA 106:4419-4424, 2009). When mutants with smaller deletions were used, only aa 51 to 400 and 851 to 900 were essential for LCL growth; aa 447 to 544, 701 to 750, 801 to 850, and 901 to 992 were important for full wt growth; and aa 4 to 50, 401 to 450, 550 to 707, and 751 to 800 were unimportant. These data reduce the EBNA3C essential residues from 68% to 40% of the open reading frame. Point mutations confirmed RBP Jkappa binding to be essential for wt growth and indicated that SUMO and CtBP binding interactions were important only for full wt growth. EBNA3C aa 51 to 150, 249 to 311, and 851 to 900 were necessary for maintaining LCL growth, but not RBP Jkappa interaction, and likely mediate interactions with other key cell proteins. Moreover, all mutants null for LCL growth had fewer S+G(2)/M-phase cells at 14 days, consistent with EBNA3C interaction with RBP-Jkappa as well as aa 51 to 150, 249 to 311, and 851 to 900 being required to suppress p16(INK4A) (S. Maruo, Y. Wu, S. Ishikawa, T. Kanda, D. Iwakiri, and K. Takada, Proc. Natl. Acad. Sci. USA 103:19500-19505, 2006). We have confirmed that EBNA3C upregulates TCL1 and discovered that EBNA3C upregulates TCL1 through RBP-Jkappa, indicating a central role for EBNA3C interaction with RBP-Jkappa in mediating cell gene transcription. PMID- 19776127 TI - Regulation of proinflammatory cytokine expression in primary mouse astrocytes by coronavirus infection. AB - Previous studies have shown that proinflammatory cytokines, such as tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), are differentially induced in primary mouse astrocytes by mouse hepatitis virus strain A59 (MHV-A59) and MHV-2. However, the signaling events that trigger TNF-alpha and IL-6 induction in these cells upon MHV infection remain unknown. In this study, we explored the potential signaling events. We found that induction of TNF-alpha and IL-6 occurred as early as 2 h postinfection and was completely dependent on viral replication. Using inhibitors specific for three mitogen-activated protein kinases, we showed that induction of TNF-alpha and IL-6 by MHV-A59 infection was mediated through activation of the Janus N-terminal kinase signaling pathway, but not through the extracellular signal-regulated kinase or p38 signaling pathway. This finding was further confirmed with knockdown experiments using small interfering RNAs specific for Janus N-terminal kinase. Interestingly, while nuclear factor kappaB (NF-kappaB), a key transcription factor required for the expression of proinflammatory cytokines in most cell types, was activated in astrocytes during MHV-A59 infection, disruption of the NF-kappaB pathway by peptide inhibitors did not significantly inhibit TNF-alpha and IL-6 expression. Furthermore, experiments using chimeric viruses demonstrated that the viral spike and nucleocapsid proteins, which play important roles in MHV pathogenicity in mice, are not responsible for the differential induction of the cytokines. These results illustrate the complexity of the regulatory mechanism by which MHV induces proinflammatory cytokines in primary astrocytes. PMID- 19776128 TI - Molecular chaperone BiP interacts with Borna disease virus glycoprotein at the cell surface. AB - Borna disease virus (BDV) is characterized by highly neurotropic infection. BDV enters its target cells using virus surface glycoprotein (G), but the cellular molecules mediating this process remain to be elucidated. We demonstrate here that the N-terminal product of G, GP1, interacts with the 78-kDa chaperone protein BiP. BiP was found at the surface of BDV-permissive cells, and anti-BiP antibody reduced BDV infection as well as GP1 binding to the cell surface. We also reveal that BiP localizes at the synapse of neurons. These results indicate that BiP may participate in the cell surface association of BDV. PMID- 19776129 TI - Packaging of host mY RNAs by murine leukemia virus may occur early in Y RNA biogenesis. AB - Moloney murine leukemia virus (MLV) selectively encapsidates host mY1 and mY3 RNAs. These noncoding RNA polymerase III transcripts are normally complexed with the Ro60 and La proteins, which are autoantigens associated with rheumatic disease that function in RNA biogenesis and quality control. Here, MLV replication and mY RNA packaging were analyzed using Ro60 knockout embryonic fibroblasts, which contain only approximately 3% as much mY RNA as wild-type cells. Virus spread at the same rate in wild-type and Ro knockout cells. Surprisingly, MLV virions shed by Ro60 knockout cells continued to package high levels of mY1 and mY3 (about two copies of each) like those from wild-type cells, even though mY RNAs were barely detectable within producer cells. As a result, for MLV produced in Ro60 knockout cells, encapsidation selectivity from among all cell RNAs was even higher for mY RNAs than for the viral genome. Whereas mY RNAs are largely cytoplasmic in wild-type cells, fractionation of knockout cells revealed that the residual mY RNAs were relatively abundant in nuclei, likely reflecting the fact that most mY RNAs were degraded shortly after transcription in the absence of Ro60. Together, these data suggest that these small, labile host RNAs may be recruited at a very early stage of their biogenesis and may indicate an intersection of retroviral assembly and RNA quality control pathways. PMID- 19776130 TI - Functional analysis and structural modeling of human APOBEC3G reveal the role of evolutionarily conserved elements in the inhibition of human immunodeficiency virus type 1 infection and Alu transposition. AB - Retroelements are important evolutionary forces but can be deleterious if left uncontrolled. Members of the human APOBEC3 family of cytidine deaminases can inhibit a wide range of endogenous, as well as exogenous, retroelements. These enzymes are structurally organized in one or two domains comprising a zinc coordinating motif. APOBEC3G contains two such domains, only the C terminal of which is endowed with editing activity, while its N-terminal counterpart binds RNA, promotes homo-oligomerization, and is necessary for packaging into human immunodeficiency virus type 1 (HIV-1) virions. Here, we performed a large-scale mutagenesis-based analysis of the APOBEC3G N terminus, testing mutants for (i) inhibition of vif-defective HIV-1 infection and Alu retrotransposition, (ii) RNA binding, and (iii) oligomerization. Furthermore, in the absence of structural information on this domain, we used homology modeling to examine the positions of functionally important residues and of residues found to be under positive selection by phylogenetic analyses of primate APOBEC3G genes. Our results reveal the importance of a predicted RNA binding dimerization interface both for packaging into HIV-1 virions and inhibition of both HIV-1 infection and Alu transposition. We further found that the HIV-1-blocking activity of APOBEC3G N terminal mutants defective for packaging can be almost entirely rescued if their virion incorporation is forced by fusion with Vpr, indicating that the corresponding region of APOBEC3G plays little role in other aspects of its action against this pathogen. Interestingly, residues forming the APOBEC3G dimer interface are highly conserved, contrasting with the rapid evolution of two neighboring surface-exposed amino acid patches, one targeted by the Vif protein of primate lentiviruses and the other of yet-undefined function. PMID- 19776131 TI - Structure-function analysis of human immunodeficiency virus type 1 gp120 amino acid mutations associated with resistance to the CCR5 coreceptor antagonist vicriviroc. AB - Vicriviroc (VCV) is a small-molecule CCR5 coreceptor antagonist currently in clinical trials for treatment of R5-tropic human immunodeficiency virus type 1 (HIV-1) infection. With this drug in development, identification of resistance mechanisms to VCV is needed to allow optimal outcomes in clinical practice. In this study we further characterized VCV resistance in a lab-adapted, VCV resistant RU570 virus (RU570-VCV(res)). We show that K305R, R315Q, and K319T amino acid changes in the V3 loop, along with P437S in C4, completely reproduced the resistance phenotype in a chimeric ADA envelope containing the C2-V5 region from RU570 passage control gp120. The K305R amino acid change primarily impacted the degree of resistance, whereas K319T contributed to both resistance and virus infectivity. The P437S mutation in C4 had more influence on the relative degree of virus infectivity, while the R315Q mutation contributed to the virus concentration-dependent phenotypic resistance pattern observed for RU570 VCV(res). RU570-VCV(res) pseudovirus entry with VCV-bound CCR5 was dramatically reduced by Y10A, D11A, Y14A, and Y15A mutations in the N terminus of CCR5, whereas these mutations had less impact on entry in the absence of VCV. Notably, an additional Q315E/I317F substitution in the crown region of the V3 loop enhanced resistance to VCV, resulting in a stronger dependence on the N terminus for viral entry. By fitting the envelope mutations to a molecular model of a recently described docked N-terminal CCR5 peptide consisting of residues 2 to 15 in complex with HIV-1 gp120 CD4, potential new interactions in gp120 with the N terminus of CCR5 were uncovered. The cumulative results of this study suggest that as the RU570 VCV-resistant virus adapted to use the drug-bound receptor, it also developed an increased reliance on the N terminus of CCR5. PMID- 19776132 TI - Protonation of individual histidine residues is not required for the pH-dependent entry of west nile virus: evaluation of the "histidine switch" hypothesis. AB - Histidine residues have been hypothesized to function as sensors of environmental pH that can trigger the activity of viral fusion proteins. We investigated a requirement for histidine residues in the envelope (E) protein of West Nile virus during pH-dependent entry into cells. Each histidine was individually replaced with a nonionizable amino acid and tested functionally. In each instance, mutants capable of orchestrating pH-dependent infection were identified. These results do not support a requirement for any single histidine as a pH-sensing "switch," and they suggest that additional features of the E protein are involved in triggering pH-dependent steps in the flavivirus life cycle. PMID- 19776133 TI - Hepatoma cell density promotes claudin-1 and scavenger receptor BI expression and hepatitis C virus internalization. AB - Hepatitis C virus (HCV) entry occurs via a pH- and clathrin-dependent endocytic pathway and requires a number of cellular factors, including CD81, the tight junction proteins claudin 1 (CLDN1) and occludin, and scavenger receptor class B member I (SR-BI). HCV tropism is restricted to the liver, where hepatocytes are tightly packed. Here, we demonstrate that SR-BI and CLDN1 expression is modulated in confluent human hepatoma cells, with both receptors being enriched at cell cell junctions. Cellular contact increased HCV pseudoparticle (HCVpp) and HCV particle (HCVcc) infection and accelerated the internalization of cell-bound HCVcc, suggesting that the cell contact modulation of receptor levels may facilitate the assembly of receptor complexes required for virus internalization. CLDN1 overexpression in subconfluent cells was unable to recapitulate this effect, whereas increased SR-BI expression enhanced HCVpp entry and HCVcc internalization, demonstrating a rate-limiting role for SR-BI in HCV internalization. PMID- 19776134 TI - Identification and mutational analysis of a Rej response element in Jaagsiekte sheep retrovirus RNA. AB - Jaagsiekte sheep retrovirus (JSRV) is a simple betaretrovirus causing a contagious lung cancer of sheep. JSRV encodes unspliced and spliced viral RNAs, among which unspliced RNA encodes Gag and Pol proteins and a singly spliced mRNA encodes Env protein. In another study we found that JSRV encodes a regulatory protein, Rej, that is responsible for synthesis of Gag polyprotein from unspliced viral RNA. Rej is encoded in the 5' end of env, and it enhances nuclear export or accumulation of cytoplasmic unspliced viral RNA in 293T cells but not in most other cell lines (A. Hofacre, T. Nitta, and H. Fan, J. Virol. 83:12483-12498, 2009). In this study, we found that mutations in the 3' end of env in the context of a cytomegalovirus-driven full-length JSRV expression construct abolished Gag protein synthesis and released viruses in 293T cells. These mutants also showed deficits in accumulation of unspliced viral RNA in the cytoplasm. These mutants defined a Rej-responsive element (RejRE). Inhibition of CRM1 but not Tap function prevented nuclear export/accumulation of cytoplasmic unspliced RNA in 293T cells, similarly to other complex retroviruses that express analogous regulator proteins (e.g., human immunodeficiency virus Rev). Structural modeling of the RejRE with Zuker M-fold indicated a region with a predicted stable secondary structure. Mutational analysis in this region indicated the importance of both secondary structures and primary nucleotide sequences in a central stem-bulge-stem structure. In contrast to 293T cells, mutations in the RejRE did not affect the levels of cytoplasmic unspliced RNA in 293 cells, although the unspliced RNA showed partial degradation, perhaps due to lack of translation. RejRE-containing RNA relocalized Rej protein from the nucleus to the cytoplasm in 293 and rat 208F cells, suggesting binding of Rej to the RejRE. PMID- 19776135 TI - Inhibition of protein kinase R activation and upregulation of GADD34 expression play a synergistic role in facilitating coronavirus replication by maintaining de novo protein synthesis in virus-infected cells. AB - A diversity of strategies is evolved by RNA viruses to manipulate the host translation machinery in order to create an optimal environment for viral replication and progeny production. One of the common viral targets is the alpha subunit of eukaryotic initiation factor 2 (eIF-2alpha). In this report, we show that phosphorylation of eIF-2alpha was severely suppressed in human and animal cells infected with the coronavirus infectious bronchitis virus (IBV). To understand whether this suppression is through inhibition of protein kinase R (PKR), the double-stranded-RNA-dependent kinase that is one of the main kinases responsible for phosphorylation of eIF-2alpha, cells infected with IBV were analyzed by Western blotting. The results showed that the level of phosphorylated PKR was greatly reduced in IBV-infected cells. Overexpression of IBV structural and nonstructural proteins (nsp) demonstrated that nsp2 is a weak PKR antagonist. Furthermore, GADD34, a component of the protein phosphatase 1 (PP1) complex, which dephosphorylates eIF-2alpha, was significantly induced in IBV-infected cells. Inhibition of the PP1 activity by okadaic acid and overexpression of GADD34, eIF-2alpha, and PKR, as well as their mutant constructs in virus-infected cells, showed that these viral regulatory strategies played a synergistic role in facilitating coronavirus replication. Taken together, these results confirm that IBV has developed a combination of two mechanisms, i.e., blocking PKR activation and inducing GADD34 expression, to maintain de novo protein synthesis in IBV infected cells and, meanwhile, to enhance viral replication. PMID- 19776136 TI - Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular disease. AB - BACKGROUND: Epidemiologic studies have suggested that flavonoid intake plays a critical role in the prevention of coronary heart disease. Because atherosclerosis is considered a low-grade inflammatory disease, some feeding trials have analyzed the effects of cocoa (an important source of flavonoids) on inflammatory biomarkers, but the results have been controversial. OBJECTIVE: The objective was to evaluate the effects of chronic cocoa consumption on cellular and serum biomarkers related to atherosclerosis in high-risk patients. DESIGN: Forty-two high-risk volunteers (19 men and 23 women; mean +/- SD age: 69.7 +/- 11.5 y) were included in a randomized crossover feeding trial. All subjects received 40 g cocoa powder with 500 mL skim milk/d (C+M) or only 500 mL skim milk/d (M) for 4 wk. Before and after each intervention period, cellular and serum inflammatory biomarkers related to atherosclerosis were evaluated. RESULTS: Adherence to the dietary protocol was excellent. No significant changes in the expression of adhesion molecules on T lymphocyte surfaces were found between the C+M and M groups. However, in monocytes, the expression of VLA-4, CD40, and CD36 was significantly lower (P = 0.005, 0.028, and 0.001, respectively) after C+M intake than after M intake. In addition, serum concentrations of the soluble endothelium-derived adhesion molecules P-selectin and intercellular adhesion molecule-1 were significantly lower (both P = 0.007) after C+M intake than after M intake. CONCLUSIONS: These results suggest that the intake of cocoa polyphenols may modulate inflammatory mediators in patients at high risk of cardiovascular disease. These antiinflammatory effects may contribute to the overall benefits of cocoa consumption against atherosclerosis. This trial was registered in the Current Controlled Trials at London, International Standard Randomized Controlled Trial Number, at controlled-trials.com as ISRCTN75176807. PMID- 19776137 TI - Food insecurity is associated with iron deficiency anemia in US adolescents. AB - BACKGROUND: Food insecurity, a condition of low or very low food security, is associated with decreased nutrient intake and poor health, which can lead to nutrient deficiency in children, including iron deficiency and iron deficiency anemia. OBJECTIVE: The purpose of this study was to formally investigate the current relation of iron status and food security status among children aged 3-19 y (n = 11,247). DESIGN: Participants of the National Health and Nutrition Examination Survey 1999-2004 were classified for food security status by using the US Children's Food Security Scale and the US Household Food Security Scale. Iron deficiency was defined as > or =2 abnormal values for transferrin saturation, serum ferritin, and erythrocyte protoporphyrin, with the addition of abnormal hemoglobin to classify iron deficiency anemia. RESULTS: The odds of iron deficiency anemia among children aged 12-15 y were 2.95 times (95% CI: 1.18, 7.37; P = 0.02) those for children in households with food insecurity among children compared with children in households with food security among children. CONCLUSIONS: The results of this study indicate a continuing need for successful interventions to reduce iron deficiency anemia among food-insecure children and to improve food security among children. PMID- 19776138 TI - Energy intake and expenditure profile in chronic peritoneal dialysis patients complicated with circulatory congestion. AB - BACKGROUND: Circulatory congestion is an adverse predictor of mortality in peritoneal dialysis (PD) patients. OBJECTIVE: This study evaluated the nutritional status, energy intake, and expenditure profile of PD patients with and without previous circulatory congestion. DESIGN: We conducted a cross sectional study in 244 PD patients, of whom 92 had previous circulatory congestion. We estimated dietary energy intake by using a locally validated 7-d food-frequency questionnaire and by assessing resting energy expenditure (REE) and total energy expenditure (TEE) with indirect calorimetry and a locally validated physical activity questionnaire, respectively. RESULTS: In comparison with those without circulatory congestion, patients with previous circulatory congestion were more malnourished by subjective global assessment (59% compared with 36%; P < 0.001), had lower handgrip strength, had lower midarm muscle circumference, had lower dietary protein (0.98 +/- 0.45 compared with 1.19 +/- 0.44 g x kg(-1) x d(-1); P < 0.001), and had lower energy intake (92.5 +/- 37.0 compared with 110.9 +/- 35.7 kJ x kg(-1) x d(-1); P < 0.001) but had higher C reactive protein (P = 0.025) and higher REE (P < 0.001). However, no difference in TEE was noted between the 2 groups, which indicated lower activity energy expenditure among patients with previous circulatory congestion. The resulting energy balance was significantly more negative for patients with previous circulatory congestion than for those without previous circulatory congestion (P = 0.050). Furthermore, the prevalence of malnutrition increased with increasing episodes of circulatory congestion (P = 0.017). CONCLUSIONS: Patients with previous circulatory congestion had significantly more inflammation, more muscle wasting, and higher REE but lower activity energy expenditure and energy and protein intakes in keeping with an anorexia-cachexia syndrome. The mechanisms of increased REE and reduced energy intake among patients with previous circulatory congestion warrant further investigation. PMID- 19776139 TI - Are energy-dense foods really cheaper? Reexamining the relation between food price and energy density. AB - BACKGROUND: The inverse relation between energy density (kcal/g) and energy cost (price/kcal) has been interpreted to suggest that produce (fruit, vegetables) is more expensive than snacks (cookies, chips). OBJECTIVE: The objective of this study was to show the methodologic weakness of comparing energy density with energy cost. DESIGN: The relation between energy density and energy cost was replicated in a random-number data set. Additionally, observational data were collected for produce and snacks from an online supermarket. Variables included total energy (kcal), total weight (g), total number of servings, serving size (g/serving), and energy density (kcal/g). Price measures included energy cost ($/kcal), total price ($), unit price ($/g), and serving price ($/serving). Two tailed t tests were used to compare price measures by food category. Relations between energy density and price measures within food categories were examined with the use of Spearman rank correlation analysis. RESULTS: The relation between energy density and energy cost was shown to be driven by the algebraic properties of these variables. Food category was strongly correlated with both energy density and food price measures. Energy cost was higher for produce than for snacks. However, total price and unit price were lower for produce. Serving price and serving size were greater for produce than for snacks. Within food categories, energy density was uncorrelated with most measures of food price, except for a weak positive correlation with serving price within the produce category. CONCLUSION: The findings suggest the relation between energy density and food price is confounded by food category and depends on which measure of price is used. PMID- 19776140 TI - Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal. AB - BACKGROUND: We have previously shown that gut microbial fermentation of prebiotics promotes satiety and lowers hunger and energy intake in humans. In rodents, these effects are associated with an increase in plasma gut peptide concentrations, which are involved in appetite regulation and glucose homeostasis. OBJECTIVE: Our aim was to examine the effects of prebiotic supplementation on satiety and related hormones during a test meal for human volunteers by using a noninvasive micromethod for blood sampling to measure plasma gut peptide concentrations. DESIGN: This study was a randomized, double blind, parallel, placebo-controlled trial. A total of 10 healthy adults (5 men and 5 women) were randomly assigned to groups that received either 16 g prebiotics/d or 16 g dextrin maltose/d for 2 wk. Meal tolerance tests were performed in the morning to measure the following: hydrogen breath test, satiety, glucose homeostasis, and related hormone response. RESULTS: We show that the prebiotic treatment increased breath-hydrogen excretion (a marker of gut microbiota fermentation) by approximately 3-fold and lowered hunger rates. Prebiotics increased plasma glucagon-like peptide 1 and peptide YY concentrations, whereas postprandial plasma glucose responses decreased after the standardized meal. The areas under the curve for plasma glucagon-like peptide 1 and breath-hydrogen excretion measured after the meal (0-60 min) were significantly correlated (r = 0.85, P = 0.007). The glucose response was inversely correlated with the breath-hydrogen excretion areas under the curve (0 180 min; r = -0.73, P = 0.02). CONCLUSION: Prebiotic supplementation was associated with an increase in plasma gut peptide concentrations (glucagon-like peptide 1 and peptide YY), which may contribute in part to changes in appetite sensation and glucose excursion responses after a meal in healthy subjects. PMID- 19776141 TI - Targeting sedentary time or moderate- and vigorous-intensity activity: independent relations with adiposity in a population-based sample of 10-y-old British children. AB - BACKGROUND: It is unclear whether subcomponents of physical activity (PA) are associated with adiposity independent of time spent while sedentary. OBJECTIVE: The objective was to examine associations between objectively measured PA and its subcomponents [ie, time spent at light-intensity PA, moderate-intensity PA (MPA), vigorous-intensity PA (VPA), and moderate-plus-vigorous-intensity PA (MVPA)], independent of sedentary time, and self-reported leisure screen time (television and electronic game use) with indexes of adiposity in a population-based sample of British children. DESIGN: A cross-sectional study was conducted in 1862 UK children aged 9-10 y. PA and sedentary activity were measured by accelerometry, and indicators of adiposity were waist circumference, body mass index (BMI), and fat mass index calculated from bioimpedance measurements. Screen time was assessed by self-report. We examined the associations between PA subcomponents and adiposity by multilevel linear models adjusted for birth weight, maternal BMI, energy intake, and sleep duration. RESULTS: Objectively measured sedentary time was positively associated with waist circumference (P = 0.04) and fat mass index (P = 0.05), independent of age and sex. However, this association was attenuated after adjustment for MVPA and other covariates. VPA (all P < 0.0001), combined MVPA (all P < 0.01), and total activity (counts/min) (all P < 0.001) were all inversely associated with each of the adiposity indexes, independent of sedentary time and other important covariates. Associations were weaker for MPA: P = 0.05, 0.87, and 0.1 for waist circumference, BMI, and fat mass index, respectively. CONCLUSIONS: Time spent in VPA appears to be more strongly associated with adiposity than sedentary time. Interventions may therefore need to incorporate higher intensity-based activities to curb the growing obesity epidemic. PMID- 19776142 TI - Characterizing extreme values of body mass index-for-age by using the 2000 Centers for Disease Control and Prevention growth charts. AB - BACKGROUND: The 2000 Centers for Disease Control and Prevention (CDC) growth charts included lambda-mu-sigma (LMS) parameters intended to calculate smoothed percentiles from only the 3rd to the 97th percentile. OBJECTIVE: The objective was to evaluate different approaches to describing more extreme values of body mass index (BMI)-for-age by using simple functions of the CDC growth charts. DESIGN: Empirical data for the 99th and the 1st percentiles of BMI-for-age were calculated from the data set used to construct the growth charts and were compared with estimates extrapolated from the CDC-supplied LMS parameters and to various functions of other smoothed percentiles. A set of reestimated LMS parameters that incorporated a smoothed 99th percentile were also evaluated. RESULTS: Extreme percentiles extrapolated from the CDC-supplied LMS parameters did not match well to the empirical data for the 99th percentile. A better fit to the empirical data was obtained by using 120% of the smoothed 95th percentile. The empirical first percentile was reasonably well approximated by extrapolations from the LMS values. The reestimated LMS parameters had several drawbacks and no clear advantages. CONCLUSIONS: Several approximations can be used to describe extreme high values of BMI-for-age with the use of the CDC growth charts. Extrapolation from the CDC-supplied LMS parameters does not provide a good fit to the empirical 99th percentile values. Simple approximations to high values as percentages of the existing smoothed percentiles have some practical advantages over imputation of very high percentiles. The expression of high BMI values as a percentage of the 95th percentile can provide a flexible approach to describing and tracking heavier children. PMID- 19776143 TI - Intermittent fasting does not affect whole-body glucose, lipid, or protein metabolism. AB - BACKGROUND: Intermittent fasting (IF) was shown to increase whole-body insulin sensitivity, but it is uncertain whether IF selectively influences intermediary metabolism. Such selectivity might be advantageous when adapting to periods of food abundance and food shortage. OBJECTIVE: The objective was to assess effects of IF on intermediary metabolism and energy expenditure. DESIGN: Glucose, glycerol, and valine fluxes were measured after 2 wk of IF and a standard diet (SD) in 8 lean healthy volunteers in a crossover design, in the basal state and during a 2-step hyperinsulinemic euglycemic clamp, with assessment of energy expenditure and phosphorylation of muscle protein kinase B (AKT), glycogen synthase kinase (GSK), and mammalian target of rapamycine (mTOR). We hypothesized that IF selectively increases peripheral glucose uptake and lowers proteolysis, thereby protecting protein stores. RESULTS: No differences in body weight were observed between the IF and SD groups. Peripheral glucose uptake and hepatic insulin sensitivity during the clamp did not significantly differ between the IF and SD groups. Likewise, lipolysis and proteolysis were not different between the IF and SD groups. IF decreased resting energy expenditure. IF had no effect on the phosphorylation of AKT but significantly increased the phosphorylation of glycogen synthase kinase. Phosphorylation of mTOR was significantly lower after IF than after the SD. CONCLUSIONS: IF does not affect whole-body glucose, lipid, or protein metabolism in healthy lean men despite changes in muscle phosphorylation of GSK and mTOR. The decrease in resting energy expenditure after IF indicates the possibility of an increase in weight during IF when caloric intake is not adjusted. This study was registered at www.trialregister.nl as NTR1841. PMID- 19776144 TI - Food label use and awareness of nutritional information and recommendations among persons with chronic disease. AB - BACKGROUND: Because of the relation between chronic disease and poor nutritional habits, the use of food labels and adherence to dietary recommendations are important for chronic disease populations. We explored whether persons with chronic disease read nutrient information on food labels and whether they were aware of dietary guidelines. OBJECTIVE: This study aimed to assess dietary information use among persons with chronic disease by using a nationally representative sample of the US population. DESIGN: A total of 5603 respondents aged > or =17 y from the 2005-2006 National Health and Nutrition Examination Survey participated in the study. This representative sample of US civilians were asked 17 questions regarding their awareness of federal nutrition information and their food label use and were given two 24-h recall dietary interviews. Participants were classified into 5 disease categories: 1) hypertension, 2) hypercholesterolemia, 3) diabetes/at risk of diabetes, 4) overweight, and 5) heart disease. RESULTS: Subjects with chronic diseases were more aware of nutritional recommendations, checked more often for specific nutrients, and used nutrition information on food labels more often than did participants without such diseases. Label use behavior was inconsistently associated with dietary guideline compliance. CONCLUSIONS: People with chronic disease generally reported better nutrition awareness and food label use and checking behaviors compared with those without chronic disease, but this did not translate into unequivocally better eating behaviors. New strategies are needed to improve the actual nutritional behaviors of persons with chronic disease. PMID- 19776147 TI - Enhancement of natural background gamma-radiation dose around uranium microparticles in the human body. AB - Ongoing controversy surrounds the adverse health effects of the use of depleted uranium (DU) munitions. The biological effects of gamma-radiation arise from the direct or indirect interaction between secondary electrons and the DNA of living cells. The probability of the absorption of X-rays and gamma-rays with energies below about 200 keV by particles of high atomic number is proportional to the third to fourth power of the atomic number. In such a case, the more heavily ionizing low-energy recoil electrons are preferentially produced; these cause dose enhancement in the immediate vicinity of the particles. It has been claimed that upon exposure to naturally occurring background gamma-radiation, particles of DU in the human body would produce dose enhancement by a factor of 500-1000, thereby contributing a significant radiation dose in addition to the dose received from the inherent radioactivity of the DU. In this study, we used the Monte Carlo code EGSnrc to accurately estimate the likely maximum dose enhancement arising from the presence of micrometre-sized uranium particles in the body. We found that although the dose enhancement is significant, of the order of 1-10, it is considerably smaller than that suggested previously. PMID- 19776145 TI - Gamma-carboxylation of osteocalcin and insulin resistance in older men and women. AB - BACKGROUND: The skeletal protein osteocalcin is gamma-carboxylated by vitamin K. High serum uncarboxylated osteocalcin reflects low vitamin K status. In vitro and animal studies indicate that high uncarboxylated osteocalcin is associated with reduced insulin resistance. However, associations between osteocalcin and measures of insulin resistance in humans are less clear. OBJECTIVE: Our aim was to examine cross-sectional and longitudinal associations between circulating forms of osteocalcin (total, uncarboxylated, and carboxylated) and insulin resistance in older men and women. DESIGN: Cross-sectional associations between serum measures of total osteocalcin, carboxylated osteocalcin, and uncarboxylated osteocalcin and insulin resistance were examined in 348 nondiabetic men and women (mean age: 68 y; 58% female) by using the homeostasis model assessment of insulin resistance (HOMA-IR). Associations between each form of osteocalcin at baseline and 3-y change in HOMA-IR were examined in 162 adults (mean age: 69 y; 63% female) who did not receive vitamin K supplementation. RESULTS: Lower circulating uncarboxylated osteocalcin was not associated with higher HOMA-IR at baseline or at 3-y follow-up. Those in the lowest tertiles of total osteocalcin and carboxylated osteocalcin at baseline had higher baseline HOMA-IR (P = 0.006 and P = 0.02, respectively). The concentration of carboxylated osteocalcin at baseline was inversely associated with a 3-y change in HOMA-IR (P = 0.002). CONCLUSIONS: In older adults, circulating uncarboxylated osteocalcin was not associated with insulin resistance. In contrast, elevated carboxylated osteocalcin and total osteocalcin were associated with lower insulin resistance, which supports a potential link between skeletal physiology and insulin resistance in humans. The role of vitamin K status in this association remains unclear and merits further investigation. This trial is registered at clinicaltrials.gov as NCT00183001. PMID- 19776146 TI - Morphological communication: exploiting coupled dynamics in a complex mechanical structure to achieve locomotion. AB - Traditional engineering approaches strive to avoid, or actively suppress, nonlinear dynamic coupling among components. Biological systems, in contrast, are often rife with these dynamics. Could there be, in some cases, a benefit to high degrees of dynamical coupling? Here we present a distributed robotic control scheme inspired by the biological phenomenon of tensegrity-based mechanotransduction. This emergence of morphology-as-information-conduit or 'morphological communication', enabled by time-sensitive spiking neural networks, presents a new paradigm for the decentralized control of large, coupled, modular systems. These results significantly bolster, both in magnitude and in form, the idea of morphological computation in robotic control. Furthermore, they lend further credence to ideas of embodied anatomical computation in biological systems, on scales ranging from cellular structures up to the tendinous networks of the human hand. PMID- 19776148 TI - Bio-electrospraying the nematode Caenorhabditis elegans: studying whole-genome transcriptional responses and key life cycle parameters. AB - Bio-electrospray, the direct jet-based cell handling approach, is able to handle a wide range of cells (spanning immortalized, primary to stem cells). Studies at the genomic, genetic and the physiological levels have shown that, post treatment, cellular integrity is unperturbed and a high percentage (more than 70%, compared with control) of cells remain viable. Although, these results are impressive, it may be argued that cell-based systems are oversimplistic. Therefore, it is important to evaluate the bio-electrospray technology using sensitive and dynamically developing multi-cellular organisms that share, at least some, similarities with multi-cell microenvironments encountered with tissues and organs. This study addressed this issue by using a well-characterized model organism, the non-parasitic nematode Caenorhabditis elegans. Nematode cultures were subjected to bio-electrospraying and compared with positive (heat shock) and negative controls (appropriate laboratory culture controls). Overall, bio-electrospraying did not modulate the reproductive output or induce significant changes in in vivo stress-responsive biomarkers (heat shock proteins). Likewise, whole-genome transcriptomics could not identify any biological processes, cellular components or molecular functions (gene ontology terms) that were significantly enriched in response to bio-electrospraying. This demonstrates that bio-electrosprays can be safely applied directly to nematodes and underlines its potential future use in the creation of multi-cellular environments within clinical applications. PMID- 19776149 TI - Quantitative analysis of the protein corona on FePt nanoparticles formed by transferrin binding. AB - Nanoparticles are finding a rapidly expanding range of applications in research and technology, finally entering our daily life in medical, cosmetic or food products. Their ability to invade all regions of an organism including cells and cellular organelles offers new strategies for medical diagnosis and therapy (nanomedicine), but their safe use requires a deep knowledge about their interactions with biological systems at the molecular level. Upon incorporation, nanoparticles are exposed to biological fluids from which they adsorb proteins and other biomolecules to form a 'protein corona'. These nanoparticle-protein interactions are still poorly understood and quantitative studies to characterize them remain scarce. Here we have quantitatively analysed the adsorption of human transferrin onto small (radius approx. 5 nm) polymer-coated FePt nanoparticles by using fluorescence correlation spectroscopy. Transferrin binds to the negatively charged nanoparticles with an affinity of approximately 26 microM in a cooperative fashion and forms a monolayer with a thickness of 7 nm. By using confocal fluorescence microscopy, we have observed that the uptake of FePt nanoparticles by HeLa cells is suppressed by the protein corona compared with the bare nanoparticles. PMID- 19776150 TI - Changes in reflectin protein phosphorylation are associated with dynamic iridescence in squid. AB - Many cephalopods exhibit remarkable dermal iridescence, a component of their complex, dynamic camouflage and communication. In the species Euprymna scolopes, the light-organ iridescence is static and is due to reflectin protein-based platelets assembled into lamellar thin-film reflectors called iridosomes, contained within iridescent cells called iridocytes. Squid in the family Loliginidae appear to be unique in which the dermis possesses a dynamic iridescent component with reflective, coloured structures that are assembled and disassembled under the control of the muscarinic cholinergic system and the associated neurotransmitter acetylcholine (ACh). Here we present the sequences and characterization of three new members of the reflectin family associated with the dynamically changeable iridescence in Loligo and not found in static Euprymna iridophores. In addition, we show that application of genistein, a protein tyrosine kinase inhibitor, suppresses ACh- and calcium-induced iridescence in Loligo. We further demonstrate that two of these novel reflectins are extensively phosphorylated in concert with the activation of iridescence by exogenous ACh. This phosphorylation and the correlated iridescence can be blocked with genistein. Our results suggest that tyrosine phosphorylation of reflectin proteins is involved in the regulation of dynamic iridescence in Loligo. PMID- 19776151 TI - Cervical lymphadenitis caused by Cryptococcus-related immune reconstitutional inflammatory syndrome. PMID- 19776152 TI - Symptom in search of a toxin: muscle spasms following bites by Old World tarantula spiders (Lampropelma nigerrimum, Pterinochilus murinus, Poecilotheria regalis) with review. AB - BACKGROUND: Tarantula spiders are widely kept and bred in captivity by both adults and children. Their bites are generally considered harmless. AIM: To explore the effects of envenoming by Old World tarantulas. DESIGN AND METHODS: Clinical studies and review of conventional literature and hobbyist web sites. RESULTS: Two men bitten on their index fingers by pet Old World tarantula spiders, Lampropelma nigerrimum (Ornithoctoninae) and Pterinochilus murinus (Harpactirinae) in England, developed intense local pain, swelling and episodic, agonising, generalised muscle cramps. In one of them, cramps persisted for 7 days and serum creatine kinase concentration was mildly elevated. A third man bitten on a finger by Poecilotheria regalis (Poecilotheriinae), suffered persistent local cramps in the affected hand. Reports since 1803, including recent ones on hobbyist web-sites, have been largely overlooked. They mentioned muscle spasms after bites by these and other genera of Old World tarantulas, including Eumenophorus, Selenocosmia and Stromatopelma. The severe muscle spasms seen in two of our patients were a challenge to medical treatment and might, under some circumstances, have been life threatening. They demand a toxinological explanation. CONCLUSION: Bites by several genera of African, Asian and Australasian tarantulas can cause systemic neurotoxic envenoming. In the absence of available antivenom, severe persistent muscle spasms, reminiscent of latrodectism, pose a serious therapeutic challenge. Discovery of the toxin responsible would be of scientific and potential clinical benefit. Tarantula keepers should be warned of the danger of handling these animals incautiously. PMID- 19776153 TI - Extensive cutaneous Mycobacterium abscessus infection due to contaminated insulin delivery system. PMID- 19776155 TI - A variant riboswitch aptamer class for S-adenosylmethionine common in marine bacteria. AB - Riboswitches that sense S-adenosylmethionine (SAM) are widely distributed throughout a variety of bacterial lineages. Four classes of SAM-binding riboswitches have been reported to date, constituting the most diverse collection of riboswitch classes that sense the same compound. Three of these classes, termed SAM-I, SAM-II, and SAM-III represent unique structures that form distinct binding pockets for the ligand. SAM-IV riboswitches carry different conserved sequence and structural features compared to other SAM riboswitches, but nucleotides and substructures corresponding to the ligand binding pocket are identical to SAM-I aptamers. In this article, we describe a fifth class of SAM binding aptamer, which we have termed SAM-V. SAM-V was discovered by analyzing GC rich intergenic regions preceding metabolic genes in the marine alpha proteobacterium "Candidatus Pelagibacter ubique." Although the motif is nearly unrepresented in cultured bacteria whose genomes have been completely sequenced, SAM-V is prevalent in marine metagenomic sequences. The consensus sequence and structure of SAM-V show some similarities to that of the SAM-II riboswitch, and it is likely that the two aptamers form similar ligand binding pockets. In addition, we identified numerous examples of a tandem SAM-II/SAM-V aptamer architecture. In this arrangement, the SAM-II aptamer is always positioned 5' of the SAM-V aptamer and the SAM-II aptamer is followed by a predicted intrinsic transcription terminator stem. The SAM-V aptamer, however, appears to use a ribosome binding site occlusion mechanism for genetic regulation. This tandem riboswitch arrangement exhibits an architecture that can potentially control both the transcriptional and translational stages of gene expression. PMID- 19776157 TI - Distinct extremely abundant siRNAs associated with cosuppression in petunia. AB - Cosuppression is a classical form of eukaryotic post-transcriptional gene silencing. It was first reported in transgenic petunia, where a sense transgene meant to overexpress the host Chalcone Synthase-A (CHS-A) gene caused the degradation of the homologous transcripts and the loss of flower pigmentation. In this work, we used deep sequencing technology to characterize in detail the small RNA population generated from the CHS-A sequence in cosuppressed transgenic petunia. Unexpectedly, two distinct small interfering RNAs (siRNAs) were found to vastly predominate. Our demonstration that they guide prominent cleavage events in CHS-A mRNA provides compelling and previously lacking evidence of a causative association between induction of individual siRNAs and an example of cosuppression. The preferential accumulation of these siRNAs provides new insights about sense cosuppression that may apply to other natural and engineered RNA silencing events. PMID- 19776156 TI - Domain-elongation NMR spectroscopy yields new insights into RNA dynamics and adaptive recognition. AB - By simplifying the interpretation of nuclear magnetic resonance spin relaxation and residual dipolar couplings data, recent developments involving the elongation of RNA helices are providing new atomic insights into the dynamical properties that allow RNA structures to change functionally and adaptively. Domain elongation, in concert with spin relaxation measurements, has allowed the detailed characterization of a hierarchical network of local and collective motional modes occurring at nanosecond timescale that mirror the structural rearrangements that take place following adaptive recognition. The combination of domain elongation with residual dipolar coupling measurements has allowed the experimental three-dimensional visualization of very large amplitude rigid-body helix motions in HIV-1 transactivation response element (TAR) that trace out a highly choreographed trajectory in which the helices twist and bend in a correlated manner. The dynamic trajectory allows unbound TAR to sample many of its ligand bound conformations, indicating that adaptive recognition occurs by "conformational selection" rather than "induced fit." These studies suggest that intrinsic flexibility plays essential roles directing RNA conformational changes along specific pathways. PMID- 19776158 TI - Combined proteomic-RNAi screen for host factors involved in human hepatitis delta virus replication. AB - Human hepatitis delta virus (HDV) is the only animal virus known to replicate its RNA genome using a host polymerase because its only virally encoded proteins, the small and large hepatitis delta antigens (HDAg-S and HDAg-L), lack polymerase activity. Although this makes HDV an ideal model system to study RNA-directed transcription in mammalian cells, little is known about the host factors involved in its replication. To comprehensively identify such host factors, we created a stable cell line carrying a functional FLAG-HDAg-S. Anti-Flag immunopurification and mass spectrometry identified >100 proteins associated with FLAG-HDAg-S, many of which had predicted roles in RNA metabolism. The biological relevance of this screen was strongly supported by the identification of nine out of the 12 subunits of the RNA polymerase II complex thought to mediate HDV replication. To further investigate the significance of these factors for HDV replication, we selected 65 proteins to look for factors that would also affect the accumulation of HDV RNA following siRNA knockdown. Fifteen and three factors were found to regulate HDV RNA accumulation negatively and positively, respectively, upon RNAi knockdown. Our results provide a valuable resource for future research to advance our mechanistic understanding of HDV replication and RNA-directed transcription in mammalian cells. PMID- 19776159 TI - Direct selection for ribozyme cleavage activity in cells. AB - Selection may prove to be a powerful tool for the generation of functional RNAs for in vivo genetic regulation. However, traditional in vitro selection schemes do not mimic physiological conditions, and in vivo selection schemes frequently use small pool sizes. Here we describe a hybrid in vitro/in vivo selection scheme that overcomes both of these disadvantages. In this new method, PCR-amplified expression templates are transfected into mammalian cells, transcribed hammerhead RNAs self-cleave, and the extracted, functional hammerhead ribozyme species are specifically amplified for the next round of selection. Using this method we have selected a number of cis-cleaving hammerhead ribozyme variants that are functional in vivo and lead to the inhibition of gene expression. More importantly, these results have led us to develop a quantitative, kinetic model that can be used to assess the stringency of the hybrid selection scheme and to direct future experiments. PMID- 19776160 TI - Altered architecture and enhanced drought tolerance in rice via the down regulation of indole-3-acetic acid by TLD1/OsGH3.13 activation. AB - Plant architecture is determined by genetic and developmental programs as well as by environmental factors. Sessile plants have evolved a subtle adaptive mechanism that allows them to alter their growth and development during periods of stress. Phytohormones play a central role in this process; however, the molecules responsible for integrating growth- and stress-related signals are unknown. Here, we report a gain-of-function rice (Oryza sativa) mutant, tld1-D, characterized by (and named for) an increased number of tillers, enlarged leaf angles, and dwarfism. TLD1 is a rice GH3.13 gene that encodes indole-3-acetic acid (IAA) amido synthetase, which is suppressed in aboveground tissues under normal conditions but which is dramatically induced by drought stress. The activation of TLD1 reduced the IAA maxima at the lamina joint, shoot base, and nodes, resulting in subsequent alterations in plant architecture and tissue patterning but enhancing drought tolerance. Accordingly, the decreased level of free IAA in tld1 D due to the conjugation of IAA with amino acids greatly facilitated the accumulation of late-embryogenesis abundant mRNA compared with the wild type. The direct regulation of such drought-inducible genes by changes in the concentration of IAA provides a model for changes in plant architecture via the process of drought adaptation, which occurs frequently in nature. PMID- 19776161 TI - Native plant and microbial contributions to a negative plant-plant interaction. AB - A number of hypotheses have been suggested to explain why invasive exotic plants dramatically increase their abundance upon transport to a new range. The novel weapons hypothesis argues that phytotoxins secreted by roots of an exotic plant are more effective against naive resident competitors in the range being invaded. The common reed Phragmites australis has a diverse population structure including invasive populations that are noxious weeds in North America. P. australis exudes the common phenolic gallic acid, which restricts the growth of native plants. However, the pathway for free gallic acid production in soils colonized by P. australis requires further elucidation. Here, we show that exotic, invasive P. australis contain elevated levels of polymeric gallotannin relative to native, noninvasive P. australis. We hypothesized that polymeric gallotannin can be attacked by tannase, an enzymatic activity produced by native plant and microbial community members, to release gallic acid in the rhizosphere and exacerbate the noxiousness of P. australis. Native plants and microbes were found to produce high levels of tannase while invasive P. australis produced very little tannase. These results suggest that both invasive and native species participate in signaling events that initiate the execution of allelopathy potentially linking native plant and microbial biochemistry to the invasive traits of an exotic species. PMID- 19776162 TI - The debate on the pathway of starch synthesis: a closer look at low-starch mutants lacking plastidial phosphoglucomutase supports the chloroplast-localized pathway. PMID- 19776163 TI - LIN, a novel type of U-box/WD40 protein, controls early infection by rhizobia in legumes. AB - The formation of a nitrogen-fixing nodule requires the coordinated development of rhizobial colonization and nodule organogenesis. Based on its mutant phenotype, lumpy infections (lin), LIN functions at an early stage of the rhizobial symbiotic process, required for both infection thread growth in root hair cells and the further development of nodule primordia. We show that spontaneous nodulation activated by the calcium- and calmodulin-dependent protein kinase is independent of LIN; thus, LIN is not necessary for nodule organogenesis. From this, we infer that LIN predominantly functions during rhizobial colonization and that the abortion of this process in lin mutants leads to a suppression of nodule development. Here, we identify the LIN gene in Medicago truncatula and Lotus japonicus, showing that it codes for a predicted E3 ubiquitin ligase containing a highly conserved U-box and WD40 repeat domains. Ubiquitin-mediated protein degradation is a universal mechanism to regulate many biological processes by eliminating rate-limiting enzymes and key components such as transcription factors. We propose that LIN is a regulator of the component(s) of the nodulation factor signal transduction pathway and that its function is required for correct temporal and spatial activity of the target protein(s). PMID- 19776164 TI - Enhanced nodulation and nitrogen fixation in the abscisic acid low-sensitive mutant enhanced nitrogen fixation1 of Lotus japonicus. AB - The phytohormone abscisic acid (ABA) is known to be a negative regulator of legume root nodule formation. By screening Lotus japonicus seedlings for survival on an agar medium containing 70 microM ABA, we obtained mutants that not only showed increased root nodule number but also enhanced nitrogen fixation. The mutant was designated enhanced nitrogen fixation1 (enf1) and was confirmed to be monogenic and incompletely dominant. The low sensitivity to ABA phenotype was thought to result from either a decrease in the concentration of the plant's endogenous ABA or from a disruption in ABA signaling. We determined that the endogenous ABA concentration of enf1 was lower than that of wild-type seedlings, and furthermore, when wild-type plants were treated with abamine, a specific inhibitor of 9-cis-epoxycarotenoid dioxygenase, which results in reduced ABA content, the nitrogen fixation activity of abamine-treated plants was elevated to the same levels as enf1. We also determined that production of nitric oxide in enf1 nodules was decreased. We conclude that endogenous ABA concentration not only regulates nodulation but also nitrogen fixation activity by decreasing nitric oxide production in nodules. PMID- 19776166 TI - Human origins and evolution: Cold Spring Harbor, deja vu. AB - The Cold Spring Harbor Symposia of the 1950s were key to integrating human evolutionary studies into biology. That integration provided a solid foundation for systematic and functional interpretations of an expanding base of fossil and molecular evidence during the latter half of the 20th century. Today, the paleontological record of human evolution amassed during the last 150 years illuminates the human clade on life's tree. However, the rise of Hennegian parsimony cladistics and punctuationalism during the end of the last century witnessed the partial abandonment of classificatory conventions cemented by Mayr, Simpson, Dobzhansky, and others at Cold Spring Harbor. This has led to an artificial, postmillennial amplification of apparent species diversity in the hominid clade. Work on a stratigraphically thick and temporally deep sedimentary sequence in the Middle Awash study area of Ethiopia's Afar Depression reveals an assembly order of hominid anatomies and behaviors that was impossible for Darwin to discern. Large parts of that record appear to reflect phyletic evolution, consistent with the lessons and expectations of Cold Spring Harbor in 1950. Molecular biology cannot reveal the assembly sequences or contexts of human origins and evolution without reference to adequate geological, geochronological, paleobiological, and archaeological records. Today's consilience of these disparate data sets would have impressed Charles Darwin. PMID- 19776165 TI - A nomadic subtelomeric disease resistance gene cluster in common bean. AB - The B4 resistance (R) gene cluster is one of the largest clusters known in common bean (Phaseolus vulgaris [Pv]). It is located in a peculiar genomic environment in the subtelomeric region of the short arm of chromosome 4, adjacent to two heterochromatic blocks (knobs). We sequenced 650 kb spanning this locus and annotated 97 genes, 26 of which correspond to Coiled-Coil-Nucleotide-Binding-Site Leucine-Rich-Repeat (CNL). Conserved microsynteny was observed between the Pv B4 locus and corresponding regions of Medicago truncatula and Lotus japonicus in chromosomes Mt6 and Lj2, respectively. The notable exception was the CNL sequences, which were completely absent in these regions. The origin of the Pv B4 CNL sequences was investigated through phylogenetic analysis, which reveals that, in the Pv genome, paralogous CNL genes are shared among nonhomologous chromosomes (4 and 11). Together, our results suggest that Pv B4-CNL was derived from CNL sequences from another cluster, the Co-2 cluster, through an ectopic recombination event. Integration of the soybean (Glycine max) genome data enables us to date more precisely this event and also to infer that a single CNL moved from the Co-2 to the B4 cluster. Moreover, we identified a new 528-bp satellite repeat, referred to as khipu, specific to the Phaseolus genus, present both between B4-CNL sequences and in the two knobs identified at the B4 R gene cluster. The khipu repeat is present on most chromosomal termini, indicating the existence of frequent ectopic recombination events in Pv subtelomeric regions. Our results highlight the importance of ectopic recombination in R gene evolution. PMID- 19776167 TI - Genome-wide mutational diversity in an evolving population of Escherichia coli. AB - The level of genetic variation in a population is the result of a dynamic tension between evolutionary forces. Mutations create variation, certain frequency dependent interactions may preserve diversity, and natural selection purges variation. New sequencing technologies offer unprecedented opportunities to discover and characterize the diversity present in evolving microbial populations on a whole-genome scale. By sequencing mixed-population samples, we have identified single-nucleotide polymorphisms (SNPs) present at various points in the history of an Escherichia coli population that has evolved for almost 20 years from a founding clone. With 50-fold genome coverage, we were able to catch beneficial mutations as they swept to fixation, discover contending beneficial alleles that were eliminated by clonal interference, and detect other minor variants possibly adapted to a new ecological niche. Additionally, there was a dramatic increase in genetic diversity late in the experiment after a mutator phenotype evolved. Still finer-resolution details of the structure of genetic variation and how it changes over time in microbial evolution experiments will enable new applications and quantitative tests of population genetic theory. PMID- 19776168 TI - When ideas have sex: the role of exchange in cultural evolution. AB - Human economic and technological progress has been dominated for the last 100,000 years by natural selection among variants of cultures, rather than among variants of genes. Evidence suggests that cultural evolution depends on exchange and trade to bring together ideas in much the same way that genetic evolution depends on sex to spread genetic mutations, or in the case of bacteria, on horizontal gene transfer. When starved of access to a large "collective brain" by isolation from trade and exchange, people may experience not just less innovation, but even regress. The capacity for ideas to have sex on the Internet is likely to accelerate cultural evolution still further. PMID- 19776169 TI - Angiotensin II and hypertonicity modulate proximal tubular aquaporin 1 expression. AB - Aquaporin 1 (AQP1) is the major water channel in the renal proximal tubule (PT) and thin descending limb of Henle, but its regulation remains elusive. Here, we investigated the effect of ANG II, a key mediator of body water homeostasis, on AQP1 expression in immortalized rat proximal tubule cells (IRPTC) and rat kidney. Real-time PCR on IRPTC exposed to ANG II for 12 h revealed a biphasic effect AQP1 mRNA increased dose dependently in response to 10(-12) to 10(-8) M ANG II but decreased by 50% with 10(-7) M ANG II. The twofold increase of AQP1 mRNA in the presence of 10(-8) M ANG II was abolished by the AT(1) receptor blocker losartan. Hypertonicity due to either NaCl or mannitol also upregulated AQP1 mRNA by three- and twofold, respectively. Immunocytochemistry and Western blotting revealed a two- to threefold increase in AQP1 protein expression in IRPTC exposed concomitantly to ANG II (10(-8)M) and hypertonic medium (either NaCl or mannitol), indicating that these stimuli were not additive. Three-dimensional reconstruction of confocal images suggested that AQP1 expression was increased by ANG II in both the apical and basolateral poles of IRPTC. In vivo studies showed that short-term ANG II infusion had a diuretic effect, while this effect was attenuated after several days of ANG II infusion. After 10 days, we observed a twofold increase in AQP1 expression in the PT and thin descending limb of Henle of ANG II-infused rats that was abolished when rats were treated with the selective AT(1)-receptor antagonist olmesartan. Thus ANG II increases AQP1 expression in vitro and in vivo via direct interaction with the AT(1) receptor, providing an important regulatory mechanism to link PT water reabsorption to body fluid homeostasis via the renin-angiotensin system. PMID- 19776171 TI - Pulse mTOR inhibitor treatment effectively controls cyst growth but leads to severe parenchymal and glomerular hypertrophy in rat polycystic kidney disease. AB - The efficacy of mammalian target of rapamycin (mTOR) inhibitors is currently tested in patients affected by autosomal dominant polycystic kidney disease. Treatment with mTOR inhibitors has been associated with numerous side effects. However, the renal-specific effect of mTOR inhibitor treatment cessation in polycystic kidney disease is currently unknown. Therefore, we compared pulse and continuous everolimus treatment in Han:SPRD rats. Four-week-old male heterozygous polycystic and wild-type rats were administered everolimus or vehicle by gavage feeding for 5 wk, followed by 7 wk without treatment, or continuously for 12 wk. Cessation of everolimus did not result in the appearance of renal cysts up to 7 wk postwithdrawal despite the reemergence of S6 kinase activity coupled with an overall increase in cell proliferation. Pulse everolimus treatment resulted in striking noncystic renal parenchymal enlargement and glomerular hypertrophy that was not associated with compromised kidney function. Both treatment regimens ameliorated kidney function, preserved the glomerular-tubular connection, and reduced proteinuria. Pulse treatment at an early age delays cyst development but leads to striking glomerular and parenchymal hypertrophy. Our data might have an impact when long-term treatment using mTOR inhibitors in patients with autosomal dominant polycystic kidney disease is being considered. PMID- 19776170 TI - Cholesterol induces renal vasoconstriction and anti-natriuresis by inhibiting nitric oxide production in anesthetized rats. AB - Although hypercholesterolemia is implicated in the pathophysiology of many renal disorders as well as hypertension, its direct actions in the kidney are not yet clearly understood. In the present study, we evaluated renal responses to administration of cholesterol (8 microg x min(-1).100 g body wt(-1); bound by polyethylene glycol) into the renal artery of anesthetized male Sprague-Dawley rats. Total renal blood flow (RBF) was measured by a Transonic flow probe, and glomerular filtration rate (GFR) was determined by Inulin clearance. In control rats (n = 8), cholesterol induced reductions of 10 +/- 2% in RBF [baseline (b) 7.6 +/- 0.3 microg x min(-1).100 g(-1)], 17 +/- 3% in urine flow (b, 10.6 +/- 0.9 microg x min(-1).100 g(-1)), 29 +/- 3% in sodium excretion (b, 0.96 +/- 0.05 mumol.min(-1).100 g(-1)) and 24 +/- 2% in nitrite/nitrate excretion (b, 0.22 +/- 0.01 nmol.min(-1).100 g(-1)) without an appreciable change in GFR (b, 0.87 +/- 0.03 ml.min(-1).100 g(-1)). These renal vasoconstrictor and anti-natriuretic responses to cholesterol were absent in rats pretreated with nitric oxide (NO) synthase inhibitor, nitro-l-arginine methylester (0.5 microg x min(-1).100 g(-1); n = 6). In rats pretreated with superoxide (O(2)(-)) scavenger tempol (50 microg x min(-1).100 g(-1); n = 6), the cholesterol-induced renal responses remained mostly unchanged, although there was a slight attenuation in anti-natriuretic response. This anti-natriuretic response to cholesterol was abolished in furosemide-pretreated rats (0.3 microg x min(-1).100 g(-1); n = 6) but remained unchanged in amiloride-pretreated rats (0.2 microg x min(-1).100 g(-1); n = 5), indicating that Na(+)/K(+)/2Cl(-) cotransport is the dominant mediator of this effect. These data demonstrate that cholesterol-induced acute renal vasoconstrictor and antinatriuretic responses are mediated by a decrease in NO production. These data also indicate that tubular effect of cholesterol on sodium reabsorption is mediated by the furosemide sensitive Na(+)/K(+)/2Cl(-) cotransporter. PMID- 19776172 TI - The farnesoid X receptor modulates renal lipid metabolism and diet-induced renal inflammation, fibrosis, and proteinuria. AB - Diet-induced obesity is associated with proteinuria and glomerular disease in humans and rodents. We have shown that in mice fed a high-fat diet, increased renal expression of the transcriptional factor sterol-regulatory element binding protein-1 (SREBP-1) plays a critical role in renal lipid accumulation and increases the activity of proinflammatory cytokines and profibrotic growth factors. In the current study, we have determined a key role of the farnesoid X receptor (FXR) in modulating renal SREBP-1 activity, glomerular lesions, and proteinuria. We found that feeding a Western-style diet to DBA/2J mice results in proteinuria, podocyte loss, mesangial expansion, renal lipid accumulation, and increased expression of proinflammatory factors, oxidative stress, and profibrotic growth factors. Treatment of these mice with the highly selective and potent FXR-activating ligand 6-alpha-ethyl-chenodeoxycholic acid (INT-747) ameliorates triglyceride accumulation by modulating fatty acid synthesis and oxidation, improves proteinuria, prevents podocyte loss, mesangial expansion, accumulation of extracellular matrix proteins, and increased expression of profibrotic growth factors and fibrosis markers, and modulates inflammation and oxidative stress. Our results therefore indicate that FXR activation could represent an effective therapy for treatment of abnormal renal lipid metabolism with associated inflammation, oxidative stress, and kidney pathology in patients affected by obesity. PMID- 19776173 TI - Regulation of Na+/H+ exchanger NHE3 by glucagon-like peptide 1 receptor agonist exendin-4 in renal proximal tubule cells. AB - The gut incretin hormone glucagon-like peptide 1 (GLP-1) is released in response to ingested nutrients and enhances insulin secretion. In addition to its insulinotropic properties, GLP-1 has been shown to have natriuretic actions paralleled by a diminished proton secretion. We therefore studied the role of the GLP-1 receptor agonist exendin-4 in modulating the activity of Na(+)/H(+) exchanger NHE3 in LLC-PK(1) cells. We found that NHE3-mediated Na(+)-dependent intracellular pH (pH(i)) recovery decreased approximately 50% after 30-min treatment with 1 nM exendin-4. Pharmacological inhibitors and cAMP analogs that selectively activate protein kinase A (PKA) or the exchange protein directly activated by cAMP (EPAC) demonstrated that regulation of NHE3 activity by exendin 4 requires activation of both cAMP downstream effectors. This conclusion was based on the following observations: 1) the PKA antagonist H-89 completely prevented the effect of the PKA activator but only partially blocked the exendin 4-induced NHE3 inhibition; 2) the MEK1/2 inhibitor U-0126 abolished the effect of the EPAC activator but only diminished the exendin-4-induced NHE3 inhibition; 3) combination of H-89 and U-0126 fully prevented the effect of exendin-4 on NHE3; 4) no additive effect in the inhibition of NHE3 activity was observed when exendin-4, PKA, and EPAC activators were used together. Mechanistically, the inhibitory effect of exendin-4 on pH(i) recovery was associated with an increase of NHE3 phosphorylation. Conversely, this inhibition took place without changes in the surface expression of the transporter. We conclude that GLP-1 receptor agonists modulate sodium homeostasis in the kidney, most likely by affecting NHE3 activity. PMID- 19776174 TI - Oxidative stress-induced JNK activation contributes to proinflammatory phenotype of aging diabetic mesangial cells. AB - Chronic inflammation and increased oxidative stress (OS) play an important role in diabetic nephropathy progression. Herein, we show that mesangial cells from streptozotocin-induced aging diabetic mice, a model of progressive diabetic nephropathy, exhibited increased OS and a proinflammatory phenotype characterized by elevated chemokines and ICAM-1 expression. This phenotypic change was consistent with the extensive inflammatory lesions present in aging diabetic kidneys and was not found in mesangial cells from old and young controls or young diabetic mice. Activation of the c-Jun NH(2)-terminal kinase (JNK) pathway was a likely contributor to the proinflammatory phenotype of aging diabetic mesangial cells since 1) phosphorylated JNK levels and JNK kinase activity were increased in these cells, 2) suppression of JNK significantly decreased monocyte chemoattractant protein-1 (MCP-1) production in these cells, and 3) activation of JNK in normal mesangial cells induced inflammation. Elevated OS in aging diabetic mesangial cells may be a cause of JNK activation and inflammation, because antioxidant treatment decreased JNK phosphorylation and MCP-1 production. Additionally, decreased expression of mitogen-activated protein kinase phosphatase 5 (MKP5) may also contribute to increased JNK and inflammation in aging diabetic mesangial cells since overexpression of MKP5 in these cells normalized phosphorylated JNK levels and reversed the proinflammatory phenotype. Moreover, knocking down of MKP5 expression in old control mesangial cells resulted in JNK activation and MCP-1 production, a phenotype seen in aging diabetic mesangial cells. Interestingly, MKP5 phosphatase activity was diminished by free radicals in vitro. Thus, OS may induce inflammation in mesangial cells by activating JNK through either a direct activation of JNK or indirectly by suppression of MKP5 activity. Proinflammatory phenotype of mesangial cells may contribute to chronic inflammatory lesions and disease progression of aging diabetic mice. PMID- 19776175 TI - Changes of renal AQP2, ENaC, and NHE3 in experimentally induced heart failure: response to angiotensin II AT1 receptor blockade. AB - Heart failure (HF) was induced by ligation of the left anterior descending artery (LAD). Left ventricular end-diastolic pressure (LVEDP) >25 mmHg (at day 23 after LAD ligation) was the inclusion criterion. The rats were divided into three groups: sham-operated (Sham, n = 23, LVEDP: 5.6 +/- 0.6 mmHg), HF (n = 14, LVEDP: 29.4 +/- 1.4 mmHg), and candesartan (1 mg.kg(-1).day(-1) sc)-treated HF (HF + Can, n = 9, LVEDP: 29.2 +/- 1.2 mmHg). After 7 days (i.e., 29 days after LAD ligation) semiquantitative immunoblotting revealed increased abundance of inner medulla aquaporin-2 (AQP2) and AQP2 phosphorylated at Ser(256) (p-AQP2) in HF. There was also markedly enhanced apical targeting of AQP2 and p-AQP2 in inner medullary collecting duct (IMCD) in HF compared with Sham rats, shown by immunocytochemistry. Candesartan treatment significantly reversed the increases in both AQP2 and p-AQP2 expression and targeting. In contrast, there were only modest changes in other collecting duct segments. Semiquantitative immunoblots revealed increased expression of type 3 Na(+)/H(+) exchanger (NHE3) and Na(+) K(+)-2Cl(-) cotransporter (NKCC2) in kidneys from HF compared with Sham rats: both effects were reversed or prevented by candesartan treatment. The protein abundance of alpha-epithelial sodium channel (alpha-ENaC) was increased while beta-ENaC and gamma-ENaC expression was decreased in the cortex and outer stripe of the outer medulla in HF compared with Sham rats, which was partially reversed by candesartan treatment. These findings strongly support an important role of angiotensin II in the pathophysiology of renal water and sodium retention associated with HF. PMID- 19776176 TI - Delphinidin suppresses ultraviolet B-induced cyclooxygenases-2 expression through inhibition of MAPKK4 and PI-3 kinase. AB - Cyclooxygenase-2 (COX-2), a key mediator of inflammation, and its product, prostaglandin E(2) (PGE(2)), enhance carcinogenesis, particularly in skin. Ultraviolet (UV) B is the most carcinogenic component of solar irradiation, and a crucial role of COX-2 in UVB-mediated skin carcinogenesis has been reported. Here, we investigated the effects of delphinidin, an abundant dietary anthocyanin, on UVB-induced COX-2 upregulation and the underlying molecular mechanism. We found that delphinidin suppressed UVB-induced COX-2 expression in JB6 P+ mouse epidermal cells. COX-2 promoter activity and PGE(2) production were also suppressed by delphinidin treatment within non-cytotoxic concentrations. Activator protein-1 and nuclear factor-kappaB, crucial transcription factors involved in COX-2 expression, were activated by UVB and delphinidin abolished this activation. UVB-induced phosphorylation of c-Jun N-terminal kinase, p38 kinase and Akt was inhibited by delphinidin. The activities of mitogen-activated protein kinase kinase (MAPKK) 4 and phosphatidylinositol-3 kinase (PI-3K) were inhibited markedly by delphinidin. A pull-down assay using delphinidin-Sepharose beads revealed that delphinidin binds directly with MAPKK4 or PI-3K in a manner that was competitive with adenosine triphosphate. Moreover, in vivo investigations using mouse skin revealed that the upregulation of COX-2 expression, MAPKK4 activity and PI-3K activity induced by UVB was abolished with delphinidin treatment. Collectively, our results demonstrated that delphinidin targets MAPKK4 and PI-3K directly to suppress COX-2 overexpression, suggesting a potential protective role for delphinidin against UVB-mediated skin carcinogenesis. PMID- 19776177 TI - Flaxseed and pure secoisolariciresinol diglucoside, but not flaxseed hull, reduce human breast tumor growth (MCF-7) in athymic mice. AB - Previous studies have shown that dietary flaxseed (FS) can reduce the growth of established human breast tumors in athymic mice with low circulating estrogen concentrations. In this study, we determined the effect of FS compared with pure lignan at the level it is present in FS [secoisolariciresinol diglucoside (SDG)] and to the lignan-rich fraction [FS hull (FH)] on human breast tumor growth and their potential mechanisms of action. Ovariectomized, athymic mice, each with an implanted 17 beta-estradiol (E2) pellet (0.36 mg), were injected with human estrogen receptor (ER) positive breast cancer cells (MCF-7). When tumors were established, the E2 pellet was removed. Mice were fed either the control basal diet (BD), FS (100 g/kg diet), SDG (1 g/kg diet), or FH (18 g/kg diet) for 8 wk. Compared with the BD, FS and SDG significantly decreased the palpable tumor size, but effects of FS, SDG, and FH did not differ from one another. All treatments significantly inhibited cell proliferation, but only FS and SDG induced significantly higher apoptosis. Both FS and SDG significantly decreased mRNA expressions of Bcl2, cyclin D1, pS2, ERalpha, and ERbeta, epidermal growth factor receptor, and insulin-like growth factor receptor. FS also reduced human epidermal growth factor receptor 2 mRNA and SDG decreased phospho-specific mitogen-activated protein kinase expression. FH did not significantly reduce these biomarkers. In conclusion, pure SDG has a similar effect as FS in reducing tumor growth and in mechanisms of action, including downregulating ER- and growth factor-mediated cell signaling. The lesser effects of FH indicate a need for a higher dose to be more effective. PMID- 19776178 TI - The pharmacokinetics of S-(-)equol administered as SE5-OH tablets to healthy postmenopausal women. AB - The soy isoflavone metabolite, S-(-)equol, has selective affinity for estrogen receptor (ER)beta and also antagonizes in vivo the action of dihydrotestosterone. It is therefore of interest as a potential new therapeutic agent in hormone dependent conditions and is under development as a nutraceutical. Our objective in this study was to define the pharmacokinetics of natural S-(-)equol after administration of SE5-OH, a newly developed S-(-)equol supplement made by incubation of the equol-producing bacterium Lactococcus garvieae with soy germ isoflavones. In a single-center, open-label, randomized, 2-period crossover design study, the pharmacokinetics of S-(-)equol administered as single-bolus oral doses of 10 and 30 mg in the form of SE5-OH tablets was determined in 12 healthy postmenopausal women. S-(-)equol was measured in plasma and urine collected at timed intervals over a 48-h period postdosing using tandem MS. Equol producer status was also determined after a soymilk challenge conducted after the pharmacokinetic sampling was complete. S-(-)equol was rapidly absorbed after oral administration and attained high plasma concentrations, with a plasma elimination half-life of 8 h. The maximum plasma concentration/dose, area under the plasma concentration-time curve from time 0 to infinity/dose, and the fraction of dose excreted in urine (%f(e,u)) were similar for the 2 doses, indicating a dose proportional response in total S-(-)equol pharmacokinetics. The systemic bioavailability of S-(-)equol was very high, as the %f(e,u) was 82% for both doses, which is greater than published data for the soy isoflavones daidzein and genistein. Three participants were determined to be equol-producers, representing a 25% frequency, and equol-producer status had no effect on natural S-(-)equol pharmacokinetics. PMID- 19776179 TI - Supplemental dietary inulin influences expression of iron and inflammation related genes in young pigs. AB - We have previously shown improved hemoglobin (Hb) repletion efficiency by supplementing a 50:50 mixture of short (P95) and long-chain (HP) inulin (Synergy 1, BENEO-Orafti) into a corn-soybean meal-basal diet (BD) for young pigs. In this study, weanling pigs (5 or 6 wk old) were fed the BD or the BD + 4% of P95, HP, or Synergy 1 (50:50 mixtures of HP and P95) for 5-7 wk. Blood Hb concentrations of pigs were measured weekly and digesta samples were collected at the end of the trial. In a replicate experiment, total RNA was isolated from the liver and mucosa of duodenum, ileum, cecum, and colon of all pigs at the end of the trial. Relative mRNA expression of 27 genes, including iron and inflammation-related genes, was quantified using real-time quantitative-PCR. Although all 3 types of inulin resulted in similar improvements (P < 0.05) in blood Hb concentration and liver ferritin protein amount, neither type of inulin was detectable in the digesta of cecum or colon. Supplemental inulin enhanced the expression of iron storing protein genes but decreased that of inflammation-related genes. Such effects were more pronounced (P < 0.05) in the mucosa of the lower than the upper gut and were seen on 7 genes in liver. In conclusion, all 3 types of inulin shared similar efficacy and possibly similar modes of action in improving dietary iron utilization by young pigs. Suppressing inflammation-induced genes that can negatively influence iron metabolism might help explain the benefit of inulin. PMID- 19776180 TI - Applying the FDA definition of whole grains to the evidence for cardiovascular disease health claims. AB - The U.S. FDA defines whole grains as consisting of the intact, ground, cracked, or flaked fruit of the grains whose principal components, the starchy endosperm, germ, and bran, are present in the same relative proportions as they exist in the intact grain. We evaluated the effect of applying the FDA definition of whole grains to the strength of scientific evidence in support of claims for risk reduction of cardiovascular disease (CVD). We concluded that using the FDA definition for whole grains as a selection criterion is limiting, because the majority of existing studies often use a broader meaning to define whole grains. When considering only whole grain studies that met the FDA definition, we found insufficient scientific evidence to support a claim that whole grain intake reduces the risk of CVD. However, a whole grain and reduced risk of CVD health claim is supported when using a broader concept of whole grain to include studies that considered intake of fiber-rich bran and germ as well as whole grain. This type of analysis is complicated by diversity in nutrients and bioactive components among different types of whole grains. PMID- 19776181 TI - Olive leaf extract and its main component oleuropein prevent chronic ultraviolet B radiation-induced skin damage and carcinogenesis in hairless mice. AB - Chronic exposure to solar UV radiation damages skin, increasing its thickness and reducing its elasticity, and causes skin cancer. Our aim in this study was to examine the effects of an olive leaf extract and its component oleuropein on skin damage and the incidence of skin tumors caused by long-term UVB irradiation in hairless mice. Male hairless mice (5 wk old) were divided into 6 groups, including a non-UVB group, a vehicle-treated UVB group (control), 2 olive leaf extract-treated UVB groups, and 2 oleuropein-treated UVB groups. Five groups were UVB irradiated (36-180 mJ/cm(2)) 3 times each week for 30 wk and skin thickness and elasticity after UVB irradiation were measured every week. Olive leaf extract (300 and 1000 mg/kg) and oleuropein (10 and 25 mg/kg) were administered orally twice daily every day for 30 wk. The extract and oleuropein significantly inhibited increases in skin thickness and reductions in skin elasticity, and skin carcinogenesis and tumor growth. Furthermore, they prevented increases in the expression of matrix metalloproteinase (MMP)-2, MMP-9, and MMP-13 as well as in levels of vascular endothelial growth factor (VEGF) and cyclooxygenase-2 (COX-2) in the skin. Based on histological evaluation, they prevented increases in the expression of Ki-67 and CD31-positive cells induced by the irradiation. These results suggest that the preventative effects of the olive leaf extract and oleuropein on chronic UVB-induced skin damage and carcinogenesis and tumor growth may be due to inhibition of the expression of VEGF, MMP-2, MMP-9, and MMP-13 through a reduction in COX-2 levels. PMID- 19776182 TI - Nationally representative surveys show recent increases in the prevalence of overweight and obesity among women of reproductive age in Bangladesh, Nepal, and India. AB - Our aims in this study were to examine trends in the prevalence of overweight obesity and underweight among women of reproductive age in 3 South Asian countries between 1996 and 2006 and to identify sociodemographic correlates of overweight in the most recent survey. Using nationally representative data from 8 Demographic and Health Surveys conducted in Bangladesh (n = 19,211), Nepal (n = 19,354), and India (n = 161,755), we examined the change in the prevalence rates of overweight-obesity (BMI > or = 25 kg/m(2)) and underweight (BMI < 18.5 kg/m(2)) over a recent 7- to 10-y period among women aged 15-49 y. The prevalence of overweight-obesity increased substantially in all countries. Comparing the first to the latest survey in Bangladesh, the prevalence of overweight-obesity increased from 2.7 to 8.9% [age and parity-adjusted prevalence ratio (PR): 2.42; 95% CI: 1.88, 3.13]; in Nepal, from 1.6 to 10.1% [adjusted PR: 4.18; 95% CI: 3.00, 5.83]; and in India, from 10.6 to 14.8% [adjusted PR: 1.28; 95% CI: 1.20, 1.36]. These increases were observed in both rural and urban areas and were greater in rural areas. During the study period, the prevalence of underweight decreased substantially in Bangladesh and only modestly in Nepal and India. Overweight-obesity was positively related to age, higher socioeconomic status, and urban residence in all countries. In conclusion, while the prevalence of underweight has remained high in Bangladesh, Nepal, and India, the prevalence of overweight-obesity in women of reproductive age has risen between 1996 and 2006. PMID- 19776183 TI - Regular consumption from fast food establishments relative to other restaurants is differentially associated with metabolic outcomes in young adults. AB - Although away-from-home eating is adversely associated with weight, other comorbidities have not been examined; therefore, we sought to determine the associations of fast food (e.g. Wendy's, McDonalds) and restaurant (sit-down style) consumption (times per week) with weight and multiple metabolic outcomes, including homeostatic model assessment insulin resistance (HOMA-IR), waist circumference, and plasma triglycerides (TG), LDL cholesterol, and HDL cholesterol (HDL-C). We used 3 waves of data (exam y 7, 10, and 20) from the Coronary Artery Risk Development in Young Adults Study, a prospective cohort study of black and white young adults [aged 25-42 y in 1992-93, n = 3643 (men, 1659; women, 1984)]. Individuals in the highest (vs. lowest) quartile of baseline (defined as the mean of y 7 and 10) fast food consumption had higher y 20 weight [adjusted mean (95% CI): 5.6 kg (CI, 2.1, 9.2); P = 0.002], HOMA-IR [0.9 (CI, 0.4, 1.3); P < 0.001], waist circumference [5.3 cm (CI, 2.8, 7.9); P < 0.000], TG concentrations [0.25 mmol/L (CI, 0.10, 0.40), 22.7 mg/dL (CI, 9.1, 36.3); P = 0.001], and lower HDL-C concentrations [-0.014 mmol/L (CI, -0.215, -0.067), 5.4 mg/dL (CI, -8.3, -2.6); P < 0.000]. Baseline restaurant consumption was unrelated to y 20 outcomes. Adjusted change in weekly restaurant (P < 0.05) and fast food intake (P < 0.001) was associated with 13-y changes in body weight [0.09 kg (CI, 0.02, 0.17) and 0.15 kg (CI, 0.06, 0.24), respectively] and waist circumference [0.08 cm (CI, 0.02, 0.14) and 0.12 cm (CI, 0.04, 0.20), respectively]. Fast food consumption may be an important target for the prevention of adverse metabolic health outcomes. PMID- 19776184 TI - Rats fed fructose-enriched diets have characteristics of nonalcoholic hepatic steatosis. AB - Nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease are increasing in adults and are likely to be increasing in children. Both conditions are hepatic manifestations of metabolic syndrome. Experimental animals fed fructose-enriched diets are widely recognized as good models for metabolic syndrome. However, few reports have described the hepatic pathology of these experimental animals. In this study, 5-wk-old Wistar specific pathogen-free rats, which are a normal strain, were fed experimental diets for 5 wk. We then evaluated the degree of steatohepatitis. The 5 diet groups were as follows: cornstarch (70% wt:wt) [control (C)], high-fructose (70%) (HFr), high-sucrose (70%) (HS), high-fat (15%) (HF), and high-fat (15%) high-fructose (50%) (HFHFr) diets. The macrovesicular steatosis grade, liver:body weight ratio, and hepatic triglyceride concentration were significantly higher in the HFr group than in the other 4 groups. However, the HFr group had a significantly lower ratio of epididymal white fat:body weight than the other 4 groups and had a lower final body weight than the HF and HFHFr groups. The HF group had a greater final body weight than the C, HFr, and HS groups, but no macrovesicular steatosis was observed. The HFr group had a significantly higher grade of lobular inflammation than the other 4 groups. The distribution of lobular inflammation was predominant over portal inflammation, which is consistent with human NASH. In conclusion, rats fed fructose-enriched diets are a better model for NASH than rats fed fat enriched diets. PMID- 19776187 TI - Diets enriched in oat bran or wheat bran temporally and differentially alter the composition of the fecal community of rats. AB - A clear understanding of how diet alters gastrointestinal communities is important given the suggested link between gut community composition and a wide variety of disease pathologies. To characterize this link for commonly consumed dietary fiber sources, we investigated the change in the fecal community of rats fed diets containing 5% nonnutritive fiber (control), 3% (wt:wt) oat bran plus 2% nonnutritive fiber (OB), or 5% (w/w) wheat bran (WB) over a 28-d feeding trial using both molecular- and cultivation-based methodologies. Pooled fecal samples from 8 rats fed the same diet were analyzed at 4 time points. On d 28, bran-fed rats had approximately twice the total cultivable bacteria than rats fed the control diet. Over the course of feeding, the cultivable community was initially dominated by bacteroides, then by bifidobacteria, lactobacilli, enterococci, and various enterics. In contrast, molecular analysis revealed the appearance of new operational taxonomic units (phylotypes) that were both temporally and inequitably distributed throughout the fecal community. The majority of change occurred in 2 major lineages within the Firmicutes: the Clostridium coccoides group and the Clostridium leptum subgroup. The time course of change depended on the source of bran, with the majority of new phylotypes appearing by d 14 (OB) or d 28 (WB), although adaptation of the fecal community was slow and continued over the entire feeding trial. Bacterial community richness was higher in bran-fed rats than in those fed the control diet. Change within the C. coccoides and C. leptum lineages likely reflect their high abundance within the gut bacterial community and the role of clostridia in fiber digestion. The results illustrate the limitations of relying solely on cultivation to assess bacterial changes and illustrate that community changes are complex in an ecosystem containing high numbers of interdependent and competing species of bacteria. PMID- 19776185 TI - Increases in plasma holotranscobalamin can be used to assess vitamin B-12 absorption in individuals with low plasma vitamin B-12. AB - Low plasma concentrations of vitamin B-12 are common in Indians, possibly due to low dietary intakes of animal-source foods. Whether malabsorption of the vitamin contributes to this has not been investigated. A rise in the plasma holotranscobalamin (holo-TC) concentration after a standard dose of oral vitamin B-12 has been proposed as a measure of gastrointestinal absorption in people with normal plasma vitamin B-12 concentrations. We studied 313 individuals (children and parents, 109 families) in the Pune Maternal Nutrition Study. They received 3 doses of 10 microg (n = 191) or 2 microg (n = 122) of cyanocobalamin at 6-h intervals. A rise in plasma holo-TC of > or =15% and >15 pmol/L above baseline was considered normal vitamin B-12 absorption. The baseline plasma vitamin B-12 concentration was <150 pmol/L in 48% of participants; holo-TC was <35 pmol/L in 98% and total homocysteine was high in 50% of participants (>10 micromol/L in children and >15 micromol/L in adults). In the 10 microg group, the plasma holo TC concentration increased by 4.8-fold from (mean +/- SD) 9.3 +/- 7.0 pmol/L to 53.8 +/- 25.9 pmol/L and in the 2 microg group by 2.2-fold from 11.1 +/- 8.5 pmol/L to 35.7 +/- 19.3 pmol/L. Only 10% of the participants, mostly fathers, had an increase less than the suggested cut-points. Our results suggest that an increase in plasma holo-TC may be used to assess vitamin B-12 absorption in individuals with low vitamin B-12 status. Because malabsorption is unlikely to be a major reason for the low plasma vitamin B-12 concentrations in this population, increasing dietary vitamin B-12 should improve their status. PMID- 19776186 TI - Linear and ponderal growth trajectories in well-nourished, iron-sufficient infants are unimpaired by iron supplementation. AB - Iron deficiency remains the most common nutritional deficiency worldwide and supplementation is recommended during periods of high risk, including infancy. However, questions have been raised about possible adverse effects of iron on growth in iron-sufficient (IS) infants and the advisability of across-the-board iron supplementation. This study examined whether short- or long-term growth was impaired in IS infants who received iron supplementation. From a longitudinal study of healthy, breast-fed, low- to middle-income Chilean infants randomly assigned to iron supplementation or usual nutrition at 6 or 12 mo, we retrospectively identified infants meeting criteria for iron sufficiency at the time of random assignment (n = 273). Using multilevel analysis, ponderal and linear growth were modeled before, during, and after iron supplementation up to 10 y in 3 comparisons: 1) iron supplementation compared with usual nutrition from 6 to 12 mo; 2) iron supplementation compared with usual nutrition from 12 to 18 mo; and 3) 15 mg/d of iron as drops compared with iron-fortified formula (12 mg/L). Growth trajectories did not differ during or after supplementation indicating no adverse effect of iron in any comparison. These results suggest that, at least in some environments, iron does not impair growth in IS infants. PMID- 19776188 TI - Iron-deficiency sensitizes mice to acute pain stimuli and formalin-induced nociception. AB - Iron deficiency has been described as a risk factor in secondary restless legs syndrome (RLS), although it has not been investigated whether iron deficiency induces sensory symptoms in RLS patients. In this study, we established a mouse model of iron deficiency by administering a purified iron-deficient (ID) diet (<8 mg/kg iron) or nonpurified standard diet [normal diet (ND)] (<179 mg/kg iron) to male C57Bl/6 mice from postnatal d 28 for 1, 4, or 15 wk. The level of iron deficiency was assessed by the plasma iron concentration. After varying durations of iron deficiency, both acute and chronic sensory components of pain were measured using hot-plate and formalin tests, which preferentially assess Adelta- and C-fibers, respectively. Based on hot-plate reaction time, ID mice had a lower acute pain threshold than the ND mice after 4 and 15 wk but not after 1 wk. In addition, ID mice had an increased chronic pain response compared with the ND mice only in the late phase of the formalin-test after 1, 4, and 15 wk of iron deficiency. This increased pain response was accompanied by an elevated expression of c-Fos immunoreactive cells at the ipsilateral dorsal horn, suggesting that iron deficiency indirectly increases cell activity at the spinal cord level. These results demonstrate that iron deficiency increases acute and chronic pain responses in mice and may cause similar alterations to the acute pain threshold and sensitivity to C-fiber-mediated chronic pain in ID RLS patients. PMID- 19776189 TI - Dietary saturated fat modulates the association between STAT3 polymorphisms and abdominal obesity in adults. AB - Signal transducer and activator of transcription 3 (STAT3) plays a key role in body weight regulation and glucose homeostasis, 2 important determinants of metabolic syndrome (MetS). Dietary fat is a key environmental factor that may interact with genotype to affect MetS risk. In this study, we investigated the relationship between STAT3 polymorphisms and MetS phenotypes and determined potential interactions with dietary fatty acids. STAT3 polymorphisms (rs8069645, rs744166, rs2306580, rs2293152, and rs10530050), biochemical measurements, and dietary fat composition were determined in the LIPGENE-SU.VI.MAX study of MetS cases and matched controls (n = 1754). STAT3 polymorphisms were not associated with MetS risk. However, minor G allele carriers for rs8069645, rs744166, and rs1053005 and major GG homozygotes for rs2293152 had increased risk of abdominal obesity compared with noncarriers [odds ratio (OR) = 2.22, P = 0.0005; OR = 2.08, P = 0.0017; OR = 2.00, P = 0.0033; and OR = 1.95, P = 0.028, respectively]. The number of risk alleles additively increased obesity risk (P = 0.0003). Dietary SFA intake exacerbated these effects; among all participants with the highest SFA intake (> or =15.5% of energy), individuals carrying >2 risk alleles had further increased risk of obesity (OR = 3.30; 95% CI = 1.50-7.28; P = 0.0079) compared with those carrying < or =1 risk allele. Interaction analysis confirmed this gene nutrient interaction whereby increasing SFA intake was predictive of increased waist circumference (P = 0.038). In conclusion, STAT3 gene polymorphisms influenced the risk of abdominal obesity, which is modulated by dietary SFA intake, suggesting novel gene-nutrient interactions. PMID- 19776191 TI - Vaccination with live Leishmania major and CpG DNA promotes interleukin-2 production by dermal dendritic cells and NK cell activation. AB - Cutaneous leishmaniasis due to Leishmania major is an emerging, chronic parasitic disease that causes disfigurement and social stigmatization. Drug therapy is inadequate, and there is no vaccine. Inoculation of virulent parasites (leishmanization) is the only intervention that has ever provided protection, because it mimics natural infection and immunity, but it was discontinued due to safety concerns (uncontrolled vaccinal lesions). In an effort to retain the benefits (immunity) while avoiding the side effects (lesions) of leishmanization, we immunized C57BL/6 mice with L. major and CpG DNA (Lm/CpG). This combination prevented lesions while inducing immunity. Also, the vaccination with live parasites and the Toll-like receptor 9 agonist enhanced innate immune responses by activating dermal dendritic cells (DCs) to produce cytokines. Here we report that the Lm/CpG vaccine induced dermal DCs, but not bone marrow-derived DCs, to produce interleukin-2 (IL-2). The release of this unusual DC-derived cytokine was concomitant with a peak in numbers of NK cells that produced gamma interferon (IFN-gamma) and also enhanced activation of proliferation of IFN-gamma+ CD4+ T cells. Parasite growth was controlled in Lm/CpG-vaccinated animals. This is the first demonstration of the ability of dermal DCs to produce IL-2 and of the activation of NK cells by vaccination in the context of leishmaniasis. Understanding how the Lm/CpG vaccine enhances innate immunity may provide new tools to develop vaccines against L. major, other chronic infectious diseases, or other conditions, such as cancer. PMID- 19776190 TI - A complex adenovirus-vectored vaccine against Rift Valley fever virus protects mice against lethal infection in the presence of preexisting vector immunity. AB - Rift Valley fever virus (RVFV) has been cited as a potential biological-weapon threat due to the serious and fatal disease it causes in humans and animals and the fact that this mosquito-borne virus can be lethal in an aerosolized form. Current human and veterinary vaccines against RVFV, however, are outdated, inefficient, and unsafe. We have incorporated the RVFV glycoprotein genes into a nonreplicating complex adenovirus (CAdVax) vector platform to develop a novel RVFV vaccine. Mice vaccinated with the CAdVax-based vaccine produced potent humoral immune responses and were protected against lethal RVFV infection. Additionally, protection was elicited in mice despite preexisting immunity to the adenovirus vector. PMID- 19776192 TI - BBK07, a dominant in vivo antigen of Borrelia burgdorferi, is a potential marker for serodiagnosis of Lyme disease. AB - One of the recently identified Borrelia burgdorferi immunogens, BBK07, is characterized for its expression in the spirochete infection cycle and evaluated for its potential use as a serodiagnostic marker for Lyme disease. We show that the BBK07 gene is expressed at extremely low levels in vitro and in ticks but is dramatically induced by spirochetes once introduced into the host and is highly expressed throughout mammalian infection. In contrast, the expression of BBK12, a paralog of BBK07 with 87% amino acid identity, although expressed in vitro, remained undetectable in vivo throughout murine infection and in ticks. BBK07 is localized in the outer membrane, and the amino-terminal domain of the antigen is exposed on the microbial surface. A truncated BBK07 protein representing the amino-terminal domain is able to effectively detect antibodies to B. burgdorferi, both in experimentally infected mice and in humans. Further characterization of the immunodominant antigens of B. burgdorferi, such as BBK07, could contribute to the development of novel serodiagnostic markers for detection of Lyme disease. PMID- 19776193 TI - Evaluation of the anti-East Asian CagA-specific antibody for CagA phenotyping. AB - The determination of the cagA genotype is generally based on sequencing the variable 3' region of the cagA gene. In a previous study, we successfully generated an anti-East Asian CagA-specific antibody (anti-EAS Ab) immunoreactive only with the East Asian CagA and not with the Western CagA. In a small number of Japanese patients, anti-EAS Ab appeared to be a useful tool for phenotyping CagA immunohistochemically. The present study was conducted to validate the anti-EAS Ab immunohistochemistry method in a larger number of patients from Vietnam and Thailand. A total of 385 Vietnamese and Thais were recruited. Helicobacter pylori status was determined by a combination of three methods, including culture, histology, and immunohistochemistry with anti-H. pylori antibody. The sensitivity, specificity, and accuracy of the anti-EAS Ab immunohistochemistry method for the diagnosis of CagA phenotype were calculated based on the results of the cagA sequencing as the gold standard. The sensitivity, specificity, and accuracy of our immunohistochemistry method were 96.7%, 97.9%, and 97.1%, respectively. Moreover, anti-EAS Ab was not cross-reactive with noninfected gastric mucosa. In conclusion, immunohistochemistry with anti-EAS Ab appears to be a good method for determination of CagA phenotype. PMID- 19776194 TI - Expression profiles of genes in Toll-like receptor-mediated signaling of broilers infected with Clostridium perfringens. AB - Toll-like receptors (TLRs) participate in detecting microbial pattern molecules for activation of the host immune response. We investigated possible roles of TLRs in the chicken response to Clostridium perfringens infection by examining the expression of TLR genes and other genes involved in TLR-mediated signaling within the spleens and ilea of C. perfringens-challenged broilers. Upregulation of a tumor necrosis factor alpha-inducing factor homolog in challenged chickens compared to naive chickens was observed, regardless of the incidence of necrotic enteritis. In addition, the members of the TLR2 subfamily were found to be most strongly involved in the host response to C. perfringens challenge, although the expression of TLR4 and TLR7 was also upregulated in spleen tissues. While the combination of TLR1.2, TLR2.1, and TLR15 appeared to play a major role in the splenic response, the expression of TLR2.2 and TLR1.1 was positively correlated to the expression of adaptor molecules MyD88, TRAF6, TRIF, and receptor interacting protein 1 in the ileal tissues, demonstrating a dynamic spatial and temporal innate host response to C. perfringens. PMID- 19776195 TI - New approach for diagnosis of candidemia based on detection of a 65-kilodalton antigen. AB - Nosocomial candidiasis is a major concern in tertiary care hospitals worldwide. This infection generally occurs in patients with degenerative and neoplastic diseases and is considered the fourth most frequent cause of bloodstream infections. Diagnosis of candidemia or hematogenous candidiasis has been problematic because clinical signs and symptoms are nonspecific, leading to delays in diagnosis and, consequently, delays in appropriate antifungal therapy. We developed an inhibition enzyme-linked immunosorbent assay (ELISA) for detection of a 65-kDa antigen in an experimental model of candidemia and for diagnosis of patients in intensive care units (ICUs) with suspected candidemia. An anti-65-kDa monoclonal antibody was tested for detection of the 65-kDa antigen produced by Candida albicans, Candida tropicalis, and Candida parapsilosis in murine candidemia models. The 65-kDa antigen was detected in sera at concentrations ranging from 0.012 to 3.25 microg/ml. A total of 20 human patients with candidemia were then evaluated with the inhibition ELISA using sequential sera. Sixteen (80%) patients had the 65-kDa antigen in concentrations ranging from 0.07 to 5.0 microg/ml. Sequential sera from patients with candidemia presented three different patterns of antigenemia of the 65-kDa molecule: (i) total clearance of antigenemia, (ii) initial clearance and relapse of antigenemia, and (iii) partial clearance of antigenemia. Our results indicate detection of the 65-kDa protein may be a valuable tool for the diagnosis of candidemia by C. albicans, C. tropicalis, and C. parapsilosis. PMID- 19776196 TI - Maternal antibodies to pneumolysin but not to pneumococcal surface protein A delay early pneumococcal carriage in high-risk Papua New Guinean infants. AB - Immunization of pregnant women can be an efficient strategy to induce early protection in infants in developing countries. Pneumococcal protein-based vaccines may have the capacity to induce pneumococcal serotype-independent protection. To understand the potential of maternal pneumococcal protein-specific antibodies in infants in high-risk areas, we studied the placental transfer of naturally acquired antibodies to pneumolysin (Ply) and pneumococcal surface protein A family 1 and 2 (PspA1 and PspA2) in relation to onset of pneumococcal nasopharyngeal carriage in infants in Papua New Guinea (PNG). In this study, 76% of the infants carried Streptococcus pneumoniae in the upper respiratory tract within the first month of life, at a median age of 19 days. Maternal and cord blood antibody titers to Ply (rho = 0.824, P < 0.001), PspA1 (rho = 0.746, P < 0.001), and PspA2 (rho = 0.631, P < 0.001) were strongly correlated. Maternal pneumococcal carriage (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.25 to 5.39) and younger maternal age (HR, 0.74; 95% CI, 0.54 to 1.00) were independent risk factors for early carriage, while higher cord Ply-specific antibody titers predicted a significantly delayed onset (HR, 0.71; 95% CI, 0.52 to 1.00) and cord PspA1-specific antibodies a significantly younger onset of carriage in PNG infants (HR, 1.57; 95% CI, 1.03 to 2.40). Maternal vaccination with a pneumococcal protein-based vaccine should be considered as a strategy to protect high-risk infants against pneumococcal disease by reducing carriage risks in both mothers and infants. PMID- 19776197 TI - Incidence of cytomegalovirus infection in Shanghai, China. AB - A city-wide cytomegalovirus serosurvey was conducted in Shanghai, China, and associated parameters were calculated by employing the catalytic model. The lowest seroprevalence was 60.37%, found in the >1- to 3-year age group. The value increased rapidly with age until 25 years, when a value of 97.03% was found, caused by the high force of infection (12.69) and by the reproductive rate (8.89). PMID- 19776198 TI - Performance of serology assays for diagnosing celiac disease in a clinical setting. AB - Diagnosis of celiac disease frequently depends upon serology assays. We set out to prospectively assess the diagnostic value of five serology tests: an enzyme linked immunosorbent assay (ELISA) for tissue transglutaminase (tTG) immunoglobulin A (IgA) and tTG-IgG, a chemiluminescence assay for tTG-IgA, an ELISA for deamidated gliadin peptide (DGP) IgG and IgA screening, and detection of endomysial antibodies (Abs) by indirect immunofluorescence. One hundred sixteen children at high risk for developing celiac disease were evaluated clinically and underwent small bowel biopsies and blood serology tests. We examined differences between younger and older children in terms of clinical presentation, test performance, and the ability of high Ab levels to correctly predict diagnosis of celiac disease. Celiac disease was diagnosed for 85 (73%) children. No significant clinical differences were observed between the biopsy positive and biopsy-negative groups. Children < or = 3 years of age revealed higher concentrations of tTG-IgA and DGP Abs than children >3 years old (P = 0.017 and 0.007, respectively). High Ab concentrations were predictive of villous atrophies, with sensitivities ranging from 92.8% to 97.9%, depending on the assay and the cutoff points applied. Sensitivities, specificities, positive predictive values, and negative predictive values varied among assays and improved after correction for best cutoff points. Assay specificities obtained in the clinical setting were lower than expected. The new tTG-IgA chemiluminescence assay demonstrated high throughput but low specificity (74.2%). The tTG-IgA ELISA exhibited the highest test efficiency, and the tTG-IgA chemiluminescence assay was suitable for large-scale screening, with reduced specificity. High concentrations of celiac disease-specific Abs bring into question the need for performance of biopsies on children at high risk. PMID- 19776201 TI - Adrenal crisis in treated Addison's disease: a predictable but under-managed event. AB - CONTEXT: Adrenal crisis is a life-threatening event that occurs regularly in Addison's patients receiving standard replacement therapy. Patient reports suggest that it is an underestimated and under-managed event. OBJECTIVE: To assess the frequency of adrenal crisis in diagnosed patients and to understand the factors contributing to the risks of adrenal crisis. DESIGN: We conducted a postal survey of Addison's patients in four countries, UK (n=485), Canada (n=148), Australia (n=123) and New Zealand (n=85) in 2003, asking about patients' experiences of adrenal crisis and their demographic characteristics. In 2006, a shorter follow-up survey was conducted in the UK (n=261). METHOD: The frequency and causes of adrenal crisis were compared across both surveys. Demographic data from the 2003 survey were analysed to establish the main variables associated with an elevated risk of crisis. RESULTS: Around 8% of diagnosed cases can be expected to need hospital treatment for adrenal crisis annually. Exposure to gastric infection is the single most important factor predicting the likelihood of adrenal crisis. Concomitant diabetes and/or asthma increase the frequency of adrenal crises reported by patients. CONCLUSION: The endocrinologist has a responsibility to ensure that Addison's patients have adequate access to life saving emergency injection materials and repeated, practical training sessions in how to use them, while the general practitioner plays a vital role as in arranging prompt emergency admissions. PMID- 19776200 TI - Glycoprotein 96-mediated presentation of human immunodeficiency virus type 1 (HIV 1)-specific human leukocyte antigen class I-restricted peptide and humoral immune responses to HIV-1 p24. AB - Viral antigens complexed to heat shock proteins (HSPs) can enhance antiviral immunity. The present study evaluated the immunogenicity of a novel human immunodeficiency virus type 1B' (HIV-1B')-specific, human leukocyte antigen A2 (HLA-A2)-restricted peptide (FLQSRPEPTA, Gag(448-457)) and the cellular immune adjuvant effect of HSP gp96 using the HLA-A2 transgenic mouse model. It was found that gp96 could augment cytotoxic-T-lymphocyte responses specific for the 10-mer peptide of HIV-1B'. This study also evaluated the humoral immune adjuvant effect of HSP gp96 and its N-terminal fragment (N336) and found that immunization of BALB/c mice with a mixture of gp96 or its N-terminal fragment and HIV-1 p24 antigen or with an p24-N336 fusion protein resulted in a significant increase in anti-HIV p24 antibody titer. These results demonstrate the possibility of using gp96 and its N fragment as adjuvants to augment cellular and humoral immune responses against HIV-1 infection. PMID- 19776199 TI - Influence of the tissue microenvironment on Toll-like receptor expression by CD11c+ antigen-presenting cells isolated from mucosal tissues. AB - It is recognized that functional activities of antigen-presenting cells (APCs) in mucosal tissue sites differ from those of systemic APCs; however, it is unknown whether there are further differences between APC populations residing in different mucosal sites. In this study, we directly compared murine CD11c+ APCs isolated from colon, lung, and spleen and found that APCs isolated from these tissues differ considerably in Toll-like receptor (TLR) expression and responses to in vitro TLR ligand stimulation. We also provide evidence that tissue microenvironments dictate distinct patterns of TLR expression by CD11c+ APCs in different mucosal tissues. Moreover, CD11c+ cells isolated from different tissues have varied capacities to induce the development of T helper 1 (Th1), Th2, or regulatory CD4+ T cells. Thus, unique tissue microenvironments have a significant influence on determining TLR expression by CD11c+ cells that migrate to and reside in each mucosal tissue and are likely to modulate their functional activities. PMID- 19776202 TI - Fibroblast growth factor 23 and its role in phosphate homeostasis. AB - Phosphate homeostasis is complex and incompletely understood. The identification of different factors involved in the regulation of phosphate balance, also called phosphatonins, has largely changed our view on the regulation of phosphate homeostasis. The active role of bone has been demonstrated clearly. Currently, maintaining phosphate homeostasis is considered the result of a complex network of endocrine feedback loops between parathyroid gland, kidney, and bone. This review describes current knowledge on fibroblast growth factor 23, which is one of the best studied phosphatonins. PMID- 19776203 TI - Benign fine-needle aspiration cytology of thyroid nodule: to repeat or not to repeat? AB - CONTEXT: Fine-needle aspiration cytology (FNAC) is the gold standard for evaluating thyroid nodules. It has a sensitivity rate of about 95%, i.e. false negative results represent up to 5% of cases. The value of repeated FNAC during follow-up is still controversial. OBJECTIVE: To evaluate the usefulness of repeating the FNAC for initially benign nodules. DESIGN AND METHODS: All 5017 patients who underwent FNAC of the thyroid nodule in years 1991-2008 were retrospectively evaluated. RESULTS: Repeated FNAC was performed in 574 nodules with initially benign results. The number of repetitions varied from one to six. Repeatedly benign results were found in 498 cases, and malignant/suspicious results with initially benign cytology were found in 76 nodules (13.2%). Carcinoma was present in 13 out of the 58 surgically treated malignant/suspicious results of initially benign cytology. CONCLUSIONS: A change from a benign FNAC result to a malignant/suspicious one was present in more than 13% of the patients with initially benign cytology; malignancy has been recognised on the basis of repeated FNAC in 2.3% patients. In the majority of cases, the repetition corrected wrong cytological interpretation of results other than colloidal goitre, especially Hashimoto's thyroiditis and regressive changes. We believe that repeating FNAC in patients with benign cytology in about a 1-year horizon can reduce the rate of undiagnosed tumours. PMID- 19776204 TI - Reliability and comparability of psychosis patients' retrospective reports of childhood abuse. AB - An increasing number of studies are demonstrating an association between childhood abuse and psychosis. However, the majority of these rely on retrospective self-reports in adulthood that may be unduly influenced by current psychopathology. We therefore set out to explore the reliability and comparability of first-presentation psychosis patients' reports of childhood abuse. Psychosis case subjects were drawn from the Aetiology and Ethnicity of Schizophrenia and Other Psychoses (AESOP) epidemiological study and completed the Childhood Experience of Care and Abuse Questionnaire to elicit abusive experiences that occurred prior to 16 years of age. High levels of concurrent validity were demonstrated with the Parental Bonding Instrument (antipathy: r(s)=0.350-0.737, P<.001; neglect: r(s)=0.688-0.715, P<.001), and good convergent validity was shown with clinical case notes (sexual abuse: kappa=0.526, P<.001; physical abuse: kappa=0.394, P<.001). Psychosis patients' reports were also reasonably stable over a 7-year period (sexual abuse: kappa=0.590, P<.01; physical abuse: kappa=0.634, P<.001; antipathy: kappa=0.492, P<.01; neglect: kappa=0.432, P<.05). Additionally, their reports of childhood abuse were not associated with current severity of psychotic symptoms (sexual abuse: U=1768.5, P=.998; physical abuse: U=2167.5, P=.815; antipathy: U=2216.5, P=.988; neglect: U=1906.0, P=.835) or depressed mood (sexual abuse: chi(2)=0.634, P=.277; physical abuse: chi(2)=0.159, P=.419; antipathy: chi(2)=0.868, P=.229; neglect: chi(2)=0.639, P=.274). These findings provide justification for the use in future studies of retrospective reports of childhood abuse obtained from individuals with psychotic disorders. PMID- 19776205 TI - A brief cognitive assessment tool for schizophrenia: construction of a tool for clinicians. AB - Cognitive impairment in schizophrenia is often severe, enduring, and contributes significantly to chronic disability. But clinicians have difficulty in assessing cognition due to a lack of brief instruments. We evaluated whether a brief battery of cognitive tests derived from larger batteries could generate a summary score representing global cognitive function. Using data from 3 previously published trials, we calculated the corrected item-total correlations (CITCs) or the correlation of each test with the battery total score. We computed the proportion of variance that each test shares with the global score excluding that test (R(t)(2)=CITC(2)) and the variance explained per minute of administration time for each test (R(t)(2)/min). The 3 tests with the highest R(t)(2)/min were selected for the brief battery. The composite score from the trail making test B, category fluency, and digit symbol correlated .86 with the global score of the larger battery in 2 of the studies and correlated between .73 and .82 with the total battery scores excluding these 3 tests. A Brief Cognitive Assessment Tool for Schizophrenia (B-CATS) using the above 3 tests can be administered in 10-11 min. The full batteries of the larger studies have administration times ranging from 90 to 210 min. Given prior research suggesting that a single factor of global cognition best explains the pattern of cognitive deficit in schizophrenia, an instrument like B-CATS can provide clinicians with meaningful data regarding their patients' cognitive function. It can also serve researchers who want an estimate of global cognitive function without requiring a full neuropsychological battery. PMID- 19776206 TI - Cognitive impairment in schizophrenia and affective psychoses: implications for DSM-V criteria and beyond. AB - It has recently been suggested that the diagnostic criteria of schizophrenia should include specific reference to cognitive impairments characterizing the disorder. Arguments in support of this assertion contend that such inclusion would not only serve to increase the awareness of cognitive deficits in affected patients, among both clinicians and researchers alike, but also increase the "point of rarity" between schizophrenia and mood disorders. The aim of the current article is to examine this latter assertion in light of the recent opinion piece provided by Keefe and Fenton (Keefe RSE, Fenton WS. How should DSM V criteria for schizophrenia include cognitive impairment? Schizophr Bull. 2007;33:912-920). Through literature review, we explore the issue of whether cognitive deficits do in fact differentiate the major psychoses. The overall results of this inquiry suggest that inclusion of cognitive impairment criteria in Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-V) would not provide a major advancement in discriminating schizophrenia from bipolar disorder and affective psychoses. Therefore, while cognitive impairment should be included in DSM-V, it should not dictate diagnostic specificity--at least not until more comprehensive evidence-based reviews of the current diagnostic system have been undertaken. Based on this evidence, we consider several alternatives for the DSM-V definition of cognitive impairment in schizophrenia, including (1) the inclusion of cognitive impairment as a specifier and (2) the definition of cognitive impairment as a dimension within a hybrid categorical-dimensional system. Given the state of current evidence, these possibilities appear to represent the most parsimonious approaches to the inclusion of cognitive deficits in the diagnostic criteria of schizophrenia and, potentially, of mood disorders. PMID- 19776207 TI - Referential failures and affective reactivity of language in schizophrenia and unipolar depression. AB - Reference failures, and their increase in affectively negative conditions (known as affective reactivity of speech), are more frequently observed in schizophrenia patients than in normal controls, but no information is available comparing schizophrenia with depression, ie, a mental disorder closely linked to the concept of affective reactivity. To address this gap in the literature, the present study compared 24 schizophrenia inpatients, 21 unipolar depression inpatients and 21 normal controls. Two 10-minute conversational speech samples (1 on negative and 1 on positive memories) were collected from each patient. The transcripts of the audiotaped interviews were analyzed blindly for frequencies of 6 types of referential failures, employing the Communication Disturbances Index, adapted for use with Italian. The schizophrenia patients made more frequent total reference failures and, specifically, more missing information references than the depression patients. The depression patients made more frequent reference failures than the normal controls, overall, and on most of the specific types of failures. Affective reactivity of speech was observed only for the schizophrenia sample and was greatest for missing information references. This study supports the viability of reference failure analysis as a measure of communication disturbance in a language other than English. The findings indicate that schizophrenia and depression both are associated with high levels of referential failures but that affective reactivity of speech is present only in schizophrenia and not in depression. PMID- 19776208 TI - The catatonia conundrum: evidence of psychomotor phenomena as a symptom dimension in psychotic disorders. AB - To provide a rational basis for reconceptualizing catatonia in Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition), we briefly review historical sources, the psychopathology of catatonia, and the relevance of catatonic schizophrenia in contemporary practice and research. In contrast to Kahlbaum, Kraepelin and others (Jaspers, Kleist, and Schneider) recognized the prevalence of motor symptoms in diverse psychiatric disorders but concluded that the unique pattern and persistence of certain psychomotor phenomena defined a "catatonic" subtype of schizophrenia, based on intensive long-term studies. The enduring controversy and confusion that ensued underscores the fact that the main problem with catatonia is not just its place in Diagnostic and Statistical Manual of Mental Disorders but rather its lack of conceptual clarity. There still are no accepted principles on what makes a symptom catatonic and no consensus on which signs and symptoms constitute a catatonic syndrome. The resulting heterogeneity is reflected in treatment studies that show that stuporous catatonia in any acute disorder responds to benzodiazepines or electroconvulsive therapy, whereas catatonia in the context of chronic schizophrenia is phenomenologically different and less responsive to either modality. Although psychomotor phenomena are an intrinsic feature of acute and especially chronic schizophrenia, they are insufficiently recognized in practice and research but may have significant implications for treatment outcome and neurobiological studies. While devising a separate category of catatonia as a nonspecific syndrome has heuristic value, it may be equally if not more important to re-examine the psychopathological basis for defining psychomotor symptoms as catatonic and to re-establish psychomotor phenomena as a fundamental symptom dimension or criterion for both psychotic and mood disorders. PMID- 19776210 TI - Family cancer caregiving and negative outcomes: the direct and mediational effects of psychosocial resources. AB - This study tested the hypothesis that various components of the stress process model were related to negative outcomes (depression, guilt, negative health) in cancer caregivers. This study also tested the hypothesis that psychosocial resources (mastery, socioemotional support) mediated the relationship between the various domains of the stress process model and negative outcomes. A total of 238 cancer caregivers were recruited from radiation medicine clinics at the University of Maryland Greenebaum Cancer Center (n = 186) and the University of Minnesota Cancer Center (n = 52). A comprehensive interview battery was administered. A multivariate regression found that primary subjective stressors were the strongest predictors of depression and negative health impact. A path analysis indicated that mastery mediated the relationship between role captivity and negative health impact. These results emphasize the importance of multidimensional assessment in cancer caregiving. The findings also suggest refinements to the stress process model when examining family cancer care. PMID- 19776211 TI - Estimates of cancer potency of 2,3,7,8-tetrachlorodibenzo(p)dioxin using linear and nonlinear dose-response modeling and toxicokinetics. AB - Linear and nonlinear toxicity criteria were derived for 2,3,7,8 tetrachlorodibenzo(p)dioxin (TCDD) using the recent National Toxicology Program rat cancer bioassay. Dose-response relationships were assessed for combined liver tumors based on lifetime average liver concentrations (LALCs) estimated with a toxicokinetic model. Rat LALC estimates at the 1% point of departure (POD) were obtained with benchmark dose (BMD) modeling to yield the BMD(01) in terms of LALC. The same toxicokinetic model was used to back-extrapolate the human equivalent external dose (HED). A linear cancer slope factor (CSF) with a value of 1 x 10(-4) per pg/kg/day was calculated as the ratio between the benchmark response rate and the HED at the lower confidence limit of the benchmark dose (BMDL)(01). A nonlinear reference dose (RfD) with a value of 100 pg/kg/day was developed from the BMD(01) value by applying uncertainty factors to rat internal and human external doses. The RfD was 100 times higher than the 10(-4) risk specific dose (RSD) based on the linear CSF. For comparison, BMD(01) and BMDL(01) values were developed for key events in the tumor promotion mode of action (MOA) of TCDD. This MOA involves dysregulation of the normal function of the aryl hydrocarbon receptor and its associated biological processes and results in pathologies that drive tumor promotion and progression. The BMD(01) values for key events were consistent with the timing of the key events within the MOA and provided support for the choices of the 1% tumor rate as a POD and dichotomous Hill model for representing receptor-mediated carcinogenicity. Because a threshold toxicity criterion most accurately reflects the MOA, the RfD for TCDD with a value of 100 pg/kg/day is considered appropriate for regulatory purposes, consistent with a 2006 NRC panel's recommendation to develop a threshold-based cancer potency factor for TCDD and with the methodology in U.S. Environmental Protection Agency's Cancer Guidelines. PMID- 19776212 TI - Use of short-term transcriptional profiles to assess the long-term cancer-related safety of environmental and industrial chemicals. AB - The process for evaluating chemical safety is inefficient, costly, and animal intensive. There is growing consensus that the current process of safety testing needs to be significantly altered to improve efficiency and reduce the number of untested chemicals. In this study, the use of short-term gene expression profiles was evaluated for predicting the increased incidence of mouse lung tumors. Animals were exposed to a total of 26 diverse chemicals with matched vehicle controls over a period of 3 years. Upon completion, significant batch-related effects were observed. Adjustment for batch effects significantly improved the ability to predict increased lung tumor incidence. For the best statistical model, the estimated predictive accuracy under honest fivefold cross-validation was 79.3% with a sensitivity and specificity of 71.4 and 86.3%, respectively. A learning curve analysis demonstrated that gains in model performance reached a plateau at 25 chemicals, indicating that the size of current data set was sufficient to provide a robust classifier. The classification results showed that a small subset of chemicals contributed disproportionately to the misclassification rate. For these chemicals, the misclassification was more closely associated with genotoxicity status than with efficacy in the original bioassay. Statistical models were also used to predict dose-response increases in tumor incidence for methylene chloride and naphthalene. The average posterior probabilities for the top models matched the results from the bioassay for methylene chloride. For naphthalene, the average posterior probabilities for the top models overpredicted the tumor response, but the variability in predictions was significantly higher. The study provides both a set of gene expression biomarkers for predicting chemically induced mouse lung tumors and a broad assessment of important experimental and analysis criteria for developing microarray-based predictors of safety-related end points. PMID- 19776213 TI - In response to 'Can sugars be produced from fatty acids? A test case for pathway analysis tools'. AB - MOTIVATION: In their article entitled 'Can sugars be produced from fatty acids? A test case for pathway analysis tools' de Figueiredo and co-authors assess the performance of three pathway prediction tools (METATOOL, PathFinding and Pathway Hunter Tool) using the synthesis of glucose-6-phosphate (G6P) from acetyl-CoA in humans as a test case. We think that this article is biased for three reasons: (i) the metabolic networks used as input for the respective tools were of very different sizes; (ii) the 'assessment' is restricted to two study cases; (iii) developers are inherently more skilled to use their own tools than those developed by other people. We extended the analyses led by de Figueiredo and clearly show that the apparent superior performance of their tool (METATOOL) is partly due to the differences in input network sizes. We also see a conceptual problem in the comparison of tools that serve different purposes. In our opinion, metabolic path finding and elementary mode analysis are answering different biological questions, and should be considered as complementary rather than competitive approaches. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 19776214 TI - SimCT: a generic tool to visualize ontology-based relationships for biological objects. AB - We present a web-based service, SimCT, which allows to graphically display the relationships between biological objects (e.g. genes or proteins) based on their annotations to a biomedical ontology. The result is presented as a tree of these objects, which can be viewed and explored through a specific java applet designed to highlight relevant features. Unlike the numerous tools that search for overrepresented terms, SimCT draws a simplified representation of biological terms present in the set of objects, and can be applied to any ontology for which annotation data is available. Being web-based, it does not require prior installation, and provides an intuitive, easy-to-use service. AVAILABILITY: http://tagc.univ-mrs.fr/SimCT. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 19776215 TI - Transplantation of young ovaries to old mice increased life span in transplant recipients. AB - Previously we reported that prepubertally ovariectomized mice that received young transplanted ovaries at a postreproductive age showed a 40% increase in life expectancy. To study this phenomenon in greater detail, 11-month-old ovariectomized and ovary-intact CBA/J mice underwent ovarian transplantation with 60-day-old ovaries or a sham surgery. Results from observations on transplant recipients in the current study extended our previous results. Whereas intact control mice lived an average of 726 days, transplant recipients lived an average of 770 days (i.e., 780 days for intact recipients and 757 days for ovariectomized recipients). If intact recipients had ceased reproductive cycling by the time of transplant, we observed a further increase in mean life span to 811 days. These results demonstrate that young ovaries enhanced longevity when transplanted to old mice and that ovarian status, examined by means of ovariectomy and ovarian transplantation, clearly influenced the potential of young transplanted ovaries to positively impact longevity. PMID- 19776216 TI - Ecological measurement of fatigue and fatigability in older adults with osteoarthritis. AB - BACKGROUND: Fatigue is associated with loss of independence in older adults; however, little is known about optimal treatment or how fatigue manifests in daily life activities. "Fatigability" was recently proposed to clarify the fatigue-activity relationship. The purpose of this study was to present a new measurement method of fatigability and begin to test its validity. METHODS: Our sample included 40 adults with knee or hip osteoarthritis (OA) and 20 healthy controls. Fatigue was measured by ecological momentary assessment several times a day along with continuous measurement of physical activity using a wrist-worn accelerometer. Fatigability was measured as the fatigue increase after a period of high activity. RESULTS: Compared with controls, participants with OA were approximately four times more likely to have an increase in fatigue after a high activity interval (37.0% vs 9.8%). Among people with OA, average fatigue and fatigability were not highly related (r = .13). Fatigue was most strongly associated with reported physical function, pain, and vitality, whereas fatigability was most strongly associated with body mass index, OA severity, and knee strength. CONCLUSIONS: Although fatigue among people with OA was more associated with subjective reports of physical function and symptoms, pairing fatigue reports with physical activity tapped objective factors that may be related to the biomechanical demands of daily life activities. Thus, fatigability measurement may help discern how symptoms relate to daily life function and help to refine treatment approaches in OA. PMID- 19776217 TI - Longitudinal association between depressive symptoms and disability burden among older persons. AB - BACKGROUND: Although depressive symptoms in older persons are common, their association with disability burden is not well understood. The authors evaluated the association between level of depressive symptoms and severity of subsequent disability over time and determined whether this relationship differed by sex. METHODS: Participants included 754 community-living persons aged 70 years or older who underwent monthly assessments of disability in four essential activities of daily living for up to 117 months. Disability was categorized each month as none, mild, and severe. Depressive symptoms, assessed every 18 months, were categorized as low (referent group), moderate, and high. Multinomial logit models invoking Generalized Estimating Equation were used to calculate odds ratios and 95% confidence intervals. RESULTS: Moderate (odds ratio = 1.30; 95% confidence interval: 1.18-1.43) and high (odds ratio = 1.68; 95% confidence interval: 1.50-1.88) depressive symptoms were associated with mild disability, whereas only high depressive symptoms were associated with severe disability (odds ratio = 2.05; 95% confidence interval: 1.76-2.39). Depressive symptoms were associated with disability burden in both men and women, with modest differences by sex; men had an increased likelihood of experiencing severe disability at both moderate and high levels of depressive symptoms, whereas only high depressive symptoms were associated with severe disability in women. CONCLUSIONS: Levels of depressive symptoms below the threshold for subsyndromal depression are associated with increased disability burden in older persons. Identifying and treating varying levels of depressive symptoms in older persons may ultimately help to reduce the burden of disability in this population. PMID- 19776218 TI - Attenuation of age-related metabolic dysfunction in mice with a targeted disruption of the Cbeta subunit of protein kinase A. AB - The cyclic adenosine monophosphate-dependent protein kinase A (PKA) pathway helps regulate both cell growth and division, and triglyceride storage and metabolism in response to nutrient status. Studies in yeast show that disruption of this pathway promotes longevity in a manner similar to caloric restriction. Because PKA is highly conserved, it can be studied in mammalian systems. This report describes the metabolic phenotype of mice lacking the PKA catalytic subunit Cbeta. We confirmed that Cbeta has high levels of expression in the brain but also showed moderate levels in liver. Cbeta-null animals had reduced basal PKA activity while appearing overtly normal when fed standard rodent chow. However, the absence of Cbeta protected mice from diet-induced obesity, steatosis, dyslipoproteinemia, and insulin resistance, without any differences in caloric intake or locomotor activity. These findings have relevant pharmacological implications because aging in mammals is characterized by metabolic decline associated with obesity, altered body fat distribution, and insulin resistance. PMID- 19776219 TI - Mice deficient in both Mn superoxide dismutase and glutathione peroxidase-1 have increased oxidative damage and a greater incidence of pathology but no reduction in longevity. AB - To test the impact of increased mitochondrial oxidative stress as a mechanism underlying aging and age-related pathologies, we generated mice with a combined deficiency in two mitochondrial-localized antioxidant enzymes, Mn superoxide dismutase (MnSOD) and glutathione peroxidase-1 (Gpx-1). We compared life span, pathology, and oxidative damage in Gpx1(-/-), Sod2(+/-)Gpx1(+/-), Sod2(+/-)Gpx1( /-), and wild-type control mice. Oxidative damage was elevated in Sod2(+/-)Gpx1( /-) mice, as shown by increased DNA oxidation in liver and skeletal muscle and increased protein oxidation in brain. Surprisingly, Sod2(+/-)Gpx1(-/-) mice showed no reduction in life span, despite increased levels of oxidative damage. Consistent with the important role for oxidative stress in tumorigenesis during aging, the incidence of neoplasms was significantly increased in the older Sod2(+/-)Gpx1(-/-) mice (28-30 months). Thus, these data do not support a significant role for increased oxidative stress as a result of compromised mitochondrial antioxidant defenses in modulating life span in mice and do not support the oxidative stress theory of aging. PMID- 19776220 TI - Cultural differences in the visual processing of meaning: detecting incongruities between background and foreground objects using the N400. AB - East Asians have been found to allocate relatively greater attention to background objects, whereas European Americans have been found to allocate relatively greater attention to foreground objects. This is well documented across a variety of cognitive measures. We used a modification of the Ganis and Kutas (2003) N400 event-related potential design to measure the degree to which Asian Americans and European Americans responded to semantic incongruity between target objects and background scenes. As predicted, Asian Americans showed a greater negativity to incongruent trials than to congruent trials. In contrast, European Americans showed no difference in amplitude across the two conditions. Furthermore, smaller magnitude N400 incongruity effects were associated with higher independent self-construal scores. These data suggest that Asian Americans are processing the relationship between foreground and background objects to a greater degree than European Americans, which is consistent with hypothesized greater holistic processing among East Asians. Implications for using neural measures, the role of semantic processing to understand cultural differences in cognition, and the relationship between self construal and neural measures of cognition are discussed. PMID- 19776221 TI - Stress reduction correlates with structural changes in the amygdala. AB - Stress has significant adverse effects on health and is a risk factor for many illnesses. Neurobiological studies have implicated the amygdala as a brain structure crucial in stress responses. Whereas hyperactive amygdala function is often observed during stress conditions, cross-sectional reports of differences in gray matter structure have been less consistent. We conducted a longitudinal MRI study to investigate the relationship between changes in perceived stress with changes in amygdala gray matter density following a stress-reduction intervention. Stressed but otherwise healthy individuals (N = 26) participated in an 8-week mindfulness-based stress reduction intervention. Perceived stress was rated on the perceived stress scale (PSS) and anatomical MR images were acquired pre- and post-intervention. PSS change was used as the predictive regressor for changes in gray matter density within the bilateral amygdalae. Following the intervention, participants reported significantly reduced perceived stress. Reductions in perceived stress correlated positively with decreases in right basolateral amygdala gray matter density. Whereas prior studies found gray matter modifications resulting from acquisition of abstract information, motor and language skills, this study demonstrates that neuroplastic changes are associated with improvements in a psychological state variable. PMID- 19776223 TI - Comment on: Clinical utility of ANA measured by ELISA compared with ANA measured by immunofluorescence. PMID- 19776222 TI - Minimally important differences in the Mahler's Transition Dyspnoea Index in a large randomized controlled trial--results from the Scleroderma Lung Study. AB - OBJECTIVE: Scleroderma Lung Study (SLS) showed that cyclophosphamide (CYC) was better than placebo (PLA) in preventing progression of forced vital capacity percentage (FVC%) predicted and dyspnoea at 12 months. Our objective was to assess minimally important difference (MID) for Mahler's Transition Dyspnoea Index (TDI) in SLS. METHODS: A total of 158 subjects participated in the SLS. Data from the two treatment groups were combined for this analysis. We used five patient-reported anchors from the short form (SF)-36 instrument to assess MID for TDI-SF-36 transition question and four questions from SF-36 pertaining to walking on a flat surface or climbing stairs. On the SF-36 transition question, patients who rated as a little better or a little worse were defined as the MID subgroup. For other questions, patients who reported improvement from 'Limited a lot' to 'Limited a little' and 'Limited a little' to 'No limit' and vice versa were defined as the MID subgroup. RESULTS: The MID estimates for the TDI improvement and worsening ranged from 1.05 to 2.16 (mean score = 1.5) U and from -0.61 to 2.55 (mean score = -1.5) U, respectively. Change in this group was larger than that of the no-change group (mean score = 0.38 U). Patients who achieved the MID for improvement at 12 months had a greater improvement in their FVC% predicted (3.6%) compared with those who did not (-3.3%; P < 0.001). CONCLUSION: A change (improvement/worsening) of 1.5 U in the TDI is the MID for SSc-related interstitial lung disease (SSc-ILD). This can aid in interpreting clinically important changes in breathlessness in SSc-ILD. PMID- 19776224 TI - Cumulative organ damage and prognostic factors in juvenile dermatomyositis: a cross-sectional study median 16.8 years after symptom onset. AB - OBJECTIVE: To describe cumulative organ damage in juvenile dermatomyositis (JDM) patients and to identify patient characteristics and early disease variables that predict organ damage. METHODS: An inception cohort of 60 patients diagnosed with JDM from 1970 to 2006 was examined, median 16.8 (2.0-38.1) years after disease onset. Disease activity was measured by the disease activity score (DAS), organ damage by the myositis damage index (MDI) and physical function by the childhood or adult HAQ (CHAQ/HAQ). Medical records were reviewed for early disease variables at diagnosis, and 6 and 12 months post-diagnosis. RESULTS: Fifty-four (90%) patients had a cumulative MDI total score >or=1 at follow-up (mean 4.2 +/- 3.1). Damage occurred most frequently in cutaneous, muscular and skeletal domains (77, 65 and 57%, respectively). Early predictors of damage were DAS and MDI 6 months post-diagnosis (beta = 0.334; P = 0.002 and 0.382, P < 0.001, respectively). Follow-up time also correlated with MDI (P = 0.010). Calcinosis, seen in 47% of the patients, was predicted by male gender [odds ratio (OR) 3.8; 95% CI 1.2, 12.1], and DAS 6 months post-diagnosis (OR 1.2; 95% CI 1.1, 1.4). The MDI score correlated with CHAQ/HAQ and DAS at follow-up (r(s) = 0.355; P = 0.005 and 0.446, P < 0.001, respectively). The DAS decreased during the first-year post diagnosis, whereas the MDI increased over time. CONCLUSIONS: The majority of JDM patients had cumulative organ damage at follow-up, which was predicted by high disease activity and organ damage 6 months post-diagnosis. PMID- 19776226 TI - Defining, delivering, and documenting the outcomes of case management by school nurses. AB - Case management is a component of school nurse practice that provides an opportunity to demonstrate the contribution that school nurses make to the health and academic success of children, particularly children with chronic health conditions. However, case management programs vary in their mission and scope, leading to confusion about what it means to be a case manager. Many programs acknowledge the difficulty in tracking outcomes and sustaining results. Using a capacity-building approach, the Case Management Project (CMP) developed a definition of case management and a set of baseline and outcome measures to assist school nurses to become effective case managers and track their outcomes. PMID- 19776225 TI - Glucocorticoid reamplification within cells intensifies NF-kappaB and MAPK signaling and reinforces inflammation in activated preadipocytes. AB - Increased expression and activity of the intracellular glucocorticoid reactivating enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) contribute to dysfunction of adipose tissue. Although the pathophysiological role of 11 beta-HSD1 in mature adipocytes has long been investigated, its potential role in preadipocytes still remains obscure. The present study demonstrates that the expression of 11 beta-HSD1 in preadipocyte-rich stromal vascular fraction (SVF) cells in fat depots from ob/ob and diet-induced obese mice was markedly elevated compared with lean control. In 3T3-L1 preadipocytes, the level of mRNA and reductase activity of 11 beta-HSD1 was augmented by TNF-alpha, IL-1 beta, and LPS, with a concomitant increase in inducible nitric oxide synthase (iNOS), monocyte chemoattractant protein-1 (MCP-1), or IL-6 secretion. Pharmacological inhibition of 11 beta-HSD1 and RNA interference against 11 beta-HSD1 reduced the mRNA and protein levels of iNOS, MCP-1, and IL-6. In contrast, overexpression of 11 beta-HSD1 further augmented TNF-alpha-induced iNOS, IL-6, and MCP-1 expression. Moreover, 11 beta-HSD1 inhibitors attenuated TNF-alpha-induced phosphorylation of NF-kappaB p65 and p38-, JNK-, and ERK1/2-MAPK. Collectively, the present study provides novel evidence that inflammatory stimuli-induced 11 beta-HSD1 in activated preadipocytes intensifies NF-kappaB and MAPK signaling pathways and results in further induction of proinflammatory molecules. Not limited to 3T3-L1 preadipocytes, we also demonstrated that the notion was reproducible in the primary SVF cells from obese mice. These findings highlight an unexpected, proinflammatory role of reamplified glucocorticoids within preadipocytes in obese adipose tissue. PMID- 19776227 TI - School nurses' knowledge of autism spectrum disorders. AB - The purpose of this study was to determine school nurses' working knowledge of autism spectrum disorders (ASDs). The current knowledge of school nurses was investigated by means of a mixed-method exploratory descriptive pilot study. Instrumentation included a scale that measured the knowledge of school nurses in regard to ASD, including medication usage and side effects, communication skills, safety issues, collaboration skills, and community resources. Survey results indicated that the majority of school nurses are knowledgeable about ASD, including symptomology and related medications. Results also suggested that school nurses are not as knowledgeable concerning communication skills, behavioral therapies, and safety issues. This study confirms a need for school nurses to enhance their knowledge of ASD, to familiarize themselves with the policy and health care networks that they collaborate with, and to communicate effectively with students, parents, educators, and community members in dealing with ASD. PMID- 19776228 TI - A policy change strategy for head lice management. AB - The purpose of this project was to formulate an effective change strategy for head lice management in a group of five separate school districts within one county. Despite a desire to use evidence to support their practice, school nurses often encounter educational system barriers that prevent independent management of health conditions. The use of collaborative community relationships, identification of underlying hierarchy structures in school policy development, and targeted system education were the catalysts for changing beliefs and ultimately policy within these school districts. The focus of this project was to develop a policy change strategy for head lice. The strategy provides direction for successful health policy advocacy using evidence-based practices for other health issues within the education setting. PMID- 19776209 TI - The mammalian ovary from genesis to revelation. AB - Two major functions of the mammalian ovary are the production of germ cells (oocytes), which allow continuation of the species, and the generation of bioactive molecules, primarily steroids (mainly estrogens and progestins) and peptide growth factors, which are critical for ovarian function, regulation of the hypothalamic-pituitary-ovarian axis, and development of secondary sex characteristics. The female germline is created during embryogenesis when the precursors of primordial germ cells differentiate from somatic lineages of the embryo and take a unique route to reach the urogenital ridge. This undifferentiated gonad will differentiate along a female pathway, and the newly formed oocytes will proliferate and subsequently enter meiosis. At this point, the oocyte has two alternative fates: die, a common destiny of millions of oocytes, or be fertilized, a fate of at most approximately 100 oocytes, depending on the species. At every step from germline development and ovary formation to oogenesis and ovarian development and differentiation, there are coordinated interactions of hundreds of proteins and small RNAs. These studies have helped reproductive biologists to understand not only the normal functioning of the ovary but also the pathophysiology and genetics of diseases such as infertility and ovarian cancer. Over the last two decades, parallel progress has been made in the assisted reproductive technology clinic including better hormonal preparations, prenatal genetic testing, and optimal oocyte and embryo analysis and cryopreservation. Clearly, we have learned much about the mammalian ovary and manipulating its most important cargo, the oocyte, since the birth of Louise Brown over 30 yr ago. PMID- 19776229 TI - Barriers to oral medication adherence for adolescents with inflammatory bowel disease. AB - OBJECTIVE: To identify family-reported, adherence-related barriers for adolescents with inflammatory bowel disease (IBD) and examine their relationship to 6-MP/azathioprine and 5-ASA medication adherence. METHODS: Participants included 74 adolescents, aged 13-17 years, diagnosed with IBD and their caregivers. Adolescents and caregivers jointly completed a measure of barriers to medication adherence. Adherence to medication was measured by family-report, pill count, and serum assay. RESULTS: Families endorsed one to seven total barriers to medication adherence. The most commonly reported barriers included forgetting, being away from home, and interference with an activity. Neither demographic nor disease severity variables were related to the total number of reported barriers. Fewer total reported barriers was related to better adherence by adolescent and maternal report. CONCLUSION: Most families experience at least one barrier to treatment adherence. Effective problem-solving around these barriers and its integration into future treatment protocols may help improve medication adherence in the pediatric IBD population. PMID- 19776230 TI - Validity of the Family Asthma Management System Scale with an urban African American sample. AB - OBJECTIVE: To examine the reliability and validity of the Family Asthma Management System Scale for low-income African-American children with poor asthma control and caregivers under stress. The FAMSS assesses eight aspects of asthma management from a family systems perspective. METHODS: Forty-three children, ages 8-13, and caregivers were interviewed with the FAMSS; caregivers completed measures of primary care quality, family functioning, parenting stress, and psychological distress. Children rated their relatedness with the caregiver, and demonstrated inhaler technique. Medical records were reviewed for dates of outpatient visits for asthma. RESULTS: The FAMSS demonstrated good internal consistency. Higher scores were associated with adequate inhaler technique, recent outpatient care, less parenting stress and better family functioning. Higher scores on the Collaborative Relationship with Provider subscale were associated with greater perceived primary care quality. CONCLUSIONS: The FAMSS demonstrated relevant associations with asthma management criteria and family functioning for a low-income, African-American sample. PMID- 19776231 TI - High interlaboratory reproducibility of matrix-assisted laser desorption ionization-time of flight mass spectrometry-based species identification of nonfermenting bacteria. AB - Matrix-assisted laser desorption ionization-time of flight mass spectrometry has emerged as a rapid, cost-effective alternative for bacterial species identification. Identifying 60 blind-coded nonfermenting bacteria samples, this international study (using eight laboratories) achieved 98.75% interlaboratory reproducibility. Only 6 of the 480 samples were misidentified due to interchanges (4 samples) or contamination (1 sample) or not identified because of insufficient signal intensity (1 sample). PMID- 19776232 TI - Reemergence of enterovirus 71 in 2008 in taiwan: dynamics of genetic and antigenic evolution from 1998 to 2008. AB - In recent years, enterovirus 71 (EV71) has been a cause of numerous outbreaks of hand-foot-and-mouth disease, with severe neurological complications in the Asia Pacific region. The reemergence in Taiwan of EV71 genotype B5 in 2008 resulted in the largest outbreak of EV71 in Taiwan in the past 11 years. Phylogenetic analyses indicated that dominant genotype changes from B to C or C to B occurred at least three times between 1986 and 2008. Furthermore, antigenic cartography of EV71 by using neutralization tests revealed that the reemerging EV71 genotype B5 strains formed a separate cluster which was antigenically distinct from the B4 and C genotypes. Moreover, analyses of full-length genomic sequences of EV71 circulating in Taiwan during this period showed the occurrence of intra- and interserotypic recombination. Therefore, continuous surveillance of EV71 including the monitoring of genetic evolution and antigenic changes is recommended and may contribute to the development of a vaccine for EV71. PMID- 19776234 TI - Biochemical characterization of the (nucleoside-2'O)-methyltransferase activity of dengue virus protein NS5 using purified capped RNA oligonucleotides (7Me)GpppAC(n) and GpppAC(n). AB - The flavivirus RNA genome contains a conserved cap-1 structure, (7Me)GpppA(2'OMe)G, at the 5' end. Two mRNA cap methyltransferase (MTase) activities involved in the formation of the cap, the (guanine-N7)- and the (nucleoside-2'O)-MTases (2'O-MTase), reside in a single domain of non-structural protein NS5 (NS5MTase). This study reports on the biochemical characterization of the 2'O-MTase activity of NS5MTase of dengue virus (NS5MTase(DV)) using purified, short, capped RNA substrates ((7Me)GpppAC(n) or GpppAC(n)). NS5MTase(DV) methylated both types of substrate exclusively at the 2'O position. The efficiency of 2'O-methylation did not depend on the methylation of the N7 position. Using (7Me)GpppAC(n) and GpppAC(n) substrates of increasing chain lengths, it was found that both NS5MTase(DV) 2'O activity and substrate binding increased before reaching a plateau at n=5. Thus, the cap and 6 nt might define the interface providing efficient binding of enzyme and substrate. K(m) values for (7Me)GpppAC(5) and the co-substrate S-adenosyl-L-methionine (AdoMet) were determined (0.39 and 3.26 microM, respectively). As reported for other AdoMet dependent RNA and DNA MTases, the 2'O-MTase activity of NS5MTase(DV) showed a low turnover of 3.25x10(-4) s(-1). Finally, an inhibition assay was set up and tested on GTP and AdoMet analogues as putative inhibitors of NS5MTase(DV), which confirmed efficient inhibition by the reaction product S-adenosyl-homocysteine (IC(50) 0.34 microM) and sinefungin (IC(50) 0.63 microM), demonstrating that the assay is sufficiently sensitive to conduct inhibitor screening and characterization assays. PMID- 19776233 TI - Large dissemination of VIM-2-metallo-{beta}-lactamase-producing pseudomonas aeruginosa strains causing health care-associated community-onset infections. AB - During a 3-year period (May 2005 to April 2008), a series of 45 outpatients presented with community-onset urinary tract infections due to carbapenem resistant Pseudomonas aeruginosa isolates. Forty of them had a history of previous hospitalization or exposure to healthcare facilities, while the remaining five had not been previously admitted to our healthcare facilities or elsewhere within the preceding 12 months. In 18 outpatients, the carbapenem resistant organisms caused recurrent community-onset urinary tract infections, while in three outpatients the organisms were also implicated in bacteremic episodes. All 45 single-patient P. aeruginosa isolates harbored the bla(VIM-2) metallo-beta-lactamase (MBL) gene in a common class 1 integron structure. They belonged to one predominant pulsed-field gel electrophoresis type and three sporadically detected types; two of the sporadic clonal types were identified among outpatients without previous exposure to healthcare facilities, while the predominant clonal type was also identified to cause infections in hospitalized patients. This is the first study documenting that MBL-producing P. aeruginosa isolates cause community-onset infections that are related or not with exposure to healthcare facilities. Community-onset infections in our patients most likely resulted from the nosocomial acquisition of MBL producers, followed by a prolonged digestive carriage. The high rate of recurrent infections in the community underlies the difficulty of constraining infections caused by such microorganisms in the extrahospital setting. PMID- 19776235 TI - Vitronectin receptors, alpha v integrins, are recognized by several non-RGD containing echoviruses in a continuous laboratory cell line and also in primary human Langerhans' islets and endothelial cells. AB - Previously published data suggest that the RGD-recognizing integrin, alphavbeta3, known as the vitronectin receptor, acts as a cellular receptor for RGD-containing enteroviruses, coxsackievirus A9 (CAV-9) and echovirus 9 (E-9), in several continuous cell lines as well as in primary human Langerhans' islets. As this receptor is also capable of binding the ligands by a non-RGD-dependent mechanism, we investigated whether vitronectin receptors, alpha v integrins, might act as receptors for other echoviruses that do not have the RGD motif. Blocking experiments with polyclonal anti-alphavbeta3 antibody showed that both primary human islets and a continuous laboratory cell line of green monkey kidney origin (GMK) are protected similarly from the adverse effects of several non-RGD containing echovirus (E-7, -11, -25, -30, -32) infections. In contrast, corresponding studies on primary human endothelial cells showed that the receptor works only for E-25, E-30, E-32 and CAV-9. The inhibitory effect of the antibody was not restricted to prototype strains of echoviruses, as GMK cells infected with several field isolates of the corresponding serotypes were also protected from virus-induced cytopathic effects. Co-localization of virus particles with the receptor molecules in both GMK and primary human endothelial cells was demonstrated by live-cell stainings and confocal microscopy. Remarkably, in spite of similar virus-receptor co-localization and a comparable protective effect of the alphavbeta3 antibody, the entry pathways of the studied virus strains seemed to be divergent. PMID- 19776236 TI - Specific hydrophobic residues in the alpha4 helix of lambdaCII are crucial for maintaining its tetrameric structure and directing the lysogenic choice. AB - The CII protein of the temperate bacteriophage lambda is the decision-making factor that determines the viral lytic/lysogenic choice. It is a homotetrameric transcription activator that recognizes and binds specific direct repeat sequences TTGCN(6)TTGC in the lambda genome. The quaternary structure of CII is held by a four-helix bundle. It is known that the tetrameric organization of CII is necessary for its activity, but the molecular mechanism behind this requirement is not known. By specific site-directed mutagenesis of hydrophobic residues in the alpha4 helix of CII that constitutes the four-helix bundle, we found that residues leu70, val74 and leu78 were crucial for maintaining the tetrameric structure of the protein. When any of these residues was substituted by a polar one, CII lost its activity and failed to promote lysogeny. This loss of activity was accompanied by the inability of CII to form tetramers, to bind DNA or to activate transcription. PMID- 19776237 TI - Glycoprotein G from pseudorabies virus binds to chemokines with high affinity and inhibits their function. AB - Pseudorabies virus (PRV), also known as suid herpesvirus, is the aetiological agent of Aujeszky's disease in swine. In other animals, except higher-order primates, PRV infection is often fatal. The mechanisms of PRV pathogenesis and immune modulation are largely unknown. PRV codes for 11 glycoproteins. Among them, glycoprotein G (gG) is the most abundant PRV protein found in the supernatant of PRV-infected cell cultures. PRV-gG has low amino acid sequence similarity with gG from other animal alphaherpesviruses and its function is unknown. gG from other animal alphaherpesviruses, with the exception of at least equine herpesvirus 4, binds to chemokines. We show here that PRV-gG binds to the human chemokine CL1 and several CC and CXC human chemokines with high affinity. Chemokine-binding activity can be detected in the supernatants of PRV-infected cell cultures, and insertional inactivation of the gene encoding gG from the PRV genome results in loss of chemokine-binding activity. Binding of PRV-gG to chemokines inhibits chemokine-mediated cell migration, suggesting a role for PRV gG in immune evasion. PMID- 19776239 TI - Involvement of the Fc gamma receptor IIA cytoplasmic domain in antibody-dependent enhancement of dengue virus infection. AB - Sub-neutralizing concentrations of antibody to dengue virus (DENV) enhance DENV infection of Fc gamma receptor-expressing cells. This phenomenon, referred to as antibody-dependent enhancement (ADE), has been hypothesized to be responsible for the severe form of DENV infection, including dengue haemorrhagic fever and dengue shock syndrome. To analyse further the mechanisms of ADE in vitro, this study introduced a series of cytoplasmic mutants into human Fc gammaRIIA. The mutated Fc gammaRIIA was then expressed on COS-7 cells to see whether these mutants could enhance DENV infection. Wild-type Fc gammaRIIA enhanced DENV infection, consistent with previous reports using Fc gammaR-positive monocytes. Disruption of the immune tyrosine activation motif (ITAM) in the cytoplasmic domain of Fc gammaRIIA or removing the sequences between the two ITAM regions eliminated ADE. These findings suggest that the specific structure of the Fc gammaRIIA cytoplasmic domain is essential for the ability of Fc gammaRIIA to mediate ADE. PMID- 19776238 TI - Genetic characterization of early isolates of Japanese encephalitis virus: genotype II has been circulating since at least 1951. AB - Japanese encephalitis virus (JEV) consists of five genotypes (GI-V). Phylogenetic characterization of 16 JEV strains isolated from the 'USSR', Japan and Korea during the 1930-1970s revealed that 15 strains fell into GIII, confirming that GIII was the predominant genotype of JEV in Japan and Korea between 1935 (isolation of the prototype strain; a GIII virus) and the 1990s (when GI supplanted GIII). One of the Korean isolates fell into GII, demonstrating that GII has been circulating for at least 19 years longer than previously thought. Formerly, GII was associated with endemic disease and this genotype had never been isolated north of Southern Thailand. Additionally, the northern border of GIII prevalence was extended from Japan to the 'USSR'. PMID- 19776240 TI - Capsid gene divergence in rabbit hemorrhagic disease virus. AB - The emergence and rapid global spread of rabbit hemorrhagic disease virus (RHDV) remains enigmatic despite two decades of study, largely due to the difficulties associated with modelling substitution processes of the RNA genome for phylogenetic inference. We used maximum-likelihood and Bayesian methods to investigate rates of molecular evolution in the capsid gene, finding evidence of positive selection and of variable substitution rates between nucleotide sites and between lineages. The maximum-likelihood and Bayesian analyses produced fully congruent topologies; however, strong support for older nodes of the phylogeny was only obtained from the Bayesian analyses that utilized the additional information of collection dates for RHDV isolates spanning 22 years. These dates also allowed calibration of the RHDV phylogenetic tree in a calendar year timescale and estimation of dates for the most recent common ancestors of virulent and benign strains. These dates suggested the divergence of RHDV approximately 20 years prior to the first report of haemorrhagic disease in rabbits. PMID- 19776241 TI - HLA-C is necessary for optimal human immunodeficiency virus type 1 infection of human peripheral blood CD4 lymphocytes. AB - The hypothesis that open conformers of HLA-C on target cells might directly exert an effect on their infectability by human immunodeficiency virus (HIV) has been suggested previously. This was tested by exploiting the peculiar specificity of monoclonal antibody (mAb) L31 for HLA-C open conformers to show that normal levels of Env-driven fusion were restored in HLA-C transfectants of a major histocompatibility complex-deleted (fusion-incompetent) cell line. The physiological relevance of this finding is now confirmed in this report, where small interfering RNA (siRNA) technology was used to silence HLA-C expression in peripheral blood lymphocytes (PBLs) from 11 healthy donors. Infectability by HIV (strains IIIB and Bal and primary isolates) was significantly reduced (P=0.016) in silenced cells compared with cells that maintained HLA-C expression in 10 of the 11 PBL donors. Normal infectability was resumed, together with HLA-C expression, when the effect of siRNA interference waned after several days in culture. Additional confirmation of the HLA-C effect was obtained in several assays employing HLA-C-positive and -negative cell lines, a number of HIV strains and also pseudoviruses. In particular, viruses pseudotyped with env genes from HIV strains AC10 and QH0692.42 were assayed on siRNA-silenced lymphocytes from three healthy donors: the differences in infection with pseudoviruses were even higher than those observed in infections with normal viruses. PMID- 19776242 TI - Neutralization of feline immunodeficiency virus by antibodies targeting the V5 loop of Env. AB - Neutralizing antibodies (NAbs) play a vital role in vaccine-induced protection against infection with feline immunodeficiency virus (FIV). However, little is known about the appropriate presentation of neutralization epitopes in order to induce NAbs effectively; the majority of the antibodies that are induced are directed against non-neutralizing epitopes. Here, we demonstrate that a subtype B strain of FIV, designated NG4, escapes autologous NAbs, but may be rendered neutralization-sensitive following the insertion of two amino acids, KT, at positions 556-557 in the fifth hypervariable (V5) loop of the envelope glycoprotein. Consistent with the contribution of this motif to virus neutralization, an additional three subtype B strains retaining both residues at the same position were also neutralized by the NG4 serum, and serum from an unrelated cat (TOT1) targeted the same sequence in V5. Moreover, when the V5 loop of subtype B isolate KNG2, an isolate that was moderately resistant to neutralization by NG4 serum, was mutated to incorporate the KT motif, the virus was rendered sensitive to neutralization. These data suggest that, even in a polyclonal serum derived from FIV-infected cats following natural infection, the primary determinant of virus-neutralizing activity may be represented by a single, dominant epitope in V5. PMID- 19776244 TI - Commentary: Societal influences on cardiovascular disease: time to assess and act. PMID- 19776243 TI - A systematic review and meta-analysis of perinatal variables in relation to the risk of testicular cancer--experiences of the mother. AB - BACKGROUND: We undertook a systematic review and meta-analysis of perinatal variables in relation to testicular cancer risk, with a specific focus upon characteristics of the mother. METHODS: EMBASE, PubMed, Scopus and Web of Science databases were searched using sensitive search strategies. Meta-analysis was undertaken using STATA 10. RESULTS: A total of 5865 references were retrieved, of which 67 met the inclusion criteria and contributed data to at least one perinatal analysis. Random effects meta-analysis found maternal bleeding during pregnancy [odds ratio (OR) 1.33, 95% confidence interval (CI) 1.02-1.73], birth order (primiparous vs not, 1.08, 95% CI 1.01-1.16; second vs first, OR 0.94, 95% CI 0.88-0.99; third vs first, OR 0.91, 95% CI 0.83-1.01; fourth vs first, OR 0.80, 95% CI 0.69-0.94) and sibship size (2 vs 1, OR 0.93, 95% CI 0.75-1.15; 3 vs 1, OR 0.89, 95% CI 0.74-1.07; 4 vs 1, OR 0.75, 95% CI 0.62-0.90) to be associated with testicular cancer risk. Meta-analyses that produced summary estimates which indicated no association included maternal age, maternal nausea, maternal hypertension, pre-eclampsia, breech delivery and caesarean section. Meta regression provided evidence that continent of study is important in the relationship between caesarean section and testicular cancer (P = 0.035), and a meta-analysis restricted to the three studies from the USA was suggestive of association (OR 1.67, 95% CI 1.07-2.56). CONCLUSIONS: This systematic review and meta-analysis has found evidence for associations of maternal bleeding, birth order, sibship size and possibly caesarean section with risk of testicular cancer. PMID- 19776246 TI - Commentary: External validity of results of randomized trials: disentangling a complex concept. PMID- 19776245 TI - Association between a 15q25 gene variant, smoking quantity and tobacco-related cancers among 17 000 individuals. AB - BACKGROUND: Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens. METHODS: We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies. RESULTS: Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96-1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39-2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23 1.38, P = 1 x 10(-18)), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19-1.35, P = 5 x 10(-13)). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01-1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour. CONCLUSIONS: This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers. PMID- 19776247 TI - Radio-toxicity of spent fuel of the advanced heavy water reactor. AB - The Advanced Heavy Water Reactor (AHWR) is a new power reactor concept being developed at Bhabha Atomic Research Centre, Mumbai. The reactor retains many desirable features of the existing Pressurised Heavy Water Reactor (PHWR), while incorporating new, advanced safety features. The reactor aims to utilise the vast thorium resources available in India. The reactor core will use plutonium as the make-up fuel, while breeding (233)U in situ. On account of this unique combination of fuel materials, the operational characteristics of the fuel as determined by its radioactivity, decay heat and radio-toxicity are being viewed with great interest. Radio-toxicity of the spent fuel is a measure of potential radiological hazard to the members of the public and also important from the ecological point of view. The radio-toxicity of the AHWR fuel is extremely high to start with, being approximately 10(4) times that of the fresh natural U fuel used in a PHWR, and continues to remain relatively high during operation and subsequent cooling. A unique feature of this fuel is the peak observed in its radio-toxicity at approximately 10(5) y of decay cooling. The delayed increase in fuel toxicity has been traced primarily to a build-up of (229)Th, (230)Th and (226)Ra. This phenomenon has been observed earlier for thorium-based fuels and is confirmed for the AHWR fuel. This paper presents radio-toxicity data for AHWR spent fuel up to a period of 10(6) y and the results are compared with the radio toxicity of PHWR. PMID- 19776248 TI - Physiological response to extreme fasting in subantarctic fur seal (Arctocephalus tropicalis) pups: metabolic rates, energy reserve utilization, and water fluxes. AB - Surviving prolonged fasting requires various metabolic adaptations, such as energy and protein sparing, notably when animals are simultaneously engaged in energy-demanding processes such as growth. Due to the intermittent pattern of maternal attendance, subantarctic fur seal pups have to repeatedly endure exceptionally long fasting episodes throughout the 10-mo rearing period while preparing for nutritional independence. Their metabolic responses to natural prolonged fasting (33.4 +/- 3.3 days) were investigated at 7 mo of age. Within 4 6 fasting days, pups shifted into a stage of metabolic economy characterized by a minimal rate of body mass loss (0.7%/day) and decreased resting metabolic rate (5.9 +/- 0.1 ml O(2)xkg(-1)xday(-1)) that was only 10% above the level predicted for adult terrestrial mammals. Field metabolic rate (289 +/- 10 kJxkg(-1)xday( 1)) and water influx (7.9 +/- 0.9 mlxkg(-1)xday(-1)) were also among the lowest reported for any young otariid, suggesting minimized energy allocation to behavioral activity and thermoregulation. Furthermore, lean tissue degradation was dramatically reduced. High initial adiposity (>48%) and predominant reliance on lipid catabolism likely contributed to the exceptional degree of protein sparing attained. Blood chemistry supported these findings and suggested utilization of alternative fuels, such as beta-hydroxybutyrate and de novo synthesized glucose from fat-released glycerol. Regardless of sex and body condition, pups tended to adopt a convergent strategy of extreme energy and lean body mass conservation that appears highly adaptive for it allows some tissue growth during the repeated episodes of prolonged fasting they experience throughout their development. PMID- 19776250 TI - Evolutionary structural and functional conservation of an ortholog of the GLUT2 glucose transporter gene (SLC2A2) in zebrafish. AB - In mammals, GLUT2 plays an essential role in glucose homeostasis. From an evolutionary perspective, relatively little is known about the biology of GLUT2, or other GLUTs, in nonmammalian vertebrates. Here, we have conducted studies to functionally characterize GLUT2 in zebrafish. First, we cloned the zebrafish ortholog of GLUT2 (zfGLUT2) encoding a protein of 504 amino acids with high sequence identity to other known vertebrate GLUT2 proteins. The zfGLUT2 gene consists of 11 exons and 10 introns, spanning 20 kb and mapping to a region of chromosome 2 that exhibits conserved synteny with human chromosome 3. When expressed in Xenopus oocytes, zfGLUT2 transported 2-deoxyglucose (2-DG) with similar affinity than mammalian GLUT2 (K(m) of 11 mM). Transport of 2-DG was competed mostly by D-fructose and D-mannose and was inhibited by cytochalasin B. During early development, zfGLUT2 expression was detected already at 10 h postfertilization and remained elevated in 5-day larvae, when it was clearly localized to the liver and intestinal bulb. In the adult, zfGLUT2 expression was highest in testis, brain, skin, kidney, and intestine, followed by liver and muscle. In the intestine, zfGLUT2 transcripts were detected in absorptive enterocytes, and its mRNA levels were altered by fasting and refeeding, suggesting that its expression in the intestine may be regulated by the nutritional status. These results indicate that the structure and function of GLUT2 has been remarkably well conserved during vertebrate evolution and open the way for the use of zebrafish as a model species in which to study the biology and pathophysiology of GLUT2. PMID- 19776249 TI - Insulin-like growth factor-II regulates maternal hemodynamic adaptation to pregnancy in rats. AB - The relationship between maternal plasma volume (PV) expansion and fetal growth is well established, but the underlying mechanisms remain unclear. Here, we examined the influence of maternal body weight and fetoplacental mass on gestational PV increment in the rat. Because IGF-I and IGF-II have growth promoting and vasoactive properties, their relationship to PV expansion and fetoplacental growth was also studied. In normal rats, the gradual expansion of PV (+35% at day 22, i.e., term) was accompanied by a rise in circulating IGF-II (+45%) and a considerable drop in IGF-I (-73%). Increased maternal body weight induced by an obesogenic diet did not influence PV and circulating IGFs compared with rats on the standard diet. Combining the results from both diets, circulating IGF-II was the principal correlate of PV. A second experiment examined the effect of fetoplacental mass reduction by surgically removing half of the gestational sacs at day 16. This procedure reduced maternal PV and circulating IGF-II at term by 14% and 20%, respectively. We then investigated the effect of a constant infusion of IGF-II (1 mgxkg(-1)xday(-1)) from day 16, which raised circulating IGF-II by 38% and found increased PV (+19%) and a larger placental trophospongial area (+29%) at term. Our results indicate that the placenta, the primary source of IGF-II synthesis in pregnancy, drives PV expansion, and that IGF-II is among the regulatory factors of the gestational PV increment. Further studies should clarify whether IGF-II directly affects vascular function and/or indirectly promotes the secretion of placenta-derived vasoactive substances. PMID- 19776251 TI - Whey protein potentiates the intestinotrophic action of glucagon-like peptide-2 in parenterally fed rats. AB - Glucagon-like peptide-2 (GLP-2) is a nutrient-regulated intestinotrophic hormone derived from proglucagon in the distal intestine. Enteral nutrients (EN) potentiate the action of GLP-2 to reverse parenteral nutrition (PN)-induced mucosal hypoplasia. The objective was to determine what enteral protein component, casein, soy, or whey protein, potentiates the intestinal growth response to GLP-2 in rats with PN-induced mucosal hypoplasia. Rats received PN and continuous intravenous infusion of GLP-2 (100 microg/kg/day) for 7 days. Six EN groups received PN+GLP-2 for days 1-3 and partial PN+GLP-2 plus EN for days 4 7. EN was provided by ad libitum intake of a semielemental liquid diet with different protein sources: casein, hydrolyzed soy, whey protein concentrate (WPC), and hydrolyzed WPC+casein. Controls received PN+GLP-2 alone. EN induced significantly greater jejunal sucrase activity and gain of body weight, and improved feed efficiency compared with PN+GLP-2 alone. EN induced greater ileal proglucagon expression, increased plasma concentration of bioactive GLP-2 by 35%, and reduced plasma dipeptidyl peptidase IV (DPP-IV) activity compared with PN+GLP 2 alone, P < 0.05. However, only whey protein, and not casein or soy, potentiated the ability of GLP-2 to reverse PN-induced mucosal hypoplasia and further increase ileal villus height, crypt depth, and mucosa cellularity compared with PN+GLP-2 alone, P < 0.05. The ability of whey protein to induce greater mucosal surface area was associated with decreased DPP-IV activity in ileum and colon compared with casein, soy, or PN+GLP-2 alone, P < 0.05. In conclusion, whey protein potentiates the action of GLP-2 to reverse PN-induced mucosal hypoplasia in association with decreased intestinal DPP-IV activity. PMID- 19776252 TI - Natural antibodies and complement modulate intimal thickening after arterial injury. AB - Immune factors are involved in modulating neointimal response to arterial wall injury, but the role of individual immune effectors in this response remains unclear. Using a carotid cuff injury model in mice, we tested the role of immunoglobulin isotypes in modulating intimal thickening by using adoptive transfer of splenocytes from WT mice, or the direct administration of IgG or IgM into immune-deficient Rag-1-/- [Rag-1 knockout (Rag-1KO)] mice. The direct role of complement was also tested by depletion of complement. Splenocytes from WT mice were isolated and adoptively transferred to Rag-1KO mice subjected to carotid cuff arterial injury. Transfer of splenocytes to Rag-1KO mice resulted in increased serum IgM and IgG within 48 h and were comparable to WT levels by 21 days after injury. Splenocyte transfer in Rag-1KO decreased intimal area by 40% compared with Rag-1KO mice without cell transfer. To further differentiate the relative contribution of IgM or IgG in reducing intimal thickening, additional groups of Rag-1KO mice were subjected to injury and given intravenous injections of pooled mouse IgG or IgM. Both IgG and IgM treatment significantly reduced intimal thickening compared with untreated Rag-1KO mice. Immunoglobulin treatments modified serum complement C3 profile and decreased C3 presence in injured arteries. Depletion of C3 using cobra venom factor in Rag-1KO mice significantly decreased intimal thickening. Our results identify the direct role of natural IgG and IgM, and complement in the modulation of neointimal response to arterial injury. PMID- 19776253 TI - Tissue-specific PAI-1 gene expression and glycosylation pattern in insulin resistant old rats. AB - Increased levels of plasminogen activator inhibitor-1 (PAI-1) have been associated with obesity, aging, insulin resistance, and type 2 diabetes, conditions that contribute to increased cardiovascular risk. PAI-1 is expressed in a variety of tissues, but the cellular origin of plasma PAI-1 is unknown. To link insulin resistance, aging, and cardiovascular disease, we examined the expression and glycosylation pattern of PAI-1 in liver and white adipose tissue (WAT) from adult (3 mo) and insulin-resistant old (24 mo) Wistar rats. Glycosylated PAI-1 protein was also purified by affinity chromatography from endothelial culture supernatans to analyze its inhibitory activity. We also analyzed the contribution of adipocytes and stromal vascular cells from WAT to PAI-1 levels with aging. Aging caused a significant increase of PAI-1 mRNA (P < 0.001) in WAT that was predominantly due to the adipocytes and not to stroma vascular cells, while there was no modification in liver from aged rats. Moreover, PAI-1 expression increased during preadipocyte differentiation (P < 0.001). Furthermore, we found a tissue-dependent PAI-1 glycosylation pattern: adipose tissue only expresses the glycosylated PAI-1 form, whereas the liver mainly expresses the nonglycosylated form. Finally, we also found evidences suggesting that the glycosylated PAI-1 form shows higher inhibitory activity than the nonglycosylated. Our data suggest that WAT may be a major source of the elevated plasma levels of PAI-1 in insulin-resistant old rats. Additionally, the high degree of PAI-1 glycosylation and activity, together with the significant increase in visceral fat in old rats, may well contribute to an increased cardiovascular risk associated with insulin-resistant states. PMID- 19776254 TI - The implicit theories of rape-prone men: an information-processing investigation. AB - It has been hypothesised that sexual offenders hold offence-supportive implicit theories (ITs) or schemata. This study aims to determine whether rape-prone men hold the same offence-supportive ITs as those that have been identified in rapists. This study adopts both an explicit and an implicit measure of ITs (a lexical decision task). In the lexical decision task, participants are primed with an incomplete sentence before being presented with a target word. The target word completes the sentence in either a rape-supportive or a non-rape-supportive manner. The authors predict that men higher on proclivity to rape-who presumably hold strong mental representations of rape-supportive themes-would be faster to respond to word completions that are rape supportive relative to men lower on rape proclivity. Using multiple regressions to determine the relative contributions of both explicit and implicit measures for predicting rape proclivity, the authors find that only the explicit self-report questionnaire was significantly related to a person's rape proclivity score. PMID- 19776255 TI - Perspectives of colorectal cancer risk and screening among Dominicans and Puerto Ricans: stigma and misperceptions. AB - Colorectal cancer is the second most common cancer among Latinos, but a lower percentage of Latinos are screened than Whites and Blacks. Along with recognized economic barriers, differences in knowledge and perceptions might impede colorectal screening among Latinos. We conducted 147 individual, qualitative interviews with Dominicans and Puerto Ricans in the northeastern United States to explore their explanatory models for colorectal cancer and screening barriers. Many participants had not previously heard of colorectal cancer. The most commonly mentioned cause of colorectal cancer was anal sex. Also considered risks were "bad food," digestion leading to constipation, and strained bowel movements. Screening barriers included stigma, misperceptions, embarrassment, and machismo. Progress toward increasing colorectal cancer screening requires normalization of this screening among Latinos. Higher patient familiarity, along with improved physician counseling and referral, might contribute to reducing stigma and other barriers, and to enhancing knowledge and Latino community support of colorectal cancer screening. PMID- 19776256 TI - Cooperation and conflict in qualitative research: a dialectical approach to knowledge production. AB - Our goal with this article is to present a dialectical approach to examining the interaction between researchers and research participants. A dialectical approach maintains that an apparent contradiction at one level might, in fact, be integrated as a synthesis of the two opposing poles at a higher level of conceptual analysis. We claim that a research approach advocating either pole might limit understanding of the complexity of the phenomenon in question. The interaction between researchers and research participants might be conceived of as creating a continuum ranging from cooperation to conflict. We adopt a dialectical perspective, and propose a whole spectrum of interactive styles between cooperation and conflict. Although some of these interactions might be perceived as a hindrance to knowledge production, we treat them as opportunities for the production of knowledge and the enhancement of interests of the study's target population. PMID- 19776257 TI - Ryanodine receptors are regulated by the circadian clock and implicated in gating photic entrainment. PMID- 19776258 TI - Role of melastatin-related transient receptor potential channel TRPM1 in the retina: Clues from horses and mice. PMID- 19776259 TI - Control of CNS synapse development by {gamma}-protocadherin-mediated astrocyte neuron contact. AB - Recent studies indicate that astrocytes, whose processes enwrap synaptic terminals, promote synapse formation both by releasing soluble factors and through contact-dependent mechanisms. Although astrocyte-secreted synaptogenic factors have been identified, the molecules underlying perisynaptic astroctye neuron contacts are unknown. Here we show that the gamma-protocadherins (gamma Pcdhs), a family of 22 neuronal adhesion molecules encoded by a single gene cluster, are also expressed by astrocytes and localize to their perisynaptic processes. Using cocultures in which either astrocytes or neurons are Pcdh-gamma null, we find that astrocyte-neuron gamma-Pcdh contacts are critical for synaptogenesis in developing cultures. Synaptogenesis can eventually proceed among neurons cocultured with Pcdh-gamma-null astrocytes, but only if these neurons themselves express the gamma-Pcdhs. Consistent with this, restricted mutation of the Pcdh-gamma cluster in astrocytes in vivo significantly delays both excitatory and inhibitory synapse formation. Together, these results identify the first known contact-dependent mechanism by which perisynaptic astrocyte processes promote synaptogenesis. PMID- 19776261 TI - Changes in rapid eye movement sleep associated with placebo-induced expectations and analgesia. AB - The experience of a sensory event is extensively shaped by past experience and expectations. Placebo analgesia, one of the most studied models of expectation mediated effects, can be induced by suggestion of analgesia and conditioning. The present study examined the possibility that sleep might contribute to the consolidation of new expectations and consequently influence the generation of expectation-mediated placebo effects. Strong expectations of analgesia were generated before sleep by conditioning manipulations wherein the intensity of thermal pain stimulation was surreptitiously reduced after the application of a topical placebo cream. Expectations and placebo analgesic effects were measured the following morning and compared with those of a control daytime group without sleep. Although placebo effects were observed in both groups, correlation analysis suggests that the mediating effect of expectations on placebo responses was strongest in the overnight group. Moreover, after exposure to a convincing analgesia experience, the relative duration of rapid eye movement (REM) sleep decreased in subjects showing higher analgesic expectations and placebo responses the next morning. In a third group exposed to less consistent analgesic experiences before sleep, expectations reported in the morning were comparable with other groups. However, expectations were positively correlated with REM sleep and did not emerge as a significant mediator of the analgesic effect. Together, these findings show that sleep-related processes may influence the association between expectations and placebo analgesia and that REM sleep can predict placebo-induced expectations of pain relief. However, equivocal previous experience with treatments may significantly alter the relationship between relief expectation, REM sleep, and placebo effects. PMID- 19776260 TI - Distinct inhibitory neurons exert temporally specific control over activity of a motoneuron receiving concurrent excitation and inhibition. AB - Recent work suggests that concurrent excitation and inhibition originating in central pattern generators (CPGs) may be used to control rhythmic motoneuronal activity. The specific roles that the inhibition plays in such cases are not well understood, however, in part because of the lack of identification of presynaptic inhibitory neurons. Here we demonstrate that, in the Aplysia feeding CPG, inhibitory inputs may be critical for flexible control of the activity of motoneurons in different forms of behavior. The feeding CPG generates ingestive and egestive motor programs, differing in the high and low activity, respectively, of the motoneuron B8 during the retraction phase of the programs. We show that, during retraction, B8 receives concurrent excitation and inhibition that produces a high-conductance state. The inhibition originates in two types of CPG neurons, B4/5 and B70, that are more active in egestion than ingestion and play a role in suppressing B8 activity during egestion. In turn, the activities of both B4/5 and B70 are suppressed by the ingestion-promoting descending interneuron CBI-3 (for cerebral-buccal interneuron 3). Thus, concurrent excitation and inhibition may be an effective means of controlling motoneuronal activity in a behavior-dependent manner. More detailed analyses reveal, furthermore, that B4/5 and B70 exert complementary actions by acting preferentially in the early and late part of retraction, respectively. Thus, the use of multiple neurons to generate inhibitory inputs to motoneurons that receive concurrent excitation and inhibition brings an additional level of flexibility that allows a temporally specific control of motoneuronal activity within a single phase of motor programs. PMID- 19776262 TI - "Black" responses dominate macaque primary visual cortex v1. AB - Achromatic visual information is transferred from the retina to the brain through two parallel channels: ON-center cells carry "white" information and OFF-center cells "black" information (Nelson et al., 1978; Schiller, 1982; Schiller et al., 1986). Responses of ON and OFF retinal and thalamic neurons are approximately equal in magnitude (Kruger and Fischer, 1975; Kremers et al., 1993), but psychophysical studies have shown that humans detect light decrements (black) better and faster than increments (white) (Blackwell, 1946; Short, 1966; Krauskopf, 1980; Whittle, 1986; Bowen et al., 1989; Chan and Tyler, 1992; Kontsevich and Tyler, 1999; Chubb and Nam, 2000; Dannemiller and Stephens, 2001). From recordings of single-cell activity in the macaque monkey's primary visual cortex (V1), we found that black-dominant neurons substantially outnumbered white dominant neurons in the corticocortical output layers 2/3, but the numbers of black- and white-dominant neurons were nearly equal in the thalamocortical input layer 4c. These results strongly suggest that the black-over-white preference is generated or greatly amplified in V1. The predominance of OFF neurons in layers 2/3 of V1, which provide visual input to higher cortical areas, may explain why human subjects detect black more easily than white. Furthermore, our results agree with human EEG and fMRI findings that V1 responses to decrements are stronger than to increments, though the OFF/ON imbalance we found in layers 2/3 of macaque V1 is much larger than in the whole V1 population in the human V1 experiments (Zemon et al., 1988, 1995; Olman et al., 2008). PMID- 19776263 TI - Motoneuron transplantation rescues the phenotype of SMARD1 (spinal muscular atrophy with respiratory distress type 1). AB - Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is a fatal form of infantile motoneuron disease. There is currently no effective treatment, although motor neuron replacement is a possible therapeutic strategy. We transplanted purified motor neurons into the spinal cord of nmd mice, an animal model of SMARD1. We also administered pharmacological treatment targeting the induction of axonal growth toward skeletal muscle target. At the end stage of the disease, donor-derived motor neurons were detected in the nmd anterior horns, extended axons into the ventral roots, and formed new neuromuscular junctions. These data correlated with improved neuromuscular function and increased life spans. The neuroprotective effect was associated with a reduction in proinflammatory molecules in treated spinal cords. This is the first report that functional restoration of motor units with transplanted motoneurons is feasible in an animal model of a human motoneuron disease, opening up new possibilities for therapeutic intervention. PMID- 19776264 TI - Heterogeneity in subcortical brain development: A structural magnetic resonance imaging study of brain maturation from 8 to 30 years. AB - Brain development during late childhood and adolescence is characterized by decreases in gray matter (GM) and increases in white matter (WM) and ventricular volume. The dynamic nature of development across different structures is, however, not well understood, and the present magnetic resonance imaging study took advantage of a whole-brain segmentation approach to describe the developmental trajectories of 16 neuroanatomical volumes in the same sample of children, adolescents, and young adults (n = 171; range, 8-30 years). The cerebral cortex, cerebral WM, caudate, putamen, pallidum, accumbens area, hippocampus, amygdala, thalamus, brainstem, cerebellar GM, cerebellar WM, lateral ventricles, inferior lateral ventricles, third ventricle, and fourth ventricle were studied. The cerebral cortex was further analyzed in terms of lobar thickness and surface area. The results revealed substantial heterogeneity in developmental trajectories. GM decreased nonlinearly in the cerebral cortex and linearly in the caudate, putamen, pallidum, accumbens, and cerebellar GM, whereas the amygdala and hippocampus showed slight, nonlinear increases in GM volume. WM increased nonlinearly in both the cerebrum and cerebellum, with an earlier maturation in cerebellar WM. In addition to similarities in developmental trajectories within subcortical regions, our results also point to differences between structures within the same regions: among the basal ganglia, the caudate showed a weaker relationship with age than the putamen and pallidum, and in the cerebellum, differences were found between GM and WM development. These results emphasize the importance of studying a wide range of structural variables in the same sample, for a broader understanding of brain developmental principles. PMID- 19776265 TI - Transformation of polarized light information in the central complex of the locust. AB - Many insects perceive the E-vector orientation of polarized skylight and use it for compass navigation. In locusts, polarized light is detected by photoreceptors of the dorsal rim area of the eye. Polarized light signals from both eyes are integrated in the central complex (CC), a group of neuropils in the center of the brain. Thirteen types of CC neuron are sensitive to dorsally presented, polarized light (POL-neurons). These neurons interconnect the subdivisions of the CC, particularly the protocerebral bridge (PB), the upper and lower divisions of the central body (CBU, CBL), and the adjacent lateral accessory lobes (LALs). All POL neurons show polarization-opponency, i.e., receive excitatory and inhibitory input at orthogonal E-vector orientations. To provide physiological evidence for the direction of information flow through the polarization vision network in the CC, we analyzed the functional properties of the different cell types through intracellular recordings. Tangential neurons of the CBL showed highest signal-to noise ratio, received either ipsilateral polarized-light input only or, together with CL1 columnar neurons, had eccentric receptive fields. Bilateral polarized light inputs with zenith-centered receptive fields were found in tangential neurons of the PB and in columnar neurons projecting to the LALs. Together with other physiological parameters, these data suggest a flow of information from the CBL (input) to the PB and from here to the LALs (output). This scheme is supported by anatomical data and suggests transformation of purely sensory E vector coding at the CC input stage to position-invariant coding of 360 degrees compass directions at the output stage. PMID- 19776266 TI - Laminin alters fyn regulatory mechanisms and promotes oligodendrocyte development. AB - Mutations in LAMA2, the gene for the extracellular matrix protein laminin-alpha2, cause a severe muscular dystrophy termed congenital muscular dystrophy type-1A (MDC1A). MDC1A patients have accompanying CNS neural dysplasias and white matter abnormalities for which the underlying mechanisms remain unknown. Here, we report that in laminin-deficient mice, oligodendrocyte development was delayed such that oligodendrocyte progenitors accumulated inappropriately in adult brains. Conversely, laminin substrates were found to promote the transition of oligodendrocyte progenitors to newly formed oligodendrocytes. Laminin-enhanced differentiation was Src family kinase-dependent and resulted in the activation of the Src family kinase Fyn. In laminin-deficient brains, however, increased Fyn repression was accompanied by elevated levels of the Src family kinase negative regulatory proteins, Csk (C-terminal Src kinase), and its transmembrane adaptor, Cbp (Csk-binding protein). These findings indicate that laminin deficiencies delay oligodendrocyte maturation by causing dysregulation of signaling pathways critical for oligodendrocyte development, and suggest that a normal role for CNS laminin is to promote the development of oligodendrocyte progenitors into myelin forming oligodendrocytes via modulation of Fyn regulatory molecules. PMID- 19776267 TI - A novel postsynaptic group II metabotropic glutamate receptor role in modulating baroreceptor signal transmission. AB - The nucleus tractus solitarius (NTS) is essential for orchestrating baroreflex control of blood pressure. When a change in blood pressure occurs, the information is transmitted by baroreceptor afferent fibers to the central network by glutamate binding to ionotropic glutamate receptors on second-order baroreceptor neurons. Glutamate also activates presynaptic group II and III metabotropic glutamate receptors (mGluRs), depressing both glutamate and GABA release to modulate baroreceptor signal transmission. Here we present a novel role for postsynaptic group II mGluRs to further fine-tune baroreceptor signal transmission at the first central synapses. In a brainstem slice with ionotropic glutamate and GABA receptors blocked, whole-cell patch-clamp recordings of second order baroreceptor neurons revealed that two group II mGluR agonists evoked concentration-dependent membrane hyperpolarizations. The hyperpolarization remained when a presynaptic contribution was prevented with Cd(2+), was blocked by a postsynaptic intervention of intracellular dialysis of the G-protein signaling inhibitor, was mimicked by endogenous release of glutamate by tractus solitarius stimulation, and was prevented by a group II mGluR antagonist. Postsynaptic localization of group II mGluRs was confirmed by fluorescent confocal immunohistochemistry and light microscopy. Group II mGluR induced currents consisted of voltage-dependent outward and inward components, prevented by tetraethylammonium chloride and tetrodotoxin, respectively. In contrast to group II mGluR-induced hyperpolarization, there was no effect on intrinsic excitability as determined by action potential shape or firing in response to depolarizing current injections. The data suggest a novel mechanism for postsynaptic group II mGluRs to fine-tune baroreceptor signal transmission in the NTS. PMID- 19776268 TI - Reliable and precise neuronal firing during sensory plasticity in superficial layers of primary somatosensory cortex. AB - Neocortical neurons show astonishing variation in the presence and timing of action potentials across stimulus trials, a phenomenon whose function and significance has been the subject of great interest. Here we present data showing that this response variability can be significantly reduced by altered sensory experience. Removal of all but one whisker from the side of the mouse face results in the rapid (within 24 h) potentiation of mean firing rates within the cortical representation of the spared whisker in young postnatal animals (postnatal days 13-16). Analysis of single-unit responses from whisker-spared animals shows that this potentiation can be attributed to an enhancement of trial to-trial reliability (i.e., reduced response failures), as well as an increase in the mean number of spikes evoked within a successful trial. Changes were confined to superficial layers 2/3 and were not observed in the input layer of the cortex, layer 4. In addition to these changes in firing rates, we also observed profound changes in the precise timing of sensory-evoked responses. Trial-to-trial temporal precision was enhanced and the absolute latency of responses was reduced after single-whisker experience. Enhanced spike-timing precision and trial-to trial reliability could also be triggered in adolescent animals with longer periods (7 d) of single-whisker experience. These experiments provide a quantitative analysis of how sensory experience can enhance both reliability and temporal precision in neocortical neurons and provide a framework for testing specific hypotheses about the role of response variability in cortical function and the molecular mechanisms underlying this phenomenon. PMID- 19776270 TI - Coding of visual space during motor preparation: Approaching objects rapidly modulate corticospinal excitability in hand-centered coordinates. AB - Defensive behaviors, such as withdrawing your hand to avoid potentially harmful approaching objects, rely on rapid sensorimotor transformations between visual and motor coordinates. We examined the reference frame for coding visual information about objects approaching the hand during motor preparation. Subjects performed a simple visuomanual task while a task-irrelevant distractor ball rapidly approached a location either near to or far from their hand. After the distractor ball appearance, single pulses of transcranial magnetic stimulation were delivered over the subject's primary motor cortex, eliciting motor evoked potentials (MEPs) in their responding hand. MEP amplitude was reduced when the ball approached near the responding hand, both when the hand was on the left and the right of the midline. Strikingly, this suppression occurred very early, at 70 80 ms after ball appearance, and was not modified by visual fixation location. Furthermore, it was selective for approaching balls, since static visual distractors did not modulate MEP amplitude. Together with additional behavioral measurements, we provide converging evidence for automatic hand-centered coding of visual space in the human brain. PMID- 19776269 TI - Discharge profiles of identified GABAergic in comparison to cholinergic and putative glutamatergic basal forebrain neurons across the sleep-wake cycle. AB - Whereas basal forebrain (BF) cholinergic neurons are known to participate in processes of cortical activation during wake (W) and paradoxical sleep (PS or P, also called REM sleep), codistributed GABAergic neurons have been thought to participate in processes of cortical deactivation and slow-wave sleep (SWS or S). To learn the roles the GABAergic neurons might play, in relation to cholinergic and glutamatergic neurons, we juxtacellularly recorded and labeled neurons during natural sleep-wake states in head-fixed rats. Neurobiotin (Nb)-labeled cells were identified immunohistochemically as choline acetyltransferase (ChAT)+, glutamic acid decarboxylase (GAD)+, or ChAT-/GAD-. Of the latter, some were identified as glutamatergic by immunostaining of their terminals with the vesicular glutamate transporter (VGluT2). In contrast to ChAT+ neurons, which all discharged maximally during W and PS, GAD+ neurons comprised multiple sleep-wake subgroups. Some GABAergic neurons discharged maximally during W and PS, as WP-max active cells (36%), and in positive correlation with gamma electroencephalographic (EEG) activity. Some discharged maximally during SWS, as S-max active cells (28%), and in positive correlation with delta EEG activity. Others increased their discharge progressively during sleep to discharge maximally during PS, as P-max active cells (36%), and in negative association with electromyographic (EMG) activity. ChAT-/GAD- cells comprised WP-max (46%), S-max (17%), P-max (17%), and W-max active cells (14%), whose discharge was positively correlated with EMG activity. GABAergic neurons would thus play similar or reciprocal roles to other cholinergic and glutamatergic BF neurons in regulating cortical activity and muscle tone along with behavior across sleep-wake states. PMID- 19776271 TI - A critical period for activity-dependent synaptic development during olfactory bulb adult neurogenesis. AB - New neurons integrate in large numbers into the mature olfactory bulb circuit throughout life. The factors controlling the synaptic development of adult-born neurons and their connectivity remain essentially unknown. We examined the role of activity-dependent mechanisms in the synaptic development of adult-born neurons by genetic labeling of synapses while manipulating sensory input or cell intrinsic excitability. Sensory deprivation induced marked changes in the density of input and output synapses during the period when new neurons develop most of their synapses. In contrast, when sensory deprivation started after synaptic formation was complete, input synapses increased in one domain without detectable changes in the other dendritic domains. We then investigated the effects of genetically raising the intrinsic excitability of new neurons on their synaptic development by delivering a voltage-gated sodium channel that triggers long depolarizations. Surprisingly, genetically increasing excitability did not affect synaptic development but rescued the changes in glutamatergic input synapses caused by sensory deprivation. These experiments show that, during adult neurogenesis in the olfactory bulb, synaptic plasticity is primarily restricted to an early period during the maturation of new neurons when they are still forming synapses. The addition of cells endowed with such an initial short-lived flexibility and long-term stability may enable the processing of information by the olfactory bulb to be both versatile and reliable in the face of changing behavioral demands. PMID- 19776272 TI - Regulation of gonadotropin-releasing hormone secretion by kisspeptin/dynorphin/neurokinin B neurons in the arcuate nucleus of the mouse. AB - Kisspeptin is encoded by the Kiss1 gene, and kisspeptin signaling plays a critical role in reproduction. In rodents, kisspeptin neurons in the arcuate nucleus (Arc) provide tonic drive to gonadotropin-releasing hormone (GnRH) neurons, which in turn supports basal luteinizing hormone (LH) secretion. Our objectives were to determine whether preprodynorphin (Dyn) and neurokinin B (NKB) are coexpressed in Kiss1 neurons in the mouse and to evaluate its physiological significance. Using in situ hybridization, we found that Kiss1 neurons in the Arc of female mice not only express the Dyn and NKB genes but also the NKB receptor gene (NK3) and the Dyn receptor [the kappa opioid receptor (KOR)] gene. We also found that expression of the Dyn, NKB, KOR, and NK3 in the Arc are inhibited by estradiol, as has been established for Kiss1, and confirmed that Dyn and NKB inhibit LH secretion. Moreover, using Dyn and KOR knock-out mice, we found that long-term disruption of Dyn/KOR signaling compromises the rise of LH after ovariectomy. We propose a model whereby NKB and dynorphin act autosynaptically on kisspeptin neurons in the Arc to synchronize and shape the pulsatile secretion of kisspeptin and drive the release of GnRH from fibers in the median eminence. PMID- 19776273 TI - Arrestin competition influences the kinetics and variability of the single-photon responses of mammalian rod photoreceptors. AB - Reliable signal transduction via G-protein-coupled receptors requires proper receptor inactivation. For example, signals originating from single rhodopsin molecules vary little from one to the next, requiring reproducible inactivation of rhodopsin by phosphorylation and arrestin binding. We determined how reduced concentrations of rhodopsin kinase (GRK1) and/or arrestin1 influenced the kinetics and variability of the single-photon responses of mouse rod photoreceptors. These experiments revealed that arrestin, in addition to its role in quenching the activity of rhodopsin, can tune the kinetics of rhodopsin phosphorylation by competing with GRK1. This competition influenced the variability of the active lifetime of rhodopsin. Biasing the competition in favor of GRK1 revealed that rhodopsin remained active through much of the single-photon response under the conditions of our experiments. This long-lasting rhodopsin activity can explain the characteristic time course of single-photon response variability. Indeed, explaining the late time-to-peak of the variance required an active lifetime of rhodopsin approximately twice that of the G-protein transducin. Competition between arrestins and kinases may be a general means of influencing signals mediated by G-protein-coupled receptors, particularly when activation of a few receptors produces signals of functional importance. PMID- 19776274 TI - Performance-related sustained and anticipatory activity in human medial temporal lobe during delayed match-to-sample. AB - The medial temporal lobe (MTL)-hippocampus and surrounding perirhinal, parahippocampal, and entorhinal cortical areas-has long been known to be critical for long-term memory for events. Recent functional neuroimaging and neuropsychological data in humans performing short-delay tasks suggest that the MTL also contributes to performance even when retention intervals are brief, and single-unit data in rodents reveal sustained, performance-related delay activity in the MTL during delayed-non-match-to-sample tasks. The current study used functional magnetic resonance imaging to examine the relationship between activation in human MTL subregions and performance during a delayed-match-to sample task with repeated (non-trial-unique) stimuli. On critical trials, the presentation of two faces was followed by a 30 s delay period, after which participants performed two-alternative forced-choice recognition. Functional magnetic resonance imaging revealed significant delay period activity in anterior hippocampus, entorhinal cortex, and perirhinal cortex over the 30 s retention interval, with the magnitude of activity being significantly higher on subsequently correct compared with subsequently incorrect trials. In contrast, posterior hippocampus, parahippocampal cortex, and fusiform gyrus activity linearly increased across the 30 s delay, suggesting an anticipatory response, and activity in parahippocampal cortex and hippocampus was greater during the probe period on correct compared with incorrect trials. These results indicate that at least two patterns of MTL delay period activation-sustained and anticipatory-are present during performance of short-delay recognition memory tasks, providing novel evidence that multiple processes govern task performance. Implications for understanding the role of the hippocampus and surrounding MTL cortical areas in recognition memory after short delays are discussed. PMID- 19776275 TI - Encoding and decoding bursts by NMDA spikes in basal dendrites of layer 5 pyramidal neurons. AB - Bursts of action potentials are important information-bearing signals in the brain, although the neuronal specializations underlying burst generation and detection are only partially understood. In apical dendrites of neocortical pyramidal neurons, calcium spikes are known to contribute to burst generation, but a comparable understanding of basal dendritic mechanisms is lacking. Here we show that NMDA spikes in basal dendrites mediate both detection and generation of bursts through a postsynaptic mechanism. High-frequency inputs to basal dendrites markedly facilitated NMDA spike initiation compared with low-frequency activation or single inputs. Unlike conventional temporal summation effects based on voltage, however, NMDA spike facilitation depended mainly on residual glutamate bound to NMDA receptors from previous activations. Once triggered by an input burst, we found that NMDA spikes in turn reliably trigger output bursts under in vivo-like stimulus conditions. Through their unique biophysical properties, NMDA spikes are thus ideally suited to promote the propagation of bursts through the cortical network. PMID- 19776276 TI - The neural network for chemotaxis to tastants in Caenorhabditis elegans is specialized for temporal differentiation. AB - Chemotaxis in Caenorhabditis elegans depends critically on the rate of change of attractant concentration computed as the worm moves through its environment. This computation depends, in turn, on the neuron class ASE, a left-right pair of pair of chemosensory neurons that is functionally asymmetric such that the left neuron is an on-cell, whereas the right neuron is an off-cell. To determine whether this coding strategy is a general feature of chemosensation in C. elegans, we imaged calcium responses in all chemosensory neurons known or in a position to contribute to chemotaxis to tastants in this organism. This survey revealed one new class of on-cells (ADF) and one new class of off-cells (ASH). Thus, the ASE class is unique in having both an on-cell and an off-cell. We also found that the newly characterized on-cells and off-cells promote runs and turns, respectively, mirroring the pattern reported previously for ASEL and ASER. Our results suggest that the C. elegans chemotaxis network is specialized for the temporal differentiation of chemosensory inputs, as required for chemotaxis. PMID- 19776277 TI - AMPA receptor ligand binding domain mobility revealed by functional cross linking. AB - Glutamate receptors mediate the majority of excitatory synaptic transmission in the CNS. The AMPA-subtype has rapid kinetics, with activation, deactivation and desensitization proceeding on the millisecond timescale or faster. Crystallographic, biochemical, and functional studies suggest that GluR2 Cys mutants which form intermolecular disulfide cross-links between the lower D2 lobes of the ligand binding cores can be trapped in a conformation that represents the desensitized state. We used multi-channel rapid perfusion techniques to examine the state dependence of cross-linking in these mutants. Under reducing conditions, both wild-type GluR2 and the G725C and S729C mutants have normal activation and desensitization kinetics, but the Cys mutants can be efficiently trapped in nonconducting states when oxidized. In contrast the I664C mutant is only partially inactivated under oxidizing conditions. For S729C, disulfide cross-links form rapidly when receptors are desensitized in the presence of glutamate, but receptors also become trapped at rest, in the absence of agonist. We assessed such spontaneous trapping in various conditions, including CNQX, a competitive antagonist; kainate, a weak partial agonist; or when desensitization was blocked by the L483Y mutation that stabilizes the D1 dimer interface. These experiments suggest that trapping in the absence of glutamate is due to two motions: Spontaneous breaking of the D1 dimer interface and hyperextension of the lower lobes of the ligand binding core. These data show that the glutamate binding domains are surprisingly mobile in the absence of ligand, which could influence receptor activity in the brain. PMID- 19776278 TI - Spatial organization of multisensory responses in temporal association cortex. AB - Neurons in sensory cortices are often topographically organized according to their response preferences. We here show that such an organization of response preferences also exists in multisensory association cortex. Using electrophysiological mappings, we probed the modality preference to auditory and visual stimuli of neurons in the superior temporal association cortex of nonhuman primates. We found that neurons preferring the same modality (auditory or visual) often co-occur in close spatial proximity or occur intermingled with bimodal neurons. Neurons preferring different modalities, in contrast, occur spatially separated. This organization at the scale of individual neurons leads to extended patches of same modality preference when analyzed at the scale of millimeters, revealing larger-scale regions that preferentially respond to the same modality. In addition, we find that neurons exhibiting signs of multisensory interactions, such as superadditive or subadditive response summation, also occur in spatial clusters. Together, these results reveal a spatial organization of modality preferences in a higher association cortex and lend support to the notion that topographical organizations might serve as a general principle of integrating information within and across the sensory modalities. PMID- 19776279 TI - Adaptive allocation of attentional gain. AB - Humans are adept at distinguishing between stimuli that are very similar, an ability that is particularly crucial when the outcome is of serious consequence (e.g., for a surgeon or air-traffic controller). Traditionally, selective attention was thought to facilitate perception by increasing the gain of sensory neurons tuned to the defining features of a behaviorally relevant object (e.g., color, orientation, etc.). In contrast, recent mathematical models counterintuitively suggest that, in many cases, attentional gain should be applied to neurons that are tuned away from relevant features, especially when discriminating highly similar stimuli. Here we used psychophysical methods to critically evaluate these "ideal observer" models. The data demonstrate that attention enhances the gain of the most informative sensory neurons, even when these neurons are tuned away from the behaviorally relevant target feature. Moreover, the degree to which an individual adopted optimal attentional gain settings by the end of testing predicted success rates on a difficult visual discrimination task, as well as the amount of task improvement that occurred across repeated testing sessions (learning). Contrary to most traditional accounts, these observations suggest that the primary function of attentional gain is not to enhance the representation of target features per se, but instead to optimize performance on the current perceptual task. Additionally, individual differences in gain suggest that the operating characteristics of low-level attentional phenomena are not stable trait-like attributes and that variability in how attention is deployed may play an important role in determining perceptual abilities. PMID- 19776280 TI - Group I mGluR activation enhances Ca(2+)-dependent nonselective cation currents and rhythmic bursting in main olfactory bulb external tufted cells. AB - In the main olfactory bulb, activation of group I metabotropic glutamate receptors (mGluRs) by olfactory nerve stimulation generates slow (2 Hz) oscillations near the basal respiratory frequency. These oscillations arise in the glomerular layer and may be generated, in part, by the intrinsic neurons, the juxtaglomerular neurons. We investigated the physiological effects of group I mGluR agonists on one population of juxtaglomerular neurons, external tufted (ET) cells, which rhythmically burst at respiratory frequencies and synchronize the intraglomerular network. Electrophysiological studies in rat main olfactory bulb slices demonstrated that the mGluR agonist 3,4-dihydroxyphenylglycine (DHPG) amplified the strength of ET cell spike bursts, principally by increasing the number of spikes per burst. Voltage-clamp and Ca(2+)-imaging studies showed that DHPG elicits a Ca(2+)-dependent nonselective cation current (I(CAN)) in the dendrites of ET cells triggered by Ca(2+) release from internal stores. The DHPG effects on bursting and membrane current were attenuated by flufenamic acid and SKF96365, agents known to antagonize I(CAN) in a variety of neurons. DHPG also elicited slow membrane current oscillations and spikelets in ET cells when synaptic transmission and intrinsic membrane channels were inoperative. These findings indicate that DHPG may passively (by increasing burst strength) or actively (by increasing conductance of gap junctions) enhance the strength of electrical synapses between ET cells. Together, these findings indicate that activation of group I mGluRs on the dendrites of ET cells play a key role in the generation of slow rhythmic oscillation in the glomerular network, which is in turn tuned to sniffing of the animal in vivo. PMID- 19776281 TI - Parallel preoptic pathways for thermoregulation. AB - Sympathetic premotor neurons in the rostral medullary raphe (RMR) regulate heat conservation by tail artery vasoconstriction and brown adipose tissue thermogenesis. These neurons are a critical relay in the pathway that increases body temperature. However, the origins of the inputs that activate the RMR during cold exposure have not been definitively identified. We investigated the afferents to the RMR that were activated during cold by examining Fos expression in retrogradely labeled neurons after injection of cholera toxin B subunit (CTb) in the RMR. These experiments identified a cluster of Fos-positive neurons in the dorsomedial hypothalamic nucleus and dorsal hypothalamic area (DMH/DHA) with projections to the RMR that may mediate cold-induced elevation of body temperature. Also, neurons in the median preoptic nucleus (MnPO) and dorsolateral preoptic area (DLPO) and in the A7 noradrenergic cell group were retrogradely labeled but lacked Fos expression, suggesting that they may inhibit the RMR. To investigate whether individual or common preoptic neurons project to the RMR and DMH/DHA, we injected CTb into the RMR and Fluorogold into the DMH/DHA. We found that projections from the DLPO and MnPO to the RMR and DMH/DHA emerge from largely separate neuronal populations, indicating they may be differentially regulated. Combined cell-specific lesions of MnPO and DLPO, but not lesions of either one alone, caused baseline hyperthermia. Our data suggest that the MnPO and DLPO provide parallel inhibitory pathways that tonically inhibit the DMH/DHA and the RMR at baseline, and that hyperthermia requires the release of this inhibition from both nuclei. PMID- 19776282 TI - NMDA receptor phosphorylation at a site affected in schizophrenia controls synaptic and behavioral plasticity. AB - Phosphorylation of the NR1 subunit of NMDA receptors (NMDARs) at serine (S) 897 is markedly reduced in schizophrenia patients. However, the role of NR1 S897 phosphorylation in normal synaptic function and adaptive behaviors are unknown. To address these questions, we generated mice in which the NR1 S897 is replaced with alanine (A). This knock-in mutation causes severe impairment in NMDAR synaptic incorporation and NMDAR-mediated synaptic transmission. Furthermore, the phosphomutant animals have reduced AMPA receptor (AMPAR)-mediated synaptic transmission, decreased AMPAR GluR1 subunit in the synapse, and impaired long term potentiation. Finally, the mutant mice exhibit behavioral deficits in social interaction and sensorimotor gating. Our results suggest that an impairment in NR1 phosphorylation leads to glutamatergic hypofunction that can contribute to behavioral deficits associated with psychiatric disorders. PMID- 19776283 TI - Glutamate controls growth rate and branching of dopaminergic axons. AB - Dopamine-releasing neurons of the substantia nigra pars compacta produce an extraordinarily dense and expansive plexus of innervation in the striatum converging with glutamatergic corticostriatal and thalamostriatal axon terminals at dendritic spines of medium spiny neurons. Here, we investigated whether glutamatergic signaling promotes arborization and growth of dopaminergic axons. In postnatal ventral midbrain cultures, dopaminergic axons rapidly responded to glutamate stimulation with accelerated growth and growth cone splitting when NMDA and AMPA/kainate receptors were activated. In contrast, when AMPA/kainate receptors were selectively activated, axon growth rate was decreased. To address whether this switch in axonal growth response was mediated by distinct calcium signals, we used calcium imaging. Combined NMDA and AMPA/kainate receptor activation elicited calcium signals in axonal growth cones that were mediated by calcium influx through L-type voltage-gated calcium channels and ryanodine receptor-induced calcium release from intracellular stores. AMPA/kainate receptor activation alone elicited calcium signals that were solely attributable to calcium influx through L-type calcium channels. We found that inhibitors of calcium/calmodulin-dependent protein kinases prevented the NMDA receptor dependent axonal growth acceleration, whereas AMPA/kainate-induced axonal growth decrease was blocked by inhibitors of calcineurin and by increased cAMP levels. Our data suggest that the balance between NMDA and AMPA/kainate receptor activation regulates the axonal arborization pattern of dopamine axons through the activation of competing calcium-dependent signaling pathways. Understanding the mechanisms of dopaminergic axonal arborization is essential to the development of treatments that aim to restore dopaminergic innervation in Parkinson's disease. PMID- 19776285 TI - Reconciling the role of serotonin in behavioral inhibition and aversion: acute tryptophan depletion abolishes punishment-induced inhibition in humans. AB - The neuromodulator serotonin has been implicated in a large number of affective and executive functions, but its precise contribution to motivation remains unclear. One influential hypothesis has implicated serotonin in aversive processing; another has proposed a more general role for serotonin in behavioral inhibition. Because behavioral inhibition is a prepotent reaction to aversive outcomes, it has been a challenge to reconcile these two accounts. Here, we show that serotonin is critical for punishment-induced inhibition but not overall motor response inhibition or reporting aversive outcomes. We used acute tryptophan depletion to temporarily lower brain serotonin in healthy human volunteers as they completed a novel task designed to obtain separate measures of motor response inhibition, punishment-induced inhibition, and sensitivity to aversive outcomes. After a placebo treatment, participants were slower to respond under punishment conditions compared with reward conditions. Tryptophan depletion abolished this punishment-induced inhibition without affecting overall motor response inhibition or the ability to adjust response bias in line with punishment contingencies. The magnitude of reduction in punishment-induced inhibition depended on the degree to which tryptophan depletion reduced plasma tryptophan levels. These findings extend and clarify previous research on the role of serotonin in aversive processing and behavioral inhibition and fit with current theorizing on the involvement of serotonin in predicting aversive outcomes. PMID- 19776284 TI - CD14 and toll-like receptors 2 and 4 are required for fibrillar A{beta} stimulated microglial activation. AB - Microglia are the brain's tissue macrophages and are found in an activated state surrounding beta-amyloid plaques in the Alzheimer's disease brain. Microglia interact with fibrillar beta-amyloid (fAbeta) through an ensemble of surface receptors composed of the alpha(6)beta(1) integrin, CD36, CD47, and the class A scavenger receptor. These receptors act in concert to initiate intracellular signaling cascades and phenotypic activation of these cells. However, it is unclear how engagement of this receptor complex is linked to the induction of an activated microglial phenotype. We report that the response of microglial cells to fibrillar forms of Abeta requires the participation of Toll-like receptors (TLRs) and the coreceptor CD14. The response of microglia to fAbeta is reliant upon CD14, which act together with TLR4 and TLR2 to bind fAbeta and to activate intracellular signaling. We find that cells lacking these receptors could not initiate a Src-Vav-Rac signaling cascade leading to reactive oxygen species production and phagocytosis. The fAbeta-mediated activation of p38 MAPK also required CD14, TLR4, and TLR2. Inhibition of p38 abrogated fAbeta-induced reactive oxygen species production and attenuated the induction of phagocytosis. Microglia lacking CD14, TLR4, and TLR2 showed no induction of phosphorylated IkappaBalpha following fAbeta. These data indicate these innate immune receptors function as members of the microglial fAbeta receptor complex and identify the signaling mechanisms whereby they contribute to microglial activation. PMID- 19776286 TI - A chimera analysis of prestin knock-out mice. AB - A chimera is a genetic composite containing a unique mix of cells derived from more than one zygote. This mouse model allows one to learn how cells of contrasting genotype functionally interact in vivo. Here, we investigate the effect that different proportions of prestin-containing outer hair cells (OHC) have on cochlear amplification. To address this issue, we developed a prestin chimeric mouse in which both ROSA26 wild-type (WT) and prestin knock-out (KO) genotypes are present in a single cochlea. The WT ROSA26 mice express a cell marker, allowing one to identify cells originating from the WT genome. Examination of cochlear tissue indicated that prestin chimeric mice demonstrate a mosaic in which mutant and normal OHCs interleave along the cochlear partition, similar to all other chimeric mouse models. The anatomical distribution of prestin-containing OHCs was compared with physiological data including thresholds and tuning curves for the compound action potential (CAP) recorded in anesthetized mice. Analysis of these measures did not reveal mixed phenotypes in which the distribution of prestin-containing OHCs impacted sensitivity and frequency selectivity to different degrees. However, by reducing the number of prestin-containing OHCs, phenotypes intermediate between WT and KO response patterns were obtained. Accordingly, we demonstrate a proportional reduction in sensitivity and in the tip length of CAP tuning curves as the number of OHCs derived from the KO genome increases; i.e., genotype ratio and phenotype are closely related. PMID- 19776287 TI - Large-scale expansion of the face representation in somatosensory areas of the lateral sulcus after spinal cord injuries in monkeys. AB - Transection of dorsal columns of the spinal cord in adult monkeys results in large-scale expansion of the face inputs into the deafferented hand region in the primary somatosensory cortex (area 3b) and the ventroposterior nucleus of thalamus. Here, we determined whether the upstream cortical areas, secondary somatosensory (S2) and parietal ventral (PV) areas, also undergo reorganization after lesions of the dorsal columns. Areas S2, PV, and 3b were mapped after long term unilateral lesions of the dorsal columns at cervical levels in adult macaque monkeys. In areas S2 and PV, we found neurons responding to touch on the face in regions in which responses to touch on the hand and other body parts are normally seen. In the reorganized parts of S2 and PV, inputs from the chin as well as other parts of the face were observed, whereas in area 3b only the chin inputs expand into the deafferented regions. The results show that deafferentations lead to a more widespread brain reorganization than previously known. The data also show that reorganization in areas S2 and PV shares a common substrate with area 3b, but there are specific features that emerge in S2 and PV. PMID- 19776288 TI - Does the middle temporal area carry vestibular signals related to self-motion? AB - Recent studies have described vestibular responses in the dorsal medial superior temporal area (MSTd), a region of extrastriate visual cortex thought to be involved in self-motion perception. The pathways by which vestibular signals are conveyed to area MSTd are currently unclear, and one possibility is that vestibular signals are already present in areas that are known to provide visual inputs to MSTd. Thus, we examined whether selective vestibular responses are exhibited by single neurons in the middle temporal area (MT), a visual motion sensitive region that projects heavily to area MSTd. We compared responses in MT and MSTd to three-dimensional rotational and translational stimuli that were either presented using a motion platform (vestibular condition) or simulated using optic flow (visual condition). When monkeys fixated a visual target generated by a projector, half of MT cells (and most MSTd neurons) showed significant tuning during the vestibular rotation condition. However, when the fixation target was generated by a laser in a dark room, most MT neurons lost their vestibular tuning whereas most MSTd neurons retained their selectivity. Similar results were obtained for free viewing in darkness. Our findings indicate that MT neurons do not show genuine vestibular responses to self-motion; rather, their tuning in the vestibular rotation condition can be explained by retinal slip due to a residual vestibulo-ocular reflex. Thus, the robust vestibular signals observed in area MSTd do not arise through inputs from area MT. PMID- 19776289 TI - Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells. AB - Glucocorticoids (GCs) are widely used as co-medication in the therapy of solid malignant tumors to relieve some of the side effects of chemotherapeutic drugs. However, recent studies have shown that GCs could render cancer cells more resistant to cytotoxic drug-induced apoptosis, but the mechanism is largely unknown. In the present study, we found that the treatment of human ovarian cancer cell lines HO-8910 and SKOV3 with synthetic GCs dexamethasone (Dex) significantly increased their adhesion to extracellular matrix (ECM) and their resistance to apoptosis induced by cytotoxic drugs cisplatin and paclitaxel. Dex also increased the protein levels of adhesion molecules integrins beta1, alpha 4, and alpha 5 in HO-8910 cells. The neutralizing antibody against integrin beta1 prevented Dex-induced adhesion and significantly abrogated the protective effect of Dex toward cytotoxic agents. We further found that transforming growth factor beta1 (TGF-beta1) alone not only increased cell adhesion and cell survival of HO 8910 cells in the presence of cisplatin, but also had synergistic pro-adhesion and pro-survival effects with Dex. Moreover, TGF-beta1-neutralizing antibody that could block TGF-beta1-induced cell adhesion and apoptosis resistance markedly abrogated the synergistic pro-adhesion and pro-survival effects of Dex and TGF beta1. Finally, we further demonstrated that Dex could up-regulate the expression of TGF-beta receptor type II and enhance the responsiveness of cells to TGF beta1. In conclusion, our results indicate that increased adhesion to ECM through the enhancement of integrin beta1 signaling and TGF-beta1 signaling plays an important role in chemoresistance induced by GCs in ovarian cancer cells. PMID- 19776290 TI - Overexpression and activation of EGFR and VEGFR2 in medullary thyroid carcinomas is related to metastasis. AB - Therapeutic options for patients with metastatic medullary thyroid carcinoma (MTC) are limited due to lack of effective treatments. Thus, there is a need to thoroughly characterize the pathways of molecular pathogenesis and to identify potential targets for therapy in MTC. Since epidermal growth factor receptor (EGFR) seems to play a crucial role for RET activation, a key feature of MTCs, and several promising EGFR/vascular endothelial growth factor receptor 2 (VEGFR2) targeted drugs have been developed, the present study was designed to investigate whether these proteins are altered in MTCs. We used a well-characterized series of 153 MTCs to evaluate EGFR activation by sequencing and FISH analysis, and to perform EGFR and VEGFR2 immunohistochemistry. EGFR tyrosine kinase domain mutations were not a feature of MTCs; however, EGFR polysomy and a strong EGFR expression were detected in 15 and 13% of the tumors respectively. Interestingly, EGFR was significantly overexpressed in metastases compared with primary tumors (35 vs 9%, P=0.002). We also studied whether specific RET mutations were associated with EGFR status, and found a decrease in EGFR polysomies (P=0.006) and a tendency towards lower EGFR expression for the most aggressive RET mutations (918, 883). Concerning VEGFR2, metastasis showed a higher expression than primary tumors (P=2.8 x 10(-8)). In this first study investigating the relationship between EGFR, RET, and VEGFR2 in a large MTC series, we found an activation of EGFR and VEGFR2 in metastasis, using both independent and matched primary/metastasis samples. This suggests that some MTC patients may benefit from existing anti-EGFR/VEFGR2 therapies, although additional preclinical and clinical evidence is needed. PMID- 19776291 TI - Association of testicular germ cell tumor with polymorphisms in estrogen receptor and steroid metabolism genes. AB - It is generally assumed that the development of testicular germ cell tumor (TGCT) is under endocrine control. In particular, unbalanced androgen/estrogen levels and/or activity are believed to represent the key events for TGCT development and progression. Furthermore, recent evidence has suggested a strong genetic component for TGCT. In this study, we analyzed whether a genetic variation in estrogen receptor (ESR) genes and steroid hormone metabolism genes is associated with TGCT. We genotyped for 17 polymorphic markers in 11 genes in 234 TGCT cases and 218 controls: ESR (ESR1 and ESR2); CYP19A1 (aromatase); 17beta-hydroxysteroid dehydrogenase types 1 and 4 (HSD17B1 and HSD17B4) dehydrogenases that convert potent androgens and estrogens to weak hormones; cytochrome P450 hydroxylating enzymes CYP1A1, CYP1A2, and CYP1B1; and the metabolic enzymes COMT, SULT1A1, and SULT1E1. We observed a significant association of rs11205 in HSD17B4 with TGCT. TGCT risk was increased twofold per copy of the minor A allele at this locus (odds ratios (OR)=2.273, 95% confidence interval (CI)=1.737-2.973). Homozygous carriage of the minor A allele was associated with an over fourfold increased risk of TGCT (OR=4.561, 95% CI=2.615-7.955) compared with homozygous carriage of the major G allele. The risk was increased both for seminoma (OR=5.327, 95% CI=2.857-9.931) and for nonseminoma (OR=3.222, 95% CI=1.471-7.059). We found for the first time an association of polymorphisms in HSD17B4 gene with TGCT. Our findings expand the current knowledge on the role of genetic contribution in testicular cancer susceptibility, and support the hypothesis that variations in hormone metabolism genes might change the hormonal environment implicated in testicular carcinogenesis. PMID- 19776292 TI - Quantitative population pharmacokinetic analysis of pravastatin using an enterohepatic circulation model combined with pharmacogenomic Information on SLCO1B1 and ABCC2 polymorphisms. AB - The aims of this study were to develop a population pharmacokinetic (PPK) model for pravastatin pharmacokinetics with regard to enterohepatic circulation (EHC) and to evaluate effects of polymorphisms in SLCO1B1 and ABCC2 on the pharmacokinetic (PK) profile of pravastatin quantitatively. A total of 636 blood samples from 57 healthy male volunteers were used. The PPK analysis was carried out using nonlinear mixed effect modeling (NONMEM) and validated by a bootstrap analysis. The PK profile of pravastatin was best described by a model of EHC with Erlang's distribution. A covariate analysis revealed that SLCO1B1(*)15 significantly influenced relative bioavailability (F(rel)); F(rel) was increased 1.50- and 1.95-fold in participants heterozygous and homozygous, respectively, for the (*)15 allele in comparison with participants without the allele. No ABCC2 polymorphism was identified as a potential covariate for pravastatin. The bootstrap analysis indicated that the PK profile of pravastatin was adequately described by the proposed PPK model. SLCO1B1(*)15 has a significant effect on F(rel), indicating that OATP1B1 is one of the determinants of systemic exposure to pravastatin. PMID- 19776293 TI - Microdose pharmacokinetics of IDX899 and IDX989, candidate HIV-1 non-nucleoside reverse transcriptase inhibitors, following oral and intravenous administration in healthy male subjects. AB - IDX899 and IDX989 are new non-nucleoside reverse-transcriptase inhibitors (NNRTIs) that exhibit potent inhibition of HIV-1 replication, including NNRTI resistant mutants. This microdose study investigates the pharmacokinetics and determined oral bioavailability. For each compound, 4 healthy male subjects are randomized to receive via a crossover design a single 100-microg oral and intravenous dose together with 100 nCi of [(14)C]-labeled drug. Plasma and urine samples are obtained over a period of 168 hours postdose and analyzed for total, unchanged drug and major metabolites using an accelerator mass spectrometry method. Based on total radioactivity, oral absorption is near complete. For the parent drug, mean absolute bioavailability is 61% and 65% for IDX899 and IDX989, respectively. Both compounds are extensively metabolized especially after oral dosing. Observed terminal phase half-lives after oral and intravenous doses range from 4 to 10 hours and are comparable for the 2 compounds. Urine excretion of radioactivity for both compounds is less than 10%. These data show for the first time that IDX899 and IDX989 possess favorable pharmacokinetic properties in humans, including high mean absolute bioavailability and long half-life. IDX899 has been selected based on these initial pharmacokinetic assessments and other criteria as the candidate for further clinical development. PMID- 19776294 TI - Rape myth acceptance among Korean college students: the roles of gender, attitudes toward women, and sexual double standard. AB - The purpose of the current study was to examine factors that influence rape myths among Korean college students. This study was particularly interested in the ways in which attitudes toward women and sexual double standard affect the relationship between gender and rape myths. Although the incidence of rape is a common concern in many current societies, within each society, the specific components of rape myths reflect the cultural values and norms of that particular society. A sample of 327 college students in South Korea completed the Korean Rape Myth Acceptance Scale-Revised, the Attitudes Toward Women Scale, and the Sexual Double Standard Scale. Structural equation modeling (SEM) was used to test hypothesized models. Results revealed that in three of the four models, rape survivor myths, rape perpetrator myths, and myths about the impact of rape, attitudes toward women were a more important predictor of rape myths than gender or sexual double standard. In the rape spontaneity myths model, on the other hand, sexual double standard was a more important predictor than gender or attitudes toward women. This study provides valuable information that can be useful in developing culturally specific rape prevention and victim intervention programs. PMID- 19776295 TI - Atenolol hepatotoxicity: report of a complicated case. AB - OBJECTIVE: To report a case of acute hepatitis related to atenolol administration in a liver transplant (LT) recipient. CASE SUMMARY: A 57-year-old woman was evaluated for LT because of liver failure due to cirrhosis of unknown origin. LT was performed in November 2006. In March 2007, results of liver function tests (LFTs) were within the reference ranges. She had received atenolol for hypertension for 3 years prior to surgery and it was reintroduced at a dose of 100 mg/day because of recurrence of hypertension. One month later, she presented with acute hepatitis. The first post-LT liver biopsy was performed. Histologic examination disclosed a combination of portal and centrilobular inflammatory lesions. The diagnosis of acute rejection was accepted and 3 bolus doses of prednisone 500 mg/day were administered. Evolution was not favorable and a second liver biopsy was obtained. Histologic examination showed the complete disappearance of portal inflammatory lesions but an increase of centrilobular lesions. Toxic hepatitis was suspected and atenolol was stopped. No other therapeutic modification was done and resolution of the toxicity was good. An objective causality assessment revealed that the adverse drug event was probable. DISCUSSION: This case report represents a very rare severe hepatotoxicity due to atenolol and illustrates the diagnostic difficulties raised by such clinical situations in the context of LT. It is noteworthy that the initial diagnosis considered in this patient was acute rejection. This diagnosis had to be reconsidered because of the unfavorable outcome, despite specific treatment of rejection. Moreover, the patient had been treated with atenolol for 3 years before LT: in the absence of any other etiology, the possibility that she had drug-induced cirrhosis may therefore be considered. The mechanism of beta-blocker related hepatotoxicity is debatable. In our case, the composition of the inflammatory infiltrates observed in the liver biopsy specimens suggests an immune-mediated mechanism. CONCLUSIONS: Despite the fact that beta-blocker induced hepatotoxicity is probably extremely rare, it must be suspected and the drug therefore discontinued. PMID- 19776296 TI - Analysis of medications returned to community pharmacies. AB - BACKGROUND: There are many causes of medication waste, including excess supply, treatment changes, and patient nonadherence to therapy. Investigating medication returns may indicate areas for targeting interventions to reduce waste. OBJECTIVE: To identify and quantify the types and amounts of medications returned to community pharmacies and, specifically, to quantify the percentage of medication returned from the original dispensing, its therapeutic category, and reasons for not being used. METHODS: Unsolicited medication returned for disposal to the 24 community pharmacies in the Taranaki region (approximately 37,000 households) of New Zealand over a 6-week period was analyzed. The results were entered into a database, recording medication, amount originally issued (if known), date of issue, Anatomical Therapeutic Chemical (ATC) classification, and reason for nonuse. Cross-tabulation of ATC category versus percentage returned as well as ATC category versus reason for returns was performed. Adjusted standardized residuals were investigated to determine specific cells that were in excess of the expected counts. RESULTS: Complete information was available for 2704 items. The majority (51%) of returns contained 75-100% of the original dispensed amount of medication. For the respiratory category, 77% of the returns were in the 75-100% group, significantly more than for any other therapeutic group. Reasons for returns were recorded as bereavement (22%), surplus to requirements (17%), expired (8%), medication change (11%), dose change (3%), and unknown (39%). The cardiovascular group and respiratory groups had a higher rate of returned drugs due to medication changes and surplus to requirements, respectively. CONCLUSIONS: The majority of returned medications contained greater than 75% of the original amount issued. Identification of therapeutic groups having higher rates of returns due to medication changes or surplus to requirements may suggest areas to target to reduce medication waste. PMID- 19776297 TI - Impact of a renal drug dosing service on dose adjustment in hospitalized patients with chronic kidney disease. AB - BACKGROUND: Appropriate drug selection and dosing for patients with chronic kidney disease (CKD) is important to avoid unwanted drug effects and ensure optimal patient outcomes. OBJECTIVE: To assess the rate of inappropriate dosing in patients with CKD in a nephrology unit and to evaluate the impact on dose adjustment, adverse drug events (ADEs), and drug cost of having a pharmacist accompany a team of physicians on their rounds. METHODS: This was a comparative study with a preintervention and postintervention design. The preintervention phase served as the control; it was prospective and observational only and was conducted from the beginning of February to the end of May 2007. The second phase (intervention phase) was conducted from the beginning of March to the end of June 2008. Two random samples of 300 patients with an estimated creatinine clearance less than or equal to 50 mL/min were included. During the intervention phase, a clinical pharmacist made rounds with the nephrology unit team and gave dosing adjustment recommendations when needed. A collection of reliable and up-to-date drug information references that are commonly used globally were used during the intervention. RESULTS: In the preintervention group, drug dosage adjustment or avoidance, based on renal function, was necessary in 607 of 2814 (21.6%) prescriptions. Of these, 322 (53.0%) did not comply with guidelines. In the intervention group, adjustment was necessary for 640 of 2981 (21.5%) prescriptions. The pharmacist made 388 recommendations related to dosing adjustment, 212 (54.6%) of which were accepted by physicians. Clinicians' noncompliance with dosing guidelines decreased to 176 (27.5%) (p < 0.001). In the preintervention group, 64 (21.3%) patients had a suspected ADE, with a total of 73 events. In the intervention group, this number was significantly lower with 49 events in 48 (16.0%) patients (p < 0.05). The intervention resulted in drug cost savings of $2250 US. CONCLUSIONS: A renal drug dosing service for patients hospitalized with CKD can increase the proportion of drug dosing that is adjusted to take into account renal function. This can save drug costs and may prevent ADEs. PMID- 19776298 TI - Derivation and validation of the ASK-12 adherence barrier survey. AB - BACKGROUND: The ASK-20 survey is a previously validated patient-report measure of barriers to medication adherence and adherence-related behavior. OBJECTIVE: To derive and validate a shorter version of the ASK-20 scale. METHODS: Patients with asthma, diabetes, and congestive heart failure were recruited from a university medical center. Participants completed the ASK-20 survey and other questionnaires. Approximately one-third of participants were randomized to a 2 week retest administration. Item performance and results of an exploratory factor analysis were examined for item reduction and subscale identification. Subsequent analyses examined reliability and validity of the shorter version of the ASK. RESULTS: A total of 112 patients participated (75.9% female; mean age 46.7 y; 53.6% African American). Eight items were dropped from the ASK-20 based on factor loadings, floor effects, Cronbach's alpha, and the ability of each item to discriminate between groups of patients differing in self-reported adherence. The new total score (ASK-12) had good internal consistency reliability (Cronbach's alpha 0.75) and test-retest reliability (intraclass correlation 0.79). Convergent validity was demonstrated through correlations with the Morisky Medication Adherence Scale (r -0.74; p < 0.001), condition-specific measures, the SF-12 Mental Component Score (r -0.32; p < 0.01), and proportion of days covered by filled medication prescriptions in the past 6 months as indicated by pharmacy claims data (r -0.20; p = 0.059). The ASK-12 total score also discriminated among groups of patients who differed in self-reported adherence indicators, including whether a dose was missed in the past week, the number of days medication was not taken as directed, and treatment satisfaction. Three subscales were identified (adherence behavior, health beliefs, inconvenience/forgetfulness), and results provided initial support for their validity. CONCLUSIONS: The ASK-12 demonstrated adequate reliability and validity, and it may be a useful brief measure of adherence behavior and barriers to treatment adherence. PMID- 19776299 TI - Efficacy of fluconazole for the treatment of onychomycosis. AB - OBJECTIVE: To evaluate the efficacy of fluconazole for the treatment of onychomycosis. DATA SOURCES: Searches of MEDLINE (1966-May 2009) and International Pharmaceutical Abstracts (1970-May 2009) were performed. Key search terms included fluconazole and onychomycosis. In addition, reference citations from identified publications were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles in English identified from the data sources were evaluated. All studies evaluating oral fluconazole for the treatment of onychomycosis were included in the review. DATA SYNTHESIS: Seven studies evaluating fluconazole treatment for onychomycosis were identified. One study used daily dosing and the rest used once-weekly dosing. Treatment doses ranged from 100 mg to 450 mg weekly and 150 mg daily, and durations ranged from 12 weeks to 12 months. Most of the studies evaluated the efficacy of fluconazole in patients with toenail onychomycosis due to dermatophyte infection. Fluconazole was superior to placebo, with mycologic eradication rates ranging from 36% to 100% in placebo-controlled studies. In one of the comparative studies, the mycologic cure rate was lower with fluconazole (31.2%) compared with terbinafine (75%) and itraconazole (61.1%). Common adverse events reported with fluconazole use were headache, gastrointestinal pain, and diarrhea. CONCLUSIONS: Fluconazole is less effective than terbinafine and itraconazole in the treatment of onychomycosis. However, fluconazole may be preferred in patients unable to tolerate other oral antifungal agents due to the dosing regimen, adverse effect profile, and drug interactions. PMID- 19776300 TI - Comparing generic and innovator drugs: a review of 12 years of bioequivalence data from the United States Food and Drug Administration. AB - BACKGROUND: In the US, manufacturers seeking approval to market a generic drug product must submit data demonstrating that the generic formulation provides the same rate and extent of absorption as (ie, is bioequivalent to) the innovator drug product. Thus, most orally administered generic drug products in the US are approved based on results of one or more clinical bioequivalence studies. OBJECTIVE: To evaluate how well the bioequivalence measures of generic drugs approved in the US over a 12-year period compare with those of their corresponding innovator counterparts. METHODS: This retrospective analysis compared the generic and innovator bioequivalence measures from 2070 single-dose clinical bioequivalence studies of orally administered generic drug products approved by the Food and Drug Administration (FDA) from 1996 to 2007 (12 y). Bioequivalence measures evaluated were drug peak plasma concentration (C(max)) and area under the plasma drug concentration versus time curve (AUC), representing drug rate and extent of absorption, respectively. The generic/innovator C(max) and AUC geometric mean ratios (GMRs) were determined from each of the bioequivalence studies, which used from 12 to 170 subjects. The GMRs from the 2070 studies were averaged. In addition, the distribution of differences between generic means and innovator means was determined for both C(max) and AUC. RESULTS: The mean +/- SD of the GMRs from the 2070 studies was 1.00 +/- 0.06 for C(max) and 1.00 +/- 0.04 for AUC. The average difference in C(max) and AUC between generic and innovator products was 4.35% and 3.56%, respectively. In addition, in nearly 98% of the bioequivalence studies conducted during this period, the generic product AUC differed from that of the innovator product by less than 10%. CONCLUSIONS: The criteria used to evaluate generic drug bioequivalence studies support the FDA's objective of approving generic drug formulations that are therapeutically equivalent to their innovator counterparts. PMID- 19776301 TI - Electrical injury, part I: Mechanisms. PMID- 19776302 TI - Evaluating the affective component of the cerebellar cognitive affective syndrome. AB - The authors performed a systematic review and meta-analysis of studies evaluating the affective component of the cerebellar cognitive affective syndrome. Depressive and anxiety symptoms and personality changes were more frequent in patients with spinocerebellar ataxia. Patients with cerebellar lesions were more likely to have depression, deficits in the ability to experience emotions, and behavioral difficulties. A meta-analysis revealed modestly higher scores on the Hamilton Depression Rating Scale (HAM-D) among patients with cerebellar disease. This review highlights the need for cohort studies using noncerebellar comparison groups, more sensitive measures, and appropriate-sized populations with isolated cerebellar lesions to thoroughly assess the affective component of the cerebellar cognitive affective syndrome. PMID- 19776303 TI - Quantitative EEG abnormalities are associated with memory impairment in recently abstinent methamphetamine-dependent individuals. AB - This study examined the association between brain electrical activity, measured using quantitative electroencephalography (QEEG), and performance on measures of episodic memory in a sample of nine methamphetamine-dependent individuals who were evaluated after 4 days of monitored abstinence and 10 non-drug-using comparison subjects. In methamphetamine users, but not in comparison subjects, increased theta power was correlated with poorer performance on the delayed recall subtests of the Rey Auditory Verbal Learning Test and the Rey-Osterrieth Complex Figure Test (p<0.05). There was no association between alpha, beta, and delta power and performance on the memory tests. These results complement previous findings by demonstrating that the electrophysiological abnormalities associated with methamphetamine dependence are likely to affect behavior in an observable and important manner (i.e., memory deficits) when users are not intoxicated. PMID- 19776304 TI - Neuroimaging correlates of apathy and depression in Alzheimer's disease. AB - A consecutive series of 79 patients with probable Alzheimer's disease were assessed with a structured psychiatric evaluation, and diagnoses of apathy and depression were made using standardized criteria. Three-dimensional MRI scans were obtained from all patients, and images were segmented into gray matter, white matter, and CSF. White matter hyperintensities were edited on segmented images, and lobar assignments (frontal, temporal, parietal, and occipital) were made based on Talairach coordinates. Patients with apathy showed a significantly larger volume of frontal white matter hyperintensities than patients without apathy. Patients with depression had a significantly larger volume of right parietal white matter hyperintensities than patients without depression. However, neither apathy nor depression was significantly associated with lobar gray or white matter atrophy. Frontal and right parietal white matter hyperintensities are the strongest brain structural correlates of apathy and depression in Alzheimer's disease. PMID- 19776305 TI - Apathy is not depression in Huntington's disease. AB - Apathy and depression are common neuropsychiatric features of Huntington's disease. The authors studied a group of 34 Huntington's disease patients. In addition to the conventional classification according to DSM-IV criteria of depression, emphasis was put on a dimensional approach using scores on several different scales. Severe depression was found in 12% and severe apathy in 52% of all study patients. The authors found that apathy and depression are not related and are clearly distinct dimensions. Apathy was related to disease characteristics such as cognitive deterioration and functional decline, whereas depression was not. PMID- 19776307 TI - Discrete shifts within the theta band between the frontal and parietal regions of the right hemisphere and the experiences of a sensed presence. AB - The attribution of personal cognition to another consciousness or sentient being is strongly correlated with altered perfusion within the frontoparietal or frontotemporal regions. The authors applied weak complex magnetic fields that produce an increased incidence of these experiences in healthy volunteers. Quantitative monopolar electroencephalographic (QEEG) measurements for each of the four lobes of the two hemispheres found that intensity of the sensed presence was significantly correlated with increased power within only the theta range over the right parietal and frontal lobes. Successive 1 Hz incremental analyses indicated specific power increases for 4 Hz-5 Hz and 7 Hz-8 Hz bands over the right parietal and frontal lobes, respectively. These results are consistent with those of other measures for both schizophrenia patients and healthy volunteers; changes in activity within these regions are associated with attribution of one's thoughts and actions to another. PMID- 19776306 TI - Apathy after hip fracture: a potential target for intervention to improve functional outcomes. AB - The authors examined apathy symptoms, their improvement, and their association with functional recovery after a hip fracture. Of 126 participants, 37% had clinically significant apathy symptoms, which predicted functional outcome (i.e., poorer recovery from the fracture among those with higher baseline apathy). Of participants with high baseline apathy, approximately one-third improved; these participants had a better functional outcome than those with persistently high apathy scores. It is concluded that apathy symptoms are common after a hip fracture, but improve in one-third of individuals, with a concomitant functional recovery after hip surgery. Interventions to prevent or improve apathy in elderly persons deserve further attention. PMID- 19776308 TI - Proteomic profiling of plasma and serum in elderly patients with delirium. AB - The aim of this study was to compare plasma and serum protein profiles in elderly acute hip fracture patients with and without delirium. The spectra from surface enhanced laser desorption ionization (SELDI) using time-of-flight (TOF) mass spectrometry of 16 patients without and 16 patients with delirium (two groups of eight and eight) scored using the Confusion Assessment Method were compared. The most discriminating peak of 15.9 kDa in plasma in a testing group of eight patients with delirium to eight patients without delirium was confirmed in an independent validation group. Taking both groups together, three discriminating peaks of 7.97, 15.9, and 16.0 kDa were found in delirious patients. These peaks presumably correspond to hemoglobin-beta, its doubly charged ion, and its glycosylated form. PMID- 19776309 TI - Evaluating patients with suspected nonepileptic psychogenic seizures. AB - The authors evaluate 26 patients with suspected psychogenic non-epileptic seizures (PNES) who were referred to prolonged intensive video EEG (VEEG) in an epilepsy diagnostic center at the University of Sao Paulo, Brazil. Following the investigative protocol, 50% of the patients received a diagnosis of PNES, 15.4% of epilepsy, and 34.6% of associated PNES and epilepsy. In all patients in our series, PNES were the pseudoneurological presentations of dissociative or conversion symptoms in patients presenting the following mental disorders: conversion disorder, somatization or undifferentiated somatoform disorder, dissociative disorder not otherwise specified, and posttraumatic stress disorder. Psychiatric comorbidities, mostly depressive disorders, were frequent. PMID- 19776311 TI - Association between preoperative anxiety in spinal stenosis patients and abnormal cerebral glucose metabolism: voxel-based statistical analysis of F-18 FDG brain PET. AB - Although a possible association between preoperative anxiety and abnormal cerebral glucose metabolism may exist, the authors are not aware of any report describing preoperative anxiety and cerebral metabolism in patients with spinal stenosis in detail. Fluorine-18 fluorodeoxyglucose positron emission tomography with statistical parametric mapping analysis was used to compare regional brain glucose metabolism between 34 spinal stenosis patients and 34 healthy comparison subjects. Spinal stenosis patients with preoperative anxiety showed several voxel clusters of significantly decreased cerebral metabolism. The largest clusters were areas of left insula and left prefrontal cortex (Brodmann's areas 9 and 11). The second largest cluster area was left prefrontal cortex (Brodmann's area 10). The other clusters were right insula (Brodmann's area 13), right superior temporal gyrus (Brodmann's area 22), and right middle frontal gyrus (Brodmann's area 8). PMID- 19776312 TI - Education effect on depression and quality of life in nondemented Parkinson's disease patients. AB - A comparison of nondemented Parkinson's disease patients with lower, intermediate, and higher educational levels indicated an independent association between longer (better) education and less severe depressive difficulties based on the Beck Depression Inventory cognitive-affective items. Well-educated patients also had a better health-related quality of life based on the Parkinson's Disease Questionnaire-39, apparently due to beneficial effects of education on cognitive performance (attention/memory, visuospatial and executive functions) and the degree of depression. More years of education favors milder depressive difficulties and a higher self-perceived life satisfaction in nondemented Parkinson's disease patients. PMID- 19776310 TI - Generalized and symptom-specific insight in behavioral variant frontotemporal dementia and primary progressive aphasia. AB - Behavioral variant frontotemporal dementia (FTD) and primary progressive aphasia (PPA) are related dementias with different presenting symptoms but with increasing symptom overlap as they progress. Loss of insight is associated with early behavioral variant FTD, but not PPA. This study used the Frontal Behavioral Inventory to compare patient and caregiver concepts of symptom presence and severity. Patients with behavioral variant FTD were found to have worse insight overall than PPA patients. However, the PPA group showed reduced insight into behavioral symptoms, and the behavioral variant FTD groups had intact insight into some language symptoms. Theoretical and clinical implications are discussed. PMID- 19776313 TI - Disinhibition due to disruption of the orbitofrontal circuit treated successfully with carbamazepine: a case series. AB - The frontal-subcortical pathways play a role in governing behavior. Injury may disrupt their functioning and produce neuropsychiatric symptoms. The authors discuss the kindling theory in the possible production of these symptoms, which significantly improved with the potent antikindling agent, carbamazepine. PMID- 19776314 TI - A pilot study revealing impaired P50 gating in antisocial personality disorder. AB - The authors investigated preattentive filtering assessed by P50 gating in nine participants with antisocial personality disorder (ASPD) and seven with adult onset antisocial behavior (AAB). Relative to 15 comparison subjects, gating was impaired in ASPD, suggesting abnormal pre-attentive filtering in pathological impulsivity. PMID- 19776315 TI - Late-life reactivation of obsessive-compulsive disorder associated with lesions in prefrontal-subcortical circuits. AB - The authors describe the reactivation of obsessive-compulsive disorder (OCD) in three patients with lesions in the prefronto-subcortical circuits after decades of being asymptomatic. The patients also reported the emergence of new OCD symptoms and motor/phonic tics as well as mental rituals thematically related to the negative experience of suffering cognitive and motor deficits. PMID- 19776316 TI - Behavioral neurology and neuropsychiatry fellowship training: the Johns Hopkins model. AB - Behavioral neurology and neuropsychiatry training has recently been codified as a unitary fellowship, under the supervision of the United Council for Neurologic Subspecialties (UCNS). The authors describe how the Johns Hopkins Behavioral Neurology & Neuropsychiatry Fellowship has approached the challenging job of providing training for an inherently multidisciplinary field. PMID- 19776317 TI - Disruption of nicotine addiction associated with paroxysmal hypersomnia. PMID- 19776318 TI - Cerebral venous sinus thrombosis may be associated with clozapine. PMID- 19776319 TI - Does a kind of over-fitting occur in the brain of autistic patients? PMID- 19776320 TI - Clozapine-induced negative myoclonus is not cataplexy. PMID- 19776321 TI - Generalized peripheral nerve hyperexcitability associated with lithium. PMID- 19776322 TI - Rosiglitazone effects to ameliorate Alzheimer's disease pathogenic features: insulin signaling and neurotrophic factors. PMID- 19776323 TI - Neurometabolic correlations of donepezil and rivastigmine in dementia patients: a different neuroprotective effect. PMID- 19776324 TI - Improvement in Pisa syndrome and tardive dyskinesia following aripiprazole treatment. PMID- 19776325 TI - Persistent akinetic mutism after bilateral paramedian thalamic infarction. PMID- 19776326 TI - Decision-making impairment in a patient with new concomitant diagnoses of Parkinson's disease and HIV. PMID- 19776327 TI - Beta oscillations as the cause of both hyper- and hypokinetic symptoms of movement disorders. PMID- 19776328 TI - Altered sexual orientation following dominant hemisphere infarct. PMID- 19776329 TI - Capgras syndrome associated with Fahr's disease. PMID- 19776330 TI - Self-induced "therapeutic seizures" for the treatment of depression. PMID- 19776331 TI - The appropriation of complexity theory in health care. AB - The way in which complexity is usually interpreted in the health care literature misses the whole point of complexity theory, thanks to an influential but misleading series of articles in the BMJ. Complexity provides an explanation of patterns and structures in certain systems by modelling known outcomes at the global level in terms of stimulus-response rules governing the unilateral, non intentional behaviour of individual units comprising the system. The BMJ articles overlook the explanatory function of complex systems, restore the link between order and design which complexity thinking disrupts, and interpret purely mathematical concepts in psychological terms. As a consequence, the health care literature typically regards complexity as a variation on democratic, collaborative, 'bottom-up' methods for the management of change in systems. PMID- 19776332 TI - Evaluation of workforce and organizational issues in establishing primary angioplasty in England. AB - OBJECTIVE: To assess workforce and organizational issues in establishing a primary angioplasty service in England. METHODS: Staff associated with the heart attack pathway at seven acute hospitals participating in the National Infarct Angioplasty Project (NIAP) completed a questionnaire, participated in focus groups and interviews, and observations were undertaken in catheter laboratories. RESULTS: All seven hospitals implemented primary angioplasty though not all provided a 24-hour service. Hospitals varied in size, number of staff involved in the delivery of angioplasty and the volume of cases. Hospitals that developed the service by incremental expansion encountered more problems than hospitals that planned for a full service at the outset. Simple, direct access to a catheter laboratory reduced delays and could be facilitated by an angioplasty gatekeeper. Little attention was paid to later cardiac rehabilitation. Multiskilling and the ability to work across traditional professional boundaries appeared to provide substantial advantages. Building relationships with key staff and auditing the heart attack pathway were critical to successful service development. Differences in remuneration and rest for staff undertaking out-of-hours working threatened sustainability. CONCLUSIONS: Primary angioplasty was feasible in varied settings and generally supported by staff. However, the participating hospitals were selected enthusiasts, only some implemented a 24-hour service and activity levels were relatively low. Organizational and workforce issues need to be addressed to achieve an efficient and sustainable service. PMID- 19776333 TI - The relationship between diabetes mellitus, depression, and missed appointments in a low-income uninsured population. AB - PURPOSE: The purpose of this project is to identify rates of depression and document mental health needs of adults with diabetes who obtained care in free clinics. Data were collected to determine if there is a relationship between diabetes and depression and missed appointments in a sample of patients who were low-income, uninsured, and represented a variety of racial groups. METHODS: A sample of 183 adults with diabetes participated by completing paper and computerized questionnaires. Instruments included the Patient Health Questionnaire 9 (to measure prevalence of depression), the RAND 36 Health Survey (to measure quality of health), the Audit of Diabetes Dependent Quality of Life (to measure diabetes-dependent quality of life), and the Diabetes Empowerment Scale (to measure self-efficacy). RESULTS: The prevalence of depression at a moderate or greater level in the sample was found to be 30.1%. Levels of quality of health and self-efficacy were found to be reduced among those with the presence of depression. A significant increase in the rate of depression was found among those who had attended the free clinic for a longer period. No significant differences were found in diabetes-dependent quality of life and missed appointments among those with depression compared with those without. CONCLUSIONS: Rates of depression among adults with diabetes in a free clinic setting were found to be comparable with the highest rates reported by other studies of insured populations. Results of this study support the need to develop mental health treatment programs for free clinic settings. PMID- 19776334 TI - Dance and peer support to improve diabetes outcomes in African American women. AB - PURPOSE: The purpose of this pilot study was to test a dance intervention and explore the role of peer support to improve the diabetes outcomes of A1C, weight, body fat, and blood pressure in African American women with type 2 diabetes. METHODS: This study was conducted in a community-based outpatient clinic. A mixed methods design was used. A total of 46 women, 26 to 83 years of age, were randomized to either the 12-week dance group or usual care group. Both between group and intraindividual group differences were analyzed from baseline to 12 weeks. Focus group interviews explored the role of peer support through semistructured discussions for the women enrolled in the dance group. RESULTS: Results showed significant group mean differences in systolic blood pressure (BP) and body fat. Paired t tests showed significant reductions in all the diabetes outcomes for the dance group and significant increases in glycolated hemoglobin (A1C) and systolic BP for the usual care group. The emergent themes of the focus groups were that a diabetes diagnosis was devastating, and changing eating habits and taking medications was often difficult. Peer support in the dance group was expressed as camaraderie, enjoyment, and laughter, which fostered attendance. CONCLUSIONS: Dancing 2 times per week for 12 weeks produced significant group differences in systolic BP and body fat and significant intraindividual changes. The implications are that dancing in a supportive environment with peers may be an effective strategy for diabetes educators to help those with diabetes to become more physically active and improve diabetes outcomes and overall health. PMID- 19776335 TI - Progranulin and beta-amyloid distribution: a case report of the brain from preclinical PS-1 mutation carrier. AB - BACKGROUND: Progranulin (PGRN) is a multifunctional growth factor that is found in many tissues. Mutations in the PGRN gene cause familial frontotemporal dementia with ubiquitin-positive inclusions. PGRN plaque-like structures have been described in Alzheimer's disease (AD), in association with beta-amyloid (Abeta) plaques. OBJECTIVE: To investigate PGRN and aggregated Abeta immunolabeling distribution in autopsied brain tissue from the participant with confirmed PS-1 (A246E) mutation, who died prior to clinical symptom onset. RESULTS: Immunolabeling for PGRN was positive and accumulated/formed plaque-like structures in all studied regions. These structures most frequently colocalized with Abeta though there were some that did not. PGRN plaques were most dense in medial temporal and frontal regions and predominated over aggregated Abeta. CONCLUSIONS: This case report illustrates PGRN accumulation and Abeta aggregation in preclinical PS-1 AD case and raises the question whether this phenomenon coincides with or precedes Abeta aggregation. PMID- 19776336 TI - A2A adenosine receptor overexpression and functionality, as well as TNF-alpha levels, correlate with motor symptoms in Parkinson's disease. AB - The antagonistic interaction between adenosine and dopamine receptors could have important pathophysiological and therapeutic implications in Parkinson's disease (PD). The primary aim of this study was to investigate the expression, affinity, and density of A(1), A(2A), A(2B), and A(3) adenosine receptors (ARs) and D(2) dopamine receptors (D(2)Rs) in PD. An increase in A(2A)AR density in putamen was found. The presence and functionality of ARs in human lymphocyte and neutrophil membranes from patients with PD revealed a specific A(2A)AR alteration compared with healthy subjects. A statistically significant linear correlation among the A(2A)AR density, functionality, or tumor necrosis factor-alpha (TNF-alpha) levels and Unified Parkinson's Disease Rating Scale (UPDRS) motor score was reported. Adenosine concentration and TNF-alpha levels were increased in plasma of patients with PD. In rat adrenal pheochromocytoma (PC12) cells, a widely useful model, adenosine antagonists decreased dopamine uptake, and an opposite effect was mediated by A(2A) agonists. This is the first report showing the presence of an A(2A)AR alteration in putamen in PD that mirrors a similar up-regulation in human peripheral blood cells. Moreover, the correlation found between A(2A)AR density or A(2A) agonist potency and UPDRS motor score highlights the central role of A(2A)ARs in the pharmacological treatment of PD. PMID- 19776337 TI - Contribution of macrophage migration inhibitory factor to the pathogenesis of dengue virus infection. AB - Dengue fever is an emerging viral disease transmitted by arthropods to humans in tropical countries. Dengue hemorrhagic fever (DHF) is escalating in frequency and mortality rates. Here we studied the involvement of macrophage migration inhibitory factor (MIF) in dengue virus (DENV) infection and its pathogenesis. Patients with DHF had elevated plasma concentrations of MIF. Both leukocytes from these patients and macrophages from healthy donors infected in vitro with DENV showed a substantial amount of MIF within lipid droplets. The secretion of MIF by macrophages and hepatocytes required a productive infection and occurred without an increase in gene transcription or cell death, thus indicating active secretion from preformed stocks. In vivo infection of wild-type and mif-deficient (Mif(-/ )) mice demonstrated a role of MIF in dengue pathogenesis. Clinical disease was less severe in Mif(-/-) mice, and they exhibited a significant delay in lethality, lower viremia, and lower viral load in the spleen than wild-type mice. This reduction in all parameters of severity on DENV infection in Mif(-/-) mice correlated with reduced proinflammatory cytokine concentrations. These results demonstrated the contribution of MIF to the pathogenesis of dengue and pointed to a possible beneficial role of neutralizing MIF as an adjunctive therapeutic approach to treat the severe forms of the disease. PMID- 19776338 TI - Effects of zone-specific superior labral detachment on biceps anchor stability. AB - PURPOSE: This study aimed to elucidate the degree of biceps anchor displacement that occurs when specific zones of the superior labrum are detached from the glenoid. STUDY DESIGN: Descriptive laboratory study. METHODS: Twelve cadaveric scapulae with intact labrums were prepared by removing the surrounding musculature with the labrum, biceps anchor, and biceps tendon carefully preserved. Pulleys were used to apply traction in 3 different directions- superior, lateral, and combined posterior/superior/lateral, to simulate the "peel back" mechanism-while a continuous 1.13 kg of traction was applied to the biceps tendon. Labral tears were created by sharp incisions in isolation and in combinations of 3 zones defined relative to the glenoid fossa: anterior, posterior, or superior. The displacement of the biceps anchor (position of the marker after the simulated lesion relative to the marker position with the labrum intact) was measured relative to a rigid reference frame. RESULTS: The greatest degree of displacement occurred with the sectioning of all 3 zones, followed by the sectioning of 2 adjacent zones. Superior traction created the least displacement in all combinations, while lateral traction created maximal displacement, with one exception: in the setting of anterosuperior/superior lesions, maximal displacement was observed using the peel-back mechanism. CONCLUSION: Biceps anchor displacement, particularly the degree and direction of displacement, is affected by the labral detachment pattern. All 3 labral zones assessed in this study have important biomechanical contributions to biceps anchor displacement. CLINICAL SIGNIFICANCE: These findings have important implications relating to the clinician's arthroscopic assessment of superior labrum anterior and posterior (SLAP) tears, as well as the determination of need for stabilization. This information is particularly useful when treating SLAP tears in certain laborers and athletes, whose activities may cause specific biceps anchor displacement patterns. PMID- 19776339 TI - Biomechanical and biologic augmentation for the treatment of massive rotator cuff tears. AB - Recent studies have reported that massive rotator cuff tears do not heal as predictably as, and may have diminished clinical outcomes compared with, smaller rotator cuff tears. An improved understanding of the biologic degeneration and the biomechanical alterations of massive rotator cuff tears should provide better strategies to optimize outcomes. The approach to patients with massive rotator cuff tears requires careful assessment of the patient and the extent of rotator cuff degeneration to determine the appropriate treatment. For a rotator cuff tear that is repairable, the goal is to produce a tension-free, anatomical repair that restores the footprint using soft tissue releases and various suturing techniques, including double-row, transosseous-equivalent suture bridges or the rip-stop stitch. For irreparable cuff tears, the surgeon may elect to proceed with 1 of 2 approaches: (1) palliative surgical treatment-that is, rotator cuff debridement, synovectomy, biceps tenotomy, tuberoplasty and/or nonanatomical repair with partial repair; or (2) salvage treatment with various tendon transfers. Even though the biomechanical constructs for rotator cuff repairs have been improved, the integrity of the repair still depends on biologic healing at the tendon-to-bone junction. There has been much interest in the development of a scaffold to bridge massive rotator cuff tears and adjuvant biologic modalities including growth factors and tenocyte-seeded scaffolds to augment tendon-to-bone healing. The treatment of rotator cuff disease has improved considerably, but massive rotator cuff tears continue to pose a challenging problem for orthopaedic surgeons. PMID- 19776340 TI - Low-energy extracorporeal shock wave therapy as a treatment for medial tibial stress syndrome. AB - BACKGROUND: Medial tibial stress syndrome (MTSS) is a pain syndrome along the tibial origin of the tibialis posterior or soleus muscle. Extracorporeal shock wave therapy (SWT) is effective in numerous types of insertional pain syndromes. HYPOTHESIS: Shock wave therapy is an effective treatment for chronic MTSS. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Forty-seven consecutive subjects with chronic recalcitrant MTSS underwent a standardized home training program, and received repetitive low-energy radial SWT (2000 shocks; 2.5 bars of pressure, which is equal to 0.1 mJ/mm(2); total energy flux density, 200 mJ/mm(2); no local anesthesia) (treatment group). Forty-seven subjects with chronic recalcitrant MTSS were not treated with SWT, but underwent a standardized home training program only (control group). Evaluation was by change in numeric rating scale. Degree of recovery was measured on a 6-point Likert scale (subjects with a rating of completely recovered or much improved were rated as treatment success). RESULTS: One month, 4 months, and 15 months from baseline, success rates for the control and treatment groups according to the Likert scale were 13% and 30% (P < .001), 30% and 64% (P < .001), and 37% and 76% (P < .001), respectively. One month, 4 months, and 15 months from baseline, the mean numeric rating scale for the control and treatment groups were 7.3 and 5.8 (P < .001), 6.9 and 3.8 (P < .001), and 5.3 and 2.7 (P < .001), respectively. At 15 months from baseline, 40 of the 47 subjects in the treatment group had been able to return to their preferred sport at their preinjury level, as had 22 of the 47 control subjects. CONCLUSION: Radial SWT as applied was an effective treatment for MTSS. PMID- 19776341 TI - Clinical and radiologic outcomes of arthroscopic glenoid labrum repair with the BioKnotless suture anchor. AB - BACKGROUND: Although arthroscopic glenoid labrum repair using the BioKnotless anchor is common, the benefits and efficacy have not been fully evaluated. HYPOTHESIS: BioKnotless suture anchor is a clinically and radiologically suitable material for arthroscopic labral repair. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Ninety-seven patients underwent arthroscopic glenoid labrum repair with BioKnotless anchor between July 2004 and December 2005. Thirty-seven patients had traumatic anterior instability and 60 patients had an isolated superior labrum, anterior-posterior (SLAP) lesion. The mean age at surgery was 36.0 years (range, 15-66); the average follow-up was 34.1 months (range, 24-54). Clinical outcomes were evaluated using range of motion and various functional evaluation scores including sports activity. Pain and patient satisfaction were measured using a visual analog scale (VAS). Computed tomography arthrography was conducted in 73 patients at least 1 year after surgery for radiologic evaluation. RESULTS: In patients with instability, the Western Ontario Shoulder Instability index and Rowe score improved from 53.2 to 85.9 and from 68.7 to 92.7, respectively. Return to normal recreation and sports were possible in 30 patients (81.1%); the mean satisfaction VAS was 9.2. There was 1 postoperative dislocation, and the apprehension test was positive in 1 case. Postoperative range of motion including external rotation was not different. In patients with a SLAP lesion, the American Shoulder and Elbow Surgeons score and Constant score improved from 67.3 to 96.0 and 79.1 to 96.8, respectively. Pain VAS decreased from 6.0 to 0.4, and the mean satisfaction VAS was 9.4. Return to normal recreation and sports were possible in 50 patients (83.3%). All labra were found to have firmly healed to bony glenoid rim without anchor-related osteolysis in postoperative CT arthrography. CONCLUSION: Clinically and radiologically, the BioKnotless anchor appears to be an acceptable alternative for arthroscopic labrum repair, and a suitable material allowing the avoidance of certain troublesome drawbacks of the conventional knot-tying suture anchor. PMID- 19776342 TI - Revision open Bankart surgery after arthroscopic repair for traumatic anterior shoulder instability. AB - BACKGROUND: Only a few studies have provided homogeneous analysis of open revision surgery after a failed arthroscopic Bankart procedure. HYPOTHESIS: Open Bankart revision surgery will be effective in a failed arthroscopic anterior stabilization but inevitably results in a loss of range of motion, especially external rotation. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Twenty-six shoulders that went through traditional open Bankart repair as revision surgery after a failed arthroscopic Bankart procedure for traumatic anterior shoulder instability were enrolled for this study. The mean patient age at the time of revision surgery was 24 years (range, 16-38 years), and the mean duration of follow-up was 42 months (range, 25-97 months). RESULTS: The preoperative mean range of motion was 173 degrees in forward flexion and 65 degrees in external rotation at the side. After revision surgery, the ranges measured 164 degrees and 55 degrees, respectively (P = .024 and .012, respectively). At the last follow-up, the mean Rowe score was 81 points, with 88.5% of the patients reporting good or excellent results. After revision surgery, redislocation developed in 3 shoulders (11.5%), all of which had an engaging Hill-Sachs lesion and associated hyperlaxity (2+ or greater laxity on the sulcus sign). CONCLUSION: Open revision Bankart surgery for a failed arthroscopic Bankart repair can provide a satisfactory outcome, including a low recurrence rate and reliable functional return. In open revision Bankart surgery after failed stabilization for traumatic anterior shoulder instability, the surgeon should keep in mind the possibility of a postoperative loss of range of motion and a thorough examination for not only a Bankart lesion but also other associated lesions, including a bone defect or hyperlaxity, to lower the risk of redislocation. PMID- 19776344 TI - Comparative cytoarchitectural analyses of striate and extrastriate areas in hominoids. AB - The visual cortex is the largest sensory modality representation in the neocortex of humans and closely related species, and its size and organization has a central role in discussions of brain evolution. Yet little is known about the organization of visual brain structures in the species closest to humans--the apes--thus, making it difficult to evaluate hypotheses about recent evolutionary changes. The primate visual cortex is comprised of numerous cytoarchitectonically distinct areas, each of which has a specific role in the processing of visual stimuli. We examined the histological organization of striate (V1) and 2 extrastriate (V2 and ventral posterior) cortical areas in humans, 5 ape species, and a macaque. The cytoarchitectural patterns of visual areas were compared across species using quantitative descriptions of cell volume densities and laminar patterns. We also investigated potential scaling relationships between cell volume density and several brain, body, and visual system variables. The results suggest that interspecific variability in the cytoarchitectural organization of visual system structures can arise independently of global brain and body size scaling relationships. In particular, species-specific differences in cell volume density seem to be most closely linked to the size of structures in the visual system. PMID- 19776343 TI - Level of executive function influences verbal memory in amnestic mild cognitive impairment and predicts prefrontal and posterior cingulate thickness. AB - This study aims to investigate the relationship between executive function and verbal memory and to explore the underlying neuroanatomical correlates in 358 individuals with amnestic mild cognitive impairment (MCI) and 222 healthy controls (HCs). The MCI participants were divided into 2 groups (high vs. low) based on executive function task performance. Results demonstrated that although both MCI groups were impaired on all memory measures relative to HCs, MCI individuals with higher executive function (HEF) demonstrated better verbal memory performance than those with lower executive function (LEF), particularly on measures of learning. The 2 MCI groups did not differ in mesial temporal morphometric measures, but the MCI LEF group showed significant thinning in dorsolateral prefrontal and posterior cingulate cortices bilaterally compared with the MCI HEF and HCs. Further, thickness in numerous regions of frontal cortex, and bilateral posterior cingulate, was significantly associated with memory performance in all MCI participants above and beyond the contribution of the mesial temporal regions known to be associated with episodic memory. Overall, these results demonstrate the importance of evaluating executive function in individuals with MCI to predict involvement of brain areas beyond the mesial temporal lobe. PMID- 19776345 TI - Retraction. Effect of superposed electromagnetic noise on DNA damage of lens epithelial cells induced by microwave radiation. PMID- 19776346 TI - The behavioral ecology of secondhand smoke exposure: A pathway to complete tobacco control. AB - INTRODUCTION: This article outlines a theoretical framework for research concerning secondhand smoke exposure (SHSe) prevention as a means to curtail the tobacco industry. METHODS: The Behavioral Ecological Model (BEM) assumes interlocking social contingencies of reinforcement (i.e., rewards or punishments) from the highest level of society (e.g., taxing cigarette sales) to physiological reactions to nicotine that influence smoking and SHSe. We review selected research concerning both policy and clinical efforts to restrict smoking and/or SHSe. RESULTS: Research to date has focused on smoking cessation with modest to weak effects. The BEM and empirical evidence suggest that cultural contingencies of reinforcement should be emphasized to protect people from SHSe, especially vulnerable children, pregnant women, the ill, the elderly, and low-income adults who have not "elected" to smoke. Doing so will protect vulnerable populations from industry-produced SHSe and may yield more and longer-lasting cessation. CONCLUSIONS: Interventions that reduce SHSe may serve as a Trojan horse to counter the tobacco industry. Future studies should: (a) guide policies to restrict SHSe; (b) develop powerful community and clinical interventions to reduce SHSe; (c) test the degree to which policies and other contexts enhance the effects of clinical interventions (e.g., media programs disclosing the disingenuous marketing by the industry); and (d) investigate the effects of all health care providers' ability to reduce SHSe and generate an antitobacco culture, by advising all clients to avoid starting to smoke, to protect their children from SHSe, and to quit smoking. PMID- 19776347 TI - Membrane insertion of the pleckstrin homology domain variable loop 1 is critical for dynamin-catalyzed vesicle scission. AB - The GTPase dynamin catalyzes the scission of deeply invaginated clathrin-coated pits at the plasma membrane, but the mechanisms governing dynamin-mediated membrane fission remain poorly understood. Through mutagenesis, we have altered the hydrophobic nature of the membrane-inserting variable loop 1 (VL1) of the pleckstrin homology (PH) domain of dynamin-1 and demonstrate that its stable insertion into the lipid bilayer is critical for high membrane curvature generation and subsequent membrane fission. Dynamin PH domain mutants defective in curvature generation regain function when assayed on precurved membrane templates in vitro, but they remain defective in the scission of clathrin-coated pits in vivo. These results demonstrate that, in concert with dynamin self assembly, PH domain membrane insertion is essential for fission and vesicle release in vitro and for clathrin-mediated endocytosis in vivo. PMID- 19776348 TI - Paxillin-kinase-linker tyrosine phosphorylation regulates directional cell migration. AB - Directed cell migration requires the coordination of growth factor and cell adhesion signaling and is of fundamental importance during embryonic development, wound repair, and pathological conditions such as tumor metastasis. Herein, we demonstrate that the ArfGAP, paxillin-kinase-linker (PKL/GIT2), is tyrosine phosphorylated in response to platelet-derived growth factor (PDGF) stimulation, in an adhesion dependent manner and is necessary for directed cell migration. Using a combination of pharmacological inhibitors, knockout cells and kinase mutants, FAK, and Src family kinases were shown to mediate PDGF-dependent PKL tyrosine phosphorylation. In fibroblasts, expression of a PKL mutant lacking the principal tyrosine phosphorylation sites resulted in loss of wound-induced cell polarization as well as directional migration. PKL phosphorylation was necessary for PDGF-stimulated PKL binding to the focal adhesion protein paxillin and expression of paxillin or PKL mutants defective in their respective binding motifs recapitulated the polarization defects. RNA interference or expression of phosphorylation mutants of PKL resulted in disregulation of PDGF-stimulated Rac1 and PAK activities, reduction of Cdc42 and Erk signaling, as well as mislocalization of betaPIX. Together these studies position PKL as an integral component of growth factor and cell adhesion cross-talk signaling, controlling the development of front-rear cell polarity and directional cell migration. PMID- 19776349 TI - Spatiotemporal regulation of chloride intracellular channel protein CLIC4 by RhoA. AB - Chloride intracellular channel (CLIC) 4 is a soluble protein structurally related to omega-type glutathione-S-transferases (GSTs) and implicated in various biological processes, ranging from chloride channel formation to vascular tubulogenesis. However, its function(s) and regulation remain unclear. Here, we show that cytosolic CLIC4 undergoes rapid but transient translocation to discrete domains at the plasma membrane upon stimulation of G(13)-coupled, RhoA-activating receptors, such as those for lysophosphatidic acid, thrombin, and sphingosine-1 phosphate. CLIC4 recruitment is strictly dependent on Galpha(13)-mediated RhoA activation and F-actin integrity, but not on Rho kinase activity; it is constitutively induced upon enforced RhoA-GTP accumulation. Membrane-targeted CLIC4 does not seem to enter the plasma membrane or modulate transmembrane chloride currents. Mutational analysis reveals that CLIC4 translocation depends on at least six conserved residues, including reactive Cys35, whose equivalents are critical for the enzymatic function of GSTs. We conclude that CLIC4 is regulated by RhoA to be targeted to the plasma membrane, where it may function not as an inducible chloride channel but rather by displaying Cys-dependent transferase activity toward a yet unknown substrate. PMID- 19776350 TI - Direct and indirect roles of cyclin-dependent kinase 5 as an upstream regulator in the c-Jun NH2-terminal kinase cascade: relevance to neurotoxic insults in Alzheimer's disease. AB - Significant increase in JNK, c-Jun, and Cdk5 activities are reported in Alzheimer's disease (AD). Inhibition of c-Jun prevents neuronal cell death in in vivo AD models, highlighting it as a major JNK effector. Both JNK and Cdk5 promote neurodegeneration upon deregulation; however, Cdk5 has not been mechanistically linked to JNK or c-Jun. This study presents the first mechanism showing Cdk5 as a major regulator of the JNK cascade. Deregulated Cdk5 induces biphasic activation of JNK pathway. The first phase revealed c-Jun as a direct substrate of Cdk5, whose activation is independent of reactive oxygen species (ROS) and JNK. In the second phase, Cdk5 activates c-Jun via ROS-mediated activation of JNK. Rapid c-Jun activation is supported by in vivo data showing c Jun phosphorylation in cerebral cortex upon p25 induction in transgenic mice. Cdk5-mediated biphasic activation of c-Jun highlights c-Jun, rather than JNK, as an important therapeutic target, which was confirmed in neuronal cells. Finally, Cdk5 inhibition endows superior protection against neurotoxicity, suggesting that Cdk5 is a preferable therapeutic target for AD relative to JNK and c-Jun. PMID- 19776351 TI - Early-arriving Syp1p and Ede1p function in endocytic site placement and formation in budding yeast. AB - Recent studies have revealed the detailed timing of protein recruitment to endocytic sites in budding yeast. However, little is understood about the early stages of their formation. Here we identify the septin-associated protein Syp1p as a component of the machinery that drives clathrin-mediated endocytosis in budding yeast. Syp1p arrives at endocytic sites early in their formation and shares unique dynamics with the EH-domain protein Ede1p. We find that Syp1p is related in amino acid sequence to several mammalian proteins one of which, SGIP1 alpha, is an endocytic component that binds the Ede1p homolog Eps15. Like Syp1p, SGIP1-alpha arrives early at sites of clathrin-mediated endocytosis, suggesting that Syp1p/Ede1p and SGIP1-alpha/Eps15 may have a conserved function. In yeast, both Syp1p and Ede1p play important roles in the rate of endocytic site turnover. Additionally, Ede1p is important for endocytic site formation, whereas Syp1p acts as a polarized factor that recruits both Ede1p and endocytic sites to the necks of emerging buds. Thus Ede1p and Syp1p are conserved, early-arriving endocytic proteins with roles in the formation and placement of endocytic sites, respectively. PMID- 19776352 TI - Dkk-1 inhibits intestinal epithelial cell migration by attenuating directional polarization of leading edge cells. AB - Wnt signaling pathways regulate proliferation, motility, and survival in a variety of human cell types. Dickkopf-1 (Dkk-1) is a secreted Wnt antagonist that has been proposed to regulate tissue homeostasis in the intestine. In this report, we show that Dkk-1 is secreted by intestinal epithelial cells after wounding and that it inhibits cell migration by attenuating the directional orientation of migrating epithelial cells. Dkk-1 exposure induced mislocalized activation of Cdc42 in migrating cells, which coincided with a displacement of the polarity protein Par6 from the leading edge. Consequently, the relocation of the microtubule organizing center and the Golgi apparatus in the direction of migration was significantly and persistently inhibited in the presence of Dkk-1. Small interfering RNA-induced down-regulation of Dkk-1 confirmed that extracellular exposure to Dkk-1 was required for this effect. Together, these data demonstrate a novel role of Dkk-1 in the regulation of directional polarization of migrating intestinal epithelial cells, which contributes to the effect of Dkk-1 on wound closure in vivo. PMID- 19776353 TI - The vesicle-inducing protein 1 from Synechocystis sp. PCC 6803 organizes into diverse higher-ordered ring structures. AB - The vesicle-inducing protein in plastids 1 (Vipp1) was found to be involved in thylakoid membrane formation in chloroplasts and cyanobacteria. In contrast to chloroplasts, it has been suggested that in cyanobacteria the protein is only tightly associated with the cytoplasmic membrane. In the present study we analyze and describe the subcellular localization and the oligomeric organization of Vipp1 from the cyanobacterium Synechocystis PCC 6803. Vipp1 forms stable dimers and higher-ordered oligomers in the cytoplasm as well as at both the cytoplasmic and thylakoid membrane. Vipp1 oligomers are organized in ring structures with a variable diameter of 25-33 nm and corresponding calculated molecular masses of approximately 1.6-2.2 MDa. Six different types of rings were found with an unusual 12-17-fold symmetrical conformation. The simultaneous existence of multiple types of rings is very unusual and suggests a special function of Vipp1. Involvement of diverse ring structures in vesicle formation is suggested. PMID- 19776354 TI - G alpha 12 inhibits alpha2 beta1 integrin-mediated Madin-Darby canine kidney cell attachment and migration on collagen-I and blocks tubulogenesis. AB - Regulation of epithelial cell attachment and migration are essential for normal development and maintenance of numerous tissues. G proteins and integrins are critical signaling proteins regulating these processes, yet in polarized cells little is known about the interaction of these pathways. Herein, we demonstrate that G alpha 12 inhibits interaction of MDCK cells with collagen-I, the major ligand for alpha2 beta1 integrin. Activating G alpha 12 (QL point mutation or stimulating endogenous G alpha 12 with thrombin) inhibited focal adhesions and lamellipodia formation and led to impaired cell migration. Consistent with G alpha 12-regulated attachment to collagen-I, G alpha 12-silenced MDCK cells revealed a more adherent phenotype. Inhibiting Rho kinase completely restored normal attachment in G alpha 12-activated cells, and there was partial recovery with inhibition of Src and protein phosphatase pathways. G alpha 12 activation led to decreased phosphorylation of focal adhesion kinase and paxillin with displacement of alpha2 integrin from the focal adhesion protein complex. Using the MDCK cell 3D-tubulogenesis assay, activated G alpha 12 inhibited tubulogenesis and led to the formation of cyst-like structures. Furthermore, G alpha 12-silenced MDCK cells were resistant to thrombin-stimulated cyst development. Taken together, these studies provide direct evidence for G alpha 12 integrin regulation of epithelial cell spreading and migration necessary for normal tubulogenesis. PMID- 19776355 TI - Yeast Sec1p functions before and after vesicle docking. AB - Sec1/Munc18 (SM) proteins bind cognate soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes and stimulate vesicle membrane fusion. Before fusion, vesicles are docked to specific target membranes. Regulation of vesicle docking is attributed to some but not all SM proteins, suggesting specialization of this earlier function. Yeast Sec1p seems to function only after vesicles are docked and SNARE complexes are assembled. Here, we show that yeast Sec1p is required before and after SNARE complex assembly, in support of general requirements for SM proteins in both vesicle docking and fusion. Two classes of sec1 mutants were isolated. Class A mutants are tightly blocked in cell growth and secretion at a step before SNARE complex assembly. Class B mutants have a SNARE complex binding defect, with a range in severity of cell growth and secretion defects. Mapping the mutations onto an SM protein structure implicates a peripheral bundle of helices for the early, docking function and a deep groove, opposite the syntaxin-binding cleft on nSec1/Munc-18, for the interaction between Sec1p and the exocytic SNARE complex. PMID- 19776356 TI - Trafficking of Crumbs3 during cytokinesis is crucial for lumen formation. AB - Although lumen generation has been extensively studied through so-called cyst formation assays in Madin-Darby canine kidney (MDCK) cells, an underlying mechanism that leads to the initial appearance of a solitary lumen remains elusive. Lumen formation is thought to take place at early stages in aggregates containing only a few cells. Evolutionarily conserved polarity protein complexes, namely the Crumbs, Par, and Scribble complexes, establish apicobasal polarity in epithelial cells, and interference with their function impairs the regulated formation of solitary epithelial lumina. Here, we demonstrate that MDCK cells form solitary lumina during their first cell division. Before mitosis, Crumbs3a becomes internalized and concentrated in Rab11-positive recycling endosomes. These compartments become partitioned in both daughter cells and are delivered to the site of cytokinesis, thus forming the first apical membrane, which will eventually form a lumen. Endosome trafficking in this context appears to depend on the mitotic spindle apparatus and midzone microtubules. Furthermore, we show that this early lumen formation is regulated by the apical polarity complexes because Crumbs3 assists in the recruitment of aPKC to the forming apical membrane and interference with their function can lead to the formation of a no-lumen or multiple-lumen phenotype at the two-cell stage. PMID- 19776357 TI - Hec1 contributes to mitotic centrosomal microtubule growth for proper spindle assembly through interaction with Hice1. AB - Previous studies have stipulated Hec1 as a conserved kinetochore component critical for mitotic control in part by directly binding to kinetochore fibers of the mitotic spindle and by recruiting spindle assembly checkpoint proteins Mad1 and Mad2. Hec1 has also been reported to localize to centrosomes, but its function there has yet to be elucidated. Here, we show that Hec1 specifically colocalizes with Hice1, a previously characterized centrosomal microtubule binding protein, at the spindle pole region during mitosis. In addition, the C terminal region of Hec1 directly binds to the coiled-coil domain 1 of Hice1. Depletion of Hice1 by small interfering RNA (siRNA) reduced levels of Hec1 in the cell, preferentially at centrosomes and spindle pole vicinity. Reduction of de novo microtubule nucleation from mitotic centrosomes can be observed in cells treated with Hec1 or Hice1 siRNA. Consistently, neutralization of Hec1 or Hice1 by specific antibodies impaired microtubule aster formation from purified mitotic centrosomes in vitro. Last, disruption of the Hec1/Hice1 interaction by overexpressing Hice1DeltaCoil1, a mutant defective in Hec1 interaction, elicited abnormal spindle morphology often detected in Hec1 and Hice1 deficient cells. Together, the results suggest that Hec1, through cooperation with Hice1, contributes to centrosome-directed microtubule growth to facilitate establishing a proper mitotic spindle. PMID- 19776358 TI - The influence of motor training on human express saccade production. AB - Express saccadic eye movements are saccades of extremely short latency. In monkey, express saccades have been shown to occur much more frequently when the monkey has been trained to make saccades in a particular direction to targets that appear in predictable locations. Such results suggest that express saccades occur in large number only under highly specific conditions, leading to the view that vector-specific training and motor preparatory processes are required to make an express saccade of a particular magnitude and direction. To evaluate this hypothesis in humans, we trained subjects to make saccades quickly to particular locations and then examined whether the frequency of express saccades depended on training and the number of possible target locations. Training significantly decreased saccade latency and increased express saccade production to both trained and untrained locations. Increasing the number of possible target locations (two vs. eight possible targets) led to only a modest increase of saccade latency. For most subjects, the probability of express saccade occurrence was much higher than that expected if vector-specific movement preparation were necessary for their production. These results suggest that vector-specific motor preparation and vector-specific saccade training are not necessary for express saccade production in humans and that increases in express saccade production are due in part to a facilitation in fixation disengagement or else a general enhancement in the ability of the saccadic system to respond to suddenly appearing visual stimuli. PMID- 19776359 TI - Modulation of visual signals in macaque MT and MST neurons during pursuit eye movement. AB - Retinal image motion is produced with each eye movement, yet we usually do not perceive this self-produced "reafferent" motion, nor are motion judgments much impaired when the eyes move. To understand the neural mechanisms involved in processing reafferent motion and distinguishing it from the motion of objects in the world, we studied the visual responses of single cells in middle temporal (MT) and medial superior temporal (MST) areas during steady fixation and smooth pursuit eye movements in awake, behaving macaques. We measured neuronal responses to random-dot patterns moving at different speeds in a stimulus window that moved with the pursuit target and the eyes. This allowed us to control retinal image motion at all eye velocities. We found the expected high proportion of cells selective for the direction of visual motion. Pursuit tracking changed both response amplitude and preferred retinal speed for some cells. The changes in preferred speed were on average weakly but systematically related to the speed of pursuit for area MST cells, as would be expected if the shifts in speed selectivity were compensating for reafferent input. In area MT, speed tuning did not change systematically during pursuit. Many cells in both areas also changed response amplitude during pursuit; the most common form of modulation was response suppression when pursuit was opposite in direction to the cell's preferred direction. These results suggest that some cells in area MST encode retinal image motion veridically during eye movements, whereas others in both MT and MST contribute to the suppression of visual responses to reafferent motion. PMID- 19776360 TI - LTD and LTP at the developing retinogeniculate synapse. AB - The purpose of the present study was to determine whether retinal activity can support long-term changes in synaptic strength in the developing dorsal lateral geniculate nucleus (LGN) of thalamus. To test for this we made use of a rodent in vitro explant preparation in which retinal afferents and the intrinsic circuitry of the LGN remain intact. We repetitively stimulated the optic tract with a tetanus protocol that approximated the temporal features of spontaneous retinal waves. We found the amplitude of extracellular field potentials evoked by retinal stimulation changed significantly after tetanus and that the polarity of these alterations was related to postnatal age. At a time when substantial pruning of retinal connections occurs (postnatal day 1 [P1] to P14), high-frequency stimulation led to an immediate and long-term depression (LTD). However, at times when pruning wanes and adult-like patterns of connectivity are stabilizing (P16 to P30), the identical form of stimulation produced a modest form of potentiation (long-term potentiation [LTP]). The LTD was unaffected by the bath application of gamma-aminobutyric acid type A and N-methyl-D-aspartate receptor antagonists. However, both LTD and LTP were blocked by L-type Ca(2+)-channel antagonists. Thus the Ca(2+) influx associated with L-type channel activation mediates the induction of synaptic plasticity and may signal the pruning and subsequent stabilization of developing retinogeniculate connections. PMID- 19776362 TI - The functional specialization of the planum temporale. AB - The planum temporale (PT) is an anatomically heterogeneous area with several architectonic subdivisions and extensive connections with other parts of the brain. Here I review a functional MRI study investigating the role of a functionally defined area (Spt) within the left PT in speech motor processing and discuss the functional properties of PT regions in the context of findings from recent neurophysiological and neuroimaging studies. PMID- 19776361 TI - Long-term potentiation of excitatory synapses on neocortical somatostatin expressing interneurons. AB - Synaptic plasticity has been extensively studied in principal neurons of the neocortex, but less work has been done on GABAergic interneurons. Interneurons consist of multiple subtypes and their synaptic properties vary between subtypes. In the present study, we have examined long-term potentiation (LTP) of excitatory synapses on somatostatin (SS)-expressing interneurons in neocortex using transgenic mice that express enhanced green fluorescent protein in these interneurons. We found that a strong theta burst stimulation was required to induce LTP in SS interneurons. LTP was associated with a reduction in paired pulse facilitation and was not blocked by an N-methyl-d-aspartate receptor (NMDAR) antagonist. LTP was not affected by chelating postsynaptic Ca(2+) with BAPTA, a fast Ca(2+) chelator, and blocking L-type voltage-dependent Ca(2+) channels with nimodipine. Application of forskolin, an activator of adenylate cyclase that increases cyclic adenosine monophosphate (cAMP) concentration, enhanced synaptic transmission and occluded subsequent induction of LTP. Finally, we found that LTP was blocked by protein kinase A (PKA) inhibitors. Our results suggest that excitatory synapses on SS interneurons express a presynaptic form of LTP that is not dependent on NMDARs or postsynaptic Ca(2+) rise but is dependent on the cAMP-PKA signaling pathway. PMID- 19776365 TI - Cerebral representation of the relief of itch by scratching. AB - Cerebral processing of itch-scratching cycles was studied with functional magnetic resonance imaging (fMRI) in healthy volunteers. The back of the hand was repetitively scratched in the absence and presence of itch induced by histamine applied close to the scratched site. Blood-oxygenation-level-dependent (BOLD) effects were assessed in predefined cortical and subcortical brain regions of interest. Scratch-related activation clusters were found in cortical and subcortical areas which had been associated before with pain processing, namely S1, S2, parietal association cortex, motor and premotor cortex, anterior and posterior insula, anterior and medial cingulum, lateral and medial frontal areas, ipsilateral cerebellum and contralateral putamen. Cortical activations were generally stronger in the contralateral hemisphere. General linear model (GLM) analysis and GLM contrast analysis revealed stronger activations during itch related trials in the motor and premotor cortex, in lateral frontal fields of both sides, and in a left medial frontal cluster. Subcortically, stronger activation during itch-related scratching trials was found in the contralateral putamen and in the ipsilateral cerebellum. Time course analysis showed significantly higher BOLD levels during the last 3-6 s before the start of scratching when the itch intensity was strongest. This effect was found in frontal areas, in the putamen, and in the somatosensory projection areas. During the scratching, no significant differences were found between itch and control conditions with the exception of the putamen, which showed stronger activations during itch-related scratch bouts. We interpret these itch-related activations anticipating the scratching as possible cerebral correlates of the itch processing and the craving for scratch. PMID- 19776363 TI - Encoding of reward and space during a working memory task in the orbitofrontal cortex and anterior cingulate sulcus. AB - Several lines of research indicate that emotional and motivational information may be useful in guiding the allocation of attentional resources. Two areas of the frontal lobe that are particularly implicated in the encoding of motivational information are the orbital prefrontal cortex (PFo) and the dorsomedial region of prefrontal cortex, specifically the anterior cingulate sulcus (PFcs). However, it remains unclear whether these areas use this information to influence spatial attention. We used single-unit neurophysiology to examine whether, at the level of individual neurons, there was evidence for integration between reward information and spatial attention. We trained two subjects to perform a task that required them to attend to a spatial location across a delay under different expectancies of reward for correct performance. We balanced the order of presentation of spatial and reward information so we could assess the neuronal encoding of the two pieces of information independently and conjointly. We found little evidence for encoding of the spatial location in either PFo or PFcs. In contrast, both areas encoded the expected reward. Furthermore, PFo consistently encoded reward more quickly than PFcs, although reward encoding was subsequently more prevalent and stronger in PFcs. These results suggest a differential contribution of PFo and PFcs to reward encoding, with PFo potentially more important for initially determining the value of rewards predicted by sensory stimuli. They also suggest that neither PFo nor PFcs play a direct role in the control of spatial attention. PMID- 19776364 TI - Functional distinction between visuomovement and movement neurons in macaque frontal eye field during saccade countermanding. AB - In the previous studies on the neural control of saccade initiation using the countermanding paradigm, movement and visuomovement neurons in the frontal eye field were grouped as movement-related neurons. The activity of both types of neurons was modulated when a saccade was inhibited in response to a stop signal, and this modulation occurred early enough to contribute to the control of the saccade initiation. We now report a functional difference between these two classes of neurons when saccades are produced. Movement neurons exhibited a progressive accumulation of discharge rate following target presentation that triggered a saccade when it reached a threshold. When saccades were inhibited with lower probability in response to a stop signal appearing at longer delays, this accumulating activity was interrupted at levels progressively closer to the threshold. In contrast, visuomovement neurons exhibited a maintained elevated discharge rate following target presentation that was followed by a further enhancement immediately before the saccade initiation. When saccades were inhibited in response to a stop signal, the late enhancement was absent and the maintained activity decayed regardless of stop-signal delay. These results demonstrate that the activity of movement neurons realizes the progressive commitment to the saccade initiation modeled by the activation of the go unit in computational models of countermanding performance. The lack of correspondence of the activity of visuomovement neurons with any elements of these models indicates that visuomovement neurons perform a function other than the saccade preparation such as a corollary discharge to update visual processing. PMID- 19776366 TI - Intraperiaqueductal gray glycine and D-serine exert dual effects on rostral ventromedial medulla ON- and OFF-cell activity and thermoceptive threshold in the rat. AB - We have studied the involvement of the N-methyl-D-aspartate receptor (NMDAR) glycine site and the strychnine-sensitive glycine receptor (GlyR) in the ventrolateral periaqueductal gray (VL-PAG) on nociceptive behavior (tail flick) and pain-related changes on neuronal activity in the rostral ventromedial medulla (RVM). Glycine or D-serine increased the tail-flick latency, reduced OFF-cell pause, and delayed its onset and increased the time between the onset of the OFF cell pause and the tail withdrawal. Conversely, they decreased the ongoing activity of the ON cell, the tail-flick-induced ON-cell firing, whereas they delayed the onset of increased tail-flick-induced ON-cell firing. Also, glycine or D-serine reduced the interval between the onset of the increased ON-cell firing and tail withdrawal. Whereas 7-Cl-kynurenic acid (7-Cl-KYN) prevented such effects, strychnine did not do so. A higher dose of 7-Cl-KYN or strychnine was per se able to reduce or increase tail-flick latency and increase or reduce ON cell activities, respectively. A higher dose of glycine was hyperalgesic in the presence of 7-Cl-KYN, whereas such an effect was prevented by strychnine. These data suggest 1) a dual role of glycine in producing hyperalgesia or analgesia by stimulating the GlyR or the NMDARs within the VL-PAG, respectively; 2) consistently that RVM ON and OFF cells display opposite firing patterns to the stimulation of the VL-PAG NMDAR glycine site and GlyR activation; and 3) a tonic role of these receptors within the VL-PAG-RVM antinociceptive descending pathway. PMID- 19776368 TI - The vasculature emerges as a potential therapeutic target in treating ADPKD liver cysts. PMID- 19776367 TI - Sphingosine-1-phosphate elicits receptor-dependent calcium signaling in retinal amacrine cells. AB - Evidence is emerging indicating that sphingosine-1-phosphate (S1P) participates in signaling in the retina. To determine whether S1P might be involved in signaling in the inner retina specifically, we examine the effects of this sphingolipid on cultured retinal amacrine cells. Whole cell voltage-clamp recordings reveal that S1P activates a cation current that is dependent on signaling through G(i) and phospholipase C. These observations are consistent with the involvement of members of the S1P receptor family of G-protein-coupled receptors in the production of the current. Immunocytochemistry and PCR amplification provide evidence for the expression of S1P1R and S1P3R in amacrine cells. The receptor-mediated channel activity is shown to be highly sensitive to blockade by lanthanides consistent with the behavior of transient receptor potential canonical (TRPC) channels. PCR products amplified from amacrine cells reveal that TRPCs 1 and 3-7 channel subunits have the potential to be expressed. Because TRPC channels provide a Ca(2+) entry pathway, we asked whether S1P caused cytosolic Ca(2+) elevations in amacrine cells. We show that S1P-dependent Ca(2+) elevations do occur in these cells and that they might be mediated by S1P1R and S1P3R. The Ca(2+) elevations are partially due to release from internal stores, but the largest contribution is from influx across the plasma membrane. The effect of inhibition of sphingosine kinase suggests that the production of cytosolic S1P underlies the sustained nature of the Ca(2+) elevations. Elucidation of the downstream effects of these signals will provide clues to the role of S1P in regulating inner retinal function. PMID- 19776369 TI - End-of-life vignette. No time for death. PMID- 19776370 TI - Noninvasive ventilation in immunosuppressed patients. AB - In immunosuppressed patients (ISP) with acute respiratory failure (ARF), invasive mechanical ventilation (IMV) is associated with high mortality rate. Noninvasive ventilation (NIV) is a type of mechanical ventilation that does not require an artificial airway. It has seen increasing use in critically ill patients to avoid endotracheal intubation. Acute respiratory failure due to pulmonary infections is an important cause of illness in ISP and their treatment. Immunosuppressive treatments have showed an increase not only in the survival but also in the susceptibility to infection. Several authors have underlined the worst prognosis for neutropenic patients with ARF requiring endotracheal intubation and IMV. The NIV seems to be an interesting alternative in ISP because of the lower risk of complications; it prevents endotracheal intubation and its associated complications with survival benefits in this population. PMID- 19776371 TI - Comfort care versus euthanasia. PMID- 19776372 TI - A comparative study of 2 sustained-release morphine preparations for pain in advanced cancer. AB - PURPOSE: Several sustained-release morphine (SRM) formulations are available internationally. This study compared 2 such products available in the United States, SR1 and SR2. PATIENTS AND METHODS: In an open-label study, patients with advanced cancer pain were randomized to receive SR1 or SR2 every 12 hours around the-clock (ATC) for 5 days, with immediate release (IR) liquid morphine for rescue dosing (RD). Efficacy, safety, and patient acceptability were determined. RESULTS: A total of 32 patients were evaluable for efficacy and toxicity. Pain scores, RD dosage, RD frequency over 5 days, RD within 3 hours before and after the scheduled SRM, and 8 of the 11 evaluated side effects were higher in the SR1 group. At presumed morphine steady state (day 3), pain scores (P = .05), RD dosage (P = .07), RD frequency (P = .07), and number of RD +/-3 hours from scheduled SRM dose (P = .05) were consistently greater in the SR1 group (despite a higher median morphine dose in that group). There was a clinically important and directionally consistent trend that favored SR2, although not all were statistically significant. Patient preference favored SR2 (P < .05). Neither group had difficulty swallowing SR1 or SR2. CONCLUSIONS: This is the first study that directly compared two 12-hour SRM formulations. The data suggested, by multiple clinically important measures, that SR2 may provide superior analgesic efficacy and less toxicity compared to SR1. It also supports the concept that it cannot be assumed that different SR formulations of a given opioid are clinically equivalent. A larger study is needed to confirm our findings. PMID- 19776373 TI - Phase II trial of mirtazapine for cancer-related cachexia and anorexia. AB - We performed an open-label single-institution phase II trial of mirtazapine (15 30 mg by mouth [po] every day [qd]), a tetracyclic antidepressant that may lead to weight gain, for 8 weeks in nondepressed patients with cancer-related cachexia/anorexia (CRCA). The primary end point was the proportion of patients who gained > or =1 kg at week 4. Secondary end points were quality of life and appetite. From June 2006 to July 2007, 17 of 58 eligible patients were enrolled. On intention-to-treat analysis at week 4, 4 of 17 patients (24%) gained 1 kg or more, 1 patient maintained weight (gain of 400 g) and 2 patients lost weight (800 g and 1.2 kg); 24% and 6% improved appetite and health-related quality of life (HQOL), respectively. Mirtazapine is a promising agent for the treatment of CRCA. PMID- 19776375 TI - Predicting treatment responses to IV immunoglobulins: can we already ask the genes? PMID- 19776376 TI - Iatrogenic immunosuppression with biologics in MS: expecting the unexpected? PMID- 19776374 TI - Autoimmune disease and risk for Parkinson disease: a population-based case control study. AB - OBJECTIVE: Inflammatory mediators are increased in autoimmune diseases and may activate microglia and might cause an inflammatory state and degeneration of dopaminergic neurons in the brain. Thus, we evaluated whether having an autoimmune disease increases the risk for developing Parkinson disease (PD). METHODS: A population based case-control study was conducted in Denmark of 13,695 patients with a primary diagnosis of PD recorded in the Danish National Hospital Register during the period 1986-2006. Each case was matched on year of birth and sex to 5 population controls selected at random from among inhabitants of Denmark who were alive at the date of the patient's diagnosis. The main exposure measure was a hospital diagnosis of 1 of 32 selected autoimmune diseases recorded 5 or more years before the index date in the files of the Danish Hospital Register. RESULTS: We observed no overall association between a diagnosis of autoimmune disease and risk for subsequent PD (odds ratio 0.96, 95% confidence interval 0.85 1.08). In a subgroup of patients with autoimmune diseases with systemic involvement, primarily rheumatoid arthritis, we saw a decrease in risk for PD of 30%. CONCLUSIONS: Our results do not support the hypothesis that autoimmune diseases increase the risk for Parkinson disease. The decreased risk observed among patients with rheumatoid arthritis might be explained by underdiagnosis of movement disorders such as Parkinson disease in this patient group or by a protective effect of the treatment with anti-inflammatory drugs over prolonged periods. PMID- 19776377 TI - Huntington disease: a tale of two genes. PMID- 19776378 TI - Responding to requests from adult patients for neuroenhancements: guidance of the Ethics, Law and Humanities Committee. AB - In the last decade, persons who have no diagnosed medical or mental health condition are increasingly seeking and utilizing, for the ostensible purpose of enhancing their memory or cognitive skills, prescription drugs that were originally developed to improve executive function or memory in persons diagnosed with disorders such as attention deficit hyperactivity disorder or Alzheimer disease. Evidence suggests that this practice, now known as neuroenhancement, is gathering momentum. As a result, neurologists may be encountering patients without a diagnosed illness asking for medications with the goal of improving their memory, cognitive focus, or attention span. Strong arguments have been made for and against this practice, often reflecting strongly held convictions concerning the appropriate practice of medicine. The purpose of this report is to provide neurologists with an overview of the ethical, legal, and social issues surrounding the use of pharmaceuticals prescribed to enhance or augment normal cognitive or affective functioning, as well as practical guidance for responding to an adult patient's request for neuroenhancement. PMID- 19776379 TI - Ocular toxoplasmosis during natalizumab treatment. PMID- 19776380 TI - Single nucleotide polymorphism of TAG-1 influences IVIg responsiveness of Japanese patients with CIDP. AB - OBJECTIVE: Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by immune-mediated peripheral demyelination. Although corticosteroid, IV immunoglobulin (IVIg) and plasma exchange have been established as the most effective therapeutics, subpopulations of patients show little or no response to either of these therapies. In this study, we examined whether particular genetic factors influence the therapeutic responsiveness of patients with CIDP. METHODS: One hundred Japanese patients categorized as responders or nonresponders to IVIg therapy participated in our study. We performed an association analysis with single nucleotide polymorphisms (SNPs) and haplotype studies between the IVIg responders and nonresponders. RESULTS: Two separate SNPs, corresponding to TAG-1 (transient axonal glycoprotein 1) and CLEC10A (C-type lectin domain family 10, member A), showed strong significant differences between responders and nonresponders. Haplotype analysis of a series of expanded SNPs, from TAG-1 or CLEC10A, showed that only TAG-1 included a significant haplotype within 1 linkage disequilibrium block, which accommodates IVIg responsiveness. Diplotype analysis of TAG-1 also supported this observation. CONCLUSIONS: Transient axonal glycoprotein 1 is a crucial molecule involved in IV immunoglobulin responsiveness in Japanese patients with chronic inflammatory demyelinating polyneuropathy. PMID- 19776382 TI - Association of Merkel cell polyomavirus-specific antibodies with Merkel cell carcinoma. AB - BACKGROUND: Merkel cell polyomavirus (MCPyV) has been detected in approximately 75% of patients with the rare skin cancer Merkel cell carcinoma. We investigated the prevalence of antibodies against MCPyV in the general population and the association between these antibodies and Merkel cell carcinoma. METHODS: Multiplex antibody-binding assays were used to assess levels of antibodies against polyomaviruses in plasma. MCPyV VP1 antibody levels were determined in plasma from 41 patients with Merkel cell carcinoma and 76 matched control subjects. MCPyV DNA was detected in tumor tissue specimens by quantitative polymerase chain reaction. Seroprevalence of polyomavirus-specific antibodies was determined in 451 control subjects. MCPyV strain-specific antibody recognition was investigated by replacing coding sequences from MCPyV strain 350 with those from MCPyV strain w162. RESULTS: We found that 36 (88%) of 41 patients with Merkel cell carcinoma carried antibodies against VP1 from MCPyV w162 compared with 40 (53%) of the 76 control subjects (odds ratio adjusted for age and sex = 6.6, 95% confidence interval [CI] = 2.3 to 18.8). MCPyV DNA was detectable in 24 (77%) of the 31 Merkel cell carcinoma tumors available, with 22 (92%) of these 24 patients also carrying antibodies against MCPyV. Among 451 control subjects from the general population, prevalence of antibodies against human polyomaviruses was 92% (95% CI = 89% to 94%) for BK virus, 45% (95% CI = 40% to 50%) for JC virus, 98% (95% CI = 96% to 99%) for WU polyomavirus, 90% (95% CI = 87% to 93%) for KI polyomavirus, and 59% (95% CI = 55% to 64%) for MCPyV. Few case patients had reactivity against MCPyV strain 350; however, indistinguishable reactivities were found with VP1 from strain 350 carrying a double mutation (residues 288 and 316) and VP1 from strain w162. CONCLUSION: Infection with MCPyV is common in the general population. MCPyV, but not other human polyomaviruses, appears to be associated with Merkel cell carcinoma. PMID- 19776383 TI - The transfer of adaptive immunity to CMV during hematopoietic stem cell transplantation is dependent on the specificity and phenotype of CMV-specific T cells in the donor. AB - The successful reconstitution of adaptive immunity to human cytomegalovirus (CMV) in hematopoietic stem cell transplantation (HSCT) recipients is central to the reduction of viral reactivation-related morbidity and mortality. Here, we characterized the magnitude, specificity, phenotype, function, and clonotypic composition of CMV-specific T-cell responses in 18 donor-recipient pairs both before and after HSCT. The principal findings were: (1) the specificity of CMV specific T-cell responses in the recipient after HSCT mirrors that in the donor; (2) the maintenance of these targeting patterns reflects the transfer of epitope specific T-cell clonotypes from donor to recipient; (3) less differentiated CD27(+)CD57(-) CMV-specific memory T cells are more likely to persist in the recipient after HSCT compared with more terminally differentiated CD27(-) CD57(+) CMV-specific memory T cells; (4) the presence of greater numbers of less differentiated CD8(+) CMV-specific T cells in the donor appears to confer protection against viral reactivation in the recipient after HSCT; and (5) CMV specific T cells acquire a more differentiated phenotype and a restricted functional profile after HSCT. Overall, these findings define the immunologic factors that influence the successful adoptive transfer of antigen-specific T cell immunity during HSCT, which enables the identification of recipients at particular risk of CMV reactivation after HSCT. PMID- 19776384 TI - Comparative effects of aprotinin and human recombinant R24K KD1 on temporal renal function in Long-Evans rats. AB - Bovine aprotinin, a reversible inhibitor of plasmin and kallikrein, has been clinically approved for over two decades to prevent perioperative blood loss during cardiac surgery. However, because of postoperative renal dysfunction in thousands of these patients, aprotinin was voluntarily withdrawn from the market. Our earlier studies indicated that a R24K mutant of the first Kunitz-type domain of human tissue factor pathway inhibitor-2 (R24K KD1) exhibited plasmin inhibitory activity equivalent to aprotinin in vitro. In this study, we compared the effects on renal function after infusion of aprotinin and recombinant R24K KD1 in chronically instrumented, conscious rats. Aprotinin-infused rats exhibited statistically significant decreases in glomerular filtration rate and effective renal plasma flow relative to rats infused with phosphate-buffered saline (PBS) or R24K KD1 dissolved in PBS. In addition, aprotinin-treated rats exhibited marked increases in serum creatinine, blood urea nitrogen, urinary protein, and effective renal vascular resistance, whereas these renal parameters remained essentially unchanged in vehicle and R24K KD1-treated rats for a one-week period. Moreover, with use of a highly sensitive apoptosis detection assay, a significant increase in the rate of early and late apoptotic events in renal tubule cells occurred in aprotinin-treated rats relative to R24K KD1-treated rats. In addition, histological examination of the rat kidney revealed markedly higher levels of protein reabsorption droplets in the aprotinin-infused rats. Our data collectively provide suggestive evidence that R24K KD1 does not induce the renal dysfunction associated with aprotinin, and may be an effective clinical alternative to aprotinin as an antifibrinolytic agent in cardiac surgery. PMID- 19776385 TI - Differential effects of arachidonic and eicosapentaenoic Acid-derived eicosanoids on polymorphonuclear transmigration across endothelial cell cultures. AB - The beneficial effects of fish oil on inflammation have been attributed to the content of eicosapentaenoic (EPA)/docosahexaenoic acid. EPA is also a substrate for arachidonic acid (AA) cascade enzymes, but it induces the production of alternative eicosanoids such as 3-series prostanoids and 5-series leukotrienes, which are considered to be less proinflammatory than AA metabolites. However, the molecular basis of this action is poorly understood. In this study, we compared the effects of prostaglandin (PG) E(2) and PGE(3) on endothelium permeability, and the effects of leukotriene (LT) B(4) and LTB(5) on endothelium permeability and mononuclear adhesion and migration. In our study, both prostaglandins increased trans-endothelial Evans blue-albumin (EBA) permeability in a concentration-dependent manner. It is interesting that the effect of PGE(3) was significantly more pronounced than the effect of PGE(2), and both were antagonized by EP(1) and EP(2) antagonists. LTB(4) and LTB(5) had a slight effect on EBA extravasation. However, we observed the enhancement of endothelial permeability in the presence of polymorphonuclear (PMN) cells, probably a consequence of an interplay between leukotriene and prostanoid effects. LTB(4) caused significant increases in the number of PMN cells adhering to endothelial cells, whereas LTB(5) did not induce a significant effect. This effect of LTB(4) appears BLT1 receptor-dependent and was mediated through the enhancement of lymphocyte function-associated antigen-1, membrane attack complex-1, E-selectin, and intercellular adhesion molecule-1 expression. Finally, we observed that, unlike LTB(5), which had a weak effect, LTB(4) was a highly potent chemoattractant. An understanding of the differences in the effects of LTB(4)/LTB(5) on PMN cell adhesion and migration may help to explain the beneficial impact of omega-3 fatty acids in inflammatory processes. PMID- 19776386 TI - Tubulointerstitial nephritis antigen-like 1 is expressed in the uterus and binds with integrins in decidualized endometrium during postimplantation in mice. AB - Extracellular matrix substrates contribute to both uterine and blastocyst functions during the peri-implantation period. Tubulointerstitial nephritis antigen-like 1 (TINAGL1, also known as adrenocortical zonation factor 1 [AZ-1] or lipocalin 7) is a novel matricellular protein that promotes cell adhesion and spreading. However, the physiological roles of TINAGL1 are still not clearly understood. We examined the expression and localization of TINAGL1 in peri implantation mouse uteri. During the preimplantation period, TINAGL1 was expressed in the basement membranes of uterine luminal epithelial cells on Days 1 and 2 of pregnancy, while its expression levels declined after Day 3. In the whole uteri, the expression levels of Tinagl1 mRNA and TINAGL1 protein were similar on Days 1-4 of pregnancy. In contrast, the expression of Tinagl1 mRNA and TINAGL1 protein increased in postimplantation uteri. From Days 6 to 8, TINAGL1 was markedly expressed in the decidual endometrium. TINAGL1 is a ligand for integrins and promotes cell adhesion in cultured cells. Therefore, to address whether TINAGL1 interacts with integrins in the uterus, immunohistochemical analysis and immunoprecipitation were performed. Immunohistochemical analysis showed that ITGA2, ITGA5, and ITGB1 were expressed in stromal cells around the implanted embryos on Days 7 and 8. Biacore and immunoprecipitation analysis determined that TINAGL1 linked with ITGA5 and ITGB1 in the decidual endometrium. These results suggest that Tinagl1 functions during the postimplantation period; in particular, it associates with ITGA5B1 in the decidualized uterine endometrium. PMID- 19776381 TI - Normal and mutant HTT interact to affect clinical severity and progression in Huntington disease. AB - OBJECTIVE: Huntington disease (HD) is an autosomal dominant neurodegenerative disorder caused by a CAG repeat expansion in the HD gene (HTT). We aimed to assess whether interaction between CAG repeat sizes in the mutant and normal allele could affect disease severity and progression. METHODS: Using linear regression and mixed-effects models, the influence of mutant and normal CAG repeat sizes interaction was assessed on 1) age at onset in 921 patients with HD, 2) clinical severity and progression in 512 of these patients with follow-up data available, and 3) basal ganglia volume on magnetic resonance images in 16 premanifest HD mutation carriers. RESULTS: Normal and mutant CAG repeat sizes interacted to influence 1) age at onset (p = 0.001), 2) severity or progression of motor, cognitive, and functional, but not behavioral, symptoms in patients with HD (all p < 0.05), and 3) in premanifest subjects, basal ganglia volumes (p < 0.05). In subjects with mutant CAG expansions in the low range, increasing size of the normal repeat correlated with more severe symptoms and pathology, whereas for those subjects with expansions in the high range, increasing size of the normal repeat correlated with less severe symptoms and pathology. CONCLUSIONS: Increasing CAG repeat size in normal HTT diminishes the association between mutant CAG repeat size and disease severity and progression in Huntington disease. The underlying mechanism may involve interaction of the polyglutamine domains of normal and mutant huntingtin (fragments) and needs further elucidation. These findings may have predictive value and are essential for the design and interpretation of future therapeutic trials. PMID- 19776387 TI - The presence and activation of two essential transcription factors (cAMP response element-binding protein and cAMP-dependent transcription factor ATF1) in the two cell mouse embryo. AB - The expression of two members of an important family of transcription factors, cAMP response element-binding protein (CREB) and cAMP-dependent transcription factor ATF1 (ATF1), is essential for normal preimplantation development. There is a high degree of functional similarity between these two transcription factors, and they can both homodimerize and heterodimerize with each other to form active transcription factors. CREB is present in all stages of mouse preimplantation embryo, and we show here that ATF1 is localized to the nucleus in all preimplantation stages. Activation of these transcription factors requires their phosphorylation, and this was only observed to occur for both transcription factors (serine 133 phosphorylation of CREB and serine 63 phosphorylation of ATF1) at the two-cell stage. Nuclear localization and phosphorylation of ATF1 were constitutive. The nuclear localization and phosphorylation of CREB showed a constitutive component that was further induced by the autocrine embryotropin Paf (1-o-alkyl-2-acetyl-sn-glycero-3-phosphocholine). Activation of CREB by Paf was independent of cAMP but was dependent on calcium, calmodulin, and calmodulin dependent kinase activity. ATF1 nuclear localization was unaffected by inhibition of the calcium/calmodulin pathway. A complex pattern of expression of calmodulin dependent kinases was observed throughout preimplantation development. At the two cell stage, only mRNAs coding for calmodulin-dependent protein kinase kinase beta, calmodulin-dependent protein kinase II gamma, and calmodulin-dependent protein kinase IV were detected. A selective antagonist for calmodulin-dependent protein kinase kinase (STO-609) and calmodulin-dependent protein kinases I, II, and IV (KN-62) blocked the Paf-induced phosphorylation of CREB. The study demonstrates a role for trophic signaling and constitutive activation of two essential transcription factors at the time of zygotic genome activation. PMID- 19776388 TI - Critical function of AP-2 gamma/TCFAP2C in mouse embryonic germ cell maintenance. AB - Formation of the germ cell lineage involves multiple processes, including repression of somatic differentiation and reacquisition of pluripotency as well as a unique epigenetic constitution. The transcriptional regulator Prdm1 has been identified as a main coordinator of this process, controlling epigenetic modification and gene expression. Here we report on the expression pattern of the transcription factor Tcfap2c, a putative downstream target of Prdm1, during normal mouse embryogenesis and the consequences of its specific loss in primordial germ cells (PGCs) and their derivatives. Tcfap2c is expressed in PGCs from Embryonic Day 7.25 (E 7.25) up to E 12.5, and targeted disruption resulted in sterile animals, both male and female. In the mutant animals, PGCs were specified but were lost around E 8.0. PGCs generated in vitro from embryonic stem cells lacking TCFAP2C displayed induction of Prdm1 and Dppa3. Upregulation of Hoxa1, Hoxb1, and T together with lack of expression of germ cell markers such Nanos3, Dazl, and Mutyh suggested that the somatic gene program is induced in TCFAP2C-deficient PGCs. Repression of TCFAP2C in TCam-2, a human PGC-resembling seminoma cell line, resulted in specific upregulation of HOXA1, HOXB1, MYOD1, and HAND1, indicative of mesodermal differentiation. Expression of genes indicative of ectodermal, endodermal, or extraembryonic differentiation, as well as the finding of no change to epigenetic modifications, suggested control by other factors. Our results implicate Tcfap2c as an important effector of Prdm1 activity that is required for PGC maintenance, most likely mediating Prdm1-induced suppression of mesodermal differentiation. PMID- 19776389 TI - Conditional knockout of Mn-SOD targeted to type IIB skeletal muscle fibers increases oxidative stress and is sufficient to alter aerobic exercise capacity. AB - In vitro studies of isolated skeletal muscle have shown that oxidative stress is limiting with respect to contractile function. Mitochondria are a potential source of muscle function-limiting oxidants. To test the hypothesis that skeletal muscle-specific mitochondrial oxidative stress is sufficient to limit muscle function, we bred mice expressing Cre recombinase driven by the promoter for the inhibitory subunit of troponin (TnIFast-iCre) with mice containing a floxed Sod2 (Sod2(fl/fl)) allele. Mn-SOD activity was reduced by 82% in glycolytic (mainly type II) muscle fiber homogenates from young TnIFastCreSod2(fl/fl) mice. Furthermore, Mn-SOD content was reduced by 70% only in type IIB muscle fibers. Aconitase activity was decreased by 56%, which suggests an increase in mitochondrial matrix superoxide. Mitochondrial superoxide release was elevated more than twofold by mitochondria isolated from glycolytic skeletal muscle in TnIFastCreSod2(fl/fl) mice. In contrast, the rate of mitochondrial H(2)O(2) production was reduced by 33%, and only during respiration with complex II substrate. F(2)-isoprostanes were increased by 36% in tibialis anterior muscles isolated from TnIFastCreSod2(fl/fl) mice. Elevated glycolytic muscle-specific mitochondrial oxidative stress and damage in TnIFastCreSod2(fl/fl) mice were associated with a decreased ability of the extensor digitorum longus and gastrocnemius muscles to produce contractile force as a function of time, whereas force production by the soleus muscle was unaffected. TnIFastCreSod2(fl/fl) mice ran 55% less distance on a treadmill than wild-type mice. Collectively, these data suggest that elevated mitochondrial oxidative stress and damage in glycolytic muscle fibers are sufficient to reduce contractile muscle function and aerobic exercise capacity. PMID- 19776390 TI - PTH-induced internalization of apical membrane NaPi2a: role of actin and myosin VI. AB - Parathyroid hormone (PTH) plays a critical role in the regulation of renal phosphorous homeostasis by altering the levels of the sodium-phosphate cotransporter NaPi2a in the brush border membrane (BBM) of renal proximal tubular cells. While details of the molecular events of PTH-induced internalization of NaPi2a are emerging, the precise events governing NaPi2a removal from brush border microvilli in response to PTH remain to be fully determined. Here we use a novel application of total internal reflection fluorescence microscopy to examine how PTH induces movement of NaPi2a out of brush border microvilli in living cells in real time. We show that a dynamic actin cytoskeleton is required for NaPi2a removal from the BBM in response to PTH. In addition, we demonstrate that a myosin motor that has previously been shown to be coregulated with NaPi2a, myosin VI, is necessary for PTH-induced removal of NaPi2a from BBM microvilli. PMID- 19776391 TI - Motoring down the microvilli. Focus on "PTH-induced internalization of apical membrane NaPi2a: role of actin and myosin VI". PMID- 19776392 TI - Filamin A is required for vimentin-mediated cell adhesion and spreading. AB - Cell adhesion and spreading are regulated by complex interactions involving the cytoskeleton and extracellular matrix proteins. We examined the interaction of the intermediate filament protein vimentin with the actin cross-linking protein filamin A in regulation of spreading in HEK-293 and 3T3 cells. Filamin A and vimentin-expressing cells were well spread on collagen and exhibited numerous cell extensions enriched with filamin A and vimentin. By contrast, cells treated with small interfering RNA (siRNA) to knock down filamin A or vimentin were poorly spread; both of these cell populations exhibited >50% reductions of cell adhesion, cell surface beta1 integrin expression, and beta1 integrin activation. Knockdown of filamin A reduced vimentin phosphorylation and blocked recruitment of vimentin to cell extensions, whereas knockdown of filamin and/or vimentin inhibited the formation of cell extensions. Reduced vimentin phosphorylation, cell spreading, and beta1 integrin surface expression, and activation were phenocopied in cells treated with the protein kinase C inhibitor bisindolylmaleimide; cell spreading was also reduced by siRNA knockdown of protein kinase C-epsilon. By immunoprecipitation of cell lysates and by pull-down assays using purified proteins, we found an association between filamin A and vimentin. Filamin A also associated with protein kinase C-epsilon, which was enriched in cell extensions. These data indicate that filamin A associates with vimentin and to protein kinase C-epsilon, thereby enabling vimentin phosphorylation, which is important for beta1 integrin activation and cell spreading on collagen. PMID- 19776393 TI - Glutamine enhances heat shock protein 70 expression via increased hexosamine biosynthetic pathway activity. AB - Glutamine (GLN) plays a key role in cellular protection following injury via enhancement of heat shock protein 70 (HSP70). The pathway by which GLN enhances HSP70 is unknown. GLN is a key substrate for the hexosamine biosynthetic pathway (HBP), which has been shown to induce HSP70. We sought to explore the role of the HBP in GLN-mediated HSP70 expression. Both chemical inhibitors and small interfering (si)RNA knockdown of key HBP enzymes were used in mouse embryonic fibroblast cells to determine the effects of the HBP on HSP70 expression. The O glycosylation, nuclear translocation, and transcriptional activation of heat shock factor-1 (HSF-1) and Sp1 were evaluated using immunoprecipitation, Western blotting, and luciferase assays. HSP70 expression levels were evaluated via ELISA and Western blotting. GLN augmented HBP activity before and after heat stress (HS). Chemical inhibition of HBP enzymes reduced GLN-mediated HSP70 expression. Specific siRNA targeting of the key HBP enzyme UDP-N-acetylglucosamine (GlcNAc): polypeptide-O-beta-acetylglucosaminyltransferase (OGT) blocked GLN-mediated HSP70 expression and attenuated GLN-mediated cellular protection post-HS. Chemical and siRNA attenuation of the HBP blocked GLN-induced nuclear translocation of Sp1 and HSF-1, which are key to maximal HSP70 expression. Finally, immunoprecipitation revealed HSF-1 was O-glycosylated, and GLN enhanced this effect. These results suggest that metabolism of GLN via the HBP enhances HSP70 expression. This effect appears to be mediated via O-glycosylation, nuclear translocation, and transcriptional activation of Sp1 and HSF-1. This is an important mechanistic description of a pathway that appears responsible for GLN-mediated HSP70 expression. PMID- 19776394 TI - A large-conductance (BK) potassium channel subtype affects both growth and mineralization of human osteoblasts. AB - The pharmacology of the large-conductance K(+) (BK) channel in human osteoblasts is not well defined, and its role in bone is speculative. Here we assess BK channel properties in MG63 cells and primary human osteoblasts and determine whether pharmacological modulation affects cell function. We used RT-PCR and patch-clamp methods to determine the expression of BK channel subunits and cell number assays in the absence and presence of BK channel modulators. RT-PCR showed the presence of KCNMA1, KCNMB1, KCNMB2, KCNMB3, and KCNMB4 subunits. The BK channel was voltage dependent, with a mean unitary conductance of 228.8 pS (n = 10) in cell-attached patches (140 mM K(+)/140 mM K(+)) and a conductance of 142.5 pS (n = 16) in excised outside-out and 155 pS (n = 6) in inside-out patches in 3 mM K(+)/140 mM K(+). The selectivity ratio (ratio of K(+) to Na(+) permeability) was 15:1. The channel was blocked by tetraethylammonium (TEA, 0.3 mM), iberiotoxin (5-60 nM), tetrandrine (5-30 microM), and paxilline (10 microM) and activated by isopimaric acid (20 microM). BK channel modulators affected MG63 cell numbers: TEA and tetrandrine significantly increased cell numbers at low concentrations (3 mM and 3 microM, respectively) and reduced cell numbers at higher concentrations (>10 mM and >10 microM, respectively). Neither iberiotoxin (20-300 nM) nor slotoxin (300 nM) affected cell numbers. The increase in cell numbers by TEA was blocked by isopimaric acid. TEA (0.1-3.0 mM) significantly increased mineralization in primary osteoblasts. In conclusion, the BK channel has a distinctive pharmacology and is thus a target for therapeutic strategies aimed at modulating osteoblast proliferation and function. PMID- 19776395 TI - Risk of confusion in dosing Tamiflu oral suspension in children. PMID- 19776396 TI - Poor substitutes--why cooperatives and triggers can't achieve the goals of a public option. PMID- 19776397 TI - Baucus's bill and the long road to reform. PMID- 19776398 TI - The cost of health care--highlights from a discussion about economics and reform. PMID- 19776399 TI - Putting U.S. health care on the right track. PMID- 19776400 TI - 21st-century health care--the case for integrated delivery systems. PMID- 19776403 TI - Images in clinical medicine. Diagnostic finding in the iris. PMID- 19776401 TI - Combined immunodeficiency associated with DOCK8 mutations. AB - BACKGROUND: Recurrent sinopulmonary and cutaneous viral infections with elevated serum levels of IgE are features of some variants of combined immunodeficiency. The genetic causes of these variants are unknown. METHODS: We collected longitudinal clinical data on 11 patients from eight families who had recurrent sinopulmonary and cutaneous viral infections. We performed comparative genomic hybridization arrays and targeted gene sequencing. Variants with predicted loss of-expression mutations were confirmed by means of a quantitative reverse transcriptase-polymerase-chain-reaction assay and immunoblotting. We evaluated the number and function of lymphocytes with the use of in vitro assays and flow cytometry. RESULTS: Patients had recurrent otitis media, sinusitis, and pneumonias; recurrent Staphylococcus aureus skin infections with otitis externa; recurrent, severe herpes simplex virus or herpes zoster infections; extensive and persistent infections with molluscum contagiosum; and human papillomavirus infections. Most patients had severe atopy with anaphylaxis; several had squamous cell carcinomas, and one had T-cell lymphoma-leukemia. Elevated serum IgE levels, hypereosinophilia, low numbers of T cells and B cells, low serum IgM levels, and variable IgG antibody responses were common. Expansion in vitro of activated CD8 T cells was impaired. Novel homozygous or compound heterozygous deletions and point mutations in the gene encoding the dedicator of cytokinesis 8 protein (DOCK8) led to the absence of DOCK8 protein in lymphocytes. CONCLUSIONS: Autosomal recessive DOCK8 deficiency is associated with a novel variant of combined immunodeficiency. PMID- 19776402 TI - Label-free quantitative analysis of lipid metabolism in living Caenorhabditis elegans. AB - The ubiquity of lipids in biological structures and functions suggests that lipid metabolisms are highly regulated. However, current invasive techniques for lipid studies prevent characterization of the dynamic interactions between various lipid metabolism pathways. Here, we describe a noninvasive approach to study lipid metabolisms using a multifunctional coherent anti-Stokes Raman scattering (CARS) microscope. Using living Caenorhabditis elegans as a model organism, we report label-free visualization of coexisting neutral and autofluorescent lipid species. We find that the relative expression level of neutral and autofluorescent lipid species can be used to assay the genotype-phenotype relationship of mutant C. elegans with deletions in the genes encoding lipid synthesis transcription factors, LDL receptors, transforming growth factor beta receptors, lipid desaturation enzymes, and antioxidant enzymes. Furthermore, by coupling CARS with fingerprint confocal Raman analysis, we analyze the unsaturation level of lipids in wild-type and mutant C. elegans. Our study shows that complex genotype-phenotype relationships between lipid storage, peroxidation, and desaturation can be rapidly and quantitatively analyzed in a single living C. elegans. PMID- 19776404 TI - Doctors as the key to health care reform. PMID- 19776405 TI - High-dose daunorubicin in older patients with acute myeloid leukemia. AB - BACKGROUND: A complete remission is essential for prolonging survival in patients with acute myeloid leukemia (AML). Daunorubicin is a cornerstone of the induction regimen, but the optimal dose is unknown. In older patients, it is usual to give daunorubicin at a dose of 45 to 50 mg per square meter of body-surface area. METHODS: Patients in whom AML or high-risk refractory anemia had been newly diagnosed and who were 60 to 83 years of age (median, 67) were randomly assigned to receive cytarabine, at a dose of 200 mg per square meter by continuous infusion for 7 days, plus daunorubicin for 3 days, either at the conventional dose of 45 mg per square meter (411 patients) or at an escalated dose of 90 mg per square meter (402 patients); this treatment was followed by a second cycle of cytarabine at a dose of 1000 mg per square meter every 12 hours [DOSAGE ERROR CORRECTED] for 6 days. The primary end point was event-free survival. RESULTS: The complete remission rates were 64% in the group that received the escalated dose of daunorubicin and 54% in the group that received the conventional dose (P=0.002); the rates of remission after the first cycle of induction treatment were 52% and 35%, respectively (P<0.001). There was no significant difference between the two groups in the incidence of hematologic toxic effects, 30-day mortality (11% and 12% in the two groups, respectively), or the incidence of moderate, severe, or life-threatening adverse events (P=0.08). Survival end points in the two groups did not differ significantly overall, but patients in the escalated-treatment group who were 60 to 65 years of age, as compared with the patients in the same age group who received the conventional dose, had higher rates of complete remission (73% vs. 51%), event-free survival (29% vs. 14%), and overall survival (38% vs. 23%). CONCLUSIONS: In patients with AML who are older than 60 years of age, escalation of the dose of daunorubicin to twice the conventional dose, with the entire dose administered in the first induction cycle, effects a more rapid response and a higher response rate than does the conventional dose, without additional toxic effects. (Current Controlled Trials number, ISRCTN77039377; and Netherlands National Trial Register number, NTR212.) PMID- 19776406 TI - Anthracycline dose intensification in acute myeloid leukemia. AB - BACKGROUND: In young adults with acute myeloid leukemia (AML), intensification of the anthracycline dose during induction therapy has improved the rate of complete remission but not of overall survival. We evaluated the use of cytarabine plus either standard-dose or high-dose daunorubicin as induction therapy, followed by intensive consolidation therapy, in inducing complete remission to improve overall survival. METHODS: In this phase 3 randomized trial, we assigned 657 patients between the ages of 17 and 60 years who had untreated AML to receive three once-daily doses of daunorubicin at either the standard dose (45 mg per square meter of body-surface area) or a high dose (90 mg per square meter), combined with seven daily doses of cytarabine (100 mg per square meter) by continuous intravenous infusion. Patients who had a complete remission were offered either allogeneic hematopoietic stem-cell transplantation or high-dose cytarabine, with or without a single dose of the monoclonal antibody gemtuzumab ozogamicin, followed by autologous stem-cell transplantation. The primary end point was overall survival. RESULTS: In the intention-to-treat analysis, high dose daunorubicin, as compared with a standard dose of the drug, resulted in a higher rate of complete remission (70.6% vs. 57.3%, P<0.001) and improved overall survival (median, 23.7 vs. 15.7 months; P=0.003). The rates of serious adverse events were similar in the two groups. Median follow-up was 25.2 months. CONCLUSIONS: In young adults with AML, intensifying induction therapy with a high daily dose of daunorubicin improved the rate of complete remission and the duration of overall survival, as compared with the standard dose. (ClinicalTrials.gov number, NCT00049517.) PMID- 19776407 TI - Comparative efficacy of inactivated and live attenuated influenza vaccines. AB - BACKGROUND: The efficacy of influenza vaccines may vary from year to year, depending on a variety of factors, and may differ for inactivated and live attenuated vaccines. METHODS: We carried out a randomized, double-blind, placebo controlled trial of licensed inactivated and live attenuated influenza vaccines in healthy adults during the 2007-2008 influenza season and estimated the absolute and relative efficacies of the two vaccines. RESULTS: A total of 1952 subjects were enrolled and received study vaccines in the fall of 2007. Influenza activity occurred from January through April 2008, with the circulation of influenza types A (H3N2) (about 90%) and B (about 9%). Absolute efficacy against both types of influenza, as measured by isolating the virus in culture, identifying it on real-time polymerase-chain-reaction assay, or both, was 68% (95% confidence interval [CI], 46 to 81) for the inactivated vaccine and 36% (95% CI, 0 to 59) for the live attenuated vaccine. In terms of relative efficacy, there was a 50% (95% CI, 20 to 69) reduction in laboratory-confirmed influenza among subjects who received inactivated vaccine as compared with those given live attenuated vaccine. The absolute efficacy against the influenza A virus was 72% (95% CI, 49 to 84) for the inactivated vaccine and 29% (95% CI, -14 to 55) for the live attenuated vaccine, with a relative efficacy of 60% (95% CI, 33 to 77) for the inactivated vaccine. CONCLUSIONS: In the 2007-2008 season, the inactivated vaccine was efficacious in preventing laboratory-confirmed symptomatic influenza A (predominately H3N2) in healthy adults. The live attenuated vaccine also prevented influenza illnesses but was less efficacious. (ClinicalTrials.gov number, NCT00538512.) PMID- 19776409 TI - Renal failure in cirrhosis. PMID- 19776410 TI - Images in clinical medicine. Pelvic spleen. PMID- 19776411 TI - Case records of the Massachusetts General Hospital. Case 30-2009. A 77-year-old man with recurrent transitional-cell carcinoma of the ureter. PMID- 19776412 TI - An old AML drug revisited. PMID- 19776408 TI - A double-blind, delayed-start trial of rasagiline in Parkinson's disease. AB - BACKGROUND: A therapy that slows disease progression is the major unmet need in Parkinson's disease. METHODS: In this double-blind trial, we examined the possibility that rasagiline has disease-modifying effects in Parkinson's disease. A total of 1176 subjects with untreated Parkinson's disease were randomly assigned to receive rasagiline (at a dose of either 1 mg or 2 mg per day) for 72 weeks (the early-start group) or placebo for 36 weeks followed by rasagiline (at a dose of either 1 mg or 2 mg per day) for 36 weeks (the delayed-start group). To determine a positive result with either dose, the early-start treatment group had to meet each of three hierarchical end points of the primary analysis based on the Unified Parkinson's Disease Rating Scale (UPDRS, a 176-point scale, with higher numbers indicating more severe disease): superiority to placebo in the rate of change in the UPDRS score between weeks 12 and 36, superiority to delayed start treatment in the change in the score between baseline and week 72, and noninferiority to delayed-start treatment in the rate of change in the score between weeks 48 and 72. RESULTS: Early-start treatment with rasagiline at a dose of 1 mg per day met all end points in the primary analysis: a smaller mean (+/ SE) increase (rate of worsening) in the UPDRS score between weeks 12 and 36 (0.09+/-0.02 points per week in the early-start group vs. 0.14+/-0.01 points per week in the placebo group, P=0.01), less worsening in the score between baseline and week 72 (2.82+/-0.53 points in the early-start group vs. 4.52+/-0.56 points in the delayed-start group, P=0.02), and noninferiority between the two groups with respect to the rate of change in the UPDRS score between weeks 48 and 72 (0.085+/-0.02 points per week in the early-start group vs. 0.085+/-0.02 points per week in the delayed-start group, P<0.001). All three end points were not met with rasagiline at a dose of 2 mg per day, since the change in the UPDRS score between baseline and week 72 was not significantly different in the two groups (3.47+/-0.50 points in the early-start group and 3.11+/-0.50 points in the delayed-start group, P=0.60). CONCLUSIONS: Early treatment with rasagiline at a dose of 1 mg per day provided benefits that were consistent with a possible disease-modifying effect, but early treatment with rasagiline at a dose of 2 mg per day did not. Because the two doses were associated with different outcomes, the study results must be interpreted with caution. (ClinicalTrials.gov number, NCT00256204.) PMID- 19776413 TI - The delayed-start study design. PMID- 19776415 TI - Treating childhood leukemia without cranial irradiation. PMID- 19776414 TI - Rendering the leukemia cell susceptible to attack. PMID- 19776416 TI - Clopidogrel plus aspirin in atrial fibrillation. PMID- 19776417 TI - Case 19-2009: Carcinoma of the gastroesophageal junction. PMID- 19776418 TI - CMS's landmark decision on CT colonography. PMID- 19776419 TI - Hypersensitivity to generic drugs with soybean oil. PMID- 19776421 TI - American Academy of Pediatrics' Chapter Breastfeeding Coordinators: extending breastfeeding promotion and support outside the medical office. PMID- 19776422 TI - Social vigilantism: measuring individual differences in belief superiority and resistance to persuasion. AB - Social vigilantism (SV) is an enduring individual difference that assesses the tendency of individuals to impress and propagate their "superior" beliefs onto others to correct others' more "ignorant" opinions. After establishing a reliable measure of SV, three studies showed that SV was associated with greater expressions of belief superiority (whether reacting to others holding dissimilar or similar beliefs) and greater resistance to persuasion (via increased rates of counterarguing and greater attitude stability after persuasion appeals) even after controlling for relevant individual differences (narcissism, dogmatism, psychological reactance, and need for cognition), as well as attitude importance and extremity. Thus, SV predicts expressions of belief superiority and resistance to persuasion above and beyond characteristics of the attitude and individual difference variables previously studied in the attitude literature. SV is a meaningful construct in increasing the understanding of persuasion, attitude resistance, and attitude dissemination that can be applied in a variety of psychological domains. PMID- 19776420 TI - Identification of five candidate lung cancer biomarkers by proteomics analysis of conditioned media of four lung cancer cell lines. AB - Detection of lung cancer at an early stage is necessary for successful therapy and improved survival rates. We performed a bottom-up proteomics analysis using a two-dimensional LC-MS/MS strategy on the conditioned media of four lung cancer cell lines of different histological backgrounds (non-small cell lung cancer: H23 (adenocarcinoma), H520 (squamous cell carcinoma), and H460 (large cell carcinoma); small cell lung cancer: H1688) to identify secreted or membrane-bound proteins that could be useful as novel lung cancer biomarkers. Proteomics analysis of the four conditioned media allowed identification of 1,830 different proteins (965, 871, 726, and 847 from H1688, H23, H460, and H520, respectively). All proteins were assigned a subcellular localization, and 38% were classified as extracellular or membrane-bound. We successfully identified the internal control proteins (also detected by ELISA), kallikrein-related peptidases 14 and 11, and IGFBP2. We also identified known or putative lung cancer tumor markers such as squamous cell carcinoma antigen, carcinoembryonic antigen, chromogranin A, creatine kinase BB, progastrin-releasing peptide, neural cell adhesion molecule, and tumor M2-PK. To select the most promising candidates for validation, we performed tissue specificity assays, functional classifications, literature searches for association to cancer, and a comparison of our proteome with the proteome of lung-related diseases and serum. Five novel lung cancer candidates, ADAM-17, osteoprotegerin, pentraxin 3, follistatin, and tumor necrosis factor receptor superfamily member 1A were preliminarily validated in the serum of patients with lung cancer and healthy controls. Our results demonstrate the utility of this cell culture proteomics approach to identify secreted and shed proteins that are potentially useful as serological markers for lung cancer. PMID- 19776423 TI - More effective home heating reduces school absences for children with asthma. AB - BACKGROUND: New Zealand homes are underheated by international standards, with average indoor temperatures below the WHO recommended minimum of 18 degrees C. Research has highlighted the connection between low indoor temperatures and adverse health outcomes, including social functioning and psychological well being. Both health effects and social effects can impact on school absence rates. The aim of this study was to determine whether more effective home heating affects school absence for children with asthma. METHODS: A single-blinded randomised controlled trial of heating intervention in 409 households containing an asthmatic child aged 6-12 years, where the previous heating was an open fire, plug-in electric heater or unflued gas heater. The intervention was the installation of a more effective heater of at least 6 kW before the winter of 2006 in half the houses. Demographic and health information was collected both before and after the intervention. Each child's school was contacted directly and term-by-term absence information for that child obtained for 2006 and previous years where available. RESULTS: Complete absence data were obtained for 269 out of 409 children. Compared with the control group, children in households receiving the intervention experienced on average 21% (p=0.02) fewer days of absence after allowing for the effects of other factors. CONCLUSION: More effective, non-indoor polluting heating reduces school absence for asthmatic children. PMID- 19776425 TI - Effectiveness of Teacher-Child Interaction Training (TCIT) in a preschool setting. AB - This research addressed the need for trained child care staff to support optimal early social-emotional development in urban, low-income, ethnic minority children. We evaluated effectiveness of Teacher-Child Interaction Training (TCIT), an approach adapted from Eyberg's Parent-Child Interaction Therapy (PCIT). TCIT focuses on increasing preschool teachers' positive attention skills and consistent discipline in order to enhance children's psychosocial functioning and prevent mental health problems. A total of 12 teachers participated in small group workshop sessions with in vivo coaching on their use of skills in the classroom. A multiple-baseline design across four classrooms (3 teachers each) evaluated effects of training on teacher behaviors during weekly classroom observations. Findings indicated systematic increases in trained skills during intervention, and consumer evaluations showed that the training was rated positively. Our results suggest that TCIT is a promising approach for enhancing positive teacher-child interactions in a preschool setting and should receive further investigation. PMID- 19776424 TI - Translesion synthesis of abasic sites by yeast DNA polymerase epsilon. AB - Studies of replicative DNA polymerases have led to the generalization that abasic sites are strong blocks to DNA replication. Here we show that yeast replicative DNA polymerase epsilon bypasses a model abasic site with comparable efficiency to Pol eta and Dpo4, two translesion polymerases. DNA polymerase epsilon also exhibited high bypass efficiency with a natural abasic site on the template. Translesion synthesis primarily resulted in deletions. In cases where only a single nucleotide was inserted, dATP was the preferred nucleotide opposite the natural abasic site. In contrast to translesion polymerases, DNA polymerase epsilon with 3'-5' proofreading exonuclease activity bypasses only the model abasic site during processive synthesis and cannot reinitiate DNA synthesis. This characteristic may allow other pathways to rescue leading strand synthesis when stalled at an abasic site. PMID- 19776426 TI - Biased processing of threat-related information rather than knowledge deficits contributes to overestimation of threat in obsessive-compulsive disorder. AB - Overestimation of threat (OET) has been implicated in the pathogenesis of obsessive-compulsive disorder (OCD). The present study deconstructed this complex concept and looked for specific deviances in OCD relative to controls. A total of 46 participants with OCD and 51 nonclinical controls were asked: (a) to estimate the incidence rate for 20 events relating to washing, checking, positive, or negative incidents. Furthermore, they were required (b) to assess their personal vulnerability to experience each event type, and (c) to judge the degree of accompanying worry. Later, participants were confronted with the correct statistics and asked (d) to rate their degree of worry versus relief. OCD participants did not provide higher estimates for OCD-related events than healthy participants, thus rendering a knowledge deficit unlikely. The usual unrealistic optimism bias was found in both groups but was markedly attenuated in OCD participants. OCD-related events worried OCD participants more than controls. Confrontation with the correct statistics appeased OCD participants less than healthy participants. Even in the case of large initial overestimations for OCD related events, correct information appeased OCD participants significantly less than healthy participants. Our results suggest that OCD is not associated with a knowledge deficit regarding OCD-related events but that patients feel personally more vulnerable than nonclinical controls. PMID- 19776428 TI - The development of the distraction-compression osteogenesis method in orthopedic surgery in Poland. AB - The dynamic development of the Ilizarov method around the world and in Poland during the last decade has been made possible by the scientific of its application, based on universal laws of physiology and biomechanics. The Ilizarov method is beyond a doubt the treatment method of choice in many serious disorders of the locomotor apparatus, and is of extremely high value in the treatment of complicated open fractures with concomitant diffuse infuries of soft tissue, and not just in Poland's flagship orthopedic centers. Even though the complication rate is fairly high, the method is well tolerated by the patients, and the majority of failures can be effectively treated by the same method. This article outlines the history of limb lengthening in the worlds and the history of the development of the Ilizarov method in Poland. PMID- 19776429 TI - Diagnostic imaging in the planning and monitoring of limb lengthening by the Ilizarov method. AB - Limb lengthening is a long and complicated process, and therefore requires monitoring by use of imaging methods. In planning the application of the Ilizarov method, it is essential to consider the pathology as a whole, and not merely the individual symptoms. This is particularly important in generalized defect on bone formation. The baseline clinical and radiological evaluation should elucidate the etiology of deformations and the extent of changes. Routine X ray examinations during limb lengthening (apart from baseline and immediate post-surgery) should be performed after two and four weeks of distraction, and then every month until the Ilizarov apparatus is removed. Bone cross-sections obtained in CT scans enable the evaluation of the rate of bone regeneration and the reconstruction of tubular bone shape. In doubtful situations CT scans of the regenerated bone three months after removal of the apparatus are also recommended. PMID- 19776427 TI - SPUD qPCR assay confirms PREXCEL-Q softwares ability to avoid qPCR inhibition. AB - Real-time quantitative polymerase chain reaction is subject to inhibition by substances that co-purify with nucleic acids during isolation and preparation of samples. Such materials alter the activity of reverse transcriptase (RT) and thermostable DNA polymerase enzymes on which the assay depends. When removal of inhibitory substances by column or reagent-based methods fails or is incomplete, the remaining option of appropriately, precisely and differentially diluting samples and standards to non-inhibitory concentrations is often avoided due to the logistic problem it poses. To address this, we invented the PREXCEL-Q software program to automate the process of calculating the non-inhibitory dilutions for all samples and standards after a preliminary test plate has been performed on an experimental sample mixture. The SPUD assay was used to check for inhibition in each PREXCEL-Q-designed qPCR reaction. When SPUD amplicons or SPUD amplicon-containing plasmids were spiked equally into each qPCR reaction, all reactions demonstrated complete absence of qPCR inhibition. Reactions spiked with about 15,500 SPUD amplicons yielded a Cq of 27.39 plus/minus 0.28 (at about 80.8% efficiency), while reactions spiked with about 7,750 SPUD plasmids yielded a Cq of 23.82 plus/minus 0.15 (at about 97.85% efficiency). This work demonstrates that PREXCEL-Q sample and standard dilution calculations ensure avoidance of qPCR inhibition. PMID- 19776430 TI - The importance of densitometric testing in the evaluation of regenerated bone during long bone lengthening by the Ilizarov method. AB - Background. Lengthening a long bone by cutting it surgically and then stretching it a process laden with numerous complications. Among the greatest threats is surely the insufficient support strength of the lengthening limb due to inadequate calcification of the newly generated bone tissue. This leads to fractures, distortion of the axis, or lack of osseous consolidation around the newly formed bone. In order to reduce the number of such complications constant diligent monitoring of the entire process is necessary, from the moment treatment is commenced until the distraction apparatus is removed. The purpose of the present study was to evaluate the usefulness of densitometric testing at various stages in the process of lengthening long bones.
Material and method. The testing involved 17 children, in 20 limbs were lengthened by the Ilizarov method. The average shortening was 4,70 cm (range 3,5-13 cm). the article compares the results of density assessments of regenerated bone using ultrasonographic testing and densitometry.
Conclusions. Densinometric testing constitutes an important supplement to the evaluation of regenerated bone. This is an easy test to perform and repeat, enabling the physician to evaluate the degree of mineralization of the regenerated bone, reach conclusions regarding its consolidation and mechanical strength, and make a decision regarding the removal of the external stabilizer. PMID- 19776431 TI - Radiological imaging of the formation of regenerated bone in distraction osteogenesis: an experimental study. AB - Introduction. One of the biological factors affecting the formation of regenerated bone in distraction osteogenesis is the method used for osteotomy. The purpose of the present study was to evaluate the course of bone regeneration using various types of osteotomy in an experimental setting.
Material and method. Our research involved 35 Merynos sheep. Single-level tibia lengthening was performed in all these sheep in the proximal segment using an Ilizarov fixator. The material was divided into 5 groups depending on the osteotomy method used: closed corticotomy, open corticotomy, the Cattaneo method, osteotomy, and osteoclasia. The regenerating bone was evaluated by x-ray examinations performed in two standard projections.
Results. The x-ray images were evaluated based on a descriptive analysis of the features of the course of bone regeneration in all the experimental groups. The regenerating bone the osteoclasia group was most abundant and homogeneous in structure.
Conclusions. The formation of regenerated bone in distraction osteogenesis is dependent on the method of osteotomy. Radiological images of the course of regeneration in the various experimental groups showed differences in the intensity and rate of formation of new bone tissue. The formation and reconstruction of regenerated bone was faster in the osteoclasia group than in the other experimental groups. PMID- 19776432 TI - Testing the differences in bioelectrical potentials occurring in distractive osteogenesis: Human and animal clinical research. AB - Background. Metal intraosseous implants cause disturbances in tissue bioelectrity.
Material and methods. Our research involved a group of 28 patients treated by distractive osteogenesis and 12 dogs treated for long bone fractures with external fixation.
Results. During the process of limb lengthening excessive electrical potentials were generated, considerably exceeding the physiological level.
Conclusions. The observed effect may have a negative effect on osteogenesis and remodeling of the regenerating bone. The application of an external fixator did not significantly increase electrical potentials in animals. PMID- 19776433 TI - An attempt to normalize excessive differences in electric potentials between the metal external distractor and the limb. AB - Background. The metal element of an external stabilizer cause changes in the electrical potential of tissue. During limb lengthening, large differences in potential are generated between the apparatus and the limb. According to some authorities this phenomenon may have a negative impact on the rebuilding of bone.
Material and methods. In 10 children undergoing limb lengthening by Ilizarov distractor, we applied an original device to eliminate undesirable electrical potentials produced by the introduction of metal distractor implants to tissues.
Results and Conclusions. It was found that the prototype "eliminator" effectively maintains the level of electrical charge within physiological limits. PMID- 19776434 TI - A point system for evaluating patients with limb shortening and deformity. AB - This article presents a scoring scale for patients with shortening and axis deformity of the upper and lower limb, as well as short stature, enabling the evaluation and comparison of treatment outcome after limb lengthening. PMID- 19776435 TI - Strategy and tactics in limb lengthening. AB - This article discusses the basic rules and operating principles in limb lengthening for patients treated for anisomelia and in persons with short statue. Among the most essential issues regarding overall strategy are the degree shortening in the limb to be lengthened, the amount of lengthening, the age at which lengthening should be undertaken, the staging of treatment, the upper age limit for treatment, the rules for correcting limb deformities, and the issue of whether or not to shorten the healthy limb or inhibit its growth. On the level of surgical tactics, the author discusses procedure in cases with considerable shortening, shortening of the entire limb shortening of one segment, and in persons with short statue or particular diseases. PMID- 19776436 TI - Long-term outcome lengthening and axis correction with the Ilizarov method in post-inflammatory shortening and deformity of the humerus. AB - Background. Post-inflammatory shortening and deformation of the humerus results from damage to the epiphyseal cartilage of this bone, and in particular to the proximal growth plate, most commonly caused by neonatal staphylococcemia. This is frequently accompanied by shortening of the femur, deformation of the hip and knee joints, the temporo-mandibular joint, and occasionally other joints as well. In the present article the authors present their own experiences with the application of osteogenesis in the post-inflammatory shortening and axis deformation of the humerus.
Material and methods. The clinical material consisted of 23 patients treated during the period 1995-2000 at the institutions represented by the authors in Wroclaw and Lodz. The average shortening was 8,5 cm (31,3%), and the average follow-up period was 2 years.
Results. The average lengthening achieved was 7,5 cm (40,5%), and the average lengthening index was 22,7 days/cm. complete axis correction was achieved in all patients with deformities of the humerus. More exact monitoring of the distraction process is necessary in the arm than in the lower limbs. Only 2 problems and 2 obstacles (according to Paley's classification of complications) were encountered in the course of treatment.
Conclusions. The results obtained indicate that the Ilizarov method is a safe and effective technique for the treatment of shortening and axis deformity of the humerus. PMID- 19776437 TI - Long-term results of forearm lengthening and deformity correction by the Ilizarov method. AB - Background. Shortening and deformity of the forearm is most frequently caused by congenital disorders or posttraumatic injury. Given its complex anatomy and biomechanics, the forearm is clearly the most difficult segment for lengthening and deformity correction.
Material and methods. We analyzed 16 patients with shortening and deformity of the forearm, treated surgically, using the Ilizarov method in our Department from 1989 to 2001. in 9 cases 1-stage surgery was sufficient, while the remaining 7 patients underwent 2-5 stages of treatment. At total of 31 surgical operations were performed. The extent of forearm shortening ranged from 1,5 to 14,5 cm (5-70%). We development a new fixator based on Schanz half-pins.
Results. The length of forearm lengthening per operative stage averaged 2,35 cm. the proportion of lengthening ranged from 6% to 48% with an average of 18,3%. The mean lengthening index was 48,15 days/cm. the per-patient rate of complications was 88% compared 45% per stage of treatment, mostly limited rotational mobility and abnormal consolidation of regenerated bone.
Conclusions. Despite the high complication rate, the Ilizarov method is the method of choice for patients with forearm shortenings and deformities. Treatment is particularly indicated in patients with shortening caused by disproportionate length of the ulnar and forearm bones. Treatment should be managed so as cause the least possible damage to arm function, even at the cost of limited lengthening. Our new stabilizer based on Schanz half-pins makes it possible to preserve forearm rotation. PMID- 19776438 TI - Lengthenin and axis correction of the thigh in various deformities of the hip joint. AB - Background. This article discusses the possibilities for using the Ilizarov, method to correct hip deformities accompanied by shortening of the thigh. This method enables multi-level, multi-plane, one-time or protracted correction of hip deformities with simultaneous limb lengthening. The authors present examples of such corrections of various type and etiologies.
Material and methods. Treatment outcomes were analyzed for 32 patients treated by the Ilizarov method for hip deformity and limb shortening as a sequela of purulent coxitis in infancy.
Results. The best outcomes were observed in patients with unstable or dislocated hip joints.
Conclusion. The results noted here should be taken under consideration in planning early surgery in children with Type IV deformity according to Choi et al. PMID- 19776439 TI - The Ilizarov method in the treatment of postinflammatory deformites of the distal epiphysis of the femur. AB - Background. We report results of the application of the Ilizarov method in the treatment of patients with shortening and deformity of the distal epiphysis of the lemur caused by neonatal osteomyelitis.
Material and methods. 28 patients were operated, ranging in age from 6-19 years (average 10). There were 15 cases of hypoplasia of the lateral condyle with 10-500 valgus deformity of the knee joint, and 11 cases of malformation of the medial condyles with 5-300 varus deformity. In 2 cases there was malformation of both condyles of the femur (2-18 cm, mean 7,5 cm) was observed in all cases. 34 surgical procedures using Ilizarov's technique were performed. The duration of treatment was 3-7 months.
Results. Lengthening of 2-9 cm was obtained. The mean lengthening index was 28 days/cm. full limb length equality was obtained in 19 cases. Full correction of the deformity was obtained in all cases. Restoration of deformed condyles was observed in 6 patients. Complications included pin-tract infections in 13 patients, limitation of knee flexion to 1100 in six cases and 1000 in two cases. There was one knee subluxation (corrected) and premature consolidation of the femur in 3 patients. No osteomyelitis, neurological complications, or vascular compromise occurred.
Conclusion. The Ilizarov method is very effective in the treatment of complex deformities of the distal epiphysis of the femur. PMID- 19776440 TI - The application of the Ilizarov method in the treatment of foot deformities. AB - Background. This article presents the indicationa and counterindications for the application of the Ilizarov method in the treatment of foot deformities. Two basic methods for the correction of deformities are described: distraction of soft tissues and distraction at the site of osteotomy. The surgical procedure for the distraction method is described, along with indications for various types of osteotomy in the vicnity of the foot (aboveankle osteotomy, U osteotomy, V osteotomy, posterior osteotomy of the calcaneal bone, osteotomies between the Lisfranic and Chopart joints). The authors also present their own alternative method for the correction of deformities, which consists in a combination of joint resection with distraction at the resection site.
Material and method. The treatment outcome is presented for 23 feet in 27 patients treated with an Ilizarov apparatus. Various surgical techniques were used.
Results. Complete and permanent correction of foot shape was achieved in 18 of the 23 patients. Is the remaining 5 patients further treatment was required.
Conclusions. The use of the Ilizarov method in treating foot deformities produces favorable results. PMID- 19776441 TI - PFC Modular Total Knee Replacement System - Middle Term Results. AB - Background. Total knee replacement, which is now the preferred solution for severe primary osteoarthritis, rheumatoid arthritis or posttraumatic osteoarthritis, is indicated in patients of various pathological changes and deformities. Every joint requires an individual treatment.
Material and method. We performed a prospective study of 500 cemented primary PFC modular total knee replacement implanted from 1991 to 2001, involving 350 prostheses (55 bilateral) in 295 patients with diagnosis of primary osteoarthritis, rheumatoid arthritis or posttraumatic osteoarthritis. The average age of our patients was 68,3 years (range 2,2-70,4 years). A survivorship curve was constructed based on revision surgery due to aseptic loosening.
Results. According to the Knee Society Clinical rating System, the results were excellent in 288 knees, good in 45 knees, poor in 13 knees and extremely poor 4 knees. We observed posterior dislocation of the tibial component in2 cases. In one patient we had to replace the implant in a two-stage procedure because of septic loosening.
Conclusions. The PFC total knee system seems to be a prosthesis of good quality, permitting, the solution of almost any problem that may arise in both primary and revision cases. We achieved good outcomes and high patient satisfaction. PMID- 19776442 TI - Arthroscopic management of chondromatosis of the elbow: a case report. AB - Background. This article describes a case of chondromatosis of the elbow in a 33 year-old male patient. An arthroscopic method was used to remove multiple loose bodies from the joint.
Case history. The patient complained of pain in the right elbow. He presented with edema in the elbow joint, pain during movement, occasional slippage, and a 300 functional reduction in elbow extension.
Procedure. After the arthroscope was introduced into the joint, numerous loose bodies were detected, covered with cartilage, pale pink synovial membrane with hyperthropied villi. The cartilage of the joint surfaces bent slighty under pressure: however, there was no sign of decay, destruction, or deep deficits. Using a punch and Pean forceps we removed ca. 20 loose chondral and condro osseous bodies ranging in diameter from 0,3 to 2,0 cm.
Outcome. There were no post-surgical complications. After several days the patient was discharged. Within a week he recovered a full range of motion in the joint and no pain. The patient continues to work in a job demanding physical exertion and plays volleyball.
Conclusion. Arthroscopy of the elbow is a good solution for the problem of loose bodies in the elbow joint, especially when they occur in both sections of the joint, where classical surgical techniques require two routes of surgical access or two-phase surgery. PMID- 19776443 TI - Selected physical and biophysical properties of ultrasonic waves used in physical therapy. AB - This article presents a review of the current literature on the impact of ultrasonic waves widely used in physiotherapy. There is also a presentation of therapeutic indications contraindications, with particular attention to phonophoresis. PMID- 19776444 TI - The role of antibiotic therapy in combined treatment for chronic osteomyelitis. AB - On the basis of many years of clinical experience, the authors discuss the role and place of antibiotics in contemporary combined treatment for chronic osteomyelitis. PMID- 19776445 TI - Assistive devices. AB - This article presents the most common assistive devices. The typical as well as modern devices for handicap people are presented. PMID- 19776446 TI - [AIE postion paper on waste management: a consumer opinion]. PMID- 19776447 TI - [Discussing on the results of clinical trials of PSA screening]. PMID- 19776448 TI - [Epidemiology and economy: should we limit their respective field of analysis or expand the common ground]. PMID- 19776449 TI - [The power of modern medicine]. PMID- 19776450 TI - [Preventive medicine or unequal distribution]. PMID- 19776451 TI - [War sufferers: a school laboratory on peace education]. PMID- 19776452 TI - [Activities of the Group of the Italian Association of Epidemiology on violent conflicts]. PMID- 19776453 TI - [AIRTUM numbers. For which tumor classes incidence is changing faster?]. PMID- 19776454 TI - [Assessing the effectiveness of local transport policies for improvements in urban air quality and public health: a review of scientific literature]. AB - OBJECTIVE: to provide a synthesis of the state of the art on the effectiveness of local transport policies on improvements in air quality and public health. DESIGN AND SETTING: we searched published scientific articles focused on the evaluation of the accountability of local transport policies on emissions levels, on air pollutants concentrations, on air pollution-related health outcomes (respiratory and cardiovascular health). RESULTS: we selected 19 articles and reviews; authors used different methods to define and to monitor environmental and health indicators and data analyses are conducted on different spatio-temporal scales. CONCLUSIONS: the evaluation of the effects of transport policies on air quality and public health is a complex research field. Different factors may influence the assessment of impacts and there is an overlap of many intervention strategies that limit the interpretation of the findings. The use of advanced instruments for environmental monitoring could improve data analyses. Transport policies are a key point for air quality improvements and for the reduction of public health risk; this implies that local interventions planning should have a relevant focus on the assessment of direct and indirect effects on air quality and population health. PMID- 19776455 TI - [Multivariate analysis models of costs referable to general practitioners based on administrative databases]. AB - OBJECTIVES: estimation of risk adjustment models based on administrative databases in order to describe the quality of care provided by General Practitioners in an ASL of the Veneto region. Particularly, it was tested whether some variables (routinely available) can describe the severity of casemix and the value of the "ticket exemption" database. METHODS: the main administrative databases of the ASL were linked through the unique personal health identifier and analyzed by means of multivariate techniques, using the tariff as the dependent variable; the explanatory ones are a number of variables describing health conditions. RESULTS: ticket exemptions, assumed as estimator of health conditions, resulted quite reliable in predicting costs, often better than the traditional sex and age. Further, for some activities, as for instance hospitalization, they almost completely explain variability among general practitioners. CONCLUSION: ticket exemptions can be considered good estimators of the prevalence of some conditions in the general population and very good predictors of the use of health resources. They could be easily improved in this respect introducing slight modifications. Data show a good level of appropriateness in the use of hospital resources by general practitioners. PMID- 19776456 TI - [Testing of interventions for prevention of heat wave related deaths: results among frail elderly and methodological problems]. AB - OBJECTIVE: to evaluate the impact of a programme based on soft home care services and an offer of social caretaking, compared to one based only on soft home care, for the prevention of heat-related health events among clinically and/or functionally frail elderly. DESIGN: cluster randomised controlled trial. SETTING AND PARTICIPANTS: the study population included 2,612 persons over 75 years of age living alone in the city of Turin, North-West Italy, who were classified as clinically (hospitalization with specific diagnoses before summer 2004) and/or functionally (were receiving a disability pension) frail. MAIN OUTCOME MEASURES: a programme' s impact was evaluated on the basis of the hospitalizations and deaths that occurred during summer 2004, using gender-specific multilevel logistic regression models, controlling first for age and then also for education and income. RESULTS: among males, a weak protection against emergency hospitalization was observed within the group randomised to soft home care services and offer of social caretaking, compared to the only soft home care group (OR=0.33, 95% CI=0.11; 0.96). Among females, the programme including social caretaking seemed to lower the overall risk of hospitalization (OR=0.96, 95% CI=0.93; 0.98). CONCLUSION: this study has two important public health implications: first, it highlights the potential impact of programmes based on both soft home care and offer of social caretaking; second, it helps to raise awareness, both among health/social work and in the community, of the need for protection during summer periods for the elderly. PMID- 19776457 TI - [A cluster of methanol-related poisonings in Sicily: case characterization and identification of unexpected sources of exposure]. AB - OBJECTIVE: To describe methanol poisoning exposures in Italy and to investigate a cluster of methanol-related deaths due to abuse occurred in Sicily among immigrants from East Europe. DESIGN: the human methanol exposures handled by the Poison Control Centre of Milan, the major national centre for toxicological advise active in Italy, were reviewed retrospectively (January 2004-September 2006) and prospectively (October 2006-October 2008). SETTING: For each case of managed human exposure, the Poison Control Centre of Milan uses a standard format to collect patient information, substance/exposure information, clinical effects, therapy, outcomes. The database arising from that procedure was searched for all cases exposed to methanol and/or reporting selected clinical signs (i.e., metabolic acidosis with ocular effects and/or central nervous system depression and/or respiratory depression). Each case was reviewed and classified according to standard criteria. MAIN OUTCOMES: Three commercial products containing more than 70% methanol available on the market in Sicily and associated with lethal exposures due to abuse among immigrants were identified. RESULTS: In the period under study, the Poison Control Centre of Milan examined 29 methanol poisoning exposures (none in 2004, 6 in 2005, 6 in 2006, 15 in 2007, and 2 in 2008). Among them, 17 occurred in Sicily, with a peak of 11 cases in 2007, and 12 in other regions. The patients included 16 men and 13 women with a median age of 49,5 years (range 1-81 years). Fifteen cases were immigrants from East Europe (14 Rumanian and one Polish). Eleven cases reported minor effects, two cases moderate effects, four cases major effects, and 12 cases died. Twelve cases were accidental exposures (5 occurred at work, 3 at home and 4 in other places), while 17 cases were intentional exposures (14 due to abuse, 2 to attempted suicide and 1 to misuse). Minor effects were reported in 11 cases, moderate effects in two cases, major effects in four cases and death in 12 cases. The most frequently reported clinical effects included: coma (13 cases), metabolic acidosis (10 cases), mydriasis (4 cases), visual loss (3 cases), gastric pyrosis (2 cases), constriction of the visual field (2 cases), and vertigo (2 cases). Blood methanol level was reported for 15 cases (< 50 mg/dL in 2 cases; 50-99 mg/dL in 2 cases; 100-499 mg/dL in 4 cases; >500 mg/dL in 1 case; positive, unknown value in 6 cases). All cases due to abuse (n. 14) and, among them, lethal (n. 12) occurred in Sicily and involved immigrants. On the other hand, all methanol poisonings occurring in the other Italian regions involved Italian citizens unintentionally exposed and with minor effects, except for one case of attempted suicide with consequent major effects. The investigations performed in Sicily lead to identifying three locally produced and marketed detergents containing more than 70% methanol, improperly labelled and packaged. Furthermore, a detergent for domestic use was identified containing 25-30% methanol without any labelling information. Two of the detergents containing more than 70% methanol were withdrawn from the market in November 2007, while the other, that was identified later, was withdrawn in July 2008. The detergent for domestic use, containing 25 30% methanol was withdrawn in December 2007. Starting from July 2008, no new cases of methanol poisonings were observed. CONCLUSION: The availability in Sicily of products containing high concentrations of methanol, improperly packaged and labelled, determined a generalised risk of accidental exposures and favoured voluptuary assumption of methanol among selected groups. The observations highlight the importance of a surveillance system of toxic exposures based on the information collected by the Poison Control Centres and its ability to provide timely identification of unexpected and dangerous events and to support preventive actions. PMID- 19776458 TI - [The contribution of HIA to waste management decision making: the case of incinerators]. PMID- 19776459 TI - [Occupational medicine: practice and ethical requirements of the new law on health and safety in the workplace (legislative decree 81/2008)]. AB - Decisions in occupational health may involve ethical conflicts arising from conflicts between stakeholders' interests. Codes of ethics can provide a practical guide to solve dilemmas. The new law on health and safety in the workplace in Italy (decree 81/2008) states that occupational health practice must comply with the code of ethics of the International Commission on Occupational Health. The universally acknowledged ethical principles of beneficience/nonmaleficience, autonomy and justice, which are the basis of the Charter of fundamental rights of the European Union, inspired this code. Although the code is not a systematic textbook of occupational health ethics and does not cover all possible aspects arising from the practice, making decisions based on it will assure their effectiveness and compliance with ethical principles, besides the formal respect of the law. PMID- 19776460 TI - [New mode of access to physical and rehabilitative care in Regione Puglia: first results]. PMID- 19776461 TI - [Bayesian approach for the cost-effectiveness evaluation of healthcare technologies]. AB - The development of Bayesian statistical methods for the assessment of the cost effectiveness of health care technologies is reviewed. Although many studies adopt a frequentist approach, several authors have advocated the use of Bayesian methods in health economics. Emphasis has been placed on the advantages of the Bayesian approach, which include: (i) the ability to make more intuitive and meaningful inferences; (ii) the ability to tackle complex problems, such as allowing for the inclusion of patients who generate no cost, thanks to the availability of powerful computational algorithms; (iii) the importance of a full use of quantitative and structural prior information to produce realistic inferences. Much literature comparing the cost-effectiveness of two treatments is based on the incremental cost-effectiveness ratio. However, new methods are arising with the purpose of decision making. These methods are based on a net benefits approach. In the present context, the cost-effectiveness acceptability curves have been pointed out to be intrinsically Bayesian in their formulation. They plot the probability of a positive net benefit against the threshold cost of a unit increase in efficacy.A case study is presented in order to illustrate the Bayesian statistics in the cost-effectiveness analysis. Emphasis is placed on the cost-effectiveness acceptability curves. Advantages and disadvantages of the method described in this paper have been compared to frequentist methods and discussed. PMID- 19776462 TI - [Environment and health in Gela (Sicily): present knowledge and prospects for future studies]. AB - The study area includes the Municipalities of Gela, Niscemi and Butera located in the South of Sicily, Italy. In 1990 it was declared Area at High Risk of Environmental Crisis. In 2000 part of it was designated as Gela Reclamation Site of National Interest, RSNI. The site includes a private industrial area, public and marine areas, for a total of 51 km(2). Gela populationin 2008 was 77,145 (54,774 in 1961). Sea level:46 m. Total area: 276 km(2). Grid reference: 37 degrees 4' 0" N, 14 degrees 15' 0" E. Niscemi and Butera are located border to Gela. Populations are respectively 26,541 and 5,063. Sea level respectively: 332 m and 402 m. Close to the city of Gela, the industrial area, operating since 1962, includes chemical production plants, a power station and an oil refinery plant, one of the larger in Europe, refining 5 millions tons of crude per year. From the beginning the workforces decreased from 7,000 to the current 3,000 units. Over the years, these industrial activities have been a major source of environmental pollution. Extremely high levels of toxic, persistent and bio accumulating chemical pollutants have been documented. Many relevant environmental and health data are available. Prior to the studies described in the present publication, their use in order to identify environmental pressures on health has been limited. Nevertheless, since several years different epidemiological studies have provided evidence of the occurrence of health outcomes significantly higher than in neighbouring areas and compared to regional data. In 2007 a Multidisciplinary Working Group has been established, to analyze the existing data on pollution-exposure-effect and to complete current knowledge on the cycle of pollutants, from migration in the environment to health impact. The present publication is a collection of contribution of this group of experts, supported by the following projects: Evaluation of environmental health impact and estimation of economic costs at of National Interest Remediation Sites coordinated by the Italian National Institute of Health on behalf of the Ministry for the Environment and Technical Assistance of WHO Health and Environment Centre to the Sicilian Region to develop plans for environmental remediation. Results describe the state of contamination of a variety of environmental matrices in the area. Other contributions are addressed to understanding action mechanisms of main pollutants and their environmental pathways, as well as to identifying crucial knowledge to be used for studying the environment-health relations. A specific attention has been paid to pollutants migration in the environment and to the potential exposure of the population. Appropriate markers of exposure and physiological changes are described and referred to the chemical substances identified in the environment in Gela. Details are given about the genotoxic and endocrine disrupting potential, and about the potential association between markers of exposure and diseases observed in excess in the same area. Indications to develop specific biomarkers for Index Substances and human biomonitoring surveys for populations exposed to environmental risk are presented and discussed. A specific multiple-exposure risk assessment procedure is proposed for Index Substances. Epidemiological studies useful to describe the health status of Gela population are summarized. One report deals with the occupational and residential analyses of male petrochemical workers, born in Sicily, employed from 1960 to the end of 1993, followed up for mortality from 1960 to 2002. Major findings were amarked healthy worker effect and an increased lung cancer risk for residence in Gela. The analyses of death certificates from 1995 to 2002 and of hospital discharge records from 2001 to 2007 confirm the potentialities of these current statistics for ecological studies: they depict the poor health conditions of Gela residents compared to other neighbouring municipalities in a 40-km range. Infact, the overall mortality rate for tumor and non-tumor causes in Gela is significantly higher for both sexes, and this is shown also in the Municipality of Niscemi, especially among the male population. Hospital discharge records for tumor causes, but especially for non-tumor ones, exceeded expectations in both genders and must be analysed taking into consideration the attraction exerted on the surrounding areas by the Gela hospital. Data analysis according to 5 ten-year birth cohorts, from 1915 to 1964, shows a decreasing mortality trend, whereas the increase of hospital admissions is confirmed in the younger generations. The issue of birth defects is recurrent in this area: a suitable register is lacking so that updated figures cannot be presented. However, data previously published showed excesses of prevalence rates of several specific birth defects, mainly urinary tract and genital anomalies. The same is worth in the incidence of new cancer cases since the development of a proper register is yet in progress. Tools and methodologies that should be applied in Gela to study environment-health relations are proposed, like Life Cycle Analysis, dispersion patterns and an air quality monitoring system. A conceptual model considering all pollution sources and different exposure patterns present in Gela, developed by the Multidisciplinary Working Group, is presented. Among the activities carried out by regional authorities, two Reports on the Regional Environment Protection Agency monitoring activity and on the EU Program SEARCH, School Environment And Respiratory Health in Children, are included. A section is devoted to understanding what is necessary to build an epidemiological monitoring system specifically designed for this area, in order to keep under permanent control environment-related health outcomes. This includes a systematic and continuative collection, storage and analysis of environmental-induced diseases, exposure and risk factors, as well as a timely dissemination of those information to the decision-makers. The final article describes the research activities carried out to design and implement a human biomonitoring survey in the area. These activities included relation-building with local communities, information collection, meetings, involvement of stake-holders. This experience will reach its climax when the community-exposure data feedback will be provided, because it will mark the consolidation of present knowledge and its possible processing into public health action plans. The present publication can represent an important tool and a model for all interest-bearers to assess environmental pollution impacts on human health in contaminated areas. A local system to assess the relation between environmental pollution and population health is therefore urgently needed to provide risk managers with ad-hoc tools to improve environmental protection and prevent further risks for local communities. PMID- 19776463 TI - [The Gela reclamation site of national interest]. PMID- 19776464 TI - [Environmental pollution in the area of Gela]. PMID- 19776465 TI - [Operation of Gela refinery and its impact on the environment]. PMID- 19776466 TI - [Investigation on pollutants in the area around the Gela petrochemical plant]. PMID- 19776467 TI - [Air pollution: general problems in the area of Gela]. PMID- 19776468 TI - [The influence of soil characteristics on contaminant mobility and the transfer into the food chain]. PMID- 19776469 TI - [Marine environmental status in the Strait of Sicily close to the Gela reclamation site]. PMID- 19776470 TI - [Endocrine disrupters: from toxicological investigation to biomarker characterization]. PMID- 19776471 TI - [Use of reference values to ascertain the exposure status in general population groups possibly exposed to high levels of selected environmental toxicants]. PMID- 19776472 TI - [Risk assessment for human health associated to combined exposures and metabolic factors of individual susceptibility]. PMID- 19776473 TI - [Study of occupational and residential risks in workers of the Gela petrochemical plant]. PMID- 19776474 TI - [The experience of the Sicilian epidemiology observatory in studying health status of population resident in Gela risk area]. PMID- 19776475 TI - [Integrated reduction and prevention of air pollution in Gela: life cycle analysis and dispersion models]. PMID- 19776476 TI - [Environmental studies for designing an air quality monitoring network in the Gela Refinery area]. PMID- 19776477 TI - [Conceptual model for the estimate of human exposure in a contaminated area: proposal for Gela National priority site]. PMID- 19776478 TI - [Indoor air quality: an environmental and health priority]. PMID- 19776479 TI - [The use of hydrocarbonoclastic bacteria for the recovery of polluted areas (monitoring of Messina, Milazzo and Augusta sites)]. PMID- 19776480 TI - [The activity of the Environmental Protection Agency of Sicily (ARPA) in the area at environmental risk of Gela]. PMID- 19776481 TI - [From descriptive studies towards epidemiologic surveillance]. PMID- 19776482 TI - [Communication and interaction with the community]. PMID- 19776483 TI - Introduction. The diffusion of screening programmes in Italy: 2007. PMID- 19776484 TI - Mammography screening in Italy: 2007 survey. AB - This report is an update of similar previous papers that have been published by the ONS (Osservatorio Nazionale Screening, National Centre for Screening Monitoring) since 2002. Data for the survey come from several different programmes that may have changed over time, and may have different settings of organisation and management. During 2007, a further increase in screening activity was recorded, with the inclusion of all Northern and Central Italian Regions, and a further development in the Southern Regions and Islands. In 2007, screening activity also started in Puglia, so today all Italian Regions have implemented screening programmes. In 2007, almost 2,210,000 women aged 50-69 years were invited to have a screening mammogram, and over 1,225,000 were screened. Theoretical extension was 81.4%, while actual extension increased from 57.2% in 2006 to 62.3% in 2007, finally rising over the critical value of about 50% registered during the last years. An imbalance in coverage is still present when comparing Northern and Central Italy to Southern Italy, which only has a 52% coverage by organised screening. The percentage of women screened during 2007 accounted for 33.3% of the national target population. During the last few years (2004-2007), participation rates were substantially stable around 55-57% for crude rate, and 59-61% for adjusted rate, respectively. A decreasing trend towards the South of Italy is evident for this parameter, too. Many programmes work with low volumes of activity (below 10,000 or even 5,000 examinations per year), and no regional mean value surpassed the desirable level of at least 20,000 examinations for each programme. Referral rates of 7.9% at first screening and 4.0% at repeat screening were recorded. Direct standardised detection rate was 6.5x1,000 at first test and 3.8 at repeat test, while benign to malignant ratio for first and repeat screening was 0.21 and 0.14, respectively. Detection rate of invasive cancers /=1 cm, with villous/tubulovillous type or with high-grade dysplasia). As expected, the corresponding figures at repeat screening were lower. The DR of cancer and adenomas increased with age and was higher among males; 25% of screen-detected cancers were in TNM stage III+. Many programmes reported some difficulties in guaranteeing TC in the appropriate time frame to SOF+ subjects: in 23.9% of cases the waiting time was longer than two months. Seven programmes employed FS as the screening test: 66.5% of the target population (about 50,000 subjects) were invited and 8,678 subjects were screened, with an attendance rate of 27.7%. Overall, 88% of FS were classified as complete. Overall TC referral rate was 11.1% and the DR per 1,000 screened subjects was 4.4 and 58.4 for invasive cancer and AA, respectively. PMID- 19776488 TI - Quality of colposcopy and treatment--data from the national survey of Italian organised cervical screening programmes: 2006 activity. AB - We collected from Italian organised cervical screening programmes data on the correlation between colposcopic findings (according to the 1990 international classification) and histology and on the treatment/management of screen-detected histologically confirmed cervical intraepithelial neoplasia (CIN). Data routinely registered by organised programmes were provided as aggregated tables. We obtained data on colpo-histological correlation from 72 programmes. Of the 18,340 reported colposcopies 37.9% were classified as normal and 20.9% as unsatisfactory. CIN2 or more severe histology was detected in 71.6% of colposcopies classified as grade 2 or higher. Of all colposcopies the outcome of which was CIN2 or more severe histology, 40.6% had a colposcopy classified as grade 2 or higher. We obtained data on treatment from 83 programmes. Of the 3,405 women with CIN1 69.3% had follow-up only. However 0.8% of them had cold-knife conisation, 7.5% were treated by diathermocoagulation and 0.1% had hysterectomy. Of the 2,597 women with CIN2 or CIN3 4.1% had not yet been treated when data were collected and no data were available for a further 8.1%. Excision by radio frequency device was the most common treatment among these women (60.9% of those with known treatment). However 0.7% of all CIN2 and 3.4% of all CIN3 had hysterectomy. Among the 100 women with invasive carcinoma, 17% (plausibly with microinvasive disease) had only excisional treatment reported. PMID- 19776489 TI - Audit system on Quality of breast cancer diagnosis and Treatment (QT): results of quality indicators on screen-detected lesions in Italy for 2006 and preliminary results for 2007. AB - Within this survey, conducted by the Italian Breast Screening Network (Gruppo Italiano per lo Screening Mammografico, GISMa), individual data are collected yearly on more than 50% of all screen-detected operated lesions in Italy. In 2006, results showed overall good diagnosis and treatment quality and an improving trend over time. Critical issues were identified in waiting times, compliance with recommendations on not performing frozen section examination on small lesions and on performing specimen X-ray. Pre-operative diagnosis reached the acceptable target, but there is a large variation between Regions and programmes. The sentinel lymph node technique (SLN) was performed on the axilla in more than 70% of screen-detected invasive cancers, avoiding a large number of potentially harmful dissections. On the other hand, potential overuse of SLN in ductal carcinoma in situ deserves further investigation. The detailed results have been distributed to regional and local screening programmes, also by means of an online database, in order to allow multidisciplinary discussion and the identification of appropriate solutions to any problems documented by the data. Specialist Breast Units with adequate case volume and enough resources would provide the best setting for making audit effective in producing quality improvement with a shortening of waiting times. PMID- 19776490 TI - Superior biocompatibility and osteogenic efficacy of micro-arc oxidation-treated titanium implants in the canine mandible. AB - The aim of this paper is to test implantation outcomes and osteogenic efficacy of plasma micro-arc oxidation (MAO)-treated titanium implants in dogs. Thirty-six pure titanium implants (18 MAO-treated, 18 untreated) were inserted into the mandibles of nine adult beagles and allowed to heal under non-weight-bearing conditions. Implant stability and interface characteristics were evaluated at 4, 8 and 12 weeks post-implantation. Methods included scanning electron microscopy, mechanical testing, histological analysis and computer-quantified tissue morphology. Osseointegration was achieved in both groups, but occurred earlier and more extensively in the MAO group. Areas of direct bone/implant contact were approximately nine times higher in the MAO group than in the control group at 12 weeks (65.85% versus 7.37%, respectively; p < 0.01). Bone-implant shear strength in the MAO group (71.4, 147.2 and 266.3 MPa at weeks 4, 8 and 12, respectively) was higher than in the control group (4.3, 7.1, and 11.8 MPa at weeks 4, 8 and 12, respectively), at all assessments (all, p < 0.01). MAO treatment of titanium implants promotes more rapid formation of new bone, and increases bone-implant shear strength compared to untreated titanium implants. PMID- 19776491 TI - Preparation of biodegradable PLA/PLGA membranes with PGA mesh and their application for periodontal guided tissue regeneration. AB - A biodegradable polylactic acid (PLA)/poly(glycolide-co-lactide) copolymer (PLGA) membrane with polyglycolic acid (PGA) mesh was prepared to aid the effective regeneration of defective periodontal tissues. The microporous membrane used in this study consists of biodegradable polymers, and seems to have a structure to provide appropriate properties for periodontal tissue regeneration. Based on the albumin permeation test, it is known that the biodegradable membrane exhibits the suitable permeability of nutrients. The membrane maintained its physical integrity for 6-8 weeks, which could be sufficient to retain space in the periodontal pocket. Cell attachment and cytotoxicity tests were performed with respect to the evaluation of biocompatibility of the membrane. As a result, the membrane did not show any cytotoxicity. The safety and therapeutic efficacies of the biodegradable membranes were confirmed in animal tests. PMID- 19776492 TI - Structure and haemocompatibility of ZnO films deposited by radio frequency sputtering. AB - ZnO films were first deposited on silicon and glass substrates using radio frequency sputtering and then annealed in air at different temperatures from 300 to 700 degrees C. The microstructures, surface energy and optical properties of ZnO films were examined by x-ray diffraction, Raman spectroscopy, contact angle test and UV-visible optical absorption spectroscopy, respectively. Results show that a perfectly oriented ZnO (0 0 2) thin film is obtained in all ZnO samples. Raman spectroscopy, in combination with those derived by UV-visible optical absorption spectroscopy, provides us with an accurate description of ZnO nature, revealing that, after annealing, ZnO films exhibit better crystallinity and narrower optical energy gap. The contact angle test denotes that the adhesive work and polar component of the surface energy of ZnO films increase steadily with the annealing temperature, which leads to more active interaction between annealed ZnO films and blood plasma. The platelet adhesion experiment shows that there are fewer platelets adhered to the surface of ZnO films compared to the polyurethane (PU) used in clinical application, suggesting ZnO's better compatibility with blood. As the annealing temperature increases, the number of platelets adhered to ZnO films increases correspondingly, which we believe is due to the narrower optical energy gap. Therefore, the appropriate surface properties and the wide optical energy gap of ZnO thin films are believed to be the main factors responsible for the excellent haemocompatibility. PMID- 19776493 TI - Non-crystalline composite tissue engineering scaffolds using boron-containing bioactive glass and poly(D,L-lactic acid) coatings. AB - The aim of this study was the fabrication of three-dimensional, highly porous, bioactive scaffolds using a recently developed bioactive glass powder, denominated '0106', with nominal composition (in wt%): 50 SiO(2), 22.6 CaO, 5.9 Na(2)O, 4 P(2)O(5), 12 K(2)O, 5.3 MgO and 0.2 B(2)O(3). The optimum sintering conditions for the fabrication of scaffolds by the foam-replica method were identified (sintering temperature: 670 degrees C and dwell time: 5 h). Composite samples were also fabricated by applying a biopolymer coating of poly((D,L) lactic acid) (PDLLA) using a dip coating process. The average compressive strength values were 0.4 MPa for uncoated and 0.6 MPa for coated scaffolds. In vitro bioactivity studies in simulated body fluid (SBF) showed that a carbonate hydroxyapatite (HCAp) layer was deposited on uncoated and coated scaffolds after only 4 days of immersion in SBF, demonstrating the high in vitro bioactivity of the scaffolds. It was also confirmed that the scaffold structure remained amorphous (no crystallization) after the specific heat treatment used, with scaffolds exhibiting mechanical properties and bioactivity suitable for use in bone tissue engineering applications. PMID- 19776494 TI - A bone-like nano-hydroxyapatite/collagen loaded injectable scaffold. AB - From a clinical perspective, the use of injectable scaffolds is very attractive as it minimizes patient discomfort, risk of infection, scar formation and the cost of treatment. Bone refers to a family of materials that are constructed by mineralized collagen fibrils. The main objective of this research was to develop a bone-like nano-hydroxyapatite/collagen (nHAC) loaded chitosan (C)/beta glycerophosphate (GP) injectable scaffold. The feasibility of developing a thermo sensitive and injectable chitosan solution in the presence of nHAC was demonstrated. Bone-marrow-derived messenchymal stem cells (MSCs) were used to measure the cell proliferation of C/GP/nHAC scaffolds based on the cell count kit 8 (CCK-8) assay. It was found that MSCs proliferated normally with the C/GP/nHAC composite scaffolds. The C/GP/nHAC composite scaffolds developed in this study exhibited good injectability, thermo-irreversible properties and solidified under mild conditions. No more than 0.02 g ml(-1) of nHAC filler was required to form a non-decaying hydrogel. PMID- 19776495 TI - Poly (ADP-Ribose) polymerase inhibition attenuates atherosclerotic plaque development in ApoE-/- mice with hyperhomocysteinemia. AB - AIM: Hyperhomocysteinemia (Hhcy) is an important and independent risk factor for atherosclerosis. Recent studies have shown that Poly (ADP-ribose) polymerase (PARP) activation may be associated with Hhcy-induced endothelial dysfunction, which is an important mechanism for Hhcy to affect atherosclerotic progress. Thus, we investigated whether PARP inhibitors may attenuate atheroscle-rotic plaque development in an Hhcy-induced experimental animal model with atherosclerosis. METHODS: Six-week-old homozygous apolipoprotein E-deficient (ApoE-/-) male mice fed a normal diet or high methionine diet randomly received intraperitoneal injections of 10 mg/kg 3-aminoben-zamide (3-AB, a PARP inhibitor) dissolved in phosphate-buffered saline (PBS), or physiological saline every other day for 12 weeks. Atherosclerotic lesion sizes and PARP activity were measured. Related inflammatory factors in atherogenesis were investigated by real-time quantitative PCR and Western blot analysis. RESULTS: Our data demonstrated that ApoE-/- mice fed a high methionine diet generated Hhcy, which subsequently increased the atherosclerotic lesion size significantly, promoted oxidative stress-associated DNA damage and PARP activation, then increased the expression of proinflammatory fac-tors within atherosclerotic plaques. Although PARP inhibition by 3-AB did not markedly inhibit plaque development in ApoE-/- mice with spontaneous hyperlipidemia by feeding a normal diet, it significantly reduced the atherosclerotic lesion size by 40% in Hhcy-induced atherosclerosis without affecting plasma homocysteine levels and lipid contents, effectively suppressed PARP activation, and inhibited nuclear translocation of nuclear factor (kappa)B (NF-(kappa)B) and subsequent production of inflam-matory factors, such as vascular cell adhesion molecule-1 (VCAM-1) and monocyte chemoattactant protein 1 (MCP-1). CONCLUSION: Our results suggest that PARP inhibition attenuates atherosclerotic plaque development under hyperhomocysteinemic conditions, through the inhibition of PARP activation, nuclear NF-kappaB translocation and subsequent expression of inflammatory factors. PMID- 19776496 TI - Contribution of parenting factors to the developmental attainment of 9-month-old infants: results from the Japan Children's Study. AB - BACKGROUND: Child development integrates several interdependent domains, but few studies have attempted to identify the common factors that contribute to these different domains of development in infancy. The aim of the present study was to identify the factors that contribute to several domains of developmental attainment in 9-month-old infants. METHODS: We used data from the Japan Children's Study, a prospective cohort study underway in Japan since 2005. Mothers completed questionnaires about their children's temperament, coparenting behaviors, maternal parenting stress, and parenting behavior. The Kinder infant development scale was used to evaluate child development outcomes. RESULTS: A total of 270 children were included in this analysis. After adjusting for the children's birth weight, gestational age, temperament, and other family environmental variables, multiple logistic regression analyses showed that greater maternal cognitive stimulation was associated with the development of receptive language, expressive language, social relationships, and feeding. Results also suggest that early supportive coparenting helped to promote development in manipulation, receptive language, and social relationships. Maternal parenting stress was stable between the infant ages of 4 and 9 months and was negatively correlated with scores for coparenting and maternal stimulation, which suggests an indirect effect of maternal parenting stress on child outcomes. CONCLUSIONS: Supportive coparenting and maternal cognitive stimulation were the most important contributors to most domains of child development. Our findings suggest that educational interventions targeting young families would help parents establish and maintain an environment of successful coparenting and cognitive stimulation as their children grow. PMID- 19776497 TI - Lifestyle and overweight among Japanese adolescents: the Toyama Birth Cohort Study. AB - OBJECTIVE: To investigate the effects of lifestyle factors on overweight among Japanese adolescents. METHODS: We studied 5753 junior high school students (2842 boys and 2911 girls) aged 12 to 13 years. The students were residents of Toyama prefecture, Japan and completed a questionnaire about their height, weight, and lifestyle factors, in June and July 2002. Subjects with a body-mass index (BMI) higher than age- and sex-specific cut-off points were defined as obese. Parental overweight was defined as a BMI of 25 or higher. Logistic regression analysis was used to examine associations between lifestyle factors and overweight. RESULTS: Skipping breakfast, eating quickly, excessive eating, physical inactivity, and long hours of TV watching were positively and significantly associated with overweight in both sexes. There was a negative association between snacking and overweight in girls (P<0.001); no such association was found in boys (P>0.05). Nighttime snacking was negatively associated with overweight in boys and girls (P<0.05). Extended video game playing (>or=2 hours; OR=2.00, P=0.012) and short sleep duration (<7 hours; OR=1.81, P=0.004) were significantly associated with overweight in girls only. The respective risks of overweight that derived from the subjects' fathers and mothers were 2.0 and 2.5 times, respectively, in boys and 1.9 and 3.0 times in girls. CONCLUSIONS: Parental overweight, skipping breakfast, eating quickly, excessive eating, long hours of TV watching, long hours of video game playing, physical inactivity, and short sleep duration were associated with adolescent overweight. Furthermore, there were significant negative associations between adolescent overweight and snacking in girls and nighttime snacking in both sexes. PMID- 19776498 TI - Diagnosis and treatment of dentinal hypersensitivity. AB - This bibliographic review provides a general view of the etiology, characteristics and treatment of dentinal hypersensitivity, so that professionals can use this information in the therapeutic management of this clinical condition. For this purpose, the authors have analyzed whole texts of relevant articles on the subject. This study showed that the predisposing factors associated with the causes of dentinal hypersensitivity must be controlled or eliminated, by educating the patient regarding the excessive intake of acidic food, as well as providing guidance on the proper tooth brushing technique and analysis of occlusion. Effective treatment must be preceded by a proper diagnosis, established after the exclusion of any other possible causes of the pain. These cases must be managed efficiently, quickly and permanently. The availability of a wide variety of treatment could be an indicator that there is still no effective desensitizing agent to completely resolve the patient's discomfort, or that it is difficult to treat, irrespective of the available treatment options. Even with the large number of published studies, it has not been possible to reach a consensus about the product that represents the gold standard in the treatment of dentinal hypersensitivity. PMID- 19776500 TI - Polymorphism in the Msx1 gene associated with hypodontia in a Brazilian family. AB - Tooth development is regulated by a reciprocal series of epithelial-mesenchymal interactions. With the large number of genes involved in the odontogenesis process, the opportunity for mutations to disrupt this process is high. Mutational analysis has revealed genes that are major causes of non-syndromic hypodontia. The most common permanent missing teeth are the third molars, second premolars, and maxillary lateral incisors. Although hypodontia does not represent a serious public health problem, it may cause masticatory and speech dysfunctions and esthetic problems. Msx1 (Muscle Segment Box) is believed to play an important role in tooth development. To further investigate the role of the gene in human hypodontia, we analyzed genotypes in a family with hypodontia using the SSCP assay. Examinations of all affected and unaffected members of the family studied indicated that 5 of the 10 family members had hypodontia, and it was possible to observe polymorphisms/mutation by SSCP as bands with an anomalous migration pattern in individuals with hypodontia. Our data suggest that Msx1 gene polymorphism is associated with hypodontia. PMID- 19776499 TI - Oral health status of mentally disabled subjects in India. AB - The aim of the study was to determine the oral health status and investigate the association of oral health status with various socio-demographic (age, gender, parent's education, income) and clinical variables (aetiology for mental disability and IQ level) among mentally disabled subjects. The study sample comprised 225 mentally retarded subjects aged 12-30 years attending a special school in Udaipur, India. Caries status, oral hygiene status and periodontal status were assessed by DMFT Index, Simplified Oral Hygiene Index (OHI-S) of Greene and Vermillion and Community Periodontal Index, respectively. Chi-square test, one way analysis of variance (ANOVA), multiple linear stepwise regression analysis, and multiple logistic regression analysis were employed for statistical analysis. There was a statistically significant difference (P = 0.001) between all the age groups in all the variables of Oral hygiene index and DMFT index. The oldest age group had the highest scores for all the indices measured. Having Down's syndrome, parents with lower educational status and low I.Q. were the most important predictors for poor oral health status. The present study highlighted that the oral health status of this mentally retarded population was poor and was influenced by aetiology of the disability, I.Q. level, and parent's level of education. PMID- 19776501 TI - Evaluation of primary stability of inclined orthodontic mini-implants. AB - The aim of this study was to investigate the initial stability of mini-implants when placed slanting or perpendicular to the bone surface, and to examine the effects of differences in tractional direction. Titanium mini-implants were inserted into rabbit nasal bones, slanting (60 degrees , 120 degrees ) or perpendicular (90 degrees ) to the bone surface. These implants were then loaded with a force of approximately 2 N, using a NiTi coil spring. The mobilities on the traction and non-traction sides were assessed using the Periotest device immediately after placement and after traction for two weeks. Then, the tissues with the mini-implants were resected, and the contact between the bone and the implant was examined by electron microscopy. There was a tendency for the mobilities of the mini-implants at 60 degrees and 120 degrees to be smaller than those at 90 degrees when measured before and after traction. The bone-implant contact lengths at 60 degrees were significantly longer than those at 90 degrees . There was no significant difference in the bone-implant contact ratio among the different angles. Correlations were evident between implant mobility and contact length or contact ratio. It is concluded that in clinical practice, implants inclined to the bone surface tend to have better primary stability. PMID- 19776502 TI - Expression of cytokeratins 10, 13, 14 and 19 in oral lichen planus. AB - OLP is a chronic inflammatory disease of unknown etiology that may develop into squamous-cell carcinoma. Cytokeratins, which are important components of the cytoskeleton, are excellent epithelial differentiation markers used to study neoplastic and inflammatory diseases. To study the profile of cytokeratins in OLP and their possible association with dysplastic alterations, monoclonal antibodies were used for cytokeratins 10, 13, 14 and 19, in 26 samples of OLP. The streptavidin-biotin technique was employed in paraffin-embedded tissue sections. Sample analysis revealed suprabasal expression of cytokeratin 10 in 16/17 samples, 14 of them with reduced expression; suprabasal expression of cytokeratin 13 in 18/23, 16 of them with delay; basal and suprabasal expression of cytokeratin 14 in all samples; and focal basal expression of cytokeratin 19 in 4/21. Expression of cytokeratins 10, 13 and 14 was altered in OLP lesions. The inflammatory process and hyperkeratosis or parakeratosis seem to have interfered with the expression of these CKs. Cytokeratin 19 was expressed in the lesions, in a pattern similar to that mentioned in the literature for the non-keratinized oral mucosa. The presence of mild dysplasia did not change the expression of the cytokeratins studied. No differences in pattern of expression were observed between keratinized and non-keratinized areas in the lesions caused by OLP. PMID- 19776503 TI - Oral squamous papilloma: clinical, histologic and immunohistochemical analyses. AB - Oral squamous papilloma (OSP) is a benign proliferation of the stratified squamous epithelium, which results in a papillary or verrucous exophytic mass. Twelve patients suspected to have oral papilloma underwent excisional biopsy for histopathologic and immunohistochemical analysis. The majority of the patients (75%) were females, and the most prevalent site was the tongue, followed by the palate. The round and whitish form was present in 58.4% of the cases. The lesions were softened/flaccid in 66.7% of cases and a pedunculated attachment was seen in 75% of the lesions. The histopathologic examination revealed hyperparakeratosis, occasional basal hyperplasia, and koilocyte-like cells in 100% of the specimens. Immunohistochemical assays utilizing BP53-12 and Pab240 antibodies for p53 protein showed negative or weak immunostaining (91.6%) for both immunomarkers in all the epithelial layers examined. The findings suggest the benign nature of the lesions and small possibility of becoming malignant. PMID- 19776504 TI - Caries-preventive effect of glass ionomer and resin-based fissure sealants on permanent teeth: a meta analysis. AB - The purpose of this quantitative systematic review was to appraise the evidence on the caries-preventive effect of glass ionomer cement (GIC) in relation to resin-based fissure sealants. Nine English and two Portuguese databases were searched (15 January 2008). Randomized clinical trials and systematic reviews were considered for inclusion. Trial exclusion criteria were: drop-out rates > 33%; no randomization; baseline differences in groups not statistically adjusted; and no clinically important outcomes were presented. Two authors reviewed the articles independently. The outcome measure for the caries preventive effect was caries absence on sealed teeth. Of the 112 identified articles, 25 were selected for review. Of these, 14 were excluded and 11 accepted (8 trials; 3 systematic reviews). The accepted reviews provided no evidence of superiority of either sealant material. Six trials were included for meta-analysis. The pooled odds ratio was 0.96, 95% CI 0.62-1.49, indicating no difference in the caries preventive effect of GIC and resin-based fissure sealant material. This systematic review with meta-analysis found no evidence that either material was superior to the other in the prevention of dental caries. Thus, both materials appear equally suitable for clinical application as a fissure sealant material. PMID- 19776505 TI - Non-bioabsorbable vs. bioabsorbable membrane: assessment of their clinical efficacy in guided tissue regeneration technique. A systematic review. AB - In a 1998 review article, Laurell and colleagues performed a meta-analysis of relevant guided tissue regeneration (GTR) articles over the previous 20 years (1). The purpose of the present research was to expand on that work, particularly searching for trends discriminating between bioabsorbable and non-bioabsorbable barriers, as well as the use of enamel matrix derivative, with respect to interproximal bony defects. The most recent periodontal journals were reviewed and a search of PubMed (National Institutes of Health) was conducted via the internet covering 1990 to the present. Forty-nine articles were found to be relevant and within established parameters. The data were analyzed using (a) a variation of the methods described in Laurell et al. (1) and (b) statistics appropriate for inter-group comparisons. In most respects, all membranes and enamel matrix derivative (EMD) delivered better outcomes, in the range of 1 to 2 mm, than open flap debridement. The use of any barrier type or EMD configuration was found to yield more Clinical Attachment Level (CAL) gain than any open flap configuration. Other than collagen without grafts versus non-bioabsorbables without grafts, no other comparison between membranes or between membranes and EMD found any significant differences (P > 0.05). GTR was confirmed to be superior to open flap debridement. PMID- 19776506 TI - Antifungal activity of alpha-mangostin against Candida albicans. AB - This study was conducted to examine the activity of alpha-mangostin against Candida albicans, the most important microorganism implicated in oral candidiasis. Its activity was compared to Clotrimazole and Nystatin. Results showed that alpha-mangostin was effective against C. albicans, the minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) were 1,000 and 2,000 microg/ml, respectively. The C. albicans killing activity of alpha-mangostin was more effective than Clotrimazole and Nystatin. The cytotoxicity of alpha-mangostin was determined and it was found that alpha mangostin at 4,000 microg/ml was not toxic to human gingival fibroblast for 480 min. The strong antifungal activity and low toxicity of alpha-mangostin make it a promising agent for treatment of oral candidiasis. PMID- 19776507 TI - Chronic hyperplastic candidosis: a pilot study of the efficacy of 0.18% isotretinoin. AB - Management of oral candidiasis depends on an accurate diagnosis, identification and elimination of predisposing factors, and, often, use of antifungal agents. Chronic hyperplastic candidosis (CHC) is considered a premalignant lesion of the oral mucosa, occurring as speckled or homogeneous white lesions. If the lesions are untreated, a minor proportion may become dysplastic and progress to carcinoma. The traditional treatment of this lesion is based on the use of antifungal agents. The aim of this study was to examine the efficacy of 0.18% isotretinoin for treatment of nystatin-resistant candidiasis. Isotretinoin was administered topically twice a day for one month to six patients affected by nystatin-resistant CHC. In all six patients, daily antimycotic topical therapy with nystatin for 30 days had failed to resolve the candidal stomatitis. After one month of isotretinoin treatment, five of the six patients were negative for Candida, whereas in untreated control patients the situation was unchanged. Only one patient with suspected sicca syndrome was found to have oral Candida 15 days after the last administration of isotretinoin. None of the patients had any complaints about the medication. These findings suggest that 0.18% isotretinoin applied twice a day for one month is able to suppress nystatin-resistant candidiasis. PMID- 19776508 TI - A stereomicroscopy study of root apices of human maxillary central incisors and mandibular second premolars in an Iranian population. AB - Mandibular second premolars and maxillary central incisors usually have one root, one canal, and one apical foramen. However, some studies have revealed anatomic variations in these teeth. The aim of the present study was to investigate such variations in canal configuration, foramina, lateral and accessory canals and apical deltas in the root apex of human maxillary central incisors and mandibular second premolars, using a clearing technique and stereomicroscopy. One hundred maxillary central incisors and 137 mandibular second premolars were collected, and India ink was injected into their canals. The teeth were then demineralized with 0.5 N nitric acid, cleared with methyl salicylate, and studied at x 5 and x 16 magnification. The incidence of one canal and one apical foramen was 100% for maxillary central incisors and 94.16% for mandibular second premolars. The main apical foramen was located in the center of the root apex in 21.89% and 17% of mandibular second premolars and maxillary central incisors, respectively. Lateral and accessory canals were found in 84.50% and 77.15% of maxillary central incisors and mandibular second premolars, respectively. Several foramina were found in 11% of maxillary central incisors and 24.08% of mandibular second premolars. Apical deltas were seen in 4.38% and 2% of mandibular second premolars and maxillary central incisors, respectively. The rate of anatomic variations in the apical part of the tooth, especially in posterior teeth, is thus considered to be high. PMID- 19776509 TI - Involvement of protein kinase C in IL-1beta-induced expression of cyclooxygenase 2 in human gingival fibroblasts. AB - Interleukin-1beta (IL-1beta) stimulates expression of the highly inducible enzyme cyclooxygenase-2 (COX-2) via activation of nuclear factor kappaB (NFkappaB), and consequently provokes prostaglandin E(2) (PGE(2)) synthesis, which induces inflammatory responses. In this study, the contribution of protein kinase C (PKC) to IL-1beta-induced PGE(2) synthesis in human gingival fibroblasts was investigated. The PKC activator phorbol 12-myristate 13-acetate (PMA) stimulated PGE(2) release and COX-2 mRNA expression, as shown in human gingival fibroblasts stimulated by IL-1beta. However, PMA showed only a weak effect on the formation of COX-2-NFkappaB DNA-protein complex, whereas IL-1beta had a clearly stimulatory effect. In cells in which PMA-dependent PKC was down-regulated, PMA failed to induce the formation of NFkappaB DNA-protein complex and reduced the release of PMA-induced PGE(2), whereas IL-1beta stimulated the formation of COX-2-NFkappaB DNA-protein complex and PGE(2) release. The atypical PKC (aPKC) inhibitor Go6983 clearly suppressed the formation of COX-2-NFkappaB DNA-protein complex and PGE(2) release stimulated by IL-1beta but not the inhibitor of conventional PKC (cPKC) and the novel PKC (nPKC) inhibitor Go6976. These observations suggest that aPKC is involved in IL-1beta-induced PGE(2) synthesis, which is controlled by transcription of the COX-2 gene via the NFkappaB-dependent pathway in human gingival fibroblasts. PMID- 19776510 TI - Comparison between the external gonial angle in panoramic radiographs and lateral cephalograms of adult patients with Class I malocclusion. AB - The external gonial angle is an important angle of the craniofacial complex. It is significant for the diagnosis of craniofacial disorders. Lateral cephalogram and orthopantomograms can be used to determine this angle. In this study, we compared the external gonial angle determined from the two mentioned radiographs in Class I patients. We collected the radiographs of 70 patients with Angle's Class I (22 men and 48 women). The patients' age ranged from 15-30 years with a mean age of 18.24 years. The data gained were statistically evaluated by t-test. The following results were obtained. The mean value of the gonial angle in the lateral cephalogram was 125.00 degrees (men, 124.9 degrees and women, 125.04 degrees ) and in the orthopantomogram was 124.17 degrees (men 123.68 degrees , women 124.39 degrees ). The difference between these rates was 0.83 degrees (men 1.22 degrees , women 0.64 degrees ) and not significant (P = 0.406). Based on the obtained results, we can conclude that panoramic radiography can be used to determine the gonial angle as accurately as a lateral cephalogram. In addition, we can determine the right and left gonial angles of a patient in the orthopantomogram without interferences due to superimposed images of anatomical structures in a lateral cephalogram. For determination of the gonial angle, an orthopantomogram may be a better choice than a lateral cephalogram. PMID- 19776511 TI - Self-etching primer systems: changes in dentin bond strength with time. AB - The purpose of this study was to investigate the development of shear bond strength of resin composites using self-etching primer systems. Four different types of self-etching primer systems with different combinations of their recommended resin composites were used. Bovine incisors were mounted in self curing resin and the facial surfaces were wet ground on #600-SiC paper to expose the dentin. The shear bond strengths of ten samples per test group were measured at a crosshead speed of 1.0 mm/min after storage for 5, 10, and 60 min, and 24 h in distilled water at 37 degrees C. One-way ANOVA followed by Dunnett's test (alpha = 0.05) was used to examine the significance of differences between the mean bond strength at 24 h and each of the other storage periods. The dentin bond strengths of all the materials tested increased with prolonged storage time. Such differences in the changes in bond strength might have clinical implications if a restoration is subjected to high stress immediately after it has been placed. It is important to consider the development of dentin bond strength to allow the materials sufficient maturation time prior to functional loading or application of other forms of external stress. PMID- 19776513 TI - Vicker's microhardness and energy dispersive x-ray analysis of fluorapatite leucite and fluorapatite ceramics cyclically immersed in acidic agents. AB - This study evaluated the microhardness and elemental composition of various ceramics immersed in acidic agents. One hundred and five discs of fluorapatite leucite (IPS d.SIGN) and fluorapatite ceramics (IPS e.max Ceram) were randomly divided into 7 groups of 15 each. Five groups were alternately immersed in acidic agents (citrate buffer solution, pineapple juice, green mango juice, cola soft drink and 4% acetic acid) for 30 min and deionized water for 5 min in 7 cycles at 37 degrees C. Two groups were continuously immersed in 4% acetic acid at 80 degrees C for 16 h and deionized water at 37 degrees C for 245 min. Vicker's microhardness and elemental composition were recorded before and after immersion. Data were analyzed using two-way repeated ANOVA and t-test at a significance level 0.05. For IPS d.SIGN, there was statistically significant difference in microhardness values between before and after immersion in the green mango, cola soft drink and 4% acetic acid for 16 h (P < 0.05). However, for IPS e.max Ceram, there was no significant difference between before and after immersion in any of the groups (P > 0.05). EDX results of both ceramics found that the elemental percentage of Na, K, Zr, Al and Si decreased after being immersed in acidic agents. PMID- 19776512 TI - Comparative evaluation of antimicrobial activity of three cements: new endodontic cement (NEC), mineral trioxide aggregate (MTA) and Portland. AB - Using the agar diffusion method, we conducted an in vitro study to evaluate the antimicrobial activity of mineral trioxide aggregate (MTA), new endodontic cement (NEC) and Portland cement at different concentrations against five different microorganisms. A base layer was made using Muller-Hinton agar for Escherichia coli (ATCC 10538) and Candida (ATCC 10231). For Actinomyces viscosus (ATCC 15987), Enterococcus faecalis (ATCC 10541) and Streptococcus mutans (ATCC 25175) blood agar medium was used. Wells were formed by removing the agar, and the materials were placed in the well immediately after manipulation. The plates were kept at room temperature for 2 h for prediffusion, and then incubated at 37 degrees C for 72 h. The inhibition zones were then measured. The data were analyzed using ANOVA and the Tukey test to compare the differences among the three cements at different concentrations. The positive controls showed bacterial growth, while the negative controls showed no bacterial growth. All materials showed antimicrobial activity against the tested strains except for Enterococcus faecalis. NEC created larger inhibition zones than MTA and Portland cement. This difference was significant for Portland cement (P < 0.05), but not for MTA (P > 0.05). Among the examined microorganisms, the largest inhibition zone was observed for Actinomyces group (P < 0.05). The antimicrobial activity of the materials increased with time and concentration (P < 0.05). It was concluded that NEC is a potent inhibitor of microorganism growth. PMID- 19776514 TI - Effects of demineralized bone matrix and a 'Ricinus communis' polymer on bone regeneration: a histological study in rabbit calvaria. AB - The aim of the present study was to histologically analyze the effects of bovine and human demineralized bone matrix and a Ricinus communis polymer on the bone regeneration process. Two surgical bone defects were created in rabbit calvaria, one on the right and the other on the left side of the parietal suture. Eighteen rabbits were divided into three groups. In Group I, the experimental defect was treated with bovine demineralized bone matrix, Group II with human demineralized bone matrix, and in Group III, the experimental cavity was treated with polyurethane resin derived from Ricinus communis oil. The control defects were filled with the animals' own blood. The animals were sacrificed after 7 and 15 weeks. Histological analysis revealed that in all groups (control and experimental), bone regeneration increased with time. The least time required for bone regeneration was noted in the control group, with a substantial decrease in the thickness of the defect. All materials proved to be biologically compatible, but polyurethane resorbed more slowly and demonstrated considerably better results than the demineralized bone matrices. PMID- 19776515 TI - Central odontogenic fibroma of the mandible: a case report. AB - Central odontogenic fibroma (COF) is a rare tumor that accounts for 0.1% of all odontogenic tumors. It has been defined as a benign neoplasm, which appears in the jaw. Clinically, the lesion grows slowly and leads to cortical expansion. Radiologically, the most common finding is multilocular radiolucency. In some cases, it may be associated with root resorption or displacement. Histologically, the lesion is characterized by mature collagen fibers and numerous fibroblasts. COF responds well to surgical enucleation with no tendency for malignancy or recurrence. Here, a case of central odontogenic fibroma of the mandible in a 71 year-old man is described. The lesion was an asymptomatic mass with well-defined borders covered by normal mucosa. The lesion presented as a multilocular radiolucency in relation to the root of the canine. The lesion was surgically removed and analyzed histopathologically. There were no postoperative complications. PMID- 19776516 TI - Multifocal diffuse oral melanoacanthoma: a case report. AB - Oral melanoacanthoma (OMA) is a rare benign lesion characterized by colonization of acanthotic epithelium by dendritic melanocytes. Although its pathogenenesis remains uncertain, its clinical behavior and spontaneous remission suggest a non neoplastic nature. Clinically, it may present as a solitary or multifocal lesion; however these two variants exhibit different features. The clinical appearance of OMA is not pathognomonic and biopsy is mandatory. OMA requires no treatment or periodic observation. Here, we report a case of OMA with diffuse lesions also affecting the tongue in a 74-year-old black woman, whose diagnosis was based essentially on clinical and histological features. The immunohistochemical profile is also presented. PMID- 19776517 TI - Odontogenic glandular cyst: a case report. AB - Glandular Odontogenic Cyst (GOC) is a rare developmental cyst of the jaws. The histological features of GOC strongly suggest an origin from the remains of dental lamina. Radiographically, GOC presents as well-defined radiolucencies with uni- or multilocular appearance. A case of GOC in a 54-year-old black female is presented here. Clinical, histological and imaging features were evaluated. Due to the high tendency of recurrence and the aggressive potential of GOC, careful clinical and radiological evaluation must be carried out. CT scans are recommended because they provide accurate information about locularity of the lesion, cortical integrity, expansion of the lesion and involvement of the contiguous soft tissue. PMID- 19776518 TI - "Taurodontism" an endodontic challenge: a case report. AB - Taurodontism can be defined as a change in tooth shape caused by the failure of the Hertwig's epithelial sheath diaphragm to invaginate at the proper horizontal level. An enlarged pulp chamber, apical displacement of the pulpal floor, and no constriction at the level of the cementoenamel junction are the characteristic features. Permanent molars are most commonly affected. Endodontic treatment of a taurodont tooth is challenging and requires special handling because of the proximity and apical displacement of the roots. Here, we report a case in which endodontic treatment of the maxillary right first molar with taurodontism was performed. In this case, the maxillary right second molar and maxillary left first and second molars were also taurodont teeth. PMID- 19776519 TI - Endodontic treatment of bilateral dens evaginatus premolars with large periapical lesions. AB - Dens evaginatus is a developmental anomaly characterized by the presence of an accessory cusp composed of enamel and dentine, usually containing pulp tissue. This condition is clinically important because of fracture or wear of the tubercle, which can frequently lead to the major complication of pulp necrosis and periapical infection. Treatment varies according to pulp condition, tubercle integrity, and stage of root development. Here we report a case of bilateral dens evaginatus with large periapical lesions. Non-surgical root canal treatment using calcium hydroxide medication was performed for both mandibular second premolars. At the 3-year postoperative recall examination, the teeth were asymptomatic and radiographically showed healing of the periapical lesions. PMID- 19776520 TI - Naso-oral fistula due to rhinolithiasis: a rare presentation. AB - Naso-oral fistula, as the name suggests, is an abnormal communication between the nasal and oral cavities. It is an extremely rare clinical entity encountered in routine rhinology clinics across the world. The occurrence of this fistula due to rhinolithiasis is much rarer. We present one such case in a 40-year-old man, who came to us for assessment of a "hole" in his palate. The cause of this naso-oral fistula was found to be a rhinolith in the right nasal cavity. This report emphasizes that trainee rhinologists should be vigilant about this little recognized and rare condition. PMID- 19776521 TI - Clear cell variant of extraosseous calcifying epithelial odontogenic tumor: a case report. AB - Calcifying epithelial odontogenic tumor (CEOT) is a benign epithelial odontogenic tumor occurring most frequently in the posterior part of the lower jaw. Extraosseous CEOT is one of the rarest forms of this tumor, and few such cases involving the maxillary gingiva have been reported in the literature. Here we present a case that showed progressive enlargement in the left maxillary gingival area over a period of 11 years. Clinical examination showed an ulcerated mass measuring 52 x 38 mm located adjacent to the lateral incisor and canine. Histologically, the tumor showed proliferation of sheets and cords of epithelial cells with granular, eosinophilic cytoplasm and round to oval nuclei. In other areas, the epithelial cells exhibited a clear, vacuolated cytoplasm and foci of eosinophilic, homogeneous material representing amyloid deposition. The present case of extraosseous CEOT with clear cells was considered to be a very rare form of this tumor. PMID- 19776522 TI - Congenital lipoma of the lip: a case report. AB - We describe a rare case of large congenital lipoma in the upper lip of a six month-old infant. Surgical excision of the tumor was successful, with satisfactory esthetic and functional results. PMID- 19776523 TI - Bactericidal activity in filtrated supernatant of Streptococcus sanguinis against multidrug-resistant Pseudomonas aeruginosa. AB - In the past decade, multidrug-resistant Pseudomonas aeruginosa (MDRP) infection has become a serious clinical problem, due to the limitation of drug choices to fight against the bacteria. Here we explored the bactericidal activity in the filtrated supernatant of Streptococcus (S.) sanguinis against Pseudomonas (P.) aeruginosa. S. sanguinis is one of the alpha-hemolytic streptococci that commonly reside in the human oral cavity. A strain of S. sanguinis, isolated from the sputum of a pulmonary-disease patient, was cultured for overnight. The filtered supernatant was tested for bactericidal effect using the minimum bactericidal concentration method on 20 strains of P. aeruginosa, including two MDRP and five mucoid-type strains. The viable number of P. aeruginosa was decreased with time after exposing to the filtrated supernatant of S. sanguinis, and collapsed bacteria were detected with electron microscopy. Of the 20 strains, 19 (95%) strains of P. aeruginosa were affected by bactericidal effect. Among other species of bacteria examined, the filtrated supernatant of S. sanguinis showed remarkable bactericidal effect on 49% of indole-positive Proteus species (4/9 strains) and 60% of Acinetobacter (A.) baumannii (6/10 strains). We next investigated the property of bactericidal activity in filtrated supernatant by treating with proteinase K or autoclave. There was no change in the bactericidal activity of the filtrated supernatant after each treatment, excluding the involvement of protein and plasmid. Here, we identify the bactericidal activity in the filtrated supernatant of S. sanguinis against MDRP. This unexpected observation may contribute to the development of a novel therapeutic drug against P. aeruginosa. PMID- 19776524 TI - Irregular sleep habits of parents are associated with increased sleep problems and daytime sleepiness of children. AB - Longitudinal studies in Japan indicate that nocturnal sleep onset has become later and sleep duration has been progressively shortened. This study aimed to investigate the relationship between sleep patterns and sleep problems among children, and to determine the association between parents and their children's sleep habits. Questionnaires about sleep problems and life habits were administered to families living in Tokyo metropolitan areas of Japan. We analyzed the data of pre-school-age (1-5 years old; n = 319, including 175 girls) and elementary school-age children (6-11 years; n = 217, including 116 girls) as well as their parents (402 mothers: 37.0 +/- 4.9 years, 402 fathers: 39.0 +/- 5.9 years). Subjects were categorized as morning (evening) type when they answered their lifestyle habit as "definitely or moderately morning (evening) type". Sleep was categorized into regular, irregular, and intermediate from the sleeping waking regularity scores. The frequency of daytime dozing is significantly high in children with evening-irregular sleep. Moreover, mothers of children (aged 1-5 and 6-11 years) with evening-irregular sleep have significantly more irregular sleep habits than those of children with morning-regular sleep. Likewise, fathers of children (aged 1-5 years) with evening-irregular sleep have significantly more irregular sleep habits. Thus, irregular late bedtime of parents is associated with sleep problems, daytime sleepiness, and irregular dietary habits of children. Mothers' sleep habits have a stronger influence on their children's sleep than fathers'. Our study indicates the importance of promoting sleep hygiene that encourages healthy sleep for all family members. PMID- 19776525 TI - Physiotherapy program through home visits for community-dwelling elderly Japanese women with mild knee pain. AB - Knee pain is extremely common among the elderly, particularly women. Hence, there is an urgent need for applicable community-based intervention models for halting the progression of knee pain and related disabilities in elderly women. We aimed to assess the efficacy of home-visit physiotherapy as a new intervention model. This non-randomized 5-month-long controlled trial enrolled elderly community dwelling women (aged 60-83 years) with mild knee pain. The intervention consisted of two home visits by a physiotherapist, with instructions on routinely performing muscle-strengthening exercises at home and implementing simple environmental modifications when necessary. Outcome measures were assessed at baseline and 5 months later. The primary outcomes were measured as the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and a newly devised seiza-style sitting score. People in Japan, especially elderly women, are accustomed to seiza-style sitting that involves kneeling on one's lower legs while resting the buttocks on the heels. The secondary outcomes included quadriceps isometric strength, knee alignment in the frontal and sagittal planes, and passive knee extension range. Forty-two subjects (20 in the intervention group and 22 in the control group) completed the study. At baseline, characteristics and the primary outcomes did not significantly differ between the 2 groups. At 5 months, the primary outcomes improved significantly in the intervention group. Estimated differences in the change from baseline for each outcome between the 2 groups were computed, adjusting for outcome variables imbalanced at baseline. Even after the adjustment, the home-visit physiotherapy regimen provides favorable improvement in the seiza-style sitting score. PMID- 19776526 TI - Detection of increased arterial stiffness in a patient with early stage of large vessel vasculitis by measuring cardio-ankle vascular index. AB - Large vessel vasculitis leads to arterial wall thickening and stiffening because of chronic inflammatory changes. The cardio-ankle vascular index (CAVI) is recently utilized for assessing arterial stiffening caused by atherosclerosis related diseases, including hypertension and diabetes, as well as aging. CAVI is mathematically calculated from stiffness index beta, which is established as a parameter of arterial stiffness independent of blood pressure. However, there are no data regarding arterial stiffness assessed by CAVI for large vessel vasculitis. We describe a patient with large vessel vasculitis who showed aortic wall thickening and increased CAVI without hypertension. A 68-year-old woman presented at our hospital with recurrent fever of 2-month duration, fatigue, neck pain, and weight loss. The images of 18F-fluorodeoxyglucose-positron emission tomography (18F-FDG-PET) demonstrated significant 18FDG uptake (indicating increased metabolic activity and presence of inflammation) in the aorta and its major branches, including the carotid and subclavian arteries. Contrast-enhanced magnetic resonance imaging demonstrated wall thickening of the thoracic aorta. These imaging findings resulted in the diagnosis of large vessel vasculitis. The patient showed normal brachial blood pressure (right, 122/72 and left, 121/66 mmHg). However, CAVIs on both sides (right, 10.3 and left, 10.4) were elevated (normal value for her age, 9.1 +/- 0.8). In conclusion, arterial stiffness in patients with large vessel vasculitis may be increased because of the arterial wall thickening and inflammatory changes. Thus, CAVI may be promising for detection of increased arterial stiffness in patients with large vessel vasculitis in the early stage, in which blood pressure is normal. PMID- 19776527 TI - Pretreatment with B-type natriuretic peptide protects the heart from ischemia reperfusion injury by inhibiting myocardial apoptosis. AB - The therapy for acute myocardial infarction (AMI) has been improved; yet, AMI remains a major cause of death and heart failure in industrialized countries. B type natriuretic peptide (BNP), a hormone secreted from the heart, has been shown cardioprotective effects during myocardial ischemia/reperfusion. In the present study, we aimed to examine whether BNP could inhibit myocardial apoptosis during ischemia/reperfusion. Rabbits were randomly divided into three groups (12 animals for each group): sham-operated control and ischemia-reperfusion animals with or without BNP treatment. Occlusion of the left circumflex coronary for 45 min was followed by 3-h reperfusion with infusion of physiological saline (untreated group) or BNP (treated group) starting 5 min before reperfusion and throughout the whole reperfusion. The infarct size, measured by triphenyltetrazolium chloride staining, was reduced by 44% with BNP treatment (P < 0.01). Accordingly, serum levels of creatine kinase and lactate dehydrogenase were markedly reduced in BNP-treated group (P < 0.05) compared with the untreated group. BNP significantly attenuated apoptotic cells (TUNEL-positive cardiomyocyte nuclei) in the myocardium (P < 0.01). The BNP-mediated attenuation of apoptosis was associated with the increased expression of an anti-apoptotic protein Bcl-2 and the reduced expression of a pro-apoptotic protein Bax. Moreover, BNP treatment significantly decreased the magnitude of caspase-3 activation caused by myocardial ischemia-reperfusion. In conclusion, pretreatment with BNP shortly before the onset of reperfusion not only reduces necrosis, but also attenuates myocardial apoptosis. BNP appears to be an ideal pharmacological agent applied as an adjuvant therapy to current myocardial reperfusion strategies. PMID- 19776528 TI - Successful repair of a critical-sized bone defect in the rat femur with a newly developed external fixator. AB - Regeneration of segmental bone defects has been a clinical challenge. Recent advances in the field of tissue engineering have developed new procedures enabling bone regeneration. Small animal models capable of supporting weight bearing femoral defects are integral parts of orthopedic biomedical research. However, a drawback of bone healing research is the lack of stable and adaptable fixation devices for small animals. Therefore, we developed and evaluated an adjustable external fixation device in the maintenance of non-healable (ie critical-sized) segmental defects, and in the fixation of tissue-engineered bone grafts in a rat model. Male Sprague-Dawley rats (n = 24) underwent a femoral osteotomy to create a non-healing segmental defect (6 mm size), which was stabilized with the fixator. A treatment group (12 rats) received tissue engineered bone graft implants consisting of biphasic calcium phosphate blocks seeded with bone mesenchymal stem cells, while other 12 animals received no bone graft (non-treatment group). The osteotomy gap remained unchanged in the non treatment group over the 12-week period, indicating that the 6-mm bone defect is really non-healable in the rat femur and that the device has sufficient stability for the management of critical-sized femoral defects. At 12 weeks, the treatment group maintained the bone length throughout the study period and showed bridging of the defect, with remarkable new bone formation. In contrast, the non-treatment group showed marginal new bone formation, but no apparent healing. In conclusion, the novel device provides substantial benefits in the maintenance of critical sized femoral defects and tissue-engineered bone grafts in a rat model. PMID- 19776529 TI - Serum amyloid-A rather than C-reactive protein is a better predictor of mortality in hemodialysis patients. AB - The most frequent cause of death in hemodialysis patients is cardiovascular disease with chronic inflammation being an epidemiologically proved risk factor. Many studies have shown C-reactive protein (CRP) as the strongest predictor of long-term mortality of hemodialysis patients, while other reports have indicated acute phase proteins as potential predictors of the mortality. The present study therefore aimed to evaluate the prevalence of chronic inflammation in hemodialysis patients and the role of acute phase proteins together with lipids and divalent ions for predicting mortality in hemodialysis patients. Chronic inflammation was defined, based on the serum level of high sensitive CRP > 8.4 mg/L and/or serum amyloid-A (SAA) > 8.9 mg/L. Acute phase proteins are defined as one whose plasma concentration increase (positive) or decreases (negative) by at least 25% during inflammation. High sensitive CRP and SAA were positive acute phase proteins measured, while albumin and fetuin-A, a calcification inhibitor, were selected as negative acute phase proteins. This prospective 36-month follow up study included 130 patients (60 males and 70 females, aged 55.1 +/- 12.9 years) maintained by hemodialysis for 107.2 +/- 54.72 months at a Nephrology Clinic in Belgrade. The prevalence of chronic inflammation was 35.4% (46 patients). During the follow-up period, 24 patients (18.5%) died and 2 patients received transplants. In multivariate analysis, potential independent predictors of mortality in hemodialysis patients are hyperphosphatemia, hypoalbuminemia, and high SAA. Considering that assays for SAA are widely used, we propose that SAA is the best predictor for outcomes of end-stage renal disease. PMID- 19776530 TI - Increase of muscle activities in hemiplegic lower extremity during driving a cycling wheelchair. AB - For the patients with severe hemiplegia, long-time wheelchair sitting is unavoidable, which however increases a risk of secondary impairments due to non use of the affected leg. A cycling wheelchair (C-W/C) has a possibility to activate paretic muscle through self-locomotion with bilateral pedaling. We therefore measured driving speed of C-W/C and electromyogram (EMG) in both legs during driving in the healthy adults and severe hemiplegic patients. Ten healthy volunteers (mean age 32.8, 26-45 years) and ten non-ambulatory post-stroke patients (mean age 69.0, 55-81 years) with complete or semi-complete hemiplegia participated in this study. EMG was recorded from the key muscles for cycling during isometric movement as baseline and during driving a C-W/C straightforward. All of the patients could drive a C-W/C with mean maximum driving speed of 46.6 (31.7-61.7) m/min, which was about half of that in the healthy subjects and within practical level. Root mean square of EMG (R-EMG) as a parameter reflecting muscle activity was compared between baseline and C-W/C driving. There was no increase in most of the values of R-EMG during driving in the healthy subjects and in the intact side of the hemiplegic patients. In contrast, significant increase was found during driving in several paretic muscles, despite that EMG of the paretic leg showed almost silent at baseline. These results suggest C-W/C can induce muscle activities of the paretic leg and provide a chance of practical locomotion even for the severe hemiplegics. Daily use of a C-W/C may contribute to restore paretic leg function. PMID- 19776531 TI - Running exercise for short duration increases bone mineral density of loaded long bones in young growing rats. AB - Running exercise is an effective therapy for the prevention of osteoporosis; however, appropriate duration of exercise has not been determined. We therefore investigated the effect of exercise duration on bone mineral density (BMD) and systemic bone metabolism using young growing rats. Fifteen 8-week-old female Wistar rats were divided into three groups according to running load: control group (no running), short duration (30 min/day) and long duration (180 min/day), and animals ran on a treadmill 5 days per week over an 8-week period. BMD of the tibia was measured using peripheral quantitative computed tomography, and serum levels of tartarate-resistant acid phosphatase (TRAP), a bone resorption marker and alkaline phosphatase (ALP), a bone formation marker were measured to know whether the treadmill exercise would affect systemic bone metabolism. Short duration running exercise (30 min/day) caused a significant increase in BMD of the metaphyseal trabecula (p < 0.05) with a reduction of serum TRAP levels (p < 0.01) and an increase in serum levels of calcium (p < 0.05) and phosphorus (p < 0.01). Conversely, long-duration exercise (180 min/day) significantly reduced BMD of the diaphyseal and metaphyseal cortex and that of the diaphyseal trabecula with a significant reduction of serum ALP levels and a significant increase in serum phosphorus. These findings suggest that short-duration exercise may increase BMD through suppression of bone resorption, whereas long-duration exercise may reduce BMD through suppression of bone formation. Exercising for short duration but not prolonged exercise is recommended to increase BMD of loaded long bones. PMID- 19776532 TI - Prevalence of and clinical factors associated with lipoatrophy in HIV-infected Koreans receiving highly active antiretroviral therapy. AB - Lipoatrophy is the long-term adverse effects developed in human immunodeficiency virus (HIV)-1-infected subjects receiving highly active antiretroviral therapy (HAART). This cross-sectional study aimed to evaluate the prevalence of and clinical factors associated with lipoatrophy in HIV-infected Koreans receiving HAART for more than 6 months. Lipoatrophy was diagnosed by concordance between physical examination and history taking performed by a single physician. Various covariates were examined, including diabetes mellitus (DM), lipid profiles after HAART, and HAART regimen and duration. Among total 144 patients (6 females and 138 males), 35 patients (24.3%) were diagnosed with lipoatrophy. The prevalence of lipoatrophy was significantly higher in females than that in males [83.3% (5/6) vs. 21.7% (30/138), p = 0.010] and higher in patients with DM than patients without DM [66.7% (4/6 DM) vs. 22.5% (31/138 non-DM), p = 0.030], or in patients with high total cholesterol levels than patients with low total cholesterol levels [31.9% (23/72 patients with high cholesterol) vs. 16.7% (12/72 patients with low cholesterol), p = 0.035]. Moreover, patients with stavudine treatment history (> 12 months) had a higher prevalence of lipoatrophy than patients who never received stavudine [50.0% (15/30) vs. 16.5% (17/103), p < 0.001]. In the multivariate logistic analysis, stavudine treatment for > 12 months (OR, 3.67; p = 0.011) and being female (OR, 24.93; p = 0.009) are independently associated with lipoatrophy. In conclusion, the prevalence of lipoatrophy in HIV-infected Koreans receiving HAART is not uncommon. Limited use of stavudine and regular monitoring are warranted to reduce lipoatrophy. PMID- 19776533 TI - High attendance at a lifestyle intervention program is important to reduce risks related to metabolic syndrome in middle-aged Japanese. AB - Evaluating attendance at health education programs is important to obtain a more comprehensive evaluation of the program impact. This study investigated whether attendance at a lifestyle intervention program in a community setting would reduce risks related to metabolic syndrome. Of 545 subjects with risks related to metabolic syndrome, i.e. overweight, hypertension, dyslipidemia or diabetes, participated in this non-randomized control study, 389 subjects aged 40-71 years completed the surveys at baseline and 27 months. Intervention group (39 males and 168 females) was provided 3 individual counseling plus 28 group sessions conducted monthly on average, whereas control group (64 males and 118 females) received only 7 health information newsletters by mail. Intervention group was subcategorized into two groups according to the median attendance (87.1%): 106 subjects with high attendance (93.8 +/- 4.7%) and 101 subjects with low attendance (68.6 +/- 16.0%). Logistic regression analyses adjusted for age and baseline value showed that among males, the proportion with dyslipidemia risk was lower only in high attendance group compared with that in control group at 27 months [Odds ratio (OR): 0.11 (95%CI 0.02 - 0.51)] and among females, the proportion of overweight was lower only in high attendance group [OR: 0.24 (95%CI 0.07 - 0.81)]. In females, the mean total risk score calculated by adding the number of the 4 risks present decreased only in high attendance group (p < 0.001). In conclusion, high attendance at a lifestyle intervention program impacts the reduction of risks related to metabolic syndrome in a Japanese community setting. PMID- 19776534 TI - Compensatory changes in the function of the remaining kidney immediately after unilateral nephrectomy in sheep. AB - Live kidney donation is an established form of organ donation but carries the risk of an unnecessary surgery in a normal individual for the benefit of the recipient. Despite a number of recent studies on the renal function of long-term kidney donors, little attention has been paid to the damaging effects of compensatory hyper-filtration on renal tubular cells immediately after donor nephrectomy. The present study therefore aimed to examine the immediate changes in renal function of the remaining kidney using a sheep model of unilateral nephrectomy. We used the gamma camera-based method to measure the glomerular filtration rate and the tubular excretion values after simultaneous injection of (99m)Tc-diethylene triamine pentaacetic acid and (131)I-ortho-iodohippurate tracers. Compared were the differences in the functions between the remaining left kidney immediately after clamping the right renal pedicle and the baseline values that were measured one week before unilateral nephrectomy. After radionuclide data acquisition was completed, the right kidney was removed. The mean glomerular filtration rate (GFR) increased by 52.3% from the baseline values (29.5 +/- 2.7 to 45.0 +/- 6.7 ml/min; n = 40, p < 0.001), while the mean effective renal plasma flow (ERPF) increased by 40% (225.5 +/- 27.8 to 357.8 +/- 38.94 ml/min; p < 0.001), respectively. Mean filtration fraction was increased from 0.117 to 0.127 immediately after nephrectomy (p < 0.001). We conclude that after unilateral nephrectomy the remaining kidney immediately compensates for the loss of a donated kidney by increasing glomerular filtration rate and effective renal plasma flow. PMID- 19776535 TI - WT1 mRNA level in peripheral blood is a sensitive biomarker for monitoring minimal residual disease in acute myeloid leukemia. AB - The Wilms' tumor gene 1 (WT1) encodes a transcription factor that is involved in normal cellular development and cell survival. WT1 mRNA is overexpressed in the minimal residual disease (MRD) of patients with hematopoietic malignancy patients, particularly acute myeloid leukemia (AML). MRD represents the condition with the low levels of leukemia cells in the bone marrow and is known as a sign of recurrence. In hematopoietic malignancies, definition of remission is based on the lack of MRD at submicroscopic level. Between December 2005 and June 2008, we started to measure WT1 mRNA levels in the peripheral blood (PB) from patients by quantitative real-time PCR in Aomori Prefectural Central Hospital. Three hundreds and eight samples from 95 patients were evaluated. The patients included AML (55 patients), acute lymphoblastic leukemia (11), myelodysplastic syndrome (20), malignant lymphoma (5), chronic myeloid leukemia (1), prostatic carcinoma (1), and leukopenia (2). Among the 55 AML patients, 21 patients were pretreated with remission induction therapy. In the clinical course of 21 patients, timely therapeutic approaches could be started for relapse by the early detection of WT1 mRNA overexpression before the morphological findings were apparent. Monitoring WT1 mRNA is helpful to identify patients at high-risk relapse. High overall survival rate (71.2%, 15/21, median: 24.6 months, range 1.1-35.6 months) was achieved in 3 years. The overall survival rate of 34 post-treatment patients was 61.7% (median: 23.5 months, range 0.13-126.5 months after treatment start). In conclusion, the WT1 mRNA level is a sensitive biomarker for monitoring MRD. PMID- 19776536 TI - Perivascular cuff and spread of Treponema pallidum. AB - BACKGROUND: The incidence of syphilis is on the rise in many cities worldwide. Both the clinical and histopathological changes do not always fulfil the typical diagnostic criteria. Immunohistochemistry is available to identify and localize Treponema pallidum. Two main patterns of T. pallidum distribution were described in the skin, namely heavy intraepidermal infiltration and scattered pattern inside the lichenoid cell infiltrate. OBJECTIVE: To search for a third pattern consistent with dissemination of the disease. METHODS: Immunohistochemistry using an antispirochete (T. pallidum and Borrelia) antibody was used in all cases of syphilis submitted to our laboratory. In addition, deposits of immunoglobulins and complement indicative of immune complexes were searched for. RESULTS: According to the cases, T. pallidum was disclosed in a combination of three patterns. The previously described epidermal and lichenoid patterns were confirmed, and a third pattern predominating in a perivascular location throughout the dermis was clearly identified in primary syphilis. The microorganisms were abundant in extracellular and intracellular locations, particularly inside endothelial cells. No deposits of immunoglobulins and complement were disclosed. CONCLUSION: The perivascular cuff of T. pallidum throughout the dermis might be representative of the dissemination phase of T. pallidum. PMID- 19776537 TI - Role of musculoskeletal disorders as concurrent chronic conditions: are they underestimated in the discharge? AB - BACKGROUND: Differences in recording concurrent chronic conditions (CCs) could change the weight of the influence of the different CCs on health status. OBJECTIVES: To determine the role of musculoskeletal disorders as concurrent CCs. METHODS: Cross-sectional study. Discharged patients with CCs were selected by random stratification. Sociodemographic and clinical variables, health status (SF 36), type and number of self-reported and hospital discharge summary CCs were recorded. Relationships were analyzed using linear regression models. RESULTS: In the 227 patients included, mean self-reported CCs were 6.22 (SD 3.37) and mean hospital discharge CCs were 3.1 (SD 1.95). The most-frequent self-reported CCs were hypertension 48.4%, back pain 40.4%, neck pain 39.6%, and musculoskeletal disorders 38.4%. The most frequent discharge CCs were arterial hypertensive disease 38.3%, all cancers 22.0%, ischemic heart diseases, and angina 15.9%. Musculoskeletal disorders had the greatest negative influence on SF-36 dimensions (p < 0.05). CONCLUSIONS: Musculoskeletal disorders were underestimated in the discharge summary in comparison with those reported by patients. PMID- 19776538 TI - Comparison of walking parameters and cardiorespiratory changes during the 6 minute walk test in healthy sexagenarians and septuagenarians. AB - BACKGROUND: The 6-minute walk test (6-MWT) is commonly used in research, with a focus on walking distance parameters rather than the physiological parameters. Even though it has been reported that the distance walked during the 6-MWT decreases with age, the adaptation of cardiorespiratory functions in healthy older adults remains to be studied. OBJECTIVES: The primary objective of this study was to compare the changes in walking distance and cardiorespiratory parameters during the 6-MWT in healthy sexagenarians and septuagenarians. A secondary objective was to determine the cardiorespiratory parameters and functional performance variables that best predict the distance covered during the 6-MWT. METHODS: Ten healthy sexagenarians (G60, mean age 63.6 +/- 3.3 years) and 10 septuagenarians (G70, mean age 76.0 +/- 3.3 years) performed the 6-MWT while the distance, heart rate and oxygen uptake (VO(2)) were recorded. The subjects also completed the Timed-Up-and-Go, the Berg Balance Scale and the Human Activity Profile to establish their functional level. RESULTS: Results showed that G60 reached significantly greater (p < 0.05) distance and VO(2) values during the 6-MWT than G70. In contrast, the energy cost of walking (O(2) cost) and heart rate did not differ between the 2 groups. Correlational analyses of the combined groups revealed that VO(2) was the variable that showed the strongest correlation with walking distance during the 6-MWT. CONCLUSION: Results revealed that, while G60 achieved a greater level of walking performance than G70, the 2 groups maintained the same level of walking efficiency (O(2) cost) during the walk. Both groups adjusted their walking speed to have an oxygen consumption rate at a level sufficient to meet the energy demands of the task and prevent early exhaustion. Therefore, the 6-MWT appears to be a simple tool that can be used to assess cardiorespiratory parameters in older adults and be sensitive enough to detect differences between sexagenarians and septuagenarians. PMID- 19776539 TI - Postural balance and self-reported balance confidence in older adults with a hip fracture history. AB - BACKGROUND: Balance dysfunction and loss of balance confidence have been associated with functional limitations and loss of independency in daily tasks. This study examined various aspects of postural balance and balance confidence between older adults with a hip fracture history and their non-fractured counterparts. A comprehensive assessment of balance capacity in older adults with a hip fracture history may help to identify aspects of postural balance that play an important role in the mobility recovery and the avoidance of further falls. METHODS: The present study comprised 79 community-dwelling older adults with a hip fracture history and 31 non-fractured subjects of the same age, who participated in balance tests including both force platform measures and functional balance testing (Berg Balance Scale, BBS). In addition, balance confidence was assessed with the Activities-Specific Balance Confidence (ABC) scale. RESULTS: Persons with a hip fracture history had a markedly poorer balance control and were significantly less confident maintaining their balance during daily activities compared to the controls. Sixty percent of the subjects in the hip fracture group versus 87% of the non-fracture group (chi(2) test, p = 0.003) were able to perform the semi-tandem standing with their eyes closed. Significantly lower scores in the BBS (hip fracture group 46.3 vs. non-fracture group 52.9) and ABC (hip fracture group 59.4 vs. non-fracture group 77.5%) tests were found among the hip fracture subjects compared to the controls. In addition, the performance time in the lateral weight-shifting task (hip fracture group 13.4 vs. non-fracture group 8.4 s) was significantly slower compared to the controls. CONCLUSIONS: Balance impairments along with the loss of balance confidence are persistent problems among community-dwelling older adults with a history of hip fracture and may contribute to mobility limitations and the risk of falling. These areas of function and behaviour in older adults with a hip fracture history should be taken into consideration when planning effective, well-targeted rehabilitation programs. PMID- 19776540 TI - Clinical and dermoscopic features of nevi in preschool children in Padua. PMID- 19776541 TI - Pityriasis rubra pilaris with preceding cytomegalovirus infection. AB - Pityriasis rubra pilaris (PRP) is a papulosquamous disorder comprising 6 clinical types. Some factors - including abnormal vitamin A metabolism, internal malignancies, autoimmune diseases, infection and trauma - are thought to be involved in the etiology. Recently, human immunodeficiency virus (HIV)-associated PRP has been reported to have distinct clinical features, such as nodulocystic acne and lichen spinulosus alongside PRP. We report here the case of a 38-year old female with onset of classical PRP after a high fever. Virological studies indicated that the patient had primary systemic cytomegalovirus (CMV) infection and not HIV infection. Our case suggested that primary CMV infection might have triggered typical PRP that was clinically different from HIV-associated PRP. PMID- 19776542 TI - Osteon classification in human fibular shaft by circularly polarized light. AB - Pattern of osteonal classification referred to collagen fiber orientation in a human fibula was studied. Along the length of the whole bone, serial 100-microm parallel cross sections were obtained and analyzed by circularly polarized light microscopy. The distribution of 3 different kinds of osteons (transversal, alternated and longitudinal-hooped) depending on their collagen fiber orientation were analyzed to determine the effect of length, anatomical quadrant and cortical thickness. Referring to length, the 3 types of osteons appeared with approximately the same relative frequency, but when the symmetry of the fibula was considered and the length was expressed as distance from the bone mid section, the alternated osteons are predominant in the mid-section. On the contrary, moving toward the epiphyses, the balance is inverted, and transversal together with longitudinal-hooped types become more frequent than the alternated type. Osteonal pattern distribution was not significantly affected by the anatomical quadrant of each section or by the thickness of the cortex. This observation seems to confirm that along the fibula shaft the orientation of collagen fibers within the osteons is consistent with the loading conditions which the bone undergoes. PMID- 19776543 TI - Public awareness and knowledge of herpes zoster: results of a global survey. AB - BACKGROUND: Herpes zoster (HZ), the reactivation of varicella zoster virus, occurs in 1 in 5 people worldwide and may result in a variety of complications, including postherpetic neuralgia (PHN). Treatment of patients with HZ represents a considerable challenge, especially among the elderly who are prone to get a more severe form of the disease and its complications. Since May 2006, a vaccine was approved for the prevention of HZ or PHN among individuals aged 50 or 60 years and older. OBJECTIVE: Since the success of any new vaccine initiative depends on public awareness of the disease, we conducted the HZ Global Awareness Survey to gauge existing levels of awareness and knowledge of HZ. METHODS: The survey was conducted by telephone or face-to-face among 8,688 adults >OR=50 years of age in 22 countries between December 2006 and January 2007 and addressed awareness, knowledge, symptoms, and treatment of HZ. RESULTS: Wide variation in HZ awareness was noted among countries. In some countries (New Zealand, Brazil, and Malaysia) nearly all individuals surveyed (97-100%) over the age of 50 years had heard of HZ. In contrast, less than 20% of individuals surveyed were aware of HZ in Turkey, India and Chile. The survey revealed almost universally poor knowledge of the causes and symptoms of HZ. Only 3% of respondents mentioned chicken pox as the cause of the disease. The majority of respondents were unaware of their risk of HZ, with 71% considering themselves unlikely or very unlikely to develop HZ. The survey also revealed that those respondents with prior HZ experience were much more likely to consider pain as the worst symptom of the disease than those without prior HZ experience. The misconception of HZ-related morbidity among individuals with no first-hand experience of the disease highlights the global educational need to raise awareness of the seriousness of HZ and its potential long-term complications. CONCLUSIONS: This survey suggests a population-wide effort to improve global awareness of HZ would be required for a successful vaccine initiative. Further studies would be required to understand regional differences in the understanding of HZ. PMID- 19776544 TI - A cross-sectional study of familial clustering in hyperhomocysteinemia. AB - BACKGROUND: Hyperhomocysteinemia is correlated with diseases and lifestyle habits. However, there is no epidemiological evidence concerning the distribution and prevalence of hyperhomocysteinemia in a local community. OBJECTIVE: The purpose of this study was to clarify the distribution and prevalence of hyperhomocysteinemia and the existence or nonexistence of familial clustering. METHODS: The subjects were participants in the Basic Health Check Service 1999. We administered a questionnaire and obtained blood samples from 865 subjects (306 men, 559 women) who agreed to participate in our study. RESULTS: Hyperhomocysteinemia was present in 52 men (17.0%) and 25 women (4.5%). Ten subjects who had hyperhomosysteinemia ha a family member who also had hyperhomocysteinemia. The odds ratio for hyperhomocysteinemia adjusted for age and sex was 4.77 (p < 0.01, 95% CI = 1.95-11.65). CONCLUSION: Hyperhomocysteinemia shows familial clustering. Men and elderly persons were more likely to have hyperhomocysteinemia. PMID- 19776545 TI - Memory complaints are frequent but qualitatively different in young and elderly healthy people. AB - BACKGROUND: Subjective memory complaints are frequently reported by the elderly. There is less information about the characterization of subjective memory complaints in young people. OBJECTIVE: To determine different memory complaints between young and elderly people with the use of the Subjective Memory Complaints (SMC) scale. METHODS: Participants were volunteers attending a health itinerant unit, a blood donor centre, a leisure centre for retired people, a senior citizens college or university. All participants were questioned about their own memory abilities using the SMC scale and assessed for the presence of depressive symptoms. RESULTS: Nine-hundred and forty-six subjects aged 18-92 years were included in the study. The mean total score on the SMC scale was 4.89 +/- 3.03, and 75.9% of the participants had at least minor complaints about their memory. Older people had more general memory complaints and reported they were more likely to become transiently confused, whereas younger people reported they were more frequently told by others that they were forgetful and would more often take notes. CONCLUSIONS: Memory complaints were frequent both in young and elderly subjects, but the detailed assessment revealed age-related differences in the type of complaints. PMID- 19776546 TI - Severe micrognathia: indications for EXIT-to-Airway. AB - The ex utero intrapartum treatment (EXIT) procedure has become an important management option in cases of fetal airway obstruction. Select cases of severe micrognathia may be candidates for EXIT-to-Airway due to high-risk of airway obstruction at birth. Here we present three successful EXIT-to-Airway procedures for the management of congenital micrognathia in its most severe manifestations. CASE 1: A 23-year-old G3P1011 with a pregnancy complicated by severe micorgnathia, jaw index <5th percentile, as well as polyhydramnios. At 36 weeks EXIT-to-Airway was performed utilizing a bronchoscopically positioned laryngeal mask airway (LMA) during 23 min of uteroplacental support followed by tracheostomy. CASE 2: A 26-year-old G4P0120 with a pregnancy complicated by severe micrognathia, jaw index <5th percentile, and an obstructed oropharynx associated with polyhydramnios. At 37 weeks EXIT-to-Airway was performed with placement of tracheostomy. CASE 3: A 36-year-old G6P3023 with fetal magnetic resonance imaging (MRI) revealing esophageal atresia, polyhydramnios, and severe micrognathia with a jaw index <5th percentile. At 35 weeks the patient underwent EXIT-to-Airway with formal tracheostomy during 35 min of uteroplacental bypass. In the most severe cases of fetal micrognathia, EXIT-to-Airway provides time to evaluate and secure the fetal airway prior to delivery. We propose indications for EXIT-to-Airway in micrognathia to include a jaw index <5%, with indirect evidence of aerodigestive tract obstruction such as polyhydramnios, glossoptosis or an absent stomach bubble. PMID- 19776547 TI - Prostate-regenerating capacity of cultured human adult prostate epithelial cells. AB - Experimentation with the progenitor/stem cells in adult prostate epithelium can be inconvenient due to a tight time line from tissue acquisition to cell isolation and to downstream experiments. To circumvent this inconvenience, we developed a simple technical procedure for culturing epithelial cells derived from human prostate tissue. In this study, benign prostate tissue was enzymatically digested and fractionated into epithelium and stroma, which were then cultured in the medium designed for prostate epithelial and stromal cells, respectively. The cultured cells were analyzed by immunocytochemical staining and flow cytometry. Prostate tissue-regenerating capacity of cultured cells in vitro was determined by co-culturing epithelial and stromal cells in dihydrotestosterone-containing RPMI. Cell lineages in formed acini-like structures were determined by immunohistochemistry. The culture of epithelial cells mainly consisted of basal cells. A minor population was negative for known lineage markers and positive for CD133. The culture also contained cells with high activity of aldehyde dehydrogenase. After co-culturing with stromal cells, the epithelial cells were able to form acini-like structures containing multiple cell lineages. Thus, the established culture of prostate epithelial cells provides an alternative source for studying progenitor/stem cells of prostate epithelium. PMID- 19776549 TI - Spontaneous differentiation of murine bone marrow-derived mesenchymal stem cells into adipocytes without malignant transformation after long-term culture. AB - Some observations have suggested that extensive culture of adult stem cells can lead to malignant transformation. Therefore, it has become commonplace to use stem cells undergoing little or no in vitro culture to circumvent this presumptive limitation. Recently, a detailed study documented that malignant transformation of adult neural stem cells can be avoided under suitable culture conditions. Here, we report the first demonstration that murine bone marrow derived mesenchymal stem cells (bMSCs) were propagated in vitro for up to 50 passages without any transformation sign under suitable conditions. However, it must be noted that although the long-term cultured bMSCs were comparable with short-term cultured bMSCs in proliferation, migration and invasion, they lost their pluripotent potential. The long-term cultured bMSCs could only differentiate into adipocytes but not into osteocytes or chondrocytes. In conclusion, murine bMSCs can be propagated in vitro for up to 50 passages with no malignant transformation sign under suitable conditions, but how to sustain their pluripotent potential requires further investigation. PMID- 19776548 TI - Myonucleus-related properties in soleus muscle fibers of mdx mice. AB - Distribution and total number of myonuclei in single soleus muscle fibers, sampled from tendon to tendon, were analyzed in mdx and wild-type (WT) mice. Apoptotic myonuclei and the microscopic structure around the myonuclei were also analyzed. Three types of muscle fibers of mdx mice with myonuclear distribution at either central, peripheral, or both central and peripheral regions were observed in the longitudinal analyses. All of the myonuclei were located at the peripheral region in WT mice. The total number of myonuclei counted in the whole length of fibers with peripheral myonuclei only was 17% less in mdx than in WT mice (p < 0.05). But the total myonuclear numbers in mdx mouse fibers with different distribution (peripheral vs. central) of myonuclei were identical, and the peripheral nucleus was noted where the central nucleus was missing. Myonuclei located between the center and peripheral regions were also seen in the cross sectional analyses of muscle fibers. The cross-sectional area and length of fibers, sarcomere number, myonuclear size, myosin heavy chain expression, satellite cell number and neuromuscular junction were identical between each type of fiber. Apoptosis was not detected in any myonuclei located either in central or peripheral regions of muscle fibers. Thus, it was suggested that apoptosis related loss of central myonuclei and regeneration-related new accretion at the peripheral region is not the cause of different distribution of myonuclei seen in muscle fibers in mdx mice. However, it was speculated that cross-sectional migration of myonuclei from central to peripheral regions may be induced in response to regeneration, because the total myonuclear numbers in fibers with different distribution of myonuclei were identical, and the peripheral nucleus was noted where the central nucleus was missing. Further, myonuclei located between the center and peripheral regions were also seen. However, the question remains as to how or why nuclei might migrate to the periphery in a regenerating muscle fiber, since there was no microscopic evidence of any structural changes around the myonuclei that may be responsible for the movement of the nucleus. PMID- 19776550 TI - Chromatin flow cytometry identifies changes in epigenetic cell states. AB - We report flow cytometric protocols that quantitatively display the levels of different histone modifications on the single cell level. This method allows the rapid and simultaneous analysis of the global levels of chromatin marks in combination with other flow cytometric features. We show that chromatin flow cytometry identifies changes in epigenetic marks, such as histone acetylation and methylation, in drug-treated and differentiated mouse embryonic stem cell populations. PMID- 19776551 TI - Consent for newborn screening: the attitudes of health care providers. AB - BACKGROUND: As newborn screening (NBS) expands to meet a broader definition of benefit, the scope of parental consent warrants reconsideration. METHODS: We conducted a mixed methods study of health care provider attitudes toward consent for NBS, including a survey (n = 1,615) and semi-structured interviews (n = 36). RESULTS: Consent practices and attitudes varied by provider but the majority supported mandatory screening (63.4%) and only 36.6% supported some form of parental discretion. Few health care providers (18.6%) supported seeking explicit consent for screening condition-by-condition, but a larger minority (39.6%) supported seeking consent for the disclosure of incidentally generated sickle cell carrier results. Qualitative findings illuminate these preferences: respondents who favored consent emphasized its ease while dissenters saw consent as highly complex. CONCLUSION: Few providers supported explicit consent for NBS. Further, those who supported consent viewed it as a simple process. Arguably, these attitudes reflect the public health emergency NBS once was, rather than the public health service it has become. The complexity of NBS panels may have to be aligned with providers' capacity to implement screening appropriately, or providers will need sufficient resources to engage in a more nuanced approach to consent for expanded NBS. PMID- 19776552 TI - China: public health genomics. AB - China is a multicultural country that has arisen from its 56 ethnicities, with a diverse population of over 1.3 billion people and an imbalanced economic development. The health care system in China is tending to be overall funded through urban and rural health insurance plans. Although China has invested in the basic research of genome science, public health genomics-related programs and services in China started late. Prenatal screening is offered as part of routine clinical prenatal services and is free of charge in some economically advanced cities. Newborn screening programs are mandated throughout the country but vary between provinces and territories in terms of organization and diseases screened for; most screening tests are paid by out-of-pocket expenses. Genetic tests are encouraged while there are only one accredited state laboratory and few territorial laboratories in China. Further national genomics policies are needed in China in a range of genetic issues and infrastructure of public health genomics. Careful measurement is essential to understanding the nature and scale of the task ahead. PMID- 19776553 TI - The German NET-registry: an audit on the diagnosis and therapy of neuroendocrine tumors. AB - AIMS: Clinical experience with neuroendocrine tumors (NETs) is difficult to acquire because they are rare and heterogeneous. The impact of guidelines on the care for NETs is not known. The German NET Registry compiled information for Germany pertaining to three questions: who provides care for NET patients; does the care comply with proposed guidelines, and are the results comparable to those described in the literature? PATIENTS AND METHODS: Between 2004 and 2007 data on 1,263 patients from 21 centers were compiled in a dedicated database. RESULTS: Tumor location, age and sex compared well with published data. Most patients were cared for in centers with more than 100 (47.9%) or between 20 and 99 patients (46.1%). Imaging (magnetic resonance tomography, computer tomography, ultrasound) was available for 79% of the patients, specific laboratory tests for 67%, somatostatin receptor scintigraphy for 56%, and pathology findings for 79%. High quality pathology reports were rare (2%). Sufficient documentation was mostly found in large centers. Surgery was the first-line therapy in 70.9%, while medical therapy was the second-line therapy in 45.7% of the patients. Median follow-up was 2.8 (0.4-6.4) and median overall survival was 2.5 (0.34-6.3) years. CONCLUSIONS: Most patients were referred to large specialized centers. Those centers adhered best to published guidelines for NETs. However, there are still significant deficiencies in the documentation of diagnostic results, mainly with regard to pathology reports. Therapeutic strategies were comparable between centers. The data provide a basis for future studies assessing improvements in documentation, diagnosis and treatment of NET. PMID- 19776554 TI - Relationship between small airway function and health status, dyspnea and disease control in asthma. AB - BACKGROUND: Small airways play important roles in the pathophysiology of asthma. However, relationships between small airway involvement and health status and dyspnea have not been investigated. OBJECTIVES: It was the aim of this study to assess the relationships between proximal and peripheral airway functions and health status, dyspnea and disease control in patients with asthma, using impulse oscillometry (IOS). METHODS: We performed IOS, spirometry and assessment of health status (Asthma Quality of Life Questionnaire and St. George's Respiratory Questionnaire), dyspnea (Baseline Dyspnea Index) and disease control (Asthma Control Questionnaire) in 65 asthmatics and evaluated their relationships. RESULTS: Peripheral airway function as evaluated by IOS [R5-R20 (the fall in resistance from 5 to 20 Hz) and X5 (reactance at 5 Hz)], in addition to the proximal airway index (R20), significantly correlated with health status, dyspnea and disease control. Multiple regression analyses revealed that peripheral airway function significantly contributes to these, independently of the proximal airway index. In contrast, forced expiratory volume in 1 s did not significantly contribute to health status or dyspnea. CONCLUSIONS: IOS correlated better with clinical symptoms and asthma control than spirometry in patients with asthma. Peripheral and proximal airway functions as assessed separately by IOS independently contribute to health status, dyspnea and disease control, indicating that peripheral airways also represent an important therapeutic target. PMID- 19776555 TI - Views on personalized medicine: do the attitudes of African American and white prescription drug consumers differ? AB - AIMS: Although recent advances in pharmacogenomics are making possible the use of genetic testing to determine the best medication for patients, little is known about how patients view such procedures. The aims for this study that were developed collaboratively as part of a community-academic partnership are: (1) What are the attitudes and perceptions of prescription drug consumers concerning personalized medicine and genetic testing for drug compatibility and how do they differ between African American and white patients? (2) What are the attitudes and perceptions of patients concerning race-based prescribing and how do they differ between African American and white patients? METHODS: We conducted 6 focus groups, 2 with white participants and 4 with African American participants. Focus groups were audio-recorded, transcribed, and analyzed to ascertain common themes. RESULTS: Our results suggest that personalized medicine and genetic testing, though not well understood by lay persons, were considered positive advances in medicine. However, participants also voiced concerns about these advances that differed by race. CONCLUSION: This study points to the need to include perspectives of at-risk communities as we move toward wider use of this technology. PMID- 19776557 TI - Erythrocyte aggregation and neutrophil function in an aging population. AB - There are limited investigations which have examined the relationship between neutrophil activation and erythrocyte aggregation in older persons. The purpose of the present study was to investigate the relationship between neutrophil activation and erythrocyte aggregation (EA) in an aging population. Twenty-eight male and female subjects were allocated into one of four groups with 7 participants in each group (group 1, 20-29 years; group 2, 30-39 years; group 3, 40-49 years; group 4, 50-59 years). EA was determined using the Myrenne aggregometer. Neutrophil function (respiratory burst and phagocytic activity) was assessed using flow cytometry. EA was found to increase with age. An ANOVA showed a significant (p < 0.05) increase for EA in autologous plasma in group 4 compared to groups 1 and 2. An ANOVA and Pearson's correlation showed that phagocytic activity decreased with age. Furthermore, a positive correlation between stimulated phagocytic activity and erythrocyte aggregability at low shear in 3% dextran-70 solution was observed. The current investigation suggests a decrease in neutrophil phagocytic activity with age and EA was increased with age. Additionally, the current study is novel as it suggests a possible relationship between neutrophil phagocytic activity and erythrocyte aggregability. PMID- 19776558 TI - Urine proteome analysis in murine nephrotoxic serum nephritis. AB - BACKGROUND: Urine contains serum proteins filtered by the glomerulus or secreted by the renal tubules and proteins produced locally by the urinary tract. Proteomic analysis of urine holds the potential as a noninvasive means of studying or monitoring disease activity. In mice, large concentrations of albumin and lipocalins have complicated the ability to identify urinary biomarkers in disease models. METHODS: Passive nephrotoxic serum nephritis was induced in mice. Urine proteins were identified and quantified by iTRAQ and MALDI-TOF mass spectrometry. Results were compared to Western blotting and multiplex immunoassays. RESULTS: Large concentrations of major urinary proteins dominate the urine proteome of mice even in the context of acute nephritis. Increased proteinuria caused by nephrotoxic serum nephritis is transient and includes increased albumin excretion. There were no alterations in chemokine excretion. Altered hepcidin excretion was identified, most likely reflecting local production and renal retention. CONCLUSION: Proteomic analysis of mouse urine remains challenging due to the abundance of a limited subset of proteins. iTRAQ analysis does not circumvent these challenges, but can provide information on post-translational processing of some proteins. Hepcidin is identified as a potential urinary marker of nephritis and its role in disease pathogenesis warrants further study. PMID- 19776559 TI - Incidence, predictors and outcomes of transplant renal artery stenosis after kidney transplantation: analysis of USRDS. AB - OBJECTIVE: We analyzed the United States Renal Data System registry to study the risks, predictors, and outcomes of transplant renal artery stenosis (TRAS) in contemporary practice. METHODS: The study sampled comprised adults with Medicare primary insurance who received kidney transplants in 2000-2005. We examined associations of recipient, donor and transplant factors with time-to-TRAS by the Kaplan-Meier method and multivariate Cox regression. Survival analysis methods were employed to estimate graft survival after TRAS, and to model TRAS as a time dependent outcome predictor. Kaplan-Meier analysis was used to estimate time to allograft loss in patients who did or did not have an angioplasty procedure for TRAS. RESULTS: There were 823 cases of TRAS among 41,867 transplant patients, with an incidence rate of 8.3 (95% CI 7.8-8.9) cases per 1,000 patient-years. Mean time to diagnosis of TRAS was 0.83 + or - 0.81 years after transplant. Factors associated with TRAS were older recipient and donor age, extended criteria donors, induction immunosuppression, delayed graft function, and ischemic heart disease. There was no association of TRAS with deceased donors, prolonged cold ischemia time, acute rejection or cytomegalovirus status. TRAS was associated with increased risk of graft loss (including death; adjusted hazard ratio 2.84, 95% CI 1.70-4.72). Among the 823 patients with TRAS, 145 (17.6%) underwent angioplasty. Graft survival after TRAS was not significantly different in patients treated with angioplasty compared to those without angioplasty. CONCLUSIONS: TRAS is an important complication that predicts adverse patient and graft outcomes. Treatment strategies for TRAS warrant prospective investigation in clinical trials. PMID- 19776561 TI - Poor nutritional health of Bedouin preschool children in Jordan: the irony of urbanization. AB - AIMS: The purpose of this cross-sectional study was to assess growth and nutritional status of Bedouin preschool children with special focus on the extent of the interaction of anemia with iron deficiency and vitamin A deficiency as possible underlying factors. METHODS: Subjects aged 6-66 months were included by recruitment of 262 mothers having either an infant or a preschool child. Nutritional assessment by anthropometric, laboratory and dietary methods was carried out, with anthropometric indices expressed in z-score units. Serum retinol concentration, alpha-tocopherol, ferritin and blood hemoglobin and hematocrit were assessed. RESULTS: Stunting, vitamin A deficiency, anemia, and iron deficiency were prevalent at rates of 21.1, 25.2, 57.3, and 20.2%, respectively. Mean serum retinol concentration was 249 +/- 64 microg/l. More than 50% of the children were at risk of vitamin A deficiency. Compared to others, subjects with vitamin A deficiency tended to have lower hemoglobin (10.0 +/- 1.9 vs. 10.95 +/- 1.99 g/dl, p < 0.001) and lower serum ferritin concentrations (9.2 +/- 3.4 vs. 16.3 +/- 6.2 microg/l, p < 0.001). Serum retinol concentration correlated with hemoglobin (r = 0.41, p < 0.001) and ferritin (r = 0.42, p < 0.001). No gender differences were found. CONCLUSIONS: Bedouin preschool children are at risk for anemia, iron deficiency, nonocular vitamin A deficiency and stunting. Vitamin A deficiency exacerbates the development of anemia and iron deficiency among children. Urbanization has led Bedouins to the verge of poverty. They have been losing their characteristic lifestyle as traditional livestock keepers, with their children deprived of milk to drink or meat to eat. Coordinated interventional actions by the socioeconomic development planners and decision makers are needed. PMID- 19776560 TI - Effect of pioglitazone on survival and renal function in a mouse model of polycystic kidney disease. AB - BACKGROUND/AIMS: Cystic epithelia in polycystic kidney disease display features similar to malignant cells. Thiazolidinediones have been shown to have anti neoplastic properties, therefore we tested the hypothesis that pioglitazone reduces cyst formation, improves renal function, and prolongs survival in a mouse model of polycystic kidney disease. METHODS: PC-Pkd1-KO mice, which have homozygous mutations of the Pkd1 gene in principal cells, were used. On the day after giving birth, mothers were fed standard mouse chow with or without pioglitazone (30 mg/kg chow). After weaning, the assigned diet was continued. At 1 month of age, blood pressure was measured and animals were sacrificed to determine kidney weight, body weight, and serum urea. Kidneys were evaluated for proliferation using Ki-67, apoptosis using TUNEL analysis, and cyst number using MRI. Survival was observed. RESULTS: Pioglitazone did not alter renal function, cell proliferation, apoptosis, or cyst formation in animals with polycystic kidney disease, however it did increase survival. Pioglitazone reduced blood pressure in PC-Pkd1-KO, but not in controls. CONCLUSION: These findings suggest that pioglitazone may have a unique antihypertensive effect in polycystic kidney disease, and that such an effect may promote improved survival. PMID- 19776562 TI - Tell me what your blood beta-carotene level is, I will tell you what your health risk is! The viewpoint of the SUVIMAX researchers. PMID- 19776563 TI - Cortical activation during a pitch discrimination task in tinnitus patients and controls--an fMRI study. AB - Chronic subjective tinnitus has been associated with aberrant activation of cortical areas involved in the perception of auditory information. This leads to the hypothesis that neural correlates of altered auditory perception may be found in tinnitus patients using functional magnetic resonance imaging. To study brain activation patterns due to acoustic stimulation in a pitch discrimination task, 6 tinnitus patients and 6 age-matched controls were investigated. Tones were presented binaurally at 5 beeps/s with three different frequencies in a block design. Using Statistical Parametrical Mapping, we found activation of secondary auditory areas in both groups. Furthermore, controls showed activation of the right-hemispheric anterior insula, whereas the middle frontal gyrus, putamen and left-hemispheric insula were activated in tinnitus patients. In the between-group analysis, activation of the caudate nucleus, superior frontal gyrus (Brodmann area 8) and cingular cortex was more pronounced in patients than in controls suggesting the perception of auditory inputs in a more emotional context in our patient group compared to controls. PMID- 19776564 TI - Inner ear function following underlay myringoplasty. AB - INTRODUCTION: Inner ear function can be modified by middle ear surgery. OBJECTIVES: This study aimed to describe bone threshold conduction changes after myringoplasty. DESIGN: Prospective study. MATERIALS AND METHODS: Determination of preoperative and 6- to 12-month postoperative bone conduction thresholds for patients consecutively treated by primary underlay myringoplasty. RESULTS: The mean bone conduction threshold improvement was 1 +/- 6 dB (p = 0.006). There were significant differences in bone conduction threshold changes by surgical approach and for patients with tympanosclerosis. There were no 'dead ears' following intervention, and only a 1% risk of impairment. CONCLUSIONS: Anatomically successful myringoplasty can partially improve bone conduction with minimal risk of impairment. PMID- 19776565 TI - Change in cochlear response in an animal model of otitis media with effusion. AB - Our previous studies confirm that middle ear mobility is reduced in the presence of otitis media with effusion (OME). Variations in middle ear function may result in changes in cochlear response in OME ears. With the long-term goal of evaluating cochlear function in OME ears, the aim of this study was to measure the displacement of the basilar membrane (BM) in guinea pig ears with OME. Vibrations of the BM at the apex and basal turn were measured in an in vitro preparation extracted 3 and 14 days after injection of lipopolysaccharide in the middle ear of guinea pigs. The results show that the displacement sensitivity of the BM at the apex and the basal turn to sound pressure in the ear canal was reduced up to 25 dB at their characteristic frequencies, respectively. Cochlear gain with respect to umbo movement was also changed in ears with OME in both groups. This study provides data for analysis of the change of BM vibration in a guinea pig OME model. PMID- 19776566 TI - The performance of Cochlin-tomoprotein detection test in the diagnosis of perilymphatic fistula. AB - BACKGROUND: Perilymphatic fistula (PLF), defined as an abnormal communication between the inner and middle ear, presents with a symptomatology of hearing loss and vestibular disorder that is indistinguishable from a number of other inner ear diseases. Methods of diagnosis remain controversial. We have previously shown that Cochlin-tomoprotein (CTP) is selectively detected in the perilymph. To establish a definite diagnostic test for PLF using CTP as a biochemical marker, we examined the diagnostic performance of the CTP detection test. METHODS: CTP detection test was performed by Western blot using recombinant human CTP (rhCTP) as a spiked standard. We evaluated the specificity of the CTP detection test by testing non-PLF cases. To describe the limitations of the test, we tested samples from patients with middle ear infection. We also studied the stability of CTP protein by storing the samples at room temperature (25 degrees C) or 4 degrees C for 55 days. The effects of repeated freezing and thawing were also evaluated. Serially diluted perilymph was tested to find out the detection limit of CTP. FINDINGS: We have established a standardized CTP detection test using high (0.27 ng) and low (0.13 ng) spiked standards of rhCTP in Western blotting. Middle ear lavages (MEL) from 54 of 55 non-PLF cases were negative in the CTP detection test, i.e. the specificity of the test is 98.2%. MEL from 43 out of 46 cases with chronic suppurative otitis media or middle ear cholesteatoma were negative for CTP. CTP is a stable protein and detection was not affected by the storage, or freezing and thawing. The detection limit of perilymph was 0.161 microl/lane in an average of 5 samples. INTERPRETATION: CTP is a stable perilymph-specific protein, and this CTP detection could be the first clinically established diagnostic tool to detect PLF with a high specificity. PLF is surgically correctable by sealing the fistula. Appropriate recognition and treatment of PLF can improve hearing and balance in afflicted patients. PMID- 19776567 TI - Uric acid and cardiovascular disease: how to solve another chicken or egg puzzle. PMID- 19776568 TI - Serum uric acid for risk stratification of patients with coronary artery disease. AB - OBJECTIVES: In patients with coronary artery disease (CAD), elevated serum uric acid (SUA) levels may predict worse cardiovascular outcomes. It is known that SUA levels are influenced by renal function. We aimed to assess the predictive value of SUA while taking into account patients' renal function. METHODS: The primary end point (PEP) risk, including fatal or nonfatal myocardial infarction (MI) or sudden death, was assessed by SUA quintiles before and after adjustment for the estimated glomerular filtration rate (eGFR) in 2,796 nondiabetic CAD patients enrolled in the Bezafibrate Infarction Prevention study. RESULTS: The PEP risk increased from the lowest (11.8%) to highest SUA quintile (18.0%), p < 0.005, respectively. After adjustment for age, sex, smoking, prior MI, metabolic syndrome variables, NYHA classes II-IV, heart rate and treatment with bezafibrate, diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, calcium channel blockers and antiplatelets, the highest SUA quintile exhibited the highest PEP risk [hazard ratio (HR): 1.47 (95% CI: 1.06-2.04)]. Patients in the highest - compared with those in the lowest - quintiles continued to demonstrate an increased PEP risk [HR: 1.46 (95% CI: 1.04-2.06)], even after additional adjustment for the eGFR. CONCLUSION: In nondiabetic patients with CAD, elevated SUA levels are associated with an increased risk of cardiac events, independent of renal function. PMID- 19776569 TI - Effects of flossing and rinsing with a fluoridated mouthwash after brushing with a fluoridated toothpaste on salivary fluoride clearance. AB - The aims of this study were to test the hypothesis that flossing after brushing with a fluoridated toothpaste may lower salivary fluoride (F), and to evaluate the consequence of subsequent F mouthwash use. Twenty adults used 3 oral hygiene regimes in a randomised order: A, brushing with an NaF toothpaste; B, as A but followed by professional flossing; C, as B followed by rinsing with an NaF mouthwash. Saliva samples were collected up to 120 min after each regime and analysed for F. The mean area under the clearance curve value for regime C was statistically significantly greater than the corresponding values for A and B (p < 0.0001), which differed little. The regime that included the mouthwash may provide better anticaries protection. PMID- 19776571 TI - Validity and reliability of laser-induced fluorescence measurements on carious root surfaces in vitro. AB - The aim was to assess the validity of laser fluorescence (LF), visual inspection and surface texture on root caries lesions in vitro, related to histological lesion depths. Agreement on interdevice, interexaminer and intra-examiner levels as well as the influence of discolouration and surface texture on LF readings were investigated. Calibrated examiners assessed lesion colour and surface texture and performed measurements with 2 LF devices in 3 separate series at intervals of 1 week. Sections (300 mum thick) of 64 out of 93 teeth were obtained and examined under the microscope. Lesion depth was assessed with 2 references: from the delineated borderline of the original exposed root surface (ref. I), or if loss of surface continuity, the absolute lesion depth (ref. II). The correlation (Spearman rho) between LF readings and histological depth was low with values ranging from 0.22 (p > 0.05) to 0.31 (p < 0.05). LF 1 and LF 2 were significantly correlated with discolouration (rho = 0.52 and 0.46, respectively) and with surface texture denoted as hard (rho = 0.34 and 0.33, respectively). A significant correlation between colour and histological depth ref. I (rho = 0.51) and ref. II (rho = 0.56) was found. No significant correlation between surface texture and histological depth was found. The reliability, evaluated as intraclass correlation coefficient was for intra-examiner 0.99, interexaminer 0.97 and interdevice level 0.98. Large differences were found between 2 consecutive measurements, and high measurement errors indicated considerable deviation of individual measurements. Based on these findings, the LF device is not suitable as a diagnostic tool for root caries. PMID- 19776570 TI - Effect of rinsing with mouthwashes after brushing with a fluoridated toothpaste on salivary fluoride concentration. AB - The aim of the study was to determine whether rinsing with a mouthwash after brushing with a fluoridated toothpaste affected oral fluoride (F) retention and clearance compared with an oral hygiene regime without mouthwash. In this supervised, single-blind study, 3 regimes were compared: (A) brushing for 1 min with 1 g of 1,450 microg F/g NaF toothpaste followed by rinsing for 5 s with 10 ml water; (B) as A but followed by rinsing for 30 s with 20 ml of 100 mg F/l NaF mouthwash, and (C) as B but rinsing for 30 s with a non-fluoridated mouthwash. Twenty-three adults applied each treatment once in a randomised order, separated by 1-week washout periods, and used a non-fluoridated toothpaste at home prior to and during the study. Whole saliva samples (2 ml), collected before each treatment commenced and 10, 20, 30, 60, 90 and 120 min afterwards, were subsequently analysed for fluoride by ion-specific electrode. The mean (SD) back transformed log (area under salivary F clearance curve) values were: A = 2.36 (+3.37, -1.39), B = 2.54 (+2.72, -1.31) and C = 1.19 (+1.10, -0.57) mmol F/l x min, respectively. The values for regimes A and B were statistically significantly greater than that for regime C (p < 0.001; paired t test). These findings suggest that use of a non-F mouthwash after toothbrushing with a F toothpaste may reduce the anticaries protection provided by toothbrushing with a F toothpaste alone. The use of a mouthwash with at least 100 mg F/l should minimise this risk. PMID- 19776572 TI - In vitro comparison of Nyvad's system and ICDAS-II with Lesion Activity Assessment for evaluation of severity and activity of occlusal caries lesions in primary teeth. AB - This in vitro study of occlusal surfaces on primary molars aimed to: (1) evaluate the reproducibility of the Nyvad and ICDAS-II visual systems in detecting caries; (2) to test the accuracy of the systems in estimating lesion depth, and (3) to examine the association between the Nyvad system and the Lesion Activity Assessment system, an adjunct to ICDAS-II. Two samples of extracted primary molars (sample 1, n = 38; sample 2, n = 69) were evaluated independently by 2 examiners. In this in vitro study, evaluation of plaque in the Nyvad system was not possible. Histology (sample 2) was used to validate lesion depth. Area under ROC curves (A(z)), sensitivity, specificity and percent agreement of both systems were calculated at D1, D2 and D3 thresholds. Both systems showed kappa for intra- and inter-examiner agreement >0.86 and good correlation with histology: Spearman rho = 0.73 (Nyvad) and 0.78 (ICDAS-II). They presented similar performances except that ICDAS-II showed significantly higher sensitivity (Nyvad 0.89; ICDAS 0.92) and A(z) (Nyvad 0.85; ICDAS 0.90) for the D1 threshold. The correlation between the systems for lesion activity (Cramer's V) was 0.71. Therefore, both visual systems are reliable and can estimate caries lesion depth on primary teeth. Under in vitro conditions, there is no major difference between the Nyvad system and Lesion Activity Assessment in assessing caries activity. PMID- 19776573 TI - Carotid and basilar artery wall shear stress in Alzheimer's disease and mild cognitive impairment. AB - BACKGROUND/AIMS: Vascular pathology is increasingly seen as a factor contributing to the development of Alzheimer's disease (AD). With this in mind we hypothesized that this vascular pathology could be directly detected in the arteries contributing to the cerebral circulation of mild cognitive impairment (MCI) and AD patients by means of wall shear stress (WSS) measurements. METHODS: In this study we investigated the mean wall shear stress (MWSS), diastolic wall shear stress (DWSS) and systolic wall shear stress (SWSS) in the carotid and basilar arteries of control subjects (mean age: 72; SD: 8.8), patients suffering from MCI (mean age: 76; SD: 6.7), and patients suffering from AD (mean age: 72; SD: 8.2) that were consecutively referred to our outpatient memory clinic using in-house developed software on gradient echo phase-contrast MRI sequences. RESULTS: We found that all these parameters were significantly lower in the carotid arteries of patients suffering from AD or MCI when compared to control subjects. In the basilar artery only DWSS was lower in MCI or AD patients compared to control subjects. In none of the arteries a difference was found for any WSS parameter between MCI and AD patients. WSS parameters were significantly associated (corrected for age and sex) with the degree of cognitive impairment. CONCLUSION: Increased vascular pathology, as expressed by lower WSS measures, was found in patients suffering from MCI and AD compared to normal controls. This might point to the involvement of vascular pathology in the development of AD. PMID- 19776574 TI - Primary health care use and reasons for hospital admissions in dementia patients in france: database study for 2007. AB - OBJECTIVES: To identify outpatient and hospital health care usage among dementia patients compared to controls. METHODS: Analysis of the French National Health Insurance general regime reimbursement database, linked to the national hospitalization database for 2007; 258,809 subjects over the age of 60 with dementia were compared to a sample of 88,296 controls. RESULTS: Dementia patients more frequently had at least one annual visit to private psychiatrists and neurologists (21.9%, relative risk, RR = 7.0), nursing care (52%, RR = 1.3), physiotherapy (37%, RR = 1.45), and hospitalization (40.8%, RR = 1.7), and they less frequently consulted other private specialists (62%, RR = 0.85). Many diagnosis groups were significantly more frequent in dementia patients: nervous system (RR = 5.3), psychiatry (RR = 9.1), respiratory medicine (RR = 1.8), unspecified (RR = 2.4). Hospitalizations for endoscopy, radiotherapy, chemotherapy, and treatment of disabilities such as cataracts (RR = 0.7) were less frequent. Higher relative levels of health care use decreased with age for dementia patients. CONCLUSIONS: Although the use of some forms of health care can be explained by the clinical condition induced by dementia, others must be interpreted in light of modes of medical and social management and ethical justification for screening and investigations. PMID- 19776575 TI - Choline acetyltransferase activity in vascular dementia and stroke. AB - BACKGROUND/AIM: Alterations in cholinergic activity have not been systematically studied in types of cerebrovascular disease. We examined cholinergic function at postmortem, focussing on stroke and vascular dementia (VaD). METHODS: Post-mortem brain tissue was studied from 61 patients with stroke or VaD (13 infarct dementia; 8 stroke/no dementia; 11 sub-cortical ischaemic VaD, SIVD; 29 VaD and concurrent Alzheimer's disease, AD), 12 patients with AD and 23 controls. Choline acetyltransferase (ChAT) was measured in Brodmann areas (BA) 9 and 20/21. RESULTS: There were significant reductions in ChAT activity in patients with VaD and concurrent AD compared to age-matched controls (BA9: t = 2.7, p = 0.009; BA20/21: t = 4.67, p = 0.000). In patients with infarct dementia, there was a significant 27% increase in ChAT activity in BA9 (t = 2.1, p = 0.047), but not in BA20/21 (t = 1.67, p = 0.106), compared to the age-matched control group. There was no relationship between ChAT activity and cognition in the VaD patients. CONCLUSIONS: Loss of cholinergic function is only evident in VaD patients with concurrent AD. A novel increase in cholinergic activity was identified in patients with infarct dementia, which may create important new treatment opportunities. PMID- 19776576 TI - Diagnostic and therapeutic double-balloon enteroscopy after small bowel Roux-en-Y reconstructive surgery. AB - BACKGROUND: Roux-en-Y reconstruction excludes the afferent limb and the biliopancreatic system from conventional endoscopic access. Postoperative problems in these excluded gastrointestinal systems are therefore often dealt with surgically. We investigated the usefulness of the therapeutic double-balloon enteroscope to perform interventional endoscopic procedures in the excluded segment of the gastrointestinal tract after Roux-en-Y reconstruction. METHODS: 30 procedures were performed in 22 patients with Roux-en-Y reconstruction after enterobiliary anastomosis, gastrectomy or bariatric gastric bypass. All procedures were performed with the therapeutic double-balloon enteroscope, under general anesthesia and with fluoroscopic control. RESULTS: ERCP at the enterobiliary anastomosis was successful in 90% (n = 10) of the procedures. ERCP at the intact papilla was successful in 60% (n = 5). Enterocutaneous fistula closure after (sub)total gastrectomy was performed in 2 procedures. Successful diagnostic procedures encompassed intubation of the excluded stomach after bariatric gastric bypass (89%, n = 9) or the afferent limb after Roux-en-Y reconstruction (75%, n = 4). The overall success rate in accessing the aimed excluded segment with the double-balloon enteroscope was 87%. Interventional procedures were able to avoid surgery in 65%. One retroperitoneal perforation occurred during ERCP which was conservatively treated. CONCLUSIONS: Excluded gastrointestinal segments after Roux-en-Y reconstruction can be accessed with a substantial success rate using double-balloon enteroscopy. Therapeutic interventions like ERCP can prevent surgery in the majority of patients. PMID- 19776577 TI - Renal dysfunction caused by oral sodium phosphate tablets for colonoscopy. PMID- 19776578 TI - Involvement of lupus enteritis in a patient with lupus cystitis and nephritis. AB - We present the case of a patient with lupus enteritis accompanied by both lupus cystitis and lupus nephritis without a history of systemic lupus erythematosus. The patient had a 2-month history of diarrhea and pollakiuria and was admitted to our hospital. Physical examination showed abdominal tenderness. Laboratory data revealed reductions in both total protein and albumin, elevated serum creatinine levels, and elevated antinuclear and anti-Smith antibodies. Urinalysis revealed proteinuria. Stool and urine cultures were negative. Abdominal computed tomography revealed diffuse edematous wall thickening, dilatation of the small intestine suggesting paralytic ileus, and irregular wall thickening of the urinary bladder. Histological results of the cystic and renal biopsies revealed interstitial cystitis and membranous nephropathy which were suggestive of lupus cystitis and lupus nephritis, respectively. The patient's gastrointestinal symptoms were finally diagnosed as resulting from lupus enteritis. After initiating 30 mg oral prednisolone daily, the diarrhea and pollakiuria subsided, and renal function became normal. Lupus enteritis should always be considered in the differential diagnosis when patients complaining of chronic diarrhea of unknown etiology are encountered. PMID- 19776579 TI - Coexisting gastric varices should not preclude prophylactic ligation of large esophageal varices in cirrhosis. AB - BACKGROUND/AIMS: Coexisting gastric varices at baseline or the risk of their formation during treatment could alter the approach for primary bleeding prophylaxis in patients with large esophageal varices. METHODS: Data analysis of 152 patients with cirrhosis and large esophageal varices included in the German multicenter trial on primary prevention of variceal bleeding. RESULTS: 20 patients (13.6%) had coexisting gastric varices at baseline (GOV+). 10 of those each received either band ligation or propranolol, respectively. During follow-up (34.4 +/- 18.9 months) new gastric varices occurred in 2/75 (2.7%, ligation) and 4/77 (5.2%, propranolol) patients, respectively. One patient with newly developed gastric varices bled (propranolol group). GOV+ patients had a better baseline liver function and overall survival. Bleeding incidence did not differ significantly between GOV+ and GOV- patients (3-year actuarial risk: 20.0 +/- 10.6% (GOV+), 38.1 +/- 4.4% (GOV-), p = 0.195). Among GOV+ patients, bleeding occurred in 3/10 patients of the propranolol group and in 0/10 in the ligation group (p = 0.038). CONCLUSION: Prophylactic band ligation of large esophageal varices is safe and effective also in patients with coexisting gastric varices. Band ligation did not increase the risk of secondary gastric varices compared to propranolol. PMID- 19776580 TI - Endoscopic therapy for early gastric cancers - from EMR to ESD, from guideline criteria to expanded criteria. PMID- 19776581 TI - Clinical outcomes of endoscopic submucosal dissection for early gastric cancer by indication criteria. AB - BACKGROUND AND STUDY AIMS: Endoscopic submucosal dissection (ESD) can remove early gastric cancer (EGC) en bloc. We sought to assess the feasibility and efficacy of ESD and the clinical outcomes based on the indication criteria. PATIENTS AND METHODS: 551 patients with 589 EGC lesions were divided into the guideline criteria group (elevated lesion < or =20 mm in diameter and depressed lesion < or =10 mm without ulceration) and the expanded criteria group (mucosal cancer without ulcer findings irrespective of tumor size; mucosal cancer with ulcer findings < or =3 cm in diameter; and minute submucosal invasive cancer < or =3 cm in size). RESULTS: En bloc, complete and curative resection were achieved in 98.6 and 93.0, 95.1 and 88.5, and 97.1 and 91.1%, for the guideline and expanded criteria lesions, respectively; the differences between the 2 groups were significant for each. The expanded criteria lesions were at significantly higher risk of ESD-associated bleeding and perforation. Overall survival was adequate irrespective of the indications, and the disease-specific survival rates were 100% in both. CONCLUSION: ESD for EGCs that met the expanded criteria was acceptable, though the resection rates and safety were decreased compared to those for the guideline criteria lesions. PMID- 19776582 TI - Mucormycosis in a Crohn's disease patient treated with infliximab. AB - We report a case of sinus mucormycosis in a patient receiving infliximab for Crohn's disease (CD). A 41-year-old white female with a history of gastroesophageal reflux disease, well-controlled diabetes, and ileocecal CD developed right-sided facial pain and high fevers, with computed tomography scan confirming sinusitis. She had been receiving both low-dose azathioprine and scheduled infliximab for her CD. A sinus biopsy was procured endoscopically which grew mucormycosis. All immunosuppressive agents were immediately discontinued, and the patient underwent multiple debridement procedures of the right sinuses. Amphotericin B lipid complex and posaconazole were administered to the patient. Repeat laboratory and imaging study demonstrated clearance of the infection approximately 30 days after diagnosis. The patient's CD did not flair during withdrawal of immunosuppressive medications, and the patient completed 6 months of posaconazole therapy. Clinicians should be aware of the possible development of this potentially catastrophic infection in patients receiving infliximab, especially if such patients have other risks for mucormycosis, such as diabetes. PMID- 19776583 TI - Changing pattern in the clinical presentation of pediatric celiac disease: a 30 year study. AB - BACKGROUND/AIMS: The incidence of celiac disease (CD) has increased in recent years due to the recognition of atypical forms and the identification of silent cases through serological screening. Our aim was to detect temporal trends in the presentation of pediatric CD in Greece. METHODS: We reviewed the medical files of all children diagnosed with CD between 1978 and 2007 at a single academic pediatric center. Cases were classified according to the year of diagnosis. We examined demographic data, presenting symptoms, delay to diagnosis, and the prevalence of associated conditions. RESULTS: During the study period, 284 new cases of CD were diagnosed. The incidence of CD was significantly increased in recent years (p < 0.05). We observed significant trends towards older age at diagnosis (p < 0.001), longer delay to diagnosis (p < 0.05) and decreased frequency of the classical and/or gastrointestinal predominant mode of presentation (p < 0.001). In recent years, diagnosis of CD was significantly more frequent due to testing of asymptomatic children with a positive family history for CD or personal history of associated conditions (p < 0.001). CONCLUSION: We report a changing pattern in the presentation of pediatric CD in Greece. CD is diagnosed more frequently in older children, oftentimes presents with atypical symptoms, and is increasingly detected through serological screening. CD should be considered in the presence of atypical presentations. PMID- 19776584 TI - Korea red ginseng on Helicobacter pylori-induced halitosis: newer therapeutic strategy and a plausible mechanism. AB - BACKGROUND: Gas chromatographic documentation of volatile sulfur compounds in Helicobacter pylori cultures and the amelioration of halitosis after eradication suggested a causal link between H. pylori infection and halitosis. AIM: We hypothesized that Korea red ginseng can relieve H. pylori-associated halitosis based on their anti-inflammatory and cytoprotective actions in H. pylori associated gastritis. METHODS: Eighty-eight functional dyspepsia patients presenting with either subjective halitosis or objective halimeter levels >100 ppb were recruited, on whom tests were repeated after 10 weeks of red ginseng administration. The expressions of cystathionine gamma-lyase (CSE), cystathionine beta-synthetase (CBS), IL-6, IL-8 and IL-1beta mRNA were compared in H. pylori infected or NaHS-treated gastric epithelial cells according to red ginseng treatment. RESULTS: After 10 weeks of red ginseng administration, 38 patients out of 68 H. pylori-positive cases became 'free of halitosis' accompanied with halimeter levels <50 ppb accordant with the subjective resolution of halitosis. Among the remaining 30 patients, 15 cases administered with both eradication regimen and red ginseng supplement showed either higher eradication rates (93.3%) or were found to be completely free of halitosis in comparison to the other 15 patients who were only administered the eradication regimen. Among 20 H. pylori negative patients, 13 patients became 'free of halitosis' with 10 weeks of red ginseng treatment alone. Red ginseng extracts significantly decreased H. pylori- or NaHS-induced CSE expressions concomitant with attenuated levels of IL-6, IL-8 and IL-1beta mRNA. CONCLUSION: The strategy consisting of Korea red ginseng supplementation after the successful eradication of H. pylori could be an effective way to fight troublesome halitosis. PMID- 19776585 TI - Effects of cigarette smoking and restraint stress on human colon tumor growth in mice. AB - BACKGROUND: Cigarette smoking is a risk factor for colon cancer. Studies suggest that stress increases the incidence and promotes the development of cancers. Cigarette smoking and stress are closely associated, as people often smoke under stressful conditions and both of them can activate the adrenergic nervous system. AIMS: To investigate the effects of cigarette smoking and restraint stress on colon cancer growth and the possible underlying mechanisms in these pathological processes. METHODS: Nude mice bearing a HT-29 human colon cancer xenograft were either exposed to cigarette smoke and/or restraint stress. Cotinine and epinephrine levels in plasma of nude mice were measured by enzyme immunoassays. Expression of cyclooxygenase-2 (COX-2) and B-cell lymphoma-2 (Bcl-2) in tumor tissues were detected by Western blot. Prostaglandin E(2) (PGE(2)) concentrations were determined by enzyme immunoassay. RESULTS: 4% cigarette smoking together with restraint stress 1 h daily for 33 days promoted tumor growth in nude mice. This was accompanied by the increase of plasma levels of cotinine and epinephrine in these animals. They also enhanced the COX-2, Bcl-2 expressions and PGE(2) levels in tumor tissues. CONCLUSION: These findings are important in understanding the pathogenesis of colon cancer, particularly related to cigarette smoking and stress. PMID- 19776586 TI - Changes in alcohol consumption in Denmark after the tax reduction on spirits. AB - AIMS: This paper examines changes in alcohol consumption in Denmark between 2003 and 2006 after the excise tax on spirits in Denmark was lowered by 45% on October 1, 2003 and travelers' allowances for the import of alcohol were increased on January 1, 2004. METHODS: Cross-sectional and panel data from Denmark from 2003 to 2006 were analyzed. Samples were collected by telephone interviews using random digit dialing. RESULTS: Panel data for Denmark revealed that alcohol consumption remained relatively stable. Similar results were found in the Danish cross-sectional data. It appears that 'substitution' rather than increased importation occurred. CONCLUSION: We found no evidence to support earlier research stating that decreased prices and increased availability is related to higher alcohol consumption. This could be partly because (1) Denmark has reached a 'saturation' level of consumption over the past 30 years and (2) the survey mode of data collection did not capture specific subpopulations who might have increased their consumption. It may be necessary to examine other indicators of alcohol use or alcohol-related harm in order to fully assess the consequences of such changes in alcohol availability. PMID- 19776587 TI - Changes in alcohol-related harm after alcohol policy changes in Denmark. AB - OBJECTIVES: This paper examines changes in alcohol-related harm in Denmark between 2003 and 2005 after changes in alcohol policies were introduced between 2003 and 2005. METHODS: Interrupted time series analysis was performed with data on violent assaults and hospitalisations for acute alcohol intoxication from 2003 through 2005. RESULTS: A 26% increase in the number of acute alcohol intoxication hospitalisations among people aged 15 years and younger was detected after the tax reduction on spirits. No significant increase in violent assaults and acute intoxication among adults was found. CONCLUSIONS: Even modest alcohol price policies can affect more vulnerable population sub-groups such as under-age youth. Policy makers should consider such consequences when forming economic policies that also have public health implications. PMID- 19776588 TI - Noninvasive assessment of cerebral perfusion and oxygenation in acute ischemic stroke by near-infrared spectroscopy. AB - BACKGROUND: In acute stroke patients, there is a need for noninvasive measurement to monitor blood flow-based therapies. We investigated the utility of near infrared spectroscopy (NIRS) to determine cerebral perfusion in these patients. METHODS: Eleven patients were investigated within 1.4 +/- 2.2 days after onset of an ischemic middle cerebral artery infarction by monitoring the kinetics of an intravenous bolus of indocyanine green (ICG). For ICG kinetics, bolus peak time, time to peak (TTP = time between 0 and 100% ICG maximum), maximum ICG concentration, rise time (time between 10 and 90% ICG maximum), slope (maximum ICG/TTP), and blood flow index (BFI = maximum ICG/rise time) were obtained. Perfusion-weighted MRI (PWI) and NIRS measurements were performed within 24 h, and the interhemispherical differences of TTP values were compared. RESULTS: Stroke patients showed an increased bolus peak time (p < 0.02), TTP (p < 0.01), and rise time (p < 0.01), whereas slope (p < 0.01) and BFI (p < 0.01) were diminished at the site of infarction as compared to the unaffected hemisphere. The interhemispherical differences of TTP as measured by PWI and NIRS were closely correlated (r = 0.86). CONCLUSIONS: Noninvasive measurements of cerebral ICG kinetics by NIRS provide a useful means of detecting cerebral perfusion deficits in patients with acute stroke, which correlate well with those obtained by PWI. PMID- 19776589 TI - Transient ischemic attacks and inhibitory seizures in elderly patients. AB - BACKGROUND: The new definition of a transient ischemic attack (TIA) makes it more difficult to distinguish it from an inhibitory seizure (IS). PURPOSE: The present study compares the characteristics of patients with an IS to those with a TIA, taking into account the old and the new definition of a TIA. PATIENTS AND METHODS: The clinical characteristics and the electroencephalogram (EEG) findings of 25 patients with an IS were compared to 252 patients with a TIA according to the old definition. Subgroups of 10 patients with an IS without structural lesions and 195 TIA patients according to the new definition were also analyzed. The differential diagnostic clues were examined. RESULTS: Differences in age, gender distribution and vascular risk factors were observed only when comparing the overall patient groups. However, these differences disappeared when the subgroups were analyzed. Temporary speech disturbance, associated with some partial amnesia for the event, was the most common clinical presentation of an IS. Additionally, specific and nonspecific postictal EEG abnormalities were observed in the majority of the IS patients, while the EEG was normal in more than 90% of the TIA patients. CONCLUSIONS: An IS must be suspected in a patient with a short temporary speech disturbance and partial amnesia for the event. In view of the new definition of a TIA, urgent EEG becomes mandatory in each patient with a brief episode of neurological dysfunction. PMID- 19776590 TI - Comparison of the effects of low intra-abdominal pressure and pentoxifylline on oxidative stress during CO2 pneumoperitoneum in rabbits. AB - BACKGROUND: The aim of this study was to investigate the effect of low-pressure pneumoperitoneum and pentoxifylline, a methylxanthine derivative, in the prevention of injury caused by free oxygen radicals generated during CO(2 )pneumoperitoneum. METHODS: Twenty-eight rabbits were allocated randomly to 4 groups. Control group rabbits (group 1) were subjected to anesthesia for 60 min; group 2 and 3 animals were subjected to a CO(2) pneumoperitoneum (15 or 7 mm Hg); and group 4 rabbits received 50 mg/kg pentoxifylline, followed by a 15-mm-Hg pneumoperitoneum. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), lipid hydroperoxide, glutathione reductase and total antioxidant status were measured. RESULTS: Compared with group 1, a significant increase in lipid hydroperoxide levels at the end of the pneumoperitoneum and 30 min after deflation and a significant decrease in total antioxidant status 24 h after deflation were recorded in group 2. In addition, a significant increase was observed in ALT, AST and LDH levels. These changes were attenuated by low-pressure pneumoperitoneum, whereas pentoxifylline pretreatment appeared to attenuate only transaminase levels. CONCLUSION: Low-pressure pneumoperitoneum could attenuate ischemia/reperfusion injury induced by CO(2 )pneumoperitoneum in a rabbit model whereas pentoxifylline pretreatment appeared to attenuate only transaminase levels. Pentoxifylline did not prevent the development of oxidative stress. PMID- 19776591 TI - Effect of liver hypothermic preservation: exploration and protection. AB - BACKGROUND/AIMS: The principal aim of conservation is to maintain the viability of grafts. This requires the addition of a cellular protector allowing better conservation of the graft. The aim of this work is to evaluate the effect of trimetazidine (TMZ) addition to Wistar rat livers conserved in Krebs-Henseleit solution, compared to the livers preserved only in Krebs-Henseleit solution (24 h at 4 degrees C). METHODS: 40 Wistar female rats divided into 5 groups were used: the first group consists of nonpreserved livers, the second consists of livers preserved only in the Krebs-Henseleit solution, and the other 3 groups consist of livers preserved in Krebs solution with different concentrations of TMZ added (16.5, 49.5 and 165 microg/ml). RESULTS: The obtained results show an improvement in the state of the liver in the presence of a high concentration of TMZ, which approaches normal physiological conditions. We note a clear diminution of transaminase activities, as well as an amelioration in metabolic capacities of the liver if the mitochondrial esterase pathway is supported in Wistar rats by a reduction of histological injuries. CONCLUSION: A TMZ concentration of 165 microg/ml clearly restored the metabolic capacities of the liver. Indeed, TMZ limited the appearance of necrotic areas and almost suppressed apoptotic cells. PMID- 19776592 TI - Should we customize fetal growth standards? AB - Several maternal and fetal physiological characteristics account for a substantial proportion of the variation in birth weight. These characteristics can be used to calculate an individualized optimal birth weight and to adjust or 'customize' the birth weight standard. Customized birth weight standards improve the distinction between constitutional and pathological smallness, and there is evidence that this finding can be extrapolated into the fetal period to evaluate intrauterine growth, but further studies are required to evaluate and quantify the effectiveness of customized versus conventional charts in improving the diagnosis of pathological smallness before birth. PMID- 19776593 TI - Acute behavioral effects of intrapleural OK-432 (Picibanil) administration in preterm fetal sheep. AB - OBJECTIVE: To develop a model to study the fetal effects of intrapleural infusion of OK-432 (Picibanil), a pleurodesis agent derived from killed Gram-positive streptococci. METHODS: OK-432 (0.1 mg, n = 5), or normal saline (n = 5) were infused over 20 min into the pleural space of chronically instrumented preterm fetal sheep at 0.7 gestation. Fetal physiological parameters, including breathing and nuchal activity were monitored in utero from 6 h before infusion until 12 h afterward, and fetuses were killed after 7 days recovery. RESULTS: OK-432 was associated with transient suppression of fetal EEG activity, breathing and body movements from 3-6 h after infusion. Hypotension and hypoxia did not occur. At postmortem, local pleural adhesions were seen around the site of OK-432 infusion but not in saline treated fetuses. CONCLUSIONS: Intrapleural administration of OK 432 is associated with marked but transient fetal behavioral effects. This model will enable preclinical investigation of the neural and cardiovascular safety of OK-432 at a clinical relevant stage of development. PMID- 19776594 TI - Improving enrichment of circulating fetal DNA for genetic testing: size fractionation followed by whole gene amplification. AB - OBJECTIVE: Among the pitfalls of using cell-free fetal DNA in plasma for prenatal diagnosis is quality of the recovered DNA fragments and concomitant presence of maternal DNA (>95%). Our objective is to provide alternative methods for achieving enrichment and high-quality fetal DNA from plasma. METHODS: Cell-free DNA from 31 pregnant women and 18 controls (10 males and 8 females) were size separated using agarose gel electrophoresis. DNA fragments of 100-300, 500-700 and 1,500-2,000 bp were excised and extracted, followed by whole genome amplification (WGA) of recovered fragments. Levels of beta-globin and DYS1 were measured. RESULTS: Distribution of beta-globin size fragments was similar among pregnant women and controls. Among control male cases, distribution of size fragments was the same for both beta-globin and DYS1. Among maternal cases confirmed to be male, the smallest size fragment (100-300 bp) accounted for nearly 50% (39.76 +/- 17.55%) of the recovered DYS1-DNA (fetal) and only 10% (10.40 +/- 6.49%) of beta-globin (total) DNA. After WGA of plasma fragments from pregnant women, DYS1 sequence amplification was best observed when using the 100 300 bp fragments as template. CONCLUSIONS: Combination of electrophoresis for size separation and WGA led to enriched fetal DNA from plasma. This novel combination of strategies is more likely to permit universal clinical applications of cell-free fetal DNA. PMID- 19776595 TI - Maternal serum activin a at 11-13 weeks of gestation in hypertensive disorders of pregnancy. AB - OBJECTIVES: To investigate whether the maternal serum concentration of activin A at 11-13 weeks of gestation in pregnancies that subsequently develop hypertensive disorders is different from those with a normal outcome and to examine whether any possible differences are related to uterine artery pulsatility index (PI), serum pregnancy-associated plasma protein A (PAPP-A) and serum tumor necrosis factor-alpha receptor-1 (TNF-R1). MATERIAL AND METHODS: Serum activin A, TNF-R1, PAPP-A and uterine artery PI were determined in a case-control study of 126 cases that developed preeclampsia, 88 that developed gestational hypertension and 214 controls. RESULTS: In preeclampsia, compared to controls, uterine artery PI, serum activin A and serum TNF-R1 were higher and serum PAPP-A was lower. In gestational hypertension, compared to controls, serum activin A was higher but uterine artery PI, serum PAPP-A and serum TNF-R1 were not significantly different. There were no significant associations between serum activin A and either uterine artery PI or serum TNF-R1 in either the hypertensive groups or the controls. DISCUSSION: The data do not support the hypothesis linking activin A with impaired trophoblastic invasion of the maternal spiral arteries, placental hypoxia and the release of cytokines which in turn cause endothelial dysfunction and the development of the clinical symptoms of the disease. PMID- 19776596 TI - Differential expression and activity of 11beta-hydroxysteroid dehydrogenase in human placenta and fetal membranes from pregnancies with intrauterine growth restriction. AB - OBJECTIVES: To study the expression and the function of the 11beta-hydroxysteroid dehydrogenase enzyme 1 (11beta-HSD1) and 2 (11beta-HSD2) in placenta and the fetal membranes from pregnancies with intrauterine growth restriction (IUGR) and from controls. METHODS: Amnion, chorion, decidua and cotyledon were separated from placenta; mRNA was analyzed by TaqMan real-time technology and proteins by Western blot; enzyme activities were measured by the conversion of 3H-cortisol to 3H-cortisone and vice versa. RESULTS: Predominant mRNA expression (p < 0.001) was found for 11beta-HSD1 in chorion and for 11beta-HSD2 in decidua and cotyledon. In pregnancies with IUGR, 11beta-HSD1 was upregulated in chorion (mean DeltaCt 11beta-HSD:18S mRNA 193.5 vs. 103.0 in controls respectively, p < 0.05) and 11beta-HSD2 was downregulated in decidua (mean DeltaCt 11beta-HSD2:18S mRNA 0.18 vs. 15.88 in controls respectively, p < 0.05). 11beta-HSD1 protein levels were reduced in amnion and 11beta-HSD1 and 11beta-HSD2 oxidase activity in decidua and cotyledon were reduced from pregnancies with IUGR. CONCLUSION: Reduced synthesis or activity of 11beta-HSD1 or 2 in cases of IUGR is shown in some but not in all tissues. The local mRNA expression of 11beta-HSD1 in chorion may reflect a mechanism on the post-transcriptional gene regulation to stimulate the formation of cortisone in IUGR. To provoke increasing activity with oxidase stimulators could be a future therapy in cases of IUGR. PMID- 19776597 TI - First-trimester uterine artery Doppler and serum pregnancy-associated plasma protein-a in preeclampsia and chromosomal defects. AB - OBJECTIVE: We examined the potential value of the uterine artery pulsatility index (PI) in pregnancies with fetal aneuploidies and in those that developed preeclampsia (PE) with the aim of distinguishing between these complications in pregnancies with low pregnancy-associated plasma protein-A (PAPP-A). METHODS: Uterine artery PI and serum PAPP-A at 11-13 weeks were measured in 165 cases of PE, including 33 that required delivery before 34 weeks (early PE) and 132 with late PE, and in 301 cases with aneuploidies, including 200 with trisomy 21. Each case of aneuploidy and PE was matched with 4 unaffected controls. RESULTS: Serum PAPP-A was lower in early PE (0.58 multiples of the normal median, MoM) and in trisomy 21 (0.54 MoM), trisomy 18 (0.22 MoM) and Turner syndrome (0.51 MoM) - but not in late PE (0.90 MoM) - than in controls (1.01 MoM). Uterine artery PI was higher in early PE (1.52 MoM), late PE (1.20 MoM), trisomy 18 (1.20 MoM) and Turner syndrome (1.29 MoM) - but not in trisomy 21 (1.02 MoM) - than in controls (1.0 MoM). CONCLUSION: The uterine artery PI at 11-13 weeks may be useful in distinguishing between low PAPP-A due to trisomy 21 and early PE. PMID- 19776598 TI - Antenatal diagnosis and perinatal management of extremely giant fetal cervicopharyngeal teratoma resulting in impossible fetal intubation: a case report. AB - We report the case of an extremely large giant neck teratoma diagnosed on routine sonogram and confirmed by 3-D and 4-D sonography and MRI in a 19-year-old primigravida at 18 weeks. Rapid growth, polyhydramnios, premature contractions and premature rupture of membranes necessitated delivery at 28 weeks. Under general anesthesia, with a multidisciplinary team attendant, efforts by the otolaryngologist to establish an airway during an EXIT (ex utero intrapartum treatment) procedure failed as did subsequent attempts by the neonatologist, leading to an early neonatal death. Although a team approach will increase the likelihood of success in securing the airway during EXIT procedures, it cannot be a guarantor in cases of giant neck teratoma. PMID- 19776599 TI - Diamniotic omphalopagus conjoined twins in a diamniotic pregnancy. AB - OBJECTIVE: To present antepartal diagnostic findings including 2D/3D ultrasonography in a rare case of conjoined twins with diamniotic placentation. METHODS: In ultrasonographic examination, a communicating structure containing solid and cystic components together with cord vessels was found between the fetuses. The long axes of the fetuses were not parallel and they moved independently. Bladder configurations were absent. A fetal membrane from the chorioidal plate was imaged. RESULTS: Postmortem pathological examination revealed that the twins were conjoined by way of fused cloacal exstrophy and omphalocele, and the separate amniotic cavities communicated via a fused allantoic cavity. The placenta was monochorionic and diamniotic. DNA analysis of the twins and the placenta confirmed the monozygotic origin. CONCLUSION: Visualization of the amniotic membrane does not rule out conjoined twins in rare cases of monochorionic twin pregnancies. PMID- 19776600 TI - Prenatal diagnosis of oral cyst caused by foregut duplication. AB - Prenatal diagnosis of oral cystic lesions is rare but is reported more frequently. The diagnosis of sublingual cyst is important because of the potential for airway obstruction. A rare case of a foregut duplication cyst associated with unilateral sclerocorneal microphthalmia is reported. The differential diagnosis and the limitations of the prenatal ultrasound and the postnatal MRI are discussed. PMID- 19776601 TI - Prenatal three-dimensional images of proximal focal femoral deficiency produced by helical computed tomography. AB - INTRODUCTION: Proximal focal femoral deficiency (PFFD) is a rare skeletal disorder characterized by failure in development of the subtrochanteric region of the femoral shaft, with varying degrees of shortening of the proximal femur. OBJECTIVE: To investigate the potential of helical computed tomography as a prenatal diagnostic tool for bony abnormalities. CASE: A 37-year-old Japanese woman was referred to our hospital at 32 weeks of gestation for the evaluation of fetal growth restriction with short femurs. An ultrasound examination revealed the fetus to have short femurs bilaterally with normal echogenicity, and a normal facial profile. Assessment by 3D CT confirmed the absence of the femoral heads bilaterally and also revealed bilateral hip dislocations and oligodactyly of the right hand. The baby was delivered by cesarean section at 37 weeks of gestation, whereupon the diagnosis of PFFD was confirmed. CONCLUSION: Helical CT is a useful prenatal diagnostic alternative for bony abnormalities that is superior to the conventional sonographic approach. PMID- 19776602 TI - Partial mole with a diploid fetus: case study and literature review. AB - OBJECTIVE: To describe an extremely rare case of a partial hydatidiform mole with a normal fetus. The etiology and clinical management of this entity are discussed. METHOD: Case report. RESULTS: We describe a rare case of partial mole and a living fetus of diploid karyotype and biparental origin confirmed by flow cytometry and PCR techniques. No malformations were observed, beta-hCG levels were high (>100,000 mIU/ml) and persistent trophoblastic disease did eventually occur. CONCLUSION: A suspected partial mole on ultrasound with increased beta-hCG and a sonographically normal living fetus of a diploid karyotype poses a dilemma for clinical management. Termination of pregnancy is not indicated if the fetus is normal; in fact, continuation to birth is possible in nearly 60% of cases with no increase in maternal risks when the patient is closely monitored after birth until beta-hCG is negative. In the case presented, however, a spontaneous abortion occurred at 21 weeks' gestation, possibly as a result of the amniocentesis. PMID- 19776603 TI - Fetal adrenal cysts with hemorrhagic appearance may be cystic neuroblastomas. PMID- 19776605 TI - Expressive and receptive language characteristics in three-year-old preterm children with extremely low birth weight. AB - OBJECTIVE: The purpose of this study was to analyze the language characteristics of a group of extremely low birth weight (ELBW) children at 3 years of age and to compare these language results with a sample of full-term children with normal birth weight (FBW). METHODS: All children were judged to be free of any major physical, sensorial and neurological impairments and had a mental developmental index of >55 on the Bayley Scales of Infant Development. The Language was tested using the Reynell Developmental Language scales. RESULTS: There was a significant difference between the ELBW group and the FBW group regarding the receptive and all the expressive language characteristics. There was a significant correlation between the mental developmental index and the language scores in the ELBW as well as in the FBW group. CONCLUSION: According to the analysis of the language characteristics, the logopedic approach to 3-year-old children born with ELBW must be focused on receptive (comprehension of 'wh'-questions, passive sentences, inferencing skills and spatial prepositions) and expressive (defining words, expressing semantic relations) morphosyntactic abilities and linguistic conceptualization. These communication disorders appear unrelated to neurological or sensorial impairments, but can be partly explained by a decreased general mental functioning. PMID- 19776606 TI - Locomotor behavior and skeletal morphology of the odd-nosed monkeys. AB - The odd-nosed monkeys are different from other Old World monkeys in having suspensory and vertical climbing behaviors as a significant portion of their locomotor and positional behaviors. This study examined the relationship between their unique locomotor behaviors and skeletal morphology. The results indicated that odd-nosed monkeys differed from other Old World monkeys in aspects of their forelimb morphology and intermembral index, approaching the conditions seen in apes and overlapping with those of atelines. Rhinopithecus was also shown to be different from other odd-nosed monkeys in its skeletal morphology. PMID- 19776607 TI - Feeding outside the forest: the importance of crop raiding and an invasive weed in the diet of gallery forest ring-tailed lemurs (Lemur catta) following a cyclone at the Beza Mahafaly special reserve, Madagascar. AB - In January 2005, a cyclone hit southern Madagascar, including the Beza Mahafaly Special Reserve, disrupting the flowering/fruiting cycle of Tamarindus indica, leaving Lemur catta without its major food resource during reproductive periods. We studied two adjacent groups of L. catta during the late gestation period, and both groups ventured outside the reserve to feed. The Red group (RG) fed daily on cultivated sweet potato (Ipomoea batatas) leaves in a nearby field, and both groups consumed leaves and stems of the invasive terrestrial flowering herb Mexican prickly poppy (Argemone mexicana), growing outside the reserve. The Green group (GG) spent significantly more time feeding than did RG, and more time feeding inside the forest compared to outside. The members of RG spent half of their time feeding in the crops, and nearly half of their diet consisted of easy to-process sweet potato leaves. Additionally, RG defended and restricted GG's access to the crop territory. Of the two non-forest foods, A. mexicana leaves were higher in protein and most minerals (P, Mg, K and Na, but not Ca) and lower in fiber than sweet potato leaves, but sweet potato leaves were preferred by RG. L. catta is a markedly flexible primate with respect to diet, and switches to fallback foods from outside the forest during periods of low food availability. In the highly seasonal and unpredictable climate of southern Madagascar, such behavioral adaptations are important to the survival of this species. PMID- 19776608 TI - Habitual physical activity and physical fitness in older Japanese adults: the Nakanojo Study. AB - BACKGROUND: Optimal patterns of habitual physical activity to ensure healthy aging remain unclear because of measurement limitations; most investigators have used either subjective questionnaires, or accelerometer or pedometer measurements limited to a single week, despite evidence of both the limited reliability/validity of questionnaires and seasonal changes in activity patterns. OBJECTIVE: This study explored possible associations between indicators of physical fitness (walking ability, upper- and lower-extremity isometric strength, and static and dynamic balance) and yearlong pedometer/accelerometer assessments of the quantity and quality of habitual physical activity in ostensibly healthy older adults. METHODS: Subjects were 76 male and 94 female Japanese aged 65-84 years. Each participant wore a pedometer/accelerometer for 1 year; measurements included the average number of steps taken each day and the duration of activity at an intensity of >3 metabolic equivalents (METs). Compliance was good, the instrument being removed for intervals of >3 h on <5% of days; data for such intervals were excluded from analysis. At the year's end, traditional laboratory techniques assessed preferred and maximal walking speeds, peak handgrip force, peak knee extension torque, total body sway, and maximal functional reach. RESULTS: After controlling data for age and/or sex, lower-extremity function (walking speeds and knee extension torque) showed significant positive relationships with the daily step count and daily duration of activity at >3 METs, especially in individuals > or = 75 years of age. On the other hand, handgrip force and body sway were unrelated to pedometer/accelerometer measurements. Linear and exponential regressions showed positive associations between walking speeds and pedometer/accelerometer scores up to the observed maxima of 13,700 steps/day and 62 min/day at >3 METs. However, when data were categorized into quartiles, walking speeds were not significantly greater in persons exceeding 7,000-8,000 steps/day and/or 15-20 min/day at >3 METs. With a few exceptions, subjects meeting these levels of habitual activity had walking speeds above the threshold predicting the development of functional dependence. CONCLUSION: The present data suggest that fitness is well maintained in elderly people who take >7,000-8,000 steps/day and/or spend >15-20 min/day at >3 METs. Nevertheless, the direction of this association merits exploration by longitudinal prospective studies and/or randomized controlled trials. PMID- 19776609 TI - Which neuromuscular or cognitive test is the optimal screening tool to predict falls in frail community-dwelling older people? AB - BACKGROUND: The use of falls risk screening tools may aid in targeting fall prevention interventions in older individuals most likely to benefit. OBJECTIVE: To determine the optimal physical or cognitive test to screen for falls risk in frail older people. METHODS: This prospective cohort study involved recruitment from 213 day-care centers in Japan. The feasibility study included 3,340 ambulatory individuals aged 65 years or older enrolled in the Tsukui Ordered Useful Care for Health (TOUCH) program. The external validation study included a subsample of 455 individuals who completed all tests. Physical tests included grip strength (GS), chair stand test (CST), one-leg standing test (OLS), functional reach test (FRT), tandem walking test (TWT), 6-meter walking speed at a comfortable pace (CWS) and at maximum pace (MWS), and timed up-and-go test (TUG). The mental status questionnaire (MSQ) was used to measure cognitive function. The incidence of falls during 1 year was investigated by self-report or an interview with the participant's family and care staff. RESULTS: The most practicable tests were the GS and MSQ, which could be administered to more than 90% of the participants regardless of the activities of daily living status. The FRT and TWT had lower feasibility than other lower limb function tests. During the 1-year retrospective analysis of falls, 99 (21.8%) of the 455 validation study participants had fallen at least once. Fallers showed significantly poorer performance than non-fallers in the OLS (p = 0.003), TWT (p = 0.001), CWS (p = 0.013), MWS (p = 0.007), and TUG (p = 0.011). The OLS, CWS, and MWS remained significantly associated with falls when performance cut-points were determined. Logistic regression analysis revealed that the TWT was a significant and independent, yet weak predictor of falls. A weighting system which considered feasibility and validity scored the CWS (at a cut-point of 0.7 m/s) as the best test to predict risk of falls. CONCLUSION: Clinical tests of neuromuscular function can predict risk of falls in frail older people. When feasibility and validity were considered, the CWS was the best test for use as a screening tool in frail older people, however, these preliminary results require confirmation in further research. PMID- 19776610 TI - Relationship between preterm labor and thrombophilic gene polymorphism: A prospective sequential cohort study. AB - OBJECTIVE: Premature labor is still the leading cause of infant mortality and morbidity worldwide. Multiple etiological factors including genetics and environment are held responsible for preterm birth. However, scientific data regarding the link between premature birth and genetics are limited. SUBJECTS AND METHODS: In this study, we included 50 women who had premature labor (group 1) but did not have any known risks for a premature delivery such as uterine anomaly, polyhydramnios, hypertension, and diabetes mellitus, and another 50 healthy women who had term labor as control (group 2). We compared these two patient groups for MTHFR C677T, MTHFR C1298T, prothrombin 20210A, factor V and ACE polymorphisms. RESULTS: We could not detect a statistical significance between groups for polymorphisms in MTHFR C677T, MTHFR C1298T, prothrombin 20210A, factor V and ACE polymorphisms. CONCLUSION: We investigated the relationship between premature and term labor and thrombophilic gene polymorphism. However, we found no associations with premature or term labor with the parameters included. PMID- 19776611 TI - Analysis of nitric oxide metabolism as a placental or maternal factor underlying the etiology of pre-eclampsia. AB - BACKGROUND: Defective nitric oxide (NO)-mediated vasodilation is widely regarded as an underlying cause of hypertension in pre-eclampsia, although there are also arguments against this hypothesis. METHODS: We examined both the mRNA levels and the presence of a Glu298Asp substitution in the NO synthase (NOS) gene, as well as the NO metabolite concentration, in placentas and maternal sera from women with pre-eclampsia and in normotensive pregnant controls (25-40 vs. 24-41 weeks of gestation). RESULTS: Pre-eclamptic and control placentas did not show any significant differences in their NO metabolite levels or their NOS expression levels as measured by quantitative RT-PCR. In addition, we did not find any association between pre-eclampsia and the occurrence of the Glu298Asp amino acid substitution in the NOS gene. In contrast, high maternal circulating NO metabolites were evident in severe pre-eclampsia (p < 0.0001). Although a positive correlation between circulating NO metabolites and blood pressure was not observed, uterine artery resistance measured by ultrasound was found to positively correlate with the maternal NO levels. CONCLUSIONS: Our current data suggest that an altered placental NOS pathway is unlikely to be the primary cause of pre-eclampsia and that the activation of this pathway is possibly in response to maternal symptoms. PMID- 19776612 TI - Identification of factors influencing the decision-to-delivery interval in emergency caesarean sections. AB - BACKGROUND: In a life-threatening context, the American College of Obstetrics and Gynecology and the Royal College of Obstetrics and Gynaecology recommend a maximum delay of 30 min between the decision to perform an emergency caesarean and the infant's birth. Our objectives were to estimate the rate of prolonged intervals and identify the factors influencing the decision-to-delivery interval. METHODS: All women who had given birth at Saint-Etienne University Hospital by a non-prophylactic caesarean section between September 1 and November 1, 2007 were included in a prospective cohort study. A linear regression analysis was performed to identify the factors influencing the decision-to-delivery interval. RESULTS: 68 women were included in the study. Regardless of the degree of emergency, the decision-to-delivery interval exceeded the recommended interval in 50% of the cases. In extremely urgent caesarean sections, the optimal interval of 15 min was exceeded in 85.7% of cases. We found that two factors contributed to delayed patient care: urgent and extremely urgent caesareans and hospitalization in a pathological pregnancy unit. This delay leads to more paediatric reanimations. CONCLUSION: This study highlights the difficulty to reach the recommended target interval. One solution is to improve the identification of the degree of urgency and the communication between the various members of the healthcare team. PMID- 19776613 TI - The replacement of cytogenetic analysis by direct chorionic villi sampling preparation with quantitative fluorescence PCR. AB - AIM: The aim of this study is to assess the replacement of chromosomal analysis of chorionic villi (CV) direct preparation samples (DIR) by quantitative fluorescence PCR (QF-PCR) and to determine its advantages in routine prenatal diagnosis. METHODS: From a total of 4,020 CV samples, rapid results were obtained either by conventional cytogenetic analysis of DIR in 2,770 samples, or by QF-PCR analysis in 1,250 samples. The final results were given after long-term culture (LTC). RESULTS: The frequencies of unbalanced fetal karyotypes were not significantly different, being 4.8% by DIR-LTC and 4.3% by QF-PCR-LTC. No false negative or false-positive results were obtained from either approach. CONCLUSION: QF-PCR can replace chromosomal analysis of CV-DIR in most cases during routine prenatal diagnosis, requiring smaller CV samples and being more labor effective. Coupled with LTC, it is a robust diagnostic approach with high predictive value for the most frequent fetal trisomies. PMID- 19776614 TI - Evaluation of estrogen treatment in an immunodeficient mouse endometriosis model. AB - BACKGROUND/AIMS: Endometriosis is known to be an estrogen-dependent disease. However, only a few studies have analyzed the effect of estrogen treatment in mice xenotransplanted with human endometrium. The objective of this study was to adapt a previously developed heterologous murine model to the study of estrogens and test the impact of estrone treatment on endometriosis development. METHODS: Human proliferative endometrium was xenotransplanted into the peritoneal cavity of castrated immunodeficient mice. These mice were treated with estrogens by means of subcutaneous estrone-releasing pellets. The effect of estrone on estradiol level, uterine histology and endometriosis development was evaluated after 21 days. RESULTS: Bioactivity of estrone pellets and their metabolization into estradiol were demonstrated. However, there was no impact on endometriosis development (no difference in lesion number, weight, size or fluorescence). This lack of response was not due to absence of estrogen receptor expression, since strong expression was found in all lesions harvested. Surprisingly, castrated nontreated mice presented with lesions showing high proliferative activity, similar to lesions found in treated mice (around 30%). CONCLUSION: The high proliferation observed in lesions recovered from ovariectomized nontreated mice questions the utility of using estrogens in heterologous murine models. PMID- 19776615 TI - Metastatic uterine cervical cancer originating in the lung: a case report. AB - We report a case of primary pulmonary adenocarcinoma which metastasized to the uterine cervix. A 69-year-old postmenopausal Japanese female was admitted to our hospital because of general fatigue and atypical genital bleeding. Four years before, she had undergone video-assisted thoracoscopic right upper lobectomy, for primary lung cancer (adenocarcinoma), stage IIIb, pT3N1M0. Gynecologic investigation showed a cauliflower-like tumor in the uterine cervix and parametrial invasion towards the bilateral pelvic wall. Metastasis of extragenital carcinoma to the cervix uteri is rare. Most such reported cases originated in the breast and gastrointestinal tract. In this case, cervical biopsy specimens were revealed to be adenocarcinomatous, similar in pathological features to the previously resected lung cancer. Immunohistochemical staining was positive for thyroid transcription factor-1 and pulmonary surfactant apoprotein A and negative for CA125 and thyroglobulin. Although rare, the respiratory tract should be considered as a possible primary site of uterine cervical metastatic carcinoma. PMID- 19776617 TI - Clarification required for the definition of hepatitis B virus subgenotypes C1 and C2. PMID- 19776616 TI - Epidemiology of human influenza A and B viruses in Myanmar from 2005 to 2007. AB - OBJECTIVES: To perform genetic analysis of influenza A and B viruses in Myanmar from 2005 to 2007 and to determine the prevalence of amantadine-resistant influenza A viruses. METHODS: Phylogenies of the HA and NA genes were analyzed and mutations in M2 that confer resistance to amantadine were screened. RESULTS: Influenza in Myanmar exhibited seasonality, which coincided during the rainy season from June to August. Out of 2,618 samples, 76 influenza A and 132 influenza B viruses were isolated. Phylogenetic analysis showed that in 2005, 11 A/H1N1 isolates formed one cluster with A/Solomon Islands/3/2006 and were amantadine-sensitive strains. One A/H3N2 isolate was amantadine-resistant harboring S31N mutation in M2 and possessing S193F and D225N substitutions in HA (clade N), similar to A/Wisconsin/67/2005. No viruses were isolated in 2006 due to sample storage failure. In 2007, all 64 A/H3N2 isolates were amantadine resistant and similar to A/Brisbane/10/2007. For influenza B, 3 Yamagata-lineage and 17 Victoria-lineage isolates were detected in 2005 and 112 Victoria-lineage viruses were isolated in 2007. All Victoria-lineage isolates were reassortants possessing NA derived from the Yamagata lineage. CONCLUSION: Continuous surveillance in tropical countries is important for elucidating the seasonality of influenza and determining the molecular characteristics of circulating strains. PMID- 19776618 TI - Genetic and nutritional determinants of the metabolic syndrome: introduction. PMID- 19776619 TI - The metabolic syndrome: definitions, prevalence and management. AB - The metabolic syndrome (MetS) refers to the clustering of various metabolic risk factors that include abdominal obesity, dyslipidemia, hypertension, and hyperglycemia. It is now well known that it is associated with an increased risk of cardiovascular disease (CVD) and of type 2 diabetes. The increasing prevalence of the MetS, associated with the substantial progression of obesity and diabetes, is therefore an important public health concern. Over the years, several definitions for the MetS have been proposed by major scientific associations. Those definitions differ somewhat in their criteria and threshold values but generally all agree on the essential components of the syndrome. The proposed definitions are intended to help identify individuals at increased long-term risk of CVD, who could benefit from early prevention. The diagnosis of the MetS should be used concurrently with standard predicting algorithms, such as the Framingham Risk Score and the Diabetes Predicting Model, which better predict short-term risks. The management of the MetS should emphasize therapeutic lifestyle modifications--weight loss, increased physical activity, healthy diet--as the first-line therapy. If the short-term risk of CVD or diabetes is high, specific risk factors should be monitored more closely according to established guidelines and drug therapy may be appropriate. PMID- 19776620 TI - Nutritional determinants of the metabolic syndrome. AB - The metabolic syndrome has attracted interest because of its relevance to major contemporary chronic diseases associated with inactive lifestyles and the abundance of food, both of which have resulted in a way of life which challenges our genetic makeup. Changing the fuel mix by the introduction of more monounsaturated and polyunsaturated fatty acids, a reduction in saturated fatty acids, an increase in fiber, and the use of low glycemic index slow-release carbohydrate foods may make a difference, as will increasing the amount of vegetable protein and plant foods such as nuts, rich in monounsaturated fatty acids and antioxidant systems. Nevertheless, these supportive measures will be overwhelmed in the absence of calorie restriction combined with adequate energy expenditure. This situation appears to be one where the subsidiary solutions are complex and the central issue is simple. PMID- 19776621 TI - Uncloaking the genetic determinants of metabolic syndrome. AB - The metabolic syndrome (MetS) is a commonly encountered cluster of clinical phenotypes, including central obesity, hypertension, hyperglycemia, and dyslipidemia. Identifying genetic determinants of MetS will lead to better understanding of its progression and pathogenesis. To further the knowledge of MetS it is important to not only study the candidate genes for each individual component but to also investigate patients with rare monogenic disorders who express a cluster of the phenotypes commonly observed in MetS, however defined. In addition, certain genetic variants have been observed to increase or decrease the risk of developing the entire syndrome. It is apparent that only through complete understanding of the gene-gene, gene-gender and gene-nutrition interactions underlying MetS, will it become possible to determine or minimize the principal complications, namely type 2 diabetes and cardiovascular disease. In this review, we focus on the current evidence for common gene polymorphisms that predispose to or protect from the development of MetS. PMID- 19776622 TI - Dietary modulators of peroxisome proliferator-activated receptors: implications for the prevention and treatment of metabolic syndrome. AB - In its simplest form, obesity is a state characterized by nutrient overabundance leading to hypertrophy of storage cells in white adipose tissue and the deposition of excess lipids into key metabolic regions, such as skeletal muscle and liver. Ever so steadily, this condition begins to manifest itself as progressive insulin resistance and thus ensues a myriad of other chronic diseases, such as type 2 diabetes, cardiovascular disease, and hypertension, which all fall into the realm of the metabolic syndrome. To offset imbalances in nutrient availability, however, it appears that nature has developed the peroxisome proliferator-activated receptors (PPARs), a family of endogenous lipid sensors that adeptly modulate our rates of macronutrient oxidation and regulate the systemic inflammatory response, which itself is tightly linked to the development of obesity-induced chronic disease. By understanding how PPARs alpha, delta and gamma act jointly to maintain metabolic homeostasis and reduce the chronic inflammation associated with obesity, we may one day discover that the machinery needed to defeat obesity and control the devastating consequences of the metabolic syndrome have been with us the entire time. PMID- 19776623 TI - Gene-nutrient interactions in the metabolic syndrome. AB - The metabolic syndrome (MetS) is a very common disease associated with an increased risk of type 2 diabetes mellitus and cardiovascular disease. The diverse clinical characteristics of the MetS illustrate the complexity of the disease process, which involves several dysregulated metabolic pathways. Thus, multiple genetic targets must be involved in the pathogenesis and progression of the disease. Research indicates a major role for genetic susceptibility to the MetS. However, the human genome has not changed markedly in the last decade but the prevalence of the condition has increased exponentially, illustrating the importance of gene-environmental interactions. Dietary fat is an important environmental factor which can modify the development of the MetS. Genetic background can interact with habitual dietary fat composition, affecting predisposition to the MetS. Recent research indicates that currently ineffective therapeutic dietary recommendations may require a 'personalised nutrition' approach, wherein the genetic profile may determine the responsiveness of patients to specific dietary fatty acid interventions. Understanding the biological impact of gene-nutrient interactions will provide a key insight into the pathogenesis and progression of diet-related polygenic disorders, including the MetS. This review will explore the interactions between genetic background and dietary exposure/nutritional therapy. PMID- 19776624 TI - Transcriptional profiling of chromosome 17 quantitative trait Loci for carbohydrate and total calorie intake in a mouse congenic strain reveals candidate genes and pathways. AB - BACKGROUND/AIMS: The genetic basis for ingestive behaviors is virtually unknown. Quantitative trait loci (QTLs) for carbohydrate and energy intake map to mouse chromosome 17 and were previously confirmed by a congenic strain bearing CAST/Ei (CAST) donor segment on the C57BL/6J (B6) background. METHODS: We used microarray technology to facilitate gene identification. Gene expression was compared between the B6.CAST-17 (BC-17) congenic and B6 strains in two diets: (1) chow, and (2) carbohydrate/protein vs. fat/protein. RESULTS: Within the QTL and unique to macronutrient selection, Agpat1 (acylglycerol-3-phosphate O-acyltransferase 1) was differentially expressed in hypothalamus. Irrespective of diet, the gene with the highest fold difference in congenic mice was trefoil factor 3 (Tff3) in liver. Several genes involved in fat metabolism were decreased in carbohydrate preferring congenic mice, while genes associated with carbohydrate metabolism were increased. In particular, the glyoxalase pathway was enhanced including Glo1, Glo2, and dLDH. Higher expression of Glo1 mRNA in BC-17 congenic mice corresponded to increased protein expression revealed by Western blot, and to higher GLO1 activity in blood. CONCLUSION: These genes represent new candidates for nutrient intake phenotypes. We propose that increased GLO1 in the BC-17 strain supports its need to protect against dietary oxidants resulting from high carbohydrate intake. PMID- 19776625 TI - A transgenic mouse model for gene-nutrient interactions. AB - Diets or nutritional supplements contain many nutrients and other components that may interact, which adds a layer of complexity to their evaluation. A well controlled experimental model that can eliminate or minimize the confounding factors of diet is critical for addressing nutrient-gene interactions. The newly generated fat-1 transgenic mouse was genetically engineered to carry a gene, namely fat-1, from the round worm Caenorhabditis elegans and is capable of converting n-6 to n-3 fatty acids (which is naturally impossible in mammals), leading to an increase in n-3 fatty acid content with a balanced n-6/n-3 fatty acid ratio in all tissues, independent of diet. Recent studies using this model indicate that balancing the tissue n-6/n-3 ratio could exert a significant effect on gene expression. The fat-1 mouse model allows carefully controlled studies to be performed in the absence of restricted diets, which can create confounding factors that limit studies of this nature. PMID- 19776626 TI - Polymorphisms in methionine synthase, methionine synthase reductase and serine hydroxymethyltransferase, folate and alcohol intake, and colon cancer risk. AB - BACKGROUND/AIMS: We examined associations among folate and alcohol intake, single nucleotide polymorphisms (SNPs) in genes involved in one-carbon metabolism, and colon cancer risk. METHODS: Colon cancer cases (294 African-Americans and 349 whites) were frequency matched to population controls (437 African-Americans and 611 whites) by age, race and sex from 33 North Carolina counties from 1996 to 2000. Folate and alcohol intakes were collected by dietary interview. Five SNPs were genotyped using DNA from whole blood: SHMT C1420T; MTRR A66G; MTR A2756G, and the previously-reported MTHFR C677T and MTHFR A1298C. Adjusted odds ratios (OR) and 95% CI were calculated using logistic regression. RESULTS: An inverse association was observed for SHMT TT genotype as compared to CC genotype in whites (OR = 0.6, 95% CI = 0.4, 1.0), but not in African Americans. Inverse associations were observed for high folate intake in individuals carrying 0 or 1 variant allele [OR 0.2 (95% CI 0.06-0.8) for African-Americans; OR 0.2 (95% CI 0.1-0.6) for whites] compared to low folate intake. Modest interactions between these SNPs and alcohol or folate intakes were observed. CONCLUSIONS: Our results are consistent with other findings and provide needed data on these associations among African-Americans. PMID- 19776627 TI - Effect of the PPAR-Alpha L162V polymorphism on the cardiovascular disease risk factor in response to n-3 polyunsaturated fatty acids. AB - BACKGROUND: Dietary n-3 polyunsaturated fatty acids (PUFAs) decrease the risk of cardiovascular disease (CVD). Yet, genetic variations of the gene encoding the peroxisome proliferator-activated receptor-alpha (PPARalpha) can also modulate CVD risk factors. Since fatty acids, including n-3 PUFAs, are natural ligands of PPARalpha, a gene-diet interaction effect could be observed. AIMS: To examine whether n-3 PUFA- induced changes in CVD risk factors are influenced by the PPARalpha L162V polymorphism. METHODS: Fourteen men, carriers of the V162 allele and 14 L162 homozygotes, were matched according to age and body mass index. Subjects followed, for 8 weeks, a low-fat diet and then were supplemented daily with 5 g of fish oil for 6 weeks. RESULTS: Baseline characteristics were similar for both genotype groups. Independently of the genotype, the supplementation was associated with a significant decrease in plasma triacylglycerol and fasting glucose concentrations, diastolic blood pressure, and with an increase in total apolipoprotein B concentrations. The extent of the decrease in plasma triacylglycerol concentrations was comparable for both genotype groups (p < 0.03). A significant genotype-by-diet interaction effect was observed for plasma C-reactive protein concentrations (p = 0.01). CONCLUSIONS: The PPARalpha L162V polymorphism may contribute to the interindividual variability in the CVD risk factor response to n-3 PUFAs. PMID- 19776628 TI - Epigenetic manifestations in diet-related disorders. AB - Epigenetic phenomena are changes in phenotype that are due to resetting of gene expression under the influence of the environment or genetic factors without changing the DNA sequence. Usually this resetting occurs at a certain stage in life and remains fixed thereafter. In humans, evidence for epigenetic involvement in diet-related complex traits and disorders is accumulating. The fetal origins theory indicates that nutrition can influence the later life risk for certain common disorders like the metabolic syndrome. In parent-of-origin effects, the risk for a common disorder like type I diabetes depends on the sex of the parent who transmits genetic risk factors. Interestingly, both dietary and genetic factors can exert their epigenetic influence over several generations. Imprinting, i.e. silencing of one copy of an autosomal pair of genes, can be part of the mechanism pointing to the importance of DNA methylation. In addition, chromatin modifications have been shown to be involved in epigenetic manifestations. The intriguing possibility that diet may influence the direction and extent of epigenetic changes opens new ways for prevention or treatment of common disorders. At the same time, maternal nutrition might be used to actively direct fetal development with consequences for later life performance such as cognitive abilities. More knowledge on those novel applications is needed. This will in part come from novel strategies to map the epigenomic regions, allowing the identification of more genes involved in epigenetics and allowing the study of their response to nutrition. PMID- 19776629 TI - Genetic polymorphisms of tumor necrosis factor-alpha modify the association between dietary polyunsaturated fatty acids and plasma high-density lipoprotein cholesterol concentrations in a population of young adults. AB - BACKGROUND/AIMS: Genetic polymorphisms in tumor necrosis factor-alpha (TNF-alpha) modify the association between polyunsaturated fatty acids (PUFA) and plasma high density lipoprotein (HDL) cholesterol in a population with type 2 diabetes. The objective of this study was to determine whether this gene x diet interaction is observed in a diabetes-free population and whether it is due to n-3 or n-6 PUFA. METHODS: Subjects (n = 595) were aged 20-29 years and genotyped for the TNF-alpha -238G>A and TNF-alpha -308G>A polymorphisms. Diet was assessed using a food frequency questionnaire. Subjects were grouped as having no minor A allele at both the -238 and -308 positions (0/0), or one minor A allele at either the -238 (1/0) or the -308 (0/1) position. RESULTS: TNF-alpha genotypes modified the association between dietary PUFA and HDL-cholesterol concentrations (p = 0.04 for interaction). Among individuals with the 0/0 genotype, total PUFA was positively associated with HDL-cholesterol in both men (p = 0.008) and women (p = 0.03), and for both n-6 (p = 0.004) and n-3 (p = 0.04) PUFA. However, an inverse relationship was observed among men carrying the 1/0 genotype (p = 0.005). CONCLUSION: These findings demonstrate that TNF-alpha genotypes modify the association between dietary PUFA and HDL-cholesterol and provide further evidence that inflammation is involved in the reverse cholesterol transport. PMID- 19776630 TI - Public health genomics and genetic test evaluation: the challenge of conducting behavioural research on the utility of lifestyle-genetic tests. AB - Human genetics research is increasingly concerned with multifactorial conditions such as diabetes and heart disease, which are influenced not only by genetic but also lifestyle factors such as diet and smoking. Although the results of 'lifestyle-genetic' tests using this information could conceivably motivate lifestyle changes in the future, companies are already selling such tests and related lifestyle advice commercially. Some academics and lobby groups have condemned the companies for selling these tests in advance of scientific support. Others are concerned that the tests may not motivate lifestyle improvements, instead causing distress in people receiving adverse test results and complacency in those receiving reassuring results. There is currently no regulatory oversight of genetic test utility, despite consensus in the Public Health Genomics community that clinical utility (including psychological and behavioural impact) of all emerging genetic tests should be evaluated before being introduced for individual use. Clearly, empirical data in this area is much needed, to inform understanding of the potential utility of these tests, and of whether stricter regulation of commercial exploitation is needed. In this article, we review the current situation regarding lifestyle-genetic tests, and discuss the challenges inherent in conducting this kind of behavioural research in the genomics era. PMID- 19776631 TI - Effect of dietary calcium and dairy proteins on the adipose tissue gene expression profile in diet-induced obesity. AB - BACKGROUND/AIMS: Calcium and dairy proteins have been postulated to explain why the intake of dairy products correlates inversely with body mass index in several populations. We have shown that a high-calcium diet with whey protein attenuates weight gain and now we describe the effects of this diet on adipose tissue gene expression. METHODS: Nine-week-old C57Bl/6J mice were divided into two groups (n = 10/group). The control diet was a standard high-fat diet (60% of energy) low in calcium (0.4%). The whey protein diet was a high-calcium (1.8%), high-fat diet with whey protein. After the 21-week treatment, adipose tissue transcript profiling (2 mice/group) was performed using Affymetrix Mouse Genome 430 2.0. RESULTS: The high-calcium diet with whey protein altered the expression of 129 genes (+/- 1.2 fold). Quantitative RT-PCR analysis confirmed the significant up regulation of Adrb3 (p = 0.002) and leptin (p = 0.0019) in the high-calcium whey group. Insulin and adipocytokine signaling pathways were enriched among the up regulated genes and the fatty acid metabolism pathway among the down-regulated genes. CONCLUSIONS: High-calcium diet with whey protein significantly modifies adipose tissue gene expression. These preliminary findings reveal that targets of a high-calcium diet with whey protein include genes for Adrb3 and leptin, and help to explain how the intake of dairy products might attenuate obesity. PMID- 19776632 TI - Influence of CYP11B2 gene polymorphism on the prevalence of hypertension and the blood pressure in Japanese men: interaction with dietary salt intake. AB - AIMS: CYP11B2 gene encodes a key enzyme for the production of aldosterone. Our aim is to investigate the association of -344T/C polymorphism with hypertension in Japanese men. The interaction between genotypes and dietary salt intake was also considered. METHODS: Three hundred and ten Japanese male workers participated in this study. Daily salt intake was calculated from a food frequency questionnaire. Melting curve analysis was used to determine CYP11B2 genotypes. RESULTS: There was a significant association between the CT + TT genotype and higher prevalence of hypertension (odds ratio: 3.03; p = 0.014). The association presented in a recessive manner and was strongest in the high-salt intake group (odds ratio: 9.44; p = 0.049). Only in the high-intake group, systolic blood pressure (SBP) was significantly higher in the CT + TT group than in the CC group (p = 0.038). The SBP had a positive correlation with salt intake in the CT + TT group (p for linear trend = 0.021), but not in the CC group (p for interaction = 0.011). CONCLUSIONS: CYP11B2 gene -344C/T polymorphism affects the risk of hypertension in Japanese men and high-salt intake levels strengthen this association. This gene-diet interaction warrants further study to elucidate the efficacy of salt restriction as an antihypertensive therapy in different genotypes. PMID- 19776633 TI - Abstracts of the 2nd Congress of the International Society of Nutrigenetics/Nutrigenomics (ISNN). October 6-8, 2008. Geneva, Switzerland. PMID- 19776634 TI - Folate nutritional genetics and risk for hypertension in an elderly population sample. AB - BACKGROUND/AIMS: 118 elderly participants (65-90 years) were assessed for any relationship between folate, related genes and hypertension. METHODS: Six B vitamin-related SNPs were genotyped in 80 normotensive and 38 hypertensive subjects. RESULTS: Of six polymorphisms (677C>T-MTHFR, 1298A>C-MTHFR, 80G>A-RFC, 2756A>G-MS, 66A>G- MSR, 19bpDHFR and 1561C>T-GCPII), only 677C>T-MTHFR was a significant risk for hypertension: OR 1.89; 95% CI 1.07-3.32 (chi2 p = 0.038). Additionally, hypertensive subjects had a significantly lower intake of dietary folate than normotensive individuals (p = 0.0221), although this did not markedly alter blood metabolite levels. Several significant linear associations between dietary folate and related blood metabolites were found in normotensive subjects (p < 0.001 for Hcy, red cell and serum folate) and were as predicted on an a priori basis -- generally weaker associations existed in hypertensive subjects (p < 0.05 for serum folate). This was true for data examined collectively or by genotype. Multiple-regression analysis for diastolic or systolic blood pressure showed significant interaction for gender and folate intake (p = 0.014 and 0.019, respectively). In both cases this interaction occurred only in females, with higher folate intake associated with decreased blood pressure. Regressing diastolic blood pressure and 677C>T-MTHFR genotype showed significance (males; p = 0.032) and borderline significance (all subjects). CONCLUSION: Dietary folate and 677C>T-MTHFR genotype may modify blood pressure. PMID- 19776635 TI - Genome-wide analysis of dietary eicosapentaenoic acid- and oleic acid-induced modulation of colon inflammation in interleukin-10 gene-deficient mice. AB - BACKGROUND/AIMS: Dietary n-3 polyunsaturated fatty acids can reduce inflammation via a range of mechanisms. This study tested the effect of dietary eicosapentaenoic acid (EPA) on intestinal inflammation using interleukin-10 gene deficient (Il10(-/-)) mice. METHODS: At 35 days of age, 12 weaned Il10(-/-) and 12 C57 mice were randomly assigned to one of two modified AIN-76A diets, supplemented with 3.7% purified ethyl esters of either EPA (n-3) or oleic acid (OA, control). To identify genes relevant to colon inflammation, transcription profiling (microarrays and qRT-PCR) and bioinformatic analyses were used. RESULTS: In this study, dietary EPA reversed the decrease in colon fatty acid beta-oxidation gene expression observed in OA-fed Il10(-/-) compared to C57 mice. Il10(-/-) mice fed the OA diet showed decreased expression of antioxidant enzyme genes, as well as those involved in detoxification of xenobiotics, compared to C57 mice on the same diet. In contrast, dietary EPA increased the expression of these genes in Il10(-/-) mice. CONCLUSIONS: These data indicate that dietary EPA induced endogenous lipid oxidation which might have a potential anti-inflammatory effect on colon tissue. This is supported by the activation of the Ppara gene that regulates the expression of pro-inflammatory and immunomodulatory genes and proteins. PMID- 19776636 TI - Change of epigenetic control of cystathionine beta-synthase gene expression through dietary vitamin B12 is not recovered by methionine supplementation. AB - BACKGROUND/AIMS: Vitamin B12 (B-12) is an essential cofactor for methionine synthase, and methionine is critical for the methylation of various biological molecules including DNA. Whether changes in B-12 levels can alter specific gene expression through DNA methylation and whether dietary methionine has any effect on general DNA methylation status still remains controversial. METHODS: We raised severely B-12-deficient rats as well severely-B-12 deficient rats but supplemented with 5% methionine. mRNA levels of methionine cycle-related enzymes were analyzed. RESULTS: Gene expression patterns changed under B-12-deficient conditions but were recovered by dietary methionine supplementation to B-12 deficient rats. However, cystathionine beta-synthase mRNA levels, which had decreased under B-12-deficient conditions, did not recover with supplementary dietary methionine. The CpG island of the cystathionine beta-synthase promoter was hypomethylated in B-12-deficient rats, and showed no recovery after methionine addition. CONCLUSIONS: Dietary B-12 can affect epigenetic machinery by regulating DNA methylation status and dietary methionine may have small effects on DNA methylation. PMID- 19776637 TI - Interaction between familial history of obesity and fat intakes on obesity phenotypes. AB - AIM: To evaluate whether familial history of obesity (FHO) interacts with dietary fat intake (DFI) on obesity-related phenotypes. METHODS: We recruited 664 participants aged between 18 and 55 years. A positive FHO (FHO+) was defined as having at least 1 obese first-degree relative and a negative FHO (FHO-) as no obese first-degree relative. Dietary intakes were collected from a food-frequency questionnaire. Body mass index, weight and waist girth were recorded using standard procedures. Fat mass and fat-free mass were assessed by electrical bioimpedance. RESULTS: Significant interaction effects (FHO x DFI) were observed for body mass index, weight, waist girth and fat mass (p interaction = 0.05, 0.04, 0.04, 0.02, respectively). Among FHO+ individuals, indices of obesity increased with an increasing amount of DFI, whereas these associations were not observed in FHO- individuals. We also found that FHO+ individuals consuming a high-fat diet were at higher risk of obesity than FHO- individuals consuming a low-fat diet (3.6, CI 2.1-6.2). CONCLUSION: These results suggest a stronger relationship between DFI and obesity-related phenotypes in individuals with FHO+. PMID- 19776638 TI - Plant polyphenol intake alters gene expression in canine leukocytes. AB - BACKGROUND/AIMS: Polyphenol compounds may explain most of the health-related beneficial effects of plants and vegetables, mainly through their antioxidant properties. The aim of the study was to assess the main changes on leukocyte gene expression of dogs caused by intake of three natural polyphenol-rich extracts and to compare them with caloric restriction. METHODS: 20 female dogs were divided into 5 groups: control fed ad libitum (C), caloric-restricted to 30% less than control (CR), and 3 groups fed ad libitum supplemented with citrus extract (CE), green tea extract (GTE) or grape seed extract (GSE). Leukocytes gene expression was analyzed in a specially designed microarray. RESULTS: CE treatment mainly downregulated genes related to inflammative (IL-8, VLA-4) and cytotoxic response (GRP 58) as well as proliferation of leukocytes. GTE induced gene expression related to leukocyte proliferation and signaling (GNAQ, PKC-B). GSE upregulated some of the genes increased by CE treatment. CR downregulated genes related with energy metabolism (ATP5A1, COX7C) and inflammatory markers (VLA-4). CONCLUSION: A chronic ingestion of citric, grape seed and green tea polyphenols is able to modulate canine leukocyte functions through changes in gene expression. CE ingestion reduces expression of some genes also diminished by a 30% caloric restriction. PMID- 19776639 TI - FADS gene cluster polymorphisms: important modulators of fatty acid levels and their impact on atopic diseases. AB - Long-chain polyunsaturated fatty acids (LC-PUFAs) play an important role in several physiological processes and their concentration in phospholipids has been associated with several complex diseases, such as atopic disease. The level and composition of LC-PUFAs in the human body is highly dependent on their intake in the diet or on the intake of fatty acid precursors, which are endogenously elongated and desaturated to physiologically active LC-PUFAs. The most important enzymes in this reaction cascade are the Delta(5) and Delta(6) desaturase. Several studies in the last few years have revealed that single nucleotide polymorphisms (SNPs) in the 2 desaturase encoding genes (FADS1 and FADS2) are highly associated with the concentration of omega-6 and omega-3 fatty acids, showing that beside nutrition, genetic factors also play an important role in the regulation of LC-PUFAs. This review focuses on current knowledge of the impact of genetic polymorphisms on LC-PUFA metabolism and on their potential role in the development of atopic diseases. PMID- 19776640 TI - A 'desaturase hypothesis' for atherosclerosis: Janus-faced enzymes in omega-6 and omega-3 polyunsaturated fatty acid metabolism. AB - The delta-5 and delta-6 desaturases are key enzymes in the metabolism of omega-3 (omega-3) and omega-6 (omega-6) polyunsaturated fatty acids (PUFA), which in turn influence cellular functions by regulating several metabolic pathways with well known effects on the cardiovascular system. At present, data about desaturase activity and cardiovascular risk remain inconclusive. In this short review we propose a 'desaturase hypothesis' of atherosclerosis, providing suggestions for the Janus-faced role of desaturases, with both more favorable (mainly related to omega-3 long-chain fatty acids) and more harmful (mainly related to omega-6 long chain fatty acids) cardiovascular effects than those obtained in subjects with lower desaturase activity. In particular in populations eating a Western diet rich in omega-6 PUFA, a high desaturase activity may promote an increased bioavailability of arachidonic acid with prevailing synthesis of arachidonic acid derived proinflammatory eicosanoids, finally favoring atherosclerotic vascular damage. In contrast, high desaturase activity in subjects consuming a diet rich in omega-3 PUFA or receiving omega-3 PUFA supplementation could result in the opposite situation with a preferential synthesis of anti-inflammatory eicosanoids. For these reasons, carriers of specific FADS haplotypes may be predisposed to more pronounced vascular inflammatory damage, but also to an increased beneficial effect with omega-3 PUFA supplementation. PMID- 19776641 TI - Polyunsaturated fatty acids and cardiovascular disease: implications for nutrigenetics. AB - Cardiovascular disease (CVD) arises as a result of genetic predisposition in the context of a disease-promoting environment. While several risk factors have been identified for CVD, such as elevated serum lipid levels and hypertension, most of the genes identified thus far do not appear to involve such 'conventional' risk factors. Moreover, the interactions between genes and environment, such as a diet high in certain fats, adds another level of complexity to CVD and renders identification of the underlying genetic factors even more difficult. Polyunsaturated fatty acids (PUFAs), such as the omega-6 and omega-3 fatty acids, which have multiple roles in membrane structure, lipid metabolism, blood clotting, blood pressure, and, in particular, inflammation, have been linked to the reduction in CVD. Linoleic (omega-6) and alpha-linolenic acid (omega-3) are essential fatty acids that can be converted into long-chain PUFAs, such as arachidonic acid (AA) and eicosapentaenoic acid (EPA)/docosahexaenoic acid (DHA), respectively. These long-chain PUFAs are metabolized by enzymatically catalyzed systems via cyclooxygenases and lipoxygenases. The 5-lipoxygenase (5 LO)/leukotriene (LT) biosynthesis pathway has been biochemically and genetically associated with CVD traits in mice and humans, particularly in the context of dietary AA and EPA/DHA. In this review, we summarize the biochemical metabolism of omega-3 and omega-6 PUFAs, evaluate the evidence for genetic and nutrigenetic contributions of 5-LO pathway genes to CVD, and discuss the potential of future studies that could identify other gene-dietary interactions between PUFAs and CVD traits. PMID- 19776643 TI - Efficacy and safety of low-dose chlorambucil in nephrotic patients with idiopathic membranous nephropathy. AB - AIM: This observational study aimed to evaluate the results of treatment with low dose chlorambucil in combination with corticosteroids in patients with idiopathic membranous nephropathy (iMGN) and nephrotic syndrome. METHODS: Thirty-two patients with nephrotic syndrome and biopsy-proven iMGN were included in the study. At presentation, 9 patients were found to be in stage 1, 13 patients in stage 2 and 10 patients in stage 3 chronic kidney disease. In all patients, i.v. methylprednisolone pulses (500 mg/day for 3 days) were administered, followed by oral prednisone at an initial dose of 1 mg/kg per day, tapered gradually after 8 weeks to the maintenance dose of 5 mg/day after 6 months, and chlorambucil 2 mg twice daily for 6 months. RESULTS: Complete remission of nephrotic syndrome was obtained in 14 patients (47.3%) and partial remission in 16 patients (50%). Two patients relapsed after 1 year of treatment. We did not record any severe side effects in treated patients, except glucose intolerance in 4 subjects on high corticosteroid doses. CONCLUSION: Immunosuppressive treatment with corticosteroids and low-dose chlorambucil seems to be effective and well tolerated in nephrotic patients with iMGN. PMID- 19776642 TI - Omega-3 fatty acids, genetic variants in COX-2 and prostate cancer. AB - Dietary intake of fish and omega-3 polyunsaturated fatty acids (omega-3 PUFAs) may decrease the risk of prostate cancer development and progression to advanced stage disease. This could reflect the anti-inflammatory effects of PUFAs, possibly through mediation of cyclooxygenase (COX), a key enzyme in fatty acid metabolism and inflammation. Despite promising experimental evidence, epidemiological studies have reported somewhat conflicting results regarding the effects of fish/PUFAs on prostate cancer development and progression. The literature suggests that fish, and particularly long-chain omega-3 PUFAs, may have a more pronounced protective effect on biologically aggressive tumors or on their progression, and less on early steps of carcinogenesis. Moreover, the impact of LC omega-3 PUFAs may be modified by variation of the COX-2 gene. Overall, results to date support the hypothesis that long-chain omega-3 PUFAs may impact prostate inflammation and carcinogenesis via the COX-2 enzymatic pathway. PMID- 19776644 TI - Study of ACEI versus ARB in managing hypertensive overt diabetic nephropathy: long-term analysis. AB - BACKGROUND: There is, to our knowledge, no study that has directly compared angiotensin-converting enzyme inhibitor (ACEI) with angiotensin receptor blocker (ARB) in hypertensive patients with overt diabetic nephropathy (DNP). We tried to analyze the outcomes of hypertensive patients with overt type 2 DNP who used only ACEIs or ARBs. METHODS: The patients who had an estimated creatinine clearance <90 ml/min and hypertension or had been using antihypertensive drug(s) at presentation were included in the study. The patients were classified as ACEI group and ARB group. RESULTS: A total of 100 patients (55 men and 45 women, mean age 61.8 +/- 9.16 years) were included in the study. Mean duration of follow-up was 24.6 +/- 14.1 months. Baseline demographics, biochemical analyses and blood pressures were similar. Renal functions and proteinuria of both groups did not show any significant changes during follow-up. Blood pressure courses were also similar. Although the mean doubling time of creatinine in the ARB group was shorter than the ACEI group, it was not statistically significant. During the follow-up period, 4 patients died (2 in the ACEI group, 2 in the ARB group) and 10 patients were started on dialysis (7 in the ACEI group, 3 in the ARB group). Serum creatinine and the amount of proteinuria were the baseline parameters which were related to the initiation of dialysis. CONCLUSION: ACEIs and ARBs have similar outcomes in overt DNP. Their renoprotective effects can be observed in spite of uncontrolled hypertension. PMID- 19776645 TI - Bioinformatic analyses of transmembrane transport: novel software for deducing protein phylogeny, topology, and evolution. AB - During the past decade, we have experienced a revolution in the biological sciences resulting from the flux of information generated by genome-sequencing efforts. Our understanding of living organisms, the metabolic processes they catalyze, the genetic systems encoding cellular protein and stable RNA constituents, and the pathological conditions caused by some of these organisms has greatly benefited from the availability of complete genomic sequences and the establishment of comprehensive databases. Many research institutes around the world are now devoting their efforts largely to genome sequencing, data collection and data analysis. In this review, we summarize tools that are in routine use in our laboratory for characterizing transmembrane transport systems. Applications of these tools to specific transporter families are presented. Many of the computational approaches described should be applicable to virtually all classes of proteins and RNA molecules. PMID- 19776646 TI - Expression of airway epithelial sodium channel in the preterm infant is related to respiratory distress syndrome but unaffected by repeat antenatal beta methasone. AB - BACKGROUND: The airway epithelial sodium channel (ENaC) is rate limiting for postnatal alveolar fluid clearance. Increased lung water content is a feature of respiratory distress syndrome (RDS), which is reduced by antenatal corticosteroid treatment in preterm infants. OBJECTIVES: Since corticosteroids also induce ENaC gene expression, we studied whether a repeat dose of antenatal beta-methasone affects postnatal expression of airway ENaC. METHODS: 17 pregnant women with imminent preterm birth were randomized to receive a single repeat dose of beta methasone (12 mg) or placebo (repeat beta-methasone: 8 infants, gestational age (GA) 30.8 +/- 2.2 weeks; placebo: 14 infants, GA 30.4 +/- 2.7 weeks). Expression of alpha-, beta- and gammaENaC subunits in nasal epithelium 1-5 and 20-29 h postnatally was analyzed with reverse transcription-PCR. RESULTS: There were no differences between the study groups in RDS incidence or ENaC subunit expression (all p > 0.38). Regression coefficients for association of alphaENaC expression at 1-5 h with GA in infants with and without RDS differed significantly (p = 0.023). At 20-29 h, alphaENaC expression was lower in infants with RDS (p = 0.048). CONCLUSIONS: A single repeat dose of antenatal beta-methasone did not increase ENaC expression, which may in part explain the absence of reduction in RDS incidence. PMID- 19776647 TI - Neonatal period: body composition changes in breast-fed full-term newborns. AB - BACKGROUND: Weight loss during initial days of life in healthy infants is known to consist of loss of both body solids and total body water. However, the nature of these body composition changes needs further investigation. OBJECTIVE: To investigate the nature of changes in body composition that accompany weight loss during the first days of life in healthy term newborns. METHODS: Body composition of healthy full-term newborns was assessed using air-displacement plethysmography. Cross-sectional (n = 262) and longitudinal samples (n = 28) were assessed during the first 4 and 5 days after delivery, respectively. RESULTS: In the cross-sectional sample, mean body weight decreased significantly through day 4 (p < 0.001), mean fat mass (FM) and %FM decreased significantly (p = 0.005 and p = 0.031, respectively) by day 3. There was a significant decrease in mean fat free mass on days 3 and 4 (p = 0.01 and p < 0.001, respectively). In the longitudinal sample, there was a significant decrease in mean body weight, FM and %FM (p < 0.001, p = 0.001, p = 0.013, respectively) by day 4. On day 5 there was a significant increase in mean body weight, FM and %FM (p < 0.001, p = 0.024, p = 0.036, respectively) when compared to day 4. There was no significant difference in mean FM and %FM values between day 1 and day 5. CONCLUSIONS: These results indicate that body composition changes are constituted by a reduction in both fat and fat free mass. However, a greater %FM is lost and consequently regained by day 5 when compared to fat-free mass. PMID- 19776648 TI - Perfluorocarbon dosing when starting partial liquid ventilation: haemodynamics and cerebral blood flow in preterm lambs. AB - BACKGROUND: Very preterm neonates can have severe lung disease and are prone to brain injury if cerebral blood flow fluctuates. Partial liquid ventilation (PLV) may benefit the lung disease, but it is unknown whether the administration of intratracheal perfluorocarbon when starting PLV affects haemodynamics or cerebral blood flow. OBJECTIVES: To determine if haemodynamics or cerebral blood flow are affected in preterm lambs receiving a dose of perfluorocarbon when starting PLV. METHODS: Sixteen preterm lambs were randomised to either PLV or conventional mechanical ventilation. An intratracheal loading dose of 30 ml/kg of perfluorocarbon liquid (PLV group) or air (sham group) was instilled over 20 min. Data were collected continuously for 30 min from the start of dosing. RESULTS: Cortical cerebral blood flow velocity, measured continuously with laser Doppler, was increased in the PLV group during the administration of perfluorocarbon and immediately thereafter (p = 0.0026); the highest mean increase in the PLV group was 27%. There was no difference in cortical cerebral blood flow variability (p = 0.96). There was a slightly lower mean arterial blood pressure in the PLV group; the heart rate did not differ between groups. The PaCO(2) was higher in the PLV group at 30 min - the difference between groups was not statistically significant (difference between means = 5.5 mm Hg, 95% confidence interval -2.7 to 13.7). CONCLUSIONS: Preterm lambs receiving a dose of tracheal perfluorocarbon at the start of PLV have an increased cortical cerebral blood flow velocity, but no change in cortical cerebral blood flow variability. PMID- 19776649 TI - Impact of oxygen saturation targets and oxygen therapy during the transport of neonates with clinically suspected congenital heart disease. AB - BACKGROUND: Although guidelines for mechanical ventilation, cardiovascular support and intravenous prostaglandin are well established, there is a lack of consensus regarding SpO(2) targets and safety of oxygen administration during transport of neonates with suspected congenital heart disease (CHD). In many centers, an SpO(2) range of 75-85% is targeted but there is no published evidence of the clinical consequences of this approach. OBJECTIVE: To determine the effect of average SpO(2) range and oxygen administration during neonatal transport on clinical markers of cardiovascular instability. METHODS: A retrospective study was conducted on neonates with suspected CHD who presented at community hospitals. Based on average SpO(2) during transport, neonates were categorized into three distinct groups: group I (SpO(2) <75%), group II (SpO(2) 75-85%), group III (SpO(2) >85%). The severity and proportion of neonates with hypoxemia, metabolic and lactic acidosis on arrival at level III NICU were compared. A comparison was also made between oxygen requirement and indicators of cardiorespiratory instability. RESULTS: Seventy-five neonates were studied and 14 (19%), 38 (50%) and 23 (31%) neonates were allocated to groups I, II and III, respectively. Therapeutic interventions during the transport stabilization process included oxygen (n = 53, 71%), mechanical ventilation (n = 56, 75%) and prostaglandin E1 (n = 63, 84%). The severity or proportion of neonates with hypoxemia, elevated lactate or metabolic acidosis was similar between the groups. Neonates receiving an oxygen requirement of FiO(2) >70% had lower arterial SpO(2) on arrival. A provisional diagnosis of CHD and/or PPHN (p = 0.01) and neonates receiving inotropes (p = 0.005) were independent risk factors for cardiovascular instability. CONCLUSION: If congenital heart disease is strongly suspected oxygen should be cautiously weaned to maintain a minimum SpO(2) >75%. Neonates receiving >70% oxygen are at greatest risk of metabolic acidosis or critical hypoxemia and may benefit from expedited transfer to a cardiac center. PMID- 19776650 TI - The oxygen conundrum for infants with suspected congenital heart disease. Commentary on S. Shivananda et al.: Impact of oxygen saturation targets and oxygen therapy during the transport of neonates with clinically suspected congenital heart disease (Neonatology 2010;97:154-162). PMID- 19776651 TI - Use of procalcitonin-guided decision-making to shorten antibiotic therapy in suspected neonatal early-onset sepsis: prospective randomized intervention trial. AB - BACKGROUND: Diagnosis of neonatal early-onset sepsis is difficult because clinical signs and laboratory tests are non-specific. Early antibiotic therapy is crucial for treatment success. OBJECTIVE: To evaluate the effect of procalcitonin (PCT)-guided decision-making on duration of antibiotic therapy in suspected neonatal early-onset sepsis. METHODS: This single-center, prospective, randomized intervention study was conducted in a tertiary neonatal and pediatric intensive care unit in the Children's Hospital of Lucerne, Switzerland, between June 1, 2005 and December 31, 2006. All term and near-term infants (gestational age >or=34 weeks) with suspected early-onset sepsis were randomly assigned either to standard treatment based on conventional laboratory parameters (standard group) or to PCT-guided treatment (PCT group). Minimum duration of antibiotic therapy was 48-72 h in the standard group, whereas in the PCT group antibiotic therapy was discontinued when two consecutive PCT values were below predefined age adjusted cut-off values. RESULTS: 121 newborns were randomly assigned either to the standard group (n = 61) or the PCT group (n = 60). The two groups were similar for baseline demographics, risk factors for early-onset sepsis, likelihood of infection as assessed by the attending physician and early conventional laboratory findings. There was a significant difference in the proportion of newborns treated with antibiotics >or=72 h between the standard group (82%) and the PCT group (55%) (absolute risk reduction 27%; odds ratio 0.27 (95% CI 0.12-0.62), p = 0.002). On average, PCT-guided decision-making resulted in a shortening of 22.4 h of antibiotic therapy. Clinical outcome was similar and favorable in both groups but sample size was insufficient to exclude rare adverse events. CONCLUSION: Serial PCT determinations allow to shorten the duration of antibiotic therapy in term and near-term infants with suspected early-onset sepsis. Before this PCT-guided strategy can be recommended, its safety has to be confirmed in a larger cohort of neonates. PMID- 19776652 TI - A defect in the antioxidant defense system in schizophrenia. AB - OBJECTIVES: Several oxidants and antioxidants have been evaluated in schizophrenia. However, previous studies frequently focused on individual parameters. Determination of the total oxidant and antioxidant status may be more useful. Therefore, we aimed to evaluate both plasma total oxidant status (TOS) and total antioxidant status (TAS) together with the oxidative stress index (OSI) in schizophrenia patients for the first time in the literature. METHODS: A total of 60 schizophrenia patients and 40 healthy volunteers were included in the study. The Positive and Negative Syndrome Scale (PANSS) and the Clinical Global Impression-severity scale (CGI-S) were used to evaluate the severity of schizophrenia in the patients. TOS and TAS were measured in plasma and the OSI was calculated for patients and controls. RESULTS: There was no difference between patients and controls with regard to TOS, but the patients' TAS and OSI were significantly lower and higher, respectively, than those of the controls. No difference was detected between the schizophrenia subtypes or between the patients on typical or atypical antipsychotic medications or a combination of the two with regard to oxidative parameters. There was a weak to moderately significant negative correlation between TAS and total, positive and general psychopathology PANSS scores. Finally, we found a weak to moderately significant negative correlation between the CGI-S score and TOS and between the CGI-S score and TAS. CONCLUSIONS: There is a defect in the antioxidant defense system in schizophrenia. Known oxidative stress that causes oxidative cell damage and thus contributes to the pathophysiology of schizophrenia may be mainly related to this defensive defect. PMID- 19776653 TI - Reduced response to reward in smokers and cannabis users. AB - BACKGROUND: Cannabis is one of the most commonly used illicit drugs. Reduced neural and behavioral reactions to reward have been demonstrated in other forms of addiction, as expressed by reduced mood reactivity and lack of striatal activation to rewards, but this effect has not yet been investigated in cannabis users. METHODS: We hypothesized that cannabis users and tobacco smokers would evidence lower positive mood ratings in rewarded conditions than control participants and that this reduction would be greater in cannabis users than in smokers. We examined the influence of reward on mood and performance in a group of regular cannabis users, a group of tobacco smokers and a group of nonsmokers while they performed a spatial recognition task with delayed response that incorporated 3 levels of difficulty. Correct responses were either not reinforced or reinforced with money. We measured the accuracy of reactions, reaction times and mood ratings throughout the trials. RESULTS: Cannabis users rated their mood as significantly worse than the smokers and nonsmokers during the easiest level of the rewarded condition. A significant positive correlation between mood ratings and monetary reward was found in the nonsmokers but not in the cannabis users and smokers. The groups did not differ with regard to task performance. CONCLUSIONS: Our results suggest that regular cannabis use affects certain aspects of motivation and that both tobacco smoking and cannabis use lead to similar motivational changes. However, the use of cannabis seems to affect motivation in a stronger way than does tobacco smoking alone. PMID- 19776654 TI - Cardiac autonomic regulation under hypnosis assessed by heart rate variability: spectral analysis and fractal complexity. AB - OBJECTIVE: This study examined the effects of hypnosis on autonomic cardiac control. We hypothesized a modification of autonomic modulation of the heart rate with an enhanced vagal tone during hypnosis compared to baseline. METHODS: In 12 healthy subjects (6 men and 6 women, 22.2 +/- 1.0 years of age) ECG was recorded at baseline and during hypnosis. Heart rate variability parameters were obtained in the frequency domain (LFnu: low frequency normalized units, and HFnu: high frequency normalized units) and from nonlinear analysis methods (detrended fluctuation analysis, DFA). RESULTS: Compared to the control condition, hypnosis showed a significantly decreased LFnu, a significantly increased HFnu, and a significantly decreased LF/HF. DFA showed a significantly decreased short-range similarity. Heart rate remained unchanged. CONCLUSION: Autonomic cardiac tone is significantly modified during hypnosis by shifting the balance of the sympathovagal interaction toward an enhanced parasympathetic modulation, accompanied by a reduction of the sympathetic tone and a decreased short-range similarity but without a concomitant change in heart rate. Central and secondary autonomous nervous system changes induced by hypnosis are a possible explanation for our results. Another highly probable explanation is given by a variation in the depth of respiration. Hypnosis appears to prevent the autonomic responses expected during neutral stimulation. PMID- 19776655 TI - Clinical and pathological observation and treatment of chronic orbital osteomyelitis. AB - PURPOSE: To evaluate diagnosis, treatment, and histopathologic changes of chronic orbital osteomyelitis. METHODS: We retrospectively analyzed the history, clinical manifestations, computed tomography (CT) scans, histopathology, treatment methods, and outcomes for 6 patients with chronic orbital osteomyelitis at the Department of Ophthalmology, West China Hospital, from January 1988 to January 2008. RESULTS: One of the 6 patients had a history of frontal sinusitis, 4 patients had a history of trauma, and the remaining patient had a history of lateral orbitotomy. All patients had red swelling of the skin at the orbital margin, fistula formation, and pus emerging repeatedly from the fistulae. CT scans showed that sequestrum and abscess had formed in all patients. Those patients were treated by radical debridement and antibiotics with satisfactory results. Histopathologic examination showed that in 6 patients the bone trabeculae disappeared from the sequestra, abscess formed around the sequestra, and vessel dilation occurred in the areas of pathologic change with inflammatory cell infiltration. Two sequestra were completely encapsulated by fibrous connective tissue and formed involucrum. CONCLUSIONS: Chronic orbital osteomyelitis was often found in patients with a traumatic history who had received improper or delayed treatment when injured. The main clinical features included low-grade inflammation, pus, sequestrum and fistulation. Pathologic characteristics were formation of sequestrum, abscess and involucrum. Clinical manifestations and CT scan allowed accurate diagnoses, and radical treatment using a combination of debridement and antibiotics provided satisfactory results. PMID- 19776656 TI - An analysis of 733 surgically treated blowout fractures. AB - PURPOSE: To evaluate current patient demographics and surgical outcomes from a large series of 733 surgically treated orbital fractures from an ophthalmologist's perspective. METHODS: We reviewed the medical records of 733 patients with orbital fracture, who were treated surgically by one of the authors at Gil Hospital, Gachon University, from May 2000 until September 2007. Data regarding patient demographics, signs and symptoms at presentation, cause of injury, nature of fracture, associated ocular and nonocular injury, surgical outcome and complications were collected. RESULTS: Male patients outnumbered female patients, and blowout fracture occurred most frequently between the ages of 20 and 29 years (mean age 30.7 years). Violent assault was the leading cause of the fractures, followed by fall/slip and traffic accidents. Common signs and symptoms were periorbital ecchymosis, ocular motility restriction, diplopia and enophthalmos. In the pediatric group, diplopia and ocular motility restriction were the most common. Subconjunctival hemorrhage, hyphema and commotio retinae were the most commonly associated ocular injuries. As for the location of fractures, medial wall fractures were the most common, followed by fractures of the inferior wall, and both medial and inferior walls, in order. The most common type of fracture was the 'comminuted' one. In the pediatric group, the percentage of trapdoor-type fracture was higher than in the adult group. Forty-four percent of the patients had diplopia preoperatively and 8.7% postoperatively. The average measurement of difference in the enophthalmos (> or = 2 mm) patient population was improved from 2.62 (+/-SD 0.9) to 1.73 (+/-SD 1.3) after surgery. Ocular motility restriction was preoperatively noted in 297 patients (40.5%), and only 18 patients (2.5%) showed restriction after surgery. CONCLUSION: Young male individuals are at the highest risk for orbital fractures. There are marked differences in the clinical symptomatology and findings between pediatric and adult orbital fractures. Diplopia, enophthalmos and ocular motility restriction improved by repair of fracture. PMID- 19776657 TI - Time between symptom onset and assessment in age-related macular degeneration with subfoveal choroidal neovascularization. AB - BACKGROUND: Therapy delay in neovascular age-related macular degeneration (NV AMD) is associated with risk of visual deterioration. METHODS: Retrospective cross section analysis including patients with NV-AMD who received fluorescein angiography (FA). The time elapsed from symptom onset to assessment was analysed in relation to different factors. Inclusion criteria were: age >50 years, symptom onset within 6 months before assessment, no previous AMD therapy, indication for vascular endothelial growth factor inhibitor treatment. RESULTS: Mean duration of symptoms was 2.272 +/- 1.683 months (n = 220); percentiles 25, 50, 75 and 90 corresponded to 1, 2, 3 and 5.383 months. A significant increase (p = 0.033) in mean symptom duration was found between age groups 65-74, 75-84 and over 84 years. Privately insured persons (assessment 1.242 +/- 1.060 months after symptom onset; n = 14) received FA 1.083 months earlier (p = 0.0089) than patients with a statutory health insurance (assessment 2.325 +/- 1.661 months after symptom onset; n = 194). CONCLUSION: In order to avoid progressive visual deterioration in patients with NV-AMD earlier assessment of these individuals should be aimed for. PMID- 19776658 TI - Limitations of PET/CT in determining need for neck dissection after primary chemoradiation for advanced head and neck squamous cell carcinoma. AB - OBJECTIVE: The purpose of our study was to evaluate PET/CT in predicting residual nodal disease after primary chemoradiation (CRT) for head and neck cancer (HNSCC) with N2 disease or greater. DESIGN: A retrospective cohort analysis was conducted. Thirty-eight patients received primary CRT for HNSCC with N2 or greater disease, PET/CT after treatment and neck dissection from January 2003 to December 2006. PET/CT results were correlated with pathology results from neck dissection specimens for each respective side. RESULTS: Forty-six neck regions were analyzed. Nine were determined to have either PET/CT result reports (n = 5) or pathology reports (n = 4) that were indeterminate. PET/CT demonstrated a sensitivity and specificity of 57.1 and 73.9%, respectively, an accuracy of 67.5%, a positive predictive value of 57.1% and a negative predictive value of 73.9% when compared to the final pathology. CONCLUSION: PET/CT is neither highly sensitive nor highly specific for identifying residual nodal metastases after CRT for advanced-stage HNSCC. Physicians should not rely solely on PET/CT to determine interventions on the neck after CRT. A standardization of language for reporting findings and risk of residual disease is needed. PMID- 19776659 TI - Influence of NR2B-selective NMDA antagonist on lindane-induced seizures in rats. AB - Ifenprodil is a novel NMDA receptor antagonist that selectively inhibits receptors containing the NR2B subunit. Lindane, a widely used pesticide and scabicide, evokes seizures mainly through the blockade of the gamma-aminobutyric acid type A receptor complex. The aim of this study was to determine the effects of ifenprodil on the behavioral and electroencephalographic (EEG) manifestations of seizures in lindane-treated rats. Adult male Wistar rats with three electrodes implanted into the skull were treated intraperitoneally (i.p.) with lindane 8 mg/kg and observed for seizure behavior and EEG during the next 30 min. Seizure behavior was assessed by incidence, severity (determined by a descriptive rating scale ranging from 0 to 4) and duration of latency. Increasing doses of ifenprodil (5, 10, 20 mg/kg, i.p.) or vehicle were injected 30 min prior to lindane administration. Ifenprodil decreased the incidence and severity of lindane seizures and prolonged the latency to seizures in a dose-dependent manner. 20 mg/kg of ifenprodil significantly decreased the incidence (p < 0.05) and severity (p < 0.05) of seizures when compared to the vehicle treatment. Latency to seizures was significantly prolonged by 10 and 20 mg/kg of ifenprodil. The estimated ED(50) value of ifenprodil was 15.53 (5.48-15.20) mg/kg. The lindane-induced bursts of spiking activity in EEG were not completely suppressed by the applied doses of ifenprodil. These results indicate that ifenprodil alleviates behavioral seizures and modifies EEG characteristics of lindane seizures in rats, thus showing the involvement of NMDA receptors containing the NR2B subunit in the mechanisms of lindane convulsions. PMID- 19776660 TI - Differential contractile impairment of fast- and slow-twitch skeletal muscles in a rat model of doxorubicin-induced congestive heart failure. AB - Congestive heart failure (CHF) is associated with exercise intolerance that cannot be entirely explained by hypoperfusion of the skeletal muscles. We studied the contractile properties of fast-twitch (extensor digitorum longus; EDL) and slow-twitch (soleus; SOL) skeletal muscles in doxorubicin-induced CHF in rats, and evaluated the defective steps of excitation-contraction coupling. Both types of muscles-obtained from CHF rats displayed significant reduction in twitch and tetanic contractions. Twitch half-relaxation times of CHF SOL muscles were prolonged while there was no significant difference in EDL muscles. High K(+) application induced lower contracture amplitudes in CHF muscles. Caffeine-induced contractures were significantly diminished in CHF SOL. Verapamil application depressed tetanic contractions in all preparations while depression was more pronounced in CHF SOL. Immunohistochemistry revealed reduced expression of sarcoplasmic reticulum Ca(2+)-ATPase-1 and -2 in CHF EDL and in CHF SOL, respectively. Sarcolemmal excitability and spontaneous neurotransmitter release were unaffected since resting membrane potential, action potential and miniature end-plate potentials were unaltered in CHF muscles. We conclude that CHF induces contractile impairment that occurs predominantly in rat slow-twitch skeletal muscles. Our results suggest that this muscle-type-specific effect of CHF is related to the defective intracellular Ca(2+) release and uptake mechanisms and reduced sarcolemmal-dihydropyridine-sensitive Ca(2+) channel activity. PMID- 19776661 TI - The effects of inhaled KP-496, a novel dual antagonist for cysteinyl leukotriene receptor and thromboxane A(2) receptor, on allergic asthmatic responses in guinea pigs. AB - AIMS: The aim of this study was to evaluate the effects of inhaled KP-496, a novel dual antagonist for cysteinyl leukotriene receptor 1 and thromboxane A(2) receptor, on the allergic asthmatic responses in guinea pigs. METHODS: Actively sensitized animals were repeatedly exposed to antigen, and KP-496 (0.01 and 0.1%) was inhaled for 5 min before every antigen exposure. After evaluating the effects of KP-496 on asthmatic responses, such as immediate and late asthmatic response (IAR and LAR) and airway hyperresponsiveness (AHR), histopathological analyses of the lungs of asthmatic animals were made. RESULTS: KP-496 significantly inhibited both antigen-induced LAR and AHR to acetylcholine, and slightly inhibited antigen induced IAR. Furthermore, histopathological analyses of the lungs of the asthmatic animals demonstrated the following: (1) KP-496 suppressed infiltration of eosinophils around airway smooth muscle, (2) KP-496 suppressed airway epithelial hypertrophy, and (3) KP-496 suppressed increased mucus production in the airway. CONCLUSION: In addition to suppression of LAR and AHR, our findings demonstrated that KP-496 inhibits features of airway inflammation. Since these broad ameliorative effects of KP-496 on asthmatic pathology are thought to result from the inhibition of multiple chemical mediators, KP-496 will be a potent agent in the treatment of bronchial asthma. PMID- 19776662 TI - The aldose reductase inhibitor fidarestat suppresses ischemia-reperfusion-induced inflammatory response in rat retina. AB - Recent studies suggest that increased aldose reductase (AR) activity plays an important role in ischemia-reperfusion injury in the retina. The mechanisms are not completely understood, but may be linked to inflammation. In the present study, we investigated whether the AR inhibitor fidarestat suppressed the retinal inflammatory response induced by ischemia-reperfusion in a rat model. The inflammatory response was manifested by increased gene expression of tumor necrosis factor-alpha and intercellular adhesion molecule-1 (ICAM-1) as well as elevated protein levels of soluble ICAM-1. This response was partially suppressed by the AR inhibitor fidarestat. The findings may reveal beneficial effects of AR inhibition on retinal inflammation associated with ischemia-reperfusion and are in agreement with recent developments in pharmacological research suggesting that pathological conditions other than diabetes may benefit from AR inhibitors. PMID- 19776663 TI - Interaction of thiazolidinediones (glitazones) with the ATP-binding cassette transporters P-glycoprotein and breast cancer resistance protein. AB - AIMS: Thiazolidinediones (glitazones) are frequently prescribed antidiabetic drugs commonly used in combination drug regimens. To evaluate the risk of drug drug interactions, we therefore aimed to systematically investigate the inhibitory and inductive effects of all glitazones on 2 of the most relevant drug transporters, P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP), in vitro. METHODS: The inhibition of P-gp and BCRP was assessed by fluorometric assays quantifying the increase in the intracellular concentration of fluorescent P-gp or BCRP substrates caused by their combination with the glitazones. The induction of mRNA expression was quantified by real-time RT-PCR after the treatment of HuH-7 cells with the respective compounds for 4 days. RESULTS: Rosiglitazone and troglitazone significantly inhibited P-gp and BCRP function and induced mRNA expression of BCRP but not of P-gp. Pioglitazone, which exhibited very low solubility, could only be tested up to 0.5 micromol/l and did not provoke an effect in any of the assays. CONCLUSIONS: After comparison of the in vitro data and published clinical studies, it seems unlikely that the inhibition of BCRP and P-gp by rosiglitazone plays a role in the clinical situation. In contrast, BCRP induction by rosiglitazone might be of relevance in vivo, but has to be verified in dedicated clinical studies. PMID- 19776664 TI - Effects of speaking rate and vowel length on formant frequency displacement in Japanese. AB - This study examined effects of phonemic vowel length and speaking rate, two factors that affect vowel duration, on the first and second formants of all vowels in Japanese. The aim was to delineate the aspects of formant displacement that are governed by the physiological proclivity of vowel production shared across languages, and the aspects that reveal language-specific phenomena. Acoustic analysis revealed that the phonemic long vowels occupied a more peripheral portion of the F1 x F2 vowel space than the phonemic short vowels (effect of vowel length), but effects of speaking rate were less clear. This was because of the significant interactions of the two effects: the formants of phonemic short vowels were more affected by speaking rates than the phonemic long vowels. Regression analyses between F2 and duration revealed that formant displacement occurs when vowels are less than 200 ms. Similarities and differences found for Japanese and English are discussed in terms of physiological proclivity of vowel production versus language-specific phonological encoding. PMID- 19776665 TI - Do listeners store in memory a speaker's habitual utterance--final phonation type? AB - Earlier studies report systematic differences across speakers in the occurrence of utterance-final irregular phonation; the work reported here investigated whether human listeners remember this speaker-specific information and can access it when necessary (a prerequisite for using this cue in speaker recognition). Listeners personally familiar with the voices of the speakers were presented with pairs of speech samples: one with the original and the other with transformed final phonation type. Asked to select the member of the pair that was closer to the talker's voice, most listeners tended to choose the unmanipulated token (even though they judged them to sound essentially equally natural). This suggests that utterance-final pitch period irregularity is part of the mental representation of individual speaker voices, although this may depend on the individual speaker and listener to some extent. PMID- 19776666 TI - Perceptual assimilation and L2 learning: evidence from the perception of Southern British English vowels by native speakers of Greek and Japanese. AB - This study examined the extent to which previous experience with duration in first language (L1) vowel distinctions affects the use of duration when perceiving vowels in a second language (L2). Native speakers of Greek (where duration is not used to differentiate vowels) and Japanese (where vowels are distinguished by duration) first identified and rated the eleven English monophthongs, embedded in /bVb/ and /bVp/ contexts, in terms of their L1 categories and then carried out discrimination tests on those English vowels. The results demonstrated that both L2 groups were sensitive to durational cues when perceiving the English vowels. However, listeners were found to temporally assimilate L2 vowels to L1 category/categories. Temporal information was available in discrimination only when the listeners' L1 duration category/categories did not interfere with the target duration categories and hence the use of duration in such cases cannot be attributed to its perceptual salience as has been proposed. PMID- 19776667 TI - A duration-dependent account of coarticulation for hyper- and hypoarticulation. AB - Previous studies investigating anticipatory coarticulation in emphatically stressed CV sequences and during fast speaking rates reported that three factors contributed to the overall extent of the documented coarticulation. These factors were: (1) vowel identity, (2) vowel space expansion (emphasis) or reduction (fast rate), and a hypothesized (3) 'deeper' and 'shallower' stop closure contact in emphatic and faster speech, respectively. The objective of the current research was to conceptually and quantitatively unify these two studies. This was accomplished by showing that the opposite changes to frequency onsets of F2 transitions due to emphatic and rapid speech systematically vary as a function of the durational changes in the stop closure interval. Specifically, the decrease in coarticulation in emphatic speech is characterized by increases in F2 onsets and longer stop closures (relative to a normal baseline); the increase in coarticulation due to rapid speech shows concomitant decreases in F2 onsets coinciding with shorter stop closure intervals. Vocal tract area function simulations corresponding to emphatic and reduced speech implicitly support 'deeper' and 'shallower' closure contacts as a third factor contributing to the overall extent of anticipatory CV coarticulation. PMID- 19776668 TI - Psychopathological correlates of lifetime anxiety comorbidity in bipolar I patients: findings from a French national cohort. AB - BACKGROUND: Despite numerous studies on the comorbidity of bipolar and anxiety disorders, there is no satisfactory psychopathological model for their overlap. METHOD: 1,090 hospitalized patients meeting DSM-IV criteria for a manic episode of bipolar I disorder were subtyped according to the presence or not of lifetime anxiety comorbidity and assessed for demographic, illness course, clinical, associated condition, temperament, and treatment characteristics. RESULTS: Lifetime anxiety comorbidity, defined as presence of at least one anxiety disorder in lifetime, was found in 27.2% (n = 297) of the sample. Compared to patients without such a comorbidity (n = 793), those who had it experienced a higher number of mood episodes and suicide attempts in the previous year, more stressors, organic disorders and less free intervals; furthermore, they showed more temperaments with depressive features and complex treatment. At study entry, they also experienced manic episodes with higher levels of depression, psychosis and hostility. The following independent variables were associated with lifetime anxiety comorbidity: higher scores on the Montgomery-Asberg Depression Rating Scale, depressive temperament, irritable temperament, higher scores on the Scale for the Assessment of Positive Symptoms, episodes without free intervals and at least one stressor before the index episode. CONCLUSIONS: Factors associated with lifetime anxiety comorbidity in bipolar I patients may be integrated into a comprehensive diathesis-stress model emphasizing the role of irritable temperament as a source of mood instability and stress, and interacting with other temperamental characteristics to trigger the outbreak of both anxiety and bipolar symptoms. PMID- 19776669 TI - Trait anxiety and defensive functioning in relation to antidepressant treatment outcome. AB - BACKGROUND: Depression can occur in patients with or without trait anxiety. Although it is assumed that assessment of defenses can be useful in planning biological treatment, no studies have confirmed this hypothesis. In this study we focus on the relation between trait anxiety and defensive functioning, and on the combined influence of these personality characteristics on response to antidepressants among inpatients with a major depressive episode. METHODS: Major depressive episode was diagnosed using the Schedule for Affective Disorders and Schizophrenia (SADS) and the severity of the depression was measured with the Hamilton Rating Scale for Depression (HAM-D). The level of trait anxiety was assessed using a questionnaire with 34 questions pertaining to trait anxiety. The Defense Style Questionnaire (DSQ 88) was used to assess defensive functioning followed by a weighted overall defensive functioning score (ODF). Partial correlations and multiple regression analyses were used to analyze the data. RESULTS: The final sample included 85 patients. A significant negative effect of trait anxiety by ODF (p: 0.000) was found on the outcome score, i.e. the combination of a high score on trait anxiety and a low score on the ODF resulted in a significantly higher final score on the HAM-D. CONCLUSIONS: The most important finding in this study is that the combination of a high level of trait anxiety and immature defensive functioning evidently had a negative effect on antidepressant treatment outcome. PMID- 19776670 TI - Relationship of the Borderline Symptom List to DSM-IV borderline personality disorder criteria assessed by semi-structured interview. AB - BACKGROUND: Borderline personality disorder (BPD) is a debilitating mental illness that affects approximately 6% of the general population and 10-20% of psychiatric patients. The Borderline Symptom List (BSL) is a self-report questionnaire designed to comprehensively assess BPD symptomatology. SAMPLING AND METHODS: The present study examined the convergence of the BSL with DSM-IV BPD assessed by semi-structured interview. To ensure variability in BPD symptoms, participants were recruited from a large college sample if they generated either high or low scores on a BPD symptom screening questionnaire. The final sample included 59 participants who completed the BSL, the BPD questions from the Structured Interview for DSM-IV Personality (SIDP-IV), and self-report measures of depression and anxiety. RESULTS: Ten participants (17%) met the full BPD criteria and 29 (49%) met 2 or more criteria. Results indicate strong convergence between the BSL and BPD assessed by semi-structured interview, even when controlling for measures of depression and anxiety. The shortened version of the BSL, the BSL-23, also correlated robustly with BPD assessed by semi-structured interview. CONCLUSIONS: Findings support the validity of the BSL (and BSL-23) as a self-report measure of BPD symptomatology. Future research should replicate results in other samples, including those drawn from psychiatric populations. PMID- 19776671 TI - The lack of negative affects as an indicator for identity disturbance in borderline personality disorder: a preliminary report. AB - BACKGROUND: Patients with borderline personality disorder (BPD) suffer from instability of their relationships, their affectivity and their identity. The purpose of the study was to investigate negative affects and identity disturbance in patients with BPD and in patients without personality disorder using questionnaire data and interview data. SAMPLING AND METHODS: Twelve patients with BPD and 12 patients with major depressive disorder without any personality disorder were assessed with the Structured Interview of Personality Organization (STIPO) and questionnaires (Inventory of Personality Organization, Beck Depression Inventory, State-Trait Anxiety Inventory). They were compared with respect to the frequency of negative affective verbal expressions using computerized content analysis methods. RESULTS: BPD patients showed higher levels of anxiety, depression and identity diffusion in the questionnaires than major depressive disorder patients without personality disorder. However, they did not report more negative affective expressions in the interview. Patients with identity disturbance of both groups showed higher values of negative mood in the questionnaires, but less anger, less anxiety and less affective intensity in the interview. CONCLUSION: The preliminary findings indicate that patients with identity disturbance show high levels of negative affects in questionnaires but only few negative affects in the interview situation. More studies are needed to enhance the understanding of negative affects and identity disturbance in BPD. PMID- 19776672 TI - TMEM25, REPS2 and Meis 1: favourable prognostic and predictive biomarkers for breast cancer. AB - BACKGROUND/AIMS: A panel of prognostic and predictive biomarkers would contribute to personalized treatment of breast cancer patients. However, many such biomarkers have yet to be identified and evaluated. The aim of this study was to investigate the relevance of 3 such putative biomarkers. METHODS: TMEM25, REPS2 and Meis 1 expression was investigated by qRT-PCR, in triplicate, in 103 breast tumour biopsies procured in 1993-1994. Normal breast tissue specimens were also analysed for comparative purposes. Univariate and multivariate analyses were used to identify associations between expression of these transcripts as well as patients' clinicopathological and survival data. RESULTS: TMEM25, REPS2 and Meis 1 transcripts were detected in approximately 52, 78 and 40% of tumour specimens, respectively. Expression of each of the 3 genes was indicative of extended survival times from diagnosis [association between relapse-free survival (RFS) and TMEM25, p = 0.0002; REPS2, p = 0.0287; association between overall survival (OS) and TMEM25, p = 0.001; REPS2, p = 0.0131; Meis 1, p = 0.0255]. Presence of TMEM25 and Meis 1 was associated with oestrogen receptor-positive (TMEM25, p < 0.0005; Meis 1, p = 0.011), lower-grade (TMEM25, p = 0.002; Meis 1, p = 0.001) tumours. Multivariate analysis indicated TMEM25 expression to be an independent prognostic factor for extended RFS (p = 0.011) and OS (p = 0.001). Furthermore, for patients who received adjuvant chemotherapy, significantly longer survival times were achieved if their tumours expressed TMEM25 (OS, p = 0.031; RFS, p = 0.0181) and REPS2 (OS, p = 0.011). While expression of these mRNAs was generally absent from triple-negative breast tumours, statistical significance was not achieved. CONCLUSION: Our results suggest that TMEM25, REPS2 and Meis 1 mRNAs may be useful members of a panel of favourable prognostic and predictive markers for breast cancer and an understanding of their function may provide useful information about this disease. PMID- 19776673 TI - Differential prognostic impact of uPA and PAI-1 in colon and rectal cancer. AB - BACKGROUND AND OBJECTIVES: Degradation of extracellular matrix is important for tumour growth and invasion, which in part is regulated by the plasminogen activation system. The aim of the study was to evaluate the protein expression of urokinase plasminogen activator (uPA) and plasminogen-activating inhibitor-1 (PAI 1) in plasma, tumour-free mucosa and tumour tissue regarding their prognostic value in colon and rectal cancer. METHODS: Patients (n = 221) undergoing surgery for colorectal cancer were prospectively included. Samples were assayed by ELISA technique. RESULTS: PAI-1 in tumour tissue (p = 0.006), plasma (<0.0001) and uPA in tumour-free mucosa (p = 0.006) were associated with survival in rectal cancer in univariate analysis. An uPA expression level below 1.1 ng/mg (log rank test, p < 0.0001) in tumour-free mucosa was associated with poor survival in rectal cancer. This was true also for patients without disseminated disease (M(0), p = 0.02). PAI-1 in plasma correlated with metastatic disease (p < 0.0001). uPA and PAI-1 were not associated with survival in either tumour tissue, mucosa or plasma in patients with colon cancer. CONCLUSIONS: uPA and PAI-1 have a differential prognostic impact in colon and rectal cancer. Preoperative mucosal uPA and plasma PAI-1 protein expression could possibly be used as prognostic factors in rectal cancer. PMID- 19776674 TI - Molecular evolution of specific human antibody against MUC1 mucin results in improved recognition of the antigen on tumor cells. AB - The MUC1 mucin is differentially expressed and glycosylated in cancer tissue as opposed to healthy tissue. Due to these differences, MUC1 is considered a potential biomarker suitable for cancer diagnosis and therapy. In a previous study, the human MUC1-specific antibody 12ESC-6 was able to bind a sequence variant of the tandem repeat of MUC1 that is not recognized by many other MUC1 specific antibodies. It was also found to bind efficiently to MUC1-carrying cells. We have now used 12ESC-6 as starting point for random mutagenesis to isolate variants with improved ability to bind MUC1 in human tumor tissue. The resulting 12ESC-6 variants were shown to recognize not only the naked MUC1 tandem repeat but even more so glycosylated variants thereof, in particular those carrying the GalNAc (Tn) glycoform. Selected variants of 12ESC-6 demonstrated improved staining of MUC1 on cell lines using flow cytometry and improved staining of the antigen in breast tumor tissue by immunohistochemistry. Molecular evolution and specific fine-tuning thus have the potential to improve the performance of antibody specificities targeting tumor-associated epitopes on MUC1 mucin. PMID- 19776675 TI - Expression and function of the inducible costimulator ligand B7-H2 in human airway smooth muscle cells. AB - BACKGROUND: B7-H2 is a ligand for the inducible costimulator (ICOS). The aim of this study was to examine the expression and function of B7-H2 in human airway smooth muscle (ASM) cells and compare them with those of CD40 or OX40 ligand (OX40L). METHODS: Expression of B7-H2, CD40 and OX40L in ASM cells and their respective counterparts in T cells was analyzed by RT-PCR or flow cytometry. The modulating effect of polyinosinic-polycytidylic acid (poly I:C) on expression of B7-H2, CD40 and OX40L was also examined. The function of these three molecules was evaluated by virtue of adhesion of anti-CD3-activated T cells, IL-6 and IL-8 production and DNA synthesis. RESULTS: ASM cells constitutively expressed B7-H2, CD40 and OX40L that mediated adhesion of activated T cells expressing ICOS, CD40L and OX40. ASM cells responded to poly I:C with upregulated expression of B7-H2, CD40 and OX40L and displayed enhanced adhesion of activated T cells. Functional analysis performed on untreated ASM cells showed that engagement of B7-H2 with ICOS-Ig clearly induced DNA synthesis, whereas that of CD40 or OX40L with trimeric CD40L or OX40-Ig greatly increased IL-6 and IL-8 production. These responses were enhanced in poly I:C-treated ASM cells. CONCLUSIONS: The data demonstrate that ASM cells express functionally active B7-H2, CD40 and OX40L and suggest that B7-H2-dependent signaling may play an active role in a proliferative response rather than in cytokine and chemokine production. In addition, the modulation of B7-H2, CD40 and OX40L expression and function by poly I:C may have important implications for the function of virus-infected ASM cells. PMID- 19776676 TI - Local induction of a specific Th1 immune response by allergen linked immunostimulatory DNA in the nasal explants of ragweed-allergic subjects. AB - BACKGROUND: Allergen immunotherapy is effective in allergic individuals however efforts are being made to improve its safety, convenience, and efficacy. It has recently been demonstrated that allergen-linked immunostimulatory DNA (ISS) is effective in stimulating an allergen-specific Th1 response with decreased allergenicity. The objective of this study is to investigate whether ISS linked to purified ragweed allergen Amb-a-1 (AIC) can inhibit local allergen-specific Th2 and induce allergen-specific Th1 responses in explanted nasal mucosa of ragweed-sensitive subjects. In addition, we set out to determine whether AIC is more effective compared to stimulation with unlinked Amb a 1 and ISS. METHODS: Tissue from ragweed-sensitive patients (n = 12) was cultured with whole ragweed allergen (RW), Amb-a-1, AIC, Amb-a-1 and ISS (unlinked), or tetanus toxoid (TT) for 24 hours. IL-4, -5, -13, TNF-alpha and IFN-gamma mRNA-positive cells were visualized by in situ hybridization and T cells, B cells and neutrophils were enumerated using immunocytochemistry. RESULTS: RW or Amb-a-1 increased the number of IL-4, IL-5, and IL-13 mRNA+ cells in the tissue compared to medium alone. AIC had similar cytokine mRNA reactivity as control tissue. AIC and TT increased IFNgamma-mRNA expression. Unlinked Amb-a-1 and ISS showed similar effects to AIC, however this response was weaker. The number of TNF mRNA+ cells, T cells, B cells and neutrophils remained unchanged. CONCLUSIONS: AIC is effective in stimulating a local allergen-specific Th1- and abolishing Th2-cytokine mRNA reactivity in the nose and may be considered as a strong candidate for an improved approach to immunotherapy in ragweed-sensitive individuals. PMID- 19776677 TI - Evaluation of novel scoring system named 5-5-5 exacerbation grading scale for allergic conjunctivitis disease. AB - BACKGROUND: The objective of this study is to evaluate the practical usefulness of a scoring system using the 5-5-5 exacerbation grading scale for allergic conjunctivitis disease (ACD). METHODS: Subjects were 103 patients with ACD including 40 patients with vernal keratoconjunctivitis (VKC), 20 patients with atopic keratoconjunctivitis (AKC), and 43 patients with allergic conjunctivitis (AC). The 5-5-5 exacerbation grading scale consists of the following 3 graded groups of clinical observations: the 100-point-grade group (100 points for each observation) includes active giant papillae, gelatinous infiltrates of the limbus, exfoliative epithelial keratopathy, shield ulcer and papillary proliferation at lower palpebral conjunctiva; the 10-point-grade group (10 points for each observation) includes blepharitis, papillary proliferation with velvety appearance, Horner-Trantas spots, edema of bulbal conjunctiva, and superficial punctate keratopathy; and the 1-point-grade group (1 point for each observation) includes papillae at upper palpebral conjunctiva, follicular lesion at lower palpebral conjunctiva, hyperemia of palpebral conjunctiva, hyperemia of bulbal conjunctiva, and lacrimal effusion. The total points in each grade group were determined as the severity score of the 5-5-5 exacerbation grading scale. RESULTS: The median severity scores of the 5-5-5 exacerbation grading scale in VKC, AKC and AC were 243 (range: 12-444), 32.5 (11-344), and 13 (2-33), respectively. The severity score of each ACD disease type was significantly different (P < 0.001, Kruskal-Wallis test). The severity of each type of ACD was classified as severe, moderate, or mild according to the severity score. CONCLUSIONS: The 5-5-5 exacerbation grading scale is a useful clinical tool for grading the severity of each type of ACD. PMID- 19776678 TI - Usefulness of wheat and soybean specific IgE antibody titers for the diagnosis of food allergy. AB - BACKGROUND: Since the first suggestion of threshold values for food specific IgE antibody levels in relation to clinical reactivity, several authors have proposed different threshold values for different allergens. We investigated the relationship between wheat/soybean specific IgE antibody levels and the outcome of wheat/soybean allergy diagnosis in children of different ages. METHODS: A retrospective study was conducted in 536 children admitted consecutively to our clinic with the suspicion of wheat and/or soybean allergy. The children underwent an oral food challenge and blood samples for specific IgE measurement were obtained. RESULTS: The children who reacted to the oral food challenge had higher specific IgE titers to the specific allergen compared to the non-reacting group. The risk for reaction increased 2.33-fold (95% CI 1.90-2.87) for wheat and 2.08 fold (95% CI 1.65-2.61) for soybean, with increasing levels of specific IgE. A significant difference between the ages of subjects pertained only to wheat. CONCLUSIONS: We found a relationship between the probability of failed challenge and the concentration of IgE antibodies to both wheat and soybean. Age influences the relationship of allergen specific IgE levels to wheat and oral food challenge outcome. Younger children are more likely to react to low levels of specific IgE antibody concentration to wheat than older children. PMID- 19776679 TI - Evaluation of molecular basis of cross reactivity between rye and Bermuda grass pollen allergens. AB - BACKGROUND: Allergenic cross reactivity between the members of the Pooids (Lolium perenne, Phleum pratense, and Poa pratensis) and Chloridoids (Cynodon dactylon and Paspalum notatum) is well established. Studies using crude extracts in the past have demonstrated limited cross reactivity between the Pooids and the Chloridoids suggesting separate diagnosis and therapy. However, little is known regarding the molecular basis for the limited cross reactivity observed between the 2 groups of grasses. The present study was undertaken to gain insights into the molecular basis of cross allergenicity between the major allergens from rye and Bermuda grass pollens. METHODS: Immunoblot inhibition tests were carried out to determine the specificity of the proteins involved in cross reactivity. Crude pollen extract and bacterially expressed and purified recombinant Lol p 1and Lol p 5 from rye grass were subjected to cross inhibition experiments with crude and purified recombinant Cyn d 1 from Bermuda grass using sera from patients allergic to rye grass pollen. RESULTS: The immunoblot inhibition studies revealed a high degree of cross inhibition between the group 1 allergens. In contrast, a complete lack of inhibition was observed between Bermuda grass group 1 allergen rCyn d 1, and rye grass group 5 allergen rLol p 5. Crude rye grass extract strongly inhibited IgE reactivity to Bermuda grass, whereas crude Bermuda grass pollen extract showed a weaker inhibition. CONCLUSIONS: Our data suggests that a possible explanation for the limited cross reactivity between the Pooids and Chloridoids may, in part, be due to the absence of group 5 allergen from Chloridoid grasses. This approach of using purified proteins may be applied to better characterize the cross allergenicity patterns between different grass pollen allergens. PMID- 19776681 TI - Uniform degradation of auditory acuity in subjects with normal hearing leads to unequal precedence effects. AB - OBJECTIVE: The aim of this study was to investigate whether a controlled unilateral reduction in auditory acuity at the higher audiometric frequencies would have an effect on the variability in responses obtained on a task designed to measure the precedence effect. DESIGN: The experiment was conducted with participants located in a large sound proof, anechoic room, and psychophysical tests were conducted with long-duration noise burst stimuli. Reduction in auditory acuity was created by inserting a specially designed earplug in the ear of participants with normal hearing. The earplugs produced a highly reliable increase in the thresholds for detecting high-frequency sounds in the blocked ear with the largest effect at the highest frequencies (4 and 8 kHz). Across participant variability in tone-detection threshold was less than +/-5 dB. The measurement of lag-burst thresholds with and without the insertion of earplugs was used to characterize the precedence effect. The lag-burst threshold was defined as the shortest lag-burst delay that yielded a perception of two different noise bursts. RESULTS: Although performance was stable across participants in the condition without the earplug, a substantial increase in variability in the lag-burst thresholds was found in the earplug condition. CONCLUSIONS: These results indicate that a uniform unilateral degradation in auditory acuity leads to increased variability in performance on tasks measuring fusion in the precedence effect. The outcome suggests that variable perception of the precedence effect by individuals with clinically diagnosed hearing loss might be due to factors other than a reduction in auditory acuity per se. PMID- 19776682 TI - American College of Cardiology/American Heart Association 2009 clinical guidelines for the diagnosis and management of heart failure in adults: update and clinical implications. PMID- 19776683 TI - The efficacy and safety of glucose control algorithms in intensive care: a pilot study of the Survival Using Glucose Algorithm Regulation (SUGAR) trial. AB - INTRODUCTION: The benefits, harms and feasibility of intensive insulin therapy in critically ill patients remain unclear. Several single center studies have attempted to demonstrate the benefit of intensive insulin therapy in critically ill patients with variable results. OBJECTIVES: We conducted a pilot randomized trial to assess the feasibility, safety and clinical outcomes of preprinted glucose management algorithms before the initiation of a large multicenter trial. PATIENTS AND METHODS: Within 48 hours of admission to the intensive care unit, we randomized mechanically ventilated patients to either the "high" group (target serum glucose concentration 9-11 mmol/l) or the "low" group (target serum glucose concentration 5-7 mmol/l). To assess feasibility we measured the time to reach target glucose range, time in target range, morning glucose concentrations, average daily glucose concentrations, and number of crossovers. To assess safety, we measured the number of hypoglycemic events (serum glucose <2.2 mmol/l), and other serious adverse events such as cardiac arrests and seizures. RESULTS: Sixty eight patients were enrolled (35 in the high group and 33 in the low group). During the first week, the median proportions of time spent in the target range were 35.7% and 53.0% for the high and low groups, respectlively (p = 0.0001). Morning glucose concentrations were 8.3 +/-1.6 mmol/l and 6.2 -/+1.2 mmol/l. One (2.9%) and 8 (24.2%) episodes of hypoglycemia (<2.2 mmol/l) occurred in the high and low groups, reflecting 0.002 and 0.03 hypoglycemic events per patient-day, respectlively. CONCLUSIONS: This pilot trial of intensive insulin therapy identified numerous challenges that helped in the preparation of an international multicenter randomized trial of intensive insulin therapy to evaluate benefits and harms. PMID- 19776684 TI - Postprandial secretion of ghrelin in hemodialysis patients with and without diabetic nephropathy. AB - INTRODUCTION: Ghrelin is a hormone produced mainly by the stomach, which enhances gastric emptying. The disturbances of ghrelin secretion and/or biodegradation may play an important role in the pathogenesis of gastroparesis in hemodialysis patients, especially those with diabetic nephropathy. OBJECTIVES: The aim of the study was to assess postprandial changes in plasma ghrelin in hemodialysis patients with diabetic or non-diabetic nephropathy. PATIENTS AND METHODS: Thirty two hemodialysis patients (16 with diabetic nephropathy [HD-DM], 16 with non diabetic nephropathies [HD]) and 15 healthy subjects (C) were enrolled into the study. Plasma ghrelin concentrations were assessed in the fasting state and at 30, 60 and 120 min after ingestion of a test meal. Gastric emptying was assessed based on changes in serum paracetamol concentrations ingested with the meal. RESULTS: In both HD groups fasting plasma ghrelin levels were significantly higher than in C. After ingestion of a test meal plasma ghrelin levels declined mostly at 60 min. In contrast to C, decreased ghrelinemia persisted over 120 min after ingestion of a test meal in both hemodialysis groups. There was no correlation between postprandial reduction in plasma ghrelin at 60 and 120 min and serum paracetamol concentration in HD and HD-DM, while in C decrease in postprandial plasma ghrelin at 60 min correlated with serum paracetamol concentrations. CONCLUSIONS: In hemodialysis patients plasma ghrelin levels are significantly elevated compared to healthy subjects. Prolonged postprandial suppression of ghrelin secretion may contribute to the pathogenesis of gastric emptying disorders in hemodialysis patients. Abnormal postprandial ghrelinemia was observed especially in patients with diabetic nephropathy. PMID- 19776685 TI - Cardiovascular abnormalities in patients with Turner syndrome according to karyotype: own experience and literature review. AB - BACKGROUND: Cardiovascular diseases account for a threefold higher mortality in women with Turner syndrome (TS). It has also been suggested that the occurrence of these diseases is dependent on karyotype. AIM: To assess the cardiovascular system by clinical examination, echocardiography and electrocardiography in female patients with TS, depending on karyotype. PATIENTS AND METHODS: Thirty four women with TS, aged 7-58 (35.2 +/-14.6) years, were evaluated. The patients were categorized into 3 groups according to karyotype: group 1 comprised 12 patients with monosomy X (45,X), group 2 comprised 19 women with mosaicism, and group 3 comprised 3 patients with structural aberrations of X chromosome. Echocardiography was performed using the Sonos 5500 machine, following the current standards. RESULTS: Congenital cardiovascular malformations were detected in 21% of TS women. Valvular heart disease was present in 50% of the entire study population, including aortic valve diseases in 24% and mitral valve diseases in 21%. The patients with mosaicism, more often than those with monosomy X, were overweight and had a tendency to higher incidence of hypertension, as well as thicker interventricular septum, and larger left ventricular mass on echocardiography. CONCLUSIONS: Congenital cardiovascular malformations are more common in TS patients compared to the general population. There were no differences in risk factors and cardiovascular abnormalities between various karyotypes except for higher incidence of overweight and tendency to higher blood pressure, thicker interventricular septum, and larger left ventricular mass observed in patients with mosaicism compared to those with monosomy X. PMID- 19776686 TI - Postprandial lipemia in diabetic men during hypolipemic therapy. AB - INTRODUCTION: Mechanisms underlying postprandial lipemia in various pathological states remain to be elucidated. OBJECTIVES: The aim of the study was to evaluate lipid homeostasis in men with type 2 diabetes mellitus (DM) after a standard meal. Moreover, the effect of short-term hypolipemic therapy on postprandial lipemia was assessed. PATIENTS AND METHODS: Twenty-six men with DM aged 53 +/-6.7 years, 27 patients with hyperlipemia and no DM (asymptomatic hyperlipemia - AH) and 60 normolipemic subjects aged 46 +/-11 years were included in the study. Treatment with simvastatin (20 mg/d) or fenofibrate (267 mg/d) was initiated in all DM patients due to fasting hyperlipemia, and in the AH group. Blood samples were drawn in the fasting state and 3 h after a meal at three time points, i.e. at baseline, after 6 and 12 weeks of treatment. Triglycerides (TG), glucose, total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), HDL2-C, and HDL3-C were assayed by routine laboratory tests; apolipoproteins A and B by immunoturbidimetry, and high sensitivity C-reactive protein (hsCRP) by immunonephelometry. RESULTS: In men with DM, changes in triglycerides induced by a meal (140 +/-68.0 mg/dl) were higher compared to normolipemic men (62.1 +/-52.5 mg/dl, p <0.001) or AH subjects (76.3 +/-80 mg/dl, p <0.05). There were no linear correlations between the levels of TG (or HDL cholesterol) and HDL3-C, or between TG and hsCRP in the DM group. Hypolipemic treatment decreased fasting lipid and hsCRP levels, significantly reduced postprandial lipemia (p <0.001) and restored some correlations between lipid variables observed in the control group, but not those with hsCRP. CONCLUSIONS: Type 2 DM is associated with increased postprandial lipemia and abnormal lipid homeostasis. Lipid intolerance detected in a postprandial lipemia test may be an indication for hypolipemic therapy. PMID- 19776687 TI - 2009 Clinical Guidelines from the American Pain Society and the American Academy of Pain Medicine on the use of chronic opioid therapy in chronic noncancer pain: what are the key messages for clinical practice? AB - Safe and effective chronic opioid therapy (COT) for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and in the assessment and management of risks associated with opioid abuse, addiction, and diversion. The American Pain Society and the American Academy of Pain Medicine commissioned a systematic review of the evidence on COT for chronic noncancer pain and convened a multidisciplinary expert panel to review the evidence and formulate recommendations based on the best available evidence. This article summarizes key clinical messages from this guideline regarding patient selection and risk stratification, informed consent and opioid management plans, initiation and titration of COT, use of methadone, monitoring of patients, use of opioids in high-risk patients, assessment of aberrant drug related behaviors, dose escalations and high-dose opioid therapy, opioid rotation, indications for discontinuation of therapy, prevention and management of opioid-related adverse effects, driving and work safety, identifying a medical home and when to obtain consultation, and management of breakthrough pain. PMID- 19776688 TI - First-line pharmacotherapies for depression - what is the best choice? AB - Major depressive disorder is a significant public health problem and the leading cause of suicide worldwide. Since the discovery of the first effective medications for depression in the late 1950s, a variety of pharmacotherapies have been developed that are useful for treating the full range of depressive disorders. The availability of safer classes of antidepressants, as well as other factors, has resulted in a large increase in the number of depressed individuals who are treated for depression by their primary care providers. This review examines the antidepressants that are currently used as the initial or "first line" therapies for major depressive disorder (MDD). These newer medications may be grouped into three classes: the selective serotonin reuptake inhibitors, the serotonin and norepinephrine reuptake inhibitors, and the norepinephrine-dopamine reuptake inhibitor. While the modern classes of antidepressants offer superior tolerability and safety over older medications such as the tricyclic antidepressants, there remains no universally effective pharmacologic treatment for MDD, and effective disease management requires careful attention to ongoing assessment of medication response and management of side effects. PMID- 19776689 TI - Dyslipidemia in chronic kidney disease: pathogenesis and intervention. AB - Dyslipidemia is a known cardiovascular risk factor in subjects without kidney disease. In patients with kidney disease, however, the relation of dyslipidemia to cardiovascular risk is confounded and the underlying pathomechanisms are complex. Statins have proven to be highly effective in patients with initial stages of chronic kidney disease (CKD). Definite evidence from prospective controlled trials in hemodialyzed (diabetic) patients and transplanted patients is not available. Although no significant impact on the primary composite endpoint was observed, significant effects on secondary endpoints were noted. In our opinion, in view of excessive cardiovascular risk statins should be administered in patients with advanced CKD as well. PMID- 19776690 TI - The role of "metabolic memory" in the natural history of diabetes mellitus. AB - There is growing evidence that early, intensive treatment of new-onset diabetes mellitus aimed at tight glucose control reduces the risk of micro- and macrovascular complications. Metabolic memory is a term used to describe beneficial effects of immediate intensive treatment of hyperglycemia and the observation that they are maintained for many years, regardless of glycemia in the later course of diabetes. This phenomenon was first observed in preclinical studies and was later confirmed in large clinical trials. It has been suggested that early glycemia normalization can halt hyperglycemia-induced pathological processes associated with enhanced oxidative stress and glycation of cellular proteins and lipids. The phenomenon of metabolic memory suggests that antioxidants and agents degrading advanced glycation end products in addition to strict hypoglycemic treatment can be used to prevent chronic diabetic complications. PMID- 19776691 TI - S-nitroso-human-albumin: a new therapeutic approach in endotoxic shock. AB - INTRODUCTION: Endotoxemia leads to induction of inducible nitric oxide synthase (iNOS) and increased expression of numerous inflammatory mediators, contributing to endotoxin-induced acute lung injury. OBJECTIVES: We examined the hypothesis that supplementation of nitric oxide (NO) with the novel NO donor, S-nitroso human-serum-albumin (S-NO-HSA), may reduce iNOS expression, lung inflammation and acute lung injury in a rat model of septic shock. MATERIAL AND METHODS: Rats were divided into 4 groups: sham-operated (no treatment), LPS (lipopolysaccharide), LPS + HSA, and LPS + S-NO-HSA. Endotoxin-induced (20 mg kg-1, iv) lung injury was characterized by measurement of wet/dry weight ratio (pulmonary edema), myeloperoxidase activity (pulmonary neutrophil infiltration), expression of intercellular adhesion molecule-1, iNOS, and cyclooxygenase-2. RESULTS: LPS induced acute lung injury involved pulmonary edema, neutrophil infiltration and a strong inflammatory response, resulting in high mortality within 6 h. S-NO-HSA prolonged survival of endotoxemic rats, reduced hypotensive response to LPS, and minimized LPS-induced lung edema by modulation of systemic inflammatory response. CONCLUSIONS: NO supplementation with S-NO-HSA after LPS administration prevents induction of iNOS, protects against endotoxin-induced acute lung injury, and reduces early mortality in endotoxic rats. The results of the study support a therapeutic role of S-NO-HSA in the treatment of endotoxemia. PMID- 19776692 TI - Graves' disease with an autonomously functioning thyroid nodule: case report. AB - We present the case of a 68-year-old woman with Graves' disease, orbitopathy and an autonomously functioning thyroid nodule. Initially, the patient was diagnosed with orbitopathy as a sign of euthyroid Graves-Basedow's disease, confirmed by the presence of thyrotropin receptor antibodies. Five years later symptoms of hyperthyroidism occurred. Thyroid scan with iodine-131 (131I) showed a hot nodule in the right lobe. Recurrences of hyperthyroidism and short remissions were observed in the course of the disease - the symptoms typical of hyperthyroidism due to an autonomously functioning thyroid nodule. Fine needle aspiration biopsy of the nodule revealed no atypical follicular cells and the patient was scheduled for 131I treatment. She has been euthyroid for over one year. PMID- 19776694 TI - Sarcoidosis: selected clinical cases. AB - Two interesting cases of sarcoidosis and associated diagnostic challenges have been presented. Clinical similarities and disparities in the course of sarcoidosis and systemic connective tissue diseases, particularly Sjogren's syndrome, have been addressed. It has been highlighted that all organs, not only the lungs but also for example the liver, can be involved in sarcoidosis. Prompt diagnosis and a proper therapeutic approach are of vital importance. PMID- 19776693 TI - Henoch-Schonlein purpura: an atypical cause of abdominal pain in a 70-year-old man: case report. AB - Henoch-Schonlein purpura (HSP) is a leukocytoclastic small-vessel vasculitis involving small vessels with the deposition of immune complexes containing immunoglobulin A and neutrophil and eosinophilic infiltration. Clinical manifestations include 4 classic signs and symptoms: skin lesions, arthralgias, abdominal pain, and renal disease. HSP primarily affects children and is uncommon in adults. However, the clinical course of HSP is more severe and prognosis worse in the adult population, despite the fact that the incidence of this disease is 20-fold lower in adults than in children. We present a 70-year-old man with HSP who has been successfully treated. PMID- 19776695 TI - Antihypertensive treatment and dementia. PMID- 19776696 TI - Changes in antioxidant status and lipid peroxidation in Nigerian patients with prostate carcinoma. AB - INTRODUCTION: Oxidative stress has been implicated in the etiology of several pathologies. OBJECTIVES: The study was designed to investigate the levels of antioxidants and lipid peroxidation (LPO) in relation to prostate-specific antigen (PSA) levels in blood of Nigerian prostate cancer (PCa) patients. PATIENTS AND METHODS: One hundred twenty PCa patients were assigned to 3 groups; group 1 (low grade) with a PSA level of 5-10 ng/ml (n = 33), group 2 (medium grade) with PSA of 11-20 ng/ml (n = 45) and group 3 (high grade) with PSA >20 ng/ml (n = 42). The control group comprised 50 healthy subjects with PSA <3.0 ng/ml. RESULTS: Subjects with a PSA level of 11-20 ng/ml and PSA >20 ng/ml had significantly lower uric acid and reduced glutathione levels (p <0.05). A significant reduction (p <0.05) in plasma vitamin C and E levels was observed in these patients. The levels of vitamins C and E decreased by 27% and 77% in subjects with PSA >20 ng/ml, and by 25% and 47% in subjects with a PSA level of 11-20 ng/ml, respectively. Serum total bilirubin, alkaline phosphatase (ALP) and LPO were significantly (p <0.05) elevated in subjects with PSA >11 ng/ml. More specifically, total bilirubin, ALP and LPO levels were elevated by 75%, 66% and 107% in subjects with PSA at 11-20 ng/ml, and by 167%, 105%, 98% in subjects with PSA > or = 20 ng/ml, respectively. Moreover, superoxide dismutase and catalase activities were lower (p <0.05) in all cancer patients. CONCLUSIONS: The results confirmed the depletion of antioxidants in PCa patients, and an inverse relationship between antioxidants and PSA values in this group. PMID- 19776697 TI - Characteristics of patients with type 2 diabetes of short duration in Poland: Rationale, design and preliminary results of the ARETAEUS1 study. AB - INTRODUCTION: There is a paucity of Polish data describing the characteristics of and assessing treatment goals in patients with relatively newly diagnosed type 2 diabetes. OBJECTIVES: The aim of the study was to describe the baseline characteristics of patients with newly diagnosed type 2 diabetes, who participated in the ARETAEUS1 study, and to assess to what degree diabetic control criteria recommended by the Polish Diabetes Association clinical practice guidelines are met. PATIENTS AND METHODS: This cross-sectional questionnaire based study was conducted from January to April 2009. It involved patients of any age and gender, diagnosed with type 2 diabetes after January 1, 2007, and recruited by randomly selected physicians, both diabetologists and non diabetologists. RESULTS: We analyzed 1714 valid questionnaires from 333 physicians: 1150 from non-diabetologists and 564 from diabetologists. Mean age of patients was 60 years, mean body mass index -- 30.6 kg/m2, proportion of females - 50%. The levels of median glycated hemoglobin (HbA1c), total cholesterol and triglycerides, mean low-density lipoprotein (LDL) cholesterol, as well as blood pressure were above the thresholds recommended in the guidelines (i.e., <6.5% for HbA1c, <4.5 mmol/l for total cholesterol, <2.6 mmol/l [or <1.8 mmol/l in patients with coronary heart disease (CHD)] for LDL cholesterol, <1.7 mmol/l for triglycerides, and <130/80 mmHg for blood pressure). Cardiovascular disease risk factors were common: hypertension was reported in over 75% of patients, lipid disorders in nearly 75%, CHD in 27% (previous acute coronary syndrome or stable CHD), previous stroke in 4%, and previous transient ischemic attack in 5.5%. Diabetic foot was reported in 1.7% of patients, nephropathy in 7%, retinopathy in 9% (in the group of diabetologists) and in 21% of patients (in the group of non diabetologists). CONCLUSIONS: We observed a relatively high prevalence of cardiovascular disease risk factors and late diabetes complications in patients with diabetes diagnosed within the previous 2 years. PMID- 19776698 TI - 2009 evidence-based clinical practice guidelines for diagnosing a first episode of lower extremities deep vein thrombosis in ambulatory outpatients. AB - INTRODUCTION: The GRADE working group has recently suggested a rigorous framework for clinical practice guidelines (CPG) addressing diagnostic tests and test strategies based on the impact of alternative approaches on patient-important outcomes. The framework mandates explicit evidence summaries, ratings of the quality of evidence, and specifying recommendations as strong or weak. OBJECTIVES: To test the feasibility and performance of the GRADE approach, we applied this framework to well-researched issues in the diagnoses of deep venous thrombosis (DVT). METHODS: A 16-member panel with interest in thromboembolism and CPG development identified pertinent clinical questions. Our search for relevant studies included existing CPG and systematic reviews. We summarized the data in form of evidence tables and developed recommendations including, when needed, a formal consensus process. RESULTS AND CONCLUSIONS: We provide three groups of recommendations for clinicians practicing in settings with access to different types of D-dimer tests -- highly sensitive, moderately sensitive, and no availability of D-dimer. We consider the use of clinical prediction rules in guiding the diagnostic process, the potential for negative D-dimer or venous ultrasound (US) to rule out disease, and the role of follow-up testing (US following positive D-dimer result, D-dimer following negative US, and serial US) depending on the probability of DVT at the start of diagnostic process. We recommend the following: that clinicians without access to a highly or moderately sensitive D-dimer test rely on US to guide DVT diagnosis; that those with access use the highly sensitive D-dimer to determine, in patients with low or moderate probability of DVT (by the Wells rule) whether US is needed; that in patients with low pre-test probability (pre-TP) and a negative D-dimer (either highly or moderately sensitive) they follow patients without further testing; that in patients with high pre-test probability they perform a compression ultrasound without D-dimer testing. PMID- 19776699 TI - Additional spirometry criteria predict postoperative complications after coronary artery bypass grafting (CABG) independently of concomitant chronic obstructive pulmonary disease: when is off-pump CABG more beneficial? AB - INTRODUCTION: Concomitant chronic obstructive pulmonary disease (COPD) is associated with an increased rate of post-coronary artery bypass grafting (CABG) complications. The ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) <70%, proposed by the Global Initiative for Chronic Obstructive Lung Disease as a criterion for the diagnosis of COPD, is criticized for not considering physiological, age-related changes in lung function. OBJECTIVES: The aim of the study was to evaluate which of the additional spirometric parameters, adjusted for age and the distribution of values in the population, represent the best predictors of post-CABG complications and to identify patients who are more likely to benefit from off-pump cardiac bypass (OPCAB) than from CABG. PATIENTS AND METHODS: In the retrospective cohort study, data from a total of 3617 CABG or OPCAB patients were recorded. Patients with COPD, diagnosed prior to admission, were classified according to the spirometry results: group 1 with FEV1/FVC <70%, group 2 with FEV1/FVC below the mean normal value adjusted to age, group 3 with FEV1/FVC below the lower limit of normal (LLN), group 4 with FEV1 11 mg/kg/day during exposure to supplemental sessions with the shortest post-injection time-out. However, parameters of cocaine choice were not significantly affected either during or after extended cocaine access. These results do not support the hypothesis that cocaine withdrawal increases the reinforcing strength of cocaine. This differs from results with the opioid agonist heroin and suggests that withdrawal may have different functions in the maintenance of opioid and stimulant abuse. PMID- 19776728 TI - The episodic memory system: neurocircuitry and disorders. AB - The ability to encode and retrieve our daily personal experiences, called episodic memory, is supported by the circuitry of the medial temporal lobe (MTL), including the hippocampus, which interacts extensively with a number of specific distributed cortical and subcortical structures. In both animals and humans, evidence from anatomical, neuropsychological, and physiological studies indicates that cortical components of this system have key functions in several aspects of perception and cognition, whereas the MTL structures mediate the organization and persistence of the network of memories whose details are stored in those cortical areas. Structures within the MTL, and particularly the hippocampus, have distinct functions in combining information from multiple cortical streams, supporting our ability to encode and retrieve details of events that compose episodic memories. Conversely, selective damage in the hippocampus, MTL, and other structures of the large-scale memory system, or deterioration of these areas in several diseases and disorders, compromises episodic memory. A growing body of evidence is converging on a functional organization of the cortical, subcortical, and MTL structures that support the fundamental features of episodic memory in humans and animals. PMID- 19776730 TI - Involvement of hippocampal jun-N terminal kinase pathway in the enhancement of learning and memory by nicotine. AB - Despite intense scrutiny over the past 20 years, the reasons for the high addictive liability of nicotine and extreme rates of relapse in smokers have remained elusive. One factor that contributes to the development and maintenance of nicotine addiction is the ability of nicotine to produce long-lasting modifications of behavior, yet little is known about the mechanisms by which nicotine alters the underlying synaptic plasticity responsible for behavioral changes. This study is the first to explore how nicotine interacts with learning to alter gene transcription, which is a process necessary for long-term memory consolidation. Transcriptional upregulation of hippocampal jun-N terminal kinase 1 (JNK1) mRNA was found in mice that learned contextual fear conditioning (FC) in the presence of nicotine, whereas neither learning alone nor nicotine administration alone exerted an effect. Furthermore, the upregulation of JNK1 was absent in beta2 nicotinic receptor subunit knockout mice, which are mice that do not show enhanced learning by nicotine. Finally, hippocampal JNK activation was increased in mice that were administered nicotine before conditioning, and the inhibition of JNK during consolidation prevented the nicotine-induced enhancement of contextual FC. These data suggest that nicotine and learning interact to alter hippocampal JNK1 gene expression and related signaling processes, thus resulting in strengthened contextual memories. PMID- 19776731 TI - Aggression, suicidality, and intermittent explosive disorder: serotonergic correlates in personality disorder and healthy control subjects. AB - Central serotonergic (5-HT) activity has long been implicated in the regulation of impulsive aggressive behavior. This study was performed to use a highly selective agent for 5-HT (d-Fenfluramine, d-FEN) in a large group of human subjects to further explore this relationship dimensionally and categorically. One hundred and fifty healthy subjects (100 with personality disorder, PD and 50 healthy volunteer controls, HV) underwent d-FEN challenge studies. Residual peak delta prolactin (DeltaPRL[d-FEN]-R; ie, after the removal of potentially confounding variables) was used as the primary 5-HT response variable. Composite measures of aggression and impulsivity were used as dimensional measures, and history of suicidal/self-injurious behavior as well as the presence of intermittent explosive disorder (IED) were used as categorical variables. DeltaPRL[d-FEN]-R responses correlated inversely with composite aggression, but not composite impulsivity, in all subjects and in males and females examined separately. The correlation with composite aggression was strongest in male PD subjects. DeltaPRL[d-FEN]-R values were reduced in PD subjects with a history of suicidal behavior but not, self-injurious behavior. DeltaPRL[d-FEN]-R values were also reduced in patients meeting Research Criteria for IED. Physiologic responses to 5-HT stimulation are reduced as a function of aggression (but not generalized impulsivity) in human subjects. The same is true for personality disordered subjects with a history of suicidal, but not self-injurious, behavior and for subjects with a diagnosis of IED by research criteria. These data have particular relevance to the notion of impulsive aggression and the biological validity of IED. PMID- 19776732 TI - Voluntary exercise and sucrose consumption enhance cannabinoid CB1 receptor sensitivity in the striatum. AB - The endogenous cannabinoid system is involved in the regulation of the central reward pathway. Running wheel and sucrose consumption have rewarding and reinforcing properties in rodents, and share many neurochemical and behavioral characteristics with drug addiction. In this study, we investigated whether running wheel or sucrose consumption altered the sensitivity of striatal synapses to the activation of cannabinoid CB1 receptors. We found that cannabinoid CB1 receptor-mediated presynaptic control of striatal inhibitory postsynaptic currents was remarkably potentiated after these environmental manipulations. In contrast, the sensitivity of glutamate synapses to CB1 receptor stimulation was unaltered, as well as that of GABA synapses to the stimulation of presynaptic GABAB receptors. The sensitization of cannabinoid CB1 receptor-mediated responses was slowly reversible after the discontinuation of running wheel or sucrose consumption, and was also detectable following the mobilization of endocannabinoids by metabotropic glutamate receptor 5 stimulation. Finally, we found that the upregulation of cannabinoid transmission induced by wheel running or sucrose had a crucial role in the protective effects of these environmental manipulations against the motor and synaptic consequences of stress. PMID- 19776733 TI - Increased basal synaptic inhibition of hippocampal area CA1 pyramidal neurons by an antiepileptic drug that enhances I(H). AB - The hyperpolarization-activated cation current (I(H)) regulates the electrical activity of many excitable cells, but its precise function varies across cell types. The antiepileptic drug lamotrigine (LTG) was recently shown to enhance I(H) in hippocampal CA1 pyramidal neurons, showing a potential anticonvulsant mechanism, as I(H) can dampen dendrito-somatic propagation of excitatory postsynaptic potentials in these cells. However, I(H) is also expressed in many hippocampal interneurons that provide synaptic inhibition to CA1 pyramidal neurons, and thus, I(H) modulation may indirectly regulate the inhibitory control of principal cells by direct modulation of interneuron activity. Whether I(H) in hippocampal interneurons is sensitive to modulation by LTG, and the manner by which this may affect the synaptic inhibition of pyramidal cells has not been investigated. In this study, we examined the effects of LTG on I(H) and spontaneous firing of area CA1 stratum oriens interneurons, as well as on spontaneous inhibitory postsynaptic currents in CA1 pyramidal neurons in immature rat brain slices. LTG (100 microM) significantly increased I(H) in the majority of interneurons, and depolarized interneurons from rest, promoting spontaneous firing. LTG also caused an increase in the frequency of spontaneous (but not miniature) IPSCs in pyramidal neurons without significantly altering amplitudes or rise and decay times. These data indicate that I(H) in CA1 interneurons can be increased by LTG, similarly to I(H) in pyramidal neurons, that I(H) enhancement increases interneuron excitability, and that these effects are associated with increased basal synaptic inhibition of CA1 pyramidal neurons. PMID- 19776735 TI - The influence of chronic renal failure on drug metabolism and transport. AB - Chronic renal failure (CRF) has been shown, in animal models and clinical studies, to significantly reduce nonrenal clearance and to alter the bioavailability of predominantly metabolized drugs. Phase II reactions and drug transporters such as P-glycoprotein (P-gp) and organic anion transporting polypeptide (OATP) are also affected. High levels of parathyroid hormone (PTH), cytokines, and uremic toxins are implicated in some of these effects, which have a clinically significant impact on drug disposition and increase the risk of adverse drug reaction. PMID- 19776736 TI - Drug development perspective on pharmacokinetic studies of new drugs in patients with renal impairment. AB - Severe renal impairment can, through diverse mechanisms, alter the pharmacokinetics (PK) of drugs that are renally eliminated and even of some drugs that are nonrenally eliminated. Consequently, dose adjustment for new molecular entities in patients with renal insufficiency is a critical issue in drug development. Clinical pharmacology studies undertaken in patients with renal impairment are generally quite small. We therefore recommend that all pertinent pharmacokinetic data relating to subjects with different degrees of renal impairment and from different clinical trials, including population pharmacokinetic evaluation, form the basis for dosage recommendations in renal impairment. The Modification of Diet in Renal Disease (MDRD) equation has gained popularity for renal insufficiency classification, but traditional equations such as the Cockcroft-Gault (C-G) formula should enjoy continued use so as to avoid confusion, particularly for drugs for which dosing guidelines have previously been developed. PMID- 19776734 TI - Human and rodent homologies in action control: corticostriatal determinants of goal-directed and habitual action. AB - Recent behavioral studies in both humans and rodents have found evidence that performance in decision-making tasks depends on two different learning processes; one encoding the relationship between actions and their consequences and a second involving the formation of stimulus-response associations. These learning processes are thought to govern goal-directed and habitual actions, respectively, and have been found to depend on homologous corticostriatal networks in these species. Thus, recent research using comparable behavioral tasks in both humans and rats has implicated homologous regions of cortex (medial prefrontal cortex/medial orbital cortex in humans and prelimbic cortex in rats) and of dorsal striatum (anterior caudate in humans and dorsomedial striatum in rats) in goal-directed action and in the control of habitual actions (posterior lateral putamen in humans and dorsolateral striatum in rats). These learning processes have been argued to be antagonistic or competing because their control over performance appears to be all or none. Nevertheless, evidence has started to accumulate suggesting that they may at times compete and at others cooperate in the selection and subsequent evaluation of actions necessary for normal choice performance. It appears likely that cooperation or competition between these sources of action control depends not only on local interactions in dorsal striatum but also on the cortico-basal ganglia network within which the striatum is embedded and that mediates the integration of learning with basic motivational and emotional processes. The neural basis of the integration of learning and motivation in choice and decision-making is still controversial and we review some recent hypotheses relating to this issue. PMID- 19776737 TI - Genetic influences on the pharmacokinetics of orally and intravenously administered digoxin as exhibited by monozygotic twins. AB - The expression and function of the drug transporter P-glycoprotein are highly variable. Environmental and genetic factors contribute to this variation. We studied the disposition of digoxin, a frequently used probe drug for P glycoprotein function in humans, in monozygotic (MZ) twins and found that digoxin pharmacokinetics after oral and intravenous administration are highly correlated within MZ twins, supporting the hypothesis of a robust contribution from genetic variance. Our study suggests that studies involving twins could be more widely applied to elucidate pharmacogenetics. PMID- 19776738 TI - Pharmacokinetics of sulfadoxine and pyrimethamine in intermittent preventive treatment of malaria in pregnancy. AB - Malaria during pregnancy is associated with maternal and fetal morbidity and mortality. In order to minimize the burden, sulfadoxine-pyrimethamine (SP) is widely used in Africa as an intermittent preventive treatment of malaria in pregnancy (IPTp). However, only limited data are available on the pharmacokinetics of sulfadoxine and pyrimethamine during pregnancy. We conducted a prospective, self-matched, multicenter study of 98 pregnant women in four African countries in order to determine the effects of pregnancy on SP pharmacokinetics. After adjusting for the effects of potential confounders, blood concentrations (associated with therapeutic efficacy) of pyrimethamine were higher (geometric mean ratio (GMR) 1.33; 95% confidence interval (CI) 1.18-1.51; P < 0.001) and those of sulfadoxine were lower (GMR 0.91; 95% CI 0.84-0.98; P = 0.013) on day 7 after SP administration during pregnancy than after the postpartum period. SP pharmacokinetic parameters differed significantly among the study sites. Given the inconsistency of changes in pharmacokinetic parameters between sulfadoxine and pyrimethamine as well as among the study sites, it is not possible to recommend any dose adjustment to prolong the therapeutic life span of the fixed dose combination of SP for IPTp on the basis of our study findings. PMID- 19776739 TI - Direct RNA sequencing. AB - Our understanding of human biology and disease is ultimately dependent on a complete understanding of the genome and its functions. The recent application of microarray and sequencing technologies to transcriptomics has changed the simplistic view of transcriptomes to a more complicated view of genome-wide transcription where a large fraction of transcripts emanates from unannotated parts of genomes, and underlined our limited knowledge of the dynamic state of transcription. Most of this broad body of knowledge was obtained indirectly because current transcriptome analysis methods typically require RNA to be converted to complementary DNA (cDNA) before measurements, even though the cDNA synthesis step introduces multiple biases and artefacts that interfere with both the proper characterization and quantification of transcripts. Furthermore, cDNA synthesis is not particularly suitable for the analysis of short, degraded and/or small quantity RNA samples. Here we report direct single molecule RNA sequencing without prior conversion of RNA to cDNA. We applied this technology to sequence femtomole quantities of poly(A)(+) Saccharomyces cerevisiae RNA using a surface coated with poly(dT) oligonucleotides to capture the RNAs at their natural poly(A) tails and initiate sequencing by synthesis. We observed transcript 3' end heterogeneity and polyadenylated small nucleolar RNAs. This study provides a path to high-throughput and low-cost direct RNA sequencing and achieving the ultimate goal of a comprehensive and bias-free understanding of transcriptomes. PMID- 19776740 TI - STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. AB - The innate immune system is critical for the early detection of invading pathogens and for initiating cellular host defence countermeasures, which include the production of type I interferon (IFN). However, little is known about how the innate immune system is galvanized to respond to DNA-based microbes. Here we show that STING (stimulator of interferon genes) is critical for the induction of IFN by non-CpG intracellular DNA species produced by various DNA pathogens after infection. Murine embryonic fibroblasts, as well as antigen presenting cells such as macrophages and dendritic cells (exposed to intracellular B-form DNA, the DNA virus herpes simplex virus 1 (HSV-1) or bacteria Listeria monocytogenes), were found to require STING to initiate effective IFN production. Accordingly, Sting knockout mice were susceptible to lethal infection after exposure to HSV-1. The importance of STING in facilitating DNA-mediated innate immune responses was further evident because cytotoxic T-cell responses induced by plasmid DNA vaccination were reduced in Sting-deficient animals. In the presence of intracellular DNA, STING relocalized with TANK-binding kinase 1 (TBK1) from the endoplasmic reticulum to perinuclear vesicles containing the exocyst component Sec5 (also known as EXOC2). Collectively, our studies indicate that STING is essential for host defence against DNA pathogens such as HSV-1 and facilitates the adjuvant activity of DNA-based vaccines. PMID- 19776741 TI - Extensive dynamic thinning on the margins of the Greenland and Antarctic ice sheets. AB - Many glaciers along the margins of the Greenland and Antarctic ice sheets are accelerating and, for this reason, contribute increasingly to global sea-level rise. Globally, ice losses contribute approximately 1.8 mm yr(-1) (ref. 8), but this could increase if the retreat of ice shelves and tidewater glaciers further enhances the loss of grounded ice or initiates the large-scale collapse of vulnerable parts of the ice sheets. Ice loss as a result of accelerated flow, known as dynamic thinning, is so poorly understood that its potential contribution to sea level over the twenty-first century remains unpredictable. Thinning on the ice-sheet scale has been monitored by using repeat satellite altimetry observations to track small changes in surface elevation, but previous sensors could not resolve most fast-flowing coastal glaciers. Here we report the use of high-resolution ICESat (Ice, Cloud and land Elevation Satellite) laser altimetry to map change along the entire grounded margins of the Greenland and Antarctic ice sheets. To isolate the dynamic signal, we compare rates of elevation change from both fast-flowing and slow-flowing ice with those expected from surface mass-balance fluctuations. We find that dynamic thinning of glaciers now reaches all latitudes in Greenland, has intensified on key Antarctic grounding lines, has endured for decades after ice-shelf collapse, penetrates far into the interior of each ice sheet and is spreading as ice shelves thin by ocean driven melt. In Greenland, glaciers flowing faster than 100 m yr(-1) thinned at an average rate of 0.84 m yr(-1), and in the Amundsen Sea embayment of Antarctica, thinning exceeded 9.0 m yr(-1) for some glaciers. Our results show that the most profound changes in the ice sheets currently result from glacier dynamics at ocean margins. PMID- 19776742 TI - The expanding universe of p53 targets. AB - The p53 tumour suppressor is modified through mutation or changes in expression in most cancers, leading to the altered regulation of hundreds of genes that are directly influenced by this sequence-specific transcription factor. Central to the p53 master regulatory network are the target response element (RE) sequences. The extent of p53 transactivation and transcriptional repression is influenced by many factors, including p53 levels, cofactors and the specific RE sequences, all of which contribute to the role that p53 has in the aetiology of cancer. This Review describes the identification and functionality of REs and highlights the inclusion of non-canonical REs that expand the universe of genes and regulation mechanisms in the p53 tumour suppressor network. PMID- 19776743 TI - p53 and E2f: partners in life and death. AB - During tumour development cells sustain mutations that disrupt normal mechanisms controlling proliferation. Remarkably, the Rb-E2f and MDM2-p53 pathways are both defective in most, if not all, human tumours, which underscores the crucial role of these pathways in regulating cell cycle progression and viability. A simple interpretation of the observation that both pathways are deregulated is that they function independently in the control of cell fate. However, a large body of evidence indicates that, in addition to their independent effects on cell fate, there is extensive crosstalk between these two pathways, and specifically between the transcription factors E2F1 and p53, which influences vital cellular decisions. This Review discusses the molecular mechanisms that underlie the intricate interactions between E2f and p53. PMID- 19776744 TI - The first 30 years of p53: growing ever more complex. AB - Thirty years ago p53 was discovered as a cellular partner of simian virus 40 large T-antigen, the oncoprotein of this tumour virus. The first decade of p53 research saw the cloning of p53 DNA and the realization that p53 is not an oncogene but a tumour suppressor that is very frequently mutated in human cancer. In the second decade of research, the function of p53 was uncovered: it is a transcription factor induced by stress, which can promote cell cycle arrest, apoptosis and senescence. In the third decade after its discovery new functions of this protein were revealed, including the regulation of metabolic pathways and cytokines that are required for embryo implantation. The fourth decade of research may see new p53-based drugs to treat cancer. What is next is anybody's guess. PMID- 19776745 TI - p53 ancestry: gazing through an evolutionary lens. AB - Evolutionary patterns indicate that primordial p53 genes predated the appearance of cancer. Therefore, wild-type tumour suppressive functions and mutant oncogenic functions that give celebrity status to this gene family were probably co-opted from unrelated primordial activities. Is it possible to deduce what these early functions might have been? And might this knowledge provide a platform for therapeutic opportunities? PMID- 19776747 TI - p53--a Jack of all trades but master of none. AB - Cancers are rare because their evolution is actively restrained by a range of tumour suppressors. Of these p53 seems unusually crucial as either it or its attendant upstream or downstream pathways are inactivated in virtually all cancers. p53 is an evolutionarily ancient coordinator of metazoan stress responses. Its role in tumour suppression is likely to be a relatively recent adaptation, which is only necessary when large, long-lived organisms acquired the sufficient size and somatic regenerative capacity to necessitate specific mechanisms to reign in rogue proliferating cells. However, such evolutionary reappropriation of this venerable transcription factor entails compromises that restrict its efficacy as a tumour suppressor. PMID- 19776749 TI - Cardiovascular disease risk, vascular health and erectile dysfunction among middle-aged, clinically depressed men. AB - Erectile dysfunction (ED) is especially common in men with major depressive disorder (MDD). This study examined the extent to which risk factors for cardiovascular disease (CVD) and vascular endothelial dysfunction were associated with ED severity in MDD patients. The sample included 46 middle-aged [M (s.d.)=53 (7) years], sedentary men diagnosed with MDD. ED severity was assessed by the Arizona Sexual Experiences Scale (ASEX), item 3. Depression severity was measured by the Beck Depression Inventory-II (BDI). The Framingham risk score was calculated as a composite measure of CVD risk factors. Vascular endothelial function was measured by flow-mediated dilation (FMD) of the brachial artery. Regression analysis showed that ASEX scores were predicted by the greater Framingham risk score (beta=0.41, P=0.008) and lower FMD (beta=-0.38, P=0.01), but not by BDI scores (beta=0.00, P=0.99). When FMD was included in the regression model, the relationship between Framingham risk and ASEX scores was partially attenuated (beta=0.27, P=0.08). ED was associated with greater CVD risk and impaired vascular endothelial function in depressed men. CVD risk factors may affect ED through impairment of vascular endothelial function. PMID- 19776746 TI - 20 years studying p53 functions in genetically engineered mice. AB - Cell and molecular biological studies of p53 functions over the past 30 years have been complemented in the past 20 years by studies that use genetically engineered mice. As expected, mice that have mutant Trp53 alleles usually develop cancers of various types more rapidly than their counterparts that have wild-type Trp53 genes. These mouse studies have been instrumental in providing important new insights into p53 tumour suppressor function. Such studies have been facilitated by the development of increasingly sophisticated genetic engineering approaches, which allow the more precise manipulation of p53 structure and function in a mammalian model. PMID- 19776750 TI - Is erectile dysfunction a predictor of cardiovascular events or stroke? A prospective study using a validated questionnaire. AB - Erectile dysfunction (ED) is linked to various cardiovascular risk factors and may therefore serve as a predictor of cardiovascular events. To gain further insight into this relationship, we reviewed all data regarding hospital admission for cardial or cerebral vascular disease that occurred until 2008 in a cohort of men who underwent a health investigation in 2001. Erectile function was assessed using the International Index of Erectile Function (IIEF-5) questionnaire. In total, 2506 men with a negative history of cardial or cerebral vascular disease were analysed. During the 6.5-year follow-up, 58 cardiovascular events (2.3%) occurred. Men without ED (IIEF-5 >22; n=1636) at baseline developed a cardiovascular event in 1.9% (n=32) as compared with 2.9% (+52%; n=26) in those with ED (IIEF-5 < or =22; n=670). In contrast to age (hazard ratio (HR): 1.6; 1.2 1.8 for every decade), hypertension (HR: 1.88; 1.1-3.1) and diabetes (HR: 2.6; 1.2-5.8), ED was not an independent risk factor for a cardiovascular event. Although men with ED were at increased risk for future cardiovascular events, ED was not an age-independent predictor of cardiovascular events in our cohort. PMID- 19776751 TI - Management of subsequent pregnancy after an unexplained stillbirth. AB - PURPOSE: To review the management of pregnancy after an unexplained stillbirth. EPIDEMIOLOGY: Approximately 1 in 200 pregnancies will end in stillbirth, of which about one-third will remain unexplained. Unexplained stillbirth is the largest single contributor to perinatal mortality. Subsequent pregnancies do not appear to have an increased risk of stillbirth, but are characterized by increased rates of intervention (induction of labor, elective cesarean section) and iatrogenic adverse outcomes (low birth weight, prematurity, emergency cesarean section and post-partum hemorrhage). CONCLUSIONS: There is no level-one evidence to guide management in this situation. Pre-pregnancy counseling is very important to detect and correct potential risk factors such as obesity, smoking and maternal disease. As timely delivery is the mainstay of management, early accurate determination of gestational age is vital. There is controversy regarding the pattern of surveillance, but evidence exists only for ultrasound and not for regular non-stress testing, nor formal fetal movement charting. There is an urgent need for more studies in this important area. PMID- 19776752 TI - Neonatal outcomes of pregnancy complicated by idiopathic thrombocytopenic purpura. AB - OBJECTIVE: The aim of this study was to determine the factors associated with the prognosis of newborns born to mothers with idiopathic thrombocytopenic purpura (ITP), and to compare the infants with/without thrombocytopenia in terms of maternal and neonatal characteristics. STUDY DESIGN: We reviewed the charts of 29 parturients with ITP and their newborns who were born between January 1998 and December 2008. RESULT: A total of 16 (55%) gravidas had been diagnosed with ITP before pregnancy and 13 (45%) were diagnosed during pregnancy. Thrombocytopenia was observed in 21 gravidas. In total, 17 (58%) gravidas received treatment to increase the platelet count. The majority of deliveries (72.5%) were vaginal. The infant platelet counts at birth ranged from 20 to 336 x 10(9) per liter. None of the neonates had complications attributable to the mode of delivery. Normal platelet counts were determined in 15 newborns, whereas 14 infants had thrombocytopenia at birth. Three (10.3%) neonates had mild, four neonates (13.7%) had moderate and seven neonates (24.1%) had severe thrombocytopenia. The age of the mothers having infants with thrombocytopenia was significantly higher (30+/ 5.3 vs 25.3+/-3.8 years), most of the infants (10/14 (71%)) were males (P<0.05). CONCLUSION: Pregnancy complicated with ITP generally has a good outcome. Although ITP in pregnancy carries a low risk, careful observation is required for the newborn of gravidas with ITP even when the infant has no bleeding complications at delivery, and infants may require treatment for thrombocytopenia. PMID- 19776753 TI - Refractory neonatal candidemia and high-dose micafungin pharmacotherapy. AB - OBJECTIVE: Preterm neonates with candidemia frequently have persistently positive blood cultures, despite the use of conventional antifungal therapy. Our institutional treatment protocol for invasive candidiasis incorporates lipid complex amphotericin B as initial therapy with the sequential addition of fluconazole and high-dose micafungin (10 mg kg(-1)) every 48 to 72 h, if cultures from a sterile site remain positive. Our study objectives were to compare the clinical profiles and outcomes of preterm neonates with candidemia that responded to or were refractory to conventional antifungals. We further evaluate the clinical efficacy of high-dose micafungin pharmacotherapy of refractory candidemia. STUDY DESIGN: A chart review was performed on preterm infants (n=29) with invasive candidiasis and demographic, microbiologic and outcome data abstracted. Proportions and continuous variables were compared between the groups using Fisher's exact two-tailed test and t-test. RESULT: The refractory (n=19) candidemia and early responder (n=10) groups had comparable mean (+/-s.d.) gestation, 27(+/-3.1) vs 27.8 (+/-2.7) weeks. The refractory group was administered antibiotics for a longer duration, 14.5 (+/-10.3) vs 7.1 (+/-5) days, had a preponderance of non-albicans infections, 11 (57.9%) vs 1 (10%) and were on enteral feeds > 20 ml kg(-1) day(-1) significantly less often (21 vs 70%). Mortality was significantly higher (53 vs 20%) and fungal clearance rates lower (63.1 vs 90%), with a longer duration to clearance in the group with refractory candidemia. Mean aspartate aminotransferase (AST) showed a statistically significant increase following micafungin treatment, although clinical significance remains unclear. CONCLUSION: Candidemia refractory to conventional antifungals is associated with prolonged antibiotic use, lack of enteral nutritive feeds and non-albicans infection. Despite high-dose micafungin pharmacotherapy in combination with conventional antifungals, infants with refractory candidemia had high mortality and poor fungal clearance. PMID- 19776754 TI - Global notes: what is the cost of being a woman? PMID- 19776755 TI - Human skin aging is associated with reduced expression of the stem cell markers beta1 integrin and MCSP. PMID- 19776756 TI - Seasonal variation in haemodynamics and blood pressure-regulating hormones. AB - Seasonal variation in blood pressure (BP) has been described in some people, although the variation is small for both systolic and diastolic BPs. The aim of this study was to elucidate underlying haemodynamic and hormonal mechanisms that may occur to defend seasonal changes in BP. Participants were 27 men and 7 women with either normal BP or early hypertension. Measurements of haemodynamics (cardiac output by dual-gas rebreathing) and hormones (resting catecholamines, renin activity, and aldosterone by radioenzymatic assay or radioimmunoassay) were performed during the summer, fall, winter, and spring seasons. Student's paired t test with Bonferroni modification and regression analyses were used to examine the data with a significance level of P<0.05. Systolic and diastolic BP remained relatively constant across seasons. Cardiac output and stroke volume significantly decreased 10 and 15%, respectively, from summer to winter, whereas heart rate and systemic vascular resistance significantly increased 5 and 11%, respectively. Plasma aldosterone (PA) significantly increased 59% from summer to winter, whereas plasma norepinephrine (PNE), plasma epinephrine, and plasma renin activity (PRA) increased 19, 2, and 17%, respectively (pNS for each). Across the four seasons, mean arterial pressure significantly correlated with PRA and PA, whereas systemic vascular resistance significantly correlated with PNE and PRA. There are dramatic counterregulatory haemodynamic and hormonal adaptations to maintain a relatively constant BP. Norepinephrine, PRA, and aldosterone have a function in mediating the changes in haemodynamics. PMID- 19776757 TI - EVI-1 interacts with histone methyltransferases SUV39H1 and G9a for transcriptional repression and bone marrow immortalization. AB - The ecotropic viral integration site-1 (EVI-1) is a nuclear transcription factor and has an essential function in the proliferation/maintenance of haematopoietic stem cells. Aberrant expression of EVI-1 has been frequently found in myeloid leukaemia as well as in several solid tumours, and is associated with a poor patient survival. It was recently shown that EVI-1 associates with two different histone methyltransferases (HMTs), SUV39H1 and G9a. However, the functional roles of these HMTs in EVI-1-mediated leukemogenesis remain unclear. In this study, we showed that EVI-1 physically interacts with SUV39H1 and G9a, but not with Set9. Immunofluorescence analysis revealed that EVI-1 colocalizes with these HMTs in nuclei. We also found that the catalytically inactive form of SUV39H1 abrogates the transcriptional repression mediated by EVI-1, suggesting that SUV39H1 is actively involved in EVI-1-mediated transcriptional repression. Furthermore, RNAi based knockdown of SUV39H1 or G9a in Evi-1-expressing progenitors significantly reduced their colony-forming activity. In contrast, knockdown of these HMTs did not impair bone marrow immortalization by E2A/HLF. These results indicate that EVI-1 forms higher-order complexes with HMTs, and this association has a role in the transcription repression and bone marrow immortalization. Targeting these HMTs may be of therapeutic benefit in the treatment for EVI-1-related haematological malignancies. PMID- 19776758 TI - Successful treatment of molecular relapse in NPM1-positive AML using 5 azacytidine. PMID- 19776759 TI - Low or undetectable numbers of Philadelphia chromosome-positive leukemic stem cells (Ph(+)CD34(+)CD38(neg)) in chronic myeloid leukemia patients in complete cytogenetic remission after tyrosine kinase inhibitor therapy. PMID- 19776760 TI - PTPN11 mutations in childhood acute lymphoblastic leukemia occur as a secondary event associated with high hyperdiploidy. PMID- 19776761 TI - Analysis of factors that affect in vitro chemosensitivity of leukaemic stem and progenitor cells to gemtuzumab ozogamicin (Mylotarg) in acute myeloid leukaemia. AB - Relapse in acute myeloid leukaemia (AML) is considered to result from the persistence of drug-resistant leukaemic stem and progenitor cells (LSPC) within a bone marrow 'niche' microenvironment. Identifying novel agents that have the potential to target these LSPC in their niche microenvironment will aid in the characterization of candidate agents for post-remission chemotherapy. Using an in vitro model, we found that 48-h culture with gemtuzumab ozogamicin (Mylotarg) resulted in a 34% reduction in CD34(+)CD38(-)CD123(+) LSPC number, whereas normal CD34(+)CD38(-) haemapoietic stem cells were insensitive to this agent. As there was considerable heterogeneity in LSPC response to Mylotarg treatment, various factors potentially underpinning the differential response were assessed. LSPC that overexpressed CD33 (P=0.01), which were P-glycoprotein-negative (P=0.008) and with internal tandem duplication (ITD) of the FLT3 gene (FLT3/ITD) status (P=0.006) responded better to Mylotarg treatment. LSPC from patient samples that have these combined characteristics as well as low LSPC burden showed significantly more chemosensitivity to Mylotarg compared with all other cases (P=0.002). In multivariate analysis, LSPC burden and FLT3 status were found to be predictors of LSPC chemosensitivity to Mylotarg treatment (P<0.0001). In conclusion, we have shown heterogeneity in the LSPC compartment of AML patients underpinning differential in vitro sensitivity to Mylotarg. PMID- 19776762 TI - Defining origins of malignant B cells: a new circulating normal human IgM(+)D(+) B-cell subset lacking CD27 expression and displaying somatically mutated IGHV genes as a relevant memory population. AB - In probing the cell of origin in malignant B cells, an imprint of somatic hypermutation (SHM) in immunoglobulin (Ig) variable (V) region genes delineates antigen encounter, and identifying the precise pathway generating SHM in the normal B-cell counterpart becomes relevant. SHM remains the definitive memory imprint in normal human B cells, but CD27 expression also delineates memory. Recently, dye extrusion adenosine triphosphate-binding transporter assays identified circulating isotype-switched memory B cells that lacked CD27, yet exhibited low levels of SHM. To extend findings, we report a pre-switched CD27( ve) circulating memory B-cell population in normal blood using comparable assays, and isolated CD19(+)IgM(+)D(+)CD27(-ve) cells (>99% purity) for the analysis of IGHV5/IGHV3-IGHM transcripts. Of these (n=334), approximately 78% were germ line and naive B cell derived. Strikingly, 21.9% of the transcripts were mutated. They showed 3-5 mutations (13.5% of sequences) and >5 mutations (8.4% of sequences) per transcript. Accrual of mutations in a subset of CD19(+)IgM(+)D(+)CD27(-ve) cells define a new circulating pre-switched memory B-cell pool, present in substantial numbers in the population harboring naive B cells. These CD19(+)IgM(+)D(+)CD27(-ve) memory B cells may have a distinct lineage and function, and seem relevant to understanding origins of malignant B cells, in particular those of hairy cell leukemia cells, which display mutated V genes yet lack CD27 expression. PMID- 19776763 TI - Inhibition of Syk protein tyrosine kinase induces apoptosis and blocks proliferation in T-cell non-Hodgkin's lymphoma cell lines. PMID- 19776764 TI - Progress and prospects: gene therapy for inherited immunodeficiencies. AB - Haematopoietic stem cell transplantation (HSCT) is now widely used to treat primary immunodeficiencies (PID). For patients with specific disorders (severe combined immunodeficiency (SCID)-X1, adenosine deaminase deficiency (ADA)-SCID, X chronic granulomatous disease (CGD) and Wiskott-Aldrich Syndrome (WAS)) who lack a suitable human leukocyte antigen (HLA)-matched donor, gene therapy has offered an important alternative treatment option. The success of gene therapy can be attributed, in part, to the selective advantage offered to gene-corrected cells, the avoidance of graft-versus-host disease and to the use of pre-conditioning in patients with chemotherapy to facilitate engraftment of corrected cells. Adverse events have been encountered and this has led to detailed characterization of retroviral vector integration profiles. A new generation of self-inactivating retroviral and lentiviral vectors have been designed to address these safety concerns, and are at an advanced stage of preparation for the next phase of clinical testing. PMID- 19776765 TI - Successional changes in bacterial communities during the development of black band disease on the reef coral, Montipora hispida. AB - Black band disease (BBD) consists of a mat-forming microbial consortium that migrates across coral colonies causing rapid tissue loss. Although BBD-associated microbial communities have been well characterized, little is known regarding how these complex bacterial consortia develop. This study analyzed successional changes in microbial communities leading to the development of BBD. Long-term monitoring of tagged corals throughout outbreaks of BBD in the central Great Barrier Reef documented cyanobacterium-infected lesions, herein termed cyanobacterial patch(es) (CP), which were macroscopically distinct from BBD and preceded the onset of BBD in 19% of the cases. Dominant cyanobacteria within CP lesions were morphologically distinct from ones dominating BBD lesions. Clone libraries and terminal restriction fragment length polymorphism analysis confirmed shifts within cyanobacterial assemblages, from Blennothrix sp. affiliated sequences dominating CP lesions, to Oscillatoria sp.-affiliated sequences, similar to those retrieved from other BBD samples worldwide, dominating BBD lesions. Bacterial 16S ribosomal RNA clone libraries also showed shifts in bacterial ribotypes during transitions from CP to BBD, with Alphaproteobacteria-affiliated sequences dominant in CP libraries, whereas gammaproteobacterial and cyanobacterial ribotypes were more abundant in BBD clone libraries. Sequences affiliated with organisms identified in sulfur cycling were commonly retrieved from lesions showing characteristic field signs of BBD. As high sulfide concentrations have been implicated in BBD-mediated coral tissue degradation, proliferation of a microbial community actively involved in sulfur cycling potentially contributes to the higher progression rates found for BBD compared with CP lesions. Results show how microbial colonization of indistinct lesions may facilitate a common coral disease with proven ecological effects on coral populations. PMID- 19776766 TI - Subsurface ecosystem resilience: long-term attenuation of subsurface contaminants supports a dynamic microbial community. AB - The propensity for groundwater ecosystems to recover from contamination by organic chemicals (in this case, coal-tar waste) is of vital concern for scientists and engineers who manage polluted sites. The microbially mediated cleanup processes are also of interest to ecologists because they are an important mechanism for the resilience of ecosystems. In this study we establish the long-term dynamic nature of a coal-tar waste-contaminated site and its microbial community. We present 16 years of chemical monitoring data, tracking responses of a groundwater ecosystem to organic contamination (naphthalene, xylenes, toluene, 2-methyl naphthalene and acenaphthylene) associated with coal tar waste. In addition, we analyzed small-subunit (SSU) ribosomal RNA (rRNA) genes from two contaminated wells at multiple time points over a 2-year period. Principle component analysis of community rRNA fingerprints (terminal-restriction fragment length polymorphism (T-RFLP)) showed that the composition of native microbial communities varied temporally, yet remained distinctive from well to well. After screening and analysis of 1178 cloned SSU rRNA genes from Bacteria, Archaea and Eukarya, we discovered that the site supports a robust variety of eukaryotes (for example, alveolates (especially anaerobic and predatory ciliates), stramenopiles, fungi, even the small metazoan flatworm, Suomina) that are absent from an uncontaminated control well. This study links the dynamic microbial composition of a contaminated site with the long-term attenuation of its subsurface contaminants. PMID- 19776767 TI - Gene-targeted-metagenomics reveals extensive diversity of aromatic dioxygenase genes in the environment. AB - Understanding the relationship between gene diversity and function for important environmental processes is a major ecological research goal. We applied gene targeted metagenomics and pyrosequencing to aromatic dioxygenase genes to obtain greater sequence depth than possible by other methods. A polymerase chain reaction (PCR) primer set designed to target a 524-bp region that confers substrate specificity of biphenyl dioxygenases yielded 2000 and 604 sequences from the 5' and 3' ends of PCR products, respectively, which passed our validity criteria. Sequence alignment showed three known conserved residues, as well as another seven conserved residues not reported earlier. Of the valid sequences, 95% and 41% were assigned to 22 and 3 novel clusters in that they did not include any earlier reported sequences at 0.6 distance by complete linkage clustering for sequenced regions. The greater diversity revealed by this gene-targeted approach provides deeper insights into genes potentially important in environmental processes to better understand their ecology, functional differences and evolutionary origins. We also provide criteria for primer design for this approach, as well as guidance for data processing of diverse functional genes, as gene databases for most genes of environmental relevance are limited. PMID- 19776768 TI - The opportunistic coral pathogen Aspergillus sydowii contains dddP and makes dimethyl sulfide from dimethylsulfoniopropionate. AB - The ascomycete Aspergillus sydowii is associated with a serious epizootic of sea fan corals in the Caribbean. Corals are rich in the compatible solute, dimethylsulfoniopropionate (DMSP), produced by their symbionts, the dinoflagellate Symbiodinium. As other Aspergillus species can catabolize DMSP, liberating dimethyl sulfide (DMS) in the process, we tested A. sydowii strains, obtained from diseased corals and other environments, for this Ddd(+) phenotype. All the strains, irrespective of their geographical or environmental origins, made DMS from DMSP, and all of them contained homologs (>87% identical) of the dddP gene, which encodes an enzyme that releases DMS from DMSP and which occurs in other Ddd(+) fungi and in some marine bacteria. The dddP gene was likely acquired by the Aspergillus fungi by inter-domain horizontal gene transfer from alpha-proteobacteria. PMID- 19776769 TI - Identification of iron-reducing microorganisms in anoxic rice paddy soil by 13C acetate probing. AB - In anoxic rice field soil, ferric iron reduction is one of the most important terminal electron accepting processes, yet little is known about the identity of iron-reducing microorganisms. Here, we identified acetate-metabolizing bacteria by RNA-based stable isotope probing in the presence of iron(III) oxides as electron acceptors. After reduction of endogenous iron(III) for 21 days, isotope probing with (13)C-labeled acetate (2 mM) and added ferric iron oxides (ferrihydrite or goethite) was performed in rice field soil slurries for 48 and 72 h. Ferrihydrite reduction coincided with a strong suppression of methanogenesis (77%). Extracted RNA from each treatment was density resolved by isopycnic centrifugation, and analyzed by terminal restriction fragment length polymorphism, followed by cloning and sequencing of 16S rRNA of bacterial and archaeal populations. In heavy, isotopically labeled RNAs of the ferrihydrite treatment, predominant (13)C-assimilating populations were identified as Geobacter spp. (approximately 85% of all clones). In the goethite treatment, iron(II) formation was not detectable. However, Geobacter spp. (approximately 30%), the delta-proteobacterial Anaeromyxobacter spp. (approximately 30%), and novel beta-Proteobacteria were predominant in heavy rRNA fractions indicating that (13)C-acetate had been assimilated in the presence of goethite, whereas none were detected in the control heavy RNA. For the first time, active acetate oxidizing iron(III)-reducing bacteria, including novel hitherto unrecognized populations, were identified as a functional guild in anoxic paddy soil. PMID- 19776770 TI - The renal complications of HIV. PMID- 19776771 TI - Dialysis: vascular access: not enough light at the end of the tunnel? PMID- 19776772 TI - Biopsy: observation time after kidney biopsy: when to discharge? PMID- 19776773 TI - Transplantation: kidney or kidney-pancreas transplant for the uremic diabetic? PMID- 19776774 TI - Trombotic microangiopathy: can liver-kidney transplantation cure aHUS? PMID- 19776775 TI - Glomerular disease: the Oxford classification--predicting progression of IgAN. PMID- 19776776 TI - Sepsis: clearing the blood in sepsis. PMID- 19776777 TI - Diagnosis: should renal biopsies be performed in the very elderly? PMID- 19776778 TI - The nephrotoxic effects of HAART. AB - With significant reductions in mortality and risk of progression to AIDS in the era of highly active antiretroviral therapy (HAART), complications of long standing HIV infection and treatment have become increasingly important. Such complications include the nephrotoxic effects of HAART, which are the subject of this Review. The most common nephrotoxic effects associated with HAART include crystal-induced obstruction secondary to use of protease inhibitors (mainly indinavir and atazanavir), and proximal tubule damage related to the nucleotide analog reverse transcriptase inhibitor tenofovir. Acute kidney injury (AKI) can occur following tenofovir-induced tubule dysfunction or as a result of severe mitochondrial dysfunction and lactic acidosis induced by nucleoside reverse transcriptase inhibitors. The potential insidious long-term renal toxicity of antiretroviral treatment is probably underappreciated in patients with HIV: a proportion of patients with treatment-related AKI did not recover their baseline renal function at 2-year follow-up, suggesting the possibility of permanent renal damage. Finally, nonspecific metabolic complications might increase the risk of vascular chronic kidney disease in patients on HAART. However, given the benefits of HAART, fear of nephrotoxic effects is never a valid reason to withhold antiretroviral therapy. Identification of patients with pre-existing chronic kidney disease, who are at increased risk of renal damage, enables appropriate dose modification, close monitoring, and avoidance or cautious use of potentially nephrotoxic medications. PMID- 19776779 TI - Controversies in the pathogenesis of HIV-associated renal diseases. AB - The two most common HIV-associated renal diseases, HIV-associated nephropathy and HIV immune-complex kidney disease, share the common pathologic finding of hyperplasia within the glomerulus. Podocyte injury is central to the pathogenesis of these diseases; however, the source of the proliferating glomerular epithelial cell remains a topic of debate. Parenchymal injury has been linked to direct infection of renal epithelial cells by HIV-1, although the mechanism of viral entry into this non-lymphoid compartment is unclear. Although transgenic rodent models have provided insight into viral proteins responsible for inducing renal disease, such models have substantial limitations. Rodent HIV-1 models, for instance, cannot replicate all features of immune activation, a process that could have an important role in the pathogenesis of the HIV-associated renal diseases. PMID- 19776783 TI - Thin-wire scatterers in chiral media. AB - The effect of the handedness of chiral materials on the differential scattering cross section of embedded conducting wires is examined. The bow-tie-shaped induced current distributions and the resulting forbidden zone of radiation are explained through fundamental physical principles. We find that thin-wire scatterers can be divided into subchiral, chiral, and superchiral classes according to the degree of chirality of the host material and the electromagnetic length of the wire. PMID- 19776780 TI - Renal transplantation in patients with HIV. AB - HIV infection has been a major global health problem for almost three decades. With the introduction of highly active antiretroviral therapy in 1996, and the advent of effective prophylaxis and management of opportunistic infections, AIDS mortality has decreased markedly. In developed countries, this once fatal infection is now being treated as a chronic condition. As a result, rates of morbidity and mortality from other medical conditions leading to end-stage liver, kidney and heart disease are steadily increasing in individuals with HIV. Presence of HIV infection used to be viewed as a contraindication to transplantation for multiple reasons: concerns for exacerbation of an already immunocompromised state by administration of additional immunosuppressants; the use of a limited supply of donor organs with unknown long-term outcomes; and, the risk of viral transmission to the surgical and medical staff. This Review examines open questions on kidney transplantation in patients infected with HIV-1 and clinical strategies that have resulted in good outcomes. It also describes the clinical concerns associated with the treatment of renal transplant recipients with HIV. PMID- 19776782 TI - Lupus activation with cerebritis following pegylated interferon in a hemodialysis patient. AB - BACKGROUND: A 20-year-old female patient with chronic hepatitis C virus infection and end-stage renal disease due to systemic lupus erythematosus was admitted to hospital with fever, pain in the abdomen, seizures and an alteration of consciousness. The patient was on maintenance dialysis and was receiving pegylated interferon monotherapy for her chronic hepatitis C virus infection. INVESTIGATIONS: Physical examination, laboratory tests including complete blood count and measurement of serum electrolyte levels, CT scans of the head and abdomen, MRI of the brain, microscopic examination of the cerebrospinal fluid, chest X-ray, echocardiography and measurement of C3 complement and anti-double stranded DNA antibody levels. DIAGNOSIS: Activation of systemic lupus erythematosus with cerebritis following pegylated interferon therapy. MANAGEMENT: Intravenous fluid, intermittent oxygen, intravenous diphenylhydantoin, intravenous pulse methylprednisolone 500 mg for 3 days followed by 40 mg per day of oral prednisolone, and temporary withdrawal of pegylated interferon. PMID- 19776784 TI - Intensity noise enhancement in the half-wave plate/polarizer attenuator. AB - The conventional optical attenuator for linearly polarized light is usually constructed with a half-wave retardation plate and a polarizer. With one axis of the polarizer aligned so as to transmit the incident beam fully, the addition of the half-wave plate causes the output power to follow a cos(2) 2theta dependence, where theta is the angle between the optic axis of the wave plate and the incident polarization. When the incident light has an additional orthogonal polarization component, the output power dependence becomes more complex and depends on the correlation between the two polarization fields ?E(x)E(y)?. More significantly, if amplitude noise in the polarization fields is correlated, the attenuator will couple the noise processes, which results in relative power fluctuations that increase as the optical power is reduced. The noise produced by this coupling may even exceed the noise of either polarization state alone. Measurements of the statistical behavior of the relative intensity noise of a cw modelocked Nd:YAG laser as a function of the wave-plate angle showed more than a tenfold increase when the output power was reduced to near minimum. In addition, the noise was found to be asymmetrical about the minimum power point, theta = 45 degrees . It is shown that the simple addition of a polarizer ahead of the wave plate strips off the unwanted polarization field and virtually eliminates this added noise effect. PMID- 19776781 TI - HIV and kidney disease in sub-Saharan Africa. AB - A wide clinical spectrum of renal diseases affects individuals with HIV. These conditions include acute kidney injury, electrolyte and acid-base disturbances, HIV-associated glomerular disease, acute-on-chronic renal disease and adverse side effects related to treatment of HIV. Studies employing varying criteria for diagnosis of kidney disease have reported a variable prevalence of these diseases in patients with HIV in sub-Saharan Africa: 6% in South Africa, 38% in Nigeria, 26% in Cote d'Ivoire, 28% in Tanzania, 25% in Kenya, 20-48.5% in Uganda and 33.5% in Zambia. Results from these studies also suggest that a broader spectrum of histopathological lesions in HIV-associated kidney disease exists in African populations than previously thought. Strategies to prevent or retard progression to end-stage renal disease of HIV-associated kidney conditions should include urinalysis and measurement of kidney function of all people with HIV at presentation. Renal replacement in the form of dialysis and transplantation should be implemented as appropriate. This Review focuses on the available evidence of renal diseases in patients with HIV infection in sub-Saharan Africa and offers practical guidelines to treat these conditions that also take into consideration challenges and obstacles that are specific to sub-Saharan Africa. PMID- 19776785 TI - Accurate numerical solution of the Helmholtz equation by iterative Lanczos reduction. AB - The Lanczos recursion algorithm is used to determine forward-propagating solutions for both the paraxial and Helmholtz wave equations for longitudinally invariant refractive indices. By eigenvalue analysis it is demonstrated that the method gives extremely accurate solutions to both equations. PMID- 19776786 TI - Pulsed-laser-induced hole burning in an aerosol medium: a new technique for flow visualization in gases. AB - A novel technique that uses Mie scattering from aerosol particles is presented for quanititative flow visualization in gases. A pulsed 80-mJ XeCl excimer laser burns a tunnel through the aerosol mass in a flowing volume of gas. A sheet of light from a cw argon-ion laser is used to illuminate this aerosol tunnel and to study its time evolution. The time evolution of such tunnels formed by a train of successive excimer laser pulses provides a simple technique for quantitative measurement of translational and rotational gas velocities in the plane of the argon-ion laser light sheet. PMID- 19776787 TI - Spatial-soliton-induced guided waves in a homogeneous nonlinear Kerr medium. AB - It has been predicted that an intense pump beam can induce the focusing of a weak probe beam at a different wavelength that is simultaneously propagating in a Kerr homogeneous material through cross-phase modulation. In Kerr-type nonlinear material, spatial solitons are the only stable waves able to propagate at high intensity levels without leading to catastrophic breakdown. We propose the use of a soliton beam to induce the stable guiding of a probe beam. Experimental results obtained with picosecond pulses are reported that evidence spatial-solitoninduced guiding. PMID- 19776788 TI - Model for second-harmonic generation in glass optical fibers based on asymmetric photoelectron emission from defect sites. AB - We present a self-consistent calculation of anomalous second-harmonic generation in glass optical fibers. Quantum interference between multiphoton absorption processes leads to asymmetric photoelectric emission from defects, creating a spatially periodic space-charge electric field. The second harmonic is found to grow exponentially along the fiber, then saturate to a maximum value proportional to the square of the fundamental intensity. The predicted conversion efficiency is in reasonable agreement with experiments. PMID- 19776789 TI - Photorefractive nonlinearities caused by the Dember space-charge field in undoped CdTe. AB - The photorefractive nonlinearity associated with the Dember space-charge field between electrons and holes produced by two-photon absorption is unambiguously isolated and studied in undoped CdTe by using a nondegenerate, forward-probing, polarization-sensitive, transient-grating technique with a temporal resolution of <5 ps. PMID- 19776790 TI - Retromodulation/conjugation using a self-pumped atomic sodium phase-conjugate mirror. AB - A self-pumped atomic sodium phase-conjugate mirror was modified to include an amplitude modulator, which thus formed a device capable of encoding temporal information onto the phase-conjugate return beam. Modulation rates of as much as 4 MHz with modulation depths in the range of 70-90% (both limited by the electronics and the modulator) have been obtained by using an intracavity acousto optic modulator. PMID- 19776791 TI - Directional coupler based on an antiresonant reflecting optical waveguide. AB - A novel waveguide coupler configuration consisting of two identical antiresonant reflecting optical waveguides is presented. The coupling length is a periodic function of the waveguide separation, and therefore a remote coupler can be realized. PMID- 19776792 TI - Frequency stabilization of a continuous-wave Ti:sapphire laser. AB - Measurements of the spectral density of frequency fluctuations are reported for an actively stabilized cw Ti:sapphire laser. For a servo loop incorporating an intracavity translatable mirror and an external-cavity acousto-optic modulator, a linewidth of 1.0 kHz rms is obtained for the fluctuations of the laser frequency as recorded within the servo loop. The modulation index associated with the frequency deviations is considerably less than one over most of the Fourier spectrum, indicating operation in a domain of small phase noise for the fluctuations of the electric field. PMID- 19776793 TI - Slope efficiency measurements of a chromium-doped forsterite laser. AB - The slope efficiency of the continuous-wave chromium-doped forsterite (Cr:Mg(2)SiO(4)) laser has been measured by using four different output mirrors. The maximum slope efficiency of 38% was achieved with an 11% output coupler. The extrapolated limiting slope efficiency in the absence of passive losses is estimated to be 65%. This value corresponds to an intrinsic quantum efficiency of 77%, which is similar to the efficiencies determined for mature tunable solid state laser systems. PMID- 19776794 TI - Synchronously pumped continuous-wave dye laser pumped by a mode-locked frequency doubled diode-pumped Nd:YLF laser. AB - We report an efficient technique of resonant frequency doubling of a mode-locked diode-pumped Nd:YLF laser for producing 250 mW of continuous-wave mode-locked output in the green region of the spectrum. The Nd:YLF laser, which was pumped by a 3-W laser-diode array, was mode locked by using frequency-modulation mode locking to produce 650-mW output in pulses of 12-ps duration at a repetition rate of 225 MHz. This output was resonantly doubled by using MgO:LiNbO(3) in an external ring enhancement cavity. Doubling efficiencies of as much as 56% were achieved to produce usable mode-locked output of 250 mW at 523.5 nm. The frequency-doubled output was used to pump synchronously a continuous-wave mode locked Rhodamine R6G dye laser. The dye laser produced pulses of approximately 1 ps duration and an output power of 40 mW. PMID- 19776795 TI - 1-mJ/pulse Tm:YAG laser pumped by a 3-W diode laser. AB - Efficient 2-microm lasers are needed for many eye-safe laser radar applications. Pumping of a Tm:YAG crystal with the output from a 3-W diode laser has resulted in a cw output power of 0.5 W and Q-switched pulse energies in excess of 1 mJ/pulse at 100 Hz. Improved pump absorption with a near-circular pump beam could result in 2-mJ pulse energies. PMID- 19776796 TI - Diode-pumped Cr:LiSrAlF(6) laser. AB - A Cr:LiSrAlF(6) laser is diode pumped with both commercial 10-mW visible laser diodes and a higher-power 100-mW cw, 265-mW pulsed diode. Polarization combination of pump diodes to reach threshold is demonstrated with two low-power lasers. Pumping with the high-power diode produced powers of 19.9 mW cw and 78 mW pulsed. Details of the Cr:LiSrAlF(6) crystal growth and high-power diode architecture are presented, along with optical characterization data for the laser resonator. Passive losses in the crystal are less than 0.1% cm(-1). PMID- 19776797 TI - Modal analysis of linear Talbot-cavity semiconductor lasers. AB - A modal analysis at threshold is presented for linear Talbot-cavity semiconductor lasers with a finite number of array elements. The analysis self-consistently calculates the array supermode profiles and the loss each incurs owing to imperfect Talbot imaging, including edge diffraction losses. It is found that the decrease in mode discrimination between supermodes incurred by fabricating larger arrays can be offset by reducing the near-field fill factor. PMID- 19776798 TI - Fully interconnected, two-dimensional neural arrays using wavelength-multiplexed volume holograms. AB - We present a compact method to provide independent weighted interconnections between every pixel in a two-dimensional input array and every pixel in a two dimensional output array. The two input dimensions and two output dimensions are connected by a four-dimensional weight matrix consisting of wavelength multiplexed volume holograms that use cryogenic spectral hole burning in a single holographic element. PMID- 19776799 TI - Optimal trade-off filters for noise robustness, sharpness of the correlation peak, and Horner efficiency. AB - Filters that have optimal trade-offs among the criteria of noise robustness, sharpness of the correlation peak, and Horner efficiency are presented, and an explicit mathematical expression is provided. Owing to their optimality, these filters provide a figure of merit and then permit a rigorous characterization of filter performances for optical pattern recognition. PMID- 19776800 TI - Wide-field-of-view heterodyne receiver using a photorefractive double phase conjugate mirror. AB - The use of a double phase-conjugate mirror to increase the angular field of view of an optical heterodyne receiver is investigated. Fields of view and overall efficiencies far larger than those predicted by the antenna theorem for conventional heterodyne systems are obtained. PMID- 19776801 TI - Refraction effects associated with multiphoton ionization and ultrashort-pulse laser propagation in plasma waveguides. AB - The problem of refraction of ultrashort, high-intensity laser pulses in underdense plasmas is discussed in the context of producing long plasma filaments by high f-number axial focusing of laser beams. For uniform gas targets, it is shown that refraction can clamp the intensity of the focused laser beam at a value near the threshold for multiphoton ionization. In order to make large volumes of underdense plasma with ultrashort pulses, it is necessary to preform a partially ionized filament with a suitable radial electron density profile. Such a structure can act as an indestructible waveguide for ultraintense, subpicosecond laser pulses. Indeed, highly ionized plasma represents the only practical optical material at wavelengths below 50 nm or at intensities above 10(13) W cm(-2). PMID- 19776802 TI - Multiplexed optically heterodyned Raman-induced Kerr-effect spectroscopy in the blue. AB - The technique of multiplexed optically heterodyned Raman-induced Kerr-effect spectroscopy is extended to the blue at 378 nm. Despite both weaker probe and pump lasers than in our previous research in the visible [Chem. Phys. Lett. 168, 579 (1990)], it is possible to obtain spectra with a good signal-to-noise ratio from simple solvents, demonstrating the feasibility of the technique in the blue and ultraviolet. PMID- 19776803 TI - Single-beam squeezed-state generation in sodium vapor and its self-focusing limitations. AB - We describe an experiment that generates squeezed states by means of forward four wave mixing in sodium vapor with a single optical beam. The single-beam arrangement maximizes the pump-probe spatial overlap in the nonlinear medium. Self-focusing (or self-defocusing) is found to be the major limiting factor in achieving optimal squeezing. PMID- 19776804 TI - Beam coupling, stimulated Brillouin scattering, and four-wave mixing. AB - Measurements of the probability density function of the mutual coherence of two stimulated-Brillouin-scattered Stokes outputs are reported. The variation of the probability density function with the polarization, relative intensities, and overlap of the pumping laser beams demonstrates that the coupling between the Stokes outputs is due to four-wave mixing. PMID- 19776805 TI - Ultranarrow line filtering using a Cs Faraday filter at 852 nm. AB - To achieve quantum-noise-limited performance, background-limited laser receivers require narrow-band optical filters. We measured and modeled the ultranarrow-band transmission spectrum of a Cs Faraday filter at 852 nm. The transmission spectrum consisted of passbands on either side of the 6 (2)S((1/2))-6 (2)P(3/2) hyperfine doublet lines, making a total of four. The passbands may be simple peaks or highly modulated, depending on the operating parameters. We observed peaked passbands of near-unity transmission with a 0.6-GHz bandwidth and modulated bands with features as sharp as 100 MHz. Excellent agreement with our calculations at 852 nm allows us to predict confidently a 0.7-GHz transmission band for Cs at 455 nm. PMID- 19776806 TI - Saturation measurements of excited-state transitions in noble gases using the optogalvanic effect. AB - Saturation intensities have been measured for 20 transitions between excited states of argon, krypton, and neon in the 1.3- and 1.5-microm regions. Values of I(sat), corrected for an incident beam with a circular Gaussian intensity profile, range from 20 to 2000 mW/cm(2). PMID- 19776807 TI - Quenching and enhancement of an optical nonlinearity by a phase-conjugate mirror. AB - The nonlinear polarizabilities of a two-level atom and a nonlinear oscillator in front of a resonant phase-conjugate mirror are calculated as functions of the mirror reflectivity. The effect of the mirror is to quench the nonlinearity of the two-level system and most anharmonic oscillators. In the case of a weakly anharmonic oscillator the nonlinear polarizability can be extremely large. PMID- 19776808 TI - Measurement of the nonlinear refractive index of semiconductors included in monolithic etalons. AB - We describe a measurement technique for the determination of the nonlinear refractive index of semiconductors embedded in a Fabry-Perot cavity. This method relates the intensity-dependent spectral shift of the resonance peak to the nonlinear index variations. The use of square pulses allows the decoupling of electronic and thermal nonlinearities. Our experimental results show that this method is particularly suitable for measuring the nonlinear-optical properties of monolithic semiconductor etalons with integrated Bragg reflectors. PMID- 19776809 TI - Simultaneous Raman scattering and laser-induced fluorescence for multispecies imaging in turbulent flames. AB - A multispecies imaging technique for single-shot, simultaneous measurement of the OH, CH, and CH(4) concentrations in turbulent nonpremixed flames is described. A unique aspect of the system is the use of a two-wavelength multipass cell to form both a visible and a UV laser sheet. The UV beam is used to excite fluorescence in the OH molecule, while Raman scattering from CH(4) molecules and fluorescence induced in CH is achieved by using the visible beam. The visible and UV lasers are operated simultaneously, and the resulting signals are recorded by two vidicon cameras. The sheet intensity provided by the multipass cell is sufficient to saturate the OH transition, which makes single-shot, laser-saturated fluorescence imaging measurements possible. PMID- 19776810 TI - Optical technique for particle measurement. AB - A novel overlapping optical field technique that transforms an optical field of Gaussian intensity into one with uniform intensity is described. Comparison of calculated and measured results demonstrates that a highly uniform optical field in one transverse dimension with efficient utilization of optical energy can be obtained by using the overlapping optical field technique. This technique can be used for particle sizing and velocimetry. PMID- 19776811 TI - Oblique-incidence liquid-crystal-tunable etalon. AB - The experimental properties and a detailed model of a nematic liquid-crystal tunable Fabry-Perot etalon with obliquely incident light are reported. As a single-wavelength switch, the etalon has an extinction ratio of 20.3 dB, an insertion loss of -1.7 dB, and a millisecond switching speed. As a filter, the etalon has a finesse of 15.1, a free spectral range of 20.4 nm, and a continuous tuning range of over 40 nm with less than 5 V. PMID- 19776812 TI - Ultrahigh-noise rejection optical filter. AB - We present the results of what is to our knowledge the first experimental demonstration of a Faraday anomalous dispersion optical filter. This optical filter has a measured bandpass of 1 GHz, a transmission of 0.63, and an out-of band rejection of 10(5). PMID- 19776813 TI - Etching of high-reflecting thin-film assemblies using ion-beam-figuring techniques. AB - Ion-beam-figuring techniques have been applied to fabricate high-power transmission gratings for use in photoacoustic spectroscopy. A thin-film assembly of SiO(2) and TiO(2) layers on an SiO(2) substrate provides a high-reflecting characteristic at a desired wavelength. With standard photolithographic techniques a grating pattern is developed on the surface of the assembly then ion etched with ion-beam-figuring techniques. These gratings exhibit an increased factor of 25 in acoustic signal levels when compared with previously used chemical-etched silicon gratings. This increase was obtained owing to higher transmission, less thermal distortion, and the ability to withstand higher incident power levels. PMID- 19776814 TI - Multiplexed fiber-optic sensors using a dual-slope frequency-modulated source. AB - We propose and demonstrate a multiplexed fiber-optic sensor system using a dual slope (triangular) frequency-modulated laser source. The restrictions in the selection of beat frequencies of the multiplexed sensors in previous studies that employed ramp modulation wave forms are eliminated. PMID- 19776815 TI - Rapidly switchable optical filter for color generation. AB - A ferroelectric liquid-crystal (FLC) color filter is described and experimentally demonstrated. The device consists of three polarizers and five smectic C* FLC cells. With the application of an appropriate electric field to each FLC cell, five outputs are observed. These consist of the three primary colors (red, green, and blue) along with white and black. With the rapid addressing speed of the FLC's, the FLC color filter can be used for color display applications, such as backlighting FLC television. PMID- 19776816 TI - All-fiber optical frequency shifter: erratum. PMID- 19776817 TI - Statistical interferometry based on the statistics of speckle phase. AB - A new technique of optical interferometry based on the statistics of the fully developed speckle field is proposed. It is revealed that the complete randomness of the speckle phase can play the role of a standard phase in a statistical sense, and the phase of the object under testing can be derived in a statistical way, in contrast to conventional interferometry. The technique is first described in relation to the phase-shifting interferometry and the compensation problem for the phase-shift error. Next the method is generalized as an independent interferometric technique. PMID- 19776818 TI - Impact of quadratic phase factors on optical Fourier transforms and imaging. AB - In the design of lens systems for coherent light processing, the occurrence of quadratic phase factors in the path of propagation is important for the determination of imaging and Fourier planes. The impact and propagation of quadratic phase factors can be described by simple fractional formulas similar to the well-known lens formula. PMID- 19776820 TI - Dark optical solitons near the zero-dispersion wavelength. AB - Propagation of a dark optical soliton is investigated in the neighborhood of the zero-group-dispersion wavelength. Analytical results are obtained in the small amplitude limit when the soliton is described by the Korteweg-de Vries equation. It is predicted that dark solitons may exist near the zero-group-dispersion point, and the region is found where they are unstable and may be transformed into bright solitons on a pedestal. PMID- 19776819 TI - Quasi-periodic motion in a hybrid optical bistable system with a short delay. AB - The dynamical behavior of a hybrid optical bistable system with a short delay is calculated numerically in detail. The quasi-periodic motion and frequency locking of the system are observed experimentally. PMID- 19776821 TI - Energy conversion in degenerate four-photon mixing in birefringent fibers. AB - We predict that the third-order parametric mixing of a pump with a pair of orthogonally polarized sidebands in a birefringent single-mode optical fiber may be spatially unstable. The interaction may exhibit both periodic and nonperiodic energy conversion and period doubling. This analysis allows us to propose a new scheme for all-optical switching as well as to predict the most efficient conditions for energy conversion when pump depletion is accounted for. PMID- 19776822 TI - Spectral profile and multiplexing of Bragg gratings in photosensitive fiber. AB - We describe a technique of optically writing several gratings in a photosensitive germanosilicate fiber. Each grating is written using the same single-frequency argon-ion laser source, but by varying the strain applied to the fiber during writing the resonant frequency of the gratings can be controlled. Frequency differences between gratings of 182 GHz have been demonstrated. The spectra of the gratings formed in the fiber were measured by periodically stretching the fiber while illuminating it with a single-frequency laser. This permits a frequency-resolved real-time analysis of the passband. The grating properties are also shown to be highly dependent on the polarization of the writing beam. PMID- 19776823 TI - Ultrafast, room-temperature, resonance-enhanced third-order optical susceptibility tensor of an AlGaAs/GaAs quantum well. AB - The ultrafast, room-temperature, resonance-enhanced third-order nonlinear susceptibility tensor of an AlGaAs/ GaAs quantum well is determined. A single 6 nm GaAs quantum well embedded in a waveguide of 382-nm mode size increases the |chi((3))| from a bulk-material level of 8 x 10(-11) esu +/-20% to 6 x 10(-10) esu +/-20%. The anisotropy of the diagonal elements |chi((3))(1111), |chi((3))(2222)| and their correlation with the off-diagonal elements |chi((3))(1212)|, |chi((3))(2121)| are consistent with the one-photon resonance mechanism. PMID- 19776824 TI - Anisotropic ring fibers with cylindrical polar principal axes. AB - Anisotropic ring fibers with cylindrical polar principal axes are examined. The ring structure is found to offer a wider range of single-mode operation compared with the corresponding rod structure. PMID- 19776825 TI - Transmission bistability in a double-coupler fiber ring resonator. AB - The transmission bistability of a two-coupler nonlinear ring resonator is demonstrated and described by using a geometrical method that provides a qualitative understanding of the operation characteristics of the device. Results showing the influence of the coupling constants and the linear phase are presented. PMID- 19776826 TI - External-cavity diode laser using a grazing-incidence diffraction grating. AB - An external cavity has been developed for use with commercial diode lasers. It uses a diffraction grating at grazing incidence for wavelength selection and output coupling. This configuration allows a GaAlAs diode laser to be tuned conveniently anywhere in a range greater than 20 nm. Also, the linewidth is reduced by a factor of more than 1000 from 40 MHz to less than 10 kHz. The new laser system should be useful for high-resolution spectroscopy, laser cooling of atoms, time standards, and coherent optical communications. PMID- 19776827 TI - High-power and high-spatial-coherence broad-area power amplifier. AB - A broad-area AlGaAs amplifier operating cw has delivered 425 mW of total power with 342 mW in a single lobe diverging at 1.02x the diffraction limit (FWHM 0.483 degrees , 87.4-microm actual aperture) for a master oscillator input power of 70 mW. The spatial coherence of the amplifier output is 0.97, and the mutual spatial coherence between the oscillator and amplifier is 0.96. PMID- 19776828 TI - GaAs/AlGaAs multiple-quantum-well vertical optical modulators on glass using the epitaxial lift-off technique. AB - A GaAs/Al(0.30)Ga(0.70)As multiple-quantum-well vertical optical modulator has been grown on a GaAs substrate using the metal-organic vapor-phase epitaxy technique. This device was removed from the original substrate and placed on a glass carrier by means of epitaxial lift-off (ELO). Photocurrent measurements before and after the ELO show clear exciton absorption peaks and indicate the development of a Fabry-Perot cavity after ELO due to multiple reflections between the front and back of the ELO film. Transmission measurements show a maximal contrast ratio of 2.9 dB and an insertion loss of 2.8 dB at a wavelength of 831 nm. PMID- 19776829 TI - Integration of planar Fresnel microlenses with vertical-cavity surface-emitting laser arrays. AB - We report a technique of integrating planar Fresnel microlenses with InGaAs/GaAs based vertical-cavity surfacee-mitting laser arrays by selectively ion-beam milling the substrate. Depending on the application, one can focus, collimate, and bend the individual laser beams using such microlenses. An example is presented where a 32 x 32 array of microlenses, each with an aperture of 80microm and a focal length of 108 microm is integrated with a laser array. As expected, arrays of focused beams, each with a 2-microm spot size, are generated at a distance of approximately 110 microm. PMID- 19776830 TI - Self-starting of an additive-pulse mode-locked color-center laser. AB - Self-starting of additive-pulse mode-locking (APM) behavior has been observed in a NaCl:OH color-center APM laser over the wavelength range of 1.52-1.60 microm. Pulses as short as 160 fs have been produced at a wavelength of 1.55 microm in a stable pulse train. High-power levels in the fiber are required for the mode locking to self-start. The large fiber power makes it difficult to stabilize the cavity length by conventional methods: The feedback signal must now be derived from the second harmonic of the laser output. The self-starting APM laser exhibits less noise than the synchronously pumped APM laser because of the lack of pulse walk-off effects that are characteristic of the synchronously pumped APM laser. PMID- 19776831 TI - Generation of 39-fs pulses at 815 nm with a synchronously pumped mode-locked dye laser. AB - We describe a synchronously pumped mode-locked dye laser that uses a novel combination of saturable absorber dyes (HITC-I and DTP) to yield satellite-free, 39-fs pulses at 815 nm. PMID- 19776832 TI - Hybrid optoelectronic neural networks using a mutually pumped phase-conjugate mirror. AB - We discuss an optical interconnection method for neural networks based on mutually pumped phase conjugation in a photorefractive crystal. Cross talk due to Bragg degeneracies is reduced by storing each connection weight in a continuum of angularly and spatially multiplexed volume gratings. PMID- 19776833 TI - Generation of programmable coherent source arrays using spatial light modulators. AB - We demonstrate and characterize arrays of coherent focused spots generated by writing multiple Fresnel zone plates on optically and electrically addressed modulators. The programmable parameters of the array are its size (number of generated spots) and the transmissivity and focal length of each lens. As expected, phase modulators have a better conversion efficiency than amplitude modulators do. PMID- 19776834 TI - Fourier-transform spectral imaging near the image plane. AB - By use of a detector array in the image plane of a Fourier spectrometer, a massively parallel Fourier spectrometer array can be constructed. This array is expected to collect efficiently spectral images with high spatial and spectral resolutions. We present a brief analysis of the signal-to-noise ratio and our first experimental results. PMID- 19776835 TI - Compact and robust incoherent holographic correlator using a surface-emitting laser-diode array. AB - A compact and robust holographic correlator using a vertical-cavity surface emitting microlaser diode array is described. The system is based on the unique coherence property of the surface-emitting microlaser array: temporally highly coherent and spatially incoherent. The performance of the system is experimentally demonstrated, and the application of the system for neural network implementations is proposed. PMID- 19776836 TI - Transient 210-nm absorption in fused silica induced by high-power UV laser irradiation. AB - Synthetic fused silica, exposed to high-power KrF excimer laser irradiation, shows the well-known induced absorption at 210 nm owing to E' center generation. Time-resolved absorption spectroscopy reveals that this induced absorption is transient in nature. The generation rate of E' centers depends strongly on the irradiation history, the OH content, and previous high-temperature processes. In order to explain the experimental observations, a nonabsorbing state of theE' center is postulated. The recovery of the induced optical absorption in high-OH fused silica is explained as a conversion from E' centers to these nonabsorbing centers. PMID- 19776837 TI - Two-beam-excited conical emission. AB - We describe a conical emission process that occurs when two beams of near resonant light intersect as they pass through sodium vapor. The light is emitted on the surface of a circular cone that is centered on the bisector of the two applied beams and has an angular extent equal to the crossing angle of the two applied beams. We ascribe the origin of this effect to a perfectly phase-matched four-wave mixing process. PMID- 19776838 TI - Solitary resonance in the velocity-selective magnetic-optical activity spectrum of the (87)Rb D(2) line. AB - We report the velocity-selective magnetic-optical activity of a (87)Rb vapor when the counterpropagating pump and probe beams are linearly cross polarized. A semiconductor laser tuned to the D(2) line (780 nm) is used to perform the experiment. When a weak axial magnetic field is applied to the vapor, the magnetic-optical activity spectrum reveals a narrow dominant peak, the solitary resonance, corresponding to the cycling transition 5S((1/2)), F = 2 ?5P(3/2), F = 3. The light-shift origin of this spectrum is discussed. PMID- 19776839 TI - Strong excitonic nonlinearity in a P-I-N photodiode incorporating narrow asymmetric coupled quantum wells. AB - Strong excitonic nonlinearity in the photoconductive response of a P-I-N photodiode incorporating narrow asymmetric coupled quantum wells has been observed at 78 K. When the P-I-N photodiode is overbiased, the heavyhole energy levels in the two coupled quantum wells are moved toward the resonance by increasing the laser intensity. Also, both the light-hole and the heavy-hole excitonic transitions undergo intensity-dependent shifts. Both these effects indicate intrinsic change of bias due to redistribution of photogenerated carriers and, therefore, the existence of an intrinsic feedback mechanism. The magnitude of the blue shift of the heavy-hole excitonic transitions significantly increases when the laser intensity is changed from 9.2 to ~270 mW/cm(2). PMID- 19776840 TI - Design of Fourier-transform holographic lenses in the presence of a recording readout wavelength shift. AB - A method for recording Fourier-transform holographic lenses, in the presence of a recording-readout wavelength shift, is presented. The method is illustrated with a holographic lens recorded at 488 nm and reconstructed at 633 nm, with high diffraction efficiencies and low aberrations over a wide field of view of +/-10 degrees . PMID- 19776841 TI - Dual-channel Faraday-effect current sensor capable of simultaneous measurement of two independent currents. AB - We describe a current sensor that uses the Faraday effect in two square rings of glass capable of measuring two independent currents simultaneously with a resolution of 1.2 A radicalHz. Pseudoheterodyne signal processing is used to recover the phase modulation produced by the Faraday effect. PMID- 19776842 TI - Technique for three-dimensional measurements of the time development of turbulent flames. AB - A three-dimensional imaging technique has been developed that permits the investigation of the time development of a scalar in turbulent reacting flows. An aerosol-seeded premixed flame was illuminated by four closely spaced parallel laser sheets of different wavelength. Lorenz-Mie scattering from the four illumination sheets was imaged onto an intensified two-dimensional charge-coupled device array. Bandpass filters and a multi-image optical component in the collection optics allowed individual sheets to be imaged onto different areas of the charge-coupled-device array. A double-pulsed Nd:YAG laser was used in conjunction with a rotating mirror in the collection optics to enable instantaneous three-dimensional images to be obtained at two times separated by 100 micros. PMID- 19776843 TI - Wavelength stability of a high-output, broadband, Er-doped superfluorescent fiber source pumped near 980 nm. AB - We report the dependence of the mean wavelength of Er-doped superfluorescent fiber sources on temperature, pump wavelength, and pump power. In particular, we measure an intrinsic temperature coefficient of between -2 and +8 parts in 10(6) (ppm) per degree Celsius depending on pump wavelength, pump power, and fiber length. Additionally, we report a pump wavelength dependence that is symmetrical about the peak pump absorption wavelength (near 976 nm) and a decrease in mean wavelength with pump power with a slope of between 0 and -93 ppm/mW. PMID- 19776844 TI - Optical polarizer using anisotropic metallic island films with a large aperture and a high extinction ratio. AB - A new type of an optical polarizer consisting of anisotropic metallic island films is proposed, and its optical properties are investigated theoretically. It is shown that an extinction ratio of 63 dB and an insertion loss of 0.02 dB at a resonance wavelength, e.g., 0.64 microm, are expected for the polarizer when silver is used as the metal. A broadband polarizer is also designed by combining several kinds of anisotropic island film. PMID- 19776846 TI - Second-harmonic generation of femtosecond pulses: observation of phase-mismatch effects: comment. PMID- 19776845 TI - Optically addressed thresholding very-large-scale-integration/liquid-crystal spatial light modulators. AB - Two 32 x 32 array optically addressed thresholding spatial light modulators consisting of a very-large-scale-integration chip and a ferroelectric liquid crystal modulator are presented. The intensity contrast ratios range from 3:1 and 11:1, and the response times range from 500 micros to 6 ms. PMID- 19776847 TI - Second-harmonic generation of femtosecond pulses: observation of phase-mismatch effects: reply to comment. PMID- 19776848 TI - Degenerate four-wave mixing in KNbO(3): picosecond and photorefractive nanosecond response. AB - Single 75-ps-long pulses at a wavelength of 532 nm are used to write phase gratings in KNbO(3) crystals. Two grating buildup processes are resolved. The faster and generally weaker one is instantaneous on a time scale of the pulses used and is attributed to intrinsic third-order processes. In a reduced crystal that shows preferentially electronic charge transport and that is oriented to show a space-charge-induced photorefractive effect, a higher diffraction builds up in some nanoseconds after the illumination of the crystal. The rise time of the photorefractive grating does not seem to depend on the grating period. Two tentative explanations are proposed: (i) a high electron mobility and a limited response time owing to ferroelectric relaxation processes and (ii) fast electron recombination. PMID- 19776849 TI - Picosecond photoinduced absorption in photorefractive BaTiO(3). AB - Picosecond photoinduced absorption in BaTiO(3) has been observed for the first time to our knowledge using picosecond laser pulses and a time delay pump-probe technique. The pump intensity dependence as well as the delay time dependence of the photoinduced absorption coefficient have been measured. The results can be explained qualitatively by a secondary-center model. From our results, the hole recombination time with secondary centers is not larger than 60 ps. PMID- 19776850 TI - Resonant frequency quadrupling of a mode-locked diode-pumped Nd:YLF laser. AB - We report on a novel method of efficient frequency quadrupling of a mode-locked diode-pumped Nd:YLF laser to 262 nm in the ultraviolet region of the spectrum using two external ring enhancement cavities in series. With 6 W of pump power the mode-locked Nd:YLF laser produced 1 W of power incident into the first enhancement cavity. The fundamental has been resonantly frequency doubled using a crystal of lithium triborate with a conversion efficiency of 60% to produce 600 mW of usable mode-locked output at 523.5 nm. Fourth-harmonic radiation was generated by frequency doubling this green output in a second ring enhancement cavity using a crystal of beta-barium borate. Conversion efficiencies from green to ultraviolet of 11% have been achieved, producing a maximum usable average power at 262 nm of 42 mW in picosecond pulses. PMID- 19776851 TI - Dynamics of the nonlinear modulational instability in optical fibers. AB - We study the nonlinear evolution in optical fibers of a modulationally unstable continuous wave. We find that a good description of the propagation can be analytically obtained by a simple truncated three-wave model. The dynamic viewpoint may give an important physical insight in different processes, such as frequency conversion of modulated signals, all-optical generation of temporal codes, and the onset of spatiotemporal chaos. PMID- 19776852 TI - Hot-carrier enhancement of photorefractive space-charge fields in zinc-blende semiconductors. AB - We observe an order-of-magnitude enhancement of the photorefractive effect in undoped CdTe on ~1-ps time scales that is caused by an overshoot in the two photon-produced Dember space-charge field associated with hot-carrier transport. PMID- 19776853 TI - Efficient second-harmonic conversion of cw single-frequency Nd:YAG laser light by frequency locking to a monolithic ring frequency doubler. AB - Efficient second-harmonic conversion of the 1064-nm output of a diode-pumped cw single-frequency Nd:YAG laser to 532 nm was obtained by frequency locking the laser to a monolithic ring resonator constructed of magnesium-oxide-doped lithium niobate. The conversion efficiency from the fundamental to the second harmonic was 65%. Two hundred milliwatts of cw single-frequency 532-nm light were produced from 310 mW of power of 1064-nm light. This represents a conversion efficiency of 20% from the 1-W diode laser used to pump the Nd:YAG laser to single-frequency 532-nm output. No signs of degradation of the 532-nm power or photo-refractive damage in the crystal were observed for over 500 h of operation of the system at green output powers greater than 100 mW. PMID- 19776854 TI - Photorefractive-damage-resistant Zn-diffused waveguides in MgO:LiNbO(3). AB - Planar waveguides were fabricated by diffusing Zn into MgO:LiNbO(3) and LiNbO(3). Zn-diffused waveguides in MgO:LiNbO(3) guide both the ordinary and extraordinary polarization and have propagation losses at 633 nm in the range of 0.4-1.2 dB/cm. Single-beam-induced in-plane scattering due to photorefractive damage was not observed at 515 nm up to intensities of as much as 90 kW/cm(2). PMID- 19776855 TI - Comparison of film thickness tolerances in waveguide grating couplers. AB - The effect of guiding-layer thickness variations on grating coupler performance is investigated for three important material systems. The sensitivity of the coupling length and coupling efficiency of these structures to guiding-layer thickness changes differs markedly between the glass, gallium arsenide, and silicon-on-insulator waveguides studied. PMID- 19776856 TI - 0.5-TW, 125-fs Ti:sapphire laser. AB - We describe a terawatt, femtosecond laser system based on Ti:sapphire amplifiers and the technique of chirpedpulse amplification. The laser output at 807 nm contains 60 mJ of energy in a 125-fs pulse duration. The laser beam is nearly diffraction limited and may be focused to an intensity of 10(18) W/cm(2) with an f/6 optic. PMID- 19776857 TI - Noise reduction in an argon laser with a phase-conjugating external cavity. AB - The reinjection of a small fraction of the output beam back into the laser cavity is shown to improve the signal-to- noise ratio of a cw multilongitudinal mode Ar(+) laser efficiently. The argon laser is coupled to an external cavity terminated by a phase-conjugate mirror in order to obtain a self-aligned coupled cavity. With the external cavity, the signal-to-noise ratio has been significantly improved. The low-frequency noise components are reduced by up to 15 dB, and the frequency components of the spectrum of the longitudinal-mode beating are attenuated by factors reaching 46 dB. PMID- 19776858 TI - Long coherence length for cw photolytic atomic iodine lasers at 1.315 microm. AB - With a low-power cw photolytic atomic iodine laser operating at 1.315 microm, coherence lengths greater than 220 m have been observed. These results are to our knowledge the first coherent length measurements of any type of atomic iodine laser. A Michelson interferometer was used to demonstrate this long-coherence length property. In addition, Fabry-Perot interferometric measurements provided a laser frequency linewidth (Deltaf < 1.0 MHz) consistent with this long-coherence length observation. Such a large coherence length should be common to all homogeneously broadened, photolytic atomic iodine lasers. PMID- 19776859 TI - Demonstration of a novel optical code-division multiple-access system at 800 megachips per second. AB - A novel optical code-division multiple-access system using Alberta codes and complementary correlation is demonstrated at 800 megachips per second. Completely passive optical multiplexing and demultiplexing is performed throughout the process. Complementary correlation permits code orthogonality because bipolar electrical signals are generated from unipolar optical ones. The correlator is implemented optoelectronically with an array of metal-semiconductor-metal photodiodes. We show that the bit-error-rate performance of the system is not degraded by interfering signals and that zero cross talk is nominally achieved. An unusual property of such systems is confirmed: The bit error rate on a channel can be reduced by the presence of an interfering channel if the two transmitters are not chip asynchronous. PMID- 19776860 TI - Time-resolved second-harmonic study of femtosecond laser-induced disordering of GaAs surfaces. AB - An abrupt (less than 100 fs) decrease in the second-harmonic intensity reflected from the surface of a GaAs (110) wafer has been observed experimentally. The linear reflectivity was found to increase on a time scale of ~1 ps. Thus the concept of fast atomic disorder induced by electronic excitation within a relatively cold lattice is given new experimental support. PMID- 19776861 TI - Actively mode-locked Ti:sapphire laser producing transform-limited pulses of 150 fs duration. AB - We report on the generation of transform-limited pulses of 150-fs duration from an actively mode-locked Ti:sapphire laser. The laser produced subpicosecond pulses over the range 780-860 nm, with a maximum average output power of 600 mW. The output spot was in the form of a near-TEM(00) spot and demonstrated longterm pulse stability. PMID- 19776862 TI - Imaging objects hidden in highly scattering media using femtosecond second harmonic-generation cross-correlation time gating. AB - A combination of 100-fs cross-correlation time gating and lock-in amplifier detection is shown to be a versatile technique to image objects hidden in highly scattering media. The image is formed from the ballistic component of the ultrafast laser pulse while the diffuse component is eliminated by time gating using cross-correlation second-harmonic generation. The low-noise lock-in amplifier detection method and the high-repetition-rate milliwatt pulsed laser enable us to image through a random medium as thick as 28 scattering mean free paths with submillimeter resolution. PMID- 19776863 TI - Femtosecond pulses from a continuously self-starting passively mode-locked Ti:sapphire laser. AB - We show that an external coupled cavity containing a nonlinear quantum-well reflector can continuously selfstart a dispersion-compensated Ti:sapphire laser, which produces stable time-transform-limited pulses as short as 70 fs in a TEM(00) mode. In this mode of operation, the quantum wells do not control the mode-locking process, as in previous research on the resonant passive mode-locked laser. By separating the mode-locking and starting processes, we show that the presence of higher-order spatial modes is not required to start or sustain mode locking. PMID- 19776864 TI - Design of phase-only, binary phase-only, and complex ternary matched filters with increased signal-to-noise ratios for colored noise. AB - An algorithm is provided for treating nonwhite additive noise in determining regions of support for phase-only filters, binary phase-only filters, and complex ternary matched filters. It is analytically shown to be optimal in the signal-to noise ratio sense. It extends earlier research that assumed white noise. PMID- 19776865 TI - Lateral inhibitory action in an optical neural network using an internal-light coupled optical device array. AB - A novel configuration of an optical lateral inhibitory neural network using a two dimensional internal-light-coupled optical device (ILCOD) array is proposed. It is experimentally certified with a test ILCOD structured with seven units in a two-dimensional hexagonal arrangement that the optical coupling between the units causes turn-off of the light emission of the unit in a specific position, which results in lateral inhibitory action of a neural network. PMID- 19776866 TI - Optical determination of Gabor coefficients of transient signals. AB - An optical Gabor coefficient evaluation scheme for transient signals is proposed. With an acousto-optic modulator as an input device, a liquid-crystal spatial light modulator as a reconfigurable window, and a two-dimensional charge-coupled device detector array, a real-time optical processing architecture that determines the Gabor coefficients of transient signals is described. Some preliminary experimental results are presented. PMID- 19776867 TI - Simplified holographic associative memory using enhanced nonlinear processing with a thermoplastic plate. AB - A simplified holographic associative memory by enhanced nonlinear recording using a thermoplastic plate is described. The system is based on two new concepts: The system utilizes the second-order diffraction instead of the first-order diffraction, and to enhance the second-order diffraction efficiency, a novel angle-tuning recording using a thermoplastic plate is employed. As a result, the size of the system is reduced by one half with a remarkable increase (as much as approximately 100 times) in light efficiency compared with that of the conventional systems, and the need for critical alignment is eliminated. Experimental results demonstrating the performance of the system are provided. PMID- 19776868 TI - Multiphoton ionization of N(2) by the third harmonic of a Nd:YAG laser: a new avenue for air diagnostics. AB - Ionization of N(2) by the third harmonic of a Nd:YAG laser is demonstrated and confirmed experimentally from both spectral and ion-collection measurements. Six photons at 355 nm excite the ground-state neutral molecule to the B(2) summation operator(+)(u) (upsilon' = 8) ionized state. Intense radiation at 391.4 nm associated with the B(2) summation operator(+)(u) (upsilon = 0) ? X(2) summation operator(+)(g) (upsilon'' = 0) transition was detected. The intensity of this line scales quadratically with the laser power. An ion concentration of 3.25 x 10(13) ions/cm(3) was detected after irradiation by a 45-mJ laser pulse focused to a diameter of 17 microm. The potential application of this ionization scheme for air velocity and temperature measurements is presented. PMID- 19776869 TI - Dynamic behavior of the optogalvanic effect in a CO(2) laser. AB - We observe the dynamic behavior of the optogalvanic effect in a CO(2) laser during the transient process due to the switching of the cavity losses. A three level model for the laser and a differential relaxation equation based on thermodynamic considerations for the temperature are used to interpret the phenomenon. PMID- 19776870 TI - Dynamic pressure sensing with a side-hole birefringent optical fiber. AB - A birefringent side-hole optical fiber is used to measure dynamic pressure with an interferopolarimetric method. The optical source is a superluminescent diode that gives white-light-type interferograms compatible with coherence multiplexing. The experiments have been conducted with standard commercial electronics. Dynamic pressure measurements are made in the range 10(-2) to 10(3) Pa and are in good agreement with two calibrated piezoelectric dynamic pressure sensors. PMID- 19776871 TI - Explaining the optical fuse. AB - Experiments show that the characteristic periodic damage pattern that results from the optical fuse can be produced by purely thermal means by heating the fiber to temperatures in the 700-1000 degrees C range in the absence of light. The nature of the damage region bubbles suggests local temperatures high enough to soften the fiber core. The additional energy required may be supplied by an exothermic mechanism. Consideration of activated interstitial diffusion of various potential oxidants: unoxidized sites with O(2) could be responsible. PMID- 19776872 TI - Anticrossing of polarization modes in liquid-crystal etalons. AB - Generally when anisotropic materials such as liquid crystals are confined in a Fabry-Perot cavity, the transmission through the device becomes sensitive to the input polarization. While continuous tunability of the refractive index is possible by application of a small electric field across the liquid crystal, it is found that under certain circumstances a forbidden gap in the transmission wavelength is observed. It is shown that this occurs because of mode mixing brought about by a slightly twisted uniaxial structure in between the Fabry-Perot structure. A theoretical model is presented to explain the experimentally observed data, and there is excellent agreement between theory and experiments. PMID- 19776874 TI - Optical resonators using graded-phase mirrors. AB - Optical resonators using graded-phase mirrors are analyzed with the help of the generalized ABCD propagation law for a real optical beam. This analysis gives the second-order moment gross characteristics of the eigenmode and indicates a design procedure. An example of a super-Gaussian output beam shows that this type of optical resonator might have large transverse-mode discrimination that could provide operation in a large fundamental-mode beamwidth. PMID- 19776873 TI - Optical interconnection method for neural networks using self-pumped phase conjugate mirrors: erratum. PMID- 19776875 TI - Diffraction by a half-plane: a generalization of the Fresnel diffraction theory. AB - A generalization of the Fresnel approximation in diffraction theory is proposed. The phase term in the diffraction integral is approximated by a parabolic variation, not by a binomial expansion but rather by matching up at the critical points for asymptotic evaluation of the integral. The method provides a correction to the optical coordinates of the Fresnel diffraction theory that extends its region of validity. It is applied to diffraction of an inclined plane wave by a half-plane. PMID- 19776876 TI - Superresolution in confocal scanning microscopy. AB - We describe three simple pupil function filters that, in conjunction with a confocal optical system, result in a transfer function that is constant for all spatial frequencies up to the cutoff. We confirm our predictions experimentally by considering a straight-edge object. Edge gradients up to 2.36 times as sharp as the unapodized confocal case are obtained. PMID- 19776877 TI - Effect of front-facet reflections on the reflectivity of Bragg reflectors. AB - Typical Bragg mirrors have an air-dielectric interface that can have a reflectivity spectrum different from that calculated by simple coupled-wave theory because of Fresnel reflection at their surface. This additional reflection can add constructively or destructively, depending on the sequence of the Bragg layers. We show a method of analysis for calculating reflectivity of Bragg mirrors in the presence of additional reflections. PMID- 19776878 TI - Imaging through a scattering wall using absorption. AB - An object hidden behind a cloudy wall is shown to become visible when the wall is made absorbing. The underlying principle is that the absorption in a random medium preferentially reduces the intensity of the multiple scattered light (noise) over the ballistic signal (image). The intensity of the noise can be reduced below the ballistic signal intensity when the medium is made sufficiently absorbing, thus allowing us to see through an otherwise opaque random scattering wall. PMID- 19776880 TI - Cladding of a crystal fiber by high-energy ion implantation. AB - The feasibility of using a multi-MeV He(+)-ion beam to convert the outer portion of a crystal fiber into cladding is demonstrated. When applied to a-axis LiNbO(3) fiber, the resulting structure has been found to show good waveguiding characteristics. PMID- 19776879 TI - Nonfrequency-shifted self-pumped phase-conjugate mirror using sodium vapor. AB - An incident cw laser beam polarized along the y direction induces a four-wave mixing oscillation polarized along the x direction in a linear cavity containing a sodium cell. The interaction of the incident field with the standing wave induces the generation of a reflected field. Reflectivities of as much as 20% inside the cell and response times shorter than 100 ns have been observed. PMID- 19776881 TI - Nonlinear wave propagation in an asymmetric converging Y junction. AB - Nonlinear wave propagation in an asymmetric converging Y junction, which consists of a nonlinear cladding, a linear film, and a linear substrate, is studied. The nonlinear dispersion curves of the successive sections of the Y junction are calculated to be used to illustrate the evolutions of the eigenmodes. The field incident from the nonlinear thinner branch can evolve into the symmetric mode of the stem with a high coupling efficiency. An insertion coupler for a time multiplexed loop is suggested. PMID- 19776882 TI - Moving grating and dc external field in photorefractive GaP at 633 nm. AB - We demonstrate that the photorefractive effect in GaP crystal at 633 nm can be enhanced using an externally applied dc field and a moving grating. A two-beam coupling gain coefficient of 2.5 cm(-1) and a steady-state phase-conjugate reflectivity of 1.9% were obtained. PMID- 19776883 TI - Simple model for spatial optical solitons in planar waveguides. AB - We use a variational method to develop a simple model for the steady-state behavior of self-trapped beams that have recently been observed in nonlinear planar waveguides. The model allows us to study the transition from two dimensional to three-dimensional self-trapping as power levels increase and also to investigate the effect of saturation on these beams. PMID- 19776884 TI - Ti:LiNbO(3) polarization splitters using an asymmetric branching waveguide. AB - Polarization splitters that use an asymmetric branching waveguide and can be fabricated along the Z axis as well as the X axis of LiNbO(3) are proposed and demonstrated. In these devices, two polarization states are converted to two different spatial modes, and these modes are split by the asymmetric branching waveguide. The extinction ratios of the two polarization splitters are shown to be less than -12 dB. PMID- 19776885 TI - Room-temperature diode-pumped Yb:YAG laser. AB - We have developed an efficient room-temperature ytterbium-doped YAG laser operating at 1.03 microm pumped by an InGaAs strained-layer diode laser operating at 968 nm. The threshold was 234 mW and 23 mW of output power was obtained for an absorbed pump power of 345 mW. This laser offers a number of advantages over AlGaAs pumped Nd:YAG lasers, such as broader absorption features, longer fluorescent lifetime, and lower thermal loading of the gain medium. PMID- 19776886 TI - Inside-pumped Nd:YAG tube laser. AB - A novel type of solid-state laser with a tubular active element made of Nd:YAG is presented. Using the tube geometry, one can achieve higher efficiency and higher output power per laser crystal than by using a rod or slab geometry. Our tube laser is pumped from the inside by four flash lamps. The slope efficiency of 9% and the total efficiency of 7.5% at as much as 400 W of output power are, to our knowledge, the highest values reported for flash-lamp-pumped Nd:YAG lasers. At 15 kW, 75% of the maximum available pumping power, the output power is 1000 W. Thermal lensing is five times lower than for an equivalent rod laser. PMID- 19776887 TI - Extended-cavity operation of rare-earth-doped glass waveguide lasers. AB - Channel waveguides fabricated in Nd-doped glass were used as gain elements for extended-cavity lasers. End-fire pumping was performed with a Ti:sapphire laser operating at 807 nm. The 4-nm FWHM output spectrum was centered near 1057 nm. Slope efficiencies were typically 4-11%, with thresholds near 20 mW. Active mode locking and Q switching were separately performed; mode-locked pulse widths were roughly 80 ps FWHM. Q-switched peak power was 1.2 W. The cw output narrowed to 7 GHz and tuned over a range of 24 nm when a grating provided feedback; single frequency operation resulted when a high-reflectivity etalon was added. PMID- 19776888 TI - Integrated-optic Nd:glass laser fabricated by flame hydrolysis deposition using chelates. AB - We have demonstrated an Nd:glass waveguide laser deposited on a silica substrate by flame hydrolysis deposition using chelates. Continuous-wave lasing at lambda = 1062 nm was verified with a threshold of 143 mW and a slope efficiency of 2.1% when the laser was pumped at 807 nm. The flame hydrolysis deposition process using rare-earth chelates produces low-loss films with high Nd concentration and is suitable for multiple rare-earth doping. PMID- 19776889 TI - 1-GHz repetition-rate frequency-modulation mode-locked neodymium lasers at 1.3 microm. AB - We report on high-repetition-rate frequency-modulation mode locking of all-solid state neodymium lasers operating at a 1.3-microm wavelength. At a repetition rate of 1 GHz, pulses of 12- and 8-ps durations with average powers of 162 and 240 mW have been obtained for 3-W diode-laser-pumped Nd:YAG and Nd:YLF lasers, respectively. Driven relaxation oscillations of a frequency-modulation mode locked cw laser are also described. PMID- 19776890 TI - Theory of passive additive-pulse mode locking. AB - The laser configuration of newly developed additive-pulse mode locking, also known as coupled-cavity mode locking, can be viewed as an intracavity interferometer. By solving the equation of motion of the two coupled cavities, a mathematical description of the self-starting mechanism is obtained. With this method, the transient pulse evolution of an initial seed pulse can be calculated and thereby optimized. The structure of the equation of motion suggests new single-cavity configurations of additive-pulse mode locking, and the same method of analysis can be applied to them. PMID- 19776891 TI - Compact 10-TW, 800-fs Nd:glass laser. AB - A tabletop Nd:phosphate glass laser system capable of producing a focused intensity in excess of 10(18) W/cm(2) is described. Optimization of chirped-pulse amplification, including spectral shaping and careful attention to beam quality, produces a transform-limited, 800-fs compressed pulse with a peak power of >10 TW in a near diffraction-limited spatially uniform beam. PMID- 19776892 TI - Large-scale two-dimensional optical Hopfield associative memory using an incoherent optical free-space interconnection. AB - An optically implemented two-dimensional Hopfield associative memory using an optical free-space interconnection constructed by time-domain polarization switching is described. The operation for 2304-element memory is also demonstrated. PMID- 19776893 TI - Squeezed light from conventionally pumped multilevel lasers. AB - We calculate amplitude squeezing spectra for the light from a variety of conventionally pumped three- and four-level lasers. Hence we extend a recent prediction that a certain three-level laser can generate nonclassical light without the need for rigged pumping. PMID- 19776894 TI - All-optical timing restoration using a hybrid time-domain chirp switch. AB - We demonstrate a hybrid time-domain chirp switch (TDCS) in which the nonlinear chirper is an AlGaAs waveguide and the soliton dispersive delay line is a polarization-maintaining fiber. The hybrid TDCS can restore timing in a switching or transmission system, and when combined with an optical amplifier, it can act as an ultrafast, all-optical regenerator for soliton pulses. The timing restoration concept is applicable to other non-linear materials with negligible walk-off, and the acceptable time window can be tailored by adjusting the width and intensity of a reference pulse. PMID- 19776895 TI - Frequency-doubling mode locker: the influence of group-velocity mismatch. AB - The influence of the group-velocity mismatch between the fundamental and the second harmonic in the frequency-doubling nonlinear mirror is investigated theoretically. The nonstationary analysis provides an estimation for the maximum pulse-shortening capabilities of the device when it is used as a passive mode locker. The pulse-shape deformation is also investigated. PMID- 19776896 TI - Multiple superheating thresholds of micrometer-sized droplets irradiated by pulsed CO(2) lasers. AB - Two distinct superheating fluence thresholds have been measured for micrometer sized droplets of liquids irradiated by pulsed CO(2) lasers. The lower, deformation, threshold results in minimal droplet mass loss, whereas the higher, disintegration, threshold (which is well defined only if observed several tens of microseconds after the heating laser pulse) leads to droplet fragmentation into many microparticles and vapor. Deformation thresholds are nearly coincident for either long (10-micros) or short (0.4-micros) laser pulses. Disintegration thresholds are higher for long-pulse irradiation and increase with decreasing absorption. A qualitative explanation is given for these phenomena based on the effects of surface tension, thermal conduction, and thermally induced optical inhomogeneities. PMID- 19776897 TI - Intensity statistics and the finesse of electromagnetic radiation in random structures. AB - The correlation function of microwave intensity with frequency shift is measured in random mixtures of Teflon and aluminum spheres at a metallic filling fraction of 0.20. We observe the first three terms in an expansion of the correlation function in a parameter that is the ratio of the spacing to the width of modes of the random medium. The expansion also applies to optical and electron waves. The expansion parameter is equivalent to the finesse of optical resonators. The intensity distribution at all sample thicknesses is found to be a stretched exponential. PMID- 19776898 TI - Enhancement of modal feedback in unstable resonators using mirrors with a phase step. AB - Numerical calculations using the Prony method have shown that the feedback coefficient in unstable laser resonators can be increased by factors of as much as 5 over the geometrical value using a mirror with a phase step at its center. A phase shift of close to pi over an area of an equivalent Fresnel number of 0.5 leads to minimum output losses. Experiments with a TEA CO(2) laser confirm the prediction. The results can be attributed to a cancellation of the output wave by destructive interference, which confines the laser beam around the resonator axis. PMID- 19776899 TI - High-resolution spectroscopy of whispering gallery modes in large dielectric spheres. AB - The mode spectrum of a 3.8-cm-diameter fused-silica sphere has been studied in the vicinity of 1.06 microm. A single-frequency Nd:YAG laser was used to excite whispering gallery modes by means of evanescent wave coupling. The spectrum is in excellent agreement with predictions from Mie theory. PMID- 19776900 TI - Electromagnetic Stark ladders in waveguide geometries. AB - We argue that the planar optical waveguide is the geometry of choice for observing electromagnetic Stark ladders. PMID- 19776901 TI - Generation in the double-conjugation scheme for a medium with a local transient response. AB - It is shown that the minimum threshold in the double-conjugation scheme for a medium with a local transient response takes place for the generated waves with angular tilting. PMID- 19776902 TI - Suppression of photorefractive beam fanning using achromatic gratings. AB - We show that achromatic grating techniques, using the 488- and 514.5-nm lines of the argon-ion laser, can suppress beam fanning while still allowing two-beam coupling to occur. The suppression is studied as a function of the ratio of the two colors used to form the achromatic grating. PMID- 19776903 TI - Coherent phenomena between incoherent pulses. AB - A coherent interaction is observed between two incoherent, temporally separated pulses, which increases the stimulated Raman scattering conversion efficiency of the delayed pulse from 14% to 27%. This coupling occurs through long-lived coherence in the Raman medium. The influence of temporal pulse spacing on the enhancement is measured. PMID- 19776904 TI - Feasibility of x-ray resonant nonlinear effects in plasmas. AB - We demonstrate the feasibility of saturation-related third-order x-ray resonant nonlinear effects, in particular, absorption saturation and nonlinear refractive index in x-ray laser and laserlike Se XXV and Mo XXXIII plasmas as well as in other plasmas with lower degrees of ionization. PMID- 19776905 TI - Milliwatt-order blue-light generation in a periodically domain-inverted LiTaO(3) waveguide. AB - We report the characterization of a quasi-phase-matched second-harmonic generation device in LiTaO(3) that has a periodically domain-inverted region and a proton-exchanged channel waveguide. A blue-light power of 2.4 mW was obtained at a 424-nm wavelength. The observed temperature bandwidth for FWHM power is approximately 3 degrees C-cm, which is three times wider than that in a similar device in LiNbO(3). It is also shown that diffraction-limited focusing of the generated blue light may be obtained. PMID- 19776906 TI - Birefringence control in close-spaced fused-fiber wavelength-division multiplexers: a comparison of three methods. AB - Three methods of controlling the polarization sensitivity of close-spaced fused fiber wavelength-division multiplexers are analyzed. Resin-packaged, optimum fusing, and twist-tuning techniques are compared. The twist-tuning technique is shown to be the favored method. PMID- 19776907 TI - Unconditionally stable procedure to propagate beams through optical waveguides using the collocation method. AB - The collocation method developed earlier for propagating beams through optical waveguides is unstable for moderately large values of the extrapolation interval. A new procedure is presented to solve the matrix propagation equation in a method that is unconditionally stable for arbitrarily large extrapolation intervals. The new method uses the Fresnel approximation. The numerical performance of the new formulation is compared with that of the original method and with the propagating beam method. PMID- 19776908 TI - Collision-induced pulse shortening in a mode-locked linear-cavity NaCl color center laser with an InGaAs/InP multiple-quantum-well saturable absorber. AB - We report collision-induced reduction of pulse widths in a linear-cavity passively mode-locked NaCl color-center laser. Colliding-pulse operation reduced the pulse widths from 800 to 430 fs. Pulses collided in the InGaAs/InP multiple quantum-well saturable absorber if the round-trip time from the absorber to the output coupler was less than 1.3 ns, which implies carrier recombination times of that order. Measurements of the gain experienced by two successive pulses indicated partial saturation of the NaCl gain medium. PMID- 19776909 TI - Y-branch waveguide glass laser and amplifier. AB - A Y-branch channel waveguide laser operating near 1057 nm was fabricated by electric-field-assisted ion exchange in Nd-doped silicate glass. The overall length was 24 mm. Optical pumping was performed with a cw Ti:sapphire laser. Mirrors were bonded to the polished waveguide facets. The slope efficiency was 5.1% when a 4%-transmitting output coupler was used. Threshold was reached at 26 mW absorbed pump power. The device exhibited a single-pass small-signal gain of 0.034 dB/mW when operated as an amplifier. The 3-dB splitting loss of the Y branch structure was overcome when the absorbed pump power was approximately 85 mW. PMID- 19776910 TI - Diode-laser-pumped monolithic Nd:YLF laser operating at 1.053 microm. AB - We describe a monolithic diode-laser-pumped Nd:YLF minilaser that operates at 1.053 microm. By aligning the c axis of the Nd:YLF crystal parallel to the laser resonator axis we are able to suppress completely lasing on the (higher-gain) 1.047-microAtmra nsition of Nd:YLE We describe the design and fabrication of the laser and report its cw and gain-switched performance. Our measurements of the laser performance agree well with calculations. PMID- 19776911 TI - Frequency control using a complex effective reflectivity in laterally coupled semiconductor laser arrays. AB - Frequency selectivity of a novel type of multielement, multisection laterally coupled semiconductor laser array is studied using the round-trip method. It is found that such a structure should lead to a strong frequency selectivity owing to a periodic dependency of the threshold gain on the frequency. A gain-guided two-coupledcavity device was fabricated. The experimental results show excellent agreement with the theoretical prediction. PMID- 19776912 TI - Kilohertz-rate continuum generation by amplification of femtosecond pulses near 1.5 microm. AB - A NaCl color-center amplifier is used to amplify femtosecond pulses from an additive-pulse mode-locked laser at wavelengths between 1.52 and 1.60 microm. Pulse energies of several microjoules are obtained with pulse widths as short as 100 fs at kilohertz repetition rates. These pulses have been used to generate a continuum in a variety of solid and liquid media for hours without optical damage. The continuum generated in BaF(2) covers the wavelength range of 400 nm < lambda < 3.5 microm. PMID- 19776913 TI - Femtosecond pulse generation from a synchronously pumped Ti:sapphire laser. AB - We report femtosecond mode locking of a Ti:sapphire laser synchronously pumped by a mode-locked, frequency-doubled Nd:YLF laser. Stable tunable 70-fs pulses are generated in a TEM(00) output without the need for stabilization of the cavity length. PMID- 19776914 TI - Photorefractive two-beam coupling with reduced spatiotemporal coherence. AB - Photorefractive two-beam coupling with reduced spatiotemporal coherence is investigated both theoretically and experimentally. Limited spatiotemporal coherence results in spatially limited grating regions. Theoretical predictions of the beam-coupling behavior in two symmetries are supported by experimental results. PMID- 19776915 TI - Normalized correlation for pattern recognition. AB - The normalization of the correlation filter response effects intensity invariance. We discuss the implications of a normalization based on the Cauchy Schwarz inequality for the discrimination problem. It is shown that normalized phase-only and synthetic discriminant functions do not provide the discrimination/recognition obtained with the classical matched filter. PMID- 19776916 TI - Limits to wideband pulsed squeezing in a traveling-wave parametric amplifier with group-velocity dispersion. AB - A theoretical method is developed to treat wideband pulsed squeezing in a traveling-wave parametric amplifier with group-velocity dispersion. Classical stochastic wave equations that are fully equivalent to operator equations of motion are developed and solved numerically. It is found that squeezing occurs over the entire phase-matching bandwidth, although the degree of squeezing decreases when the pump-pulse duration is shorter than the inverse of this bandwidth. PMID- 19776917 TI - Broadly tunable difference-frequency generation of VUV using two-photon resonances in H(2) and Kr. AB - We report generation of tunable VUV radiation in the range 117-150 nm by four wave difference-frequency mixing of a tunable ArF excimer laser with an Nd:YAG pumped dye laser. The four-wave mixing occurs through two-photon resonant enhancement of X((3)) through the E,F(1)Sigma(g)+ (E,' = 2, J' = 0-3) state(s) of H(2) or the 4p(5)6p(3/2)(2) state of Kr in the process (2omega(193) - omega(dye) = omega(VUV)). An estimate of energy efficiency yields 3 x 10(-5) near 133 nm for both H(2) and Kr. Even though several rotational resonances fall within the natural 193-nm bandwidth, mixing with broadband ArF output in H(2) yields single line VUV output with a FWHM of 3.5 cm(-1) at half the efficiency compared with that of line-narrowed operation. PMID- 19776918 TI - High-resolution distance measurement by dynamical spectral filtering of a superluminescent source. AB - A nonincremental interferometer is shown in which the dynamical spectral filtering of a superluminescent source induces a broadband sinusoidal frequency modulation. The method reaches very high resolution limits in distance measurements (a theoretical expectation of 10(-12) m/ radicalHz is obtained) while maintaining all the advantages of heterodyne phase-recovery processing. Comparison with other nonincremental interferometric approaches is given. PMID- 19776919 TI - Application of fast-Fourier-transform techniques to the discrete-dipole approximation. AB - We show how fast-Fourier-transform methods can be used to accelerate computations of scattering and absorption by particles of arbitrary shape using the discrete dipole approximation. PMID- 19776920 TI - Wavelength-flattened 2 x 2 splitters made of identical single-mode fibers. AB - The fabrication of a new design of fused single-mode-fiber wavelength-flattened 2 x 2 couplers is reported. The device consists of a slightly unbalanced all-fiber Mach-Zehnder interferometer made with identical single-mode fibers; it is compact ( approximately 2 cm) and shows good coupling-ratio uniformity (50 +/- 2.5% over 300 nm) with low excess loss (<0.1 dB. PMID- 19776921 TI - Photorefractive square-law converter. AB - We demonstrate a new type of optically addressed spatial light modulator. By imaging an external grating into a photorefractive material, we write holographic gratings without the need for interference between our input image and a coherent reference beam. This technique allows us to obtain the high contrast and resolution of photorefractive holography while permitting writing with incoherent input images. We evaluate and discuss various performance parameters such as resolution, contrast, and sensitivity that characterize the device. PMID- 19776922 TI - Digital integrating fiber-optic gyroscope with electronic phase tracking. AB - A novel demodulation scheme for interferometers with optical phase modulation is described. The optical phase shift is measured by mixing a train of square digital pulses with a photodetector current and adjusting the pulse spacing by using an electronic closed loop. The optical phase shift is tracked with deviation less than 0.007 rad, which can be easily corrected by using a look-up table. An experimental optically open-loop fiber-optic gyroscope that uses this demodulation shows a linear scale factor in good agreement with theory. PMID- 19776923 TI - Passive demodulation of miniature fiber-optic-based interferometric sensors using a time-multiplexing technique. AB - A passive demodulation technique suitable for interferometric interrogation of short optical cavities is described. It is based on time multiplexing of two low finesse Fabry-Perot interferometers subject to the same measurand and with a differential optical phase of pi/2 (modulo 2pi). Independently of the cavity length, two optical outputs in quadrature are generated, which permits signal reading free of fading. The concept is demonstrated for the measurement of vibration using a simple processing scheme. PMID- 19776924 TI - Enhanced detection of atmospheric-turbulence-distorted 1-microm coherent lidar returns using a two-dimensional heterodyne detector array. AB - We have employed a two-dimensional multielement heterodyne detector array and demonstrated, for the first time to our knowledge, the enhanced detection efficiency of atmospheric-turbulence-distorted 1-microm coherent lidar returns. The heterodyne lidar signal intensity and statistical signal fluctuation were measured for both a 2 x 2 detector array and a single detector as a function of the atmospheric turbulence parameter C(n)(2). The detector array improved the lidar detection efficiency by a factor of approximately 4, and the statistical signal distribution changed from Rayleigh to Gaussian. This improvement is shown to be consistent with a firstorder analysis. PMID- 19776925 TI - Optical bus interconnection system using Selfoc lenses. AB - A novel optical bus interconnection system that uses Selfoc lenses is proposed. The technique can be categorized as one of free-space interconnects, and it has the potential to overcome the problems associated with the free-space optical system, such as difficulties of achieving precise assembling, compact mounting, and high durability. Its concept, fabrication techniques, features, and possible applications are discussed, along with an experimental result. PMID- 19776926 TI - Phase-conjugate Nd:YAG laser with internal acousto-optic beam steering. AB - We propose and experimentally demonstrate a stimulated Brillouin scattering phase conjugate Nd:YAG laser source with beam-steering capability. The laser, designed in an oscillator-amplifier configuration, incorporates a TeO(2) acousto-optic deflector on the low-energy beam. Output pulse energies in the range of 100-185 mJ and a 2.7 degrees full angular bandwidth with 40 resolved beam directions are reported. Electronically controlled random beam pointing with a 5-micros access time and a beam divergence twice the diffraction limit is performed. PMID- 19776927 TI - Optical switching with photorefractive polarization holograms. AB - A switching technique that uses the polarization sensitivity of photorefractive holograms in crystals is experimentally demonstrated. The design is capable of handling a large number of 2 x 2 switching channels with only four holograms. The concept is applicable to either synchronous or asynchronous switching and also to a variety of photorefractive materials. PMID- 19776928 TI - Stability of solitons in randomly varying birefringent fibers. AB - The effects of randomly varying birefringence on solitons are studied. It is shown analytically that the evolution equation can be reduced to the nonlinear Schrodinger equation if the variation length is much shorter than the soliton period. The soliton does not split at high values of the average birefringence, but it does undergo spreading and loss of polarization. A soliton with a temporally constant initial state of polarization is still largely polarized after 40z(0) if the normalized birefringence is delta 10(16) W/cm(2)) subpicosecond (~600 fs) ultraviolet (248 nm) irradiation have been studied under conditions for which no interfering prepulse plasma is generated. Time and spatially integrated measurements of the x-ray emission for H like and He-like Mg and Si were found to be consistent with LASNEX calculations that model the laser-target interaction. PMID- 19776939 TI - Electrons in the interference field as a system for effective nonlinear transformations of superintense laser pulses. AB - The interaction of relativistic electron beams with the superintense interference laser fields is investigated. The possibility of electron channeling, collimation, and bunching is shown. The new methods of parametric conversion and harmonic generation are discussed. PMID- 19776940 TI - High-sensitivity stimulated-emission detector for soft-x-ray laser research. AB - A novel, extremely sensitive system for the detection of stimulated emission is proposed. The principle of the detection method relies on the major difference between stimulated and spontaneous emission, its directionality. A unique feature of the system is the use of a separate spontaneous-emission source. The system is predicted to be sensitive to gain-length products down to 0.1 and below, a capability that would be useful in media in which stimulated emission is weak compared with spontaneous emission. This will have important applications to the development of soft-x-ray lasing in novel systems. PMID- 19776941 TI - Frequency splitting of degenerate spherical cavity modes: stimulated Raman scattering spectrum of deformed droplets. AB - High-resolution interferometric spectra of the stimulated Raman scattering (SRS) spectra from flowing ethanol droplets are presented. The linewidths of the SRS peaks are less than 0.005 cm(-1), and the equal frequency spacings of the SRS peaks are an order of magnitude smaller than the spacings for morphology dependent resonances of a perfect sphere. The observed results from droplets that are deformed by inertial effects are consistent with T-matrix and perturbation predictions of frequency splitting into the various azimuthal modes of a (2n + 1) degenerate morphology-dependent resonance with angular momentum n in a perfect sphere. PMID- 19776942 TI - Storage limit of two-photon-based three-dimensional memories with parallel access. AB - For systems that use parallel access by simultaneous writing or reading of bits located in an entire common plane, diffraction sets a limit to the storage density that is far smaller than that for sequential operation. Comparable densities can be achieved by using a three-dimensional waveguiding structure. PMID- 19776943 TI - Programmable optical interconnections by multilevel synthetic acousto-optic holograms. AB - Reconfigurable high-fidelity, high-efficiency weighted optical interconnection patterns are demonstrated for the first time to our knowledge with the aid of optimized multilevel phase gratings achieved electronically as phase-modulated sinusoidal refractive-index variations propagating in an acousto-optic Bragg cell. PMID- 19776944 TI - Simultaneous acquisition of spectral image information. AB - A technique for the simultaneous acquisition of spectral image information, which implies spectral and spatial intensity distributions of light sources, is described. With this technique projections of an intensity distribution of the source o(x, y, lambda) onto the xy plane are detected simultaneously, and the original distribution is numerically reconstructed from them by using an algorithm of computed tomography. Five projections are obtained experimentally as shared images by means of an imaging system equipped with a transmission grating and detected by a monochromatic television camera. The spatial and spectral distributions of the objects are reconstructed with the multiplicative algebraic reconstruction technique. PMID- 19776945 TI - Fast optical absorption tomography. AB - The design for a fast absorption tomography instrument is presented. The instrument is capable of generating 100 projections of 100 elements each in less than 200 ns. It comprises temporally multiplexed fiber-optic fanbeam sources and large-area fast photodiodes. The spectral operating range is 200 to 1100 nm when silicon photodiodes are used. The sensitivity of the instrument is limited by laser speckle noise created by the fiber optic. The performance was evaluated by using a prototype system. PMID- 19776947 TI - Effect of degenerate four-wave mixing on pulse amplification and compression in the degenerate cross-phase-modulation process: erratum. PMID- 19776946 TI - Normal-incidence x-ray mirror for 7 nm. AB - Multilayer (ML) structures composed of alternating, ultrathin layers of Ru and B(4)C have been grown by dc magnetron sputtering. The ML microstructure has been characterized using x-ray diffraction and highresolution transmission electron microscopy, and the normal-incidence reflectivity has been measured using synchrotron radiation. It is found that, under optimum deposition conditions, the ML structures exhibit smooth and compositionally abrupt interfaces, with a normal incidence reflectivity as high as 20% at 7.2 nm. The reflectivity decreases when the ML structures are annealed at 500 degrees C owing to interdiffusion and com pound formation at the interfaces. PMID- 19776948 TI - Q-switched operation of microchip lasers: erratum. PMID- 19776949 TI - Temperature-dependent index-of-refraction changes in BaTiO(3). AB - We investigate thermally induced changes in the index of refraction of BaTiO(3) that are caused by optical absorption. We show that the absorption of a 900-mW optical beam will change the surface temperature of a BaTiO(3) crystal by more than 40 degrees C and cause the extraordinary index of refraction to change by more than 10(-2). For a 900-mW beam incident upon a BaTiO(3) crystal that is not mounted on a heat sink, the surface temperature and the extraordinary index of refraction are still changing after more than 10 min. We also demonstrate that the thermally induced time-dependent index change is partially responsible for the frequency-shifted return from a two-internal-reflection or Cat self-pumped phase-conjugate mirror that has not reached thermal equilibrium. PMID- 19776950 TI - Laser-diode frequency control by resonant phase-conjugate reflection from an atomic vapor. AB - We report our first results on the frequency control of an AlGaAs laser diode by resonant phase-conjugate reflection from an atomic rubidium vapor. When the electrical feedback technique is used, the Allan variance reaches a flicker floor such that sigma(y)(2)(tau) = 1.6 x 10(-19) tau(0) for tau > 1s. We also demonstrate that laser frequency locking can be achieved by using the phase conjugate reflection directly as a resonant optical feedback. This approach leads to a self-controlled optical frequency standard at 780 nm. PMID- 19776951 TI - Diffraction of a light beam by doubly periodic structures. AB - Theoretical and experimental results are presented for the diffraction of light by doubly periodic structures that consist of two gratings separated by a uniform thin film. We observe the appearance of many diffracted beams that are due to the interactions through evanescent fields between the two gratings. PMID- 19776952 TI - Enhancement of backscattered intensity in a random medium. AB - When high-frequency radiation traverses twice through random inhomogeneities there arise a number of effects not observed along one-directional propagation paths. To correlate the forward-backward-propagating events, we consider here a paired field measure in which the random information along the propagation path is preserved and apply an approximate analytical solution for the high-frequency propagator of that measure obtained by the multiscale expansion asymptotic procedure. From this function all even statistical moments can be generated. The test of the solution is performed on a canonical backscattering problem based on a point-sourcepoint-scatterer configuration, which justifies its application for construction of the coherence measures of the retroreflected field. We show that the intensity enhancement effect depends on the geometry of the wave front of the incident field. PMID- 19776953 TI - Bulk-darkening threshold of flux-grown KTiOPO(4). AB - A quantitative assessment of the bulk-darkening phenomenon for flux-grown KTiOPO(4) is reported. Measurements were made for KTiOPQ(4) use as a component for second-harmonic generation of 1064-nm Nd:YAG radiation operating in a pulsed mode. The results show that the bulk-darkening severity increases with fluence and exposure time. Irreversible bulk darkening has been observed at laser energies ranging from 8.8 to 18 J/cm(2) depending on the shot count. Fluences exceeding 15 J/cm(2) can cause catastrophic damage. Data taken at elevated temperatures indicate an improved reliability. The onset of slight bulk darkening revealed no adverse effects on conversion efficiency. PMID- 19776954 TI - Observations of Descartes ring stimulated Raman scattering in micrometer-sized water droplets. AB - Stimulated Raman scattering (SRS) from micrometer-sized droplets, which results from coupling of spontaneous Raman emission to droplet morphology-dependent resonances (MDR's), exhibits unique characteristics. Spatial patterns consist of bright SRS arcs on the droplet rim. A second source of SRS emission has recently been observed from a ringlike region encircling the droplet axis near the geometric focus (the Descartes ring). Investigation of the time and spectral characteristics of Descartes ring SRS and its suppression by the addition of absorptive dye to the droplet reveals it to be an additional manifestation of droplet MDR's. We conjecture that the Descartes ring results when the MDR light is scattered by refractive-index inhomogeneities produced by the intense pump field within the droplet. PMID- 19776955 TI - Self-pumped optical phase conjugation with a sodium Raman laser. AB - We report self-pumped optical phase conjugation in which the pumps are self induced as standing waves in a linear Raman laser. Self-pumped reflectivities approaching 5% are obtained for input intensities of 20 W/cm(2). This low optical input intensity combined with predicted submicrosecond response times suggests that the resonant Raman interaction may provide the basis for a promising new class of nonlinear-optical material. PMID- 19776957 TI - Geometric formulation of unstable-resonator design and application to self collimating unstable-resonator diode lasers. AB - A new set of design parameters for unstable resonators is presented that yields simpler expressions for the mirror and beam radii and magnification than those given by the usual g parameters. The new formalism is applied to determine the design of a solid unstable resonator of index n with a self-collimated output beam, applicable to unstable-resonator diode lasers. PMID- 19776956 TI - Numerical determination of planar waveguide modes using the analyticity of the dispersion relation. AB - The modes of a planar multilayer waveguide can readily be determined by using an algorithm that exploits the analyticity of the waveguide dispersion relation. No prior knowledge of the number of solutions or their approximate locations is required; the algorithms finds all the solutions within the region of interest without risk of confusion because of degeneracy or near degeneracy. This method finds both leaky and bound modes in structures of transparent and lossy materials. PMID- 19776958 TI - Correction of optical path differences using phase conjugation in single-mode diode lasers. AB - Intracavity four-wave mixing in single-mode diode lasers operating above threshold is shown to phase conjugate optical path differences. This capability, in conjunction with observed conjugate reflectivities in excess of 10(4), makes diode-laser conjugators an attractive and potentially monolithically integratable conjugator technology for semiconductor optoelectronics. PMID- 19776959 TI - Effect of phase-conjugate feedback on semiconductor laser dynamics. AB - The effect of phase-conjugate feedback on the dynamic response of semiconductor lasers is studied by using a rate-equation approach. The steady state exists only for certain well-defined values of the phase of the intracavity optical field. Depending on the amount of phase-conjugate feedback, the steady state becomes unstable through two independent instabilities, referred to as fold and Hopf instabilities. The fold instability is due solely to the phase-conjugate nature of the feedback and does not occur in the case of normal feedback. In the instability region, the laser output is found to become chaotic by following a period-doubling or quasi-periodic route to chaos, depending on the amount of feedback. PMID- 19776960 TI - Buildup of steady-state picosecond pulses in an actively mode-locked laser-diode array. AB - We have studied experimentally the temporal and spectral characteristics of an actively mode-locked laserdiode array in an external cavity as it evolves to the steady state. It is found that the buildup time to steadystate picosecond pulses takes less than 45 round trips. The number of clusters of the longitudinal-mode spectrum reduces during the evolution and finally approaches a steady-state spectral distribution with the pulse energy mainly distributed among a few clusters near the line center. PMID- 19776961 TI - Self-starting of passively mode-locked lasers. AB - The self-starting condition of passively mode-locked lasers, including those locked by additive-pulse mode locking, is reexamined. A quantitative model is developed for a threshold intensity for self-starting based on the hypothesis that spurious reflections have to be overcome by coherent injection signals of sufficient amplitude. PMID- 19776962 TI - Measurement of ultrafast optical nonlinearities using a modified Sagnac interferometer. AB - A method for the measurement of fast, intensity-dependent refractive-index changes with the use of a modified Sagnac ring interferometer is presented. The measurement is not degraded by slowly responding background index changes. Nonlinear refractive-index changes in an undoped silicon wafer, and in poly-bis toluene sulfonate polydiacetylene and dye-doped polymethyl methacrylate waveguides, were measured with the use of a cw mode-locked Nd:YAG laser. PMID- 19776963 TI - Average soliton dynamics of a high-gain erbium fiber laser. AB - Soliton propagation in a fiber described by the nonlinear Schrodinger equation in the presence of large periodic energy variations is examined. Stable propagation can be achieved provided that the soliton period is long compared with the period of energy variation and the (associated) average soliton (peak) pulse power equals the fundamental soliton (peak) pulse power. The result is used to interpret recent experiments on mode-locked, high-gain erbium fiber lasers. PMID- 19776964 TI - Femtosecond accumulated photon echo in Er-doped fibers. AB - We report the observation of accumulated photon echo in Er-doped fibers. We also demonstrate time reversal and autoconvolution of femtosecond pulses, which suggest that Er-doped fibers are a promising medium for femtosecond time-domain optical signal processing. PMID- 19776965 TI - Photorefractive parallel matrix-matrix multiplier. AB - We demonstrate the operation of a parallel matrix-matrix multiplier that uses a photorefractive crystal in conjunction with an array of mutually incoherent laser sources. A complex set of gratings is written in parallel with the aid of the mutually incoherent laser source array whose spatial modulation is the desired matrix-matrix product. PMID- 19776966 TI - Polarization dependence of the phase of interference between single- and two photon ionization. AB - The interference between single-photon and two-photon ionization has been observed for electrons ejected in the direction n from the photomultiplier cathode exposed simultaneously to the picosecond pulse of a Nd laser E(omega) and its second harmonic E(2omega). The change of the phase difference of such interference was measured for the switch of the polarizations from E(omega) ||n, E(2omega) ||n to E(omega) ? n, E(2omega) || n. PMID- 19776967 TI - Spatial modification of a Gaussian beam on reflection from a saturable absorber. AB - We calculate the reflection coefficient of a dielectric-gas interface including the nonlinear local field, saturation, and self-reflected wave effects. We specialize to collisionally broadened gases with absorption lengths that are necessarily small compared with an optical wavelength and preclude the use of the slowly varying amplitude approximation. The dependence of the reflectivity on the intensity of the incoming field is revealed through the changes that it induces in the transverse profile of a reflected Gaussian beam. These changes derive principally from effective aperturing effects in amplitude and phase. PMID- 19776968 TI - Polarization pinhole interferometer. AB - A polarization pinhole interferometer is based on the principles of pinhole diffraction, a common light path, and the polarization technique in its design. It has many advantages, such as adjustable contrast of the fringes, nondestructive testing, and less sensitivity to environmental factors. The instrument can be used extensively in optical element testing and glue-layer testing. The accuracy of the fringe pattern analysis is controlled by the number of sampled points in the fringes. The analysis results of the closed fringe pattern are given. PMID- 19776969 TI - Simple fiber-optic low-temperature sensor that uses microbending loss. AB - A simple fiber-optic temperature sensor is constructed that uses the temperature dependence of microbending loss. The sensor is tested and shows high sensitivity and a strict linear scale over a wide range from 20 to 180 K. It is shown that a proper choice of signal wavelength can be used either to make the sensor more sensitive or to make it independent of changes in laser wavelength. PMID- 19776970 TI - Distributed laser Doppler velocimeter. AB - A monobeam laser Doppler velocimeter that permits continuous recovery of the flow velocity profile along the beam is described. The scheme applies the coherence multiplexing concept to backscattering Doppler detection. A theoretical analysis of the distributed velocimeter is given, along with a description of an experiment with a superluminescent diode source inserted in an all-fiber-optic scheme. The velocity profile of water flow in a duct is reported. The results confirm the exceptional capabilities offered by this velocimeter in experimental fluid mechanics. PMID- 19776972 TI - Huygens's wave propagation principle corrected. PMID- 19776971 TI - Atmospheric-turbulence measurements using a synthetic beacon in the mesospheric sodium layer. PMID- 19776973 TI - Dynamic effects of Kerr nonlinearity and spatial diffraction on self-phase modulation of optical pulses. PMID- 19776975 TI - Induced phase modulation by noisy fields. PMID- 19776974 TI - Fundamental media considerations for the propagation of phase-conjugate waves. PMID- 19776976 TI - Stimulated-Brillouin-scattering properties of SnCl(4). PMID- 19776978 TI - Soliton annihilation and fusion from resonant inelastic collisions in birefringent optical fibers. PMID- 19776977 TI - Guiding-center soliton in fibers with periodically varying dispersion. PMID- 19776979 TI - Ultraviolet-induced distributed-feedback gratings in Ce(3+) -doped silica optical fibers. PMID- 19776980 TI - Femtosecond external-cavity surface-emitting InGaAs/InP multiple-quantum-well laser. PMID- 19776981 TI - High-power visible upconversion laser. PMID- 19776982 TI - Frequency doubling with KNbO(3) in an external cavity. PMID- 19776983 TI - Wideband frequency noise reduction and FM equalization in AlGaAs lasers using electrical feedback. PMID- 19776984 TI - Multiterawatt, 100-fs laser. PMID- 19776985 TI - High-power femtosecond optical pulse compression by using spatial solitons. PMID- 19776986 TI - Direct time integration of Maxwell's equations in linear dispersive media with absorption for scattering and propagation of femtosecond electromagnetic pulses. PMID- 19776987 TI - 4 x 4 free-space optical switching using real-time binary phase-only holograms generated by a liquid-crystal display. PMID- 19776988 TI - Nonlinear-optical processing by means of phase coding. PMID- 19776989 TI - Adaptive optical interconnection. PMID- 19776991 TI - Digital diffusers for optical holography. PMID- 19776990 TI - Avalanche upconversion in Tm:YALO(3). PMID- 19776992 TI - Curved holographic elements for optical coordinate transformations. PMID- 19776993 TI - Jagged appearance of Rayleigh-backscatter signal in ultrahigh-resolution optical time-domain reflectometry based on low-coherence interference. PMID- 19776994 TI - Two-color interferometry using a detuned frequency-doubling crystal. PMID- 19776995 TI - Logic gate modules using opto-optical birefringence switching. PMID- 19776996 TI - Photorefractive optical lock-in detector. PMID- 19776997 TI - Fiber-optic dc and low-frequency electric-field sensor. PMID- 19776998 TI - Interrogation of a conventional current transformer by a fiber-optic interferometer. PMID- 19776999 TI - Antispecular enhancement in s- and p-polarized electromagnetic waves scattered from random gratings. AB - The scattering of electromagnetic plane waves incident upon a random grating whose grooves are not perpendicular to the plane of incidence is studied. The results display a new effect associated with the weak localization of surface electromagnetic waves in random surfaces. This new effect is similar to enhanced backscattering in the sense that a peak in the intensity of the incoherent component of the scattered light is in a direction opposite to the specular direction, but it differs from enhanced backscattering in that this direction does not coincide with the retroreflection direction and in that it is observed in both p and s polarizations. PMID- 19777000 TI - Heterostructure multilevel binary optics. AB - A method for forming multilevel diffractive elements (kinoforms) that have highly accurate level heights so as to obtain high diffraction efficiencies is presented. The method, which leads to heterostructure multilevel binary optical elements, relies on conventional deposition technology, selective etching, and multimask lithography. As an illustration, a reflective multilevel element for 10.6-microm radiation is designed, recorded, and tested. PMID- 19777001 TI - Pattern formation and flow control of fine particles by laser-scanning micromanipulation. AB - A novel micromanipulation technique is proposed for aligning fine particles on micrometer-scale spatial patterns and for moving the particles continuously along the formed patterns. This technique is based on the repetitive scanning of a focused trapping laser beam. The velocity of the particle flow can be controlled by scan speed and laser power. The origin of the driving force is considered theoretically and experimentally. PMID- 19777002 TI - Evolution of optical coatings in Earth orbit. AB - High-resolution medium-energy backscattering analyses have been performed on SiO and SiO(2) optical coatings that were exposed to the space environment aboard the NASA long-duration experiment module flight (LDEF). The data show an increase in areal density of 1% (resolved at the l0sigma level) in the SiO film as a result of this exposure. It appears that this effect has been produced by the incorporation of atomic oxygen from the ambient environment. Data on the SiO(2) film are less compelling but are consistent with some loss of material from the surface. These analyses set a new standard for profiling film thicknesses by ion backscattering. PMID- 19777003 TI - Stimulated Raman scattering and four-wave mixing from a mixture of carbon disulfide and phenylethanol in a hollow optical fiber. AB - We observe, for what is to our knowledge the first time, stimulated Raman scattering and four-wave mixing in a liquid-core optical fiber filled with a mixture of carbon disulfide and phenylethanol pumped by the frequencydoubled output of a Q-switched YAG laser (lambda = 532.1 nm). The frequencies of the stimulated Raman scattering and four-wave mixing spectra are specified, and theoretical interpretations are also given. PMID- 19777004 TI - Experimental spatial soliton trapping and switching. AB - We show experimentally the trapping of two spatial solitons of the same wavelength but with slightly different propagation directions, which results from the collision of two initially overlapped solitons beams. This is the spatial analog of soliton pulse trapping in birefringent optical fibers. Adjustment of the phase shift between each beam permits the switching of one soliton to the other without disturbing their trajectory. PMID- 19777005 TI - Directionally scattered optical second-harmonic generation with surface plasmons. AB - The spatial distribution of scattered optical second-harmonic generation owing to prism-coupled surface plasmon excitation at a silver-quartz crystal interface is studied. This spatial pattern, which has the shape of a limited arc radiated in the direction normal to the interface, can geometrically be explained in terms of the beating between the forward incident and backward scattered surface plasmons. The observed intensity distribution of the scattered harmonic light cannot be fitted by a single-scattering theory; thus the dominant contribution to the scattering arises from multiply scattered surface plasmons that may be interpreted in terms of enhanced backscattering. PMID- 19777006 TI - Universality in the dynamics of phase grating formation in optical fibers. AB - We find that a universal parameter exists in the local two-photon bleaching model of phase grating formation that reduces the coupled partial differential equations describing the system to ordinary differential equations. We use these equations to prove that there exists a fixed point of the grating growth process that corresponds to a perfectly phase-matched grating and that it is stable. PMID- 19777007 TI - Low-noise amplification of ultraweak optical wave fronts in photorefractive Bi(12)SiO(20). AB - We propose and demonstrate a technique for suppressing the optical noise of the photorefractive amplifiers that exhibit a sharp gain resonance around an optimum pump-to-signal angle. The amplification of extremely weak images is achieved when the entrance face of the crystal is tilted with respect to the pump beam direction. In Bi(12)SiO(20) subpicowatt optical signals are detected with this technique. PMID- 19777009 TI - Preparation of frequency-doubling fibers under UV excitation. AB - Germanium-doped silica fibers were prepared for frequency doubling of 1.06-microm wavelength radiation under the simultaneous presence of the first, second, and fourth harmonics of the laser light. It was found that the preparation rate for frequency doubling was dramatically increased by the presence of the fourth harmonic. The experiments also showed that a metastable excited state plays a significant role in the process. PMID- 19777008 TI - Soliton fusion and steering by the simultaneous launch of two different-color solitons. AB - Two optical solitons with different center frequencies simultaneously launched into an optical fiber are considered. By numerical simulation and by experiment, it is shown that if their frequency separation is small, they will either merge into a single pulse (fusion) or form two pulses with different velocities (steering), depending on their phase difference. With a 400-m fiber and ~2.5-ps solitons at 1457.7 and 1460.7 nm, fusion and steering of as much as 7 ps are demonstrated. PMID- 19777010 TI - Billiard-ball soliton interaction gates. AB - We demonstrate a cascadable, Boolean complete, conservative-logic interaction gate that is based on elastic collisions between temporal solitons in optical fibers. The two identical-frequency and polarization inputs are initially separated by 4.5 pulse widths, and they interact in a 7.5 walk-off length of polarization-maintaining fiber. The group velocity of one of the inputs is altered by passing the pulse through a beam splitter with a wavelength-dependent reflection coefficient. Although details within the interaction region depend on the phase between the two inputs, after the pulses separate the result is phase independent. We find that each of two 17-pJ solitons is displaced after interaction by 3.5 pulse widths so as to increase the pulses' separation. PMID- 19777011 TI - 6.5-W, 532-nm radiation by cw resonant external-cavity second-harmonic generation of an 18-W Nd:YAG laser in LiB(3)O(5). AB - We report 6.5 W of TEM(00) cw 532-nm radiation generated by external resonant doubling in a LiB(3)O(5) crystal. An 18-W, cw, injection-locked single-frequency Nd:YAG laser was used to generate 532-nm second-harmonic output with a 3-dB heterodyne linewidth of 15 kHz. PMID- 19777012 TI - Elliptic-mode cavity for diode-pumped lasers. AB - A novel laser resonator capable of producing a strongly elliptic TEM(00) mode in the gain medium is analyzed. Careful design results in an axially symmetric output beam, while the squeezed mode volume in the active medium allows an optimum exploitation of the inversion generated by end pumping the laser with a high-power laser-diode array. When a single array is used, the pump threshold can be typically reduced by an order of magnitude as compared with conventional (circular-mode) end-pumped systems without compromising any other laser characteristics. The combination of the presented cavity design with geometric multiplexing of diode arrays provides an efficient means for scaling end-pumped lasers to high powers. PMID- 19777013 TI - Gain cross saturation and spectral hole burning in wideband erbium-doped fiber amplifiers. AB - Cross-saturation characteristics are investigated in broadband 1.48-microm pumped and 980-nm pumped gainshaped erbium-doped fiber amplifiers. Gain shaping is shown to give a more uniform spectral gain compression on saturation. In addition, a degree of room-temperature spectral gain hole burning is observed for what is to our knowledge the first time. PMID- 19777014 TI - 5-GHz mode locking of a Nd:YLF laser. AB - A frequency-modulated Nd:YLF laser has been mode locked at a repetition rate of 5.4 GHz by using 20 mW of microwave power applied to a LiTaO(3) electro-optic phase modulator in a short (2-cm) laser cavity. The 13-ps pulse duration is shorter than expected on the basis of mode-locking theory for homogeneously broadened transitions and is attributed to inhomogeneity associated with spatial hole burning. PMID- 19777015 TI - Picosecond pulse generation in Nd:BEL with a high-frequency acousto-optic mode locker. AB - By using a high-frequency acousto-optic mode locker, 7.5-ps FWHM pulses were obtained from a diode-pumped Nd:BEL laser. After the pulses were compressed with a fiber-grating compressor, l.0-ps FWHM pulse durations were achieved. PMID- 19777016 TI - Femtosecond single-shot phase-sensitive autocorrelator for the ultraviolet. AB - A single-shot phase-sensitive autocorrelator for the investigation of high intensity ultraviolet laser pulses is developed and tested. The fluorescence of the two-photon-excited self-trapped excitons in BaF(2) is used as a nonlinear detector. Simultaneous measurements of subpicosecond KrF laser are reported. PMID- 19777017 TI - Four-wave mixing in the far infrared from free carriers in n-type indium antimonide. AB - Far-infrared techniques have been developed that make possible the first observation to our knowledge of resonant four-wave mixing of submillimeter-wave radiation in n-type InSb maintained at 2 K. The dependences of the emission strength on dc magnetic field, circular polarization, and carrier concentration demonstrate that the resonant nonlinear process involves the collective excitations of the electron gas. PMID- 19777019 TI - Squeezed vacuum from amplitude squeezed states. AB - Squeezed vacuum permits adjustment of its relative phase to a chosen signal. If the signal is used as the probe in an interferometric measurement, the signal-to noise ratio can be improved. We propose a system that generates squeezed vacuum, which consists of a laser diode that produces amplitude squeezed states and is phaselocked to a coherent signal, and an alternate system consisting of two phase locked laser diodes. PMID- 19777018 TI - Laser spectroscopy and lifetime measurements of Dy I states. AB - The dysprosium spectrum is studied in the range of 273-284 nm by using pulsed laser excitation in an atomic beam and fluorescence detection. Lifetimes and branching ratios for the decay to the ground term are determined from the analysis of fluorescence signals for 27 high-lying odd-parity levels. PMID- 19777020 TI - Fixable complementary gratings in photorefractive BaTiO(3). AB - A complementary photorefractive grating was created and stored in BaTiO(3). For a grating wave vector oriented along the crystal's c axis, the grating first appeared above 80 degrees C and would remain indefinitely after the crystal was cooled to room temperature. If the grating wave vector was aligned perpendicular to the c axis, the complementary grating could be created at room temperature but would last only a few hours. We attribute the formation of the complementary grating to the movement of ions in the crystal. PMID- 19777021 TI - Two-wavelength laser-diode interferometry that uses phase-shifting techniques. AB - Two-wavelength phase-measuring interferometry with dual laser-diode sources has been developed that is based on a phase-shifting method that uses two wavelengths varied stepwise by separately changing the currents in two laser diodes. A synthetic wavelength is produced by the addition of two single-wavelength interferograms without the need for auxiliary techniques. The phases are equally shifted in opposite directions to each other on an unbalanced interferometer. The fringe shifts that result from modulated phases are monitored with an electronic sensor to ensure accuracy. Our experimental result shows measurements of the profile of a step object with a 4.6-microm synthetic wavelength. PMID- 19777022 TI - Observation of the beat between two independent light sources by a method of time delayed laser-induced double gratings. AB - A novel method of time-delayed laser-induced double gratings has been proposed to study the beat between two independent light sources. Our experimental results indicate that we can obtain good interference patterns even when the coherence time of the laser source is only a few picoseconds. This new technique can be used to measure the frequency difference between two laser fields. PMID- 19777023 TI - Ultrafast vibration and laser acoustics in thin transparent films. AB - Picosecond laser pulses are used to excite and detect stress pulses in thin transparent films on opaque substrates. The reflectance variation, measured for silica films, is modeled as a sum of different contributions: an echo contribution from stress-induced modulation of the substrate reflectance, an interference contribution from light reflected by the stress pulse in the transparent film, and a contribution from stressinduced vibrations of the order of 10(-3)nm of the film surface, observed for what is to our knowledge the first time. We show how both the thickness and sound velocity of the film can be determined, provided that its refractive index is known. PMID- 19777024 TI - Quantitative evaluation of phase-conjugate novelty filters. AB - A Michelson interferometer whose signal arm is terminated by a self-pumped BaTiO(3) phase conjugator records phase-change distributions in times short compared with the conjugator rewrite time that correspond quantitatively to a single (not a double) traversal of the phase disturbance. The proffered explanation, which is experimentally substantiated, also places limitations on the pictorial accuracy of intensity-change novelty filters. PMID- 19777025 TI - Optical spectrum analysis from zero crossings. AB - A practical method of computing the spectral components directly from measured zero crossings of interferograms is presented. The method requires the sampling of only one zero crossing per Nyquist interval and yields results with a normalized mean-square error that is better than 10(-6) with respect to the fast Fourier transformation when the zero crossing is located within the Nyquist interval with an accuracy of one part in 10(6). The method is also robust against error frequencies that may arise owing to the finite range in the floating-point representation of numbers in a computer. The error frequencies appear whenever a large number of crossings is processed. This type of error is not related to the accuracy of locating the zero crossings and limits the operational bandwidth of a zero-crossing-based optical spectrum analyzer. PMID- 19777026 TI - Fiber frequency shifter based on generation of stimulated Brillouin scattering in high-finesse ring resonators. AB - We demonstrate, for the first time to our knowledge, a discretely tunable all fiber frequency shifter based on mixing the outputs of two stimulated Brillouin scattering fiber ring resonator lasers. The frequency tuning was achieved by differentially heating the rings. The observed temperature dependence of the frequency shift was as expected, with the discrete frequency jumps being equal to the free spectral range of the resonator. PMID- 19777027 TI - Photoinduced refractive-index changes in two-mode, elliptical-core fibers: sensing applications. AB - Photoinduced refractive-index changes in two-mode, elliptical-core optical fibers are shown to affect the differential phase modulation between the LP(01) and the LP(11)(even) modes. This change in beat length is dependent on the amount of strain induced in the fiber while the grating is being formed. We present experimental results that agree with conventional coupled-mode theory and propose the use of such sensors for weighted and distributed applications. PMID- 19777028 TI - High-power beam steering using phase conjugation through Brillouin-induced four wave mixing. AB - We report an experimental demonstration of a beam-steering concept. A high reflectivity phase-conjugate mirror is used to steer a high-power phase-conjugate beam using a low-power signal beam. The high reflectivity phase conjugation is achieved using Brillouin-induced four-wave mixing in a cell containing carbon disulfide. PMID- 19777029 TI - Determination of intrinsic mid-infrared absorption of a fluoride glass. AB - The intrinsic mid-infrared optical absorption of a ZrF(4)-BaF(2)-LaF(3)-AlF(3) NaF (ZBLAN) glass has been determined by combining laser calorimetry and spark source mass spectrographic analysis. The total optical absorption of four samples of varying purity was measured at 3.9 microm with laser calorimetry. The extrinsic contribution to the total absorption for each glass was calculated from the measured concentration of rare-earth impurity ions and known extinction coefficients. The intrinsic absorption of this glass at 3.9 microm determined from the difference between the total measured absorption and the calculated extrinsic absorption is 6.11 (+/-0.61) x 10(-4) cm(-1). PMID- 19777030 TI - Diffraction-limited soft-x-ray projection imaging using a laser plasma source. AB - Projection imaging of 0.1-microm lines and spaces is demonstrated with a Mo/Si multilayer coated Schwarzschild objective and 14-nm illumination from a laser plasma source. This structure has been etched into a silicon wafer by using a trilevel resist and reactive ion etching. Low-contrast modulation at 0.05-microm lines and spaces is observed in polymethylmethacrylate. PMID- 19777031 TI - Propagation of solitonlike pulses under cross-phase modulation. AB - I identify regions in which different two-soliton combinations can copropagate under cross-phase modulation. Subsoliton-power and supersoliton-power solitons are considered in the context of optical switching. The stability of these pairs to different perturbing factors is also discussed. PMID- 19777032 TI - Three-dimensional simulation of guided-wave second-harmonic generation in the form of coherent Cerenkov radiation. AB - We implement a direct three-dimensional calculation of Cerenkov-radiation-type frequency doubling in an optical channel waveguide by using a finite-element guided-beam simulator. The simulator can predict an optimum configuration and the conversion efficiency of miniaturized frequency doublers that utilize guided-to radiation-mode interactions in nonlinear channel waveguides. Computed results are shown for blue-light generation through the frequency doubling in a proton exchanged MgO:LiNbO(3) channel waveguide. PMID- 19777033 TI - Self-injected spatial mode locking and coherent all-optical FM/AM switching based on modulational instability. AB - A geometric analysis of modulational instability reveals that spatiotemporally stable amplitude and frequency modulations may propagate in a nonlinear dispersive fiber, owing to self-injected locking of the temporal modes. We describe the close connection between the coherent nonlinear switching of an intense carrier by means of a weak modulating signal and similar instabilities in birefringent fibers and nonlinear directional couplers. PMID- 19777034 TI - Generation of 30-fs pulses tunable over the visible spectrum. AB - The generation of 30-fs pulses of several microjoules of energy, continuously tunable from 420 to 650 nm, is achieved by selective amplification and compression of a continuum that is generated in quartz. The pump pulses are provided by a compact excimer-laser-pumped pulsed dye-laser system operating at 500 nm. The whole arrangement including the final amplifiers uses only a single excimer laser as a pump source. This provides excellent pulse-to-pulse stability of < +/-5%. PMID- 19777035 TI - Scattering due to randomly distributed charge particles in photorefractive crystals. AB - Scattering due to noisy gratings produced by randomly distributed charge particles in photorefractive crystals is considered. The scattering cross section is analyzed in terms of the fluctuation of the refractive index introduced by the random space-charge field through the Pockels effect. We also consider the noise in photorefractive gratings due to such scattering. A signal-to-noise ratio of 1 leads to a minimum modulation depth for an index grating. PMID- 19777036 TI - Self-induced transparency in a dispersive and nonlinear Kerr host medium. AB - A steady-state solution that describes pulse propagation in inhomogeneously broadening two-level atoms embedded in a dispersive and nonlinear Kerr lossless host medium has been found. The solution is of an unchirped hyperbolic-secant form with a linear spatial phase delay. The features of the solution are (i) the group velocity, the amplitude, and the width of the pulse are uniquely determined for given parameters of the medium and the carrier frequency; (ii) the group velocity is independent of the density of the resonant atoms; and (iii) the solution can exist in the positive dispersion region. PMID- 19777037 TI - Dark-soliton jitter in amplified optical transmission systems. AB - The transmission of dark solitons in ultralong transmission systems with optical amplification is numerically investigated. We show that amplifier noise is responsible for a random frequency shift with a resulting time jitter radical2 times lower than that observed for bright solitons. PMID- 19777038 TI - Exclusive anti-Stokes Raman scattering using coherent material excitation. AB - A new process capable of scattering intense anti-Stokes waves that uses stimulated electronic Raman scattering in metal vapor is proposed. The coherent material excitation produced by a prepump pulse couples with the forthcoming main pulse exclusively to create polarization that radiates the anti-Stokes wave. The selection rule governed by angular momentum conservation is the key to cause such strong coupling to induce unidirectional upconversion without any population inversion. The power conversion efficiency from the pump wave to the anti-Stokes wave is theoretically expected to reach 100% in this process. PMID- 19777039 TI - Attainment of high efficiencies in optical parametric oscillators. AB - Major practical requirements relevant to achieving high conversion efficiencies in optical parametric oscillators have been identified. In particular, an experimental comparison has been made between critically and noncritically phase matched geometries in beta-barium borate (BBO) and lithium triborate (LBO), respectively, when they are pumped by an excimer laser at 308 nm. We report pump depletions of 40% in LBO and 50% in BBO when 385- and 1540-nm radiation is parametrically generated. Pump depletions of 64% have been obtained in BBO when 540- and 700-nm radiation is generated. Optimization of external efficiencies has been studied, and values of 30% have been obtained in LBO by resonating the low energy wave. PMID- 19777040 TI - Picosecond pulsed diode ring-laser gyroscope. AB - We have demonstrated a novel solid-state ring-laser gyroscope, which utilizes as the gain media a pair of semi-conductor diodes in an external ring cavity. The use of homogeneously broadened gain media is made possible by actively mode locking the laser. We observe no evidence of frequency locking between the counterpropagating optical pulse trains generated in the cavity to within the limit of our experimental resolution. PMID- 19777041 TI - Injection locking of a highly coherent and high-power diode laser at 1.5 microm. AB - Injection locking has been employed to improve the coherence of a high-power diode laser at 1.5 microm. The injected high-power laser emitted in a single mode with a side-mode suppression ratio of larger than 30 dB and an output power of 40 mW. The FM noise of the slave laser was nearly the same as that of the submegahertz-linewidth master laser. We have also demonstrated the coherent addition of the master and the injection-locked slave laser with a residual phase error of deltao < 0.2 rad. PMID- 19777042 TI - Prepulse-free 30-TW, 1-ps Nd:glass laser. AB - A 30-TW,1.0-ps laser pulse at 1053 nm has been generated by chirped-pulse amplification in a large-aperture Nd:phosphate glass laser system. A peak-to prepulse intensity ratio of better than 10(7) was obtained by temporal windowing of a self-phase-modulated chirped pulse before amplification and compression. PMID- 19777043 TI - Femtosecond response time in a polarization-rotation switch using semiconductor doped glasses. AB - A polarization-rotation switch is demonstrated that is based on semiconductor doped glasses. The response time is shorter than 50 fs, and an on-off ratio of 38:1 could be obtained at a pulse fluence of 1.5 x 10(-6) J/cm(2), which corresponds to an intensity of 10 MW/cm(2). PMID- 19777044 TI - 100-MHz optical counter that uses directional coupler switches. AB - We have constructed what is to our knowledge the first speed-of-light 100-MHz digital optical counter using directional coupler switches and single-mode fibers. The counter has operated with both 4- and 6-bit counts, with the use of two different counter designs. In addition, we have demonstrated operation of two simultaneous and independent 4-bit counters running on the same hardware by time division multiplexing the hardware. This approach allows effective clock rates many times the individual machine clock rate and is limited only by the switching speed. For large latency systems, this approach offers the promise of gigahertz clock rates for digital optical computers. PMID- 19777045 TI - Mirror-array optical interconnected neural network. AB - A high-light-efficiency optical neural network that uses a mirror-array interconnection is proposed. Design considerations for the mirror array and experimental demonstration are given. PMID- 19777046 TI - Method for increasing the velocity acceptance of stimulated laser cooling. AB - A new method is proposed for laser cooling atoms with Doppler shifts an order of magnitude larger than the homogeneous linewidth of the atomic transition. Two traveling waves cross at an oblique angle and form long-wavelength standing waves. The resulting broadband stimulated cooling forces are predicted to stop 0.1% of the flux of a 500-K atomic sodium beam in a distance of 300 microm and a time of a few microseconds. This is more than 100 times faster than current methods. PMID- 19777047 TI - Transient response of a thresholdless microdroplet dye laser. AB - Lasing in a cavity formed by a dye-doped micrometer-sized liquid droplet showed a new thresholdless steady-state behavior and a time-dependent response. The thresholdless behavior is associated with enhancement and inhibition of the spontaneous emission. The time-dependent response is related to various quality factors of the cavity modes and was determined to be 8 x 10(8). PMID- 19777048 TI - Remote infrared chemical sensing using highly durable AlF(3)-based glass fibers. AB - Unclad, low-loss AlF(3)-based glass fibers with enhanced chemical durability have been successfully used for the first time to our knowledge as intrinsic evanescent infrared sensors for monitoring liquid chemicals. Different liquids with absorption bands between 1 and 4.5 microm, such as alcohol, acetonitrile, and mixtures of alcohol/acetonitrile and water/acetonitrile, have been tested. These fibers have also been used successfully as distributed sensors for simultaneous monitoring of different chemical species. PMID- 19777049 TI - Reflection-grating photorefractive self-pumped ring mirror. AB - A reflection-grating self-pumped passive ring mirror is experimentally fabricated in a photorefractive KNbO(3) crystal. The observed values of nonlinear reflectivity are as much as 50%, and the response time of the mirror is several milliseconds. PMID- 19777050 TI - Theoretical model for a Faraday anomalous dispersion optical filter. AB - A model for the Faraday anomalous dispersion optical filter is presented. Our model predicts a bandwidth of 0.6 GHz and a transmission peak of 0.98 for a filter operating on the Cs (D(2)) line. The model includes hyperfine effects and is valid for arbitrary magnetic fields. PMID- 19777051 TI - Lamp-pumped thallium atomic line filter at 535.046 nm. AB - We present a new atomic line filter concept for the detection of frequency doubled Nd:BEL laser radiation. Advantage is taken of the thallium 6(2)P(3/2) metastable energy level whose large lifetime can be preserved even in small vapor cells. The filter is pumped intermittently by a low-power spectral lamp and thereby combines the benefits of active and passive operation. Analysis of a proposed final design shows that simple engineering solutions exist, and excellent filter properties can be deduced. We have experimentally demonstrated the new operating principle in a preliminary setup. PMID- 19777052 TI - Borane Complexes of the H(3)PO(2) P(III) Tautomer: Useful Phosphinate Equivalents. AB - The preparation and reactivity of novel (R(1)O)(R(2)O)P(BH(3))H [R(1), R(2) = Et, TIPS] synthons is investigated. The direct alkylation of these compounds with lithium hexamethyldisilazide (LiHMDS) and various electrophiles, provided new series of phosphonite-borane complexes, which can be converted into H phosphinates and boranophosphonates. PMID- 19777053 TI - Effect of pi-electron conjugation length on the solvent-dependent S(1) lifetime of peridinin. AB - Peridinin exhibits an anomalous solvent dependence of its S(1) excited state lifetime attributed to the presence of an intramolecular charge transfer (ICT) state. The nature of this state has yet to be elucidated. Ultrafast time-resolved optical spectroscopy has been performed on a synthetic analog, C(35)-peridinin, having one less conjugated double bond than peridinin. The data reveal the lifetime decreases from 1.5 ns in n-hexane to 9.2 ps in methanol, an order of magnitude larger than peridinin. This is the strongest solvent dependence on the lifetime of an S(1) state of a carotenoid yet reported. The data support the view that the S(1) and ICT states are strongly coupled. PMID- 19777054 TI - miR-155 inhibition sensitizes CD4+ Th cells for TREG mediated suppression. AB - BACKGROUND: In humans and mice naturally occurring CD4(+)CD25(+) regulatory T cells (nTregs) are a thymus-derived subset of T cells, crucial for the maintenance of peripheral tolerance by controlling not only potentially autoreactive T cells but virtually all cells of the adaptive and innate immune system. Recent work using Dicer-deficient mice irrevocably demonstrated the importance of miRNAs for nTreg cell-mediated tolerance. PRINCIPAL FINDINGS: DNA Microarray analyses of human as well as murine conventional CD4(+) Th cells and nTregs revealed a strong up-regulation of mature miR-155 (microRNA-155) upon activation in both populations. Studying miR-155 expression in FoxP3-deficient scurfy mice and performing FoxP3 ChIP-Seq experiments using activated human T lymphocytes, we show that the expression and maturation of miR-155 seem to be not necessarily regulated by FoxP3. In order to address the functional relevance of elevated miR-155 levels, we transfected miR-155 inhibitors or mature miR-155 RNAs into freshly-isolated human and mouse primary CD4(+) Th cells and nTregs and investigated the resulting phenotype in nTreg suppression assays. Whereas miR-155 inhibition in conventional CD4(+) Th cells strengthened nTreg cell-mediated suppression, overexpression of mature miR-155 rendered these cells unresponsive to nTreg cell-mediated suppression. CONCLUSION: Investigation of FoxP3 downstream targets, certainly of bound and regulated miRNAs revealed the associated function between the master regulator FoxP3 and miRNAs as regulators itself. miR-155 is shown to be crucially involved in nTreg cell mediated tolerance by regulating the susceptibility of conventional human as well as murine CD4(+) Th cells to nTreg cell-mediated suppression. PMID- 19777055 TI - Adenosine triphosphate stimulates Aquifex aeolicus MutL endonuclease activity. AB - BACKGROUND: Human PMS2 (hPMS2) homologues act to nick 5' and 3' to misincorporated nucleotides during mismatch repair in organisms that lack MutH. Mn(++) was previously found to stimulate the endonuclease activity of these homologues. ATP was required for the nicking activity of hPMS2 and yPMS1, but was reported to inhibit bacterial MutL proteins from Thermus thermophilus and Aquifex aeolicus that displayed homology to hPMS2. Mutational analysis has identified the DQHA(X)(2)E(X)(4)E motif present in the C-terminus of PMS2 homologues as important for endonuclease activity. METHODOLOGIES/PRINCIPAL FINDINGS: We examined the effect ATP had on the Mn(++) induced nicking of supercoiled pBR322 by full-length and mutant A. aeolicus MutL (Aae MutL) proteins. Assays were single time point, enzyme titration experiments or reaction time courses. The maximum velocity for MutL nicking was determined to be 1.6+/-0.08x10(-5) s(-1) and 4.2+/-0.3x10(-5) s(-1) in the absence and presence of ATP, respectively. AMPPNP stimulated the nicking activity to a similar extent as ATP. A truncated Aae MutL protein composed of only the C-terminal 123 amino acid residues was found to nick supercoiled DNA. Furthermore, mutations in the conserved C-terminal DQHA(X)(2)E(X)(4)E and CPHGRP motifs were shown to abolish Aae MutL endonuclease activity. CONCLUSIONS: ATP stimulated the Mn(++) induced endonuclease activity of Aae MutL. Experiments utilizing AMPPNP implied that the stimulation did not require ATP hydrolysis. A mutation in the DQHA(X)(2)E(X)(4)E motif of Aae MutL further supported the role of this region in endonclease activity. For the first time, to our knowledge, we demonstrate that changing the histidine residue in the conserved CPHGRP motif abolishes endonucleolytic activity of a hPMS2 homologue. Finally, the C-terminal 123 amino acid residues of Aae MutL were sufficient to display Mn(++) induced nicking activity. PMID- 19777056 TI - The AUXIN BINDING PROTEIN 1 is required for differential auxin responses mediating root growth. AB - BACKGROUND: In plants, the phytohormone auxin is a crucial regulator sustaining growth and development. At the cellular level, auxin is interpreted differentially in a tissue- and dose-dependent manner. Mechanisms of auxin signalling are partially unknown and the contribution of the AUXIN BINDING PROTEIN 1 (ABP1) as an auxin receptor is still a matter of debate. METHODOLOGY/PRINCIPAL FINDINGS: Here we took advantage of the present knowledge of the root biological system to demonstrate that ABP1 is required for auxin response. The use of conditional ABP1 defective plants reveals that the protein is essential for maintenance of the root meristem and acts at least on the D-type CYCLIN/RETINOBLASTOMA pathway to control entry into the cell cycle. ABP1 affects PLETHORA gradients and confers auxin sensitivity to root cells thus defining the competence of the cells to be maintained within the meristem or to elongate. ABP1 is also implicated in the regulation of gene expression in response to auxin. CONCLUSIONS/SIGNIFICANCE: Our data support that ABP1 is a key regulator for root growth and is required for auxin-mediated responses. Differential effects of ABP1 on various auxin responses support a model in which ABP1 is the major regulator for auxin action on the cell cycle and regulates auxin-mediated gene expression and cell elongation in addition to the already well known TIR1-mediated ubiquitination pathway. PMID- 19777057 TI - Human telomerase reverse transcriptase (hTERT) Q169 is essential for telomerase function in vitro and in vivo. AB - BACKGROUND: Telomerase is a reverse transcriptase that maintains the telomeres of linear chromosomes and preserves genomic integrity. The core components are a catalytic protein subunit, the telomerase reverse transcriptase (TERT), and an RNA subunit, the telomerase RNA (TR). Telomerase is unique in its ability to catalyze processive DNA synthesis, which is facilitated by telomere-specific DNA binding domains in TERT called anchor sites. A conserved glutamine residue in the TERT N-terminus is important for anchor site interactions in lower eukaryotes. The significance of this residue in higher eukaryotes, however, has not been investigated. METHODOLOGY/PRINCIPAL FINDINGS: To understand the significance of this residue in higher eukaryotes, we performed site-directed mutagenesis on human TERT (hTERT) Q169 to create neutral (Q169A), conservative (Q169N), and non conservative (Q169D) mutant proteins. We show that these mutations severely compromise telomerase activity in vitro and in vivo. The functional defects are not due to abrogated interactions with hTR or telomeric ssDNA. However, substitution of hTERT Q169 dramatically impaired the ability of telomerase to incorporate nucleotides at the second position of the template. Furthermore, Q169 mutagenesis altered the relative strength of hTERT-telomeric ssDNA interactions, which identifies Q169 as a novel residue in hTERT required for optimal primer binding. Proteolysis experiments indicate that Q169 substitution alters the protease-sensitivity of the hTERT N-terminus, indicating that a conformational change in this region of hTERT is likely critical for catalytic function. CONCLUSIONS/SIGNIFICANCE: We provide the first detailed evidence regarding the biochemical and cellular roles of an evolutionarily-conserved Gln residue in higher eukaryotes. Collectively, our results indicate that Q169 is needed to maintain the hTERT N-terminus in a conformation that is necessary for optimal enzyme-primer interactions and nucleotide incorporation. We show that Q169 is critical for the structure and function of human telomerase, thereby identifying a novel residue in hTERT that may be amenable to therapeutic intervention. PMID- 19777058 TI - Purification and characterization of a collagenolytic enzyme from a pathogen of the great barrier reef sponge, Rhopaloeides odorabile. AB - BACKGROUND: In recent years there has been a global increase in reports of disease affecting marine sponges. While disease outbreaks have the potential to seriously impact on the survival of sponge populations, the ecology of the marine environment and the health of associated invertebrates, our understanding of sponge disease is extremely limited. METHODOLOGY/PRINCIPAL FINDINGS: A collagenolytic enzyme suspected to enhance pathogenicity of bacterial strain NW4327 against the sponge Rhopaloeides odorabile was purified using combinations of size exclusion and anion exchange chromatography. After achieving a 77-fold increase in specific activity, continued purification decreased the yield to 21 fold with 7.2% recovery (specific activity 2575 collagen degrading units mg( 1)protein) possibly due to removal of co-factors. SDS-PAGE of the partially pure enzyme showed two proteins weighing approximately 116 and 45 kDa with the heavier band being similar to reported molecular weights of collagenases from Clostridium and marine Vibrios. The enzyme degraded tissue fibres of several sponge genera suggesting that NW4327 could be deleterious to other sponge species. Activity towards casein and bird feather keratin indicates that the partially purified collagenase is either a non-selective protease able to digest collagen or is contaminated with non-specific proteases. Enzyme activity was highest at pH 5 (the internal pH of R. odorabile) and 30 degrees C (the average ambient seawater temperature). Activity under partially anaerobic conditions also supports the role of this enzyme in the degradation of the spongin tissue. Cultivation of NW4327 in the presence of collagen increased production of collagenase by 30%. Enhanced enzyme activity when NW4327 was cultivated in media formulated in sterile natural seawater indicates the presence of other factors that influence enzyme synthesis. CONCLUSIONS/SIGNIFICANCE: Several aspects of the sponge disease etiology were revealed, particularly the strong correlation with the internal tissue chemistry and environmental temperature. This research provides a platform for further investigations into the virulence mechanisms of sponge pathogens. PMID- 19777060 TI - Selection of medical diagnostic codes for analysis of electronic patient records. Application to stroke in a primary care database. AB - BACKGROUND: Electronic patient records from primary care databases are increasingly used in public health and health services research but methods used to identify cases with disease are not well described. This study aimed to evaluate the relevance of different codes for the identification of acute stroke in a primary care database, and to evaluate trends in the use of different codes over time. METHODS: Data were obtained from the General Practice Research Database from 1997 to 2006. All subjects had a minimum of 24 months of up-to standard record before the first recorded stroke diagnosis. Initially, we identified stroke cases using a supplemented version of the set of codes for prevalent stroke used by the Office for National Statistics in Key health statistics from general practice 1998 (ONS codes). The ONS codes were then independently reviewed by four raters and a restricted set of 121 codes for 'acute stroke' was identified but the kappa statistic was low at 0.23. RESULTS: Initial extraction of data using the ONS codes gave 48,239 cases of stroke from 1997 to 2006. Application of the restricted set of codes reduced this to 39,424 cases. There were 2,288 cases whose index medical codes were for 'stroke annual review' and 3,112 for 'stroke monitoring'. The frequency of stroke review and monitoring codes as index codes increased from 9 per year in 1997 to 1,612 in 2004, 1,530 in 2005 and 1,424 in 2006. The one year mortality of cases with the restricted set of codes was 29.1% but for 'stroke annual review,' 4.6% and for 'stroke monitoring codes', 5.7%. CONCLUSION: In the analysis of electronic patient records, different medical codes for a single condition may have varying clinical and prognostic significance; utilisation of different medical codes may change over time; researchers with differing clinical or epidemiological experience may have differing interpretations of the relevance of particular codes. There is a need for greater transparency in the selection of sets of codes for different conditions, for the reporting of sensitivity analyses using different sets of codes, as well as sharing of code sets among researchers. PMID- 19777059 TI - FGF4 independent derivation of trophoblast stem cells from the common vole. AB - The derivation of stable multipotent trophoblast stem (TS) cell lines from preimplantation, and early postimplantation mouse embryos has been reported previously. FGF4, and its receptor FGFR2, have been identified as embryonic signaling factors responsible for the maintenance of the undifferentiated state of multipotent TS cells. Here we report the derivation of stable TS-like cell lines from the vole M. rossiaemeridionalis, in the absence of FGF4 and heparin. Vole TS-like cells are similar to murine TS cells with respect to their morphology, transcription factor gene expression and differentiation in vitro into derivatives of the trophectoderm lineage, and with respect to their ability to invade and erode host tissues, forming haemorrhagic tumours after subcutaneous injection into nude mice. Moreover, vole TS-like cells carry an inactive paternal X chromosome, indicating that they have undergone imprinted X inactivation, which is characteristic of the trophoblast lineage. Our results indicate that an alternative signaling pathway may be responsible for the establishment and stable proliferation of vole TS-like cells. PMID- 19777061 TI - Highly sensitive detection of individual HEAT and ARM repeats with HHpred and COACH. AB - BACKGROUND: HEAT and ARM repeats occur in a large number of eukaryotic proteins. As these repeats are often highly diverged, the prediction of HEAT or ARM domains can be challenging. Except for the most clear-cut cases, identification at the individual repeat level is indispensable, in particular for determining domain boundaries. However, methods using single sequence queries do not have the sensitivity required to deal with more divergent repeats and, when applied to proteins with known structures, in some cases failed to detect a single repeat. METHODOLOGY AND PRINCIPAL FINDINGS: Testing algorithms which use multiple sequence alignments as queries, we found two of them, HHpred and COACH, to detect HEAT and ARM repeats with greatly enhanced sensitivity. Calibration against experimentally determined structures suggests the use of three score classes with increasing confidence in the prediction, and prediction thresholds for each method. When we applied a new protocol using both HHpred and COACH to these structures, it detected 82% of HEAT repeats and 90% of ARM repeats, with the minimum for a given protein of 57% for HEAT repeats and 60% for ARM repeats. Application to bona fide HEAT and ARM proteins or domains indicated that similar numbers can be expected for the full complement of HEAT/ARM proteins. A systematic screen of the Protein Data Bank for false positive hits revealed their number to be low, in particular for ARM repeats. Double false positive hits for a given protein were rare for HEAT and not at all observed for ARM repeats. In combination with fold prediction and consistency checking (multiple sequence alignments, secondary structure prediction, and position analysis), repeat prediction with the new HHpred/COACH protocol dramatically improves prediction in the twilight zone of fold prediction methods, as well as the delineation of HEAT/ARM domain boundaries. SIGNIFICANCE: A protocol is presented for the identification of individual HEAT or ARM repeats which is straightforward to implement. It provides high sensitivity at a low false positive rate and will therefore greatly enhance the accuracy of predictions of HEAT and ARM domains. PMID- 19777062 TI - Glutamate uptake triggers transporter-mediated GABA release from astrocytes. AB - BACKGROUND: Glutamate (Glu) and gamma-aminobutyric acid (GABA) transporters play important roles in regulating neuronal activity. Glu is removed from the extracellular space dominantly by glial transporters. In contrast, GABA is mainly taken up by neurons. However, the glial GABA transporter subtypes share their localization with the Glu transporters and their expression is confined to the same subpopulation of astrocytes, raising the possibility of cooperation between Glu and GABA transport processes. METHODOLOGY/PRINCIPAL FINDINGS: Here we used diverse biological models both in vitro and in vivo to explore the interplay between these processes. We found that removal of Glu by astrocytic transporters triggers an elevation in the extracellular level of GABA. This coupling between excitatory and inhibitory signaling was found to be independent of Glu receptor mediated depolarization, external presence of Ca(2+) and glutamate decarboxylase activity. It was abolished in the presence of non-transportable blockers of glial Glu or GABA transporters, suggesting that the concerted action of these transporters underlies the process. CONCLUSIONS/SIGNIFICANCE: Our results suggest that activation of Glu transporters results in GABA release through reversal of glial GABA transporters. This transporter-mediated interplay represents a direct link between inhibitory and excitatory neurotransmission and may function as a negative feedback combating intense excitation in pathological conditions such as epilepsy or ischemia. PMID- 19777063 TI - A computational study on the role of gap junctions and rod Ih conductance in the enhancement of the dynamic range of the retina. AB - Recent works suggest that one of the roles of gap junctions in sensory systems is to enhance their dynamic range by avoiding early saturation in the first processing stages. In this work, we use a minimal conductance-based model of the ON rod pathways in the vertebrate retina to study the effects of electrical synaptic coupling via gap junctions among rods and among AII amacrine cells on the dynamic range of the retina. The model is also used to study the effects of the maximum conductance of rod hyperpolarization activated current I(h) on the dynamic range of the retina, allowing a study of the interrelations between this intrinsic membrane parameter with those two retina connectivity characteristics. Our results show that for realistic values of I(h) conductance the dynamic range is enhanced by rod-rod coupling, and that AII-AII coupling is less relevant to dynamic range amplification in comparison with receptor coupling. Furthermore, a plot of the retina output response versus input intensity for the optimal parameter configuration is well fitted by a power law with exponent approximately 0.5. The results are consistent with predictions of more theoretical works and suggest that the earliest expression of gap junctions along the rod pathways, together with appropriate values of rod I(h) conductance, has the highest impact on vertebrate retina dynamic range enhancement. PMID- 19777064 TI - A high-throughput approach for identification of novel general anesthetics. AB - Anesthetic development has been a largely empirical process. Recently, we described a GABAergic mimetic model system for anesthetic binding, based on apoferritin and an environment-sensitive fluorescent probe. Here, a competition assay based on 1-aminoanthracene and apoferritin has been taken to a high throughput screening level, and validated using the LOPAC(1280) library of drug like compounds. A raw hit rate of approximately 15% was reduced through the use of computational filters to yield an overall hit rate of approximately 1%. These hits were validated using isothermal titration calorimetry. The success of this initial screen and computational triage provides feasibility to undergo a large scale campaign to discover novel general anesthetics. PMID- 19777065 TI - Lymphocyte display: a novel antibody selection platform based on T cell activation. AB - Since their onset, display technologies have proven useful for the selection of antibodies against a variety of targets; however, most of the antibodies selected with the currently available platforms need to be further modified for their use in humans, and are restricted to accessible antigens. Furthermore, these platforms are not well suited for in vivo selections. We present here a novel cell based antibody display platform, which takes advantage of the functional capabilities of T lymphocytes. The display of antibodies on the surface of T lymphocytes, as a part of a chimeric-immune receptor (CIR) mediating signaling, may ideally link the antigen-antibody interaction to a demonstrable change in T cell phenotype, due to subsequent expression of the early T cell activation marker CD69. In this proof-of-concept, an in vitro selection was carried out using a human T cell line lentiviral-transduced to express a tumor-specific CIR on the surface, against a human tumor cell line expressing the carcinoembryonic antigen. Based on an effective interaction between the CIR and the tumor antigen, we demonstrated that combining CIR-mediated activation with FACS sorting of CD69(+) T cells, it is possible to isolate binders to tumor specific cell surface antigen, with an enrichment factor of at least 10(3)-fold after two rounds, resulting in a homogeneous population of T cells expressing tumor-specific CIRs. PMID- 19777066 TI - Regulation of adipose tissue stromal cells behaviors by endogenic Oct4 expression control. AB - BACKGROUND: To clarify the role of the POU domain transcription factor Oct4 in Adipose Tissue Stromal Cells (ATSCs), we investigated the regulation of Oct4 expression and other embryonic genes in fully differentiated cells, in addition to identifying expression at the gene and protein levels. The ATSCs and several immature cells were routinely expressing Oct4 protein before and after differentiating into specific lineages. METHODOLOGY/PRINCIPAL FINDINGS AND CONCLUSIONS: Here, we demonstrated the role of Oct4 in ATSCs on cell proliferation and differentiation. Exogenous Oct4 improves adult ATSCs cell proliferation and differentiation potencies through epigenetic reprogramming of stemness genes such as Oct4, Nanog, Sox2, and Rex1. Oct4 directly or indirectly induces ATSCs reprogramming along with the activation of JAK/STAT3 and ERK1/2. Exogenic Oct4 introduced a transdifferentiation priority into the neural lineage than mesodermal lineage. Global gene expression analysis results showed that Oct4 regulated target genes which could be characterized as differentially regulated genes such as pluripotency markers NANOG, SOX2, and KLF4 and markers of undifferentiated stem cells FOXD1, CDC2, and EPHB1. The negatively regulated genes included FAS, TNFR, COL6A1, JAM2, FOXQ1, FOXO1, NESTIN, SMAD3, SLIT3, DKK1, WNT5A, BMP1, and GLIS3 which are implicated in differentiation processes as well as a number of novel genes. Finally we have demonstrated the therapeutic utility of Oct4/ATSCs were introduced into the mouse traumatic brain, engrafted cells was more effectively induces regeneration activity with high therapeutic modality than that of control ATSCs. Engrafted Oct4/ATSCs efficiently migrated and transdifferentiated into action potential carrying, functionally neurons in the hippocampus and promoting the amelioration of lesion cavities. PMID- 19777067 TI - Safety and tolerability of flexible dosages of prolonged-release OROS methylphenidate in adults with attention-deficit/hyperactivity disorder. AB - The osmotic release oral system (OROS) methylphenidate formulation is a prolonged release medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in children, adolescents, and adults. We conducted a seven-week open-label extension of a double-blind study to assess the safety and tolerability of OROS methylphenidate in a flexible dose regimen (18-90 mg daily) for the treatment of adults diagnosed with ADHD (N =370). Medication was adjusted to optimize efficacy and tolerability for each patient. Adverse events, vital signs, and laboratory parameters were assessed. Most patients (337; 91%) completed the seven-week treatment and the final dispensed dose was 18 mg (8%), 36 mg (29%), 54 mg (34%), 72 mg (20%), or 90 mg (9%). Adverse events were reported in 253 (68%) patients and most were mild or moderate in severity; most frequently reported included headache (17%), decreased appetite (13%), and insomnia (11%). Adverse events were rarely serious (<1%; 2/370). Small mean increases in systolic and diastolic blood pressure (both 2.4 mmHg) and pulse (3.2 bpm) were observed. Body weight decreased slightly (-1.5 kg). The results provide additional support for the safety and tolerability of prolonged-release OROS methylphenidate in a flexible dose regimen (18-90 mg/day) for the treatment of adults with ADHD. PMID- 19777068 TI - Review of levetiracetam, with a focus on the extended release formulation, as adjuvant therapy in controlling partial-onset seizures. AB - Levetiracetam is a second-generation antiepileptic drug (AED) with a unique chemical structure and mechanism of action. The extended release formulation of levetiracetam (Keppra XR(); UCB Pharma) was recently approved by the Food and Drug Administration for adjunctive therapy in the treatment of partial-onset seizures in patients 16 years of age and older with epilepsy. This approval is based on a double-blind, randomized, placebo-controlled, multicenter, multinational trial. Levetiracetam XR allows for once-daily dosing, which may increase compliance and, given the relatively constant plasma concentrations, may minimize concentration-related adverse effects. Levetiracetam's mode of action is not fully elucidated, but it has been found to target high-voltage, N-type calcium channels as well as the synaptic vesicle protein 2A (SV2A). Levetiracetam has nearly ideal pharmacokinetics. It is rapidly and almost completely absorbed after oral ingestion, is <10% protein-bound, demonstrates linear kinetics, is minimally metabolized through a pathway independent of the cytochrome P450 system, has no significant drug-drug interactions, and has a wide therapeutic index. The most common reported adverse events with levetiracetam XR were somnolence, irritability, dizziness, nausea, influenza, and nasopharyngitis. Levetiracetam XR provides an efficacious and well-tolerated treatment option for adjunctive therapy in the treatment of partial-onset seizures. PMID- 19777069 TI - Body dysmorphic disorder: A complex and polymorphic affection. AB - BACKGROUND: Body dysmorphic disorder (BDD) is defined as a syndrome characterized by an excessive preoccupation because of a presumed or minimal physical flaw in appearance that polarizes the energies of the subject. So far, its specular aspect, represented by the presence of an evident physical defect that is not recognized or is even denied and neglected, has been disregarded. The aim of our study was to examine the individual and relational meaning of BDD and to evaluate the efficacy of cognitive-behavioral and medical-aesthetical treatments. METHODS AND RESULTS: We describe two subjects with BDD, diagnosed by clinical interviews and test. Both patients were compliant to cognitive-behavioral approach. One out of two subjects underwent aesthetical treatments. CONCLUSIONS: Cognitive behavioral therapy stimulates self-consciousness, rebuilds the body image, promotes health care, and improves relational capacity. Moreover, it ensures the success of any medical and/or surgical procedures by preventing unrealistic expectations. Lastly, it contributes to the definition of worldwide shared behavioral models. PMID- 19777071 TI - N-Alkoxyl Templates for Diastereoselective Pyrrolidine Synthesis. AB - Intramolecular cyclization of N-alkoxyl amines are studied for the stereoselective preparation of 2, 4-disubstituted pyrrolidine derivatives. Reduction of oximes under acidic conditions by NaBH(3)CN afforded the corresponding nucleophilic hydroxylamine derivatives, which subsequently cyclized via S(N)2' mechanism to give the desired N-alkoxyl pyrrolidines. PMID- 19777070 TI - Glioblastoma Multiforme Oncogenomics and Signaling Pathways. AB - In the adult population, glioblastoma multiforme is one of the most common primary brain tumors encountered. Unfortunately, this highly malignant tumor represents over 50% of all types of primary central nervous system gliomas. The vast majority of GBMs develops quite rapidly without clinical, radiological, or morphologic evidence of a less malignant precursor lesion (primary or de novo GBMs), as compared to secondary GBMs that develop slowly by progression from diffuse low-grade astrocytomas. These GBM subtypes must be kept in mind because they may constitute distinct disease entities. Even though they look histologically quite similar, they likely involve different genetic alterations and signaling pathways. Decades of surgical therapy, radiotherapy, and chemotherapy have failed to drastically change survival. Clearly, we do not fully understand this tumor; however, the exciting genetic revolution in glioma research over the past decade is providing a promising outlook for exploring this tumor at the genetic level. Science has begun to elucidate the numerous genetic alterations and critical signaling pathways, and it has opened new exciting areas of research such as glioma stem cell biology and neoangiogenesis. This work has already begun to improve our understanding of GBM cell proliferation, migration, and invasion. Indeed, exciting novel targeted therapies are making their way to clinical trials based on this increased knowledge. This review provides the current understanding of GBM oncogenomics, signaling pathways, and glioma stem cell biology and discusses the potential new therapeutic targets on the horizon. PMID- 19777072 TI - Incident heart failure prediction in the elderly: the health ABC heart failure score. AB - BACKGROUND: Despite the rising heart failure (HF) incidence and aging United States population, there are no validated prediction models for incident HF in the elderly. We sought to develop a new prediction model for 5-year risk of incident HF among older persons. METHODS AND RESULTS: Proportional hazards models were used to assess independent predictors of incident HF, defined as hospitalization for new-onset HF, in 2935 elderly participants without baseline HF enrolled in the Health ABC study (age, 73.6 +/- 2.9 years, 47.9% males, 58.6% whites). A prediction equation was developed and internally validated by bootstrapping, allowing the development of a 5-year risk score. Incident HF developed in 258 (8.8%) participants during 6.5 +/- 1.8 years of follow-up. Independent predictors of incident HF included age, history of coronary disease and smoking, baseline systolic blood pressure and heart rate, serum glucose, creatinine, and albumin levels, and left ventricular hypertrophy. The Health ABC HF model had a c-statistic of 0.73 in the derivation dataset, 0.72 by internal validation (optimism-corrected), and good calibration (goodness-of-fit 2 6.24, P=0.621). A simple point score was created to predict incident HF risk into 4 risk groups corresponding to <5%, 5% to 10%, 10% to 20%, and >20% 5-year risk. The actual 5-year incident HF rates in these groups were 2.9%, 5.7%, 13.3%, and 36.8%, respectively. CONCLUSION: The Health ABC HF prediction model uses common clinical variables to predict incident HF risk in the elderly, an approach that may be used to target and treat high-risk individuals. PMID- 19777073 TI - Individual Variability in Brain Activity: A Nuisance or an Opportunity? AB - Functional imaging research has been heavily influenced by results based on population-level inference. However, group average results may belie the unique patterns of activity present in the individual that ordinarily are considered random noise. Recent advances in the evolution of MRI hardware have led to significant improvements in the stability and reproducibility of blood oxygen level dependent (BOLD) measurements. These enhancements provide a unique opportunity for closer examination of individual patterns of brain activity. Three objectives can be accomplished by considering brain scans at the individual level; (1) Mapping functional anatomy at a fine grained analysis; (2) Determining if an individual scan is normative with respect to a reference population; and (3) Understanding the sources of intersubject variability in brain activity. In this review, we detail these objectives, briefly discuss their histories and present recent trends in the analyses of individual variability. Finally, we emphasize the unique opportunities and challenges for understanding individual differences through international collaboration among Pacific Rim investigators. PMID- 19777074 TI - Parenting Behavior and Adolescent Conduct Problems: Reciprocal and Mediational Effects. AB - This research examined the relationship between parenting practices and adolescent conduct problems and the mediation of these relationships by two parent-adolescent relationship variables, conflict and psychological autonomy. Autoregressive latent trajectory (ALT) analyses were used to assess relationships over time between parent practices and adolescent conduct problems. Participants were 2,453 students recruited from 7 public middle schools and assessed 5 times between fall of 6(th) and 9(th) grades on the following measures: Parent Monitoring; Parent Knowledge; adolescent Psychological Autonomy; parent adolescent Conflict; and adolescent Conduct Problems. Adolescent Conduct Problems and parenting practices were associated in both cross-sectional and prospective analyses. In time-lagged autoregressive modeling as a part of ALT analyses, adolescent Conduct Problems and parenting practices were reciprocally related from Time 1 to Time 2, but there after only Parent Monitoring was consistently associated with adolescent Conduct Problems over time. Adolescent Psychological Autonomy positively mediated the relationships between adolescent Conduct Problems and Parent Monitoring, but not the relationship between Parental Knowledge and Conduct Problems; while Conflict partially mediated the relationships between the slope of Conduct Problems and the slopes of both parenting behaviors and the relationship between the slopes of Conduct Problems and Psychological Autonomy. The findings provide evidence of reciprocal relationships between Conduct Problems and parenting behaviors and parent-teen relationship variables. Mediational analyses indicated relationships with Conduct Problems unmediated by Autonomy and partially mediated by Conflict. The findings provide support for the hypothesis that associations over time between parenting practices and adolescent Conduct Problems depend in part on the parent-adolescent relationship. PMID- 19777075 TI - Fabrication of Nanoscale Bioarrays for the Study of Cytoskeletal Protein Binding Interactions Using Nanoimprint Lithography. AB - We describe a high throughput patterning process used to create arrays of molecular-scale features for the study of cytoskeletal protein binding interactions. The process uses a shadow-evaporated metal mask to facilitate lift off of features defined by nanoimprint lithography. This simple and robust approach alleviates difficulties in pattern transfer of ultra-small features and results in arrays of highly ordered sub-10 nm features which are then functionalized with extracellular matrix proteins. Application of these arrays is demonstrated in cell spreading assays. PMID- 19777076 TI - Impulsivity and its Relationship to Risky Sexual Behaviors and Drug Abuse. AB - We examined a mediational model of the inter-relationship of drug use, sexual risk and impulsivity in a sample of young adults (N = 89), of which almost half displayed highly disruptive behaviors as children. We chose a mediational model given the emerging evidence that impulsivity is an underlying risk factor for many youth health risk problems, including sexual risk behaviors. The findings supported a partial mediational model in that the three target variables were significantly related to each other, yet the association of drug use and sexual risk was significantly reduced (although not to zero) when controlled by impulsivity. The findings support the view that the association of drug use and sexual risk behaviors is partially mediated by impulsivity, as well as the broader theory that youth with deficits in self-regulatory behavioral systems confer a greater likelihood of engaging in risky behaviors. Study implications and limitations are discussed. PMID- 19777077 TI - Becoming a Fluent Reader: Reading Skill and Prosodic Features in the Oral Reading of Young Readers. AB - Prosodic reading, or reading with expression, is considered one of the hallmarks of fluent reading. The major purpose of the study was to learn how reading prosody is related to decoding and reading comprehension skills. Suprasegmental features of oral reading were measured in 2nd- and 3rd-grade children (N = 123) and 24 adults. Reading comprehension and word decoding skills were assessed. Children with faster decoding speed made shorter and less variable intersentential pauses, shorter intrasentential pauses, larger sentence-final fundamental frequency (F(0)) declinations, and better matched the adult prosodic F(0) profile. Two structural equation models found evidence of a relationship between decoding speed and reading prosody as well as decoding speed and comprehension. There was only minimal evidence that prosodic reading was an important mediator of reading comprehension skill. PMID- 19777078 TI - Multimodal and Multi-tissue Measures of Connectivity Revealed by Joint Independent Component Analysis. AB - The human brain functions as an efficient system where signals arising from gray matter are transported via white matter tracts to other regions of the brain to facilitate human behavior. However, with a few exceptions, functional and structural neuroimaging data are typically optimized to maximize the quantification of signals arising from a single source. For example, functional magnetic resonance imaging (FMRI) is typically used as an index of gray matter functioning whereas diffusion tensor imaging (DTI) is typically used to determine white matter properties. While it is likely that these signals arising from different tissue sources contain complementary information, the signal processing algorithms necessary for the fusion of neuroimaging data across imaging modalities are still in a nascent stage. In the current paper we present a data driven method for combining measures of functional connectivity arising from gray matter sources (FMRI resting state data) with different measures of white matter connectivity (DTI). Specifically, a joint independent component analysis (J-ICA) was used to combine these measures of functional connectivity following intensive signal processing and feature extraction within each of the individual modalities. Our results indicate that one of the most predominantly used measures of functional connectivity (activity in the default mode network) is highly dependent on the integrity of white matter connections between the two hemispheres (corpus callosum) and within the cingulate bundles. Importantly, the discovery of this complex relationship of connectivity was entirely facilitated by the signal processing and fusion techniques presented herein and could not have been revealed through separate analyses of both data types as is typically performed in the majority of neuroimaging experiments. We conclude by discussing future applications of this technique to other areas of neuroimaging and examining potential limitations of the methods. PMID- 19777079 TI - Prosody of Syntactically Complex Sentences in the Oral Reading of Young Children. AB - Prosodic, or expressive, reading is considered to be one of the essential features of the achievement of reading fluency. The purpose of this study was to determine (a) the degree to which the prosody of syntactically complex sentences varied as a function of reading speed and accuracy and (b) the role that reading prosody might play in mediating individual differences in comprehension. Spectrographic analysis of 80 third graders' and 29 adults' reading of a syntactically complex text was carried out. Oral reading skill was measured through standardized assessments. Pitch changes (changes in fundamental frequency) and pause duration were measured for sentence-final words of basic declarative sentences, basic declarative quotatives, wh questions, and yes-no questions; words preceding commas in complex adjectival phrases; and words preceding phrase-final commas. Children who had quick and accurate oral reading had shorter and more adultlike pause structures, larger pitch declinations at the end of basic declarative sentences, and larger pitch rises at the end of yes-no questions. Furthermore, children who showed larger basic declarative sentence declinations and larger pitch rises following yes-no questions tended to demonstrate greater reading comprehension skills. PMID- 19777080 TI - Online Planning Algorithms for POMDPs. AB - Partially Observable Markov Decision Processes (POMDPs) provide a rich framework for sequential decision-making under uncertainty in stochastic domains. However, solving a POMDP is often intractable except for small problems due to their complexity. Here, we focus on online approaches that alleviate the computational complexity by computing good local policies at each decision step during the execution. Online algorithms generally consist of a lookahead search to find the best action to execute at each time step in an environment. Our objectives here are to survey the various existing online POMDP methods, analyze their properties and discuss their advantages and disadvantages; and to thoroughly evaluate these online approaches in different environments under various metrics (return, error bound reduction, lower bound improvement). Our experimental results indicate that state-of-the-art online heuristic search methods can handle large POMDP domains efficiently. PMID- 19777081 TI - Facilitators of barebacking among emergent adult gay and bisexual men: implications for HIV prevention. AB - We undertook a qualitative study to develop a greater understanding of "intentional" unprotected anal intercourse among drug-using gay and bisexual men, also known colloquially as barebacking. In our analysis, we investigated this behavior in a subset of 12 HIV-negative men in the early adulthood stage of life to disentangle factors that functioned as facilitators of barebacking, a behavior that may place these men at risk for HIV infection. Based on thematic analysis of life-history interviews, we delineated 4 main themes associated with barebacking: drug use, the role of responsibility for safer sex, misunderstandings about HIV transmission, and underlying mental health issues. The data suggest that lack of knowledge about HIV transmission is insufficient in explaining risk-taking. Rather, rationalization processes may be a factor in the sexual risk-taking behaviors of young HIV-negative men, and moreover, deep intrapsychic processes (often heightened by concurrent substance use), and the desire to please sexual partners may drive the decision-making of these men. Future intervention strategies must motivate and empower young men to seek support for the states that drive sexual risk-taking. PMID- 19777082 TI - Peer social preference and depressive symptoms of children in Italy and the United States. AB - This study examined the role of low social preference in relation to subsequent depressive symptoms, with particular attention to prior depressive symptoms, prior and concurrent aggression, mutual friendships, and peer victimization. Italian children (N = 288) were followed from grade 6 through grade 8, and American children (N = 585) were followed from kindergarten through grade 12. Analyses demonstrate that low social preference contributes to later depressive symptoms. The effects are not accounted for by depressive symptoms or aggression experienced prior to low social preference but are mostly accounted for by the co occurrence of depressive symptoms with concurrent aggressive behavior; gender, mutual friendships, and peer victimization generally did not moderate these associations. We conclude that peer relationship problems do predict later depressive symptoms, and a possible mechanism through which this effect occurs is through the effect of poor peer relationships on increasing aggressive behavior, which is associated with depressive symptoms. PMID- 19777083 TI - NORMAL QUALITY OF LIFE AFTER THE COX MAZE PROCEDURE FOR ATRIAL FIBRILLATION. AB - BACKGROUND/OBJECTIVE: Atrial fibrillation(AF) has been shown in numerous studies to significantly decrease patient quality of life. The Cox-Maze procedure has excellent long-term efficacy in curing AF. However, it is unknown whether this procedure improves long-term quality of life in these patients. The purpose of this study was to examine late quality of life in patients that underwent a lone Cox-Maze procedure. METHODS: Between 1987 and 2003, 163 patients underwent a Cox Maze procedure for lone AF at our institution. Of these, 68 patients agreed and completed the Medical Outcomes Study Short Form 36 Health Survey. Scores from the age-matched general US population were normalized to a mean of 50 and standard deviation of 10 to facilitate comparison. Collected data were compared to the norm-based score for each domain using a one-sample t-test. Four patients were removed from analysis because of AF recurrence. RESULTS: There were 52 males(81%). Mean age was 52.6+/-9.5 years. Preoperatively, 37 patients(58%) had paroxysmal and 25 patients(39%) had persistent or permanent AF. The mean duration of AF before surgery was 9.8+/-8.2 years. There was no statistical difference in norm-based scores between the Cox-Maze procedure group and the age-matched general US population in any of the eight health domains at a mean follow-up of 8.7+/-3.7 years. CONCLUSION: Our results suggest that the Cox-Maze procedure cures atrial fibrillation in the majority of patients, and that those patients that are cured obtain a normal quality of life as compared to the general population at late follow-up. PMID- 19777084 TI - Disentangling Ethnic and Contextual Influences Among Parents Raising Youth in High-Risk Communities. AB - This article reports on analyses examining contextual influences on parenting with an ethnically and geographically diverse sample of parents (predominantly mothers) raising 387 children (49% ethnic minority; 51% male) in high-risk communities. Parents and children were followed longitudinally from first through tenth grades. Contextual influences included geographical location, neighborhood risk, SES, and family stress. The cultural variable was racial socialization. Parenting constructs created through the consensus decision-making of the Parenting Subgroup of the Study Group on Race, Culture, and Ethnicity (see Le et al., 2008) included Monitoring, Communication, Warmth, Behavioral Control and Parenting Efficacy. Hierarchical regressions on each parenting construct were conducted for each grade for which data were available. Analyses tested for initial ethnic differences and then for remaining ethnic differences once contextual influences were controlled. For each construct, some ethnic differences did remain (Monitoring, ninth grade; Warmth, third grade; Communication, kindergarten; Behavioral Control, eighth grade; and Parenting Efficacy, kindergarten through fifth grade). Ethnic differences were explained by contextual differences in the remaining years. Analyses examining the impact of cultural influences revealed a negative relation between racial socialization messages and Communication or Monitoring. PMID- 19777085 TI - Racial/ethnic variation in the relationship between physical limitation and fear of crime: An examination of mediating and moderating factors. AB - This study has four objectives. First, we confirm the previously observed association between physical limitations and fear of crime. Second, we assess the role of age in this relationship. Third, we identify factors that mediate this relationship. Fourth, we assess whether this relationship is observed across racial/ethnic groups. Adjusting for perceptions of personal control and disability-related stigma reduces the magnitude of this relationship to non significance for black and white respondents, but not for Hispanics. Also, we find that age is inversely related to fear of crime for blacks and whites. PMID- 19777086 TI - Immobilization of Myoglobin from Horse Skeletal Muscle in Hydrophilic Polymer Networks. AB - This work examines the immobilization of myoglobin from horse skeletal muscle in hydrophilic polymer networks. Due to specific changes in the spectroscopic properties of hemoproteins during ligand binding, they could be employed in optical sensing devices. Two immobilization techniques were considered: imbibition and entrapment. Anionic hydrogels composed of methacrylic acid (MAA), cationic hydrogels composed of dimethylamino ethyl methacrylate (DMAEM), and neutral hydrogels composed of poly(ethylene glycol) monomethyl ether monomethacrylate (PEGMA; molecular weight = 200, 400, or 1000), all crosslinked with poly(ethylene glycol) dimethacrylate (PEGDMA) (molecular weight = 200, 600, or 1000), were synthesized by free-radical solution polymerization. By the imbibition method, MAA-based hydrogels incorporated the highest amount of myoglobin in comparison with PEGMA or DMAEM polymers. The evaluation of the correlation length of the networks revealed that MAA hydrogels had the highest correlation length in comparison with PEGMA-containing matrices or DMAEM hydrogels. Release experiments from MAA hydrogels at pHs 5.8 and 7.0 showed that the solute-transport mechanism was a combination of Fickian and chain relaxation diffusion. Myoglobin-loaded MAA hydrogels retained their heme reactivity after the immobilization process. The release of myoglobin incorporated by entrapment in MAA-PEGDMA hydrogels was highly influenced by the chain relaxation process. The diffusion coefficients of myoglobin incorporated by entrapment into anionic hydrogels were 2 orders of magnitude smaller (~10-13) than those for myoglobin incorporated by imbibition (10-11), both evaluated at pH 7.0. Substrate binding studies indicated that the protein biological activity was not compromised in those hydrogels loaded by the imbibition method, whereas prepolymeric solutions showed detrimental effects on protein stability. PMID- 19777087 TI - Stigma in families of individuals in early stages of psychotic illness: family stigma and early psychosis. AB - AIM: Stigma is pervasive among families of individuals with psychotic disorders and includes both general and 'associative' stigma - that is, the process by which a person is stigmatized by virtue of association with another stigmatized individual. These forms of stigma may present a barrier to help seeking. However, little is known about stigma in the early stages of evolving psychotic disorder. METHODS: Family members of 11 individuals at clinical high risk and of nine patients with recent-onset psychosis were evaluated for generalized and associative stigma using the Opinions about Mental Illness (modified) and the Family Experiences Interview Schedule. RESULTS: In this small study, the level of stigma was low, as families endorsed many supportive statements, for example, patients should be encouraged to vote, patients want to work, mental illness should be protected legally as a disability and parity should exist in insurance coverage. Families also endorsed that both talking and a belief in God and prayer can help someone get better. Only ethnic minority families of individuals with recent-onset psychosis endorsed a sense of shame and need to conceal the patient's illness. CONCLUSIONS: This preliminary study suggests that family stigma is low in the early stages of psychotic disorder, a finding that requires further investigation in a larger and more representative sample. This may be an opportune time to engage young people and families, so as to reduce duration of untreated illness. Ethnic differences in stigma, if replicated, highlight the need for cultural sensitivity in engaging individuals and their families in treatment. PMID- 19777088 TI - Conformational Entropy of an Ideal Cross-Linking Polymer Chain. AB - We present a novel analytical method to calculate conformational entropy of ideal cross-linking polymers from the configuration integral by employing a Mayer series expansion. Mayer-functions describing chemical bonds within the chain and for cross-links are sharply peaked over the temperature range of interest, and, are well approximated as statistically weighted Dirac delta-functions that enforce distance constraints. All geometrical deformations consistent with a set of distance constraints are integrated over. Exact results for a contiguous series of connected loops are employed to substantiate the validity of a previous phenomenological distance constraint model that describes protein thermodynamics successfully based on network rigidity. PMID- 19777090 TI - Selective probing of mRNA expression levels within a living cell. AB - We report on a selective and nondestructive measurement of mRNA (messenger ribonucleic acid) expression levels within a living cell. We first modify an atomic force microscope tip to create a tapered nanoscale coaxial cable. Application of an ac (alternating potential) between the inner and outer electrodes of this cable creates a dielectrophoretic force attracting mRNA molecules toward the tip-end which is pretreated with gene specific primers. We selectively extracted and analyzed both high ( approximately 2500) and extremely low (11 0) copy number mRNA from a living cell mRNA in less than 10 s. PMID- 19777089 TI - The Influence of Integration on the Expenditures and Costs of Mental Health and Substance Use Care: Results from the randomized PRISM-E Study. AB - We compared the healthcare costs associated with an integrated care model to an enhanced referral model for the treatment of depression, anxiety, and at-risk drinking from the randomized Primary Care Research in Substance Abuse and Mental Health for the Elderly study. We examined total healthcare costs and cost components, separately for Veteran's Affairs and non-VA participants. No differences in total health expenditures were detected between study arms. No differences in behavioral health expenditures were detected for non-VA sites, but the VA integrated arm had slightly higher ($38; p<0.05) behavioral health costs. Differences in other types of services use were detected. PMID- 19777091 TI - Highly parallel measurements of interaction kinetic constants with a microfabricated optomechanical device. AB - We used mechanical trapping of molecular interactions to demonstrate a highly parallel approach to measure the kinetics of biomolecular interactions. This approach consumes 25 fmol of material per measurement and permits 320 measurements in a single experiment. We measured association and dissociation curves for the interactions of 6-His and T7 epitope tags with their antibodies, from which we determined the off rates, on rates, and dissociation constants. PMID- 19777092 TI - A pharmacy preregistration course using online teaching and learning methods. AB - OBJECTIVE: To design and evaluate a preregistration course utilizing asynchronous online learning as the primary distance education delivery method. DESIGN: Online course components including tutorials, quizzes, and moderated small-group asynchronous case-based discussions were implemented. Online delivery was supplemented with self-directed and face-to-face learning. ASSESSMENT: Pharmacy graduates who had completed the course in 2004 and 2005 were surveyed. The majority felt they had benefited from all components of the course, and that online delivery provided benefits including increased peer support, shared learning, and immediate feedback on performance. A majority of the first cohort reported that the workload associated with asynchronous online discussions was too great. The course was altered in 2005 to reduce the online component. Participant satisfaction improved, and most felt that the balance of online to face-to-face delivery was appropriate. CONCLUSION: A new pharmacy preregistration course was successfully implemented. Online teaching and learning was well accepted and appeared to deliver benefits over traditional distance education methods once workload issues were addressed. PMID- 19777093 TI - Health promotion integrated into a Thai PharmD curriculum to improve pharmacy practice skills. AB - OBJECTIVE: To implement and evaluate 5 integrated teaching modules in the fifth year doctor of pharmacy (PharmD) curriculum to increase students' ability to promote patients' health as part of their pharmacy practice. DESIGN: Activity based learning was added to each module: (1) a practice experience in which students provided health information and counseling to the public; (2) academic debates on current issues in pharmacy (3) journal clubs on articles from the pharmacy literature; and (4) research projects relating to ongoing faculty research on diabetes. Students on 12-week practice experiences had visits to patients in inpatient wards, outpatient clinics, and either primary care units or community pharmacies. ASSESSMENT: Practice examinations at the end of the first semester, the average student score was above 80% as determined by preceptors in experience sites and from faculty members. Group interviews found that students were positive about the benefits of integrated teaching. CONCLUSION: The integration of the teaching between modules in the same semester is possible and greatly benefits student learning. PMID- 19777094 TI - A peer review process for classroom teaching. AB - OBJECTIVE: Describe the planning, implementation, and faculty perceptions of a classroom peer-review process, including an evaluation tool. DESIGN: A process for peer evaluation of classroom teaching and its evaluation tool were developed and implemented by a volunteer faculty committee within our department. At the end of the year, all faculty members were asked to complete an online anonymous survey to evaluate the experience. ASSESSMENT: The majority of faculty members either agreed or strongly agreed that the overall evaluation process was beneficial for both evaluators and for those being evaluated. Some areas of improvement related to the process and its evaluation tool also were identified. SUMMARY: The process of developing and implementing a peer-evaluation process for classroom teaching was found to be beneficial for faculty members, and the survey results affirmed the need and continuation of such a process. PMID- 19777095 TI - An evidence-based elective on dietary supplements. AB - OBJECTIVE: To implement and evaluate the effectiveness of a pharmacy elective on dietary supplements that emphasized evidence-based care. DESIGN: A 3-credit elective that employed both traditional lectures and a variety of active-learning exercises was implemented. The course introduction provided a background in dietary supplement use and evidence-based medicine principles before addressing dietary supplements by primary indication. ASSESSMENT: Student learning was assessed through quizzes, case assignments, discussion board participation, and completion of a longitudinal group project. Precourse and postcourse surveys were conducted to assess students' opinions, knowledge, and skills related to course objectives. CONCLUSION: The course was an effective way to increase students' knowledge of dietary supplements and skills and confidence in providing patient care in this area. PMID- 19777096 TI - A cultural competency course for pharmacy students. AB - OBJECTIVE: To design, implement, and evaluate a course on health promotion and literacy. DESIGN: Course objectives such as the development of cultural competency skills, awareness of personal biases, and appreciation of differences in health beliefs among sociocultural groups were addressed using a team-based learning instructional strategy. Student learning outcomes were enhanced using readiness assessment tests (RATs), group presentations, portfolio reflections, and panel discussions. ASSESSMENT: Comparing precourse and postcourse Inventory for Assessing the Process of Cultural Competence among Healthcare Professionals (IAPCC-R) scores and portfolio responses indicated enhanced progress toward cultural competency. The Student Evaluation of Teaching (SET) provided suggestions for course enhancements. CONCLUSIONS: Evidence supporting enhanced cultural competency after completing the course affirms its value as we prepare pharmacy students to provide patient-centered care in a culturally diverse world. PMID- 19777097 TI - Barriers to expanding advanced pharmacy practice experience site availability in an experiential education consortium. AB - OBJECTIVES: To compare 2006-2007 and projected 2010-2011 advanced pharmacy practice experience (APPE) availability and needs for 4 colleges and schools of pharmacy in Georgia and Alabama and to examine barriers and offer potential solutions to increase APPE site and preceptor availability. METHODS: Data on APPE needs and availability were gathered prospectively and evaluated relative to current and projected enrollment and planned programmatic changes. RESULTS: Combined 2006-2007 non-community APPE needs and availabilities were 3,590 and 4,427, respectively, with a surplus availability of 837. Combined projected 2010 2011 non-community APPEs were estimated at 4,309. Assuming 2006-2007 non community availability remained unchanged, the surplus availability declined to 118. CONCLUSIONS: The need for quality experiential education represents a significant barrier and rate-limiting step to the matriculation of the increased numbers of pharmacists. Barriers to expanding APPE availability include: introductory pharmacy practice experience (IPPE) and APPE expansion, growth of new and existing pharmacy programs, financial instability of acute care facilities, and lack of preceptor development resources. Regional experiential education consortiums can provide a constructive approach to improve access to quality sites and preceptors through standardizing processes and leveraging resources. PMID- 19777098 TI - Factors influencing pharmacy students' attendance decisions in large lectures. AB - OBJECTIVES: To identify reasons for pharmacy student attendance and absenteeism in large lectures and to determine whether certain student characteristics affect student absenteeism. METHODS: Pharmacy students' reasons to attend and not attend 3 large lecture courses were identified. Using a Web-based survey instrument, second-year pharmacy students were asked to rate to what degree various reasons affected their decision to attend or not attend classes for 3 courses. Bivariate analyses were used to assess the relationships between student characteristics and degree of absenteeism. RESULTS: Ninety-eight students (75%) completed the survey instrument. The degree of student absenteeism differed among the 3 courses. Most student demographic characteristics examined were not related to the degree of absenteeism. Different reasons to attend and not to attend class were identified for each of the 3 courses, suggesting that attendance decisions were complex. CONCLUSIONS: Respondents wanted to take their own notes and the instructor highlighted what was important to know were the top 2 common reasons for pharmacy students to attend classes. Better understanding of factors influencing student absenteeism may help pharmacy educators design effective interventions to facilitate student attendance. PMID- 19777099 TI - Rufus A. Lyman: pharmacy's lamplighter. AB - Rufus Ashley Lyman, a physician, was one of the most prominent leaders in US pharmacy education during the first half of the 20th century. He remains the only individual to be the founding dean at colleges of pharmacy at 2 state universities. His role in the creation and sustenance of the American Journal of Pharmaceutical Education provided a platform for a national community and a sounding board for faculty members and others interested in professional education. His efforts to increase pharmacy educational standards were instrumental in the abandonment of the 2-year graduate in pharmacy (PhG) degree and the universal acceptance of the 4-year bachelor of science (BS) degree. Lyman's simple approach and fierce championship of his beliefs led to his recognition as a lamplighter for the profession.Curt P. Wimmer, chair of the New York Branch of the American Pharmaceutical Association (now the American Pharmacists Association (APhA), introduced the 1947 Remington Honor Medalist, Rufus Ashley Lyman. Wimmer mentioned that Lyman worked as a lamplighter in Omaha, Nebraska, during medical school. Continuing the lamplighter analogy, Wimmer cited Lyman's work as a pharmacy educator and editor: "in the councils of your colleagues, your lamp became a torch emitting red hot sparks that often burnt and seared and scorched -- but always made for progress."1 This description provides an evocative image of one of the most prominent pharmacy educators and leaders of the first half of the 20th century. PMID- 19777100 TI - Comparison of small-group training with self-directed internet-based training in inhaler techniques. AB - OBJECTIVES: To compare the effectiveness of small-group training in correct inhaler technique with self-directed Internet-based training. DESIGN: Pharmacy students were randomly allocated to 1 of 2 groups: small-group training (n = 123) or self-directed Internet-based training (n = 113). Prior to intervention delivery, all participants were given a placebo Turbuhaler and product information leaflet and received inhaler technique training based on their group. Technique was assessed following training and predictors of correct inhaler technique were examined. ASSESSMENT: There was a significant improvement in the number of participants demonstrating correct technique in both groups (small group training, 12% to 63%; p < 0.05; and Internet-based training, 9% to 59%; p < 0.05) post intervention, with no significant difference between the groups in the percent change (n = 234, p > 0.05). Increased student confidence following the intervention was a predictor for correct inhaler technique. CONCLUSIONS: Self directed Internet-based training is as effective as small-group training in improving students' inhaler technique. PMID- 19777101 TI - A technology-enhanced patient case workshop. AB - OBJECTIVES: To assess the impact of technology-based changes on student learning, skill development, and satisfaction in a patient-case workshop. DESIGN: A new workshop format for a course was adopted over a 3-year period. Students received and completed patient cases and obtained immediate performance feedback in class instead of preparing the case prior to class and waiting for instructors to grade and return their cases. The cases were designed and accessed via an online course management system. ASSESSMENT: Student satisfaction was measured using end-of course surveys. The impact of the technology-based changes on student learning, problem-solving, and critical-thinking skills was measured and compared between the 2 different course formats by assessing changes in examination responses. Three advantages to the new format were reported: real-life format in terms of time constraint for responses, a team learning environment, and expedient grading and feedback. Students overwhelmingly agreed that the new format should be continued. Students' examination scores improved significantly under the new format. CONCLUSION: The change in delivery of patient-case workshops to an online, real-time system was well accepted and resulted in enhanced learning, critical thinking, and problem-solving skills. PMID- 19777102 TI - A model for continuing pharmacy education. AB - OBJECTIVE: To develop and implement a continuing pharmacy education (CPE) program at Kaiser Permanente Colorado (KPCO) DESIGN: To address the continuing education needs of its diverse pharmacy staff, an internal continuing pharmacy education (CPE) program was developed. The pharmacy department became an accredited provider by the Accreditation Council for Pharmacy Education (ACPE). Live, interactive, and evidence-based CPE programs, presented by highly qualified internal staff members, utilized videoconferencing and a Web-based learning management system. Cross-accreditation of medical and pharmacy educational programs was offered to KPCO staff members. ASSESSMENT: Annual needs assessments were conducted to ensure the provision of relevant educational topics and to assess learning needs. To demonstrate outcomes of the CPE programs, 2 methods were utilized: objective effectiveness assessment and knowledge acquisition assessment. This program met the objectives for CPE activities a large majority of the time (usually over 90%), demonstrated statistically significant (p < 0.05) improvement in knowledge from before to after the CPE activity in 11 of 13 questions asked, and minimized the cost to acquire CPE credit for both the pharmacy department and its staff members. CONCLUSION: The KPCO continuing pharmacy education program has developed a high quality and cost-favorable system that has resulted in significant improvements in attendee knowledge. PMID- 19777103 TI - Achieving equivalent academic performance between campuses using a distributed education model. AB - OBJECTIVES: To demonstrate that students in competency-based anatomy and pharmaceutical calculations courses performed similarly whether enrolled in the classes through distance education or face-to-face lectures. METHODS: Student outcomes data including module examination scores, final course grades, and student demographics data were collected, merged, and analyzed. RESULTS: Mean module examination final scores and final course grades did not significantly differ between students at the lecture site and students at the remote site. CONCLUSIONS: The competency-based anatomy and pharmaceutical calculations courses, whether remote or at the lecture site, provided equitable learning opportunities and roughly equivalent learning outcomes for students. PMID- 19777104 TI - Meet the President. PMID- 19777105 TI - Patient-centered care: it's about time. PMID- 19777106 TI - PharmD or needs based education: which comes first? PMID- 19777107 TI - Proposed guidelines for uniformity of postgraduate industry-affiliated fellowships. PMID- 19777108 TI - Industry or academia -- the proverbial question. PMID- 19777109 TI - Comparison of two lecture delivery platforms in a hybrid distance education program. AB - OBJECTIVE: To compare students' preferences for and academic performance using 2 different distance education course content delivery platforms. METHODS: A randomized, crossover research design was used to compare traditional video with a 4-panel platform among learners on multiple campuses within 1 college of pharmacy.(1) The outcomes were students' preferences for delivery platform and examination scores. Rasch analysis was used to assess unidimensionality and the difficulty of examination items. Hierarchical logistic and multiple regression models were used to assess students' preferences and academic performance. RESULTS: The logistic model predicting preference for the 4-panel or traditional platform was not significant, but African-Americans and Hispanics were more likely to prefer the 4-panel platform than Caucasian and Asian students. The delivery platform did not impact students' academic performance. Students who did well on the semester's previous 2 examinations scored higher on the questions related to schizophrenia. Students with higher Pharmacy College Admission Test (PCAT) scores performed better on the bipolar questions than students who preferred the traditional video platform. CONCLUSION: The additional faculty time, effort, and cost invested in presenting the class material in a 4-panel platform, and the students' extra time and effort spent viewing the 4-panel platform did not produce a comparable benefit in student preference and performance. PMID- 19777110 TI - Attributes of colleges and schools of pharmacy in the United States. AB - OBJECTIVES: To compare the attributes of US colleges and schools of pharmacy and describe the extent of change to the pharmacy education enterprise associated with the addition of new schools. METHODS: Attributes analyzed included whether the college or school of pharmacy was old or new, public or private, secular or faith-based, and on or not on an academic health center (AHC) campus; had 3- or 4 year programs; and had PhD students enrolled. PharmD student enrollment-to faculty ratios and junior-to-senior faculty ratios also were examined. RESULTS: Of the new colleges/schools, 76% were private and 79% were not located on a campus with an AHC; 6% had PhD enrollment compared with 80% of old colleges/schools. Faculty ratios were related to several college/school attributes, including the presence or absence of PhD students and whether the college/school was public or private. CONCLUSIONS: Attributes of new colleges and schools of pharmacy have changed the overall profile of all colleges and schools of pharmacy. For example, smaller percentages of all colleges and schools of pharmacy are public and have PhD enrollees. PMID- 19777111 TI - Integrated care in the daily work: coordination beyond organisational boundaries. AB - OBJECTIVES: In this paper, integrated care in an inter-organisational cooperative setting of in-home elderly care is studied. The aim is to explore how home care workers coordinate their daily work, identify coordination issues in situ and discuss possible actions for supporting seamless and integrated elderly care at home. METHOD: The empirical findings are drawn from an ethnographic workplace study of the cooperation and coordination taking place between home care workers in a Swedish county. Data were collected through observational studies, interviews and group discussions. FINDINGS: The paper identifies a need to support two core issues. Firstly, it must be made clear how the care interventions that are currently defined as 'self-treatment' by the home health care should be divided. Secondly, the distributed and asynchronous coordination between all care workers involved, regardless of organisational belonging must be better supported. CONCLUSION: Integrated care needs to be developed between organisations as well as within each organisation. As a matter of fact, integrated care needs to be built up beyond organisational boundaries. Organisational boundaries affect the planning of the division of care interventions, but not the coordination during the home care process. During the home care process, the main challenge is the coordination difficulties that arise from the fact that workers are distributed in time and/or space, regardless of organisational belonging. A core subject for future practice and research is to develop IT tools that reach beyond formal organisational boundaries and processes while remaining adaptable in view of future structure changes. PMID- 19777113 TI - The ultimate goal of disease management: improved quality of life by patient centric care. PMID- 19777112 TI - Integrated primary health care in Greece, a missing issue in the current health policy agenda: a systematic review. AB - BACKGROUND: Over the past years, Greece has undergone several endeavors aimed at modernizing and improving national health care services with a focus on PHC. However, the extent to which integrated primary health care has been achieved is still questioned. PURPOSE: This paper explores the extent to which integrated primary health care (PHC) is an issue in the current agenda of policy makers in Greece, reporting constraints and opportunities and highlighting the need for a policy perspective in developing integrated PHC in this Southern European country. METHODS: A systematic review in PubMed/Medline and SCOPUS, along with a hand search in selected Greek biomedical journals was undertaken to identify key papers, reports, editorials or opinion letters relevant to integrated health care. RESULTS: Our systematic review identified 198 papers and 161 out of them were derived from electronic search. Fifty-three papers in total served the scope of this review and are shortly reported. A key finding is that the long-standing dominance of medical perspectives in Greek health policy has been paving the way towards vertical integration, pushing aside any discussions about horizontal or comprehensive integration of care. CONCLUSION: Establishment of integrated PHC in Greece is still at its infancy, requiring major restructuring of the current national health system, as well as organizational culture changes. Moving towards a new policy-based model would bring this missing issue on the discussion table, facilitating further development. PMID- 19777114 TI - Does mental health service integration affect compulsory admissions? AB - BACKGROUND: Over recent years, the number of compulsory admissions in many countries has increased, probably as a result of the shift from inpatient to outpatient mental health care. This might be mitigated by formal or collaborative relationships between services. METHODS: In a retrospective record linkage study, we compared two neighboring districts, varying in level of service integration. Two periods were combined: 1991-1993 and 2001-2003. We included patients aged 18 60, who had a first emergency compulsory admission (n=830). Their psychiatric history was assessed, and service-use after admission was monitored over a 12 month follow-up. RESULTS: Over a 10-year period, compulsory admission rates increased by 47%. Difference in relative increase between the integrated and non integrated services was 14%. Patient characteristics showed different profiles in the two districts. Length of stay was >10 days shorter in the integrated district, where the proportion of involuntary readmissions decreased more, and where aftercare was swift and provided to about 10% more patients than in the non integrated district. CONCLUSIONS: Services outcomes showed better results where mental healthcare was more integrated. However, limited effects were found and other factors than integration of services may be more important in preventing compulsory admissions. PMID- 19777116 TI - Is leading and managing in inter-agency settings really that different? PMID- 19777115 TI - Prioritising integrated care initiatives on a national level. Experiences from Austria. AB - INTRODUCTION AND BACKGROUND: Based on a policy initiative and the foundation of the Competence Centre for Integrated Care by the Austrian Social Security Institutions in 2006, the aim of the project was to identify and prioritise potential diseases and target groups for which integrated care models should be developed and implemented within the Austrian health system. The project was conducted as a cooperation between the Competence Centre for Integrated Care of the Viennese Health Insurance Fund and the Institute of Social Medicine of the Medical University Vienna to ensure the involvement of both, theory and practice. PROJECT REPORT: The focus of the project was to develop an evidence-based process for the identification and prioritisation of diseases and target groups for integrated care measures. As there was no evidence of similar projects elsewhere, the team set out to design the prioritisation process and formulate the selection criteria based on the work in a focus group, literature reviews and a scientific council of national and international experts. The method and criteria were evaluated by an expert workshop. DISCUSSION: The active involvement of all stakeholders from the beginning was crucial for the success. The time constraint proved also beneficial since it allowed the project team to demand focus and cooperation from all experts and stakeholders included. CONCLUSION: Our experience demonstrates that, with a clear concept and model, an evidence-based prioritisation including all stakeholders can be achieved. Ultimately however, the prioritisation is a political discussion and decision. Our model can only help base these decisions on sound and reasonable assumptions. PMID- 19777118 TI - Computational study of fluorescence scattering by silver nanoparticles. AB - We study the nature of fluorescence scattering by a radiating fluorophore placed near a metal nanoparticle with the finite-difference time-domain method. Angle resolved light-scattering distributions are contrasted with those that result when ordinary plane waves are scattered by the nanoparticle. For certain sized nanoparticles and fluorophore dipoles oriented parallel to the metal surface, we find that the highest scattered fluorescence emission is directed back toward the fluorophore, which is very different from plane-wave scattering. The largest enhancements of far-field radiation are found when the dipole is oriented normal to the surface. We also examined the effect of the fluorophore on the near field around the particle. The fields can be enhanced or quenched compared to the isolated fluorophore and exhibit strong dependence on fluorophore orientation, as well as interesting spatial variations around the nanoparticle. PMID- 19777119 TI - A new proof of geometric convergence for general transport problems based on sequential correlated sampling methods. AB - In [J. Halton, Sequential Monte Carlo, Proc. Comb. Phil. Soc. 58 (1962), J. Halton, Sequential Monte Carlo Techniques for the Solution of Linear Systems, J. Sci. Comp. 9 (1994) 213-257] Halton introduced a strategy to be used in Monte Carlo algorithms for the efficient solution of certain matrix problems. We showed in [R. Kong, J. Spanier, Sequential correlated sampling methods for some transport problems, in: Harold Niederreiter, Jerome Spanier (Eds.), Monte-Carlo and Quasi Monte-Carlo Methods 1998: Proceedings of a Conference at the Claremont Graduate University, Springer-Verlag, New York, 2000, R. Kong, J. Spanier, Error analysis of sequential Monte Carlo methods for transport problems, in: Harold Niederreiter, Jerome Spanier (Eds.), Monte-Carlo and Quasi Monte-Carlo Methods 1998: Proceedings of a Conference at the Claremont Graduate University, Springer Verlag, New York, 2000] how Halton's method based on correlated sampling can be extended to continuous transport problems and established their geometric convergence for a family of transport problems in slab geometry. In our algorithm, random walks are processed in batches, called stages, each stage producing a small correction that is added to the approximate solution developed from the previous stages. In this paper, we demonstrate that strict error reduction from stage to stage can be assured under rather general conditions and we illustrate this rapid convergence numerically for a simple family of two dimensional transport problems. PMID- 19777117 TI - SOLUBLE CD40 LIGAND IN DEMENTIA. AB - Some 15-20% of the population over the age of 65 years suffer from dementia, currently one of the leading causes of death behind cardiovascular diseases, cancer and cerebrovascular diseases. The major forms of dementia share in common overactivation of the CD40-CD40-L complex, leading to high levels of proinflammatory cytokine production by immune cells of the central nervous system (CNS), including microglia and astrocytes. Consequently, both neuronal survival and signaling are negatively affected, leading to the characteristic progressive loss of higher cortical functions. We have reviewed the literature concerning the involvement of this complex in the pathology of three major forms of dementia: Alzheimer's-type, HIV-associated and vascular dementia. This is followed by a discussion of current preclinical and clinical therapies that may influence this interaction, and thus point the way toward a future neuroimmunological approach to inhibiting the effects of CD40-CD40-L in neuropsychiatric disease. PMID- 19777120 TI - Escape from gregarine parasites affects the competitive interactions of an invasive mosquito. AB - When a species is introduced into a new location, it may escape, at least temporarily, from its natural enemies. In field surveys, we found that when the exotic, invasive mosquito, Aedes albopictus, invades new sites, it initially experiences reduced infection by its gut parasite, Ascogregarina taiwanensis. To determine the effect of this escape from parasitism on the competitive ability of A. albopictus, we performed a laboratory competition experiment in which infected and uninfected A. albopictus larvae were reared in microcosms alone and in competition with larvae of the native mosquito, Ochlerotatus triseriatus. We analyzed the effect of parasitism by A. taiwanensis on A. albopictus performance when subjected to intra- and interspecific competition across a range of larval densities, as well as the effect of A. albopictus parasitism by A. taiwanensis on the competitive impact of A. albopictus on O. triseriatus. At a density of 30 O. triseriatus larvae, O. triseriatus survivorship was significantly reduced by the addition of 30 unifected A. albopictus, but not by addition of 30 infected A. albopictus, and not by addition of 15 A. albopictus whether infected or uninfected. Although estimated finite rate of population increase (lambda') showed similar trends, and was significantly affected by treatments, no pairwise differences in rate of increase were significant. Infection by A. taiwanensis also significantly prolonged A. albopictus female development time and reduced the intraspecific competitive effect of increased density of A. albopictus, but did not affect A. albopictus survivorship, mass, or estimated finite rate of population increase. Thus, when A. albopictus escapes from this parasite as it colonizes new sites, this escape may give it a small, but significant, added competitive advantage over O. triseriatus, which may facilitate range expansion of A. albopictus and enhance A. albopictus's initial impact on resident species. PMID- 19777121 TI - Real-time implementation of distortion corrections for a tiled EMCCD-based Solid State X-ray Image Intensifier (SSXII). AB - The new Solid State X-ray Image Intensifier (SSXII) is being designed based on a modular imaging array of Electron Multiplying Charge Couple Devices (EMCCD). Each of the detector modules consists of a CsI(Tl) phosphor coupled to a fiber-optic plate, a fiber-optic taper (FOT), and an EMCCD sensor with its electronics. During the optical coupling and alignment of the modules into an array form, small orientation misalignments, such as rotation and translation of the EMCCD sensors, are expected. In addition, barrel distortion will result from the FOTs. Correction algorithms have been developed by our group for all the above artifacts. However, it is critical for the system's performance to correct these artifacts in real-time (30 fps). To achieve this, we will use two-dimensional Look-Up-Tables (LUT) (each for x and y coordinates), which map the corrected pixel locations to the acquired-image pixel locations. To evaluate the feasibility of this approach, this process is simulated making use of parallel coding techniques to allow real-time distortion corrections for up to sixteen modules when a standard quad processor is used. The results of this simulation confirm that tiled field-of-views (FOV) comparable with those of flat panel detectors can be generated in ~17 ms (>30 fps). The increased FOV enabled through correction of tiled images, combined with the EMCCD characteristics of low noise, negligible lag and high sensitivity, should make possible the practical use of the SSXII with substantial advantages over conventional clinical systems. PMID- 19777123 TI - The dynamics of HDAC activity on memory formation. AB - Histone deacetylases (HDACs) have previously been shown to be critical for the formation of long-term memories. Recent findings now show that a specific HDAC isoform, HDAC2, negatively regulates formation of hippocampus-dependent memory. These recent findings published in Nature highlight potential new therapeutic interventions for the treatment of memory impairments associated with human neurological disorders. PMID- 19777122 TI - The occurrence of tissue-specific twitchin isoforms in the mussel Mytilus galloprovincialis. AB - The catch state in Mytilus anterior byssus retractor muscle is regulated by phosphorylation and dephosphorylation of twitchin, a member of the titin/connectin superfamily, and involves two serine residues, Ser-1075 (D1) and Ser-4316 (D2). This study was undertaken to examine whether isoforms of twitchin were expressed in various muscles of the mussel Mytilus galloprovincialis by reverse transcription-polymerase chain reaction. Mussel tissues, including both catch and non-catch muscles, contained various twitchin isoforms that all contained the D2 site and the kinase domain. However, sequence alterations were detected around the D1 site, notably a potential deletion of the D1 site. All isoforms from catch muscles contained both the D1 and D2 sites, whereas those from non-catch muscles also expressed the D2 site, but some of them lacked the D1 site. This suggests that the D1 site of twitchin is essential to the mechanism of catch. Genomic DNA analysis revealed that twitchin isoforms are produced by alternative splicing. PMID- 19777124 TI - Scientific Autonomy and Public Oversight. AB - When scientific research collides with social values, science's right to self governance becomes an issue of paramount concern. In this article, I develop an account of scientific autonomy within a framework of public oversight. I argue that scientific autonomy is justified because it promotes the progress of science, which benefits society, but that restrictions on autonomy can also be justified to prevent harm to people, society, or the environment, and to encourage beneficial research. I also distinguish between different ways of limiting scientific autonomy, and I argue that government involvement in scientific decision-making should usually occur through policies that control the process of science, rather than policies that control the content of science. PMID- 19777125 TI - Ethnic dimensions of habitus among homeless heroin injectors. AB - Ten years of participant-observation fieldwork and photography among a multi ethnic social network of homeless heroin injectors and crack smokers in California reveal hierarchical interpersonal relations between African Americans, whites and Latinos despite the fact that they all share a physical addiction to heroin and live in indigent poverty in the same encampments. Focusing on tensions between blacks and whites, we develop the concept of 'ethnicized habitus' to understand how divisions drawn on the basis of skin color are enforced through everyday interaction to produce 'intimate apartheid' in the context of physical proximity and shared destitution. Specifically, we examine how two components of ethnic habitus are generated. One is a simple technique of the body, a preference for intravenous versus intramuscular or subcutaneous heroin injection. The second revolves around income-generation strategies and is more obviously related to external power constraints. Both these components fit into a larger constellation of ethnic distinction rooted in historically entrenched political, economic and ideological forces. An understanding of the generative forces of the ethnic dimensions of habitus allows us to recognize how macro-power relations produce intimate desires and ways of being that become inscribed on individual bodies and routinized in behavior. These distinctions are, for the most part, interpreted as natural attributes of genetics and culture by many people in the United States, justifying a racialized moral hierarchy. PMID- 19777126 TI - The science of ultrasound therapy for fracture healing. AB - Fracture healing involves a complex interplay of cellular processes, culminating in bridging of a fracture gap with bone. Fracture healing can be compromised by numerous exogenous and endogenous patient factors, and intense research is currently going on to identify modalities that can increase the likelihood of successful healing. Low-intensity pulsed ultrasound (LIPUS) has been proposed as a modality that may have a benefit for increasing reliable fracture healing as well as perhaps increasing the rate of fracture healing. We conducted a review to establish basic scince evidence of therapeutic role of lipus in fracture healing. An electronic search without language restrictions was accomplished of three databases (PubMed, Embase, Cinahl) for ultrasound-related research in osteocyte and chondrocyte cell culture and in animal fracture models, published from inception of the databases through December, 2008. Studies deemed to be most relevant were included in this review. Multiple in vitro and animal in vivo studies were identified. An extensive body of literature exists which delineates the mechanism of action for ultrasound on cellular and tissue signaling systems that may be related to fracture healing. Research on LIPUS in animal fracture models has demonstrated promising results for acceleration of fracture healing and for promotion of fracture healing in compromised tissue beds. A large body of cellular and animal research exists which reveals that LIPUS may be beneficial for accelerating normal fracture healing or for promoting fracture healing in compromised tissue beds. Further investigation of the effects of LIPUS in human fracture healing is warranted for this promising new therapy. PMID- 19777127 TI - Use of silver nanoparticles to enhance surface plasmon-coupled emission (SPCE). AB - We report that self-assembled monolayers of colloidal silver nanoparticles can increase the intensity of the surface plasmon-coupled emission (SPCE) signal from sulforhodamine 101 (S101). The S101 was spin coated on a glass slide coated with a layer of continuous silver, and a silica layer upon which the nanoparticle layer was self-assembled. Of the various colloid sizes studied, the 40 nm colloids showed both the highest enhancements in the SPCE signal and the largest extent of plasmon coupling, defined as the ratio of SPCE to Free Space signal. Our findings reveal a new technique that can be potentially employed to increase the sensitivity of SPCE applications. PMID- 19777128 TI - What's "right" in language comprehension: ERPs reveal right hemisphere language capabilities. AB - Although the term "nonverbal" is often applied to the right cerebral hemisphere (RH), a growing body of work indicates that the RH can comprehend language and, indeed, that it makes critical contributions to normal language functions. Reviewed here are studies that have examined RH language capabilities by combining visual half-field presentation methods with event-related potential (ERP) measures. Because they afford temporal and functional specificity and can be obtained as participants simply process language for meaning, ERPs provide especially valuable insights into RH language functions. Such studies suggest that the RH appreciates word and message-level meaning information, and that it may play a particularly important role in the processing of relatively unpredictable semantic relationships. In addition, this work suggests that patterns observed for everyday language processing may often be an emergent property of multiple, distinct mechanisms operating in parallel as the left and right hemispheres jointly comprehend language. PMID- 19777129 TI - Optimization of a Genome-Wide Disordered Lentivector-Based Short Hairpin RNA Library. AB - To obtain a whole genome library that suppresses the total diversity of human mRNAs, lentiviral vector constructs and a short hairpin RNA (shRNA) expression cassette were optimized. The optimization of the vector increased the virus titer in preparations by 15-20 times. A simple shRNA structure with a 21-bp stem proved to be the most effective. Lentivector-based shRNA expression constructs were obtained by using puro(R), copGFP, or H-2K(k) as a selectable marker. The efficiency of the optimized library was demonstrated when screening for shRNAs reactivating the tumor suppressor p53 in HeLa cells. Cells carried a reporter construct ensuring p53-responsive synthesis of a fluorescent protein, which allowed selection of cells with reactivated p53 by flow cytometry. PMID- 19777130 TI - Systematic Computational Study of the Effect of Silver Nanoparticle Dimers on the Coupled Emission from Nearby Fluorophores. AB - We use the finite-difference time-domain method to predict how fluorescence is modified if the fluorophore is located between two silver nanoparticles of a dimer system. The fluorophore is modeled as a radiating point dipole with orientation defined by its polarization. When a fluorophore is oriented perpendicular to the metal surface, there is a large increase in total power radiated through a closed surface containing the dimer system, in comparison to the isolated fluorophore and the case of a fluorophore near a single nanoparticle. The increase in radiated power indicates increases in the relative radiative decay rates of the emission near the nanoparticles. The angle-resolved far-field distributions of the emission in a single plane are also computed. This is informative as many experimental conditions involve collection optics and detectors that collect the emission along a single plane. For fluorophores oriented perpendicular to the metal surfaces, the dimer systems lead to significant enhancements in the fluorescence emission intensity in the plane. In contrast, significant emission quenching occurs if the fluorophores are oriented parallel to the metal surfaces. We also examine the effect of the fluorophore on the near-field around the nanoparticles and correlate our results with surface plasmon excitations. PMID- 19777131 TI - Dipyridodiazepinone derivatives; synthesis and anti HIV-1 activity. AB - Ten dipyridodiazepinone derivatives were synthesized and evaluated for their anti HIV-1 reverse transcriptase activity against wild-type and mutant type enzymes, K103N and Y181C. Two of them were found to be promising inhibitors for HIV-1 RT. PMID- 19777132 TI - Radical carbonylations using a continuous microflow system. AB - Radical-based carbonylation reactions of alkyl halides were conducted in a microflow reactor under pressurized carbon monoxide gas. Good to excellent yields of carbonylated products were obtained via radical formylation, carbonylative cyclization and three-component coupling reactions, using tributyltin hydride or TTMSS as a radical mediator. PMID- 19777133 TI - Gold film-catalysed benzannulation by microwave-assisted, continuous flow organic synthesis (MACOS). AB - Methodology has been developed for laying down a thin gold-on-silver film on the inner surface of glass capillaries for the purpose of catalysing benzannulation reactions. The cycloaddition precursors are flowed through these capillaries while the metal film is being heated to high temperatures using microwave irradiation. The transformation can be optimized rapidly, tolerates a wide number of functional groups, is highly regioselective, and proceeds in good to excellent conversion. PMID- 19777134 TI - Regioselective alkynylation followed by Suzuki coupling of 2,4-dichloroquinoline: synthesis of 2-alkynyl-4-arylquinolines. AB - A two step synthesis of 2-alkynyl-4-arylquinolines has been accomplished via Pd/C mediated regioselective C-2 alkynylation of 2,4-dichloroquinoline in water followed by Suzuki coupling at C-4 of the resulting 4-chloro derivative. PMID- 19777136 TI - Synthesis of phosphonate and phostone analogues of ribose-1-phosphates. AB - The synthesis of phosphonate analogues of ribose-1-phosphate and 5-fluoro-5 deoxyribose-1-phosphate is described. Preparations of both the alpha- and beta phosphonate anomers are reported for the ribose and 5-fluoro-5-deoxyribose series and a synthesis of the corresponding cyclic phostones of each alpha-ribose is also reported. These compounds have been prepared as tools to probe the details of fluorometabolism in S. cattleya. PMID- 19777135 TI - Mitomycins syntheses: a recent update. AB - Mitomycins are a class of very potent antibacterial and anti-cancer compounds having a broad activity against a range of tumours. They have been used in clinics since the 1960's, and the challenges represented by their total synthesis have challenged generations of chemists. Despite these chemical and medicinal features, these compounds, in racemic form, have succumbed to total synthesis only four times over the last 30 years. PMID- 19777138 TI - New evidence for complex climate change in MIS 11 from Hoxne, Suffolk, UK. AB - The climatic signal of Marine Isotope Stage (MIS) 11 is well-documented in marine and ice-sheet isotopic records and is known to comprise at least two major warm episodes with an intervening cool phase. Terrestrial records of MIS 11, though of high resolution, are often fragmentary and their chronology is poorly constrained. However, some notable exceptions include sequences from the maar lakes in France and Tenaghi Philippon in Greece. In the UK, the Hoxnian Interglacial has been considered to correlate with MIS 11. New investigations at Hoxne (Suffolk) provide an opportunity to re-evaluate the terrestrial record of MIS 11. At Hoxne, the type Hoxnian Interglacial sediments are overlain by a post Hoxnian cold-temperate sequence. The interglacial sediments and the later temperate phase are separated by the so-called 'Arctic Bed' from which cold climate macroscopic plant and beetle remains have been recovered. The later temperate phase was deposited during an episode of boreal woodland and is associated with the artefacts, a diverse vertebrate fauna and molluscs. New amino acid geochronological data and biostratigraphical considerations suggest that the post-Hoxnian sequence correlates with late substages of MIS 11. The paper further investigates the correlation of the sequence at Hoxne with the palynological sequences found elsewhere in Europe and adjacent offshore areas. PMID- 19777137 TI - Acid-mediated reactions under microfluidic conditions: a new strategy for practical synthesis of biofunctional natural products. AB - Microfluidic conditions were applied to acid-mediated reactions, namely, glycosylation, reductive opening of the benzylidene acetal groups, and dehydration, which are the keys to the practical synthesis of N-glycans and the immunostimulating natural product, pristane. A distinctly different reactivity from that in conventional batch stirring was found; the vigorous micromixing of the reactants with the concentrated acids is critical especially for the "fast" reactions to be successful. Such a common feature might be due to the integration of all favorable aspects of microfluidic conditions, i.e., efficient mixing, precise temperature control, and the easy handling of the reactive intermediate by controlling the residence time. The microfluidic reactions cited in this review indicate the need to reinvestigate the traditional or imaginary reactions which have so far been performed and evaluated only in batch apparatus, and therefore they could be recognized as a new strategy in synthesizing natural products of prominent biological activity in a "practical" and a "industrial" manner. PMID- 19777139 TI - Synthesis and Diels-Alder cycloaddition reaction of norbornadiene and benzonorbornadiene dimers. AB - Dimeric forms of norbornadiene and benzonorbornadiene were synthesized starting with known monobromide derivatives. The Diels-Alder cycloaddition reaction of dimers with TCNE and PTAD was investigated and new norbornenoid polycyclics were obtained. All compounds were characterized properly using NMR spectroscopy. PMID- 19777140 TI - Dispositional Mindfulness as a Predictor of the Severity of Gambling Outcomes. AB - Two studies were conducted to test and explain the relation of mindfulness to the severity of gambling outcomes among frequent gamblers. In both studies, dispositional mindfulness related to less severe gambling outcomes as measured by a DSM-IV-based screen for pathological gambling, even after controlling for gambling frequency and dispositional self-control. Study 2 extended this finding in showing that the association between mindfulness and lower pathological gambling was partially mediated by better performance on two risk-taking tasks that capture overconfidence, risky bet acceptance, and myopic focus on reward. These studies suggest a role for mindfulness in lessening the severity of gambling problems and making adaptive decisions, especially in risk-relevant contexts. PMID- 19777141 TI - Exercise and Children's Intelligence, Cognition, and Academic Achievement. AB - Studies that examine the effects of exercise on children's intelligence, cognition, or academic achievement were reviewed and results were discussed in light of (a) contemporary cognitive theory development directed toward exercise, (b) recent research demonstrating the salutary effects of exercise on adults' cognitive functioning, and (c) studies conducted with animals that have linked physical activity to changes in neurological development and behavior. Similar to adults, exercise facilitates children's executive function (i.e., processes required to select, organize, and properly initiate goal-directed actions). Exercise may prove to be a simple, yet important, method of enhancing those aspects of children's mental functioning central to cognitive development. PMID- 19777142 TI - The Upside of Being Socially Anxious: Psychopathic Attributes and Social Anxiety are Negatively Associated. AB - Psychopathy is characterized by a lack of concern for other people and social norms. In contrast, individuals with high social anxiety are overly concerned about the approval of others and violating social norms. Therefore, we hypothesized that social anxiety is negatively associated with psychopathic attributes, with males being more psychopathic than females. In order to test this hypothesis, we administered self-report measures of social anxiety, psychopathic attributes, and academic misconduct as an index of adherence to social norms to a sample of 349 undergraduate college students (244 females and 105 males). Males had more psychopathic attributes than females. Social anxiety and psychopathic attributes showed a weak but significant negative correlation in the total sample and also in the subgroup of males and females. Psychopathic attributes were further positively associated with academic misconduct behaviors among females, but not among males. These findings are consistent with the notion that social anxiety and psychopathic attributes are negatively associated. PMID- 19777143 TI - Preparation, characterization, and circularly polarized luminescence of lanthanum and europium 1,1'-binaphthyl-2,2'-diyl phosphate complexes. AB - Solvated tris-complexes of (R)- and (S)-1,1'-binaphthyl-2,2'-dyil phosphate with lanthanum(III) and europium(III) centers were prepared and characterized by spectroscopic methods and elemental analysis. Circularly polarized luminescence (CPL) spectra for the optically active isomers of the europium complexes are also reported. PMID- 19777144 TI - 3D Finite Element Meshing from Imaging Data. AB - This paper describes an algorithm to extract adaptive and quality 3D meshes directly from volumetric imaging data. The extracted tetrahedral and hexahedral meshes are extensively used in the Finite Element Method (FEM). A top-down octree subdivision coupled with the dual contouring method is used to rapidly extract adaptive 3D finite element meshes with correct topology from volumetric imaging data. The edge contraction and smoothing methods are used to improve the mesh quality. The main contribution is extending the dual contouring method to crack free interval volume 3D meshing with feature sensitive adaptation. Compared to other tetrahedral extraction methods from imaging data, our method generates adaptive and quality 3D meshes without introducing any hanging nodes. The algorithm has been successfully applied to constructing the geometric model of a biomolecule in finite element calculations. PMID- 19777145 TI - An Implementation of Bayesian Adaptive Regression Splines (BARS) in C with S and R Wrappers. AB - BARS (DiMatteo, Genovese, and Kass 2001) uses the powerful reversible-jump MCMC engine to perform spline-based generalized nonparametric regression. It has been shown to work well in terms of having small mean-squared error in many examples (smaller than known competitors), as well as producing visually-appealing fits that are smooth (filtering out high-frequency noise) while adapting to sudden changes (retaining high-frequency signal). However, BARS is computationally intensive. The original implementation in S was too slow to be practical in certain situations, and was found to handle some data sets incorrectly. We have implemented BARS in C for the normal and Poisson cases, the latter being important in neurophysiological and other point-process applications. The C implementation includes all needed subroutines for fitting Poisson regression, manipulating B-splines (using code created by Bates and Venables), and finding starting values for Poisson regression (using code for density estimation created by Kooperberg). The code utilizes only freely-available external libraries (LAPACK and BLAS) and is otherwise self-contained. We have also provided wrappers so that BARS can be used easily within S or R. PMID- 19777146 TI - Assessment of Population Structure and Its Effects on Genome-Wide Association Studies. AB - Large-scale genome-wide association studies are promising for unraveling the genetic basis of complex diseases. However, population structure is a potential problem, the effects of which on genetic association studies are controversial. Quantification of the effects of population structure on large scale genetic association studies is needed for valid analysis of data and correct interpretation of results. In this study, we performed extensive coalescent-based simulation study with varying levels of population structure to investigate the effects of population structure on large-scale genetic association studies. The effects of population structure are measured by the multiplicative changes of the probability of type I error, which is then correlated with the levels of population structure. It is found that at each nominal level of association tests, there is a positive relationship between the level of population structure and its effects, which could be summarized well with a regression function. It is also found that at a specific level of population structure, its effect on association study increases drastically as the significance level of the test decreases. The type I error is inflated by an amount approximately equal to Wright's F(ST), a measure that is used to quantify the magnitude of population structure. Therefore, in genome-wide association studies, the effects of population structure cannot be safely ignored, and must be accounted for with proper methods. This study provides quantitative guidelines to account for the effects of population structure on genome-wide association studies in admixed populations. PMID- 19777147 TI - Depression among Arabs and Jews in Israel: a population-based study. AB - INTRODUCTION: Depression is the second most common chronic disorder seen by primary care physicians. Risk factors associated with depression include medical and psychosocial factors. While in Israel, the rate and risk factors for depression are considered similar to those in other Western countries, population based data are limited. The present study aims to estimate the prevalence of depression among Jews and Muslim Arabs, and to consider possible associations with demographic, socioeconomic, and health factors. METHODS: The study group (N = 872) was equally divided according to ethnicity, gender, and age group. Depression was measured by the Harvard Department of Psychiatry National Depression Screening Day Scale (HANDS). RESULTS: The rate of depression scores in the likely/very likely range was 2.5 times higher among Arabs than among Jews (24.9 vs. 10.6%; P < 0.001). Women were more likely to express symptoms of depressive episode than were men (22.0 vs. 13.6%; P = 0.001), and the depression rate increased with age, from 11.0% in the youngest group (26-35) to 25.0% in the oldest (P = 0.001). The rate of increase in depression by age was different for the genders, rising more steeply for women than for men. However, the age-gender differential was not identical for the two ethnic groups. The differences in depression prevalence between Arabs and Jews were maintained after controlling for confounding variables, except that when controlling for education, the difference between the ethnic groups was no longer significant. After adjusting for all variables in the analysis, no significant association remained between ethnicity and depression (OR = 0.80; 95% CI = 0.45-1.40). PMID- 19777148 TI - Pelvic organ support among primiparous women in the first year after childbirth. AB - INTRODUCTION AND HYPOTHESIS: This study describes pelvic organ support after childbirth. METHODS: This ancillary analysis of the Childbirth and Pelvic Symptoms Imaging Study compares pelvic organ prolapse quantification 6-12 months after childbirth among three cohorts of primiparous women: vaginal delivery with sphincter tear (n = 106), vaginal delivery without sphincter tear (n = 108), and cesarean without labor (n = 39). RESULTS: Of participants, 31.2% had stage II support. Prolapse to or beyond the hymen was present in 14% after vaginal delivery with sphincter tear (95% confidence interval 8%, 22%), 15% (9%, 24%) after vaginal delivery without sphincter tear, and 5% (1%, 17%) after cesarean without labor (p = 0.23). A study of 132 women per group would be required for 80% power to test differences between 5% and 15%. CONCLUSIONS: While these data provide insufficient power to dismiss a difference in pelvic organ support between modes of delivery, they add to our understanding of support following childbirth. PMID- 19777149 TI - An overview of the introns-first theory. AB - We review the introns-first hypothesis a decade after it was first proposed. It is that exons emerged from non-coding regions interspersed between RNA genes in an early RNA world, and is a subcomponent of a more general 'RNA-continuity' hypothesis. The latter is that some RNA-based systems, especially in RNA processing, are 'relics' that can be traced back either to the RNA world that preceded both DNA and encoded protein synthesis or to the later ribonucleoprotein (RNP) world (before DNA took over the main coding role). RNA-continuity is based on independent evidence-in particular, the relative inefficiency of RNA catalysis compared with protein catalysis-and leads to a wide range of predictions, ranging from the origin of the ribosome, the spliceosome, small nucleolar RNAs, RNases P and MRP, and mRNA, and it is consistent with the wide involvement of RNA processing and regulation of RNA in modern eukaryotes. While there may still be cause to withhold judgement on intron origins, there is strong evidence against introns being uncommon in the last eukaryotic common ancestor (LECA), and expanding only within extant eukaryotic groups-the 'very-late' intron invasion model. Similarly, it is clear that there are selective forces on numbers and positions of introns; their existence may not always be neutral. There is still a range of viable alternatives, including introns first, early, and 'latish' (i.e. well established in LECA), and regardless of which is ultimately correct, it pays to separate out various questions and to focus on testing the predictions of sub theories. PMID- 19777150 TI - Origin of self-replicating biopolymers: autocatalytic feedback can jump-start the RNA world. AB - Life is based on biopolymers that have the ability to replicate themselves. Here we consider how a self-replicating RNA system may have originated. We consider a reaction system in which polymerization is possible by the addition of an activated monomer to the end of a chain. We suppose that a small fraction of polymers longer than some minimum length L have the ability to act as polymerase ribozymes. Polymerization can occur spontaneously at a slow rate and can also be catalyzed by polymerase ribozymes, if these ribozymes exist. The system contains autocatalytic feedback: increasing the polymerization rate causes the ribozyme concentration to increase, which causes the polymerization rate to further increase. For an infinite volume, the dynamics are deterministic. There are two stable states: a 'dead' state with a very low concentration of ribozymes and a polymerization rate almost equal to the spontaneous rate, and a 'living' state with a high concentration of ribozymes and a high rate of polymerization occurring via ribozyme catalysis. In a finite volume, such as the interior of a lipid vesicle or other small compartment, the reaction dynamics is stochastic and concentration fluctuations can occur. Using a stochastic simulation, we show that if a small number of ribozymes is initially formed spontaneously, this can be enough to drive the system from the dead to the living state where ribozyme catalyzed synthesis of large numbers of additional ribozymes occurs. This transition occurs most easily in volumes of intermediate size. PMID- 19777151 TI - The complete chloroplast genome of Coix lacryma-jobi and a comparative molecular evolutionary analysis of plastomes in cereals. AB - Graminoid molecular evolution was investigated by chloroplast genome (plastome) scale analyses. A complete plastome from Coix lacryma-jobi (Poaceae) and a draft plastome from Joinvillea plicata (Joinvilleaceae) were sequenced and analyzed. The draft plastome included conserved protein-coding loci routinely analyzed in previous studies plus one additional locus of demonstrated phylogenetic utility. The methodological approach was to directly sequence overlapping amplicons from known plastome regions. Over 100 pairs of amplification and sequencing primers were designed and positioned to flank overlapping 1,200-base pair fragments around the entire plastome. Newly determined sequences were analyzed with published plastomes from representatives of Panicoideae, Ehrhartoideae, and Pooideae. Considerable variation was found for studies within the family and even within Andropogoneae. Readily interpreted mutation patterns were observed, such as small inversions in hairpin-loop regions and indels, which were common in intergenic spacers. Maximum or near-maximum bootstrap support was observed in all analyses resolving relationships between subfamilies. However, the addition of characters from noncoding regions increased the number of parsimony-informative characters and lengthened short internal branches (Andropogoneae), better defining intergeneric relationships. Thus, characters in complete plastomes can be used over a wide scope of phylogenetic studies. PMID- 19777152 TI - An ecological risk assessment of the acute and chronic effects of the herbicide clopyralid to rainbow trout (Oncorhynchus mykiss). AB - Clopyralid (3,6-dichloro-2-pyridinecarboxylic acid) is a pyridine herbicide frequently used to control invasive, noxious weeds in the northwestern United States. Clopyralid exhibits low acute toxicity to fish, including the rainbow trout (Oncorhynchus mykiss) and the threatened bull trout (Salvelinus confluentus). However, there are no published chronic toxicity data for clopyralid and fish that can be used in ecological risk assessments. We conducted 30-day chronic toxicity studies with juvenile rainbow trout exposed to the acid form of clopyralid. The 30-day maximum acceptable toxicant concentration (MATC) for growth, calculated as the geometric mean of the no observable effect concentration (68 mg/L) and the lowest observable effect concentration (136 mg/L), was 96 mg/L. No mortality was measured at the highest chronic concentration tested (273 mg/L). The acute:chronic ratio, calculated by dividing the previously published 96-h acutely lethal concentration (96-h ALC(50); 700 mg/L) by the MATC was 7.3. Toxicity values were compared to a four-tiered exposure assessment profile assuming an application rate of 1.12 kg/ha. The Tier 1 exposure estimation, based on direct overspray of a 2-m deep pond, was 0.055 mg/L. The Tier 2 maximum exposure estimate, based on the Generic Exposure Estimate Concentration model (GEENEC), was 0.057 mg/L. The Tier 3 maximum exposure estimate, based on previously published results of the Groundwater Loading Effects of Agricultural Management Systems model (GLEAMS), was 0.073 mg/L. The Tier 4 exposure estimate, based on published edge-of-field monitoring data, was estimated at 0.008 mg/L. Comparison of toxicity data to estimated environmental concentrations of clopyralid indicates that the safety factor for rainbow trout exposed to clopyralid at labeled use rates exceeds 1000. Therefore, the herbicide presents little to no risk to rainbow trout or other salmonids such as the threatened bull trout. PMID- 19777153 TI - Late supra-diaphragmatic lymph node recurrence following resection of a fibrolamellar hepatocarcinoma: an unusual case. AB - We report the case of a patient who presented with a supra-diaphragmatic lymph node recurrence 8 years after resection of a right liver fibrolamellar carcinoma. Treatment of this recurrence consisted of local excision by a right thoracotomy approach. Postoperative course was uneventful and the patient did not experience recurrence within 2 years. Based on this observation, we describe the major lymphatic vessels of the liver, in order to explain this unusual metastatic site occurrence. PMID- 19777154 TI - Internal architecture of calcaneus: correlations with mechanics and pathoanatomy of calcaneal fractures. AB - BACKGROUND: Available studies on internal architecture of the calcaneus are cursory and contradictory. Present study focused on elaborate descriptions of the different trabecular groups and their correlation with the fractures of this bone. METHOD: To study the internal architecture, 50 dry adult human calcanei were sectioned in various planes and grossly dissected. RESULTS: Six different groups (A-F) of lamellae were identified. Based on the observations of trabecular architecture, potential weak areas in this bone were identified. The predicted weak zones correlate well with the fracture lines described in the calcaneus and provide anatomical basis for their occurrence. CONCLUSIONS: This study underscores the major influence of the internal architecture of the calcaneus in predicting the fracture lines. The findings can be utilized to classify fractures of calcaneus, which has been a topic of ongoing debate. Knowledge of weak zones will aid clinicians to improve the techniques of internal fixation. PMID- 19777155 TI - Complete nucleotide sequence of four RNA segments of fig mosaic virus. AB - The complete sequence of four viral RNA segments of fig mosaic virus (FMV) was determined. Each of the four RNAs comprises a single open reading frame (ORF) 7,093, 2,252, 1,490 and 1,472 nucleotides in size, respectively. These ORFs encode the following proteins in the order: RNA-dependent RNA polymerase (p1 264 kDa), a putative glycoprotein (p2 73 kDa), a putative nucleocapsid protein (p3 35 kDa) and a protein with unknown function (p4 40.5 kDa). All RNA segments possess untranslated regions containing at the 5' and 3' termini a 13-nt complementary sequence. A conserved motif denoted premotif A was found to be present in addition to the five RdRp motifs A-F in RNA-1. In phylogenetic trees constructed with the amino acid sequences of RNA-1 and RNA-2, FMV clustered consistently with European mountain ash ringspot-associated virus (EMARaV) in a clade close to those comprising members of the genera Hantavirus, Orthobunyavirus and Tospovirus. The amino acid sequence of the putative FMV nucleocapsid protein encoded by RNA-3 shared identity with comparable sequences of EMARaV and the unclassified viruses pigeonpea sterility mosaic virus (PPSMV) and maize red stripe virus (MRSV). The nucleocapsid sequences rooted the four viruses in a clade close to the genus Tospovirus. Based on molecular, morphological and epidemiological features, FMV appears to be very closely related to PPSMV and MRSV. All these viruses are phylogenetically related to EMARaV and therefore seem to be eligible for classification in the proposed genus Emaravirus, which, in turn, may find a taxonomic allocation in the family Bunyaviridae. PMID- 19777156 TI - Complete nucleotide sequence of double-stranded RNA viruses from Fusarium graminearum strain DK3. AB - The complete genomes two different dsRNA mycoviruses, Fusarium graminearum virus 3 (FgV3) and Fusarium graminearum virus 4 (FgV4), was sequenced and analyzed. The viral genome of FgV3 is 9,098 base pairs (bp) long and contains two open reading frames (ORF) encoding a putative RNA-dependent RNA polymerase (RdRp) and a protein of unknown function. The FgV4 genome is composed of two dsRNA genome segments of 2,383 bp and 1,739 bp. FgV4 dsRNA-1 contains a single ORF, which has a conserved RdRp motif, while FgV4 dsRNA-2 contains two putative ORFs coding for products of unknown function. Both the genome organization and phylogenetic analysis indicated that FgV3 was closely related to members of the families Totiviriridae and Chrysoviridae, but it was placed outside of their main clusters, whereas FgV4 formed a distinct clade with the family Partitiviridae. This is the first report of the full-length nucleotide sequences of FgV3 and FgV4 infecting Fusarium graminearum. PMID- 19777157 TI - Unemployment and its association with health-relevant actions: investigating the role of time perspective with German census data. AB - OBJECTIVE: In this study, we seek to explain how unemployment is related to an increase in health-damaging actions. A short time perspective, that is an orientation towards the present rather than the future, is hypothesised to account for this effect. The concept of time perspective is located within an action theoretical framework and the hypothesis is tested empirically. METHODS: We investigated the unemployed people's smoking behaviour and body-mass index (BMI) using German microcensus data from 2003. Data from 77,766 respondents (88.60% employed and 11.40% unemployed) were analysed. Multivariate regression analysis was applied to test our hypotheses. RESULTS: Unemployment is associated with a 46% higher probability to smoke and with a 0.37 unit increase in BMI compared to employment. The likelihood of smoking steadily increases with the duration of unemployment, while only unemployment spells of 4 years and longer are significantly related to BMI. Yet, the smoking probability of those unemployed who have a long time perspective is 74% lower and their BMI is 1.81 lower than those who do not have a long time perspective. CONCLUSION: Unemployment is negatively associated with health-relevant actions. This effect varies according to persons' time perspectives. Our approach delivers an innovative view on why unemployed individuals exercise more health-damaging actions than the employed. PMID- 19777158 TI - The impact of age and gender on the striatal astrocytes activation in murine model of Parkinson's disease. AB - OBJECTIVE: The aim of the present study was to determine how aging and gender influence the response of astrocytes to 1-methyl-4-phenyl-1,2,3,6 tetrahydropiridine (MPTP) intoxication. MATERIALS AND METHODS: To asses the MPTP induced astrocytes activation in nigro-striatal system, we measured the temporal changes in mRNA and protein expression of the specific astrocytic marker, glial fibrillary acidic protein (GFAP; by RT-PCR and Western blot), in the striatum of male and female C57BL/6 mice (2 and 12-month old) after 6 h and 1, 3, 7, 14 and 21 days post-intoxication. RESULTS: We observed the increases of GFAP mRNA level post-MPTP intoxication in both young and aging males only at early time points, whereas in females (both ages) also at later time points. We noticed maximal increase of GFAP protein content on the 3rd day post-intoxication in young and aged males, whereas in females at the 7-daytime point. CONCLUSIONS: The present results provide additional information of potential relevance to understand the mechanisms of gender and age-related difference in susceptibility of nigro striatal system to MPTP insult. PMID- 19777159 TI - Preclinical activity of F14512, designed to target tumors expressing an active polyamine transport system. AB - We have exploited the polyamine transport system (PTS) to deliver selectively a spermine-drug conjugate, F14512 to cancer cells. This study was aimed to define F14512 anticancer efficacy against tumor models and to investigate whether fluorophor-labeled polyamine probes could be used to identify tumors expressing a highly active PTS and that might be sensitive to F14512 treatments. Eighteen tumor models were used to assess F14512 antitumor activity. Cellular uptake of spermine-based fluorescent probes was measured by flow cytometry in cells sampled from tumor xenografts by needle biopsy. The accumulation of the fluorescent probe within B16 tumors in vivo was assessed using infrared fluorescence imaging. This study has provided evidence of a major antitumor activity for F14512. Significant responses were obtained in 67% of the tumor models evaluated, with a high level of activity recorded in 33% of the responsive models. Complete tumor regressions were observed after i.v., i.p. or oral administrations of F14512 and its antitumor activity was demonstrated over a range of 2-5 dose levels, providing evidence of its good tolerance. The level of cellular fluorescence emitted by the fluorescent probes was higher in cells sampled from tumors sensitive to F14512 treatments than from F14512-refractory tumors. We suggest that these probes could be used to identify tumors expressing a highly active PTS and guide the selection of patients that might be treated with F14512. These results emphasize the preclinical interest of this novel molecule and support its further clinical development. PMID- 19777161 TI - Molecular cytogenetic study of three common Mediterranean limpets, Patella caerulea, P. rustica and P. ulyssiponensis (Archaeogastropoda, Mollusca). AB - The present paper shows the results of chromosome banding and rDNA-FISH study performed on several specimens of different populations of Patella caerulea, Patella rustica and Patella ulyssiponensis. The taxonomic attribution of specimens was ascertained by the molecular phylogenetic analysis of the mitochondrial 16S rRNA gene. P. caerulea and P. rustica had 2n = 18 chromosomes with first seven of biarmed pairs and the remaining two uniarmed pairs. P. ulyssiponensis had 2n = 16 with all biarmed chromosomes. Ag-NOR loci were on the short arms of the first metacentric pair in the three studied limpets, whereas they showed a different pattern of heterochromatin distribution and composition. A chromosome mosaicism was observed in several P. caerulea specimens, which exhibited an unpaired metacentric element and loss of a telocentric pair. The obtained results suggest that in the genus Patella specific diversification was accompanied by variations in heterochromatin distribution and composition and reduction of chromosome number by Robertsonian centric fusion. PMID- 19777162 TI - Functional salvage of a mangled lower limb using custom-made endoprosthetic replacement. AB - Functional salvage of a severely injured extremity is a challenge for the patient and the treating surgeon. We report a case of a woman presenting with severely injured lower limb and bone loss, which was managed using a custom-made endoprosthetic replacement for successful functional outcome. Despite being complicated by bone loss, nerve injury and infection; a planned staged surgical treatment and rehabilitation have resulted in satisfactory outcome. At 3-year follow-up, the functional score according to the Musculoskeletal Tumor Society International Symposium on Limb Salvage System was 70% and the Toronto Extremity Salvage Score was 62%. Endoprosthetic replacements may have a limited role in managing selected patients with mangled extremity and can lead to a good functional outcome to these patients. PMID- 19777160 TI - Synergistic efficacy of sorafenib and genistein in growth inhibition by down regulating angiogenic and survival factors and increasing apoptosis through upregulation of p53 and p21 in malignant neuroblastoma cells having N-Myc amplification or non-amplification. AB - Neuroblastoma is an extracranial, solid, and heterogeneous malignancy in children. The conventional therapeutic modalities are mostly ineffective and thus new therapeutic strategies for malignant neuroblastoma are urgently warranted. We examined the synergistic efficacy of combination of sorafenib (SF) and genistein (GST) in human malignant neuroblastoma SK-N-DZ (N-Myc amplified) and SH-SY5Y (N Myc non-amplified) cell lines. MTT assay showed dose-dependent decrease in cell viability and the combination therapy more prominently inhibited the cell proliferation in both cell lines than either treatment alone. Apoptosis was confirmed morphologically by Wright staining. Flow cytometric analysis of cell cycle phase distribution and Annexin V-FITC/PI staining showed increase in subG1 DNA content and early apoptosis, respectively, after treatment with the combination of drugs. Apoptosis was further confirmed by scanning electron microscopy. Combination therapy showed activation of caspase-8, cleavage of Bid to tBid, increase in p53 and p21 expression, down regulation of anti-apoptotic Mcl-1, and increase in Bax:Bcl-2 ratio to trigger apoptosis. Down regulation of MDR, hTERT, N-Myc, VEGF, FGF-2, NF-kappaB, p-Akt, and c-IAP2 indicated suppression of angiogenic and survival pathways. Mitochondrial release of cytochrome c and Smac into cytosol indicated involvement of mitochondia in apoptosis. Increases in proteolytic activities of calpain and caspase-3 were also confirmed. Our results suggested that combination of SF and GST inhibited angiogenic and survival factors and increased apoptosis via receptor and mitochondria mediated pathways in both neuroblastoma SK-N-DZ and SH-SY5Y cell lines. Thus, this combination of drugs could be a potential therapeutic strategy against human malignant neuroblastoma cells having N-Myc amplification or non amplification. PMID- 19777163 TI - Removal of a broken intramedullary femoral nail with an unusual pattern of breakage: a case report. AB - To the best of our knowledge, only 3 cases, including the present case, have been reported with a three part broken pattern. However, this is the first case associated with a distal locking screw broken. We report the case of a 31-year old patient who sustained an open femoral shaft fracture . The fracture was stabilized with a Kuntcher femoral nail. After 7 months of the initial surgery he presented with a three part broken intramedullary nail and the distal locking screw broken. We used a combined technique for the removal of the nail through the nonunion fracture site; we used a pull out technique for the middle fragment and a curved thin hook for the distal fragment. Then we applied bone allograft and stabilized with a cannulated intramedullary femoral nail (Synthes, Oberdorf, Switzerland). After 2 years of follow up the nonunion was consolidated and the patient presented a good clinical outcome. This is of particular interest because it is a unique case and the association with a broken distal locking screw is reported for the first time in this study. A combination of methods through the nonunion site approach and an alternative instrumental is a good method for the removal of a hollow femoral intramedullary nail with this unusual pattern of breakage. PMID- 19777164 TI - Pulmonary arterial hypertension. PMID- 19777165 TI - Emergency department use by the uninsured after health care reform in Massachusetts. AB - The objective of this article is to determine if health care reform in Massachusetts in 2006 was associated with a change in ED utilization by the uninsured for asthma and upper respiratory tract infection (URI). We performed a retrospective pre-post study in an urban tertiary-care teaching hospital. Subjects included all patients, ages 2-54, who presented to the ED with asthma or URI from January 1 to July 31 for each of the 3 years before health care reform and for the period after the insurance mandate officially went into effect on January 1, 2008. We used chi-square analysis to compare the frequency of utilization of the ED by uninsured patients before and after the implementation of an individual health insurance mandate in Massachusetts. For the period before the implementation of health reform, an annual average of 301 ED visits for patients with either URI (average n = 131) or asthma (average n = 170) were identified. After health care reform, there were 366 visits found for URI (n = 132) and asthma (n = 234) over a similar time period. There was a statistically significant decrease in ED utilization by the uninsured for URI but not for asthma. As a secondary analysis, visits for patients covered by the uncompensated care pool (UCP) before health care reform was not different from the combined frequency of visits by the remaining uninsured covered by a health safety net pool and those who qualified for the state subsidized Commonwealth Care program after health care reform. In this study, health care reform was associated with a decrease in the number of uninsured patients who presented to the ED with URI but not asthma. This study is limited by its analysis of a single large institution and a limited set of diagnoses. PMID- 19777167 TI - Trace minerals status and antioxidant enzymes activities in calves with dermatophytosis. AB - The aim of this study was to determine the levels of trace minerals Zn, Cu, and Se, the effect of dermatophytosis on the level of thiobarbituric acid reactive substances (TBARS) as an indicator of lipid peroxidation, the status of enzymatic and nonenzymatic antioxidants, and the relationship between the mentioned trace minerals and antioxidant defense system in calves with dermatophytosis. A total of 21 Holstein calves with clinically established diagnosis of dermatophytosis and an equal number of healthy ones were included in this study. Results showed that 81% of mycotic isolates were Trichophyton verrucosum, while 19% were Trichophyton mentagrophytes. The level of Zn, Cu, Se, and glutathione (GSH) and the activity of the antioxidant enzymes, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) were significantly (P 0.05). Intratumoral LVD did not show significant differences according to lymphatic invasion and differentiation, which were positive predictors for lymph node metastasis in EGC. Using multivariate logistic regression, intratumoral LVD was an independent factor, with the above two factors and depth of invasion, for the prediction of lymph node metastasis in EGC with a relative risk of 3.570 in high intratumoral-LVD group compared with low-intratumoral-LVD group (P = 0.022). CONCLUSION: Intratumoral LVD may be a useful, independent predictor for lymph node metastasis, especially in combination with previously established predictors in EGC. PMID- 19777180 TI - Induction chemotherapy with S-1 plus cisplatin followed by surgery for treatment of gastric cancer with peritoneal dissemination. AB - BACKGROUND: The prognosis of gastric cancer patients with peritoneal dissemination is poor. Recently, chemotherapy with S-1 plus cisplatin has been shown to be highly effective for advanced gastric cancer. METHODS: In 41 patients diagnosed with either macro- or microscopic peritoneal dissemination by staging laparoscopy, and receiving induction chemotherapy with S-1 plus cisplatin between August 2002 and February 2008, response of peritoneal lesions to the induction chemotherapy and the outcome of the following surgery were retrospectively evaluated. RESULTS: Of 41 patients identified, 38 patients (93%) completed two cycles. Among grade 3 or 4 adverse effects, neutropenia was most frequently observed (9 patients; 22%). After chemotherapy, 32 patients (78%) underwent surgery and R0 resection was accomplished in 22 patients. Although objective response by Response Evaluation Criteria in Solid Tumors (RECIST) was recorded in only four patients (10%), peritoneal dissemination disappeared in 19 patients (46%). Patients with limited peritoneal metastasis, negative peritoneal cytology, or response of the primary lesion were more likely to exhibit disappearance of the peritoneal dissemination. Median survival time of all patients was 20.4 months. Patients with R0 resection had median survival time of 43.2 months, which was significantly longer than for those with noncurative resection (12.6 months) or without surgery (10.3 months). CONCLUSIONS: Limited peritoneal dissemination of gastric origin is highly sensitive to induction chemotherapy with S-1 plus cisplatin. Resection after disappearance of peritoneal metastasis could cure some patients. PMID- 19777181 TI - Axillary recurrence rate following negative sentinel node biopsy for invasive breast cancer: long-term follow-up. AB - OBJECTIVE: Sentinel lymph node (SLN) biopsy has replaced axillary lymph node dissection (ALND) as the definitive nodal staging procedure for breast cancer. SLN biopsy has been proven to cause less morbidity and be more cost effective than complete ALND. Short-term follow-up has shown that lymphatic mapping and SLN have a low false-negative rate, but there is limited data demonstrating long-term outcomes within a large consecutive series of patients. METHODS: Retrospective review of a prospective database of breast cancer patients at our institution was performed. The initial mapping of 1,530 patients with invasive breast cancer who demonstrated a negative sentinel node biopsy and no axillary dissection between January 1995 and June 2003 were collated and reviewed to achieve a long-term follow-up. These 1,530 patients were reviewed for follow-up time, local recurrences, distant metastases, and survival. RESULTS: 1,530 consecutively mapped invasive breast cancer patients had a negative SLN biopsy and no ALND. The mean invasive tumor size was 1.40 cm. Of 1,530 patients, 73% (1,121) underwent lumpectomy and 27% (409) underwent mastectomy. Mean follow-up was 4.92 years (range 0-12.0 years). There have been 4 (0.26%) patients presenting with local axillary recurrences, 54 (3.53%) patients presenting with local recurrences in the ipsilateral breast/chest wall, and 24 (1.57%) presenting with distant metastases. CONCLUSION: These data confirm that SLN biopsy is an effective and safe alternative to ALND for detection of nodal metastases in patients with invasive breast cancer and should be used as the standard tool for nodal staging. PMID- 19777183 TI - Can axillary lymph node dissection be safely omitted for early-stage breast cancer patients with sentinel lymph node micrometastasis? PMID- 19777182 TI - Influence of laparoscopic gastrectomy on the detection rate of free gastric cancer cells in the peritoneal cavity. AB - BACKGROUND: Whether laparoscopic gastrectomy affects the number of gastric cancer cells exfoliated from the cancer-invaded serosa remains unclear. This study aimed to compare the detection rate of free gastric cancer cells in the peritoneal cavity during laparoscopic and open gastrectomy. METHODS: Intraoperative peritoneal washings were collected from 83 gastric cancer patients undergoing laparoscopic gastrectomy and 81 patients undergoing open surgery. Hematoxylin and eosin (H&E) staining and real-time reverse-transcription polymerase chain reaction (RT-PCR) were used to examine the free cancer cells. RESULTS: The postoperative positive rates of free cancer cells detected by cytological and real-time RT-PCR were 39.76 and 43.20% in the laparoscopic and open groups, respectively. Depth of tumor invasion, area of invaded serosa, regional lymph node involvement, and higher pathological staging were significantly associated with presence of free cancer cells. CONCLUSION: The laparoscopic techniques used in gastric cancer surgery did not increase the detection rate of free cancer cells in the peritoneal cavity compared with conventional techniques. PMID- 19777184 TI - Outcome of low-volume surgery for esophageal cancer in a high-volume referral center. AB - BACKGROUND: There is a known inverse relationship between the number of esophagectomies and in-hospital mortality. Our institute is a tertiary referral center with a high caseload of esophageal cancer patients, but with a low annual volume of esophagectomies. The objective of our study was to evaluate the results of esophageal cancer surgery in our institute and to compare these results with published data from high-surgical-volume institutions. METHODS: Between 1995 and 2007, 1,499 patients with esophageal cancer were referred: for a second opinion only (n = 568), following earlier treatment (n = 103), for palliative treatment (n = 665) or for potentially curative treatment (local endoscopic therapy n = 5, definitive chemoradiotherapy n = 71, or surgery n = 87). The surgically treated patients were studied in detail, and compared with patients treated in high surgical-volume hospitals. RESULTS: Surgery consisted of a transhiatal (n = 71) or transthoracic (n = 12) esophagectomy, or exploration only (n = 4). Fifty-six (64%) patients received neoadjuvant treatment. A microscopic radical resection was achieved in 96%. Pathologic complete response rate was 25%. Forty-four (53%) patients had a complicated postoperative course, and one (1%) patient died. At a median postoperative follow-up of 30 (1-149) months, 1- and 3-year overall survival rates were 89% and 60%, respectively. No major differences were observed between our results and those presented in six large study cohorts with high operative volumes. CONCLUSIONS: Outcome of low-volume esophageal surgery can be comparable to published high-surgical-volume results. More relevant factors other than hospital volume alone should be taken into account to improve outcome of esophageal cancer surgery. PMID- 19777185 TI - Association analysis of Wnt pathway genes on prostate-specific antigen recurrence after radical prostatectomy. AB - BACKGROUND: Approximately one-third of prostate cancer (PCa) patients show biochemical failure after radical prostatectomy (RP) and are prone to develop metastasis with significant mortality. Although aberrant Wnt/beta-catenin (CTNNB1) signaling has been observed in numerous types of human cancers, including PCa, to our knowledge there is currently no information on the role of Wnt signaling gene polymorphisms in PCa. METHODS: We comprehensively studied the contribution of genetic variations in CTNNB1 and adenomatous polyposis coli (APC), one of the key genes encoding the CTNNB1 destruction complex, to PCa risk and prognosis after RP using a hospital-based case-control study. We selected and genotyped 13 tagged single-nucleotide polymorphisms (tSNP) to predict common variants across entire APC and CTNNB1 genes in 307 patients with clinically localized PCa who received RP and 371 unaffected controls. RESULTS: Four tSNPs (rs3846716, rs2431238, rs41115, and rs565453) and a specific haplotype (GTAAGA) in the APC tumor suppressor gene were associated with a 0.57- to 0.71-fold lower risk of localized PCa. The association of tSNPs with prostate-specific antigen (PSA) recurrence in PCa patients was then analyzed by Kaplan-Meier analysis and Cox regression model. Interestingly, we found that the APC rs3846716 GA/AA genotypes were also significantly associated with poorer PSA-free survival (log rank test, P = 0.037) compared with the GG genotype. CONCLUSIONS: This is the first report documenting the potential prognostic role of the APC rs3846716 GA/AA genotype on PSA recurrence after RP. PMID- 19777186 TI - Intraoperative assessment of sentinel lymph nodes after neoadjuvant chemotherapy in patients with breast cancer. AB - BACKGROUND: Sentinel lymph node (SLN) biopsy has been shown to be both accurate and feasible for women who receive neoadjuvant chemotherapy (NAC). This study was designed to evaluate the ability of intraoperative assessment to predict metastasis in the sentinel node after NAC and to compare it with patients not treated with NAC. METHODS: Thirty-seven patients with invasive breast cancer and SLN biopsy after NAC and 461 patients with invasive breast cancer not treated with NAC were included in the study. The SLN was identified by the gamma probe and sent to pathology for frozen (FS) and H&E paraffin-sections. If the SLN was negative by H&E paraffin-sections, then immunohistochemistry was performed. RESULTS: The sensitivity of FS in the NAC group ranged from 78.5% for micro and isolated tumor cells to 100% for macrometastasis. The sensitivity of FS in the non-NAC group ranged from 82% for micro and isolated tumor cells to 97.4% for macrometastasis. There were no statistically differences between the sensitivities of FS in the two groups. Nine (64.2%) of the 14 patients in the NAC group with metastasis to the SLN had other non-SLN metastasis. CONCLUSIONS: After NAC, FS is an effective method for detecting macrometastasis in the SLN. As in the adjuvant setting, the sensitivity of FS is lower for SLN micro and sub micrometastasis. Intraoperative FS of the SLN after NAC is indicated to avoid a second surgery because 60% of patients with a positive SLN will have additional positive axillary nodes. PMID- 19777187 TI - Ambulatory intercostal drainage for the management of malignant pleural effusion: a single center experience. AB - BACKGROUND: Malignant pleural effusions are common and can be difficult to manage. We have reviewed our use of ambulatory drains (Pleurex drains) in this regard with particular reference to hospital stay, duration of drainage, and incidence of complications. MATERIALS AND METHODS: Of 125 patients with malignant pleural effusion with trapped lung or failed previous pleurodesis who underwent insertion of ambulatory pleural drain, 41 patients were under local anesthesia and 84 patients were under general anesthesia. Mean age was 66.5 years with male:female = 80:45. Data were collected retrospectively from the clinical notes, and the family doctors' clinics were contacted to enquire about the patients' survival. RESULTS: When data collection concluded, 48 patients (38.4%) had died, giving mean survival following drain insertion of 84.1 days. There were no in hospital deaths related to the procedure. One procedure was converted to a mini thoracotomy to control bleeding from a lung tear. Mean duration of catheter placement was 87.01 days (5-434). Video-assisted thoracoscopic surgery was used in 77 patients (61.6%), and Seldinger's technique was used in 48 patients (38.4%). Mesothelioma was the most common malignant cause. Minor complications were encountered in 15 patients (12%), and they were managed as outpatients. CONCLUSION: The use of ambulatory pleural catheters for managing malignant pleural effusion is a safe and effective strategy. It has only minor complications that are related to prolonged drainage. We feel that this strategy should be considered the first choice option for these patients. PMID- 19777188 TI - Nipple-sparing mastectomy: overcoming oncological outcomes challenges. PMID- 19777189 TI - CD98 expression is associated with poor prognosis in resected non-small-cell lung cancer with lymph node metastases. AB - BACKGROUND: The purpose of this study was to evaluate the prognostic value of L type amino acid transporter 1 (LAT1) and 4F2 heavy chain (CD98) expression in resectable non-small-cell lung cancer (NSCLC) patients with N1 and N2 nodal involvement. METHODS: A total of 220 consecutive patients were retrospectively reviewed. Immunohistochemical expression of LAT1, CD98, Ki-67 labeling index, vascular endothelial growth factor (VEGF), and microvessel density (MVD) was correlated with clinical features and prognosis of patients after complete resection of the tumor. RESULTS: Positive expression of LAT1 and CD98 was recognized in 60% (132/220) and 47% (103/220), respectively (P = 0.021). A positive rate of LAT1 expression was significantly higher in squamous cell carcinoma (SQC) (91%; 65/71) and large cell carcinoma (LCC) (82%; 9/11) than in adenocarcinoma (AC) (42%; 58/138). Moreover, a positive rate of CD98 expression was also significantly higher in SQC (76%; 54/71) and LCC (73%; 8/11) than in AC (30%; 42/138). LAT1 expression was significantly correlated with CD98, Ki-67 labeling index, VEGF, and MVD. The 5-year survival rates of LAT1-positive and LAT1-negative patients and CD98-positive and CD98-negative patients, were 43% and 48% (P = 0.1043), respectively and 39% and 50% (P = 0.0239), respectively. Multivariate analysis confirmed that positive expression of CD98 was an independent factor for predicting a poor prognosis. CONCLUSIONS: In our limited series, CD98 is a pathological factor that predicts prognosis in resectable adenocarcinoma patients with N2 disease. PMID- 19777190 TI - Survival data justifies resection for pancreatic metastases. AB - BACKGROUND: Pancreatic metastases are uncommon and little is known about the oncologic outcome after resection or prognostic parameters. This study was designed to evaluate perioperative and follow-up results after resection for pancreatic metastases and to define prognostic factors. METHODS: From a prospective database, all consecutive resections performed at our institution for pancreatic metastases between October 2001 and July 2008 were identified. Clinicopathological details, perioperative, and follow-up results were analyzed. Uni- and multivariate analysis were performed to identify parameters associated with overall and disease-free survival. RESULTS: Forty-four resections were performed for pancreatic metastases. Primary tumors included 31 (70%) renal cell carcinomas (RCC) and 13 other primary tumors. Morbidity was 33% and mortality 4.4%. Pancreatic metastases occurred after a median interval of 6.9 years after resection of the primary tumor. Twenty-five patients (57%) had additional extrapancreatic disease. With a median follow-up of 32.1 months, overall 3- and 5 year survivals were 70.2% and 56.8%, disease-free 3- and 5-year survivals were 37.2% and 33%, respectively. Patients with isolated pancreatic metastases had an overall 3- and 5-year survival of 85.6% and 74.9%. Additional extrapancreatic disease, a disease-free interval of less than 36 months, and non-RCC entity were associated with shorter overall survival. Previous recurrence, non-RCC primary tumors, and a disease-free interval of less than 36 months were associated with shorter disease-free survival. CONCLUSIONS: Resection for pancreatic metastases can be performed safely and with good follow-up results and can be recommended as part of an interdisciplinary treatment. Especially in patients with isolated pancreatic metastases, long-term survival can be expected. PMID- 19777191 TI - Does chemoradiotherapy improve outcomes for surgically resected adenocarcinoma of the stomach or esophagus? AB - BACKGROUND: To use a population-based registry to evaluate the effect of chemotherapy or radiation on survival for patients undergoing curative-intent surgery for adenocarcinoma of the esophagus or stomach. METHODS: A linked data set between the Florida Cancer Data System and the Florida Agency for Health Care Administration from 1998 to 2003 was queried. RESULTS: Overall, 3,378 patients underwent surgical extirpation with curative intent, 636 patients had esophageal adenocarcinoma (EAC), and 2,742 patients had gastric adenocarcinoma (GAC). Outcomes were adjusted for patient comorbidities and hospital teaching status. Overall, no benefit was observed for adjuvant therapies for EAC patients. A small improvement in survival was observed with adjuvant therapies for GAC. For localized EAC or GAC there was no additional survival benefit associated with adjuvant therapies. For patients with regional EAC, chemotherapy (20.0 vs. 13.0 months, P < .001) and radiation (18.6 vs. 13.5 months, P = .007) were associated with a statistically significant survival benefit. In multivariate analysis, independent predictors of improved survival for regional EAC include chemotherapy (hazard ratio [HR] .535, P < .001) and radiotherapy (HR .656, P = .01). For GAC, patients with regional disease showed an improved median survival with chemotherapy (21.1 vs. 11.2 months, P < .001) and radiotherapy (22.6 vs. 12.3 months, P < .001). In multivariate analysis, independent predictors of improved survival for regional GAC include chemotherapy (HR .629, P < .001) and radiation (HR .603, P < .001). CONCLUSIONS: Patients with regional adenocarcinoma of the esophagus or stomach, but not those with localized disease, derive a statistically significant survival benefit from the addition of chemotherapy and radiation to surgical resection. PMID- 19777192 TI - Liver resection for metastatic melanoma with postoperative tumor-infiltrating lymphocyte therapy. AB - BACKGROUND: Patients with metastatic melanoma to the liver (MML) have a median survival of 4 to 6 months. This study evaluated patients who underwent liver resection with intent to receive postoperative tumor-infiltrating lymphocyte (TIL) therapy. METHODS: Retrospective analysis of a prospective database identified patients with MML who underwent liver resection from 1980 to 2008. RESULTS: A total of 539 patients had MML, and 39% (204 of 539) had tumor collected for TIL. A total of 17% (35 of 204) underwent liver resection for TIL. The 3-year overall survival was 53%. Lack of extrahepatic disease (P = .026), negative margin (P = .056), and single hepatic metastasis (P = .04) predicted survival after univariate analysis. Only lack of extrahepatic disease remained a significant predictor of survival after multivariate analysis (P = .043). A total of 31% (11 of 35) underwent complete resection without TIL, and 69% (24 of 35) underwent resection with synchronous intrahepatic and extrahepatic disease with intent to receive TIL. For 9 of 11 patients (2 of 11 excluded for gene therapy), 3-year survival was 80%. A total of 4 (44%) of 9 experienced recurrence, with a median disease-free survival of 1.2 years. For 24 patients (69%) with residual disease, 3-year survival was 51% (2 of 24 excluded for gene therapy). A total of 63% (15 of 24) received postoperative TIL (3-year survival 65%), and 29% (7 of 24) did not. A total of 40% (6 of 15) had disease that partially responded to TIL; the disease of 67% (4 of 6) had not progressed at median follow-up of 55 months (range, 42-197+ months). The seven patients who did not receive TIL had a median survival of 4.6 months. CONCLUSIONS: Resection of MML with TIL should be considered because it can result in prolonged survival in a highly selected group of patients. PMID- 19777193 TI - Follow-up strategy after curative resection of gastric cancer: a nationwide survey in Korea. AB - BACKGROUND: To date, guidelines for follow-up after curative resection in patients with gastric cancer have not been reported. Thus, most centers have managed the process according to institution-specific protocols. We investigated current follow-up practices after curative resection of gastric cancer using a nationwide survey in Korea, where gastric cancer is epidemic. METHODS: From July to September 2007, questionnaires were sent out to 205 members of the Korean Gastric Cancer Association (KGCA). The questionnaire packet contained a covering letter, general information, and a questionnaire about follow-up schedules and methodologies. RESULTS: Forty-six percent (96/205) of the members of the KGCA returned the survey. The majority of responders indicated that patients with early gastric cancer were followed up every 6 months (64.4%) for the first year, every 12 months (47.9%) for the next 4 years, and every 12 months (68.8%) from the fifth year after surgery on. For patients with advanced gastric cancer, follow-up studies were carried out every 3 months (43.8%) for the first year, every 6 months for the next 4 years, and every 12 months (75.0%) from the fifth year onward. After surgery, most responders used computed tomography for imaging, carcinoembryonic antigen (CEA) and carbohydrate antigen (CA)19-9 as tumor markers, and serum iron among follow-up measures. CONCLUSIONS: Clinicians have a variety of approaches regarding the extent of follow-up and methodologies used after curative resection for gastric cancer. Therefore, a multicenter randomized trial will be needed to compare routine follow-up with intensive schedules. Our results could facilitate the design of such studies. PMID- 19777194 TI - Treatment strategy of papillary thyroid carcinoma in children and adolescents: clinical significance of the initial nodal manifestation. AB - BACKGROUND: Risk factors and treatment strategy in younger patients with papillary thyroid carcinoma are still controversial. METHODS: We reviewed 120 consecutive papillary thyroid carcinoma patients younger than 20 years who underwent initial surgery between 1977 and 2004 (14 male and 106 female subjects; mean age, 16.3 years; mean follow-up, 11.6 years). Outcomes were evaluated initially, and risk factors for disease-free survival (DFS) were analyzed statistically. Cox proportional multivariate analysis revealed that initial nodal manifestation (P < .001, hazard ratio 2.97) was the most statistically significant risk factor for DFS. The outcomes were then compared between four subgroups on the basis of the initial nodal manifestation and node dissection: 17 patients in group A (no lymphadenopathy, no or only prophylactic central dissection), 30 patients in group B (no lymphadenopathy, prophylactic modified neck dissection, MND), 46 patients in group C (nonpalpable lymphadenopathy detected by radiological or operative findings, therapeutic MND), and 27 patients in group D (palpable lymphadenopathy, therapeutic MND). RESULTS: Subtotal/total thyroidectomy and radioactive iodine therapy were performed for 47.1 and 0% in group A, 33.3 and 0% in group B, 43.4 and 10.9% in group C, and 85.1 and 48.1% in group D, respectively. In groups A, B, C, and D, 0%, 3.3%, 28.3%, and 48.1% developed recurrence, respectively (P < .001). DFS Kaplan-Meier curves differed significantly among the four subgroups (P < .0005). CONCLUSIONS: Initial nodal manifestation is useful to predict DFS in younger papillary thyroid carcinoma patients. Our findings will be beneficial to determine the treatment strategy. Conservative therapy is considered acceptable for patients without risk factors. PMID- 19777195 TI - Prognostic significance of lymph node metastases in pancreatic head cancer treated with extended lymphadenectomy: not just a matter of numbers. AB - BACKGROUND: The prognostic significance of variables related to nodal involvement (node status, number of disease-positive nodes [posNn], node ratio [Nr], and site of nodal metastases) in patients with resected pancreatic head cancer remains poorly defined. METHODS: Clinical, operative, and pathologic data, including indexes of the burden and extent of nodal involvement, were analyzed in a consecutive series of 77 patients who underwent resection with extended lymphadenectomy for adenocarcinoma of the pancreatic head. RESULTS: Fifty-nine patients (77%) were found to have lymph node (LN) metastases. Median LN count, posNn, and Nr were 28 (10-54), 4 (1-29), and 14% (2%-55%), respectively. Twenty six patients (44% of N1) had metastases limited to node level (NL) 1 (i.e., peripancreatic nodes); metastases up to NL2 (nodes along main arteries and hepatic hilum) and NL3 (preaortic nodes) were found in 21 (36%) and 12 (20%) patients, respectively. Interestingly, survival of patients with positive LN limited to NL1 was similar to that of node-negative patients (P = 0.407). posNn, Nr, and NL were all significant predictors of survival (P < 0.015). posNn and Nr proved to be an accurate proxy of NL involvement. The best cutoff of posNn was 2 and of and Nr was 10%. CONCLUSIONS: The level of nodal metastatic spread is a statistically significant prognostic factor in cancer of the pancreatic head. Both posNn and Nr are accurate proxy of NL and may improve patients' risk stratification. PMID- 19777197 TI - [Chronic inflammatory intestinal diseases. Pathophysiology and therapy]. AB - The pathogenesis and therapy of chronic inflammatory intestinal diseases are characterized by an obvious discrepancy. There is extensive agreement that the pathogenesis is substantially based on a disruption of the barrier of the intestinal mucous membrane against luminal bacteria. This has been demonstrated in recent years by evidence from various disciplines, in particular from genetics, microbiology, morphology and innate immunology. However, there is also the evidence-based therapy which, as in the past, is aimed against the effectors of the adaptive immune system. In this case the therapy with biologicals is more aggressive and takes the risk of a series of undesired side-effects. This dichotomy of pathological knowledge and therapeutic innovation is not only medically unsatisfactory but also makes it difficult to present a consistent picture of these symptoms. Despite this an attempt will be made to bridge these inconsistencies and to demonstrate possible future developments which will lead to a final causal therapy. An extended version of this article appears in our newly published book "Colitis ulcerosa und Morbus Crohn". PMID- 19777196 TI - Increase in gamma-globin mRNA content in human erythroid cells treated with angelicin analogs. AB - The aim of the present study was to identify molecular analogs of angelicin (ANG) able to increase erythroid differentiation of K562 cells and expression of gamma globin genes in human erythroid precursor cells, with low effects on apoptosis. ANG-like molecules are well-known photosensitizers largely used for their antiproliferative activity in the treatment of different skin diseases (i.e., psoriasis, vitiligo, eczema, and mycosis fungoides). To verify the activity of these derivatives, we employed three experimental cell systems: (1) the human leukemic K562 cell line, (2) K562 cell clones stably transfected with a pCCL construct carrying green-EGFP under the gamma-globin gene promoter, and (3) the two-phase liquid culture of human erythroid progenitors isolated from normal donors and beta-thalassemia patients. The results of our study suggest that trimethyl ANG is a powerful inducer of erythroid differentiation, compared with known inducers, such as ANG, cytosine arabinoside, mithramycin, and cisplatin. These data could have practical relevance, because pharmacologically mediated regulation of human gamma-globin gene expression, with the consequent induction of fetal hemoglobin, is considered a potential therapeutic approach in hematological disorders including beta-thalassemia and sickle cell anemia. PMID- 19777198 TI - [University benchmarking. A current status analysis]. AB - Lump sum reimbursement and the resulting concentration of medical treatment in maximum care clinics have led to substantial increase in economic pressure on university hospitals. Nearly all hospitals have introduced business ratios to economically judge each department. In order to evaluate the validity and comparability the business ratios of seven university traumatology departments were evaluated. Structural data as well as cost calculation results in different cost groups were evaluated. Major differences could be identified despite the fact that the cost calculations were all based on the same method (InEK method). In particular the costs for distribution to other medical specialties such as radiology or anesthesiology differed widely. Costs for infrastructure also showed a great variation. Differences in efficiency cannot be the only cause for these discrepancies and lacking standardization of cost calculation methodology is also another major cause. All the business ratios analyzed must be looked at critically and unless a thoroughly standardized methodology of cost calculation is implemented, cost ratios will have a limited potential for hospital benchmarking. PMID- 19777199 TI - [Medical care reality in trauma surgical clinics in Germany. A survey of the professional committee of the German Society for Trauma Surgery]. AB - Due to revised conditions of medical care in Germany, in particular the introduction of the newly designated specialist for orthopaedics and trauma surgery, the working conditions in trauma surgical clinics in Germany has changed. In May 2008 the professional committee of the German Trauma Society conducted a survey at the 729 trauma surgical clinics and departments in order to establish the true level of care at these particular sites. The results of the 90,000 variables presented in the following article, reflect the changes in trauma care as well as in the medical care structures and emphasize the increased work load. In particular the lack of qualified candidates underlines the main explanation for vacant posts and is also evaluated in this article. PMID- 19777200 TI - Release from bats: genetic distance and sensoribehavioural regression in the Pacific field cricket, Teleogryllus oceanicus. AB - The auditory thresholds of the AN2 interneuron and the behavioural thresholds of the anti-bat flight-steering responses that this cell evokes are less sensitive in female Pacific field crickets that live where bats have never existed (Moorea) compared with individuals subjected to intense levels of bat predation (Australia). In contrast, the sensitivity of the auditory interneuron, ON1 which participates in the processing of both social signals and bat calls, and the thresholds for flight orientation to a model of the calling song of male crickets show few differences between the two populations. Genetic analyses confirm that the two populations are significantly distinct, and we conclude that the absence of bats has caused partial regression in the nervous control of a defensive behaviour in this insect. This study represents the first examination of natural evolutionary regression in the neural basis of a behaviour along a selection gradient within a single species. PMID- 19777201 TI - [Options for pain therapy of urologic chronic pelvic pain syndrome (UCPPS)]. AB - Approximately 10% of the population suffers from chronic pain in the urogenital region. The multidimensionality of this chronic pain syndrome must be taken into consideration.The cause of urologic chronic pelvic pain syndrome (UCPPS) is mostly unclear. Treatment of these patients should be carried out in specialized institutions. PMID- 19777202 TI - [Chronic pelvic pain in women from a gynecologic viewpoint]. AB - Chronic pelvic pain in women is a difficult subject that challenges the gynecologist in practice. Possible gynecological causes are endometriosis, adhesions/PID, pelvic varicosis and ovarian retention syndrome/ovarian remnant syndrome. Other somatic causes are irritable bowel syndrome, bladder pain syndrome and fibromyalgia.Confirmed psychosocial factors contributing to chronic pelvic pain are comorbidity with anxiety disorders, substance abuse or depression, but the influence of social factors is less certain. The connection to physical and sexual abuse also remains unclear. Important diagnostic steps are studying the patient's history, a gynecological examination and laparoscopy. Multidisciplinary therapeutic approaches are helpful. Basic psychosomatic care and psychotherapy should be integrated into the therapeutic concept at an early stage of the disease. PMID- 19777203 TI - [Special pain conditions in urology. Summary, literature review and suggestions]. AB - The diagnosis of acute or chronic pain syndromes of the urogenital system can be verified and successfully treated by exact exploration of the patients medical history, the physical examination and a few image-guided or laboratory analyses Pain conditions which remain of unknown etiology even after extensive investigations are difficult to treat by the urologist alone. In cases where no causally determined morphological changes can be found or the alteration is disproportionate to the discomfort sensed by the patient, a multidisciplinary therapy strategy offers an approach to find a solution. PMID- 19777204 TI - ["Work hardening" for chonic back pain. An integral component of multimodal therapy programs]. AB - Work hardening is aimed at a reestablishment of the potentials needed in occupational everyday life. Fundamental motor abilities, such as strength, stability, flexibility and persistence, are restored and merged into the everyday life so that psychological contents, such as fear avoidance behavior will be positively affected. The design of work hardening is interdisciplinary in the sense of a holistic approach to back pain. Handling the pain under load requires sophisticated treatment and the training demands a high degree of individual design. A trusting and mutual agreement between therapist and patient is essential. Work hardening represents an important part of the therapy of chronic back pain and greatly supports regaining confidence in the physical efficiency and the ability to control the body. PMID- 19777205 TI - [Orthopedic specialists in an interdisciplinary setting. Multimodal therapy for chronic back pain]. AB - Chronic back pain compels a new therapeutic strategy. A therapeutic team setting and consequent consideration of proven treatments are required. The orthopedic specialist should manage a cooperating team with a psychologist and a physiotherapist, and information should be continuously exchanged according to the criteria for interdisciplinary multimodal pain therapy. The team's therapeutic tasks should be determined and distributed according to the individual patient's problems. Questionably relevant - in particular, somatic oriented - diagnostic and therapeutic measures should be avoided. The team setting facilitates optimal task sharing and simultaneous professional application of the most effective therapy for chronic back pain: pharmaceutical therapy, including peridural infiltrations by the medical doctor; systematic and controlled increased load by the physiotherapist; and psychosocial assistance from the psychologist. PMID- 19777206 TI - Glucontrol, no control, or out of control? PMID- 19777207 TI - Early enteral nutrition, provided within 24 h of injury or intensive care unit admission, significantly reduces mortality in critically ill patients: a meta analysis of randomised controlled trials. AB - PURPOSE: To determine whether the provision of early standard enteral nutrition (EN) confers treatment benefits to critically ill patients. METHODS: Medline and EMBASE were searched. Hand citation review of retrieved guidelines and systematic reviews were undertaken, and academic and industry experts were contacted. Methodologically sound randomised controlled trials (RCTs) conducted in critically ill patient populations that compared the delivery of standard EN, provided within 24 h of intensive care unit (ICU) admission or injury, to standard care were included. The primary analysis was conducted on clinically meaningful patient-oriented outcomes. Secondary analyses considered vomiting/regurgitation, pneumonia, bacteraemia, sepsis and multiple organ dysfunction syndrome. Meta-analyses were conducted using the odds ratio (OR) metric and a fixed effects model. The impact of heterogeneity was assessed using the I (2) metric. RESULTS: Six RCTs with 234 participants were analysed. The provision of early EN was associated with a significant reduction in mortality [OR = 0.34, 95% confidence interval (CI) 0.14-0.85] and pneumonia (OR = 0.31, 95% CI 0.12-0.78). There were no other significant differences in outcomes. A sensitivity analysis and a simulation exercise confirmed the presence of a mortality reduction. CONCLUSION: Although the detection of a statistically significant reduction in mortality is promising, overall trial quality was low, trial size was small, and the findings may be restricted to the patient groups enrolled into included trials. The results of this meta-analysis should be confirmed by the conduct of a large multi-centre trial enrolling diverse critically ill patient groups. PMID- 19777208 TI - Non-adherence to guidelines: an avoidable cause of failure of empirical antimicrobial therapy in the presence of difficult-to-treat bacteria. AB - PURPOSE: To identify the risk factors of ventilator-associated pneumonia (VAP) due to difficult-to-treat (DTT) bacteria (i.e., Pseudomonas aeruginosa, Acinetobacter baumannii and oxacillin-resistant Staphylococcus aureus), and to assess the rate and the causes of inappropriateness of empirical antimicrobial therapy. METHODS: In an intensive care unit of a university hospital, patients with VAP were empirically treated with antibiotics without activity against DTT bacteria if the patients had no prior hospitalization or prior administration of antibiotics, according to local guidelines. RESULTS: Overall, the empirical antimicrobial therapy was appropriate in 190 (87%) out of 218 patients with VAP. Fifty (23%) patients developed problems due to DTT bacteria. The risk factors for VAP due to DTT bacteria were shock state, prior antimicrobial therapy, prior stay in long-term care facilities and late-onset VAP. Empirical antimicrobial therapy was inappropriate in 20 (40%) patients with VAP due to DTT bacteria and 8 (5%) patients with VAP due to non-DTT (P = 0.001). Guidelines violations (nine patients), bacteria not included in antibiotic spectrum (eight patients) and bacterial resistance (three patients) were the causes of inappropriateness in case of DTT bacteria. CONCLUSION: Despite the abundant information for the treatment of VAP and the establishment of guidelines, too many patients with DTT bacteria received inappropriate antimicrobial therapy. Since 45% of the cases are related to non-adherence to the local protocol, there is room for improvement by implementing educational programs. Also, since DTT bacteria are found in 23% of late-onset VAP, empirical antibiotic treatment should be directed against these pathogens. PMID- 19777209 TI - Response to different oxidants of Saccharomyces cerevisiae ure2Delta mutant. AB - Growth of Saccharomyces cerevisiae ure2Delta mutant strain was investigated in the presence of diverse oxidant compounds. The inability of the strain to grow on a medium supplemented with H(2)O(2) was confirmed and a relationship between diminishing levels of glutathione (GSH) and peroxide sensitivity was established. Data for the lack of significant effect of URE2 disruption on the cellular growth in the presence of paraquat and menadione were obtained. The possible role of Ure2p in acquiring sensitivity to oxidative stress by means of its regulatory role in the GATA signal transduction pathway was discussed. It was suggested that the susceptibility of ure2Delta mutant to the exogenous hydrogen peroxide can result from increased GSH degradation due to the deregulated localization of the gamma-glutamyl transpeptidase activating factors Gln3/Gat1. The important role of Ure2p in in vivo glutathione-mediated reactive oxygen species (ROS) scavenging was shown by measuring the activity of antioxidant enzymes glutathione peroxidase, superoxide dismutase (SOD) and catalase in an URE2 disrupted strain. A time-dependent increase in SOD and catalase activity was observed. More importantly, it was shown that the ure2 mutation could cause significant disturbance in cellular oxidant balance and increased ROS level. PMID- 19777210 TI - Toxicology at the interface of basic, applied, and clinical sciences. PMID- 19777211 TI - The human cardiac K2P3.1 (TASK-1) potassium leak channel is a molecular target for the class III antiarrhythmic drug amiodarone. AB - Two-pore-domain (K(2P)) potassium channels mediate background potassium currents, stabilizing resting membrane potential and expediting action potential repolarization. In the heart, K(2P)3.1 (TASK-1) channels are implicated in the cardiac plateau current, I ( KP ). Class III antiarrhythmic drugs target cardiac K(+) currents, resulting in action potential prolongation and suppression of atrial and ventricular arrhythmias. The objective of this study was to investigate acute effects of the class III antiarrhythmic drug amiodarone on human K(2P)3.1 channels. Potassium currents were recorded from Xenopus oocytes using the two-microelectrode voltage clamp technique. Amiodarone produced concentration-dependent inhibition of hK(2P)3.1 currents (IC(50) = 0.40 microM) with maximum current reduction of 58.1%. Open rectification properties that are characteristic to hK(2P)3.1 currents were not altered by amiodarone. Channels were blocked in open and closed states in reverse frequency-dependent manner. hK(2P)3.1 channel inhibition was voltage-independent at voltages between -40 and +60 mV. Modulation of protein kinase C activity by amiodarone does not contribute to hK(2P)3.1 current reduction, as pre-treatment with the protein kinase C inhibitor, staurosporine, did not affect amiodarone block. Amiodarone is an inhibitor of cardiac hK(2P)3.1 background channels. Amiodarone blockade of hK(2P)3.1 may cause prolongation of cardiac repolarization and action potential duration in patients with high individual plasma concentrations, possibly contributing to the antiarrhythmic efficacy of the class III drug. PMID- 19777212 TI - Tunicamycin induces resistance to camptothecin and etoposide in human hepatocellular carcinoma cells: role of cell-cycle arrest and GRP78. AB - Hepatocellular carcinoma is chemoresistant to many anticancer drugs. Tunicamycin, an N-glycosylation inhibitor, causes unfolded protein response and is widely used as pharmacological inducer of endoplasmic reticulum stress. In this study, several designs were used to investigate the resistance mechanism to camptothecin and etoposide in hepatocellular carcinoma Hep3B cells. Tunicamycin significantly inhibited apoptosis induced by camptothecin or etoposide. Tunicamycin neither modified the topoisomerase levels nor inhibited the ATM activation caused by camptothecin and etoposide. The data suggest that tunicamycin-induced resistance may result from the downstream events of drug-trapped topoisomerase-DNA complexes and DNA double-strand breaks. Camptothecin and etoposide caused an increase of protein expression of several cell-cycle regulators and induced the cleavage of Bcl-2 family of proteins. These intracellular molecular events were abolished by tunicamycin. A design of postaddition of tunicamycin demonstrated that G1 checkpoint arrest contributed to the resistance mechanism. Curcumin, another G1 arrest-inducing agent in this study, was able to induce a similar resistant effect. Furthermore, the cells transfected with GRP78 siRNA were partly resistant to tunicamycin-induced apoptosis but not the inhibitory effect on cell-cycle regulators indicating that GRP78 and G1 arrest are two independent factors to tunicamycin-induced resistance mechanism. In conclusion, the data suggest that tunicamycin induces the resistance to topoisomerase inhibitors through GRP78 up regulation and G1 arrest of the cell cycle. The findings also prompt the deliberation that the resistance can be caused during combined administration of chemotherapeutic drugs and Chinese herbal medicines, which induce endoplasmic reticulum stress and/or cell-cycle arrest in cancer cells. PMID- 19777213 TI - Determining the subjective and physiological effects of BZP on human females. AB - BACKGROUND: "Party pills" containing benzylpiperazine (BZP) used to be widely and legally available as recreational drugs in New Zealand. There are only two published trials on human subjects (1973), which suggested that 100 mg of BZP produced subjective and physiological effects similar to 10 mg of dexamphetamine. The purpose of this study is to further investigate the subjective and physiological responses to BZP in females. METHODS/STUDY DESIGN: In a randomised, double blind, placebo-controlled study, the subjective and physiological effects of BZP were investigated in 27 healthy, right-handed non-smoking females (mean age 22 +/- 3 years). Two groups were tested before and approximately 120 minutes after administration of a single oral dose of either 200 mg BZP (n = 14) or placebo (n = 13). Participants were required to comment on the subjective effects of BZP using three rating scales-the Addiction Centre for Research Inventory, the Profile of Mood States and the Visual Analogue Scale. Participants' blood pressure, heart rate and temperature were also measured. RESULTS/FINDINGS: Statistical analysis using a split-plot analysis of variance and t tests revealed that BZP significantly increases blood pressure and heart rate (p < 0.05) Likewise, the subjective reports revealed that BZP has significant stimulant effects, increases euphoria and dysphoria and increases sociability and drug liking (p < 0.05). DISCUSSION/INTERPRETATION: Physiological and subjective data reflected a clear similarity between the effects of BZP and those of other commonly known stimulants such as amphetamine and 3,4 methylenedioxymethamphetamine. PMID- 19777214 TI - A comparison of the effects of caffeine following abstinence and normal caffeine use. AB - RATIONALE: Caffeine typically produces positive effects on mood and performance. However, tolerance may develop following habitual use, and abrupt cessation can result in withdrawal symptoms, such as fatigue. This study investigated whether caffeine has a greater stimulant effect in a withdrawn state compared to a normal caffeinated state, among moderate daily caffeine consumers. MATERIALS AND METHODS: Using a within-subjects design, 17 caffeine consumers (mean +/- sd = 375 +/- 101 mg/day) ingested placebo or caffeine (250 mg) following 30-h of caffeine abstention or normal dietary caffeine use on four separate days. Self-reported mood and performance on choice reaction time, selective attention, and memory tasks were measured. RESULTS: Caffeine had a greater effect on mood and choice reaction time in the abstained state than in the normal caffeinated state, but caffeine improved selective attention and memory in both states. CONCLUSIONS: Although improvements in mood and reaction time may best explained as relief from withdrawal symptoms, other performance measures showed no evidence of withdrawal and were equally sensitive to an acute dose of caffeine in the normal caffeinated state. PMID- 19777215 TI - Response to, "Cognitive, psychomotor and subjective effects of sodium oxybate and triazolam in healthy volunteers," 2009; 206(1):141-154. PMID- 19777216 TI - Cocaine craving and use during daily life. AB - RATIONALE: Craving is often assumed to cause ongoing drug use and relapse and is a major focus of addiction research. However, its relationship to drug use has not been adequately documented. OBJECTIVES: The aim of this study was to investigate the relationship between craving and drug use in real time and in the daily living environments of drug users. METHODS: In a prospective, longitudinal, cohort design (ecological momentary assessment), 112 cocaine-abusing individuals in methadone maintenance treatment rated their craving and mood at random times (two to five times daily, prompted by electronic diaries) as they went about their everyday activities. They also initiated an electronic diary entry each time they used cocaine. Drug use was monitored by thrice-weekly urine testing. RESULTS: During periods of urine-verified cocaine use, ratings of cocaine craving increased across the day and were higher than during periods of urine-verified abstinence. During the 5 h prior to cocaine use, ratings of craving significantly increased. These patterns were not seen in ratings of heroin craving or mood (e.g., feeling happy or bored). CONCLUSIONS: Cocaine craving is tightly coupled to cocaine use in users' normal environments. Our findings provide previously unavailable support for a relationship that has been seriously questioned in some theoretical accounts. We discuss what steps will be needed to determine whether craving causes use. PMID- 19777217 TI - Liquid chromatography with complementary electrospray and inductively coupled plasma mass spectrometric detection of ferrocene-labelled peptides and proteins. AB - Succinimidylferrocenyl propionate (SFP) is introduced as labelling agent for amino functions in peptides and proteins. The resulting derivatives are characterised by considerably lower polarity compared with the native analytes and can thus be well separated by means of reversed phase liquid chromatography (RP-LC). The reaction products are characterised by electrospray ionisation mass spectrometry (ESI-MS) and inductively coupled plasma mass spectrometry (ICP-MS). A further advantage of the method is a simple and straightforward derivatisation protocol. Different basic and acidic model proteins as lysozyme, beta lactoglobulin A and insulin were derivatised using SFP. Furthermore, the first dual-labelling strategy of thiol and amino groups with ferrocene-based reagents is presented. Whereas the amino groups were derivatised with SFP, the thiol groups were functionalised by reaction with ferrocenecarboxylic acid(2 maleimidoyl)ethylamide. Again, LC/ESI-MS is a suitable tool to characterise the modified peptides and proteins. PMID- 19777218 TI - Sensitive fluorescent probes for determination of hydrogen peroxide and glucose based on enzyme-immobilized magnetite/silica nanoparticles. AB - Sensitive fluorescent probes for the determination of hydrogen peroxide and glucose were developed by immobilizing enzyme horseradish peroxidase (HRP) on Fe(3)O(4)/SiO(2) magnetic core-shell nanoparticles in the presence of glutaraldehyde. Besides its excellent catalytic activity, the immobilized enzyme could be easily and completely recovered by a magnetic separation, and the recovered HRP-immobilized Fe(3)O(4)/SiO(2) nanoparticles were able to be used repeatedly as catalysts without deactivation. The HRP-immobilized nanoparticles were able to activate hydrogen peroxide (H(2)O(2)), which oxidized non fluorescent 3-(4-hydroxyphenyl)propionic acid to a fluorescent product with an emission maximum at 409 nm. Under optimized conditions, a linear calibration curve was obtained over the H(2)O(2) concentrations ranging from 5.0 x 10(-9) to 1.0 x 10(-5) mol L(-1), with a detection limit of 2.1 x 10(-9) mol L(-1). By simultaneously using glucose oxidase and HRP-immobilized Fe(3)O(4)/SiO(2) nanoparticles, a sensitive and selective analytical method for the glucose detection was established. The fluorescence intensity of the product responded well linearly to glucose concentration in the range from 5.0 x 10(-8) to 5.0 x 10(-5) mol L(-1) with a detection limit of 1.8 x 10(-8) mol L(-1). The proposed method was successfully applied for the determination of glucose in human serum sample. PMID- 19777219 TI - An approach to the spectral simulation of infrared hollow waveguide gas sensors. AB - Optical simulations enable to model an entire chemical gas sensing platform based on hollow waveguides (HWGs) operating in the mid-infrared spectral regime using a three-dimensional representation of the sensor components and taking the spectral response to virtual analytes into account. Furthermore, a strategy for including the spectral response of dielectrically coated HWGs is demonstrated. Utilizing experimentally obtained spectroscopic data recorded at well-defined conditions, the complex refractive indices of selected target analytes (i.e., methane, butane, and isobutylene) have been derived based on a refined harmonic oscillator model. In turn, these parameters have enabled to directly assign the dielectric functions of these analytes to virtual objects representing the analyte within the modeled sensor setup. In a next step, spectroscopic sensor response functions have been simulated as absorbance spectra across selected wavelength regimes utilizing spectrally resolved ray-tracing techniques and have been compared to experimental data. PMID- 19777220 TI - Timing of conditioned eyeblink responses is impaired in children with attention deficit/hyperactivity disorder. AB - Structural changes of the cerebellum have been reported in several psychiatric diseases like schizophrenia, autism and attention-deficit/hyperactivity disorder (ADHD). Beside behavioral deficits children with ADHD often show slight motor abnormalities. Cerebellar malfunction may contribute. The cerebellum is a structure essential for motor coordination, various forms of motor learning and timing of motor responses. In the present study, eyeblink conditioning was applied to investigate learning and timing of motor responses both in children with ADHD and children with cerebellar lesions. Acquisition, timing and extinction of conditioned eyeblink responses were investigated in children with ADHD, children with chronic surgical cerebellar lesions and controls using a standard delay paradigm with two different interstimulus intervals. Timing of conditioned eyeblink responses was significantly impaired in children with ADHD in the long interstimulus interval condition. Also in children with cerebellar lesions conditioned responses (CR) tended to occur earlier than in controls. Incidences of CRs were significantly reduced in children with cerebellar lesions and tended to be less in children with ADHD than in controls. Extinction of the CRs was impaired in children with cerebellar lesions in both interstimulus interval conditions and in children with ADHD in the long interstimulus interval condition. Cerebellar malfunction may contribute to disordered eyeblink conditioning in ADHD. However, because CR abnormalities differed between ADHD and cerebellar subjects, dysfunction of non-cerebellar structures cannot be excluded. PMID- 19777223 TI - Pediatric salivary gland imaging. PMID- 19777224 TI - Post-traumatic osteolysis of the distal clavicle. PMID- 19777221 TI - BDNF signaling in the formation, maturation and plasticity of glutamatergic and GABAergic synapses. AB - In the past 15 years numerous reports provided strong evidence that brain-derived neurotrophic factor (BDNF) is one of the most important modulators of glutamatergic and GABAergic synapses. Remarkable progress regarding localization, kinetics, and molecular mechanisms of BDNF secretion has been achieved, and a large number of studies provided evidence that continuous extracellular supply of BDNF is important for the proper formation and functional maturation of glutamatergic and GABAergic synapses. BDNF can play a permissive role in shaping synaptic networks, making them more susceptible for the occurrence of plastic changes. In addition, BDNF appears to be also an instructive factor for activity dependent long-term synaptic plasticity. BDNF release just in response to synaptic stimulation might be a molecular trigger to convert high-frequency synaptic activity into long-term synaptic memories. This review attempts to summarize the current knowledge in synaptic secretion and synaptic action of BDNF, including both permissive and instructive effects of BDNF in synaptic plasticity. PMID- 19777226 TI - Biogas production: current state and perspectives. AB - Anaerobic digestion of energy crops, residues, and wastes is of increasing interest in order to reduce the greenhouse gas emissions and to facilitate a sustainable development of energy supply. Production of biogas provides a versatile carrier of renewable energy, as methane can be used for replacement of fossil fuels in both heat and power generation and as a vehicle fuel. For biogas production, various process types are applied which can be classified in wet and dry fermentation systems. Most often applied are wet digester systems using vertical stirred tank digester with different stirrer types dependent on the origin of the feedstock. Biogas is mainly utilized in engine-based combined heat and power plants, whereas microgas turbines and fuel cells are expensive alternatives which need further development work for reducing the costs and increasing their reliability. Gas upgrading and utilization as renewable vehicle fuel or injection into the natural gas grid is of increasing interest because the gas can be used in a more efficient way. The digestate from anaerobic fermentation is a valuable fertilizer due to the increased availability of nitrogen and the better short-term fertilization effect. Anaerobic treatment minimizes the survival of pathogens which is important for using the digested residue as fertilizer. This paper reviews the current state and perspectives of biogas production, including the biochemical parameters and feedstocks which influence the efficiency and reliability of the microbial conversion and gas yield. PMID- 19777227 TI - Strain improvement of Sporolactobacillus inulinus ATCC 15538 for acid tolerance and production of D-lactic acid by genome shuffling. AB - Improvement of acid tolerance and production of D-lactic acid by Sporolactobacillus inulinus ATCC 15538 was performed by using recursive protoplast fusion in a genome shuffling format. The starting population was generated by ultraviolet irradiation, diethyl sulfate mutagenesis, and pH gradient filter and then, subjected for the recursive protoplast fusion. The concentration of lysozyme, time, and temperature for enzyme treatment were optimized by response surface methodology based on the central composite design. Based on contour plots and variance analysis, the model predicted a maximum Y (multiply protoplasts formation ratio by protoplasts regeneration ratio), 60.4%, and the corresponding above used values were 7.75 mg/ml lysozyme, 1.59 h, and 38 degrees C. A pH-5-resistant recombinant, F3-4, was obtained after three rounds of genome shuffling and its production of D-lactic acid reached 93.4 g/l in a 5 L bioreactor, which was increased by 39.8% and 119% in comparison with that of UV generated strain and the original strain S. inulinus ATCC 15538, respectively. The subculture experiments indicated that F3-4 was genetically stable. PMID- 19777225 TI - Identification of novel MHC class I sequences in pig-tailed macaques by amplicon pyrosequencing and full-length cDNA cloning and sequencing. AB - Pig-tailed macaques (Macaca nemestrina) provide important animal models in biomedical research, but utility of this species for HIV and other disease pathogenesis research is limited by incomplete knowledge of major histocompatibility complex (MHC) class I genetics. Here, we describe comprehensive MHC class I genotyping of 24 pig-tailed macaques, using pyrosequencing to evaluate a 367- bp complementary DNA (cDNA)-PCR amplicon spanning the highly polymorphic peptide-binding region of MHC class I transcripts. We detected 29 previously described Mane transcripts, 90 novel class I sequences, and eight shared MHC class IB haplotypes. We used this genotyping data to inform full-length MHC class I cDNA allele discovery, characterizing 66 novel full-length transcripts. These new full-length sequences nearly triple the number of Mane-B cDNA sequences previously characterized. The comprehensive genotypes and full-length Mane transcripts described herein add value to pig tailed macaques as model organisms in biomedical research; furthermore, the coordinated method for MHC genotyping and allele discovery is extensible to other less well-characterized nonhuman primate species. PMID- 19777228 TI - Genes regulated by AoXlnR, the xylanolytic and cellulolytic transcriptional regulator, in Aspergillus oryzae. AB - XlnR is a Zn(II)2Cys6 transcriptional activator of xylanolytic and cellulolytic genes in Aspergillus. Overexpression of the aoxlnR gene in Aspergillus oryzae (A. oryzae xlnR gene) resulted in elevated xylanolytic and cellulolytic activities in the culture supernatant, in which nearly 40 secreted proteins were detected by two-dimensional electrophoresis. DNA microarray analysis to identify the transcriptional targets of AoXlnR led to the identification of 75 genes that showed more than fivefold increase in their expression in the AoXlnR overproducer than in the disruptant. Of these, 32 genes were predicted to encode a glycoside hydrolase, highlighting the biotechnological importance of AoXlnR in biomass degradation. The 75 genes included the genes previously identified as AoXlnR targets (xynF1, xynF3, xynG2, xylA, celA, celB, celC, and celD). Thirty-six genes were predicted to be extracellular, which was consistent with the number of proteins secreted, and 61 genes possessed putative XlnR-binding sites (5'-GGCTAA 3', 5'-GGCTAG-3', and 5'-GGCTGA-3') in their promoter regions. Functional annotation of the genes revealed that AoXlnR regulated the expression of hydrolytic genes for degradation of beta-1,4-xylan, arabinoxylan, cellulose, and xyloglucan and of catabolic genes for the conversion of D-xylose to xylulose-5 phosphate. In addition, genes encoding glucose-6-phosphate 1-dehydrogenase and L arabinitol-4- dehydrogenase involved in D-glucose and L-arabinose catabolism also appeared to be targets of AoXlnR. PMID- 19777229 TI - Precursor for biosynthesis of sugar moiety of doxorubicin depends on rhamnose biosynthetic pathway in Streptomyces peucetius ATCC 27952. AB - The doxorubicin biosynthetic gene cluster in Streptomyces peucetius ATCC 27952 contains a TDP-D-glucose 4,6-dehydratase gene, dnmM, that is putatively involved in the biosynthesis of daunosamine, but the gene contains a frameshift in the DNA sequence that would cause premature termination of translation. In pursuit of another TDP-D-glucose 4,6-dehydratase in S. peucetius, a homologue gene, rmbB, was found, whose deduced product exhibits high sequence similarity to a number of TDP-D-glucose 4,6-dehydratases. The gene was located within a putative rhamnose biosynthetic gene cluster at another locus in the genome. RmbB was verified to be a functional TDP-D-glucose 4,6-dehydratase by enzyme assay as it catalyzed the conversion of TDP-D-glucose into TDP-4-keto-6-deoxy-D-glucose. Inactivation of rmbB in the S. peucetius genome abolished the production of doxorubicin while complementation of the same gene in an rmbB knockout mutant restored the doxorubicin production. Hence, rmbB provides TDP-4-keto-6-deoxy-D-glucose as a nucleotide sugar precursor for the biosynthesis of doxorubicin. PMID- 19777230 TI - Increasing diterpene yield with a modular metabolic engineering system in E. coli: comparison of MEV and MEP isoprenoid precursor pathway engineering. AB - Engineering biosynthetic pathways in heterologous microbial host organisms offers an elegant approach to pathway elucidation via the incorporation of putative biosynthetic enzymes and characterization of resulting novel metabolites. Our previous work in Escherichia coli demonstrated the feasibility of a facile modular approach to engineering the production of labdane-related diterpene (20 carbon) natural products. However, yield was limited (<0.1 mg/L), presumably due to reliance on endogenous production of the isoprenoid precursors dimethylallyl diphosphate and isopentenyl diphosphate. Here, we report incorporation of either a heterologous mevalonate pathway (MEV) or enhancement of the endogenous methyl erythritol phosphate pathway (MEP) with our modular metabolic engineering system. With MEP pathway enhancement, it was found that pyruvate supplementation of rich media and simultaneous overexpression of three genes (idi, dxs, and dxr) resulted in the greatest increase in diterpene yield, indicating distributed metabolic control within this pathway. Incorporation of a heterologous MEV pathway in bioreactor grown cultures resulted in significantly higher yields than MEP pathway enhancement. We have established suitable growth conditions for diterpene production levels ranging from 10 to >100 mg/L of E. coli culture. These amounts are sufficient for nuclear magnetic resonance analyses, enabling characterization of enzymatic products and hence, pathway elucidation. Furthermore, these results represent an up to >1,000-fold improvement in diterpene production from our facile, modular platform, with MEP pathway enhancement offering a cost effective alternative with reasonable yield. Finally, we reiterate here that this modular approach is expandable and should be easily adaptable to the production of any terpenoid natural product. PMID- 19777231 TI - Osteotomy around young deformed knees: 38-year super-long-term follow-up to detect osteoarthritis. AB - Since 1969 corrective osteotomy has been performed at our institute in young patients (under 40 years) with bowlegs, knock knees and flexion or rotational deformities around the knee. Fifty-seven knees (29 left, 28 right) of 45 patients (19 boys, 26 girls) were followed-up for a period ranging from 30 to 38 years in seven patients with seven knees, from 20 to 29 years in nine patients with 11 knees, and from ten to 19 years in 29 patients with 39 knees. Supracondylar femoral osteotomy was performed on 12 knees (11 patients), high tibial osteotomy above the tibial tuberosity on eight knees (six patients) and below the tuberosity on 37 knees (28 patients). At the final follow-up (age range 42-73 years), all of the deformities were satisfactorily corrected, with no symptoms apart from nine knees, seven of which had dull pain after strenuous sport with osteophytes, etc. in the radiograph. Total knee arthroplasty was performed in the remaining two knees, at ten and 26 years, respectively, after the initial osteotomy. Osteoarthritis developed in the contralateral knee to the initial osteotomy in two patients after 34 years at age 73 and after 33 years at age 67. PMID- 19777232 TI - Stomatocytosis heralding a case of acute Wilsonian crisis. PMID- 19777233 TI - Bexarotene: a promising anticancer agent. AB - Retinoids are biologically active derivatives of vitamin A, which play essential roles in embryonic or adult cell behavior modulating cell proliferation, differentiation and apoptosis. The biologic effects of retinoids are mediated by two distinct families of intracellular receptors: retinoid acid receptors (RARs) alpha, -beta and -gamma and retinoid X receptors (RXR)-alpha, -beta and -gamma. Bexarotene is a selective RXR agonist, which exerts its effects in blocking cell cycle progression, inducing apoptosis and differentiation, preventing multidrug resistance, and inhibiting angiogenesis and metastasis, making it a promising chemopreventive agent against cancer. PMID- 19777234 TI - Adaptive dynamics: a framework to model evolution in the ecological theatre. PMID- 19777235 TI - The -283C/T polymorphism of the DNMT3B gene influences the progression of joint destruction in rheumatoid arthritis. AB - The objective of this study is to investigate the association between the -283C/T polymorphism at the promotor of DNMT3B gene and susceptibility to rheumatoid arthritis (RA) and to evaluate the effect of the polymorphism on clinical features such as progression of joint destruction in RA. A total of 309 patients with RA were compared with 297 control subjects. Genotyping of the -283C/T polymorphism was performed by real-time sequencing using Pyrosequencer. The genotype frequencies of the polymorphism at position -283 were not significantly different between patients with RA and controls. There were significantly positive correlations between the modified Sharp score and the disease duration for carriers of each genotype (y = 9.546x + 19.998, p < 0.001, for T allele carriers, y = 6.185x + 34.424, p < 0.001 for CC homozygotes). The slope of regression line of the T allele carriers was significantly steeper than that of the CC homozygotes (p = 0.014). In conclusion, our results suggest that the 283C/T polymorphism of the DNMT3B gene is a genetic marker related to the joint destruction of RA. PMID- 19777236 TI - MEFV mutations in Egyptian patients suffering from familial Mediterranean fever: analysis of 12 gene mutations. AB - The objective of the study is to screen 12 MEFV gene mutations in Egyptian patients with familial Mediterranean fever (FMF) and to study the initial hypothesis that the phenotypic expression of the disease may be attributable to the existence of a particular mutation. We enrolled 136 Egyptian patients (74 males, and 62 females) with a clinical diagnosis of FMF. DNA was amplified by PCR and subjected to reverse hybridization for the detection of 12 MEFV gene mutations. The phenotypic expression of the disease was compared in two subgroups according to the presence of homozygote E148Q and M694V gene mutations. The most frequent gene mutations in the studied group were V726A, M694V, M680I, E148Q and M694I in 41.2, 32.4, 29.4, 25 and 20.6%, respectively. At least one of these main five founder mutations was present in 132 patients (97.1%). Thirty-two patients (23.5%) were homozygote for one of the main five founder mutations. The most common homozygote gene mutations were E148Q and M694V, each in 12 patients (8.8%). Significant increase in abdominal pain and arthritis was found in patients with homozygote M694V mutation compared to those with E148Q mutation. All patients with amyloidosis had M694V gene mutation. The increased frequency of V726A gene mutation and the rarity of amyloidosis in this study suggest that Egyptian patients may have a milder form of FMF compared to other populations. The five main founder mutations account for the vast majority of cases of FMF. M694V gene mutation may be associated with increased frequency of abdominal pain, arthritis and the presence of amyloidosis. PMID- 19777237 TI - Clinical significance of 18F-fluoro-dexoxyglucose positron emission tomography in patients with adult-onset Still's disease: report of two cases and review of literatures. AB - Adult-onset Still's disease (AOSD) is a multi-systemic inflammatory disease that usually presents with high fever and variable systemic features. The pathogenesis and etiology of AOSD have not yet been clearly determined. In addition, there is no diagnostic test for AOSD. Even though some useful diagnostic criteria or laboratory findings, such as serum ferritin levels, have been proposed, useful imaging studies for the diagnosis or follow-up of AOSD have not been developed. We performed (18)F-fluoro-dexoxyglucose positron emission tomography ((18)F-FDG PET) on two AOSD patients who presented with a fever of unknown origin. In these patients, we initially identified abnormally increased FDG uptake in multiple lymph nodes, the spleen, or bone marrow. We then identified significantly decreased uptake during a follow-up study. On the basis of these cases, we suggest that (18)F-FDG PET may have the potential in the diagnosis of AOSD, as well as monitor clinical changes in the disease. More further investigation of (18)F-FDG PET in AOSD is needed in larger population. PMID- 19777238 TI - Wegener's granulomatosis presenting with life-threatening lung hemorrhage in a 7 year-old child. AB - Wegener's granulomatosis (WG) is an idiopathic systemic disease that usually onsets in adolescence and is rare in young children. Its diagnosis is usually based on the presence of fever with arthralgia and weight loss, associated with symptoms of upper and/or lower respiratory tract involvement and renal disorders. We describe the appearance of a life-threatening lung hemorrhage in the absence of hemoptysis in a 7-year-old girl with a completely negative previous clinical history, who was subsequently diagnosed as having WG. The teaching message is that immediate bronchoscopy with bronchoalveolar lavage seems to be advisable in the presence of severe respiratory distress and bilateral lung as well as renal involvement. When a diffuse alveolar hemorrhage syndrome is demonstrated, WG should be considered among the main etiologies even in a relatively young child without a clinically suggestive history. PMID- 19777239 TI - Periodic fever responds to vitamin B12 treatment. AB - Periodic fever of childhood is a group of diseases that cause repeated febrile illnesses with various associated symptoms. In our article, we present the case of a 6-year-old girl with unusual appearance of periodic fever syndrome. Our patient suffered from repeated episodes of high fever from the age of 2 years old. Each episode usually lasted 24-48 h, the interval between events was 1-3 weeks long. During high fever episodes the child usually felt well, without associated accompanying complaints. As a rule, the physical examination did not reveal any pathologic finding explaining the fever. During the 4 years of follow up the patient sustained treatment attempts with prednisone for a number of months and half a year with colchicine without any response. We considered treatment with sublingual tablets of vitamin B12 (VIT B12). Beyond all expectation, we witnessed complete resolution of attacks during the first 2 months following treatment. After a long episode-free period, the parents withheld the treatment on their own accord, and in a short time the disease recurred. We advised to renew the treatment with VIT B12, and during approximately half year of follow-up there were no recurrences of periodic fever. CONCLUSION: we believe that our observation raises interest in systematic evaluation of the therapeutic role of VIT B12 as a treatment option for disorders of the periodic fever spectrum. PMID- 19777240 TI - What is the relationship between disease activity, severity and damage in a large Canadian systemic sclerosis cohort? Results from the Canadian Scleroderma Research Group (CSRG). AB - We studied the relationships between physician-assessed damage, severity and activity in a large, multicentre systemic sclerosis (SSc, scleroderma) cohort. We hypothesized that there is a relationship between disease activity and severity and damage, but that severity would be more strongly related to damage. A total of 520 SSc patients (87% women, mean age 56 years, mean 8.6 years disease duration, 39% diffuse SSc) were studied. The correlations between physician's global assessments of damage, activity and severity were determined overall and in a subset of early, diffuse SSc (n = 74). The mean (SD) patient global health score was 3.6 (2.4) on a 0-10 scale. Physician-rated severity, activity and damage were 2.8 (2.2), 2.3 (2.0), and 3.4 (2.4) respectively. Damage was more strongly related to severity (r = 0.744, P < 0.001) than activity (r = 0.596, P < 0.001). Damage was not related to disease duration (r = 0.046, P = 0.3). In early diffuse SSc, the correlations were: damage and severity 0.771 (P < 0.001), damage and activity 0.596 (P < 0.001), severity and activity 0.809 (P < 0.001). The relationships vary in the overall cohort versus the early diffuse SSc subset where activity, severity and damage appear more strongly related. Thus, the exact nature of the relationship between damage, activity and severity will depend upon the characteristics of the population studied. PMID- 19777242 TI - Clinical characteristics of Behcet's disease in China. AB - To evaluate the prevalence of clinical findings in Behcet's disease (BD) in Chinese population. The clinical data of 170 consecutive BD patients were, retrospectively, analyzed and compared with previous reports. The mean age at onset was 34.4 years (range 6-72) and the mean age of diagnosis was 39.1 years (range 8-72). Mean delay in diagnosis was 5.7 years. The male to female ratio was 1.3:1. Recurrent aphthous ulceration (64.7%), skin lesion (18.2%), and genital ulceration (8.2%) were the commonest onset-presentations of the disease. During the disease course, the commonest presenting features were oral ulcer (100%), cutaneous involvement (68.2%), genital ulcer (63.5%), arthritis (37.1%), and ocular lesion (14.1%). As for the minor clinical manifestations, gastrointestinal lesion (10.0%), vascular lesion (8.8%), and cardiac lesion (4.7%) occurred occasionally. The pathergy skin test showed positive in 63.5% of the patients and revealed a higher positive rate in the females (76.7%) than in the males (53.6%). Less ocular lesion and genital ulcer were present in Chinese BD patients. PMID- 19777241 TI - Effects of (-)-epigallocatechin-3-gallate on cyclooxygenase 2, PGE(2), and IL-8 expression induced by IL-1beta in human synovial fibroblasts. AB - The objective of this study was to examine the effects of (-)-epigallocatechin-3 gallate (EGCG) on cyclooxygenase 2 (COX-2), prostaglandin E(2) (PGE(2)), and interleukin 8 (IL-8) expression induced by IL-1beta in human synovial fibroblasts. Cells were enzymatically isolated from synovial tissue taken from patients undergoing joint replacement surgery for osteoarthritis. Reverse transcriptase-polymerase chain reaction, immunocytochemistry, and western blotting were used to assess the COX-2 gene and protein expression with the associated mechanisms. PGE(2) and IL-8 secretion into the culture medium was assayed by enzyme-linked immunosorbent assay. COX-2 upregulation in synovial fibroblasts induced by IL-1beta was significantly suppressed by EGCG in a dose dependent manner. PGE(2) and IL-8 secretion was also induced by IL-1beta stimulation and significantly suppressed by EGCG. The mechanism was associated with the phosphorylation of IKKbeta. EGCG may inhibit the expression of inflammatory mediators, such as COX-2, PGE(2), and IL-8, induced by IL-1beta in human synovial fibroblasts. EGCG may be of value in the treatment of synovial inflammation. PMID- 19777243 TI - Extraperitoneal radical cystectomy with extraperitonealization of the ileal neobladder: a comparison to the transperitoneal technique. AB - PURPOSE: Transperitoneal radical cystectomy with intraperitoneal ileal neobladder is the standard surgical treatment for muscle-invasive bladder cancer. To reduce morbidity, we established in 2002 an extraperitoneal approach including extraperitonealization of the ileal neobladder. This retrospective study compares the results of the two procedures with a focus on the peri- and postoperative course. METHODS: Ninety-five male patients with invasive urothelial cancer who underwent radical cystectomy with ileal neobladder at our hospital from January 1998 to May 2007 were analyzed. Forty-seven patients underwent transperitoneal radical cystectomy with intraperitoneal ileal neobladder. The remaining 48 were submitted to the extraperitoneal technique with extraperitonealization of the neobladder. We compared both methods regarding operating time, intraoperative blood loss, complications and oncological outcome. RESULTS: The incidence of postoperative ileus was significantly lower after the extraperitoneal than after the transperitoneal approach (2/48 vs. 10/47 cases; p = 0.012). However, pelvic lymphoceles were more frequent (6 vs. 0 cases; p = 0.014). The two techniques did not differ with regard to the other major and minor complications, the operating time (mean 377.4 vs. 405.4 min) or the intraoperative blood loss (mean 363 vs. 412 ml). Oncological outcome disclosed no difference between both techniques. CONCLUSIONS: The extraperitoneal technique with extraperitonealization of the ileal neobladder is comparable in safety and reliability to the transperitoneal surgical approach and yields good peri- and postoperative results with regard to the parameters we examined. Noteworthy are the significant reduction of postoperative ileus and the higher incidence of lymphoceles. Both may be caused by the separate extraperitoneal regional healing processes. PMID- 19777244 TI - [Expression of matrix metalloproteinase-19 in the human cornea. Wound healing in the MMP-19 knock-out mouse model]. AB - BACKGROUND: At present there are no data in the literature on the expression of matrix metalloprotein-19 in the human cornea. The aim of this study was to analyze the expression of matrix metalloproteinase-19 in the human cornea and to investigate its potential role in corneal wound healing using a MMP-19 knock-out mouse model. METHODS: A method with Western blotting and immunohistological staining for MMP-19 was performed using paraffin embedded human corneas. Excimer laser keratectomy was performed in wild type (wt) and MMP-19 knock-out (ko) mice and the rate of re-epithelialization was analyzed after 8 h and 18 h. RESULTS: MMP-19 was strongly expressed in the human corneal epithelium mainly in the basal cell layer. MMP-19 was not expressed in the corneal stroma. In the mouse model the size of the corneal lesion after 8 h was 83% (wt) and 89.9% (ko) of the initial area (p=0.09). After 18 h the lesion was 17% (wt) and 13.3% (ko) of the initial area (p=0.01). Laminin-5 was expressed in the migrating epithelial cells with no differences between wild type and knock-out mouse. CONCLUSION: MMP-19 showed a strong expression in the basal cells of the human corneal epithelium. Corneal re-epithelialization was slightly faster in the MMP-19 knock-out mouse. No differences in the expression of laminin-5 could be detected. PMID- 19777245 TI - [Erdheim-Chester disease of the orbit with compressive optic neuropathy]. AB - A 60-year-old man presented with left exophthalmos and deterioration in visual acuity of slow evolution. Bilateral orbital Erdheim-Chester disease was diagnosed. Systemic evaluation revealed a retroperitoneal fibrosis. Treatment with interferon-alpha followed, but bilateral compressive optic neuropathy with visual acuity deterioration and visual field defects evolved. Bilateral orbital decompression was performed. PMID- 19777246 TI - [Results of 308 consecutive femtosecond laser cuts for LASIK]. AB - OBJECTIVE: For technical reasons, the rotating knives (microkeratomes) commonly used for flap creation in LASIK may induce cut complications such as buttonholes or incomplete flaps. Femtosecond (femto) lasers should reduce these risks because, compared with microceratomes, femtolasers work more precisely and individually, so the flap can be individualized according to the patient's eye condition. Therefore, surgery should be less of a strain to patients, vision should recover faster, and optical quality should be optimized. METHODS: In this study, 308 consecutive femtolaser cuts for myopic LASIK performed with the IntraLase FS60 between August 2006 and March 2008 were evaluated and compared with the approved key literature. RESULTS: For all cuts, just three complications (incomplete ring cuts of about 20 degrees) occurred. All were completed with a diamond knife without any further problems. No other complications - including the typical microceratome-induced cut complications - were observed. CONCLUSIONS: In this small series of 308 operations, femto-LASIK induced no major cut complications. PMID- 19777247 TI - Biophysical effects of the natural product euplotin C on the Paramecium membrane. AB - The effect of euplotin C--a cytotoxic secondary metabolite produced by the protist ciliate Euplotes crassus--on the voltage-dependent Ca(2+) channel activity was studied in a single-celled system by analyzing the swimming behavior of Paramecium. When the intraciliary Ca(2+) concentration associated with plasma membrane depolarization increases, a reversal in the direction of ciliary beating occurs, and consequently the swimming direction changes. The ciliary reversal duration is correlated with the amount of Ca(2+) influx. The present study demonstrates that the duration of continuous ciliary reversal (CCR), triggered by high external KCl concentrations, is longer in euplotin C-treated cells. Using selective Ca(2+) channel blockers, we demonstrate that euplotin C modulates Ca(2+) channels similar to the T- and L-types that occur in mammalian cells. Indeed, the increase of CCR duration significantly decreased when flunarizine and nimodipine-verapamil blockers were employed. Membrane fluidity measurements using a fluorescent dye, 6-lauroyl-2-dimethylaminonaphtalene (laurdan), indicated that membranes in euplotin C-treated cells are more tightly packed and ordered than membranes in control cells. Our data suggest that euplotin C enhances backward swimming in our unicellular model system by interacting with the ciliary Ca(2+) channel functions through the reduction of cell membrane fluidity. PMID- 19777248 TI - Large post-traumatic subarticular cystic lesion following avulsion injury of PCL mimicking tumour. AB - We describe a patient with a large subarticular cystic lesion in the proximal tibia developed following traumatic avulsion of PCL. There was a demonstrable communication between the cyst and the joint cavity and ingrowth of the synovial tissue was the most probable pathogenetic mechanism for the development of the cyst. We recommend that the post-traumatic cyst must be kept as a differential diagnosis in a patient presenting with cystic lesion around a joint, especially if there is a history of significant trauma in recent past. PMID- 19777249 TI - Conservative management of placenta increta after first trimester abortion by transcatheter arterial chemoembolization: a case report and review of the literature. AB - INTRODUCTION: Placenta increta is a potentially life-threatening condition that may complicate a first trimester abortion in rare occasion. However, the therapeutic value of transcatheter arterial chemoembolization for the conservative management of this disorder is not described. CASE REPORT: A 27-year old woman (gravida 3, para 1) with significant obstetric history for one previous lower segment cesarean section and one dilatation and curettage for missed abortion had uncomplicated dilatation and curettage for missed abortion. Eight weeks after curettage, the patient presented with increased amounts of vaginal bleeding. Image diagnostic modalities localized the heterogeneous mass within the myometrium in the fundal portion of the uterine corpus. Initially, arteriovenous fistula formation after abortion was suspected. However, an elevated serum hCG value indicated the presence of retained placental tissue and gave the diagnosis of persistent placenta increta after a first trimester abortion. Transcatheter arterial chemoembolization with dactinomycin was initiated to achieve immediate hemostasis and cytocidal effects on the placental tissue. The post-interventional course was uneventful. Twenty days after chemoembolization, the serum hCG value decreased to a normal level and the mass lesion disappeared on ultrasonography without secondary hemorrhagic complications. CONCLUSIONS: After precise diagnostic imaging, transcatheter arterial chemoembolization is a useful minimally invasive procedure to achieve uterine preservation in women with placenta increta masquerading as arteriovenous fistula after a first trimester abortion. PMID- 19777250 TI - Predictive power of sexual hormones and tumor markers in endometrial cancer. AB - OBJECTIVE: The purpose of the present study was to investigate the predictive power of sexual hormones and tumor markers in endometrial cancer. METHODS: A total of 135 healthy women were prospectively compared with 135 women who had histopathologically confirmed endometrial cancer. Both the groups of women were matched by age and body mass index. RESULTS: When compared with healthy controls, women with endometrial cancer had significantly higher serum levels of CA-125, CA 19-9, prolactin and thyroid-stimulating hormone, whereas significantly lower serum concentrations of alpha-fetoprotein, CA 15-3, follicle-stimulating hormone and luteinizing hormone (LH). Tumor stage correlated positively and significantly with serum levels of prolactin, CA-125 and CA 19-9 as did tumor grade with serum concentrations of LH, estradiol, prolactin and CA-125. Serum CA-125 levels >35 U/ml were found to have a sensitivity of 42.2%, specificity of 87.4%, positive predictive value of 77.0% and negative-predictive value of 60.2%. Besides endometrial cancer could be diagnosed with 16.3% sensitivity, 100.0% specificity, 100.0% positive- and 54.4% negative-predictive values with serum prolactin levels >30 ng/ml. CONCLUSIONS: Because serum concentrations of CA-125 can be elevated in various malignancies, it is obvious that it is neither specific nor accurately diagnostic for endometrial tumors. What is more, the distinct effects of physiological factors on prolactin secretion shadow the credibility of this hormone in early diagnosis of endometrial tumors. Thus, either prolactin or CA 125 is far from being utilized as the sole entity for screening endometrial cancer. Therefore, both parameters should be regarded as the components of a biochemical screening panel that is to be developed in future. PMID- 19777251 TI - A comparison of modelling procedures used to estimate the power-exhaustion time relationship. AB - This study aimed to test the consistency of using the power required to elicit maximal oxygen uptake during incremental test (P (t)) to demarcate the range of power intensity in the modelling of the power-exhaustion time relationship. Different mathematical procedures were tested using data from ten subjects exercising on a cycle ergometer. After the determination of P (t) and the power at the ventilatory threshold, the subjects did six tests at constant power to exhaustion within 2-15 min. Estimates were obtained from a segmented model using two distinct equations of the anaerobic contribution to power below and above P (t), respectively. This model fit the overall data with a better adequacy than the simple hyperbolic model (standard error of 29.2 +/- 25.2 vs. 42.3 +/- 25.2 s). The power asymptotes were 225.7 +/- 27.3 W from the segmented model, 226.2 +/ 27.3 and 283.3 +/- 20.5 W from the simple model applied to data below and above P (t), respectively. The estimates from the segmented model were strongly correlated with their analogues from the simple model applied only to data below P (t) (R = 1.00 for power asymptote and curvature coefficient). They were not correlated with their analogues from the simple model applied only to data above P (t). These discrepancies between modelling procedures could arise from the method used to determine P (t) and the oversimplification of the oxygen uptake kinetics. These limitations could lead the segmented model to an overestimation of the anaerobic contribution which was around 15% of total energy expended at P (t). PMID- 19777252 TI - Panoramic ultrasonography is a valid method to measure changes in skeletal muscle cross-sectional area. AB - The purpose of this study was to examine the reliability and validity of the "panoramic" brightness mode ultrasonography (US) method to detect training induced changes in muscle cross-sectional area (CSA) by comparison with results obtained using magnetic resonance imaging (MRI). Out of 27 young male volunteers, 20 subjects were assigned to training group and seven to non-training control group. Muscle CSAs of vastus lateralis were analyzed by MRI and US before and after 21 weeks of either heavy resistance training or control period. Measured by both the US and MRI, the resistance training induced significant increases (~13 14%, P < 0.001) in muscle CSA, whereas no changes were observed in control group. A high repeatability was found between the two consequent US measurements (intraclass correlation coefficient, ICC of 0.997) with standard error of measurement (SEM) of 0.38 cm(2) and smallest detectable difference of 1.1 cm(2). Validity of the US method against MRI in assessing CSA of VL produced ICC of 0.905 and SEM of 0.87 cm(2) with high limits of agreement analyzed by Bland and Altman method. However, the MRI produced systematically (10 +/- 4%, P < 0.01) larger CSA values than the US method. The US showed high agreement against MRI in detecting changes in muscle CSA (ICC of 0.929, SEM of 0.94 cm(2)). The results of this study showed that the panoramic US method provides repeatable measures of a muscle CSA although MRI produced larger absolute CSA values. Moreover, this US method detects training-induced changes in muscle CSA with a comparable degree of precision to MRI. PMID- 19777253 TI - Leg dominancy in relation to fast isometric torque production and squat jump height. AB - We hypothesized that maximal unilateral isometric knee extensor torque, the rate of torque development during maximally fast isometric contractions and unilateral squat jump performance would be better with the dominant than non-dominant leg. Limb dominancy was established using the step up, balance recovery, and ball kick test. On two days, eight men (21.5 +/- 2.2 years, means +/- SD) performed unilateral maximal isometric contractions with their knee extensors (120 degrees knee angle) with superimposed electrical stimulation to determine maximal torque and voluntary activation for both limbs. In addition, maximally fast isometric contractions without countermovement and unilateral squat jumps (SJ) starting from 120 degrees knee angles were performed. Torque time integral (contractile impulse) over the first 40 ms after torque onset (TTI40) and maximal rates of torque development (MRTD) during voluntary and maximal electrical nerve stimulation were used to quantify initial torque rise. Limb dominancy tests were very consistent, but none of the parameters was (or tended to be) significantly different between limbs, neither during maximal electrical stimulation nor during voluntary attempts. Between limbs there were significant relationships for voluntary TTI40 (r (2) = 0.94) and maximal SJ height (r (2) = 0.88) and both parameters were significantly related in both limbs (r (2) = 0.69 and 0.75). In conclusion, unilateral fast torque generating capacity, muscle activation and squat jump performance were similar in both limbs, but differed substantially among subjects, with strong correlations between fast voluntary isometric torque development and jump height. These findings further challenge the concept of lower limb dominancy in dynamometry testing in sports and rehabilitation. PMID- 19777254 TI - Resting state networks in human cervical spinal cord observed with fMRI. AB - It has been reported that spontaneous fluctuations of blood oxygen level dependent (BOLD) signals can be detected in human brain and constitute resting state networks. It has not been reported whether resting state networks also exist in human spinal cord. In the present study, we investigate spontaneous BOLD signal changes in human cervical spinal cord during resting state. fMRI data were analyzed with independent component analysis and SPM software package. Acceptable reproducibility of spatial maps of BOLD signal changes was found across sessions, with the highest correlation values ranging from 0.18 to 0.44. The dominant frequency of signal changes from independent components with the highest correlation values was approximately the frequency range of the respiratory circle. Activities of spinal motor neurons innervating the scalenes were considered as a major factor in the production of BOLD signal fluctuations were observed in this study. Our findings suggest that BOLD fMRI can be applied to study the features of low-frequency rhythmic activities and corresponding mechanisms in the spinal cord during resting state. PMID- 19777256 TI - The importance of precise pT diagnosis for prognostic prediction of uterine cervical cancer--a single institutional report at a Japanese comprehensive cancer hospital. AB - We previously reported that the majority of Japanese pathologists misunderstand the International Union against Cancer-pT2 criteria for uterine cervical cancer (UCC). We compared the prognosis of originally diagnosed pT2 (ori-pT) UCC cases at our hospital with reclassified pT2 (re-pT) cases to assess the importance of making a correct pT diagnosis. There were 43 International Federation of Gynecology and Obstetrics (FIGO) II (i.e., cT2) and/or ori-pT2 UCC cases who received surgery without neoadjuvant chemotherapy at Shikoku Cancer Center from 1991 to 2003. The cases (seven ori-pT1 and 36 ori-pT2; 43 cN0 with six pN1) were reclassified as 22 re-pT1 and 21 re-pT2. Fifteen of the 23 ori-pT2a cases (65%) were re-pT1 because their vaginal extension had only been intraepithelial. The difference in the 5-year survival rate (5Y-SR) was not significant between the ori-pT1 and ori-pT2 cases using Fisher's exact test (F test): P = 0.236 > 0.05, whereas 5Y-SR of re-pT1 cases was significantly higher than re-pT2, including pN1 cases and excluding them (F test: P = 0.00164 < 0.01 and P = 0.0108 < 0.05, respectively). The 5Y-SR of ori-pT2-re-pT1 (overdiagnosed pT2) was significantly higher that of ori-pT2-re-pT2 (true pT2) including pN1 cases and excluding them (F test: P = 0.00694 < 0.01 and P = 0.0305 < 0.05, respectively). These results indicated that pT2 of UCC could be frequently misdiagnosed at an institutional level, and that misdiagnosed pT2 might impair the evidence-based medicine of UCC. Multi-institutional assessment of the accuracy of pTNM is recommended, because it is not likely that this is an endemic problem to our hospital. PMID- 19777255 TI - Regulation and function of the pepper pectin methylesterase inhibitor (CaPMEI1) gene promoter in defense and ethylene and methyl jasmonate signaling in plants. AB - Analysis of the promoters of defense-related genes is valuable for determining stress signaling and transcriptional activation during pathogen infection. Here, we have isolated and functionally characterized the promoter region of the pepper (Capsicum annuum) pectin methylesterase inhibitor 1 (CaPMEI1) gene in transiently transformed tobacco plants and stably transformed Arabidopsis plants. Among four 5' deletion constructs analyzed, the -958-bp CaPMEI1 promoter induced a high level of GUS reporter activity in tobacco leaf tissue, driven by pathogen infection as well as by ethylene and methyl jasmonate (MeJA) treatment. The 204 bp region from -958 bp to -754 bp of the CaPMEI1 promoter is responsible for the stress-responsive expression. In addition, the pepper transcription factor CARAV1 activated the CaPMEI1 promoter in tobacco leaves, whereas the transcription factor CAbZIP1 did not. In the transgenic Arabidopsis plants, the -958 bp CaPMEI1 promoter was functionally regulated by developmental cues, bacterial and oomycete pathogen infections, and treatment with ethylene and MeJA. Histochemical GUS staining analyses of Arabidopsis tissues revealed that the CaPMEI1 promoter was mainly activated in leaf veins in response to various biotic and abiotic stimuli. Together, these results suggest that CaPMEI1 promoter activation may be a critical molecular event for host defense response and ethylene- and MeJA mediated CaPMEI1 gene expression. PMID- 19777257 TI - US-guided interstitial chemotherapy using paclitaxel temperature-responsive gel for breast cancer treatment in rat. AB - INTRODUCTION: This study aims to investigate the therapeutic effect of paclitaxel temperature-responsive gel (PTRG) for interstitial chemotherapy on breast cancer, and to explore a new minimally invasive treatment for breast cancer. MATERIALS AND METHODS: Breast cancer models were induced in rats using subcutaneous transplantation of tumor cells. The rats were then divided into control, paclitaxel injection, gel injection and paclitaxel-gel (PG) group. Following treatment, all animals were checked regularly by ultrasonography to observe changes in the tumors. Biopsy tumor tissues were processed for histopathological examination, and apoptotic index was determined by the terminal deoxynucleotidyl transferase dUTP nick end labeling method. In addition, blood cell count and liver transaminase activity were monitored, and the survival time of rats with cancer recorded. RESULTS: Rats in PG group exhibited liquefaction necrosis of tumors. Ninety days after the experiment, four rats exhibited complete extinction of tumors, indicating full recovery. Pathological examination revealed that the tumor tissues in these rats were mostly necrotic, and the apoptotic index of tumor cells increased markedly compared to PI group. Also, the red blood cell, hemoglobin and white blood cell levels declined significantly in the PI group compared with PG group, while glutamic-pyruvic transaminase and glutamic oxalacetic transaminase activities significantly increased. Meanwhile, no toxicity due to treatment was observed in PG group. CONCLUSION: Interstitial chemotherapy mediated by PTRG appeared to be a safe and effective treatment for breast cancer in rats. It might have clinical applications for treating human breast cancer. PMID- 19777259 TI - Phase II study of capecitabine plus oxaliplatin (XELOX) as first-line treatment and followed by maintenance of capecitabine in patients with metastatic colorectal cancer. AB - PURPOSE: The aim of this study is to evaluate the safety and efficacy of the combination of capecitabine and oxaliplatin (XELOX) as first-line treatment in Chinese patients with metastatic colorectal carcinoma (mCRC). Furthermore, we aimed to explore whether a maintenance therapy with oral capecitabine in patients who were non-progression to the XELOX regimen was able to improve the duration of disease control (DDC). PATIENTS AND METHODS: One hundred twenty-four patients with mCRC received a 3-weekly regimen of oxaliplatin plus capecitabine (XELOX) as first-line treatment. Patients without progressive disease after six cycles of XELOX could stop treatment or continue to receive oral capecitabine until disease progression or unacceptable toxicity. RESULTS: A total of 637 cycles (median 6 cycles) of XELOX were given to 124 patients (males 58.1%, median age 52 years). The response rate was 49.1% (complete response in 11 patients and partial response in 50 patients). The median overall survival and progression-free survival were 20.0 and 8.0 months, respectively. Main drug-related grade 3-4 toxicities included neutrapenia (5.6%), nausea/vomiting (4%), thrombocytopenia (2.4%), diarrhea (2.4%) and hand-foot syndrome (2.4%). Among 62 patients achieving objective response or stable disease after at least 6 cycles of XELOX, there were 22 patients received oral capecitabine as maintenance therapy. The median DDC was significantly longer for maintenance therapy group than those of no maintenance group (14 vs. 9 months; P = 0.041). CONCLUSIONS: XELOX is a highly effective first-line treatment for Chinese mCRC patients. The response rate, TTP, and overall survival of patients treated with this regimen are similar to those treated with FU/leucovorin/oxaliplatin. Furthermore, our preliminary data show maintenance therapy with capecitabine for those patients without progressive disease after at least six cycles of XELOX can significantly improve DDC; and further prospective randomized control trial is warranted. PMID- 19777258 TI - Clinical outcomes of advanced non-small cell lung cancer patients screened for epidermal growth factor receptor gene mutations. AB - PURPOSE: To evaluate the relationship between the epidermal growth factor receptor (EGFR) mutation status and the effectiveness of gefitinib monotherapy or chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: We retrospectively analyzed a cohort of 100 patients with stage IIIB/IV NSCLC screened for two major EGFR mutations (exon 19 deletions and L858R mutation). RESULTS: Forty-six out of 48 EGFR mutation-positive patients (96%) received gefitinib, whereas only 3 out of 52 EGFR mutation-negative patients (6%) received gefitinib. Favorable objective response rates to gefitinib as first- and second-line treatment (87 and 80%, respectively) were observed in EGFR mutation positive patients. Overall response rate to chemotherapy as first-line treatment did not differ significantly between patients with EGFR mutations and those without mutation (32 vs. 28%, respectively; P = 0.7198). As to first-line treatment, EGFR mutation-positive patients treated with gefitinib experienced significantly longer progression-free survival (PFS) than did patients who received chemotherapy (median survival, 7.8 months vs. 5.1 months, respectively; P = 0.0323). Similarly, as to second-line treatment, EGFR mutation-positive patients treated with gefitinib had significantly longer PFS than did patients who received chemotherapy (median survival, 6.5 months vs. 4.0 months, respectively; P = 0.0048). Patients with EGFR mutations survived longer than those without EGFR mutations after first-line treatment (median, 24.3 vs. 12.6 months, respectively; P = 0.0029). CONCLUSION: EGFR mutation-positive patients benefit from either first- or second-line gefitinib monotherapy. Further large scale prospective studies to confirm this finding are needed. PMID- 19777260 TI - Cysteine proteinases from promastigotes of Leishmania (Viannia) braziliensis. AB - Leishmania (Viannia) braziliensis is the major causative agent of American tegumentary leishmaniasis, a disease that has a wide geographical distribution and is a severe public health problem. The cysteine proteinase B (CPB) from Leishmania spp. represents an important virulence factor. In this study, we characterized and localized cysteine proteinases in L. (V.) braziliensis promastigotes. By a combination of triton X-114 extraction, concanavalin A affinity, and ion exchange chromatographies, we obtained an enriched fraction of hydrophobic proteins rich in mannose residues. This fraction contained two proteinases of 63 and 43 kDa, which were recognized by a CPB antiserum, and were partially sensitive to E-64 in enzymatic assays with the peptide Glu-Phe-Leu. In confocal microscopy, the CPB homologues localized in the peripheral region of the parasite. This data together with direct agglutination and flow cytometry assays suggest a surface localization of the CPB homologues. The incubation of intact promastigotes with phospholipase C reduced the number of CPB-positive cells, while anti-cross-reacting determinant and anti-CPB antisera recognized two polypeptides (63 and 43 kDa) derived from phospholipase C treatment, suggesting that some CPB isoforms may be glycosylphosphatidylinositol-anchored. Collectively, our results suggest the presence of CPB homologues in L. braziliensis surface and highlight the need for further studies on L. braziliensis cysteine proteinases, which require enrichment methods for enzymatic detection. PMID- 19777261 TI - Physiological changes in Lymnaea columella (Say, 1817) (Mollusca, Gastropoda) in response to Echinostoma paraensei Lie and Basch, 1967 (Trematoda: Echinostomatidae) infection. AB - The physiological interaction between the digenean Echinostoma paraensei larvae and the intermediate snail host Lymnaea columella was studied. The carbohydrate content was significantly altered in the digestive gland tissue of snails, decreasing after 20 days postinfection. At the end of the prepatent period, the carbohydrate content was reduced by 60% when compared to uninfected snails. The total protein was reduced by 80.01% and 76.42% in the hemolymph and digestive gland, respectively. The end products resulting from nitrogen degradation were also analyzed. The urea was significantly increased in both the hemolymph and digestive gland. In the former, the highest concentration was detected at day 10 postinfection and then decreased until the end of the prepatent period. In digestive glands from infected snails, urea was significantly higher than in uninfected ones after 20 days. The uric acid content was reduced by 94.72% in the hemolymph and 43.75% in digestive glands after 10 days postinfection. The ammonia was undetectable under the experimental conditions employed. PMID- 19777262 TI - A novel nuclear marker, Pm-int9, for phylogenetic studies of Opisthorchis felineus, Opisthorchis viverrini, and Clonorchis sinensis (Opisthorchiidae, Trematoda). AB - Opisthorchis felineus, O. viverrini, and Clonorchis sinensis, the trematodes of the family Opisthorchiidae, are important human parasites. Two previous studies (Kang et al. Parasitol Int 57:191-197, 2008; Katokhin et al. Dokl Biochem Biophys 421:214-217, 2008) have provided evidence using ribosomal and mitochondrial sequences that O. viverrini, O. felineus, and C. sinensis are closely related. We developed a novel nuclear marker, Pm-int9, which included the ninth intron of the paramyosin gene and flanking exon sequences. Samples of O. felineus from four localities of West Siberia, C. sinensis from the Russian Far East, and O. viverrini from Thailand were genotyped by Pm-int9. Little variation was detected in exon sequences, however, intron sequences turned out to be more variable than ribosomal internal transcribed spacers. We can conclude that Pm-int9 is valuable for interspecific variation studies. Phylogenetic analysis based on Pm-int9 revealed that O. viverrini and C. sinensis were closer to each other than either of them to O. felineus, supporting the opinion that C. sinensis should be considered the sister species of Opisthorchis spp. PMID- 19777264 TI - Malate dehydrogenase is negatively regulated by miR-1 in Trichomonas vaginalis. AB - MicroRNAs are highly conserved small noncoding RNAs that can suppress protein translation through complementary binding to target mRNAs. We used a novel approach to identify miRNA targets in the protist Trichomonas vaginalis by comparing the levels of differentially expressed proteins and genes in the trophozoite and amoeboid stages. We observed that the T. vaginalis malate dehydrogenase (Tv_MDH) gene was upregulated 20-fold in the amoeboid stage, but the protein level was reduced by 4.5-fold. Bioinformatics analysis revealed that the Tv_MDH mRNA contains putative target sites of the miR-1 family. The expression level of endogenous tva-miR-1 in the amoeboid stage was 50-fold higher than in the trophozoite stage. Transfection of trophozoites with tva-miR-1 mimics reduced Tv_MDH protein expression by 60%. Based on these experimental data, we conclude that Tv_MDH is negatively regulated by tva-miR-1. The results of this study demonstrate that a combination of proteomic and transcriptomic approaches is a powerful tool for identifying miRNA targets. PMID- 19777263 TI - Identification of a vaccine candidate antigen, PfMAg-1, from Plasmodium falciparum with monoclonal antibody M26-32. AB - Monoclonal antibody M26-32 has been shown to strongly inhibit the growth of Plasmodium falciparum in vitro. To identify the target antigen of M26-32, a P. falciparum Dd2 asexual stage cDNA expression library was screened with this antibody, and a full open reading frame cDNA was obtained. This gene, named pfmag 1, encodes a polypeptide of 589 amino acids. The protein PfMAg-1 was characterized as a membrane-associated protein that expressed on the surface of merozoite during erythrocytic stage. Remarkably, at the C terminus of PfMAg-1, there are 14 copies of a deca-peptide sequence of QTDEIKND (H/N) I. This tandem repeat domain was identified to harbor the epitope of the protective M26-32 monoclonal antibody, and was also recognized by sera of patients infected with P. falciparum. Rabbit antibody elicited against this deca-peptide repeat domain effectively inhibited P. falciparum invasion in vitro. Our work suggests that PfMAg-1 is a promising malaria vaccine candidate. PMID- 19777265 TI - Interactions of multiple predators with different foraging modes in an aquatic food web. AB - Top predators can have different foraging modes that may alter their interactions and effects on food webs. Interactions between predators may be non-additive resulting from facilitation or interference, whereas their combined effects on a shared prey may result in emergent effects that are risk enhanced or risk reduced. To test the importance of multiple predators with different foraging modes, we examined the interaction between a cruising predator (largemouth bass, Micropterus salmoides) and an ambush predator (muskellunge, Esox masquinongy) foraging on a shared prey (bluegill sunfish, Lepomis macrochirus) with strong anti-predator defense behaviors. Additive and substitution designs were used to compare individual to combined predator treatments in experimental ponds. The multiple predator interaction facilitated growth of the cruising predator in the combined predator treatments, whereas predator species had substitutable effects on the growth of the ambush predator. The combined predator treatments created an emergent effect on the prey; however, the direction was dependent on the experimental design. The additive design found a risk-reducing effect, whereas the substitution design found a risk-enhancing effect for prey fish. Indirect effects from the predators weakly extended to lower trophic levels (i.e., zooplankton community). Our results highlight the need to consider differences in foraging mode of top predators, interactions between predators, and emergent effects on prey to understand food webs. PMID- 19777266 TI - Ascomycete fungal communities associated with early decaying leaves of Spartina spp. from central California estuaries. AB - Ascomycetous fungi play an important role in the early stages of decomposition of Spartina alterniflora, but their role in the decomposition of other Spartina species has not been investigated. Here we use fingerprint (terminal restriction fragment length polymorphism) and phylogenetic analyses of the 18S to 28S internal transcribed spacer region to compare the composition of the ascomycete fungal communities on early decay blades of Spartina species (Spartina alterniflora, Spartina densiflora, Spartina foliosa, and a hybrid (S. alterniflora x S. foliosa)) collected from three salt marshes in San Francisco Bay and one in Tomales Bay, California, USA. Phaeosphaeria spartinicola was found on all samples collected and was often dominant. Two other ascomycetes, Phaeosphaeria halima and Mycosphaerella sp. strain 2, were also common. These three species are the same ascomycetes previously identified as the dominant fungal decomposers on S. alterniflora on the east coast. Ascomycetes appeared to exhibit varying degrees of host specificity, demonstrated by grouping patterns on phylogenetic trees. Neither the exotic S. alterniflora nor the hybrid supported fungal flora different from that of the native S. foliosa. However, S. densiflora had a significantly different fungal community than the other species, and hosted at least two unique ascomycetes. Significant differences in the fungal decomposer communities were also detected within species (two clones of S. foliosa), but these were minor and may be due to morphological differences among the plants. PMID- 19777267 TI - Spectral properties of plant leaves pertaining to urban landscape design of broad spectrum solar ultraviolet radiation reduction. AB - Human exposure to harmful ultraviolet (UV) radiation has important public health implications. Actual human exposure to solar UV radiation depends on ambient UV irradiance, and the latter is influenced by ground reflection. In urban areas with higher reflectivity, UV exposure occurs routinely. To discover the solar UV radiation regulation mechanism of vegetation, the spectral reflectance and transmittance of plant leaves were measured with a spectrophotometer. Typically, higher plants have low leaf reflectance (around 5%) and essentially zero transmittance throughout the UV region regardless of plant species and seasonal change. Accordingly, incident UV radiation decreases to 5% by being reflected and is reduced to zero by passing through a leaf. Therefore, stratified structures of vegetation are working as another terminator of UV rays, protecting whole terrestrial ecosystems, while vegetation at waterfronts contributes to protect aquatic ecosystems. It is possible to protect the human population from harmful UV radiation by urban landscape design of tree shade and the botanical environment. Even thin but uniformly distributed canopy is effective in attenuating UV radiation. To intercept diffuse radiation, UV screening by vertical structures such as hedges should be considered. Reflectivity of vegetation is around 2%, as foliage surfaces reduce incident UV radiation via reflection, while also eliminating it by transmittance. Accordingly, vegetation reduces incident UV radiation to around 2% by reflection. Vegetation influence on ambient UV radiation is broad-spectrum throughout the UV region. Only trees provide cool UV protective shade. Urban landscapes aimed at abating urban heat islands integrated with a reduction of human UV over-exposure would contribute to mitigation of climate change. PMID- 19777268 TI - Short-term effects of extreme hot summer temperatures on total daily mortality in Barcelona, Spain. AB - The summer of 2003 was exceptionally hot, leading to an excess of mortality in Europe. Here, we assess the short-term effects of extreme hot summer temperatures on total daily mortality in Barcelona (Spain). Daily mortality from burial records, maximum temperature, relative humidity and photochemical pollutants, were collected for the period 1999-2003. Data was analysed using Poisson regression with generalised additive models. Mortality shows a considerable increase when maximum temperatures are over a threshold temperature of 30.5 degrees C. The risk of death associated with an increase of 1 degrees C above the threshold was 6%, 7% and 5% after 1, 2 and 3 days, respectively. Exposure to extreme hot temperatures leads to an significant increase in mortality. PMID- 19777269 TI - Sexual concerns in cancer patients: a comparison of GI and breast cancer patients. AB - PURPOSE: Although sexual concerns have been examined in breast cancer (BC), these concerns remain understudied and undertreated for patients with gastrointestinal (GI) cancer. Objectives were to: (1) assess sexual concerns in GI cancer patients compared with breast cancer patients; (2) examine whether sexual concerns are stable over time in GI and breast cancer patients; and (3) evaluate whether sexual concerns in GI and breast cancer are significantly associated with quality of life, symptom severity, and disease interference, and whether these associations change over time. METHODS: Data were collected from GI and breast cancer patients during four outpatient clinic visits over 6 months. Measures included sexual concerns (reduced sexual enjoyment, interest, or performance), quality of life (FACT-G), symptom severity, disease interference (MD Anderson Symptom Inventory), and disease-related distress (NCCN Distress Scale). Linear mixed model analyses were conducted. RESULTS: Sexual concerns were common in both samples, with 57% of GI cancer patients and 53% of breast cancer patients reporting at least mild sexual concerns. Sexual concerns were stable over time and were significantly associated with lower levels of functioning in multiple domains (e.g., quality of life, symptom severity, disease interference, and disease-related distress), irrespective of length of time since diagnosis. Cancer type (GI/breast cancer) was not a moderator of this relationship. CONCLUSIONS: Self-reported sexual concerns were common, stable, and related significantly to quality of life, symptom severity, disease interference, and disease-related distress for both GI and breast cancer patients. Limitations and implications for future research are discussed. PMID- 19777270 TI - Ranked importance of outcomes of first-line versus repeated chemotherapy among ovarian cancer patients. AB - PURPOSE: To examine the importance of possible outcomes of first-line versus repeated chemotherapy to ovarian cancer patients and to compare doctors' treatment intentions with patients' beliefs about cure. METHODS: Women with newly diagnosed (74) or relapsed (48) ovarian cancer were prospectively followed over 2 years. The level of importance they ascribed to four chemotherapy outcomes and their beliefs about cure were assessed. Their doctors independently specified intent of successive treatments. RESULTS: Approximately half (54%) of newly diagnosed ovarian cancer patients (65% with residual disease >2 cm and 49% with no or < or =2 cm residual disease) ranked 'tumour shrinkage (or decrease in blood levels of CA125)' as 'most important' during first-line chemotherapy. Approximately two thirds (65-70%) of all women whose disease had relapsed also ranked 'tumour shrinkage' as 'most important' during repeated chemotherapy. Few women (<8%) rated symptom relief or absence of side-effects as most important. While both patients' and doctors' belief about cure decreased over successive treatments, patients grew more optimistic relative to doctors over time. Women's reports of advice by doctors about cure were consistent with doctors' stated intent for repeat chemotherapy. However, discordance between doctors' actual treatment intent and patients' beliefs about cure increased from 24% at first line to 83% by fourth-line chemotherapy. CONCLUSIONS: Women prioritise tumour response as the most important outcome of chemotherapy for ovarian cancer. This priority predominates in women with residual and relapsed disease despite declining likelihood of cure. Women may still hope for a cure while acknowledging their doctor's advice that their disease is incurable. PMID- 19777271 TI - Differentiation between deep and superficial fibers of the lumbar multifidus by magnetic resonance imaging. AB - The purpose of this study was to investigate the differentiation in muscle tissue characteristics and recruitment between the deep and superficial multifidus muscle by magnetic resonance imaging. The multifidus is a very complex muscle in which a superficial and deep component can be differentiated from an anatomical, biomechanical, histological and neuromotorial point of view. To date, the histological evidence is limited to low back pain patients undergoing surgery and cadavers. The multifidus muscles of 15 healthy subjects were investigated with muscle functional MRI. Images were taken under three different conditions: (1) rest, (2) activity without pain and (3) activity after experimentally induced low back muscle pain. The T2 relaxation time in rest and the shift in T2 relaxation time after activity were compared for the deep and superficial samples of the multifidus. At rest, the T2 relaxation time of the deep portion was significantly higher compared to the superficial portion. Following exercise, there was no significant difference in shift in T2 relaxation time between the deep and superficial portions, and in the pain or in the non-pain condition. In conclusion, this study demonstrates a higher T2 relaxation time in the deep portion, which supports the current assumption that the deep multifidus has a higher percentage of slow twitch fibers compared to the superficial multifidus. No differential recruitment has been found following trunk extension with and without pain induction. For further research, it would be interesting to investigate a clinical LBP population, using this non-invasive muscle functional MRI approach. PMID- 19777272 TI - Laser-evoked potentials: prognostic relevance of pain pathway defects in patients with acute radiculopathy. AB - The radicular pain syndrome is a major problem in public health care that can lead to chronic back and leg pain in 30%. Ischalgia and back pain are the most prominent signs of dorsal root affection. Until now, no clinical or neurophysiological test procedure exists that evaluates the function of the dorsal root and predicts the prognosis of patients suffering from RPS. We have recently demonstrated that laser-evoked potentials (LEP) are able to demonstrate dorsal root damage. With this study, we investigated 54 patients with acute radicular symptoms and compared LEP parameters (side to side difference of latency and amplitude, transformed to a z-score) with their state of health after 3 months to calculate their predictive value for outcome prognosis. Most significantly, the latency difference between the LEP of the affected dermatome relative to the contralateral healthy dermatome was able to predict the prognosis. Latency z score above two demonstrates a 91% specificity (33% sensitivity) for a poor outcome at 3 months. A significant relation between amplitude changes and the main outcome measure could not be shown. Only extreme changes (z score >10) in amplitude show a high specificity for the persistence of ischialgia in particular (specificity 0.94; sensitivity 0.35). All other parameters, such as clinical scores or other LEP parameters, were not able to predict the outcome of patients. We propose that clinical testing using LEP with latency analysis is a useful tool for estimating the course of disease, so that patients with poor predictive parameters can be treated more invasively at early disease stages to avoid persistence of radiculopathy. PMID- 19777273 TI - Progressive retinal atrophy in Schapendoes dogs: mutation of the newly identified CCDC66 gene. AB - Canine generalized progressive retinal atrophy (gPRA) is characterized by continuous degeneration of photoreceptor cells leading to night blindness and progressive vision loss. Until now, mutations in 11 genes have been described that account for gPRA in dogs, mostly following an autosomal recessive inheritance mode. Here, we describe a gPRA locus comprising the newly identified gene coiled-coil domain containing 66 (CCDC66) on canine chromosome 20, as identified via linkage analysis in the Schapendoes breed. Mutation screening of the CCDC66 gene revealed a 1-bp insertion in exon 6 leading to a stop codon as the underlying cause of disease. The insertion is present in all affected dogs in the homozygous state as well as in all obligatory mutation carriers in the heterozygous state. The CCDC66 gene is evolutionarily conserved in different vertebrate species and exhibits a complex pattern of differential RNA splicing resulting in various isoforms in the retina. Immunohistochemically, CCDC66 protein is detected mainly in the inner segments of photoreceptors in mouse, dog, and man. The affected Schapendoes retina lacks CCDC66 protein. Thus this natural canine model for gPRA yields superior potential to understand functional implications of this newly identified protein including its physiology, and it opens new perspectives for analyzing different aspects of the general pathophysiology of gPRA. PMID- 19777274 TI - How do African grey parrots (Psittacus erithacus) perform on a delay of gratification task? AB - Humans and other animals often find it difficult to choose a delayed reward over an immediate one, even when the delay leads to increased pay-offs. Using a visible incremental reward procedure, we tested the ability of three grey parrots to maintain delay of gratification for an increasingly valuable food pay-off. Up to five sunflower seeds were placed within the parrot's reach, one at a time, at a rate of one seed per second. When the parrot took a seed the trial was ended and the birds consumed the accumulated seeds. Parrots were first tested in daily sessions of ten trials and then with single daily trials. For multiple trial sessions, all three parrots showed some limited improvement across 30 sessions. For single trial sessions, only one parrot showed any increase in seed acquisition across trials. This parrot was also able to consistently obtain two or more seeds per trial (across both multiple and single trial conditions) but was unable to able to wait 5 s to obtain the maximum number of seeds. This parrot was also tested on a slower rate of seed presentation, and this significantly reduced her mean seed acquisition in both multiple and single trial conditions, suggesting that both value of reward available and delay duration impact upon self-control. Further manipulation of both the visibility and proximity of seeds during delay maintenance had little impact upon tolerance of delays for both parrots tested in this condition. This task demanded not just a choice of delayed reward but the maintenance of delayed gratification and was clearly difficult for the parrots to learn; additional training or alternative paradigms are required to better understand the capacity for self-control in this and other species. PMID- 19777275 TI - Facilitation of learning spatial relations among locations by visual cues: generality across spatial configurations. AB - Spatial pattern learning permits the learning of the location of objects in space relative to each other without reference to discrete visual landmarks or environmental geometry. In the present experiment, we investigated conditions that facilitate spatial pattern learning. Specifically, human participants searched in a real environment or interactive 3-D computer-generated virtual environment open-field search task for four hidden goal locations arranged in a diamond configuration located in a 5 x 5 matrix of raised bins. Participants were randomly assigned to one of three groups: Pattern Only, Landmark + Pattern, or Cues + Pattern. All participants experienced a Training phase followed by a Testing phase. Visual cues were coincident with the goal locations during Training only in the Cues + Pattern group whereas a single visual cue at a non goal location maintained a consistent spatial relationship with the goal locations during Training only in the Landmark + Pattern group. All groups were then tested in the absence of visual cues. Results in both environments indicated that participants in all three groups learned the spatial configuration of goal locations. The presence of the visual cues during Training facilitated acquisition of the task for the Landmark + Pattern and Cues + Pattern groups compared to the Pattern Only group. During Testing the Landmark + Pattern and Cues + Pattern groups did not differ when their respective visual cues were removed. Furthermore, during Testing the performance of these two groups was superior to the Pattern Only group. Results generalize prior research to a different configuration of spatial locations, isolate spatial pattern learning as the process facilitated by visual cues, and indicate that the facilitation of learning spatial relations among locations by visual cues does not require coincident visual cues. PMID- 19777276 TI - Enhanced mitochondrial complex gene function and reduced liver size may mediate improved feed efficiency of beef cattle during compensatory growth. AB - Growing ruminants under extended dietary restriction exhibit compensatory growth upon ad libitum feeding, which is associated with increased feed efficiency, lower basal energy requirements, and changes in circulating concentrations of metabolic hormones. To identify mechanisms contributing to these physiological changes, 8-month-old steers were fed either ad libitum (control; n = 6) or 60-70% of intake of control animals (feed-restricted; n = 6) for a period of 12 weeks. All steers were fed ad libitum for the remaining 8 weeks of experimentation (realimentation). Liver was biopsied at days -14, +1, and +14 relative to realimentation for gene expression analysis by microarray hybridization. During early realimentation, feed-restricted steers exhibited greater rates of gain and feed efficiency than controls and an increase in expression of genes functioning in cellular metabolism, cholesterol biosynthesis, oxidative phosphorylation, glycolysis, and gluconeogenesis. Gene expression changes during feed restriction were similar to those reported in mice, indicating similar effects of caloric restriction across species. Based on expression of genes involved in cell division and growth and upregulation of genes encoding mitochondrial complex proteins in early realimentation, it was concluded that reduced hepatic size and increased mitochondrial function may contribute to improved feed efficiency observed during compensatory growth. PMID- 19777277 TI - Single flexible and semiflexible polymers at high shear: non-monotonic and non universal stretching response. AB - Using Brownian hydrodynamic simulation techniques, we study single polymers in shear. We investigate the effects of hydrodynamic interactions, excluded volume, chain extensibility, chain length and semiflexibility. The well-known stretching behavior with increasing shear rate [Formula: see text] is only observed for low shear [Formula: see text] < [Formula: see text] , where [Formula: see text] is the shear rate at maximum polymer extension. For intermediate shear rates [Formula: see text] < [Formula: see text] < [Formula: see text] the radius of gyration decreases with increasing shear with minimum chain extension at [Formula: see text] . For even higher shear [Formula: see text] < [Formula: see text] the chain exhibits again shear stretching. This non-monotonic stretching behavior is obtained in the presence of excluded-volume and hydrodynamic interactions for sufficiently long and inextensible flexible polymers, while it is completely absent for Gaussian extensible chains. We establish the heuristic scaling laws [Formula: see text] approximately N (-1.4) and [Formula: see text] approximately N (0.7) as a function of chain length N , which implies that the regime of shear-induced chain compression widens with increasing chain length. These scaling laws also imply that the chain response at high shear rates is not a universal function of the Weissenberg number Wi = [Formula: see text] [Formula: see text] anymore, where [Formula: see text] is the equilibrium relaxation time. For semiflexible polymers a similar non-monotonic stretching response is obtained. By extrapolating the simulation results to lengths corresponding to experimentally studied DNA molecules, we find that the shear rate [Formula: see text] to reach the compression regime is experimentally realizable. PMID- 19777278 TI - Adhesion and membrane tension of single vesicles and living cells using a micropipette-based technique. AB - The fundamental study of the adhesion of cells to each other or to a substrate is a key research topic in cellular biophysics because cell adhesion is important to many biological processes. We report on the adhesion of a model cell, a liposome, and a living HeLa cell to a substrate measured with a novel experimental technique. The cells are held at the end of a micropipette mounted on a micromanipulator and brought into contact with a surface. The adhesion energy and membrane tension are measured directly using the deflection of the micropipette when binding or unbinding the cell from the substrate. Since the force applied on the cells is known throughout the experiment, the technique presented enables the measurement of dynamics such as changes in the adhesion, elasticity, and membrane tension with time. PMID- 19777279 TI - Flow-correlated dilution of a regular network leads to a percolating network during tumor-induced angiogenesis. AB - We study a simplified stochastic model for the vascularization of a growing tumor, incorporating the formation of new blood vessels at the tumor periphery as well as their regression in the tumor center. The resulting morphology of the tumor vasculature differs drastically from the original one. We demonstrate that the probabilistic vessel collapse has to be correlated with the blood shear force in order to yield percolating network structures. The resulting tumor vasculature displays fractal properties. Fractal dimension, Micro-Vascular Density (MVD), blood flow and shear force have been computed for a wide range of parameters. PMID- 19777280 TI - Ground-state properties of tubelike flexible polymers. AB - In this work we investigate the structural properties of native states of a simple model for short flexible homopolymers, where the steric influence of monomeric side chains is effectively introduced by a thickness constraint. This geometric constraint is implemented through the concept of the global radius of curvature and affects the conformational topology of ground-state structures. A systematic analysis allows for a thickness-dependent classification of the dominant ground-state topologies. It turns out that helical structures, strands, rings, and coils are natural, intrinsic geometries of such tubelike objects. PMID- 19777281 TI - Obstructive sleep apnea as a risk factor for coronary events or cardiovascular death. AB - PURPOSE: This study aims to determine whether obstructive sleep apnea independently increases the risk of coronary events, including death from cardiovascular causes. METHODS: We conducted an observational cohort study among consecutive patients >or=50 years of age who were referred during 1997-2001 to the Yale Center for Sleep Medicine for suspected sleep-disordered breathing and were followed longitudinally for subsequent coronary events or cardiovascular death. Each study participant underwent an overnight polysomnography; obstructive sleep apnea was defined as an apnea-hypopnea index >or=5/h. The composite outcome during a mean duration of follow-up of 2.9 years was myocardial infarction, coronary artery revascularization procedures (angioplasty, stent placement, or coronary artery bypass graft surgery), or death from cardiovascular causes. RESULTS: Among 1,436 enrolled patients, 1,024 (71%) had an apnea-hypopnea index >or=5/h. In an unadjusted analysis, obstructive sleep apnea was associated with an increased risk of coronary events or cardiovascular death (hazard ration (HR) 2.57, 95% confidence interval (CI) 1.39-4.72, P = 0.003). After adjustment for traditional cardiovascular risk factors (including body mass index and hypertension), obstructive sleep apnea retained a statistically significant association with this composite outcome (HR 2.06, 95% CI 1.10-3.86, P = 0.024). CONCLUSION: Obstructive sleep apnea increases the risk of coronary events or death from cardiovascular causes. PMID- 19777283 TI - Ezetimibe inhibits expression of acid sphingomyelinase in liver and intestine. AB - Ezetimibe inhibits cholesterol absorption in the intestine. Sphingomyelin has strong interactions with cholesterol. We investigated the effects of ezetimibe on Sphingomyelinase (SMase) expression in intestine and liver. After feeding rats with ezetimibe (5 mg/kg per day) for 14 days, acid SMase activities in the liver and in the proximal part of small intestine were reduced by 34 and 25%, respectively. Alkaline SMase (alk-SMase) was increased in the proximal part of the small intestine. Administration of lower doses of ezetimibe reduced acid SMase only in the liver by 14% (P < 0.05). In cell culture studies, ezetimibe decreased acid SMase activity in Hep G2 and Caco-2 cells dose-dependently. The reductions were more rapid for Hep G2 cells than for Caco-2 cells. Western blot showed that acid SMase protein was decreased in both Hep G2 and Caco-2 cells by 100 microM ezetimibe. The SM content was increased in Hep G2 cells but not Caco-2 cells, and total cholesterol content was increased in both cell lines 24 h after stimulation with 100 microM ezetimibe. Mevastatin, the inhibitor of cholesterol synthesis, induced a mild increase in acid SMase activity in Hep G2 cells but not Caco-2 cells. Following the reduction of acid SMase, ezetimibe at high dose slightly increased alk-SMase activity. In conclusion, the study demonstrates an inhibitory effect of ezetimibe on acid SMase activity and expression in both liver and intestine. PMID- 19777284 TI - Multimodal visualization of a retrocardial bronchial artery aneurysm with rare origin from the distal descending aorta. PMID- 19777282 TI - Suppression in mevalonate synthesis mediates antitumor effects of combined statin and gamma-tocotrienol treatment. AB - Statins directly inhibit 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) activity, while gamma-tocotrienol, an isoform of vitamin E, enhances the degradation and reduces cellular levels of HMGR in various tumor cell lines. Since treatment with statins or gamma-tocotrienol alone induced a dose-responsive inhibition, whereas combined treatment with subeffective doses of these agents resulted in a synergistic inhibition in +SA mammary tumor cell growth, studies were conducted to investigate the role of the HMGR pathway in mediating the antiproliferative effects of combined low dose statin and gamma-tocotrienol. Treatment with 8 microM simvastatin inhibited cell growth and isoprenylation of Rap1A and Rab6, and supplementation with 2 microM mevalonate reversed these effects. However, the growth inhibitory effects of 4 microM gamma-tocotrienol were not dependent upon suppression in mevalonate synthesis. Treatment with subeffective doses of simvastatin (0.25 microM), lovastatin (0.25 microM), mevastatin (0.25 microM), pravastatin (10 microM), or gamma-tocotrienol (2 muM) alone had no effect on protein prenylation or mitogenic signaling, whereas combined treatment with these agents resulted in a significant inhibition in +SA cell growth, and a corresponding decrease in total HMGR, Rap1A and Rab6 prenylation, and MAPK signaling, and mevalonate supplementation reversed these effects. These findings demonstrate that the synergistic antiproliferative effects of combined low dose statin and gamma-tocotrienol treatment are directly related to an inhibition in HMGR activity and subsequent suppression in mevalonate synthesis. PMID- 19777285 TI - Anaplastic oligo-astrocytoma occurring after resection of a cerebral cavernous malformation; malignant transformation? Case report and review on etiology. AB - We report a 71-year-old woman who presented with a cerebral cavernous malformation in the right frontal lobe for which she underwent total resection. Three years later, she was admitted with seizures and neuroimaging revealed a partially calcified lesion in the area of the earlier cavernous malformation, consistent with a residual malformation. A few months later she presented with cognitive decline and neuroimaging now revealed a large mass lesion in the same area as the cavernous malformation, irregularly enhancing, spreading through the corpus callosum to the left frontal lobe. Histological examination showed an anaplastic oligo-astrocytoma. These findings suggest that cerebral cavernous malformations, or at least a subgroup, have the potential for oligodendrocytic and astrocytic transformation. Various hypotheses to explain the etiology of these rare cases are discussed. PMID- 19777286 TI - Relationship among psychopathological dimensions, coping mechanisms, and glycemic control in a Croatian sample of adolescents with diabetes mellitus type 1. AB - Psychopathological factors associated with metabolic control in juvenile insulin dependent diabetes mellitus (IDDM) deserve further investigation. This study assessed the relationship among specific psychopathological dimensions, coping mechanisms, and metabolic control in a Croatian clinical sample of adolescents with IDDM. One-hundred and one adolescents (aged 11-18) with IDDM filled out the youth self report (YSR) assessing psychopathological dimension and the scale of coping with stress (SCS). Glycemic control was estimated by the percentage of glycated hemoglobin (HbA1c). Subjects were divided into three groups according to HbA1C values: "optimal", "suboptimal control", and "at high risk". Subjects in optimal glycemic control presented with significantly lower scores in most of YSR scales compared to subjects at high risk. Moreover, they had significantly lower scores in avoidance and emotional reactivity and significantly higher scores in cognitive restructuring and problem solving SCS subscales. Regression models revealed that both internalizing and externalizing YSR scores, as well as emotional reactivity coping scores, independently contributed to explain variability of HbA1C values. Both internalizing and externalizing psychopathological dimensions, as well as emotion-oriented coping strategies, are independently associated with poor metabolic control in both boys and girls with IDDM, thus representing potential interest targets of psychotherapeutic interventions aimed at improving glycemic control in this population. PMID- 19777287 TI - Childhood loneliness as a predictor of adolescent depressive symptoms: an 8-year longitudinal study. AB - Childhood loneliness is characterised by children's perceived dissatisfaction with aspects of their social relationships. This 8-year prospective study investigates whether loneliness in childhood predicts depressive symptoms in adolescence, controlling for early childhood indicators of emotional problems and a sociometric measure of peer social preference. 296 children were tested in the infant years of primary school (T1 5 years of age), in the upper primary school (T2 9 years of age) and in secondary school (T3 13 years of age). At T1, children completed the loneliness assessment and sociometric interview. Their teachers completed externalisation and internalisation rating scales for each child. At T2, children completed a loneliness assessment, a measure of depressive symptoms, and the sociometric interview. At T3, children completed the depressive symptom assessment. An SEM analysis showed that depressive symptoms in early adolescence (age 13) were predicted by reports of depressive symptoms at age 8, which were themselves predicted by internalisation in the infant school (5 years). The interactive effect of loneliness at 5 and 9, indicative of prolonged loneliness in childhood, also predicted depressive symptoms at age 13. Parent and peer related loneliness at age 5 and 9, peer acceptance variables, and duration of parent loneliness did not predict depression. Our results suggest that enduring peer-related loneliness during childhood constitutes an interpersonal stressor that predisposes children to adolescent depressive symptoms. Possible mediators are discussed. PMID- 19777288 TI - Arterial supply to the pancreas; variations and cross-sectional anatomy. AB - The pancreas has complex arterial supplies. Therefore, special attention should be paid in pancreatic arterial intervention for patients with acute pancreatitis and pancreatic carcinomas. Knowledge of pancreatic arterial anatomy and arterial territory is important not only to perform pancreatic arterial intervention, but to read the pancreatic angiography and cross-sectional image. We reviewed 226 selective abdominal angiography and CT scans during selective arteriography (CTA) of common hepatic artery, superior mesenteric artery, splenic artery, or peripancreatic arteries including posterior superior pancreaticoduodenal artery, anterior superior pancreaticoduodenal artery, inferior pancreaticoduodenal artery, and dorsal pancreatic artery. CTA images were evaluated to clarify the cross-sectional anatomy of the pancreatic arterial territory. Variations of the peripancreatic arteries were also investigated. In this exhibit, schemes and illustrative cases demonstrate pancreatic arterial territory and variations. PMID- 19777289 TI - Invasive carcinomas originating from intraductal papillary mucinous neoplasms of the pancreas: conspicuity and primary sites of the solid masses on triple-phase dynamic CT imaging. AB - OBJECTIVE: To assess the conspicuity of invasive carcinomas (solid masses) originating from pancreatic intraductal papillary mucinous neoplasms (invasive IPMNs) and the primary sites of the solid masses on thin-slice dynamic CT. METHODS: Twenty patients with pathologically proven invasive IPMNs underwent triple-phase dynamic CT examinations (arterial, portal, and delayed phases). Qualitative and quantitative analyses of conspicuity of the solid masses were performed for all phases. The primary sites [branch duct and/or main pancreatic duct (MPD)] of the solid masses were evaluated on CT in comparison to the pathologic findings. RESULTS: The qualitative and quantitative analyses of the conspicuity of the solid masses showed that the arterial phase images were superior to those of the portal and delayed phases. The primary sites of the solid mass were histopathologically diagnosed as branch ducts in 6 (30%) patients, MPD in 13 (65%), and both branch ducts and the MPD in one (5%). The sensitivity and specificity of the CT evaluation of the primary sites were 100% for the branch ducts, and for the MPD 93% and 100%, respectively. CONCLUSION: Arterial phase images are useful for the diagnosis of invasive IPMNs, and attention should be paid to pancreatic parenchyma surrounding the MPD when detecting invasive carcinomas. PMID- 19777290 TI - CT colonography versus double-contrast barium enema for screening of colorectal cancer: comparison of radiation burden. AB - Our aim is to compare the radiation dose associated with a low-dose CT colonography (CTC) protocol for colorectal cancer screening with that delivered by double-contrast barium enema (DCBE). CTC of twenty asymptomatic individuals (M:F = 10:10) participating to a colorectal cancer screening program and DCBE of fifteen patients (M:F = 6:9) were evaluated. For CTC, absorbed dose was determined by calculating the dose-length product for each CTC examination from measurements on a CT dose phantom equipped with a CT ion chamber. For DCBE, the free-in-air Kerma at the patient's X-ray entry surface and the Kerma-area product during fluoroscopy and fluorography were measured with a Barracuda system, with fluoroscopy times being recorded blinded to the performing operator. Effective dose at CTC was 2.17 +/- 0.12 mSv, with good and excellent image quality in 14/20 (70%) and 6/20 cases (30%), respectively. With DCBE, effective patient dose was 4.12 +/- 0.17 mSv, 1.9 times greater than CTC (P < 0.0001). Our results show that effective dose from screening CTC is substantially lower than that from DCBE, suggesting that CTC is the radiological imaging technique of the large bowel with the lowest risk of stochastic radiation effects. PMID- 19777291 TI - Assessing critical source areas in watersheds for conservation buffer planning and riparian restoration. AB - A science-based geographic information system (GIS) approach is presented to target critical source areas in watersheds for conservation buffer placement. Critical source areas are the intersection of hydrologically sensitive areas and pollutant source areas in watersheds. Hydrologically sensitive areas are areas that actively generate runoff in the watershed and are derived using a modified topographic index approach based on variable source area hydrology. Pollutant source areas are the areas in watersheds that are actively and intensively used for such activities as agricultural production. The method is applied to the Neshanic River watershed in Hunterdon County, New Jersey. The capacity of the topographic index in predicting the spatial pattern of runoff generation and the runoff contribution to stream flow in the watershed is evaluated. A simple cost effectiveness assessment is conducted to compare the conservation buffer placement scenario based on this GIS method to conventional riparian buffer scenarios for placing conservation buffers in agricultural lands in the watershed. The results show that the topographic index reasonably predicts the runoff generation in the watershed. The GIS-based conservation buffer scenario appears to be more cost-effective than the conventional riparian buffer scenarios. PMID- 19777292 TI - An empirical analysis of the effects of China's Land Conversion Program on farmers' income growth and labor transfer. AB - In this article, we hypothesize that in addition to participation status and household characteristics, the impact of China's Sloping Land Conversion Program on income growth and labor transfer is determined by local economic conditions, program range, and political leadership, and the degree of impact on income may vary among different economic sectors. To test these propositions, we have compiled a panel data set of 600 households in three counties in the Loess Plateau region, with observations for times both prior to and after the program's inception (1999 and 2006), for both aggregate and categorical incomes, and for both participating and non-participating households. Using a difference in differences model and repeated cross-sectional data, we find that participation status, local economic conditions, program extent, and political leadership indeed have significant impacts on household income and off-farm employment. Moreover, the effects of participation on crop production income, animal husbandry income, and off-farm income vary substantially. These results carry major policy implications in terms of how to improve the effectiveness and impact of ecological restoration efforts in and outside of China. PMID- 19777293 TI - Landscapes of protection: forest change and fragmentation in Northern West Bengal, India. AB - In the tropics and sub-tropics, where high levels of biodiversity co-exist with some of the greatest levels of population density, achieving complete exclusion in protected area contexts has proved close to impossible. There is a clear need to recognize that parks are significantly impacted by human-environment interactions in the larger landscape within which they are embedded, and to move the frontier of research beyond the boundaries of protected areas in order to examine larger landscapes where multiple forms of ownership and access are embedded. This research evaluates forest change and fragmentation between 1990 and 2000, in a landscape surrounding the Mahananda Wildlife Sanctuary in the Indian state of West Bengal. This protected forest is bounded to the south by a less intensively protected area, the Baikunthapur Reserve Forest, and surrounded by a mosaic of unprotected, largely private land holdings. Results indicate differences in the extent and spatial pattern of forest cover change in these three zones, corresponding to different levels of government protection, access and monitoring. The two protected areas experience a trend toward forest regrowth, relating to the cessation of commercial logging by park management during this period. Yet, there is still substantial clearing toward peripheral areas that are well connected to illegal timber markets by transportation networks. The surrounding landscape, although experiencing some forest regrowth within less intensively cultivated tea plantations, is also becoming increasingly fragmented, with potentially critical impacts on the maintenance of effective wildlife corridors in this ecologically critical region. PMID- 19777294 TI - Superfund, hedonics, and the scales of environmental justice. AB - Environmental justice (EJ) is prominent in environmental policy, yet EJ research is plagued by debates over methodological procedures. A well-established economic approach, the hedonic price method, can offer guidance on one contentious aspect of EJ research: the choice of the spatial unit of analysis. Environmental managers charged with preventing or remedying inequities grapple with these framing problems. This article reviews the theoretical and empirical literature on unit choice in EJ, as well as research employing hedonic pricing to assess the spatial extent of hazardous waste site impacts. The insights from hedonics are demonstrated in a series of EJ analyses for a national inventory of Superfund sites. First, as evidence of injustice exhibits substantial sensitivity to the choice of spatial unit, hedonics suggests some units conform better to Superfund impacts than others. Second, hedonic estimates for a particular site can inform the design of appropriate tests of environmental inequity for that site. Implications for policymakers and practitioners of EJ analyses are discussed. PMID- 19777295 TI - Residents' yard choices and rationales in a desert city: social priorities, ecological impacts, and decision tradeoffs. AB - As a dominant land use in urban ecosystems, residential yards impact water and other environmental resources. Converting thirsty lawns into alternative landscapes is one approach to water conservation, yet barriers such as cultural norms reinforce the traditional lawn. Meanwhile, the complex social and ecological implications of yard choices complicate programs aimed at changing grass and other yard features for particular purposes. In order to better understand individual landscape decisions, we qualitatively examined residents' rationales for their preferred yard types in the desert metropolis of Phoenix, Arizona. After briefly presenting landscape choices across two survey samples, the dominant reasons for preferences are discussed: appearance, maintenance, environment, recreation, microclimate, familiarity, and health/safety. Three broader analytical themes emerged from these descriptive codes: (1) residents' desires for attractive, comfortable landscapes of leisure encompassing pluralistic tastes, lifestyles, and perceptions; (2) the association of environmental benefits and impacts with different landscape types involving complex social and ecological tradeoffs; and (3) the cultural legacies evident in modern landscape choices, especially in terms of a dichotomous human-nature worldview among long-time residents of the Phoenix oasis. Given these findings, programs aimed at landscape change must recognize diverse preferences and rationalization processes, along with the perceived versus actual impacts and tradeoffs of varying yard alternatives. PMID- 19777298 TI - Ultrasound-guided vacuum-assisted breast biopsy system for diagnosis and minimally invasive excision of intraductal papilloma without nipple discharge. AB - BACKGROUND: As intraductal papilloma (IP) includes both benign and malignant lesions, it is difficult to decide whether the patient should merely be followed up. The purpose of this study is to validate the ultrasound (US)-guided vacuum assisted breast biopsy system (Mammotome) for diagnosis and minimally invasive excision of IP. METHODS: Six women with breast cystic-solid lesions without nipple discharge underwent B-US-guided 8-gauge Mammotome biopsy. Interval US surveillance was performed at a median time of 7 months (range 5-12 months). RESULTS: All lesions were removed accurately and thoroughly with satisfactory cosmetic outcomes. All of them were histologically diagnosed as IP. No clinically significant hematoma developed. CONCLUSIONS: The US-guided 8-gauge Mammotome biopsy provides an accurate pathologic diagnosis and successful complete excision of cystic-solid breast lesions. This technique appears to be an alternative to surgical biopsy in IP patients without nipple discharge. PMID- 19777296 TI - Early reoperation after laparoscopic fundoplication: the importance of routine postoperative contrast studies. AB - BACKGROUND: The necessity for routine postoperative contrast studies following laparoscopic fundoplication for either gastroesophageal reflux disease or paraesophageal hernia is unclear. METHODS: To determine whether a routine contrast X-ray film influenced surgical decision making following laparoscopic fundoplication, we reviewed records from a prospective database of 1,894 patients who underwent a primary laparoscopic fundoplication for gastroesophageal reflux disease or paraesophageal hernia between October 1991 and June 2008, and identified those who underwent early reoperation. The value of early routine postoperative barium swallow examinations in the management of these patients was then determined. RESULTS: The review showed that 53 patients (2.8%) underwent reoperative procedures within seven days of their original operation: 21 had originally undergone surgery for a paraesophageal hernia, and 32 for reflux. Of the 53 patients who underwent reoperation, 25 (47.2%) were treated for dysphagia, 17 (32.1%) for acute paraesophageal hernia, 6 (11.3%) for a gastrointestinal leak, and 5 (9.4%) for bleeding or peritonitis. Fifteen of the 17 patients who underwent repair of an acute hiatus hernia (0.8% of all patients) had no symptoms and underwent reoperative surgery because of radiological findings alone. Primary surgery for a large hiatus hernia was associated with a higher incidence of early reoperation (5.2 vs. 2.2%; P = 0.001). CONCLUSIONS: Approximately 1 in 125 patients who underwent laparoscopic surgery for reflux or a large hiatus hernia had an important finding on an early postoperative contrast swallow, and benefited from this investigation by undergoing early reoperative intervention. PMID- 19777299 TI - Ultrasound-guided radiofrequency thermal ablation of uterine fibroids: medium term follow-up. AB - Previous studies have shown that radiofrequency thermal ablation (RFA) of uterine fibroids through a percutaneous ultrasound (US)-guided procedure is an effective and safe minimally invasive treatment, with encouraging short-term results. The aim of this study was to assess the results in terms of volume reduction and clinical symptoms improvement in the midterm follow-up of fibroids with a diameter of up to 8 cm. Eleven premenopausal females affected by symptomatic fibroids underwent percutaneous US-guided RFA. Symptom severity and reduction in volume were evaluated at 1, 3, 6, 9, and 12 months. The mean symptom score (SSS) before the procedure was 50.30 (range 31.8-67.30), and the average quality of life (QOL) score value was 62 (range 37.20-86.00). The mean basal diameter was 5.5 cm (range 4.4-8) and the mean volume was 101.5 cm(3) (range 44.58-278 cm(3)). The mean follow-up was 9 months (range 3-12 months). The mean SSS value at the end of the follow-up was 13.38 (range 0-67.1) and the QOL 90.4 (range 43.8-100). At follow-up the mean diameter was 3.0 cm (range 1.20-4.5 cm), and the mean volume was 18 cm(3) (range 0.90-47.6 cm(3)). In 10 of 11 patients we obtained total or partial regression of symptoms. In one case the clinical manifestations persisted and it was thus considered unsuccessful. In conclusion, US-guided percutaneous RFA is a safe and effective treatment even for fibroids up to 8 cm. PMID- 19777300 TI - Percutaneous intraluminal recanalization of long, chronic superficial femoral and popliteal occlusions using the Frontrunner XP CTO device: a single-center experience. AB - The purpose of this study was to examine the safety and efficacy of the Frontrunner XP CTO (chronic total occlusion) Catheter (Cordis) for recanalization of long femoropopliteal artery occlusions. A Frontrunner catheter was used to treat 26 CTOs in SFA after guidewire failure (68.3 +/- 8.8 years). Sixty-seven percent of patients had severe claudication. Critical lower limb ischemia with rest pain or minor tissue loss was present in three and eight patients, respectively. All the lesions were considered complex (TASC B, C, and D); 68% of the lesions were heavily calcified. The mean lesion length was 17.6 cm (range, 10 42 cm). The initial attempt to cross the occlusion with the CTO guidewire V18 was unsuccessful in 26 of 76 limbs (34.26%). A secondary attempt using the Frontrunner catheter (crossover approach, 27%; antegrade, 73%) performed in all 26 failed cases was successful in 17 limbs (65.38%), increasing the technical success rate to 88.12%. The main reasons for failure with the Frontrunner were inability to cross the lesion due to heavy calcification (six of nine) and inability to re-enter the true lumen after subintimal passage of the occluded segment (three of nine). The mean fluoroscopy time was 22.9 min. Minor complications included one distal extension of the dissection with involvement of the first popliteal segment and one perforation in the occluded segment. No major complications were seen. In conclusion, recanalization with the Frontrunner CTO catheter is a simple and safe method with a high technical success rate in the endovascular treatment of long superficial femoral artery occlusions and should be an alternative method after guidewire failure. PMID- 19777301 TI - Molecular and biochemical approaches for characterization of antifungal trait of a potent biocontrol agent Bacillus subtilis RP24. AB - Bacillus subtilis strain RP24, isolated from rhizoplane of field grown pigeon pea, exhibited in vitro antagonism against a wide range of phytopathogenic fungi. An attempt was made to partially purify and characterize the diffusible antifungal metabolite/s produced by the strain RP24 and its negative mutant (NM) in potato dextrose medium. High performance liquid chromatography (HPLC) of partially purified extract of RP24 showed the presence of lipopeptide antibiotic iturin as a major peak that was comparable to that of standard iturin A (5.230 min) from Sigma-Aldrich whereas the corresponding peak was absent in extract of NM. The structure was further confirmed by liquid chromatographic mass spectrometric (LCMS) analysis as iturin A. LCMS analysis also showed the presence of surfactin and fengycin besides iturin A. Amplification of the lpa-14 (encodes the 4'-phosphopantetheinyl transferase required for the maturation of template enzyme of iturin A) and ituD (encodes a putative malonyl coenzyme A transacylase, whose disruption results in a specific deficiency in iturin A production) genes of iturin operon of strain RP24 was carried out and the sequences obtained were compared with the existing database of NCBI. The sequences of lpa-14 and ituD gene of RP24 showed 98% and 97% homology with lpa-14 and ituD genes of B. subtilis in the existing database. The results indicated that strain RP24 harbors iturin operon in its genome and a chemical mutation in this operon might have resulted in loss of antifungal activity in the negative mutant. PMID- 19777302 TI - ISSR as new markers for identification of homokaryotic protoclones of Agaricus bisporus. AB - To accelerate the breeding of Agaricus bisporus, quick and reliable methods to identify the infrequent homokaryons are necessary. A new marker, inter simple sequence repeat (ISSR) fingerprinting, is described for differentiation of homo- and hetero-karyotic protoclones. Nine slow growing protoclones, two strandy and seven appressed, were analyzed for the first time with ISSR amplifications. The patterns were highly polymorphic and very reproducible. Among 40 primers tested, 7 ISSR primers were selected for the analysis of genomic DNA and generated a total of 68 ISSR fragments. ISSR fingerprinting detected 44.12% polymorphic loci. All appressed homokaryons carried a subset of ISSR markers found in the heterokaryons, and clustered separately in dendrogram. These were not able to produce a fruiting body. A test of cross-fertility and the following fruiting trial proved that 7 of the 9 protoclones with different ISSR fingerprints were homokaryons. These results demonstrated that ISSR markers provide an efficient alternate for identification of homokaryons and suggest these markers be considered as new tools for the survey of Agaricus species. PMID- 19777303 TI - Succinic acid production with Actinobacillus succinogenes ZT-130 in the presence of succinic acid. AB - Glucose fermentation with Actinobacillus succinogenes was carried out at different initial concentrations of succinic acid (SA(0)) to determine its effect on growth and on the production of succinic acid itself. The specific rates of biomass production, succinic, formic and acetic acids decreased with SA(0) (0-40 g/l). The partially dissociated form of succinic acid had a higher effect on cell growth and production of succinic acid as compared to the non-dissociated forms of the acids, a fact that has not been reported until now. Cell growth fitted the Jerusalimski model, and the Aiba-Shoda model was suitable for quantification of the inhibition for the production of succinic acid. The growth inhibition constants K(is) and K(ip) and their summatory were consistent with the experimental values obtained, i.e., 22 g/l for the produced acids and 38 g/l for total acids that were the limits at which the biomass formation ceased. PMID- 19777304 TI - Occurrence of methanogenic Archaea in highly polluted sediments of tropical Santos-Sao Vicente Estuary (Sao Paulo, Brazil). AB - Little is known about the ability of methanogens to grow and produce methane in estuarine environments. In this study, traditional methods for cultivating strictly anaerobic microorganisms were combined with Fluorescence in situ hybridization (FISH) technique to enrich and identify methanogenic Archaea cultures occurring in highly polluted sediments of tropical Santos-Sao Vicente Estuary (Sao Paulo, Brazil). Sediment samples were enriched at 30 degrees C under strict anaerobic and halophilic conditions, using a basal medium containing 2% of sodium chloride and amended with glucose, methanol, and sodium salts of acetate, formate and lactate. High methanogenic activity was detected, as evidenced by the biogas containing 11.5 mmol of methane at 20 days of incubation time and methane yield of 0.138-mmol CH(4)/g organic matter/g volatile suspense solids. Cells of methanogenic Archaea were selected by serial dilution in medium amended separately with sodium acetate, sodium formate, or methanol. FISH analysis revealed the presence of Methanobacteriaceae and Methanosarcina sp. cells. PMID- 19777305 TI - Xylitol and erythritol decrease adherence of polysaccharide-producing oral streptococci. AB - Xylitol consumption decreases counts of mutans streptococci. However, the mechanism behind this decrease is not well understood. We studied not only type strains and clinical isolates of mutans streptococci, but also other polysaccharide-forming oral streptococci. Growth inhibition and adherence of cells to a smooth glass surface-reflecting synthesis of water-insoluble polysaccharides were studied in the presence of 2% (0.13 mol/l) and 4% (0.26 mol/l) xylitol. The effect of xylitol was compared to a novel polyol sweetener, erythritol. Except for Streptococcus mutans 10449 and S. sobrinus OMZ 176, the glass surface adhesion of most polysaccharide-forming streptococci was reduced by the presence of both 4% xylitol and erythritol. For the S. mutans and S. sobrinus type strains, the growth inhibition with 4% xylitol and erythritol was 36-77% and for the clinical S. mutans isolates 13-73%. Of the other oral streptococci, only S. sanguinis was inhibited with 4% xylitol (45-55%). For both polyols, the magnitude of the growth inhibition observed was not associated with the magnitude of the decrease in adherence (xylitol: r = -0.18; erythritol: r = 0.49). In conclusion, both xylitol and erythritol can decrease polysaccharide-mediated cell adherence contributing to plaque accumulation through a mechanism not dependent on growth inhibition. PMID- 19777306 TI - Cryptococcus shivajii sp. nov.: a novel basidiomycetous yeast isolated from biogas reactor. AB - Five yeast morphotypes were isolated from biogas reactors at North Wyke Research, Okehampton, UK. Out of the five morphotypes, four were identified as known species. In contrast, the fifth morphotype strain, Bio10(T), was found to differ from Bullera dendrophila and Kwoniella mangroviensis, its closest phylogenetic neighbours, by 2.6-2.9% with respect to the nucleotide sequence of the D1/D2 domain of the 26S rRNA gene and by 5.6-6.2% with respect to the internal transcribed spacer 1 (ITS1)-5.8S rRNA gene-ITS2 region. Bio10(T) also differs from these two species by a number of phenotypic characteristics. Thus, based on the phenotypic differences and phylogenetic analysis, strain Bio10(T) is assigned the status of a new species of Cryptococcus, for which the name Cryptococcus shivajii sp. nov. is proposed. The type strain is Bio10(T) (NCYC 3541(T) = CBS 11374(T)). PMID- 19777307 TI - Antimicrobial activity, inhibition of urogenital pathogens, and synergistic interactions between lactobacillus strains. AB - Lactobacillus fermentum strain L23 and L. rhamnosus strain L60 were selected as an alternative treatment to prevent or treat urogenital infections based on their probiotic properties and production of bacteriocins. The objectives of the present work were to study the inhibitory activities of these two bacteriocin producing strains, and to analyze the interactions between pairs of bacteriocins that inhibit urogenital pathogens. Antimicrobial activity tests of L23 and L60 were performed by a diffusion method with 207 bacterial strains, isolated from female patients presenting a urogenital infection. Inhibitory substances interaction tests were carried out by using a streak-diffusion method on agar plates. One hundred percent of the clinical isolates showed sensitivity to the antimicrobial substances produced by L23 and L60. The selected lactobacilli produced larger inhibition halos when compared to several antibiotics commonly used for treating these infections. Synergistic interactions and indifferent interactions were recorded in 68.6% and 31.4% of the cases, respectively. No antagonistic interactions were observed. In conclusion, the bacteriocin-producing strains L23 and L60 are potential candidates for probiotic prophylaxis and treatment of urogenital disorders in women. PMID- 19777308 TI - A species-generalized probabilistic model-based definition of CpG islands. AB - The DNA of most vertebrates is depleted in CpG dinucleotides, the target for DNA methylation. The remaining CpGs tend to cluster in regions referred to as CpG islands (CGI). CGI have been useful as marking functionally relevant epigenetic loci for genome studies. For example, CGI are enriched in the promoters of vertebrate genes and thought to play an important role in regulation. Currently, CGI are defined algorithmically as an observed-to-expected ratio (O/E) of CpG greater than 0.6, G+C content greater than 0.5, and usually but not necessarily greater than a certain length. Here we find that the current definition leaves out important CpG clusters associated with epigenetic marks, relevant to development and disease, and does not apply at all to nonvertabrate genomes. We propose an alternative Hidden Markov model-based approach that solves these problems. We fit our model to genomes from 30 species, and the results support a new epigenomic view toward the development of DNA methylation in species diversity and evolution. The O/E of CpG in islands and nonislands segregated closely phylogenetically and showed substantial loss in both groups in animals of greater complexity, while maintaining a nearly constant difference in CpG O/E between islands and nonisland compartments. Lists of CGI for some species are available at http://www.rafalab.org . PMID- 19777309 TI - Developing and verifying the psychometric integrity of the certification examination for imaging informatics professionals. AB - The American Board of Imaging Informatics (ABII) was founded in 2005 by the Society of Imaging Informatics in Medicine (SIIM) and the American Registry of Radiologic Technologists (ARRT). ABII's mission is to enhance patient care, professionalism, and competence in imaging informatics. This is accomplished primarily through the development and administration of a certification examination. The creation of the exam has been an exercise in open community involvement with SIIM providing access to the PACS community and ARRT providing skilled psychometric support to ensure a balanced and comprehensive examination. The process to generate the exam required several years and the efforts of dozens of subject matter experts active who volunteered to submit and validate questions for the examination. This article describes the organizational and statistical processes used to generate test items, assemble test forms, set performance standards, and validate test scores. PMID- 19777310 TI - Feeding deterrence and detrimental effects of pyrrolizidine alkaloids fed to honey bees (Apis mellifera). AB - Recent studies have shown the occurrence of plant derived pyrrolizidine alkaloids (PAs) in retail honeys and pollen loads, but little is known about how these compounds influence the fitness of foraging honey bees. In feeding experiments, we tested a mix of tertiary PAs and the corresponding N-oxides from Senecio vernalis, pure monocrotaline, and 1,2-dihydromonocrotaline in 50% (w/w) sucrose solutions. The bees were analyzed chemically to correlate the observed effects to the ingested amount of PAs. PA-N-oxides were deterrent at concentrations >0.2%. 1,2-Unsaturated tertiary PAs were toxic at high concentrations. The observed PAs mortality could be linked directly to the presence of the 1,2-double bond, a well established essential feature of PA cytotoxicity. In contrast, feeding experiments with 1,2-dihydromonocrotaline revealed no toxic effects. Levels of less than 50 microg 1,2-unsaturated tertiary PAs per individual adult bee were tolerated without negative effects. PA-N-oxides fed to bees were reduced partially to the corresponding tertiary PAs. Unlike some specialized insects, bees are not able to actively detoxify PAs through N-oxidation. To gain insight into how PAs are transmitted among bees, we tested for horizontal PA transfer (trophallaxis). Under laboratory conditions, up to 15% of an ingested PA diet was exchanged from bee to bee, disclosing a possible route for incorporation into the honey comb. In the absence of alternative nectar and pollen sources, PA containing plants might exhibit a threat to vulnerable bee larvae, and this might affect the overall colony fitness. PMID- 19777311 TI - Corymbia species and hybrids: chemical and physical foliar attributes and implications for herbivory. AB - Hybridization is an important biological phenomenon that can be used to understand the evolutionary process of speciation of plants and their associated pests and diseases. Interactions between hybrid plants and the herbivores of the parental taxa may be used to elucidate the various cues being used by the pests for host location or other processes. The chemical composition of plants, and their physical foliar attributes, including leaf thickness, trichome density, moisture content and specific leaf weight were compared between allopatric pure and commercial hybrid species of Corymbia, an important subtropical hardwood taxon. The leaf-eating beetle Paropsis atomaria, to which the pure taxa represented host (C. citriodora subsp. variegata) and non-host (C. torelliana) plants, was used to examine patterns of herbivory in relation to these traits. Hybrid physical foliar traits, chemical profiles, and field and laboratory beetle feeding preference, while showing some variability, were generally intermediate to those exhibited by parent taxa, thus suggesting an additive inheritance pattern. The hybrid susceptibility hypothesis was not supported by our field or laboratory studies, and there was no strong relationship between adult preference and larval performance. The most-preferred adult host was the sympatric taxon, although this species supported the lowest larval survival, while the hybrid produced significantly smaller pupae than the pure species. The results are discussed in relation to plant chemistry and physical characteristics. The findings suggest a chemical basis for host selection behavior and indicate that it may be possible to select for resistance to this insect pest in these commercially important hardwood trees. PMID- 19777312 TI - Surgical gastrostomy for pancreatobiliary and duodenal access following Roux en Y gastric bypass. AB - BACKGROUND: Pancreatobiliary access following Roux-en-Y gastric bypass (RYGBP) is challenging. We reviewed 32 cases of surgical gastrostomy for complex transgastric upper gastrointestinal endoscopy. METHODS: Retrospective review of prospectively collected database of patients with history of RYGBP that had surgical gastrostomy for pancreatobiliary and duodenal access at a single institution from 2004-2008. Indication for procedure, surgical findings, successful cannulation, and complications are reported. RESULTS: Thirty patients (25 female), with age ranging from 27 to 72, underwent 32 procedures. The indications to access the gastric remnant were sphincter of Oddi dysfunction (13), pancreatitis (six), common bile duct stone/obstruction (five), cholangitis (three), pancreatic mass evaluation (two), gastrointestinal bleed (two), and cystic duct leak after cholecystectomy (one). Mean operative time was 200 min (98 338) and estimated blood loss (mean) 85 cc (10-500). Laparoscopic gastrostomy was attempted in 28 cases with one conversion to open (3.6%). Four planned open procedures were also performed. All 30 patients underwent successful endoscopy and 28 had an endoscopic retrograde cholangiopancreatography, all with successful cannulation of the pancreatobiliary tree (100%). CONCLUSIONS: Surgical gastrostomy is an effective means to gain access to the upper GI tract and pancreatobiliary tree following RYGBP. This technique should be considered when traditional endoscopic approaches are impossible. PMID- 19777313 TI - Is esophagectomy the paradigm for volume-outcome relationships? AB - INTRODUCTION: Esophagectomy is considered one of the most complicated, difficult to perform, and physiologically altering operations performed by surgeons. DISCUSSION: Outcome, not only depends upon surgeon and hospital volume but also involves a "supporting cast" of health professionals, such as physical therapy and ICU. The complementary skill set of the surgeon may also influence esophagectomy outcomes. CONCLUSIONS: Young surgeons can perform esophagectomy with low mortality while their volume increases if they engage and involve all of the components in this paradigm. PMID- 19777314 TI - Initial experience with new intraluminal devices for GERD, Barrett's esophagus, and obesity. AB - BACKGROUND: Transoral intraluminal surgery is less painful. However, endoscopic antireflux procedures have been unsuccessful, endoscopic foregut mucosal excision procedures are often difficult to perform, and endoscopic intra-luminal suturing is both imprecise and too shallow. We have endeavored to correct these deficiencies and report here new devices for GERD, obesity, and Barrett's mucosal excision. METHOD: A retrospective review of ex vivo and in vivo animal experiments using sharp blade mucosal excision for esophageal and gastric mucosa and a suturing device with transverse needles designed to full thickness penetrate the gastric wall were completed. A total of 338 excisions were performed in 134 ex vivo tissue experiments and in 119 in vivo attempts. Suture needle testing was performed in ex vivo human stomachs and porcine stomachs and in in vivo canine and baboon stomachs. RESULTS: One excision perforation (0.9%) occurred in a live animal. Satisfactory mucosal excision depth for the Barrett's device was reproducible. Progressive suture actuation reliability improved from 83% during ex vivo testing to 96.7% in in vivo experiments. CONCLUSION: The results demonstrate feasibility, reliability, and safety for gastric and esophageal mucosal excision. Suturing reliability improved and further studies will be performed to finalize the instrument designs, the operative techniques, and the other device applications. PMID- 19777315 TI - Tumor relapse after pancreatic cancer resection is detected earlier by 18-FDG PET than by CT. AB - INTRODUCTION: Pancreatic cancer recurrence is often difficult to detect by conventional imaging. Our aim was to evaluate the impact of fluorodeoxyglucose positron emission tomography (FDG-PET) in the diagnosis of recurrent pancreatic cancer. METHODS: One-hundred thirty-eight patients were followed after resection for pancreatic cancer. Sixty-six underwent only CT and were excluded. Seventy-two patients also had FDG-PET. Recurrent patients were divided in two groups: group 1, CT positive and group 2, CT non diagnostic, FDG-PET positive. Characteristics and survival curves of the two groups were compared. Significance was set at p < 0.05. RESULTS: Overall, tumors recurred in 63 of 72 (87.5%) patients; two patients had a second cancer resected, thanks to FDG-PET. Tumor relapse was detected by CT in 35 patients and by FDG-PET in 61. Prognostic factors were similar in groups 1 and 2. Five out of 35 group 1 patients underwent surgery (two R0, two bypass, and one exploratory). Ten out of 28 group 2 patients underwent surgery (four R0, two R2, two bypass, and two exploratory). FDG-PET influenced treatment strategies in 32 of 72 patients (44.4%). Group 2 patients survived longer (P = 0.09), but the difference was not significant. Disease-free survival was similar in groups 1 and 2. CONCLUSION: Tumor relapse is detected earlier by FDG-PET than by CT. FDG-PET can help select the best candidates for surgical exploration, although the real benefit is still to be defined. It influences treatment strategies in a significant percentage of patients. An earlier diagnosis did not influence survival due to the lack of effective therapies. PMID- 19777316 TI - Proximally versus fully porous-coated femoral stems: a multicenter randomized trial. AB - There are two broad-based categories of cementless femoral component designs: proximally porous-coated and fully porous-coated. While both have been widely used, there remains debate regarding differences in clinical outcome scores, relative incidence of thigh pain, and development of stress shielding. We investigated these variables in a multicenter prospective randomized blinded clinical trial of 388 patients from three centers: 198 patients had a proximally porous-coated tapered cementless femoral component and 190 patients had a fully porous-coated cementless femoral component. A minimum followup of 2 years (mean, 6.7 years; range, 2.0-8.65 years) was available in 367 of the 388 patients (95%). We observed no differences in age at surgery, body mass index, or preoperative clinical outcome scores (WOMAC, SF-12, Harris hip score, UCLA activity, thigh pain) with the two groups. We determined serial bone density changes in a subcohort of 72 patients from two of the three centers. The postoperative clinical outcome scores were similar at all followup intervals, and we observed no differences in the incidence of thigh pain at any time. Bone density reduction in Gruen Zone 7 was greater with the fully coated stem than the proximally coated stem (24% versus 15% reduction, respectively). Both fully and proximally coated stems performed well, with no clinical differences at 2 years' followup, except in bone mineral density evaluations. LEVEL OF EVIDENCE: Level I, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 19777318 TI - A case of mitochondrial cardiomyopathy with pericardial effusion evaluated by (99m)Tc-MIBI myocardial scintigraphy. AB - Heart failure is important in determining the prognosis of cardiomyopathy caused by mitochondrial gene abnormalities. We report herein the case of a patient with pericardial effusion and heart failure in whom mitochondrial cardiomyopathy was definitively diagnosed. A 56-year-old woman consulted her primary physician with exertional dyspnea. Examination revealed edema and pericardial effusion, and diuretics were prescribed. However, after marked left ventricular hypertrophy (LVH) was noted, she was admitted to our hospital for further evaluation. Further examination revealed short stature, ptosis, generalized muscle atrophy, and sensorineural hearing loss. Echocardiography showed LVH, a global decrease in wall motion, and pericardial effusion. Physical and laboratory findings, including glucose intolerance and elevated serum lactate, suggested mitochondrial cardiomyopathy. Genetic testing confirmed cardiomyopathy due to a mitochondrial a3243g mutation. After treatment to improve heart failure, marked washout was shown on (99m)Tc-MIBI (methoxyisobutylisonitrile) myocardial scintigraphy, suggesting a correlation with mitochondrial dysfunction. PMID- 19777317 TI - Incremental value of combining 64-slice computed tomography angiography with stress nuclear myocardial perfusion imaging to improve noninvasive detection of coronary artery disease. AB - BACKGROUND: To compare the accuracy of combined 64-slice computed tomography angiography (CTA) and stress nuclear myocardial perfusion imaging (MPI) in the noninvasive detection of coronary artery disease (CAD) with that of 64-slice CTA alone. METHODS AND RESULTS: One hundred thirty symptomatic patients with suspected CAD underwent both 64-slice CTA and stress thallium-201 MPI before invasive coronary angiography (ICA). Coronary lesions with >or=50% luminal narrowing were considered as significant stenoses on CTA and ICA. Of 390 arteries in 130 patients, 54 (14%) were nonevaluable by CTA due to severe calcifications, motion artifacts, and/or poor opacification. All nonevaluable arteries were considered positive. The sensitivity, specificity, PPV and NPV were 95%, 80%, 69%, and 97%, respectively, for CTA alone and 94%, 92%, 85%, and 97%, respectively, for CTA with stress nuclear MPI for all nonevaluable arteries on CTA. Per-patient analysis showed significant increase in specificity and PPV. The majority (75%, 9/12) of nonevaluable severely calcified vessels in the left anterior descending artery were positive on stress nuclear MPI, whereas the majority (89%, 8/9) of nonevaluable vessels with motion artifacts in the right coronary artery were negative. CONCLUSIONS: Combined CTA and stress nuclear MPI provide improved diagnostic accuracy for the noninvasive detection of CAD. PMID- 19777319 TI - Correction for respiration artefacts in myocardial perfusion SPECT is more effective when reconstructions supporting collimator detector response compensation are applied. AB - PURPOSE: To assess the impact of respiration on myocardial perfusion imaging (MPI) SPECT processed with advanced algorithmic reconstructions. METHODS: SPECT studies obtained from a phantom simulation and 49 respiratory-gated,one-day 99mTc sestamibi scans were corrected for respiratory-related cardiac movement. Three types of reconstruction algorithms: (a) filtered back projection (FBP), (b) ordered subset expectation maximization in which collimator detector response was incorporated (OSEMCDR), and (c) OSEM-CDR with additional attenuation and scatter corrections (OSEM-CDRACSC) were applied to the corrected and uncorrected sets and analyzed quantitatively and qualitatively. RESULTS: A discrepancy between the corrected and uncorrected bull's eye maps > or = 10% wasfound in 2%, 10%, and 20% of the FBP, OSEM-CDR, and OSEM-CDR-ACSC scans, respectively. In studies with more than 10-mm respiratory motion, the effect of motion was greater in OSEM-CDR and OSEM-CDR-ACSC datasets as compared to FBP processing.Qualitative and quantitative differences between corrected and uncorrected sets were significantly larger in OSEM-CDR and OSEM-CDR-ACSC data than in those of FBP data. CONCLUSIONS: Respiratory-related cardiac motion significantly affects MPI-SPECT reconstructed with advanced high-resolution reconstruction algorithms such as OSEM-CDR and OSEM CDR-ACSC and thus may justifies the application of respiratory gating. PMID- 19777320 TI - Cardiomyopathy of uncertain etiology: Complementary role of multimodality imaging with cardiac MRI and 18FDG PET. PMID- 19777321 TI - A study on the mechanisms by which minocycline protects against MDMA ('ecstasy') induced neurotoxicity of 5-HT cortical neurons. AB - 3,4-Methylenedioxymethamphetamine (MDMA, 'ecstasy') is a selective 5-HT neurotoxin in rat brain which has been shown to produce acute neuroinflammation characterized by activation of microglia and release of interleukin-1beta (IL 1beta). We aimed to determine whether or not minocycline, a semi-synthetic tetracycline antibiotic capable of inhibiting microglial activation, could prevent the inflammatory response and reduce the toxicity induced by MDMA. Adult male Dark Agouti rats were given minocycline twice a day for 2 days (45 mg/kg on the first day and 90 mg/kg on the second day; 12-h apart, i.p.). MDMA (12.5 mg/kg; i.p.) was given after the third minocycline injection and animals were killed either 1 h later for the determination of NFkappaB binding activity, 3 h later for the determination of IL-1beta, 24 h later for the determination of microglial activation or 7 days later for the determination of [(3)H]-paroxetine binding as a measure of 5-HT neurotoxicity. MDMA increased NFkappaB activation, IL-1beta release and microglial activation both in the frontal cortex and in the hypothalamus and 7 days later produced a reduction in the density of 5-HT uptake sites in both these brain areas. Minocycline prevented the MDMA-induced increase in NFkappaB activation, IL-1beta release and microglial activation in the frontal cortex and prevented the 5-HT neurotoxicity 7 days later. However, in the hypothalamus, in spite of preventing MDMA-induced microglial activation, minocycline failed to prevent MDMA-induced NFkappaB activation, IL-1beta release and neurotoxicity. This suggests that the protective mechanism of minocycline against MDMA-induced neurotoxicity in frontal cortex involves inhibition of MDMA induced NFkappaB activation possibly through a reduction in IL-1beta signalling. PMID- 19777323 TI - Susceptibility of Pseudomonas aeruginosa to catechol-substituted cephalosporin is unrelated to the pyochelin-Fe transporter FptA. AB - Previously it has been postulated that the pyochelin-Fe outer membrane transporter, FptA, is involved in the uptake of catechol-substituted cephalosporins in Pseudomonas aeruginosa. Iron uptake and antibacterial activity studies on different mutants showed clearly that FptA is unable to bind and transport these antibiotics. PMID- 19777322 TI - Optical tomography of breast cancer-monitoring response to primary medical therapy. AB - Diffuse optical imaging and spectroscopy use near-infrared light to derive physiological parameters such as total hemoglobin concentration and tissue oxygen saturation. Numerous clinical studies have been carried out, either using stand alone optical methods or in combination with alternative imaging techniques. Studies have demonstrated that diffuse optical imaging and spectroscopy are able to distinguish malignant lesions from benign tissues. Breast cancer is characterized by an increase in total hemoglobin and a decrease in tissue oxygen saturation. Benign lesions such as cysts and fibroadenomas have also been studied, with less conclusive results. As diffuse optical imaging and spectroscopy do not use ionizing radiation, they are a suitable technique for performing repeated scans, such as for monitoring treatment response. This provides a unique functional and dynamic imaging method that reflects changes in tumor angiogenesis and hypoxia. When breast cancers are treated with primary medical therapy, this can result in a selective antiangiogenic effect that could help predict response to treatment earlier than by assessment of tumor size. Diffuse optical imaging and spectroscopy have been used to scan women at several points prior to and during their neoadjuvant chemotherapy treatment, with images and data showing physiological changes in the tumor in response to treatment. In the women who respond to therapy, the total hemoglobin concentration decreases and the level of oxygenation increases in the tumor over the course of the treatment. It is possible to predict a response to treatment as little as 4 days after the start of treatment. These findings demonstrate that optical techniques could play a role in the monitoring of changes in angiogenesis, apoptosis and hypoxia due to neoadjuvant chemotherapy. PMID- 19777324 TI - Imaging of human glioma cells by means of a Syndecan-4 directed DOTA-conjugate. AB - The extracellular glycoprotein Tenascin-C (TN-C) is highly upregulated in gliomas. Therefore, many chemotherapies with radiolabeled antibodies against TN-C have been performed. However, TN-Cs binding partner Syndecan-4 did not play any role as a therapeutic or imaging target in gliomas. We constructed an imaging compound containing the magnetic resonance imaging (MRI) contrast agent gadolinium (Gd)-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), the fluorescence dye sulforhodamine and a synthetic Syndecan-4-specific 21 amino acid peptide derived from TN-C. Magnetic resonance relaxometry, confocal laser scanning microscopy, and flow cytometry showed that the Syndecan-4-DOTA-Rhodamine conjugate was taken up into the cytoplasm of human U373 glioma cells without any cytotoxic effects. Competition experiments indicate that this uptake was receptor mediated. This conjugate might be used for future MRI studies of brain tumors after systemic or intraoperative local application. PMID- 19777325 TI - An N- and C-terminal truncated isoform of zinc finger X-linked duplicated C protein represses MHC class II transcription. AB - The zinc finger X-linked duplicated A (ZXDA) and ZXDC proteins are both required for robust transcription of major histocompatibility complex class II (MHC II) genes. Aside from the full length ZXDC mRNA transcript, at least one additional mRNA is produced by the ZXDC gene, in which transcription initiates within the first exon and terminates within the seventh intron. The protein product produced from this transcript, which we have named ZXDC2, is truncated on both the N- and C-terminus. We demonstrate here that ZXDC2 functions to repress MHC II transcription induced in HeLa cells treated with IFN-gamma. We further demonstrate that ZXDC2 interacts with both ZXDA and ZXDC, suggesting a mechanism by which ZXDC2 may inhibit MHC II transcription. These studies not only provide additional support for the role of ZXD proteins in regulating MHC II transcription, but also demonstrate a unique mechanism for the synthesis of a mRNA isoform. PMID- 19777326 TI - Exercise training decreases hepatic SCD-1 gene expression and protein content in rats. AB - Stearoyl-CoA desaturase-1 (SCD-1) is the rate limiting enzyme in the biosynthesis of saturated-derived monounsaturated fats that are the major constituents of very low-density-lipoproteins-triacylglycerol (VLDL-TAG) and are involved in regulating cellular metabolism. The purpose of this study was to evaluate the effects of an 8-week exercise training program on the hepatic gene expression of this crucial enzyme. Female rats either trained (TR) or kept sedentary (Sed) for 8 weeks were submitted either to standard (SD) diet for 8 or for 6 weeks followed by high-fat (HF; 42% kcal) diet for 2 weeks. The 2-week-high fat feeding resulted in an increase in liver triacylgycerol (TAG), plasma free-fatty-acids (FFA), abdominal fat mass, sterol-regulatory-element-binding protein-1c (SREBP-1c), and carbohydrate-response-element-binding protein (ChREBP) gene expression in liver along with a decrease in SCD-1 gene expression and plasma and liver SCD-1 desaturation index (C16:1/C16:0). Liver TAG, plasma FFA, SREBP-1c mRNA, and SCD-1 desaturation indexes (C16:1/C16:0; C18:1/C18:0) were not changed in liver or in plasma by the training program. Nevertheless, training resulted in an important decrease in fat mass (P < 0.01), hepatic SCD-1 mRNA levels (P < 0.01), and protein content (P < 0.05) in both SD and HF fed rats. It is concluded that despite an absence of decreased liver TAG, exercise training contributes to the proper regulation of fat metabolism by down-regulating hepatic SCD-1 gene expression and protein content. PMID- 19777327 TI - Igf-I stimulates in vivo thymopoiesis after stem cell transplantation in a child with Omenn syndrome. AB - CONTEXT: Children with severe combined immunodeficiency who receive a T cell depleted hematopoietic stem cell transplantation (HSCT) have delayed immune reconstitution. OBJECTIVE: To examine the use of recombinant human insulin-like growth factor-I (rhIGF-I) therapy to stimulate thymopoiesis after HSCT. CLINICAL CASE: A child with Omenn syndrome failed T cell reconstitution 6 months after HSCT. She started rhIGF-I therapy just before age 18 months. The initial dose (40 microg/kg twice daily) was increased every 2 weeks to a maximum dose of 120 microg/kg twice daily. RESULTS: The patient's absolute T cells increased from 7 to 132/mm(3) and 662/mm(3) after 3 and 5 months of rhIGF-I therapy, respectively, and her blastogenic response to phytohemagglutinin normalized. Three months after discontinuation of rhIGF-I therapy, the T cells continued to increase (to 2,427/mm(3)) although the blastogenic response to phytohemagglutinin decreased. CONCLUSION: This is the first known use of rhIGF-I therapy to help restore thymopoiesis in a child. PMID- 19777328 TI - Oxidatively modified, mitochondria-relevant brain proteins in subjects with Alzheimer disease and mild cognitive impairment. AB - Alzheimer disease (AD) is an age-related neurodegenerative disorder, characterized histopathologically by the presence of senile plaques (SP), neurofibrillary tangles and synapse loss in selected brain regions. Positron emission tomography (PET) studies of glucose metabolism revealed decreased energetics in brain of subjects with AD and arguably its earliest form, mild cognitive impairment (MCI), and this decrease correlated with brain structural studies using MRI. The main component of senile plaques is amyloid beta-peptide (Abeta), a 40-42 amino acid peptide that as oligomers is capable of inducing oxidative stress under both in vitro and in vivo conditions and is neurotoxic. In the mitochondria isolated from AD brain, Abeta oligomers that correlated with the reported increased oxidative stress markers in AD have been reported. The markers of oxidative stress have been localized in the brain regions of AD and MCI that show pathological hallmarks of this disease, suggesting the possible role of Abeta in the initiation of the free-radical mediated process and consequently to the build up oxidative stress and AD pathogenesis. Using redox proteomics our laboratory found a number of oxidatively modified brain proteins that are directly in or are associated with the mitochondrial proteome, consistent with a possible involvement of the mitochondrial targeted oxidatively modified proteins in AD progression or pathogenesis. The precise mechanistic link between mitochondrial oxidative damage and role of oligomeric Abeta has not been explicated. In this review, we discuss the role of the oxidation of mitochondria relevant brain proteins to the pathogenesis and progression of AD. PMID- 19777329 TI - Mitochondrial damage as death inducer in heart-derived H9c2 cells: more than one way for an early demise. AB - The release of cytochrome c from mitochondria induced by 10 microM thapsigargin was linked to rapid loss of the mitochondrial membrane potential whereas that induced by 50 nM staurosporine was mediated by Bax activation and occurred in polarized mitochondria. Similar levels of cytochrome c were observed when induced by either thapsigargin or staurosporine indicating that the release magnitude was independent of the mechanism involved in membrane permeabilization. In any case caspase 3 activation was subsequent to cytochrome c release. Mitochondrial dysfunction and release of cytochrome c occurred earlier when induced by thapsigargin even though morphological alteration of the cell and chromatin condensation were developed earlier in the presence of staurosporine. In addition, a general and irreversible caspase inhibitor did not protect against chromatin condensation induced by staurosporine. It is also shown that earlier mitochondrial damage does not always correlate with earlier cell demise. This can be attributed to the existence of alternative caspase-independent cell death programmes. PMID- 19777330 TI - Protective effects of isolated polyphenolic and alkaloid fractions of Ruta graveolens L. on acute and chronic models of inflammation. AB - Ruta graveolens L. (Rutaceae) are traditionally used for the treatment of rheumatism, arthritis and other inflammatory conditions in the traditional medicine of India, were evaluated for their protective effect in acute and chronic models of inflammation. Carrageenan induced rat paw edema and adjuvant induced arthritis were employed as the experimental models of acute and chronic inflammation respectively. Isolated polyphenolic and alkaloid fraction (AFR) from Ruta graveolens and evaluated its anti inflammatory activity in carrageenan induced acute model. AFR with a dose 10 mg/kg showed higher anti inflammatory effect than polyphenols and standard drug diclofenec. AFR significantly decreased the paw edema in arthritic rats. TBARS, COX-2, 5-LOX and MPO level were decreased and the levels of antioxidant enzymes and GSH level were increased on treatment with AFR. The increment in CRP level and ceruloplasmin level observed in arthritic animals were also found to be significantly restored in AFR treated rats. The results demonstrated the potential beneficiary effect of isolated polyphenolic and alkaloid fraction of Ruta graveolens L. on acute and chronic models of inflammation in rats. PMID- 19777331 TI - Brief report: Signals enhance the suppressive effects of noncontingent reinforcement. AB - The effects of noncontingent reinforcement (NCR) schedules on responding were assessed across two parameters: presence of signal and schedule density. Results indicated that signaled NCR schedules were correlated with greater overall reductions in responding and quicker reductions relative to NCR schedules without a signal. The clinical significance of these findings is discussed. PMID- 19777332 TI - Further empirical data on the psychoeducational profile-revised (PEP-R): reliability and validation with the Vineland adaptive behavior scales. AB - The PEP-R (psychoeducational profile revised) is an instrument that has been used in many countries to assess abilities and formulate treatment programs for children with autism and related developmental disorders. To the end to provide further information on the PEP-R's psychometric properties, a large sample (N = 137) of children presenting Autistic Disorder symptoms under the age of 12 years, including low-functioning individuals, was examined. Results yielded data of interest especially in terms of: Cronbach's alpha, interrater reliability, and validation with the Vineland Adaptive Behavior Scales. These findings help complete the instrument's statistical description and augment its usefulness, not only in designing treatment programs for these individuals, but also as an instrument for verifying the efficacy of intervention. PMID- 19777333 TI - Brief Report: Self-defining and everyday autobiographical memories in adults with autism spectrum disorders. AB - Autobiographical memory impairments in autism spectrum disorders (ASD) have been attributed to a failure in using the self as an effective memory organisational system. To explore this hypothesis, we compared self-defining and everyday memories in adults with and without ASD. Results demonstrated that both groups were able to distinguish between self-defining and everyday memories, although the ASD group generated fewer specific memories overall. Despite qualitative similarities between the narratives of the two groups, the adults with ASD extracted less meaning from their narratives. Difficulties in eliciting meaning from memories suggests a failure in using past experiences to update the self. We therefore propose that the self-memory relationship might be static, rather than dynamic, in ASD. PMID- 19777334 TI - The DSM diagnostic criteria for hypoactive sexual desire disorder in women. AB - Hypoactive Sexual Desire Disorder (HSDD) is one of two sexual desire disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and is defined by the monosymptomatic criterion "persistently or recurrently deficient (or absent) sexual fantasies and desire for sexual activity" that causes "marked distress or interpersonal difficulty." This article reviews the diagnosis of HSDD in prior and current (DSM-IV-TR) editions of the DSM, critiques the existing criteria, and proposes criteria for consideration in DSM-V. Problems in coming to a clear operational definition of desire, the fact that sexual activity often occurs in the absence of desire for women, conceptual issues in understanding untriggered versus responsive desire, the relative infrequency of unprovoked sexual fantasies in women, and the significant overlap between desire and arousal are reviewed and highlight the need for revised DSM criteria for HSDD that accurately reflect women's experiences. The article concludes with the recommendation that desire and arousal be combined into one disorder with polythetic criteria. PMID- 19777335 TI - The DSM diagnostic criteria for female sexual arousal disorder. AB - This article reviews and critiques the DSM-IV-TR diagnostic criteria for Female Sexual Arousal Disorder (FSAD). An overview of how the diagnostic criteria for FSAD have evolved over previous editions of the DSM is presented and research on prevalence and etiology of FSAD is briefly reviewed. Problems with the essential feature of the DSM-IV-TR diagnosis-"an inability to attain, or to maintain...an adequate lubrication-swelling response of sexual excitement"-are identified. The significant overlap between "arousal" and "desire" disorders is highlighted. Finally, specific recommendations for revision of the criteria for DSM-V are made, including use of a polythetic approach to the diagnosis and the addition of duration and severity criteria. PMID- 19777336 TI - Adolescent behavioral risk screening and use of health services. AB - This study assessed whether primary care based computerized screening for substance use, mental health issues and suicidal thoughts affects subsequent use of medical and behavioral health care services in adolescents. Administrative claims data were used to determine service use 6 months after a visit where screening could have occurred. Controlling for previous service use, screened youths were more likely to have post screening use than those not screened. Among the screened patients, medical service use did not differ by screening result. However, behavioral service use was higher for screened youths who screened positive for depression or suicidal thoughts. PMID- 19777338 TI - Introduction to special issue on social ecological approaches to community health research and action. AB - We have the potential to make new, substantive contributions to resolving our most pressing community health problems. However, to do so we must adopt a philosophy of science that is directed towards understanding the dynamic complexity and full contextual reality surrounding these issues. A social ecological approach to science is ideally suited to this challenge. This framework is systems-oriented and defines research problems in terms of structures and processes, generating research outcomes that give insight into the dynamic interaction of individuals with their environment across time and space. Though community psychology is built upon social ecological principles, researchers from other disciplines have also noted its utility and implemented interventions based on this framework. In our introductory article to this special issue on social ecological approaches to community health research and action, we present a brief review of the theoretical foundations of the social ecological approach, present highlights from our selected manuscripts, and conclude with some reflections about the need to build further capacity to conduct effective social ecological research to foster community health and well being. PMID- 19777337 TI - Developmental precursors of moral disengagement and the role of moral disengagement in the development of antisocial behavior. AB - The purpose of the study was to advance our understanding of the developmental precursors of Moral Disengagement (MD) and the role of MD in the development of antisocial behavior from early risk among an ethnically diverse sample of 187 low income boys followed prospectively from ages 1.5 to 17. Results indicated associations between early rejecting parenting, neighborhood impoverishment, and child empathy and later MD. The link between some of these early constructs and later antisocial behavior was mediated by MD. Finally, in an exploratory path model both MD and biases in social information processing were found to mediate separate paths from early risk factors to later antisocial behavior. Results were partially consistent with the notion that adolescent MD was predicted by a combination of early family, neighborhood, and child risk factors, and that MD may be a mechanism underlying some boys' risk of antisocial behavior. PMID- 19777339 TI - VERB summer scorecard: findings from a multi-level community-based physical activity intervention for tweens. AB - The benefits of physical activity for adolescents are well established. Multi level interventions may be especially effective in establishing and sustaining health-enhancing behaviors. This study explored the influences of a multi-level community intervention aimed at increasing physical activity among tweens (youth 9-13). Two Florida school districts far apart served as intervention and comparison sites in a quasi-experimental post-test design. Youth in grades 5 through 8 in the intervention community (n = 1,253) and comparison community (n = 866) completed an anonymous post-intervention survey. An intent-to-treat analysis did not show any statistically significant group differences for the physical activity outcomes examined. However, a subset analysis revealed that students who reported participating in the intervention were more likely to be physically active than youth in the comparison group, as well as youth in the intervention community who reported not participating. Participating in the intervention was significantly related to meeting recommendations for vigorous physical activity (OR = 2.08, P = 0.0259), being physically active on weekends (OR = 1.84, P = 0.0017), and reporting more days of trying a new game or sport (OR = 1.49, P = 0.046) after controlling for grade, gender, race/ethnicity, and SES. These findings support the efficacy of multi-level interventions to create effective health behavior change, especially when linkages among community, media, schools, and the home are present. PMID- 19777340 TI - Regulation of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) by anti-parkinsonian drug therapy in vivo. AB - Available treatment for Parkinson's disease (PD) is mainly symptomatic instead of halting or reversing degenerative processes affecting the disease. Research on the molecular pathogenesis of PD has suggested reduced trophic support as a possible cause or mediator of neurodegeneration. In animal models of the disease, neurotrophic factors prevent neurodegeneration and induce behavioral recovery. Some anti-Parkinsonian drugs show neuroprotective activity, but it is not known whether the drug-induced neuroprotection is mediated by neurotrophic factors. In this study, we have investigated the influence of two neuroprotective anti Parkinsonian drugs, the monoamine oxidase B inhibitor selegiline and the adenosine A(2A) antagonist SCH 58261, on the levels of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) in the mouse brain. Protein levels of BDNF and CDNF were quantified by western blot after 2 weeks of treatment with either of the drugs or placebo. CDNF levels were not significantly influenced by selegiline or SCH 58261 in any brain area studied. Selegiline treatment significantly increased BDNF levels in the anterior cingulate cortex (1.55 +/- 0.22, P < 0.05, Student's t-test). In the striatum, selegiline increased BDNF content by 32%, but this change did not reach statistical significance (1.32 +/- 0.15, P < 0.13, Student's t-test). Our data suggest that neurotrophic factors, particularly BDNF may play a role in the neuroprotective effects of selegiline, but do not support the hypothesis that anti-Parkinsonian drugs would work by increasing the levels of CDNF in brain. PMID- 19777341 TI - Neuroprotective effects of IGF-I following kainic acid-induced hippocampal degeneration in the rat. AB - Insulin-like growth factor I (IGF-I) has been shown to act as a neuroprotectant both in in vitro studies and in in vivo animal models of ischemia, hypoxia, trauma in the brain or the spinal cord, multiple and amyotrophic lateral sclerosis, Alzheimer's and Parkinson's disease. In the present study, we investigated the neuroprotective potential of IGF-I in the "kainic acid-induced degeneration of the hippocampus" model of temporal lobe epilepsy. Increased cell death--as detected by FluoroJade B staining--and extensive cell loss--as determined by cresyl violet staining--were observed mainly in the CA3 and CA4 areas of the ipsilateral and contralateral hippocampus, 7 days following intrahippocampal administration of kainic acid. Kainic acid injection also resulted in intense astrogliosis--as assessed by the number of glial fibrillary acidic protein (GFAP) immunopositive cells--in both hemispheres, forming a clear astroglial scar ipsilaterally to the injection site. Heat-shock protein 70 (Hsp70) immunopositive cells were also observed in the ipsilateral dentate gyrus (DG) following kainic acid injection. When IGF-I was administered together with kainic acid, practically no signs of degeneration were detected in the contralateral hemisphere, while in the ipsilateral, there was a smaller degree of cell loss, reduced number of FluoroJade B-stained cells, decreased reactive gliosis and fewer Hsp70-positive cells. Our present results extend further the cases in which IGF-I is shown to exhibit neuroprotective properties in neurodegenerative processes in the CNS. PMID- 19777342 TI - Feline immunodeficiency virus as a gene transfer vector in the rat nucleus tractus solitarii. AB - Gene transfer has been used to examine the role of putative neurotransmitters in the nucleus tractus solitarii (NTS). Most such studies used adenovirus vector mediated gene transfer although adenovirus vector transfects both neuronal and non-neuronal cells. Successful transfection in the NTS has also been reported with lentivirus as the vector. Feline immunodeficiency virus (FIV), a lentivirus, may preferentially transfect neurons and could be a powerful tool to delineate physiological effects produced by altered synthesis of transmitters in neurons. However, it has not been studied in NTS. Therefore, we sought to determine whether FIV transfects rat NTS cells and to define the type of cell transfected. We found that injection of FIV encoding LacZ gene (FIVLacZ) into the NTS led to transfection of numerous NTS cells. Injection of FIVLacZ did not alter immunoreactivity (IR) for neuronal nitric oxide synthase, which we have shown resides in NTS neurons. A majority (91.7 +/- 3.9%) of transfected cells contained IR for neuronal nuclear antigen, a neuronal marker; 2.1 +/- 3.8% of transfected cells contained IR for glial fibrillary acidic protein, a glial marker. No transfected neurons or fibers were observed in the nodose ganglion, which sends afferents to the NTS. We conclude that FIV almost exclusively transfects neurons in the rat NTS from which it is not retrogradely transported. The cell-type specificity of FIV in the NTS may provide a molecular method to study local physiological functions mediated by potential neurotransmitters in the NTS. PMID- 19777343 TI - Induction of the small heat shock protein alphaB-crystallin by genotoxic stress is mediated by p53 and p73. AB - The small heat shock protein alphaB-crystallin is a molecular chaperone that is induced by stress and protects cells by inhibiting protein aggregation and apoptosis. To identify novel transcriptional regulators of the alphaB-crystallin gene, we examined the alphaB-crystallin promoter for conserved transcription factor DNA-binding elements and identified a putative response element for the p53 tumor suppressor protein. Ectopic expression of wild-type p53 induced alphaB crystallin mRNA and protein with delayed kinetics compared to p21. Additionally, the induction of alphaB-crystallin by genotoxic stress was inhibited by siRNAs targeting p53. Although the p53-dependent transactivation of an alphaB-crystallin promoter luciferase reporter required the putative p53RE, chromatin immunoprecipitation failed to detect p53 binding to the alphaB-crystallin promoter. These results suggested an indirect mechanism of transactivation involving p53 family members p63 or p73. DeltaNp73 was dramatically induced by p53 in a TAp73-dependent manner, and silencing p73 suppressed the transcriptional activation of alphaB-crystallin by p53. Moreover, ectopic expression of DeltaNp73alpha (but not other p73 isoforms) increased alphaB-crystallin mRNA levels in the absence of p53. Collectively, our results link the molecular chaperone alphaB-crystallin to the cellular genotoxic stress response via a novel mechanism of transcriptional regulation by p53 and p73. PMID- 19777344 TI - Inhibition of mitochondrial respiratory chain in the brain of adult rats after acute and chronic administration of methylphenidate. AB - Methylphenidate (MPH) is frequently prescribed for the treatment of attention deficit/hyperactivity disorder. It was previously demonstrated that MPH altered brain metabolic activity. Most cell energy is obtained through oxidative phosphorylation, in the mitochondrial respiratory chain. However, there are still few studies about MPH effects on the brain of adult rats. Thus, in the present study we evaluated the effect of acute or chronic administration of MPH on the activities of mitochondrial respiratory chain complexes I-IV in the brain of adult rats. For acute administration, a single injection of MPH was given to 60 day-old rats. For chronic administration, MPH injections were given to 60-day-old rats once daily for 28 days. Our results showed that complexes I, II, III and IV were inhibited after acute or chronic MPH administration in the hippocampus, prefrontal cortex, striatum and cerebral cortex. On the other hand, cerebellum was not affected. PMID- 19777345 TI - Brain mitochondrial dysfunction in ovariectomized mice injected with D-galactose. AB - Our previous studies reveal that long-term exposure of ovariectomized rodents to D: -galactose results in pathophysiologic alterations associated with Alzheimer's disease. The current study was to address whether mitochondrial dysfunction was involved in the pathogenesis of this model. Ovariectomized mice were administered intraperitoneally with D: -galctose (100 mg/kg body weight) once a day for 8 weeks. Brain tissues from model mice showed decreases in reduced glutathione level, total antioxidative capabilities, total superoxide dismutase activity and glutathione peroxidase activity but an increase in malondialdehyde level, compared with those from sham-operated plus saline-injected mice. Activities of brain mitochondrial respiratory chain (complex I, II, III and IV) were reduced in model group. In contrast, ATP synthase (F(1)F(0)-ATPase) activity was not significantly different between the two groups. Moreover, electron microscopy identified ultrastructural impairments of hippocampal mitochondria in model mice. These results demonstrated that brain mitochondrial degeneration caused by oxidative stress participated in the etiology of ovarian hormone deprivation and D-galactose-induced neurodegeneration. PMID- 19777346 TI - Neuroprotective effect of DAHK peptide in an occlusive model of permanent focal ischemia in rats. AB - This study examined the neuroprotective ability of tetrapeptide L-Asp-Ala-His-Lys (DAHK) in permanent middle cerebral artery occlusion in rats. One DAHK dose (16 mg/kg) or saline solution were i.v. administered 30 min after occlusion and neurological deficit was evaluated at 2, 24, 48, 72 and 96 h using Longa scoring scale. The striatum infarction area was evaluated until 96 h after occlusion in both groups after staining with hematoxylin-eosin. DAHK-treated group showed a significant (P < 0.05) protection of 70% of neurological deficit at 96 h after occlusion, in comparison with the control-group that showed permanent neurological deficit. The DAHK-treated group showed a significant (P < 0.05) reduction of 52% infarction area in the striatum, as compared to control values. Results presented here support the possible therapeutic application of DAHK as a neuroprotective agent in human patients with stroke, as the peptide is part of human serum albumin, already being tested in clinical trials. PMID- 19777347 TI - Trauma and posttraumatic stress disorder (PTSD) in patients with schizophrenia or schizoaffective disorder. AB - Trauma and posttraumatic stress disorder (PTSD) have high prevalence among individuals with severe mental illness, such as schizophrenia or schizoaffective disorder. This study examined whether trauma and PTSD are under-detected in this population, and whether the cognitive theory of PTSD is applicable to these individuals. Traumatic experiences, PTSD symptoms and negative posttraumatic cognitions were directly measured with questionnaires, and compared to information obtained via chart-review. Results showed clear evidence of under report of trauma and under-diagnosis of PTSD in patients' charts. Furthermore, negative posttraumatic cognitions were positively related to PTSD symptom severity, supporting the cognitive model of PTSD. These findings underscore the importance of assessing trauma history as well as PTSD in the routine evaluation of patients with schizophrenia or schizoaffective disorder in outpatient clinical settings. Furthermore, the finding of negative posttraumatic cognitions suggests that the cognitive model of PTSD may be applicable to patients with schizophrenia or schizoaffective disorder. PMID- 19777348 TI - The effects of integrative reminiscence on depressive symptomatology and mastery of older adults. AB - A quasi-experimental (non-randomized) study was conducted to study the effects of a new intervention The story of your life that combines integrative reminiscence with narrative therapy. The program consists of seven sessions of two hours and one follow-up session after 8 weeks. It is directed at community-dwelling people of 55 years and older with mild to moderate depressive symptoms. After the intervention the participants showed significantly less depressive symptoms and higher mastery, also in comparison with a waiting-list control group. Demographic factors and initial levels of depressive symptomatology and mastery were not found to moderate the effects. The effects were maintained at 3 months after completion of the intervention. Although the new program was positively evaluated by the majority of the participants there is room for improvement. Adaptations should be made, and evaluated in a randomised controlled trial. PMID- 19777350 TI - Polymorphism of IL-8 in 251 allele and gastric cancer susceptibility: a meta analysis. AB - BACKGROUND: The relationship of gastric cancer to the presence of interleukin-8 (IL-8) 251 T/A has been reported with conflicting results. AIM: To further explore the association of IL-8 251 allele polymorphism with gastric cancer susceptibility. METHODS: We performed an extensive search of relevant studies and carried out a meta-analysis, including ten studies with 2,195 gastric cancer cases and 3,505 controls, to obtain a more precise estimate. RESULTS: The combined results based on all studies showed that the IL-8 251 allele AA genotype was a risk factor for gastric cancer [AA versus TT: odds ratio (OR) = 1.363, 95% confidence interval (CI): 1.199-1.527]. In subgroup analysis, a clear effect of AA in IL-8 251 allele was shown in Asians (AA versus TT: OR = 1.593, 95% CI: 1.013-2.173) but not in Caucasians or Mexicans. When stratified by Lauren classification, we found that the IL-8 251 allele TA and AA polymorphism was significantly associated with the diffuse type of gastric cancer (TA versus TT: OR = 1.448, 95% CI: 1.177-1.720; AA versus TT: OR = 1.586, 95% CI: 1.128-2.044). The IL-8 251 AA genotype was found to be a risk factor for cardiac gastric cancer (AA versus TT: OR = 1.840, 95% CI: 1.112-2.568) but not for noncardiac gastric cancer. CONCLUSIONS: This meta-analysis suggested that IL-8 251 allele A>T polymorphism might be a risk factor for gastric cancer. PMID- 19777351 TI - Fabrication of three-dimensional microarray structures by controlling the thickness and elasticity of poly(dimethylsiloxane) membrane. AB - In this paper, we propose a method to construct three-dimensional curved microstructures with easy control of the size, position and shape, by exploiting the elasticity of poly(dimethylsiloxane) (PDMS) membranes and basic physics. For this end, we developed the method to handle thin PDMS membrane safely, and to replicate PDMS microstructure from the PDMS mold. Using this method, we demonstrated two potential applications: (1) the use of concave well for the formation of embryoid body (EB) to differentiate into neuronal cells, and (2) the fabrication of SU-8 and hydrogel microparticles having diverse curved shapes. The curved structures were successfully fabricated with simple process, and EBs were formed in the concave well and differentiated into the neuronal cells. Microparticles with diverse shapes were fabricated from a range of materials for potential use as drug carrier and pH responsive micro-actuator elements. PMID- 19777352 TI - Expression of clock genes in the suprachiasmatic nucleus: effect of environmental lighting conditions. AB - The suprachiasmatic nucleus (SCN) is the anatomical substrate for the principal circadian clock coordinating daily rhythms in a vast array of behavioral and physiological responses. Individual SCN neurons are cellular oscillators and are organized into a multi-oscillator network following unique spatiotemporal patterns. The rhythms generated in the SCN are generally entrained to the environmental light dark cycle, which is the most salient cue influencing the network organization of the SCN. The neural network in the SCN is a heterogeneous structure, containing two major compartments identified by applying physiological and functional criteria, namely the retinorecipient core region and the highly rhythmic shell region. Changes in the environmental lighting condition are first detected and processed by the core region, and then conveyed to the rest of the SCN, leading to adaptive responses of the entire network. This review will focus on the studies that explore the responses of the SCN network by examining the expression of clock genes, under various lighting paradigms, such as acute light exposure, lighting schedules or exposure to different light durations. The results will be discussed under the framework of functionally distinct SCN sub regions and oscillator groups. The evidence presented here suggests that the environmental lighting conditions alter the spatiotemporal organization of the cellular oscillators within the SCN, which consequently affect the overt rhythms in behavior and physiology. Thus, information on how the SCN network elements respond to environmental cues is key to understanding the human health problems that stem from circadian rhythm disruption. PMID- 19777353 TI - The role of retinal photoreceptors in the regulation of circadian rhythms. AB - The circadian clock is an evolutionarily, highly conserved feature of most organisms. This internal timing mechanism coordinates biochemical, physiological and behavioral processes to maintain synchrony with the environmental cycles of light, temperature and nutrients. Several studies have shown that light is the most potent cue used by most organisms (humans included) to synchronize daily activities. In mammals, light perception occurs only in the retina; three different types of photoreceptors are present within this tissue: cones, rods and the newly discovered intrinsically photosensitive retinal ganglion cells (ipRGCs). Researchers believe that the classical photoreceptors (e.g., the rods and the cones) are responsible for the image-forming vision, whereas the ipRGCs play a key role in the non-image forming vision. This non-image-forming photoreceptive system communicates not only with the master circadian pacemaker located in the suprachiasmatic nuclei of the hypothalamus, but also with many other brain areas that are known to be involved in the regulation of several functions; thus, this non-image forming system may also affect several aspects of mammalian health independently from the circadian system. PMID- 19777354 TI - The current state of pediatric obesity treatment. PMID- 19777355 TI - Increased mortality in the slim elderly: a 42 years follow-up study in a general population. AB - The Bergen Clinical Blood Pressure Study in Norway was used to examine the relationship between body mass index (BMI (kg/m(2))) and total mortality in different age segments. Of 6,811 invited subjects, 5,653 (84%) participated in the study (1965-1971) and 4,520 (66%) died during 182,798 person-years of follow up (1965-2007). Mean age at baseline was 47.5 years; range 22-75 years. BMI (kg/m(2)) was calculated from standardized measurements of body height and weight and divided into four groups (<22.0, 22.0-24.9, 25.0-27.9, > or =28.0). The 20 years cumulative risk of death related to baseline BMI was U-shaped in the elderly (aged 65-75 years), whereas the pattern was more linear in the youngest age group (20-44 years). In contrast to the younger age groups, the highest mortality in the elderly was in the lower BMI range (<22.0 kg/m(2)) (adjusted Cox proportional Hazard Ratio 1.39, 95% Confidence Interval 1.10, 1.75) compared to the BMI reference group (22.0-24.9 kg/m(2)). This pattern persisted after 72 months of early follow-up exclusion and it was robust to adjustments for a wide range of possible confounders including gender, history of cardiovascular disease, respiratory disease or hypertension, smoking habits, physical activity, socioeconomic status, physical appearance and other anthropometric measures. The study shows that a low BMI is an appreciable independent risk factor of total mortality in the elderly, and not a result of subclinical disease or confounding factors such as current or previous smoking. Awareness of this issue ought to be emphasized in advice, care and treatment of elderly subjects. PMID- 19777356 TI - Effects of Euseius stipulatus on establishment and efficacy in spider mite suppression of Neoseiulus californicus and Phytoseiulus persimilis in clementine. AB - The two-spotted spider mite, Tetranychus urticae, is one of the most problematic phytophagous pests in Spanish clementine orchards. The most abundant predatory mites in this ecosystem are Euseius stipulatus, Phytoseiulus persimilis and Neoseiulus californicus. Euseius stipulatus is dominant but poorly adapted to utilize T. urticae as prey. It mainly persists on pollen and citrus red mite, Panonychus citri. A recent study suggested that the more efficacious T. urticae predators P. persimilis and N. californicus are negatively affected by lethal and non-lethal intraguild interactions with E. stipulatus. Here, we investigated the potential of N. californicus and P. persimilis to colonize and thrive on young clementine trees infested by T. urticae in presence and absence of E. stipulatus. Presence of E. stipulatus interfered with establishment and abundance of P. persimilis and negatively affected the efficacy of N. californicus in T. urticae suppression. In contrast, the abundance of E. stipulatus was not affected by introduction of a second predator. Trait-mediated effects of E. stipulatus changing P. persimilis and N. californicus behavior and/or life history were the most likely explanations for these outcomes. We conclude that superiority of E. stipulatus in intraguild interactions may indeed contribute to the currently observed predator species composition and abundance, rendering natural control of T. urticae in Spanish clementine orchards unsatisfactory. Nonetheless, stronger reduction of T. urticae and/or plant damage in the predator combination treatments as compared to E. stipulatus alone indicates the possibility to improve T. urticae control via repeated releases of N. californicus and/or P. persimilis. PMID- 19777357 TI - Experimental study on possible transmission of the bacterium Erysipelothrix rhusiopathiae to chickens by the poultry red mite, Dermanyssus gallinae. AB - The vector potential of the poultry red mite, Dermanyssus gallinae De Geer (Acari: Dermanyssidae), in relation to chicken erysipelas was investigated under experimental conditions. Chickens were inoculated intramuscularly with the bacterium Erysipelothrix rhusiopathiae, and mites were allowed to feed on the inoculated chickens for 5 days. After 20 days of starvation, the mites were allowed to feed on healthy chickens to enable transmission of bacteria. Blood samples were collected from the birds and analysed for the presence of E. rhusiopathiae, and ELISA tests were performed for seropositivity. The internal presence of E. rhusiopathiae in the mites after feeding of inoculated birds was also investigated. It could not be demonstrated that mites take up and transmit E. rhusiopathiae under the experimental conditions described. However, since there are case reports as well as other in vitro studies indicating the potential of D. gallinae to act as a reservoir and potential vector for infections agents, we cannot exclude the possibility that the red poultry mite transmits E. rhusiopathiae between chickens under field conditions. PMID- 19777358 TI - The association between fruit and vegetable consumption and HPV viral load in high-risk HPV-positive women with cervical intraepithelial neoplasia. AB - We evaluated the relationship between the dietary intake of vegetables and fruits, and the risk of cervical intraepithelial neoplasia (CIN) and determined whether these associations were modified by human papillomavirus (HPV) viral load. We enrolled 1,096 women aged 18-65 to participate in a HPV cohort study from March 2006 up to present. For this analysis, we included 328 HPV-positive women (166 controls, 90 CIN I and 72 CIN II/III). The multivariate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were estimated by multinomial logistic methods. After controlling for potential confounders, we found that a higher HPV viral load was associated with an increased risk of CIN I (OR = 2.68, 95% CI, 1.19-6.04) and CIN II/III (OR = 2.78, 95% CI, 1.15-6.72). The relationships between HPV infection, dietary intake of vegetables and fruits and risk of CIN were not statistically significant. However, subjects with lower intake of vegetables and fruits, and a higher viral load (> or =15.5) have a higher risk of CIN II/III (OR = 2.84(1.26-6.42), interaction p = 0.06 for vegetables; OR = 2.93(1.25-6.87), interaction p = 0.01 for fruits), compared with subjects with lower intake of vegetables and fruits, and a lower viral load (<15.5). Our findings suggest that the dietary intake of vegetables and fruits is associated with the progression of cervical carcinogenesis. PMID- 19777359 TI - Race, healthcare access and physician trust among prostate cancer patients. AB - OBJECTIVE: To study the effect of healthcare access and other characteristics on physician trust among black and white prostate cancer patients. METHODS: A three timepoint follow-up telephone survey after cancer diagnosis was conducted. This study analyzed data on 474 patients and their 1,320 interviews over three time periods. RESULTS: Among other subpopulations, black patients who delayed seeking care had physician trust levels that were far lower than that of both Caucasians as well as that of the black patients overall. Black patients had greater variability in their levels of physician trust compared to their white counterparts. CONCLUSIONS: Both race and access are important in explaining overall lower levels and greater variability in physician trust among black prostate cancer patients. Access barriers among black patients may spill over to the clinical encounter in the form of less physician trust, potentially contributing to racial disparities in treatment received and subsequent outcomes. Policy efforts to address the racial disparities in prostate cancer should prioritize improving healthcare access among minority groups. PMID- 19777361 TI - Using reflective learning to improve the impact of continuing education in the context of work rehabilitation. AB - Reflective learning has been described as a promising approach for ameliorating the impact of continuing education (CE) programs. However, there are still very few studies that have investigated how occupational therapists use reflection to improve the integration of CE program content in their decision-making processes. The study objectives were to describe how these professionals, working in the sector of work rehabilitation, used reflective learning to integrate research evidence into their clinical decision-making process and to identify the factors that influenced the reflective learning process. A collaborative research study was conducted. Eight occupational therapists were recruited to participate to the group that was convened for 12 meetings and held during a 15-month period. The strategies used were critical analysis of ill-structured and authentic clinical situations, peer support, reflective journal writing and complementary reading. The group facilitator acted as a research evidence mentor and guided the group process. The data collected was analyzed using the grounded theory method. The reflective learning process, used by the participants, enabled them to change their perspective at six different stages in their decision-making process. The participants developed their ability to use different types of reflective thinking: introspection, concept attainment, self-attribution, problem solving, action planning and reorganization. The factors that most influenced learning were: ease in sharing experience, normative beliefs, coping with negative emotions, perceived self-efficacy, social support and risk taking. Results led to the development of the Model of Research Utilization Grounded in Critical Reflection. PMID- 19777360 TI - Capillary arterialization requires the bone-marrow-derived cell (BMC)-specific expression of chemokine (C-C motif) receptor-2, but BMCs do not transdifferentiate into microvascular smooth muscle. AB - Chemokine (C-C motif) receptor-2 (CCR2) regulates arteriogenesis and angiogenesis, facilitating the MCP-1-dependent recruitment of growth factor secreting bone marrow-derived cells (BMCs). Here, we tested the hypothesis that the BMC-specific expression of CCR2 is also required for new arteriole formation via capillary arterialization. Following non-ischemic saphenous artery occlusion, we measured the following in gracilis muscles: monocyte chemotactic protein-1 (MCP-1) in wild-type (WT) C57Bl/6J mice by ELISA, and capillary arterialization in WT-WT and CCR2(-/-)-WT (donor-host) bone marrow chimeric mice, as well as BMC transdifferentiation in EGFP(+)-WT mice, by smooth muscle (SM) alpha-actin immunochemistry. MCP-1 levels were significantly elevated 1 day after occlusion in WT mice. In WT-WT mice at day 7, compared to sham controls, arterial occlusion induced a 34% increase in arteriole length density, a 46% increase in SM alpha actin(+) vessels, and a 45% increase in the fraction of vessels coated with SM alpha-actin, indicating significant capillary arterialization. However, in CCR2( /-)-WT mice, no differences were observed between arterial occlusion and sham surgery. In EGFP(+)-WT mice, EGFP and SM alpha-actin never colocalized. We conclude that BMC-specific CCR2 expression is required for skeletal muscle capillary arterialization following arterial occlusion; however, BMCs do not transdifferentiate into smooth muscle. PMID- 19777362 TI - Nutritive value of some tropical grasses used by traditional small farms in the highlands of Burundi. AB - The objective was to estimate--according to the French feeding system--the nutritive value of three tropical grasses (Eragrostis olivacea, Setaria sphacelata and Tripsacum laxum) used in traditional small farms of Burundi. Dry matter (DM) yield was monitored on anti-erosive hedges or on small fields in 60 small farms for eight consecutive years. DM intake and digestibility values were measured on seven steers or seven male sheep. Degradability values were determined on three sheep. S. sphacelata exhibited higher DM yield (t ha(-1)), energy (UF, kg(-1) DM) and protein (PDI, g kg(-1) DM) values (17.3, 0.73 and 68, respectively) than T. laxum (9.11, 0.64 and 47) and E. olivacea (not determined, 0.46 and 42). The UF and PDI intakes of these grass species were able to meet only 51% to 92% of the energy and 59% to 133% of the protein requirements for maintenance of the experimental animals. PMID- 19777363 TI - Torque teno virus infection in hemodialysis patients in North India. AB - This study describes the prevalence and association of Torque teno virus (TTV) infection with blood-transmitted viral hepatitis including hepatitis B virus (HBV) and hepatitis C virus (HCV) infections in patients with chronic renal failure (CRF) on maintenance hemodialysis (HD). TTV infection was diagnosed by detection of TTV-DNA in serum, using the polymerase chain reaction (PCR) technique. TTV-DNA was estimated in a total number of one hundred patients with CRF and in 100 voluntary blood donors as controls. The markers of HBV and HCV were also tested in sera samples of these patients. TTV-DNA was detected in 39 of 100 patients (39%) with CRF and in 27 of 100 (27%) healthy controls. The analysis of the results demonstrated HBsAg, IgM anti-HBc, anti-HCV, and HCV core antigen in 5.0, 3.0, 6.0, and 4.0% of patients, respectively. This study could not show any association of TTV with HBV and HCV infections for the transmission pattern or any impact on severity of diseases caused by these viruses in CRF patients. TTV also could not show any association with demographic characteristics of patients, duration of dialysis, number of blood transfusions and renal/liver function of the patients. As such, this study concludes that TTV appears as a benign pathogen, showing no sign of renal/liver damage or any change in the severity of diseases caused by blood-borne hepatitis viruses. PMID- 19777364 TI - Evaluating amplified rDNA restriction analysis assay for identification of bacterial communities. AB - Amplified ribosomal DNA restriction analysis (ARDRA) and restriction fragment length polymorphism were originally used for strain typing and for screening clone libraries to identify phylogenetic clusters within a microbial community. Here we used ARDRA as a model to examine the capacity of restriction-based techniques for clone identification, and the possibility of deriving phylogenetic information from ARDRA-based dendrograms. ARDRA was performed in silico on 48,759 sequences from the Ribosomal Database Project, and it was found that the fragmentation profiles were not necessarily unique for each sequence in the database, resulting in different species sharing fragmentation profiles. Although ARDRA-based clusters separated clones into different genera, these phylogenetic clusters did not overlap with trees constructed according to sequence alignment,calling into question the intra-genus ARDRA based phylogeny. It is thus suggested that the prediction power of ARDRA clusters in identifying clone phylogeny be regarded with caution. PMID- 19777366 TI - Prescribing errors during hospital inpatient care: factors influencing identification by pharmacists. AB - OBJECTIVE: To investigate the prevalence of prescribing errors identified by pharmacists in hospital inpatients and the factors influencing error identification rates by pharmacists throughout hospital admission. SETTING: 880 bed university teaching hospital in North-west England. METHODS: Data about prescribing errors identified by pharmacists (median: 9 (range 4-17) collecting data per day) when conducting routine work were prospectively recorded on 38 randomly selected days over 18 months. MAIN OUTCOME MEASURES: Proportion of new medication orders in which an error was identified; predictors of error identification rate, adjusted for workload and seniority of pharmacist, day of week, type of ward or stage of patient admission. RESULTS: 33,012 new medication orders were reviewed for 5,199 patients; 3,455 errors (in 10.5% of orders) were identified for 2,040 patients (39.2%; median 1, range 1-12). Most were problem orders (1,456, 42.1%) or potentially significant errors (1,748, 50.6%); 197 (5.7%) were potentially serious; 1.6% (n = 54) were potentially severe or fatal. Errors were 41% (CI: 28-56%) more likely to be identified at patient's admission than at other times, independent of confounders. Workload was the strongest predictor of error identification rates, with 40% (33-46%) less errors identified on the busiest days than at other times. Errors identified fell by 1.9% (1.5 2.3%) for every additional chart checked, independent of confounders. CONCLUSIONS: Pharmacists routinely identify errors but increasing workload may reduce identification rates. Where resources are limited, they may be better spent on identifying and addressing errors immediately after admission to hospital. PMID- 19777365 TI - Improvement of diabetes indices of care by a short pharmaceutical care program. AB - OBJECTIVE: Diabetes mellitus is a serious health problem associated with an increased mortality and morbidity. The association of improved glycemic control with sustained decrease in the rate of complications has been shown in randomized clinical trials. Pharmaceutical care is a relatively new concept in Turkey; yet, there are no recorded routine pharmaceutical care programs. Therefore, we aimed to assess the impact of a short pharmaceutical care program conducted in the community pharmacy setting, on the indices of diabetes care of type 2 diabetic patients, particularly those regarding glycemic control and high blood pressure management. SETTING: The study was carried out at eight community pharmacies in Pendik district of Istanbul. METHOD: All patients who visited any of the eight pharmacies through the pre-determined 1-week period were questioned for the presence of type 2 diabetes. Patients who reported to be type 2 diabetic (n = 67) were informed about the study and invited to involve. During this prospective longitudinal study, pharmaceutical care was provided to the patients by the same clinical pharmacist. The 3 month pharmaceutical care period consisted of six pharmacy visits. MAIN OUTCOME MEASURE: The main outcome measures were the improvement in glycemic control and blood pressure control; while, weight control, self-monitoring of blood glucose, compliance and being under physician control were also assessed. RESULTS: The study was conducted on 43 patients who accepted to involve. Fasting blood glucose was lowered by a mean of 23% over 3 months from an initial value of 167.2 mg/dl. Number of patients reaching the desired blood glucose goals increased from 16.3% to 39.5%. Systolic and diastolic blood pressures also significantly fell over 3 months (mean reductions were 10.9 mmHg for the systolic and 9.3 mmHg for the diastolic blood pressure). Number of patients reaching the desired blood pressure goal increased from 30.2% to 51.2%. CONCLUSION: Our short-course pharmaceutical care program yielded measurable improvements in clinical indicators of diabetes and comorbidity management. The results suggest that the pharmacist is a beneficial key component of integrated care for patients with type 2 diabetes. We think that the positive results observed in this first reported pharmaceutical care program on diabetes in Turkey can be motivating and encouraging for all community pharmacists. PMID- 19777367 TI - Stent implant follow-up in intravascular optical coherence tomography images. AB - The objectives of this article are (i) to utilize computer methods in detection of stent struts imaged in vivo by optical coherence tomography (OCT) during percutaneous coronary interventions (PCI); (ii) to provide measurements for the assessment and monitoring of in-stent restenosis by OCT post PCI. Thirty-nine OCT cross-sections from seven pullbacks from seven patients presenting varying degrees of neointimal hyperplasia (NIH) are selected, and stent struts are detected. Stent and lumen boundaries are reconstructed and one experienced observer analyzed the strut detection, the lumen and stent area measurements, as well as the NIH thickness in comparison to manual tracing using the reviewing software provided by the OCT manufacturer (LightLab Imaging, MA, USA). Very good agreements were found between the computer methods and the expert evaluations for lumen cross-section area (mean difference = 0.11 +/- 0.70 mm(2); r (2) = 0.98, P < 0.0001) and the stent cross-section area (mean difference = 0.10 +/- 1.28 mm(2); r (2) = 0.85, P value < 0.0001). The average number of detected struts was 10.4 +/- 2.9 per cross-section when the expert identified 10.5 +/- 2.8 (r (2) = 0.78, P value < 0.0001). For the given patient dataset: lumen cross-sectional area was on the average (6.05 +/- 1.87 mm(2)), stent cross-sectional area was (6.26 +/- 1.63 mm(2)), maximum angle between struts was on the average (85.96 +/- 54.23 degrees ), maximum, average, and minimum distance between the stent and the lumen were (0.18 +/- 0.13 mm), (0.08 +/- 0.06 mm), and (0.01 +/- 0.02 mm), respectively, and stent eccentricity was (0.80 +/- 0.08). Low variability between the expert and automatic method was observed in the computations of the most important parameters assessing the degree of neointimal tissue growth in stents imaged by OCT pullbacks. After further extensive validation, the presented methods might offer a robust automated tool that will improve the evaluation and follow-up monitoring of in-stent restenosis in patients. PMID- 19777369 TI - Obstruction and sequestration: a case of apical hypertrophic cardiomyopathy concomitant with subaortic obstruction, apical sequestration, and valvular aortic stenosis. AB - We presented an unique case of apical hypertrophic cardiomyopathy concomitant with subaortic obstruction, apical sequestration, and valvular aortic stenosis. The echocardiographic findings were conflicting and characterized by quadruple pressure gradients within the left ventricle, which were compatible with the findings of 64-slice computed tomography imaging and cardiac catheterization. PMID- 19777368 TI - Imaging features of intramural hematoma of the aorta. AB - Intramural hematoma (IMH) is defined as localized hemorrhage within the aortic wall and is included in the acute aortic syndrome spectrum with aortic dissection and penetrating aortic ulcer. The mortality from IMH is similar to classic aortic dissection (21%). 16% of patients with IMH will evolve to classic aortic dissection over time. Despite this confusion exists regarding the precise definitions and radiologic features of IMH versus penetrating ulcers with mural thrombus and overt aortic dissection. PMID- 19777370 TI - Molecular analysis of an actin gene, CarACT1, from chickpea (Cicer arietinum L.). AB - Actins are ubiquitous and highly conserved proteins that play key roles in cell formation and cellular activities. In this study, an actin gene was isolated from chickpea for the first time and designated as CarACT1 (for Cicer arietinum L. actin gene 1; Genbank accession no. EU529707). It encoded a putative protein with 377 amino acids and contained five exons and four introns within genomic DNA sequence. CarACT1 was localized in cytoplasm and showed high similarity to other well known actins from various species. Reverse transcription-polymerase chain reaction (RT-PCR) assay proved that CarACT1 transcripts were ubiquitously accumulated in all major organs, such as seedling roots, stems, leaves, flowers, young pods, and seeds, as well as in diverse developmental stages, such as leaf senescence, seed development and germination. Our results suggested that CarACT1 is an actin gene with physiological functions and may be served as a potential reference gene for transcription level of interesting genes in chickpea. PMID- 19777371 TI - Structural diversity and differential expression of novel human intersectin 1 isoforms. AB - Intersectin 1 (ITSN1) is an evolutionarily conserved adaptor protein that functions in clathrin-mediated endocytosis, cell signalling and cytoskeleton rearrangements. The ITSN1 gene encodes two main isoforms: a short form (ITSN1-s), which is ubiquitously expressed and consists of two Eps15 homology (EH) domains and five Src homology 3 (SH3) domains, and a long form (ITSN1-l), which is predominantly expressed in the brain and contains three additional domains, a Dbl homology (DH) domain, a Pleckstrin homology (PH) domain and a C2 domain. Using computational analysis of the EST database and 3' RACE we determined the length of the 3' untranslated region of ITSN1-l and demonstrated that the polyadenylation site is located 11,559 nt downstream of the stop codon of the ITSN1-l mRNA. Recently, additional splicing events affecting ITSN1 transcripts were reported, but full-length transcriptional isoforms with different combinations of alternatively spliced exons remained unknown. Here we report the identification of fifteen novel transcriptional isoforms of the human ITSN1 gene with full-length coding sequences that are the result of different combinations of the alternatively spliced exons 5, 6/6', 20, 23, 25, 26, 26a and 35. The isoforms identified differ in domain organization and expression level in different tissues and more likely contribute to the modulation of many complex protein interactions in which ITSN1 participates. PMID- 19777372 TI - Molecular medicine and concepts of disease: the ethical value of a conceptual analysis of emerging biomedical technologies. AB - Although it is now generally acknowledged that new biomedical technologies often produce new definitions and sometimes even new concepts of disease, this observation is rarely used in research that anticipates potential ethical issues in emerging technologies. This article argues that it is useful to start with an analysis of implied concepts of disease when anticipating ethical issues of biomedical technologies. It shows, moreover, that it is possible to do so at an early stage, i.e. when a technology is only just emerging. The specific case analysed here is that of 'molecular medicine'. This group of emerging technologies combines a 'cascade model' of disease processes with a 'personal pattern' model of bodily functioning. Whereas the ethical implications of the first are partly familiar from earlier--albeit controversial--forms of preventive and predictive medicine, those of the second are quite novel and potentially far reaching. PMID- 19777373 TI - The comparative responsiveness of the EQ-5D and SF-6D to change in patients with inflammatory arthritis. AB - PURPOSE: Comparative evidence regarding the responsiveness of the EQ-5D and SF-6D in arthritis patients is conflicting and insufficient across the range of disease severity. We examined the comparative responsiveness of the EQ-5D and SF-6D in cohorts of patients with early inflammatory disease through to severe rheumatoid arthritis (RA). METHODS: Responsiveness was tested using the effect size (ES) and standardised response mean (SRM). Correlation of change in EQ-5D and SF-6D with disease specific measures was tested using Pearson correlations and the Steiger's Z test. Treatment response and self-reported change were used as anchors of important change. RESULTS: The EQ-5D was more responsive to deterioration (ES ratio (EQ-5D/SF-6D): 1.6-3.0) and the SF-6D more responsive to improvement (ES ratio (SF-6D/EQ-5D): 1.1-1.8) in health. The SF-6D did not respond well to deterioration in patients with established severe RA (ES and SRM 0.08). The EQ-5D provided larger absolute mean change estimates but with greater variance compared to the SF-6D. CONCLUSIONS: The comparative responsiveness of the EQ-5D and SF-6D differs according to the direction of change. The level of mean change of the EQ 5D relative to the SF-6D has implications for cost-effectiveness analysis. Use of the SF-6D in patients with severe progressive disease may be inappropriate. PMID- 19777374 TI - Increased circulating heat shock protein 70 levels in pregnant asthmatics. AB - Asthma is one of the most common diseases complicating pregnancy and represents a risk factor for several maternal and perinatal complications. The natural history of asthma is known to change in pregnancy, but very few data are available in the terms of pathomechanism of this change during gestation. Circulating heat shock protein 70 (Hsp70) levels are decreased in healthy pregnancy, which might reflect physiological immunotolerance. The aim of our study was to determine the serum levels of Hsp70 in asthmatic women during gestation. Forty pregnant women with bronchial asthma and 40 healthy pregnant women matched for maternal and gestational age were involved in this case-control study. Serum Hsp70 levels were measured using the ELISA Kit of R&D Systems. Spirometry and oxygen saturation measurements were performed in asthmatic patients. In asthmatic pregnant women, an increase of serum Hsp70 levels was observed compared to healthy pregnant women (median (25-75 percentile): 0.44 ng/ml (0.36-0.53) versus 0.21 ng/ml (0-0.27), p < 0.001). Fetal birth weight of asthmatic mothers was significantly smaller than of healthy controls, but in the normal range (3,230 g (2,690-3,550) versus 3,550 g (3,450-3,775), p < 0.05). A statistically significant negative correlation between maternal age and serum Hsp70 concentrations (Spearman R = -0.48, p = 0.0018) and a significant positive correlation between gestational age and serum Hsp70 levels (Spearman R = 0.83, p < 0.001) were detected in healthy pregnant women. In conclusion, this study proves an elevation of circulating Hsp70 levels during asthmatic pregnancy compared to healthy pregnant women. However, further studies are warranted to determine the role of circulating Hsp70 in the pathogenesis of maternal and perinatal complications of asthma in pregnancy. PMID- 19777375 TI - Versatility of the small heat shock protein HSPB6 (Hsp20). AB - The recently published review by Dreiza et al. (Cell Stress and Chaperones DOI 10.1007/s12192-0090127-8 ) dealing with the functional role of HSPB6 in muscle regulation is critically analyzed. Published data indicate that the chaperone like activity of HSPB6 is comparable with that of HSPB5 and that phosphorylation of HSPB6 does not affect its oligomeric structure. Different hypotheses concerning the molecular mechanisms of HSPB6 action on smooth muscle contraction and on the reorganization of the cytoskeleton are compared, and it is concluded that although HSPB6 is not a genuine actin-binding protein, it can affect the actin cytoskeleton indirectly. Phosphorylated HSPB6 interacts with 14-3-3 and thereby displaces other binding partners of 14-3-3; among them, certain phosphatases, protein kinases, and various actin-binding proteins, which can participate in the reorganization of the actin cytoskeleton. In addition, HSPB6 seems to regulate the activity of certain protein kinases. All of these processes are dependent on HSPB6 phosphorylation which in turn might be regulated by the formation of heterooligomeric complexes of HSPB6 with other small heat shock proteins. PMID- 19777376 TI - First cellular approach of the effects of global warming on groundwater organisms: a study of the HSP70 gene expression. AB - Whereas the consequences of global warming at population or community levels are well documented, studies at the cellular level are still scarce. The study of the physiological or metabolic effects of such small increases in temperature (between +2 degrees C and +6 degrees C) is difficult because they are below the amplitude of the daily or seasonal thermal variations occurring in most environments. In contrast, subterranean biotopes are highly thermally buffered (+/-1 degrees C within a year), and underground water organisms could thus be particularly well suited to characterise cellular responses of global warming. To this purpose, we studied genes encoding chaperone proteins of the HSP70 family in amphipod crustaceans belonging to the ubiquitous subterranean genus Niphargus. An HSP70 sequence was identified in eight populations of two complexes of species of the Niphargus genus (Niphargus rhenorhodanensis and Niphargus virei complexes). Expression profiles were determined for one of these by reverse transcription and quantitative polymerase chain reaction, confirming the inducible nature of this gene. An increase in temperature of 2 degrees C seemed to be without effect on N. rhenorhodanensis physiology, whereas a heat shock of +6 degrees C represented an important thermal stress for these individuals. Thus, this study shows that although Niphargus individuals do not undergo any daily or seasonal thermal variations in underground water, they display an inducible HSP70 heat shock response. This controlled laboratory-based physiological experiment constitutes a first step towards field investigations of the cellular consequences of global warming on subterranean organisms. PMID- 19777377 TI - Rehabilitative treatment in flexible flatfoot: a perspective cohort study. AB - Paediatric valgus flexible flatfoot is a common childhood paramorphism. Its treatment options consist of rehabilitation, corrective footwear and, if necessary, surgical intervention. The aim of our study was to compare a group of children who followed a rehabilitative programme versus a historical group of children who had been treated with insoles and orthopaedic footwear. Over a 2 year period (1995-1997), 300 children (mean age was 3.4-184 male, 116 female) with bilateral flexible flatfoot (600 feet) were recruited and underwent a rehabilitative programme for a mean period of 2.75 years. The feet were classified according to Viladot's method: 386 feet presented a type III degree deformity and 214 feet presented a type II degree deformity. The rehabilitative programme consisted of simple therapeutic exercises, which could be easily learnt by both patients and their caregivers. These children were compared to a historical group of children (674 feet) who had been treated in our department for infantile flexible flatfoot with the use of orthosis. In these groups, 396 feet presented a type III degree deformity and 278 feet presented a type II degree deformity. In the group of children who underwent the rehabilitative protocol, during follow-up at the age of eight, 352 of the 386 type III degree feet could be classified as normal and 210 of the 214 type II degree cases became normal. In the historical cohort of children treated with orthosis, at the age of eight, 214 of the 396 type III degree feet could be classified as normal; and 248 of the 278 type II degree cases became normal. Our results show that comparing the percentage of success (changing from type III or II degree to type I or N) in the two groups (children treated with rehabilitation and children treated with orthosis), the rehabilitative approach seems to be more effective. Probably it has a marginal influence on the natural history of paediatric valgus flexible flatfoot even though it plays a role in maintaining good flexibility of the flatfoot thus limiting functional impairment. PMID- 19777378 TI - The total anterior tenoarthrolysis in the treatment of the stiffness in flexion of the fingers. AB - The total anterior tenoarthrolysis (TATA) allows tenolysis, arthrolysis and skin repair in the same operation, avoiding combined different surgical procedures. The authors present a series of personal and original indications and propose a partial anterior tenoarthrolysis (PATA) for the treatment of isolated stiffness of the proximal interphalangeal joint or in the presence of less severe flexion contractures. The etiology was wide various, and the TATA revealed to be extremely useful also in tetraplegia or spasticity, permitting respectively the following tendon transfer and the hygienic improvement, and in the presence of global stiffness following complex lesions, reflex sympathetic algodystrophy or psychotic contracture. The performed additional procedures, at the skin and tendon level, further expanded the inclusion criteria. In the presence of appropriate indications, the TATA is a very useful tool with excellent outcome and represents a salvage procedure in the more severe deformities, avoiding joint fusion, with shortage of the digit, or amputation. PMID- 19777379 TI - Optimization of biodiesel production catalyzed by fungus cells immobilized in fibrous supports. AB - A circulating packed-bed bioreactor system using fibrous nonwoven fabric as the immobilization matrix was suitable for simultaneous cell growth and immobilization of Rhizopus oryzae fungus cells, which could be used for lipase mediated production of biodiesel by methanolysis of soybean oil. Response surface methodology and 5-level-5-factor central composite rotatable design was proved to be a powerful tool for the optimization of methanolysis conditions catalyzed by immobilized R. oryzae whole cell biocatalyst. A quadratic polynomial regression model was used to analyze the relationship between the yield and the significant reaction parameters. The analysis confirmed that water content, molar ratio of methanol to oil, cell weight, and reaction time were the significant factors affecting the yield at a 95% confidence level (p < 0.05). Under the optimum condition at 10.97% (w/w) water content, 0.64 molar ratio of methanol to oil, 2.25% (w/w) cell weight, and 23.3 h reaction time, the predicted value of yield was 72.6%. Validation experiments with yields of 70.77 +/- 2.46% verified the availability and the accuracy of the model. PMID- 19777380 TI - An elementary framework for judging the cardiovascular toxicity of carbon soot: experiences from an occupational health survey of diamond industry workers. AB - Carbon soot is produced in the process of diamond manufacture. Recent experimental and epidemiological studies have associated exposure to carbon nanoparticles with effects on cardiovascular system and blood cells. The objective of this study is to assess the cardiovascular effects consequent to chronic respiratory exposure of carbon soot. A cross-sectional occupational health survey was conducted in all consenting workers who employed in the production wing of diamond-processing industries. Blood pressure, ECGs, height, weight, and blood counts were measured and evaluated. Blood pressure measurements revealed a high prevalence of hypertension in young workers. Left atrial abnormality (LAA) was the major finding in the electrocardiograms. We found a high prevalence of hypertension in young diamond workers. The LASER saw operators had highest prevalence of LAA. White cell count and prevalence of hypertension was highest for the workers in grinder operations. PMID- 19777381 TI - Anorexic vs. metabolic effects of central leptin infusion in rats of various ages and nutritional states. AB - Age-related obesity is known to be adjoined by leptin resistance. It has not been clarified whether the resistance is cause or result of obesity. In the present experiments, the anorexic (suppressing food intake and body weight) and hypermetabolic (increasing body temperature (Tc), activity, and heart rate (HR), indicating metabolic rate) responses to 7-day-long intracerebroventricular leptin infusion were compared in 2- and 6-month-old normally fed (NF2 and NF6 groups), 6 month-old high-fat-diet-induced obese (HF6), and 6-month-old calorie-restricted (CR6) rats. The anorexic effects were inversely related to fat content: They were most pronounced in NF2, less in NF6, non-significant in HF6 rats, but also absent in CR6 animals of the lowest fat content. This virtual leptin resistance in CR6 rats was due to their high orexigenic activity (enhanced feeding response to NPY). In contrast, CR6 rats were hypersensitive to the metabolic effects of leptin infusion (rise in Tc and HR; biotelemetric measurements), NF2 were still sensitive, while NF6 and HF6 rats exhibited moderate or low sensitivity. In conclusion, leptin resistance depends on body fat content rather than on age itself, although with age the proportion of fat tissue increases and contributes to self-perpetuating rise in body weight. PMID- 19777382 TI - Transient protective effect of B-vitamins in experimental epilepsy in the mouse brain. AB - The regulation of programmed cell death in the nervous system of vertebrates is a complex mechanism aimed to remove superfluous or damaged cells. Epileptic seizures can lead to an activation of pathways resulting in neuronal cell death. B-vitamins might have a neuroprotective potential reducing cell death following appropriate stimulation. Here, the role of the B-vitamins B(1) (thiamine), B(6) (pyridoxine), and B(12) (cobalamine) was investigated in a mouse model of experimental epilepsy induced by kainate. B-vitamin pre-treated animals showed a significantly reduced epileptic score during the first 15 min after kainate injection. The molecular response to kainate showed a bi-phased time course with early induction of Bcl-2 expression within 12 h and a second induction after 7 days of kainate exposure. B-vitamin pre-treatment resulted in significant higher Bcl-2 expression in control animals (no kainate) and at 12 h within the early phase. Bcl-2 expression was not affected by B-vitamins within the second phase. BAX expression was not significantly influenced during the whole experiment. Three days after kainate stimulation, the number of TdT-mediated dUTP-biotin nick end labeling-positive cells in the hippocampal region was lower in B-vitamin treated animals. Therefore, B-vitamin pre-treatment may attenuate the response to epileptic stimulation. PMID- 19777383 TI - Ultra-fast versus sustained cholinergic transmission: a variety of different mechanisms. AB - Although synaptic transmission was assumed to use the same mechanisms in the case of different synapses of the central and peripheral nervous system, recent research revealed a great variety of different processes. Time might be a crucial factor to be considered in this diversity. It is recalled that the speed of a chemical reaction is inversely related to affinity. "Time is gained at the expense of sensitivity" as noticed by Bernard Katz (1989). Therefore, synaptic transmission will occur at a high speed only if it is supported by low affinity reactions. In the present work, we compare two examples of ultra-rapid transmission (the Torpedo nerve electroplaque synapse and the rat hippocampus mossy fiber/CA3 synapses), with a cholinergic process operating with high affinity but at a low speed: the release of glutamate elicited by nicotine from mossy fibers of the rat hippocampus. PMID- 19777384 TI - High-mobility group box 1 protein in CSF of patients with subarachnoid hemorrhage. AB - BACKGROUND: High-mobility group box 1 protein (HMGB1) is a nuclear factor that is a potent proinflammatory mediator, and may trigger increases in other inflammatory cytokines. The inflammatory cytokines in the cerebrospinal fluid (CSF) of patients with subarachnoid hemorrhage (SAH) have been reported previously, but HMGB1 has not. In this study, we measured HMGB1 and the inflammatory cytokines in the CSF of patients with SAH. METHODS: CSF samples were collected on days 3, 7, and 14 from the drainage tubes of the postaneurysm clips of 39 patients with SAH. HMGB1, interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha (TNF-alpha) were measured in the CSF, and compared between the patients with favorable (good recovery and moderate disability) and unfavorable outcomes (severe disability, vegetative state, and death) at 3 months. RESULTS: In the unfavorable outcome group, HMGB1 (P = 0.017), IL-6 (P = 0.003), IL-8 (P = 0.041), and TNF-alpha (P = 0.002) were significantly increased. HMGB1 correlated significantly with IL-6, IL-8, and TNF-alpha (R = 0.672, 0.421, and 0.697, respectively). CONCLUSIONS: HMGB1 was increased in the CSF of SAH patients with an unfavorable outcome, as were the other cytokines. These results suggest that HMGB1 and cytokines are related to the brain damage observed after SAH. HMGB1 might play a key role in the inflammatory response in the CNS of SAH patients. PMID- 19777385 TI - Efficiency and safety of a standardized protocol for intravenous insulin therapy in ICU patients with neurovascular or head injury. AB - BACKGROUND: To evaluate the safety and efficiency of a protocol for glycemic control in intensive care unit (ICU) patients with neurovascular or head injury. METHODS: Two cohorts of 50 consecutive patients admitted to the ICU with an admission diagnosis of neurovascular or head injury before and after protocol implementation were evaluated. All patients in the interventional cohort received insulin using a standardized intravenous insulin infusion protocol targeting blood glucose levels of 7-9 mmol/l. Efficiency (time to reach and time within target range), safety (hypoglycemia), and nursing compliance (protocol violations) were evaluated. RESULTS: The median time to reach the target blood glucose range was shorter in the interventional cohort than the conventional cohort (5.0 h [0.5-20.5 h] vs. 12.9 h [1.3-90.3 h]; P < 0.001). More time was spent within target range in the interventional cohort than in the conventional cohort (36.4 +/- 16.3% vs. 27.1 +/- 19.0%; P < 0.001). The median prevalence of mild (<4.9 mmol/l) hypoglycemia (0 [0-1.11]% vs. 0.58 [0-2.79]%; P < 0.001) and moderate (<3.9) hypoglycemia (0[0-0.55]% vs. 0 [1-1.25]%; p < 0.001) was significantly lower in the interventional cohort. CONCLUSIONS: The intravenous insulin infusion protocol improved the safety and efficiency of glycemic control for ICU patients with neurovascular or head injury. PMID- 19777386 TI - Factors associated with the development of anemia after subarachnoid hemorrhage. AB - INTRODUCTION: Anemia is common after subarachnoid hemorrhage (SAH) and may exacerbate the reduction in oxygen delivery that underlies delayed cerebral ischemia. Fall in hemoglobin may relate to blood loss as well as inflammatory suppression of erythropoiesis. Identifying factors associated with anemia may facilitate targeted interventions, such as the use of erythropoiesis-stimulating agents, which could minimize the burden of anemia and reduce red blood cell (RBC) transfusion requirements. METHODS: We analyzed a cohort of patients with spontaneous SAH admitted over a 3-year period who survived at least 4 days. All patients had daily hematocrit values drawn while in the ICU. Multivariate regression was performed to determine baseline and early post-admission variables associated with development of anemia (defined as hematocrit < 30%). RESULTS: Anemia developed in 47% of 243 patients with SAH after a mean of 3.5 days (median 2 days). Admission variables independently associated with anemia were female gender (OR 3.7, 95% CI 1.8-7.6), baseline hematocrit < 36% (OR 3.9, 1.5-10.1 compared to 36-45%), history of hypertension (OR 2.1, 1.05-4.2), and poor clinical grade (OR 5.9, 2.3-15.0). Surgical aneurysm treatment (OR 13.5, 6.0 30.3) and greater admission SIRS score (OR 5.7, 1.7-19.2 if 3-4 criteria for systemic inflammatory response syndrome were met on day of admission compared to none) were also associated with fall in hematocrit. CONCLUSIONS: It may be possible to predict those most likely to develop anemia using simple baseline clinical variables. Anemia was strongly related to surgery, likely through greater blood loss, and greater systemic inflammatory response on admission, possibly explained by cytokine-mediated inhibition of RBC production. PMID- 19777387 TI - Revascularization of Onyx induced intra-operative occlusion of vertebro-basilar artery using the Merci device. AB - INTRODUCTION: Endovascular embolization is an important modality in the treatment of cerebral arteriovenous malformations (AVMs). Onyx is an ethylene vinyl alcohol copolymer dissolved in dimethyl sulfoxide that is approved for use as an embolic agent for brain AVMs. CASE REPORT: We describe a case of revascularization of an occluded vertebro-basilar artery during embolization of an AVM with Onyx, by using the Merci device. CONCLUSION: Reflux embolization of patent vessels is a rare complication of using Onyx to treat AVMs. It can be successfully managed by retrieving the Onyx substance using mechanical retrieval devices like the Merci device. PMID- 19777389 TI - Mitochondria--a neglected drug target. PMID- 19777388 TI - Clinical presentation and long-term outcome of cerebral venous thrombosis. AB - BACKGROUND: Despite recent advances, the clinical features of cerebral venous thrombosis (CVT) remain incompletely characterized. To our knowledge, no case series have been reported from North American centers with detailed long-term outcome data, and few studies have evaluated recanalization rates. METHODS: All cases of CVT at a single tertiary care hospital between 1995 and 2004 were retrospectively reviewed. Follow-up information was obtained from direct patient interviews. RESULTS: Follow-up data were available for 58 of 61 CVT patients (median 50 months). Average age was 40, and 66% were women. Headache and focal neurological deficits were noted in 82% and 72%, respectively. Intracranial hemorrhage was seen in 44%. Hypercoagulable risk factors were identified in 84%. Anticoagulation was initiated acutely in 84%, including in all patients with intraparenchymal hemorrhage (IPH). The percentage of patients with a modified Rankin Score (mRS) of 0 to 2 at admission, hospital discharge and last follow-up were 41%, 67%, 90%, respectively; the rate of favorable long-term outcome did not differ significantly between patients with and without IPH. In the subset of 21 patients with follow-up imaging available for direct review, 90% had partial or complete recanalization. CONCLUSIONS: The demographics, clinical presentation, imaging findings, and risk factors in this large North American cohort of CVT patients strongly support the observations of previous European case series. In addition, the favorable long-term outcome and recanalization rates observed lend further support to the safety and efficacy of acute heparin therapy for the treatment of symptomatic CVT (irrespective of the presence of ICH). PMID- 19777390 TI - The significance of new somatostatin analogs as therapeutic agents. AB - The effects of somatostatin, or somatotropin release-inhibiting factor (SRIF), and SRIF analogs in human diseases have been widely investigated to potentially expand the therapeutic applications of commercially available and newly designed compounds belonging to this class of agents. Several preclinical studies and clinical trials have demonstrated the antiproliferative and antisecretory effects of SRIF and its analogs. This review discusses results from studies investigating the secretory activity and cell viability of SRIF analogs, and the potential of new therapeutic applications of these drugs in endocrine diseases and, in particular, as a treatment for endocrine neoplasia. PMID- 19777391 TI - Resistance pathways relevant to insulin-like growth factor-1 receptor-targeted therapy. AB - The dysregulation of insulin-like growth factor (IGF) signaling has been implicated as a critical contributor to malignant transformation, proliferation, survival, migration and resistance to anticancer therapies. As a result, IGF signaling has become an attractive target for the development of novel anticancer agents, and a large number of compounds, including blocking antibodies and tyrosine kinase inhibitors targeting the key signaling kinase of the IGF system, the IGF-1 receptor (IGF-1R), are in preclinical and clinical development. Although most tumors express the IGF-1R, expression alone is unlikely to be sufficient for sensitivity to IGF-targeted treatment. An understanding of the IGF signaling system and its downstream effectors is important, as this information will allow appropriate molecular markers of sensitivity to be determined, thus providing the rationale for combining IGF-1R blockade with other therapies to overcome resistance. This review highlights some of the preclinical and early clinical data on determinants of sensitivity to IGF targeting in human cancers, and reviews the rationale for targeting other tyrosine kinases, such as the insulin receptor and members of the EGFR family, to overcome intrinsic resistance to targeted IGF-1R therapy. PMID- 19777392 TI - Experimental antipsychotics and metabolic adverse effects--findings from clinical trials. AB - Initial optimism regarding the introduction of second-generation antipsychotic drugs has decreased because of accumulating concerns regarding efficacy and safety issues, particularly in terms of weight gain and disturbances in glucose and lipid metabolism. These adverse effects, in addition to posing serious health risks, significantly compromise patient compliance and contribute to overall lack of therapy effectiveness. Consequently, research efforts have been directed toward the development of new pharmacological treatment options for schizophrenia and bipolar disorder that are both efficacious and well tolerated. This review discusses some of the most recently developed antipsychotic compounds that have undergone clinical assessment from the perspective of their metabolic impact. PMID- 19777394 TI - Adipokines: emerging therapeutic targets. AB - Adipose tissue can affect human physiology through its secreted products, collectively termed adipokines, which mediate complex crosstalk between organs. Adipokines have been linked to a wide range of pathologies in many tissues; however, the pathophysiological significance of these cytokines remains poorly understood, and more research is needed in this area. Adipokines may have both beneficial and potentially harmful effects; for example, leptin reduces body weight, but also impairs immune responses. A cautious approach is therefore warranted when considering the pharmacological manipulation of adipokines to treat diseases, and novel approaches may be required to target specific organs or actions to reduce the potential for adverse effects. PMID- 19777395 TI - Antagonists of the renin-angiotensin system and the prevention of obesity. AB - In addition to its role as an energy store, adipose tissue also acts as an endocrine organ, synthesizing and secreting hormones and cytokines. This review discusses angiotensin II (Ang-II), the biologically active component of the renin angiotensin system (RAS). Evidence suggests that a functioning RAS is present in adipose tissue. Animal studies have demonstrated that modifying the amount of Ang II in the body (eg, using RAS knockout/transgenic animal models or the pharmacological treatment of animal models to prevent the formation or action of Ang-II) directly influences body weight and adiposity. In humans, body fat is correlated with levels of angiotensinogen, a precursor of Ang-II. Thus, the treatment of obesity could be improved through the use of substances that interfere with Ang-II. PMID- 19777396 TI - Bariatric surgery: what is the effect on type 2 diabetes? AB - Type 2 diabetes mellitus (T2DM) is a costly chronic disease that is associated with increased morbidity and mortality. Despite the development of numerous pharmacological agents, diet and exercise programs, and behavior-modification protocols, bariatric surgery remains the most effective tool for the durable reversal of T2DM. This review discusses the known effects of bariatric surgery on T2DM, with a particular focus on Roux-en-Y gastric bypass. PMID- 19777393 TI - Insulin resistance and neurodegeneration: roles of obesity, type 2 diabetes mellitus and non-alcoholic steatohepatitis. AB - Recent studies have linked obesity, type 2 diabetes mellitus (T2DM) or non alcoholic steatohepatitis (NASH) to insulin resistance in the brain, cognitive impairment and neurodegeneration. Insulin resistance compromises cell survival, metabolism and neuronal plasticity, and increases oxidative stress, cytokine activation and apoptosis. T2DM/NASH has been demonstrated to be associated with increased ceramide generation, suggesting a mechanistic link between peripheral insulin resistance and neurodegeneration because ceramides mediate insulin resistance and can cross the blood-brain barrier (BBB). Peripheral insulin resistance diseases may potentially cause brain insulin resistance via a liver brain axis of neurodegeneration as a result of the trafficking of ceramides across the BBB. Therapy that includes insulin-sensitizing agents may help prevent brain insulin resistance-mediated cognitive impairment. PMID- 19777397 TI - Bone as a target of type 2 diabetes treatment. AB - Clinical evidence suggests that bone health is affected in some patients with type 2 diabetes mellitus (T2DM). T2DM is associated with an increased incidence of bone fractures. Although factors associated with T2DM, such as an increased risk of falls, may be in part responsible for the higher risk of fracture, decreased bone quality may also play an important role. In addition, treatment with thiazolidinediones (TZDs), a class of antidiabetic drugs, causes bone loss and further increases fracture risk. In vitro and in vivo animal studies have demonstrated that TZD-mediated PPARgamma activation increases bone resorption and reduces the formation of new bone. Aging and estrogen deficiency are sensitizing factors to bone loss as a result of TZD therapy. Biguanides and sulfonylureas do not appear to have adverse effects on bone, whereas insulin increases the incidence of fractures, although the underlying mechanism responsible for this increase is unknown. Preclinical evidence suggests that incretin-based drugs may be beneficial for bone, but clinical evidence to support this hypothesis is not yet available. In summary, bone is a target of certain antidiabetic therapies and, therefore, caution is necessary in the choice of treatment for patients who are at risk of skeletal complications. PMID- 19777398 TI - Linagliptin, a dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes. AB - Boehringer Ingelheim Corp is developing the novel, xanthine-based dipeptidyl peptidase (DPP)-4 inhibitor linagliptin for the potential treatment of type 2 diabetes mellitus. In vitro assays suggested that linagliptin was a potent DPP-4 inhibitor, with good selectivity for DPP-4 compared with other DPPs and proteases. The inhibition of DPP-4 by linagliptin was also demonstrated in vivo, resulting in increased glucagon-like peptide 1 levels and improved glucose tolerance in both healthy animals and models of disease. Furthermore, linagliptin exhibited prolonged pharmacodynamic activity, with long-lasting DPP-4 inhibition across different species. The prolonged DPP-4 inhibition observed in preclinical models has translated to humans; linagliptin demonstrated approximately 80% inhibition of DPP-4 activity at daily doses as low as 5 mg in phase II clinical trials. The effects were sustained, and no signs or symptoms of hypoglycemia were observed, even at high doses of up to 600 mg. The low therapeutic dose of linagliptin, the long-lasting inhibition of DPP-4 activity and the good safety/tolerability profile exhibited thus far suggest that linagliptin may be superior to competitors. The results from ongoing phase III clinical trials will provide further information on such aspects; however, from the available data, linagliptin appears to have promise for market success. PMID- 19777400 TI - Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity. AB - Contrave, under development by Orexigen Therapeutics Inc for the potential treatment of obesity, is an oral, sustained-release combination of the dopamine and norepinephrine reuptake antagonist bupropion and the opioid antagonist naltrexone. The proposed dual mechanism of action of the compound involves complementary stimulation of central melanocortin pathways, resulting in increased energy expenditure and reduced appetite. At the time of publication, Contrave was being assessed in phase III clinical trials. Preliminary data demonstrated placebo-subtracted weight losses of 3 to 7% and improvements in obesity-related comorbidities and cardiovascular risk factors. The primary adverse effect leading to discontinuation of treatment was nausea. Assuming that the results of the Contrave phase III clinical program reaffirm the efficacy and safety of the drug combination, this agent could be approved and launched to become a market leader in the anti-obesity therapeutic arena. PMID- 19777399 TI - Tesofensine, a monoamine reuptake inhibitor for the treatment of obesity. AB - Tesofensine, a monoamine reuptake inhibitor, is under development by NeuroSearch A/S for the potential treatment of obesity. In vitro, the compound potently blocked dopamine, norepinephrine and serotonin reuptake. Initial development, which was conducted by NeuroSearch in collaboration with Boehringer Ingelheim Corp, demonstrated that although tesofensine was ineffective as a treatment for neurodegenerative conditions, a notable occurrence of unintended weight loss was observed in individuals treated with the drug. Preclinical data from diet-induced obese rats supported the hypothesis that tesofensine reduces body weight, and NeuroSearch has since pursued the development of the compound as an oral anti obesity drug. In phase II clinical trials with tesofensine in obese individuals, dose-related reductions in body weight, body fat and waist circumference, as well as improvements in other obesity-related endocrine factors, were observed. Overall, tesofensine was associated with minor adverse events. Tesofensine caused dose-dependent elevations in heart rate, with significant increases in blood pressure at the highest dose tested. The initial positive findings suggest that tesofensine may be a well-tolerated long-term treatment for obesity, with minimal cardiovascular effects; this view appears to be shared by the FDA, which recently endorsed the phase III trial program for the agent. PMID- 19777410 TI - Is there a preventive value in non-invasive cardiac imaging? Debate on the case of a marathon runner. AB - HISTORY: A 64-year old male marathon runner noted during training an asymptomatic sudden increase in heart rate as recorded on his heart rate monitor. But this was not verifiable on subsequent Holter-ECG monitoring. However, treadmill exercise testing revealed unexpected signs of ischemia, which required further diagnostic tests. INVESTIGATIONS: Cardiac computed tomography (CT) demonstrated advanced coronary atherosclerosis, with suspected morphologically significant stenosis after contrast injection. Because of the absence of angina, a myocardial perfusion scintigraphy was done which gave no evidence of ischemia, and there was no late enhancement on magnetic resonance imaging. In view of these findings invasive coronary angiography was not performed. TREATMENT AND COURSE: The patient received aggressive risk modifying therapy. He is still running regularly event-free after nine months. CONCLUSION: This case shows that the use of modern non-invasive cardiovascular imaging can have an impact in preventive clinical decision making. PMID- 19777411 TI - [Preventive cardiology: from prevention to optimal patient care]. PMID- 19777412 TI - [Prehospital assessment and treatment decisions of a suspected acute coronary syndrome: what are the problems? Results of the "Emergency Doctor and Acute Myocardial Infarction" study (NAAMI)]. AB - BACKGROUND: Interpretation of prehospital 12-lead electrocardiograms (ECG) in acute ST-elevation myocardial infarction (STEMI) remains a diagnostic challenge in many cases. The aim of this study was to determine whether board-certified emergency physicians (BCEP) are able to distinguish STEMI from non-STEMI in a large proportion of cases, thus assuring more precise prehospital triage and treatment. METHODS: Electrocardiograms of eight patients with acute non-traumatic chest pain (with 6 ECGs demonstrating STEMI, one with pericarditis, and one with pulmonary embolism) were assessed in a blinded fashion by 73 BCEP (19 female, mean age 37 +/- 5.3 years). Decisions had to be made by them regarding the diagnosis (STEMI or not) and treatment (immediate reperfusion or transfer to the nearest hospital without facilities for percutaneous coronary intervention). RESULTS: In the ECGs with STEMI 83% of BCEPs made the correct diagnosis without significant differences between the subgroups. But in cases of non-STEMI-ECG only 30% of BECP made the correct diagnosis. The results in interpreting non-STEMI were better in older (> 50 years) BCEPs and in those with a background in internal medicine (p = 0.045, and p = 0.01, respectively). In case of STEMI 75% of BCEPs initiated the correct therapy, without significant differences between the subgroups. In case of non-STEMI ECG only 33% of BECPs made the correct diagnosis. Also, the therapeutic decisions in case of non-STEMI were better in older (> 50 years) BCEPs and in those with a background in internal medicine (p = 0.04, and p = 0.02 respectively). CONCLUSION: In cases of acute non-traumatic chest pain the interpretation of the electrocardiogram by prehospital emergency doctors give to unsatisfactory results. The present study suggests, that additional training in ECG interpretation may be a critical component of the education of physicians who care for patients presenting with acute coronary syndrome. PMID- 19777414 TI - [Challenging emergency ECG in a 19-year-old woman]. PMID- 19777415 TI - [Modern risk scores in cardiology]. PMID- 19777416 TI - [Intima-media thickness is a suitable surrogate marker for systemic atherosclerosis - pro]. PMID- 19777417 TI - [Intima-media thickness is a suitable surrogate marker for systemic atherosclerosis - contra]. PMID- 19777418 TI - [Risk prediction using cardiovascular magnetic resonance imaging]. PMID- 19777419 TI - [Ankle-brachial index]. PMID- 19777420 TI - [Role of biomarkers for risk stratification in the prevention of cardiovascular diseases]. PMID- 19777421 TI - [Integration of a new risk marker into cardiovascular prevention, using coronary calcium as an example]. PMID- 19777422 TI - Sodium balance during U. S. football training in the heat: cramp-prone vs. reference players. AB - U. S. football players with a history of heat cramps were evaluated for the effect of physical training, sodium intake, and loss of sweat sodium on whole blood sodium concentration (BNa). Athletes (n=14 males, 24+/-1 y) were recruited and studied based on medical history, age, and position. The reference group (R, n=8 without a cramping history) and cramp-prone group (C, n=6, history of whole body cramps associated with extensive sweat loss during exercise in the heat) were measured for body mass and BNa (ISTAT) before and after team training of 2.2 h in hot conditions (WBGT=29-32 degrees C). Intake and loss of fluid and sodium were also measured to determine respective acute balance. In R, BNa was stable pre- to post-training (138.9+/-1.8 to 139.0+/-2.0 mmol/L) while it tended to decline in C (137.8+/-2.3 to 135.7+/-4.9 mmol/L), and three subjects in C had BNa values below 135 mmol/L (131.7+/-2.9 mmol/L). C consumed a greater percentage of total fluid as water (p<0.05). Mean sweat sodium concentration was (52.6+/-29.2 mmol/L for C and 38.3+/-18.3 mmol/L for R (p>0.05). Compared to R, C tended to experience a decline in BNa and greater acute sodium imbalance. These changes may place cramp-prone players at greater risks for developing acute sodium deficits during training. PMID- 19777423 TI - Naphthoquinones, anthraquinones and naphthalene derivatives from the bulbs of Eleutherine americana. AB - A new naphthoquinone, named eleuthinone A ( 8), two new anthraquinones, named eleuthraquinone A and B ( 12, 13), a naphthalene derivative, named eleucanarol ( 14) were isolated from the bulbs of ELEUTHERINE AMERICANA, together with two new natural products previously synthesized, and nine known compounds. Their structures were established based on spectroscopic evidence. Their antibacterial activities against STAPHYLOCOCCUS AUREUS ATCC25923 and ATCC27664, an enterotoxin producing strain were investigated. PMID- 19777425 TI - EFSUMB Newsletter meets Norway (interview by Professor Michael Bachmann Nielsen). PMID- 19777426 TI - Appendix 13: Intensive care ultrasound - minimum training requirements for the practice of medical ultrasound in Europe. PMID- 19777438 TI - [title in Romanian]. PMID- 19777439 TI - [The health system in the Netherlands: a system with three pillars]. PMID- 19777440 TI - Controlled systemic release of interleukin-12 after gene electrotransfer to muscle for cancer gene therapy alone or in combination with ionizing radiation in murine sarcomas. AB - BACKGROUND: The present study aimed to evaluate the antitumor effectiveness of systemic interleukin (IL)-12 gene therapy in murine sarcoma models, and to evaluate its interaction with the irradiation of tumors and metastases. To avoid toxic side-effects of IL-12 gene therapy, the objective was to achieve the controlled release of IL-12 after intramuscular gene electrotransfer. METHODS: Gene electrotransfer of the plasmid pORF-mIL12 was performed into the tibialis cranialis in A/J and C57BL/6 mice. Systemic release of the IL-12 was monitored in the serum of mice after carrying out two sets of intramuscular IL-12 gene electrotransfer of two different doses of plasmid DNA. The antitumor effectiveness of IL-12 gene electrotransfer alone or in combination with local tumor or lung irradiation with X-rays, was evaluated on subcutaneous SA-1 and LPB tumors, as well as on lung metastases. RESULTS: A synergistic antitumor effect of intramuscular gene electrotransfer combined with local tumor irradiation was observed as a result of the systemic distribution of IL-12. The gene electrotransfer resulted in up to 28% of complete responses of tumors. In combination with local tumor irradiation, the curability was increased by up to 100%. The same effect was observed for lung metastases, where a potentiating factor of 1.3-fold was determined. The amount of circulating IL-12 was controlled by the number of repeats of gene electrotransfer and by the amount of the injected plasmid. CONCLUSIONS: The present study demonstrates the feasibility of treatment by IL-12 gene electrotransfer combined with local tumor or lung metastases irradiation on sarcoma tumors for translation into the clinical setting. PMID- 19777441 TI - Engineering adeno-associated virus serotype 2-based targeting vectors using a new insertion site-position 453-and single point mutations. AB - BACKGROUND: Genetic modification of capsid proteins by peptide insertion has created the possibility of using adeno-associated viral (AAV) vectors for receptor specific gene transfer (AAV targeting). The most common site used for insertion in AAV serotype 2 capsids are amino acid positions 587 and 588 located at the second highest capsid protrusion. Reasoning that peptide insertions at the most exposed position augments target receptor interaction, we explored position 453 as a new insertion site. METHODS: Position 453 was identified in silico. Capsid mutants carrying the model ligand RGD-4C in position 453 with and without R585A/R588A substitutions were compared with respective mutants carrying the ligand in position 587. The accessibility of the inserted ligand was determined by an enzyme-linked immunosorbent assay, whereas the transduction efficiency and specificity of receptor binding were assayed by gene transfer and competition experiments, respectively. Vector biodistribution was determined in mice by quantitative polymerase chain reaction analysis. RESULTS: Initially, RGD-4C, inserted at position 453, failed to efficiently bind its target receptor. R585 and R588, located at the neighboring peak and known to mediate primary receptor binding, were identified as interfering residues. R585A and R588A substitutions rendered position 453 mutants superior to those with the ligand in position 587 in target receptor binding and cell transduction efficiency. The in vivo biodistribution was independent of the insertion site, but directed by the inserted ligand when primary receptor binding was avoided. CONCLUSIONS: Position 453 emerged as a prominent site for the development of targeting mutants. Furthermore, we show for the first time that linearly distant residues can be critical for the efficiency of inserted peptide ligands. PMID- 19777442 TI - ERK-1 MAP kinase prevents TNF-induced apoptosis through bad phosphorylation and inhibition of Bax translocation in HeLa Cells. AB - Extracellular signal-regulated kinase (ERK) 1/2 signaling is involved in tumor cell survival through the regulation of Bcl-2 family members. To explore this further and to demonstrate the central role of the mitochondria in the ERK1/2 pathway we used the HeLa cellular model where apoptosis was induced by tumor necrosis factor (TNF) and cycloheximide (CHX). We show that HeLa cells overexpressing ERK-1 displayed resistance to TNF and CHX. HeLa cells overexpressing a kinase-deficient form of ERK-1 (K71R) were more sensitive to TNF and CHX. In the ERK-1 cells, Bad was phosphorylated during TNF + CHX treatment. In the HeLa wt cells and in the K71R clones TNF and CHX decreased Bad phosphorylation. ERK-1 cells treated with TNF and CHX did not release cytochrome c from the mitochondria. By contrast, HeLa wt and K71R clones released cytochrome c. Bax did not translocate to the mitochondria in ERK-1 cells treated with TNF + CHX. Conversely, HeLa wt and K71R clones accumulated Bax in the mitochondria. In the HeLa wt cells and in both ERK-1 transfectants Bid was cleaved and accumulated in the mitochondria. The caspase-8 inhibitor IETD-FMK and the mitochondrial membrane permeabilization inhibitor bongkrekic acid (BK), partially prevented cell death by TNF + CHX. Anisomycin, a c-Jun N-terminal kinases activator, increased TNF-killing. The ERK-1 cells were resistant to TNF and anisomycin, whereas K71R clones resulted more sensitive. Our study demonstrates that in HeLa cells the ERK-1 kinase prevents TNF + CHX apoptosis by regulating the intrinsic mitochondrial pathway through different mechanisms. Inhibition of the intrinsic pathway is sufficient to almost completely prevent cell death. PMID- 19777443 TI - Autoregulation of co-chaperone BAG3 gene transcription. AB - The Bcl-2-associated athanogene, BAG, protein family through their BAG domain associates with the heat shock protein 70 (HSP-70) and modulates its chaperone activity. One member of this family, BAG3, appears to play an important role in protein homeostasis, as its expression promotes cell survival. Expression of BAG3 is enhanced by a variety of stress-inducing agents. Here we describe a role for BAG3 to modulate transcription of its own promoter through a positive feedback loop involving its 5'-UTR sequence. Activation of the BAG3 promoter is mediated by the BAG domain and is independent of BAG3 association with the UTR sequence. Autoactivation of the BAG3 gene is observed in several cultures of human glial cells including gliomas, but not in several other non-glial cell lines such as He La and others. Results from cell fractionation and immunocytochemistry showed BAG3 in the cytoplasm as well as the nuclei of glial cells. These observations suggest that BAG3 gene expression is controlled by its own product and that this may be critical for the biological activity of BAG3 in some cell types. PMID- 19777444 TI - Experimental hyperthyroidism in rats increases the expression of the ubiquitin ligases atrogin-1 and MuRF1 and stimulates multiple proteolytic pathways in skeletal muscle. AB - Muscle wasting is commonly seen in patients with hyperthyroidism and is mainly caused by stimulated muscle proteolysis. Loss of muscle mass in several catabolic conditions is associated with increased expression of the muscle-specific ubiquitin ligases atrogin-1 and MuRF1 but it is not known if atrogin-1 and MuRF1 are upregulated in hyperthyroidism. In addition, it is not known if thyroid hormone increases the activity of proteolytic mechanisms other than the ubiquitin proteasome pathway. We tested the hypotheses that experimental hyperthyroidism in rats, induced by daily intraperitoneal injections of 100 microg/100 g body weight of triiodothyronine (T3), upregulates the expression of atrogin-1 and MuRF1 in skeletal muscle and stimulates lysosomal, including cathepsin L, calpain-, and caspase-3-dependent protein breakdown in addition to proteasome-dependent protein breakdown. Treatment of rats with T3 for 3 days resulted in an approximately twofold increase in atrogin-1 and MuRF1 mRNA levels. The same treatment increased proteasome-, cathepsin L-, and calpain-dependent proteolytic rates by approximately 40% but did not influence caspase-3-dependent proteolysis. The expression of atrogin-1 and MuRF1 remained elevated during a more prolonged period (7 days) of T3 treatment. The results provide support for a role of the ubiquitin-proteasome pathway in muscle wasting during hyperthyroidism and suggest that other proteolytic pathways as well may be activated in the hyperthyroid state. PMID- 19777445 TI - Purification and characterization of heparan sulfate from human primary osteoblasts. AB - Heparan sulfate (HS) is a linear, highly variable, highly sulfated glycosaminoglycan sugar whose biological activity largely depends on internal sulfated domains that mediate specific binding to an extensive range of proteins. In this study we employed anion exchange chromatography, molecular sieving and enzymatic cleavage on HS fractions purified from three compartments of cultured osteoblasts-soluble conditioned media, cell surface, and extracellular matrix (ECM). We demonstrate that the composition of HS chains purified from the different compartments is structurally non-identical by a number of parameters, and that these differences have significant ramifications for their ligand binding properties. The HS chains purified of conditioned medium had twice the binding affinity for FGF2 when compared with either cell surface or ECM HS. In contrast, similar binding of BMP2 to the three types of HS was observed. These results suggest that different biological compartments of cultured cells have structurally and functionally distinct HS species that help to modulate the flow of HS-dependent factors between the ECM and the cell surface. PMID- 19777446 TI - Compensatory induction of the TRPV6 channel in a calbindin-D9k knockout mouse: Its regulation by 1,25-hydroxyvitamin D3. AB - Active calcium transport is carried out by calcium channel proteins, cytosolic buffering or transfer proteins, and pump proteins. Several components of this transport system have recently been verified using gene knockout (KO) models. We previously generated calbindin-D9k (CaBP-9k) KO mice and reported that induction of expression of some calcium transport proteins can compensate for the CaBP-9k gene deficiency. In the current study, we have further clarified the compensatory regulation of calcium transport genes by two calcium regulating hormones, 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) and parathyroid hormone (PTH), in CaBP-9k KO mice, because the levels of these hormones differ between the KO and wild-type (WT) mice. The induction of transient receptor potential cation channel, subfamily V, member 6 (TRPV6) in the duodenum was observed in adult KO male mice but induction was not modified by physiologic doses of 1,25(OH)(2)D(3). Duodenal TRPV6 transcription in WT and female KO mice were modulated by 1,25(OH)(2)D(3) in a dose-dependent manner. This compensatory gene induction was not detected in the mice fed a vitamin D(3)-deficient diet. Compensatory gene induction was not affected by PTH. Thus, the compensatory expression of duodenal TRPV6 in the KO male mice may be tightly correlated with serum 1,25(OH)(2)D(3). Vitamin D receptor (VDR) transcription and protein levels were measured to examine whether VDR expression mediates differential regulation of duodenal TRPV6 between WT and KO mice, but expression and levels of VDR were similar in both genotypes. The compensatory TRPV6 transcripts in KO mice may be modulated by endogenous vitamin D(3) via other factors of VDR signaling complexes. PMID- 19777453 TI - Detection of adulterations in processed coffee with cereals and coffee husks using capillary zone electrophoresis. AB - The proposed method for the identification of adulteration was based on the controlled acid hydrolysis of xylan and starch present in some vegetable adulterants, followed by the analysis of the resulting xylose and glucose, which are the monosaccharides that compose, respectively, the two polysaccharides. The acid hydrolysis with HCl increases the ionic strength of the sample, which impairs the electrophoretic separation. Thus, a neutralization step based on anion exchange resin was necessary. The best separations were obtained in NaOH 80 mmol/L, CTAB 0.5 mmol/L, and methanol 30% v/v. Because of the high value of pH, monosaccharides are separated as anionic species in such running electrolyte. The LOQ for both monosaccharides was 0.2 g for 100 g of dry matter, which conforms to the tolerable limits. PMID- 19777447 TI - Lanthanum suppresses osteoblastic differentiation via pertussis toxin-sensitive G protein signaling in rat vascular smooth muscle cells. AB - A major cellular event in vascular calcification is the phenotypic transformation of vascular smooth muscle cells (VSMCs) into osteoblast-like cells. After demonstrating that lanthanum chloride (LaCl(3)) suppresses hydrogen peroxide enhanced calcification in rat calcifying vascular cells (CVCs), here we report its effect on the osteoblastic differentiation of rat VSMCs, a process leading to the formation of CVCs. Cells were isolated from aortic media of male SD rats, and passages between three and eight were cultured in Dulbeccol's Modified Eagle's Medium (DMEM) containing 10% fetal bovine serum (FBS) and 10 mM beta glycerophosphate (beta-GP) in the presence or absence of LaCl(3). Exposure of cells to LaCl(3) suppressed the beta-GP-induced elevations in calcium deposition, alkaline phosphatase (ALP) activity, and Cbfa1/Runx2 expression, as well as the concomitant loss of SM alpha-actin. Furthermore, LaCl(3) activated the phosphorylation of extracellular signal-regulated kinase (ERK) and c-Jun N terminal kinase (JNK), and the blockage of either pathway with a specific inhibitor abolished the effects of LaCl(3). In addition, pretreatment of the cells with pertussis toxin (PTx), an inhibitor of G protein-mediated signaling pathway, repealed all the changes induced by LaCl(3). These findings demonstrate that LaCl(3) suppresses the beta-GP-induced osteoblastic differentiation and calcification in rat VSMCs, and its effect is mediated by the activation of both ERK and JNK MAPK pathways via PTx-sensitive G proteins. PMID- 19777454 TI - Dispersion-solidification liquid-liquid microextraction for volatile aromatic hydrocarbons determination: comparison with liquid phase microextraction based on the solidification of a floating drop. AB - Two microextraction techniques--liquid phase microextraction based on solidification of a floating organic drop (LPME-SFO) and dispersive liquid-liquid microextraction combined with a solidification of a floating organic drop (DLLME SFO)--are explored for benzene, toluene, ethylbenzene and o-xylene sampling and preconcentration. The investigation covers the effects of extraction solvent type, extraction and disperser solvents' volume, and the extraction time. For both techniques 1-undecanol containing n-heptane as internal standard was used as an extracting solvent. For DLLME-SFO acetone was used as a disperser solvent. The calibration curves for both techniques and for all the analytes were linear up to 10 microg/mL, correlation coefficients were in the range 0.997-0.998, enrichment factors were from 87 for benzene to 290 for o-xylene, detection limits were from 0.31 and 0.35 microg/L for benzene to 0.15 and 0.10 microg/L for o-xylene for LPME-SFO and DLLME-SFO, respectively. Repeatabilities of the results were acceptable with RSDs up to 12%. Being comparable with LPME-SFO in the analytical characteristics, DLLME-SFO is superior to LPME-SFO in the extraction time. A possibility to apply the proposed techniques for volatile aromatic hydrocarbons determination in tap water and snow was demonstrated. PMID- 19777455 TI - New SPE loading material for affinity-based separation of cyclodextrins from drug:CD complexes in order to overcome Beer's law deviations. AB - Molecular inclusion of guest molecules within CDs is known to alter guest molecule spectrophotometric absorptivity, making their determination, based on spectrophotometric data, inaccurate. Therefore specific analytical methods capable of quantifying the drugs as free molecules must be developed and validated. SPE was selected to simplify sample and avoid more time-consuming alternatives. A new solid phase was synthesized and characterized by infrared spectrometry, differential scanning calorimetry and elemental analysis. The competitive complexation of adamantane groups immobilized on the silica substrate facilitates drug:CD complex dissociation and elimination of CD from samples. The drug molecules, now free from CD, can be easily analysed by an already available HPLC method. This new SPE loading material was employed in the determination of ketoprofen in its CD complex as a representative example of the utility of this novel material. The calculated analytical errors were reduced from a maximum of 20.79% (without SPE) to a minimum of 3.99%. PMID- 19777456 TI - A liquid chromatographic method optimization for the assessment of low and high molar mass carbonyl compounds in wines. AB - Carbonyl compounds (CC) play an important role in beverage aroma since they may affect flavor of wines, brandies, and beers, among others. For this reason, it is necessary to identify and quantify CC through adequate analytical techniques. This study is a proposal of both developing and optimization of a new analytical methodology that allows investigate C(1)-C(8 )CC in wines simultaneously by quantifying even those ones that are predominantly present in the adduct form hydroxylalkylsulfonic acids (HASA). The HASA dissociation is undertaken by specific alkaline media (pH 11). The developed methodology employed the LC with UV/VIS detection (lambda = 365 nm) technique under gradient elution in the way to reach both free-CC and bound-CC quantification. Results showed that binary gradient system using eluent A (MeOH/ACN/H(2)O 74.5:0.5:25% v/v/v) and eluent B (MeOH) reached the best separation condition of both lower and higher molecular mass CC. This proposed method allowed simultaneous quantification of formaldehyde, acetaldehyde, propanone, furfuraldehyde, butyraldehyde, benzaldehyde, hexanaldehyde, 2-ethyl-hexanaldehyde, E-pent-2-en-1-al, and cyclohexanone--all of them were found in white wine (Moscato Canelli) and red wine (Shiraz) produced in the Sao Francisco Valley, in the Northeastern Region of Brazil--although this optimized method may probably be suitable for quantification of propionaldehyde, isobutyraldehyde, heptanaldehyde, octanaldehyde, benzaldehyde, and E-hex-2-en-1-al as well. We could not prove if this method is also able to determine the latter CC group since we have not found these substances present in detectable levels in our real samples considered in this study. PMID- 19777457 TI - Microfluidic HPLC-Chip devices with integral channels containing methylstyrenic based monolithic media. AB - Polyimide HPLC-Chip devices containing poly(methylstyrene-bis-p vinylphenyl)ethane (MS/BVPE) stationary phase within the device channels and with wall attachment were prepared by thermally initiated free radical polymerization. The microfluidic devices were coupled to both UV and MS detectors. The potential of the MS/BVPE monolith as an alternative separation media within chip devices was investigated by side-by-side comparisons to particulate media within commercial devices. The chromatographic behavior of this stationary phase was comparable to particulate media for separations of proteins as the average peak width at half-height was equal (6.2 s) for a separation within 8 min under gradient elution conditions. The ability to control the porosity characteristics of the MS/BVPE monolith with changes in polymerization time also extended its utility into small analyte (< 500 Da) applications, although more optimization is needed to match conventional RP media for these applications. The good mechanical stability of the MS/BVPE monolith within the microdevices enabled excellent run to-run repeatability (%RSD retention time (< or = 0.16) and chip-to-chip reproducibility (%RSD retention time (1.4). The use of this material within enrichment channels also shows its potential value in more complex work flows. PMID- 19777458 TI - Determination of ethyl glucuronide in human serum by capillary zone electrophoresis and an immunoassay. AB - Ethyl glucuronide (EtG) is a marker of recent alcohol consumption. For the optimization of the analysis of EtG by CZE with indirect absorbance detection, the use of capillaries with permanent and dynamic wall coatings, the composition of the BGE, and various sample preparation procedures, including dilution with water, ultrafiltration, protein precipitation, and SPE, were investigated. Two validated screening assays for the determination of EtG in human serum, a CZE based approach and an enzyme immunoassay (EIA), are described. The CZE assay uses a coated capillary, 2,4-dimethylglutaric acid as an internal standard, and a pH 4.65 BGE comprising 9 mM nicotinic acid, epsilon-aminocaproic acid and 10% v/v ACN. Proteins are removed via precipitation with ACN prior to analysis and the LOQ is 0.50 mg/L. The EIA is based upon commercial reagents which are promoted for the determination of urinary EtG. Krebs-Ringer solution containing 5% BSA is used as a calibration matrix. All samples are ultrafiltered prior to analysis of the ultrafiltrate on a Mira Plus analyzer. Assay calibration ranged between 0 and 2 mg/L and the upper reference limit was determined to be 0.05 mg/L. Both assays proved to be suitable for the analysis of samples from different individuals. For EtG levels above 0.50 mg/L, good agreement was observed for the comparison of the results of the two methods. PMID- 19777461 TI - Chemical, electrochemical, and structural properties of endohedral metallofullerenes. AB - Ever since the first experimental evidence of the existence of endohedral metallofullerenes (EMFs) was obtained, the search for carbon cages with encapsulated metals and small molecules has become a very active field of research. EMFs exhibit unique electronic and structural features, with potential applications in many fields. Furthermore, functionalized EMFs offer additional potential applications because of their higher solubility and their ease of characterization by X-ray crystallography and other techniques. Herein we review the general field of EMFs, particularly of functionalized EMFs. We also address their structures and their (electrochemical) properties, as well as applications of these fascinating compounds. PMID- 19777463 TI - Statistical tests based on new composite hypotheses in clinical trials reflecting the relative clinical importance of multiple endpoints quantitatively. AB - In clinical trials, several endpoints (EPs) are often evaluated to compare treatments in some therapeutic area. Suppose that there are two EPs in a clinical trial. We propose a new set of composite hypotheses for continuous variables, taking the relative clinical importance of the EPs into account. The main hypotheses were formulated to show that a treatment is so superior to the control treatment, which is not necessarily a placebo, in one EP, that the possible non inferiority of the treatment by at most a certain value in the other EP can be compensated sufficiently, taking the clinical point of view into account. The maximum non-inferiority margin of one EP might not be a biologically unimportant difference in exchange for much superiority of the other EP. This formulation leads to a new composite EP and a very simple test statistic. The intersection union principle was employed to derive the proposed test. PMID- 19777464 TI - Chemically responsive gels prepared from microspheres dispersed in liquid crystals. AB - Liquid-crystalline materials are a promising class of stimuli-responsive materials that have been demonstrated to undergo surface-induced orientational ordering transitions that can be highly sensitive and specific to chemical species. However, past studies demonstrating surface-induced transitions in liquid crystals (LCs) have employed thin films of low-molecular-weight LCs that are difficult to stabilize (due to dewetting of the LC on a surface). Here, it is reported that it is possible to prepare liquid-crystalline gels using a mixture of polystyrene microspheres and nematic LCs that undergo changes in orientational order, and thus optical appearance, in response to exposure to specific chemical compounds. These colloid-in-liquid-crystal (CLC) gels are mechanically stable and can be molded on chemically functionalized surfaces into thin films containing micrometer-sized LC-rich domains that span the two interfaces of the gels. In contrast to other reports of LC gels, where the presence of a polymeric or self assembled small-molecule gelator network within a nematic LC frustrates ordering transitions from propagating through the gels over distances, it is demonstrated that thin films of CLC gels, when supported on chemically functionalized surfaces, do undergo easily visualized ordering transitions upon exposure to organophosphonate compounds. Because these optically responsive CLC gels are mechanically robust and can be molded, this class of composite LC material may be broadly useful for the design of chemically responsive LC devices. PMID- 19777465 TI - Molecular imprinting in separation science. PMID- 19777469 TI - Effect of temperature on permeation of low-density lipoprotein particles through human carotid artery tissues. AB - Quantification of the diffusion of small molecules and large lipid transporting lipoproteins across arterial tissues could be useful in elucidating the mechanism(s) of atherosclerosis. Optical coherence tomography (OCT) was used to determine the effect of temperature on the rate of diffusion of glucose and low density lipoproteins (LDL) in human carotid endarterectomy tissue in vitro. The permeability rate for glucose was calculated to be (3.51 +/- 0.27) x 10(-5) cm/s (n = 13) at 20 degrees C, and (3.70 +/- 0.44) x 10(-5) cm/s (n = 5) at 37 degrees C; for LDL the rate was (2.42 +/- 0.33) x 10(-5) cm/s (n = 5) at 20 degrees C and (4.77 +/- 0.48) x 10(-5) cm/s (n = 7) at 37 degrees C, where n is the number of samples. These results demonstrate that temperature does not significantly influence the permeation of small molecules (e.g. glucose), however, raising the temperature does significantly increase the permeation of LDL. These results provide new information about the capacity of an atherogenic lipoprotein to traverse the intimal layer of the artery. These results also demonstrate the potential of OCT for elucidating the dynamics of lipoprotein perfusion across the arterial wall. PMID- 19777466 TI - Patellar tendon orientation and patellar tracking in male and female knees. AB - Knowledge of patellofemoral joint biomechanics is important for understanding sex related dimorphism in patellofemoral pathologies and advancement of related treatments. We evaluated the hypotheses that sex differences exist in patellar tendon (PT) orientation and patellar tracking during weight-bearing knee flexion and that they relate to differences in tibiofemoral rotation. The PT orientation and patellar tracking were measured in healthy subjects (18 male, 13 female) during weight-bearing knee flexion, using magnetic resonance and dual fluoroscopic imaging. These data were analyzed for sex differences and correlation with previously reported tibiofemoral rotation data. The results indicated a significant effect of sex on PT orientation, particularly at low flexion angles. In females, the PT was oriented more anteriorly in the sagittal plane, more medially in the coronal plane, and showed greater external tilt in the transverse plane of the tibia (p < 0.05). Significant correlations between tibiofemoral rotation and PT orientation (p < 0.01) indicated that sex differences in coronal and transverse plane orientation of the PT relate to differences in tibiofemoral rotation. Patellar tracking did not show significant sex differences or correlation to tibiofemoral rotation. Further studies are warranted to determine implications for patellofemoral pathologies and treatments like total knee arthroplasty. PMID- 19777473 TI - Polarized diffuse reflectance measurements on cancerous and noncancerous tissues. AB - We report the measurement of polarization parameters (linear retardance, diattenuation and depolarization) of normal and malignant tissue from human oral cavity and breast over the spectral range 390 nm to 550 nm. These parameters were determined using the 3 x 3 Mueller matrix, the elements of which could be determined using linear polarization measurements only. The significant differences observed in the polarization parameters of the normal and malignant tissues appear to arise because of the changes in the collagen matrix in the two tissue types. PMID- 19777478 TI - Editorial: methods and advances in biotech. PMID- 19777483 TI - Tools and ingredients for the biocatalytic synthesis of metabolites. AB - Metabolic networks have been an interesting starting point not only for the design of synthetic routes in a similar sequence of reactions, e.g., in biomimetic syntheses, but also for assembling a number of biocatalytic steps by preparing the required enzymes and auxiliary reagents. Retrosynthetic analysis involving multiple biocatalytic reactions steps therefore needs to consider the practically realized biocatalytic single steps. The opportunities for route selection are enlarged if novel synthetic reactions connecting easily available starting materials and products are found, and/or both biocatalytic and classical reactions of organic chemistry are utilized. Tools and ingredients for biocatalytic synthesis are of special interest for reactions difficult to achieve by classical organic synthesis. Densely and differentially functionalized small molecules do not allow much space for protecting or activating groups. Biocatalytic reactions have therefore performed well for a number of useful metabolites in enantiopure form to achieve full functionality. Although many well known metabolites from classical biochemistry have only been prepared in racemic form, it is of fundamental interest to have these available in enantiomerically pure form. Biocatalytic reactions with nature's privileged chiral catalysts appear to be a promising synthetic strategy towards these metabolites, especially when sensitive or stable-isotope-labeled metabolites are to be prepared. The main applications for these metabolites are as references materials in metabolomics, as enzyme substrates for the characterization of metabolic enzyme activities and as potential pharmaceuticals in biomedical research. The use of stable-isotope labeled metabolites can thereby simplify in vivo applications and metabolic flux analyses. PMID- 19777486 TI - Dermal fibroblast-mediated BMP2 therapy to accelerate bone healing in an equine osteotomy model. AB - This study evaluated healing of equine metacarpal/metatarsal osteotomies in response to percutaneous injection of autologous dermal fibroblasts (DFbs) genetically engineered to secrete bone morphogenetic protein-2 (BMP2) or demonstrate green fluorescent protein (GFP) gene expression administered 14 days after surgery. Radiographic assessment of bone formation indicated greater and earlier healing of bone defects treated with DFb with BMP2 gene augmentation. Quantitative computed tomography and biomechanical testing revealed greater mineralized callus and torsional strength of DFb-BMP2-treated bone defects. On the histologic evaluation, the bone defects with DFb-BMP2 implantation had greater formation of mature cartilage and bone nodules within the osteotomy gap and greater mineralization activity on osteotomy edges. Autologous DFbs were successfully isolated in high numbers by a skin biopsy, rapidly expanded without fastidious culture techniques, permissive to adenoviral vectors, and efficient at in vitro BMP2 protein production and BMP2-induced osteogenic differentiation. This study demonstrated an efficacy and feasibility of DFb-mediated BMP2 therapy to accelerate the healing of osteotomies. Skin cell-mediated BMP2 therapy may be considered as a potential treatment for various types of fractures and bone defects. PMID- 19777487 TI - Expression patterns of collagen types I and III in the capsule of a rat knee contracture model. AB - Our objective was to determine the changes in expression of collagen types I and III in the capsule of a rat knee contracture model. The unilateral knee joints of adult male rats were rigidly immobilized at 150 degrees of flexion using a rigid plastic plate and screws for 3 days, 1, 2, 4, 8, and 16 weeks (immobilized group). Sham-operated animals had holes drilled in the femur and tibia with screws inserted without a plate (control group). The expression patterns of collagen types I and III in the anterior and posterior capsule were evaluated by in situ hybridization (ISH), quantitative real-time polymerase chain reaction (qPCR), immunohistochemistry (IHC), and Western blotting (WB). Expressions of collagen types I and III were decreased after immobilization compared to the control group by ISH and qPCR. The expression was not changed after immobilization compared to the control group by IHC and WB. The expression of mRNA and protein levels of collagen types I and III were not increased after immobilization, which indicated that accumulation of the two types of collagen was not the etiology of joint contracture. Another process, such as capsule and synovial adhesions, may be one possible cause of joint contracture. PMID- 19777488 TI - Identification of the murine AAVrh32.33 capsid-specific CD8+ T cell epitopes. AB - BACKGROUND: Adeno-associated virus (AAV) is an ideal gene therapy vector and is non-immunogenic in many small animal models. The stable gene expression commonly seen in murine models does not necessarily translate to nonhuman primates and higher-order species, highlighting the need for a better understanding of immune activation to these vectors. One capsid variant, AAVrh32.33, demonstrates a unique phenotype in murine muscle, reminiscent of what is often seen in higher order species. AAVrh32.33 generates a strong CD8+ T-cell response to both capsid and encoded transgene antigens in a manner independent of transgene product or major histocompatability complex haplotype, making it an ideal candidate for studying immune activation to AAV in the mouse. METHODS: To map the H-2b and H-2d dominant epitopes of the AAVrh32.33 capsid, C57BL/6 or Balb/C mice received an intramuscular injection of 1 x 10(11) genome copies of AAV2/rh32.33.CB.nLacZ. Three weeks later, splenocytes were harvested and stimulated in vitro with pooled or individual peptides from the AAVrh32.33 capsid peptide library and analysed by an interferon (IFN)-gamma enzyme-linked immunosorbent spot assay or intracellular cytokine staining. RESULTS: The immunodominant epitopes within the AAVrh32.33 capsid responsible for driving CD8+ T-cell responses to the capsid protein in C57BL/6 (SSYELPYVM) and Balb/C (KIPASGGNAL) mice were defined. CONCLUSIONS: Identification of dominant capsid epitopes will make it possible to monitor cellular responses to the AAV capsid in vivo, facilitating mechanistic studies critical to defining how cellular immunity to the AAV capsid arises and, ultimately, how the generation of capsid-specific T cells can be avoided to ensure safety in a gene therapy setting. PMID- 19777489 TI - Dependence of maternal serum [AFP]/[hCG] median ratios on age of gestation: comparison of trisomy 21 to euploid pregnancies. AB - BACKGROUND: Current risk calculations for trisomy 21, which are based on multiples of median (MoM), do not take into account possible differences between euploid and trisomy 21 pregnancies that may develop with gestational age. In order to optimize the predictive value of screening tests, we calculated the ratio between maternal serum concentration of alpha-fetoprotein (AFP) and that of human chorionic gonadotropin (hCG) in euploid and in trisomy 21 pregnancies. METHODS: The medians of the concentration ratios, [AFP]/[hCG] at 16-21 weeks of gestation, were plotted as a function of gestational age for 307 cases of trisomy 21 and were compared with the medians of 30 549 normal karyotype cases. RESULTS: [AFP]/[hCG] ratio medians were independent of body weight and maternal age. There was a significant difference in the [AFP]/[hCG] ratio when comparing trisomy 21 and euploid pregnancies at each week. This difference became greater with advancing gestational age (P < 0.01). CONCLUSION: There is a significant difference in ratios of [AFP]/[hCG] between euploid and trisomy 21 pregnancies, which may be used to improve detection rates of Down syndrome screening. PMID- 19777490 TI - Expression of X-linked inhibitor of apoptosis protein in human colorectal cancer and its correlation with prognosis. AB - BACKGROUND: X-linked inhibitor of apoptosis protein (XIAP) is a member of the inhibitor of apoptosis family of proteins and deregulation of XIAP can result in tumorigenicity. The objective of this study was to evaluate the prognostic significance of XIAP expression in colorectal cancer (CRC). METHODS: RT-PCR was performed to detect the expression of XIAP mRNA in CRC cells and tissues. The expression of XIAP protein in tissues was measured by immunohistochemistry. The correlation of XIAP expression with clinicopathologic factors and prognosis of CRC patients was evaluated. RESULTS: CRC cells showed significantly higher levels of XIAP mRNA expression than normal human intestinal epithelial cell. The expression level of XIAP mRNA in CRC samples was significantly higher than that in corresponding non-tumor samples. XIAP staining was positive in the cytoplasm of CRC cells. Higher XIAP protein expression was significantly correlated with tumor differentiation (P = 0.016), venous invasion (P = 0.039), and Duke's staging (P = 0.002). Moreover, XIAP-high group showed lower disease-free (P = 0.0136) and overall survival (P = 0.0084) rates than XIAP-low group. Multivariate analysis indicated that the status of XIAP expression was an independent prognostic factor for CRC (P = 0.0206; HR: 2.730; 95% CI: 1.226-5.445). CONCLUSION: The status of XIAP expression might become an independent prognostic marker for CRC. PMID- 19777491 TI - An information-theoretic approach to the prediction of protein structural class. AB - An information-theoretical approach, which combines a sequence decomposition technique and a fuzzy clustering algorithm, is proposed for prediction of protein structural class. This approach could bypass the process of selecting and comparing sequence features as done previously. First, distances between each pair of protein sequences are estimated using a conditional decomposition technique in information theory. Then, the fuzzy k-nearest neighbor algorithm is used to identify the structural class of a protein given as set of sample sequences. To verify the strength of our method, we choose three widely used datasets constructed by Chou and Zhou. It is shown by the Jackknife test that our approach represents an improvement in the prediction of accuracy over existing methods. PMID- 19777492 TI - Model studies of the optical rotation, and theoretical determination of its sign for beta-pinene and trans-pinane. AB - We have carried out extensive studies on the basis set dependence of the calculated specific optical rotation (OR) in molecules at the level of the time dependent Hartree-Fock and density functional approximations. To reach the limits of the basis set saturation, we have devised an artificial model, the asymmetrically deformed (chiral) methane (CM) molecule. This small system permits to use basis sets which are prohibitively large for real chiral molecules and yet shows all the important features of the basis set dependence of the OR values. The convergence of the OR has been studied with n-aug-cc-pVXZ basis sets of Dunning up to the 6-zeta. In a parallel series of calculations, we have used the recently developed large polarized (LPolX) basis sets. The relatively small LPolX sets have been shown to be competitive to very large n-aug-cc-pVXZ basis sets. The conclusions reached in calculations of OR in CM concerning the usefulness of LPolX basis sets have been further tested on (S)-methyloxirane and (S)-fluoro oxirane. The smallest set of the LPolX family (LPol-ds) has been found to yield OR values of similar quality as those obtained with much larger Dunning's aug-cc pVQZ basis set. These results have encouraged us to carry out the OR calculations with LPol-ds basis sets for systems as large as beta-pinene and trans-pinane. In both cases, our calculations have lead to the correct sign of the OR value in these molecules. This makes the relatively small LPol-ds basis sets likely to be useful in OR calculations for large molecules. PMID- 19777493 TI - Linear mixed models for replication data to efficiently allow for covariate measurement error. AB - It is well known that measurement error in the covariates of regression models generally causes bias in parameter estimates. Correction for such biases requires information concerning the measurement error, which is often in the form of internal validation or replication data. Regression calibration (RC) is a popular approach to correct for covariate measurement error, which involves predicting the true covariate using error-prone measurements. Likelihood methods have previously been proposed as an alternative approach to estimate the parameters in models affected by measurement error, but have been relatively infrequently employed in medical statistics and epidemiology, partly because of computational complexity and concerns regarding robustness to distributional assumptions. We show how a standard random-intercepts model can be used to obtain maximum likelihood (ML) estimates when the outcome model is linear or logistic regression under certain normality assumptions, when internal error-prone replicate measurements are available. Through simulations we show that for linear regression, ML gives more efficient estimates than RC, although the gain is typically small. Furthermore, we show that RC and ML estimates remain consistent even when the normality assumptions are violated. For logistic regression, our implementation of ML is consistent if the true covariate is conditionally normal given the outcome, in contrast to RC. In simulations, this ML estimator showed less bias in situations where RC gives non-negligible biases. Our proposal makes the ML approach to dealing with covariate measurement error more accessible to researchers, which we hope will improve its viability as a useful alternative to methods such as RC. PMID- 19777494 TI - Bounds on causal effects in randomized trials with noncompliance under monotonicity assumptions about covariates. AB - In randomized trials with nonrandom noncompliance, the causal effects of a treatment among the entire population cannot be estimated in an unbiased manner. Therefore, several authors have considered the bounds on the causal effects. Here, we propose bounds by applying an idea of VanderWeele (Biometrics 2008; 64:702-706), who showed that the sign of the unmeasured confounding bias can be determined under monotonicity assumptions about covariates in the framework of observational studies. In randomized trials with noncompliance by switching the treatment, we show that the lower or upper bound on the expectation of the potential outcome becomes the expectation from the per-protocol analysis under monotonicity assumptions similar to those of VanderWeele. In particular, the monotonicity assumptions can yield both the lower and the upper bounds on causal effects when the monotonic relationship between the covariates and the treatment actually received depends on the treatment assigned. The results are extended to cases of noncompliance by subjects not receiving any treatment. Although the monotonicity assumptions are not themselves identifiable, they are nonetheless reasonable in some situations. PMID- 19777498 TI - Protective effects of 3'-deoxy-4-O-methylepisappanol from Caesalpinia sappan against glutamate-induced neurotoxicity in primary cultured rat cortical cells. AB - To examine the neuroprotective effects of Caesalpinia sappan L., we tested its protection against the glutamate-induced neurotoxicity in primary cortical cultured neurons. We found that an aqueous extract of this medicinal plant exhibited significant protection against glutamate-induced toxicity in primary cultured rat cortical cells. In order to clarify the neuroprotective mechanism(s) of this observed effect, isolation was performed to seek and identify active fractions and components. By such fractionation, two known compounds - sappanchalcone and 3'-deoxy-4-O-methylepisappanol - were isolated from the methanol extracts from the air-dried and chipped C. sappan. Among these two compounds, 3'-deoxy-4-O-methylepisappanol exhibited significant neuroprotective activities against glutamate-induced toxicity, exhibiting cell viability of about 50%, at concentrations ranging from 0.1 microM to 10 microM. Therefore, the neuroprotective effect of C. sappan might be due to the inhibition of glutamate induced toxicity by the protosappanin derivative it contains. PMID- 19777499 TI - Rapid simultaneous acquisition of T1 and T2 mapping images using multishot double spin-echo EPI and automated variations of TR and TE (ms-DSEPI-T12). AB - A rapid method of simultaneous T(1) and T(2) measurement is presented which uses a segmented echo-planar readout with varying repetition times (TR) and echo times (TE). This method is useful in T(1) mapping for analysis of dynamic contrast enhanced MRI (DCE-MRI), where T(1) can be used to estimate contrast agent concentration. In the application of this method to dynamic imaging, the equilibrium magnetization is measured on pre-contrast images and incorporated into post-contrast T(1) calculations for improved accuracy. Simultaneous T(2) measurement allows correction of T(2) effects in the T(1) map which may occur at high contrast agent concentrations, and is performed without significant imaging time penalty. Phantom and in vivo results show the usefulness of this technique for analysis of contrast enhancement kinetics. Accurate rapid contrast agent concentration measurement may be useful for analyzing the distribution and kinetics of contrast agents or labeled pharmaceuticals. PMID- 19777500 TI - Psychometric testing of four transtheoretical model questionnaires for the behavior, completing health care proxies. AB - The purpose of the study was to develop four questionnaires based on the transtheoretical model (TTM) to assess the behavior, completing a healthcare proxy (HCP). The aims were to (a) operationalize the four TTM constructs for completing a HCP and (b) evaluate the psychometric properties of the questionnaires. The questionnaires were constructed and content validity established using an expert panel. Internal consistency values for each questionnaire and subscales within each questionnaire were >.79. Confirmatory factor analysis provided evidence that decisional balance and the processes of change questionnaires each contained two factors. Our data support validity and reliability of the TTM questionnaires related to HCP completion. PMID- 19777501 TI - Intravoxel water diffusion heterogeneity imaging of human high-grade gliomas. AB - This study aimed to determine the potential value of intravoxel water diffusion heterogeneity imaging for brain tumor characterization and evaluation of high grade gliomas, by comparing an established heterogeneity index (alpha value) measured in human high-grade gliomas to those of normal appearing white and grey matter landmarks. Twenty patients with high-grade gliomas prospectively underwent diffusion-weighted magnetic resonance imaging using multiple b-values. The stretched-exponential model was used to generate alpha and distributed diffusion coefficient (DDC) maps. The alpha values and DDCs of the tumor and contralateral anatomic landmarks were measured in each patient. Differences between alpha values of tumors and landmark tissues were assessed using paired t-tests. Correlation between tumor alpha and tumor DDC was assessed using Pearson's correlation coefficient. Mean alpha of tumors was significantly lower than that of contralateral frontal white matter (p = 0.0249), basal ganglia (p < 0.0001), cortical grey matter (p < 0.0001), and centrum semiovale (p = 0.0497). Correlation between tumor alpha and tumor DDC was strongly negative (Pearson correlation coefficient, -0.8493; p < 0.0001). The heterogeneity index alpha of human high-grade gliomas is significantly different from those of normal brain structures, which potentially offers a new method for evaluating brain tumors. The observed negative correlation between tumor alpha and tumor DDC requires further investigation. PMID- 19777502 TI - Correlates of physical activity in low income college students. AB - The importance of physical activity as a health promoting behavior has been well documented. We examined the relationship of social support, self-efficacy, and commitment to a plan of physical activity on physical activity behaviors in a sample of low income college students. Those with higher levels of social support, self-efficacy, and commitment to a plan of physical activity reported more physical activity behaviors. Commitment to a plan of physical activity mediated the relationships of social support and physical activity behavior, and of self-efficacy and physical activity behavior. The results support the importance of exploring the psychosocial correlates of physical activity in explaining the decision process that underlies physical activity behavior. PMID- 19777503 TI - Diuretic and antioxidant effects of Cacti-Nea, a dehydrated water extract from prickly pear fruit, in rats. AB - Dehydrated extract of the prickly pear fruit Opuntia ficus indica, Cacti-Nea, was evaluated for its chronic diuretic and antioxidant effects in Wistar rats. Cacti Nea was orally administered daily for seven days at the dose of 240 mg/kg/day. A positive group was orally treated with hydrochlorothiazide at the dose of 10 mg/kg/day and a control group with vehicle. Daily measurements of body weight, urine volume, and concentration of sodium, potassium and uric acid in urine were performed for each rat. At the end of the study, the blood globular level of glutathione peroxidase was determined. Cacti-Nea significantly increased the urine volumes excreted by rats in comparison with the control group and it showed a trend to reduce significantly the body weight gain of rats. No significant differences were observed in the urine concentration of sodium, potassium and uric acid in comparison with the control group. The chronic diuretic effects of Cacti-Nea were comparable with that of the standard drug hydrochlorothiazide. Chronic oral administration of Cacti-Nea significantly increased the blood globular levels of glutathione peroxidase in comparison with control and hydrochlorothiazide groups. The prickly pear fruit extract Cacti-Nea demonstrated chronic diuretic and antioxidant effects in Wistar rats with respect to the excretion of the metabolites. PMID- 19777504 TI - Inhibitory effect of curcumin on motility of human oral squamous carcinoma YD-10B cells via suppression of ERK and NF-kappaB activations. AB - Oral squamous cell carcinomas (OSCCs) are characterized by a marked propensity for local invasion, so the identification of agents inhibiting the onset and progression of OSCC has recently gained interest. Here, we found that curcumin inhibited cell proliferation and motility with decreased activities of matrix metalloproteinase (MMP)-2/9 and decreased mRNA expressions of urokinase-type plasminogen activator (uPA) and its receptor uPAR in the highly invasive human YD 10B OSCC cells. Western blot analysis showed that curcumin inhibited the activation of MAP kinases (especially ERK) and NF-kappaB, which are involved in the transcriptional regulation of proteolytic enzymes. In conclusion, curcumin is one of the strong phytochemicals with antimotility activity of OSCC; the inhibitory effect of curcumin on the motility of YD-10B cells could result from its potential to inhibit the activation of ERK/MAP kinase and NF-kappaB that consequently down-regulate the mRNA expressions and activities of proteolytic enzymes such as uPA and MMP-2/9. PMID- 19777505 TI - Influence of green tea on erythrocytes antioxidant status of different age rats intoxicated with ethanol. AB - The aim of this paper is to evaluate the effect of green tea on the erythrocyte antioxidant system of ethanol-intoxicated rats, as well as its efficacy in the prevention of lipid peroxidation. Rats (2, 12 and 24 months old) were fed on a control or an ethanol Lieber-DeCarli diet with and without green tea (7 g/L) for 5 weeks. Examination included the activity of antioxidant enzymes and the level of both non-enzymatic antioxidants and lipid peroxidation marker in rat erythrocytes. It was shown that ageing was accompanied by changes in the antioxidant enzymes activity - increase in the SOD and CAT activity and decrease in GSSG-R and GSH-Px activity, as well as in the level of non-enzymatic antioxidants - GSH, vitamin A and vitamin E. The increase in the level of lipid peroxidation marker - MDA - was also observed. Green tea consumption partially prevented lipid peroxidation process, especially in erythrocytes of 2- and 12 month-old rats. It was proved that ethanol administration caused a statistically significant decrease in the activity/level of the examined antioxidants in all age groups (the most significant in the case of 24-month-old rats) of rats, as well as an increase in the MDA level. However, ingestion of green tea by ethanol intoxicated rats partially prevented the decrease in activity/level of all examined antioxidant parameters, as well as protected lipids against peroxidation in all age groups of rats. Obtained results confirm the beneficial effect of green tea on erythrocyte antioxidant abilities. PMID- 19777507 TI - Modulation of excited-state proton transfer of 2-(2'-hydroxyphenyl)benzimidazole in a macrocyclic cucurbit[7]uril host cavity: dual emission behavior and pK(a) shift. AB - The effect of the macrocyclic host, cucurbit[7]uril (CB7), on the photophysical properties of the 2-(2'-hydroxyphenyl)benzimidazole (HPBI) dye have been investigated in aqueous solution by using ground-state absorption and steady state and time-resolved fluorescence measurements. All three prototropic forms of the dye (cationic, neutral, and anionic) form inclusion complexes with CB7, with the largest binding constant found for the cationic form (K approximately 2.4x10(6) M(-1)). At pH approximately 4, the appearance of a blue emission band upon excitation of the HPBI cation in the presence of CB7 indicates that encapsulation into the CB7 cavity retards the deprotonation process of the excited cation, and hence reduces its subsequent conversion to the keto form. Excitation of the neutral form (pH approximately 8.5), however, leads to an increase in the keto form fluorescence, indicating an enhanced excited-state intramolecular proton-transfer process for the encapsulated dye. In both the ground and excited states, the two pK(a) values of the HPBI dye show upward shifts in the presence of CB7. The prototropic equilibrium of the CB7-complexed dye is represented by a six-state model, and the pH-dependent changes in the binding constants have been analyzed accordingly. It has been observed that the calculated pK(a) values using this six-state model match well with the values obtained experimentally. The changes in the pK(a) values in the presence of CB7 have been corroborated with the modulation of the proton-transfer process of the dye within the host cavity. PMID- 19777506 TI - Reproducibility of serial whole-brain MR spectroscopic imaging. AB - The reproducibility of serial measurements using a volumetric proton MR Spectroscopic Imaging (MRSI) acquisition implemented at 3 Tesla and with lipid suppression by inversion-recovery has been evaluated. Data were acquired from two subjects at five time points, and processed using fully-automated procedures that included rigid registration between studies. These data were analyzed to determine coefficients of variance (COV) for each metabolite and for metabolite ratio images based on an individual voxel analysis, as well as for average and grey-matter and white-matter values from atlas-defined brain regions. The volumetric MRSI acquisition was found to obtain data of sufficient quality for analysis over 70 +/- 6% of the total brain volume, and spatial distributions of the resultant COV values were found to reflect the known distributions of susceptibility-induced magnetic field inhomogeneity. Median values of the resultant voxel-based COVs were 6.2%, 7.2%, and 9.7% for N-acetylaspartate, creatine, and choline respectively. The corresponding mean values obtained following averaging over lobar-scale brain regions within the cerebrum were 3.5%, 3.7%, and 5.2%. These results indicate that longitudinal volumetric MRSI studies with post-acquisition registration can provide an intra-subject reproducibility for voxel-based analyses that is comparable to previously-reported single-voxel MRS measurements, while additionally enabling increased sensitivity by averaging over larger tissue volumes. PMID- 19777508 TI - Xanthones and oxepino[2, 3-b]chromones from three endophytic fungi. AB - Three new metabolites, microsphaeropsones A-C (1-3) with a unique oxepino[2,3 b]chromen-6-one (ring-enlarged xanthone) skeleton, were isolated from the endophytic fungus Microsphaeropsis species, co-occurring with their putative biogenetic anthraquinoide precursors citreorosein (4) and emodin (5). From another Microsphaeropsis species, large amounts of fusidienol A (8 a), smaller amounts of emodin (5), the known aromatic xanthones 9 a and 9 b, the new 3,4 dihydrofusidienol A (8 b), and the new aromatic xanthone 9 c were isolated. The endophyte Seimatosporium species produced a new aromatic xanthone, seimatoxanthone A (10), and 3,4-dihydroglobosuxanthone A (12), closely related to alpha-diversolonic ester (13) from Microdiplodia sp.. The structures were determined mainly by extensive 1D and 2D NMR experiments and supported by X-ray single-crystal analysis of 1 and the oxidation product 7. The absolute configurations of the microsphaeropsones A-C (1-3) were established by comparison of the electronic and vibrational circular dichroism (ECD and VCD) spectra of 1 with time-dependent DFT (TDDFT) and DFT calculations by using either the solid state structures or DFT-optimized geometries as inputs. Preliminary studies indicated that 1, 2, and enone 7 showed antibacterial, fungicidal, and algicidal properties. PMID- 19777509 TI - Directional control and supramolecular protection allowing the chemo- and regioselective transformation of a triamine. AB - A Zn(II)-funnel complex based on a calix[6]arene ligand decorated with three tris(imidazolyl) arms at one end of the cone and three NH(2) substituents at the other end, acts as a multipoint recognition host for polyfunctionalized guests. The selectivity is ensured by coordination to Zn(II), CH-pi interaction within the calix cone, and H-bonding at both rims of the cavity. As a result of these multiple interactions, the host can wrap and orient an unsymmetrical triamine guest with a high selectivity. Furthermore, a proton-monitored switch between the regio-isomeric adducts allows reversible inversion of the directionality of the system. Thanks to this directional control, the regioselective mono carbamoylation of the unsymmetrical triamine guest was successfully achieved on a preparative scale. This case study shows that a funnel-like receptor can be used as a supramolecular protecting tool allowing a transformation which would be impracticable with conventional covalent chemistry. PMID- 19777511 TI - Inhibition of the in vitro replication of DNA by an aptamer-protein complex in an autonomous DNA machine. AB - DNA replication plays a central role in living organisms. Unregulated or uncontrollable DNA replication is well known to result in many pathological states, such as cancer, autoimmune diseases, and viral/bacterial infections. We report that an aptamer-protein complex could indirectly inhibit in vitro replication of DNA. An isothermal DNA machine based on the strand-displacement amplification is employed to support our assumption. An antithrombin aptamer sequence is rationally encoded into the DNA replication template. Once thrombin binds to the template, the as-formed aptamer-protein complexes can, in turn, become a barrier to the polymerase and inhibit the DNA replication activities in both static and dynamic modes. The inhibition is successfully confirmed by both fluorescence and gel-electrophoresis experiments. Considering the availability of a broad library of aptamers and the existence of various DNA/protein interactions, our results imply the possibility for the rational regulation of DNA replication in vivo. PMID- 19777510 TI - Enhanced catalytic activity and unexpected products from the oxidation of cyclohexene by organic nanoparticles of 5,10,15,20-tetrakis-(2,3,4,5,6 pentafluorophenyl)porphyrinatoiron(III) in water by using O2. AB - The catalytic oxidation of alkenes by most iron porphyrins using a variety of oxygen sources, but generally not dioxygen, yields the epoxide with minor quantities of other products. The turnover numbers for these catalysts are modest, ranging from a few hundred to a few thousand depending on the porphyrin structure, axial ligands, and other reaction conditions. Halogenation of substituents increases the activity of the metalloporphyrin catalyst and/or makes it more robust to oxidative degradation. Oxidation of cyclohexene by 5,10,15,20 tetrakis-(2,3,4,5,6-pentafluorophenyl)porphyrinato iron(III), ([Fe(III)(tppf(20))]) and H(2)O(2) is typical of the latter: the epoxide is 99 % of the product and turnover numbers are about 350.1-4 Herein, we report that dynamic organic nanoparticles (ONPs) of [Fe(III)(tppf(20))] with a diameter of 10 nm, formed by host-guest solvent methods, catalytically oxidize cyclohexene with O(2) to yield only 2-cyclohexene-1-one and 2-cyclohexene-1-ol with approximately 10-fold greater turnover numbers compared to the non-aggregated metalloporphyrin in acetonitrile/methanol. These ONPs facilitate a greener reaction because the reaction solvent is 89 % water and O(2) is the oxidant in place of synthetic oxygen sources. This reactivity is unexpected because the metalloporphyrins are in close proximity and oxidative degradation of the catalyst should be enhanced, thus causing a significant decrease in catalytic turnovers. The allylic products suggest a different oxidative mechanism compared to that of the solvated metalloporphyrins. These results illustrate the unique properties of some ONPs relative to the component molecules or those attached to supports. PMID- 19777512 TI - Theoretical study of the cycloaddition reaction of a tungsten-containing carbonyl ylide. AB - The [3+2] cycloaddition reaction of a tungsten-containing carbonyl ylide with methyl vinyl ether and the insertion reactions of the nonstabilized carbene complex intermediates produced have been investigated through the use of B3LYP density functional theory. The [3+2] cycloaddition reaction of the tungsten containing carbonyl ylide has been proven to proceed concertedly, reversibly, and with high endo selectivity. The intermolecular Si-H insertion reactions of the carbene complex intermediates have been proven to be favored over the intramolecular C-H insertion, in good agreement with experimental results. Moreover, the kinetic endo/exo ratio of the [3+2] cycloaddition reaction has been shown to determine the endo/exo selectivity of the Si-H insertion products. In addition, secondary orbital interactions involving the benzene ring and the carbonyl ligand on the metal center have turned out to strongly influence the high endo selectivity of the [3+2] cycloaddition reaction with methyl vinyl ether. PMID- 19777513 TI - Ionic liquids as performance additives for electroenzymatic syntheses. AB - Electroenzymatic syntheses combine oxidoreductase-catalysed reactions with electrochemical reactant supply. The use of ionic liquids as performance additives can contribute to overcoming existing limitations of these syntheses. Here, we report on the influence of different water-miscible ionic liquids on critical parameters such as conductivity, biocatalyst activity and stability or substrate solubility for three typical electroenzymatic syntheses. In these investigations promising ionic liquids were identified and have been used as additives for batch electrolyses on preparative scale for the three electroenzymatic systems. It was possible to improve the space-time-yield for the electrochemical regeneration of NADPH by a factor of three. For an amino acid oxidase catalysed resolution of a methionine racemate with ferrocene-mediated electrochemical regeneration of the enzyme-bound cofactor FAD a 50% increase in space time yield and 140% increase in catalyst utilisation (TTN) were achieved. Furthermore, for the chloroperoxidase-catalysed synthesis of (R) phenylmethylsulfoxide with electrochemical generation of the required cosubstrate H2O2 the space time yield and the catalyst utilisation were improved by a factor of up to 4.2 depending on the ionic liquids used. PMID- 19777514 TI - Copper-catalyzed amine-alkyne-alkyne addition reaction: an efficient method for the synthesis of gamma,delta-alkynyl-beta-amino acid derivatives. AB - A simple and efficient method for the synthesis of gamma,delta-alkynyl-beta-amino acid derivatives by a copper-catalyzed three-component amine-alkyne-alkyne addition reaction was developed. Various gamma,delta-alkynyl-beta-amino acid derivatives were synthesized in moderate to good yields in one step. With chiral prolinol derivatives employed as the amine component, excellent diastereoselectivities (up to >99:1 diastereomeric ratio (dr)) were obtained. The scope of the reaction and further transformations of the resulting amino acid derivatives, such as deprotection and cyclization are also described. PMID- 19777515 TI - The stereochemistry of 1,2,3-triols revealed by 1H NMR spectroscopy: principles and applications. AB - The conformational compositions of the tris(alpha-methoxy-alpha-phenylacetic acid) ester derivatives of 1,2,3-prim,sec,sec-triols are presented. These conformations have been determined by theoretical and experimental data (i.e., energy- and chemical-shift calculations, circular dichroism (CD) experiments, coupling-constant analysis, enantioselective deuteration experiments, and low temperature NMR spectroscopic studies). A detailed analysis of the anisotropic effects due to the most significant conformers in the (1)H NMR spectra supported the correlation between the (1)H NMR spectra (Delta delta(RS) value of H(3') and |Delta(Delta delta(RS))| parameters) and the absolute configuration of the substrate. The study also allows the identification of the pro-R and pro-S methylene protons from their vicinal coupling constants and relative chemical shifts. PMID- 19777516 TI - Organocatalytic addition on 1,2-bis(sulfone)vinylenes leading to an unprecedented rearrangement. PMID- 19777517 TI - Oligomeric tectonics: supramolecular assembly of double-stranded oligobisnorbornene through pi-pi stacking. AB - Self-assembly at the molecular level in solutions or on a surface is a subject of current interest. Herein we describe the tailoring of oligobisnorbornene 1, which represents an innovative concept of a preorganized building block on the tens of nanometer scale. The rodlike 1 has vinyl and styrenyl end groups. Scanning tunneling microscopy (STM) reveals that the oligomers aggregate anisotropically along the long axis and form a one-dimensional assembly in which, remarkably, no interstitial gap appears between neighboring oligomers. Dynamic light-scattering (DLS) measurements indicate that the assembly develops in solution. With a shear treatment for dropcast films, a unidirectionally ordered domain with a defect density less than 0.5 % can be prepared. Simulation results by molecular dynamics suggest that there may be multiple interactions such as pi-pi stacking and dipolar attractions taking place between the termini of the oligomers. To demonstrate the importance of double bonds in the oligomeric backbones and termini towards the tectonic assembly, a hydrogenated analogue was synthesized; pi-pi interactions are thus less significant and the film morphology is completely different from that of 1. This work extends the concept of molecular tectonics to preorganized oligomers and opens up a new avenue of nanopatterning toward nanodevices. PMID- 19777518 TI - Condensation of beta-diester titanium enolates with carbonyl substrates: a combined DFT and experimental investigation. AB - The condensation of dialkyl beta-diesters with various aldehydes promoted by TiCl4 has been studied by DFT approaches and experimental methods, including NMR, IR and UV/Vis spectroscopy. Various possible reaction pathways have been investigated and their energy profiles evaluated to find out a plausible mechanism of the reaction. Theoretical results and experimental evidence point to a three-step mechanism: 1) Ti-induced formation of the enolate ion; 2) aldol reaction between the enolate ion and the aldehyde, both coordinated to titanium; and 3) intramolecular elimination that leads to a titanyl complex. The presented mechanistic hypothesis allows one to better understand the pivotal role of titanium(IV) in the reaction. PMID- 19777519 TI - Lewis base behavior of bridging nitrido ligands of titanium polynuclear complexes. AB - The Lewis base behavior of mu3-nitrido ligands of the polynuclear titanium complexes [{Ti(eta5-C5Me5)(mu-NH)}3(mu3-N)] (1) and [{Ti(eta5-C5Me5)}4(mu3-N)4] (2) to MX Lewis acids has been observed for the first time. Complex 1 entraps one equivalent of copper(I) halide or copper(I) trifluoromethanesulfonate through the basal NH imido groups to give cube-type adducts [XCu{(mu3-NH)3Ti3(eta5 C5Me5)3(mu3-N)}] (X=Cl (3), Br (4), I (5), OSO2CF3 (6)). However, the treatment of 1 with an excess (> or = 2 equiv) of copper reagents afforded complexes [XCu{(mu3-NH)3Ti3(eta5-C5Me5)3(mu4-N)(CuX)}] (X=Cl (7), Br (8), I (9), OSO2CF3 (10)) by incorporation of an additional CuX fragment at the mu3-N nitrido apical group. Similarly, the tetranuclear cube-type nitrido derivative 2 is capable of incorporating one, two, or up to three CuX units at the mu3-N ligands to give complexes [{Ti(eta5-C5Me5)}4(mu3-N)(4-n){(mu4-N)CuX}n] (X=Br (11), n=1; X=Cl (12), n=2; X=OSO2CF3 (13), n=3). Compound 2 also reacts with silver(I) trifluoromethanesulfonate (> or = 1 equiv) to give the adduct [{Ti(eta5 C5Me5)}4(mu3-N)3{(mu4-N)AgOSO2CF3}] (14). X-ray crystal structure determinations have been performed for complexes 8-13. Density functional theory calculations have been carried out to understand the nature and strength of the interactions of [{Ti(eta5-C5H5)(mu-NH)}3(mu3-N)] (1') and [{Ti(eta5-C5H5)}4(mu3-N)4] (2') model complexes with copper and silver MX fragments. Although coordination through the three basal NH imido groups is thermodynamically preferred in the case of 1', in both complexes the mu3-nitrido groups act as two-electron donor Lewis bases to the appropriate Lewis acids. PMID- 19777520 TI - The (3)[ndsigma*(n+1)psigma] emissions of linear silver(I) and gold(I) chains with bridging phosphine ligands. AB - The complexes [Au(3)(dcmp)(2)][X](3) {dcmp=bis(dicyclohexylphosphinomethyl)cyclohexylphosphine; X=Cl(-) (1), ClO(4) ( ) (2), OTf(-) (3), PF(6) (-) (4), SCN(-)(5)}, [Ag(3)(dcmp)(2)][ClO(4)](3) (6), and [Ag(3)(dcmp)(2)Cl(2)][ClO(4)] (7) were prepared and their structures were determined by X-ray crystallography. Complexes 2-4 display a high-energy emission band with lambda(max) at 442-452 nm, whereas 1 and 5 display a low-energy emission with lambda(max) at 558-634 nm in both solid state and in dichloromethane at 298 K. The former is assigned to the (3)[5dsigma*6psigma] excited state of [Au(3)(dcmp)(2)](3+), whereas the latter is attributed to an exciplex formed between the (3)[5dsigma*6psigma] excited state of [Au(3)(dcmp)(2)](3+) and the counterions. In solid state, complex [Ag(3)(dcmp)(2)][ClO(4)](3) (6) displays an intense emission band at 375 nm with a Stokes shift of approximately 7200 cm(-1) from the (1)[4dsigma*-->5psigma] absorption band at 295 nm. The 375 nm emission band is assigned to the emission directly from the (3)[4dsigma(*)5psigma] excited state of 6. Density functional theory (DFT) calculations revealed that the absorption and emission energies are inversely proportional to the number of metal ions (n) in polynuclear Au(I) and Ag(I) linear chain complexes without close metalanion contacts. The emission energies are extrapolated to be 715 and 446 nm for the infinite linear Au(I) and Ag(I) chains, respectively, at metalmetal distances of about 2.93-3.02 A. A QM/MM calculation on the model [Au(3)(dcmp)(2)Cl(2)](+) system, with Au...Cl contacts of 2.90-3.10 A, gave optimized Au...Au distances of 2.99-3.11 A in its lowest triplet excited state and the emission energies were calculated to be at approximately 600-690 nm, which are assigned to a three-coordinate Au(I) site with its spectroscopic properties affected by Au(I)...Au(I) interactions. PMID- 19777521 TI - Rectification in supramolecular zinc porphyrin/fulleropyrrolidine dyads self organized on gold(111). AB - Self-assembled donor/acceptor dyads are of current interest as they are biomimetic to the natural photosynthetic conversion system. Herein, we present an ultrahigh-vacuum scanning tunneling microscopy and scanning tunneling spectroscopy (UHV-STM/STS) study of ex situ self-assembled supramolecular dyads consisting of fulleropyrrolidines (PyC(2)C(60)) axially ligated to zinc(II) tetraphenylporphyrin (ZnTPP), self organized on a 4-aminothiophenol (4-ATP) self assembled monolayer on gold(111). These dyads show both bias-polarity-dependent apparent height in STM images and highly rectifying behavior in tunneling spectroscopy. First-principles density functional theory calculations clarify the conformational and electronic properties of the 4-ATP/ZnTPP/PyC(2)C(60) system. Interestingly, we find easier tunneling for electrons moving from the acceptor side of the dyads to the donor side, in the inverse-rectifying sense with respect to previously reported molecular rectifiers. Such behavior cannot be explained as an elastic resonant tunneling process, but it can by using a model based on the Aviram-Ratner mechanism. PMID- 19777522 TI - Enhancing electron collection efficiency and effective diffusion length in dye sensitized solar cells. AB - Intensity-modulated photocurrent spectroscopy and intensity-modulated photovoltage spectroscopy are employed to measure the dynamics of electron transport and recombination in the ZnO nanowire (NW) array-ZnO/layered basic zinc acetate (LBZA) nanoparticle (NP) composite dye-sensitized solar cells (DSSCs). The roles of the vertical ZnO NWs and insulating LBZA in the electron collection and transport in DSSCs are investigated by comparing the results to those in the TiO(2)-NP, horizontal TiO(2)-NW and vertical ZnO-NW-array DSSCs. The electron transport rate and electron lifetime in the ZnO NW/NP composite DSSC are superior to those in the conventional TiO(2)-NP cell due to the existence of the vertical ZnO NWs and insulating LBZA. It indicates that the ZnO NW/NP composite anode is able to sustain efficient electron collection over much greater thickness than the TiO(2)-NP cell does. Consequently, a larger effective electron diffusion length is available in the ZnO composite DSSC. PMID- 19777523 TI - Activators of P-glycoprotein: Structure-activity relationships and investigation of their mode of action. AB - P-glycoprotein (P-gp), a 170 kDa plasma membrane protein, is one of the most relevant ABC transporters involved in the development of multidrug resistance (MDR). Understanding its mechanism of transport as well as its interactions with various substrates are basic requirements for the development of adequate therapeutic approaches to overcome this kind of resistance against a broad spectrum of structurally unrelated cytostatic drugs. P-gp modulators (activators) that exert various effects on the intracellular accumulation of distinct P-gp substrates are useful tools for investigating the interactions between multiple drug binding sites of this transport protein. In this study, a series of 27 different imidazobenzothiazoles and imidazobenzimidazoles structurally related to the known P-gp activators QB102 and QB11 was designed, and their modulating properties were investigated. Most of them were able to stimulate P-gp-mediated efflux of daunorubicin and rhodamine 123 in a concentration-dependent manner, but some compounds also displayed weak inhibitory effects. Additionally, P-gp mediated efflux of vinblastine and colchicine was inhibited by several compounds. Therefore, we concluded that the novel compounds bind to the H site of P-gp and activate the efflux of specific substrates of the R site in a positive cooperative manner, whereas binding of H-type substrates is inhibited competitively. This hypothesis is confirmed by the observation that the modulators do not influence hydrolysis of ATP or its affinity toward P-gp. PMID- 19777524 TI - Transport diffusivity of CO2 in the highly flexible metal-organic framework MIL 53(Cr). PMID- 19777525 TI - Coupling reactions of zirconate complexes induced by carbonyl compounds. PMID- 19777526 TI - Graphite-supported gold nanoparticles as efficient catalyst for aerobic oxidation of benzylic amines to imines and N-substituted 1,2,3,4-tetrahydroisoquinolines to amides: synthetic applications and mechanistic study. AB - Selective oxidation of amines using oxygen as terminal oxidant is an important area in green chemistry. In this work, we describe the use of graphite-supported gold nanoparticles (AuNPs/C) to catalyze aerobic oxidation of cyclic and acyclic benzylic amines to the corresponding imines with moderate-to-excellent substrate conversions (43-100%) and product yields (66-99%) (19 examples). Oxidation of N substituted 1,2,3,4-tetrahydroisoquinolines in the presence of aqueous NaHCO3 solution gave the corresponding amides in good yields (83-93%) with high selectivity (up to amide/enamide=93:4) (6 examples). The same protocol can be applied to the synthesis of benzimidazoles from the reaction of o phenylenediamines with benzaldehydes under aerobic conditions (8 examples). By simple centrifugation, AuNPs/C can be recovered and reused for ten consecutive runs for the oxidation of dibenzylamine to N-benzylidene(phenyl)methanamine without significant loss of catalytic activity and selectivity. This protocol "AuNPs/C+O2" can be scaled to the gram scale, and 8.9 g (84 % isolated yield) of 3,4-dihydroisoquinoline can be obtained from the oxidation of 10 g 1,2,3,4 tetrahydroisoquinoline in a one-pot reaction. Based on the results of kinetic studies, radical traps experiment, and Hammett plot, a mechanism involving the hydrogen-transfer reaction from amine to metal and oxidation of M-H is proposed. PMID- 19777527 TI - Socio-economic and other correlates of Kaposi sarcoma-associated herpesvirus seroprevalence among older adults in Sicily. AB - The virus that causes Kaposi sarcoma, KS-associated herpesvirus (KSHV, also known as human herpesvirus 8) has an unusual distribution and poorly characterized modes of transmission. To clarify these issues, socio-demographic correlates of KSHV seroprevalence were examined in a population-based study. In 1,154 randomly sampled adults (aged 32- 92, mean 71 years) throughout Sicily, KSHV antibodies were detected with four assays and a conservative algorithm. Seroprevalence was re-weighted to the population. Odds ratios with 95% confidence intervals (OR, CI) from multivariate logistic regression were used to estimate associations of seroprevalence with interview data. KSHV seroprevalence was 8.5%, including 5.3% among men (N = 848) and 11.5% among women (N = 306, P = 0.22). Seroprevalence was higher with residence in a smaller community during childhood (P(trend) = 0.03) and working with plants/soil during adulthood (OR 2.9, CI 1.1-7.9); these were especially strong among women. Among men, seroprevalence was significantly associated with lower education (OR 2.6, CI 1.1-5.9) and migration to a larger community (OR 0.3, CI 0.1-0.9). Other demographic and household variables were unrelated to seroprevalence. From these data, KSHV in Sicily appears to be related to low socio-economic status, but micro-endemicity in small communities cannot be excluded. PMID- 19777529 TI - Trizygotic dichorionic triplets with 46,XX/46,XY chimerism in both fetuses of the monochorionic pair. PMID- 19777528 TI - Mathematical modelling of the impact of haematopoietic stem cell-delivered gene therapy for HIV. AB - BACKGROUND: Gene therapy represents a new treatment paradigm for HIV that is potentially delivered by a safe, once-only therapeutic intervention. METHODS: Using mathematical modelling, we assessed the possible impact of autologous haematopoietic stem cell (HSC) delivered, anti-HIV gene therapy. The therapy comprises a ribozyme construct (OZ1) directed to a conserved region of HIV-1 delivered by transduced HSC (OZ1+HSC). OZ1+HSC contributes to the CD4+ T lymphocyte and monocyte/macrophage cell pools that preferentially expand under the selective pressure of HIV infection. The model was used to predict the efficacy of OZ1 in a highly active antiretroviral therapy (HAART) naive individual and a HAART-experienced individual undergoing two structured treatment operations. In the standard scenario, OZ1+HSC was taken as 20% of total body HSC. RESULTS: For a HAART-naive individual, modelling predicts a reduction of HIV RNA at 1 and 2 years post-OZ1 therapy of 0.5 log(10) and 1 log(10), respectively. Eight years after OZ1 therapy, the CD4+ T-lymphocyte count was 271 cells/mm(3) compared to 96 cells/mm(3) for an untreated individual. In a HAART-experienced individual HIV RNA was reduced by 0.34 log(10) and 0.86 log(10) at 1 and 2 years. The OZ1 effect was maximal when both CD4+ T lymphocytes and monocytes/macrophages were protected from successful, productive infection by OZ1. CONCLUSIONS: The modelling indicates a single infusion of HSC cell-delivered gene therapy can impact on HIV viral load and CD4 T-lymphocyte count. Given that gene therapy avoids the complications associated with HAART, there is significant potential for this approach in the treatment of HIV. PMID- 19777530 TI - Maternal serum placental protein 13 at 11-13 weeks of gestation in preeclampsia. AB - OBJECTIVE: To examine the potential value of maternal serum concentration of placental protein 13 (PP13) at 11-13 weeks' gestation in screening for preeclampsia (PE). METHODS: Serum PP13, PAPP-A and uterine artery pulsatility index (PI) were determined in a case-control study of 208 cases that developed PE including 48 that required delivery before 34 weeks (early-PE) and 416 unaffected controls. RESULTS: Serum PP13 levels, expressed as multiples of the median (MoM) in the unaffected group, were significantly reduced in early-PE (0.83 MoM) but not in late-PE (0.96 MoM). In both early- and late-PE serum PAPP-A (0.55 and 0.84 MoM) was reduced and uterine artery PI (1.61 and 1.25 MoM) was increased. In PE pregnancies there was a significant association between serum PP13 and both uterine artery PI and serum PAPP-A (p < 0.0001 for both). Logistic regression analysis demonstrated that serum PP13 did not improve significantly the prediction of early-PE provided by a combination of maternal factors, uterine artery PI and PAPP-A. CONCLUSION: PP13 is implicated in the pathogenesis of impaired placentation and subsequent development of early-PE but measurement of this placental product is unlikely to be useful in screening for the disease at 11-13 weeks. PMID- 19777531 TI - Trisomy 16 detected by first trimester screening. PMID- 19777532 TI - Validity, reliability and clinical feasibility of a Needs Assessment Tool for people with progressive cancer. AB - BACKGROUND: Needs assessment is a valuable approach for determining the way health and social services allocate resources to people with cancer and their caregivers. AIM: To assess the reliability, validity and acceptability of a Needs Assessment Tool (NAT) in a palliative care clinical setting. METHODS: Psychometric properties of the NAT were initially explored in a pilot study involving filmed simulated advanced cancer patient and caregiver consultations. Further testing was undertaken in a clinical setting to determine the inter-rater reliability, validity and feasibility of the NAT. RESULTS: The results of the pilot study suggested good reliability and acceptability in a simulated setting. Further testing indicated that the patient daily living item was positively correlated with the Resource Utilisation Groups-Activities of Daily Living (r=0.74) and negatively correlated with the Australian Karnofsky Performance Scale (r=-0.84). Prevalence- and bias-adjusted kappa values also indicated adequate agreement between Palliative Care Problem Severity Score items and the patient physical item (0.48), psychological item (0.45) and caregiver well-being item (0.42). CONCLUSIONS: Needs assessment not only facilitates the identification of people who have specific concerns or are dissatisfied with some aspect of their care, but also determines the person's desire for assistance and involvement with services. The NAT is a highly acceptable and efficient tool that can be used by health professionals with a range of clinical expertise to identify individuals' needs, thereby enabling a better match of interventions of specialist services more closely linked to needs. PMID- 19777533 TI - Phynx: an open source software solution supporting data management and web-based patient-level data review for drug safety studies in the general practice research database and other health care databases. AB - PURPOSE: To develop a software solution that supports management and clinical review of patient data from electronic medical records databases or claims databases for pharmacoepidemiological drug safety studies. METHODS: We used open source software to build a data management system and an internet application with a Flex client on a Java application server with a MySQL database backend. The application is hosted on Amazon Elastic Compute Cloud. This solution named Phynx supports data management, Web-based display of electronic patient information, and interactive review of patient-level information in the individual clinical context. This system was applied to a dataset from the UK General Practice Research Database (GPRD). RESULTS: Our solution can be setup and customized with limited programming resources, and there is almost no extra cost for software. Access times are short, the displayed information is structured in chronological order and visually attractive, and selected information such as drug exposure can be blinded. External experts can review patient profiles and save evaluations and comments via a common Web browser. CONCLUSIONS: Phynx provides a flexible and economical solution for patient-level review of electronic medical information from databases considering the individual clinical context. It can therefore make an important contribution to an efficient validation of outcome assessment in drug safety database studies. PMID- 19777534 TI - Prevalence and safety-relevance of drug-related problems in German community pharmacies. AB - PURPOSE: The purpose of this study was to assess prevalence and characteristics, including safety-relevance, of drug-related problems (DRPs) detectable in community pharmacy routine service, and to investigate the influence of relevant risk factors. METHODS: Patients in 69 community pharmacies in Berlin were surveyed using a checklist for quality assurance of DRP detection in order to enable quantitative detection. An expert committee assessed the safety-relevance of detected DRPs by use of an algorithm. Logistic regression analysis was applied to investigate the influence of different risk factors. RESULTS: Of the 3040 surveyed patients, 638 (21.0%) were affected by DRPs. Among these, 455 (71.3%) had problems of low, 170 (26.6%) of significant and 13 (2.0%) of high safety relevance. Significant risk factors identified were self-medication and new medication, especially new prescriptions. Age, gender and the number of dispensed drugs had little influence on occurrence of DRPs. The two major groups of DRPs were therapeutic errors, often correlating with self-medication, and information problems, often correlating with new medications. Drug classes most frequently associated with DRPs were analgesics/NSAID, antibiotics, nasal preparations and cough medications. CONCLUSION: DRPs are frequent among patients in German community pharmacies. Advanced research in this field (DRP-pharmacovigilance) and implementation of methods for quality assurance of pharmaceutical counselling, that is exhaustive DRP detection, may improve the safety of drug therapies significantly. In particular, pharmaceutical counselling is an important instrument for assuring treatment appropriateness and safety of OTC drugs. PMID- 19777535 TI - The association of depression and anxiety with health-related quality of life in cancer patients with depression and/or pain. AB - OBJECTIVES: Depression is known to be a major problem in cancer patients, and evidence is emerging about the importance of anxiety. Because the disorders are highly comorbid, we examined the relationship of anxiety and depression with health-related quality of life (HRQL) in cancer patients. METHODS: Sample included 405 adult oncology patients participating in a randomized controlled trial of telecare management for pain and depression. This secondary cross sectional analysis of baseline data examined independent and additive effects of anxiety and depression on HRQL, disability, and somatic symptom severity. RESULTS: In 397 patients who screened positive for either pain or depression or both, 135 had comorbid anxiety and depression, 174 had depression but not anxiety, and 88 had neither. Differences existed across all nonphysical HRQL domains and were more pronounced incrementally across the three groups in the expected direction. In GLM modeling, anxiety and depression were each associated with all the domains when modeled separately (p<0.0001). When modeled together, anxiety and depression had independent and additive effects on the mental health domains of HRQL and on somatic symptom burden. In other domains (vitality, perceived disability, overall quality of life, and general health perceptions), only depression had an effect. CONCLUSION: Anxiety and depression have strong and independent associations with mental health domains and somatic symptom burden in cancer patients. However, depression has a more pervasive association with multiple other domains of HRQL. Paying attention to both anxiety and depression may be particularly important when addressing mental health needs and somatic symptom distress. PMID- 19777537 TI - Comment on 'New confidence bounds for QT studies' by Dennis D. Boos, David Hoffman, Robert Kringle and Ji Zhang, Statistics in Medicine 2007; 26:3801-3817. PMID- 19777538 TI - 'Why I feel bad': refinement of the Effects of Prostate Cancer Upon Lifestyle Questionnaire and an initial exploration of its links with anxiety and depression among prostate cancer patients. AB - OBJECTIVE: To psychometrically refine a standardized scale for identifying those lifestyle changes that were most likely to contribute to anxiety and depression among prostate cancer (PCa) patients. METHODS: Three hundred and eighty-one PCa patients who had received their initial diagnosis between one and 96 months completed a survey of background variables, anxiety and depression inventories and the 36-item Effects of Prostate Cancer upon Lifestyle Questionnaire (EPCLQ). RESULTS: Levels of anxiety (24%) and depression (26%) were similar to those previously reported for PCa patients. The EPCLQ was shown to have satisfactory psychometric properties and significantly predicted anxiety and depression scores and the presence of psychological clinicity among this sample. Factor analysis of the EPCLQ showed that adverse emotions and social withdrawal, plus loss of cognitive ability, were the most powerful predictors of fear, physiological arousal, discomfort and pain factors underlying anxiety; these factors also predicted pessimism and fatigue factors underlying depression. conclusions: The EPCLQ was shown to be a reliably sound and valid instrument for assessing important lifestyle changes that predict anxiety and depression among PCa patients. In addition, links between receiving a diagnosis and treatment for PCa and development of psychosocial disturbance via emotional negativity, decreased cognitive performance and withdrawal from others appear to warrant further investigation. PMID- 19777540 TI - Epiphyseal punctate calcifications (stippling) in complete trisomy 9. PMID- 19777541 TI - Rapid flow cytometric method for measuring senescence associated beta galactosidase activity in human fibroblasts. AB - Senescence associated-beta-galactosidase (SA-beta-gal) activity is a widely used marker for cellular senenescence. SA-beta-gal activity is routinely detected cytochemically, manually discriminating negative from positive cells. This method is time-consuming, subjective and therefore prone to operator-error. We aimed to optimize a flow cytometric method described by other workers using endothelial cells to better differentiate between populations of fibroblasts in degrees of SA beta-gal activity. Skin fibroblasts were isolated from young (mean age +/- SD: 25.5 +/- 1.8) and very old (age 90.2 +/- 0.3) subjects. Different pH modulators were tested for toxicity. To induce stress-induced senescence, fibroblasts were exposed to rotenone. Senescence was assessed measuring SA-beta-gal activity by cytochemistry (X-gal) and by flow cytometry (C(12)FDG). The pH modulator Bafilomycin A1 (Baf A1) was found to be least toxic for fibroblasts and to differentiate best between nonstressed and stressed fibroblast populations. Under nonstressed conditions, fibroblasts from very old subjects showed higher SA-beta gal activity than fibroblasts from young subjects. This difference was found for both the flow cytometric and cytochemical methods (P = 0.013 and P = 0.056 respectively). Under stress-induced conditions the flow cytometric method but not the cytochemical method revealed significant higher SA-beta-gal activity in fibroblasts from very old compared to young subjects (P = 0.004 and P = 0.635 respectively). We found the modified flow cytometric method measuring SA-beta-gal activity superior in discriminating between degrees of senescence in different populations of fibroblasts. PMID- 19777542 TI - Prenatal diagnosis of lower urinary tract obstruction associated with penoscrotal transposition. PMID- 19777543 TI - Involvement of the PKC family in regulation of early development. AB - Protein kinase C (PKC) isotypes have been implicated in a number of key steps during gametogenesis, fertilization, and early development. The 11-member family of PKC isotypes, many with different cofactor requirements for activation, can provide for differential activation of the specific kinases. In addition the enrichment of particular PKC isotypes to unique locations within gametes, zygotes, and early embryos likely promotes specific substrate interactions. Evidence exists to indicate involvement of PKC isotypes during sperm capacitation and the acrosome reaction, during resumption of meiosis in the oocytes, regulating the spindle organization in meiosis I and II, at fertilization, in the pronuclei, in the mitotically dividing blastomeres of the embryo, and at the plasma membranes of blastomeres at the time of embryonic compaction. Evidence also exists for crosstalk with other signaling pathways and one or more isotypes of PKC appear to be active at each major developmental transition. PMID- 19777544 TI - False positive reporting of Hirschsprung's disease in Alaska: an evaluation of Hirschsprung's disease surveillance, birth years 1996-2007. AB - BACKGROUND: Hirschsprung's disease (HSCR) is a potentially fatal congenital intestinal obstruction syndrome. For birth years 1996-2002, reported HSCR prevalence in Alaska was approximately six times higher than the national estimate of two per 10,000 live births. In 2008 we completed a case verification study of HSCR reported to the Alaska Birth Defects Registry (ABDR) to verify prevalence and evaluate sensitivity and predictive value of HSCR surveillance. METHODS: We abstracted medical records for children reported with HSCR who were born in 1996-2007 and matched to an Alaska birth certificate. We categorized reports as confirmed, ruled out, or inconclusive. ABDR sensitivity was validated by cross-referencing hospital discharge data with confirmed HSCR cases. RESULTS: Overall sensitivity of the ABDR was 94.4%, and positive predictive value (PPV) was 31.1%. Following case verification, HSCR prevalence was three per 10,000 live births statewide and 5.6 and 2.1 per 10,000 live births for Alaska Natives and non-Natives, respectively. Positive predictive value was twice as high for the Alaska Native population as the non-Native population. CONCLUSIONS: Multiple source passive surveillance methodology resulted in high sensitivity for HSCR ascertainment; however, case verification was required to rule out false-positive reports, which obscured the true distribution of Alaska Native versus non-Native HSCR cases. PMID- 19777545 TI - Macroscopic assessment of mesorectal excision. PMID- 19777546 TI - MMP-mediated collagen breakdown induced by activated protein C in equine cartilage is reduced by corticosteroids. AB - The plasma serine protease activated protein C (APC) is synthesized by human chondrocytes at sites of pathological cartilage fibrillation. APC levels are increased in osteoarthritis (OA) synovial fluid, and in vitro APC has been shown to synergize with interleukin-1beta (IL-1) to promote degradation from ovine cartilage. A model of equine cartilage degradation was established and used to explore corticosteroid activities. Intraarticular corticosteroids are a commonly prescribed treatment for joint disease, however their role in disease modification remains unclear. APC synergized with IL-1 or tumor necrosis factor alpha (TNFalpha), promoting significant collagen degradation from equine cartilage explants within 4 days, but did not augment glycoaminoglycan (GAG) release. APC activated pro-matrix metalloproteinases (MMP)-2 but not pro-MMP-9, as assessed by gelatin zymography. APC did not directly activate pro-MMP-13. Dexamethasone, triamcinolone, and methylprednisolone acetate (MPA) were evaluated at concentrations between 10(- 5)M and 10(-10)M. High concentrations significantly increased GAG release from IL-1+APC-treated explants. With the exception of MPA at 10(-10)M, all concentrations of corticosteroids caused significant decreases in IL-1+APC-driven hydroxyproline loss. Treatment with corticosteroids suppressed expression of MMP-1, -3, and -13 mRNA. The collagenolysis associated with IL-1+APC synergy, and the inhibition of this effect by corticosteroids may involve gelatinase activation and downregulation of MMP expression, respectively. PMID- 19777547 TI - Flow cytometry and the stability of phycoerythrin-tandem dye conjugates. AB - Routine clinical flow cytometric procedures demand rigorous, simple, and reproducible procedures for spectral compensation. The current, often laborious, spectral compensation procedures are the result of variability in instrument settings, instrument performance, and variability in reagents. In particular, the use of tandem dye conjugates necessitates elaborate spectral compensation procedures that need to be applied frequently. Manufacturer, lot number, and handling procedures are considered the key aspects affecting the fluorescence characteristics of tandem dyes. A better understanding of how specific conditions affect the variability in emission spectra of tandem dyes can lead to a considerable increase in reliability of measurements and a potential simplification of setup procedures for routine, clinical flow cytometry. We investigated the effect of light exposure, handling, and storage conditions on the fluorescence characteristics of some common phycoerythrin tandem fluorochromes. In general, PE-Cy5 showed the lowest degradation rates, whereas PE Cy7 showed the highest. During storage, long-term degradation rates were lowest for reagents packaged using an extra light protective approach. Under these conditions, a degradation rate of 0.9%/month of a PE-Cy7 conjugate decreased to 0.3%/month. As degradation rates were minimized, we studied the effect of slow degradation of a set of tandem dye conjugates on compensation matrix values over several months. Finally, we explored the effect of slow degradation on flow cytometric analysis using the same compensation settings for extended periods for an analysis template with preset regions and gating strategies. PMID- 19777548 TI - eIF4E-binding proteins are differentially modified after ammonia versus intracellular calcium activation of sea urchin unfertilized eggs. AB - Fertilization of sea urchin eggs triggers a rise of protein synthesis mainly dependent on the cap-binding protein eIF4E, which is released from its repressor 4E-BP and associates with eIF4G. Association of eIF4G with eIF4E is a crucial event for the onset of the first mitotic division following fertilization. Artificial activation of unfertilized eggs with the calcium ionophore A23187 results in the activation of protein synthesis comparable to the one triggered by fertilization, while increasing the intracellular pH by ammonia treatment results in partial activation of protein synthesis. Nevertheless, artificial activation does not induce the mitotic division. Here we investigate the effect of calcium ionophore and ammonia treatment of unfertilized eggs on eIF4E and its two antagonist partners, 4E-BP and eIF4G. We show that the addition of calcium ionophore to unfertilized eggs induces permanent dissociation between eIF4E and 4E-BP, whereas a reversible dissociation of the complex occurs after ammonia treatment. The regulation of the complex correlates with permanent or reversible 4E-BP disappearance depending on the treatment used to trigger artificial activation. Furthermore, while calcium ionophore treatment of unfertilized eggs induces eIF4G modifications comparable to those observed following fertilization, ammonia treatment does not. These results suggest that ionophore and ammonia treatments of unfertilized eggs induce differential protein synthesis activation by targeting eIF4E availability and specific regulation through its two partners 4E-BP and eIF4G. PMID- 19777549 TI - Utility of lyophilized PMA and ionomycin to stimulate lymphocytes in whole blood for immunological assays. AB - BACKGROUND: The need to implement robust biomarkers in clinical trials has never been greater, and such efforts can be easily compromised by reagent instability or simple human error during assay set-up. Many biotechnology and pharmaceutical companies are introducing efforts to conduct biomarker studies under more rigorous settings, and the use of plates or tubes pre-loaded with stimulation or staining reagents could be of value for studies that involve flow cytometry. METHODS: Five reagents lyophilized from ethanol or CHAPS buffer stock solution of phorbol 12-myristate 13-acetate (PMA) and ionomycin were benchmarked against standard DMSO liquid formulation for their stimulation equivalency. The median fluorescence intensity of phosphorylated ribosomal protein S6 in lymphocytes was assessed on a BD FACSCalibur. RESULTS: We demonstrate here that tubes pre-loaded with lyophilized versions of the liquid reagents can provide equivalent stimulation in healthy volunteer specimens. CONCLUSIONS: The value of this approach is that it safeguards against omission or erroneous addition of bulk liquid formulations of PMA and ionomycin to the reaction vessel (i.e., plate or tube) and also lends itself to extended stability/shelf-life of these reagents. On the basis of this initial success, we plan to expand our evaluation of lyophilized reagents so that they can be incorporated into our clinical biomarker campaigns as appropriate. PMID- 19777550 TI - Cone-beam computed tomography of the maxillofacial region--an update. AB - BACKGROUND: During the last few years, craniomaxillofacial diagnosis of the head has been confronted with an increasing number of innovations and improvements. The main progress occurred following the introduction of cone-beam technology in computed tomography in the 1990s. The number of manufacturers and devices using this technology for the maxillofacial region is growing rapidly and they are now becoming readily available. MATERIALS: This article focuses on cone-beam computed tomography (CBCT) devices applied to the maxillofacial region. CBCT serves as a bridge from two dimensions (2D) to three dimensions (3D), with lower irradiation than conventional CT. Different manufacturers and models are now available to satisfy the different needs of clinicians. RESULTS: A recent review of the manufacturers found 23 CBCT devices on the market. The specifications, applications and other issues of currently available CBCT devices are presented and discussed. CONCLUSIONS: 3D imaging is developing at a very fast pace. New technologies and machines are emerging and CBCT is becoming readily available. Due to the growing demand for the technology based on the needs of clinicians, there is now a wide and growing selection of devices on the market. Some of the new advances now mean that CBCT imaging should be a well-considered option in maxillofacial imaging. PMID- 19777552 TI - Disorder-specific dysfunction in right inferior prefrontal cortex during two inhibition tasks in boys with attention-deficit hyperactivity disorder compared to boys with obsessive-compulsive disorder. AB - BACKGROUND: Inhibitory dysfunction is a key behavioral and cognitive phenotype of attention-deficit hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD). Both disorders show neuropsychological deficits and fronto-striatal dysfunction during tasks of motor response inhibition and cognitive flexibility. This study investigates differences and commonalities in functional neural networks mediating inhibitory control between adolescents with ADHD and those with OCD to identify disorder-specific neurofunctional markers that distinguish these two inhibitory disorders. METHODS: Event-related fMRI was used to compare brain activation between 20 healthy boys, 18 (Stop task) or 12 boys (Switch task) with ADHD, and 10 boys with OCD during a tracking Stop task that measures inhibition and stopping failure and during a visual-spatial switching task measuring cognitive flexibility. RESULTS: Both patient groups shared brain dysfunction compared to healthy controls in right orbitofrontal (successful inhibition) and left dorsolateral prefrontal cortices (failed inhibition). Right inferior prefrontal dysfunction, however, was disorder-specific to ADHD during both tasks. Left inferior prefrontal dysfunction during the Switch task was significant in children with ADHD relative to controls, but only reached a trend in patients with OCD. Patients with ADHD furthermore showed disorder-specific dysfunction in left basal ganglia and cingulate gyrus during the Switch task. CONCLUSIONS: Patients with ADHD compared to those with OCD have both common and distinct dysfunctions during inhibitory control. The most consistently reported functional abnormality in children with ADHD in right inferior prefrontal cortex during inhibitory control appears to be disorder-specific when compared to patients with OCD and may be a specific neurofunctional biomarker of ADHD. PMID- 19777553 TI - Source-based morphometry of gray matter volume in men with first-episode schizophrenia. AB - OBJECTIVES: There is a lot of variability between the results of studies reporting the pattern of gray matter volume changes in schizophrenia. Methodological issues may play an important role in this heterogeneity. The aim of the present study was to replicate the better performance of multivariate "source-based morphometry" (SBM) over the mass-univariate approach. EXPERIMENTAL DESIGN: Voxel-based morphometry of Jacobian-modulated gray matter volume images, using voxel and cluster level inference, and SBM were performed in a group of first-episode schizophrenia patients (N = 49) and healthy controls (N = 127). RESULTS: Using SBM we were able to find a significant reduction of gray matter volume in fronto-temporo-cerebellar areas whereas no significant results were obtained using voxel-based morphometry. CONCLUSION: Multivariate analysis of gray matter volume seems to be a suitable method for characterization of the pattern of changes at the beginning of the illness in schizophrenia subjects. PMID- 19777554 TI - The neural response to changing semantic and perceptual complexity during language processing. AB - Speech comprehension involves processing at different levels of analysis, such as acoustic, phonetic, and lexical. We investigated neural responses to manipulating the difficulty of processing at two of these levels. Twelve subjects underwent positron emission tomographic scanning while making decisions based upon the semantic relatedness between heard nouns. We manipulated perceptual difficulty by presenting either clear or acoustically degraded speech, and semantic difficulty by varying the degree of semantic relatedness between words. Increasing perceptual difficulty was associated with greater activation of the left superior temporal gyrus, an auditory-perceptual region involved in speech processing. Increasing semantic difficulty was associated with reduced activity in both superior temporal gyri and increased activity within the left angular gyrus, a heteromodal region involved in accessing word meaning. Comparing across all the conditions, we also observed increased activation within the left inferior prefrontal cortex as the complexity of language processing increased. These results demonstrate a flexible system for language processing, where activity within distinct parts of the network is modulated as processing demands change. PMID- 19777555 TI - Role of A-type potassium currents in excitability, network synchronicity, and epilepsy. AB - A range of ionic currents have been suggested to be involved in distinct aspects of epileptogenesis. Based on pharmacological and genetic studies, potassium currents have been implicated, in particular the transient A-type potassium current (K(A)). Epileptogenic activity comprises a rich repertoire of characteristics, one of which is synchronized activity of principal cells as revealed by occurrences of for instance fast ripples. Synchronized activity of this kind is particularly efficient in driving target cells into spiking. In the recipient cell, this synchronized input generates large brief compound excitatory postsynaptic potentials (EPSPs). The fast activation and inactivation of K(A) lead us to hypothesize a potential role in suppression of such EPSPs. In this work, using computational modeling, we have studied the activation of K(A) by synaptic inputs of different levels of synchronicity. We find that K(A) participates particularly in suppressing inputs of high synchronicity. We also show that the selective suppression stems from the current's ability to become activated by potentials with high slopes. We further show that K(A) suppresses input mimicking the activity of a fast ripple. Finally, we show that the degree of selectivity of K(A) can be modified by changes to its kinetic parameters, changes of the type that are produced by the modulatory action of KChIPs and DPPs. We suggest that the wealth of modulators affecting K(A) might be explained by a need to control cellular excitability in general and suppression of responses to synchronicity in particular. Wealso suggest that compounds changing K(A)-kinetics may be used to pharmacologically improve epileptic status. PMID- 19777557 TI - Sensorimotor network rewiring in mild cognitive impairment and Alzheimer's disease. AB - This study aimed at elucidating whether (a) brain areas associated with motor function show a change in functional magnetic resonance imaging (fMRI) signal in amnestic mild cognitive impairment (aMCI) and Alzheimer's disease (AD), (b) such change is linear over the course of the disease, and (c) fMRI changes in aMCI and AD are driven by hippocampal atrophy, or, conversely, reflect a nonspecific neuronal network rewiring generically associated to brain tissue damage. FMRI during the performance of a simple motor task with the dominant right-hand, and structural MRI (i.e., dual-echo, 3D T1-weighted, and diffusion tensor [DT] MRI sequences) were acquired from 10 AD patients, 15 aMCI patients, and 11 healthy controls. During the simple-motor task, aMCI patients had decreased recruitment of the left (L) inferior frontal gyrus compared to controls, while they showed increased recruitment of L postcentral gyrus and head of L caudate nucleus, and decreased activation of the cingulum compared with AD patients. Effective connectivity was altered between primary sensorimotor cortices (SMC) in aMCI patients vs. controls, and between L SMC, head of L caudate nucleus, and cingulum in AD vs. aMCI patients. Altered fMRI activations and connections were correlated with the hippocampal atrophy in aMCI and with the overall GM microstructural damage in AD. Motor-associated functional cortical changes in aMCI and AD mirror fMRI changes of the cognitive network, suggesting the occurrence of a widespread brain rewiring with increasing structural damage rather than a specific response of cognitive network. PMID- 19777556 TI - The Iowa Gambling Task in fMRI images. AB - The Iowa Gambling Task (IGT) is a sensitive test for the detection of decision making impairments in several neurological and psychiatric populations. Very few studies have employed the IGT in functional magnetic resonance imaging (fMRI) investigations, in part, because the task is cognitively complex. Here we report a method for exploring brain activity using fMRI during performance of the IGT. Decision-making during the IGT was associated with activity in several brain regions in a group of healthy individuals. The activated regions were consistent with the neural circuitry hypothesized to underlie somatic marker activation and decision-making. Specifically, a neural circuitry involving the dorsolateral prefrontal cortex (for working memory), the insula and posterior cingulate cortex (for representations of emotional states), the mesial orbitofrontal and ventromedial prefrontal cortex (for coupling the two previous processes), the ventral striatum and anterior cingulate/SMA (supplementary motor area) for implementing behavioral decisions was engaged. These results have implications for using the IGT to study abnormal mechanisms of decision making in a variety of clinical populations. PMID- 19777559 TI - Stimulatory effect of undecylenic acid on mouse osteoblast differentiation. AB - Natural compounds with bone-forming (or anabolic) activity have been recently focused on in bone research. The present study investigated the effect of undecylenic acid (UA) on osteoblast differentiation in mouse osteoblastic MC3T3 E1 subclone 4 cells and primary mouse calvarial cells. Low concentrations of UA (up to 5 microM) exhibited no cytotoxicity and significantly increased the expression and activity of alkaline phosphatase (early differentiation marker of osteoblast) and calcium deposition with the induction of expression of the osteocalcin gene in both cells. Interestingly, at low concentration of UA, the induction of NF-kappaB p65 translocation into nucleus and the up-regulation of AP 1 and NFATc1 transcript levels were also observed, suggesting that the stimulatory effect of UA on osteoblast differentiation could be mediated through the activation of transcription factors. Additionally, although the patterns of UA-induced activation of MAP kinases (JNK and p38) were not completely consistent with the increase of both ALP activity and calcium deposition by UA, MAP kinases might be partially involved in the biological function of UA during the early and late stages of osteoblast differentiation. PMID- 19777558 TI - Influx of calcium through L-type calcium channels in early postnatal regulation of chloride transporters in the rat hippocampus. AB - During the early postnatal period, GABA(B) receptor activation facilitates L-type calcium current in rat hippocampus. One developmental process that L-type current may regulate is the change in expression of the K(+)Cl(-) co-transporter (KCC2) and N(+)K(+)2Cl(-) co-transporter (NKCC1), which are involved in the maturation of the GABAergic system. The present study investigated the connection between L type current, GABA(B) receptors, and expression of chloride transporters during development. The facilitation of L-type current by GABA(B) receptors is more prominent in the second week of development, with the highest percentage of cells exhibiting facilitation in cultures isolated from 7 day old rats (37.5%). The protein levels of KCC2 and NKCC1 were investigated to determine the developmental timecourse of expression as well as expression following treatment with an L-type channel antagonist and a GABA(B) receptor agonist. The time course of both chloride transporters in culture mimics that seen in hippocampal tissue isolated from various ages. KCC2 levels increased drastically in the first two postnatal weeks while NKCC1 remained relatively stable, suggesting that the ratio of the chloride transporters is important in mediating the developmental change in chloride reversal potential. Treatment of cultures with the L-type antagonist nimodipine did not affect protein levels of NKCC1, but significantly decreased the upregulation of KCC2 during the first postnatal week. In addition, calcium current facilitation occurs slightly before the large increase in KCC2 expression. These results suggest that the expression of KCC2 is regulated by calcium influx through L-type channels in the early postnatal period in hippocampal neurons. PMID- 19777560 TI - The effect of smoking on MAOA promoter methylation in DNA prepared from lymphoblasts and whole blood. AB - Prior work using lymphoblast DNA prepared from 192 subjects from the Iowa Adoption Studies (IAS) demonstrated that decreased MAOA promoter methylation was associated with lifetime symptom count for nicotine dependence (ND) and provided suggestive evidence that the amount of methylation is genotype dependent. In the current investigation, we replicate and extend these prior findings in three ways using another 289 IAS subjects and the same methodologies. First, we show that methylation is dependent on current smoking status. Second, we introduce a factor analytic approach to DNA methylation, highlighting three distinct regions of the promoter that may function in somewhat different ways for males and females. Third, we directly compare the methylation signatures in DNA prepared from whole blood and lymphoblasts from a subset of these subjects and provide suggestive evidence favoring the use of lymphoblast DNA. We conclude that smoking reliably decreases MAOA methylation, but exact characterization of effects on level of methylation depend on genotype, smoking history, current smoking status, gender, and region of the promoter-associated CpG Island examined. PMID- 19777562 TI - Evidence for the involvement of genetic variation in the oxytocin receptor gene (OXTR) in the etiology of autistic disorders on high-functioning level. AB - An increasing number of animal studies advert to a substantial role of the neuropeptide oxytocin in the regulation of social attachment and affiliation. Furthermore, animal studies showed anxiety and stress-reduced effects of oxytocin. First human studies confirm these findings in animal studies and implicate a crucial role of oxytocin in human social attachment behavior and in social interactions. Thus, the oxytocin system might be involved in the impairment of social interaction and attachment in autism spectrum disorders (ASD). The human oxytocin receptor gene (OXTR) represents a plausible candidate gene for the etiology of ASD. To analyze whether genetic variants in the OXTR gene are associated with ASD we performed family-based single-marker and haplotype association analyses with 22 single nucleotide polymorphisms (SNPs) in the OXTR and its 5' region in 100 families with autistic disorders on high functioning level (Asperger syndrome (AS), high-functioning autism (HFA), and atypical autism (AA)). Single-marker and haplotype association analyses revealed nominally significant associations of one single SNP and one haplotype with autism, respectively. Furthermore, employing a "reverse phenotyping" approach, patients carrying the haplotype associated with autism showed nominally significant impairments in comparison to noncarriers of the haplotype in items of the Autism Diagnostic Interview-Revised algorithm describing aspects of social interaction and communication. In conclusion, our results implicate that genetic variation in the OXTR gene might be relevant in the etiology of autism on high functioning level. PMID- 19777561 TI - Craniofacial skeletal defects of adult zebrafish Glypican 4 (knypek) mutants. AB - The heparan sulfate proteoglycan Glypican 4 (Gpc4) is part of the Wnt/planar cell polarity pathway, which is required for convergence and extension during zebrafish gastrulation. To observe Glypican 4-deficient phenotypes at later stages, we rescued gpc4(-/-) (knypek) homozygotes and raised them for more than one year. Adult mutants showed diverse cranial malformations of both dermal and endochondral bones, ranging from shortening of the rostral-most skull to loss of the symplectic. Additionally, the adult palatoquadrate cartilage was disorganized, with abnormal chondrocyte orientation. To understand how the palatoquadrate cartilage normally develops, we examined a juvenile series of wild type and mutant specimens. This identified two novel domains of elongated chondrocytes in the larval palatoquadrate, which normally form prior to endochondral ossification. In contrast, gpc4(-/-) larvae never form these domains, suggesting a failure of chondrocyte orientation, though not differentiation. Our findings implicate Gpc4 in the regulation of zebrafish cartilage and bone morphogenesis. PMID- 19777563 TI - Linkage analysis of Tourette syndrome in a large Utah pedigree. AB - Tourette syndrome (TS) is a neuropsychiatric disorder characterized by multiple motor and phonic tics. The heritability of TS has been well established, yet there is a lack of consensus in genome-wide linkage studies. The purpose of this study was to conduct a genome-wide linkage analysis on a unique, large, high-risk TS Utah pedigree. We examined a qualitative trait (TS1) where cases had a definitive diagnosis of TS as observed by a clinical interviewer (n = 66) and a quantitative phenotype based on the total Yale global motor and phonic tic severity scores (n = 102). Both parametric and non-parametric multipoint linkage analyses based on MCMC methods were performed using a 10 cM spaced micro satellite autosomal marker set. Two regions of interest were identified under affecteds-only recessive models; a LOD score of 3.3 on chromosome 1p for Yale tic severity and a LOD score of 3.1 on chromosome 3p for the TS1 phenotype. Twenty seven individuals shared linked segregating haplotypes for the 1p region. They had significantly higher Yale tic phonic scores than non-sharers (P = 0.01). There were 46 haplotype sharers on chromosome 3p with significantly higher percentage of females among these individuals compared to the non-sharers (P = 0.03). The significant linkage peaks on chromosomes 1p and 3p are in new areas of the genome for TS, and replication of these findings is necessary. PMID- 19777565 TI - Rotenone induces apoptosis in MCF-7 human breast cancer cell-mediated ROS through JNK and p38 signaling. AB - Rotenone is an inhibitor of the mitochondrial electron transport chain complex I, resulting in the generation of reactive oxygen species (ROS). Rotenone has been shown to display anticancer activity through the induction of apoptosis in various cancer cells. However, the underlying mechanism is still not fully understood. Here, rotenone showed a strong growth inhibitory effect against human breast cancer MCF-7 cells. DNA flow cytometric analysis, chromatin condensation, and poly (ADP-ribose) polymerase (PARP) cleavage indicated rotenone actively induced apoptosis in MCF-7 cells. The antiapoptotic protein, Bcl-2, was decreased, whereas the apoptotic protein, Bax, was increased in a time-dependent manner in rotenone-induced apoptosis. Moreover, the treatment of rotenone in MCF 7 cells caused the activation of c-jun N-terminal kinase (JNK) and p38 mitogen activated protein kinases (MAPKs), and the inactivation of extracellular signal regulated protein kinase 1/2 (ERK1/2). The pharmacological inhibition of JNK and p38 MAPK revealed significant protection against rotenone-induced apoptosis. Taken together, these results indicate rotenone may induce apoptosis through ROS and JNK/p38 MAPKs activation in MCF-7 cells. PMID- 19777564 TI - Expression and function of CD9 in melanoma cells. AB - CD9, a member of the tetraspanin family, functions as an organizer in "tetraspanin webs," through interacting with other cell adhesion molecules. It plays a role in differentiation, fertilization, and cell migration. We investigated the expression and function of CD9 in melanoma. CD9 protein expression in B16 mouse melanoma and six human melanoma cell lines was decreased compared to normal melanocytes. B16F1 clones stably overexpressing CD9 had reduced ability to form colonies in soft agar; however, paradoxically these overexpressing clones had increased ability to invade Matrigel. Similarly, transient overexpression of CD9 in the human metastatic melanoma cell line WM9 dramatically decreased anchorage-independent growth, while transient overexpression of CD9 in the radial growth phase cell line SbCl2 resulted in the gain of Matrigel invasion activity. DNA sequencing of CD9 cDNA from all six human melanoma cell lines did not show deletions, insertions, or mutations. Treatment of all six human melanoma cell lines with the histone deacetylase inhibitor trichostatin A increased CD9 levels. The DNA methylation inhibitor 5-aza-cytidine also increased CD9 protein levels with greater increases seen in cell lines derived from more malignant melanomas. PMID- 19777566 TI - Aberrant DNA methylation occurs in colon neoplasms arising in the azoxymethane colon cancer model. AB - Mouse models of intestinal tumors have advanced our understanding of the role of gene mutations in colorectal malignancy. However, the utility of these systems for studying the role of epigenetic alterations in intestinal neoplasms remains to be defined. Consequently, we assessed the role of aberrant DNA methylation in the azoxymethane (AOM) rodent model of colon cancer. AOM induced tumors display global DNA hypomethylation, which is similar to human colorectal cancer. We next assessed the methylation status of a panel of candidate genes previously shown to be aberrantly methylated in human cancer or in mouse models of malignant neoplasms. This analysis revealed different patterns of DNA methylation that were gene specific. Zik1 and Gja9 demonstrated cancer-specific aberrant DNA methylation, whereas, Cdkn2a/p16, Igfbp3, Mgmt, Id4, and Cxcr4 were methylated in both the AOM tumors and normal colon mucosa. No aberrant methylation of Dapk1 or Mlt1 was detected in the neoplasms, but normal colon mucosa samples displayed methylation of these genes. Finally, p19(Arf), Tslc1, Hltf, and Mlh1 were unmethylated in both the AOM tumors and normal colon mucosa. Thus, aberrant DNA methylation does occur in AOM tumors, although the frequency of aberrantly methylated genes appears to be less common than in human colorectal cancer. Additional studies are necessary to further characterize the patterns of aberrantly methylated genes in AOM tumors. PMID- 19777568 TI - Variability of human foramen magnum size. AB - The foramen magnum is an important landmark of the skull base and is of particular interest for anthropology, anatomy, forensic medicine, and other medical fields. Despite its importance, few osteometric studies of the foramen magnum have been published so far. A total of 110 transverse and 111 sagittal diameters from Central European male and female dry specimens dating from the Pleistocene to modern times were measured, and related to sex, age, stature, ethnicity, and a possible secular trend. Only a moderate positive correlation between the transverse and the sagittal diameter of the foramen magnum was found. Surprisingly, neither sexual dimorphism, individual age-dependency, nor a secular trend was found for either diameter. Furthermore, the relationship between the individual stature and foramen magnum diameters was weak: thus foramen magnum size cannot be used as reliable indicator for stature estimation. Further consideration of possible factors influencing the variability of human foramen magnum size shall be explored in larger and geographically more diverse samples, thus serving forensic, clinical, anatomical, and anthropological interests in this body part. PMID- 19777567 TI - Cold-inducible RNA-binding protein contributes to human antigen R and cyclin E1 deregulation in breast cancer. AB - The cell cycle regulator cyclin E1 is aberrantly expressed in a variety of human cancers. In breast cancer, elevated cyclin E1 correlates with poor outcome, as do high cytoplasmic levels of the stress-induced RNA-binding protein human antigen R (HuR). We showed previously that increased cytoplasmic HuR elevates cyclin E1 in MCF-7 breast cancer cells by stabilizing its mRNA. We show here that cold inducible RNA-binding protein (CIRP) co-regulates cyclin E1 with HuR in breast cancer cells. CIRP had been shown to interact with HuR in Xenopus laevis oocytes and to be decreased in endometrial cancer. To investigate if human CIRP and HuR co-regulate cyclin E1, HuR and CIRP levels were altered in MCF-7 cells and effects on cyclin E1 assessed. Altering HuR expression resulted in a reciprocal change in CIRP expression, while altering CIRP expression resulted in corresponding changes in HuR and cyclin E1 expression. CIRP and HuR co precipitated in the presence of RNA and CIRP enhanced HuR binding to the cyclin E1 mRNA and increased cyclin E1 mRNA stability. CIRP co-localized with HuR predominantly in the nucleus, but also in discrete cytoplasmic foci identified as stress granules (SGs). CIRP overexpression increased the number of HuR-containing SGs, while its knockdown decreased them. Our results suggest that CIRP positively regulates HuR, ultimately resulting in increased protein synthesis of at least one of its targets. PMID- 19777569 TI - Optic foramen morphology and activity pattern in birds. AB - The optic nerve is the sole output of visual information from the ganglion cell layer of the retina to the brain in vertebrates. The size of the optic nerve is predicted to be closely associated with activity pattern, and, in many birds, the size of the optic foramen approximates the size of the optic nerve. Specifically, nocturnal species should have relatively smaller optic foramina than diurnal species because of differences in retinal pooling between activity patterns. If optic foramen morphology varies predictably with activity pattern in birds, this variable may be useful for interpreting activity pattern for birds that do not have soft tissue available for study, specifically for fossils. Across 177 families (from 27 orders), we describe four different optic foramen morphologies, only one of which corresponds well with the size of the optic nerve and is therefore appropriate for activity pattern analyses. Here, we test our hypothesis that nocturnal species will have relatively smaller optic foramina than diurnal species, across all species that we measured that have a discrete optic foramen. Regression analyses using species as independent data points and using comparative methods yielded significant differences in optic foramen size between nocturnal and diurnal species relative to three variables: head length, orbit depth, and sclerotic ring inner diameter. Nocturnal species consistently exhibit significantly smaller relative optic foramen diameters than diurnal species. Our results indicate that optic foramen diameter, in combination with either the sclerotic ring or the orbit diameter, can be used to predict activity pattern. PMID- 19777570 TI - 1H-NMR spectroscopic study of the effect of aging vascular prostheses made of poly(ethylene terephthalate) on the macromolecular weight. AB - Trichloroacetyl isocyanate reacts rapidly and quantitatively with both acid and hydroxyl chain ends to form derivatives that can be readily determined by (1)H NMR spectroscopy. This method provides a convenient mean for characterization of polyethylene terephthalate (PET) end-groups. The (1)H-NMR spectroscopy has been applied to describe the chemical aging of the PET vascular prostheses by determination of the hydroxyl and carboxyl end-group concentrations and therefore the macromolecular weight. To validate (1)H-NMR results, we used chemical titration of the end-groups and classical viscosimetric method as complementary techniques. The analyses made on the explants of different lifetime demonstrated a significant deterioration compared with the virgin prostheses. A high degradation of macromolecular weight is observed. This phenomenon is explained by a random scission of the ester linkages. PMID- 19777571 TI - Close mimicry of lung surfactant protein B by "clicked" dimers of helical, cationic peptoids. AB - A family of peptoid dimers developed to mimic SP-B is presented, where two amphipathic, cationic helices are linked by an achiral octameric chain. SP-B is a vital therapeutic protein in lung surfactant replacement therapy, but its large scale isolation or chemical synthesis is impractical. Enhanced biomimicry of SP B's disulfide-bonded structure has been previously attempted via disulfide mediated dimerization of SP-B(1-25) and other peptide mimics, which improved surface activity relative to the monomers. Herein, the effects of disulfide- or "click"-mediated (1,3-dipolar cycloaddition) dimerization, as well as linker chemistry, on the lipid-associated surfactant activity of a peptoid monomer are described. Results revealed that the 'clicked' peptoid dimer enhanced in vitro surface activity in a DPPC:POPG:PA lipid film relative to its disulfide-bonded and monomeric counterparts in both surface balance and pulsating bubble surfactometry studies. On the pulsating bubble surfactometer, the film containing the "clicked" peptoid dimer outperformed all presented peptoid monomers and dimers, and two SP-B derived peptides, attaining an adsorbed surface tension of 22 mN m(-1), and maximum and minimum cycling values of 42 mN m(-1) and near-zero, respectively. PMID- 19777572 TI - Fluorescence spectroscopy of H-ras transfected murine fibroblasts: a comparison with Monte Carlo simulations. AB - Autofluorescence properties of tissues have been widely used to diagnose various types of malignancies. In this study, we measured the autofluorescence properties of H-ras transfected murine fibroblasts and the counterpart control cells. The pair of cells is genetically identical except for the transfected H-ras gene. We applied Monte Carlo simulations to evaluate the relative contributions of Rayleigh and Mie scattering effects towards fluorescence in an in vitro model system of normal and H-ras transfected fibroblasts. The experimental results showed that fluorescence emission intensity was higher for normal cells than the malignant counterpart cells by about 30%. In normal cells, linearity in emission intensity was observed for cell densities of up to 1.0 x 10(6) cells/ml whereas for transformed cells it was up to 1.4 x 10(6) cells/ml. Nuclear volume changes give good account for the differences in the intrinsic fluorescence between normal and malignant cells. The Monte Carlo (MC) code, newly developed for this study, explains both predominant experimental features: the large fluorescence intensity differences between the transfected and the corresponding control cells as well as the phenomena of the red shift in the excitation spectra as a function of cell density. The contribution of Rayleigh scattering was found to be predominant compared to Mie scattering. PMID- 19777573 TI - Evaluation of the immunogenicity and cell compatibility of avian collagen for biomedical applications. AB - There have been concerns regarding the suitability of bovine collagen as a biomaterial since the emergence of bovine spongiform encephalopathy. Consequently, collagens from other species may be used if they can meet appropriate standards, including negligible or lack of immunogenicity. In this study, the potential immunogenicity of both monomeric and pepsin-solubilized chicken collagens have been compared with a commercial, pepsin-solubilized bovine collagen that is approved for biomedical implantation. All collagens were poor immunogens compared with ovalbumin. No IgE responses were detected in sera of three strains of mice, and no hypersensitivity reactions were found in guinea pigs in maximization and Buehler tests. IgG(1) antibodies were found although the titre was substantially lower than against ovalbumin. All responses in mice and rabbits were found only when immunizations were performed with adjuvant, and after multiple injections over a long period of time. The response from the monomeric chicken collagen was less than for pepsin-solubilized collagens. Collagen sponges prepared from the two chicken collagen preparations both supported the attachment and growth of mouse fibroblasts. These data indicate that chicken collagen, particularly when monomeric, may be useful in certain biomedical applications. PMID- 19777574 TI - Ceramic/polymer nanocomposites with tunable drug delivery capability at specific disease sites. AB - Pharmaceutical agents are often used to stimulate new bone formation for the treatment of bone injuries or diseases (such as osteoporosis). However, there are several problems associated with current orthopedic drug delivery methods. First, conventional systemic administration of pharmaceutical agents may not effectively reach targeted sites and, thus, they can cause nonspecific bone formation in areas not affected by injury or disease. Second, even if intentionally delivered or implanted locally to the damaged bone tissue, these agents tend to rapidly diffuse into adjacent tissues due to weak physical bonding to their drug carriers, which limits their potential to promote prolonged bone formation in targeted areas of bone disease. Therefore, in this study, biodegradable ceramic/polymer nanocomposites were explored as novel drug carriers for orthopedic applications to prolong local drug release and, thus, improve drug effectiveness at bone disease sites. Specifically, a bone morphogenetic protein (BMP-7) derived peptide (DIF-7c) was used as a model drug in this study and was first loaded onto nanocrystalline hydroxyapatite (nano-HA) by either covalent chemical attachment or physical adsorption. These drug-carrying nano-HA particles were then dispersed into a degradable polymer (poly-lactide-co-glycolide or PLGA) matrix to create an implantable system capable of long-term drug release. The aminophase silane covalent chemical immobilization process was utilized in this study. These nanocomposite-based drug delivery systems were then characterized for drug loading efficiency and in vitro drug release. Results demonstrated that DIF-7c was successfully immobilized onto nano-HA placed in PLGA. Moreover, a greater prolonged two-phase release profile (of more than 3 months) was achieved when using aminophase silane chemical immobilization to nano-HA particles. Since previous studies have demonstrated greater in vivo bone growth on nano- compared with micron-HA particles placed in rat calvaria, this study continued to demonstrate that ceramic/polymer nanocomposites are promising candidates as novel orthopedic materials to promote bone regeneration. PMID- 19777575 TI - Functionalization of chitosan/poly(lactic acid-glycolic acid) sintered microsphere scaffolds via surface heparinization for bone tissue engineering. AB - Scaffolds exhibiting biological recognition and specificity play an important role in tissue engineering and regenerative medicine. The bioactivity of scaffolds in turn influences, directs, or manipulates cellular responses. In this study, chitosan/poly(lactic acid-co-glycolic acid) (chitosan/PLAGA) sintered microsphere scaffolds were functionalized via heparin immobilization. Heparin was successfully immobilized on chitosan/PLAGA scaffolds with controllable loading efficiency. Mechanical testing showed that heparinization of chitosan/PLAGA scaffolds did not significantly alter the mechanical properties and porous structures. In addition, the heparinized chitosan/PLAGA scaffolds possessed a compressive modulus of 403.98 +/- 19.53 MPa and a compressive strength of 9.83 +/ 0.94 MPa, which are in the range of human trabecular bone. Furthermore, the heparinized chitosan/PLAGA scaffolds had an interconnected porous structure with a total pore volume of 30.93 +/- 0.90% and a median pore size of 172.33 +/- 5.89 mum. The effect of immobilized heparin on osteoblast-like MC3T3-E1 cell growth was investigated. MC3T3-E1 cells proliferated three dimensionally throughout the porous structure of the scaffolds. Heparinized chitosan/PLAGA scaffolds with low heparin loading (1.7 microg/scaffold) were shown to be capable of stimulating MC3T3-E1 cell proliferation by MTS assay and cell differentiation as evidenced by elevated osteocalcin expression when compared with nonheparinized chitosan/PLAGA scaffold and chitosan/PLAGA scaffold with high heparin loading (14.1 microg/scaffold). This study demonstrated the potential of functionalizing chitosan/PLAGA scaffolds via heparinization with improved cell functions for bone tissue engineering applications. PMID- 19777576 TI - A common variant in MTHFD1L is associated with neural tube defects and mRNA splicing efficiency. AB - Polymorphisms in folate-related genes have emerged as important risk factors in a range of diseases including neural tube defects (NTDs), cancer, and coronary artery disease (CAD). Having previously identified a polymorphism within the cytoplasmic folate enzyme, MTHFD1, as a maternal risk factor for NTDs, we considered the more recently identified mitochondrial paralogue, MTHFD1L, as a candidate gene for NTD association. We identified a common deletion/insertion polymorphism, rs3832406, c.781-6823ATT(7-9), which influences splicing efficiency and is strongly associated with NTD risk. Three alleles of rs3832406 were detected in the Irish population with varying numbers of ATT repeats: Allele 1 consists of ATT(7), whereas Alleles 2 and 3 consist of ATT(8) and ATT(9), respectively. Allele 2 of this triallelic polymorphism showed a decreased case risk as demonstrated by case-control logistic regression (P=0.002) and by transmission disequilibrium test (TDT) (P=0.001), whereas Allele 1 showed an increased case risk. Allele 3 showed no influence on NTD risk and represents the lowest frequency allele (0.15). Additional single nucleotide polymorphism (SNP) genotyping in the same genomic region provides additional supportive evidence of an association. We demonstrate that two of the three alleles of rs3832406 are functionally different and influence the splicing efficiency of the alternate MTHFD1L mRNA transcripts. PMID- 19777577 TI - CC2D2A mutations in Meckel and Joubert syndromes indicate a genotype-phenotype correlation. AB - Meckel-Gruber syndrome (MKS) is a lethal fetal disorder characterized by diffuse renal cystic dysplasia, polydactyly, a brain malformation that is usually occipital encephalocele, and/or vermian agenesis, with intrahepatic biliary duct proliferation. Joubert syndrome (JBS) is a viable neurological disorder with a characteristic "molar tooth sign" (MTS) on axial images reflecting cerebellar vermian hypoplasia/dysplasia. Both conditions are classified as ciliopathies with an autosomal recessive mode of inheritance. Allelism of MKS and JBS has been reported for TMEM67/MKS3, CEP290/MKS4, and RPGRIP1L/MKS5. Recently, one homozygous splice mutation with a founder effect was reported in the CC2D2A gene in Finnish fetuses with MKS, defining the 6th locus for MKS. Shortly thereafter, CC2D2A mutations were also reported in JBS. The analysis of the CC2D2A gene in our series of MKS fetuses, identified 14 novel truncating mutations in 11 cases. These results confirm the involvement of CC2D2A in MKS and reveal a major contribution of CC2D2A to the disease. We also identified three missense CC2D2A mutations in two JBS cases. Therefore, and in accordance with the data reported regarding RPGRIP1L, our results indicate phenotype-genotype correlations, as missense and presumably hypomorphic mutations lead to JBS while all null alleles lead to MKS. PMID- 19777578 TI - Resting state and task-induced deactivation: A methodological comparison in patients with schizophrenia and healthy controls. AB - Changes in the default mode network (DMN) have been linked to multiple neurological disorders including schizophrenia. The anticorrelated relationship the DMN shares with task-related networks permits the quantification of this network both during task (task-induced deactivations: TID) and during periods of passive mental activity (extended rest). However, the effects of different methodologies (TID vs. extended rest) for quantifying the DMN in the same clinical population are currently not well understood. Moreover, several different analytic techniques, including independent component analyses (ICA) and seed-based correlation analyses, exist for examining functional connectivity during extended resting states. The current study compared both methodologies and analytic techniques in a group of patients with schizophrenia (SP) and matched healthy controls. Results indicated that TID analyses, ICA, and seed-based correlation all consistently identified the midline (anterior and posterior cingulate gyrus) and lateral parietal cortex as core regions of the DMN, as well as more variable involvement of temporal lobe structures. In addition, SP exhibited increased deactivation during task, as well as decreased functional connectivity with frontal regions and increased connectivity with posterior and subcortical areas during periods of extended rest. The increased posterior and reduced anterior connectivity may partially explain some of the cognitive dysfunction and clinical symptoms that are frequently associated with schizophrenia. PMID- 19777579 TI - Real-time imaging of the medullary circuitry involved in the generation of spontaneous muscle sympathetic nerve activity in awake subjects. AB - To understand the central neural processes involved in blood pressure regulation we recorded muscle sympathetic nerve activity (MSNA) via a tungsten microelectrode in the common peroneal nerve while performing functional magnetic resonance imaging (fMRI) of the brainstem at 3T. Blood oxygen level dependent (BOLD) changes in signal intensity were measured over 4 s every 8 s (200) volumes; MSNA was recorded during the previous 4 s epoch, which takes into account peripheral conduction delays along unmyelinated axons and neurovascular coupling delays. Analysis of temporal coupling between BOLD signal intensity and nerve signal intensity revealed sites in which the two signals covaried, but only in the medulla. Because scans were conducted in a caudorostral direction, we could constrain the analysis to the medulla by only examining the first 1 s of the fMRI and nerve signals. Increases in MSNA were associated with robust bilateral increases in signal intensity in the dorsolateral region of the medulla that corresponds to the human equivalent of the rostal ventrolateral medulla (RVLM). Reciprocal decreases in signal intensity occurred in the regions of the nucleus tractus solitarius (NTS) and caudal ventrolateral medulla (CVLM). Group analysis also revealed increases in signal intensity in the caudal pressor area (CPA), medullary raphe (MR), and dorsal motor nucleus of the vagus (DMX). We have shown for the first time that this combined approach of recording sympathetic neural activity and fMRI provides real-time imaging of the neural processes responsible for the generation of sympathetic nerve activity in awake human subjects. PMID- 19777580 TI - BAK and BAX deletion using zinc-finger nucleases yields apoptosis-resistant CHO cells. AB - Anoxic and metabolic stresses in large-scale cell culture during biopharmaceutical production can induce apoptosis. Strategies designed to ameliorate the problem of apoptosis in cell culture have focused on mRNA knockdown of pro-apoptotic proteins and over-expression of anti-apoptotic ones. Apoptosis in cell culture involves mitochondrial permeabilization by the pro apoptotic Bak and Bax proteins; activity of either protein is sufficient to permit apoptosis. We demonstrate here the complete and permanent elimination of both the Bak and Bax proteins in combination in Chinese hamster ovary (CHO) cells using zinc-finger nuclease-mediated gene disruption. Zinc-finger nuclease cleavage of BAX and BAK followed by inaccurate DNA repair resulted in knockout of both genes. Cells lacking Bax and Bak grow normally but fail to activate caspases in response to apoptotic stimuli. When grown using scale-down systems under conditions that mimic growth in large-scale bioreactors they are significantly more resistant to apoptosis induced by starvation, staurosporine, and sodium butyrate. When grown under starvation conditions, BAX- and BAK-deleted cells produce two- to fivefold more IgG than wild-type CHO cells. Under normal growth conditions in suspension culture in shake flasks, double-knockout cultures achieve equal or higher cell densities than unmodified wild-type cultures and reach viable cell densities relevant for large-scale industrial protein production. PMID- 19777581 TI - Computational study of the drag and oscillatory movement of biofilm streamers in fast flows. AB - Hydrodynamic conditions have a significant impact on the biofilm lifecycle. Not well understood is the fact that biofilms, in return, also affect the flow pattern. A decade ago, it was already shown experimentally that under fast flows, biofilm streamers form and oscillate with large amplitudes. This work is a first attempt to answer the questions on the mechanisms behind the oscillatory movement of the streamers, and whether this movement together with the special streamlined form of the streamers, have both a physical and biological benefit for biofilms. In this study, a state of the art two-dimensional fluid-structure interaction model of biofilm streamers is developed, which implements a transient coupling between the fluid and biofilm mechanics. Hereby, it is clearly shown that formation of a Karman vortex street behind the streamer body is the main source of the periodic oscillation of the streamers. Additionally it is shown that the formation of streamers reduces the fluid forces which biofilm surface experiences. PMID- 19777582 TI - An unbiased sensitivity analysis reveals important parameters controlling periodicity of circadian clock. AB - To assess the importance of model parameters in kinetic models, sensitivity analysis is generally employed to provide key measures. However, it is quite often that no information is available for a significant number of parameters in biochemical models. Therefore, the results of sensitivity analysis that heavily rely on the accuracy of parameters are largely ambiguous. In this study, we propose a computational approach to determine the relative importance of parameters controlling the performance of the circadian clock in Drosophila. While previous attempts to sensitivity analysis largely depend on the knowledge of model parameters which are generally unknown, our study depicts a consistent picture of sensitivity assessment for a large number of parameters, even when the values of these parameters are not available in vivo. The resulting parametric sensitivity analysis suggests that PER/TIM negative loop is critical to maintain the stable periodicity of the circadian clock, which is consistent to the previously experimental and computational findings. Furthermore, our analysis generates a rich hypothesis of important parameters in the circadian clock that can be further tested experimentally. This approach can also be extended to assess the sensitivity of parameters in any biochemical system where a large number of parameters have unknown values. PMID- 19777583 TI - Integrated solution to purification challenges in the manufacture of a soluble recombinant protein in E. coli. AB - Apolipoprotein A 1 Milano (ApoA-1M), the protein component of a high-density lipoprotein (HDL) mimic with promising potential for reduction of atherosclerotic plaque, is produced at large scale by expression in E. coli. Significant difficulty with clearance of host cell proteins (HCPs) was experienced in the original manufacturing process despite a lengthy downstream purification train. Analysis of purified protein solutions and intermediate process samples led to identification of several major HCPs co-purifying with the product and a bacterial protease potentially causing a specific truncation of ApoA-1M found in the final product. Deletion of these genes from the original host strain succeeded in substantially reducing the levels of HCPs and the truncated species without adversely affecting the overall fermentation productivity, contributing to a much more efficient and robust new manufacturing process. PMID- 19777584 TI - Metabolic flux analysis for recombinant protein production by Pichia pastoris using dual carbon sources: Effects of methanol feeding rate. AB - The intracellular metabolic fluxes through the central carbon pathways in the bioprocess for recombinant human erythropoietin (rHuEPO) production by Pichia pastoris (Mut(+)) were calculated to investigate the metabolic effects of dual carbon sources (methanol/sorbitol) and the methanol feed rate, and to obtain a deeper understanding of the regulatory circuitry of P. pastoris, using the established stoichiometry-based model containing 102 metabolites and 141 reaction fluxes. Four fed-batch operations with (MS-) and without (M-) sorbitol were performed at three different constant specific growth rates (h(-1)), and denoted as M-0.03, MS-0.02, MS-0.03, and MS-0.04. Considering the methanol consumption pathway, the M-0.03 and MS-0.02 conditions produced similar effects and had >85% of formaldehyde flux towards the assimilatory pathway. In contrast, the use of the dual carbon source condition generated a shift in metabolism towards the dissimilatory pathway that corresponded to the shift in dilution rate from MS 0.03 to MS-0.04, indicating that the methanol feed exceeded the metabolic requirements at the higher micro(0). Comparing M-0.03 and MS-0.03 conditions, which had the same methanol feeding rates, sorbitol addition increased the rHuEPO synthetic flux 4.4-fold. The glycolysis, gluconeogenesis, and PPP pathways worked uninterruptedly only at MS-0.02 condition. PPP and TCA cycles worked with the highest disturbances at MS-0.04 condition, which shows the stress of increased feeding rates of methanol on cell metabolism. PMID- 19777585 TI - High stability of self-assembled peptide nanowires against thermal, chemical, and proteolytic attacks. AB - Understanding the self-assembly of peptides into ordered nanostructures is recently getting much attention since it can provide an alternative route for fabricating novel bio-inspired materials. In order to realize the potential of the peptide-based nanofabrication technology, however, more information is needed regarding the integrity or stability of peptide nanostructures under the process conditions encountered in their applications. In this study, we investigated the stability of self-assembled peptide nanowires (PNWs) and nanotubes (PNTs) against thermal, chemical, proteolytic attacks, and their conformational changes upon heat treatment. PNWs and PNTs were grown by the self-assembly of diphenylalanine (Phe-Phe), a peptide building block, on solid substrates at different chemical atmospheres and temperatures. The incubation of diphenylalanine under aniline vapor at 150 degrees C led to the formation of PNWs, while its incubation with water vapor at 25 degrees C produced PNTs. We analyzed the stability of peptide nanostructures using multiple tools, such as electron microscopy, thermal analysis tools, circular dichroism, and Fourier-transform infrared spectroscopy. Our results show that PNWs are highly stable up to 200 degrees C and remain unchanged when incubated in aqueous solutions (from pH 1 to 14) or in various chemical solvents (from polar to non-polar). In contrast, PNTs started to disintegrate even at 100 degrees C and underwent a conformational change at an elevated temperature. When we further studied their resistance to a proteolytic environment, we discovered that PNWs kept their initial structure while PNTs fully disintegrated. We found that the high stability of PNWs originates from their predominant beta-sheet conformation and the conformational change of diphenylalanine nanostructures. Our study suggests that self-assembled PNWs are suitable for future nano-scale applications requiring harsh processing conditions. PMID- 19777586 TI - Serum-free, chemically defined medium with TGF-beta(3) enhances functional properties of nucleus pulposus cell-laden carboxymethylcellulose hydrogel constructs. AB - Degeneration of the nucleus pulposus (NP) has been implicated as a major cause of low back pain. Tissue engineering strategies may provide a viable NP replacement therapy; however, culture conditions must be optimized to promote functional tissue development. In this study, a standard serum-containing medium formulation was compared to a chemically defined, serum-free medium to determine the effect on matrix elaboration and functional properties of NP cell-laden carboxymethylcellulose (CMC) hydrogels. Additionally, both media were further supplemented with transforming growth factor-beta 3 (TGF-beta(3)). Glycosaminoglycan (GAG) content increased in both TGF-beta(3)-treated groups and was highest for treated, serum-free constructs (9.46 +/- 1.51 microg GAG/mg wet weight), while there were no quantifiable GAGs in untreated serum-containing samples. Histology revealed uniform, interterritorial staining for chondroitin sulfate proteoglycan throughout the treated, serum-free constructs. Type II collagen content was greater in both serum-free groups and highest in treated, serum-free constructs. The equilibrium Young's modulus was highest in serum-free samples supplemented with TGF-beta(3) (18.54 +/- 1.92 kPa), and the equilibrium weight swelling ratio of these constructs approached that of the native NP tissue (22.19 +/- 0.46 vs. 19.94 +/- 3.09, respectively). Taken together, these results demonstrate enhanced functional matrix development by NP cells when cultured in CMC hydrogels maintained in serum-free, TGF-beta(3) supplemented medium, indicating the importance of medium formulation in NP construct development. PMID- 19777587 TI - Selective interaction between Trf3 and Taf3 required for early development and hematopoiesis. AB - In zebrafish, TATA-box-binding protein (TBP)-related factor 3, Trf3, is required for early development and initiation of hematopoiesis, and functions by promoting expression of a single target gene, mespa. Recent studies have shown that in murine muscle cells, TRF3 interacts with the TBP-associated factor TAF3. Here we investigate the role of Taf3 in zebrafish embryogenesis. We find that like Trf3 depleted zebrafish embryos, Taf3-depleted embryos exhibit multiple developmental defects and fail to undergo hematopoiesis. Both Trf3 and Taf3 are selectively bound to the mespa promoter and are required for mespa expression. Significantly, Taf3 interacts with Trf3 but not Tbp, and a Trf3 mutant that disrupts this interaction fails to support mespa transcription, early development, and hematopoiesis. Thus, a selective interaction between Trf3 and Taf3 is required for early zebrafish development and initiation of hematopoiesis. Finally, we provide evidence that TRF3 and TAF3 are also required for hematopoiesis initiation in the mouse. PMID- 19777588 TI - Surface-directed assembly of cell-laden microgels. AB - Cell-laden microscale hydrogels (microgels) can be used as tissue building blocks and assembled to create 3D tissue constructs with well-defined microarchitecture. In this article, we present a bottom-up approach to achieve microgel assembly on a patterned surface. Driven by surface tension, the hydrophilic microgels can be assembled into well-defined shapes on a glass surface patterned with hydrophobic and hydrophilic regions. We found that the cuboidic microgels ( approximately 100 200 microm in width) could self-assemble into defined shapes with high fidelity to the surface patterns. The microgel assembly process was improved by increasing the hydrophilicity of the microgels and reducing the surface tension of the surrounding solution. The assembled microgels were stabilized by a secondary crosslinking step. Assembled microgels containing cells stained with different dyes were fabricated to demonstrate the application of this approach for engineering microscale tissue constructs containing multiple cell types. This bottom-up approach enables rapid fabrication of cell-laden microgel assemblies with pre-defined geometrical and biological features, which is easily scalable and can be potentially used in microscale tissue engineering applications. PMID- 19777589 TI - Neural stem cell self-renewal requires the Mrj co-chaperone. AB - The Mrj co-chaperone is expressed throughout the mouse conceptus, yet its requirement for placental development has prohibited a full understanding of its embryonic function. Here, we show that Mrj(-/-) embryos exhibit neural tube defects independent of the placenta phenotype, including exencephaly and thin walled neural tubes. Molecular analyses revealed fewer proliferating cells and a down-regulation of early neural progenitor (Pax6, Olig2, Hes5) and neuronal (Nscl2, SCG10) cell markers in Mrj(-/-) neuroepithelial cells. Furthermore, Mrj( /-) neurospheres are significantly smaller and form fewer secondary neurospheres indicating that Mrj is necessary for self-renewal of neural stem cells. However, the molecular function of Mrj in this context remains elusive because Mrj does not colocalize with Bmi-1, a self-renewal protein. Furthermore, unlike in Mrj(-/ ) placentas, intermediate filament-containing aggregates do not accumulate in Mrj(-/-) neuroepithelium, ruling out nestin as a substrate for Mrj. Regardless, Mrj plays an important role in neural stem cell self-renewal. PMID- 19777591 TI - Retinoic acid receptors exhibit cell-autonomous functions in cranial neural crest cells. AB - Previous work has emphasized the crucial role of retinoic acid (RA) in the ontogenesis of the vast majority of mesenchymal structures derived from the neural crest cells (NCC), which migrate through, or populate, the frontonasal process and branchial arches. Using somatic mutagenesis in the mouse, we have selectively ablated two or three retinoic acid receptors (i.e., RARalpha/RARbeta, RARalpha/RARgamma and RARalpha/RARbeta/RARgamma) in NCC. By rigorously analyzing these mutant mice, we found that survival and migration of NCC is normal until gestational day 10.5, suggesting that RAR-dependent signaling is not intrinsically required for the early steps of NCC development. However, ablation of Rara and Rarg genes in NCC yields an agenesis of the median portion of the face, demonstrating that RARalpha and RARgamma act cell-autonomously in postmigratory NCC to control the development of structures derived from the frontonasal process. In contrast, ablation of the three Rar genes in NCC leads to less severe defects of the branchial arches derived structures compared with Rar compound null mutants. Therefore, RARs exert a function in the NCC as well as in a separated cell population. This work demonstrates that RARs use distinct mechanisms to pattern cranial NCC. PMID- 19777590 TI - Prdm1a is necessary for posterior pharyngeal arch development in zebrafish. AB - Multiple tissue interactions and signaling within the pharyngeal arches are required for development of the craniofacial skeleton. Here, we focus on the role of the transcription factor prdm1a in the differentiation of the posterior skeleton. prdm1a is expressed in the presumptive pharyngeal arch region and later in an endodermal pouch, the otic vesicle, and pharyngeal teeth. prdm1a mutants display a reduction in pharyngeal arch markers, a loss of posterior ceratobranchial cartilages, and a reduction in most neural crest-derived dermal bones. This is likely caused by a decrease in the number of proliferating cells but not an increase in cell death. Finally, a reduction in two key developmental signaling pathways, Fgf and retinoic acid, alters prdm1a expression, suggesting that prdm1a expression is mediated by these signaling pathways to pattern the posterior craniofacial skeleton. Together, these results indicate an essential role for prdm1a in the development of the zebrafish craniofacial skeleton. PMID- 19777592 TI - Altered hypoxia-inducible factor-1 alpha expression levels correlate with coronary vessel anomalies. AB - The outflow tract myocardium and other regions corresponding to the location of the major coronary vessels of the developing chicken heart, display a high level of hypoxia as assessed by the hypoxia indicator EF5. The EF5-positive tissues were also specifically positive for nuclear-localized hypoxia inducible factor-1 alpha (HIF-1alpha), the oxygen-sensitive component of the hypoxia inducible factor-1 (HIF-1) heterodimer. This led to our hypothesis that there is a "template" of hypoxic tissue that determines the stereotyped pattern of the major coronary vessels. In this study, we disturbed this template by altering ambient oxygen levels (hypoxia 15%; hyperoxia 75-40%) during the early phases of avian coronary vessel development, in order to alter tissue hypoxia, HIF-1alpha protein expression, and its downstream target genes without high mortality. We also altered HIF-1alpha gene expression in the embryonic outflow tract cardiomyocytes by injecting an adenovirus containing a constitutively active form of HIF-1alpha (AdCA5). We assayed for coronary anomalies using anti-alpha-smooth muscle actin immunohistology. When incubated under abnormal oxygen levels or injected with a low titer of the AdCA5, coronary arteries displayed deviations from their normal proximal connections to the aorta. These deviations were similar to known clinical anomalies of coronary arteries. These findings indicated that developing coronary vessels may be subject to a level of regulation that is dependent on differential oxygen levels within cardiac tissues and subsequent HIF-1 regulation of gene expression. PMID- 19777595 TI - High-throughput microarray profiling of cell wall polymers during hydrothermal pre-treatment of wheat straw. AB - Lignocellulosic plant material is potentially a sustainable source of fermentable sugars for bioethanol production. However, a barrier to this is the high resistance or recalcitrance of plant cell walls to be hydrolyzed. Therefore, a detailed knowledge of the structural features of plant cell walls that contribute to recalcitrance is important for improving the efficiency of bioethanol production. In this work we have used a technique known as Comprehensive Microarray Polymer Profiling (CoMPP) to analyze wheat straw before and after being subjected to hydrothermal pre-treatments at four different temperatures. The CoMPP technique combines the specificity of monoclonal antibodies with the high-throughput capacity of microarrays. Changes in the relative abundance of cell wall polysaccharides could be tracked during processing, and a reduction in xylan, arabinoxylans, xyloglucan, and mixed-linked glucan epitopes was detected at the two highest temperatures of pre-treatment used. This work demonstrates the potential of CoMPP as a complementally technique to conventional methods for analyzing biomass composition. PMID- 19777593 TI - An endoderm-specific transcriptional enhancer from the mouse Gata4 gene requires GATA and homeodomain protein-binding sites for function in vivo. AB - Several transcription factors function in the specification and differentiation of the endoderm, including the zinc finger transcription factor GATA4. Despite its essential role in endoderm development, the transcriptional control of the Gata4 gene in the developing endoderm and its derivatives remains incompletely understood. Here, we identify a distal enhancer from the Gata4 gene, which directs expression exclusively to the visceral and definitive endoderm of transgenic mouse embryos. The activity of this enhancer is initially broad within the definitive endoderm but later restricts to developing endoderm-derived tissues, including pancreas, glandular stomach, and duodenum. The activity of this enhancer in vivo is dependent on evolutionarily-conserved HOX- and GATA binding sites, which are bound by PDX-1 and GATA4, respectively. These studies establish Gata4 as a direct transcriptional target of homeodomain and GATA transcription factors in the endoderm and support a model in which GATA4 functions in the transcriptional network for pancreas formation. PMID- 19777596 TI - Evaluation of exchange-correlation functionals for time-dependent density functional theory calculations on metal complexes. AB - The electronic absorption spectra of a range of copper and zinc complexes have been simulated by using time-dependent density functional theory (TD-DFT) calculations implemented in Gaussian03. In total, 41 exchange-correlation (XC) functionals including first-, second-, and third-generation (meta-generalized gradient approximation) DFT methods were compared in their ability to predict the experimental electronic absorption spectra. Both pure and hybrid DFT methods were tested and differences between restricted and unrestricted calculations were also investigated by comparison of analogous neutral zinc(II) and copper(II) complexes. TD-DFT calculated spectra were optimized with respect to the experimental electronic absorption spectra by use of a Matlab script. Direct comparison of the performance of each XC functional was achieved both qualitatively and quantitatively by comparison of optimized half-band widths, root-mean-squared errors (RMSE), energy scaling factors (epsilon(SF)), and overall quality-of-fit (Q(F)) parameters. Hybrid DFT methods were found to outperform all pure DFT functionals with B1LYP, B97-2, B97-1, X3LYP, and B98 functionals providing the highest quantitative and qualitative accuracy in both restricted and unrestricted systems. Of the functionals tested, B1LYP gave the most accurate results with both average RMSE and overall Q(F) < 3.5% and epsilon(SF) values close to unity (>0.990) for the copper complexes. The XC functional performance in spin-restricted TD-DFT calculations on the zinc complexes was found to be slightly worse. PBE1PBE, mPW1PW91 and B1LYP gave the most accurate results with typical RMSE and Q(F) values between 5.3 and 7.3%, and epsilon(SF) around 0.930. These studies illustrate the power of modern TD-DFT calculations for exploring excited state transitions of metal complexes. PMID- 19777594 TI - Prx1 and Prx2 cooperatively regulate the morphogenesis of the medial region of the mandibular process. AB - Mice lacking both Prx1 and Prx2 display severe abnormalities in the mandible. Our analysis showed that complete loss of Prx gene products leads to growth abnormalities in the mandibular processes evident as early as embryonic day (E) 10.5 associated with changes in the survival of the mesenchyme in the medial region. Changes in the gene expression in the medial and lateral regions were related to gradual loss of a subpopulation of mesenchyme in the medial region expressing eHand. Our analysis also showed that Prx gene products are required for the initiation and maintenance of chondrogenesis and terminal differentiation of the chondrocytes in the caudal and rostral ends of Meckel's cartilage. The fusion of the mandibular processes in the Prx1/Prx2 double mutants is caused by accelerated ossification. These observations together show that, during mandibular morphogenesis, Prx gene products play multiple roles including the cell survival, the region-specific terminal differentiation of Meckelian chondrocytes and osteogenesis. PMID- 19777597 TI - Similarity/dissimilarity studies of protein sequences based on a new 2D graphical representation. AB - A (two-dimensional) 2D graphical representation of protein sequences based on six physicochemical properties of amino acids is outlined. The numerical characterization of protein graphs is given as descriptors of protein sequences. It is not only useful for comparative study of proteins but also for encoding innate information about the structure of proteins. The coefficient of determination is proposed as a new similarity/dissimilarity measure. Finally, a simple example is taken to highlight the behavior of the new similarity/dissimilarity measure on protein sequences taken from the ND6 (NADH dehydrogenase subunit 6) proteins for eight different species. The results demonstrate the approach is convenient, fast, and efficient. PMID- 19777598 TI - CHO gene expression profiling in biopharmaceutical process analysis and design. AB - Increase in both productivity and product yields in biopharmaceutical process development with recombinant protein producing mammalian cells can be mainly attributed to the advancements in cell line development, media, and process optimization. Only recently, genome-scale technologies enable a system-level analysis to elucidate the complex biomolecular basis of protein production in mammalian cells promising an increased process understanding and the deduction of knowledge-based approaches for further process optimization. Here, the use of gene expression profiling for the analysis of a low titer (LT) and high titer (HT) fed batch process using the same IgG producing CHO cell line was investigated. We found that gene expression (i) significantly differed in HT versus LT process conditions due to differences in applied chemically defined, serum-free media, (ii) changed over the time course of the fed batch processes, and that (iii) both metabolic pathways and 14 biological functions such as cellular growth or cell death were affected. Furthermore, detailed analysis of metabolism in a standard process format revealed the potential use of transcriptomics for rational media design as is shown for the case of lipid metabolism where the product titer could be increased by about 20% based on a lipid modified basal medium. The results demonstrate that gene expression profiling can be an important tool for mammalian biopharmaceutical process analysis and optimization. PMID- 19777599 TI - Analysis of exposed cellulose surfaces in pretreated wood biomass using carbohydrate-binding module (CBM)-cyan fluorescent protein (CFP). AB - In enzymatic saccharification of lignocellulosics, the access of the enzymes to exposed cellulose surfaces is a key initial step in triggering hydrolysis. However, knowledge of the structure-hydrolyzability relationship of the pretreated biomass is still limited. Here we used fluorescent-labeled recombinant carbohydrate-binding modules (CBMs) from Clostridium josui as specific markers for crystalline cellulose (CjCBM3) and non-crystalline cellulose (CjCBM28) to analyze the complex surfaces of wood tissues pretreated with NaOH, NaOH-Na(2)S (kraft pulping), hydrothermolysis, ball-milling, and organosolvolysis. Japanese cedar wood, one of the most recalcitrant softwood species was selected for the analysis. The binding analysis clarified the linear dependency of the exposure of crystalline and non-crystalline cellulose surfaces for enzymatic saccharification yield by the organosolv and kraft delignification processes. Ball-milling for 5 30 min increased saccharification yield up to 77%, but adsorption by the CjCBM cyan fluorescent proteins (CFPs) was below 5%. Adsorption of CjCBM-CFPs on the hydrothermolysis pulp were less than half of those for organosolvolysis pulp, in coincidence with low saccharification yields. For all the pretreated wood, crystallinity index was not directly correlated with the overall saccharification yield. Fluorescent microscopy revealed that CjCBM3-CFP and CjCBM28-CFP were site specifically adsorbed on external fibrous structures and ruptured or distorted fiber surfaces. The assay system with CBM-CFPs is a powerful measure to estimate the initiation sites of hydrolysis and saccharification yields from chemically delignified wood pulps. PMID- 19777600 TI - Green fiber lasers: an alternative to traditional DPSS green lasers for flow cytometry. AB - Green and yellow diode-pumped solid-state (DPSS) lasers (532 and 561 nm) have become common fixtures on flow cytometers, due to their efficient excitation of phycoerythrin (PE) and its tandems, and their ability to excite an expanding array of expressible red fluorescent proteins. Nevertheless, they have some disadvantages. DPSS 532-nm lasers emit very close to the fluorescein bandwidth, necessitating optical modifications to permit detection of fluorescein and GFP. DPSS 561-nm lasers likewise emit very close to the PE detection bandwidth and also cause unwanted excitation of APC and its tandems, requiring high levels of crossbeam compensation to reduce spectral overlap into the PE tandems. In this article, we report the development of a new generation of green fiber lasers that can be engineered to emit in the range between 532 and 561 nm. A 550-nm green fiber laser was integrated into both a BD LSR II cuvette and FACSVantage DiVa jet in-air cell sorter. This laser wavelength avoided both the fluorescein and PE bandwidths and provided better excitation of PE and the red fluorescent proteins DsRed and dTomato than a power-matched 532 nm source. Excitation at 550 nm also caused less incidental excitation of APC and its tandems, reducing the need for crossbeam compensation. Excitation in the 550 nm range, therefore, proved to be a good compromise between 532- and 561-nm sources. Fiber laser technology is, therefore, providing the flexibility necessary for precisely matching laser wavelengths to our flow cytometry applications. PMID- 19777601 TI - Variants of folate metabolism genes and risk of left-sided cardiac defects. AB - BACKGROUND: Congenital heart defects (CHDs) are the most common, serious group of birth defects. Although relatively little is known about the causes of these conditions and there are no established prevention strategies, evidence suggests that the risk of CHDs may be related to maternal folate status as well as genetic variants in folate-related genes. Efforts to establish the relationships between these factors and CHD risk have, however, been hampered by a number of factors, including small study sample sizes and phenotypic heterogeneity. METHODS: The present study examined the relationship between nine genetic variants in eight folate-related genes and a relatively homogeneous group of left-sided cardiac defects in a cohort of 386 case-parent triads. Log-linear analyses were used to assess both maternal and inherited genetic effects. RESULTS: Analyses of the study data provided marginal evidence that the maternal MTR A2756G (unadjusted p = 0.01) and the inherited BHMT G742A (unadjusted p = 0.06) genotypes influence the risk of this subset of CHDs. However, neither association achieved significance when the false-discovery rate was controlled at 0.05. CONCLUSIONS: These results, which are based on the largest study sample and most comprehensive assessment of the relationship between left-sided cardiac defects and folate related genes reported to date, provide little evidence that this subset of CHDs is folate related. However, even larger studies and more comprehensive evaluations of the folate pathway genes are required to fully explore the relationship between folate and left-sided cardiac defects. PMID- 19777602 TI - Sterile granuloma formation following radial artery facilitated coronary catheterization. PMID- 19777603 TI - Interatrial shunt closure devices in patients with nickel allergy. AB - We assessed outcomes in nickel allergic patients treated with percutaneous interatrial shunt device closure with the Helex device. Nickel toxicity has been well described in patients undergoing interatrial shunt closure with the Amplatzer device, which has a nitinol design. There have been no reports using Helex in nickel allergic patients. Ninety-five consecutive patients underwent percutaneous interatrial shunt closure at a single US center by one operator. In those with possible nickel allergy, patch testing with the North American Contact Dermatitis Group standard series and a metal series was performed. The mean age was 48 +/- 16 years (range 18-81), 48% were male, 21 (22%) had atrial septal defect, and 74 (78%) had patent foramen ovale. Six patients had a positive skin test to nickel and underwent successful closure with Helex. Of the remaining 89 patients, 88 were closed with Amplatzer and one with Helex. All procedures were successful with no deaths, myocardial infarctions, strokes, or systemic emboli at six-month followup. None of the Helex patients developed an allergic reaction, significant chest pain, or arrhythmia. Of those without pre-procedural known nickel allergy, 12% had palpitations, 5% had atrial fibrillation, and 13% had chest pain. When compared with a published report that 89% of nickel-allergic patients developing an allergic reaction to the Amplatzer or Premere device, Helex appeared far safer in nickel allergic patients (P < 0.001). In patients with nickel allergy, percutaneous interatrial shunt device closure with Helex device is safe, and is not associated with allergy to nickel. PMID- 19777604 TI - Balloon mitral valvotomy in patients with mitral stenosis and left atrial thrombus. AB - OBJECTIVES: To evaluate the safety and efficacy of balloon mitral valvotomy (BMV) in symptomatic rheumatic mitral stenosis (MS) patients with left atrial (LA) thrombus and to address the technical issues. BACKGROUND: LA thrombus in patients with MS has long been regarded as a contraindication for BMV. There are few reports of BMV in presence of LA appendage (LAA) thrombus and reports of BMV in presence of LA body thrombus are still rare. METHODS: 2,763 patients with suitable valve morphology were screened for BMV. 194 patients had LA/LAA thrombus and were put on adequate anticoagulation for 8-12 weeks. A total of 108 patients with persistent LA thrombus who satisfied the inclusion criteria (LA thrombus type Ia, Ib, and IIa) formed the study group and the remaining 2,622 patients who did not have any LA thrombus constituted the control group. All patients in the study group underwent BMV by modified over the wire technique. RESULTS: There was significant and comparable improvement in the mitral valve area, mitral valve gradient, LA mean and pulmonary artery systolic pressure following the procedure in both groups. In the study group, there were no thromboembolic episodes during the procedure. However, there was one case of transient ischemic attack in the study group which occurred 6 hr after a successful BMV. In the study group, one patient had cardiac tamponade needing aspiration and there was no in-hospital death. CONCLUSIONS: In selected patients of mitral stenosis with LA thrombus (type Ia, Ib, and IIa), BMV can be performed safely with the modified over the wire technique. Systemic thromboembolism, technical failures and other complications are very rare when performed by experienced operators. PMID- 19777605 TI - Artichoke leaf extract reduces oxidative stress and lipoprotein dyshomeostasis in rats fed on high cholesterol diet. AB - Hypercholesterolemia and lipid peroxidation play complementary role in atherosclerosis. Artichoke leaf extract (ALE) is rich in natural antioxidants and has a cholesterol-reducing effect. However, there is no study investigating the effect of ALE on lipid levels and lipid peroxidation in experimental hypercholesterolemic conditions. Rats were fed on 4% (w/w) cholesterol and 1% (w/w) cholic acid supplemented diet for 1 month. ALE (1.5 g/kg/day) was given by gavage during the last 2 weeks. Serum lipid composition, malondialdehyde (MDA) and diene conjugate (DC) levels and plasma antioxidant activity (AOA) were measured. In addition, endogenous DC and copper-induced MDA levels were determined in apo B-containing lipoproteins (LDL+VLDL fraction). Serum cholesterol and triglyceride levels and the ratio of cholesterol to HDL cholesterol decreased due to ALE treatment in rats fed on HC diet. Significant decreases in serum MDA and DC levels and increases in plasma AOA were detected in serum in ALE-treated hypercholesterolemic rats. Endogenous DC and copper-induced MDA levels were also lower in LDL+VLDL fraction due to ALE-treatment in hypercholesterolemic rats. Our results indicate that ALE may be useful for the prevention of hypercholesterolemia-induced pro-oxidant state in LDL+VLDL fraction and the reduction of increased serum cholesterol and triglyceride levels. PMID- 19777606 TI - Antioxidant therapy in the management of acute, chronic and post-ERCP pancreatitis: a systematic review. AB - We systematically reviewed the clinical trials which recruited antioxidants in the therapy of pancreatitis and evaluated whether antioxidants improve the outcome of patients with pancreatitis. Electronic bibliographic databases were searched for any studies which investigated the use of antioxidants in the management of acute pancreatitis (AP) or chronic pancreatitis (CP) and in the prevention of post-endoscopic retrograde cholangio-pancreatography (post-ERCP) pancreatitis (PEP) up to February 2009. Twenty-two randomized, placebo controlled, clinical trials met our criteria and were included in the review. Except for a cocktail of antioxidants which showed improvement in outcomes in three different clinical trials, the results of the administration of other antioxidants in both AP and CP clinical trials were incongruent and heterogeneous. Furthermore, antioxidant therapy including allopurinol and N acetylcysteine failed to prevent the onset of PEP in almost all trials. In conclusion, the present data do not support a benefit of antioxidant therapy alone or in combination with conventional therapy in the management of AP, CP or PEP. Further double blind, randomized, placebo-controlled clinical trials with large sample size need to be conducted. PMID- 19777607 TI - Adenosine: an immune modulator of inflammatory bowel diseases. AB - Inflammatory bowel disease (IBD) is a common and lifelong disabling gastrointestinal disease. Emerging treatments are being developed to target inflammatory cytokines which initiate and perpetuate the immune response. Adenosine is an important modulator of inflammation and its anti-inflammatory effects have been well established in humans as well as in animal models. High extracellular adenosine suppresses and resolves chronic inflammation in IBD models. High extracellular adenosine levels could be achieved by enhanced adenosine absorption and increased de novo synthesis. Increased adenosine concentration leads to activation of the A2a receptor on the cell surface of immune and epithelial cells that would be a potential therapeutic target for chronic intestinal inflammation. Adenosine is transported via concentrative nucleoside transporter and equilibrative nucleoside transporter transporters that are localized in apical and basolateral membranes of intestinal epithelial cells, respectively. Increased extracellular adenosine levels activate the A2a receptor, which would reduce cytokines responsible for chronic inflammation. PMID- 19777608 TI - Iron increases HMOX1 and decreases hepatitis C viral expression in HCV-expressing cells. AB - AIM: To investigate effects of iron on oxidative stress, heme oxygenase-1 (HMOX1) and hepatitis C viral (HCV) expression in human hepatoma cells stably expressing HCV proteins. METHODS: Effects of iron on oxidative stress, HMOX1, and HCV expression were assessed in CON1 cells. Measurements included mRNA by quantitative reverse transcription-polymerase chain reaction, and protein levels by Western blots. RESULTS: Iron, in the form of ferric nitrilotriacetate, increased oxidative stress and up-regulated HMOX1 gene expression. Iron did not affect mRNA or protein levels of Bach1, a repressor of HMOX1. Silencing the up regulation of HMOX1 nuclear factor-erythroid 2-related factor 2 (Nrf2) by Nrf2 siRNA decreased FeNTA-mediated up-regulation of HMOX1 mRNA levels. These iron effects were completely blocked by deferoxamine (DFO). Iron also significantly decreased levels of HCV core mRNA and protein by 80%-90%, nonstructural 5A mRNA by 90% and protein by about 50% in the Con1 full length HCV replicon cells, whereas DFO increased them. CONCLUSION: Excess iron up-regulates HMOX1 and down regulates HCV gene expression in hepatoma cells. This probably mitigates liver injury caused by combined iron overload and HCV infection. PMID- 19777609 TI - EGFR and HER2 expression in advanced biliary tract cancer. AB - AIM: To analyze the pathogenetic role and potential clinical usefulness of the epidermal growth factor receptor (EGFR) and the human epidermal growth factor receptor 2 (HER2) in patients with advanced biliary tract cancer (BTC). METHODS: EGFR and HER2 expression was studied in biopsy samples from 124 patients (51% women; median age 64.8 years), with advanced BTC diagnosed between 1997 and 2004. Five micrometers sections of paraffin embedded tissue were examined by standard, FDA approved immunohistochemistry. Tumors with scores of 2+ or 3+ for HER2 expression on immunochemistry were additionally tested for HER2 gene amplification by fluorescence in situ hybridisation (FISH). RESULTS: 34/124 patients (27.4%) had gallbladder cancer, 47 (37.9%) had intrahepatic BTC and 43 (34.7%) had extrahepatic or perihilar BTC. EGFR expression was examined in a subset of 56 samples. EGFR expression was absent in 22/56 tumors (39.3%). Of the remaining samples expression was scored as 1+ in 12 (21.5%), 2+ in 13 (23.2%) and 3+ in 9 (16%), respectively. HER2 expression was as follows: score 0 73/124 (58.8%), score 1+ 27/124 (21.8%), score 2+ 21/124 (17%) and score 3+ 4/124 (3.2%). HER2 gene amplification was present in 6/124, resulting in an overall amplification rate of 5%. CONCLUSION: Our data suggest that routine testing and therapeutic targeting of HER2 does not seem to be useful in patients with BTC, while targeting EGFR may be promising. PMID- 19777610 TI - Protein interaction network related to Helicobacter pylori infection response. AB - AIM: To understand the complex reaction of gastric inflammation induced by Helicobacter pylori (H pylori) in a systematic manner using a protein interaction network. METHODS: The expression of genes significantly changed on microarray during H pylori infection was scanned from the web literary database and translated into proteins. A network of protein interactions was constructed by searching the primary interactions of selected proteins. The constructed network was mathematically analyzed and its biological function was examined. In addition, the nodes on the network were checked to determine if they had any further functional importance or relation to other proteins by extending them. RESULTS: The scale-free network showing the relationship between inflammation and carcinogenesis was constructed. Mathematical analysis showed hub and bottleneck proteins, and these proteins were mostly related to immune response. The network contained pathways and proteins related to H pylori infection, such as the JAK STAT pathway triggered by interleukins. Activation of nuclear factor (NF)-kappaB, TLR4, and other proteins known to function as core proteins of immune response were also found. These immune-related proteins interacted on the network with pathways and proteins related to the cell cycle, cell maintenance and proliferation, and transcription regulators such as BRCA1, FOS, REL, and zinc finger proteins. The extension of nodes showed interactions of the immune proteins with cancer-related proteins. One extended network, the core network, a summarized form of the extended network, and cell pathway model were constructed. CONCLUSION: Immune-related proteins activated by H pylori infection interact with proto-oncogene proteins. The hub and bottleneck proteins are potential drug targets for gastric inflammation and cancer. PMID- 19777611 TI - Attenuation of portal hypertension by natural taurine in rats with liver cirrhosis. AB - AIM: To investigate the inhibitory effect of natural taurine (NTau) on portal hypertension (PHT) in rats with experimentally-induced liver cirrhosis (LC). METHODS: Experimentally-induced LC Wistar rats (20 rats/group) were treated with either oral saline or oral NTau for 6 consecutive weeks. Evaluation parameters included portal venous pressure (PVP), portal venous resistance (PVR), portal venous flow (PVF), splanchnic vascular resistance (SVR) and mean arterial pressure (MAP). Vasoactive substance levels including nitric oxide (NO), nitric oxide synthase (NOS) and cyclic guanosine monophosphate (cGMP) were also measured. Histological investigation of type I and III collagen (COL I and III) and transforming growth factor-beta(1) (TGF-beta1) was also performed. RESULTS: Treatment with NTau (1) significantly decreased PVP, PVR and PVF, and increased MAP and SVP; (2) markedly increased the vascular compliance and reduced the zero stress of the portal vein; (3) markedly decreased the amount of NO and cGMP and activity of NOS; and (4) improved the pathological status of the liver tissue and reduced the expression of COL I, COL III and TGF-beta1. CONCLUSION: NTau inhibited the LC-induced PHT by improving hyperdynamic circulation, morphology of liver and biomechanical properties of the portal vein in experimentally-induced LC rats. PMID- 19777613 TI - Effects of lysophosphatidic acid on human colon cancer cells and its mechanisms of action. AB - AIM: To study the effects of lysophosphatidic acid (LPA) on proliferation, adhesion, migration, and apoptosis in the human colon cancer cell line, SW480, and its mechanisms of action. METHODS: Methyl tetrazolium assay was used to assess cell proliferation. Flow cytometry was employed to detect cell apoptosis. Cell migration was measured by using a Boyden transwell migration chamber. Cell adhesion assay was performed in 96-well plates according to protocol. RESULTS: LPA significantly stimulated SW480 cell proliferation in a dose-dependent and time-dependent manner compared with the control group (P < 0.05) while the mitogen-activated protein kinase (MAPK) inhibitor, PD98059, significantly blocked the LPA stimulation effect on proliferation. LPA also significantly stimulated adhesion and migration of SW480 cells in a dose-dependent manner (P < 0.05). Rho kinase inhibitor, Y-27632, significantly inhibited the up-regulatory effect of LPA on adhesion and migration (P < 0.05). LPA significantly protected cells from apoptosis induced by the chemotherapeutic drugs, cisplatin and 5-FU (P < 0.05), but the phosphoinositide 3-kinase (PI3K) inhibitor, LY294002, significantly blocked the protective effect of LPA on apoptosis. CONCLUSION: LPA stimulated proliferation, adhesion, migration of SW480 cells, and protected from apoptosis. The Ras/Raf-MAPK, G12/13-Rho-RhoA and PI3K-AKT/PKB signal pathways may be involved. PMID- 19777612 TI - Induction of apoptosis and cell cycle arrest in human HCC MHCC97H cells with Chrysanthemum indicum extract. AB - AIM: To investigate the effects of Chrysanthemum indicum extract (CIE) on inhibition of proliferation and on apoptosis, and the underlying mechanisms, in a human hepatocellular carcinoma (HCC) MHCC97H cell line. METHODS: Viable rat hepatocytes and human endothelial ECV304 cells were examined by trypan blue exclusion and MTT assay, respectively, as normal controls. The proliferation of MHCC97H cells was determined by MTT assay. The cellular morphology of MHCC97H cells was observed by phase contrast microscopy. Flow cytometry was performed to analyze cell apoptosis with annexin V/propidium iodide (PI), mitochondrial membrane potential with rhodamine 123 and cell cycle with PI in MHCC97H cells. Apoptotic proteins such as cytochrome C, caspase-9, caspase-3 and cell cycle proteins, including P21 and CDK4, were measured by Western blotting. RESULTS: CIE inhibited proliferation of MHCC97H cells in a time- and dose-dependent manner without cytotoxicity in rat hepatocytes and human endothelial cells. CIE induced apoptosis of MHCC97H cells in a concentration-dependent manner, as determined by flow cytometry. The apoptosis was accompanied by a decrease in mitochondrial membrane potential, release of cytochrome C and activation of caspase-9 and caspase-3. CIE arrested the cell cycle in the S phase by increasing P21 and decreasing CDK4 protein expression. CONCLUSION: CIE exerted a significant apoptotic effect through a mitochondrial pathway and arrested the cell cycle by regulation of cell cycle-related proteins in MHCC97H cells without an effect on normal cells. The cancer-specific selectivity shown in this study suggests that the plant extract could be a promising novel treatment for human cancer. PMID- 19777614 TI - Early graft dysfunction following adult-to-adult living-related liver transplantation: predictive factors and outcomes. AB - AIM: To describe a condition that we define as early graft dysfunction (EGD) which can be identified preoperatively. METHODS: Small-for-size graft dysfunction following living-related liver transplantation (LRLT) is characterized by EGD when the graft-to-recipient body weight ratio (GRBWR) is below 0.8%. However, patients transplanted with GRBWR above 0.8% can develop dysfunction of the graft. In 73 recipients of LRLT (GRBWR > 0.8%), we identified 10 patients who developed EGD. The main measures of outcomes analyzed were overall mortality, number of re transplants and length of stay in days (LOS). Furthermore we analyzed other clinical pre-transplant variables, intra-operative parameters and post transplant data. RESULTS: A trend in favor of the non-EGD group (3-mo actuarial survival 98% vs 88%, P = 0.09; 3-mo graft mortality 4.7% vs 20%, P = 0.07) was observed as well as shorter LOS (13 d vs 41.5 d; P = 0.001) and smaller requirement of peri operative Units of Plasma (4 vs 14; P = 0.036). Univariate analysis of pre transplant variables identified platelet count, serum bilirubin, INR and Meld-Na score as predictors of EGD. In the multivariate analysis transplant Meld-Na score (P = 0.025, OR: 1.175) and pre-transplant platelet count (P = 0.043, OR: 0.956) were independently associated with EGD. CONCLUSION: EGD can be identified preoperatively and is associated with increased morbidity after LRLT. A prompt recognition of EGD can trigger a timely treatment. PMID- 19777615 TI - COX-2 polymorphisms -765G-->C and -1195A-->G and colorectal cancer risk. AB - AIM: To determine the possible modulating effect of the COX-2 polymorphisms, 765G-->C and -1195A-->G, on the risk of colorectal cancer (CRC) in a Dutch population. METHODS: This case-control study includes 326 patients with CRC and 369 age- and gender-matched controls. Genotypes of the COX-2 polymorphisms -765G- >C and -1195A-->G were determined by polymerase chain reaction-based restriction fragment length polymorphism. COX-2 genotypes and haplotypes were analyzed and odds ratios with 95% confidence intervals were estimated by logistic regression. RESULTS: The -765GG genotype was associated with an increased risk of developing CRC (OR, 1.45; 95% CI, 1.03-2.04). No significant difference was observed in the genotype distribution of the -1195A-->G polymorphism between patients and controls. The GG/AC haplotype was present significantly less often in patients than in controls (OR 0.44; 95% CI, 0.22-0.85). When the AC, AG and GG haplotypes were investigated separately, the AC haplotype showed a tendency to be less frequent in patients than in controls (OR((AG/AC)) 0.78; 95% CI, 0.57-1.06). CONCLUSION: The -765GG genotype is associated with an increased risk of developing CRC and the GG/AC haplotype seems to protect against CRC. These findings suggest a modulating role for the COX-2 polymorphisms -765G-->C and 1195A-->G in the development of CRC in a Dutch population. PMID- 19777616 TI - Lack of correlation between p53 codon 72 polymorphism and anal cancer risk. AB - AIM: To investigate the potential role of p53 codon 72 polymorphism as a risk factor for development of anal cancer. METHODS: Thirty-two patients with invasive anal carcinoma and 103 healthy blood donors were included in the study. p53 codon 72 polymorphism was analyzed in blood samples through polymerase chain reaction restriction fragment length polymorphism and DNA sequencing. RESULTS: The relative frequency of each allele was 0.60 for Arg and 0.40 for Pro in patients with anal cancer, and 0.61 for Arg and 0.39 for Pro in normal controls. No significant differences in distribution of the codon 72 genotypes between patients and controls were found. CONCLUSION: These results do not support a role for the p53 codon 72 polymorphism in anal carcinogenesis. PMID- 19777617 TI - Hemoperfusion with polymyxin B-immobilized fiber column improves liver function after ischemia-reperfusion injury. AB - AIM: To investigate the usefulness of direct hemoperfusion with a polymyxin B immobilized fiber column (DHP-PMX therapy) for warm hepatic ischemia-reperfusion (I/R) injury after total hepatic vascular exclusion (THVE) using a porcine model. METHODS: Eleven Mexican hairless pigs weighing 22-38 kg were subjected to THVE for 120 min and then observed for 360 min. The animals were divided into two groups randomly: the DHP-PMX group (n = 5) underwent DHP-PMX at a flow rate of 80 mL/min for 120 min (beginning 10 min before reperfusion), while the control group did not (n = 6). The rate pressure product (RPP): heart rate x end-systolic arterial blood pressure, hepatic tissue blood flow (HTBF), portal vein blood flow (PVBF), and serum aspartate aminotransferase (AST) levels were compared between the two groups. RESULTS: RPP and HTBF were significantly (P < 0.05) higher in the DHP-PMX group than in the control group 240 and 360 min after reperfusion. PVBF in the DHP-PMX group was maintained at about 70% of the flow before ischemia and differed significantly (P < 0.05) compared to the control group 360 min after reperfusion. The serum AST increased gradually after reperfusion in both groups, but the AST was significantly (P < 0.05) lower in the DHP-PMX group 360 min after reperfusion. CONCLUSION: DHP-PMX therapy reduced the hepatic warm I/R injury caused by THVE in a porcine model. PMID- 19777618 TI - Epithelioid angiomyolipoma of the liver: cross-sectional imaging findings of 10 immunohistochemically-verified cases. AB - AIM: To retrospectively evaluate the computed tomography (CT)/magnetic resonance imaging (MRI) imaging features of epithelioid angiomyolipoma of the liver (Epi HAML), with pathology as a reference. METHODS: The CT/MRI findings (number, diameter, lobar location, and appearance of lesions) in a series of 10 patients with 12 pathologically proven epithelioid angiomyolipomas of the liver were retrospectively analyzed. The imaging features, including attenuation/signal intensity characteristics, presence of fat, hypervascular, outer rim, and vessels within lesion, were evaluated and compared with that of non-Epi-HAML in 11 patients (13 lesions). The Fisher exact test was used to compare difference in probability of imaging features between the two types. RESULTS: For 21 patients, CT images of 15 patients and MR images of six patients were available. No patient underwent two examinations. For the 15 patients with a CT scan, all HAML lesions in the two groups (10 Epi-HAML and seven non-Epi-HAML) manifested as hypoattenuation. For the six patients with MRI, all lesions (two Epi-HAML and six non-Epi-HAML) were hypointense on T1WI (fat suppression) and hyperintense on T2WI. There were 10 non-Epi-HAML, but only two Epi-HAML lesions showed the presence of fat, which significantly different between the two types (P = 0.005). On the dynamic contrast enhancement (DCE) imaging, eight Epi-HAML, and 13 non-Epi lesions manifested as hypervascular. Punctate or curved vessels were displayed in 10 Epi-HAML as well as in nine non-Epi lesions and outer rim enhancement could be found with eight Epi-HAML as well as six non-Epi lesions. CONCLUSION: Little or no presence of adipose tissue was found to be an imaging feature of Epi-HAML, compared with the non-Epi type. In addition, hypervascularity with opacification of central punctiform or filiform vessels on DCE would be a characteristic enhancement pattern for Epi-HAML. PMID- 19777619 TI - Effect of preoperative transcatheter arterial chemoembolization on angiogenesis of hepatocellular carcinoma cells. AB - AIM: To evaluate the effects of four types of preoperative transcatheter arterial chemoembolization (TACE) on angiogenesis of hepatocellular carcinoma (HCC) cells. METHODS: A total of 136 patients with HCC underwent liver resection. One to five courses of TACE prior to liver resection were performed in 79 patients (TACE group), in which one to four courses of chemotherapy alone were performed in 11 patients (group A); one to five courses of chemotherapy combined with iodized oil were performed in 33 patients (group B); one to three courses of chemotherapy combined with iodized oil and gelatin sponge were performed in 23 patients (group C); one to three courses of chemotherapy combined with iodized oil, ethanol and gelatin sponge were performed in 12 patients (group D). The other 57 patients only received liver resection (non-TACE group). The microvessels were marked by CD31. The expression of CD31 and vascular endothelial growth factor (VEGF) protein were detected by immunohistochemical methods. RESULTS: The mean microvessel density (MVD) in HCC cells was significantly higher in groups A, B, C and D than in the non-TACE group (P < 0.05). The expression of VEGF protein in HCC cells were significantly higher in groups A, B, C and D than in the non-TACE group (P < 0.05). MVD and the expression of VEGF protein were positively correlated. Mean MVD and the expression of VEGF protein were closely related to the number of courses of TACE and the interval of TACE. CONCLUSION: Four different types of preoperative TACE regimens enhanced angiogenesis in HCC cells by up-regulating the expression of VEGF protein. It is necessary to repress angiogenesis of liver cancer after TACE. PMID- 19777621 TI - Repetitive response to gemcitabine that led to curative resection in cholangiocarcinoma. AB - This study reports a case of unresectable intrahepatic mass-forming cholangiocarcinoma which showed a dramatic response to gemcitabine that led to curative resection and a long-term survival of more than five years. Six and five cycles of gemcitabine monotherapy were administered separately over a three-year period and a radical excision was performed at 4.5 years after diagnosis. This case indicates the role of gemcitabine as a neoadjuvant chemotherapeutic agent for cholangiocarcinoma and guarantees a randomized controlled prospective study. PMID- 19777620 TI - Pseudolymphoma of the liver associated with primary biliary cirrhosis: a case report and review of literature. AB - We report a case of two pseudolymphomas of the liver in a 63-year-old Japanese woman with primary biliary cirrhosis. One of the lesions was found incidentally during a medical examination, presenting as a 10 mm hypodense nodule that revealed hyperdensity in the early phase and hypodensity in the late phase in computed tomography (CT) after injection of contrast medium. Retrospectively, the 10 mm nodule had first been discovered as a 4 mm nodule during CT 4 years previously. Superparamagnetic iron oxide-enhanced MRI revealed another 4 mm hyperintense nodule in segment 6 in addition to the 10 mm hyperintense nodule in segment 7. CT during arterial portography revealed two hypointense nodules. Findings with other imaging modalities such as ultrasonography, magnetic resonance imaging, and hepatic angiography were consistent with hepatocellular carcinoma. A right posterior segmentectomy was performed, and the lesions were microscopically diagnosed as pseudolymphoma. To the best of our knowledge, only 31 other cases of this disease have ever been reported, with a highly asymmetrical male:female ratio of 1:9.7. Although we could find only one case of transformation of hepatic pseudolymphoma into lymphoma in the liver, the exact nature of development from benign pseudolymphoma to malignant lymphoma is still not fully understood and cases of hepatic lymphoma need to be followed carefully. PMID- 19777622 TI - Post-gastrectomy acute pancreatitis in a patient with gastric carcinoma and pancreas divisum. AB - Gastrectomy is commonly performed for both benign and malignant lesions. Although the incidence of post-gastrectomy acute pancreatitis (PGAP) is low compared to other well-recognized post-operative complications, it has been reported to be associated with a high mortality rate. In this article, we describe a 70-year-old man with asymptomatic pancreatic divisum who underwent palliative subtotal gastrectomy for an advanced gastric cancer with liver metastasis. His post operative course was complicated by acute pancreatitis and intra-abdominal sepsis. The patient eventually succumbed to multiple organ failure despite surgical debridement and drainage, together with aggressive antibiotic therapy and nutritional support. For patients with pancreas divisum or dominant duct of Santorini who fail to follow the normal post-operative course after gastrectomy, clinicians should be alert to the possibility of PGAP as one of the potential diagnoses. Early detection and aggressive treatment of PGAP might improve the prognosis. PMID- 19777623 TI - Hemorrhagic hepatic cysts mimicking biliary cystadenoma. AB - The hemorrhagic simple hepatic cyst is extremely rare and can sometimes be confused with biliary cystadenoma or cystadenocarcinoma. Here we present two cases of huge hemorrhagic simple hepatic cysts. Case 1 was a 43-year-old man with a cystic lesion measuring 13 cm x 12 cm in the right hepatic lobe. Ultrasound and computed tomography showed several mural nodules on the irregularly thickened wall and high-density straps inside the cyst. Case 2 was a 60-year-old woman with a huge cyst measuring 15 cm x 14 cm in the central liver. Ultrasound and magnetic resonance imaging showed the cystic wall was unevenly thickened and there were some flame-like prominences on the wall. The iconographic representations of the two cases mimicked biliary cystadenoma. Cystectomy and left hepatectomy were performed for the two patients, respectively. Both patients recovered quickly after their operations and showed no recurrence. PMID- 19777624 TI - Acute monocytic leukemia in pregnancy. Report of a case treated with 6 mercaptopurine in the first trimester. AB - 6-Mercaptopurine given during pregnancy to a patient suffering from acute monocytic leukemia (histiocytic or Schilling's type) permitted the birth of a premature but otherwise normal infant. The drug was given from the sixth to the eighth week and from the twenty-eighth to the thirty-first week of pregnancy, in doses sufficient to cause two remissions and two episodes of hypoplastic anemia. PMID- 19777625 TI - Microangiography in bone healing. I. Undisplaced closed fractures. AB - The blood supply of healing undisplaced closed fractures of the radius and tibia in adult mongrel dogs was studied by means of microangiograms and histological preparations. The microangiograms were prepared from decalcified longitudinal slices across the fracture site, one millimeter in thickness. The corresponding histological preparations were made from the same slices of tissue. The vascular pattern at the site of fracture, at intervals from one day to eight weeks after fracture, was compared with the normal vascular pattern. Immediately after fracture there was a marked opening up of the existing arterial tree. With the advancement of healing, both medullary and periosteal circulations increased greatly by the development of new blood vessels; but the medullary arterial system, when intact, played the major role in the supply of blood to the uniting callus and in the revascularization of the necrotic cortex at the fracture site. The ascendency of the medullary blood supply increased as healing progressed. In the dog the normal configuration of the blood supply of the compacta is similar to that in man; the inner two-thirds of the cortex is supplied by branches of the nutrient artery. Our experimental findings in the dog support clinical experience. The periosteal circulation of long bones can take over when the medullary circulation has been interrupted by displacement of the fracture fragments or by surgery-as will be described in subsequent reports of experiments in progress. However, the medullary arterial supply, when available, dominates the vascular picture in rapid fracture healing. PMID- 19777626 TI - The effect of high-dosage ultrasonic energy on femora of the dog: a roentgenographic, histological, and microangiographic study. AB - The femora of thirteen dogs were exposed to high levels of ultrasonic energy. Alterations became evident on roentgenograms two weeks after such exposure. Death of cortical bone was evident histologically three and four weeks after exposure, the shortest time interval after exposure that bone was studied histologically. The periosteal and the endosteal responses proximal and distal to the area of necrosis consisted of periosteal and endosteal formation of new bone with a marked increase of the periosteal and endosteal vessels. These changes are interpreted as being secondary to the death of the segment of diaphyscal bone exposed to ultrasonic energy. Whether the death so produced is purely thermal or is due also to non-thermal effects is not known to us at this time. That ultrasonic energy can be focally destructive to bone and its blood supply seems apparent. PMID- 19777627 TI - The in vivo distribution of tetracyclines in canine bone. AB - The in vivo distribution of tetracycline in canine bone was studied by determining the location and intensity of tetracycline fluorescence in undemineralized sections of bone from multiple skeletal sites in fifteen animals which received varying doses of the different tetracyclines. The tetracycline fluorescence was compared with mineral content, as revealed by microradiography and, in one animal, with the in vivo distribution of Ca45 as determined by autoradiography.The tetracyclines were incorporated into every surface that was undergoing active deposition of new bone and they remained there indefinitely. Resorption cavities and inactive surfaces showed tetracycline fluorescence immediately after an intravenous dose, but this fluorescence rapidly disappeared. The tetracyclines were also incorporated into the skeleton in three other ways which were, probably, not related to new-bone formation:1. Tetracycline was firmly and diffusely bound at low concentrations to areas that were not sites of the elaboration and mineralization of new matrix. This diffuse component paralleled closely the diffuse distribution of Ca45 and appeared to follow the calcium distribution pattern of secondary mineralization and long-term exchange.2. Tetracycline fluorescence was seen surrounding many lacunae. This may be either an additional form of tetracycline incorporation into bone or an artefact.3. Tetracycline was also incorporated into the surface of many systems, which were interpreted as non-growing systems, in conjunction with the process termed edge sclerosis.The presence of tetracycline incorporation into the skeleton by means which are not related to new-bone growth makes it impossible to estimate skeletal accretion accurately from a chemical determination of the total tetracycline content of a bone sample.The extreme non-homogeneity of the distribution of active new-bone growth sites throughout the skeleton was impressive. This means that an interpretation of metabolic activity based on observations made on a limited sample is very hazardous.The tetracyclines, however, do mark all sites of active new-bone formation and can be used as reliable intravital stains in properly designed and properly controlled experiments for the accurate determination of rates of accretion of bone. PMID- 19777628 TI - Arthrography of the shoulder joint: study of the findings in adhesive capsulitis of the shoulder. Study of the findings in adhesive capsulitis of the shoulder. AB - 1. Arthrography of the shoulder demonstrates the gross pathological changes in adhesive capsulitis of the shoulder. In true adhesive capsulitis, or frozen shoulder, arthrography shows a very definite decrease in joint capacity with obliteration of the reflected axillary fold. In many instances the subscapularis bursa is decreased in size or not visualized at all but, as a rule, the bicipital sheath is well outlined. 2. This procedure can serve as a diagnostic aid to differentiate true adhesive capsulitis from stiff and painful shoulder due to other causes. 3. A mixture of twelve cubic centimeters of 35 per cent diodrast and four cubic centimeters of 1 per cent procaine appears to be the ideal solution to use for injection of shoulder joints. This amount gives arthrograms with excellent detail, and the procaine prevents any pain when the solution is injected into the joint. PMID- 19777629 TI - Pathological changes in the hip in cerebral palsy: incidence, pathogenesis, and treatment: a preliminary report. PMID- 19777630 TI - Flexor carpi ulnaris transplant and its use in cerebral palsy. AB - In our experience, transplantation of the flexor carpi ulnaris is the single best procedure to improve function of the wrist and hand in cerebral palsy. It aids dorsiflexion and supination and, at the same time, preserves active motion of the wrist. This is highly desirable since finger control may be seriously impaired in cerebral palsy and the additional motion provided at the wrist may be most helpful. In fact, since using this procedure we have found that fusion of the wrist is rarely indicated. A good result from a flexor carpi ulnaris transplant depends first upon the careful choice of the patient for the procedure.Requirements for the best function from the transplant include reasonable finger control preoperatively with passive flexibility of the hand, wrist, and forearm; stereognosis of the involved hand; reasonable intelligence; high motivation of the patient and family; and a thorough postoperative regimen.The difference between a good result and a poor result was often the thoroughness of the postoperative care. The value of both exercise and support for the part cannot be overemphasized nor can one underestimate the importance of the interest and ambitions of the patient and his family. The procedure should be postponed until the age when the individual may be expected to cooperate in the training of the transplant. PMID- 19777631 TI - Troublesome lipomata of the upper extremity. AB - Lipomata are generally regarded as harmless tumors occurring anywhere on the body but rarely found in the hand. This report concerns lipomata involving the upper extremity, including the hand and fingers. Four cases are reported in two of which there was disturbance of a peripheral nerve caused by compression by lipoma. PMID- 19777632 TI - Flexor-tendon grafts in the less-than-optimum situation. AB - A series of forty-six flexor-tendon grafts in forty-one patients is evaluated. All of these patients presented less-than-optimum situations for tendon-grafting due to persistent joint stiffness, deep cicatrix, preliminary skin-grafting procedures, nerve damage, or severe multiple injuries.The results show a worth while gain of flexion in the proximal interphalangeal joint of the fingers, but a poor gain in the distal interphalangeal joint. In the thumb this gain in flexion is less important for function if the intrinsic muscles are adequate. However, the importance of a flexor-tendon graft in the severely injured hand is judged by the contribution to the over-all function rather than the exact degree of motion obtained. PMID- 19777633 TI - Resurfacing of the thumb following major skin loss. AB - The repair of areas of skin loss on the hand and in particular on the thumb demands a careful appraisal of the type of tissue used to close the wound. In this report on the closure of avulsed wounds of the thumb, emphasis is placed on the superiority of local pedicle tissue, as compared with pedicle flaps obtained from a distance. Abundant pedicle skin is available on the dorsum of the hand of close partial or complete circumferential defects of the thumb from the level of the metacarpophalangeal joint distally.The main advantage of a local pedicle flap is that the tissue more closely simulates the physical characteristics of volar skin. Neither local nor distant pedicle flaps regain functional sensation. If sensation is essential for satisfactory function it must be supplied by normally innervated volar skin added to the thumb by means of a neurovascular island flap. PMID- 19777634 TI - Isolated traumatic dislocation of the distal end of the ulna or distal radio ulnar joint. AB - Three of our five cases and approximately one-half the cases reported were misdiagnosed at the time of original injury. Increased awareness of this lesion and alertness to the relationship of the radius and ulna on lateral roentgenograms of the wrist would probably reduce the incidence of faulty diagnosis markedly.We believe that early closed reduction and adequate immobilization should result in excellent function in most cases. Delay in diagnosis will probably result in protracted disability and the necessity for surgical correction. PMID- 19777635 TI - Dislocation of the lesser multangular: report of a case. PMID- 19777636 TI - Central spinal cord syndrome in hyper-extension injuries of the cervical spine. AB - The syndrome of acute central cervical spinal-cord damage, as originally described by Bailey and subsequently by Schneider, Cherry, and Pantek, consists of disproportionately greater weakness in the upper extremities as compared with the lower, with various sensory changes at or below the site of the lesion, and urinary bladder dysfunction. Three patients with this problem are presented. The mechanism of injury is discussed and related to pre-existing conditions such as cervical spondylosis as well as acute pathological entities causing central cord damage, such as hematomyelia, contusion, cord swelling, and ischemia. The treatment and prognosis of patients with this type of spinal-cord injury is outlined. PMID- 19777637 TI - Radical resection for tumors of the shoulder with preservation of a functional extremity. AB - A series of patients have been presented to illustrate radical methods of dealing with malignant tumors of the shoulder. Emphasis has been placed on the cosmetic and functional results which can be obtained in selected cases in which it appears feasible to avoid amputation. Certain lesions lend themselves to this type of surgery, in particular, chondrosarcoma, fibrosarcoma, and giant-cell tumor. A thorough knowledge of the specific growth characteristics of these, as well as certain other less common tumors, will in certain instances aid the surgeon in selecting radical resectional surgical procedures and thus preserve a normal elbow and hand. PMID- 19777638 TI - Controversy over prostate-specific antigen screening has shifted from mortality to overtreatment issues. PMID- 19777639 TI - Retraction to "Siah-1 facilitates ubiquitination and degradation of factor inhibiting HIF-1a (FIH)" [Biochem. Biophys. Res. Commun. 353 (2) (2007) 324-329]. PMID- 19777640 TI - Retracted notice to: "Obestatin reduces food intake and suppresses body weight gain in rodents" [Biochem. Biophys. Res. Commun. 357(1) (2007) 264-269]. PMID- 19777641 TI - Retracted notice to: "Baculovirus surface-displayed hemagglutinin of H5N1 influenza virus sustains its authentic cleavage, hemagglutination activity, and antigenicity" [Biochem. Biophys. Res. Commun. 358(2) (2007) 404-409]. PMID- 19777642 TI - Pioneer in EEG/MEG research: a tribute to Werner Lutzenberger. AB - Werner Lutzenberger died on November 22, 2008. This obituary recalls his scientific career and highlights his contributions to research on human brain function using electro- and magnetoencephalography. PMID- 19777649 TI - Easier access to motor neurone drug. PMID- 19777643 TI - Cyanobacteria contain a structural homologue of the Hfq protein with altered RNA binding properties. AB - Hfq proteins are common in many species of enterobacteria, where they participate in RNA folding and translational regulation through pairing of small RNAs and messenger RNAs. Hfq proteins share the distinctive Sm fold, and form ring-shaped structures similar to those of the Sm/Lsm proteins regulating mRNA turnover in eukaryotes. However, bacterial Hfq proteins are homohexameric, whereas eukaryotic Sm/Lsm proteins are heteroheptameric. Recently, Hfq proteins with poor sequence conservation were identified in archaea and cyanobacteria. In this article, we describe crystal structures of the Hfq proteins from the cyanobacteria Synechocystis sp. PCC 6803 and Anabaena PCC 7120 at 1.3 and 2.3 A resolution, respectively, and show that they retain the classic Sm fold despite low sequence conservation. In addition, the intersubunit contacts and RNA-binding site are divergent, and we show biochemically that the proteins bind very weakly to known Escherichia coli Hfq target RNAs in vitro. Moreover, when expressed in E. coli, the proteins cannot mediate Hfq-dependent RNA regulation. It therefore appears that the cyanobacterial proteins constitute a specialized subfamily of Hfq proteins that bind relatively weakly to A/U-rich tracks of regulatory RNAs. The results have implications for our understanding of the evolution of the Sm fold and the Hfq proteins in the bacterial kingdom in general. PMID- 19777664 TI - Amended IV policy dismays enrolled nurse. PMID- 19777670 TI - Impact of admixture time and diluent order on metaraminol concentration. PMID- 19777671 TI - A difficult airway in a patient with extensive cervical lymphadenopathy. PMID- 19777672 TI - Multienzyme complexes and hydrogen transfer: the work of Perry Frey. PMID- 19777673 TI - Getting your vitamins and minerals through diet. The benefits of multivitamins are looking doubtful. Can we do without them? PMID- 19777674 TI - Left behind after suicide. People bereaved by a suicide often get less support because it's hard for them to reach out--and because others are unsure how to help. PMID- 19777675 TI - Routine ovary removal during hysterectomy ill-advised for most women. PMID- 19777677 TI - [Current status and problems with thyroid cytodiagnosis]. PMID- 19777678 TI - [An approach from the nasal sinus to the orbit]. PMID- 19777676 TI - By the way, doctor. I've been diagnosed with pseudogout, which I understand is caused by a buildup of calcium crystals in the joints. Should I be concerned about taking a calcium supplement? PMID- 19777679 TI - [Current status of problems of policies concerning tuberculosis in Japan (9) "Policies for the people outside the reach of tuberculosis policies: the practice at the Airin Area"]. PMID- 19777680 TI - [Determination of psycho-social factors (3) Development of scales. 1. Sequences and analyses of parameters]. PMID- 19777681 TI - 2009 Rho Chi Lecture: interdisciplinary health professions education: a systems approach to bridging the gaps. PMID- 19777682 TI - [Dare to speak of another progress]. PMID- 19777683 TI - Invited Commentary. Selectivity of weakness among different muscles or muscle groups has always fascinated the clinicians in arriving at specific diagnosis of motor system disease. PMID- 19777684 TI - Invited commentary. Carpal tunnel syndrome is one of the most common peripheral entrapment neuropathies and is associated with substantial direct medical costs and with economic costs in terms of man day loss and possible continuing disability. PMID- 19777685 TI - The influence of corrective exercises in a water environment on the shape of the antero-posterior curves of the spine and on the functional status of the locomotor system in children with Io scoliosis. AB - BACKGROUND: There has been a growing interest in studies examining the importance of the aquatic environment in non-invasive treatment of scoliosis. The water environment is an important element in the correction of body posture abnormalities. The aim of this paper is to evaluate the influence of corrective exercises in a water environment on the shape of the antero-posterior curves of the spine and on the functional status of the locomotor system of children with Io scoliosis. MATERIAL AND METHODS: The study involved a group of 94 children aged 8-13 years with Cobb Io scoliosis. Computer-aided photogrammetry was used to analyse the shape of the antero-posterior curves of the spine. The functional evaluation of the children's musculoskeletal system involved several functional tests: the Dega wall test, Thomas test, Lasegue test, and Kraus-Weber test. The tests were carried out twice: before a 6-month programme of corrective exercises in a water environment, and immediately on completion of the rehabilitation programme. The programme included swimming and corrective exercises in water. RESULTS: A statistical analysis of the dimensions of the anterio-posterior curves of the spine revealed a significant increase in the total length of the spine and the length of thoracic kyphosis. Besides, the bending angle of the trunk, the angle of thoracic kyphosis and the angle of lumbar lordosis were reduced. The analysis also showed an increase in the bending angle of the upper spine. Shoulder mobility also increased significantly following the programme of corrective aquatic exercises. CONCLUSIONS: 1. The programme of corrective exercises had an influence on the length and angle of thoracic kyphosis. 2. The muscle strength of the lower part of the erector spinae also increased, as did shoulder mobility measured by the Dega test. PMID- 19777686 TI - Meiosis. Volume 2, cytological methods. Preface. PMID- 19777687 TI - The Early History of Psychoanalysis in San Francisco. AB - The early history of psychoanalysis in San Francisco begins in 1918 and ends in 1953. During those 35 years the San Francisco Bay Area witnessed the awakening of interest in psychoanalysis, the arrival of the European emigre analysts and the emergence of individuals and groups engaging in extraordinarily creative work and doing so in an ecumenical spirit and with a social commitment. This article provides an overview of this illustrious history and the people who participated in it. PMID- 19777688 TI - The place of psychoanalysis in the history of the Jews. AB - Situating psychoanalysis in the context of Jewish history, this paper takes up Freud's famous 1930 question: what is left in Judaism after one has abandoned faith in God, the Hebrew language and nationalism, and his answer: a great deal, perhaps the very essence, but an essence that we do not know. On the one hand, it argues that "not knowing" connects psychoanalysis to Judaism's ancestral preoccupation with God, a preoccupation different from that of the more philosophical Greek, Latin and Christian traditions of theology. On the other hand, "not knowing" connects psychoanalysis to a post-Enlightenment conception of the person (i.e. of personal life), as opposed to the more abstract notion of the subject associated with Kant. PMID- 19777689 TI - Diverging opinions on interferon therapy for melanoma. PMID- 19777690 TI - The impact of non-melanoma skin cancer. PMID- 19777691 TI - Data on sentinel lymph node metastases in ductal carcinoma in situ. PMID- 19777692 TI - Basal cell and squamous cell skin cancers. Clinical practice guidelines in oncology. PMID- 19777693 TI - NMSC in organ transplant recipients and other high-risk groups. AB - Non-melanoma skin cancers (NMSCs) are the most commonly occurring malignancies in the United States, with over 1 million cases annually. Several subsets of patients within the general population are particularly susceptible to the development of basal cell carcinomas and squamous cell carcinomas. These groups include patients with xeroderma pigmentosum, basal cell nevus syndrome, epidermodysplasia verruciformis, and chronic lymphocytic leukemia as well as organ transplant recipients. Organ transplant recipients are the largest and best characterized of these subsets of patients. Review of the available data regarding the epidemiology, etiology, and clinical features of NMSC in organ transplant patients provides insight into the care of other high-risk patients. PMID- 19777694 TI - Melanoma. Clinical practice guidelines in oncology. AB - It should be emphasized that these treatment practice guidelines are guidelines, not absolute recommendations for treatment. They represent an effort to distill and simplify an enormous body of knowledge and experience into fairly simple management algorithms. In general, treatment recommendations for primary tumors are based on better data than the recommendations for treating recurrent disease. Few, if any, firm recommendations can be made about more controversial issues such as the extent of work-up or intensity of follow-up of the melanoma patient. These guidelines are intended as a point of departure, recognizing all clinical decisions about individual patient management must be tempered by the clinician's judgment, and factors such as local resources and expertise and the individual patient's needs, wishes, and expectations. Furthermore, these guidelines are undergoing continual revision and upgrading as new data become available. PMID- 19777695 TI - Point: Interferon-alpha for adjuvant therapy for melanoma patients. AB - Interferon-alpha is possibly the most controversial adjuvant therapy for any solid tumor, and multiple trials involving varying doses, routes, schedules, and formulations of interferon-alpha have increased the confusion. Clinicians are left in a quandary, because high-dose interferon-alpha-2b (HDI) remains the only FDA-approved adjuvant therapy for high-risk melanoma. Of the three prospective randomized trials involving high-dose interferon-alpha-2b, all show a significant improvement in disease-free survival and two show a significant improvement in overall survival. Despite this strong evidence, data from studies involving alternate doses, concerns regarding cost and toxicity, and the promise of future therapies have led opponents of interferon to overlook these results. Based on the available clinical evidence, however, high-dose interferon should be offered as standard care for patients with high-risk, resected melanoma. Informed patients who have elected to forego interferon and patients with lower risk lesions can be offered participation in clinical trials with a no-treatment control arm. PMID- 19777696 TI - Counterpoint: The case against adjuvant high-dose interferon-alpha for melanoma patients. AB - High dose interferon-alpha (HD IFN) is approved by the United States Food and Drug Administration for adjuvant treatment of patients with stage III melanoma after complete surgical resection. Despite this, clinicians and patients around the world and in many parts of the US have failed to embrace this treatment option because of the lack of overall survival benefit and minimal other clinical benefits seen in randomized trials, combined with the therapy's substantial toxicity. This article reviews the data from the randomized trials that lead to this conclusion and discuss why arguments often advanced in favor of using HD IFN are not persuasive. New treatment options are needed for adjuvant therapy of melanoma. In the meantime, the data from the randomized trials make it difficult for many clinicians and patients to have enthusiasm for adjuvant HD IFN. PMID- 19777697 TI - Dermatofibrosarcoma protuberans. Clinical practice guidelines in oncology. PMID- 19777698 TI - Merkel cell carcinoma. Clinical practice guidelines in oncology. PMID- 19777699 TI - Treatment options for Merkel cell carcinoma. AB - Merkel cell carcinoma (MCC) or neuroendocrine carcinoma of the skin is uncommon, often aggressive, and has a poor prognosis. Complete surgical excision with histologic documentation of clear resection margins is recommended for the primary cancer. Retrospective analysis of clinical data strongly suggests that adjuvant radiotherapy improves local control of MCC, but no evidence has been published that it prolongs survival. Sentinel lymph node biopsy is a useful method of determining the need for regional lymph node dissection in stage I patients. Chemotherapy regimens similar to those employed for small cell carcinoma of the lung have been recommended for advanced MCC. Patients often show an initial response to therapy, but it is usually short-lived. The three-year overall survival for patients with MCC is 31%. Before an improvement in long-term survival can be realized, early detection, appropriate use of surgery and radiation therapy, and the development of effective systemic chemotherapy are required. PMID- 19777700 TI - Treating and preventing lung cancer. PMID- 19777701 TI - Non-small cell lung cancer. Clinical practice guidelines in oncology. PMID- 19777702 TI - Predictive molecular markers: has the time come for routine use in lung cancer? AB - Although some evidence exists to support the use of clinical factors such as performance status and weight loss to predict response and toxicity to therapy in non-small cell lung cancer (NSCLC) patients, researchers have shown little prospective data on the use of molecular markers to facilitate selection of specific chemotherapy or new molecularly targeted agents in this patient population. Breast cancer exemplifies the growing role that molecular markers are playing, not only as prognostic factors, but also in predicting response to targeted treatments such as hormonal therapy, and more recently, trastuzumab (Herceptin). Although several studies have examined molecular markers in lung cancer and have shown promising potential value, these studies were retrospective and require prospective validation. To identify molecular markers that reliably predict response and to be able to individualize cytotoxic and targeted therapy for NSCLC patients are the ultimate goals of future trials. This article focuses on a selected number of promising markers under study in lung cancer, including those thought to play roles in response to DNA damaging chemotherapy (excision repair cross-complementing [ERCC1], xeroderma pigmentosum group D [XPD]), taxane resistance (beta-tubulin III), antimetabolite therapy (RRM1), irinotecan metabolism (UGT1A1) and epidermal growth factor receptor (EGFR) pathway inhibition. To date, none of these markers can be recommended for routine use in clinical practice. PMID- 19777703 TI - Small cell lung cancer. Clinical practice guidelines in oncology. PMID- 19777704 TI - Surgery in the management of small cell lung cancer. AB - Because most patients with small cell cancer of the lung present with distant metastatic disease, the treatment is almost always medical therapies without surgery. However, a small number of patients present with resectable disease, and this review summarizes the available literature addressing the possible role for surgery in the treatment of these patients. PMID- 19777705 TI - Novel targets for therapeutic agents in small cell lung cancer. AB - Small cell lung cancer (SCLC) is known to have an aggressive phenotype and often presents with distant metastasis. Despite frequent initial response to chemotherapy, it inevitably relapses within 2 years in the majority of patients. Because of the poor overall prognosis of the disease and its unique tumor biology, the opportunity for improving clinical outcome of patients with development of novel therapeutics is great. This review provides current insights into the novel molecular targets in SCLC. Cellular signal transduction pathways and their relationship to cellular functions also are discussed. Discussion of the role receptor tyrosine kinases (RTKs) have in SCLC therapeutic inhibition is emphasized. In particular, the recent development of small molecule inhibitors of RTKs such as c-Kit, c-Met, and VEGF-R and the potential for clinical trials are highlighted. PMID- 19777706 TI - Documentation of pain in comprehensive cancer centers in the United States: a preliminary analysis. AB - The National Comprehensive Cancer Network (NCCN), an organization of 19 of the world's leading cancer centers, developed and communicated a cancer pain treatment guideline. NCCN seeks to implement guidelines through performance measurement using a NCCN Oncology Outcomes Database. This is a preliminary report from the NCCN Cancer Pain Management Database Project. The primary objective of this NCCN Cancer Pain Management Database Project study is to evaluate the frequency, methods, and extent of documentation of cancer pain assessment and management at NCCN institutions. A pain data dictionary and related data collection forms were first developed. The records of 209 breast cancer patients with bone metastases were then studied. The frequency of pain mentions, type of pain assessment tool used, pain characteristics, type of clinician documenting pain, location in the medical record, and pain treatment characteristics were noted. The majority of clinical encounters included pain mentions, although considerable variability was found in pain documentation between providers and between inpatient and outpatient settings. Nurses more frequently recorded pain, usually as a numeric pain intensity score. Pain specialists were more likely to record a complete description of pain. A significant minority of patients experienced moderate to severe pain. In a small subgroup of patients with moderate to severe pain, pain treatment was not recorded. The undertreatment of cancer pain has been a focus of investigation and review for the past two decades. Quality improvement efforts to raise the standard of pain management have been underway. The results of this study highlight the need for standardization of pain documentation in comprehensive cancer centers as a prerequisite for the proper assessment of cancer pain and the improvement of clinical outcomes of pain management. PMID- 19777707 TI - Chronic fatigue syndrome: traditional and community-based approaches to rehabilitation. AB - Chronic fatigue syndrome (CFS) is a controversial condition defined by 6 months or more of unexplained fatigue, and at least four out of eight cognitive and physical symptoms. Over the past 2 decades, CFS has been the subject of significant debate regarding its definition, cause and recommended treatment. Because a cure for the syndrome has not yet been located, efforts to improve functioning and overall quality of life through rehabilitation represent the most practised form of treatment to date. However, controversy remains as to which approach to rehabilitation is most effective for individuals with CFS. Interventions which take place within real-world environments and utilise community-based organizations such as centres for independent living offer a newly explored means of support and rehabilitation. The present paper reviews a variety of approaches to rehabilitation for individuals with CFS, describing their applications with different types of patients, and providing critical commentary on the research methodologies used to evaluate them. Innovative community-based rehabilitation programmes and their outcomes are described as an alternative with some promise that may compliment more traditional approaches. PMID- 19777708 TI - Differences in the process of diabetic care between south Asian and white patients in inner-city practices in Nottingham, UK. AB - The prevalence and complication rate of diabetes is higher amongst British south Asians when compared to the rest of the adult population. There is some evidence to suggest that there are differences in access to healthcare in the UK for different ethnic groups, but there has been little research examining differences in processes of care between ethnic groups and place of delivery of diabetic care. The present study was a retrospective, multi-practice audit exploring differences in the processes of diabetic care provided to white and south Asian patients. Data were obtained from eight practices located in deprived areas in Nottingham, UK. A review of the evidence-based protocols for the monitoring of diabetic care generated a list of process criteria to be measured. All primary care data sources were examined over a 12-month period by a single investigator. The data were analysed with respect to patient ethnicity and place of diabetic care after adjusting for confounders. Eight hundred and thirty-nine diabetic patients were included in the audit and 671 (80.0%) received a formal annual diabetic review. One hundred and five (12.5%) patients were classified as south Asian. They were significantly less likely to have their blood pressure [86% versus 89%, odds ratio (OR) = 0.62, 95% confidence interval (95% CI) = 0.54-0.72] or serum creatinine (67% versus 76%, OR = 0.41, 95% CI = 0.32-0.52) measured when compared to white patients. Patients receiving shared care from a hospital-based diabetic team were more likely to have a range of items of the annual review recorded. When examined by ethnicity, south Asians receiving shared care were again less likely than white patients to have their blood pressure and serum creatinine measured. There was also some evidence that they may be less likely to have their body mass index recorded and their feet examined. The findings of the present study showed that, although most diabetic patients received a formal annual clinical review, scope for improvement remained. Shared care of patients with a hospital-based team produced better results when processes of care were examined. However, this benefit did not apply equally to south Asian and white patients. Further studies are indicated to confirm these results, which may have wider implications for the planning and provision of diabetic care. PMID- 19777709 TI - Autonomy and modernisation: the management of change in an English primary care trust. AB - Recent New Labour policy for the 'modernisation' of Government places a good deal of emphasis on decentralisation. This emphasis is particularly marked in relation to the organisation of primary care. However, like hospitals and other National Health Service institutions, primary care trusts (PCTs) are subject to a substantial raft of centrally established performance targets and indicators, including those which contribute to the public award of between zero and three performance 'stars'. This raises questions about the extent to which employees can exercise autonomy in the context of rigid top-down directives. This paper presents findings from a study using participant observation and interviews to examine the impact of a training course aimed ostensibly at increasing employee autonomy in an English PCT. The suggestion is that attempts to make employees more autonomous can be seen as a strategy for increasing central control based upon the internalisation by the employees of centrally promulgated values. The attraction of such strategies is that they may be potentially more effective and less costly than alternative strategies of direct control. However, the study suggests that the outcome of attempts by such methods as programmes to increase employee autonomy may be very different from those intended. PMID- 19777710 TI - Measuring the health of Scottish drug users. AB - Information on how individuals perceive their own health is important for providing appropriate health-related support and monitoring health over time. The Short Form 36 (SF-36) Health Status Questionnaire is one of the most widely used generic measures of self-perceived health status. Despite this, there has been no large-scale research documenting the SF-36 scores of problem drug users in the UK. The present paper has two aims: (1) to compare the self-perceived health of a sample of problem drug users with that of a sample from the general population; and (2) to investigate differences between the self-perceived health of various subgroups of problem drug users. In total, 1179 individuals starting a new episode of drug misuse treatment in Scotland were invited to complete a structured questionnaire that included the SF-36. Out of these, 1033 (87.6%) agreed and 990 successfully completed all SF-36 questions. The 990 completers were more likely than the 43 partial completers to be male [odds ratio (OR) = 0.45; 95% confidence interval (95% CI) = 0.24-0.85) and not in prison (OR = 0.36; 95% CI = 0.19-0.68). The reliability of the SF-36--measured by internal consistency--was very good (Cronbach's alpha > 0.7 for all eight dimensions). Comparing the respondents' mean dimension scores with those of a sample from the UK general population revealed that the drug users' health was consistently worse than that of the general population (> 20 points on seven out of the eight scales). Differences between the mean SF-36 scores of various subcategories of respondents were analysed using t-tests or an analysis of variance, as appropriate. The factors considered were: sex; age; imprisonment; relationship status; homelessness; and recent drug injection. Significant differences between particular groups of respondents were identified. Despite limitations with the data presented, the paper highlights the utility of the SF36 for drug misuse treatment providers. PMID- 19777711 TI - Facilitating choice and control for older people in long-term care. AB - The community care reforms enabled some older people with severe disabilities to remain at home with domiciliary care services, as an alternative to institutional admission. This paper explores the extent to which the reforms actually enabled older people receiving domiciliary care to have greater choice and control in their daily lives than older people living in institutions. Findings are reported from a comparative study carried out in Greater Belfast, Northern Ireland, that determined the extent to which the subjective quality of life of older people- particularly autonomy--varied according to the type of setting. The older people were interviewed using a structured interview schedule and subjective autonomy was assessed using a measure of perceived choice. The measure consisted of 33 activities relating to aspects of everyday life such as what time to get up, when to see visitors or friends, and how much privacy was available. Qualitative data were also recorded which informed on the older people's perspectives on their own lives, particularly the extent to which they exercised choice on a daily basis. Two-hundred and fourteen residents in 45 residential and nursing homes were interviewed, as were 44 older people receiving domiciliary care in private households. The study found that older people living in institutions perceived themselves to have greater decisional autonomy in their everyday lives than did older people receiving domiciliary care. Indeed, it was clear that living at home did not ensure that one's decisional autonomy would be supported. However, living alone may facilitate exercising a relatively higher degree of autonomy when living at home. Whilst the community care reforms have provided some older people who have severe disabilities with the option of receiving care at home, this has not necessarily enabled them to have greater choice and control in their everyday lives than older people admitted to institutions. PMID- 19777712 TI - Tackling the needs of the homeless: a controlled trial of health advocacy. AB - The objective of the present study was to assess the effectiveness of a health advocate's casework with homeless people in a primary care setting in terms of improvements in health-related quality of life (QoL). The impact of the health advocacy intervention was assessed in a quasi-experimental, three-armed controlled trial. Homeless people moving into hostels or other temporary accommodation in the Liverpool 8 area of the UK and patients registering at an inner-city health centre as temporary residents were allocated in alternating periods to health advocacy (with or without outreach registration) or 'usual care' over a total intake period of 3 years. Health-related QoL outcomes were assessed using three independent self-report measures: the Life Fulfilment Scale; the Delighted-Terrible Faces Scale; and the Nottingham Health Profile. Out of the 326 homeless people who were given baseline questionnaires at registration, 222 (68%) returned usable questionnaires. Out of these individuals, 171 (77.0%) were traceable at follow-up, and 117 (68.4%) follow-up questionnaires were returned. The majority of respondents (n = 117) were women (72%) who were under 30 years of age (74%), white British (91%), and single (63%) or separated (23%), many of whom were living with their children (41%) in either women's refuges (30%) or family hostels (25%). Improvements in health-related QoL were greatest in people recruited and supported by a health advocate early in their stay in temporary housing, in comparison with those in the control group given 'usual care' at the health centre. The model of streamlined care for patients with complex psycho social needs is shown to be a worthwhile and effective option for primary healthcare providers. PMID- 19777713 TI - Do people in rural and remote Queensland delay using health services to manage the episodes of incapacity? AB - The research project described in the present paper aimed to explore the types of self-reported management which families in relatively 'high', 'moderate' and 'low' medically resourced areas use for episodes of incapacity and the length of time from an initial symptom to the management behaviours. A telephone survey was conducted in rural and remote Queensland, Australia, to explore one or more types of management for the most recent incapacity episode of family members. A respondent indicated at least one type of management for any one episode. These included using a home remedy, self-treatment and an ambulatory doctor's visit. Data were analysed descriptively and analytically. Log transformations were used for all outcomes prior to using bivariate analyses which incorporated the correlation between observations to compare the time from initial symptom to management between groups. Among 394 households contacted, 270 provided information about 697 household members, 269 (38.5%) of whom had had at least one episode of incapacity in the previous 12 months. Among people in each of the three resourced areas, there was a significant difference in the length of time taken to visit accident and emergency (A&E) units. Men visited the units and consulted books earlier than women. Although age was not quite significantly related to the use of A&E units (P = 0.06), data suggested that people 35 years or older tended to take a longer time to use the services than the younger age groups. After taking into account that the members of the same household might take the same time from initial symptoms to management, people who were incapacitated and lived in areas with different levels of medical resources and gender were likely to be different in the time taken to use services at the A&E units. PMID- 19777714 TI - Lay perceptions of neighbourhood health. AB - While research has focused on objective indicators of community health, less attention has been paid to subjective indicators. Lay perceptions of neighbourhood health are explored in the present research through the analysis of survey data from 918 middle-aged individuals in Victoria, Canada. Socio demographic variables, including neighbourhood socioeconomic status (SES), were included in a binary logistic regression model, along with health status and perceptions of the neighbourhood context. Additional logistic regression analyses were also performed to assess predictors of neighbourhood perceptions. Overall, individuals had no difficulty rating neighbourhood health: 77% rated it as very/somewhat healthy; and 23% as very/somewhat unhealthy. Individual measures of SES were not associated with neighbourhood health ratings, but the odds of rating a neighbourhood as healthy were three times higher among those who lived in high income areas compared with those who did not. Additional salient factors in perceived neighbourhood health are perceptions of personal safety, and to a lesser extent, sense of belonging and not identifying groups of 'undesirable' people in the area. PMID- 19777715 TI - What types of home are closing? The characteristics of homes which closed between 1996 and 2001. AB - Closures of care homes have received considerable public attention. Fee levels and the cost of upgrading homes to meet the national minimum standards have been identified as the main factors influencing closures. The present paper compares private residential homes, dual-registered homes and nursing homes for older people which have closed between 1996 and 2001 with homes which have remained open. Homes which closed tended to be: smaller; to have had lower occupancy levels in 1996; to be the only home run by the organisation; to occupy converted buildings; to occupy multi-storey buildings, and if so, to have no lift; to have more shared bedrooms; and to have en suite facilities in none or only some of the bedrooms. These factors were interrelated and the effect of these variables in combination was examined using multivariate (logistic regression) analysis. Among the homes which remained open, only 34% provided at least 80% of places in single rooms, which was to have become the national minimum standard for existing homes until the standards were amended in March 2003. A separate analysis of data on social climate found that the homes with a more positive social environment were those most likely to have closed. The findings support the view that there is likely to be an increase in the importance of homes run by corporate providers relative to homes run as single, owner-managed homes, with a consequent reduction in choice for potential residents. At the same time, projections of future demand in a range of countries indicate that a considerable increase in provision will be required to meet the expected growth in the population of dependent older people, while developments in alternative forms of accommodation are unlikely to meet the growth in demand in the foreseeable future. PMID- 19777716 TI - Use of osteopathic or chiropractic services among people with back pain: a UK population survey. AB - Questionnaires covering health and the use of complementary, alternative and conventional health services were mailed to a random sample of 14 868 adults aged 18-64 years living in four counties of England in 1997. The present study examined the use of osteopathy/chiropractic among the 15% (n = 1377) of respondents reporting back pain. Osteopaths/chiropractors were seen by 13.4% (n = 184) of respondents with back pain during the past 3 months compared with 9.8% (n = 135) who consulted physiotherapists. The presence of back pain and non-manual social class were the strongest predictors of consultation with both types of practitioner. Women, older respondents, non-smokers and those who exercised for 30 minutes at least once a week were more likely to use osteopathy/chiropractic. The only other significant predictor of physiotherapy use was desire for more physical exercise. While those reporting back pain had Short-Form 36 (SF-36) scores suggesting very significant levels ofdisability, respondents with back pain who consulted osteopaths/chiropractors reported better health in all dimensions of the SF-36 than those using physiotherapy services. Although they reported worse pain scores than people not consulting any practitioners, their mental health, physical functioning, energy and health perception were better. It is impossible to disentangle cause and effect in this cross-sectional study, but the data suggest that people who can afford to pay are more likely to choose osteopath/chiropractor treatments than physiotherapy. The possibility that osteopath/chiropractor treatment has a generalised positive effect on health, allowing people with back pain to function better than those not receiving such treatment, warrants further investigation. PMID- 19777717 TI - Preparing young adults with disability for employment. AB - Young people with disabilities are often excluded from the labour market. The present paper describes an evaluation of an innovative 2-year pilot initiative called Vocational Opportunities in Training for Employment (VOTE) implemented in Northern Ireland to provide employment training and support for vulnerable young adults with a wide range of disabilities. The principal aims of the study were to assess the impact of the new service in the extent to which: (1) it had created and developed training and employment opportunities for young people; and (2) promoted inclusive working partnerships. Documentary analysis was used as a basis for describing and assessing the project objectives in combination with face-to face interviews with a small number of key stakeholders. A total of 122 young people participated in the initiative in the pilot period, during which time 160 qualifications were obtained. Key stakeholders expressed positive views about the initiative, and in particular, its therapeutic benefits and the extent of interagency working and shared learning. The VOTE initiative achieved considerable success in enabling a significant proportion of young adults to engage in society by developing social and employment skills, and by improving their employment opportunities and prospects. Factors critical to the continued success of this and similar initiatives include: the close involvement of parents; addressing the concerns of local employers; the sympathetic treatment of workplace issues; and effective partnership working. PMID- 19777718 TI - More than technology and access: primary care patients' views on the use and non use of health information in the Internet age. AB - Over the past decade, there has been considerable interest in the transmission of health information made available though the Internet with increasing confidence being placed in the potential power of the Internet to transform communication, clinical practice and relationships with patients. Subsequent to the failure of a primary-care-based initiative designed to provide free assistance and access to health information via the Internet, a survey was conducted. Findings from this survey suggested that facilitating access to e-information is necessary, but not in itself sufficient, to encourage current non-users to start exploring the Internet. The qualitative study reported here was aimed at exploring the way in which people use and perceive the utility of Internet information for managing health and illness and engaging with the health service system. Data was gathered from two sources. Interviews and observations of a sample who had used a free primary-care-based Internet service (n = 5) and interviews with a sample drawn from a survey of patient attitudes to using the Internet for health information (n = 12). The less-considered aspects of access and the use of e-information for health matters related to the varied existing relationships respondents had to computers, health information and health professionals. One of the main reasons why some respondents do not use the Internet to access health information is related to a lack of perceived utility and pertinence of such information for managing their healthcare. The optimal and equitable use of the Internet as a means of complimenting health-service utilisation will not emerge merely from increasing access to e-information. The potential for narrowing or increasing inequality between the information rich and poor needs to be viewed in a broader psychosocial context. The latter includes the nature of existing relationships which people have with the health service and the value that people place on their own capacity to make use of information in managing their healthcare. PMID- 19777719 TI - 'Part of the family': sources of job satisfaction amongst a group of community based dementia care workers. AB - The development of community-based services for people with dementia brings new challenges for health and social care providers, not least that of sustaining an enthusiastic workforce who are motivated to provide care and support under potentially isolating and difficult conditions. The present paper, based on interview data gathered from a group of community-based dementia care workers, seeks to identify their sources of job satisfaction and reward. Interviews were conducted with seven workers at two points in time and the data were analysed using a case by theme matrix approach. The results indicate that there were high levels of job satisfaction amongst the group, which were enhanced by several factors, including: good organisational support; day-to-day autonomy; the ability to maintain relationships with people with dementia and their families; and staffs' feelings of contributing to and improving the status and quality of life of people with dementia. Implications for workforce development are briefly considered. PMID- 19777720 TI - Evaluation of an early intervention Tier 2 child and adolescent mental health service. AB - While the recommendation issued by the Health Advisory Service in 1995 is for a tiered child and adolescent mental health service, there is little published evidence about the outcomes of such services. Our objective was to evaluate an innovative community-based child and adolescent mental health service in South and East Leeds using before and after measures. The client group of the service was children and families with emotional and behavioural problems and/or parenting difficulties. Standardised assessment of families and young people was followed by brief intervention (solution-focused therapy) to the child and family. Descriptive demographic and referral pathway details were recorded, as were baseline and postintervention Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA) scores. South Leeds generated almost four times as many referrals in the 9 months after the Tier 2 Child and Adolescent Mental Health Service (CAMHS) was set up. Clinically and statistically significant decreases in symptom scores were found for families completing work with the Tier 2 workers. Families referred on to Tier 3 had complex but not more severe problems. The new service encountered previously unmet need among troubled young people in the community, whilst freeing specialist Tier 3 staff to concentrate on complex, chronic problems. PMID- 19777721 TI - 'Not everything that can be counted counts and not everything that counts can be counted'--towards a critical exploration of modes of satisfaction measurement in sheltered housing. AB - This paper reflects on a research project funded by a consortium of leading sheltered housing (SH) providers and their regulatory body, the Housing Corporation. The project aimed to ascertain which aspects of SH older people perceived to be central to their satisfaction and the methods they judged most appropriate to measuring this. We outline key policy developments of importance to SH (specifically the development of performance measurement regimes), and changes in the nature of SH, which are driving providers to re-evaluate how they measure user satisfaction. We discuss the aims of the project, our methodology and findings, and conclude by raising critical questions about the process of measuring satisfaction within an increasingly managerialised housing system. We argue that this favours standardised methods of information gathering (such as questionnaires) rather than engage with clients in order to develop methods and systems capable of eliciting qualitative issues of concern to them. Our conclusions are, we believe, applicable to health and social care provision, where similar tensions exist around performance measurement and user satisfaction. PMID- 19777722 TI - Social work, general practice and evidence-based policy in the collaborative care of older people: current problems and future possibilities. AB - While collaborative (or joint) working between social services and primary healthcare continues to rise up the policy agenda, current policy is not based on sound evidence of benefit to either patients or the wider community. Both sets of practitioners report benefits for their own work from adopting new arrangements for collaboration. The underlying assumption behind much of this activity is that a greater degree of integration provides benefits to both users and their carers, a perspective that at times obscures the issue of resource availability, especially in the form of practical community services such as district nursing and home help. At the present time there is insufficient evidence to demonstrate that formal arrangements for collaborative working (CW) are better than those forged informally between committed individuals or teams. Furthermore, arrangements for CW have not hitherto been widely evaluated in systematic studies with a comparative design and focus on outcomes for users and carers rather than on processes. In this paper we propose a number of process measures for future evaluation of CW: (1) study populations must be comparable; (2) details of how services are actually delivered must be obtained and colocation should not be assumed to mean collaboration; (3) care packages in areas of comparable resources should be examined; (4) both destinational outcomes and user-defined evaluations of benefit should be considered; (5) possible disadvantages of integrated care also need to be actively considered; (6) evaluations should include an economic analysis. Those implementing new policies in Primary Care Trusts have, at present, little sound evidence to guide them in their innovative work. However, they should take the opportunity to rigorously test the advantages and disadvantages of collaboration. PMID- 19777723 TI - Home chemotherapy for children with cancer: perspectives from health care professionals. AB - The goal of this study was to determine the perspectives of healthcare professionals (HPs) from community and hospital settings involved in a paediatric home chemotherapy programme. Using a prospective descriptive study design, HPs including paediatricians, community nurses, hospital clinic nurses, administrators and pharmacists were interviewed using a moderately structured open-ended approach. Through inductive content analysis, data were categorised under three themes reflecting HPs' perspectives on the programme: (1) perceived family benefits, (2) human resources and service delivery considerations and (3) impact on the role of the HP. All HPs reported that home chemotherapy helped reduce both disruption to family life and psychological stress. Community-based HPs reported increased job satisfaction, increased workload and increased frustration related to scheduling challenges. Hospital-based HPs reported decreased patient interaction and discrepancies in workload changes. Both groups emphasised the need for consistency in care and for specific chemotherapy training. Service delivery issues included the need for more clarity in the programme process, improved eligibility criteria, a focus on community laboratory coordination and development of centralised communications. PMID- 19777724 TI - Diversity in intermediate care. AB - This paper discusses the evolution of intermediate care (IC) and presents interim observations from a survey of providers in England being conducted as part of a national evaluation. Telephone interviews covering various issues concerning the level of provision and style of delivery have been conducted with 70 services to date. Data from these are used to discuss the progress, range and nature of IC in relation to clinician viewpoints and academic and official literature on the subject. IC 'on the ground' is a multiplicitous entity, with provision apparently evolving in accordance with the particularities of local need. While protocols for medical involvement in IC generally appear to be well established, there are some tensions concerning integration of services in a locality, care management processes and questions of flexibility and inclusiveness in relation to eligibility criteria. PMID- 19777725 TI - 'It was like my little acorn, and it's going to grow into a big tree': a qualitative study of a community support project. AB - Government initiatives aimed at reducing health inequalities and combating poverty amongst families increasingly take an area-based approach, and seek to involve local families in building community capacity. Sure Start is one such initiative, and was set up to develop services for pre-school children and their families, and improve child health and well-being. Based on a local evaluation of a Sure Start programme, the present paper describes the development of a community support project aimed at engaging local people in supporting the parents and carers of young children. This paper draws on qualitative data to explore stakeholders' experiences of the project. These are then described from two main perspectives: the personal and the wider community. It also explores the organisational conditions necessary to encourage lay involvement in such initiatives. The paper concludes that policies aimed at involving local people in delivering services to families need to take account of long-standing structural problems in disadvantaged communities if they are not to be perpetuated. PMID- 19777726 TI - Rural America is ripe for growth. PMID- 19777727 TI - Quality conversations. PMID- 19777728 TI - Words that save. Ensuring that "never events" never happen. PMID- 19777729 TI - Crossing the Rubicon. Healthcare faces critical changes in the years ahead. PMID- 19777730 TI - The new age of healthcare communications. PMID- 19777731 TI - Going mobile. Sites created specifically for mobile devices tap a growing audience. PMID- 19777732 TI - Time for a marketing facelift? Usability testing provides insider view for web site development. PMID- 19777733 TI - Healthcare reform and consumers--five changes ahead. PMID- 19777734 TI - [Antibiotic resistance: a success story? ]. PMID- 19777735 TI - [Agomelatine]. AB - In February 2009 the European Medicines Agency (EMEA) approved agomelatine (Valdoxan), a sleep modulating antidepressant, for the treatment of major depressive disorders in adults. Agomelatine is an agonist of melatonergic MT1 and MT2 receptors and a serotonin 5-HT2C receptor antagonist. Thereby it can normalize altered circadian rhythms, improve slow wave sleep and enhance the release of dopamine and noradrenaline in the prefrontal cortex which has positive effects on mood, impulse and anxiety. Clinical trials have shown superior efficacy compared to placebo and equal efficacy compared to standard antidepressants, rapid onset of action and low extent of adverse events. PMID- 19777736 TI - [Antimycotic therapy of Tinea unguium and other onychomycoses]. AB - Mycosis of foot or finger nails (onychomycosis) is the second most common fungal skin infection in industrialized countries. In Germany, estimated 10 to 17% of the total adult population and almost one half of all people beyond the age of 65 are suffering from an onychomycosis. In most cases, mycoses of toe nails are caused by a dermatophyte species (Tinea unguium), especially Trichophyton rubrum and T. mentagrophytes. Onychomycosis of finger nails are frequently due to Candida yeasts such as C. albicans, C. parapsilosis and C. tropicalis. In addition, non-dermatophyte moulds, alone or in combination with other fungi, are associated with onychomycoses. For successful antimycotic treatment, generally referred as mycological and clinical cure, the aetiological agent, principal form of mycosis and severity of disease should be considered. In some cases, distal/ lateral subungual onychomycosis, the most prevalent form of nail mycosis, and superficial white onychomycosis (leukonychia trichophytica) can be successfully treated with topical antimycotics, provided that there is no severe course and infection of the nail matrix can be excluded. Systemic antifungals should be used for treatment of all remaining forms of onychomycosis, i. e., proximal subungual onychomycosis, onychia et paronychia candidosa and total dystrophic onychomycosis. If nail matrix is infected, a systemic treatment approach is generally recommended (independent of onychomycosis form). The prospects of success of local and systemic therapy can be enlarged applying nail abrasion and chemical avulsion of the diseased part of the nail. An improved effectiveness of systematic treatment is also achieved by concomitant application of topical antifungals. PMID- 19777737 TI - [Postmarketing surveillance studies in community pharmacies]. AB - Postmarketing surveillance of prescription medicines is a routine practice, yet similar evaluation of non-prescription medicines is uncommon. In order to get insights into the validity of pharmacy-based observational studies 22 postmarketing surveillance studies in the German community of pharmacies involving non-prescription medications have been investigated. The objective was to evaluate their contribution to the knowledge about drug use in self medication. The results of the comparative evolution show that postmarketing surveillance studies with non-prescription medications deliver valid and meaningful findings about the usage, effectiveness and safety. Statements to the efficacy of the drug often serve marketing interests. PMID- 19777738 TI - [Doping in the workplace - no longer a taboo subject. Deutschen Angestellten Karnkenkasse health report 2009 ]. PMID- 19777739 TI - [Can a lithium-induced polyuria be treated with an amiloride / hydrochlorothiazide combination? ]. PMID- 19777740 TI - Framing our case for reform. PMID- 19777741 TI - Religion, style and the public square. PMID- 19777742 TI - Dreaming together about the future we want. PMID- 19777743 TI - Does community-oriented mission fit with health reform? PMID- 19777744 TI - The ministry of business. Do everything for the glory of God. PMID- 19777745 TI - Forming leaders: handing on the tradition. PMID- 19777746 TI - Mission leadership: kicking it up a notch. New competency model positions the mission leader as an indispensable contributor to an organization's identity, strategy and vision. PMID- 19777747 TI - When knowledge and skill aren't enough. Leadership formation takes leaders to new levels. PMID- 19777748 TI - Ministry leadership formation: engaging with leaders. Four years into the program, participants report positive results. PMID- 19777749 TI - The promise and challenge of board formation. Ascension Health's program aims to enhance understanding and commitment to the ministry. PMID- 19777750 TI - Health care sponsorship: from charism to ecclesial ministry. A lay leadership model may offer resources for reimagining sponsorship for the future. PMID- 19777751 TI - Pope Benedict XVI's new encyclical: implications for Catholic health care. 'Caritas in Veritate' contains challenges to the practices of Catholic health care. PMID- 19777752 TI - A pandemic is not a game--and here's a game to prove it. PMID- 19777753 TI - Traveling exhibit showcases Catholic sisters meeting needs. "Women & Spirit" captures women religious' contributions toward health care, education and social justice. PMID- 19777754 TI - Health care reform: a political and policy balancing act. Finding middle ground on three hot-button issues will determine if new comprehensive legislation is enacted. PMID- 19777755 TI - Promoting goodwill and respect in the workplace. Cardinal Theodore McCarrick leads the effort to overcome differences between employers and unions. PMID- 19777756 TI - Learning from the Guyanese. PMID- 19777757 TI - The Saint Francis Health Center at AT&T Park, San Francisco. Ballpark facility is a hit with neighborhood residents. PMID- 19777759 TI - Choosing treatment for stage I seminoma: who should get what? AB - We agree that physicians should choose active surveillance for their patients if they have the means to afford health insurance and are relatively stable within their careers. Prophylactic radiotherapy should be offered to patients who need a relaxed follow-up schedule for financial, emotional, or compliance reasons. For adjuvant carboplatin, longer follow-up data are needed to better define survival, long-term toxicities, frequency of second primary testicular cancers, quality of life, and cost to the healthcare system. PMID- 19777758 TI - Therapeutic options following orchiectomy for stage I seminoma. AB - Stage I seminoma represents the paradigm of a curable malignancy, with survival of 100% an expected outcome no matter what treatment option is chosen. However, consensus has not been reached among urologists and oncologists regarding the optimal postoperative management in men with clinical stage I testicular seminoma. Currently, men are offered active surveillance, adjuvant radiation therapy, or single-agent chemotherapy. Active surveillance is associated with an 80% chance of no relapse, with all such events salvageable. Radiotherapy has an almost universal cure rate but has the potential for long-term toxicities and an overtreatment rate of about 80%. Chemotherapy efficacy and toxicity data are still immature. Recent guidelines recognize that the options of surveillance, chemotherapy, and radiotherapy are appropriate in the treatment of patients with clinical stage I seminoma. We believe active surveillance to be the best option, then radiotherapy (considering the efficacy and safety data), with single-agent chemotherapy emerging as a possible alternative. PMID- 19777760 TI - Surveillance for stage I seminoma: better the devil you know than the devil you don't? PMID- 19777761 TI - Optimal treatment in the postorchiectomy management of clinical stage I seminoma. PMID- 19777762 TI - New directions in the systemic treatment of metastatic thyroid cancer. AB - Medical oncologists have traditionally had little to offer patients with metastatic radioactive iodine-resistant thyroid cancer. The 3-year survival rate of patients with differentiated thyroid cancer is less than 50%, with little response obtained from standard cytotoxic chemotherapies. In recent years, however, huge advances have been made in understanding the molecular pathways and cellular pathogenesis of this disease. This knowledge has in turn led to the development of a range of targeted therapies, some specific to thyroid cancer genetic alterations such as the RET/PTC translocation, and others that exploit general malignant properties such as angiogenesis. This review highlights novel targeted agents for the treatment of differentiated and medullary thyroid cancers being studied at this time, and the results of recently published trials. We propose that such patients should be managed, whenever possible, within a clinical trial, in order to access the most promising new drugs for thyroid cancer. In cases where trials are unavailable, we recommend off-label use of the currently available oral multikinase inhibitors such as sorafenib and sunitinib rather than traditional chemotherapies. PMID- 19777763 TI - Radioiodine-resistant differentiated thyroid cancer: hope for the future. PMID- 19777764 TI - Thyroid cancer update: dramatic changes in the treatment of a rare disease. PMID- 19777765 TI - Early-stage BRCA2-linked breast cancer diagnosed in the first trimester of pregnancy associated with a hypercoagulable state. AB - This patient was found to have a BRCA2 gene mutation. She underwent lumpectomy and axillary lymph node dissection without any evidence of lymph node metastasis. Systemic chemotherapy with doxorubicin and cyclophosphamide for four cycles was administered beginning in the second trimester. She was treated with prophylactic LMWH until delivery and then for 6 weeks postpartum. She delivered a healthy baby boy and, after a period of breast-feeding, underwent bilateral mastectomy with immediate reconstruction. She remains well and is expecting her second child. Prophylactic oophorectomy is planned after completion of this pregnancy. PMID- 19777767 TI - Testicular granulosa cell tumors: rare tumors need to be studied too. PMID- 19777766 TI - Response to antiangiogenesis therapy in a patient with advanced adult-type testicular granulosa cell tumor. AB - As granulosa cell tumors of the adult type are extremely uncommon testicular neoplasms, relatively few case reports and case series have been published. Treatment for localized, small-volume, or oligometastatic disease is generally surgical resection alone. Visceral or widely metastatic disease is relatively rare, so there is no consensus approach to treatment. We report the case of an advanced granulosa cell tumor of the testis with a confirmed partial response to an angiogenesis inhibitor after initial resistance to cytotoxic chemotherapy. PMID- 19777768 TI - Complementary therapies, herbs, and other OTC agents. Metabolic therapies. PMID- 19777769 TI - Planning for a pandemic. Better communication critical for hospitals if H1N1 returns this fall. Interview by Haydn Bush. PMID- 19777770 TI - Pursuing excellence: AHA initiative demonstrates value of teamwork in improving safety. AB - Focusing on ways to improve patient outcomes, the American Hospital Association has launched Hospitals in Pursuit of Excellence. This effort to transform patient care through shared innovations highlights achievements at various hospitals around the country in areas including patient safety, reducing health care acquired infections, medication management and patient throughput. As this report illustrates, the roles of materials management, nursing, infection control specialists and others are critically important to this effort. PMID- 19777771 TI - Use evidence to put prevention in context. How to make sense of the many studies on anti-infective catheters. AB - From randomized controlled studies to meta-analysis research covering data from a wide range of sources, there is a vast amount of information on anti-infective central venous catheters (AICVC). These studies have examined everything from when these devices should be used to the various types of coatings used in AICVCs. So how can value analysis coordinators, infection control professionals and nurses best make sense of all the research when making purchasing decisions? Here's a no-nonsense approach to understanding the evidence. PMID- 19777772 TI - Fresh approaches stem MRSA tide. AB - The theory of positive deviance holds that in any group, some people are more effective than others even when they have the same resources at hand. The object is to identify those people, see what they're doing differently and share it with the larger group. The Plexus Institute and the Robert Wood Johnson Foundation recently collaborated on a six-hospital positive-deviance study that reduced methicillin-resistant Staphylococcus aureus (MRSA) infection rates by 70 percent. What these hospitals learned may help others cut their MRSA rates. PMID- 19777773 TI - Prevent the spread of MRSA. PMID- 19777774 TI - Changing attitudes strengthen culture of prevention. PMID- 19777775 TI - [Film and science: transitions, contexts and parallelisms. An introduction]. PMID- 19777776 TI - [Popular science: metamorphosis of knowledge in film]. AB - Far from being merely a medium of simplification and conveyance of scientific facts, motion pictures exhibit an important epistemic function. On the one hand, the medium film is itself a product of research in various fields, on the other hand, it retroacts on perception and problem-solving in science, thereby influencing and changing research practices. The paper aims at describing these reciprocal effects and synergies by discussing two examples: first by the film "The principles of Einstein's theory of relativity", first released in Germany in 1922, second by the film "Mathematical image of the struggle for life", produced in 1937 for the inauguration of the "Palace of discoveries" in Paris, demonstrating the latest developments in evolutionary theory. It becomes evident that picture media have the capacity to transform the symbolic dimension of things and bodies, thereby offering new access to reality, which not only fascinated the spectators, but also inspired scientific research. PMID- 19777777 TI - [Describe and convince: visual rhetoric of cinematography in medicine]. AB - The tools of visualisation occupy a central place in medicine. Far from being simple accessories of glance, they literally constitute objects of medicine. Such empirical acknowledgement and epistemological position open a vast field of investigation: visual technologies of medical knowledge. This article studies the development and transformation of medical objects which have permitted to assess the role of temporality in the epistemology of medicine. It firstly examines the general problem of the relationships between cinema, animated image and medicine and secondly, the contribution of the German doctor Martin Weiser to medical cinematography as a method. Finally, a typology is sketched out organising the variety of the visual technology of movement under the perspective of the development of specific visual techniques in medicine. PMID- 19777778 TI - [Affect, medicine and public enlightenment: the origin of the film genre "Deutscher Kulturfilm"]. AB - This article describes the process of professionalisation of medical films in Germany between 1910 and 1920. At the beginning of this decade, government institutions showed a growing interest in hygiene campaigns and started to cooperate with medical experts as well as with professional advertisers. When the German film industry was nationalised at the end of World War I, these informal structures were strengthened. New theories described the film as a most powerful tool for propaganda purposes. This profoundly changed the expectations towards medical films. Now their content had to be bedded into the dramatised form of a photoplay. After 1918, in anticipation of the reprivatisation of the German film industry, government officials of the Weimar Republic developed complex measures to obtain and keep control over a new genre of documentary film which was now called "Deutscher Kulturfilm". Some of the political expectations linked to the Kulturfilm can be exemplified in the first documentary of feature length released by the Berlin-based Universal Film Corporation in 1920. It contained elements of medical films that had been shot during the last decade of the German Empire, and it was newly composed in 1919 to meet the presumable needs of a broader public in an uncertain democratic future. PMID- 19777779 TI - [Film and sciences of the mind in 1900: neurosis, paramnesia, trance]. AB - In this article, conceived of in an epistemological perspective, film history and history of psychology intersect in order to show how subject models are circulating around 1900 which are impregnated with scientific culture and social modernity. These models have the special quality of being defined first in pathological terms because they result from a diagnosis of the evils caused by the new industrial and capitalist society. However, the position required by the cinematic apparatus produces a spectator who is described as a subject-machine with the particular psychophysiological states that precisely concern the neurotic, the paramnesiac and the sleepwalker. If our point is to show how close the (para)medical and cinematic subjects are, we will also try to see how far cinema interacts with phenomena related to urbanity and other developments of Western civilisation, the latter being considered as a transforming agent of the psychic apparatus. PMID- 19777780 TI - Moving pictures and medicine in the first half of the 20th century: some notes on international historical developments and the potential of medical film research. PMID- 19777781 TI - Habitat and plant communities in the Nile Delta of Egypt. II. Irrigation and drainage canal bank habitat. AB - The present study provides quantitative analysis of the vegetation and spatial variations of environmental factors controlling the abundance and distribution of vegetation in canal and drain banks in the Nile Delta region of Egypt. Five vegetation groups have been recognized: group A codominated by Arundo donax and Polygonum equisetiforme, group B codominated by Rumex dentatus and Polypogon monspeliensis, group C dominated by Eichhornia crassipes, group D codominated by Phragmites australis and Echinochloa stagnina and group E dominated by Typha domingensis. The total number of weeds recorded in the study area is 113 species belonging to 36 families. Therophytes (48.67%) and geophytes (14.16%) are the most frequent life-forms. The major chorotypes in the study area are Mediterranean (42.48%), Cosmpolitan (19.47%), Pantropical (13.27%) and Palaeotropical (12.39%). The relationships between the vegetation gradients and edaphic factors showed that, potassium and sodium cations, potassium adsorption ratio, chlorides, sodium cation adsorption ratio, pH value and water-holding capacity are the main controlling edaphic factors. PMID- 19777782 TI - Karyotype of Malayan Gaur (Bos gaurus hubbacki), Sahiwal-Friesian cattle and Gaur x cattle hybrid backcrosses. AB - Interspecific hybridization has been reported for a wide variety of vertebrate species either spontaneous or by organized crossing of bovine species. The hybrids were often carrying intermediate characters genetically and phenotypically of the parents. Thus, status information of both aspects is valuable in animal production for selection and breeding management. The Gaur cattle hybrids was reported to be superior in production value compared to their parent cattle but fertility status was still questionable. The project was abandoned due to their fertility issue and the hybrids were kept within the cattle in a dairy farm. Cytogenetic status and breeding record of the remaining herd were unavailable since then. The herd was then translocated to a deer farm (PTH Lenggong) and kept freely in the paddock. Recently, two female calves were born via inter se mating. Peripheral blood cultures of Malayan Gaur, Sahiwal Friesian cattle and Gaur x cattle hybrid backcrosses were analyzed via Giemsa stained metaphase. The Gaur and cattle were having diploid chromosome number (2n) of 56 and 60, respectively. Interestingly, the backcrosses from the hybrids by cattle bulls were found to have two chromosome arrangements, which are 2n = 58 and 2n = 60. PMID- 19777783 TI - Applying Benthic Index of Biotic Integrity in a soft bottom ecosystem in North of the Persian Gulf. AB - In this study, the Chesapeake Bay Benthic Index of Biotic Integrity (B-IBI) was selected in an attempt to describe ecological health of soft bottom channels (Khowr-e Musa) in North of the Persian Gulf. Most of study area was found to be in degraded or severely degraded conditions. B-IBI scores were ranged between 1 and 3.86. Comparison ofmacrobenthos abundance and organic content between two developmental periods showed significant difference (p < 0.05). After the establishment and development of petrochemical industries, the abundance of macrofauna decreased (809 to 239 individuals m(-2)) and organic content increased leading to organic enrichment (15.3 to 22.4%). Three new sources of organic matter were found to be important namely industrial waste, sewage and mangrove litter. After 1999 about 6 millions Avicennia marina tree were planted near petrochemical zone in the area. Study area changed rapidly in the last decade and region is under severely anthropogenic impacts. The present study showed that Khowr-e Musa is under both natural stress and anthropogenic impacts and two main impacts could be attributed to the organic enrichment and to the dredging. Choice of suitable management plans and metric controls could help to the salvage of the largest tidal channel complex in Persian Gulf. PMID- 19777784 TI - Mother-to-child HIV and HHV-8 transmission in neonates at Saint Camille Medical Centre in Burkina Faso. AB - In Sub-Saharan Africa, many HIV infected people are co-infected with Human Herpes Virus 8 (HHV-8). Therefore, the present study aimed to: (1) identify the pregnant women co-infected by HIV and HHV-8 at Saint Camille Medical Centre; (2) use three molecules (Zidovudine, Nevirapine and Lamivudine) to interrupt the vertical transmission of HIV and (3) use the PCR technique to diagnose children, who were infected by these viruses, in order to offer them an early medical assistance. A total of 107 pregnant women, aged from 19 to 42 years were diagnosed to be HIV positive at Saint Camille Centre; among them 13 were co-infected with HHV-8. All included women received the HAART. Two to six months after childbirth their babies underwent PCR diagnosis for HIV and HHV-8. The results revealed that, among these mothers, 68.2% were housewives, 34.6% were illiterates and 60.7% did not have university degree. The prevalence of HHV-8 among these pregnant women was 12.15% and the rate of vertical transmission of both HIV and HHV-8, was 0.0%. The issue of this study revealed that the antiretroviral therapy increased the mother CD4 T-cells, prevented the transcription of the mRNA of HHV-8 and blocked HIV vertical transmission. PMID- 19777785 TI - Non-radioactive labeled probe preparation for hbs gene detection. AB - Among some Bacillus species, a protein highly homologous to HU, classified HB and coded by hbs gene. According to the recent studies, the sequence of hbs gene just in one strain of Bacillus subtilis exists in gene bank (ATCC 23857). In this study, DNA from Bacillus subtilis ATCC 6633 was extracted and investigated by PCR. The PCR product was sequenced and shown to differ in just one nucleotide from B. subtilis ATCC 23857. Hence, it was chosen as reference and for the first time, used for non-radioactive labeled probe preparation. The PCR product in Bacillus subtilis with ATCC 6633 was labeled using non-radioactive DIG-labeled nucleotides and conditions of probe preparation and hybridization were optimized and checked it by Southern blotting. PMID- 19777786 TI - In vitro antiplasmodial and antibacterial activities of Canthium multiflorum Schum and Thonn (Rubiacea) extracts. AB - Because of the resistance of pathogens to actually available drugs, there is a continuous need for new agents to cure several diseases such as malaria and microbial infections. In the establishment of new drugs, plant are often a source of new leads, indeed aqueous, acetone and methanol extracts of Canthium multiflorum were tested for antiplasmodial and antibacterial activities. The antiplasmodial activity was performed on fresh clinical strains of Plasmodium falciparum using light microscopy. The results revealed that the methanol extract was the most active with IC50 of 4.69 microg mL(-1). The NCCLS microdilution method performed on clinical and reference strains of pathogenic bacteria yielded MIC and MBC values ranging from 312 to 1250 and 625 to 2500 microg mL(-1), respectively. The qualitative analysis of the extract revealed the presence of several chemical groups such as alkaloids, terpens and tannins that might be responsible for the activity of the plant. The issue of this study showed that C. multiflorum is a plant that many attention should be paid to because of it pharmacological potentials. PMID- 19777787 TI - Effects of propylene glycol powder on productive performance of lactating cows. AB - An experiment was conducted by eight lactating Holstein cows with an average milk production of 32.75 kg day(-1) and body weight of 643.6 kg to evaluate the effects of propylene glycol (PG) on productive performance, blood metabolites and nutrients digestibilities. In this experiment a balanced change-over design with four treatments and four periods with 21 days were employed. Treatments included: (1) Control (without PG), (2) 250 g PG/cow/day, (3) 500 g PG/cow/day and (4) 750 g PG/cow/day. Daily milk yield recorded and milk samples were taken during seven and two last days of each period. The results show that dry matter intake, milk yield, fat corrected milk yield, milk compositions were not affected (p > 0.05) by different levels of PG. Supplementing diets with 500 and 750 g PG/cow/day, significantly increased plasma glucose (p < 0.05) but other blood metabolites such as blood urea nitrogen, triglyceride and cholesterol were not affected (p > 0.05) by PG. Apparent digestibility of dry matter and organic matte was not affected (p > 0.05) by PG administration. In conclusion, plasma glucose was increased by using 500 and 750 g PG/cow/day (as powder) in the first and mid lactation stage, but the levels of 250 g PG/cow/day did not have any significant effect on dry matter intake, milk yield, milk compositions and other blood metabolites. PMID- 19777788 TI - Expression of P27, Ki67 and P53 in squamous cell carcinoma, actinic keratosis and Bowen disease. AB - This study aims at evaluating the expression of P27, Ki67 and P53 in Squamous Cell Carcinoma (SCC), Actinic Keratosis (AK) and Bowen Disease (BD) specimens. In an analytic-descriptive setting, skin biopsy specimens of 45 patients were evaluated in three 15-case groups including BD, AK and SCC specimens. Fifteen normal skin biopsy specimens were obtained and used as the control group. Immunohistochemical staining was performed in all the specimens and the expression rates and patterns of Ki67, P27 and P53 were determined. The results were compared between the four groups. Ki67 was expressed in 0.8, 23.7, 12.3 and 19.3% of the cells in the normal skin, AK, BD and SCC groups, respectively. No significant difference was seen between the three pathological conditions regarding the expression rate of Ki67. P27 was positive in 23.4, 26.2, 25.9 and 4.5% of specimens in the normal skin, AK, BD and SCC groups, respectively. This rate was significantly the lowest in the SCC group. P53 expression was detected in 26.6, 41.8 and 54.6% of the assessed cells in the AK, BD and SCC groups, respectively. There was no expression of P53 in the normal skin specimens. This rate was significantly the highest again in the SCC group. Based on these results, the quantitative and qualitative (pattern of distribution) evaluation of the expressions of Ki67, P27 and P53 may be helpful in differentiating malignant and premalignant epidermal lesions, particularly in unsatisfactory or fragmented specimens. PMID- 19777789 TI - Correlation between the in vitro iron chelating activity and poly phenol and flavonoid contents of some medicinal plants. AB - Iron chelating activity of 16 extracts from 11 medicinal plants has been determined to find alternative sources with lower side effects in thalassemic patients. Thalassemia is characterized by iron overload and chelation therapy reduces iron-related complications and thereby improves quality of life and overall survival. Because of poor oral bioavailability, short plasma half-life and severe side effects of available chelators, this screening may be useful in this area. Extracts were prepared by soaking dry material of the selected plant in appropriate solvent. Phenol and flavonoid content of the extract were measured by Folin Ciocalteu and AlCl3 colorimetric assays. Phenol content of the extracts varied between 8.4-194.9 mg g(-1) of extract. The highest chelating activity was found in aerial parts of Leonurus cardiana and Grammosciadium platycarpum which had high amount of phenol and flavonoid contents. All extracts contained various amount of flavonoids from 5.9 to 90.9 mg g(-1) of extract. Weak correlations were found between phenolic and flavonoids contents and iron chelatory activity with R2 = 0.40. Extracts with high phytochemicals and chelating activity can be candidate as a good source of new agents for thalassemic patients. PMID- 19777790 TI - Individuals with Disabilities Act of 2004 and the John H. Chafee Foster Care Independence Act of 1999: What are the policy implications for youth with disabilities transitioning from foster care? AB - Youth with disabilities who are transitioning out of foster care are at high risk for poor adult outcomes. Although there are not definitive studies, research estimates that between 50% and 80% of youth in the child welfare system are youth with disabilities (United Cerebral Palsy & Children's Rights, 2006). The John H. Chafee Foster Care Independence Act of 1999 expanded transition services for youth aging out of foster care; the Individuals with Disabilities Education Act of 2004 continues the federal commitment to transition supports for youth with disabilities through special education services. This article examines the similarities and differences between the transition mandates in each of the two laws and makes recommendations for policy improvements. PMID- 19777791 TI - The voices of grandchildren of grandparent caregivers: a strengths-resilience perspective. AB - This paper presents the perspectives of grandchildren who are cared for by 20 grandparents or great-grandparents. It is based on videotaped family interviews that were analyzed qualitatively, and it shows how the grandchildren portray their parents and how they talk about their grandparents, as well as the grandchildren's strengths and resources. This inquiry demonstrates the nature of the grandchildren's attachments to their grandparents and their resilience. Implications for child welfare practice are identified. PMID- 19777792 TI - Emerging issues at the intersection of immigration and child welfare: results from a transnational research and policy forum. AB - In July 2006, the American Humane Association and the Loyola University Chicago School of Social Work facilitated a roundtable to address the emerging issue of immigration and its intersection with child welfare systems. More than 70 participants from 10 states and Mexico joined the roundtable, representing the fields of higher education, child welfare, international immigration, legal practice, and others. This roundtable created a transnational opportunity to discuss the emerging impact of migration on child welfare services in the United States and formed the basis of a continued multidisciplinary collaboration designed to inform and impact policy and practice at the local, state, and national levels. This paper presents the results of the roundtable discussion and summarizes the emerging issues that participants identified as requiring attention by child welfare systems to facilitat positive outcomes of child safety, permanency, and well-being. Suggestions for further research and implications for policy and practice are also presented. PMID- 19777793 TI - The legal and ethical context for knowing and using the latest child welfare research. AB - Many child welfare researchers, policymakers, and practitioners are embracing evidence-based practice as a means of promoting more effective services. This article explores the implications of this movement, including the potential for malpractice liability, limiting the discretion of child welfare professionals, complications with informed consent, and other legal and ethical risks. PMID- 19777794 TI - Mental health and substance abuse indicators among homeless youth in Denver, Colorado. AB - We report the results of mental health evaluations from 182 homeless youth residing in a Denver, Colorado, shelter. The literature on homeless youth, although developing, is still somewhat limited as it relates to mental health, substance abuse, and trauma. This study was motivated by clinically observed high rates of mental illness, trauma, dangerousness issues, and drug and alcohol abuse. Using archival data from mental health evaluations conducted over two years, variables including gender, age, ethnicity, primary diagnosis, drug of choice, trauma history, suicidal ideation, homicidal ideation, and legal history were assessed. Results discovered significantly higher than expected diagnoses of mental illness and associations between drug of choice and diagnosis, trauma history and suicidal ideation, and trauma history and diagnosis. Results suggest a strong need for co-occurring treatment, trauma-focused therapy, and attention to both mental illness and substance abuse in homeless youth. PMID- 19777795 TI - Overlooked: children with disabilities in residential care. AB - While estimates suggest that 10% to 31% of children in residential care are identified as with a disability, little is known about their characteristics or functioning as compared to nondisabled peers. This study evaluated data of 123 children with (n=34) and without (n=89) disabilities in residential care to determine demographic, behavioral, mental health, and educational characteristics. Data included demographic, behavior checklist, and standardized mental health and academic measures. Results indicated that both groups presented elevated risks; however, scores for children with disabilities revealed even greater levels of need. Primary risks were found on indicators of behaviors (e.g., social functioning), mental illness (e.g., anxiety), and academic performance (e.g., general knowledge and reading). Implications, limitations, and recommendations for future research are discussed. PMID- 19777796 TI - Effects of early maltreatment on development: a descriptive study using the Vineland Adaptive Behavior Scales-II. AB - Children with histories of chronic early maltreatment within a caregiving relationship may develop complex trauma or developmental trauma and suffer from a variety of deficits in many domains. This study explored the effects of complex trauma on the development of 57 children, as measured by the Vineland Adaptive Behavior Scales-II. This is the first descriptive study to report on the significant discrepancies between chronological and developmental ages in adopted and foster children. This study found that adopted and foster children with a psychiatric diagnosis of reactive attachment disorder show developmental delay in the domains of communication, daily living skills, and socialization. The average adaptive behavior composite score for the children in this study yielded a developmental age (age equivalency) of 4.4 years, while the average chronological age was 9.9 years. PMID- 19777797 TI - Enhancement effects of hypercapnia on the acute lung injury caused by acid aspiration. AB - Acid aspiration or intrapulmonary instillation of gastric particles causes lung inflammation leading to acute lung injury (ALI). Hypercapnia exerts different effects on ALI caused by various insults. The effects of hypercapnia on lung inflammation and injury due to acid aspiration are yet to be determined. The present study was designed to investigate the involvement of inducible nitric oxide synthase (iNOS) and other mediators in acid-aspiration-induced ALI. We also sought to evaluate the effects of hypercapnia on the lung and associated changes induced by acid aspiration. We used Spague-Dawley rats anesthetized with intraperitioneal pentobarbital (40 mg/kg). Gastric acid particles were prepared from the stomach contents of rats at necropsy. The rats were randomly assigned to receive intratracheal instillation of physiological saline solution (PSS) at pH 7.24 (Control group), PSS at pH 1.25 (Low pH, LPH group), gastric particles (GP group), and GP with low pH PSS (GPLPH group). There were 10 rats in each group. The animals were observed for 6 hrs. To evaluate the effects of hypercapnia, we carried out two series of experiments: one under normocapnia and the other under hypercapnia with alteration of CO2 fraction in inspired air. Arterial pressure (AP) was monitored from the femoral arterial catheter. Heart rate was obtained from AP traicing. We determined the blood gases and acid-base status. Lung weight to body weight (LW/BW) ratio, LW gain (LWG), protein concentration in bronchoalveolar lavage (PCBAL) and leakage of Evans blue dye tracer were measured. Plasma nitrate/nitrite, methyl guanidine (MG), myeloperoxidase (MPO), phospholipase A2 (PLA2), proinflammatory cytokines were assessed. Histopathological examination of the lung tissue was performed. We employed reverse-transcriptase polymerase chain reaction to detect the expression of iNOS mRNA. GP and GPLPH caused hypotension, decreases in PaO2, pH and SaO2, and an increase in PaCO2. The insults also elevated LW/BW, LWG, PCBAL and dye leakage, plasma nitrate/nitrite, MG, MPO, PLA2, tumor necrosis factor(alpha), interleukin beta and interleukin-6. The lung pathology was characterized by alveolar edema and hemorrhage with inflammatory cells infiltration. Assessment of lung injury score revealed that GP and GPLPH caused ALI. Furthermore, hypercapnia significantly enhanced ALI and associated changes following LPH, GP and GPLPH. Intratracheal instillation of GP in normal or low pH PSS causes ALI accompanied with biochemical changes. The release of nitric oxide via iNOS isoform is detrimental to the lung. Hypercapnia tended to enhance ALI and associated changes induced by gastric acid instillation. PMID- 19777798 TI - Effects of Antrodia camphorata extracts on the viability, apoptosis, [Ca2+]i, and MAPKs phosphorylation of OC2 human oral cancer cells. AB - The effect of Antrodia camphorata (AC) on human oral cancer cells has not been explored. This study examined the effect of AC on the viability, apoptosis, mitogen-activated protein kinases (MAPKs) phosphorylation and Ca2+ regulation of OC2 human oral cancer cells. AC at a concentration of 25 microM induced an increase in cell viability, but AC at concentrations > or = 50 microg/ml decreased viability in a concentration-dependent manner. AC at concentrations of 100-200 microg/ml induced apoptosis in a concentration-dependent manner as demonstrated by propidium iodide staining. AC (25 microg/ml) did not alter basal [Ca2+]i, but decreased the [Ca2+]i increases induced by ATP, bradykinin, histamine and thapsigargin. ATP, bradykinin, and histamine increased cell viability whereas thapsigargin decreased it. AC (25 microg/ml) pretreatment failed to alter ATP-induced increase in viability, potentiated bradykinin-induced increase in viability, decreased histamine-induced increase in viability and reversed thapsigargin-induced decrease in viability. Immunoblotting suggested that AC induced phosphorylation of ERK and JNK MAPKs, but not p38 MAPK. Collectively, for OC2 cells, AC exerted multiple effects on their viability and [Ca2+]i, induced their ERK and JNK MAPK phosphorylation, and probably evoked their apoptosis. PMID- 19777799 TI - Effects of arginine supplementation on post-exercise metabolic responses. AB - This study investigated the effects of arginine supplementation on acute metabolic responses during recovery after a single bout of endurance exercise in trained athletes. Twelve healthy male judo athletes were randomly divided into two groups and performed a single bout of exercise at a speed estimated to correspond to 75%VO2max for 60 min, and then took either a placebo or arginine at 0.1 g/kg-wt. Blood samples of each athlete were collected before exercise, and 0, 15, 30, 45, 60, 90, 120 min after exercise, respectively. The experiment was repeated two weeks later, but treatments were exchanged for the two groups. The concentrations of glucose, insulin, free fatty acid (FFA), glycerol, lactate, ammonia, creatine kinase, and NOx (NO2(-) + NO3(-)) in blood were examined. No differences in the levels of glycerol, lactate, ammonia, creatine kinase, or NOx between the two groups were observed at any of the time points. However, the concentration of glucose was significantly higher in the arginine group as compared to that in the placebo group at the 15-min recovery point. The insulin concentration was also higher in the arginine group as compared to that in the placebo group at the 30-min recovery point. Furthermore, the free fatty acid levels at the 30, and 45-min recovery points were significantly lower in the arginine group compared to those in the placebo group. The results indicated that arginine supplementation during the exercise recovery period could increase glucose and insulin concentrations, and decrease FFA availability in the blood. PMID- 19777800 TI - Comparative study of c-Fos expression in rat dorsal vagal complex and nucleus ambiguus induced by different durations of restraint water-immersion stress. AB - Restraint water-immersion stress (RWIS) of rats induces vagally-mediated gastric dysfunction. The present work explored the effects of different durations of RWIS on neuronal activities of the dorsal vagal complex (DVC) and the nucleus ambiguous (NA) in rats. Male Wistar rats were exposed to RWIS for 0, 30, 60, 120, or 180 min. Then, a c-Fos immunoperoxidase technique was utilized to assess neuronal activation. Resumptively, c-Fos expression in DVC and NA peaked at 60 min of stress, subsequently decreased gradually with increasing durations of RWIS. Interestingly, the most intense c-Fos expression was observed in the dorsal motor nucleus of the vagus (DMV) during the stress, followed by NA, nucleus of solitary tract (NTS) and area postrema (AP). The peak of c-Fos expression in caudal DMV appeared at 120 min of the stress, slower than that in rostral and intermediate DMV. The c-Fos expression in intermediate and caudal NTS was significantly more intense than that in rostral NTS. These results indicate that the neuronal hyperactivity of DMV, NA, NTS and AP, the primary center that control gastric functions, especially DMV and NA, may play an important role in the disorders of gastric motility and secretion induced by RWIS. PMID- 19777801 TI - Supplementary catechins attenuate cooking-oil-fumes-induced oxidative stress in rat lung. AB - Cooking-oil-fumes containing toxic components may induce reactive oxygen species (ROS) to oxidize macromolecules and lead to acute lung injury. Our previous study showed that a decaffineated green tea extract containing (+)-catechin, (-) epicatechin, (+)-gallocatechin, (-)-epigallocatechin, (-)-epicatechin gallate, and (-)-epigallocatechin gallate can inhibit oxidation, inflammation, and apoptosis. We determined whether the catechins supplement may reduce cooking-oil fumes-induced acute lung injury in rat. In the urethane-anesthetized Wistar rat subjected to 30-120 min of cooking-oil-fumes exposure, blood ROS significantly increased in the recovery stage. After 30-min cooking-oil-fumes exposure, the enhanced blood ROS level further increased in a time-dependent manner during the recovery stage (321 +/- 69 counts/10 s after 1 h, 540 +/- 89 counts/10 s after 2 h, and 873 +/- 112 counts/10 s after 4 h). Four hours after 30-min cooking-oil fumes exposure, lung lavage neutrophils and ROS as well as lung tissue dityrosine and 4-hydroxy-2-nonenal increased significantly. Two weeks of catechins supplememnt significantly reduced the enhanced lavage ROS, lung dityrosine and 4 hydroxy-2-nonenal level. Cooking-oil-fumes-induced oxidative stress decreased lung Bcl-2/Bax ratio and HSP70 expression, but catechins treatment preserved the downregulation of Bcl-2/Bax ratio and HSP70 expression. We conclude that catechins supplement attenuates cooking-oil-fumes-induced acute lung injury via the preservation of oil-smoke induced downregulation of antioxidant, antiapoptosis, and chaperone protein expression. PMID- 19777802 TI - Inhibitory effect of piperlonguminine/ dihydropiperlonguminine on the production of amyloid beta and APP in SK-N-SH cells. AB - The study was undertaken to explore whether piperlonguminine/dihydropiperlonguminine could inhibit the production of amyloidbeta (Abeta) in human neuroblastoma cells (SK-N-SH) and to examine the underlying mechanism of this effect. Piperlonguminine/dihydropiperlonguminine components (1:0.8) were extracted from Futokadsura stem, and then used to treat SK-N-SH cells at three different concentrations: 3.13 microg/ml, 6.25 microg/ml and 12.50 microg/ml. Subsequently, the production of Abeta42 and Abeta40 were measured by Western blot analysis and enzyme linked immunosorbent assay (ELISA). On the other hand, the expressions of amyloid precursor protein (APP), Notch1 (Notch intracellular domain) and beta-site amyloid precursor protein cleavage enzyme (BACE-1) were also examined by Western blot assay. The activities of beta secretase and gamma-secretase were detected at the same time. Furthermore, Abeta42 level was detected by immunocytochemistry staining. We demonstrated that the treatment of piperlonguminine/dihydropiperlonguminine could significantly decrease the levels of APP, Abeta42 and Abeta40 peptide in SK-N-SH cells, despite the fact that the activities of beta-secretase and gamma-secretase were not affected significantly. These data suggest that piperlonguminine/dihydropiperlonguminine components could significantly inhibit the level of APP, Abeta42 and Abeta40 peptide without affecting the activity of beta-secretase and gamma-secretase in SK-N-SH cells. PMID- 19777803 TI - A hyperbaric oxygen therapy approach to heat stroke with multiple organ dysfunction. AB - Here in we report the case of a patient who displayed a classic heat stroke with multiple organ dysfunction and hypercoagulable state resistant to conventional whole body cooling and antipyretic therapy, and necessitating the use of hyperbaric oxygen therapy (HBOT) to rescue him from death. A 49-year-old male laborer, suffering from heat stroke syndromes (e.g., hyperpyrexia, seizure and coma, and hypotension), was admitted to an emergency unit of a medical center hospital. The patient displayed multiple organ dysfunction with rhabdomyolysis, hepatic, renal, respiratory, and cerebral dysfunction, and disseminated intravascular coagulation (DIC). Both hyperpyrexia and multiple organ dysfunction were resistant to conventional treatment measures. HBOT was adopted to rescue the patient from heat stroke-induced death. Before HBOT, analyses of serum revealed hypercoagulable state or DIC as well as signs of rhabdomyolysis, and renal and hepatic failure. In addition, pulmonary edema, coma, hypotension, and hyperpyrexia occurred. HBOT was used successfully to combat these syndromes and to rescue the patient from heat stroke death. This case suggests that HBOT is useful for treatment of heat stroke with multiple organ dysfunction. PMID- 19777804 TI - [Novel methods and strategies for strain improvement]. AB - Improvement of the productivity of industrial strains is an important field in micro-biology, because wild-type strains isolated from nature usually produce only a low level of antibiotics. Although random screening and simple rational screening are still effective without using genomic information, they are always time- and labor-consuming. With the broad application of recombinant DNA technology, protoplast fusion and X-omics, novel methods and strategies such as metabolic engineering, genome shuffling, system biology and system biotechnology, ribosome engineering, epigenetic modification are being exploited for the industry microbiology. In this review, we will focus on the progress of these novel methods and strategies for strain improvement in recent years. PMID- 19777805 TI - [Comparison of antiviral activities of porcine interferon type I and type II]. AB - Interferons (IFNs) are natural proteins produced by wide variety of cells in response to viral infection or other biological inducers, and they execute diversified functions as antiviral defense, immune activation and cell growth regulation. Four genes encoding porcine interferons (PoIFN), PoIFN-alpha, PoIFN gamma, PoIFN-alphagamma or PolFN-omega, were cloned and sequenced. The four types of porcine interferon genes were subcloned into the pET-His vector, and expressed in Escherichia coli Rosetta (DE3). The recombinant products were purified and renaturalized from inclusion bodies to obtain a native state of well biological activity. Antiviral activity assays for porcine interferons were performed and evaluated by standard procedures in following cell/virus test systems: Marc 145/PRRSV, Marc-145/VSV, PK-15/VSV, Vero/VSV or MDBK/VSV. The data showed that both PoIFN-alpha and PoIFN-alpagamma demonstrated significant antiviral activities, and the titer of them against PRRSV was up to 10(8) U/mg. PoIFN-gamma had approximately half or one-thirds antiviral activity of PoIFN-alpha. PoIFN omega showed inconspicuous antiviral activity. PMID- 19777806 TI - [Induction of immune response after oral inoculation of mice with Lactobacillus casei surface-displayed porcine epidemic diarrhea viral N protein]. AB - To evaluate the immune responses of recombinant Lactobacillus casei 393 expressing Porcine Epidemic Diarrhea Viral (PEDV) N protein as oral vaccine, n gene of PEDV was subcloned into the expression vector pPG-1, and then transformed into L. casei 393 by electroporation, resulting in recombinant strain pPG-1-n/L, casei 393. The recombinant strains were induced to express interest protein, which was detected by Western blotting, immunofluorescence microscopy and the whole bacteria ELISA. And then BALB/C mice were used as an animal model immunized with recombinant strains by oral administration, and the immune efficacy was analyzed. The recombinant PEDV N protein showed the antigenic specificity, and was located on the bacterial cell walls of pPG-1-n transformed L. casei. The results of ELISA showed that the mice immunized with recombinant strains could produce remarkable special sIgA level in the feces, and high level of anti-PEDV N protein IgG in the serum (P < 0.01), but the induced antibodies in serum did not demonstrated neutralizing effect. Statistical significant difference was observed among the spleen lymphocyte proliferation index (LPI) among the immunization groups of mice and control groups. And there was significant increase. of IFN gamma and IL-4 contents in the supernatant of spleen cell culture in immunized group. In conclusion, the oral immunizations with recombinant L. casei 393 can induce significant specific mucosal PEDV N-specific IgA response as well as serum IgG responses, and can evoke both mucosal immune and system immune responses. PMID- 19777808 TI - [Identification of the regulation elements in heat-inducible Lehsp23.8 promoter]. AB - The promoter of mitochondria-localized small heat shock protein gene in Lycopersicon esculentum (Lehsp23.8) is characterized as strongly heat-inducible. In this study, to determine how the expression of Lehsp23.8 is regulated, we conducted five expression vectors carrying the gus gene driven by the 5' deletion products of the Lehsp23.8 promoter. The corresponding transgenic tobacco plants were generated via Agrobacterium tumefaciens-mediated transformation. Transgenic plants were identified by PCR and Southern blotting analysis. GUS activities under heat-shock conditions were characterized in transgenic tobacco plants. After heat shock, obvious GUS staining was detected in the leaves, shoots, roots, flowers and fruits of the transgenic tobacco plants. The result of fluorometric GUS assays in leaves showed that the heat-induced GUS activity of the 565 bp promoter was the strongest, while that of the 255 bp promoter was the lowest. Deletion analysis shows that the smallest promoter fragment (-255 bp to -23 bp) is sufficient for heat induction. It also indicates that the sequences between 255 bp and -565 bp serve as enhancers, while the sequences between -565 bp and 871 bp can repress the heat-induced activity of the Lehsp23.8 promoter. PMID- 19777807 TI - [Cloning, expression and functional analysis of the dhbC gene from the siderophore producing bacterium Bacillus subtilis CAS15]. AB - We amplified dhbC gene from the siderophore producing bacterium CAS15 by PCR. After ligated the PCR product to pMD18-T vector and then sequenced, we obtained a 1197 bp fragment. The blast result showed that the nucleotide acids of dhbC gene (Accession No. FJ194456) of CAS15 shared 99.7% identity with that of dhbC gene of Bacillus subtilis (GenBank Accession No. Z99120), and was predicted to encode a 43.8 kD polypeptide with 398 amino acid residues. We cloned the dhbC gene into expression vector pET-30a(+) and then transformed into Escherichia coli BL21(DE3) via calcium chloride transformation method, and obtained the recombinant E. coli BL21(DE3)/pET-30a-dhbC. Induced by 1 mmol/L IPTG the fusion protein 6His-DhbC, a 48.8 kD polypeptide was successfully expressed mainly in soluble form in E. coli BL21(DE3), and the amount reached highest at 30 degrees C for 4 h. According to the N-terminal fusion 6 His-tag, we purified the recombinant polypeptide by Ni2+ metal affinity chromatography and finally identified it by Western blotting. The result indicated that the recombinant DhbC had the antigenicity to rabbit anti his-tag polyclonal antibody, which provides the basis for the study of practical utilization in production and the biocontrol mechanism of B. subtilis. Finally, we deleted dhbC gene by gene knockout and then retransformed it into the dhbC gene-delected mutant, which confirmed that dhbC gene play an important role in siderophore biosynthesis. PMID- 19777809 TI - [Cloning of phzIR from the endophytic Pseudomonas sp. G5 and its expression in Escherichia coli]. AB - We isolated a new strain of endophytic Pseudomonas G5 from the stems of Chinese parsley (Coriandrum sativum L.), and it is tentatively identified as Pseudomonas aurantiaca according to analysis of the entire substrate utilization profiles using BIOLOG Microstation system (BIOLOG, Inc, Hayward CA). An array of evidence established that many Gram-negative bacteria employ Quorum sensing (QS) system to regulate gene expression in response to cell density using small diffusible signal molecules, N-acyl homoserine lactones (AHLs), and control diverse phenotypic traits in plant-associated bacteria. In this study, we showed that Pseudomonas sp. strain G5 can produce several types of AHLs at a detectable level using Thin Layer Chromatography (TLC) analysis combined with bioreporter Chromobacterium violaceum CV026 bioassay, and N-hexanoyl-homoserine lactone (HHL, C6-HSL) with Rf value 0.4 is the major signal molecule. Furthermore, we have identified its quorum sensing system composed of PhzI and PhzR by cloning and sequencing of phzI-phzR. PhzI is responsible for synthesis of AHLs signal molecules, and PhzR is a transcriptional regulator. Finally, we heterologously expressed the recombinant plasmid pMD-phzIR in Escherichia coli JM109 and verified it using C. violaceum CV026 bioassay. The phylogenetic analysis using MEGA4 revealed highly similarities exist among the phzIR homologs, suggesting it is evolutionary well conserved in the genus Pseudomonas. PMID- 19777810 TI - [Extraction and structural identification of the antifungal metabolite of Streptomyces lydicus A02]. AB - We isolated a high efficient antifungal strain A02 from forest soil in a suburb of Beijing. The result of polyphasic taxonomy confirmed that strain A02 belongs to Streptomyces lydicus. The fermented broth of the strain presented a stable and strong inhibiting activity against many plant pathogenic fungi. The purpose of this study was to ascertain the substance base of the antifungal activity of strain A02. We extracted the antifungal metabolite of A02 by using column chromatography with X-5 macroporous resin and 100-200 mesh silica gel respectively, and then purified it by LC-9101 recycling preparative HPLC with a SP-120-15 column (JAIGEL-ODS-AP). An active compound with purity over 99.845% was finally obtained. The chemical structure of the active compound was determined with spectroscopy methods, including ultraviolet spectrometry, infrared spectrometry, high resolution mass spectrometry and nuclear magnetic resonance. According to the analysis results, we identified the active compound as a tetraene macrolide antibiotic with the molecular weight of 665, the molecular formula C33H47No3 and the same chemical structure as natamycin. Our research revealed a new biosynthetic function for S. lydicus to produce natamycin, and an expanding application field for natamycin to be used for the control of fungal plant diseases. PMID- 19777811 TI - [Analysis of geldanamycin analogues in trace amounts by LC-MS/MS]. AB - Ansamycins, such as rifamycin and ansamitocin, usually consist of a group of structural similar components. Geldanamycin, a benzenic ansamycin, has been found to consist of four structural similar components. We analyzed the geldanamycin (GDM) preparation from Streptomyces hygroscopicus 17997 by LC-ESI(+)-MS/MS, and discovered five novel and one known GDM analogues in trace amounts. Based on the ESI(+)-MS/MS spectra of these GDM analogues, and the present understanding of GDM biosynthesis, we proposed the possible chemical structures of these GDM analogues. Three novel GDM analogues, all having the same molecular formula of C29H42N2O10, were GDM biosynthetic derivatives with one of the three C-C double bonds between C2-C3, C4-C5 and C8-C9 in GDM changed to mono-hydroxylated C-C single bond. The other two novel GDM analogues, having the same molecular formula of C28H38N2O8, were 17(or 12, or 4)-desmethoxylgeldanamycin and 4,5-dihydro-10,11 dehydrate-17-desmethyl-17-hydroxylgeldanamycin, respectively. The known GDM analogue, having the molecular formula of C29H42N2O9, was 4, 5 dihydrogeldanamycin, an intermediate in GDM biosynthesis. The discovery of novel GDM analogues provided us new insights in understanding the biosynthetic details of GDM, and clues of obtaining GDM derivatives by gene-disruption and combinatorial biosynthesis. PMID- 19777812 TI - [Transient expression in microplasmodia of Physarum polycephalum]. AB - The plasmodium of Physarum polycephalum is a suitable eukaryotic cell for cell cycle investigation, but there is no compatible transient expression system for the plasmodium. Using the promoter and terminator of ardC actin of Physarum polycephalum substituted the CMV IE and SV40 polyA of plasmid pDsRedl-N1, using cassette PardC-MCS-DsRed1-TardC substituted the cassette PardC-hph-TardC of plasmid pTB38, we constructed plasmids pXM1 and pXM2 for transient expression of red fluorescent protein (RFP) in Physarum polycephalum respectively. After reconstituting the transcription elongation factor homologous gene (pelf1) of Physarum polycephalum into the pXM2, we generated a plasmid pXM2-pelf1. After the plasmid pXM1, pXM2 and pXM2-pelf1 were electroporated into the plasmodium of Physarum polycephalum, we observed optimum RFP and PELF1-RFP expression under fluoroscope and confocal microscope between 24-48 h after electroporation, and found that ELF1-RFP expression was accumulated in nucleus of microplasmodium, the optimum electroporation parameters were 40 V/cm electric field, 1 ampere current, and 70 micros electric shock time. The results suggest that this expression system is qualified for transient expression of specific protein in plasmodium of Physarum polycephalum. PMID- 19777813 TI - [Medium optimization for enhanced production of carbonyl reductase by Candida tropicalis 104 by response surface methodology]. AB - Using response surface method, we optimized the medium for the asymmetric whole cell biotransformation by Candida tropicalis 104. This strain was used for microbial reduction of 1-[3,5-bis(trifluoromethyl)phenyl] ethanone to (S)-l-[3,5 bis(trifluoromethyl)phenyl] alcohol, with enantiomeric excess(e.e.) reached more than 99.9%. Fractional factorial design was used to evaluate the effects of medium components on carbonyl reductase activity of Candida tropicalis 104. Yeast extract, glucose and NH4Cl were the most important factors among six tested variables that influence the enzyme activity for the biotransformation process. Based on the experimental results, the path of steepest ascent was undertaken to approach the optimal region of these factors. Central composite design and response surface analysis were subsequently employed for further optimization. The optimal medium for Candida tropicalis 104 was composed of (in g/L): glucose 47.14, yeast extract 13.25, NH4Cl 2.71, MgSO4.7H2O 0.4, KH2PO4 1, K2HPO4 1. Under the optimum conditions, the maximum enzyme activity of 852.75 U/L in theory and 851.13 U/L in the experiment were obtained, with an increase of 65.2% compared to the original medium components. PMID- 19777814 TI - [Screening and characterization of lipase from a metagenome library of dairy rumen microflora]. AB - Using lipase segregation agar containing trioleoylglycerol, we obtained 18 lipase positive clones by screening from a metagenome library of dairy rumen microflora containing 15,360 clones. The average insert size of lipase positive clones was about 60 kb. Lipase enzyme activity analysis by p-NPP method indicated that Lipase6, Lipase7 and Lipase8 had higher lipolytic activities to substrates of p nitrophenyl palmitate (C16), p-nitrophenyl alaurate (C12) and p-nitrophenyl palmitate (C16) respectively. The optimum pH of Lipase 6, Lipase 7 and Lipase 8 were 7.5. The halflife period of Lipase 8 with the value of 15 min in 70 degrees C decreased with the increase of temperature. In conclusion, the lipases screened in this study had different substrates specificity and good thermo stability, which laid a basis for large-scale industrial application. PMID- 19777815 TI - [Effects of mutational sptl5 gene to xylose utilization of Saccharomyces cerevisiae]. AB - We used genetic methods to get a mutational spt15 gene from the recombinant strain Saccharomyces cerevisiae YPH499-3, screened by global transcription machinery engineering (gTME) approach. We transformed the gene into the original strain Saccharomyces cerevisiae YPH499 using the vector pYX212, then got a new recombinant strain. We studied the characteristic of this strain and found that it could metabolize xylose and co-ferment xylose and glucose. Under the fermentation condition of 30 degrees C, 200 r/min, 72 h, the utilization ratio of xylose was 82.0%, with 32.4% of ethanol yield when the carbon source in the media was 50 g/L xylose, while the utilization ratio of xylose and glucose was 80.4% and 100% respectively, with the 31.4% of ethanol yield when the carbon source was 50 g/L glucose/xylose (1:1). Meanwhile, the concentration of the by-product xylitol was very low. This study demonstrates the effect which the forward mutation of spt15 gene makes to the co-fermentation of xylose and glucose to ethanol by Saccharomyces cerevisiae. PMID- 19777816 TI - [Effects of medicinal insect Catharsius molossus on submerged fermentation and in vivo anti-hepatoma activity of Ganoderma lucidum]. AB - We studied the effects of Catharsius molossus (a Chinese medicinal insect) on the cell growth, fermentation kinetics of key bioactive substances and anti-cancer activity of Ganoderma lucidum in submerged fermentation. The results showed that C. molossus at all the tested concentrations had no stimulatory effect on the cell growth. However, addition of C. molossus at 5 g/L lead to significant effects on the fermentation kinetics of polysaccharides and triterpenoids of G lucidum, and at 7th day in fermentation process, the yields of polysaccharides and triterpenoids reached 2.81 g/L and 539.0 mg/L, respectively, while they were 2.25 g/L and 428.2 mg/L in control. In vivo anti-cancer studies showed that the inhibitory rates of control fermented G lucidum (CFG) and a combination of water extract from C. molossus and CFG on the developed tumor (Heps) in mice were 41.61% and 42.24%, respectively. Moreover, the inhibitory rate of the G lucidum fermented with C. molossus (GFC) reached 57.21%, which was enhanced 37.49%, compared to the inhibitory rate of the control fermented G lucidum. These results suggest that supplementation of C. molossus in submerged fermentation of G lucidum lead to a significant enhancement of the anti-cancer activity of cultured G lucidum. PMID- 19777817 TI - [Effect of initial substrate concentrations and pH on hydrogen production from xylose with Clostridium butyricum T4]. AB - We studied the effect of initial pH and substrate concentrations on the conversion of xylose to hydrogen by Clostridium butyrium T4 at pH 5.0-8.5 and substrate concentrations 5-40 g/L. The cumulative hydrogen volume and the specific hydrogen production rate increased and then decreased with increasing initial pH or substrate concentrations. At initial pH 6.5 and substrate concentration 20 g/L, the cumulative hydrogen production and the specific hydrogen production rate reached the maximum value of 4.26 L/L and 18.86 mmol H2/h g-DCW (dry cell weight). PMID- 19777818 TI - [Biodehydrogenation of 11beta-hydroxyl melroxyprogesterone by Arthrobacter simplex UR016 in microemulsion system]. AB - To improve mass transfer and enhance the yield for C(1,2) biodehydrogenation of steroid 11beta-hydroxyl medroxyprogesterone, we carried out the dehydrogenation reaction of 11beta-hydroxyl medroxyprogesterone in an oil-in-water (O/W) microemulsion by Arthrobacter simplex UR016. We studied the effects of system composition, dehydrogenation temperature and substrate concentration on microbial transformation. We formulated a suitable O/W microemulsion system with Arthrobacter simplex UR016 culture broth as aqueous phase, 10 g/L of edible oil as oil phase, 4 g/L of Tween-O80 and 7% (V/V) alcohol as surfactant and cosurfactant. The optimal dehydrogenation temperature was 33 degrees C. The results showed that in Tween-80/alcohol/edible oil/water microemulsion system, the hydrophobic steroid was solubilised and diffused effectively, with the maximum conversion rate of 88.6% at 46 h under 4 g/L substrate concentration, an increase of 66.2% compared to that in aqueous system. The C(1,2) biodehydrogenation of 11beta-hydroxyl medroxyprogesterone is more efficient in water-edible oil microemulsion system than in aqueous system. PMID- 19777819 TI - [Biodegradation of nicotine in tobacco extracts for making reconstituted tobacco by strain DN2]. AB - The purpose of the study is to use O. intermedium DN2 to degrade nicotine in tobacco extracts for making reconstituted tobacco. Firstly, we studied the effects of various factors on degradation of nicotine in the extracts by strain DN2. When we added 0.1% yeast extract into the extracts, adjusted its pH value to 7.0 by ammonia solution, inoculated 15% cultures and maintained fermentation temperature of 30 degrees C, the degradation rate of nicotine by strain DN2 was the fastest. Furthmore, under these conditions, we studied the degradation rates of nicotine in three fed batches culture which carried out in a 30-L reactor, the result showed that the average degradation rate of nicotine by strain DN2 was 140.55 mg/L/h, which was much higher than that reported in other studies. These results indicated that strain DN2 may be useful for reducing nicotine content of reconstituted tobacco. PMID- 19777820 TI - [Advance in dihydroxyacetone production by microbial fermentation]. AB - We reviewed the fermentation for dihydroxyacetone production. Microbial fermentation is better for dihydroxyacetone production as compared to chemical methods. Gluconobacter oxydans was recognized as the most important strain for industrial production of dihydroxyacetone. The dihydroxyacetone yield is associated with many factors such as substrate, product, oxygen and biomass concentration. Repeated fed-batch fermentation and immobilization fermentation were recognized as the most potential process in various fermentation mode. Construction of recombinant microorganism and optimization of process are future directions of dihydroxyacetone production. PMID- 19777821 TI - [Controllable bio-fabrication based on microbes]. AB - Microorganisms in nature have rich variety, whose sizes are from nano scale to micro scale. Therefore, microbes can be used as natural "building blocks" in nano/micro multi-level fabrication processes. At present, most of the bio manufacturing methods do not apply to direct control of living microbes. Their microbiological global functions and superiorities are not available. In this paper, two novel nano/micro bio-fabrication approaches, micro-fluidic control method and magnetic control method have been established. The living microbes could be manipulated to form micro-scaled patterns or to move orientedly. By these approaches, living microbes are taken as nano/micro robots. We could employ their specific biological functions and regulate their controllable self assembly, which is expected to design and create a series of new special functional materials and devices. PMID- 19777822 TI - [Effects of medicinal insect, Catharsius molossus on biosynthesis of polysaccharides from Ganoderma lucidum in submerged culture]. AB - We studied the effects of several medicinal insects on biosynthesis of polysaccharides from Ganoderma lucidum in submerged culture. The results showed that the medicinal insect, Catharsius molossus at 5 g/L significantly promoted the biosynthesis of intracellular polysaccharides (IPS) and extracellular polysaccharides (EPS) of G. lucidum, and compared with control, IPS and EPS yields markedly enhanced from (1.93 +/- 0.09) g/L to (2.41 +/- 0.12) g/L and (520.3 +/- 20.2) mg/L to (608.9 +/- 20.2) mg/L, respectively (P < 0.05). Both IPS and EPS consisted of five kinds of components, and IPS-1 and EPS-1 were the major components of IPS and EPS, respectively. Further separation studies showed that IPS-1 was made up of three single compounds, while EPS-1 was made up of two single compounds. There were no new components in both IPS and EPS obtained from G lucidum in submerged culture by the addition of the insect, C. molossus, suggesting the biosynthetic pathways of the major components of IPS and EPS had not been changed. PMID- 19777823 TI - [Cloning, expression and characterization of mannanase from Armillariella tabescens EJLY2098 in Pichia pastoris]. AB - We used reverse transcriptase polymerase chain reaction (RT-PCR) and rapid amplification of cDNA end (RACE) techniques to obtain the full-length cDNA of beta-mannanase (EC 3.2.1.78) from Armillariella tabescens EJLY2098 (an edible fungus). Sequence analysis of the 1481 bp full-length cDNA encoding 445 amino acid residues indicated that the gene contained two structural domains, cellulose binding domains (CBD) and glycoside hydrolase family 5 (GHF5) domains, other than the conserved beta-mannanase domain. Thus, we classified this gene as a member of glycoside hydrolase family 5. Next, we cloned a 1308 bp fragment encoding the beta-mannanase mature peptide (re-atMAN47) into the expression vector pPICZalphaA and expressed it in Pichia pastoris. The yield was 440 mg/L. Enzyme activity reached a maximum of 1.067 IU/mL after 72 h of methanol induction. The re-atMAN47 had an optimal temperature of 60 degrees C and an optimal pH of 5.5. It manifested broad thermostability from 30 degrees C-65 degrees C, and was stable between pH 4.5-7.0. This study represents the first record of a beta-mannanase from Armillariella tabescens EJLY2098 and provides a new source of carbohydrate hydrolysis enzyme with good biosafety, thermostability and wide pH stability. It is a good approach for the industrial needs of feed, food and pharmaceutical manufacturers. PMID- 19777824 TI - [Saturation mutagenesis of three amino acid positions consisting of the active site of an endoglucanase from termite Coptotermes formosanus]. AB - Functional improvement to one component of the cellulase, endo-beta-1, 4 glucanase, has been a focus of the recent research in this area. We report here the saturation mutagenesis of the active site of an endoglucanase (CfEG) from termite Coptotermes formosanus. First, three dimensional structure of CfEG was built via homology modeling by using a close-related (79% homology in sequence) endo-beta-1,4-glucanase (NtEG PDB id = 1ks8) from higher termite Nasutitermes takasagoensis as a template. Second, we identified three corresponding amino acid positions at the active site of CfEG by structural superposition onto NtEG. These three putative amino acids for the active site of CfEG, i.e., Asp53, Asp56 and Glu411, were subjected to saturation mutagenesis using degenerate primers. Among the mutants, Asp53Glu and Asp56Cys showed somewhow higher activities than the wildtype, with the latter having more than 3-fold decrease in Km. Double mutation Asp53Leu/Asp56IIe showed nearly 2-fold increase in specific activity and in the same time 2-fold decrease in Km. Saturation mutagenesis to the position Glu411 produced no active mutant, even changing Glu411 explicitly into its similar amino acids such as Glu411Asp and Glu411Gln could not result in any active mutant. These imply that position Glu411 could be extremely important and therefore indispensable for CfEG functionality. PMID- 19777825 TI - [Coculture of actinomycetes with Bacillus subtilis and its effect on the bioactive secondary metabolites]. AB - To explore the effect of coculturing actinomycetes with Bacillus subtilis on the production of bioactive secondary metabolites, we studied the difference between fermentation products of monocultures and the corresponding cocultures of 22 actinomycetes by antimicrobial assay and HPLC-PDA analysis. We selected Streptomyces strain FXJ2.014 with high bioactivity for further analysis and found additional metabolites in fermentation extracts of cocultures of strains FXJ2.014, FXJ1.296 and AS 4.1252 respectively with B. subtilis. Quinomycin A was the main bioactive metabolite produced by the monoculture of strain FXJ2.014, while a new quinomycin-like component named FXJ2.014-HB was produced when strain FXJ2.014 was cocultured with B. subtilis. Further tests of antimicrobial and antitumor activities indicated that FXJ2.014-HB and Quinomycin A had significant differences in terms of bioactivity. Moreover, the inhibitory activity of FXJ2.014-HB to a variety of tumor cell lines was weaker than the highly toxic Quinomycin A, indicating its potential to be an antibiotic with low cell toxicity. In conclusion, coculture can be used as a promising approach to discover bioactive secondary metabolites from actinomycetes. PMID- 19777826 TI - [Synthesis of biodiesel from crude oil by immobilized lipase]. AB - We used immobilized lipase from Candida sp. 99-125 to produce fatty acid methyl esters (FAMEs) from crude oil and methanol. We studied the effects of phospholipids on activity of immobilized lipase, reaction velocity, stability of immobilized lipase and the stability of immobilized lipase in crude and refined oil. Results showed that the activity of the lipase immersed in petroleum ether with 1% phospholipids dropped more quickly than the lipase in petroleum ether without phospholipids. When soybean oil was used without phospholipids as material, the FAMEs yield of 15 min was 26.2%, whereas the yield decreased to 12.4% when there were 5% phospholipids in the soybean oil. However when the phospholipids content was below 1%, the stability of the lipase did not change obviously. The lipase was stable when used to catalyze crude soybean oil and crude jatropha oil, after 10 cycles the FAMEs yield was still above 70%. This lipase showed great potential for industrial production of biodiesel from crude oil. PMID- 19777827 TI - [Construction and fermentation of a recombinant Candida glycerinogenes strain with high glycerol production]. AB - Candida glycerinogenes WL2002-5 (C.g) is an important industrial strain for glycerol production. To further improve glycerol production, we reconstructed a binary vector pCAM3300-zeocin-CgGPD1, introduced it to Agrobacterium tumefaciens LBA4404 by electroporation, and then transformed the T-DNA harboring the CgGPD1 to Candida glycerinogenes by Agrobacterium tumefaciens-mediated transformation (ATMT). After 96 h fermentation with glucose as the substrate, we screened a transformant named C.g-G8 with high glycerol production. Compared with the wild strain, the glucose consumption rate of C.g-G8 and the glycerol production were 12.97% and 18.06% higher, respectively. During the fermentation, the activity of glycerol-3-phosphate dehydrogenase of C.g-G8 was 27.55% higher than that of the wild strain. The recombinant Candida glycerinogenes with high glycerol production was successful constructed by ATMT method. PMID- 19777828 TI - [DNA fragment isolation of genomic microsatellite in Pinellia ternata by magnesphere]. AB - OBJECTIVE: To develop microsatellite primers with the method of isolation of genomic microsatellite in Pinellia ternata by magnesphere. METHOD: By taking advantage of the high binding affinity of biotin to streptavidin, microsatellite probe of the 5' end biotin was combined with magnesphere paramagnetic particles, and then combinations were hybridized with the digested P. ternata DNA fragments in which both ends of them connected with special adaptor, the other DNA fragments were eluted out. The microsatellite library was established. The crossed fragments were used as the template to conduct PCR amplification with the adapter sequences as primers, the products were cloned directly, subsequently screened by bacterium liquid PCR, and DNA sequencing was carried out. RESULT: Fifteen microsatellites of P. ternata were obtained, development efficiency was 93.75%. CONCLUSION: The result demonstrates that magnesphere is a fast and efficient method to develop microsatellite. PMID- 19777829 TI - [Population structure and ecological distribution of rhizospheric microorganisms of Angelica sinensis]. AB - OBJECTIVE: To study the population structure and ecological distribution of the rhizosperic microorganisms of Angelica sinensis. METHOD: The isolation, culture and identification of microorganisms were studied by the biological methods, and the achieved data were analyzed by the statistical methods for analysis of species diversity. RESULT: With the growing stages of A. sinensis from Min county of Gansu province, Heqing of Yunnan province and Baoxing of Sichuan province, the quantity of rhizosperic microorganisms increased; and it had reduced since October. In the area of Min county Gansu province, the number ratio of bacteria and fungi was higher than that in the other two areas. In addition, the population diversity and dynamic change were different in three areas. In the area of Min county Gansu province, the number of dominant microbial populations and the population diversities of bacteria, actinomyces and fungi in the rhizosphere were greater than those in the other two areas. CONCLUSION: The microecological system and microbial population structure in the rhizosphere of Min county Gansu province were stable. And it was suitable for the growth of A. sinensis in this area. PMID- 19777830 TI - [Effect of phosphorus on copper tolerance in Achyranthes bidentata]. AB - OBJECTIVE: To study the effect of phosphorus on copper tolerance in Achyranthes bidentata. METHOD: A PVC pipe experiment was conducted to study the interactive effects of phosphorus (P) and copper (Cu), on growth, elemental accumulation and chemical constituents of A. bidentata. Two levels of elemental P were applied at 0 (P0) and 100 ( P100) mg x kg(-1) soil with 5 levels of Cu at 0 (Cu0), 100 (Cu100), 200 (Cu200), 200 (Cu400), 200 (Cu600) mg x kg(-1) soil, respectively. RESULT AND CONCLUSION: The biomass production between different Cu treatments, phosphorus treatment showed significant differences. The biomass reached the maximum value as the concentration of Cu and P was 100 mg x kg(-1). Low concentration of Cu improved the growth of A. bidentata. The growth was blocked as Cu concentration reached 200 mg x kg(-1) in soil, however the contents of oleanolic acid and ecdysterone in roots of A. bidentata had not influenced by Cu. P could improved the copper tolerance in A. bidentata and increased root yield. The Cu concentration in soil of the cultivation bases must be below 200 mg x kg( 1) in order to produce good quality of medicinal material. PMID- 19777831 TI - Leaf epidermal features of 21 medicinal plants of Euonymus in China. AB - OBJECTIVE: To accumulate taxonomic data of the leaf epidermal features of the medicinal species of Euonymus. METHOD: Twenty-nine materials of 21 taxa (including 16 species, 4 varieties and 1 form) representing 5 sections of Euonymus are examined by using both of light microscopy and scanning electron microscopy. RESULT: The form of epidermal cells in Euonymus is usually polygonal or irregular. The stomata were anomocytic in all the species examined except E. maackii and E. bungeanus var. semipersistens. Stomatal types of all species studied may be anomocytic, anisocytic, cycolocytic or the transitional types among them. CONCLUSION: The results show that some characteristics (including cuticular membrane, shape of guard cells, inner margin of outer stomatal rim, outer stomatal rim and stomata type) of the leaf epidermis can provide some anatomical evidence for the classification. The characteristics of leaf epidermis support following treatments: E. acanthocarpus var. longipes, E. acanthocarpus var. scandens and E. acanthocarpus var. sutchuanensis should be merged into E. acanthocarpus; E. bungeanus var. semipersistens should be merged into E. maackii; E. hamiltonianus f. lanceifolius should be merged into E. hamiltonianus. PMID- 19777832 TI - [Oral absorption enhancers of Ophiopogon japonicas polysaccharides]. AB - OBJECTIVE: To investigate suitable oral absorption enhancer (s) for Ophiopogon japonicas polysaccharides (OJP) and provide bases of utilizing the absorption enhancer to realize the oral administration of OJP. METHOD: The absorption enhancement effects and cytotoxicity of clove oil, peppermint oil, borneol, Sanqi saponins, Maidong saponins, Ginseng saponin Rg1, Sanqi saponin R1 and sodium caprate (SC) were evaluated via Caco-2 cell culture model. The absorption of OJP from rat intestinal segments and the absorption enhancement effect of SC were investigated by in situ experiments of rat intestinal segments. RESULT: SC was an effective and safe absorption enhancer. However, the absorption enhancement effects of clove oil, peppermint oil and Maidong saponins were highly correlated with their cytotoxicity. OJP alone was poorly absorbed from all the rat intestinal segments. It was rapidly absorbed when co-administered with SC, and the absorption increase was significant and the best absorption enhancing site of SC for OJP was colon. CONCLUSION: The absorption enhancement effects of absorption enhancers are often correlated with their cytotoxicity. Co administrating a powerful and safe absorption enhancer is an effective and valuable method of enhancing oral absorption of OJP. PMID- 19777833 TI - [Development of Silymarin nanocrystals lyophilized power applying nanosuspension technology]. AB - OBJECTIVE: To prepare silymarin nanosuspension and lyophilized power for enhancing the dissilution of poorly soluble drugs. METHOD: The precipitation technique was adapted to produce the silymarin nanosuspensions respectivly applying Tween 80, SDS and Poloxamer188 as stabilizers. The lyophilized formula contained 5% mannitol as cryoprotectant. Particle size, Polydispersity index and Zeta potential were detected by Mastersizer nano ZS (Malvern England). Morphological character was observed with Transmission Electron Microscopy. The product's structure was performed with X-ray diffractometer. RESULT: The silymarin nanosuspension was successfully prepared, in which the drug particle size was about 100-300 nm,and the particles had ball-like shape and good dispersive properties. CONCLUSION: This study provided potential for the neotype dosage form development of the Chinese Traditional Medicine. PMID- 19777834 TI - [Determination of leonurine in leonurus granule and extractum by UPLC]. AB - OBJECTIVE: To develop an UPLC method for the determination of leonurine in traditional Chinese medicines. METHOD: An Acquity UPLC BEH C18 column (2.1 mm x 100 mm) with 1.7 microm particle size was used. The mobile phase was composed of methanol and ammonium formate buffer (pH 4.0) in gradient mode. The flow rate was 0.3 mL x min(-1) and the chromatograpic run time was 18 min for one sample. RESULT: The results showed that there was significant difference in the content of leonurine in the leonurus products from different pharmaceutical companies. The leonurine content in those products is in the range of 45.6-193 microg x g( 1). CONCLUSION: The method is simple, reproducible and reliable. It can be used to control the quality of related drugs. PMID- 19777835 TI - [Chemical constituents of fresh celery]. AB - OBJECTIVE: To study the chemical constituents of the whole plant of fresh celery (Apium graveolens). METHOD: The constituents were isolated and purified by silica gel, Sephadex LH-20, ODS column chromatography, PTLC, HPLC, and their structures were elucidated on the basis of spectral evidences. RESULT: Twenty compounds were obtained and identified as falcariondiol (1), (9Z) 1,9-heptadecadiene-4,6-diyne 3,8,11-triol (2), oplopandiol (3), bergapten (4), 5,8-dimethoxy psoralen (5), isofraxidin (6), eugenic acid (7), trans-ferulic acid (8), trans-cinnamic acid (9), p-hydroxyphenylethanol ferulate (10), caffeoylquinic acid (11), 5-p-trans coumaroylquinic acid (12), sedanolide (13), lunularin (14), lunularic acid (15), 2-(3-methoxy-4-hydroxyphenol)-propane-1,3-diol (16), D-allitol (17), beta sitosterol (18), benzolic acid (19), succinic acid (20). CONCLUSION: Compounds 2, 3, 6, 10, 12, 14-17 were isolated from genus Apium for the first time. PMID- 19777836 TI - [Synthesis of (2'-bromo-4', 5'-dimethoxy-phenyl)-(2,3-dibromo-4,5-dimethoxy phenyl)-methane as PTP1B inhibitor]. AB - OBJECTIVE: To synthesize (2'-bromo-4',5'-dimethoxy-phenyl)-( 2,3- dibromo-4,5 dimethoxy-phenyl)-methane (6) as protein tyrosine phosphatase 1B (PTP1B) inhibitor. METHOD: Compound 6 was synthesized by Friedel-Crafts reaction, bromination and decarbonylation and screened inhibitory activity against PTP1B by the colorimetric assay. The structure of synthetic intermediates and target product were identified on the basis of spectral analysis. RESULT: Compound 6 was synthesized successfully in four steps and evaluated for its PTP1B inhibitory activity, the screening result shown that compound 6 displayed good inhibitory activity against PTP1B. CONCLUSION: The target compound 6 was synthesized with the overall yield of 20%, which was a new compound and shown good inhibitory activity against PTP1B (inhibition 40.16% at 5 mg x L(-1)). PMID- 19777837 TI - [Chemical constituents from Centipeda minima]. AB - OBJECTIVE: To study the chemical constituents from Centipeda minima. METHOD: The constituents were isolated by column chromatography on silica gel, Sephadex LH-20 and HPLC-ODS, and identified by spectroscopic methods. RESULT: Ten compounds, (-) cis-chrysanthenol-O-beta-D-glucopyranoside (1), methy 3,5-dicaffeoylquinate (2), 3,5-di-O-caffeoyl quinicacid (3), tricin (4), 2-amino-4-methyl-pentanoicacid (5), 2-amino-3-phenyl-propionic acid (6), 4-amino-4-carboxychroman-2-one (7), brevilin A (8), arnicolide C (9), arnicolide D (10) were isolated and identified. CONCLUSION: Compounds 1-7 were isolated from the plant for the first time. PMID- 19777838 TI - [Two en-kaurene diterpenoids from Tibetan medicine Caryopteris toroetii]. AB - OBJECTIVE: To study the chemical constituents of Tibetan medicine Caryopteris toroetii. METHOD: The crude drug was extracted with 95% EtOH and isolated by repeated chromatographic methods. The structures of the isolated compounds were elucidated on the basis of spectral analysis. RESULT: Two en-kaurene diterpenoid compounds: oridonin (1) and nodosin (2), were obtained from C. toroetii and their 1H and 13C-NMR data in CD3OD were reported for the first time. CONCLUSION: The en kaurene diterpenoid compounds were obtained from genus Caryopteris for the first time. PMID- 19777839 TI - [Raman spectroscopic analysis of cinnabar as a traditional Chinese medicine]. AB - OBJECTIVE: To develop a new quality control method for cinnabar, in order to ensure the safety application of cinnabar. METHOD: Three inorganic mercury compounds (HgS, HgO, and HgCl2) and cinnabar samples were analyzed by laser Raman spectroscopy. The cinnabar samples were identified by comparing the Raman band in the Raman spectrum with pure HgS. RESULT: Different Raman bands were observed among three inorganic mercury compounds. The Raman spectroscopic results indicated that cinnabar samples showed the same Raman band as pure HgS, consisting with the HgS contents by XRF analysis. CONCLUSION: The Raman spectroscopic method is simple, rapid, and reliable. It can be applied as an alternative quality control method for cinnabar. PMID- 19777840 TI - [Effects of Xuefu Zhuyu decoction on serum asymmetric dimethylarginine in atherosclerosis rabbits]. AB - OBJECTIVE: To observe the effect of Xuefu Zhuyu decoction on serum asymmetric dimethylarginine (ADMA) level of the atherosclerosis rabbits. METHOD: Twenty-four male rabbits were randomly divided into three groups: control group (n = 8) was fed with normal diet; the model group (n = 8) was fed with high fat/high cholesterol diet; and Xuefu Zhuyu decoction group (n = 8) was fed with high fat/high cholesterol diet and intragastric administrated with Xuefu Zhuyu decoction 7.10 g x kg(-1) x d(-1). Concentrations of serum total cholesterol (TC), total triglyceride (TG), low density lipoprotein (LDL), serum ADMA and serum nitric oxide (NO) were measured after eight weeks. Rabbits' aorta were made into the pathological section to observe the pathology changes degree and atherosclerotic plaqu mean gray value and plaque area were analyzed by OPTIMAS image analysis system. RESULT: 1) Compared with the aortic atherosclerotic plaqu mean gray value of Xuefu Zhuyu decoction group 175.56 +/- 12.30, those of the model group 198.91 +/- 5.08 were significant higher (P < 0.01). Significant difference were found between the the aortic atherosclerotic plaque area of the model group (4.80 +/- 0.83) mm2 and Xuefu Zhuyu decoction group (1.96 +/- 0.48) mm2 (P < 0.01). There were no atherosclerotic plaque in the control group rabbits' aorta. 2) The serum TC (23.42 +/- 7.80) mmol x L(-1), TG (2.37 +/- 0.42) mmol x L(-1) and LDL (17.24 +/- 8.29) mmol x L(-1) of the model group were higher than those of Xuefu Zhuyu decoction group (P < 0.01); Compared with control group, the serum TC (15.63 +/- 4.12) mmol x L(-1) and LDL (7.64 +/- 2.36) mmol x L(-1) of the Xuefu Zhuyu decoction group increased significantly, while there were no significant changes between serum TG of control group (1.11 +/- 0.26) mmol x L(-1) and serum TG of Xuefu Zhuyu decoction group (1.43 +/- 0.34) mmol x L(-1). The serum ADMA of the model group (1.57 +/- 0.17) micromol x L(-1) were higher than those of Xuefu Zhuyu decoction group (1.01 +/- 0.13) micromol x L(-1) (P < 0.01), while the serum NO of the model group (8.76 +/- 2.42) micromol x L( 1) were significantly lower than those of Xuefu Zhuyu decoction group (15.90 +/- 2.38) micromol x L(-1) (P < 0.01). There were no significant difference between the serum ADMA of the control group (0.93 +/- 0.11) micromol x L(-1) and Xuefu Zhuyu decoction group. Compared with Xuefu Zhuyu decoction group, the serum NO of the control group (17.88 +/- 3.34) micromol x L(-1) have no significant difference. 3) The serum ADMA of all rabbits negatively correlated to the serum NO (r = -0.773), (P < 0.01). CONCLUSION: Xuefu Zhuyu decoction can decrease the serum ADMA level in atherosclerosis rabbits. The effect of Xuefu Zhuyu decoction on anti-atherosclerosis may be related to the decreased serum ADMA level. PMID- 19777841 TI - [Gastrodine represses expression of IL-1 beta, IL-6 induced by hyperglycemia in gitter cells]. AB - OBJECTIVE: Inflammatory factors have been known to induce nerve cells apoptosis and decrease learning capacity of diabetics. The aim of this study is to evaluate the inhibitory effect of Gastrodine on the expression of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) in culturing for gitter cells (BV-2 cells) induced by high concentration of glucose. METHOD: The BV-2 cells incubated in vitro with different concentrations of glucose and gastrodine were divided into five groups: control group (glucose: 25 mmol x L(-1)), high concetration of glucose (glucose: 45 mmol x L(-1) HCG) group and Gastrodine groups (glucose 45 mmol x L(-1) with gastrodine 25 mg x L(-1) (LG), 50 mg x L(-1) (MG), 100 mg x L(-1) (HG). After culturing for 24 h, morphological changes of cells were observed by inverted phase contrast microscope. The supernatant protein of IL-1 beta and IL-6 was detected by ELISA. The mRNA expression of IL-1 beta and IL-6 was assessed by Reverse transcription polymerase chain reaction (RT-PCR). RESULT: The cells were proned to aggregate, some of them with hypertrophy, distinct nucleoli and branch shaped hyperplasy in HCG group, while less change in Gastrodine groups. The supernatant protein of IL-1 beta is higher in HCG group than control group (119.53 +/- 15.91) ng x L(-1) vs (25.74 +/- 15.72) ng x L(-1) (P < 0.01), but lower in the gastrodine groups than HCG LG (99.32 +/- 19.66) ng x L(-1), MG (76.94 +/- 17.16) ng x L(-1), HG (88.35 +/- 18.72) ng x L(-1) vs (119.53 +/ 15.91) ng x L(-1) (P < 0.05). The supernatant protein of IL-6 protein also higher in HCG than control group (393.7 +/- 17.51) ng x L(-1) vs (125.85 +/- 36.62) ng x L(-1) (P < 0.01), and lower in the gastrodine groups than HCG (LG 327.06 +/- 23.53) ng x L(-1), MG (217.36 +/- 28.81) ng x L(-1), HG (263.17 +/- 22.32) ng x L(-1) vs (393.7 +/- 17.51) ng x L(-1), P < 0.05). The mRNA expression of IL-1 beta was increased significantly higher in HCG than control group (2.77 +/- 0.29) vs (1.13 +/- 0.27) (P < 0.05), but decreased significantly in gastrodine groups than HCG LGA (2.66 +/- 0.31), MGA (2.1 +/- 0.41), HGA (2.4 +/- 0.28) vs (2.77 +/- 0.29) (P < 0.05). The mRNA Expression of IL-6 was higher in HCG than control group (3.97 +/- 0.33) vs (1.05 +/- 0.13) (P < 0.05, but lower in gastrodine groups than HCG LG (3.28 +/- 0.3), MG (2.65 +/- 0.33), HG (3.04 +/- 0.26), vs (3.97 +/- 0.33) (P < 0.05). CONCLUSION: Gastrodine can inhibit the expression of IL-1 beta, IL-6 in cultured BV-2 cells induced by high concentration of glucose. PMID- 19777842 TI - [Metabolic study of ginsenoside Re in rats]. AB - OBJECTIVE: To systemically study the metabolism of ginsenoside Re in rats. METHOD: Six SD rats were used divided into 3 groups. After oral administration of ginsenoside Re at a dosage of 100 mg x kg(-1), feces were collected at 12, 24, 36, 48, and 60 h. The microbial transformation metabolites of ginsenoside Re were used as standard references. HPLC-ESI-MS/MS analysis was used in the metabolism studies. RESULT: Six metabolites of ginsenoside Re were detected in rat feces by HPLC-ESI-MS/MS analysis. Their structures were identified as 20(S)-ginsenoside Rg2, 20(S)-ginsenoside Rh1, 20(R)-ginsenoside Rh1, ginsenoside F1, 3-oxo ginsenoside Rh1 and protopanaxatriol. CONCLUSION: Ginsenoside Re has the same metabolic pathway with microorganisms, to some extent, justified the use of microbial models for mammalian metabolism studies. PMID- 19777843 TI - [Mechanisms of delay endothelial cell replicative senescence by extracts from Panax ginseng, Panax notoginseng and Ligusticum chuanxiong]. AB - OBJECTIVE: To explore effect of extracts from Panax ginseng, P. notoginseng and Ligusticum chuanxiong on human umbilical endothelial cells (HUVECs) replicative senescence. METHOD: HUVECs were induced to aging by generation cultivating to the eighth cells in order to establish a model of endothelial cells replicative senescence. The cultured HUVECs in vitro were divided into 4 groups, the eighth generation cell-senescence untreated group, Vitamin E group, herbal treated high dose and low dose groups. Changes of HUVECs aging were observed by method of SA beta-gal stained HUVECs and cells cycle were analyzed. Contents of ROS in cells, the levels of anti-superoxide (O2-) and nitric oxide (NO) in cell mediums were examined. Western blot were used to analyse protein expression of NADPH oxidase p47phox, angiotensin type 1 and 2 receptor (AT1R, AT2R). RESULT: Compared with Vitamin E group, the positive cell numbers of beta-gal stained HUVECs were enhanced, cell proliferation was depressed, and the fluorescence intensity of ROS was increased, at the same time, less NO and more O2- in cells were produced in the eighth generation cell-senescence untreated group. Protein expression of p47phox, AT1R and AT2R in cells increased compared with Vit E group. Chinese herbs of high dose and low dose could improve condutions of HUVECs aging. Chinese herbs of high dose and low dose could reduce the positive cell numbers of beta gal stained HUVEC, increase cell proliferation and decrease fluorescence intensity of ROS in cells, at the same time, cells secreting more NO and less O2 . Protein expression of p47phox, AT1R and AT2R in cells treated with Chinese herbs of high dose and low dose were decreased compared with Vit E group. CONCLUSION: The study indicated that extracts from P. ginseng, P. notoginseng and L. chuanxiong could delay endothelial cell replicative senescence. Herbal extracts downregulate the expression of NAD (P) H oxidase subunit-p47phox by means of ROS, hence decrease O2- production and ultimately delay HUVECs in vitro senescence. PMID- 19777844 TI - [Anti-thrombosis effect and its mechanism of Qingkailing injection]. AB - OBJECTIVE: To investigate the anti-thrombosis effect and its mechanism of Qingkailing injection (QKL). METHOD: SD rats were randomly divided into control group, model group and QKL 2.5, 5.0, 10 groups. QKL were given (i.p.) to rats once a day for successively 4 days. The rats in all groups but control were pretreated with carrageenin (Ca) i.p. at 16 h before the last dose of QKL and followed by intravenous injection of endotoxin ( LPS fom E. coli O111:B4) 50 microg x kg(-1) 30 min after the last dosing of QKL. Thrombosis in rat tails were observed at 24 h after injection of LPS. The number of white blood cells and platelets, serum TNF-alpha, IL-6 level, CD11b/CD18 expression of white blood cells and platelet aggregation were analysed. RESULT: QKL obviously inhibited the LPS/Ca-induced thrombosis as showed a reduced infarction range due to thrombosis in tails. The sera concentration of TNF-alpha and IL-6, expression of CD11b/CD18 in WBC and platelet coagulation rate were reduced after QKL treatment. CONCLUSION: The anti-thrombosis action of QKL is associated with inhibition of WBC activation and adherence, reduction of inflammatory factor release and abating of platelet coagulation rate. The anti-thrombosis mechanism of QKL is consistent with its function of clearing away heat-evil and toxic materials. PMID- 19777845 TI - [Apoptosis of U937 cell line promoted by matrine through MAPK signal transduction pathway]. AB - OBJECTIVE: To study the anti-cancer effect of matrine (Mat) on U937 cell line and its possible molecular mechanism. METHOD: The cells were cultured in medium containing either 0.1, 0.2, 0.3, 0.4, or 0.5 g x L(-1) of Mat. The morphological alteration was observed by inverted microscopy and electron microscopy. Cell proliferation was analyzed by Try pan blue staining and MTT. The method of Western Blot was used to detect phosphorylation activity of MAPK. RESULT: Matrine had a significant inhibitory effect on proliferation of U937 cell line at the concentration of 0.2 g x L(-1). Treated with matrine of 0.2 g x L(-1) for 48 h, U937 cells became smaller and appeared more round than previously. The number of U937 cells showing apoptosis increased with elevation of the concentration of the matrine. Matrine had an ability of inhibiting the activity of ERK and increasing the activities of p38 and JNK to some degree in U937 cells. CONCLUSION: Matrine can inhibit the proliferation of U937 cell line in vitro and induce its apoptosis possibly through inhibiting the activity of ERK and increasing the activities of p38 and JNK in U937 cells. PMID- 19777846 TI - [Effects of Shenwu capsule and its component tetrahydroxystilbene glucoside on expression of neurotrophic factors in lumbar spinal cord of aged rats]. AB - OBJECTIVE: To investigate the effects of Shenwu capsule (SW) and its component tetrahydroxystilbene glucoside (TSG) on the expression of neurotrophic factors in lumbar spinal cord of aged rats. METHOD: SD rats were divided into 6 groups, including 6-months-old group, 24-months-old group, 24-months-old + low dose SW (0.8 g x kg(-1)), high dose SW (1.6 g x kg(-1)), low dose TSG (0.03 g x kg(-1)) and high dose TSG (0.06 g x kg(-1)). Western blot was used to detect the expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), gliacyte-derived neurotrophic factor (GDNF) in the lumbar spinal cord of rats. RESULT: Compared with 6-month-old young rats, the expression of NGF, BDNF and GDNF in the lumbar spinal cord was significantly decreased in the 24-month old rats (P < 0.05, P < 0.01). Intragastric administration of SW for 3 months obviously enhanced the expression of NGF, BDNF and GDNF in the lumbar spinal cord of aged rats (P < 0.05, P < 0.01), and TSG significantly enhanced the expression of GDNF (P < 0.05). CONCLUSION: SW capsule and its component TSG elevated the expression of neurotrophic factors in the lumbar spinal cord of aged rats, suggesting that these drugs may retard aging process of the spinal cord. PMID- 19777847 TI - [Antidepressant-like effects of piperine and its neuroprotective mechanism]. AB - OBJECTIVE: To observe the antidepressant effect of piperine and its neuroprotective mechanism. METHOD: The behavioral studies were performed in forced swimming test (FST) and tail suspension test (TST). To further explore the mechanisms underlying their antidepressant-like activities, CORT-induced neuroblastoma SH-SY5Y cells and isolated and cultured neural progenitor cells. By using MTT assay, the effect of piperine on neural cells proliferation was observed. RESULT: The research results indicated that after a week of administration, piperine (10, 20 mg x kg(-1)) could significantly reduce the duration of immobility in both FST and TST. Piperine has the protective effect on neuroblastoma cells and increased proliferation of hippocampus neural progenitor cells. CONCLUSION: In the present study, we demonstrated that the antidepressant like effects of piperine and its mechanisms might be involved by up-regulation of the progenitor cell proliferation of hippocampus and cytoprotective activity. PMID- 19777848 TI - [Effects of Xijiao Dihuang decoction on the expressions of bcl-2, caspase-3, TNF alpha and IL-6 after acute intracerebral hemorrhage in rats]. AB - OBJECTIVE: To study the effects of xijiao dihuang decoction on the expressions of Bcl-2 and caspase-3 protein positive cells in brain tissue, TNF-alpha and IL-6 in blood after acute intracerebral hemorrhage in rat. METHOD: The experimental ICH model was established by injection of non-heparinized autologous arterial blood into the right basal ganglia. Immunohistochemistry and radioimmunity methods were used to detect expressions of Bcl-2 and caspase-3 protein positive cells in brain tissue, TNF-alpha and IL-6 in blood. RESULT: After ICH, caspase-3 protein positive cells in brain tissue, TNF-alpha and IL-6 in blood increased obviously in the model group, caspase-3 protein positive cells, TNF-alpha and IL-6 were significantly reduced by treatment with Xijiao Dihuang decoction, on the contrary, Bcl-2 protein positive cells in brain tissue increased markedly. CONCLUSION: Xijiao Dihuang decoction can pretect nerve cell by reducing the expression of caspase-3, TNF-alpha and IL-6, increasing the expression of Bcl-2 after ICH in hemorrhagic brain damage. PMID- 19777849 TI - [Anti-tumor activity and mechanism with SSCE of Spatholobus suberctus]. AB - OBJECTIVE: To observe the effect of anti-tumor and mechanism of the extract of Spatholobus suberctus (SSCE) in vivo. METHOD: The mouse model of Lewis lung carcinoma was used to investigate the effects of SSCE on tumor growth and metastasis. Furthermore, we explored the mechanism of anti-tumor by analyze the cell cycle and determine the apoptosis. RESULT: The studies demonstrated that the tumor inhibitory rate of SSCE in low dose group was the highest (30.65%) on Lewis lung cancer. SSCE can resist metastasis, at the same time, it can induce cell cycle arrested in G1 phase, whereas, there was no significant difference in apoptotic rate each group. CONCLUSION: We verified that SSCE exits anti-tumor effect and resist metastasis, furthermore, it can arrest function cell in G1 phase. PMID- 19777850 TI - [Effect of Huzhang on expression of lung fibroblasts' MMP-2/TIMP-1mRNA in pulmonary fibrosis rats]. AB - OBJECTIVE: To observe the effect of Huzhang on the progress of pulmonary fibrosis in rats, evaluate the role of Huzhang in this process and explore its mechanism. METHOD: Wistar male rats were randomized into 7 groups (normal control group, model group, positive control group, prophylactic group, 3rd day treatment group, 7th day treatment group and 14th day treatment group). Bleomycin was administered by intratracheal injection to produce pulmonary fibrosis groups except the normal control group. The positive control group began to be given DXM (4 mL x kg(-1) x d(-1)) on the day of the model-making. The normal control group and model group were given NS (4 mL x kg(-1) x d(-1)) on the day of the model-making. The prophylactic group was given reagent (4 mL x kg(-1) x d(-1)) 2 days ahead of the model-making, whereas the 3rd day treatment group, the 7th day treatment group and the 14th day treatment group given the same dose respectively on the third day, the seventh day and the fourth day behind of the model-making. Lung tissue was stained with hematoxylin-eosin (HE) and Masson's trichrome to determine the pathological grading. The lung fibroblast (LF) was cultured in vitro by way of pancreatic enzyme digestion, which was used to detect the contents of the expression of MMP-2 and TIMP-1mRNA with RT-PCR method. RESULT: Compared with those in the model group, the alveolitis, pulmonary fibrosis and collagen accumulation were significantly alleviated in the positive control group, Huzhang prophylactic group and each treatment groups. In the positive control group, Huzhang prophylactic group, the 3rd day treatment group, the 7th day treatment group and the 14th day treatment group, the expression of MMP-2 mRNA was weaker significantly than that in the BLM model group (P < 0.05 or P < 0.01) except that on the 42nd day. The expression of TIMP-1mRNA was also weaker significantly than that in the BLM model group at all set times in all treatment groups (P < 0.05 or P < 0.01). The inhibition of TIMP-1 lasted until the 42nd day. CONCLUSION: Huzhang inhibited the expression of MMP-2mRNA and TIMP-1mRNA of lung fibroblast in different periods to reduce the alveolitis and pulmonary fibrosis, which was probably one of the anti-fulmonary fiborsis mechanisms of Huzhang. PMID- 19777851 TI - [Influence of gingko extract on metabolism of simvastatin]. AB - OBJECTIVE: To conclude the possible interaction between gingko extract and simvastatin, by studing the effect of gingko extract on vitro metabolism of simvastatin and involving critical metabolic enzyme, which can guide the clinicians to use them rationally (propose good guideline for rational using of the two medicine mentioned above). METHOD: Thirty-two female SD rats were randomly separated into 4 groups, including negative control group. High dose of gingko extract. Low dose of gingko extract and positive control group. All groups were administered for 10 days with stomach tube, and then the quantity of liver microsome protein, the activity of CYP3A were determined by spectrophotograph simvastatin was incubated with the liver microsome, and the effect of gingko extract on its metabolism was estimated by measuring the amount of simvastatin by HPLC. RESULT: Comparing with the negative contrast group: the quantity of liver microsome protein, the activity of CYP3A and the metabolism of simvastatin in positive control group were all increased markly (P < 0.05). In high dose group, the quantity of liver microsome protein and the activity of CYP3A were both increased significantly (P < 0.05), and the metabolism of simvastatin also accelerate obviously (P < 0.05). But in the low dose group significant distinction of every index was not found. CONCLUSION: High dose of gingko extract can induce the activity of CYP3A, and promote the metabolism of simvastatin, so the medical interaction should be focused when gingko extract is coadministered with simvastatin and other substracts of CYP3A. PMID- 19777852 TI - [Effect of Chaihu Shihuang soup on blood serum level TNF, IL-6 and IL-10 of severe acute pancratitis (SAP)]. AB - OBJECTIVE: To make a study of the effect of Chaihu Shihuang soup on blood serum level TNF, IL-6 and IL-10 of severe acute pancratitis. METHOD: Sixty SAP cases were divided at random into treatment group and control group (30 cases each). The treatment group were given chai-hu-shi-huang-soup once a day; the control group were given Dachaihu soup once daily, with both treatment period for 7 days. The tumor necrosis factor-alpha (TNF-alpha), interleukin level 6 (IL-6) and 10 (IL-10) of both groups were determined before and after the treatment. We also had 30 healthy cases. RESULT: IL-10 level in both groups was lower than healthy group while TNF-alpha and IL-6 were higher than healthy group (P < 0.01). After treatment, the treatment group's TNF-alpha, IL-6 level were comparatively lower than that in the control group (P < 0.01), and IL-10 level were clearly higher than that of the control group (P < 0.01), comparison of the treatment group before treatment (P < 0.01). CONCLUSION: Chaihu Shihuang soup can significantly regulate cytokine and improve early recovery of SAP. PMID- 19777853 TI - [Advances in herbal volatile oil and aromatic herbs]. AB - The herbal volatile oil and aromatic herbs are traditional Chinese medicine which have some unique characteristics of volatility, special smell, complicated chemical constituents and the water insoluble property. The aromatic herbs from different sources have biodiversity effects on the cardiovascular, central nervous, respiratory and gastrointestinal system. They also play important roles in antibiosis, anti-inflammation, anticancer, antivirus and absorption enhancement, etc. In recent years, the herbal volatile oil and aromatic herbs have been widely reported to show broad prospect in medicinal application. In order to support various developmental works, the latest research results on herbal volatile oil and aromatic herbs are reviewed in this article in respect of chemical constituents, pharmacological action, and absorption enhancement. PMID- 19777855 TI - [Debate personification of property of peaceful property of drug in cooperation of prescription of traditional Chinese medicine]. AB - The cognition of the drug property of peaceful property of drug exist dispute in successive dynasties, now special subject study about the compatibility of peaceful property of drug is still absent. This articles do some approach on the personification of the feature of the peaceful property of drug in cooperation of prescription of TCM, T/C: The peaceful property of drug compatible with others has especial outpocketing effect in "bulk utility", "correlative utility", "mesomerism accommodate". Through compatibility can personify the three feature of the drug property of peaceful property of drug: "body mild utility bias", "two way apply", "condition dominancy". Scent compatibility is the main route to personify the effect on "adjust yin-yang", "use bias rectify bias" of peaceful property of drug. PMID- 19777854 TI - [Application of thermoplastic elastomer in hot-melt pressure sensitive adhesives for transtermal drug delivery]. AB - Development of drug dosage forms to a great extent depends on the development of drug auxiliary materials. The development of a new type of polymeric drug auxiliary materials will bring on the developing of a novel dosage forms technology and a flood of new drug dosage forms. Thermoplastic elastomer is a new type of drug polymeric auxiliary materials, at present, which has a broad application in the field of hot-melt pressure sensitive adhesives. This review mainly discussed a new transtermal Chinese drug delivery system, including matrix composition of the formula, modified thermoplastic elastomer for hot-melt pressure sensitive adhesives and their development prospects in the traditional Chinese drug delivery system. It suggested that thermoplastic elastomer of hot melt pressure sensitive adhesives has broad development prospects in the field of the transtermal drug delivery system for traditional Chinese medicine. PMID- 19777856 TI - A pioneer in optimism: the legacy of Donald Munro, MD. PMID- 19777857 TI - Effect of exercise on disorders of carbohydrate and lipid metabolism in adults with traumatic spinal cord injury: systematic review of the evidence. AB - BACKGROUND/OBJECTIVE: Carbohydrate and lipid metabolism disorders may affect adults with spinal cord injuries (SCIs) differently than able-bodied individuals because of reduced physical activity in the SCI population. The objective of this study was to conduct a systematic review to determine the effectiveness of exercise to improve carbohydrate and lipid metabolism disorders in adults with chronic SCI. METHODS: Studies were identified in MEDLINE (1996-2008), Cochrane Library, bibliographies of identified articles, and expert recommendations. English language articles were included if they evaluated adults with chronic SCI; evaluated exercise; and reported carbohydrate-, lipid-, and/or cardiovascular disease-related outcomes. RESULTS: Twenty-two studies met inclusion criteria, including 15 intervention case-series and 7 cross-sectional surveys using self-reported physical activity measures. Intervention protocols involved active (n=7) or electrically stimulated (n=7) exercise or an educational program (n ) from 8 to 52 weeks in duration. Frequency of exercise was typically 2 to 3 sessions/week, lasting 30 to 60 minutes/session. Totals of 150 and 369 subjects participated in studies with carbohydrate (n=12) or lipid and cardiovascular (n=16) outcomes, respectively; 78% were men. Level of SCI ranged from C4 to L5 and included both incomplete and complete lesions. Outcomes measures included fasting and postload blood glucose and insulin concentrations and serum cholesterol levels. Small sample sizes and variations in study design, intervention, SCI characteristics, and reported outcomes precluded quantitative pooling of results or reliable assessment of metabolic efficacy. No intervention studies assessed cardiovascular outcomes. CONCLUSIONS: Evidence is insufficient to determine whether exercise improves carbohydrate and lipid metabolism disorders among adults with SCI. Expert consensus, based on the preliminary evidence, is needed to inform future studies. PMID- 19777858 TI - A guidance channel seeded with autologous Schwann cells for repair of cauda equina injury in a primate model. AB - BACKGROUND/OBJECTIVE: To evaluate an implantable guidance channel (GC) seeded with autologous Schwann cells to promote regeneration of transected spinal nerve root axons in a primate model. METHODS: Schwann cells were obtained from sural nerve segments of monkeys (Macaca fascicularis; cynomolgus). Cells were cultured, purified, and seeded into a PAN/PVC GC. Approximately 3 weeks later, monkeys underwent laminectomy and dural opening. Nerve roots of the L4 through L7 segments were identified visually. The threshold voltage needed to elicit hindlimb muscle electromyography (EMG) after stimulation of intact nerve roots was determined. Segments of 2 or 3 nerve roots (each approximately 8-15 mm in length) were excised. The GC containing Schwann cells was implanted between the proximal and distal stumps of these nerve roots and attached to the stumps with suture. Follow-up evaluation was conducted on 3 animals, with survival times of 9 to 14 months. RESULTS: Upon reexposure of the implant site, subdural nerve root adhesions were noted in all 3 animals. Several of the implanted GC had collapsed and were characterized by thin strands of connective tissue attached to either end. In contrast, 3 of the 8 implanted GC were intact and had white, glossy cables entering and exiting the conduits. Electrical stimulation of the tissue cable in each of these 3 cases led to low-threshold evoked EMG responses, suggesting that muscles had been reinnervated by axons regenerating through the repair site and into the distal nerve stump. During harvesting of the GC implant, sharp transection led to spontaneous EMG in the same 3 roots showing a low threshold to electrical stimulation, whereas no EMG was seen when harvesting nerve roots with high thresholds to elicit EMG. Histology confirmed large numbers of myelinated axons at the midpoint of 2 GC judged to have reinnervated target muscles. CONCLUSIONS: We found a modest rate of successful regeneration and muscle reinnervation after treatment of nerve root transection with a Schwann cell-seeded, implanted synthetic GC. Newer treatments, which include the use of absorbable polymers, neurotrophins, and antiscar agents, may further improve spinal nerve regeneration for repair of cauda equina injury. PMID- 19777859 TI - Scapular stabilization in patients with spinal cord injury. AB - BACKGROUND: Severe scapular instability can be a considerable problem for people with high-level cervical spinal cord injury. Scapular instability reduces the effectiveness of the already weakened shoulder flexors and abductors, thereby limiting hand-to-mouth and hand-to-head activities. The winged scapula may cause inferior pole skin breakdown, as well as neck and shoulder pain. OBJECTIVE: To report the efficacy of a fusionless scapular stabilization procedure as a means to enhance function in a consecutive group of patients with high-level cervical spinal cord injury. METHODS: Four people with spinal cord injury at C4-C5 (2 male, 2 female; mean age = 17.3 years, range = 14-20 years) underwent scapular stabilization via scapulothoracic fusion (N=2) or by tethering the scapula to the rib cage with Mersilene tape as a fusionless stabilization (N=2). One patient died of unrelated causes 18 months after surgery, and the remaining 3 were followed for 26, 39, and 41 months, respectively. Data collection included radiographic analysis, active range of motion measures, and functional assessment. RESULTS: Active shoulder flexion and abduction remained unchanged in 2 patients, but functional scores improved with regard to feeding and grooming capability. All patients reported satisfaction with postoperative appearance, and 3 patients reported considerable reduction in shoulder pain after surgery. Radiographs demonstrated maintenance of stable scapular alignment in all patients at final follow up. Wound breakdown, requiring removal of instrumentation, occurred in 2 patients. CONCLUSION: Scapular stabilization with or without fusion is a viable option to improve appearance, pain, and upper extremity function in people with high-level tetraplegia and scapular instability. PMID- 19777860 TI - Acute suppression of bone turnover with calcium infusion in persons with spinal cord injury. AB - BACKGROUND: Some people with chronic spinal cord injury (SCI) have low vitamin D levels and secondary hyperparathyroidism. OBJECTIVE: To determine whether, and to what extent, an acute calcium infusion decreased levels of N-telopeptide (NTx), a marker of osteoclastic activity, in individuals with chronic SCI. STUDY DESIGN: Case series. SUBJECTS: Eight men with chronic SCI. A relatively low serum 25 hydroxyvitamin D concentration (25[OH]D < or =20 ng/mL) and/or a high parathyroid hormone (PTH) (>55 pg/mL) was a prerequisite for study inclusion. METHODS: Calcium gluconate bolus 0.025 mmol elemental calcium/kg over 20 minutes followed by a constant infusion of 0.025 mmol/kg per hour for 6 hours was infused; blood samples were collected every 2 hours for measurement of serum total calcium, creatinine, NTx, and PTH. RESULTS: All results are expressed as means (+/- SDs). Baseline serum 25-hydroxyvitamin D level was 14.5 +/- 3.5 ng/mL (range: 10.2-19.6 ng/mL); PTH, 70 +/- 25 pg/mL (range: 37-100 pg/mL); and NTx, 21 +/- 7 nM bone collagen equivalents (BCE) (range: 14-34 nM). At 2, 4, and 6 hours after the calcium infusion, serum calcium rose from 9.3 +/- 0.2 to 10.8 +/- 0.9, 10.5 +/- 0.8, and 10.6 +/- 0.6 mg/d; PTH was suppressed from 70 +/- 25 pg/mL to 18 +/- 12, 16 +/- 9, and 15 +/- 9 pg/mL, respectively; NTx fell from 21 +/- 8 nM BCE to 17 +/- 5, 12 +/- 4, and 12 +/- 3 nM BCE, respectively. CONCLUSIONS: Serum NTx is a marker for bone collagen catabolism, and its reduction suggests that bone turnover was decreased. A relative deficiency of vitamin D associated with chronically elevated levels of PTH would be expected to increase bone turnover and to worsen the bone loss associated with immobilization. PMID- 19777861 TI - Colonoscopic lesions in patients with spinal cord injury. AB - BACKGROUND/OBJECTIVE: In spinal cord injury (SCI), loss of central or peripheral neural control causes neurogenic bowel. Patients may not exhibit the typical signs and symptoms of gastrointestinal disease. Few studies have looked at the risk of gastrointestinal disease in this group and the indications for preventive screening. The objective of this study was to study colonoscopic lesions in patients with SCI and determine whether there are any differences in the prevalence of lesions between SCI and control patients. DESIGN: Case control study. METHODS: Twenty-five patients with SCI were compared with 41 control patients who received colonoscopy at the same time. Mann-Whitney test for continuous variable, and Fisher exact test for frequency variables were used. OUTCOME MEASURES: Demographic information, duration of SCI, and colonoscopy findings were gathered. RESULTS: Colonic lesions were observed in 52% of patients with SCI and in 41.5% of control patients. Most frequent lesions in SCI group were inflammatory bowel disease (16%) and polyp (16%), followed by proctitis (12%) and hemorrhoid (12%). In the control group, hemorrhoid (17.1%) was most common, followed by polyp (12.2%) and melanosis coli (9.8%). No significant differences were found between the 2 groups. In the SCI group, no significant differences in lesions were found among the patients with cervical, thoracic, and lumbar SCI in the SCI group. Duration of SCI did not affect the pattern of colonoscopic lesions. CONCLUSION: Patients with SCI had the same incidence of colonscopic lesions as control patients. Inflammatory bowel disease, which is a risk factor for cancer, was the most common findings in the SCI group, although there was no significant difference from the control group. In patients with SCI, colonoscopy screening is warranted at the same frequency as for the general population. PMID- 19777862 TI - Factors associated with oral problems among adults with spinal cord injury. AB - OBJECTIVE: To explore factors associated with self-reported current oral (tooth and gum) problems and oral pain in the past 12 months among adults with spinal cord injury. METHODS: An online oral health survey on the South Carolina Spinal Cord Injury Association website. Respondents were 192 adult residents of the US who identified themselves as having spinal cord injury at least 1 year before the survey date. RESULTS: Approximately 47% of respondents reported having oral problems at the time of the survey, and 42% reported experiencing oral pain in the 12 months before the survey date. Multiple predictor analyses (controlling for age, gender, income, and dental insurance) indicated that current oral problems were positively associated with dry mouth symptoms, financial barriers to dental care access, smoking, and paraplegia. Oral pain experienced in the past 12 months was positively associated with dry mouth symptoms, financial barriers to dental care access, minority race, and paraplegia. CONCLUSIONS: Adults with spinal cord injury reported a high prevalence of oral problems and oral pain. Those with paraplegia were more likely to report problems than those with tetraplegia. Because dry mouth and smoking were significantly associated with these problems, patient education from both dental and medical providers should emphasize awareness of the side effects of xerostomia-causing medications, dry mouth management, and smoking cessation. Findings also indicate unmet needs for low-cost preventive and treatment dental services for this vulnerable population. PMID- 19777863 TI - Serum leptin levels following acute experimental spinal cord injury. AB - BACKGROUND/OBJECTIVE: Spinal cord injury influences many hormones that are known to be involved in the modulation of neurotrophic, neurogenic, and neuroprotective events. Recent studies showed that leptin could be neuroprotective, enhancing neuronal survival in vitro and in vivo. The objective of this study was to evaluate the pattern of the serum leptin levels in rats during acute traumatic SCI. METHODS: Forty male Sprague-Dawley rats were divided randomly into 4 groups. In the control group, neither laminectomy nor SCI was performed; only laminectomy was performed without SCI in the sham group. In the cervical and thoracic spinal trauma groups, laminectomies were performed following the same trauma procedure. Blood samples were drawn 2, 6, 12, and 24 hours after the procedures and assayed immediately. RESULTS: In the first 2 hours, levels of leptin were similar in control and sham-operated groups and higher in neurotrauma groups (P < 0.05). At the sixth hour, leptin levels increased in the sham-operated group, decreased in the neurotrauma groups (P < 0.05), and did not change in the control group (P > 0.05). At the 12th hour, the levels of leptin increased in all groups (P > 0.05). At the 24th hour, they decreased in the control, sham-operated, and cervical groups (P < 0.05); levels did not change in the thoracic group (P > 0.05). The decrease was higher in the control group than in the other groups (P < 0.05). CONCLUSIONS: Activation of endogenous leptin secretion started immediately after the SCI. The level of neurologic lesion (either cervical or thoracic regions) affected the levels of serum leptin differently, but with the exception of the first 12-hour period, this difference did not reach a statistically significant level. PMID- 19777864 TI - Nosocomial transmission of highly resistant microorganisms on a spinal cord rehabilitation ward. AB - BACKGROUND/OBJECTIVE: To study the mechanism of nosocomial transmission of highly resistant microorganisms (HRMOs). DESIGN: A prospective observational study. SETTING: A spinal cord ward of a rehabilitation center. PARTICIPANTS: Patients admitted to the spinal cord rehabilitation ward. OUTCOME MEASURES: HRMOs present in urine and feces. HRMOs, Enterobacteriaceae: (1) that produced an extended spectrum beta-lactamase (ESBL), (2) that were resistant to carbapenems, (3) that fluoroquinolones and aminoglycosides (for Escherichia coli and Klebsiella species), or other Enterobacteriaceae species that were resistant to 2 of 3 of the following types of antibiotics (fluoroquinolones, aminoglycosides, cotrimoxazole). METHODS: Bacterial growth, identification and sensitivity were tested in urine cultures of 46 patients and faeces cultures of 15 patients. Data were collected on demographic characteristics, underlying diseases, reason and date of admission, room number, method of catheterization (suprapubic, clean intermittent catheterization or indwelling Foley catheter) and antibiotic use. RESULTS: Nine different HRMOs (7 E. coli, 1 Enterobacter cloacae, and 1 Citrobacter koseri) were isolated in urine samples from 15 patients. E. coli resistant to gentamicin, tetracycline, amoxicillin, cotrimoxazole, and ciprofloxacin were isolated from 8 patients during the study (cluster 1). One strain of multiresistant E coli found before the start of the study was not found during the study period (cluster 2). E coli strains producing an ESBL and resistant to tetracycline, cotrimoxazole, and ciprofloxacin were isolated from urine samples of 3 patients (cluster 3). Ciprofloxacin-resistant E. coli were present in feces of 3 patients (2 in cluster 1). Catheterization was found to be significantly more prevalent in patients with HRMOs. Most of the patients in cluster 1 were treated with antibiotics before the first isolation of the strain. CONCLUSIONS: HRMOs from urine samples were strongly correlated with the use of catheterization. A close correlation was found between prior use of antibiotics and colonization of the urinary tract on the level of the individual patient, which has been rarely described in the literature. PMID- 19777865 TI - Prevalence of spinal cord injury in Tehran, Iran. AB - BACKGROUND/OBJECTIVE: To determine the prevalence of traumatic spinal cord injury (SCI) in Tehran, Iran. METHODS: A population-based study was performed. In a random cluster sampling, 100 addresses were selected as the starting point of the survey for each cluster consisting of 25 households. To expand the geographic dimension of each cluster, the interviewers skipped 3 of 4 houses in gathering data for each study unit. Each person with traumatic SCI was evaluated initially by a nurse and then by a neurosurgeon by physical examination and spinal imaging at the hospital or at home. RESULTS: Ninety-seven percent of all surveyed agreed to participate in the study (2425 households, or 9006 persons). Four cases of SCI were identified. The point prevalence of SCI was 4.4 [95% CI = 1.2-11.4] per 10,000 people. Over the 5-year period from january 2003 through January 2008, the reported incidence rate of SCI was 2.2 (95% CI = 0.27-8.00) per 10,000 people. CONCLUSIONS: In this, the first published population-based study from Iran, the prevalence of traumatic SCI in Tehran ranged from 1.2 to 11.4 per 10,000 people. More research is required to determine the patterns and causes of SCI. Development of a nationwide SCI registry or surveillance system is fundamental to an understanding of the epidemiology, and hence the prevention, of this costly health problem. PMID- 19777866 TI - Vulnerability of the femoral nerve during complex anterior and posterior spinal surgery. AB - BACKGROUND: Femoral nerve palsy is not a common adverse effect of lumbar spinal surgery. OBJECTIVE: To report 3 unique cases of femoral nerve neuropathy due to instrumentation and positioning during complex anterior and posterior spinal surgery. METHODS: Case series RESULTS: All 3 patients demonstrated femoral nerve neuropathy. The first patient presented postoperatively but after 6 months, the palsy resolved. Femoral nerve malfunctioning was documented in the second and third patients intraoperatively; however, with rapid patient repositioning and removal of offending instrumentation, postoperative palsy was avoided. CONCLUSIONS: Use of motor evoked potential monitoring of the femoral nerve during surgery is vital for the prevention of future neuropathies, an avoidable complication of spinal surgery. PMID- 19777867 TI - Intractable pruritus after traumatic spinal cord injury. AB - BACKGROUND: This report describes a young woman with incomplete traumatic cervical spinal cord injury and intractable pruritus involving her dorsal forearm. METHOD: Case report. FINDINGS: Anatomic distribution of the pruritus corresponded to the dermatomal distribution of her level of spinal cord injury and vertebral fusion. Symptoms were attributed to the spinal cord injury and possible cervical root injury. Pruritus was refractory to all treatments, including topical lidocaine, gabapentin, transcutaneous electrical nerve stimulation, intravenous Bier block, stellate ganglion block, and acupuncture. CONCLUSIONS: Further understanding of neuropathic pruritus is needed. Diagnostic workup of intractable pruritus should include advanced imaging to detect ongoing nerve root compression. If diagnostic studies suggest radiculopathy, epidural steroid injection should be considered. Because the autonomic nervous system may be involved in complex chronic pain or pruritic syndromes, sympatholysis via such techniques as stellate ganglion block might be effective. PMID- 19777868 TI - Scavenger receptor CD163 and its biological functions. AB - CD163 is a member of scavenger receptor super family class B of the first subgroup. It is mapped to the region p13 on chromosome 12. Five different isoforms of CD163 have been described, which differ in the structure of their cytoplasmic domains and putative phosporylation sites. This scavenger receptor is selectively expressed on cells of monocytes and macrophages lineage exclusively. CD163 immunological function is essentially homeostatic. It also has other functions because participates in adhesion to endothelial cells, in tolerance induction and tissues regeneration. Other very important function of CD163 is the clearance of hemoglobin in its cell-free form and participation in anti inflammation in its soluble form, exhibiting cytokine-like functions. We review the biological functions of CD163 which have been discovered until now. It seems apparent from this review that CD163 scavenger receptor can be used as biomarker in different diseases and as a valuable diagnostic parameter for prognosis of many diseases especially inflammatory disorders and sepsis. PMID- 19777869 TI - The potential benefit of intracarpal pressure measurement in endoscopic carpal tunnel syndrome surgery--an analysis of EMG findings and pressure values. AB - Endoscopic carpal tunnel syndrome surgery is a modern minimally invasive method of carpal tunnel decompression. However, the method does also have its critics, who emphasize that there is an increased rate of complications in comparison to open procedures. To further improve and optimize results of endoscopic surgery we used an intracarpal pressure sensor to verify the effect of carpal tunnel decompression. The endoscopic single portal approach was used in all cases. Median nerve conduction studies were performed prior to and 3 months after surgery. Two groups, those with pressure studies and those without, were then compared according to several EMG parameters such as: median nerve distal motor latency, amplitude of motor response, sensory nerve conduction velocity to the index finger, and amplitude of sensory nerve action potential. In both groups, we observed similarly significant improvements in all conduction parameters, except the amplitude of motor response, which did not change in either group, i.e. no difference in postoperative EMG between the two groups was observed. Despite this fact, intracarpal pressure measurement is still useful in localising the point in which the median nerve is compressed and provides valuable functional information on the level decompression achieved. PMID- 19777870 TI - Tissue specific sensitivity of mitochondrial permeability transition pore to Ca2+ ions. AB - Ca(2+)-induced opening of the mitochondrial permeability transition pore (MPTP) is involved in induction of apoptotic and necrotic processes. We studied sensitivity of MPTP to calcium using the model of Ca(2+)-induced, cyclosporine A sensitive mitochondrial swelling. Presented data indicate that the extent of mitochondrial swelling (dA520/4 min) induced by addition of 25 microM Ca2+ is seven-fold higher in liver than in heart mitochondria (0.564 +/- 0.08/0.077 +/- 0.01). The extent of swelling induced by 100 microM Ca2+ was in liver tree times higher than in heart mitochondria (0.508 +/- 0.05/ 0.173 +/- 0.02). Cyclosporine A sensitivity showed that opening of the MPTP is involved. We may thus conclude that especially at low Ca2+ concentration heart mitochondria are more resistant to damaging effect of Ca2+ than liver mitochondria. These finding thus support hypothesis that there exist tissue specific strategies of cell protection against induction of the apoptotic and necrotic processes. PMID- 19777871 TI - Disease phobia in patients with temporomandibular joint pain assessed by the Illness Attitude Scale. AB - Disease phobia refers to a psychological state when the person continuously thinks that he/she is sick and improvement from the condition is impossible. Disease phobia in patients suffering from pain, secondary to temporomandibular disorders (TMDs), is usually the consequence of long-term problems; diagnosis and treatment of this group is a real challenge for healthcare professionals. AIM: The purpose of this prospective study was to objectively evaluate the role of Illness Attitude Scale (Kellner or IAS) in measuring cancerophobia and heart disease phobia in patients suffering from pain, as a consequence of TMDs. SUBJECTS AND METHODS: The cohort included 22 patients with TMDs who underwent evaluation of these phobias; pain was acute in 7 and chronic in 15. The patients were asked to complete the "Kellner" questionnaire, and this was followed by full clinical examination of the temporomandibular region. RESULTS: When measuring the correlation between the cancerophobia and heart disease phobia patients, the outcome was found significant in the total cohort, p < 0.01. Comparisons were carried out in the chronic group (n = 15) and was significant (p = 0.034 and r = 0.549); while in the acute group no significance was identified. CONCLUSION: Cancerophobia and heart disease phobia in TMD patients are factors that need to be taken in consideration when managing chronic pain in this group. PMID- 19777872 TI - Subgaleal migration of the distal catheter of a ventriculoperitoneal shunt. AB - Proximal migration of the distal end of a ventriculoperitoneal shunt has been observed much more rarely than other numerous shunt-related complications. Subgaleal migration of the peritoneal end is one of the samples. In the preset report we have discussed a case of subgaleal migration of the peritoneal end detected as a result of the examinations performed for shunt dysfunction. There was ventricular dilatation on CT scan of the brain. X-ray examinations confirmed proper ventricular catheter and shunt valve placement but a complete migration of distal (peritoneal) catheter into the subgaleal space. Then the patient's shunt was revised. When our case and the literature were examined, we observed that this complication was frequently encountered during the first postoperative months, in the pediatric ages and in patients with advanced hydrocephalus. Besides, we have detected that the peritoneal catheters had tendency to migration into the subgaleal tissues similar to pre-insertion forms of the preoperatively original packages. PMID- 19777873 TI - Giant renal cyst mimicking ascites on abdominal ultrasonography. AB - An article describes diagnostic difficulties in patient with giant renal cyst, erroneously diagnosed as ascites on ultrasonographic examination. Patient was initially suspected to have disseminated intraabdominal malignancy. Abdominal paracentesis of supposed ascites was performed. The diagnosis of giant renal cyst was finally made by CT and patient was treated surgically. The limitations of ultrasonographic examination are pointed out are and a brief review of similar cases is given. PMID- 19777874 TI - Updates in radiation therapy. PMID- 19777875 TI - How have advances in radiation technology increased quality of life for your patients? PMID- 19777876 TI - Safety devices help prevent needle-stick injuries. PMID- 19777878 TI - Celebrities may help bring positive media attention to cancer. PMID- 19777877 TI - Prevent extravasation injury with the use of antidotes. PMID- 19777879 TI - Low-dose chemotherapy for non-Hodgkin lymphoma in Africa improves survival. PMID- 19777880 TI - Planktonic and biofilm communities from 7-day-old chicken cecal microflora cultures: characterization and resistance to Salmonella colonization. AB - Information implicating bacterial biofilms as contributory factors in the development of environmental bacterial resistance has been increasing. There is a lack of information regarding the role of biofilms within the microbial ecology of the gastrointestinal tract of food animals. This work used a continuous-flow chemostat model derived from the ceca of 7-day-old chicks to characterize these communities and their ability to neutralize invasion by Salmonella enterica serovar Typhimurium. We characterized and compared the biofilm and planktonic communities within these microcosms using automated ribotyping and the Analytical Profile Index biotyping system. Eleven species from eight different genera were identified from six culture systems. Klebsiella pneumoniae was isolated from all planktonic communities and four of the biofilm communities. Three of the communities resisted colonization by Salmonella enterica serovar Typhimurium, two communities suppressed growth, and one community succumbed to colonization. In cultures that resisted colonization, no Salmonella could be isolated from the biofilm; in cultures that succumbed to colonization, Salmonella was consistently found within the biofilms. This study was one of a series that provided a molecular-based characterization of both the biofilm and planktonic communities from continuous-flow culture systems derived from the cecal microflora of chicks, ranging in age from day-of-hatch to 14 days old. The one common factor relating to successful colonization of the culture was the presence of Salmonella within the biofilm. The capacity to sequester the introduced Salmonella into the biofilm appears to be a contributing factor to the inability of these cultures to withstand colonization by the Salmonella. PMID- 19777881 TI - Contamination profiles of Escherichia coli and enterococci in steamed chicken meat products. AB - This study determined the sources of contamination by Escherichia coli and enterococci in frozen ready-to-eat chicken products. The efficiency of the heat treatment process was sufficient to eliminate E. coli or enterococci. However, the prevalence of E. coli and enterococci in cooked chicken after chilling was 2.7%, and after slicing and dicing it was 1.3 and 9.3%, respectively. These results indicated that contamination occurred after cooking. In the finished product, E. coli was absent, while enterococcus prevalence was reduced to 1.3%. The environment at each production step, such as the machine surfaces, workers' gloves, and the condensate, was sampled to determine the correlation with the contamination in products. E. coli and enterococci were found on the machine surfaces in all production steps, but E. coli contamination was mostly from the infeed transfer belt at the chilling step, while the enterococcus contamination arose mostly from the slicing or dicing steps, especially from the dicing machine belt, which directly contacts the products. Indeed, E. coli and enterococci were detected on food contact surfaces throughout the production period, including prior to its commencement. These results indicated that the cleaning before and during the production process was ineffective. In addition, cleaning and sanitizing food contact surfaces followed by nonfood contact surfaces (floor and drains) by use of a high-pressure water hose created aerosol with microbes from the floors and drains and spread such microbes onto already cleaned food contact surfaces. PMID- 19777882 TI - Prevalence of Campylobacter spp. in raw retail poultry on sale in Northern Ireland. AB - A year-long survey of fresh, retail poultry products on sale in Northern Ireland was undertaken to define the prevalence of Campylobacter spp. by using protocols based on ISO (standard) 10272-1:2006. Incubation at 37 and 42 degrees C was undertaken to increase the diversity of isolates obtained. Overall, 652 isolates were identified as Campylobacter spp. by using PCR and amplified fragment length polymorphic typing. Phenotyping wrongly identified 21% of isolates. Prevalences of Campylobacter found were chicken, 91% (n = 336); turkey, 56% (n = 77); and duck, 100% (n = 17). Prevalence rates for chicken produced in Northern Ireland, Scotland, England, and Wales were similar, with a mean value of 91%. The prevalences in product from the latter two countries were much higher than were found in two United Kingdom-wide surveys of chicken. The incubation temperature did not affect the relative proportions of the species isolated (P > 0.05). Campylobacter jejuni composed 64.6% of isolates, Campylobacter coli, 27.4%, and Campylobacter lari, 1%. Most cases of human campylobacteriosis are caused by C. jejuni and C. coli. The overall Campylobacter prevalence results are consistent with Northern Ireland surveys undertaken since 2000, and indicate that United Kingdom strategies to control Campylobacter in chicken have not had a significant effecton the prevalence of this pathogen in retail products on sale in Northern Ireland. PMID- 19777883 TI - Campylobacter transfer from naturally contaminated chicken thighs to cutting boards is inversely related to initial load. AB - Foods prepared in the kitchen can become cross-contaminated with Campylobacter by contacting raw products, particularly skinned poultry. We measured the percent transfer rate from naturally contaminated poultry legs purchased in supermarkets. Transfer of Campylobacter from skin (n = 43) and from meat (n = 12) to high density polyethylene cutting board surfaces was quantitatively assessed after contact times of 1 and 10 min. The percent transfer rate was defined as the ratio between the number of Campylobacter cells counted on the cutting board surface and the initial numbers of Campylobacter naturally present on the skin (i.e., the sum of Campylobacter cells on the skin and board). Qualitative transfer occurred in 60.5% (95% confidence interval, 45.5 to 75.4) of the naturally contaminated legs studied and reached 80.6% (95% confidence interval, 63.0 to 98.2) in the subpopulation of legs that were in contact with the surface for 10 min. The percent transfer rate varied from 5 x 10(-2)% to 35.7% and was observed as being significantly different (Kruskall-Wallis test, P < 0.025) and inversely related to the initial counts on poultry skin. This study provides quantitative data describing the evolution of the proportion of Campylobacter organisms transferred from naturally contaminated poultry under kitchen conditions. We emphasize the linear relationship between the initial load of Campylobacter on the skin and the value of the percent transfer rate. This work confirms the need for modeling transfer as a function of initial load of Campylobacter on leg skin, the weight of poultry pieces, and the duration of contact between the skin and surface. PMID- 19777884 TI - Molecular characterization of biofilm formation and attachment of Salmonella enterica serovar typhimurium DT104 on food contact surfaces. AB - The molecular mechanism of biofilm formation by Salmonella Typhimuriun DT104 was characterized for a better understanding of its attachment and colonization in food processing environments. A library of random mutagenized clones was screened for phenotypic analyses of their ability to form biofilm, pellicle, curli, and cellulose. The genes identified were involved in lipopolysaccharide synthesis, assembly of flagella, regulation of rRNA biosynthesis, and outer membrane transportation and signaling. The insertion of transposon in flgK, rfbA, nusB, and pnp genes resulted in decreased biofilm formation. Alterations of flagellar and lipopolysaccharide production were confirmed in the flgK mutant and rfbA mutant, respectively. Biofilm formation by these four mutants in meat and poultry broths and their attachment on surfaces of stainless steel and glass were significantly reduced compared with those of the wild-type strain (P < 0.05). On the contrary, the mutation of STM4263 and yjcC genes in Salmonella Typhimuriun DT104 resulted in increased biofilm formation and attachment of the species in tested broths and on contact surfaces. Our findings suggest that many factors, such as production of exopolymeric substances and their efficient transportation through outer membrane, expression of flagella, and regulation of exoribonucleases and RNA-binding protein, could be involved in biofilm formation and attachment of Salmonella Typhimurium DT104 on contact surfaces. PMID- 19777885 TI - Escherichia coli O157 prevalence in different cattle farm types and identification of potential risk factors. AB - Although the prevalence of Escherichia coli O157 on cattle farms has been examined extensively, the relationship between this pathogen and farm type has been established only rarely. A large-scale study was designed to determine the prevalence of E. coli O157 in the Flemish region of Belgium on farms of dairy cattle, beef cattle, mixed dairy and beef cattle, and veal calves. The effect of various factors on the occurrence at the pen level also was evaluated. In 2007, 180 farms were randomly selected based on region, farm size, and number of animals purchased and were examined using the overshoe sampling method. When possible, overshoes used in areas containing animals in three different age categories (< 8 months, 8 to 30 months, and > 30 months) were sampled on each farm. In total, 820 different pens were sampled and analyzed for the presence of E. coli O157 by enrichment, immunomagnetic separation, and plating on selective agar. Presumptive E. coli O157 colonies were identified using a multiplex PCR assay for the presence of the rfb(O157) and fliC(H7) genes. The statistical analysis was carried out with Stata SE/10.0 using a generalized linear regression model with a logit link function and a binomial error distribution. The overall farm prevalence of E. coli O157 was 37.8% (68 of 180 farms). The highest prevalence was found on dairy cattle farms (61.2%, 30 of 49 farms). The prevalences on beef, mixed dairy and beef, and veal calf farms were 22.7% (17 of 75 farms), 44.4% (20 of 45 farms), and 9.1% (1 of 11 farms), respectively. A significant positive correlation between age category and E. coli O157 prevalence was found only on mixed dairy and beef farms and dairy farms. No influence of farm size or introduction of new animals was demonstrated. PMID- 19777886 TI - Reduction of Escherichia coli O157:H7 on produce by use of electrolyzed water under simulated food service operation conditions. AB - Treatment of fresh fruits and vegetables with electrolyzed water (EW) has been shown to kill or reduce foodborne pathogens. We evaluated the efficacy of EW in killing Escherichia coli O157:H7 on iceberg lettuce, cabbage, lemons, and tomatoes by using washing and/or chilling treatments simulating those followed in some food service kitchens. Greatest reduction levels on lettuce were achieved by sequentially washing with 14-A (amperage) acidic EW (AcEW) for 15 or 30 s followed by chilling in 16-A AcEW for 15 min. This procedure reduced the pathogen by 2.8 and 3.0 log CFU per leaf, respectively, whereas washing and chilling with tap water reduced the pathogen by 1.9 and 2.4 log CFU per leaf. Washing cabbage leaves for 15 or 30 s with tap water or 14-A AcEW reduced the pathogen by 2.0 and 3.0 log CFU per leaf and 2.5 to 3.0 log CFU per leaf, respectively. The pathogen was reduced by 4.7 log CFU per lemon by washing with 14-A AcEW and 4.1 and 4.5 log CFU per lemon by washing with tap water for 15 or 30 s. A reduction of 5.3 log CFU per lemon was achieved by washing with 14-A alkaline EW for 15 s prior to washing with 14-A AcEW for 15 s. Washing tomatoes with tap water or 14-A AcEW for 15 s reduced the pathogen by 6.4 and 7.9 log CFU per tomato, respectively. Application of AcEW using procedures mimicking food service operations should help minimize cross-contamination and reduce the risk of E. coli O157:H7 being present on produce at the time of consumption. PMID- 19777887 TI - Comparison of enrichment conditions for rapid detection of low numbers of sublethally injured Escherichia coli O157 in food. AB - A comparative study of lag phases and growth rates of healthy, stressed, and sublethally injured Escherichia coli O157 cells in 10 enrichment broths was performed. The evaluation of enrichment protocols was validated by different end point detection methods (two PCR and two combined capture-plate methods). Tryptic soy broth b [TSB (b)] provided the fastest growth (max = 1.00 1 0.06 h- ) but failed to recover oxidative-stressed E. coli O157. TSB (a), TSB-yeast extract medium, TSB supplemented with 8 mg/liter novobiocin plus 16 mg/liter vancomycin (TSB+), buffered peptone water (BPW), and BPW supplemented with 8 mg/liter vancomycin (BPW+V) enabled resuscitation of E. coli O157 cells independent from precultural conditions. Modified TSB plus 10 mg/liter novobiocin (mTSB+N), EC medium, EC reduced bile salts medium (ECred), TSB (b), and TSB supplemented with 8 mg/liter novobiocin plus 16 mg/liter vancomycin plus 2 mg/liter rifampin plus 1 mg/liter K-Telluriet plus 1.5 g/liter bile salts no. 3 (TSB++) all failed to recover E. coli O157 cells for at least one type of stress. The use of TSB (a), TSB+, BPW, and BPW+V was compared with that of mTSB+N (International Organization for Standardization reference broth) for reliable detection of low numbers of healthy, stressed, and sublethally injured E. coli O157 (approximately 10 CFU/10 g) from foods (sprouted seeds, fermented sausage, raw milk, and raw ground beef). When low numbers of healthy cells were inoculated, BPW, BPW+V, TSB, TSB+, and mTSB+N enabled growth until detectable numbers within 6 h of enrichment at 41.5 degrees C. Results showed that mTSB+N failed to recover to detectable numbers E. coli O157 cells sublethally injured by freeze and food stresses, in contrast to what was obtained with BPW and BPW+V. This study highlights that using mTSB+N for recovery of E. coli O157 from foods may yield false-negative results. PMID- 19777888 TI - Prevalence and level of Listeria monocytogenes and other Listeria species in selected retail ready-to-eat foods in the United Kingdom. AB - Although listeriosis is a rare cause of human disease in the United Kingdom, an increase in the number of cases has been observed since 2001, almost exclusively in persons older than 60 years. This increase prompted this study on the microbiological safety of ready-to-eat (RTE) foods, which included those types potentially linked to cases of listeriosis. Between May 2006 and April 2007, 6,984 RTE foods were sampled (2,168 sliced meats, 1,242 hard cheese, 1,088 sandwiches, 878 butter, 725 spreadable cheese, 515 confectionery products containing cream, and 368 probiotic drinks). The food types with the highest prevalence of Listeria monocytogenes were sandwiches (7.0%) and sliced meats (3.7% within shelf life, 4.2% end of shelf life). L. monocytogenes at > 100 CFU/g (exceeding the European Commission's food safety criteria limit) only occurred in sandwiches (0.4%) and sliced meats (0.7% within shelf life, 1.0% end of shelf life). Contamination with L. monocytogenes at >100 CFU/g was more frequent in meats that were prepacked and/or of pack size > or = 300 g and in sandwiches that were supplied prepacked that contained salad vegetables as an ingredient. Satisfactory microbiological quality was associated with premises on which the management was trained in food hygiene and those that complied with hazard analysis and critical control point principles. This study provides important information about the microbiological safety of RTE foods and demonstrates that the control of L. monocytogenes in such foods, and in particular sandwiches and sliced meats, is essential in order to minimize the risk of this bacterium being present at levels hazardous to health at the point of consumption. PMID- 19777889 TI - Safety-based shelf life model for frankfurters based on time to detect Listeria monocytogenes with initial inoculum below detection limit. AB - The growth of Listeria monocytogenes inoculated on frankfurters at four inoculum levels (0.1, 0.04, 0.01, and 0.007 CFU/g) was examined at 4, 8, and 12 degrees C until the time L. monocytogenes populations reached a detectable limit of at least 2 CFU/g. A scaled-down assumption was made to simulate a 25-g sample from a 100-lb batch size in a factory setting by using a 0.55-g sample from a 1,000-g batch size in a laboratory. Samples of 0.55 g were enriched in PDX-LIB selective medium, and presumptive results were confirmed on modified Oxford agar. Based on the time to detect (TTD) from each inoculum level and at each temperature, a shelf life model was constructed to predict the detection or risk levels reached by L. monocytogenes on frankfurters. The TTD increased with reductions in inoculum size and storage temperature. At 4 degrees C the TTDs (+/- standard error) observed were 42.0 +/- 1.0, 43.5 +/- 0.5, 50.7 +/- 1.5, and 55.0 +/- 3.0 days when the inoculum sizes were 0.1, 0.04, 0.01, and 0.007 CFU/g, respectively. From the same corresponding inoculum sizes, the TTDs at 8 degrees C were 4.5 +/- 0.5, 6.5 +/- 0.5, 7.0 +/- 1.0, and 8.5 +/- 0.5 days. Significant differences (P < 0.05) between TTDs were observed only when the inoculum sizes differed by at least 2 log. On a shelf life plot of 1n (TTD) versus temperature, the Q10 (increase in TTD for a 10 degrees C increase in temperature) values ranged from 24.5 to 44.7 and with no significant influence from the inoculum densities. When the observed TTDs were compared with the expected detection times based on the data obtained from a study with an inoculum size of 10 to 20 CFU/g, significant deviations were noted at lower inoculum levels. These results can be valuable in designing a safety-based shelf life model for frankfurters and in performing quantitative risk assessment of listeriosis at low and practical contamination levels. PMID- 19777890 TI - Effects of mussel processing soils on the adherence of Listeria monocytogenes to polypropylene and stainless steel. AB - A comparative study of adhesion kinetics of L. monocytogenes (strains CECT 5873, CECT 936, CECT 911, and CECT 4032, representing serotypes 1/2a, 1/2b, 1/2c, and 4b, respectively) to polypropylene (PP) and stainless steel (SS) under two surface contamination conditions in plants processing cooked mussel was carried out. The conditions were either (i) contamination of clean surfaces with mussel cooking juice carrying L. monocytogenes or (ii) contamination with L. monocytogenes after soiling with mussel cooking juice, i.e., conditioning film (CF). The kinetics of adhesion were successfully described by a modified logistic model. Adhesion to PP was higher than to SS in all strains, except CECT 5873. Adhesion was initially higher in the presence of CF, but numbers of adherent cells decreased sharply in the late phase of study in three of eight cases as a result of cell detachment. Combinations of strain, surface material, and surface conditioning where adhesion was most enhanced were defined as the worst-case scenarios (CECT 911-PP, 4032-PP-CF, 5873-SS, and 4032-SS-CF). Subsequently, adhesion in worst-case scenarios was compared with a similar contamination event taking place in plants processing live mussels, using intervalvar water of mussel as a food residue matrix. Adhesion levels were higher in intervalvar water than in cooking juice, especially in both cases with no CF; this was attributed to more space available for adhesion or to physicochemical conditions enhancing cells to adhere. PMID- 19777891 TI - Properties of whey protein-based films containing organic acids and nisin to control Listeria monocytogenes. AB - Whey protein isolate and glycerol were mixed to form a matrix to incorporate antimicrobial agents and produce edible films with antimicrobial activity against Listeria monocytogenes strains isolated from cheeses. Various organic acids were used to decrease pH down to approximately 3. In a preliminary assay without nisin, the effect of each organic acid was evaluated with respect to the rheological properties of the film solutions and the inhibitory and mechanical properties of the films. Lactic, malic, and citric acids (3%, wt/vol), which were used in a subsequent study of their combined inhibitory effect with nisin (50 IU/ml), had significantly higher antilisterial activity (P < 0.05) compared with the control (2 N HCl, 3% [wt/vol], with nisin). The largest mean zone of inhibition was 4.00 +/- 0.92 mm for malic acid with nisin. Under small-amplitude oscillatory stress, the protein-glycerol-acid film solutions exhibited a predominantly viscous behavior or a weak gel behavior, with the storage modulus (G') slightly higher than the loss modulus (G"). The malic acid-based solution was the only one whose viscosity was not influenced by the addition of nisin. The addition of nisin resulted in a nonsignificant (P > 0.05) increase in the percentage of elongation at break. Results from tensile and puncture stress were variable, but in general no significant differences were found after the incorporation of nisin. The overall results support the use of malic acid with nisin to produce effective antimicrobial films to control L. monocytogenes growth. PMID- 19777893 TI - Rapid differentiation of Bacillus strains using hydrophobic grid membranes and attenuated total reflectance Infrared microspectroscopy. AB - Bacillus species may be resistant to processing and sanitation procedures, making their control an important issue in the food industry. The objective of this study was to develop a rapid method for the differentiation of Bacillus cells at the strain level using infrared microspectroscopy and multivariate pattern recognition techniques. Aliquots (10 ml) of vegetative cells (approximately 10(3) CFU/ml) from four strains of each of three Bacillus species (B. cereus, B. mycoides, and B. thuringiensis) were filtered onto hydrophobic grid membranes. The membranes were placed on tryptic soy agar and incubated at 42 degrees C for 24 h and then removed from the agar and dried, and the biomass of individual vegetative colonies was directly measured by attenuated total reflectance infrared (ATR-IR) microspectroscopy. Soft independent modeling of class analogy models generated from second derivative transformed spectra in the 1,300 to 900 cm(-1) region exhibited clusters that permitted accurate strain-level classification of all isolates. Major discrimination was related to the signal from phosphate-containing compounds, likely phospholipids. Results indicate that a simple ATR-IR microspectroscopy technique combined with multivariate analysis could provide the food industry with a rapid and reagent-free screening procedure to complement more elaborate molecular identification methods. PMID- 19777892 TI - Probabilistic risk model for staphylococcal intoxication from pork-based food dishes prepared in food service establishments in Korea. AB - Foodborne illness contracted at food service operations is an important public health issue in Korea. In this study, the probabilities for growth of, and enterotoxin production by, Staphylococcus aureus in pork meat-based foods prepared in food service operations were estimated by the Monte Carlo simulation. Data on the prevalence and concentration of S. aureus as well as compliance to guidelines for time and temperature controls during food service operations were collected. The growth of S. aureus was initially estimated by using the U.S. Department of Agriculture's Pathogen Modeling Program. A second model based on raw pork meat was derived to compare cell number predictions. The correlation between toxin level and cell number as well as minimum toxin dose obtained from published data was adopted to quantify the probability of staphylococcal intoxication. When data gaps were found, assumptions were made based on guidelines for food service practices. Baseline risk model and scenario analyses were performed to indicate possible outcomes of staphylococcal intoxication under the scenarios generated based on these data gaps. Staphylococcal growth was predicted during holding before and after cooking, and the highest estimated concentration (4.59 log CFU/g for the 99.9th percentile value) of S. aureus was observed in raw pork initially contaminated with S. aureus and held before cooking. The estimated probability for staphylococcal intoxication was very low, using currently available data. However, scenario analyses revealed an increased possibility of staphylococcal intoxication when increased levels of initial contamination in the raw meat, andlonger holding time both before and after cooking the meat occurred. PMID- 19777894 TI - Disinfection of iceberg lettuce by titanium dioxide-UV photocatalytic reaction. AB - Securing the physical quality and microbial safety of fresh foods has been a major focus in the food industry. To improve quality and increase the shelf life of fresh produce, disinfection methods have been developed. Titanium dioxide (TiO2) photocatalytic reactions under UV radiation produce hydroxyl radicals that can be used for disinfection of foodborne pathogenic bacteria. We investigated the effects of TiO2-UV photocatalytic disinfection on the shelf life of iceberg lettuce. Counts of natural microflora (total aerobic bacteria, coliforms, psychrotrophic bacteria, and yeasts and molds) and inoculated pathogenic bacteria (Escherichia coli, Listeria monocytogenes, Staphylococcus aureus, and Salmonella Typhimurium) on iceberg lettuce were determined after 20-min treatments with TiO2 UV, UV radiation, a sodium hypochlorite (NaOCl) solution, and tap water. TiO2-UV treatment reduced the number of microorganisms by 1.8 to 2.8 log CFU/g compared with reductions of 0.9 to 1.4 and 0.7 to 1.1 log CFU/g obtained with UV radiation and NaOCl treatments, respectively. Treatment with tap water was used as a control and resulted in no reductions. Counts of microflora for iceberg lettuce at 4 and 25 degrees C were determined during a 9-day period. TiO2-UV treatment resulted in 1.2- and 4.3-log increases in the counts of total aerobic bacteria at 4 and 25 degrees C, respectively, compared with 1.3- to 1.6-log and 4.4- to 4.8 log increases due to UV radiation and NaOCl treatments. PMID- 19777895 TI - Assessment of antibiotic resistance in probiotic strain Lactobacillus brevis KB290. AB - Our purpose was to investigate the safety of the probiotic strain Lactobacillus brevis KB290. The European Qualified Presumption of Safety (QPS) evaluation approach was applied to the strain. We determined the strain's antibiotic resistance, verified it at the genetic level, and determined whether it could be transferred to intestinal microflora. Of 14 antibiotics tested, 11 showed MICs within the limits of the QPS criteria. However, the L. brevis KB290 MICs of ciprofloxacin (a fluoroquinolone), tetracycline, and vancomycin were two, four, and eight times, respectively, the breakpoint MICs suggested by the European Scientific Committee on Animal Nutrition, and the MIC of tetracycline was eight times the breakpoint MIC suggested by the European Scientific Panel on Additives and Products or Substances Used in Animal Feed. Using analysis of gapped-genome sequences, we found no known transferable determinants for tetracycline or vancomycin resistance, and we found no mutations in the quinolone resistance determining regions of the genes encoding GyrA or ParC for ciprofloxacin resistance associated with insertion sequences, integrons, or transposons. These data were confirmed by using PCR primers specific for the respective genes. We assessed the transferability of the resistance traits in conjugation experiments with enterococci and obtained no transconjugants, strongly suggesting that the resistance traits were not transferable. This study demonstrated that the antibiotic resistance observed in L. brevis KB290 was due not to dedicated mechanisms but to intrinsic resistance. According to the QPS criteria, these results provide safety assurance for the ongoing use of L. brevis KB290 as a probiotic. PMID- 19777896 TI - Use of a nisin-producing starter culture of Lactococcus lactis subsp, lactis to improve traditional fish fermentation in Senegal. AB - Lactococcus lactis subsp. lactis strain CWBI B1410, which produces various antibacterial compounds including organic acids and nisin, was used as a starter culture to improve the traditional Senegalese fish fermentation in which fish are mostly transformed to guedj by spontaneous fermentation for 24 to 48 h at ambient temperatures near 30 degrees C followed by salting (with NaCl) and sun drying. Assays were performed on lean fish (Podamasys jubelini) and fat fish (Arius heudelotii) purchased at a local market. The total viable microbial counts in raw fillets of P. jubelini and A. heudelotii were 5.78 and 5.39 log CFU/g, respectively. Populations of enteric bacteria (which can include pathogenic bacteria) in P. jubelini and A. heudelotii were 4.08 and 4.12 log CFU/g, respectively. Spontaneous fermentation of raw fillets at 30 degrees C led to the proliferation of enteric bacteria to 9 log CFU/g after 24 h in fermented P. jubelini and A. heudelotii fillets with pH values of 6.83 and 7.50, respectively. When raw fish fillets were supplemented with glucose (1%, wt/wt) and inoculated with Lactococcus lactis (10(7) CFU/g), the pH decreased to about 4.60 after 10 h at 30 degrees C, and nisin activity was detected in juice from the fillets. Traditionally fermented fillets of P. jubelini and A. heudelotii contained enteric bacteria at higher levels of 4 and 2 log CFU/g, respectively, than did fillets of the same fish supplemented with glucose and fermented with the starter culture. These data suggest that this new fish fermentation strategy combined with salting and drying can be used to enhance the safety of guedj. PMID- 19777897 TI - Identification of tetramine, a toxin in whelks, as the cause of a poisoning incident in Korea and the distribution of tetramine in fresh and boiled whelk (Neptunea intersculpta). AB - An investigation was conducted into the clinical symptoms and causative agent associated with a whelk poisoning incident that occurred in March 2005 in Korea. The whelk consumed in the poisoning incident was identified as Neptunea intersculpta. All of the 17 patients suffered from eyeball pain, headache, dizziness, abdominal pain, and nausea but no diarrhea. The causative agent was identified as tetramine, based on results from liquid chromatography-tandem mass spectrometry. Based on the tetramine concentration in the leftover whelk meat and the amount of meat consumed, the amount of tetramine ingested by the patients was estimated to be > or = 10 mg. This is the first report of the identification of tetramine as the causative agent in whelk poisoning in Korea. The anatomical distribution of tetramine in fresh and boiled N. intersculpta was examined. The toxin concentration in the meat was higher in specimens boiled in the shell than in fresh specimens collected on the same date. In meat boiled separately after removing the shell, the salivary gland, and the midgut gland, the tetramine concentration was much lower than that in fresh specimens or those boiled in the shell. This result suggests that boiling the meat after removing the salivary gland is a suitable way to prevent tetramine poisoning. PMID- 19777898 TI - Radiometric analysis of farmed fish (sea bass, gilthead bream, and rainbow trout) from Tenerife Island, Spain. AB - This study analyzed the content of gamma-emitting radionuclides in fish farmed on the island of Tenerife (Canary Islands, Spain). The fish species included in this study were sea bass, gilthead bream, and rainbow trout. The first two species are produced in offshore enclosures, while the third is produced in a freshwater fish farm. All measurements were performed using two high-purity germanium gamma-ray detectors. The content of gamma-emitting radionuclides in the fodder used to feed the different species of farmed fish studied was also determined. The following nuclides were often detected in the analyzed samples: 137Cs, 40K, 235U, 228Ac, 214Bi, 208Tl, 212Pb, and 214Pb. As a complement to this analysis, 210Po concentrations in two fish samples were determined by alpha spectrometry. The nuclide presenting the highest concentration was, as expected, the naturally occurring 40K, with an average concentration of 0.13 +/- 0.01 Bq/g (wet weight) (Bq/gww) in gilthead bream and sea bass and 0.12 +/- 0.01 Bq/gww in rainbow trout. The 235U concentrations determined in the same fish species were 0.6 +/- 0.5, 0.8 +/- 0.7, and 1.6 +/- 1.0 mBq/gww, respectively. This nuclide is seldom reported in fish samples. The concentrations of 137Cs (the only artificial nuclide determined in this study) in gilthead bream and sea bass were 0.026 +/- 0.006 and 0.044 +/- 0.01 mBq/gww, respectively. In addition to the radiometric analysis, the contribution of the analyzed nuclides to the effective dose from the mean daily intake of the fish was calculated. The calculated contribution, in terms of dose per person, produced by intake of the analyzed fish was 0.8 microSv/year. This value does not represent a significant risk to the local population. PMID- 19777899 TI - A statistical approach to identifying the batch of origin of mixed-meat products using DNA profiles. AB - Comparison of DNA samples at different points of a supply chain offers a powerful means of verifying tracing systems for primal cuts of meat. However, this approach is problematic for products made from ground (or mixed) meat because such products are typically made from an unknown (and random) number of unidentified animals. We present a statistical method that uses DNA profiles to verify or refute the contention that a particular mixed-meat product came from a particular manufacturing batch. This method involves randomly isolating a number of individual DNA samples (comprising an unknown number of individual genotypes) from the end product and comparing them with a set of DNA samples (also comprising an unknown number of individuals) that had been collected randomly before preparation of a manufacturing batch. Confidence levels are given for refuting spurious claims, and the development of optimum sampling strategies is discussed. The results are discussed in relation to batch verification of mixed meat products in the food industry, with an emphasis on traceability issues. PMID- 19777901 TI - Exploring historical Canadian foodborne outbreak data sets for human illness attribution. AB - Human illness attribution has been recently recognized as an important tool to better inform food safety decisions. Analysis of outbreak data sets has been used for that purpose. This study was conducted to explore the usefulness of three comprehensive Canadian foodborne outbreak data sets covering 30 years for estimating food attribution in cases of gastrointestinal illness, providing Canadian food attribution estimates from a historical perspective. Information concerning the microbiological etiology and food vehicles recorded for each outbreak was standardized between the data sets. The agent-food vehicle combinations were described and analyzed for changes over time by using multiple correspondence analysis. Overall, 6,908 foodborne outbreaks were available for three decades (1976 through 2005), but the agent and the food vehicle were identified in only 2,107 of these outbreaks. Differences between the data sets were found in the distribution of the cause, the vehicle, and the location or size of the outbreaks. Multiple correspondence analysis revealed an association between Clostridium botulinum and wild meat and between C. botulinum and seafood. This analysis also highlighted changes in food attribution over time and generated the most up-to-date food attribution values for salmonellosis (29% of cases associated with produce, 15% with poultry, and 15% with meat other than poultry, pork, and beef), campylobacteriosis (56% of cases associated with poultry and 22% with dairy products other than fluid milk), and Escherichia coli infection (37% of cases associated with beef, 23% with cooked multi-ingredient dishes, and 11% with meat other than beef, poultry, and pork). Because of the inherent limitations of this approach, only the main findings should be considered for policy making. The use of other human illness attribution approaches may provide further clarification. PMID- 19777900 TI - Differential features of foodborne gastroenteritis outbreaks of known and unknown etiology. AB - Foodborne diseases (FBD) are a major cause of disease and death, but their etiologies are not always known. Factors associated with determination of the etiologic agent of FBD outbreaks reported to the Department of Health in Catalonia (Spain) during 2002 to 2005 were studied. For each outbreak, the year, number of persons affected, hospitalization, and availability of samples from patients, food handlers, and foods were collected. The delay between the date of onset of symptoms of the second case and the report to the surveillance unit was calculated. The relationship between explanatory variables and determination of the cause of each outbreak was studied by logistic regression. The causal agent was identified in 242 (73.3%) of 330 outbreaks. Factors associated with determining the etiologic agent of the outbreak in the univariate analysis were availability of samples from cases (odd ratio [OR] of 6.0, 95% confidence interval [CI] of 3.2 to 11.1), hospitalization (OR of 5.1, 95% CI of 2.6 to 11.1), availability of samples from food handlers (OR of 2.7, 95% CI of 1.6 to 4.5), size > or = 10 cases (OR of 2.2, 95% CI of 1.3 to 3.2), availability of samples from food (OR of 1.8, 95% CI of 1.1 to 3.0), and the last year (2005) of the study period (OR of 1.9, 95% CI of 1.0 to 3.6). In the multivariate analysis, hospitalization (adjusted OR of 5.1, 95% CI of 2.4 to 11.2), size > or = 10 cases (adjusted OR of 2.1, 95% CI of 1.2 to 3.7), and the year 2005 (OR of 2.1, 95% CI of 1.1 to 4.0) remained associated. Collection and processing of clinical samples from cases and appropriate laboratory diagnoses of all possible etiologies of FBD, including viruses, are very important. Efforts by physicians and public health services to coordinate and improve their activity in these areas may help provide more accurate knowledge concerning the etiologies of FBD outbreaks and lead to more effective preventive procedures. PMID- 19777902 TI - Comparison between the Vitek Immunodiagnostic Assay System and PCR for the detection of pathogenic microorganisms in an experimental dry sausage during its curing process. AB - The comparison between the Vitek Immunodiagnostic Assay System (VIDAS) and PCR methods for the detection of the pathogenic microorganisms Salmonella Typhimurium, Listeria monocytogenes, Escherichia coli O157:H7, Clostridium perfringens, and Staphylococcus aureus in salchich6n (a type of Spanish fermented dry sausage) was studied. The automated mini-VIDAS method and the PCR method were used to detect the presence of these microorganisms in 90 samples grouped into six batches (one control batch, and five batches inoculated with Salmonella Typhimurium, L. monocytogenes, E. coli O157:H7, S. aureus, and C. perfringens, respectively). The determinations were carried out on fresh sausage, semicured (14 days), and finished product (28 days of curing). The concordance between both methods was 100%. For salchichon-type sausage samples, both the VIDAS method and PCR (in comparison to traditional methods) permit a significant reduction in the time required for the detection of the pathogens assayed. The absence of Salmonella Typhimurium, E. coli O157:H7, L. monocytogenes, S. aureus, their enterotoxins, and C. perfringens were verified in the control batch. Conversely, for batches inoculated with these pathogens, the results were positive in the fresh sausage up to 14 days of curing and in the finished product; this demonstrated the null or scant influence of the curing conditions and the constitutive lactic acid biota on the pathogens investigated. PMID- 19777903 TI - Comparison of enrichment procedures for shiga toxin-producing Escherichia coli in wastes from commercial swine farms. AB - Three methods for enrichment of Shiga toxin-producing Escherichia coli (STEC) were compared using waste pit samples from swine production facilities housing 50 to 3,000 animals. The STEC gene stx2 was detected in 5 of 17 pooled samples using a U.S. Department of Agriculture (USDA) enrichment procedure, 6 of 17 samples using a U.S. Food and Drug Administration (FDA) enrichment procedure, and 8 of 17 samples using an experimental acid enrichment. All isolates were non-O157 and 5 of 6 were positive for enterotoxigenic E. coli-associated heat stable toxins a and b. The three enrichment procedures were also tested for their ability to support growth of 31 strains of STEC. The acid enrichment media supported growth of 100% of the strains, the FDA medium supported 77% of the strains, and the USDA medium supported 16% of the strains. PMID- 19777904 TI - Detection of gram-negative histamine-producing bacteria in fish: a comparative study. AB - Poisoning due to ingestion of foods with elevated levels of biogenic amines (histamine, putrescine, cadaverine, and tyramine) is well documented. Histamine fish poisoning largely is due to growth of naturally occurring bacteria associated with scombroid fish species. A rapid and reliable method is needed to screen for the presence of histamine-forming bacteria in fish. This study included a comparison of three methods for the detection of histamine-producing bacteria. A total of 152 histamine-producing and non-histamine-producing bacteria from multiple sources were screened using a modified Niven's agar method, a potentiometric method, and a PCR-based assay targeting a 709-bp fragment of the histidine decarboxylase gene. Histamine production by bacterial isolates was confirmed by high-performance liquid chromatography (HPLC). Bacterial strains were categorized as producing high amounts of histamine, low amounts of histamine, or no histamine. Of the 152 strains tested, 128 (84%) were positive with the Niven's agar method, 73 (48%) were positive with the potentiometric technique, and 74 (49%) were positive with the PCR assay. Overall, a 38% false positive rate was observed with the modified Niven's agar method, although this method detected both low-histamine and high-histamine strains. There was a high degree of concordance (> 99%) between results of the potentiometric and PCR methods, but neither of these methods detected low-histamine bacteria. These observations support the need for a simple and straightforward yet sensitive method for detecting histamine-producing bacteria in seafood and environmental samples. PMID- 19777905 TI - Growth and survival of antibiotic-resistant Salmonella typhimurium DT104 in liquid egg products. AB - Since 11 September 2001, quality and food safety are no longer the concerns of only consumers, industry, regulatory agencies, or other government officials. Liquid foods that are prepared or stored in bulk, including liquid egg products, are considered to be at potential risk for sabotage. Because of their versatility, low price, and functional properties, many of these products are being marketed. Four of the most common products of this type are whole egg, egg albumen, 10% sugared yolk, and 10% salted yolk. Although all of the serotypes of Salmonella enterica may cause illness, multidrug-resistant Salmonella Typhimurium DT104 has become widespread and can cause severe illness that is difficult to treat. Studies were conducted to determine growth patterns of Salmonella Typhimurium DT104 in four commercial liquid egg products held at 4, 10, 20, 30, 37, and 42 degrees C for 0 to 384 h. All experiments were performed in duplicate and repeated twice. Standard methods were used to estimate cell numbers, and log CFU per gram of egg product was plotted against time. The number of cells of Salmonella Typhimurium DT104 increased to 8 to 9 log CFU/g in whole egg and 10% sugared yolk, increased by 1 log CFU/g in liquid albumen, but decreased by 3 log CFU/g in 10% salted yolk. Data from this study have been archived in the ComBase database to further assist policy makers or other scientists interested in Salmonella growth characteristics in liquid eggs. However, based on data generated in this study, Salmonella Typhimurium DT104 probably does not constitute a food threat agent in liquid eggs. PMID- 19777906 TI - Thermal inactivation of H5N2 high-pathogenicity avian influenza virus in dried egg white with 7.5% moisture. AB - High-pathogenicity avian influenza viruses (HPAIV) cause severe systemic disease with high mortality in chickens. Isolation of HPAIV from the internal contents of chicken eggs has been reported, and this is cause for concern because HPAIV can be spread by movement of poultry products during marketing and trade activity. This study presents thermal inactivation data for the HPAIV strain A/chicken/PA/1370/83 (H5N2) (PA/83) in dried egg white with a moisture content (7.5%) similar to that found in commercially available spray-dried egg white products. The 95% upper confidence limits for D-values calculated from linear regression of the survival curves at 54.4, 60.0, 65.5, and 71.1 degrees C were 475.4, 192.2, 141.0, and 50.1 min, respectively. The line equation y = [0.05494 x degrees C] + 5.5693 (root mean square error = 0.0711) was obtained by linear regression of experimental D-values versus temperature. Conservative predictions based on the thermal inactivation data suggest that standard industry pasteurization protocols would be very effective for HPAIV inactivation in dried egg white. For example, these calculations predict that a 7-log reduction would take only 2.6 days at 54.4 degrees C. PMID- 19777907 TI - Concentration method for the detection of enteric viruses from large volumes of foods. AB - Enteric viruses are the major cause of outbreaks of foodborne viral disease worldwide, and vegetables and fruits are considered significant vectors of virus transmission. In this study, we compared viral elution concentration methods in strawberry and lettuce and tested the secondary concentration step for concentrating viruses from large volumes of lettuce samples. Among the tested procedures, the combination of a 0.05 M glycine plus 100 mM Tris elution buffer (pH 9.5) and a polyethylene glycol precipitation concentration was most efficient for the detection of norovirus genogroup II from strawberries (50% of samples) and lettuce (2.9% of samples). The secondary concentration step using ultrafiltration devices could be applied to large lettuce samples without any decrease in detection limit and efficiency, and other cultivable enteric viruses including enteroviruses, adenoviruses, and rotaviruses were recovered from lettuce at efficiencies of 11.4, 9.05, and 11.3%, respectively. This method could be useful for detecting enteric viruses in fresh foods. PMID- 19777908 TI - Biological strategies to counteract the effects of mycotoxins. AB - Mycotoxins are fungal secondary metabolites that if ingested can cause a variety of adverse effects on both humans and animals, ranging from allergic responses to death. Therefore, exposure to mycotoxins should be minimized. A variety of physical, chemical, and biological methods have been developed for decontamination and/or detoxification of mycotoxins from contaminated foods and feeds. This overview details the latest developments in the biological control of both fungal infection and mycotoxin formation and describes the detoxification of many of the most important mycotoxins by microorganisms. This review also addresses the potential for use of microorganisms as mycotoxin binders in the gastrointestinal tract of both humans and animals, thereby reducing the potential deleterious effects of exposure to these toxins. PMID- 19777909 TI - [Clinical cases, a panacea view of medicine: from the simple anecdote to teaching practice]. PMID- 19777910 TI - [Sporadic Birt-Hogg-Dube syndrome]. AB - Birt-Hogg-Dube is a rare syndrome which is sporadic or hereditary with a dominant autosomal transmission. Various organs, in particular the skin, can be affected. In the presently reported case, skin was covered by hundreds of small molluscoid papules corresponding to trichodiscomas, fibrofolliculomas and skin tags. PMID- 19777911 TI - [Neuroendocrine tumors of the appendix]. AB - An 19-year-old woman was admitted for acute appendicitis. The histological study of the appendix revealed a tubular variant of endocrine carcinoma of the appendix. Neuroendocrine tumors ("NETs") of the appendix are rare tumors which are usually detected incidentally, affecting 0.3% to 0.9% of appendectomies. Depending on their size, but also on some other factors, including histologic type, these tumors will require specific treatment; sometimes appendectomy will not be sufficient. PMID- 19777912 TI - [Cerebral toxoplasmosis complicating an allograft with hematopoietic stem cells from peripheral blood]. AB - We report the occurrence of a cerebral toxoplasmosis 52 days after a non myeloablative allogeneic stem cell transplantation as treatment for acute myeloid leukemia. PMID- 19777913 TI - [Elevation of cardiac biomarkers after strenuous physical exertion]. AB - We present the case of a patient who felt faint after a strenuous exercise. A coronary angiography was performed because of an elevated level of troponin, but it failed to demonstrat any significant coronary stenosis. We discuss the effect of strenuous exercise on cardiac biomarkers. Most previous published studies involved young trained populations. The frequency of these abnormalities in older, less trained people is unknown. Moreover, the possible impact of these abnormalities on mid- or long-term outcome is a matter of debate. Seniors practising intensive sport activities should systematically be submitted to a cardiological evaluation. PMID- 19777914 TI - [An unusual interstitial pneumonitis]. AB - We report the case of a twenty-six-years-old patient who developed acute silicosis after only five years of professional exposure. He also succeedingly presented in the course of the disease progressive massive fibrosis, rest hypoxia, and eventually spontaneous pneumothorax. Monopulmonary transplantation was finally successfully performed. PMID- 19777915 TI - [Acute exacerbation of asthma: a disease that still remains life-threatening]. AB - Severe exacerbations of asthma can be life-threatening if not aggressively treated. Despite the publication of therapeutic guidelines developed by experts in this field and people education programs, early recognition and characterization of patients at risk for fatal asthma remain scarce. We report the case of a young lady suffering from acute exacerbation of asthma responsible for intensive care admission with long term mechanical ventilation due to the lack in initial appropriate care. PMID- 19777916 TI - [Epiploic appendagitis, an ignored diagnosis]. AB - Epiploic appendagitis is the term used to describe the inflammation of an epiploic appendage. These small masses of fat distributed along the colon, from the caecum to the recto-sigmoid junction can inflammate by torsion, spontaneously or secondarily with the inflammation of an anatomical structure in the neighbourhood. Symptomatology may mimic retro-caecal appendicitis or diverticulitis and the diagnosis by CT avoids unnecessary surgery or hospitalization. Indeed, under conservative treatment by AINS and analgesics, symptomatology regresses in about five days. In this article, we relate the case of a patient with a typical clinical presentation, to remind the elements of this pathological entity. PMID- 19777917 TI - [Germinoma responsible for central diabetes insipidus]. AB - We report the case of a 20-year-old woman who presented with sudden onset of polydipsia and polyuria. A diagnosis of diabetes insipidus was confirmed and the MRI showed a pituitary stalk enlargement. The patient was treated with Minirin. Two years later, she developed a panhypopituitarism. The MRI showed an intrasellar mass with an enlargement of the pituitary gland. A biopsy confirmed a germinoma. The patient was treated with radiotherapy with a partial response as only a part of the mass disappeared. This case highlights the importance of the clinical and radiological follow-up of central diabetes insipidus, especially when it is of unknown origin. The differential diagnosis will be reviewed. PMID- 19777919 TI - [Adenocarcinoma of the small intestines complicating coeliac disease in an adult: case report]. AB - Coeliac disease is an auto-immune disease due to gluten intolerance. One per cent of the European population is concerned. This small bowel adenocarcinoma is rare and concerns less than 5% of the digestive neoplasias. However the frequency of this rare cancer is higher in presence of coeliac disease. We are reporting the case of a 67-years-old woman whose coeliac disease has been complicated 5 years thereafter by a jejunal adenocarcinoma. The latter was found during an etiology search for iron deficiency anemia. PMID- 19777918 TI - [Mycobacterium malmoense infection in an immunocompetent patient]. AB - We report the case of a 57-year-old patient in whom we found a pulmonary infection due to Mycobacterium malmoense. This patient had no immunodeficiency and responded quite rapidly to anti-tuberculous therapy. He was treated for 6 months by levofloxacine, myambutol, and nicotibine, followed by 3 months of clarithromycine, levofloxacine and myambutol. The patient improved clinically to become asymptomatic and the cavitary lesion shown at the CT-scan slightly decreased. The patient is still currently treated by clarithromycine and ciproxine. PMID- 19777920 TI - [Severe hyponatremia revealing Sheehan's syndrome]. AB - We describe the case of a young woman admitted for severe hyponatremia due to hypopituitarism caused by a Sheehan's syndrome. Sheehan's syndrome is a rare disorder. It develops after obstetrical hemorrhage that causes ischemic necrosis of the pituitary gland. In most cases, illness appears progressively and diagnosis is made after variable delay. Acute syndrome may develop immediately after delivery in some rare cases. Hyponatremia is a frequent manifestation and may be severe. It is principally caused by secondary adrenal failure. PMID- 19777921 TI - [Myxoid liposarcoma]. AB - Soft-tissue sarcoma is a rare pathology. Due to restricted symptomatology, the diagnosis is often late. Any soft tissues swelling requires at first an ultrasound exam and a radiography, though MRI remains the most appropriate investigation. Treatment will be selected according to the tumor type and its histological grading, these parameters being determined after a surgical or a needle biopsy. The surgical care is often complemented by radiotherapy and sometimes chemotherapy. PMID- 19777922 TI - [Zolpidem dependence and withdrawal seizure]. AB - Zolpidem is an imidazopiridine with hypnotic properties. Compared to benzodiazepines, zolpidem has a mechanism of action that is thought to reduce the risk of dependence or abuse. However, in the past 10 years, several cases of zolpidem abuse, dependence and withdrawal reactions have been described in the litterature. Here, we describe a case of dependence and withdrawal seizure. PMID- 19777923 TI - [Angiosarcoma in chronic lymphoedema: a case of Stewart-Treves syndrome]. AB - The Stewart-Treves Syndrome is defined as an angiosarcoma (very aggressive malignant tumor originating from endothelial cells) appearing in a specific clinical setting. This tumor develops in patients suffering from chronic lymphedema of the upper limb following mastectomy and axillary lymph node dissection for breast cancer. The diagnosis relies on medical history, clinical examination and a histological assesment (biopsy or resection). This syndrome represents a rare clinical entity. Unfortunately, the prognosis is poor. A large surgical resection is the treatment of choice if the patient is a candidate for a surgical resection with a curative intent Radiotherapy is sometimes used as a palliative local treatment. Chemotherapy is only used in more advanced cases, not curable by surgery alone. PMID- 19777924 TI - [Giant lipoma on the back]. AB - Solitary lipoma is the most frequent soft tissue tumor, often appearing between 40 and 60 years of age. It is described as "giant" beyond 1 kg of weight and 10 cm of diameter. Its volume is the source of a good many problems in social life (camouflage, difficulties to dress) and causes multiple health problems such as pain, difficulties to sleep, compressions of nerves or vital structures, infections, etc. The diagnosis is primarily clinical. However, it is necessary to systematically exclude a malignant process. Surgical biopsy is recommended if the diagnosis cannot be asserted by the clinic or an imagery. The therapeutic attitude is abstention in case of small volume without functional impairment. Otherwise, total surgical excision is indicated with pathological analysis. We describe the clinical history of a patient suffering from a giant dorsal lipoma. PMID- 19777926 TI - Morbidly watching obesity's growth. PMID- 19777925 TI - [Practical advices for writing a case report]. AB - Case reports are the most accessible publications to the medical student or the practitioner. The appropriate selection of the clinical case that deserves publication is an important first step in the process. Afterwards, the report of the case requests much attention, as far as both content and presentation are concerned. The key-message emerging from the clinical case should be emphasized and supported by a clear-cut argumentation. Such an exercise, which might appear difficult at first glance, represents a valuable training for further more complex scientific publications. Here we give some practical advices to help the student or the practitioner who would like to present or publish a case report. PMID- 19777927 TI - Quantum cultural change. PMID- 19777928 TI - You've got mail. PMID- 19777929 TI - Vision policy: safety and savings. PMID- 19777930 TI - Why have a safety eyewear program? PMID- 19777931 TI - What do you want me to do, exactly? PMID- 19777932 TI - Water safety: new directions in irrigation and hydration. PMID- 19777933 TI - Where's the leak? PMID- 19777934 TI - Clearing a path to floor safety. PMID- 19777935 TI - Tweaking your CPR response. PMID- 19777936 TI - Message from your AMA delegation. PMID- 19777937 TI - Will you be a survivor or a victim? PMID- 19777938 TI - Endograft repair of type B aortic dissection with three-year follow-up. AB - Type B aortic dissections have remained a difficult management problem. Open surgical techniques have had a very high perioperative mortality, and medical management has not produced satisfactory long-term results. Endovascular grafting techniques may provide a favorable alternative therapy. However, there are currently no endovascular stents approved by the United States Food and Drug Administration for treating Type B aortic dissections. Also, there is very little data from United States centers on the long-term efficacy of endovascular stents used "off-label" to treat aortic dissections. This report discusses the care of a patient with a Type B aortic dissection successfully treated by an endograft in a community hospital. In addition, serial follow-up computerized tomography demonstrates the durability of this repair at three years. PMID- 19777939 TI - Cardiovascular care: a challenge for Kentucky. AB - Kentucky has a high incidence of cardiovascular (CV) disease, usually ranking it in the top 5 states of the United States as part of this dubious distinction. The most likely explanation lies in poor health habits with an elevated occurrence of cigarette smoking, diabetes, poor diet, obesity, physical inactivity, and a consistent presence of at least 3 of the 5 major components which define the term Metabolic Syndrome. Since 1980, there has been an explosion in the availability of CV technology and CV care throughout Kentucky, yet the state has maintained its undesirable high ranking for CV disease in the United States. Treating CV disease is clearly not enough; lifestyle habits need to be changed before CV disease develops. PMID- 19777940 TI - Insurance. PMID- 19777941 TI - [Regeneration formation index--new method of quantitative evaluation of distraction osteogenesis]. AB - INTRODUCTION: One of the most common techniques for limb lengthening is the Ilizarov method. The course of osteogenesis is usually monitored using classic X ray in this way determining the moment of fixator removal. Classic x-ray evaluation is subjective and therefore errors may easily be encountered. New techniques for objective and quantitative evaluation of radiologic documentation are needed. Computer assisted image analysis offers this possibility. AIM OF PAPER: Aim of this prospective study is to determine a quantitative, measurable method of regenerate description during distraction osteogenesis, based on classic radiography and computer assisted image analysis. MATERIAL AND METHODS: Material consists of 40 patients, in whom long bone lengthening procedures were performed. Altogether 40 lengthening were performed, 16-femur, 20-tibia, 4 humeral. Radiographic data, obtained in standard conditions, were than analyzed digitally. A mathematical bone model was created and later compared with obtained regenerate images. Computer processing lead to determining a new value, called regeneration formation index (RFI). For the model bone, the value is one. RESULTS: Average femur lengthening was 5.4 cm, tibia lengthening was 5.6 cm, and humeral 8.0 cm. During distraction osteogenesis the RFI, at the end of distraction phase, and the beginning of stabilization phase reached the lowest values, to increase steadily with the progress of osteogenesis, finally at the end of stabilization phase reaching the original values. The pace of RFI increase correlated with the presence of potential complications that require surgical treatment. CONCLUSION: Quantitative evaluation of regenerate using the regeneration formation index allows to precisely analyze the course of distraction osteogenesis, particularly to precisely estimate the timing of fixator removal and avoid complications. PMID- 19777942 TI - [The effect of lateral thoracotomy on the development of scoliosis in patients with patent ductus arteriosus]. AB - INTRODUCTION: Surgery, particularly thoracotomy in the thoracic area in infancy has been implicated in the development of scoliosis of thoracogenic origin. The aim of this study was to determine the influence of lateral thoracotomy on scoliosis development in subjects with patent ductus arteriosus. MATERIAL AND METHODS: A group of 69 patients with patent ductus arteriosus was evaluated. 38 patients were operated using left lateral thoracotomy and 31 patients were treated non-operatively using intravascular coil implantation. A spinal examination together with the evaluation of spinal roentgenograms was conducted. RESULTS: There was clinical scoliosis in 55% of operated, in 16% of non-operated patients. Scoliosis ranged between 10 and 42 degrees. 76% of operated patients with scoliosis had thoracic curves and in 57% of them left sided curves were found. All curves were right sided in non-operated subjects. Scoliosis in the operated group occurred in 68% of males and in 37% of females. CONCLUSIONS: Prevalence of scoliosis after thoracotomy was significantly higher than in the average population and after non-surgical methods of treatment of patent ductus arteriosus. The rate of single thoracic and the rate of left thoracic curves in patients after thoracotomy is higher than the rate in non-operated patients and in idiopathic scoliosis. Female to male ratio with scoliosis and after thoracotomy is significantly lower than in idiopathic scoliosis. PMID- 19777943 TI - [Chosen aspects of the surgical procedure during shoulder arthroplasty]. AB - Chosen aspects of the surgical-technique during shoulder arthroplasty were presented. In the description the most important stages of the implantation of shoulder prosthesis were taken into account. The necessity of the warnings during the surgical procedure of basic aspects of the anatomy and rules of shoulder biomechanics was pointed out. One underlined that an experience of the operator and correctly managed postoperative rehabilitation influence good final result of shoulder arthroplasty. PMID- 19777944 TI - [Derotational osteotomy of humerus in the treatment of children with persistent brachial plexus palsy]. AB - Patients with persistent brachial plexus palsy, advanced secondary deformity of gleno-humeral joint and rigid adduction and internal rotation contracture are candidates for external derotation osteotomy of the humerus. The aim of the study was to analyze the clinical results of patients treated with humeral derotational osteotomy. The analysis was performed on 9 patients in the average age of 12.5 years. Before surgery 4 of them had dislocation, 2 subluxation and 3 advanced deformity of gleno-humeral joint. After the operation active external rotation improved 46 degrees and passive 55 degrees. In all patients improvement of shoulder function of 5 points according to Mallet classification was noted. Active internal rotation decreased from 6 to 4 points according to our own classification, and passive internal rotation deteriorated from 6 to 5 points. Flexion and abduction in gleno-humeral joint as well as flexion contracture of the elbow has not changed significantly. The trumpet sign was present in any of our patients. The follow up ranged from 1 to 8 years. Our results confirms that external derotational osteotomy of the humerus significantly improves shoulder function in patients with persistent brachial plexus palsy. This is a valuable method of treatment in patients with advanced gleno-humeral dysplasia that are not candidates for soft tissue releases and muscle transfers. PMID- 19777945 TI - [Treatment of the femoral, tibia and humeral shaft fractures in children with the use of intramedullary nailing or external fixation, a long term study]. AB - The treatment of long bones shaft fractures with intramedullary nailing and external fixation is gaining popularity nowadays. The aim of this study was to analyze operative methods of treatment of the long bones shafts fractures in children. We compared outcomes of surgical treatment with the use of external fixation and flexible nails. The study group consisted of 127 patients (4 to 18 years old) who were operated on in our hospital during the period 1990-2005: 90 patients with femoral shaft fractures, 31 with tibia fractures and 6 with humeral fractures. In 81 children we performed fixation with Wagner's tool and in 46 cases we used Prevot or Ender nails. The follow up (performed at least one year after treatment cessation) included clinical examination and X-ray imaging. Union in an almost anatomical position was obtained in 126 patients. There was one fracture-healing complication ( nonunion- due to to early hardware removal). The study showed many advantages of the surgical treatment: minimal invasiveness, short hospitalization period, early rehabilitation. In our group both methods of management were comparable. We recommend intramedullary nailing in closed, transverse fractures and external fixator in open, multifragmentary and possibly unstable fractures. PMID- 19777946 TI - [Conduct and tactics of infections after hip arthroplasty]. AB - The number of arthroplasty surgeries is growing globally, bringing about an increase in the absolute number of infected complications. No precise statistics of complications are available in Poland. The present paper discusses the main causes of infected complications of hip arthroplasty. The object is to present both pre-surgery prophylaxis and the treatment of an infected complication adjacent to the endoprosthesis. Infections are commonly divided after Coventry and Fitzgerald. The most common pathogens in infected endoprostheses include Staphylococcus aureus and Staphylococcus epidermidis, while the treatment of infections with the Gram-negative flora poses many problems. Discussed within treatment of infected complications of hip arthroplasty has been one- and two stage surgical treatment with temporary implants--"spacers"--combines with prolonged antibiotic therapy. Important within the post-surgery treatment is prolonged monitoring of the infective agents (CRP and SR). PMID- 19777947 TI - [Early experiences in the use of Mayo stem in hip arthroplasty]. AB - The aim of this study was early clinical and radiological examination of patients after THR with Mayo stem. In the years 2004-2007 at Orthopaedic and Traumatology Department, Medical University in Lublin 38 Mayo stems were implanted in 35 patients. There were: 5 women and 30 men in the age from 27 to 67 years (average 51 years). The main cause of surgery was primary coxarthritis in 17 hips, AVN in 17, and DDH in 4. Follow-up is from 12 to 48 months (average 24.2 months). Preoperative Harris Hip Score varied from 32 to 45 pts. (average 38 pts.) and increased to 75-100 pts. (average 96 pts.) at longest postoperative follow up. There was one postoperative dislocation of THR 3 weeks after the surgery. There was one Mayo stem migration nine months after the surgery (15 mm) with radiolucent lines in all Gruen's zones. Conclusions. 1) Operative technique of Mayo stem is easy even with minimalny invasive technique. 2) The use of metal on metal bearing surfaces with short metaphyseal stem in THR gives possibility for good durable clinical result PMID- 19777948 TI - [The use of small diameter cups in total uncemented hip replacement]. AB - The aim of the study was to analyze early results of total uncemented hip replacement with use of small diameter acetabular components. In the group of 13 patients (15 hips) with severe dysplastic coxarthrosis mean age at surgery was 43.6 years. There were 8 right and 7 left hips operated. For clinical assessment Merle d'Aubigne and Postel classification modified by Charnley was used. Radiographs were evaluated according to Engh and Massini, De Lee and Charnley as well as Gruen classification system. The mean follow up was almost 18 months. There were 11 good and 4 satisfactory results. No very good and poor results were found. Subjective assessment of patients was much better than with use of Merle d'Aubigne and Postel classification. The use of small uncemented cups in a valuable method witch allows good positioning of acetabular component. Implantation of this type of cups gives satisfactory fixation without use of bone grafts but limits possibility of limb length inequality correction. PMID- 19777949 TI - [Radiosynovectomy of the knee--experience thereof]. AB - The aim of the study was the evaluation of 90Y radiosynovectomy performed in chronic exudative knee synovitis. The analyzed material comprised 81 90Y injections made between 2004 and 2008. The circumference of a knee, the volume of removed exudate, the knee mobility, the presence of pain, the temperature of a knee and the presence of floating patella (exudate) were evaluated. The percentage of pain-free patients increased from 12% to 50% after 1 year; an additional 10% of patients reported pain relief. The patient percentage with an increased knee temperature fell from 42% to 31% and the patients percentage with exudates decreased from 76% to 27. No improvement was found with respect to knee circumference. The knee mobility improvement (the patients percentage with full mobility) increased from 25% to 59% one month after the treatment) and exudate volume reduction was found only in the subgroup of patients suffering from pigmented villonodular synovitis. The obtained results permit the conclusion that 90Y radiosynovectomy for chronic exudative knee synovitis is an effective treatment modality; it relieves pain and reduces the patients percentage with exudate and increased knee temperature, and in the subgroup of patients suffering from the pigmented villonodular synovitis improves the knee mobility and reduces the volume of evacuated exudate. PMID- 19777950 TI - [Results evaluation of children flexible flatfoot operative treatment according to Mittelmeier method]. AB - The aim of the study is to evaluate results of the operative treatment of children flexible flatfoot. The investigative material consisted of 16 children (7 girls, 9 boys) treated between 1995-2004. The age at the time of operation was 9-15 years (mean 11.5 year). The average follow up period was 4.5 year (from 1 to 10 years). Clinical examination consisted of physical and subjective examination performed before and after operation. Subjective examination was performed on the basis of questinnaire. Physical examination was completed with hindfoot valgus angle measurement and with podoscopy (Clark's angle and Godunow-Sztriter index measurement). We decided to do surgery in children when conservative treatment failed. Operation was performed according to Mittelmeier method. After surgery we applied short leg cast with 10 degrees foot supination for 4 weeks. We allowed patients to walk without weight bearing by using elbow crutches for 8 weeks, and recommended rehabilitation 2-6 weeks after cast removing. According to static foot parameter we obtained 4 very good, 8 good and 4 sufficient results. According to patients subjective evaluation we obtained 5 very good, 8 good and 3 sufficient results. In two cases we had postoperative complications (prolonged wound healing). On the basis of presented material we can state that surgery according to Mittelmeier method at children above 9 years old could be benefit and should be take into consideration in treatment flexible flatfoot. PMID- 19777951 TI - [Are conduction studies in the median nerve obligatory for the diagnosis of the carpal tunnel syndrome: a review]. AB - Most the of doctors, including surgeons, who deal with diagnosing and treatment of carpal tunnel syndrome believe that median nerve conduction studies are obligatory for accurate diagnosis of the syndrome, providing various arguments to support this opinion. Based on available, current literature, a critical analysis of such an attitude was conducted. There is no definitive scientific evidence supporting a greater diagnostic importance of abnormal conduction in median nerve, than classical symptoms and signs of carpal tunnel syndrome. There is no enough evidence that electrophysiological studies are necessary for differential diagnosis, because clinical features of other pathologies are sufficiently different from classical carpal tunnel syndrome to avoid a false diagnosis. Relief of the symptoms and signs, but not normalisation of the conduction in median nerve is enough substantial as an evidence of effective therapy. The available evidence suggests the need of treatment of patients with typical symptoms of carpal tunnel syndrome associated with normal conduction studies, and non-treatment of those, with abnormal conduction but asymptomatic. Electrophysiological studies are thus not really a gold standard for carpal tunnel diagnosis and doing them in all patients presenting with typical history is not justified. Presence of classical features is enough convincing to make a diagnosis and qualify to the treatment. Nerve conduction studies may be helpful in cases with atypical history, when more than one site of compression is suspected, in failures and complications of surgery. The presented approach is associated with undoubted advantages of reducing time from referral to operation, costs and workload of neurophysiologists. There is no account for fear that meeting these rules may deteriorate results of the treatment of carpal tunnel syndrome. PMID- 19777952 TI - Molecular mechanisms underlying female sex determination--antagonism between female and male pathway. AB - Molecular interactions in a developing gonad are crucial for an individual since they determine its phenotypic sex. The process of sex determination is complicated because of the antagonistic interactions between the male and female pathway. Factors responsible for the determination of femaleness make the female pathway. This pathway has to inhibit a complex network of male-determining factors and also has to induce the expression of genes that drive differentiation of the ovary. Morphological description of the ovary development suggests that this process is simple, however, the analysis of the robust gene expression indicates that genetic control of the ovary differentiation is active and complicated at the molecular level. A plethora of genes is expresed in developing gonads. Nevertheless, there are only a couple of genes the role in ovary development of which has been described till now. RSPO1 seems the main gene participating in the establishment of the ovary fate. The loss of functional R spondin1 causes the complete female-to-male sex reversal in human. The second important factor is WNT4 which plays an opposite role to R-spondin1 in the gonad but also is decisive for the ovarian fate. WNT4 and RSPO1 drive the disposition of beta-catenin in cells and thus these factors regulate gene transcription and cell-cell adhesion. Foxl2 is another gene contributing to the development of the ovary. In females also germ cells seem to play important role in sex determination. PMID- 19777953 TI - Gonadogenesis in chub Squalius (Leuciscus) cephalus (L. 1758). AB - The chub is an opportunistic, rheophilic cyprinid species and popular gamefish distributed throughout almost all of Europe, South Caucasus and part of Anatolia. It is most abundant in small rivers and large streams. The process of anatomical and cytological differentiation was analyzed in chub gonads. Material used in the study was derived from artificial spawning of adult individuals caught in the Lyna River in April 2002. The results showed that gonadal sex differentiation develops faster in females than males. Morphological differentiation of gonads was noted about 98 days after hatching when fish weight varied between 0.483 g and 1.014 g and body length varied between 3.7 to 4.8 cm. Developing ovaries were spindle-shaped and male gonads were pear-shaped. Final cytological differentiation took place 154 days after hatching when single previtellogenic oocytes were observed in ovaries, contrary to males in which testes filled with spermatogonia not before the 190th day post hatching. PMID- 19777954 TI - Storage time and eggshell colour of pheasant eggs vs. the number of blastodermal cells and hatchability results. AB - The aim of this study was to investigate the number of the embryo blastodermal cells and hatchability of pheasant from eggs of different eggshell colours depending on the length of the storage period before hatching. On the day of collection, dark-brown and olive eggs were characterised by a similar and significantly higher (by about 48%) number of embryo BCs in comparison with light brown and blue eggs. Dark-brown eggs stored longer than one day had the highest, while blue-shelled eggs the lowest, number of BCs. The number of BCs found in eggs with blue and light-brown coloured eggshells stored for 10 days was similar and significantly lower (by 27.7%) in comparison with dark-brown eggs. With the lengthening of the storage period, the number of blastodermal cells in eggs of all eggshell colours declined as a result of necrobiosis. In comparison with the dark-brown and olive-shelled eggs, eggs with blue eggshells had higher (by about 7.0%) weight loss during the 21 days until hatching. The dark-brown and olive eggs were found to have a 10.3% higher proportion of eggs considered as fertilised in comparison with the blue-shelled eggs. Eggs with dark-brown shells stored for 2-4 days prior to hatching, in comparison with blue-shelled eggs, had a higher proportion of fertilised eggs. The dark-brown and olive eggs stored for 7 and more days before hatching possessed a higher value of this trait in comparison with the eggs of light-brown and blue eggshells (x = 80.9 against 66.4%). The highest drop in the share of fertilised eggs, which amounted on average to 3.25% for each day of storage, was observed in the blue-shelled eggs. The dark-brown eggs stored for 7 days before being placed in an incubator had higher hatchability from fertilised eggs (by 17.8%) in comparison with the eggs with blue eggshells. In the case of eggs stored for 8 to 10 days, values for this trait were higher for the dark-brown and olive-coloured eggs than for the blue shelled eggs. The highest mean decrease of chick hatchability from fertilised eggs was observed in the case of the blue-shelled eggs (7.93% for each day). The dark-brown eggs had significantly higher (by about 22.0%) chick hatchability from fertilised eggs than the blue-shelled eggs. Moreover, the dark-brown and olive eggs, in comparison with the blue-shelled eggs, were characterised by a significantly higher hatchability after each period of storage before incubation. The highest negative trend-cycle was observed for eggs with blue shells, while the smallest--for olive-shelled eggs. Directly after laying, pheasant eggs differed with regard to the developmental advancement of the blastodermal embryo depending on eggshell colour. Longer storage time caused the numbers of blastodermal cells in eggs to decrease. The group with blue shells had a lower proportion of fertilised eggs and lower hatching results than the dark-brown eggshell group. It was also demonstrated that the value of hatchability indices decreased significantly irrespective of eggshell colour after seven days of storage prior to hatching. PMID- 19777955 TI - Ultrastructure and transovarial transmission of endosymbiotic microorganisms in Conomelus anceps and Metcalfa pruinosa (Insecta, Hemiptera, Fulgoromorpha). AB - Endosymbiotic microorganisms commonly occur in fulgoromorphans, as in other plant sap-sucking hemipterans. Large syncytial organs termed mycetomes are present in the body cavities of Conomelus anceps (Delphacidae) and Metcalfa pruinosa (Flatidae), in the close vicinity of the ovaries. The mycetomes are surrounded by a one-layered epithelium. The mycetome cytoplasm is filled with yeast-like symbiotic microorganisms (YLSs). The YLSs are transovarially transmitted to the next generation. The endosymbionts are released from the mycetomes and migrate towards the ovarioles containing vitellogenic oocytes. The YLSs pass through the cells of the ovariole stalk (pedicel) and enter the perivitelline space. Then, a deep depression is formed at the posterior pole of the oocyte. The YLSs accumulate in the oocyte depression and form a characteristic "symbiont ball". The mycetome cytoplasm of Metcalfa pruinosa as well as epithelial cells surrounding the mycetome contain small, rod-shaped bacteria. PMID- 19777956 TI - Aluminium deposition in hydras. AB - The aim of this research was to explore, compare and explain the appearance, purpose and possible distribution of aluminium depositions in symbiotic and aposymbiotic hydra species. Al deposition in treated hydras appeared pink as single and multiple aluminium depositions or as clusters in the shape of globular or spot-like structures inside the cytoplasm of the hydra cells. Areas ofaluminium deposits were also present. Endosymbiotic algae in the green hydra were occasionally coloured pink. Authors suggest that the mesoglea represented a buffer of some sort as the depositions were almost completely absent in some parts of the body such as the gastroderm of brown hydras or the ectoderm in some concentrations of green hydras, or the mesoglea may have the ability to dispose of all the present aluminium and the occurrence and distribution ofthese depositions may be a mechanism of cellular detoxification and might be species specific. PMID- 19777957 TI - Identification and structure of lampbrush sex bivalents prior to and after the reproductive period of the European domestic goose Anser anser. AB - Lampbrush chromosomes (LBCs) present in bird oocytes are a new model in cytogenetics with particular significance for bird chromosome analysis. The fact that female birds are heterogametic makes it possible to observe both sex chromosomes in the form of decondensed structures typical of lampbrush chromosomes. A change in transcription activity associated with physiological processes in geese prior to and after the reproductive season is reflected in chromosome morphology. Lampbrush chromosomes obtained after the reproductive period have reduced side loops, sites of intensive transcriptional activity. However, noticeable characteristics in the chromosomes include inactive chromomeres. Chiasms, PBs, large side loops (ML) and telomeric loops (T, TLL, and GLL) are structures that undergo degradation latest after the termination of reproduction, and as a result, constitute the basis of identification of individual bivalents in different periods of the cell's transcriptional activity. PMID- 19777958 TI - Genetic constitution of parthenogenetic form of Polydrusus inustus (Coleoptera: Curculionidae)--hints of hybrid origin and recombinations. AB - Asexual reproduction among insects may arise spontaneously, as a result of infectious agents or hybridization between phylogenetically distinct organisms. Polyploidy, which may be the result of auto- or allopoliploidization (also associated with hybridization), is often connected with parthenogenesis. However, all studied parthenogens of weevils were apomictic, rare meiotic stages have been observed in a few of them what could suggests in their genomes besides the mutational changeability also recombination may occurs. We studied the level of heterozygosity in Internal Transcribed Spacer 2 sequences, and congruence ofmitochondrial (cytochrome B) and nuclear genealogies among individuals of parthenogenetic form of Polydrusus inustus. High frequency (87.0%) of heterozygotes in ITS2 sequences may indicate a hybrid origin of the parthenogen. It is possible that this parthenogenetic form arose via a hybridization event between phylogenetically distinct lineages of bisexual P. inustus, known only from Georgia and Turkey, or between this species and one of the closely relatives from the subgenus Scythodrusus. Although result of partition- homogeneity test did not show significant incongruence of mitochondrial and nuclear genealogies, in the network was detected one loop. Most probable explanations for existence of that loop in parthenogenetic form and for origin of rare homozygotes, which were detected in ITS2 sequences, is gene conversion. It is supported by recently cytogenetic studies indicating rare meiotic stages during the oogenesis of triploids of P. inustus. PMID- 19777959 TI - The distribution and population sex ratio of Cacopsylla myrtilli (W. Wagner, 1947) (Hemiptera: Psylloidea). AB - In Cacopsylla myrtilli (W. Wagner, 1947) bisexual populations, all-female populations and populations heavily biased towards females have been described. In the present paper all the available data on the distribution and population sex ratio of C. myrtilli are summarized. New data obtained by the authors are also presented. First records for Russia are described from Siberia and the southern part of the Far East. PMID- 19777960 TI - B chromosomes in four different populations of Rhamdia quelen (Siluriformes, Heptapteridae): a comparative study of frequency and distribution. AB - In the present study 25 specimens of Rhamdia quelen from four different localities were analyzed cytogenetically. All showed a diploid number of 58 chromosomes, with a karyotypic formula of 36m + 16sm + 6st and FN = 116. Metacentric B chromosomes showing inter- and intraindividual variation were observed in all populations. C-banding revealed differences in the heterochromatin distribution pattern, with evidence of completely heterochromatic B chromosomes in three populations: Agua das Pedras, Agua dos Patos and Taquari rivers, and partially heterochromatic B chromosomes in the population at the fish farm station in Timbo/SC. The occurrence of B chromosomes in such distinct populations suggests that they could have arisen from the same ancestral state, before the geographic dispersal of this species. PMID- 19777961 TI - Differentiated evolutionary conservatism and lack of polymorphism of crucial sex determination genes (SRY and SOX9) in four species of the family Canidae. AB - The sex determination process is under the control of several genes of which two (SRY and SOX9), encoding transcription factors, play a crucial role. It is well known that mutations at these genes may cause the development of an intersexual phenotype. The aim of this study was to conduct a comparative analysis of the coding sequence and 5'-flanking regions of both genes in four species of the family Canidae (the dog, red fox, arctic fox and Chinese raccoon dog). Similarity of the coding sequence of the SOX9 gene among the studied species was higher (99.7-99.9%) than in the case of the SRY gene (96.7-97.3%). Only single nucleotide changes were found in the compared coding sequences, whereas in the 5' flanking region of both genes nucleotide substitutions, as well as insertions and deletions were observed. None of the changes detected in the 5'-flanking region occurred within the potential consensus sequences for transcription factors. No polymorphism was found for either of these genes in any of the analyzed species. PMID- 19777962 TI - Cytogenetic and morphological characterization of Corbicula fluminalis (O. F. Muller, 1774) (Bivalvia: Veneroida: Corbiculidae): taxonomic status assessment of a freshwater clam. AB - Chromosomes of Corbicula fluminalis were characterized by karyotype analysis and nucleolar organizer region (NORs) localization. The triploid chromosome number was confirmed as 54; the karyotype is composed of 3 metacentric, 15 submetacentric and 36 subtelo-acrocentic chromosomes. Silver staining revealed nucleolar organizers on the telomeric regions of three subtelo-acrocentic chromosomes. This is the first study on chromosomes of C. fluminalis. The results are discussed with regards to Corbicula species as well as its relationships to other mollusc species based on cytogenetic characters and morphometric of the shells. PMID- 19777963 TI - The effects of muscarinic cholinergic receptor antagonist on slow bursting neuronal activity in the rat intergeniculate leaflet. AB - The intergeniculate leaflet (IGL) of the thalamus is an important neuronal element of the mammalian circadian time-keeping system. It receives direct input from retinal ganglion cells. In addition, there are, among other projections, afferents to the IGL from the brainstem cholinergic nuclei. The aim of the present study was to determine the influence of intravenous (i.v.) application of atropine--a muscarinic acetylcholine receptor antagonist, on the ultra-slow isoperiodic oscillations of the IGL neurons. Spontaneous neuronal activity was extracellularly recorded from the rat IGL. Different concentrations of atropine were administrated after recording baseline activity. In all experiments, the period of oscillation became longer after injection of atropine. In some of cases we also noted a temporary disturbance of the oscillatory pattern of neuronal activity. These data suggest that the oscillatory firing of IGL cells can be modulated by cholinergic influence. PMID- 19777964 TI - Differences between sexes in digestive efficiency of the white stork Ciconia ciconia under experimental conditions. AB - Sex differences in digestive performance may be related to food contents, to body size as well as many other physiological traits. However, evidence for sex differences in the digestion of birds, especially in the case of predators, is scarce. Therefore we studied digestive efficiency, and also body size, intestine length and food selection of the wild white stork (Ciconia ciconia), under experimental conditions in the Poznan Zoo. Altogether 29 individuals of this species were investigated (9 males, 20 females). During 5-day- long experimental cycles, the diet of the birds consisted of mammals, birds, fishes and insects. The mean daily wet food intake (weight of the food eaten) during the experiment was 272.8g +/- 89.3 g for males and 342.7g +/- 157.4 g for females, but the difference between sexes was not significant (P = 0.226). The mean digestive efficiency showed a significant difference, i.e. in male white storks it amounted to 70.87% +/- 14.43%, whereas in females this value was 77.53% +/- 3.99% (P = 0.049). Digestive efficiency was slightly influenced by changes in body weight of storks during the experiment. Correlation coefficients between sexes also differed significantly (P = 0.037). The study showed that the digestive efficiency is positively correlated with the quantity of food intake and body weight. PMID- 19777965 TI - Renal regulation of calcium-phosphate metabolism in single- and twin pregnant goats. AB - The aim of this study was the clearance assessment of renal function in single- and twin-pregnant goats and a comparison of selected parameters associated with calcium-phosphate management in terms of litter size. Clearance studies were carried out on 16 pregnant Polish White Improved goats (8 single pregnancies and 8 twin pregnancies). It was demonstrated that the kidneys of pregnant goats regulate the calcium-phosphate balance to a great extent. In spite of observed differences in parameters of renal functions, plasma calcium and inorganic phosphorus concentrations were comparable with normal reference values in further weeks of pregnancy. Significant differences in renal function between single and twin pregnancies were not observed. Gut absorption and/or bone tissue metabolism seem important for the maintenance of appropriate calcium-phosphate status. PMID- 19777966 TI - Evaluation of biological activity of Uncaria tomentosa (Willd.) DC. using the chicken embryo model. AB - The biological activity of Uncaria tomentosa (Willd.) DC. (cat's claw) was evaluated by application of the chicken embryo model. Among three groups of eggs (n = 360) with twelve-day old embryos, two were injected with different doses of cat's claw extracts (0.0492 and 0.492 mg/200 lambda). To the third control group 200 lambda of physiological salt was applied. All eggs were incubated in conventional forced-air apparatus until hatched. Hatchability, chicken weight and wholesomeness were analyzed. Selected parameters of blood including number of erythrocytes (RBC), number of leukocytes (WBC), mean red cell volume (MCV), hematocrit (HCT), hemoglobin concentration (HGB), mean amount of cell hemoglobin (MCH), mean cell hemoglobin concentration (MCHC) and embryo weight (MAS) were assayed and compared. Significant differences with ANOVA were observed for MCV (P = 0.002), MCHC (P = 0.00001) and MCH (P = 0.02). Applying the chicken embryo model brought new information about the biological activity of U. tomentosa showing an unfavourable effect on some morphological blood parameters. PMID- 19777967 TI - The level of selected hormones in peripheral blood in female polar foxes (Alopex lagopus L.) in relation to age. AB - The objective of the study was to determine the concentration profile of selected hormones in the blood serum of blue polar fox vixens at various ages during the non-mating period, three months after lactation. The investigation was performed on 50 clinically healthy female polar foxes derived from a domestic reproductive farm. The animals were divided into 5 age groups (n = 10) ranging from the 1 to 5 years of life. In the blood serum the contents of insulin, triiodothyronine (total and free), thyroxin (total and free), leptin and ghrelin (total and active) were determined. No significant, female age-dependent differences were found in the contents of insulin, total and free triiodothyronine and total ghrelin in the blood serum. Significant (P < 0.05) differences were observed in the concentration of total and free thyroxin (the highest in the blood of 4-year old females) as well as leptin and active ghrelin (the lowest and the highest content in 3-year old vixens). However, no distinct, female age-dependent tendencies for change in the content of these hormones in the blood serum were observed. PMID- 19777968 TI - Systematics of Scorpaeniformes species in the Mediterranean Sea inferred from mitochondrial 16S rDNA sequence and morphological data. AB - Genetic and morphological divergence and phylogenetic relationships of Scorpaeniformes fish including two genera and six species, Helicolenus dactylopterus, Scorpaena maderensis, Scorpaena porcus, Scorpaena elongata, Scorpaena scrofa, Scorpaena notata, living in the Mediterranean Sea, were investigated with morphological and mitochondrial 16S rDNA sequence data. The mean nucleotide diversity was found to be 0.0792. Average sequence divergence between species of Sebastidae and Scorpaenidae was 8.4%, and 6.4%. between species of the genus Scorpaena. For congeneric comparisions, the lowest genetic divergence (0.7%) was observed between S. porcus and S. notata, and the highest divergence (10.8%) was detected between S. maderensis and S. notata. High levels of nucleotide divergence were detected between species of two families, and the maximum value was found to be 14.5% between H. dactylopterus and S. elongata. The two phylogenetic methods (NJ and MP) identified two major lineages. In the NJ tree S. elongata was the sister group to S. scrofa. S. maderensis was more divergent from these groups. Another lineage contained S. porcus and S. notata. The topology of the MP tree is similar to that of the NJ tree. The pattern and degree of morphological differentiation was not congruent with the genetic differentiation. The Euclidiean distances of morphological data revealed very high morphological divergence between the two families. The highest morphological divergence was observed between H. dactylopterus and S. porcus, and the lowest was detected between S. elongata and S. notata. The present genetic and morphological data support the present monophyletic status of the Scorpaena genus. PMID- 19777970 TI - [A multi-step procedure for extraction of diagnostic parameters of the radial artery pulse signal]. PMID- 19777969 TI - [A microfocal method of phase-contrast x-ray imaging]. PMID- 19777971 TI - [Design of neuro-controlled prosthetic devices]. PMID- 19777972 TI - [Optimization of bipolar impulses for external defibrillators using the repolarization hypothesis]. PMID- 19777973 TI - [Laser therapy in oncological diseases and its hardware implementation]. PMID- 19777974 TI - [Software for the complexity of speech signal research in patients with malignant diseases of the throat]. PMID- 19777975 TI - [Design of network-based fuzzy knowledge bases for medical decision-making support]. PMID- 19777976 TI - [Use of neural networks for identification of artifacts in electroencephalographic signals decomposed using the wavelet packet transform]. PMID- 19777977 TI - Thoracic endometriosis: an unusual cause of hemothorax. AB - In this report we describe the clinical presentation, diagnosis, treatment and outcome of a 45-year-old woman with thoracic endometriosis. Four clinical presentations have been described. The majority have presented with catamenial pneumothorax, followed by hemothorax, hemoptysis and lung nodules. Our patient presented with right-sided hemothorax and lung nodules. Video-assisted thoracoscopic aurgery confirmed the presence of endometrial tissue embedded in the diaphragmatic pleura. Talc pleurodesis alongwith atotal abdominal hysterectomy and bilateral salpingo-oophorectomy led to a clinical and radiological resolution. PMID- 19777978 TI - Chronic idiopathic intestinal pseudo-obstruction: a case report and discussion. PMID- 19777979 TI - When the diagnosis is a zebra: pulmonary artery aneurysm. AB - Some ailments maypresent so distinctively that the diagnosis is often unquestionable. Other cases, however, may present typically, but have atypical findings. We describe a case of a patient who presented to our institution with recurrent hemoptysis. The clinical features were suggestive of an underlying infection or malignancy. When these were ruled out, the search for a zebra had begun. The patient underwent sixty four-slice computerizedtomographic angiography (CTA) which revealed a right pulmonary artery aneurysm (PAA). Timely involvement of interventional radiologists and thoracic surgeons prevented a potentiallylife threatenninghemorrhage. This case underlines the importance of awareness of this condition in the formulation of a differential diagnosis forhemoptysis. PAAis a rare condition that is either congenital or acquired. Common acquired etiologies include chronic thromboembolic pulmonary hypertension, infections (syphilis and tuberculosis), vasculitis (Behcet's and Hughes-Stovin syndromes), neoplasms (primaryandmetastatic), andtrauma(most often iatrogenic). PMID- 19777981 TI - Update on dexmedetomidine for adult ICU sedation. PMID- 19777980 TI - Prenatal diagnosis of an umbilical vein aneurysm: a case report. AB - Aneurysm of the umbilical vessels is a rare abnormality and has seldom been diagnosed prenatally. We report a case in which dilatation of the intra-amniotic umbilical cord was seen on prenatal ultrasound at 34-weeks gestation. This was believed to represent an umbilical vein aneurysm and was confirmed on subsequent pathological examination after delivery. A review of the literature concerning these uncommon vascular abnormalities of the umbilical cord is presented. PMID- 19777982 TI - Health-care reform: "the cost conundrum". PMID- 19777983 TI - Heretical thoughts on saving primary-care. PMID- 19777984 TI - Patient-centered medical home: improving health care by shifting the focus to patients. PMID- 19777985 TI - It's time for a home inspection. One payer's perspective on the patient-centered medical home. PMID- 19777986 TI - Medical home: a reinvention for 21st-century health care. PMID- 19777987 TI - The medical home--ready for prime time? PMID- 19777988 TI - The medical home--will it be the cure that ails us? PMID- 19777989 TI - The patient-centered medical home. PMID- 19777990 TI - The physician views financing of hospital and medical care. PMID- 19777991 TI - What should doctors believe? PMID- 19777992 TI - Re: Hooked on drugs. PMID- 19777993 TI - Soluble MHC-peptide complexes: tools for the monitoring of T cell responses in clinical trials and basic research. AB - Soluble MHC-peptide complexes, commonly known as tetramers, allow the detection and isolation of antigen-specific T cells. Although other types of soluble MHC peptide complexes have been introduced, the most commonly used MHC class I staining reagents are those originally described by Altman and Davis. As these reagents have become an essential tool for T cell analysis, it is important to have a large repertoire of such reagents to cover a broad range of applications in cancer research and clinical trials. Our tetramer collection currently comprises 228 human and 60 mouse tetramers and new reagents are continuously being added. For the MHC II tetramers, the list currently contains 21 human (HLA DR, DQ and DP) and 5 mouse (I-A(b)) tetramers. Quantitative enumeration of antigen-specific T cells by tetramer staining, especially at low frequencies, critically depends on the quality of the tetramers and on the staining procedures. For conclusive longitudinal monitoring, standardized reagents and analysis protocols need to be used. This is especially true for the monitoring of antigen-specific CD4+ T cells, as there are large variations in the quality of MHC II tetramers and staining conditions. This commentary provides an overview of our tetramer collection and indications on how tetramers should be used to obtain optimal results. PMID- 19777994 TI - A mammalian reductive deiodinase has broad power to dehalogenate chlorinated and brominated substrates. AB - Iodotyrosine deiodinase is essential for iodide homeostasis and proper thyroid function in mammals. This enzyme promotes a net reductive deiodination of 3 iodotyrosine to form iodide and tyrosine. Such a reductive dehalogenation is uncommon in aerobic organisms, and its requirement for flavin mononucleotide is even more uncommon in catalysis. Reducing equivalents are now shown to transfer directly from the flavin to the halogenated substrate without involvement of other components typically included in the standard enzymatic assay. Additionally, the deiodinase has been discovered to act as a debrominase and a dechlorinase. These new activities expand the possible roles of flavin in biological catalysis and provide a foundation for determining the mechanism of this unusual process. PMID- 19777995 TI - Flip-flop is the rate-limiting step for transport of free fatty acids across lipid vesicle membranes. AB - The mechanism of transport of free fatty acids (FFA) across lipid bilayer membranes remains a subject of debate. The debate is whether the rate-limiting step for transport is flip-flop across the membrane or dissociation into the aqueous phase. Recently, a new method for assessing dissociation was described in which fluorescein phosphatidylethanolamine (FPE) introduced into the outer leaflet of lipid vesicles was used to monitor FFA dissociation. Transport of FFA into vesicles containing both FPE in the outer leaflet and pyranine trapped in the inside aqueous phase revealed identical rate constants for quenching of FPE and pyranine fluorescence. Because no difference was observed in the time for FFA binding to the outer surface and flip-flop across the bilayer, it was concluded that dissociation was slower than flip-flop. Here, we used FPE and BSA to assess dissociation of oleate from lipid vesicles. In separate pyranine- or ADIFAB containing vesicles, we assessed flip-flop. We found that the FPE and BSA transfer methods yielded equivalent rate constants for dissociation, which were 3 10-fold faster than that of flip-flop. We found that in vesicles containing both FPE and pyranine, pyranine fluorescence cannot be separated from FPE fluorescence. The identical rate constants for FPE and pyranine observed with vesicles containing both fluorophores reflected the dominance (20-fold) of FPE fluorescence at pyranine excitation and emission wavelengths. Because the dissociation rate constants are 3-10 times faster than the rate constants for flip-flop, flip-flop must be the rate-limiting step for the transport of FFA across lipid vesicles. PMID- 19777996 TI - Classification of cytochrome P450 inhibitors with respect to binding free energy and pIC50 using common molecular descriptors. AB - Virtual screening of chemical libraries following experimental assays of drug candidates is a common procedure in structure based drug discovery. However, the relationship between binding free energies and biological activities (pIC50) of drug candidates is still an unsolved issue that limits the efficiency and speed of drug development processes. In this study, the relationship between them is investigated based on a common molecular descriptor set for human cytochrome P450 enzymes (CYPs). CYPs play an important role in drug-drug interactions, drug metabolism, and toxicity. Therefore, in silico prediction of CYP inhibition by drug candidates is one of the major considerations in drug discovery. The combination of partial least-squares regression (PLSR) and a variety of classification algorithms were employed by considering this relationship as a classification problem. Our results indicate that PLSR with classification is a powerful tool to predict more than one output such as binding free energy and pIC50 simultaneously. PLSR with mixed-integer linear programming based hyperboxes predicts the binding free energy and pIC50 with a mean accuracy of 87.18% (min: 81.67% max: 97.05%) and 88.09% (min: 79.83% max: 92.90%), respectively, for the cytochrome p450 superfamily using the common 6 molecular descriptors with a 10 fold cross-validation. PMID- 19777997 TI - A practical synthesis of m-prostaglandin E synthase-1 inhibitor MK-7285. AB - A practical, kilogram-scale chromatography-free synthesis of mPGE synthase I inhibitor MK-7285 is described. The route features a convergent assembly of the core phenanthrene unit via amide-directed ortho-metalation and proximity-induced anionic cyclization, followed by imidazole synthesis and late-stage cyanation. PMID- 19777998 TI - A benzannulation protocol to prepare substituted aryl amines using a Michael aldol reaction of beta-keto sulfones. AB - A practical benzannulation method to prepare variously substituted aryl amines and sulfides was developed. The approach involves a Michael-aldol reaction of beta-keto sulfones with enones followed by a subsequent condensation of the initial adduct with various amines. The base-induced Michael-aldol cascade proceeds smoothly with a number of different beta-keto sulfones, affording the adducts as single diastereomers. Heating the resulting Michael-aldol product with an amine in toluene at 120 degrees C results in the formation of a transient enamine, which then undergoes loss of phenyl sulfenic acid to furnish the aromatized amine in good yield. A related reaction also occurred when the Michael aldol product was heated with thiols or alcohols, giving rise to aryl-substituted sulfides or ethers. PMID- 19777999 TI - Convenient large-scale synthesis of D-glucaro-1,4:6,3-dilactone. AB - Calcium D-glucarate was converted into D-glucaro-1,4:6,3-dilactone on 32-g, 1-kg, and 22-kg scale, using azeotropic distillation with methyl isobutyl ketone to drive the dehydration. The crystalline product was > or = 99.5% pure by GC and NMR, and overall yield was as high as 72%. PMID- 19778000 TI - Real-time monitoring of oxidative burst from single plant protoplasts using microelectrochemical sensors modified by platinum nanoparticles. AB - Oxidative bursts from plants play significant roles in plant disease defense and signal transduction; however, it has not hitherto been investigated on individual living plant cells. In this article, we fabricated a novel sensitive electrochemical sensor based on electrochemical deposition of Pt nanoparticles on the surface of carbon fiber microdisk electrodes via a nanopores containing polymer matrix, Nafion. The numerous hydrophilic nanochannels in the Nafion clusters coated on the electrode surface served as the molecular template for the deposition and dispersion of Pt, which resulted in the uniform construction of small Pt nanoparticles. The novel sensor displayed a high sensitivity for detection of H(2)O(2) with a detection limit of 5.0 x 10(-9) M. With the use of this microelectrochemical sensor, the oxidative burst from individual living plant protoplasts have been real-time monitored for the first time. The results showed that oxidative burst from single protoplasts triggered by a pathogen analogue were characterized by quanta release with a large number of "transient oxidative microburst" events, and protoplasts from the transgenic plants biologically displayed better disease-resistance and showed a distinguished elevation and longer-lasting oxidative burst. PMID- 19778001 TI - Dissecting the inhibition mechanism of cytosolic versus transmembrane carbonic anhydrases by ESR. AB - Spin-labeled sulfonamides incorporating TEMPO moieties showed efficient activity as inhibitors of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) and, in particular, of the physiologically relevant isoenzymes hCA II, hCA IX, and hCA XIV. Here we report a detailed analysis of this class of inhibitors by means of ESR and X-ray crystallography, in comparison with inhibition tests against all mammalian CA isoforms, CA I-XIV. Local dynamics and structure were manifested in the ESR signal through modulation of internal magnetic anisotropies. Analysis and fitting of the ESR spectra of several spin-labeled sulfonamides with isoforms CA II (cytosolic), CA IX (catalytic domain and full length transmembrane, tumor associated isoform) and CA XIV (transmembrane isozyme) provided information about polarity and dynamics of specific microenvironments sensed by the nitroxyl group within the active site cavity of these isozymes. The comparison of ESR and crystallographic data of hCA II complexed with one of these inhibitors constitutes a useful tool for the understanding of molecular hindrance and ordering within the enzyme active site, and provides theoretical bases to use these inhibitors for imaging purposes of hypoxic tumors overexpressing the transmembrane isozyme CA IX. Combining the sulfonamide zinc-binding group with the TEMPO moiety thus allowed to dissect the selective inhibition mechanism of different cytosolic and transmembrane carbonic anhydrases. PMID- 19778002 TI - On the interactions between amino acids and ionic liquids in aqueous media. AB - The understanding of the molecular-level interactions between biomolecules and ionic liquids (ILs) in aqueous media is crucial for the optimization of a number of relevant biotechnological processes. In this work, the influence of a series of amino acids on the liquid-liquid equilibria between 1-butyl-3 methylimidazolium tricyanomethane and water was studied to evaluate the preferential interactions between these three compounds. The solubility effects observed are dependent on the polarity, size, and charge distribution of the amino acid side chains and are explained in terms of a refined version of the model proposed earlier (Freire et al. J. Phys. Chem. B 2009, 113, 202; Tome et al. J. Phys. Chem. B 2009, 113, 2815) for ion specific effects on aqueous solutions of imidazolium-based ILs. Although acting through different mechanisms, salting-in and salting-out phenomena possess a common basis which is the competition between water-amino acid side chain, IL-amino acid side chain, and water-IL interactions. The delicate balance between these interactions is dependent on the relative affinities of the biomolecules to water molecules or to IL cation and anion and determines the trend and magnitude of the solubility effect observed. PMID- 19778003 TI - Temperature-induced molecular structural changes of linear poly(ethylene imine) in water studied by mid-infrared and near-infrared spectroscopies. AB - The chain conformation and hydration structure of an aqueous solution of linear poly(ethylene imine) (LPEI) have been studied by the use of mid-infrared (mid-IR) and near-infrared (NIR) spectrometries to explore the molecular mechanism of an upper critical solution temperature (UCST)-type solubility change. When LPEI was dissolved in water, the solution became a gel at room temperature. Mid-IR and NIR absorption bands of the LPEI gel appeared at the same positions as the bands of the dihydrate crystal of LPEI in a film, which suggested that LPEI formed dihydrate crystallite in water at room temperature. This means that LPEI is in a planar-zigzag structure even in water at room temperature. When the gel was heated, it was changed to a transparent aqueous solution. Both mid-IR and NIR bands of an LPEI aqueous solution above 64 degrees C exhibited a broader bandwidth than those at room temperature. Judging from the change of the bandwidth, the LPEI chain in water was disordered by heating to take a random coil form. In addition, band locations of the CH stretching first-overtone vibration bands in a NIR spectrum of the solution above 64 degrees C were higher than those of melted dry LPEI, which was reasonably understandable that the disordered LPEI chains in the aqueous solution were in a highly hydrated state. These spectral results have revealed that the change from the planar-zigzag form to the random-coil one in water is a trigger to begin the UCST-like solubility change on heating followed by hydration. PMID- 19778004 TI - Amphiphilic lauryl ester derivatives from aromatic amino acids: significance of chemical architecture in aqueous aggregation properties. AB - Lauryl esters of L-tyrosine (LET) and L-phenylalanine (LEP) were, in a previous interface adsorption study, found to adopt very different interfacial conformations. The present study is an investigation of their aqueous aggregation properties with the goal of elucidating the effects of the presence in LET and absence in LEP of the phenolic OH group on their aqueous aggregate structures and micellar conformations of the surfactant monomers. The measured properties included aggregation numbers from time-resolved fluorescence quenching (TRFQ), interface hydration index and microviscosity by electron spin resonance (ESR), chemical shifts of (1)H resonance lines by NMR, and Krafft temperatures and enthalpies of structural transitions by differential scanning calorimetry (DSC). The TRFQ, ESR, and NMR experiments were conducted at various temperatures from 23 to 70 degrees C for various surfactant concentrations from 0.050 to 0.200 M. Markedly different temperature dependences of aggregation number and (1)H NMR chemical shifts are exhibited by LET and LEP micelles. LET and LEP form ionic micelles. The aggregation number of LEP decreases as is characteristic of ionic micelles, but that of LET increases slightly with temperature. The changes with temperature in the NMR chemical shifts and width of the resonance lines are significantly greater for the various LEP protons than for those of LET. The differences in these properties and other fluorescence decay characteristics of fluorophores incorporated into the micelles could be attributed to the difference in the micellar conformations of LET and LEP which are postulated to be similar to that at oil-water interfaces. The phenolic group is hypothesized to be in the micelle-water interface as part of the headgroup in LET micelles, and its location does not change with temperature. On the other hand, in LEP micelles, the phenyl ring is folded into the core overlapping with the flexible hydrophobic chains. The resulting closer proximity between the phenyl ring and the flexible hydrocarbon chain causes interdependence of the phenyl ring and chain proton resonances, leading to the observed temperature dependence of the chemical shifts in LEP. The TRFQ and ESR data are combined together in a molecular space-filling model, referred to as the polar shell model, to derive the geometrical properties of the micelle. The DSC scans in the temperature range 10-55 degrees C showed the presence of distinctly different endotherms for LET and LEP. The Krafft temperatures, K(T), and the enthalpies were determined. The higher K(T) and broader peak of the DSC endotherm of LET as compared to LEP are attributed to the stabilization of fiberlike structures below the Krafft temperature due to its chirality and the hydrogen bonding capability of the phenolic OH and also to the ion-dipole interactions. Thus, all of the observed differences between LET and LEP could be attributed to the difference in their chemical architecture. PMID- 19778005 TI - Synthesis of 2-fluoro-3-phenylthio-1,3-butadiene and 2-trifluoromethyl-3 phenylthio-1,3-butadiene and their reactivities toward various dienophiles. AB - A general approach for the synthesis of novel 2-fluoro-3-phenylthio-1,3-butadiene (8) and 2-trifluoromethyl-3-phenylthio-1,3-butadiene (9) from monobromoalkene and dibromoalkenes has been developed. Subsequent Diels-Alder reactions of these dienes with symmetrical and unsymmetrical dienophiles in the presence of Lewis acids gave a variety of fluorinated six-membered carbocycles in moderate to high yields. PMID- 19778006 TI - Revealing substrate promiscuity of 1-deoxy-D-xylulose 5-phosphate synthase. AB - A study of DXP synthase has revealed flexibility in the acceptor substrate binding pocket for nonpolar substrates and has uncovered new details of the catalytic mechanism to show that pyruvate can act as both donor and acceptor substrate. PMID- 19778007 TI - Real time monitoring of sickle cell hemoglobin fiber formation by UV resonance Raman spectroscopy. AB - In sickle cell hemoglobin, individual tetramers associate into long fibers as a consequence of the mutation at the beta6 position. In this study UV resonance Raman spectroscopy is used to monitor the formation of Hb S fibers in real time through aromatic amino acid vibrational modes. The intermolecular contact formed by the mutation site ((1)beta(1)6 Glu-->Val) of one tetramer and the (2)beta(2)85 Phe-(2)beta(2)88 Leu hydrophobic pocket on a different tetramer is observed by monitoring the increase in signal intensity of Phe vibrational modes as a function of time, yielding kinetic progress curves similar to those obtained by turbidity measurements. Comparison of individual spectra collected at early time points (<1000 s) show small Phe intensity changes, which are attributed to weak transient associations of Hb S tetramers during the initial stages of the polymerization process. At later times (1000-2000 s) Phe signal intensity steadily increases because of increasing hydrophobicity of local Phe environment, a consequence of forming more stable (1)beta(1)-(2)beta(2) contacts. Tyr and Trp vibrational modes monitor H-bond strength between critical residues at the alpha(1)beta(2) interface of individual tetramers. Kinetic progress curves generated from these signals exhibit two distinct transitions at 2040 and 7340 s. These transitions, which occur later in time than those detected either by turbidity (1560 s) or by Phe signal intensity (1680 s), are attributed to initial fiber formation and subsequent formation of larger assemblies, such as macrofibers or gels. These results provide molecular insight into the interactions governing Hb S fiber formation. PMID- 19778009 TI - A molecular cage that selectively complexes three different guests in solution. AB - A system based on a molecular cage, in which bisdiazonium, bispyridinium, and anthraquinone guests can be complexed to the host sequentially through the application of suitable stimuli, is reported. PMID- 19778010 TI - A method for parallel solid-phase synthesis of iodinated analogues of the CB1 receptor inverse agonist rimonabant. AB - A method for the parallel solid-phase synthesis (SPS) of iodinated analogues of Sanofi-Aventis' type 1 cannabinoid (CB1) receptor inverse agonist rimonabant (acomplia) has been developed. The method allows the synthesis of a range of C3 amide/hydrazide derivatives from a resin-bound C3 ester precursor. The C-Ge linkage to the Hypogel-200 resin is stable to the diversification conditions but allows ipso-iododegermylative cleavage using NaI/NCS even for the products containing the oxidatively labile hydrazide moiety. PMID- 19778008 TI - Total synthesis and biological evaluation of (+)- and (-)-bisanthraquinone antibiotic BE-43472B and related compounds. AB - The bisanthraquinone antibiotic BE-43472B [(+)-1] was isolated by Rowley and co workers from a streptomycete strain found in a blue-green algae associated with the ascidian Ecteinascidia turbinata and has shown promising antibacterial activity against clinically derived isolates of methicillin-susceptible, methicillin-resistant, and tetracyclin-resistant Staphylococcus aureus (MSSA, MRSA, and TRSA, respectively) and vancomycin-resistant Enterococcus faecalis (VRE). Described herein is the first total synthesis of both enantiomers of this bisanthraquinone antibiotic, the determination of its absolute configuration, and the biological evaluation of these and related compounds. The developed synthesis relies on a highly efficient cascade sequence involving an intermolecular Diels Alder reaction between diene (R)-61 and dienophile 55, followed by an intramolecular nucleophilic aromatic ipso substitution. Late-stage transformations included a remarkable photochemical alpha,beta-epoxyketone rearrangement [80 --> (+)-1]. Interestingly, the unnatural enantiomer [(-)-1] of antibiotic BE-43472B exhibited antibacterial properties comparable to those of the natural enantiomer [(+)-1]. PMID- 19778011 TI - Total synthesis of oidiodendrolides and related norditerpene dilactones from a common precursor: metabolites CJ-14,445, LL-Z1271gamma, oidiolactones A, B, C, and D, and nagilactone F. AB - An efficient, high-yielding strategy has been developed for the asymmetric total synthesis of seven norditerpenoid dilactones known for their diverse biological properties. The three key steps employed to obtain a tricyclic lactone intermediate involved a Morita-Baylis-Hillman reaction, the stereocontrolled construction of a gamma-lactone through bromolactonization, and an efficient catalytic Reformatsky-type reaction. Access to CJ-14,445, LL-Z1271gamma, oidiolactones A, B, C, and D, and nagilactone F was possible from a common intermediate. Structures and stereochemistry were determined by X-ray analysis. PMID- 19778012 TI - Enantioselective synthesis of 2-methyl-1,2-syn- and 2-methyl-1,2-anti-3 butenediols via allene hydroboration-aldehyde allylboration reaction sequences. AB - The hydroboration of allene 7 with ((d)Ipc)(2)BH at 0 degrees C provides the kinetic allylborane 12Z with >20:1 selectivity. However, when the hydroboration is performed at 85 degrees C, the kinetically formed allylborane isomerizes to give the thermodynamic allylborane 12E with >or=12:1 selectivity. Subsequent treatment of 12Z or 12E with aldehydes at -78 degrees C, followed by oxidative workup, provides the 2-methyl-1,2-diols 8 and 9 in good yield and with 80-92% e.e. PMID- 19778013 TI - Interaction between cardiotonic steroids and Na,K-ATPase. Effects of pH and ouabain-induced changes in enzyme conformation. AB - The Na,K-ATPase belongs to the P-type ATPase family of primary active cation pumps. It maintains the transmembrane gradients of Na(+) and K(+) across the cell membrane essential for cell homeostasis. The Na,K-ATPase is specifically inhibited by cardiotonic steroids like ouabain, which bind to the extracellular side of the enzyme and is of significant therapeutic value in the treatment of congestive heart failure. In order to further characterize the binding of cardiotonic steroids to shark Na,K-ATPase, we compared the strength and rate of inhibition at varying pH of two cardiac glycosides with either an unsaturated (ouabain) or saturated (dihydroouabain) lactone ring and three aglycons with either a 5-membered (ouabagenin and digitoxigenin) or a 6-membered (bufalin) lactone. Inhibition by ouabain and dihydroouabain, and especially the aglycon ouabagenin, was found to be strongly dependent on pH with an increase in IC(50) by factors of approximately 6, approximately 20, and approximately 66, respectively, when pH increased from 6.5 to 8.5. The finding that ouabagenin was the most pH-sensitive inhibitor indicates that the steroid hydroxyl side chains are pivotal for this pH effect, whereas the lactone ring saturation was less important. The sugar moiety is important in compensating for the pH effect. In contrast, the IC(50) of the two genins bufalin and digitoxigenin increased by a factor of only approximately 2 when pH increased from 6.5 to 8.5, indicating that the pH effect does not relay on whether the lactone is 5- or 6-membered. The rate of inhibition was retarded much more significantly by increasing pH for the glycosides than for the aglycons. Finally, we demonstrate a change in enzyme subconformations following binding of cardiotonic steroids to Na,K-ATPase phosphoenzymes using fluoride analogues of phosphoenzyme intermediates. The results are discussed with reference to the recent high-resolution crystal structures of shark Na,K-ATPase in the unbound and ouabain-bound conformation. PMID- 19778014 TI - Conformational effects in diastereoselective aryne Diels-Alder reactions: synthesis of benzo-fused [2.2.1] heterobicycles. AB - It was found that the diastereoselectivity of the Diels-Alder reaction between arynes and substituted furans is highly sensitive to substitution, which affects the reactive conformation. By varying the location of the groups on the diene partner, it is possible to obtain both excellent chemical yields and high stereoselectivity. This methodology offers rapid and convenient access to enantiomerically pure bicyclic scaffolds which are difficult to prepare by other means. PMID- 19778016 TI - "Clicking" polymer brushes with thiol-yne chemistry: indoors and out. AB - Thiol-yne click chemistry is demonstrated as a modular platform for rapid and practical fabrication of highly functional, multicomponent surfaces under ambient conditions. The principle is illustrated using a postmodification strategy in which poly(propargyl methacrylate) brushes were generated via surface-initiated photopolymerization and sequentially functionalized using the radical-mediated thiol-yne reaction. Brush surfaces expressing a three-dimensional configuration of "yne" functionalities were modified with high efficiency and short reaction times using a library of commercially available thiols, including functional thiols that demonstrate applicability for pH responsive surfaces and for bioconjugation. Sequential thiol-yne reactions in conjunction with simple UV photolithography were also applied to afford micropatterned, multicomponent surfaces. The practicality of the platform was further demonstrated by carrying out thiol-yne surface reactions in sunlight, suggesting the possibility of large scale modifications using renewable energy resources. Considering the mild reaction conditions, rapid throughput, and compatibility with orthogonal chemistries, we expect this platform to find widespread use among the materials science community. PMID- 19778015 TI - Polyvalent oligonucleotide gold nanoparticle conjugates as delivery vehicles for platinum(IV) warheads. AB - Amine-functionalized polyvalent oligonucleotide gold nanoparticles (DNA-Au NPs) were derivatized with a cisplatin prodrug, and the resulting DNA-Au NP conjugates were used to internalize multiple platinum centers. A platinum(IV) complex, c,c,t [Pt(NH(3))(2)Cl(2)(OH)(O(2)CCH(2)CH(2)CO(2)H)], was tethered to the surface of DNA-Au NPs through amide linkages. The platinum-tethered gold nanoparticles were taken into several cancer cells. The drop in intracellular pH facilitated reductive release of cisplatin from the prodrug, which then formed 1,2-d(GpG) intrastrand cross-links in the cell nuclei, as confirmed by an antibody specific for this adduct. The cytotoxicity of the platinum(IV) complex increases significantly in several cancer cell lines when the complex is attached to the surface of the DNA-Au NPs and in some instances exceeds that of cisplatin. PMID- 19778017 TI - Counterion atmosphere and hydration patterns near a nucleosome core particle. AB - The chromatin folding problem is an exciting and rich field for modern research. On the most basic level, chromatin fiber consists of a collection of protein nucleic acid complexes, known as nucleosomes, joined together by segments of linker DNA. Understanding how the cell successfully compacts meters of highly charged DNA into a micrometer size nucleus while still enabling rapid access to the genetic code for transcriptional processes is a challenging goal. In this work we shed light on the way mobile ions condense around the nucleosome core particle, as revealed by an extensive all-atom molecular dynamics simulation. On a hundred nanosecond time scale, the nucleosome exhibited only small conformational fluctuations. We found that nucleosomal DNA is better neutralized by the combination of histone charges and mobile ions compared with free DNA. We provide a detailed physical explanation of this effect using ideas from electrostatics in continuous media. We also discovered that sodium condensation around the histone core is dominated by an experimentally characterized acidic patch, which is thought to play a significant role in chromatin compaction by binding with basic histone tails. Finally, we found that the nucleosome is extensively permeated by over a thousand water molecules, which in turn allows mobile ions to penetrate deeply into the complex. Overall, our work sheds light on the way ionic and hydration interactions within a nucleosome may affect internucleosomal interactions in higher order chromatin fibers. PMID- 19778018 TI - Direct growth of semiconducting single-walled carbon nanotube array. AB - By introducing the UV beam into our homemade chemical vapor deposition system, we had obtained a well aligned SWNT array on an ST-cut quartz substrate. After transfer onto a SiO(2)/Si substrate, the SWNT array was detected by Raman spectroscopy and electrical measurement, which showed that over 95% of the SWNTs were semiconducting ones. It is proposed that the selection process took place at the very beginning of the SWNT formation rather than destroying the metallic SWNTs after growth. This approach has solved one of the most important problems in SWNT application. PMID- 19778019 TI - Tandem asymmetric Aza-Darzens/ring-opening reactions: dual functionality from the silane lewis acid. AB - The addition of a stabilized sulfur ylide (generated by the rhodium-catalyzed reaction of Ph(2)S with ethyl diazoacetate) to N-acylhydrazones promoted by a chiral silane Lewis acid leads to the highly diastereo- and enantioselective synthesis of beta-chloro-alpha-hydrazido esters. The addition of electron-rich arenes and ZnCl(2) to the reaction mixture leads to the highly diastereo- and enantioselective one-pot synthesis of diarylalanine derivatives. In both cases, the silane Lewis acid responsible for the first reaction performs the second function of activating the aziridine intermediate toward nucleophilic attack. PMID- 19778020 TI - Computational studies of the relative rates for migratory insertions of alkenes into square-planar, methyl, -amido, and -hydroxo complexes of rhodium. AB - The relative rates of the migratory insertions of alkenes into the M-X bonds of (PMe(3))(2)Rh(eta(2)-CH(2) horizontal lineCHR)(X) (R = H, Me; X = CH(3), NH(2), OH) have been analyzed by DFT calculations. These insertions are computed to form metallacycles containing a metal-carbon bond and either an agostic interaction, a dative metal-nitrogen bond, or a dative metal-oxygen bond. The computed barriers for migratory insertion into the metal-hydroxo and metal-amido bonds are lower than those for insertion into the metal-methyl bond. Application of Bader's atoms in-molecules analysis and natural localized molecular orbital analysis implies that the barriers for alkene insertion into M-X bonds are controlled by the degree of M-X bonding in the transition state, which correlates with the degree of M-X bonding in the initial product. The Rh-X bond orders in the transition states for migratory insertion of ethylene into the Rh-NH(2) and Rh-OH bonds in (PH(3))(2)Rh(eta(2)-C(2)H(4))(NH(2)) and (PH(3))(2)Rh(eta(2)-C(2)H(4))(OH) are much larger than that in the transition state for insertion into the Rh-C bond of (PH(3))(2)Rh(eta(2)-C(2)H(4))(CH(3)). The free energy barriers for 1,2- and 2,1 insertions of propene into the rhodium complexes were also calculated, and the barrier for 1,2-insertion was found to be lower than that for 2,1-insertion. Most striking, the DeltaDeltaG(double dagger) values for 1,2- versus 2,1-insertion of propene into these rhodium complexes were calculated to increase in the order X = CH(3) < NH(2) < OH. The increasing stability of the 1,2-insertion product with increasing polarity of the C-X bonds parallels the relative stabilities of linear versus branched alkanes, amines, and alcohols. PMID- 19778021 TI - Pd-catalyzed borylative cyclization of allenynes and enallenes. AB - Pd-catalyzed cyclization of 1,5- and 1,6-allenynes and 1,5-enallenes with bis(pinacolato)diboron affords synthetically useful allylboronates and alkylboronates under smooth conditions in a formal hydroborylative carbocyclization reaction. One C-C and one C-B bond are formed in a single operation. The reaction outcome implies that different mechanisms operate for the reactions of allenynes and enallenes, respectively, the actual pathway depending on the relative reactivity of the alkyne or the alkene versus the allene moiety. The cyclized boronates obtained can be functionalized by oxidation or allylation reaction with aldehydes. PMID- 19778022 TI - Confined electrodeposition of CdS in the holes left by the selective desorption of 3-mercapto-1-propionic acid from a binary self-assembled monolayer formed with 1-octanethiol. AB - Confined electrodeposition can be achieved through the use of suitable templates, by which the electrodeposition occurs in natural or artificial holes of an insulating layer on a conducting substrate. Here, we present the electrodeposition of CdS on the holes left by the selective desorption of 3 mercaptopropionic acid (MPA) from a binary self-assembled monolayer (SAM) formed on Ag(111) with 1-octanethiol (OT). The electrodeposition of a compound is quite demanding, since it requires the right stoichiometry. In addition, the surface underpotential deposition phenomena exploited by electrochemical atomic layer epitaxy (ECALE) technique ensures that the surface available for electrodeposition after the selective desorption is still Ag(111). Parallel electrochemical experiments show that the amount of compound electrodeposited is consistent with this free Ag(111) surface, and the morphological analysis performed both by atomic force microscopy (AFM) and by lateral force microscopy (LFM) confirm the electrochemical data. PMID- 19778023 TI - Electrophile affinity: a reactivity measure for aromatic substitution. AB - The reactivity and regioselectivity of the electrophilic chlorination, nitration, and alkylation of benzene derivatives were rationalized by comparing literature data for the partial rate factors (ln f) for these S(E)Ar processes with theoretical reactivity parameters. The Electrophile Affinity (Ealpha), a new quantity, is introduced to characterize reactivity and positional selectivity. Ealpha is evaluated theoretically by the energy change associated with formation of an arenium ion by attachment of a model electrophile to the aromatic ring. The dependence between Ealpha and ln f values for chlorination for 11 substitutions of benzene and methyl benzenes had a high correlation coefficient (r = 0.992). Quite satisfactory correlations between Ealpha values and partial rate factors also were obtained for the nitration of substituted benzenes (r = 0.971 for 12 processes) and benzylation of benzene and halobenzenes (r = 0.973 for 13 processes). These results provide clear evidence for the usefulness of the electrophile affinity in quantifying reactivity and regiochemistry. Satisfactory relationships (r >0.97) also were found between EPN (electrostatic potential at nuclei) values, which reflect the variations of electron density at the different arene ring positions, and the experimental partial rate factors (ln f) for the chlorination and nitration reactions, but not for the benzylation. This disaccord is attributed to strong steric influences on the reaction rates for substitutions involving the bulky benzyl moiety. PMID- 19778024 TI - Discovery of a 2,4-disubstituted pyrrolo[1,2-f][1,2,4]triazine inhibitor (BMS 754807) of insulin-like growth factor receptor (IGF-1R) kinase in clinical development. AB - This report describes the biological activity, characterization, and SAR leading to 9d (BMS-754807) a small molecule IGF-1R kinase inhibitor in clinical development. PMID- 19778025 TI - On the role of carbon radical insertion reactions in the growth of diamond by chemical vapor deposition methods. AB - Potential energy profiles for the insertion of gas phase C atoms, and CH, CH(2), C(2), C(2)H, and C(3) radicals, into C-H and C-C bonds on a 2 x 1 reconstructed, H-terminated diamond {100} surface have been explored using both quantum mechanical (density functional theory) and hybrid quantum mechanical/molecular mechanical (QM/MM) methods. Both sets of calculations return minimum energy pathways for inserting a C atom, or a CH(X), C(2)(X), or CH(2)(a) radical into a surface C-H bond that are essentially barrierless, whereas the barriers to inserting any of the investigated species into a surface C-C bond are prohibitively large. Reactivity at the diamond surface thus parallels behavior noted previously with alkanes, whereby reactant species that present both a filled sigma orbital and an empty p(pi) orbital insert readily into C-H bonds. Most carbon atoms on the growing diamond surface under typical chemical vapor deposition conditions are H-terminated. The present calculations thus suggest that insertion reactions, particularly reactions involving C((3)P) atoms, could make a significant contribution to the renucleation and growth of ultrananocrystalline diamond (UNCD) films. PMID- 19778026 TI - Photophysics of soret-excited tetrapyrroles in solution. IV. Radiationless decay and triplet-triplet annihilation investigated using tetraphenylporphinato Sn(IV). AB - The S(2) population decay rates and triplet-triplet annihilation efficiencies of Sn(IV)Cl(2)TPP have been measured in fluid solutions using its weak S(2)-S(0) fluorescence as a metric. A detailed description of the excited-state photophysics of Sn(IV)Cl(2)TPP has allowed comparisons to be made between this rigid, D(4h) axially coordinated molecule and axially uncoordinated tetrapyrroles of greater flexibility and lower symmetry. S(2)-S(1) internal conversion is the major S(2) population decay path for Sn(IV)Cl(2)TPP as it is for the S(2) states of all other d(0) and d(10) metalated tetrapyrroles. The S(2) state of Sn(IV)Cl(2)TPP exhibits S(2)-S(1) relaxation rates that follow the energy gap law of radiationless transition theory and are only slightly faster than those exhibited by MgTPP and the weak coupling limit. Differences in S(2)-S(1) radiationless decay rates among the series MTPP (M = Mg, Zn, Cd, SnCl(2)) cannot be traced to differences in the displacements of the S(2) and S(1) potential surfaces. Instead, the most likely source of the large differences in S(2)-S(1) radiationless decay rates between CdTPP and Sn(IV)Cl(2)TPP is the lower symmetry of the former (near C(4v)), which permits a much larger number of vibrations to participate in S(2)-S(1) vibronic coupling. Triplet-triplet annihilation of the type 2T(1) --> S(2) + S(0) has been observed in Sn(IV)Cl(2)TPP for the first time, but is of substantially lower efficiency than seen in ZnTPP in noncoordinating solvents because of its shorter triplet lifetime and the shielding effects of its axial Cl ligands, which tend to block the short-range interaction needed for Dexter energy transfer. PMID- 19778027 TI - Modification of galactitol dehydrogenase from Rhodobacter sphaeroides D for immobilization on polycrystalline gold surfaces. AB - Galactitol dehydrogenase (GatDH) from Rhodobacter sphaeroides is a multifunctional enzyme that catalyzes in the presence of oxidized beta nicotinamide adenine dinucleotide (NAD(+)) the interconversion of various multivalent aliphatic alcohols to the corresponding ketones. The recombinant GatDH was provided with an N-terminal His(6)-tag to which distally up to three cysteine residues were attached. This protein construct maintained nearly full enzymatic activity, and it could be covalently immobilized via thiol bonds onto the surface of a gold electrode. Binding of GatDH onto the gold electrode was verified by SPR measurements, and residual enzyme activity was measured by cyclic voltammetry using 1,2-hexanediol as substrate, the cofactor NAD(+) and the redox mediator CTFM (4-carboxy-2,5,7-trinitrofluorenyliden-malonnitrile) in solute form. The results demonstrate the possibility of a directed functional immobilization of proteins on gold surfaces, which represents a proof-of-concept for the development of reactors for electrochemical synthon preparation using dehydrogenases. PMID- 19778028 TI - Fourier transform infrared spectroscopy study of CO electro-oxidation on Pt(111) in alkaline media. AB - In this work we investigate the electro-oxidation of CO on Pt(111) in alkaline solution by using Fourier transform infrared spectroscopy (FTIRS), to determine the adsorption sites of the CO, the intermediate species and the final oxidation product as a function of the applied potential. Multiple CO vibration bands (on top, bridge and 3-fold hollow site) are observed on the Pt(111) electrode, their distribution and potential dependence being strongly dependent on the surface treatment. Spectroscopic results show that the final reaction product is carbonate and suggest that adsorbed carbonate blocks the access of CO from the (111) terrace to the active sites (i.e., step and kink sites). PMID- 19778029 TI - Automatized parametrization of SCC-DFTB repulsive potentials: application to hydrocarbons. AB - In this work, we derive and test a new automatized strategy to construct repulsive potentials for the self-consistent charge density functional tight binding (SCC-DFTB) method. This approach allows one to explore the parameter space in a systematic fashion in order to find optimal solutions. We find that due to the limited flexibility of the SCC-DFTB electronic part, not all properties can be optimized simultaneously. For example, the optimization of heats of formation is in conflict with the optimization of vibrational frequencies. Therefore, a special parametrization for vibrational frequencies is derived. It is shown that the performance of SCC-DFTB can be significantly improved using a more elaborate fitting strategy. A new fit for C and H is presented, which results in an average error of 2.6 kcal/mol for heats of formations for a large set of hydrocarbons, indicating that the performance of SCC-DFTB can be systematically improved also for other elements. PMID- 19778030 TI - Open-sandwich enzyme immunoassay for one-step noncompetitive detection of corticosteroid 11-deoxycortisol. AB - A noncompetitive immunoassay has the potential for improved sensitivity and working range compared with corresponding competitive assays. However, monovalent antigens with less than 1000 in molecular weight are not susceptible to sandwich assays due to their small size. As a noncompetitive immunoassay that can be performed with a clone of an antibody, an open-sandwich immunoassay (OS-IA) based on the antigen-dependent stabilization of the antibody variable region (V(H) + V(L)) was applied to the quantification of 11-deoxycortisol (11-DC; M(r) 346.5), a corticosteroid serving as a diagnostic index for pituitary-adrenal function, as a model target hapten. By one step OS-IA detection of enzyme-labeled V(H) fragment bound to immobilized V(L) in the presence of sample in microplate wells, 11-DC was measured with a femtomolar detection limit and the working range was wider than that with corresponding competitive assay. In addition, the selectivity against analogues was found almost identical to that of conventional assays. The effect of the mutagenesis of a V(H) residue at the V(H)/V(L) interface to reduce background signal was also shown, implying the wider application of OS-IA in small molecule analyses. PMID- 19778031 TI - Temperature dependence of the reduction of P(700)(+) by tightly bound plastocyanin in vivo. AB - The kinetics of reduction of P(700)(+), the stably oxidized electron donor of Photosystem I, by plastocyanin (PC) has been investigated by pump-probe optical spectroscopy in living cells of the green alga Chlamydomonas reinhardtii, between 277 and 318 K. The reduction of P(700)(+) in vivo is described by two kinetic components with lifetimes of 6 +/- 0.5 and 56 +/- 1 micros at room temperature. The rapid reduction phase, which is attributed to reduction of P(700)(+) by prebound PC, is thermally activated with an apparent activation barrier of 105 115 meV. The analysis of the in vivo reaction is consistent with (i) reduced PC and PS I forming a relatively tight binary complex that does not undergo kinetically limiting conformational reconfiguration and (ii) the activation barrier being determined principally by enthalpic contributions to the free energy change. Under the approximation that entropic contributions to the free energy change associated with this electron transfer reaction are negligible, a lower boundary value of the reorganization energy is estimated to be 0.54-0.63 eV, which is on the lower range of the distribution for intraprotein electron transfer reactions. This low activation barrier is discussed in terms of the optimization of primary donor reduction. PMID- 19778032 TI - The identity of the nucleophile substitution may influence metal interactions with the cleavage site of the minimal hammerhead ribozyme. AB - Potential metal interactions with the cleavage site of a minimal hammerhead ribozyme (mHHRz) were probed using (31)P NMR-detected Cd(2+) titration studies of HHRz constructs containing a phosphorothioate (PS) modification at the cleavage site. The mHHRz nucleophile position was replaced by either a 2'-F or a 2'-NH(2) in order to block cleavage activity during the study. The 2'-F/PS cleavage site mHHRz construct, in which the 2'-F should closely imitate the atom size and electronegativity of a 2'-OH, demonstrates low levels of metal ion association (<1 ppm (31)P chemical shift changes). This observation indicates that having an atom size and electrostatic properties that are similar to the 2'-OH are not the governing factors in allowing metal interactions with the scissile phosphate of the mHHRz. With a 2'-NH(2) substitution, a large upfield change in (31)P NMR chemical shift of the phosphorothioate peak (Delta approximately 3 ppm with 6 equiv of added Cd(2+)) indicates observable Cd(2+) interactions with the substituted site. Since a 2'-NH(2), but not a 2'-F, can serve as a metal ligand, these data suggest that a metal ion interaction with the HHRz cleavage site may include both the scissile phosphate and the 2' nucleophile. Control samples in which the 2'-NH(2)/PS unit is placed either next to the mHHRz cleavage site (at U16.1), in a duplex, or in a (am)U(PS)U dinucleotide show much weaker interactions with Cd(2+). Results with these control samples indicate that simply the presence of a 2'-NH(2)/PS unit does not create a strong metal binding site, reinforcing the possibility that the 2'-NH(2)-moderated Cd-PS interaction is specific to the mHHRz cleavage site. Upfield chemical shifts of both (31)P and H 2' (1)H resonances in (am)U(PS)U are observed with addition of Cd(2+), consistent with the predicted metal coordination to both 2'-NH(2) and phosphorothioate ligands. These data suggest that metal ion association with the HHRz cleavage site may include an interaction with the 2'-OH nucleophile. PMID- 19778033 TI - Desorption electrospray ionization: achieving rapid sampling rates. AB - The sampling rate and imaging capabilities of desorption electrospray ionization (DESI) are examined using a rotating sample platform combined with Hadamard transform time-of-flight mass spectrometry (HTTOFMS), a multiplexed time-of flight technique that allows for millisecond acquisition of full mass-to-charge ratio scans. DESI-compatible dyes are used to produce spatially defined sample patterns on poly(methyl methacrylate) discs. Control of disk rotation rate sets the residence time of the sample spots in the DESI plume, and thus the sampling rate. Surface patterns of alternating analytes are spectrally resolved up to 80 samples/s and single-analyte spots up to 50 samples/s. The rapid movement of the surface under the DESI plume allows for high DESI solution flow rates without blurring the chemical information on the surface. Data from multiple rotations can be additively combined, generating a chemical image of the surface with improved signal-to-noise characteristics. This multipass data enables analysis of the rising and falling edges of the analyte signal, placing a lower limit on both the temporal resolution of DESI and the maximum achievable sampling rate. Multipass analysis is proposed as a method for DESI surface imaging. PMID- 19778035 TI - Solid-phase synthesis of 3-hydroxy-6-nitroquinolin-4(1H)-ones with two diversity positions. AB - The efficient solid-phase synthesis of 3-hydroxy-2,7-disubstituted-6 nitroquinolin-4(1H)-ones using Rink amide resin is described. Synthesis starts from immobilized 4-chloro-5-nitroanthranilic acid which, after the nucleophilic replacement of the chlorine atom with various amines and subsequent esterification with bromoacetophenones, afforded substituted phenacylanthranilates. Their cyclization by heating in sulfuric acid gave corresponding hydroxyquinolinones of excellent purity. PMID- 19778036 TI - Bacteriogenic manganese oxides. AB - Microorganisms control the redox cycling of manganese in the natural environment. Although the homogeneous oxidation of Mn(II) to form manganese oxide minerals is slow, solid MnO(2) is the stable form of manganese in the oxygenated portion of the biosphere. Diverse bacteria and fungi have evolved the ability to catalyze this process, producing the manganese oxides found in soils and sediments. Other bacteria have evolved to utilize MnO(2) as a terminal electron acceptor in respiration. This Account summarizes the properties of Mn oxides produced by bacteria (bacteriogenic MnO(2)) and our current thinking about the biochemical mechanisms of bacterial Mn(II) oxidation. According to X-ray absorption spectroscopy and X-ray scattering studies, the MnO(2) produced by bacteria consists of stacked hexagonal sheets of MnO(6) octahedra, but these particles are extremely small and have numerous structural defects, particularly cation vacancies. The defects provide coordination sites for binding exogenous metal ions, which can be adsorbed to a high loading. As a result, bacterial production of MnO(2) influences the bioavailability of these metals in the natural environment. Because of its high surface area and oxidizing power, bacteriogenic MnO(2) efficiently degrades biologically recalcitrant organic molecules to lower molecular-mass compounds, spurring interest in using these properties in the bioremediation of xenobiotic organic compounds. Finally, bacteriogenic MnO(2) is reduced to soluble Mn(II) rapidly in the presence of exogenous ligands or sunlight. It can therefore help to regulate the bioavailability of Mn(II), which is known to protect organisms from superoxide radicals and is required to assemble the water-splitting complex in photosynthetic organisms. Bioinorganic chemists and microbiologists have long been interested in the biochemical mechanism of Mn(IV) oxide production. The reaction requires a two-electron oxidation of Mn(II), but genetic and biochemical evidence for several bacteria implicate multicopper oxidases (MCOs), which are only known to engage one electron transfers from substrate to O(2). In experiments with the exosporium of a Mn(II)-oxidizing Bacillus species, we could trap the one-electron oxidation product, Mn(III), as a pyrophosphate complex in an oxygen-dependent reaction inhibited by azide, consistent with MCO catalysis. The Mn(III) pyrophosphate complex can further act as a substrate, reacting in the presence of the exosporium to produce Mn(IV) oxide. Although this process appears to be unprecedented in biology, it is reminiscent of the oxidation of Fe(II) to form Fe(2)O(3) in the ferritin iron storage protein. However, it includes a critical additional step of Mn(III) oxidation or disproportionation. We shall continue to investigate this biochemically unique process with purified enzymes. PMID- 19778037 TI - Introduction to "cellular metal homeostasis and trafficking". PMID- 19778038 TI - Characterization of pollen carotenoids with in situ and high-performance thin layer chromatography supported resonant Raman spectroscopy. AB - Raman signatures of the carotenoid component are studied in individual pollen grains from different species of trees. The information is obtained as differences in the strong pre-resonant Raman spectra measured before and after photodepletion of the carotenoid molecules. The results provide the first in situ evidence of interspecies differences in pollen carotenoid content, structure, and/or assembly between plant species without prior purification. The analysis of carotenoids in situ is confirmed by high-performance thin-layer chromatography (HPTLC)-supported resonance Raman data measured directly on the HPTLC plates after separation of carotenoids in pollen extracts. Utilization of the in situ, extraction-free procedure in carotenoid analysis will improve sensitivity and structural selectivity and provides insight into carotenoid structure and composition in single pollen grains. PMID- 19778039 TI - Rod-like micelles thicken CO(2). AB - A new approach to thicken dense liquid CO(2) is described using the principles of self-assembly of custom-made CO(2) compatible fluorinated dichain surfactants. Solutions of surfactants in CO(2) have been investigated by high-pressure phase behavior, small-angle neutron scattering (HP-SANS) and falling cylinder viscosity experiments. The results show that it is possible to control surfactant aggregation to generate long, thin reversed micellar rods in dense CO(2), which at 10 wt % can lead to viscosity enhancements of up to 90% compared to pure CO(2). This represents the first example of CO(2) viscosity modifiers based on anisotropic reversed micelles. PMID- 19778040 TI - Redox switch-off of the ferromagnetic coupling in a mixed-spin tricobalt(II) triple mesocate. AB - A prelude to redox-based, ferromagnetic "metal-organic switches" is exemplified by a new trinuclear oxalamide cobalt triple mesocate that presents two redox states (ON and OFF) with dramatically different magnetic properties; the two terminal high-spin d(7) Co(II) ions (S = (3)/(2)) that are ferromagnetically coupled in the homovalent tricobalt(II) reduced state (2) become uncoupled in the heterovalent tricobalt(II,III,II) oxidized state (2(ox)) upon one-electron oxidation of the central low-spin d(7) Co(II) ion (S = (1)/(2)) to a low-spin d(6) Co(III) ion (S = 0). PMID- 19778041 TI - Micron-sized main-chain liquid crystalline elastomer actuators with ultralarge amplitude contractions. AB - Responsive surfaces composed of cylindrical or square micrometer-sized thermoresponsive pillars made of thiol-ene nematic main-chain liquid crystalline elastomers (LCEs) are produced by replica molding. The individual pillars behave as microactuators, showing ultralarge and reversible contractions of around 300 400% at the nematic to isotropic phase transition. The nematic main-chain LCE microactuators described here present contractions as large as the best macroscopic systems reported in the literature. Moreover, the contraction observed for this new system outperforms the best values already reported for other LCE microsystems. PMID- 19778042 TI - Supramolecular aggregation of inorganic molecules at Au(111) electrodes under a strong ionic atmosphere. AB - Neutral inorganic molecules are generally weak in surface adsorption and intermolecular interactions. Self-assembly of such types of molecule would provide valuable information about various interactions. At electrochemical interfaces, the relative strength of these interactions may be modified through control of electrode potential and electrolyte, which may lead to the discovery of new structures and new phenomena. However, studies of this nature are as yet lacking. In this work, we consider the covalent-bound semimetal compound molecules, XCl(3) (X = Sb, Bi), as model systems of neutral inorganic molecules to investigate their self-assembly at electrochemical interfaces under a high ionic atmosphere. To fulfill such investigations, in situ STM and cyclic voltammetry are employed, and comparative experiments are performed on Au(111) in ionic liquids as well as aqueous solutions with high ionic strength. In the room temperature ionic liquid of 1-butyl-3-methylimidazolium tetrafluoroborate (BMIBF(4)), potential-dependent partial charge transfer between the Au surface and XCl(3) molecules creates a molecule-surface interaction and provides the driving force for adsorption of the molecules. Supramolecular aggregations of adsorbed XCl(3) are promoted through chlorine-based short-range intermolecular correlation under crystallographic constraint, while repulsive Coulombic interactions created between the partially charged aggregations facilitate their long-range ordering. For SbCl(3) molecules, hexagonally arranged 6- or 7-member clusters are formed at 0.08 to -0.2 V (vs Pt), which assemble into a secondary ( radical31 x radical31)R8.9 degrees structure. For BiCl(3) molecules, both the 6 membered hexagonal and 3-membered trigonal clusters are formed in the narrow potential range -0.3 to -0.35 V, and are also arranged into an ordered secondary structure. Comparative studies were performed with SbCl(3) in concentrated aqueous solutions containing 2 M HCl to simulate the strong ionic strength of the ionic liquid. Almost identical 6-/7-member clusters and long-range ( radical31 x radical31)R8.9 degrees structure are observed at -0.1 V, demonstrating the crucial role of strong ionic strength in such supramolecular aggregations. However, such supramolecular structures are modified and eventually destroyed as ionic strength is further increased by addition of NaClO(4) up to 6 M. The destructive changes of the supramolecular structures are attributed to the alteration of ion distribution in the double layer from cation-rich to anion-rich at increasing NaClO(4) concentration. This modifies and eventually breaks the balance of intermolecular and molecule-electrolyte interactions. Finally, the dynamic behavior of the SbCl(3) assembly is investigated down to molecular level. It has been demonstrated that the initial stage of assembly follows a two dimensional nucleation and growth mechanism and has a potential-dependent rate that is closely related to the surface mobility of the SbCl(3) clusters. There is a probability that clusters can escape from an existing assembly domain or insert into a vacancy in such a domain while they can also relax with central or ring members in a dynamic fashion. These phenomena indirectly reflect the dynamic properties of cations from electrolytes at the interface. The rich information contained in the self-assembly behavior of SbCl(3) and BiCl(3) demonstrates that neutral inorganic molecules can be employed for fundamental studies of a variety of interesting issues, especially the interplay of various interfacial interactions. PMID- 19778043 TI - Enzymatic tailoring of ornithine in the biosynthesis of the Rhizobium cyclic trihydroxamate siderophore vicibactin. AB - To acquire iron, the N(2)-fixing, symbiotic bacterium Rhizobium sp. produce the cyclic trihydroxamate siderophore vicibactin, containing a 30-membered trilactone scaffold. Herein we report the overproduction and purification of the six proteins VbsACGOLS in the bacterial host Escherichia coli and the reconstitution of the biosynthesis of vicibactin from primary metabolites. The flavoprotein VbsO acts as a pathway-initiating l-ornithine N(5)-hydroxylase, followed by VbsA, which transfers (R)-3-hydroxybutyryl- from the CoA thioester to N(5) hydroxyornithine to yield N(5)-((R)-3-hydroxybutyryl)-N(5)-hydroxy-l-ornithine. VbsL is a PLP-dependent epimerase acting at C(2) of the 10 atom monomer unit. VbsS, a nonribosomal peptide synthetase free-standing module, then activates N(5) ((R)-3-hydroxybutyryl)-N(5)-hydroxy-d-ornithine as the AMP anhydride on the way to cyclotrimerization to the vicibactin scaffold. The last step, tris-acetylation of the C(2) amino group of desacetyl-d-vicibactin to the mature siderophore vicibactin, is catalyzed distributively by VbsC, using three molecules of acetyl CoA. PMID- 19778045 TI - Computational and experimental analyses converge to reveal a coherent yet malleable aptamer structure that controls chemical reactivity. AB - As short nucleic acids, aptamers in solution are believed to be structurally flexible. Consistent with this view, most aptamers examined for this property have been shown to bind their target molecules by mechanisms that can be described as "induced fit". But, it is not known to what extent this structural flexibility affects the integrity of the target-aptamer interaction. Using the malachite green aptamer (MGA) as a model system, we show that the MGA can protect its bound target, malachite green (MG), from oxidation over several days. Protection is reversed by an oligonucleotide complementary to the MGA binding pocket. Computational cavity analysis of the MGA-MG structure predicted that MG oxidation is protected because a molecule as small as an OH(-) is sterically excluded from the C1 position of the bound MG. These results suggest that, while the MGA-MG interface is sufficiently coherent to prevent OH(-) penetration, the bases involved in the interaction are sufficiently mobile that they can exchange out of the MG binding interface to hybridize with a complementary oligonucleotide. The computational predictions were confirmed experimentally using variants of the MGA with single base changes in the binding pocket. This work demonstrates the successful application of molecular dynamics simulations and cavity analysis in determining the effects of sequence variations on the structure of a small single-stranded nucleic acid. It also shows that a nucleic acid aptamer can control access to specific chemical groups on its target, which suggests that aptamers might be applied for selectively protecting small molecules from modification. PMID- 19778044 TI - Mechanism of amido-thiourea catalyzed enantioselective imine hydrocyanation: transition state stabilization via multiple non-covalent interactions. AB - An experimental and computational investigation of amido-thiourea promoted imine hydrocyanation has revealed a new and unexpected mechanism of catalysis. Rather than direct activation of the imine by the thiourea, as had been proposed previously in related systems, the data are consistent with a mechanism involving catalyst-promoted proton transfer from hydrogen isocyanide to imine to generate diastereomeric iminium/cyanide ion pairs that are bound to catalyst through multiple noncovalent interactions; these ion pairs collapse to form the enantiomeric alpha-aminonitrile products. This mechanistic proposal is supported by the observation of a statistically significant correlation between experimental and calculated enantioselectivities induced by eight different catalysts (P << 0.01). The computed models reveal a basis for enantioselectivity that involves multiple stabilizing and destabilizing interactions between substrate and catalyst, including thiourea-cyanide and amide-iminium interactions. PMID- 19778046 TI - Primary photoinduced protein response in bacteriorhodopsin and sensory rhodopsin II. AB - Essential for the biological function of the light-driven proton pump, bacteriorhodopsin (BR), and the light sensor, sensory rhodopsin II (SRII), is the coupling of the activated retinal chromophore to the hosting protein moiety. In order to explore the dynamics of this process we have performed ultrafast transient mid-infrared spectroscopy on isotopically labeled BR and SRII samples. These include SRII in D(2)O buffer, BR in H(2)(18)O medium, SRII with (15)N labeled protein, and BR with (13)C(14)(13)C(15)-labeled retinal chromophore. Via observed shifts of infrared difference bands after photoexcitation and their kinetics we provide evidence for nonchromophore bands in the amide I and the amide II region of BR and SRII. A band around 1550 cm(-1) is very likely due to an amide II vibration. In the amide I region, contributions of modes involving exchangeable protons and modes not involving exchangeable protons can be discerned. Observed bands in the amide I region of BR are not due to bending vibrations of protein-bound water molecules. The observed protein bands appear in the amide I region within the system response of ca. 0.3 ps and in the amide II region within 3 ps, and decay partially in both regions on a slower time scale of 9-18 ps. Similar observations have been presented earlier for BR5.12, containing a nonisomerizable chromophore (R. Gross et al. J. Phys. Chem. B 2009, 113, 7851 7860). Thus, the results suggest a common mechanism for ultrafast protein response in the artificial and the native system besides isomerization, which could be induced by initial chromophore polarization. PMID- 19778047 TI - Building block syntheses of gallic acid monomers and tris-(O-gallyl)-gallic acid dendrimers chemically attached to graphite powder: a comparative study of their uptake of Al(III) ions. AB - A synthesis of graphite powder covalently modified with gallic acid (3,4,5 trihydroxybenzoic acid), via a 1,2-diaminoethane "linker" molecule, to form gallylaminoethylaminocarbonyl graphite (gallic-carbon) is reported. The synthesis was used as a model for a "ground-upwards building-block" approach to a primary dendrimer of gallic acid covalently attached to the surface of graphite powder, tris-(O-gallyl)-gallylaminoethylaminocarbonyl graphite (TGGA-carbon). The resulting modified carbon materials were characterized at each stage of the syntheses using X-ray photoelectron spectroscopy (XPS) analysis. The effects of increasing the modifier's structural complexity from monomeric gallic-carbon to the analogous primary dendrimer TGGA-carbon were explored by comparing each material's efficacy toward the adsorption of Al(III) ions from water. The uptake of Al(III) ions by gallic-carbon and TGGA-carbon was measured using UV-vis spectroscopy. In comparison to the case of monomeric gallic-carbon, the rate of adsorption of Al(III) ions by the TGGA-carbon was found to be 2.3 times more rapid. Furthermore, the total uptake of Al(III) ions was greater (reducing the concentration of 1000 ppb Al(III) solutions to below the WHO legal limit of 100 ppb in less than 5 min) and irreversible, in contrast to the gallic-carbon where the adsorption was found to be under thermodynamic control and to follow a Freundlich isotherm. PMID- 19778049 TI - Activity and thermal stability improvements of glucose oxidase upon adsorption on core-shell PMMA-BSA nanoparticles. AB - The interaction and adsorption of enzyme, glucose oxidase (GOx), on poly(methyl methacrylate)-bovine serum albumin (PMMA-BSA) particles were studied by using a quartz crystal microbalance with dissipation (QCM-D) and laser light scattering (LLS). The enzyme was irreversibly immobilized on the PMMA-BSA particle surface. The amount of enzyme immobilized on PMMA-BSA particles and the enzymatic activity were determined by UV/vis measurements. The influences of pH and ionic strength on the adsorption indicate that the electrostatic interaction plays a major role on the immobilization. The adsorbed GOx can retain at least 80% of the free enzyme activity. Thermal stability studies reveal that the adsorbed GOx only losses 28% of its activity in comparison with a 64% activity loss of free GOx when it is incubated at 50 degrees C for 35 h. PMID- 19778050 TI - McMurry chemistry on TiO(2)(110): Reductive C=C coupling of benzaldehyde driven by titanium interstitials. AB - Selective reductive coupling of benzaldehyde to stilbene is driven by subsurface Ti interstitials on vacuum-reduced TiO(2)(110). A combination of temperature programmed reaction spectroscopy and scanning tunneling microscopy (STM) provides chemical and structural information which together reveal the dependence of this surface reaction on bulk titanium interstitials. Benzaldehyde reductively couples to stilbene with 100% selectivity and conversions of up to 28% of the adsorbed monolayer in temperature programmed reaction experiments. The activity for coupling was sustained for at least 20 reaction cycles, which indicates that there is a reservoir of Ti interstitials available for reaction and that surface O vacancies alone do not account for the coupling. Reactivity was unchanged after predosing with water so as to fill surface oxygen vacancies, which are not solely responsible for the coupling reaction. The reaction is nearly quenched if O(2) is adsorbed first-a procedure that both fills defects and reacts with Ti interstitials as they migrate to the surface. New titania islands form after reductive coupling of benzaldehyde, based on scanning tunneling microscope images obtained after exposure of TiO(2)(110) to benzaldehyde followed by annealing, providing direct evidence for migration of subsurface Ti interstitials to create reactive sites. The reliance of the benzaldehyde coupling on subsurface defects, and not surface vacancies, over reduced TiO(2)(110), may be general for other reductive processes induced by reducible oxides. The possible role of subsurface, reduced Ti interstitials has broad significance in modeling oxide-based catalysis with reduced crystals. PMID- 19778048 TI - Evolving a polymerase for hydrophobic base analogues. AB - Hydrophobic base analogues (HBAs) have shown great promise for the expansion of the chemical and coding potential of nucleic acids but are generally poor polymerase substrates. While extensive synthetic efforts have yielded examples of HBAs with favorable substrate properties, their discovery has remained challenging. Here we describe a complementary strategy for improving HBA substrate properties by directed evolution of a dedicated polymerase using compartmentalized self-replication (CSR) with the archetypal HBA 5-nitroindole (d5NI) and its derivative 5-nitroindole-3-carboxamide (d5NIC) as selection substrates. Starting from a repertoire of chimeric polymerases generated by molecular breeding of DNA polymerase genes from the genus Thermus, we isolated a polymerase (5D4) with a generically enhanced ability to utilize HBAs. The selected polymerase. 5D4 was able to form and extend d5NI and d5NIC (d5NI(C)) self-pairs as well as d5NI(C) heteropairs with all four bases with efficiencies approaching, or exceeding, those of the cognate Watson-Crick pairs, despite significant distortions caused by the intercalation of the d5NI(C) heterocycles into the opposing strand base stack, as shown by nuclear magnetic resonance spectroscopy (NMR). Unlike Taq polymerase, 5D4 was also able to extend HBA pairs such as Pyrene: varphi (abasic site), d5NI: varphi, and isocarbostyril (ICS): 7 azaindole (7AI), allowed bypass of a chemically diverse spectrum of HBAs, and enabled PCR amplification with primers comprising multiple d5NI(C)-substitutions, while maintaining high levels of catalytic activity and fidelity. The selected polymerase 5D4 promises to expand the range of nucleobase analogues amenable to replication and should find numerous applications, including the synthesis and replication of nucleic acid polymers with expanded chemical and functional diversity. PMID- 19778051 TI - Novel walnut-like multihollow polymer particles: synthesis and morphology control. AB - Novel walnut-like multihollow polymer particles were first prepared by gamma-ray radiation emulsion polymerization using cross-linked and sulfonated polystyrene spheres (CSPs) as the template. The formation process was studied in detail, and the morphology of walnut-like multihollow polystyrene particles could be controlled by the content of cross-linking agent, sulfonation time of CSP particles, and the weight ratio of monomer/CSP. In addition, an application of walnut multihollow polymer particles on bonding Ag nanoparticles onto the surface was achieved, which could be extended to other noble metal nanoparticles and could have a wide range of potential applications, such as catalysts, sensors, solar cells, and photonic crystals. PMID- 19778052 TI - Patterns of diacetylene-containing peptide amphiphiles using polarization holography. AB - The polarization dependence of a diacetylene polymerization was studied. For this purpose, peptide amphiphile fibers with a diacetylene moiety, which could only polymerize in the direction of the fiber, were employed. If nonaligned samples were illuminated with polarized light, only the fibers parallel to the polarization direction of the light were polymerized. With magnetically aligned fibers, spatially selective polymerization was accomplished using polarization holography. PMID- 19778053 TI - Self-assembled monolayers of alkanethiols on InAs. AB - We describe the deposition and properties of self-assembled monolayers (SAMs) of methyl-terminated alkanethiols on InAs(001) surface. For these model hydrophobic films, we used water contact angle measurements to survey the preparation of alkanethiol monolayers from base-activated ethanolic solutions as a function of the solution and deposition parameters, including chain length of alkanethiols, deposition time, and solution temperature and pH. We then used X-ray photoelectron spectroscopy (XPS), ellipsometry, and electrochemistry to characterize the composition and structure of octadecanethiol (ODT) monolayers deposited on InAs under optimized conditions. When applied to a thoroughly degreased InAs(001) wafer surface, the basic ODT solution removes the native oxide without excessively etching the underlying InAs(001) substrate. The resulting film contains approximately one monolayer of ODT molecules, attached to the InAs surface almost exclusively via thiolate bonds to In atoms, with organic chains extended away from the surface. These ODT monolayers are stable against degradation and oxidation in air, organic solvents, and aqueous buffers. The same base-activated ODT treatment can also be used to passivate exposed InAs/AlSb quantum well (QW) devices, preserving the unique electronic properties of InAs surfaces and allowing the operation of such passivated devices as continuous flow pH-sensors. PMID- 19778054 TI - Computational study of dispersion and extent of mutated and duplicated sequences of the H5N1 influenza neuraminidase over the period 1997-2008. AB - Study of mutational changes in neuraminidase (NA) gene sequences is important to track the effectiveness of the inhibitors to the H5N1 avian flu virus that targets this component of the viral apparatus. Our analysis based on numerical characterization studies of 682 complete neuraminidase gene and protein sequences available in the database, updated to March 2009, and which extends our previous work based on a sample of 173 sequences has revealed several interesting features. We have noticed that identical sequences have appeared over significant distances in space and time, raising the need for a deeper understanding of the longevity of such viral strains in the environment. Structural sections like transmembrane, stalk, body, and C-terminal tail regions have shown independent recombinations between strains from various species including human and avian hosts highlighting influenza's flexibility in host selection and recombination. Our analysis confirmed a biased nature in mutational accumulation in structural segments: a highly conserved 50-base C-terminal tail section identified in our earlier paper seems to accumulate mutational changes at a rate of about a fifth to an eighth of transmembrane and stalk regions, although the length is about half of these. Parallel study of the equivalent section to the C-terminal region in protein sequences reveals only 13 separate varieties, and all the other 669 sequences are duplicates to three of these varieties showing the highly conserved nature of this segment. Our analysis of active site related bases and amino acids showed highly conserved characteristic of those constructs, whereas the rest of the segments demonstrated rather large mutational changes. These kinds of high level of mutation in major part of the H5N1 NA sequences and recombinations within structural segments coupled with strong conservation of a few select segments show that the potential of rapid mutations to more virulent forms of this variety of avian flu continue to remain of concern, especially with the possibility of long duration dormancy of some of these viral strains, whereas islands of highly conserved segments could signify potential regions for inhibitor designs. PMID- 19778055 TI - Microwave-assisted Ullmann C-S bond formation: synthesis of the P38alpha MAPK clinical candidate VX-745. AB - Microwave irradiation promotes the rapid and efficient reaction of a thiophenol and aryl or heteroaryl halide using a copper or palladium catalyst and a range of ligands, depending upon substrate. Of particular utility is the use of copper(I) iodide (5 mol %) and trans-cyclohexane-1,2-diol as ligand under basic conditions and microwave irradiation to give the corresponding sulfide in high yield. This method for C-S bond formation is applied in the four-step synthesis of the clinical candidate VX-745 in 38% overall yield. The inhibitory activity of VX-745 against p38alpha MAPK is confirmed in Werner syndrome dermal fibroblasts at 1.0 microM concentration by immunoblot assay. PMID- 19778056 TI - Isotope labeling studies on the origin of 3,4-hexanedione and 1,2-butanedione in an alanine/glucose model system. AB - Although the importance of alpha-dicarbonyl compounds as reactive intermediates in the Maillard reaction and as precursors of heterocyclic and odor-active compounds is well-established, however, the detailed origin of many alpha dicarbonyl compounds such as 3,4-hexanedione and 1,2-butanedione still remains unknown. Using glucose and glyoxal with labeled [(13)C-1]alanine, [(13)C 2]alanine, [(13)C-3]alanine, and [(15)N]alanine, the mechanism of their formation was investigated using the label incorporation pattern of the pyrazines derived through the Strecker reaction. Taking into account the non-oxidative mechanism of pyrazine formation, the data indicated that all of the ethyl-substituted pyrazines identified in the glyoxal/alanine model system incorporated C-2' and C 3' atoms of alanine, and not that of free acetaldehyde, as the ethyl group carbon atoms. This was achieved through spiking experiments using unlabeled acetaldehyde in the presence of labeled alanine. Furthermore, the data also indicated the occurrence of a chain elongation process of sugar-derived alpha-dicarbonyl compounds assisted by alanine. On the basis of the proposed mechanism, the glyoxal interaction with alanine through a decarboxylative aldol addition reaction can lead to the formation of 1,2-butanedione with the terminal ethyl carbon atoms originating from C-2' and C-3' atoms of alanine, and the similar interaction of 1,2-butanedione with a second molecule of alanine can lead to the formation of 3,4-hexanedione with both terminal ethyl carbon atoms originating from C-2' and C-3' atoms of alanine. PMID- 19778057 TI - Assessment of primer/template mismatch effects on real-time PCR amplification of target taxa for GMO quantification. AB - GMO quantification, based on real-time PCR, relies on the amplification of an event-specific transgene assay and a species-specific reference assay. The uniformity of the nucleotide sequences targeted by both assays across various transgenic varieties is an important prerequisite for correct quantification. Single nucleotide polymorphisms (SNPs) frequently occur in the maize genome and might lead to nucleotide variation in regions used to design primers and probes for reference assays. Further, they may affect the annealing of the primer to the template and reduce the efficiency of DNA amplification. We assessed the effect of a minor DNA template modification, such as a single base pair mismatch in the primer attachment site, on real-time PCR quantification. A model system was used based on the introduction of artificial mismatches between the forward primer and the DNA template in the reference assay targeting the maize starch synthase (SSIIb) gene. The results show that the presence of a mismatch between the primer and the DNA template causes partial to complete failure of the amplification of the initial DNA template depending on the type and location of the nucleotide mismatch. With this study, we show that the presence of a primer/template mismatch affects the estimated total DNA quantity to a varying degree. PMID- 19778058 TI - Antioomycete activity of gamma-oxocrotonate fatty acids against P. infestans. AB - Infections with Phytophthora infestans, the causal agent of potato and tomato late blight disease, are difficult to control and can lead to considerable agricultural losses. Thus, the development of new effective agents against the pathogen is of great interest. In previous work, (E)-4-oxohexadec-2-enoic acid (3) was isolated from Hygrophorus eburneus, which exhibited fungicidal activity against Cladosporium cucumerinum. Here, the inhibitory effect of 3 on P. infestans spore germination and mycelium growth in vitro is demonstrated. The in vivo effect on infections of whole potato plants was investigated by spraying plants with the sodium salt of 3, sodium (2E)-4-oxohexadec-2-enoic acid (4), prior to P. infestans inoculation. Additionally, the influence of 3 on mycelium growth of Colletotrichum coccodes, the causal agent of potato black dot disease, was analyzed. In all approaches, a significant inhibition of pathogen development was achieved. Importantly, the unsaturated fatty acid exerted no toxic effect when sprayed on plants, a prerequisite for its commercial use. PMID- 19778059 TI - The forage and grain of MON 87460, a drought-tolerant corn hybrid, are compositionally equivalent to that of conventional corn. AB - MON 87460 contains a gene that expresses cold shock protein B (CSPB) from Bacillus subtilis. Expression of this gene confers a yield advantage when yield is limited by water availability. Compositional analyses of MON 87460 and a conventional corn variety with similar background genetics were conducted on forage and grain harvested from multiple replicated field sites across the United States during the 2006 growing season and across Chile during the 2006-2007 growing season. The U.S. field trials were conducted under typical agronomic practices, whereas the Chilean field trials incorporated a strip-plot design that included well-watered and water-limited treatments. Results demonstrated that levels of the components analyzed were comparable between MON 87460, the conventional control, and the commercially available corn hybrids. PMID- 19778060 TI - Influence of gamma-radiation on the nutritional and functional qualities of lotus seed flour. AB - In the present study, we investigated the physicochemical and functional properties of lotus seed flour exposed to low and high doses of gamma-radiation (0-30 kGy; the dose recommended for quarantine and hygienic purposes). The results indicated raw seed flour to be rich in nutrients with minimal quantities of antinutritional factors. Irradiation resulted in a dose-dependent increase in some of the proximal constituents. The raw and gamma-irradiated seeds meet the Food and Agricultural Organization-World Health Organization recommended pattern of essential amino acids. Some of the antinutritional factors (phytic acid, total phenolics, and tannins) were lowered with gamma-irradiation, while the seed flours were devoid of lectins, L-3,4-dihydroxyphenylalanine, and polonium-210. The functional properties of the seed flour were significantly improved with gamma-radiation. gamma-radiation selectively preserved or improved the desired nutritional and functional traits of lotus seeds, thus ensuring a safe production of appropriate nutraceutically valued products. PMID- 19778061 TI - Investigation on the interaction of newly designed anticancer Pd(II) complexes with different aliphatic tails and human serum albumin. AB - The pharmacokinetics and pharmacodynamics of any drug will depend, largely, on the interaction that it has with human serum albumin (HSA), the most abundant plasma protein. The interaction between newly synthesized Pd(II) complexes, 2,2' bipyridin octyl dithiocarbamato Pd(II) nitrate (Octpd), 2,2'-bipyridin butyl dithiocarbamato Pd(II) nitrate (ButPd), 2,2'-bipyridin ethyl dithiocarbamato Pd(II) nitrate (EtPd), antitumor components, with human serum albumin, a carrier protein, were studied at different temperatures of 27 and 37 degrees C by fluorescence spectroscopy, far UV circular dichroism (CD), and spectrophotometric and differential scanning calorimetry (DSC) techniques. By the analysis of fluorescence intensity, it was observed that Pd(II) complexes have strong abilities to quench the intrinsic fluorescence of HSA through a dynamic quenching procedure. The binding parameters were evaluated by the fluorescence quenching method. The thermodynamic parameters, including DeltaH degrees , DeltaS degrees , and DeltaG degrees , were calculated by the fluorescence quenching method and indicated that hydrophobic forces play a major role in the interaction of Pd(II) complexes with HSA. Far-UV-CD results represented that Pd(II) complexes induced a decrease in content of the alpha helical structure of protein. The binding of newly designed drugs (Pd(II) complexes) on the blood carrier protein of HSA resulted in significant alterations on the structure and conformation of protein via decreasing stability of HSA by decreasing the T(m), a red shift in maximum fluorescence intensity, a decrease in content of the alpha-helical structure, and the increase of the nonpolar or accessible hydrophobic surface of HSA to solvent. PMID- 19778062 TI - Hofmeister effects of common monovalent salts on the beetle antifreeze protein activity. AB - Antifreeze proteins (AFPs) noncolligatively depress the freezing point of a solution and produce a difference between the melting and freezing points termed thermal hysteresis (TH). While the mechanism of the enhancement effect is not well understood, various low-molecular-mass solutes including neutral salts have been identified to enhance the TH activities of AFPs. Here, the effect of monovalent salts on salting out an AFP from the beetle Dendroides canadensis (DAFP-1) on the ice was treated using a simple classical theory, and the relationship between the TH activity and the salt concentration was developed. The TH activities of DAFP-1 in the presence of the series of monovalent salts were assessed by differential scanning calorimetry (DSC), and the salting-out constants of DAFP-1 by these salts were determined. This study demonstrates an indirect way to determine the salting-out constants of AFPs by these salts. The results suggest that the Hofmeister effect is a potential mechanism for the TH enhancement effects of some common monovalent salts. PMID- 19778063 TI - Syntheses of biodegradable and biocompatible polymers by means of bismuth catalysts. PMID- 19778064 TI - Characterization of a signaling complex composed of sensory rhodopsin I and its cognate transducer protein from the eubacterium Salinibacter ruber. AB - Sensory rhodopsin I (SRI) exists in the cell membranes of microorganisms such as the archaeon Halobacterium salinarum and is a photosensor responsible for positive and negative phototaxis. SRI forms a signaling complex with its cognate transducer protein, HtrI, in the membrane. That complex transmits light signals to the flagellar motor through changes in protein-protein interactions with the kinase CheA and the adaptor protein CheW, which controls the direction of the rotation of the flagellar motor. Recently, we cloned and characterized Salinibacter sensory rhodopsin I (SrSRI), which is the first SRI-like protein identified in eubacteria [Kitajima-Ihara, T., et al. (2008) J. Biol. Chem. 283, 23533-23541]. Here we cloned and expressed SrSRI with its full-length transducer protein, SrHtrI, as a fusion construct. We succeeded in producing the complex in Escherichia coli as a recombinant protein with high quality having all-trans retinal as a chromophore for SRI, although the expression level was low (0.10 mg/L of culture). In addition, we report here the photochemical properties of the SrSRI-SrHtrI complex using time-resolved laser flash spectroscopy and other spectroscopic techniques and compare them to SrSRI without SrHtrI. PMID- 19778065 TI - Direct observation of bifunctional electrocatalysis during CO oxidation at Ru(theta=0.37)/Pt{111} surfaces via surface stress measurements. AB - The surface stress response during the electrooxidation of CO at Pt{111}, Ru{0001}, and Ru(theta=0.37)/Pt{111} textured electrodes was studied in 0.1 M HClO(4) electrolytes. The surface stress signal resolves for the first time the adsorption of OH(-) at the CO-covered Ru{0001} surface prior to significant CO oxidation, a phenomenon that is not discernible in the voltammetry. The surface stress signal shows that significant tensile surface stress occurs upon oxidation of the adsorbed CO and occurs at nearly the same potential on Ru{0001} and Ru/Pt{111} surfaces. These observations demonstrate that the mechanism of bifunctionality is the OH(ads) provided to the Pt surface sites via Ru sites. PMID- 19778067 TI - Cytotoxic acacic acid glycosides from the roots of Albizia coriaria. AB - Two new oleanane-type saponins, coriariosides A (1) and B (2), along with a known saponin, gummiferaoside C (3), were isolated from the roots of Albizia coriaria. Their structures were established by extensive analysis of 1D and 2D NMR experiments (COSY, ROESY, TOCSY, HSQC, and HMBC) and mass spectrometry. Compounds 1 and 3 when tested for cytotoxicity against two colorectal human cancer cells showed activity against the HCT 116 (IC50 4.2 microM for 1 and 2.7 microM for 3) and HT-29 (IC50 6.7 microM for 1 and 7.9 microM for 3) cell lines. PMID- 19778068 TI - Cytotoxic and antiplasmodial compounds from the roots of Strophioblachia fimbricalyx. AB - The known phenanthrenone trigonostemone (1), along with a new phenanthrenone, 9-O demethyltrigonostemone (2), and two new phenanthropolones, 3,6,9 trimethoxyphenanthropolone (3) and 4,6,9-trimethoxyphenanthropolone (4), were isolated from the roots of Strophioblachia fimbricalyx. Compound 2 showed cytotoxicity against NCI-H187, KB, and MCF7 cancer cells with IC50 values of 0.8, 0.8, and 2.9 microg/mL, respectively, while 3 and 4 showed reduced cytotoxicity. Compounds 2 and 3 displayed antiplasmodial activity in vitro (IC50 values of 2.7 and 3.2 microg/mL, respectively) against Plasmodium falciparum (K1, resistant strain). In addition, the antioxidant activity of 1-4 toward DPPH radicals was determined, but only compound 2 showed any discernible activity. PMID- 19778066 TI - Energetics of displacing water molecules from protein binding sites: consequences for ligand optimization. AB - A strategy in drug design is to consider enhancing the affinity of lead molecules with structural modifications that displace water molecules from a protein binding site. Because success of the approach is uncertain, clarification of the associated energetics was sought in cases where similar structural modifications yield qualitatively different outcomes. Specifically, free-energy perturbation calculations were carried out in the context of Monte Carlo statistical mechanics simulations to investigate ligand series that feature displacement of ordered water molecules in the binding sites of scytalone dehydratase, p38-alphaMAP kinase, and EGFR kinase. The change in affinity for a ligand modification is found to correlate with the ease of displacement of the ordered water molecule. However, as in the EGFR example, the binding affinity may diminish if the free energy increase due to the removal of the bound water molecule is not more than compensated by the additional interactions of the water-displacing moiety. For accurate computation of the effects of ligand modifications, a complete thermodynamic analysis is shown to be needed. It requires identification of the location of water molecules in the protein-ligand interface and evaluation of the free-energy changes associated with their removal and with the introduction of the ligand modification. Direct modification of the ligand in free-energy calculations is likely to trap the ordered molecule and provide misleading guidance for lead optimization. PMID- 19778069 TI - Molecular solvent model of spherical electric double layers: a systematic study by Monte Carlo simulations and density functional theory. AB - The structure of spherical electric double layers is studied using Monte Carlo simulation and density functional theory by considering solvent as the third component. In this molecular solvent model (MSM), ions and solvent molecules are considered as charged and neutral hard spheres, respectively, having equal diameter. The macroion is considered as an isolated hard sphere having uniform surface charge density surrounded by the electrolyte and the solvent. The theory is partially perturbative as the hard-sphere contribution to the one particle correlation function is evaluated using suitably averaged weighted density, and the ionic part is obtained through a second-order functional Taylor expansion around the bulk electrolyte. The Monte Carlo simulations have been performed in a canonical ensemble. The system is studied at varying concentrations of electrolytes, and the solvent molecules, at different valences of the electrolyte, at different macroion radii, and at varying surface charge densities. The theory is found to be in good agreement with the simulation results over a wide range of parametric conditions. The excluded volume effects due to the molecular nature of the solvent are shown to have much richer features in diffuse layer phenomena like layering and charge inversion. PMID- 19778071 TI - The second-generation anticancer drug Nedaplatin: a theoretical investigation on the hydrolysis mechanism. AB - The hydrolysis reaction processes of the second-generation platinum derivative Nedaplatin have been studied using density functional theory (DFT) combined with the conductor-like dielectric continuum model (CPCM) approach, in order to obtain detailed data on its mechanism of action. The first and the second hydrolysis of Nedaplatin, corresponding to the ring opening followed by the loss of the ligand, respectively, have been explored in neutral and acid conditions. The influence of an extra water molecule which could assist the degradation processes has also been considered including in our models an explicit water molecule other than the reactive one. The computed potential energy surfaces show that the rate limiting step in neutral conditions is the first hydrolysis process and, consequently, the double hydrated complex is suggested to be the species reacting with the DNA purine bases, while in acid conditions the trend is different, with the second hydrolysis process being the rate limiting step. The results obtained in this work allow us to make a comparison with the trends previously found for the other platinum anticancer drugs currently used in the medical protocols. PMID- 19778070 TI - The effects of hairpin loops on ligand-DNA interactions. AB - Hairpin nucleic acids are frequently used in physical studies due to their greater thermal stability compared to their equivalent duplex structures. They are also good models for more complex loop-containing structures such as quadruplexes, i-motifs, cruciforms, and molecular beacons. Although a connecting loop can increase stability, there is little information on how the loop influences the interactions of small molecules with attached base-paired nucleic acid regions. In this study, the effects of different hairpin loops on the interactions of A/T specific DNA minor groove binding agents with a common stem sequence have been investigated by spectroscopic and surface plasmon resonance (SPR) biosensor methods. The results indicate that the hairpin loop has little influence on the specific site interactions on the stem but significantly affects nonspecific binding. The use of a non-nucleotide loop (with a reduced negative charge) not only enhances the thermal stability of the hairpin but also reduces the nonspecific binding at the loop without compromising the primary binding affinity on the stem. PMID- 19778072 TI - Conformational analysis in a multidimensional energy landscape: study of an arginylglutamate repeat. AB - The identification of the distinct conformation classes of a molecule is a common and often crucial step in establishing structure-function relationships. Many different methods have been suggested for that purpose which differ in their choice of a (dis)similarity measure and clustering algorithm. The present study discusses and analyzes these issues, proposing a method based on principal component analysis (PCA), which is applied to conformations obtained from molecular dynamics (MD) simulations of an arginylglutamate repeat. Simulations are done at different pH values, using both standard MD and constant-pH MD methods, with the peptide displaying a very high conformational variety. The conformational analysis starts with a comprehensive comparison of different sets of conformational coordinates and of their ability to preserve structural similarity between conformations. The selected set of conformational coordinates is then used to investigate the preservation of structural similarity after PCA transformation, concluding the need of using a multidimensional conformation space. This conformation space is then used to derive a multidimensional probability density and the corresponding energy landscape. The application of a simple cutoff algorithm to the resulting multidimensional landscape is then shown to produce a consistent set of distinct and homogeneous conformation classes. Overall, this methodology provides an efficient way to identify the major conformation classes of a molecule in a way that directly reflects the density of states in the multidimensional conformation space, contrasting with the more heuristic nature of standard clustering methods. PMID- 19778073 TI - Bimetallic flowers, beads, and buds: synthesis, characterization, and Raman imaging of unique mesostructures. AB - We demonstrate the creation of a new class of nano/mesostructures, such as Au/Ag flowers, Au/Pt buds, and Au/Pt beads, through the directed overgrowth of Ag or Pt on Au/oligoaniline nanowires (Au/OA NWs). Different stages of the formation of these mesostructures have been studied using various spectroscopic and microscopic techniques. The surface plasmon resonance (SPR) of the Au/OA NWs can be tuned by the incorporation of bimetallicity into the nanowire. Raman based spectral imaging of the bimetallic Au/Ag mesoflower and Au/Pt mesobud revealed the molecular details and the nature of interaction of oligoaniline with the different metal domains. Raman study also suggested a substrate effect due to the different domains of the mesostructures, and spectral images distinguished these two regions. The single particle spectral images suggest that the material is surface-enhanced Raman active. PMID- 19778075 TI - Evaporation behavior of microliter- and sub-nanoliter-scale water droplets on two different fluoroalkylsilane coatings. AB - The evaporation behavior of microliter (2.0 microL) and subnanoliter (0.8 nL) scale water droplets was investigated on two smooth hydrophobic and hydrophilic fluoroalkylsilane coatings prepared using chemical vapor deposition. The contact angle was constant in the second stage of evaporation for a 2.0 microL droplet on the hydrophobic coating, but it was slightly decreased in the case of a 0.8 nL droplet. The contact angle decreased gradually in the same stage of evaporation for a 2.0 microL droplet on the hydrophilic coating, but it was almost constant for a 0.8 nL droplet. These differences in evaporation behavior are expected to originate from the differences of their magnitudes and signs of line tension. PMID- 19778076 TI - Folding of aromatic amide-based oligomers induced by benzene-1,3,5-tricarboxylate anion in DMSO. AB - In this paper, we describe the folding of a series of linear arylamide oligomers in DMSO that is induced by benzene-1,3,5-tricarboxylate anion. The oligomers are comprised of naphthalene-2,7-diamine and 1,3,5-benzenetricarboxylic acid segments with two (tert-butoxycarbonylamino) groups at the ends and two to four hydrophilic N,N-bis(2-(2-(2-methoxyethoxy)ethoxy)ethyl)amino groups at one side of the backbones. (2D NOESY) (1)H NMR, fluorescence and UV-vis studies indicate that the oligomers do not adopt defined conformations in DMSO but fold into compact structures in the presence of the anion. It is revealed that the folded conformation is induced by intermolecular hydrogen bonds between the amide and aromatic hydrogen atoms of the oligomers and the oxygen atoms of the anion. (1)H NMR and UV-vis titrations support a 1:1 binding stoichiometry, and the associated constants are determined, which are found to increase with the elongation of the oligomers. PMID- 19778077 TI - Gold-catalyzed one-pot cascade construction of highly functionalized pyrrolo[1,2 a]quinolin-1(2H)-ones. AB - An efficient protocol was developed for the synthesis of fused heterocyclic multiring compounds pyrrolo[1,2-a]quinolin-1(2H)-ones via a AuBr(3)/AgSbF(6) catalyzed cascade transformation. Significantly, the strategy affords a straightforward and efficient approach to construction of tricyclic lactam molecular architectures in which two new C-C bonds and one new C-N bond are formed in a one-pot synthetic operation from simple starting materials. Moreover, a broad spectrum of substrates can participate in the process effectively to produce the desired products in good yields and with excellent regio- and chemoselectivities. PMID- 19778078 TI - Photochemistry of fluorinated 4-iodophenylnitrenes: matrix isolation and spectroscopic characterization of phenylnitrene-4-yls. AB - The photochemistry of a series of fluorinated p-iodophenyl azides 2 has been investigated using matrix isolation IR and EPR spectroscopy. In all cases, the corresponding phenylnitrenes 1 were formed as primary photoproducts. Further irradiation of the nitrenes 1 resulted in the formation of azirines 3, ketenimines 4, and nitreno radicals 5. The yield of 5 depends on the number of ortho fluorine substituents: with two ortho fluorine atoms the highest yield is observed, whereas without fluorine atoms the yield is too low for IR spectroscopic detection. The interconversion between the isomers 1, 3, and 4 proved to be rather complex. If the fluorine atoms are distributed unsymmetrically, two isomers of azirines 3 and ketenimines 4 can be formed. The yields of these isomers depend critically on the irradiation conditions. PMID- 19778079 TI - The synthesis of velloziolide via Nicholas reaction based gamma-carbonyl cations. AB - The total synthesis of the 9,11-seco-rosane diterpene velloziolide (1) has been accomplished by employing the Nicholas reaction chemistry of 2a as a gamma carbonyl cation equivalent. An initial model study demonstrated the utility of Nicholas reactions of 2 in the generation of 4-arylalkynoate-Co(2)(CO)(6) complexes, and in conjunction with Gilman cuprate addition and Johnson-Claisen rearrangement chemistry, the preparation of a 3-methyl-3-vinyl-4-arylalkanoate model for velloziolide. The Nicholas reaction/gamma-carbonyl cation methodology was then employed twice in the total synthesis to incorporate onto 3,4 methylenedioxytoluene the 4-carbon unit that became the gem-dimethyltetralin portion of the velloziolide and, subsequently, to incorporate the gamma arylalkanoate function of the epsilon-lactone. PMID- 19778080 TI - Fluorescence properties of simple N-substituted aldimines with a B-N interaction and their fluorescence quenching by a cyanide ion. AB - N-Aryl, N-alkyl, N-alkoxy, and N-amino derivatives of 2 [bis(pentafluorophenyl)boryl]benzylideneamine were synthesized by the condensation reactions of 2-[bis(pentafluorophenyl)boryl]benzaldehyde with the corresponding amines. Their structures were investigated by NMR and X-ray crystallographic analysis. Their properties were investigated by UV-vis and fluorescence spectroscopy. The boryl-substituted N-arylimines show blue or green fluorescence in hexane at room temperature, and their fluorescence efficiency is much higher than that of N-benzylideneaniline. In particular, the boryl substituted N-(4-dimethylaminophenyl)imine showed strong green emissions with at least 7000 times higher fluorescence quantum yield (0.73) compared with that of N benzylideneaniline. The boryl-substituted N-(1-indolyl)- and N-(9 carbazolyl)imines showed dual emissions, one of which was assignable as arising from the lowest singlet excited state and the other from the local excited state of the substituent on the imine nitrogen. The fluorescent properties of the boryl substituted N-butyl- and N-methoxyimines were also investigated. Reactions of the N-arylimine derivatives with cyanide ion gave the corresponding cyanide adducts and quenched the fluorescence, indicating that these 2 [bis(pentafluorophenyl)boryl]benzylideneamine derivatives have a potential as a cyanide ion sensor. PMID- 19778081 TI - Protecting-group-free total synthesis of (+/-)-subincanadine F. AB - With chemoselective Dieckmann condensation as the key step, the protective-group free total synthesis of (+/-)-subincanadine F was accomplished in 7 steps from the commercially available tryptamine in 33% overall yield. PMID- 19778082 TI - Diastereoselective synthesis of indanes via a domino Stetter-Michael reaction. AB - N-Heterocyclic carbenes were found to catalyze a domino Stetter-Michael reaction for the synthesis of indanes. The products were obtained in good yield and diastereomeric ratio, allowing access to highly functionalized indanes under mild conditions. In addition, the functional groups present on the indanes could be used for the synthesis of polycyclic pyrroles. PMID- 19778083 TI - Syntheses and configuration determination of (+)-villatamines A and B, two marine natural products. AB - The first total syntheses of (+)-villatamines A and B have been realized in six and five steps, respectively. The stereogenic center present in these two naturally occurring alkaloids should have an (S)-configuration based on our results. PMID- 19778084 TI - One-pot synthesis of 2-pyridones via chemo- and regioselective tandem Blaise reaction of nitriles with propiolates. AB - The Blaise reaction intermediate, generated in situ from Reformatsky reagent and nitrile, reacted with propiolates in a chemo- and regioselective manner to afford 2-pyridone derivatives in good to excellent yields. PMID- 19778086 TI - Triterpenoids and flavonoids from celery (Apium graveolens). AB - Three new triterpenoids, 11,21-dioxo-2beta,3beta,15alpha-trihydroxyurs-12-ene-2-O beta-D-glucopyranoside (1), 11,21-dioxo-3beta,15alpha,24-trihydroxyurs-12-ene-24 O-beta-D-glucopyranoside (2), and 11,21-dioxo-3beta,15alpha,24-trihydroxyolean-12 ene-24-O-beta-D-glucopyranoside (3), and two new flavonoids, apigenin-7-O-[2''-O (5'''-O-feruloyl)-beta-D-apiofuranosyl]-beta-D-glucopyranoside (4) and chrysoeriol-7-O-[2''-O-(5'''-O-feruloyl)-beta-D-apiofuranosyl]-beta-d glucopyranoside (5), were isolated from the whole plant of fresh celery (Apium graveolens), together with 10 known flavonoids. The structures of the new compounds were elucidated by analysis of spectroscopic data. The inhibitory effects of the compounds isolated on nitric oxide production in lipopolysaccaride activated macrophages were evaluated. PMID- 19778085 TI - Synthesis of (+)-CP-99,994 via Pd(0)-catalyzed asymmetric allylic and homoallylic C-H Diamination of terminal olefin. AB - This paper describes an asymmetric synthesis of the potent substance P receptor antagonist (+)-CP-99,994 from 4-phenyl-1-butene via Pd(0)-catalyzed asymmetric allylic and homoallylic C-H diamination. PMID- 19778087 TI - Drimane sesquiterpenoids from the fungus Aspergillus ustus isolated from the marine sponge Suberites domuncula. AB - Seven new drimane sesquiterpenoids (1-3, 6-9), along with the known compounds deoxyuvidin B (4), strobilactone B (5), and RES-1149-2 (10), were obtained from cultures of the fungus Aspergillus ustus, which was isolated from the marine sponge Suberites domuncula. Their structures were established by means of spectroscopic analyses including one- and two-dimensional NMR spectroscopy and high-resolution MS. Compounds 6, 7, and 10 showed cytotoxic activity against a panel of tumor cell lines, including L5178Y, HeLa, and PC12 cells, with 7 being the most active (EC(50) against L5178Y cell line: 0.6 microg/mL). PMID- 19778088 TI - Cembranoid diterpenes from the Caribbean sea whip Eunicea knighti. AB - Three new cembranoid diterpenes, knightol (1), knightol acetate (2), and knightal (3), along with the known asperdiol (4) and asperdiol acetate (5), were isolated as major compounds from the sea whip Eunicea knighti collected from the Colombian Caribbean. The structures and absolute configurations of 1-5 were determined on the basis of spectroscopic analyses and by a combination of chemical and NMR methods, multiple correlations observed in a ROESY experiment, and using the modified Mosher method. Additionally, five semisynthetic compounds, 6-10, obtained during the chemical transformations of the natural compounds are here reported for the first time. All compounds were tested for antimicrobial activity against marine bacteria associated with heavily fouled surfaces and were also screened for antiquorum sensing (QS) activity. Compounds 1, 3, and 8 showed significant antimicrobial activity against bacterial isolates, and 1, 3, 7, and 8 showed excellent anti-QS inhibition activity measured by means of bioluminescence inhibition with biosensor model systems. PMID- 19778089 TI - Eucalmaidins A-E, (+)-oleuropeic acid derivatives from the fresh leaves of Eucalyptus maideni. AB - Five new (+)-oleuropeic acid derivatives, eucalmaidins A-E (1-5), together with 12 known compounds (6-17), were isolated from the fresh leaves of Eucalyptus maideni. Structures of the new compounds were determined on the basis of spectroscopic analyses (HSQC, HMBC, and (1)H-(1)H COSY), chemical degradation, and enzymatic hydrolysis. Of the tested compounds, only quercetin showed slight anti-herpes simplex virus 1 (HSV-1) activity in vitro. PMID- 19778090 TI - Carteriosulfonic acids A-C, GSK-3beta inhibitors from a Carteriospongia sp. AB - Modulators of Wnt signaling have therapeutic potential in a number of human diseases. A fractionated library from marine invertebrates was screened in a luciferase assay designed to identify modulators of Wnt signaling. A fraction from a Carteriospongia sp. sponge activated Wnt signaling and was subsequently shown to inhibit GSK-3beta, which inhibits Wnt signaling through phosphorylation of beta-catenin. Three novel natural products, carteriosulfonic acids A (1), B (2), and C (3), were identified as active constituents. The carteriosulfonic acids contain unprecedented 4,6,7,9-tetrahydroxylated decanoic acid subunits. Their structures were elucidated through analysis of NMR data and a detailed analysis of pseudo MS(3) spectra. PMID- 19778092 TI - Ortho-para mixing interaction in the vinyl radical detected by millimeter-wave spectroscopy. AB - Ortho-para mixing interaction due to the coupling of nuclear and electron spins was detected for the first time by millimeter-wave spectroscopy of the deuterated vinyl radical H(2)CCD. The ground state of H(2)CCD is split by the deuteron tunneling into two components 0(+) and 0(-) separated by DeltaE(0)=1186.794(16) MHz. Rotational levels in the 0(+) and 0(-) states, one being an ortho level and the other a para level, are coupled by the interaction expressed by 0(+/-)mid R:H(')mid R:0(-/+)=(deltaa(F)/2)S(I(1)-I(2)), where I(1) and I(2) are spins of the two protons and S is the electron spin. The deltaa(F) constant has been determined to be 68.06(52) MHz. The para to ortho conversion rate constant is predicted to be 1.2x10(5) s(-1) torr(-1). PMID- 19778091 TI - Effects of the endocrine disruptors atrazine and PCB 153 on the protein expression of MCF-7 human cells. AB - Polychlorinated biphenyls (PCBs) and a number of pesticides can act as endocrine disrupting compounds (EDCs). These molecules exhibit hormonal activity in vivo, and can therefore interact and perturb normal physiological functions. Many of these compounds are persistent in the environment, and their bioaccumulation may constitute a significant threat for human health. Physiological abnormalities following exposure to these xenobiotic compounds go along with alterations at the protein level of individual cells. In this study, MCF-7 cells were exposed to environmentally relevant concentrations of atrazine, PCB153 (100 ppb, respectively), 17-beta estradiol (positive control, 10 nM) and a negative control (solvent) for t = 24 h (n = 3 replicates/exposure group). After trizol extraction and protein solubilization, protein expression levels were studied by 2D-DIGE. Proteins differentially expressed were excised, trypsin-digested, and identified by MALDI-ToF-ToF, followed by NCBInr database search. 2D-DIGE experiments demonstrated that 49 spots corresponding to 29 proteins were significantly differentially expressed in MCF-7 cells (>1.5-fold, P < 0.05, Student's paired t test). These proteins belonged to various cellular compartments (nucleus, cytosol, membrane), and varied in function; 88% of proteins were down-regulated during atrazine exposure, whereas 75% of proteins were up-regulated by PCB153. Affected proteins included those regulating oxidative stress such as superoxide dismutase and structural proteins such as actin or tropomyosin, which may explain morphological changes of cells already observed under the microscope. This study highlights the susceptibility of human cells to compounds with endocrine disrupting properties. PMID- 19778093 TI - Diversity of kinetic pathways in amyloid fibril formation. AB - The kinetics of peptide oligomerization was investigated using Langevin Dynamics simulations and a coarse-grained peptide model. The simulations show a rich diversity of aggregation pathways, modulated by the beta-sheet propensity (flexibility) of the peptide. Aggregation into amyloidlike fibrils occurs via three main mechanisms: (i) formation of fibrils directly from the assembly of early ordered oligomers, (ii) fibril formation via the formation of on-pathway, nonfibrillar aggregates high in beta-sheet content, and (iii) formation of amorphous aggregates followed by reorganization to beta-sheet aggregates and to fibrils. beta-sheet, nonfibrillar aggregates also appeared as long-lived, "off pathway" end-product species. PMID- 19778094 TI - All-electron calculation of nonadiabatic couplings from time-dependent density functional theory: Probing with the Hartree-Fock exact exchange. AB - We present the all-electron scheme of calculating nonadiabatic couplings (NACs) from time-dependent density functional theory (TDDFT) using atomic orbital basis. The formal expression for calculating NAC from linear response TDDFT [Hu et al., J. Chem. Phys. 127, 064103 (2007)] can be straightforwardly adapted to the all electron TDDFT scheme. However, in contrast to the planewave basis, the nuclear coordinate dependence of atomic orbital basis needs to be considered when constructing the matrix elements of the nuclear derivative of Hamiltonian. Practical calculations show that the contribution of atomic orbital basis ("Pulay term") is significant and comparable to that of the Hellmann-Feynman term. In particular, we probe the all-electron formalism of NAC with the Hartree-Fock exact exchange, which serves as the prerequisite for hybrid functionals. It is validated that in the present framework the sum rule of NAC is rigorously satisfied, which has not been the case in the pseudopotential planewave calculations. Reasonably good results can be obtained in the vicinity of various Renner-Teller (and also Jahn-Teller) intersections when the intersection point is not too closely approached, while further tests show that correlation effects should be taken into account in general cases. PMID- 19778095 TI - A thermal self-consistent field theory for the calculation of molecular vibrational partition functions. AB - A new approach for the calculation of anharmonic molecular vibrational partition functions is developed based on a separable ansatz to the thermal density matrix. The parameters appearing in the effective single particle Hamiltonians that generate the thermal density matrices are determined variationally. The resulting equations are the thermal analogs of the vibrational self-consistent field approximation. The method has the formal property that the free energy calculated by this approach is an upper bound to the exact free energy. Thermodynamic quantities calculated by this approach are generally in good agreement with the results of numerically converged calculations. This approach is more efficient than the standard sum over state approaches in that the computational resources scale with N(4) where N is the number of vibrational degrees of freedom. Thus it can be applied to fairly large systems. PMID- 19778096 TI - Accounting for the exact degeneracy and quasidegeneracy in the automerization of cyclobutadiene via multireference coupled-cluster methods. AB - The automerization of cyclobutadiene (CBD) is employed to test the performance of the reduced multireference (RMR) coupled-cluster (CC) method with singles and doubles (RMR CCSD) that employs a modest-size MR CISD wave function as an external source for the most important (primary) triples and quadruples in order to account for the nondynamic correlation effects in the presence of quasidegeneracy, as well as of its perturbatively corrected version accounting for the remaining (secondary) triples [RMR CCSD(T)]. The experimental results are compared with those obtained by the standard CCSD and CCSD(T) methods, by the state universal (SU) MR CCSD and its state selective or state specific (SS) version as formulated by Mukherjee et al. (SS MRCC or MkMRCC) and, wherever available, by the Brillouin-Wigner MRCC [MR BWCCSD(T)] method. Both restricted Hartree-Fock (RHF) and multiconfigurational self-consistent field (MCSCF) molecular orbitals are employed. For a smaller STO-3G basis set we also make a comparison with the exact full configuration interaction (FCI) results. Both fundamental vibrational energies-as obtained via the integral averaging method (IAM) that can handle anomalous potentials and automatically accounts for anharmonicity- and the CBD automerization barrier for the interconversion of the two rectangular structures are considered. It is shown that the RMR CCSD(T) potential has the smallest nonparallelism error relative to the FCI potential and the corresponding fundamental vibrational frequencies compare reasonably well with the experimental ones and are very close to those recently obtained by other authors. The effect of anharmonicity is assessed using the second-order perturbation theory (MP2). Finally, the invariance of the RMR CC methods with respect to orbital rotations is also examined. PMID- 19778097 TI - A computationally less demanding charge-on-spring model for the water molecule. AB - We developed a new charge-on-spring model for the water molecule with the advantage of being computationally less demanding. We start from the basic geometry of Lamoureux et al. [J. Chem. Phys. 119, 5185 (2003); Chem. Phys. Lett. 418, 245 (2006)] in order to have a good approximation for the quadrupole moment of the gas phase molecule, but we use only four charged sites. We polarize the molecules in two steps. First, the three sites of the equilibrium gas phase molecule are polarized and this process is accompanied by a charge rearrangement. This step creates the massless spring particle connected to the uncharged oxygen atom. The equilibrium position of the spring particle is found by iteration. We describe the construction of the model and present details of the results obtained by molecular dynamics simulation for the properties of liquid water, hexagonal ice, and gas clusters. Our results are comparable in quality to that of Lamoureux et al. [Chem. Phys. Lett. 418, 245 (2006)] and show good agreements with experiments. PMID- 19778098 TI - A global search algorithm of minima exploration for the investigation of low lying isomers of clusters from density functional theory-based potential energy surfaces: The example of Si(n) (n=3,15) as a test case. AB - Using an effective generation algorithm coupled with a PBE0/LANL2DZdp level of theory, 905 stable structures of Si(n) (n=3,15) have been found. This global search algorithm of minima exploration includes two original parts: the spheroidal generation, allowing the generation of rings, sphericals, m rings cylinders, and planar structures, and the raking optimization, which discards step by step the conformations that become physically unreasonable during the optimization process. The 142 isomers lying below 1 eV are reported and include the 28 structures reported in the literature. Conformational energies are well reproduced with respect to the values previously published (DeltaE=0,00+/-0,09 eV). PMID- 19778099 TI - Potentialphilicity and potentialphobicity: Reactivity indicators for external potential changes from density functional reactivity theory. AB - In analogy to the electrophilicity, we define potentialphilicity indicators that represent energetically favorable ways to change the external potential of a molecule at fixed electron number. Similarly, we define a potentialphobicity to represent the least favorable way to change the external potential of a molecule. The resulting indicators should be useful for describing how molecular geometries change and predicting favorable and unfavorable ways for a reagent to approach a molecule. The linear response function enters plays a very important role in this approach, analogous to the role of the hardness for the electrophilicity or the hardness kernel for the Fukui function. The mathematical properties of the response function and its implications for these reactivity indicators are discussed in depth. PMID- 19778100 TI - Configuration interaction calculations of potential curves and annihilation rates for positronic complexes of alkali monoxides. AB - Ab initio multireference single- and double-excitation configuration interaction calculations have been carried out to compute the potential curves and annihilation rates (ARs) of positronic molecular complexes of a series of alkali monoxides. The dissociation limit for the lowest states of these systems consists of the positive alkali ion ground state (M(+)) and the OPs (e(+)O(-)) complex formed by attaching the positron to O(-), even though the ground state of the corresponding neutral molecule always correlates with uncharged fragments (M+O). The positron affinity of the neutral oxide (2)Pi state is greater than that of (2)Sigma(+) in each case, so that the e(+)MO ground state always has (3,1)Pi symmetry, despite the fact that both KO and RbO have (2)Sigma(+) ground states. The bonding in the positronic systems is highly ionic at all internuclear distances and this causes their ARs to decrease gradually as the positive alkali ion approaches the OPs fragment. PMID- 19778101 TI - Divide-and-conquer-based linear-scaling approach for traditional and renormalized coupled cluster methods with single, double, and noniterative triple excitations. AB - We have reported the divide-and-conquer (DC)-based linear-scaling correlation treatment of coupled-cluster method with single and double excitations (CCSD) [Kobayashi and Nakai, J. Chem. Phys. 129, 044103 (2009)]. In the DC-CCSD method, the CCSD equations derived from subsystem orbitals are solved for each subsystem in order to obtain the total correlation energy by summing up subsystem contributions using energy density analysis. In this study, we extend the DC-CCSD method for treating noniterative perturbative triple excitations using CCSD T(1) and T(2) amplitudes, namely, CCSD(T). In the DC-CCSD(T) method, the so-called (T) corrections are also computed for each subsystem. Numerical assessments indicate that DC-CCSD(T) reproduces the CCSD(T) results with high accuracy and significantly less computational cost. We further extend the DC-based correlation method to renormalized CCSD(T) [Kowalski and Piecuch, J. Chem. Phys. 113, 18 (2000)] for avoiding the divergence that occurs in multireference problems such as bond dissociation. PMID- 19778102 TI - Local correlation calculations using standard and renormalized coupled-cluster approaches. AB - The linear scaling local correlation approach, termed "cluster-in-molecule" (CIM), is extended to the coupled-cluster (CC) theory with singles and doubles (CCSD) and CC methods with singles, doubles, and noniterative triples, including CCSD(T) and the completely renormalized CR-CC(2,3) approach. The resulting CIM CCSD, CIM-CCSD(T), and CIM-CR-CC(2,3) methods are characterized by (i) the linear scaling of the CPU time with the system size, (ii) the use of orthonormal orbitals in the CC subsystem calculations, (iii) the natural parallelism, (iv) the high computational efficiency, enabling calculations for much larger systems and at higher levels of CC theory than previously possible, and (v) the purely noniterative character of local triples corrections. By comparing the results of the canonical and CIM-CC calculations for normal alkanes and water clusters, it is shown that the CIM-CCSD, CIM-CCSD(T), and CIM-CR-CC(2,3) approaches accurately reproduce the corresponding canonical CC correlation and relative energies, while offering savings in the computer effort by orders of magnitude. PMID- 19778103 TI - Determination of the solid-liquid interfacial free energy along a coexistence line by Gibbs-Cahn integration. AB - We calculate the solid-liquid interfacial free energy gamma(sl) for the Lennard Jones (LJ) system at several points along the pressure-temperature coexistence curve using molecular-dynamics simulation and Gibbs-Cahn integration. This method uses the excess interfacial energy (e) and stress (tau) along the coexistence curve to determine a differential equation for gamma(sl) as a function of temperature. Given the values of gamma(sl) for the (100), (110), and (111) LJ interfaces at the triple-point temperature (T( *)=kT/varepsilon=0.618), previously obtained using the cleaving method by Davidchack and Laird [J. Chem. Phys. 118, 7657 (2003)], this differential equation can be integrated to obtain gamma(sl) for these interfaces at higher coexistence temperatures. Our values for gamma(sl) calculated in this way at T( *)=1.0 and 1.5 are in good agreement with those determined previously by cleaving, but were obtained with significantly less computational effort than required by either the cleaving method or the capillary fluctuation method of Hoyt, Asta, and Karma [Phys. Rev. Lett. 86, 5530 (2001)]. In addition, the orientational anisotropy in the excess interface energy, stress and entropy, calculated using the conventional Gibbs dividing surface, are seen to be significantly larger than the relatively small anisotropies in gamma(sl) itself. PMID- 19778104 TI - Non-Markovian theory for the waiting time distributions of single electron transfers. AB - We derive a non-Markovian theory for waiting time distributions of consecutive single electron transfer events. The presented microscopic Pauli rate equation formalism couples the open electrodes to the many-body system, allowing to take finite bias and temperature into consideration. Numerical results reveal transient oscillations of distinct system frequencies due to memory in the waiting time distributions. Memory effects can be approximated by an expansion in non-Markovian corrections. This method is employed to calculate memory landscapes displaying preservation of memory over multiple consecutive electron transfers. PMID- 19778105 TI - Perturbative triples correction for the equation-of-motion coupled-cluster wave functions with single and double substitutions for ionized states: Theory, implementation, and examples. AB - A noniterative N(6) triples energy correction is presented for the equation-of motion coupled-cluster method with single and double substitutions for ionized states (EOM-IP-CCSD). The correction, which is size intensive, is derived using a second-order Rayleigh-Schrodinger perturbative treatment and is similar to the approach of Stanton and Gauss [Theor. Chim. Acta 93, 303 (1996)]. In the present implementation, only the target EOM-IP states are corrected, and the reference state is described by CCSD; the method is therefore more useful for the study of the target states themselves than ionization potentials. The performance of the correction, which demonstrates the caveat above, is demonstrated by applications to singlet methylene, BNB(-), nitrogen, carbon monoxide, acetylene, benzene, thymine, and adenine. PMID- 19778107 TI - Vibration-rotation pattern in acetylene. II. Introduction of Coriolis coupling in the global model and analysis of emission spectra of hot acetylene around 3 microm. AB - A high temperature source has been developed and coupled to a high resolution Fourier transform spectrometer to record emission spectra of acetylene around 3 mum up to 1455 K under Doppler limited resolution (0.015 cm(-1)). The nu(3) ground state (GS) and nu(2)+nu(4)+nu(5) (Sigma(u) (+) and Delta(u))-GS bands and 76 related hot bands, counting e and f parities separately, are assigned using semiautomatic methods based on a global model to reproduce all related vibration rotation states. Significantly higher J-values than previously reported are observed for 40 known substates while 37 new e or f vibrational substates, up to about 6000 cm(-1), are identified and characterized by vibration-rotation parameters. The 3 811 new or improved data resulting from the analysis are merged into the database presented by Robert et al. [Mol. Phys. 106, 2581 (2008)], now including 15 562 lines accessing vibrational states up to 8600 cm(-1). A global model, updated as compared to the one in the previous paper, allows all lines in the database to be simultaneously fitted, successfully. The updates are discussed taking into account, in particular, the systematic inclusion of Coriolis interaction. PMID- 19778106 TI - Full-electron calculation of effective electronic couplings and excitation energies of charge transfer states: Application to hole transfer in DNA pi stacks. AB - In this work I develop and apply a theoretical method for calculating effective electronic couplings (or transfer integrals) between redox sites involved in hole or electron transfer reactions. The resulting methodology is a refinement and a generalization of a recently developed approach for transfer integral evaluation. In fact, it holds for any overlap between the charge-localized states used to represent charge transfer (CT) processes in the two-state model. The presented theoretical and computational analyses show that the prototype approach is recovered for sufficiently small overlaps. The method does not involve any empirical parameter. It allows a complete multielectron description, therefore including electronic relaxation effects. Furthermore, its theoretical formulation holds at any value of the given reaction coordinate and yields a formula for the evaluation of the vertical excitation energy (i.e., the energy difference between the adiabatic ground and first-excited electronic states) that rests on the same physical quantities used in transfer integral calculation. In this paper the theoretical approach is applied to CT in B-DNA base dimers within the framework of Density Functional Theory (DFT), although it can be implemented in other computational schemes. The results of this work, as compared with previous Hartree-Fock (HF) and post-HF evaluations, support the applicability of the current implementation of the method to larger pi-stacked arrays, where post-HF approaches are computationally unfeasible. PMID- 19778108 TI - Weakly bound complexes trapped in quantum matrices: Structure, energetics, and isomer coexistence in (para-H(2))(N)(ortho-D(2))(3) clusters. AB - The ground state of mixed (para-H(2))(N)(ortho-D(2))(3) clusters of sizes ranging from N=8 to 37 is examined by means of the path integral ground state method. The chemical potential is calculated and reveals that magic numbers are consistent with those found in pure para-H(2) and ortho-D(2) clusters. The structural features of the mixed clusters are examined by analyzing density profiles, one dimensional Pekeris distribution functions of the (ortho-D(2))(3) subsystem, and by direct visualization of density isosurfaces of the systems. The heavier (ortho D(2))(3) complex resides in the center of the cluster for the various sizes under consideration. It is found that certain cluster sizes favor either equilateral, or near-linear isosceles (ortho-D(2))(3) configurations, while others show a coexistence between those two triangular geometries. PMID- 19778109 TI - Born-Oppenheimer quantum dynamics of the C((1)D)+H(2) reaction on the CH(2) a (1)A(1) and b (1)B(1) surfaces. AB - We present the Born-Oppenheimer coupled-channel dynamics of the reaction (12)C((1)D)+(1)H(2)(X (1)Sigma(g) (+))-->CH(X (2)Pi)+H((2)S), considering the uncoupled CH(2) states a (1)A(1) and b (1)B(1), the permutation-inversion symmetry, and Coriolis interactions. Using accurate MRCI potential energy surfaces (PESs), we obtain initial-state-resolved reaction probabilities, cross sections, and rate constants through the time-dependent, real wavepacket (WP) and flux methods, taking into account the proton-spin statistics for both electronic species. Comparing results on both PESs, we point out the role of the b (1)B(1) upper state on the initial-state-resolved dynamics and on the thermal kinetic rate. WP probabilities at J=0 and cross sections at E(col)=0.080 eV agree quite well with quantum-mechanical time-independent findings. Probabilities and WP snapshots show the different reaction mechanisms on the PESs, i.e., an a (1)A(1) indirect perpendicular insertion and a b (1)B(1) direct sideways collision, associated with many and few sharp resonances, respectively. All cross sections are very large at low E(col), decrease at high energies, and that of the lowest reactant state presents some weak resonances. As the temperature increases from 100 to 400 K, the a (1)A(1) rate constant increases slightly from 1.37x10(-10) to 1.43x10(-10) cm(3) s(-1), whereas the b (1)B(1) one decreases from 1.30x10(-10) to 0.98x10(-10) cm(3) s(-1). In this temperature range, the b (1)B(1) contribution to the total rate constant thus decreases from 49% to 41%. At 300 K, the WP and experimental rates are equal to (2.45+/-0.08)x10(-10) and (2.0+/ 0.6)x10(-10) cm(3) s(-1), respectively. PMID- 19778110 TI - Laser-induced electron dynamics including photoionization: A heuristic model within time-dependent configuration interaction theory. AB - We report simulations of laser-pulse driven many-electron dynamics by means of a simple, heuristic extension of the time-dependent configuration interaction singles (TD-CIS) approach. The extension allows for the treatment of ionizing states as nonstationary states with a finite, energy-dependent lifetime to account for above-threshold ionization losses in laser-driven many-electron dynamics. The extended TD-CIS method is applied to the following specific examples: (i) state-to-state transitions in the LiCN molecule which correspond to intramolecular charge transfer, (ii) creation of electronic wave packets in LiCN including wave packet analysis by pump-probe spectroscopy, and, finally, (iii) the effect of ionization on the dynamic polarizability of H(2) when calculated nonperturbatively by TD-CIS. PMID- 19778111 TI - Structural characterization of (C(2)H(2))(1-6) (+) cluster ions by vibrational predissociation spectroscopy. AB - Vibrational predissociation spectra are reported for the cationic acetylene clusters, (C(2)H(2))(n) (+), n=1-6, in the region of the C-H stretching fundamentals. For n=1 and 2, predissociation could only be observed for the Ar tagged clusters. These were prepared by charge-transfer collisions of Ar(k) (+) with C(2)H(2) to create C(2)H(2) (+)Ar(m) clusters, which were then converted into larger members of the (C(2)H(2))(n) (+)Ar series by sequential addition of acetylene molecules. The (C(2)H(2))(2) (+)Ar spectrum indicates that this species is predominantly present as the cyclobutadiene cation. Although mobility measurements on the electron-impact-generated (C(2)H(2))(3) (+) ion indicated that it primarily occurs as the benzene cation, [P. O. Momoh, J. Am. Chem. Soc. 128, 12408 (2006)] photofragmentation of (C(2)H(2))(3) (+)Ar in the C-H stretching region is dominated by the loss of C(2)H(2) in addition to the weakly bound Ar atom. This suggests that the dominant n=3 species formed by sequential addition of C(2)H(2) is based on a covalently bound C(4)H(4) (+) core ion. Interestingly, the spectrum of this core C(4)H(4) (+) species is different from that found for the cyclobutadiene cation, displaying instead a new band pattern that is retained in the higher (C(2)H(2))(3-6) (+) clusters. Multiple isomers are clearly involved, as yet another pattern of bands is recovered when the (C(2)H(2))(3) (+)Ar action spectrum is recorded in the (minor) Ar loss fragmentation channel. One of these features does appear in the location of the single band characteristic of the Ar-tagged benzene cation reported earlier [Phys. Chem. Chem. Phys. 4, 24 (2002)], supporting a scenario where the benzene cation is one of the isomers present. We then compare the Ar predissociation results with (C(2)H(2))(n) (+) spectra obtained when the ions are prepared by electron impact ionization of neutral acetylene clusters. The photofragmentation behavior and vibrational spectra indicate that the dominant species formed in this way also occur with a covalently bound C(4)H(4) (+) core. There are absorptions, however, which are consistent with a minor contribution from (C(2)H(2))(n) (+) clusters based on the benzene cation. PMID- 19778113 TI - Cross sections for electron impact excitation of the C (1)Pi and D (1)Sigma(+) electronic states in N(2)O. AB - Differential and integral cross sections for electron-impact excitation of the dipole-allowed C (1)Pi and D (1)Sigma(+) electronic states of nitrous oxide have been measured. The differential cross sections were determined by analysis of normalized energy-loss spectra obtained using a crossed-beam apparatus at six electron energies in the range 15-200 eV. Integral cross sections were subsequently derived from these data. The present work was undertaken in order to check both the validity of the only other comprehensive experimental study into these excitation processes [Marinkovic et al., J. Phys. B 32, 1949 (1998)] and to extend the energy range of those data. Agreement with the earlier data, particularly at the lower common energies, was typically found to be fair. In addition, the BEf-scaling approach [Kim, J. Chem. Phys. 126, 064305 (2007)] is used to calculate integral cross sections for the C (1)Pi and D (1)Sigma(+) states, from their respective thresholds to 5000 eV. In general, good agreement is found between the experimental integral cross sections and those calculated within the BEf-scaling paradigm, the only exception being at the lowest energies of this study. Finally, optical oscillator strengths, also determined as a part of the present investigations, were found to be in fair accordance with previous corresponding determinations. PMID- 19778112 TI - Postionization fragmentation of rare-gas trimers revisited with new theoretical approaches. AB - A new theoretical approach is presented for the general treatment of nonadiabatic hybrid dynamics (mixing classical and quantum approach) and applied to the postionization of rare-gas trimers. There was an important disagreement between trajectory surface hopping (TSH) or mean field (MF) approaches and the experimental results; noteworthy, with the new method qualitative and almost quantitative agreement is found for the fragmentation ratios of ionic monomers and dimers. For the first time in the theory as in the experiment, the dimers prevail for argon while monomers strongly dominate for the heavier rare gases, krypton and xenon. A new compromise between MF and TSH approaches is proposed and the new method is found quite robust with results not too sensitive to various possible implementations. PMID- 19778114 TI - Must Kohn-Sham oscillator strengths be accurate at threshold? AB - The exact ground-state Kohn-Sham (KS) potential for the helium atom is known from accurate wave function calculations of the ground-state density. The threshold for photoabsorption from this potential matches the physical system exactly. By carefully studying its absorption spectrum, we show the answer to the title question is no. To address this problem in detail, we generate a highly accurate simple fit of a two-electron spectrum near the threshold, and apply the method to both the experimental spectrum and that of the exact ground-state Kohn-Sham potential. PMID- 19778115 TI - Dissociation dynamics of C(6)H(6) and C(6)H(5)F molecules following carbon 1s and fluorine 1s photoionization studied by three-dimensional momentum imaging method. AB - Benzene and fluorobenzene molecules were multiply ionized through Auger decay following from the C 1s or the F 1s photoionization and their subsequent dissociations were studied utilizing position-sensitive time-of-flight measurements. The angular correlation between the momenta of (H(+)-H(+)) and (H(+)-F(+)) fragment ions derived from the multiply ionized benzene or fluorobenzene clearly reflects the hexagonal structure of the parent molecules, though the dissociations are not described by the simple Coulomb explosion model. Also, analysis on the planarity between the momentum of H(+), C(+), and F(+) reveals that these three ions are emitted almost in a single plane. PMID- 19778116 TI - Heavy atom nitroxyl radicals. I: An ab initio study of the ground and lower electronic excited states of the H(2)As=O free radical. AB - A series of ab initio calculations have been undertaken to predict the spectroscopic properties of the ground and first two excited states of the recently discovered arsenyl (H(2)AsO) free radical. This 13 valence electron species can be viewed as similar to the formaldehyde radical anion with a ground state electron configuration of cdots, three dots, centered(pi)(2)(n)(2)(pi( *))(1). The arsenyl radical is nonplanar (pyramidal) in the ground state with a 59 degrees out-of-plane angle and a 1.67 A AsO bond length. It has a low-lying n pi( *)(A (2)A(")) excited state (T(e) approximately 5000 cm(-1)) which has a much larger out-of-plane angle (86 degrees ) and longer AsO bond length (1.81 A). The pi-pi( *)(B (2)A(')) excited state at approximately 20 500 cm(-1) is less pyramidal (out-of-plane angle=70 degrees ) and has a somewhat shorter AsO bond (1.77 A). Similar trends are found for the H(2)PO and H(2)NO free radicals, although the latter has a planar ground state, due to sp(2) hybridization of the N atom, and a very long B state AsO bond length. The geometric variations of the ground and excited states of the H(2)EO (E=N, P, As) radicals, as well as the ground states of the corresponding anions and cations, can be readily rationalized from the Walsh diagram of the anion. The variations in the E-O bond length are a result of changes in both the orbital occupancy and pyramidalization of the molecule. The results of the present work have been employed in the analysis of the B (2)A(')-X (2)A(') electronic band system of the H(2)AsO free radical as reported in the companion paper. PMID- 19778117 TI - Heavy atom nitroxyl radicals. II: Spectroscopic detection of H(2)As=O, the prototypical arsenyl free radical. AB - The previously unknown arsenyl (H(2)AsO) free radical has been identified in the gas phase through a combination of laser-induced fluorescence and single vibronic level emission spectroscopy in a supersonic expansion. Three isotopologues, H(2)AsO, HDAsO, and D(2)AsO have been detected as products of an electric discharge in mixtures of arsine or deuterated arsines, CO(2), and argon. The observed spectra are assigned as due to the B (2)A(')-X (2)A(') electronic transition in which an electron in the ground state pi orbital is promoted to the pi( *) orbital. Rotational analysis of high-resolution spectra proves that the radical is nonplanar in both electronic states with the following r(0) structures: r(")(As-H)=1.513(4) A, r(")(As-O)=1.672(1) A, theta(")(HAsH)=101.8(4) degrees , ground state out-of-plane angle=63.1 degrees ; r(')(As-H)=1.525(10) A, r(')(As-O)=1.806(3) A, theta(')(HAsH)=93.4(10) degrees , and excited state out-of plane angle=70.7 degrees . Small hyperfine splittings in the spectra have enabled the determination of the arsenic Fermi contact parameter in both states. The results of our ab initio studies of the ground and excited state of this radical (see immediately preceding paper) are in good agreement with the spectroscopic analysis. PMID- 19778118 TI - Density-functional study of structural, electronic, and magnetic properties of the EuSi(n) (n=1-13) clusters. AB - The geometries, stabilities, and electronic and magnetic properties of europium encapsulated EuSi(n) (n=1-13) clusters have been investigated systematically by using relativistic density functional theory with generalized gradient approximation. Starting from n=12, the Eu atom completely falls into the center of the Si frame, i.e., EuSi(12) is the smallest fully endohedral Eu silicon cluster. The interesting finding is in good agreement with the recent experimental results on the photoelectron spectroscopy of the europium silicon clusters [A. Grubisic, H. P. Wang, Y. J. Ko, and K. H. Bowen, J. Chem. Phys. 129, 054302 (2008)]. The magnetic moments of the EuSi(n) (n=1-13) clusters are also studied, and the results show that the total magnetic moments of the EuSi(n) clusters and the magnetic moments on Eu do not quench when the Eu is encapsulated in the Si outer frame cage. It is concluded that most of the 4f electrons of the Eu atom in the EuSi(12) cluster do not interact with the silicon cage and the total magnetic moments are overwhelming majority contributed by the 4f electrons of the Eu atom. According to the binding energy per atom, the second difference in energy (Delta(2)E), and vertical ionization potential, the EuSi(n) (n=4,9,12) clusters are very stable. PMID- 19778119 TI - Strong double excitation and open-shell features in the near-edge x-ray absorption fine structure spectroscopy of ferrocene and ferrocenium compounds. AB - We have recorded the iron 2p and carbon 1s near-edge x-ray absorption fine structure (NEXAFS) spectra of decamethyl ferrocene (Fe 3d(6)) and ferrocenium hexafluorophosphate (Fe 3d(5)), two low spin compounds with closed- and open shell electron configurations, respectively. These species have a similar covalent bonding environment but a different electron configuration, allowing us to examine the role of ligand-metal interactions and electron correlation responsible for their NEXAFS spectra. We have interpreted these spectra with the aid of ab initio configuration interaction (CI) calculations. The CI calculations indicate that double excitation is essential to interpret the Fe 2p NEXAFS spectra of not only the open-shell ferrocenium ion but also the closed-shell ferrocene species, even though the ground states of both species are well described within the Hartree-Fock single-configuration approximation. PMID- 19778120 TI - Fragmentation patterns of doubly charged acrylonitrile molecule following carbon core ionization. AB - Dissociation of acrylonitrile into pairs of cations and neutral fragments following molecular core ionization was investigated using the photoelectron photoion-photoion coincidence (PEPIPICO) technique. The fragment ion mass spectra were recorded in coincidence with the carbon 1s photoelectrons. Deuterated and (13)C-substituted samples were used for resolving fragment mass ambiguities. Slope analysis of the PEPIPICO patterns was used in determining the fragment separation sequences in case of multiparticle processes. The results show that there are several fragmentation channels producing a wide range of charged coincident fragments. The dynamics of the dominant fragmentation processes is investigated in detail. PMID- 19778121 TI - The permanent electric dipole moments of cobalt monofluoride, CoF, and monohydride, CoH. AB - The optical Stark spectra of the R(4) and Q(4) lines of the [18.8](3)Phi(4)-X (3)Phi(4)(0,0) band systems of cobalt monofluoride, CoF, and the A(') (3)Phi(4)-X (3)Phi(4)(0,0) band systems of cobalt monohydride, CoH, have been recorded using laser induced fluorescence technique. The shifts and splittings caused by the static electric field have been analyzed to give the permanent electric dipole moments, mu(e), of 4.51(5) and 2.82(5) D for the [18.8](3)Phi(4) and X (3)Phi(4) states of CoF, and 0.01(8) and 1.88(8) D for the A(') (3)Phi(4) and X (3)Phi(4) states of CoH. The experimental dipole moments are compared with theoretical predictions. A molecular orbital correlation description is used to explain the relative ground state mu(e) values for CoH and CoF. PMID- 19778122 TI - Remarkable two-photon absorption in open-shell singlet systems. AB - Remarkable enhancement of two-photon absorption (TPA) peak is theoretically predicted in symmetric open-shell singlet diradical systems with intermediate diradical character as compared to closed-shell and pure diradical systems. It is revealed that the largest TPA peak intensities occur for open-shell singlet diradicals having a ferromagnetically coupled ground state and strongly depend on the ratio between damping factors of the excited states. This result confirms that open-shell singlet conjugated molecules with intermediate diradical characters have precedence over conventional closed-shell conjugated systems in resonant third-order nonlinear optical properties. PMID- 19778123 TI - Anomalous properties of the local dynamics in polymer glasses. AB - We show how changes in a local, high frequency dynamic process are correlated with the macroscopic behavior of glassy polymers. Polyvinylethylenes vitrified by different chemical and thermodynamic pathways exhibit different densities in the glassy state. We find that the rate and amplitude of a high frequency relaxation mode (the Johari-Goldstein process involving local motion of segments of the chain backbone) can either correlate or anticorrelate with the density. This implies that neither the unoccupied (free) volume nor the configurational entropy governs the local dynamics in any general sense. Rather it is the magnitude of the fluctuations in local density that underlie these nanometer-scale motions. We show how properties of the dynamics and the density fluctuations can both be interpreted in terms of an asymmetric double well potential. Although the results herein are for polymers, the principles are expected to be generally applicable to glassy materials. PMID- 19778124 TI - High-density amorphous ice: Molecular dynamics simulations of the glass transition at 0.3 GPa. AB - Based on several force fields (COMPASS, modified TIP3P and SPC/E) high-density amorphous ice is simulated by use of isothermal-isobaric molecular dynamics at a pressure of p approximately 0.3 GPa in the temperature range from 70 to 300 K. Starting at low temperature a large number of heating/cooling cycles are performed and several characteristic properties (density, total energy, and mobility) are traced as functions of temperature. While the first cycles are showing irreversible structural relaxation effects data points from further cycles are reproducible and give clear evidence for the existence of a glass-to liquid transition. Although, the observed transition temperatures T(g) are dependent on the actual force field used and slightly dependent on the method adopted the results indicate that high-density amorphous ices may indeed be low temperature structural proxies of ultraviscous high-density liquids. PMID- 19778125 TI - Pressure-induced collapse of ice clathrate and hexagonal ice mixtures formed by freezing. AB - We report thermal conductivity kappa measurements of the pressure-induced collapse of two mixtures of ice and tetrahydrofuran (THF) clathrate hydrate formed by freezing aqueous solutions, THF23 H(2)O and THF20 H(2)O, one containing twice as much excess water than the other. On pressurizing, kappa of the solid mixture first decreases at the onset pressure of approximately 0.8 GPa, as occurs for collapse of pure ice, reaches a local minimum at a pressure of approximately 1.0 GPa, and then increases as occurs for the collapse of the pure clathrate THF17 H(2)O. This shows that in the apparently homogeneous mixture, the ice and the clathrate collapse as if the two were in a mechanically mixed state. The manner in which the clathrate aggregate can arrange in the solid indicates that ice occupies the interstitial space in the tightly packed aggregates and H(2)O molecules belonging to the lattice of one form hydrogen bond with that of the other, a feature that is preserved in their collapsed states. On decompression, the original clathrate is partially recovered in the THF20 H(2)O mixture, but the collapsed ice does not transform to the low density amorph. We surmise that on irreversible transformation to the original clathrate, the aggregates expand. Any pressure thus exerted on the small domains of the collapsed ice with a hydrogen bonded interface with the clathrate aggregates could prevent it from transforming to the low density amorph. Measurements of kappa are useful in investigating structural collapse of crystals when dilatometry is unable to do so, as kappa seems to be more sensitive to pressure-induced changes than the volume. PMID- 19778126 TI - On the dielectric conductivity of molecular ionic liquids. AB - The contribution of the conductivity to the spectrum of the generalized dielectric constant or susceptibility of molecular ionic liquids is analyzed, both in theoretical terms and computationally by means of molecular dynamics simulation of the concrete system 1-ethyl-3-methyl-imidazolium dicyanoamide at 300 K. As a central quantity the simulated current autocorrelation function is modeled by a carefully designed fit function. This not only gives a satisfactory numerical representation but yields the correct conductivity upon integration. In addition the fit function can be Fourier-Laplace transformed analytically. Both, the real and imaginary parts of the transform show expected behavior, in particular, the right limits for zero frequency. This altogether demonstrates that the components of the fit function are of physical relevance. PMID- 19778127 TI - Thermodiffusion in multicomponent hydrocarbon mixtures: Experimental investigations and computational analysis. AB - In an unprecedented experimental investigation, a ternary and a four component hydrocarbon mixture at high pressure have been studied in a nearly convection free environment to understand the thermodiffusion process. A binary mixture has also been investigated in this environment. Experimental investigations of the three mixtures have been conducted in space onboard the spacecraft FOTON-M3 thereby isolating the gravity-induced convection that otherwise interferes with thermodiffusion experiments on Earth. The experimental results have also been used to test a thermodiffusion model that has been calibrated based on the results of previous experimental investigations. It was found that with an increase in the number of components in the mixtures, the performance of the thermodiffusion model deteriorated. Computational analysis was also made to estimate the possible sources of errors. Simulations showed that the vibrations of the spacecraft could influence the estimates of thermodiffusion factors. It was also found that they are sensitive to slight variations in the temperature of the mixture. PMID- 19778128 TI - Crossover from nucleation to spinodal decomposition in a condensing vapor. AB - The mechanism controlling the initial step of a phase transition has a tremendous influence on the emerging phase. We study the crossover from a purely nucleation controlled transition toward spinodal decomposition in a condensing Lennard-Jones vapor using molecular dynamics simulations. We analyze both the kinetics and at the same time the thermodynamics by directly reconstructing the free energy of cluster formation. We estimate the location of the spinodal, which lies at much deeper supersaturations than expected. Moreover, the nucleation barriers we find differ only by a constant from the classical nucleation theory predictions and are in very good agreement with semiempirical scaling relations. In the regime from very small barriers to the spinodal, growth controls the rate of the transition but not its nature because the activation barrier has not yet vanished. Finally, we discuss in detail the influence of the chosen reaction coordinate on the interpretation of such simulation results. PMID- 19778129 TI - Theoretical study of phase transitions in Kr and Ar clathrate hydrates from structure II to structure I under pressure. AB - The theory developed in our earlier papers is extended to predict dynamical and thermodynamic properties of clathrate structures by accounting for the possibility of multiple filling of cavities by guest molecules. The method is applied to the thermodynamic properties of argon and krypton hydrates, considering both structures I (sI) and II (sII), in which the small cages can be singly occupied and large cages of sII can be singly or doubly occupied. It was confirmed that the structure of the clathrate hydrate is determined by two main factors: intermolecular interaction between guest and host molecules and the configurational entropy. It is shown that for guests weakly interacting with water molecules, such as argon or krypton, the free energy of host lattices without the contribution of entropy is the main structure-determining factor for clathrate hydrates, and it is a cause of hydrate sII formation at low pressure with these guests. Explicit account of the entropy contribution in the Gibbs free energy allows one to determine the stability of hydrate phases and to estimate the line of structural transition from sII to sI in P-T plane. The structural transition between sII and sI in argon and krypton hydrates at high pressure is shown to be the consequence of increasing intermolecular interaction and the degree of occupancy of the large cavities. PMID- 19778131 TI - Auto-oligomerization and hydration of pyrrole revealed by x-ray absorption spectroscopy. AB - Near edge x-ray absorption fine structure spectra have been measured at the carbon and nitrogen K-edges of the prototypical aromatic molecule, pyrrole, both in the gas phase and when solvated in water, and compared with spectra simulated using a combination of classical molecular dynamics and first principles density functional theory in the excited state core hole approximation. The excellent agreement enabled detailed assignments. Pyrrole is highly reactive, particularly in water, and reaction products formed by the auto-oligomerization of pyrrole are identified. The solvated spectra have been measured at two different temperatures, indicating that the final states remain largely unaffected by both hydration and temperature. This is somewhat unexpected, since the nitrogen in pyrrole can donate a hydrogen bond to water. PMID- 19778130 TI - Static and alternating electric field and distance-dependent effects on carbon nanotube-assisted water self-diffusion across lipid membranes. AB - Water-self-diffusion through single-walled carbon nanotubes (SWCNTs) inserted normal to a phospholipid membrane has been studied using equilibrium and nonequilibrium molecular dynamics simulations in the presence of static and alternating electrical fields. Four different SWCNTs were investigated: (5,5), (6,6), (8,8), and (11,11) and also three arrays of four (6,6) SWCNTs separated by 15, 20, and 25 A, respectively. The (5,5) system shows interesting behavior, where an increase in the applied field frequency in the z direction decreases the water permeation rates, reaching values at higher frequencies similar to zero field conditions. The (6,6) arrays simulations demonstrated that there is a friction effect, when the nanotubes are closely packed, which retards the movement of the individual water files. PMID- 19778132 TI - Formation mechanisms of oxygen atoms in the O((1)D(2)) state from the 157 nm photoirradiation of amorphous water ice at 90 K. AB - Vacuum ultraviolet photolysis of water ice in the first absorption band was studied at 157 nm. Translational and internal energy distributions of the desorbed species, O((1)D) and OH(v=0,1), were directly measured with resonance enhanced multiphoton ionization method. Two different mechanisms are discussed for desorption of electronically excited O((1)D) atoms from the ice surface. One is unimolecular dissociation of H(2)O to H(2)+O((1)D) as a primary photoprocess. The other is the surface recombination reaction of hot OH radicals that are produced from photodissociation of hydrogen peroxide as a secondary photoprocess. H(2)O(2) is one of the major photoproducts in the vacuum ultraviolet photolysis of water ice. PMID- 19778134 TI - Transition path sampling of water exchange rates and mechanisms around aqueous ions. AB - The rates and mechanisms of water exchange around two aqueous ions, namely, Na(+) and Fe(2+), have been determined using transition path sampling. In particular, the pressure dependence of the water exchange rates was computed to determine activation volumes. A common approach for calculating water exchange rates, the reactive flux method, was also employed and the two methods were compared. The water exchange rate around Na(+) is fast enough to be calculated by direct molecular dynamics simulations, thus providing a reference for comparison. Both approaches predicted exchange rates and activation volumes in agreement with the direct simulation results. Four additional sodium potential models were considered to compare the results of this work with the only activation volume for Na(+) previously determined from molecular simulation [D. Spangberg et al., Chem. Phys. Lett. 276, 114 (1997)] and provide the best possible estimate of the activation volume based on the ability of the models to reproduce known properties of the aqueous sodium ion. The Spangberg and Hermansson [D. Spangberg and K. Hermansson, J. Chem. Phys. 120, 4829 (2004)] and X-Plor/Charmm-22 [M. Patra and M. Karttunen, J. Comput. Chem. 25, 678 (2004)] models performed best and predicted activation volumes of -0.22 and -0.78 cm(3) mol(-1), respectively. For water exchange around Fe(2+), transition path sampling predicts an activation volume of +3.8 cm(3) mol(-1), in excellent agreement with the available experimental data. The potential of mean force calculation in the reactive flux approach, however, failed to sufficiently sample appropriate transition pathways and the opposite pressure dependence of the rate was predicted as a result. Analysis of the reactive trajectories obtained with the transition path sampling approach suggests that the Fe(2+) exchange reaction takes place via an associative interchange mechanism, which goes against the conventional mechanistic interpretation of a positive activation volume. Collectively, considerable insight was obtained not only for the exchange rates and mechanisms for Na(+) and Fe(2+) but also for identifying the most robust modeling strategy for these purposes. PMID- 19778133 TI - Formation mechanisms of oxygen atoms in the O((3)P(J)) state from the 157 nm photoirradiation of amorphous water ice at 90 K. AB - Desorption of ground state O((3)P(J=2,1,0)) atoms following the vacuum ultraviolet photolysis of water ice in the first absorption band was directly measured with resonance-enhanced multiphoton ionization (REMPI) method. Based on their translational energy distributions and evolution behavior, two different formation mechanisms are proposed: One is exothermic recombination reaction of OH radicals, OH+OH-->H(2)O+O((3)P(J)) and the other is the photodissociation of OH radicals on the surface of amorphous solid water. The translational and internal energy distributions of OH radicals as well as the evolution behavior were also measured by REMPI to elucidate the roles of H(2)O(2) and OH in the O((3)P(J)) formation mechanisms. PMID- 19778135 TI - Glass formation and structure in the MgSiO(3)-Mg(2)SiO(4) pseudobinary system: From degraded networks to ioniclike glasses. AB - A series of glasses xMgO-(1-x)SiO(2) with compositions from enstatite MgSiO(3) (x=0.5) to forsterite Mg(2)SiO(4) (x=0.667) in mole fraction intervals of x approximately 0.02 have been prepared by containerless levitation techniques and CO(2) laser heating. Polarized and depolarized Raman spectra measured at ambient conditions for all these glasses show systematic and smooth band intensity changes with composition. Analysis of the Raman band contours in terms of vibrations due to different oxygen bridged SiO(4) tetrahedra (Q(i), species analysis) undoubtedly shows that bridging oxygens are present in all glasses studied even in the limit of the forsterite composition where bridged Si(2)O(7) (6-) ionic dimers are formed. Furthermore the relative amounts of the Q(i) species change smoothly with composition while at high MgO content "free" oxygens are present presumably forming Mg-O-Mg bridges, which contribute to the glass stability at these compositions. Raman spectra measurements at different temperature below T(g) show small alterations in the Q(i) species in the MgSiO(3) region while no changes were observed in the Mg(2)SiO(4) region. The Boson peak frequency is practically invariant on both composition and temperature and this is in contrast to the systematics followed by most silicate glasses. It is suggested that at compositions near the forsterite ioniclike glasses are formed arising from a very fragile liquid. PMID- 19778136 TI - Cluster size effects on sintering, CO adsorption, and implantation in Ir/SiO(2). AB - A series of planar model catalysts have been prepared via deposition of Ir(n) (+) on thermally grown amorphous SiO(2)/Si(100) and ion scattering spectroscopy was used to probe surface structure as a function of cluster size, impact energy, and surface temperature. Deposition of Ir(2) or Ir(10) at low energies and room temperature results in stable clusters forming one- or two-dimensional single layer islands on the oxide surface. Heating the samples to 750 K leads to agglomeration, forming multilayer structures on the surface. Ir(1) deposited under similar conditions sinters into large clusters at room temperature. Deposition at 110 K at least partially stabilizes the Ir atoms with respect to diffusion and sintering. At higher deposition energies, partial implantation into the surface is observed, but this appears to be insufficient to stabilize the clusters against sintering at elevated temperature. At low temperatures, substrate-mediated adsorption of CO is found to be highly efficient, leading to near saturation coverages of CO bound atop the Ir(n) clusters. The CO can be removed by careful He(+) sputtering. The deposition/binding behavior of Ir(n) on SiO(2) is quite different from Ir(n)/TiO(2)(110), for which the clusters bind in three-dimensional morphology, starting at Ir(5). That system also shows substrate mediated adsorption of CO, but the CO preferentially binds at the periphery of the clusters rather than on top. PMID- 19778137 TI - What zeroth-order Hamiltonian for CASPT2 adiabatic energetics of Fe(II)N(6) architectures? AB - Complete active space self-consistent field (CASSCF) calculations and subsequent second-order perturbative treatment (CASPT2) have been carried out on a series of metallic complexes based on a Fe(II)N(6) core. These compounds play a determinant role in the elaboration of potential bistable architectures such as spin crossover materials. The adiabatic energies between the high-spin (HS) (S=2) and low-spin (LS) (S=0) states are evaluated with respect to the value of the shift ionization potential-electronic affinity (IPEA shift) recently introduced in the zeroth-order Hamiltonian [Ghigo et al., Chem. Phys. Lett. 396, 142 (2004)]. Based upon a series of experimental data, it is concluded that the commonly applied IPEA shift value (0.25 a.u.) is not satisfactory to properly discriminate the open-shell HS and closed-shell LS states. We suggest that a 0.50-0.70 a.u. value would be preferable for these specific adiabatic gap calculations. PMID- 19778138 TI - Vibration-induced inelastic effects in the electron transport through multisite molecular bridges. AB - We theoretically analyzed inelastic effects in the electron transport through molecular junctions originating from electron-vibron interactions. The molecular bridge was simulated by a periodical chain of identical hydrogenlike atoms with the nearest neighbors interaction thus providing a set of energy states for the electron tunneling. To avoid difficulties inevitably arising when advanced computational techniques are employed to study inelastic electron transport through multilevel bridges, we propose and develop a semiphenomenological approach. The latter is based on Buttiker's dephasing model within the scattering matrix formalism. We apply the proposed approach to describe features associated with electron energy transfer to vibrational phonons that appear in the second derivative of the current in the junction with respect to the bias voltage. In the particular case of a single level bridge our results agree with those obtained by proper calculations carried out within the nonequilibrium Green's functions method indicating the usefulness of the suggested approach. PMID- 19778139 TI - Slow kinetics of phase transformation in a dipole-functionalized discotic liquid crystal. AB - The kinetics of phase transformation from the liquid crystalline mesophase to the crystalline phase has been studied in a model dipole-functionalized hexabenzocoronene derivative by x-ray diffraction, solid state NMR recoupling techniques, and dielectric spectroscopy. These probes revealed long-lived metastability and an intermediate state involving a change in the unit cell prior to crystallization. The barrier properties were dominant and amount to 1 and 2.5 eV, respectively, for the unit cell transformation and crystallization processes. These effects should be considered in the design of discotic liquid crystals for electronic applications. PMID- 19778140 TI - Crystalline-to-plastic phase transitions in molecularly thin n-dotriacontane films adsorbed on solid surfaces. AB - Crystalline-to-rotator phase transitions have been widely studied in bulk hydrocarbons, in particular in normal alkanes. But few studies of these transitions deal with molecularly thin films of pure n-alkanes on solid substrates. In this work, we were able to grow dotriacontane (n-C(32)H(66)) films without coexisting bulk particles, which allows us to isolate the contribution to the ellipsometric signal from a monolayer of molecules oriented with their long axis perpendicular to the SiO(2) surface. For these submonolayer films, we found a step in the ellipsometer signal at approximately 331 K, which we identify with a solid-solid phase transition. At higher coverages, we observed additional steps in the ellipsometric signal that we identify with a solid-solid phase transition in multilayer islands ( approximately 333 K) and with the transition to the rotator phase in bulk crystallites ( approximately 337 K), respectively. After considering three alternative explanations, we propose that the step upward in the ellipsometric signal observed at approximately 331 K on heating the submonolayer film is the signature of a transition from a perpendicular monolayer phase to a denser phase in which the alkane chains contain on average one to two gauche defects per molecule. PMID- 19778141 TI - Defect-induced chemisorption of nitrogen oxides on (10,0) single-walled carbon nanotubes: Insights from density functional calculations. AB - The interactions of NO(x) (x=1,2,3) with the defective semiconducting (10,0) carbon nanotubes were studied by the density functional theory. Optimized geometries, binding energies, and electronic structures of the NO(x)-adsorbed nanotubes were determined on the basis of calculations. Effects of the defect density and the electric field on the binding energy and charge transfer have been investigated. In sharp contrast with the case of perfect nanotube, the adsorption of NO(x) at the defect site of (10,0) tube is generally chemical, and after the chemisorption of one NO(2) or one NO(3) the carbon nanotubes with various defects behave as conductors, while the consecutive adsorption of the second NO(2) or the second NO(3) makes these tubes become semiconductors again. Calculations show that the NO(2) adsorption at a topological defect is a barrier free process, while the NO(3) adsorption experiences a barrier due to transition of the pi<-->s electronic configuration of the NO(3) moiety. PMID- 19778142 TI - Photophysics and rotational relaxation dynamics of cationic phenazinium dyes in anionic reverse micelles: Effect of methyl substitution. AB - We present here, a detailed photophysical and rotational relaxation dynamical study of three structurally analogous cationic dyes, namely, phenosafranin (PSF), safranin-T (ST), and safranin-O (SO), carried out in well characterized, monodispersed biomimicking anionic reverse micellar nanocavities composed of sodium bis(2-ethylhexyl)sulfosuccinate (AOT)/heptane with increasing water contents. The dyes belong to the phenazinium family and they differ in terms of methyl substitution on the planar phenazinium skeleton. The objective of the present study is to investigate the modification in the photophysical and dynamical behavior of the dyes with the change in the size of the water pool of the reverse micelle and thereby to explore the role of methyl substitution. Steady state and time resolved emission and anisotropy studies have been exploited for the purpose. The dyes are found to exhibit a marked decrease in the fluorescence anisotropy with increasing water/surfactant mole ratio (w), i.e., the water pool size in the reverse micellar core, implying that overall motional restriction experienced by the molecules are decreased with increasing hydration. Some of the depth dependent fluorescence parameters such as fluorescence maximum, fluorescence anisotropy (r) have been monitored for exploring the microenvironment around the probes in the reverse micelles. Fluorescence studies suggest that at low w values, the probes do not penetrate into the reverse micellar core; rather it binds at the interfacial region. Estimates of the micropolarity at the binding sites of the probe molecule have been determined as a function of w. Finally, dynamic studies reveal that both the lifetime and rotational relaxation time decrease with an increase in w for all the three probes, the extent of the decrease being more for PSF than ST and SO. This indicates a stronger binding of the reverse micelle with ST and SO compared to that with PSF which is rationalized in terms of an increase in the hydrophobicity of the former two dyes because of the methyl substitution on the phenazinium moiety. PMID- 19778143 TI - Orientational bonding model for temperature dependent micellization and solubility of diblock surfactants. AB - A lattice model for diblock surfactants that incorporates orientational bonding has been developed for studying self-assembly in dilute solutions. Using grand canonical Monte Carlo simulations with histogram reweighting and mixed field finite size scaling, we examine the effect of amphiphile architecture on phase transitions and distinguish between first order transitions that create a disordered liquid phase and higher order transitions that indicate the formation of finite sized aggregates. As the solution temperature increases, we find that the critical micelle concentration for the orientational bonding model surfactants reaches a minimum value at a temperature that can be controlled by varying the number of bonding orientations between the solvophobic surfactant monomers and the implicit solvent. This trend is qualitatively similar to experimental data for ionic and nonionic surfactants in aqueous solutions. A comparable dependence on temperature is observed in the limit of amphiphile solubility for phase separating systems. None of the model surfactants considered here undergo both a first and a higher order transition over the range of densities and temperatures examined. PMID- 19778144 TI - Determination of colloidal interaction potentials from small angle scattering data. AB - The scattering curves of monodisperse, globular particles measured by small angle scattering are products of a form factor and of a structure factor. The form factor contains the information on particle shape and size and can often be measured for dilute samples. The structure factor contains the contributions due to particle interactions. It should be approximated by a structure factor model based on the Percus-Yevik, hypernetted chain, or soft mean spherical approximation closure relations. Combining these relations with a flexible model for the interaction potential, it is possible to determine the interaction potential from the scattering data. Scattering curves of charged spherical colloids and of spheres interacting by depletion forces are therefore simulated and evaluated, resulting in potentials that are close to the ones used for the simulation. The applicability of the approach is finally tested on a 5% solution of lysozyme at pH 4.5, which gave an interaction potential that agreed well with the one expected for such a sample. PMID- 19778145 TI - Exact solution of the Poisson-Nernst-Planck equations in the linear regime. AB - Based on the Poisson-Nernst-Planck equations (PNP), the spatiotemporal charge, concentration profile, and the electric field in polyelectrolytes are analyzed. The system is subjected to a dc applied voltage. Different to recent papers we obtain an exact analytical solution of the PNP in the linear regime, which is characterized by an inevitable coupling between the spatial and the temporal behavior. In the long time limit the systems tends in a nonexponential manner to the steady state predicted by the Debye-Hueckel theory, where the time scale for the crossover into the steady state is determined by the Debye screening length and the initial concentration. The higher the initial concentration is the faster the system evolves into the stationary state. The Debye screening length characterizes not only the asymptotic behavior but also the spatiotemporal evolution of the system at finite times. Using experimental data the concentration profile and the electric field is shown to be on a master curve parametrized by the screening length. PMID- 19778146 TI - The structure of nanochannels formed by block copolymer solutions confined in nanotubes. AB - Monte Carlo simulations are employed to obtain information about the radius and the roughness of the inner surface of the channels, which are generated by a family of block copolymer solutions confined in nanotubes. The fluctuations of the above quantities also have been calculated. The simulations have been carried out by varying the interactions between various kinds of segments and those between segments and the wall of the nanotubes, as well as the chemical structure of the copolymer and the nanotube diameter. The present simulations provide insight regarding the structure of ionic and water channels formed by protein in the phospholipid bilayers of the cell membrane. PMID- 19778147 TI - Application of the entropy theory of glass formation to poly(alpha-olefins). AB - The entropy theory of glass formation, which has previously been developed to describe general classes of polymeric glass-forming liquids, is extended here to model the thermodynamic and dynamic properties of poly(alpha-olefins). By combining this thermodynamic theory with the Adam-Gibbs model (which relates the configurational entropy to the rate of structural relaxation), we provide systematic computations for all four characteristic temperatures (T(A), T(c), T(g), T(0)), governing the position and breadth of the glass transition, and the fragility parameters (D,m) describing the strength of the temperature dependence of the structural relaxation time, where T(A) is the temperature below which the relaxation is non-Arrhenius, T(c) is the crossover or empirical mode-coupling temperature, T(g) is the glass transition temperature, and T(0) is the temperature at which the extrapolated relaxation time diverges. These temperatures and fragility parameters are evaluated as a function of molar mass, pressure, and the length n of the alpha-olefin side chains. The nearest neighbor interaction energy and local chain rigidities are found to strongly influence the four characteristic temperatures and the low temperature fragility. We also observe an "internal plasticization" of the poly(alpha-olefins) wherein the fragility decreases as the number n of "flexible" side group units increases. Our computations provide solid support for a pressure counterpart of the Vogel Fulcher-Tammann relation. The entropy theory of glass formation predicts systematic changes in fragility with chain stiffness, cohesive energy, polymerization index, and side chain length, and qualitative trends in these parameters are discussed. PMID- 19778148 TI - Primitive chain network simulations for entangled DNA solutions. AB - Molecular theories for polymer rheology are based on conformational dynamics of the polymeric chain. Hence, measurements directly related to molecular conformations appear more appealing than indirect ones obtained from rheology. In this study, primitive chain network simulations are compared to experimental data of entangled DNA solutions [Teixeira et al., Macromolecules 40, 2461 (2007)]. In addition to rheological comparisons of both linear and nonlinear viscoelasticities, a molecular extension measure obtained by Teixeira et al. through fluorescent microscopy is compared to simulations, in terms of both averages and distributions. The influence of flow on conformational distributions has never been simulated for the case of entangled polymers, and how DNA molecular individualism extends to the entangled regime is not known. The linear viscoelastic response and the viscosity growth curve in the nonlinear regime are found in good agreement with data for various DNA concentrations. Conversely, the molecular extension measure shows significant departures, even under equilibrium conditions. The reason for such discrepancies remains unknown. PMID- 19778150 TI - A simple model of directional interactions for proteins. AB - We study a simple two patch model of globular protein solutions. The model consists of a hard sphere interaction, together with a weak isotropic attraction, decorated with stronger attractive patch-patch interactions. The isotropic and anisotropic attractions are modeled with square well potentials with an interaction range of 1.2sigma, where sigma is the hard sphere diameter. We have calculated its phase diagram and found a metastable fluid-fluid phase separation curve. We have also obtained the different stable crystal structures at various temperatures. The orientationally ordered, body-centered crystal (bcc-o) lattice is the crystal structure that has the lowest energy; it is stable at lower temperatures and moderate pressures. The orientationally ordered face-centered crystal (fcc) lattice has a higher energy and becomes stable with respect to bcc o at high pressures and lower temperatures. Finally, at high temperatures when the entropy effect becomes important, the orientational order is lost and an orientationally disordered fcc lattice becomes stable. PMID- 19778149 TI - Phase transitions of a single polymer chain: A Wang-Landau simulation study. AB - A single flexible homopolymer chain can assume a variety of conformations which can be broadly classified as expanded coil, collapsed globule, and compact crystallite. Here we study transitions between these conformational states for an interaction-site polymer chain comprised of N=128 square-well-sphere monomers with hard-sphere diameter sigma and square-well diameter lambdasigma. Wang-Landau sampling with bond-rebridging Monte Carlo moves is used to compute the density of states for this chain and both canonical and microcanonical analyses are used to identify and characterize phase transitions in this finite size system. The temperature-interaction range (i.e., T-lambda) phase diagram is constructed for lambda1.06 these two states are separated by an intervening collapsed globule phase and thus, with decreasing temperature a chain undergoes a continuous coil-globule (collapse) transition followed by a discontinuous globule-crystal (freezing) transition. For well diameters lambda<1.06 the collapse transition is pre-empted by the freezing transition and thus there is a direct first-order coil-crystal phase transition. These results confirm the recent prediction, based on a lattice polymer model, that a collapsed globule state is unstable with respect to a solid phase for flexible polymers with sufficiently short-range monomer-monomer interactions. PMID- 19778151 TI - How hydrophobic hydration responds to solute size and attractions: Theory and simulations. AB - We focus on the hydration of a methane and spherical single and multisite C60 and C180 solutes over a range of solute-water attractions to quantify the vicinal water structure and their hydration thermodynamics using extensive molecular dynamics simulations and theory. We show that water structure near larger solutes is more sensitive to solute-water attractions compared to that near smaller ones. To understand the sensitivity, we separate the solute-water potential of mean force into a direct solute-water interaction and an indirect or solvent contribution [omega(r)]. In the absence of omega(r), water density in the solute vicinity would increase exponentially with solute-water interactions. Instead, omega(r) becomes increasingly repulsive with strengthening of solute-water attractions thereby opposing those direct interactions. We term this phenomenon "competitive expulsion," which characterizes the repulsion of a test water molecule by the hydration shell solvent waters. We develop a physically motivated theoretical approach to predict changes in omega(r) with attractions. We call this approach the modified-EXP (M-EXP) approximation owing to the similarity of ideas and especially our final expression with that of the EXP approximation of Chandler and Andersen [J. Chem. Phys. 57, 1930 (1972)]. Solute-water radial distribution functions and chemical potentials calculated using the M-EXP approach are in good agreement with simulation data. These calculations highlight the sensitivity of hydration structure and thermodynamics of bucky ball like solutes to solute-water interactions. We find that excess chemical potentials of bucky balls with standard alkane-like carbon-water interactions parameters are negative, suggesting the need for a careful calibration of those parameters for predictions of solubility, wetting, and water-mediated interactions using molecular simulations. PMID- 19778152 TI - Induced fit for mRNA/TIS11d complex. AB - TIS11d tandem zinc finger (TZF) domain can bind the class II AU-rich element of target mRNA and regulate mRNA turnover by promoting or inhibiting degradation. NMR spectra show that TIS11d(TZF) undergoes a transition from disordered to well folded upon binding to Zn and mRNA. To gain an insight into the mechanism, we have performed explicit-solvent molecular dynamics simulations (MD) for both bound and apo-TIS11d(TZF) to study the interdependence of binding and folding in the mRNA-TIS11d(TZF) complex. These results are in qualitative agreement with NMR experiment. Furthermore, this method could be used to other study about protein folding upon ligand binding. PMID- 19778153 TI - Intersegment interactions and helix-coil transition within the generalized model of polypeptide chains approach. AB - The generalized model of polypeptide chains is extended to describe the helix coil transition in a system comprised of two chains interacting side-by-side. The Hamiltonian of the model takes into account four possible types of interactions between repeated units of the two chains, i.e., helix-helix, helix-coil, coil helix, and coil-coil. Analysis reveals when the energy I(hh)+I(cc) of (h-h, c-c) interactions overwhelms the energy I(hc)+I(ch) of mixed (h-c, c-h) interactions, the correlation length rises substantially, resulting in narrowing of the transition interval. In the opposite case, when I(hh)+I(cc) 0.05), MNCV in group 4 were significantly lower than in groups 2 and 3 (p < 0.05). NTE activities were significantly lower in PSP and PSP+lasalocid groups than in control and lasalocid group (p < 0.05). Onset of ataxia in group 4 appeared early and was exacerbated compared to groups 2 and 3. In conclusion, PSP and lasalocid could induce a significant decrease in MNCV and produce ataxia. Neuropathic OPs could be exacerbated by polyether ionophore lasalocid. PMID- 19778213 TI - Acute and subchronic toxicity of danshensu in mice and rats. AB - Danshensu (3-(3,4-dihydroxyphenyl) lactic acid), a natural phenolic acid, is isolated from Salvia miltiorrhiza root, and is the most widely used traditional Chinese medicine for the treatment of various cardiovascular diseases. It has been reported to have potential protective effects from oxidative injury. However, there is a little information about its possible toxicity. In this study, acute and subchronic toxicity of danshensu in mice and rats have been evaluated. In the acute study, danshensu intraveniouslly administered to rats failed to induce any signs of toxicity or mortality up to a maximum practical dosage of 1500 mg/kg body weight. Test substance administered acutely to mice caused dose-dependent general behavior adverse effects and mortality with the medial lethal dose of 2356.33 mg/kg. The no observed adverse effect level and the lowest observed adverse effect level were 1835 mg/kg and 2000 mg/kg, respectively. In the subchronic study, rats were tested by daily intraperitoneal injection of danshensu at the doses of 50, 150, and 450 mg/kg for 90 days, resulting in no mortality, no changes in body weight, food consumption, hematological and serum chemistry parameters, organ weights, or gross pathology or histopathology. The only treatment-related finding was transient writhing response observed in the 450 mg/kg group after administration. PMID- 19778212 TI - Role of inflammatory cytokines and DNA damage repair proteins in sulfur mustard exposed mice liver. AB - Sulfur mustard (bis-(2-chloroethyl) sulfide) is an alkylating agent, and produces blisters on skin and causes systemic toxicity and DNA strand breaks. The mechanism and role of inflammatory cytokines, receptors, and DNA damage signaling pathway specific genes were studied in sulfur mustard (SM) exposed mouse liver. Female mice were exposed percutaneously with 1.0 L.D50 of SM (8.1 mg/kg body weight). Inflammatory cytokine gene expression profiles were determined at 1 and 3 days post-exposure to SM and DNA damage signaling pathway specific, double strand break repair proteins gene expression profile at 1, 3, and 7 days were examined by DNA microarrays and semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). Anti-inflammatory cytokines and receptors were down-regulated from day 1 to day 3. Pro-inflammatory genes TNF-alpha, TNF receptors were up-regulated from day 1 to day 3. Double strand DNA break repair proteins Rad23, Rad50, Rad51, Rad52, and Rad54l were down-regulated from day 1 to day 7. This result indicates sulfur mustard causes inflammatory response, activates the cascade of events in the signal transduction pathway, and promotes irreversible double strand DNA breaks in chromosomal DNA, which is leading to cell death. PMID- 19778214 TI - Protective role of dark soy sauce against acrylamide-induced neurotoxicity in rats by antioxidative activity. AB - Dark soy sauce (DSS) exerts antioxidant activity in vitro or in vivo. To test the possibility of chemoprevention by such dietary supplements on acrylamide (ACR) induced subacute toxicity, Sprague-Dawley male rats were administered DSS dissolved in water (0.5 ml/kgbw x d) for 2 weeks after, before or during ACR exposure (0.2 mg/L in distillate water). DSS significantly improved the body weight gain, relative brain weights, and the gait abnormalities of ACR-treated rats when DSS treated at the same time as ACR-exposure (p < 0.05). DSS significantly improved the axonal degeneration, the ratio of myelinated nerves < 3 microm in diameter, degree of central chromatolysis of the ganglion neurons in peripheral nerves, and numbers of SYP (+) aberrant dots per mm cortex in the cerebellar molecular layer of ACR-treated rats no matter before, after, or during ACR-exposure (p < 0.05). DSS significantly decreased the malondialdehyde level and increased the superoxide dismutase activity in brain of ACR-treated rats when DSS treated during ACR-exposure (p < 0.05). These findings suggest that DSS plays a protective role against ACR-developed neurotoxicity and, partly at least, through an anti-oxidative mechanism. And it is worthy to note that DSS treatment at the same time as ACR exposure plays a more effective protective role than before or after ACR exposure. PMID- 19778215 TI - Post-mortem alcohol analysis in synovial fluid: an alternative method for estimation of blood alcohol level in medico-legal autopsies? AB - To evaluate the effectiveness of synovial fluid alcohol concentration in prediction of blood alcohol concentration, synovial fluid and blood was studied of 50 autopsy cases and the alcohol levels determined by using Head Space Gas Chromatography method. To exclude the effect of decomposition on alcohol levels, corpses with post-mortem intervals less than 24 hours and not showing signs of decomposition were selected. Of 50 cases, alcohol was detected in 15 cases both in blood and in synovial fluid. In 35 cases alcohol analysis was negative both in blood and synovial fluid. No false positive results were seen in terms of synovial fluid. In two of the 15 cases, the alcohol determined was methyl alcohol and in others the alcohol was ethyl alcohol. In these 15 cases, only in one case was SAC level lower than the BAC level, and in 14 cases; SAC levels were higher than those of BAC. BAC (Blood Alcohol Concentration)/SAC (Synovial Fluid Alcohol Concentration) ratios were determined, and in 13 ethanol cases the mean ratio was determined to be 0.95 (0.90 +/- 0.07). The regression analysis showed a fairly linear relationship between the BAC and SAC, with a correlation coefficient of 0.984 (y = 0.86x + 10.4). The present study demonstrates that the synovial fluid is a valuable body fluid that can be used in prediction of blood alcohol concentration in forensic autopsy cases in which blood can not be properly obtained. PMID- 19778216 TI - Looking back to the future: from the development of the gene concept to toxicogenomics. AB - Initial progress in the science of 'genetics' in the first half of the 20th century was mainly driven by studies utilizing mutations and consequent changes in phenotype. The structural and functional nature of the gene was far from being understood. That state of understanding started changing from the 1940s. In the following decades, with the discovery of the double helix followed by the discoveries on gene structure and expression, there was a period when the structural and functional aspects of the gene could be conceived in terms of one entity, the cistron. However, the discovery of intervening sequences caused this unified concept to fall apart, making the gene concept a subject of philosophical debate again. Meanwhile, over time, technological progress in molecular biology had the field forge ahead rapidly, ultimately leading to the sequencing of the human genome and genomes of other species, and giving birth to the science of genomics. Developments in genomics have given rise to certain applied sub disciplines like pharmacogenomics and toxicogenomics. While the full potential of pharmaco- and toxicogenomics is yet to be harnessed, they nevertheless have had an impact in drug development and safety assessment, such that the future promise of genomics seems achievable. At present, it is a good opportunity to revisit the path from the development of the initial gene concept and the philosophical debate surrounding the meaning of the term 'gene' to the current state of understanding of genes and genomes and their role in health and disease. PMID- 19778217 TI - hERG in vitro interchange factors--development and verification. AB - Literature data analysis shows that the hERG interactions experiments carried out in different conditions with use of different in vitro systems for the same substance can result with different IC50 values. One of the initial components of the proposed drug development supporting system is a set of extrapolation factors enabling the unrestricted choice of some elements of the experimental procedure without resultin significant depreciation. Therefore the main objective of this work was to develop the extrapolation factors allowing inter-system (HEK, CHO, XO) and inter-temperature (room and physiological) IC50 values comparison based on the collected and analyzed hERG IC50 data. The efficiency of the obtained factors was then verified in comparison with the native HEK IC50 values at the physiological temperature. Low values of all the error estimates for the proposed factors evidence their good predictive value which, in turn, ground their application during drug candidates' cardiotoxic risk evaluation or further in silico modeling. Utilization of the proposed factors during drug development process allows a more flexible choice of experimental model to exploit in the electrophysiological investigations, as well as makes it possible to experiment in ambient temperature, which is more convenient. The factors also facilitate data comparisons and allow one to draw reasonable conclusions for further extrapolation. PMID- 19778218 TI - Long-term exposure to various types of dietary fat modulates acrylamide-induced preneoplastic lesions of colon mucosa through Wnt/beta-catenin signaling in rats. AB - This study investigated whether various dietary fats affected the Wnt signaling pathway of preneoplastic lesions of colon mucosa in acrylamide (ACR)-treated rats. Male Sprague-Dawley rats were given intraperitoneal injections of ACR at a dose of 5 mg/kgbw and diets supplemented with 10% corn, olive, beef, or fish oil for 8 weeks; and then rats were still fed with diets supplemented with 10% oil for other 40 weeks. Aberrant crypt foci (ACF) were examined at 12 weeks post-ACR exposure. At 48 weeks, normal appearing colon mucosal proliferation and apoptosis were evaluated by 5-bromo-2'-deoxyuridine (BrdU) incorporation and percentages of fragmented DNA, respectively; the expressions of beta-catenin, cyclin D1, Wnt2, Wnt3, and Wnt5a of normal appearing colon mucosa were analyzed by Western blot analysis. Results from this study showed that long-term exposure of rats to dietary corn oil and beef tallow enhanced ACF formation in ACR rats. In contrast, olive and fish oil weakened the ACF formation. Dietary corn oil and beef tallow increased BrdU incorporation, expression of cytosolic beta-catenin and cyclin D1; and decreased apoptosis in the colon mucosa of ACR rats. ACR rats fed beef tallow showed increased expressions of Wnt2 and Wnt3. ACR rats fed corn oil showed increased expressions of Wnt5a. These findings suggest that long-term high intake of corn oil and beef tallow enhanced, whereas olive and fish oil weakened cell proliferation through Wnt signaling, which might contribute to promoting effects in preneoplastic lesions of colon mucosa. PMID- 19778219 TI - Quantitative evaluation in vivo of the degree of differentiation of hindlimb cartilage in a rat clubfoot model. AB - The Limb Morphogenetic Differentiation Scoring system introduced by Neubert and Barrach in 1977 has been used in drug testing as a measure of the degree of cartilage growth inhibition especially for forelimb in vitro. There is no scoring system to quantify the degree of hindlimb bud cartilage differentiation in vivo. A total of 60 female Sprague-Dawley rats weighing 220-250 g were assigned at random to six control groups and six experimental groups on day 0 of pregnancy. The experimental groups were treated with all-trans-retinoic acid (ATRA). A new limb morphogenetic differentiation scoring system was developed and used to quantify the degree of development of the hindlimb buds from the fetuses at embryonic days E13 to E18. The differentiation of cartilages assessed by the new scoring system showed a statistically significant difference between the experimental group and the control group from E13 to E18 (T-test, p < 0.05). Cartilage growth (the proximodistal length) in the control group increased gradually from E14, reaching its peak at E17, but in the experimental group the growth at E13, E16, E17, and E18 was significantly shorter (p < 0.05). In conclusion, the new limb morphogenetic differentiation scoring system described here can be used to quantify the degree of inhibition of the hindlimb bud development by teratogenic drugs or materials, and morphogenetic differentiation in vivo. PMID- 19778220 TI - Effect of Neem (Azadirchta indica) on serum glycoprotein contents of rats administered 1,2 dimethylhydrazine. AB - The present study was designed to investigate the effects of aqueous Azadirchta Indica leaf extract (AAILE) on serum glycoprotein contents and tumor incidence rate in colon of rats subjected to Dimethylhydrazine (DMH) treatment. Forty rats were divided equally and randomly into four groups viz., Group I (normal control), Group II (DMH-treated), Group III (AAILE) and Group IV (DMH + AAILE treated). Group II and IV animals were injected subcutaneously every week with DMH (30 mg/kg b.wt.) for two durations of 10 and 20 weeks. AAILE was given orally three times a week on alternate days (100 mg/kg b.wt.) to animals belonging to groups III and IV. Blood samples were drawn from all the animals by ocular vein puncture every month for the estimation of Total Sialic Acid (TSA) and Lipid Bound Sialic Acid (LSA), which served as markers for the cancer. No incidence of tumor was recorded in the animals given DMH treatment for 10 weeks. However, DMH treatment for 20 weeks showed 100% tumor incidence. Animals treated with DMH for both the time durations showed a significant increase in the levels of TSA in comparison to normal control, which however were decreased significantly following AAILE supplementation. There was no significant difference between LSA levels of DMH-treated animals and normal controls. The present study suggested that supplementation of AAILE in cancer-bearing animals attenuates considerably the molecular events that initiate the development of tumors. PMID- 19778221 TI - Nitrosative stress and glutathione redox system in four different tissues of alloxan-induced hyperglycemic animals. AB - In hyperglycemia a reduction of the antioxidant power and an increased production of nitric oxide (NO) have been reported. Because nitrotyrosine (NT) is a stable end-product of nitrosative stress, assessment of its concentration is considered a useful marker of NO-dependent damages. The level of nitrotyrosine and four antioxidant parameters were evaluated in pancreas, kidney, heart, and testis of alloxan-induced hyperglycemic rabbits after 6 and 10 weeks of persistent hyperglycemia. In hyperglycemic groups, the level of nitrotyrosine was elevated by 44 and 39%, 92 and 95%, and by 155 and 138% in pancreas, kidney, and heart, respectively, while the testicular level of NT was unaffected. The pancreatic activities of glutathione peroxidase (GPX) and catalase (CAT) increased by 64% and 50%, and by 49 and 70%, while the level of glutathione (GSH) and the activity of glutathione reductase (GR) decreased by 37 and 38%, and by 57 and 42%. In the kidney the significant changes occurred as decreases in GR activity and GSH level by 36 and 35%, and by 28 and 23%, respectively. In the heart, a significant increase in CAT activity by 90 and 23% was observed. In the testis, the CAT, GPX, and GR activities were increased by 67 and 77%, 72 and 27%, and 33 and 28%, respectively, while the level of GSH was increased by 22 and 17%. These results confirm that tissues from hyperglycemic animals differ in neutralizing nitrosative stress. This may be due to different adaptive responses of their glutathione redox cycle. PMID- 19778222 TI - Determination of acute and chronic effects of cadmium on the cardiovascular system of rats. AB - In this study, the systemic hemodynamics induced by acute and chronic cadmium (Cd+2) intoxication in the cardiovascular system of rats using thoracic electrical bioimpedance were examined and the acute and chronic effects of Cd+2 intoxication on the activities of antioxidant enzymes and malondialdehyde (MDA) were compared. Also, in this study, ultrastructural changes in the heart and aorta of rats were evaluated. Thirty-eight male Wistar albino rats were randomly divided into control, acute, and chronic groups. Chronic group was administered by oral gavage an aqueous solution of CdCl2 for 60 days, at dose of 15 mg Cd+2/kg/day. Acute group was administered by oral gavage an aqueous solution of CdCl2 with a single dose of 15 mg Cd+2/kg. Cadmium increased the stroke volume and cardiac output of rats in the chronic group, but did not change the heart rate significantly. Antioxidant enzymes activities and MDA level significantly increased in the chronic group. In ultrastructural examination, there were widespread degenerative changes in heart muscle cells of the chronic group but endothelial cells and smooth muscle cells in the aorta tissue samples had normal morphological features in all groups. All of the findings indicate that Cd+2 toxication can cause deformation in heart muscle cells due to an increase in free radicals and lipid peroxidation. Also, this study has confirmed that a long-term Cd+2 exposure increased stroke volume (SV) and cardiac output (CO), but did not change the heart rate (HR). PMID- 19778223 TI - Potentiation of neurotoxicity of Lathyrus sativus by manganese: alterations in blood-brain barrier permeability. AB - Environmental factors have been speculated to play an important role in potentiating the neurotoxicity of Lathyrus sativus (LS). Hence, blood-brain barrier permeability and neurotoxicity studies were carried out in manganese- and LS-exposed animals. Dietary feeding of LS (80%) plus Mn (0.4 mg/100 g diet) for 90 days to guinea pigs showed significant (p < 0.05) decrease in brain nucleotidase and ATPase activities when compared to control or LS alone treated groups. Combined treatment of LS and Mn showed a significant (p < 0.05) decrease in neuronal aryl hydrocarbon hydroxylase (36-40%), ethoxyresorufin-O-deethylase (40-45%), glutathione-S-transferase (27-31%), and quinone reductase (24-25%) activities when compared to control and LS alone treated animals. Lipid peroxidation, a marker for membrane damage, was found to be relatively more enhanced (58-141%) along with significant (p < 0.05) depletion of GSH levels in LS+Mn-treated animals when compared to control, Mn alone, and LS alone treated groups. The neuronal catalase activity of lathyrus plus Mn-treated animals showed a pronounced decrease (37-49%) when compared to control, Mn, and lathyrus alone treated groups. On the contrary, glutathione peroxidase in brain of Mn and lathyrus alone treated animals indicated a respective increase (p < 0.05) of 18% and 20%, while the combined effect of lathyrus plus Mn exhibited an increase of almost 50% when compared to control guinea pigs. Single parenteral administration of Mn (15 mg/kg b.wt) to guinea pigs followed by single oral intubation of beta-N oxalyl-L-alpha, beta-diamino propionic acid (ODAP, 75 mg/guinea pig) resulted in a significant increase (143%) in neuronal ODAP content. ODAP (50 mg/kg,iv) treatment to mice pretreated with MnCl2 (10 mg/kg b.wt for 3 days or 40 mg/kg b.wt for 1 day), caused an enhancement in blood-brain barrier (BBB) permeability (129-196%), while ODAP and Mn alone showed relatively less enhancement (66-87%). The lumbar region of LS+Mn showed a number of vacuolated areas of variegated size and chromatolytic neurons, along with a few degenerated neurons. These results suggest that Mn may potentiate the neurotoxicity of lathyrus/ODAP by altering the BBB permeability. PMID- 19778224 TI - Efficacy of two new asymmetric bispyridinium oximes (K-27 and K-48) in rats exposed to diisopropylfluorophosphate: comparison with pralidoxime, obidoxime, trimedoxime, methoxime, and HI-6. AB - Introduction. The new K-oximes, K-27 [1-(4-hydroxyimino-methylpyridinium)-4-(4 carbamoylpyridinium) propane dibromide] and K-48 [1-(4-hydroxyimino methylpyridinium)-4-(4-carbamoylpyridinium) butane dibromide], show good in vitro efficacy in protecting acetylcholinesterase from inhibition by different organophosphorus compounds (OPCs), including nerve agents. To assess their efficacy in vivo, the extent of oxime-conferred protection from mortality induced by diisopropylfluorophosphate (DFP) was quantified and compared with that of five established oximes. Materials and Methods. Rats received DFP intraperitoneally in a dosage of 6, 8, or 10 micromol/rat and immediately thereafter intraperitoneal injections of K-27, K-48, pralidoxime, obidoxime, trimedoxime, methoxime, or HI 6. The relative risk (RR) of death over time (48 h) was estimated by Cox survival analysis, comparing results with the no-treatment group. Results. Best protection was observed when K-27 was used, reducing the RR of death to 19% of control RR (p < or = 0.005), whereas obidoxime (RR = 26%, p < or = 0.01), K-48 (RR = 29%, p < or = 0.005) and methoxime (RR = 26%, p < or = 0.005) were comparable. The RR of death was reduced only to about 35% of control by HI-6, to 45% by trimedoxime, and to 59% by 2-PAM (p < or = 0.005). Whereas the differences between the best oximes (K-27, obidoxime, methoxime, and K-48) were not statistically significant; these four oximes were significantly more effective than 2-PAM (p < or = 0.05). The efficacy of K-27 was also significantly higher than that of HI-6, trimedoxime, and 2-PAM (p < or = 0.05). Conclusion. Our data provide further evidence that K-27 is a very promising candidate for the treatment of intoxication with a broad spectrum of OPCs. PMID- 19778225 TI - Comments on "Efficacy of two new asymmetric bispyridinium oximes (K-27 and K-48) in rats exposed to diisopropylfluorophosphate: comparison with pralidoxime, obidoxime, trimedoxime, methoxime, and HI 6". PMID- 19778227 TI - Investigation of the content and of the distribution of chemical elements in human nails by SRXRF. AB - The purpose of this investigation is to analyze 20 nails in individuals (and several persons) for the definition of how chemical elements distribute from nail to nail. The aim was to determine whether it will be rightful to take only one nail for the elemental analysis for the diagnostic of human state in future or not? Another purpose of the research is to analyze the elemental content of nails in temporal dynamic (in several persons). Analytical determinations of 20 nails of nine donors (healthy persons), nails of both hands and both feet were carried out. The analysis was performed by SRXRF. Symmetry of the elemental distribution in nails of right and left hands and right and left feet was found. The analysis of the distribution of chemical elements on the total area of a nail (55 points) was performed. The nail cutaway reflects adequately the distribution of several chemical elements over the nail plate area. In this study the elemental concentrations in nails of three donors in a 6-month period was determined. This study found the content of the chemical elements in donors' nails changes with time, individually. PMID- 19778228 TI - Effect of sulfite treatment on erythrocyte deformability in young and aged rats. AB - It is known that aging is associated with marked effects on integrity and function of cell membrane. These effects may also be exacerbated by exogenous chemicals, e.g. sulfite. Thus, the aim of this paper is to examine the influence of sulfite on hemorheological and related hematological parameters in rats of various ages. In this study, male Wistar rats at the age of 3 and 18 months were used and the following parameters were evaluated: Mean Cell Volume (MCV), Mean Corpuscular Hemoglobin Concentration (MCHC), Red blood Cell (RBC) deformability and aggregation. The results show that aging is associated with a decrease in RBC deformability and MCHC, an increase in MCV. Sulfite administration significantly increased RBC deformability in both young and aged rats. Although MCHC was decreased in young rats, it was increased in aged rats in response to sulfite exposure. Additionally, sulfite induced a decrement in MCV of aged rats. Neither aging nor sulfite treatment caused significant alterations in RBC aggregation parameters in all experimental groups. In conclusion, these findings suggest that RBC deformability impairs with age and sulfite has ameliorating effects on RBC deformability in both young and aged rats. PMID- 19778229 TI - Activity of antioxidative enzymes in erythrocytes after a single dose administration of doxorubicin in rats pretreated with fullerenol C(60)(OH)(24). AB - In earlier in vitro investigations, fullerenol was shown to have a strong antioxidative capability. The present study examined the role of fullerenol as a potential antioxidative protector for doxorubicin-induced oxidative stress in the blood of rats through an investigation of the activity of glutathione-dependent enzymes (glutathione-S-transferase and glutathione peroxidase). It also assessed the influence of fullerenol on the number of blood cells (leukocytes and erythrocytes) as well as on the content of hemoglobin after a single dose administration of doxorubicin. Experiments were performed on six groups of adult male Wistar rats, each group containing eight individuals. Doxorubicin was administrated i.v. (tail vein) in a single dose of 10 mg/kg. Fullerenol C(60)(OH)(24) was administrated to the treated animals i.p. (in doses 50, 100, 200 mg/kg) 30 min before the dosing with doxorubicin. The control group animals were given saline (1 ml/kg; i.p.). One group of animals was treated only with fullerenol (100 mg/kg i.p.). The animals were sacrificed 2 and 14 days after the treatment. Each experiment was repeated twice. The results may indicate that fullerenol induces a decrease in the antioxidative capacity of erythrocytes in oxidative stress conditions, whereas, without doxorubicin, the application of fullerenol did not induce any changes in the enzyme activity of erythrocytes. The results of GST activity might indicate that 50 mg/kg are not sufficient to protect from doxorubicin toxicity, while 200 mg/kg might be toxic for animals, judging from the increase in GST activity. PMID- 19778231 TI - Unsuitability of the northern bobwhite as a model species for the assessment of reproductive behavior in toxicological studies. AB - The northern bobwhite (Colinus virginianus) is used in numerous wildlife toxicity studies, however no published reports could be located that mention the measurement of reproductive behavior in this species. Changes in reproductive behavior can be potentially more sensitive to environmental contaminant exposures and less resilient than more traditional physiological responses. Male bobwhite copulatory behaviors were measured similarly to those that are well established for use in Japanese quail (Coturnix japonica). Time to initiate mating, time to achieve a successful copulation, the number of mating attempts, and the number of successful copulations were recorded daily for four consecutive days over a period of 3 min for each male/female pair of birds per day. When females were introduced to male cages, males were more occupied with shows of aggression towards neighboring males than attempts to mate with the female sharing their space. Only one male successfully mated with a female over the entire 4 days of the test. Future attempts at assessing reproductive behavior in this species may be more successful if birds are separated from the rest of the group when paired. The Japanese quail seems to be a more appropriate species for overall reproductive tests due to: willingness of males to copulate in the presence of other males, consistent egg laying ability, and the short time required for embryonic development and reproductive maturity. PMID- 19778230 TI - Enzymes as biomarkers of cypermethrin toxicity: response of Clarias batrachus tissues ATPase and glycogen phosphorylase as a function of exposure and recovery at sublethal level. AB - The present study was conducted to evaluate the sublethal effects of a synthetic pyrethroid, cypermethrin on ATPase, and glycogen phosphorylase in gill, kidney, liver, and muscle tissue of freshwater fish, Clarias batrachus (Linn) during exposure and cessation of exposure. Thirty-six fish were exposed to 1/3 of LC 50 concentration i, e. 0.07 mg/L cypermethrin for 10 days. After 10 days, 18 fish were transferred to freshwater and 10 days recovery response was observed. Thirty six fish were kept as a control group. The effect of cypermethrin intoxication was studied on total, Mg(+2), Na(+)-K(+) ATPase, glycogen, and glycogen phosphorylase (a) and (ab) in various physiological tissues at the end of 1, 5, and 10 days of exposure and recovery period. Cypermethrin intoxication resulted in a significant inhibition in the activities of total, Mg(+2), and Na(+)-K(+) ATPase enzyme and glycogen content, whereas it caused a significant induction in the levels of glycogen phosphorylase (a). The activity level of glycogen phosphorylase (ab) showed mixed response. When exposed fish were released into freshwater, they were able to normalize the activities of ATPase enzyme in liver tissue whereas gill, kidney, and muscle tissues showed slight recovery. At the end of 10 days of recovery period, glycogen and glycogen phosphorylase activities in kidneys recover better than muscle. Therefore, the present study clearly suggests that ATPase and glycogen phosphorylase enzymes can be used as biomarkers of exposure to aquatic organisms under cypermethrin intoxication. PMID- 19778232 TI - Decreased ubiquinone availability and impaired mitochondrial cytochrome oxidase activity associated with statin treatment. AB - In order to investigate the potential involvement of mitochondrial electron transport chain (ETC) dysfunction in myotoxicity associated with 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor (statin) treatment, assessment was made of ETC activity and ubiquinone status in two patients experiencing myopathy following treatment with simvastatin (40 mg/day) and cyclosporin (patient 1) and simvastatin (40 mg/day) and itraconazole (patient 2). Analysis of skeletal muscle biopsies revealed a decreased ubiquinone status (77 and 132; reference range: 140-580 pmol/mg) and cytochrome oxidase (complex IV) activity (0.006 and 0.007 reference range: 0.014-0.034). To assess statin treatment in the absence of possible pharmacological interference from cyclosporin or itraconazole, primary astrocytes were cultured with lovastatin (100 microM). Lovastatin treatment resulted in a decrease in ubiquinone (97.9 +/- 14.9; control: 202.9 +/- 18.4 pmol/mg; p < 0.05), and complex IV activity (0.008 +/- 0.001; control: 0.011 +/- 0.001; p < 0.05) relative to control. These data, coupled with the patient findings, indicate a possible association between statin treatment, decreased ubiquinone status, and loss of complex IV activity. PMID- 19778234 TI - GSTM1, GSTT1, and GSTP1 polymorphism in north Indian population and its influence on the hydroquinone-induced in vitro genotoxicity. AB - Glutathione S transferase (GST) gene polymorphism examined among north Indians and correlated with hydroquinone (HQ) genotoxicity to help in clinical prediction of susceptibility of HQ toxicity. Lymphocytes of individuals with/without GSTM1, GSTT1, and GSTP1 (ile/ile or val/val) were exposed to HQ (20, 40, or 80 microM) and examined chromosomal aberrations (CA) or cytokinesis-block micronucleus assays. Among north Indians the frequencies of GSTM1 (null), GSTT1 (null), and both null were found to be 41.1, 21.9, and 12.7%, whereas frequencies of GSTP1 with (ile/ile) or (ile/val), or (val/val) were 52, 42.1, or 5.9%, respectively. Individuals with null GSTM1, GSTT1, and GSTP1 (val/val) showed inhibition of mitotic index (MI) and significant (p < 0.01) induction of CA as compared to individuals with GSTM1, GSTT1, and GSTP1 (ile/ile). Micronucleus formation was found to be significant (p < 0.05 or 0.01) in both the genotypes. Results indicate that GSTM1, GSTT1 (null), and GSTP1 (val/val) are sensitive to HQ genotoxicity. PMID- 19778233 TI - Silica-induced TNF-alpha and TGF-beta1 expression in RAW264.7 cells are dependent on Src-ERK/AP-1 pathways. AB - The cytokines secreted by lung macrophages have been shown to play a critical role in the pathogenesis of silicosis, tumor necrosis factor-alpha (TNF-alpha), and transforming growth factor-beta1 (TGF-beta1) are prominent cytokines in silicosis, but the underlying mechanism remains to be determined. The aim of the present study was to investigate the roles of Src-mitogen-activated protein kinase (MAPKs)/activator protein-1 (AP-1) signaling pathways in silica-induced TNF-alpha and TGF-beta1 expression in macrophage cells (RAW264.7). It was found that silica activated Src, p38 kinase, and extracellular signal-regulated kinase (ERK) in RAW264.7 cells. The induction of TNF-alpha and TGF-beta1 by silica was suppressed by Src inhibitor (PP1), ERK inhibitor (PD98059), but not by p38 kinase inhibitor (SB203580). Dominant negative mutant c-Jun (TAM67) inhibited silica induced AP-1 DNA binding activity and downregulated the TNF-alpha and TGF-beta1 expression. In addition, PD98059 but not SB203580 inhibited the AP-1 DNA binding activity induced by silica. Based on these findings, it was conclude that Src ERK/AP-1 signaling pathways are involved in the TNF-alpha and TGF-beta1 expression induced by silica in macrophages. PMID- 19778235 TI - Involvement of hydrogen peroxide in the manganese-induced myocytes mitochondrial membrane potential loss. AB - Isolated rat ventricular myocytes were incubated in different manganese concentrations and after that the reactive oxygen species (ROS) generation, the level of reduced glutathione (GSH), and the changes of mitochondrial membrane potential (Deltapsi m) were investigated by a flow cytometer (FACScan) as well as laser scanning confocal microscopy (LSCM). Results showed that, although the total ROS in the cell were increased after manganese treatment, hydrogen peroxide (H(2)O(2)) was the main elevated species while superoxide anion (O(2).(-)) was nearly unchanged. The generation of H(2)O(2) became obvious when the myocytes were incubated in the higher concentration of manganese. The content of GSH in myocytes also decreased after manganese exposure. When the myocytes were incubated with both manganese and GSH-ethylester (GSH-EE), which is permeable to the cell membrane, the generation of H(2)O(2) decreased greatly. The loss of the mitochondrial membrane potential (Deltapsi m) was also induced by manganese incubation. However, with the existence of extracellular GSH-EE the Deltapsi m were rescued. The results suggested that manganese action may lead to the ROS stress upon myocytes which most probably rise from high generation of intracellular H(2)O(2). GSH-EE could effectively clean the over-production of H(2)O(2), indicating that the low level of intracellular GSH was another main reason to the high accumulation of H(2)O(2). The mitochondrial membrane potential was also affected by manganese and rescued by GSH-EE, suggesting that H(2)O(2) was also involved in the manganese damages to the mitochondrial membrane potential. PMID- 19778236 TI - Influence of Aloe Vera gel on dermal wound healing process in rat. AB - In this topical study the influence of Aloe Vera, on the wound healing process was investigated in 63 male rats with microscopic and cell count methods. On the day of surgery a round wound, of diameter 20 mm, was created on the back of rats necks under sterile conditions. The surgery day was determined as day zero (0). Then the rats were divided randomly into control and experimental groups 1 and 2. Animals in each group were sub-divided to three smaller groups, investigated every 4, 7, and 14 days. From day 0, wound surfaces were covered with gel once daily in experimental group 1 and twice daily, for 12 h interval, in experimental group 2. Each rat received 30 g of the gel. The wound surface and healing were assessed on days 4, 7, and 14, and then a sample from the wound was prepared and investigated microscopically. The results show that the number of neutrophil, macrophage, and fibroblast cells and the wound thickness in the control group were statistically different from the experimental groups. It was found that the wound diameter thickness in the experimental group was greatly lower due to twice administration of gel and the power of wound healing was more than other groups. PMID- 19778238 TI - In vivo oxime administration does not influence Ellman acetylcholinesterase assay results. AB - Organophosphorus compounds (OPs) are potent inhibitors of acetylcholinesterase (AChE). Treatment for OP poisoning is by administration of atropine sulfate, an oxime, and diazepam. Oximes such as 2-PAM are used to reactivate OP-inhibited AChE so as to restore normal enzymatic function and serve as a true antidote. There are reports of non-enzymatic hydrolysis by oximes of acetylthiocholine in in vitro preparations in the widely used Ellman assay for AChE activity, which may confound the interpretation of AChE activity by producing elevated results. The purpose of this experiment was to determine if there is appreciable interference by therapeutic levels of oximes on the results of the Ellman assay in assessing AChE reactivation by oxime compounds in vivo. When therapeutic doses of oximes (2-PAM, HI-6, MMB-4, or MINA) were administered intramuscularly to guinea pigs and samples collected 60 min later, there was no statistical difference between oxime and saline control groups in measured AChE activity in various tissue samples, including blood. With appropriate dilution of samples prior to spectrophotometric assay, the Ellman assay is an acceptable method to measure in vivo oxime reactivation of inhibited AChE. Inclusion of an oxime control group to insure that this particular type of interference is not causing false readings in the assay is a prudent step. PMID- 19778239 TI - Evaluation of nine oximes on in vivo reactivation of blood, brain, and tissue cholinesterase activity inhibited by organophosphorus nerve agents at lethal dose. AB - The capability of several oximes (HI-6, HLo7, MMB-4, TMB-4, carboxime, ICD 585, ICD 692, ICD 3805, and 2-PAM) to reactivate in vivo AChE inhibited by the nerve agents sarin, cyclosarin, VX, or VR in blood, brain regions, and peripheral tissues in guinea pigs was examined and compared. Animals were injected subcutaneously with 1.0 LD(50) of sarin, cyclosarin, VR, or VX, and treated intramuscularly 5 min later with one of these compounds. Toxic signs and lethality were monitored, and tissue AChE activities were determined at 60 min after nerve agent. The animals exposed to sarin or cyclosarin, alone or with non oxime treatment, some died within 60 min; however, when treated with an oxime, no animal died. For VR or VX, all animals survived for 60 min after exposure, with or without non-oxime or oxime therapy. These nerve agents caused differential degrees of inhibition: in whole blood sarin = cyclosarin > VR = VX; in brain regions sarin > cyclosarin > VX > VR; and in peripheral tissues sarin > VX > cyclosarin > VR. These oximes exhibited differential potency in reactivating nerve agent-inhibited AChE in various peripheral tissues, but not AChE activity in the brain regions. There was no difference in the AChE reactivating potency between the dichloride and dimethanesulfonate salts of HI-6. AChE inhibited by sarin was the most and cyclosarin the least susceptible to oxime reactivation. Overall, MMB-4 appeared to be, among all oximes tested, the most effective in vivo AChE reactivator against the broadest spectrum of nerve agents. PMID- 19778240 TI - Fluorescent detection of lipid peroxidation derived protein adducts upon in-vitro cigarette smoke exposure. AB - Oxidative stress in biological systems can result in radical-induced lipid peroxidation (LPO), which can lead to the production of secondary reactive by products such as 4-hydroxy-2-nonenal (HNE), malondialdehyde (MDA), acrolein, and acetaldehyde. These deleterious compounds are known to react with and concomitantly modify nucleophilic amino acid residues on proteins. Oxidative stress induced by cigarette smoke (CS) has been put forth as a major mechanism for tobacco-induced pathologies. At present, there are few reliable biomarkers for measuring the extent of oxidatively-induced damage resulting from CS exposure in vivo. This study has utilized a previously reported CS exposure system to expose cultured cells in-vitro to whole CS and determine the extent of LPO resulting from CS exposure by quantifying the increase in HNE within the exposure media versus controls via gas chromatography mass spectrometry. Additionally, we obtained protein enriched cell lysate post-CS exposures and measured the fluorescent signal obtained via direct injection fluorescent analysis at 375 nm ex./415 nm em. This study determined that the fluorescent signal intensity was directly proportional to the quantity increase of HNE in CS exposed media. It further tested this correlation by performing HNE titration addition experiments to cultured cells and Western blot analysis on proteins obtained from cell lysates. Finally, the fluorescent signal increase from authentic BSA solutions incubated with increasing concentrations of HNE was measured. It is proposed that the fluorescent signal observed from the protein lysate of CS exposed cultured cells corresponds to the extent of biological damage resulting from secondary reactive by-products formed from LPO induced via CS exposure and represented by HNE. The fluorescent signals increased in intensity upon increasing CS dose up to 20 min and remained elevated over 24 h after cessation of CS exposure. PMID- 19778241 TI - Gas-liquid chromatography for fenvalerate residue analysis: in vivo alterations in the acetylcholinesterase activity and acetylcholine in different tissues of the fish, Labeo rohita (Hamilton). AB - The disruption of acetylcholinesterase activity (AChE) in the freshwater fish, Labeo rohita is demonstrated in the present study using acetylthiocholine iodide as substrate. L. rohita on exposure to lethal (6 microg/L) and sub-lethal (0.75 microg/L) concentrations of fenvalerate showed time- and dose-dependent inhibition in the activity of AChE, suggesting a decrease in the cholinergic transmission and consequent accumulation of acetylcholine (ACh) in the tissues (brain, gill, liver, and muscle) leading to continuous nerve impulses, causing prolonged muscle contraction which, as a consequence, causes paralysis and results in death. These also have lead to behavioral changes and create widespread disturbance in the normal neural physiology of the fish. Residue analysis using a gas-liquid chromatography technique (GLC) revealed that highest quantity of fenvalerate accumulated in gill followed by liver and muscle under lethal concentrations, whereas in sub-lethal concentrations muscle accumulated the highest concentration followed by gill and liver. The results suggest that in a biomonitoring program AChE activity can be a good diagnostic tool for assessing fenvalerate toxicity. The lipophilic nature of fenvalerate is of concern, since L. rohita is an important staple fish species, which may lead to the phenomenon of biomagnification. PMID- 19778242 TI - Measurement of methamphetamine on surfaces using surface plasmon resonance. AB - Field methods are needed to assess the contamination of surfaces by methamphetamine from illicit drug manufacturing. This study performed a feasibility study on the use of a surface plasmon resonance (SPR) based instrument (SensiQ Discovery) in the evaluation of surface contamination by methamphetamine. The main goal was to see if the method could be sensitive enough for field measurements. A competitive immunochemical assay was developed for the instrument which was able to measure methamphetamine at 9 ng/ml with a range of 9 250 ng/ml. Methamphetamine was spiked onto ceramic tiles and the assay was able to detect methamphetamine contamination at 25 ng/100 cm(2), which is below the 50 ng/100 cm(2) standard used for surface cleanup assessment. The instrument is compact and mobile and is sensitive enough for use for measurement of methamphetamine on surfaces, so it is a candidate for a field method for methamphetamine surface contamination. Its use for this application will require further development of the instrument to make it more convenient to use. Also further evaluation of ruggedness and use of the instrument under various environmental conditions such as temperature and humidity are needed to define conditions under which the instrument can be employed in field measurements. PMID- 19778243 TI - Detection of cocaine and benzoylecgonine in formalin fixed rat tissues. AB - The stability of drugs in formalin solution is an important factor in forensic investigation. Tissues (liver, lung, kidney, brain) taken from rats, which have been poisoned acutely with cocaine, were preserved in two different conditions, analyzed by GC-MS, and then compared. Organs of the first group were preserved and stored at -20 degrees C without adding formalin, whereas the organs of the second group were preserved and stored in formalin solution at room temperature (25 degrees C). Serum samples were taken immediately after poisoning and studied as well. In specimens stored at -20 degrees C, cocaine and its metabolite benzoylecgonine were detected in the tissues. Only benzoylecgonine was detected both in tissues and their formalin solution. It was observed that the distribution of cocaine in tissues had differed depending on the preservation conditions. The formalin solution in which benzoylecgonine was mostly detected was from liver. As a result, cocaine was detected in tissues stored at -20 degrees C. It is recommended that both the formalin-fixed tissues and formalin solution should be analyzed concurrently to assure the accurate results (LOD = 3 ng/ml). PMID- 19778244 TI - Cytogenetic monitoring in human oral cancers and other oral pathology: the micronucleus test in exfoliated buccal cells. AB - Oral cancer is a lifestyle-related cancer, with tobacco as a primary factor. Progression of oral cancer develops over several years from the stage of leukoplakia, erythroplakia, etc. A micronucleus test was applied to oral mucosal cells, considering them as the target site for carcinogens and cytogenetic damage. The test has been established as a reliable biomarker for differential prevalence of MN indices among oral cancers, pre-cancers, non-malignant oral pathologies, and healthy controls for the first time. Buccal scrapings were collected from 63 patients with cancer and pre-cancerous lesions, 42 with non malignant oral problems, and 100 healthy controls. The analysis revealed that MN frequencies in cancer and pre-cancerous cases were 4-fold elevated (p < 0.001) and 3.87-fold (p < 0.002) elevated for other non-malignant pathologies. Significant associations between use of tobacco in various forms and development of oral pathologies are also established. The relative cancer risk for smoking healthy controls with a definite MN frequency was also found to be significant. The results indicate the validity of the MN test as a cytogenetic marker for the development of several oral pathologies. PMID- 19778245 TI - The moderating role of dark soy sauce to acrylamide-induced oxidative stress and neurophysiological perturbations in rats. AB - To evaluate the protective effects of dark soy sauce (DSS) against acrylamide (ACR)-induced neurotoxicity in rats, 60 adult Sprague Dawley female rats were given DSS (0.5 ml/kg body weight/day) before, after, and during ACR treatment (10 mg/kg body weight/day) for 8 weeks in total. Treatment only with ACR resulted in a significant increase in lipid peroxidation level, lactate dehydrogenase, and serum creatine kinase activity, but a significant decrease in superoxide dismutase activity in brain homogenate. Moreover, serum serotonin, corticosterone, 3, 5, 3'-triiodothyronine, and L-thyroxine, thyroid stimulating hormone, estradiol, progesterone, and plasma adrenaline decreased significantly in ACR rats. Treatment with DSS before, during, and after ACR treatment partially antagonized the effects induced by ACR. In conclusion, DSS exhibited a protective action against ACR-induced oxidative stress and biochemical perturbations in rats; and treatment with DSS during ACR exposure was more effective than after or before ACR treatment. PMID- 19778246 TI - Study on toxicity of danshensu in beagle dogs after 3-month continuous intravenous infusion. AB - Danshensu (3-(3,4-dihydroxyphenyl) lactic acid), a natural phenolic acid, is isolated from root of Salvia miltiorrhiza, and is widely used as a traditional Chinese medicine for treatment of various cardiovascular diseases. In the present study, toxicity of danshensu was evaluated in male and female dogs after 3-month continuous intravenous infusion. Beagle dogs were treated with danshensu at doses of 17, 50, and 150 mg/kg/day, and observed for 90 days followed by recovery periods. Measurements included clinical observations, body weight, food consumption, temperature, electro-cardiography (EGC), hematology, blood chemistry, urinalysis, gross necropsy, organ weight, and histopathology. No significant adverse effects on these parameters were observed. The only treatment related finding was a hard knot at injection site observed in the 150 mg/kg group after 2-3 weeks continuous administration, and returned to normal after 3-4 days withdrawal. From these results, it might be concluded that danshensu did not produce any significant cumulative toxicity at the doses administered, as reflected by the various parameters investigated. PMID- 19778247 TI - Safety and toxicological evaluation of demethylatedcurcuminoids; a novel standardized curcumin product. AB - Turmeric is a well recognized and highly recommended herb in ayurvedic systems of medicine and it has also been used for culinary purposes for thousands of years. Bis-O-demethylatedcurcumin (BDMC) was found to be more efficacious than curcumin and the increased potentcy was attributed to a higher number of phenolic groups in BDMC. A novel demethylatedcurcuminoid composition (DC) comprising minimum 95% of total demethylatedcurcuminoids (67.8% bisdemethylcurcumin, 20.7% demethylmonodemethoxycurcumin, 5.86% bisdemethoxycurcumin, 2.58% demethylcurcumin) was prepared (PCT/IN05/00337, dated October 13, 2005) starting from Curcuma longa extract containing 95% total curcuminoids (C95). DC exhibited superior neuroprotective and anti-inflammatory efficacy compared to C95 in a GeneChip study. Based on these interesting findings, this study sought to determine the broad-spectrum safety of DC. Acute oral, acute dermal, primary skin and eye irritation, and dose-dependent 90 day sub-chronic toxicity studies were conducted. The acute oral LD50 of DC was found to be > 5000 mg/kg in female SD rats. No changes in body weight or adverse effects were observed following necropsy. Acute dermal LD50 of DC was found to be > 2000 mg/kg. Based on the data from primary skin irritation test conducted on New Zealand Albino rabbits, DC was classified as minimally irritating. Similarly, primary eye irritation test was conducted with DC on rabbits and based on the test outcome DC was classified as mildly irritating to the eye. A dose-dependent 90-day sub-chronic toxicity study demonstrated no significant changes in selected organ weights and as percentages of body and brain weights. DC supplementation did not cause changes in hepatic DNA fragmentation. Hematology, clinical chemistry, and histopathological evaluations did not show any adverse effects in any of the organs tested. These results demonstrate the broad spectrum safety of DC. PMID- 19778248 TI - Reduction of copper-induced histopathological alterations by calcium exposure in Nile tilapia (Oreochromis niloticus). AB - This study was undertaken to determine whether calcium could render any protection against copper (Cu) toxicity in Nile tilapia with emphasis on histopathological and histochemical analysis. The copper LC(50) values for 24, 48, 72, and 96 h to tilapia in the laboratory were 210.27, 213.34, 193.30, and 185. 75 mg/L, respectively. Prior to Cu exposure, fish were exposed to 0 (G1 and G3) and 30 mg/L calcium carbonate (G2 and G4) for 4 days. After that, fish were exposed to 46 mg/L copper, which corresponds to 25% of the 96 h LC(50) (G3 and G4) for 96 h and 7 days. In the gills of the copper treatment group, primary filament cell hyperplasia, epithelial lifting, or edema, secondary lamellar fusion, and aneurysm were observed. Swollen hepatocytes showing vacuoles and congestion in sinusoids were observed. Necrosis was observed in some areas. In the kidney, glomerulus's atrophy, tubular swelling, and also necrosis were seen. Fish that were pre-exposed to calcium showed slight alteration when compared to copper alone-treatment groups. Histochemical staining for calcium and copper by alizarin red S and rhodanine staining, respectively, indicated no accumulation of calcium and copper in kidney, liver, gills, and muscle. In conclusion, calcium appears to be beneficial in reducing the effects of heavy metal contaminations in aquatic organisms. PMID- 19778249 TI - Comparative proteomics analysis of cardiac muscle samples from pufferfish Takifugu rubripes exposed to excessive fluoride: initial molecular response to fluorosis. AB - Comparative proteomics was performed to identify proteins in the cardiac muscle of Takifugu rubripes in initial response to excessive fluoride. Sixteen fish were randomly divided into a control group and an experimental group. The control group was raised in softwater alone (F(-) = 0.4 mg/L), and the experimental group was raised in the same water with sodium fluoride at a high concentration of 35 mg/L. After 3 days, proteins were extracted from the fish cardiac muscle and then were subjected to 2D PAGE analysis. The matrix assisted laser desorption ionization time of flight mass spectrometry (Maldi TOF MS) was applied to identify the proteins that were differentially expressed from the two groups of fish. Average of 318 and 275 proteins detected in the control and the experimental group, respectively, 167 spots were matched and 21 highly differentially expressed proteins were further analyzed by Maldi TOF-TOF MS, and 15 were identified by MASCOT. These 15 proteins include Telomerase reverse transcriptase, 4SNc-Tudor domain protein, protein disulfide isomerase ER-60, Tuba1 protein, mitogen-activated protein kinase 10, and SMC4 protein. Consistent with their previously known functions, these identified proteins seem to be involved in apoptosis and other functions associated with fluorosis. These results will contribute to our understanding for the effects of fluoride exposure on the physiological and biochemical functions of takifugu, and the toxicological mechanism of fluoride causing fluorosis in both fish and human. PMID- 19778250 TI - Effects of Fusarium mycotoxin butenolide on myocardial mitochondria in vitro. AB - Fusarium mycotoxin toxicosis has been implicated in the etiology of Keshan disease, an endemic mitochondrial cardiomyopathy prevailing in certain areas of China. Butenolide (4-acetamido-4-hydroxy-2-butenoic acid gamma-lactone) is one of the Fusarium mycotoxins which are frequently detected from cereal grains in endemic areas. A recent study indicates that this mycotoxin induces rat cardiotoxicity, but its effect on the myocardial mitochondria remains unclear. The present study is therefore undertaken to explore the toxic effect potential of butenolide on the myocardial mitochondria. Exposure of cultured cardiac myocytes to 50 microg/ml of butenolide provoked dissipation of mitochondrial membrane potential. Incubation of isolated rat myocardial mitochondria with butenolide of 100 microg/ml for 60 min resulted in mitochondrial swelling, indicating the occurrence of mitochondrial permeability transition. Furthermore, marked oxidative damage in myocardial mitochondria was observed after incubation of isolated myocardial mitochondria with butenolide ranging from 0 to 50 microg/ml for 60 min, as manifested by concentration-dependent increases in the production of thiobarbituric acid reactive substances, the indicator of lipid peroxidation. Contrarily, a representative antioxidant glutathione significantly alleviated this oxidative mitochondrial damage induced by butenolide. In conclusion, these observations clearly show that butenolide can induce dysfunction of myocardial mitochondria, and oxidative damage appears to play a crucial role in these deleterious effects. The present study supports the hypothesis that mycotoxin toxicosis is a probable etiological factor of Keshan disease, the mitochondrial cardiomyopathy. PMID- 19778251 TI - Effect of copper-hydroquinone complex on oxidative stress-related parameters in human erythrocytes (in vitro). AB - The effect of in vitro exposure of human erythrocytes to micromolar concentrations of hydroquinone and copper simultaneously on oxidative status related biochemical parameters was studied. Hydroquinone is a component of cigarette smoke and serum copper level is increased in smokers. Copper forms a complex with hydroquinone and enhances its auto-oxidation to benzoquinone which covalently binds to sulfhydryl group containing compounds like reduced glutathione. In this study, copper increased H(2)O(2) production by hydroquinone. Hydroquinone either alone or in the presence of copper produced a decrease of reduced glutathione level without altering methemoglobin concentration and erythrocyte lipid peroxidation. Catalase inhibition by sodium azide depleted reduced glutathione level further. Copper-hydroquinone complex mediated glutathione depletion in the catalase containing RBC was not decreased by antioxidant, butylated hydroxytoluene. From the known facts and above findings, it is suggested that depletion of reduced glutathione by hydroquinone in the presence of copper in catalase active RBC may be due to the formation of 1, 4 benzoquinone adduct of reduced glutathione and to some extent due to binding of copper to the thiol group of reduced glutathione rather than conversion to oxidized glutathione via reactive oxygen species. Depletion of reduced glutathione by N-ethylmaleimide pretreatment followed by copper-hydroquinone treatment had no effect on methemoglobin level or lipid peroxidation. Furthermore, copper-hydroquinone complex did not increase erythrocyte susceptibility to oxidative stress. This suggests hydroquinone in the presence of copper does not contribute to erythrocyte membrane lipid peroxidation seen in smokers. Criteria for ideal antioxidant supplementation in smokers were suggested. PMID- 19778252 TI - On the relation of oxidative stress in delivery mode in pregnant women; a toxicological concern. AB - The objective was to investigate the effect two modes of labor (vaginal delivery and elective cesarean section) on thiobarbituric reactive substances (TBARS) as markers of lipid peroxidation, total antioxidant power (ferric reducing ability, TAP), and total thiol molecules (TTM) in blood of mothers and their newborns. One hundred and twenty women with normal pregnancy and normal blood biochemical parameters were divided into groups of vaginal delivery (VD) and elective cesarean surgery (ECS). Blood samples were obtained firstly in the time 37-40 weeks of pregnancy and secondly during labor phase for VD or during ECS. Blood samples from umbilical cord arterial of newborns were also obtained at birth after separation of cord. Plasma levels of TBARS, TAP, and TTM were determined. There was no significant differences between VD and ECS mothers before labor in plasma levels of TBARS, TTM, and TAP. Mothers in the VD group showed a significant increase in TBARS (p < 0.05) after delivery. And TTM level showed a significant increase in ECS group (p < 0.05) as compared to pre-delivery levels. Comparing oxidative stress variables between VD and ECS groups after labor, plasma levels of TBARS, and TTM significantly increased (p < 0.05) in VD mothers. TAP was not significantly different between VD and ECS groups. Newborn of VD mothers showed a significant increase in TBARS (p < 0.05), and TAP (p < 0.05) as compared to newborn of ECS. TTM was not significantly different between two groups of newborns. The results indicate that mothers in VD and their newborns are in more oxidative stress than those who underwent ECS for delivery. Linking oxidative stress to severe neonatal diseases, it may be reasonable to assess whether antioxidant supplementation during pregnancy may reduce the frequency of neonatal diseases. PMID- 19778253 TI - In vitro nicotine-induced oxidative stress in mice peritoneal macrophages: a dose dependent approach. AB - The immune cells use reactive oxygen species (ROS) for carrying out their normal functions while an excess amount of ROS can attack cellular components that lead to cell damage. In the present study, peritoneal macrophages (6 x 10(6) cells, >95% viable) isolated from male Swiss mice were treated with nicotine (1 mM, 5 mM, 10 mM, 25 mM, and 50 mM) in vitro for 12 h and the superoxide anion generation, lipid peroxidation, protein oxidation and antioxidant enzymes status were monitored. Maximum superoxide radical generation was found at the dose of 10 mM nicotine. The lipid peroxidation and protein oxidation were increased significantly (p < 0.05) along with the increasing dose of nicotine. The reduced glutathione level, catalase, superoxide dismutase, glutathione peroxidase, and glutathione reductase activities were decreased significantly (p < 0.05), and oxidized glutathione level was increased significantly (p < 0.05) with the increasing dose of the nicotine. From these experiments, it was also observed that all the changes in peritoneal macrophages with 10 mM, 25 mM, and 50 mM nicotine had no significant difference. To observe the effect of nicotine in vivo, this study examined the liver and spleen antioxidant status after nicotine administration (1 mg/kg BW) intraperitoneally in mice and found the diminished SOD activity and GSH level. It may be concluded that nicotine is able to enhance the production of ROS that produced oxidative stress in murine peritoneal macrophages. It also suggested that, 10 mM in vitro nicotine treatment for 12 h is the effective dose. PMID- 19778254 TI - Effect of bentazon on growth and physiological responses of marine diatom: Chaetoceros gracilis. AB - The herbicide bentazon (CASRN 25057-89-0) is extensively used in agriculture in Brittany (France) to replace atrazine. Bentazon is not readily adsorbed by soil and therefore it enters adjacent freshwater ecosystems, making its way to estuarine and marine waters areas. Information regarding its effects on marine ecosystems is scarce. Phytotoxicity assessments were conducted in the laboratory on the common diatom Chaetoceros gracilis using both the active ingredient and its formulated product (Basamais). The 3 day EC(50) using cell counts were, respectively, 150 mg/L and 60 microg/L for bentazon active ingredient and for bentazon-formulated while cellular volume was increased. Although bentazon is known as a photosystem II inhibitor, it produced an increase of pigment (chlorophylls a, c, and carotenoids) content, ATP synthesis, rates of photosynthesis and respiration, and TBARS formation. Therefore, pigments cannot be used as biomarkers of toxicity. Algal cell recovery from bentazon effects occurred after 6-9 days, suggesting a tolerance mechanism. PMID- 19778255 TI - Induction of alcohol-metabolizing enzymes and heat shock protein expression by ethanol and modulation by fenugreek seed polyphenols in Chang liver cells. AB - The present study investigated the effect of fenugreek seed polyphenolic extract (FPEt) on ethanol-induced protein expression in Chang liver cells. Cells were incubated with either 30 mM EtOH alone or together in the presence of FPEt for 24 h. Cells were harvested and assessed for expression of alcohol metabolizing enzymes-alcohol dehydrogenase (ADH(2) isoform), aldehyde dehydrogenase (ALDH(2) isoform), cytochrome P450 (CYP2E1), the electron transport component (cytochrome c), and the heat shock proteins. The expression of ADH(2), ALDH(2), and CYP2E1 were upregulated, whereas the expression of cytochrome-c was downregulated in the ethanol-treated cells. The expression of cellular heat shock proteins-HSP70, HSC70, HSC92, and mitochondrial protein mtHSP70 were induced in ethanol-treated Chang liver cells. FPEt modulated the protein expression changes induced by ethanol and had no effect when incubated with normal Chang liver cells. FPEt might exert cytoprotective action on ethanol-induced liver cell damage, possibly by enhancing cellular redox status. PMID- 19778256 TI - Loop system for creating jet fuel vapor standards used in the calibration of infrared spectrophotometers and gas chromatographs. AB - A whole body inhalation study of mixed jet fuel vapor and its aerosol necessitated the development of a method for preparing vapor only standards from the neat fuel. Jet fuel is a complex mixture of components which partitions between aerosol and vapor when aspirated based on relative volatility of the individual compounds. A method was desired which could separate the vapor portion from the aerosol component to prepare standards for the calibration of infrared spectrophotometers and a head space gas chromatography system. A re-circulating loop system was developed which provided vapor only standards whose composition matched those seen in an exposure system. Comparisons of nominal concentrations in the exposure system to those determined by infrared spectrophotometry were in 92-95% agreement. Comparison of jet fuel vapor concentrations determined by infrared spectrophotometry compared to head space gas chromatography yielded a 93% overall agreement in trial runs. These levels of agreement show the loop system to be a viable method for creating jet fuel vapor standards for calibrating instruments. PMID- 19778258 TI - Assessment of cadmium genotoxicity in peripheral blood and bone marrow tissues of male Wistar rats. AB - In this study, Cadmium (Cd) genotoxicity was investigated in both bone marrow and peripheral blood treatment using rat micronucleus technique as genotoxicity test at acute and chronic treatment in the same animals. This study evaluated the frequency of micronuclei in the peripheral blood and bone marrow of male rats treated with unique cadmium dose (15 mg/kg. body w/day) by gavage for 60 days and acute treatment for 24 h, respectively. Mitomycin C (MMC) 2 mg/kg body wt was used as a positive control. This study shows that cadmium chloride treatment significantly induced the frequency of micronucleus in polychromatic erythrocytes in both tibia bone marrow and peripheral blood (p < 0.001, p < 0.01, respectively). This increase in micronucleus frequency shows that cadmium has a genotoxic effect on bone marrow and peripheral blood at this level. Also, in order to determine cytotoxicity in bone marrow and peripheral blood, the ratio of polychromatic erythrocytes to normochromatic erythrocytes was calculated in bone marrow and peripheral blood. Cd treatment decreased this ratio in only bone marrow. The results of this study demonstrate that Cd has both toxic and genotoxic potential in bone marrow and only genotoxic potential in peripheral blood. There is a significant difference between the control group and exposed group, including acute and chronic treatment for blood Cd level (p < 0.001). No significant difference was found between acute and chronic exposure group (p > 0.05). PMID- 19778257 TI - Hepatic perturbations provoked by azathioprine: a paradigm to rationalize the cytoprotective potential of Ficus hispida Linn. AB - The present study was embarked upon in an endeavor to ascertain whether Ficus hispida leaf extract (FHLE) modulates azathioprine-induced hepatic damage. Azathioprine treated rats displayed a plethora of pathological events, which include loss of hepatocellular membrane integrity, mitochondrial dysfunction, and nuclear damage; whilst FHLE pretreated rats significantly precluded these abnormalities. These data were in harmony with the transmission electron microscopic studies. Observations from this investigation directed us to propose the plausible mechanisms through which FHLE thwarts the repercussions of azathioprine-induced hepatocellular necrosis: upholding of thiol homeostasis, curtailing the membrane effects, and perpetuation of adenine nucleotide status. These data offer credence to the notion that FHLE might be a beneficial intervention in the prevention of hepatotoxicity in azathioprine therapy. PMID- 19778259 TI - Subacute effects of carbofuran on enzyme functions in rat small intestine. AB - The effect of carbofuran administration to rats has been studied on enzymes functions in rat intestine. Carbofuran was administrated 4.0 mg/kg body weight for 7 days or 2.8 mg/kg body weight for 30 days daily by Ryle's tube. Animals given carbofuran for 30 days exhibited retarded growth compared to control group. The activities of sucrase (56%), alkaline phosphatase (62%), leucine aminopeptidase (56%), and gamma-glutamyl trans peptidase (84%) were enhanced in animals given carbofuran for 7 days. Enhancement in the activities of alkaline phosphatase and leucine amino peptidase (92-96%) was also observed in animals exposed to carbofuran for 30 days, but the activities of sucrase (28%) and gamma glutamyl transpeptidase (49%) were reduced under these conditions. There was no change in activities of maltase, lactase, and trehalase in pesticide-treated animals for 7 or 30 days. The activity of lactate dehydrogenase was enhanced (p < 0.001) in 7 days and 30 days induced carbofuran toxicity. The activities of glucose-6-phosphatase and glutamate pyruvate transaminase were also enhanced (p < 0.001) in pesticide-treated animals for 7 days, but were reduced by 46% and 26%, respectively, after 30 days of carbofuran exposure. The activity of glutamate oxaloacetate transaminase was unaltered in carbofuran toxicity. Kinetic analysis of brush border enzymes revealed a change in V(max) with no change in apparent Km. Western blot analysis of brush border sucrase, alkaline phosphatase, and leucine aminopeptidase corroborated the enzyme activity data. Intestinal histological revealed distruption of the villi, and comet assay showed disintegration of DNA in enterocytes of animals exposed to carbofuran for 30 days. These findings suggest that carbofuran toxicity may modulate digestive functions in rat intestine. PMID- 19778260 TI - Protective effect of an adenosine A1 receptor agonist against metamidophos induced toxicity and brain oxidative stress. AB - The aim of this study was to evaluate the effects of different doses of an adenosine A(1) selective agonist, phenylisopropyl adenosine (PIA), on metamidophos-induced cholinergic symptoms, mortality, diaphragm muscle necrosis, and brain oxidative stress. A LD(50) dose of metamidophos (20 mg/kg body weight, p.o.) was followed by 1 mL/kg body weight of 0.9% NaCl or 1 mg/kg, 2 mg/kg, 3 mg/kg, or 5 mg/kg body weight PIA ip. Incidence of clinical signs including chewing, salivation, convulsion, and respiratory distress did not show any significant difference among all treatment groups (p > 0.05). PIA was found to be effective to reverse the necrotic changes in diaphragm muscle induced by metamidophos significantly in all groups. Brain Thiobarbituric Acid Reactive Substance (TBARS) levels were significantly increased after the metamidophos poisoning. Administration of 2 to 5 mg/kg body weight PIA decreased brain TBARS levels compared to 0.9% NaCl treated rats. The results indicate that, although different doses of PIA reduced the OP-induced oxidative stress and diaphragm necrosis, a single dose of PIA was not able to recover cholinergic signs and symptoms of metamidophos poisoning. PMID- 19778261 TI - Oxygen glucose deprivation model of cerebral stroke in PC-12 cells: glucose as a limiting factor. AB - Optimum time points for oxygen-glucose deprivation (OGD) and re-oxygenation have been identified to suggest the suitability of PC-12 cells as rapid and sensitive in vitro model of cerebral stroke. Further, the precise role of glucose as one of the limiting factors was ascertained. PC-12 cells were subjected to receive OGD of 1-8 h followed by re-oxygenation for 6 to 96 h in medium having glucose 0-10 mg/ml. Loss of cell viability was assessed using trypan blue dye exclusion and MTT assays. The significant (p < 0.05) reduction in percent viable cell count was started at 2 h of OGD (80.7 +/- 2.0) and continued in further OGD periods (3, 4, 5, 6, 7, and 8 h), i.e. 65.7 +/- 3.5, 59.7 +/- 4.6, 54.3 +/- 3.2, 44.7 +/- 2.9, 20.3 +/- 4.3, 5.7 +/- 2.0 of counted cells, respectively. Cells growing in glucose-free medium have shown a gradual (p < 0.001) decrease in cell viability throughout the re-oxygenation. Re-oxygenation of 24 h was found to be first statistically significant time point for all the glucose concentrations. Glucose concentration during re-oxygenation was found to be one of the key factors involved in the growth and proliferation in PC-12 cells. The OGD of 6 h followed by a re-oxygenation period of 24 h with 4-6 mg/ml glucose concentration could be recorded as optimum conditions under our experimental conditions. PMID- 19778262 TI - Role of apoptosis in mediating salicylic acid-induced teratogenesis in vitro. AB - Salicylic acid (SAL) is among the most commonly used drugs worldwide and is known to cause congenital malformations and fetal death in animals. In this study, the effect of SAL on major organogenesis period and the role of apoptosis in mediating congenital malformations have been carried out. In the present study, post-implantation rat embryos of day 11 were cultured for 24 h with various concentrations of SAL, i.e. 10, 100, and 1000 microg/ml cultures, respectively. The growth and developmental of each embryo was evaluated and compared with control ones for the presence of any malformations. The SAL decreased all growth and developmental parameters in a concentration-dependent manner, when compared with control. However, exposure to SAL at 10 microg/ml culture did not show any significant effect on embryonic growth and development. Parallel to this, flow cytometric analysis (cell cycle and annexin V binding) and DNA fragmentation assay were carried out followed by quantitation by 3'-OH labeling of cultured rat embryos to evaluate the role of apoptosis in bringing about SAL-induced teratogenesis. All results were found to be dose-dependent and an increase in apoptosis in embryonic tissues may be related to the increased risk of congenital malformations. The data suggested that apoptosis might be involved in mediating teratogenesis of SAL in vitro. PMID- 19778263 TI - Co-administration of monoisoamyl dimercaptosuccinic acid and Moringa oleifera seed powder protects arsenic-induced oxidative stress and metal distribution in mice. AB - Arsenic contamination of groundwater in the West Bengal basin in India is unfolding as one of the worst natural geo-environmental disasters to date. Chelation therapy with chelating agents is considered to be the best known treatment against arsenic poisoning; however, they are compromised with certain serious drawbacks/side-effects. Efficacy of combined administration of Moringa oleifera (M. oleifera) (English: Drumstick tree) seed powder, a herbal extract, with a thiol chelator monoisoamyl DMSA (MiADMSA) post-arsenic exposure in mice was studied. Mice were exposed to 100 ppm arsenic in drinking water for 6 months, followed by 10-days treatment with M. oleifera seed powder (500 mg/kg, orally through gastric gavage, once daily), MiADMSA (50 mg/kg, intraperitoneally, once daily) either individually or in combination. Arsenic exposure caused significant decrease in blood glutathione, delta-aminolevulinic acid dehydratase (ALAD), accompanied by increased production of reactive oxygen species in blood and soft tissues. Significant inhibition of superoxide dismutase, catalase, and glutathione peroxidase activities in tissues (liver in particular) along with significant increase in thiobarbituric acid reactive substances and metallothionein levels in arsenic intoxicated mice was also noted. Combined administration of MiADMSA with M. oleifera proved better than all other treatments in the recovery of most of the above parameters accompanied by more pronounced depletion of arsenic. The results suggest that concomitant administration of M. oleifera during chelation treatment with MiADMSA might be a better treatment option than monotherapy with the thiol chelator in chronic arsenic toxicity. PMID- 19778264 TI - Inhibition of tumor necrosis factor and nitrosative/oxidative stresses by Ziziphora clinopoides (Kahlioti); a molecular mechanism of protection against dextran sodium sulfate-induced colitis in mice. AB - Inflammatory bowel disease (IBD) is a chronic condition of the intestine with unknown etiology involving multiple immune genetic and environmental factors. The authors were interested in examining the protective effect of Ziziphora clinopoides methanolic extract, an Iranian folk herbal medicine, on inflammatory mediators in experimental colitis. Colitis in NMRI mice was induced by oral administration of dextran sodium sulfate (DSS, 3%). Z. clinopoides was administrated orally at doses of 75, 150, and 300 mg/kg/day for 7 days. The level of lipid peroxidation (LP), total antioxidant capacity (TAC), total thiol molecules (TTM), antioxidant enzymes including superoxide dismutase (SOD) and catalase (CAT), and nitric oxide (NO) as a marker of nitrosative stress, and tumor necrosis factor alpha (TNF-alpha) as a mediator of inflammation and apoptosis were measured in the colon homogenate. Treatment by DSS increased bowel LP, NO, and TNF-alpha while decreasing TAC, SOD, CAT, and TTM. All measured parameters were improved by Z. clinopoides treatment and reached close to normal levels. The present study further supports the role of oxidative/nitrosative stresses and TNF-alpha in the pathogenesis of colitis and protective effects of this herb. The data are promising for further preclinical studies directed towards understanding mechanism of action and cross-species and cross-model comparisons for potential protective effects. PMID- 19778266 TI - Pulmonary targeting with biodegradable salbutamol-loaded nanoparticles. AB - BACKGROUND: Aerosol therapy using particulate drug carriers has become an increasingly attractive method to deliver therapeutic or diagnostic compounds to the lung. Polymeric nanoparticles are widely investigated carriers in nanomedicine. The targeted and controlled release of drugs from nanoparticles for pulmonary delivery, however, is a research field that has been so far rather unexploited. Therefore, the objective of this study was to compare the pulmonary absorption and distribution characteristics of salbutamol after aerosolization as solution or entrapped into novel polymeric nanoparticles in an isolated rabbit lung model (IPL). METHODS: Physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, stability of nanoparticles to nebulization, as well as pulmonary drug absorption and distribution after nebulization in the IPL were investigated. RESULTS: Salbutamol-loaded poly(D,L-lactide-co-glycolide) (PLGA) and poly(vinyl sulfonate-co-vinyl alcohol)-graft-poly(D,L-lactide-co glycolide) (VS(72)-10) nanoparticles were prepared by a modified solvent displacement technique with a mean particle size of approximately 120 nm and a polydispersity index below 0.150. VS(72)-10 nanoparticles showed a more negative zeta-potential of -54.2 +/- 3.3 mV compared to PLGA nanoparticles (-36.5 +/- 2.6 mV). Salbutamol encapsulation efficiency was 25.2 +/- 4.9% and 63.4 +/- 3.5% for PLGA and VS(72)-10 nanoparticles, respectively. After nebulization utilizing the MicroSprayer physicochemical properties of salbutamol-loaded VS(72)-10 nanoparticles were virtually unchanged, whereas nebulized salbutamol-loaded PLGA nanoparticles showed a significant increase in mean particle size and polydispersity. In vitro release studies demonstrated a sustained release of the encapsulated salbutamol from VS(72)-10 nanoparticles. In parallel, a sustained salbutamol release profile was observed after aerosol delivery of these particles to the IPL as reflected by a lower salbutamol recovery in the perfusate (40.2 +/- 5.8%) when compared to PLGA nanoparticles (55.2 +/- 9.1%) and salbutamol solution (62.8 +/- 7.1%). CONCLUSIONS: The current study suggests that inhalative delivery of biodegradable nanoparticles may be a viable approach for the treatment of respiratory diseases. PMID- 19778265 TI - Inhalable lactose-based dry powder formulations of low molecular weight heparin. AB - BACKGROUND: Currently low molecular weight heparin (LMWH) is administered as subcutaneous injection. This study sought to investigate the feasibility of LMWH as an inhalable dry powder (DPI) formulation and evaluate the interaction of the drug with lactose when used as a carrier. The study also compares the extent of pulmonary absorption of LMWH administered as a dry powder with that administered as an aerosolized aqueous solution. METHODS: The formulations were prepared by mixing LMWH in an aqueous solution of lactose followed by lyophilization of the resulting solution. The lyophilized preparation was then ground and sieved. Physical characterization of the formulations was performed by Fourier transform infrared spectroscopy (FTIR), X-ray powder diffraction (XRD), scanning electron microscopy (SEM), particle size analysis, and determination of aerodynamic diameter. For in vivo studies, formulations were administered to anesthetized rats, and drug absorption was monitored by measuring plasma antifactor Xa activity. RESULTS AND CONCLUSIONS: In the FTIR scan, all characteristic peaks of lactose and LMWH were observed, suggesting that there was no strong interaction between lactose and LMWH. Although the aerodynamic diameter of the formulation (DPI-2) that was sieved through 170- and 230-mesh screens was similar to that of the formulation (DPI-1) sieved through 120- and 170-mesh screens, the particle sizes of the two formulations were significantly different. Dry powder formulations of LMWH were better absorbed compared to an inhalable solution of LMWH. One of the dry powder formulations (DPI-2) produced an almost 1.5-fold increase in the relative bioavailability (41.6%) compared to the liquid formulation of LMWH (32.5%). Overall, the data presented here suggest that lactose does not adversely affect the physical-chemical characteristics of the drug, and that lactose can be used as a carrier for pulmonary delivery of LMWH. PMID- 19778267 TI - Prevalence and associated factors of oropharyngeal side effects in users of inhaled corticosteroids in a real-life setting. AB - BACKGROUND: Inhaled corticosteroids (ICS) are extensively used to treat asthma, and more recently, chronic obstructive pulmonary disease (COPD). Oropharyngeal disorders represent the most frequent side effect of these drugs, which may have a negative impact on adherence. OBJECTIVES: To evaluate the prevalence of oropharyngeal disorders in users of ICS in a real-life setting and investigate the factors associated with their occurrence. METHODS: For this observational cross-sectional study, general practitioners and pulmonologists were contacted and asked to include patients suffering from asthma or COPD treated by ICS. Physicians collected data during a medical examination. A multivariate regression model for the occurrence of oropharyngeal disorders was constructed. RESULTS: A total of 1778 physicians included 6740 patients. The mean (SD) age was 51.3 (18.5) years, 44.0% had no smoking history, and the ICS indication was asthma in 63.9% of subjects. Of the study subjects, 52.3% used beclometasone (43.4% without a long-acting ss(2)-agonist, LABA); 22.1% used budesonide (18.8% with a LABA), and 25.6% used fluticasone (19.3% with a LABA in a single inhaler). One-third (34.7%) of subjects suffered from at least one oropharyngeal disorder; the most frequently reported were hoarseness, tingling, mouth irritation, and reddening. Multivariate regression analysis found that the factors positively associated with oropharyngeal disorders were COPD indication [odds ratio (OR) 1.600; 95% confidence intervals (95% CI) 1.391, 1.839], nominal daily dose (OR = 1.388; 95% CI 1.227, 1.569), decreased adherence (OR = 1.318; 95% CI 1.104, 1.574) and the use of fluticasone (OR = 1.176; 95% CI 1.008, 1.372), whereas those negatively associated were the absence of smoking history (OR = 0.837; 95% CI 0.742, 0.945), increased adherence (OR = 0.663; 95% CI 0.581, 0.755), and beclometasone use (OR = 0.630; 95% CI 0.543, 0.732). CONCLUSIONS: The high prevalence of oropharyngeal disorders and the association of adherence with these must be taken into account by prescribers, especially in patients suffering from COPD, a relatively new group of ICS users. PMID- 19778268 TI - Characterization of stability and nasal delivery systems for immunization with nanoemulsion-based vaccines. AB - BACKGROUND: Many infectious diseases that cause significant morbidity and mortality, especially in the developing world, could be preventable through vaccination. The effort to produce safe, thermally stable, and needle-free mucosal vaccines has become increasingly important for global health considerations. We have previously demonstrated that a thermally stable nanoemulsion, a mucosal adjuvant for needle-free nasal immunization, is safe and induces protective immunity with a variety of antigens, including recombinant protein. The successful use of nanoemulsion-based vaccines, however, poses numerous challenges. Among the challenges is optimization of the formulation to maintain thermal stability and potency and another is accuracy and efficiency of dispensing the vaccines to the nasal mucosa in the anterior and turbinate region of the nasal cavity or potentially to the nasopharynx-associated lymphoid tissue. METHODS: We have examined the effects of different diluents [phosphate-buffered saline (PBS) and 0.9% NaCl] on the stability and potency of nanoemulsion-based vaccines. In addition, we have determined the efficiency of delivering them using commercially available nasal spray devices (Pfeiffer SAP-62602 multidose pump and the BD Hypak SCF 0.5 ml unit dose Accuspray(TM)). RESULTS: We report the stability and potency of PBS-diluted ovalbumin-nanomeulsion mixtures for up to 8 months and NaCl-diluted mixtures up to 6 months when stored at room temperature. Significant differences in spray characteristics including droplet size, spray angle, plume width, and ovality ratios were observed between the two pumps. Further, we have demonstrated that the nanoemulsion-based vaccines are not physically or chemically altered and retain potency following actuation with nasal spray devices. Using either device, the measured spray characteristics suggest deposition of nanoemulsion-based vaccines in inductive tissues located in the anterior region of the nasal cavity. CONCLUSIONS: The results of this study suggest that nanoemulsion-based vaccines do not require specially engineered delivery devices and support their potential use as nasopharyngeal vaccine adjuvants. PMID- 19778269 TI - Short communication: RNA interference directed against Axin1 upregulates human immunodeficiency virus type 1 gene expression by activating the Wnt signaling pathway in HeLa-derived J111 cells. AB - Axin1, a regulator of Wnt signaling, was previously identified as playing a negative role in the late phase of human immunodeficiency virus type 1 (HIV-1) replication in HeLa-derived J111 cells. In this report, we studied the molecular mechanism of how Axin1 regulates HIV-1 replication. HIV-1 transactivator, Tat dependent viral reporter gene expression was enhanced in J111 cells transfected with small interfering RNA (siRNA) against Axin1. In addition, viral transcription was upregulated in J111 cells transfected with siRNA against Axin1. In contrast, HIV-1 gene expression was not enhanced by transfecting HeLa cells with siRNA against Axin1. The expression levels of T cell factor-4 (TCF4) and beta-catenin were higher in J111 than HeLa cells. In addition, siRNAs against TCF4 and beta-catenin inhibited the Axin1 siRNA-dependent enhancement of HIV-1 gene expression in J111 cells. These results suggest that Axin1 plays a negative role in HIV-1 transcription through the Wnt signaling pathway in J111 cells under normal cell culture conditions. PMID- 19778270 TI - Response to nonnucleoside reverse transcriptase inhibitor-based therapy in HIV infected children with perinatal exposure to single-dose nevirapine. AB - We set out to investigate whether there are clinically significant consequences when children with perinatal exposure to single-dose nevirapine are initiated on a nonnucleoside reverse transcriptase inhibitor (NNRTI) containing a highly active antiretroviral therapy (HAART) regimen. We carried out a chart and database review of 104 HIV-infected children, who had initiated HAART with an NNRTI at JCRC and were less than or equal to 5 years of age, 35 (33.7%) of whom had prior exposure to perinatal single-dose nevirapine. We studied the viral load and CD4 percentage at baseline, at week 24, and at week 48 after the start of HAART in children exposed and not exposed to perinatal single-dose nevirapine, as well as the results of genotypic resistance testing done for the children who had failed to achieve virologic suppression on HAART. At weeks 24 and 48 after initiating HAART, children not exposed to single-dose nevirapine were 3.28 times [OR = 3.28, 95% CI: (1.37 to 9.20), p = 0.0167] and 3.47 times [OR = 3.47, 95% CI: (1.28 to 9.37), p = 0.0091] more likely to achieve virologic suppression compared to children exposed to single-dose nevirapine, respectively. However, the CD4 cell response at weeks 24 and 48 was not worse in the children exposed to single-dose nevirapine. In 10 children with perinatal exposure to single-dose nevirapine, NNRTI resistance mutations, mostly K103N, Y181C, and G109A, were identified. HIV-infected children with perinatal exposure to single-dose nevirapine are less likely to achieve short-term virologic suppression when started on an NNRTI-containing regimen, when compared to those who were not exposed to it, probably because the exposure predisposes them to developing NNRTI resistance mutations. PMID- 19778271 TI - Maternal effects increase within-family variation in offspring survival. AB - Maternal effects are environmental components of phenotypes that complicate relationships between natural selection and evolution because they often affect phenotypes and fitness simultaneously. We studied the effects of egg size variation on juvenile survival in a population of American coots (Fulica americana). We experimentally evaluated egg size variation at three levels: across the population, within natal nests, and within foster nests. Natal nests accounted for the most variation in population egg size. Within clutches, early laid eggs were larger than later-laid eggs, with the exception of first-laid eggs, which were small. In the fostering experiment, posthatching survival was most strongly related to egg size relative to natal siblings and natal hatching order and less so to egg size within foster nests. These effects on survival were found even though young from natal nests were neither raised together nor raised by genetic parents. These results indicate that females allocate resources unequally among offspring such that offspring from larger, early-laid eggs have higher survival than offspring from smaller, later-laid eggs, regardless of their size relative to foster siblings or to mean population egg size. These results suggest that egg size variation can be maintained through selection on maternal investment strategies and not on egg size per se. PMID- 19778273 TI - The distribution of stars most likely to harbor intelligent life. AB - Simple heuristic models and recent numerical simulations show that the probability of habitable planet formation increases with stellar mass. We combine those results with the distribution of main-sequence stellar masses to obtain the distribution of stars most likely to possess habitable planets as a function of stellar lifetime. We then impose the self-selection condition that intelligent observers can only find themselves around a star with a lifetime greater than the time required for that observer to have evolved, T(i). This allows us to obtain the stellar timescale number distribution for a given value of T(i). Our results show that for habitable planets with a civilization that evolved at time T(i) = 4.5 Gyr the median stellar lifetime is 13 Gyr, corresponding approximately to a stellar type of G5, with two-thirds of the stars having lifetimes between 7 and 30 Gyr, corresponding approximately to spectral types G0-K5. For other values of T(i) the median stellar lifetime changes by less than 50%. PMID- 19778272 TI - Three-dimensional morphological and textural complexity of Archean putative microfossils from the Northeastern Pilbara Craton: indications of biogenicity of large (>15 microm) spheroidal and spindle-like structures. AB - We recently reported a diverse assemblage of carbonaceous structures (thread like, film-like, spheroidal, and spindle-like) from chert in the ca. 3.0 Ga Farrel Quartzite of the Gorge Creek Group in the Pilbara Craton, Western Australia. Results from a rigorous examination of occurrence, composition, morphological complexity, size distributions, and taphonomy provided presumptive evidence for biogenicity. In this study, we present new data of morphological and textural complexity of large (>15 microm) spheroidal and spindle-like structures, using an in-focus, 3-D image reconstruction system, which further raises the scale of credibility that these structures are microfossils. While many of the large spheroids are single-walled, and the wall is irregularly folded, a few specimens are partially blistered, double walled, or have a dimpled wall. The wall-surface texture varies from smooth and homogeneous (hyaline) to patchy, granular or reticulate. Such variation is best explained as resulting from taphonomic processes. Additionally, an inner solitary body, present in some large spheroids, is hollow and partially broken, which indicates a primary origin for this substructure. Spindle-like structures have two types of flange-like appendage; one is attached at the equatorial plane of the body, whereas the other appears to be attached peripherally. In both cases, the appendage tends to have a flat geometry, a tapering thickness, and constancy in shape, proportions, and dimensions. Spindle-wall surfaces are variously textured and heterogeneous. These morphological and textural complexities and heterogeneity refute potential abiogenic formation models for these structures, such as crystals coated with organic matter, fenestrae, and the diagenetic redistribution of carbonaceous matter. When coupled with other data from Raman spectroscopy, NanoSIMS analysis, and palynology, the evidence that these large carbonaceous structures are biogenic appears compelling, though it is still equivocal as to whether they are cells or outer envelopes of colonies of smaller cells. PMID- 19778274 TI - Cryptic photosynthesis--extrasolar planetary oxygen without a surface biological signature. AB - On Earth, photosynthetic organisms are responsible for the production of virtually all the oxygen in the atmosphere. On land, vegetation reflects in the visible and leads to a "red edge," which developed about 450 million years ago on Earth and has been proposed as a biosignature for life on extrasolar planets. However, in many regions on Earth, particularly where surface conditions are extreme--in hot and cold deserts, for example--photosynthetic organisms can be driven into and under substrates where light is still sufficient for photosynthesis. These communities exhibit no detectable surface spectral signature to indicate life. The same is true of the assemblages of photosynthetic organisms at more than a few meters' depth in water bodies. These communities are widespread and dominate local photosynthetic productivity. We review known cryptic photosynthetic communities and their productivity. We have linked geomicrobiology with observational astronomy by calculating the disk-averaged spectra of cryptic habitats and identifying detectable features on an exoplanet dominated by such a biota. The hypothetical cryptic photosynthesis worlds discussed here are Earth analogues that show detectable atmospheric biosignatures like our own planet but do not exhibit a discernable biological surface feature in the disc-averaged spectrum. PMID- 19778275 TI - Investigation of neutron radiation effects on polyclonal antibodies (IgG) and fluorescein dye for astrobiological applications. AB - Detecting life in the Solar System is one of the great challenges of new upcoming space missions. Biochips have been proposed as a way to detect organic matter on extraterrestrial objects. A biochip is a miniaturized device composed of biologically sensitive systems, such as antibodies, which are immobilized on a slide. In the case of in situ measurements, the main concern is to ensure the survival of the antibodies under space radiation. Our recent computing simulation of cosmic ray interactions with the martian environment shows that neutrons are one of the dominant species at soil level. Therefore, we have chosen, in a first approach, to study antibody resistance to neutrons by performing irradiation experiments at the Applications Interdisciplinaires des Faisceaux d'Ions en Region Aquitaine (AIFIRA) platform, a French ion beam facility at the Centre d'Etudes Nucleaires de Bordeaux-Gradignan in Bordeaux. Antibodies and fluorescent dyes, freeze-dried and in buffer solution, were irradiated with 0.6 MeV and 6 MeV neutrons. Sample analyses demonstrated that, in the conditions tested, antibody recognition capability and fluorescence dye intensity are not affected by the neutrons. PMID- 19778276 TI - Bacterial spores in granite survive hypervelocity launch by spallation: implications for lithopanspermia. AB - Bacterial spores are considered good candidates for endolithic life-forms that could survive interplanetary transport by natural impact processes, i.e., lithopanspermia. Organisms within rock can only embark on an interplanetary journey if they survive ejection from the surface of the donor planet and the associated extremes of compressional shock, heating, and acceleration. Previous simulation experiments have measured each of these three stresses more or less in isolation of one another, and results to date indicate that spores of the model organism Bacillus subtilis can survive each stress applied singly. Few simulations, however, have combined all three stresses simultaneously. Because considerable experimental and theoretical evidence supports a spallation mechanism for launch, we devised an experimental simulation of launch by spallation using the Ames Vertical Gun Range (AVGR). B. subtilis spores were applied to the surface of a granite target that was impacted from above by an aluminum projectile fired at 5.4 km/s. Granite spall fragments were captured in a foam recovery fixture and then recovered and assayed for shock damage by transmission electron microscopy and for spore survival by viability assays. Peak shock pressure at the impact site was calculated to be 57.1 GPa, though recovered spall fragments were only very lightly shocked at pressures of 5-7 GPa. Spore survival was calculated to be on the order of 10(-5), which is in agreement with results of previous static compressional shock experiments. These results demonstrate that endolithic spores can survive launch by spallation from a hypervelocity impact, which lends further evidence in favor of lithopanspermia theory. PMID- 19778277 TI - Laser-induced fluorescence emission (L.I.F.E.): in situ nondestructive detection of microbial life in the ice covers of Antarctic lakes. AB - Laser-induced fluorescence emission (L.I.F.E.) images were obtained in situ following 532 nm excitation of cryoconite assemblages in the ice covers of annual and perennially frozen Antarctic lakes during the 2008 Tawani International Expedition to Schirmacher Oasis and Lake Untersee in Dronning Maud Land, Antarctica. Laser targeting of a single millimeter-scale cryoconite results in multiple neighboring excitation events secondary to ice/air interface reflection and refraction in the bubbles surrounding the primary target. Laser excitation at 532 nm of cyanobacteria-dominated assemblages produced red and infrared autofluorescence activity attributed to the presence of phycoerythrin photosynthetic pigments. The method avoids destruction of individual target organisms and does not require the disruption of either the structure of the microbial community or the surrounding ice matrix. L.I.F.E. survey strategies described may be of interest for orbital monitoring of photosynthetic primary productivity in polar and alpine glaciers, ice sheets, snow, and lake ice of Earth's cryosphere. The findings open up the possibility of searching from either a rover or from orbit for signs of life in the polar regions of Mars and the frozen regions of exoplanets in neighboring star systems. PMID- 19778278 TI - Habitable zones exposed: astrosphere collapse frequency as a function of stellar mass. AB - Stellar astrospheres--the plasma cocoons carved out of the interstellar medium by stellar winds--are one of several buffers that partially screen planetary atmospheres and surfaces from high-energy radiation. Screening by astrospheres is continually influenced by the passage of stars through the fluctuating density field of the interstellar medium (ISM). The most extreme events occur inside dense interstellar clouds, where the increased pressure may compress an astrosphere to a size smaller than the liquid-water habitable-zone distance. Habitable planets then enjoy no astrospheric buffering from exposure to the full flux of galactic cosmic rays and interstellar dust and gas, a situation we call "descreening" or "astrospheric collapse." Under such conditions the ionization fraction in the atmosphere and contribution to radiation damage of putative coding organisms at the surface would increase significantly, and a series of papers have suggested a variety of global responses to descreening. These possibilities motivate a more careful calculation of the frequency of descreening events. Using a ram-pressure balance model, we compute the size of the astrosphere in the apex direction as a function of parent-star mass and velocity and ambient interstellar density, emphasizing the importance of gravitational focusing of the interstellar flow. The interstellar densities required to descreen planets in the habitable zone of solar- and subsolar-mass stars are found to be about 600(M/M[middle dot in circle])(-2) cm(-3) for the Sun's velocity relative to the local ISM. Such clouds are rare and small, indicating that descreening encounters are rare. We use statistics from two independent catalogues of dense interstellar clouds to derive a dependence of descreening frequency on the parent-star mass that decreases strongly with decreasing stellar mass, due to the weaker gravitational focusing and smaller habitable-zone distances for lower-mass stars. We estimate an uncertain upper limit to the absolute frequency of descreening encounters as 1-10 Gyr(-1) for solar-type stars and 10(2) to 10(9) times smaller for stars between 0.5 and 0.1 M[middle dot in circle]. Habitable-zone planets orbiting late-K to M stars are virtually never exposed to the severe consequences that have been proposed for astrospheric descreening events, but descreening events at a moderate rate may occur for stars with the Sun's mass or larger. PMID- 19778279 TI - Formation of uracil from the ultraviolet photo-irradiation of pyrimidine in pure H2O ices. AB - The detection of nucleobases in carbonaceous chondrites such as Murchison supports the scenario in which extraterrestrial organic molecules could have contributed to the origin of life on Earth. However, such large molecules have not been observed to date in astrophysical environments, in particular, comets and the interstellar medium (ISM). The physico-chemical conditions under which nucleobases and, more generally, N-heterocycles were formed are unknown, as are their mechanisms of formation. In this work, H2O:pyrimidine ice mixtures were irradiated with UV photons under interstellar/cometary-relevant conditions to study the formation of pyrimidine derivatives, including the nucleobase uracil. Liquid and gas chromatography analyses of the samples produced in our experiments revealed the presence of numerous photoproducts among which 4(3H)-pyrimidone and uracil could be conclusively identified. The photostability of pyrimidine against UV photons was also studied, and we showed that it would survive from the ISM to the solar nebula if formed and preserved in ice mantles on the surface of cold grains. We propose pathways for the formation of 4(3H)-pyrimidone and uracil under astrophysically relevant conditions and discuss the possibility for such molecules to survive from the ISM to their delivery to Earth and other Solar System bodies. PMID- 19778281 TI - Insertion/deletion polymorphism in the promoter region of NFKB1 gene increases susceptibility for superficial bladder cancer in Chinese. AB - Recently, a functional insertion/deletion polymorphism (-94 insertion/deletion ATTG) in the promoter of NFKB1 gene, which encodes the p50 subunit of nuclear factor-kappaB protein complex, was identified. The aim of this study was to explore the association between this polymorphism and bladder cancer in a Chinese population. The NFKB1 polymorphism was assessed in 207 patients with superficial transitional cell carcinomas in bladder and in 228 age-, sex-, and smoking matched healthy volunteers. The polymerase chain reaction assay was used to determine the NFKB1 genotypes. Genomic DNA used for the assay was extracted from peripheral blood lymphocytes. This study found that the frequency of ATTG(2) allele in bladder cancer patients was significantly higher than that in control subjects (65.2% vs. 56.1%, p = 0.006, odds ratio = 1.465), suggesting that the functional NFKB1 promoter polymorphism is associated with increased risk for superficial transitional cell carcinoma of the bladder. PMID- 19778282 TI - Interferon-gamma of the giant panda (Ailuropoda melanoleuca): complementary DNA cloning, expression, and phylogenetic analysis. AB - Interferon-gamma (IFN-gamma) is the only member of type II IFN and is vital in the regulation of immune and inflammatory responses. Herein we report the cloning, expression, and sequence analysis of IFN-gamma from the giant panda (Ailuropoda melanoleuca). The open reading frame of this gene is 501 base pair in length and encodes a polypeptide consisting of 166 amino acids. All conserved N linked glycosylation sites and cysteine residues among carnivores were found in the predicted amino acid sequence of the giant panda. Recombinant giant panda IFN gamma with a V5 epitope and polyhistidine tag was expressed in HEK293 host cells and confirmed by Western blotting. Phylogenetic analysis of mammalian IFN-gamma coding sequences indicated that the giant panda IFN-gamma was closest to that of carnivores, then to ungulates and dolphin, and shared a distant relationship with mouse and human. These results represent a first step into the study of IFN-gamma in giant panda. PMID- 19778283 TI - Lack of association between FXIII-Val34Leu, FVII-323 del/ins, and transforming growth factor beta1 (915G/T) gene polymorphisms and bronchopulmonary dysplasia: a single-center study. AB - Bronchopulmonary dysplasia (BPD) is a multifactorial disease of preterm infants that is characterized by airway injury, inflammation, and parenchymal remodeling. Extravascular fibrin deposits in septae and alveoli due to the altered fibrin turnover are the pathological hallmarks of BPD that strongly indicates the importance of the imbalance in the competing activities of coagulation and fibrinolysis. Activation of the coagulation cascade leads to intraalveolar fibrin deposition in many inflammatory pulmonary disorders. Increased fibrin formation or decreased fibrinolysis may cause extravascular fibrin deposition. We evaluated the association between FXIII-Val34Leu, FVII-323 del/ins, and transforming growth factor beta1 (TGF-beta(1)) (915G/T) gene polymorphisms in patients with BPD. The study group consisted of 98 preterm infants with BPD. Ninety-four of the 192 preterm neonates were without BPD and sampled for the control group. Restriction fragment size analyses were performed by examining digested PCR products for FXIII-Val34Leu, FVII-323 del/ins, and TGF-beta(1) (915G/C) genotypes. No significant associations were found between FXIII-Val34Leu, FVII-323 del/ins, TGF beta(1) (915G/C) gene polymorphisms and BPD phenotype in our population. Further studies with other genes are required for the identification of molecular predisposing factors for BPD that may help in the development of new treatments and hence might allow for targeting of this treatment to a "high-risk" subgroup, reducing unnecessary exposure to potentially harmful therapies. PMID- 19778284 TI - Association between IRF-5 polymorphisms and risk of acute coronary syndrome. AB - Previous studies suggested that genetic polymorphisms in interferon regulatory factor 5 (IRF-5) are implicated in the susceptibility to a range of autoimmune diseases, including rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. Recently, IRF-5 has been implicated in inflammatory processes that are associated with excessive remodeling and atherosclerosis. Our purpose was to investigate the association between the IRF-5 polymorphisms and the risk of acute coronary syndrome (ACS) in a Chinese population. The 5 bp indel (insertion/deletion) (CGGGG) polymorphism, located 64 bp upstream of the alternative exon 1a of IRF-5 gene, and the deletion of 30 bp in exon 6 of IRF-5 gene were analyzed among 148 patients with ACS and 246 controls in a Chinese population, using a polymerase chain reaction-restriction fragment length polymorphism strategy and direct sequencing. The frequencies of (CGGGG)(3)(CGGGG)(4) genotype and (CGGGG)(4) allele in ACS patients were significantly higher than those in control subjects (p = 0.018, odds ratio [OR] = 1.76, 95% confidence interval [CI]: 1.10-2.81; p = 0.028, OR = 1.62, 95% CI: 1.05 2.50, respectively). However, no significant relationship between the 30 bp exon 6 polymorphism of the IRF-5 gene and the risk of ACS was observed (p = 0.770, OR = 0.96, 95% CI: 0.72-1.28). The 5 bp indel (CGGGG) polymorphism of the IRF-5 gene may be associated with susceptibility to ACS. PMID- 19778285 TI - Adaptation to oxidative stress, chemoresistance, and cell survival. AB - The discovery of some additional properties and functions of reactive oxygen species (ROS), beyond their toxic effects, provides a novel scenario for the molecular basis and cell regulation of several pathophysiologic processes. ROS are generated by redox-sensitive, prosurvival signaling pathways and function as second messengers in the transduction of several extracellular signals. A complex intracellular redox buffering network has developed to adapt and protect cells against the dangerous effects of oxidative stress. However, pathways involved in ROS-adaptive response may also play a critical role in protecting cells against cytotoxic effects of anticancer agents, thus supporting the hypothesis of a correlation between adaptation/resistance to oxidative stress and resistance to anticancer drugs. This review summarizes the main systems involved in the adaptive responses: an overview on the pathophysiologic relevance of mitochondria on redox-sensitive transcription factors and genes and main antioxidant networks in tumor cells is provided. One of the major aims is to highlight the adaptive mechanisms and their interplay in the intricate connection between oncogenic signaling, oxidative stress, and chemoresistance. Clarification of these mechanisms has tremendous application potential, in terms of developing novel molecular-targeted anticancer therapies and innovative strategies for rational combination of these agents with chemotherapeutic or tumor-specific biologic drugs. PMID- 19778286 TI - A new turbidimetric method for assaying serum C-reactive protein based on phosphocholine interaction. AB - BACKGROUND: C-reactive protein (CRP) is able to bind phospholipids (mainly phosphocholine) in the presence of calcium ions. We investigated the use of this property for developing an affordable turbidimetrical CRP assay based on diluted soy oil. METHODS: Serum (or heparinized plasma) was mixed with Intralipid 20% in Tris-calcium buffer (pH 7.5). After 30 min of incubation at 37 degrees C, the CRP phospholipids complexes were measured by turbidimetry (660 nm/700 nm) with a Cobas 6000 analyzer (Roche). Results were compared with those obtained using a typical immunoturbidimetric method (Roche). RESULTS: Good correlation (r(2)=0.931) was obtained between the functional and the immunoturbidimetric CRP assay. Within-run and between-run %CV values for the functional assay were 2.4% (100 mg/L); 6.0% (50 mg/L); 10% (20 mg/L), and 3.6% (100 mg/L); 8.0% (50 mg/L); 11% (20 mg/L), respectively. The limit of detection was 7 mg/L. Results were not affected by serum calcium, triglyceride, or phospholipid concentrations. CONCLUSIONS: The functional CRP assay allowed measurement of CRP in serum and plasma in the range of 7 mg/L-400 mg/L. The assay is particularly suited in conditions where resources are restricted. Since the assay is species independent, the described functional CRP assay could be used for veterinary purposes as well. PMID- 19778287 TI - The rate of manual peripheral blood smear reviews in outpatients. AB - BACKGROUND: The International Consensus Group for Hematology Review recommends manual blood smears for new findings from automated complete blood cell (CBC) tests. However, in outpatients, the rate of peripheral manual blood smear reviews is uncertain, as is the effect of historical results on this rate. METHODS: In a prospective cohort study of 687,955 members of a health maintenance organization, we extracted 39,759 consecutive automated CBC test results and determined the rate of manual peripheral smear reviews that were indicated using different triggering criteria, and historical results. RESULTS: Individual triggering values increased from 10.7% to 19.5% when comparing our criteria to those of the consensus criteria. The proportion of CBC test results with at least one triggering value was 7.2% using our criteria, compared to 13.9% with the inclusion of a mean corpuscular volume <75 and a plus one immature granulocyte flag according to the consensus committee. Availability of historical data decreased our peripheral smear review rate to 2.6%. CONCLUSIONS: The peripheral smear review rate in outpatients using the consensus criteria was higher than with our less stringent criteria. If historical data are available and no clinical utility is demonstrated for the additional consensus criteria, an acceptable out-patient review rate might be as low as 2.6%. PMID- 19778288 TI - Journal Impact Factor: it will go away soon. PMID- 19778289 TI - Markers of infection in inpatients and outpatients with acute Q-fever. AB - BACKGROUND: Query-fever (Q-fever) is a zoonotic infection caused by the intracellular Gram-negative coccobacillus Coxiella burnetii. A large ongoing outbreak of Q-fever has been reported in the Netherlands. We studied various markers of infection in inpatients (hospitalised) and outpatients (treated by a general physician) with acute Q-fever in relation to disease severity. METHODS: Leukocyte counts, C-reactive protein (CRP) and procalcitonin (PCT) concentrations were measured in 25 inpatients and 40 outpatients upon presentation with acute Q fever. Chest X-rays, if available, were analysed and confusion, urea, respiratory rate, blood pressure-age 65 (CURB-65) scores, indicating severity of pneumonia, were calculated. RESULTS: CRP was the only marker that significantly differentiated between inpatients and outpatients. It was increased in all patients from both groups. Leukocyte counts and PCT concentrations did not differ between inpatients and outpatients. Overall, only 13/65 patients had an increased leukocyte count and only 11/65 patients presented with PCT concentrations indicative of possible bacterial respiratory tract infection. Infiltrative changes on the chest X-ray were observed in the majority of patients. CURB-65 score was 0+/-1 (mean+/-SD). CONCLUSIONS: Acute Q-fever, a relatively mild pneumonia with low CURB-65 scores, specifically induces a response in CRP, while PCT concentrations and leukocytes are within the normal range or increased only marginally. PMID- 19778290 TI - Serum albumin fragmentation in end-stage renal disease patients--a pilot study. AB - BACKGROUND: The goal of this study was to detect modification in the expression of plasma proteins and/or post-translational modifications of their structure in patients with end stage renal disease. METHODS: Serum samples from 19 adult patients treated by maintenance hemodialysis (MHD) were analyzed in comparison to sera from six healthy controls using sodium dodecylsulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and two-dimensional electrophoresis (2DE). Spots of interest were identified by mass spectrometry analysis. In addition, the 2DE maps were incubated with a human anti-albumin polyclonal antibody. RESULTS: SDS-PAGE gels, 2DE maps and matrix-assisted laser desorption/ionization time of flight analysis indicated over-expression of low-molecular weight proteins (LMWP) in sera from patients. Unexpectedly, another 15 spots with estimated M(r) of 12.5-29 kDa from the 2DE maps of six patients were identified as fragments of albumin. 2D immunoblotting of sera from 12 other patients detected numerous albumin fragments. CONCLUSIONS: These results indicate that in addition to increased expression of LMWP, a relevant amount of albumin fragments are detectable in the serum of patients undergoing MHD. Uremia appears to facilitate the fragmentation of albumin and/or the retention of albumin fragments in blood. PMID- 19778291 TI - Comparison of visual vs. automated detection of lipemic, icteric and hemolyzed specimens: can we rely on a human eye? AB - BACKGROUND: Results from hemolyzed, icteric, and lipemic samples may be inaccurate and can lead to medical errors. These preanalytical interferences may be detected using visual or automated assessment. Visual inspection is time consuming, highly subjective and not standardized. Our aim was to assess the comparability of automated spectrophotometric detection and visual inspection of lipemic, icteric and hemolyzed samples. METHODS: This study was performed on 1727 routine biochemistry serum samples. Automated detection was performed using the Olympus AU2700 analyzer. We assessed: 1) comparability of visual and automated detection of lipemic, icteric and hemolyzed samples, 2) precision of automated detection, and 3) inter-observer variability for visual inspection. RESULTS: Weighted kappa coefficients for comparability of visual and automated detection were: 0.555, 0.529 and 0.638, for lipemic, icteric and hemolyzed samples, respectively. The precision for automated detection was high for all interferences, with the exception of samples being only slightly lipemic. The best overall agreement between observers was present in assessing lipemia (mean weighted kappa=0.698), whereas the lowest degree of agreement was observed in assessing icterus (mean weighted kappa=0.476). CONCLUSIONS: Visual inspection of lipemic, icteric and hemolyzed samples is highly unreliable and should be replaced by automated systems that report serum indices. PMID- 19778292 TI - Discordant total and free prostate-specific antigen (PSA) assays: does calibration with WHO reference materials diminish the problem? AB - Prostate-specific antigen (PSA) assay-dependent variations could result in misinterpretation of individual PSA values. Therefore, the situation for clinical interpretation of PSA or percent free PSA (%fPSA) results is complicated. This review summarizes the differences in various total PSA (tPSA) and free PSA (fPSA) assays, and results obtained using the new World Health Organization (WHO) calibrated Access assays from various studies. Method comparisons between the traditionally calibrated Hybritech PSA and fPSA assays and the new "standardized" WHO calibrated assays yield results that are approximately 25% lower for PSA and fPSA. A PSA cut-off of 3 or 3.1 microg/L should be considered for WHO calibrated assays in order to achieve the same sensitivity/specificity profile as with a cut off of 4 microg/L in traditionally calibrated assays. The %fPSA cut-offs could be retained. PMID- 19778293 TI - Extracellular redox status regulates Nrf2 activation through mitochondrial reactive oxygen species. AB - The redox status of the extracellular compartment has only just been elucidated as a mechanism controlling intracellular signal transduction and correlates with aging, diabetes, heart disease and lung fibrosis. In the present paper, we describe a mechanism by which oxidizing extracellular environments, as maintained by the cysteine/cystine (Cys/CySS) redox couple, induce mitochondria-derived ROS (reactive oxygen species) generation and cause the activation of Nrf2 (nuclear factor-erythroid 2-related factor 2), inducing an antioxidant response. NIH 3T3 cells were cultured in medium with extracellular Cys/CySS redox potentials (Eh), ranging from 0 to -150 mV. Cellular and mitochondrial ROS production significantly increased in cells incubated under more oxidizing extracellular conditions (0 and -46 mV). Trx2 (thioredoxin-2) is a mitochondrial-specific oxidoreductase and antioxidant and became oxidized in cells incubated at 0 or -46 mV. MEFs (mouse embryonic fibroblasts) from Trx2-overexpressing transgenic (Trx2 Tg) mice produced less intracellular ROS compared with WT (wild-type) MEFs at the more oxidizing extracellular conditions. Nrf2 activity was increased in WT MEFs at the 0 or -46 mV conditions, but was inhibited in Trx2 Tg MEFs under the same conditions. Furthermore, Nrf2-regulated gene expression was significantly increased in the WT MEFs, but not in the Trx2 Tg MEFs. These results show that the Cys/CySS redox status in the extracellular compartment regulates intracellular ROS generated primarily in the mitochondria, which play an important role in the activation of Nrf2 and up-regulation of antioxidant and detoxification systems. PMID- 19778294 TI - Bone mass acquisition in female rhythmic gymnasts during puberty: no direct role for leptin. AB - OBJECTIVES: Although hypoleptinaemia has been reported in female peripubertal athletes, data are lacking on leptin and bone mass variations in puberty and the effects of leptin on bone mineralization during this period. This study therefore investigated the variations in leptin level and bone mineral density (BMD) in young elite female rhythmic gymnasts (FRG) according to pubertal stage. The effects of leptin, IGF-1 and sex hormones on bone mineral acquisition were also evaluated. PATIENTS AND MEASUREMENTS: Plasma leptin levels were analysed in 43 elite FRG (mean age: 13.3 +/- 1.8 years range: 10.6-17.2, body mass index: 17.52 +/- 1.85 kg/m(2), training status: 17.9-23.8 h/week) according to their pubertal stage (Tanner I, n = 7; II, n = 10; III, n = 9; IV, n = 8; V, n = 9). IGF-1, IGFBP-3 and sex hormones were also evaluated. BMD was measured by dual-energy X ray absorptiometry at various bone sites. RESULTS: Plasma leptin increased throughout pubertal growth and the values measured in Tanner stages IV-V were significantly higher than in stages I-II. Gains in BMD were measured throughout puberty at all bone sites, particularly between Tanner stages II and IV. In simple correlation analysis, BMD at all bone sites was positively correlated with plasma leptin, age, bone age, BMI, oestrogen, testosterone, IGF-1 and IGFBP-3. However, multivariate analysis using a linear regression model by block (including bone age, anthropometric data and biological parameters) was then performed to determine the factors independently associated with each BMD site, and only bone age, fat-free soft tissue and BMI remained independent predictors. CONCLUSION: In FRG characterized by high training volume and low fat mass, plasma leptin levels increased throughout puberty and were partially related to body composition changes. Despite the simultaneous increases in plasma leptin and BMD during pubertal growth, it was not possible to differentiate the leptin impact on bone independently from anthropometric parameters. PMID- 19778295 TI - Lower numbers of circulating Natural Killer T (NK T) cells in individuals with human T lymphotropic virus type 1 (HTLV-1) associated neurological disease. AB - Human T lymphotropic virus type 1 (HTLV-1) infects 10-20 million people worldwide. The majority of infected individuals are asymptomatic; however, approximately 3% develop the debilitating neurological disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is also currently no cure, vaccine or effective therapy for HTLV-1 infection, and the mechanisms for progression to HAM/TSP remain unclear. NK T cells are an immunoregulatory T cell subset whose frequencies and effector functions are associated critically with immunity against infectious diseases. We hypothesized that NK T cells are associated with HAM/TSP progression. We measured NK T cell frequencies and absolute numbers in individuals with HAM/TSP infection from two cohorts on two continents: Sao Paulo, Brazil and San Francisco, CA, USA, and found significantly lower levels when compared with healthy subjects and/or asymptomatic carriers. Also, the circulating NK T cell compartment in HAM/TSP subjects is comprised of significantly more CD4(+) and fewer CD8(+) cells than healthy controls. These findings suggest that lower numbers of circulating NK T cells and enrichment of the CD4(+) NK T subset are associated with HTLV-1 disease progression. PMID- 19778296 TI - Comparison of antifungal MICs for yeasts obtained using the EUCAST method in a reference laboratory and the Etest in nine different hospital laboratories. AB - In routine laboratory practice, the determination of MICs of antifungals for yeasts often relies on the Etest, because of a good correlation with reference methods. However, this correlation was established through predesigned studies, rather than prospective testing. The surveillance programme of fungaemia (YEASTS programme), implemented since 2003, facilitated our comparison of the Etest and the EUCAST results, obtained on a routine basis in nine different hospitals and in a reference laboratory, respectively. The analysis included 690 isolates recovered from blood culture (362 Candida albicans, 113 Candida glabrata, 69 Candida parapsilosis, 55 Candida tropicalis, 31 Cryptococcus neoformans, and 60 other yeast species) that were tested for their susceptibility to amphotericin B (n = 655), fluconazole (n = 669), itraconazole (n = 198), voriconazole (n = 588), flucytosine (n = 314), and caspofungin (n = 244). Agreement between the Etest and EUCAST datasets was calculated and categorized on the basis of previously published breakpoints. The level of agreement at +/-2 dilutions was 75% for amphotericin B and 90% for flucytosine; for the azoles, it ranged from 71% for itraconazole to 87% for voriconazole. No significant difference was observed among the yeast species, except for Cryptococcus neoformans and flucytosine, with an agreement <40%. Categorical agreement ranged from 60% for itraconazole to 90% for flucytosine. Major and very major discrepancies occurred in <12% and 6%, respectively. The Etest, even when performed on a routine basis, shows a >=71% agreement with the EUCAST reference method. PMID- 19778297 TI - Hepatitis E virus seroepidemiology and its change during 1 year in primary school students in Ankara, Turkey. AB - The Hepatitis E virus (HEV) is widespread throughout the world. The purpose of this study was to evaluate the time-related change of antibody levels against Hepatitis E in primary school children. In this cross sectional study, the samples of 515 students were examined at two times. The mean age of the students was 7(6-13) years. The seroprevalences of anti-HEV were 1.7% and 2.1% at the first and second visits respectively. There was no statistically significant differences between anti-HEV seropositivity and the parents' education and employment status (p >0.05). This serosurvey shows that there is not a high prevalence of enterically transmitted viral hepatitis in Ankara, Turkey, which is a situation similar to developed countries. PMID- 19778298 TI - Circulation of international clones of levofloxacin non-susceptible Streptococcus pneumoniae in Taiwan. AB - Levofloxacin susceptibility testing was carried out for a total of 2539 Streptococcus pneumoniae isolates obtained from January 2001 to February 2008 at the National Taiwan University Hospital (NTUH) and a further 228 pneumococcal isolates obtained from January 2004 to December 2006 at three other hospitals in different geographical areas in Taiwan. Levofloxacin non-susceptible S. pneumoniae isolates were subsequently analysed for serotype and molecular epidemiology. Rates of levofloxacin non-susceptibility of S. pneumoniae increased significantly from 1.2% in 2001 to 4.2% in 2007 at NTUH. A total of 30 isolates of levofloxacin non-susceptible S. pneumoniae isolates (MIC >= 4 mg/L) were available for evaluation of serotype, antimicrobial susceptibility, nucleotide sequence of the quinolone resistance-determining regions of parC, gyrA, parE and gyrB, reserpine effect on quinolone susceptibility and multilocus sequence type. Among these isolates, seven (23.3%) were from children, and two (6.7%; one from a 3- and one from a 93-year-old patient) were from blood. One levofloxacin resistant isolate (MIC = 8 mg/L) was recovered from a previously healthy child with bacteraemic necrotizing pneumonia complicated by empyema and a haemolytic uraemic syndrome. All isolates except two had Ser79 and/or Asp83 changes in ParC, and/or Ser81 or Glu85 changes in GyrA. An efflux phenotype concerning levofloxacin was detected in only one (3.3%) isolate. A novel clone (ST3642), genetically related to Spain(9V)-3 and belonging to serotype 11A, was identified. Dissemination of clonal complexes related to Spain(23F)-1, Taiwan(19F)-14, Spain(9V)-3 and Taiwan(23F)-15 has contributed to levofloxacin non-susceptibility among these S. pneumoniae isolates from Taiwan. PMID- 19778299 TI - Easily available adjustment criteria for the comparison of antibiotic consumption in a hospital setting: experience in France. AB - Hospitals in France are encouraged to monitor antibiotic consumption (AbC) and it is known that this differs among hospitals. The aim of the current study was to identify relevant and easily available adjustment criteria for the purpose of benchmarking. We analysed data from 34 public non-teaching hospitals and 43 private hospitals located in south-western France and overseas departments using retrospective data from 2005. This study investigated the relationship between AbC expressed as defined daily doses per 1000 patient-days (DDD/1000 PDs) or per 100 admissions (DDD/100 admissions) and the number of venous central lines, the number of episodes of bacteraemia and various hospital characteristics. The relationship was tested using multiple linear analyses. The median total AbC in public hospitals was 395 DDD/1000 PDs (range, 196-737) and 341 DDD/100 admissions (range, 180-792). In private hospitals this was 422 DDD/1000 PDs (range, 113-717) and 212 DDD/100 admissions (range, 38-510). The best model for public hospitals included the proportion of PDs in surgery, intensive care and medical wards and explained 84% of the variability in AbC expressed as DDD/1000 PDs. For private hospitals, the mean length of stay and the proportion of PDs in surgery and medical wards explained 68% of the variability in AbC expressed as DDD/100 admissions. Overall, this French experience shows that relevant adjustment criteria for the comparison among hospitals are easily available. It is important that each country establish its own model considering the intrinsic peculiarities of the hospital system and taking into account both indicators (DDD/1000 PDs or DDD/100 admissions) to design the best model. PMID- 19778300 TI - Leptospirosis pulmonary haemorrhage syndrome is associated with linear deposition of immunoglobulin and complement on the alveolar surface. AB - Leptospirosis is a zoonotic infection associated with severe diseases such as leptospirosis pulmonary haemorrhage syndrome (LPHS). The cause of pulmonary haemorrhage is unclear. Understanding which mechanisms and processes are involved in LPHS will be important in treatment regimens under development for this life threatening syndrome. In the present study, we evaluated 30 lung specimens from LPHS patients and seven controls using histology and immunohistochemistry (detection of IgM, IgG, IgA and C3) in order to describe the pathological features associated with this syndrome. Immunoglobulin deposits were detected on the alveolar surface in 18/30 LPHS patients. Three staining patterns were observed for the immunoglobulins and C3 in the lung tissues of LPHS patients: AS, delicate linear staining adjacent to the alveolar surface, which was indicative of a membrane covering the luminal surface of type I and II pneumocyte cells; S, heterogeneous staining which was sporadically distributed along the alveolar septum; and IA, weak, focal intra-alveolar granular staining. Human LPHS is associated with individual and unique histological patterns that differ from those of other causes of pulmonary haemorrhage. In the present study, it was found that the linear deposition of immunoglobulins (IgA, IgG and IgM) and complement on the alveolar surface may play a role in the pathogenesis of pulmonary haemorrhage in human leptospirosis. PMID- 19778301 TI - Performance of VITEK-2 Compact and overnight MicroScan panels for direct identification and susceptibility testing of Gram-negative bacilli from positive FAN BacT/ALERT blood culture bottles. AB - We describe the reliability of the VITEK-2 Compact and overnight MicroScan panels for direct identification and susceptibility testing from the BacT/ALERT blood culture system when using FAN (FA and FN) bottles. A simple procedure, in two centrifugation steps, was designed to remove the charcoal particles present in FA and FN bottles. A total of 113 positive blood cultures showing Gram-negative rods were investigated. Enterobacteriaceae were isolated in 104 cases, and Pseudomonas aeruginosa in nine. The MicroScan system correctly identified 106 (93.8%) of the 113 isolates. The seven identificaction errors included P. aeruginosa (three), Enterobacter cloacae (one), Escherichia coli (one), Klebsiella oxytoca (one), and Klebsiella pneumoniae (one). The VITEK-2 system correctly identified 109 (96.5%) of the 113 samples obtained directly from the blood culture bottles. The four unidentified isolates were Enterobacter cloacae (two), Escherichia coli (one), and P. aeruginosa (one). MicroScan yielded 4/779 (0.5%) very major errors and 28/2825 (0.9%) minor errors. VITEK-2 yielded 2/550 (0.36%) very major errors, 1/1718 (0.05%) major error, and 32/2373 (1.3%) minor errors. Both systems provided excellent identification (correlation of >90%) and susceptibility (correlation of >98%) results. The average times required to obtain identification and susceptibility results using the direct test applied to the VITEK-2 Compact system were 4.57 +/- 1.37 h and 6.52 +/- 1.64 h, respectively. The VITEK-2 compact system provided results on the same day that the blood culture was found to be positive. PMID- 19778302 TI - Pregnancy and Crimean-Congo haemorrhagic fever. AB - Crimean-Congo Hemorrhagic fever (CCHF) is a potentially fatal viral infection with reported case fatality rates of 5-30%. Humans become infected through tick bites, by contact with a patient with CCHF during the acute phase of infection, or by contact with blood or tissues from viraemic livestock. In this first report in the literature, we present the characteristics of three pregnant women with CCHF infection and the outcome of their babies. Transmission of the CCHF infection could be either intrauterine or perinatal. In endemic regions, CCHF infection should be considered in the differential diagnosis of HELLP syndrome (haemolytic anaemia, elevated liver enzymes, low platelet count), and obstetricians should be familiar with the characteristics of CCHF infection. In the aetiology of necrotising enterocolitis, CCHF should be considered. PMID- 19778303 TI - A serosurvey of Orientia tsutsugamushi from patients with scrub typhus. AB - Many countries where scrub typhus is endemic use their own cutoff values for antibody titres to differentiate between cured cases and current infections. To establish an antibody titre cutoff value, one needs to investigate the seroprevalence in endemic areas, and the duration of the increase in titre after complete cure. We conducted a follow-up study of anti-Orientia tsutsugamushi antibody titres using indirect immunofluorescence assays (IFA) and passive haemagglutination assays (PHA) in patients with scrub typhus. After the onset of symptoms, IgM antibody titres increased gradually over 2-3 weeks, peaked at about 4 weeks, and started to decrease rapidly between 4 and 5 weeks. At 1-year follow up, the median IgM value was 1:10. Out of 77 patients who were tested at that time, 36 (47%) had IgM titres > or =1:20, and none had titres exceeding 1:80. Over the first 2 weeks, IgG antibody titres increased sharply, peaked at about 4 weeks and decreased rather gradually thereafter, with a median titre of 1:128 maintained up to the 18th month. At 1-year follow-up, five out of 77 patients (6.5%) had titres > or =1:1,024 and 57% had titres > or =1:128. Based on these results, a cutoff value of > or =1:160 for IgM antibody should differentiate between previous and current infections in endemic areas such as Korea and Japan, where scrub typhus occurs mainly in the autumn. PMID- 19778304 TI - A retrospective study comparing the accuracy of prehistology diagnosis and surgical excision of malignant melanomas by general practitioners and hospital specialists. AB - A retrospective study was carried out to compare the overall standard of surgical excision of malignant melanomas (MMs) between general practitioners (GPs) and hospital specialists before and after the introduction of the UK melanoma guidelines between 1989 and 2006. In total, 213 melanoma excision reports were examined and surgical excision margins recorded. The results showed a significant difference in the rate of adequate surgical excision margins (at all levels of Breslow thickness) between GPs and hospital specialists, with hospital specialists excising melanomas with safe surgical excision margins at a significantly higher rate compared with GPs. Since the introduction of the guidelines in 2002, GPs showed a significant improvement in the completeness of melanoma excision but remained poor at prehistology diagnosis and in particular at taking adequate excision margins. Implementation of the guidelines has not produced significant improvements in adequacy of excision margins in both primary and secondary care. The results show that hospital specialists maintained a high standard of prehistological diagnosis and completeness of excision throughout the time of the study, performing at a significantly higher standard compared with GPs. Our conclusions concur with the UK melanoma guidelines and the National Institute for Health and Clinical Excellence guidelines, which suggest that lesions suspicious for melanoma should be urgently referred to a dermatologist or plastic surgeon for surgical excision and should not be surgically excised in primary care, particularly if lesions have a Breslow thickness > 2 mm. We suggest that the new guidelines need to be more aggressively implemented in primary care and guidance introduced to improve the accuracy of diagnosis, with better training provided for GPs. PMID- 19778305 TI - Induction of skin carcinogenicity by alcohol and ultraviolet light. AB - In western societies, casual consumption of alcohol during such outdoor activities as barbecuing and sunbathing is common. The current literature shows that alcohol drinkers have increased episodes of sunburn and a higher prevalence of skin cancer. Moreover, recent evidence suggests that the combination of subcarcinogenic (minimal) ultraviolet (UV) exposure with other behavioural, environmental and xenobiotic factors has resulted in increased incidents of skin related health problems that also result in skin-cancer formation. We hypothesize that the combination of alcohol consumption with UV radiation can potentiate the skin carcinogenic effects through the intermediate biproducts or metabolites of alcohol, which serve as the photosensitizers, consequently enhancing the cellular damage. We have proposed a mechanism that explains the combined alcohol-UV radiation carcinogenicity and its potential involvement in enhancing skin damage in the multistep skin carcinogenesis process. Previous literature has explored this mutual effect but no studies have definitively ascribed the reasons for increased skin cancer prevalence among alcohol drinkers. Nevertheless, the preceding epidemiological data and clinical studies recognize this matter, making the further testing of this hypothesis necessary. PMID- 19778306 TI - Increased expression of human beta-defensin 3 in mollusca contagiosum. AB - The human beta defensins (hBDs)-2 and -3 are inducible antimicrobial peptides present in human skin. Besides an important role in fighting bacteria, they also have an antiviral function. Molluscum contagiosum (MC) is a cutaneous viral disease caused by the MC virus. Lesions show a tendency towards spontaneous regression, which might be caused by antiviral proteins such as defensins. We report a marked increase in hBD-3 immunoreactivity in MC lesions in contrast to hBD-2, which was only marginally increased. We suggest a role for the hBD-3 peptide in MC pathogenesis. PMID- 19778307 TI - Anetoderma in cutaneous marginal-zone B-cell lymphoma. AB - Anetoderma is a rare condition, consisting of well-circumscribed areas of slack skin, in which dermal elastic fibres are destroyed or deficient. We present the case of a 45-year-old man with a 25-year history of deep nodules and plaques gradually progressing to areas of anetoderma. Histological examination found an infiltrate composed of neoplastic cells with lymphoplasmocytoid morphology. The cells were positive for CD20, CD38 and CD138, and there was a monoclonal kappa light chain gene rearrangement of plasma cells. A diagnosis of cutaneous marginal zone B-cell lymphoma was made. The pathogenesis of anetoderma remains unknown, but it is possible that cytokines or other soluble factors produced by the infiltrating lymphocytes have a role in this process. PMID- 19778308 TI - Autosomal dominant chronic mucocutaneous candidiasis and primary hypothyroidism complicated by oesophageal carcinoma. AB - We describe three generations of a white family with autosomal dominant chronic mucocutaneous candidiasis (CMCC) and primary hypothyroidism, which was complicated by squamous cell carcinoma (SCC) of the oesophagus in the index case. We report this family to increase awareness of this rare autosomal dominant variant of CMCC endocrinopathy syndrome associated with primary hypothyroidism without evidence of autoimmune endocrinopathy, and to highlight the risk of developing oesophageal SCC at a young age as a fatal complication of CMCC. PMID- 19778309 TI - Eruptive disseminated Spitz naevi: dermatoscopic features. AB - Eruptive disseminated Spitz naevi is a rarely reported condition. Although the dermatoscopic features of nondisseminated, solitary forms of Spitz naevi are well known, there are no reports describing the dermatoscopic features of eruptive disseminated variant. We report an additional case and describe the dermatoscopic features. Two patterns were observed. In all pink lesions, the vascular pattern was seen, composed of dotted, linear or comma-like vessels located at the centre of the meshes of the reticular depigmentation. In all brown lesions, we observed only the reticular pattern, which is quite interesting as the reticular pattern is a rare feature of Spitz naevi. This observation may be a special feature particularly seen in the eruptive disseminated variant. A superficial black network also accompanied reticular pattern in some lesions. In dichromatic lesions, both patterns were observed in different areas of the body. PMID- 19778310 TI - Dapsone hypersensitivity syndrome with circulating 190-kDa and 230-kDa autoantibodies. AB - Dapsone has potent anti-inflammatory effects, and is used in the treatment of leprosy, cutaneous vasculitis, neutrophilic dermatoses, and dermatitis herpetiformis and other blistering disorders. However, it may cause severe adverse reactions such as hypersensitivity syndrome, which is characterized by fever, skin rash, hepatitis and lymphadenopathy. We report a 44-year-old female Korean patient with dapsone hypersensitivity syndrome (DHS) that presented as a bullous skin eruption. The patient had a 1-year history of urticarial vasculitis, treated with antihistamines, prednisolone and dapsone. Although the skin lesions improved, she reported fever, nausea, abdominal pain, jaundice, fatigue and skin rashes. On physical examination, there were generalized erythematous macules and purpura with facial oedema that developed into vesicles on the upper limbs. Histological examination of a skin biopsy of a vesicular lesion found subepidermal oedema with a mixed inflammatory cell infiltrate, including eosinophils in the dermis. Indirect immunofluorescence testing using normal foreskin as substrate revealed IgG deposits in the basement membrane zone. Circulating autoantibodies against antigens of 190 and 230 kDa were found by immunoblotting analysis using epidermal extracts. This case illustrates DHS with the formation of circulating autoantibodies. PMID- 19778311 TI - Idiopathic pustular vulvitis. AB - A 31-year-old woman presented in the 23rd week of her third pregnancy with extremely painful pustular vulvitis, unresponsive to antibiotics. Although the histological findings were was consistent with a diagnosis of hidradenitis suppurativa (HS), bridged comedones, the hallmark of this disease, were absent and there were no dermal sinuses. Incision and drainage of the pustules provided only temporary improvement, which was briefly maintained with oral clindamycin and topical steroids. After the birth, a course of isotretinoin produced almost total clearance, a response not typically found in HS. This patient's condition may represent a variant of HS, and if so, it would be the first case report of de novo HS in pregnancy, but its clinical features and evolution differed so much from those in HS that the possibility of a previously unrecognised condition cannot be excluded. PMID- 19778312 TI - Simultaneous occurrence of anti-BP180 mucous membrane pemphigoid and mucosal dominant pemphigus vulgaris. AB - We describe the simultaneous initial coexistence of mucous membrane pemphigoid (MMP) with blepharosynechia and anti-bullous pemphigoid (BP)180 antibodies and pemphigus vulgaris (PV) with lesions limited to the oral mucosa, with the presence of anti-desmoglein (Dsg)3 antibodies. A 75-year-old woman had severe oropharyngeal erosions and ulcers with blisters, and blepharoconjunctivitis and blepharosynechia of the left eye. Histopathological examination of the oral mucosa found acantholysis. Indirect immunofluorescence revealed IgG antikeratinocyte cell surface antibodies, and ELISA disclosed anti-Dsg3 antibodies. Immunoblotting found positive reactivity with recombinant proteins of both the BP180-NC16a domain and the BP180 C-terminal domain. To our knowledge, the simultaneous initial occurrence of MMP and PV has never been reported previously. We present a rare case of concurrent PV and anti-BP180 MMP, the diagnosis of which was confirmed by ELISA and immunoblotting assays. PMID- 19778313 TI - Antiretroviral-induced toxic epidermal necrolysis in a patient positive for human immunodeficiency virus. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are two variants on a spectrum of severe systemic hypersensitivity characterized by blistering maculopapular lesions and desquamation of the skin and mucus membranes. Although several causative agents, including infections, have been reported for SJS/TEN, medications remain the most common cause. We report the case of a 42-year-old man with human immunodeficiency virus (HIV) who developed TEN 4 months after starting treatment with darunavir and abacavir. The patient presented with upper body lesions, oral mucosal ulcerations, and impending airway compromise. He was intubated and admitted to the burns unit. Score for Toxic Epidermal Necrolysis (SCORTEN) was 5, with > 90% predicted mortality. However, after intravenous immunoglobulin and supportive treatment, the patient made a remarkable recovery. Abacavir and darunavir may be associated with SJS/TEN. TEN should be considered a risk for patients with HIV and should be monitored for cutaneous eruptions for several months after changes in treatment regimen. PMID- 19778314 TI - Congenital tufted angioma with persistent low-grade coagulopathy. AB - A female infant, born with a tufted angioma, developed a coagulopathy with prolonged bleeding time, with the risk of progression to Kasabach-Merritt phenomenon. The difficulty in this case was judging the degree of this risk and therefore the most appropriate management. We opted for a conservative approach of observation, which was vindicated by the outcome. PMID- 19778315 TI - Dynactin subunit p150Glued isoforms notable for differential interaction with microtubules. AB - Dynactin is a multiprotein complex that enhances dynein activity. The largest dynactin subunit, p150Glued, interacts with microtubules through its N-terminal region that contains a globular cytoskeleton-associated protein (CAP)-Gly domain and basic microtubule-binding domain of unknown structure. The p150Glued gene has a complicated intron-exon structure, and many splice isoforms of p150Glued protein have been predicted. Here we describe novel natural 150 kDa isoforms: the p150Glued-1A isoform, whose basic domain is composed of 41 amino acids, and p150Glued-1B with a basic domain of 21 aa because of the lack of exons 5-7 in the corresponding messenger RNA (mRNA). According to reverse transcriptase-polymerase chain reaction (RT-PCR) and western blot data, p150Glued-1A is expressed in nerve tissues, in cultured cells and in embryonic tissues, while 1B is expressed ubiquitously. Overexpression of GFP-p150Glued-1A and -1B fusion proteins and immunostaining of cultured cells with 1A-specific antibodies show that the p150Glued-1A isoform is distributed along microtubules, whereas 1B is associated with microtubule plus-ends. The higher affinity of the p150Glued-1A isoform for microtubules is confirmed by a co-pelleting assay. In fibroblast-like cells, the interaction of p150Glued-1A with microtubules is less dependent on EB1/EB3 and CLIP170 proteins, compared with p150Glued-1B. In polarized cells, p150Glued-1A decorates microtubules that face the leading edge of the cell. The pattern of p150Glued-1A and p150Glued-1B interaction with microtubules and their tissue specific expression patterns suggest that these isoforms might be involved in cell differentiation and proliferation. PMID- 19778316 TI - Implementation of evidence-based practice in nursing using action research: a review. AB - BACKGROUND: As is often reported in the literature exploring the research practice gap, applying the principles of evidence-based practice is easier said than done. Action research is a methodology with an explicit intent of linking the worlds of research and practice. This review attempts to answer the question: What is known about implementing evidence-based practice in nursing through action research? APPROACH: A total of 21 action research studies have been used to answer this question. To prevent possible confusion over terminology, we used a conceptual framework that distinguishes various influencing factors in terms of four target groups (ranging from the individual end user to society as a whole) at whom the strategy is aimed and various strategies (ranging from individual feedback to contracting care providers) related to the same four target groups. FINDINGS: Studies often failed to name the implementation strategies applied, necessitating deduction from the text by the reader. In most of the studies the implementation strategy was directed at a combination of target groups. Many of the projects reviewed reported positive contextual outcomes, "knowledge improvement" among nurses, and to a lesser degree, improved "performance." Patient outcomes were the least reported outcome measure. CONCLUSION: With an element of caution, this review concludes that the implementation of evidence based practice using action research is a promising approach. Caution is needed because of the lack of detailed descriptions of implementation strategies, and their intensity and frequency prevents us from drawing firm conclusions. These are important considerations for any action researcher intending to implement EBP using this approach. PMID- 19778317 TI - Gene frequencies of platelet-specific antigens in Croatian population. AB - The human platelet antigens (HPA) are genetically defined polymorphisms expressed on platelet membrane glycoproteins. As platelet antigens are very important in several clinical situations and in population genetics, we used the polymerase chain reaction with sequence-specific primers (PCR-SSP) to investigate HPA-1, -2, -3 and -5 allele frequencies in the Croatian population. The HPA frequencies obtained in 219 Croatians were: 1a-0.854, 1b-0.146, 2a-0.890, 2b-0.110, 3a-0.575, 3b-0.425, 5a-0.895 and 5b-0.105. These data are similar to the frequencies reported in most European studies with some significant differences in HPA-2 when compared with the Dutch and German population, in HPA-3 when compared with the Swiss population and in HPA-5 when compared with the Finnish population. The three most common condensed HPA genotypes in the Croatian population were: HPA 1a/a, -2a/a, -3a/b, -5-a/a (0.283), HPA-1a/a, -2a/a, -3a/a, -5-a/a (0.137) and HPA-1a/b, -2a/a, -3a/b, -5-a/a (0.087). Data obtained in this study can be used for better understanding and treatment of immune-mediated platelet disorders in our population. PMID- 19778318 TI - Solvent-detergent filtered (S/D-F) fresh frozen plasma and cryoprecipitate minipools prepared in a newly designed integral disposable processing bag system. AB - Solvent-detergent (S/D) viral inactivation was recently adapted to the treatment of single plasma donations and cryoprecipitate minipools. We present here a new process and a new bag system where the S/D reagents are removed by filtration and the final products subjected to bacterial (0.2 microm) filtration. Recovered and apheresis plasma for transfusion (FFP) and cryoprecipitate minipools (400 +/- 20 mL) were subjected to double-stage S/D viral inactivation, followed by one oil extraction and a filtration on a S/D and phthalate [di(2-ethylhexyl) phthalate (DEHP)] adsorption device and a 0.2 microm filter. The initial and the final products were compared for visual appearance, blood cell count and cell markers, proteins functional activity, von Willebrand factor (VWF) multimers and protein profile by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE). Tri (n-butyl) phosphate (TnBP) was quantified by gas chromatography and Triton X 45 and DEHP by high-performance-liquid chromatography (HPLC). General safety tests were by 6.5 mL/kg intravenous injection in rats. The treated plasmas and cryoprecipitates were very clear and the protein content and functionality, VWF multimers and SDS-PAGE profiles were well preserved. TnBP and Triton X-45 were < 1 and <25 ppm, respectively, and DEHP (about 5 ppm) was less than it was in the starting materials. Blood cell counts and CD45, CD61 and glycophorin A markers were negative. There was no enhanced toxicity in rats. Thus, plasma and cryoprecipitate can be S/D-treated in this new CE-marked disposable integral processing system under conditions preserving protein function and integrity, removing blood cells, S/D agents and DEHP, and ensuring bacterial sterility. This process may offer one additional option to blood establishments for the production of virally inactivated plasma components. PMID- 19778319 TI - Economical impact of plasma fractionation project in Iran on affordability of plasma-derived medicines. AB - In Iran all transfusion services are concentrated under authority of one public and centralized transfusion organization which has created the opportunity of using plasma produced in its blood centers for fractionation. In 2008 voluntary and non remunerated Iranian donors donated 1.8 million units of blood. This indicates a 25/1000 donation index. After responding to the needs for fresh plasma and cryoprecipitate each year about 150000 L of recovered plasma are reserved for fractionation. In an attempt to improve both blood safety profile and availability and affordability of plasma derived medicines, Iran's national transfusion service has entered into a contract fractionation agreement for surplus of plasma produced from donated blood by voluntary non remunerated donors. In order to ensure safety of product produced, Iran has chosen to collaborate with international fractionators based in highly regulated countries. The main objective of this study was to evaluate the impact of contract plasma fractionation on the affordability of the plasma derived medicines in Iran. During 2006-2008, Iran's contract fractionation project was able to produce 46%, 18% and 6% of IVIG, Albumin and FVIII consumed in Iran's market, respectively. In contrary to IVIG and Albumin, due to fairly high consumption of FVIII in Iran, the role of fractionation project in meeting the needs to FVIII was not substantial. However, Iran's experience has shown that contract plasma fractionation, through direct and indirect effects on price of plasma derived medicines, could substantially improve availability and affordability of such products in national health care system. PMID- 19778320 TI - Complete genomic sequence of a novel HLA-B*1325 allele observed in a Chinese Han individual. AB - The complete genomic sequence of HLA-B*1325 allele shows one nucleotide difference from B*130101 at nt 302 where A --> G resulting in an amino acid substitution from Asn(AAC) to Ser(AGC) at codon 77 in exon 2. PMID- 19778321 TI - High resolution definition of HLA-DRB haplotypes by a simplified microsatellite typing technique. AB - In humans, the region configurations DR1, DR8, DR51, DR52 and DR53 are known to display copy number as well as allelic variation, rendering high resolution typing of HLA-DRB haplotypes cumbersome. Advantage was taken of microsatellite D6S2878, present in all DRB genes/pseudogenes with an intact exon 2-intron 2 segment. This DRB-STR is highly polymorphic in composition and length. Recently, it was proven that all exon 2 sequences could be linked to a certain DRB-STR that segregates with the respective DRB allele. Because haplotypes show differential copy numbers and compositions of exon 2-positive DRB genes/pseudogenes, unique DRB-STR patterns could be described that appear to be specific for a particular DRB haplotype. The aim of this workshop project was to approve and to qualify this simple typing protocol in a larger panel covering different European populations. All participants succeeded in correctly defining the DRB-STR amplicons varying from 135 to 222 base pair (bp) lengths. The panel of 101 samples covered 50 DRB alleles distributed over 37 different haplotypes as defined by exon 2 sequence-based typing. These haplotypes could be refined into 105 haplotypes by DRB-STR typing. Thus, discrimination of exon 2-identical DRB alleles was feasible, as well as the exact description of three different crossing-over events that resulted in the generation of hybrid DR region configurations. This typing procedure appears to be a quick and highly robust technique that can easily be performed by different laboratories, even without experience in microsatellite typing; thus, it is suitable for a variety of researchers in diverse research areas. PMID- 19778322 TI - Overeruption of periodontally affected unopposed molars in adult rats. AB - BACKGROUND AND OBJECTIVE: In clinical practice, anterior teeth with periodontal disease exhibiting signs of overeruption are occasionally encountered. However, the influence of periodontitis on unopposed teeth needs to be further elucidated. This study investigated, in rats, the overeruption pattern of unopposed mandibular molars with experimentally induced periodontitis. MATERIAL AND METHODS: Sixty adult male rats were divided equally into four groups. In two groups, periodontitis was induced by a silk thread placed around the cervix of the right mandibular molar. In two groups with and without experimentally induced periodontitis, the crowns of the right maxillary molars were reduced occlusally by grinding to simulate unopposed teeth. After 4 wk, the animals were killed and scanned using micro-computed tomography to measure the vertical position of molars and the buccal and lingual alveolar bone levels. RESULTS: There were no significant differences in the overeruption of opposed molars with and without periodontitis. However, the alveolar bone level of opposed molars with periodontitis was lower than that of healthy molars. Healthy unopposed molars were extruded when compared to molars with an antagonist. The alveolar bone level of healthy unopposed molars was not influenced by molar overeruption. Unopposed molars with periodontitis exhibited significantly larger extrusion than healthy unopposed molars. The lingual alveolar bone level of unopposed molars with periodontitis was lower than that of other healthy and periodontally affected teeth. CONCLUSION: The loss of antagonist causes overeruption of the unopposed tooth, which becomes more prominent in the presence of periodontitis. PMID- 19778323 TI - Gingival and periodontal ligament fibroblasts differ in their inflammatory response to viable Porphyromonas gingivalis. AB - BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis is an oral pathogen strongly associated with destruction of the tooth-supporting tissues in human periodontitis. Gingival fibroblasts (GF) and periodontal ligament fibroblasts (PDLF) are functionally different cell types in the periodontium that can participate in the host immune response in periodontitis. This study aimed to investigate the effects of viable P. gingivalis on the expression of genes associated with inflammation and bone degradation by these fibroblast subsets. MATERIAL AND METHODS: Primary human GF and PDLF from six healthy donors were challenged in vitro with viable P. gingivalis W83 for 6 h. Gene expression of inflammatory cytokines in GF and PDLF was analyzed using real-time PCR, and protein expression was analyzed using ELISA. RESULTS: Viable P. gingivalis induced a strong in vitro inflammatory response in both GF and PDLF. We found increased gene expression of interleukin (IL)-1beta, IL-6, IL-8, tumor necrosis factor-alpha, monocyte chemotactic protein-1 and regulated upon activation, normal T-cell expressed and secreted (RANTES). Macrophage colony-stimulating factor was induced and the expression of osteoprotegerin was decreased in GF, but not in PDLF. In nonchallenged cells, a higher level of expression of IL-6 was observed in GF than in PDLF. Between individual donors there was large heterogeneity in responsiveness to P. gingivalis. Also, in each individual, either GF or PDLF was more responsive to P. gingivalis. CONCLUSION: Considerable heterogeneity in responsiveness to P. gingivalis exists both between GF and PDLF and between individuals, which may be crucial determinants for the susceptibility to develop periodontitis. PMID- 19778324 TI - Effects of N-acyl homoserine lactone analogues on Porphyromonas gingivalis biofilm formation. AB - BACKGROUND AND OBJECTIVE: The gram-negative anaerobic rod Porphyromonas gingivalis in oral biofilms is a primary etiological agent of periodontal disease. Biofilm formation of various gram-negative bacteria is regulated by a quorum-sensing circuit that relies on N-acyl homoserine lactones (HSLs). Some synthetic N-acyl HSL analogues act as quorum-sensing inhibitors and suppress biofilm formation in Pseudomonas aeruginosa. Development of chemical control agents against oral biofilms is necessary, because until now, biofilms have been removed only by mechanical debridement. The present study investigated the effect of N-acyl HSL analogues on P. gingivalis biofilm formation, with the aim of developing new drugs that inhibit oral biofilm formation. MATERIAL AND METHODS: A flow-cell model was used for P. gingivalis biofilm formation. Seventeen synthetic N-acyl HSL analogues were quantitatively assessed by spectrophotometry. The effects of three antagonistic compounds against P. gingivalis biofilm formation were further examined by confocal laser scanning microscopy, and investigated for primary attachment using spectrophotometry and phase contrast microscopy. RESULTS: Ten out of 17 analogues affected P. gingivalis biofilm formation. Three out of 10 analogues significantly decreased biofilm-forming cells (p < 0.05), and these biofilm structures were less well formed three-dimensionally. There were no quantitative or qualitative differences in cell attachment between the control and the three analogue-treated groups. CONCLUSION: Three synthetic N-acyl HSL analogues inhibited biofilm formation in P. gingivalis. We suggest that these analogues influence the development stage of P. gingivalis biofilm formation. PMID- 19778325 TI - Localization of SOST/sclerostin in cementocytes in vivo and in mineralizing periodontal ligament cells in vitro. AB - BACKGROUND AND OBJECTIVE: Cementum and bone are rather similar hard tissues, and osteocytes and cementocytes, together with their canalicular network, share many morphological and cell biological characteristics. However, there is no clear evidence that cementocytes have a function in tissue homeostasis of cementum comparable to that of osteocytes in bone. Recent studies have established an important role for the secreted glycoprotein sclerostin, the product of the SOST gene, as an osteocyte-derived signal to control bone remodelling. In this study, we investigated the expression of sclerostin in cementocytes in vivo as well as the expression of SOST and sclerostin in periodontal ligament cell cultures following induction of mineralization. MATERIAL AND METHOD: Immunolocalization of sclerostin was performed in decalcified histological sections of mouse and human teeth and alveolar bone. Additionally, periodontal ligament cells from human donors were cultured in osteogenic conditions, namely in the presence of dexamethasone, ascorbic acid and beta-glycerophosphate, for up to 3 wk. The induction of calcified nodules was visualized by von Kossa stain. SOST mRNA was detected by real-time PCR, and the presence of sclerostin was verified using immunohistochemistry and western blots. RESULTS: Expression of sclerostin was demonstrated in osteocytes of mouse and human alveolar bone. Distinct immunolocalization in the cementocytes was shown. In periodontal ligament cultures, following mineralization treatment, increasing levels of SOST mRNA as well as of sclerostin protein could be verified. CONCLUSION: The identification of SOST/sclerostin in cementocytes and mineralizing periodontal ligament cells adds to our understanding of the biology of the periodontium, but the functional meaning of these findings can only be unravelled after additional in vitro and in vivo studies. PMID- 19778326 TI - Detection of oxidized low-density lipoproteins in gingival crevicular fluid from dental patients. AB - BACKGROUND AND OBJECTIVE: Oxidative modification of low-density lipoprotein (LDL) occurs in various diseased tissues and sites of local inflammation. For example, an increased plasma oxidized low-density lipoprotein (OxLDL) level is a well known risk marker for cardiovascular diseases. Gingival crevicular fluid, the exudate from gingival tissues into the sulci, can be easily collected in a non invasive manner. However, the possible presence of OxLDL in gingival crevicular fluid has not been studied. In this study, we established a procedure to measure OxLDL in human gingival crevicular fluid. MATERIAL AND METHODS: Human gingival crevicular fluid was sampled with paper points or paper strips. The gingival crevicular fluid samples from healthy gingival sulci (pocket depth < 4 mm, n = 14) were subjected to western blot and/or sandwich ELISA. The amounts of OxLDL and LDL were measured by sandwich ELISA using an anti-oxidized phosphatidylcholine monoclonal antibody and two anti-apolipoprotein B antibodies. Venous blood samples were analyzed biochemically. RESULTS: We tested two methods of gingival crevicular fluid collection, namely paper points and paper strips. Gingival crevicular fluid could be collected very safely with paper points and they showed good recovery of LDL and OxLDL throughout the analysis. Apolipoprotein B, the major protein component in LDL, was detected in gingival crevicular fluid by western blot, and OxLDL was found to be present in gingival crevicular fluid by ELISA. The OxLDL/LDL ratio in gingival crevicular fluid was 17.0 times higher than that in plasma. CONCLUSION: This is the first report to show the presence of apolipoprotein B and apolipoprotein B- oxidized phosphatidylcholine complex, which correspond to LDL and OxLDL, respectively, in gingival crevicular fluid. PMID- 19778327 TI - Enhanced monocyte migration and pro-inflammatory cytokine production by Porphyromonas gingivalis infection. AB - BACKGROUND AND OBJECTIVE: Porphyromonas gingivalis, a major periodontal pathogen, has been reported to be involved in atherogenesis. In order to further understand this pathogen's link with systemic inflammation and vascular disease, we investigated its influence on murine monocytes and macrophages from three different sources. MATERIAL AND METHODS: Concanavalin A-elicited peritoneal macrophages, peripheral blood monocyte-derived macrophages and WEHI 274.1 monocytes were infected with either P. gingivalis 381 or its non-invasive fimbriae-deficient mutant, DPG3. RESULTS: Infection with P. gingivalis 381 markedly induced monocyte migration and significantly enhanced production of the pro-inflammatory cytokines, tumor necrosis factor-alpha and interleukin-6. Consistent with a role for this pathogen's major fimbriae and/or its invasive capacity, infection with DPG3 had a minimal effect on both monocyte attraction and pro-inflammatory cytokine production. CONCLUSION: Since monocyte recruitment and activation are important steps in the development of vascular inflammation and atherosclerosis, these results suggest that P. gingivalis infection may be involved in these processes. PMID- 19778328 TI - Influence of serum on interaction of Porphyromonas gingivalis ATCC 33277 and Aggregatibacter actinomycetemcomitans Y4 with an epithelial cell line. AB - BACKGROUND AND OBJECTIVE: The purpose of this study was to investigate the influence of serum on the interaction of periodontal pathogens with epithelial cells using an epithelial cell line (KB cells). This is important because serum is a key component of gingival crevicular fluid and may influence inflammatory responses in epithelial cells exposed to periodontal pathogens. MATERIAL AND METHODS: Porphyromonas gingivalis ATCC 33277 and Aggregatibacter actinomycetemcomitans Y4 were co-cultured with KB cells either with or without the addition of up to 10% human serum or 50 mg/mL human serum albumin. The numbers of free-floating, adherent and intracellular bacteria were determined up to 18 h after exposure of the epithelial cells to the pathogens. Additionally, the concentrations of interleukin (IL)-6 and IL-8 produced by the epithelial cells in response to exposure to the bacteria were determined. RESULTS: Serum and human serum albumin reduced the number of internalized A. actinomycetemcomitans Y4 organisms in the epithelial cells, increased the levels of IL-6 and IL-8 in the supernatants of infected cells (those with internalized A. actinomycetemcomitans) and influenced non-infected epithelial cells. Increased IL 6 and IL-8 concentrations were also detected in the supernatants of KB cells infected with P. gingivalis ATCC 33277. Interleukin-6 and IL-8 were detectable after addition of serum, probably as a result of inhibition of the activity of P. gingivalis cysteine proteinases by serum. CONCLUSION: Serum promotes the release of the cytokines IL-6 and IL-8 by epithelial cells. This mechanism is influenced by periodontal pathogens and may maintain clinical periodontal inflammation. PMID- 19778329 TI - Matrix metalloproteinase-3 gene polymorphism in renal transplant patients with gingival overgrowth. AB - BACKGROUND AND OBJECTIVE: Gingival enlargement frequently occurs in transplant patients receiving immunosuppressive drugs. It was hypothesized that gingival enlargement associated with cyclosporine use results from reduced degradation of extracellular matrix in the gingiva. Matrix metalloproteinase-3 (MMP-3) is involved in biodegradation of the extracellular matrix, and its inhibition may contribute to an abnormal accumulation of fibronectin and proteoglycans, which are MMP-3 substrates. The aim of this study was to investigate whether an association exists between MMP-3 genotypes and gingival enlargement in kidney transplant patients medicated with cyclosporine A. MATERIAL AND METHODS: Sixty four unrelated kidney transplant patients suffering from gingival overgrowth, as well as 111 control transplant patients without gingival overgrowth, were enrolled in the study. Gingival overgrowth was assessed 6 mo after transplantation. During the post-transplant period all patients were given cyclosporine A as a principal immunosuppressive agent. MMP-3 polymorphism was determined using a PCR restriction fragment length polymorphism assay. RESULTS: In kidney transplant patients suffering from gingival overgrowth the mean gingival overgrowth score was 1.35 +/- 0.57, whereas in control subjects the mean gingival overgrowth score was 0.0. The distribution of MMP-3-1178A/dupA alleles among all kidney transplant patients, as well as in the two study subgroups, did not differ significantly from Hardy-Weinberg equilibrium. The frequency of the MMP-3-1171A/A genotype (28.1% for gingival overgrowth vs. 26.1% for controls) and of the MMP-3-1171dupA/dupA genotype (32.8% for gingival overgrowth vs. 22.5% for controls) was similar for both study groups. The risk of gingival overgrowth was lowest among patients carrying the MMP-3-1171A/dupA genotype (odds ratio 0.52), but this did not differ markedly from the other genotypes. CONCLUSION: No association between MMP-3 gene polymorphism and gingival overgrowth was revealed in kidney transplant patients administered cyclosporine A. PMID- 19778330 TI - Periodontitis as a risk factor for cerebrovascular accident: a case-control study in the Indian population. AB - BACKGROUND AND OBJECTIVE: Chronic infections have been reported to be risk factors for coronary heart disease and ischemic stroke. However, the association of coronary heart disease and ischemic stroke with periodontal disease, which is also a chronic inflammatory disease, needs to be evaluated. The present case control study was designed to determine if an association exists between periodontal disease and cerebrovascular accident in the Indian population. MATERIAL AND METHODS: This case-control study consisted of 200 subjects (100 cases and 100 controls) who were 33-68 years of age. Cases were examined within 5 d after their first acute ischemic attack. Clinical parameters recorded included plaque index, gingival index, probing pocket depth and clinical attachment loss. The medical questionnaire collected information on family history of stroke, dietary history, history of smoking and history of alcohol consumption. Cases were additionally scrutinized for diabetes, hypertension and total serum cholesterol level. The education level of patients was also considered. RESULTS: The mean plaque index, gingival index, probing pocket depth and clinical attachment loss values of subjects with cerebrovascular accident were significantly higher when compared with those of the control group (p < 0.05). In fully adjusted logistic regression analysis, a probing pocket depth of > 4.5 mm was found to be the most significant factor for stroke (odds ratio = 8.5; confidence interval = 1.1-68.2) followed by hypertension (odds ratio = 7.6; confidence interval = 3.3-17.1) and smoking (odds ratio = 3.1; confidence interval = 1.3-7.4). CONCLUSION: The data from this study support the proposed link between periodontitis and cerebrovascular accident in the Indian population. However, further studies are necessary to verify and quantify the role of oral infections and genetic factors in the process of atherosclerosis. PMID- 19778331 TI - Changes in cell characteristics due to retinoic acid; specifically, a decrease in the expression of claudin-1 and increase in claudin-4 within tight junctions in stratified oral keratinocytes. AB - BACKGROUND AND OBJECTIVE: It has been reported that retinoic acid disintegrates the desmosome formation of squamous epithelium, resulting in inhibition of stratification. In contrast, it is not known whether retinoic acid influences the integration of tight junctions. Therefore, our objective of this study is to disclose effects of retinoic acid on the formation and maintenance of tight junction. MATERIAL AND METHODS: In the present study, the alteration of expression of tight junction constituent proteins and keratin peptides in immortalized oral mucosal epithelial cells (GE1) induced by 1 microm retinoic acid was analyzed by immunofluorescence, electron microscopy and reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The stratifying GE1 cells expressed claudin-1, claudin-4, claudin-5, occludin and zonula occludens 1 in the control culture. The RT-PCR showed that retinoic acid significantly reduced the expression of claudin-1 mRNA, whereas it dramatically enhanced expression of claudin-4 mRNA. Immunofluorescence showed that claudin-1 was present at cell-to-cell contact sites in the flattened uppermost layers of the control culture. In the culture with retinoic acid, the flattened uppermost cells were absent and there claudin-1 was less present, but claudin-4 was prominently present in all layers. Claudin-5 was present in a variety of patterns, regardless of the presence of retinoic acid. Along with the change of claudin species, the expressions of keratin 7, keratin 8 and keratin 18, as markers for the simple epithelium, were clearly stimulated by retinoic acid. CONCLUSION: Retinoic acid changed the expression of tight junction constituent molecules, such as claudin-1 and claudin-4, in oral keratinocytes. These findings suggest that long-term application of retinoids in clinical therapy should be carefully performed. PMID- 19778332 TI - Short-term induction of thrombocytopenia delays periodontal healing in rats with periodontal disease: participation of endostatin and vascular endothelial growth factor. AB - BACKGROUND AND OBJECTIVE: Platelets contain factors, including VEGF and endostatin, that can modulate the healing process. We evaluated the effects of severe thrombocytopenia on periodontal healing in rats and determined the contribution of VEGF and endostatin to the healing process. MATERIAL AND METHODS: Rats were distributed into three test groups and two control groups. Cotton ligatures were placed at the gingival margin level of the lower first molar in the test groups. Sham-operated rats and rats in one of the periodontitis groups were killed 15 days later. Rats in the remaining two periodontitis groups had the ligatures removed in order to study the spontaneous recovery from the periodontal disease 15 days later, and these rats were treated with rabbit antiplatelet serum, in order to induce thrombocytopenia, or normal rabbit serum. An additional group without ligatures received antiplatet serum in the same period. RESULTS: After ligature removal, rats treated with normal rabbit serum showed reduced myeloperoxidase activity, decreased alveolar bone loss and increased numbers of blood vessels. Thrombocytopenia caused a delay in alveolar bone regeneration, a decrease in the number of vessels and a modest decrease in myeloperoxidase activity. In the rats with periodontitis, serum endostatin concentrations were slightly decreased and serum VEGF remained unchanged compared with sham-operated animals. After ligature removal, a significant VEGF increase and endostatin decrease were observed in the rats treated with normal rabbit serum. Thrombocytopenia led to a dramatic fall in both VEGF and endostatin concentrations. CONCLUSION: Thrombocytopenia leads to a delay of periodontal healing in the situation of experimental periodontitis, which might be mediated in part by a decrease in the serum concentration of VEGF and endostatin derived from the platelets. However, other factors derived from the platelets may also have contributed to a delay of periodontal healing in the rats with thrombocytopenia. PMID- 19778333 TI - Analysis of matrix metalloproteinase (MMP-8 and MMP-2) activity in gingival crevicular fluid from children with Down's syndrome. AB - BACKGROUND AND OBJECTIVE: High levels of colonization by periodontopathic bacteria and a high prevalence of chronic inflammatory periodontal disease have been reported in children with Down's syndrome. Matrix metalloproteinases (MMPs) are mediators of extracellular matrix degradation and remodelling, and are deeply involved in the course of periodontal disease. To clarify the relationship between Down's syndrome and periodontitis, we investigated levels of MMP-2 and MMP-8 in gingival crevicular fluid (GCF) and detection of periodontopathic bacteria from subgingival plaque. MATERIAL AND METHODS: Samples of GCF and plaque were isolated from central incisors. Levels of MMPs were evaluated by enzyme linked immunosorbent assay, and periodontopathic bacteria were detected by polymerase chain reaction. RESULTS: Levels of MMP-2 and MMP-8 in Down's syndrome patients were higher than those in healthy control subjects. In the Down's syndrome group, increases in these MMPs were observed in GCF from patients with an oral hygiene index score of < 2 and in GCF from sites that were negative for bleeding on probing. The detection rate of periodontopathic bacteria in Down's syndrome patients was higher than that in the control subjects. Matrix metalloproteinase-2 levels in sites harbouring Porphyromonas gingivalis or Aggregatibacter (Actinobacillus) actinomycetemcomitans were lower than in those without these microorganisms. CONCLUSION: These results suggest an increase in MMP-2 and MMP-8 in Down's syndrome patients, regardless of whether inflammation of periodontal tissue is present or not. PMID- 19778334 TI - Expression of receptor activator of nuclear factor kappaB ligand in ligature induced periodontitis in osteoporotic and non-osteoporotic rats. AB - BACKGROUND AND OBJECTIVE: This study investigated the expression of a key mediator that regulates differentiation of osteoclasts, receptor activator of nuclear factor kappaB ligand (RANKL), in rats with or without osteoporosis and periodontitis, to provide a better understanding of the association between these two diseases. MATERIAL AND METHODS: Forty adult Albino rats were divided into four groups: (1) control group; (2) experimentally induced periodontitis group; (3) experimentally induced osteoporosis group; and (4) experimentally induced osteoporosis and periodontitis group. At the end of the experimental period, blood samples were obtained and animals were sacrificed. Serum alkaline phosphatase (ALP) activity levels were measured. Histological evaluation and immunohistochemical detection of RANKL in the periodontal ligament and bone tissues were performed. RESULTS: There were significantly higher ALP levels in all of the experimental groups than in the control group. The pathology observed in the histological sections from group 4 was more severe than in either group 2 or group 3. The percentage of RANKL-immunoreactive cells in both the periodontal ligament and bone tissues in group 4 (16.8 +/- 5.1 and 11.2 +/- 5.2%, respectively) was significantly higher (p < 0.001) than in the other groups. In the periodontal ligament, the percentage of RANKL-immunoreactive cells in group 2 (10.1 +/- 1.9%) was significantly higher (p < 0.001) than in group 3 (5.3 +/- 2.7%) and the control group (4.12 +/- 1.5%). CONCLUSION: The increased bone loss observed in group 4 compared with either group 2 or group 3 supports the existence of an additive pathological effect of the two disease conditions. This is consistent with the increased RANKL expression observed in group 4. PMID- 19778335 TI - Recent advances in laboratory assays for nonhemolytic transfusion reactions. AB - Nonhemolytic transfusion reactions (NHTRs) are the most common transfusion reactions and include transfusion-related acute lung injury (TRALI) and allergic and febrile reactions. White blood cell (WBC) antibodies (Abs) against human leukocyte antigen (HLA) and human neutrophil antigen (HNA) in blood components are frequently implicated in NHTRs, especially in TRALI. Recently, we established a five-cell-lineage immunofluorescence test, a modified granulocyte immunofluorescence test, and a panel of cell lines stably expressing HNAs for efficient detection of Abs against well-known HNA-1 to HNA-5, and also Abs against neutrophil antigens other than HNA-1 to HNA-5. Using these techniques, we found that most of the non-HLA WBC Abs detected in NHTR cases were against antigens other than HNA-1 to HNA-5. In addition, using our newly established neutrophil activation test, which assesses neutrophil activation elicited by immunologic stimuli such as WBC Abs and immune complex, we found that heparin binding protein is a potential final effector molecule that induces NHTRs, including TRALI. More recently, we reported that the basophil activation test, which was originally developed to identify allergens in the field of allergic diseases, might be useful in transfusion medicine. In this review, we summarize these new techniques and other related tests. PMID- 19778336 TI - A prospective study of multiple donor exposure blood recipients: surveillance value and limitations for hemovigilance. AB - BACKGROUND: There have been few recent systematic studies of blood recipients for direct evidence of blood safety, especially for emerging pathogens that may pose a threat to the blood supply. STUDY DESIGN AND METHODS: Recipients who would likely require transfusion from multiple donors were recruited and a blood specimen was collected before their first study transfusion and at intervals after their study transfusion(s). Blood samples associated with the units that were transfused to enrolled recipients were also collected. Part of each recipient specimen and selected donor specimens was tested for the targeted blood borne agents, parvovirus B19 (B19) and Chlamydia pneumoniae (Cp), that were piloted in this study, and the remaining material was kept in a repository. RESULTS: Between April 2004 and December 2006, a total of 120 recipients were recruited with 4047 subsequent donor exposures. On average, each recipient was followed up seven times. Of recipients who were adequately followed up and were initially immunoglobulin G antibody negative, one in 31 and one to two in 49 seroconverted to B19 and Cp after a total of 922 and 1413 evaluable transfusions, respectively. The detection of seroconversion was complicated by passively acquired donor antibodies for these two seroprevalent agents. Negative results for nucleic acids of the agents limited our ability to further clarify the relationship of these seroconversions to transfusion-transmitted infection. CONCLUSION: The risk of transfusion-associated B19 infection appears to be low but no conclusion of transfusion transmission can be made for Cp. The approach piloted through this study offers added value beyond the current hemovigilance strategy in the United States. PMID- 19778337 TI - Effects of anemia and blood transfusion in acute myocardial infarction in rats. AB - BACKGROUND: The optimal hemoglobin (Hb) level in acute myocardial infarction (MI) is unknown. The goal of this study was to determine the optimal Hb concentration in acute MI and whether transfusion of fresh blood to correct anemia reduces myocardial injury and improves outcome. STUDY DESIGN AND METHODS: Anemia was induced in rats by an iron-deficient diet and phlebotomy. MI was induced by left coronary artery ligation. Some rats received transfusion of fresh blood. Survival, hemodynamic measurements, and infarct size were determined 24 hours after MI. RESULTS: Reduction of Hb to 80 to 90 and 70 to 80 g/L decreased 24-hour survival after MI to 42 and 47%, respectively (p < 0.05). Infarct size was increased in both 70 to 80 and 80 to 90 g/L anemic groups compared to the normal Hb group (p < 0.05). Cardiac function was decreased in anemic groups after MI (p < 0.01). Transfusion of fresh blood to increase Hb from 80 to 90 g/L to 100 g/L decreased infarct size (p < 0.05) and improved cardiac function (p < 0.05), and a trend toward better survival (73%) was observed. Transfusion from 80 to 90 g/L Hb to 120 g/L Hb was associated with larger infarct size (p < 0.05), decreased cardiac function (p < 0.05), and no improvement in survival (47%, p = NS). CONCLUSION: Anemia increases infarct size and decreases cardiac function and survival in acute MI. Transfusion of anemic animals up to 100 g/L Hb with fresh blood reduces infarct size and improves cardiac function. However, transfusion to 120 g/L Hb did not demonstrate any additional benefit and was associated with larger infarcts. PMID- 19778338 TI - Core temperature changes in resuspended red blood cells (RBCs) and pediatric RBCs removed from refrigerated storage. AB - BACKGROUND: The 30-minute rule, whereby intact red blood cell (RBC) products may be returned to stock if returned to 4 degrees C storage within 30 minutes of issue, was established many years ago. It was based on observations that the core temperature of units of whole blood removed from storage temperatures of 1 to 6 degrees C, and left at room temperature, would reach 10 degrees C at between 45 minutes and 1 hour. STUDY DESIGN AND METHODS: Forty-one units of RBCs resuspended leukoreduced and 8 units of pediatric RBCs resuspended leukoreduced were exposed to ambient temperature for periods of time between 0 and 60 minutes. Core temperatures of all units were measured at 1-minute or 5-minute intervals. RESULTS: Resuspended RBCs units reached a mean core temperature of 10 degrees C at 15 minutes, 12.7 degrees C at 30 minutes, and 15 degrees C at 60 minutes. Pediatric RBCs reached a mean core temperature of 12.8 degrees C at 15 minutes, 15.5 degrees C at 30 minutes, and 17.8 degrees C at 60 minutes. CONCLUSION: In view of our results, and the range of RBC products now available, it may be timely for blood services to review and reduce the 30-minute rule. PMID- 19778339 TI - A new cold autoagglutinin specificity: the third external loop of band 3. AB - BACKGROUND: Cold autoagglutinins (CAs) are almost always of immunoglobulin (Ig)M class and specific for carbohydrate antigens. We report a case of hemolytic anemia caused by a mixture of IgM and IgG cold agglutinins. Both agglutinins were specific for the third extracellular loop of band 3. CASE REPORT: The patient, a 46-year-old man with no medical history, was admitted for an acute, life threatening hemolytic anemia caused by a cold agglutinin. Improvement was obtained after plasmapheresis, red blood cell (RBC) transfusions, and steroid therapy. Recovery was complete and no etiology was found. STUDY DESIGN AND METHODS: Conventional serologic procedures and immunochemical methods were used. RESULTS: The patient's autoantibody was directed to an antigen equally expressed by adult and cord RBCs, resistant to papain, neuraminidase, and endo-beta galactosidase treatments. This pattern of reactivity excluded all known specificities of cold agglutinins. The antibody failed to react with RBCs treated by alpha-chymotrypsin or pronase, suggesting that it may be directed to the third extracellular loop of band 3. Serum fractionation showed that the cold agglutinin was composed of IgM and IgG class antibodies. Antibody specificity was confirmed by blocking tests using murine monoclonal antibodies against band 3 and by immunoprecipitation. CONCLUSION: This is to our knowledge the first observation of a CA specific for band 3. The coexistence of IgM and IgG molecules, a very unusual feature for a CA, may be related to the peptidic nature of the target antigen. PMID- 19778340 TI - Partial C antigen in sickle cell disease patients: clinical relevance and prevention of alloimmunization. AB - BACKGROUND: Partial Rh antigens have been widely described in black individuals. Carriers are prone to immunization when exposed to the normal antigens. In sickle cell disease (SCD), patient alloimmunization is a major cause of transfusion failure. The potential of individuals with partial C antigen to make anti-C has not been investigated. We sought partial C status and anti-C production in a cohort of SCD patients with the C+ phenotype, to determine whether exposure to normal C antigen should be avoided. STUDY DESIGN AND METHODS: We constituted a cohort of 177 randomly selected SCD patients expressing C antigen. We screened for (C)ce(s) and R(N) haplotypes, presumably associated with partial C antigen in Afro-Caribbeans, and we recorded the number of transfused C+ red blood cell (RBC) units, immunization status, and extended phenotype. RESULTS: Forty-nine patients carried abnormal C antigen, deduced from the presence of (C)ce(s) and/or R(N), not compensated by a normal RHC allele in trans. Among patients with partial C phenotype exposed repeatedly to C+ RBCs, 30% produced anti-C. Two patients experienced hemolysis. In our hospital, with 22% of SCD patients expressing C, prevention of anti-C immunization for all individuals with partial C antigen would require a 7% increase in the use of C- RBC units. These RBCs are already in short supply for SCD patients who are C-. CONCLUSION: This study demonstrates the need to detect partial C within C+ SCD patients and to prevent immunization. A larger number of Afro-Caribbeans donors is needed to provide these patients with C- RBCs. PMID- 19778341 TI - Education in donation coping strategies encourages individuals to give blood: further evaluation of a donor recruitment brochure. AB - BACKGROUND: This study extends our prior assessment of a blood donation recruitment brochure by assessing persistence of observed changes in attitudes toward donation as well as the effects that such changes have on the behavior of registering to give blood. STUDY DESIGN AND METHODS: Participants were randomly assigned to read 1) a study brochure addressing common donor concerns and suggesting specific coping strategies, 2) a blood center brochure, or 3) a control brochure on healthy eating and exercise. Measures of blood donation attitudes, donation-related anxiety, confidence in ability to avert vasovagal reactions, and intentions to give blood in the near future were completed before and after reading the brochures and again approximately 1 week later. In addition, participants were given the opportunity to sign up for an upcoming blood drive immediately after reading the brochure. RESULTS: Relative to the control brochure, the study brochure was associated with improvements in donation attitude, anxiety, confidence, and intention, and all of these effects persisted at follow-up. Further, participants who read the study brochure were more likely to volunteer to give blood, an effect that was mediated by enhanced confidence in their ability to avoid vasovagal reactions. CONCLUSIONS: Exposure to a brief educational brochure can enhance prospective donor confidence and increase the likelihood that they will volunteer to give blood. PMID- 19778342 TI - Analysis of sexual functions in male nondiabetic hemodialysis patients and renal transplant recipients. AB - SUMMARY: Disturbance of sexual functions among hemodialysis patients and renal transplant recipients (RTRs) is controversial. Diabetes mellitus (DM) is known to have a significant negative impact on sexual functions. Most previous studies concerning the issue of disturbance of sexual functions among hemodialysis patients and renal transplant recipients have included diabetic patients also, which might have influenced their results. The aim of this study was to evaluate sexual functions of nondiabetic male (NDM) dialysis patients and RTRs, and to compare our findings with those of the others. Twenty-five nondiabetic male RTRs, 25 age-matched NDM hemodialysis patients, and 25 age-matched NDM controls were the subjects of this study. Sexual functions of all subjects were assessed using the International Index of Erectile Function (IIEF) questionnaire. Statistical analysis was performed using appropriate statistical tests with the level of significance set at P < 0.05. Data were described using mean, standard deviation (SD), median and interquartile range (IQR). Renal transplant recipients (RTRs) and hemodialysis patients had depressed erectile function (EF) and Intercourse satisfaction (IS) function, but normal orgasmic (OF) function. Sexual desire (SxD) function of RTRs group, although subnormal, was better than that of hemodialysis patients. Overall satisfaction (OS) of RTRs, unlike that of hemodialysis patients, was normal. Sexual dysfunction is prevalent even in NDM hemodialysis patients and RTRs. Although ED is equally prevalent among these two groups, it is more profound among the former one. OF is spared in these patients. Renal transplantation seems to normalize OS and improve SxD function of nondiabetic male renal transplant recipients (NDM RTRs). PMID- 19778343 TI - 'When good kidneys pump badly': outcomes of deceased donor renal allografts with poor pulsatile perfusion characteristics. PMID- 19778344 TI - Characterization of enterococci populations collected from a subsurface flow constructed wetland. AB - AIMS: The aim of this study was to identify and characterize the population of Enterococcus sp. in domestic wastewater as it flows through a constructed wetland. METHODS AND RESULTS: Four hundred and eighty-four Enterococcus isolates were collected from the inlet, various sites within and from the outlet of a plastic lined constructed wetland in College Station, TX. The wetland treated septic tank effluent that passed sequentially through two 1.89 m(3) septic tanks and a 1.89 m(3) pump tank allowing 48 l doses at a 24 l min(-1) rate. The Enterococcus isolates were identified to species using the commercial Biolog system. The 484 Enterococcus isolates were comprised of ten different species, including Enterococcus faecalis (30.6%), Enterococcus pseudoavium (24.0%), Enterococcus casseliflavus (12.8%), Enterococcus faecium (11.2%), Enterococcus mundtii (7.9%), Enterococcus gallinarum (6.2%), Enterococcus dispar (3.7%), Enterococcus hirae (2.1%), Enterococcus durans and Enterococcus flavescens both 0.8%. Of the 88 isolates collected from the inlet, only 9.1% of the isolates were identified as Ent. faecalis and Ent. pseudoavium (36.4%) was identified as the predominant species. Whereas of the 74 isolates collected from the outlet, the predominant species were identified as Ent. faecalis (29.7%). Species identification varied among sites within the wetland, but often Ent. faecalis was the predominant species. CONCLUSIONS: Our data suggest that while Ent. faecalis is the predominant species of Enterococcus found in domestic wastewater, the populations may shift during treatment as the wastewater flows through the constructed wetland. SIGNIFICANCE AND IMPACT OF THE STUDY: We found that shifts in Enterococcus species composition occurred during domestic wastewater treatment. This has implications for the identification of faecal pollution based on the presence of specific bacterial types associated with domestic wastewater. PMID- 19778345 TI - Purification, crystal structure and antimicrobial activity of phenazine-1 carboxamide produced by a growth-promoting biocontrol bacterium, Pseudomonas aeruginosa MML2212. AB - AIM: To purify and characterize an antimicrobial compound produced by a biocontrol bacterium, Pseudomonas aeruginosa MML2212, and evaluate its activity against rice pathogens, Rhizoctonia solani and Xanthomonas oryzae pv. oryzae. METHODS AND RESULTS: Pseudomonas aeruginosa strain MML2212 isolated from the rice rhizosphere with wide-spectrum antimicrobial activity was cultured in Kings'B broth using a fermentor for 36 h. The extracellular metabolites were isolated from the fermented broth using ethyl acetate extraction and purified by two-step silica-gel column chromatography. Three fractions were separated, of which a major compound was obtained in pure state as yellow needles. It was crystallized after dissolving with chloroform followed by slow evaporation. It is odourless with a melting point of 220-222 degrees C. It was soluble in most of the organic solvents and poorly soluble in water. The molecular mass of purified compound was estimated as 223.3 by mass spectral analysis. Further, it was characterized by IR, (1)H and (13)C NMR spectral analyses. The crystal structure of the compound was elucidated for the first time by X-ray diffraction study and deposited in the Cambridge Crystallographic Data Centre (http://www.ccde.com.ac.uk) with the accession no. CCDC 617344. CONCLUSION: The crystal compound was undoubtedly identified as phenazine-1-carboxamide (PCN) with the empirical formula of C(13)H(9)N(3)O. SIGNIFICANCE AND IMPACT OF THE STUDY: As this is the first report on the crystal structure of PCN, it provides additional information to the structural chemistry. Furthermore, the present study reports the antimicrobial activity of purified PCN on major rice pathogens, R. solani and X. oryzae pv. oryzae. Therefore, the PCN can be developed as an ideal agrochemical candidate for the control of both sheath blight and bacterial leaf blight diseases of rice. PMID- 19778346 TI - Sensitivity to acetic acid, ability to colonize abiotic surfaces and virulence potential of Listeria monocytogenes EGD-e after incubation on parsley leaves. AB - AIM: To investigate how the survival of Listeria monocytogenes on parsley leaves may affect its ability to sustain process-related harsh conditions and its virulence. METHODS AND RESULTS: Parsley seedlings were spot inoculated with stationary phase cells of L. monocytogenes EGD-e and incubated for 15 days. Each day, bacterial cells were harvested and enumerated, and their ability to survive acetic acid challenge (90 min, pH 4.0), to colonize abiotic surfaces and to grow as biofilms was assessed. After a 3-log decrease over the first 48 h, the population stabilized to about 10(6) CFU g(-1) until the sixth day. After the sixth day, L. monocytogenes was no longer detected, even after specific enrichment. Incubation on parsley leaves affected the ability of L. monocytogenes to survive acetic acid challenge (90 min, pH 4.0) and to adhere to stainless steel although the ability to grow as biofilm was preserved. To further investigate these physiological alterations, the mRNA levels of six target genes (bsh, clpC, groEL, inlA, opuC, prfA) was quantified using reverse transcription qPCR after 5 h of incubation on parsley leaves. A decrease was observed in all but one (bsh) target, including groEL and clpC which are involved in resistance to salt and acid. Moreover, the decrease in the levels of inlA, prfA and opuC transcripts after incubation on parsley suggested a repression of some genes involved in pathogenicity. In vitro assessment of mammalian cell adherence and invasion using Caco-2 cells confirmed the repression of the virulence factor InlA; however, the virulence potential in vivo in the chick embryo model was not affected. CONCLUSION: Listeria monocytogenes did undergo rapid changes to adapt its physiology to the phyllosphere. SIGNIFICANCE AND IMPACT OF THE STUDY: This study highlights the physiological changes undergone by L. monocytogenes during/after survival on parsley leaves. PMID- 19778347 TI - Do European Standard Disinfectant tests truly simulate in-use microbial and organic soiling conditions on food preparation surfaces? AB - AIMS: The results from European standard disinfectant tests are used as one basis to approve the use of disinfectants in Europe. The design of these laboratory based tests should thus simulate as closely as possible the practical conditions and challenges that the disinfectants would encounter in use. No evidence is available that the organic and microbial loading in these tests simulates actual levels in the food service sector. METHODS AND RESULTS: Total organic carbon (TOC) and total viable count (TVC) were determined on 17 visibly clean and 45 visibly dirty surfaces in two restaurants and the food preparation surfaces of a large retail store. These values were compared to reference values recovered from surfaces soiled with the organic and microbial loading, following the standard conditions of the European Surface Test for bactericidal efficacy, EN 13697. CONCLUSIONS: The TOC reference values for clean and dirty conditions were higher than the data from practice, but cannot be regarded as statistical outliers. This was considered as a conservative assessment; however, as additional nine TOC samples from visibly dirty surfaces were discarded from the analysis, as their loading made them impossible to process. Similarly, the recovery of test organisms from surfaces contaminated according to EN 13697 was higher than the TVC from visibly dirty surfaces in practice; though they could not be regarded as statistical outliers of the whole data field. No correlation was found between TVC and TOC in the sampled data, which re-emphasizes the potential presence of micro-organisms on visibly clean surfaces and thus the need for the same degree of disinfection as visibly dirty surfaces. SIGNIFICANCE AND IMPACT OF THE STUDY: The organic soil and the microbial burden used in EN disinfectant standards represent a realistic worst-case scenario for disinfectants used in the food service and food-processing areas. PMID- 19778348 TI - The effect of subminimal inhibitory concentrations of antibiotics on virulence factors expressed by Staphylococcus aureus biofilms. AB - AIMS: The effect of subminimal inhibitory concentrations (sub-MICs) of cefalexin, ciprofloxacin and roxithromycin was investigated on some virulence factors [e.g. coagulase, Toxic Shock Syndrome Toxin 1 (TSST-1) and biofilm formation] expressed by Staphylococcus aureus biofilms. METHODS AND RESULTS: Biofilms were grown with and without the presence of 1/16 MIC of antibiotics on Sorbarod filters. Eluate supernatants were collected, and coagulase and TSST-1 production were evaluated. Coagulase production was reduced in eluates exposed to roxithromycin when compared to control, while TSST-1 production was reduced in biofilms exposed to cefalexin and to a lesser extent, ciprofloxacin. In addition, the ability of Staph. aureus to produce biofilm in microtitre plates in the presence of sub-MIC antibiotics indicated that cefalexin induced biofilm formation at a wide range of sub-MICs. TSST-1 produced from the challenged and control biofilms was purified, and its proliferative activity was studied on single cell suspension of mouse splenocytes using MTS/PMS assay. No significant difference in the activity between the treated toxin and the control has been observed. CONCLUSIONS: Antibiotics at sub-MIC levels interfere with bacterial biofilm virulence expression depending on the type and concentration of antibiotic used. SIGNIFICANCE AND IMPACT OF THE STUDY: The establishment of sub-MICs of antibiotics in clinical situations may result in altered virulence states in pathogenic bacteria. PMID- 19778349 TI - Survival and spread of Shiga toxin-producing Escherichia coli in alpine pasture grasslands. AB - AIMS: To determine the fate of Shiga toxin-producing Escherichia coli (STEC) strains defecated onto alpine grassland soils. METHODS AND RESULTS: During the summers of 2005 and 2006, the field survival of STEC was monitored in cowpats and underlying soils in four different alpine pasture units. A most probable number (MPN)-PCR stx assay was used to enumerate STEC populations. STEC levels ranged between 3.9 and 5.4 log(10) CFU g(-1) in fresh cowpats and slowly decreased until their complete decay (inactivation rates k < 0.04 day(-1)). PFGE typing of STEC strains isolated from faecal and soil samples assessed the persistence of various clonal types for at least 2 months in cowpats and their vertical dispersal down through the soil at a depth up to at least 20 cm. STEC cells counts in soil were always below 2 log(10) CFU g(-1), regardless of the pasture unit investigated. The soil became rapidly free of detectable STEC once the cowpat had decomposed. The eight STEC strains isolated during this study belonged to six distinct serotypes and tested positive for the gene(s) stx2, including the stx2g and stx2 NV206 variants. CONCLUSIONS: STEC were able to persist in cowpats and disseminate down through the soil but were unable to establish. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides useful information concerning the ecology of STEC in alpine pasture grasslands and may have implications for land and cattle management. PMID- 19778350 TI - Validation of a real-time PCR for Haemophilus parasuis. AB - AIMS: To validate a real-time PCR test for the diagnosis of Glasser's disease, a major pig disease caused by Haemophilus parasuis. METHODS AND RESULTS: The specificity of a real-time PCR amplifying the inf B gene was validated with 68 H. parasuis isolates and 36 strains of closely related species. As well, 239 samples of DNA from tissues and fluids of 16 experimentally challenged animals were tested with the real-time PCR, and the results were compared with culture and a conventional PCR. The real-time PCR produced significantly more positive results than the conventional PCR (165 vs 86). CONCLUSIONS: The sensitivity of the real time PCR combined with high specificity makes it a very valuable tool for the diagnosis of Glasser's disease. SIGNIFICANCE AND IMPACT OF STUDY: This new method will improve the ability of laboratories to diagnose Glasser's disease, especially in laboratories where the culture method for H. parasuis is not optimal. PMID- 19778351 TI - Effect of pharynx epithelial cells surface desialylation on receptor-mediated adherence of Staphylococcus aureus. AB - AIMS: To characterize the interaction between cell surface carbohydrates and Staphylococcus aureus. METHODS AND RESULTS: In the present study, in vitro adherence of S. aureus to Detroit 562 cells, amount of cell surface desialylation and effect of subterminal monosaccharides on desialylated glycoproteins on adherence was studied with colony counting, HPLC, fluorescence microscopy and fluorometric techniques. According to our findings, S. aureus adherence to pharynx cells was enhanced (40%) after neuraminidase treatment, and neuraminidase also cleave great amount of Detroit 562 cells surface sialic acid (39-60%). Adherence assay with various monosaccharides-pretreated bacteria, and lectin competitive inhibition, showed that the residual subterminal galactose, fucose and N-acetyl-D-glucosamine remaining on desialylated Detroit 562 cell surface glycoproteins responsible for this binding. CONCLUSION: The results are the first to show that galactose, fucose and N-acetyl-D-glucosamine remaining on desialylated pharynx cell surface glycoproteins serve as the adhesine receptors for S. aureus. SIGNIFICANCE AND IMPACT OF THE STUDY: This study may explain the predisposition of severe S. aureus pneumonia complication in respiratory viral infections. PMID- 19778352 TI - Genomic characterization and selection of wine yeast to conduct industrial fermentations of a white wine produced in a SW Spain winery. AB - AIMS: To analyse the diversity of wild yeast in spontaneous fermentations of a white wine and to select the most suitable autochthonous starter yeasts. The selected yeasts would be used for inoculation of industrial fermentations in several years. METHODS AND RESULTS: Yeasts were characterized by applying electrophoretic karyotyping. This technique was chosen because it can reveal the large-scale mutations in the yeast genome induced by gross chromosomal rearrangements. This type of mutation is considered one of the main forces behind the rapid evolution of industrial yeasts. A heterogeneous population of yeast strains was observed in the spontaneous fermentations during two consecutive years. Four of the most abundant strains were isolated and tested for microbiological features of industrial importance. The selected autochthonous strains were used as starter yeasts for the following 7 years. In the majority of these experiences, we obtained homogeneous yeast populations, in which the karyotype of one of the inoculated strains--karyotype V--emerged as clearly dominant. CONCLUSIONS: The inoculation of the selected strain with karyotype V and a proper handling of the inoculum scaling-up process led to the substitution of the spontaneous fermentations by controlled fermentations producing a highly satisfactory final product. SIGNIFICANCE AND IMPACT OF THE STUDY: We monitored the wine yeast population of an industrial system for a total of 9 years. Our work is one of the first examples made at industrial scale showing how molecular techniques can be successfully applied to improve the efficiency of the winemaking process. PMID- 19778353 TI - Characteristics and function of Alcaligenes sp. NBRC 14130 esterase catalysing the stereo-selective hydrolysis of ethyl chrysanthemate. AB - AIMS: Alcaligenes sp. NBRC 14130 was found as a strain hydrolysing a mixture of (+/-)-trans- and (+/-)-cis ethyl chrysanthemates to (1R,3R)-(+)-trans chrysanthemic acid. The Alcaligenes cells also have hydrolytic activity for 6 aminohexanoate-cyclic dimer (6-AHCD, 1,8-diazacyclotetradecane-2,9-dione). The correlation of function on the enzyme from the Alcaligenes strain with hydrolysis activities for both ethyl chrysanthemate and 6-AHCD was demonstrated. METHODS AND RESULTS: The esterase was purified to homogeneity. The purified esterase hydrolysed 20 mmol l(-1) ester including the four stereoisomers to the corresponding (+)-trans acid with a 37% molar conversion of ethyl (+)-trans chrysanthemate. The esterase showed high hydrolytic activity for various short chain fatty acid esters, n-hexane amide and 6-AHCD. The amino acid sequence of the Alcaligenes esterase was identical to that of Arthrobacter 6-AHCD hydrolase (EC 3.5.2.12) and similar to that of fatty acid amide hydrolase (EC 3.5.1.4) from Rattus norvegicus, having both serine and lysine residues of the catalytic site and the consensus motif Gly-X-Ser-X-Gly. CONCLUSION: The stereo-selective hydrolytic activity was found in Alcaligenes sp. NBRC14130 by screening of ethyl chrysanthemate-hydrolysing activity in micro-organisms, and the purified esterase also acted on fatty acid esters and amides. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has demonstrated that there are great differences in the enzymatic properties, amino acid sequence and catalytic motif of esterases in both Alcaligenes and Arthrobacter globiformis with excellent stereo-selectivity for (+)-trans-ethyl chrysanthemate, but the amino acid sequence of Alcaligenes esterase is identical to that of Arthrobacter 6-AHCD hydrolase. PMID- 19778354 TI - Identification and antimicrobial susceptibility of porcine bacteria that inhibit the growth of Brachyspira hyodysenteriae in vitro. AB - AIMS: To identify bacilli, lactic acid bacteria and bifidobacteria that inhibit the growth of Brachyspira hyodysenteriae. METHODS AND RESULTS: A total of 80 isolates were obtained from various porcine intestinal compartments using selective conditions and grouped into 15 similarity clusters based on whole-cell protein profiles. Random amplified polymorphic DNA PCR patterns identified 24 genotypes. 16S rDNA sequencing assigned all genotypes, except eight aerobes, to established species (Bacillus subtilis, Enterococcus faecium, Lactobacillus salivarius, Lactobacillus mucosae, Lactobacillus reuteri, Lactobacillus amylovorus, Bifidobacterium thermophilum). According to their minimum inhibitory concentrations, four strains (Ent. faecium, Lact. reuteri, Lact. amylovorus, Bif. thermophilum) were susceptible to all clinically relevant antibiotics. Two lactobacilli showing multiresistance harboured the erm(B) determinant. A cross section of eight representative strains was examined for growth suppression of two strains of Brach. hyodysenteriae, the aetiological agent of swine dysentery, and compared with intestinal strains derived from other animal sources. The Brachyspira strains were inhibited by strains of Lact. salivarius, Bif. thermophilum, Ent. faecium and B. subtilis. CONCLUSIONS: Three porcine strains of Ent. faecium, Bif. thermophilum and B. subtilis were found to be suitable as probiotic candidates because of their well-established identity, antibiotic susceptibility and antagonistic activity. SIGNIFICANCE AND IMPACT OF THE STUDY: For the first time, antagonistic activity of well-characterized porcine strains against Brach. hyodysenteriae is presented. These findings suggest that certain intestinal strains might have a potential as probiotic feed additives for prevention of swine dysentery. PMID- 19778356 TI - Treatment of trichostasis spinulosa with a 755-nm long-pulsed alexandrite laser. AB - BACKGROUND: Trichostasis spinulosa (TS) is a common disorder of hair follicle, characterized by spinous plugs. Topical treatments offer temporary relief but permanent removal of the abnormal follicles using hair removal lasers may result in a definite cure. OBJECTIVE: To evaluate the safety and efficacy of 755-nm alexandrite laser for the treatment of TS lesions. PATIENTS AND METHODS: Two consecutive 755-nm alexandrite laser treatments were performed one month apart. The clinical response and adverse effects were assessed four weeks after the first and second treatments and 20 weeks after the second treatment. RESULTS: Thirty one patients with skin phototypes II to IV completed the study. At the last follow up visit, a decrease in dark-plug density of greater than 50% was noted in 16 patients (51.3%), while only three patients (9.7%) had an improvement of greater than 75%. Ten of the 21 patients (47.6%) with skin type III and six of the seven patients (85.7%) with skin type IV achieved at least 50% improvement in lesions at the last follow up visit (P = 0.1). CONCLUSION: The 755-nm alexandrite laser can safely and effectively reduce TS lesions lasting for a relatively long time in patients with skin types III-IV. PMID- 19778355 TI - Calcineurin A-beta is required for hypertrophy but not matrix expansion in the diabetic kidney. AB - Calcineurin is an important signalling protein that regulates a number of molecular and cellular processes. Previously, we found that inhibition of calcineurin with cyclosporine reduced renal hypertrophy and blocked glomerular matrix expansion in the diabetic kidney. Isoforms of the catalytic subunit of calcineurin are reported to have tissue specific expression and functions. In particular, the beta isoform has been implicated in cardiac and skeletal muscle hypertrophy. Therefore, we examined the role of calcineurin beta in diabetic renal hypertrophy and glomerular matrix expansion. Type I diabetes was induced in wild-type and beta(-/-) mice and then renal function, extracellular matrix expansion and hypertrophy were evaluated. The absence of beta produced a significant decrease in total calcineurin activity in the inner medulla (IM) and reduced nuclear factor of activated T-cells (NFATc) activity. Loss of beta did not alter diabetic renal dysfunction assessed by glomerular filtration rate, urine albumin excretion and blood urea nitrogen. Similarly, matrix expansion in the whole kidney and glomerulus was not different between diabetic wild-type and beta(-/-) mice. In contrast, whole kidney and glomerular hypertrophy were significantly reduced in diabetic beta(-/-) mice. Moreover, beta(-/-) renal fibroblasts demonstrated impaired phosphorylation of Erk1/Erk2, c-Jun N-terminal kinases (JNK) and mammalian target of rapamycin (mTOR) following stimulation with transforming growth factor-beta and did not undergo hypertrophy with 48 hrs culture in high glucose. In conclusion, loss of the beta isoform of calcineurin is sufficient to reproduce beneficial aspects of cyclosporine on diabetic renal hypertrophy but not matrix expansion. Therefore, while multiple signals appear to regulate matrix, calcineurin beta appears to be a central mechanism involved in organ hypertrophy. PMID- 19778357 TI - PTH-independent hypercalcaemia and non-melanoma skin cancer. AB - BACKGROUND: Recently, it became more evident that skin is a target for neuroendocrine signals. AIMS: (1) To evaluate the relationship between tumour aggressiveness and hypercalcaemia in patients with non-melanoma skin cancer; (2) to identify clinical, functional, biological alterations caused by this setting; (3) calcium redistribution from extracellular fluids to intracellular compartments; (4) to describe several molecular aspects of hypercalcaemia development. MATERIALS AND METHODS: This study was conducted between January 2000 and May 2009 in Dermatoveneorological Center, Bucharest. From the 1232 cases that were investigated, there were 32 patients with keratoachantoma, 468 patients with basal cell carcinoma, 412 patients with squamous cell carcinoma and 320 healthy volunteers. All the patients were screened by clinical and paraclinical examinations (haematology, biochemistry, immunology). After biochemical confirmation of hypercalcaemia, patients had endocrine tests, electrocardiography and imagistic approaches. Total serum calcium was measured in extracellular fluids (serum, urine) by spectrophotometric methods. Ionized calcium was calculated depending on total serum calcium and total proteins. Corrected serum total calcium (cTCa) levels were calculated using albumin and total serum calcium levels. In tumour tissues and intact skin, calcium was assayed by physical methods of analysis: Instrumental Neutron Activation Analysis (INAA), Proton Induced X-ray Emission (PIXE). Intact PTH was measured by ELISA. RESULTS: PTH independent hypercalcaemia prevalence is low in SCC patients (1.21%). Hypercalcaemia manifestations are multiple including: digestive, renal, neuromuscular, and cardiovascular abnormalities. In these patients, intact PTH (iPTH) is normal, urinary calcium is decreased, serum albumin is reduced, and calcium concentration in tumour tissue is significantly increased compared to healthy tissue. CONCLUSIONS: PTH-independent hypercalcaemia has a low prevalence in SCC patients. Hypercalcaemia is correlated with susceptibility to develop metastases in SCC. A possible mechanism is PTHrp hypersecretion by malignant keratinocytes. PMID- 19778358 TI - Knowledge, attitude and performance study of secondary school teachers of Yazd city regarding skin cancer. AB - BACKGROUND: The cancers are a major health problem and skin cancers are the most prevalent cancers. It is clear that teachers play an important role in the health education of students and their families. OBJECTIVE: This study was done to determine the knowledge, attitude and performance levels of teachers in Yazd city regarding skin cancer in order to plan programs for increasing their respective levels. Methods Samples of this cross sectional study selected randomly from the schools of Yazd. The data were collected by completion of questionnaire. anova, Kruskal-Wallis, T-test and Pearson Correlations statistical tests were used for analysis. RESULTS: Of the total, 170 were men and 270 were women with a mean age of 37.98 +/- 6.28 years. The mean knowledge, attitude and performance score of the teachers respectively was 24.17 +/- -5.27, 28.09 +/- -5.79 and 6.34 +/- 3.42. The knowledge levels were significantly related to the attitude (P = 0.05) and performance levels (P = 0.01). There was an inverse relation between age and performance levels (P = 0.01). The performance levels of women were better than men (P = 0.001). The field of study and education of the teachers was related to the knowledge (P = 0.001) and attitude levels (P = 0.02). CONCLUSION: Skin cancers are the most common form of cancers in our state, but my teachers do not have appropriate knowledge and performance levels about this disease. It is therefore proposed that related information should be given to them during continuous and regular educational programs. PMID- 19778359 TI - Carpet weaving: an occupational risk for onychomycosis? AB - BACKGROUND: Some occupations carry a risk for fungal infections. OBJECTIVE: To investigate the prevalence of onychomycosis in carpet weavers. METHODS: Seventy seven weavers (the mean age +/- SD = 32.97 +/- 12.38) from three factories and 77 controls (the mean age +/- SD = 38.32 +/- 12.38) were examined for onychomycosis. Samples from nails and the carpets, which were being weaved, were taken for mycological investigations. RESULTS: Direct microscopic examination of only two controls' normal-appearing nails was positive. Fungal growth was observed in the culture of four weavers' normal-appearing nails. It was watched over that most of the weavers had polished-appearing nails and were using a glue containing cyanoacrylate to restore their broken nails due to weaving. CONCLUSION: The fungal growth observed in weavers' nails has been accepted as colonization. There is no data about the presence of fungi on normal-appearing nails. So, we thought that the weavers with fungal colonization should be followed for the development of onychomycosis. PMID- 19778361 TI - Phototherapy with ultraviolet radiation: a study of hormone parameters and psychological effects. AB - BACKGROUND AND OBJECTIVES: Patients report well-being as they are treated with phototherapy. We investigated hormone parameters and psychological well-being after phototherapy in a placebo-controlled study. METHODS: A total of 77 patients with dermatological conditions and 22 healthy volunteers were divided into four groups. The patients received phototherapy either on the whole body or only on hands and/or feet. The volunteers were given either whole-body phototherapy or placebo light. Serum or plasma samples were analysed for cortisol, calcium, magnesium, phosphate, TSH, T(4), T(3) and 25-hydroxyvitamin D, and urine samples for cortisol. Patients and volunteers answered a questionnaire before and 6 weeks after phototherapy/placebo light. Psychiatric ratings were performed according to the Comprehensive Psychopathological Self-rating Scale for Affective Syndromes, a self-report version of which has been transformed to correspond to the Montgomery Asberg Depression Rating Scale (MADRS). RESULTS: In the patients who received whole-body irradiation, we observed a significant improvement in both MADRS score and cognitive-symptom score after the completion of phototherapy. We also observed a significantly higher level of 25-hydroxyvitamin D after phototherapy, but no difference in the other hormone parameters. CONCLUSION: Whole-body phototherapy of patients with dermatological conditions results in improved well being and significantly higher levels of 25-hydroxyvitamin D in serum. PMID- 19778362 TI - Electrochemotherapy-induced virus disappearance in HHV-8-positive skin nodules of Kaposi sarcoma: first histological and immunohistochemical demonstration of efficacy. PMID- 19778363 TI - Plant functioning in a changing global environment. PMID- 19778364 TI - Nitrogen balance in forest soils: nutritional limitation of plants under climate change stresses. AB - Forest ecosystems with low soil nitrogen (N) availability are characterized by direct competition for this growth-limiting resource between several players, i.e. various components of vegetation, such as old-growth trees, natural regeneration and understorey species, mycorrhizal fungi, free-living fungi and bacteria. With the increase in frequency and intensity of extreme climate events predicted in current climate change scenarios, also competition for N between plants and/or soil microorganisms will be affected. In this review, we summarize the present understanding of ecosystem N cycling in N-limited forests and its interaction with extreme climate events, such as heat, drought and flooding. More specifically, the impacts of environmental stresses on microbial release and consumption of bioavailable N, N uptake and competition between plants, as well as plant and microbial uptake are presented. Furthermore, the consequences of drying-wetting cycles on N cycling are discussed. Additionally, we highlight the current methodological difficulties that limit present understanding of N cycling in forest ecosystems and the need for interdisciplinary studies. PMID- 19778365 TI - Why and how terrestrial plants exchange gases with air. AB - This work is intended as a review of gas exchange processes between the atmosphere and the terrestrial vegetation, which have been known for more than two centuries since the discovery of photosynthesis. The physical and biological mechanisms of exchange of carbon dioxide, water vapour, volatile organic compounds emitted by plants and air pollutants taken up by them, is critically reviewed. The role of stomatal physiology is emphasised, as it controls most of these processes. The techniques used for measurement of gas exchange fluxes between the atmosphere and vegetation are outlined. PMID- 19778367 TI - Effects of temperature, ultraviolet radiation and pectin methyl esterase on aerobic methane release from plant material. AB - This study examines the effects of different irradiance types on aerobic methane (CH(4)) efflux rates from terrestrial plant material. Furthermore, the role of the enzyme pectin methyl esterase (PME) on CH(4) efflux potential was also examined. Different types of plant tissue and purified pectin were incubated in glass vials with different combinations of irradiation and/or temperature. Purified dry pectin was incubated in solution, and with or without PME. Before and after incubation, the concentration of CH(4) was measured with a gas chromatograph. Rates of CH(4) emission were found to depend exponentially on temperature and linearly on UV-B irradiance. UV-B had a greater stimulating effect than UV-A, while visible light had no effect on emission rates. PME was found to substantially reduce the potential for aerobic CH(4) emissions upon demethylation of pectin. PMID- 19778366 TI - Metabolic-dependent changes in plant cell redox power after ozone exposure. AB - The tropospheric level of the phytotoxic air pollutant ozone has increased considerably during the last century, and is expected to continue to rise. Long term exposure of higher plants to low ozone concentrations affects biochemical processes prior to any visible symptoms of injury. The current critical level of ozone used to determine the threshold for damaging plants (biomass loss) is still based on the seasonal sum of the external concentration above 40 nl.l(-1) (AOT40). Taking into account stomatal conductance and the internal capacity of leaf defences, a more relevant concept should be based upon the 'effective ozone flux', the balance between the stomatal flux and the intensity of cellular detoxification. The large decrease in the Rubisco/PEPc ratio reflects photosynthetic damage from ozone, and a large increase in activity of cytosolic PEPc, which allows increased malate production. Although the direct detoxification of ozone (and ROS produced from its decomposition) is carried out primarily by cell wall ascorbate, the existing level of this antioxidant is not sufficient to indicate the degree of cell sensitivity. In order to regenerate ascorbate, NAD(P)H is needed as the primary supplier of reducing power. It is hypothesised that increased activity of the catabolic pathways and associated shunts (glucose-6-phosphate dehydrogenase, NADP-dependent glyceraldehyde-3 phosphate dehydrogenase, isocitrate dehydrogenase and malic enzyme) can provide sufficient NAD(P)H to maintain intracellular detoxification. Thus, measurement of the level of redox power would contribute to determination of the 'effective ozone dose', serving ultimately to improve the ozone risk index for higher plants. PMID- 19778368 TI - Juniperus communis: victim of the combined action of climate warming and nitrogen deposition? AB - Research on the combined effects of climate change and nitrogen deposition on reproductive traits, and especially on the production of viable seeds, is still scarce despite their importance for population persistence and expansion. Hence, in this study we set out to investigate the direct and indirect effects of the above-mentioned global change drivers on seed viability in the coniferous shrub Juniperus communis L. In many parts of its European range, juniper is increasingly threatened, partly because of a lack of sexual reproduction. We hypothesised that this regeneration failure is partly due to poor seed viability. Using data from 39 populations throughout Europe, we were able to demonstrate that a strong, triangular-shaped relationship exists between the percentage of viable seeds produced and the percentage of juniper seedlings occurring in a population, which indicates that the species is indeed partly seed limited. Furthermore, based on an extended dataset of 42 populations, we found that seed viability was negatively affected by temperature, measured as mean annual growing degree-days, and nitrogen deposition (but not by drought). Suggestions are made about the processes behind the observed patterns, but more research is required. Nevertheless, our results do raise serious concerns for the conservation of juniper in light of the predicted rise in temperature and global nitrogen emissions. Furthermore, it is likely that similar patterns can also be observed for other species. PMID- 19778369 TI - Effects of elevated CO2 on grain yield and quality of wheat: results from a 3 year free-air CO2 enrichment experiment. AB - Spring wheat (Triticum aestivum L. cv. TRISO) was grown for three consecutive seasons in a free-air carbon dioxide (CO(2)) enrichment (FACE) field experiment in order to examine the effects on crop yield and grain quality. CO(2) enrichment promoted aboveground biomass (+11.8%) and grain yield (+10.4%). However, adverse effects were predominantly observed on wholegrain quality characteristics. Although the thousand-grain weight remained unchanged, size distribution was significantly shifted towards smaller grains, which may directly relate to lower market value. Total grain protein concentration decreased significantly by 7.4% under elevated CO(2), and protein and amino acid composition were altered. Corresponding to the decline in grain protein concentration, CO(2) enrichment resulted in an overall decrease in amino acid concentrations, with greater reductions in non-essential than essential amino acids. Minerals such as potassium, molybdenum and lead increased, while manganese, iron, cadmium and silicon decreased, suggesting that adjustments of agricultural practices may be required to retain current grain quality standards. The concentration of fructose and fructan, as well as amounts per area of total and individual non-structural carbohydrates, except for starch, significantly increased in the grain. The same holds true for the amount of lipids. With regard to mixing and rheological properties of the flour, a significant increase in gluten resistance under elevated CO(2) was observed. CO(2) enrichment obviously affected grain quality characteristics that are important for consumer nutrition and health, and for industrial processing and marketing, which have to date received little attention. PMID- 19778370 TI - Differential ozone sensitivity of rice cultivars as indicated by visible injury and grain yield. AB - Surface ozone pollution may cause reductions in rice (Oryza sativa L.) yield. Ozone sensitivity in rice cultivars is often evaluated based on visible leaf injury at an early growth stage. However, it is not clear whether reduction in grain yield is related to visible injury. Therefore, visible damage and grain yield reduction were examined in Japanese and Asian rice cultivars exposed to ozone. In experiment 1, 3-week-old rice seedlings were exposed to ozone (min.: 20 nl.l(-1), max.:120 nl.l(-1)) for 12 h in open-top chambers (OTCs). Visible leaf injury was quantified according to a leaf bronzing score. In experiment 2, rice plants were exposed to ozone in OTCs throughout the cropping season until grain harvest. Daily mean ozone concentrations were maintained at 2, 23, 28, 42, and 57 nl.l(-1) with a regular diurnal pattern of exposure. After harvest, grain yield was determined. Based on visible injury to the uppermost fully expanded leaf, the indica cultivar 'Kasalath' was most tolerant, and the japonica cultivar 'Kirara 397' was most sensitive to ozone. However, grain yields for both 'Kasalath' and 'Kirara 397' were significantly decreased after ozone exposure. The indica cultivar 'Jothi' suffered severe injury after ozone exposure but had no reduction in grain yield. Therefore, ozone sensitivity of rice cultivars evaluated by visible injury did not coincide with that evaluated by the reductions in grain yield. These results suggest that mechanisms that induce acute leaf injury do not relate to chronic ozone toxicity that reduces yield. PMID- 19778371 TI - Growth and nutritive value of cassava (Manihot esculenta Cranz.) are reduced when grown in elevated CO. AB - Global food security in a changing climate depends on both the nutritive value of staple crops as well as their yields. Here, we examined the direct effect of atmospheric CO(2) on cassava (Manihot esculenta Cranz., manioc), a staple for 750 million people worldwide. Cassava is poor in nutrients and contains high levels of cyanogenic glycosides that break down to release toxic hydrogen cyanide when damaged. We grew cassava at three concentrations of CO(2) (C(a): 360, 550 and 710 ppm) supplied together with nutrient solution containing either 1 mM or 12 mM nitrogen. We found that total plant biomass and tuber yield (number and mass) decreased linearly with increasing C(a). In the worst-case scenario, tuber mass was reduced by an order of magnitude in plants grown at 710 ppm compared with 360 ppm CO(2). Photosynthetic parameters were consistent with the whole plant biomass data. It is proposed that since cassava stomata are highly sensitive to other environmental variables, the decrease in assimilation observed here might, in part, be a direct effect of CO(2) on stomata. Total N (used here as a proxy for protein content) and cyanogenic glycoside concentrations of the tubers were not significantly different in the plants grown at elevated CO(2). By contrast, the concentration of cyanogenic glycosides in the edible leaves nearly doubled in the highest C(a). If leaves continue to be used as a protein supplement, they will need to be more thoroughly processed in the future. With increasing population density, declining soil fertility, expansion into marginal farmland, together with the predicted increase in extreme climatic events, reliance on robust crops such as cassava will increase. The responses to CO(2) shown here point to the possibility that there could be severe food shortages in the coming decades unless CO(2) emissions are dramatically reduced, or alternative cultivars or crops are developed. PMID- 19778372 TI - Photosynthesis, photochemistry and antioxidative defence in response to two drought severities and with re-watering in Allocasuarina luehmannii. AB - Gas exchange, chlorophyll fluorescence and water potentials, together with ascorbate and glutathione concentrations, were studied during moderate and severe drought stress and in response to re-watering in Allocasuarina luehmannii seedlings. Moderate drought stress (MS) decreased stomatal conductance (g(s)) and net CO(2) assimilation rates (A) to approximately 40% and approximately 60% of control values, respectively, and caused decreases in internal CO(2) concentration (C(i)) and maximum light use efficiency of light-acclimated photosystem II (PSII) centres (Fv'/Fm'). Severe drought stress (SS) decreased g(s) and A to approximately 5% and approximately 15% of the control values, respectively, and caused increases in C(i) and PSII excitation pressure (1 - qP), as well as decreases in water potentials, effective quantum yield of PSII (PhiPSII), maximum efficiency of PSII (Fv/Fm) and Fv'/Fm'. Ascorbate and glutathione concentrations remained unaffected by drought treatments, but ascorbate became more oxidised under severe stress. MS seedlings recovered within 1 day (C(i), Fv'/Fm') to 1 week (A, g(s)) of re-watering. In comparison, SS seedlings had longer-lasting after-stress effects, with recovery of many variables (g(s), water potentials, Fv/Fm, PhiPSII, Fv'/Fm') taking between 1 and 3 weeks from re-watering. We found no indication that interaction with antioxidants played a significant role in recovery. In conclusion, A. luehmannii seedlings appear to function normally under moderate drought, but do not seem to have particular metabolic tolerance mechanisms to endure severe drought, which may have implications for its persistence under climate change at the drier margins of its distribution. PMID- 19778373 TI - Needle traits of an evergreen, coniferous shrub growing at wind-exposed and protected sites in a mountain region: does Pinus pumila produce needles with greater mass per area under wind-stress conditions? AB - Snow depth is one of the most important determinants of vegetation, especially in mountainous regions. In such regions, snow depth tends to be low at wind-exposed sites such as ridges, where stand height and productivity are limited by stressful environmental conditions during winter. Siberian dwarf pine (Pinus pumila Regel) is a dominant species in mountainous regions of Japan. We hypothesized that P. pumila produces needles with greater mass per area at wind exposed sites than at wind-protected sites because it invests more nitrogen (N) in cell walls at the expense of N investment in the photosynthetic apparatus, resulting in increased photosynthetic N use efficiency (PNUE). Contrary to our hypothesis, plants at wind-exposed site invested less resources in needles, as exhibited by lower biomass, N, Rubisco and cell wall mass per unit area, and had higher photosynthetic capacity, higher PNUE and shorter needle life-span than plants at a wind-protected site. N partitioning was not significantly different between sites. These results suggest that P. pumila at wind-exposed sites produces needles at low cost with high productivity to compensate for a short leaf life-span, which may be imposed by wind stress when needles appear above the snow surface in winter. PMID- 19778374 TI - Effects of elevated ozone on photosynthesis and stomatal conductance of two soybean varieties: a case study to assess impacts of one component of predicted global climate change. AB - Global climatic change scenarios predict a significant increase in future tropospheric ozone (O(3)) concentrations. The present investigation was done to assess the effects of elevated O(3) (70 and 100 ppb) on electron transport, carbon fixation, stomatal conductance and pigment concentrations in two tropical soybean (Glycine max L.) varieties, PK 472 and Bragg. Plants were exposed to O(3) for 4 h.day(-1) from 10:00 to 14:00 from germination to maturity. Photosynthesis of both varieties were adversely affected, but the reduction was higher in PK 472 than Bragg. A comparison of chlorophyll a fluorescence kinetics with carbon fixation suggested greater sensitivity of dark reactions than light reactions of photosynthesis to O(3) stress. The O(3)-induced uncoupling between photosynthesis and stomatal conductance in PK 472 suggests the reduction in photosynthesis may be attributed to a factor other than reduced stomatal conductance. An increase in internal CO(2) concentration in both O(3)-treated soybean varieties compared suggests that the reduction in photosynthesis was due to damage to the photosynthetic apparatus, leading to accumulation of internal CO(2) and stomatal closure. The adverse impact of O(3) stress increased at higher O(3) concentrations in both soybean varieties leading to large reductions in photosynthesis. This study suggests that O(3)-induced reductions in photosynthesis in tropical and temperate varieties are similar. PMID- 19778375 TI - Canopy CO2 exchange of sugar beet under different CO2 concentrations and nitrogen supply: results from a free-air CO2 enrichment study. AB - Sugar beet (Beta vulgaris ssp. altissima Doll) was grown in the field under free air CO(2) enrichment (FACE, 550 ppm) and different nitrogen (N) supply (2001: 126 (N100) and 63 kg.ha(-1) (N50); 2004: 156 (N100) and 75 kg.ha(-1)) during two crop rotations. Canopy CO(2) exchange rates (CCER) were measured during the main growth phase (leaf area index > or =2) using a dynamic chamber system. Canopy CO(2) exchange data were analysed with respect to treatment effects on seasonal means and light use efficiency and light response characteristics. CO(2) enrichment enhanced CCER throughout the season. However, in both years, CCER declined after the second half of August independent of radiation and [CO(2)]. Elevated [CO(2)] strongly stimulated CCER on a seasonal basis, whereas the reduction of CCER caused by low N was below 10% and not significant. There were no effects of N on daily radiation use efficiency of carbon gain calculated from CCER data, but a strong enhancement by CO(2) enrichment. CCER closely tracked diurnal variations in incident photosynthetic photon flux density (PPFD, mumol.m( 2).s(-1)). The relationship between CCER and incident PPFD was curvilinear. In both seasons, initial slopes and maximum rates (CCER(max)) were determined from two 6-day periods using these relationships. The first period was measured after canopy closure (first half of July) and the second in the second half of August. In the first period, elevated [CO(2)] increased the initial slopes. Low N supply affected neither the initial slopes nor their response to elevated [CO(2)] in either period. In contrast to initial slopes, N stress limited the [CO(2)] response of CCER(max) in the first period. In the second period, however, this interaction of [CO(2)] and N on CCER(max) was completely dominated by a general decline of CCER(max) whereas no general decline of the initial slopes occurred in the second period. This response of light response parameters to [CO(2)] and N suggests that, in sugar beet, the decline of CCER in the late season may rely on limiting mechanisms such as photosynthetic acclimation responses to elevated [CO(2)] caused by sink limitations. PMID- 19778376 TI - Assessment of transpiration efficiency in peanut (Arachis hypogaea L.) under drought using a lysimetric system. AB - Transpiration efficiency (TE) is an important trait for drought tolerance in peanut (Arachis hypogaea L.). The variation in TE was assessed gravimetrically using a long time interval in nine peanut genotypes (Chico, ICGS 44, ICGV 00350, ICGV 86015, ICGV 86031, ICGV 91114, JL 24, TAG 24 and TMV 2) grown in lysimeters under well-watered or drought conditions. Transpiration was measured by regularly weighing the lysimeters, in which the soil surface was mulched with a 2-cm layer of polythene beads. TE in the nine genotypes used varied from 1.4 to 2.9 g kg(-1) under well-watered and 1.7 to 2.9 g kg(-1) under drought conditions, showing consistent variation in TE among genotypes. A higher TE was found in ICGV 86031 in both well-watered and drought conditions and lower TE was found in TAG-24 under both water regimes. Although total water extraction differed little across genotypes, the pattern of water extraction from the soil profile varied among genotypes. High water extraction within 24 days following stress imposition was negatively related to pod yield (r(2) = 0.36), and negatively related to water extraction during a subsequent period of 32 days (r(2) = 0.73). By contrast, the latter, i.e. water extraction during a period corresponding to grain filling (24 to 56 days after flowering) was positively related to pod yield (r(2) = 0.36). TE was positively correlated with pod weight (r(2) = 0.30) under drought condition. Our data show that under an intermittent drought regime, TE and water extraction from the soil profile during a period corresponding to pod filling were the most important components. PMID- 19778377 TI - Identification of pY19-caveolin-2 as a positive regulator of insulin-stimulated actin cytoskeleton-dependent mitogenesis. AB - Mitogenic regulation by caveolin-2 in response to insulin was investigated. Insulin triggered phosphorylation of caveolin-2 on tyrosine 19. Insulin increased the interaction between pY19-caveolin-2 and phospho-ERK, and that interaction was inhibited by a MEK inhibitor U0126. Insulin-induced interaction of caveolin-2 with phospho-ERK was prevented when tyrosine 19 is mutated to alanine. Insulin relocalized phospho-ERK and pY19-caveolin-2 to the nucleus and their nuclear co localization was impaired by U0126. Down-regulation of caveolin-2 by caveolin-2 siRNA arrested the insulin-induced nuclear localization of ERK with no change in the insulin-stimulated ERK activation. Of consequence, the caveolin-2 siRNA attenuated the ERK-mediated c-Jun and cyclinD1 expression and DNA synthesis by insulin. In addition, actin cytoskeleton influenced the nuclear translocation of caveolin-2-ERK complex. Collectively, our findings underscore the importance of pY19-caveolin-2 with the spatial coordination by insulin in ERK-mediated mitogenic regulation of insulin signalling and indicate that the phosphorylation of pY19-caveolin-2 is required for actin cytoskeleton-dependent ERK nuclear import. PMID- 19778378 TI - U2OS cells lacking Chk1 undergo aberrant mitosis and fail to activate the spindle checkpoint. AB - Chk1 is a conserved protein kinase originally identified in fission yeast, required to delay entry of cells with damaged or unreplicated DNA into mitosis. The requirement of Chk1 for both S and G2/M checkpoints has been elucidated while only few studies have connected Chk1 to the mitotic spindle checkpoint. We used a small interference RNA strategy to investigate the role of Chk1 in unstressed conditions. Chk1 depletion in U2OS human osteosarcoma cells inhibited cell proliferation and raised the percentage of cells with a 4N DNA content, which correlated with accumulation of giant polynucleated cells morphologically distinct from apoptotic cells, while no increased number of cells in G2 or mitosis could be detected. Down-regulation of Chk1 also caused accumulation of cells in the last step of cytokinesis, and of tetraploid cells in G1 phase, which coincided with activation of p53 and increased levels of p21. In addition, Chk1 depleted U2OS cells failed to arrest in mitosis after spindle disruption by nocodazole and showed decreased protein levels of Mad2 and BubR1. These studies show that U2OS cells lacking Chk1 undergo abnormal mitosis and fail to activate the spindle checkpoint, suggesting a role of Chk1 in this checkpoint. PMID- 19778382 TI - Where the rare species are. AB - Prioritizing geographic areas for conservation attention is important - time and money are in short supply but endangered species are not - and difficult. One popular perspective highlights areas with many species found nowhere else (Myers et al. 2000). Another identifies areas that contain species with fewer close relatives elsewhere (Faith 1992). One might characterize the first as focusing on geographic, and the second on phylogenetic, rarity. To the extent that geographically rare species are at greater risk of extinction (Gaston & Fuller 2009), and that phylogenetically rare species contribute disproportionally to overall biodiversity (Crozier 1997), it would seem reasonable to formally integrate the two approaches. In this issue, Rosauer et al. (2009) do just that; their elegant combined metric pinpoints areas missed out when the two types of rarity are looked at in isolation. PMID- 19778379 TI - DIP/WISH-deficient mice reveal Dia- and N-WASP-interacting protein as a regulator of cytoskeletal dynamics in embryonic fibroblasts. AB - DIP/WISH binds to mammalian diaphanous and N-WASP, and functions as a scaffold protein by binding to Nck protein (called SPIN90). In addition, DIP/WISH accelerates actin polymerization through integration with N-WASP and is involved in cytoskeletal dynamics. We previously reported that DIP controls the activities of Rho GTPases in a Src-dependent manner, and accordingly contributes to cell motility (Meng et al. 2004). Here, we made the mice lacking DIP/WISH and demonstrated that DIP/WISH is critical for cell motility and adhesion by using murine embryonic fibroblasts (MEF). Rho activity was higher in DIP/WISH-deficient MEF cells even before platelet-derived growth factor (PDGF) or adhesion stimulation. Cell motility and adhesion were impaired in DIP/WISH-deficient MEF cells, and the MEF cells moved little probably due to the deficiency of tail retractions although they had many small membrane ruffles. Consistent with high Rho activity, DIP/WISH-deficient MEF cells exhibited many stress fibers due to clustering pre-existing actin filament. Thus, DIP/WISH is a negative regulator of Rho and modulates cell adhesion by controlling the integration of adhesion molecules. PMID- 19778383 TI - Intergenerational reproductive parasitism in a stingless bee. AB - Insect colonies have been traditionally regarded as closed societies comprised of completely sterile workers ruled over by a single once-mated queen. However, over the past 15 years, microsatellite studies of parentage have revealed that this perception is far from the truth (Beekman & Oldroyd 2008). First, we learned that honey bee queens are far more promiscuous than we had previously imagined (Estoup et al. 1994), with one Apis dorsata queen clocked at over 100 mates (Wattanachaiyingcharoen et al. 2003). Then Oldroyd et al. (1994) reported a honey bee colony from Queensland, where virtually all the males were sons of a single patriline of workers - a clear case of a cheater mutant that promoted intra colonial reproductive parasitism. Then we learned that both bumble bee colonies (Lopez-Vaamonde et al. 2004) and queenless honey bee colonies (Nanork et al. 2005, 2007) are routinely parasitized by workers from other nests that fly in and lay male-producing eggs that are then reared by the victim colony. There is even evidence that in a thelytokous honey bee population, workers lay female-destined eggs directly into queen cells, thus reincarnating themselves as a queen (Jordan et al. 2008). And let us not forget ants, where microsatellite studies have revealed equally bizarre and totally unexpected phenomena (e.g. Cahan & Keller 2003; Pearcy et al. 2004; Fournier et al. 2005). Now, in this issue, Alves et al. (2009) use microsatellites to provide yet another shocking and completely unexpected revelation about the nefarious goings-on in insect colonies: intergenerational reproductive parasitism by stingless bee workers. PMID- 19778384 TI - Cognitive Hearing Science: the view from hearing impairment and deafness. Editorial. PMID- 19778385 TI - The emergence of cognitive hearing science. AB - Cognitive Hearing Science or Auditory Cognitive Science is an emerging field of interdisciplinary research concerning the interactions between hearing and cognition. It follows a trend over the last half century for interdisciplinary fields to develop, beginning with Neuroscience, then Cognitive Science, then Cognitive Neuroscience, and then Cognitive Vision Science. A common theme is that an interdisciplinary approach is necessary to understand complex human behaviors, to develop technologies incorporating knowledge of these behaviors, and to find solutions for individuals with impairments that undermine typical behaviors. Accordingly, researchers in traditional academic disciplines, such as Psychology, Physiology, Linguistics, Philosophy, Anthropology, and Sociology benefit from collaborations with each other, and with researchers in Computer Science and Engineering working on the design of technologies, and with health professionals working with individuals who have impairments. The factors that triggered the emergence of Cognitive Hearing Science include the maturation of the component disciplines of Hearing Science and Cognitive Science, new opportunities to use complex digital signal-processing to design technologies suited to performance in challenging everyday environments, and increasing social imperatives to help people whose communication problems span hearing and cognition. Cognitive Hearing Science is illustrated in research on three general topics: (1) language processing in challenging listening conditions; (2) use of auditory communication technologies or the visual modality to boost performance; (3) changes in performance with development, aging, and rehabilitative training. Future directions for modeling and the translation of research into practice are suggested. PMID- 19778386 TI - The signal-cognition interface: interactions between degraded auditory signals and cognitive processes. AB - A hearing loss leads to problems with speech perception; this is exacerbated when competing noise is present. The speech signal is recognized by the cognitive system of the listener; noise and distortion tax the cognitive system when interpreting it. The auditory system must interact with the cognitive system for optimal signal decoding. This article discusses this interaction between the signal and cognitive system based on two models: an auditory model describing signal transmission and degeneration due to a hearing loss and a cognitive model for Ease of Language Understanding. The signal distortion depends on the specifics of the hearing impairment and thus differently distorted signals can affect the cognitive system in different ways. Consequently, the severity of a hearing loss may not only depend on the lesion itself but also on the cognitive recourses required to interpret the signal. PMID- 19778387 TI - Cognition and hearing aids. AB - The perceptual information transmitted from a damaged cochlea to the brain is more poorly specified than information from an intact cochlea and requires more processing in working memory before language content can be decoded. In addition to making sounds audible, current hearing aids include several technologies that are intended to facilitate language understanding for persons with hearing impairment in challenging listening situations. These include directional microphones, noise reduction, and fast-acting amplitude compression systems. However, the processed signal itself may challenge listening to the extent that with specific types of technology, and in certain listening situations, individual differences in cognitive processing resources may determine listening success. Here, current and developing digital hearing aid signal processing schemes are reviewed in the light of individual working memory (WM) differences. It is argued that signal processing designed to improve speech understanding may have both positive and negative consequences, and that these may depend on individual WM capacity. PMID- 19778388 TI - Cognition and aided speech recognition in noise: specific role for cognitive factors following nine-week experience with adjusted compression settings in hearing aids. AB - The working memory model for Ease of Language Understanding (ELU) proposes that language understanding under taxing conditions is related to explicit cognitive capacity. We refer to this as the mismatch hypothesis, since phonological representations based on the processing of speech under established conditions may not be accessed so readily when input conditions change and a match becomes problematic. Then, cognitive capacity requirements may differ from those used for processing speech hitherto. In the present study, we tested this hypothesis by investigating the relationship between aided speech recognition in noise and cognitive capacity in experienced hearing aid users when there was either a match or mismatch between processed speech input and established phonological representations. The settings in the existing digital hearing aids of the participants were adjusted to one of two different compression settings which processed the speech signal in qualitatively different ways ("fast" or "slow"). Testing took place after a 9-week period of experience with the new setting. Speech recognition was tested under different noise conditions and with match or mismatch (i.e. alternative compression setting) manipulations of the input signal. Individual cognitive capacity was measured using a reading span test and a letter monitoring test. Reading span, a reliable measure of explicit cognitive capacity, predicted speech recognition performance under mismatch conditions when processed input was incongruent with recently established phonological representations, due to the specific hearing aid setting. Cognitive measures were not main predictors of performance under match conditions. These findings are in line with the ELU model. PMID- 19778389 TI - Spoken word recognition by eye. AB - Spoken word recognition is thought to be achieved via competition in the mental lexicon between perceptually similar word forms. A review of the development and initial behavioral validations of computational models of visual spoken word recognition is presented, followed by a report of new empirical evidence. Specifically, a replication and extension of Mattys, Bernstein & Auer's (2002) study was conducted with 20 deaf participants who varied widely in speechreading ability. Participants visually identified isolated spoken words. Accuracy of visual spoken word recognition was influenced by the number of visually similar words in the lexicon and by the frequency of occurrence of the stimulus words. The results are consistent with the common view held within auditory word recognition that this task is accomplished via a process of activation and competition in which frequently occurring units are favored. Finally, future directions for visual spoken word recognition are discussed. PMID- 19778390 TI - Visual discrimination of vowel duration. AB - Discrimination of vowel duration was explored with regard to discrimination threshold, error bias, and effects of modality and consonant context. A total of 122 normal-hearing participants were presented with disyllabic-like items such as /lal-lal/ or /mam-mam/ in which the lengths of the vowels were systematically varied and were asked to judge whether the first or second vowel was longer. Presentation was either visual, auditory, or audiovisual. Vowel duration differences varied in 24 steps: 12 with a longer first /a/ and 12 with a longer last /a/ (range: +/-33-400 ms). RESULTS: 50% JNDs were smaller than the lowest tested step size (33 ms); 75% JNDs were in the 33-66 ms range for all conditions but V /lal/, with a 75% JND at 66-100 ms. Errors were greatest for visual presentation and for /lal-lal/ tokens. There was an error bias towards reporting the first vowel as longer, and this was strongest for /mam-mam/ and when both vowels were short, possibly reflecting a sublinguistic processing strategy. PMID- 19778391 TI - Role of speechreading in audiovisual interactions during the recovery of speech comprehension in deaf adults with cochlear implants. AB - Speechreading is an important form of communicative activity that improves social adaptation in deaf adults. Cochlear implantation allows interaction between the visual speechreading abilities developed during deafness and the auditory sensory experiences acquired through use of the cochlear implant. Crude auditory information provided by the implant is analyzed in parallel with conjectural information from speechreading, thus creating new profiles of audiovisual integration with implications for brain plasticity. Understanding the peculiarities of change in speechreading after cochlear implantation may improve our understanding of brain plasticity and provide useful information for functional rehabilitation of implanted patients. In this article, we present a generalized review of our recent studies and indicate perspectives for further research in this domain. PMID- 19778392 TI - Is there an alternative cerebral network associated with enhanced phonological processing in deaf speech-users? An exceptional case. AB - Most people born deaf and exposed to oral language show scant evidence of sensitivity to the phonology of speech when processing written language. In this respect they differ from hearing people. However, occasionally, a prelingually deaf person can achieve good processing of written language in terms of phonological sensitivity and awareness, and in this respect appears exceptional. We report the pattern of event-related fMRI activation in such a deaf reader while performing a rhyme-judgment on written words with similar spelling endings that do not provide rhyme clues. The left inferior frontal gyrus pars opercularis and the left inferior parietal lobe showed greater activation for this task than for a letter-string identity matching task. This participant was special in this regard, showing significantly greater activation in these regions than a group of hearing participants with a similar level of phonological and reading skill. In addition, SR showed activation in the left mid-fusiform gyrus; a region which did not show task-specific activation in the other respondents. The pattern of activation in this exceptional deaf reader was also unique compared with three deaf readers who showed limited phonological processing. We discuss the possibility that this pattern of activation may be critical in relation to phonological decoding of the written word in good deaf readers whose phonological reading skills are indistinguishable from those of hearing readers. PMID- 19778393 TI - Perspectives on multisensory experience and cognitive development in infants with cochlear implants. AB - Infants learn about their environment through sensory exploration, acquiring knowledge that is important for cognitive development. However, little is known about the sensory exploration of infants with profound hearing loss before or after they receive cochlear implants. This paper reviews aspects of sensory perception and cognitive development in hearing infants, discusses the implications of delayed access to auditory information for multisensory perception and cognitive development in infants who use cochlear implants, and suggests several new directions for research addressing multisensory exploration and cognitive development in infants with cochlear implants. PMID- 19778394 TI - Cognitive development, reading and prosodic skills in children with cochlear implants. AB - This report summarizes some of the results of studies in our laboratory exploring the development of cognitive, reading and prosodic skills in children with cochlear implantation (CI). The children with CI performed at significantly lower levels than the hearing comparison group on the majority of cognitive tests, despite showing levels of nonverbal ability. The differences between children with CI and hearing children were most pronounced on tasks with relatively high phonological processing demands, but they were not limited to phonological processing. Impairment of receptive and productive prosody was also evident in children with CI. Despite these difficulties, 75% of the children with CI reached a level of reading skill comparable to that of hearing children. The results are discussed with respect to compensation strategies in reading. PMID- 19778395 TI - Development of social-cognitive and communication skills in children born deaf. AB - Central to the interface of social-cognitive and communicative development is the growth of a theory of mind (ToM). ToM is mastered by most hearing children and deaf children of signing deaf parents by the age of 5 or 6 but is often seriously delayed in deaf children of hearing parents. This paper reviews recently published research on deaf children's ToM development and presents an original study consisting of eight longitudinal case histories that collectively map late signing deaf children's ToM performance from 44 to 158 months of age. While five tentative conclusions can be posited from the collective research so far, further investigation of each of these possibilities is clearly needed. PMID- 19778397 TI - Working memory, deafness and sign language. AB - Working memory (WM) for sign language has an architecture similar to that for speech-based languages at both functional and neural levels. However, there are some processing differences between language modalities that are not yet fully explained, although a number of hypotheses have been mooted. This article reviews some of the literature on differences in sensory, perceptual and cognitive processing systems induced by auditory deprivation and sign language use and discusses how these differences may contribute to differences in WM architecture for signed and speech-based languages. In conclusion, it is suggested that left hemisphere reorganization of the motion-processing system as a result of native sign-language use may interfere with the development of the order processing system in WM. PMID- 19778396 TI - Aided speech-identification performance in single-talker competition by older adults with impaired hearing. AB - This study examined the effects of increased processing load on the closed-set speech-identification performance of young and older adults in a one-talker background. Since the older adults had impaired hearing, speech-identification performance was measured for spectrally shaped stimuli comparable to those experienced when wearing well-fit hearing aids. There were three groups of listeners: (1) 19 older adults with high-frequency sensorineural hearing loss; (2) 10 young adults with normal hearing who were assessed with the same spectrally shaped stimuli as the older adults; (3) 9 young adults with normal hearing who were assessed without spectral shaping and at a poorer target-to competition ratio in an effort to equate overall performance to that of the older adults. In addition to this group factor, there were three within-participant repeated-measures independent variables designed to increase the demands on processing for the target and competing speech stimuli. These were: (1) competition meaningfulness (played in forward or reverse direction); (2) gender match between target and competing talkers (same or different gender); and (3) talker uncertainty (either the same target/competition talker pair or one of many such pairs on each trial). These three repeated-measures independent variables were examined in a 2 x 2 x 2 factorial design. They showed roughly independent and additive effects on speech-identification such that combinations of these variables decreased performance cumulatively. Older adults performed worse than young adults across the board, but also showed diminished relative improvement as the processing load was decreased. Individual differences in performance among the older adults were also examined. PMID- 19778398 TI - Measuring cognitive factors in speech comprehension: the value of using the Text Reception Threshold test as a visual equivalent of the SRT test. AB - The ability to comprehend speech in noise is influenced by bottom-up auditory and top-down cognitive capacities. Separate examination of these capacities is relevant for various purposes. Speech-Reception-Threshold (SRT) tests measure an individual's ability to comprehend speech. This paper addresses the value of the Text-Reception-Threshold (TRT) test (a visual parallel of the SRT test) to assess the cognitive capacities allocated during speech comprehension. We conducted a secondary data analysis, including 87 normally-hearing adults (aged 18 to 78 years). Correlation coefficients between age, TRT, working memory (Spatial Span) and SRT were examined. The TRT and SRT correlated significantly (r = 0.30), supporting the value of TRT in explaining inter-individual differences in SRTs. The relations between age and TRT and between SSP and TRT were non-significant. The results indicate that the current TRT test does not fully cover the cognitive aspects relevant in speech comprehension. Adaptation of the test is required before clinical implementation can be considered. PMID- 19778399 TI - Tinnitus and short-term serial recall in stable versus intermittent masking conditions. AB - The relation between tinnitus and short-term memory performance in varying background sounds is not well understood. In the present study a sample of 18 persons with tinnitus completed a serial recall test in three conditions, silence, masking and intermittent masking. The performance of a matched control group without tinnitus was also investigated. Based on the literature on the "irrelevant sound effect" we expected that the tinnitus group would perform worse during intermittent masking and that they would score lower overall compared to the control group. Results revealed no statistically significant differences between the groups, nor any group interaction within sound conditions for the serial recall test. Groups did however differ regarding subjective measures of concentration problems, anxiety and depression. Results are discussed in relation to thought suppression and distraction from tinnitus. PMID- 19778401 TI - Actin dynamics regulates voltage-dependent calcium-permeable channels of the Vicia faba guard cell plasma membrane. AB - Free cytosolic Ca(2+) ([Ca(2+)](cyt)) is an ubiquitous second messenger in plant cell signaling, and [Ca(2+)](cyt) elevation is associated with Ca(2+)-permeable channels in the plasma membrane and endomembranes regulated by a wide range of stimuli. However, knowledge regarding Ca(2+) channels and their regulation remains limited in planta. A type of voltage-dependent Ca(2+)-permeable channel was identified and characterized for the Vicia faba L. guard cell plasma membrane by using patch-clamp techniques. These channels are permeable to both Ba(2+) and Ca(2+), and their activities can be inhibited by micromolar Gd(3+). The unitary conductance and the reversal potential of the channels depend on the Ca(2+) or Ba(2+) gradients across the plasma membrane. The inward whole-cell Ca(2+) (Ba(2+)) current, as well as the unitary current amplitude and NP(o) of the single Ca(2+) channel, increase along with the membrane hyperpolarization. Pharmacological experiments suggest that actin dynamics may serve as an upstream regulator of this type of calcium channel of the guard cell plasma membrane. Cytochalasin D, an actin polymerization blocker, activated the NPo of these channels at the single channel level and increased the current amplitude at the whole-cell level. But these channel activations and current increments could be restrained by pretreatment with an F-actin stabilizer, phalloidin. The potential physiological significance of this regulatory mechanism is also discussed. PMID- 19778402 TI - The distribution of japonica rice cultivars in the lower region of the Yangtze River valley is determined by its photoperiod-sensitivity and heading date genotypes. AB - There are generally four recognized classes of japonica rice cultivars grown in the lower region of the Yangtze River valley. The geographical distribution of the four classes is latitude-dependent. Variation for heading date (HD) among 29 japonica rice cultivars grown in the lower region of the Yangtze River valley and belonging to the four classes was characterized, and their sensitivity to variations in photoperiod and temperature was analyzed. All of the cultivars were sensitive to both photoperiod and temperature. A regression analysis showed that HD is closely correlated with photoperiod sensitivity (PS). The PS of the four classes increased gradually from the medium maturing middle (MMM) types, through the late maturing middle (LMM) and early maturing late (EML) types to the medium maturing late (MML) types. Crosses with tester lines established that almost all of the cultivars carry the dominant early-heading allele at Ef-1, the photoperiod insensitive allele e(2) and the PS alleles E(1) or E(1) (t). Most of the MMM, LMM and MML types carry the insensitive allele e(3), while EML types have either E(3) or E(3) (t). At Se-1, MMM and LMM types have Se-1(e), some EML types have Se-1(e) and others Se-1(n), while the MML types are mostly Se-1(n). The PS of some MMM, LMM and EML types is reduced by the presence of hd2. These results show that the distribution of the four rice cultivar classes from high latitude to low latitude regions depended on a gradual increase in PS, which is mainly determined by its HD genotypes. PMID- 19778403 TI - Characterization of kiwifruit xyloglucan. AB - Structural characteristics of xyloglucan are constant in the pericarp cell walls of kiwifruit (Actinidia deliciosa) throughout fruit enlargement and maturation. Most of the xyloglucan (XG) persists in the cell walls of ripe kiwifruit. XG from the pericarp tissues of 36-h ethylene-treated kiwifruit was extracted as hemicellulose II (HC-II) with 4.28 M KOH containing 0.02% NaBH(4), and purified using iodine precipitation and subsequent anion-exchange chromatography. This purifying protocol increased XG purity from 50 mol% in HC-II fraction to 62 mol% in the purified XG powder. The molar ratio of glucose: xylose: galactose: fucose in the purified XG was 10: 6.9: 2.1: 0.3. Gel permeation chromatography indicated that purified XG had an average molecular-mass of 161 KDa, a value that exceeds the 95 KDa M(r) determined for total polymeric sugars. Sugar linkage analysis confirmed the lack of fucose in the kiwifruit XG, but a small amount of arabinoxylan and low M(r) glucomannan remained associated with this fraction. PMID- 19778404 TI - Different responses of plant growth and antioxidant system to the combination of cadmium and heat stress in transgenic and non-transgenic rice. AB - A comparative study of just cadmium (Cd) or heat and their combination treatments on some physiological parameters and the antioxidant systems in transgenic rice (Oryza sativa L. cv. Zhonghua No.11) carrying glutathione-S-transferase (GST, EC. 2.5.1.18) and catalase1 (CAT1, EC. 1.11.1.6) and non-transgenics was conducted. The results revealed improved resistance in the transgenics to Cd and the combined Cd and heat stress than non-transgenics. Data showed that the activities of CAT, GST, superoxide dismutase (EC.1.15.1.1) and all components of the ascorbate-glutathione cycle measured in the stressed transgenics shoots are significantly different from those of non-transgenics. Results indicated that co expression of GST and CAT1 had an important effect on the antioxidant system, in particular, the whole ascorbate-glutathione cycle. The less oxidative damage induced by Cd and the stress combination in the transgenics resulted not only from the GST and CAT1 transgene but also from the coordination of the whole ascorbate-glutathione cycle. PMID- 19778405 TI - Endogenous hydrogen peroxide plays a positive role in the upregulation of heme oxygenase and acclimation to oxidative stress in wheat seedling leaves. AB - Pretreatment of lower H(2)O(2) doses (0.05, 0.5 and 5 mM) for 24 h was able to dose-dependently attenuate lipid peroxidation in wheat seedling leaves mediated by further oxidative damage elicited by higher dose of H(2)O(2) (150 mM) for 6 h, with 0.5 mM H(2)O(2) being the most effective concentrations. Further results illustrated that 0.5 mM H(2)O(2) pretreatment triggered the biphasic production of H(2)O(2) during a 24 h period. We also noticed that only peak I (0.25 h) rather than peak II (4 h) was approximately consistent with the enhancement of heme oxygenase (HO) activity, HO-1 gene expression. Meanwhile, enhanced superoxide dismutase (SOD) activity, Mn-SOD and Cu,Zn-SOD transcripts might be a potential source of peak I of endogenous H(2)O(2). Further results confirmed that 0.5 mM H(2)O(2) treatment for 0.5 h was able to upregulate HO gene expression, which was detected by enzyme activity determination, semi-quantitative reverse transcription-polymerase chain reaction and western blotting. Meanwhile, the application of N,N'-dimethylthiourea, a trap for endogenous H(2)O(2), not only blocked the upregulation of HO, but also reversed the corresponding oxidation attenuation. Together, the above results suggest that endogenous H(2)O(2) production (peak I) plays a positive role in the induction of HO by enhancing its mRNA level and protein expression, thus leading to the acclimation to oxidative stress. PMID- 19778406 TI - Induction of protection against paraquat-induced oxidative damage by abscisic acid in maize leaves is mediated through mitogen-activated protein kinase. AB - Mitogen-activated protein kinase (MAPK) cascade has been shown to be important components in stress signal transduction pathway. In the present study, protection of maize seedlings (Zea mays L.) against paraquat-generated oxidative toxicity by abscisic acid (ABA), its association with MAPK and ZmMPK5, a candidate for MAPK were investigated. Treatment of maize leaves with exogenous ABA led to significant decreases in the content of malondialdehyde, the percentage of ion leakage and the level of protein oxidation (in terms of carbonyl groups) under paraquat (PQ) stress. However, such decreases were blocked by the pretreatment with two MAPK kinase inhibitors PD98059 and U0126. The damage caused by PQ was further aggravated by inhibitors. Two inhibitors also suppressed the total activities of the antioxidant enzymes superoxide dismutase (SOD, EC 1.15.1.1), catalase (CAT, EC 1.11.1.6), ascorbate peroxidase (APX, EC 1.11.1.11), and glutathione reductase (GR, EC 1.6.4.2). Besides, treatment with PQ stimulated the activation of a 46 kDa MAPK, which was identified as ZmMPK5 by in-gel kinase assay with immunoprecipitation. These results reveal that ABA-induced protection against PQ-generated oxidative damage is mediated through MAPK cascade in maize leaves, in which ZmMPK5, a candidate for MAPK, is demonstrated to be involved. PMID- 19778407 TI - Potential autonomous selfing in Gesneria citrina (Gesneriaceae), a specialized hummingbird pollinated species with variable expression of herkogamy. AB - Species with mixed mating systems often demonstrate variable expression of breeding system characteristics and thus represent the opportunity to understand the factors and mechanisms that promote both outcrossed and selfed seed production. Here, we investigate variation in levels of herkogamy (variation in stigma-anther separation distance) in a Puerto Rican population of hummingbird pollinated Gesneria citrina Urban. There is significant variation in herkogamy levels among individuals of this species and stigma-anther separation is negatively associated with the ability to set fruits and seeds in the absence of pollinators. The variation in levels of herkogamy may represent a mechanism to ensure the production of some self-fertilized progeny in the absence of hummingbird pollinators. We also describe a novel breeding system in G. citrina, where stamens elongate over time to reach stigma height, but stamen elongation is accelerated by pollination. These results suggest that once the flowers are pollinated, stamen elongation may favor increased pollen removal and siring success, while the reduction in stigma-anther distance no longer imposes the risk of interference between male and female functions. We discuss our findings of breeding system variation in the context of pollination system evolution in an island setting (Antillean islands). PMID- 19778409 TI - Opinion on moderate/low cancer genetic risk markers in medical practice. PMID- 19778412 TI - Central nesfatin-1-expressing neurons are sensitive to peripheral inflammatory stimulus. AB - Recently, a novel factor with anorexigenic properties was identified and called nesfatin-1. This protein (82 aac) is not only expressed in peripheral organs but it is also found in neurons located in specific structures including the hypothalamus and the brainstem, two sites strongly involved in food intake regulation. Here, we studied whether some of the neurons that become activated following an injection of an anorectic dose of lipopolysaccharides (LPS) exhibit a nesfatin-1 phenotype. To this end, we used double immunohistochemistry to target the expression of the immediate-early gene c-fos and of nesfatin-1 on coronal frozen sections of the rat brain. The number of c-Fos+/nesfatin-1+ neurons was evaluated in the immunosensitive structures reported to contain nesfatin-1 neurons; i.e. paraventricular hypothalamic nucleus (PVN), supraoptic nucleus (SON), arcuate nucleus (ARC) and nucleus of the solitary tract (NTS). LPS strongly increased the number of c-Fos+/nesfatin-1+ neurons in the PVN, SON and NTS, and to a lesser extent in the ARC. Triple labeling showed that a portion of the nesfatin-1 neurons activated in response to LPS within the NTS are catecholaminergic since they co-express tyrosine hydroxylase (TH). Our data therefore indicate that a portion of nesfatin-1 neurons of both the hypothalamus and brainstem are sensitive to peripheral inflammatory signals, and provide the first clues suggesting that centrally released nesfatin-1 may contribute to the neural mechanisms leading to endotoxaemic anorexia. PMID- 19778411 TI - Prenatal exposure to tetrachloroethylene-contaminated drinking water and the risk of congenital anomalies: a retrospective cohort study. AB - BACKGROUND: Prior animal and human studies of prenatal exposure to solvents including tetrachloroethylene (PCE) have shown increases in the risk of certain congenital anomalies among exposed offspring. OBJECTIVES: This retrospective cohort study examined whether PCE contamination of public drinking water supplies in Massachusetts influenced the occurrence of congenital anomalies among children whose mothers were exposed around the time of conception. METHODS: The study included 1,658 children whose mothers were exposed to PCE-contaminated drinking water and a comparable group of 2,999 children of unexposed mothers. Mothers completed a self-administered questionnaire to gather information on all of their prior births, including the presence of anomalies, residential histories and confounding variables. PCE exposure was estimated using EPANET water distribution system modeling software that incorporated a fate and transport model. RESULTS: Children whose mothers had high exposure levels around the time of conception had an increased risk of congenital anomalies. The adjusted odds ratio of all anomalies combined among children with prenatal exposure in the uppermost quartile was 1.5 (95% CI: 0.9, 2.5). No meaningful increases in the risk were seen for lower exposure levels. Increases were also observed in the risk of neural tube defects (OR: 3.5, 95% CI: 0.8, 14.0) and oral clefts (OR 3.2, 95% CI: 0.7, 15.0) among offspring with any prenatal exposure. CONCLUSION: The results of this study suggest that the risk of certain congenital anomalies is increased among the offspring of women who were exposed to PCE-contaminated drinking water around the time of conception. Because these results are limited by the small number of children with congenital anomalies that were based on maternal reports, a follow-up investigation should be conducted with a larger number of affected children who are identified by independent records. PMID- 19778413 TI - The predictive effect of fear-avoidance beliefs on low back pain among newly qualified health care workers with and without previous low back pain: a prospective cohort study. AB - BACKGROUND: Health care workers have a high prevalence of low back pain (LBP). Although physical exposures in the working environment are linked to an increased risk of LBP, it has been suggested that individual coping strategies, for example fear-avoidance beliefs, could also be important in the development and maintenance of LBP. Accordingly, the main objective of this study was to examine (1) the association between physical work load and LBP, (2) the predictive effect of fear-avoidance beliefs on the development of LBP, and (3) the moderating effect of fear-avoidance beliefs on the association between physical work load and LBP among cases with and without previous LBP. METHODS: A questionnaire survey among 5696 newly qualified health care workers who completed a baseline questionnaire shortly before completing their education and a follow-up questionnaire 12 months later. Participants were selected on the following criteria: (a) being female, (b) working in the health care sector (n = 2677). Multinomial logistic regression analysis was used to evaluate the effect of physical work load and fear-avoidance beliefs on the severity of LBP. RESULTS: For those with previous LBP, physical work load has an importance, but not among those without previous LBP. In relation to fear-avoidance beliefs, there is a positive relation between it and LBP of than 30 days in both groups, i.e. those without and with previous LBP. No moderating effect of fear-avoidance beliefs on the association between physical work load and LBP was found among cases with and without LBP. CONCLUSION: Both physical work load and fear-avoidance beliefs matters in those with previous LBP. Only fear-avoidance beliefs matters in those without previous LBP. The study did not find a moderating effect of fear avoidance beliefs on the association between physical work load and LBP. PMID- 19778414 TI - Who uses firearms as a means of suicide? A population study exploring firearm accessibility and method choice. AB - BACKGROUND: The 1996 Australian National Firearms Agreement introduced strict access limitations. However, reports on the effectiveness of the new legislation are conflicting. This study, accessing all cases of suicide 1997-2004, explores factors which may impact on the choice of firearms as a suicide method, including current licence possession and previous history of legal access. METHODS: Detailed information on all Queensland suicides (1997-2004) was obtained from the Queensland Suicide Register, with additional details of firearm licence history accessed from the Firearm Registry (Queensland Police Service). Cases were compared against licence history and method choice (firearms or other method). Odds ratios (OR) assessed the risk of firearms suicide and suicide by any method against licence history. A logistic regression was undertaken identifying factors significant in those most likely to use firearms in suicide. RESULTS: The rate of suicide using firearms in those with a current license (10.92 per 100,000) far exceeded the rate in those with no license history (1.03 per 100,000). Those with a license history had a far higher rate of suicide (30.41 per 100,000) compared to that of all suicides (15.39 per 100,000). Additionally, a history of firearms licence (current or present) was found to more than double the risk of suicide by any means (OR = 2.09, P < 0.001). The group with the highest risk of selecting firearms to suicide were older males from rural locations. CONCLUSION: Accessibility and familiarity with firearms represent critical elements in determining the choice of method. Further licensing restrictions and the implementation of more stringent secure storage requirements are likely to reduce the overall familiarity with firearms in the community and contribute to reductions in rates of suicide. PMID- 19778415 TI - Scribble mutants promote aPKC and JNK-dependent epithelial neoplasia independently of Crumbs. AB - BACKGROUND: Metastatic neoplasias are characterized by excessive cell proliferation and disruptions to apico-basal cell polarity and tissue architecture. Understanding how alterations in cell polarity can impact upon tumour development is, therefore, a central issue in cancer biology. The Drosophila gene scribble (scrib) encodes a PDZ-domain scaffolding protein that regulates cell polarity and acts as a tumour suppressor in flies. Increasing evidence also implicates the loss of human Scrib in cancer. In this report, we investigate how loss of Scrib promotes epithelial tumourigenesis in Drosophila, both alone and in cooperation with oncogenic mutations. RESULTS: We find that genetically distinct atypical protein kinase C (aPKC)-dependent and Jun N terminal kinase (JNK)-dependent alterations in scrib mutants drive epithelial tumourigenesis. First, we show that over-expression of the apical cell polarity determinants Crumbs (Crb) or aPKC induces similar cell morphology defects and over-proliferation phenotypes as scrib loss-of-function. However, the morphological and proliferative defects in scrib mutants are independent of Crb function, and instead can be rescued by a dominant negative (kinase dead) aPKC transgene. Secondly, we demonstrate that loss of Scrib promotes oncogene-mediated transformation through both aPKC and JNK-dependent pathways. JNK normally promotes apoptosis of scrib mutant cells. However, in cooperation with oncogenic activated Ras or Notch signalling, JNK becomes an essential driver of tumour overgrowth and invasion. aPKC-dependent signalling in scrib mutants cooperates with JNK to significantly enhance oncogene-mediated tumour overgrowth. CONCLUSION: These results demonstrate distinct aPKC and JNK-dependent pathways through which loss of Scrib promotes tumourigenesis in Drosophila. This is likely to have a direct relevance to the way in which human Scrib can similarly restrain an oncogene-mediated transformation and, more generally, on how the outcome of oncogenic signalling can be profoundly perturbed by defects in apico-basal epithelial cell polarity. PMID- 19778416 TI - Introducing the national COPD resources and outcomes project. AB - BACKGROUND: We report baseline data on the organisation of COPD care in UK NHS hospitals participating in the National COPD Resources and Outcomes Project (NCROP). METHODS: We undertook an initial survey of participating hospitals in 2007, looking at organisation and performance indicators in relation to general aspects of care, provision of non-invasive ventilation (NIV), pulmonary rehabilitation, early discharge schemes, and oxygen. We compare, where possible, against the national 2003 audit. RESULTS: 100 hospitals participated. These were typically larger sized Units. Many aspects of COPD care had improved since 2003. Areas for further improvement include organisation of acute care, staff training, end-of-life care, organisation of oxygen services and continuation of pulmonary rehabilitation. CONCLUSION: KEY POINTS: positive change occurs over time and repeated audit seems to deliver some improvement in services. It is necessary to assess interventions such as the Peer Review used in the NCROP to achieve more comprehensive and rapid change. PMID- 19778417 TI - Ten-year fatal and non-fatal myocardial infarction incidence in elderly populations in Spain: the EPICARDIAN cohort study. AB - BACKGROUND: In Spain, more than 85% of coronary heart disease deaths occur in adults older than 65 years. However, coronary heart disease incidence and mortality in the Spanish elderly have been poorly described. The aim of this study is to estimate the ten-year incidence and mortality rates of myocardial infarction in a population-based large cohort of Spanish elders. METHODS: A population-based cohort of 3729 people older than 64 years old, free of previous myocardial infarction, was established in 1995 in three geographical areas of Spain. Any case of fatal and non-fatal myocardial infarction was investigated until December 2004 using the "cold pursuit method", previously used and validated by the the WHO-MONICA project. RESULTS: Men showed a significantly (p < 0.001) higher cumulative incidence of myocardial infarction (7.2%; 95%CI: 5.94 8.54) than women (3.8%; 95%CI: 3.06-4.74). Although cumulative incidence increased with age (p < 0.05), gender-differences tended to narrow. Adjusted incidence rates were higher in men (957 per 100 000 person-years) than in women (546 per 100 000 person-years) (p < 0.001) and increased with age (p < 0.001). The increase was progressive in women but not in men. Adjusted mortality rates were also higher in men than in women (p < 0.001), being three times higher in the age group of > or = 85 years old than in the age group of 65-74 years old (p < 0.001). CONCLUSION: Incidence of fatal and non-fatal myocardial infarction is high in the Spanish elderly population. Men show higher rates than women, but gender differences diminish with age. PMID- 19778419 TI - Challenges for automatically extracting molecular interactions from full-text articles. AB - BACKGROUND: The increasing availability of full-text biomedical articles will allow more biomedical knowledge to be extracted automatically with greater reliability. However, most Information Retrieval (IR) and Extraction (IE) tools currently process only abstracts. The lack of corpora has limited the development of tools that are capable of exploiting the knowledge in full-text articles. As a result, there has been little investigation into the advantages of full-text document structure, and the challenges developers will face in processing full text articles. RESULTS: We manually annotated passages from full-text articles that describe interactions summarised in a Molecular Interaction Map (MIM). Our corpus tracks the process of identifying facts to form the MIM summaries and captures any factual dependencies that must be resolved to extract the fact completely. For example, a fact in the results section may require a synonym defined in the introduction. The passages are also annotated with negated and coreference expressions that must be resolved.We describe the guidelines for identifying relevant passages and possible dependencies. The corpus includes 2162 sentences from 78 full-text articles. Our corpus analysis demonstrates the necessity of full-text processing; identifies the article sections where interactions are most commonly stated; and quantifies the proportion of interaction statements requiring coherent dependencies. Further, it allows us to report on the relative importance of identifying synonyms and resolving negated expressions. We also experiment with an oracle sentence retrieval system using the corpus as a gold-standard evaluation set. CONCLUSION: We introduce the MIM corpus, a unique resource that maps interaction facts in a MIM to annotated passages within full-text articles. It is an invaluable case study providing guidance to developers of biomedical IR and IE systems, and can be used as a gold standard evaluation set for full-text IR tasks. PMID- 19778418 TI - Mutagenesis of the fusion peptide-like domain of hepatitis C virus E1 glycoprotein: involvement in cell fusion and virus entry. AB - BACKGROUND: Envelope (E) glycoprotein E2 of the hepatitis C virus (HCV) mediates binding of the virus to target cell receptors. Nevertheless, the precise role of E1 in viral entry remains elusive. METHODS: To understand the involvement of the fusion peptide-like domain positioned at residues 264 to 290 within envelope glycoprotein E1 in HCV infection, mutants with Ala and Asn substitutions for residues conserved between HCV and E proteins of flaviviruses or the fusion proteins of paramyxoviruses were constructed by site-directed mutagenesis and their effects on membrane fusion and viral infectivity were examined. RESULTS: None of these mutations affected the synthesis or cell surface expression of envelope proteins, nor did they alter the formation of a non-covalent E1-E2 heterodimer or E2 binding to the large extracellular loop of CD81. The Cys residues located at positions 272 and 281 were unlikely involved in intra- or intermolecular disulfide bond formation. With the exception of the G267A mutant, which showed increased cell fusion, other mutants displayed reduced or marginally inhibited cell fusion capacities compared to the wild-type (WT) E1E2. The G267A mutant was also an exception in human immunodeficiency virus type 1 (HIV-1)/HCV E1E2 pseudotyping analyses, in that it showed higher one-cycle infectivity; all other mutants exhibited greatly or partially reduced viral entry versus the WT pseudotype. All but the G278A and D279N mutants showed a WT-like profile of E1E2 incorporation into HIV-1 particles. Since C272A, C281A, G282A, and G288A pseudotypes bound to Huh7 cells as effectively as did the WT pseudotype, the reduced infectivity of these pseudotypes was due to their ability to inhibit cell fusion. CONCLUSION: Our results indicate that specific residues, but not the structure, of this fusion peptide-like domain are required for mediating cell fusion and viral entry. PMID- 19778420 TI - Regulatory activity of azabisphosphonate-capped dendrimers on human CD4+ T cell proliferation enhances ex-vivo expansion of NK cells from PBMCs for immunotherapy. AB - BACKGROUND: Adoptive cell therapy with allogenic NK cells constitutes a promising approach for the treatment of certain malignancies. Such strategies are currently limited by the requirement of an efficient protocol for NK cell expansion. We have developed a method using synthetic nanosized phosphonate-capped dendrimers allowing such expansion. We are showing here that this is due to a specific inhibitory activity towards CD4+ T cell which could lead to further medical applications of this dendrimer. METHODS: Mononuclear cells from human peripheral blood were used to investigate the immunomodulatory effects of nanosized phosphonate-capped dendrimers on interleukin-2 driven CD4+T cell expansion. Proliferation status was investigated using flow cytometry analysis of CFSE dilution and PI incorporation experiments. Magnetic bead cell sorting was used to address activity towards individual or mixed cell sub-populations. We performed equilibrium binding assay to assess the interaction of fluorescent dendrimers with pure CD4+ T cells. RESULTS: Phosphonate-capped dendrimers are inhibiting the activation, and therefore the proliferation; of CD4+ T cells in IL-2 stimulated PBMCs, without affecting their viability. This allows a rapid enrichment of NK cells and further expansion. We found that dendrimer acts directly on T cells, as their regulatory property is maintained when stimulating purified CD4+ T cells with anti-CD3/CD28 microbeads. Performing equilibrium binding assays using a fluorescent analogue, we show that the phosphonate capped-dendrimers are specifically interacting with purified CD4+ T cells. Ultimately, we found that our protocol prevents the IL-2 related expansion of regulatory T cells that would be deleterious for the activity of infused NK cells. CONCLUSION: High yield expansion of NK cells from human PBMCs by phosphonate-capped dendrimers and IL-2 occurs through the specific inhibition of the CD4+ lymphocyte compartment. Given the specificity of the interaction of dendrimers with CD4+ T cell, we hypothesize that regulatory activity may signal through a specific receptor that remains to be identified. Therefore phosphonate-capped dendrimers constitute not only tools for the ex-vivo expansion of NK cells in immunotherapy of cancers but their mode of action could also lead to further medical applications where T cell activation and proliferation need to be dampened. PMID- 19778421 TI - Ovarian cancer survival population differences: a "high resolution study" comparing Philippine residents, and Filipino-Americans and Caucasians living in the US. AB - BACKGROUND: In contrast to most other forms of cancer, data from some developing and developed countries show surprisingly similar survival rates for ovarian cancer. We aimed to compare ovarian cancer survival in Philippine residents, Filipino-Americans and Caucasians living in the US, using a high resolution approach, taking potential differences in prognostic factors into account. METHODS: Using databases from the SEER 13 and from the Manila and Rizal Cancer Registries, age-adjusted five-year absolute and relative survival estimates were computed using the period analysis method and compared between Filipino-American ovarian cancer patients with cancer patients from the Philippines and Caucasians in the US. Cox proportional hazards modelling was used to determine factors affecting survival differences. RESULTS: Despite more favorable distribution of age and cancer morphology and similar stage distribution, 5-year absolute and relative survival were lower in Philippine residents (Absolute survival, AS, 44%, Standard Error, SE, 2.9 and Relative survival, RS, 49.7%, SE, 3.7) than in Filipino-Americans (AS, 51.3%, SE, 3.1 and RS, 54.1%, SE, 3.4). After adjustment for these and additional covariates, strong excess risk of death for Philippine residents was found (Relative Risk, RR, 2.45, 95% confidence interval, 95% CI, 1.99-3.01). In contrast, no significant differences were found between Filipino Americans and Caucasians living in the US. CONCLUSION: Multivariate analyses disclosed strong survival disadvantages of Philippine residents compared to Filipino-American patients, for which differences in access to health care might have played an important role. Survival is no worse among Filipino-Americans than among Caucasians living in the US. PMID- 19778422 TI - Characteristics and outcomes of trauma patients with ICU lengths of stay 30 days and greater: a seven-year retrospective study. AB - INTRODUCTION: Prolonged intensive care unit lengths of stay (ICU LOS) for critical illness can have acceptable mortality rates and quality of life despite significant costs. Only a few studies have specifically addressed prolonged ICU LOS after trauma. Our goals were to examine characteristics and outcomes of trauma patients with LOS >or= 30 days, predictors of prolonged stay and mortality. METHODS: All trauma ICU admissions over a seven-year period in a level 1 trauma center were analyzed. Admission characteristics, pre-existing conditions and acquired complications in the ICU were recorded. Logistic regression was used to identify independent predictors of prolonged LOS and predictors of mortality among those with prolonged LOS after univariate analyses. RESULTS: Of 4920 ICU admissions, 205 (4%) had ICU LOS >30 days. These patients were older and more severely injured. Age and injury severity score (ISS) were associated with prolonged LOS. After logistic regression analysis, sepsis, acute respiratory distress syndrome, and several infectious complications were important independent predictors of prolonged LOS. Within the group with ICU LOS >30 days, predictors of mortality were age, pre-existing renal disease as well as the development of renal failure requiring dialysis. Overall mortality was 12%. CONCLUSIONS: The majority of patients with ICU LOS >or= 30 days will survive their hospitalization. Infectious and pulmonary complications were predictors of prolonged stay. Further efforts targeting prevention of these complications are warranted. PMID- 19778423 TI - Effect of the G72 (DAOA) putative risk haplotype on cognitive functions in healthy subjects. AB - BACKGROUND: In the last years, several susceptibility genes for psychiatric disorders have been identified, among others G72 (also named D-amino acid oxidase activator, DAOA). Typically, the high-risk variant of a vulnerability gene is associated with decreased cognitive functions already in healthy individuals. In a recent study however, a positive effect of the high-risk variant of G72 on verbal working memory was reported. In the present study, we therefore examined the relationship between G72 genotype status and a broad range of cognitive functions in 423 healthy individuals. METHODS: The G72 carrier status was assessed by the two single nucleotide polymorphisms (SNPs) M23 and M24. Subjects were divided into three risk groups (low, intermediate and high risk). RESULTS: G72 status influenced a number of cognitive functions, such as verbal working memory, attention, and, at a trend level, spatial working memory and executive functions. Interestingly, the high-risk allele carriers scored better than one or even both other groups. CONCLUSION: Our data show that the putative high-risk haplotype (i.e. homozygote C/C-allele carriers in SNP M23 and homozygote T/T allele carriers in SNP M24) is in healthy individuals not necessarily associated with worse performance in cognitive functions, but even with better performance in some domains. Further work is required to identify the mechanisms of G72 on brain functions. PMID- 19778424 TI - The accuracy of frozen section analysis in ultrasound- guided core needle biopsy of breast lesions. AB - BACKGROUND: Limited data are available to evaluate the accuracy of frozen section analysis and ultrasound- guided core needle biopsy of the breast. METHODS: In a retrospective analysis data of 120 consecutive handheldultrasound- guided 14- gauge automated core needle biopsies (CNB) in 109 consecutive patients with breast lesions between 2006 and 2007 were evaluated. RESULTS: In our outpatient clinic120 CNB were performed. In 59/120 (49.2%) cases we compared histological diagnosis on frozen sections with those on paraffin sections of CNB and finally with the result of open biopsy. Of the cases 42/59 (71.2%) were proved to be malignant and 17/59 (28.8%) to be benign in the definitive histology. 2/59 (3.3%) biopsies had a false negative frozen section result. No false positive results of the intraoperative frozen section analysis were obtained, resulting in a sensitivity, specificity and positive predicting value (PPV) and negative predicting value (NPV) of 95%, 100%, 100% and 90%, respectively. Histological and morphobiological parameters did not show up relevance for correct frozen section analysis. In cases of malignancy time between diagnosis and definitive treatment could not be reduced due to frozen section analysis. CONCLUSION: The frozen section analysis of suspect breast lesions performed by CNB displays good sensitivity/specificity characteristics. Immediate investigations of CNB is an accurate diagnostic tool and an important step in reducing psychological strain by minimizing the period of uncertainty in patients with breast tumor. PMID- 19778425 TI - A unique genetic code change in the mitochondrial genome of the parasitic nematode Radopholus similis. AB - BACKGROUND: Mitochondria (mt) contain their own autonomously replicating DNA, constituted as a small circular genome encoding essential subunits of the respiratory chain. Mt DNA is characterized by a genetic code which differs from the standard one. Interestingly, the mt genome of nematodes share some peculiar features, such as small transfer RNAs, truncated ribosomal RNAs and - in the class of Chromadorean nematodes - unidirectional transcription. FINDINGS: We present the complete mt genomic sequence (16,791 bp) of the plant-parasitic nematode Radopholus similis (class Chromadorea). Although it has a gene content similar to most other nematodes, many idiosyncrasies characterize the extremely AT-rich mt genome of R. similis (85.4% AT). The secondary structure of the large (16S) rRNA is further reduced, the gene order is unique, the large non-coding region contains two large repeats, and most interestingly, the UAA codon is reassigned from translation termination to tyrosine. In addition, 7 out of 12 protein-coding genes lack a canonical stop codon and analysis of transcriptional data showed the absence of polyadenylation. Northern blot analysis confirmed that only one strand is transcribed and processed. Furthermore, using nucleotide content bias methods, regions for the origin of replication are suggested. CONCLUSION: The extraordinary mt genome of R. similis with its unique genetic code appears to contain exceptional features correlated to DNA decoding. Therefore the genome may provide an incentive to further elucidate these barely understood processes in nematodes. This comprehension may eventually lead to parasitic nematode-specific control targets as healthy mitochondria are imperative for organism survival. In addition, the presented genome is an interesting exceptional event in genetic code evolution. PMID- 19778426 TI - Do the mutations of C1GALT1C1 gene play important roles in the genetic susceptibility to Chinese IgA nephropathy? AB - BACKGROUND: The deficiency of beta1,3 galactose in hinge region of IgA1 molecule played a pivotal role in pathogenesis of IgA nephropathy (IgAN). Cosmc, encoded by C1GALT1C1 gene, was indispensable to beta1,3 galactosylation of IgA1. We designed a serial study to investigate the relationship between the mutations of C1GALT1C1 gene and the genetic susceptibility to IgAN. METHODS: Nine hundred and thirty-eight subjects, including 661 patients with IgAN and 277 healthy controls were enrolled in the study. Firstly, single nucleotide polymorphisms (SNPs) in the promoter region of C1GALT1C1 gene were screened. Then the c.-347-190G>A was analyzed by PCR-restriction fragment length polymorphism (PCR-RFLP) for further case-control association analysis. Secondly the somatic mutations of DNAs from peripheral blood B lymphocytes were detected in 15 patients and 7 normal controls. RESULTS: No significant association was observed between the different alleles or genotypes of c.-347-190G>A and IgAN. The patients with different genotypes of C1GALT1C1 gene did not significantly associate with clinical manifestations, including hematuria, proteinuria, and serum creatinine of patients with IgAN. There was no somatic mutation detected in total 202 clones of 22 individuals. CONCLUSION: The c.-347-190G>A polymorphism and the somatic mutation of encoding region of C1GALT1C1 gene were not significantly related to the genetic susceptibility to IgAN in Northern Chinese population. PMID- 19778427 TI - Skeletal Plasmacytoma: progression of disease and impact of local treatment; an analysis of SEER database. AB - BACKGROUND: Previous reports suggest an as yet unidentifiable subset of patients with plasmacytoma will progress to myeloma. The current study sought to establish the risk of developing myeloma and determine the prognostic factors affecting the progression of disease. METHODS: Patients with plasmacytoma diagnosed between 1973 and 2005 were identified in the SEER database(1164 patients). Patient demographics and clinical characteristics, treatment(s), cause of death, and survival were extracted. Kaplan-Meier, log-rank, and Cox regression were used to analyze prognostic factors. RESULTS: The five year survival among patients initially diagnosed with plasmacytoma that later progressed to multiple myeloma and those initially diagnosed with multiple myeloma were almost identical (25% and 23%; respectively). Five year survival for patients with plasmacytoma that did not progress to multiple myeloma was significantly better (72%). Age > 60 years was the only factor that correlated with progression of disease (p = 0.027). DISCUSSION: Plasmacytoma consists of two cohorts of patients with different overall survival; those patients that do not progress to systemic disease and those that develop myeloma. Age > 60 years is associated with disease progression. Identifying patients with systemic disease early in the treatment will permit aggressive and novel treatment strategies to be implemented. PMID- 19778428 TI - Prevalence and antimicrobial resistance pattern of bacterial meningitis in Egypt. AB - Infectious diseases are the leading cause of morbidity and mortality in the developing world. In Egypt bacterial diseases constitute a great burden, with several particular bacteria sustaining the leading role of multiple serious infections. This article addresses profound bacterial agents causing a wide array of infections including but not limited to pneumonia and meningitis. The epidemiology of such infectious diseases and the prevalence of Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae are reviewed in the context of bacterial meningitis. We address prevalent serotypes in Egypt, antimicrobial resistance patterns and efficacy of vaccines to emphasize the importance of periodic surveillance for appropriate preventive and treatment strategies. PMID- 19778429 TI - Critical care in the emergency department: an assessment of the length of stay and invasive procedures performed on critically ill ED patients. AB - INTRODUCTION: Critically ill patients commonly present to the ED and require aggressive resuscitation. Patient transfer to an ICU environment in an expedient manner is considered optimal care. However, this patient population may remain in the ED for prolonged periods of time. The goal of this study is to describe the ED length of stay, and the invasive procedures performed in critically ill ED patients. METHODS: This is a retrospective medical record review of all patients who presented to the study center over a 1 year period. Patient demographic data, in addition to the times of ED presentation and ICU admission were recorded. Invasive procedures performed in the pre-hospital, ED and the initial 24 hours of ICU care were also recorded. RESULTS: Overall, 178 patients' required direct admission to an ICU from the ED, with a mortality rate of 21.9%. The median LOS in the ED for critically ill patients requiring ICU admission was 4.9 h (mean 6.5 h, range 1.4-28.2 h). Seventy percent of patients (125,178, 70.2%) required endotracheal intubation with the majority (118/125, 94.4%) being performed in the ED (80/125, 64.0%) or the prehospital setting (38/125, 30.4%). Central venous access was obtained in 56/178 patients (31.5%), with 17.9% (10/56) completed in the ED. Similarly, arterial catheters were inserted in 99/178 patients (55.6%) with 14.1% (14/99) inserted in the ED. CONCLUSION: Critically ill patients are managed in the emergency department for a significant length of time. Although the majority of airway intervention occurs in the prehospital setting and ED, relatively few patients undergo invasive procedures while in the emergency department. PMID- 19778430 TI - Expansion of seasonal influenza vaccination in the Americas. AB - BACKGROUND: Seasonal influenza is a viral disease whose annual epidemics are estimated to cause three to five million cases of severe illness and 250,000 to 500,000 deaths worldwide. Vaccination is the main strategy for primary prevention. METHODS: To assess the status of influenza vaccination in the Americas, influenza vaccination data reported to the Pan American Health Organization (PAHO) through 2008 were analyzed. RESULTS: Thirty-five countries and territories administered influenza vaccine in their public health sector, compared to 13 countries in 2004. Targeted risk groups varied. Sixteen countries reported coverage among older adults, ranging from 21% to 100%; coverage data were not available for most countries and targeted populations. Some tropical countries used the Northern Hemisphere vaccine formulation and others used the Southern Hemisphere vaccine formulation. In 2008, approximately 166.3 million doses of seasonal influenza vaccine were purchased in the Americas; 30 of 35 countries procured their vaccine through PAHO's Revolving Fund. CONCLUSION: Since 2004 there has been rapid uptake of seasonal influenza vaccine in the Americas. Challenges to fully implement influenza vaccination remain, including difficulties measuring coverage rates, variable vaccine uptake, and limited surveillance and effectiveness data to guide decisions regarding vaccine formulation and timing, especially in tropical countries. PMID- 19778431 TI - Site-specific relapse pattern of the triple negative tumors in Chinese breast cancer patients. AB - BACKGROUND: It has been reported that triple negative phenotype is characterized by aggressive clinical history in Western breast cancer patients, however its pattern of metastatic spread had never been reported in the Chinese population. Considering racial disparities, we sought to analyze the spread pattern for different sites of first recurrence in Chinese triple negative breast cancers. METHODS: A retrospective study of 1662 patients was carried out from a large database of breast cancer patients undergoing surgery between January 1, 2000 and March 31, 2004 at the Cancer Hospital, Fudan University, Shanghai, China. Survival curves were generated using the Kaplan-Meier method and annual relapse hazards were estimated by the hazard function. RESULTS: We found a statistically significant difference in relapse-free survival (RFS) for locoregional and visceral recurrence (P = 0.007 and P = 0.025, respectively) among the triple negative, ERBB2+ and HR+/ERBB2- subgroups in univariate analysis. In the multivariate Cox proportional hazards regression analysis, RFS for either locoregional or visceral relapse in the triple negative category was inferior to that in HR+/ERBB2- patients (P = 0.027 and P = 0.005, respectively), but comparable to that in ERBB2+ women (both P >0.05). Furthermore, the early relapse peak appeared later in the triple negative group than that in the ERBB2+ counterpart for both locoregional and visceral relapse. On the other hand, when compared with triple negative breast cancers, a significantly lower risk of developing bone relapse was discerned for ERBB2+ women (P = 0.048; HR = 0.384, 95% CI 0.148-0.991), with the borderline significance for HR+/ERBB2- breast cancers (P = 0.058; HR = 0.479, 95% CI 0.224-1.025). In terms of bone metastasis, the hazard rate remained higher for the triple negative category than that for the ERBB2+ subtype. CONCLUSION: Based on the site-specific spread pattern in different subgroups, the triple negative category of breast cancers in the Chinese population exhibits a different pattern of relapse, which indicates that different organotropism may be due to the different intrinsic subtypes. A better knowledge of the triple negative category is warranted for efficacious systemic regimens to decrease and/or delay the relapse hazard. PMID- 19778433 TI - Socio-cultural predictors of health-seeking behaviour for febrile under-five children in Mwanza-Neno district, Malawi. AB - BACKGROUND: Prompt access to effective treatment for malaria is unacceptably low in Malawi. Less than 20% of children under the age of five with fever receive appropriate anti-malarial treatment within 24 hours of fever onset. This study assessed socio-cultural factors associated with delayed treatment of children with fever in Mwanza district, Malawi. METHODOLOGY: It was a qualitative study using focus group discussions and key informant interviews. RESULTS: A total of 151 caregivers and 46 health workers participated in the focus group discussions. The majority of caregivers were able to recognize fever and link it to malaria. Despite high knowledge of malaria, prompt treatment and health-seeking behaviour were poor, with the majority of children first being managed at home with treatment regimens other than effective anti-malarials. Traditional beliefs about causes of fever, unavailability of anti-malarial drugs within the community, barriers to accessing the formal health care system, and trust in traditional medicine were all associated with delays in seeking appropriate treatment for fever. CONCLUSION: The study has demonstrated important social cultural factors that negatively influence for caregivers of children under five. To facilitate prompt and appropriate health-seeking behaviour, behavioral change messages must address the prevailing local beliefs about causes of fever and the socio-economic barriers to accessing health care. PMID- 19778432 TI - Tumor necrosis factor alpha-dependent aggrecan cleavage and release of glycosaminoglycans in the meniscus is mediated by nitrous oxide-independent aggrecanase activity in vitro. AB - INTRODUCTION: Little is known about factors that induce meniscus damage. Since joint inflammation appears to be a causative factor for meniscal destruction, we investigated the influence of tumor necrosis factor (TNFalpha) on glycosaminoglycan (GAG) release and aggrecan cleavage in an in vitro model. METHODS: Meniscal explant disks (3 mm diameter x 1 mm thickness) were isolated from 2-year-old cattle. After 3 days of TNFalpha-treatment GAG release (DMMB assay), biosynthetic activity (sulfate incorporation), nitric oxide (NO) production (Griess assay), gene expression of matrix-degrading enzymes (quantitative RT-PCR, zymography), and immunostaining of the aggrecan fragment NITEGE were determined. RESULTS: TNFalpha induced release of GAG as well as production of NO in a dose-dependent manner, while sulfate incorporation was decreased. TNFalpha increased matrix metalloproteinase (MMP)-3 and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4 mRNA expression, whereas collagen type I was decreased, and aggrecan, collagen type II as well as MMP-1, -2, -13 and ADAMTS-5 were variably affected. Zymography also showed a TNFalpha-dependent increase in MMP-3 expression, but pre-dominantly in the pro form. TNFalpha-dependent formation of the aggrecanase-specific aggrecan neoepitope NITEGE was induced. Tissue inhibitor of metalloproteinases (TIMP)-3, but not TIMP-1 or -2 inhibited TNFalpha-dependent GAG release and NITEGE production, whereas inhibition of TNFalpha-dependent NO generation with the NO synthetase inhibitor L-NMMA failed to inhibit GAG release and NITEGE production. CONCLUSIONS: Our study shows that aggrecanase activity (a) is responsible for early TNFalpha-dependent aggrecan cleavage and GAG release in the meniscus and (b) might be involved in meniscal degeneration. Additionally, the meniscus is a TNFalpha-dependent source for MMP-3. However, the TNFalpha-dependent NO production seems not to be involved in release of proteoglycans under the given circumstances. PMID- 19778434 TI - Critical role of glycosylation in determining the length and structure of T cell epitopes. AB - BACKGROUND: Using a combined in silico approach, we investigated the glycosylation of T cell epitopes and autoantigens. The present systems biology analysis was made possible by currently available databases (representing full proteomes, known human T cell epitopes and autoantigens) as well as glycosylation prediction tools. RESULTS: We analyzed the probable glycosylation of human T cell epitope sequences extracted from the ImmuneEpitope Database. Our analysis suggests that in contrast to full length SwissProt entries, only a minimal portion of experimentally verified T cell epitopes is potentially N- or O glycosylated (2.26% and 1.22%, respectively). Bayesian analysis of entries extracted from the Autoantigen Database suggests a correlation between N glycosylation and autoantigenicity. The analysis of random generated sequences shows that glycosylation probability is also affected by peptide length. Our data suggest that the lack of peptide glycosylation, a feature that probably favors effective recognition by T cells, might have resulted in a selective advantage for short peptides to become T cell epitopes. The length of T cell epitopes is at the intersection of curves determining specificity and glycosylation probability. Thus, the range of length of naturally occurring T cell epitopes may ensure the maximum specificity with the minimal glycosylation probability. CONCLUSION: The findings of this bioinformatical approach shed light on fundamental factors that might have shaped adaptive immunity during evolution. Our data suggest that amino acid sequence-based hypo/non-glycosylation of certain segments of proteins might be substantial for determining T cell immunity/autoimmunity. PMID- 19778435 TI - Choropleth map legend design for visualizing community health disparities. AB - BACKGROUND: Disparities in health outcomes across communities are a central concern in public health and epidemiology. Health disparities research often links differences in health outcomes to other social factors like income. Choropleth maps of health outcome rates show the geographical distribution of health outcomes. This paper illustrates the use of cumulative frequency map legends for visualizing how the health events are distributed in relation to social characteristics of community populations. The approach uses two graphs in the cumulative frequency legend to highlight the difference between the raw count of the health events and the raw count of the social characteristic like low income in the geographical areas of the map. The approach is applied to mapping publicly available data on low birth weight by town in Connecticut and Lyme disease incidence by town in Connecticut in relation to income. The steps involved in creating these legends are described in detail so that health analysts can adopt this approach. RESULTS: The different health problems, low birth weight and Lyme disease, have different cumulative frequency signatures. Graphing poverty population on the cumulative frequency legends revealed that the poverty population is distributed differently with respect to the two different health problems mapped here. CONCLUSION: Cumulative frequency legends can be useful supplements for choropleth maps. These legends can be constructed using readily available software. They contain all of the information found in standard choropleth map legends, and they can be used with any choropleth map classification scheme. Cumulative frequency legends effectively communicate the proportion of areas, the proportion of health events, and/or the proportion of the denominator population in which the health events occurred that falls within each class interval. They illuminate the context of disease through graphing associations with other variables. PMID- 19778436 TI - Menthol increases human glioblastoma intracellular Ca2+, BK channel activity and cell migration. AB - This study examined the effect of menthol, an agonist for transient receptor potential melastatin 8 (TRPM8) ion channels, to increase intracellular Ca2+ concentration, [Ca2+]i, in human glioblastoma cells (DBTRG cells), which resulted in activation of the large-conductance Ca2+-activated K+ membrane ion channels (BK channels). Voltage ramps applied over 300 ms from -100 to 100 mV resulted in membrane currents with marked inwardly- and outwardly-rectifying components. Paxilline (2 microM) abolished the outwardly-rectifying current. Outwardly rectifying on-cell patch currents were increased markedly by menthol (100 microM) added to the bath. The estimated on-cell conductance of these channels was 253 pS. Kinetic analysis showed that added menthol increased channel open probability and mean open frequency after 5 min. In a similar time course menthol increased [Ca2+]i, and this increase was abolished either by added paxilline, tetraethylammonium ion or by Ca2+-free external solution. Finally, menthol stimulated the rate of DBTRG cell migration into scratch wounds made in confluent cells, and this also was inhibited by paxilline or by tetraethylammonium ion. We conclude that menthol, a TRPM8 agonist, increases DBTRG cell [Ca2+]i that in turn activates membrane BK ion channels. Inhibition of BK channels by paxilline reverses menthol-stimulated increase of [Ca2+]i and of cell migration. Thus, BK channels function to maintain elevations in [Ca2+]i needed to sustain increases in DBTRG cell migration. PMID- 19778437 TI - Brazilian network for the surveillance of maternal potentially life threatening morbidity and maternal near-miss and a multidimensional evaluation of their long term consequences. AB - BACKGROUND: It has been suggested that the study of women who survive life threatening complications related to pregnancy (maternal near-miss cases) may represent a practical alternative to surveillance of maternal morbidity/mortality since the number of cases is higher and the woman herself is able to provide information on the difficulties she faced and the long-term repercussions of the event. These repercussions, which may include sexual dysfunction, postpartum depression and posttraumatic stress disorder, may persist for prolonged periods of time, affecting women's quality of life and resulting in adverse effects to them and their babies. OBJECTIVE: The aims of the present study are to create a nationwide network of scientific cooperation to carry out surveillance and estimate the frequency of maternal near-miss cases, to perform a multicenter investigation into the quality of care for women with severe complications of pregnancy, and to carry out a multidimensional evaluation of these women up to six months. METHODS/DESIGN: This project has two components: a multicenter, cross sectional study to be implemented in 27 referral obstetric units in different geographical regions of Brazil, and a concurrent cohort study of multidimensional analysis. Over 12 months, investigators will perform prospective surveillance to identify all maternal complications. The population of the cross-sectional component will consist of all women surviving potentially life-threatening conditions (severe maternal complications) or life-threatening conditions (the maternal near miss criteria) and maternal deaths according to the new WHO definition and criteria. Data analysis will be performed in case subgroups according to the moment of occurrence and determining cause. Frequencies of near miss and other severe maternal morbidity and the association between organ dysfunction and maternal death will be estimated. A proportion of cases identified in the cross-sectional study will comprise the cohort of women for the multidimensional analysis. Various aspects of the lives of women surviving severe maternal complications will be evaluated 3 and 6 months after the event and compared to a group of women who suffered no severe complications in pregnancy. Previously validated questionnaires will be used in the interviews to assess reproductive function, posttraumatic stress, functional capacity, quality of life, sexual function, postpartum depression and infant development. PMID- 19778438 TI - Increased expression of the oxidative pentose phosphate pathway and gluconeogenesis in anaerobically growing xylose-utilizing Saccharomyces cerevisiae. AB - BACKGROUND: Fermentation of xylose to ethanol has been achieved in S. cerevisiae by genetic engineering. Xylose utilization is however slow compared to glucose, and during anaerobic conditions addition of glucose has been necessary for cellular growth. In the current study, the xylose-utilizing strain TMB 3415 was employed to investigate differences between anaerobic utilization of glucose and xylose. This strain carried a xylose reductase (XYL1 K270R) engineered for increased NADH utilization and was capable of sustained anaerobic growth on xylose as sole carbon source. Metabolic and transcriptional characterization could thus for the first time be performed without addition of a co-substrate or oxygen. RESULTS: Analysis of metabolic fluxes showed that although the specific ethanol productivity was an order of magnitude lower on xylose than on glucose, product yields were similar for the two substrates. In addition, transcription analysis identified clear regulatory differences between glucose and xylose. Respiro-fermentative metabolism on glucose during aerobic conditions caused repression of cellular respiration, while metabolism on xylose under the same conditions was fully respiratory. During anaerobic conditions, xylose repressed respiratory pathways, although notably more weakly than glucose. It was also observed that anaerobic xylose growth caused up-regulation of the oxidative pentose phosphate pathway and gluconeogenesis, which may be driven by an increased demand for NADPH during anaerobic xylose catabolism. CONCLUSION: Co factor imbalance in the initial two steps of xylose utilization may reduce ethanol productivity by increasing the need for NADP+ reduction and consequently increase reverse flux in glycolysis. PMID- 19778439 TI - High resolution transcriptome maps for wild-type and nonsense-mediated decay defective Caenorhabditis elegans. AB - BACKGROUND: While many genome sequences are complete, transcriptomes are less well characterized. We used both genome-scale tiling arrays and massively parallel sequencing to map the Caenorhabditis elegans transcriptome across development. We utilized this framework to identify transcriptome changes in animals lacking the nonsense-mediated decay (NMD) pathway. RESULTS: We find that while the majority of detectable transcripts map to known gene structures, >5% of transcribed regions fall outside current gene annotations. We show that >40% of these are novel exons. Using both technologies to assess isoform complexity, we estimate that >17% of genes change isoform across development. Next we examined how the transcriptome is perturbed in animals lacking NMD. NMD prevents expression of truncated proteins by degrading transcripts containing premature termination codons. We find that approximately 20% of genes produce transcripts that appear to be NMD targets. While most of these arise from splicing errors, NMD targets are enriched for transcripts containing open reading frames upstream of the predicted translational start (uORFs). We identify a relationship between the Kozak consensus surrounding the true start codon and the degree to which uORF containing transcripts are targeted by NMD and speculate that translational efficiency may be coupled to transcript turnover via the NMD pathway for some transcripts. CONCLUSIONS: We generated a high-resolution transcriptome map for C. elegans and used it to identify endogenous targets of NMD. We find that these transcripts arise principally through splicing errors, strengthening the prevailing view that splicing and NMD are highly interlinked processes. PMID- 19778441 TI - In silico investigation of ADAM12 effect on TGF-beta receptors trafficking. AB - BACKGROUND: The transforming growth factor beta is known to have pleiotropic effects, including differentiation, proliferation and apoptosis. However the underlying mechanisms remain poorly understood. The regulation and effect of TGF beta signaling is complex and highly depends on specific protein context. In liver, we have recently showed that the disintegrin and metalloproteinase ADAM12 interacts with TGF-beta receptors and modulates their trafficking among membranes, a crucial point in TGF-beta signaling and development of fibrosis. The present study aims to better understand how ADAM12 impacts on TGF-beta receptors trafficking and TGF-beta signaling. FINDINGS: We extracted qualitative biological observations from experimental data and defined a family of models producing a behavior compatible with the presence of ADAM12. We computationally explored the properties of this family of models which allowed us to make novel predictions. We predict that ADAM12 increases TGF-beta receptors internalization rate between the cell surface and the endosomal membrane. It also appears that ADAM12 modifies TGF-beta signaling shape favoring a permanent response by removing the transient component observed under physiological conditions. CONCLUSION: In this work, confronting differential models with qualitative biological observations, we obtained predictions giving new insights into the role of ADAM12 in TGF-beta signaling and hepatic fibrosis process. PMID- 19778440 TI - Rapid serological detection of autoantibodies associated with Sjogren's syndrome. AB - BACKGROUND: Sjogren's syndrome (SjS) is a relatively common autoimmune disease characterized by oral and ocular dryness. There is an increasing need for simple, sensitive and rapid technologies for the diagnosis of SjS and other autoimmune diseases. Here we investigated whether a quick version of luciferase immunoprecipitation systems (QLIPS) could be used to produce a rapid, specific and quantitative test to detect autoantibodies associated with SjS. METHODS: Using QLIPS, which requires only ten minutes of incubation, a cohort of control and SjS sera were tested for antibodies to three SjS autoantigens (La, Ro60 and Ro52). Sensitivity and specificity of the QLIPS tests were compared with LIPS and existing ELISA data. The QLIPS test for Ro52 was then evaluated with a new validation cohort and its diagnostic performance determined. RESULTS: Using QLIPS, autoantibodies to three SjS antigens, La, Ro60, and Ro52 were detected in 49%, 56% and 70%, respectively, of the SjS patients and none of the controls (100% specificity). With antibody titers in the Ro52-seropositive SjS samples approximately 1,000 times higher than the healthy controls, not only was Ro52 the most informative, but detection of anti-Ro52 antibodies under these non equilibrium conditions was improved compared to the standard 2 hour LIPS format. Validation of the anti-Ro52 QLIPS test in a new, independent cohort of SjS and control serum samples showed 66% sensitivity and 100% specificity. CONCLUSION: Together these results suggest that the QLIPS format for Ro52 yields both a more rapid and more discriminating test for detecting Ro52 autoantibodies than existing immunoassays and has the potential to be adapted for point-of-care evaluation of patients with SjS and other rheumatologic diseases. PMID- 19778442 TI - Predicting protein-protein binding sites in membrane proteins. AB - BACKGROUND: Many integral membrane proteins, like their non-membrane counterparts, form either transient or permanent multi-subunit complexes in order to carry out their biochemical function. Computational methods that provide structural details of these interactions are needed since, despite their importance, relatively few structures of membrane protein complexes are available. RESULTS: We present a method for predicting which residues are in protein-protein binding sites within the transmembrane regions of membrane proteins. The method uses a Random Forest classifier trained on residue type distributions and evolutionary conservation for individual surface residues, followed by spatial averaging of the residue scores. The prediction accuracy achieved for membrane proteins is comparable to that for non-membrane proteins. Also, like previous results for non-membrane proteins, the accuracy is significantly higher for residues distant from the binding site boundary. Furthermore, a predictor trained on non-membrane proteins was found to yield poor accuracy on membrane proteins, as expected from the different distribution of surface residue types between the two classes of proteins. Thus, although the same procedure can be used to predict binding sites in membrane and non-membrane proteins, separate predictors trained on each class of proteins are required. Finally, the contribution of each residue property to the overall prediction accuracy is analyzed and prediction examples are discussed. CONCLUSION: Given a membrane protein structure and a multiple alignment of related sequences, the presented method gives a prioritized list of which surface residues participate in intramembrane protein-protein interactions. The method has potential applications in guiding the experimental verification of membrane protein interactions, structure-based drug discovery, and also in constraining the search space for computational methods, such as protein docking or threading, that predict membrane protein complex structures. PMID- 19778443 TI - Analysis of induced components in electroencephalograms using a multiple correlation method. AB - BACKGROUND: Evoked and induced activities are two typical components in the EEG and MEG time series after a stimulation. While evoked activity is phase-locked to the stimulus, induced activity is not. Present analysis methods are able to detect non-phase-locked parts of the signal, however, they do not improve the signal-to-noise ratio (SNR) of these signal components. RESULTS: We present a new method for estimating induced activation in EEG multi-trial data sets. It is based on the multiple correlation of single trials. Our method not only detects induced components within the EEG signal, it also improves their SNR. The method is successfully tested with artificial data sets. Application to real data is exemplified using EEG data recorded in a photic driving experiment. CONCLUSION: We show that the SNR of the induced activity is enhanced by our method, and the method found longer lasting induced activity after the end of stimulation compared with a conventional method. PMID- 19778444 TI - Damage control surgery by keeping the abdomen open during pregnancy: favorable outcome, a case report. AB - BACKGROUND: Acute abdomen in advanced pregnancy is one of the most challenging surgical situations. In life-threatening situations, despite optimal management, foetus distress and preterm delivery may occur. Although laparostomy is a useful treatment of abdominal sepsis, its successful management has not been reported previously in pregnant women. CASE: 30-year-old woman at 23 week of pregnancy was investigated for non-specific abdominal pain. Surgical exploration revealed extensive ischemic bowel necrosis. Multiple segmental resections were performed and abdomen was left open with vacuum assisted dressing, maintained for 48 hours. At the third surgical look the continuity was restored and abdominal wall closed. The foetal condition stayed unperturbed under pharmacologic tocolysis. Pregnancy was carried to full term delivery. CONCLUSION: Open abdomen strategy can be successfully applied in pregnant woman. PMID- 19778446 TI - What are the risk factors of colonoscopic perforation? AB - BACKGROUND: Knowledge of the factors influencing colonoscopic perforation (CP) is of decisive importance, especially with regard to the avoidance or minimization of the perforations. The aim of this study was to determine the incidence and risk factors of CP in one of the endoscopic training centers accredited by the World Gastroenterology Organization. METHODS: The prospectively collected data were reviewed of all patients undergoing either colonoscopy or flexible sigmoidoscopy at the Faculty of Medicine Siriraj Hospital, Bangkok, Thailand between January 2005 and July 2008. The incidence of CP was evaluated. Eight independent patient-, endoscopist- and endoscopy-related variables were analyzed by a multivariate model to determine their association with CP. RESULTS: Over a 3.5-year period, 10,124 endoscopic procedures of the colon (8,987 colonoscopies and 1,137 flexible sigmoidoscopies) were performed. There were 15 colonic perforations (0.15%). Colonoscopy had a slightly higher risk of CP than flexible sigmoidoscopy (OR 1.77, 95%CI 0.23-13.51; p = 1.0). Patient gender, emergency endoscopy, anesthetic method, and the specialty or experience of the endoscopist were not significantly predictive of CP rate. In multivariate analysis, patient age of over 75 years (OR = 6.24, 95%CI 2.26-17.26; p < 0.001) and therapeutic endoscopy (OR = 2.98, 95%CI 1.08-8.23; p = 0.036) were the only two independent risk factors for CP. CONCLUSION: The incidence of CP in this study was 0.15%. Patient age of over 75 years and therapeutic colonoscopy were two important risk factors for CP. PMID- 19778445 TI - The rapamycin-regulated gene expression signature determines prognosis for breast cancer. AB - BACKGROUND: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase involved in multiple intracellular signaling pathways promoting tumor growth. mTOR is aberrantly activated in a significant portion of breast cancers and is a promising target for treatment. Rapamycin and its analogues are in clinical trials for breast cancer treatment. Patterns of gene expression (metagenes) may also be used to simulate a biologic process or effects of a drug treatment. In this study, we tested the hypothesis that the gene-expression signature regulated by rapamycin could predict disease outcome for patients with breast cancer. RESULTS: Colony formation and sulforhodamine B (IC50 < 1 nM) assays, and xenograft animals showed that MDA-MB-468 cells were sensitive to treatment with rapamycin. The comparison of in vitro and in vivo gene expression data identified a signature, termed rapamycin metagene index (RMI), of 31 genes upregulated by rapamycin treatment in vitro as well as in vivo (false discovery rate of 10%). In the Miller dataset, RMI did not correlate with tumor size or lymph node status. High (>75th percentile) RMI was significantly associated with longer survival (P = 0.015). On multivariate analysis, RMI (P = 0.029), tumor size (P = 0.015) and lymph node status (P = 0.001) were prognostic. In van 't Veer study, RMI was not associated with the time to develop distant metastasis (P = 0.41). In the Wang dataset, RMI predicted time to disease relapse (P = 0.009). CONCLUSION: Rapamycin regulated gene expression signature predicts clinical outcome in breast cancer. This supports the central role of mTOR signaling in breast cancer biology and provides further impetus to pursue mTOR-targeted therapies for breast cancer treatment. PMID- 19778447 TI - MALS: an efficient strategy for multiple site-directed mutagenesis employing a combination of DNA amplification, ligation and suppression PCR. AB - BACKGROUND: Multiple approaches for the site-directed mutagenesis (SDM) have been developed. However, only several of them are designed for simultaneous introduction of multiple nucleotide alterations, and these are time consuming. In addition, many of the existing multiple SDM methods have technical limitations associated with type and number of mutations that can be introduced, or are technically demanding and require special chemical reagents. RESULTS: In this study we developed a quick and efficient strategy for introduction of multiple complex mutations in a target DNA without intermediate subcloning by using a combination of connecting SDM and suppression PCR. The procedure consists of sequential rounds, with each individual round including PCR amplification of target DNA with two non-overlapping pairs of oligonucleotides. The desired mutation is incorporated at the 5' end of one or both internal oligonucleotides. DNA fragments obtained during amplification are mixed and ligated. The resulting DNA mixture is amplified with external oligonucleotides that act as suppression adapters. Suppression PCR limits amplification to DNA molecules representing full length target DNA, while amplification of other types of molecules formed during ligation is suppressed. To create additional mutations, an aliquot of the ligation mixture is then used directly for the next round of mutagenesis employing internal oligonucleotides specific for another region of target DNA. CONCLUSION: A wide variety of complex multiple mutations can be generated in a short period of time. The procedure is rapid, highly efficient and does not require special chemical reagents. Thus, MALS represents a powerful alternative to the existing methods for multiple SDM. PMID- 19778448 TI - Characterization of the Lassa virus GP1 ectodomain shedding: implications for improved diagnostic platforms. AB - BACKGROUND: There is a significant requirement for the development and acquisition of reagents that will facilitate effective diagnosis, treatment, and prevention of Lassa fever. In this regard, detection of early markers of Lassa virus (LASV) infection may improve diagnosis and ultimately successful treatment with antivirals. Characterization of LASV GP1 ectodomain shedding is an important step toward developing sensitive diagnostics to detect circulating levels of this viral glycoprotein in infected patient sera. RESULTS: Secretion of GP1 from mammalian cells expressing a native LASV GPC gene was not mediated by proteolytic cleavage, as determined by treatment with a panel of matrix metalloprotease (MMP) inhibitors. The shedding of GP1 was also not the result of over-expression of GPC under the control of a strong intron-A containing CMV promoter, as the soluble component could be immunoprecipitated from supernatants of cells expressing low levels of GPC under the control of an intronless promoter. Cells transfected with GPC retained surface membrane-associated expression of GP1 as determined by immunofluorescence assay, in addition to secreting the glycoprotein.Secreted GP1 derived from GPC expression has a higher content of high mannose N-linked glycosylation than sGP1 expressed independently from the GP2 portion of the protein. Neither GP1 isoform contains sialylated N-glycans, O-linked carbohydrate chains, or galactose-beta(1-4)-N-acetylglucosamine commonly present in complex and hybrid N-glycan structures. CONCLUSION: These results demonstrate the non proteolytic secretory nature of GP1 shedding during expression of the arenaviral glycoprotein complex. This phenomenon parallels shedding of a secretory glycoprotein component in filovirus replication. The glycosylation pattern of soluble GP1 resulting from expression of GPC was different from that of a soluble GP1 construct (sGP1-RRAA-FLAG), highlighting the intricately orchestrated post translational processing of the LASV glycoprotein complex. PMID- 19778449 TI - An ecological study on the relationship between supply of beds in long-term care institutions in Italy and potential care needs for the elderly. AB - BACKGROUND: The ageing population in Europe is putting an ever increasing demand on the long-term care (LTC) services provided by these countries. This study analyses the relationship between the LTC institutional supply of beds and potential care needs, taking into account the social and health context, the supply of complementary and alternative services, along with informal care. METHODS: An observational, cross-sectional, ecological study was carried out. Statistical data were obtained from the Italian National Institute of Statistics and Ministry of Health. Indicators, regarding 5 areas (Supply of beds in long term care institutions, Potential care needs, Social and health context, Complementary and alternative services for the elderly, Informal care), were calculated at Local Health Unit (LHU) level and referred to 2004.Two indicators were specifically used to measure supply of beds in long term care institutions and potential care needs for the elderly. Their values were grouped in tertiles. LHU were classified according to the combination of tertiles in three groups: A. High level of supply of beds in long term care institutions associated with low level of potential care needs; B. Low level of supply of beds in long term care institutions associated with high level of potential care needs; C. Balanced level of supply of beds in long term care institutions with potential care needs. For each group the indicators of 5 areas were analysed.The Index Number (IN) was calculated for each of these indicators. RESULTS: Specific factors that need to be carefully considered were highlighted in each of the three defined groups. The highest level of alternative services such as long-stay hospital discharges in residence region (IN = 125), home care recipients (HCR) (IN = 123.8) were reported for Group A. This group included North regions. The highest level of inappropriate hospital discharges in (IN = 124.1) and out (IN = 155.8) the residence region, the highest value of families who received help (IN = 106.4) and the lowest level of HCR (IN = 68.7) were found in Group B. South regions belong to this group. The highest level of families paying a caregiver (IN = 115.8) was shown in Group C. Central regions are included in third group. CONCLUSION: Supply of beds in long term care institutions substantially differs across Italian regions, showing in every scenario some imbalances between potential care needs and other studied factors. Our study suggests the need of a comprehensive rethinking of care delivery "system". PMID- 19778450 TI - Expressed sequence tag analysis of adult human optic nerve for NEIBank: identification of cell type and tissue markers. AB - BACKGROUND: The optic nerve is a pure white matter central nervous system (CNS) tract with an isolated blood supply, and is widely used in physiological studies of white matter response to various insults. We examined the gene expression profile of human optic nerve (ON) and, through the NEIBANK online resource, to provide a resource of sequenced verified cDNA clones. An un-normalized cDNA library was constructed from pooled human ON tissues and was used in expressed sequence tag (EST) analysis. Location of an abundant oligodendrocyte marker was examined by immunofluorescence. Quantitative real time polymerase chain reaction (qRT-PCR) and Western analysis were used to compare levels of expression for key calcium channel protein genes and protein product in primate and rodent ON. RESULTS: Our analyses revealed a profile similar in many respects to other white matter related tissues, but significantly different from previously available ON cDNA libraries. The previous libraries were found to include specific markers for other eye tissues, suggesting contamination. Immune/inflammatory markers were abundant in the new ON library. The oligodendrocyte marker QKI was abundant at the EST level. Immunofluorescence revealed that this protein is a useful oligodendrocyte cell-type marker in rodent and primate ONs. L-type calcium channel EST abundance was found to be particularly low. A qRT-PCR-based comparative mammalian species analysis reveals that L-type calcium channel expression levels are significantly lower in primate than in rodent ON, which may help account for the class-specific difference in responsiveness to calcium channel blocking agents. Several known eye disease genes are abundantly expressed in ON. Many genes associated with normal axonal function, mRNAs associated with axonal transport, inflammation and neuroprotection are observed. CONCLUSION: We conclude that the new cDNA library is a faithful representation of human ON and EST data provide an initial overview of gene expression patterns in this tissue. The data provide clues for tissue-specific and species-specific properties of human ON that will help in design of therapeutic models. PMID- 19778451 TI - Differentiation of neurons from neural precursors generated in floating spheres from embryonic stem cells. AB - BACKGROUND: Neural differentiation of embryonic stem (ES) cells is usually achieved by induction of ectoderm in embryoid bodies followed by the enrichment of neuronal progenitors using a variety of factors. Obtaining reproducible percentages of neural cells is difficult and the methods are time consuming. RESULTS: Neural progenitors were produced from murine ES cells by a combination of nonadherent conditions and serum starvation. Conversion to neural progenitors was accompanied by downregulation of Oct4 and NANOG and increased expression of nestin. ES cells containing a GFP gene under the control of the Sox1 regulatory regions became fluorescent upon differentiation to neural progenitors, and ES cells with a tau-GFP fusion protein became fluorescent upon further differentiation to neurons. Neurons produced from these cells upregulated mature neuronal markers, or differentiated to glial and oligodendrocyte fates. The neurons gave rise to action potentials that could be recorded after application of fixed currents. CONCLUSION: Neural progenitors were produced from murine ES cells by a novel method that induced neuroectoderm cells by a combination of nonadherent conditions and serum starvation, in contrast to the embryoid body method in which neuroectoderm cells must be selected after formation of all three germ layers. PMID- 19778452 TI - Treatment of secondary hyperparathyroidism in haemodialysis patients: a randomised clinical trial comparing paricalcitol and alfacalcidol. AB - BACKGROUND: Secondary hyperparathyroidism is a common feature in patients with chronic kidney disease. Its serious clinical consequences include renal osteodystrophy, calcific uremic arteriolopathy, and vascular calcifications that increase morbidity and mortality.Reduced synthesis of active vitamin D contributes to secondary hyperparathyroidism. Therefore, this condition is managed with activated vitamin D. However, hypercalcemia and hyperphosphatemia limit the use of activated vitamin D.In Denmark alfacalcidol is the primary choice of vitamin D analog.A new vitamin D analog, paricalcitol, may be less prone to induce hypercalcemia and hyperphosphatemia.However, a randomised controlled clinical study comparing alfacalcidol and paricalcitol has never been performed.The primary objective of this study is to compare alfacalcidol and paricalcitol. We evaluate the suppression of the secondary hyperparathyroidism and the tendency towards hyperphosphatemia and hypercalcemia. METHODS/DESIGN: This is an investigator-initiated cross-over study. Nine Danish haemodialysis units will recruit 117 patients with end stage renal failure on maintenance haemodialysis therapy.Patients are randomised into two treatment arms. After a wash out period of 6 weeks they receive increasing doses of alfacalcidol or paricalcitol for a period of 16 weeks and after a further wash out period of 6 weeks they receive the contrary treatment (paricalcitol or alfacalcidol) for 16 weeks. DISCUSSION: Hyperparathyroidism, hypercalcemia and hyperphosphatemia are associated with increased cardiovascular mortality in patients with chronic kidney disease.If there is any difference in the ability of these two vitamin D analogs to decrease the secondary hyperparathyroidism without causing hypercalcemia and hyperphosphatemia, there may also be a difference in the risk of cardiovascular mortality depending on which vitamin D analog that are used. This has potential major importance for this group of patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT00469599. PMID- 19778453 TI - Autism Genetic Database (AGD): a comprehensive database including autism susceptibility gene-CNVs integrated with known noncoding RNAs and fragile sites. AB - BACKGROUND: Autism is a highly heritable complex neurodevelopmental disorder, therefore identifying its genetic basis has been challenging. To date, numerous susceptibility genes and chromosomal abnormalities have been reported in association with autism, but most discoveries either fail to be replicated or account for a small effect. Thus, in most cases the underlying causative genetic mechanisms are not fully understood. In the present work, the Autism Genetic Database (AGD) was developed as a literature-driven, web-based, and easy to access database designed with the aim of creating a comprehensive repository for all the currently reported genes and genomic copy number variations (CNVs) associated with autism in order to further facilitate the assessment of these autism susceptibility genetic factors. DESCRIPTION: AGD is a relational database that organizes data resulting from exhaustive literature searches for reported susceptibility genes and CNVs associated with autism. Furthermore, genomic information about human fragile sites and noncoding RNAs was also downloaded and parsed from miRBase, snoRNA-LBME-db, piRNABank, and the MIT/ICBP siRNA database. A web client genome browser enables viewing of the features while a web client query tool provides access to more specific information for the features. When applicable, links to external databases including GenBank, PubMed, miRBase, snoRNA-LBME-db, piRNABank, and the MIT siRNA database are provided. CONCLUSION: AGD comprises a comprehensive list of susceptibility genes and copy number variations reported to-date in association with autism, as well as all known human noncoding RNA genes and fragile sites. Such a unique and inclusive autism genetic database will facilitate the evaluation of autism susceptibility factors in relation to known human noncoding RNAs and fragile sites, impacting on human diseases. As a result, this new autism database offers a valuable tool for the research community to evaluate genetic findings for this complex multifactorial disorder in an integrated format. AGD provides a genome browser and a web based query client for conveniently selecting features of interest. Access to AGD is freely available at http://wren.bcf.ku.edu/. PMID- 19778455 TI - Validity of self-reported weight, height, and body mass index among university students in Thailand: Implications for population studies of obesity in developing countries. AB - BACKGROUND: Large-scale epidemiological studies commonly use self-reported weights and heights to determine weight status. Validity of such self-reported data has been assessed primarily in Western populations in developed countries, although its use is widespread in developing countries. We examine the validity of obesity based on self-reported data in an Asian developing country, and derive improved obesity prevalence estimates using the "reduced BMI threshold" method. METHODS: Self-reported and measured heights and weights were obtained from 741 students attending an open university in Thailand (mean age 34 years). Receiver operator characteristic techniques were applied to derive "reduced BMI thresholds." RESULTS: Height was over-reported by a mean of 1.54 cm (SD 2.23) in men and 1.33 cm (1.84) in women. Weight was under-reported by 0.93 kg (3.47) in men and 0.62 kg (2.14) in women. Sensitivity and specificity for determining obesity (Thai BMI threshold 25 kg/m2) using self-reported data were 74.2% and 97.3%, respectively, for men and 71.9% and 100% for women. For men, reducing the BMI threshold to 24.5 kg/m2 increased the estimated obesity prevalence based on self-reports from 29.1% to 33.8% (true prevalence was 36.9%). For women, using a BMI threshold of 24.4 kg/m2, the improvement was from 12.0% to 15.9% (true prevalence 16.7%). CONCLUSION: Young educated Thais under-report weight and over report height in ways similar to their counterparts in developed countries. Simple adjustments to BMI thresholds will overcome these reporting biases for estimation of obesity prevalence. Our study suggests that self-reported weights and heights can provide economical and valid measures of weight status in high school-educated populations in developing countries. PMID- 19778454 TI - Blockade of Wnt-1 signaling leads to anti-tumor effects in hepatocellular carcinoma cells. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is an aggressive cancer, and is the third leading cause of cancer death worldwide. Standard therapy is ineffective partly because HCC is intrinsically resistant to conventional chemotherapy. Its poor prognosis and limited treatment options make it critical to develop novel and selective chemotherapeutic agents. Since the Wnt/beta-catenin pathway is essential in HCC carcinogenesis, we studied the inhibition of Wnt-1-mediated signaling as a potential molecular target in HCC. RESULTS: We demonstrated that Wnt-1 is highly expressed in human hepatoma cell lines and a subgroup of human HCC tissues compared to paired adjacent non-tumor tissues. An anti-Wnt-1 antibody dose-dependently decreased viability and proliferation of Huh7 and Hep40 cells over-expressing Wnt-1 and harboring wild type beta-catenin, but did not affect normal hepatocytes with undetectable Wnt-1 expression. Apoptosis was also observed in Huh7 and Hep40 cells after treatment with anti-Wnt-1 antibody. In these two cell lines, the anti-Wnt-1 antibody decreased beta-catenin/Tcf4 transcriptional activities, which were associated with down-regulation of the endogenous beta-catenin/Tcf4 target genes c-Myc, cyclin D1, and survivin. Intratumoral injection of anti-Wnt-1 antibody suppressed in vivo tumor growth in a Huh7 xenograft model, which was also associated with apoptosis and reduced c Myc, cyclin D1, and survivin expressions. CONCLUSION: Our results suggest that Wnt-1 is a survival factor for HCC cells, and that the blockade of Wnt-1-mediated signaling may offer a potential pathway-specific therapeutic strategy for the treatment of a subgroup of HCC that over-expresses Wnt-1. PMID- 19778456 TI - No evidence for promoter region methylation of the succinate dehydrogenase and fumarate hydratase tumour suppressor genes in breast cancer. AB - BACKGROUND: Succinate dehydrogenase (SDH) and fumarate hydratase (FH) are tricarboxylic acid (TCA) cycle enzymes that are also known to act as tumour suppressor genes. Increased succinate or fumarate levels as a consequence of SDH and FH deficiency inhibit hypoxia inducible factor-1alpha (HIF-1alpha) prolyl hydroxylases leading to sustained HIF-1alpha expression in tumours. Since HIF 1alpha is frequently expressed in breast carcinomas, DNA methylation at the promoter regions of the SDHA, SDHB, SDHC and SDHD and FH genes was evaluated as a possible mechanism in silencing of SDH and FH expression in breast carcinomas. FINDINGS: No DNA methylation was identified in the promoter regions of the SDHA, SDHB, SDHC, SDHD and FH genes in 72 breast carcinomas and 10 breast cancer cell lines using methylation-sensitive high resolution melting which detects both homogeneous and heterogeneous methylation. CONCLUSION: These results show that inactivation via DNA methylation of the promoter CpG islands of SDH and FH is unlikely to play a major role in sporadic breast carcinomas. PMID- 19778457 TI - Sepsis-associated microvascular dysfunction measured by peripheral arterial tonometry: an observational study. AB - INTRODUCTION: Sepsis has a high mortality despite advances in management. Microcirculatory and endothelial dysfunction contribute to organ failure, and better tools are needed to assess microcirculatory responses to adjunctive therapies. We hypothesised that peripheral arterial tonometry (PAT), a novel user independent measure of endothelium-dependent microvascular reactivity, would be impaired in proportion to sepsis severity and related to endothelial activation and plasma arginine concentrations. METHODS: Observational cohort study in a 350 bed teaching hospital in tropical Australia. Bedside microvascular reactivity was measured in 85 adults with sepsis and 45 controls at baseline and 2-4 days later by peripheral arterial tonometry. Microvascular reactivity was related to measures of disease severity, plasma concentrations of L-arginine (the substrate for nitric oxide synthase), and biomarkers of endothelial activation. RESULTS: Baseline reactive hyperaemia index (RH-PAT index), measuring endothelium dependent microvascular reactivity; (mean [95% CI]) was lowest in severe sepsis (1.57 [1.43-1.70]), intermediate in sepsis without organ failure (1.85 [1.67 2.03]) and highest in controls (2.05 [1.91-2.19]); P < 0.00001. Independent predictors of baseline RH-PAT index in sepsis were APACHE II score and mean arterial pressure, but not plasma L-arginine or markers of endothelial activation. Low baseline RH-PAT index was significantly correlated with an increase in SOFA score over the first 2-4 days (r = -0.37, P = 0.02). CONCLUSIONS: Endothelium-dependent microvascular reactivity is impaired in proportion to sepsis severity and suggests decreased endothelial nitric oxide bioavailability in sepsis. Peripheral arterial tonometry may have a role as a user-independent method of monitoring responses to novel adjunctive therapies targeting endothelial dysfunction in sepsis. PMID- 19778458 TI - A HIV-1 heterosexual transmission chain in Guangzhou, China: a molecular epidemiological study. AB - BACKGROUND: We conducted molecular analyses to confirm four clustering HIV-1 infections (Patient A, B, C & D) in Guangzhou, China. These cases were identified by epidemiological investigation and suspected to acquire the infection through a common heterosexual transmission chain. METHODS: Env C2V3V4 region, gag p17/p24 junction and partial pol gene of HIV-1 genome from serum specimens of these infected cases were amplified by reverse transcription polymerase chain reaction (RT-PCR) and nucleotide sequenced. RESULTS: Phylogenetic analyses indicated that their viral nucleotide sequences were significantly clustered together (bootstrap value is 99%, 98% and 100% in env, gag and pol tree respectively). Evolutionary distance analysis indicated that their genetic diversities of env, gag and pol genes were significantly lower than non-clustered controls, as measured by unpaired t-test (env gene comparison: p < 0.005; gag gene comparison: p < 0.005; pol gene comparison: p < 0.005). CONCLUSION: Epidemiological results and molecular analyses consistently illustrated these four cases represented a transmission chain which dispersed in the locality through heterosexual contact involving commercial sex worker. PMID- 19778459 TI - Limitations of the MELD score in predicting mortality or need for removal from waiting list in patients awaiting liver transplantation. AB - BACKGROUND: Decompensated cirrhosis is associated with a poor prognosis and liver transplantation provides the only curative treatment option with excellent long term results. The relative shortage of organ donors renders the allocation algorithms of organs essential. The optimal strategy based on scoring systems and/or waiting time is still under debate. METHODS: Data sets of 268 consecutive patients listed for single-organ liver transplantation for nonfulminant liver disease between 2003 and 2005 were included into the study. The Model for End Stage Liver Disease (MELD) and Child-Turcotte-Pugh (CTP) scores of all patients at the time of listing were used for calculation. The predictive ability not only for mortality on the waiting list but also for the need for withdrawal from the waiting list was calculated for both scores. The Mann-Whitney-U Test was used for the univariate analysis and the AUC-Model for discrimination of the scores. RESULTS: In the univariate analysis comparing patients who are still on the waiting list and patients who died or were removed from the waiting list due to poor conditions, the serum albumin, bilirubin INR, and CTP and MELD scores as well as the presence of ascites and encephalopathy were significantly different between the groups (p < 0.05), whereas serum creatinine and urea showed no difference. Comparing the predictive abilities of CTP and MELD scores, the best discrimination between patients still alive on the waiting list and patients who died on or were removed from the waiting list was achieved at a CTP score of >or=9 and a MELD score of >or=14.4. The sensitivity and specificity to identify mortality or severe deterioration for CTP was 69.0% and 70.5%, respectively; for MELD, it was 62.1% and 72.7%, respectively. This result was supported by the AUC analysis showing a strong trend for superiority of CTP over MELD scores (AUROC 0.73 and 0.68, resp.; p = 0.091). CONCLUSION: The long term prediction of mortality or removal from waiting list in patients awaiting liver transplantation might be better assessed by the CTP score than the MELD score. This might have implications for the development of new improved scoring systems. PMID- 19778461 TI - Equine parasites: diagnosis and control - a current perspective. PMID- 19778460 TI - The NF-kappa B inhibitor, celastrol, could enhance the anti-cancer effect of gambogic acid on oral squamous cell carcinoma. AB - BACKGROUND: Gambogic acid (GA) is a major active ingredient of gamboge, a widely used traditional Chinese medicine that has been reported to be a potent cytotoxic agent against some malignant tumors. Many studies have shown that the NF-kappa B signaling pathway plays an important role in anti-apoptosis and the drug resistance of tumor cells during chemotherapy. In this study, the effects and mechanisms of GA and the NF-kappa B inhibitor celastrol on oral cancer cells were investigated. METHODS: Three human oral squamous cell carcinoma cell lines, Tca8113, TSCC and NT, were treated with GA alone, celastrol alone or GA plus celastrol. Cytotoxicity was assessed by MTT assay. The rate of apoptosis was examined with annexin V/PI staining as well as transmission electronic microscopy in Tca8113 cells. The level of constitutive NF-kappa B activity in oral squamous cell carcinoma cell lines was determined by immunofluorescence assays and nuclear extracts and electrophoretic mobility shift assays (EMSAs) in vitro. To further investigate the role of NF-kappa B activity in GA and celastrol treatment in oral squamous cell carcinoma, we used the dominant negative mutant SR-IkappaBalpha to inhibit NF-kappa B activity and to observe its influence on the effect of GA. RESULTS: The results showed that GA could inhibit the proliferation and induce the apoptosis of the oral squamous cell carcinoma cell lines and that the NF kappa B pathway was simultaneously activated by GA treatment. The minimal cytotoxic dose of celastrol was able to effectively suppress the GA-induced NF kappa B pathway activation. Following the combined treatment with GA and the minimal cytotoxic dose of celastrol or the dominant negative mutant SR IkappaBalpha, proliferation was significantly inhibited, and the apoptotic rate of Tca8113 cells was significantly increased. CONCLUSION: The combination of GA and celastrol has a synergistic antitumor effect. The effect can be primarily attributed to apoptosis induced by a decrease in NF-kappa B pathway activation. The NF-kappa B signaling pathway plays an important role in this process. Therefore, combining GA and celastrol may be a promising modality for treating oral squamous cell carcinoma. PMID- 19778462 TI - Equine cyathostomins: a review of biology, clinical significance and therapy. AB - The small strongyles of horses, also known as cyathostomins, are considered the most prevalent and pathogenic parasites of horses today. The clinical syndrome of larval cyathostominosis which occurs as a result of mass emergence of inhibited stages has a high fatality rate despite the best standard of care given to affected horses. Management of the challenge level of cyathostomins to prevent the syndrome is preferable. Many different management programmes have been tried over the past two decades, with mixed success. Programmes have relied heavily on repeated use of anthelmintic treatments throughout the life of a horse. The widespread incidence of resistance to certain anthelmintics is reducing these options. An understanding of the biology of cyathostomins, risk factors for infection and appropriate strategic use of still effective anthelmintics is essential for the future management of this parasite group. This review highlights the necessity to use currently available anthelmintics that are appropriately suited to the biology of cyathostomins, and to maintain heir efficacy through an appropriate treatment strategy. PMID- 19778463 TI - Anthelmintic resistance in cyathostomin populations from horse yards in Italy, United Kingdom and Germany. AB - BACKGROUND: A large survey was carried out in 2008 in Europe to evaluate the efficacy of fenbendazole (FBZ), pyrantel (PYR), ivermectin (IVM) and moxidectin (MOX), i.e. the major anthelmintic molecules used in current practice against cyathostomins affecting horses. A total of 102 yards and 1704 horses was studied in three countries: 60 yards and 988 horses from Italy, 22 and 396 from the UK, 20 and 320 from Germany. The survey consisted of Faecal Egg Count Reduction Tests (FECRTs) with a faecal egg count reduction (FECR) categorization of (I) resistance present if FECR <90% and the lower 95% confidence limit (LCL) <90%, (II) resistance suspected if FECR >/= 90% and/or LCL <90% and (III) no resistance if FECR >/= 90% and LCL >90%. The calculation of FECR data was performed employing bootstrap analysis of group arithmetic means. RESULTS: The testing of FBZ on a total of 80 yards resulted in resistance present on more than 80% of the UK and German yards and on significantly fewer in Italy, i.e. in 38% (p < 0.01). PYR, IVM and MOX were tested on a total of 102 yards. For PYR resistance present was found in 25% of the yards with no significant differences between countries. For IVM resistance present was encountered in one Italian and two UK yards (3%), resistance present to MOX was not found in any yard in any country. CONCLUSION: The results indicate that single and/or multiple drug resistance in equine cyathostomins is present in the three countries, is widespread particularly for FBZ and/or PYR and in one UK yard multiple resistance present was detected to FBZ, PYR and IVM. Macrocylic lactones proved to be the most effective drugs, with some evidence of resistance to IVM and highest activity of MOX, despite a single case of reduced efficacy in Germany. These data call for the development and implementation, among practitioners, owners and managers, of further plans to reduce the expansion of the anthelmintic resistant populations and to use those anthelmintics that remain effective in a manner that preserves their efficacy as long as possible. PMID- 19778464 TI - Effects of worm control practices examined by a combined faecal egg count and questionnaire survey on horse farms in Germany, Italy and the UK. AB - BACKGROUND: For the control of worm infections, the strategic use of anthelmintics, often accompanied by additional farm and/or pasture management procedures, is currently applied on most horse farms in industrialized countries. However, the particular effects of the specific worm control procedures are often unclear and have only been investigated to a limited extent. We examined faecal egg count (FEC), faecal egg count reduction (FECR) and questionnaire data on farm and pasture management procedures. The aim of this study was to determine whether specific worm control practices reported to be applied in European horse farms affect worm prevalence. RESULTS: This study involved 20 German, 26 Italian and 16 UK horse farms for each of which FEC were performed on a minimum of 16 horses. In total, 2029 horse faecal samples were quantitatively analysed for helminth eggs, resulting in 56.3% of the faecal samples being positive for strongylid eggs. The prevalence in the 742 German horse samples (48.1%) was significantly lower than that in the 737 Italian (61.1%) and the 550 UK (60.9%) samples. As expected, a significant effect of horse age on the infection prevalence was observed, with adult horses showing lower prevalences and lower mean FEC than foals and yearlings. The majority of the participating farms were stud farms (n = 29), followed by riding stables (n = 27) and racehorse stables (n = 6). The prevalence of strongyle infection by farm type differed between countries. While in Germany, horses on riding farms were significantly less often strongyle positive, in the UK horses on stud farms showed the lowest strongyle prevalences, whereas in Italy, no significant difference between farm types were seen. On all farms, horses received routine/preventive anthelmintic treatment. An effect of treatment frequency on strongyle prevalence was only encountered with adult horses. On farms performing more than one annual treatment, faecal samples were significantly less often positive. Furthermore, by comparing the FECR results of individual horses with their pre-treatment FEC, it was found that high pre treatment FEC were associated with a significantly higher probability for a FECR below 90%. CONCLUSION: Overall, age-dependent strongyle infection patterns and general worm control approaches were found to be similar on horse farms in the three countries. Also, a negative association of pre-treatment FEC and treatment efficacy was consistently found in all countries. However, mean strongyle prevalences and frequencies of anthelmintic treatments were considerably different. In addition to the age-dependent prevalence patterns, the finding of a possible negative association between high FEC and reduced FECR might argue for a focus on horses showing high pre-treatment FEC when monitoring anthelmintic treatment efficacy in the field. PMID- 19778465 TI - Faecal Cyathostomin Egg Count distribution and efficacy of anthelmintics against cyathostomins in Italy: a matter of geography? AB - BACKGROUND: In the framework of a trial carried out in 2008 in Europe to evaluate the efficacy of major parasiticides against horse cyathostomins, pre- and/or post treatment Faecal Egg Counts (FEC) were evaluated in a total of 84 yards and 2105 horses from nine different regions from the South, the Center, the North-Center and North-East of Italy. Specifically, on the basis of FECs of the horses present in each property, 60 out of the 84 yards were enrolled for a Faecal Egg Count Reduction Test (FECRT) using fenbendazole, pyrantel, ivermectin and moxidectin. RESULTS: Of the 1646 horses bred in the 60 recruited yards, 416 animals had a FEC between 50 and 150 Eggs Per Gram (EPG) of faeces and 694 a FEC >150 EPG (i.e. with total of 1110 positive animals). Of the 1110 positive animals, those with the highest FECs (i.e. 988) were included in the FECRT. The FECRT for four anthelmintic compounds showed remarkable differences in terms of prevalence of reduced and equivocal efficacy against cyathostomins in the different areas of Italy. Administration of fenbendazole and pyrantel resulted in resistance present or suspected in about half of the yards examined while resistance to ivermectin was found in one yard from central Italy and suspected resistance was detected in three more yards, one in each the North, the Center and the South. Treatment with moxidectin was 100% effective in all yards examined. CONCLUSION: Cyathostomin populations in the South and the Center of Italy were more susceptible to fenbendazole and pyrantel than the populations present in the Center-North and North-Eastern areas of Italy. Fenbendazole and/or pyrantel were ineffective in almost all properties from the North of Italy. The reasons for such a difference among the Italian regions in terms of FECs and efficacy of antiparasitic drugs are discussed, together with the role that veterinarians, and horse owners and managers should have for effective worm control programs in this country. PMID- 19778466 TI - Moxidectin: a review of chemistry, pharmacokinetics and use in horses. AB - This article reviews the current knowledge of the use of moxidectin (MOX) in horses, including its mode of action, pharmacokinetic and pharmacodynamic properties, efficacy, safety and resistance profile.Moxidectin is a second generation macrocyclic lactone (ML) with potent endectocide activity. It is used for parasite control in horses in an oral gel formulation. The principal mode of action of MOX and of other MLs is binding to gamma-aminobutyric (GABA) and glutamate-gated chloride channels. Moxidectin is different from other MLs in that it is a poor substrate for P-glycoproteins (P-gps) and therefore less susceptible to elimination from parasite cells through this mechanism. Due to its unique physicochemical and pharmacokinetic characteristics, MOX provides broad distribution into tissues, long half-life, significant residual antiparasitic activity, and high efficacy against encysted cyathostomin larvae. These characteristics allow for high efficacy and longer treatment interval against all important nematodes, when compared to other equine anthelmintics. A combination of MOX with praziquantel provides expanded spectrum of activity by adding activity against cestodes. Appropriate use of MOX allows for the development of strategic anthelmintic programmes that are different from those with conventional anthelmintics. Fewer treatments are required over a period of time, and therefore impose less frequent selection pressure for resistance. PMID- 19778467 TI - Determination of genomic DNA sequences for beta-tubulin isotype 1 from multiple species of cyathostomin and detection of resistance alleles in third-stage larvae from horses with naturally acquired infections. AB - BACKGROUND: Genetic resistance against benzimidazole (BZ) anthelmintics is widespread in cyathostomins, the commonest group of intestinal parasitic nematodes of horses. Studies of BZ-resistant nematodes of sheep, particularly Haemonchus contortus, have indicated that an anthelmintic resistance-conferring T/A polymorphism, encoding an F (phenylalanine) to Y (tyrosine) substitution, in beta-tubulin isotype 1 is present at two loci, codons 167 and 200 (F167Y, F200Y). Recent studies using complementary (c) DNA derived from BZ-susceptible and resistant cyathostomins identified statistical differences in the frequency of the BZ-resistant A allele at these loci. However, the lack of high-throughput genomic DNA-based detection of polymorphisms limits the study of eggs or larvae from field isolates. In the present study, we report genomic DNA sequences for beta-tubulin isotype 1 from multiple cyathostomin species, thus facilitating the development of pyrosequencing assays to genetically characterize third-stage larvae (L3s) of cyathostomins from mixed-species field isolates. RESULTS: Sequence analysis of the beta-tubulin isotype 1 gene in a common species, Cylicocyclus nassatus, indicates a revised genomic structure to published data, revealing that codons 167 and 200 are located on separate exons. A consensus sequence was generated from 91 and 76 individual cyathostomins for the regions spanning codons 167 and 200, respectively. A multi-species genomic DNA-based assay was established to directly pyrosequence individual L3 from field samples of unknown species and BZ sensitivity in a 96-well plate. In this format, the assay to detect F167Y gave a 50-90% success rate. The optimisation of the assay at codon 200 is currently underway. Subsequently, the genotype at F167Y was determined for 241 L3s, collected prior to and after BZ treatment. These results demonstrated a reduction in the heterozygous genotype, TTC/TAC, and an increase in the homozygous resistant genotype TAC/TAC in post-treatment samples. However, the differences in allele frequencies determined before and after BZ treatment were not statistically significant. CONCLUSION: Extensive genomic DNA sequence, spanning codons 167 and 200 of the beta-tubulin isotype 1 gene, was generated from multiple cyathostomin species. The data facilitated the development of a pyrosequencing assay, capable of detecting the genotype of individual cyathostomin L3s derived from mixed-species field samples. Differences in codon 167 allele frequencies were observed in L3s isolated pre- and post-BZ treatment. PMID- 19778468 TI - Restrictions of anthelmintic usage: perspectives and potential consequences. AB - Given the increasing levels of anthelmintic resistance in equine parasites, parasitologists now recommend traditional treatment approaches to be abandoned and replaced by more sustainable strategies. It is of crucial importance to facilitate veterinary involvement to ensure that treatment decisions are based on parasitic knowledge. Despite recommendations given for the past two decades, strategies based on the selective therapy principle have not yet been implemented on a larger scale in equine establishments. In contrast, treatment regimens appear to be derived from recommendations originally given in 1966. The province of Quebec in Canada, and an increasing number of European countries, have implemented prescription-only restrictions on anthelmintic drugs. Denmark introduced this legislation ten years ago, and some evidence has been generated describing potential consequences. It is without dispute that Danish veterinarians are now deeply involved with parasite management in equine establishments. However, little is known about the impact on levels of anthelmintic resistance and the risk of parasitic disease under these circumstances. In addition, the legislation makes huge demands on diagnosis and parasite surveillance. No data have been published evaluating fecal egg count techniques and larval culture methods as clinical diagnostic tools, and very little is known about potential correlations with actual worm burdens. This article provides a general review of anthelmintic strategies currently used in equine establishments and outlines the recommendations now given for parasite control. Preliminary experience with prescription-only restrictions in Denmark is presented and current research needs to further evaluate this approach are discussed. PMID- 19778469 TI - Diagnosis and control of anthelmintic-resistant Parascaris equorum. AB - Since 2002, macrocyclic lactone resistance has been reported in populations of Parascaris equorum from several countries. It is apparent that macrocyclic lactone resistance developed in response to exclusive and/or excessively frequent use of ivermectin or moxidectin in foals during the first year of life. The development of anthelmintic resistance was virtually inevitable, given certain biological features of Parascaris and unique pharmacologic characteristics of the macrocyclic lactones. Practitioners can utilize the Fecal Egg Count Reduction Test to detect anthelmintic resistance in Parascaris, and the same technique can be applied regularly to confirm the continued efficacy of those drugs currently in use. In the face of macrocyclic lactone resistance, piperazine or anthelmintics of the benzimidazole or pyrimidine classes can be used to control ascarid infections, but Parascaris populations that are concurrently resistant to macrocyclic lactones and pyrimidine drugs have been reported recently from Texas and Kentucky. Compared to traditional practices, future recommendations for ascarid control should feature: 1) use of only those anthelmintics known to be effective against indigenous populations, 2) initiation of anthelmintic treatment no earlier than 60 days of age, and 3) repetition of treatments at the longest intervals which prevent serious environmental contamination with Parascaris eggs. In the interest of decreasing selection pressure for anthelmintic resistance, horse owners and veterinarians must become more tolerant of the passage of modest numbers of ascarid eggs by some foals. Anthelmintic resistance is only one of several potential responses to genetic selection. Although still only theoretical, changes in the immunogenicity of ascarid isolates or reduction of their prepatent or egg reappearance periods could pose far greater challenges to effective control than resistance to a single class of anthelmintics. PMID- 19778470 TI - Predicting children's word-reading accuracy for common English words: the effect of word transparency and complexity. AB - The effects of printed word frequency and transparency measures on single word reading accuracy were examined in 105 six-year-old children. The results indicated that it may be necessary to re-appraise notions of orthography-to phonology correspondences for children of this age. The influence of orthographic neighbourhood size appeared to derive from word frequency and graphemic complexity. The results also indicated that sonograph frequency was more predictive of reading accuracy than the GPC rules and weighted correspondences currently embodied in dual route and connectionist models of skilled reading. PMID- 19778472 TI - How do you solve the problem of recurrent miscarriage? AB - Recurrent miscarriage is the loss of two or more consecutive pregnancies and affects 1% of couples trying to conceive. It has proven to be frustrating for both patient and clinician. The majority of investigations and treatments offered remain controversial. However, practice must be evidence based and unproven investigations and treatments should be abandoned. Psychological support is of paramount importance since a significant number of women attending RM clinics have high levels of anxiety or are clinically depressed. Setting up a RM clinic is important to provide a dedicated service to couples with RM so as to avoid unnecessary and potentially harmful treatments, and also to recruit patients in trials that will delineate causes and efficacy of treatments. PMID- 19778474 TI - Analytical identification of additional impurities in urinary-derived gonadotrophins. AB - Advances in proteomic technology have enabled contaminant proteins to be identified from complex protein mixtures. The purity of two purified urinary gonadotrophin products, human menopausal gonadotrophin (u-HMG) and human FSH (u hFSH), was compared with a preparation of recombinant human FSH (r-hFSH). After separation by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS PAGE), western blot analysis showed that the recombinant preparation contained only FSH, whereas the urine-derived preparations exhibited several non-FSH or LH related bands. These urinary components were further investigated by a proteomic approach using two-dimensional SDS-PAGE followed by mass spectrometric identification. The proteomic approach detected a total of 23 non-gonadotrophin related proteins, at variable levels in different batches of the urine-derived preparations. Of these, 16 co-purified proteins have not been previously reported to be present in urine-derived gonadotrophins. These results indicate that the process used to purify urinary gonadotrophins may not remove all non gonadotrophin proteins. By using a comprehensive proteomic approach, it has been shown that the recombinant FSH preparation has greater purity than either of the urine-derived preparations. PMID- 19778475 TI - Effects of ovulation induction agents on ovarian surface epithelium in rats. AB - The aim of this study was to examine the effects of ovulation induction agents on the ovarian surface epithelium in rats. Sixty adult females were randomly divided into six groups, each containing 10 rats. In four of these groups ovulation induction was applied with six cycles of clomiphene citrate, human menopausal gonadotrophin (HMG), recombinant FSH (rFSH) or human chorionic gonadotrophin (HCG), respectively, followed by unilateral oophorectomy, and another six cycles of the same treatment. After a total of 12 cycles of ovulation induction, the remaining ovary was taken out and the alterations in ovarian surface epithelium were examined. No malignancies were observed on the ovarian surface epithelium of the rats that were given clomiphene citrate, rFSH or HMG as ovulation induction agents, while identification rates of histopathological parameters constituting epithelial dysplasia were found to be significant (P < 0.05). There was no significant dysplasia in the epithelium of the group which was given HCG only, relative to control groups. The findings suggest that the ovulation induction agents except for HCG bring about dysplasia in the ovarian surface epithelium. It is not clear whether these dysplasias are precursory lesions of ovarian malignancies. PMID- 19778476 TI - Association of thyroid-stimulating hormone with insulin resistance and androgen parameters in women with PCOS. AB - There is a relationship between thyroid function and insulin sensitivity and alterations in lipids and metabolic parameters. Little information is available regarding this relationship in women with polycystic ovary syndrome. However all those pathologies are also described as often affecting women with polycystic ovary syndrome. The association between thyroid-stimulating hormone <2.5 mIU/l and > or =2.5 mIU/l with insulin resistance and endocrine parameters in 103 women with polycystic ovary syndrome was studied. Clinical, metabolic and endocrine parameters were obtained and an oral glucose tolerance test was performed with calculation of insulin resistance indices. Women with thyroid-stimulating hormone > or =2.5 mIU/l had a significantly higher body mass index (P = 0.003), higher fasting insulin concentrations (P = 0.02) and altered insulin resistance indices (P = 0.007), higher total testosterone (P = 0.009) and free androgen indices (P = 0.001) and decreased sex hormone-binding globulin concentrations (P = 0.01) in comparison with women with thyroid-stimulating hormone <2.5 mIU/l. Generally, all of these parameters correlated significantly (P < 0.05) with thyroid-stimulating hormone only in women with thyroid-stimulating hormone > or =2.5 mIU/l. Women with polycystic ovary syndrome and with thyroid-stimulating hormone > or =2.5 mIU/l had significantly altered endocrine and metabolic changes. PMID- 19778477 TI - From ultrastructural flagellar sperm defects to the health of babies conceived by ICSI. AB - The objective of this retrospective study was to describe a population of patients displaying impaired sperm motility due to ultrastructural flagellar defects and to analyse the intracytoplasmic sperm injection (ICSI) results and neonatal outcomes in this population. The fertilization rate, embryo quality, clinical pregnancy rate, implantation rate, birth rate and perinatal health of babies were determined. Patients (n = 20) were divided into seven categories according to ultrastructural flagellar abnormalities. The type of flagellar abnormality significantly affected the fertilization rate (P <0.025). Two types of flagellar abnormalities showed slower early embryo cleavage kinetics (P <0.001) when axonemal central structures and periaxonemmal columns were abnormal or absent. Of 53 ICSI attempts, 14 resulted in clinical pregnancies (26.4% per cycle) after fresh and frozen embryo transfer. Three (21.4%) of these pregnancies ended in miscarriages and, in the remaining, 12 infants were born (7.2% of transferred embryos). The outcomes differed according to the ultrastructural defect. This study demonstrates that a high proportion of patients could father a child (45.0%). However, flagellar abnormalities appear to influence ICSI results and fetal development. PMID- 19778478 TI - Costs and outcomes associated with IVF using recombinant FSH. AB - Cost and outcome estimates based on clinical trial data may not reflect usual clinical practice, yet they are often used to inform service provision and budget decisions. To expand understanding of assisted reproduction treatment in clinical practice, an economic evaluation of IVF/intracytoplasmic sperm injection (ICSI) data from a single assisted conception unit (ACU) in England was performed. A total of 1418 IVF/ICSI cycles undertaken there between October 2001 and January 2006 in 1001 women were analysed. The overall live birth rate was 22% (95% CI: 19.7-24.2), with the 30- to 34-year age group achieving the highest rate (28%). The average recombinant FSH (rFSH) dose/cycle prescribed was 1855 IU. Average cost of rFSH/cycle was 646 pound(SD: 219 pound), and average total cost/cycle was 2932 pound (SD: 422 pound). Economic data based on clinical trials informing current UK guidance assumes higher doses of rFSH dose/cycle (1750-2625 IU), higher average cost of drugs/cycle (1179 pound), and higher average total cost/cycle (3266 pound). While the outcomes in this study matched UK averages, total cost/cycle was lower than those cited in UK guidelines. Utilizing the protocols and (lower) rFSH dosages reported in this study may enable other ACU to provide a greater number of IVF/ICSI cycles to patients within given budgets. PMID- 19778479 TI - Effect of different gonadotrophin priming on IVM of oocytes from women with normal ovaries: a prospective randomized study. AB - This study was designed to determine if the efficiency of in-vitro maturation (IVM) in women with normal ovaries can be improved by gonadotrophin administration. 400 women were randomly allocated in four groups: group A, non primed cycles; group B, human chorionic gonadotrophin (HCG)-primed cycles; group C, FSH-primed cycles; and group D, FSH- plus HCG-primed cycles. There were significant differences in the IVM rate among the groups. In groups where HCG was used, the overall maturation rate was higher (57.9% in group B and 77.4% in group D; 48.4% in group A and 50.8% in group C) and the percentage of total available metaphase II-stage oocytes was higher (60.4% in group B and 82.1% in group D; 48.4% in group A and 50.8% in group C). The overall clinical pregnancy rate per transfer (CPR) was 18.3% and the implantation rate (IR) was 10.6%. There was a difference in CPR among the groups: group D (29.9%) versus group A (15.3%), P = 0.023; group D versus group B (7.6%), P < 0.0001; group D versus group C (17.3%), P = 0.046. The results of this study are clearly in favour of FSH plus HCG priming. FSH priming and HCG priming alone showed no significant effects on clinical outcome. PMID- 19778481 TI - Cryopreservation of immature and in-vitro matured human oocytes by vitrification. AB - The objective of this study was to determine the efficacy of vitrification of human oocytes before and after in-vitro maturation (IVM). The immature oocytes recovered (n = 472) were divided into two groups: (i) immature oocytes (n = 219) vitrified at the germinal vesicle (GV) stage; and (ii) immature GV-stage oocytes (n = 253) that were firstly matured in vitro (MII-stage oocytes; n = 178), then vitrified (n = 79). The remaining oocytes (n = 99), which were not vitrified, were processed as controls. After warming, the oocyte survival, maturation and fertilization rates, as well as embryonic development, were compared. The results showed no significant difference between the survival rates of the oocytes vitrified at GV stage and those vitrified at MII stage (85.4% versus 86.1%). However, oocyte maturation rates were significantly reduced (P < 0.05) when oocytes were vitrified at immature GV stage followed by IVM (50.8%) in comparison with the control group (70.4%). Following insemination by intracytoplasmic sperm injection, there was no difference in the fertilization (62.1% versus 58.8%), cleavage (69.5% versus 67.5%) and blastocyst development (0.0% versus 0.0%) rates between these two groups. However, these results were significantly lower (P < 0.05) than those achieved in the control group. This suggests that better results can be achieved by vitrifying mature oocytes rather than immature oocytes. PMID- 19778480 TI - Aurora kinase B, epigenetic state of centromeric heterochromatin and chiasma resolution in oocytes. AB - Aurora kinases comprise a family of phosphoproteins performing multiple functions in mitosis and meiosis. Because Aurora kinase B (AURKB) expression is altered in aged oocytes and there is only limited information on its function in meiosis, it was decided to study the spatial distribution and co-localization of AURKB with other regulatory proteins at centromeres during mouse oocyte maturation. AURKB associates with chromosomes after germinal vesicle breakdown, is enriched at centromeres from prometaphase I and transits to the spindle midzone at late anaphase I. Preferential inhibition of AURKB by low concentrations of ZM 447439 inhibitor prevents polar body formation and affects spindle formation and chromosome congression at meiosis I, associated with expression of BubR1 checkpoint protein at kinetochores. Release of cohesion between sister chromatids appears inhibited resulting in failure of chiasma resolution in oocytes progressing to anaphase I. Concomitantly, the inhibitor reduces histone H3 lysine 9 trimethylation at centromeric heterochromatin and affects chromosome condensation. The cytokinesis arrest protects young, healthy oocytes from errors in chromosome segregation although increasing polyploidy. This study shows that changes in activity of AURKB may increase risks for chromosome non-disjunction and aneuploidy in mammalian oocytes, irrespective of age. PMID- 19778482 TI - Long-term cryostorage does not adversely affect the outcome of oocyte thawing cycles. AB - This multi-centre study evaluated systematically the influence of the duration of cryostorage on the outcome of thawing cycles when using slow-frozen oocytes. The thawing cycles were retrospectively divided into three main groups based on cryostorage duration: group A, 1-3 months; group B, 4-6 months; and group C, 7-48 months. Group C was subsequently divided into three subgroups: group C1, 7-9 months; group C2, 10-12 months; and group C3, 13-48 months. Main outcome measures observed were oocyte survival after thawing, fertilization, cleavage; embryo quality and development, implantation, and birth. No significant differences in main outcome measures were observed between all the groups studied. In conclusion, human oocytes can be safely cryostored for several years. This finding could encourage the wider use of oocyte cryopreservation as a clinical procedure in assisted reproduction. PMID- 19778483 TI - Outcomes of natural cycles versus programmed cycles for 1677 frozen-thawed embryo transfers. AB - The study compares outcomes for patients with frozen embryos who had frozen thawed embryo transfer (FET) timed to their natural ovulation cycle versus cycles in which endometrial timing was programmed with oestrogen and progesterone. A total of 1205 patients undergoing 1677 FET cycles between 1 January 2000 and 31 December 2006 were analysed. Comparisons were made for patients undergoing modified natural versus programmed FET cycles, as well as between patients using their own eggs for frozen embryos versus those using donor-egg-derived embryos. Clinical pregnancy (gestational sac on 7 week ultrasound) rates (CPR), as well as miscarriage rates, were significantly higher in programmed FET cycles in patients using their own eggs (106/262, 40.5% per embryo transfer, P = 0.015) However, there was not a difference in delivered pregnancies between cycle types in own egg patients (natural cycle delivery rate 245/862, 28.4%; programmed cycle delivery rate 77/262, 29.4%). Furthermore, CPR were not different in natural (38/129, 29.5%) versus programmed cycles (144/424, 34.0%) for ovum donor recipients, nor were delivered pregnancy rates different in natural (33/129, 25.6%) versus programmed cycles (114/424, 26.9%) for ovum donor recipients. In conclusion, there is no significant difference in delivery rates for FET in natural (278/991, 28.1%) versus programmed (191/686, 27.8%) cycles using both own embryos and donor-egg-derived embryos. PMID- 19778484 TI - Relevance of triple CGG repeats in the FMR1 gene to ovarian reserve. AB - Most individuals demonstrate 29-30 CGG triple repeats on the FMR1 gene. This may functionally represent a normal range in regard to ovarian reserve. Higher counts reflect risk towards premature ovarian senescence, but lower counts have not been investigated before and, therefore, were the principal subject of this investigation. Amongst 316 consecutive infertility patients, 94 demonstrated <28 repeats (group A), 163 28-33 repeats (group B, considered normal repeat numbers) and 59 > or =34 repeats (group C). The three groups did not differ in age, FSH or anti-Mullerian hormone (AMH) concentrations. Neither FSH nor AMH correlated in linear regression with <28 CGG repeats. In logistic regression, AMH of < or =0.8 ng/ml (indicative of diminished ovarian reserve at all ages) was, however, significantly associated with number of repeats (P < 0.001). Every decrease by five CGG repeats in group A increased the likelihood of diminished ovarian reserve by 40%, while every increase by five CGG repeats in group C increased risk by 50% (both P < 0.002). AMH of < or =0.8 ng/ml statistically correlated overall with decreasing triple CGG repeats throughout all ranges (P < 0.001). Approximately 29-30 CGG repeats appear reflective of normal ovarian reserve, with higher and lower counts denoting similar risks towards premature ovarian senescence. PMID- 19778485 TI - Endometrial mRNA expression of matrix metalloproteinases, their tissue inhibitors and cell adhesion molecules in unexplained infertility and implantation failure patients. AB - The aim of this study was to analyse whether some cases of unexplained infertility and implantation failure after IVF could be explained by different expression levels of the matrix metalloproteinases (MMP-2, 9), their tissue inhibitors (TIMP-2, 3) and intercellular (ICAM-1) and vascular (VCAM-1) adhesion molecules in endothelial cells. Total RNA was extracted from the endometrial tissues of 41 women (unexplained infertile, group 1, n = 15; fertile volunteers, group 2, n = 15 and patients with implantation failure after IVF, group 3, n = 11). MMP-2, MMP-9, TIMP-2, TIMP-3, ICAM-1 and VCAM-1 mRNA expression levels were measured quantitatively using real-time polymerase chain reaction. In the endometrium from women with unexplained infertility and implantation failure after IVF, MMP-2 and TIMP-3 expression were significantly decreased when compared with the fertile group (P < 0.05 and P 93% for all loci with maximum allele dropout rates of 4%. Microsatellite analysis excluded external contamination and confirmed biallelic inheritance. Proof of principle for the simplicity and flexibility of the assay was demonstrated through its application to clinical PGD cycles for lipoid congenital adrenal hyperplasia, which presents a more severe clinical course in males, and Duchenne muscular dystrophy. PMID- 19778491 TI - Neural progenitors derived from monkey embryonic stem cells in a simple monoculture system. AB - A simple monoculture system, combined with a chemically defined medium containing hepatocyte growth factor (HGF) and G5 supplement, was used to induce rhesus monkey embryonic stem cells (rESC) directly into neuroepithelial (NE) cells. Under these conditions, the generation of NE cells did not require the formation of embryoid bodies or co-culture with other cell types. The NE cells could further develop to generate neurons, astrocytes and oligodendrocytes. These results demonstrate a simple approach to obtain enriched and expandable populations of neural progenitors. Importantly, unlike other systems, the neural progenitors obtained using this approach may possess the potential to differentiate into various regional neural cells. Finally, the results suggest that the time-dependent shift in the differentiation potential of the rESC derived neural progenitors in vitro reflects the developmental events that occur during neurogenesis in vivo. Thus, this system can be used to study the mechanisms of cell fate specification during non-human primate neurogenesis. PMID- 19778492 TI - Towards a clinically useful classification of OHSS. PMID- 19778493 TI - Rapid testing for group B streptococcus during labour: a test accuracy study with evaluation of acceptability and cost-effectiveness. AB - OBJECTIVE: To determine the accuracy, acceptability and cost-effectiveness of polymerase chain reaction (PCR) and optical immunoassay (OIA) rapid tests for maternal group B streptococcal (GBS) colonisation at labour. DESIGN: A test accuracy study was used to determine the accuracy of rapid tests for GBS colonisation of women in labour. Acceptability of testing to participants was evaluated through a questionnaire administered after delivery, and acceptability to staff through focus groups. A decision-analytic model was constructed to assess the cost-effectiveness of various screening strategies. SETTING: Two large obstetric units in the UK. PARTICIPANTS: Women booked for delivery at the participating units other than those electing for a Caesarean delivery. INTERVENTIONS: Vaginal and rectal swabs were obtained at the onset of labour and the results of vaginal and rectal PCR and OIA (index) tests were compared with the reference standard of enriched culture of combined vaginal and rectal swabs. MAIN OUTCOME MEASURES: The accuracy of the index tests, the relative accuracies of tests on vaginal and rectal swabs and whether test accuracy varied according to the presence or absence of maternal risk factors. RESULTS: PCR was significantly more accurate than OIA for the detection of maternal GBS colonisation. Combined vaginal or rectal swab index tests were more sensitive than either test considered individually [combined swab sensitivity for PCR 84% (95% CI 79-88%); vaginal swab 58% (52-64%); rectal swab 71% (66-76%)]. The highest sensitivity for PCR came at the cost of lower specificity [combined specificity 87% (95% CI 85-89%); vaginal swab 92% (90-94%); rectal swab 92% (90 93%)]. The sensitivity and specificity of rapid tests varied according to the presence or absence of maternal risk factors, but not consistently. PCR results were determinants of neonatal GBS colonisation, but maternal risk factors were not. Overall levels of acceptability for rapid testing amongst participants were high. Vaginal swabs were more acceptable than rectal swabs. South Asian women were least likely to have participated in the study and were less happy with the sampling procedure and with the prospect of rapid testing as part of routine care. Midwives were generally positive towards rapid testing but had concerns that it might lead to overtreatment and unnecessary interference in births. Modelling analysis revealed that the most cost-effective strategy was to provide routine intravenous antibiotic prophylaxis (IAP) to all women without screening. Removing this strategy, which is unlikely to be acceptable to most women and midwives, resulted in screening, based on a culture test at 35-37 weeks' gestation, with the provision of antibiotics to all women who screened positive being most cost-effective, assuming that all women in premature labour would receive IAP. The results were sensitive to very small increases in costs and changes in other assumptions. Screening using a rapid test was not cost-effective based on its current sensitivity, specificity and cost. CONCLUSIONS: Neither rapid test was sufficiently accurate to recommend it for routine use in clinical practice. IAP directed by screening with enriched culture at 35-37 weeks' gestation is likely to be the most acceptable cost-effective strategy, although it is premature to suggest the implementation of this strategy at present. PMID- 19778494 TI - Outcome evaluation of a structured educational wellness program in patients with severe mental illness. AB - OBJECTIVE: Obesity is increasing at an alarming rate in the United States, as is the obesity rate in patients with schizophrenia. Our study retrospectively evaluated the effectiveness of the Solutions for Wellness and Team Solutions programs, 2 structured educational patient programs, and evaluated the effects on obesity and other metabolic markers in a large, naturalistic inpatient sample. METHOD: Between September 18, 2006, and September 15, 2007, 275 inpatients with DSM-IV-TR-diagnosed chronic mental illness admitted to a tertiary care psychiatric facility were included in the 36-week comprehensive and manualized educational program for healthy lifestyles for patients with chronic mental illness incorporating psychoeducational small-group curricula. Patients were tested before and after each of three 12-week group periods by 30 knowledge assessment questions, and metabolic markers were recorded at baseline, midpoint, and endpoint. RESULTS: Of the 275 included inpatients, 50.5% completed more than 5 modules, 20.4% completed less than or equal to 2 or fewer modules, and 5.1% completed all 11 modules. Significant increases in scores were observed for 7 of the 11 modules in the knowledge assessments (P < .001). Eighty-seven patients (43.72%) had a body mass index (BMI) >/=30 (indicating obesity) at the start of the program. There was a significant mean weight loss of 4.88 lb (P = .035) together with a significant decrease in mean BMI (P = .045). Patients with diabetes showed a reduction in mean weight of 5.98 lb. Significant reductions were observed in glucose and triglyceride levels (both P < .05). Patients with impaired glucose tolerance showed a significantly greater decrease in glucose level (P = .000). Sixty-nine patients (25.46%) met criteria for metabolic syndrome at baseline, and this number was reduced to 53 patients (19.56%) at endpoint; this decrease was significant (P = .027). Regarding relationship of change in knowledge after completion of the modules and metabolic changes, we found a significant correlation between reduction in weight and change in Fitness and Exercise score (r = 0.62, P = .001) and a significant correlation between the change score on Nutrition/Healthy Lifestyles and change in glucose values (r = 0.56, P = .001). CONCLUSIONS: We found that a structured wellness program using a psychoeducational curriculum can be successfully implemented in a large, naturalistic psychiatric setting with unselected, chronically mentally ill inpatients. Results may help both clinicians and hospital managers to implement similar programs or to include successful components in existing programs for psychiatric patients. PMID- 19778495 TI - Olanzapine-divalproex combination versus divalproex monotherapy in the treatment of bipolar mixed episodes: a double-blind, placebo-controlled study. AB - OBJECTIVE: This 6-week, randomized, double-blind, placebo-controlled trial used simultaneous depression and mania criteria to compare a single mood stabilizer, divalproex, with and without adjunctive olanzapine in patients with bipolar I disorder experiencing acute mixed episodes. METHOD: Two hundred two adults, aged 18 to 60 years, who met DSM-IV-TR criteria for bipolar disorder with a current mixed episode and had been taking divalproex for >or=14 days at levels of 75 to 125 microg/mL with inadequate efficacy (21-item Hamilton Depression Rating Scale [HDRS-21] and Young Mania Rating Scale [YMRS] scores >or=16) were randomly assigned to olanzapine 5 to 20 mg/d versus placebo augmentation. HDRS-21, YMRS, Clinical Global Impressions for Bipolar Disorder (CGI-BP), hospitalizations, concomitant medications, and adverse events were assessed. Comparisons included changes in both HDRS-21 and YMRS (primary outcome measure), time to partial response and time to response, CGI-BP improvement, hospitalizations, and safety (secondary outcome measures). The study was conducted from December 2006 to February 2008. RESULTS: Mean (SD) baseline HDRS-21 and YMRS scores were 22.2 (4.5) and 20.9 (4.4), respectively, with 59% female and 51% white subjects. Mean +/- SE score changes from baseline across the 6-week treatment period for adjunctive olanzapine (n = 100) versus adjunctive placebo (n = 101) arms, respectively, were -9.37 +/- 0.55 versus -7.69 +/- 0.54, P = .022, on the HDRS-21 and -10.15 +/- 0.44 versus -7.68 +/- 0.44 P < .001, on the YMRS. Mean +/- SE score changes from baseline to last observation carried forward for CGI-BP measures were -1.34 +/- 0.11 for adjunctive olanzapine versus -1.06 +/- 0.11 for adjunctive placebo, P = .056. Time to partial response (>or=25% HDRS-21 and YMRS decreases, median 7 versus 14 days) and time to response (>or=50% HDRS-21 and YMRS decreases, median 25 versus 49 days) were significantly shorter with adjunctive olanzapine. Increases in weight (total and >or=7%) and fasting blood glucose were significantly greater with adjunctive olanzapine. CONCLUSION: Adjunctive olanzapine yielded greater and earlier reduction of manic and depressive symptoms in mixed-episode patients with inadequate response to at least 2 weeks of divalproex. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00402324. PMID- 19778496 TI - Effectiveness of pharmacotherapy for severe personality disorders: meta-analyses of randomized controlled trials. AB - CONTEXT: There has been little systematic attempt to validate current pharmacologic treatment algorithms and guidelines for severe personality disorder. OBJECTIVE: We evaluated studies on the effectiveness of psychoactive drugs on specific symptom domains for borderline and/or schizotypal personality disorder. DATA SOURCES: The literature was searched for placebo-controlled randomized clinical trials (PC-RCTs) on the effectiveness of psychopharmacologic drugs in personality disorder patients. The PubMed, PsychINFO, PiCarta, Cochrane, and Web of Science databases were searched using the search terms borderline personality, schizotypal personality, personality disorder, cluster A, cluster B, treatment, drug, pharmacotherapy, antipsychotic, antidepressant, mood stabilizer, effect, outcome, review, and meta-analysis for studies published between 1980 and December 2007, and references were identified from bibliographies from articles and books. STUDY SELECTION: Placebo-controlled randomized clinical trials on the efficacy of antipsychotics, antidepressants, and mood stabilizers regarding cognitive-perceptual symptoms, impulsive-behavioral dyscontrol, and affective dysregulation (with subdomains depressed mood, anxiety, anger, and mood lability) were selected in patients with well defined borderline and/or schizotypal personality disorder. Studies whose primary emphasis was on the treatment of Axis I disorders were excluded. Meta-analyses were conducted using 21 retrieved studies. RESULTS: Antipsychotics have a moderate effect on cognitive-perceptual symptoms (5 PC-RCTs; standardized mean difference [SMD]=0.56) and a moderate to large effect on anger (4 PC-RCTs; SMD=0.69). Antidepressants have no significant effect on impulsive-behavioral dyscontrol and depressed mood. They have a small but significant effect on anxiety (5 PC-RCTs; SMD=0.30) and anger (4 PC-RCTs; SMD=0.34). Mood stabilizers have a very large effect on impulsive-behavioral dyscontrol (6 PC-RCTs; SMD=1.51) and anger (7 PC-RCTs; SMD=1.33), a large effect on anxiety (3 PC-RCTs; SMD=0.80), but a moderate effect on depressed mood (5 PC RCTs; SMD=0.55). Mood lability as an outcome measure was seldomly assessed. Mood stabilizers have a more pronounced effect on global functioning (3 PC-RCTs; SMD=0.79) than have antipsychotics (5 PC-RCTs; SMD=0.37). The effect of antidepressants on global functioning is negligible. CONCLUSIONS: Drug therapy tailored to well-defined symptom domains can have a beneficial effect on patients with severe personality disorder. The findings from this study raise questions on current pharmacologic algorithms. PMID- 19778497 TI - How DISC1 regulates postnatal brain development: girdin gets in on the AKT. AB - In this issue of Neuron, Kim et al. and Enomoto et al. show that DISC1 plays a key role in regulating postnatal brain development though interaction with Girdin. Girdin in turn regulates AKT signaling. Thus, another facet of the role of DISC1 is established, shedding more light on fundamental brain processes and the developmental basis of major psychiatric disorders. PMID- 19778498 TI - MicroRNAs in memory processing. AB - MicroRNAs are a class of small RNA molecules that regulate the expression of a wide variety of genes. In this issue of Neuron, Rajasethupathy and colleagues identify 170 distinct microRNAs in Aplysia, including one, miR-124, that plays a critical role in the regulation of signaling molecules underlying synaptic plasticity and memory. PMID- 19778499 TI - Computational sophistication at a single GABAergic connection. AB - Diverse computational roles of GABAergic inhibition are often assumed to reflect heterogeneity in the sources of GABA and in the receptors sensing the neurotransmitter. New data suggest that distinct effects on integration of excitatory inputs by cerebellar granule cells might result from different modes of signaling by individual interneurons. PMID- 19778500 TI - Resting our cortices by going DOWN to sleep. AB - In this issue of Neuron, Vyazovskiy et al. reports on progressive changes in cortical unit activity within extended wakefulness and within extended sleep paralleling changes in EEG slow-wave sleep activity. Sleep debt may be integrated at the level of individual cortical neurons, providing support for the synaptic homeostasis theory. PMID- 19778501 TI - Conceptual representation and the making of new decisions. AB - A key feature of an adaptive decision making mechanism is its ability to guide behavior even in new situations. In this issue of Neuron, Kumaran et al. report that conceptual representations, which allow generalization from one situation to another through their shared features, can guide decisions even when new problems are encountered via the hippocampus. PMID- 19778502 TI - Confidence and corrections: how we make and un-make up our minds. AB - Single neurons in several brain areas intervening between sensation and action signal the accumulation of sensory evidence favoring a particular behavioral response. Two new studies show that these same neurons encode decision confidence and that decision makers continue to process relevant sensory information even after a choice has been made. PMID- 19778503 TI - Cortical enlightenment: are attentional gamma oscillations driven by ING or PING? AB - The response of a neuron to sensory stimuli can only give correlational support for functional hypotheses. To experimentally test causal function, the neural activity needs to be manipulated in a cell-type-specific as well as spatially and temporally precise way. We review recent optogenetic experiments on parvalbumin positive cortical interneurons that link modeling studies of synchronization to experimental studies on attentional modulation of gamma oscillations in primates. PMID- 19778504 TI - The neurobiology of decision: consensus and controversy. AB - We review and synthesize recent neurophysiological studies of decision making in humans and nonhuman primates. From these studies, the basic outline of the neurobiological mechanism for primate choice is beginning to emerge. The identified mechanism is now known to include a multicomponent valuation stage, implemented in ventromedial prefrontal cortex and associated parts of striatum, and a choice stage, implemented in lateral prefrontal and parietal areas. Neurobiological studies of decision making are beginning to enhance our understanding of economic and social behavior as well as our understanding of significant health disorders where people's behavior plays a key role. PMID- 19778505 TI - Automated analysis of cellular signals from large-scale calcium imaging data. AB - Recent advances in fluorescence imaging permit studies of Ca(2+) dynamics in large numbers of cells, in anesthetized and awake behaving animals. However, unlike for electrophysiological signals, standardized algorithms for assigning optically recorded signals to individual cells have not yet emerged. Here, we describe an automated sorting procedure that combines independent component analysis and image segmentation for extracting cells' locations and their dynamics with minimal human supervision. In validation studies using simulated data, automated sorting significantly improved estimation of cellular signals compared to conventional analysis based on image regions of interest. We used automated procedures to analyze data recorded by two-photon Ca(2+) imaging in the cerebellar vermis of awake behaving mice. Our analysis yielded simultaneous Ca(2+) activity traces for up to >100 Purkinje cells and Bergmann glia from single recordings. Using this approach, we found microzones of Purkinje cells that were stable across behavioral states and in which synchronous Ca(2+) spiking rose significantly during locomotion. PMID- 19778507 TI - Roles of disrupted-in-schizophrenia 1-interacting protein girdin in postnatal development of the dentate gyrus. AB - Disrupted-In-Schizophrenia 1 (DISC1), a susceptibility gene for major psychiatric disorders, regulates neuronal migration and differentiation during mammalian brain development. Although roles for DISC1 in postnatal neurogenesis in the dentate gyrus (DG) have recently emerged, it is not known how DISC1 and its interacting proteins govern the migration, positioning, and differentiation of dentate granule cells (DGCs). Here, we report that DISC1 interacts with the actin binding protein girdin to regulate axonal development. DGCs in girdin-deficient neonatal mice exhibit deficits in axonal sprouting in the cornu ammonis 3 region of the hippocampus. Girdin deficiency, RNA interference-mediated knockdown, and inhibition of the DISC1/girdin interaction lead to overextended migration and mispositioning of the DGCs resulting in profound cytoarchitectural disorganization of the DG. These findings identify girdin as an intrinsic factor in postnatal development of the DG and provide insights into the critical role of the DISC1/girdin interaction in postnatal neurogenesis in the DG. PMID- 19778506 TI - DISC1 regulates new neuron development in the adult brain via modulation of AKT mTOR signaling through KIAA1212. AB - Disrupted-in-schizophrenia 1 (DISC1), a susceptibility gene for major mental illnesses, regulates multiple aspects of embryonic and adult neurogenesis. Here, we show that DISC1 suppression in newborn neurons of the adult hippocampus leads to overactivated signaling of AKT, another schizophrenia susceptibility gene. Mechanistically, DISC1 directly interacts with KIAA1212, an AKT binding partner that enhances AKT signaling in the absence of DISC1, and DISC1 binding to KIAA1212 prevents AKT activation in vitro. Functionally, multiple genetic manipulations to enhance AKT signaling in adult-born neurons in vivo exhibit similar defects as DISC1 suppression in neuronal development that can be rescued by pharmacological inhibition of mammalian target of rapamycin (mTOR), an AKT downstream effector. Our study identifies the AKT-mTOR signaling pathway as a critical DISC1 target in regulating neuronal development and provides a framework for understanding how multiple susceptibility genes may functionally converge onto a common pathway in contributing to the etiology of certain psychiatric disorders. PMID- 19778508 TI - The microRNA bantam functions in epithelial cells to regulate scaling growth of dendrite arbors in drosophila sensory neurons. AB - In addition to establishing dendritic coverage of the receptive field, neurons need to adjust their dendritic arbors to match changes of the receptive field. Here, we show that dendrite arborization (da) sensory neurons establish dendritic coverage of the body wall early in Drosophila larval development and then grow in precise proportion to their substrate, the underlying body wall epithelium, as the larva more than triples in length. This phenomenon, referred to as scaling growth of dendrites, requires the function of the microRNA (miRNA) bantam (ban) in the epithelial cells rather than the da neurons themselves. We further show that ban in epithelial cells dampens Akt kinase activity in adjacent neurons to influence dendrite growth. This signaling between epithelial cells and neurons receiving sensory input from the body wall synchronizes their growth to ensure proper dendritic coverage of the receptive field. PMID- 19778509 TI - Characterization of small RNAs in Aplysia reveals a role for miR-124 in constraining synaptic plasticity through CREB. AB - Memory storage and memory-related synaptic plasticity rely on precise spatiotemporal regulation of gene expression. To explore the role of small regulatory RNAs in learning-related synaptic plasticity, we carried out massive parallel sequencing to profile the small RNAs of Aplysia californica. We identified 170 distinct miRNAs, 13 of which were novel and specific to Aplysia. Nine miRNAs were brain enriched, and several of these were rapidly downregulated by transient exposure to serotonin, a modulatory neurotransmitter released during learning. Further characterization of the brain-enriched miRNAs revealed that miR 124, the most abundant and well-conserved brain-specific miRNA, was exclusively present presynaptically in a sensory-motor synapse where it constrains serotonin induced synaptic facilitation through regulation of the transcriptional factor CREB. We therefore present direct evidence that a modulatory neurotransmitter important for learning can regulate the levels of small RNAs and present a role for miR-124 in long-term plasticity of synapses in the mature nervous system. PMID- 19778510 TI - High-affinity kainate receptor subunits are necessary for ionotropic but not metabotropic signaling. AB - Kainate receptors signal through both ionotropic and metabotropic pathways. The high-affinity subunits, GluK4 and GluK5, are unique among the five receptor subunits, as they do not form homomeric receptors but modify the properties of heteromeric assemblies. Disruption of the Grik4 gene locus resulted in a significant reduction in synaptic kainate receptor currents. Moreover, ablation of GluK4 and GluK5 caused complete loss of synaptic ionotropic kainate receptor function. The principal subunits were distributed away from postsynaptic densities and presynaptic active zones. There was also a profound alteration in the activation properties of the remaining kainate receptors. Despite this, kainate receptor-mediated inhibition of the slow afterhyperpolarization current (I(sAHP)), which is dependent on metabotropic pathways, was intact in GluK4/GluK5 knockout mice. These results uncover a previously unknown obligatory role for the high-affinity subunits for ionotropic kainate receptor function and further demonstrate that kainate receptor participation in metabotropic signaling pathways does not require their classic role as ion channels. PMID- 19778511 TI - Precise subcellular input retinotopy and its computational consequences in an identified visual interneuron. AB - The Lobula Giant Movement Detector (LGMD) is a higher-order visual interneuron of Orthopteran insects that responds preferentially to objects approaching on a collision course. It receives excitatory input from an entire visual hemifield that anatomical evidence suggests is retinotopic. We show that this excitatory projection activates calcium-permeable nicotinic acetylcholine receptors. In vivo calcium imaging reveals that the excitatory projection preserves retinotopy down to the level of a single ommatidium. Examining the impact of retinotopy on the LGMD's computational properties, we show that sublinear synaptic summation can explain orientation preference in this cell. Exploring retinotopy's impact on directional selectivity leads us to infer that the excitatory input to the LGMD is intrinsically directionally selective. Our results show that precise retinotopy has implications for the dendritic integration of visual information in a single neuron. PMID- 19778512 TI - Dynamics of fast and slow inhibition from cerebellar golgi cells allow flexible control of synaptic integration. AB - Throughout the brain, multiple interneuron types influence distinct aspects of synaptic processing. Interneuron diversity can thereby promote differential firing from neurons receiving common excitation. In contrast, Golgi cells are the sole interneurons regulating granule cell spiking evoked by mossy fibers, thereby gating inputs to the cerebellar cortex. Here, we examine how this single interneuron class modifies activity in its targets. We find that GABA(A)-mediated transmission at unitary Golgi cell --> granule cell synapses consists of varying contributions of fast synaptic currents and sustained inhibition. Fast IPSCs depress and slow IPSCs gradually build during high-frequency Golgi cell activity. Consequently, fast and slow inhibition differentially influence granule cell spike timing during persistent mossy fiber input. Furthermore, slow inhibition reduces the gain of the mossy fiber --> granule cell input-output curve, while fast inhibition increases the threshold. Thus, a lack of interneuron diversity need not prevent flexible inhibitory control of synaptic processing. PMID- 19778513 TI - Representations of odor in the piriform cortex. AB - Olfactory perception is initiated by the recognition of odorants by a large repertoire of receptors in the sensory epithelium. A dispersed pattern of neural activity in the nose is converted into a segregated map in the olfactory bulb. How is this representation transformed at the next processing center for olfactory information, the piriform cortex? Optical imaging of odorant responses in the cortex reveals that the piriform discards spatial segregation as well as chemotopy and returns to a highly distributed organization in which different odorants activate unique but dispersed ensembles of cortical neurons. Neurons in piriform cortex, responsive to a given odorant, are not only distributed without apparent spatial preference but exhibit discontinuous receptive fields. This representation suggests organizational principles that differ from those in neocortical sensory areas where cells responsive to similar stimulus features are clustered and response properties vary smoothly across the cortex. PMID- 19778514 TI - Cortical firing and sleep homeostasis. AB - The need to sleep grows with the duration of wakefulness and dissipates with time spent asleep, a process called sleep homeostasis. What are the consequences of staying awake on brain cells, and why is sleep needed? Surprisingly, we do not know whether the firing of cortical neurons is affected by how long an animal has been awake or asleep. Here, we found that after sustained wakefulness cortical neurons fire at higher frequencies in all behavioral states. During early NREM sleep after sustained wakefulness, periods of population activity (ON) are short, frequent, and associated with synchronous firing, while periods of neuronal silence are long and frequent. After sustained sleep, firing rates and synchrony decrease, while the duration of ON periods increases. Changes in firing patterns in NREM sleep correlate with changes in slow-wave activity, a marker of sleep homeostasis. Thus, the systematic increase of firing during wakefulness is counterbalanced by staying asleep. PMID- 19778515 TI - Spatial attention decorrelates intrinsic activity fluctuations in macaque area V4. AB - Attention typically amplifies neuronal responses evoked by task-relevant stimuli while attenuating responses to task-irrelevant distracters. In this context, visual distracters constitute an external source of noise that is diminished to improve attended signal quality. Activity that is internal to the cortex itself, stimulus-independent ongoing correlated fluctuations in firing, might also act as task-irrelevant noise. To examine this, we recorded from area V4 of macaques performing an attention-demanding task. The firing of neurons to identically repeated stimuli was highly variable. Much of this variability originates from ongoing low-frequency (<5 Hz) fluctuations in rate correlated across the neuronal population. When attention is directed to a stimulus inside a neuron's receptive field, these correlated fluctuations in rate are reduced. This attention dependent reduction of ongoing cortical activity improves the signal-to-noise ratio of pooled neural signals substantially more than attention-dependent increases in firing rate. PMID- 19778516 TI - Tracking the emergence of conceptual knowledge during human decision making. AB - Concepts lie at the very heart of intelligence, providing organizing principles with which to comprehend the world. Surprisingly little, however, is understood about how we acquire and deploy concepts. Here, we show that a functionally coupled circuit involving the hippocampus and ventromedial prefrontal cortex (vMPFC) underpins the emergence of conceptual knowledge and its effect on choice behavior. Critically, the hippocampus alone supported the efficient transfer of knowledge to a perceptually novel setting. These findings provide compelling evidence that the hippocampus supports conceptual learning through the networking of discrete memories and reveal the nature of its interaction with downstream valuation modules such as the vMPFC. Our study offers neurobiological insights into the remarkable capacity of humans to discover the conceptual structure of related experiences and use this knowledge to solve exacting decision problems. PMID- 19778517 TI - Bayesian reconstruction of natural images from human brain activity. AB - Recent studies have used fMRI signals from early visual areas to reconstruct simple geometric patterns. Here, we demonstrate a new Bayesian decoder that uses fMRI signals from early and anterior visual areas to reconstruct complex natural images. Our decoder combines three elements: a structural encoding model that characterizes responses in early visual areas, a semantic encoding model that characterizes responses in anterior visual areas, and prior information about the structure and semantic content of natural images. By combining all these elements, the decoder produces reconstructions that accurately reflect both the spatial structure and semantic category of the objects contained in the observed natural image. Our results show that prior information has a substantial effect on the quality of natural image reconstructions. We also demonstrate that much of the variance in the responses of anterior visual areas to complex natural images is explained by the semantic category of the image alone. PMID- 19778518 TI - A novel virus-like particle based on hepatitis B core antigen and substrate binding domain of bacterial molecular chaperone DnaK. AB - Hepatitis B virus core (HBc) protein has been proved to be an attractive carrier for foreign epitopes, and can display green fluorescent protein (GFP) on its surface. The structure of substrate-binding domain of DnaK [DnaK (394-504 aa), DnaK SBD] is similar to GFP, we therefore reasoned that DnaK SBD might also be tolerated. Electron microscopic observations suggested that the chimeric proteins containing the truncated HBc (HBcDelta) and DnaK SBD could self-assemble into virus-like particle (VLP). Then the accessibility of DnaK SBD and the adjuvanticity of VLP HBcDelta-SBD were demonstrated by two recombinant peptide vaccines against gonadotropin-releasing hormone (GnRH), GhM and GhMNR. The latter carries in addition the peptide motif NRLLLTG which is known to bind to DnaK and DnaK SBD. The combination of VLP HBcDelta-SBD and GhMNR elicited stronger humoral responses and caused further testicular atrophy than the combinations of VLP HBcDelta and GhMNR or VLP HBcDelta-SBD and GhM in Balb/c mice. These findings indicate VLP HBcDelta-SBD might serve as an excellent carrier for GhMNR and some other peptide vaccines. PMID- 19778519 TI - Detection of Plasmodium vivax infection in the Republic of Korea by loop-mediated isothermal amplification (LAMP). AB - Loop-mediated isothermal amplification (LAMP) is a novel technique that rapidly amplifies target DNA in isothermal conditions. In a previous study, the sensitivities and specificities of LAMP, microscopy, and nested PCR were compared in the context of rapid malaria detection. In the present study, LAMP detected vivax malaria parasites in 115 of 117 microscopically positive samples (sensitivity, 98.3%; 95% CI, 97.4-100%), which agreed well with the nested PCR results (sensitivity, 99.1%; 95% CI: 96.0-100%). No positive cases of malaria were detected by LAMP or nested PCR in 50 consecutive feverish patients other than malaria from malaria endemic areas. LAMP performed on DNA extracted from heat-treated blood had a sensitivity of 93.3% (28/30, 95% CI: 84.4-100%) and specificity of 100% (30/30, 95% CI: 100%). The present study shows that LAMP based assays have high sensitivity, specificity, and amplification efficiencies for Plasmodium vivax detection. The authors recommend that LAMP can be considered as a rapid nucleic acid amplification assay for the molecular diagnosis of P. vivax in both clinical laboratories and malaria clinics in areas where vivax malaria is endemic. PMID- 19778520 TI - A simple approach to improve the sensitivity of enzyme-linked immunosorbent assay: using the IMAPlate 5RC96 for result readout. AB - In this article, we describe a new enzyme-linked immunosorbent assay (ELISA) setup to improve the sensitivity of commercial or homemade ELISAs. In the new ELISA setup, an IMAPlate 5RC96, a disposable multi-utility lab device developed by NCL New Concept Lab is used as a self-uptaking microcuvette array to read out the result of the ELISA that is performed in the normal 96-well plate with reduced substrate solution and stop solution. A commercial interleukin-6 (IL-6) ELISA reagent kit was used for the evaluation. Compared with the conventional ELISA setup, the new ELISA setup could easily increase the absorbance values by up to more than 10-fold. Therefore, the sensitivity (change in absorbance/change in concentration [DeltaAbs/DeltaConc]) is increased accordingly. In addition, methods to extend the upper detection limit of plate readers for the IMAPlate 5RC96 are described. This new ELISA setup may be more notable for the approach employed than for the specific analyte. It should generally be applicable to any conventional ELISA and should serve as an example of a simple solution that increases the detection sensitivity and/or detection range of other assays as well. We expect the approach to have a substantial practical impact on analytical methods and to accelerate discovery, research, and application of analytes at low concentration in life sciences and diagnostics. PMID- 19778521 TI - Silibinin inhibits expression of HIF-1alpha through suppression of protein translation in prostate cancer cells. AB - Silibinin is a polyphenolic flavonoid isolated from the milk thistle (Silybum marianum) and is reported to exhibit anticancer properties. Recently, it has been reported that silibinin inhibits hypoxia-inducible factor-1alpha (HIF-1alpha) expression in cancer cells. However, the precise mechanism by which silibinin decreases HIF-1 expression is not fully understood. In this study, silibinin inhibited basal and hypoxia induced expression levels of HIF-1alpha protein in LNCaP and PC-3 prostate cancer cells, while the rate of HIF-1alpha protein degradation and mRNA levels were not affected. We found that the decrease in HIF 1 protein by silibinin correlated with suppression of de novo synthesis of HIF 1alpha protein. Silibinin inhibited global protein synthesis coincided with reduction of eIF4F complex formation and induction of phosphorylation of the translation initiation factor 2alpha (eIF-2alpha) which can cause inhibition of general protein synthesis. These results suggest that silibinin's activity to inhibit HIF-1alpha protein expression is associated with the suppression of global protein translation. PMID- 19778522 TI - Induction of oncogene addiction shift to NF-kappaB by camptothecin in solid tumor cells. AB - The biological basis of the resistance of solid tumor cells to chemotherapy is not well understood. While addressing this problem, we found that gastric cancer cell line St-4/CPT, lung cancer cell line A549/CPT, and colon cancer cell line HT 29/CPT, all of which are resistant to camptothecin (CPT), showed strong and constitutive nuclear factor (NF)-kappaB activity driven by IkappaB kinase compared with their parental cell lines St-4, A549, and HT-29. A new NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), reduced viability and induced apoptosis in St-4/CPT, A549/CPT, and HT-29/CPT cell lines, while their parental cell lines were resistant to DHMEQ. The results in this study present an example of the shift in signals that support the survival of solid tumor cells to NF kappaB during the acquisition of resistance to CPT. The results also indicate that solid tumor cells that become resistant to chemotherapy may be more easily treated by NF-kappaB inhibitors. PMID- 19778523 TI - Wnt modulators, SFRP-1, and SFRP-2 are expressed in osteoblasts and differentially regulate hematopoietic stem cells. AB - Wnt signaling has been implicated in the self-renewal of hematopoietic stem cells (HSCs). Secreted frizzled-related proteins (SFRPs) are a family of soluble proteins containing a region homologous to a receptor for Wnt, Frizzled, and are thought to act as endogenous modulators for Wnt signaling. This study examined the role of SFRPs in HSC regulation. Among the four family members, SFRP-1 and SFRP-2 are specifically induced in the bone marrow in response to myelosuppression, and immunostaining revealed that both proteins were expressed in osteoblasts. Interestingly, SFRP-1 reduced the number of multipotent progenitors in in vitro culture of CD34(-)KSL cells, while SFRP-2 did not. Furthermore, SFRP-1 compromised the long-term repopulating activity of HSCs, whereas SFRP-2 did not affect or even enhanced it in the same setting. These results indicate that although both SFRP-1 and SFRP-2 act as inhibitors for Wnt signaling in vitro, they differentially affect the homeostasis of HSCs. PMID- 19778524 TI - ATP hydrolysis is essential for Bag-1M-mediated inhibition of the DNA binding by the glucocorticoid receptor. AB - The 70-kDa heat shock protein (Hsp70) is involved in providing the appropriate conformation of various nuclear hormone receptors, including the glucocorticoid receptor (GR). The Bcl-2 associated athanogene 1M (Bag-1M) is known to downregulate the DNA binding by the GR. Also, Bag-1M interacts with the ATPase domain of Hsp70 to modulate the release of the substrate from Hsp70. In this study, we demonstrate that ATP hydrolysis enhances Bag-1M-mediated inhibition of the DNA binding by the GR. However, the inhibitory effect of Bag-1M was abolished when the intracellular ATP was depleted. In addition, a Bag-1M mutant lacking the interaction with Hsp70 did not influence the GR to bind DNA, suggesting the interaction of Bag-1M with Hsp70 in needed for its negative effect. These results indicate that ATP hydrolysis is essential for Bag-1M-mediated inhibition of the DNA binding by the GR and Hsp70 is a mediator for this process. PMID- 19778525 TI - Transcription factor AP2 beta involved in severe female alcoholism. AB - Susceptibility to alcoholism and antisocial behavior exhibits an evident link to monoaminergic neurotransmission. The serotonin system in particular, which is associated with regulation of mood and behavior, has an influence on personality characters that are firmly connected to risk of developing alcoholism and antisocial behavior, such as impulsiveness, and aggression. The transcription factor TFAP2b has repeatedly been shown to be involved in monoaminergic transmission, likely due to a regulatory effect on genes that are fundamental to this system, e.g. monoamine oxidase type A, and the serotonin transporter. Recent research has identified a functional polymorphism in the gene encoding TFAP2B that regulates its level of expression. In the present study we have compared a sample of female alcoholics (n=107), sentenced to institutional care for their severe addiction, contrasted against a control sample of adolescent females (n=875). The results showed that parental alcohol misuse was significantly more common among the alcoholic females, and also that parental alcohol misuse was associated with a reduction in age of alcohol debut. We also addressed the question of whether a functional TFAP2b polymorphism was associated with alcoholism. Results showed that the high-functioning allele was significantly more common among the female alcoholics, compared to the non-alcoholic controls. Furthermore, the results also indicated that psychosocial factors, in terms of parental alcohol misuse, depression or psychiatric disorder, had an influence on the association. It was observed that the genetic association was restricted to the subset of cases that had not experienced these negative psychosocial factors. PMID- 19778526 TI - Hepatic antioxidant status and hematological parameters in rainbow trout, Oncorhynchus mykiss, after chronic exposure to carbamazepine. AB - Recently, residual pharmaceuticals are generally recognized as relevant sources of aquatic environmental pollutants. However, the toxicological effects of these contaminants have not been adequately researched. In this study, the chronic toxic effect of carbamazepine (CBZ), an anticonvulsant drug commonly present in surface and ground water, on hepatic antioxidant status and hematological parameters of rainbow trout were investigated. Fish were exposed at sublethal concentrations of CBZ (1.0mug/l, 0.2mg/l and 2.0mg/l) for 7, 21 and 42 days. Compared to the control group, fish exposed at higher concentration (0.2mg/l or 2.0mg/l) of CBZ showed significantly higher levels of hemoglobin, ammonia and glucose, and significantly higher plasma enzymes activities. During the exposure duration, erythrocyte count, hematocrit, mean erythrocyte hemoglobin, mean erythrocyte volume, mean color concentration and total protein content in all groups were not significantly different. At the highest test concentration (2.0mg/l) of CBZ, oxidative stress was apparent as reflected by the significant higher lipid peroxidation and protein carbonyl levels in liver after 42 days exposure, associated with an inability to induce antioxidant enzymes activities including superoxide dismutase, glutathione peroxidase and glutathione reductase. After 42 days exposure, reduced glutathione level was significantly decreased in the fish exposed at 0.2mg/l CBZ, compared with the control. In short, CBZ-induced physiological and biochemical responses in fish were reflected in the oxidant stress indices and hematological parameters. These results suggest that hepatic antioxidant responses and hematological parameter could be used as potential biomarkers for monitoring residual pharmaceuticals present in aquatic environment. PMID- 19778527 TI - Use of interval-specific likelihood ratios improves clinical interpretation of serum FLC results for the diagnosis of malignant plasma cell disorders. AB - BACKGROUND: We examined whether the use of test result interval-specific likelihood ratios (LR) could improve the clinical interpretation of serum FLC kappa/lambda ratio for the diagnosis of malignant plasma cell disorders. METHODS: We calculated LRs for different FLC kappa/lambda intervals using sera from patients diagnosed with intact multiple myeloma (MM), light chain MM (LCMM), non secretory MM (NSMM) and light chain amyloidosis (AL-A). Consecutive patients with a clinical suspicion of a monoclonal B-cell disorder that were diagnosed with MGUS or no B-cell monoclonal disorder served as the disease control group. RESULTS: Using LRs for different test result intervals, a distinction can be made between FLC kappa/lambda ratios that are within the normal diagnostic range, ratios that are inconclusive (1.66-5.0, LR+/-1), ratios that indicate the possible presence of a malignant plasma cell disorder (0.05-0.25 and >5.0-10, LR+/-10) and ratios that were suggestive of a malignant plasma cell disorder (<0.05 or >10; LR+/-50). A FLC kappa/lambda ratio within the normal diagnostic range virtually excluded LCMM and AL-A, but not intact MM or NSMM. CONCLUSIONS: Interpreting serum FLC kappa/lambda ratios using LRs for different result intervals improves the clinical interpretation for the diagnosis of malignant plasma cell disorders excluding plasmacytoma. PMID- 19778528 TI - New real-time PCR-based method for the joint genotyping of JAK2 (V617F) with inherited thrombophilic F5 and F2 mutations. AB - BACKGROUND: During the last years the appearance of the acquired V617F mutation of the Janus Kinase 2 gene (JAK2) in patients suffering different thrombotic events has been described. We decided to develop a new and rapid multiplex real time Polymerase Chain Reaction (PCR) in order to detect the V617F mutation together with the inherited prothrombotic mutations of factors F5 and F2. DESIGN AND METHODS: The method was carried out on the LightCycler 2.0 (Roche Diagnostics, Mannheim, Germany) and consisted in a first step of simultaneous amplification by real-time PCR of the three genes to be genotyped, in a 20microl closed tube, using a primer pair together with the correspondent FRET hybridization probes for each gene. RESULTS: We assayed 41 samples in the multiplex PCR reaction, 19 were positive (46.34%) for V617F mutation. From the V617F positive samples we found 1 sample heterozygous for F2 (5.26%) and 1 sample heterozygous for F5 (5.26%), so a 10.52% of the samples tested combine V617F mutation with inherited thrombophilic mutations. Results were clear, rapid and reliable allowing a significant time saving. CONCLUSIONS: The technique presented in this manuscript is a new achievement in the field of the molecular diagnosis that combines the genotyping of F5 and F2 with the assessment of the JAK2 (V617F) mutation load. PMID- 19778529 TI - Genetic variants in mitochondrial tRNA genes are associated with essential hypertension in a Chinese Han population. AB - BACKGROUND: Of multiple factors contributing to essential hypertension, mitochondrial variants exhibited the trends for serving as molecular and genetic markers for the disease in last five years. However, previous studies focused on African-American or Caucasian pedigrees, knowledge of mitochondrial tRNA genes and population-based Chinese hypertensives were limited. METHODS: We performed sequence analysis in tRNA genes, hot spots for cardiovascular diseases, in 270 Chinese Han essential hypertensives and 270 controls. Lymphoblastoid cell lines were immortalized by transformation with the Epstein-Barr virus. Rates of oxygen consumption in intact cells were determined with a YSI 5300 oxygraph (Yellow Springs Instruments) on samples, harboring variants in tRNA genes. RESULTS: There were 26 variants in tRNA genes that were found in hypertensives and these variants were not in controls. Functional analysis found that these variants may lead to deficiencies in tRNA 3' end metabolism and/or impairment of critical subunits of the respiratory chain. Most importantly, the oxygen consumption rate in cells harboring variants T4454C (P=0.0010) and A4263G (P=0.0001) decreased as compared to the average level of control cell lines. CONCLUSIONS: Variants located in mitochondrial tRNA genes may have biologic plausibility to implicate in the pathogenesis of Chinese essential hypertension. PMID- 19778530 TI - Application of the DHPLC method for mutational detection of the CYP21A2 gene in congenital adrenal hyperplasia. AB - BACKGROUND: More than 90% of cases of congenital adrenal hyperplasia (CAH) are caused by a steroid 21-hydroxylase deficiency. Approximately 75% of the defective CYP21A2 genes are generated through an intergenic recombination with the neighboring CYP21A1P pseudogene. These 2 duplicated genes share a 98% nucleotide sequence homology. Therefore, precisely identifying the CYP21A2 gene in CAH patients is absolutely necessary. METHODS: We describe an established PCR-based amplification method, a denaturing high-performance liquid chromatography (DHPLC) analysis, to directly identify 11 different mutations commonly appearing in the CYP21A1P gene. Among these 11 mutations, 9 are found in CAH patients and 2 created mutations were from normal individuals. RESULTS: From the DHPLC analysis using 6 fragments of amplicons, the elution profiles of the 11 mutation sites were successfully used to distinguish these common disease-causing mutations of the CYP21A2 gene. Based on this resolution, we were able to rapidly search existing sequences of mutations in the CYP21A1P gene for this malady. CONCLUSION: DHPLC is an efficient and specific means to undertake such a program for screening patients with CAH caused by defects of the CYP21A2 gene resulting from the neighboring CYP21A1P pseudogene. PMID- 19778531 TI - The fatty acid profile changes in marine invertebrate larval cells during cryopreservation. AB - The development of cryopreservation methods for embryonic cells and larvae of sea animals offers a great potential for marine biotechnology. Larval cells of bivalves and sea urchins were frozen to -196 degrees C using traditional cryoprotectants (Me(2)SO and trehalose) and the cryoprotective mixture developed by us. In addition to Me(2)SO and trehalose, this mixture contained an exogenous lipid extract from mussel tissues and antioxidants. A positive effect of antioxidants (alpha-tocopherol acetate, ascorbic acid or echinochrome, the quinoid pigment of sea urchins) on cell viability became significant only in the presence of exogenous lipids. Antioxidants added to cryoprotective mixtures did not reveal visible cryoprotective activity when used separately. To better understand the mechanism of the protective effect of exogenous lipids on cell membranes of sea animals, a comparative analysis of the fatty acid (FA) composition of total lipids in larval cells before and after freezing was carried out using a gas-liquid chromatography. The results indicate that freezing-thawing has direct effects on the FA composition of major lipid classes in marine invertebrate cells, and these effects can vary depending on the provenance of the cells. We have found that (I) both cell viability and the FA profile of cell lipids after cryopreservation depend on the cryoprotectants used; (II) an amount of saturated, monoenic and polyenic FAs changes significantly after cryopreservation. We assume that the addition of the exogenous lipid extract in form of liposomes could promote a renewal of disturbance areas and prevent from membrane damages during freezing-thawing. PMID- 19778532 TI - Morphogenesis of epithelial tubes: Insights into tube formation, elongation, and elaboration. AB - Epithelial tubes are a fundamental tissue across the metazoan phyla and provide an essential functional component of many of the major organs. Recent work in flies and mammals has begun to elucidate the cellular mechanisms driving the formation, elongation, and branching morphogenesis of epithelial tubes during development. Both forward and reverse genetic techniques have begun to identify critical molecular regulators for these processes and have revealed the conserved role of key pathways in regulating the growth and elaboration of tubular networks. In this review, we discuss the developmental programs driving the formation of branched epithelial networks, with specific emphasis on the trachea and salivary gland of Drosophila melanogaster and the mammalian lung, mammary gland, kidney, and salivary gland. We both highlight similarities in the development of these organs and attempt to identify tissue and organism specific strategies. Finally, we briefly consider how our understanding of the regulation of proliferation, apicobasal polarity, and epithelial motility during branching morphogenesis can be applied to understand the pathologic dysregulation of these same processes during metastatic cancer progression. PMID- 19778533 TI - Noggin producing, MyoD-positive cells are crucial for eye development. AB - A subpopulation of cells expresses MyoD mRNA and the cell surface G8 antigen in the epiblast prior to the onset of gastrulation. When an antibody to the G8 antigen was applied to the epiblast, labeled cells were later found in the ocular primordia and muscle and non-muscle forming tissues of the eyes. In the lens, retina and periocular mesenchyme, G8-positive cells synthesized MyoD mRNA and the bone morphogenetic protein inhibitor Noggin. MyoD expressing cells were ablated in the epiblast by labeling them with the G8 MAb and lysing them with complement. Their ablation in the epiblast resulted in eye defects, including anopthalmia, micropthalmia, altered pigmentation and malformations of the lens and/or retina. The right eye was more severely affected than the left eye. The asymmetry of the eye defects in ablated embryos correlated with differences in the number of residual Noggin producing, MyoD-positive cells in ocular tissues. Exogenously supplied Noggin compensated for the ablated epiblast cells. This study demonstrates that MyoD expressing cells serve as a Noggin delivery system to regulate the morphogenesis of the lens and optic cup. PMID- 19778534 TI - An imprinted GFP insertion reveals long-range epigenetic regulation in embryonic lineages. AB - Imprinted genes are often grouped in clusters at defined chromosomal locations. Long-range regulatory effects are implicated in the control of imprinting and these could be co-opted in the emergence of novel imprinted genes during evolution. We present a detailed analysis of a novel imprinted GFP mouse line. Tel7KI is a new insertion allele near the Ins2 locus within a cluster of imprinted genes on distal mouse Chr7. The GFP reporter becomes regulated by the host domain in two notable fashions. First, transcription of GFP is imprinted and active exclusively from the maternally inherited allele in the embryo. Second, the expressed maternal allele is subject to position effects reflecting a distinct pattern of expression. The GFP reporter acquires silencing DNA methylation marks on the paternal allele after fertilization. This imprinting is not acquired in the placenta, where GFP is active from both parental alleles, demonstrating key epigenetic differences between embryonic and extraembryonic lineages. Our analysis shows that imprinted clusters can provide environments conducive to the acquisition of imprinting upon novel inserted transcriptional units. The Tel7KI line offers new powerful avenues to explore both genetic and environmental factors implicated in the acquisition and maintenance of imprinted transcription in mammals. PMID- 19778535 TI - Myocardial protection by F 15845, a persistent sodium current blocker, in an ischemia-reperfusion model in the pig. AB - The specific persistent sodium current blocker F 15845 was tested in two myocardial ischemia-reperfusion models in the pig in order to evaluate its cardioprotective effects. In the first protocol, the left circumflex coronary artery was ligated for 60-min and then reperfused for 48-h. F 15845 (2.5+2.5 and 5+5mg/kg) was administered by i.v. infusion, starting before ischemia to the beginning of reperfusion. The second protocol attempted to evaluate F 15845 (5+5mg/kg) response in a more pathological state of the heart. To this end, a non necrotic ligation of the left circumflex coronary artery was applied for 15 min one week before the actual 60 min occlusion. For both protocols, infarct size was determined at the end of the reperfusion period and was assessed by histochemistry (tetrazolium staining). Plasma levels of biochemical markers (myoglobin and troponin I) were also evaluated. In protocol 1, F 15845 significantly reduced the infarct size by 27+/-3 and 43+/-5% at 2.5+2.5 and 5+5mg/kg, respectively. At 5+5mg/kg, F 15845 decreased plasma levels of myoglobin and cardiac troponin I. In protocol 2, F 15845 (5+5mg/kg) significantly reduced myocardial infarct size by 54+/-15% and lowered the plasma myoglobin and troponin I levels relative to vehicle-treated animals. In conclusion, the highly effective persistent sodium current blocker F 15845 exerts remarkable cardioprotective activities. It reduces both myocardial infarct size and the release of biochemical markers in healthy pigs as well in pigs previously exposed to an ischemic episode. PMID- 19778536 TI - Marrow stromal fibroblastic cell cultivation in vitro on decellularized bone marrow extracellular matrix. AB - The in vitro biocompatibility of decellularized bone marrow extracellular matrix was evaluated. Following a freeze-thaw cycle, sectioned discs of fresh frozen rat metaphyseal bone were sequentially incubated in solutions of hypertonic, then hypotonic Ringer's solution, followed by deoxycholic acid, then DNAase I. The adequacy of decellularization of marrow stroma was examined by light microscopy. Marrow stromal fibroblastic cells were harvested by dispersion of rat long bone marrow, followed by concentration by discontinuous Ficoll-Paque gradient centrifugation. The fibroblastic cells were expanded by in vitro cultivation, and second passage cells were cryopreserved until needed. Cryopreserved marrow stromal cells were applied dropwise to sections of decellularized bone marrow extracellular matrix, and cultured in BJGb medium with 20% fetal bovine serum for ten days. Mature cultures were formalin fixed, decalcified, and embedded in paraffin. Light microscopy of hematoxylin and eosin stained sections showed individual spindle cells invading the upper portion of the decellularized extracellular matrix, and also a monolayer of spindle cells on the upper surfaces of exposed trabecular and cortical bone. This experiment showed that decellularized marrow extracellular matrix is a biocompatible three dimensional in vitro substrate for marrow stromal fibroblastic cells. PMID- 19778537 TI - Inactivation of LGI1 expression accompanies early stage hyperplasia of prostate epithelium in the TRAMP murine model of prostate cancer. AB - The LGI1 gene has been implicated in tumor cell invasion through regulation of the ERK pathway. To determine whether human prostate cancer cells (PC3, 22RV, Du145) are similarly affected by exposure to LGI1, we conducted scratch wound assays and demonstrated that the secreted LGI1 protein can reduce cell motility, an essential component of invasion and metastasis. These studies have now been extended to an in vivo mouse model of prostate cancer. Using a BAC transgenic mouse expressing a GFP reporter gene under the control of cis regulatory elements, we demonstrated that LGI1 is highly expressed in the normal prostate epithelium. To determine whether loss of LGI1 expression is associated with development and progression of murine prostate cancer, we bred the GFP reporter BAC transgenic mice with TRAMP mice which undergo early hyperplasia and progressive stages of prostate cancer. In the F1 animals, although the surrounding normal prostate epithelium expressed high levels of LGI1 in the double transgenic mice, the LGI1 gene had been inactivated even at the earliest stages of hyperplasia. This observation supports the suggestion that inactivation of LGI1 in certain cell types is related to tumor progression. Taken together these results suggest that LGI1 may be an important molecule for the arrest of prostate cancer cell invasion and possibly as a biomarker for early detection of prostate hyperplasia. PMID- 19778539 TI - Hypothalamic oxytocin neurons modulate hypophagic effect induced by adrenalectomy. AB - Glucocorticoids have major effects on food intake, as demonstrated by the decrease of food intake following adrenalectomy (ADX); however, the mechanisms leading to these effects are not well understood. Oxytocin (OT) has been shown to reduce food intake. We evaluated the effects of glucocorticoids on OT neuron activation and OT mRNA expression in the hypothalamic paraventricular (PVN) and supraoptic (SON) nuclei induced by feeding. We also evaluated the effect of pretreatment with OT-receptor antagonist ([d(CH2)5,Tyr(Me)2,Orn8]-vasotocin, OVT) on food intake in ADX rats. Fos/OT neurons in the posterior parvocellular subdivision of the PVN were increased after refeeding, with a higher number in the ADX group, compared with sham and ADX+corticosterone (B) groups, with no difference in the medial parvocellular and magnocellular subdivisions of the PVN. ADX increased OT mRNA expression in the PVN both in fasting and refeeding condition, compared with sham and ADX+B groups. In the SON, refeeding increased the number of Fos/OT neurons, with a higher number in the ADX+B group. In fasted condition, OT mRNA expression in the SON was increased in ADX and ADX+B, compared with sham group. Pretreatment with OVT reversed the ADX-induced hypophagia, with no difference between sham and ADX+B animals. The present results show that glucocorticoid withdrawal induces a higher activation of PVN OT neurons in response to feeding, and an increase of OT mRNA expression in the PVN and OT receptor antagonist reverses the anorexigenic effect induced by ADX. These data indicate that PVN OT neurons might mediate the hypophagic effect induced by adrenalectomy. PMID- 19778538 TI - Physiology, injury, and recovery of interstitial cells of Cajal: basic and clinical science. PMID- 19778540 TI - Homology of olfactory receptor neuron response characteristics inferred from hybrids between Asian and European corn borer moths (Lepidoptera: Crambidae). AB - First generation hybrid males from crosses between the Asian corn borer (ACB), Ostrinia furnacalis, and the "univoltine Z-strain" European corn borer (ECB), Ostrinia nubilalis, were examined with respect to behavioral and physiological responses to ACB and ECB pheromones. The hybrid males often flew to the pheromone of ECB Z-strain, but very rarely to the ACB pheromone. We mapped the tuning profiles of each ORN of the F(1) hybrids with respect to the relevant pheromone components and a common behavioral antagonist by employing differential cross adaptation and varying doses of the ligands. In the trichoid sensilla of F(1) hybrid males, the three co-compartmentalized ORNs produced spikes that were very difficult to distinguish by size, unlike the parental populations. Comparing the responses to ACB and ECB components at different doses reveals overlapping profiles similar to males of both parental types, but more responsiveness to the ECB pheromone components. We were unable to detect any differences in the ORN tuning profiles when comparing males with different behavioral phenotypes. While the two ECB pheromone races have similar ORN tuning properties that are different from those in ACB, the spike-amplitude patterns of ECB E-strain and ACB have greater homology when compared to ECB Z-strain. PMID- 19778541 TI - Hepatocyte growth factor prevents advanced glycation end products-induced injury and oxidative stress through a PI3K/Akt-dependent pathway in human endothelial cells. AB - AIMS: Advanced glycation end products (AGEs) trigger an oxidative reaction which then accelerates endothelial cell apoptosis; this is a critical event in the process of diabetic vascular complications. We previously demonstrated that hepatocyte growth factor (HGF) protects human endothelial cells against AGE induced injury. The present study was designed to investigate the possible involvement of MAPK and PI3K/Akt signaling in the action of HGF. MAIN METHODS: HUVECs were treated with AGEs in the presence or absence of HGF. For detection of apoptosis, the morphological Acridine Orange staining, flow cytometry, and caspase-3 activity assay were used. Generation of reactive oxygen species (ROS) and the change in mitochondrial membrane potential were measured using flow cytometry and fluorescence immune analysis. The activation of MAPK and Akt was assayed by Western blot. KEY FINDINGS: HGF exerted its prosurvival effect by inhibiting the overproduction of intracellular ROS and the depolarization of mitochondrial membrane, induced by AGEs. HGF-induced survival correlated with Akt activity and was inhibited by the specific PI3K inhibitor. ERK also was activated by HGF and rescued cells from apoptosis, although the cytoprotective effect was less marked than for PI3K/Akt. HGF-mediated survival was independent of JNK and p38MAPK pathways. Furthermore, blocking the PI3K and Akt activities with PI3K inhibitors or transfection of HUVECs with the dominant-negative p85 or Akt effectively abolished the inhibition of the intracellular ROS production and mitochondrial damage. SIGNIFICANCE: Our studies suggest that HGF, via PI3K/Akt signaling, prevents AGE-induced apoptosis and oxidative stress through the inhibition of mitochondrial damage in HUVECs. PMID- 19778543 TI - Subjective and physical dimensions of bodily self-consciousness, and their dis integration in anorexia nervosa. AB - The present investigation concerns the multidimensionality of self-consciousness. I will specifically address this general issue by focusing on bodily self consciousness and by considering how one is conscious of one's body through consciousness of both its physicality and its subjectivity. Here, physicality is defined as the belongingness to the physical world; subjectivity is defined as the fact of being a subject of conscious experience. Once subjectivity and physicality are differentiated from each other, the difficulty is to clarify the integration of these dimensions of bodily self-consciousness into a single experience of one's body: how does the consciousness of one's body integrate one's consciousness of one's body-as-subjective and one's consciousness of one's body-as-physical? In this investigation, I describe different forms of bodily self-consciousness in ways that shed light on the intermingling of subjectivity and physicality. I argue that being conscious of one's body-as-subjective involves experiencing one's belongingness to the physical world; conversely, being conscious of one's body-as-physical involves experiencing it as one's own; either way, such forms of bodily self-consciousness involve experiencing both the subjectivity and the physicality of one's body. The hypothesis here is that the imbalance of these dimensions relative to each other would be pathological. I will thus underline the normal multidimensionality of bodily self-consciousness by considering its pathological breakdown as it happens in anorexia nervosa. PMID- 19778542 TI - Cells deficient in PARP-1 show an accelerated accumulation of DNA single strand breaks, but not AP sites, over the PARP-1-proficient cells exposed to MMS. AB - Poly(ADP-ribose) polymerase-1 (PARP-1) is a base excision repair (BER) protein that binds to DNA single strand breaks (SSBs) and subsequently synthesizes and transfers poly(ADP-ribose) polymers to various nuclear proteins. Numerous biochemical studies have implicated PARP-1 as a modulator of BER; however, the role of PARP-1 in BER in living cells remains unclear partly due to lack of accurate quantitation of BER intermediates existing in cells. Since DT40 cells, chicken B lymphocytes, naturally lack PARP-2, DT40 cells allow for the investigation of the PARP-1 null phenotype without confounding by PARP-2. To test the hypothesis that PARP-1 is necessary for efficient BER during methylmethane sulfonate (MMS) exposure in vertebrate cells, intact DT40 cells and their isogenic PARP-1 null counterparts were challenged with different exposure scenarios for phenotypic characterization. With chronic exposure, PARP-1 null cells exhibited sensitivity to MMS but with an acute exposure did not accumulate base lesions or AP sites to a greater extent than wild-type cells. However, an increase in SSB content in PARP-1 null cell DNA, as indicated by glyoxal gel electrophoresis under neutral conditions, suggested the presence of BER intermediates. These data suggest that during exposure, PARP-1 impacts the stage of BER after excision of the deoxyribosephosphate moiety from the 5' end of DNA strand breaks by polymerase beta. PMID- 19778544 TI - 6-hydroxydopamine lesions enhance progesterone-facilitated lordosis of rats and hamsters, independent of effects on motor behavior. AB - The Ventral Tegmental Area (VTA) is an important brain area for progesterone (P(4))'s effects to facilitate female sexual behavior of rodents. We investigated the importance of dopaminergic neurons in the VTA, and two dopaminergic projection sites, the Nucleus Accumbens (NAc), and Caudate Nucleus of the Striatum (CN), in modulating P(4)-facilitated sex and motor behavior. Ovariectomized (ovx) rats and hamsters, administered estradiol benzoate (10 microg) and P(4) (0, 50, 100, 200, or 500 microg), were tested for motor behavior in a chamber that automatically records horizontal beam breaks, and for sexual behavior in response to a sexually-experienced male. Animals were tested once a week until each P(4) dosage was received; animals then had bilateral 6 hydroxydopamine (6-OHDA) or sham lesions to the VTA, NAc, or CN and were re tested at each P(4) dosage on subsequent weeks. Fixed brains were stained with cresyl violet and processed for dopamine transporter (DAT) immunoreactivity. The number of cresyl violet stained cells was significantly lower in all 6-OHDA infusion sites compared to non-6-OHDA infusion sites of rats and hamsters. Also, in rats, the number of DAT-immunoreactive neurons was lower in all 6-OHDA infusion sites compared to non-6-OHDA infusion sites. In rats, 6-OHDA but not sham, lesions to the VTA, NAc, or CN produced P(4)-dependent increases in lordosis quotients and resulted in modest increases in motor behavior. In hamsters, 6-OHDA, but not sham, lesions to the VTA, NAc, or CN produced P(4) dependent increases in total lordosis durations and produced modest decreases in motor behavior. This suggests that the dopaminergic output neurons of midbrain VTA may play an important role in modulation of P(4)-facilitated sexual lordosis among rodents. PMID- 19778545 TI - The epithelial sodium channel (ENaC): Mediator of the aldosterone response in the vascular endothelium? AB - In the kidney the epithelial sodium channel (ENaC) is regulated by the mineralocorticoid hormone aldosterone, which is essential for long-term blood pressure control. Evidence has accumulated showing that ENaC is expressed in endothelial cells. Moreover, its activity modifies the biomechanical properties of the endothelium. Therefore, the vascular system is also an important target for aldosterone and responds to the hormone with an increase in cell volume, surface area, and mechanical stiffness. These changes occur in a concerted fashion from minutes to hours and can be prevented by the specific sodium channel blocker amiloride and the mineralocorticoid receptor (MR) blocker spironolactone. Aldosterone acts on cells of the vascular system via genomic and non-genomic pathways. There is evidence that the classical cytosolic MR could mediate both types of response. Using a nanosensor covalently linked to aldosterone, binding sites at the plasma membrane were identified by atomic force microscopy. The interaction of aldosterone and this newly identified surface receptor could precede the slow classic genomic aldosterone response resulting in fast activation of endothelial ENaC. Recent data suggest that aldosterone-induced ENaC activation initiates a sequence of cellular events leading to a reduced release of vasodilating nitric oxide. We propose a model in which ENaC is the key mediator of aldosterone-dependent blood pressure control in the vascular endothelium. PMID- 19778546 TI - The platelet as a model system for the acute actions of nuclear receptors. AB - Platelets are circulating cell fragments which play a critical role in thrombosis, and whose activity is associated with the progress of cardiovascular diseases, diabetes, inflammation, and cancer cell metastasis. Recently, a number of nuclear receptors have been found present in human platelets, including the receptors for sex steroids, and glucocorticoids, along with peroxisome proliferator-activated receptors (PPAR)s and retinoid X receptors (RXR)s. Although the platelet contains no nucleus, selective ligands for these receptors activate their respective platelet nuclear receptors and regulate platelet aggregation and activation. The human platelet, because of its abundance and accessibility therefore represents an excellent model system to study the rapid non-genomic mechanism of nuclear receptors. Moreover, since targeting platelets is a major clinical therapeutic area, analysis of platelet nuclear receptors may provide clues for new drug targets as well as provide important information regarding the physiological roles of nuclear receptors in the circulation. PMID- 19778547 TI - Interaction of estrogen receptors with insulin-like growth factor-I and Wnt signaling in the nervous system. AB - Estradiol signaling through estrogen receptors in the nervous system involves a variety of rapid membrane/cytoplasm-initiated events that are integrated with different mechanisms of transcriptional regulation. Here we review the role of glycogen synthase kinase 3 (GSK3) and beta-catenin in the coordination of membrane/cytoplasm-initiated and nuclear-initiated estrogen receptor signaling. Estradiol activates in vitro and in vivo the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway in neural cells. By activating this pathway through estrogen receptors, estradiol increases the levels of inactive GSK3beta (phosphorylated in serine 9). In turn, the inhibition of GSK3beta increases the stability of beta catenin and its nuclear translocation. Then, beta-catenin exerts two different transcriptional effects: (i) regulates beta-catenin/T cell factor (TCF) mediated transcription in a similar but not identical way as Wnt ligands and (ii) regulates estrogen receptor mediated transcription after its association with estrogen receptor alpha. In addition, by the regulation of PI3K/Akt/GSK3/beta catenin pathway, other factors such as insulin-like growth factor-I (IGF-I) regulate estrogen receptor mediated transcription. Therefore, GSK3 and beta catenin allow the interaction of membrane/cytoplasm-initiated estrogen receptor signaling, IGF-I signaling, Wnt signaling and nuclear-initiated estrogen receptor signaling in the nervous system. PMID- 19778548 TI - Quantitative determination of biological activity of botulinum toxins utilizing compound muscle action potentials (CMAP), and comparison of neuromuscular transmission blockage and muscle flaccidity among toxins. AB - The biological activity of various types of botulinum toxin has been evaluated using the mouse intraperitoneal LD(50) test (ip LD(50)). This method requires a large number of mice to precisely determine toxin activity, and so has posed a problem with regard to animal welfare. We have used a direct measure of neuromuscular transmission, the compound muscle action potential (CMAP), to evaluate the effect of different types of botulinum neurotoxin (NTX), and we compared the effects of these toxins to evaluate muscle relaxation by employing the digit abduction scoring (DAS) assay. This method can be used to measure a broad range of toxin activities the day after administration. Types A, C, C/D, and E NTX reduced the CMAP amplitude one day after administration at below 1 ip LD(50), an effect that cannot be detected using the mouse ip LD(50) assay. The method is useful not only for measuring toxin activity, but also for evaluating the characteristics of different types of NTX. The rat CMAP test is straightforward, highly reproducible, and can directly determine the efficacy of toxin preparations through their inhibition of neuromuscular transmission. Thus, this method may be suitable for pharmacology studies and the quality control of toxin preparations. PMID- 19778549 TI - Plasma protein binding of tetrodotoxin in the marine puffer fish Takifugu rubripes. AB - To elucidate the involvement of plasma protein binding in the disposition of tetrodotoxin (TTX) in puffer fish, we used equilibrium dialysis to measure protein binding of TTX in the plasma of the marine puffer fish Takifugu rubripes and the non-toxic greenling Hexagrammos otakii, and in solutions of bovine serum albumin (BSA) and bovine alpha-1-acid glycoprotein (AGP). TTX (100-1000 microg/mL) bound to protein in T. rubripes plasma with low affinity in a non saturable manner. The amount of bound TTX increased linearly with the TTX concentration, reaching 3.92+/-0.42 microg TTX/mg protein at 1000 microg TTX/mL. Approximately 80% of the TTX in the plasma of T. rubripes was unbound in the concentration range of TTX examined, indicating that TTX exists predominantly in the unbound form in the circulating blood of T. rubripes at a wide range of TTX concentrations. TTX also bound non-specifically to H. otakii plasma proteins, BSA, and bovine AGP. The amount of the bound TTX in the plasma of H. otakii and BSA, respectively, was 1.86+/-0.36 and 4.65+/-0.70 microg TTX/mg protein at 1000 microg TTX/mL, and that in the bovine AGP was 8.78+/-0.25 microg TTX/mg protein at 200 microg TTX/mL. PMID- 19778550 TI - Analyses of paralytic shellfish toxins and biomarkers in a southern Brazilian reservoir. AB - The Alagados Reservoir (Brazil) is an important source for the supply of water, recreation and fishery. Since 2002, the occurrence of cyanobacterial blooms (paralytic shellfish toxins - PST producers) have been noted. This study was aimed at the monitoring of PST occurrence in the Reservoir's water and fish. Biomarkers such as ethoxyresorufin-O-deethylase (EROD), glutathione S-transferase (GST), catalase (CAT), and acetylcholinesterase (AchE) activities, lipoperoxidation (LPO), histopathology, and comet assay were analyzed in fish. Water and fish were sampled in spring, summer and autumn. The PST concentrations in water were 5.15, 43.84, and 50.78 ng equiv Saxitoxin/L in the spring, summer and autumn, respectively. The PST muscle concentration was below the limit for shellfish. Gonyautoxins (GTX) were found in water samples and fish muscle, and GTX 5 was the major analogous found in muscle. In the summer samples, the LPO, genetic damage, and the GST and AchE activities increased while in the autumn an increase in EROD activity and genetic damage were observed. In all samplings, histopathological alterations in the fish gills and liver were found. The results showed a seasonal variation in the fishes health, which could be related also to farming activities and to the contaminants bioavailability during the year. PMID- 19778552 TI - Does regular practice of physical activity reduce the risk of dysphonia? AB - OBJECTIVE: The purpose of this study was to investigate the association between regular physical activity and the prevalence of dysphonia. METHOD: A cross sectional study was conducted with 3142 teachers from 129 municipal public schools in the city of Belo Horizonte, Brazil. The dependent variable, dysphonia, was classified (absent or present) according to reported symptoms (fatigue when speaking and loss of voice quality), their frequency (occasionally and daily), and duration (past 15 days). The independent variable was regular physical activity. The degree of association was estimated based on the prevalence ratio and a 95% confidence interval obtained by the Poisson regression adapted for cross-sectional studies. RESULTS: In the study sample, the prevalence of dysphonia in teachers was 15.63%. Nearly half (47.52%) of the teachers reported no regular practice of physical exercises. The remaining teachers (52.48%) walked and did physical exercises, sports, and other activities; 31.25% undertook these activities once or twice a week, and 21.23% exercised three or more times a week. Teachers who did not practice physical activity were more likely to present dysphonia compared to those that exercised three or more times a week. CONCLUSION: Regular physical activity was associated positively with the prevalence of dysphonia. PMID- 19778551 TI - Mecamylamine, dihydro-beta-erythroidine, and dextromethorphan block conditioned responding evoked by the conditional stimulus effects of nicotine. AB - Current smokers express the desire to quit. However, the majority find it difficult to remain abstinent. As such, research efforts continually seek to develop more effective treatment. One such area of research involves the interoceptive stimulus effects of nicotine as either a discriminative stimulus in an operant drug discrimination task, or more recently as a conditional stimulus (CS) in a discriminated goal-tracking task. The present work investigated the potential role nicotinic acetylcholine receptors play in the CS effects of nicotine (0.4mg/kg) using antagonists with differential selectivity for beta2*, alpha7*, alpha6beta2*, and alpha3beta4* receptors. Methyllycaconitine (MLA) had no effect on nicotine-evoked conditioned responding. Mecamylamine and dihydro beta-erythroidine (DHbetaE) dose-dependently blocked responding evoked by the nicotine CS. In a time-course assessment of mecamylamine and DHbetaE, each blocked conditioned responding when given 5min before testing and still blocked conditioned responding when administered 200min before testing. Two novel bis picolinium analogs (N, N'-(3, 3'-(dodecan-1,12-diyl)-bis-picolinium dibromide [bPiDDB], and N, N'-(decan-1,10-diyl)-bis-picolinium diiodide [bPiDI]) did not block nicotine-evoked conditioned responding. Finally, pretreatment with low dose combinations of mecamylamine, dextromethorphan, and/or bupropion was used to target alpha3beta4* receptors. No combination blocked conditioned responding evoked by the training dose of nicotine. However, a combination of mecamylamine and dextromethorphan partially blocked nicotine-evoked conditioned responding to a lower dose of nicotine (0.1mg/kg). These results indicate that beta2* and potentially alpha3beta4* nicotinic acetylcholine receptors play a role in the CS effects of nicotine and are potential targets for the development of nicotine cessation aids. PMID- 19778553 TI - Diagnosis of abdominal tuberculosis by T-cell-based assays on peripheral blood and peritoneal fluid mononuclear cells. AB - OBJECTIVES: Diagnosing abdominal tuberculosis (TB) remains a challenge. A recently developed RD-1 gene-based assay for diagnosing tuberculosis infection shows promising results. We evaluated the diagnostic usefulness of this assay compared with conventional tests in patients with suspected abdominal TB in clinical practice. METHODS: All patients with suspected abdominal TB were prospectively enrolled in a tertiary hospital during a 1-year period. In addition to the conventional tests for diagnosing TB, the IFN-gamma-producing T-cell response to ESAT-6 and CFP-10 by ELISPOT assay using peripheral blood mononuclear cells (PBMC) and peritoneal fluid mononuclear cells (PF-MC) were performed. RESULTS: Forty eight patients with suspected abdominal TB were enrolled. Of these patients, 30 (63%) were classified as abdominal TB including 14 TB peritonitis (12 confirmed + 1 probable + 1 possible), 6 abdominal TB lymphadenitis (3 confirmed + 3 probable), 4 hepatic TB (3 confirmed + 1 possible), 2 intestinal TB (1 confirmed + 1 probable), 3 renal TB (1 confirmed + 2 probable), and 1 pancreatic TB (1 confirmed). Eighteen (38%) were classified as not TB. ELISPOT assay using PBMC was performed on samples from all 48 subjects. The sensitivity and specificity of the PBMC ELISPOT assay were 89% (95% CI, 71-98%) and 78% (95% CI, 52-94%), respectively. In the 11 patients in whom PF-MC ELISPOT assay was performed, it was positive in 5 of 6 patients with TB peritonitis, and negative in all 5 patients with not TB. CONCLUSIONS: The ELISPOT assay using PBMC and PF MC is a useful adjunct to the current tests for diagnosing abdominal TB. PMID- 19778554 TI - In vitro and in vivo evaluation of efficacy of citrate/methylene blue/parabens/IPA solution as a skin disinfectant. AB - OBJECTIVE: The objective of this study was to evaluate the bactericidal activity of a new antiseptic in an in vitro model using reference bacterial strains and on abdominal and inguinal skin of healthy human subjects. ZuraPrep (C/MB/P/IPA) contains citrate, methylene blue, parabens and isopropyl alcohol 70%. METHODS: In vitro and in vivo studies evaluate immediate and persistent activity of the tested solution using bovine rawhides inoculated with single strains of microorganisms and natural bacterial flora on skin of adult human subjects. Depending upon the anatomical site (abdominal or inguinal), several different configurations of test times were executed. Post-prep surface cultures were performed at 10 min and 6h after application of the test solution. RESULTS: Tested solution showed high efficiency in log reduction of viable microbes both in vitro and in vivo. Post-prep activity 10 min after application ranged from 2.5 to 3 log(10) reduction from baseline on abdominal sites and 3.5-4.5 on inguinal sites. Similar levels of reduction persisted 6h after application. CONCLUSION: The level of antisepsis provided by the tested solution is similar or greater than that obtained with other antiseptics currently in use, and further clinical testing of the new antiseptic is warranted. PMID- 19778555 TI - Dendritic cells integrate signals from the tumor microenvironment to modulate immunity and tumor growth. AB - Dendritic cells (DCs) are professional antigen presenting cells with the ability to either initiate or prevent the induction of antigen-specific T cell responses. The conventional DC-centric paradigm of DC-T cell interactions emphasizes the induction of T cell tolerance by immature DCs and the induction of T cell immunity by mature DCs. However, current evidence suggests that DCs can exist in a multitude of functional states other than simply immature or mature and the immunogenic capacity of the DC may be conditioned by the microenvironment. It is likely that DCs are important for the induction of tumor immune surveillance or promoting immune evasion. In this review, we have highlighted how signal transducer and activator of transcription 3 (Stat3) hyperactivation and inflammatory mediators associated with chronic inflammation can disarm DCs and subvert protective immune surveillance of cancers. PMID- 19778556 TI - The combination of marker gene swapping and fluorescence-activated cell sorting improves the efficiency of recombinant modified vaccinia virus Ankara vaccine production for human use. AB - Modified vaccinia virus Ankara (MVA) is employed as a human vaccine vector for the high expression of heterologous genes and the lack of replication in mammalian cells. This study demonstrates that cells infected by recombinant viruses can be obtained by fluorescence-activated cell sorting. Recombinant viruses are generated by a swapping event between a red fluorescent protein gene in the acceptor virus and a plasmid cassette coding for both a green fluorescent marker and a transgene. To prevent the carry-over of parental virus, due to superinfection of the cells harbouring recombinant viruses, the sorting is performed on cells infected at low m.o.i. in the presence of a reversible inhibitor of viral particle release. Terminal dilution cloning is then used to isolate both green and marker-free recombinant viruses, which can be identified by whole-plate fluoroimaging. The differential visualization of all the viral types involved allows a stepwise monitoring of all recombinations and leads to a straightforward and efficient flow cytometry-based cell sorting purification protocol. As an example of the efficacy of this sorting procedure, the construction of rMVA's coding for the rat nuclear protein HMGB1 and H5N1 influenza A virus hemagglutinin is reported. The entire recombinant MVA production process is carried out in serum-free media employing primary chicken embryo fibroblasts (CEF), which are certified for the preparation of human vaccines. This rMVA production method is faster, simpler and more reliable than any other available procedure for obtaining safe vaccine stocks for human use. PMID- 19778557 TI - Relaxin-3 and receptors in the human and rhesus brain and reproductive tissues. AB - Evidence suggests that relaxin-3 may have biological functions in the reproductive and central nervous systems. To date, however, relaxin-3 biodistribution has only been investigated in the mouse, rat, pig and teleost fish. Characterizing relaxin-3 gene structure, expression patterns, and function in non-human primates and humans is critical to delineating its biological significance. Experiments were performed to clone the rhesus macaque orthologues of the relaxin-3 peptide hormone and its cognitive receptors (RXFP1 and RXFP4). An investigation of rhesus relaxin-3 bioactivity and RXFP1 binding properties was also performed. Next we sought to investigate relaxin-3 immunoreactivity in human and rhesus macaque tissues. Immunohistofluorescence staining for relaxin-3 in the brain, testis, and prostate indicated predominant immunostaining in the ventral and dorsal tegmental nuclei, interstitial space surrounding the seminiferous tubules, and prostatic stromal cells, respectively. Further, in studies designed towards exploring biological functions, we observed neuroprotective actions of rhesus relaxin-3 on human neuronal cell cultures. Taken together, this study broadens the significance of relaxin-3 as a peptide involved in both neuronal cell function and reproductive tissues in primates. PMID- 19778558 TI - Random transposon vectors pUTTns for the markerless integration of exogenous genes into gram-negative eubacteria chromosomes. AB - A set of random transposon vectors pUTTns that facilitates the markerless integration of new functions into the chromosome of gram-negative bacteria has been developed. The vectors, which are derived from mini-Tn5 transposons, are located on a R6K-based suicide delivery plasmid that provides the IS50(R) transposase tnp gene in cis, but they are external to the mobile element. The vectors' conjugal transfer to recipients is mediated by RP4 mobilization functions in the donor. Internal to the mini-Tn5 element is a cassette that contains a selectable antibiotic resistance marker (kanamycin, chloramphenicol, or tetracycline resistance gene), a counter-selectable marker (sacB), a 430-bp repeat of the sacB gene 3' end acted as the directly-repeated (DR) sequence, and modified multiple cloning sites (MCS). After two total rounds of transposon integration and recombination between the two DRs, only the exogenous DNA inserted into the MCS (passenger genes) and a single 430-bp scar sacBDR fragment remained in the chromosome after excision. The utility of these vectors was demonstrated by integrating the organophosphorus insecticide hydrolase gene (mpd) into the chromosome of Escherichia, Pseudomonas, Sphingomonas, and Paracoccus species. Sequential integration of another organophosphorus insecticide hydrolase gene (oph) into the previously engineered bacteria, without bringing any selectable markers, was also successful. These engineered bacteria were relatively stable. Cell viability and original degrading characteristics were not affected compared with the original recipients. This shows that the developed system is very useful for the markerless integration of exogenous genes into the chromosome of gram-negative eubacteria. PMID- 19778559 TI - Flow cytometry for rapid size determination and sorting of nucleic acid containing nanoparticles in biological fluids. AB - A method based on flow cytometry was developed which allows measurement of particle size distributions of nanoparticles directly in biological fluids and preparative sorting into distinct size fractions. Fluorescently labelled beads of distinct sizes (0.1-2 microm) were used to establish a correlation between diameter and side scattering intensity (SSC). Simultaneous detection of fluorescence and SSC allowed us to set a threshold on fluorescence thereby providing the possibility to distinguish nanoparticles of interest from other particulate matter (e.g. low density lipoproteins or other serum components) which is frequently present in biological fluids. Finally, a proof of principle was established for sorting a heterogeneous submicron particle population into separate size fractions. PMID- 19778560 TI - Simultaneous delivery of doxorubicin and immunostimulatory CpG motif to tumors using a plasmid DNA/doxorubicin complex in mice. AB - To achieve delivery of doxorubicin (DXR), a very commonly used anticancer agent, to tumor tissues, it was intercalated to plasmid DNA to obtain a plasmid DNA/DXR complex. The cytotoxic effects of DXR, DNA and their complex were examined in colon26/Luc cells, a murine adenocarcinoma clone stably expressing firefly luciferase, co-cultured with RAW264.7 murine macrophage-like cells. Both CpG motif-containing plasmid DNA (CpG plasmid DNA) and DXR significantly inhibited the proliferation of colon26/Luc cells, but their complex was the most effective among those examined. Non-CpG plasmid DNA was less effective than the CpG plasmid DNA. When injected into mice bearing hepatic metastases of colon26/Luc cells, the CpG plasmid DNA/DXR complex produced a significant level of IL-12 in the serum and liver. The amount of DXR delivered to tumor tissues in the liver was greater when DXR was injected as a CpG plasmid DNA/DXR complex than as free DXR. The CpG plasmid DNA/DXR complex effectively inhibited the proliferation of colon26/Luc cells in the liver compared with free DXR, CpG plasmid DNA, or non-CpG plasmid DNA/DXR complex. These results indicate that CpG plasmid DNA is an effective polymer that inhibits tumor growth by delivering both a proinflammatory signal and anticancer agent to tumor tissues. PMID- 19778561 TI - Two capa-genes are expressed in the neuroendocrine system of Rhodnius prolixus. AB - CAPA-peptides have been isolated from a broad range of insect species and are typical of the neurosecretory system of the abdominal ventral nerve cord. In Rhodnius prolixus, which is known to transmit Chagas' disease, CAPA-peptides have potent antidiuretic effects. Recently, two capa-genes were isolated from this hemipteran insect; it was the first description of the occurrence of multiple capa-genes from a single insect species. The expression of peptides from one of these capa-genes was confirmed by mass spectrometry Paluzzi (2008) [10]. In this study, the abdominal neuroendocrine system of R. prolixus was screened for the occurrence of products of the second annotated capa-gene. Single nerve preparations of abdominal segmental nerves 1-3 of R. prolixus were analyzed by MALDI-TOF mass spectrometry and the products of both capa-genes were identified by tandem mass spectrometry. The co-occurrence of the different CAPA-peptides, including CAPA-precursor peptides, in all spectra from abdominal segmental nerves 1 to 3 suggests a common expression of both capa-genes in the same neuroendocrine cells. A comparison of mass spectra obtained from abdominal segmental nerves with those of the subesophageal ganglion (SEG) revealed an obvious differential processing of the CAPA-precursors within the CNS. PMID- 19778562 TI - Antimicrobial specificity and mechanism of action of disulfide-removed linear analogs of the plant-derived Cys-rich antimicrobial peptide Ib-AMP1. AB - Ib-AMP1 is a 20-residue disulfide-linked beta-sheet antimicrobial peptide found in the seeds of Impatiens balsamina. In order to investigate the effects of the 2 disulfide bonds on the antimicrobial specificity, to determine the mechanism of antimicrobial action of Ib-AMP1 and to develop novel cell-selective antimicrobial peptides with improved antimicrobial specificity as compared to wild-type Ib AMP1, we synthesized a disulfide-removed linear analog of Ib-AMP1 with L-Pro, D Pro or peptoid residues (Nala and Nlys) at the central position of the molecule. All linear analogs displayed a 3.7-4.8-fold higher antimicrobial specificity than wild-type Ib-AMP1, indicating that the disulfide bonds of Ib-AMP1 analogs are not essential for its antimicrobial specificity. Circular dichroism spectra revealed that the peptoid residues, as well as the proline at the central position of disulfide bond-removed Ib-AMP1 analogs, induce a beta-turn structure in a negatively charged bacterial membrane-mimicking environment. Ib-AMP1 was not effective in depolarizing the cytoplasmic membranes of Staphylococcus aureus and showed almost no leakage of calcein from negatively charged bacterial membranes mimicking lipid vesicles. In contrast, all linear analogs caused very weak dye leakage from negatively charged vesicles, but they almost completely depolarized the membrane potential of S. aureus cells. Collectively, our results suggest that the target of Ib-AMP1 may not be the cytoplasmic membranes of bacteria but their intracellular components. All linear analogs exhibit lethality due to their ability to form small channels that permit the transit of ions or protons and not molecules as large as calcein, and not by disrupting membranes. PMID- 19778563 TI - Ghrelin and peptide YY (PYY) profiles in gastrointestinal tissues and the circulation of the rat during pregnancy and lactation. AB - Plasma and tissue profiles of gastrointestinal hormones ghrelin and peptide YY (PYY) were investigated in different female rat reproductive states. Neither plasma nor tissue ghrelin concentrations were suppressed during pregnancy despite elevated leptin. The highest concentrations of stomach ghrelin were measured in late pregnancy. PYY concentrations in plasma, descending colon and rectum tissues were increased (P<0.001) throughout pregnancy and lactation. PYY peaked at day 5 of lactation in plasma, as well as descending colon and rectum tissues (proestrus vs day 5 of lactation: 25+/-3.0 pmol/l vs 55+/-8.0 pmol/l; 85+/-4.5 pmol/g wwt vs 418+/-45.0 pmol/g wwt; 23+/-3.0 pmol/g wwt vs 78+/-9.1 pmol/g wwt). This PYY peak was temporally associated with the luteinizing hormone peak on day 1 of lactation. Following weaning, dam adiposity and plasma leptin increased whereas ghrelin stomach peptide decreased. Relative PYY concentrations in the tissues of the gut varied in the different states suggesting regional alterations taking place in the colon. The ascending colon produced the highest concentrations in non-pregnant rats, the descending colon the highest concentrations during lactation with the pregnant rats and the dams postweaning in a transition state between. It is unclear what role the increased PYY in various tissues observed has during pregnancy and lactation as it would be expected to be reduced in these states of greatly increased appetite. PYY may have an influence on maternal dietary adaptation, intestinal hypertrophy and weight gain during pregnancy and lactation although it is still unclear precisely how it acts. PMID- 19778564 TI - Nmnat2 delays axon degeneration in superior cervical ganglia dependent on its NAD synthesis activity. AB - Axon degeneration is an active program of self-destruction observed in many physiological and pathological settings. There are three Nicotinamide mononucleotide adenylyl transferase (Nmnat, EC2.7.7.1) in mammals. Overexpression of Nmnat1 or Nmnat3 can delay axon degeneration, while the role of Nmnat2 in axon degeneration remains largely unknown. Here we found that Nmnat2 was specifically and highly expressed in brain compared with Nmnat1 and Nmnat3. Furthermore, we found brain Nmnat2 was correlated with Alzheimer's disease in APPswe/PS1dE9 transgenic mice. Nmnat2 delayed Wallerian degeneration in cultured superior cervical ganglia (SCGs) from morphological changes, microtubule destruction and neurofilament degradation, mutation of the conserved enzyme activity site in Nmnat2 disrupted its enzyme activity as well as the axon-protective function. Our results demonstrate that the brain-specific Nmnat2 delays injury-induced axon degeneration dependent on its NAD synthesis activity. These findings provide new clues to further study the molecular mechanisms of axon degeneration and the related neurodegenerative diseases. PMID- 19778565 TI - NF-kappaB mediates MPP+-induced apoptotic cell death in neuroblastoma cells SH EP1 through JNK and c-Jun/AP-1. AB - Parkinson's disease (PD) is characterized by a progressive loss of dopaminergic neurons in substantia nigra with unknown etiology. Neuropathology seen in the brains of PD patients can be closely mimicked by MPP(+)-induced neurotoxicity in vitro. In this study, we used an S-type human neuroblastoma cell line (SH-EP1) as a model to investigate the involvement of NF-kappaB and JNK pathways in MPP(+) induced neurotoxicity. We show that NF-kappaB was activated by MPP(+) as evidenced by NF-kappaB p65 nuclear translocation, the increased DNA binding activity and a rapid phosphorylation of NF-kappaB inhibitor (IkappaBalpha). NF kappaB partially mediated the neurotoxicity of MPP(+), as suggested by the reduction of MPP(+)-induced cell death by both a specific IkappaB kinase (IKK) inhibitor and a dominant negative form of IkappaBalpha (IkappaBalpha-M). Besides NF-kappaB, JNK and c-Jun/AP-1 were also activated upon MPP(+) stimulation. Inhibition of JNK activation with a specific JNK inhibitor partially reduced the MPP(+)-mediated cell death. Similarly, inhibition of c-Jun/AP-1 activation, either by a dominant negative c-Jun or c-Jun/AP-1 inhibitor, significantly attenuated MPP(+)-mediated cell death. These results suggest that both JNK and c Jun/AP-1 activation are pro-apoptotic. Furthermore, we provide clear evidence for the existence of a crosstalk between the NF-kappaB and JNK signaling as MPP(+) induced activation of JNK and c-Jun/AP-1 was strongly down-regulated in IkappaBalpha-M cells. In conclusion, we demonstrate that in SH-EP1 cells MPP(+) induced neurotoxicity is partially mediated by NF-kappaB which in turn acts on the activation of JNK and c-Jun/AP-1. These results may point to a combined inhibition of NF-kappaB and JNK as a new approach to PD therapy. PMID- 19778566 TI - +49G > A polymorphism in the cytotoxic T-lymphocyte antigen-4 gene increases susceptibility to hepatitis B-related hepatocellular carcinoma in a male Chinese population. AB - Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important regulator and functions negatively in immune response. Its nonsynonymous polymorphism +49G > A (dbSNP: rs231775) has been linked to an elevated risk of T-cell-mediated autoimmune diseases, infectious diseases, and even carcinomas. Here, we examined the genotypes at rs231775 of 1003 subjects in a Han Chinese population to detect the association between this single-nucleotide polymorphism (SNP) and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) susceptibility, including 375 HBV-related HCC patients, 209 non-HCC patients with HBV infection, and 419 healthy controls. Our results indicated a weak trend for the relationship between rs231775 and HBV-related HCC susceptibility, although the statistical level was not significant. However, a significant difference was identified in males between HBV-related HCC patients and healthy controls. The data revealed that the frequency of the A/A genotype was higher in patients compared with healthy controls (odds ratio [OR] = 1.79, 95% confidence interval [95% CI] 1.05-3.08). The G allele appeared to have a protective effect in developing HBV-related HCC. Subjects with the A allele had higher HCC susceptibility than those with the G allele (OR = 1.31, 95% CI 1.03-1.66). These results suggested that the A/A genotype and A allele of rs231775 increased the risk of developing HBV-related HCC in a male Chinese population. PMID- 19778567 TI - Resolution of tardive dystonia in a patient with bipolar disorder treated with clozapine: a case report. PMID- 19778569 TI - Oxidative stress in tardive dyskinesia: genetic association study and meta analysis of NADPH quinine oxidoreductase 1 (NQO1) and Superoxide dismutase 2 (SOD2, MnSOD) genes. AB - INTRODUCTION: Tardive dyskinesia (TD) is a potentially irreversible side effect of antipsychotic medication treatment that occurs in approximately 25% of chronically treated schizophrenia patients. Oxidative stress has been one of the proposed mechanisms influencing TD risk. Pae et al. (2004) originally reported a significant association between TD and the NADPH quinine oxidoreductase 1 (NQO1) gene Pro187Ser (C609T, rs1800566) polymorphism in Korean schizophrenia patients; however, subsequent studies have not consistently replicated these findings. Similarly, Hori et al. (2000) reported an association between TD and the Manganese superoxide dismutase SOD2 (MnSOD) gene Ala9Val (rs4880) polymorphism in a Japanese sample, but most research groups failed to replicate their positive findings. AIMS: We investigated the role of the NQO1 polymorphism Pro187Ser and SOD2 (Ala9Val) in a group of well-characterized schizophrenia patients (N=223) assessed for TD. We also performed a meta-analysis of all the previously published TD studies, including data from our sample, on these polymorphisms, Pro187Ser (N=5 studies) and Ala9Val (N=9 studies). RESULTS: We did not observe a significant association of the Pro187Ser or Ala9Val polymorphism with TD occurrence or AIMS scores in our Caucasian and African American samples when analyzed independently. Meta-analysis did not reveal a significant association of the Pro187Ser/Ala9Val alleles or genotypes with TD occurrence. CONCLUSIONS: Neither the NQO1 Pro187Ser nor the SOD2 Ala9Val appear to play a major role in TD risk, although additional polymorphisms should be tested before the role of NQO1 and SOD2 in TD can be completely excluded. PMID- 19778568 TI - The kynurenine pathway in adolescent depression: preliminary findings from a proton MR spectroscopy study. AB - BACKGROUND: Cytokine induction of the enzyme indoleamine 2,3-dioxygenase (IDO) has been implicated in the development of major depressive disorder (MDD). IDO metabolizes tryptophan (TRP) into kynurenine (KYN), thereby decreasing TRP availability to the brain. KYN is further metabolized into several neurotoxins. The aims of this pilot were to examine possible relationships between plasma TRP, KYN, and 3-hydroxyanthranilic acid (3-HAA, neurotoxic metabolite) and striatal total choline (tCho, cell membrane turnover biomarker) in adolescents with MDD. We hypothesized that MDD adolescents would exhibit: i) positive correlations between KYN and 3-HAA and striatal tCho and a negative correlation between TRP and striatal tCho; and, ii) the anticipated correlations would be more pronounced in the melancholic subtype group. METHODS: Fourteen adolescents with MDD (seven with melancholic features) and six healthy controls were enrolled. Minimums of 6 weeks MDD duration and a severity score of 40 on the Children's Depression Rating Scale-Revised were required. All were scanned at 3T with MRI, multi-voxel 3 dimensional, high, 0.75 cm(3), spatial resolution proton magnetic resonance spectroscopic imaging. Striatal tCho concentrations were assessed using phantom replacement. Spearman correlation coefficients were Bonferroni-corrected. RESULTS: Positive correlations were found only in the melancholic group, between KYN and 3-HAA and tCho in the right caudate (r=0.93, p=0.03) and the left putamen (r=0.96, p=.006), respectively. CONCLUSIONS: These preliminary findings suggest a possible role of the KYN pathway in adolescent melancholic MDD. Larger studies should follow. PMID- 19778570 TI - Posttraumatic brain injury psychosis successfully treated with olanzapine. PMID- 19778571 TI - Rash and lamotrigine in bipolar patients. PMID- 19778573 TI - Serious generalized tonic-clonic seizures induced by aripiprazole. PMID- 19778574 TI - Duloxetine related binge eating behaviors: a case report. PMID- 19778575 TI - Dietary polyphenols generate nitric oxide from nitrite in the stomach and induce smooth muscle relaxation. AB - Nitrite, considered a biological waste and toxic product, is being regarded as an important physiological molecule in nitric oxide (NO) biochemistry. Because the interaction of dietary phenolic compounds and nitrite would be kinetically (due to the high concentrations achieved) and thermodynamically (on basis of the redox potentials) feasible in the stomach, we have studied the potential reduction of nitrite by polyphenols present in several dietary sources. By measuring the time courses of *NO production in simulated gastric juice (pH 2), the efficiency of the compounds studied is as follows: Epicatechin-3-O gallate>quercetin>procyanidin B8 dimer>oleuropein>procyanidin B2 dimer>chlorogenic acid>epicatechin>catechin>procyanidin B5 dimer. The initial rates of *NO production fall in a narrow range (ca. 1-5 microMs(-1)) but the distinct kinetics of the decay of *NO signals suggest that competition reactions for *NO are operative. The proof of concept that, in the presence of nitrite, phenol-containing dietary products induce a strong increase of *NO in the stomach was established in an in vivo experiment with healthy volunteers consuming lettuce, onions, apples, wine, tea, berries and cherries. Moreover, selected mixtures of oleuropein and catechin with low nitrite (1 microM) were shown to induce muscle relaxation of stomach strips in a structure-dependent way. Data presented here brings strong support to the concept that polyphenols consumed in a variety of dietary products, under gastric conditions, reduce nitrite to *NO that, in turn, may exert a biological impact as a local relaxant. PMID- 19778576 TI - AhR and ARNT modulate ER signaling. AB - The aryl hydrocarbon receptor (AhR), in complex with its binding partner ARNT, mediates the cellular response to xenobiotic compounds such as the environmental pollutant dioxin. In addition, the AhR has important regulatory roles in normal physiology. For instance, there is extensive data showing an intricate relationship between the AhR and estrogen receptor (ER) pathways. This review focuses on the regulatory roles of AhR and ARNT, beyond the response to xenobiotics. In particular, the effects of AhR agonists on the estrogen signaling pathways and the role of ARNT as a modulator of ER activity are discussed. PMID- 19778577 TI - Contraceptive steroids from pharmaceutical waste perturbate junctional communication in Sertoli cells. AB - The potential health impact of pharmaceutical waste is now a growing concern. Contraceptive steroids are prominent environmental contaminants and thus may act as endocrine disruptors. Numerous xenobiotics hamper Sertoli cells junctional communication which is known to participate in spermatogenesis control. This has been associated with male subfertility and testicular cancer. We investigated three contraceptive molecules found in the environment for their potential impact on Sertoli cells gap junction functionality: 17a-ethynylestradiol, medroxyprogesterone acetate and levonorgestrel. Four other non-steroid drugs also found in the environment were included in the study. Communication disruption was analyzed in vitro in murine seminiferous tubules and the 42GPA9 Sertoli cell line. Steroids modulated connexin43 trafficking and impaired junctional communication through rapid effects apparently acting on the cell membrane but not on Cx43 expression. The 4 non-steroid compounds showed no effect. Longer exposure to steroids increased gap junction impairment, which was associated in part with Na/K ATPase internalization. Estrogen receptors (ER) did not appear to be involved in gap junction disruption: Sertoli cells are devoid of ERalpha and only express the cytoplasmic beta isoform. ERbeta localization was not modified by either steroid. The threshold level was surprisingly low, around 10(-16) M. We conclude that steroidal pollutants disrupt Sertoli cells junctional communication in vitro at concentrations that can be found in the environment. PMID- 19778578 TI - Differential scanning calorimetric and spectroscopic studies on the unfolding of Momordica charantia lectin. Similar modes of thermal and chemical denaturation. AB - Thermal stability of Momordica charantia seed lectin (MCL) was investigated as a function of protein concentration, pH, scan rate, and at different ligand concentrations by using high-sensitivity differential scanning calorimetry (DSC). The DSC endotherm obtained at pH 7.4 consists of two entities with transition temperatures at ca. 333.7 K, and 338 K. The unfolding process is irreversible and could be described by a three-state model. For MCL tetramer DeltaH(c)/DeltaH(v) ratio is close to 4 for the first transition and approximately 2 for the second transition, suggesting that four and two cooperative units are involved in the first and second transitions, respectively. In the presence of lactose both transitions shifted to higher temperatures, suggesting that ligand binds preferentially to the native conformation of MCL. Endotherms recorded as a function of pH indicate that MCL is more stable at lower pH. Chemical unfolding of MCL, induced by Gdn.HCl, was investigated by monitoring the intrinsic fluorescence properties of the protein. The results obtained indicate that chemical denaturation of MCL can also be described by a three-state process, involving an intermediate populated at approximately 3-4 M Gdn.HCl. These observations suggest that the chemical and thermal unfolding processes are similar in that both of them proceed via an intermediate. The far UV and near UV CD spectra of MCL were nearly identical at different pH values and indicate that its secondary and tertiary structure do not change significantly with pH, suggesting that the structure of the protein is stable over a wide pH range. PMID- 19778579 TI - FSH-stimulated PTEN activity accounts for the lack of FSH mitogenic effect in prepubertal rat Sertoli cells. AB - Follicle-stimulating hormone (FSH) controls the proliferation and differentiation of Sertoli cells of the testis. FSH binds a G protein-coupled receptor (GPCR) to stimulate downstream effectors of the phosphoinositide-3 kinase (PI3K)-dependent pathway, without enhancing PI3K activity. To clarify this paradox, we explored the activity of phosphatase and tensin homolog deleted in chromosome 10 (PTEN), the PI3K major regulator, in primary cultures of rat Sertoli cells. We show that, within minutes, FSH increases PTEN neo-synthesis, requiring the proteasomal degradation of an unidentified intermediate, as well as PTEN enzymatic activity. Importantly, introducing an antisense cDNA of PTEN into differentiating Sertoli cells restores FSH-dependent cell proliferation. In conclusion, these results provide a new mechanism of PTEN regulation, which could serve to block entry into S phase of Sertoli cells, while they are proceeding through differentiation in prepubertal animals. PMID- 19778580 TI - Vesicular glutamate transporter 1 and vesicular glutamate transporter 2 synapses on cholinergic neurons in the sublenticular gray of the rat basal forebrain: a double-label electron microscopic study. AB - The basal forebrain (BF) comprises morphologically and functionally heterogeneous cell populations, including cholinergic and non-cholinergic corticopetal neurons that are implicated in sleep-wake modulation, learning, memory and attention. Several studies suggest that glutamate may be among inputs affecting cholinergic corticopetal neurons but such inputs have not been demonstrated unequivocally. We examined glutamatergic axon terminals in the sublenticular substantia innominata in rats using double-immunolabeling for vesicular glutamate transporters (Vglut1 and Vglut2) and choline acetyltransferase (ChAT) at the electron microscopic level. In a total surface area of 30,000 microm(2), we classified the pre- and postsynaptic elements of 813 synaptic boutons. Vglut1 and Vglut2 boutons synapsed with cholinergic dendrites, and occasionally Vglut2 axon terminals also synapsed with cholinergic cell bodies. Vglut1 terminals formed synapses with unlabeled dendrites and spines with equal frequency, while Vglut2 boutons were mainly in synaptic contact with unlabeled dendritic shafts and occasionally with unlabeled spines. In general, Vglut1 boutons contacted more distal dendritic compartments than Vglut2 boutons. About 21% of all synaptic boutons (n=347) detected in tissue that was stained for Vglut1 and ChAT were positive for Vglut1, and 14% of the Vglut1 synapses were made on cholinergic profiles. From separate cases stained for Vglut2 and ChAT, 35% of all synaptic boutons (n=466) were positive for Vglut2, and 23% of the Vglut2 synapses were made on cholinergic profiles. On average, Vglut1 boutons were significantly smaller than Vglut2 synaptic boutons. The Vglut2 boutons that synapsed cholinergic profiles tended to be larger than the Vglut2 boutons that contacted unlabeled, non-cholinergic postsynaptic profiles. The presence of two different subtypes of Vgluts, the size differences of the Vglut synaptic boutons, and their preference for different postsynaptic targets suggest that the action of glutamate on BF neurons is complex and may arise from multiple afferent sources. PMID- 19778581 TI - Expression of connexin 35/36 in retinal horizontal and bipolar cells of carp. AB - Connexin 35/36 (Cx35/36) gap junction protein is expressed in various regions of the brain, including the retina. In this work, the expression of Cx35/36 in the outer retina of carp was studied by immunocytochemistry. By light microscopy, strong punctate Cx35/36-immunoreactivity was observed in the outer plexiform layer. Double labeling experiments on vertical retinal sections showed that Cx35/36 puncta were localized beneath cone pedicles, stained by recoverin, but not on them. In addition, few of the dendrites of rod-dominant ON type bipolar cells (rod-ON-BCs), stained by PKCalpha, were labelled with Cx35/36 in the retinal sections. In isolated cell preparations, Cx35/36 was clearly expressed on the dendrites of cone-dominant ON type bipolar cells (cone-ON-BCs), but the expression was much less on rod-ON-BCs. Moreover, Cx35/36 puncta were found in the dendrites of isolated horizontal cells (labelled by GAD 65/67) driven by cones, including H1 and H2 cells, but not in those of cells driven by rods (H4 cells). At the ultrastructural level, reaction product was found in H1 and H2 cell dendrites invaginating cone terminals, but not in H4 cell dendrites invaginating rod terminals. Moreover, dendrites of cone-ON-BCs, were also labebed. These results suggest that Cx35/36 could be specifically involved in modulation of the cone signal pathway in the outer retina of carp. PMID- 19778582 TI - Effect of resiniferatoxin on glutamatergic spontaneous excitatory synaptic transmission in substantia gelatinosa neurons of the adult rat spinal cord. AB - The transient receptor potential (TRP) vanilloid type 1 (TRPV1) agonist, capsaicin, enhances glutamatergic spontaneous excitatory synaptic transmission in CNS neurons. Resiniferatoxin (RTX) has a much higher affinity for TRPV1 than capsaicin, but its ability to modulate excitatory transmission is unclear. We examined the effect of RTX on excitatory transmission using the whole-cell patch clamp technique in substantia gelatinosa (SG) neurons of adult rat spinal cord slices. Bath-applied RTX dose-dependently increased the frequency, but not the amplitude, of spontaneous excitatory postsynaptic current (sEPSC), independent of its application time. In about a half of the neurons tested, this effect was accompanied by an inward current at -70 mV that was sensitive to glutamate receptor antagonists. Repeated application of RTX did not affect excitatory transmission. RTX was more potent than capsaicin but showed similar efficacy. RTX activity could be blocked by capsazepine or SB-366791, a TRPV1 antagonist, but not tetrodotoxin, a Na(+)-channel blocker, and could be inhibited by pretreatment with capsaicin but not the TRPA1 agonist, allyl isothiocyanate. RTX enhances the spontaneous release of L-glutamate from nerve terminals with similar efficacy as capsaicin and produces a membrane depolarization by activating TRPV1 in the SG, with fast desensitization and slow recovery from desensitization. These results indicate a mechanism by which RTX can modulate excitatory transmission in SG neurons to regulate nociceptive transmission. PMID- 19778583 TI - The effects of antipsychotic drugs administration on 5-HT1A receptor expression in the limbic system of the rat brain. AB - Increasing evidence suggests that 5-HT1A receptors are involved in the pathophysiology and treatment of schizophrenia. This paper investigated 5-HT1A receptor mRNA expression and binding density in female rats treated with aripiprazole (2.25 mg/kg/day), olanzapine (1.5 mg/kg/day), haloperidol (0.3 mg/kg/day) or vehicle (control) orally three times/day for 1 or 12 weeks. Animals were sacrificed 48 h after the last administration. Aripiprazole significantly increased 5-HT1A receptor binding density by 33% in the CA1 region of the hippocampus and by 21% in the medial posterodorsal nuclei of posterior amygdala (MeP) compared to the control group after 1 week of treatment. Olanzapine significantly decreased 5-HT1A receptor binding density by 17-22% in Layers I-IV of the cingulate cortex after 1 week of treatment. Neither of these antipsychotic drugs affected 5-HT1A receptor binding density after 12 weeks drug treatment. As expected, haloperidol treatment did not have any significant effect on 5-HT1A binding density after 1 or 12 weeks of treatment. 5-HT1A receptor mRNA expression was not altered by antipsychotic treatment in any brain region. The results indicate that aripiprazole and olanzapine have differential effects on 5-HT1A receptor expression, which may contribute to their distinct profiles in improving negative symptoms and cognitive deficits in schizophrenia. Aripiprazole and olanzapine may produce adaptation and desensitization of 5-HT1A receptor expression after long term treatment. PMID- 19778584 TI - Variations in ventral root axon morphology and locomotor behavior components across different inbred strains of mice. AB - Locomotion is a complex behavior affected by many different brain- and spinal cord systems, as well as by variations in the peripheral nervous system. Recently, we found increased gene expression for EphA4, a gene intricately involved in motor neuron development, between high-active parental strain C57BL/6J and the low-active chromosome substitution strain 1 (CSS1). CSS1 mice carry chromosome 1 from A/J mice in a C57BL/6J genetic background, allowing localization of quantitative trait loci (QTL) on chromosome 1. To find out whether differences in motor neuron anatomy, possibly related to the changes in EphA4 expression, are involved in the motor activity differences observed in these strains, motor performance in various behavioral paradigms and anatomical differences in the ventral roots were investigated. To correlate the behavioral profiles to the spinal motor neuron morphology, not only CSS1 and its parental strains C57BL/6J (host) and A/J (donor) were examined, but also a set of other mouse inbred strains (AKR/J, 129x1/SvJ and DBA/2J). Significant differences were found between inbred strains on home cage motor activity levels, the beam balance test, grip test performance, and on alternating versus synchronous hind limb movement (hind limb hopping). Also, considerable differences were found in spinal motor neuron morphology, with A/J and CSS1 showing smaller, possibly less developed, motor neuron axons compared to all other inbred strains. For CSS1 and C57BL/6J, only genetically different for chromosome 1, a correlation was found between motor activity levels, synchronous hind limb movement and neuro anatomical differences in spinal motor neurons. Inclusion of the other inbred strains, however, did not show this direct correlation. These data verifies the complex nature of the mammalian motor system that may be further dissected using genetic mapping populations derived from these inbred strains. PMID- 19778586 TI - The striatum beyond reward: caudate responds intensely to unpleasant pictures. AB - The involvement of striatum in affective processes has been consistently reported in recent years. However, studies within this field have mainly focused on positive affect, revealing the involvement of striatum in reward situations. The present research aimed to explore the involvement of striatum in negative affect through fMRI. To that aim, participants (n=18) were presented with negative, positive and neutral pictures while they performed an indirect task, a strategy repeatedly recommended to avoid cognitive interferences. Positive and negative stimuli did not differ in their arousal levels, as assessed by participants themselves. Analyses of variance showed that caudate nucleus was sensitive to the emotional content of stimulation, negative pictures eliciting greater caudate responses than positive and neutral. Regression analyses indicated that both valence and arousal content of visual stimuli synergically contributed to explain the activation of caudate, whose strong response to negative pictures supports models proposing striatum as a key element in withdrawal situations. PMID- 19778585 TI - Brain derived neurotrophic factor and neurotrophic factor 3 modulate neurotransmitter receptor expressions on developing spiral ganglion neurons. AB - Cochlear spiral ganglion neurons (SGN) provide the only pathway for transmitting sound evoked activity from the hair cells to the central auditory system. Neurotrophic factor 3 (NT-3) and brain derived neurotrophic factor (BDNF) released from hair cells and supporting cells exert a profound effect on SGN survival and neural firing patterns; however, it is unclear what the effects NT-3 and BDNF have on the type of neurotransmitter receptors expressed on SGN. To address this question, the whole-cell patch clamp recording technique was used to determine what effect NT-3 and BDNF had on the function and expression of glutamate, GABA and glycine receptors (GlyR) on SGN of cochlea from postnatal C57 mouse. Receptor currents induced by the agonist of each receptor were recorded from SGN cultured with or without BDNF or NT-3. NT-3 and BDNF exerted different effects. NT-3, and to a lesser extent BDNF, enhanced the expression of GABA receptors and had comparatively little effect on glutamate receptors. Absence of BDNF and NT-3 resulted in the emergence of glycine-induced currents; however, GlyR currents were absent from the short term cultured SGN. In contrast, NT-3 and BDNF suppressed GlyR expression on SGN. These results indicate that NT-3 and BDNF exert a profound effect on the types of neurotransmitter receptors expressed on postnatal SGN, results that may have important implications for neural development and plasticity. PMID- 19778587 TI - 5-Lipoxygenase and epigenetic DNA methylation in aging cultures of cerebellar granule cells. AB - 5-Lipoxygenase (5-Lox), an enzyme involved in the metabolism of arachidonic acid participates in the modulation of the proliferation and differentiation of neural stem cells and cerebellar granule cell (CGC) precursors. Since epigenetic mechanisms including DNA methylation regulate 5-LOX expression and have been suggested as possible modulators of stem cell differentiation and aging, using primary cultures of mouse CGC (1, 5, 10, 14, 30 days in vitro; DIV), we studied DNA methylation patterns of the 5-LOX promoter and 5-LOX mRNA levels. We also measured the mRNA and protein content of the DNA methyltransferases DNMT1 and DNMT3a. 5-LOX, DNMT1, and DNMT3a mRNA levels were measured by real-time PCR. We observed that 5-LOX expression and the expression of maintenance DNMT1 is maximal at 1 DIV (proliferating neuronal precursors), whereas the expression of the de novo DNA methyltransferase DNMT3a mRNA increased in aging cultures. We analyzed the methylation status of the 5-LOX promoter using the methylation-sensitive restriction endonucleases AciI, BstUI, HpaII, and HinP1I, which digest unmethylated CpGs while leaving methylated CpGs intact. The 5-LOX DNA methylation increased with the age of the cells. Taken together, our data show that as cultured CGC mature and age in vitro, a decrease in 5-LOX mRNA content is accompanied by an increase in the methylation of the gene DNA. In addition, an increase in DNMT3a but not DNMT1 expression accompanies an increase of 5-LOX methylation during in vitro maturation. PMID- 19778588 TI - Augmentation in gap junction-mediated cell coupling in dorsal root ganglia following sciatic nerve neuritis in the mouse. AB - Recent findings highlight the participation of central glial cells in chronic pain, but less is known of a comparable role for satellite glial cells (SGCs), in dorsal root ganglia (DRG). Our previous work showed that sciatic nerve axotomy augmented SGC coupling by gap junctions. The aim of the present research was to find out whether similar changes occur in a mouse inflammation model. Sciatic nerve neuritis was induced by complete Freund's adjuvant (CFA), and isolated ganglia were examined 1 week later. Cell coupling was monitored by intracellular injection of the fluorescent dye Lucifer Yellow. Changes in gap junctions were assessed quantitatively by electron microscopy. Withdrawal threshold in the foot on the side of the inflamed nerve decreased from an average of 3.9 g in control to 0.94 g using Von Frey hairs (P<0.05). In CFA-treated animals dye coupling incidence between SGCs belonging to different glial envelopes increased from 6.9% in controls to 22.5% (P<0.05). Whereas in controls there was no coupling between neurons or between neurons and SGCs, after CFA application the incidence of neuron-neuron and neuron-SGC coupling was 8%. Electron microscopy showed formation of bridges between SGC sheaths surrounding different neurons, which were completely absent in controls. The mean number of gap junctions/100 microm(2) of surface of the section occupied by SGCs increased from 0.215 in controls to 0.709 (P<0.01) in CFA-treated mice. The size of individual gap junctions remained the same. This is the first evidence for ultrastructural changes in SGCs following inflammation. The results support the idea that SGCs are sensitive to a variety of peripheral nerve injuries. We propose that the observed changes may alter signal transmission in DRG and thus may contribute to chronic pain. PMID- 19778590 TI - Selective effects of neonatal handling on rat brain N-methyl-D-aspartate receptors. AB - Neonatal handling, an experimental model of early life experiences, is known to affect the hypothalamic-pituitary-adrenal axis function thus increasing adaptability, coping with stress, cognitive abilities and in general brain plasticity-related processes. A molecule that plays a most critical role in such processes is the N-methyl-D-aspartate (NMDA) receptor, a tetramer consisting of two obligatory, channel forming NR1 subunits and two regulatory subunits, usually a combination of NR2A and NR2B. Since the subunit composition of the NMDA receptor affects brain plasticity, in the present study we investigated the effect of neonatal handling on NR1, NR2A and NR2B mRNA levels using in situ hybridization, and on NR2B binding sites, using autoradiography of in vitro binding of [(3)H]-ifenprodil, in adult rat limbic brain areas. We found that neonatal handling specifically increased NR2B mRNA and binding sites, while it had no effect on the NR1 and NR2A subunits. More specifically, neonatally handled animals, both males and females, had higher NR2B mRNA and binding sites in the dorsal CA1 hippocampal area, as well as the prelimbic, the anterior cingulate and the somatosensory cortex, compared to the non-handled. Moreover NR2B binding sites were increased in the dorsal CA3 area of handled animals of both sexes. Furthermore, neonatal handling had a sexually dimorphic effect, increasing NR2B mRNA and binding sites in the central and medial amygdaloid nuclei only of the females. The neonatal handling-induced increase in the NR2B subunit of the NMDA receptor could underlie the higher brain plasticity, which neonatally handled animals exhibit. PMID- 19778589 TI - Bi-directional modulation of bed nucleus of stria terminalis neurons by 5-HT: molecular expression and functional properties of excitatory 5-HT receptor subtypes. AB - Activation of neurons in the anterolateral bed nucleus of the stria terminalis (BNST(ALG)) plays an important role in mediating the behavioral response to stressful and anxiogenic stimuli. Application of 5-HT elicits complex postsynaptic responses in BNST(ALG) neurons, which includes (1) membrane hyperpolarization (5-HT(Hyp)), (2) hyperpolarization followed by depolarization (5-HT(Hyp-Dep)), (3) depolarization (5-HT(Dep)) or (4) no response (5-HT(NR)). We have shown that the inhibitory response is mediated by activation of postsynaptic 5-HT(1A) receptors. Here, we used a combination of in vitro whole-cell patch clamp recording and single cell reverse transcriptase polymerase chain reaction (RT-PCR) to determine the pharmacological properties and molecular profile of 5 HT receptor subtypes mediating the excitatory response to 5-HT in BNST(ALG) neurons. We show that the depolarizing component of both the 5-HT(Hyp/Dep) and the 5-HT(Dep) response was mediated by activation of 5-HT(2A), 5-HT(2C) and/or 5 HT(7) receptors. Single cell RT-PCR data revealed that 5-HT(7) receptors (46%) and 5-HT(1A) receptors (41%) are the most prevalent receptor subtypes expressed in BNST(ALG) neurons. Moreover, 5-HT receptor subtypes are differentially expressed in type I-III BNST(ALG) neurons. Hence, 5-HT(2C) receptors are almost exclusively expressed by type III neurons, whereas 5-HT(7) receptors are expressed by type I and II neurons, but not type III neurons. Conversely, 5 HT(2A) receptors are found predominantly in type II neurons. Finally, bi directional modulation of individual neurons occurs only in type I and II neurons. Significantly the distribution of 5-HT receptor subtypes in BNST(ALG) neurons predicted the observed expression pattern of 5-HT responses determined pharmacologically. Together, these results suggest that 5-HT can differentially modulate the excitability of type I-III neurons, and further suggest that bi directional modulation of BNST(ALG) neurons occurs primarily through an interplay between 5-HT(1A) and 5-HT(7) receptors. Hence, modulation of 5-HT(7) receptor activity in the BNST(ALG) may offer a novel avenue for the design of anxiolytic medications. PMID- 19778591 TI - Vesicle recycling at ribbon synapses in the finely branched axon terminals of mouse retinal bipolar neurons. AB - In retinal bipolar neurons, synaptic ribbons mark the presence of exocytotic active zones in the synaptic terminal. It is unknown, however, where compensatory vesicle retrieval is localized in this cell type and by what mechanism(s) excess membrane is recaptured. To determine whether endocytosis is localized or diffuse in mouse bipolar neurons, we imaged FM4-64 to track vesicles in cells whose synaptic ribbons were tagged with a fluorescent peptide. In synaptic terminals, vesicle retrieval occurred at discrete sites that were spatially consistent over multiple stimuli, indicative of endocytotic "hot spots." Retrieval sites were spatially correlated with fluorescently labeled synaptic ribbons. Electron microscopy (EM) analysis of bipolar cell terminals after photoconversion of internalized FM dye revealed that almost all of the dye was contained within vesicles approximately 30 nm in diameter. Clathrin-coated vesicles were observed budding from the plasma membrane and within the cytosol, and application of dynasore, a dynamin inhibitor, arrested membrane retrieval just after the budding stage. We conclude that synaptic vesicles in the fine branches of mouse bipolar axon terminals are retrieved locally near active zones, at least in part via a clathrin-mediated pathway. PMID- 19778592 TI - A novel cyclic nucleotide-gated ion channel enriched in synaptic terminals of isotocin neurons in zebrafish brain and pituitary. AB - Cyclic nucleotide-gated (CNG) channels are nonselective cation channels opened by binding of intracellular cyclic GMP or cyclic AMP. CNG channels mediate sensory transduction in the rods and cones of the retina and in olfactory sensory neurons, but in addition, CNG channels are also expressed elsewhere in the CNS, where their physiological roles have not yet been well defined. Besides the CNG channel subtypes that mediate vision and olfaction, zebrafish has an additional subtype, CNGA5, which is expressed almost exclusively in the brain. We have generated CNGA5-specific monoclonal antibodies, which we use here to show that immunoreactivity for CNGA5 channels is highly enriched in synaptic terminals of a discrete set of neurons that project to a subregion of the pituitary, as well as diffusely in the brain and spinal cord. Double labeling with a variety of antibodies against pituitary hormones revealed that CNGA5 is located in the terminals of neuroendocrine cells that secrete the nonapeptide hormone/transmitter isotocin in the neurohypophysis, brain, and spinal cord. Furthermore, we show that CNGA5 channels expressed in Xenopus oocytes are highly permeable to Ca(2+), which suggests that the channels are capable of modulating isotocin release in the zebrafish brain and pituitary. Isotocin is the teleost homolog of the mammalian hormone oxytocin, and like oxytocin, it regulates reproductive and social behavior. Therefore, the high calcium permeability of CNGA5 channels and their strategic location in isotocin-secreting synaptic terminals suggest that activation of CNGA5 channels in response to cyclic nucleotide signaling may have wide-ranging neuroendocrine and behavioral effects. PMID- 19778593 TI - C-type natriuretic peptide decreases hippocampal network oscillations in adult rats in vitro. AB - C-type natriuretic peptide (CNP) is an abundant neuropeptide in the human brain and the cerebrospinal fluid. CNP is involved in anxiogenesis and exerts its effects through the natriuretic peptide receptor B (NPR-B), which is expressed in the hippocampus. Hippocampal network oscillations of distinct frequency bands like gamma (gamma)-oscillations and sharp wave-ripple complexes (SPW-Rs) are likely involved in various cognitive functions such as the storage of information and memory consolidation in vivo. Here, we tested the effects of CNP on distinct network oscillations in horizontal slices of rat hippocampus. We found that CNP decreased the power of stimulus- and ACh/physostigmine-induced gamma oscillations. In contrast to stimulus-induced gamma-oscillations, CNP increased the frequency of ACh-induced, persistent network oscillations. Moreover, the peptide hormone reduced the incidence of LTP-associated SPW-Rs in area CA3 and CA1. Immunohistochemistry indicates that the peptide binds to receptors expressed on a subset of GAD 65-67-immunopositive cells in addition to binding to principal and other presumably non-neuronal cells. CNP caused a hyperpolarization of CA3 neurons increased their input resistance and decreased inhibitory conductance. Together, our data suggest that the effects of CNP on synchronized hippocampal network oscillations might involve effects on hippocampal interneurons. PMID- 19778595 TI - Quantification of tympanic membrane elasticity parameters from in situ point indentation measurements: validation and preliminary study. AB - Correct quantitative parameters to describe tympanic membrane elasticity are an important input for realistic modeling of middle ear mechanics. In the past, several attempts have been made to determine tympanic membrane elasticity from tensile experiments on cut-out strips. The strains and stresses in such experiments may be far out of the physiologically relevant range and the elasticity parameters are only partially determined. We developed a setup to determine tympanic membrane elasticity in situ, using a combination of point micro-indentation and Moire profilometry. The measuring method was tested on latex phantom models of the tympanic membrane, and our results show that the correct parameters can be determined. These parameters were calculated by finite element simulation of the indentation experiment and parameter optimization routines. When the apparatus was used for rabbit tympanic membranes, Moire profilometry showed that there is no measurable displacement of the manubrium during the small indentations. This result greatly simplifies boundary conditions, as we may regard both the annulus and the manubrium as fixed without having to rely on fixation interventions. The technique allows us to determine linear elastic material parameters of a tympanic membrane in situ. In this way our method takes into account the complex geometry of the membrane, and parameters are obtained in a physiologically relevant range of strain. PMID- 19778596 TI - Mutagenic and antimutagenic activities of aqueous and methanol extracts of Euphorbia hirta. AB - Euphorbia hirta (E. hirta) is a weed commonly found in tropical countries and has been used traditionally for asthma, bronchitis and conjunctivitis. However, one of the constituents in this plant, quercetin, was previously reported to be mutagenic. This work aimed to determine the level of quercetin in the aqueous and methanol plant extracts and to investigate the mutagenic effects of quercetin and the extracts in the Ames test utilising the mutant Salmonella typhimurium TA98 and TA100 strains. The antimutagenic activity of Euphorbia hirta aqueous and methanol extracts was also studied in Salmonella typhimurium TA98. HPLC analyses showed that quercetin and rutin, a glycosidic form of quercetin, were present in the acid-hydrolysed methanol extract and non-hydrolysed methanol extract respectively. The quercetin concentration was negligible in both non-hydrolysed and acid-hydrolysed aqueous extracts. The total phenolic contents in Euphorbia hirta were determined to be 268 and 93 mg gallic acid equivalent (GAE) per gram of aqueous and methanol extracts, respectively. Quercetin (25 microg/mL) was found to be strongly mutagenic in Salmonella typhimurium TA98 in the absence and presence of S-9 metabolic activation. However, both the aqueous and methanol extracts did not demonstrate any mutagenic properties when tested with Salmonella typhimurium TA98 and TA100 strains at concentrations up to 100 microg/mL in the absence and presence of S-9 metabolic activation. In the absence of S-9 metabolic activation, both the extracts were unable to inhibit the mutagenicity of the known mutagen, 2-nitrofluorene, in Salmonella typhimurium TA98. On the other hand, the aqueous extracts at 100 microg/mL and methanol extracts at 10 and 100 microg/mL exhibited strong antimutagenic activity against the mutagenicity of 2 aminoanthracene, a known mutagen, in the presence of S-9 metabolic activating enzymes. The results indicated that these extracts could modulate the xenobiotic metabolising enzymes in the liver at the higher concentrations. PMID- 19778594 TI - The vomeronasal organ is required for the male mouse medial amygdala response to chemical-communication signals, as assessed by immediate early gene expression. AB - Many species use chemical signals to convey information relevant to social and reproductive status between members of the same species (conspecific), but some chemical signals may also provide information to another species (heterospecific). Both of these types of complex chemical signals may be detected by the vomeronasal organ, which sends projections to the accessory olfactory bulb and on to the medial amygdala. Previous reports in hamster and mouse suggest that the medial amygdala sorts this complex chemosensory information categorically, according to its biological relevance (salience). In the present set of experiments, male mice having undergone vomeronasal removal surgery (VNX) or a sham-operation (SHAM) were exposed to conspecific (male and female mouse urine) or heterospecific (hamster vaginal fluid and worn cat collar) chemical stimuli. Similarly to our previous report with intact male mice [Samuelsen and Meredith (2009) Brain Res 1263:33-42], SHAM mice exhibit different immediate early gene (IEG) expression patterns in the medial amygdala dependent upon the biological relevance of the chemical stimuli. However, regardless of biological relevance, vomeronasal organ removal eliminates all responses in the medial amygdala to any of the chemical stimuli. Interestingly, VNX also disrupts the avoidance of (an unfamiliar) predator odor, worn cat collar. Here we show that the medial amygdala response to the tested chemical signals is dependent upon an intact vomeronasal organ. PMID- 19778597 TI - Characterisation of the anti-inflammatory potential of Vitex trifolia L. (Labiatae), a multipurpose plant of the Pacific traditional medicine. AB - AIM OF THE STUDY: Vitex trifolia L. (Labiatae) is a plant commonly employed against Ciguatera Fish Poisoning (CFP) in the Pacific region. Here, the anti inflammatory potential of an aqueous extract of Vitex trifolia leaves was evaluated by monitoring its effects on the modulation of cytokines, the mediators of inflammation, as well as on the expression profiles of inducible nitric oxide synthase (iNOS) which produces the free radical nitric oxide (NO). MATERIALS AND METHODS: We prepared an aqueous extract from Vitex trifolia leaves and evaluated its anti-inflammatory potency by monitoring its effect on the lipopolysaccharide (LPS)-induced cytokines and iNOS mRNA over-production in RAW 264.7 macrophages using quantitative Polymerase Chain Reaction (qPCR) and Enzyme-Linked Immunosorbent Assay (ELISA) methods. RESULTS: Aqueous extract of Vitex trifolia leaves showed significant dose- and time-dependent inhibitory activity on interleukin (IL)-1 beta, IL-6 and iNOS mRNA synthesis, but slight effect on tumor necrosis factor (TNF)-alpha, all of which are involved in the inflammatory response. Moreover, the plant extract seemed to induce the LPS-dependent IL-10 anti-inflammatory cytokine. These results were further confirmed by ELISA using specific antibodies to mouse IL-6, IL-10 and TNF-alpha. CONCLUSION: The anti inflammatory effects of Vitex trifolia could validate its utilization as a traditional remedy against CFP and emphasises its potential therapeutic value against other inflammatory diseases. Therefore, this plant is a promising candidate for further screening of its active compounds through activity-guided fractionation. PMID- 19778598 TI - Biotechnological strategies applied to the decontamination of soils polluted with heavy metals. AB - Soils have been submitted to several contaminants that vary in concentration and composition. Heavy metals can be widely spread and accumulated in those environments due to some inappropriate actions. In this present review some remediation techniques to remediate soils are presented, focusing on the use of plants that are capable of surviving in soils with heavy metals along with the function of some microorganisms in the restoration process. PMID- 19778599 TI - A single nucleotide mutation results in loss of enzymatic activity in the hyaluronate lyase gene of Streptococcus pyogenes. AB - Group A streptococci produce a variety of extracellular proteins, many of which are considered to be virulence factors. One of these is hyaluronate lyase (HylA), an enzyme capable of degrading the extracellular matrix of the host as well as the bacterial capsule. The current study examined three genotypes of hylA (full, truncated and deleted). Only isolates containing a full-length gene produced an enzymatically active hyaluronate lyase; however, truncation of the protein was not the reason for loss of activity. A single nucleotide substitution, resulting in an amino acid change at position 199 of the lyase was present in a highly conserved region of the protein in isolates not producing active enzyme. In serotypes 4 and 22, those producing active enzymes, this residue was an aspartic acid, in serotypes not showing hyaluronate lyase activity, it was a valine. Site directed mutagenesis indicated the loss of enzymatic activity of the hyaluronate lyase is in part determined by the mutation resulting in an amino acid residue change. This mutation results in an inactive form of the enzyme and is found in the more virulent serotypes of Streptococcus pyogenes, suggesting that hyaluronate lyase could interfere with the disease process, in essence being an anti-virulence factor. PMID- 19778600 TI - Protective effects of myricetin against ultraviolet-B-induced damage in human keratinocytes. AB - Myricetin is a flavonoid similar to quercetin, which is commonly found in natural foods such as berries, vegetables, teas, wine, and herbs. It is considered to be an antioxidant which is capable of quenching photoaging-causing free radicals within the skin. In this study, we investigated the mechanisms underlying protective effect of myricetin on ultraviolet-B (UVB)-induced damage to keratinocytes. We found that myricetin concentration-dependently attenuated UVB induced keratinocyte death as determined by a cell viability assay. Pretreatment with myricetin also reduced the UVB-induced malondialdehyde level. Moreover, UVB induced H(2)O(2) generation in keratinocytes was inhibited by myricetin according to flow cytometry, suggesting that myricetin can act as a free radical scavenger when keratinocytes experience photodamage. Furthermore, UVB-induced activation of c-jun-NH(2) terminal kinase (JNK) in keratinocytes was inhibited by myricetin. UVB-induced pre-G(1) phase arrest leading to apoptotic changes in keratinocytes was blocked by myricetin. Taken together, the protective mechanisms of keratinocyte by myricetin against UVB-induced photodamage occur by the inhibition of UVB-induced intracellular hydrogen peroxide production, lipid peroxidation and JNK activation. Therefore, myricetin is suitable for further development as an anti-aging agent for skin care. PMID- 19778601 TI - In vitro mammalian cytotoxicological study of PAMAM dendrimers - towards quantitative structure activity relationships. AB - Dendritic polymer nanoparticles such as polyamidoamine dendrimers (PAMAM) show exciting potential for biomedical applications. While the potential commercial applications of such dendrimers have received considerable attention, little is known about their possible adverse effects on both humans and the environment. In this study, the in vitro cytotoxicocity of full generation PAMAM dendrimers to two mammalian cell lines was investigated. Generations G4, G5 and G6 were chosen. Metabolic, lysosomal and mitochondrial activities were evaluated after 24h exposure. Long term toxicity was evaluated using the clonogenic assay. Particle size and zeta potential were measured in all media. In culture medium, the particle size was largely unchanged from that observed in phosphate buffer. The zeta potential changed significantly, however, from positive in deionized water to negative in culture medium. A linear correlation was found between the change in zeta potential of the dendrimers in media and their surface area measured in phosphate buffer. The interaction of the dendrimer nanoparticles with 5% FBS supplemented media was also studied using UV/visible spectroscopy. The data suggest significant interaction of nanoparticles with FBS and other media components which increased with dendrimer generation. The toxicity also correlated linearly with the zeta potential and notably the change in zeta potential in the media, further pointing towards indirect toxic mechanisms. A trend of generation dependent toxic response and interaction of the dendrimers with the cell culture media was observed which may lay the basis of structure activity relationships. PMID- 19778602 TI - Peptidomics and genomics analysis of novel antimicrobial peptides from the frog, Rana nigrovittata. AB - Much attention has been paid on amphibian peptides for their wide-ranging pharmacological properties, clinical potential, and gene-encoded origin. More than 300 antimicrobial peptides (AMPs) from amphibians have been studied. Peptidomics and genomics analysis combined with functional test including microorganism killing, histamine-releasing, and mast cell degranulation was used to investigate antimicrobial peptide diversity. Thirty-four novel AMPs from skin secretions of Rana nigrovittata were identified in current work, and they belong to 9 families, including 6 novel families. Other three families are classified into rugosin, gaegurin, and temporin family of amphibian AMP, respectively. These AMPs share highly conserved preproregions including signal peptides and spacer acidic peptides, while greatly diversified on mature peptides structures. In this work, peptidomics combined with genomics analysis was confirmed to be an effective way to identify amphibian AMPs, especially novel families. Some AMPs reported here will provide leading molecules for designing novel antimicrobial agents. PMID- 19778603 TI - A critical evaluation of cpYFP as a probe for superoxide. PMID- 19778604 TI - Pro-oxidant and proapoptotic effects of cholesterol oxidation products on human colonic epithelial cells: a potential mechanism of inflammatory bowel disease progression. AB - With the aim of investigating whether cholesterol oxidation products could contribute to the pathogenesis of the intestinal epithelial barrier dysfunction that occurs in human inflammatory bowel disease (IBD), differentiated versus undifferentiated CaCo-2 cells, an accepted model for human intestinal epithelial cells, were challenged with a dietary-representative mixture of oxysterols. Only differentiated colonic cells were susceptible to the proapoptotic action of the oxysterol mixture, checked both by enzymatic and by morphological methods, mainly because of a very low AKT phosphorylation pathway compared to the undifferentiated counterparts. Enhanced production of reactive oxygen species by a colonic NADPH oxidase hyperactivation seemed to represent the key event in oxysterol-induced up-regulation of the mitochondrial pathway of programmed death of differentiated CaCo-2 cells. These in vitro findings point to the pro-oxidant and cytotoxic potential of cholesterol oxidation products, of both dietary and endogenous origin, as an important mechanism of induction and/or worsening of the functional impairment of enteric mucosa that characterizes IBD. PMID- 19778605 TI - Regulated intramembrane proteolysis in the control of extracytoplasmic function sigma factors. AB - There is growing evidence that proteolytic degradation of membrane-spanning regulatory proteins such as anti-sigma factors is involved in a variety of important transmembrane signaling processes in bacteria. This mechanism of regulated intramembrane proteolysis (RIP) enables them to respond to extracellular signals and stresses. Here, we summarize current knowledge of RIP controlling extracytoplasmic function sigma factors. PMID- 19778606 TI - Proteases in bacterial pathogenesis. AB - Bacterial pathogens rely on proteolysis for protein quality control under adverse conditions experienced in the host, as well as for the timely degradation of central virulence regulators. We have focused on the contribution of the conserved Lon, Clp, HtrA and FtsH proteases to pathogenesis and have highlighted common biological processes for which their activities are important for virulence. PMID- 19778607 TI - Enantioselective retention of beta-blocking agents on human serum albumin and alpha 1-acid glycoprotein HPLC columns: relationships with different scales of lipophilicity. AB - The enantioselective retention of thirteen beta-blockers on HPLC stationary phases supporting human serum albumin (HSA) or alpha(1)-acid glycoprotein (AGP) was investigated. Eight beta-blockers were enantiomerically resolved on the AGP column whereas only four beta-blockers were resolved on the HSA column. Moreover, interactions between beta-blockers and AGP were much stronger than those with HSA. Retention values on both HSA and AGP for less retained enantiomers related well with various lipophilicity parameters, with the best relationships found with log k(w)(IAM) values obtained on HPLC stationary phases supporting phospholipids, i.e. the so-called Immobilized Artificial Membrane (IAM). Differently from n-octanol lipophilicity values, these values encode both lipophilic. Electrostatic intermolecular recognition forces which may be involved in the interaction between ionized analytes, such as beta-blockers, and proteins. However, their effectiveness to describe non-specific interactions with serum proteins for other classes of drugs needs further investigations. Analyses performed on AGP with eluent containing dimethyloctylamine (DMOA) as the displacer demonstrated that enantioselective sites bind to both (-)-forms and (+) forms, but the binding to (-)-forms is stronger. The enantiomer competition to bind to a same site may be relevant from a pharmacokinetic point of view when racemic mixtures are administered. Finally, in contrast to previously reported data in the literature, we found that AGP can bind enantioselectively not only the more lipophilic congeners but also the less lipophilic ones. PMID- 19778608 TI - Scratch resistance of plasticized hydroxypropyl methylcellulose (HPMC) films intended for tablet coatings. AB - Scratch resistance (SR) of externally plasticized hydroxypropyl methylcellulose (HPMC) films intended for tablet film coatings was studied. Special attention was paid to effects of short-term aging and ultraviolet (UV) treatment on the SR properties of these films. Controlled scratching of the films was performed with a Lloyd LRX materials tester featuring a spherical steel tip. Scratch surface profiles were measured by scanning white light interferometry (SWLI). The influence of using an external plasticizer on the SR was studied by comparing scratch dimensions in non-plasticized films to samples plasticized either with glycerol or polyethylene glycol (PEG) 400. The study demonstrates that both the amount and type of plasticizer influences the SR of aqueous HPMC films. It also shows that SWLI can quantitatively evaluate the effect of plasticizer content and aging on the SR of pharmaceutical films. This knowledge could be used to optimize pharmaceutical film coating formulations. PMID- 19778609 TI - Progress in aromatase research and identification of key future directions. AB - The IX International Aromatase Conference focused upon key developments in research related to the aromatase enzyme that had occurred since the last meeting. A session took place at the conclusion of conference discussing key areas for future research and issues currently facing researchers in the field. While significant progress on understanding structural elements of the enzyme and regulatory mechanisms of both the gene and protein provides an excellent basis for development of improved aromatase inhibitors and exploration of the important problem of aromatase inhibitor resistance, significant challenges remain. Increasing the speed with which findings are translated into clinical practice and finding an appropriate balance between basic and translational research were identified as areas which require further attention before the next meeting in 2010. PMID- 19778610 TI - Aromatase resistance mechanisms in model systems in vivo. AB - Aromatase inhibitors (AIs) have now been shown to be more effective than the anti estrogen (AE) tamoxifen and have few side effects in ER+ breast cancer patients. However, some patients may not respond and resistance to treatment may develop in others. To investigate the mechanisms involved in the loss of sensitivity of the tumors to AIs, we have studied athymic mice with tumors grown from human estrogen receptor (ER) positive breast cancer cells (MCF-7) stably transfected with aromatase (MCF-7Ca). Treatment with letrozole upregulated Her-2 after four weeks despite continued responsiveness of tumor growth to letrozole. Furthermore, the level of Her-2 protein in letrozole refractory tumors was found to be six fold higher than the control tumors. Cells isolated from these tumors also had increased levels of Her-2 along with lower expression of ERalpha and aromatase and apparent estradiol independent growth. When Her-2 was inhibited by trastuzumab (antibody against Her-2) ERalpha levels in the cells were restored indicating that Her-2 is a negative regulator of ERalpha. This interaction between Her-2 and ER suggests that inhibition of both the Her-2 and estrogen signaling pathways is required to prolong the responsiveness of the tumors to endocrine therapies. Thus, when treatment with trastuzumab and letrozole was combined, ER was restored and tumor growth markedly inhibited compared to treatment with either drug alone. These findings demonstrate that tumor cells under the stress of treatment can adapt and utilize alternate pathways. Thus, when letrozole treatment was stopped, tumor Her-2 levels declined and ER levels were restored to those of hormone sensitive tumors. A second course of letrozole treatment inhibited tumors growth to the same extent and for as long as the initial treatment. These and other strategies to restore aromatase and ERalpha resulting in sensitivity to hormone therapy could be of substantial benefit to patients who have acquired resistance to AIs. PMID- 19778611 TI - Effect of testosterone on E1S-sulfatase activity in non-malignant and cancerous breast cells in vitro. AB - INTRODUCTION: Testosterone (T) is a therapeutic option for women with hypoactive sexual desire disorder. T may have an impact on the mammary gland by altering local estrogen synthesis. The aim of the present study was to measure the effect of T on estrone-sulfate (E1S)-sulfatase (STS) expression, and activity using hormone-dependent BC cells with high and low aggressive potential (BT-474, MCF 7), and HBL-100 as a breast cell line of non-malignant origin. METHODS: Cells were incubated in RPMI 1640 medium containing 5% steroid-depleted fetal calf serum for 3d, and subsequently incubated in absence or presence of T alone, and combined with anastrozole (A) at 10(-8)M, and 10(-6)M at 37 degrees C for either 24h or directly in cell extracts ("direct"). STS protein expression was measured by dot-blot (immunoblotting), and STS, HSD17B1 and HSD17B2 mRNA levels by quantitative RT-PCR. STS activity was evaluated by incubating homogenized breast cells with [(3)H]-E1S and separating the products E1, and E2 by thin layer chromatography. RESULTS: Basal STS mRNA expression did not reveal group differences. However, STS mRNA was decreased by T+A in MCF-7 cells. 17HSDB1 expression was decreased by T+A in BT-474 cells, and 17HSDB2 expression was decreased by A and T+A treatment in MCF-7 cells. Basal and T treated STS protein expression was significantly higher in malignant compared to non-malignant breast cells. However, T did not induce significant intra-cell line differences. Similarly, basal and T treated STS activity was significantly higher in highly malignant compared to non-malignant breast cells. Regardless of cell lines, T slightly decreased STS activity after "direct" incubation, but led to an increase of local estrogen formation after 24h which was attenuated, and partly reversed by A, respectively. CONCLUSIONS: The more aggressive the breast cell line, the higher the local estrogen formation. The transition from normal to malignant seems to be accompanied by an altered autoregulation. The given local endocrine milieu seems to be essential for response to T. PMID- 19778612 TI - Antioxidant effects of mycophenolate mofetil in a murine pleurisy model. AB - Generation of oxidative stress induced by reactive oxygen species (ROS) and nitrogen (RNS) is believed to be a primary factor in the etiology of various inflammatory diseases. Although, the process of generation of oxygen species is a physiological event, in the inflammatory process this event is increased and produces large amounts of reactive species that leads to lipid peroxidation and to cell death. Mycophenolate mofetil (MMF) is a drug effective in protecting against chronic allograft failure and recently was introduced as an alternative for the treatment of various inflammatory diseases such as glomerulopathies, systemic lupus erythematosus and systemic vasculitis. Based on studies of the anti-inflammatory effect of MMF the aim of this study was to evaluate the effects of MMF on the inhibition of leukocytes and exudation, as well as myeloperoxidase and some antioxidant enzyme activities using carrageenan-induced pleurisy in mice. Our results showed that MMF significantly decreased leukocyte influx (P<0.01), exudation (P<0.01), superoxide dismutase (P<0.05), catalase (P<0.05), glutathione peroxidase (P<0.01), glutathione S-transferase (P<0.01) activities, levels of lipid peroxidation (P<0.05), as well as myeloperoxidase activity (P<0.05) on both phases (4h and 48h) of the inflammatory response induced by carrageenan into the mice pleural cavity. In conclusion, the anti-inflammatory effect of MMF may be, at least in part, via inhibition of ROS and/or NRS overgeneration, and consequently, attenuating the related oxidative stress. PMID- 19778613 TI - Immunohistochemical analysis of human brain suggests pathological synergism of Alzheimer's disease and diabetes mellitus. AB - It has been extensively reported that diabetes mellitus (DM) patients have a higher risk of developing Alzheimer's disease (AD), but a mechanistic connection between both pathologies has not been provided so far. Carbohydrate-derived advanced glycation endproducts (AGEs) have been implicated in the chronic complications of DM and have been reported to play an important role in the pathogenesis of AD. The earliest histopathological manifestation of AD is the apparition of extracellular aggregates of the amyloid beta peptide (Abeta). To investigate possible correlations between AGEs and Abeta aggregates with both pathologies, we have performed an immuhistochemical study in human post-mortem samples of AD, AD with diabetes (ADD), diabetic and nondemented controls. ADD brains showed increased number of Abeta dense plaques and receptor for AGEs (RAGE)-positive and Tau-positive cells, higher AGEs levels and major microglial activation, compared to AD brain. Our results indicate that ADD patients present a significant increase of cell damage through a RAGE-dependent mechanism, suggesting that AGEs may promote the generation of an oxidative stress vicious cycle, which can explain the severe progression of patients with both pathologies. PMID- 19778615 TI - GATEWAY technology and E. coli recombinant system produce a properly folded and functional recombinant allergen of the lipid transfer protein of apple (Mal d 3). AB - The lipid transfer protein of apple fruit, Mal d 3, has been produced as a soluble recombinant protein in transformed Escherichia coli cells using the GATEWAY technology. Circular dichroism spectra showing the protein essentially consists of alpha-helices indicate that the rMal d 3 is properly folded. The (1)H NMR spectra also indicates a correct fold for the recombinant allergen. The reactivity of rMal d 3 towards IgE from apple allergic patients and in vitro degranulation activity measured on transformed rat basophil leukemia cells expressing the human Fc epsilon RI alpha-subunit of rMal d 3 is similar to those of the native allergen purified from apple fruits. The expression of active rMal d 3 in E. coli is readily feasible and offers an interesting alternative to the production of recombinant allergen in the yeast Pichia pastoris. This expression in E. coli open the way to the modification of Mal d 3 by site-directed mutagenesis for immunotherapy purposes. PMID- 19778614 TI - CD36 gene deletion decreases oleoylethanolamide levels in small intestine of free feeding mice. AB - Oleoylethanolamide (OEA) is an endogenous lipid mediator that decreases food intake and enhances lipid catabolism. Dietary fat stimulates OEA mobilization in the proximal small intestine, through a mechanism that requires the participation of the membrane glycoprotein CD36 (fatty acid translocase, FAT). CD36 is highly expressed in small-intestinal enterocytes and is involved in fatty acid uptake and intracellular signaling. Here, we analyze the impact of genetic CD36 deletion on OEA production in various mouse tissues under free-feeding conditions and at different times of the light/dark cycle. CD36 ablation decreases OEA levels in jejunum and plasma during the dark phase, when mice consume most of their daily food. CD36 deletion is also associated with reduced OEA levels in kidney, but not in other tissues including duodenum, stomach, adrenals, white and brown fat, heart, liver, pancreas, skeletal muscle and brain. The results underscore the important role of CD36 in jejunal OEA production linked to feeding. PMID- 19778616 TI - Purification and molecular characterization of a novel diadenosine 5',5''' P(1),P(4)-tetraphosphate phosphorylase from Mycobacterium tuberculosis H37Rv. AB - In this study, Rv2613c, a protein that is encoded by the open reading frame Rv2613c in Mycobacterium tuberculosis H37Rv, was expressed, purified, and characterized for the first time. The amino acid sequence of Rv2613c contained a histidine triad (HIT) motif consisting of H-phi-H-phi-H-phi-phi, where phi is a hydrophobic amino acid. This motif has been reported to be the characteristic feature of several diadenosine 5',5'''-P(1),P(4)-tetraphosphate (Ap4A) hydrolases that catalyze Ap4A to adenosine 5'-triphosphate (ATP) and adenosine monophosphate (AMP) or 2 adenosine 5'-diphosphate (ADP). However, enzymatic activity analyses for Rv2613c revealed that Ap4A was converted to ATP and ADP, but not AMP, indicating that Rv2613c has Ap4A phosphorylase activity rather than Ap4A hydrolase activity. The Ap4A phosphorylase activity has been reported for proteins containing a characteristic H-X-H-X-Q-phi-phi motif. However, no such motif was found in Rv2613c. In addition, the amino acid sequence of Rv2613c was significantly shorter compared to other proteins with Ap4A phosphorylase activity, indicating that the primary structure of Rv2613c differs from those of previously reported Ap4A phosphorylases. Kinetic analysis revealed that the K(m) values for Ap4A and phosphate were 0.10 and 0.94mM, respectively. Some enzymatic properties of Rv2613c, such as optimum pH and temperature, and bivalent metal ion requirement, were similar to those of previously reported yeast Ap4A phosphorylases. Unlike yeast Ap4A phosphorylases, Rv2613c did not catalyze the reverse phosphorolysis reaction. Taken together, it is suggested that Rv2613c is a unique protein, which has Ap4A phosphorylase activity with an HIT motif. PMID- 19778617 TI - Relating BOLD fMRI and neural oscillations through convolution and optimal linear weighting. AB - The exact relationship between neural activity and BOLD fMRI is unknown. However, several recent findings, recorded invasively in both humans and monkeys, show a positive correlation of BOLD to high-frequency (30-150 Hz) oscillatory power changes and a negative correlation to low-frequency (8-30 Hz) power changes arising from cortical areas. In this study, we computed the time series correlation between BOLD GE-EPI fMRI at 7 T and neural activity measures from noninvasive MEG, using a time-frequency beam former for source localisation. A sinusoidal drifting grating was presented visually for 4 s followed by a 20 s rest period in both recording modalities. The MEG time series were convolved with either a measured or canonical haemodynamic response function (HRF) for comparison with the measured BOLD data, and the BOLD data were deconvolved with either a measured or a canonical HRF for comparison with the measured MEG. In the visual cortex, the higher frequencies (mid-gamma=52-75 Hz and high-gamma=75-98 Hz) were positively correlated with BOLD whilst the lower frequencies (alpha=8-12 Hz and beta=12-25 Hz) were negatively correlated with BOLD. Furthermore, regression including all frequency bands predicted BOLD better than stimulus timing alone, although no individual frequency band predicted BOLD as well as stimulus timing. For this paradigm, there was, in general, no difference between using the SPM canonical HRF compared to the subject-specific measured HRF. In conclusion, MEG replicates findings from invasive recordings with regard to time series correlations with BOLD data. Conversely, deconvolution of BOLD data provides a neural estimate which correlates well with measured neural effects as a function of neural oscillation frequency. PMID- 19778618 TI - High efficiency, low distortion 3D diffusion tensor imaging with variable density spiral fast spin echoes (3D DW VDS RARE). AB - We present an acquisition and reconstruction method designed to acquire high resolution 3D fast spin echo diffusion tensor images while mitigating the major sources of artifacts in DTI-field distortions, eddy currents and motion. The resulting images, being 3D, are of high SNR, and being fast spin echoes, exhibit greatly reduced field distortions. This sequence utilizes variable density spiral acquisition gradients, which allow for the implementation of a self-navigation scheme by which both eddy current and motion artifacts are removed. The result is that high resolution 3D DTI images are produced without the need for eddy current compensating gradients or B(0) field correction. In addition, a novel method for fast and accurate reconstruction of the non-Cartesian data is employed. Results are demonstrated in the brains of normal human volunteers. PMID- 19778619 TI - Estimating the transfer function from neuronal activity to BOLD using simultaneous EEG-fMRI. AB - Previous studies using combined electrical and hemodynamic measurements of brain activity, such as EEG and (BOLD) fMRI, have yielded discrepant results regarding the relationship between neuronal activity and the associated BOLD response. In particular, some studies suggest that this link, or transfer function, depends on the frequency content of neuronal activity, while others suggest that total neuronal power accounts for the changes in BOLD. Here we explored this dependency by comparing different frequency-dependent and -independent transfer functions, using simultaneous EEG-fMRI. Our results suggest that changes in BOLD are indeed associated with changes in the spectral profile of neuronal activity and that these changes do not arise from one specific spectral band. Instead they result from the dynamics of the various frequency components together, in particular, from the relative power between high and low frequencies. Understanding the nature of the link between neuronal activity and BOLD plays a crucial role in improving the interpretability of BOLD images as well as on the design of more robust and realistic models for the integration of EEG and fMRI. PMID- 19778620 TI - Verification of fetal brain responses by coregistration of fetal ultrasound and fetal magnetoencephalography data. AB - Fetal magnetoencephalography (fMEG) is used to study neurological functions of the developing fetus by measuring magnetic signals generated by electrical sources within the fetal brain. For this aim either auditory or visual stimuli are presented and evoked brain activity or spontaneous activity is measured at the sensor level. However a limiting factor of this approach is the low signal to noise ratio (SNR) of recorded signals. To overcome this limitation, advanced signal processing techniques such as spatial filters (e.g., beamformer) can be used to increase SNR. One crucial aspect of this technique is the forward model and, in general, a simple spherical head model is used. This head model is an integral part of a model search approach to analyze the data due to the lack of exact knowledge about the location of the fetal head. In the present report we overcome this limitation by a coregistration of volumetric ultrasound images with fMEG data. In a first step we validated the ultrasound to fMEG coregistration with a phantom and were able to show that the coregistration error is below 2 cm. In the second step we compared the results gained by the model search approach to the exact location of the fetal head determined on pregnant mothers by ultrasound. The results of this study clearly show that the results of the model search approach are in accordance with the location of the fetal head. PMID- 19778622 TI - The long way to diversity--phylogeny and evolution of the Heterobranchia (Mollusca: Gastropoda). AB - Heterobranchia are one of the most species rich groups within Gastropoda, with poorly resolved phylogenetic relationships especially in basal taxa. In order to resolve phylogenetic relationships within the Heterobranchia, we pursued a molecular systematic approach by sequencing and analysing a variety of genetic markers (including nuclear 28S rDNA+18S rDNA and mitochondrial 16S rDNA+COI sequences). Maximum likelihood as well as Bayesian inference methods were used for phylogenetic reconstruction. Moreover, data quality was estimated for the purpose of proving the plausibility of the novel phylogenetic hypothesis using a variety of statistical tests as well as network analyses. Finally, a case study was conducted in order to estimate divergence ages using a "relaxed" molecular clock approach with fossils as minimum age constraints. All phylogenetic analyses revealed the Heterobranchia as monophyletic. Within the Heterobranchia, several well supported clades could be resolved. However, the traditional classification based on morphological data could not be confirmed due to paraphyletic Euthyneura as well as paraphyletic Pulmonata and polyphyletic Opisthobranchia. The estimation of data quality yielded a high degree of substitution saturation in many of the nucleotide positions while the Relative-Rate-Test revealed the highest evolution rates within the "Lower Heterobranchia". Although the dataset shows much conflict, many of the proposed hypotheses are supported by splits of the network analysis. The molecular clock approach was able to confirm some evolutionary hypotheses based on fossils such as the late occurrence of Pulmonata and Stylommatophora, respectively, during the Mesozoic. However, large 95% highest posterior density (HPD) intervals at some of the nodes made a precise dating of these nodes difficult. This molecular phylogenetic investigation provides the most comprehensive molecular study of relationships within the Heterobranchia to date. Due to the outstanding taxon sampling of the "Lower Heterobranchia", which have been poorly represented in earlier morphological and molecular studies, substantial insights into the evolution and phylogeny of this enigmatic taxon have been gained. PMID- 19778621 TI - The folding fingerprint of visual cortex reveals the timing of human V1 and V2. AB - Primate neocortex contains over 30 visual areas. Recent techniques such as functional magnetic resonance imaging (fMRI) have successfully identified many of these areas in the human brain, but have been of limited value for revealing the temporal dynamics between visual areas. The electroencephalogram (EEG) provides information with high temporal precision, but has had limited success separating out the signals from individual neighboring cortical areas. Consequently, controversies exist over the temporal dynamics across cortical areas. In order to address this problem we developed a new method to identify the sources of the EEG. An individual's unique cortical pattern of sulci and gyri along with a visual area's functional retinotopic layout provides a folding fingerprint that predicts specific scalp topographies for stimuli presented in different parts of the visual field. Using this folding fingerprint with a 96 or 192 location stimulus severely constrains the solution space making it relatively easy to extract the temporal response of multiple visual areas to multiple stimulus locations. The large number of stimuli also provides a means to validate the waveforms by comparing across stimulus sets, an important feature not present in most EEG source identification procedures. Using this method our data reveal that both V1 and V2 waveforms have similar onset latencies, and their temporal dynamics provide new information regarding the response latencies of these areas in humans. Our method enables the previously unattainable separation of EEG responses from neighboring brain areas. While we applied the method to the first two cortical visual areas, V1 and V2, this method is also applicable to somatosensory areas that have defined mappings. This method provides a means to study the rapid information flow in the human brain to reveal top-down and bottom up cognitive processes. PMID- 19778623 TI - Fecal bacteriotherapy for recurrent Clostridium difficile infection. AB - Clostridium difficile infection (CDI) has emerged as a major complication associated with the use of systemic antimicrobial agents. Broad-spectrum antimicrobial agents disrupt the ecological bacterial balance in the colon and create an opportunity for C. difficile overgrowth with attendant production of toxins and clinical symptoms of colitis. Recommended therapies for CDI include oral administration of metronidazole or vancomycin for 10-14 days. However, 5% to 35% of patients experience infection relapse after completion of treatment. Recently, patients who failed to resolve their infection with conventional therapies and went on to develop chronic relapsing CDI were successfully treated with fecal bacteriotherapy. Stool obtained from a healthy individual was instilled from either end of the GI tract. Although the published experience with fecal bacteriotherapy is still limited, the published treatment results for 100 patients have demonstrated an average success-rate close to 90%. Fecal bacteriotherapy is a low tech procedure which is easy to perform, and breaks the cycles of repeated antibiotic use, which in turn reduces the risk of antibiotic associated resistance and adds potential cost savings when compared to repeated antibiotic administration and hospitalizations. PMID- 19778624 TI - Varied prevalence of Clostridium difficile in an integrated swine operation. AB - The objectives of this study were to compare the prevalence of Clostridium difficile (Cd) among different age and production groups of swine in a vertically integrated swine operation in Texas in 2006 and to compare our isolates to other animal and human isolates. Results are based on 131 Cd isolates from 1008 swine fecal samples and pork trim samples (overall prevalence of 13%). The prevalence (number positive/number tested in production type) of Cd was different between the groups (P100 microm). In conclusion, the modulation of these biological factors by surface modification of titanium implants with low concentrations of HF using cathodic reduction may explain their improved osseointegration properties. PMID- 19778644 TI - Traumatic diaphragmatic hernia-our experience. AB - OBJECTIVE: To review our experience in the management of traumatic diaphragmatic hernia. MATERIALS AND METHODS: The records of all patients operated for diaphragmatic hernia between January 1998 and October 2008 at S.D.S Sanitorium and Rajiv Gandhi Institute of Chest Diseases, Bangalore, India were reviewed. Details of their clinical presentation, mode of diagnosis, operative findings and postoperative outcome were analysed. RESULTS: Twenty nine patients underwent surgery for traumatic diaphragmatic hernia. The cause of rupture was blunt trauma in 24(83%) patients and penetrating trauma in 5(17%) patients. In 21 (72%) patients the diagnosis was made within 24 hrs and in 8(28%) patients the diagnosis was made after 24 hrs. Thoracotomy was the most common surgical approach used in 20(69%) patients. Post operative morbidity was 24% and mortality was 13.8%. CONCLUSION: X-ray chest is still very useful in the diagnosis of diaphragmatic ruptures. Right sided ruptures are difficult to diagnose. Diaphragmatic hernia repair can be done through a thoracotomy with acceptable results in patients without concomitant intra abdominal injuries. PMID- 19778645 TI - Quantitative erythrocyte membrane proteome analysis with Blue-native/SDS PAGE. AB - The erythrocyte membrane plays a pivotal role in erythrocyte functioning. Many membrane protein aberrations are known that result in hemolytic anemia, however, the origin of numerous disorders is not known to date. To extend the current set of diagnostic tools, we used a novel proteome-wide approach to quantitatively analyze membrane proteins of healthy donor and patient erythrocytes. Blue-native PAGE has proven to be a powerful tool for separation of membrane proteins and their complexes, but has hitherto not been applied to erythrocyte membranes to find biomarkers. Using this technique, we detected almost 150 protein spots, from which more than 500 proteins could be identified by LC-MS/MS. Further, we successfully assessed the potential of using CyDye labeling to quantify the membrane proteins. Our final goal was to determine if this approach is suited to detect protein level changes in disordered erythrocyte membranes, and we could successfully confirm that erythrocyte spectrin levels were dramatically decreased for a hemolytic anemia patient. This approach provides a new tool to detect potential biomarkers and can contribute to an improved understanding of the causes of erythrocyte membrane defects in patients suffering from hemolytic anemia. PMID- 19778646 TI - Candidate verification of iron-regulated Neisseria meningitidis proteins using isotopic versions of tandem mass tags (TMT) and single reaction monitoring. AB - Tandem Mass Tags (TMT) are suited to both global and targeted quantitation approaches of proteins and peptides. Different versions of these tags allow for the generation of both isobaric and isotopic sets of reagents sharing the same common structure. This feature allows for a straightforward transfer of data obtained during discovery studies into targeted investigations. In prior discovery studies, an isobaric set of these reagents was used to identify Neisseria meningitidis proteins expressed under iron-limitation. Here, we apply isotopic versions of those reagents in combination with single reaction monitoring to verify selected candidates found to be differentially regulated in these discovery studies, representing both well-known and novel iron-regulated proteins, such as the MtrCDE drug efflux pump. In this targeted approach (TMT SRM), the selectivity of SRM is maintained while allowing the incorporation of an internal reference standard into the experiment. By monitoring 184 transitions, TMT-SRM resulted in the quantitation of 33 peptides representing 12 proteins. The acquired data corroborated the results obtained during the discovery phase. Furthermore, these data obtained by MS-based quantitation of peptides were independently confirmed by western blotting results, an orthogonal approach based on quantitation at the protein level. PMID- 19778647 TI - Predicting driver drowsiness using vehicle measures: recent insights and future challenges. AB - INTRODUCTION: Driver drowsiness is a significant contributing factor to road crashes. One approach to tackling this issue is to develop technological countermeasures for detecting driver drowsiness, so that a driver can be warned before a crash occurs. METHOD: The goal of this review is to assess, given the current state of knowledge, whether vehicle measures can be used to reliably predict drowsiness in real time. RESULTS: Several behavioral experiments have shown that drowsiness can have a serious impact on driving performance in controlled, experimental settings. However, most of those studies have investigated simple functions of performance (such as standard deviation of lane position) and results are often reported as averages across drivers, and across time. CONCLUSIONS: Further research is necessary to examine more complex functions, as well as individual differences between drivers. IMPACT ON INDUSTRY: A successful countermeasure for predicting driver drowsiness will probably require the setting of multiple criteria, and the use of multiple measures. PMID- 19778648 TI - Work environment risk factors for injuries in wood processing. AB - PROBLEM: The reported injury rate for wood product manufacturing in Maine, 1987 2004, was almost twice the state-wide average for all jobs. METHOD: A case control study was conducted in wood processing plants to determine preventable risk factors for injury. A total of 157 cases with injuries reported to workers' compensation and 251 controls were interviewed. RESULTS: In multivariable analyses, variables associated with injury risk were high physical workload, machine-paced work or inability to take a break, lack of training, absence of a lockout/tagout program, low seniority, and male gender. Different subsets of these variables were significant when acute incidents and overexertions were analyzed separately and when all injuries were stratified by industry sub-sector. IMPACT ON INDUSTRY: Generalizability may be limited somewhat by non representative participation of workplaces and individuals. Nevertheless, these findings provide evidence that many workplace injuries occurring in wood processing could be prevented by application of ergonomics principles and improved work organization. PMID- 19778649 TI - Estimating the variance in before-after studies. AB - PROBLEM: To simplify the computation of the variance in before-after studies, it is generally assumed that the observed crash data for each entity (or observation) are Poisson distributed. Given the characteristics of this distribution, the observed value (x(i)) for each entity is implicitly made equal to its variance. However, the variance should be estimated using the conditional properties of this observed value (defined as a random variable), that is, f(x(i)/mu(i)), since the mean of the observed value is in fact unknown. METHOD: Parametric and non-parametric bootstrap methods were investigated to evaluate the conditional assumption using simulated and observed data. RESULTS: The results of this study show that observed data should not be used as a substitute for the variance, even if the entities are assumed to be Poisson distributed. Consequently, the estimated variance for the parameters under study in traditional before-after studies is likely to be underestimated. CONCLUSIONS: The proposed methods offer more accurate approaches for estimating the variance in before-after studies. PMID- 19778650 TI - The role of production and teamwork practices in construction safety: a cognitive model and an empirical case study. AB - PROBLEM: In construction, the challenge for researchers and practitioners is to develop work systems (production processes and teams) that can achieve high productivity and high safety at the same time. However, construction accident causation models ignore the role of work practices and teamwork. This study investigates the mechanisms by which production and teamwork practices affect the likelihood of accidents. METHOD: The paper synthesizes a new model for construction safety based on the cognitive perspective (Fuller's Task-Demand Capability Interface model, 2005) and then presents an exploratory case study. The case study investigates and compares the work practices of two residential framing crews: a 'High Reliability Crew' (HRC)--that is, a crew with exceptional productivity and safety over several years, and an average performing crew from the same company. RESULTS: The model explains how the production and teamwork practices generate the work situations that workers face (the task demands) and affect the workers ability to cope (capabilities). The case study indicates that the work practices of the HRC directly influence the task demands and match them with the applied capabilities. These practices were guided by the 'principle' of avoiding errors and rework and included work planning and preparation, work distribution, managing the production pressures, and quality and behavior monitoring. SUMMARY: The Task Demand-Capability model links construction research to a cognitive model of accident causation and provides a new way to conceptualize safety as an emergent property of the production practices and teamwork processes. The empirical evidence indicates that the crews' work practices and team processes strongly affect the task demands, the applied capabilities, and the match between demands and capabilities. IMPACT ON INDUSTRY: The proposed model and the exploratory case study will guide further discovery of work practices and teamwork processes that can increase both productivity and safety in construction operations. Such understanding will enable training of construction foremen and crews in these practices to systematically develop high reliability crews. PMID- 19778651 TI - Effects of safety climate on safety norm violations: exploring the mediating role of attitudinal ambivalence toward personal protective equipment. AB - PROBLEM: Research on the role of organizational and psychosocial factors in influencing risk behaviors and the likelihood of injury at work showed that safety climate also has great impact on workers' behavior. However, the mechanisms through which this impact operates are still partially unclear. METHOD: In order to explore the role that attitudinal ambivalence toward wearing PPE might play in mediating the impact of safety climate on safety norm violations, a questionnaire was administered to 345 Italian workers. RESULTS: Three dimensions of safety climate (i.e., company safety concern, senior managers' safety concern, supervisors' attitudes towards safety) were found to be positively associated with the individual ambivalence level, whereas the fourth one (i.e., work pressure) was negatively correlated with it. In turn, low levels of ambivalence were associated with a lower tendency to break the safety norms, even though the perception of a good safety climate also maintained a direct effect on unsafe behaviors. IMPACT ON INDUSTRY: Designers of training program for the prevention of work related injuries must pay great attention to the psycho social factors (such as the effects of the safety climate perception by employees on their attitudes and behaviors), and include specific contents into the prevention programs in order to improve workers compliance with safety norms. PMID- 19778652 TI - The Long Beach/Fort Lauderdale relative risk study. AB - PROBLEM: The role of alcohol as a major factor in traffic crash causation has been firmly established. However, controversy remains as to the precise shape of the relative risk function and the BAC at which crash risk begins to increase. METHODS: This study used a case-control design in two locations: Long Beach, California, and Fort Lauderdale, Florida. Data were collected on 2,871 crashes of all severities and a matched control group of drivers selected from the same time, location, and direction of travel as the crash drivers. Of the 14,985 sample drivers, 81.3% of the crash drivers and 97.9% of the controls provided a valid BAC specimen. RESULTS: When adjusted for covariates and nonparticipation bias, increases in relative risk were observed at BACs of .04-.05, and the elevations in risk became very pronounced when BACs exceeded .10. DISCUSSION: The results provide strong support for .08 per se laws and for state policies that increase sanctions for BACs in excess of .15. IMPACT ON INDUSTRY: This study provides further precision on the deleterious effects of alcohol on driving and, by implication, on other complex tasks. PMID- 19778653 TI - Falls from height during the floor slab formwork of buildings: current situation in Spain. AB - PROBLEM: One of the phases with the highest risk of falls from a height in the construction of a building is during the floor slab formwork stage. This paper analyzes this particular risk, as well as the most frequently used fall protection systems. METHOD: A survey was carried out to define the current situation in Spain with regard to falls from a height during floor slab formwork and the fall-protection systems used to prevent such a risk. RESULTS: The results of the survey clarified the current situation in Spain with regard to this risk, and made it clear that there is considerable risk of falling from a height during the floor slab formwork stage. DISCUSSION: All the safety systems analyzed presented a series of weak points that should be studied in detail before they can be used on building sites. IMPACT ON INDUSTRY: The risk of falling associated with floor slab formwork and the most frequently used protection systems are analyzed. As no research had been carried out to date on this type of risk, we consider the research presented in this article to be a pioneer in the field. PMID- 19778654 TI - Self-assessed driver competence among novice drivers--a comparison of driving test candidate assessments and examiner assessments in a Dutch and Finnish sample. AB - PROBLEM: This study examined novice drivers' overconfidence by comparing their self-assessed driver competence with the assessments made by driving examiners. METHOD: A Finnish (n=2,739) and a Dutch sample (n=239) of drivers license candidates assessed their driver competence in six areas and took the driving test. RESULT AND DISCUSSION: In contrast to previous studies where drivers have assessed their skill in comparison to the average driver, a smaller proportion overestimated and a larger proportion made realistic self-assessments of their driver competence in the present study, where self-assessments were compared with examiner assessments. Between 40% and 50% of the candidates in both samples made realistic assessments and 30% to 40% overestimated their competence. The proportion of overestimation was greater in the Dutch than in the Finnish sample, which might be explained by greater possibilities for practicing self-assessment in the Finnish driver education system. Similar to other self-assessment studies that indicate that incompetence is related to overestimation, a larger proportion of candidates that failed the test overestimated their skill compared to those who passed. In contrast to other studies, males did not overestimate their skills more than females, and younger driver candidates were not more overconfident than older drivers. IMPACT ON TRAFFIC SAFETY: Although a great proportion of the candidates made a realistic assessment of their own driver competence, overestimation is still a problem that needs to be dealt with. To improve the accuracy of novice drivers' self-assessment, methods for self-assessment training should be developed and implemented in the driver licensing process. PMID- 19778655 TI - Analysis of teenage seat belt use: from the 2007 Missouri high school seat belt survey. AB - INTRODUCTION: This study analyzed high school teenagers' seat belt use based on the observational surveys of more than 15,000 teenagers at 150 schools and was conducted in the state of Missouri, U.S., in 2007. Since fatal car accidents involving high school teenagers are disproportionately high, and increased seat belt use saves lives in what would otherwise be fatal accidents, it is imperative that teenagers' safety be protected through an increase in use. METHOD: This study investigated various personal, vehicle, school, and locational factors associated with high school teenagers' seat belt use. Descriptive and binary logit analyses were conducted. RESULTS: We find that low seat belt use is associated with males, African-Americans, pick-up trucks, accompanying occupants, weekends, inclement driving conditions, small size of school, lower socio economic status, and rural county school locations. Several factors influencing teenage seat belt use are quite similar to those affecting adult seat belt use, in addition to certain risky behaviors to which teenagers are prone, supporting the importance of early intervention. CONCLUSIONS: Programs in schools, the adoption of primary seat belt laws, GDL provisions requiring seat belt use, targeted education and campaign efforts for African-American teenagers, seat belt reminder systems, and more resources for rural counties on safety education and enforcement may help increase seat belt use in this vulnerable age group, though other research questions are implied. PMID- 19778656 TI - Using conditional inference forests to identify the factors affecting crash severity on arterial corridors. AB - INTRODUCTION: The study aims at identifying traffic/highway design/driver-vehicle information significantly related with fatal/severe crashes on urban arterials for different crash types. Since the data used in this study are observational (i.e., collected outside the purview of a designed experiment), an information discovery approach is adopted for this study. METHOD: Random Forests, which are ensembles of individual trees grown by CART (Classification and Regression Tree) algorithm, are applied in numerous applications for this purpose. Specifically, conditional inference forests have been implemented. In each tree of the conditional inference forest, splits are based on how good the association is. Chi-square test statistics are used to measure the association. Apart from identifying the variables that improve classification accuracy, the methodology also clearly identifies the variables that are neutral to accuracy, and also those that decrease it. RESULTS: The methodology is quite insightful in identifying the variables of interest in the database (e.g., alcohol/ drug use and higher posted speed limits contribute to severe crashes). Failure to use safety equipment by all passengers and presence of driver/passenger in the vulnerable age group (more than 55 years or less than 3 years) increased the severity of injuries given a crash had occurred. A new variable, 'element' has been used in this study, which assigns crashes to segments, intersections, or access points based on the information from site location, traffic control, and presence of signals. IMPACT: The authors were able to identify roadway locations where severe crashes tend to occur. For example, segments and access points were found to be riskier for single vehicle crashes. Higher skid resistance and k factor also contributed toward increased severity of injuries in crashes. PMID- 19778657 TI - Emergency department visits for alcohol-related unintentional traumatic injuries, United States, 2001. PMID- 19778658 TI - Acute knee dislocation: review of an elusive entity. AB - The knee consists of three articulations: the patellofemoral, the tibiofemoral, and the proximal tibiofibular joint. Any of these joints can dislocate. Dislocations are uncommon, tend to spontaneously reduce, and can be difficult to detect on clinical examination. There are, however, telltale imaging features and the radiologist may be the first to suggest the correct diagnosis. A timely diagnosis is important as some forms are associated with limb-threatening complications. Lateral patellofemoral dislocation, in the acute setting, is typically an injury of young athletes and usually spontaneously reduces at the time of trauma. In transient lateral dislocation, contusions may be seen in the inferomedial pole of the patella and the anterior lateral aspect of the nonarticular portion of the femur. The important magnetic resonance imaging findings include this characteristic contusion pattern and injury to the medial patellar soft-tissue restraints. These are frequently associated with osteochondral fractures, which may be an indication for surgery. Recurrent patellofemoral dislocations tend to be associated with abnormalities of bony and/or soft-tissue restraints. The important imaging considerations are the length of patellar tendon, the depth of trochlear groove, and the position of patella in relation to the trochlear groove. Tibiofemoral dislocations are rare and are usually associated with high-impact trauma. These are multi-ligamentous injuries, which most often involve both cruciate ligaments with either medial and/or lateral ligament tears. There is an associated risk of popliteal artery and peroneal nerve injury, even if reduced, at the time of presentation. Dislocations of the tibiofibular joint are also rare and are classified based on location of fibular head. The tibiofibular joint is lax in flexion, and thus, most dislocations tend to occur in the flexed knee position. Anterolateral dislocation is the most common, while posteromedial dislocation is frequently associated with peroneal nerve injury. The purpose of this article is to review the epidemiology of knee dislocations, important imaging findings, and the most common complications. PMID- 19778659 TI - Multidetector computed tomography findings of dense pulmonary emboli in oncologic patients. AB - Pulmonary embolism is a frequent condition for which multidetector computed tomography (MDCT) plays an important role in its detection. Occasionally, on MDCT studies, dense linear branching opacities may be found within the pulmonary vessels. They represent dense emboli within the pulmonary arteries (DEPA). These may occur in oncologic patients that undergo specific treatments or interventional procedures, such as cement embolus from vertebroplasty, catheter or coil migration after embolization procedures, radioactive seed embolus in patients treated with local brachytherapy for prostate, lung, or liver cancer, and also in chronic pulmonary embolism. Usually DEPA does not have any clinical significance but may be fatal when massive or when in patients with impaired cardiopulmonary function. Being familiar with their radiologic appearance and knowing about the good clinical outcome of these patients will avoid unnecessary imaging testing. In this article, we describe some examples of DEPA. Based on the MDCT imaging findings, these emboli have very few or no side effects on the underlying lung parenchyma. We would like to stress the need for using bone window values for identifying these emboli. We provide examples of dense linear nonvascular images (pulmonary calcification secondary to tuberculosis (TBC) or radiotherapy, calcified mucous plugs, lung sutures, etc) that may mimic DEPA. PMID- 19778660 TI - Computed tomographic appearances of hepatic vascular lesions. AB - Improvements in Imaging technology have revolutionized liver imaging and allowed the recognition of abnormalities arising from various architectural components such as vessels and biliary ducts of the liver. A spectrum of various hepatic vascular disorders as demonstrated by multidetector CT (MDCT) is presented in this review article. PMID- 19778661 TI - Value and limitations of existing scores for the assessment of cardiovascular risk: a review for clinicians. AB - Atherosclerotic cardiovascular diseases (CVDs) are the biggest causes of death worldwide. In most people, CVD is the product of a number of causal risk factors. Several seemingly modest risk factors may, in combination, result in a much higher risk than an impressively raised single factor. For this reason, risk estimation systems have been developed to assist clinicians to assess the effects of risk factor combinations in planning management strategies. In this article, the performances of the major risk estimation systems are reviewed. Most perform usably well in populations that are similar to the one used to derive the system, and in other populations if calibrated to allow for different CVD mortality rates and different risk factor distributions. The effect of adding "new" risk factors to age, sex, smoking, lipid status, and blood pressure is usually small, but may help to appropriately reclassify some of those patients who are close to a treatment threshold to a more correct "treat/do not treat" category. Risk estimation in the young and old needs more research. Quantification of the hoped for benefits of the multiple risk estimation approach in terms of improved outcomes is still needed. But, it is likely that the widespread use of such an approach will help to address the issues of both undertreatment and overtreatment. PMID- 19778662 TI - The role of biomarkers and genetics in peripheral arterial disease. AB - Men and women with lower extremity peripheral arterial disease (PAD) have higher levels of inflammatory biomarkers than those without PAD. Observational studies link higher levels of several inflammatory biomarkers, including C-reactive protein (CRP), interleukin-6, tumor necrosis factor-alpha, and soluble adhesion molecules, to 1 or more of the following outcomes in people with PAD: more severe PAD, greater lower extremity functional impairment, more adverse calf skeletal muscle characteristics, greater declines in the ankle brachial index, greater declines in lower extremity performance, and higher rates of cardiovascular morbidity and mortality. Higher levels of inflammatory biomarkers are also associated with poorer outcomes after lower extremity revascularization, including graft restenosis and mortality. Increasing levels of CRP are associated with increased mortality and faster functional decline among people with PAD. Statin therapies reduce cardiovascular event rates and may improve walking performance in men and women with PAD, perhaps in part because statins can reduce inflammation. However, no clinical trials have been performed to establish whether therapies that specifically block or lower inflammatory biomarkers improve outcomes in patients with PAD. Family studies show that heritability of PAD ranges from approximately 20% to 45% after adjusting for atherosclerotic risk factors. A genetic marker for PAD has the potential to identify individuals at increased risk for PAD and may also uncover proteins that can help determine mechanisms of development of lower extremity atherosclerosis. However, a genetic marker for PAD has not been identified. PMID- 19778663 TI - Paraoxonase variants relate to 10-year risk in coronary artery disease: impact of a high-density lipoprotein-bound antioxidant in secondary prevention. AB - OBJECTIVES: We investigated the effects of paraoxonase (PON)-1 variants on long term clinical outcome in patients with coronary artery disease (CAD). BACKGROUND: PON-1 is a potential therapeutic target to further reduce cardiovascular risk because it is a detoxifying esterase with antioxidant properties. The PON-1 knockout models result in higher susceptibility to atherosclerosis, and PON activity contributes to cardiovascular risk in humans. Human gene variants determine PON activity; however, the impact of these variants on recurrent cardiovascular events in vascular disease is as of yet unknown. METHODS: We conducted a 10-year follow-up study of 793 CAD patients in the REGRESS (REgression GRowth Evaluation Statin Study) trial cohort, using nationwide registries. Genotypes were obtained of 2 PON-1 isotypes (L55M, rs854560, and Q192R, rs662), which were previously associated with PON activity. Absolute and relative risks by genotype were estimated using Kaplan-Meier and proportional hazards analyses. RESULTS: Carriership of the PON-1 glutamine isotype at codon 192 and methionine at codon 55 was associated with a higher risk of death due to ischemic heart disease. Hazard ratios per allele copy were 1.71 (95% confidence interval: 1.0 to 2.8, p=0.03) for the glutamine isotype at codon 192 and 1.56 (95% confidence interval: 1.1 to 2.3, p=0.03) for methionine at codon 55. Both isotypes had previously been related to lower PON activity. No effect was observed on all-cause mortality. CONCLUSIONS: PON-1 gene variants influence the 10-year risk of fatal complications from CAD in male patients, despite no effect on all-cause mortality. These long-term findings confirm functional data on PON-1 activity, emphasize the relevance of this pathway in vascular disease, and enforce its putative role as a target to modify and estimate cardiovascular risk. PMID- 19778664 TI - Cardiovascular event risk: high-density lipoprotein and paraoxonase. PMID- 19778665 TI - Cardiovascular effect of bans on smoking in public places: a systematic review and meta-analysis. AB - OBJECTIVES: A systematic review and a meta-analysis were performed to determine the association between public smoking bans and risk for hospital admission for acute myocardial infarction (AMI). BACKGROUND: Secondhand smoke (SHS) is associated with a 30% increase in risk of AMI, which might be reduced by prohibiting smoking in work and public places. METHODS: PubMed, EMBASE, and Google Scholar databases plus bibliographies of relevant studies and reviews were searched for peer-reviewed original articles published from January 1, 2004, through April 30, 2009, using the search terms "smoking ban" and "heart" or "myocardial infarct." Investigators supplied additional data. All published peer reviewed original studies identified were included. Incidence rates of AMI per 100,000 person-years before and after implementation of the smoking bans and incidence rate ratios (IRRs) with 95% confidence intervals (CIs) were calculated. Random effects meta-analyses estimated the overall effect of the smoking bans. Funnel plot and meta-regression assessed heterogeneity among studies. RESULTS: Using 11 reports from 10 study locations, AMI risk decreased by 17% overall (IRR: 0.83, 95% CI: 0.75 to 0.92), with the greatest effect among younger individuals and nonsmokers. The IRR incrementally decreased 26% for each year of observation after ban implementation. CONCLUSIONS: Smoking bans in public places and workplaces are significantly associated with a reduction in AMI incidence, particularly if enforced over several years. PMID- 19778666 TI - Public smoking bans are good for the heart. PMID- 19778667 TI - Induced cardiovascular procedural costs and resource consumption patterns after coronary artery calcium screening: results from the EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) study. AB - OBJECTIVES: We prospectively evaluated procedural costs and resource consumption patterns in the EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) study after coronary calcium (CAC) measurements. BACKGROUND: Controversy surrounds expansion of cardiovascular disease (CVD) screening to include atherosclerosis imaging as the result of concern whether induced costs will outweigh any benefit. METHODS: Detailed risk factor and CAC measurements with 4-year follow-up for CVD death or myocardial infarction and procedures were performed. Costs were estimated with the use of Medicare reimbursement rates (discounted and inflation corrected). Cox survival analysis was used to estimate procedures and events. RESULTS: CAC scores varied widely but were skewed toward low scores with 56.7% of screened subjects having CAC scoresor=400. Noninvasive testing was infrequent and medical costs were low among subjects with low CAC scores, both rising progressively with increasing CAC scores (p<0.001), particularly in the 31 (2.2% of subjects) that had CAC scores>or=1,000. Similarly, invasive coronary angiography rose progressively with increasing scores (p<0.001) but occurred exclusively among subjects first undergoing noninvasive testing and overall, was performed in only 19.4% of subjects with CAC scores>or=1,000. CONCLUSIONS: CAC scanning is associated with a marked differential in downstream frequency of medical tests and costs, ranging from a very low frequency of testing and invasive procedures among a predominantly large percentage of subjects with low CAC scores, to selectively concentrated testing and procedures among a small number of subjects with CAC scores>400. Thus, CAC scanning appears to foster efficient selective testing patterns among asymptomatic individuals at risk for CVD. PMID- 19778668 TI - Selective use of coronary artery calcium screening: worth the cost? PMID- 19778669 TI - Cost effectiveness of enoxaparin in acute ST-segment elevation myocardial infarction: the ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction 25) study. AB - OBJECTIVES: We used a U.S. model of health care costs to examine the cost effectiveness of enoxaparin compared with unfractionated heparin (UFH) as adjunctive therapy for fibrinolysis in patients with ST-segment elevation myocardial infarction (STEMI). BACKGROUND: The ExTRACT-TIMI 25 (Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis In Myocardial Infarction 25) study, a large, randomized, multinational trial, demonstrated a reduction in death or nonfatal myocardial infarction when enoxaparin was used instead of UFH as adjunctive therapy for fibrinolysis in patients with STEMI. METHODS: We used patient-level clinical outcomes and resource use from the ExTRACT-TIMI 25 trial and estimates of life expectancy gains as a result of the prevention of the clinical events on the basis of the Framingham Heart Study. RESULTS: Index hospitalization costs trended lower by $126 in the enoxaparin group (95% confidence interval [CI]: -$295 to $49). Thirty day costs trended higher by $102 for enoxaparin (95% CI: $108 to $314). Patients receiving enoxaparin gained an average of 0.12 life-years relative to patients given UFH. Estimated total lifetime costs were $1,207 higher in the enoxaparin group (95% CI: $491 to $1,923). The incremental cost-effectiveness ratio of enoxaparin compared with UFH was $5,700 per life-year gained, with 99.9% of bootstrap-derived estimates <$50,000 per life-year gained. Using a probabilistic sensitivity analysis, there is a 90% probability that enoxaparin is cost effective for lifetime, provided that the willingness-to-pay value exceeds $50,000. CONCLUSIONS: Based on a U.S. model of health care economics, the strategy of using enoxaparin instead of UFH as adjunctive therapy for fibrinolysis in patients with STEMI is cost effective according to commonly used benchmarks. PMID- 19778671 TI - Registries and health care quality improvement. PMID- 19778670 TI - Quality of care for atrial fibrillation among patients hospitalized for heart failure. AB - OBJECTIVES: This study sought to examine quality of care and warfarin use at discharge in patients with atrial fibrillation (AF) and heart failure (HF). BACKGROUND: Atrial fibrillation is common in HF, and national guidelines recommend discharge on warfarin for stroke prophylaxis. However, the frequency and factors associated with the guideline adherence are poorly described. METHODS: We analyzed 72,534 HF admissions from January 2005 through March 2008 at 255 hospitals participating in the American Heart Association's Get With The Guidelines HF program. Multivariable logistic regression was used to identify independent factors associated with warfarin use at discharge. RESULTS: In this HF population, 20.5% (n=14,901) had AF on admission, whereas another 13.7% (n=9,918) had a prior history of AF but were in a regular rhythm at admission. Contraindications to warfarin therapy were documented in 9.2%. Among eligible HF patients without contraindications, the median prevalence of warfarin therapy at discharge was 64.9% (interquartile range 55.5 to 73.4) and did not improve during the 3.5 years of study. After adjustment, major factors associated with no warfarin use at discharge included increasing age, nonwhite race, anemia, and treatment in the south. Warfarin use also varied inversely with CHADS2 (congestive heart failure, hypertension, age>75, diabetes, and prior stroke or transient ischemic attack) risk (70.9% to 59.5% for CHADS2 score 1 to 6, p<0.0001). CONCLUSIONS: Guideline-recommended warfarin use in patients with AF and HF is less than optimal, has not improved over time, and varies significantly according to age, race, risk profile, region, and hospital site. PMID- 19778672 TI - Gastrointestinal bleeding in patients with acute coronary syndromes: incidence, predictors, and clinical implications: analysis from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. AB - OBJECTIVES: We assessed the incidence, predictors, and outcomes of gastrointestinal bleeding (GIB) in patients with acute coronary syndromes (ACS). BACKGROUND: GIB is a potential hemorrhagic complication in patients with ACS treated with antithrombotic and/or antiplatelet medications. The clinical outcomes associated with GIB in this setting have not been systematically studied. METHODS: In the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial, 13,819 patients with moderate- and high-risk ACS, enrolled at 450 centers in 17 countries between August 2003 and December 2005, were randomized to the open-label use of 1 of 3 antithrombin regimens (heparin plus a glycoprotein IIb/IIIa inhibitor, bivalirudin plus a glycoprotein IIb/IIIa inhibitor, or bivalirudin monotherapy). RESULTS: GIB within 30 days occurred in 178 patients (1.3%). Older age, baseline anemia, longer duration of study drug administration before angiogram, smoking, ST-segment deviation>or=1 mm, and diabetes were identified as independent predictors of GIB. On multivariable analysis, GIB was strongly associated with 30-day all-cause mortality (hazard ratio [HR]: 4.87 [interquartile range (IQR) 2.61 to 9.08], p<0.0001), cardiac mortality (HR: 5.35 [IQR 2.71 to 10.59], p<0.0001), and composite ischemia (HR: 1.94 [IQR 1.14 to 3.30], p=0.014), as well as with 1-year all-cause mortality (HR: 3.97 [IQR 2.64 to 5.99], p<0.0001), cardiac mortality (HR: 3.77 [IQR 2.14 to 6.63], p<0.0001), myocardial infarction (HR: 1.74 [IQR 1.01 to 3.02], p=0.047), and composite ischemia (HR: 1.90 [IQR 1.37 to 2.64], p=0.0001). Patients who experienced GIB had significantly higher rates of stent thrombosis compared with patients without GIB (5.8% vs. 2.4%, p=0.009). CONCLUSIONS: GIB is a serious condition in the scenario of ACS and is independently associated with mortality and ischemic complications. PMID- 19778673 TI - Optimal medical therapy with or without percutaneous coronary intervention in older patients with stable coronary disease: a pre-specified subset analysis of the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) trial. AB - OBJECTIVES: Our aim was to access clinical effectiveness of percutaneous coronary intervention (PCI) when added to optimal medical therapy (OMT) in older patients with stable coronary artery disease (CAD). BACKGROUND: While older patients with CAD are at increased risk for cardiac events compared with younger patients, it is unclear whether PCI may mitigate this risk more effectively than OMT alone or, alternatively, may be associated with more complications. METHODS: We conducted a pre-specified analysis of outcomes in stable CAD patients stratified by age and randomized to PCI+OMT or OMT alone in the COURAGE (Clinical Outcomes Utilizing Revascularization and Aggressive druG Evaluation) trial. RESULTS: A total of 1,381 patients (60%) were <65 years of age (mean 56+/-6 years) and 904 patients (40%) were >or=65 years of age (mean 72+/-5 years). Achieved treatment targets for blood pressure, low-density lipoprotein cholesterol, adherence to diet and exercise, and angina-free status did not differ by age or treatment assignment. Among older patients, there was a 2- to 3-fold higher death rate, but similar rates of myocardial infarction, stroke, and major cardiac events compared with younger patients. The addition of PCI to OMT did not improve or worsen clinical outcomes in patients>or=65 years of age during a median 4.6 year follow-up. CONCLUSIONS: These data support adherence to American College of Cardiology/American Heart Association clinical practice guidelines that advocate OMT as an appropriate initial management strategy, regardless of age. (Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation [COURAGE]; NCT00007657). PMID- 19778674 TI - Activating autoantibodies to the beta-1 adrenergic and m2 muscarinic receptors facilitate atrial fibrillation in patients with Graves' hyperthyroidism. AB - OBJECTIVES: We studied activating autoantibodies to beta-1 adrenergic receptors (AAbeta1AR) and activating autoantibodies to M2 muscarinic receptors (AAM2R) in the genesis of atrial fibrillation (AF) in Graves' hyperthyroidism. BACKGROUND: Atrial fibrillation frequently complicates hyperthyroidism. Both AAbeta1AR and AAM2R have been described in some patients with dilated cardiomyopathy and AF. We hypothesized that their copresence would facilitate AF in autoimmune Graves' hyperthyroidism. METHODS: Immunoglobulin G purified from 38 patients with Graves' hyperthyroidism with AF (n=17) or sinus rhythm (n=21) and 10 healthy control subjects was tested for its effects on isolated canine Purkinje fiber contractility with and without atropine and nadolol. Immunoglobulin G electrophysiologic effects were studied using intracellular recordings from isolated canine pulmonary veins. Potential cross-reactivity of AAbeta1AR and AAM2R with stimulating thyrotropin receptor (TSHR) antibodies was evaluated before and after adsorption to Chinese hamster ovary cells expressing human TSHRs using flow cytometry and enzyme-linked immunosorbent assays. RESULTS: The frequency of AAbeta1AR and/or AAM2R differed significantly between patients with AF and sinus rhythm (AAbeta1AR=94% vs. 38%, p<0.001; AAM2R=88% vs. 19%, p<0.001; and AAbeta1AR+AAM2R=82% vs. 10%, p<0.001). The copresence of AAbeta1AR and AAM2R was the strongest predictor of AF (odds ratio: 33.61, 95% confidence interval: 1.17 to 964.11, p=0.04). Immunoglobulin G from autoantibody-positive patients induced hyperpolarization, decreased action potential duration, enhanced early afterdepolarization formation, and facilitated triggered firing in pulmonary veins by local autonomic nerve stimulation. Immunoadsorption studies showed that AAbeta1AR and AAM2R were immunologically distinct from TSHR antibodies. CONCLUSIONS: When present in patients with Graves' hyperthyroidism, AAbeta1AR and AAM2R facilitate development of AF. PMID- 19778675 TI - Effects of cardiac resynchronization therapy on left ventricular twist. AB - OBJECTIVES: This study explored the effects of cardiac resynchronization therapy (CRT) on left ventricular (LV) twist, particularly in relation to LV lead position. BACKGROUND: LV twist is emerging as a comprehensive index of LV function. METHODS: Eighty heart failure patients were included. Two-dimensional echocardiography was performed at baseline, immediately after CRT, and at 6-month follow-up. Speckle-tracking analysis was applied to assess LV twist. The LV lead was placed preferably in a (postero)lateral vein, and at fluoroscopy, the position was classified as basal, midventricular, or apical. Response to CRT was defined as reduction of LV end-systolic volume>or=15% at 6-month follow-up. A control group comprised 30 normal subjects. RESULTS: Peak LV twist in heart failure patients was 4.8+/-2.6 degrees compared with 15.0+/-3.6 degrees in the control subjects (p<0.001). At 6-month follow-up, peak LV twist significantly improved only in responders (56%), from 4.3+/-2.4 degrees to 8.5+/-3.2 degrees (p<0.001). The strongest predictor of response to CRT was the improvement of peak LV twist immediately after CRT (odds ratio: 1.899, 95% confidence interval: 1.334 to 2.703, p<0.001). Furthermore, LV twist significantly improved in patients with an apical (from 4.3+/-3.1 degrees to 8.6+/-3.0 degrees, p=0.001) and midventricular (from 4.8+/-2.2 degrees to 6.4+/-3.9 degrees, p=0.038) but not with a basal (5.0+/-3.3 degrees vs. 4.1+/-3.2 degrees, p=0.28) LV lead position. Similarly, LV ejection fraction significantly increased in patients with an apical (from 26+/-7% to 37+/-7%, p<0.001) and midventricular (from 26+/-6% to 33+/-8%, p<0.001) but not with a basal (26+/-5% vs. 28+/-8%, p=0.30) LV lead position. CONCLUSIONS: An immediate improvement of LV twist after CRT predicts LV reverse remodeling at 6-month follow-up. PMID- 19778676 TI - Delayed untwisting: the mechanistic link between dynamic obstruction and exercise tolerance in patients with hypertrophic obstructive cardiomyopathy. AB - OBJECTIVES: We sought to determine the mechanisms linking dynamic obstruction and exercise tolerance in patients with hypertrophic obstructive cardiomyopathy (HOCM). BACKGROUND: Patients with HOCM have reduced exercise tolerance. However, the association between dynamic obstruction and peak oxygen consumption (VO2max) is weak. METHODS: We enrolled 25 patients with HOCM, 20 with hypertrophic cardiomyopathy (HCM), and 20 normal control patients. Two-dimensional, Doppler, strain, and left ventricular (LV) twist mechanics by speckle tracking echocardiography were obtained. The 25 HOCM patients had left heart catheterization, and 16 were re-examined after septal reduction. RESULTS: Deformation measurements were the lowest in HOCM patients and increased (p<0.05) after septal reduction. Twist and untwisting rate were not different between patients with HCM and control patients, but untwisting was significantly delayed in HCM patients and longest in HOCM patients. The delay related well with LV end diastolic pressure (r=0.76) and volume (r=-0.73), and VO2max (r=-0.75, all p<0.01). After septal reduction, untwisting occurred earlier and accounted for the increase in end-diastolic volume (r=0.65), and VO2max (r=0.74, both p<0.05). CONCLUSIONS: Dynamic obstruction leads to delayed untwisting in HOCM, which accounts well for the increased LV filling pressures, the reduced LV volumes, and VO2max. After septal reduction, untwisting occurs earlier and leads to an improvement in LV filling and exercise tolerance. PMID- 19778677 TI - Magnetic resonance imaging for monitoring the efficacy of thrombolytic therapy in subacute pulmonary artery embolism. PMID- 19778679 TI - ACCF/AHA 2009 performance measures for primary prevention of cardiovascular disease in adults: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Performance Measures (Writing Committee to Develop Performance Measures for Primary Prevention of Cardiovascular Disease) developed in collaboration with the American Academy of Family Physicians; American Association of Cardiovascular and Pulmonary Rehabilitation; and Preventive Cardiovascular Nurses Association: endorsed by the American College of Preventive Medicine, American College of Sports Medicine, and Society for Women's Health Research. PMID- 19778680 TI - Glutamatergic neurotransmission in the nucleus tractus solitarii: structural and functional characteristics. AB - Glutamate is the main excitatory transmitter in the central nervous system. As such, it plays a major role in transmitting and processing visceral sensory information within the nucleus tractus solitarii (NTS). Here, we review current knowledge on NTS glutamatergic transmission. We describe the main organizational features of NTS glutamatergic synapses as determined by work performed during the last decade using antibodies against glutamate receptors and transporters proteins. In light of these recent neuronatomical findings, we discuss some functional properties of developing and adult NTS glutamatergic synapses. PMID- 19778678 TI - ACCF/AHA/ACP 2009 competence and training statement: a curriculum on prevention of cardiovascular disease: a report of the American College of Cardiology Foundation/American Heart Association/American College of Physicians Task Force on Competence and Training (Writing Committee to Develop a Competence and Training Statement on Prevention of Cardiovascular Disease): developed in collaboration with the American Academy of Neurology; American Association of Cardiovascular and Pulmonary Rehabilitation; American College of Preventive Medicine; American College of Sports Medicine; American Diabetes Association; American Society of Hypertension; Association of Black Cardiologists; Centers for Disease Control and Prevention; National Heart, Lung, and Blood Institute; National Lipid Association; and Preventive Cardiovascular Nurses Association. PMID- 19778682 TI - Neurochemistry of the paraventricular nucleus of the hypothalamus: implications for cardiovascular regulation. AB - The paraventricular nucleus of the hypothalamus (PVN) is an important site for autonomic and endocrine homeostasis. The PVN integrates specific afferent stimuli to produce an appropriate differential sympathetic output. The neural circuitry and some of the neurochemical substrates within this circuitry are discussed. The PVN has at least three neural circuits to alter sympathetic activity and cardiovascular regulation. These pathways innervate the vasculature and organs such as the heart, kidney and adrenal medulla. The basal level of sympathetic tone at any given time is dependent upon excitatory and inhibitory inputs. Under normal circumstances the sympathetic nervous system is tonically inhibited. This inhibition is dependent upon GABA and nitric oxide such that nitric oxide potentiates local GABAergic synaptic inputs onto the neurones in the PVN. Excitatory neurotransmitters such as glutamate and angiotensin II modify the tonic inhibitory activity. The neurotransmitters oxytocin, vasopressin and dopamine have been shown to affect cardiovascular function. These neurotransmitters are found in neurones of the PVN and within the spinal cord. Oxytocin and vasopressin terminal fibres are closely associated with sympathetic preganglionic neurones (SPNs). Sympathetic preganglionic neurones have been shown to express receptors for oxytocin, vasopressin and dopamine. Oxytocin causes cardioacceleratory and pressor effects that are greatest in the upper thoracic cord while vasopressin cause these effects but more significant in the lower thoracic cord. Dopaminergic effects on the cardiovascular system include inhibitory or excitatory actions attributed to a direct PVN influence or via interneuronal connections to sympathetic preganglionic neurones. PMID- 19778683 TI - Advances in Wound and Bone Healing. Foreword. PMID- 19778684 TI - Advances in Wound and Bone Healing. Preface. PMID- 19778681 TI - Glutamatergic neurons say NO in the nucleus tractus solitarii. AB - Both glutamate and nitric oxide (NO) may play an important role in cardiovascular reflex and respiratory signal transmission in the nucleus tractus solitarii (NTS). Pharmacological and physiological data have shown that glutamate and NO may be linked in mediating cardiovascular regulation by the NTS. Through tract tracing, multiple-label immunofluorescent staining, confocal microscopic, and electronic microscopic methods, we and other investigators have provided anatomical evidence that supports a role for glutamate and NO as well as an interaction between glutamate and NO in cardiovascular regulation in the NTS. This review article focuses on summarizing and discussing these anatomical findings. We utilized antibodies to markers of glutamatergic neurons and to neuronal NO synthase (nNOS), the enzyme that synthesizes NO in NTS neurons, to study the anatomical relationship between glutamate and NO in rats. Not only were glutamatergic markers and nNOS both found in similar subregions of the NTS and in vagal afferents, they were also frequently colocalized in the same neurons and fibers in the NTS. In addition, glutamatergic markers and nNOS were often present in fibers that were in close apposition to each other. Furthermore, N-methyl-d aspartate (NMDA) type glutamate receptors and nNOS were often found on the same NTS neurons. Similarly, alpha-amino-3-hydroxy-5-methylisoxozole-proprionic acid (AMPA) type glutamate receptors also frequently colocalized with nNOS in NTS neurons. These findings support the suggestion that the interaction between glutamate and NO may be mediated both through NMDA and AMPA receptors. Finally, by applying tracer to the cut aortic depressor nerve (ADN) to identify nodose ganglion (NG) neurons that transmit cardiovascular signals to the NTS, we observed colocalization of vesicular glutamate transporters (VGluT) and nNOS in the ADN neurons. Thus, taken together, these neuroanatomical data support the hypothesis that glutamate and NO may interact with each other to regulate cardiovascular and likely other visceral functions through the NTS. PMID- 19778685 TI - Extracellular matrix biomaterials for soft tissue repair. AB - The biological and physical augmentation provided by extracellular matrix (ECM) derived implants continues to challenge and refine the conventional wisdom of biomaterials. It is now appreciated that different tissue-processing methodologies can produce ECM devices with characteristic post-implantation responses ranging from the classic foreign body encapsulation of a permanent implant, to one where the implant is degraded and resorbed, to one where the processed ECM implant is populated by local fibroblasts and supporting vasculature to generate a new, metabolically active tissue (gTissue). This article reviews the multiple ECM devices available clinically and highlights the impact of tissue source and processing on physicomechanical properties and host implant interactions, with regard to surgical applications and clinical considerations. PMID- 19778686 TI - The role of collagen bioscaffolds, foamed collagen, and living skin equivalents in wound healing. AB - Collagen is one of the fundamental building blocks of skin and plays a critical role in wound healing. This article looks at the wide array of collagen and living skin equivalent products containing collagen and living cells, and at how these may be used in the treatment of diabetic foot ulcers. Solid collagen, foamed collagen, living skin equivalents, and living cadaveric skin are considered. Clinical examples are included, along with a brief discussion of wound dressings that may help to enhance the incorporation of these materials. PMID- 19778687 TI - Bioscaffolds and the reconstruction of ligaments and tendons in the foot and ankle. AB - Biologic scaffolds have become an integral part of surgical soft tissue reconstruction in recent years. The increased use of these materials can be partially attributed to poor long-term outcomes with synthetic products as well as the cost and morbidity associated with allografts and autografts. Bioscaffolds can augment natural healing processes of tendons and ligaments while providing additional structural support. Although these implants lack the mechanical strength of synthetics and other transplants, proper preparation can optimize their load-sharing capacity. This article presents methods that can improve these characteristics of bioscaffolds. Available studies in foot and ankle applications have shown minimal complications in a variety of techniques. PMID- 19778688 TI - Augmentation of atrophic plantar soft tissue with an acellular dermal allograft: a series review. AB - Treatment of plantar fat pad migration and atrophy has caused concern for decades. Patients can present with pain, callus formation, or ulceration. The purpose of this article is to review the results of a consecutive series of patients treated for fat pad atrophy of the plantar foot, using a minimally invasive implantation of an acellular human dermal allograft as a tissue augmentation. This material was chosen for the fat pad supplementation because of previous reports of success in tendon and ligament augmentation, wound healing, and interpositional arthroplasty. PMID- 19778689 TI - Bone and wound healing augmentation with platelet-rich plasma. AB - Over the past two decades, autologous platelets that have been sequestered, concentrated, and mixed with thrombin to generate growth factor-concentrated platelet-rich plasma for application to bone and wounds to aide healing have been a subject of great interest. This article reviews the literature related to the use of autologous platelet-rich plasma in bone and wound healing, and reviews the processes necessary to secure a high concentration of viable platelets. Although not yet definitive, autologous platelet-rich plasma has been shown to be safe, reproducible, and effective in mimicking the natural process of bone and wound healing. PMID- 19778690 TI - Bone graft substitutes and allografts for reconstruction of the foot and ankle. AB - In reconstructive foot and ankle surgery, the use of bone graft is common. Whether for trauma, acquired or congenital deformities, arthrodeses, joint replacement, bone loss from infection, or bone tumor resection, the foot and ankle surgeon must be knowledgeable about current bone grafting options to make informed decisions. Innovation and technologic advances have produced an impressive and exciting array of options, advancing us closer to mimicking the gold standard: autograft. However, the sheer volume of available products makes it challenging for the foot and ankle surgeon to stay abreast of current bone graft technology. The purpose of this article is to simplify and classify current bone grafting options, discuss advantages and disadvantages, and provide relevant clinical examples. PMID- 19778691 TI - Bone growth stimulation for foot and ankle nonunions. AB - During the last few decades, electrical current stimulation has gone from an investigational modality to an accepted method of treatment to assist with bone healing. This article provides an overview of electrical bone stimulation for nonunions in the foot and ankle. PMID- 19778692 TI - An overview of negative pressure wound therapy for the lower extremity. AB - Since its introduction into the market, negative pressure wound therapy (NPWT), also known as topical negative pressure, has become an important adjuvant therapy for the treatment of many types of wounds. Surgeons and physicians of all subspecialties have adopted NPWT into their practices. NPWT has become a mainstay in the management of lower extremity soft tissue pathology, especially in patients with traumatic, diabetic, postsurgical, and peripheral vascular disease associated wounds. This article reviews the background, currently understood mechanisms of action, applications, contraindications, reported complications, advantages, criticisms, and techniques in the lower extremity. PMID- 19778693 TI - Biologic resurfacing of the ankle and first metatarsophalangeal joint: case studies with a 2-year follow-up. AB - The goal of biologic resurfacing is to provide a smooth joint surface with a low coefficient of friction, which allows the joint to function with near normal biomechanics, as well as provide intermittent pressure, to the subchondral and cancellous bone. This unique combination often results in the formation of a "neocartilage-like" structure that can reduce pain and restore biomechanics. As well as giving a brief history of cutis arthroplasty, this article describes cases in which the ankle and first metatarsophalangeal joint underwent biologic resurfacing, with a 2-year postoperative follow up. PMID- 19778694 TI - Use of soft tissue matrices as an adjunct to achilles repair and reconstruction. AB - The Achilles tendon is the thickest and strongest tendon in the human body. In spite of this, it is also one of the most frequently ruptured tendons. This article reviews the history of and debate about the appropriate course of treatment. A case study of an Achilles repair illustrates that the use soft tissue matrices is a successful adjunct to both the primary repair and gastrocnemius recession, with full return to activity and no inflammatory response at long-term follow up. The authors anticipate that the use of soft tissue matrices for the repair of tendon and soft tissue defects will expand over time as this material has distinct advantages over synthetics and highly crosslinked biologic materials. PMID- 19778696 TI - Preface. PMID- 19778695 TI - Management of allosensitized cardiac transplant candidates. AB - Cardiac transplantation remains the best treatment in patients with advanced heart failure with a high risk of death. However, an inadequate supply of donor hearts decreases the likelihood of transplantation for many patients. Ventricular assist devices (VADs) are being increasingly used as a bridge to transplantation in patients who may not survive long enough to receive a heart. This expansion in VAD use has been associated with increasing rates of allosensitization in cardiac transplant candidates. Anti-HLA antibodies can be detected before transplantation using different techniques. Complement-dependent lymphocytotoxicity assays are widely used for measurement of panel-reactive antibody (PRA) and for crossmatch purposes. Newer assays using solid-phase flow techniques feature improved specificity and offer detailed information concerning antibody specificities, which may lead to improvements in donor-recipient matching. Allosensitization prolongs the wait time for transplantation and increases the risk of post transplantation complications and death; therefore, decreasing anti-HLA antibodies in sensitized transplant candidates is of vital importance. Plasmapheresis, intravenous immunoglobulin, and rituximab have been used to decrease the PRA before transplantation, with varying degrees of success. The most significant post-transplantation complications seen in allosensitized recipients are antibody-mediated rejection (AMR) and cardiac allograft vasculopathy (CAV). Often, AMR manifests with severe allograft dysfunction and hemodynamic compromise. The underlying pathophysiology is not fully understood but appears to involve complement-mediated activation of endothelial cells resulting in ischemic injury. The treatment of AMR in cardiac recipients is largely empirical and includes high-dose corticosteroids, plasmapheresis, intravenous immunoglobulin, and rituximab. Diffuse concentric stenosis of allograft coronary arteries due to intimal expansion is a characteristic of CAV. Its pathophysiology is unclear but may involve chronic complement-mediated endothelial injury. Sirolimus and everolimus can delay the progression of CAV. In some nonsensitized cardiac transplant recipients, the de novo formation of anti HLA antibodies after transplantation may increase the likelihood of adverse clinical outcomes. Serial post-transplantation PRAs may be advisable in patients at high risk of de novo allosensitization. PMID- 19778697 TI - Vascular anatomy: the head, neck, and skull base. AB - Knowledge of the anatomy of the vasculature of the head and neck from the thorax to the skull base is critical to the approach to diagnosis and treatment of cerebrovascular disease. Awareness of the anatomic variations that may be encountered, common and uncommon, is necessary to avoid diagnostic pitfalls and to avert therapeutic disasters. Careful anatomic analysis and understanding of collateral pathways and dangerous anastomoses facilitates cross-sectional and angiographic diagnosis and the development of surgical and endovascular treatment strategies. PMID- 19778698 TI - The vascular anatomy of the vertebro-spinal axis. AB - This article discusses the vascular anatomy of the vertebra-spinal axis and covers such topics as vascular supply to the spine, spinal dura, and paraspinal musculature; vascular supply to the spinal cord; and spinal veins. PMID- 19778700 TI - Intracranial collateral anastomoses: relevance to endovascular procedures. AB - An in-depth knowledge of intracranial and extracranial collateral anastomoses, overt or hidden, is crucial for an interventionist to devise optimal endovascular strategies to manage a host of pathologic conditions; to ascertain potential pitfalls; and, ultimately, to avoid complications that could have been prevented by a better understanding of underlying vascular anatomy. As the scope and extent of endovascular interventions for cerebrovascular and cranial disease continues to expand, the recognition of these putative anastomoses will continue to become a larger part of diagnostic evaluation and interventional design. This article provides a brief overview of cranial vascular development, followed by specific clinically relevant examples of extracranial and intracranial anastomoses and the internal carotid artery and vertebrobasilar anastomoses. PMID- 19778699 TI - Neurovascular anatomy: a practical guide. AB - Students of cerebrovascular anatomy and physiology tend to model their learning based on normal patterns of blood flow. As such, the focus tends toward arterial physiology and pathology with less than adequate understanding of the significance of the venous system. This article presents a different approach to neurovascular anatomy, starting with the venous system and demonstrating both normal and pathologic states. It reviews the cerebral circulation with attention to the microsurgical relationships, angiographic patterns, and fusion of dual volume imaging. The importance of bony, sulcal, and ventricular anatomy is presented as it relates to the angiographic representation of pathologic lesions. Examples are given of anatomic variants seen with the operating microscope, biplanar angiography, and three-dimensional rotational angiography." Note that in the synopsis and throughout the article, first person usage has been changed to third person per journal style. PMID- 19778701 TI - Advanced imaging applications for endovascular procedures. AB - Advanced imaging techniques, particularly in CT and MRI, have become state-of-the art to support the performance of interventional neuroradiologic procedures. Multidetector CT scanners with submillimeter detectors and real-time workstations have allowed the use of a noninvasive study, CT angiography, as a first-line diagnostic study at many institutions to detect and evaluate the morphology of aneurysms. Follow-up for postsubarachnoid spasm now includes transcranial Doppler, CT angiography, and sometimes perfusion to guide therapy. While both intracranial and extracranial stenosis have long been well evaluated by MR and CT angiography, information about the intimal wall and plaque morphology is now possible. In the setting of acute ischemia, CT with perfusion or MR with diffusion and perfusion has increased the ability to separate territory at risk from infarcted tissue, and can help to guide more appropriate intervention. This article addresses current state-of the-art imaging applications as well as a few techniques on the horizon that show great promise in helping to characterize those lesions amenable to endovascular therapy. PMID- 19778702 TI - Techniques and devices in neuroendovascular procedures. AB - The management of patients who have cerebrovascular disorders is challenging. Historically, treatments have been limited to medical therapy and open surgical procedures. Our current ability to treat complex vascular disorders in a minimally invasive fashion is improving at a remarkable rate because of advances in neuroendovascular technology. As treatment options in patients with cerebral aneurysms, cerebral arteriovenous malformations, ischemic stroke, and intracranial stenosis continue to increase, patient morbidity and mortality continue to decline. This article reviews and discusses many of the currently available techniques and devices in the neuroendovascular arena. PMID- 19778703 TI - Percutaneous vertebroplasty. AB - Vertebroplasty, the augmentation of vertebral compression fractures by image controlled intracorporeal injection of polymethylmethacrylate cement, has shown a steady increase in use. Its chief indication is to palliate pain after a failure of noninvasive therapies. Other benefits include preventing further compression of the treated vertebra and fusing unstable fractures. Controversies include questions regarding its long-term benefit compared with natural history, claims of height restoration, biomechanical compromise of adjacent vertebrae, and its performance compared with kyphoplasty. Complications are uncommon but can be devastating with reported cases of procedural death and paralysis. New operators should be adequately trained and respect the dangers of this procedure. PMID- 19778704 TI - Inferior petrosal sinus sampling in the diagnosis of sellar neuropathology. AB - Because no single test is definitive for Cushing's disease (CD), establishing the diagnosis has remained a challenge that relies on building a critical mass of evidence. The differential diagnosis of corticotropin (ACTH)-dependent Cushing's syndrome (CS) traditionally has rested on noninvasive biochemical and radiologic testing. Bilateral inferior petrosal sinus sampling (BIPSS) is an invasive procedure that has become part of the diagnostic armamentarium surrounding CD. When used appropriately-that is, for patients who have biochemically confirmed ACTH-dependent CS but discordant biochemical or radiologic studies-BIPSS is the reference standard confirmatory test for CD. PMID- 19778705 TI - Intracranial endovascular balloon test occlusion-indications, methods, and predictive value. AB - The balloon test occlusion is one method by which surgeons evaluate whether a patient will be able to tolerate permanent occlusion of an extracranial or intracranial vessel. This article discusses the indications, methods, predictive value, and complications of the balloon test occlusion. It also briefly describes the Wada test in the context of preoperative evaluation of patients who are candidates for temporal lobectomy. PMID- 19778706 TI - Introduction. PMID- 19778707 TI - Genetic basis of neural tube defects. AB - Neural tube defects (NTDs) represent a common group of severe congenital malformations of the central nervous system. They result from failure of neural tube closure during early embryonic life. Their etiology is complex, involving environmental and genetic factors that interact to modulate the incidence and severity of the developing phenotype. Despite a long history of etiologic studies, the molecular and cellular pathogenic mechanisms underlining NTDs remain poorly understood. The major epidemiologic finding in NTDs is the protective effect of perinatal folic acid supplementation that reduces their risk by 60% 70%. Genetic studies in NTDs have focused mainly on folate-related genes and identified a few significant associations between variants in these genes and an increased risk for NTDs. The candidate gene approach investigating genes involved in neurulation and inferred from animal models has faced limited success in identifying major causative genes predisposing to NTDs. However, we are witnessing a rapid and impressive progress in understanding the genetic basis of NTDs, based mainly on the development of whole genome innovative technologies and the powerful tool of animal models. PMID- 19778708 TI - Diffusion imaging of congenital brain malformations. AB - Diffusion imaging is a magnetic resonance imaging modality that measures the microscopic molecular motion of water to yield information about brain structure. The technique has been used increasingly in recent years to investigate congenital brain malformations. This article aims to provide a brief overview of diffusion imaging, and to review recent advances in our understanding of congenital brain malformations because of diffusion imaging. The technique has been successfully applied to conditions ranging from rare hindbrain malformations, such as horizontal gaze palsy with progressive scoliosis, to conditions that are undetectable using conventional neuroimaging, such as grapheme-color synesthesia. Though diffusion imaging has already yielded considerable insight into the pathogenesis and clinical features of congenital malformations, recent advances in imaging techniques promise to provide much more extensive knowledge of these conditions in the future. PMID- 19778709 TI - Genetics and biology of microcephaly and lissencephaly. AB - Genetic microcephaly and lissencephaly are 2 of the most common brain malformations. Each of them is a heterogeneous group of disorders caused by mutations of many different genes. They are a significant cause of neurological morbidity in children worldwide, responsible for many cases of mental retardation, cerebral palsy, and epilepsy. Recent advances in molecular genetics have led to the identification of several genes causing these disorders, and thus accurate molecular diagnosis and improved genetic counseling has become available for many patients and their families. More recently identified genes include STIL, causing primary autosomal recessive microcephaly (microcephaly vera), and TUBA1A, causing lissencephaly. Numerous other disease genes are likely still to be identified. Functional studies of genes that cause microcephaly and lissencephaly have provided valuable insight into the molecular mechanisms of human brain development. PMID- 19778710 TI - Understanding the mechanisms of callosal development through the use of transgenic mouse models. AB - The cerebral cortex is the area of the brain where higher-order cognitive processing occurs. The 2 hemispheres of the cerebral cortex communicate through one of the largest fiber tracts in the brain, the corpus callosum. Malformation of the corpus callosum in human beings occurs in 1 in 4000 live births, and those afflicted experience an extensive range of neurologic disorders, from relatively mild to severe cognitive deficits. Understanding the molecular and cellular processes involved in these disorders would therefore assist in the development of prognostic tools and therapies. During the past 3 decades, mouse models have been used extensively to determine which molecules play a role in the complex regulation of corpus callosum development. This review provides an update on these studies, as well as highlights the value of using mouse models with the goal of developing therapies for human acallosal syndromes. PMID- 19778711 TI - Joubert syndrome: insights into brain development, cilium biology, and complex disease. AB - Joubert syndrome (JS) is a primarily autosomal recessive condition characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation (the "molar tooth sign"). Variable features include retinal dystrophy, cystic kidney disease, liver fibrosis and polydactyly. Recently, substantial progress has been made in our understanding of the genetic basis of JS, including identification of seven causal genes (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67/MKS3, ARL13B and CC2D2A). Despite this progress, the known genes account for <50% of cases and few strong genotype-phenotype correlations exist in JS; however, genetic testing can be prioritized based on clinical features. While all seven JS genes have been implicated in the function of the primary cilium/basal body organelle (PC/BB), little is known about how the PC/BB is required for brain, kidney, retina and liver development/function, nor how disruption of PC/BB function leads to diseases of these organs. Recent work on the function of the PC/BB indicates that the organelle is required for multiple signaling pathways including sonic hedgehog, WNT and platelet derived growth factor. Due to shared clinical features and underlying molecular pathophysiology, JS is included in the rapidly expanding group of disorders called ciliopathies. The ciliopathies are emerging as models for more complex diseases, where sequence variants in multiple genes contribute to the phenotype expressed in any given patient. PMID- 19778714 TI - Aileron staples peptides. PMID- 19778712 TI - Model organisms inform the search for the genes and developmental pathology underlying malformations of the human hindbrain. AB - Congenital malformations of the human hindbrain, including the cerebellum, are poorly understood largely because their recognition is a relatively recent advance for imaging diagnostics. Cerebellar malformations are the most obvious and best characterized hindbrain malformations due to their relative ease of viewing by magnetic resonance imaging and the recent identification of several causative genes (Millen et al. Curr Opin Neurobiol 18:12-19, 2008). Malformations of the pons and medulla have also been described both in isolation and in association with cerebellar malformations (Barkovich et al. Ann Neurol 62:625 639, 2007). Although little is understood regarding the specific developmental pathologies underlying hindbrain malformations in humans, much is known regarding the mechanisms and genes driving hindbrain development in vertebrate model organisms. Thus, studies in vertebrate models provide a developmental framework in which to categorize human hindbrain malformations and serve to provide information regarding disrupted developmental processes and candidate genes. Here, we survey the basic principles of vertebrate hindbrain development and integrate our current knowledge of human hindbrain malformations into this framework. PMID- 19778715 TI - Mastering the chemical language of bacteria. AB - The publication of the crystal structures of a bacterial quorum sensing receptor complexed with a variety of ligands (Zou and Nair, 2009) provides a much-needed molecular rationale for the modulation of this intercellular signaling process, which may facilitate the development of new therapeutic agents. PMID- 19778716 TI - Punching holes in an enzyme. AB - Schramm and coworkers have punched holes into human purine nucleoside phosphorylase by substitution of glycine for aromatic amino acid residues at a protein lid. The results of studies on the enzymes with holes illuminate hidden chemistry that occurs at the enzyme active site. PMID- 19778717 TI - Reassembling biological machinery in vitro. AB - Inspired by the specialized glycolytic system of flagella of mammalian sperm, Mukai et al. (2009) describe the controlled immobilization of two enzymes constituting the first steps in the glycolytic pathway. Extension of this work may provide "power converters" for bionanodevices, which transduce chemical energy from glucose to ATP. PMID- 19778718 TI - Making strides in peptide-based therapeutics. AB - In a recent report published in PNAS, Gellman and coworkers describe the design, characterization, and potent activity of alpha/beta-peptides that mimic a long alpha helix involved in HIV viral entry. PMID- 19778719 TI - High-throughput screening and chemical biology: new approaches for understanding circadian clock mechanisms. AB - Most organisms exhibit daily changes in physiology and metabolism under the control of a cell-autonomous circadian clock. In the core clock mechanism, clock genes form a transcription factor network to generate circadian rhythms of gene expression. Clock protein phosphorylation and histone modifications are also important for the clock regulation. Pharmacological approaches have been making significant contributions to the clock research, for example, in characterizing the roles of protein kinases CKIdelta, CKIepsilon, CK2, and GSK-3beta. Recently, high-throughput circadian functional assays have been established. Chemical biology approaches utilizing high-throughput compound screening together with RNAi-based genomic screening will open a new way for the circadian clock field. Finding a set of compounds that potently affect the clock function will lead to the identification of novel clock components and form the basis for therapeutic strategies directed toward circadian disorders. PMID- 19778721 TI - Inorganic mercury detection and controlled release of chelating agents from ion responsive liposomes. AB - A liposome system that can detect and detoxify mercury in aqueous solution is demonstrated. The system consists of 1,2-dioleoyl-sn-glycero-3 phosphoethanolamine and 20% PEG-PE (PEG MW 2000 Da) that forms liposome, which encapsulates self-quenching fluorescein for detection, and chelating agent meso 2,3-dimercaptosuccinic acid (meso-DMSA) for chelating detoxification through Hg(2+)-responsive release of fluorescein and meso-DMSA. This system can detect mercury levels as low as 10 nM with high selectivity. In particular, the release profile of meso-DMSA by the local concentration of Hg can be modulated, so that more chelators are released in regions of high concentration and less chelators are released in regions of low concentration. The design has been demonstrated both in vitro and in HeLa cells. This "budgeted" release profile is particularly useful in situations in which the local levels of Hg contamination vary, or if such contamination is time dependent. PMID- 19778720 TI - The alpha,alpha-difluorinated phosphonate L-pSer-analogue: an accessible chemical tool for studying kinase-dependent signal transduction. AB - This overview focuses on the (alpha,alpha-difluoromethylene)phosphonate mimic of phosphoserine (pCF(2)Ser) and its application to the study of kinase-mediated signal transduction-pathways of great interest to drug development. The most versatile modes of access to these chemical biological tools are discussed, organized by method of PCF(2)-C bond formation. The pCF(2)-Ser mimic may be site specifically incorporated into peptides (SPPS) and proteins (expressed protein ligation). This isopolar, dianionic pSer mimic results in a "constitutive phosphorylation" phenotype and is seen to support native protein-protein interactions that depend on serine phosphorylation. Signal transduction pathways studied with this chemical biological approach include the regulation of p53 tumor suppressor protein activity and of melatonin production. Given these successes, the future is bright for the use of such "teflon phospho-amino acid mimics" to map kinase-based signaling pathways. PMID- 19778722 TI - A peptidomimetic approach to targeting pre-amyloidogenic states in type II diabetes. AB - Protein fiber formation is associated with diseases ranging from Alzheimer's to type II diabetes. For many systems, including islet amyloid polypeptide (IAPP) from type II diabetes, fibrillogenesis can be catalyzed by lipid bilayers. Paradoxically, amyloid fibers are beta sheet rich while membrane-stabilized states are alpha-helical. Here, a small molecule alpha helix mimetic, IS5, is shown to inhibit bilayer catalysis of fibrillogenesis and to rescue IAPP-induced toxicity in cell culture. Importantly, IAPP:IS5 interactions localize to the putative alpha-helical region of IAPP, revealing that alpha-helical states are on pathway to fiber formation. IAPP is not normally amyloidogenic as its cosecreted partner, insulin, prevents self-assembly. Here, we show that IS5 inhibition is synergistic with insulin. IS5 therefore represents a new approach to amyloid inhibition as the target is an assembly intermediate that may additionally restore functional IAPP expression. PMID- 19778723 TI - Analysis of two additional signaling molecules in Streptomyces coelicolor and the development of a butyrolactone-specific reporter system. AB - gamma-Butyrolactone bacterial hormones regulate antibiotic production and morphological differentiation in Streptomyces species. One gamma-butyrolactone, SCB1, has been previously characterized in Streptomyces coelicolor. Here we report the characterization of two additional gamma-butyrolactones, named SCB2 (2 [1'-hydroxyoctyl]-3-hydroxymethylbutanolide) and SCB3 (2-[1'-hydroxy-6' methyloctyl]-3-hydroxymethylbutanolide), possessing an antibiotic stimulatory activity. To elucidate the specificity determinants of these ligands for the receptor protein, ScbR, 30 chemically synthesized gamma-butyrolactone analogs were tested by utilizing the release of ScbR from DNA upon binding to a gamma butyrolactone, which can be detected by kanamycin resistance. The butyrolactone detection method developed here revealed that ScbR shows preference toward a ligand possessing a 7-10 carbon C-2 side chain, a C-1'-beta-hydroxyl group, and a C-6'-methyl branch that coincides with SCB3. Moreover, this method was successfully used to screen for potential gamma-butyrolactone producers from commercial-antibiotic-producing Streptomyces. PMID- 19778724 TI - Molecular basis for the recognition of structurally distinct autoinducer mimics by the Pseudomonas aeruginosa LasR quorum-sensing signaling receptor. AB - The human pathogen Pseudomonas aeruginosa coordinates the expression of virulence factors using quorum sensing, a signaling cascade triggered by the activation of signal receptors by small-molecule autoinducers. These homoserine lactone autoinducers stabilize their cognate receptors and activate their functions as transcription factors. Because quorum sensing regulates the progression of infection and host immune resistance, significant efforts have been devoted toward the identification of small molecules that disrupt this process. Screening efforts have identified a class of triphenyl compounds that are structurally distinct from the homoserine lactone autoinducer, yet interact specifically and potently with LasR receptor to modulate quorum sensing (Muh et al., 2006a). Here we present the high-resolution crystal structures of the ligand binding domain of LasR in complex with the autoinducer N-3-oxo-dodecanoyl homoserine lactone (1.4 A resolution), and with the triphenyl mimics TP-1, TP-3, and TP-4 (to between 1.8 A and 2.3 A resolution). These crystal structures provide a molecular rationale for understanding how chemically distinct compounds can be accommodated by a highly selective receptor, and provide the framework for the development of novel quorum sensing regulators, utilizing the triphenyl scaffold. PMID- 19778725 TI - Ribocation transition state capture and rebound in human purine nucleoside phosphorylase. AB - Purine nucleoside phosphorylase (PNP) catalyzes the phosphorolysis of 6-oxy purine nucleosides to the corresponding purine base and alpha-D-ribose 1 phosphate. Its genetic loss causes a lethal T cell deficiency. The highly reactive ribocation transition state of human PNP is protected from solvent by hydrophobic residues that sequester the catalytic site. The catalytic site was enlarged by replacing individual catalytic site amino acids with glycine. Reactivity of the ribocation transition state was tested for capture by water and other nucleophiles. In the absence of phosphate, inosine is hydrolyzed by native, Y88G, F159G, H257G, and F200G enzymes. Phosphorolysis but not hydrolysis is detected when phosphate is bound. An unprecedented N9-to-N3 isomerization of inosine is catalyzed by H257G and F200G in the presence of phosphate and by all PNPs in the absence of phosphate. These results establish a ribocation lifetime too short to permit capture by water. An enlarged catalytic site permits ribocation formation with relaxed geometric constraints, permitting nucleophilic rebound and N3-inosine isomerization. PMID- 19778727 TI - The platelet integrin alphaIIbbeta3 binds to the RGD and AGD motifs in fibrinogen. AB - Fibrinogen (Fbg) mediates platelet aggregation by binding the alphaIIbbeta3 integrin receptor, but the interaction of the receptor with peptide motifs of Fbg remains unresolved. This paper describes the use of self-assembled monolayers (SAMs) to study the adhesion of alphaIIbbeta3-transfected CHO cells to the GRGDS and HHLGGAKQAGDV motifs within Fbg. Cells adhered to and spread on monolayers presenting either peptide. Cell adhesion could be inhibited by either soluble peptide, demonstrating that the peptides bind competitively to the integrin. A peptide array was used to show that AGD was the minimal binding sequence in HHLGGAKQAGDV and that the receptor recognizes ligands of the form GXGDSC, where X is a hydrophobic or basic residue. This work revises our understanding of the alphaIIbbeta3 specificity and also suggests a new class of antithrombotic agents. PMID- 19778726 TI - Chemical probes identify a role for histone deacetylase 3 in Friedreich's ataxia gene silencing. AB - We recently identified a class of pimelic diphenylamide histone deacetylase (HDAC) inhibitors that show promise as therapeutics in the neurodegenerative diseases Friedreich's ataxia (FRDA) and Huntington's disease. Here, we describe chemical approaches to identify the HDAC enzyme target of these inhibitors. Incubation of a trifunctional activity-based probe with a panel of class I and class II recombinant HDAC enzymes, followed by click chemistry addition of a fluorescent dye and gel electrophoresis, identifies HDAC3 as a unique high affinity target of the probe. Photoaffinity labeling in a nuclear extract prepared from human lymphoblasts with the trifunctional probe, followed by biotin addition through click chemistry, streptavidin enrichment, and Western blotting also identifies HDAC3 as the preferred cellular target of the inhibitor. Additional inhibitors with different HDAC specificity profiles were synthesized, and results from transcription experiments in FRDA cells point to a unique role for HDAC3 in gene silencing in Friedreich's ataxia. PMID- 19778728 TI - Direct measurement of cathepsin B activity in the cytosol of apoptotic cells by an activity-based probe. AB - Cells control their own death through a program termed apoptosis, which is indispensable for development and homeostasis in all metazoans. Lysosomal cysteine proteases are not normally thought of as participating in apoptosis; however, recent reports have shown that the cathepsin proteases can be released from the lysosome during apoptosis, where they can participate in cell death. We report here the development of an activity-based probe that, under optimized conditions, reports on cathepsin B activity only in apoptotic cells by reading out the release of cathepsin B from the lysosomes. Biochemical characterization of apoptosis in cells from cathepsin B null mice shows delayed and suboptimal activation of caspases. Our data further supports a role for cathepsin B in the cytosol as a positive regulator of a cell death feed-forward loop and provides a chemical tool for future investigations. PMID- 19778729 TI - Sequential reactions of surface- tethered glycolytic enzymes. AB - The development of complex hybrid organic-inorganic devices faces several challenges, including how they can generate energy. Cells face similar challenges regarding local energy production. Mammalian sperm solve this problem by generating ATP down the flagellar principal piece by means of glycolytic enzymes, several of which are tethered to a cytoskeletal support via germ-cell-specific targeting domains. Inspired by this design, we have produced recombinant hexokinase type 1 and glucose-6-phosphate isomerase capable of oriented immobilization on a nickel-nitrilotriacetic acid modified surface. Specific activities of enzymes tethered via this strategy were substantially higher than when randomly adsorbed. Furthermore, these enzymes showed sequential activities when tethered onto the same surface. This is the first demonstration of surface tethered pathway components showing sequential enzymatic activities, and it provides a first step toward reconstitution of glycolysis on engineered hybrid devices. PMID- 19778730 TI - Retrobulbar hematoma associated with selective serotonin reuptake inhibitor: a case report. AB - OBJECTIVE: The aim was to raise awareness among surgeons performing orbital surgery of the risk of hemorrhage associated with selective serotonin reuptake inhibitors. STUDY DESIGN: This is an observational case report. RESULTS: An 80 year-old woman who used paroxetine developed a retrobulbar hematoma with impaired vision immediately after surgery for an orbital blowout fracture. CONCLUSION: Surgeons should be aware of the increased risk of hemorrhage among patients on selective serotonin reuptake inhibitors who require orbital surgery. PMID- 19778731 TI - Necrotizing stomatitis: a possible periodontal manifestation of deferiprone induced agranulocytosis. AB - Thalassemia major is a rare inherited anemia, and affected children require blood transfusions every 2-4 weeks to survive. Repeated blood transfusions lead to a build-up of toxic levels of iron in the body, causing organ damage and premature death, primarily due to iron-induced heart disease. Deferiprone is one of a few drugs that are routinely used in medicine for the treatment of iron overload in thalassemic patients. This drug is usually administered daily at high doses (50 100 mg/kg) with a very low toxicity. Agranulocytosis is the most serious side effect of deferiprone, with a reported incidence of 0.6 per 100 patient-years. We document an illustrated case report of necrotizing gingivostomatitis, an oral manifestation of agranulocytosis secondary to deferiprone use involving the gingiva and palatal mucosa of a thalassemia major patient. Various causes of precipitation of agranulocytosis in these patients and a possible relationship of necrotizing gingivostomatitis with deferiprone are highlighted in this case report. PMID- 19778732 TI - Adenomatoid odontogenic tumor concomitant with cystic complex odontoma: case report. AB - This case report describes a 10-year-old female patient with an adenomatoid odontogenic tumor developing together with a cystic complex odontoma. This occurrence is considered very unusual. Immunohistochemical detection of cytokeratins AE1/AE3, CK5, CK8, CK10, CK14, CK19 and Ki-67 was performed. PMID- 19778733 TI - In vitro performance of methods of approximal caries detection in primary molars. AB - OBJECTIVE: The aim was to compare the performance of different methods in detecting approximal caries lesions primary molars ex vivo. STUDY DESIGN: One hundred thirty-one approximal surfaces were examined by 2 observers with visual inspection (VI) using the International Caries Detection and Assessment System, radiographic interpretation, and clinically using the Diagnodent pen (LFpen). To achieve a reference standard, surfaces were directly examined for the presence of white spots or cavitations, and lesion depth was determined after sectioning. The area under the receiver operating characteristic curve (A(z)), sensitivity, specificity, and accuracy were calculated, as well as the interexaminer reproducibility. RESULTS: Using the cavitation threshold, all methods presented similar sensitivities. Higher A(z) values were achieved with VI at white spot threshold, and VI and LFpen had higher A(z) values at cavitation threshold. VI presented higher accuracy and A(z) than radiographic and LFpen at both enamel and dentin depth thresholds. Higher reliability values were achieved with VI. CONCLUSIONS: VI performs better, but both radiographic and LFpen methods also show good performance in detecting more advanced approximal caries lesions. PMID- 19778734 TI - Trabecular pattern in the mandible as bone fracture predictor. AB - OBJECTIVE: This investigation analyzed the use of mandibular sparse trabeculation as a fracture risk indicator. STUDY DESIGN: Trabeculation was classified as sparse, alternating dense and sparse, or dense using intraoral radiographs from 274 men and women (50-87 years old) including 56 with previous reported fractures. Mandibular bone texture was assessed on digitized radiographs. RESULTS: Forty-eight percent of subjects with sparse trabeculation reported fractures, compared with 19% with alternating sparse and dense trabeculation and 2% with dense trabeculation (Kruskal-Wallis test: P < .00001). Logistic regression analysis showed that sparse trabeculation (odds ratio [OR] = 5.9; 95% CI 3.0-11.1; P < .0001) and lowest bone texture classes (OR = 2.2; 95% CI 1.0 4.5; P = .04) were associated with an increased fracture risk, especially for subjects > or =75 years (OR = 7.1; 95% CI 2.5-20.0; P = .0002). CONCLUSIONS: Fracture risk was increased in subjects with sparse alveolar trabecular pattern. Dentists may be able to identify high-risk subjects before fracture. PMID- 19778735 TI - Clinical and stereologic evaluation of osteochondroma. AB - Osteochondroma is a benign tumor that is unusual in the maxillofacial region. Anatomy of the region, especially the mandible, is important for surgical intervention for the condylar osteochondroma. The present case report describes evaluation of condylar hyperplasia with emphasis on the advantages and disadvantages of sterolithographic solid model and stereologic techniques for preoperative surgical planning, operation time, and prognosis. Condylar osteochondoma was diagnosed by panoramic radiograph and 3-dimensional computerized tomography (3DCT) as well as histopathologic analysis in a male patient. Before surgery, a stereolithographic model was created and stereologic method was used based upon 3DCT. PMID- 19778736 TI - Influence of the NiTi rotary system on the debridement quality of the root canal space. AB - OBJECTIVE: The present study was designed to test the null hypothesis that there is no significant difference in debridement quality promoted by 3 nickel-titanium (NiTi) rotary systems. STUDY DESIGN: Sixty-seven vital mandibular molars that were prospectively collected in vivo were used. The teeth were extracted and then pulp tissue fixed by 10% formalin. The use of different NiTi rotary systems resulted in 3 experimental groups with 20 specimens each: G1: Hero 642; G2: K3; and G3: ProTaper Universal. Afterward, the specimens were histologically prepared and serial 0.5 microm cross-sections were obtained every 0.2 mm from the 1-3 mm apical levels. The remaining pulp tissue was assessed using a morphometric approach. The cross-sectional area of each root canal and remaining pulp tissue were measured (mcirom(2)). Thus, the percentages of remaining pulp tissue area were calculated for each root canal. RESULTS: Overall, the pooled data obtained from all levels revealed a variable amount of remaining pulp tissue for all experimental groups. Remaining pulp tissue existed in every specimen. However, the Kruskal-Wallis H test was unable to show significant differences among the experimental groups (P > .05) for the pooled data from all levels. CONCLUSIONS: The present study did not find a significant difference in the quality of canal debridement between different NiTi rotary systems, because an adequate tapered shape is obtained. PMID- 19778737 TI - Endodontic management of a mandibular first molar with three distal canals confirmed with the aid of spiral computerized tomography: a case report. AB - Identification and treatment of extra canals is the cornerstone to successful endodontic practice. Over the years, many diagnostic aids have evolved to facilitate the clinician in detection of hidden canals and to familiarize with the internal radicular anatomy. This case report highlights the rare incidence of 3 canals in the distal root of a permanent mandibular first molar. A spiral computerized tomography scan was used as a noninvasive diagnostic tool to confirm the diagnosis. PMID- 19778739 TI - Palatal ulcerations and midfacial swelling. PMID- 19778740 TI - Salivary dehydroepiandrosterone (DHEA) levels in patients with the complaint of burning mouth: a case-control study. AB - OBJECTIVE: This study was conducted to evaluate salivary dehydroepiandrosterone (DHEA) levels, salivary flow rate (SFR), depression, and hopelessness in patients with the complaint of burning mouth (BM). STUDY DESIGN: Thirty female patients with BM and 30 age-matched control women without any complaint of burning mouth were enrolled. After anamnesis and oral examination, the salivary flow rate was determined. Depression and hopelessness were evaluated by the application of inventories. Two saliva samples were collected for DHEA analysis. RESULTS: Dysgeusia (P = .045) and xerostomia (P = .003) were significantly higher in the BM group. The BM patients showed significantly lower salivary flow rate, both under stimulation (P = .001) and at rest (P < .001). Significant differences between the groups were not found in the depression (P = .416) or hopelessness (P = .597) scores. The BM group revealed significantly lower salivary DHEA levels in the morning samples (P = .003). CONCLUSION: Patients with BM exhibit decreased morning salivary DHEA as well as dysgeusia and hyposalivation more frequently than control subjects. Additional investigations are needed to clarify this association. PMID- 19778741 TI - Immunoglobulin G4-related sclerosing sialadenitis: report of two cases and review of the literature. AB - A new concept of IgG4-related disease characterized by a high serum IgG4 level and tissue infiltration of IgG4-positive plasmacytes that can involve salivary glands has been proposed. In this article, 2 patients with IgG4-related sclerosing sialadenitis involving the submandibular glands are reported. One patient presented with bilateral and painless swelling of the submandibular glands. He had already been treated with systemic prednisolone owing to the occurrence of retrobulbar neuritis. Laboratory examinations showed high serum IgG4 concentrations, and a biopsy of the submandibular gland revealed the infiltration of IgG4-positive plasmacytes. Abdominal computerized tomography demonstrated tumefaction in the tail of the pancreas, thus suggesting localized autoimmune pancreatitis. The other patient also showed bilateral and painless swelling of the submandibular glands, but there was no involvement of any other organs. These patients were effectively treated with corticosteroids, which resulted in a reduction of the swelling of the submandibular gland and increased saliva. When a patient is suspected of having sclerosing sialadenitis, it is important to consider that the patient may have a systemic IgG4-related plasmacytic disease. PMID- 19778743 TI - Case report of extragingival peripheral ameloblastoma in buccal mucosa. AB - A peripheral ameloblastoma (PA) is a rare variant of ameloblastoma that generally occurs in the extraosseous region; an extragingival PA is extremely rare. There have been 5 cases reported of a PA occurring in the buccal mucosa and 1 in the oral floor. We present the sixth known case of extragingival PA in the buccal mucosa, which occurred in an 88-year-old woman. PMID- 19778742 TI - Influence of oral hygiene in patients with fixed appliances in the oral carriage of antimicrobial-resistant Escherichia coli and Enterococcus isolates. AB - OBJECTIVES: The aim was to study the oral carriage of Enterococcus and Escherichia coli isolates and their content in antimicrobial-resistance and virulence genes in patients with fixed appliances and in healthy volunteers. STUDY DESIGN: Samples from supragingival plaques/tooth surfaces/fixed orthodontic appliances were taken in patients with fixed appliances (n = 46) and in healthy volunteers (n = 55). Samples were seeded on specific media for enterococcal and E. coli recovery, and 1 isolate of each type per sample was selected. Antimicrobial susceptibility and the presence of genes encoding antimicrobial resistance, bacteriocins, and virulence factors were checked by polymerase chain reaction. RESULTS: Enterococci or E. coli were not recovered from healthy volunteers. Nevertheless, 10 isolates (5 E. faecium, 3 E. faecalis, and 2 E. coli) were obtained from 19.5% of patients with fixed appliances, and poor oral hygiene was evidenced in all of the these patients. Percentages of antimicrobial resistance and the resistance genes detected among the enterococci were: erythromycin: 100%, erm(B); kanamycin: 75%, aph(3')-IIIa; tetracycline: 50%, tet(L) with/without tet(M); streptomycin: 37%, ant(6)-Ia; chloramphenicol: 12%, catA. One E. coli isolate showed a phenotype of multiresistance containing 5 resistance genes and class 1 and 2 integrons. All enterococci produced gelatinase, and 4 isolates contained genes encoding enterocins L50A/B and P. The esp virulence gene was found in 1 multiresistant E. faecalis isolate. CONCLUSIONS: Poor or improper oral hygiene in individuals with fixed appliances favors the oral carriage of antimicrobial-resistant E. coli and enterococci. Additional investigations are needed to assess its implication in human health. PMID- 19778744 TI - Dr. Allan G. Farman installed as President, American Academy of Oral and Maxillofacial Radiology, October 2009. PMID- 19778745 TI - Microanatomy of the incisive canal using three-dimensional reconstruction of microCT images: an ex vivo study. AB - OBJECTIVES: The purpose of this study was to investigate the general structure of the incisive canal (IC) using 3-dimensional reconstruction and to classify into various types according to several criteria. STUDY DESIGN: The materials used in the study were 56 anterior maxillae harvested from human cadavers. The specimens were scanned with microscopic computerized tomography (microCT), and the resulting microCT images were reconstructed in 3 dimensions. RESULTS: Many ICs had 1 foramen inferiorly and 2 foramina superiorly, and the separating level was just beneath the nasal floor. The middle part of the IC was not always a single hollow canal. Single-channel, 2-channel, 3-channel, and even 4-channel ICs were observed. The ICs were classified into 4 types according to the lateral shape of the canal: vertical-straight, vertical-curved, slanted-straight, and slanted curved. CONCLUSIONS: This study disclosed the detailed morphologic features of the IC, which will be helpful in the placement of local anesthesia or implants. PMID- 19778746 TI - Distortional effect of beam-hardening artefacts on microCT: a simulation study based on an in vitro caries model. AB - OBJECTIVE: The aim of this study was to assess quantitatively the degrading effect of artefacts caused by beam hardening on the microscopic computerized tomography (microCT) measurements of an in vitro caries model. STUDY DESIGN: A simulation-based method was described, with which the degrading effect of microCT artefacts on certain parameters of the observed structure could be determined. Simulations were carried out with polychromatic and monochromatic X-ray source, and a linearization method with a second-order polynomial fit algorithm was used in specific cases to correct the beam hardening artefact. The virtual test object was a half-crown of a tooth with an artificial caries lesion. RESULTS: For simulation with monochromatic X-ray source, the relative error of lesion depth and thickness measurements of the remineralized layer was found to be 1%-2%. For polychromatic X-ray source, and omitting beam hardening correction, the relative error exceeded 6%. After appropriate beam-hardening correction, the relative error of the measurement could be reduced to 1%-2%. CONCLUSION: With the adjustment simulated in this study, microCT having polychromatic X-ray source resulted in the same level of error as with monochromatic source if the linearization method to correct the beam hardening was used. The presented simulation-based method is a useful way to determine artefact-caused distortions for other studies testing objects with different material and geometry. PMID- 19778747 TI - The development and initial validation of a new measure of male body dissatisfaction. AB - The purpose of this research was to develop, and establish the initial psychometric properties of, the Male Body Dissatisfaction Scale (MBDS). Ninety five male students were recruited over three phases. An item-remainder analysis was performed in phase I, convergent and discriminant validity assessed in phase II, and test-retest reliability and factor structure assessed in phase III. The MBDS achieved an alpha level of 0.93 and was inversely related to body esteem (p=0.02) and self-esteem (p=0.03), and positively related to how much participants' opinion of themselves was based on their body shape and weight (p<0.01). The MBDS was not related to measures of affect, and was able to distinguish between males endorsing, and not endorsing, elevated body shape and weight concerns (p<0.05). Finally, the MBDS displayed a test-retest reliability coefficient of 0.96 (p<0.01). Findings suggest that the MBDS may fill the need for a reliable and valid measure of body dissatisfaction that allows men to weight particular aspects of their body image according to personal importance. PMID- 19778748 TI - Associations among body size dissatisfaction, perceived dietary control, and diet history in African American and European American women. AB - European American (EA) women report greater body dissatisfaction and less dietary control than do African American (AA) women. This study investigated whether ethnic differences in dieting history contributed to differences in body dissatisfaction and dietary control, or to differential changes that may occur during weight loss and regain. Eighty-nine EA and AA women underwent dual-energy X-ray absorptiometry to measure body composition and completed questionnaires to assess body dissatisfaction and dietary control before, after, and one year following, a controlled weight-loss intervention. While EA women reported a more extensive dieting history than AA women, this difference did not contribute to ethnic differences in body dissatisfaction and perceived dietary control. During weight loss, body satisfaction improved more for AA women, and during weight regain, dietary self-efficacy worsened to a greater degree for EA women. Ethnic differences in dieting history did not contribute significantly to these differential changes. Although ethnic differences in body image and dietary control are evident prior to weight loss, and some change differentially by ethnic group during weight loss and regain, differences in dieting history do not contribute significantly to ethnic differences in body image and dietary control. PMID- 19778750 TI - Confirmatory and exploratory factor analysis of the distress tolerance scale (DTS) in a clinical sample of eating disorder patients. AB - A confirmatory factor analysis of the factor structure of the Distress Tolerance Scale (DTS) created by Corstorphine et al. [Corstorphine, E., Mountford, V., Tomlinson, S., Waller, G., & Meyer, C. (2007). Distress tolerance in the eating disorders. Eating Behaviors, 8, 91-97.] was conducted to assess whether the scale's purported three factors emerged in a clinical sample of patients with a DSM-IV diagnosed eating disorder. The original three-factor model was generally considered to be a poor fit for the data. Subsequent exploratory factor analysis indicated that a better fit emerged using a four-factor structure. Significant associations were observed between behavioral avoidance of positive affect and eating disorder psychopathology. Implications for use of the DTS with eating disorder patients are discussed. PMID- 19778749 TI - Energy density at a buffet-style lunch differs for adolescents born at high and low risk of obesity. AB - The energy density (ED; kcal/g) of foods, when manipulated in the laboratory, affects short-term energy intake. The aim of this study was to examine if, when given a choice, dietary ED (foods only) and energy intake (expressed as a percentage of subjects' estimated daily energy requirement; EER) at a self selected, single meal differ for teens born with a different familial predisposition to obesity and as a function of their sex. Subjects (13 males, 17 females) were 12years of age and born at high risk (HR; n=15) or low risk (LR; n=15) for obesity based on maternal pre-pregnancy body mass index (BMI; kg/m(2)). The buffet meal, served for lunch and consumed ad libitum, consisted of a variety of foods and beverages with a range in ED. HR subjects consumed a more energy dense meal (foods only) than LR subjects (1.84 vs. 1.42kcal/g; P=0.02) and males consumed a more energy-dense meal than females (1.83 vs. 1.43kcal/g; P=0.03). Total energy intake, when expressed as a percentage of subjects' daily EER, did not differ between HR and LR subjects (42% vs. 33%; P=0.16). Males, compared to females, consumed ~59% more energy from foods and beverages during the meal (46 vs. 29%; P=0.008). During a single multi-item lunch meal, teens with a familial predisposition to obesity and males, independent of their obesity risk status, self-selected a more energy-dense meal. Familial risk for obesity, through either genetic or environmental pathways, may facilitate a more energy-dense diet. PMID- 19778751 TI - Adherence and weight loss outcomes associated with food-exercise diary preference in a military weight management program. AB - The more consistently someone records their food intake the more likely they are to lose weight. We hypothesized that subjects who kept track via their preferred method would demonstrate higher adherence and therefore improved outcomes compared to those who used a non-preferred method. Participants were randomly assigned to use a paper, PDA, or Web-based diary and classified as "Preferred" if they used their preferred method and "Non-Preferred" if they did not. Days adherent to diary use were collected for 12 weeks. Weight, % body fat, waist circumference, and self-efficacy scores were measured at baseline, 6 and 12 weeks. Thirty nine participants completed the 12 week study. Fifty nine percent were male. The mean age was 35 and mean baseline BMI was 33 kg/m(2) (+/-3.5). Forty four % (n=17) used their "Preferred" diary method and 56% (n=22) did not. Participants who used their preferred diary were more adherent to recording both food intake (64.2% vs. 43.4%, p=.015) and exercise (60.6% vs. 31.2%, p=.001). Though no difference was seen between groups on weight management outcomes, these results suggest that diary preference affects adherence to diary use. PMID- 19778752 TI - Bulimic symptoms in undergraduate men and women: Contributions of mindfulness and thought suppression. AB - Experiential avoidance, the refusal to accept contact with unpleasant private experiences, is believed to play a role in the onset and maintenance of eating disorders. Preliminary evidence suggests that mindfulness- and acceptance-based interventions that reduce avoidance may be effective in treating disordered eating behaviors. The purpose of the current investigation was to examine whether one form of experiential avoidance (thought suppression) and the theoretically opposing construct of dispositional mindfulness are associated with bulimic symptoms. Undergraduate men (n=219) and women (n=187) completed questionnaires assessing mindful attention and awareness, chronic thought suppression, and bulimic symptoms. A series of hierarchical regression analyses revealed that thought suppression and mindfulness accounted for unique variance in bulimic symptoms among men and women after accounting for BMI. Results are discussed in terms of the role of dispositional mindfulness and thought suppression in disordered eating. PMID- 19778753 TI - Moderators of physical activity and obesity during adolescence. AB - The purpose of this study was to examine possible moderators of the relation between physical activity and obesity in adolescence. Adolescents (N=168; mean age=15.20 years; 52.4% girls; 76.8% African American) were recruited from low income primary care medical facilities in a large southern city. Measures included Body Mass Index (BMI) percentile, physical activity, shared family physical activity, and self-efficacy for healthful eating. Multiple regression analyses were conducted to investigate a) independent contributions of physical activity, shared family activity, and self-efficacy for healthful eating to the prediction of adolescent BMI percentile; b) interactions between shared and individual physical activity in the prediction of BMI percentile; c) interactions between self-efficacy for healthful eating and physical activity in the prediction of BMI percentile; and d) interactions among all three variables. Findings revealed self-efficacy for healthful eating was a significant moderator of the adolescent physical activity and BMI percentile relation. Conclusions emphasize the interactive nature among obesity risk factors. PMID- 19778755 TI - The utility of considering interpersonal problems in the assessment of bulimic features. AB - Previous research suggests that heterogeneity in bulimic features can be explained in part by pathoplastic, or varying, interpersonal problems. The present study compared groups of women with bulimic features (N=110) defined by varying interpersonal problems (warm-dominant, warm-submissive, cold-submissive, or cold-dominant) with regard to comorbid psychopathology, personality characteristics, and the influences of dietary restraint and negative affectivity on bulimic psychopathology. As predicted, group differences were not explained by severity of eating-related pathology, socially desirable responding, or the interpretability of interpersonal profiles, although groups unexpectedly differed in depressive symptoms. The warm-submissive group had highest scores on adaptive personality characteristics, including, agreeableness, extraversion, and conscientiousness. As hypothesized, the influence of negative affect and dietary restraint on bulimic symptoms differed as a function of interpersonal style, perhaps suggesting that interpersonal problem heterogeneity may mark different etiological pathways for bulimic psychopathology. Finally, interpersonal problems incremented bulimic features in predicting depressive symptoms. Overall, these results highlight the added value of considering pathoplastic interpersonal problems in addition to clinical diagnoses in the assessment of eating disorders. PMID- 19778754 TI - Beverage consumption and adult weight management: A review. AB - Total energy consumption among United States adults has increased in recent decades, and energy-containing beverages are a significant contributor to this increase. Because beverages are less satiating than solid foods, consumption of energy-containing beverages may increase energy intake and lead to weight gain; trends in food and beverage consumption coinciding with increases in overweight and obesity support this possibility. The purpose of this review is to present what is known about the effect of beverage consumption on short-term (i.e., meal) energy intake, as well as longer-term effects on body weight. Specific beverages addressed include water, other energy-free beverages (diet soft drinks, coffee and tea), and energy-containing beverages (soft drinks, juices and juice drinks, milk and soy beverages, alcohol). Existing evidence, albeit limited, suggests that encouraging water consumption, and substituting water and other energy-free beverages (diet soft drinks, coffee and tea) for energy-containing beverages may facilitate weight management. Energy-containing beverages acutely increase energy intake, however long-term effects on body weight are uncertain. While there may be health benefits for some beverage categories, additional energy provided by beverages should be compensated for by reduced consumption of other foods in the diet. PMID- 19778756 TI - Pandemic influenza: the new wave. PMID- 19778757 TI - Immigrant tuberculosis: beyond screening and surveillance. PMID- 19778758 TI - Cefepime and mortality. PMID- 19778759 TI - The availability of drugs for rich and poor people in developing countries. PMID- 19778760 TI - Beyond cholera-the Zimbabwe health crisis. PMID- 19778761 TI - Dogs can harbour more than fleas. PMID- 19778762 TI - Influenza as a trigger for acute myocardial infarction or death from cardiovascular disease: a systematic review. AB - Cardiac complications of influenza infection, such as myocarditis, are well recognised, but the role of influenza as a trigger of acute myocardial infarction is less clear. We did a systematic review of the evidence that influenza (including influenza-like illness and acute respiratory infection) triggers acute myocardial infarction or cardiovascular death. We examined the effectiveness of influenza vaccines at protecting against cardiac events and did a meta-analysis of data from randomised controlled trials. 42 publications describing 39 studies were identified. Many observational studies in different settings with a range of methods reported consistent associations between influenza and acute myocardial infarction. There was weaker evidence of an association with cardiovascular death. Two small randomised trials assessed the protection provided by influenza vaccine against cardiac events in people with existing cardiovascular disease. Whereas one trial found that influenza vaccination gave significant protection against cardiovascular death, the other trial was inconclusive. A pooled estimate from a random-effects model suggests a protective, though non-significant, effect (relative risk 0.51, 95% CI 0.15-1.76). We believe influenza vaccination should be encouraged wherever indicated, especially in people with existing cardiovascular disease, among whom there is often suboptimum vaccine uptake. Further evidence is needed on the effectiveness of influenza vaccines to reduce the risk of cardiac events in people without established vascular disease. PMID- 19778763 TI - Global emm type distribution of group A streptococci: systematic review and implications for vaccine development. AB - emm sequence typing is the most widely used method for defining group A streptococcal (GAS) strains, and has been applied to isolates in all regions of the world. We did a systematic review of the global distribution of GAS emm types. 102 articles and reports were included (38 081 isolates). Epidemiological data from high-income countries were predominant, with sparse data from low income countries. The epidemiology of GAS disease in Africa and the Pacific region seems to be different from that in other regions, particularly high-income countries. In Africa and the Pacific, there were no dominant emm types, a higher diversity of emm types, and many of the common emm types in other parts of the world were less common (including emm 1, 4, 6, and 12). Our data have implications for the development of GAS vaccines. On the basis of the available data, the current formulation of the experimental multivalent emm vaccine would provide good coverage in high-income countries, particularly USA, Canada, and Europe, but poor coverage in Africa and the Pacific, and only average coverage in Asia and the Middle East. PMID- 19778764 TI - Susceptibility relationship between vancomycin and daptomycin in Staphylococcus aureus: facts and assumptions. AB - The decrease in vancomycin treatment efficacy that is accompanying increases in vancomycin minimum inhibitory concentration (MIC) within the susceptible range (so-called MIC creep) has led to the suggestion that vancomycin is losing its potency in treating serious Staphylococcus aureus infections. Understanding the clinical importance of the microbiological effects of glycopeptides on bacterial lipopeptides and lipoglycopeptides will be crucial in treating serious meticillin resistant S aureus infections. We review the observed effects of reduced glycopeptide susceptibility on the activities of daptomycin in S aureus in vitro and in vivo. Factors associated with loss of susceptibility and ways to reduce the risk of resistance to daptomycin are reviewed, including the importance of prompt mechanical reduction of bacterial inoculum through surgery or through potent or combination antibiotic therapy, as well as optimisation of daptomycin pharmacodynamic exposure. PMID- 19778767 TI - Not always HIV. PMID- 19778766 TI - Successes, challenges, and limitations of current antiretroviral therapy in low income and middle-income countries. AB - As a result of the scale-up of antiretroviral treatment (ART) programmes and substantial financial support worldwide, an increasing number of HIV-infected individuals in low-income and middle-income countries (LIMCs) now have access to ART. Despite this progress, important questions remain on the best use of ART and how patients should be maintained on a successful regimen. This Review addresses some of the issues faced by those managing the epidemic in LMICs, including when to start treatment, choice of first-line ART, and when to switch regimens. Although the first priority must be continued expansion of access to ART, there should be a move towards starting ART earlier to treat individuals before they reach advanced stages of disease, to reduce early mortality, and to build support for improved monitoring of treatment failure. There is also a need for more randomised controlled studies to identify the long-term outcomes, cost effectiveness of ART, and use of virological monitoring in LMICs. PMID- 19778765 TI - Progressive multifocal leukoencephalopathy in HIV-1 infection. AB - Progressive multifocal leukoencephalopathy is caused by the JC polyomavirus (JCV) and is one of the most feared complications of HIV-1 infection. Unlike other opportunistic infections, this disease can present when CD4 counts are higher than those associated with AIDS and when patients are receiving combined antiretroviral therapy, either shortly after starting or, more rarely, during long term successful treatment. Clinical suspicion of the disease is typically when MRI shows focal neurological deficits and associated demyelinating lesions; however, the identification of JCV in cerebrospinal fluid or brain tissue is needed for a definitive diagnosis. Although no specific treatment exists, the reversal of immunosuppression by combined antiretroviral therapy leads to clinical and MRI stabilisation in 50-60% of patients with the disease, and JCV clearance from cerebrospinal fluid. A substantial proportion of patients treated with combined antiretroviral therapy develop inflammatory lesions, which can be associated with either a favourable outcome or clinical worsening. The reasons for variability in the natural history of progressive multifocal leukoencephalopathy and treatment responses are largely undefined, and more specific and rational approaches to management are needed. PMID- 19778768 TI - Transcatheter aortic valve implantation: review of the nature, management, and avoidance of procedural complications. AB - Transcatheter aortic valve implantation (TAVI) is becoming a reality in the management of patients with severe aortic stenosis and high or prohibitive risk for standard surgical management. Current understanding of the potential adverse events associated with this procedure is limited. Risks associated with TAVI differ from those related to surgical valve replacement and include vascular injury; stroke; cardiac injury such as heart block, coronary obstruction, and cardiac perforation; paravalvular leak; and valve misplacement. The clinical experience of multiple centers experience with different valve implantation systems and techniques was reviewed. Awareness of how complications occur might help in their avoidance, recognition, and management. Ultimately, improved understanding of the potential complications associated with TAVI might help improve outcomes and allow wider application of this therapy. PMID- 19778769 TI - Determinants of significant paravalvular regurgitation after transcatheter aortic valve: implantation impact of device and annulus discongruence. AB - OBJECTIVES: The aim of this study was to assess prosthesis/annulus discongruence and its impact on the occurrence of significant aortic regurgitation (AR) immediately after transcatheter aortic valve implantation (TAVI). BACKGROUND: Paravalvular AR might occur after TAVI, but its determinants remain unclear. METHODS: Comprehensive echocardiographic examinations were performed in 74 patients who underwent TAVI with a balloon expandable device. Congruence between annulus and device was appraised with the cover index: 100 x (prosthesis diameter - transesophageal echocardiography annulus diameter)/prosthesis diameter. RESULTS: At baseline aortic valve area was 0.67 +/- 0.2 cm(2), and mean gradient was 50 +/- 15 mm Hg. The TAVI used transfemoral approach in 46 patients (62%) and transapical access in 28 (38%). Prosthesis size was 23 mm in 24 patients (34%) and 26 mm in 50 patients (66%). After TAVI, paravalvular AR was absent in 5 patients (7%), graded 1/4 in 53 (72%), 2/4 in 12 (16%), and 3/4 in 4 (5%). Occurrence of AR >or=2/4 was related to greater patient height, larger annulus, and smaller cover index (all p < 0.002) but not to ejection fraction, severity of stenosis, or prosthesis size. AR >or=2/4 was never observed in patients with aortic annulus <22 mm or with a cover index >8%. Significant improvements were observed from the first 20 cases (AR >or=2/4, 40%) to the last 54 (AR >or=2/4, 15%) (p = 0.02). In multivariate analysis, independent predictors of AR >/=2/4 were low cover index (odds ratio: 1.22; per confidence interval: 1.03 to 1.51 per 1% decrease, p = 0.02) and first versus last procedures (odds ratio: 2.24; 95% confidence interval: 1.07 to 5.22, p = 0.03). CONCLUSIONS: Our study shows that the occurrence of AR >or=2/4 is related to prosthesis/annulus discongruence even after adjustment for experience. Hence, to minimize paravalvular AR, appropriate annular measurements and prosthesis sizing are critical. PMID- 19778770 TI - Expanding the eligibility for transcatheter aortic valve implantation the trans subclavian retrograde approach using: the III generation CoreValve revalving system. AB - OBJECTIVES: Our aim was to assess the safety and feasibility of the retrograde trans-subclavian approach to transcatheter aortic valve implantation (TAVI) in selected high-risk patients with aortic stenosis (AS) and severe peripheral vasculopathy. BACKGROUND: TAVI is an emerging therapeutic option to treat inoperable/high-risk patients affected by symptomatic AS. However, these patients are also often affected by severe iliac-femoral arteriopathy, rendering the transfemoral approach unemployable for percutaneous revalving procedure. METHODS: From among those patients in our department between May 2007 and December 2008, who were refused surgical aortic valve replacement because of high surgical risk and were ineligible for transfemoral percutaneous aortic valve replacement, we scheduled 3 for TAVI by the subclavian approach. Procedures were performed by a combined team of cardiologists, cardiac surgeons, and anesthetists in the catheterization laboratory. The III generation CoreValve Revalving System (CoreValve Inc., Irvine, California) with an 18-F delivery system was introduced in all cases by the left subclavian artery. RESULTS: Prosthetic valves were successfully implanted in all 3 cases, leading to a fall in transvalvular gradient without significant paravalvular regurgitation. No intraprocedural or periprocedural complications occurred. Two patients developed an atrioventricular block requiring the implantation of a permanent pacemaker. All patients were discharged in asymptomatic status, with good prosthesis performance. No adverse events occurred within the 3-month follow-up. CONCLUSIONS: TAVI by subclavian retrograde approach seems safe and feasible in inoperable/high-risk patients with AS and peripheral vasculopathy, who are neither eligible for surgical valve replacement nor transfemoral percutaneous aortic valve implantation. Further studies are needed to evaluate the long-term efficacy of this new therapy. PMID- 19778771 TI - Retrograde techniques and the impact of operator volume on percutaneous intervention for coronary chronic total occlusions an early U.S. experience. AB - OBJECTIVES: Our purpose was to determine if "Japanese style" technical strategies can be successfully applied in the U.S. practice environment and to better understand the learning curve for chronic total occlusion (CTO) percutaneous coronary intervention (PCI). BACKGROUND: Procedural technical success remains the major limiting factor for CTO PCI, and has been unchanged over time. METHODS: Demographic, procedural, and outcome data were collected on 636 consecutive patients between January 2005 and March 2008 having CTO PCI (514 antegrade, 122 retrograde attempts) at 2 U.S. medical centers. Operators were divided into 2 groups: higher CTO volume, retrograde operators (ROs) (>75 total CTO PCI cases and >20 retrograde attempts during the study period) and lower CTO volume, nonretrograde operators (NROs) to evaluate the impact of CTO-specific operator case volume and retrograde techniques on procedural outcomes. RESULTS: Two operators met the criteria for RO category and 10 were NRO. ROs performed 395 CTO PCI cases (mean total CTO case experience = 197.5, 60 retrograde) and NROs performed 241 CTO PCI cases (mean total CTO case experience = 24.1, <1 retrograde) during the observed timeframe. The overall technical success was 58.9% for NROs and 75.2% for ROs (p < 0.0001). The technical success rate of NROs did not change, but the technical success for the ROs increased to 90% over time (p < 0.0001 for trend, 94.4% for retrograde and 85.7% for antegrade approaches). Observed major adverse events were similar between ROs and NROs. CONCLUSIONS: Complex antegrade and retrograde "Japanese style" PCI approaches can be applied in the U.S. practice environment with high technical success and low adverse event rates. Higher CTO-specific operator case volume is associated with improved technical success rates. PMID- 19778772 TI - Import and export of interventional technique: something to declare at the border. PMID- 19778773 TI - Intravascular ultrasound comparison of the retrograde versus antegrade approach to percutaneous intervention for chronic total coronary occlusions. AB - OBJECTIVES: We sought to evaluate the results of the antegrade versus retrograde chronic total occlusion (CTO) technique with intravascular ultrasound (IVUS) imaging. BACKGROUND: The most common failure mode of CTO interventions remains the inability to successfully cross the occlusion with a guidewire. Recently, the retrograde approach through collateral channels has been introduced to cross complex CTOs. METHODS: Between October 2002 and April 2008, IVUS was performed in 48 de novo CTO lesions after guidewire crossing +/- pre-dilation with a 1.5- to 2.0-mm balloon. Twenty-three lesions were treated via the antegrade approach (Ante), and 25 lesions were treated via the retrograde approach (Retro). RESULTS: Right coronary artery (RCA) CTOs were treated more frequently via the Retro technique. Although the CTO length was much longer in the Retro group (45 +/- 26 mm vs. 18 +/- 9 mm, p < 0.0001), at the end of the procedure Thrombolysis In Myocardial Infarction flow grade 3 was obtained in all patients. There were no significant differences between the 2 groups in minimum stent area and stent expansion. However, the incidence of the composite end point-subintimal wiring, angiographic extravasation, coronary hematoma, or IVUS-detected coronary perforation-was higher in the Retro group (68% vs. 30%, p = 0.01); and the guidewire was more often subintimal in the Retro group (40% vs. 9%, p = 0.02). CONCLUSIONS: The retrograde approach is a promising option for complex CTO segments, especially long RCA CTOs. Intravascular ultrasound can be a useful tool for the detection of procedure-related vessel damage and subintimal wire tracking. PMID- 19778774 TI - Clinical presentation and angiographic characteristics of saphenous vein graft failure after stenting: insights from the SOS (stenting of saphenous vein grafts) trial. AB - OBJECTIVES: We sought to compare the clinical presentation and angiographic patterns of saphenous vein graft (SVG) failure after stenting with a paclitaxel eluting stent (PES) versus a similar bare-metal stent (BMS). BACKGROUND: The mode of SVG failure after stenting has been poorly characterized. METHODS: The SOS (Stenting Of Saphenous Vein Grafts) trial enrolled 80 patients with 112 lesions in 88 SVGs who were randomized to a BMS or PES. Angiographic follow-up at 12 months was available in 83% of the patients. RESULTS: Binary angiographic restenosis occurred in 51% (24 of 47) of BMS-treated lesions versus 9% (4 of 43) of PES-treated lesions (p < 0.0001). Graft occlusion occurred in 9 of the 21 SVGs (43%) that failed in the BMS group and in 2 of 4 SVGs (50%) that failed in the PES group. SVG failure after stenting presented as an acute coronary syndrome in 10 of the 24 patients (42%) (7 of those 10 patients presented with non-ST-segment elevation acute myocardial infarction), stable angina in 9 (37%) patients, and without symptoms in 5 (21%) patients. Of the 19 patients (with 20 grafts) who developed symptomatic graft failure, repeat SVG revascularization was successfully performed in all 13 (100%) subtotally obstructed SVGs but was attempted (and successful) in only 1 of 7 (14%) occluded SVGs. Revascularization of a native coronary artery was performed in an additional 4 of 7 (57%) symptomatic patients with an occluded SVG. CONCLUSIONS: SVG failure after stenting often presents as acute myocardial infarction and with SVG occlusion. Compared with BMS, PES reduce SVG failure. PMID- 19778775 TI - Impact of vessel size on angiographic and clinical outcomes of revascularization with biolimus-eluting stent with biodegradable polymer and sirolimus-eluting stent with durable polymer the LEADERS trial substudy. AB - OBJECTIVES: We assessed the impact of vessel size on outcomes of stenting with biolimus-eluting degradable polymer stent (BES) and sirolimus-eluting permanent polymer stent (SES) within a randomized multicenter trial (LEADERS). BACKGROUND: Stenting of small vessels might be associated with higher rates of adverse events. METHODS: "All-comer" patients (n = 1,707) were randomized to BES and SES. Post-hoc-stratified analysis of angiographic and clinical outcomes at 9 months and 1 year, respectively, was performed for vessels with reference diameter 2.75 mm. RESULTS: Of 1,707 patients, 429 patients in the BES group with 576 lesions and 434 patients in the SES group with 557 lesions had only small vessels treated (50.6% of the patient cohort). In patients with small vessels there was no significant difference in overall major adverse cardiac events (MACE) rate (12.1% vs. 11.8%; p = 0.89) or target lesion revascularization (TLR) rate (9.6% vs. 7.4%; p = 0.26) between BES and SES. The MACE and TLR rates in the small-vessel patient population were higher than in the large-vessel population. The TLR rate was 9.6% versus 2.6%, and MACE rate was 12.1% versus 7.1% for small versus large vessels in the BES arm (TLR: hazard ratio [HR] = 3.724, p = 0.0013; MACE: HR = 1.720, p = 0.0412). In the SES arm, TLR was 7.4% versus 5.1%, and MACE was 11.8% versus 10.3% in small versus large vessels (TLR: HR = 1.435, p = 0.2594; MACE: HR = 1.149, p = 0.5546). CONCLUSIONS: Prevalence of small vessel disease is high in an "all-comer" population with higher TLR and MACE rates. The BES and SES seem equivalent in treatment outcomes of small vessels in this "all-comer" patient population. PMID- 19778776 TI - Comparison of safety and efficacy of bivalirudin versus unfractionated heparin in percutaneous peripheral intervention: a single-center experience. AB - OBJECTIVES: The aim of this study was to determine the efficacy and safety of bivalirudin versus low-dose unfractionated heparin (UFH) in percutaneous peripheral intervention (PPI). BACKGROUND: Anticoagulation strategies used in PPI are based primarily on studies of percutaneous coronary intervention where higher doses of heparin are used usually in combination with a glycoprotein IIb/IIIa inhibitor. There are no studies comparing bivalirudin alone versus low-dose heparin in PPI. METHODS: Consecutive patients who underwent PPI at our institution were treated with either bivalirudin or low-dose UFH. Patients were assessed prospectively during index hospital stay for procedural success and bleeding complications. Of 236 patients, 111 were dosed with UFH at 50 U/kg (goal activated clotting time of 180 to 240 s), and 125 were dosed with bivalirudin at 0.75-mg/kg/h bolus followed by a 1.75-mg/kg infusion. Procedural success was defined as <20% post-procedure residual stenosis with no flow-limiting dissections or intravascular thrombus formation and major bleeding as intracranial or retroperitoneal hemorrhage or a fall in hemoglobin >or=5 g/dl. Anticoagulation cost analysis was conducted. RESULTS: Procedural success and major bleeding rates were similar with bivalirudin versus heparin (98% vs. 99% and 2.4% vs. 0.9%, respectively). There were no differences in minor bleeding, time to ambulation, and length of hospital stay. The hospital cost for bivalirudin was $547 and <$1.22 for heparin (10,000 U). Two activated clotting time levels cost $4.00. CONCLUSIONS: Low-dose UFH is as effective and safe as bivalirudin when used as an anticoagulation strategy in patients undergoing PPI, and low-dose UFH is less costly than bivalirudin. Larger randomized studies are required to further evaluate these findings. PMID- 19778777 TI - Stent implantation for coarctation of the aorta in children <30 kg. AB - OBJECTIVES: Our aim was to determine key characteristics of stents commonly implanted in the aorta through bench testing and to describe our technique and acute results in patients weighing <30 kg. BACKGROUND: Despite the increasing use of stents for interventional treatment for coarctation of the aorta (CoA) in larger patients, use of large stents is controversial in small children. METHODS: Methods included bench testing of large stents, and retrospective review of all patients over 1 year of age who had stent implantation for treatment of CoA. Patients were divided into 2 groups based on weight. Paired comparisons were made before and after stent implantation, and group outcomes were compared. RESULTS: Sixty patients comprised the entire sample, with 22 patients assigned to group I (<30 kg) and 38 patients assigned to group II (>or=30 kg). The mean minimum diameters of the CoA (group I 5.0 to 10.7 mm; group II 8.0 to 15.0 mm) and the ratio of the coarctation diameter to the descending aorta diameter measured at the level of the diaphragm (CoA/DAo ratio) (group I 0.4 to 0.93; group II 0.46 to 0.94) increased significantly in both groups (all p < 0.05). The mean systolic gradient decreased significantly in both groups (group I 23.0 to 2.0 mm Hg; group II 24.0 to 2.8 mm Hg; both p = 0.001). No difference was found between the groups in the CoA/DAo ratio, residual systolic gradients, or the decrease in systolic gradient after stent implantation. There were no significant complications in patients under 30 kg. CONCLUSIONS: As in larger patients, use of large stents for treatment of CoA in small children is effective and safe in the short term. In these patients, stent redilations will be required, and follow-up is ongoing. PMID- 19778778 TI - Stents in the management of aortic coarctation in young children. PMID- 19778779 TI - Complications of carotid stenting during live transmissions. AB - OBJECTIVES: We sought to examine the acute and subacute results of carotid stenting performed during live transmissions. BACKGROUND: Teaching courses focusing on live demonstrations of carotid interventions have been the key educational facility for physicians interested in learning state-of-the-art interventional techniques of carotid stenosis treatment. However, starting with the very first live demonstration of interventional procedures, there has been an ongoing discussion whether patients treated during live transmissions are at higher risk. METHODS: Between March 1, 2001, and June 30, 2008, 186 high-grade lesions of the internal carotid artery in 186 patients have been treated by stent implantation during live transmissions to 22 interventional conferences at 3 high volume centers. Technical success was defined as the ability to perform carotid stent implantation. The combined end point of death, major stroke, minor stroke, or myocardial infarction was defined as primary end point. RESULTS: The procedure was technically successful in 185 of 186 (99.5%) interventions. Seventeen patients had 1 of the following acute in-hospital complications: major stroke in 2 (1.1%), minor stroke in 3 (1.6%), transient ischemic attack in 11 (5.9%), and amaurosis of the ipsilateral eye due to an occlusion of the retinal artery in 1 (0.5%). None of the patients died, and no myocardial infarctions occurred. The composite primary end point occurred in 6 (3.2%) patients. CONCLUSIONS: In this consecutive series of carotid stent cases performed by expert operators during live demonstration courses, the procedural and 30-day clinical outcomes were similar to the results appearing in the contemporary published data. PMID- 19778780 TI - Ethical considerations of live case transmissions. PMID- 19778781 TI - Reduced reimbursement for cardiovascular services by the Centers for Medicare and Medicaid Services: perspective from interventional cardiology. PMID- 19778782 TI - Transfemoral aortic valve implantation with pre-existent mechanical mitral prosthesis: evidence of feasibility. PMID- 19778783 TI - Is the pen mightier than the stent? PMID- 19778784 TI - [Relationship between myocardial systolic, diastolic functions and perfusion in coronary artery stenosis]. AB - OBJECTIVE: To evaluate the relationship between myocardial systolic, diastolic functions and perfusion in coronary artery stenosis using velocity vector imaging (VVI) and myocardial contrast echocardiography (MCE). METHODS: Stenoses in the anterior descending branch of the coronary artery were induced in 8 dogs. Before and after coronary artery stenosis, two-dimensional images of the left ventricular mastoid muscle section on the short axis at rest and in the peak dose of dobutamine were obtained for evaluation of VVI and MCE. The myocardial blood flow A.beta values, peak systolic strain rate (SRsys) and peak diastolic strain rate (SRdia) in the direction of the circumference of the short axis were measured. RESULTS: At rest, only severe coronary stenosis resulted in significantly lowered SRsys, SRdia and A.beta value of the stenotic bed compared to the values before the stenosis (-1.1-/+0.50 vs -1.62-/+0.50, 1.19-/+0.48 vs 1.75-/+0.51, 0.4-/+0.21 vs 0.80-/+0.47, P<0.05). In stress, SRsys, SRdia and A.beta value of the stenotic bed gradually decreased as coronary stenosis worsened (-4.31-/+1.14 vs -3.20-/+0.98 vs -1.18-/+0.64, 4.51-/+1.13 vs 3.39 /+0.98 vs 1.37-/+0.64. 3.54-/+1.95 vs 1.81-/+0.89 vs 0.82-/+0.42, P<0.05). Both at rest and in stress, good correlations were noted between SRsys and SRdia (r(rest)=0.88, r(stress)=0.96, P<0.01), between SRsys and the standard A.beta values (r(rest)0.56, r(stress)=0.71, P<0.01), and between SRdia and A.beta (r(rest)=0.57, r(stress)=0.72, P<0.01) in the direction of the circumference of the short axis. CONCLUSIONS: Using VVI and MCE, the changes in myocardial perfusion and the systolic and diastolic functions in the direction of the circumference can be observed dynamically. VVI may help assess the condition of myocardial perfusion by evaluating the systolic and diastolic function. PMID- 19778785 TI - [Effects of RNA interference against aggrecanase 1 gene on extracellular matrix metabolism of cultured chondrocytes in vitro]. AB - OBJECTIVE: To study the effect of RNA interference (RNAi)-mediated aggrecanase-1 gene silencing on extracellular matrix metabolism of cultured rat costochondral chondrocytes. METHODS: Rat costochondral chondrocyte monolayers were obtained by microdissection and digestion. The growth and morphological changes of the chondrocytes were observed after RNAi of aggrecanase-1 gene. The mRNA expression of aggrecanase-1 was detected by RT-PCR method, and aggrecan content was determined by Western blotting. RESULTS: The specific inhibition of aggrecanase-1 by RNAi produced no adverse effect on the morphology and growth of the chondrocytes. The mRNA of aggrecanase-1 decreased and aggrecan content increased significantly after transfection of the chondrocytes. CONCLUSION: Inhibition of aggrecanase-1 decreases aggrecan degradation in cultured rat chondrocytes. RNAi technique can be a useful means for studying extracellular matrix metabolism in the cartilage. PMID- 19778786 TI - [Neuroprotective effect of rAAV-mediated rhBDNF gene transfection on rabbit retina against acute high intraocular pressure]. AB - OBJECTIVE: To investigate the neuroprotective effect of human brain-derived neurotrophic factor gene transfection into rabbit retina against acute high intraocular pressure (HIOP). METHODS: Acute HIPO was induced in one eye of 24 white rabbits via saline perfusion into the anterior chamber (model group), and the contralateral eye without treatment served as the control group. In another 24 rabbits, 10 microl recombinant adeno-associated virus (rAAV) vector containing human BDNF gene (rAAV-BDNF) was injected into the vitreous body of one of the eyes 3 days before the operation for HIPO (BDNF group). At 1, 3, 7, and 14 days after HIOP model establishment, 6 eyes in each group were excised to observe the number of retinal ganglion cells (RGCs) and the thickness of the inner retina layer. For the eyes dissected on day 14, electroretinogram b (ERG-b) wave was detected 30 min before (baseline) and on days 1, 3, 7 and 14 after HIOP. Another 5 rabbits were used for ultrastructural observation of the RGCs using transmission electron microscopy, including 1 without treatment, 2 with unilateral HIOP and 2 with rAAV-BDNF transfection before HIOP. RESULTS: The amplitude of ERG-b wave showed no significant difference between the 3 groups before HIOP (P>0.05). In HIOP model group and BDNF group, the amplitude decreased to the lowest at 1 day after HIOP and failed to recover the baseline level at 14 days (P<0.01); at the end of the observation, the amplitude was significantly higher in BDNF group than in the model group (P<0.01). Decreased number of RGCs and thickness of inner retina layer occurred in the model group, but these changes were milder in BDNF group (P<0.05, P<0.01). Electron microscopy revealed ultrastructural changes in the RGCs following acute HIOP, and transfection with rAAV-BDNF ameliorated these changes. CONCLUSION: rAAV-BDNF transfection protects the retinal structure and improves the amplitude of ERG-b wave after acute high IOP suggesting its neuroprotective effects. PMID- 19778788 TI - [Inhibitory effects of rosiglitazone on angiotensin II-induced toll-like receptor 4 expression and myeloperoxidase activity in RAW264.7 cells]. AB - OBJECTIVE: To investigate the effect of rosiglitazone on angiotensin II (Ang II) induced mRNA and protein expressions of toll-like receptor 4 (TLR4) and myeloperoxidase (MPO) activity in RAW264.7 cells to explore its anti- inflammatory and anti-atherosclerotic mechanisms. METHODS: Murine RAW264.7 cells were pretreated with rosiglitazone at 2.5, 5, and 10 micromol/L prior to exposure to AngII (0.1 micromol/L). TLR4 mRNA level was analyzed by RT-PCR, and TLR4 protein expression by Western blotting. MPO activity in the cell supernatant was assayed by colorimetry. In another experiment, the cells were pretreated with a neutralizing anti-TLR4 antibody (1 mg/L) for 1 h prior to rosiglitazone (10 micromol/L) treatment for 1 h, and subsequently stimulated with AngII or LPS (100 micromol/L) for 24 h to observe the change of MPO activity. RESULTS: Rosiglitazone downregulated AngII-induced mRNA and protein expressions of TLR4, and inhibited MPO activity in RAW264.7 cells in a concentration-dependent manner. The TLR4 blocker partially antagonized the effect of AngII on MPO activity, and the inhibitory effect was markedly enhanced by rosiglitazone. Rosiglitazone significantly inhibited LPS (a specific TLR4 ligand)-induced MPO activity in RAW264.7 cells. CONCLUSION: Rosiglitazone downregulates Ang II-induced TLR4 expression in RAW264.7 cells and inhibits MPO secretion possibly by interfering with TLR4 to relieve the inflammatory reaction, which may be one of its anti atherosclerotic mechanisms. PMID- 19778787 TI - [Serum proteomic analysis on metastasis-associated proteins of hepatocellular carcinoma]. AB - OBJECTIVE: To screen the serum proteins associated with the metastasis of hepatocellular carcinoma (HCC) using a comparative proteomic approach. METHODS: The serum samples of HCC patients with the same disease background were divided into metastatic (n=20) and non-metastatic (n=20) groups. The proteins extracted from the patients and 20 normal subjects, after depletion of the highly abundant proteins, underwent two-dimensional gel electrophoresis (2-DE). Comparative analyses of the 2-DE protein patterns between the 3 groups were conducted using a computerized image analysis system. The proteins with statistically significant differential expression between the metastatic and non-metastatic patients were identified by mass spectrometry. Western blotting was performed to examine the differential expression of the candidate proteins. RESULTS: Four protein spots were identified by mass spectrometry among the 12 differentially expressed protein spots in the serum samples of HCC patients with intrahepatic metastasis, and confirmed by searching in MASCOT database. Of the 4 proteins, cytokeratin 9 (CK9) was up-regulated by 2 folds, and inter-alpha (globulin) inhibitor H4, complement factor H-related protein 1 precursor (FHR-1), and apolipoprotein E were down-regulated by 2 folds. CK9 was found to be specifically over-expressed in the metastatic group in comparison with the non-metastatic group, as confirmed by Western blotting. CONCLUSION: The metastasis of HCC might be correlated to the specific variation of protein expression profiles. The overexpression of CK9 may play a crucial role in HCC metastasis, and can be used as a potential serum marker for predicting HCC metastasis. PMID- 19778789 TI - [Infusion of autologous mesenchymal stem cells prolongs the survival of dogs receiving living donor liver transplantation]. AB - OBJECTIVE: To investigate the mechanism of autologous mesenchymal stem cells (MSCs) in prolonging the survival of dogs receiving living donor liver transplantation. METHODS: Canine models of allogenic living donor liver transplantation was established in 14 beagle dogs by non-venous by-pass method, and in 7 of the recipients, autologous MSCs labeled by BrdU was infused into the portal vein, with the other 7 dogs as the control. The survival time of the two groups of the dogs was observed after the operation. The liver function (AST and ALT levels), liver pathologies and the differentiation of the transplanted cells were also evaluated postoperatively. RESULTS: Compared with the control group, the dogs receiving MSC transplantation showed significantly increased median survival time (P<0.001) with lowered levels of AST and ALT (P<0.01). The two groups exhibited similar graft rejection after the operation. In dogs with MSC transplantation, the BrdU-labeled MSCs differentiated into liver-like cells in the liver and secreted albumin. CONCLUSION: Autologous MSCs infusion through the portal vein during allogenic living donor liver transplantation can prolong the survival of the recipient dogs. The stem cells transplanted can differentiate into mature liver-like cells and secrete albumin in the hepatic tissue. PMID- 19778790 TI - [Biocompatibility of a novel cavernous nickel-titanium alloy with rat bone marrow stromal cells in vitro]. AB - OBJECTIVE: To investigate the biocompatibility of a novel cavernous nickel titanium alloy with rat bone marrow stromal cells (BMSCs) in vitro. METHODS: Rat BMSCs were cultured on the surface of compact, microporous and macroporous nickel titanium alloys, and the cell proliferation on day 3 during the culture was assessed using MTT assay. On day 7 of the cell culture, the cells were labeled with Hoechst33342 for cell counting under a fluorescence microscope. Scanning electron microscopy (SEM) was performed on day 7 of cell culture to observe the morphological changes of the cells. RESULTS: The cell proliferation rate and cell numbers differed significantly between the cavernous alloy groups and the compact alloy group (P<0.05), but similar between the former two groups (P>0.05). SEM showed that compared with the compact alloy, microporous and macroporous nickel titanium alloys had better biocompatibility with the BMSCs, and the cells on the surface of the cavernous alloys had normal cell morphology. CONCLUSION: Cavernous nickel-titanium alloy has good biocompatibility and can promote the adhesion, aggregation and proliferation of rat BMSCs in vitro. PMID- 19778791 TI - [Quantitative real-time PCR for detecting the expression levels of TCR Vgamma subfamilies in patients with graft-versus-host disease following allogenic hematopoietic stem cell transplantation]. AB - OBJECTIVE: To investigate the expression of T cell receptor (TCR) Vgamma genes in patients with graft-versus-host disease (GVHD) after allogenic hematopoietic stem cell transplantation (allo-HSCT). METHODS: The expression levels of the TCR Vgamma I-III genes in peripheral blood mononuclear cells (PBMNCs) from 18 patients with GVHD following allo-HSCT were determined using real-time fluorescence quantitative PCR, with 12 healthy individuals serving as the normal controls. RESULTS: The expression level of TCR Vgamma II gene in the PBMNCs from patients with GVHD was significant lower than that in the normal controls. The expression patterns of TCR Vgamma I-III subfamilies also underwent alterations in patients with GVHD, and the expression level of TCR Vgamma II gene was significantly lower than that of TCR Vgamma I gene or TCR Vgamma III gene. CONCLUSION: The low expression of TCR Vgamma II subfamily might be related to the pathogenesis of GVHD in patients receiving allo-HSCT. PMID- 19778792 TI - [Effects of different parts of the follicle-unit grafts subjected to controlled injury]. AB - OBJECTIVE: To study the shaft elongation and morphological changes of follicle unit (FUs) grafts subjected to controlled injury in different parts. METHODS: Human FUs were isolated by microdissection under a dissecting microscope. The single hair of anagen FUs were randomly divided into A, B and C groups, and A and B groups were subjected to controlled injury with microsurgery imposed to the dermal papilla and the bulge of FUs, respectively, with C as the control group without any treatment. HE staining was used to detect the histological changes of the cells, and organ culture for 10 days was conducted to observe the morphological changes and elongation of FUs. RESULTS: There were no histological or morphological changes in A, B and C groups. The average elongation of hair shaft was 1.293-/+0.245, 2.116-/+0.423 and 2.235-/+0.379 mm, respectively. There were significant differences between groups A and B (P<0.05) and between groups A and C (P<0.05). No significant difference was found between groups B and C (P>0.05). CONCLUSION: Damage of the dermal papilla should be avoided in hair transplantation surgery. PMID- 19778793 TI - [Expression of oxyntomodulin in bifidobacteria and effect of oxyntomodulin transformed bifidobacteria on the body weight of obese mice]. AB - OBJECTIVE: To observe the effect of pBBADs-OXM-transformed bifidobacteria on the body weight of obese mice. METHODS: B. longum was transformed with pBBADs-OXM by electroporation, and arabopyranose-induced oxyntomodulin expression by the bacterium was detected by ELISA. pBBADs-OXM-transformed bifidobacteria was administered orally obese mice on a daily basis with pBBADs-GFP-transformed bifidobacteria as the negative control, and the body weight changes of the mice were observed. RESULTS: OXM was detected by ELISA not only in the supernatant but also the precipitant of the transformed bacterial culture. The body weight of the obese mice fed with pBBADs-OXM-transformed bifidobacteria decreased significantly compared with that of the mice in the obese model group (P<0.05). CONCLUSION: Administration of pBBADs-OXM-transformed B.longum can reduce the body weight of obese mice. PMID- 19778794 TI - [Serum proteomics in patients with RAEB myelodysplastic syndromes]. AB - OBJECTIVE: To screen the molecular markers for refractory anemia with excess blasts in transformation (RAEB) in myelodysplastic syndromes (MDS) by serum proteome profiling. METHODS: The serum protein were isolated from patients with RAEB, acute myeloid leukemia or normal subjects by 2-dimensional electrophoresis (2-DE), and the electrophoresis gels were obtained to identify the differentially reacting protein spots. The replica gels of the differentially reacting proteins were analyzed to locate the matching protein spots, which were identified by peptide mass fingerprint based on matrix-assisted laser desorption/ionization time of-flight mass spectrometry (MALDI-TOF-MS) and database searching. RESULTS: Seven differentially expressed proteins in RAEB were found by 2-DE. Of the 7 proteins, 4 were identified by MALDI-TOF-MS to have significantly differential expression in RAEB, including dipeptidyl peptidase (DPP/CD26), polymerase (DNA directed) kappa, PRO2044 and an albumin-like protein. CONCLUSION: 2-DE-based serum proteome profiling helps identify serum proteomic biomarkers related to MDS. DDP/CD26 has increased expression in the serum in RAEB subtype MDS, suggesting its possible role in advanced MDS. PMID- 19778795 TI - [Expressions of receptor-interacting protein and caspase-8 in oral squamous cell carcinoma and oral precancerous lesions]. AB - OBJECTIVE: To detect the expressions of receptor-interacting protein (RIP) and caspase-8 and investigate their roles in oral squamous cell carcinoma (OSCC) and oral precancerous lesions. METHODS: SABC immunohistochemical methods were used to detect the expressions of RIP and caspase-8 in 22 specimens of OSCC, 14 specimens of oral lichen planus (OLP), 14 specimens of oral leukoplakia (OLK) and 10 specimens of normal oral mucosa (NOM). RESULTS: The rate of weak or negative expression of RIP in normal mucosa was 50% (5/10). The rates of weak and positive expression of RIP in OLP, OLK and OSCC were 75% (36/50), and the rate of positive and strong expression of RIP was 63.7% (14/22) in OSCC, significantly higher that in the others groups (P<0.05). The rates of weak, positive and strong positive expression of caspase-8 in NOM, OLP, OLK and OSCC were 80% (8/10), 100% (14/14), 85.7% (12/14), and 100% (22/22), respectively. CONCLUSION: Both RIP and caspase-8 may play important roles in the occurrence and progression of OSCC and oral precancerous lesions. PMID- 19778796 TI - [Phage display random peptide library for screening the peptides that specifically bind to hepatocellular carcinoma cells]. AB - OBJECTIVE: To screen the peptides that bind specifically to the hepatoma cells using phage display random peptides library. METHODS: Three rounds of panning were conducted in vitro targeting HepG2 cell lines. In nude mice bearing HepG2 tumor, one round of panning was conducted, and 30 phage clones were randomly selected for sequence analysis to identify the consensus sequence. Immunocytochemistry and immunohistochemistry were performed to determine the specificity of the phages to the hepatoma cells. RESULTS: After three rounds of panning in vitro and one round of panning in vivo, the phages binding to HepG2 cells were enriched. Sequence analysis of the randomly selected clones identified the peptide sequence VRKRSECLGAHD as the most frequent sequence. Immunocytochemistry and immunohistochemistry confirmed the specificity of the phage binding to the hepatoma cells. CONCLUSIONS: Specific peptides against hepatoma cells can be obtained from a phage- display peptide library, which provides an experimental basis for developing therapeutic agents targeting hepatoma cells. PMID- 19778797 TI - [Isolation, purification and functional identification of Syrian golden hamster islets]. AB - OBJECTIVE: To establish the methods for isolation, purification and function identification of Syrian golden hamster islets. METHODS: The Langerhans islets were isolated and purified from golden hamster pancreas by intra-ductal collagenase V perfusion and discontinuous Ficoll density gradient centrifugation. After isolation, the islet yield and purity were evaluated with DTZ staining. The islet function was assessed using glucose-stimulated insulin secretion test. RESULTS: The total number of purified islets from one donor hamster was 359-/+35 islet equivalent (IEQ), with the purity and viability of the isolated islets of more than 90%. In response to glucose stimulations at 5.8 and 16.7 mmol/L, the secretion of insulin by the islets was 3.29-/+0.3 and 11.12-/+0.57 mU/L, respectively, showing a 2.28-fold higher insulin release by high-concentration than by low- concentration glucose stimulation (P<0.01). CONCLUSION: The methods of collagenase V digestion and gradient centrifugation result in high yield and high purity of the isolated hamster islets. PMID- 19778798 TI - [Preparation and application of Epstein-Barr virus genome-wide genechip]. AB - OBJECTIVE: To prepare an Epstein-Barr virus (EBV) microarray using known and predicted EBV-coded genes as the cDNA probes to detect the EBV gene expression in nasopharyngeal carcinoma (NPC) tissues. METHODS: The EBV gene probes were amplified by PCR using a pair of primers designed in both sides of the multiple clone site (MCS) of the T/A vector. After purification of the PCR products, 85 EBV genes and 8000 human genes were printed onto the same slide as the detection chip consisting of both EBV and human genes. This genechip was used to detect the differential gene expression in NPC and non-cancerous nasopharynx (NP) tissues. RESULTS: Detection of the human gene expression profile using the prepared genechip resulted in the identification of numerous human genes in the tissue specimens. Some EBV genes were also detected in the tissues using the genechip, but the signals of the genes appeared rather weak without distinctly visible fluorescence, and were not comparable to the strong signal intensities of the human genes. CONCLUSION: The EBV microarray, though constructed successfully, can not meet the needs for clinical application due to the limited detection sensitivity and the relative small quantity of EBV gene expression in NPC samples. Further improvements of the research methods are warranted. PMID- 19778800 TI - [Distribution of the muscle spindles in human masticatory muscles]. AB - OBJECTIVE: To investigate the characteristics in the topographic distribution of the muscle spindles in human masticatory muscles. METHODS: The muscle spindles of the masticatory muscles on both sides of 3 human corpses fixed in formalin for more than 1 year were observed histologically and analyzed quantitatively using an image analysis system. RESULTS: The mean muscle spindle density was 32.11/g in the masseter, significantly higher in the deep muscular fibers (70.76/g) with high proportion of spindle complexes than in the superficial layers of the muscle belly (P<0.05). The mean spindle density in the temporalis was 5.44/g, higher in the anterior portion (7.44/g) than in the posterior portion (3.78/g, P<0.01). The medial pterygoid had a mean spindle density of 4.43/g. CONCLUSION: These results indicate a heterogeneous distribution of muscle spindles in the masticatory muscles with different morphologies or in different portions of the same muscle, depending on muscle fiber type and muscular architecture. PMID- 19778799 TI - [Association of Bmi-1 expression with clinicopathological features and prognosis of colorectal cancer]. AB - OBJECTIVE: To investigate the expression of B cell specific MLV integration site 1 (Bmi-1) in colorectal cancer (CRC) and its correlation to the clinicopathological features and prognosis of CRC. METHODS: Sixty CRC, 30 adenomas and 20 normal colorectal mucosal tissues were collected to detect the expression of Bmi-1 protein using immunohistochemistry, and the results were analyzed in comparison with the clinicopathological features and survival rate of patients. RESULTS: The positivity rate of Bmi-1 expression in CRC tissue was 51.7%. In CRC, the rate of Bmi-1 overexpression was 25.0%, significantly higher than that in the adenomas and normal colorectal mucosal tissues (6.67% and 0%, respectively, P<0.05). The overexpression of Bmi-1 protein in CRC was obviously associated with distant metastasis and the TNM stage (P<0.05), but not with gender, age, tumor size, tumor site, histological type, differentiation degree and lymph node metastasis (P>0.05). But logistic regression analysis showed that Bmi-1 protein overexpression in CRC was associated only with distant metastasis (P<0.01,OR>1); Kaplan-Meier survival analysis showed that the survival rate of the patients with high Bmi-1 expression was significantly lower than that in patients with low expression (P<0.05). CONCLUSION: The overexpression of Bmi-1 protein was significantly correlated to the tumorigenesis, metastasis and prognosis of CRC, and may serve as an indicator for evaluating the prognosis of CRC. PMID- 19778801 TI - [Ginsenoside Rg3 induces apoptosis of human lung squamous cell carcinoma SK-MES-1 cell line]. AB - OBJECTIVE: To investigate the effect of ginsenoside Rg3 on the apoptosis and survivin expression in human lung squamous cell carcinoma cell line SK-MES-1. METHODS: SK-MES-1 cells were divided into Rg3 treatment group, blank control group and positive control (arsenic trioxide) group. The apoptotic rate of the cells in each group was determined using flow cytometry, and the expression of survivin protein and mRNA was detected by immunocytochemistry and RT-PCR, respectively. RESULTS: A 48-h treatment with Ginsenoside Rg3 induced increased apoptotic rate of SK-MES-1 cells in a dose-dependent manner. Ginsenoside Rg3 significantly downregulated the expressions of survivin protein and mRNA as compared with the expression levels in the blank control group (P<0.05). CONCLUSION: Ginsenoside Rg3 can induce the apoptosis of SK-MES-1 cells, the mechanism of which may involve inhibited survivin expression. PMID- 19778802 TI - [Effect of targeted therapy with cisplatin-loaded magnetic nanoparticles combined with radiotherapy for nasopharyngeal carcinoma in nude mice]. AB - OBJECTIVE: To investigate the effect of target therapy with cisplatin (CDDP) loaded magnetic nanoparticles (MNP) in combination with chemoradiotherapy against nasopharyngeal carcinoma cell growth in nude mice. METHODS: Thirty-six BALB/c mice with implanted tumor of CNE-2 cells were randomly divided into 6 groups (n=6), including the control group, radiotherapy group, CDDP group, CDDP plus radiotherapy group, CDDP-MNP group, and CDDP-MNP plus radiotherapy group. The mice were given 0.3 ml normal saline (control) or corresponding agents (3 mg/kg) via the tail vein, and 0.5 ml saline was administered intragastrically before the injections. Before and after the treatment, the body weight, tumor volume and weight, and the tumor inhibition rates were measured. The proliferating cell nuclear antigen (PCNA) index was calculated on the basis of immunohistochemical staining. RESULTS: Except for the cisplatin group, all the treated groups showed significantly reduced tumor volume as compared with that in the control group (P<0.05) with lowered body weight. Compared with the cisplatin group, the combined treatment groups showed significantly higher tumor inhibition rate (P<0.05), but the effect showed no significant difference from that in the radiotherapy group (P>0.05). CONCLUSION: Targeted therapy with CDDP-loaded MNP alone or in combination with radiotherapy can effectively inhibit the growth of nasopharyngeal carcinoma in nude mice without increasing the toxicity. PMID- 19778803 TI - [Construction of a recombinant lentiviral expression vector carrying carcinoembryonic antigen gene and its expression in dendritic cells]. AB - OBJECTIVE: To construct a lentiviral expression vector of human carcinoembryonic antigen (CEA), and identify its expression in dendritic cells (DCs). METHODS: Human CEA-encoding sequence was amplified, purified, ligated with lentiviral vector plasmid pLentiGFP and verified by sequencing. The verified recombinant vector plasmid (pLentiGFP-CEA), the packaging plasmid p 8.2 and pVSV-G were transfected into 293T cells by Lipofectamine(TM) 2000 reagent. The supernatant of the cultured 293T cells was collected to infect the DCs. The expression of CEA in the transfected DCs was assayed by RT-PCR and Western blotting. RESULTS: CEA lentiviral vector was highly expressed in the transfected DCs as observed using fluorescence microscope 48 h after the the transfection. The human CEA gene was successfully amplified by RT-PCR with a length of about 2100 bp. Western blotting also showed CEA expression in the transfected DCs. CONCLUSION: The human CEA lentiviral expression vector has been successfully constructed and the functional CEA protein can be expression in the transfected DCs. This facilitates further studies of the function of CEA at the molecular level. PMID- 19778804 TI - [Screening and identification of polypeptides specifically binding to human B type natriuretic peptide from 12TM phage display peptide library]. AB - OBJECTIVE: To identify and characterize the polypeptides specifically binding to human B type natriuretic peptide (BNP) screened from 12TM phage display peptide library. METHODS: The BNP-binding peptides were screened from 12TM phage display peptide library and identified by ELISA. RESULTS: After 4 rounds of screening, 10 of the 16 phage clones were identified as the positive clones which could bind to BNP. Five amino acid sequences were obtained in the 10 positive clones. Dose dependent ELISA results demonstrated that the screened polypeptides could specifically bind to BNP. CONCLUSION: These screened polypeptides can bind specifically to BNP, which provides a basis for further research on expression and purification of anti-BNP polypeptides and the development of the detection kit of BNP. PMID- 19778805 TI - [Effects of intrathecal escin and clonidine in the treatment of neuropathic pain in rats]. AB - OBJECTIVE: To investigate the effects of intrathecal escin and clonidine, used alone or in combination, in the treatment of neuropathic pain in rats and the possible mechanism. METHODS: Ninety-six male SD rats weighing 250-300 g were chronically implanted with lumbar intrathecal catheters. One week later, the left L5 and L6 spinal nerve roots were ligated to establish the model of spinal nerve ligation neuropathic pain (SNL). The rats were then randomly divided into 16 groups (n=6), including the control (saline), escin, clonidine, escin+clonidine, and the antagonist groups. Mechanical withdrawal threshold was assessed before and at 5, 10, 20, 30, 40, 50 and 60 min after intrathecal administration was evaluated. The maximal possible effect (MPE) was calculated and the effect of the treatments on the neuropathic pain. Isobolographic analysis was performed to characterize any potential interactions between the drugs. RESULTS: MPE was significantly higher in escin group (20, 40 microg), clonidine group (2, 5, 10 microg) and escin+clonidine group [1/4, 1/2 (escin ED(50)+clonidine ED(50))] than in the saline group (P<0.05). Intrathecal escin (5-40 microg) or clonidine (1-10 microg) alone dose-dependently alleviated neuropathic pain. Isobolographic analysis suggested a synergistic effect between escin and clonidine. Intrathecal pretreatment with yohimbine (20 microg) antagonized the effects of clonidine (P<0.01) and attenuated the action of the combination treatment with escin and clonidine (P<0.05). CONCLUSION: Intrathecal escin and clonidine alone can dose dependently relieve neuropathic pain. Escin and clonidine produce a synergistic effect for pain relief, which may involve the actions of alpha(2) receptor and Ca(2+) channel. PMID- 19778806 TI - [Synthesis of 2-hydroxyl-5-butyramidobenzoic acid and its effect on acetic acid induced colitis in rats]. AB - OBJECTIVE: To study the method for synthesis of 2-hydroxyl-5- butyramidobenzoic acid and test its effect on acetic acid-induced colitis in rats. METHODS: 2 hydroxyl-5-butyramidobenzoic acid was synthesized from 5-aminosalicylic acid and butyric acid by amidation, esterification and hydrolization. The effect of 2 hydroxyl-5-butyramidobenzoic acid on acetic acid enema-induced colitis in rats was investigated. RESULTS: The structure of 2-hydroxyl-5-butyramidobenzoic acid was identified by IR and 1H-NMR. After treatment with acetic acid, the colon mucosal damage index (CMDI), fecal occult blood (OB) test, and activity of myelperoxidase (MPO) increased significantly in the rats as compared to the control levels. 2-hydroxyl-5- butyramidobenzoic acid obviously reduced the CMDI and OB, and reduced the level of MPO in the rats with colitis. CONCLUSION: The synthesis of 2-hydroxyl-5-butyramidobenzoic acid requires only mild conditions with simple procedures, and the synthesized 2-hydroxyl-5-butyramidobenzoic acid shows obvious therapeutic effects on mucosal damage of in rats with acetic acid induced colitis. PMID- 19778807 TI - [Changes of peripheral blood chromosomal centromere aberration in patients with cytomegalovirus infection after anti-viral treatment]. AB - OBJECTIVE: To study the changes of peripheral blood chromosomal centromere aberration in patents with cytomegalovirus (CMV) infection after anti-viral treatment. METHODS: Sixty-two patients with early spontaneous abortion and CMV infection analyzed for their peripheral blood chromosomal centromere using simultaneous silver staining before and after anti-viral treatment. RESULTS: The patients with CMV infection had high rate of centromere aberration, which was decreased significantly after anti-viral treatment (P<0.0001). CONCLUSION: CMV infection is a risk factor for peripheral blood chromosomal centrimere aberration. Anti-viral treatment can decrease the rate of centrimere aberration aberration. Detection of peripheral blood chromosomal centrimere aberration allows the assessment of the severity of infection and the condition after treatment. PMID- 19778808 TI - [Therapeutic effect of low-dose thyroxin in elderly patients with refractory heart failure and euthyroid sick syndrome]. AB - OBJECTIVE: To investigate the therapeutic effect of low-dose thyroxin in elderly patients with refractory heart failure (RHF) and euthyroid sick syndrome (ESS). METHODS: Fifty-four elderly patients with RHF and ESS were randomized into conventional treatment group (n=32) and L-thyroxine group with additional oral L thyroxine at the daily dose of 6.25-25 microg (n=22). The changes in the plasma levels of brain natriuretic peptides (BNP), left ventricular ejection fraction (LVEF), and cardiac function (NYHA level) of the two groups were compared after 1 month of treatment. RESULTS: Five patients receiving conventional treatment died due to severe arrhythmia during the treatment, and in the other 27 patients, the levels of plasma BNP, LVEF, and cardiac function showed no significant improvements after 1 month of treatment (P>0.01). In L-thyroxine group, no death or severe arrhythmia occurred, and the levels of plasma BNP, LVEF, and cardiac function were significantly improved after the treatment (P<0.01). No thyrotoxicosis occurred during the administration of L-thyroxine in the latter group. CONCLUSION: Low-dose L-thyroxine in addition to the conventional treatments may enhance the therapeutic effect in elderly patients with RHF and ESS. PMID- 19778809 TI - [Antineoplastic effect of koumine in mice bearing H22 solid tumor]. AB - OBJECTIVE: To investigate the antitumor effects of koumine in mice bearing H22 solid tumor and its effect on the immune system of the mice. METHODS: The changes in spleen and tumor weights and blood cell count were observed after koumine treatment in BALB/c athymic mice bearing H22 solid tumor, using normal saline solution and 5-Fu as the controls. RESULTS: Koumine significantly inhibited the tumor growth in a dose-dependent manner. The spleen index and blood cell counts in koumine group showed no significant differences from those in the saline control group, but higher than those in 5-Fu group. CONCLUSION: Koumine can significantly inhibit the growth of H22 solid tumor without obvious inhibitory effect on the immune system in mice. PMID- 19778810 TI - [Expression of Aurora-B in non-small cell lung cancer and its clinical significance]. AB - OBJECTIVE: To study the expression of Aurora-B in non-small cell lung cancer (NSCLC) tissues and NSCLC cell lines. METHOD: Aurora-B expression was examined using immunohistochemical SP method in 91 stage I and 69 stage II-III NSCLC tissues and 40 adjacent tissues. The mRNA and protein expressions of Aurora-B in NSCLC cell lines (A549, H460 and H1299) were examined by RT-PCR and Western blotting, respectively. RESULTS: The protein expression of Aurora-B was detected in 77.7% (94/121) of the tumor tissues and 9.8% (4/41) of the adjacent tissues, showing a significant difference between them (P<0.01). The positivity rate of Aurora-B protein was not related with the gender and age of NSCLC patients, but with lymph node metastasis, differentiation and histological type of NSCLC (P<0.05). Aurora-B was expressed in all the NSCLC cell lines (A549, H460 and H1299) at both mRNA and protein levels. A549 cells showed the highest expression of Aurora-B. CONCLUSION: Aurora-B protein is highly expressed in NSCLC tissues and cell lines, and may play a crucial role in the invasion, metastasis and development of NSCLC. The mRNA and protein expression levels of Aurora-B differ significantly between different NSCLC cell lines. PMID- 19778811 TI - [Morphological observation of cellular uptake of beta amyloid protein in cultured human neuroblastoma cells]. AB - OBJECTIVE: To observe the cellular uptake of beta amyloid protein (Abeta) by cultured human neuroblastoma (SH-SY5Y) cells and the location of Abeta in the subcellular structures. METHODS: The time course of cellular uptake of Abeta1-42 fluo in the SH-SY5Y cells was observed directly under laser scanning confocal microscope (LSCM). Image analysis was conducted to compare the differences of cellular Abeta uptake after treatment of the cells with different concentrations of extracellular Abeta for 24 h. Multiple immunofluorescence staining was employed to identify the location of Abeta in the subcellular structures. RESULTS: SH-SY5Y cells showed Abeta internalization after incubation with Abeta1 42-fluo (200 nmol/L) for 1 h, and the quantity of Abeta uptake was time dependent. A higher concentration of extracellular Abeta1-42-fluo resulted in increased Abeta uptake, which differed significantly between the 3 groups with treatment at different concentrations (P<0.01 or 0.05). Immunofluorescence staining revealed a co-localization of part of the Abeta and Lamp-1 (a lysosome marker) in the cytosome. CONCLUSION: SH-SY5Y cells can clear Abeta through a time and dose-dependent cellular uptake mechanism. Part of the Abeta uptaken in the cytoplasm is located in the lysosome . PMID- 19778812 TI - [Role of sphingosine 1-phosphate receptor signaling in hematopoietic stem/progenitor cell transmigration]. AB - OBJECTIVE: To determine the role of sphingosine 1-phosphate receptor (S1PRs ) signaling in CD34+ hematopoietic stem/progenitor cell transmigration. METHODS: CD34(+) cells were separated by Ficoll density gradient centrifugation and incubated in DMEM medium with 10% fetal calf serum. The cells were pretreated by FTY720, with or without pertussis toxin (PTX) and antiCXCR4 mAb in the medium, followed by addition of 100 ng/ml SDF-1 into the lower chamber of a Costar 24 well transwell. The migrated cells were counted using FACS and the migrating rates were determined. The expressions of sphingosine 1-phosphate receptors were analyzed in CD34(+) cells before and after the transmigration by reverse transcriptase- polymerase chain reaction (RT-PCR). Cord blood CD34(+) cells were treated with or without FTY720 (10(+) mol/L), and the expressions of CD49d (VLA 4), CD11a (LFA-1), and CD62L (L-selectin) were analyzed at 1, 8, and 16 h after the treatment. RESULTS: While FTY720 did not affect spontaneous migration, a substantial increase of SDF-1-induced transmigration was observed in the presence of FTY720 (15.26 2.14 to 28.64 2.37). The FTY720-enhanced transmigration was completely blocked by addition of PTX or antiCXCR4 mAb. S1p1-5 was expressed in fresh isolated cord blood CD34(+) cells. The migrating cells stimulated by FTY720 and SDF-1 only expressed S1P1, S1P3, and S1P4. The expressions of CD49d, CD11a and CD62L on CD34(+) cells treated with FTY720 remained unchanged at the selected time points as compared with the control. CONCLUSIONS: S1PRs are involved the transmigration of CD34(+) cells. The activation of S1PRs results in increased chemotactic response of CD34(+) to SDF-1. These effects are mediated through CXCR4 and PTX-sensitive Gi proteins. Only the CD34(+) cells expressing the specific receptors can rapidly transmigrate. The activation of the S1PRs does not affect the expressions of the adhesion molecules on cord blood CD34(+) cells. PMID- 19778813 TI - [Value of three-dimensional contrast-enhanced magnetic resonance angiography in the diagnosis of mesenteric arteriosclerosis]. AB - OBJECTIVE: To assess the clinical value of three-dimensional contrast-enhanced magnetic resonance angiography (3D-CE-MRA) in the diagnosis of mesenteric arteriosclerosis. METHODS: 3D-CE-MRA of the mesenteric arteries was performed in 21 patients with 23 healthy subjects as the control. After 3D image reconstruction and maxi intense projection, and the abnormalities of the mesenteric arteries were observed and analyzed. The diameter and number of the arterial branches were compared between the patients and the control subjects. RESULTS: All the 21 patients suffered arteriosclerosis in the arteries other than the mesenteric arteries. On 3D-CE-MRA, mesenteric arteriosclerosis was characterized by thinning of the arterial trunk, luminal stenosis, irregular arterial margins and homo- or heterogeneous thickening of vascular walls. Multiple filling defects were found in the mesenteric artery lumens with reduced second order branches, which showed rigid lining with dashed line appearance or disappeared in some cases. The inferior mesenteric arteries were seen in only 2 patients. The diameters of superior and inferior mesenteric arteries were 3.8 /+0.32 mm and 1.20-/+0.12 mm in the patients, significantly smaller than those of in the control subjects (6.51-/+1.01 mm and 2.90-/+0.90 mm, respectively, P<0.01). The number of the mesenteric artery branch of the patients was also significantly reduced as compared with that in the control subjects (P<0.05). In som cases, the intestinal enhancement was attenuated with the intestinal contraction, dilatation and lowering of the intestinal tension. CONCLUSION: 3D-CE MRA can clearly display mesenteric arteriosclerosis and secondary intestinal changes, and provides a useful means for the diagnosis and assisting the therapy of mesenteric arteriosclerosis. PMID- 19778814 TI - [Construction and identification of CerbB-2 siRNA expression plasmid and its transfer into human colon cancer cell lines HT-29]. AB - OBJECTIVE: To construct a plasmid carrying small interfering RNA (siRNA) targeting human C-erbB2 gene (pGenesil- erbB2) and test its effect on Her-2 expression at the post-transcriptional level in human colon cancer cell lines HT 29 cells that highly express erbB2. METHODS: A HT-29 cell line that highly expressed CerbB-2 was selected using immunohistochemical method. The double stranded siRNA targeting human CerbB-2 cDNA and the negative control fragment were cloned into pGenesil-1 vector, and after identification and sequence analysis, the constructed pGenesil-erbB2 plasmid was transfected into the selected HT-29 cell line. RESULTS: The pGenesil-erbB2 plasmid was successfully constructed and stably transferred into HT-29 cells. The transfection resulted in significant inhibition of Her-2 protein expression in the HT-29 cells, as shown by Western blotting. CONCLUSION: The pGenesil-erbB plasmid we constructed can be stably transfected into HT-29 cells to inhibit the expression of Her-2 protein, and can be useful in further studies of increasing the radiosensitivity of HT-29 cell lines. PMID- 19778815 TI - [Evaluation of a rabbit model of abdominal aorta atherosclerosis]. AB - OBJECTIVE: To explore the methods for non-invasive evaluation of a rabbit model of aorta atherosclerosis model. METHODS: Sixteen male New Zealand rabbits (n=16) were randomized into the experimental group and control group and fed with high cholesterol diet and normal diet after balloon injury in the abdominal aorta, respectively. Eight weeks later, pathological examination, angiography and surface ultrasonography were carried out to evaluate the plaques in the aorta. RESULTS: After feeding with high-cholesterol diet for 8 weeks, the weight, total cholesterol (TC), triglycerides (TG) and low-density lipoprotein (LDL) were significantly increased in the rabbits (P<0.001), and atherosclerosis in the abdominal aorta was directly observed using angiography and surface ultrasonography. The rate of vasoconstriction showed significant difference between the experimental group and control group (t=5.921, P=0.000). In the experimental rabbits, the vasoconstriction increased obviously after drug stimulation with high lumen eccentricity index. A significant positive correlation was noted between the lumen eccentricity index and the rate of vasoconstriction (r=0.983, P=0.000). CONCLUSION: A rabbit model of abdominal aorta atherosclerosis can be established rapidly by balloon injury and high cholesterol diet. The aortic wall thickness, lumen diameter and lumen eccentricity index determined by surface ultrasonography can be used to evaluate the validity of the model establishment and the nature of the plaque. PMID- 19778816 TI - [Living-related kidney transplantation: report of 175 cases]. AB - OBJECTIVE: To analyze the clinical characteristics of living-related kidney transplantation (LRKT). METHODS: From January, 2004 to December, 2008, 175 LRKT were performed including 63 cases (36%) of parent-child relations and 49 cases (28%) of sibling relations between the recipients and donors. Out of 175 donors, 52 were 50 years old or above, 4 had microscopic hematuria (including 2 with also hypertension), 2 had kidney stone, and 2 had high body mass index (BMI). Zero point graft biopsy was performed in 59 donors, and abnormalities were found in 15 of them. The recipients were at the age of 33-/+10.5 years, and the primary diseases are mainly dominant glomerular nephritis (72.6%, 127/175), and with a few cases of diabetes (4%, 7/175) and hypertensive nephropathy (4%, 7/175). RESULTS: Serum creatinine of the donors was 102-/+22.5 micromol/L at 7 days postoperatively, and 92-/+19.1 micromol/L at one month. One recipient died of severe pulmonary infection. Two recipients underwent graft nephrectomy due to anastomotic stenosis with concomitant acute graft rejection and renal arterial embolism. The one-year survival rates of the patients and grafts were 99.3% and 98.2%, respectively. The incident rates of accelerated rejection and acute rejection were 1.1% and 14.9%, respectively. Other complications included impaired liver function (22.3%), infection (9.7%) and leucopenia (4.6%). The renal arterial stenosis occurred in 2.3% (4/175) of the recipients. CONCLUSIONS: The recipients of living-related and cadaveric kidney transplant have different primary kidney disease spectrums. Differential diagnosis and treatment of acute rejection and renal artery or anastomotic stenosis can be of vital importance. Marginal donor kidneys with appropriate inclusion criteria can be safely used for transplantation. With good short-term patient and graft survival, LRKT needs further study to evaluate its long-term effect. PMID- 19778817 TI - [Reversion transcriptional expression of DAPK in bladder cancer T24 cells 5-aza 2'-deoxycytidine]. AB - OBJECTIVE: To investigate the methylation status of the promoter of resion death associated protein kinase (DAPK) gene in bladder cancer cell (T24), and study the effect of 5-aza-2'-deoxycytidine (5-aza-dc) on DAPK gene reactive expression in T24 and its inhibitory effect on T24. METHODS: The bladder cancer cell T24 was treated with different doses of 5-aza-dc. The inhibitory effect and apoptosis rate were detected by MTT and flow cytometry, and the changes of DAPK mRNA and protein expression and the methylation status of DAPK promoter were assessed by RT-PCR, Western blotting, and methylation specific PCR, respectively. RESULTS: The growth of bladder cancer cell was inhibited significantly and the maximal apoptosis rate detected by flow cytometry was (24.12-/+1.4)%. DAPK mRNA was not expressed in bladder cancer cell T24 in normal conditions. DAPK mRNA and protein re-expressed after 5-aza-dc (12.5 micromol/L) treatment in cell line T24 for 24 h, and DAPK promoter became unmethylated. CONCLUSIONS: The promoter methylation can be an important factor for silencing the expression of DAPK in bladder cancer cell. 5-aza-dc can inhibit the growth and induce apoptosis of bladder cancer cells through reversing unmethylation status of DAPK promoter. PMID- 19778818 TI - [Effects of Tongxinluo on MMP-3, 9 and PPARgamma expressions in atherosclerotic rabbits]. AB - OBJECTIVE: To study the effects of Tongxinluo on the expressions of matrix metalloproteinase-3 (MMP-3), MMP-9 and peroxisome proliferators-activated receptor gamma (PPARgamma) in atherosclerotic rabbits and explore the mechanism of its anti-atherosclerotic effect. METHODS: Twenty-four rabbits were randomized equally into control group, atherosclerotic model group (fed with high-fat diet for 14 weeks) and Tongxinluo group. The expressions of MMP-3, 9 and PPARgamma in the 3 groups were observed by means of immunohistochemistry. RESULTS: The expressions of MMP-3, 9 and PPARgamma in the model group and Tongxinluo group were significantly higher than those in the control group (P<0.01). After high fat diet feeding for 14 weeks, Tongxinluo group showed significantly lower expressions of MMP-3 and 9 but higher expression of PPARgamma than the model group (P<0.01). CONCLUSION: Tongxinluo can inhibit the expression of MMP-3 and 9 and increase the expression of PPARgamma, which might be the mechanism of its anti-atherosclerotic effect. PMID- 19778819 TI - [Adeno-associated virus-mediated Her2/neu gene transfection enhances the immunostimulatory capacity of human dendritic cells in vitro]. AB - OBJECTIVE: To evaluate the immunostimulatory capacity of human peripheral blood dendritic cells (DCs) with Her2/neu gene transfection mediated by adeno associated virus. METHODS: The HLA genotypes of the breast cancer cells SK-BR-3 and MCF7 were determined, and the mononuclear cells from healthy donors with matching HLA genotype were isolated by Ficoll-Hypaque density gradient separation. The isolated cells were divided into two groups with or without transfection with the recombinant virus harboring Her2/neu gene. The cells were cultured for 7 days in RPMI 1640 medium supplemented with 10% AB human serum, GM CSF, interleukin-4 (IL-4) and tumor necrosis factor-alpha (TNF-alpha). The mature DCs were then harvested from the cell culture and their phenotypes were identified using flow cytometry. MTT assay was employed to examine the specific killing activity of the T cells induced by the DCs. RESULTS: The DCs transfected with the recombinant adeno-associated virus expressed CD1a, CD86 and CD83 at the rate of 98.10%, 99.42%, and 84.59%, and those without the viral transfection expressed the markers at the rate 92.69%, 98.07%, and 82.72%, respectively, showing no obvious differences in the phenotypes of the two DCs. The transfected DCs, however, showed markedly higher expression rates of CD40 and CD80 than the non-transfected DCs (61.02% vs 36.19%, and 97.61% vs 55.5%, respectively). The DCs, irrespective of the transfection, showed comparable capacities in stimulating T cell proliferation. The transfected DCs exhibited the capacity of inducing the T cells to specifically kill the target tumor cells, with the highest killing rate of (39.7-/+7.2)%. CONCLUSION: The immunostimulatory capacity of human peripheral blood DCs are enhanced by Her2/neu gene transfection mediated by adeno-associated virus. PMID- 19778820 TI - [Application of two auricular cartilage-perichondrium complexes in tympanoplasty]. AB - OBJECTIVE: To compare the effects of cartilage-perichondrium palisade complex and cartilage-perichondrium horseshoe complex in tympanoplasty for large tympanic membrane perforation. METHODS: Nineteen patients (19 ears) undergoing tympanoplasty with cartilage-perichondrium palisade complex and 20 patients (20 ears) with cartilage-perichondrium horseshoe complex were compared for postoperative hearing and closure rate of tympanic membrane perforation. RESULTS: The closure rates of the tympanic membrane were all 100% in both groups 3 months after the operation, while tympanoplasty with cartilage- perichondrium horseshoe complex resulted in significantly greater improvement of the postoperative air bone gap in speech frequency. CONCLUSION: Both of the two auricular cartilage perichondrium complexes produced good effects for repair large tympanic membrane perforation, but cartilage-perichondrium horseshoe complex can achieve better results in speech frequency. PMID- 19778821 TI - [MTT assay for detecting osteosarcoma cell apoptosis]. AB - OBJECTIVE: To assess the feasibility of using MTT assay for detecting the apoptosis of osteosarcoma cells following chemotherapy. METHODS: The osteosarcoma cells derived form surgical specimens were cultured in RPMI 1640 medium supplemented with 10% calf serum. Chemotherapeutic agents were administered in the cell culture, and MTT assay was used to observe the cell apoptosis under optical microscope. RESULTS: MTT staining accurately identified apoptosis of the osteosarcoma cells, and the apoptotic cells were easily distinguished from normal cells and dead cells. CONCLUSION: MTT staining is convenient and practical for detecting osteosarcoma cell apoptosis. PMID- 19778822 TI - [Epidemiological survey of rheumatic heart disease in schoolchildren in Guangdong and Xinjiang]. AB - OBJECTIVE: To investigate the prevalence of rheumatic heart disease (RHD) among schoolchildren in Guangdong Province and Xinjiang Uygur Autonomous Region. METHODS: Using a cluster sampling method, an epidemiological survey of RHD was conducted in 16 682 primary and high school students by auscultation in Guangdong Province and Xinjiang Uygur Autonomous Region from 2005 to 2006. Review of the clinical records, RHD survey in adults, and examination of the positivity rate of group A beta-hemolytic Streptococcus (GAS) by throat swab cultures in the students aged between 9 and 12 years in the sampled schools were also carried out. RESULTS: No RHD patient was found in the sampled population. In Xinjiang, the prevalence of RHD was 12.9/1000 among adults, higher than that (2.2/1000) in Guangdong Province. The GAS-positive rate in the schoolchildren in Xinjiang ranged from 9.8% to 12.6%, higher than that in Guangdong (2.3%-3.9%). CONCLUSION: The GAS-positive rate among children and incidence of RHD in adults are higher in Xinjiang than in Guangdong. The prevalence of RHD among the schoolchildren shows a reduction compared with that in 1994. PMID- 19778823 TI - [Bio-Oss collagen bone grafting in the treatment of endodontic-periodontic lesion]. AB - OBJECTIVE: To study the effect of Bio-Oss collagen for bone grafting in the treatment of endodontic-periodontic lesion. METHODS: Thirty patients (37 teeth) with endodontic-periodontic lesions received root canal therapy and periodontal treatment. Four weeks after the treatment, Bio-Oss collagen was grafted in these teeth. Clinical examinations were performed 1, 3, 6, 9, and 12 months after the surgery. RESULTS: The mobility of these teeth improved 1 month after the surgery. At 3, 6, 9, and 12 months after the surgery, the pocket depth reduced obviously good attachment and further improvement of the tooth mobility. CONCLUSION: Bio Oss collagen for bone grafting can achieve good therapeutic effect for endodontic periodontic lesions. PMID- 19778824 TI - [High-performance capillary electrophoresis for determining caffeic acid content in compound Yinhuangjiedu decoction]. AB - OBJECTIVE: To establish a method for determining the content of caffeic acid in compound Yinhuangjiedu decoction using high-performance capillary electrophoresis (HPCE). METHODS: The optimized HPCE for determining caffeic acid content utilized a fused-silica capillary tube (75 microm x 60 cm, effective length of 53 cm) with 20 mmol/L borate as the running buffer (pH=9.18), a constant voltage of 12 kV, a sampling time of 5 s at 25 degrees celsius, and UV detection wavelength at 313 nm. RESULTS: The linear range of caffeic acid was 20-100 microg/ml. CONCLUSION: HPCE is simple, rapid, and sensitive for quality control of the compound Yinhuangjiedu decoction. PMID- 19778825 TI - [Clinical application of the Epworth sleepiness score in pregnant women with obstructive sleep apnea-hypopnea syndrome]. AB - OBJECTIVE: To provide a convenient method for screening obstructive sleep apnea hypopnea syndrome (OSAHS) in pregnant women. METHODS: Seventy-eight pregnant women with suspected OSAHS were calculated for the EP index using Epworth sleepiness score (ESS) with also measurement of the neck circumference (NC) and body mass index (BMI). The apnea/hypopnea index (AHI) was calculated and the lowest SaO(2) (LSaO(2)) measured through a 7-h polysomnography (PSG). The women were then divided into 4 groups according to the AHI and LSaO(2). The ESS was compared with the PSG-AHI and the receiver operating characteristic curve (ROC) was generated. RESULTS: All the clinical indexes (NC, BMI, EP, AHI, and LSaO(2)) showed significant differences between the 4 groups (P<0.05). EP and PSG were found to have greater correlations to AHI (r=0.759, P=0.000) than NC (r=0.668) and BMI (r=0.663). The area under the ROC of the EP (0.825) was greater than that of NC (0.772) and BMI (0.784). The index of EP showed greater clinical diagnostic value of OSAHS in pregnancy. Base on the ROC, EP at the optimal operating point of 7.5 had a sensitivity of 76.8% and specificity of 68.2% for diagnosis of OSAHS in pregnant women. CONCLUSION: The ESS is an economic and convenient method for screening OSAHS in pregnant women with high diagnostic sensitivity and specificity. PMID- 19778826 TI - [Correlation between oligohydramnios and abnormal expressions of TXA2, PGI2 and TXA2R in the umbilical arterial blood and placenta]. AB - OBJECTIVE: To investigate the roles of thromboxane A(2) (TXA(2)) and prostaglandin I(2) (PGI(2)) in development of oligohydramnios. METHODS: The concentration of TXB(2) and 6-keto-PGF1 in umbilical cord blood collected from 30 normal parturients (control) and 30 parturients with oligohydramnios was detected by radioimmunoassay to calculate the TXA(2)/PGI(2) ratio. Immunohistochemistry was performed to detect the contents of TXA(2)R in vascular endothelial cell in the placental villi. RESULTS: Compared with the control group, the concentration of umbilical cord blood TXB(2) in oligohydramnios group was significantly increased (P<0.01), but the elevation of 6-keto-PGF(2) concentration was not statistically significant (P>0.05). The oligohydramnios group showed significantly higher positivity rates of TXB2 and 6-keto-PGF1 in than the control group (P<0.01), and the positivity rate of TXA(2)R in the vascular endothelial cells in the placental villi was also significantly higher in the oligohydramnios group (22/30, 77.3% vs 11/30, 36.7%, P<0.05). Most of the TXA(2)R-positive cases in the oligohydramnios group showed strong positivities of TXA(2)R. CONCLUSION: Abnormal elevation of TXA(2) concentration in the umbilical cord blood and the TXA(2)/PGI(2) imbalance are responsible for the development of oligohydramnios. PMID- 19778827 TI - [Diagnosis of total anomalous pulmonary venous connection using multi-slice spiral CT]. AB - OBJECTIVE: To assess the value of multi-slice spiral computed tomography (MSCT) in the diagnosis of total anomalous pulmonary venous connection (TAPVC). METHODS: A retrospective analysis was conducted in 12 patients with the diagnosis of TAPVC established by MSCT. Multi-planar reconstruction (MPR), curved-planar reconstruction (CPR), volume rendering (VR), maximum intensity projection (MIP) and minimum intensity projection were performed in all the cases, and the results were analyzed in comparison with those of ultrasound echocardiography (12 cases) and surgical findings (10 cases). Cardiovascular angiography was performed in 2 cases. RESULTS: In the 10 patients receiving surgical interventions, 7 presented with supracardiac TAPVC, 2 with cardiac TAPVC, and 1 with infracardiac TAPVC. MSCT allowed qualitative diagnosis and identified the location of the lesions in all the 10 surgical patients, whereas echocardiography established the diagnosis in only 5 patients. In the 2 cases undergoing cardiovascular angiography, the diagnosis was established in only 1 case without clear display of the draining vein. CONCLUSION: MSCT combined with 3-dimensional reconstruction provides a noninvasive and accurate means for the diagnosis of TAPVC. PMID- 19778828 TI - Beyond Texas City: the state of process safety in the unionized U.S. oil refining industry. AB - The March 2005 British Petroleum (BP) Texas City Refinery disaster provided a stimulus to examine the state of process safety in the U.S. refining industry. Participatory action researchers conducted a nation-wide mail-back survey of United Steelworkers local unions and collected data from 51 unionized refineries. The study examined the prevalence of highly hazardous conditions key to the Texas City disaster, refinery actions to address those conditions, emergency preparedness and response, process safety systems, and worker training. Findings indicate that the key highly hazardous conditions were pervasive and often resulted in incidents or near-misses. Respondents reported worker training was insufficient and less than a third characterized their refineries as very prepared to respond safely to a hazardous materials emergency. The authors conclude that the potential for future disasters plagues the refining industry. In response, they call for effective proactive OSHA regulation and outline ten urgent and critical actions to improve refinery process safety. PMID- 19778829 TI - The social construction of occupational health and safety: barriers to environmental-labor health coalitions. AB - Occupational and environmental health advocates promote the potential of alliances between workers and community members to address shared health problems resulting from industrial processes. Advocates recognize the need to overcome job blackmail, which has successfully pitted these groups against one another by threatening job loss in the face of calls for improved standards. This strategic form of issue management represents a dualism between good health and clean environments on one hand and jobs and tax bases on the other. The author argues that overcoming job blackmail requires attention not only to this dualism, but to the broader social construction of occupational and environmental health. The article describes a series of oppositional constructions, in both strategic organizational rhetoric and everyday cultural discourse, which reinforces job blackmail and impedes the development of solidarity among workers, neighbors, and environmental advocates. These dualisms polarize our views of work and environment, science, and social identity, thereby producing barriers to coalition formation. Understanding these reifications helps to build an activist agenda and identify potential resources for organizing to overcome these barriers. PMID- 19778830 TI - Genuine worker participation-an indispensable key to effective global OHS. AB - Working conditions, including workplace safety, in global supply chains of products sold by transnational corporations have only marginally improved over the last 15 years despite the development of hundreds of corporate "codes of conduct," code monitoring systems, and an elaborate new "corporate social responsibility" industry. The two underlying reasons for the lack of significant change are: 1) a schizophrenic business model which fatally undermines "socially responsible" sourcing programs with unyielding dictates for the lowest possible production costs; and 2) the lack of any meaningful participation by shop-floor workers in plant safety programs. Only when trained, empowered, and active workers are an integral part of workplace safety programs will conditions improve over the long term. PMID- 19778831 TI - It will take persistence: the dynamics of a university-community partnership to sustain the New England worker health and safety movement. AB - The New England Consortium (TNEC) is a university-community partnership that since 1987 has delivered health and safety training for hazardous waste operations and emergency response (HAZWOPER) workers. Through two decades of the relative loss of power by the labor and environmental movements and subsequent reductions in state support for worker health and safety, this selective history of TNEC demonstrates its ability to sustain a worker health and safety movement in New England. The evolution of TNEC's partnership process and the principles and policies by which it operates have helped to resolve several critical conflicts and strengthen its working relationships. Partnership dynamics are explored within their political and economic contexts and the need of member organizations to balance fiscal solvency with political objectives. PMID- 19778832 TI - Who's sick at school: linking poor school conditions and health disparities for Boston's children. AB - A recent review of student asthma rates and environmental audits of school buildings suggests that schools with poor indoor air quality have higher-than average rates of asthma. Many Boston Public School (BPS) children and staff are learning and working in poor indoor environmental conditions that not only can exacerbate asthma, but also lead to other problems ranging from allergies and sinus infections to adverse academic performance [1]. The Boston Urban Asthma Coalition (BUAC) conducted a preliminary analysis of 2004-05 childhood asthma rates for BPS students and compared them to the 2004-05 environmental audits of the top 10 schools with environmental problems. This analysis suggests that schools with the highest rates of leaks, mold, and pest infestations also have higher-than-average asthma rates for children. PMID- 19778833 TI - Teaching, training, and partnering for justice-an interview with Lulu Odom. PMID- 19778837 TI - Leukemia research, 2008. PMID- 19778838 TI - Flavopiridol in chronic lymphocytic leukemia: a concise review. AB - Patients with chronic lymphocytic leukemia (CLL) with high-risk cytogenetic features such as del(17p13) have limited treatment options and decreased overall survival. Dysfunction of p53 leads to resistance to fludarabine-based therapies. Cyclin-dependent kinase inhibitors (CDKi) are a novel class of agents that induce apoptosis in CLL cells independent of p53 mutational status. The synthetic flavone flavopiridol demonstrated promising in vitro activity in CLL. In initial phase I studies using a continuous infusion dosing schedule in a variety of malignancies, no clinical activity was observed. Detailed pharmacokinetic modeling led to the development of a novel dosing schedule designed to achieve target drug concentrations in vivo. In phase I testing, this dosing schedule resulted in acute tumor lysis syndrome (TLS) as the dose-limiting toxicity. With the implementation of a standardized protocol to prevent severe TLS, flavopiridol was administered safely, and responses were observed in heavily pretreated, fludarabine-refractory patients, cytogenetically high-risk patients, and patients with bulky lymphadenopathy. In a pharmacokinetic analysis, flavopiridol area under the plasma concentration-time curve (AUC) correlated with clinical response and cytokine release syndrome. Phase II studies are under way with encouraging preliminary results. Flavopiridol is currently under active investigation in combination with other agents and as a means to eradicate minimal residual disease in patients following cytoreductive chemotherapy. Several other investigational CDKi in preclinical and early clinical development are briefly discussed in this review. PMID- 19778839 TI - Transplantation in chronic lymphocytic leukemia: timing and expectations. AB - Stem cell transplantation in chronic lymphocytic leukemia (CLL) is an evolving field. Younger patients with high-risk disease might derive the greatest benefit from this approach and the availability of reduced-intensity conditioning regimens has made allogeneic stem cell transplantation more relevant to patients with CLL. Patient selection, timing of transplantation, and method of conditioning, stem cell delivery and immunosuppression appear to influence outcomes. We collect and review the available data to assist clinical decision making in this field. PMID- 19778840 TI - Familial chronic lymphocytic leukemia: what does it mean to me? AB - Though B-chronic lymphocytic leukemia (CLL) is known to be a heterogeneous disease, only recently has the familial component of CLL been more thoroughly investigated. This entity is seen in approximately 5%-10% of all patients with CLL and can be associated with earlier age of diagnosis, higher female prevalence, and increased incidence of other lymphoproliferative disorders (LPDs), such as non-Hodgkin lymphoma and the more recently described monoclonal B cell lymphocytosis CLL in family members. The prognostic parameters and clinical course of familial CLL is not clearly distinguishable from that of sporadic disease. In addition, it is not clear that the treatment responses for progressive disease has any discernible difference in familial versus sporadic CLL. The genetic etiology of CLL is unknown, and early work on familial CLL has not yet uncovered any obvious gene or group of genes that can be clearly related to the pathophysiology of CLL. However, the detailed genetic study of familial CLL is likely to be critical in uncovering relevant genes. At present it is best to indicate to concerned CLL patients that their relatives are at relatively low risk of developing CLL or other LPDs. PMID- 19778841 TI - The antiproliferative effect of kefir cell-free fraction on HuT-102 malignant T lymphocytes. AB - Kefir is produced by adding kefir grains (a mass of proteins, polysaccharides, bacteria, and yeast) to pasteurized milk; it has been shown to control several cellular types of cancer, such as Sarcoma 180 in mice, Lewis lung carcinoma, and human mammary cancer. Human T-cell lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia, which is a fatal disease with no effective treatment. The current study aims at investigating the effect of a cell free fraction of kefir on HuT-102 cells, which are HTLV-1-positive malignant T lymphocytes. Cells were incubated with different kefir concentrations: the cytotoxicity of the compound was evaluated by determining the percentage viability of cells. The effect of all the noncytotoxic concentrations of kefir cell-free fraction on the proliferation of HuT-102 cells was then assessed. The levels of transforming growth factor (TGF)-alpha mRNA upon kefir treatment were then analyzed using reverse transcriptase polymerase chain reaction. Finally, the growth inhibitory effects of kefir on cell cycle progression and/or apoptosis were assessed by flow cytometry. The maximum cytotoxicity recorded at 80 microg/microL for 48 hours was only 43%. The percent reduction in proliferation was very significant, dose and time dependent, and reached 98% upon 60 microg/microL treatment for 24 hours. Kefir cell-free fraction caused the downregulation of TGF-alpha, which is a cytokine that induces the proliferation and replication of cells. Finally, a marked increase in cell cycle distribution was noted in the pre-G1 phase. In conclusion, kefir is effective in inhibiting proliferation and inducing apoptosis of HTLV-1-positive malignant T-lymphocytes. Therefore, further in vivo investigation is highly recommended. PMID- 19778843 TI - Transplantations in adult acute lymphoblastic leukemia--grounds for optimism? AB - The large MRC/ECOG Adult Acute Lymphoblastic Leukemia Study establishes the value of sibling donor allogeneic transplantation in patients with standard risk, demonstrating superior outcome to conventional chemotherapy. The small but significant number of patients having matched unrelated donor transplantations on this study protocol appear to do well and might establish the value of such an approach for those without a sibling. Reduced-intensity conditioning might begin to address the transplantation-related mortality problems of the older patients. The youngest adults might not need to undergo transplantation at all. If they are now treated on pediatric chemotherapy protocols, their outcome appears to improve significantly. PMID- 19778842 TI - Therapeutic targeting of NOTCH1 signaling in T-cell acute lymphoblastic leukemia. AB - The recent identification of activating mutations in NOTCH1 in the majority of T cell acute lymphoblastic leukemias (T-ALLs) has brought major interest toward targeting the NOTCH signaling pathway in this disease. Small-molecule gamma secretase inhibitors (GSIs), which block a critical proteolytic step required for NOTCH1 activation, can effectively block the activity of NOTCH1 mutant alleles. However, the clinical development of GSIs has been hampered by their low cytotoxicity against human T-ALL and the development of significant gastrointestinal toxicity derived from the inhibition of NOTCH signaling in the gut. Improved understanding of the oncogenic mechanisms of NOTCH1 and the effects of NOTCH inhibition in leukemic cells and the intestinal epithelium are required for the design of effective anti-NOTCH1 therapies in T-ALL. PMID- 19778844 TI - T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia: a separate entity? AB - T-cell acute lymphoblastic leukemia (T-ALL) and T-cell lymphoblastic lymphoma (T LBL) are considered the same disease, differing by the extent of bone marrow infiltration. According to recent gene expression profiling data, T-ALL and T-LBL can be separated by prediction analysis of microarrays showing an overexpression of MML1 in T-LBL and CD47 in T-ALL. Immunophenotypes of T-LBL and T-ALL are identical but differ in frequency, with a higher rate of cortical or mature immunophenotypes in T-LBL, which is probably related to the higher rate (> 90%) of mediastinal tumors. Treatment approaches in T-LBL changed from conventional non-Hodgkin lymphoma (NHL) protocols to intensive NHL protocols but recently to ALL-designed protocols. T-ALL remission rates are 90%, and overall survival (OS) has improved to 60%-70%. Mediastinal tumors resolve in most cases of T-ALL with chemotherapy only, whereas in T-LBL additional mediastinal irradiation seems to be beneficial. Strategies for stem cell transplantation (SCT) in T-LBL and T-ALL differ. Autologous SCT in complete remission (CR) in T-LBL gives a 70% survival rate, which is similar to chemotherapy alone. In T-ALL, the subtypes of early and mature T-ALL have a poor outcome with chemotherapy alone (< 30%) and might profit from an allogeneic transplantation in first CR (OS > 50%). There seems to be no need for transplantation in thymic T-ALL in first CR. Prognostic factors are published for T-ALL but not for T-LBL. MRD may guide further treatment strategies in T-ALL and probably also in T-LBL as indications for a SCT or for the evaluation of novel, particularly T-cell-specific, drugs. PMID- 19778846 TI - Burkitt lymphoma/leukemia: improving prognosis. AB - Burkitt lymphoma/leukemia (BL) has become a very curable mature B-cell neoplasm. Current standard regimens, focused on the unique characteristics of this disease, are composed of cyclical intensive chemotherapy and aggressive intrathecal prophylaxis. Using this approach, complete response rates of 80%-90% are routinely achieved, and survival is now approaching 80% with the addition of rituximab to these intensive regimens. Prophylactic cranial irradiation and prolonged maintenance have no proven benefit and are not recommended. The more widespread use of highly active antiretroviral therapy in the HIV patient with BL has allowed the use of similar aggressive therapies that are used for the non-HIV BL patients, with commensurate improvements in outcomes in this high-risk population. Future improvements for patients with BL could rely on standardization of gene expression profiling (to ensure more accurate diagnoses and prognostication of disease and to understand mechanisms of treatment resistance) and to develop novel biologically targeted approaches to treatment. The next generation of clinical trials to further improve survival will have the challenge of identifying high-risk patients who might be candidates for novel agents that could be incorporated into existing regimens with the goal of curing all patients with this disease. PMID- 19778845 TI - High-risk childhood acute lymphoblastic leukemia. AB - Although most children with acute lymphoblastic leukemia (ALL) are cured, certain subsets have a high risk of relapse. Relapse risk can be predicted by early response to therapy, clinical and pharmacogenetic features of the host, and genetic characteristics of leukemic cells. Though early treatment response can be assessed by the peripheral blast cell count after 1 week of single-agent glucocorticoid treatment or percent of bone marrow blasts by morphology after 1 or 2 weeks of multiagent induction treatment, determination of minimal residual disease by polymerase chain reaction (PCR) or flow cytometry after 2 to 6 weeks of induction is the most precise and useful measure. Augmented therapy has improved outcome for the poor responders to initial treatment. Infants with mixed lineage leukemia (MLL)-rearranged ALL comprise a very poor-risk group wherein further intensification of chemotherapy causes significant toxicity. Hybrid protocols incorporating drugs effective for acute myeloid leukemia could improve survival, a strategy being tested in international trials. Studies on the biology of MLL-induced leukemogenesis have prompted the development of novel targeted agents, currently under evaluation in clinical trials. Short-term outcomes of patients with Philadelphia chromosome (Ph)-positive ALL have improved significantly by adding tyrosine kinase inhibitors to standard chemotherapy regimens. New agents and methods to overcome resistance are under investigation, and allogeneic stem cell transplantation is recommended for certain subsets of patients, for example those with Ph+ and T-cell ALL with poor early response. Genome-wide interrogation of leukemic cell genetic abnormalities and germline genetic variations promise to identify new molecular targets for therapy. PMID- 19778847 TI - T-cell prolymphocytic leukemia. AB - T-cell prolymphocytic leukemia is a rare postthymic malignancy with distinctive clinical, morphologic, immunophenotypic, and cytogenetic features. The clinical course is typically aggressive with poor response to conventional chemotherapy and short survival. Treatment with purine analogues and alemtuzumab has resulted in significantly higher response rates and improved survival. Nevertheless, responses are relatively short, and the only potential curative treatment is allogeneic stem cell transplantation. The age and comorbidities of many of the patients has limited this option, but the growing use of nonmyeloablative transplantation has now widened the patient eligibility for this approach. PMID- 19778849 TI - Hairy cell leukemia. AB - Progress in the treatment of patients with hairy cell leukemia (HCL) has led to a significant change in the natural history of the disease. With current regimens, the majority of patients achieve a complete remission, and their survival curves are similar to those for appropriate age-matched individuals without the disease. At the same time, new technologies are allowing better understanding of the molecular mechanisms responsible for the pathogenesis of this and other indolent lymphoid neoplasms. Several studies using modern techniques with different sensitivities have demonstrated the persistence of minimal residual disease (MRD) after therapy with nucleoside analogues in majority of patients. However, it is not clear whether such MRD would invariably lead to leukemia recurrence or what level of MRD can predict relapse. The role of monoclonal antibodies, naked or conjugated with toxins, in the management of HCL and their ability to eradicate MRD is under investigation. Whether such strategies of chemoimmunotherapy would lead to further improvements in the outcome of patients with HCL needs to be further investigated. PMID- 19778850 TI - Nonmyeloablative allogeneic stem cell transplantation for chronic myelogenous leukemia in the imatinib era. AB - Allogeneic stem cell transplantation (ASCT) is a potentially curative treatment for patients with chronic myelogenous leukemia (CML) and was previously considered the preferred treatment for newly diagnosed CML. The success of imatinib has changed treatment recommendations, and allogeneic transplants are now reserved for imatinib treatment failures. Previous imatinib treatment does not compromise the results of ASCT, but patients with overt transformed disease have poor results. It is unclear whether patients whose disease is considered to have failed imatinib should be referred immediately for ASCT or receive treatment with a second-generation tyrosine kinase inhibitors (TKI). Patients whose disease fails 2 TKIs should receive ASCT if possible. Nonmyeloablative preparative regimens reduce the toxicity and treatment-related mortality associated with the transplantation procedure and allow transplantations to be performed in older and medically infirm patients. This approach, including posttransplantation treatment with TKIs and donor lymphocyte infusion, produces a high fraction of durable molecular complete remissions. PMID- 19778851 TI - Measuring minimal residual disease in chronic myeloid leukemia: fluorescence in situ hybridization and polymerase chain reaction. AB - The outlook for newly diagnosed patients with chronic myeloid leukemia (CML) in the imatinib era is excellent for most patients. However, imatinib failure is observed in around 25%-30% of patients. With the availability of second-line tyrosine kinase inhibitor therapy and/or allogeneic transplantation, many of these patients with imatinib failure can still achieve durable cytogenetic and molecular responses. Early evidence of imatinib resistance, when the biology of the emerging leukemia might still be relatively favorable, is the best time to switch to second-line therapy. Close cytogenetic and molecular monitoring will facilitate early intervention in appropriate cases. However, caution should be used when interpreting minimal residual disease data, and the danger of inappropriate changes in therapy based on assay fluctuations should be recognized. A significant increase in the level of BCR-ABL to a level > 0.1% on the international scale (major molecular response) should prompt a repeat BCR-ABL assay, a mutation screen, and possibly marrow cytogenetics. What constitutes a significant increase depends on the laboratory-specific measurement reliability. The possibilities of poor compliance or drug interactions should be considered. If the repeat BCR-ABL assay, fluorescence in situ hybridization assay, or cytogenetics confirms loss of complete cytogenetic response or if a mutation is identified, a dose increase or a switch in therapy to a second-line kinase inhibitor might be indicated. At least until complete molecular response is achieved, regular real-time polymerase chain reaction monitoring reinforces the fact that leukemia is still present and that compliance is a challenge that requires ongoing vigilance from the patient and the clinician. PMID- 19778848 TI - Never say die: survival signaling in large granular lymphocyte leukemia. AB - Large granular lymphocyte (LGL) leukemia is a rare disorder of mature cytotoxic T or natural killer cells. Large granular lymphocyte leukemia is characterized by the accumulation of cytotoxic cells in blood and infiltration in the bone marrow, liver, and spleen. Herein, we review clinical features of LGL leukemia. We focus our discussion on known survival signals believed to play a role in the pathogenesis of LGL leukemia and their potential therapeutic implications. PMID- 19778852 TI - Second-line therapy and beyond resistance for the treatment of patients with chronic myeloid leukemia post imatinib failure. AB - Chronic myeloid leukemia (CML) is characterized at the molecular level by the presence of the Philadelphia chromosome (Ph) and the resultant oncogenic signaling by the BCR-ABL fusion protein. The treatment and outlook for CML were revolutionized by the introduction of imatinib, but resistance is a substantial barrier to successful treatment in many patients. Introduction of the second generation tyrosine kinase inhibitors (TKI) dasatinib and nilotinib has provided effective therapeutic options for many patients with resistance to front-line imatinib. However, the T315I mutation remains a significant clinical issue because it is insensitive to all currently available agents. A number of new agents are in development and many hold the promise of activity in T315I-mutated disease. Successful treatment of patients with disease harboring T315I might lie in the effective combination or sequencing of these new agents with existing TKI therapies. PMID- 19778854 TI - Progress in myelodysplastic syndromes. AB - During the past 5 years, we have witnessed an explosion in our understanding, classification, and number of therapeutic opportunities for patients with myelodysplastic syndromes (MDS). These include the development of new histologic classifications, scoring systems, supportive care measures, and most importantly, effective treatments that are safe and can modify the natural history of this complex group of hematopoietic disorders. In this brief review, and as part of the Leukemia 2008, Fourth International Conference, held in Houston during September 2008, I summarize some of the most important recent developments in the field of MDS and try to identify new problems and opportunities for patients and researchers in this area. PMID- 19778853 TI - Minimal residual disease quantitation in acute myeloid leukemia. AB - The prognosis for patients with acute myeloid leukemia (AML) is heterogeneous. A minority of patients have clinical and biologic features associated with a very high risk of relapse. For the remaining patients, no clear prognostic factors can be identified at diagnosis. The degree of treatment response is likely to be an informative predictor of outcome for these patients. Modern assays to detect AML cells that are undetectable by conventional morphologic techniques, ie, minimal residual disease (MRD), can potentially improve measurements of treatment response. It is plausible that modifications to treatment based on the results of these assays will improve clinical management and ultimately increase cure rates. Established MRD assays for AML are based on either polymerase chain reaction amplification of genetic abnormalities or flow cytometric detection of abnormal immunophenotypes. Residual disease and treatment response can be measured by these assays in a manner that is much more sensitive and objective than that afforded by conventional morphologic examination. The expanding use of MRD testing is beginning to change the definitions of treatment response and of remission. Other clinically informative uses of MRD testing include the detection of early relapse and the evaluation of the efficacy of new antileukemic agents. PMID- 19778855 TI - Advances in stem cell transplantation: making it better and safer. AB - The development of reduced-intensity regimens has allowed physicians and patients to explore this option even in older patients. Current results underscore that age by itself should no longer be a contraindication for allogeneic transplantation in these patients, and long-term disease control with good quality of life is possible. Future trials combining novel antileukemic therapies and novel transplantation technologies are being explored. These trials should allow more patients with acute myeloid leukemia or myelodysplastic syndromes to achieve long and productive lives. PMID- 19778857 TI - Lenalidomide--a transforming therapeutic agent in myelodysplastic syndromes. AB - Lenalidomide is an immunomodulatory drug (IMiD) with erythropoietic activity in myelodysplastic syndromes (MDS) that is karyotype dependent. The MDS-003 multicenter registration trial in deletion of chromosome 5q (del[5q]) showed that lenalidomide suppresses the del(5q) clone in patients who achieve transfusion independence and is a prerequisite for sustained restoration of effective erythropoiesis. Long-term outcome data indicate that cytogenetic response to lenalidomide might confer a survival advantage compared with cytogenetic nonresponders, with a corresponding reduced risk for acute myeloid leukemia (AML) progression. In lower-risk, transfusion-dependent patients with MDS without del(5q), lenalidomide has significant, albeit less erythropoietic, activity that could relate to dual effects on both the MDS clone and the bone marrow environment. The most common adverse effects are neutropenia and thrombocytopenia, which occur early and with greater frequency in patients with del(5q), consistent with the drug's action to suppress the MDS clone. Combination strategies are now in both MDS and AML that could further broaden the therapeutic potential of lenalidomide. PMID- 19778856 TI - What are the endpoints of therapy for acute leukemias? Old definitions and new challenges. AB - Acute leukemias are complex diseases on multiple levels, and laboratory efforts over the past 3 decades have focused on better understanding of the molecular underpinnings and their stem cell biology. We now have a panoply of technologic advances that allow us to characterize individual leukemias by molecular profiles that relate directly to clinical behavior, to detect minimal residual disease, and to begin to develop "targeted" therapeutic strategies based on molecular considerations. There are a number of challenges surrounding this task: first, how to combine these agents with traditional chemotherapeutics and/or with each other to maximize leukemic cell kill and increase the cure rate; second, how to use these targeted agents in the minimal residual disease with potential curative intent; third, for patients unable to tolerate or unlikely to benefit from aggressive approaches, how to use one or more of these agents to reduce tumor bulk and either permit some restoration of normal marrow function or induce morphologic and functional differentiation of the leukemic clone to overcome the leukemia-associated bone marrow failure; and lastly, how to measure the effects of these agents on the molecular and cellular biologic levels in ways that correlate with and might even predict overall clinical outcome. These challenges are further complicated by the inherent heterogeneity in host biology; disease etiology and biology; and interactions among host, disease, and treatment that ultimately determine individual clinical outcomes. Toward this end, we will discuss selected issues surrounding new clinical trial designs and the development of clinically relevant molecular endpoints that might facilitate the development of new treatment approaches that will improve the outlook for adults with acute leukemias. PMID- 19778858 TI - Red blood cell transfusion therapy and iron chelation in patients with myelodysplastic syndromes. AB - Anemia is the most frequent peripheral cytopenia observed in myelodysplastic syndromes (MDS) and has been recognized among the most important factors affecting the outcome of patients with MDS. In patients who are not candidates for potentially curative approaches, therapeutic options for symptomatic anemia include red blood cell (RBC) transfusion and iron chelation, hematopoietic growth factors, immunosuppression, immune-modulatory drugs, and hypomethylating agents. In about 40% of patients, regular RBC transfusions are the only therapeutic option that can be offered. The onset of a regular transfusion requirement significantly worsens the survival of patients with MDS. Transfusion-dependent patients invariably develop secondary iron overload. Elevated serum ferritin was proven to be associated with worse survival in transfusion-dependent patients, and recent data obtained using magnetic resonance imaging show both hepatic and myocardial iron accumulation in heavily transfused patients. According to evidence-based guidelines, patients with sideroblastic anemia, 5q- syndrome, or other forms of refractory anemia, in whom long-term transfusion therapy is likely, are recognized as the best candidates to receive iron chelation therapy. In addition, patients who are candidates for allogeneic stem cell transplantation might also benefit from chelation therapy because iron overload is associated with increased transplantation-related mortality. RBC transfusions and iron chelation are the mainstay of therapy for many individuals with MDS. However, critical issues remain to be clarified in order to optimize treatment, including the identification of target hemoglobin levels to prevent anemia-related morbidity and more accurate information on the effect of iron-mediated organ damage on the outcome of patients with MDS. PMID- 19778859 TI - RNA inhibition, microRNAs, and new therapeutic agents for cancer treatment. AB - Over the past few years, molecular oncology research has revealed that abnormalities in both protein-coding genes (PCGs) and noncoding RNAs (ncRNAs) can be identified in tumors and that the interplay between PCGs and ncRNAs is causally involved in the initiation, progression, and metastases of human cancers. MicroRNAs (miRNAs), which are among the most studied ncRNAs, are small 19- to 25-nucleotide genes involved in the regulation of PCGs and other ncRNAs. With the recent findings of miRNAs' involvement in cancer, RNA inhibition can be used to treat cancer patients in two ways: (1) by using RNA or DNA molecules as therapeutic drugs against messenger RNA of genes involved in the pathogenesis of cancers and (2) by directly targeting ncRNAs that participate in cancer pathogenesis. In this review, we focus on the possible use of miRNAs or compounds interacting with miRNAs as new therapeutic agents in cancer patients. PMID- 19778860 TI - Stem cells and somatic cells: reprogramming and plasticity. AB - Recent seminal discoveries have significantly advanced the field of stem cell research and received worldwide attention. Improvements in somatic cell nuclear transfer (SCNT) technology, enabling the cloning of Dolly the sheep, and the derivation and differentiation of human embryonic stem cells raised hopes that normal cells could be generated to replace diseased or injured tissue. At the same time, in vitro and in vivo studies demonstrated that somatic cells of one tissue are capable of generating cells of another tissue. It was theorized that any cell might be reprogrammed, by exposure to a new environment, to become another cell type. This concept contradicts two established hypotheses: (1) that only specific tissues are generated from the endoderm, mesoderm, and ectoderm and (2) that tissue cells arise from a rare population of tissue-specific stem cells in a hierarchical fashion. SCNT, cell fusion experiments, and most recent gene transfer studies also contradict these hypotheses, as they demonstrate that mature somatic cells can be reprogrammed to regain pluripotent (or even totipotent) stem cell capacity. On the basis of the stem cell theory, hierarchical cancer stem cell differentiation models have been proposed. Cancer cell plasticity is an established phenomenon that supports the notion that cellular phenotype and function might be altered. Therefore, mechanisms of cellular plasticity should be exploited and the clinical significance of the cancer stem cell theory cautiously assessed. PMID- 19778861 TI - Molecular and genetic bases of myeloproliferative disorders: questions and perspectives. AB - The discovery of the JAK2V617F mutation followed by the discovery of JAK2 exon 12 and MPLW515 mutations has completely modified the understanding, diagnosis, and management of the classic myeloproliferative disorders (MPDs), which include polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Nonetheless, genetic defects have not yet been identified in about 40% of ET and PMF. There is now strong evidence that these mutations are the oncogenic events that drive these disorders and are responsible for most biologic and clinical abnormalities. In addition, there are convincing data indicating that the number of JAK2V617F copies (homozygosity vs. heterozygosity) is important in explaining how a single mutation can be associated with several disorders. However, it is still uncertain whether these mutations are sufficient to explain the full development, heterogeneity, and progression of MPD, or if other genetic or epigenetic events are also necessary. In this review, we discuss different hypothetical models of MPD pathogenesis supported by recent findings. Further characterization of the molecular events operating in these disorders will be essential in fully understanding their pathogenesis and in developing new therapeutic approaches. PMID- 19778862 TI - JAK2 inhibitors: A reality? A hope? AB - Myelofibrosis (MF; primary or post-polycythemia vera/essential thrombocythemia) carries the worst prognosis among BCR-ABL-negative myeloproliferative neoplasms (MPNs). Stem cell transplantation is the only curative approach but is hampered by significant nonrelapse mortality. Thus, effective, targeted therapies are needed. A mutated Janus kinase 2 (JAK2) gene (JAK2(V617F)), found in a significant portion of patients with MPN, results in increased JAK2 tyrosine kinase activity, leading to clonal proliferation; several small molecules inhibit the growth of hematopoietic colonies harboring JAK2(V617). Several JAK2 inhibitors have reached the clinical trial stage and are reviewed here. The most developed among them is INCB018424, which has demonstrated noteworthy clinical activity, with a rapid and profound reduction in splenomegaly and associated improvement in constitutional symptoms in MF patients receiving 10-25 mg orally twice daily, continuously. Thrombocytopenia (reversible) was the most common adverse event, seen in 30% of patients treated with 25 mg twice daily but not with 10 mg twice daily. Interestingly, INCB018424 was equally active in patients with and without JAK2 mutation. Other JAK2 inhibitors are less developed but show a similar type of clinical benefit. Conclusively, JAK2 inhibitors, particularly INCB018424, are clinically active in MF and are well tolerated. Whether they have an effect on the natural course of MF in treated patients remains to be elucidated. PMID- 19778863 TI - New thrombopoietic growth factors. AB - Thrombopoietin (TPO) is the physiologic regulator of platelet production and works by binding to its receptor on megakaryocyte precursor cells, thereby activating a large number of antiapoptotic and cell maturation pathways. "First generation" recombinant forms of TPO were developed over a decade ago and were found to increase the platelet count in patients undergoing nonmyeloablative chemotherapy, in patients with immune thrombocytopenic purpura (ITP) and myelodysplasia, as well as in platelet apheresis donors. Thrombopoietin did not improve platelet counts in patients undergoing stem cell transplantation or acute leukemia induction. Further development ended when antibodies formed against one of the recombinant proteins. Subsequently, 2 "second-generation" TPO mimetics have been developed and are entering clinical practice: romiplostim and eltrombopag. Romiplostim is an injectable peptide TPO mimetic that activates the TPO receptor just like native TPO. Eltrombopag is an oral nonpeptide TPO mimetic that activates the TPO receptor by binding to a different region of the TPO receptor that does not compete with TPO binding. Both increased the platelet counts in healthy subjects and in over two thirds of patients with ITP both before and after splenectomy; responses were maintained for at least 1 year. Romiplostim and eltrombopag are now US Food and Drug Administration approved for the second-line treatment of patients with ITP. Adverse events have been few, but long-term assessment for reticulin formation, increased bone marrow blasts, and thromboembolism is ongoing. Studies are under way to assess the efficacy of these drugs in the treatment of other thrombocytopenic disorders associated with chemotherapy, myelodysplasia, and chronic hepatitis. PMID- 19778864 TI - The use of new and better antibiotics for bacterial infections in patients with leukemia. AB - Bacterial infection is the most common complication of chemotherapy-induced neutropenia particularly in patients with hematologic malignancies. Bacterial infections predominate during the initial phases of neutropenic episodes. The spectrum of bacterial infection continues to evolve globally and locally at the institutional level, as do patterns of antimicrobial susceptibility/resistance. These trends are often associated with local treatment practices (eg, use of antimicrobial prophylaxis, open versus restricted formularies, clinical pathways and/or guidelines) and have a significant effect on the nature of empiric antimicrobial therapy. Increasing rates of resistance among gram-positive and gram-negative bacteria are posing new therapeutic challenges. These challenges can to some extent be overcome by new drug development. Many novel agents for the treatment of resistant gram-positive infections have been developed and are being evaluated in clinical trials. Newer agents for the treatment of Clostridium difficile associated diarrhea are also in the pipeline. Far fewer options to treat multi-drug resistant gram-negative infections exist, and new drug development is lagging behind. Consequently, the judicious use of currently available agents is essential. This is best achieved by the development of multidisciplinary antibiotic stewardship teams that gather baseline data, make recommendations for appropriate antimicrobial usage, and provide monitoring and feedback services to clinical care providers. Along with strict adherence to infection control policies, antimicrobial stewardship provides the best strategies for the management of infectious complications in patients with hematologic malignancies and other high-risk settings. PMID- 19778865 TI - microRNA: human disease and development. AB - microRNAs or miRNAs are an abundant class of highly conversed, small non-coding RNAs that present an entirely new theme of post-transcriptional gene regulation. miRNAs play a key role in diverse biological systems, such as virology, embryogenesis, differentiation, inflammation and cancer research. Research showed the importance of these non-coding small RNAs on immune system development and response. It plays important regulatory roles in various metabolic pathways in most eukaryotes. miRNAs are found to be involved in the regulation of immunity, including the development and differentiation of immune cells, antibody production and the inflammatory mediator release. PMID- 19778866 TI - Scatter search algorithm for protein structure prediction. AB - In this paper, we present a Scatter Search (SS) algorithm for predicting 3D structures of proteins based on torsion angles representation. Given the protein's sequence of Amino Acids (AAs), our algorithm produces a 3D structure that aims to minimise the energy function associated with the structure. SS is an evolutionary approach that is based on a population of candidate solutions. These candidates undergo evolutionary operations that combine search intensification and diversification over a number of iterations. We evaluate our algorithm on three proteins taken from a Protein Data Bank (PDB). The results show that our algorithm is able to produce 3D structures with good sub-optimal energy values. Also, the Root Mean Square Deviations (RMSD) of these structures from the reference proteins are promising within limits imposed by the assumptions made. PMID- 19778867 TI - Three dimensional structure of the closed conformation (active) of human merlin reveals masking of actin binding site in the FERM domain. AB - We modelled the structure of human merlin using the structure of moesin from Spodoptera frugiperda as the template. The present model suggests an interaction of its extreme C-terminal region with the subdomains B and C of FERM domain, masking the binding site of beta II spectrin. Modelling the complete structure of merlin revealed a novel central alpha helical domain with a helix-coil-helix. The actin binding site in the carboxy terminal is absent in merlin and in its closed conformation the indirect actin binding site in the FERM domain is also not available for the interaction of other proteins with it. PMID- 19778868 TI - In silico analysis of motifs in promoters of differentially expressed genes in rice (Oryza sativa L.) under anoxia. AB - The aim of this study was to characterise the molecular mechanisms of transcriptional regulation of Differentially Expressed Genes (DEGs) in rice coleoptiles under anoxia by identifying motifs that are common in the promoter region of co-regulated genes. Un-changed DEGs (<2 fold and >-2), up-regulated DEGs (>or=2 fold) and down-regulated DEGs (or=4000 g) by application of a correction factor to the gestation-adjusted projection (GAP) method. METHODS: A review was performed of 411 singleton pregnancies delivered at term. On the basis of ultrasonographic examinations previously performed between 34.0 and 36.9 weeks' gestation, an EBW was calculated for each patient by the GAP method (EBW(GAP)). Using linear regression, a correction factor was developed that minimized the systematic error in the EBW(GAP). The model was then tested retrospectively on a second group of 317 patients. RESULTS: The GAP method systematically overestimated weights of the heavier fetuses in our population. The model we derived showed improved accuracy compared with the GAP method. When applied to a second group of 317 patients, our correction to the GAP method improved specificity for macrosomia from 94.7% to 98.6% (P = .003). Stated differently, the false-positive rate was reduced from 5.3% to 1.4%. The difference in sensitivity for macrosomia was not significant: 41.2% and 35.3% (P = .68). CONCLUSIONS: Application of our model to our study population reduced the number of false-positive results for fetal macrosomia. PMID- 19778883 TI - Paradoxical motion: a useful tool in the prenatal diagnosis of congenital diaphragmatic hernias and eventrations. AB - OBJECTIVE: The purpose of this series was to determine whether paradoxical motion of the diaphragm reliably identifies congenital diaphragmatic hernias (CDHs). METHODS: Sonographic evaluation of diaphragmatic motion was attempted in all fetuses undergoing a targeted examination for findings suggestive of a possible CDH. During any respiratory motion or hiccupping, the posterior chest and abdomen were visualized in a coronal plane at the level of the descending aorta to evaluate ascent and descent of the hemidiaphragms. Normal motion was defined as descent of both during inspiration. Paradoxical motion was defined as descent of one hemidiaphragm and ascent of the opposite one during inspiration. If no breathing motion was observed during the examination, the results were termed "poor visualization." If there was poor visualization, the diaphragm was reevaluated at any return visits. In the second part of this study, diaphragmatic motion in 120 fetuses of at least 15 weeks' gestational age without abnormalities was evaluated. The diagnosis of a CDH needed to be confirmed by pathologic examination or surgery. RESULTS: No fetus without abnormalities showed paradoxical breathing. There were 15 fetuses who had a confirmed CDH and showed breathing during an examination. Fourteen of 15 had paradoxical motion; the fetus who did not had a very small defect containing a single loop of bowel. Thirteen fetuses had CDHs, and 2 had eventrations. CONCLUSIONS: Paradoxical motion is specific for CDHs and eventrations and can be seen as early as 17 weeks' gestation. PMID- 19778884 TI - Preload index of the inferior vena cava as a possible predictive marker of hydropic changes in fetuses with Ebstein anomaly. AB - OBJECTIVE: We aimed to investigate whether the preload index of the inferior vena cava (PLI-IVC) is of diagnostic value in predicting hydropic changes in fetuses with Ebstein anomaly. METHODS: Five cases of prenatally diagnosed Ebstein anomaly, which were managed at our institution between 1999 and 2008, were retrospectively reviewed. The PLI-IVC was calculated as the ratio between the reversed flow velocity from the right atrium and the forward velocity of the IVC. RESULTS: The PLI-IVC was high in all the cases. In 2 cases, PLI-IVC values tended to increase gradually before hydropic changes were recognized. In the cases without hydrops, PLI-IVC values exhibited a nonlinear trend throughout gestation and did not show any apparent increase. CONCLUSIONS: The upward trend of the PLI IVC rather than the maintenance of a high value can be considered a sign of cardiac failure. The blood flow pattern in the IVC should be carefully monitored in fetuses with Ebstein anomaly for the early identification of fetal impairment. PMID- 19778885 TI - Prenatal diagnosis of coarctation of the aorta with the multiplanar display and B flow imaging using 4-dimensional sonography. PMID- 19778886 TI - Prenatal diagnostic challenges and pitfalls for schizencephaly. PMID- 19778887 TI - Prenatal sonographic diagnosis of congenital megalourethra with in utero spontaneous resolution. PMID- 19778888 TI - Prenatal sonographic diagnosis of a buried penis. PMID- 19778889 TI - Membranous aplasia cutis congenita: a recognizable lesion on prenatal sonography. PMID- 19778890 TI - First-trimester diagnosis of familial split-hand/split-foot malformation. PMID- 19778891 TI - Sonographic and magnetic resonance imaging of a massive epidermoid cyst of the pelvis and buttock. PMID- 19778892 TI - Color Doppler sonographic features of a Brenner tumor in pregnancy. PMID- 19778893 TI - Ovarian dysgerminoma: a challenging clinical and sonographic diagnosis. PMID- 19778894 TI - Angiomyofibroblastoma of the vulva: sonographic and computed tomographic findings with pathologic correlation. PMID- 19778895 TI - Spontaneously infarcted fibroadenoma mimicking breast cancer. PMID- 19778896 TI - The retroverted incarcerated uterus in pregnancy: imagers beware. PMID- 19778897 TI - Interactions between EB1 and microtubules: dramatic effect of affinity tags and evidence for cooperative behavior. AB - Plus end tracking proteins (+TIPs) are a unique group of microtubule binding proteins that dynamically track microtubule (MT) plus ends. EB1 is a highly conserved +TIP with a fundamental role in MT dynamics, but it remains poorly understood in part because reported EB1 activities have differed considerably. One reason for this inconsistency could be the variable presence of affinity tags used for EB1 purification. To address this question and establish the activity of native EB1, we have measured the MT binding and tubulin polymerization activities of untagged EB1 and EB1 fragments and compared them with those of His-tagged EB1 proteins. We found that N-terminal His tags directly influence the interaction between EB1 and MTs, significantly increasing both affinity and activity, and that small amounts of His-tagged proteins act synergistically with larger amounts of untagged proteins. Moreover, the binding ratio between EB1 and tubulin can exceed 1:1, and EB1-MT binding curves do not fit simple binding models. These observations demonstrate that EB1 binding is not limited to the MT seam, and they suggest that EB1 binds cooperatively to MTs. Finally, we found that removal of tubulin C-terminal tails significantly reduces EB1 binding, indicating that EB1 tubulin interactions are mediated in part by the same tubulin acidic tails utilized by other MAPs. These binding relationships are important for helping to elucidate the complex of proteins at the MT tip. PMID- 19778898 TI - JNK and ceramide kinase govern the biogenesis of lipid droplets through activation of group IVA phospholipase A2. AB - The biogenesis of lipid droplets (LD) induced by serum depends on group IVA phospholipase A(2) (cPLA(2)alpha). This work dissects the pathway leading to cPLA(2)alpha activation and LD biogenesis. Both processes were Ca(2+) independent, as they took place after pharmacological blockade of Ca(2+) transients elicited by serum or chelation with 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid tetrakis(acetoxymethyl ester). The single mutation D43N in cPLA(2)alpha, which abrogates its Ca(2+) binding capacity and translocation to membranes, did not affect enzyme activation and formation of LD. In contrast, the mutation S505A did not affect membrane relocation of the enzyme in response to Ca(2+) but prevented its phosphorylation, activation, and the appearance of LD. Expression of specific activators of different mitogen activated protein kinases showed that phosphorylation of cPLA(2)alpha at Ser-505 is due to JNK. This was confirmed by pharmacological inhibition and expression of a dominant-negative form of the upstream activator MEKK1. LD biogenesis was accompanied by increased synthesis of ceramide 1-phosphate. Overexpression of its synthesizing enzyme ceramide kinase increased phosphorylation of cPLA(2)alpha at Ser-505 and formation of LD, and its down-regulation blocked the phosphorylation of cPLA(2)alpha and LD biogenesis. These results demonstrate that LD biogenesis induced by serum is regulated by JNK and ceramide kinase. PMID- 19778899 TI - Localization, purification, and functional reconstitution of the P4-ATPase Atp8a2, a phosphatidylserine flippase in photoreceptor disc membranes. AB - P(4)-ATPases comprise a relatively new subfamily of P-type ATPases implicated in the energy-dependent translocation of aminophospholipids across cell membranes. In this study, we report on the localization and functional properties of Atp8a2, a member of the P(4)-ATPase subfamily that has not been studied previously. Reverse transcription-PCR revealed high expression of atp8a2 mRNA in the retina and testis. Within the retina, immunofluorescence microscopy and subcellular fractionation studies localized Atp8a2 to outer segment disc membranes of rod and cone photoreceptor cells. Atp8a2 purified from photoreceptor outer segments by immunoaffinity chromatography exhibited ATPase activity that was stimulated by phosphatidylserine and to a lesser degree phosphatidylethanolamine but not by phosphatidylcholine or other membrane lipids. Purified Atp8a2 was reconstituted into liposomes containing fluorescent-labeled phosphatidylserine to measure the ability of Atp8a2 to flip phosphatidylserine across the lipid bilayer. Fluorescence measurements showed that Atp8a2 flipped fluorescent-labeled phosphatidylserine from the inner leaflet of liposomes (equivalent to the exocytoplasmic leaflet of cell membranes) to the outer leaflet (equivalent to cytoplasmic leaflet) in an ATP-dependent manner. Our studies provide the first direct biochemical evidence that purified P(4)-ATPases can translocate aminophospholipids across membranes and further implicates Atp8a2 in the generation and maintenance of phosphatidylserine asymmetry in photoreceptor disc membranes. PMID- 19778900 TI - Substrate binding and active site residues in RNases E and G: role of the 5' sensor. AB - The paralogous endoribonucleases, RNase E and RNase G, play major roles in intracellular RNA metabolism in Escherichia coli and related organisms. To assay the relative importance of the principal RNA binding sites identified by crystallographic analysis, we introduced mutations into the 5'-sensor, the S1 domain, and the Mg(+2)/Mn(+2) binding sites. The effect of such mutations has been measured by assays of activity on several substrates as well as by an assay of RNA binding. RNase E R169Q and the equivalent mutation in RNase G (R171Q) exhibit the strongest reductions in both activity (the k(cat) decrease approximately 40- to 100-fold) and RNA binding consistent with a key role for the 5'-sensor. Our analysis also supports a model in which the binding of substrate results in an increase in catalytic efficiency. Although the phosphate sensor plays a key role in vitro, it is unexpectedly dispensable in vivo. A strain expressing only RNase E R169Q as the sole source of RNase E activity is viable, exhibits a modest reduction in doubling time and colony size, and accumulates immature 5 S rRNA. Our results point to the importance of alternative RNA binding sites in RNase E and to alternative pathways of RNA recognition. PMID- 19778901 TI - DGAT1 expression increases heart triglyceride content but ameliorates lipotoxicity. AB - Intracellular lipid accumulation in the heart is associated with cardiomyopathy, yet the precise role of triglyceride (TG) remains unclear. With exercise, wild type hearts develop physiologic hypertrophy. This was associated with greater TG stores and a marked induction of the TG-synthesizing enzyme diacylglycerol (DAG) acyltransferase 1 (DGAT1). Transgenic overexpression of DGAT1 in the heart using the cardiomyocyte- specific alpha-myosin heavy chain (MHC) promoter led to approximately a doubling of DGAT activity and TG content and reductions of approximately 35% in cardiac ceramide, 26% in DAG, and 20% in free fatty acid levels. Cardiac function assessed by echocardiography and cardiac catheterization was unaffected. These mice were then crossed with animals expressing long-chain acyl-CoA synthetase via the MHC promoter (MHC-ACS), which develop lipotoxic cardiomyopathy. MHC-DGAT1XMHC-ACS double transgenic male mice had improved heart function; fractional shortening increased by 74%, and diastolic function improved compared with MHC-ACS mice. The improvement of heart function correlated with a reduction in cardiac DAG and ceramide and reduced cardiomyocyte apoptosis but increased fatty acid oxidation. In addition, the survival of the mice was improved. Our study indicates that TG is not likely to be a toxic lipid species directly, but rather it is a feature of physiologic hypertrophy and may serve a cytoprotective role in lipid overload states. Moreover, induction of DGAT1 could be beneficial in the setting of excess heart accumulation of toxic lipids. PMID- 19778902 TI - Oncogenic ras-induced down-regulation of autophagy mediator Beclin-1 is required for malignant transformation of intestinal epithelial cells. AB - Detachment of non-malignant epithelial cells from the extracellular matrix causes their growth arrest and, ultimately, death. By contrast, cells composing carcinomas, cancers of epithelial origin, can survive and proliferate without being attached to the extracellular matrix. These properties of tumor cells represent hallmarks of malignant transformation and are critical for cancer progression. Previously we identified several mechanisms by which ras, a major oncogene, blocks detachment-induced apoptosis of intestinal epithelial cells, but mechanisms by which Ras promotes proliferation of those cells that remain viable following detachment are unknown. We show here that detachment of non-malignant intestinal epithelial cells promotes formation of autophagosomes, vacuole-like structures that mediate autophagy (a process of cellular self-cannibalization), and that oncogenic ras prevents this autophagosome formation. We also found that ras activates a GTPase RhoA, that RhoA promotes activation of a protease calpain, and that calpain triggers degradation of Beclin-1, a critical mediator of autophagy, in these cells. The reversal of the effect of ras on Beclin-1 (achieved by expression of exogenous Beclin-1) promoted autophagosome formation following cell detachment, significantly reduced the fraction of detached cells in the S phase of the cell cycle and their rate of proliferation without affecting their viability. Furthermore, RNA interference-induced Beclin-1 down regulation in non-malignant intestinal epithelial cells prevented detachment dependent reduction of the fraction of these cells in the S phase of the cell cycle. Thus, ras oncogene promotes proliferation of those malignant intestinal epithelial cells that remain viable following detachment via a distinct novel mechanism that involves Ras-induced down-regulation of Beclin-1. PMID- 19778903 TI - Blocking L-type voltage-gated Ca2+ channels with dihydropyridines reduces gamma aminobutyric acid type A receptor expression and synaptic inhibition. AB - Gamma-aminobutyric acid type A receptors (GABA(A)Rs) are the major sites of fast inhibitory neurotransmission in the brain, and the numbers of these receptors at the cell surface can determine the strength of GABAergic neurotransmission. Chronic changes in neuronal activity lead to an adaptive modulation in the efficacy of GABAergic synaptic inhibition, brought about in part by changes in the number of synaptic GABA(A)Rs, a mechanism known as homeostatic synaptic plasticity. Reduction in the number of GABA(A)Rs in response to prolonged neuronal activity blockade is dependent on the ubiquitin-proteasome system. The underlying biochemical pathways linking chronic activity blockade to proteasome dependent degradation of GABA(A)Rs are unknown. Here, we show that chronic blockade of L-type voltage-gated calcium channels (VGCCs) with nifedipine decreases the number of GABA(A)Rs at synaptic sites but not the overall number of inhibitory synapses. In parallel, blockade of L-type VGCCs decreases the amplitude but not the frequency of miniature inhibitory postsynaptic currents or expression of the glutamic acid decarboxylase GAD65. We further reveal that the activation of L-type VGCCs regulates the turnover of newly translated GABA(A)R subunits in a mechanism dependent upon the activity of the proteasome and thus regulates GABA(A)R insertion into the plasma membrane. Together, these observations suggest that activation of L-type VGCCs can regulate the abundance of synaptic GABA(A)Rs and the efficacy of synaptic inhibition, revealing a potential mechanism underlying the homeostatic adaptation of fast GABAergic inhibition to prolonged changes in activity. PMID- 19778904 TI - The endoplasmic reticulum of dorsal root ganglion neurons contains functional TRPV1 channels. AB - Transient receptor potential vanilloid type 1 (TRPV1) is a plasma membrane Ca(2+) channel involved in transduction of painful stimuli. Dorsal root ganglion (DRG) neurons express ectopic but functional TRPV1 channels in the endoplasmic reticulum (ER) (TRPV1(ER)). We have studied the properties of TRPV1(ER) in DRG neurons and HEK293T cells expressing TRPV1. Activation of TRPV1(ER) with capsaicin or other vanilloids produced an increase of cytosolic Ca(2+) due to Ca(2+) release from the ER. The decrease of [Ca(2+)](ER) was directly revealed by an ER-targeted aequorin Ca(2+) probe, expressed in DRG neurons using a herpes amplicon virus. The sensitivity of TRPV1(ER) to capsaicin was smaller than the sensitivity of the plasma membrane TRPV1 channels. The low affinity of TRPV1(ER) was not related to protein kinase A- or C-mediated phosphorylations, but it was due to inactivation by cytosolic Ca(2+) because the sensitivity to capsaicin was increased by loading the cells with the Ca(2+) chelator BAPTA. Decreasing [Ca(2+)](ER) did not affect the sensitivity of TRPV1(ER) to capsaicin. Disruption of the TRPV1 calmodulin-binding domains at either the C terminus (Delta35AA) or the N terminus (K155A) increased 10-fold the affinity of TRPV1(ER) for capsaicin, suggesting that calmodulin is involved in the inactivation. The lack of TRPV1 sensitizers, such as phosphatidylinositol 4,5-bisphosphate, in the ER could contribute to decrease the affinity for capsaicin. The low sensitivity of TRPV1(ER) to agonists may be critical for neuron health, because otherwise Ca(2+) depletion of ER could lead to ER stress, unfolding protein response, and cell death. PMID- 19778905 TI - Structural elements for the generation of sustained currents by the acid pain sensor ASIC3. AB - ASIC3 is an acid-sensing ion channel expressed in sensory neurons, where it participates in acidic and inflammatory pain. In addition to the "classical" transient current, ASIC3 generates a sustained current essential for pain perception. Using chimeras between the ASIC3 and ASIC1a channels we show that the first transmembrane domain (TM1), combined with the N-terminal domain, is the key structural element generating the low pH (<6.5)-evoked sustained current. The TM1 domain also modulates the pH-dependent activation of the fast transient current thus contributing to a constitutive window current, another type of sustained current present near physiological pH. The C-terminal and the TM2 domains negatively regulate both types of sustained current, and the extracellular loop affects its kinetics. These data provide new information to aid understanding the mechanisms of the multifaceted pH gating of ASIC3. Together with the peak current, both components of the sustained current (window and sustained at pH <6.5) allow ASIC3 to adapt its behavior to a wide range of extracellular pH variations by generating transient and/or sustained responses that contribute to nociceptor excitability. PMID- 19778906 TI - Preferred sequences within a defined cleavage window specify DNA 3' end-directed cleavages by retroviral RNases H. AB - The RNase H activity of reverse transcriptase carries out three types of cleavage termed internal, RNA 5' end-directed, and DNA 3' end-directed. Given the strong association between the polymerase domain of reverse transcriptase and a DNA 3' primer terminus, we asked whether the distance from the primer terminus is paramount for positioning DNA 3' end-directed cleavages or whether preferred sequences and/or a cleavage window are important as they are for RNA 5' end directed cleavages. Using the reverse transcriptases of human immunodeficiency virus, type 1 (HIV-1) and Moloney murine leukemia virus (M-MuLV), we determined the effects of sequence, distance, and substrate end structure on DNA 3' end directed cleavages. Utilizing sequence-matched substrates, our analyses showed that DNA 3' end-directed cleavages share the same sequence preferences as RNA 5' end-directed cleavages, but the sites must fall in a narrow window between the 15th and 20th nucleotides from the recessed end for HIV-1 reverse transcriptase and between the 17th and 20th nucleotides for M-MuLV. Substrates with an RNA 5' end recessed by 1 (HIV-1) or 2-3 (M-MuLV) bases on a longer DNA could accommodate both types of end-directed cleavage, but further recession of the RNA 5' end excluded DNA 3' end-directed cleavages. For HIV-1 RNase H, the inclusion of the cognate dNTP enhanced DNA 3' end-directed cleavages at the 17th and 18th nucleotides. These data demonstrate that all three modes of retroviral RNase H cleavage share sequence determinants that may be useful in designing assays to identify inhibitors of retroviral RNases H. PMID- 19778907 TI - Explaining occupational class differences in sickness absence: results from middle-aged municipal employees. AB - OBJECTIVES: Low socioeconomic position is consistently associated with higher rates of sickness absence. We aimed to examine whether working conditions, health related behaviours and family-related factors explain occupational class differences in medically certified sickness absence. METHODS: The study included 5470 women and 1464 men employees of the City of Helsinki, surveyed in 2000-2002. These data were prospectively linked to sickness absence records until the end of 2005, providing a mean follow-up time of 3.9 years. Poisson regression was used to examine the occurrence of medically certified sickness absence episodes lasting 4 days or more. RESULTS: Medically certified sickness absence was roughly three times more common among manual workers than among managers and professionals in both women and men. Physical working conditions were the strongest explanatory factors for occupational class differences in sickness absence, followed by smoking and relative weight. Work arrangements and family related factors had very small effects only. The effects of psychosocial working conditions were heterogeneous: job control narrowed occupational class differences in sickness absence while mental strain and job demands tended to widened them. Overall, the findings were quite similar in women and men. CONCLUSIONS: Physical working conditions provided strongest explanations for occupational class differences in sickness absence. Smoking and relative weight, which are well-known determinants of health, also explained part of the excess sickness absence in lower occupational classes. Applying tailored work arrangements to employees on sick leave, reducing physically heavy working conditions and promoting healthy behaviours provide potential routes to narrow occupational class differences in sickness absence. PMID- 19778908 TI - Rates and types of hospitalisations for children who have subsequent contact with the child protection system: a population based case-control study. AB - OBJECTIVES: To determine whether children who have child maltreatment allegation or substantiation have a higher rate of general hospital admissions and injury related admissions when compared to other children and to investigate other types of admissions, such as mental health, infections and admissions due to external causes. STUDY DESIGN: A prospective matched case-control study of children born in Western Australia between 1990 and 2005 using de-identified record linked Child Protection and Hospital Morbidity data. Rates of prior hospital admissions for cases versus controls were calculated, and conditional logistic regression was used to estimate the effect of hospital admission rate on the risk of child maltreatment allegation and substantiated allegation. RESULTS: Children with child maltreatment allegations and substantiations had higher mean prior admission rates compared to controls. Higher rates of general admissions and admissions for injuries, infections, mental and behavioural disorders, and external causes of morbidity, were associated with a markedly increased risk of child maltreatment allegations and substantiation. CONCLUSIONS: The hospital system plays not only an important role both in the surveillance of maltreatment related injuries and conditions but also in the role of prevention in the referral of families who may need support and assistance in ensuring the health and safety of their children. This research highlights the importance of moving to electronic patient records in identifying children who have high rates of admissions and the types of conditions they have previously presented with, particularly for injuries, mental and behavioural disorders and external causes of admissions. PMID- 19778909 TI - Predictors of time spent outdoors among children: 5-year longitudinal findings. AB - BACKGROUND: Given the importance of physical activity for health and age-related declines in physical activity, understanding influences on related behaviours, such as time outdoors, is crucial. This study aimed to understand individual, social and physical environmental influences on longitudinal changes in urban children's time outdoors. METHODS: The time children spent outdoors in 2001, 2004 and 2006 (aged 5-6 and 10-12 years at baseline) was reported by their parents (n=421). In 2001, individual, social and physical environmental factors were self reported by parents. Generalized estimating equations examined longitudinal relationships between baseline predictors and average change in time outdoors over 5 years. RESULTS: Children's time outdoors significantly declined over time. "Indoor tendencies" inversely predicted time outdoors among younger and older boys, and younger girls. Social opportunities positively predicted time outdoors among younger boys, while "outdoor tendencies" positively predicted time outdoors among older boys. Parental encouragement for activity positively predicted time outdoors among younger and older girls, while lack of adult supervision for active play outdoors after school inversely predicted time outdoors among older girls and older boys. CONCLUSION: Individual (indoor and outdoor tendencies) and social factors (social opportunities, parental encouragement and parental supervision) predicted children's time outdoors over 5 years. Interventions targeting reduced indoor tendencies, increased outdoor play with others, and increased parental encouragement and supervision are warranted. PMID- 19778910 TI - Paroxysmal staccato tinnitus: a carbamazepine responsive hyperactivity dysfunction symptom of the eighth cranial nerve. AB - Hyperactive disorders related to neurovascular compression have been described for several cranial nerves of which trigeminal neuralgia and hemifacial spasm are the best known. The present report on four patients, in conjunction with previous reports, suggests that paroxysmal staccato tinnitus might be considered an auditory hyperactivity disorder of the eighth cranial nerve. The present patients reported attacks, usually lasting 10-20 s, of loud monaural tinnitus with a staccato character (eg, clattering or sounding like a machine gun). The attacks occurred very frequently, sometimes every minute. The attacks were spontaneous but they were also provoked by certain head positions or by exposure to loud sounds. Most of the patients did not reveal any significant eighth cranial nerve sensory loss and thus it is probably not advisable to rely on any specific test result for this diagnosis. Instead, it is suggested that a diagnosis of paroxysmal staccato tinnitus can be based on the history as the symptoms are both stereotypic and very specific. Furthermore, low doses of carbamazepine, although not effective for the general population of tinnitus patients, relieved the symptoms. PMID- 19778911 TI - The neuroanatomy of asomatognosia and somatoparaphrenia. AB - OBJECTIVES: Asomatognosia is broadly defined as unawareness of ownership of one's arm, while somatoparaphrenia is a subtype in which patients also display delusional misidentification and confabulation. Studies differ with regard to the underlying neuroanatomy of these syndromes. METHODS: Three groups of patients with right-hemisphere strokes and left hemiplegia were analysed: G1, asomatognosia+neglect; G2, non-asomatognosia+neglect; G3, hemiplegia only. The asomatognosic group was further subdivided into somatoparaphrenia (G1-SP: asomatognosia+delusions/confabulation) and simple asomatognosia (G1-SA; asomatognosia without delusions/confabulation). RESULTS: Patients with all forms of asomatognosia (G1) had larger lesions than non-asomatognosic patients in all sectors. While patients with or without asomatognosia had significant temporoparietal involvement, we found that the subset of patients with somatoparaphrenia had the largest lesions overall, and somatoparaphrenia cases had significantly more frontal involvement than patients with simple asomatognosia. All patients with asomotognosia (G1-SP and G1-SA) had significant medial frontal damage, suggesting that this region may play a role in the development of asomatognosia in general. Somatoparaphrenia cases also had greater orbitofrontal damage than simple asomatognosia cases, suggesting that the orbitofrontal lesion was critical in the development of somatoparaphrenia. CONCLUSIONS: Asomatognosia results from large lesions involving multiple- including temporoparietal--sectors, but the addition of medial frontal involvement appears important. The addition of orbitofrontal dysfunction distinguishes somatoparaphrenia from simple asomatognosia. The data indicate roles for the right medial and orbitofrontal regions in confabulation and self related systems. PMID- 19778912 TI - Association of TNFSF4 (OX40L) polymorphisms with susceptibility to systemic sclerosis. AB - OBJECTIVE: It is increasingly being appreciated that multiple autoimmune diseases share common susceptibility genes. The tumour necrosis factor ligand superfamily member 4 gene (TNFSF4, OX40L), which encodes for the T cell costimulatory molecule OX40 ligand, has been identified as a susceptibility gene for the development of systemic lupus erythematosus (SLE). Accordingly, the aim of the current study was to investigate the possible association of the TNFSF4 gene region with systemic sclerosis (SSc), an autoimmune disease that leads to the development of cutaneous and visceral fibrosis. METHODS: A total of 9 single nucleotide polymorphisms (SNPs) in the TNFSF4 gene region, previously associated with susceptibility to SLE, were tested for association with SSc in a collection of 1059 patients with SSc and 698 controls. RESULTS: Case-control comparisons revealed a significant association between susceptibility to SSc and the minor alleles at SNPs rs1234314 (OR 1.20, 95% CI 1.04 to 1.4, p(FDR)=0.019), rs2205960 (OR 1.24, 95% CI 1.10 to 1.50, p(FDR)=0.019) and rs844648 (OR 1.16, 95% CI 1.01 to 1.30, p(FDR)=0.032). The minor allele at rs844644 was protective (OR 0.84, 95% CI 0.70 to 0.97, p(FDR)=0.038). Analysis of subsets of patients with SSc demonstrated significant associations of the TNFSF4 SNPs with limited and diffuse SSc as well as specific SNPs that were associated with SSc-associated autoantibodies. Finally, the analyses suggest a potential interaction between two TNFSF4 SNPs, rs2205960 and rs844648, with regards to SSc susceptibility. CONCLUSIONS: Polymorphisms in the TNFSF4 gene region are associated with susceptibility to SSc and its clinical and autoantibody subsets. TNFSF4 may be another gene that confers risk to multiple autoimmune diseases. PMID- 19778913 TI - The IL1-like cytokine IL33 and its receptor ST2 are abnormally expressed in the affected skin and visceral organs of patients with systemic sclerosis. AB - BACKGROUND: Early endothelial cell (EC) activation/damage and profibrotic Th2 associated cytokines play a pivotal role in systemic sclerosis (SSc). Interleukin 33 (IL33) is a novel member of the IL1 family that promotes Th2 responses and inflammation through the ST2 receptor. IL33 is also a chromatin-associated transcriptional regulator in ECs. OBJECTIVE: To investigate the role of the IL33/ST2 axis in SSc. METHODS: Skin biopsies were obtained from 30 patients with SSc (15 early/15 late stage) and 10 healthy subjects. Lung, kidney, heart, oesophagus, stomach, placenta biopsies and bronchoalveolar lavage cells from patients with SSc and controls were also analysed. IL33/ST2 expression was investigated by immunohistology, confocal immunofluorescence microscopy, western blotting and RT-PCR. RESULTS: In skin biopsies from control subjects, constitutive nuclear IL33 protein expression was found in dermal ECs and keratinocytes, while ST2 was weakly expressed in ECs and fibroblasts. In skin biopsies from patients with early SSc, IL33 protein was downregulated or absent in ECs and epidermis while IL33 mRNA was normally expressed or even upregulated. Moreover, ECs, perivascular infiltrating mast cells, CD68-positive macrophages, CD3-positive T cells, CD20-positive B cells and activated fibroblasts/myofibroblasts exhibited strong ST2 expression. In skin biopsies from patients with late SSc, IL33 was constitutively found in most ECs while ST2 immunostaining was weaker. In early SSc, the loss of endothelial IL33 protein and the overexpression of ST2 involved all affected organs. Dermal and pulmonary fibroblasts showed IL33 expression in SSc. CONCLUSION: IL33 and ST2 are abnormally expressed in SSc. In early SSc, upon EC activation/damage IL33 may be mobilised from ECs to signal through ST2 in key profibrotic players such as inflammatory/immune cells and fibroblasts/myofibroblasts. PMID- 19778914 TI - Intranasal administration of recombinant human cartilage glycoprotein-39 as a treatment for rheumatoid arthritis: a phase II, multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding trial. AB - BACKGROUND: Autoantigen-specific immunotherapy by mucosal tolerance induction via the intranasal route is an attractive therapeutic option for the treatment of autoimmune diseases, including rheumatoid arthritis (RA). Human cartilage glycoprotein-39 (HC gp-39) has been identified as a potential key autoantigen in RA. Based on animal studies, intranasal administration of the autoantigen is hypothesised to induce immunological tolerance in patients with RA and to ameliorate disease activity. In a phase I/IIA clinical trial in patients with RA, intranasal application of HC gp-39 was safe and well tolerated. OBJECTIVE: To investigate the efficacy of intranasally administered fully human, recombinant HC gp-39 (Org 39141) by a large clinical study. METHODS: In a 13-week multicentre, double-blind, randomised, placebo-controlled, parallel-group, dose-finding, proof of-concept trial, patients with RA (disease-modifying antirheumatic drug (DMARD) naive or after washout of DMARD treatment) were randomised to receive either intranasal applications of placebo or HC gp-39 in doses of 30, 150, 300 or 600 microg, once a week. The primary efficacy variable was the 28 joint count Disease Activity Score (DAS28). RESULTS: During the treatment period the DAS28 decreased similarly for all treatment groups-including placebo-indicating lack of efficacy of intranasal HC gp-39 treatment in the current setting. Safety variables were similar for all study groups. CONCLUSION: It was concluded that with the treatment protocol used (dose levels and frequency of dosing), intranasal treatment with Org 39141 was safe but did not result in more clinical improvement than in placebo-treated patients. PMID- 19778915 TI - Test security in medicolegal cases: proposed guidelines for attorneys utilizing neuropsychology practice. AB - In the context of forensic neuropsychological assessments, the professional interaction of law and psychology is viewed primarily as one where the retaining attorney or court dictates its needs to psychologists when resolving legal disputes. While this perspective is conceptually accurate, the positive and practical collaboration of law and psychology also relies on attorneys adhering to basic protections of sensitive psychological assessment procedures and tests. Objective testing is undermined when a practitioner of law engages in actions prior to, during, or following a neuropsychological examination in a manner that threatens the test security. An appreciation among practitioners of law and psychology regarding the necessity of test security is essential. This article reviews attorney actions that can affect test security, proposes a distinction by psychology between appropriate and problematic client preparation for a neuropsychological examination, integrates the available legal precedent regarding test security, and suggests productive measures to protect test security in medicolegal settings. PMID- 19778916 TI - The diagnostic accuracy of symptom validity tests when used with postsecondary students with learning disabilities: a preliminary investigation. AB - The current exploratory investigation examined the diagnostic accuracy of the Word Memory Test (WMT), Test of Memory Malingering (TOMM), and Word Reading Test (WRT) with three groups of postsecondary students: controls, learning disability (LD) simulators, and a presumed honest LD group. Each measure achieved high overall diagnostic accuracy, yet each contributed differently to suboptimal effort detection. False-negative classifications varied by measure, yet no simulator went undetected by all three tests. The WMT and WRT identified different members of the presumed honest LD group as demonstrating poor effort, whereas the TOMM identified none. Each measure contributed unique variance in a logistic regression, with effort status best predicted by WMT Consistency. Findings provided preliminary evidence that all three measures may be useful when assessing effort during postsecondary LD evaluations. Implications for future practice and research are discussed. PMID- 19778917 TI - Decreased fluoroquinolone susceptibility in mutants of Salmonella serovars other than Typhimurium: detection of novel mutations involved in modulated expression of ramA and soxS. AB - OBJECTIVES: Mutants of five Salmonella enterica serovars were investigated for structural changes in regulatory regions known to be involved in the up regulation of efflux pumps. METHODS: Five Salmonella field isolates and mutants, in which efflux pump inhibitor tests previously pointed towards an up-regulation of efflux, plus one negative control were included in the study. MIC values were determined of antibiotics that were indicative of AcrAB overexpression. The regulatory regions acrRA, soxRS, marORAB, acrSE and ramRA of original strains and mutants were sequenced and compared. The gene expression of acrA, tolC, ramA and soxS was assessed by quantitative real-time PCR. Conjugation experiments and tet gene PCRs were performed to explain unexpected variations in MIC values of tetracycline. RESULTS: In four mutant strains, changes in the ramRA regulatory region, causing up-regulation of ramA, were detected. These changes comprised point mutations and deletions of 10 or 15 bp within the ramR gene and a single bp exchange located in the binding site of the RamR protein in Salmonella Infantis, Paratyphi and Livingstone mutants. An insertion of 49 bp within the soxR gene was involved in soxS up-regulation and enhanced efflux activity in the fifth mutant from Salmonella Virchow. The loss of tetracycline resistance in one Salmonella Paratyphi mutant could be explained by the loss of a plasmid carrying a tet(A) gene. CONCLUSIONS: Changes in the ramR-ramA region as well as in the soxR gene occur in mutants of Salmonella serovars other than Typhimurium and seem to be involved in the up-regulation of efflux activity. PMID- 19778918 TI - The impact of natural disasters on myocardial infarction. PMID- 19778919 TI - Type D personality and depressive symptoms are independent predictors of impaired health status following acute myocardial infarction. AB - OBJECTIVE: In this prospective follow-up study we investigated whether the type D personality construct (the tendency to experience negative emotions and to be socially inhibited) exerts an independent effect on disease-specific health status in post-myocardial infarction (MI) patients, after adjustment for disease severity and depressive symptoms. METHODS: Patients (n = 503) were assessed on demographic and clinical variables and completed the type D scale (DS14) and Beck Depression Inventory (BDI) within the first week of hospital admission for acute MI. Two months post-MI, all patients completed the WHO Composite International Diagnostic Interview (CIDI) interview. After 18 months, they filled out the Seattle Angina Questionnaire (SAQ) to assess disease-specific health status. RESULTS: At follow-up, type D patients had significantly lower mean scores on all SAQ subscales, indicating worse disease-specific health status, compared to non type D patients (all p values <0.01). After adjustment for disease severity and depression in multivariate analysis, type D patients still had more physical limitations (mean SAQ score: 49 versus 54; p = 0.014), less angina stability (62 versus 71; p = 0.002) and a less accurate disease perception (52 versus 61; p < or = 0.001) compared with non-type D patients. Depressed patients (BDI > or = 10) also reported significantly lower SAQ scores compared to non-depressed patients. CONCLUSIONS: The type D construct is an independent predictor of impaired disease specific health status. Type D personality, in addition to depression, may thus be an important psychological factor that deserves attention during the period of rehabilitation in post-MI patients. PMID- 19778920 TI - A randomised trial of target-vessel versus multi-vessel revascularisation in ST elevation myocardial infarction: major adverse cardiac events during long-term follow-up. AB - BACKGROUND: Few reports described outcomes of complete compared with infarct related artery (IRA)-only revascularisation in patients with ST-elevation myocardial infarction (STEMI) and multivessel coronary artery disease (CAD). Moreover, no studies have compared the simultaneous treatment of non-IRA with the IRA treatment followed by an elective procedure for the other lesions (staged revascularisation). METHODS: The outcomes of 263 [corrected] consecutive patients with STEMI and multivessel CAD undergoing primary angioplasty were studied. Before the first angioplasty patients were randomly assigned to three different strategies: culprit vessel angioplasty-only (COR group); staged revascularisation (SR group) and simultaneous treatment of non-IRA (CR group). RESULTS: During a mean follow-up of 2.5 years, 42 (50.0%) patients in the COR group experienced at least one major adverse cardiac event (MACE), 13 (20.0%) in the SR group and 15 (23.1%) in the CR group, p<0.001. Inhospital death, repeat revascularisation and re-hospitalisation occurred more frequently in the COR group (all p<0.05), whereas there was no significant difference in re-infarction among the three groups. Survival free of MACE was significantly reduced in the COR group but was similar in the CR and SR groups. CONCLUSIONS: Culprit vessel-only angioplasty was associated with the highest rate of long-term MACE compared with multivessel treatment. Patients scheduled for staged revascularisation experienced a similar rate of MACE to patients undergoing complete simultaneous treatment of non-IRA. PMID- 19778921 TI - Early discharge after primary percutaneous coronary intervention. AB - The length of hospital stay after a successful percutaneous coronary intervention (PCI) for acute myocardial infarction is subject of debate. Patients should not be kept in hospital longer than strictly needed in terms of safety, psycho-social reasons, adequate mobilisation and patient comfort. In many tertiary centres with a busy PCI program insufficient bed capacity is an ongoing concern. Moreover, it seems obvious that shorter hospital stay will lead to a significant cost reduction. In order to know if very early discharge after primary PCI is feasible and safe one should identify the events that might threaten the patient as well as the timing of occurrence of such events. As a result a relatively large proportion of patients with a very low risk of early complications can be defined and in those patients very early discharge is indicated. PMID- 19778922 TI - Psychotropic medication: curing illness or creating problems? PMID- 19778923 TI - What do you say about risk? PMID- 19778924 TI - Are the standard criteria for TAVI too lax or too strict? PMID- 19778925 TI - Is there evidence for prognostic benefit following PCI in stable patients? COURAGE and its implications: an interventionalist's view. AB - The COURAGE study has stimulated intensive discussion about the optimal approach to treatment of patients with stable angina. To some, the study implied that PCI has no clinical benefit versus optimal medical therapy but this is open to alternative considered interpretation. To the interventionalist who deploys optimal medical therapy responsibly, the study highlights the importance of the concept of an ischaemia driven approach. The availability of the pressure wire has provided cardiologists with an important additional tool with which to tailor the delivery of revascularisation to not just the ischaemic patient but also to the ischaemic lesion. Such a strategy applied to COURAGE (and perhaps also to SYNTAX) might provide a very different comparative outcome. PMID- 19778926 TI - RIP140 in thyroid hormone-repression and chromatin remodeling of Crabp1 gene during adipocyte differentiation. AB - Cellular retinoic acid binding protein 1 (Crabp1) gene is biphasically (proliferation versus differentiation) regulated by thyroid hormone (T3) in 3T3 L1 cells. This study examines T3-repression of Crabp1 gene during adipocyte differentiation. T3 repression of Crabp1 requires receptor interacting protein 140 (RIP140). During differentiation, the juxtaposed chromatin configuration of Crabp1 promoter with its upstream region is maintained, but the 6-nucleosomes spanning thyroid hormone response element to transcription initiation site slide bi-directionally, with the third nucleosome remaining at the same position throughout differentiation. On the basal promoter, RIP140 replaces coactivators GRIP1 and PCAF and forms a repressive complex with CtBP1, HDAC3 and G9a. Initially active chromatin marks on this promoter, histone modifications H3-Ac and H3K4-me3, are weakened whereas repressive chromatin marks, H3K9-me3 and H3K27 me3 modification and recruitment of G9a, HP1alpha, HP1gamma and H1, are intensified. This is the first study to examine chromatin remodeling, during the phase of hormone repression, of a bi-directionally regulated hormone target gene, and provides evidence for a functional role of RIP140 in chromatin remodeling to repress hormone target gene expression. PMID- 19778927 TI - Two Dot1 isoforms in Saccharomyces cerevisiae as a result of leaky scanning by the ribosome. AB - Dot1 is a conserved histone methyltransferase that methylates histone H3 on lysine 79. We previously observed that in Saccharomyces cerevisiae, a single DOT1 gene encodes two Dot1 protein species. Here, we show that the relative abundance of the two isoforms changed under nutrient-limiting conditions. A mutagenesis approach showed that the two Dot1 isoforms are produced from two alternative translation start sites as a result of leaky scanning by the ribosome. The leaky scanning was not affected by the 5'- or 3'-untranslated regions of DOT1, indicating that translation initiation is determined by the DOT1 coding sequence. Construction of yeast strains expressing either one of the isoforms showed that both were sufficient for Dot1's role in global H3K79 methylation and telomeric gene silencing. However, the absence of the long isoform of Dot1 altered the resistance of yeast cells to the chitin-binding drug Calcofluor White, suggesting that the two Dot1 isoforms have a differential function in cell wall biogenesis. PMID- 19778929 TI - The long shadow of the past: risk pooling and the political development of health care reform in the States. AB - Why do the states seem to be pursuing different types of policy innovation in their health reform? Why so some seem to follow a "solidarity principle," while others seem guided by a commitment to "actuarial fairness"? Our analysis highlights the reciprocal influence of stakeholder mobilization and public policy over time. We find that early policy choices about how to achieve cost containment led the states down different paths of reform. In the 1970s and 1980s, states that featured oligopolistic or near-monopolistic markets for private insurance (usually dominated by Blue Cross) and strong urban-academic hospitals tended to adopt regulatory strategies for cost containment that led to broader forms of pooling and financing the costs of health risks--which subsequently positioned them to pursue major, solidaristic reform on favorable terms. On the other hand, states with competitive markets for private insurance and weak, decentralized hospitals tended to adopt market-based strategies for cost containment that led to the hypersegmentation of risk and the uneven financing of costs--thereby encouraging the proliferation of incremental policies that reinforce the principle of actuarial fairness. We illustrate our analysis with a brief comparison of Massachusetts and California, and we conclude with some thoughts on what our findings imply for the federal role in catalyzing health reform. PMID- 19778928 TI - Does abdominal obesity have a similar impact on cardiovascular disease and diabetes? A study of 91,246 ambulant patients in 27 European countries. AB - AIMS: Differences in cardiovascular risk factors across Europe provide an opportunity to examine the impact of adiposity on the frequency of diabetes and cardiovascular disease (CVD). METHODS AND RESULTS: The International Day for Evaluation of Abdominal obesity (IDEA) study evaluated the prevalence of abdominal obesity, elevated body mass index (BMI), and other cardiometabolic risk factors among primary care patients. Abdominal obesity predicted increased diabetes risk, despite socio-economic, demographic, and risk factor differences. Cardiovascular disease was at least two-fold more frequent in Eastern Europe vs. Northwest Europe (P < 0.0001) and 2.5-fold more vs. Southern Europe (P < 0.0001). Waist circumference (WC) predicted increased (P < 0.0001) age- and BMI-adjusted risks of CVD and diabetes. In women, odds ratios (95% confidence intervals) for CVD per 1 SD increase in WC were: Northwest Europe 1.28 (1.18-1.40); Southern Europe 1.26 (1.16-1.37); and Eastern Europe 1.10 (1.03-1.18). Values for diabetes were 1.72 (1.58-1.88), 1.45 (1.35-1.56), and 1.59 (1.46-1.73), with similar findings in men. CONCLUSION: Abdominal obesity impacted similarly on the frequency of diabetes across Europe, despite regional differences in cardiovascular risk factors and CVD rates. Increasing abdominal obesity may offset future declines in CVD, even where CVD rates are lower. PMID- 19778930 TI - Pay for performance in Medicare: evidentiary irony and the politics of value. AB - Pay for performance (P4P) is of growing importance in the Medicare program. Pay for-performance policy has the support of political actors in both parties and in the legislative and executive branches; of experts, business, and consumer interests; and in a qualified way, of health care providers. The evidence that P4P improves quality or reduces cost, however, is scant, although P4P proponents claim that the program is evidence based. This article reviews the history of Medicare P4P, documents its widespread support, and evaluates both the evidence of its effectiveness and the expert discourse about that evidence. The article analyzes the political reasons for Medicare P4P's popularity despite its evidentiary deficiencies and emphasizes its role in the politics of value. Pay for performance allows Medicare policy makers to (1) reformulate intractable cost and quality problems as more malleable value problems; (2) offer an acceptable quid pro quo for payment negotiations with providers; and (3) reach a rare, if shallow, consensus based on the ideological ambiguity of P4P. PMID- 19778931 TI - Paying for performance in primary medical care: learning about and learning from "success" and "failure" in England and California. AB - Paying physicians to hit performance targets is becoming increasingly fashionable, as evidenced by the growing number of "pay-for-performance" programs in the United States and beyond. This article compares pay-for-performance initiatives in two nations--the United Kingdom and the United States. It pays particular attention to the context in which the initiatives were conceived and implemented, factors which are largely neglected in the pay-for-performance literature. Despite some glowing reviews of the UK national pay-for-performance program for primary care doctors, we suggest that such programs face significant technical obstacles in all cases and particularly severe institutional obstacles in the United States. PMID- 19778932 TI - Quality information and fragmented markets: patient responses to hospital volume thresholds. AB - Over the last two decades, information dissemination policies to improve patient hospital choice have emerged. But during this same period, policy makers have also generally adopted a market-oriented approach vis-a-vis hospitals, with limited regulation of facility expansion and few restrictions on hospital mergers and ownership changes. These policies may be in tension, and this analysis examines whether there have been changes over time in patient responses to information about the value of high-volume hospitals and the degree to which hospital market changes may have limited these patient responses. The results indicate modest changes consistent with an increase in quality-seeking behavior for several services for which research indicates a volume-outcome relationship. At the same time, there are services for which trends have been moving in the opposite direction--toward greater local-care seeking--and changes for the remaining services have been fairly small. Even for services with a trend toward greater patient sensitivity to volume as a marker for quality, however, hospital market changes have reduced the change over time in high-volume hospital use. These results highlight some of the limitations of market-oriented strategies for increasing patient use of high-quality hospitals. PMID- 19778934 TI - Radiation transport calculations and simulations. AB - This article is an introduction to the Monte Carlo method as used in particle transport. After a description at an elementary level of the mathematical basis of the method, the Boltzmann equation and its physical meaning are presented, followed by Monte Carlo integration and random sampling, and by a general description of the main aspects and components of a typical Monte Carlo particle transport code. In particular, the most common biasing techniques are described, as well as the concepts of estimator and detector. After a discussion of the different types of errors, the issue of quality assurance is briefly considered. PMID- 19778933 TI - Prognostic significance of hypoxia-inducible factor-1alpha, TWIST1 and Snail expression in resectable non-small cell lung cancer. AB - BACKGROUND: Metastasis is the most common cause of disease failure and mortality for non-small cell lung cancer (NSCLC) after surgical resection. Snail and TWIST1 are epithelial-mesenchymal transition (EMT) regulators which induce metastasis. Intratumoral hypoxia followed by stabilisation of hypoxia-inducible factor 1alpha (HIF-1alpha) promotes metastasis through regulation of certain EMT regulators. The aim of this study was to evaluate the prognostic value of HIF-1alpha, TWIST1 and Snail expression in patients with resectable NSCLC. METHODS: A retrospective analysis of 87 patients with resectable NSCLC from Taipei Veterans General Hospital between 2003 and 2004 was performed using immunohistochemistry to analyse HIF-1alpha, TWIST1 and Snail expression. The association between HIF 1alpha, TWIST1 and Snail expression and patients' overall and recurrence-free survivals was investigated. RESULTS: Overexpression of HIF-1alpha, TWIST1 or Snail was shown in 32.2%, 36.8% and 55.2% of primary tumours, respectively. Overexpression of HIF-1alpha, TWIST1 or Snail in primary NSCLCs was associated with a shorter overall survival (p = 0.005, p = 0.026, p = 0.009, respectively), and overexpression of HIF-1alpha was associated with a shorter recurrence-free survival (p = 0.016). We categorised the patients into four groups according to the positivity of HIF-1alpha/TWIST1/Snail to investigate the accumulated effects of these markers on survival. Co-expression of more than two markers was an independent prognostic indicator for both recurrence-free survival and overall survival (p = 0.004 and p<0.001, respectively, by multivariate Cox proportional hazards model). CONCLUSIONS: Co-expression of more than two markers from HIF 1alpha, TWIST1 and Snail is a significant prognostic predictor in patients with NSCLC. PMID- 19778935 TI - High-level dosimetric methods. AB - This article gives an overview of selected high-dose dosimetric methods suitable for use in accelerators in research and medicine for reference, transfer and routine dosimetry. This comprises solid state, glass, plastic and liquid chemical systems as well as ionisation chambers and calorimeters. The dose covered varies from 0.1 Gy to the MGy range. A summary comparing the main characteristics of these dosemeters is also given. PMID- 19778936 TI - Understanding and characterisation of the risks to human health from exposure to low levels of radiation. AB - Exposure to ionising radiation can lead to a wide variety of health effects. Cancer is judged to be the main risk from radiation at low doses and low dose rates, and controlling this risk has been the main factor in developing radiation protection practice. Conventional paradigms of radiobiology and radiation carcinogenesis have served to guide extrapolations of epidemiological data on exposed human populations, so as to estimate risks at low doses and low dose rates, to other types of ionising radiation and to non-uniform exposures. These paradigms are founded on a century of experimental and theoretical studies, but nevertheless there remain many uncertainties. Major assumptions and simplifications have been introduced to achieve a practical system of additive doses (and implied risks) for radiation protection. Advancing epidemiological studies and experimental research continue to reduce uncertainties in some areas while, in others, they raise new challenges to the generality and applicability of the conventional paradigms. PMID- 19778937 TI - Operational radiation protection issues specific to high-intensity beams. AB - This paper describes operational radiation protection issues specific to high intensity accelerators, aimed at the radiological safety of high-intensity accelerators during construction and operation. The paper is composed of chapters on safety characteristics, radiological safety design and safety management systems of high-intensity accelerators. The Japan Proton Accelerator Research Complex (J-PARC) is taken as a reference, because J-PARC was recently completed after collecting and referring to experiences with existing accelerator facilities all over the world. PMID- 19778938 TI - An investigation on radon and thoron response of alpha-track detectors used in the Winnipeg case-control study. AB - The alpha-track detector was well designed for long-term radon measurements in the 1992 Winnipeg case-control study. However, its diffusion characteristic for thoron in comparison to radon was yet unknown. An investigation on radon and thoron response of these detectors was undertaken. The results showed that the relative sensitivity between thoron and radon is 2 %, i.e. the detector sensitivity to radon is about 50 times higher than the sensitivity to thoron. It can be concluded that there was no significant influence of thoron on the radon measurements with these detectors. PMID- 19778939 TI - Predicting behavior during interracial interactions: a stress and coping approach. AB - The social psychological literature maintains unequivocally that interracial contact is stressful. Yet research and theory have rarely considered how stress may shape behavior during interracial interactions. To address this empirical and theoretical gap, the authors propose a framework for understanding and predicting behavior during interracial interactions rooted in the stress and coping literature. Specifically, they propose that individuals often appraise interracial interactions as a threat, experience stress, and therefore cope-they antagonize, avoid, freeze, or engage. In other words, the behavioral dynamics of interracial interactions can be understood as initial stress reactions and subsequent coping responses. After articulating the framework and its predictions for behavior during interracial interactions, the authors examine its ability to organize the extant literature on behavioral dynamics during interracial compared with same-race contact. They conclude with a discussion of the implications of the stress and coping framework for improving research and fostering more positive interracial contact. PMID- 19778940 TI - PKA-dependent phosphorylation of serum response factor inhibits smooth muscle specific gene expression. AB - OBJECTIVE: Our goal was to identify phosphorylation sites that regulate serum response factor (SRF) activity to gain a better understanding of the signaling mechanisms that regulate SRF's involvement in smooth muscle cell (SMC)-specific and early response gene expression. METHODS AND RESULTS: By screening phosphorylation-deficient and mimetic mutations in SRF(-/-) embryonic stem cells, we identified T159 as a phosphorylation site that significantly inhibits SMC specific gene expression in an embryonic stem cell model of SMC differentiation. This residue conforms to a highly conserved consensus cAMP-dependent protein kinase (PKA) site, and in vitro and in vivo labeling studies demonstrated that it was phosphorylated by PKA. Results from gel shift and chromatin immunoprecipitation assays demonstrated that T159 phosphorylation inhibited SRF binding to SMC-specific CArG elements. Interestingly, the myocardin factors could at least partially rescue the effects of the T159D mutation under some conditions, but this response was promoter specific. Finally, PKA signaling had much less of an effect on c-fos promoter activity and SRF binding to the c-fos CArG. CONCLUSIONS: Our results indicate that phosphorylation of SRF by PKA inhibits SMC-specific transcription suggesting a novel signaling mechanism for the control of SMC phenotype. PMID- 19778941 TI - Actin-binding rho activating protein (Abra) is essential for fluid shear stress induced arteriogenesis. AB - OBJECTIVE: Arteriogenesis, the development of a collateral circulation, is important for tissue survival but remains functionally defective because of early normalization of fluid shear stress (FSS). Using a surgical model of chronically elevated FSS we showed that rabbits exhibited normal blood flow reserve after femoral artery ligature (FAL). Inhibition of the Rho pathway by Fasudil completely blocked the beneficial effect of FSS. In a genome-wide gene profiling we identified actin-binding Rho activating protein (Abra), which was highly upregulated in growing collaterals. METHODS AND RESULTS: qRT-PCR and Western blot confirmed highly increased FSS-dependent expression of Abra in growing collaterals. NO blockage by L-NAME abolished FSS-generated Abra expression as well as the whole arteriogenic process. Cell culture studies demonstrated an Abra triggered proliferation of smooth muscle cells through a mechanism that requires Rho signaling. Local intracollateral adenoviral overexpression of Abra improved collateral conductance by 60% in rabbits compared to the natural response after FAL. In contrast, targeted deletion of Abra in CL57BL/6 mice led to impaired arteriogenesis. CONCLUSIONS: FSS-induced Abra expression during arteriogenesis is triggered by NO and leads to stimulation of collateral growth by smooth muscle cell proliferation. PMID- 19778942 TI - Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice. AB - OBJECTIVE: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) is a member of the tumor necrosis factor superfamily of cytokines. TWEAK binds and activates the Fn14 receptor, and may regulate apoptosis, inflammation, and angiogenesis, in different pathological conditions. We have evaluated the effect of exogenous TWEAK administration as well as the role of endogenous TWEAK on proinflammatory cytokine expression and vascular and renal injury severity in hyperlipidemic ApoE-knockout mice. METHODS AND RESULTS: ApoE(-/-) mice were fed with hyperlipidemic diet for 4 to 10 weeks, then randomized and treated with saline (controls), TWEAK (10 microg/kg/d), anti-TWEAK neutralizing mAb (1000 microg/kg/d), TWEAK plus anti-TWEAK antibody (10 microg TWEAK +1000 microg anti TWEAK/kg/d), or nonspecific IgG (1000 microg/kg/d) daily for 9 days. In ApoE(-/-) mice, exogenous TWEAK administration in ApoE(-/-) mice induced activation of NF kappaB, a key transcription factor implicated in the regulation of the inflammatory response, in vascular and renal lesions. Furthermore, TWEAK treatment increased chemokine expression (RANTES and MCP-1), as well as macrophage infiltration in atherosclerotic plaques and renal lesions. These effects were associated with exacerbation of vascular and renal damage. Conversely, treatment of ApoE(-/-) mice with an anti-TWEAK blocking mAb decreased NF-kappaB activation, proinflammatory cytokine expression, macrophage infiltration, and vascular and renal injury severity, indicating a pathological role for endogenous TWEAK. Finally, in murine vascular smooth muscle cells or tubular cells, either ox-LDL or TWEAK treatment increased expression and secretion of both RANTES and MCP-1. Furthermore, ox-LDL and TWEAK synergized for induction of MCP-1 and RANTES expression and secretion. CONCLUSIONS: Our results suggest that TWEAK exacerbates the inflammatory response associated with a high lipid-rich diet. TWEAK may be a novel therapeutic target to prevent vascular and renal damage associated with hyperlipidemia. PMID- 19778943 TI - Eotaxin increases monolayer permeability of human coronary artery endothelial cells. AB - OBJECTIVE: The objective of this study was to determine the effects and molecular mechanisms of eotaxin, a newly discovered chemokine (CCL11), on endothelial permeability in the human coronary artery endothelial cells (HCAECs). METHODS AND RESULTS: Cells were treated with eotaxin, and the monolayer permeability was studied by using a costar transwell system with a Texas Red-labeled dextran tracer. Eotaxin significantly increased monolayer permeability in a concentration dependent manner. In addition, eotaxin treatment significantly decreased the mRNA and protein levels of endothelial junction molecules including zonula occludens-1 (ZO-1), occludin, and claudin-1 in a concentration-dependent manner as determined by real-time RT-PCR and Western blot analysis, respectively. Increased oxidative stress was observed in eotaxin-treated HCAECs by analysis of cellular glutathione levels. Furthermore, eotaxin treatment substantially activated the phosphorylation of MAPK p38. HCAECs expressed CCR3. Consequently, antioxidants (ginkgolide B and MnTBAP), specific p38 inhibitor SB203580, and anti-CCR3 antibody effectively blocked the eotaxin-induced permeability increase in HCAECs. Eotaxin also increased the phosphorylation of Stat3 and nuclear translocation of NF-kappaB in HCAECs. CONCLUSIONS: Eotaxin increases vascular permeability through CCR3, the downregulation of tight junction proteins, increase of oxidative stress, and activation of MAPK p38, Stat3, and NF-kB pathways in HCAECs. PMID- 19778944 TI - The ADMA/DDAH pathway regulates VEGF-mediated angiogenesis. AB - OBJECTIVE: Asymmetrical dimethylarginine (ADMA) is a nitric oxide synthase (NOS) inhibitor and cardiovascular risk factor associated with angiogenic disorders. Enzymes metabolising ADMA, dimethylarginine dimethylaminohydrolases (DDAH) promote angiogenesis, but the mechanisms are not clear. We hypothesized that ADMA/DDAH modifies endothelial responses to vascular endothelial growth factor (VEGF) by affecting activity of Rho GTPases, regulators of actin polymerization, and focal adhesion dynamics. METHODS AND RESULTS: The effects of ADMA on VEGF induced endothelial cell motility, focal adhesion turnover, and angiogenesis were studied in human umbilical vein endothelial cells (HUVECs) and DDAH I heterozygous knockout mice. ADMA inhibited VEGF-induced chemotaxis in vitro and angiogenesis in vitro and in vivo in an NO-dependent way. ADMA effects were prevented by overexpression of DDAH but were not associated with decreased proliferation, increased apoptosis, or changes in VEGFR-2 activity or expression. ADMA inhibited endothelial cell polarization, protrusion formation, and decreased focal adhesion dynamics, resulting from Rac1 inhibition after decrease in phosphorylation of vasodilator stimulated phosphoprotein (VASP). Constitutively active Rac1, and to a lesser extent dominant negative RhoA, abrogated ADMA effects in vitro and in vivo. CONCLUSIONS: The ADMA/DDAH pathway regulates VEGF induced angiogenesis in an NO- and Rac1-dependent manner. PMID- 19778945 TI - High factor VIII levels independently predict venous thromboembolism in cancer patients: the cancer and thrombosis study. AB - OBJECTIVE: Patients with cancer are at an increased risk for venous thromboembolism (VTE). Clotting factor VIII activity (FVIII) has been established as risk factor of primary and recurrent VTE. We investigated FVIII as predictive parameter of VTE in cancer patients. METHODS AND RESULTS: The prospective observational Cancer and Thrombosis Study (CATS) includes patients with newly diagnosed cancer or disease progression, study end point is symptomatic VTE. FVIII was measured on a Sysmex CA 7000 analyzer. Data on 840 patients (median age: 62 years, 25th to 75th percentile 53 to 68, 378 women) were available for analyses, of these 111 patients had hematologic malignancies and 729 solid cancer. During a median observation time of 495 days 62 events occurred. Cumulative probability of VTE after 6 months was 14% in patients with elevated FVIII-levels and 4% in those with normal levels (P=0.001). The association was strongest in younger patients: whereas in 40-year-old patients a 2-fold VTE risk per factor VIII increase of 20% was observed (HR=2.0 [95% CI: 1.5 to 2.7], P<0.0001), this association was still present but attenuated in older patients. CONCLUSIONS: FVIII is independently associated with an increased risk of VTE in cancer patients. The association between FVIII and VTE risk declines with increasing age. PMID- 19778947 TI - Dynamic observation of mechanically-injured mouse femoral artery reveals an antiinflammatory effect of renin inhibitor. AB - OBJECTIVE: The renin-angiotensin-aldosterone system (RAS) plays a central role in atherosclerosis. To investigate the effects of a direct renin inhibitor aliskiren on vascular inflammation, we conducted leukocyte adhesion assays in vivo and in vitro using a novel real-time imaging system. METHODS AND RESULTS: Aliskiren (10 mg/kg/d) or PBS was administered to C57BL/6 mice (6-7 weeks of age; Oriental Yeast, Tokyo, Japan) for 2 weeks via an osmotic pump. Blood pressure was not significantly changed in the 2 groups throughout the experimental period. A perivascular cuff injury was then introduced to the femoral artery and real-time intravital microscopic observation was conducted 24 hours after injury. The number of adherent leukocytes was elevated in the injured mice without aliskiren (43.8+/-9.3/10(-2) mm(2)), whereas that was significantly reduced in the mice with aliskiren (18.4+/-4.4, P<0.05). Treatment of human umbilical vein endothelial cells (HUVECs) with aliskiren significantly reduced the adhesion of THP-1 cells to TNF-alpha-activated HUVECs (P<0.05). Interestingly, TNF-alpha induced renin activity and angiotensin II production in HUVECs were also blunted by aliskiren. Furthermore, exogenous renin and angiotensin II abrogated the aliskiren-mediated reduction of THP-1 cell adhesion to HUVECs. CONCLUSIONS: Our in vivo and in vitro findings indicate a pivotal role for renin inhibition in vascular inflammation independent of blood pressure. PMID- 19778946 TI - Expression of human apoAII in transgenic rabbits leads to dyslipidemia: a new model for combined hyperlipidemia. AB - OBJECTIVE: Apolipoprotein AII (apoAII) is the second major apolipoprotein in high density lipoprotein (HDL). However, the physiological functions of apoAII in lipoprotein metabolism have not been fully elucidated. METHODS AND RESULTS: We generated human apoAII transgenic (Tg) rabbits, a species that normally does not have an endogenous apoAII gene. Plasma levels of human apoAII in Tg rabbits were approximately 30 mg/dL, similar to the plasma levels in healthy humans. The expression of human apoAII in Tg rabbits resulted in increased levels of plasma triglycerides, total cholesterol, and phospholipids accompanied by a marked reduction in HDL-cholesterol levels compared with non-Tg littermates. Analysis of lipoprotein fractions showed that hyperlipidemia exhibited by Tg rabbits was caused by elevated levels of very-low-density lipoproteins (VLDL) and intermediate-density lipoproteins. Furthermore, postheparin lipoprotein lipase activity significantly decreased in Tg rabbits compared with non-Tg rabbits. CONCLUSIONS: These results indicate that apoAII plays an important role in both VLDL and HDL metabolism, possibly through the inhibition of lipoprotein lipase activity. ApoAII Tg rabbits may become a new model for the study of human familial combined hyperlipidemia. PMID- 19778948 TI - Proteomics of apolipoproteins and associated proteins from plasma high-density lipoproteins. AB - Proteomics studies have extended the list of identified apolipoproteins and associated proteins present in HDL and its subclasses. These proteins appear to cluster around specific functions related to lipid metabolism, inflammation, the immune system, hormone-binding, hemostasis, and antioxidant properties. Small studies suggest that there are substantial differences between the HDL proteome from cardiovascular disease patients and that from controls. Furthermore, dyslipidemia therapy shifts the HDL proteome from patients toward the profile observed in healthy controls. In addition, the proteome of HDL and LDL from patients with insulin resistance and peripheral atherosclerosis show significant differences with that of matched healthy controls. The proteome of HDL and LDL density subclasses have apolipoproteins and associated proteins profiles that suggest subclass-specific functions. However, proteomics studies of lipoproteins are few and small and should be interpreted with caution. Nonetheless rapid technical progress in proteomic platforms suggest that soon analysis time will be reduced and precise measurement of identified proteins will be possible. This, combined with controlled purification steps of HDL and its subclasses should provide further information about proteins involved in the particles postulated spectrum of functions, including those believed to be atheroprotective. PMID- 19778949 TI - Genomic assessment of follicular marker genes as pregnancy predictors for human IVF. AB - Embryo selection efficiency in human IVF procedure is still suboptimal as shown by low pregnancy rates with single embryo transfer (SET). Bidirectional communication between the oocyte and follicular cells (FC) is essential to achieve developmental competence of the oocyte. Differences in the gene expression profile of FCs from follicles leading to pregnancy could provide useful markers of oocyte developmental competence. FCs were recovered by individual follicle puncture. FC expression levels of potential markers were assessed by Q-PCR with an intra-patient and an inter-patient analysis approach. Using gene expression, a predictive model of ongoing pregnancy was investigated. Using intra-patient analysis, four candidate genes, phosphoglycerate kinase 1 (PGK1), regulator of G-protein signalling 2 (RGS2), regulator of G-protein signalling 3 (RGS3) and cell division cycle 42 (CDC42) showed a difference between FCs from follicles leading to a pregnancy or developmental failure. The best predictors for ongoing pregnancy were PGK1 and RGS2. Additionally, inter patient analysis revealed differences in FC expression for PGK1 and CDC42 between follicles leading to a transferred embryo with positive pregnancy results and those with negative results. Both inter-patient and intra-patient approaches must be taken into consideration to delineate gene expression variations in the context of follicular competence. A predictor model using biomarkers could improve the efficiency of predicting developmental competence of oocytes. These new approaches provide useful tools in the context of embryo selection and in the improvement of pregnancy rates with SET. PMID- 19778950 TI - Genomic changes detected by array CGH in human embryos with developmental defects. AB - Developmental abnormalities of human embryos can be visualized in utero using embryoscopy. Our previous embryoscopic and genetic evaluations detected developmental abnormalities in the majority of both euploid (74%) and aneuploid or polyploid (90%) miscarriages. Since we found the pattern of morphological changes to be similar in euploid and non-euploid embryos, we proposed that lethal submicroscopic changes, not detected by standard chromosome testing, may be responsible for miscarriage of euploid embryos. Whole genome oligo and bacterial artificial chromosome array comparative genome hybridization (CGH) was used to screen for submicroscopic chromosomal changes (DNA copy number variants or CNVs) in 17 euploid embryonic miscarriages, with a range of developmental abnormalities documented by embryoscopy. The CNV breakpoints were refined using a custom array (Agilent) with high resolution coverage of the CNVs. Six unique CNVs, previously not reported, were identified in 5 of the 17 embryos (29% of all cases or 50% of cases studied with higher resolution arrays). All six unique CNVs were <250 kb in size. On the basis of parental array CGH analysis, a de novo origin of a CNV was determined for one embryo (at 13q32.1) and suspected for another (at 10p15.3). Three CNVs, at Xq28, 1q25.3 and 7p14.3, were inherited and a CNV at 17p13.1 was of unknown origin. The genes contained within these unique CNVs will be discussed, with specific reference to rearrangements of syntaxin and tryptophan aspartic acid (WD) repeat genes. Our report describes for the first time, de novo and inherited unique CNVs in euploid human embryos with specific developmental defects. PMID- 19778951 TI - A genome-sequence survey for Ascogregarina taiwanensis supports evolutionary affiliation but metabolic diversity between a Gregarine and Cryptosporidium. AB - We have performed a whole-genome-sequence survey for the gregarine, Ascogregarina taiwanensis and herein describe both features unique to this early diverging apicomplexan and properties that unite it with Cryptosporidium, the Coccidia, and the Apicomplexa. Phylogenetic trees inferred from a concatenated protein sequence comprised of 10,750 amino acid positions, as well as the large subunit rRNA genes, robustly support phylogenetic affinity of Ascogregarina with Cryptosporidium at the base of the apicomplexan clade. Unlike Cryptosporidium, Ascogregarina possesses numerous mitochondrion-associated pathways and proteins, including enzymes within the Krebs cycle and a cytochrome-based respiratory chain. Ascogregarina further differs in the capacity for de novo synthesis of pyrimidines and amino acids. Ascogregarina shares with Cryptosporidium a Type I fatty acid synthase and likely a polyketide synthase. Cryptosporidium and Ascogregarina possess a large repertoire of multidomain surface proteins that align it with Toxoplasma and are proposed to be involved in coccidian-like functions. Four families of retrotransposable elements were identified, and thus, retroelements are present in Ascogregarina and Eimeria but not in other apicomplexans that have been analyzed. The sum observations suggest that Ascogregarina and Cryptosporidium share numerous molecular similarities, not only including coccidian-like features to the exclusion of Haemosporidia and Piroplasmida but also differ from each other significantly in their metabolic capacity. PMID- 19778952 TI - Images in vascular medicine: asymptomatic internal carotid artery stent fracture. PMID- 19778953 TI - Chronic exposure to nicotine impairs cholinergic angiogenesis. AB - Cholinergic angiogenesis is mediated by an endothelial nicotinic acetylcholine receptor (EC nAChR). Short-term administration of nicotine stimulates angiogenesis via EC nAChRs.The long-term effects of nicotine upon cholinergic angiogenesis are unknown. The objective of this study was to determine whether chronic nicotine exposure blunts angiogenesis. We exposed C57/Bl6 male mice (n = 42) to nicotine (200 microg/ml drinking water) or vehicle for 8 or 16 weeks. Subsequently, hindlimb ischemia was induced by ligation of the left femoral artery. After surgery, animals in the vehicle-treated group were re-randomized to vehicle (vehicle group) or nicotine (acute exposure group) for 2 weeks; whereas animals that had been previously treated (for 8 or 16 weeks with nicotine) continued to receive nicotine (8 WK or 16 WK groups). After 2 weeks, animals were sacrificed for immunohistochemical, gene expression, and angiogenesis studies. Capillary density of the ischemic hindlimb was increased by nicotine in naive animals (vehicle vs acute exposure: 2.40 +/- 0.09 vs 2.82 +/- 0.10 capillaries/myocyte, p < 0.05). However, prior exposure to nicotine for 16 weeks (16 WK) abolished the effects of nicotine to increase capillary density in the ischemic hindlimb (acute vs 16 WK: 2.82 +/- 0.10 vs 2.47 +/- 0.03 capillaries/ myocyte; p < 0.05). The impairment of cholinergic angiogenesis was associated with a reduction in nAChR expression and plasma VEGF levels. Chronic exposure to nicotine impaired capillary sprouting of aortic segments ex vivo (vehicle vs 16 WK: 0.303 +/- 0.029 vs 0.204 +/- 0.017 mm(2), p < 0.05, n = 3 in each group). In conclusion, the current study shows for the first time that chronic exposure to nicotine impairs cholinergic angiogenesis, an effect mediated by downregulation of the vascular nAChR, and attenuation of nicotine-induced VEGF release. These studies may explain the impairment in angiogenic processes observed in long-term smokers. PMID- 19778954 TI - Increase in plasma free haemoglobin during cardiopulmonary bypass in heart valve surgery: assessment of renal dysfunction by RIFLE classification. AB - Heart valve surgery carries a high risk of renal insufficiency as an independent risk factor due to prolonged cardiopulmonary bypass. Multiple causes of cardiopulmonary bypass-associated renal damage have been described, and haemoglobin-induced renal injury is presently being investigated. Forty-three patients scheduled for heart valve surgery (mostly combined) were enrolled in the prospective study. Plasma free haemoglobin (PFH) levels were evaluated by photocolorimetric measurement at the start of procedures (t(0)) and before the end of extracorporeal circulation (t(1)). A statistically significant increase in PFH levels during cardiopulmonary bypass was detected [median values (interquartile range) - t(0): 62.0 (53.4) mg/L, t(1): 320.4 (352.2) mg/L], P < 0.001. A significant regression relationship between the duration of cardiopulmonary bypass and the increased PFH was found (Spearman's correlation coefficient 0.628, P < 0.001). In some elderly patients, the tendency towards a high release of PFH during cardiopulmonary bypass was more pronounced, but the overall association between age and PFH levels was of borderline significance (P = 0.077). The correlation between PFH and post-operative serum creatinine was low and non-significant, but the latter correlated highly with the pre-operative serum creatinine values (Spearman's correlation coefficient reached values of 0.6 0.7, P < 0.001). Patients were classified according to the Risk of renal failure, Injury to the kidney, Failure of kidney function, Loss of kidney function and End stage renal failure (RIFLE) classification for acute renal dysfunction during post-operative days 1 - 4; the influence of PFH levels at t(1) on the consequent RIFLE classification was not proven (P=0.648), but 4 patients in the Injury category had shown a higher median value of PFH (433.6 mg/L) in comparison with the others (29 patients with no acute renal dysfunction - 313.7 mg/L, 10 patients at Risk - 330.1 mg/L). PMID- 19778955 TI - Mucocutaneous manifestations in 150 HIV-infected Indian patients and their relationship with CD4 lymphocyte counts. AB - Mucocutaneous findings in 150 HIV+ve cases (F, 79; M, 71) were evaluated over a one-year period. Mucocutaneous manifestations were seen in 96% with 2.9 mean number of dermatoses and mean cluster of differentiation (CD4) count of 196.33 cells/mm(3). The highest number of mean dermatoses, 3.29, was seen in individuals with severe immunosuppression. The most common mucocutaneous manifestation seen was candidiasis (35.33%), followed by seborrhoeic dermatitis (31.33%), oral pigmentation (29.33%), xerosis/ichthyosis (22.67%), pyodermas (22%), periodontitis (17.33%) and nail pigmentation (16.67%). Patient stratification according to the WHO immunological staging, according to CD4 counts, showed a statistically significant association (P < 0.05) for candidiasis, scabies, paronychia, oral pigmentation and diffuse hair loss. Nail and oral pigmentary changes, trichomegaly and subcutaneous fungal infections caused by dermatophytes were highlights of the study. Incidences of xerosis/ichthyosis, pyodermas, scabies and molluscum contagiosum reported in our study were higher and pruritic popular eruptions was lower than those in previous Indian studies. Cutaneous neoplasms were not seen in the present study. PMID- 19778956 TI - Which patient undergoing mitral valve surgery should also have the tricuspid repair? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'Which patient undergoing mitral valve surgery should also have the tricuspid repair?' Altogether 390 papers were found using the reported search, of which 17 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. While a general agreement exists for tricuspid valve (TV) repair in cases of severe regurgitation and concomitant multivalvular disease requiring surgical intervention, current guidelines provide more vague indications for patients with less severe tricuspid regurgitation (TR). Since this condition has a lower event-free survival rate and the prognosis after symptoms development is dismal, a lower threshold and a more aggressive strategy for intervention is needed. In rheumatic valve disease, mitral valve involvement and disease spreading to TV may be responsible for further regurgitation. Although patients with pulmonary hypertension (PH) may benefit from mitral valve replacement (MVR) or balloon valvotomy, many studies found that preoperative PH does not predict late TR. However, patients with high pulmonary pressure have a lower occurrence of late TR. Tricuspid annular dilation is probably the most important factor for late TR. Once established, it might be irreversible even after resolution of PH as well as absence of 'reverse remodelling'. It has been proposed to treat TR independently from the grade of regurgitation when the annular dimension is over 21 mm/m(2) or > or =3.5 cm at echo measurement or when the intra-operative tricuspid annulus (TA) diameter is >70 mm. TV repair should be accomplished in patients with preoperative atrial fibrillation (AF), since it may cause late significant TR development and affect the patient's long-term survival. The presence of a trans-tricuspid pacemaker lead is another known factor for late TR development secondary to adhesions and fibrous retraction. TV repair is probably better than replacement in non-severe organic TV disease. Annuloplasty ring repair has better outcome compared with non-ring based repair techniques; the beneficial effect is also independent of the type of mitral valve surgery performed. PMID- 19778957 TI - Can stunned hearts be resuscitated? Evaluation of aspartate/glutamate secondary blood cardioplegia using magnetic resonance spectroscopy. AB - Objectives: Reperfusion of ischemic hearts with warm, substrate-enriched, blood cardioplegia may alleviate post-ischemic metabolic and functional derangements. This study investigates this possibility using (31)P magnetic resonance (MR) spectroscopy. Methods: Fifteen blood-perfused Langendorff pig hearts were subjected to 30 min of total, normothermic ischemia. Control hearts (n=8) were reperfused with blood for 40 min. Experimental hearts (n=7) received 20 min of aspartate/glutamate (asp/glu) enriched blood cardioplegic solution, followed by 20 min of normal blood. (31)P MR spectroscopy was used to observe cellular energetics and intracellular pH (pHi) throughout the experiments. Left ventricular function and myocardial oxygen consumption were evaluated before and after ischemia. Results: MR spectra showed no improvement in the rate or extent of high-energy phosphate recovery with asp/glu cardioplegia, but showed a transient increase in pHi during cardioplegic reperfusion (p<0.05). This, however, did not affect post-ischemic recovery of high energy metabolites, myocardial function or oxygen consumption. Conclusions: This study raises questions regarding the potential beneficial effects of asp/glu enriched secondary cardioplegic solution on functional or metabolic status of stunned pig hearts. Extrapolation of these results to humans should be viewed with caution. Keywords: Magnetic resonance; Pig heart; Aspartate; Glutamate; Cardioplegia; Myocardial stunning. PMID- 19778958 TI - Neural modulation of temporal encoding, maintenance, and decision processes. AB - Time perception emerges from an interaction among multiple processes that are normally intertwined. Therefore, a challenge has been to disentangle timekeeping from other processes. Though the striatum has been implicated in interval timing, it also modulates nontemporal processes such as working memory. To distinguish these processes, we separated neural activation associated with encoding, working memory maintenance, and decision phases of a time-perception task. We also asked whether neuronal processing of duration (i.e., pure tone) was distinct from the processing of identity (i.e., pitch perception) or sensorimotor features (i.e., control task). Striatal activation was greater when encoding the duration than the pitch or basic sensory features, which did not differentially engage the striatum. During the maintenance phase, striatal activation was similar for duration and pitch but at baseline in the control task. In the decision phase, a stepwise reduction in striatal activation was found across the 3 tasks, with activation greatest in the timing task and weakest in the control task. Task related striatal activations in different cognitive phases were distinguished from those of the supplementary motor area, inferior frontal gyrus, thalamus, frontoparietal cortices, and the cerebellum. Our results were consistent with a model in which timing emerges from context-dependent corticostriatal interactions. PMID- 19778959 TI - Characterization of a broad-host-range flagellum-dependent phage that mediates high-efficiency generalized transduction in, and between, Serratia and Pantoea. AB - A phage (PhiOT8) isolated on Serratia sp. ATCC 39006 was shown to be flagellum dependent, and to mediate generalized transduction with high efficiency (up to 10(-4) transductants per p.f.u.). PhiOT8 was shown to have a broad host range because it also infected a strain of Pantoea agglomerans isolated from the rhizosphere. Transduction of plasmid-borne antibiotic resistance between the two bacterial genera was demonstrated, consistent with purported ecological roles of phages in dissemination of genes between bacterial genera. Serratia sp. ATCC 39006 and P. agglomerans produce a number of interesting secondary metabolites that have potential applications in cancer therapy and biocontrol of fungal infections. PhiOT8 has utility as a powerful functional genomics tool in these bacteria. PMID- 19778961 TI - Autophagy-deficient Schizosaccharomyces pombe mutants undergo partial sporulation during nitrogen starvation. AB - Autophagy is triggered when organisms sense radical environmental changes, including nutritional starvation. During autophagy, cytoplasmic components, including organelles, are enclosed within autophagosomes and are degraded upon lysosome-vacuole fusion. In this study, we show that processing of GFP-tagged Atg8 can serve as a marker for autophagy in the fission yeast Schizosaccharomyces pombe. Using this marker, 13 Atg homologues were also found to be required for autophagy in fission yeast. In budding yeast, autophagy-deficient mutants are known to be sterile, whereas in fission yeast we found that up to 30 % of autophagy-defective cells with amino acid auxotrophy were able to recover sporulation when an excess of required amino acids was supplied. Furthermore, we found that approximately 15 % of the autophagy-defective cells were also able to sporulate when a prototrophic strain was subjected to nitrogen starvation, which suggested that fission yeast may store sufficient intracellular nitrogen to allow partial sporulation under nitrogen-limiting conditions, although the majority of the nitrogen source is supplied by autophagy. Monitoring of the sporulation process revealed that the process was blocked non-specifically at various stages in the atg1Delta and atg12Delta mutants, possibly due to a shortage of amino acids. Taking advantage of this partial sporulation ability of fission yeast, we sought evidence for the existence of a recycling system for nitrogen sources during starvation. PMID- 19778962 TI - AI-2 quorum-sensing inhibitors affect the starvation response and reduce virulence in several Vibrio species, most likely by interfering with LuxPQ. AB - The increase of disease outbreaks caused by Vibrio species in aquatic organisms as well as in humans, together with the emergence of antibiotic resistance in Vibrio species, has led to a growing interest in alternative disease control measures. Quorum sensing (QS) is a mechanism for regulating microbial gene expression in a cell density-dependent way. While there is good evidence for the involvement of auto-inducer 2 (AI-2)-based interspecies QS in the control of virulence in multiple Vibrio species, only few inhibitors of this system are known. From the screening of a small panel of nucleoside analogues for their ability to disturb AI-2-based QS, an adenosine derivative with a p methoxyphenylpropionamide moiety at C-3' emerged as a promising hit. Its mechanism of inhibition was elucidated by measuring the effect on bioluminescence in a series of Vibrio harveyi AI-2 QS mutants. Our results indicate that this compound, as well as a truncated analogue lacking the adenine base, block AI-2 based QS without interfering with bacterial growth. The active compounds affected neither the bioluminescence system as such nor the production of AI-2, but most likely interfered with the signal transduction pathway at the level of LuxPQ in V. harveyi. The most active nucleoside analogue (designated LMC-21) was found to reduce the Vibrio species starvation response, to affect biofilm formation in Vibrio anguillarum, Vibrio vulnificus and Vibrio cholerae, to reduce pigment and protease production in V. anguillarum, and to protect gnotobiotic Artemia from V. harveyi-induced mortality. PMID- 19778960 TI - SLA2 mutations cause SWE1-mediated cell cycle phenotypes in Candida albicans and Saccharomyces cerevisiae. AB - The early endocytic patch protein Sla2 is important for morphogenesis and growth rates in Saccharomyces cerevisiae and Candida albicans, but the mechanism that connects these processes is not clear. Here we report that growth defects in cells lacking CaSLA2 or ScSLA2 are associated with a cell cycle delay that is influenced by Swe1, a morphogenesis checkpoint kinase. To establish how Swe1 monitors Sla2 function, we compared actin organization and cell cycle dynamics in strains lacking other components of early endocytic patches (Sla1 and Abp1) with those in strains lacking Sla2. Only sla2 strains had defects in actin cables, a known trigger of the morphogenesis checkpoint, yet all three strains exhibited Swe1-dependent phenotypes. Thus, Swe1 appears to monitor actin patch in addition to actin cable function. Furthermore, Swe1 contributed to virulence in a mouse model of disseminated candidiasis, implying a role for the morphogenesis checkpoint during the pathogenesis of C. albicans infections. PMID- 19778963 TI - A distinct physiological role of MutY in mutation prevention in mycobacteria. AB - Oxidative damage to DNA results in the occurrence of 7,8-dihydro-8-oxoguanine (8 oxoG) in the genome. In eubacteria, repair of such damage is initiated by two major base-excision repair enzymes, MutM and MutY. We generated a MutY-deficient strain of Mycobacterium smegmatis to investigate the role of this enzyme in DNA repair. The MutY deficiency in M. smegmatis did not result in either a noteworthy susceptibility to oxidative stress or an increase in the mutation rate. However, rifampicin-resistant isolates of the MutY-deficient strain showed distinct mutations in the rifampicin-resistance-determining region of rpoB. Besides the expected C to A (or G to T) mutations, an increase in A to C (or T to G) mutations was also observed. Biochemical characterization of mycobacterial MutY (M. smegmatis and M. tuberculosis) revealed an expected excision of A opposite 8 oxoG in DNA. Additionally, excision of G and T opposite 8-oxoG was detected. MutY formed complexes with DNA containing 8-oxoG : A, 8-oxoG : G or 8-oxoG : T but not 8-oxoG : C pairs. Primer extension reactions in cell-free extracts of M. smegmatis suggested error-prone incorporation of nucleotides into the DNA. Based on these observations, we discuss the physiological role of MutY in specific mutation prevention in mycobacteria. PMID- 19778965 TI - Biodiversity of cyanobacteria and green algae on monuments in the Mediterranean Basin: an overview. AB - The presence and deteriorating action of micro-organisms on monuments and stone works of art have received considerable attention in the last few years. Knowledge of the microbial populations living on stone materials is the starting point for successful conservation treatment and control. This paper reviews the literature on cyanobacteria and chlorophyta that cause deterioration of stone cultural heritage (outdoor monuments and stone works of art) in European countries of the Mediterranean Basin. Some 45 case studies from 32 scientific papers published between 1976 and 2009 were analysed. Six lithotypes were considered: marble, limestone, travertine, dolomite, sandstone and granite. A wide range of stone monuments in the Mediterranean Basin support considerable colonization of cyanobacteria and chlorophyta, showing notable biodiversity. About 172 taxa have been described by different authors, including 37 genera of cyanobacteria and 48 genera of chlorophyta. The most widespread and commonly reported taxa on the stone cultural heritage in the Mediterranean Basin are, among cyanobacteria, Gloeocapsa, Phormidium and Chroococcus and, among chlorophyta, Chlorella, Stichococcus and Chlorococcum. The results suggest that cyanobacteria and chlorophyta colonize a wide variety of substrata and that this is related primarily to the physical characteristics of the stone surface, microclimate and environmental conditions and secondarily to the lithotype. PMID- 19778964 TI - Remnant signal peptides on non-exported enzymes: implications for the evolution of prokaryotic respiratory chains. AB - The twin-arginine translocation (Tat) pathway is a prokaryotic protein targeting system dedicated to the transmembrane translocation of folded proteins. Substrate proteins are directed to the Tat translocase by signal peptides bearing a conserved SRRxFLK 'twin-arginine' motif. In Escherichia coli, most of the 27 periplasmically located Tat substrates are cofactor-containing respiratory enzymes, and many of these harbour a molybdenum cofactor at their active site. Molybdenum cofactor-containing proteins are not exclusively located in the periplasm, however, with the major respiratory nitrate reductase (NarG) and the biotin sulfoxide reductase (BisC), for example, being located at the cytoplasmic side of the membrane. Interestingly, both NarG and BisC contain 'N-tail' regions that bear some sequence similarity to twin-arginine signal peptides. In this work, we have examined the relationship between the non-exported N-tails and the Tat system. Using a sensitive genetic screen for Tat transport, variant N-tails were identified that displayed Tat transport activity. For the NarG 36-residue N tail, six amino acid changes were needed to induce transport activity. However, these changes interfered with binding by the NarJ biosynthetic chaperone and impaired biosynthesis of the native enzyme. For the BisC 36-residue N-tail, only five amino acid substitutions were needed to restore Tat transport activity. These modifications also impaired in vivo BisC activity, but it was not possible to identify a biosynthetic chaperone for this enzyme. These data highlight an intimate genetic and evolutionary link between some non-exported redox enzymes and those transported across membranes by the Tat translocation system. PMID- 19778966 TI - PssA is required for alpha-amylase secretion in Antarctic Pseudoalteromonas haloplanktis. AB - Extracellular protein secretion is an essential feature in bacterial physiology. The ability to efficiently secrete diverse hydrolytic enzymes represents a key nutritional strategy for all bacteria, including micro-organisms living in extreme and hostile habitats, such as cold environments. However, little is known about protein secretion mechanisms in psychrophilic bacteria. In this study, the recombinant secretion of a cold-adapted alpha-amylase in the Antarctic Gram negative Pseudoalteromonas haloplanktis TAC125 was investigated. By a combination of several molecular techniques, the function of the pssA gene was related to alpha-amylase secretion in this psychrophilic bacterium. Deletion of the pssA gene completely abolished amylase secretion without affecting the extracellular targeting of other substrates mediated by canonical secretion systems. The pssA gene product, PssA, is a multidomain lipoprotein, predicted to be localized in the bacterial outer membrane, and displaying three TPR (tetratricopeptide repeat) domains and two LysM modules. Based on functional annotation of these domains, combined with the experimental results reported herein, we suggest a role for PssA as a molecular adaptor, in charge of recruiting other cellular components required for specific alpha-amylase secretion. To the best of our knowledge, no proteins exhibiting the same domain organization have previously been linked to protein secretion. PMID- 19778967 TI - Null mutation analysis of an afsA-family gene, barX, that is involved in biosynthesis of the {gamma}-butyrolactone autoregulator in Streptomyces virginiae. AB - Virginiae butanolide (VB) is a gamma-butyrolactone autoregulator that triggers production of the streptogramin antibiotic virginiamycin in Streptomyces virginiae. Our previous studies suggested that the barX gene, an afsA-family gene, is likely to participate in the regulatory pathway for the production of VB, rather than in the biosynthetic pathway of VB itself, in contrast to the function of other afsA-family genes. Mutation analysis now shows that BarX at least plays an enzymic role in the VB biosynthetic pathway. Heterologous expression of the afsA gene from Streptomyces griseus into the barX mutant partially restored the deficiency of virginiamycin production, suggesting that afsA-family genes have a common ability to synthesize the gamma-butyrolactone autoregulators. Taken together with previous works relating to the function of an afsA-family gene, these results support the idea that streptomycetes have two biosynthetic pathways for the gamma-butyrolactone autoregulators. PMID- 19778968 TI - Role of PvdQ in Pseudomonas aeruginosa virulence under iron-limiting conditions. AB - PvdQ, an acylase from Pseudomonas aeruginosa PAO1, has been shown to have at least two functions. It can act as a quorum quencher due to its ability to degrade long-chain N-acylhomoserine lactones (AHLs), e.g. 3-oxo-C12-HSL, leading to a decrease in virulence factors. In addition, PvdQ is involved in iron homeostasis by playing a role in the biosynthesis of pyoverdine, the major siderophore of P. aeruginosa. In accordance with earlier studies on RNA level, we could show at the protein level that PvdQ is only expressed when iron is present at very low concentrations. We therefore set out to investigate the two functions of PvdQ under iron-limiting conditions. Gene deletion of pvdQ does not affect growth of P. aeruginosa but abrogates pyoverdine production, and results in an accumulation of 3-oxo-C12-HSL. Phenotypic analyses of our DeltapvdQ mutant at low iron concentrations revealed that this mutant is impaired in swarming motility and biofilm formation. Additionally, a plant and a Caenorhabditis elegans infection model demonstrated that the deletion of pvdQ resulted in reduced virulence. None of the phenotypes in the present study could be linked to the presence or absence of AHLs. These results clearly indicate that under iron limiting conditions PvdQ plays a major role in swarming motility, in biofilm development and in infection that is more likely to be linked to the pyoverdine pathway rather than the LasI/LasR/3-oxo-C12-HSL quorum-sensing circuit. PMID- 19778969 TI - Prostate specific antigen for early detection of prostate cancer: longitudinal study. AB - OBJECTIVE: To evaluate if prostate specific antigen test attains validity standards required for screening in view of recent prostate cancer screening trial results. DESIGN: Case-control study nested in longitudinal cohort. SETTING: Vasterbotten Intervention Project cohort, Umea, Sweden. PARTICIPANTS: 540 cases and 1034 controls matched for age and date of blood draw. MAIN OUTCOME MEASURE: Validity of prostate specific antigen for prediction of subsequent prostate cancer diagnosis by record linkage to cancer registry. RESULTS: Blood samples were drawn on average 7.1 (SD 3.7) years before diagnosis. The area under the curve for prostate specific antigen was 0.84 (95% confidence interval 0.82 to 0.86). At prostate specific antigen cut-off values of 3, 4, and 5 ng/ml, sensitivity estimates were 59%, 44%, and 33%, and specificity estimates were 87%, 92%, and 95%. The positive likelihood ratio commonly considered to "rule in disease" is 10; in this study the positive likelihood ratios were 4.5, 5.5, and 6.4 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. The negative likelihood ratio commonly considered to "rule out disease" is 0.1; in this study the negative likelihood ratios were 0.47, 0.61, and 0.70 for prostate specific antigen cut-off values of 3, 4, and 5 ng/ml. For a cut-off of 1.0 ng/ml, the negative likelihood ratio was 0.08. CONCLUSIONS: No single cut-off value for prostate specific antigen concentration attained likelihood ratios formally required for a screening test. Prostate specific antigen concentrations below 1.0 ng/ml virtually ruled out a prostate cancer diagnosis during the follow-up. Additional biomarkers for early detection of prostate cancer are needed before population based screening for prostate cancer should be introduced. PMID- 19778970 TI - Prostate specific antigen for detecting early prostate cancer. PMID- 19778971 TI - Screening for prostate cancer remains controversial. PMID- 19778972 TI - Guidelines spell out when someone assisting a suicide risks prosecution. PMID- 19778973 TI - What can we learn from German health incentive schemes? PMID- 19778974 TI - Can the NHS get connected? PMID- 19778975 TI - Chitosan may decrease serum valproate and increase the risk of seizure reappearance. PMID- 19778976 TI - A patient's journey. Anorexia nervosa. PMID- 19778977 TI - Can financial incentives improve health equity? PMID- 19778978 TI - Migrants in Europe are losing out on care they are entitled to. PMID- 19778979 TI - Does socio-economic status moderate the associations between psychosocial predictors and fruit intake in schoolchildren? The Pro Children study. AB - This study tested whether socio-economic status (SES) moderated the association between the psychosocial constructs included in the attitude-social influence self-efficacy (ASE) model and fruit intake in Norwegian schoolchildren. The sample consisted of 962 Norwegian sixth graders, mean age 11.3 years. They were split into three SES groups, and multi-group structural equation modeling (MSEM) was used. Children in the highest SES group reported eating fruit more frequently and reported more positive ASE variables than children in the lower SES groups. This was particularly true for social environmental factors, home availability of fruit and intention to eat fruit. MSEM showed that the relationships specified in the adapted ASE model were moderated by SES, as we did not find support for equal model structure across the three samples. Model modification for each SES group separately showed that the relation between home availability and fruit intake was not significant for the medium and low SES groups, and the relation between self-efficacy and intention to eat fruit was not significant for the medium SES group. Future interventions aiming at increasing fruit intake in children need to be sensitive to such SES-related differences and should in particular affect factors that may impede fruit intake in the lower SES groups. PMID- 19778980 TI - Comparison of gluteus medius muscle electromyographic activity during forward and lateral step-up exercises in older adults. AB - BACKGROUND: Step-up exercises often are suggested for strengthening the hip abductor muscles and improving balance in older adults. Little is known, however, about whether the forward or lateral version of these exercises is best for activating the hip abductor muscles. OBJECTIVE: The purpose of this study was to examine the electromyographic (EMG) amplitude of the gluteus medius (GM) muscles bilaterally during forward and lateral step-up exercises. DESIGN: The study design involved single-occasion repeated measures. METHODS: Twenty-seven community-dwelling adults (7 men and 20 women) with a mean (SD) age of 79.4 (8.0) years performed forward and lateral step-up exercises while the surface EMG activity of the GM muscles was recorded bilaterally. Pressure switches and dual forceplates were used to identify the ascent and descent phases. Subjects were instructed to lead with the right lower extremity during ascent and the left lower extremity during descent. Differences in normalized root-mean-square EMG amplitudes with exercise direction (forward versus lateral) and phase (ascent versus descent) were examined by use of separate repeated-measures analyses of variance for the right and left lower extremities. The alpha level was set at .05. RESULTS: Gluteus medius muscle EMG activity was significantly greater for lateral than for forward step-up exercises for the left lower extremity during the ascent phase and for both lower extremities during the descent phase. In addition, right GM muscle EMG activity was significantly greater during ascent than during descent for both exercise directions. LIMITATIONS: Study limitations include use of a convenience sample and collection of limited information about participants. CONCLUSIONS: Step-up exercises are effective in activating the GM muscle, with lateral step-up exercises requiring greater GM muscle activation than forward step-up exercises. Further study is needed to determine whether exercise programs for hip abductor muscle strengthening in older adults should preferentially include lateral over forward step-up exercises. PMID- 19778981 TI - An intensive, progressive exercise program reduces disability and improves functional performance in patients after single-level lumbar microdiskectomy. AB - BACKGROUND: Restoration of physical function following lumbar microdiskectomy may be influenced by the postoperative care provided. OBJECTIVE: The purpose of this study was to examine the effectiveness of a new interventional protocol to improve functional performance in patients who have undergone a single-level lumbar microdiskectomy. SETTING: The study was conducted in physical therapy outpatient clinics. DESIGN AND PARTICIPANTS: Ninety-eight participants (53 male, 45 female) who had undergone a single-level lumbar microdiskectomy were randomly allocated to receive education only or exercise and education. INTERVENTION AND MEASUREMENTS: The exercise intervention consisted of a 12-week periodized program of back extensor strength (force-generating capacity) and endurance training and mat and upright therapeutic exercises. The Oswestry Disability Index (ODI) and physical measures of functional performance were tested 4 to 6 weeks postsurgery and 12 weeks later, following completion of the intervention program. Because some participants sought physical therapy outside of the study, postintervention scores were analyzed for both an as-randomized (2-group) design and an as-treated (3-group) design. RESULTS: In the 2-group analyses, exercise and education resulted in a greater reduction in ODI scores and a greater improvement in distance walked. In the 3-group analyses, post hoc comparisons showed a significantly greater reduction in ODI scores following exercise and education compared with the education-only and usual physical therapy groups. LIMITATIONS: The limitations of this study include a lack of adherence to group assignment, disproportionate therapist contact time among treatment groups, and multiple use of univariate analyses. CONCLUSIONS: An intensive, progressive exercise program combined with education reduces disability and improves function in patients who have undergone a single-level lumbar microdiskectomy. PMID- 19778982 TI - Declines in physical activity and higher systolic blood pressure in adolescence. AB - The authors examined the potential association between changes in the number of moderate-to-vigorous physical activity (MVPA) sessions per week, adiposity, and systolic blood pressure (SBP) during adolescence. SBP and anthropometric factors were assessed biannually (1999/2000, 2002, and 2004) in a cohort of 1,293 Canadian adolescents aged 12-13 years in 1999. Self-reported 7-day recall data on MVPA sessions >or=5 minutes in duration were collected every 3 months over the 5 year period. Estimates of initial level and rate of decline in number of MVPA sessions per week from individual growth models were used as predictors of SBP in linear regression models. A decline of 1 MVPA session per week with each year of age was associated with 0.29-mm Hg and 0.19-mm Hg higher SBPs in girls and boys, respectively, in early adolescence (ages 12.8-15.1 years) and 0.40-mm Hg and 0.18 mm Hg higher SBPs, respectively, in late adolescence (ages 15.2-17.0 years). The associations were not attenuated by changes in body mass index, waist circumference, or skinfold thickness in girls during late adolescence. Although weaker, associations were evident in boys during late adolescence, as well as in both girls and boys during early adolescence. These results support prevention of declines in MVPA during adolescence to prevent higher blood pressure in youth. PMID- 19778985 TI - Amblyopia: what does the future hold? PMID- 19778983 TI - Antenatal and postnatal iron supplementation and childhood mortality in rural Nepal: a prospective follow-up in a randomized, controlled community trial. AB - The long-term benefits of antenatal iron supplementation in child survival are not known. In 1999-2001, 4,926 pregnant women in rural Nepal participated in a cluster-randomized, double-masked, controlled trial involving 4 alternative combinations of micronutrient supplements, each containing vitamin A. The authors examined the impact on birth weight and early infant mortality in comparison with controls, who received vitamin A only. They followed the surviving offspring of these women at approximately age 7 years to study effects of in utero supplementation on survival. Of 4,130 livebirths, 209 infants died in the first 3 months and 8 were lost to follow-up. Of those remaining, 3,761 were followed, 150 died between ages 3 months and 7 years, and 152 were lost to follow-up. Mortality rates per 1,000 child-years from birth to age 7 years differed by maternal supplementation group, as follows: folic acid, 13.4; folic acid-iron, 10.3; folic acid-iron-zinc, 12.0; multiple micronutrients; 14.0; and controls, 15.2. Hazard ratios were 0.90 (95% confidence interval (CI): 0.65, 1.22), 0.69 (95% CI: 0.49, 0.99), 0.80 (95% CI: 0.58, 1.11), and 0.93 (95% CI: 0.66, 1.31), respectively, in the 4 supplementation groups. Maternal iron-folic acid supplementation reduced mortality among these children by 31% between birth and age 7 years. These results provide additional motivation for strengthening antenatal iron-folic acid programs. PMID- 19778986 TI - Iris claw lenses in aphakia. PMID- 19778987 TI - Saint Lucy, the Patron Saint of the Blind. PMID- 19778988 TI - Implantation of the multifocal ReSTOR apodised diffractive intraocular lens in adult anisometropic patients with mild to moderate amblyopia. AB - AIM: To assess subjective and objective parameters of visual function after implantation of the AcrySof ReSTOR in amblyopic patients. METHODS: Phacoemulsification and IOL implantation were performed in six eyes of three patients with anisometropic amblyopia. Patients were examined after 16-18 months for uncorrected and distance-corrected visual acuity (VA) for distance, intermediate and near. A defocus curve, the extent of crowding, contrast sensitivity and stereo acuity were recorded. RESULTS: The mean age of the patients was 56 years (range 53-60). In the non-amblyopic eye, the uncorrected distance VA was 20/25 or better, and the best corrected distance VA was 20/20 or better; in the amblyopic eye, the VA was two to four lines worse. The near VA of the non-amblyopic and the amblyopic eye was equivalent to the distance VA. The defocus curve showed a clear bifocal profile, even in the amblyopic eye. Stereo acuity was found in the Titmus test but not in the random dot tests (Lang-chart and TNO test). All patients had a crowding phenomenon in the amblyopic eye. Binocular contrast sensitivity was within normal limits. Photic phenomena were not reported by any patient, and none of the patients required glasses for any distance, resulting in a high patient satisfaction. CONCLUSION: Anisometropic amblyopic patients may benefit from implantation of an AcrySof ReSTOR; no unwanted side effects were detected. PMID- 19778989 TI - Ultrastructural appearance of iris flocculi associated with a thoracic aortic aneurysm and dissections. PMID- 19778990 TI - Tachosil: a new alternative for the treatment of non-traumatic corneal perforations. PMID- 19778991 TI - Critical role of IFN-gamma in CFA-mediated protection of NOD mice from diabetes development. AB - IFN-gamma signaling-deficient non-obese diabetic (NOD) mice develop diabetes with similar kinetics to those of wild-type NOD mice. However, the immunization of IFN gamma signaling-deficient NOD mice with CFA failed to induce long-term protection, whereas wild-type NOD mice receiving CFA remained diabetes-free. CFA also failed to protect IFN-gamma receptor-deficient (IFN-gammaR(-/-)) NOD mice from the autoimmune rejection of transplanted islets, as it does in diabetic NOD mice, and from disease transfer by spleen cells from diabetic NOD mice. These data clearly show that the pro-inflammatory cytokine IFN-gamma is necessary for the CFA-mediated protection of NOD mice from diabetes. There is no difference in the T(h)1/T(h)17 balance between IFN-gammaR(-/-) NOD and wild-type NOD mice. There is also no difference in the total numbers and percentages of regulatory T (Treg) cells in the lymph node CD4(+) T-cell populations between IFN-gammaR(-/-) NOD and wild-type NOD mice. However, pathogenic T cells lacking IFN-gammaR are resistant to the suppressive effect of Treg cells, both in vivo and in vitro. Therefore, it is likely that CFA-mediated protection against diabetes development depends on a change in the balance between Treg cells and pathogenic T cells, and IFN-gamma signaling seems to control the susceptibility of pathogenic T cells to the inhibitory activity of Treg cells. PMID- 19778993 TI - A comparison of abstinence outcomes among gay/bisexual and heterosexual male smokers in an intensive, non-tailored smoking cessation study. AB - INTRODUCTION: Smoking rates are higher among lesbian/gay/bisexual (LGB) than heterosexual (HT) individuals. However, there is scant information regarding smoking cessation treatments and outcomes in LGB populations. This study examined abstinence outcome in response to a high intensity smoking cessation program not specifically tailored to LGB smokers. METHODS: A total of 54 gay/bisexual (GB) and 243 HT male smokers received 8-week open treatment with nicotine patch, bupropion, and counseling. Participants reported biologically verified abstinence at multiple time points during the study. RESULTS: Demographic, smoking, and psychological characteristics at baseline were similar according to sexual orientation. During the first 2 weeks after quit day, abstinence rates were higher among GB smokers (Week 1: GB = 89%, HT = 82%; Week 2: GB = 77%, HT = 68%; ps < .05); abstinence rates converged subsequently, becoming nearly identical at the end of treatment (Week 8, GB = 59% vs. HT = 57%). In mixed effects longitudinal analysis of end-of-treatment outcome, sexual orientation (b = 1.40, SEM = 0.73, p = .056) and the Sexual Orientation x Time interaction (b = -0.146; SEM = 0.08, p = .058) approached statistical significance, reflecting the higher initial abstinence rates among GB smokers and the later convergence in abstinence rates by sexual orientation. DISCUSSION: This first report comparing smoking cessation treatment response by sexual orientation found higher initial and similar end-of-treatment abstinence rates in GB and HT smokers. Further work is needed to determine whether these observations from GB smokers who displayed a willingness to attend a non-tailored program and broad similarity with their HT counterparts in many baseline characteristics will replicate in other groups of GB smokers. PMID- 19778994 TI - Intention to quit smoking among lesbian, gay, bisexual, and transgender smokers. AB - INTRODUCTION: Smoking is highly prevalent among lesbian, gay men, bisexual, and transgender (LGBT) persons and contributes to health disparities. Guided by the theory of planned behavior (TPB), we identified beliefs related to attitudes, perceived behavioral control, and subjective norms, as well as LGBT-specific variables, to explain variance in intention to quit smoking in the next 6 months in LGBT smokers. METHODS: Individual interviews (n = 19) identified beliefs about quitting smoking and LGBT-salient variables and aided in survey development. Surveys were sent to a random sample from an LGBT community center's mailing list and center attendees, with a 25.4% response rate. Bivariate and multivariate analyses were conducted with the final sample of 101 smokers. RESULTS: No sociodemographic or LGBT-specific variables beyond the TPB constructs were related to intention to quit smoking. A multivariate TPB model explained 33.9% of the variance in quitting intention. More positive attitudes and specific beliefs that cessation would make smokers feel more like their ideal selves and improve health and longevity were related to greater intention to quit (p values < .05). Subjective norm and perceived behavioral control were marginally significant, with perceived approval of partners and others and beliefs that life goal achievement would make it easier to quit positively related to intention. Depression and stress levels were high. DISCUSSION: This is among the first studies to examine theoretically grounded variables related to intention to quit smoking in LGBT smokers. We identified specific behavioral, normative, and control beliefs that can serve as intervention targets to reduce smoking in the LGBT community. PMID- 19778995 TI - Peripheral concentrations of inhibin A, ovarian steroids, and gonadotropins associated with follicular development throughout the estrous cycle of the sow. AB - We investigated changes in peripheral concentrations of inhibin A, total inhibin, steroids, and gonadotropins throughout the intact estrous cycle of the sow in relation to ovarian changes determined by daily transrectal ultrasonography. All visible follicles of 3 mm or more in diameter were classified as small (> or =3 and <6 mm) or large (> or =6 mm). Follicular recruitment was identified in two periods of the cycle: one from the late luteal to the follicular phase, characterized by an increase in the number of small follicles followed by the appearance of large follicles; and another during the early luteal phase, consisting only of increased numbers of small follicles. Plasma concentrations of inhibin A increased (P<0.05), coinciding with the two periods of follicle emergence. Estradiol (E(2)) levels increased (P<0.05) during the follicular phase, but not during the early luteal phase. An inverse relationship (P<0.01) between the patterns of inhibin and FSH concentrations was noted around the two periods of follicle emergence, but there was no relationship (P> or =0.1) between the patterns of plasma E(2) and FSH during the early luteal phase. In conclusion, measurement of plasma inhibin A levels combined with ultrasonographic examination of the ovaries revealed two periods of synchronous follicular growth during the sow's estrous cycle. The results strongly suggest that inhibin A functions as a negative feedback regulator of FSH secretion throughout the estrous cycle, whereas E(2) appears to influence FSH secretion only during the follicular phase. PMID- 19778996 TI - 3-Phosphoglycerate dehydrogenase expression is regulated by HOXA10 in murine endometrium and human endometrial cells. AB - 3-Phosphoglycerate dehydrogenase (PHGDH, 3-PGDH) is an enzyme necessary for de novo l-serine biosynthesis. HOXA10 expression is required for endometrial receptivity; however, few target genes of HOXA10 regulation are known. Using a microarray we identified Phgdh as a target of HOXA10 regulation in murine endometrium and confirmed this regulatory relationship in human endometrial cells. PHGDH was downregulated 2.0-fold by HOXA10 and upregulated 4.4-fold by HOXA10 antisense in vivo. In human endometrial cells, real-time PCR results show that pcDNA3.1/HOXA10 transfection decreased PHGDH mRNA expression to 40% of pretreatment level (P<0.05), while PHGDH mRNA expression was increased 2.1-fold (P<0.05) by HOXA10 siRNA. Western blot results confirmed the regulatory relationship in both primary human endometrial stromal and epithelial cells, as well as in human endometrial stromal cells and Ishikawa cells. In human cycling endometrial tissue, immunohistochemical results showed that PHGDH expression is relatively high in the proliferative phase in glandular cells and lower in the secretory phase. Here we report novel expression and regulation of PHGDH in murine and human endometrium. PHGDH is expressed in both endometrial epithelial and stromal cells. HOXA10 represses endometrial PHGDH expression. PHGDH is necessary for serine biosynthesis, which serves as a substrate for protein synthesis. One mechanism by which HOXA10 regulates cellular differentiation may involve limiting protein synthesis in the secretary phase. PMID- 19778997 TI - Dynamics of constitutive heterochromatin: two contrasted kinetics of genome restructuring in early cloned bovine embryos. AB - Efficient reprograming of the donor cell genome in nuclear transfer (NT) embryos is linked to the ability of the embryos to sustain full-term development. As the nuclear architecture has recently emerged as a key factor in the regulation of gene expression, we questioned whether early bovine embryos obtained from transfer of cultured fibroblasts into enucleated oocytes would adopt an embryo like nuclear organization. We studied the dynamics of constitutive heterochromatin in the stages prior to embryonic genome activation by distribution analysis of heterochromatin protein CBX1 (HP1), centromeric proteins CENPA and CENPB, and histone H3 three-methylated at lysine 9. Then we applied descriptive, quantitative, and co-localization analyses. A dramatic reorganization of heterochromatic blocks of somatic donor cells was first observed in the late one-cell stage NT embryos. Then at two- and four-cell stages, we found two types of NT embryos: one displaying noncondensed heterochromatin patches similar to IVF embryos, whereas the second type displayed condensed heterochromatin blocks, normally observed in IVF embryos only after the eight-cell stage. These analyses discriminate for the first time two contrasted types of nuclear organization in NT embryos, which may correspond to different functional states of the nuclei. The relationship with the somatic nucleus reprograming efficiency is discussed. PMID- 19778999 TI - Recurrent orbital myositis mimicking sixth nerve palsy: diagnosis with MR imaging. AB - We present a case with recurrent orbital myositis sequentially affecting both lateral rectus muscles separately. In the first episode, the absence of the required symptoms for the diagnosis of orbital myositis led to the erroneous diagnosis of sixth nerve palsy. Eventually, the correct diagnosis was established with cerebral MR imaging. Orbital myositis should be included in the differential diagnosis of what appears clinically to be abducens palsy, and MR imaging with a focus on the orbita is mandatory in such patients. PMID- 19778998 TI - Disruption of the murine dynein light chain gene Tcte3-3 results in asthenozoospermia. AB - To elucidate the role of the mouse gene Tcte3 (Tctex2), which encodes a putative light chain of the outer dynein arm of cilia and sperm flagella, we have inactivated this gene in mice using targeted disruption. Breeding of heterozygous males and females resulted in normal litter size; however, we were not able to detect homozygous Tcte3-deficent mice using standard genotype techniques. In fact, our results indicate the presence of at least three highly similar copies of the Tcte3 gene (Tcte3-1, Tcte3-2, and Tcte3-3) in the murine genome. Therefore, quantitative real-time PCR was established to differentiate between mice having one or two targeted Tcte3-3 alleles. By this approach, Tcte3-3(-/-) animals were identified, which were viable and revealed no obvious malformation. Interestingly, some homozygous Tcte3-3-deficient male mice bred with wild-type female produced no offspring while other Tcte3-3-deficient males revealed decreased sperm motility but were fertile. In infertile Tcte3-3(-/-) males, spermatogenesis was affected and sperm motility was reduced, too, resulting in decreased ability of Tcte3-3-deficient spermatozoa to move from the uterus into the oviduct. Impaired flagellar motility is not correlated with any gross defects in the axonemal structure, since outer dynein arms are detectable in sperm of Tcte3-3(-/-) males. However, in infertile males, deficient Tcte3-3 function is correlated with increased apoptosis during male germ cell development, resulting in a reduction of sperm number. Moreover, multiple malformations in developing haploid germ cells are present. Our results support a role of Tcte3-3 in generation of sperm motility as well as in male germ cell differentiation. PMID- 19779000 TI - Persistent falcine sinus: is it really rare? AB - BACKGROUND AND PURPOSE: The falcine sinus has been considered as a rare variation of the venous pathway between the dural layers of the falx cerebri. The purpose of this study was to evaluate the incidence of falcine sinus and its anatomic characteristics by using CTA. MATERIALS AND METHODS: A total of 586 consecutive patients were enrolled in this study. A falcine sinus on CTA was defined as a midline venous structure connecting the vein of Galen or the internal sagittal sinus with the superior sagittal sinus. When present, anatomic features of the falcine sinus were evaluated. RESULTS: Falcine sinuses were present in 12 patients (2.1%). Only 1 case was associated with a congenital anomaly, a dysplastic tentorium. Eight patients had absent or rudimentary straight sinuses, and 4 patients had normal straight sinuses. CONCLUSIONS: In contrast to previous reports, falcine sinuses were not rare in the adult population, and most falcine sinuses were not associated with a congenital anomaly or sinus occlusion. Knowledge and recognition of these falcine sinuses are useful and important during the interpretation of brain CTA. PMID- 19779001 TI - Geometric and compositional appearance of atheroma in an angiographically normal carotid artery in patients with atherosclerosis. AB - BACKGROUND AND PURPOSE: Arterial remodeling may enable atherosclerotic disease without luminal stenosis. We sought to assess the prevalence and characteristics of atherosclerosis in angiographically normal carotid arteries. MATERIALS AND METHODS: Forty-six arteries with 0% stenosis by MRA were evaluated with multicontrast carotid MR imaging at 3T. For each artery, the percentage wall volume (wall volume/[lumen volume + wall volume] x 100%) and the presence versus absence of an LRNC, calcification, IPH, and fibrous cap rupture were recorded. In addition, the relative size of each plaque component (eg, percentage LRNC = LRNC volume/wall volume x 100%), when present, was calculated. RESULTS: The mean of percentage wall volume in arteries with 0% stenosis was 43.0 +/- 6.9% with a range from 31.6% to 60.1%. An LRNC was present in 67.4% (31/46) of arteries, calcification was present in 65.2% (30/46), IPH was present in 8.7% (4/46), and fibrous cap rupture was present in 4.3% (2/46). In arteries with an LRNC (n = 31), the average percentage LRNC volume was 8.8 +/- 7.3% with a range from 1.0% to 31.5%. For calcification (n = 30), the mean percentage calcification volume was 3.8 +/- 4.2% with a range of 0.1%-17.4%. The mean percentage IPH volume (n = 4) was 2.7 +/- 1.7% with a range of 0.5%-4.1%. CONCLUSIONS: These findings indicate that stenosis by MRA may underestimate the presence of carotid atherosclerosis, and they demonstrate the need for improved methods for accurately identifying carotid atherosclerotic plaque severity. PMID- 19779002 TI - Significant temporal evolution of diffusion anisotropy for evaluating early response to radiosurgery in patients with vestibular schwannoma: findings from functional diffusion maps. AB - BACKGROUND AND PURPOSE: Outcome evaluation in clinical oncology is conventionally based on long-term volumetric changes in the tumor size. The purpose of this study was to prospectively investigate the usefulness of fDMs in incorporating anisotropic diffusion in the evaluation of early response after radiosurgery in patients with vestibular schwannoma. MATERIALS AND METHODS: The MD, FA, and IVDC were calculated by using simple averaging methods and fDMs. Six patients with vestibular schwannoma treated with stereotactic radiosurgery underwent longitudinal DTI studies on a 3T MR imaging scanner (maximum follow-up, 6 months). Posttreatment DTI data were spatially coregistered with pretreatment scans. RESULTS: Tumors did not change significantly in size until 6 months after treatment. Diffusion indices changed significantly during the study period. There was a transient decrease in averaged MD followed by a significant increase. IVDC showed an opposite behavior compared with MD. FA decreased continuously throughout the study period. Functional diffusion maps showed a heterogeneous response of tumors to treatment, thereby providing complementary information to simple averaged values. CONCLUSIONS: DTI allows early detection of therapeutic induced changes in patients with vestibular schwannoma. Functional diffusion maps incorporating anisotropic diffusion may aid in assessing the heterogeneity of the therapeutic response in this patient group. PMID- 19779003 TI - Sinonasal and laryngeal carcinoma in children: correlation of imaging characteristics with clinicopathologic and cytogenetic features. AB - BACKGROUND AND PURPOSE: Pediatric upper airway carcinoma is uncommon, symptoms are nonspecific, and diagnosis is often delayed. In this study, we describe the imaging, cytogenetics, and clinical courses of 4 patients with pediatric upper airway carcinoma. MATERIALS AND METHODS: Four patients with upper airway carcinoma were identified during a 2.5-year period. CT (n = 4) and MR imaging (n = 3) studies, tumor histopathologic features and cytogenetics, patient treatment, and clinical course were reviewed. RESULTS: Patients were aged 12 to 15 years. One tumor involved the larynx with poorly defined margins and heterogeneous enhancement; 1 heterogeneously enhancing tumor involved the epiglottis with necrotic cervical lymphadenopathy. There were 2 enhancing sinonasal tumors with bony destruction in 1 tumor. Tumors had a relatively short relaxation time on FSEIR MR imaging. Histopathologic examination revealed poorly differentiated squamous cell carcinoma (n = 3) and well-differentiated squamous cell carcinoma (n = 1). Cytogenetic analysis revealed chromosomal abnormalities in 3 tumors: 2 showed a chromosomal translocation t(15;19), and 1 showed a chromosomal translocation t(1;5) and loss of a portion of chromosome 22q. Results of in situ hybridization for EBV were negative (n = 3). Treatment included tumor resection (n = 2), chemotherapy (n = 4), and radiation therapy (n = 3). Patients with t(15;19) died months after diagnosis. Two patients were alive at 8-year follow up. CONCLUSIONS: Childhood carcinoma of the upper airway is uncommon but should be considered in the diagnosis of upper airway tumors that display aggressive imaging characteristics. Carcinoma with t(15;19) is rare but has been reported, usually in young patients with midline carcinoma of the neck or mediastinum, with a rapidly fatal course. PMID- 19779004 TI - The safety of dedicated-team catheter-based diagnostic cerebral angiography in the era of advanced noninvasive imaging. AB - BACKGROUND AND PURPOSE: Given the current high quality and usefulness of noninvasive cerebrovascular imaging, invasive angiographic evaluation of the cerebrovascular system is justified if the procedural risk for a neurologic complication is far below the anticipated benefit. The purpose of this study was to evaluate the safety of diagnostic cerebral angiography provided by a dedicated neurointerventional team in a high-volume university hospital. MATERIALS AND METHODS: A consecutive cohort of 1715 patients undergoing diagnostic cerebral angiography at our institution from 2000 to 2008 was retrospectively assessed for incidence of stroke or TIA related to cerebral angiography. In the subgroup of patients (n = 40) who serendipitously underwent DWI within the first 30 days after cerebral angiography, the presence of new DWI hyperintensities found in territories explored during angiography was tabulated. Complications related to the catheter technique and sheath placement were also studied. RESULTS: No stroke or permanent neurologic deficit was seen in any of the 1715 patients undergoing diagnostic neuroangiography. One patient experienced a TIA. Nonneurologic complications without long-term sequelae occurred in 9 patients. Two patients had punctate areas of restricted diffusion in territories that had been angiographically explored. CONCLUSIONS: Within a high-volume neurointerventional practice, the risk for neurologic complications related to catheter-based diagnostic cerebral angiography can approach zero. As the absolute number of invasive diagnostic procedures diminishes with time, diagnostic cerebral angiography remains a useful tool while providing a foundation for neuroendovascular interventions, and should preferably be performed in institutions with high-volume operators also capable of managing unanticipated complicating adverse events. PMID- 19779005 TI - Generic or global outcome measures in rehabilitation: are they appropriate for measuring (and improving) service quality? PMID- 19779006 TI - Measuring outcomes in the longer term after a stroke. PMID- 19779007 TI - Development and initial validation of the Northwick Park Therapy Dependency Assessment. AB - OBJECTIVES: To describe the development and initial validation of the Northwick Park Therapy Dependency Assessment (NPTDA) as a measure of therapy interventions in neurorehabilitation. DESIGN: An iterative development process, followed by comparison with systemic prospective activity analysis, and parallel application of prospective and retrospective scores. SETTING: A tertiary specialist inpatient neurorehabilitation service. PARTICIPANTS: A total of 37 patients (M:F 21:16, mean age 41.8 (SD 14.7) years) with complex neurological disability in two consecutive cross-sectional cohorts. METHODS: The NPTDA was developed and refined over 18 months, together with an algorithm that converts ordinal scores to estimated therapy hours/week. NPTDA-estimated hours were compared with 'actual' therapy hours/week, identified from activity analysis. In a subsequent cohort analysis, prospectively rated NPTDA scores (reflecting intended levels of intervention) were compared with retrospective NPTDA scores (actual interventions). RESULTS: NPTDA-estimated therapy hours/week were strongly correlated with those identified from activity analysis, for total scores (Spearman rho 0.77, P<0.0001), and also for all five subdomains for direct (hands on) intervention (rho 0.70-0.93, P<0.0001). The initial test algorithm overestimated therapy hours (Wilcoxon z =3.9, P<0.001). After adjustment, reanalysis using a revised algorithm showed this bias to be removed (Wilcoxon z =1.4 P =0.15). Prospective and retrospectively applied total NPTDA scores were strongly correlated (rho 0.61, P<0.0001). Although intended levels of intervention were higher than those actually delivered (Wilcoxon z =3.30, P<0.001), the differences corresponded to real deviations from intended practice. CONCLUSION: In this initial evaluation, after revision of the algorithm, the NPTDA provided acceptable estimate of therapy interventions. Further evaluation is now required in other populations and settings. PMID- 19779009 TI - Customized strategies for discovering distant ncRNA homologs. AB - A large fraction of non-coding RNAs is short and/or poorly conserved in sequence. Most of the longer examples, furthermore, consist of a collection of conserved structural motifs rather than a coherent globally conserved secondary structure. As a consequence, the conceptually simple problem of homology search becomes a complex and technically demanding task. Despite the best efforts of databases such as Rfam, the situation is complicated further by the sparsity of information in many--in particular prokaryotic--RNA families. In this contribution, we review recent efforts to customize sequence-based search tools for ncRNA applications. In particular, semi-global alignments and the development of methods for fragmented pattern search have brought significant practical advances. Current developments in this area focus on the integration of fragmented sequence pattern search with search algorithms for secondary structure patterns. We focus here, in particular, on strategies that can be successful in the 'twilight zone' where generic approaches from blast to infernal to start to fail. PMID- 19779008 TI - Using Complementary and Alternative Medicines to Target the Host Response during Severe Influenza. AB - It is now accepted that an overwhelming inflammatory response is the cause of human deaths from avian H5N1 influenza infection. With this in mind we sought to examine the literature for examples of complementary and alternative medicines that reduce inflammation, and to place the results of this search in the context of our own work in a mouse model of influenza disease, using a pharmaceutical agent with anti-inflammatory properties. Two Chinese herbs, Angelica sinensis (Dang Gui) and Salvia miltiorrhiza (Danshen), have been recently shown to protect mice during lethal experimental sepsis via inhibition of the novel inflammatory cytokine High Mobility Group Box 1 protein (HMGB1). Biochanin A, a ligand of the peroxisome proliferator activated receptors (PPAR) alpha and gamma and the active isoflavone in Trifolium pratense (red clover), has anti-inflammatory properties, and thus could be used as an influenza treatment. This is of great interest since we have recently shown that gemfibrozil, a drug used to treat hyperlipidemia in humans and a synthetic ligand of PPAR alpha, significantly reduces the mortality associated with influenza infections in mice. The inflammation-modulating abilities of these natural agents should be considered in light of what is now known about the mechanisms of fatal influenza, and tested as potential candidates for influenza treatments in their own right, or as adjunct treatments to antivirals. PMID- 19779010 TI - Effect of meal volume and calorie load on postprandial gastric function and emptying: studies under physiological conditions by combined fiber-optic pressure measurement and MRI. AB - This study assessed the effects of meal volume (MV) and calorie load (CL) on gastric function. MRI and a minimally invasive fiber-optic recording system (FORS) provided simultaneous measurement of gastric volume and pressure changes during gastric filling and emptying of a liquid nutrient meal in physiological conditions. The gastric response to 12 iso-osmolar MV-CL combinations of a multinutrient drink (MV: 200, 400, 600, 800 ml; CL: 200, 300, 400 kcal) was tested in 16 healthy subjects according to a factorial design. Total gastric volume (TGV) and gastric content volume (GCV = MV + secretion) were measured by MRI during nasogastric meal infusion and gastric emptying over 60 min. Intragastric pressure was assessed at 1 Hz by FORS. The dynamic change in postprandial gastric volumes was described by a validated three-component linear exponential model. The stomach expanded with MV, but the ratio of GCV:MV at t(0) diminished with increasing MV (P < 0.01). Postprandial changes in TGV followed those of GCV. Intragastric pressure increased with MV, and this effect was augmented further by CL (P = 0.02); however, the absolute pressure rise was <4 mmHg. A further postprandial increase of gastric volumes was observed early on before any subsequent volume decrease. This "early" increase in GCV was greater for smaller than larger MV (P < 0.01), indicating faster initial gastric emptying of larger MV. In contrast, volume change during filling and in the early postprandial period were unaffected by CL. In the later postprandial period, gastric emptying rate continued to be more rapid with high MVs (P < 0.001); however, at any given volume, gastric emptying was slowed by higher CL (P < 0.001). GCV half-emptying time decreased with CL at 18 +/- 6 min for each additional 100-kcal load (P < 0.001). These findings indicate that gastric wall stress (passive strain and active tone) provides the driving force for gastric emptying, but distal resistance to gastric outflow regulates further passage of nutrients. The distinct early phase of gastric emptying with relatively rapid, uncontrolled passage of nutrients into the small bowel, modulated by meal volume but not nutrient composition, ensures that the delivery of nutrients in the later postprandial period is related to the overall calorie load of the meal. PMID- 19779011 TI - Secretagogue stimulation enhances NBCe1 (electrogenic Na(+)/HCO(3)(-) cotransporter) surface expression in murine colonic crypts. AB - A Na(+)/HCO(3)(-) cotransporter (NBC) is located in the basolateral membrane of the gastrointestinal epithelium, where it imports HCO(3)(-) during stimulated anion secretion. Having previously demonstrated secretagogue activation of NBC in murine colonic crypts, we now asked whether vesicle traffic and exocytosis are involved in this process. Electrogenic NBCe1-B was expressed at significantly higher levels than electroneutral NBCn1 in colonic crypts as determined by QRT PCR. In cell surface biotinylation experiments, a time-dependent increase in biotinylated NBCe1 was observed, which occurred with a peak of +54.8% after 20 min with forskolin (P < 0.05) and more rapidly with a peak of +59.8% after 10 min with carbachol (P < 0.05) and which corresponded well with the time course of secretagogue-stimulated colonic bicarbonate secretion in Ussing chamber experiments. Accordingly, in isolated colonic crypts pretreated with forskolin and carbachol for 10 min, respectively, and subjected to immunohistochemistry, the NBCe1 signal showed a markedly stronger colocalization with the E-cadherin signal, which was used as a membrane marker, compared with the untreated control. Cytochalasin D did not change the observed increase in membrane abundance, whereas colchicine alone enhanced NBCe1 membrane expression without an additional increase after carbachol or forskolin, and LY294002 had a marked inhibitory effect. Taken together, our results demonstrate a secretagogue-induced increase of NBCe1 membrane expression. Vesicle traffic and exocytosis might thus represent a novel mechanism of intestinal NBC activation by secretagogues. PMID- 19779012 TI - Cystitis increases colorectal afferent sensitivity in the mouse. AB - Studies in humans and rodents suggest that colon inflammation promotes urinary bladder hypersensitivity and, conversely, that cystitis contributes to colon hypersensitivity, events referred to as cross-organ sensitization. To investigate a potential peripheral mechanism, we examined whether cystitis alters the sensitivity of pelvic nerve colorectal afferents. Male C57BL/6 mice were treated with cyclophosphamide (CYP) or saline, and the mechanosensitive properties of single afferent fibers innervating the colorectum were studied with an in vitro preparation. In addition, mechanosensitive receptive endings were exposed to an inflammatory soup (IS) to study sensitization. Urinary bladder mechanosensitive afferents were also tested. We found that baseline responses of stretch-sensitive colorectal afferents did not differ between treatment groups. Whereas IS excited a proportion of colorectal afferents CYP treatment did not alter the magnitude of this response. However, the number of stretch-sensitive fibers excited by IS was increased relative to saline-treated mice. Responses to IS were not altered by CYP treatment, but the proportion of IS-responsive fibers was increased relative to saline-treated mice. In bladder, IS application increased responses of muscular afferents to stretch, although no differences were detected between saline- and CYP-treated mice. In contrast, their chemosensitivity to IS was decreased in the CYP-treated group. Histological examination revealed no changes in colorectum and modest edema and infiltration in the urinary bladder of CYP treated mice. In conclusion, CYP treatment increased mechanical sensitivity of colorectal muscular afferents and increased the proportion of chemosensitive colorectal afferents. These data support a peripheral contribution to cross-organ sensitization of pelvic organs. PMID- 19779013 TI - Human duodenum responses to vitamin D metabolites of TRPV6 and other genes involved in calcium absorption. AB - Calcium absorption by the intestine is necessary for bone mineralization. Much has been learned about this process and the role of vitamin D metabolites in gene transcription from animal studies, but the molecular mechanisms in humans are less well understood. We have used samples of normal human duodenal mucosa, obtained at endoscopy, to investigate the effects of the vitamin D metabolites, 1alpha-dihydroxycholecalciferol [1,25(OH)(2)D(3)] and 25-hydroxycholecalciferol (25OHD), on transcripts on genes involved in calcium absorption and vitamin D metabolism. TRPV6 transcripts were significantly higher after incubation for 6 h with 1,25(OH)(2)D(3) (10(-9) mol/l) than after control incubations (median difference 3.1-fold, P < 0.001). Unexpectedly, TRPV6 expression was also higher (2.4-fold, P < 0.02) after incubation with 25OHD (10(-7) mol/l). Transcripts for the calcium-ATPase, PMCA1, were significantly higher with 1,25(OH)(2)D(3); CYP24 transcripts were reliably detected after incubation with either metabolite, but calbindin-D9k transcripts were unaffected. The response of TRPV6 to 25OHD and the expression of transcripts for CYP27B1, the 25OHD-1alpha-hydroxylase, were significantly correlated (r = 0.82, P < 0.02). Basal duodenal expression of TRPV6 and CYP27B1 were significantly associated (r = 0.72, P < 0.001) in a separate previously reported series of subjects. Multiple regression analysis of the associations with basal duodenal TRPV6 expression identified CYP27B1 expression and serum 1,25(OH)(2)D as major factors. Expression of the CYP27B1 protein was demonstrated immunohistochemically in duodenal mucosa. This study has shown that human duodenal TRPV6, PMCA1, and CYP24 transcripts respond rapidly to 1,25(OH)(2)D(3) and provides evidence suggesting that local duodenal production of 1,25(OH)(2)D(3) by 25OHD-1alpha-hydroxylase may have a role in human calcium absorption. PMID- 19779014 TI - Alternative promoter and GATA5 transcripts in mouse. AB - GATA5 is a member of the GATA zinc finger transcription factor family involved in tissue-specific transcriptional regulation during cell differentiation and embryogenesis. Previous reports indicate that null mutation of the zebrafish GATA5 gene results in embryonic lethality, whereas deletion of exon 1 from the mouse GATA5 gene causes only derangement of female urogenital development. Here, we have identified an alternate promoter within intron 1 of the mouse GATA5 gene that transcribes a 2.5-kb mRNA that lacks exon 1 entirely but includes 82 bp from intron 1 and all of exons 2-6. The alternative promoter was active during transient transfection in cultured airway myocytes and bronchial epithelial cells, and it drove reporter gene expression in gastric epithelial cells in transgenic mice. The 2.5-kb alternative transcript encodes an NH(2)-terminally truncated "short GATA5" comprising aa 226-404 with a single zinc finger, which retains ability to transactivate the atrial natriuretic factor promoter (albeit less efficiently than full-length GATA5). Another new GATA5 transcript contains all of exons 1-5 and the 5' portion of exon 6 but lacks the terminal 1143 bp of the 3'-untranslated region from exon 6. These findings extend current understanding of the tissue distribution of GATA5 expression and suggests that GATA5 expression and function are more complex than previously appreciated. PMID- 19779015 TI - Stimulation of stellate cells by injured acinar cells: a model of acute pancreatitis induced by alcohol and fat (VLDL). AB - Mechanisms leading to acute pancreatitis after a fat-enriched meal combined with excess alcohol are incompletely understood. We have studied the effects of alcohol and fat (VLDL) on pancreatic acinar cell (PAC) function, oxidative stress, and repair mechanisms by pancreatic stellate cells (PSC) leading to fibrogenesis. To do so, PAC (rat) were isolated and cultured up to 24 h. Ethanol and/or VLDL were added to PAC. We measured PAC function (amylase, lipase), injury (lactic dehydrogenase), apoptosis (TUNEL, Apo2.7, annexin V binding), oxidative stress, and lipid peroxidation (conjugated dienes, malondialdehyde, chemoluminescence); we also measured PSC proliferation (bromodeoxyuridine incorporation), matrix synthesis (immunofluorescence of collagens and fibronectin, fibronectin immunoassay), and fatty acids in PAC supernatants (gas chromatography). Within 6 h, cultured PAC degraded and hydrolyzed VLDL completely. VLDL alone (50 microg/ml) and in combination with alcohol (0.2, 0.5, and 1% vol/vol) induced PAC injury (LDL, amylase, and lipase release) within 2 h through generation of oxidative stress. Depending on the dose of VLDL and alcohol, apoptosis and/or necrosis were induced. Antioxidants (Trolox, Probucol) reduced the cytotoxic effect of alcohol and VLDL. Supernatants of alcohol/VLDL treated PAC stimulated stellate cell proliferation and extracellular matrix synthesis. We concluded that, in the presence of lipoproteins, alcohol induces acinar cell injury. Our results provide a biochemical pathway for the clinical observation that a fat-enriched meal combined with excess alcohol consumption can induce acinar cell injury (acute pancreatitis) followed by repair mechanisms (proliferation and increased matrix synthesis in PSC). PMID- 19779016 TI - Angiotensin II receptors are expressed and functional in human esophageal mucosa. AB - Only few studies have been devoted to the actions of the renin-angiotensin system (RAS) in the human gastrointestinal tract. The present study was undertaken to elucidate the expression and action of RAS in the human esophageal mucosa. Mucosal specimens with normal histological appearance were obtained from healthy subjects undergoing endoscopy and from patients undergoing esophagectomy due to neoplasm. Gene and protein expressions of angiotensin II (Ang II) receptor type 1 (AT(1)) and type 2 (AT(2)) and angiotensin-converting enzyme (ACE) were analyzed. In vivo functionality in healthy volunteers was reflected by assessing transmucosal potential difference (PD). Ussing chamber technique was used to analyze the different effects of Ang II on its AT(1) and AT(2) receptors. Immunoreactivity to AT(1) and AT(2) was localized to stratum superficiale and spinosum in the epithelium. ACE, AT(1), and AT(2) were found in blood vessel walls. Transmucosal PD in vivo increased following administration of the AT(1) receptor antagonist candesartan. In Ussing preparations mean basal transmural PD was -6.4 mV, epithelial current (I(ep)) 34 muA/cm(2), and epithelial resistance (R(ep)) 321 Omega.cm(2). Serosal exposure to Ang II increased PD as a result of increased I(ep), whereas R(ep) was constant. Ang II given together with the selective AT(1)-receptor antagonist losartan, or AT(2) agonist C21 given alone, resulted in a similar effect. Ang II given in presence of the AT(2)-receptor antagonist PD123319 did not influence PD, but I(ep) decreased and R(ep) increased. In conclusion, Ang II receptors and ACE are expressed in the human esophageal epithelium. The results suggest that AT(2)-receptor stimulation increases epithelial ion transport, whereas the AT(1) receptor inhibits ion transport and increases R(ep). PMID- 19779017 TI - Polysome trafficking of transcripts and microRNAs in regenerating liver after partial hepatectomy. AB - Liver regeneration after 70% partial hepatectomy (PH) in rats induces >95% of hepatocytes to undergo two rounds of semisynchronous cell replication. Gene expression is controlled primarily by posttranscriptional processing, including changes in mRNA stability. However, the translational activity of a specific mRNA can also be modulated after PH, resulting in significant uncoupling of protein and transcript levels relative to quiescent liver for many genes including c-myc and p53. Although the precise mechanism by which this uncoupling occurs is unknown, the polysomal association of mRNA and microRNA (miRNA) can significantly modulate rate of decay as well as translational activity. Thus we characterized the association of c-myc and p53 mRNAs and miRNAs in free and cytoskeleton- and membrane-bound polysome populations 3, 6, and 24 h after PH. The transcripts for c-myc and p53 were differentially distributed in the three discrete polysome populations, and this was dramatically modulated during liver regeneration. Nascent polysome-associated p53 and c-myc proteins were also differentially expressed in the free and cytoskeleton- and membrane-bound polysomes and significantly uncoupled from transcript levels relative to nonresected liver. At least 85 miRNAs were associated with the three polysome populations, and their abundance and distribution changed significantly during liver regeneration. These data suggest that posttranscriptional control of c-myc and p53 protein expression is associated with the translocation of transcripts between the different polyribosomes. The alteration of expression for the same transcript in different polysome populations may, in part, be due to the action of miRNAs. PMID- 19779018 TI - Galanin potentiates supramaximal caerulein-stimulated pancreatic amylase secretion via its action on somatostatin secretion. AB - Galanin inhibits pancreatic amylase secretion from mouse lobules induced by physiological concentrations of caerulein via an insulin-dependent mechanism. We aimed to determine the effect and elucidate the mechanism of action of exogenous galanin on pancreatic amylase secretion induced by supramaximal concentrations of caerulein. Amylase secretion from isolated murine pancreatic lobules was measured. Lobules were coincubated with galanin (10(-12)-10(-7) M) and caerulein (10(-7) M). Lobules were preincubated with atropine (10(-5) M), tetrodotoxin (10( 5) M), diazoxide (10(-7) M), or the galanin antagonist galantide (10(-12)-10(-7) M) for 30 min followed by incubation with caerulein alone, or combined with galanin (10(-12) M). Lobules were also coincubated with combinations of galanin (10(-12) M), caerulein, octreotide (10(-12)-10(-7) M) or cyclo-(7-aminoheptanoyl Phe-D-Trp-Lys-Thr[BZL]), a somatostatin receptor antagonist (10(-9) M). Amylase secretion was expressed as percent of total lobular amylase. Caerulein stimulated amylase secretion to 124% of control. Diazoxide pretreatment abolished the caerulein-stimulated amylase secretion, whereas atropine or tetrodotoxin caused a partial inhibition. Galanin (10(-12)-10(-7) M) potentiated caerulein-stimulated amylase secretion to 160% of control. Preincubation with a combination of atropine and diazoxide abolished the potentiating effect of galanin, indicating muscarinic receptor and insulin mediation. Preincubation with galantide abolished the galanin effect, implying galanin receptor involvement. Coincubation with caerulein, galanin, and octreotide significantly reduced the potentiating effect galanin. However, coincubation with the somatostatin receptor antagonist, alone or in combination with galanin, significantly increased caerulein-stimulated amylase secretion to a level comparable to the galanin potentiation. Taken together, these data suggest that, at supramaximal caerulein concentrations, galanin acts via its receptors to further increase caerulein-stimulated amylase secretion by inhibiting the caerulein-induced release of somatostatin. PMID- 19779019 TI - Spontaneous oscillations in intracellular Ca(2+) concentration via purinergic receptors elicit transient cell swelling in rat parotid ducts. AB - Using multiphoton microscopy, we established that rat parotid ductal cells exhibit spontaneous oscillations in intracellular Ca(2+) concentration ([Ca(2+)](i)). These oscillatory Ca(2+) responses were observed during continuous perfusion with a physiological salt solution at 37 degrees C in the absence of calcium mobilizing agonist stimulation. The timing and patterns of these spontaneous Ca(2+) oscillations varied among individual ductal cells, and the average number of Ca(2+) responses in a single responding ductal cell was 2.1 in a 10-min recording period. High-speed scanning (0.6 s/image) revealed that most spontaneous elevations in [Ca(2+)](i) were initiated at the luminal side of ductal cells and spread toward the basal side within 2 s. Electron microscopic analysis after Ca(2+) imaging indicated that spontaneously oscillating ducts contained numerous granules at the luminal side, which is characteristic of granular ducts. These Ca(2+) oscillations were completely blocked by the purinergic receptor inhibitors 4-[[4-formyl-5-hydroxy-6-methyl-3 [(phosphonooxy)methyl]-2-pyridinyl]azo]-1,3-benzenedisulfonic acid (PPADS) and suramin but were not blocked by the muscarinic antagonist atropine or the alpha adrenergic antagonist phentolamine. Simultaneous observation of fura-2 fluorescence and differential interference contrast (DIC) images showed that spontaneous elevations of [Ca(2+)](i) were well correlated with changes in shape of ductal cells. Using a plasma membrane fluorescence probe, SynaptoGreen C4, we found that the changes in DIC images reflected spontaneous cell swelling of ductal cells. Our findings present the possibility that purinergic receptors mediate spontaneous Ca(2+) oscillations in parotid ductal cells and regulate electrolyte reabsorption from the primary saliva in the resting state. PMID- 19779020 TI - Immunoglobulins from scleroderma patients inhibit the muscarinic receptor activation in internal anal sphincter smooth muscle cells. AB - Systemic sclerosis (SSc) IgGs affecting the M(3)-muscarinic receptor (M(3)-R) have been proposed to be responsible for the gastrointestinal (GI) dysmotility in this disease. However, the effect of SSc IgGs on smooth muscle cell (SMC) function has not been studied. We determined the effect of SSc IgGs on the muscarinic receptor activation by bethanechol (BeCh; methyl derivate of carbachol) in SMC and smooth muscle strips from rat internal anal sphincter. IgGs were purified from GI-symptomatic SSc patients and normal volunteers, with protein G-Sepharose columns. SMC lengths were determined via computerized digital micrometry. The presence of M(3)-R and IgG-M(3)-R complex was determined by Western blot. IgGs from SSc patients but not from normal volunteers caused significant and concentration-dependent inhibition of BeCh response (P < 0.05). The maximal shortening of 22.2 +/- 1.2% caused by 10(-4) M BeCh was significantly attenuated to 8.3 +/- 1.2% by 1 mg/ml of SSc IgGs (P < 0.05). Experiments performed in smooth muscle strips revealed a similar effect of SSc IgG that was fully reversible. In contrast to the effect on BeCh, the SSc IgGs caused no significant effect (P > 0.05) on K(+) depolarization and alpha(1)-adrenoceptor activation by phenylephrine. Western blot studies revealed the specific presence of SSc IgG-M(3)-R complex. SSc IgGs attenuated M(3)-R activation, which was reversible with antibody removal. These data suggest that SSc GI dysmotility may be caused by autoantibodies that inhibit the muscarinic neurotransmission. Future treatment of SSc patients may be directed at the removal or neutralization of these antibodies. PMID- 19779021 TI - TLR3-mediated NF-{kappa}B signaling in human esophageal epithelial cells. AB - Despite its position at the front line against ingested pathogens, very little is presently known about the role of the esophageal epithelium in host innate immune defense. As a key player in the innate immune response, Toll-like receptor (TLR) signaling has not been well characterized in human esophageal epithelial cells. In the present study, we investigated the inflammatory response and signaling pathways activated by TLR stimulation of human esophageal cells in vitro. Using quantitative RT-PCR, we profiled the expression pattern of human TLRs 1-10 in primary esophageal keratinocytes (EPC2), immortalized nontransformed esophageal keratinocytes (EPC2-hTERT), and normal human esophageal mucosal biopsies and found that TLRs 1, 2, 3, and 5 were expressed both in vivo and in vitro. Using the cytokine IL-8 as a physiological read out of the inflammatory response, we found that TLR3 is the most functional of the expressed TLRs in both primary and immortalized esophageal epithelial cell lines in response to its synthetic ligand polyinosinic polycytidylic acid [poly(I:C)]. Through reporter gene studies, we show that poly(I:C)-induced NF-kappaB activation is critical for the transactivation of the IL-8 promoter in vitro and that nuclear translocation of NF-kappaB occurs at an early time point following poly(I:C) stimulation of esophageal epithelial cells. Importantly, we also show that poly(I:C) stimulation induces the NF-kappaB-dependent esophageal epithelial expression of TLR2, leading to enhanced epithelial responsiveness of EPC2-hTERT cells to TLR2 ligand stimulation, suggesting an important regulatory role for TLR3-mediated NF-kappaB signaling in the innate immune response of esophageal epithelial cells. Our findings demonstrate for the first time that TLR3 is highly functional in the human esophageal epithelium and that TLR3-mediated NF-kappaB signaling may play an important regulatory role in esophageal epithelial homeostasis. PMID- 19779022 TI - FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. AB - Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22 q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5' and 3' of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies. PMID- 19779023 TI - Mutant SOD1 in neuronal mitochondria causes toxicity and mitochondrial dynamics abnormalities. AB - Amyotrophic lateral sclerosis (ALS) is a fatal neurological disorder characterized by motor neuron degeneration. Mutations in Cu,Zn-superoxide dismutase (SOD1) are responsible for 20% of familial ALS cases via a toxic gain of function. In mutant SOD1 transgenic mice, mitochondria of spinal motor neurons develop abnormal morphology, bioenergetic defects and degeneration, which are presumably implicated in disease pathogenesis. SOD1 is mostly a cytosolic protein, but a substantial portion is associated with organelles, including mitochondria, where it localizes predominantly in the intermembrane space (IMS). However, whether mitochondrial mutant SOD1 contributes to disease pathogenesis remains to be elucidated. We have generated NSC34 motor neuronal cell lines expressing wild-type or mutant SOD1 containing a cleavable IMS targeting signal to directly investigate the pathogenic role of mutant SOD1 in mitochondria. We show that mitochondrially-targeted SOD1 localizes to the IMS, where it is enzymatically active. We prove that mutant IMS-targeted SOD1 causes neuronal toxicity under metabolic and oxidative stress conditions. Furthermore, we demonstrate for the first time neurite mitochondrial fragmentation and impaired mitochondrial dynamics in motor neurons expressing IMS mutant SOD1. These defects are associated with impaired maintenance of neuritic processes. Our findings demonstrate that mutant SOD1 localized in the IMS is sufficient to determine mitochondrial abnormalities and neuronal toxicity, and contributes to ALS pathogenesis. PMID- 19779024 TI - Interaction of child maltreatment and 5-HTT polymorphisms: suicidal ideation among children from low-SES backgrounds. AB - OBJECTIVE: To investigate whether genotypic variation of the serotonin transporter gene-linked promoter region (5-HTTLPR) moderates the effect of maltreatment on suicidal ideation in school-aged children. METHODS: Eight hundred and fifty low-income children (478 maltreated; 372 non-maltreated) provided DNA samples and self-reported depressive and suicidal symptoms. Genotypes of 5-HTTLPR (s/s or s/l vs. l/l) were determined by fragment analyses. RESULTS: Higher suicidal ideation was found among maltreated than non-maltreated children; the groups did not differ in 5-HTTLPR genotype frequencies. Children with one to two maltreatment subtypes and s/s or s/l genotypes had higher suicidal ideation than those with the l/l genotype; suicidal ideation did not differ in non-maltreated children or children with three to four maltreatment subtypes based on 5-HTTLPR variation. The results were applicable to emotionally maltreated/neglected and to physically/sexually abused children. Gene-environment interaction was not found for depressive symptoms. CONCLUSION: The protective effect of the 5-HTTLPR l/l genotype on suicidal ideation was limited to maltreated children experiencing fewer subtypes. PMID- 19779025 TI - Short-term treatment with olanzapine does not modulate gut hormone secretion: olanzapine disintegrating versus standard tablets. AB - BACKGROUND: Treatment with olanzapine (atypical antipsychotic drug) is frequently associated with various metabolic anomalies, including obesity, dyslipidemia, and diabetes mellitus. Recent data suggest that olanzapine orally disintegrating tablets (ODT), which dissolve instantaneously in the mouth, might cause less weight gain than olanzapine standard oral tablets (OST). DESIGN AND METHODS: Ten healthy men received olanzapine ODT (10 mg o.d., 8 days), olanzapine OST (10 mg o.d., 8 days), or no intervention in a randomized crossover design. At breakfast and dinner, blood samples were taken for measurement of pancreatic polypeptide, peptide YY, glucagon-like peptide-1, total glucagon, total ghrelin, and cholecystokinin (CCK) concentrations. RESULTS: With the exception of pre- and postprandial concentration of ghrelin at dinner and preprandial CCK concentrations at breakfast, which were all slightly increased (respectively P=0.048, P=0.034 and P=0.042), olanzapine did not affect gut hormone concentrations. Thus, olanzapine ODT and OST had similar effects on gut hormone secretion. CONCLUSION: Short-term treatment with olanzapine does not have major impact on the plasma concentration of gut hormones we measured in healthy men. Moreover, despite pharmacological difference, gut hormone concentrations are similar during treatment with olanzapine ODT and OST. The capacity of olanzapine to induce weight gain and diabetes is unlikely to be caused by modulation of the secretion of gut hormones measured here. We cannot exclude the possibility that olanzapine's impact on other gut hormones, to impair insulin sensitivity and stimulate weight gain, exists. PMID- 19779026 TI - Association of myocardial infarctions with COX-2 inhibition may be related to immunomodulation towards a Th1 response resulting in atheromatous plaque instability: an evidence-based interpretation. AB - Cyclooxygenase (COX) inhibitors remain a major class of drugs in rheumatology and their widespread use is expected to continue. The view that a prothrombotic effect explains the increase in myocardial infarction (MI) associated with both COX-2 selective and traditional NSAIDs (tNSAIDs) has been increasingly questioned. We review the evidence that prostanoids direct the immune response away from a Th1 response and that consequently inhibition of prostaglandin synthesis results in augmentation of the Th1 response by limiting prostanoid synthesis. Although the role of prostanoids as mediators of inflammation in the periphery is well understood, the systemic immunomodulatory role of prostanoids shifting the immune response away from a Th1 type is less appreciated. Atherosclerosis is an inflammatory arterial disease driven by a Th1 type immune response. Moreover, the vulnerable phenotype of atheroma is associated with the cellular Th1 immune response in contrast to the stable plaque phenotype associated with a Th2 type response. We propose a class effect of COX-2 selective and tNSAIDs, which results in augmentation of Th1-mediated atherogenesis/ production of pro-atherogenic cytokines associated with detrimental plaque remodeling, instability, rupture and embolization resulting in MI. Understanding of the Th1 mediated immunity, which underlies the cardiovascular, and the non Th1, which underlies gastrointestinal adverse effects associated with the use of COX inhibitors, should lead to better risk assessment and the development of anti inflammatory treatments with improved safety. Our explanation also emphasizes the pharmacological effects and consequences of immunomodulation in the inflammation associated with atherosclerosis and other Th1- as well as non-Th1-driven diseases. PMID- 19779027 TI - Numerical scoring for the Classic BILAG index. AB - OBJECTIVE: To develop an additive numerical scoring scheme for the Classic BILAG index. METHODS: SLE patients were recruited into this multi-centre cross sectional study. At every assessment, data were collected on disease activity and therapy. Logistic regression was used to model an increase in therapy, as an indicator of active disease, by the Classic BILAG score in eight systems. As both indicate inactivity, scores of D and E were set to 0 and used as the baseline in the fitted model. The coefficients from the fitted model were used to determine the numerical values for Grades A, B and C. Different scoring schemes were then compared using receiver operating characteristic (ROC) curves. Validation analysis was performed using assessments from a single centre. RESULTS: There were 1510 assessments from 369 SLE patients. The currently used coding scheme (A = 9, B = 3, C = 1 and D/E = 0) did not fit the data well. The regression model suggested three possible numerical scoring schemes: (i) A = 11, B = 6, C = 1 and D/E = 0; (ii) A = 12, B = 6, C = 1 and D/E = 0; and (iii) A = 11, B = 7, C = 1 and D/E = 0. These schemes produced comparable ROC curves. Based on this, A = 12, B = 6, C = 1 and D/E = 0 seemed a reasonable and practical choice. The validation analysis suggested that although the A = 12, B = 6, C = 1 and D/E = 0 coding is still reasonable, a scheme with slightly less weighting for B, such as A = 12, B = 5, C = 1 and D/E = 0, may be more appropriate. CONCLUSIONS: A reasonable additive numerical scoring scheme based on treatment decision for the Classic BILAG index is A = 12, B = 5, C = 1, D = 0 and E = 0. PMID- 19779028 TI - Autoimmunity and atherosclerosis: the presence of antinuclear antibodies is associated with decreased carotid elasticity in young women. The Cardiovascular Risk in Young Finns Study. AB - OBJECTIVE: There is ample evidence demonstrating that accelerated atherosclerosis prevails in autoimmune rheumatic diseases, particularly in SLE, and that the risk is due not only to traditional cardiovascular risk factors but also to the disease itself. ANAs are a hallmark of SLE and are known even to antedate the development of SLE. Our aim was to investigate whether positive ANAs in young adults are associated with risk factors for atherosclerosis or subclinical markers of atherosclerosis. METHODS: ANAs were examined by IIF using HEp-2 cells as substrate in 2278 participants in the Cardiovascular Risk in Young Finns Study for whom detailed data on cardiovascular risk factors and markers of subclinical atherosclerosis (including brachial flow-mediated dilatation, carotid compliance and carotid intima-media thickness) were available. RESULTS: In multivariate analyses, adjusted for age, BMI, serum concentrations of CRP, triglycerides, high density lipoprotein and low-density lipoprotein cholesterol, blood pressure and smoking habits, ANA positivity (titre > 160) was inversely associated (beta = 0.145; P = 0.034) with carotid compliance in women. CONCLUSIONS: Our results indicate that ANA positivity is associated with decreased carotid elasticity in women, suggesting that mechanisms resulting in ANA production may be involved in the development of early atherosclerosis. PMID- 19779029 TI - A quadruplex real-time PCR assay for rapid detection and differentiation of the Clostridium botulinum toxin genes A, B, E and F. AB - Clostridium botulinum is the aetiological agent of botulism, a disease marked by flaccid paralysis that can progress to asphyxiation and death. This species is defined by the production of one of the botulinum neurotoxins (BoNTs), which are the most potent toxins known. Because of their potency, these toxins have the potential to be used as biological weapons, and therefore C. botulinum has been classified as a category A select agent. There are four related but antigenically distinct BoNT types that cause disease in humans, A, B, E and F. The mouse bioassay is the current gold standard by which BoNTs are confirmed. However, this method is expensive, slow and labour-intensive. Although PCR-based assays have been used extensively for the detection of BoNT-producing bacteria in food, animals and faecal samples, and recently to help diagnose disease in humans, no real-time quantitative PCR (qPCR) assay has yet been developed that can identify and differentiate all four BoNTs that cause disease in humans. This report describes the development of a qPCR single-tube assay that uniquely identifies these four BoNTs responsible for human disease. A total of 79 C. botulinum isolates with varying toxin types was evaluated in this study, as well as numerous near-neighbours and other bacterial species. The results showed that this quadruplex assay was capable of detecting any of the four toxin genes in a given sample at a sensitivity of about 130-840 fg genomic DNA and could detect the presence of up to all four BoNT genes simultaneously in a given sample. The assay was also functional in the presence of extraneous organic matter commonly found in various environmental samples. PMID- 19779030 TI - Evaluation of internal transcribed spacer 2-RFLP analysis for the identification of dermatophytes. AB - A total of 95 isolates, belonging to 33 species of five dermatophyte genera, i.e. Arthroderma (15 species), Chrysosporium (two), Epidermophyton (one), Microsporum (three) and Trichophyton (12), were studied using internal transcribed spacer 2 (ITS2)-PCR-RFLP analysis (ITS2-RFLP), consisting of amplification of the ITS2 region, restriction digestion with BstUI (CG/CG) and restriction fragment length determination by capillary electrophoresis. ITS2-RFLP analysis proved to be most useful for identification of species of the genera Arthroderma, Chrysosporium and Epidermophyton, but could not distinguish between several Trichophyton species. The identification results are in agreement with established and recent taxonomical insights into the dermatophytes; for example, highly related species also had closely related and sometimes difficult-to-discriminate ITS2-RFLP patterns. In some cases, several ITS2-RFLP groups could be distinguished within species, again mostly in agreement with the taxonomic delineations of subspecies and/or genomovars, confirming the relevance of ITS2-RFLP analysis as an identification technique and as a useful taxonomic approach. PMID- 19779031 TI - VopF, a type III effector protein from a non-O1, non-O139 Vibrio cholerae strain, demonstrates toxicity in a Saccharomyces cerevisiae model. AB - VopF, a type III effector protein, has been identified as a contributory factor to the intestinal colonization of type III secretion system-positive, non-O1, non O139 Vibrio cholerae strains. To gain more insight into the function of VopF, a yeast model was developed. Using this model, it was found that ectopic expression of VopF conferred toxicity in yeast. PMID- 19779032 TI - An anticancer effect of curcumin mediated by down-regulating phosphatase of regenerating liver-3 expression on highly metastatic melanoma cells. AB - Phosphatase of regenerating liver-3 (PRL-3) has been suggested as a potential target for anticancer drugs based on its involvement in tumor metastasis. However, little is known about a small-molecule inhibitor against PRL-3. In this study, we report that curcumin, the component of the spice turmeric, shows its antitumor effect by selectively down-regulating the expression of PRL-3 but not its family members PRL-1 and -2 in a p53-independent way. Curcumin inhibited the phosphorylation of Src and stat3 partly through PRL-3 down-regulation. Cells with PRL-3 stably knocked down show less sensitivity to curcumin treatment, which reveals that PRL-3 is the much further upstream target of curcumin. Curcumin treatment also remarkably prevented B16BL6 from invading the draining lymph nodes in the spontaneous metastatic tumor model, which is probably of relevance to PRL 3 down-regulation. Our results reveal a novel capacity of curcumin to down regulate oncogene PRL-3, raising its possibility in therapeutic regimen against malignant tumor. PMID- 19779033 TI - Agonists and allosteric modulators of the calcium-sensing receptor and their therapeutic applications. AB - The calcium-sensing receptor (CaR) belongs to the G protein-coupled receptor superfamily, with a characteristic structure consisting of seven transmembrane helices, an intracellular C-terminal and an extracellular N terminal domain. The primary physiological function of the CaR is the maintenance of constant blood Ca2+ levels, as a result of its ability to sense very small changes in extracellular Ca2+ (Ca2+(o)). Nevertheless, in addition to being expressed in tissues involved in Ca2+(o) homeostasis, the CaR is also expressed in tissues not involved in mineral homeostasis, suggestive of additional physiological functions. Numerous agonists and modulators of the CaR are now known in addition to Ca2+(o), including various divalent and trivalent cations, aromatic l-amino acids, polyamines, and aminoglycoside antibiotics. The signaling of the CaR is also regulated by extracellular pH and ionic strength. The activated CaR couples mainly to the phospholipase Cbeta and extracellular signal-regulated kinase 1/2 signaling pathways, and it decreases intracellular cAMP levels, leading to various physiological effects. The recent identification of synthetic allosteric modulators of the CaR has opened up a new field of research possibilities. Calcimimetics and calcilytics, which increase and decrease agonist signaling via the CaR, respectively, may facilitate the manipulation of the CaR and thus aid in further investigations of its precise signaling. These allosteric modulators, as well as strontium, have been demonstrated to have therapeutic potential for the treatment of disorders involving the CaR. This review discusses the various agonists and modulators of the CaR, differences in their binding and signaling, and their roles as therapeutics in various diseases. PMID- 19779034 TI - MicroRNAs and prostate cancer. AB - Despite much progress in prostate cancer management, new diagnostic, prognostic and therapeutic tools are needed to predict disease severity, choose among the available treatments and establish more effective therapies for advanced prostate cancer. In the last few years, compelling evidence has documented the role of microRNAs as new broad-spectrum oncogenes or tumour suppressor genes, thus their use as diagnostic, prognostic and therapeutic biomolecules is envisaged. This review extensively and critically summarizes the current knowledge about microRNA deregulation in prostate cancer disease, underlining present limits and future perspectives. PMID- 19779035 TI - The role of let-7 in cell differentiation and cancer. AB - MicroRNAs (miRNAs or miRs) are small noncoding RNAs capable of regulating gene expression at the translational level. Current evidence suggests that a significant portion of the human genome is regulated by microRNAs, and many reports have demonstrated that microRNA expression is deregulated in human cancer. The let-7 family of microRNAs, first discovered in Caenorhabditis elegans, is functionally conserved from worms to humans. The human let-7 family contains 13 members located on nine different chromosomes, and many human cancers have deregulated let-7 expression. A growing body of evidence suggests that restoration of let-7 expression may be a useful therapeutic option in cancers, where its expression has been lost. In this review, we discuss the role of let-7 in normal development and differentiation, and provide an overview of the relationship between deregulated let-7 expression and tumorigenesis. The regulation of let-7 expression, cancer-relevant let-7 targets, and the relationship between let-7 and drug sensitivity are highlighted. PMID- 19779037 TI - Pharmacokinetics and pharmacodynamics of a bolus and infusion of cangrelor: a direct, parenteral P2Y12 receptor antagonist. AB - The purpose of this study is to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of cangrelor administered as an intravenous bolus plus a continuous infusion in healthy volunteers. Twenty-two healthy volunteers are randomized to receive 1 of 2 intravenous cangrelor dosing regimens: a 15-microg/kg bolus followed by a 2-microg/kg/min infusion or a 30 microg/kg bolus followed by a 4-microg/kg/min infusion. The infusion is continued for 60 minutes, and serial blood samples are obtained for evaluation of pharmacokinetic and pharmacodynamic parameters. Administration of an intravenous bolus followed by a continuous infusion rapidly achieves maximum concentrations of cangrelor that are associated with extensive platelet inhibition within 2 minutes. Moreover, extensive platelet inhibition is maintained throughout the infusion period with near-full recovery of platelet function within 60 to 90 minutes of terminating the infusion. The effect of high-dose cangrelor is more consistent and demonstrates a greater level of inhibition on adenosine diphosphate-induced P-selectin expression; how ever, no significant differences are observed between the 2 dosing regimens with regard to platelet aggregation or time to recovery of platelet function. Cangrelor administered as an intravenous bolus followed by a continuous infusion in healthy volunteers offers rapid and reversible inhibition of platelet function. PMID- 19779036 TI - Intracellular expression of reactive oxygen species-generating NADPH oxidase NOX4 in normal and cancer thyroid tissues. AB - NADPH oxidase 4 (NOX4) belongs to the NOX family that generates reactive oxygen species (ROS). Function and tissue distribution of NOX4 have not yet been entirely clarified. To date, in the thyroid gland, only DUOX1/2 NOX systems have been described. NOX4 mRNA expression, as shown by real-time PCR, was present in normal thyroid tissue, regulated by TSH and significantly increased in differentiated cancer tissues. TSH increased the protein level of NOX4 in human thyroid primary culture and NOX4-dependent ROS generation. NOX4 immunostaining was detected in normal and pathologic thyroid tissues. In normal thyroid tissue, staining was heterogeneous and mostly found in activated columnar thyrocytes but absent in quiescent flat cells. Papillary and follicular thyroid carcinomas displayed more homogeneous staining. The p22(phox) protein that forms a heterodimeric enzyme complex with NOX4 displayed an identical cellular expression pattern and was also positively regulated by TSH. ROS may have various biological effects, depending on the site of production. Intracellular NOX4-p22(phox) localization suggests a role in cytoplasmic redox signaling, in contrast to the DUOX localization at the apical membrane that corresponds to an extracellular H(2)O(2) production. Increased NOX4-p22(phox) in cancer might be related to a higher proliferation rate and tumor progression but a role in the development of tumors has to be further studied and established in the future. PMID- 19779038 TI - Pharmacokinetics and safety of sunitinib malate in subjects with impaired renal function. AB - This phase I, open-label, single-dose study evaluates the effects of severe renal impairment and end-stage renal disease (ESRD) requiring hemodialysis on the pharmacokinetics, safety, and tolerability of sunitinib and its primary active metabolite, SU12662. Subjects with normal renal function (creatinine clearance > 80 mL/min), severe renal impairment (creatinine clearance < 30 mL/min), and ESRD requiring hemodialysis receive a single dose of sunitinib 50 mg. Serial blood samples are collected for quantification of plasma concentrations using a validated liquid chromatography with tandem mass spectrometry assay. Safety is monitored. Twenty-four subjects complete the study. Pharmacokinetics in subjects with severe renal impairment appear similar to those with normal renal function. Plasma exposure to sunitinib and SU12662 appears lower in subjects with ESRD compared with subjects with normal renal function or severe renal impairment. Single-dose sunitinib 50 mg is well tolerated regardless of renal function. The currently approved starting dose of sunitinib 50 mg on Schedule 4/2 is expected to be appropriate for patients with renal impairment; any subsequent dose modifications should be based on patients' ability to tolerate treatment. PMID- 19779039 TI - The transcription factors STAT5A/B regulate GM-CSF-mediated granulopoiesis. AB - Neutrophils play a vital role in the immune defense, which is evident by the severity of neutropenia causing life-threatening infections. Granulocyte macrophage-colony stimulating factor (GM-CSF) controls homeostatic and emergency development of granulocytes. However, little is known about the contribution of the downstream mediating transcription factors signal transducer and activator of transcription 5A and 5B (STAT5A/B). To elucidate the function of this pathway, we generated mice with complete deletion of both Stat5a/b genes in hematopoietic cells. In homeostasis, peripheral neutrophils were markedly decreased in these animals. Moreover, during emergency situations, such as myelosuppression, Stat5a/b-mutant mice failed to produce enhanced levels of neutrophils and were unable to respond to GM-CSF. Both the GM-CSF-permitted survival of mature neutrophils and the generation of granulocytes from granulocyte-macrophage progenitors (GMPs) were markedly reduced in Stat5a/b mutants. GMPs showed impaired colony-formation ability with reduced number and size of colonies on GM CSF stimulation. Moreover, continuous cell fate analyses by time-lapse microscopy and single cell tracking revealed that Stat5a/b-null GMPs showed both delayed cell-cycle progression and increased cell death. Finally, transcriptome analysis indicated that STAT5A/B directs GM-CSF signaling through the regulation of proliferation and survival genes. PMID- 19779040 TI - Dasatinib treatment of chronic-phase chronic myeloid leukemia: analysis of responses according to preexisting BCR-ABL mutations. AB - Dasatinib is a BCR-ABL inhibitor with 325-fold higher potency than imatinib against unmutated BCR-ABL in vitro. Imatinib failure is commonly caused by BCR ABL mutations. Here, dasatinib efficacy was analyzed in patients recruited to phase 2/3 trials with chronic-phase chronic myeloid leukemia with or without BCR ABL mutations after prior imatinib. Among 1043 patients, 39% had a preexisting BCR-ABL mutation, including 48% of 805 patients with imatinib resistance or suboptimal response. Sixty-threedifferent BCR-ABL mutations affecting 49 amino acids were detected at baseline, with G250, M351, M244, and F359 most frequently affected. After 2 years of follow-up, dasatinib treatment of imatinib-resistant patients with or without a mutation resulted in notable response rates (complete cytogenetic response: 43% vs 47%) and durable progression-free survival (70% vs 80%). High response rates were achieved with different mutations except T315I, including highly imatinib-resistant mutations in the P-loop region. Impaired responses were observed with some mutations with a dasatinib median inhibitory concentration (IC(50)) greater than 3nM; among patients with mutations with lower or unknown IC(50), efficacy was comparable with those with no mutation. Overall, dasatinib has durable efficacy in patients with or without BCR-ABL mutations. All trials were registered at http://www.clinicaltrials.gov as NCT00123474, NCT00101660, and NCT00103844. PMID- 19779041 TI - Selectin-mediated activation of endothelial cells induces expression of CCL5 and promotes metastasis through recruitment of monocytes. AB - Hematogenous metastasis is promoted by interactions of tumor cells with leukocytes, platelets, and the endothelium in the local intravascular microenvironment. Here we show that the activation of the microvascular endothelium results in recruitment of monocytes to metastatic tumor cells and promotes the establishment of the metastatic microenvironment. This inflammatory like endothelial response was observed in microvascular endothelial cells only. Microarray analysis of microvascular endothelial cells cocultured with tumor cells in the presence of leukocytes and platelets revealed a specific gene expression profile. Selectin-mediated interactions of tumor cells with platelets and leukocytes activated endothelial cells and induced production of C-C chemokine ligand 5 (CCL5). Inhibition of CCL5-dependent monocyte recruitment during the early phase of metastasis by a CCL5 receptor antagonist strongly reduced tumor cell survival and attenuated metastasis. Collectively, these findings demonstrate that the endothelial expression of CCL5 contributes to the formation of a permissive metastatic microenvironment. PMID- 19779042 TI - NK antibody therapy: KIR-ative intent. PMID- 19779043 TI - "Tax-ing" the cancer stem cell. PMID- 19779044 TI - Missteps in "tango" for epigenome targeting. PMID- 19779045 TI - HIV: getting to the heart of DARCness. PMID- 19779046 TI - Platelet integrin signaling: wherefore art thou? PMID- 19779047 TI - Super factor B-gets atypical HUS. PMID- 19779048 TI - Role of TNFRSF13B variants in patients with common variable immunodeficiency. PMID- 19779049 TI - Identification of monoclonal B-cell lymphocytosis among sibling transplant donors for chronic lymphocytic leukemia patients. PMID- 19779050 TI - The role of CBFbeta in AML1-ETO's activity. PMID- 19779051 TI - Outdoor and indoor falls as predictors of mobility limitation in older women. PMID- 19779052 TI - Re: Jenni Burt, Rosalind Raine. The effect of age on referral to and use of specialist palliative care services in adult cancer patients: a systematic review. Age and Ageing (2006). Received 1 November 2005; accepted in revised form 2 February 2006 (pp. 1-8). PMID- 19779053 TI - Non-pharmacological prevention of delirium. PMID- 19779054 TI - Perceptions of active ageing in Britain: divergences between minority ethnic and whole population samples. AB - OBJECTIVE: to identify perceptions of, and associations with, active ageing among ethnically diverse and homogeneous samples of older people in Britain. DESIGN AND SETTING: cross-sectional and longitudinal surveys of older people living at home in Britain. MEASURES: active ageing, health, psych-social, socio-economic circumstances, and indicators of quality of life. RESULTS: respondents defined active ageing as having health, fitness, and exercise; psychological factors; social roles and activities; independence, neighbourhood and enablers. The ethnically diverse sample respondents were less likely to define active ageing as having physical health and fitness, and were less likely to rate themselves as ageing actively, than more homogeneous sample respondents. The lay-based measure of quality of life used was independently and consistently associated with self rated active ageing in each sample CONCLUSION: Policy models of active ageing were reflected in lay views, although the latter had a more multidimensional focus. Lay definitions of active ageing were also more dynamic, compared with definitions of quality of life and successful ageing. Differences in self-rated active ageing and perceptions of this concept by ethnic group need further exploration. PMID- 19779056 TI - Evaluation of the CSEC Community Intervention Project (CCIP) in five U.S. Cities. AB - In response to the commercial sexual exploitation of children (CSEC) within five U.S. cities, the CSEC Community Intervention Project (CCIP) was created to enhance collaboration among nongovernmental organization (NGO) representatives, law enforcement officials and prosecutors in Chicago, Atlantic City, Denver, Washington, D.C., and San Diego. A total of 211 participants were surveyed during a 3-day CCIP training institute held in each city. Evaluation data suggest that participants were positively influenced in their knowledge, skills, and attitudes regarding CSEC. Our findings inform NGO representatives, law enforcement officials, and prosecutors of the importance of professional training and the benefits of cross-disciplinary collaboration in addressing CSEC. PMID- 19779055 TI - ADHD symptomatology and adjustment to college in China and the United States. AB - This study examined ADHD symptomatology and college adjustment in 420 participants--147 from the United States and 273 from China. It was hypothesized that higher levels of ADHD symptoms in general and the inattentive symptom group in particular would be related to decreased academic and social adjustment, career decision-making self-efficacy, and poorer study skills in both countries. Results generally supported the hypotheses, indicating that the difficulties associated with inattention are cross-cultural and not specific to the United States. PMID- 19779057 TI - Standing with those who seek justice. PMID- 19779058 TI - Socially responsible investing is no "sell out". PMID- 19779059 TI - Views on trying to change the tobacco industry: health justice and marginalization of tobacco companies. PMID- 19779061 TI - Brazil: Sao Paulo takes the lead. PMID- 19779064 TI - Japanese street smoking bans: a Japan Tobacco foil to prevent clean indoor air policy? PMID- 19779065 TI - The tobacco health nexus? Health messages in narghile advertisements. PMID- 19779066 TI - A murine model of myeloma that allows genetic manipulation of the host microenvironment. AB - Multiple myeloma, and the associated osteolytic bone disease, is highly dependent upon cellular interactions within the bone marrow microenvironment. A major limitation of existing myeloma models is the requirement for a specific host strain of mouse, preventing molecular examination of the bone marrow microenvironment. The aim of the current study was to develop a model of myeloma in which the host microenvironment could be modified genetically. The Radl 5T murine model of myeloma is well characterized and closely mimics human myeloma. In the current study, we demonstrate 5T myeloma establishment in recombination activating gene 2 (RAG-2)-deficient mice, which have improper B- and T-cell development. Importantly, these mice can be easily bred with genetically modified mice to generate double knockout mice, allowing manipulation of the host microenvironment at a molecular level. Inoculation of 5TGM1 myeloma cells into RAG-2(-/-) mice resulted in myeloma development, which was associated with tumor growth within bone and an osteolytic bone disease, as assessed by microcomputed tomography (microCT), histology and histomorphometry. Myeloma-bearing RAG-2(-/-) mice displayed many features that were similar to both human myeloma and the original Radl 5T model. To demonstrate the use of this model, we have examined the effect of host-derived matrix metalloproteinase 9 (MMP-9) in the development of myeloma in vivo. Inoculation of 5TGM1 myeloma cells into mice that are deficient in RAG-2 and MMP-9 resulted in a reduction in both tumor burden and osteolytic bone disease when compared with RAG-2-deficient wild-type myeloma bearing mice. The establishment of myeloma in RAG-2(-/-) mice permits molecular examination of the host contribution to myeloma pathogenesis in vivo. PMID- 19779067 TI - Episodic ataxia type 1 mutations differentially affect neuronal excitability and transmitter release. AB - Heterozygous mutations of KCNA1, the gene encoding potassium channel Kv1.1 subunits, cause episodic ataxia type 1 (EA1), which is characterized by paroxysmal cerebellar incoordination and interictal myokymia. Some mutations are also associated with epilepsy. Although Kv1.1-containing potassium channels play important roles in neuronal excitability and neurotransmitter release, it is not known how mutations associated with different clinical features affect the input output relationships of individual neurons. We transduced rat hippocampal neurons, which were cultured on glial micro-islands, with lentiviruses expressing wild-type or mutant human KCNA1, and injected either depolarizing currents to evoke action potentials or depolarizing voltage commands to evoke autaptic currents. alpha-Dendrotoxin and tetraethylammonium allowed a pharmacological dissection of potassium currents underlying excitability and neurotransmission. Overexpression of wild-type Kv1.1 decreased both neuronal excitability and neurotransmitter release. By contrast, the C-terminus-truncated R417stop mutant, which is associated with severe drug-resistant EA1, had the opposite effect: increased excitability and release probability. Another mutant, T226R, which is associated with EA1 that is complicated by contractures and epilepsy, had no detectable effect on neuronal excitability; however, in common with R417stop, it markedly enhanced neurotransmitter release. The results provide direct evidence that EA1 mutations increase neurotransmitter release, and provide an insight into mechanisms underlying the phenotypic differences that are associated with different mutations. PMID- 19779069 TI - Accessing pre-appraised evidence: fine-tuning the 5S model into a 6S model. PMID- 19779068 TI - The role of gamma interferon in innate immunity in the zebrafish embryo. AB - The zebrafish genome contains ten genes that encode class II cytokine-like peptides, of which the two that are related most closely to mammalian interferon gamma (IFN-gamma) were named IFN-gamma1 and IFN-gamma2. Although the zebrafish has become a popular model system to study immune mechanisms, and although interferons are central regulators of immunity, which zebrafish cytokines correspond functionally to mammalian IFN-gamma has not been established. We used zebrafish embryos to assay the functions of IFN-gamma1 and IFN-gamma2, and have identified a subset of zebrafish homologs of the mammalian IFN-responsive genes as IFN-gamma targets in the zebrafish embryo: these genes are upregulated in response to raised levels of either IFN-gamma1 or IFN-gamma2. Infection studies using two different pathogens show that IFN-gamma signalling is required for resistance against bacterial infections in the young embryo and that the levels of IFN-gamma need to be regulated tightly: raising IFN-gamma levels sensitizes fish embryos against bacterial infection. Embryos injected with high doses of Escherichia coli are able to clear the bacteria within a day, and the gamma interferons are necessary for this defence reaction. The protective response to Yersinia ruckeri, a natural fish pathogen that is lethal at low doses, also requires IFN-gamma. As in the induction of target genes, the two interferons act at least partly redundantly. Together with the previously demonstrated type III interferon response, these results show that the counterparts of the mammalian viral and bacterial interferon-dependent defence functions are in place in zebrafish embryos, and suggest that zebrafish IFN-gamma1 and IFN-gamma2 are functionally equivalent to mammalian IFN-gamma. PMID- 19779071 TI - Using decision analysis to integrate evidence into decision making. PMID- 19779072 TI - Review: inhaled corticosteroids reduce wheezing and asthma exacerbations in infants and preschool children. PMID- 19779073 TI - Review: culture-specific programmes improve some asthma-related outcomes in children and adults from ethnic minority groups. PMID- 19779074 TI - Review: high-quality evidence on the effectiveness of laxatives for functional constipation in children is limited. PMID- 19779075 TI - Review: cancer-related decision aids improve patient knowledge overall and reduce anxiety in screening settings. PMID- 19779076 TI - Diets with different targets for intake of fat, protein, and carbohydrates achieved similar weight loss in obese adults. PMID- 19779077 TI - A behavioural weight-loss programme reduced urinary incontinence more than an education programme in overweight and obese women. PMID- 19779078 TI - A very low calorie diet plus lifestyle counselling improved mild obstructive sleep apnoea in overweight patients. PMID- 19779079 TI - Nurse-led care was non-inferior to physician-directed care in symptomatic moderate to severe obstructive sleep apnoea. PMID- 19779080 TI - Below-knee cast and Aircast brace improved ankle function at 3 months in acute severe ankle sprain. PMID- 19779082 TI - Intravascular catheter dressings with chlorhexidine-impregnated sponges reduced infections in the ICU. PMID- 19779081 TI - Review: mechanical bowel preparation before colorectal surgery does not provide any benefit and may be harmful. PMID- 19779083 TI - Review: compression was effective for healing venous ulcers, and multicomponent systems were better than single-component ones. PMID- 19779084 TI - Review: silver-releasing dressings improve healing and quality of life in patients with non-healing chronic wounds. PMID- 19779085 TI - Review: little evidence exists for type of dressing or support surface or for nutritional supplements for pressure ulcers. PMID- 19779086 TI - Review: exercise interventions improve functional and physical performance but not activities of daily living in older adults. PMID- 19779087 TI - A combination of 4 health behaviours was associated with increasing risk of stroke. PMID- 19779088 TI - Review: anger and hostility increase risk of coronary heart disease events in healthy people and those with existing CHD. PMID- 19779089 TI - Smoking increased risk of cervical cancer, independent of infection with high risk HPV types. PMID- 19779090 TI - Absolute CVD risk, stratified by risk score, was 20% higher in primary care patients with CVD than in those without CVD. PMID- 19779091 TI - Women who coped successfully with progressive MS learned to confront their diagnosis and live with its unpredictable changes. PMID- 19779092 TI - 6 themes described how women with early-stage breast cancer perceived and experienced treatment decision making. PMID- 19779093 TI - Men experienced and responded to the embodied and emotional effects of prostate cancer in different ways. PMID- 19779094 TI - Patients' attitudes, the hospital environment, and staff behaviour affected patients' dignity on a surgical ward. PMID- 19779095 TI - Loss of continuity and lack of closure in therapeutic relationships were associated with feelings of abandonment at the transition to end of life care. PMID- 19779096 TI - An investigation of the ECST-R in male pretrial patients: evaluating the effects of feigning on competency evaluations. AB - Forensic clinicians have the option of employing well-validated structured interviews when conducting competency to stand trial (CST) evaluations to ensure adequate coverage of the three prongs delineated in Dusky v. United States. This study evaluates the effects of feigning on the Evaluation of Competency to Stand Trial-Revised (ECST-R) in a sample of 100 male defendants undergoing CST evaluations. The ECST-R competency scales are reliable, with good alpha coefficients and interrater reliabilities, and differentiate patients found competent from those found not competent. The current study suggests that feigning may bridge both psychopathology and cognitive abilities and that clinicians should consider each when conducting CST evaluations. These results are discussed in the context of conducting comprehensive evaluations integrating response style assessments in CST evaluations. PMID- 19779098 TI - A bioluminescent orthotopic mouse model of human osteosarcoma that allows sensitive and rapid evaluation of new therapeutic agents In vivo. AB - Osteosarcoma (OSA) is the most common primary malignant bone tumor in children, 30% of whom develop lung metastases despite aggressive treatment. Our objective was to develop a mouse model of OSA for preclinical studies that (i) incorporates the natural history of OSA including tumor growth in bone and development of lung metastasis and (ii) is amenable to non-invasive detection methods. A human OSA cell line that expresses high levels of luciferase was created. Following subcutaneous injection, nine out of ten mice showed tumor growth. Eight out of ten mice showed tumor growth following orthotopic injection into the proximal tibia. Thirty percent of mice showed pulmonary metastasis by bioluminescent imaging eight to 10 weeks following orthotopic injection. Animals receiving cisplatin treatment showed reduced tumor volume compared to animals treated with vehicle alone. This model allows real-time detection of tumors and can be used to study mechanisms of OSA metastasis and test new therapeutic agents. PMID- 19779099 TI - Investigation of the effects of aging on homologous recombination in long-term bone marrow cultures. AB - Fluorescent yellow direct repeat (FYDR) mice carry a transgenic reporter for homologous recombination (HR) and have been used to reveal an age-dependent increase in HR in the pancreas. An established in vitro model system for accelerated aging of the marrow is the mouse long-term bone marrow culture (LTBMC) system. To determine whether the FYDR system, in which an HR event can lead to a fluorescent cell, can be used to study the effects of aging in LTBMCs, clonally expanded hematopoietic and marrow stromal cells in FYDR, positive control FYDR-Recombined (FYDR-Rec), and negative control wild-type C57BL/6NHsd (WT) LTBMCs were analysed. All groups of cultures demonstrated equivalent parameters of continuous hematopoiesis including generation of multilineage colony forming CFU-GM progenitor cells for over 22 weeks and age associated senescence of hematopoiesis. Results indicate that low expression of the FYDR transgene in bone marrow cells in vivo and in vitro prevents the use of the FYDR mice to study rare combination events in bone marrow. Using an alternative approach for detecting HR, namely the sister chromatid exchange (SCE) assay, a statistically significant increase in the number of SCEs per chromosome was observed in adherent cells subcultured from 20-week-compared to 4-week-old LTBMCs. These data suggest that adherent marrow stromal cells from LTBMCs become increasingly susceptible to HR events during aging. PMID- 19779101 TI - Ethyl-eicosapentaenoic acid reduces liver lipids and lowers plasma levels of lipids in mice fed a high-fat diet. AB - Fatty liver disease is characterized by a wide spectrum of liver damage, i.e. simple steatosis may progress to advanced fibrosis and to cryptogenic cirrhosis via steatohepatitis, and ultimately to hepatocellular carcinoma. Eicosapentaenoic acid (EPA), a marine-derived n-3 fatty acid like docosahexaenoic acid (DHA), is an anti-thrombotic and hypolipidemic agent, and is an antagonist of platelet aggregation and an inhibitor of cholesterol and lipoprotein. In an attempt to confirm the hypolipidemic action of this agent, the effects of EPA on liver and plasma levels of lipids in mice fed a high-fat diet were investigated. EPA markedly reduced the fatty droplets in the liver cells and the liver weight, also lowering plasma levels of total cholesterol, free total cholesterol, phospholipids and triglyceride. It is suggested that n-3 fatty acid intake and fish consumption may be able to prevent the occurrence not only of metabolic syndrome, but also of fatty liver and non-alcohlic steatohepatitis. PMID- 19779100 TI - Acetylcholinesterase and HHV-8 in squamous cell carcinoma and retinoblastoma. AB - Acetylcholinesterase (AChE) and human herpesvirus type 8 (HHV-8) antigens were studied in tissue sections from 56 squamous cell carcinomas (SCC) and five retinoblastomas (Rb). Approximately 62.5% of SCC and 80% of Rb showed positive staining for AChE. AChE staining in tumors was much higher than in normal control tissue. However, only 21.4% of SCC and 60% of Rb contained HHV-8 antigens. Of the 56 SCC, 17.9% were positive for both AChE and HHV-8 antigens, whereas 60% Rb were positive for both markers. The co-existence of AChE and HHV-8 antigens may play a role in the development of SCC and Rb. A possible mechanism for the development of these tumors is discussed. PMID- 19779097 TI - Transgenic mice expressing constitutively active Akt in oral epithelium validate KLFA as a potential biomarker of head and neck squamous cell carcinoma. AB - BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a common human neoplasia, of poor prognosis and survival, which frequently displays Akt overactivation. Previously, we reported that mice expressing high levels of constitutively Akt activity (myrAkt) in oral epithelia develop lesions and tumors in the oral cavity. MATERIALS AND METHODS: Functional genomics of primary keratinocytes from different transgenic mouse lines and immunostaining of mouse and human samples were performed in order to identify and validate putative biomarkers of oral cancer progression. RESULTS: The expression of KLF4 was found to be increased only in tumor prone samples from mice bearing overactivation of Akt. Such increased expression was confirmed in oral dysplasias and tumors arising in those mice. Tissue microarray analysis of human samples confirmed the association between active Akt and increased KLF4 expression. CONCLUSION: These data support the notion that KLF4 is potentially a reliable marker of HNSCC, and that myrAkt transgenic mice are valuable tools for preclinical research of HNSCC. PMID- 19779102 TI - Inhibition of NO production in LPS-stimulated mouse macrophage-like cells by benzo[b]cyclohept[e] [1,4]oxazine and 2-aminotropone derivatives. AB - The aim of this study was to investigate whether a total of twenty benzo[b]cyclohept[e][1,4]oxazines and their S-analogs, and 2-aminotropone derivatives affect the function of activated macrophages. These compounds inhibited the production of pro-inflammatory substances such as nitric oxide (NO) by lipopolysaccharide (LPS)-activated mouse macrophage-like RAW264.7 cells to different extents. Among them, benzo[b]cyclohept[e][1,4]oxazin-6(11H)-one [5] and 7-bromo-2-(4-hydroxyanilino)tropone [16] showed the highest inhibitory effects at concentrations that did not affect cellular viability (selectivity index=74.89 and 54.15, respectively). Western blot and RT-PCR analyses showed that [16] inhibited the expression of both inducible NO synthase (iNOS) and cyclooxygenase (COX)-2 at both protein and mRNA levels, whereas [5] inhibited only iNOS protein expression. Electron-spin resonance (ESR) spectroscopy revealed that both [5] and [16] scavenged nitric oxide (generated from NOC-7) and superoxide anion (generated by HX-XOD reaction) only at much higher concentration. These data suggest that [16] but not [5] exerts its anti-inflammatory action against macrophages via the inhibition of iNOS and COX-2 protein expressions. PMID- 19779103 TI - Erythropoietin receptors in endometrial carcinoma as related to HIF1{alpha} and VEGF expression. AB - Erythropoietin receptors (EpoRs) are expressed in a large percentage of cells in many human malignancies, including endometrial adenocarcinoma. In such tumors, administration of recombinant human erythropoietin (rhEpo) during radiotherapy and chemotherapy may oppose tumor progression by interfering with growth and invasion pathways. In the present study, a strong EpoR expression was demonstrated in 58.8% of 72 stage I endometrial adenocarcinomas, and this pattern was linked with a high degree of tumor differentiation (p=0.01), deep myometrial invasion (p=0.04) and, marginally, with poor prognosis (p=0.06). In addition, a strong association with the immunohistochemical expression of hypoxia-inducible factor 1alpha (HIF1alpha) and the downstream angiogenic protein vascular endothelial growth factor (VEGF) was noted. In multivariate analysis, HIF1alpha, but not EpoR, was associated with the depth of myometrial invasion (p=0.04) and marginally with prognosis (p=0.07). It is concluded that EpoR are common constituents of endometrial adenocarcinomas and are related to tumor aggressiveness, although this is probably a result of their involvement in an active HIF pathway. PMID- 19779104 TI - Expression of Breast Cancer Resistance Protein (BCRP-1) in canine mammary adenocarcinomas and adenomas. AB - BACKGROUND: Among the recognized factors which induce multi-drug resistance, an increased activity of proteins belonging to the ATP-binding casette family, including breast cancer resistance protein 1 (BCRP-1), is regarded as the most important. Localization and intensity of BCRP-1 expression was evaluated in mammary adenocarcinomas and adenomas in dogs. The obtained results were compared to the grade of malignancy (G) of the tumours. MATERIALS AND METHODS: Materials for the study were sampled in the course of surgery from 54 dogs, of various breeds, aged 6 to 16 years (36 cases of mammary adenocarcinoma and 18 cases of mammary adenoma). The tumours were histopathologically verified and immunohistochemical reactions were performed to evaluate expression of BCRP-1. The microscopic patterns were photographed and subjected to computer-assisted analysis taking advantage of MultiScanBase Ver. 14.02 software. RESULTS: Expression of BCRP-1 was detected in over 85% of adenocarcinomas and almost 28% of adenomas. Samples of tumours with a higher grade of malignancy demonstrated an increased expression of BCRP-1. The two variables manifested a moderate positive correlation (r=0.35; p<0.05). CONCLUSION: The results point to a role of BCRP-1 protein in biology of tumour cells in dogs. PMID- 19779105 TI - Modelling of tumour--host coexistence In vitro in the presence of serine protease inhibitors. AB - The activities of cell surface serine proteases are markedly enhanced in malignant tumours. Proteolytic degradation of the extracellular matrix and basal membrane of normal cells is an important event for tumour cell growth and invasion. Two well-known broad-spectrum inhibitors of serine protease, Foy-305 and Ono-3403, were evaluated for their ability to affect the growth rate and survival of MCF7 breast cancer cells co-cultured with MRC5 lung fibroblasts as feeder cells in the absence of serum. Flow cytometry and differential staining demonstrated that in the mixed culture, the rate of tumor growth was dependent upon the presence of the feeder MRC5 lung fibroblasts and could be obviated by the additional presence of the inhibitors of serine proteases. PMID- 19779106 TI - The mitochondria-targeted nitroxide JP4-039 augments potentially lethal irradiation damage repair. AB - It was unknown if a mitochondria-targeted nitroxide (JP4-039) could augment potentially lethal damage repair (PLDR) of cells in quiescence. We evaluated 32D cl 3 murine hematopoietic progenitor cells which were irradiated and then either centrifuged to pellets (to simulate PLDR conditions) or left in exponential growth for 0, 24, 48 or 72 h. Pelleted cells demonstrated cell cycle arrest with a greater percentage in the G(1)-phase than did exponentially growing cells. Irradiation survival curves demonstrated a significant radiation damage mitigation effect of JP4-039 over untreated cells in cells pelleted for 24 h. No significant radiation mitigation was detected if drugs were added 48 or 72 h after irradiation. Electron paramagnetic resonance spectroscopy demonstrated a greater concentration of JP4-039 in mitochondria of 24 h-pelleted cells than in exponentially growing cells. These results establish a potential role of mitochondria-targeted nitroxide drugs as mitigators of radiation damage to quiescent cells including stem cells. PMID- 19779107 TI - Endothelial nitric oxide synthase is up-regulated in the umbilical cord in pregnancies complicated with intrauterine growth retardation. AB - BACKGROUND: NO and NO synthases (NOS) play an important role in the physiology of the fetomaternal blood circulation, although their expression in pathological conditions is unclear. Intrauterine growth retardation (IUGR) is a disorder most probably caused by abnormality of the fetomaternal bloodflow. MATERIALS AND METHODS: The expression of endothelial NOS (ecNOS) from arteria umbilicalis and the nitrite and peroxynitrite level of umbilical blood were determined. Major consequences of peroxynitrite toxicity are lipid peroxidation and glutathione depletion; these parameters were also measured. Finally, superoxide dismutase (SOD) activity was assayed to evaluate the level of superoxide anions. RESULTS: Elevated expression of ecNOS was found to be coupled with significantly lower SOD activity and glutathione level, and increased lipid peroxidation in IUGR neonates. CONCLUSION: The increased NO indices could represent a compensatory effort to improve placental bloodflow, but in IUGR neonates it is coupled with inadequate antioxidant defence, resulting in significant oxidative stress. PMID- 19779108 TI - Effect of melatonin on melanoma cells subjected to UVA and UVB radiation in In vitro studies. AB - Studies performed in vivo and in vitro have shown that exogenous melatonin (Mel) exerts oncostatic effects on melanoma cells. Although the protective effect of Mel on skin and cells exposed mainly to UVB has been documented, effects of Mel have not yet been examined on melanoma cells exposed to UVA. Our investigations aimed at examination of the effect of Mel alone (0, 10(-3), 10(-6) and 10(-9) M), and after its addition to the culture medium for 30 minutes before exposure of melanoma cells to UVA (15 J/cm(2)) or UVB (30 mJ/cm(2), 60 mJ/cm(2)). Viability of the cells was examined using the colorimetric sulphorhodamine B test. Mel added to the medium at concentrations of 10(-3)-10(-8) M was found to increase the number of melanoma cells as compared to the control (cells with no Mel) after 24 hours. Compared to exposed cells without Mel, at 10(-3) M Mel, melanoma cells exposed to 30 mJ/cm(2) UVB increased in number and at 10(-9) M increased the survival of those exposed to 60 mJ/cm(2) UVB. The cells exposed to UVA (15 J/cm(2)) were protected by Mel at 10(-6) and 10(-9) M. Physiological concentrations of Mel exerted no oncostatic effects on the BM cell line used here. In addition, the pharmacological Mel concentrations stimulated proliferation of the cells. Beyond doubt, we have confirmed that Mel represents a substance which protects cells from UVA and UVB action in in vitro experiments. PMID- 19779109 TI - Effect of melatonin on human keratinocytes and fibroblasts subjected to UVA and UVB radiation In vitro. AB - Skin represents one of the extrapineal sites of melatonin (Mel) synthesis. In the skin Mel plays, for example, the role of an antioxidant which scavenges and inactivates free radicals arising due to UV irradiation. Although the protective effect of Mel on skin and cells irradiated mainly with UVB has been documented, to date no comparison has been made for the effects of Mel on cells exposed to UVA. Our study aimed at evaluating the effect of Mel (0, 10(-3), 10(-6) or 10(-9) M) added to culture medium 30 minutes before exposure of keratinocytes and fibroblasts to irradiation with UVA (15 J/cm(2)) and UVB (30 mJ/cm(2), 60 mJ/cm(2)). Viability of the cells was evaluated using sulphorhodamine (SRB) colorimetric test. Mel at 10(-3) M increased the number of surviving keratinocytes and at 10(-6) M increased the number of surviving fibroblasts exposed to UVB (30 mJ/cm(2), 60 mJ/cm(2)) as compared to cells exposed only to radiation. In addition, 10(-6) M protected keratinocytes exposed to the dose of 30 mJ/cm(2). Mel at 10(-3) M exerted a protective effect on both types of cells irradiated with UVA (15 J/cm(2)). As documented by our studies, Mel protects skin cells from the action of UVA and UVB. The protective effect of different Mel concentrations might result from variable expression of melatonin receptors. PMID- 19779110 TI - Hepatoprotection of chlorella against carbon tetrachloride-induced oxidative damage in rats. AB - The effects of 80% ethanolic chlorella extracts (GPE) on carbon tetrachloride (CCl(4))-induced hepatic damage were investigated in Sprague-Dawley rats. The rats were orally treated with GPE (0.5 g/kg body weight) or silymarin (0.2 g/kg body weight) over four consecutive weeks with administration of CCl(4) (20% CCl(4), 0.5 ml/rat twice a week). The GPE had a significant protective effect against liver injuries, as well as oxidative stress induced by CCl(4), resulting in reduced lipid peroxidation and improved serum biochemical parameters such as aspartate aminotransferase and alanine aminotransferase. The reduced levels of glutathione, vitamin C, superoxide dismutase, and catalase in the CCl(4)-treated rats were significantly increased by treatment with GPE. Furthermore, the activity of GPE was comparable to the standard drug silymarin. In conclusion, chlorella may be useful as a hepatoprotective agent against chemical-induced liver damage in vivo. PMID- 19779111 TI - Gandoderma lucidum extract promotes immune responses in normal BALB/c mice In vivo. AB - Enhanced fruit and vegetable consumption is closely related to reduced cancer incidence as shown in epidemiological studies. Ganoderma lucidum, one of the most well-known traditional Chinese medicines, has been demonstrated to have pharmacological activities and antitumor effects, in Asian populations. However, the promotion of immune responses in normal BALB/c mice is unclear. In the present study, we investigated the immune responses of BALB/c mice after treatment with G. lucidum extract in vivo. The results demonstrated that G. lucidum extract was able to promote the proliferation of splenocytes under Concanavalin A or lipopolysaccharide stimulation. Compared with the control group, phagocytosis of macrophage was significantly enhanced by intraperitoneal administration of G. lucidum extract at both 3 and 6 mg/kg. Compared with the control group, natural killer cell activity was significantly enhanced by intraperitoneal administration of G. lucidum extract (6 mg/kg). Results of cytometric bead array and flow cytometry indicated that the expressions of interleukin-6 and interferon-gamma also increased (p<0.001) by treatment with G. lucidum extract (3 and 6 mg/kg). In conclusion, the findings of this study implied that G. lucidum extract was able to effectively promote immune responses in BALB/c mice. PMID- 19779112 TI - Effects of Agaricus blazei Murill extract on immune responses in normal BALB/c mice. AB - Agaricus blazei Murill (ABM) has shown particularly strong results in treating and preventing cancer and has also traditionally been used as a food source in Brazil. However, the exact immune responses regarding the phagocytosis of macrophage and, the activity of natural killer (NK) cells in normal mice after exposure to ABM extract was unclear. The goal of this study was to investigate whether or not ABM extract can promote immune responses in normal BALB/c mice. BALB/c mice were treated with different doses of ABM extract for different time periods. The results indicated that ABM extract significantly promoted the proliferation of splenocytes both in vitro and in vivo. ABM extract promoted the levels of interleukein-6 (IL-6) and, interferon-gamma (IFN-gamma) but reduced the levels of IL-4 in vitro and in vivo. The percentage of macrophages with phagocytosis after ABM extract treatment increased and these effects were of dose dependent manners, both in vitro and in vivo. YAC-1 target cells were killed by NK cells from the mice after treatment with ABM extract at 3 and 6 mg/kg/day for up to 14 days at target cell ratios of 25:1 and 50:1. Taken together, these results show that ABM extract promoted immunomodulations in normal BALB/c mice in vitro and in vivo. PMID- 19779113 TI - Breast cancer and cyclin D1 gene polymorphism in Turkish women. AB - BACKGROUND: Cyclin D1 protein plays an important part in regulating the progress of the cell during the G(1) phase of the cell cycle. It has been suggested that G870A polymorphism at the exon4/intron4 splicing region of the CCND1 gene may play a role in tumorigenesis and invasiveness. PATIENTS AND METHODS: A case control study was performed to test the association between G870A polymorphisms in the CCND1 gene and breast cancer risk and cancer progression. For this purpose, 38 patients with breast cancer and 64 healthy women controls were included in the study. The CCND1 G870A polymorphisms in our study groups were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) using peripheral blood samples. RESULTS: A significant difference was found in the distribution of the GG, AG and AA genotypes between the patient group and the control group (p=0.021). A lower risk (odds ratio 0.435, 95% confidence interval 0.223-0.846) was found to be associated with heterozygote AG individuals when compared with homozygote allele carriers in breast cancer. The cyclin D1 A870G genotype was associated with capsular invasion (p=0.02). CONCLUSION: The risk of breast cancer development and prognosis may be associated with genetic variation in the CCND1 genotype, which may be used as a biomarker for further studies. PMID- 19779114 TI - Effect of Sasa senanensis Rehder extract on NO and PGE2 production by activated mouse macrophage-like RAW264.7 cells. AB - Alkaline extract of Sasa senanensis Rehder (SE) has shown diverse biological activity. As an extension, whether SE affects the function of activated macrophages was investigated. SE inhibited the nitric oxide (NO) production by lipopolysaccharide (LPS)-activated mouse macrophage-like RAW264.7 cells. Western blot and RT-PCR analyses demonstrated that this was due to the inhibition of inducible NO synthase (iNOS) expression at both protein and mRNA levels. ESR spectroscopy shows that SE dose-dependently scavenged the NO radical produced by NOC-7. In order to confirm the anti-inflammatory potency, possible effects on prostaglandin (PG) E(2) production and expression of enzymes involved in the arachidonic acid pathway were next investigated. It was found that SE effectively inhibited the PGE(2) production by LPS-stimulated RAW264.7 cells, although the extent of inhibition of PGE(2) was slightly less than that of NO production. SE inhibited cyclooxygenase (COX)-2 expression at both protein and mRNA levels, but to much lesser extents as compared with those for iNOS expression. SE contained much lower concentration of arginine, precursor of NO, as compared with the culture medium. These data suggest that SE exerts a weak anti-inflammatory activity. PMID- 19779115 TI - Muscle regeneration: cellular and molecular events. AB - Muscle injury induces strong changes in muscle cells and extracellular matrix. Muscle regeneration after injury has similarities to muscle development during embryogenesis and seems to follow the same procedure. The initial phase of muscle repair is characterized by inflammation and degeneration of the damaged tissue. Almost simultaneously, previous quiescent myogenic cells, called satellite cells, are activated, proliferate, differentiate and fuse to form multinucleated myofibers. Other non-muscle stem cells may also take part in this process. Secreted factors, such as hepatocyte growth factor (HGF), fibroblast growth factors (FGFs), transforming growth factor-betas (TGF-betas), insulin-like growth factors (IGFs), tumour necrosis factor alpha (TNFalpha) and others, are released during muscle repair and guide muscle regeneration, however, their exact functions and effects on muscle remodeling remain unknown. Intensive research is currently addressing the regenerative mechanisms which are involved in acute muscle injuries and chronic muscle diseases. PMID- 19779116 TI - Genetic determinants of cardiovascular disease: the renin-angiotensin-aldosterone system, paraoxonases, endothelin-1, nitric oxide synthase and adrenergic receptors. AB - Apart from conventional risk factors such as cigarette smoking, obesity, hypertension, diabetes mellitus, hypercholesterolemia, physical inactivity and metabolic syndrome, a family history of coronary artery disease (CAD) seems to be important, especially in young people. Among the genes that may potentially influence the onset and the progression of CAD, there are those controlling the following: renin-angiotensin-aldosterone system (RAAS), adrenergic receptors, paraoxonases, endothelin and nitric oxide synthase. They may modulate the risk of disease onset, as well as its progression and patient prognosis. The unravelling of genetic determinants of CAD may be the first step towards a better understanding of the pathological process involved, the early identification of those at risk and individualizing treatment. PMID- 19779117 TI - Single-step therapy -- feasibility and safety of simultaneous transarterial chemoembolization and radiofrequency ablation for hepatic malignancies. AB - BACKGROUND: Radiofrequency thermal ablation (RFA) has been demonstrated to be useful for the treatment of liver neoplasms. The study aimed to evaluate the feasibility and safety of the combination of transarterial chemoembolization (TACE) and RFA, performed simultaneously to treat primary and secondary liver neoplasms. PATIENTS AND METHODS: From July 2006 to October 2007, 34 patients (21 with HCC and 13 with liver metastases) underwent 37 sessions of treatment. The schedule consisted of: induction TACE (with epirubicin, mitomycin C and lipiodol, or with doxorubicin/irinotecan loaded on microspheres), percutaneous RFA and second TACE. Monopolar RFA was used on 52 nodules, whereas the bipolar multiprobe technique was used in 6 cases. RESULTS: The treatment was well tolerated, with moderate hepatic and hematological toxicity. In total 51 nodules were evaluable for response, with technical success in 45/51 cases (88%). CONCLUSION: Combined TACE plus RFA is feasible and safe; the preliminary data make it a promising procedure with regard to efficacy and support further investigation. PMID- 19779118 TI - Bolus 5-Fluorouracil as an alternative modality to infusion 5-Fluorouracil in a patient with rectal cancer and capecitabine-induced cardiotoxicity. AB - 5-Fluorouracil (5-FU) is the backbone of the chemotherapy regimens approved for treatment of colorectal cancer. Incidence of cardiotoxicity associated with 5-FU ranges between 1.5% to 18%; 48% as anginal symptoms and 2% as cardiogenic shock. Cardiotoxicity is unpredictable and no alternatives have been defined so far. A 35-year-old man treated for stage III A rectal cancer developed chest pain typical of angina on treatment with capecetabine initially and 5-FU infusion afterwards. Scheduled dosing of 5-FU was changed from infusion to a bolus type. He was asymptomatic with no electrocardiographic (ECG) changes on 24-h Holter monitoring after changing the mode of administration to bolus 5-FU. Here, we report the first case in the English literature where a change in the mode of 5 FU administration to bolus is an alternative to infusion 5-FU-induced cardiotoxicity. In conclusion, Bolus 5-FU can be used in patients developing cardio-toxicity due to 5-FU infusion. PMID- 19779119 TI - Circulating cytokine levels in prostate cancer patients undergoing radiation therapy: influence of neoadjuvant total androgen suppression. AB - BACKGROUND: The purpose of this study was to investigate the immunological impact of combining neoadjuvant total androgen suppression (TAS) with radiotherapy (xRT) in the treatment of prostate cancer by monitoring blood cytokine levels. PATIENTS AND METHODS: Participants were stage I-II prostate cancer patients receiving xRT alone (n=18) or TAS+xRT (n=19) under the procedures outlined in RTOG protocols #94-08 and #94-13. Peripheral blood samples were collected immediately prior to TAS (xRT+TAS group), immediately prior to xRT, 24 hours after initiation of xRT, and weekly during xRT. Samples were monitored for the immunoregulatory cytokines interleukin (IL)-1beta, IL-6 and transforming growth factor (TGF)beta using ELISA procedures. RESULTS: Following initiation of xRT, both patient groups demonstrated an immediate elevation of the proinflammatory cytokines IL-1beta and IL-6 in their plasma. These cytokine levels appeared to peak after 1-2 weeks of xRT before returning toward pre xRT levels. In contrast, the profibrotic cytokine TGFbeta appeared to decrease immediately following initiation of xRT, but, subsequently, underwent two distinct waves of elevation, occurring at 1-2 weeks and 5-6 weeks into the xRT. Surprisingly, while the temporal pattern of plasma cytokine response was similar in both treatment groups, the magnitude of cytokine expression was noticeably different, appearing to be significantly affected by the addition of TAS. Indeed, administration of neoadjuvant TAS appeared to bring about a marked elevation of IL-1beta and IL-6 and a significant reduction in TGFbeta when compared to patients receiving xRT alone. CONCLUSION: The precise mechanisms underlying this TAS-related increase of the proinflammatory cytokines IL-1beta and IL-6 and decrease of the profibrotic cytokine TGFbeta remain unclear. However, previous reports have documented that androgens tend to be immunosuppressive in nature. It is conceivable, therefore, that administration of TAS shifts the ratio of proinflammatory and profibrotic cytokines toward a more immunostimulatory state. PMID- 19779120 TI - Paraneoplastic cerebellar degeneration in a patient with pseudomyxoma peritonei and breast cancer: case report and literature review. AB - The case of a 31-year-old woman with progressive cerebellar degeneration preceding by several months the diagnosis and treatment of breast cancer initially and pseudomyxoma peritonei (PMP) with evidence of causative association with the latter is presented. Despite various chemotherapeutic and surgical manipulations, the patient did not substantially improve and succumbed 20 months following initial diagnosis of the neurological disorder. Interestingly, neurological symptoms partially regressed transiently only after surgical debulking of the PMP and not after the remission of breast cancer after various chemotherapeutic regimens suggesting an etiological relationship of the former and the cerebellar degeneration. Early recognition and appropriate therapy of this rare complication of PMP is imperative as it may be crucial for the outcome. PMID- 19779121 TI - Detection of herpes simplex virus in first trimester pregnancy loss using molecular techniques. AB - BACKGROUND: The etiology of early pregnancy loss is multifactorial and may include viral pathogens. The aim of this study was to investigate the presence of herpes simplex virus (HSV) in gestational tissues of first trimester pregnancy loss using molecular techniques. PATIENTS AND METHODS: Gestational tissue from 95 women with first trimester pregnancy loss and 36 women with elective termination of pregnancy was investigated by nested polymerase chain reaction (PCR) and in situ hybridization techniques. RESULTS: HSV was detected by the nested PCR technique in 41 out of the 95 (43.2%) cases of early pregnancy loss and in 6 out of the 36 (16.7%) cases of elective pregnancy termination (p=0.03). The HSV positive cases in the early pregnancy loss group were observed between the 6th and the 12th gestational week and mostly in the 9th, 8th and 6th week. The in situ hybridization technique was successful in 18 out of 25 PCR-positive cases (72%) and revealed that the hybridization signal was mostly localized in the nuclei of the decidual and intermediate trophoblastic cells and less commonly in the chorionic villous trophoblastic cells. CONCLUSION: HSV seems to play a significant role in first trimester pregnancy loss and its detection by sensitive and accurate molecular techniques would permit prompt antiviral therapy for a successful future pregnancy. PMID- 19779122 TI - The role of postoperative radiotherapy in the management of patients with thymic tumors -- a retrospective study. AB - BACKGROUND: Thymomas are the most common tumor arising in the anterior mediastinum. Surgery is the cornerstone for the management of these tumors. The role of postoperative radiotherapy in Masaoka stage II thymomas remains controversial, but it is well established in the advanced stages. The aim of this study was to investigate the role of postoperative radiotherapy in the overall management of thymomas, and the evaluation of potential prognostic factors. PATIENTS AND METHODS: Between 1989 and 2007, 41 thymoma patients underwent surgery and 27 of them received radiotherapy with a curative intent. The Masaoka staging system was used. The histopathological records and specimens of patients were thoroughly reviewed. Clinical and radiological evaluations took place every 6 months. The mean patient follow-up was 69 months (range: 2-212). RESULTS: DFS (disease free survival), TS (total survival) and DSS (disease specific survival) differed significantly between stages and histological types (p<0.04). Stage I patients were managed only surgically, with none recurring or dying. Concerning stage II patients, TS was significantly longer in non-irradiated cases (10/21) (p=0.025). Stage III (n=8) and IV (n=8) patients underwent postoperative radiotherapy, with 4/8 of stage IV disease also receiving induction chemotherapy. Six out of 8 stage III-IV patients recurred (1 distant and 5 intrathoracic failure), out of whom 4 died due to disease progression despite further treatment (all type C histology). The mean DFS and TS for stage III patients were 49.2 and 50.3 months respectively, with the corresponding values for stage IV being 14.5 and 29.1 months. Patients with myasthenia had a favorable outcome and the ones with complete resection a significantly longer DFS (p=0.0003) and DSS (p=0.039). The Cox regression analysis showed that myasthenia and tumor size are important prognostic factors for DFS (p<0.05). CONCLUSION: Myasthenic patients have a more favorable prognosis. Radiotherapy can be omitted in totally resected stage I-II patients, whereas it is beneficial in more advanced stages. PMID- 19779123 TI - Evaluation of early dynamic splinting versus static splinting for patients with transposition of the extensor carpi radialis longus to the extensor pollicis longus. AB - We present a group of 20 patients who underwent transposition of the extensor carpi radialis longus to the extensor pollicis longus between April 2003 and September 2007. The group was divided into ten patients with an early dynamic splint and ten patients with a static plaster cast following the standard rehabilitation protocols. We compared these two rehabilitation protocols. The post-rehabilitation total range of motion was 87.5 degrees in the dynamic group and 58.75 degrees in the patients treated by the static protocol. The total time of rehabilitation was 10.2 weeks in the dynamic and 14.2 weeks in the static group. The overall mean follow-up was 12.2 weeks. We conclude that early dynamic splinting brings shorter recovery time, shorter time off work and significantly better movement of the thumb. PMID- 19779124 TI - Changes in the mechanical properties of human quadriceps muscle after eccentric exercise. AB - Muscular adaptation which occurs following eccentric exercise-induced muscle damage has been associated with changes in the mechanical properties of muscle manifested as a shift in the length-tension relationship towards longer muscle lengths. However, it is not clear whether this shift is a long term adaptation to eccentric exercise. The purpose of this study was to investigate functional adaptations to skeletal muscle damage in humans, tracking such responses several days into muscle recovery. Ten healthy young men performed an eccentric exercise protocol involving the quadriceps muscle and functional measurements were performed before and on days 1, 2, 5, 8, 12 and 16 post-exercise. Blood samples were also withdrawn before and at 6 h, and 2 days, 5 days and 16 days post exercise. The exercise protocol resulted in muscle damage, indicated by changes in clinical markers including increased serum creatine kinase activity and muscle soreness compared to pre-exercise levels (p<0.05-0.001). An acute, but not sustained shift in the quadriceps isokinetic and isometric angle-torque curves towards longer muscle lengths was observed post-exercise (p<0.05). It was speculated that the functional adaptations following eccentric exercise might be affected by the short resting and functional length of the quadriceps muscle, relative to its optimum. More studies are needed to confirm the hypothesis that a sustained shift in the muscle's length-tension relationship, as an adaptation after lengthening contraction-induced damage, is muscle specific. PMID- 19779125 TI - Pulmonary function testing in women with breast cancer treated with radiotherapy and chemotherapy. AB - BACKGROUND: The frequency and grade of pulmonary complications after radiotherapy for breast cancer are still debated. This study evaluated changes in pulmonary function tests (PFTs) after radiotherapy in women with breast cancer. PATIENTS AND METHODS: Thirty-five consecutive eligible women with breast cancer underwent pulmonary function testing before and 3 months after adjuvant radiotherapy. Twenty-one of them also received chemotherapy. RESULTS: A significant decrease of forced vital capacity, forced expiratory volume in one second and carbon monoxide diffusing capacity was observed in the women treated with locoregional adjuvant radiotherapy and chemotherapy, whereas no decrease of the above parameters was evidenced in women treated exclusively with local adjuvant radiotherapy. CONCLUSION: Local adjuvant radiotherapy is not associated with any reduction in lung function parameters, however, locoregional adjuvant radiotherapy combined with chemotherapy shows a significant reduction in PFTs 3 months after radiotherapy completion. PMID- 19779126 TI - Custom-made Reduction Mammaplasty. AB - BACKGROUND: Macromastia is a health problem that requires the coordination of surgical and medical specialists. Goals of reduction mammaplasty are to alleviate physical, emotional and psychosocial discomforts and to restore a conical-shaped breast, maintaining scars as short as possible. We report our approach for reduction mammaplasty with superior pedicle. MATERIALS AND METHODS: Our method combines advantages of round block with vertical scar, using a dermal flap that is fixed to the new mammary crease. We analyzed skin and glandular resection customizing the mammaplasty. RESULTS: The dermal flap works against the weight of residual tissue, maintaining the crease at the desired position with a natural result. Benefits are an excellent projection, short scar, suitable reshaping and patient satisfaction. CONCLUSION: This technique can be used for mild to severe hypertrophy with various degrees of ptosis. It results in a successful aesthetic outcome with minimal scarring, suitable breast remodeling and natural long lasting projection. PMID- 19779128 TI - Transplacental pharmacokinetics of glyburide, rhodamine 123, and BODIPY FL prazosin: effect of drug efflux transporters and lipid solubility. AB - Breast cancer resistance protein (BCRP) and P-glycoprotein (P-gp) are the most abundantly expressed ATP-binding cassette (ABC) drug transporters in the placenta. They recognize a large, partly overlapping spectrum of chemically unrelated compounds and affect their transplacental passage. In this study we investigate the effect of Bcrp and P-gp on the transplacental pharmacokinetics of their specific and common substrates employing the technique of dually perfused rat placenta. We show that the clearance of rhodamine 123 (P-gp substrate), glyburide (BCRP substrate) and BODIPY FL prazosin (P-gp and BCRP substrate) in fetal-to-maternal direction is 11, 11.2 and 4 times higher, respectively, than that in the maternal-to-fetal direction. In addition, all of these substances were found to be transported from the fetal compartment even against concentration gradient. We thus demonstrate the ability of placental ABC transporters to hinder maternal-to-fetal and accelerate fetal-to-maternal transport in a concentration-dependent manner. However, by means of pharmacokinetic modeling we describe the inverse correlation between lipid solubility of a molecule and its active transport by placental ABC efflux transporters. Therefore, in the case of highly lipophilic substrates, such as BODIPY FL prazosin in this study, the efficacy of efflux transporters to pump the molecule back to the maternal circulation is markedly limited. PMID- 19779129 TI - Quantitative pharmacology or pharmacokinetic pharmacodynamic integration should be a vital component in integrative pharmacology. AB - Pharmacodynamics (PD) examines the relationship between drug concentration and onset, intensity, and duration of the pharmacological effect. Pharmacokinetics (PK) is the science of the time course of drugs in the organism. The quantitative pharmacological approach focuses on concentration-response and response-time relationships, with special emphasis on the proposed impact of the drug on the disease. The review aims to raise awareness among pharmacologists with regard to why pharmacokinetic-pharmacodynamic (PKPD) integration is essential in basic pharmacology research to improve interpretation of data. Quantitative pharmacology is vital in drug discovery for target validation, optimizing the development of lead compounds, and scaling compounds to humans and has become mandatory for regulatory bodies. However, its use is still comparatively rare in experimental pharmacology, and its absence diminishes the interpretative value of published experimental data and can allow the presentation of misleading information. A primary requirement for PKPD integration is establishing the inter relationships between in vitro and in vivo PK and PD properties and extrapolation to the known or possible future clinical use of a compound. This review examines the use of PKPD in experimental pharmacology by reviewing drug exposure measurements, plasma protein binding, exposure-effect relationships, and the measurement of active metabolites. It examines the significance of dosing schedules, the importance of target engagement, and problems in examining time response relationships. It shows how quantitative pharmacology adds significant value to study design and examines why ignoring pharmacokinetics can lead to misleading results and conclusions. Finally, a guide list of points to be considered when performing studies is provided. PMID- 19779130 TI - Nicotinamide glycolates antagonize CXCR2 activity through an intracellular mechanism. AB - The chemokine receptors CXCR1/2 are involved in a variety of inflammatory diseases, including chronic obstructive pulmonary disease. Several classes of allosteric small-molecule CXCR1/2 antagonists have been developed. The data presented here describe the cellular pharmacology of the acid and ester forms of the nicotinamide glycolate pharmacophore, a potent antagonist of CXCR2 signaling by the chemokines CXCL1 and CXCL8. Ester forms of the nicotinamide glycolate antagonized CXCL1-stimulated chemotaxis (IC(50) = 42 nM) and calcium flux (IC(50) = 48 nM) in human neutrophils, but they were inactive in cell-free assays of (125)I-CXCL8/CXCR2 binding and CXCL1-stimulated guanosine 5'-O-(3 [(35)S]thio)triphosphate ([(35)S]GTPgammaS) exchange. Acid forms of the nicotinamide glycolate were inactive in whole-cell assays of chemotaxis and calcium flux, but they inhibited (125)I-CXCL8/CXCR2 binding and CXCL1-stimulated [(35)S]GTPgammaS exchange. The (3)H ester was internalized by neutrophils and rapidly converted to the (3)H acid in a concentrative process. The (3)H acid was not internalized by neutrophils but was sufficient alone to inhibit CXCL1 stimulated calcium flux in neutrophils that were permeabilized by electroporation to permit its direct access to the cell interior. Neutrophil efflux of the acid was probenecid-sensitive, consistent with an organic acid transporter. These data support a mechanism wherein the nicotinamide glycolate ester serves as a lipophilic precursor that efficiently translocates into the intracellular neutrophil space to liberate the active acid form of the pharmacophore, which then acts at an intracellular site. Rapid inactivation by plasma esterases precluded use in vivo, but the mechanism elucidated provided insight for new nicotinamide pharmacophore classes with therapeutic potential. PMID- 19779131 TI - Benzodiazepine binding site occupancy by the novel GABAA receptor subtype selective drug 7-(1,1-dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3 (2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazine (TPA023) in rats, primates, and humans. AB - The GABA(A) receptor alpha2/alpha3 subtype-selective compound 7-(1,1 dimethylethyl)-6-(2-ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4 triazolo[4,3-b]pyridazine (TPA023; also known as MK-0777) is a triazolopyridazine that has similar, subnanomolar affinity for the benzodiazepine binding site of alpha1-, alpha2-, alpha3-, and alpha5-containing GABA(A) receptors and has partial agonist efficacy at the alpha2 and alpha3 but not the alpha1 or alpha5 subtypes. The purpose of the present study was to define the relationship between plasma TPA023 concentrations and benzodiazepine binding site occupancy across species measured using various methods. Thus, occupancy was measured using either in vivo [(3)H]flumazenil binding or [(11)C]flumazenil small-animal positron emission tomography (microPET) in rats, [(123)I]iomazenil gamma-scintigraphy in rhesus monkeys, and [(11)C]flumazenil PET in baboons and humans. For each study, plasma-occupancy curves were derived, and the plasma concentration of TPA023 required to produce 50% occupancy (EC(50)) was calculated. The EC(50) values for rats, rhesus monkeys, and baboons were all similar and ranged from 19 to 30 ng/ml, although in humans, the EC(50) was slightly lower at 9 ng/ml. In humans, a single 2-mg dose of TPA023 produced in the region of 50 to 60% occupancy in the absence of overt sedative-like effects. Considering that nonselective full agonists are associated with sedation at occupancies of less than 30%, these data emphasize the relatively nonsedating nature of TPA023. PMID- 19779132 TI - Species difference in the effect of grapefruit juice on intestinal absorption of talinolol between human and rat. AB - Bioavailability of talinolol, a beta(1)-adrenergic receptor antagonist, was enhanced by coadministration with grapefruit juice (GFJ) in rats, whereas GFJ ingestion markedly reduced the absorption of talinolol in humans. Because our recent study indicated that the inhibitory effect of GFJ on organic anion transporting polypeptide (Oatp)- and P-gp-mediated talinolol absorption depends on the concentration of naringin in ingested GFJ, the apparent inconsistent findings may be explained by the species difference in the affinity of naringin for OATP/Oatp and P-gp multidrug resistance 1 (MDR1/Mdr1) between humans and rats. Although human MDR1-mediated talinolol transport was not inhibited by 2000 microM naringin, naringin inhibited human OATP1A2-, rat Oatp1a5-, and rat Mdr1a mediated talinolol transport with IC(50) values of 343, 12.7, and 604 microM, respectively, in LLC-PK1 cell and Xenopus laevis oocyte systems. Because the naringin concentration in commercially prepared GFJ was found to be approximately 1200 microM, these results suggested that GFJ would reduce the intestinal absorption of talinolol through inhibition of OATP1A2-mediated talinolol uptake in humans, whereas an increase of talinolol absorption is mainly through inhibition of Mdr1a-mediated efflux in rats. The rat intestinal permeability of talinolol measured by the in situ closed loop method was indeed significantly increased in the presence of GFJ, whereas a significant decrease was observed with 6-fold diluted GFJ, in which the naringin concentration was approximately 200 microM. The present study indicated that the species difference in the effect of GFJ on intestinal absorption of talinolol between humans and rats may be due to differences in the affinity of naringin for OATP/Oatp and MDR1/Mdr1 transporters between the two species. PMID- 19779133 TI - Design and validation of a conformation sensitive capillary electrophoresis-based mutation scanning system and automated data analysis of the more than 15 kbp spanning coding sequence of the SACS gene. AB - In this study, we developed and analytically validated a fully automated, robust confirmation sensitive capillary electrophoresis (CSCE) method to perform mutation scanning of the large SACS gene. This method facilitates a rapid and cost-effective molecular diagnosis of autosomal recessive spastic ataxia of Charlevoix-Saguenay. Critical issues addressed during the development of the CSCE system included the position of a DNA variant relative to the primers and the CG content of the amplicons. The validation was performed in two phases; a retrospective analysis of 32 samples containing 41 different known DNA variants and a prospective analysis of 20 samples of patients clinically suspected of having autosomal recessive spastic ataxia of Charlevoix-Saguenay. These 20 samples appeared to contain 73 DNA variants. In total, in 32 out of the 45 amplicons, a DNA variant was present, which allowed verification of the detection capacity during the validation process. After optimization of the original design, the overall analytical sensitivity of CSCE for the SACS gene was 100%, and the analytical specificity of CSCE was 99.8%. In conclusion, CSCE is a robust technique with a high analytical sensitivity and specificity, and it can readily be used for mutation scanning of the large SACS gene. Furthermore this technique is less time-consuming and less expensive, as compared with standard automated sequencing. PMID- 19779134 TI - A new chromosome x exon-specific microarray platform for screening of patients with X-linked disorders. AB - Recent studies and advances in high-density oligonucleotide arrays have shown that microdeletions and microduplications occur at a high frequency in the human genome, causing various genetic conditions including mental retardation. Thus far little is known about the pathways leading to this disease, and implementation of microarrays is hampered by their increasing cost and complexity, underlining the need for new diagnostic tools. The aim of this study was to introduce a new targeted platform called "chromosome X exon-specific array" and to apply this new platform to screening of 20 families (including one blind positive control) with suspected X-linked mental retardation, to identify new causative X-linked mental retardation genes. The new microarray contains of 21,939 oligonucleotides covering 92.9% of all exons of all genes on chromosome X. Patient screening resulted in successful identification of the blind positive control included in the sample of 20 families, and one of the remaining 19 families was found to carry a 1.78-kilobase deletion involving all exons of pseudogene BRAF2. The BRAF2 deletion segregated in the family and was not found in 200 normal male samples, and no copy number variations are reported in this region. Further studies and focused investigation of X-linked disorders have the potential to reveal the molecular basis of human genetic pathological conditions that are caused by copy number changes in chromosome X genes. PMID- 19779135 TI - Enrichment of cholesterol in microdissected Alzheimer's disease senile plaques as assessed by mass spectrometry. AB - Extensive knowledge of the protein components of the senile plaques, one of the hallmark lesions of Alzheimer's disease, has been acquired over the years, but their lipid composition remains poorly known. Evidence suggests that cholesterol contributes to the pathogenesis of Alzheimer's disease. However, its presence within senile plaques has never been ascertained with analytic methods. Senile plaques were microdissected from sections of the isocortex in three Braak VI Alzheimer's disease cases and compared with a similar number of samples from the adjoining neuropil, free of amyloid-beta peptide (A beta) deposit. Two cases were apo epsilon 4/apo epsilon 3, and one case was apo epsilon 3/apoepsilon3. A known quantity of (13)C-labeled cholesterol was added to the samples as a standard. After hexane extraction, cholesterol content was analyzed by liquid chromatography coupled with electrospray ionization mass spectrometry. The mean concentration of free cholesterol was 4.25 +/- 0.1 attomoles/microm(3) in the senile plaques and 2.2 +/- 0.49 attomoles/microm(3) in the neuropil (t = 4.41, P < 0.0009). The quantity of free cholesterol per senile plaque (67 +/- 16 femtomol) is similar to the published quantity of A beta peptide. The highly significant increase in the cholesterol concentration, associated with the increased risk of Alzheimer's disease linked to the apo epsilon 4 allele, suggests new pathogenetic mechanisms. PMID- 19779136 TI - Advanced glycation end product receptor-1 transgenic mice are resistant to inflammation, oxidative stress, and post-injury intimal hyperplasia. AB - The high levels of oxidative stress (OS) and inflammation associated with cardiovascular disease are linked to pro-oxidants such as advanced glycation end products (AGEs). AGEs interact with multiple receptors, including receptor 1 (AGER1), which promotes AGE removal and blocks OS and inflammation, and RAGE, which enhances inflammation. In this study, we evaluated metabolic and vascular changes in AGER1 transgenic mice (AGER1-tg) subjected to an atherogenic diet and arterial wire-injury. Both baseline and postatherogenic diet serum and tissue AGEs as well as plasma 8-isoprostane levels were lower in AGER1-tg mice than in wild-type mice. The levels of injected (125)I-AGE in tissues were decreased as well in AGER1-tg mice. After ingesting a high-fat diet, AGER1-tg mice had a normal glucose tolerance and only 7% were hyperglycemic, whereas 53% of wild-type mice had stable hyperglycemia. After wire-injury, intimal lesions in AGER1-tg mice were small, whereas wild-type mice had diffuse intimal hyperplasia, a high intima/media ratio, and inflammatory cell infiltrates. In addition, AGER1 staining, prominent in AGER1-tg mice, was attenuated in 30 to 40% of wild-type cells, although all cells were strongly positive for AGEs. Thus, AGER1 overexpression in mice reduces basal levels of AGEs and OS, enhances resistance to diet-induced hyperglycemia and OS, and protects against injury-induced arterial intimal hyperplasia and inflammation, providing protection against OS and inflammation induced by AGEs and high-fat diets in vivo. PMID- 19779137 TI - Degenerating synaptic boutons in prion disease: microglia activation without synaptic stripping. AB - A growing body of evidence suggests that the loss of synapses is an early and major component of a number of neurodegenerative diseases. Murine prion disease offers a tractable preparation in which to study synaptic loss in a chronic neurodegenerative disease and to explore the underlying mechanisms. We have previously shown that synaptic loss in the hippocampus underpins the first behavioral changes and that there is a selective loss of presynaptic elements. The microglia have an activated morphology at this stage but they have an anti inflammatory phenotype. We reasoned that the microglia might be involved in synaptic stripping, removing synapses undergoing a degenerative process, and that this gives rise to the anti-inflammatory phenotype. Analysis of synaptic density revealed a progressive loss from 12 weeks post disease initiation. The loss of synapses was not associated with microglia processes; instead, we found that the postsynaptic density of the dendritic spine was progressively wrapped around the degenerating presynaptic element with loss of subcellular components. Three dimensional reconstructions of these structures from Dual Beam electron microscopy support the conclusion that the synaptic loss in prion disease is a neuron autonomous event facilitated without direct involvement of glial cells. Previous studies described synapse engulfment by developing and injured neurons, and we suggest that this mechanism may contribute to developmental and pathological changes in synapse numbers. PMID- 19779138 TI - Lipopolysaccharide-induced epithelial monoamine oxidase mediates alveolar bone loss in a rat chronic wound model. AB - Reactive oxygen species (ROS) production is an antimicrobial response to pathogenic challenge that may, in the case of persistent infection, have deleterious effects on the tissue of origin. A rat periodontal disease model was used to study ROS-induced chronic epithelial inflammation and bone loss. Lipopolysaccharide (LPS) was applied for 8 weeks into the gingival sulcus, and histological analysis confirmed the onset of chronic disease. Junctional epithelium was collected from healthy and diseased animals using laser-capture microdissection, and expression microarray analysis was performed. Of 19,730 genes changed in disease, 42 were up-regulated >/=4-fold. Three of the top 10 LPS induced genes, monoamine oxidase B (MAO/B) and flavin-containing monooxygenase 1 and 2, are implicated in ROS signaling. LPS-associated induction of the ROS mediator H(2)O(2), as well as MAO/B and tumor necrosis factor (TNF)-alpha levels were validated in the rat histological sections and a porcine junctional epithelial cell culture model. Topical MAO inhibitors significantly counteracted LPS-associated elevation of H(2)O(2) production and TNF-alpha expression in vivo and in vitro, inhibited disease-associated apical migration and proliferation of junctional epithelium and inhibited induced systemic H(2)O(2) levels and alveolar bone loss in vivo. These results suggest that LPS induces chronic wounds via elevated MAO/B-mediated increases in H(2)O(2) and TNF-alpha activity by epithelial cells and is further associated with more distant effects on systemic oxidative stress and alveolar bone loss. PMID- 19779139 TI - Autocrine loop between vascular endothelial growth factor (VEGF)-C and VEGF receptor-3 positively regulates tumor-associated lymphangiogenesis in oral squamoid cancer cells. AB - Numerous past studies have suggested a critical role of the paracrine effect between tumor vascular endothelial growth factor (VEGF)-C and lymphatic FLT-4 in solid tumor-associated lymphangiogenesis. In contrast, the pathophysiological role of tumor cell-associated FLT-4 in tumor progression remains to be elucidated. Here, we investigated this role using a tumor implantation model. SAS cells, an oral squamous carcinoma cell line expressing both VEGF-C and FLT-4 but neither FLK-1/KDR nor VEGF-D were adopted for experiments. Stable transformants of dominant-negative (dn) SAS cells were established in which the cytoplasmic domain-deleted FLT-4 was exogenously overexpressed, which can lead to inactivation of endogenous FLT-4 through competitive antagonism and is associated with down-activation of endogenous FLT-4-related intracellular signals. In vitro and in vivo proliferation assays showed lower proliferative activity of dn-SAS cells. An immunohistochemical study revealed that the tumor lymphangiogenesis was significantly suppressed, and the level of human VEGF-C mRNA was significantly lower in dn-SAS cell-derived tumor tissues. Moreover, in vitro studies demonstrated that the significant suppression of VEGF-C and VEGF-A expression was evident in dn-SAS cells or wild-type SAS cells treated with either the FLT-4 kinase inhibitor MAZ51 or the inhibitor of FLT-4-related signals. These findings together suggested that the VEGF-C/FLT-4 autocrine loop in tumor cells was a potential enhancer system to promote cancer progression, and FLT-4 in tumor tissue might become an effective target for cancer therapy. PMID- 19779140 TI - Nitric oxide induces the progression of abdominal aortic aneurysms through the matrix metalloproteinase inducer EMMPRIN. AB - Nitric Oxide (NO) is involved in the development and progression of abdominal aortic aneurysms (AAA). We found that inhibition of inducible NO synthase (iNOS) protects mice in an elastase-induced AAA model, significantly inhibiting the production of matrix metalloproteinase-13 (MMP-13). The extracellular MMP inducer (EMMPRIN; CD147) was increased in human AAA biopsies and in wild-type murine AAA but not in AAA from iNOS null mice. In cells overexpressing ectopic EMMPRIN, MMP 13 secretion was stimulated, whereas silencing of EMMPRIN by RNA interference led to significant inhibition of MMP-13 expression. In addition, elastase infusion of MMP-13 null mouse aortas induced a significant increase of EMMPRIN but reduced aortic dilatation when compared with wild-type mice, suggesting that NO-mediated AAA may be mediated through EMMPRIN induction of MMP-13. These findings were further verified in elastase-infused iNOS null mice, in which daily administration of NO caused a significant aortic dilatation and the expression of EMMPRIN and MMP-13. By contrast, in iNOS wild-type mice, pharmacological inhibition of iNOS by administration of 1400 W induced a reduction of aortic diameter and inhibition of MMP-13 and EMMPRIN expression when compared with control mice. Our results suggest that NO may regulate the development of AAA in part by inducing the expression of EMMPRIN and modulating the activity of MMP-13 in murine and human aneurysms. PMID- 19779141 TI - Pain catastrophizing mediates the relationship between self-reported strenuous exercise involvement and pain ratings: moderating role of anxiety sensitivity. AB - OBJECTIVE: To investigate the cross-sectional associations among self-reported weekly strenuous exercise bouts, anxiety sensitivity, and their interaction with pain catastrophizing and pain responses to the cold pressor task (CPT) in healthy, ethnically diverse young adults (n = 79). Exercise involvement has been shown to have hypoalgesic effects and cognitive factors may partially explain this effect. Particularly, alterations in pain catastrophizing have been found to mediate the positive pain outcomes of multidisciplinary treatments incorporating exercise. Further, recent evidence suggests that exercise involvement and anxiety sensitivity may act together, as interacting factors, to exert an effect on catastrophizing and pain outcomes; however, further research is needed to clarify the nature of this interaction. METHODS: Before the CPT, participants were asked to complete the Godin Leisure-Time Exercise Questionnaire, the Beck Depression Inventory, and the Anxiety Sensitivity Index. After the CPT, participants completed a modified version of the Pain Catastrophizing Scale and the Short Form McGill Pain Questionnaire. RESULTS: At a high level of anxiety sensitivity, controlling for depressive symptoms, CPT immersion time, and sex differences, a bias-corrected (BC), bootstrapped confidence interval revealed that pain catastrophizing significantly mediated the relationship between self-reported weekly strenuous exercise bouts and pain response (95% BC Confidence Interval = 9.558, -0.800 with 1000 resamples). At intermediate and low levels of anxiety sensitivity, no significant mediation effects were found. CONCLUSIONS: These findings support that, for pain catastrophizing to mediate the strenuous exercise pain response relation, individuals must possess a high level of anxiety sensitivity. PMID- 19779142 TI - A meta-analytic review of the effects of childhood abuse on medical outcomes in adulthood. AB - OBJECTIVE: To summarize the relationship between abuse during childhood and physical health outcomes in adulthood and to examine the role of potential moderators, such as the type of health outcome assessed, gender, age, and the type of abuse. Studies using self-report assessment methods were compared with studies using objective or independently verifiable methods. METHOD: The current study is a quantitative meta-analysis comparing results from 78 effect sizes across 24 studies including 48,801 individuals. RESULTS: Experiencing child abuse was associated with an increased risk of negative physical health outcomes in adulthood (effect size d = 0.42, 95% Confidence Interval = 0.39-0.45). Neurological and musculoskeletal problems yielded the largest effect sizes, followed by respiratory problems, cardiovascular disease, gastrointestinal and metabolic disorders. Effect sizes were larger when the sample was exclusively female and when the abuse was assessed via self-report rather than objective, independently verifiable methods. CONCLUSIONS: Child abuse is associated with an increased risk of poor physical health in adulthood. The magnitude of the risk is comparable to the association between child abuse and poor psychological outcomes. However, studies often fail to include a diverse group of participants, resulting in a limited ability to draw conclusions about the population of child abuse survivors as a whole. Important methodological improvements are also needed to better understand potential moderators. PMID- 19779143 TI - A general enhancement of autonomic and cortisol responses during social evaluative threat. AB - OBJECTIVE: To examine the Social Self Preservation Theory, which predicts that stressors involving social evaluative threat (SET) characteristically activate the hypothalamic-pituitary-adrenal (HPA) axis. The idea that distinct psychosocial factors may underlie specific patterns of neuroendocrine stress responses has been a topic of recurrent debate. METHODS: Sixty-one healthy university students (n = 31 females) performed a challenging speech task in one of three conditions that aimed to impose increasing levels of SET: performing the task alone (no social evaluation), with one evaluating observer, or with four evaluating observers. Indices of sympathetic (preejection period) and parasympathetic (heart rate variability) cardiac drive were obtained by impedance and electrocardiography. Salivary cortisol was used to index HPA activity. Questionnaires assessed affective responses. RESULTS: Affective responses (shame/embarrassment, anxiety, negative affect, and self-esteem), cortisol, heart rate, sympathetic and parasympathetic activation all differentiated evaluative from nonevaluative task conditions (p < .001). The largest effect sizes were observed for cardiac autonomic responses. Physiological reactivity increased in parallel with increasing audience size (p < .001). An increase in cortisol was predicted by sympathetic activation during the task (p < .001), but not by affective responses. CONCLUSION: It would seem that SET determines the magnitude, rather than the pattern, of physiological activation. This potential to perturb broadly multiple physiological systems may help explain why social stress has been associated with a range of health outcomes. We propose a threshold activation model as a physiological explanation for why engaging stressors, such as those involving social evaluation or uncontrollability, may seem to induce selectively cortisol release. PMID- 19779144 TI - Impaired role functioning and treatment rates for mental disorders and chronic physical disorders in metropolitan China. AB - OBJECTIVES: To compare impairments in role functioning and treatment rate of mental disorders and chronic physical disorders in the general population of metropolitan China. METHOD: Face-to-face household interviews of 5201 people aged 18 to 70 years in Beijing and Shanghai were conducted from November 2001 to February 2002, using a multistage household probability sampling method. The World Mental Health version of the Composite International Diagnostic Interview (WMH-CIDI) was used for assessing sociodemographic characteristics, diagnoses, and treatment. The Sheehan Disability Scale (SDS) was used to measure disorder specific role impairment. RESULTS: Respondents generally attributed greater impairment to mental disorders than to chronic physical disorders, although there were some variations among specific disorders. This general pattern was supported by within-person comparison of impairment associated with a mental disorder versus any chronic physical disorder. Depression, generalized anxiety disorder, and specific phobia were the most impairing mental disorders. Diabetes, headaches, and asthma were the most impairing physical disorders. Comorbid mental and physical disorders were associated with more severe impairment. A much lower percentage of respondents with mental disorders (3.0%) than chronic physical disorders (42.8%) received treatment in the previous 12 months. CONCLUSION: Common mental disorders were associated with greater impairment than chronic physical disorders but were markedly undertreated. They warrant prioritization in the allocation of healthcare resources in China. PMID- 19779145 TI - Depressive symptomatology, rather than neuroticism, predicts inflated physical symptom reports in community-residing women. AB - OBJECTIVE: To examine the roles of depressive symptomatology and neuroticism/negative affect (N/NA) on common physical symptom reporting in a sample of community residents. METHODS: Community-residing women (n = 108) participated in a combined concurrent-retrospective design. Physical symptoms were assessed concurrently over 21 consecutive days followed by a retrospective assessment of the collective symptom experience for the same time period. RESULTS: Based on evidence of differences in cognitive processing of emotion relevant material, we predicted and found that depressive symptomatology (at baseline) was a stronger predictor of inflated physical symptom recall than N/NA. Depressive symptomatology was also a stronger, independent predictor of concurrent physical symptoms. Notably, these results were obtained even when physical depressive symptoms in both the physical symptom checklist and the baseline depression assessment were eliminated. CONCLUSIONS: The results suggest that the classic symptom perception hypothesis should be refined and operationalized in terms of depressive symptomatology rather than N/NA. This study demonstrates how cognitive-affective processing differences associated with depressive symptomatology can shed additional light on the psychology of symptom perception. Implications for treatment seeking, medical diagnoses, and treatment decisions are discussed. PMID- 19779147 TI - Planetary science. A lunar waterworld. PMID- 19779146 TI - Autonomy of autonomic dysfunction in major depression. AB - OBJECTIVE: To investigate cardiac autonomic dysfunction in patients with major depressive disorder (MDD). Research in this area has faced several limitations because of the heterogeneity of the disease, the influence of medication, and methodological shortcomings. METHODS: Participants were 75 patients suffering from an acute recurrent episode of MDD and 75 matched controls. All participants were assessed at baseline for linear and nonlinear parameters of heart rate variability, QT variability and baroreflex sensitivity. Participants with MDD were reassessed after 7 to 9 days of treatment with either a selective serotonin reuptake inhibitor (SSRI) or a serotonin and noradrenaline selective reuptake inhibitor (SNRI) antidepressant. RESULTS: In the initial examination, patients showed an overall shift of autonomic balance toward sympathetic predominance as compared with matched controls, with a decrease in parasympathetic parameters and baroreflex sensitivity, and an increase in sympathetically influenced QT variability. Overall, antidepressant treatment exacerbated this imbalance, with differential effects observed for SSRI and SNRI treatment. In contrast to autonomic dysfunction in other disorders, such as schizophrenia, autonomic dysfunction in MDD appeared to be independent of disease severity. CONCLUSIONS: Patients suffering from MDD show profound autonomic dysfunction, which is exacerbated by SNRI and to a lesser degree by SSRI treatment. This information could prove important when selecting antidepressant medication for patients at risk for cardiac arrhythmias. PMID- 19779149 TI - Temporal and spatial variability of lunar hydration as observed by the Deep Impact spacecraft. AB - The Moon is generally anhydrous, yet the Deep Impact spacecraft found the entire surface to be hydrated during some portions of the day. Hydroxyl (OH) and water (H2O) absorptions in the near infrared were strongest near the North Pole and are consistent with <0.5 weight percent H2O. Hydration varied with temperature, rather than cumulative solar radiation, but no inherent absorptivity differences with composition were observed. However, comparisons between data collected 1 week (a quarter lunar day) apart show a dynamic process with diurnal changes in hydration that were greater for mare basalts (approximately 70%) than for highlands (approximately 50%). This hydration loss and return to a steady state occurred entirely between local morning and evening, requiring a ready daytime source of water-group ions, which is consistent with a solar wind origin. PMID- 19779148 TI - Amyloid-beta dynamics are regulated by orexin and the sleep-wake cycle. AB - Amyloid-beta (Abeta) accumulation in the brain extracellular space is a hallmark of Alzheimer's disease. The factors regulating this process are only partly understood. Abeta aggregation is a concentration-dependent process that is likely responsive to changes in brain interstitial fluid (ISF) levels of Abeta. Using in vivo microdialysis in mice, we found that the amount of ISF Abeta correlated with wakefulness. The amount of ISF Abeta also significantly increased during acute sleep deprivation and during orexin infusion, but decreased with infusion of a dual orexin receptor antagonist. Chronic sleep restriction significantly increased, and a dual orexin receptor antagonist decreased, Abeta plaque formation in amyloid precursor protein transgenic mice. Thus, the sleep-wake cycle and orexin may play a role in the pathogenesis of Alzheimer's disease. PMID- 19779151 TI - Character and spatial distribution of OH/H2O on the surface of the Moon seen by M3 on Chandrayaan-1. AB - The search for water on the surface of the anhydrous Moon had remained an unfulfilled quest for 40 years. However, the Moon Mineralogy Mapper (M3) on Chandrayaan-1 has recently detected absorption features near 2.8 to 3.0 micrometers on the surface of the Moon. For silicate bodies, such features are typically attributed to hydroxyl- and/or water-bearing materials. On the Moon, the feature is seen as a widely distributed absorption that appears strongest at cooler high latitudes and at several fresh feldspathic craters. The general lack of correlation of this feature in sunlit M3 data with neutron spectrometer hydrogen abundance data suggests that the formation and retention of hydroxyl and water are ongoing surficial processes. Hydroxyl/water production processes may feed polar cold traps and make the lunar regolith a candidate source of volatiles for human exploration. PMID- 19779152 TI - Detection of adsorbed water and hydroxyl on the Moon. AB - Data from the Visual and Infrared Mapping Spectrometer (VIMS) on Cassini during its flyby of the Moon in 1999 show a broad absorption at 3 micrometers due to adsorbed water and near 2.8 micrometers attributed to hydroxyl in the sunlit surface on the Moon. The amounts of water indicated in the spectra depend on the type of mixing and the grain sizes in the rocks and soils but could be 10 to 1000 parts per million and locally higher. Water in the polar regions may be water that has migrated to the colder environments there. Trace hydroxyl is observed in the anorthositic highlands at lower latitudes. PMID- 19779150 TI - Detection of gamma rays from a starburst galaxy. AB - Starburst galaxies exhibit in their central regions a highly increased rate of supernovae, the remnants of which are thought to accelerate energetic cosmic rays up to energies of approximately 10(15) electron volts. We report the detection of gamma rays--tracers of such cosmic rays--from the starburst galaxy NGC 253 using the High Energy Stereoscopic System (H.E.S.S.) array of imaging atmospheric Cherenkov telescopes. The gamma-ray flux above 220 billion electron volts is F = (5.5 +/- 1.0(stat) +/- 2.8(sys)) x 10(-13) cm(-2) s(-1), implying a cosmic-ray density about three orders of magnitude larger than that in the center of the Milky Way. The fraction of cosmic-ray energy channeled into gamma rays in this starburst environment is five times as large as that in our Galaxy. PMID- 19779153 TI - Microgravity alters respiratory abdominal and rib cage motion during sleep. AB - The abdominal and rib cage contributions to tidal breathing differ between rapid eye-movement (REM) and non-NREM sleep. We hypothesized that abdominal relative contribution during NREM and REM sleep would be altered in different directions when comparing sleep on Earth with sleep in sustained microgravity (microG), due to conformational changes and differences in coupling between the rib cage and the abdominal compartment induced by weightlessness. We studied respiration during sleep in five astronauts before, during, and after two Space Shuttle missions. A total of 77 full-night (8 h) polysomnographic studies were performed; abdominal and rib cage respiratory movements were recorded using respiratory inductive plethysmography. Breath-by-breath analysis of respiration was performed for each class: awake, light sleep, deep sleep, and REM sleep. Abdominal contribution to tidal breathing increased in microG, with the first measure in space being significantly higher than preflight values, followed by a return toward preflight values. This was observed for all classes. Preflight, rib cage, and abdominal movements were found to be in phase for all but REM sleep, for which an abdominal lead was observed. The abdominal leading role during REM sleep increased while deep sleep showed the opposite behavior, the rib cage taking a leading role in-flight. In microG, the percentage of inspiratory time in the overall breath, the duty cycle (T(I)/T(Tot)), decreased for all classes considered when compared with preflight, while normalized inspiratory flow, taking the awake values as reference, increased in-flight for light sleep, deep sleep, and REM. Changes in abdominal-rib cage displacements probably result from a less efficient operating point for the diaphragm and a less efficient coupling between the abdomen and the apposed portion of the rib cage in microG. However, the preservation of total ventilation suggests that short-term adaptive mechanisms of ventilatory control compensate for these mechanical changes. PMID- 19779154 TI - Doxorubicin acts through tumor necrosis factor receptor subtype 1 to cause dysfunction of murine skeletal muscle. AB - Cancer patients receiving doxorubicin chemotherapy experience both muscle weakness and fatigue. One postulated mediator of the muscle dysfunction is an increase in tumor necrosis factor-alpha (TNF), a proinflammatory cytokine that mediates limb muscle contractile dysfunction through the TNF receptor subtype 1 (TNFR1). Our main hypothesis was that systemic doxorubicin administration would cause muscle weakness and fatigue. Systemic doxorubicin administration (20 mg/kg) depressed maximal force of the extensor digitorum longus (EDL; P < 0.01), accelerated EDL fatigue (P < 0.01), and elevated serum TNF levels (P < 0.05) 72 h postinjection. Genetic TNFR1 deficiency prevented the fall in specific force caused by systemic doxorubicin, without protecting against fatigue (P < 0.01). These results demonstrate that clinical doxorubicin concentrations disrupt limb muscle function in a TNFR1-dependent manner. PMID- 19779155 TI - Coupling between the blood lactate-to-pyruvate ratio and MCA Vmean at the onset of exercise in humans. AB - Activation-induced increase in cerebral blood flow is coupled to enhanced metabolic activity, maybe with brain tissue redox state and oxygen tension as key modulators. To evaluate this hypothesis at the onset of exercise in humans, blood was sampled at 0.1 to 0.2 Hz from the radial artery and right internal jugular vein, while middle cerebral artery mean flow velocity (MCA V(mean)) was recorded. Both the arterial and venous lactate-to-pyruvate ratio increased after 10 s (P < 0.05), and the arterial ratio remained slightly higher than the venous (P < 0.05). The calculated average cerebral capillary oxygen tension decreased by 2.7 mmHg after 5 s (P < 0.05), while MCA V(mean) increased only after 30 s. Furthermore, there was an unaccounted cerebral carbohydrate uptake relative to the uptake of oxygen that became significant 50 s after the onset of exercise. These findings support brain tissue redox state and oxygenation as potential modulators of an increase in cerebral blood flow at the onset of exercise. PMID- 19779156 TI - Impaired overload-induced hypertrophy in obese Zucker rat slow-twitch skeletal muscle. AB - The effect of insulin resistance (IR) on the adaptation of skeletal muscle loading is not well understood. Here we examine whether the soleus muscles of the lean Zucker (LZ) and insulin-resistant obese Zucker (OZ) rat exhibit differences in their ability to undergo muscle hypertrophy following 8 wk of mechanical overload. Four-week-old male LZ (n = 5) and OZ (n = 5) rats underwent unilateral surgical ablation of the gastrocnemius muscle while the contralateral hindlimb was used as an internal control. Mechanical overload increased soleus muscle wet weight (LZ 57% and OZ 33%, respectively; P < 0.05) and average type 1 fiber cross sectional area (LZ 32% and OZ 5%, respectively; P < 0.05) in LZ and OZ rats, while the magnitude of these increases was greater in the LZ animals (P < 0.05). The reduced degree of muscle hypertrophy observed in the OZ animals was associated with decreases in the ability of the OZ soleus muscle to phosphorylate p70s6k(Thr 389) and mTOR, while phosphorylation of p70s6k(Thr 389) was increased in the LZ overloaded soleus by 83% (P < 0.05). The amount of Tuberin/TSC2 phosphorylation, an inhibitor of mTOR, was unchanged in the LZ soleus after overload while it was increased (68.3%, P < 0.05) in OZ animals. Conversely, AMPK phosphorylation was decreased in the LZ (-22.77%, P < 0.05) but increased (57%, P < 0.05) in the OZ soleus with overload. Taken together, these data suggest that IR or other related comorbidities may impair the ability of the soleus to activate mTOR signaling and undergo load-induced muscle hypertrophy. PMID- 19779157 TI - Carbon capture and sequestration. PMID- 19779158 TI - Human exploration. Obama facing tough decision on whether to keep aiming for the moon. PMID- 19779159 TI - National Institutes of Health. Grants 'below payline' rise to help new investigators. PMID- 19779161 TI - Life sciences. A new biology to mend society's woes. PMID- 19779164 TI - Germany. Election heats up nuclear debate. PMID- 19779162 TI - Profile: Kim Chin-Kyung. The force behind North Korea's new science university. PMID- 19779165 TI - Astronomy. Who will pay for China's planned X-ray satellite? PMID- 19779166 TI - Psychology. The theory? Diet causes violence. The lab? Prison. PMID- 19779167 TI - Astronomy. Exotic telescopes prepare to probe era of first stars and galaxies. PMID- 19779168 TI - The Gonzo Scientist. Do scientists like green porno? PMID- 19779169 TI - Geophysics. Scoping out unseen forces shaping North America. PMID- 19779171 TI - Forecast for reproducible data: partly cloudy. PMID- 19779172 TI - Preserving starry nights. PMID- 19779173 TI - Life in science. Having a blast in Kenya. PMID- 19779174 TI - Immune system: not so superior. PMID- 19779175 TI - Comment on "Infants' perseverative search errors are induced by pragmatic misinterpretation". AB - Topal et al. (Reports, 26 September 2008, p. 1831) proposed that infants' perseverative search errors can be explained by ostensive cues from the experimenter. We use the dynamic field theory to test the proposal that infants encode locations more weakly when social cues are present. Quantitative simulations show that this account explains infants' performance without recourse to the theory of natural pedagogy. PMID- 19779176 TI - Science education. Revising the AP biology curriculum. PMID- 19779177 TI - Physiology. Unraveling traveling. PMID- 19779178 TI - Chemistry. A new departure in fluorination chemistry. PMID- 19779179 TI - Chemistry. Tin takes ethylene on--and off. PMID- 19779180 TI - Chemistry. Emergent or just complex? PMID- 19779181 TI - Materials science. Simulating multifunctional structures. PMID- 19779182 TI - Cell biology. Evolving cell signals. PMID- 19779183 TI - Carbon capture and sequestration. Clearing the air. Introduction. PMID- 19779184 TI - Round and round: a guide to the carbon cycle. PMID- 19779185 TI - Carbon sequestration. PMID- 19779186 TI - China grapples with a burning question. PMID- 19779187 TI - Carbon capture and storage: how green can black be? AB - The capture of carbon dioxide at the point of emission from coal- or gas-burning power plants is an attractive route to reducing carbon dioxide emissions into the atmosphere. To commercialize carbon capture, as well as transport of liquified carbon dioxide and its storage in exploited oil fields or saline formations, many technological, commercial, and political hurdles remain to be overcome. Urgent action is required if carbon capture and storage is to play a large role in limiting climate change. PMID- 19779188 TI - Amine scrubbing for CO2 capture. AB - Amine scrubbing has been used to separate carbon dioxide (CO2) from natural gas and hydrogen since 1930. It is a robust technology and is ready to be tested and used on a larger scale for CO2 capture from coal-fired power plants. The minimum work requirement to separate CO2 from coal-fired flue gas and compress CO2 to 150 bar is 0.11 megawatt-hours per metric ton of CO2. Process and solvent improvements should reduce the energy consumption to 0.2 megawatt-hour per ton of CO2. Other advanced technologies will not provide energy-efficient or timely solutions to CO2 emission from conventional coal-fired power plants. PMID- 19779189 TI - Why capture CO2 from the atmosphere? AB - Air capture is an industrial process for capturing CO2 from ambient air; it is one of an emerging set of technologies for CO2 removal that includes geological storage of biotic carbon and the acceleration of geochemical weathering. Although air capture will cost more than capture from power plants when both are operated under the same economic conditions, air capture allows one to apply industrial economies of scale to small and mobile emission sources and enables a partial decoupling of carbon capture from the energy infrastructure, advantages that may compensate for the intrinsic difficulty of capturing carbon from the air. PMID- 19779190 TI - Onshore geologic storage of CO2. AB - The possibility that substantial quantities of CO2 can be injected into subsurface porous rock formations has been investigated sufficiently to show that pore space available to contain the CO2 is abundant. Multiple rock types and physical mechanisms can be used to trap the CO2 indefinitely. With careful site selection and operations, leakage to the near-surface region can be avoided. The next step is to test these injection processes at the scale of a large power plant. PMID- 19779191 TI - Storage of carbon dioxide in offshore sediments. AB - The battle to reduce greenhouse gas emissions and prevent the most dangerous consequences of climate change will be waged across multiple fronts, including efforts to increase energy efficiency; efforts to deploy nonfossil fuel sources, including renewable and nuclear energy; and investment in adaptation to reduce the impacts of the climate change that will occur regardless of the actions we take. But with more than 80% of the world's energy coming from fossil fuel, winning the battle also requires capturing CO2 from large stationary sources and storing that CO2 in geologic repositories. Offshore geological repositories have received relatively little attention as potential CO2 storage sites, despite their having a number of important advantages over onshore sites, and should be considered more closely. PMID- 19779192 TI - Oceanic spawning migration of the European eel (Anguilla anguilla). AB - European eels (Anguilla anguilla) undertake a approximately 5000-kilometer (km) spawning migration from Europe to the Sargasso Sea. The larvae are transported back to European waters by the Gulf Stream and North Atlantic Drift. However, details of the spawning migration remain unknown because tracking eels in the Atlantic Ocean has, so far, eluded study. Recent advances in satellite tracking enable investigation of migratory behavior of large ocean-dwelling animals. However, sizes of available tags have precluded tracking smaller animals like European eels. Here, we present information about the swimming direction, depth, and migratory behavior of European eels during spawning migration, based on a miniaturized pop-up satellite archival transmitter. Although the tagging experiment fell short of revealing the full migration to the Sargasso Sea, the data covered the first 1300 km and provided unique insights. PMID- 19779193 TI - Reversible reactions of ethylene with distannynes under ambient conditions. AB - Ethylene's cycloadditions to unsaturated hydrocarbons occupy well-established ground in classical organic chemistry. In contrast, its reactivity toward alkene and alkyne analogs of carbon's heavier-element congeners silicon, germanium, tin, or lead has been little explored. We show here that treatment of the distannynes Ar(iPr4)SnSnAr(iPr4) [Ar(iPr4) = C6H3-2,6(C6H3-2,6-iPr2)2, 1] or Ar(iPr8)SnSnAr(iPr8) [Ar(iPr8) = C6H-2,6(C6H2-2,4,6-iPr3)2-3,5-iPr2, 2] with ethylene under ambient conditions affords the cycloadducts Ar(iPr4) Sn(mu2:nu1:n1 C2H4)2Sn Ar(iPr4 (3) or Ar(iPrs) Sn(mu2:nu1:nu1-C2H4)2Sn AriPrs (4) that were structurally and spectroscopically characterized. Ethylene incorporation in 3 and 4 involves tin-carbon sigma bonding and is shown to be fully reversible under ambient conditions; hydrocarbon solutions of 3 or 4 revert to the distannynes 1 or 2 with ethylene elimination under reduced pressure or upon standing at approximately 25 degrees C. Variable-temperature proton nuclear magnetic resonance studies showed that the enthalpies of reaction were near -48 (3) and 27 (4) kilojoules per mole. PMID- 19779194 TI - Coordinatively unsaturated Al3+ centers as binding sites for active catalyst phases of platinum on gamma-Al2O3. AB - In many heterogeneous catalysts, the interaction of metal particles with their oxide support can alter the electronic properties of the metal and can play a critical role in determining particle morphology and maintaining dispersion. We used a combination of ultrahigh magnetic field, solid-state magic-angle spinning nuclear magnetic resonance spectroscopy, and high-angle annular dark-field scanning transmission electron microscopy coupled with density functional theory calculations to reveal the nature of anchoring sites of a catalytically active phase of platinum on the surface of a gamma-Al2O3 catalyst support material. The results obtained show that coordinatively unsaturated pentacoordinate Al3+ (Al3+penta) centers present on the (100) facets of the gamma-Al2O3 surface are anchoring Pt. At low loadings, the active catalytic phase is atomically dispersed on the support surface (Pt/Al3+penta = 1), whereas two-dimensional Pt rafts form at higher coverages. PMID- 19779195 TI - Distribution of mid-latitude ground ice on Mars from new impact craters. AB - New impact craters at five sites in the martian mid-latitudes excavated material from depths of decimeters that has a brightness and color indicative of water ice. Near-infrared spectra of the largest example confirm this composition, and repeated imaging showed fading over several months, as expected for sublimating ice. Thermal models of one site show that millimeters of sublimation occurred during this fading period, indicating clean ice rather than ice in soil pores. Our derived ice-table depths are consistent with models using higher long-term average atmospheric water vapor content than present values. Craters at most of these sites may have excavated completely through this clean ice, probing the ice table to previously unsampled depths of meters and revealing substantial heterogeneity in the vertical distribution of the ice itself. PMID- 19779196 TI - Holocene glacier fluctuations in the Peruvian Andes indicate northern climate linkages. AB - The role of the tropics in triggering, transmitting, and amplifying interhemispheric climate signals remains a key debate in paleoclimatology. Tropical glacier fluctuations provide important insight on regional paleoclimatic trends and forcings, but robust chronologies are scarce. Here, we report precise moraine ages from the Cordillera Vilcabamba (13 degrees 20'S) of southern Peru that indicate prominent glacial events and associated climatic shifts in the outer tropics during the early Holocene and late in the "Little Ice Age" period. Our glacier chronologies differ from the New Zealand record but are broadly correlative with well-dated glacial records in Europe, suggesting climate linkages between the tropics and the North Atlantic region. PMID- 19779197 TI - Chloroquine transport via the malaria parasite's chloroquine resistance transporter. AB - The emergence and spread of chloroquine-resistant Plasmodium falciparum malaria parasites has been a disaster for world health. Resistance is conferred by mutations in the Chloroquine Resistance Transporter (PfCRT), an integral membrane protein localized to the parasite's internal digestive vacuole. These mutations result in a marked reduction in the accumulation of chloroquine (CQ) by the parasite. However, the mechanism by which this occurs is unclear. We expressed both wild-type and resistant forms of PfCRT at the surface of Xenopus laevis oocytes. The resistant form of PfCRT transported CQ, whereas the wild-type protein did not. CQ transport via the mutant PfCRT was inhibited by CQ analogs and by the resistance-reverser verapamil. Thus, CQ resistance is due to direct transport of the drug via mutant PfCRT. PMID- 19779198 TI - Global analysis of Cdk1 substrate phosphorylation sites provides insights into evolution. AB - To explore the mechanisms and evolution of cell-cycle control, we analyzed the position and conservation of large numbers of phosphorylation sites for the cyclin-dependent kinase Cdk1 in the budding yeast Saccharomyces cerevisiae. We combined specific chemical inhibition of Cdk1 with quantitative mass spectrometry to identify the positions of 547 phosphorylation sites on 308 Cdk1 substrates in vivo. Comparisons of these substrates with orthologs throughout the ascomycete lineage revealed that the position of most phosphorylation sites is not conserved in evolution; instead, clusters of sites shift position in rapidly evolving disordered regions. We propose that the regulation of protein function by phosphorylation often depends on simple nonspecific mechanisms that disrupt or enhance protein-protein interactions. The gain or loss of phosphorylation sites in rapidly evolving regions could facilitate the evolution of kinase-signaling circuits. PMID- 19779199 TI - Evolution of a novel phenolic pathway for pollen development. AB - Metabolic plasticity, which largely relies on the creation of new genes, is an essential feature of plant adaptation and speciation and has led to the evolution of large gene families. A typical example is provided by the diversification of the cytochrome P450 enzymes in plants. We describe here a retroposition, neofunctionalization, and duplication sequence that, via selective and local amino acid replacement, led to the evolution of a novel phenolic pathway in Brassicaceae. This pathway involves a cascade of six successive hydroxylations by two partially redundant cytochromes P450, leading to the formation of N1,N5 di(hydroxyferuloyl)-N10-sinapoylspermidine, a major pollen constituent and so-far overlooked player in phenylpropanoid metabolism. This example shows how positive Darwinian selection can favor structured clusters of nonsynonymous substitutions that are needed for the transition of enzymes to new functions. PMID- 19779200 TI - On universality in human correspondence activity. AB - The identification and modeling of patterns of human activity have important ramifications for applications ranging from predicting disease spread to optimizing resource allocation. Because of its relevance and availability, written correspondence provides a powerful proxy for studying human activity. One school of thought is that human correspondence is driven by responses to received correspondence, a view that requires a distinct response mechanism to explain e mail and letter correspondence observations. We demonstrate that, like e-mail correspondence, the letter correspondence patterns of 16 writers, performers, politicians, and scientists are well described by the circadian cycle, task repetition, and changing communication needs. We confirm the universality of these mechanisms by rescaling letter and e-mail correspondence statistics to reveal their underlying similarity. PMID- 19779201 TI - Antennal circadian clocks coordinate sun compass orientation in migratory monarch butterflies. AB - During their fall migration, Eastern North American monarch butterflies (Danaus plexippus) use a time-compensated Sun compass to aid navigation to their overwintering grounds in central Mexico. It has been assumed that the circadian clock that provides time compensation resides in the brain, although this assumption has never been examined directly. Here, we show that the antennae are necessary for proper time-compensated Sun compass orientation in migratory monarch butterflies, that antennal clocks exist in monarchs, and that they likely provide the primary timing mechanism for Sun compass orientation. These unexpected findings pose a novel function for the antennae and open a new line of investigation into clock-compass connections that may extend widely to other insects that use this orientation mechanism. PMID- 19779204 TI - What is in a name? Research about case management. PMID- 19779203 TI - Effect of rising chemotherapy costs on the cost savings of colorectal cancer screening. AB - BACKGROUND: Although colorectal cancer screening is cost-effective, it requires a considerable net investment by governments or insurance companies. If screening was cost saving, governments and insurance companies might be more inclined to invest in colorectal cancer screening programs. We examined whether colorectal cancer screening would become cost saving with the widespread use of the newer, more expensive chemotherapies. METHODS: We used the MISCAN-Colon microsimulation model to assess whether widespread use of new chemotherapies would affect the treatment savings of colorectal cancer screening in the general population. We considered three scenarios for chemotherapy use: the past, the present, and the near future. We assumed that survival improved and treatment costs for patients diagnosed with advanced stages of colorectal cancer increased over the scenarios. Screening strategies considered were annual guaiac fecal occult blood testing (FOBT), annual immunochemical FOBT, sigmoidoscopy every 5 years, colonoscopy every 10 years, and the combination of sigmoidoscopy every 5 years and annual guaiac FOBT. Analyses were conducted from the perspective of the health-care system for a cohort of 50-year-old individuals who were at average risk of colorectal cancer and were screened with 100% adherence from age 50 years to age 80 years and followed up until death. RESULTS: Compared with no screening, the treatment savings from preventing advanced colorectal cancer and colorectal cancer deaths by screening more than doubled with the widespread use of new chemotherapies. The lifetime average treatment savings were larger than the lifetime average screening costs for screening with Hemoccult II, immunochemical FOBT, sigmoidoscopy, and the combination of sigmoidoscopy and Hemoccult II (average savings vs costs per individual in the population: Hemoccult II, $1398 vs $859; immunochemical FOBT, $1756 vs $1565; sigmoidoscopy, $1706 vs $1575; sigmoidoscopy and Hemoccult II $1931 vs $1878). Colonoscopy did not become cost saving, but the total net costs of this strategy decreased from $1317 to $296 per individual in the population. CONCLUSIONS: With the increase in chemotherapy costs for advanced colorectal cancer, most colorectal cancer screening strategies have become cost saving. As a consequence, screening is a desirable approach not only to reduce colorectal cancer incidence and mortality but also to control the costs of colorectal cancer treatment. PMID- 19779205 TI - A novel isoform of human LZIP negatively regulates the transactivation of the glucocorticoid receptor. AB - The human leucine zipper protein (LZIP) is a basic leucine zipper transcription factor that is involved in leukocyte migration, tumor suppression, and endoplasmic reticulum stress-associated protein degradation. Although evidence suggests a diversity of roles for LZIP, its function is not fully understood, and the subcellular localization of LZIP is still controversial. We identified a novel isoform of LZIP and characterized its function in ligand-induced transactivation of the glucocorticoid receptor (GR) in COS-7 and HeLa cells. A novel isoform of human LZIP designated as "sLZIP" contains a deleted putative transmembrane domain (amino acids 229-245) of LZIP and consists of 345 amino acids. LZIP and sLZIP were ubiquitously expressed in a variety of cell lines and tissues, with LZIP being much more common. sLZIP was mainly localized in the nucleus, whereas LZIP was located in the cytoplasm. Unlike LZIP, sLZIP was not involved in the chemokine-mediated signal pathway. sLZIP recruited histone deacetylases (HDACs) to the promoter region of the mouse mammary tumor virus luciferase reporter gene and enhanced the activities of HDACs, resulting in suppression of expression of the GR target genes. Our findings suggest that sLZIP functions as a negative regulator in glucocorticoid-induced transcriptional activation of GR by recruitment and activation of HDACs. PMID- 19779206 TI - Neural tube defects in the north of Jordan: is there a seasonal variation? AB - Neural tube defects are serious birth defects of the brain and the spinal cord due to interference with neural tube closure about the 28th day after fertilization. Seasonal variation in the development of neural tube defects has been reported. The objective of this study was to demonstrate any association between the season of conception and the development of neural tube defects in the north of Jordan. For a 7-year period between January 2000 and December 2006, data of 78 neonates born with neural tube defect were analyzed regarding dates of conception in relation to the development of neural tube defects. More affected babies were conceived in the late summer and early autumn. The study demonstrated that seasonality affected the incidence of neural tube defects in the north of Jordan. PMID- 19779207 TI - Modified Atkins diet for the treatment of nonconvulsive status epilepticus in children. AB - The authors describe the use of a modified Atkins diet for the treatment of 2 children with nonconvulsive status epilepticus. Patient 1 was a 4-year-and-11 month-old girl diagnosed with frontal lobe epilepsy. Since the age of 3 years and 10 months, she had daily nonconvulsive status epilepticus resistant to antiepileptic agents. Patient 2 was a 5-year-and-5-month-old girl with subcortical band heterotopia. She had nonconvulsive status epilepticus daily since the age of 5 years. They were treated with the modified Atkins diet, in which carbohydrate intake was restricted to 10 g/d without restriction on protein, caloric, or fluid intake. The nonconvulsive status epilepticus disappeared 5 and 10 days after the initiation of the diet treatment, respectively. They have been on the diet treatment and free from nonconvulsive status epilepticus for 19 and 4 months, respectively. The modified Atkins diet appears to be very effective for the treatment of nonconvulsive status epilepticus. PMID- 19779208 TI - Efficacy and safety of levetiracetam as an add-on therapy in children aged less than 4 years with refractory epilepsy. AB - In the past decade, most studies on levetiracetam were conducted on patients aged > or = 4 years of age. The authors sought to assess the efficacy and safety of levetiracetam as an adjunctive treatment of children <4 years of age with refractory epilepsy. The mean levetiracetam dosage used on the 24 patients in this study was 38.85 mg/kg per day, and the mean duration of treatment was 40 weeks. During the study, levetiracetam was tapered off in 2 patients due to seizure worsening and was discontinued in other 2 patients due to unacceptable adverse effects. Levetiracetam therapy was effective in 58.3% of patients, with 20.8% achieving seizure freedom. Eight patients showed no obvious response and the remaining 2 patients showed divergent responses. Although adverse effects were seen in 37.5% of patients, all adverse effects were tolerable or resolved with time or discontinuation. Therefore, the authors conclude that levetiracetam treatment is effective and safe in young children with refractory epilepsy. PMID- 19779209 TI - Symmetric atrophy of bilateral distal upper extremities and hyperIgEaemia in a male adolescent with Hirayama disease. AB - Hirayama disease is a rare neuromuscular disorder with peak age of onset at 15 to 17 years among young males. We report a male adolescent presenting with symmetric weakness and atrophy of bilateral upper extremities progressing for 2 years before stabilizing. Otherwise, he did not complain of any sensory disturbance. Electrophysiological findings revealed motor neuron damage at the C7-T1 spinal segments. Cervical magnetic resonance imaging revealed a high-signal mass of posterior dural sac at the C5-T5 vertebral level during neck flexion. Specifically, he had elevated serum total immunoglobulin E level, which had been postulated to be a precipitating factor in Hirayama disease. Early recognition and intervention of this unique neuromuscular disorder is important to avoid ongoing damage to motor neurons. Through this report, we would like to emphasize the crucial role of a pediatric neurologist in averting the progression of Hirayama disease at an early stage. PMID- 19779210 TI - Raised inflammatory markers in semen from men with asymptomatic chlamydial infection. AB - The aim of this study was to determine whether interleukin (IL)-6 and IL-8 concentrations, as well as numbers of seminal leukocytes in a population of infertile men, some of whom were Chlamydia trachomatis positive, were related to chlamydial infection. Our patient group included 255 men attending for diagnostic semen analysis as part of infertility investigations. Significantly raised levels of IL-8, but not IL-6, were found in C trachomatis-infected patients but not in uninfected patients. Raised IL-8 levels in semen were also associated with an increase in semen volume. There was a relationship between C trachomatis infection and lower progressive motile sperm, as well as an increase in seminal leukocytes. The overall prevalence rate for C trachomatis was 6.2%, and more infections were detected in semen than in first void urine. This study supports the suggestion that IL-8 might be used as a marker for male genital tract infection, especially when due to C trachomatis. In this study, there was a relationship between the presence of C trachomatis in semen and alterations of some semen parameters. Further investigations should be performed to understand the disparities of first void urine and semen testing for detection of C trachomatis in males. PMID- 19779212 TI - Nanobacteria may be linked to testicular microlithiasis in infertility. AB - Testicular microlithiasis (TM) in infertility is an uncommon pathologic condition of unclear etiology that is characterized by calcium deposits within the seminiferous tubules. Nanobacteria (NB), as novel microorganisms mediating tissue calcification, have been discovered in some diseases. In this study, we hypothesized that NB may participate in the pathogenesis of TM, particularly in infertility. Seventeen infertility patients with TM detected by scrotal color Doppler ultrasonography and 17 infertility patients without TM as controls were enrolled in the study. The NB were isolated and cultured from semen samples and urine samples. After 3 to 6 weeks of culture, 10 of 17 (58.8%) semen samples and 2 urine samples from infertile patients with TM showed the growth of white granular microbes that firmly attached to the bottom of the culture flask and were visible to the naked eye. In the control group, only 1 of 17 (5.9%) semen samples from infertile patients without TM showed the growth of white granular microbes. The cultured microbes were identified by indirect immunofluorescent staining (IIFS), transmission electron microscopy (TEM), and 16s rRNA gene expression. IIFS and TEM revealed NB to be coccoid and 100 to 500 nm in diameter. The BLAST result revealed that the 16s rRNA gene sequence from the cultured microbes was 97% the same as that of the known NB. Our results showed that NB may be linked to the development of TM, which may provide a potential target for the diagnosis and treatment of infertility with TM. PMID- 19779211 TI - Serum LH correlates highly with intratesticular steroid levels in normal men. AB - Sex steroids are essential for spermatogenesis; however, normal intratesticular concentrations of these hormones in man have not been extensively studied. To improve our understanding of intratesticular hormone concentrations, we performed bilateral testicular aspirations in a group of normal men, determined sex steroid concentrations within each testis, and compared these levels to serum hormone concentrations. Ten healthy human subjects aged 20-49 underwent bilateral testicular aspirations. Intratesticular hormone concentrations of testosterone, dihydrotestosterone (DHT), and estradiol were measured using liquid chromatography-tandem mass spectrometry. Intratesticular testosterone concentrations ranged from 119 to 1251 ng/mL, with a mean of 635 +/- 368 ng/mL. Intratesticular estradiol ranged from 0.41 to 3.9 ng/mL, with a mean of 2.4 +/- 1.3 ng/mL. Intratesticular DHT ranged from 1.1 to 7.9 ng/mL, with a mean of 3.5 +/- 3.2 ng/mL. Intratesticular testosterone and estradiol concentrations correlated highly with serum luteinizing hormone (LH; r = 0.87 and r = 0.70 respectively, P < .01). Intratesticular testosterone correlated highly with serum testosterone. Moreover, a significant correlation between the right and left testes was observed for testosterone (r = 0.82, P = .003), but not for estradiol or DHT. Intratesticular hormone concentrations can be safely assessed by testicular aspiration. Intratesticular testosterone and estradiol correlate highly with serum LH concentrations, and variation in serum LH accounts for most of the variation in intratesticular testosterone among men. In addition, intratesticular testosterone is highly correlated between testes in a given individual. Direct measurement of intratesticular testosterone will improve our understanding of the relationship between intratesticular sex steroids and spermatogenesis, and may have implications for the development of male hormonal contraception. PMID- 19779213 TI - Quantitative contrast-enhanced mammography for contrast medium kinetics studies. AB - Quantitative contrast-enhanced mammography, based on a dual-energy approach, aims to extract quantitative and temporal information of the tumour enhancement after administration of iodinated vascular contrast media. Simulations using analytical expressions and optimization of critical parameters essential for the development of quantitative contrast-enhanced mammography are presented. The procedure has been experimentally evaluated using a tissue-equivalent phantom and an amorphous silicon active matrix flat panel imager. The x-ray beams were produced by a tungsten target tube and spectrally shaped using readily available materials. Measurement of iodine projected thickness in mg cm(-2) has been performed. The effect of beam hardening does not introduce nonlinearities in the measurement of iodine projected thickness for values of thicknesses found in clinical investigations. However, scattered radiation introduces significant deviations from slope equal to unity when compared with the actual iodine projected thickness. Scatter correction before the analysis of the dual-energy images provides accurate iodine projected thickness measurements. At 10% of the exposure used in clinical mammography, signal-to-noise ratios in excess of 5 were achieved for iodine projected thicknesses less than 3 mg cm(-2) within a 4 cm thick phantom. For the extraction of temporal information, a limited number of low-dose images were used with the phantom incorporating a flow of iodinated contrast medium. The results suggest that spatial and temporal information of iodinated contrast media can be used to indirectly measure the tumour microvessel density and determine its uptake and washout from breast tumours. The proposed method can significantly improve tumour detection in dense breasts. Its application to perform in situ x-ray biopsy and assessment of the oncolytic effect of anticancer agents is foreseeable. PMID- 19779214 TI - Cardiac phase-specific shimming (CPSS) for SSFP MR cine imaging at 3 T. AB - The application of steady-state-free-precession (SSFP) techniques at 3 T systems is still limited by their sensitivity to magnetic field inhomogeneities. Especially during imaging of the heart, the arising signal voids and distortions in the myocardium currently often limit the diagnostic value of the resulting images. Dedicated shim systems providing higher order shimming capabilities have been applied to improve the field homogeneity across the heart. In this study, the potential benefit of applying a cardiac phase-specific shim (CPSS) was investigated. The cardiac phase dependence of the magnetic field distortions over the heart was assessed and the potential gain in field homogeneity by CPSS was evaluated. CPSS was successfully applied in volunteers and yielded significant improvement in the main magnetic field homogeneity over the entire cardiac cycle. PMID- 19779215 TI - Dipole estimation errors due to not incorporating anisotropic conductivities in realistic head models for EEG source analysis. AB - EEG source analysis is a valuable tool for brain functionality research and for diagnosing neurological disorders, such as epilepsy. It requires a geometrical representation of the human head or a head model, which is often modeled as an isotropic conductor. However, it is known that some brain tissues, such as the skull or white matter, have an anisotropic conductivity. Many studies reported that the anisotropic conductivities have an influence on the calculated electrode potentials. However, few studies have assessed the influence of anisotropic conductivities on the dipole estimations. In this study, we want to determine the dipole estimation errors due to not taking into account the anisotropic conductivities of the skull and/or brain tissues. Therefore, head models are constructed with the same geometry, but with an anisotropically conducting skull and/or brain tissue compartment. These head models are used in simulation studies where the dipole location and orientation error is calculated due to neglecting anisotropic conductivities of the skull and brain tissue. Results show that not taking into account the anisotropic conductivities of the skull yields a dipole location error between 2 and 25 mm, with an average of 10 mm. When the anisotropic conductivities of the brain tissues are neglected, the dipole location error ranges between 0 and 5 mm. In this case, the average dipole location error was 2.3 mm. In all simulations, the dipole orientation error was smaller than 10 degrees . We can conclude that the anisotropic conductivities of the skull have to be incorporated to improve the accuracy of EEG source analysis. The results of the simulation, as presented here, also suggest that incorporation of the anisotropic conductivities of brain tissues is not necessary. However, more studies are needed to confirm these suggestions. PMID- 19779216 TI - A comprehensive study of the most likely path formalism for proton-computed tomography. AB - We investigate some generalizations of the most likely path formalism developed for proton-computed tomography. The stochastic path of a proton inside a homogeneous medium is replaced by a deterministic smooth path that maximizes the probability of the proton passing through the points on this curve, given measured entrance and exit parameters for each individual proton. We study various factors that influence this curve and the associated error envelopes. These factors are the influence of the energy loss, a logarithmic correction factor in the small angle Coulomb scattering and the importance of path length versus material thickness. We develop a method for further constraining the possible proton paths by including energy information in the derivation of the most likely path, utilizing an infinite-dimensional constrained functional analysis method. It is shown that while there is an additional uncertainty on the most likely path that is difficult to determine experimentally, the associated error envelopes are smaller, resulting in possibly slightly improved spatial resolution for proton-computed tomography. PMID- 19779217 TI - The accuracy of EGSnrc, Geant4 and PENELOPE Monte Carlo systems for the simulation of electron scatter in external beam radiotherapy. AB - Three widely used Monte Carlo systems were benchmarked against recently published measurements of the angular distribution of 13 MeV and 20 MeV electrons scattered from foils of different atomic numbers and thicknesses. Source and geometry were simulated in detail to calculate electron fluence profiles 118.2 cm from the exit window. Results were compared to the measured fluence profiles and the characteristic angle where the fluence drops to 1/e of its maximum value. EGSnrc and PENELOPE results, on average, agreed with measurement within 1 standard deviation experimental uncertainty, with EGSnrc estimating slightly lower scatter than measurement and PENELOPE slightly higher scatter. Geant4.9.2 overestimated the characteristic angle for the lower atomic number foils by as much as 10%. Retuning of the scatter distributions in Geant4 led to a much better agreement with measurement, close to that achieved with the other codes. The 3% differences from measurement seen with all codes for at least some of the foils would result in clinically significant errors in the fluence profiles (2%/4 mm), given accurate knowledge of the electron source and treatment head geometry used in radiotherapy. Further improvement in simulation accuracy is needed to achieve 1%/1 mm agreement with measurement for the full range of beam energies, foil atomic number and thickness used in radiotherapy. EGSnrc would achieve this accuracy with an increase in thickness of the mylar sheets in the monitor chamber, PENELOPE with a decrease in thickness. PMID- 19779218 TI - Reduction of the secondary neutron dose in passively scattered proton radiotherapy, using an optimized pre-collimator/collimator. AB - Proton radiotherapy represents a potential major advance in cancer therapy. Most current proton beams are spread out to cover the tumor using passive scattering and collimation, resulting in an extra whole-body high-energy neutron dose, primarily from proton interactions with the final collimator. There is considerable uncertainty as to the carcinogenic potential of low doses of high energy neutrons, and thus we investigate whether this neutron dose can be significantly reduced without major modifications to passively scattered proton beam lines. Our goal is to optimize the design features of a patient-specific collimator or pre-collimator/collimator assembly. There are a number of often contradictory design features, in terms of geometry and material, involved in an optimal design. For example, plastic or hybrid plastic/metal collimators have a number of advantages. We quantify these design issues, and investigate the practical balances that can be achieved to significantly reduce the neutron dose without major alterations to the beamline design or function. Given that the majority of proton therapy treatments, at least for the next few years, will use passive scattering techniques, reducing the associated neutron-related risks by simple modifications of the collimator assembly design is a desirable goal. PMID- 19779219 TI - Comparison of diffraction-enhanced computed tomography and monochromatic synchrotron radiation computed tomography of human trabecular bone. AB - Diffraction-enhanced imaging (DEI) is an x-ray-based medical imaging modality that, when used in tomography mode (DECT), can generate a three-dimensional map of both the apparent absorption coefficient and the out-of-plane gradient of the index of refraction of the sample. DECT is known to have contrast gains over monochromatic synchrotron radiation CT (SRCT) for soft tissue structures. The goal of this experiment was to compare contrast-to-noise ratio (CNR) and resolution in images of human trabecular bone acquired using SRCT with images acquired using DECT. All images were acquired at the National Synchrotron Light Source (Upton, NY, USA) at beamline X15 A at an x-ray energy of 40 keV and the silicon [3 3 3] reflection. SRCT, apparent absorption DECT and refraction DECT slice images of the trabecular bone were created. The apparent absorption DECT images have significantly higher spatial resolution and CNR than the corresponding SRCT images. Thus, DECT will prove to be a useful tool for imaging applications in which high contrast and high spatial resolution are required for both soft tissue features and bone. PMID- 19779220 TI - Modeling silicon diode energy response factors for use in therapeutic photon beams. AB - Silicon diodes have good spatial resolution, which makes them advantageous over ionization chambers for dosimetry in fields with high dose gradients. However, silicon diodes overrespond to low-energy photons, that are more abundant in scatter which increase with large fields and larger depths. We present a cavity theory-based model for a general response function for silicon detectors at arbitrary positions within photon fields. The model uses photon and electron spectra calculated from fluence pencil kernels. The incident photons are treated according to their energy through a bipartition of the primary beam photon spectrum into low- and high-energy components. Primary electrons from the high energy component are treated according to Spencer-Attix cavity theory. Low-energy primary photons together with all scattered photons are treated according to large cavity theory supplemented with an energy-dependent factor K(E) to compensate for energy variations in the electron equilibrium. The depth variation of the response for an unshielded silicon detector has been calculated for 5 x 5 cm(2), 10 x 10 cm(2) and 20 x 20 cm(2) fields in 6 and 15 MV beams and compared with measurements showing that our model calculates response factors with deviations less than 0.6%. An alternative method is also proposed, where we show that one can use a correlation with the scatter factor to determine the detector response of silicon diodes with an error of less than 3% in 6 MV and 15 MV photon beams. PMID- 19779221 TI - A feasibility study of markerless fluoroscopic gating for lung cancer radiotherapy using 4DCT templates. AB - A major difficulty in conformal lung cancer radiotherapy is respiratory organ motion, which may cause clinically significant targeting errors. Respiratory gated radiotherapy allows for more precise delivery of prescribed radiation dose to the tumor, while minimizing normal tissue complications. Gating based on external surrogates is limited by its lack of accuracy, while gating based on implanted fiducial markers is limited primarily by the risk of pneumothorax due to marker implantation. Techniques for fluoroscopic gating without implanted fiducial markers (markerless gating) have been developed. These techniques usually require a training fluoroscopic image dataset with marked tumor positions in the images, which limits their clinical implementation. To remove this requirement, this study presents a markerless fluoroscopic gating algorithm based on 4DCT templates. To generate gating signals, we explored the application of three similarity measures or scores between fluoroscopic images and the reference 4DCT template: un-normalized cross-correlation (CC), normalized cross-correlation (NCC) and normalized mutual information (NMI), as well as average intensity (AI) of the region of interest (ROI) in the fluoroscopic images. Performance was evaluated using fluoroscopic and 4DCT data from three lung cancer patients. On average, gating based on CC achieves the highest treatment accuracy given the same efficiency, with a high target coverage (average between 91.9% and 98.6%) for a wide range of nominal duty cycles (20-50%). AI works well for two patients out of three, but failed for the third patient due to interference from the heart. Gating based on NCC and NMI usually failed below 50% nominal duty cycle. Based on this preliminary study with three patients, we found that the proposed CC-based gating algorithm can generate accurate and robust gating signals when using 4DCT reference template. However, this observation is based on results obtained from a very limited dataset, and further investigation on a larger patient population has to be done before its clinical implementation. PMID- 19779222 TI - Absorbed fractions for photons in ellipsoidal volumes. AB - We studied through Monte Carlo simulation in Geant4 the absorbed fractions for photons, characterized by energies ranging from 10 keV to 1000 keV, which can be emitted by gamma radionuclides uniformly distributed in ellipsoidal volumes of soft tissue. The same analytical relationship between absorbed fraction and the 'generalized radius' as introduced in a previous paper was found, and the dependence of its parameters rho(0) and s on photon energy is discussed and fitted by suitably chosen parametric functions. As a consequence, the absorbed fraction for photons in the 10-1000 keV energy range can be calculated for all volumes and for every ellipsoidal shape of practical interest. Such results can be a useful complement for the dosimetry of beta- and gamma-emitting radionuclides during internal radiotherapy or gamma emitters employed in diagnostic nuclear medicine. PMID- 19779223 TI - The influence of x-ray contrast agents in computed tomography on the induction of dicentrics and gamma-H2AX foci in lymphocytes of human blood samples. AB - The aim of this study was to investigate and quantify two biomarkers for radiation exposure (dicentrics and gamma-H2AX foci) in human lymphocytes after CT scans in the presence of an iodinated contrast agent. Blood samples from a healthy donor were exposed to CT scans in the absence or presence of iotrolan 300 at iodine concentrations of 5 or 50 mg ml(-1) blood. The samples were exposed to 0.025, 0.05, 0.1 and 1 Gy in a tissue equivalent body phantom. Chromosome aberration scoring and automated microscopic analysis of gamma-H2AX foci were performed in parts of the same samples. The theoretical physical dose enhancement factor (DEF) was calculated on the basis of the mass energy-absorption coefficients of iodine and blood and the photon energy spectrum of the CT tube. No significant differences in the yields of dicentrics and gamma-H2AX foci were observed in the absence or presence of 5 mg iodine ml(-1) blood up to 0.1 Gy, whereas at 1 Gy the yields were elevated for both biomarkers. At an iodine concentration of 50 mg ml(-1) serving as a positive control, a biological DEF of 9.5 +/- 1.4 and 2.3 +/- 0.5 was determined for dicentrics and gamma-H2AX foci, respectively. A physical DEF of 1.56 and 6.30 was calculated for 5 and 50 mg iodine ml(-1), respectively. Thus, it can be concluded that in the diagnostic dose range (radiation and contrast dose), no relevant biological dose-enhancing effect could be detected, whereas a clear biological dose-enhancing effect could be found for a contrast dose well outside the diagnostic CT range for the complete radiation dose range with both methods. PMID- 19779224 TI - Comparison of objective methods to classify the pattern of respiratory sinus arrhythmia during mechanical ventilation and paced spontaneous breathing. AB - Respiratory sinus arrhythmia (RSA) is a fluctuation of heart period that occurs during a respiratory cycle. It has been suggested that inspiratory heart period acceleration and expiratory deceleration during spontaneous ventilation (henceforth named positive RSA) improve the efficiency of gas exchange compared to the absence or the inversion of such a pattern (negative RSA). During mechanical ventilation (MV), for which maximizing the efficiency of gas exchange is of critical importance, the pattern of RSA is still the object of debate. In order to gain a better insight into this matter, we compared five different methods of RSA classification using the data of five mechanically ventilated piglets. The comparison was repeated using the data of 15 volunteers undergoing a protocol of paced spontaneous breathing, which is expected to result in a positive RSA pattern. The results showed that the agreement between the employed methods is limited, suggesting that the lack of a consensus about the RSA pattern during MV is, at least in part, of methodological origin. However, independently of the method used, the pattern of RSA within the respiratory cycle was not consistent among the subjects and conditions of MV considered. Also, the outcomes showed that even during paced spontaneous breathing a negative RSA pattern might be present, when a low respiratory frequency is imposed. PMID- 19779225 TI - Entropy driven spontaneous formation of highly porous films from polymer nanoparticle composites. AB - Nanoporous materials have become indispensable in many fields ranging from photonics, catalysis and semiconductor processing to biosensor infrastructure. Rapid and energy efficient process fabrication of these materials is, however, nontrivial. In this communication, we describe a simple method for the rapid fabrication of these materials from colloidal dispersions of Polymethyl Silsesquioxane nanoparticles. Nanoparticle-polymer composites above the decomposition temperature of the polymer are examined and the entropic gain experienced by the nanoparticles in this rubric is harnessed to fabricate novel highly porous films composed of nanoparticles. Optically smooth, hydrophobic films with low refractive indices (as low as 1.048) and high surface areas (as high as 1325 m(2) g(-1)) have been achieved with this approach. In this communication we address the behavior of such systems that are both temperature and substrate surface energy dependent. The method is applicable, in principle, to a variety of nanoparticle-polymer systems to fabricate custom nanoporous materials. PMID- 19779226 TI - Solution-processible fabrication of large-area patterned and unpatterned gold nanostructures. AB - Solution-processible fabrication of large-area plasmonic nanostructures using colloidal gold nanoparticles has proven its advantages not only in its simplicity, low cost, high speed, and high flexibility, but also in the realization of some nanoscale optoelectronic devices that cannot be achieved by conventional methods. We demonstrate in this paper a variety of techniques for fabricating different plasmonic nanostructures using solution-processible gold nanoparticles and differently designed annealing processes. Using interference lithography and low- (<300 degrees Celsius) or high-temperature (>350 degrees Celsius) annealing processes, we succeeded in fabricating high-quality one- and two-dimensional metallic photonic crystals which exhibit promising optical responses for the exploration of new optoelectronic devices. Furthermore, using direct high-temperature (>350 degrees Celsius) annealing of a thin film of colloidal gold nanoparticles, we succeeded in fabricating large-area unpatterned isolated gold nano-island structures with a mean diameter tunable from about 35 to 100 nm and a mean height from 20 to 70 nm by controlling the concentration of the gold nanoparticle colloid, the annealing temperature, and the surface properties of the substrate. The corresponding optical response is thus tunable in the visible spectral range by changing the fabrication parameters. This introduces a new lithography-free technique for the preparation of gold nanostructures. These flexible fabrication techniques constitute a systematic route for the realization of plasmonic nanodevices. PMID- 19779227 TI - Quantum-dot-modified microbubbles with bi-mode imaging capabilities. AB - The aim of this paper was to develop a novel bi-mode ultrasound/fluorescent imaging agent through stepwise layer-by-layer deposition of poly(allylamine hydrochloride) (PAH) and CdTe quantum dots (QDs) onto ST68 microbubbles (MBs) produced by sonication of a mixture of surfactants (Span 60 and Tween 80). The experiments using photoluminescence spectroscopy and confocal laser scanning microscopy confirmed that CdTe nanoparticles were successfully adsorbed on the outer surface of the MBs. The static light scattering measurements showed that size distributions of MBs before and after QD deposition met the size requirements for clinical application. The in vitro and in vivo ultrasonography indicated that the QD-modified MBs maintained good contrast enhancement properties as the original MBs. Furthermore, the in vitro ultrasound-targeted microbubble destruction (UTMD) experiment of the QD-MB composites was carried out to validate the ability of MBs to deliver QDs for fluorescent imaging. The results showed that the QD-modified MBs not only maintained the capability of ultrasound imaging, but also could be used as a targeted-drug controlled-release system to deliver the QDs for cell and tissue fluorescent imaging by UTMD. The novel dual-functional imaging agent has potential for a variety of biological and medical applications. PMID- 19779228 TI - The fabrication of high-aspect-ratio, size-tunable nanopore arrays by modified nanosphere lithography. AB - A modified nanosphere lithographic process for producing high aspect ratio and size-tunable nanopore arrays is described. A self-assembled bilayer nanosphere template is created as an etch mask for a deep reactive ion etching (DRIE) process. The size of the nanopores is tuned by reducing the diameter of the top layer nanospheres using oxygen etching. Nanopore arrays with mean in-plane widths ranging from 120.9 to 343 nm and depths up to 2 microm have been achieved. This process offers excellent control over the nanopore size, aspect ratio and pitch of the fabricated nanostructures. The approach can also be extended to fabricate nanopore arrays of a wide range of materials. PMID- 19779229 TI - Positively charged and pH self-buffering quantum dots for efficient cellular uptake by charge mediation and monitoring cell membrane permeability. AB - Positively charged and pH self-buffering quantum dots (Tren-QDs) were achieved by surface functionalization with tris(2-aminoethyl)amine (Tren) derivatives, which are attached to the inorganic cores of QDs through bidentate chelating of dithiocarbamates. The Tren-QDs exhibit pH buffering capability by absorbing or releasing protons due to the surface polyamine groups as the surrounding pH fluctuates. Such self-buffering capability stabilizes the photoluminescence of the Tren-QDs against acid. The Tren-QDs bear positive charges through protonation of the surface polyamine groups under physiological conditions and the surface positive charges improve their cellular uptake efficiency by charge mediation, which has been demonstrated by BV-2 microglia cells. The photoluminescence of Tren-QDs shows a selective Stern-Volmer response to copper ions and this property has been preliminarily evaluated for investigating the BV-2 cell membrane structure by monitoring the photoluminescence of intracellular Tren-QDs. PMID- 19779230 TI - Nanomechanical properties of vimentin intermediate filament dimers. AB - The cell's cytoskeleton, providing the cell with structure and shape, consists of a complex array of structural proteins, including microtubules, microfilaments and intermediate filaments. Intermediate filaments play a crucial role in mechanotransduction and in providing mechanical stability to cells, in particular under large deformation. By utilizing molecular simulation, here we report a nanomechanical analysis of vimentin intermediate filament dimers, the basic building blocks of intermediate filaments. We describe a detailed analysis of the mechanical properties and associated deformation mechanisms, and find that mechanical stretch induces a transition from alpha-helices to beta-sheets, a phenomenon known as alpha-beta transition. A comparison of the Young's modulus predicted from simulation with experimental measurements is provided, and good agreement is found. We present an analysis of structural changes during deformation, domain unfolding patterns, rate dependence of the rupture force and associated changes in the energy landscape, and conclude with a discussion of potential implications for mechanobiology and the development of de novo protein materials. PMID- 19779231 TI - Self-assembled growth of nanocomposites consisting of TiO(2) nanopillars and Pb(Zr(0.52)Ti(0.48))O(3) thin films. AB - We report for the first time the self-assembled growth of nanocomposites of 'TiO(2) nanopillars on Pb(Zr(0.52)Ti(0.48))O(3) (PZT) thin films' using a modified sol-gel processing. Both TiO(2) nanopillars and PZT thin films are simultaneously formed during the post-annealing process. The growth behaviours of TiO(2) nanopillars are controlled by adjusting the Ti excess amounts of PZT solutions and the post-annealing conditions. The self-assembled growth can be explained on the basis of the combined effects of five factors which can have influence during the annealing process: a Ti ion diffusion to the film surface, a phase separation of PZT and TiO(2), a void formation on the film surface, a Ti oxidation at the film surface under oxygen atmosphere, and a nanopillar growth on the film surface. PMID- 19779232 TI - A nanosized photodetector fabricated by electron-beam-induced deposition. AB - A sensitive nanosized molybdenum oxide (MoO(x)) photodetector is manufactured at a desired position by electron-beam-induced deposition (EBID). As-deposited MoO(x) had a conductivity approximately 300 S cm(-1). After 2 h annealing at 573 K, the conductivity of nanowires decreased 10 times to approximately 30 S cm(-1) and MoO(x) had photoconductivity. Nanosized MoO(x) wires enhanced the sensitivity of optical devices due to an increased surface area to volume ratio. PMID- 19779233 TI - Nanoengineering and characterization of gold dipole nanoantennas with enhanced integrated scattering properties. AB - In this paper we present our approach for engineering gold dipole nanoantennas. Using electron-beam lithography we have been able to produce arrays of single gold antennas with dimensions from 70 to 300 nm total length with a highly reproducible nanoengineering protocol. Characterizing these gold nanoantenna architectures by optical means via dark-field microscopy and scattering spectroscopy gives the linear optical response function as a figure-of-merit for the antenna resonances, spectral linewidth and integrated scattering intensity. We observe an enhanced integrated scattering probability for two arm gold dipole nanoantennas with an antenna feed gap compared to antennas of the size of one arm without a gap. PMID- 19779234 TI - Germanium-oxide-coated carbon nanotubes. AB - An ultrathin coating of individual multi-wall carbon nanotubes with germanium oxide was developed. Coated carbon nanotubes were prepared by in situ gelation of tetramethoxy germanium, forming an amorphous germanium oxide layer. The resulting germanium oxide/carbon nanotube nanocables were characterized by transmission electron microscopy (TEM), TEM/energy-dispersive x-ray spectroscopy, x-ray photoelectron spectroscopy (XPS) and current-voltage measurements. The approximately 10 nm thin germanium oxide layer provides excellent electrical insulating properties for individual carbon nanotubes. PMID- 19779235 TI - Heterostructures of germanium nanowires and germanium-silicon oxide nanotubes and growth mechanisms. AB - We report on a method to fabricate one-dimensional heterostructures of germanium nanowires (GeNWs) and germanium-silicon oxide nanotubes (GeSiO(x)NTs). The synthesis of the wire-tube heterostructures is carried out using a simple furnace set-up with germanium tetraiodide and germanium powders as growth precursors, gold-dotted silicon wafers as substrates and by controlling the temperature ramp rate/sequence of the growth precursors. Two types of wire-tube heterostructures resulting from distinct growth mechanisms are obtained. The type-1 heterostructure consists of a GeNW, grown via a gold-catalyzed vapour-liquid solid process, at the lower end and a GeSiO(x)NT at the upper end. In contrast, the type-2 heterostructure is made up of a solid wire at the upper end and a hollow tube at the lower end. The solid wire portion of the type-2 heterostructure is formed through an oxide-assisted growth process. PMID- 19779236 TI - Local tuning of CoPt nanoparticle size and density with a focused ion beam nanowriter. AB - Ultra-small CoPt nanoparticles (NPs) with a mean diameter of 1.3 nm (around 100 atoms) were deposited on a thin 5 nm self-supported amorphous carbon membrane. The effects of focused irradiation with a newly developed Ga(+) ion source were studied by transmission electron microscopy. While the overall coverage of the NPs remained constant, the mean diameter and the density of the NPs evolve in the dose range from 5 x 10(13) to 1 x 10(15) ions cm(-2). The local tuning of the size and density of CoPt NPs by means of ion irradiation could be used in magnetic data storage applications. PMID- 19779237 TI - Writing to and reading from a nano-scale crossbar memory based on memristors. AB - We present a design study for a nano-scale crossbar memory system that uses memristors with symmetrical but highly nonlinear current-voltage characteristics as memory elements. The memory is non-volatile since the memristors retain their state when un-powered. In order to address the nano-wires that make up this nano scale crossbar, we use two coded demultiplexers implemented using mixed-scale crossbars (in which CMOS-wires cross nano-wires and in which the crosspoint junctions have one-time configurable memristors). This memory system does not utilize the kind of devices (diodes or transistors) that are normally used to isolate the memory cell being written to and read from in conventional memories. Instead, special techniques are introduced to perform the writing and the reading operation reliably by taking advantage of the nonlinearity of the type of memristors used. After discussing both writing and reading strategies for our memory system in general, we focus on a 64 x 64 memory array and present simulation results that show the feasibility of these writing and reading procedures. Besides simulating the case where all device parameters assume exactly their nominal value, we also simulate the much more realistic case where the device parameters stray around their nominal value: we observe a degradation in margins, but writing and reading is still feasible. These simulation results are based on a device model for memristors derived from measurements of fabricated devices in nano-scale crossbars using Pt and Ti nano-wires and using oxygen-depleted TiO(2) as the switching material. PMID- 19779238 TI - Diameter- and current-density-dependent growth orientation of hexagonal CdSe nanowire arrays via electrodeposition. AB - Controlling the growth orientation of semiconductor nanowire arrays is of vital importance for their applications in the fields of nanodevices. In the present work, hexagonal CdSe nanowire arrays with various preferential growth orientations have been successfully yielded by employing the electrodeposition technique using porous alumina as templates (PATs). We demonstrate by experimental and theoretical efforts that the growth orientation of the CdSe nanowires can be effectively manipulated by varying either the nanopore diameter of the PATs or the deposited current density, which has significant effects on the optical properties of the CdSe nanowires. The present study provides an alternative approach to tuning the growth direction of electrodeposited nanowires and thus is of importance for the fabrication of nanodevices with controlled functional properties. PMID- 19779239 TI - The size dependence of tin oxide atomic cluster nanowire field effect transistors. AB - Tin oxide (SnO(2)) cluster nanowires have been fabricated using atomic clusters as building blocks. Nanowires with widths of less than 100 nm were defined using electron beam lithography followed by deposition of Sn clusters which were subsequently thermally oxidized. The cluster nanowires were used to fabricate field effect transistors. The transistors were n-type and demonstrated a clear size-dependent behaviour. With zero gate bias the narrowest wires were depleted, both the carrier concentration and the conduction quickly increasing with wire width. This behaviour is attributed to the formation of a surface depletion region caused by Fermi level pinning. The width of the depletion region was estimated using the carrier concentration calculated from the transistor threshold voltages. The change in the wire conductance with UV illumination was also investigated. Illumination with 365 nm light increases the conduction by up to 40 times. This is attributed to a combination of an increase in carriers due to photo-desorption of oxygen from the surface of the wires and an increase in the mobility due to a reduction of inter-grain potential barrier height. PMID- 19779241 TI - Investigation of confinement effects in ZnO quantum dots. AB - We report a simple method for the synthesis of Na(+) doped and stable zinc oxide quantum dots, using the quantum confinement atom method. An intense broad green photoluminescence (PL) was observed with a maximum located at approximately 535 nm when excited by UV radiation of 332 nm. The PL peak intensity is found to be highly dependent on the size of the quantum dots (QDs). Electron microscopy observation revealed that the radius of the QD was approximately 1 nm, which clearly indicated that the QDs are in the strong quantum confinement region (exciton Bohr radius, r(B), for bulk ZnO is 1.8 nm). Phase purity of ZnO and the presence of Na(+) was confirmed by x-ray diffraction (XRD) and atomic absorption spectroscopy (AAS), respectively. The results are well incremented by x-ray photoelectron spectroscopy (XPS) studies. Intentional ageing of QDs for several days under controlled experimental conditions such as temperature, relative humidity and pH etc, facilitated the formation of various nanostructures with a slight red shift in the PL peak position. Time resolved emission spectroscopy measurements indicated that PL decay time changes from 35 ns for QDs to 1660 micros for nanocrystals. The observed high-intensity and stable green PL emissions have been analyzed and thoroughly discussed. PMID- 19779240 TI - The biocompatibility of fluorescent nanodiamonds and their mechanism of cellular uptake. AB - The labeling of cells with fluorescent nanoparticles is promising for various biomedical applications. The objective of this study is to evaluate the biocompatibility and the mechanism of the cellular uptake of fluorescent nanodiamonds (FNDs) in cancer cells (HeLa) and pre-adipocytes (3T3-L1). With flow cytometry and the use of a battery of metabolic and cytoskeletal inhibitors, we found that the mechanism of the FND uptake in both cells is by energy-dependent clathrin-mediated endocytosis. In addition, the surface charge of FND influences its cellular uptake, as the uptake of poly-L-lysine-coated FNDs is better than that of oxidative-acid-purified FNDs at the same concentration in regular medium with or without serum. We also confirm that the proliferative potential of FND treated and untreated cells does not exhibit any significant differences when measured at bulk cultures, and more stringently at clonal cell density. Further biocompatibility studies indicate that the in vitro differentiation of 3T3-L1 pre adipocytes and 489-2 osteoprogenitors is not affected by the FND treatment. Our results show that FNDs are biocompatible and ideal candidates for potential applications in human stem cell research. PMID- 19779242 TI - White-light electroluminescence from ZnO nanorods/polyfluorene by solution-based growth. AB - We report bright white-light electroluminescence (EL) from a diode structure consisting of a ZnO nanorod (NR) and a p-type conducting polymer of poly(fluorine) (PF) fabricated using a hydrothermal method. ZnO NRs are successfully grown on an organic layer of PF using a modified seeding layer. The EL spectrum shows a broad emission band covering the entire visible range from 400 to 800 nm. White-light emission is possible because the ZnO-defect-related emission from the ZnO NR/PF heterostructure is enhanced to become over thousand times stronger than that from the usual ZnO NR structure. This strong green yellow emission associated with the ZnO defects, combined with the blue PF related emission, results in the white-light emission. Enhancement of the ZnO defect emission is caused by the presence of Zn(OH)(2) at the interface between the ZnO NRs and PF. Fourier transform infrared spectroscopy reveals that the absorption peaks at 3441, 3502, and 3574 cm(-1) corresponding to the OH group are formed at the ZnO NR/PF heterostructure, which confirms the enhancement of defect emission from the ZnO NR/PF heterostructure. The processing procedure revealed in this work is a convenient and low-cost way to fabricate ZnO-based white-light emitting devices. PMID- 19779243 TI - Comparative efficiencies of photothermal destruction of malignant cells using antibody-coated silica@Au nanoshells, hollow Au/Ag nanospheres and Au nanorods. AB - Three Au-based nanomaterials (silica@Au nanoshells, hollow Au/Ag nanospheres and Au nanorods) were evaluated for their comparative photothermal efficiencies at killing three types of malignant cells (A549 lung cancer cells, HeLa cervix cancer cells and TCC bladder cancer cells) using a CW NIR laser. Photodestructive efficiency was evaluated as a function of the number of nanoparticles required to destroy the cancer cells under 808 nm laser wavelength at fixed laser power. Of the three nanomaterials, silica@Au nanoshells needed the minimum number of particles to produce effective photodestruction, whereas Au nanorods needed the largest number of particles. Together with the calculated photothermal conversion efficiency, the photothermal efficiency rankings are silica@Au nanoshells > hollow Au/Ag nanospheres > Au nanorods. Additionally, we found that HeLa cells seem to present better heat tolerance than the other two cancer cell lines. PMID- 19779244 TI - Modulated self-assembly of 4,4'-diphenyltetrathiafulvalene molecules on highly oriented pyrolytic graphite by n-tetradecane solvent. AB - We report the formation of a binary-component self-assembled monolayer (SAM) comprising 4,4'-diphenyltetrathiafulvalene (DP-TTF) and n-tetradecane (n C(14)H(30)) molecules with periodic strip-like phase separation structures on a highly oriented pyrolytic graphite (HOPG) surface. Scanning tunneling microscopy (STM) imaging reveals that ordered DP-TTF single- and double-lamella are periodically tuned by ordered n- C(14)H(30) single- and double-lamella, respectively. This finding can be qualitatively understood in terms of a phase field model, in which the interplay of three ingredients, including free energy of the binary-component solution monolayer, phase boundary energy and surface stress, determines the final equilibrium sizes of the ordered DP-TTF and n- C(14)H(30) phases in the binary-component SAM. Furthermore, anisotropy of the surface stress breaks the symmetry of the substrate and causes the n- C(14)H(30) molecules to arrange along preferential substrate 010 directions. The orientation of the n-C(14)H(30) molecule stripes further guides the directions of the DP-TTF lamellar structures. In addition, scanning tunneling spectra (STS) of the individual DP-TTF and n- C(14)H(30) molecules in the ordered monolayer show a remarkable difference in I(V) curves on the HOPG substrate. PMID- 19779245 TI - Quantum confinement effects in gallium nitride nanostructures: ab initio investigations. AB - We present ab initio density functional investigations of the atomic and electronic structure of gallium nitride nanodots and nanowires. With increasing diameter, the average Ga-N bond length in the nanostructures increases, as does the relative stability (heat of formation), approaching the values for bulk GaN. As the diameter decreases, the band gap increases, with the variation for the nanodots greater than that for the nanowires, in qualitative accordance with expectations based on simple geometrical quantum confinement considerations. Interestingly, in contrast to nanowires, the lowest unoccupied states of the nanodots exhibit an extended delocalized (Ga-derived) character, weighted in the centre of the nanodot. PMID- 19779246 TI - Electron field emission from screen-printed graphene films. AB - The electron field emission performance of screen-printed graphene cathode was studied. High-yield graphene was prepared by a modified Hummers method and hydrazine hydrate reduction process, and screen printing technology was used to prepare the graphene field emission cathode. This cathode structure satisfies the requirements of both good electrical conductivity and a high surface field enhancement factor, leading to excellent and stable field emission properties with a low threshold field ( approximately 1.5 V microm(-1)). Our work introduced a simple and convenient method suitable for large scale on different substrates, paving the way for more applications of graphene films. PMID- 19779247 TI - Strained arrays of colloidal nanoparticles: conductance and magnetoresistance enhancement. AB - Colloidal nanoparticles are very popular as building blocks of functional arrays for electronic and optical applications. However, there is a problem in achieving electrical conductivity in such nanoarrays due to their molecular shells. These shells, which are inherent to colloidal particles, physically separate the nanoparticles in an array and act as very effective insulators. Post-assembly thinning of the shells is therefore required to enhance the array conductivity to a sensible value. Here, we introduce a conceptually new approach to the thinning, using compressive stress applied to the array by the supporting matrix. The stress arises from polymerization-induced shrinkage of the matrix as an integral step during device assembly. Using arrays of oleic-acid-covered magnetite nanoparticles in conjunction with an HDDA-polymer (HDDA: 1,6-hexanediol diacrylate) matrix, we have achieved a significant steady current in the array along with an unprecedented value of the magnetoresistance. Our results serve as a proof-of-concept for other colloidal nanoparticles. PMID- 19779248 TI - The fabrication and characteristics of indium-oxide covered porous InP. AB - Uniform and vertical indium-oxide nanotube (IONT) arrays embedded well in n-type InP single crystal have been successfully prepared in situ by porous InP-template assisted chemical vapor deposition (CVD). This IONT/InP nanostructure reveals high sensitivity to humidity at room temperature, which is ascribed to the ultrahigh surface-to-volume ratio of this nanostructure and the large number of oxygen defected states in IONTs. Such a nanostructure of IONT arrays embedded in a III-V semiconductor substrate could be expected to have potential applications, such as superior gas sensors. This work provides a novel approach for fabricating low-melting metal oxide semiconductor nanotubes. PMID- 19779249 TI - Gel-derived bioglass as a compound of hydroxyapatite composites. AB - Despite the excellent biocompatibility of hydroxyapatite and bioglass, their clinical applications are limited to non-load-bearing implants and implant coatings due to their low mechanical properties. We have developed two different composites made of hydroxyapatite (HA) and gel-derived bioglasses designated S2 (80 mol% SiO(2)-16 mol% CaO-4 mol% P(2)O(5)) or A2 (40 mol% SiO(2)-54 mol% CaO-6 mol% P(2)O(5)). We show that the combination of hydroxyapatite with either bioglass results in better composite bioactivity and biocompatibility compared to HA alone. We used a commercially available hydroxyapatite that was sintered with varying additions (10%, 50%) of A2 or S2 bioglass. Scanning electron microscopy and x-ray diffraction were used to characterize the microstructure and phases of the composites. The elastic properties of bioglass/HA composites were analyzed with the use of the pulse ultrasonic technique. The bioactivity (surface activity) of the composites was assessed by determining the changes of surface morphology and composition after soaking in simulated body fluid (SBF) for 7 and 14 days. The biocompatibility of the obtained composites was then assessed in vitro using adult human bone marrow stromal cells. Cells were seeded on the material surfaces at a density of 10(4) cells cm(-2) and cultured for 7 days in non-differentiating and osteogenic conditions. The number of live cells was estimated in both standard and osteogenic cultures, followed by alkaline phosphatase (ALP) activity assay in osteogenic cultures. We determined that 10 wt% addition of A2 (E = 12.24 GPa) and 50 wt% addition of S2 (E = 16.96 GPa) to the HA base results in higher Young's modulus of the composites compared to pure hydroxyapatite (E = 9.03 GPa). The rate of Ca-P rich layer formation is higher for bioglass/HA composites containing A2 bioglass compared to the composites containing S2 bioglass. Evaluation of cell growth on the bioglass/HA composites showed that the incorporation of either 50 wt% S2 or 50 wt% A2 into the hydroxyapatite base significantly improves cell viability when compared to cells grown on pure HA. Also the cellular activity of ALP, an early marker of osteoblasts, increases with the amount of bioglass addition to the composites. PMID- 19779250 TI - Biological evaluation of collagen-chitosan scaffolds for dermis tissue engineering. AB - Three-dimensional collagen-chitosan scaffolds were fabricated with type I collagen and chitosan through freeze drying and glutaraldehyde cross-linking. Dermal fibroblasts were isolated from neonatal Sprague-Dawley rat skin by dispase II/collagenase I digestion. The fibroblasts were then seeded into the scaffolds to construct tissue-engineered dermis. The microstructure of the scaffolds as well as the fibroblasts' proliferation, cytokine secretion and cell cycle were investigated. Flow cytometry analysis indicated that cells in the scaffolds proliferated steadily. IL-6 concentration measurement by the ELISA test suggested that the scaffolds could promote secretion of the fibroblasts' cytokine. These results show that the fibroblasts and the scaffolds interact well with each other, and the fibroblasts have better proliferation ability and biological activity in the scaffolds than in monolayer culture. The scaffolds are a promising candidate for tissue repair and regeneration with enhanced biostability and good cytocompatibility. PMID- 19779251 TI - The effects of dynamic and three-dimensional environments on chondrogenic differentiation of bone marrow stromal cells. AB - Articular cartilage is subjected to complex loading, which plays a major role in its growth, development and maintenance. Previously, we found that mechanical stimuli enhanced the development and function of engineered cartilage tissues in elastic mechano-active poly(lactide-co-caprolactone) (PLCL) scaffolds. In addition, it is well known that the three-dimensional spatial organization of cells and extracellular matrices in hydrogels is crucial to chondrogenesis. This study was conducted to enhance the chondrogenic differentiation of bone marrow stromal cells (BMSCs) in the hybrid scaffolds of fibrin gels and PLCL scaffolds in dynamic environments by compression. A highly elastic scaffold was fabricated from very elastic PLCL with 85% porosity and a 300-500 microm pore size using a gel-pressing method. A mixture of rabbit BMSCs and fibrin gels was then seeded onto the PLCL scaffolds and subjected to continuous compressive deformation of 5% strain at 0.1 Hz for 10 days in a chondrogenic medium containing 10 ng ml(-1) TGF beta(1). The BMSCs-seeded scaffold constructs were then implanted subcutaneously into nude mice. As a control, the cell-PLCL scaffold constructs were cultured under dynamic conditions or the cell-PLCL/fibrin hybrid scaffold constructs and the cell-PLCL scaffold constructs were cultured under static conditions for 10 days in vitro. The results revealed that cells adhered onto the hybrid scaffolds of fibrin gels and PLCL scaffolds cultured under dynamic conditions. In addition, the accumulation of the extracellular matrix of cell-scaffold constructs, which was increased through mechanical stimulation, showed that chondrogenic differentiation was sustained and enhanced significantly in the stimulated hybrid scaffold constructs. Overall, the results of this study indicate that the proper periodic application of dynamic compression and the three-dimensional environments of the hybrid scaffolds composed of fibrin gels and elastic PLCL can encourage BMSCs to differentiate into chondrocytes, maintain their phenotypes and enhance GAGs production, thereby improving the quality of cartilaginous tissue formed in vitro and in vivo. PMID- 19779252 TI - Optimization of scaled-up chitosan microparticles for bone regeneration. AB - The aim of this study was to scale-up and optimize the chitosan (CS) microparticles (MPs) from 1x batch (41-85 mg) to 4x batch (270-567 mg) to be used in bone regeneration. The MPs used in the present study were prepared by double emulsification technique using CS as a base material under physiologically friendly conditions throughout the process. Structural integrity of MPs was improved creating cross-links between amine groups in CS and phosphate groups in tripolyphosphate (TPP) which has been used as an ionic cross-linking agent. The cross-linking density was varied using different amounts of TPP to CS such as 0%, 8%, 32%, 64% and 110% (w/w). The CS MPs were approximately spherical in shape with a size of 30-50 microm according to scanning electron microscopy results. X ray diffraction data revealed having TPP in the CS MPs. The evidence of ionic cross-links in the CS MPs was analyzed using Fourier Transform Infra Red. When we scaled-up the yield of MPs, we investigated that 64% TPP cross-linking density provided the best quality MPs. In addition, those MPs provided the yield from 75 mg to 310 mg when scaled up from 1x to 4x batch, respectively. The MPs developed have a great potential to be used as an injectable scaffold for bone regeneration including orthopedic and craniofacial applications using minimally invasive conditions compared with conventional three-dimensional scaffolds. PMID- 19779253 TI - Diabetes--role of epigenetics, genetics, and physiological factors. AB - Cells of organ systems are endowed with a relatively similar genome while epigenome niches keep varying chronologically and defined explicitly in the respective tissues. The genome of an individual is always influenced by parental, embryonic, tissue-specific, and environmental epigenomes and the same must have been the possible reason for invariable inquiries relating to familial, environmental and life style patterns in the preliminary investigations of diabetic complications. Unprecedented methylation of lysine residues of histones and cytosines of CpG islands of promoter DNA impede the transcription of genes and homocysteine is the metabolic key player of methyl groups. Gck and COX7A1 are the 2 examples in the present review to elucidate the epigenetic influence on the onset of diabetes. miRNAs are additional promising cellular components influencing both at transcriptional and translational levels and promoting either in favour or against (i.e., feed back) TFs, signaling factors and proteins through their pliotropic effects and thus are reported to regulate cellular physiology. miR-124a and miR-9 are primarily endemic to nervous tissue and they are now being exploited in islets for their function in executing exocytosis of insulin, which of course is one of the fundamental canons of diabetes. miR-375 persuades beta cells for glucose-induced insulin gene expression. The current approach to evaluate the constellation of genes and their products involved in diabetes in huge number of samples through GWA studies may unravel intricacies involved in the management of diabetes and its associated consequences. PMID- 19779254 TI - Concentration of protoporphyrin IX in cancer tissues and blood in patients with colorectal cancer at early stage. AB - OBJECTIVE: To determine the concentration difference in protoporphyrin in cancerous intestine and to discuss its application in laser-induced autofluorescence diagnosis for colorectal cancer at early stage. METHODS: We detected the concentration of protoporphyrin IX in 30 patients with colorectal cancer and 30 control patients, as well as that in 60 cases of intestinal tissues (30 control tissues and 30 cancer tissues). RESULTS: The concentration of blood protoporphyrin IX in patients with colorectal cancer was significantly higher than that in the controls (P<0.05). Protoporphyrin IX concentration in the cancer tissue was significantly higher than that in the control tissues (P<0.05). CONCLUSION: That the concentration of protoporphyrin in cancerous intestine becomes abnormally high may be the material basis for spectrum intensity peak of (644.3+/-5.7) nm in laser-induced autofluorescence diagnosis for colorectal cancer at early stage. PMID- 19779256 TI - [Expression of hypoxia inducible factor-1alpha and erythropoietin in the hippocampus of aging rats]. AB - OBJECTIVE: To explore the expression of hypoxia inducible factor-1alpha (HIF 1alpha) and erythropoietin in the hippocampus of aging rats, and to investigate the role of HIF-1alpha and erythropoietin in the aging of nervous system. METHODS: The expression of Nissl body, HIF-1alpha, and erythropoietin in the CA1 region of the hippocampus in different months was observed by Nissl staining and immunohistochemical technique. RESULTS: Nerve cells became bigger and appeared sparse, and the Nissl bodies decreased with age. HIF-1alpha positive cells increased significantly with age in the CA1 region of the hippocampus (P<0.05). The expression of erythropoietin presented a parabola with aging in the CA1 region of the hippocampus. The increase from 3 to 18 months and the reduction from 18 to 30 months of erythropoietin positive cells had statistical significance (both P<0.05). CONCLUSION: HIF-1alpha and erythropoietin are parallelly incremental before middle age, and are separated after middle age, suggesting decreased activity of HIF-1alpha and recession of protein synthesis function may be the main reasons for decreased expression of erythropoietin in the brain during aging. Strengthened endogenous HIF-1alpha activity and supply of exogenous erythropoietin may delay the aging of the nervous system. PMID- 19779255 TI - [Effect of antipsychotic drugs on life quality of schizophrenic patients: one year follow-up study]. AB - OBJECTIVE: To compare the effect of 7 antipsychotic drugs on the life quality of schizophrenia patients including chlorpromazine, sulpiride, clozapine, risperidone, olanzapine, quetiapine, and aripiprazole. METHODS: A total of 1,227 stable schizophrenic patients within 5 years onset who took 1 of the 7 study medications as maintenance treatment were followed up for 1 year at 10 China sites. Patients were evaluated by the short form-36 health survey (SF-36) at the baseline and at the end of 1 year. RESULTS: The life quality was improved obviously at the end of the follow-up. There was significant difference in body pain, vitality, and mental health (P<0.05) among these antipsychotic drugs. CONCLUSION: All 7 antipsychotic drugs can improve the life quality of schizophrenia patients. Atypical antipsychotic drugs, especially olazapine and quetiapine, are superior to typical antipsychotic drugs in improving life quality. PMID- 19779257 TI - [Risk factors for acute kidney injury following 5100 cardiac surgeries with extracorporeal circulation]. AB - OBJECTIVE: To determine the incidence and risk factors associated with acute kidney injury (AKI) in patients after cardiac surgery with extracorporeal circulation. METHODS: A retrospective case control study was done in patients who underwent cardiac surgery from 2003 to 2007 in Second Xiangya Hospital, with 340 patients in an AKI group and the other 4 760 patients without AKI as a control group. All variables were analyzed by univariate analysis, Mann-Whitney U test and logistic regression. RESULTS: AKI occurred in the 340 patients (6.7% incidence). Univariate analysis revealed that age, preoperative serum creatinine, preoperative ejection fraction (EF), preoperative beta2-microglobulin, preoperative blood albumin, preoperative blood uric acid, intraoperative cardiopulmonary bypass time, intraoperative aortic cross-clamp time, and dosage of mannitol were significantly related to AKI following cardiac surgery with extracorporeal circulation. Logistic multivariate regression analysis showed that preoperative serum creatinine (P<0.001), preoperative ejection fraction (EF) (P<0.001), preoperative beta2-microglobulin (P=0.002), preoperative blood uric acid (P=0.015), intraoperative cardiopulmonary bypass time (P<0.001), and intraoperative aortic cross-clamp time (P<0.001) were independent risk factors for AKI. CONCLUSION: The incidence of AKI after cardiac surgery with extracorporeal circulation is closely related with a variety of perioperative risk factors. Our data suggest that patients planning to accept cardiac surgery with extracorporeal circulation should be more comprehensively assessed and monitored, thereby preventing the occurrence of AKI. PMID- 19779258 TI - [Living-related donor kidney transplantation in 158 patients]. AB - OBJECTIVE: To introduce clinical experience for living-related donor kidney transplantation (LDKT) by reviewing LDKT clinical data. METHODS: A total of 158 patients underwent LDKT. Expect for 7 patients donated by their spouses, the others had blood relationship donors. Donor-recipient HLA matching showed 2 patients had 5-loci mismatch, 5 with 4-loci mismatch, 88 with 3-loci mismatch, 50 with 2-loci mismatch, 12 with 1-loci mismatch, the other 1 with 0-loci mismatch. All of the 158 donors underwent open nephrectomy, 35 of whom donated the right kidneys and the other 123 donated the left kidneys. Triple immunosuppressive regimen consisted of calcineurin inhibitors or FK506, MMF or AZa, and steroid. RESULTS: All donors were healthy after the operation. All donors were followed up for 6 to 12 months and blood exams showed that inosine levels were normal. The longest kidney transplant functional survival time was 10 years to up June 2008. The one year patient/graft survival rate was 95.5%. Delayed graft function (DGF) occurred in 5 patients, 4 of whom recovered in 2-5 weeks. Five patients died, 4 of whom died of post-operational pulmonary infection within 3-5 months, with no transplantational complications. The other one died of pulmonary bleeding during dialysis while treating for DGF. One patient received a second deceased kidney transplant because of hyperacute rejection during the surgery. Five developed acute rejection 1 month after the operation (incidence rate 3.16%), 4 of whom were cured by administration of methylprednisolone, and the other one returned to dialysis because of renal toxicity of cyclosporine. Three patients had positive chronic rejection, 2 of whom lost graft function in 1.5-3.5 years. Eight patients developed pulmonary infection and 4 of them were cured. CONCLUSION: Sufficient LDKT pre-operational assessment, satisfactory tissue matching and reduced ischemia time may result in lower incidence of DGF, acute rejection and higher patient/graft survival rate. In LDKT, importance should also be attached to the prevention of DGF and graft rejection. Rational dosage of immunosuppressants is advocated to prevent secondary infective complications. Donor specifications and all around evaluation of the living-related donors should also be emphasized to minimize the harm to the donors. Long term follow-up is also essential to ensure donors' post-operational healthy life. PMID- 19779260 TI - [Dosimetric verification and clinical efficacy of intensity modulated radiotherapy in nasopharyngeal carcinoma]. AB - OBJECTIVE: To investigate dosimetric characteristics and to evaluate the clinical efficacy of intensity modulated radiotherapy (IMRT) as compared with conventional radiotherapy in nasopharyngeal carcinoma (NPC). METHODS: Forty-seven NPC patients who accepted IMRT served as the IMRT group, and conventional radiotherapy plan was also made for each patient in this group using the treatment planning system. Dosiological evaluation of the 2 radiotherapy plans was made through dose volume histogram, 95% target volume dose (V(95)) and normal tissue complication probability. Another 47 patients who underwent conventional radiotherapy (CRT) at the same period formed the control group. The therapeutic effect as well as the acutes and late toxicities of normal tissues in the 2 groups were observed. RESULTS: V(95) of the IMRT was more than 96% (96.83%-99.99%) for each target area, obviously superior to CRT in the sub-clinical target area. The radiation dose of normal tissues such as the brainstem and the spinal cord in the IMRT was much less than that in the CRT. Consistant with this, the part and complete remission rate, the 3-year loco-regional progress free survival rate, and overall survival rate in the IMRT group were all higher than those in the CRT group. For most patients in the IMRT group, the grade of acute toxicities was much lower than that in the CRT group. Patients in the IMRT group showed no more than grade 3 xerostomia, while in the CRT group still 21% of the patients suffered grade 3 or higher xerostomia a year later. CONCLUSION: Compared with CRT, IMRT can improve the target volume dose and decrease the dose of surrounding tissues, resulting in higher control rate and fewer side effects. PMID- 19779259 TI - [Expression of Foxp3 mRNA in peripheral blood monocytes in patients after kidney transplantation]. AB - OBJECTIVE: To investigate the relationship between the level of Foxp3 mRNA in the peripheral blood monocytes (PBMCs) with acute rejection or chronic allograft nephropathy after kidney allotransplantation. METHODS: Real-time quantitative polymerase chain reaction was used to examine Foxp3 mRNA expression in the PBMCs from 16 patients with acute rejection, 8 patients with chronic allograft nephropathy, 8 patients at stable stage after kidney transplantation, 8 patients of end-stage renal disease, and 8 normal controls. RESULTS: The level of Foxp3 mRNA in the PBMCs was significantly lower in patients with acute rejection than that in patients with chronic allograft nephropathy (P<0.01). Foxp3 mRNA expression was significantly lower in patients with chronic allograft nephropathy than that in the normal controls, the end-stage renal disease group, and stable stage group (P<0.01). The level of Foxp3 mRNA was not significantly different in the PBMCs among the normal controls, the end-stage renal disease group, and the stable stage group (P>0.05). CONCLUSION: The level of Foxp3 mRNA expressed in PBMCs can reflect the status of renal allograft, and may be a noninvasive biomarker for diagnosing acute rejection and chronic allograft nephropathy. PMID- 19779261 TI - [Expression of DLK1 gene in acute leukemias and its function in erythroid differentiation of K562 cell line]. AB - OBJECTIVE: To determine the expression of DLK1 gene in acute leukemias (AL) and its function in erythroid differentiation of K562 cells. METHODS: We detected the expression of DLK1 gene in 65 different acute leukemia categories (a test group) and 34 normal bone marrow controls (a control group) with RT-PCR. DLK1 protein in 20 out of the 65 AL patients and 13 of the 34 controls was assayed by Western blot. The K562 cell line was induced to erythroid differentiation by hemin. We observed the relationship between its expression and erythroid differentiation. RESULTS: Both leukemia cells and normal marrow cells expressed DLK1. The expression of DLK1 mRNA in patients in the test group was higher than that in the control group (P=0.018), while there was no significance between acute lymphoblastic leukemia and acute myelogenous leukemia (P>0.05).The expression of DLK1 mRNA in the test group at onset had no relation with the WBC and platelet count in the total peripheral blood, and the same was true for blast cell rates in bone marrow cells.The level of DLK1 protein in the test group was higher than that in the control group, which was consistent with the mRNA expression (P=0.042). The expression of DLK1 mRNA decreased gradually with K562 cells towards hemin-induced erythroid differentiation. CONCLUSION: DLK1 gene may be involved in leukemia,but the mRNA level of DLK1 has no relation with some clinical characteristics of AL patients at onset. DLK1 may inhibit the erythroid differentiation of K562 cells. PMID- 19779262 TI - [Expression of Raf kinase inhibitor protein and E-cadherin in prostate cancer tissues]. AB - OBJECTIVE: To detect the expression of Raf kinase inhibitor protein (RKIP) and epithelial cadherin (E-cadherin) in human prostate cancer tissues, and their correlation. METHODS: We discussed the relationship between RKIP and E-cadherin and the clinical stage and pathological classification of prostate cancer by immunofluorescence histochemistry staining in the test of expression of RKIP in 26 prostate cancer tissues and 14 BPH tissues, and analyzed the correlation between them. RESULTS: The expression of RKIP and E-cadherin in prostate cancer tissues was obviously lower than that in the benign prostatic hypertrophy tissues. The expression of RKIP and E-cadherin in the dys-good differentiation group (Gleason 8-10) was significantly lower than that in the good differentiation group(Gleason0.05). CONCLUSION: In this study, no significant differences are detected in the efficacy and the safety of EBL vs. EHP for bleeding due to Dieulafoy lesions in the upper gastrointestinal tract. PMID- 19779266 TI - [Nonalcoholic fatty liver disease in 210 patients]. AB - OBJECTIVE: To analyze the clinical characteristics of nonalcoholic fatty liver disease. METHODS: We compared the weight, waistline, blood pressure, fasting plasma glucose (FPG), triglyceride (TG), total cholesterol (TC), alanine aminotransferase (ALT), uric acid (UA), and complication of cholecystolithiasis of 210 patients with nonalcoholic fatty liver disease who were diagnosed either clinically or by B ultrasound and/or CT (NAFLD group) and 248 normal persons (control group) from January 2008 to June 2009 in Third Xiangya Hospital. RESULTS: The weight, weight index, waistline, blood pressure, FPG, TG, ALT, and UA in the NAFLD group were higher than those in the control group (P<0.01). Patients with nonalcoholic fatty liver disease had higher incidence of cholecystolithiasis (P<0.01). CONCLUSION: The occurrence of nonalcoholic fatty liver disease is related to weight, weight index, waistline, blood pressure, FPG, TG, ALT, UA, and cholecystolithiasis. PMID- 19779267 TI - [Periodontal status in patients with oral submucous fibrosis]. AB - OBJECTIVE: To investigate the periodontal status in patients with oral submucous fibrosis (OSF), and to provide reference for the treatment and prophylaxis in patients with OSF and betel chewers. METHODS: Fifty samples clinically and pathologically diagnosed as OSF patients were selected as the OSF group, another 50 age-matched healthy volunteers in the similar living condition were compared with the OSF patients and non-betel nut chewers were classified as the control group. The 5 periodontal clinical parameters were collected and recorded, including plaque index, periodontal probing depth, clinical attachment loss, gingival index, and tooth count of bleeding of probing. RESULTS: There was a significant difference in plaque index (PLI) between the OSF group (2.14+/-0.64) and the control group (1.7+/-0.89) (P<0.01). Periodontal probing depth (PD) was (1.98+/-0.70) mm in the control group, and (5.57+/-2.39) mm in the OSF group, with significant difference in PD (P<0.01). There was no significant difference in clinical attachment loss, gingival index, and tooth count of bleeding on probing between the 2 groups (P>0.05). CONCLUSION: OSF patients tend to accumulate plaque, and have deep periodontal pocket, periodontal inflammation or severe periodontal damage. PMID- 19779268 TI - [Effect of Dahuang Zhechong pills on arterial thrombosis in rabbits]. AB - OBJECTIVE: To investigate the effect of Dahuang Zhechong pills (DZ) on arterial thrombotic model in vivo. METHODS: Sixty-five rabbits were randomly divided into 7 groups: normal, model (collagen encapsulated thread-drawing),model+aspirin (ASA), model+clopidogrel (CP),model+ASA+CP, model+ low dosage DZ (DZL), and model+high dosage DZ (DZH). All rabbits except the normal group were fed with the drugs repectively for 8 days,and sacrificed at 2 hours after the last feeding, obtained aortae. The pathological changes in the aortae were observed under microscope,and the level of FDP, D-dimer and tissue factor (TF) were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: The vascular vessels were filled with thrombi in the model group and the elastic membranes of the vessel wall were seriously injured. The arterial thrombi were observed around the vascular wall in the DZL group, but some of the thrombi were dissolved. The number of thrombi was remarkably decreased in the DZH group, and most thrombi were dissolved and the vascular intimal membranes were intact. Compared with the model group, the dry and wet weight of the thrombi and the level of D-dimer, FDP, and TF in the plasma were significantly attenuated (P<0.01) in all the treatment groups. There were no significant difference between the DZL group and the ASA group in the dry weight, D-Dimer, and FDP (P>0.05). The pathological changes in the vascular vessel and the elevation of plasma parameters in the DZL group were similar to those in the ASA and CP groups (P>0.05). The dry and wet weight, D dimer, FDP, and TF in the plasma in the DZH group were significantly lower than those in the DZL group (P<0.01 or P<0.05, separatively), and closed to those in the ASA+CP group. CONCLUSION: Dahuang Zhechong pills are potential novel anti thromobotic agent for arterial thrombosis. PMID- 19779270 TI - Abstracts of the Italian Association for the Study of the Pancreas (AISP) 33rd National Congress. Rozzano, Italy. October 15-17, 2009. PMID- 19779269 TI - [Effect of GnRH-II on VEGF secreted by stromal cells from endometrium of endometriosis]. AB - OBJECTIVE: To inspect the effect of gonadotropin-releasing hormonel II (GnRH II)on the secretion of VEGF by eutopic and ectopic endometrial stromal cells cultured in vitro. METHODS: Eutopic and ectopic stromal cells cultured in vitro were treated with different concentrations (1x10(-10) - 1x10(-6) mol/L) of GnRH II,and the control group was not treated by GnRH-II.Enzyme-linked immunosorbent assay (ELISA) was used to measure the VEGF protein in the medium of the above 2 groups. RESULTS: There was no difference between the VEGF protein expressed by eutopic and ectopic stromal cells in the medium after culturing in vitro for 48 hours (P>0.05). The 1x10(-10) - 1x10(-6) mol/L GnRH-II could dose-dependently reduce VEGF protein secreted by endometrial stromal cells (P<0.01), and the inhibition to ectopic endometrial stromal cells was stronger than that to eutopic endometrial stromal cells (P<0.01). CONCLUSION: Ectopic stromal cells cultured in vitro can secrete VEGF, and so can eutopic stromal cells. This may play an important role in the formation and development of endometriosis. GnRH-II can reduce VEGF protein secreted by ectopic endometrial stromal cells cultured in vitro, and its inhibition is stronger than that of eutopic endometrial stromal cells. PMID- 19779271 TI - Role of purkinje fibers in the maintenance of ventricular fibrillation. PMID- 19779272 TI - Diagnosis with O(2) kinetics. Old but new. PMID- 19779273 TI - From 4-links to 5-links of "chain of survival". Post-resuscitation care is critical for good neurological recovery. PMID- 19779274 TI - Critical balance of dendritic cells is destined for plaque rupture. PMID- 19779275 TI - Ear-lobe crease as a marker of carotid artery arthrosclerosis. PMID- 19779277 TI - Endocrinologists and the future of medical research in Japan. PMID- 19779278 TI - Hydrogen sulfide intoxication with dilated cardiomyopathy. PMID- 19779279 TI - Broken sperm, cytoplasmic droplets and reduced sperm motility are principal markers of decreased sperm quality due to organophosphorus pesticides in rats. AB - OBJECTIVES: Recent reports have shown significant associations between organopshophorus pesticide (OP) exposure and decreased sperm motility in workers and laboratory animals. However, the notion that OPs possess spermatotoxicity has yet to be established. The aim of this study was to clarify the effects of OP exposure on detailed sperm toxicity markers, i.e., motility, morphology and sperm adenine nucleotide contents, and the histopathology of the testis and epididymis. METHODS: Ten-week-old Wistar rats were divided into 4 groups (n=10) and orally administered corn oil, dichlorvos (DDVP; 5, 10 mg/kg) or diazinon (DZN; 3 mg/kg) 6 days a week for 9 wk. Sperm motility and morphology markers were analyzed with a computer-assisted sperm analysis (CASA) system. RESULTS: In addition to a significant decrease in acetylcholinesterase (AChE) activities and a significant increase in urinary OP metabolites, DDVP and DZN significantly reduced sperm motility, but they did not influence sperm adenine nucleotide contents. The OPs also significantly increased the percentage of broken sperm, and DDVP significantly increased the percentage of cytoplasmic droplets. Importantly, both OPs significantly increased cytoplasmic vacuolation and nuclear shrinkage in the epithelial cells of the ductus epididymis, whereas the testes did not show significant histopathological changes. CONCLUSIONS: The broken sperm and cytoplasmic droplets as well as reduced sperm motility were the relevant spermatotoxicity makers of DDVP and DZN. To our knowledge, this is the first report to suggest that the above-mentioned OP-induced spermatotoxicity is related to histopathological impairment of the caput epididymis. PMID- 19779280 TI - Predictive equations for lung function based on a large occupational population in North China. AB - OBJECTIVES: The currently used predictive equations of lung function in North China were derived from early study and have not been updated for nearly two decades. METHODS: Using American Thoracic Society (ATS) standards, sex-specific spirometric predictive equations for forced vital capacity (FVC), forced expiratory volume in one second (FEV(1)), ratio of FEV(1) to FVC (FEV(1)%) and forced expiratory flow at 25-75% of forced vital capacity (FEF(25-75%)) were derived from 2,897 asymptomatic, lifelong non-smokers (1,208 males, 1,689 females) from a large occupational population in North China. Stepwise multiple regressions were carried out to identify the best predictors of lung function parameters and predictive equations. Independent variables considered for inclusion in predictive equations including age, height, weight and chest circumference were examined. RESULTS: Age and height were found to be necessary variables for all lung function parameters. Weight was a significant variable in only half of our equations. Chest circumferences (expired or inspired) was excluded as they are not practical in use. Data from 255 apparently healthy non smokers were used to validate the equations by comparing percentage predicted values and proportion of subjects with normal predicted values with those from the study group, and a high accordance was obtained. Other equations published and used in North China do not appear to offer advantages over these equations. CONCLUSIONS: These newly developed predictive equations should ideally be applied to calculate lung function for adult individuals and populations as reference values in North China. PMID- 19779281 TI - Involvement of hypoxia-inducible factor-1alpha and vascular endothelial growth factor in the mechanism of development of chronic subdural hematoma. AB - Vascular endothelial growth factor (VEGF), a potent inducer of angiogenesis and vascular permeability in diverse physiological and pathological conditions, may be involved in the pathophysiology of chronic subdural hematoma (CSDH). The present study investigated the source and mechanisms for the induction of VEGF in CSDH by measuring the concentration of VEGF in the hematoma of 102 patients (122 hematomas) using the enzyme-linked immunosorbent assay technique. The relationship between the VEGF concentration in hematoma and the intrahematoma membranous structure confirmed by preoperative T(2)(*)-weighted magnetic resonance image was examined in 46 of these patients. VEGF and hypoxia-inducible factor-1alpha (HIF-1alpha) expression was immunohistochemically studied and microvessel density (MVD) in the outer membrane was identified using anti-CD31 antibody in 30 patients. VEGF and HIF-1alpha were positive in the outer membranes of all 30 patients. VEGF expression was significantly correlated to HIF-1alpha expression (r(s) = 0.651, p = 0.0084) and VEGF concentration in the hematoma (r(s) = 0.654, p = 0.0013). VEGF concentration in layered hematomas, which have intrahematoma membranous structure, was significantly higher than in non-layered hematomas (p < 0.01). Although MVDs of the outer membranes were comparable to those described in tumors, there was no significant relationship with VEGF expression. The present study suggests that VEGF in CSDH, which may be induced in the neomembrane by HIF-1 release, may give rise to the excessive development of fragile microvessels and hyperpermeability, resulting in the enlargement of CSDH. PMID- 19779282 TI - Cerebral ischemic lesions detected with diffusion-weighted magnetic resonance imaging after carotid artery stenting: Comparison of several anti-embolic protection devices. AB - Distal embolism is an important periprocedural technical complication with carotid angioplasty and carotid artery stenting (CAS). We evaluated the safety and efficacy of protection devices used during CAS by detecting new cerebral ischemic lesions using diffusion-weighted magnetic resonance imaging in 95 patients who underwent 98 CAS procedures: 34 using single PercuSurge GuardWire, 31 using double balloon protection, 15 using proximal flow reverse protection devices, 14 using Naviballoon, and 4 using filter anti-embolic devices. Diffusion weighted imaging was performed preoperatively and postoperatively to evaluate the presence of any new embolic cerebral lesions. Postoperative diffusion-weighted imaging revealed 117 new ischemic lesions. Three patients had new ischemic stroke, two minor and one major, all ipsilateral to the treated carotid artery. The remaining patients had clinically silent ischemia. The incidence of new embolic lesions was lower using the proximal flow reverse protection device than with the double balloon protection (33% vs. 48.4%), but the volume of ipsilateral new ischemic lesions per patient was 136.6 mm(3) vs. 86.9 mm(3), respectively. Neuroprotection with Naviballoon yielded ipsilateral lesions of large volume (86.6 mm(3)) and higher number (5.7 lesions per patient) than using the filter anti-embolic device (34.8 mm(3) and 1 lesion per patient). New cerebral ischemic lesions after neuroprotected CAS are usually silent. The lower incidence of distal ischemia using proximal flow reverse and double balloon protection devices is limited by the larger volume and higher number of ischemic lesions. PMID- 19779283 TI - Differential diagnosis between radiation necrosis and glioma progression using sequential proton magnetic resonance spectroscopy and methionine positron emission tomography. AB - Differential diagnosis between radiation necrosis and tumor recurrence is important in the clinical management of glioma. Multi-modality imaging including proton magnetic resonance spectroscopy ((1)H-MRS) and positron emission tomography (PET) with L-[methyl-(11)C]methionine (MET) was evaluated. Eighteen patients underwent sequential (1)H-MRS and MET-PET. The expressions of metabolites including choline-containing compounds (Cho), creatine phosphate (Cre), and lactate (Lac) were calculated as the ratios of Cho to Cre (Cho/Cre) and Lac to Cho (Lac/Cho). The uptake of MET was determined as the ratio of the lesion to the contralateral reference region (L/R). The final diagnoses were determined by histological examination and/or follow-up MR imaging and clinical course. The Lac/Cho ratio was 0.63 +/- 0.25 (mean +/- standard deviation) in recurrence (7 cases) and 2.35 +/- 1.81 in necrosis (11 cases). The Lac/Cho ratio was significantly different between the two groups (p < 0.01). Consecutive investigation of (1)H-MRS revealed temporary elevation of Cho in 4 of 9 cases of necrosis, which could be identified as false positive findings for recurrence. Including those cases, MET-PET demonstrated significant difference in the L/R ratio between the two groups (2.18 +/- 0.42 vs. 1.49 +/- 0.35, p < 0.01). According to a 2 x 2 factorial table analysis, the borderline values of Lac/Cho and L/R to differentiate recurrence from necrosis were 1.05 and 2.00, respectively. (1)H-MRS is reliable and accessible for the differentiation of recurrence and necrosis, although the temporary elevation of Cho in the course of necrosis should be recognized. Additional MET-PET imaging can establish the diagnosis. PMID- 19779284 TI - Intracranial aneurysms in patients with CREST syndrome. AB - CREST syndrome is a variant of scleroderma characterized by calcinosis, Raynaud's phenomenon, esophageal hypomotility, sclerodactyly, and telangiectasia, and is a collagen vascular disease characterized by inflammation and fibrosis of multiple organs/tissues. Neurological and cerebrovascular abnormalities are uncommon in CREST syndrome. Here, we report two patients with CREST syndrome harboring intracranial aneurysms. A 53-year-old woman with a 6-month history of CREST syndrome had multiple intracranial aneurysms that arose from the right middle cerebral artery, the left middle cerebral artery, the choroidal segment of the left internal carotid artery, and the left anterior cerebral artery. A 64-year old woman with a 2-year history of CREST syndrome had a fusiform aneurysm located on the insular segment of the left middle cerebral artery. These patients were treated surgically and good outcome was achieved in both cases. The pathogenesis of cerebral aneurysms associated with collagen diseases, including CREST syndrome, remains unclear. Early treatment of CREST syndrome and other collagen diseases may prevent arteritis from progressing to affect the intracranial arteries and thus reduce the occurrence of aneurysms. The prognosis for patients with collagen diseases after rupture of cerebral aneurysm seems to be poor because the multiplicity, atypical morphology, and atypical location of their aneurysms make treatment difficult. Thus, early detection and treatment are important to improve the prognosis. PMID- 19779285 TI - Arteriovenous fistula arising from the persistent primitive olfactory artery with dual supply from the bilateral anterior ethmoidal arteries. AB - A 59-year-old male presented with generalized seizure. The patient had not been aware of any traumatic head injuries or preceding infection, and had no contributory medical history. On admission, he was alert and well oriented, without neurological impairment or headache. He was afebrile and blood examination showed no abnormal findings. Computed tomography revealed an irregular intracerebral hematoma, 3 x 1.5 cm in diameter, in the left rectal gyrus. Cerebral angiography showed an arteriovenous fistula (AVF) in the anterior cranial fossa supplied only by the persistent primitive olfactory artery (PPOA) originating from the anterior cerebral artery, forming a shunt to an ascending cortical vein, and drained by the superior sagittal sinus. The patient underwent endovascular obliteration of the AVF via the transarterial route. Immediately after successful isolation, angiography showed that the bilateral anterior ethmoidal arteries supplied the AVF. The feeding branches from the left anterior ethmoidal artery were completely occluded via the ophthalmic artery, but introduction of the catheter into the right ophthalmic artery markedly decreased the stump pressure. Follow-up angiography performed at 3 and 8 weeks following embolization showed spontaneous resolution of the residual AVF without findings of recanalization or new abnormal channels. AVF arising in the anterior cranial fossa may be associated with an unusual pattern of the blood supply when including the PPOA. PMID- 19779286 TI - Dural cavernous hemangioma of the cerebellar falx. AB - A 47-year-old man presented with a rare case of dural cavernous hemangioma of the cerebellar falx incidentally detected as a mass lesion in the posterior cranial fossa. Neurological examination revealed no deficits or physical symptoms. Computed tomography demonstrated a well-demarcated hyperdense mass, with no calcification, in the cerebellar vallecula. Magnetic resonance imaging showed the extra-axial mass as homogeneously isointense on T(1)-weighted images, and hyperintense on T(2)-weighted images, compared to the adjacent cerebellar parenchyma that had no hypointense halo. The cerebellar vermis was slightly compressed ventrally, the adjacent brain parenchyma was not swollen, and there was no evidence of hydrocephalus. The mass and the attached cerebellar falx were homogeneously enhanced by contrast medium. The dural enhancement was considered a dural tail. No other intracranial vascular malformations were found. The preoperative diagnosis was posterior cranial fossa meningioma attached to the cerebellar falx. Median suboccipital craniotomy exposed the reddish mass attached to the cerebellar falx. The arachnoid plane was well preserved. Total en bloc resection was performed with minimal blood loss. The postoperative course was unremarkable. The resected mass had a reddish-brown mulberry appearance, with spongy cross section with multiple blood-filled spaces. Histological examination identified dilated blood-containing channels lined with flattened endothelium and separated by fibrous tissue, but no luminal thrombus or hemorrhage. The histological diagnosis was dural cavernous hemangioma of the cerebellar falx. Preoperative radiosurgery or embolization is recommended for most of the dural cavernous hemangiomas, but surgery for the present dural cavernous hemangioma of the cerebellar falx was performed safely. PMID- 19779288 TI - Cerebellar hemangioblastoma manifesting as hearing disturbance. AB - A 49-year-old man presented with a rare case of cerebellar hemangioblastoma manifesting as only hearing disturbance. He had suffered from hearing difficulty in the right ear for a few months. Magnetic resonance imaging revealed a cystic mass lesion with an internal fluid level and surrounding flow voids in the right cerebellopontine (CP) angle. Cerebral angiography disclosed a vascular-rich tumor fed by both the superior cerebellar and anterior inferior cerebellar arteries. En bloc resection of the tumor was planned under a preoperative diagnosis of cerebellar hemangioblastoma. The tumor protruded into the CP cistern and compressed cranial nerve VIII. The feeding arteries were meticulously coagulated and the tumor was successfully removed. The histological diagnosis was hemangioblastoma. After the operation, the patient's hearing acuity improved dramatically. Cerebellar hemangioblastoma should be considered in the differential diagnosis of CP angle tumors associated with hearing disturbance. PMID- 19779287 TI - Recurrent subacute in-stent restenosis after carotid artery stenting due to plaque protrusion. AB - A 70-year-old male presented with transient ischemic attacks manifesting as right hemiparesis and motor aphasia due to severe left cervical internal carotid artery stenosis. Carotid artery stenting (CAS) using a flow-reversal system was performed without complications. However, the patient exhibited transient right hemiparesis and motor aphasia 10 days after CAS. Emergent angiography demonstrated in-stent restenosis. In-stent percutaneous transluminal angioplasty and CAS were performed successfully using a distal protection system. However, duplex ultrasound scanning revealed progressive in-stent restenosis, 3 and 6 days after the re-treatment. Emergent angiography again demonstrated in-stent restenosis. Urgent stent removal and carotid endarterectomy were performed. Plaque had prolapsed through the stent. Histological examination revealed that the specimen was mainly plaque consisting of cholesterol crystals and macrophages. The patient was able to return to independent life without neurological deficit. Repeated endovascular surgery with appropriate antiplatelet and anticoagulation therapy should be attempted initially to treat in-stent restenosis. Endarterectomy with stent removal should be considered as a rescue option, especially if plaque protrusion is identified. PMID- 19779289 TI - Spontaneous regression after standard transsphenoidal surgery in a huge pituitary adenoma with epidural extension. AB - A 59-year-old female presented with a huge non-functioning pituitary adenoma which mainly extended from the intrasellar region to the epidural space of the anterior cranial base, manifesting as a 2-year history of disturbance of the visual field. Transsphenoidal surgery was performed to decompress the optic pathway as the first step of a two-staged operation. Postoperative magnetic resonance images unexpectedly showed spontaneous regression of the major portion of the epidural tumor which had not been manipulated during the first operation. The reason for the spontaneous regression remains unclear. PMID- 19779290 TI - Central tumor necrosis of a large meningioma following acute anemia caused by hysterectomy. AB - A 55-year-old woman, with a one-year history of headache, gait disturbance, and slight aphasia, was transferred to our hospital after head injury. Magnetic resonance (MR) imaging and computed tomography revealed a large meningioma with peripheral edema. However, priority was given to previously planned gynecological surgery for uterine cancer. She developed severe anemia after the surgery, followed by consciousness disturbance. MR imaging revealed spontaneous tumor necrosis. The meningioma was totally removed. Her consciousness improved, and she was discharged with no neurological deficit. Patients with large meningioma may suffer deterioration of symptoms due to central tumor necrosis triggered by acute anemia. PMID- 19779291 TI - Glioblastoma masquerading as a hypertensive putaminal hemorrhage: a diagnostic pitfall. AB - A 58-year-old man presented with a rare case of glioblastoma masquerading as intracerebral hemorrhage (ICH). He had been medicated for hypertension and diabetes for 10 years before collapsing at home. Brain computed tomography (CT) showed ICH in the right putamen, but CT with contrast medium showed no underlying lesion. He was treated initially with intravenous administration of anti hypertensive agent under a diagnosis of hypertensive putaminal hemorrhage. ICH aspiration surgery was performed, and serial CT showed ICH resorption. However, he was again admitted for unstable gait and mildly altered mental status 3 months after discharge. Magnetic resonance (MR) imaging with gadolinium showed an enhanced ring-shaped mass around the hematoma cavity. Open biopsy was performed. The histological diagnosis was glioblastoma multiforme, and he was treated with radiation therapy and oral chemotherapy with temozolomide. MR imaging showed marked shrinkage of the tumor, but he died of pneumonia 3 months after the second surgery. In this case, the cause of the hemorrhage was not identified after the seemingly successful hematoma evacuation surgery, and no definitive diagnosis was made until tumor regrowth. Brain tumor should be suspected as a cause of ICH even if the patient has a history of hypertension and the location is typical for hypertensive ICH. Clinical/radiological follow up is essential for detecting subtle neurological deterioration to avoid diagnostic delay. PMID- 19779292 TI - Proton magnetic resonance spectroscopy and diffusion-weighted imaging of tumefactive demyelinating plaque. AB - Proton magnetic resonance spectroscopy, diffusion-weighted axonography, and diffusion tensor tractography in a patient with tumefactive demyelination plaque (TDP) were evaluated for differential diagnosis from glioblastoma. The findings of glutamate and glutamine elevations on magnetic resonance spectroscopy and apparent tracts within the lesion on axonography and tractography were unlikely to represent glioblastoma, and were thus useful for the preoperative diagnosis of TDP. PMID- 19779294 TI - Malignant fibrous histiocytoma of the thoracic spine manifesting as rapidly progressive compressive myelopathy. AB - A 75-year-old woman presented with an extremely rare case of malignant fibrous histiocytoma (MFH) arising in the thoracic spine, causing compression fracture and manifesting as rapidly progressive compressive myelopathy resulting in progressive gait disturbance and weakness of the bilateral legs. Computed tomography and magnetic resonance imaging demonstrated a solid enhanced intravertebral mass destroying the vertebral bodies at the T7 and T8 levels. Maximum resection of the lesion was performed through wide laminectomy from T7 through T9, followed by vertebroplasty using calcium phosphate paste and posterior fixation with a spinal fixation system. Histological examination showed proliferation of pleomorphic spindle-shaped cells having large irregular nuclei with hyperchromasia with storiform pattern and collagenous stroma, consistent with a diagnosis of MFH. This case illustrates the possibility of rapid maximum decompression surgery from the posterolateral side if MFH manifests as progressive transverse myelopathy. PMID- 19779293 TI - Symptomatic syringomyelia associated with a dermoid tumor in the posterior fossa. AB - A 28-year-old female presented with a dermoid tumor in the posterior fossa associated with symptomatic syringomyelia. Magnetic resonance (MR) imaging revealed cervical syringomyelia and tonsillar herniation concomitant with an intradural posterior fossa tumor which was totally removed. The histological diagnosis was dermoid tumor. Her symptoms subsided and MR imaging demonstrated complete resolution of the syrinx 12 months after tumor removal. Benign congenital intracranial tumor may cause tonsillar herniation resulting in symptomatic cervical syringomyelia. However, both tonsillar herniation and cervical syrinx may clinically and radiologically resolve following removal of the intracranial lesion and posterior fossa decompression. PMID- 19779295 TI - Recurrent epidermoid cyst with malignant transformation into squamous cell carcinoma. AB - A 50-year-old male presented with a recurrent epidermoid cyst with malignant transformation into squamous cell carcinoma. The patient was first hospitalized for intermittent seizures in 2000. Computed tomography (CT) showed a hypodense lesion with enhanced capsule but no peripheral edema in the right temporal lobe. Craniotomy was performed and the lesion was completely removed. The histological diagnosis was epidermoid cyst. Six years later, the patient experienced blurred vision and hemiparesis in the left extremities. CT showed a hyperdense mass with peripheral edema in the right temporal lobe. Repeat CT 2 months later revealed a larger mass. The recurrent lesion was removed, and the histological diagnosis was squamous cell carcinoma. Intracranial epidermoid cyst is a benign tumor which often appears hypodense on CT, so change to hyperdensity in the recurrent tumor may indicate malignant transformation. PMID- 19779296 TI - Selenoprotein P, rather than glutathione peroxidase, as a potential marker of septic shock and related syndromes. AB - BACKGROUND/AIMS: Oxidative stress is involved in sepsis-related endothelium dysfunction. Selenoprotein-P (Sel-P), the main plasma selenoprotein, may have high antioxidant potential, and binds to endothelium. We hypothesize that, in septic shock, and similar syndromes such as systemic inflammatory response syndrome (SIRS), Sel-P binds massively to endothelium, causing a drop in Sel-P plasma concentration. METHODS: Plasma Se, Sel-P and albumin concentrations, and glutathione peroxidase (GPx) activity were measured in patients with septic shock and SIRS with organ failure (S group, n = 7 and n = 3, respectively) admitted to the intensive care unit (ICU) and compared to non-SIRS patients (NS group, n = 11) and healthy volunteers (HV group, n = 7). RESULTS: On ICU admission, plasma Sel-P concentrations were 70% lower in the S group than in the other groups [15 (10-26) vs. 44 (29-71) and 50 (45-53) nmol/l] and were lower in nonsurviving septic-shock patients. GPx activity did not differ between groups. Sel-P was significantly lower before ICU death in the 3 deceased patients of the S group (septic shock) than in the 3 patients of the non-SIRS group. CONCLUSIONS: Early decrease in Sel-P plasma concentrations was specifically observed in septic shock and was similar in SIRS patients whereas GPx activity remained unchanged. Further studies are needed to determine whether Sel-P can be an early marker of septic shock linked to microvascular injury. PMID- 19779297 TI - Clinical evaluation of total IgE in tears of patients with allergic conjunctivitis disease using a novel application of the immunochromatography method. AB - BACKGROUND: The determination of total IgE in tears is useful as a diagnostic tool in allergic conjunctivitis disease (ACD). We evaluated the efficacy of this diagnostic tool for ACD, which is a clinically applicable novel immunochromagraphic method to determine total IgE in tears. METHODS: The subjects comprised 4 groups: 15 patients with vernal keratoconjunctivitis (VKC group), 8 patients with atopic keratoconjunctivitis (AKC group), 18 patients with allergic conjunctivitis (AC group), and 7 normal healthy volunteers as a control (control group). Tears were sampled using filter paper, and the total IgE in tears was determined by immunochromatography assay. Semiquantitative determination was carried out by examining the intensity of the colored line using an immunochromatoreader (IgE index). The relationship between IgE indices in tears and total IgE levels in serum or between IgE indices and the clinical scores of ACD was examined. RESULTS: The positive ratio obtained by this novel application of the immunochromatography assay was 38 of the 41 in the patients with ACD and none in the 7 controls. IgE indices for the VKC group, AKC group and AC group were 27.5 +/- 15.6, 19.8 +/- 15.8, and 4.0 +/- 3.1 (mean +/- SD), respectively. IgE indices in tears showed significant correlation with both total IgE levels in serum (P < 0.001, r = 0.76) and clinical scores of ACD (P < 0.001, r = 0.57). CONCLUSIONS: The novel application of the immunochromatography assay to assess the total IgE in tears is a useful clinical tool to investigate ACD. PMID- 19779298 TI - DNA vaccines: a safe and efficient platform technology for responding to emerging infectious diseases. PMID- 19779299 TI - Opportunities in field research. PMID- 19779300 TI - Emergency repair of a broken Jarvik 2000 power connector using a paper-clip. AB - The power connectors of assist devices that link the controller to the driveline are exposed to extreme mechanical stress, especially if they are implanted for permanent use. We report the case of a successful emergency repair of a power connector of a Jarvik 2000 left ventricular assist device by using a paper-clip in a patient who was supported with the device for >7 years at our institution. PMID- 19779301 TI - HeartMate left ventricular assist system exchange: results and technical considerations. AB - The duration times of left ventricular assist system (LVAS) support have increased because of prolonged wait times for transplant and the more frequent use of devices for destination therapy. The HeartMate LVAS, the only device approved for bridge to transplant and destination therapy, has limited durability, making replacement increasingly necessary. Since 1996, we have exchanged 19 left ventricular assist devices in 15 patients (11 men: mean age, 57.1 years; range, 33-77 years). Most of the devices (14) were replaced with the HeartMate vented electric/extended-lead vented electric pump; five devices were exchanged for a HeartMate II LVAS. Bearing failure was the most frequent reason for exchange (15 of 19 pumps); four of the 19 pumps also had active device related infections at the time of exchange. There were no early deaths (30 days). Overall survival (Kaplan-Meier) was 85% at 1 year, 67% at 2 years, and 56% at 3 years. Three patients had transplants (mean, 518 days); six patients died during support (mean, 934 days), and six patients remain on LVAS support (mean, 1,219 days). One patient has been on device for over 6 years. Left ventricular assist devices exchange is becoming increasingly likely and can be associated with acceptably low-operative mortality rates and good intermediate-term survival. PMID- 19779302 TI - Evaluation of a respiratory assist catheter that uses an impeller within a hollow fiber membrane bundle. AB - Respiratory assist using an intravenous catheter may be a potential treatment for patients suffering from acute or acute-on-chronic lung failure. The objective of this study was to evaluate a novel respiratory catheter that uses an impeller within the fiber bundle to enhance gas exchange efficiency, thus requiring a smaller fiber bundle and insertional size (25 Fr) and permitting simple percutaneous insertion. Bench testing of gas exchange in deionized water was used to evaluate eight impeller designs. The three best performing impeller designs were evaluated in acute studies in four calves (122 + or - 10 kg). Gas exchange increased significantly with increasing impeller rotation rate. The degree of enhancement varied with impeller geometry. The maximum gas exchange efficiency (exchange per unit surface area) for the catheter with the best performing impeller was 529 + or - 20 ml CO(2)/min/m(2) and 513 + or - 21 ml CO(2)/min/m(2) for bench and animal studies, respectively, at a rotation rate of 20,000 rpm. Absolute CO(2) exchange was 37 and 36 ml CO(2)/min, respectively. Active mixing by rotating impellers produced 70% higher gas exchange efficiency than pulsating balloon catheters. The sensitivity of gas exchange to impeller design suggests that further improvements can be made by computational fluid dynamics-based optimization of the impeller. PMID- 19779303 TI - Swirling flow can suppress flow disturbances in endovascular stents: a numerical study. AB - To test the hypothesis that by intentionally inducing swirling flow in an endovascular stent, hemodynamic performance of the stent can be improved, we numerically analyzed the flow characteristics in a simplified model of a stent within a straight segment of an artery in which swirling flow was introduced intentionally. The study was designed with two purposes: 1) to investigate whether swirling flow is beneficial to suppress flow disturbance in the stent; and 2) to determine the minimum helical strength of the swirling flow required in the design of a swirling flow stent. The numerical simulation showed that the swirling flow indeed reduced the size of the disturbed flow zones, enhanced the average wall shear stress, and lowered oscillatory shear index in the stent, which have been believed to be adverse factors involved in the development of arterial restenosis after stent deployment. The minimum inlet helicity density (or strength) of the swirling flow required was approximately 6.5 m/s(2). Based on the study, it is also believed that a stent with a structure that possesses intrinsic characteristics to automatically induce swirling flow in the stent is better than a stent with a front swirling flow inducer in terms of hemodynamics. PMID- 19779304 TI - Assessment of right ventricle function during exercise echocardiography by using tissue Doppler imaging in patients with coronary artery disease. AB - BACKGROUND: Assessing right ventricle (RV) function is difficult primarily because of its complex shape. Worsening RV function or dilatation during stress tests in patients with coronary artery disease may indicate proximal right coronary artery (RCA) narrowing. The aim of this study was to obtain quantitative diagnostic criteria for impaired RV function by tissue Doppler imaging (TDI) during exercise echocardiography, which could detect a significant lesion of the RCA in patients with coronary artery disease. METHODS AND RESULTS: We evaluated regional systolic and diastolic function using pulsed-wave TDI in two myocardial segments of the RV free wall during exercise stress tests in 160 patients with suspected coronary artery disease. The diagnostic criteria were obtained by comparing TDI and coronary angiography data. The accuracy, sensitivity, and specificity of the TDI diagnostic model for RCA disease were 81.1, 88.0, and 72.3%, respectively. CONCLUSION: TDI is a highly accurate method for the detection of RV dysfunction and RCA disease at rest and during exercise stress echocardiography in group of patients with known or suspected coronary artery disease. PMID- 19779305 TI - Characteristics and clinical course of primary sclerosing cholangitis in France: a prospective cohort study. AB - BACKGROUND/AIMS: Primary sclerosing cholangitis (PSC) is a rare disease, and large-scale report of PSC in France is lacking. We initiated a prospective multisite observational study. METHODS: One hundred and fifty PSC patients (90 with associated inflammatory bowel disease) were included. At entry, 11 patients had a diagnosis of hepatobiliary or colon malignancy (cholangiocarcinoma: n = 5, hepatocellular carcinoma: n = 2, gallbladder carcinoma: n = 1 and colorectal cancer: n = 4). One hundred and forty-one patients (94%) were treated with ursodeoxycholic acid (UDCA) (median dose: 13.1 mg/kg/day), including 118 with UDCA started before inclusion. RESULTS: During follow-up [3.9 (0.1-7.2) years], colorectal cancer was diagnosed in four patients and biliary carcinoma in two (incidences: 0.76 and 0.38 for 100 patient-years, respectively). Kaplan-Meier transplant-free survival at 4 years was 79%. Main causes of death (n = 10) were cancer (n = 5, including three colorectal cancers and two cholangiocarcinoma) or liver failure (n = 4). Indications for transplantation (n = 25) were end-stage liver disease (n = 16), biliary cancer (known or suspected) (n = 5), recurrent acute cholangitis (n = 3) or pruritus (n = 1). Independent predictive factors of death or transplantation were alkaline phosphatase at least 3 upper limit of normal values, platelets less than or equal to 150000/mm3 and bilirubin at least 23 micromol/l. Observed and predicted survivals were similar. CONCLUSION: PSC in France shares common features with other series and is almost universally treated with UDCA. Under standard-dose UDCA, PSC remains a rather severe disease. However, the low incidence of cholangiocarcinoma is compatible with a potential chemoprotective effect of UDCA against biliary neoplasia development. PMID- 19779306 TI - Efficacy of trichloroacetic acid in the treatment of anal intraepithelial neoplasia in HIV-positive and HIV-negative men who have sex with men. AB - BACKGROUND: Anal intraepithelial neoplasia (AIN), particularly AIN 3 is a precursor to anal cancer. Most cases of AIN are intraanal, but few treatments for intraanal AIN are currently available. Topical 85% trichloroacetic acid (TCA) is an inexpensive method used to treat perianal condyloma, a form of AIN 1, but its efficacy to treat intraanal AIN as first-line therapy is unknown. METHODS: Retrospective review of medical records was performed for all patients with AIN treated at the University of California San Francisco Anal Neoplasia Clinic with TCA as the first-line therapy from January 2000 to December 2004. Clearance was defined as the absence of AIN confirmed by high-resolution anoscopy and cytology after up to 4 TCA treatments. RESULTS: Thirty-five HIV-positive men and 19 HIV negative men met the enrollment criteria. In multivariate analysis, greater clearance was seen in patients 41-48 years of age versus >49 years [odds ratio (OR): 8.4, confidence interval (CI): 1.1 to 94, P: 0.04]. Among HIV-positive men, those with 2 or fewer lesions showed greater clearance (OR: 14.3, CI: 1.5 to 662, P: 0.01). 32% of patients with AIN 2/3 cleared to no lesions. On a per lesion basis, 73% of AIN 1 and 71% AIN 2/3 cleared to no lesion or AIN 1 or less, respectively. CONCLUSIONS: Topical 85% TCA was safe and well tolerated. It was more effective in younger patients and among HIV-positive patients, those with 2 or fewer lesions. A high proportion of AIN 2/3 lesions responded to TCA treatment. PMID- 19779307 TI - Low-frequency K103N strengthens the impact of transmitted drug resistance on virologic responses to first-line efavirenz or nevirapine-based highly active antiretroviral therapy. AB - BACKGROUND: There are conflicting data on the impact of low-frequency transmitted drug-resistant mutants on responses to first-line highly active antiretroviral therapy (HAART). METHODS: Patients started nevirapine or efavirenz with two or more nucleoside/nucleotide reverse transcriptase inhibitors in 1998-2007 without a prior resistance test at a median 1.0 (interquartile range, 0.0-3.4) year after diagnosis and with a median 218 (interquartile range, 131-296) CD4 cells/mm3, and had at least 24 weeks of follow up. Pre-HAART plasma samples were tested retrospectively by bulk genotyping and sensitive real-time polymerase chain reaction targeting reverse transcriptase K65R, K103N, Y181C, M184V, and G190A (interpretative cutoff 0.3%-0.9%). RESULTS: Among 93 patients, seven of 18 who experienced virologic failure and zero of 75 who maintained virologic suppression showed pre-HAART resistance, including three with high-frequency mutations detectable by bulk genotyping (two K103N, one G190A) and four with low-frequency K103N detectable only by polymerase chain reaction. Detection of either bulk (P = 0.006) or low-frequency (P = 0.001) resistance was significantly associated with the odds of virologic failure; combining the two markedly increased the strength of the association (P < 0.0001). At failure, the pre-HAART mutations were detected by bulk genotyping in five of seven patients alongside additional reverse transcriptase mutations. CONCLUSIONS: Low-frequency K103N mutants were as prevalent as bulk-detectable variants before starting HAART. Both high- and low frequency mutants were significantly associated with virologic failure. PMID- 19779308 TI - Detectable HIV viral load is associated with metabolic syndrome. AB - BACKGROUND: The aim of our study was to assess the association between HIV viral load (HIV-VL) and metabolic syndrome (MS) in a cohort of HIV-infected patients. METHODS: This is a cross-sectional study including 1324 consecutive HIV-infected patients on stable antiretroviral therapy regimens. RESULTS: Variables significantly associated with MS in univariate analysis were: age [mean +/- SD: 47.04 +/- 7.41 vs 44.07 +/- 6.82, (P < 0.0001)]; male sex [224 (69.35%) vs 614 (61.34%) (P = 0.009)]; Apo B (mg/dL) [111.51 +/- 29.64 vs 100.57 +/- 31.22, (P < 0.0001)]; homeostasis model assessment equation [median (interquartile range), 5.14 (3.00-8.15) vs 2.95 (1.93-4.57), (P < 0.0001)]; body mass index [25.17 +/- 4.40 vs 22.80 +/- 3.38, (P < 0.0001)]; protease inhibitor current use (%) [199 (61.61) vs 529 (52.85), (P = 0.006)]; and log10 HIV-VL [2.17 +/- 0.94 vs 2.02 +/- 0.79, (P = 0.0048)]. MS associated variables in multivariable analysis were: log10 HIV-VL [odds ratio (OR): 1.25; P = 0.003], age (per 10-year increment) [OR: 1.60; P < 0.0001], homeostasis model assessment equation > or =3.8 [OR: 2.77; P < 0.0001]. CONCLUSIONS: Persistent viremia is a significant predictor for the development of MS. Viral control through effective antiretroviral therapy is paramount not only for the control of HIV disease progression but also for the prevention of MS and associated cardiovascular disease. PMID- 19779310 TI - Sixty-four slice multidetector computed tomographic angiography in the evaluation of vascular trauma. AB - BACKGROUND: Artifacts produced by metallic fragments and orthopedic hardware limit the usefulness of conventional computed tomography in many military trauma patients. Contemporary literature suggests that multidetector computed tomographic angiography (MDCTA) by resolving these limitations may provide a useful noninvasive alternative to invasive arteriography. The objective of this study is to review the utility of MDCTA in the evaluation of recent combat casualties with vascular injuries. METHODS: Data on all vascular trauma patients seen by our service has been collected prospectively and entered into a database. A retrospective review was conducted of patients seen from August through December 2006 who underwent MDCTA. Patient demographics, mechanism of injury, modality of evaluation, and findings were recorded. RESULTS: Twenty patients underwent MDCTA. Thirteen patients were injured by blast fragments. Seven patients were injured by gunshot wounds. Nineteen of 20 studies were diagnostic and one was judged to be indeterminate. Studies in nine patients identified arterial injuries. Multiple extremities were evaluated with a single study in 16 patients. Fifteen studies assessed the lower extremities, four the upper extremities and two the neck. Fourteen patients in this series had retained fragments, 10 had external fixators or intramedullary rods, and only 4 had neither retained fragments nor orthopedic hardware. MDCTA allowed for assessment of the arterial runoff despite hardware or fragments in 15 of 16 (94%) patients. Comparative studies were available in four patients in addition to MDCTA. There were no missed injuries in these four patients. CONCLUSIONS: MDCTA yielded high resolution images that were very useful for the delayed evaluation of combat casualties. The presence of metallic fragments or orthopedic hardware did not significantly interfere with MDCTA. It is a reliable and promising alternative to traditional arteriography for evaluating clinically occult vascular trauma. PMID- 19779311 TI - Clavicle fracture prediction: simulation of shoulder lateral impacts with geometrically personalized finite elements models. AB - BACKGROUND: Human body numerical models can help to develop protection devices against effects of road crashes. In the context of a side impact, a shoulder model able to predict shoulder injuries and more especially clavicle fracture would be helpful. METHODS: A shoulder model derived from an existing finite element model of the human body representing an average male (50th percentile), HUMOS1, has been upgraded. An isolated clavicle model was assessed thanks to experimental corridors derived from dynamic tests up to failure. Then, the whole upgraded shoulder model was evaluated by comparison with results from experimental side impact tests on the shoulder. Eventually, the upgraded model was geometrically personalized toward the anthropometry of the subjects and its ability to simulate fractures was assessed. RESULTS: The isolated clavicle model was assessed as validated. The upgraded 50th percentile shoulder model provided accurate results in the subinjurious domain. At higher velocities, the personalized models produced realistic shoulder injuries: clavicle fracture was accurately predicted in four cases of six, the model was conservative for the two other cases. CONCLUSION: The upgraded shoulder model presented here was successfully submitted to a rigorous assessment process. Once geometrically personalized, it provided positive results for clavicle fracture prediction. As clavicle fracture is the major shoulder injury, this model could help the design of safety devices for shoulder protection. Furthermore, this study enhances the need for geometrical personalization methods when using finite element model for injury risk prediction. PMID- 19779312 TI - Screening adolescent patients admitted to the trauma service for high-risk behaviors: who is responsible? AB - BACKGROUND: Trauma remains the leading cause of death for adolescents in the United States. Adolescents are a hard to access medical population, with few opportunities for providers to screen for high-risk behaviors. The trauma team has a unique opportunity to screen for concurrent risk behaviors. The objective of this study was to assess surgeon knowledge, attitudes, and current practice of screening for high-risk behaviors in injured adolescents. METHODS: From June 2007 to September 2007, a 16-item survey was mailed to 880 trauma surgeons assess their current screening practices of their adolescent patients (14-18 years); their perception of patients' risk taking; the perceived need for additional screening; and the surgeons' willingness to add routine screening to their workup. RESULTS: The majority of trauma surgeons believed screening for risk behaviors in their adolescent patients was an important part of the trauma admission, although most thought it was not their personal responsibility. The highest rate of screening was for substance abuse, whereas the lowest was for gun ownership and sexual behavior. The majority of surgeons (74.4%) were willing to routinely consult specialists in adolescent medicine/pediatrics to assess for and manage risk behaviors in their adolescent trauma patients. CONCLUSION: The majority of trauma surgeons agree that risk screening is an important part of the trauma treatment for adolescent patients and are interested in involving adolescent medicine and pediatric specialists to ensure adequate screening, management, and follow-up of risk behaviors in their patients. PMID- 19779309 TI - Tonsillar application of AT-2 SIV affords partial protection against rectal challenge with SIVmac239. AB - BACKGROUND: Although mucosal responses are important for preventing infections with HIV, the optimal strategies for inducing them remain unclear. To evaluate vaccine strategies targeting the oral mucosal lymphoid tissue inductive sites as an approach to provide immunity at distal sites, we vaccinated healthy macaques via the palatine/lingual tonsils with aldrithiol 2 (AT-2) inactivated Simian immunodeficiency virus (SIV)mac239, combined with CpG-C immunostimulatory oligonucleotide (CpG-C ISS-ODN, C274) as the adjuvant. METHODS: Macaques received 5 doses of C274 or control ODN C661 and AT-2 SIV on the tonsillar tissues every 6 weeks before being challenged rectally with SIVmac239, 8 weeks after the last immunization. RESULTS: Although no T-cell or B-cell responses were detected in the blood before challenge, antibody (Ab) responses were detected in the rectum. Immunization with AT-2 SIV significantly reduced the frequency of infection compared with nonimmunized controls, irrespective of adjuvant. In the vaccinated animals that became infected, peak viremias were somewhat reduced. SIV-specific responses were detected in the blood once animals became infected with no detectable differences between the differently immunized groups and the controls. CONCLUSION: This work provides evidence that vaccine immunogens applied to the oral mucosal associated lymphoid tissues can provide benefit against rectal challenge, a finding with important implications for mucosal vaccination strategies. PMID- 19779313 TI - Pulmonary embolism after injury: more common than we think? AB - BACKGROUND: We have previously demonstrated that pulmonary embolism (PE) can occur early and explain hypoxia immediately after injury. We hypothesized that an increased awareness of early PE would result in an increased incidence, an earlier diagnosis, and a decreased mortality of PE after injury. METHODS: The trauma registry identified patients diagnosed with a PE between time period (TP) 1 (June 1999 and December 2004) and TP 2 (January 2005 and December 2006). Demographics, injury specific data, time from injury to diagnosis, diagnostic modality, and mortality were compared with a t test for the two TPs. RESULTS: There were 35,424 and 15,022 patients, respectively, treated in our trauma center during the two study periods. During TP1, 94 (0.27%) patients were diagnosed with PE. Mean age was 45 years (+/-18.5) and mean Injury Severity Score (ISS) was 23 (+/-11.4); 81.9% were men and 91.6% sustained blunt trauma. Eighty-three (0.55%) patients in TP2 were identified with a PE. Mean age was 43 years (+/-17.4) and mean ISS was 23 (+/-13.0); 78.3% were men and 86.7% sustained blunt trauma. In TP1, the diagnosis was confirmed by a computed tomography (CT) in 76 of 94 (80.9%) patients. In TP2, the CT scan diagnosed 80 of 83 (96.4%) patients. Time to diagnosis was postinjury day 11.8 (+/-14) in TP1 and 9.2 (+/-11.5) in TP2. Mortality in patients diagnosed with PE was 10.6% in TP1 and 9.6% in TP2. CONCLUSION: Our incidence of PE has doubled from 0.27% to 0.55% in a 6-year TP when mean ISS and thromboembolic prophylaxis protocols have remained the same. We attribute this increase in incidence to heightened awareness through recent publications, as well as 24 hour availability of multiple multidetector-row spiral CT scanners and not necessarily an increase in prevalence of PE. PMID- 19779314 TI - Altering the propensity for density: the benefits and risks of selective estrogen receptor modulators. PMID- 19779315 TI - Screening the postmenopausal ovary. PMID- 19779316 TI - Lactate is an alternative energy fuel to glucose in neurons under anesthesia. AB - The uptake of [14C]lactate was measured in the brains of mice anesthetized with pentobarbital or chloral hydrate. The results showed significant increase of the [14C]lactate uptake in the brain under both anesthesia. Despite energy metabolism in the brain being suppressed by both pentobarbital and chloral hydrate, the [14C]lactate uptake was unexpectedly increased under anesthesia. [14C]Lactate uptake in rat brain injured by infusion of quinolic acid was significantly decreased, and the reduction of [14C]lactate uptake was parallel to neural cell death, suggesting that exogenous lactate might be selectively taken up by neuron. These results indicated that lactate rather than glucose might serve as an energy substrate for neuron in intact brain under anesthesia. PMID- 19779317 TI - Experimental model of intravitreal injection techniques. AB - PURPOSE: To evaluate the amount of drug reflux and vitreous leakage from the needle tract after various intravitreal (IVT) injection techniques in porcine cadaver eyes. METHODS: The reflux after IVT injection was quantified by methylene blue injection through the pars plana of fresh pig eyes (0.05 mL per eye, n = 150) and the vitreous incarceration measured after balanced salt solution (BSS) IVT injection (0.05 mL per eye, n = 150) into eyes with vitreous previously stained with methylene blue. Blue spots observed on the ocular surface after injection quantified both reflux and vitreous incarceration. We tested different needle sizes (27, 30, and 32 gauge) and different techniques (depth and speed of injection). We used an ocular endoscope to observe the flow and diffusion of injected methylene blue and the vitreous incarceration at the puncture site after IVT injection using the different techniques. RESULTS: Thirty-gauge needles showed less drug reflux than the 32-gauge or 27-gauge needles (P < 0.01). Thirty two-gauge needles demonstrated less incarceration of vitreous at the tract site (P < 0.01), but with the endoscope, all needle tracts showed vitreous incarceration at their internal aspect. Deep IVT injection showed less reflux than superficial IVT injection, but vitreous incarceration did not differ. The delay between the scleral puncture and the injection did not modify the reflux or the vitreous incarceration. CONCLUSION: Thirty-gauge needles and deep placement of the needle tip into the vitreous before injection may reduce reflux and vitreous incarceration. This could maximize the therapeutic effect of IVT injection and may decrease the rates of severe complications such as retinal detachment and endophthalmitis. PMID- 19779318 TI - Orally exposed uninfected individuals have systemic anti-HIV responses associating with partners' viral load. AB - OBJECTIVES: To determine whether oral HIV-1 exposure incites a persistent systemic anti-HIV-1 response in exposed uninfected individuals of discordant couples of men who have sex with men, and whether this response associates with HIV-1 exposure measured by viral load in the HIV-positive partners. METHODS: Plasma were collected from exposed uninfected individuals (n = 25), HIV-positive partners (n = 25) and low-risk controls (n = 22). A peripheral blood mononuclear cells-based neutralization assay was used to test these samples against three primary HIV-1 isolates. Self-reported questionnaires described routes of HIV-1 exposure, and clinical records documented viral loads in HIV-positive partners. RESULTS: At enrollment, plasma samples from seven of 25 exposed uninfected individuals neutralized at least two of the three HIV-1 isolates. No samples from the 22 controls neutralized any HIV-1 isolate (P = 0.01). Of these seven exposed uninfected individuals, six retained neutralization capacity during follow-up. Neutralization capacity among exposed uninfected individuals associated with the highest measured viral load of their respective partners (P = 0.01) and also time since highest viral load (P = 0.02). Purified plasma immunoglobulin (Ig) A1 mediated neutralization was observed in six of the seven samples, whereas none of the IgA1-depleted plasma samples neutralized HIV-1. The neutralizing IgA1 was not HIV envelope specific as detected by ELISA and western blot. CONCLUSION: Orally exposed uninfected men who have sex with men can mount neutralizing anti HIV-1 activity in plasma, mediated primarily by non-HIV envelope-specific IgA1. Neutralization was associated with previous measured highest viral load in the HIV-positive partner, as well as time elapsed since the peak viral load. Neutralization also persisted over time in spite of a continuous low viral exposure. PMID- 19779319 TI - CYP2B6, CYP2A6 and UGT2B7 genetic polymorphisms are predictors of efavirenz mid dose concentration in HIV-infected patients. AB - OBJECTIVE: UDP-glucuronosyltransferase (UGT) 2B7 was recently identified as the main enzyme mediating efavirenz N-glucuronidation. In this study, we determined whether selected UGT2B7 polymorphisms could be used to enhance the prediction of efavirenz plasma concentrations from CYP2B6 and CYP2A6 genotypes. METHODS: Mid dose efavirenz plasma concentrations were determined in 94 HIV-infected Ghanaian patients at 2-8 weeks of antiretroviral therapy. CYP2B6 and CYP2A6 genotypes had been previously reported. UGT2B7 exon 2 single-nucleotide polymorphisms (SNPs) c.735A>G (UGT2B7*1c; rs28365062) and c.802C>T (H268Y; UGT2B7*2; rs7439366) were determined by direct sequencing with UGT2B7*1a defined as the reference allele. Relationships between efavirenz plasma concentrations, demographic variables and genotypes were evaluated by univariate and multivariate statistical approaches. RESULTS: The mean (+/-SD) mid-dose efavirenz plasma concentration was 3218 (+/ 3905) ng/ml with coefficient of variation of 121%. Independent predictors of efavirenz concentration included CYP2B6 c.516TT genotype (4030 ng/ml increase; 95% confidence interval 2882-5505 ng/ml, P < 0.001), UGT2B7*1a carrier status (475 ng/ml increase; 95% confidence interval 138-899 ng/ml, P = 0.004) and CYP2A6*9 and/or *17 carrier status (372 ng/ml increase; 95% confidence interval 74-742 ng/ml, P = 0.013). Overall, CYP2B6 c.516TT genotype, UGT2B7*1a carrier status and CYP2A6*9 or *17 carrier status accounted for 45.2, 10.1 and 8.6% of the total variance, respectively. CONCLUSION: Our findings demonstrate independent effects of CYP2A6 and UGT2B7 genetic variation on efavirenz disposition beyond that of the CYP2B6 polymorphisms. The development and testing of a pharmacogenetic algorithm for estimating the appropriate dose of efavirenz should incorporate genotypic data from both the oxidative and glucuronidation pathways. PMID- 19779321 TI - Activity, pharmacokinetics and safety of lersivirine (UK-453,061), a next generation nonnucleoside reverse transcriptase inhibitor, during 7-day monotherapy in HIV-1-infected patients. AB - OBJECTIVE: To investigate the effects on viral load and assess dose-response relationships, pharmacokinetics, safety and tolerability of lersivirine (UK 453,061), a next-generation nonnucleoside reverse transcriptase inhibitor, in asymptomatic HIV-1-infected patients. DESIGN: Randomized, double-blind, placebo controlled, parallel group, multicenter phase IIa clinical study. METHODS: Forty eight HIV-1-infected patients were enrolled for the study of once-daily or twice daily lersivirine at total daily doses ranging from 20 to 1000 mg. The primary endpoint was the change in log10 plasma HIV-1 RNA viral load from baseline to day 8. Secondary endpoints related to pharmacokinetics, safety and tolerability and potential development of viral resistance and genotyping patterns. RESULTS: Patients treated with lersivirine achieved day 8 mean viral load reductions of 0.3, 0.8, 1.3 and 1.6 log10 after receiving 10, 30, 100 and 500 mg twice daily, respectively, and 0.9, 1.7 and 1.8 log10 after receiving 100, 500 and 750 mg once daily, respectively. Mean changes from baseline to day 8 were small in patients receiving placebo. For all dose regimens, plasma exposure increased approximately in line with lersivirine dose. Median plasma concentrations of lersivirine at steady state were above the IC90 for lersivirine at once-daily doses of at least 500 mg and twice-daily doses of at least 100 mg. The most commonly reported treatment-emergent adverse events were headache, fatigue and nausea. CONCLUSION: Seven-day monotherapy with lersivirine achieved mean viral load reductions up to 1.8 log10. Lersivirine was safe and well tolerated. Further studies of lersivirine in combination with other antiretroviral drugs to assess long-term durability of antiviral response, safety and tolerability are warranted. PMID- 19779320 TI - Prognosis of patients treated with cART from 36 months after initiation, according to current and previous CD4 cell count and plasma HIV-1 RNA measurements. AB - OBJECTIVES: CD4 cell count and plasma viral load are well known predictors of AIDS and mortality in HIV-1-infected patients treated with combination antiretroviral therapy (cART). This study investigated, in patients treated for at least 3 years, the respective prognostic importance of values measured at cART initiation, and 6 and 36 months later, for AIDS and death. METHODS: Patients from 15 HIV cohorts included in the ART Cohort Collaboration, aged at least 16 years, antiretroviral-naive when they started cART and followed for at least 36 months after start of cART were eligible. RESULTS: Among 14 208 patients, the median CD4 cell counts at 0, 6 and 36 months were 210, 320 and 450 cells/microl, respectively, and 78% of patients achieved viral load less than 500 copies/ml at 6 months. In models adjusted for characteristics at cART initiation and for values at all time points, values at 36 months were the strongest predictors of subsequent rates of AIDS and death. Although CD4 cell count and viral load at cART initiation were no longer prognostic of AIDS or of death after 36 months, viral load at 6 months and change in CD4 cell count from 6 to 36 months were prognostic for rates of AIDS from 36 months. CONCLUSIONS: Although current values of CD4 cell count and HIV-1 RNA are the most important prognostic factors for subsequent AIDS and death rates in HIV-1-infected patients treated with cART, changes in CD4 cell count from 6 to 36 months and the value of 6-month HIV-1 RNA are also prognostic for AIDS. PMID- 19779322 TI - Viral hepatitis is associated with reduced bone mineral density in HIV-infected women but not men. AB - OBJECTIVE: Few studies have examined the impact of viral hepatitis on bone mineral density (BMD), and none have done so among HIV-infected patients. Our objective was to determine whether viral hepatitis was associated with low BMD in HIV. DESIGN: : A cross-sectional study among 1237 HIV-infected patients (625 with viral hepatitis). METHODS: Dual-energy X-ray absorptiometry scans of the lumbar spine and femoral neck were obtained. Clinical data, hepatitis B and C status, and markers of bone metabolism were determined at dual-energy X-ray absorptiometry scanning. Multivariable logistic regression examined the association between hepatitis and low BMD (Z-score < or =-2.0 at the lumbar spine, femoral neck, or both). RESULTS: Mean BMD Z-scores were lower among hepatitis-coinfected women at the lumbar spine {-0.15 versus +0.29; difference = 0.44 [95% confidence Interval (CI) -0.65 to -0.23]; P < 0.001} and femoral neck [ 0.64 versus -0.39; difference = -0.25 (95% CI -0.44 to -0.06); P = 0.009] compared with HIV-monoinfected women. No differences in mean BMD Z-scores were observed between coinfected and monoinfected men. After adjustment for age, BMI, duration of HIV, antiretroviral use, physical activity, and smoking, viral hepatitis was associated with low BMD among women (adjusted odds ratio 2.87, 95% CI 1.31-6.29) but not men (adjusted odds ratio 1.19, 95% CI 0.74-1.91). Coinfected women had lower mean parathyroid hormone (60.1 versus 68.1 pg/ml; P = 0.02) but similar mean 25-hydroxyvitamin D (19.1 versus 19.6 ng/ml; P = 0.6) and osteocalcin (3.0 versus 3.2 ng/ml; P = 0.8) concentrations than HIV-monoinfected women. CONCLUSION: Viral hepatitis was associated with a higher risk of low BMD among HIV-infected women but not men. PMID- 19779324 TI - A validation study of a retrospective venous thromboembolism risk scoring method. AB - OBJECTIVES: Validate a retrospective venous thromboembolism (VTE) risk scoring method, which was developed at the University of Michigan Health System and based on the Caprini risk assessment model, and assess the confounding effects of VTE prophylaxis. BACKGROUND: Assessing patients for risk of VTE is essential to initiating appropriate prophylaxis and reducing the mortality and morbidity associated with deep vein thrombosis and pulmonary embolism. METHODS: VTE risk factors were identified for 8216 inpatients from the National Surgical Quality Improvement Program using the retrospective scoring method. Logistic regression was used to calculate odds ratios (OR) for VTE within 30 days after surgery for risk factors and risk level. A bivariate probit model estimated the effects of risk while controlling for adherence to prophylaxis guidelines. RESULTS: Distribution of the study population by risk level was highest, 52.1%; high, 36.5%; moderate, 10.4%; and low, 0.9%. Incidence of VTE within 30 days was overall 1.4%; by risk level: highest, 1.94%; high, 0.97%; moderate, 0.70%; low, 0%. Controlling for length of hospitalization (>2 d) and fiscal year, pregnancy or postpartum (OR = 8.3; 1.0-68, P < 0.05), recent sepsis (4.0; 1.4-10.9, P < 0.01), malignancy (2.3; 1.5-3.3, P < 0.01), history of VTE (2.1; 1.1-4.1, P < 0.05), and central venous access (1.8; 1.1-3.0, P < 0.05) were significantly associated with VTE. Risk level was significantly associated with VTE (1.9; 1.3 2.6, P < 0.01). The bivariate probit demonstrated significant correlation between the probability of VTE and lack of adherence to prophylaxis guidelines (rho = 0.299, P = 0.013). CONCLUSION: The retrospective risk scoring method is valid and supports use of individual patient assessment of risk for VTE within 30 days after surgery. PMID- 19779323 TI - Erythropoiesis stimulating agent administration improves survival after severe traumatic brain injury: a matched case control study. AB - OBJECTIVE: Erythropoiesis stimulating agent (ESA) administration may reduce mortality in severe traumatic brain injury (sTBI). SUMMARY BACKGROUND DATA: It has been established that the administration of ESA in critically ill trauma victims has been associated with improved outcomes. Recent experimental and clinical data showed neuroprotective effects of ESA, however, the literature regarding impact on outcome in sTBI is lacking. METHODS: : A retrospective matched case control study in patients with sTBI [head Abbreviated Injury Scale (AIS), >or=3] receiving ESA while in the surgical intensive care unit from January 1, 1996 to December 31, 2007 (n = 89), were matched 1 to 2 (n = 178) by age, gender, mechanism of injury, Glasgow Coma Scale, presence of hypotension on admission, Injury Severity Score, AIS for all body regions, and presence of anemia with patients who did not receive the agent. Each case's controls were chosen to have surgical intensive care unit length of stay more than or equal to the time from admission to first dose of ESA. The primary outcome measure in this study was mortality. RESULTS: Cases and controls had similar age, gender, mechanisms of injury, incidence of hypotension, Glasgow Coma Scale on admission, Injury Severity Score, and AIS for all body regions. Although the ESA+ patients experienced protracted hospital length of stay and comparable surgical intensive care unit free days, they demonstrated a significantly lower in-hospital mortality in comparison to controls at 7.9% versus 24.2%, respectively (OR: 0.27; 95% CI = 0.12-0.62; P = 0.001). CONCLUSIONS: Erythropoiesis stimulating agent administration in sTBI is associated with a significant in-hospital survival advantage without increase in morbidity. Prospective validation of our findings is warranted. PMID- 19779325 TI - Differentiated thyroid carcinoma presenting with distant metastasis at initial diagnosis clinical outcomes and prognostic factors. AB - OBJECTIVES: Distant metastasis (DM) is seldom observed at initial presentation of differentiated thyroid carcinoma (DTC), making it difficult to assess the clinical characteristics and treatment outcomes of DTC patients with DM. We therefore retrospectively assessed these parameters in DTC patients who presented with DM between July 1994 and December 2007. In addition, we compared biologic behaviors and prognostic factors between patients presenting with DM and those developing DM after initial treatment. METHODS: Among 1560 DTC patients who underwent thyroidectomies during the 13.5-year study period, 91 patients were included in this study; 52 patients (3.4%) displayed DM at initial presentation and 39 (2.5%) developed DM after initial 131 radiacitive iodine (RI) treatment. Metastatic lesions were treated with high dose RI (94.5%), surgical resection (14.3%), external beam radiation therapy (31.9%), embolization of feeding vessels (1.1%), and/or chemotherapy (1.1%). Median duration of follow-up was 75 months (range, 12-158 months). RESULTS: Mean patient age was 57 years (range, 13-80 years), and the female-to-male ratio was 2.03:1. Metastases were detected in the lung only (68.1%), bone only (16.5%), and multiple sites (15.4%). When clinical and tumor characteristics were considered, metastatic lesion iodine avidity was significantly higher in patients presenting with DM. At 5 and 10 years, the overall survival (OS) rates in patients presenting with DM were 83.8% and 72.1%, respectively, and the disease-specific survival (DSS) rates were 68.5% and 26.8%. OS did not differ significantly between patients presenting with DM and those developing DM after initial treatment. However, those with initial DM enjoyed significantly improved DSS compared with patients who developed DM after initial treatment. At last follow-up, 22 patients (24.2%) were alive without disease, 48 (52.7%) were alive with disease, and 21 (23.1%) had died of disease in study patients. Multivariate Cox's regression analyses showed that complete local control was a significant predictor of OS and DSS in all study patients. In patients developing DM after initial treatment, metastatic lesion iodine avidity was also associated with both OS and DSS. In contrast, avidity was associated only with DSS in patients presenting with DM. CONCLUSIONS: Our study showed that DTC patients presenting with initial DM appear to have relatively favorable outcomes compared with DTC patients who developed DM after initial treatment. Complete local control may be the most important prognostic indicator in all DM patients. Metastatic lesion iodine avidity had a significant impact on both OS and DSS in patients developing DM after initial treatment, but significantly influenced only DSS in patients presenting with initial DM. PMID- 19779326 TI - Immediate postoperative low platelet count is associated with delayed liver function recovery after partial liver resection. AB - OBJECTIVE: To evaluate whether a low postoperative platelet count is associated with a poor recovery of liver function in patients after partial liver resection. BACKGROUND: Experimental studies in rodents have recently suggested that blood platelets play a critical role in the initiation of liver regeneration. It remains unclear whether platelets are also involved in liver regeneration in humans. METHODS: In a series of 216 consecutive patients who underwent partial liver resection for colorectal liver metastases, we studied postoperative mortality and liver dysfunction in relation to the immediate postoperative platelet count. All patients had normal preoperative liver function and none of them had liver fibrosis or cirrhosis. Delayed postoperative recovery of liver function was defined as serum bilirubin >50 micromol/L or prothrombin time >20 seconds at any time point between postoperative day 1 and 5. RESULTS: Patients with a low (<100 x10(9)/L) immediate postoperative platelet count had worse postoperative liver function, higher serum markers of liver injury, and increased mortality compared with patients with normal platelet counts (>100/L). A low immediate postoperative platelet count was identified as an independent risk factor of delayed postoperative recovery of liver function (OR, 11.5; 95% CI, 1.1 122.4; P = 0.04 in multivariate analysis). CONCLUSION: After partial liver resection, a low platelet count is an independent predictor of delayed postoperative liver function recovery and is associated with increased risk of postoperative mortality. These clinical findings are in accordance with the accumulating evidence from experimental studies, indicating that platelets play a critical role in liver regeneration. PMID- 19779327 TI - Obesity, surgical site infection, and outcome following renal transplantation. AB - OBJECTIVE: We sought to understand whether obesity imparts detriment in outcome beyond risk of developing surgical site infection (SSI). SUMMARY BACKGROUND DATA: Obesity is a risk factor for SSI following renal transplantation, and has been implicated in inferior patient and graft survival postoperatively. METHODS: We conducted a retrospective review of all adult kidney-only transplants performed at the University of Michigan between September 2003 and April 2008. The primary exposure variable was recipient body mass index (BMI). Cox multivariable regression and Kaplan-Meier analysis were used to identify factors associated with SSI, graft loss, and patient death. RESULTS: In total, 869 recipients were studied, including 351 with BMI >30. Multivariate analysis revealed recipient age, delayed graft function, and BMI >30 to be independent risk factors for SSI. SSI was a significant risk factor for graft loss (HR: 2.194, 95% CI: 1.357-3.546) and approached significance as a risk factor for patient death (HR: 1.689, 95% CI: 0.941-3.028). Obesity had no independent effect on graft or patient outcome. CONCLUSIONS: SSI is associated with detriment to patient and graft survival following renal transplantation. The prevalence of SSI is higher among obese recipients, but those who avoid SSI have comparable outcomes to nonobese recipients. These findings redemonstrate the importance of SSI prevention following renal transplantation. PMID- 19779328 TI - Positive predictive value of the AHRQ accidental puncture or laceration patient safety indicator. AB - OBJECTIVE: Patient Safety Indicator (PSI) 15, or "Accidental Puncture or Laceration" (APL), of the US Agency for Healthcare Research and Quality was recently endorsed as a consensus standard for quality of care by the National Quality Forum. We sought to determine the positive predictive value (PPV) of this indicator. METHODS: We conducted a retrospective cross-sectional study of hospitalization records that met PSI 15 criteria. We sampled cases from 32 geographically diverse hospitals, including both teaching and nonteaching hospitals, between October 1, 2005 and March 31, 2007. Trained abstractors from each center reviewed randomly sampled medical records, using a standard instrument. We determined the PPV of the indicator and conducted descriptive analyses of the cases. RESULTS: Of the 249 cases that met PSI 15 criteria, 226 (91%; 95% CI: 88%-94%) represented true APL. Fifty-six of the true APL cases (24%) represented injuries that generally would be expected to heal without repair, yielding, from the standpoint of clinical relevance, a PPV of 68% (95% CI: 62%-74%). True positive cases that would typically warrant repair (n=170) were most likely to involve the gastrointestinal tract (30%), bladder (25%), dura (19%), or an important blood vessel (16%). In 97 of the true APL cases (43%), adhesions or other scar tissue were thought to have contributed to the complication. The 23 false-positive cases involved no apparent event other than normal operative conduct (n=7), a complication other than APL (bleeding, infection, dislodgement of a gastrostomy tube, or fracture) (7), an APL present on admission (5), or a disease-related lesion (4). CONCLUSIONS: Although PSI 15 is highly predictive of APL from a coding perspective, the indicator is less predictive of APL that could be considered clinically important. A significant proportion of cases represent relatively inconsequential injuries or injuries for which the risk may have been acceptable relative to the goals of the procedure. PMID- 19779329 TI - Hypothyroidism following hemithyroidectomy: a retrospective review. AB - OBJECTIVE: To investigate the incidence, time to onset, and risk factors for the development of hypothyroidism after hemithyroidectomy. BACKGROUND: The incidence and risk factors for hypothyroidism in patients undergoing partial thyroid surgery remains unclear. Hypothyroidism is an under appreciated sequel of hemithyroidectomy. The early recognition of this postoperative complication may prevent symptoms of hypothyroidism and recurrent thyroid disease. METHODS: We conducted a retrospective review of all patients undergoing hemithyroidectomy from August 1992 to June 2006 by a single surgeon. Patients were analyzed for age, sex, family history of thyroid disease, thyroid antibody levels, pre- and postoperative thyroid stimulating hormone (TSH), histologic diagnosis, weight of resected tissue, histologic evidence of thyroiditis, and lag time to diagnosis of hypothyroidism. chi or Fisher exact test or Student t test were performed. RESULTS: Hypothyroidism was diagnosed in 10.9% of 294 patients. The mean time to diagnosis was 8.2 +/- 10.9 months. The mean thyroxine dose was 69.4 +/- 31.6 micrograms. Patients with postoperative hypothyroidism had a higher incidence of a high-normal preoperative TSH level (TSH: 2.5-4.0 mIU/L, 18.8% vs. 3.8%; P < 0.01), thyroiditis on histology (46.8% vs. 11.8%; P < 0.01) and elevated thyroid antibodies levels (47.8% vs. 11.5%; P < 0.01). Age, gender, family history of thyroid disease, thyroid pathology, and weight of resected tissue were not significant risk factors for hypothyroidism. CONCLUSIONS: An incidence of 10.9% is higher than anticipated and all patients should have postoperative thyroid function assessment. However, a high-normal preoperative TSH, elevated thyroid antibody levels, and the presence of thyroiditis on histology are indications for close monitoring. PMID- 19779330 TI - The influence of six cardiovascular polymorphisms on a first event of ischemic heart disease is modified by sex and age. AB - OBJECTIVE: To examine the contribution of six cardiovascular polymorphisms to the occurrence of a first event of ischemic heart disease (IHD) in a primary care population with a high prevalence of hypertension. Furthermore, we specified the data for sex and age. METHODS: In this cross sectional case-control study, patients with a first event of IHD (157) and event-free controls (571) were studied. Both the groups were genotyped for the angiotensin II type 1 receptor (A1166C), angiotensinogen (M235 T), angiotensin converting enzyme (4656rpt), endothelial nitric oxide synthase (E298D), G-protein beta3 subunit (C825 T), and alpha-adducin (G460W) polymorphisms. Univariate and multivariate odds ratios (ORs) were calculated to assess the association between a first ischemic event and these polymorphisms. Sliding mean analyses were performed to show age specific associations. RESULTS: Multivariate ORs indicated a protective association for the carrier status of the T-allele of AGT, overall [OR = 0.69 (0.34-0.90)] and for males [OR = 0.58 (0.27-0.89)]. Sliding mean analyses showed a continuous protective association with IHD of the T-allele of AGT with increasing age in males, whereas in females an increased risk for IHD was observed with a maximum OR of 1.6 at the age of 56 years. CONCLUSION: In this population the T-allele of the AGT polymorphism is protective for a first event of IHD in males. PMID- 19779331 TI - Bioinformatics services related to diagnosis of primary immunodeficiencies. AB - PURPOSE OF REVIEW: Most primary immunodeficiencies (PIDs) have overlapping signs and symptoms - presenting a challenge for diagnosis. The information available from the Internet for over 200 PIDs is scattered between numerous services and databases. Patient information has been collected in different patient registries. Several software tools have been developed in order to build the databases, expert systems and other information systems useful in diagnosis or prediction. RECENT FINDINGS: Previously released services have been significantly improved and some new bioinformatics tools have been developed to help in diagnosis, prediction, mutation analysis and classification of PIDs. Several national initiatives have been launched for centralized PID information services. The very latest additions are tools and approaches for PID candidate gene prioritization, systematic classification and a medical expert system to help in diagnosis. SUMMARY: Many bioinformatics tools for PIDs are already freely available over the Internet. We expect bioinformatics tools to further help healthcare professionals in diagnosis, analysis and prediction. Currently, most of the resources are stand-alone and thus their integration will be a challenge for the future. Another challenge is to develop terminologies, ontologies and standards to achieve semantic interoperability. PMID- 19779332 TI - New insights into the pathogenesis of adenosine deaminase-severe combined immunodeficiency and progress in gene therapy. AB - PURPOSE OF REVIEW: Adenosine deaminase (ADA)- deficient severe combined immunodeficiency (SCID) is a complex metabolic and immunological disorder, characterized by a severe immunodeficiency due to the accumulation of purine metabolites in plasma and cells. This review summarizes recent findings on the pathogenesis of immunological and nonimmunological defects in ADA deficiency and the successful outcome of gene therapy trials for this condition. RECENT FINDINGS: Recent reports show that ADA-SCID is associated with an increased frequency of autoimmune manifestations and high risk of central nervous system (CNS) complications even after bone marrow transplantation. It remains unclear to what extent infection-related or disease-specific factors correlate with this divergent outcome.Recent trials represented the first demonstration of long-term clinical efficacy of HSC gene therapy for ADA-SCID, underlining that gene therapy has a favorable safety profile and is effective in restoring normal purine metabolism and immune functions. Molecular studies showed that the retroviral integration profile after successful gene therapy did not cause selection or expansion of malignant cell clones in vivo. SUMMARY: Gene therapy for ADA deficient SCID is an effective treatment, providing long-term clinical benefit for affected patients. Future research will be needed to address the occurrence of autoimmune manifestations and nonimmunological defects in order to improve patients' long-term prospects. PMID- 19779333 TI - Recurrent first trimester pregnancy loss: revised definitions and novel causes. AB - PURPOSE OF REVIEW: First trimester pregnancy loss affects up to 15% of clinically recognized pregnancies. Whereas most couples will proceed to have successful subsequent pregnancies, 2-4% will suffer recurrent losses, often with no identifiable cause. In fact, up to 40-50% of patients suffering recurrent pregnancy loss (RPL) will have no identifiable cause for their losses. Whereas the high incidence of spontaneous fetal aneuploidy will ensure that this number will never fall to zero, its level suggests that additional causes and appropriate diagnostic testing await discovery. The definition, diagnostic work up and appropriate interventions among patients with RPL remain controversial. Here, we will review those papers published in the last 1-2 years that improve our understanding of the definition of RPL, that confirm the utility of present testing paradigms or that pose novel causes and diagnostic approaches to patients with a history of RPL. RECENT FINDINGS: Standard definitions of RPL have been suggested by the American Society of Reproductive Medicine. Suggested potential diagnostic testing for RPL has been expanded to include male factors and new paradigms that address placental function, including the role of vascular endothelial growth factor, thrombosis and maternal-fetal immunology. SUMMARY: Standardized definitions for RPL and standardized approaches to initiating the RPL work-up will aid in study design and improve the applicability and implications of published findings. Appropriate investigation of novel causes for RPL may decrease the percentage of patients carrying the diagnosis of unexplained RPL. PMID- 19779334 TI - Diabetes and fractures: an overshadowed association. AB - PURPOSE OF REVIEW: To review recent literature on fracture risk in patients with type 1 and type 2 diabetes. RECENT FINDINGS: Observational and population studies have reported a higher risk of fractures in patients with type 1 and type 2 diabetes, especially at the hip. Type 2 diabetic patients have a higher bone mineral density compared with the general population, and yet, remain unprotected from fractures. Type 1 diabetic patients have a greater risk of fractures and a lower bone mineral density compared with the general population. Their lower bone mineral density, however, does not fully account for the raised fracture risk. Therefore, impaired bone quality rather than lower bone density appears to mediate the increased fracture risk in patients with type 1 and 2 diabetes.Recently, studies have shown an association between advanced glycation end products with increased fracture risk in diabetic patients. These studies support the hypothesis of poor glycemic control and chronic hyperglycemia having a direct detrimental effect on bone quality. In addition, increased fracture risk has been reported in patients with peripheral and autonomic neuropathy, recurrent hypoglycemic events, vitamin D deficiency, and those receiving thiazolidinedione therapy. SUMMARY: Diabetes is associated with an increased risk of fractures in patients with type 1 and type 2 diabetes. Appropriate measures aimed at fracture prevention should be considered in the complex care of the diabetic patient. PMID- 19779335 TI - What's the deal with niacin development: is laropiprant add-on therapy a winning strategy to beat a straight flush? AB - PURPOSE OF REVIEW: Niacin is a B-complex vitamin used as a lipid-altering drug since the 1950s. Niacin improves multiple lipid parameters. Atherosclerotic coronary heart disease outcome studies support niacin's efficacy in reducing coronary heart disease events, either as monotherapy or when used in combination with other lipid-altering drugs. The most commonly reported reason for the lack of its more widespread clinical use is niacin-induced flushing. RECENT FINDINGS: Laropiprant is a highly selective prostaglandin D2 receptor 1 antagonist that mitigates niacin-induced flushing. SUMMARY: This review examines the history and provides a perspective regarding the extended-release niacin/laropiprant development program, which was designed to better allow patients to achieve a more therapeutic niacin dose of 2 g/day, without the need for titration. Ongoing coronary heart disease outcome studies will provide better insight as to the benefits of niacin in general, and the safety and efficacy of extended-release niacin/laropiprant specifically. PMID- 19779336 TI - Thiazolidinediones and the liver in humans. AB - PURPOSE OF REVIEW: To review recent advances in the understanding of the mechanism of action of thiazolidinediones (TZDs) in humans. RECENT FINDINGS: The liver is characterized by excess fat accumulation due to nonalcoholic causes (non alcoholic fatty liver disease) in most patients with the metabolic syndrome and type 2 diabetes. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH) and cirrhosis. Both of the commercially available antihyperglycemic TZD agonists, pioglitazone and rosiglitazone, are markedly effective in reducing liver fat content by 30-50% and sensitizing the liver to insulin. This reduces the amount of endogenous and exogenous insulin needed to inhibit hepatic glucose production. Decreases in liver fat are closely correlated with increases in serum adiponectin, which is an insulin-sensitizing adipokine produced exclusively by adipose tissue. Both TZDs are equally effective in reducing liver fat. Regarding lipid metabolism, enhanced hepatic insulin sensitivity would be predicted to lower VLDL and serum triglycerides and increase HDL-cholesterol. Pioglitazone and rosiglitazone have different effects on serum lipids, which cannot be attributed to simple insulin sensitization. Very recently, TZDs have been shown to reduce not only steatosis but possibly also hepatocellular damage in NASH. SUMMARY: Given the uncertainties in benefits of TZDs in reducing cardiovascular disease in type 2 diabetes, as well as other side-effects (heart failure, fractures), TZDs may in the future be increasingly used in patients with nonalcoholic steatohepatitis. PMID- 19779337 TI - The role of hypoxia, increased oxygen consumption, and hypoxia-inducible factor-1 alpha in progression of chronic kidney disease. AB - PURPOSE OF REVIEW: Tubulointerstitial hypoxia in the kidney has been considered a hallmark of injury and mediator of disease progression. This review focuses on hypoxia-inducible factor (HIF)-1, a master transcription factor in cellular adaptation to hypoxia. RECENT FINDINGS: HIF-1alpha is expressed in the hypoxic tubular epithelium as well in as the papillary interstitium and glomerular epithelial cells. Although HIF-1 plays a protective role in a number of acute kidney injury models when overexpressed, its activation in chronic kidney disease results in multiple phenotypic changes, depending on the pathological context. SUMMARY: Hypoxia, especially HIF-1, is a critical mediator in the pathogenesis of chronic kidney disease. Underlying molecular mechanisms, together with responsible HIF target genes, are currently under investigation. PMID- 19779338 TI - Systematic approach for the management of chronic kidney disease: moving beyond chronic kidney disease classification. AB - PURPOSE OF REVIEW: This review has two aims: to summarize the evolution of classification criteria for chronic kidney disease (CKD) for diagnosis, prognosis and forecasting population burden of illness; to move the discussion beyond classification to intervention by introducing an approach we describe as the 'Systematic Approach for the Management of CKD' (SAM-CKD). RECENT FINDINGS: There is now ample evidence against the use of estimated GFR (eGFR) as the sole criterion for classifying CKD for the purpose of diagnosis, risk stratification and prediction of progression. There is ample evidence that significant proteinuria is a powerful predictor of progression but even more so when combined with reduced eGFR for individual and population risk projection. Hypertension also is an important indicator in CKD progression but not in all studies. Beyond classification, there are no studies addressing standardization of management of CKD to achieve the outcomes articulated by any of the practice guidelines. SUMMARY: In this article we have moved the discussions of CKD beyond classification by introducing a clinical management tool, SAM-CKD, which couples a broader classification model with a systematic tool for management to foster standardization of CKD management for the future. PMID- 19779339 TI - Management strategies for the prevention of preterm birth: Part II - Update on cervical cerclage. AB - PURPOSE OF REVIEW: Cerclage was devised more than 50 years ago based on the hypothesis that for some women, weakness or malfunction of the cervix has a causative role in the pathway to preterm birth (PTB). There have been many theories around the concept of cervical insufficiency but not much in the way of convincing evidence. The purpose of this review was to follow the recent developments in risk identification and prognostication of PTB in connection with appropriately targeted prophylactic interventions. RECENT FINDINGS: Sonographic cervical length measurement has emerged as an effective prognosticator for PTB in all populations studied so far, independently of obstetric history, consequently deriving a wider applicability than other predictors of PTB. However, the mechanisms leading to cervical shortening are poorly understood, and it cannot be assumed that all cases with a short cervix would benefit from cerclage. Specific conditions may actually reduce the efficacy and advisability of cerclage. For this reason, attempts have been made recently to further characterize the short cervix, leading to the conclusion that only women with a short cervix in the absence of infection/inflammation may be candidates for cerclage. Furthermore, two recent randomized trials of cerclage in women with short cervix on a second trimester ultrasound suggested a benefit with cerclage in PTB rate reduction only in those cases with a cervical length of less than 15 mm. SUMMARY: The existent literature has treated PTB prevention focusing exclusively on either progesterone use or cerclage, leaving the practitioners without any guidance on when to proceed with medical or surgical prophylaxis. Understanding that high-risk populations are not homogeneous and no single-approach modality is likely to be generally applicable, we have combined the available evidence on both progesterone and cerclage to provide guidance on how to identify subgroups of women at significantly increased risk for PTB and how to preferentially consider progesterone versus cerclage. PMID- 19779340 TI - Cardiac disease in pregnancy. AB - PURPOSE OF REVIEW: The past 15 years have seen a five-fold increase in the incidence of acquired heart disease as a cause of maternal mortality in the UK, and advances in the surgical correction of congenital heart disease have enabled many more women to survive childhood and present at the antenatal clinic. This review updates the reader on these important conditions. RECENT FINDINGS: The major increased incidence of acute myocardial infarction during pregnancy has been attributed to an increasing proportion of older women having babies (risk 30 fold greater for women over 40 years compared with women under 20 years of age). The obesity epidemic is associated with increases in diabetes and hypertension. Percutaneous coronary intervention with stenting is the treatment of choice. Although aortopathies, cardiomyopathy and valvular heart disease present continuing problems, improvements in the management of pulmonary vascular disease (in particular, the use of sildenafil) have reduced mortality from this condition. Prophylaxis against endocarditis has been abandoned except for the highest risk cases. SUMMARY: Cardiac disease in pregnancy is of growing importance both in terms of numbers of women affected and mortality. Improvements in care have occurred particularly in relation to ischaemic heart disease and pulmonary hypotension. PMID- 19779341 TI - Improving islet transplantation: a road map for a widespread application for the cure of persons with type I diabetes. AB - PURPOSE OF REVIEW: The widespread application of replacement therapies for type I diabetes is at present limited by the side-effects of systemic immunosuppression. Results obtained in several animal models show that islet encapsulation can control the rejection process without systemic side-effects. However, results have, in general, been disappointing when transferred to large animal models or to humans. RECENT FINDINGS: Growing insights into how cells respond to mechanical forces and surrounding extracellular matrixes indicate that differences in the Young's modulus (the resistance to deformation) between the implanted biomaterial and surrounding tissues induce inflammation and fibrosis. A valid approach would be to select for implantation a tissue having a higher value of the Young's modulus, for example, bone, allowing direct contact with the highly vascularized bone marrow providing nutrient and oxygen support as well as a rapid distribution of released insulin to the systemic circulation. SUMMARY: Development of a biochamber with bone-integrating properties will allow initiation of clinical trials with allogeneic human islets, xenogeneic pig islets or insulin-producing cells generated from human embryonic stem cell (hESC)/inducible pluripotent stem cell (iPSC). PMID- 19779343 TI - The effects of low oxygen on self-renewal and differentiation of embryonic stem cells. AB - PURPOSE OF REVIEW: To summarize recent reports on the effects of low oxygen on the undifferentiated phenotype and differentiation of embryonic stem cells (ESCs). RECENT FINDINGS: The oxygen level to which ESCs are exposed is an important environmental parameter. Under conditions maintaining the undifferentiated phenotype, low oxygen reduces spontaneous differentiation of human ESCs but reduces pluripotency gene expression in mouse ESCs, although reports are conflicting. Differentiation under low oxygen increases generation of neurons, cardiomyocytes, hematopoietic progenitors, endothelial cells, and chondrocytes. Many of the effects of low oxygen have been attributed to action by hypoxia inducible factor-1alpha (HIF-1alpha). The oxygen level in the gas phase (pO2gas) is often different than that experienced by the cells (pO2cell) and is unrecognized by investigators, which makes interpretation of the literature difficult. This difference increases with high cell densities, high cellular oxygen consumption rates, and large medium heights. The problem can be addressed by use of oxygen-permeable culture dishes and by estimation of pO2cell with mathematical models. SUMMARY: Low oxygen influences aspects of ESC pluripotency and differentiation. A better understanding of its effects and mechanism along with better estimation and control of pO2cell is important for applying low oxygen culture to regenerative medicine applications. PMID- 19779342 TI - Memory T-cell-specific therapeutics in organ transplantation. AB - PURPOSE OF REVIEW: This review details the role of memory T cells in physiologic and allospecific immunity, and summarizes the effects of immunosuppressive agents used to manipulate their function in the context of organ transplantation. RECENT FINDINGS: Memory T cells are lymphocytes with characteristics that are thought to promote anamnestic immune responses. They have a unique capacity to generate rapid effector functions upon secondary exposure to a pathogen, and this capacity is achieved through truncated requirements for antigen presentation, reduced activation thresholds, and enhanced trafficking and adhesion mechanisms. In general, these same mechanisms also appear to evoke improved efficiency in mediating allograft rejection. The phenotype of these cells has been increasingly well defined and associated with a characteristic pattern of susceptibility to immunosuppressive agents. This knowledge is now being exploited in the development of immune therapeutic regimens to selectively mollify T memory cell effects. SUMMARY: A specific targeting of memory T cells has potential to prevent allograft rejection in a more precise manner than current means of immunosuppression. However, these benefits will be balanced by the reciprocal risk of susceptibility to recurrent infection. PMID- 19779344 TI - Pretransplant immune risk assessment. AB - PURPOSE OF REVIEW: Despite the introduction of advanced immunosuppressive drug therapies, clinical and subclinical rejections still occur in many graft recipients with a negative impact on the long-term transplant outcome. The immunological status of the patients awaiting the transplantation is a key factor for these processes. Here we summarize the recent efforts to identify and develop biomarkers and functional assays that allow an individual pretransplant risk assessment. RECENT FINDINGS: New sensitive techniques assessing T-cell memory and B-cell activation have been developed. Furthermore, the expression level of soluble and molecular markers reflecting the activation state of the immune system and donor graft intrinsic factors have been shown to influence graft outcome. SUMMARY: A variety of parameters and assays that determine the pretransplant immune activation status has been developed. Some of these assays have already been used prospectively to define high-risk patients receiving advanced immunosuppressive induction therapy.However, the conflicting results obtained in different studies show that biomarker analysis and functional assays performance need to be further standardized and validated in large prospective trials before they can be routinely implemented into a pretransplant risk assessment. Subsequently, a combined effort to design pretransplant risk stratification algorithms should lead to personalized immunosuppressive treatment regimes and improved graft survival and long-term graft function. PMID- 19779345 TI - Stem cells for liver repopulation. AB - PURPOSE OF REVIEW: The capacity of the liver to regenerate and maintain a constant size despite injury is unique. However, the exact mechanisms are not completely clear. Cell transplantation has been proposed as an alternative treatment of liver diseases. Recent progress has been reported on the generation of stem/progenitor cells that may differentiate toward the hepatic lineage. However, it is currently difficult to determine which of the stem/progenitor cell populations are the best for therapy of a given disease. RECENT FINDINGS: The limited access to donor human hepatocytes has led to a great interest in the generation of hepatocyte-like cells. Several potential cell sources have been identified. However, general standardization of the methods to evaluate these cells is particularly important for the promise of stem/progenitor-derived hepatocyte-based therapies. Moreover, innovations aimed at improving hepatocyte delivery, survival, and engraftment have recently opened the field of organ engineering that may improve liver repopulation. SUMMARY: Here we review current evidence reported from the perspective of potential clinical applications of different hepatic cell sources with repopulation capacities and the future perspectives and tools that can facilitate the translation of laboratory work into clinical success. PMID- 19779346 TI - Choanal atresia: current concepts and controversies. AB - PURPOSE OF REVIEW: Choanal atresia is a common and widely recognized craniofacial disorder characterized by obliteration of the posterior nasal aperture. Given the long time since its original description, controversy persists regarding pathogenesis and optimal surgical techniques. This review addresses current literature on choanal atresia and identifies areas of debate and future opportunities in research. RECENT FINDINGS: Recent molecular mechanisms in retinoic acid receptor development have been described in the pathogenesis of choanal atresia. Whereas surgical treatment is generally believed to be effective in alleviating respiratory symptoms, consistent data confirming efficacy are scarce regarding best surgical approach with and without endoscopic sinus techniques, adjuvant use of stents, use of antiproliferative agents and laser assisted surgery. Recent studies regarding each technique are discussed. SUMMARY: Despite vigorous research, the pathogenesis remains elusive and unproven. Many surgical techniques have been advocated; however, there is no dominant approach. Trends in treatment are directed towards the use of highly advanced endoscopic approaches with the use of microdebriders, small drill bits and telescopes to minimize traumatic injury that leads to postoperative scarring and restenosis. PMID- 19779347 TI - True vocal fold nodules: the role of differential diagnosis. AB - PURPOSE OF REVIEW: The present article aims to discuss the current reviews and the literature published regarding the differential diagnosis of vocal fold nodules with emphasis on diagnosis and nomenclature. RECENT FINDINGS: Benign lesions of the vocal folds, including nodules, continue to challenge practitioners in nomenclature uniformity and even histologic diagnosis. Utilization of molecular techniques is helping to better understand Reinke's space and to better differentiate these lesions. This more accurate diagnosis may help guide appropriate treatment indicating behavioral versus surgical therapy. SUMMARY: Further study with the application of new technology in the laboratory and clinic will continue to refine our differential diagnosis and understanding of vocal fold nodules. PMID- 19779348 TI - Use of the microdebrider in pediatric endoscopic airway surgery. AB - PURPOSE OF REVIEW: Pediatric patients can present with a variety of airway problems that require surgical intervention. A number of modalities are available to the surgeon to address many different types of lesions and deformities. The microdebrider has become an indispensable tool for some surgeons and has supplanted the use of older instruments and techniques. All surgeons participating in the care of pediatric patients should be aware of the potential uses of the microdebrider. RECENT FINDINGS: Microdebriders have been developed over the past decade specifically for use in surgery in the lower airway and also in pediatric patients. These instruments have their roots in older instruments used in orthopedic arthroscopic procedures and endoscopic sinus surgery. A limited number of publications have identified the usefulness of the microdebrider in adult patients to address lesions of the larynx and lower airway. Even fewer articles have been published in the pediatric literature. The microdebrider has been found, in many clinical scenarios, to be a more efficient, less traumatic, and less costly instrument to use than traditional methods. Some older surgical techniques have been enhanced and found to have better outcomes when a microdebrider is used. SUMMARY: Microdebriders have been shown to be an important tool in the armamentarium of many surgeons who care for pediatric patients with airway problems. Modifications in existing instruments and developments of new instruments have made it possible to apply this technology to lesions and deformities anywhere from the nasal cavity to the proximal bronchi. PMID- 19779349 TI - Laryngeal steroid injection. AB - PURPOSE OF REVIEW: Vocal nodules are generally caused by vocal abuse and conservative treatments such as voice therapy - mainly voice rest and medical management - are used as a first choice. However, as patients with vocal nodules often have voice-related occupations, voice rest and voice therapy are sometimes difficult to perform, which makes treatment difficult. This study reviews the literature and discusses the usefulness of laryngeal steroid injection for the treatment of vocal fold nodules. RECENT FINDINGS: Steroid injection using a laryngeal telescope or a laryngeal flexible endoscope under topical anesthesia enables surgical manipulation under a good visual field through a monitor and an easy and accurate approach to the lesion on an outpatient basis. Although the literature is limited, steroid injection improves maximum phonation time and mean flow rate of the cases with vocal nodules. SUMMARY: Steroid injection using a laryngeal telescope or a laryngeal flexible endoscope is an easy and useful treatment option of vocal nodules. PMID- 19779350 TI - Bone anchored hearing aids in children. AB - PURPOSE OF REVIEW: Bone anchored hearing aids are an acceptable and now widely available form of aural rehabilitation for both adults and children. Their benefit from both audiological and quality of life perspectives has been very successful to date. The paediatric population presents a variety of challenges to those clinicians who undertake bone anchored hearing aid (BAHA) surgery: medical conditions, anatomical considerations and higher risk of trauma to both abutment and sound processor are just a few common problems. This review aims to highlight the important issues that surround the provision of a BAHA service for children. RECENT FINDINGS: Over the past 18 months there has been an increase in the number of centres worldwide providing a BAHA service for children. The indications for BAHA in children have evolved. The outcomes and quality of life have proved to be very successful. The surgical techniques are now quite varied and the timing of surgery varies between surgeons. Serious complications are fortunately very rare. SUMMARY: The bone anchored hearing aid in children is an effective means of aural rehabilitation that has been shown to improve the overall quality of life of the child. Although, it is a 'well tolerated' and relatively 'simple' procedure it is not without risk. A multidisciplinary team approach combined with careful patient selection and an understanding of the problems that present in children should result in a successful outcome for the child. PMID- 19779351 TI - The effect of age on the sinusoidal harmonic acceleration test, pseudorandom rotation test, velocity step test, caloric test, and vestibular-evoked myogenic potential test. AB - OBJECTIVES: Age-related anatomical and morphologic vestibular deterioration has already been elaborated. Demonstrating a corresponding degradation in physiologic function, however, entails a much higher challenge. The objective of this study was to investigate age-related changes using rotational tests, caloric tests, and the vestibular-evoked myogenic potentials (VEMP) test. DESIGN: Eighty healthy human subjects (38 men and 42 women) ranging in age from 18 to 80 yrs participated in this study and were subjected to an extensive vestibular test battery. Function tests included sinusoidal harmonic acceleration tests, a pseudorandom rotation test, velocity step tests, a caloric test, and a VEMP test. RESULTS: No significant age trends were noted for the sinusoidal harmonic acceleration test and velocity step tests response parameters, in contrast to subtle decreasing gain values with advancing age for the pseudorandom rotation test. Increasing slow-component velocity values were measured with the caloric test, whereas the frequency parameter showed no relevant age changes. The largest age trends were detected with the VEMP, with decreasing amplitudes, increasing thresholds, and decreasing N1 latencies. All asymmetry parameters remained stable across the different age categories. CONCLUSIONS: Only subtle age changes could be demonstrated with the rotational and caloric tests, in contrast to more pronounced age trends with the VEMP. PMID- 19779352 TI - The impact of preoperative hepatic hydrothorax on the outcome of adult liver transplantation. AB - INTRODUCTION: Hepatic hydrothorax is an uncommon, but severe complication of cirrhosis. Orthotopic liver transplantation (OLT) is the best option in case of end-stage liver disease. The impact of hepatic hydrothorax on pre-transplant and post-transplant courses has not been clearly investigated. PATIENTS AND METHODS: Eleven patients (group 1) with hepatic hydrothorax and end-stage liver disease out of 346 consecutive patients who underwent OLT between January 2002 and December 2006 were studied. First, pretransplant and posttransplant symptoms and management of hepatic hydrothorax were compared in this group. Second, postoperative complications and survival were compared with two control groups of 11 patients, matched for age, sex, year of transplant, and severity of cirrhosis. Group 2 included patients with tense ascites, but no hepatic hydrothorax. Group 3 included patients without ascites. RESULTS: In group 1, 73% of patients needed thoracentesis in the pre-transplant course (55% more than once) and none of the patients needed thoracenthesis in the post-transplant course. Comparing the postoperative period between the three groups, no significant differences in the duration of mechanical ventilation, intensive care unit stay, and in-hospital stay were observed. There were no significant differences in terms of incidence of sepsis and early postoperative death. One-year survival was also similar. CONCLUSION: Liver transplantation is a good definitive therapeutic option for cirrhotic patients with hepatic hydrothorax and end-stage liver disease. The need of thoracentesis decreases in the posttransplant course, and the presence of preoperative hepatic hydrothorax did not have a significant negative influence on postoperative outcome. PMID- 19779353 TI - Acute hepatitis E infection associated with a false-positive serology against Epstein-Barr virus. AB - Hepatitis E virus is a major cause of acute viral hepatitis. The diagnosis of acute viral hepatitis E is based essentially on antibodies and hepatitis E virus RNA. We describe herein a case of acute hepatitis E associated with a false positive serology for Epstein-Barr virus (EBV). This case report suggests that anti-viral capsid antigen IgM must be interpreted with caution in acute E hepatitis. When positive, EBV RNA polymerase chain reaction can be useful as a false positivity of anti-viral capsid antigen IgM and can be misinterpreted as an acute infection. EBV false positivity was probably related to polyclonal stimulation of the immune system, favoured by hepatitis E. PMID- 19779354 TI - Discontinuation symptoms and taper/poststudy-emergent adverse events with desvenlafaxine treatment for major depressive disorder. AB - The objective of this study was to assess discontinuation symptoms with desvenlafaxine (administered as desvenlafaxine succinate) treatment for major depressive disorder. Data were analyzed from nine 8-week, double-blind (DB), placebo-controlled studies of desvenlafaxine (50, 100, 200, or 400 mg/day; placebo, n = 319; desvenlafaxine, n = 578) and a relapse-prevention study [12 week, open-label (OL) 200 or 400 mg/day desvenlafaxine (n = 373); 6-month DB placebo (n = 73) or desvenlafaxine (n = 118)]. Rates of taper/poststudy-emergent adverse events were summarized. Discontinuation-Emergent Signs and Symptoms (DESS) checklist scores were analyzed in treatment completers at the end of OL and DB treatment. The most common (> or = 5%) taper/poststudy-emergent adverse events among desvenlafaxine patients were dizziness, nausea, headache, irritability, diarrhea, anxiety, abnormal dreams, fatigue, and hyperhidrosis. In the short-term studies, the highest DESS scores observed for desvenlafaxine groups occurred at first assessment after discontinuation of all active treatment (1.9-5.7). Desvenlafaxine 50- and 100-mg/day groups had significantly increased scores versus placebo (P values < or = 0.028). DESS scores increased significantly for patients discontinuing 12-week, OL desvenlafaxine 200 and 400 mg/day doses compared with those continuing desvenlafaxine (P values < or = 0.022). After the 6-month DB phase, DESS scores increased significantly compared with placebo for patients discontinuing 400 mg/day only (P = 0.029). In conclusion, cessation of desvenlafaxine use is associated with discontinuation symptoms after both short-term and long-term treatment. PMID- 19779355 TI - Early weaning of HIV-exposed uninfected infants and risk of serious gastroenteritis: Findings from two perinatal HIV prevention trials in Kampala, Uganda. AB - Objective: To assess serious gastroenteritis risk and mortality associated with early cessation of breastfeeding in infants enrolled in 2 prevention of maternal to-child HIV-transmission trials in Uganda.Methods: We used hazard rates to evaluate serious gastroenteritis events by month of age and mortality among HIV exposed uninfected infants enrolled in the HIV Network for Prevention Trials (HIVNET 012) (1997-2001) and HIV hyperimmune globulin (HIVIGLOB)/nevirapine (NVP) (2004-2007) trials. HIV-infected mothers were counseled using local infant feeding guidelines current at the time.Results: Breastfeeding cessation occurred earlier in HIVIGLOB/NVP compared with HIVNET 012 (median 4.0 versus 9.3 months,P,0.001). Rates of serious gastroenteritis were higher in HIVIGLOB/NVP (8.0/1000 child-months) than in HIVNET 012 (3.1/1000 child-months; P , 0.001). Serious gastroenteritis events also peaked earlier at 3-4 and 7-8 months (16.2/1000 and 15.0/1000 child-months,respectively) compared with HIVNET 012 at 9 10 months (20.8/1000 child-months). All cause infant mortality did not statistically differ between the HIVIGLOB/NVP and the HIVNET 012 trials [3.2/1000 versus 2.0/1000 child-months, respectively (P = 0.10)].Conclusions: Early breastfeeding cessation seen in the HIVIGLOB/NVP trial was associated with increased risk of serious gastroenteritis among HIV-exposed uninfected infants when compared with later breastfeeding cessation in the HIVNET 012 trial.Testing interventions, which could decrease HIV transmission through breastfeeding and allow safe PMID- 19779356 TI - Genetic and functional mitochondrial assessment of HIV-infected patients developing HAART-related hyperlactatemia. AB - BACKGROUND: Mitochondrial damage of HIV and antiretrovirals, especially nucleoside-analogue interference on mitochondrial DNA (mtDNA) replication, is reported to underlay highly active antiretroviral therapy (HAART)-related hyperlactatemia, but scarce approaches have been performed to correlate clinical manifestations and mitochondrial abnormalities. METHODS: We obtained lymphocytes and monocytes of 26 HIV-infected and treated patients who developed hyperlactatemia and after recovery, 28 nonhyperlactatemic HIV subjects on HAART, 31 naive individuals, and 20 uninfected controls. Mitochondrial replication and transcription analysis were performed by quantitative real-time PCR, mitochondrial translation quantification by western blot and mitochondrial enzymatic activities by spectrophotometry. RESULTS: Mitochondrial parameters decreased during hyperlactatemia and improved at recovery. Mitochondrial replication and transcription species were reduced (P = 0.16 and P = 0.71), but the most significant decay was observed on mitochondrial protein content (P < 0.05) and mitochondrial complexes III and IV activities (P < 0.01 and P < 0.001). During hyperlactatemia lactate level correlated complexes III and IV function (P < 0.05). After recovery mitochondrial parameters achieved values of nonhyperlactatemic HIV individuals, which were lower than ranges of naive subjects and uninfected controls. CONCLUSIONS: HIV and HAART-related hyperlactatemia is associated with a general mitochondrial impairment which reverts after recovery. Mitochondrial biochemistry show a better correlation with lactate levels than mitochondrial genetics suggesting that mitochondrial function could be a better marker of hyperlactatemia development than mtDNA content. PMID- 19779357 TI - Association of oncogenic and nononcogenic human papillomavirus with HIV incidence. AB - OBJECTIVE: Little is known about the interaction between human papillomavirus (HPV) and HIV. This study aimed to explore the association of oncogenic (high risk) and nononcogenic (low risk) HPV with HIV incidence. METHODS: We used 1683 urethral swabs collected at the last follow-up visit of a male circumcision trial conducted in Orange Farm (South Africa). Swabs analyses and HPV genotyping were performed by polymerase chain reaction. We estimated HIV adjusted incidence rate ratios (aIRRs) and 95% confidence intervals (CIs) using survival analysis. Background characteristics, male circumcision status, sexual behavior, HPV status, and other sexually transmitted infections were used as covariates. RESULTS: The prevalence of HR and LR HPV was 14.0% (95% CI: 12.4 to 15.7) and 17.3% (95% CI: 15.6 to 19.2), respectively. When controlling for HR-HPV status, LR-HPV status was not associated with HIV incidence (aIRR = 1.13, 95% CI: 0.40 to 3.16; P = 0.82). When controlling for all covariates, HIV incidence increased significantly with HR-HPV positivity (aIRR = 3.76, 95% CI: 1.83 to 7.73, P < 0.001) and with the number of HR-HPV genotypes (adjusted-P linear trend = 0.0074). CONCLUSIONS: Several explanations could account for our findings. One is that HR-HPV facilitates HIV acquisition. The association of HPV with HIV acquisition requires further investigations. PMID- 19779362 TI - Body mass index in celiac disease: beneficial effect of a gluten-free diet. AB - BACKGROUND: There is concern about celiac disease patients being overweight and gaining more weight while on a gluten-free diet (GFD). AIM: To investigate body mass index (BMI) and effect of GFD on BMI of celiac disease patients in the United States where obesity is a systematic problem. METHODS: BMI at diagnosis and after 2.8 years (mean) on a GFD were compared with national data. RESULTS: Among our patients (n=369, 67.2% female), 17.3% were underweight, 60.7% normal, 15.2% overweight, and 6.8% obese. All patients were followed by a dietitian. Compared with national data, females had lower BMI (21.9 vs. 24.2, P<0.0001) and fewer were overweight (11% vs. 21%, P<0.0001); more males had a normal BMI (59.5% vs. 34%, P<0.0001) and fewer were underweight (9.1% vs. 26.7%, P<0.0001). Factors associated with low BMI were female sex, Marsh IIIb/c histology, and presentation with diarrhea. On GFD, 66% of those who were underweight gained weight, whereas 54% of overweight and 47% of obese patients lost weight. CONCLUSIONS: A GFD had a beneficial impact on BMI, underweight patients gained weight and overweight/obese patients lost weight. The improvement in BMI adds to the impetus to diagnose celiac disease. Expert dietary counseling may be a major factor in the beneficial effects we noted. PMID- 19779364 TI - Usefulness of small-bowel mucosal transglutaminase-2 specific autoantibody deposits in the diagnosis and follow-up of celiac disease. AB - BACKGROUND: Diagnosis of celiac disease may be problematic in that small-bowel villous atrophy sometimes occurs in conjunction with other enteropathies, develops gradually and may be patchy. Furthermore, as the often compromised quality of biopsy specimens renders diagnosis difficult, new diagnostic tools are warranted. GOALS: As the celiac disease-specific autoantibodies are found deposited at their production site, in the small-bowel mucosa, they may be useful in diagnostics, especially in problematic cases. We therefore systematically assessed the occurrence of celiac-specific autoantibody deposits in a large cohort of celiac patients, and established how IgA deposits decline after initiation of a gluten-free diet. METHODS: Transglutaminase-2 specific mucosal IgA autoantibody deposits were determined from small-bowel mucosal biopsies in 261 untreated, 71 short-term (1 y), and 105 long-term (2 to 41 y) treated celiac disease patients and in 78 nonceliac controls. The presence of the deposits was compared with celiac serology, mucosal villous morphology and density of intraepithelial lymphocytes. RESULTS: All untreated celiac disease patients had mucosal autoantibody deposits and their intensity was moderate or strong in 90% of cases. In contrast, 18% of the controls had weak depositions. During a gluten free diet the intensity of the deposits diminished, but was still faintly positive in 56% of long-term treated celiac patients. The efficiency of the test in determining mucosal autoantibody deposits was superior to serology and inflammatory markers. CONCLUSIONS: Mucosal transglutaminase-2 specific autoantibody deposits proved to be accurate gluten-dependent markers of celiac disease and would thus be of value in the diagnostics and dietary monitoring of this disorder. PMID- 19779365 TI - Anesthetic concerns and perioperative complications in repair of myelomeningocele: a retrospective review of 135 cases. AB - Myelomeningocele (MMC) a complex congenital spinal anomaly, results from neural tube defect during first 4 weeks of gestation. Medical records of 135 children who underwent excision and repair of MMC from January 2003 to December 2006 were analyzed, retrospectively. Data on associated illnesses, anesthetic management, perioperative complications, and outcome were recorded. The patient population consisted of older infants with unrepaired MMC. The average age of presentation was 1 year and 8 months. The commonest site of presentation was lumbar (39.3%). Leaking MMC was present in 19.3% of cases, most had associated electrolyte imbalance. Hydrocephalus was the commonest association (67.4%) followed by Chiari II malformation (58.4%). Renal abnormality was present in 9% of cases and 24.4% of children had scoliosis. Two infants (1.5%) presented with inspiratory stridor. Intraoperative cardiac and respiratory problems were observed in 15.6% and 11.1%, of cases, respectively. Two children (1.5%) suffered cardiac arrest; both had associated Chiari-II malformation and hydrocephalus. Postoperative ventilation was required in 8.9% of children, primarily due to inadequate reversal from neuromuscular blockade. Infection, cerebrospinal fluid leak, and pseudomeningocele were common surgical complications. Improvement of motor, sensory, and sphincteric function was observed in 30.5%, 22.9%, and 14.1%, respectively. To conclude, surgical repair of MMC may at times pose life threatening complications mostly because of associated anomalies. Children with associated Chiari malformation and/or hydrocephalus need special attention during perioperative period. PMID- 19779363 TI - Complementary and alternative medicine use in chronic liver disease patients. AB - GOALS: To examine a wide range of sociodemographic and clinical characteristics as potential predictors of complementary and alternative medicine (CAM) use among chronic liver disease (CLD) patients, with a focus on CAM therapies with the greatest potential for hepatotoxicity and interactions with conventional treatments. BACKGROUND: There is some evidence that patients with CLD commonly use CAM to address general and CLD-specific health concerns. STUDY: Patients enrolled in a population-based surveillance study of persons newly diagnosed with CLD between 1999 and 2001 were asked about current use of CAM specifically for CLD. Sociodemographic and clinical information was obtained from interviews and medical records. Predictors of CAM use were examined using univariate and multivariate logistic regression analysis. RESULTS: Of the 1040 participants, 284 (27.3%) reported current use of at least 1 of 3 CAM therapies of interest. Vitamins or other dietary supplements were the most commonly used therapy, reported by 188 (18.1%) patients. This was followed by herbal medicine (175 patients, 16.8%) and homeopathy (16 patients, 1.5%). Several characteristics were found to be independent correlates of CAM use: higher education and family income, certain CLD etiologies (alcohol, hepatitis C, hepatitis C and alcohol, and hepatitis B), and prior hospitalization for CLD. CONCLUSIONS: Use of CAM therapies that have the potential to interact with conventional treatments for CLD was quite common among this population-based sample of patients with CLD. There is a need for patient and practitioner education and communication regarding CAM use in the context of CLD. PMID- 19779366 TI - The incidence, volume, absorption, and timing of supratentorial pneumocephalus during posterior fossa neurosurgery conducted in the sitting position. AB - BACKGROUND: Supratentorial pneumocephalus (STP) is a known complication of neurosurgical procedures of the posterior fossa when conducted in the sitting position. Few studies have examined STP as differentiated from pneumocephalus in the operative field. METHODS: Ninety-five of 106 consecutive patients had postoperative radiographic studies and median nerve somatosensory evoked potential (SSEP) recording during surgery. STP was identified on postoperative skull films or computerized tomography (CT). STP volume was measured on CT scans. SSEP changes were identified in the monitoring records. RESULTS: STP was identified in 40 patients (42.1%). STP volume on CT scans within 4 hours of surgery ranged from 6 to 280 cm3 (cubic centimeters). An extraventricular drain or ventriculo-peritoneal shunt did not increase the incidence of STP (P=0.85). The absorption of STP in 5 patients with multiple CT scans showed an immediate reduction of 24% followed by exponential decay with an half life of 1.5 days. Four patients with an extraventricular drain or ventriculo-peritoneal shunt had excessive volume of STP when measured at 1 day or later. Six patients with significant SSEP amplitude reductions attributed to STP had volumes exceeding 90 cm3 on a CT scan within 4 hours of surgery. The onset of these changes occurred at various times from dural opening to closing. CONCLUSIONS: STP is common after posterior fossa neurosurgical procedures conducted in the sitting position. Further studies are needed to fully characterize the absorption of air and the timing of the entry. PMID- 19779367 TI - Evaluation of posttetanic motor evoked potentials--the influences of repetitive use, the residual effects of tetanic stimulation to peripheral nerve, and the variability. AB - BACKGROUND: Recently, we developed a new technique to augment myogenic motor evoked potentials (MEPs), called as posttetanic MEPs (p-MEPs), in which tetanic stimulation is applied to peripheral nerve before transcranial stimulation. However, the data on p-MEPs are limited. This study was conducted; (1) to evaluate the influences of repetitive use of p-MEPs on p-MEP amplitudes, (2) to evaluate the residual effects of use of p-MEPs on subsequent conventional MEPs (c MEPs), and (3) to compare the variability of p-MEPs with that of c-MEPs. METHODS: Sixty patients under propofol/fentanyl anesthesia with partial neuromuscular blockade were enrolled. For p-MEP measurements, tetanic stimulation was applied to posterior tibial nerve 1 second before transcranial stimulation. In study 1, p MEPs were repetitively recorded with intervals of 10 or 60 seconds. In study 2, the amplitudes of c-MEPs recorded 15, 30, 60, and 120 seconds after p-MEP recordings were compared with those of control. In study 3, the coefficients of variation of c-MEP and p-MEP responses were compared. RESULTS: The repetitive use of p-MEP with an interval of 10 seconds, but not 60 seconds, induced a significant reduction of p-MEP amplitude. Amplitudes of c-MEP were significantly increased when applied within 60 seconds after p-MEP recordings. The coefficient of variations of p-MEPs was similar to those of c-MEPs. CONCLUSIONS: The results indicated that the amplitudes of p-MEP and c-MEP might be affected when applied with a short interval after p-MEP recording. PMID- 19779368 TI - Cardiac asystole after nasal infiltration of lidocaine with epinephrine in a transsphenoidal hypophysectomy patient with hypertrophic cardiomyopathy. PMID- 19779369 TI - Head size and body mass in infants with hydrocephalus. PMID- 19779370 TI - Postoperative and preincisional electrical nerve stimulation TENS reduce postoperative opioid requirement after major spinal surgery. AB - BACKGROUND AND OBJECTIVE: Preincisional and postoperative transcutaneous electrical nerve stimulation (TENS) administration reduces postoperative opioid demand in abdominal surgery. Aim of this study was to find out whether a comparable effect of TENS applies in major spinal surgery. METHODS: Thirty-eight patients of both sex scheduled for lumbar interbody fusion were enrolled and divided randomly into 3 groups. Group A received TENS preincisional and postoperative, group B received this treatment postoperative only, and group C was the sham controlled. The postoperative demand on piritramid to achieve a visual anlog scale pain score <3 was delivered either by nurse or by a patient controlled analgesia pump, when the patients were alert. The setting of the patient-controlled analgesia pump, bolus of piritramid 2 mg intravenously (IV), lockout time of 20 minutes, and maximum dose of piritramid 15 mg within 4 hours, the coanalgesic therapy diclofenac 75 mg IV, and the rescue medication metamizol 1 g IV was identical for all patients. The total amount of piritramid administered over the first 24 hours after surgery and an optional rescue medication were recorded. RESULTS: All groups were compared by pairs. The postoperative demand on piritramid differed significantly A versus B (P<0.05), A versus C (P<0.05), and B versus C (P<0.05). Neither sex, body mass index, current, duration, and type of operation nor the occurrence of hypotensive phases showed any significant association with postoperative piritramid demand. The necessity of rescue medication was significantly higher in group C than in group A. CONCLUSIONS: Postoperative TENS as well as the combination of preincisional and postoperative TENS therapy reduce the postoperative demand of piritramid in major spinal surgery in a safe and simple way free of systemic side effects. PMID- 19779371 TI - Report on the first Congress of Asian Society for Neuroanesthesia and Critical Care (ASNACC). PMID- 19779372 TI - Epinephrine infiltration of scalp or nasal mucosa induces what kind of changes in blood pressure under general anesthesia: hypertension or hypotension? PMID- 19779373 TI - Acromegalic and "Mallampati class zero" airway--an unusual finding! PMID- 19779374 TI - Preventive effects of intraperitoneal selenium on cerebral vasospasm in experimental subarachnoid hemorrhage. AB - Vasospasm is an important cause of morbidity and mortality with subarachnoid hemorrhage (SAH). The effect of intraperitoneal administration of selenium, which is an antioxidant on cerebral vasospasm was investigated in an experimental model. By means of intracisternal blood injection model, SAH was induced in 24 rabbits, which were randomly divided into 3 groups (group 1= control group, group 2=SAH alone group, and group 3=SAH plus selenium group). Basilar artery angiography was performed on day 0 and day 3 as described. Intraperitoneal selenium (0.05 mg/kg) treatment was started after the induction of SAH and administered once a day. Three days later, the animals were killed and the basilar artery was examined histologically for the luminal diameter and thickness of the arterial muscular wall. The mean values for the measurements of angiographic luminal diameter, pathologic luminal area, muscular wall thickness derived from the blind observer were analyzed statistically. There was no statistically significant difference in basal angiographic luminal diameter evaluation between groups 1-2-3 (P>0.005). But in third day angiography; comparison of group 2 and group 1-3 showed statistically significant differences (P<0.001). In pathologic investigation; there was statistically significant difference in luminal area and muscular wall thickness of the basilar artery between groups 1, 2, and 3 (P<0.005). Intraperitoneal selenium treatment was found effective by increasing the angiographic diameter; pathologic luminal area and reducing muscular wall thickness measurements. This is the first study to show that intraperitoneal administration of selenium is effective in preventing vasospasm after SAH in rabbits. PMID- 19779375 TI - Ischemic ulcerative colitis in juvenile dermatomyositis. PMID- 19779377 TI - Childhood Plasmodium vivax malaria with severe thrombocytopenia and bleeding manifestations. AB - Thrombocytopenia of varying magnitude, usually without hemorrhagic manifestations, is commonly observed in Plasmodium falciparum and Plasmodium vivax malaria. However, severe thrombocytopenia associated with bleeding manifestations in malarial infection is distinctly unusual. The pathogenesis of this condition remains speculative till date, although several hypotheses have been put forward. We report a case of 4-year-old boy with P. vivax malaria, who developed severe thrombocytopenia during the course of his infection manifested by bleeding from skin and mucosal surfaces. He improved with antimalarial and intravenous immunoglobulin therapy. Clinicians caring for children should be aware of potential bleeding manifestations that may be the result of apparently innocuous infection like vivax malaria. PMID- 19779376 TI - Oral gancyclovir therapy for immunocompetent infants with cytomegalovirus associated hemorrhagic or intractable enterocolitis. AB - Three infants, who had prenatal or immediately postnatal cytomegalovirus (CMV) infection associated with persistently severe enterocolitis requiring total parenteral or nasal gastric feeding, were treated with gancyclovir. The intestinal CMV involvement was shown by the detection of CMV-DNA in the stools of all 3 infants and in the enteral sample from 1 of 2 biopsied infants. Gancyclovir, when given intravenously to the infants, was not followed by CMV clearance or stable clinical improvement. On the contrary, oral gancyclovir that was given for 1- to 2-month courses at the dosage of 70 mg/kg, was associated with clinical improvement or recovery and reintroduction of oral feeding. Cytomegalovirus-DNA detection became persistently negative in the stools of the infants within 17 months after starting oral gancyclovir. Each child showed normal growth and sensorial, mental, and motor development at the age of 4.7 to 6 years. Oral gancyclovir may be suggested for treatment of CMV-associated chronic hemorrhagic or intractable enterocolitis. PMID- 19779378 TI - Hepatitis-associated aplastic anemia presenting as a familial bone marrow failure syndrome. AB - Hepatitis-associated aplastic anemia is a well-described entity after idiopathic fulminant hepatic failure. The hematologic disease ranges from mild-to-severe aplastic anemia and the cause of the disease is unknown. We describe 2 siblings with bone marrow failure. The older child presented with idiopathic fulminant hepatic failure and an early onset of rapidly progressive severe aplastic anemia that developed into myelodysplastic syndrome postliver transplantation. In the process of family screening to locate a donor for hematopoietic stem cell transplantation, the younger sibling was found to have hypocellular bone marrow and later developed acute lymphoblastic leukemia. These familial cases raise the possibility of an inherited bone marrow failure syndrome and suggest that severe hepatitis-associated aplastic anemia may not be always an acquired condition. PMID- 19779379 TI - Glutaric aciduria type II [corrected] and brain tumors: a case report and review of the literature. AB - Heritable diseases associated with childhood tumors are sometimes defined as a probable etiologic factor or a coincidence. First of all, we must know the actual number of patients. Herein a case with medulloblastoma associated with glutaric aciduria type II [corrected] is reported for this purpose. A 5-year-old boy was admitted with nausea, vomiting, and lethargy. In medical history, consanguinity and siblings with mental-motor retardation and epilepsy are remarkable. Growth retardation, macrocephaly, lethargy, tremor, bilateral nistagmus, and papilledema were prominent features in physical examination. Noncontrast computed tomography of the brain showed a hyper dense mass in the cerebellar vermis. Gross total resection was made and the histopathology of the tumor was medulloblastoma. Besides medical history and physical findings, radiologic white matter changes in the subcortical, periventricular regions, bilateral basal ganglia, and caudate nuclei in magnetic resonance images other than tumor led us to investigate the child for glutaric aciduria type II [corrected]. The level of the 2-OH glutaric acid was determined as being 12-fold high in the urine. Chemo-radiotherapy was performed after surgery. Our case was the third patient with medulloblastoma in the literature and is still alive with no evidence of the disease 19 months after the initial diagnosis. PMID- 19779380 TI - Metachronous mediastinal seminoma occurring after intracranial germinoma in an adolescent. AB - We report a case of a mediastinal seminoma occurring 19 months after the resolution of a pineal germinoma. A 15-year-old boy with headaches and visual changes was diagnosed with a pineal germinoma by biopsy and mildly elevated beta human chorionic gonadatropin (beta-HCG) in serum and cerebral spinal fluid. Radiation therapy leads to the resolution of his pineal germinoma and normalization of the beta-HCG. A mediastinal seminoma (germinoma) was diagnosed nearly 2 years later because of rising serum beta-HCG. There was no evidence of recurrent central nervous system disease. The patient underwent systemic chemotherapy with the complete resolution of the mediastinal seminoma. PMID- 19779381 TI - Successful treatment of congenital acute myeloid leukemia (AML-M6) in a premature infant. AB - Congenital acute myeloid leukemia (AML), and especially AML-M6 is a rare disease with a poor prognosis. Moreover, reports of treatment outcome of congenital AML M6 in premature infants are not available. We report the first treated case of congenital AML-M6 in a premature girl, who received a full AML protocol. She presented with blueberry-muffin spots, anemia, high white blood cell count, and serious cardiopulmonary distress. Peripheral blood smears showed AML-M6 blasts. After treatment with a sequential low-dose cytarabine after birth and full-dose AML treatment according to the MRC-12 protocol at the age of 2 months, she now is in continuous complete remission for 4 years. PMID- 19779382 TI - A randomized, placebo- and active-controlled trial of bazedoxifene/conjugated estrogens for treatment of moderate to severe vulvar/vaginal atrophy in postmenopausal women. AB - OBJECTIVES: The primary objective of the Selective estrogen Menopause And Response to Therapy 3 (SMART-3) trial was to compare the efficacy and safety of two doses of bazedoxifene (BZA)/conjugated estrogens (CE) versus placebo for the treatment of moderate to severe vulvar/vaginal atrophy (VVA) associated with menopause. METHODS: This was a phase 3, multicenter, double-blind, randomized, placebo-controlled, and active comparator-controlled study. Healthy postmenopausal women (n = 664; aged 40-65 y) were randomized to BZA 20 mg/CE 0.625 mg, BZA 20 mg/CE 0.45 mg, BZA 20 mg, or placebo once daily for 12 weeks. Changes in vaginal maturation, vaginal pH, and severity of the most bothersome symptom of VVA from baseline were assessed at screening and at weeks 4 and 12. Adverse events were recorded throughout the study. RESULTS: BZA 20 mg/CE 0.625 or CE 0.45 mg significantly (P < 0.01) increased superficial cells and decreased parabasal cells compared with placebo. Vaginal pH and most bothersome symptom significantly improved with BZA 20 mg/CE 0.625 mg compared with placebo (P < 0.05). Improvements in vaginal dryness were also observed with both BZA/CE doses (P G 0.05). The incidence of treatment-related adverse events were similar across treatment groups. CONCLUSIONS: BZA/CE is effective in treating moderate to severe VVA and vaginal symptoms. These data further support the use of a tissue selective estrogen complex containing BZA/CE as a new menopausal therapy for postmenopausal women. PMID- 19779383 TI - Peripheral vision and preferential emotion processing. AB - This study investigated the preferential processing of emotional scenes, which were presented in the periphery of the visual field. Building on well-established affective modulations of event-related potentials, which were observed for foveal stimuli, emotional and neutral images were presented at several locations in the visual field, while participants either viewed the pictures or were engaged by a distractor task. The findings clearly show that emotional processing varied with picture eccentricity, with emotional effects being maximal in the center and absent in the far periphery. Moreover, near-peripheral emotional stimuli modulated event-related potentials only when participants were passively viewing them. These results suggest that perceptual processing resources are needed for identification and emotional processing of peripheral stimuli. PMID- 19779384 TI - Asymmetric hearing loss: audiometric screening criteria. PMID- 19779385 TI - Effect of ossicular prosthesis biofilms on middle ear scarring and hearing outcomes. AB - OBJECTIVES: Microbial biofilms have been associated with poor outcomes with a variety of biomedical implants; however, this relationship has not been established with ossicular chain reconstruction prostheses (ORPs). The purpose of this study was to determine if biofilms are present on ORPs in patients undergoing revision ossicular chain reconstruction and if their presence correlates with middle ear scarring or hearing outcomes. STUDY DESIGN: Prospective and blinded. SETTING: Tertiary referral center. PATIENTS: Patients undergoing revision ossicular chain reconstruction with previous ORP placement were enrolled. INTERVENTION/MAIN OUTCOME MEASURE: Ossicular chain reconstruction prostheses associated with poor hearing and residual or recurrent disease were cultured and examined using scanning electron microscopy. Audiometric thresholds and middle ear scarring scores were recorded. RESULTS: Twelve patients were included in the study. Of the prostheses, 25% were culture positive, and 67% had microscopic evidence of biofilm. No difference was found between the middle ear scarring scores (p = 0.31) and hearing outcomes (p = 0.11) of biofilm and nonbiofilm prostheses. There was no correlation between middle ear scarring and degree of conductive hearing loss (R2 = 0.04; p = 0.54). CONCLUSION: Biofilms are commonly found on ORPs at the time of revision ossicular chain reconstruction. The interaction between biofilms and the host environment is complex. Many factors besides biofilms may impact middle ear scarring and hearing. PMID- 19779386 TI - Jugular foramen tumors: clinical characteristics and treatment outcomes. AB - OBJECTIVE: To describe the diagnosis, management, and treatment outcome of jugular foramen (JF) tumors. STUDY DESIGN: Retrospective chart review. METHODS: Charts of the 83 patients diagnosed with JF tumors between January 1997 and May 2008 were reviewed. Presenting symptoms, otologic and neurotologic examination, audiologic thresholds, treatment procedure, surgical technique, tumor size and classification, and postoperative complications were recorded. Facial nerve function was graded using the House-Brackmann scale. Extent of tumor removal was determined at time of surgery, followed by routine radiographic follow-up. RESULTS: The mean age of patients with JF tumors was 48.5 years (standard deviation, 16.3 yr), and women (79.5%) outnumbered men (20.5%). Most had glomus jugulare (GJ) tumors (n = 67, 80.7%); 9 patients had lower cranial nerve schwannomas (10.8%), and 7 patients had meningiomas (8.4%). The most frequent initial symptoms included pulsatile tinnitus (84.3%), conductive hearing loss (75.9%), and hoarseness (34.9%). Sixty-one patients (73.5%) underwent surgery, 18.1% had radiotherapy, and 8.4% were observed. Total tumor removal was achieved in 81% of surgery cases. New lower cranial nerve (CN) deficits occurred after surgery in 18.9% of GJ, 22.2% of schwannoma, and 50% of the 4 meningiomas. At last follow-up, 88.1% of surgical patients had normal or near-normal (House Brackmann I or II) facial function. CONCLUSION: Total resection of GJ tumors, meningiomas, and lower CN schwannomas can be a curative treatment. However, subtotal removal may be required to preserve CN function, vital vascular structures, and the brainstem. Postoperative radiotherapy is used to control residual tumor. When postoperative complications develop in patients, early rehabilitation is important to decrease mortality and morbidity. Therefore, patients should be closely followed. PMID- 19779387 TI - Presence of otosclerosis and paget lesions in the same temporal bone. PMID- 19779388 TI - Prospective electrophysiologic findings of round window stimulation in a model of experimentally induced stapes fixation. AB - HYPOTHESIS: Mechanical stimulation of the round window (RW) with an active middle ear implant (AMEI) with and without experimentally induced stapes fixation (SF) results in equivalent electrophysiologic measures of cochlear microphonic (CM), compound action potential (CAP), and auditory brainstem response (ABR). BACKGROUND: Where normal oval window functionality is mitigated, the RW provides a pathway to mechanically stimulate the inner ear. METHODS: Measurements of the CM, CAP, and ABR were made in 5 ears of 4 chinchillas with acoustic stimulation and with application of the AMEI to the RW with and without experimentally induced SF using pure-tone stimuli (0.25-20 kHz) presented at differing intensities (-20 to 80 dB SPL vs. 0.01 mV to 3.16 V). RESULTS: Morphologies of the CM, CAP, and ABR were similar between acoustic and RW stimulation with and without SF. Stapes fixation increased CM thresholds relative to RW stimulation without fixation by a frequency-dependent 4- to 13-dB mV (mean, 7.9 +/- 3.2 dB mV). Although the thresholds changed with SF, CM sensitivities and amplitude dynamic range were identical to normal. The CAP in all conditions demonstrated equivalent decreasing amplitudes and increasing latency with decreasing intensity (decibel sound pressure level versus decibel millivolt). Stapes fixation increased the CAP thresholds at all frequencies, ranging from 9 to 24 dB mV (mean, 17.7 +/- 4.9 dB mV). Auditory brainstem response waveforms were preserved across experimental conditions. CONCLUSION: Mechanical stimulation of the RW in an animal model of SF generates functionally similar inputs to the cochlea as normal acoustic and RW mechanical inputs but with increased thresholds. With further study, AMEIs may provide a surgical option for correction of otosclerosis and ossicular chain disruption. PMID- 19779389 TI - Middle ear mechanics of cartilage tympanoplasty evaluated by laser holography and vibrometry. AB - GOALS: To assess the effects of thickness and position of cartilage used to reconstruct the tympanic membrane (TM) using a novel technique, time-averaged laser holography. BACKGROUND: Cartilage is commonly used in TM reconstruction to prevent formation of retraction pockets. The thickness, position, and shape of the cartilage graft may adversely affect TM motion and hearing. We sought to systematically investigate these parameters in an experimental setting. METHODS: Computer-assisted optoelectronic laser holography was used in 4 human cadaveric temporal bones to study sound-induced TM motion for 500 Hz to 8 kHz. Stapes velocity was measured with a laser Doppler vibrometer. Baseline (control) measurements were made with the TM intact. Measurements were repeated after a 0.5 or 1.0-mm-thick oval piece of conchal cartilage was placed on the medial TM surface in the posterior-superior quadrant. The cartilage was rotated so that it was either in contact with the bony tympanic rim and manubrium or not. RESULTS: At frequencies less than 4 kHz, the cartilage graft had only minor effects on the overall TM fringe patterns. The different conditions had no effects on stapes velocity. Greater than 4 kHz, TM motion was reduced over the grafted TM, both with 0.5- and 1.0-mm-thick grafts. No significant differences in stapes velocity were seen with the 2 different thicknesses of cartilage compared with control. CONCLUSION: Computer-assisted optoelectronic laser holography is a promising technique to investigate middle ear mechanics after tympanoplasty. Such positioning may prevent postoperative TM retraction. These findings and conclusions apply to cartilage placed in the posterior-superior TM quadrant. PMID- 19779391 TI - Congenital transmission of human immunodeficiency virus, cytomegalovirus, and toxoplasmosis in a premature infant. AB - We report a preterm infant with congenital HIV-1, CMV, and toxoplasmosis coinfection, whose mother succumbed to probable cerebral toxoplasmosis. Despite repeated neuroimaging, retinal examinations and infant serologic tests, during the first 36 days of life, there was no evidence of congenital toxoplasmosis. However, subsequent tests showed cerebral calcifications, bilateral chorioretinitis, antitoxoplasma IgM antibody, and Toxoplasma gondii DNA in the cerebrospinal fluid by polymerase chain reaction. PMID- 19779390 TI - Outbreak of Salmonella Wandsworth and Typhimurium infections in infants and toddlers traced to a commercial vegetable-coated snack food. AB - OBJECTIVE: Human outbreaks of Salmonella infection have been attributed to a variety of food vehicles. Processed snack foods are increasingly consumed by children. In May 2007, state and local health departments and the Centers for Disease Control and Prevention investigated human infections from Salmonella Wandsworth, an extremely rare serotype. MATERIALS AND METHODS: Serotyping and pulsed-field gel electrophoresis were used to identify outbreak-associated illnesses. Food history questionnaires and open-ended interviews were used to generate exposure hypotheses. A nationwide case-control study was conducted to epidemiologically implicate a source. Public health laboratories cultured implicated product from patient homes and retail stores. RESULTS: Sixty-nine patients from 23 states were identified; 93% were aged 10 months to 3 years. Eighty-one percent of child patients had bloody diarrhea; 6 were hospitalized. No deaths were reported. The case-control study strongly associated illness with a commercial puffed vegetable-coated ready-to-eat snack food (mOR = 23.3, P = 0.0001), leading to a nationwide recall. Parents of 92% of interviewed case children reported that children consumed the food during the week before their illness began; 43% reported daily consumption. Salmonella Wandsworth, 3 additional Salmonella serotypes and Chronobacter (formerly Enterobacter) sakazaki were all cultured from this product, leading to the identification of 18 human outbreak-related Salmonella Typhimurium illnesses. CONCLUSIONS: This report documents a nationwide outbreak associated with a commercial processed ready-to eat snack food. Cases occurred primarily in infants and toddlers, many of whom frequently consumed the food. Measures are needed to ensure that ingredients added to ready-to-eat foods after the final lethal processing step are free of pathogens. PMID- 19779392 TI - Safety experience with caspofungin in pediatric patients. AB - We analyzed the caspofungin safety experience in 5 clinical registration studies in 171 pediatric patients, 1 week to 17 years of age. Caspofungin was administered for 1 to 87 (mean 12.1) days. The most common drug-related adverse events were fever, increased AST, increased ALT, and rash; few events were serious or required treatment discontinuation. Caspofungin was well tolerated in this pediatric population. PMID- 19779393 TI - Laryngeal involvement in two severe cases of childhood tuberculosis. AB - Laryngeal tuberculosis in children is seldom reported in the literature. We present 2 children from Cape Town, South Africa who had disseminated tuberculosis involving the cervical lymph nodes and the larynx. The cases emphasize the pathophysiology, the clinical picture, the bronchoscopic appearance, and the response to therapy in laryngeal tuberculosis. PMID- 19779394 TI - Protease inhibitor resistance in South African children with virologic failure. AB - BACKGROUND: In South Africa, first-line antiretroviral therapy for children younger than 3 years of age combines a protease inhibitor (PI) with 2 nucleoside reverse transcription inhibitors. In our study, some pediatric patients received ritonavir (RTV) as single PI (RTV-sPI) and others ritonavir-boosted lopinavir (LPV/r), which has a higher resistance barrier. We explored antiretroviral resistance mutations in pediatric patients failing PI-based antiretroviral therapy and the predictors of major PI resistance mutations (MPIRM) in these patients. MATERIALS AND METHODS: We studied pediatric HIV patients at Tygerberg Academic Hospital experiencing virologic failure on a PI regimen. Mixed-effects linear- and mixed-effect logistic regression modeling, were used to explore predictors of MPIRM. RESULTS: MPIRM were found in 12 of 17 patients exposed to RTV-sPI compared with 1 of 13 patients treated with LPV/r. Exposure to RTV-sPI was significantly associated with MPIRM, with both exposure time and estimated failing time on RTV-sPI being significant positive predictors of MPIRM. Neither CD4 count, viral load, age at first visit nor receiving rifampin predicted MPIRM. CONCLUSIONS: RTV-sPI in infants and children poses a significant risk of MPIRM which is dependent on the exposure time and time failing while receiving the regimen. PMID- 19779395 TI - EJPRM systematic continuous update on Cochrane reviews in rehabilitation: news from the second issue 2009. AB - The aim of the present paper is to systematically review all the new rehabilitation papers published in the second issue of 2009 from the Cochrane Library in order to provide to physicians involved in the field a summary of the best evidence nowadays available. The authors systematically searched all the new papers of rehabilitative interest from the second issue 2009 of the Cochrane Library. The retrieved papers are then divided in subgroups according to their topic. This review included eight papers: three dealing with neurological rehabilitation, two about pain management, one about orthopedic rehabilitation, one about physical therapy and another about workplace interventions. Some new evidence are now available, even if more studies are needed. The Cochrane Collaboration and the Cochrane Library are really relevant instruments to improve evidence based medicine in medical practice and thus also in the rehabilitation field. The present paper can help rehabilitation specialists to easily retrieve the conclusions of the most relevant and updated reviews in order to change their clinical practice in a more rapid and effective way. PMID- 19779396 TI - Orthogate and Orthopaedia: orthopedic information on the web. AB - The aim of this contribution was to present orthogate, a subject gateway for orthopedic resources on the web, and Orthopaedia, a collaborative knowledge base. PMID- 19779397 TI - Performance of rapid influenza diagnostic tests during two school outbreaks of 2009 pandemic influenza A (H1N1) virus infection - Connecticut, 2009. AB - During May 2009, a few weeks after 2009 pandemic influenza A (H1N1) infection was first detected in the United States, outbreaks among students from two schools were detected in Greenwich, Connecticut. Staff members from Greenwich Hospital and the Connecticut Department of Public Health collected data on symptoms for 63 patients and submitted nasopharyngeal washings for testing using a rapid influenza diagnostic test (RIDT) for influenza A and B and real-time reverse transcription--polymerase chain reaction (rRT-PCR) assay, thereby affording an opportunity to assess the field performance of the RIDT. A total of 49 patients had infections with pandemic influenza A (H1N1) confirmed by rRT-PCR. This report summarizes the findings from this performance assessment, which indicated that, compared with rRT-PCR, the sensitivity of the RIDT for detecting infection in patients with 2009 pandemic influenza A (H1N1) was 47%, and the specificity was 86%. Sensitivity and specificity did not vary substantially by the presence or absence of CDC-defined influenza-like illness (ILI) or by time from symptom onset to specimen acquisition. In this group of patients, although positive RIDT results performed well in predicting confirmed infection with pandemic H1N1 virus (positive predictive value: 92%), negative tests did not accurately predict the absence of infection (negative predictive value: 32%). These results affirm recent CDC recommendations against using negative RIDT results for management of patients with possible 2009 pandemic influenza A (H1N1) infection. PMID- 19779398 TI - Anaplasmosis and ehrlichiosis - Maine, 2008. AB - Anaplasmosis and ehrlichiosis are rickettsial tickborne diseases that have had at least a twofold increase in prevalence in the United States since 2000. Despite similar clinical presentations, the causative organisms are carried by different ticks with distinct geographic and ecologic associations. Surveillance efforts are complicated by ambiguous terminology and serologic testing with antibody cross-reactivity. Although anaplasmosis historically has been reported in Maine, ehrlichiosis has been reported infrequently. During 2007-2008, the number of physician-reported anaplasmosis cases nearly doubled in Maine, and ehrlichiosis cases increased more than fourfold. To examine this increase, the Maine Department of Health and Human Services (MDHHS) analyzed available data on tick burden and physician-reported cases of anaplasmosis and ehrlichiosis during 2000 2008. This report describes the results of that analysis, which indicated that Ixodes scapularis (the tick vector for Anaplasma phagocytophilum) was broadly distributed in Maine, whereas Amblyomma americanum (the tick vector for Erhlichia chaffeenisis) was scarce. Moreover, 95% of physician-reported ehrlichiosis cases lacked a concurrent serologic assessment to exclude anaplasmosis, suggesting that antibody cross-reactivity might have resulted in misclassification. In 2008, Maine modified case classification to enhance specificity; ehrlichiosis cases that lack a concurrent test for anaplasmosis are now classified as suspect rather than probable and therefore are not included in national surveillance summaries. The accuracy of case classification and surveillance can be improved by educating health-care providers regarding 1) the expected geographic distribution of tick vectors and 2) recommendations for confirmatory testing to distinguish between the causative organisms of anaplasmosis and ehrlichiosis. PMID- 19779399 TI - Progress toward measles control - African region, 2001-2008. AB - In 2001, the countries of the World Health Organization (WHO) African Region (AFR) became part of a global initiative with a goal of reducing the number of measles deaths by 50% by 2005, compared with 1999. Recommended strategies for measles mortality reduction included 1) increasing routine coverage for the first dose of measles-containing vaccine (MCV1) for all children, 2) providing a second opportunity for measles vaccination through supplemental immunization activities (SIAs), 3) improving measles case management, and 4) establishing case-based surveillance with laboratory confirmation of all suspected measles cases. Before introduction of MCV throughout AFR, approximately 1 million measles cases had been reported each year in the early 1980s. After strengthening measles-control activities, annual reported cases declined to an estimated 300,000- -580,000 during the 1990s. This report summarizes the progress made during 2001- -2008 toward improving measles control in AFR. During 2001- -2008 estimated MCV1 coverage increased from 57% to 73%, SIAs vaccinated approximately 398 million children, and reported measles cases decreased by 93%, from 492,116 in 2001 to 32,278 in 2008. By 2005, global measles deaths had decreased by 60%, and the AFR goal had been achieved; AFR adopted a new goal to reduce deaths by 90%, compared with 2000, and that goal was achieved in 2006. However, inaccuracies in reported vaccination coverage exist, surveillance is suboptimal, and measles outbreaks continue to occur in AFR countries. Further progress in measles control will require full implementation of recommended strategies, including validation of vaccination coverage. PMID- 19779400 TI - Updated recommendation from the Advisory Committee on Immunization Practices (ACIP) for revaccination of persons at prolonged increased risk for meningococcal disease. AB - The Advisory Committee on Immunization Practices (ACIP) recommends quadrivalent meningococcal conjugate vaccine, (MCV4) (Menactra, Sanofi Pasteur, Swiftwater, Pennsylvania) for all persons aged 11-18 years and for persons aged 2-55 years at increased risk for meningococcal disease. MCV4 is licensed as a single dose. Because of the high risk for meningococcal disease among certain groups and limited data on duration of protection, at its June 2009 meeting ACIP recommended that persons previously vaccinated with either MCV4 or MPSV4 (Menomune, Sanofi Pasteur) who are at prolonged increased risk for meningococcal disease should be revaccinated with MCV4. Persons who previously were vaccinated at age >or=7 years and are at prolonged increased risk should be revaccinated 5 years after their previous meningococcal vaccine, and persons who previously were vaccinated at ages 2-6 years and are at prolonged increased risk should be revaccinated 3 years after their previous meningococcal vaccine. Persons at prolonged increased risk for meningococcal disease include 1) persons with increased susceptibility such as persistent complement component deficiencies (e.g., C3, properdin, Factor D, and late complement component deficiencies), 2) persons with anatomic or functional asplenia, and 3) persons who have prolonged exposure (e.g., microbiologists routinely working with Neisseria meningitidis, or travelers to or residents of countries where meningococcal disease is hyperendemic or epidemic). This report provides the rationale for the new recommendation and updates and replaces previous recommendations for revaccination with MCV4. PMID- 19779406 TI - What's wrong with UNESCO. PMID- 19779405 TI - Earth's boundaries? PMID- 19779401 TI - In utero and ex vivo electroporation for gene expression in mouse retinal ganglion cells. AB - The retina and its sole output neuron, the retinal ganglion cell (RGC), comprise an excellent model in which to examine biological questions such as cell differentiation, axon guidance, retinotopic organization and synapse formation. One drawback is the inability to efficiently and reliably manipulate gene expression in RGCs in vivo, especially in the otherwise accessible murine visual pathways. Transgenic mice can be used to manipulate gene expression, but this approach is often expensive, time consuming, and can produce unwanted side effects. In chick, in ovo electroporation is used to manipulate gene expression in RGCs for examining retina and RGC development. Although similar electroporation techniques have been developed in neonatal mouse pups, adult rats, and embryonic murine retinae in vitro, none of these strategies allow full characterization of RGC development and axon projections in vivo. To this end, we have developed two applications of electroporation, one in utero and the other ex vivo, to specifically target embryonic murine RGCs. With in utero retinal electroporation, we can misexpress or downregulate specific genes in RGCs and follow their axon projections through the visual pathways in vivo, allowing examination of guidance decisions at intermediate targets, such as the optic chiasm, or at target regions, such as the lateral geniculate nucleus. Perturbing gene expression in a subset of RGCs in an otherwise wild-type background facilitates an understanding of gene function throughout the retinal pathway. Additionally, we have developed a companion technique for analyzing RGC axon growth in vitro. We electroporate embryonic heads ex vivo, collect and incubate the whole retina, then prepare explants from these retinae several days later. Retinal explants can be used in a variety of in vitro assays in order to examine the response of electroporated RGC axons to guidance cues or other factors. In sum, this set of techniques enhances our ability to misexpress or downregulate genes in RGCs and should greatly aid studies examining RGC development and axon projections. PMID- 19779407 TI - Biobanks need pharma. PMID- 19779414 TI - Journal club. A biologist praises a mouse model of autism inheritance. PMID- 19779421 TI - Buoy damage blurs El Nino forecasts. PMID- 19779422 TI - German science looks to new political players. PMID- 19779423 TI - The elephant and the neutrino. PMID- 19779424 TI - Genomics shifts focus to rare diseases. PMID- 19779425 TI - Gold rush for algae. PMID- 19779427 TI - Physics: The edge of physics. PMID- 19779428 TI - Atmospheric science: Cloudy, with a chance of science. PMID- 19779429 TI - Overzealous use of decimal places has wrong kind of impact. PMID- 19779430 TI - Politics and priorities behind Greek research reforms. PMID- 19779431 TI - A communication wipeout by gabbling presenters. PMID- 19779432 TI - Luxury bushmeat trade threatens lemur conservation. PMID- 19779433 TI - A safe operating space for humanity. PMID- 19779438 TI - Archaeology: Maya, Khmer and Inca. PMID- 19779440 TI - Climate change: The El Nino with a difference. PMID- 19779439 TI - Developmental biology: Rise of the source-sink model. PMID- 19779441 TI - Chemical biology: Caught in the activation. PMID- 19779442 TI - Astrophysics: Inner workings of a star. PMID- 19779443 TI - Developmental biology: A bad boy comes good. PMID- 19779444 TI - Human genetics: Tracing India's invisible threads. PMID- 19779445 TI - Reconstructing Indian population history. AB - India has been underrepresented in genome-wide surveys of human variation. We analyse 25 diverse groups in India to provide strong evidence for two ancient populations, genetically divergent, that are ancestral to most Indians today. One, the 'Ancestral North Indians' (ANI), is genetically close to Middle Easterners, Central Asians, and Europeans, whereas the other, the 'Ancestral South Indians' (ASI), is as distinct from ANI and East Asians as they are from each other. By introducing methods that can estimate ancestry without accurate ancestral populations, we show that ANI ancestry ranges from 39-71% in most Indian groups, and is higher in traditionally upper caste and Indo-European speakers. Groups with only ASI ancestry may no longer exist in mainland India. However, the indigenous Andaman Islanders are unique in being ASI-related groups without ANI ancestry. Allele frequency differences between groups in India are larger than in Europe, reflecting strong founder effects whose signatures have been maintained for thousands of years owing to endogamy. We therefore predict that there will be an excess of recessive diseases in India, which should be possible to screen and map genetically. PMID- 19779446 TI - Seismic evidence for the loss of stellar angular momentum before the white-dwarf stage. AB - White-dwarf stars represent the final products of the evolution of some 95% of all stars. If stars were to keep their angular momentum throughout their evolution, their white-dwarf descendants, owing to their compact nature, should all rotate relatively rapidly, with typical periods of the order of a few seconds. Observations of their photospheres show, in contrast, that they rotate much more slowly, with periods ranging from hours to tens of years. It is not known, however, whether a white dwarf could 'hide' some of its original angular momentum below the superficial layers, perhaps spinning much more rapidly inside than at its surface. Here we report a determination of the internal rotation profile of a white dwarf using a method based on asteroseismology. We show that the pulsating white dwarf PG 1159-035 rotates as a solid body (encompassing more than 97.5% of its mass) with the relatively long period of 33.61 +/- 0.59 h. This implies that it has lost essentially all of its angular momentum, thus favouring theories which suggest important angular momentum transfer and loss in evolutionary phases before the white-dwarf stage. PMID- 19779447 TI - Violation of Bell's inequality in Josephson phase qubits. AB - The measurement process plays an awkward role in quantum mechanics, because measurement forces a system to 'choose' between possible outcomes in a fundamentally unpredictable manner. Therefore, hidden classical processes have been considered as possibly predetermining measurement outcomes while preserving their statistical distributions. However, a quantitative measure that can distinguish classically determined correlations from stronger quantum correlations exists in the form of the Bell inequalities, measurements of which provide strong experimental evidence that quantum mechanics provides a complete description. Here we demonstrate the violation of a Bell inequality in a solid state system. We use a pair of Josephson phase qubits acting as spin-1/2 particles, and show that the qubits can be entangled and measured so as to violate the Clauser-Horne-Shimony-Holt (CHSH) version of the Bell inequality. We measure a Bell signal of 2.0732 +/- 0.0003, exceeding the maximum amplitude of 2 for a classical system by 244 standard deviations. In the experiment, we deterministically generate the entangled state, and measure both qubits in a single-shot manner, closing the detection loophole. Because the Bell inequality was designed to test for non-classical behaviour without assuming the applicability of quantum mechanics to the system in question, this experiment provides further strong evidence that a macroscopic electrical circuit is really a quantum system. PMID- 19779448 TI - Stable isotope constraints on Holocene carbon cycle changes from an Antarctic ice core. AB - Reconstructions of atmospheric CO(2) concentrations based on Antarctic ice cores reveal significant changes during the Holocene epoch, but the processes responsible for these changes in CO(2) concentrations have not been unambiguously identified. Distinct characteristics in the carbon isotope signatures of the major carbon reservoirs (ocean, biosphere, sediments and atmosphere) constrain variations in the CO(2) fluxes between those reservoirs. Here we present a highly resolved atmospheric delta(13)C record for the past 11,000 years from measurements on atmospheric CO(2) trapped in an Antarctic ice core. From mass balance inverse model calculations performed with a simplified carbon cycle model, we show that the decrease in atmospheric CO(2) of about 5 parts per million by volume (p.p.m.v.). The increase in delta(13)C of about 0.25 per thousand during the early Holocene is most probably the result of a combination of carbon uptake of about 290 gigatonnes of carbon by the land biosphere and carbon release from the ocean in response to carbonate compensation of the terrestrial uptake during the termination of the last ice age. The 20 p.p.m.v. increase of atmospheric CO(2) and the small decrease in delta(13)C of about 0.05 per thousand during the later Holocene can mostly be explained by contributions from carbonate compensation of earlier land-biosphere uptake and coral reef formation, with only a minor contribution from a small decrease of the land biosphere carbon inventory. PMID- 19779449 TI - El Nino in a changing climate. AB - El Nino events, characterized by anomalous warming in the eastern equatorial Pacific Ocean, have global climatic teleconnections and are the most dominant feature of cyclic climate variability on subdecadal timescales. Understanding changes in the frequency or characteristics of El Nino events in a changing climate is therefore of broad scientific and socioeconomic interest. Recent studies show that the canonical El Nino has become less frequent and that a different kind of El Nino has become more common during the late twentieth century, in which warm sea surface temperatures (SSTs) in the central Pacific are flanked on the east and west by cooler SSTs. This type of El Nino, termed the central Pacific El Nino (CP-El Nino; also termed the dateline El Nino, El Nino Modoki or warm pool El Nino), differs from the canonical eastern Pacific El Nino (EP-El Nino) in both the location of maximum SST anomalies and tropical midlatitude teleconnections. Here we show changes in the ratio of CP-El Nino to EP-El Nino under projected global warming scenarios from the Coupled Model Intercomparison Project phase 3 multi-model data set. Using calculations based on historical El Nino indices, we find that projections of anthropogenic climate change are associated with an increased frequency of the CP-El Nino compared to the EP-El Nino. When restricted to the six climate models with the best representation of the twentieth-century ratio of CP-El Nino to EP-El Nino, the occurrence ratio of CP-El Nino/EP-El Nino is projected to increase as much as five times under global warming. The change is related to a flattening of the thermocline in the equatorial Pacific. PMID- 19779450 TI - An epistatic ratchet constrains the direction of glucocorticoid receptor evolution. AB - The extent to which evolution is reversible has long fascinated biologists. Most previous work on the reversibility of morphological and life-history evolution has been indecisive, because of uncertainty and bias in the methods used to infer ancestral states for such characters. Further, despite theoretical work on the factors that could contribute to irreversibility, there is little empirical evidence on its causes, because sufficient understanding of the mechanistic basis for the evolution of new or ancestral phenotypes is seldom available. By studying the reversibility of evolutionary changes in protein structure and function, these limitations can be overcome. Here we show, using the evolution of hormone specificity in the vertebrate glucocorticoid receptor as a case-study, that the evolutionary path by which this protein acquired its new function soon became inaccessible to reverse exploration. Using ancestral gene reconstruction, protein engineering and X-ray crystallography, we demonstrate that five subsequent 'restrictive' mutations, which optimized the new specificity of the glucocorticoid receptor, also destabilized elements of the protein structure that were required to support the ancestral conformation. Unless these ratchet-like epistatic substitutions are restored to their ancestral states, reversing the key function-switching mutations yields a non-functional protein. Reversing the restrictive substitutions first, however, does nothing to enhance the ancestral function. Our findings indicate that even if selection for the ancestral function were imposed, direct reversal would be extremely unlikely, suggesting an important role for historical contingency in protein evolution. PMID- 19779455 TI - PARP-1 transcriptional activity is regulated by sumoylation upon heat shock. AB - Heat shock and other environmental stresses rapidly induce transcriptional responses subject to regulation by a variety of post-translational modifications. Among these, poly(ADP-ribosyl)ation and sumoylation have received growing attention. Here we show that the SUMO E3 ligase PIASy interacts with the poly(ADP ribose) polymerase PARP-1, and that PIASy mediates heat shock-induced poly sumoylation of PARP-1. Furthermore, PIASy, and hence sumoylation, appears indispensable for full activation of the inducible HSP70.1 gene. Chromatin immunoprecipitation experiments show that PIASy, SUMO and the SUMO-conjugating enzyme Ubc9 are rapidly recruited to the HSP70.1 promoter upon heat shock, and that they are subsequently released with kinetics similar to PARP-1. Finally, we provide evidence that the SUMO-targeted ubiquitin ligase RNF4 mediates heat-shock inducible ubiquitination of PARP-1, regulates the stability of PARP-1, and, like PIASy, is a positive regulator of HSP70.1 gene activity. These results, thus, point to a novel mechanism for regulating PARP-1 transcription function, and suggest crosstalk between sumoylation and RNF4-mediated ubiquitination in regulating gene expression in response to heat shock. PMID- 19779456 TI - Emerging common themes in regulation of PIKKs and PI3Ks. AB - Phosphatidylinositol-3 kinase-related kinases (PIKKs) comprise a family of protein kinases that respond to various stresses, including DNA damage, blocks in DNA replication, availability of nutrients and errors in mRNA splicing. PIKKs are characterized by the presence of a conserved kinase domain (KD), whose activity is regulated by two C-terminal regions, referred to as PIKK-regulatory domain (PRD) and FRAP-ATM-TRRAP-C-terminal (FATC), respectively. Here, we review functional and structural data that implicate the PRD and FATC domains in regulation of PIKK activity, drawing parallels to phosphatidylinositol-3 kinases (PI3K), lipid kinases that have sequence similarity to PIKKs. The PI3K C terminus, which we propose to be equivalent to the PRD and FATC domains of PIKKs, is in close proximity to the activation loop of the KD, suggesting that in PIKKs, the PRD and FATC domains may regulate kinase activity by targeting the activation loop. PMID- 19779457 TI - Jmjd3 contributes to the control of gene expression in LPS-activated macrophages. AB - Jmjd3, a JmjC family histone demethylase, is induced by the transcription factor NF-kB in response to microbial stimuli. Jmjd3 erases H3K27me3, a histone mark associated with transcriptional repression and involved in lineage determination. However, the specific contribution of Jmjd3 induction and H3K27me3 demethylation to inflammatory gene expression remains unknown. Using chromatin immunoprecipitation-sequencing we found that Jmjd3 is preferentially recruited to transcription start sites characterized by high levels of H3K4me3, a marker of gene activity, and RNA polymerase II (Pol_II). Moreover, 70% of lipopolysaccharide (LPS)-inducible genes were found to be Jmjd3 targets. Although most Jmjd3 target genes were unaffected by its deletion, a few hundred genes, including inducible inflammatory genes, showed moderately impaired Pol_II recruitment and transcription. Importantly, most Jmjd3 target genes were not associated with detectable levels of H3K27me3, and transcriptional effects of Jmjd3 absence in the window of time analysed were uncoupled from measurable effects on this histone mark. These data show that Jmjd3 fine-tunes the transcriptional output of LPS-activated macrophages in an H3K27 demethylation independent manner. PMID- 19779458 TI - ATM and Artemis promote homologous recombination of radiation-induced DNA double strand breaks in G2. AB - Homologous recombination (HR) and non-homologous end joining (NHEJ) represent distinct pathways for repairing DNA double-strand breaks (DSBs). Previous work implicated Artemis and ATM in an NHEJ-dependent process, which repairs a defined subset of radiation-induced DSBs in G1-phase. Here, we show that in G2, as in G1, NHEJ represents the major DSB-repair pathway whereas HR is only essential for repair of approximately 15% of X- or gamma-ray-induced DSBs. In addition to requiring the known HR proteins, Brca2, Rad51 and Rad54, repair of radiation induced DSBs by HR in G2 also involves Artemis and ATM suggesting that they promote NHEJ during G1 but HR during G2. The dependency for ATM for repair is relieved by depleting KAP-1, providing evidence that HR in G2 repairs heterochromatin-associated DSBs. Although not core HR proteins, ATM and Artemis are required for efficient formation of single-stranded DNA and Rad51 foci at radiation-induced DSBs in G2 with Artemis function requiring its endonuclease activity. We suggest that Artemis endonuclease removes lesions or secondary structures, which inhibit end resection and preclude the completion of HR or NHEJ. PMID- 19779459 TI - The mechanism of vault opening from the high resolution structure of the N terminal repeats of MVP. AB - Vaults are ubiquitous ribonucleoprotein complexes involved in a diversity of cellular processes, including multidrug resistance, transport mechanisms and signal transmission. The vault particle shows a barrel-shaped structure organized in two identical moieties, each consisting of 39 copies of the major vault protein MVP. Earlier data indicated that vault halves can dissociate at acidic pH. The crystal structure of the vault particle solved at 8 A resolution, together with the 2.1-A structure of the seven N-terminal domains (R1-R7) of MVP, reveal the interactions governing vault association and provide an explanation for a reversible dissociation induced by low pH. The structural comparison with the recently published 3.5 A model shows major discrepancies, both in the main chain tracing and in the side chain assignment of the two terminal domains R1 and R2. PMID- 19779460 TI - A ribosome-nascent chain sensor of membrane protein biogenesis in Bacillus subtilis. AB - Proteins in the YidC/Oxa1/Alb3 family have essential functions in membrane protein insertion and folding. Bacillus subtilis encodes two YidC homologs, one that is constitutively expressed (spoIIIJ/yidC1) and a second (yqjG/yidC2) that is induced in spoIIIJ mutants. Regulated induction of yidC2 allows B. subtilis to maintain capacity of the membrane protein insertion pathway. We here show that a gene located upstream of yidC2 (mifM/yqzJ) serves as a sensor of SpoIIIJ activity that regulates yidC2 translation. Decreased SpoIIIJ levels or deletion of the MifM transmembrane domain arrests mifM translation and unfolds an mRNA hairpin that otherwise blocks initiation of yidC2 translation. This regulated translational arrest and yidC2 induction require a specific interaction between the MifM C-terminus and the ribosomal polypeptide exit tunnel. MifM therefore acts as a ribosome-nascent chain complex rather than as a fully synthesized protein. B. subtilis MifM and the previously described secretion monitor SecM in Escherichia coli thereby provide examples of the parallel evolution of two regulatory nascent chains that monitor different protein export pathways by a shared molecular mechanism. PMID- 19779461 TI - RNase Y, a novel endoribonuclease, initiates riboswitch turnover in Bacillus subtilis. AB - In contrast to Escherichia coli, initiation of mRNA decay in Gram-positive organisms is poorly understood. We studied the fate of the highly structured RNAs generated by premature transcription termination of S-adenosylmethionine (SAM) dependent riboswitches in Bacillus subtilis. An essential protein of earlier unknown function, YmdA, was identified as a novel endoribonuclease (now called RNase Y) that was capable of preferential cleaving in vitro of the 5' monophosphorylated yitJ riboswitch upstream of the SAM-binding aptamer domain. Antiterminated full-length yitJ mRNA was not a substrate for RNase Y in vivo and in vitro, transcripts capable of forming the antiterminator were only cleaved in the presence of SAM. Turnover of 10 other SAM-dependent riboswitches was also initiated by RNase Y. Depletion of this ribonuclease increased the half-life of bulk mRNA more than two-fold. This indicates that RNase Y might be not only important for riboswitch RNA turnover but also as a key player in the initiation of mRNA decay in B. subtilis. About 40% of the sequenced eubacterial species have an RNase Y orthologue. PMID- 19779464 TI - Genetic factors are relevant and independent determinants of antihypertensive drug effects in a multiracial population. AB - BACKGROUND: The success of antihypertensive drugs may be improved by better prediction of their efficacy in individual patients. The objective of our study was to determine whether genetic variation predicts the individual systolic blood pressure (SBP) response to antihypertensive drugs and to assess to what extent the individual treatment response could be explained by the combined effects of known demographic, environmental, and genetic factors. METHODS: A population based, crossover, open-label randomized treatment study stratified for ethnicity in 102 mildly hypertensive patients aged 35-60 years in an outpatient hypertension clinic (the ROTATE study). Patients underwent five successive 6-week treatment episodes of single-drug treatment in a randomized order with representatives of the major antihypertensive drug classes. The primary outcome measure was the DeltaSBP after 6-week drug therapy. RESULTS: Participants (n = 97) completed 407 treatment episodes. The estimated unpredictable natural variation of SBP within individuals was 65% of the total study variance. The primary analysis model that considered the effects of environmental, demographic, and genetic factors and their interactions to SBP response to antihypertensive drugs, explained 23% of the total variance accounting for 66% of the predictable variance. Ethnicity, low sodium intake, and ADD1 614G-->T polymorphism were the only drug-related predictors. A number of genetic variants (ADD1 614G-->T, ADRB1 145A-->G, ADRB2 79C-->G, CYP11B2 -344C-->T, and SLC12A3 78G-->A) contributed significantly (9%) to the total variance of the SBP response. The contribution of each individual single-nucleotide polymorphism (SNP) ranged from 1.1 to 2.4%. CONCLUSIONS: Genetic factors are relevant and independent determinants of antihypertensive drug effects in a multiracial population. PMID- 19779463 TI - Curved FtsZ protofilaments generate bending forces on liposome membranes. AB - We have created FtsZ-YFP-mts where an amphipathic helix on the C-terminus tethers FtsZ to the membrane. When incorporated inside multi-lamellar tubular liposomes, FtsZ-YFP-mts can assemble Z rings that generate a constriction force. When added to the outside of liposomes, FtsZ-YFP-mts bound and produced concave depressions, bending the membrane in the same direction as the Z ring inside liposomes. Prominent membrane tubules were then extruded at the intersections of concave depressions. We tested the effect of moving the membrane-targeting sequence (mts) from the C-terminus to the N-terminus, which is approximately 180 degrees from the C-terminal tether. When mts-FtsZ-YFP was applied to the outside of liposomes, it generated convex bulges, bending the membrane in the direction opposite to the concave depressions. We conclude that FtsZ protofilaments have a fixed direction of curvature, and the direction of membrane bending depends on which side of the bent protofilament the mts is attached to. This supports models in which the FtsZ constriction force is generated by protofilament bending. PMID- 19779462 TI - The MRT-1 nuclease is required for DNA crosslink repair and telomerase activity in vivo in Caenorhabditis elegans. AB - The telomerase reverse transcriptase adds de novo DNA repeats to chromosome termini. Here we define Caenorhabditis elegans MRT-1 as a novel factor required for telomerase-mediated telomere replication and the DNA-damage response. MRT-1 is composed of an N-terminal domain homologous to the second OB-fold of POT1 telomere-binding proteins and a C-terminal SNM1 family nuclease domain, which confer single-strand DNA-binding and processive 3'-to-5' exonuclease activity, respectively. Furthermore, telomerase activity in vivo depends on a functional MRT-1 OB-fold. We show that MRT-1 acts in the same telomere replication pathway as telomerase and the 9-1-1 DNA-damage response complex. MRT-1 is dispensable for DNA double-strand break repair, but functions with the 9-1-1 complex to promote DNA interstrand cross-link (ICL) repair. Our data reveal MRT-1 as a dual-domain protein required for telomerase function and ICL repair, which raises the possibility that telomeres and ICL lesions may share a common feature that plays a critical role in de novo telomere repeat addition. PMID- 19779465 TI - Association between insurance gaps and continued antihypertension medication usage in a US national representative population. AB - BACKGROUND: Medication persistence is important for adequate control of blood pressure. In this article, we assess the association between gaps in insurance coverage and continued antihypertensive medication using a US national representative sample. METHODS: We used three recent panels from the Medical Expenditure Panel Survey (MEPS). Our sample included hypertensive individuals 18 65 years of age. We identified four insurance categories: (i) continuous coverage by private insurance, (ii) continuous coverage by public insurance, (iii) single or multiple gaps in coverage, and (iv) continuously uninsured. Binary logit models were used to analyze the association between interruptions in medication and insurance after controlling for socioeconomic factors. Patients with continuous private insurance were used as the reference group. Results were weighted to adjust for oversampling and clustering in the survey. RESULTS: There was no statistically significant difference in the probability of medication persistence between individuals with continuous private insurance (the reference group) and individuals with continuous public insurance (adjusted odds ratio (AOR) 1.324, 95% confidence interval (CI) 0.774-2.266, P = 0.304). Compared to the reference group, individuals with insurance gaps had lower odds of continuing their medication (AOR 0.636, 95% CI 0.418-0.0.969, P = 0.035). Continuously uninsured individuals had even lower odds of medication persistence (AOR 0.462, 95% CI 0.282-0.757, P = 0.002). Age, marital status, body mass index (BMI) change, and years of education were also associated with continued medication usage. CONCLUSION: Studies focusing on current insurance status may underestimate the impact of health insurance gaps and the population at risk. Continuous insurance coverage is needed to increase continued antihypertensive medication usage. PMID- 19779466 TI - Toll-like receptor 3 activation during pregnancy elicits preeclampsia-like symptoms in rats. AB - BACKGROUND: Preeclampsia (PE), a pregnancy-specific hypertensive syndrome, is one of the leading causes of premature births as well as fetal and maternal death. There is strong evidence that maternal immune system activation, of which Toll like receptors (TLRs) play a major role, contributes to the development of PE. Viral infections, sensed by TLR3, are associated with hypertensive disorders of pregnancy. We tested the hypothesis that TLR3 activation during pregnancy would cause hypertension, endothelial dysfunction, proteinuria, and intrauterine growth restriction in normal pregnant rats. METHODS: We treated pregnant and nonpregnant rats with the viral mimetic polyinosinic:polycytidylic acid (poly I:C) or vehicle every other day beginning at day 10 of gestation and measured systolic blood pressure, aortic vasodilation, urinary protein concentration, fetal growth, and serum and placental cytokine levels. RESULTS: Pregnant rats treated with poly I:C displayed significantly elevated systolic blood pressures compared to pregnant rats and nonpregnant rats treated with poly I:C on day 18 of gestation. Poly I:C treated pregnant rats also exhibited significantly decreased aortic vasodilation, significantly increased urinary protein concentrations, and had more malformed pups/litter. Additionally, poly I:C-treated rats exhibited a significant increase in placental TLR3 expression and proinflammatory/anti-inflammatory cytokine ratio compared to vehicle-treated rats. Poly I:C treatment of nonpregnant control rats had no effect on systolic blood pressure, aortic vasodilation, or urinary protein concentrations. CONCLUSION: These findings demonstrate that sustained maternal immune system activation via TLR3 during pregnancy causes PE-like symptoms in rats and suggest that viral infection during pregnancy may contribute to the development of PE. PMID- 19779467 TI - Oral calcium supplementation ambulatory blood pressure and relation to changes in intracellular ions and sodium-hydrogen exchange. AB - BACKGROUND: Calcium (Ca2+) supplementation has been shown paradoxically to reduce intracellular Ca2+ and induce vascular relaxation. The aim of the study was to assess 24-h blood pressure (BP) change after Ca2+ supplementation and to investigate its relation to changes in intracellular ions and the activity of the first isoform of sodium-hydrogen exchange (NHE-1) in subjects with hypertension and type 2 diabetes. METHODS: This parallel, randomized controlled, single blinded trial, consisted of 31 patients with type 2 diabetes, and hypertension who were allocated to receive 1,500 mg of Ca2+ per day (n = 15) or no treatment (n = 16) for 8 weeks. RESULTS: In the Ca2+ group a decrease of 1.7 +/- 2.7 mm Hg (mean +/- SE) P = 0.52 for mean 24-h systolic BP (SBP) and 2.1 +/- 1.5 mm Hg, P = 0.19 for mean 24-h diastolic BP (DBP) was recorded. Whereas in the control group an increase of 1.4 +/- 2.7 mm Hg, P = 0.59 for mean 24-h SBP and 1.2 +/- 2.8 mm Hg, P = 0.83 for mean 24-h DBP was observed. Intraplatelet Ca2+ decreased whereas intraplatelet magnesium (Mg2+) and erythrocyte K+ increased in the intervention group. Change in mean 24-h SBP in the pooled group correlated with both change in intraplatelet Ca2+ (r = 0.49, P < 0.05) and NHE-1 activity (r = 0.6, P < 0.001). The contribution of intraplatelet Ca2+ was attenuated when both parameters were entered in a multivariate regression model. CONCLUSIONS: The present study shows a weak, statistically nonsignificant trend towards association of Ca2+ supplementation on 24-h BP in hypertensive subjects with type 2 diabetes. However, our results indicated an interrelation of [Ca2+]i levels and NHE-1 activity on BP in patients with hypertension and type 2 diabetes. PMID- 19779468 TI - A single-nucleotide polymorphism in the gene encoding osteoprotegerin is associated with diastolic blood pressure in older men. AB - BACKGROUND: Osteoprotegerin (OPG) has been associated with cardiovascular events but currently the mechanisms underlying this association are unknown. OPG is thought to play a role in controlling artery calcification and small studies have suggested that it may influence artery structure. We examined the association between single nucleotide polymorphisms (SNPs) in the gene encoding OPG (tumor necrosis factor receptor superfamily, member 11b, TNFRSF11B), with blood pressure in a large cohort of elderly men. METHODS: 21 tagging SNPs in the region encoded by TNFRSF11B were examined in 1,071 men recruited in a population-based study of elderly men. Genotyping was carried out using the Illumina Golden Gate assay. SNPs were investigated for their association with resting systolic and diastolic blood pressure after adjusting for other variables using linear regression. The association of SNPs in the region encoded by TNFRSF11B with plasma OPG was assessed in a random subset of 467 men. RESULTS: One SNP, rs11573901, was significantly associated with diastolic blood pressure, after adjusting for other risk factors and multiple testing (coefficient -4.36, P = 0.001). Men with the TC genotype had lower diastolic blood pressure than those with the common cc variation. this snp was not associated with plasma opg in the 467 men in which this was examined. CONCLUSIONS: This study suggests that a SNP within the region encoded by TNFRSF11B, which is believed to code for OPG, is associated with blood pressure. The mechanism underlying this observed association is currently unclear. PMID- 19779469 TI - P-wave dispersion and its relationship to aortic elasticity in young prehypertensive patients. AB - BACKGROUND: Prolonged P-wave duration (P(dur)) and increased P-wave dispersion (PWD) are independent predictors of atrial fibrillation (AF) in patients with hypertension. This study was designed to evaluate the possible relationship between aortic elasticity and PWD in young prehypertensive patients. METHODS: Twenty-five newly diagnosed prehypertensive patients (18 men, mean age = 34 +/- 6 years) and 25 healthy control subjects (16 men, mean age = 33 +/- 6 years) were enrolled in the study. The P(dur) measurements were calculated using a 12-lead surface electrocardiogram (ECG). Aortic elasticity parameters were derived from aortic diameters measured by echocardiography, and simultaneous blood pressure (BP) measurements by sphygmomanometry. RESULTS: The baseline characteristics of patients with prehypertension were homogeneous with those of the controls. PWD and P(maximum) values were found to be higher in patients with prehypertension as compared to those of the controls (PWD; 65 ms vs. 35 ms, P < 0.001; P(maximum); 110 ms vs. 80 ms, P < 0.001). However, P(minimum) values were not significantly different between the two groups (40 ms vs. 45 ms, P = 0.358). Also, a moderate positive correlation was found between stiffness index (SI) and PWD (r = 0.500, P = 0.011), and a moderate negative correlation between aortic elasticity parameters (aortic distensibility and strain indexes) and PWD (for aortic distensibility, r = -0.498, P = 0.011; for strain index, r = -0.578, P = 0.002), in patients with prehypertension. CONCLUSIONS: Young patients with prehypertension have increased PWD and arterial stiffness. These parameters are correlated and may pose additional risk factors for future cardiovascular events. PMID- 19779470 TI - Aortic pulse pressure is associated with carotid IMT in chronic kidney disease: report from Chronic Renal Insufficiency Cohort. AB - BACKGROUND: Patients with chronic kidney disease (CKD) have a disproportionate risk of cardiovascular disease. This study was designed to assess the association between two noninvasive measures of cardiovascular risk, pulse wave analysis (PWA), and carotid intima-media thickness (IMT), in a cohort of CKD patients enrolled in the Chronic Renal Insufficiency Cohort (CRIC) study. METHODS: Three hundred and sixty-seven subjects with CKD enrolled in the CRIC study at the University of Pennsylvania site (mean age 59.9 years, blood pressure 129/74 mm Hg, estimated glomerular filtration rate 48 ml/min/1.73 m2, IMT 0.8 mm) had both carotid IMT and PWA measurements. Carotid ultrasound was also used to determine the presence of plaque. PWA was used to determine augmentation index (AI), amplification ratio (AMPR), aortic pulse pressure (C_PP), and central aortic systolic pressure (C_SP). RESULTS: IMT was significantly associated with all PWA derived measures. However, on multivariable linear regression analysis, only AMPR (regression coefficient -0.072, P = 0.006), C_PP (regression coefficient 0.0025, P < 0.001), and C_SP (regression coefficient 0.0017, P < 0.001) remained significantly associated with IMT. The prevalence of carotid plaque in the cohort was 59%. Of the PWA-derived measures, only C_PP was significantly associated with the presence of carotid plaque (P < 0.001). CONCLUSIONS: PWA-derived measures are associated with carotid IMT and plaque in the CKD. Of these measures, C_PP was most associated with carotid IMT and plaque. PMID- 19779472 TI - Antioxidant treatment with tempol and apocynin prevents endothelial dysfunction and development of renovascular hypertension. AB - BACKGROUND: Two-kidney-one-clip (2K-1C) rats develop renovascular hypertension associated with endothelial dysfunction and elevated levels of oxidative stress. The role of oxidative damage is unknown in vascular dysfunction coupled with 2K 1C hypertension. The aims of this study were to evaluate the effects of chronic treatment with a superoxide dismutase (SOD) mimetic (tempol) and an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase (apocynin) on the development of hypertension, endothelial dysfunction, and oxidative damage in 2K-1C rats. METHODS: 2K-1C rats and sham-operated rats were treated with tempol or apocynin for 40 days, while the corresponding nontreated groups received tap water. Blood pressure (BP), mesenteric arterial reactivity, plasma and mesentery oxidative damage, mesenteric protein expression, and antioxidant activities were compared among the four groups. RESULTS: Chronic treatment with tempol (1 mmol/l) or apocynin (33 microg/kg/day) impaired the development of hypertension in 2K-1C rats and did not change the BP in control animals. The reduction in vasodilatory effect induced by acetylcholine (ACh) in the mesenteric arterial beds (MABs) of 2K-1C rats was restored by tempol and apocynin. Plasma and mesentery levels of malondialdehyde (MDA) were higher in 2K-1C rats, and these levels were significantly reduced by the administration of tempol and apocynin. Mesenteric SOD activity and expression were higher in 2K-1C rats than in the controls, and treatment with tempol resulted in a reduction in SOD activity. CONCLUSIONS: The data suggest that a compromised mechanism of antioxidant defense and an increase in oxidative damage contribute to the development of hypertension and associated vascular dysfunction in 2K-1C rats, and that tempol and apocynin prevent these effects. PMID- 19779471 TI - Attenuation of angiotensin II-induced hypertension and cardiac hypertrophy in transgenic mice overexpressing a type 1 receptor mutant. AB - BACKGROUND: The angiotensin II (AngII) type 1 receptor (AT1) regulates cardiovascular function by activating various signal pathways. The purpose of this study was to evaluate the effects of a mutant AT1 receptor on AngII responding blood pressure and cardiac hypertrophy in conjunction with altered AngII activation of RhoA and Akt. METHODS: A mutant AT1 receptor was constructed and overexpressed in C57BL mice using a ubiquitous-expression vector pCAGGS. The phenotype and signal transduction of the transgenic (TG) mice were compared with the wild-type (WT) mice. RESULTS: The TG mice showed a similar baseline phenotype as WT mice, but their blood pressure in response to continuous AngII infusion was significantly lower, as measured on days 3, 4, 7, and 14, with a difference of 20 mm Hg by day 14. There was also a significantly larger heart-to-total-body-weight ratio in the WT mice, whose heart weight (HW) was 0.441 +/- 0.008% of total body weight (BW) compared to the TG mice at 0.416 +/- 0.008%. Aortic endothelial cells isolated from these TG mice displayed an altered signaling profile, such as diminished activation of Akt and RhoA in response to AngII. In contrast, Galphaq coupling and ERK/JNK activation did not change. CONCLUSION: The expression of an AT1 mutant receptor in the presence of WT receptor can effectively modulate AngII effected signaling. Furthermore, the elimination of Akt and RhoA activation by AngII significantly reduces but does not eliminate its hypertensive effect. PMID- 19779473 TI - Ultrasound measurements of visceral and subcutaneous abdominal thickness to predict abdominal adiposity among older men and women. AB - Accurate measures of visceral and abdominal subcutaneous fat are essential for investigating the pathophysiology of obesity. Classical anthropometric measures such as waist and hip circumference cannot distinguish between these two fat depots. Direct imaging methods such as computed tomography and magnetic resonance imaging (MRI) are restricted in large-scale studies due to practical and ethical issues. We aimed to establish whether ultrasound is a valid alternative method to MRI for the quantitative assessment of abdominal fat depots in older individuals. The study population comprised 74 white individuals (41 men and 33 women, aged 67 76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial. Anthropometry included height, weight, waist and hip circumferences. Abdominal fat was measured by ultrasound in two compartments: visceral fat defined as the depth from the peritoneum to the lumbar spine; and subcutaneous fat defined as the depth from the skin to the abdominal muscles and compared to reference measures by MRI (10-mm single-slice image). Ultrasound measures were positively correlated with MRI measures of visceral and subcutaneous fat (visceral: r = 0.82 and r = 0.80 in men and women, respectively; subcutaneous: r = 0.63 and 0.68 in men and women, respectively). In multiple regression models, the addition of ultrasound measures significantly improved the prediction of visceral fat and subcutaneous fat in both men and women over and above the contribution of standard anthropometric variables. In conclusion, ultrasound is a valid method to estimate visceral fat in epidemiological studies of older men and women when MRI and computed tomography are not feasible. PMID- 19779474 TI - Identification of an obese eating style in 4-year-old children born at high and low risk for obesity. AB - This study tested whether children's eating behavior and parental feeding prompts during a laboratory test meal differ among children born at high risk (HR) or low risk (LR) for obesity and are associated with excess child weight gain. At 4 years of age, 32 HR children (mean maternal prepregnancy BMI = 30.4 kg/m(2)) and 29 LR children (maternal BMI = 19.6 kg/m(2)) consumed a test meal in which their eating behavior was assessed, including rate of caloric consumption, mouthfuls/min, and requests for food. Parental prompts for the child to eat also were measured at year 4, and child body composition was measured at ages 4 and 6 years. T-tests, and logistic and multiple regression analyses tested study aims. Results indicated that HR and LR children did not differ in eating rate or parental feeding prompts. Greater maternal BMI, child mouthfuls of food/min, and total caloric intake/min during the test meal predicted an increased risk of being overweight or obese at age 6, whereas greater active mealtime was associated with a reduced risk of being overweight or obese. Regression analyses indicated that only mouthfuls of food/min predicted changes in BMI from 4 to 6 years, and mouthfuls of food/min and gender predicted 2-year changes in sum of skinfolds and total body fat. Thus, a rapid eating style, characterized by increased mouthfuls of food/min, may be a behavioral marker for the development of childhood obesity. PMID- 19779475 TI - Increase in the prevalence of obesity in Switzerland 1982-2007: birth cohort analysis puts recent slowdown into perspective. AB - Although the prevalence of obesity continues to increase in Switzerland, the latest figures suggest a slowdown in the rate of increase. In order to elucidate whether this could be the onset of a trend reversal, we analyzed cross-sectional data by birth cohort. We assessed the prevalence of overweight+ (BMI > or =25 kg/m(2)) and obesity (BMI > or =30 kg/m(2)) in six population surveys with self reported height and weight values (Switzerland, N = 68,829, 1982-2007, men (45%) and women (55%), aged 20-84 years) by 10-year birth cohorts (from the decade 1910 1919 through to 1970-1979). We found that increases in the prevalence of overweight+ and obesity occurred mainly in the cohort born 1930 to 1939, and again in the cohorts born 1960 to 1979. The accelerated increase in the prevalence of overweight+ in the youngest birth cohort and the lower prevalence in the oldest birth cohorts suggest that the current slowdown seen in Switzerland may not herald the onset of a trend reversal. As this example shows, simple comparisons of prevalence rates over time could provide a misleading picture of actual trends. Birth cohort analysis may offer a valuable alternative. PMID- 19779476 TI - Sex differences in the effects of inherited bitter thiourea sensitivity on body weight in 4-6-year-old children. AB - Previous studies have shown that inherited taste blindness to bitter compounds like 6-n-propylthiouracil (PROP) may be a risk factor for obesity, but this literature has been highly controversial. The objectives of this study were (i) to confirm findings that show an interaction between PROP status and sex on BMI z score, and (ii) to determine if sex also interacts with variations in TAS2R38 (phenylthiocarbamide (PTC) genotype) to influence weight status in 4-6 year olds. Also, we tested whether nontaster children consumed more fat and total energy at laboratory-based meals. Seventy-two ethnically diverse children who ranged in weight status were classified as tasters (N = 52) or nontasters (N = 20) using a standard PROP screening solution. Anthropometric measures were taken, and at the end of each visit, children ate ad libitum from test meals intended for exploratory purposes. Genomic DNA was extracted from saliva and alleles at TAS2R38 were genotyped for A49P polymorphisms. In 75.8% of children, PTC genotype predicted PROP phenotype, whereas in 24.4%, genotype did not predict phenotype. PROP nontaster males had higher BMI z-scores than taster-males and females in both groups (P < 0.05), but due to a three-way interaction between PROP phenotype, TAS2R38 genotype, and sex, this relationship was only true for children who were homozygous for the bitter-insensitive allele (P < 0.0005). There were no differences in test-meal intake as a function of PROP phenotype or TAS2R38 genotype. These results suggest that the TAS2R38 variation, PROP phenotype, and sex interact to impact obesity risk in children. Future studies should be done to determine how this trait influences energy balance. PMID- 19779477 TI - Dairy protein attenuates weight gain in obese rats better than whey or casein alone. AB - Evidence suggests that dietary calcium (Ca) and particularly dairy foods may attenuate weight gain and improve symptoms of the metabolic syndrome. The purpose of this study was to determine the effect of different Ca-enriched dairy protein sources on the prevention of weight gain in Sprague-Dawley diet-induced obese (DIO) rats. Twelve week-old DIO rats were assigned to one of eight ad libitum diets that varied in protein source (casein, whey, or complete dairy), Ca content (0.67 or 2.4%) and energy level (high fat/high sucrose (HFHS); or normal calorie density (NC)). Body composition and response to a meal tolerance test (MTT) were measured. Average daily caloric intake did not differ within normal or high energy density groups. At the end of 8 weeks, the dairy/HFHS/0.67% and 2.4% groups had significantly lower body weight than all other HFHS groups. The dairy/HFHS/0.67% and 2.4% groups also had lower body fat and greater lean mass expressed as a percent (P < 0.05). Homeostatic model assessment of insulin resistance (HOMA(IR)) was lowest for dairy/HFHS/0.67% and significantly different from whey/HFHS/0.67% and 2.4%. Independent of protein source, high Ca decreased plasma insulin at 30 min in the MTT more so than low Ca (P < 0.05). Hepatic sterol regulatory element-binding protein (SREBP1c) and peroxisome proliferator activated receptor-gamma (PPARgamma) mRNA was downregulated by dairy and whey compared to casein in the HFHS/0.67% diets. Overall, these data suggest that complete dairy improves body composition and insulin sensitivity to a greater extent than whey or casein alone. PMID- 19779478 TI - The Great Chinese Famine leads to shorter and overweight females in Chongqing Chinese population after 50 years. AB - This study investigated a possible association between early nutritional status during the famine, and the risk of overweight and obesity in adulthood in Chongqing Chinese population. The body weight, height, and BMI data were obtained from records of population (17,023) that had annual physical evaluations in the Public Health Center (in our hospital). Subjects born during 1956-1964 were divided into three groups: toddler group, all subjects who were born 1-3 years before the famine (1956-1958); gestational group, who were born during the famine period (1959-1961), and control group, who were born after the famine (1962 1964). The body weight and BMI were significantly higher, but the body height was significantly lower in the toddler and gestational groups (P < 0.05) in the female population as compared to the control group. The odds ratio of being overweight in females is more pronounced in the toddler group (1.48 times, 95% confidence interval (CI): 1.288-1.689) than in the gestational group (1.26 times, 95% CI: 1.089-1.457). The odds ratio of being obese in females is significantly higher in the toddler group (1.46 times, 95% CI: 1.288-1.689) than the control group. For males, the famine had no impact at all on the adulthood body weight in males. The Great Chinese Famine that affected the Chongqing population during 1959-1961 leads to shorter and overweight females, and the former is a risk factor for increased BMI in Chongqing. Second, the famine seems to be producing shorter but slimmer males in Chongqing. Furthermore, toddler's and maternal's malnutrition during the famine had important late consequences on the health status. PMID- 19779479 TI - Mice deficient in phosphofructokinase-M have greatly decreased fat stores. AB - Synthesis of triacylglycerol requires the glucose-derived glycerol component, and glucose uptake has been viewed as the rate-limiting step in glucose metabolism in adipocytes. Furthermore, adipose tissue contains all three isoforms of the glycolytic enzyme phosphofructokinase (PFK). We here report that mice deficient in the muscle isoform PFK-M have greatly reduced fat stores. Mice with disrupted activity of the PFK-M distal promoter were obtained from Lexicon Pharmaceuticals, developed from OmniBank OST#56064. Intra-abdominal fat was measured by magnetic resonance imaging of the methylene proton signal. Lipogenesis from labeled glucose was measured in isolated adipocytes. Lipolysis (glycerol and free fatty acid release) was measured in perifused adipocytes. Intra-abdominal fat in PFK-M deficient female mice (5-10 months old) was 17 +/- 3% of that of wild-type littermates (n = 4; P < 0.02). Epididymal fat weight in 15 animals (7-9.5 months) was 34 +/- 4% of control littermate (P < 0.002), with 10-30% lower body weight. Basal and insulin-stimulated lipogenesis in PFK-M-deficient epididymal adipocytes was 40% of the rates in cells from heterozygous littermates (n = 3; P < 0.05). The rate of isoproterenol-stimulated lipolysis in wild-type adipocytes declined approximately 10% after 1 h and 50% after 2 h; in PFK-M-deficient cells it declined much more rapidly, 50% in 1 h and 90% in 2 h, and lipolytic oscillations appeared to be damped (n = 4). These results indicate an important role for PFK-M in adipose metabolism. This may be related to the ability of this isoform to generate glycolytic oscillations, because such oscillations may enhance the production of the triacylglycerol precursor alpha-glycerophosphate. PMID- 19779481 TI - Response to "A complementary explanation on the relationship of obesity and oxidative stress via protons". PMID- 19779483 TI - Inter-subunit interaction and quaternary rearrangement defined by the central stalk of prokaryotic V1-ATPase. AB - V-type ATPases (V-ATPases) are categorized as rotary ATP synthase/ATPase complexes. The V-ATPases are distinct from F-ATPases in terms of their rotation scheme, architecture and subunit composition. However, there is no detailed structural information on V-ATPases despite the abundant biochemical and biophysical research. Here, we report a crystallographic study of V1-ATPase, from Thermus thermophilus, which is a soluble component consisting of A, B, D and F subunits. The structure at 4.5 A resolution reveals inter-subunit interactions and nucleotide binding. In particular, the structure of the central stalk composed of D and F subunits was shown to be characteristic of V1-ATPases. Small conformational changes of respective subunits and significant rearrangement of the quaternary structure observed in the three AB pairs were related to the interaction with the straight central stalk. The rotation mechanism is discussed based on a structural comparison between V1-ATPases and F1-ATPases. PMID- 19779484 TI - RelA/p65 functions to maintain cellular senescence by regulating genomic stability and DNA repair. AB - Nuclear factor (NF)-kappaB is a positive regulator of tumour development and progression, but how it functions in normal cells leading to oncogenesis is not clear. As cellular senescence has proven to be an intrinsic tumour suppressor mechanism that cells must overcome to establish deregulated growth, we used primary fibroblasts to follow NF-kappaB function in cells transitioning from senescence to subsequent immortalization. Our findings show that RelA/p65(-/-) murine fibroblasts immortalize at considerably faster rates than RelA/p65(+/+) cells. The ability of RelA/p65(-/-) fibroblasts to escape senescence earlier is due to their genomic instability, characterized by high frequencies of DNA mutations, gene deletions and gross chromosomal translocations. This increase in genomic instability is closely related to a compromised DNA repair that occurs in both murine RelA/p65(-/-) fibroblasts and tissues. Significantly, these results can also be duplicated in human fibroblasts lacking NF-kappaB. Altogether, our findings present a fresh perspective on the role of NF-kappaB as a tumour suppressor, which acts in pre-neoplastic cells to maintain cellular senescence by promoting DNA repair and genomic stability. PMID- 19779485 TI - Metabolic syndrome is a significant and independent risk factor for increased arterial stiffness in Japanese subjects. AB - Metabolic syndrome (MetS) has been recognized as a risk factor for cardiovascular disease; however, the impact of MetS on arterial stiffness has not been fully established in the general Japanese population. We analyzed the relationship between MetS and the severity of arterial stiffness using brachial-ankle pulse wave velocity (baPWV) in 2744 male and 358 female subjects aged 38-62 years, adjusted for conventional risk factors and C-reactive protein. The prevalence rates of MetS identified by Japanese criteria were 22.7% (n=624) and 7.8% (n=28) in male and female subjects, respectively. The subjects with MetS had significantly greater mean values of baPWV than those without MetS among both male and female subjects (1444+/-209 vs. 1294+/-165 cm/s in male subjects, P<0.001; 1379+/-151 vs. 1220+/-171 cm/s in female subjects, P<0.001). After adjustment for atherosclerotic variables such as age, smoking habits, total cholesterol and C-reactive protein, the odds ratio (OR) of MetS for increased baPWV was 3.65 in male subjects (95% confidence interval (CI): 2.99-4.47, P<0.001) and 8.02 in female subjects (95% CI: 3.18-20.25 P<0.001). In conclusion, MetS was identified as a significant and independent risk factor for increased arterial stiffness in both the male and female general population in Japan. PMID- 19779486 TI - Uncontrolled hypertension based on morning and evening home blood pressure measurements from the J-HOME study. AB - We evaluated the control condition of morning and evening home blood pressure (BP) and compared patients who had isolated uncontrolled morning hypertension and those who had sustained uncontrolled (morning and evening) hypertension using data from the Japan Home versus Office Blood Pressure Measurement Evaluation study. We evaluated 3303 treated hypertensive patients (mean age, 66.2+/-10.5 years; men, 44.7%) in Japan. We classified patients into controlled hypertension, isolated uncontrolled evening hypertension, isolated uncontrolled morning hypertension and sustained uncontrolled hypertension, based on the cutoff value of 135/85 mm Hg for both morning and evening home BP. Of the 3303 patients evaluated, 24.6% had isolated uncontrolled morning hypertension, and 42.0% had sustained uncontrolled hypertension. Factors associated with isolated uncontrolled morning hypertension included taking evening BP measurement after drinking alcohol or bathing. Factors associated with sustained uncontrolled hypertension were male gender, diabetes mellitus and renal disease. The regimen of antihypertensive medication was more complex in patients with uncontrolled morning hypertension than in controlled hypertension. Determinants of the difference between patients with isolated uncontrolled morning hypertension and those with sustained uncontrolled hypertension were diabetes mellitus, renal disease and lower prevalence in measuring evening BP after drinking alcohol or bathing. More than a half of the treated patients were classified into uncontrolled morning hypertension, which were associated with poorer prognosis. Classification of morning hypertensive patients into groups with or without evening hypertension may be useful for evaluating patients' total cardiovascular disease risk. Physicians should also consider evening BP measuring condition for adequate evaluation of evening BP values. PMID- 19779487 TI - Validity and repeatability of the Vicorder apparatus: a comparison with the SphygmoCor device. AB - Aortic stiffness, an independent predictor of cardiovascular risk and all-cause mortality, can be estimated non-invasively by measuring carotid to femoral (aortic) pulse wave velocity (aPWV). The Vicorder device has been developed to measure aPWV with little operator training in a non-intrusive manner. The aim of this study was to assess the repeatability of aPWV measured with the Vicorder device and to compare aPWV values with those obtained using the SphygmoCor system. Vicorder and SphygmoCor aPWV was assessed in 122 subjects (53+/-18 years, 46 male) using both the manufacturers' and a standardized approach. Vicorder aPWV measurement proved to be highly repeatable (within-subject coefficient of variation 2.8%). Transit time differed significantly between the two devices (mean difference 22+/-9 ms, P<0.001), independent of the different algorithms used to calculate transit time. However, aPWV was similar between the two devices (mean difference 0.31+/-1.54 m s(-1), P<0.001) though with an inherent bias toward lower Vicorder aPWV values at high values of SphygmoCor aPWV. Bias was reduced by subtracting the additional femoral artery segment measured by the Vicorder device, also bringing the measure of transit time in closer agreement to SphygmoCor values (mean difference 5+/-9 ms, P<0.001). Transit time values significantly differed between the two devices and the Vicorder device reported lower aPWV values at higher SphygmoCor values of aPWV. This difference in transit time and inherent bias was reduced when adjustment for the additional femoral artery segment measured by the Vicorder device was made. PMID- 19779488 TI - Enhanced hypertension prevalence in non-Han Chinese minorities from Xinjiang Province, China. AB - Hypertension and its risk factors have been thoroughly investigated in multiple population studies, but little is known about Chinese minorities. In this study, we examined the association of hypertension prevalence with its risk factors in Han and non-Han minorities from Xinjiang Province, China, who have distinct lifestyles. A total of 9551 Han and non-Han Chinese (Han 83.9%, non-Han 16.1%) 17 81-years old participated in this clinical survey and anthropometric screening. Physical examination was performed on each participant, including measurement of systolic and diastolic blood pressure and body mass index (BMI). The prevalence of hypertension in non-Hans was found to be significantly greater than in Hans, in both men (39.92% vs. 28.55%, P<0.001) and women (19.49% vs. 10.29%, P<0.001) among the 36-55-year old age group. BMI was also found to be significantly higher in non-Hans than Hans in men (BMI: 26.54+/-3.23 vs. 24.82+/-2.77 kgm(-2), P<0.001) and women (BMI: 26.92+/-3.20 vs. 24.19+/-3.16 kgm(-2), P<0.001) in the same age group, but not in those <36-years old. Although Han women had normal weights or were slightly overweight (age >36, BMI=22.25-24.19 kgm(-2)), non-Han women from the same age group were found to be severely overweight (ages 36-55, BMI=24.94 kgm(-2), ages >56, BMI=26.92 kgm(-2)). A strong association between increased BMI and hypertension was shown in all ethnic and gender groups. The prevalence of hypertension in overweight (BMI> or =24 kgm(-2)) and obese (BMI> or =28 kgm(-2)), aged (36-81), male, and non-Han participants was significantly greater than in lean (BMI <24 kgm(-2)), young (17-35), female Hans, after adjustment for these variables in a multivariate logistic regression analysis (P<0.001). A high prevalence of hypertension in overweight and obese elderly non Han men suggests that BMI, age, sex and race are important risk factors for hypertension in this Chinese population. PMID- 19779490 TI - Comparison of central blood pressure and cardio-ankle vascular index for association with cardiac function in treated hypertensive patients. AB - Recent automated applanation tonometry can measure radial pulse wave-derived central blood pressure (CBP), which has shown a prognostic value independently of peripheral blood pressure. However, CBP's clinical significance has not been fully established. We examined the associations between CBP and cardiac structure and function by comparing them with those of arterial stiffness assessed by cardio-ankle vascular index (CAVI) in treated hypertensive patients. Enrolled in the study were 102 patients (71+/-7 years) with treated hypertension. The transmitral early-to-atrial velocity ratio (E/A), peak systolic (S'), early diastolic (E') mitral annular velocities and the Tei index were measured as indexes of cardiac function derived from conventional and tissue Doppler echocardiography. Left ventricular mass index (LVMI) was measured as an index of LV hypertrophy. CBP and CAVI were measured just after echocardiographic examination. CBP, but not CAVI, correlated with LVMI (r=0.306, P<0.01). Although CBP correlated only with the Tei index (r=0.201, P<0.05), CAVI correlated with E/A (r=-0.387, P<0.001), S' (r=-0.270, P<0.01), E' (r=-0.362, P<0.01) and the Tei index (r=0.339, P<0.01). Stepwise regression analysis revealed that neither CBP nor CAVI was independently associated with E/A, S' or E'. However, CAVI, but not CBP, was independently associated with the Tei index (beta coefficient=0.311, P<0.001), reflecting both LV systolic and diastolic function. In conclusion, CBP may be suitable for detecting LV hypertrophy. In contrast, CAVI may be suitable for detecting LV dysfunction. This difference, suggesting the clinical value of each parameter, should be kept in mind when we use CBP and CAVI for assessing arteriosclerosis in treated hypertension. PMID- 19779489 TI - Prenatal dehydration alters renin-angiotensin system associated with angiotensin increased blood pressure in young offspring. AB - The renin-angiotensin system (RAS) has an important role in cardiovascular homeostasis. This study determined the influence of water deprivation during pregnancy on the development of the RAS in rats, and examined blood pressure (BP) in the adolescent offspring. Pregnant rats were water deprived for 3 days at late gestation, and we examined fetal cardiac ultrastructure, as well as heart angiotensin (Ang) II receptor protein and mRNA, liver angiotensinogen and plasma Ang II concentrations. We also tested cardiovascular responses to i.v. Ang II in the young offspring. In utero exposure to maternal water deprivation significantly decreased fetal body and heart weight, and increased fetal plasma sodium and osmolality. Fetal liver angiotensinogen mRNA, plasma Ang I and Ang II concentrations were also increased. Although fetal AT(1a) and AT(1b) receptor mRNA and AT(1) protein were not changed, AT(2) receptor mRNA and protein levels in the heart were significantly increased following maternal dehydration. Prenatal exposure to maternal water deprivation had no effect on baseline BP; however, it significantly increased BP in response to i.v. Ang II infusion, and decreased baroreflex sensitivity in the offspring. In addition, the heart AT(2) receptor mRNA and protein were higher in the offspring exposed to prenatal dehydration. The results of this study demonstrate that prenatal dehydration affected the RAS development associated with an Ang II-increased BP in fetal origin. PMID- 19779491 TI - Evaluation of arterial stiffness in morning hypertension under high-dose valsartan compared to valsartan plus low-dose diuretic. AB - Morning hypertension has been reported to be an important risk factor for cardiovascular events, and arterial stiffness bears a relationship with cardiovascular risk. The aim of this study was to evaluate whether high-dose angiotensin II receptor blocker (ARB) treatment has a more beneficial effect on arterial stiffness than regular-dose ARB plus low-dose diuretic treatment in patients with morning hypertension. Forty-three patients, in whom the home systolic blood pressure (BP) in the morning was higher than 140 mm Hg and in the evening was lower than 135 mm Hg, despite treatment with 80 mg valsartan, were randomly assigned to receive 160 mg valsartan (V group, n=22) or 80 mg valsartan plus low-dose trichlormethiazide (1 mg) (V+D group, n=21) for 6 months. There were no differences in the patient background characteristics between the two groups. There were no significant differences in BP measured at home between the two groups. The brachial-ankle pulse wave velocity (baPWV) at the time of diagnosis of morning hypertension was similar in the two groups; however, after 6 months of treatment, a greater degree of reduction of the baPWV and a greater degree of reduction of BP in the supine position were observed in the V group compared with the V+D group. Thus, though both high-dose valsartan and valsartan plus diuretic reduced the BP to a similar degree in patients with morning hypertension, high-dose valsartan exerted a greater beneficial effect on arterial stiffness than did valsartan plus diuretic. PMID- 19779492 TI - p53-mediated apoptosis prevents the accumulation of progenitor B cells and B-cell tumors. AB - We propose that the apoptotic function of p53 has an important role in B-cell homeostasis, which is important for the prevention of B-cell lymphomas. We created a mouse model (mDeltapro) that lacked residues 58-88 of the proline-rich domain of p53. mDeltapro is defective for apoptosis, but is able to arrest cell cycle progression in hematopoietic tissues. mDeltapro develops late-onset B-cell lymphoma, but not the thymic T-cell tumors found in p53-null mice. Interestingly, mDeltapro lymphomas comprised incorrectly differentiated B cells. B-cell irregularities were also detected in mDeltapro before tumor onset, in which aged mice showed an increased population of inappropriately differentiated B cells in the bone marrow and spleen. We predict that by keeping B-cell populations in check, p53-dependent apoptosis prevents irregular B cells from eventuating in lymphomas. PMID- 19779493 TI - Escape from p53-mediated tumor surveillance in neuroblastoma: switching off the p14(ARF)-MDM2-p53 axis. AB - A primary failsafe program against unrestrained proliferation and oncogenesis is provided by the p53 tumor suppressor protein, inactivation of which is considered as a hallmark of cancer. Intriguingly, mutations of the TP53 gene are rarely encountered in neuroblastoma tumors, suggesting that alternative p53-inactivating lesions account for escape from p53 control in this childhood malignancy. Several recent studies have shed light on the mechanisms by which neuroblastoma cells circumvent the p53-driven antitumor barrier. We review here these mechanisms for evasion of p53-mediated growth control and conclude that deregulation of the p14(ARF)-MDM2-p53 axis seems to be the principal mode of p53 inactivation in neuroblastoma, opening new perspectives for targeted therapeutic intervention. PMID- 19779494 TI - Caspase-mediated inhibition of sphingomyelin synthesis is involved in FasL triggered cell death. AB - Ceramide can be converted into sphingomyelin by sphingomyelin synthases (SMS) 1 and 2. In this study, we show that in human leukemia Jurkat cells, which express mainly SMS1, Fas ligand (FasL) treatment inhibited SMS activity in a dose- and time-dependent manner before nuclear fragmentation. The SMS inhibition elicited by FasL (1) was abrogated by benzyloxycarbonyl valyl-alanyl-aspartyl-(O-methyl) fluoromethylketone (zVAD-fmk), a broad-spectrum caspase inhibitor; (2) did not occur in caspase-8-deficient cells and (3) was not affected in caspase-9 deficient cells. Western blot experiments showed SMS1 cleavage in a caspase dependent manner upon FasL treatment. In a cell-free system, caspase-2, -7, -8 and -9, but not caspase-3 and -10, cleaved SMS1. In HeLa cells, SMS1 was Golgi localized and relocated throughout the cytoplasm in cells exhibiting an early apoptotic phenotype on FasL treatment. zVAD-fmk prevented FasL-induced SMS1 relocation. Thus, FasL-mediated SMS1 inhibition and relocation depend on caspase activation and likely represent proximal events in Fas signaling. FasL-induced ceramide production and cell death were enhanced in cells stably expressing an siRNA against SMS1. Conversely, in cells stably overexpressing SMS1, FasL neither increased ceramide generation nor efficiently induced cell death. Altogether, our data show that SMS1 is a novel caspase target that is functionally involved in the regulation of FasL-induced apoptosis. PMID- 19779495 TI - Contrasting patterns of Bim induction and neuroprotection in Bim-deficient mice between hippocampus and neocortex after status epilepticus. AB - Prolonged seizures (status epilepticus) are associated with brain region-specific regulation of apoptosis-associated signaling pathways. Bcl-2 homology domain 3 only (BH3) members of the Bcl-2 gene family are of interest as possible initiators of mitochondrial dysfunction and release of apoptogenic molecules after seizures. Previously, we showed that expression of the BH3-only protein, Bcl-2 interacting mediator of cell death (Bim), increased in the rat hippocampus but not in the neocortex after focal-onset status epilepticus. In this study, we examined Bim expression in mice and compared seizure damage between wild-type and Bim-deficient animals. Status epilepticus induced by intra-amygdala kainic acid (KA) caused extensive neuronal death within the ipsilateral hippocampal CA3 region. Hippocampal activation of factors associated with transcriptional and posttranslational activation of Bim, such as CHOP and c-Jun NH(2)-terminal kinases, was significant within 1 h. Upregulation of bim mRNA was evident after 2 h and Bim protein increased between 4 and 24 h. Hippocampal CA3 neurodegeneration was reduced in Bim-deficient mice compared with wild-type animals after seizures in vivo, and short interfering RNA molecules targeting bim reduced cell death after KA treatment of hippocampal organotypic cultures. In contrast, neocortical Bim expression declined after status epilepticus, and neocortex damage in Bim deficient mice was comparable with that in wild-type animals. These results show region-specific differential contributions of Bim to seizure-induced neuronal death. PMID- 19779496 TI - p27(BBP)/eIF6 acts as an anti-apoptotic factor upstream of Bcl-2 during Xenopus laevis development. AB - p27(BBP)/eIF6 (beta4-binding protein/eukaryotic initiation factor 6) regulates the joining of 40S and 60S ribosomal subunits, on receptor for activated C kinase 1 binding and protein kinase C phosphorylation in serine 235. In Xenopus, p27(BBP)/eIF6 is abundantly expressed in the majority of the embryonic anlagen. Although p27(BBP)/eIF6 abundance may be required for a general regulation of protein synthesis, our data suggest that p27(BBP)/eIF6 may target the translation of specific mRNAs. We injected Xp27(BBP)/eIF6 mRNA in one blastomere of two-cell stage embryos and obtained a bent phenotype, the curvature being lateral with respect to the embryo antero-posterior axis. The injected side had fewer apoptotic cells than the uninjected side, whereas cell proliferation appeared unaffected. Accordingly, in Xp27(BBP)/eIF6 morphants, endogenous apoptosis increased. Injection of Xp27(BBP)/eIF6 point mutants indicated that the anti apoptotic action of Xp27(BBP)/eIF6 requires the conserved S235. The bent phenotype was also obtained with B-cell lymphoma gene-2 (Bcl-2) overexpression and was rescued by Bcl-2-associated X protein (Bax)/Xp27(BBP)/eIF6 co-injection. In addition, embryos overexpressing Xp27(BBP)/eIF6 had a higher amount of Bcl-2 and an unchanged amount of Bax with respect to controls. In Xp27(BBP)/eIF6 morphants, Bcl-2 levels were unaffected and Bax levels were higher than in the controls. Thus, we propose that Xp27(BBP)/eIF6 is part of a mechanism acting on the specific translation of messengers regulating cell survival. In particular, we suggest that Xp27(BBP)/eIF6 may regulate the translation of factors upstream of Bcl-2/Bax. PMID- 19779497 TI - p73 is essential for vitamin D-mediated osteoblastic differentiation. AB - The secosteroid hormone vitamin D3 (VD3) exerts its biological actions through its cognate receptor, the vitamin D receptor (VDR). Vitamin D3 and VDR have a key function in bone formation and keratinocyte differentiation, exert antiproliferative actions in human cancer, and is widely used as a chemotherapeutic agent for cancer. In addition, VD3 promotes differentiation of human osteosarcoma cells by up-regulating genes involved in cell cycle arrest and osteoblastic differentiation. Although considerable work has been carried out in understanding the molecular mechanisms underlying the VD3-mediated differentiation of human osteosarcoma cells, the upstream regulation of VD3 signaling pathway is still unclear. In this study, we show that p73 acts as an upstream regulator of VD3-mediated osteoblastic differentiation. Transcription factor p73, a p53 homolog, has been shown to have a function in development and recently been termed as a tumor suppressor. Silencing p73 results in a significant reduction of VD3-mediated osteoblastic differentiation; although DNA damage induced p73 leads to an increase in VD3-mediated differentiation of osteosarcoma cells. Together, our data implicate a novel function for p73 in vitamin D-mediated differentiation of human osteosarcoma cells. PMID- 19779498 TI - Novel roles for GAPDH in cell death and carcinogenesis. AB - Growing evidence points to the fact that glucose metabolism has a central role in carcinogenesis. Among the enzymes controlling this energy production pathway, glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is of particular interest. Initially identified as a glycolytic enzyme and considered as a housekeeping gene, this enzyme is actually tightly regulated and is involved in numerous cellular functions. Particularly intriguing are recent reports describing GAPDH as a regulator of cell death. However, its role in cell death is unclear; whereas some studies point toward a proapoptotic function, others describe a protective role and suggest its participation in tumor progression. In this study, we highlight recent findings and discuss potential mechanisms through which cells regulate GAPDH to fulfill its diverse functions to influence cell fate. PMID- 19779499 TI - Novel CACNA1S mutation causes autosomal dominant hypokalemic periodic paralysis in a South American family. AB - Hypokalaemic periodic paralysis (HypoPP) is an autosomal dominant disorder, which is characterized by periodic attacks of muscle weakness associated with a decrease in the serum potassium level. A major disease-causing gene for HypoPP has been identified as CACNA1S, which encodes the skeletal muscle calcium channel alpha-subunit with four transmembrane domains (I-IV), each with six transmembrane segments (S1-S6). To date, all CACNA1S mutations identified in HypoPP patients are located within the voltage-sensor S4 segment. In this study we report a novel CACNA1S mutation in a new region of the protein, the S3 segment of domain III. We characterized a four-generation South American family with HypoPP. Genetic analysis identified a novel V876E mutation in all HypoPP patients in the family, but not in normal family members or 160 control people. Clinical analysis indicates that mutation V876E is associated with a severe outcome as characterized by a very early age of onset, complete penetrance and a severe prognosis including death. These results identify a new mutation in CACNA1S and expand the spectrum of CACNA1S mutations associated with HypoPP. PMID- 19779500 TI - Screening and evaluation of new inhibitors of hepatic glucose production. AB - In the course of our screening program for inhibitors of hepatic glucose production in rat hepatoma H4IIE-C3 cells, which were used as model liver cells, five naphtoquinone derivatives-javanicin, solaniol, 9-O-methylfusarubin, 5,10 dihydroxy-1,7-dimethoxy-3-methyl-1H-naphtho[2,3-c]pyran-6,9-dione, 9-O methylbostrycoidin-and vanillin were selected from our natural product library. These naphtoquinone derivatives inhibited hepatic glucose production at IC(50) values of 3.8-29 microM, but showed cytotoxicity against hepatic cells after incubation for 48 h. However, vanillin showed an IC(50) value of 32 microM without exhibiting cytotoxicity at 50 microM. Therefore, we examined 12 vanillin derivatives to investigate their inhibitory activities against glucose production. Among these analogs, 4-hydro-3-methoxyacetophenone and 5 nitrosalicylaldehyde exhibited stronger inhibition than the other compounds at IC(50) values of 25 and 24 microM, respectively, with no cytotoxicity at a concentration of 50 microM. Hence, 4-hydro-3-methoxyacetophenone and 5 nitrosalicylaldehyde may be useful as a lead compound of anti-type 2 diabetic drugs. PMID- 19779501 TI - Evaluation of in vivo denture plaque assessment methods. AB - BACKGROUND: Measurement and assessment of denture plaque can provide valuable information regarding an individual's oral health status and assessment of new treatments or products. Current methods tend to rely on subjective indices or image analysis derived planimetric (area measurement) assessment of stained plaque on dentures. Plaque indices are most commonly used to assess plaque coverage without image capture. This is not ideal because the methods are subjective, examiner bias may occur, there is no reproducibility between studies, the methods have lower accuracy and sensitivity than image analysis, and there is no record. To the authors' knowledge, no standardised published method of denture plaque assessment is currently employed for product development and testing. METHOD: In this study visual and planimetric plaque assessment methods were compared using reference dentures. In addition, an in vivo study compared these methods for evaluating denture cleanser efficacy. RESULTS AND CONCLUSIONS: The results show that blinded image scoring is more representative of the true plaque area coverage than 'live' denture scoring, detecting significant decreases in plaque coverage. Planimetric analysis provides a more sensitive and less subjective technique with greater differentiation between treatments. However, analysis is very time consuming. Thus, a number of recommendations are made regarding quantification of denture plaque for the assessment of cleanser products. PMID- 19779502 TI - Over here and over there. PMID- 19779503 TI - Ethical dental age assessment. PMID- 19779504 TI - All in her head. PMID- 19779505 TI - Submucous cleft palate. PMID- 19779515 TI - Digital dental photography. Part 10: printing, publishing and presentations. AB - The final part of this series on digital dental photography details how to use images to their maximum potential. The purpose and uses of dental photography have previously been covered in Part 2, and the ensuing discussion concentrates on the technical aspects of printing, publishing and audio-visual presentations. PMID- 19779516 TI - A national study of cross infection control: 'are we clean enough?'. AB - OBJECTIVE: To establish what cross infection control policies and procedures are in place within UK orthodontic departments and how they compare with recommended guidelines. DESIGN: A hospital-based cross-sectional study investigating UK orthodontic departments between March 2007 and January 2008. SUBJECTS AND METHODS: The main outcome measure was a questionnaire constructed for the study, based on current cross infection control guidelines. All orthodontic departments within district general hospitals were invited to participate via email and the response rate was 48%. RESULTS: Five key areas were explored, which included a) training, education and personal protection, b) the clinical environment, c) decontamination of instruments, d) decontamination of appliances and impressions and e) disposal of waste. Ninety-eight percent of departments provided training in cross infection control and 98% also had a policy to check staff immunisation status. With respect to the clinical environment, 97% of the departments surveyed had separate 'clean' and 'dirty' zones. Half of all departments used central sterile services departments (CSSD) for instrument sterilisation. Seventy-eight percent of departments had a policy to decontaminate impressions/appliances at the chairside and all departments used 'yellow bags' for clinical waste and puncture-proof containers for sharps waste. CONCLUSIONS: UK orthodontic departments have implemented policies and procedures which would ensure a high standard of cross infection control. In particular, this related to the decontamination of surfaces and instruments, the use of personal protection and disposal of clinical waste. Most departments had policies and procedures in place for staff education and training in cross infection control and personal protection. PMID- 19779517 TI - Should we screen for hypertension in general dental practice? AB - Hypertension is reported by the World Health Organisation as one of the most important causes of premature morbidity and mortality, although it is often asymptomatic. Approximately 40% of the UK population are thought to be affected, however, only one third of these are currently detected. Dental practice offers an ideal opportunity to screen for hypertension, due to the large cohort of the general population who regularly attend. A pilot study was carried out to screen for hypertension and associated risk factors in 114 consecutive patients who attended a city general dental practice. Results revealed that 39% (44) of the population screened had a high blood pressure reading but only 18% (8) of these were previously diagnosed as hypertensive, and 16% (7) had systolic readings greater than 160 mmHg. Of those currently receiving treatment for hypertension, the blood pressure was still elevated in 63% (5). This suggests that screening for hypertension in general dental practice may be of benefit to the population at large. PMID- 19779524 TI - Evaluation of a course on the operation and management of a local decontamination unit for undergraduate dental students. AB - OBJECTIVE: Describe the formulation of learning outcomes and evaluate a new course for undergraduate dental students in managing a local decontamination unit (LDU). DESIGN, SAMPLE AND SETTING: This was a retrospective analysis of questionnaire data from the first cohort of dental students completing the LDU managers course in a UK dental school. METHODS: All final year dental students were invited to complete a course evaluation. Data were collated via an anonymous semi-structured questionnaire distributed at a post-course session. RESULTS: A response rate of 95% was achieved. The majority (89%) improved their knowledge of decontamination and felt that the course material was relevant (81%) to their future role as a dental practitioner. Students stated that the practical elements of the course provided a valuable educational experience, while tutorials on health and safety and quality management systems proved less popular. The use of an e-learning programme to support the lectures and practical sessions was also useful in achieving the learning outcomes. The one-week intensive course proved challenging for both students and staff. We identified short comings both locally and nationally in the availability of appropriately trained staff to teach this core topic. CONCLUSION: We describe a series of learning outcomes to support competencies in instrument decontamination for dental undergraduates and a purpose built training facility. The evaluation of the course suggests this model meets current and future General Dental Council (GDC) requirements for training of dental undergraduates. We identified a shortage of appropriately qualified teachers in this subject area and recommend that these deficiencies are addressed as part of a coordinated national strategy. PMID- 19779542 TI - A genome-wide association analysis identified a novel susceptible locus for pathological myopia at 11q24.1. AB - Myopia is one of the most common ocular disorders worldwide. Pathological myopia, also called high myopia, comprises 1% to 5% of the general population and is one of the leading causes of legal blindness in developed countries. To identify genetic determinants associated with pathological myopia in Japanese, we conducted a genome-wide association study, analyzing 411,777 SNPs with 830 cases and 1,911 general population controls in a two-stage design (297 cases and 934 controls in the first stage and 533 cases and 977 controls in the second stage). We selected 22 SNPs that showed P-values smaller than 10(-4) in the first stage and tested them for association in the second stage. The meta-analysis combining the first and second stages identified an SNP, rs577948, at chromosome 11q24.1, which was associated with the disease (P = 2.22x10(-7) and OR of 1.37 with 95% confidence interval: 1.21-1.54). Two genes, BLID and LOC399959, were identified within a 200-kb DNA encompassing rs577948. RT-PCR analysis demonstrated that both genes were expressed in human retinal tissue. Our results strongly suggest that the region at 11q24.1 is a novel susceptibility locus for pathological myopia in Japanese. PMID- 19779543 TI - Conserved expression patterns predict microRNA targets. AB - microRNAs (miRNAs) are major regulators of gene expression and thereby modulate many biological processes. Computational methods have been instrumental in understanding how miRNAs bind to mRNAs to induce their repression but have proven inaccurate. Here we describe a novel method that combines expression data from human and mouse to discover conserved patterns of expression between orthologous miRNAs and mRNA genes. This method allowed us to predict thousands of putative miRNA targets. Using the luciferase reporter assay, we confirmed 4 out of 6 of our predictions. In addition, this method predicted many miRNAs that act as expression enhancers. We show that many miRNA enhancer effects are mediated through the repression of negative transcriptional regulators and that this effect could be as common as the widely reported repression activity of miRNAs. Our findings suggest that the indirect enhancement of gene expression by miRNAs could be an important component of miRNA regulation that has been widely neglected to date. PMID- 19779544 TI - Brief overview of bioinformatics activities in Singapore. PMID- 19779545 TI - A novel scoring approach for protein co-purification data reveals high interaction specificity. AB - Large-scale protein interaction networks (PINs) have typically been discerned using affinity purification followed by mass spectrometry (AP/MS) and yeast two hybrid (Y2H) techniques. It is generally recognized that Y2H screens detect direct binary interactions while the AP/MS method captures co-complex associations; however, the latter technique is known to yield prevalent false positives arising from a number of effects, including abundance. We describe a novel approach to compute the propensity for two proteins to co-purify in an AP/MS data set, thereby allowing us to assess the detected level of interaction specificity by analyzing the corresponding distribution of interaction scores. We find that two recent AP/MS data sets of yeast contain enrichments of specific, or high-scoring, associations as compared to commensurate random profiles, and that curated, direct physical interactions in two prominent data bases have consistently high scores. Our scored interaction data sets are generally more comprehensive than those of previous studies when compared against four diverse, high-quality reference sets. Furthermore, we find that our scored data sets are more enriched with curated, direct physical associations than Y2H sets. A high confidence protein interaction network (PIN) derived from the AP/MS data is revealed to be highly modular, and we show that this topology is not the result of misrepresenting indirect associations as direct interactions. In fact, we propose that the modularity in Y2H data sets may be underrepresented, as they contain indirect associations that are significantly enriched with false negatives. The AP/MS PIN is also found to contain significant assortative mixing; however, in line with a previous study we confirm that Y2H interaction data show weak disassortativeness, thus revealing more clearly the distinctive natures of the interaction detection methods. We expect that our scored yeast data sets are ideal for further biological discovery and that our scoring system will prove useful for other AP/MS data sets. PMID- 19779547 TI - Ten simple rules for chairing a scientific session. PMID- 19779546 TI - Imprinting of the polycomb group gene MEDEA serves as a ploidy sensor in Arabidopsis. AB - Balanced maternal and paternal genome contributions are a requirement for successful seed development. Unbalanced contributions often cause seed abortion, a phenomenon that has been termed "triploid block." Misregulation of imprinted regulatory genes has been proposed to be the underlying cause for abnormalities in growth and structure of the endosperm in seeds with deviating parental contributions. We identified a mutant forming unreduced pollen that enabled us to investigate direct effects of unbalanced parental genome contributions on seed development and to reveal the underlying molecular mechanism of dosage sensitivity. We provide evidence that parent-of-origin-specific expression of the Polycomb group (PcG) gene MEDEA is causally responsible for seed developmental aberrations in Arabidopsis seeds with increased paternal genome contributions. We propose that imprinted expression of PcG genes is an evolutionary conserved mechanism to balance parental genome contributions in embryo nourishing tissues. PMID- 19779548 TI - A computational analysis of ATP binding of SV40 large tumor antigen helicase motor. AB - Simian virus 40 large tumor antigen (LTag) is an efficient helicase motor that unwinds and translocates DNA. The DNA unwinding and translocation of LTag is powered by ATP binding and hydrolysis at the nucleotide pocket between two adjacent subunits of an LTag hexamer. Based on the set of high-resolution hexameric structures of LTag helicase in different nucleotide binding states, we simulated a conformational transition pathway of the ATP binding process using the targeted molecular dynamics method and calculated the corresponding energy profile using the linear response approximation (LRA) version of the semi macroscopic Protein Dipoles Langevin Dipoles method (PDLD/S). The simulation results suggest a three-step process for the ATP binding from the initial interaction to the final tight binding at the nucleotide pocket, in which ATP is eventually "locked" by three pairs of charge-charge interactions across the pocket. Such a "cross-locking" ATP binding process is similar to the binding zipper model reported for the F1-ATPase hexameric motor. The simulation also shows a transition mechanism of Mg2+ coordination to form the Mg-ATP complex during ATP binding, which is accompanied by the large conformational changes of LTag. This simulation study of the ATP binding process to an LTag and the accompanying conformational changes in the context of a hexamer leads to a refined cooperative iris model that has been proposed previously. PMID- 19779549 TI - Disease-aging network reveals significant roles of aging genes in connecting genetic diseases. AB - One of the challenging problems in biology and medicine is exploring the underlying mechanisms of genetic diseases. Recent studies suggest that the relationship between genetic diseases and the aging process is important in understanding the molecular mechanisms of complex diseases. Although some intricate associations have been investigated for a long time, the studies are still in their early stages. In this paper, we construct a human disease-aging network to study the relationship among aging genes and genetic disease genes. Specifically, we integrate human protein-protein interactions (PPIs), disease gene associations, aging-gene associations, and physiological system-based genetic disease classification information in a single graph-theoretic framework and find that (1) human disease genes are much closer to aging genes than expected by chance; and (2) diseases can be categorized into two types according to their relationships with aging. Type I diseases have their genes significantly close to aging genes, while type II diseases do not. Furthermore, we examine the topological characters of the disease-aging network from a systems perspective. Theoretical results reveal that the genes of type I diseases are in a central position of a PPI network while type II are not; (3) more importantly, we define an asymmetric closeness based on the PPI network to describe relationships between diseases, and find that aging genes make a significant contribution to associations among diseases, especially among type I diseases. In conclusion, the network-based study provides not only evidence for the intricate relationship between the aging process and genetic diseases, but also biological implications for prying into the nature of human diseases. PMID- 19779550 TI - Statistical use of argonaute expression and RISC assembly in microRNA target identification. AB - MicroRNAs (miRNAs) posttranscriptionally regulate targeted messenger RNAs (mRNAs) by inducing cleavage or otherwise repressing their translation. We address the problem of detecting m/miRNA targeting relationships in homo sapiens from microarray data by developing statistical models that are motivated by the biological mechanisms used by miRNAs. The focus of our modeling is the construction, activity, and mediation of RNA-induced silencing complexes (RISCs) competent for targeted mRNA cleavage. We demonstrate that regression models accommodating RISC abundance and controlling for other mediating factors fit the expression profiles of known target pairs substantially better than models based on m/miRNA expressions alone, and lead to verifications of computational target pair predictions that are more sensitive than those based on marginal expression levels. Because our models are fully independent of exogenous results from sequence-based computational methods, they are appropriate for use as either a primary or secondary source of information regarding m/miRNA target pair relationships, especially in conjunction with high-throughput expression studies. PMID- 19779551 TI - An RNA transport system in Candida albicans regulates hyphal morphology and invasive growth. AB - Localization of specific mRNAs is an important mechanism through which cells achieve polarity and direct asymmetric growth. Based on a framework established in Saccharomyces cerevisiae, we describe a She3-dependent RNA transport system in Candida albicans, a fungal pathogen of humans that grows as both budding (yeast) and filamentous (hyphal and pseudohyphal) forms. We identify a set of 40 mRNAs that are selectively transported to the buds of yeast-form cells and to the tips of hyphae, and we show that many of the genes encoded by these mRNAs contribute to hyphal development, as does the transport system itself. Although the basic system of mRNA transport is conserved between S. cerevisiae and C. albicans, we find that the cargo mRNAs have diverged considerably, implying that specific mRNAs can easily move in and out of transport control over evolutionary timescales. The differences in mRNA cargos likely reflect the distinct selective pressures acting on the two species. PMID- 19779552 TI - Balancing selection of a frame-shift mutation in the MRC2 gene accounts for the outbreak of the Crooked Tail Syndrome in Belgian Blue Cattle. AB - We herein describe the positional identification of a 2-bp deletion in the open reading frame of the MRC2 receptor causing the recessive Crooked Tail Syndrome in cattle. The resulting frame-shift reveals a premature stop codon that causes nonsense-mediated decay of the mutant messenger RNA, and the virtual absence of functional Endo180 protein in affected animals. Cases exhibit skeletal anomalies thought to result from impaired extracellular matrix remodeling during ossification, and as of yet unexplained muscular symptoms. We demonstrate that carrier status is very significantly associated with desired characteristics in the general population, including enhanced muscular development, and that the resulting heterozygote advantage caused a selective sweep which explains the unexpectedly high frequency (25%) of carriers in the Belgian Blue Cattle Breed. PMID- 19779553 TI - Notch is a critical component of the mouse somitogenesis oscillator and is essential for the formation of the somites. AB - Segmentation of the vertebrate body axis is initiated through somitogenesis, whereby epithelial somites bud off in pairs periodically from the rostral end of the unsegmented presomitic mesoderm (PSM). The periodicity of somitogenesis is governed by a molecular oscillator that drives periodic waves of clock gene expression caudo-rostrally through the PSM with a periodicity that matches somite formation. To date the clock genes comprise components of the Notch, Wnt, and FGF pathways. The literature contains controversial reports as to the absolute role(s) of Notch signalling during the process of somite formation. Recent data in the zebrafish have suggested that the only role of Notch signalling is to synchronise clock gene oscillations across the PSM and that somite formation can continue in the absence of Notch activity. However, it is not clear in the mouse if an FGF/Wnt-based oscillator is sufficient to generate segmented structures, such as the somites, in the absence of all Notch activity. We have investigated the requirement for Notch signalling in the mouse somitogenesis clock by analysing embryos carrying a mutation in different components of the Notch pathway, such as Lunatic fringe (Lfng), Hes7, Rbpj, and presenilin1/presenilin2 (Psen1/Psen2), and by pharmacological blocking of the Notch pathway. In contrast to the fish studies, we show that mouse embryos lacking all Notch activity do not show oscillatory activity, as evidenced by the absence of waves of clock gene expression across the PSM, and they do not develop somites. We propose that, at least in the mouse embryo, Notch activity is absolutely essential for the formation of a segmented body axis. PMID- 19779554 TI - Chemically based mathematical model for development of cerebral cortical folding patterns. AB - The mechanism for cortical folding pattern formation is not fully understood. Current models represent scenarios that describe pattern formation through local interactions, and one recent model is the intermediate progenitor model. The intermediate progenitor (IP) model describes a local chemically driven scenario, where an increase in intermediate progenitor cells in the subventricular zone correlates to gyral formation. Here we present a mathematical model that uses features of the IP model and further captures global characteristics of cortical pattern formation. A prolate spheroidal surface is used to approximate the ventricular zone. Prolate spheroidal harmonics are applied to a Turing reaction diffusion system, providing a chemically based framework for cortical folding. Our model reveals a direct correlation between pattern formation and the size and shape of the lateral ventricle. Additionally, placement and directionality of sulci and the relationship between domain scaling and cortical pattern elaboration are explained. The significance of this model is that it elucidates the consistency of cortical patterns among individuals within a species and addresses inter-species variability based on global characteristics and provides a critical piece to the puzzle of cortical pattern formation. PMID- 19779555 TI - Bayesian phylogeography finds its roots. AB - As a key factor in endemic and epidemic dynamics, the geographical distribution of viruses has been frequently interpreted in the light of their genetic histories. Unfortunately, inference of historical dispersal or migration patterns of viruses has mainly been restricted to model-free heuristic approaches that provide little insight into the temporal setting of the spatial dynamics. The introduction of probabilistic models of evolution, however, offers unique opportunities to engage in this statistical endeavor. Here we introduce a Bayesian framework for inference, visualization and hypothesis testing of phylogeographic history. By implementing character mapping in a Bayesian software that samples time-scaled phylogenies, we enable the reconstruction of timed viral dispersal patterns while accommodating phylogenetic uncertainty. Standard Markov model inference is extended with a stochastic search variable selection procedure that identifies the parsimonious descriptions of the diffusion process. In addition, we propose priors that can incorporate geographical sampling distributions or characterize alternative hypotheses about the spatial dynamics. To visualize the spatial and temporal information, we summarize inferences using virtual globe software. We describe how Bayesian phylogeography compares with previous parsimony analysis in the investigation of the influenza A H5N1 origin and H5N1 epidemiological linkage among sampling localities. Analysis of rabies in West African dog populations reveals how virus diffusion may enable endemic maintenance through continuous epidemic cycles. From these analyses, we conclude that our phylogeographic framework will make an important asset in molecular epidemiology that can be easily generalized to infer biogeogeography from genetic data for many organisms. PMID- 19779557 TI - Wonderful life: an interview with Herb Boyer. [Interview by Jane Gitschier]. PMID- 19779556 TI - Network-state modulation of power-law frequency-scaling in visual cortical neurons. AB - Various types of neural-based signals, such as EEG, local field potentials and intracellular synaptic potentials, integrate multiple sources of activity distributed across large assemblies. They have in common a power-law frequency scaling structure at high frequencies, but it is still unclear whether this scaling property is dominated by intrinsic neuronal properties or by network activity. The latter case is particularly interesting because if frequency scaling reflects the network state it could be used to characterize the functional impact of the connectivity. In intracellularly recorded neurons of cat primary visual cortex in vivo, the power spectral density of V(m) activity displays a power-law structure at high frequencies with a fractional scaling exponent. We show that this exponent is not constant, but depends on the visual statistics used to drive the network. To investigate the determinants of this frequency-scaling, we considered a generic recurrent model of cortex receiving a retinotopically organized external input. Similarly to the in vivo case, our in computo simulations show that the scaling exponent reflects the correlation level imposed in the input. This systematic dependence was also replicated at the single cell level, by controlling independently, in a parametric way, the strength and the temporal decay of the pairwise correlation between presynaptic inputs. This last model was implemented in vitro by imposing the correlation control in artificial presynaptic spike trains through dynamic-clamp techniques. These in vitro manipulations induced a modulation of the scaling exponent, similar to that observed in vivo and predicted in computo. We conclude that the frequency-scaling exponent of the V(m) reflects stimulus-driven correlations in the cortical network activity. Therefore, we propose that the scaling exponent could be used to read-out the "effective" connectivity responsible for the dynamical signature of the population signals measured at different integration levels, from Vm to LFP, EEG and fMRI. PMID- 19779558 TI - Five questions about microsporidia. PMID- 19779559 TI - Bacillus anthracis lethal toxin disrupts TCR signaling in CD1d-restricted NKT cells leading to functional anergy. AB - Exogenous CD1d-binding glycolipid (alpha-Galactosylceramide, alpha-GC) stimulates TCR signaling and activation of type-1 natural killer-like T (NKT) cells. Activated NKT cells play a central role in the regulation of adaptive and protective immune responses against pathogens and tumors. In the present study, we tested the effect of Bacillus anthracis lethal toxin (LT) on NKT cells both in vivo and in vitro. LT is a binary toxin known to suppress host immune responses during anthrax disease and intoxicates cells by protective antigen (PA)-mediated intracellular delivery of lethal factor (LF), a potent metalloprotease. We observed that NKT cells expressed anthrax toxin receptors (CMG-2 and TEM-8) and bound more PA than other immune cell types. A sub-lethal dose of LT administered in vivo in C57BL/6 mice decreased expression of the activation receptor NKG2D by NKT cells but not by NK cells. The in vivo administration of LT led to decreased TCR-induced cytokine secretion but did not affect TCR expression. Further analysis revealed LT-dependent inhibition of TCR-stimulated MAP kinase signaling in NKT cells attributable to LT cleavage of the MAP kinase kinase MEK-2. We propose that Bacillus anthracis-derived LT causes a novel form of functional anergy in NKT cells and therefore has potential for contributing to immune evasion by the pathogen. PMID- 19779560 TI - Molecular phylodynamics of the heterosexual HIV epidemic in the United Kingdom. AB - The heterosexual risk group has become the largest HIV infected group in the United Kingdom during the last 10 years, but little is known of the network structure and dynamics of viral transmission in this group. The overwhelming majority of UK heterosexual infections are of non-B HIV subtypes, indicating viruses originating among immigrants from sub-Saharan Africa. The high rate of HIV evolution, combined with the availability of a very high density sample of viral sequences from routine clinical care has allowed the phylodynamics of the epidemic to be investigated for the first time. Sequences of the viral protease and partial reverse transcriptase coding regions from 11,071 patients infected with HIV of non-B subtypes were studied. Of these, 2774 were closely linked to at least one other sequence by nucleotide distance. Including the closest sequences from the global HIV database identified 296 individuals that were in UK-based groups of 3 or more individuals. There were a total of 8 UK-based clusters of 10 or more, comprising 143/2774 (5%) individuals, much lower than the figure of 25% obtained earlier for men who have sex with men (MSM). Sample dates were incorporated into relaxed clock phylogenetic analyses to estimate the dates of internal nodes. From the resulting time-resolved phylogenies, the internode lengths, used as estimates of maximum transmission intervals, had a median of 27 months overall, over twice as long as obtained for MSM (14 months), with only 2% of transmissions occurring in the first 6 months after infection. This phylodynamic analysis of non-B subtype HIV sequences representing over 40% of the estimated UK HIV-infected heterosexual population has revealed heterosexual HIV transmission in the UK is clustered, but on average in smaller groups and is transmitted with slower dynamics than among MSM. More effective intervention to restrict the epidemic may therefore be feasible, given effective diagnosis programmes. PMID- 19779561 TI - Selective inhibition of type III secretion activated signaling by the Salmonella effector AvrA. AB - Salmonella enterica utilizes a type III secretion system (TTSS) encoded in its pathogenicity island 1 to mediate its initial interactions with intestinal epithelial cells, which are characterized by the stimulation of actin cytoskeleton reorganization and a profound reprogramming of gene expression. These responses result from the stimulation of Rho-family GTPases and downstream signaling pathways by specific effector proteins delivered by this TTSS. We show here that AvrA, an effector protein of this TTSS, specifically inhibits the Salmonella-induced activation of the JNK pathway through its interaction with MKK7, although it does not interfere with the bacterial infection-induced NF kappaB activation. We also show that AvrA is phosphorylated at evolutionary conserved residues by a TTSS-effector-activated ERK pathway. This interplay between effector proteins delivered by the same TTSS highlights the remarkable complexity of these systems. PMID- 19779562 TI - Streptococcus pneumoniae serotype 1 capsular polysaccharide induces CD8CD28 regulatory T lymphocytes by TCR crosslinking. AB - Zwitterionic capsular polysaccharides (ZPS) of commensal bacteria are characterized by having both positive and negative charged substituents on each repeating unit of a highly repetitive structure that has an alpha-helix configuration. In this paper we look at the immune response of CD8(+) T cells to ZPSs. Intraperitoneal application of the ZPS Sp1 from Streptococcus pneumoniae serotype 1 induces CD8(+)CD28(-) T cells in the spleen and peritoneal cavity of WT mice. However, chemically modified Sp1 (mSp1) without the positive charge and resembling common negatively charged polysaccharides fails to induce CD8(+)CD28( ) T lymphocytes. The Sp1-induced CD8(+)CD28(-) T lymphocytes are CD122(low)CTLA 4(+)CD39(+). They synthesize IL-10 and TGF-beta. The Sp1-induced CD8(+)CD28(-) T cells exhibit immunosuppressive properties on CD4(+) T cells in vivo and in vitro. Experimental approaches to elucidate the mechanism of CD8(+) T cell activation by Sp1 demonstrate in a dimeric MHC class I-Ig model that Sp1 induces CD8(+) T cell activation by enhancing crosslinking of TCR. The expansion of CD8(+)CD28(-) T cells is independent, of direct antigen-presenting cell/T cell contact and, to the specificity of the T cell receptor (TCR). In CD8(+)CD28(-) T cells, Sp1 enhances Zap-70 phosphorylation and increasingly involves NF-kappaB which ultimately results in protection versus apoptosis and cell death and promotes survival and accumulation of the CD8(+)CD28(-) population. This is the first description of a naturally occurring bacterial antigen that is able to induce suppressive CD8(+)CD28(-) T lymphocytes in vivo and in vitro. The underlying mechanism of CD8(+) T cell activation appears to rely on enhanced TCR crosslinking. The data provides evidence that ZPS of commensal bacteria play an important role in peripheral tolerance mechanisms and the maintenance of the homeostasis of the immune system. PMID- 19779563 TI - Intraspecific epitopic variation in a carbohydrate antigen exposed on the surface of Trichostrongylus colubriformis infective L3 larvae. AB - The carbohydrate larval antigen, CarLA, is present on the exposed surface of all strongylid nematode infective L3 larvae tested, and antibodies against CarLA can promote rapid immune rejection of incoming Trichostrongylus colubriformis larvae in sheep. A library of ovine recombinant single chain Fv (scFv) antibody fragments, displayed on phage, was prepared from B cell mRNA of field-immune sheep. Phage displaying scFvs that bind to the surface of living exsheathed T. colubriformis L3 larvae were identified, and the majority of worm-binding scFvs recognized CarLA. Characterization of greater than 500 worm surface binding phage resulted in the identification of nine different anti-CarLA scFvs that recognized three distinct T. colubriformis CarLA epitopes based on blocking and additive ELISA. All anti-CarLA scFvs were specific to the T. colubriformis species of nematode. Each of the three scFv epitope classes displayed identical Western blot recognition patterns and recognized the exposed surface of living T. colubriformis exsheathed L3 larvae. Surprisingly, each of the anti-CarLA scFvs was able to bind to only a subset of worms. Double-labelling indirect immunofluorescence revealed that the three classes of anti-CarLA scFvs recognize distinct, non-overlapping, T. colubriformis sub-populations. These results demonstrate that individual T. colubriformis L3 larvae display only one of at least three distinct antigenic forms of CarLA on their surface at any given time, and suggest that antigenic variation within CarLA is likely a mechanism of immune evasion in strongylid nematodes. PMID- 19779564 TI - A cyclic GMP signalling module that regulates gliding motility in a malaria parasite. AB - The ookinete is a motile stage in the malaria life cycle which forms in the mosquito blood meal from the zygote. Ookinetes use an acto-myosin motor to glide towards and penetrate the midgut wall to establish infection in the vector. The regulation of gliding motility is poorly understood. Through genetic interaction studies we here describe a signalling module that identifies guanosine 3', 5' cyclic monophosphate (cGMP) as an important second messenger regulating ookinete differentiation and motility. In ookinetes lacking the cyclic nucleotide degrading phosphodiesterase delta (PDEdelta), unregulated signalling through cGMP results in rounding up of the normally banana-shaped cells. This phenotype is suppressed in a double mutant additionally lacking guanylyl cyclase beta (GCbeta), showing that in ookinetes GCbeta is an important source for cGMP, and that PDEdelta is the relevant cGMP degrading enzyme. Inhibition of the cGMP dependent protein kinase, PKG, blocks gliding, whereas enhanced signalling through cGMP restores normal gliding speed in a mutant lacking calcium dependent protein kinase 3, suggesting at least a partial overlap between calcium and cGMP dependent pathways. These data demonstrate an important function for signalling through cGMP, and most likely PKG, in dynamically regulating ookinete gliding during the transmission of malaria to the mosquito. PMID- 19779565 TI - Enterovirus 71 3C protease cleaves a novel target CstF-64 and inhibits cellular polyadenylation. AB - Identification of novel cellular proteins as substrates to viral proteases would provide a new insight into the mechanism of cell-virus interplay. Eight nuclear proteins as potential targets for enterovirus 71 (EV71) 3C protease (3C(pro)) cleavages were identified by 2D electrophoresis and MALDI-TOF analysis. Of these proteins, CstF-64, which is a critical factor for 3' pre-mRNA processing in a cell nucleus, was selected for further study. A time-course study to monitor the expression levels of CstF-64 in EV71-infected cells also revealed that the reduction of CstF-64 during virus infection was correlated with the production of viral 3C(pro). CstF-64 was cleaved in vitro by 3C(pro) but neither by mutant 3C(pro) (in which the catalytic site was inactivated) nor by another EV71 protease 2A(pro). Serial mutagenesis was performed in CstF-64, revealing that the 3C(pro) cleavage sites are located at position 251 in the N-terminal P/G-rich domain and at multiple positions close to the C-terminus of CstF-64 (around position 500). An accumulation of unprocessed pre-mRNA and the depression of mature mRNA were observed in EV71-infected cells. An in vitro assay revealed the inhibition of the 3'-end pre-mRNA processing and polyadenylation in 3C(pro) treated nuclear extract, and this impairment was rescued by adding purified recombinant CstF-64 protein. In summing up the above results, we suggest that 3C(pro) cleavage inactivates CstF-64 and impairs the host cell polyadenylation in vitro, as well as in virus-infected cells. This finding is, to our knowledge, the first to demonstrate that a picornavirus protein affects the polyadenylation of host mRNA. PMID- 19779566 TI - Axon-myelin interactions during a viral infection of the central nervous system. PMID- 19779568 TI - Ion-abrasion scanning electron microscopy reveals surface-connected tubular conduits in HIV-infected macrophages. AB - HIV-1-containing internal compartments are readily detected in images of thin sections from infected cells using conventional transmission electron microscopy, but the origin, connectivity, and 3D distribution of these compartments has remained controversial. Here, we report the 3D distribution of viruses in HIV-1 infected primary human macrophages using cryo-electron tomography and ion abrasion scanning electron microscopy (IA-SEM), a recently developed approach for nanoscale 3D imaging of whole cells. Using IA-SEM, we show the presence of an extensive network of HIV-1-containing tubular compartments in infected macrophages, with diameters of approximately 150-200 nm, and lengths of up to approximately 5 microm that extend to the cell surface from vesicular compartments that contain assembling HIV-1 virions. These types of surface connected tubular compartments are not observed in T cells infected with the 29/31 KE Gag-matrix mutant where the virus is targeted to multi-vesicular bodies and released into the extracellular medium. IA-SEM imaging also allows visualization of large sheet-like structures that extend outward from the surfaces of macrophages, which may bend and fold back to allow continual creation of viral compartments and virion-lined channels. This potential mechanism for efficient virus trafficking between the cell surface and interior may represent a subversion of pre-existing vesicular machinery for antigen capture, processing, sequestration, and presentation. PMID- 19779567 TI - TbPIF5 is a Trypanosoma brucei mitochondrial DNA helicase involved in processing of minicircle Okazaki fragments. AB - Trypanosoma brucei's mitochondrial genome, kinetoplast DNA (kDNA), is a giant network of catenated DNA rings. The network consists of a few thousand 1 kb minicircles and several dozen 23 kb maxicircles. Here we report that TbPIF5, one of T. brucei's six mitochondrial proteins related to Saccharomyces cerevisiae mitochondrial DNA helicase ScPIF1, is involved in minicircle lagging strand synthesis. Like its yeast homolog, TbPIF5 is a 5' to 3' DNA helicase. Together with other enzymes thought to be involved in Okazaki fragment processing, TbPIF5 localizes in vivo to the antipodal sites flanking the kDNA. Minicircles in wild type cells replicate unidirectionally as theta-structures and are unusual in that Okazaki fragments are not joined until after the progeny minicircles have segregated. We now report that overexpression of TbPIF5 causes premature removal of RNA primers and joining of Okazaki fragments on theta structures. Further elongation of the lagging strand is blocked, but the leading strand is completed and the minicircle progeny, one with a truncated H strand (ranging from 0.1 to 1 kb), are segregated. The minicircles with a truncated H strand electrophorese on an agarose gel as a smear. This replication defect is associated with kinetoplast shrinkage and eventual slowing of cell growth. We propose that TbPIF5 unwinds RNA primers after lagging strand synthesis, thus facilitating processing of Okazaki fragments. PMID- 19779569 TI - A screen for spore wall permeability mutants identifies a secreted protease required for proper spore wall assembly. AB - The ascospores of Saccharomyces cerevisiae are surrounded by a complex wall that protects the spores from environmental stresses. The outermost layer of the spore wall is composed of a polymer that contains the cross-linked amino acid dityrosine. This dityrosine layer is important for stress resistance of the spore. This work reports that the dityrosine layer acts as a barrier blocking the diffusion of soluble proteins out of the spore wall into the cytoplasm of the ascus. Diffusion of a fluorescent protein out of the spore wall was used as an assay to screen for mutants affecting spore wall permeability. One of the genes identified in this screen, OSW3 (RRT12/YCR045c), encodes a subtilisin-family protease localized to the spore wall. Mutation of the active site serine of Osw3 results in spores with permeable walls, indicating that the catalytic activity of Osw3 is necessary for proper construction of the dityrosine layer. These results indicate that dityrosine promotes stress resistance by acting as a protective shell around the spore. OSW3 and other OSW genes identified in this screen are strong candidates to encode enzymes involved in assembly of this protective dityrosine coat. PMID- 19779570 TI - DNA BARCODING IN LAND PLANTS: DEVELOPING STANDARDS TO QUANTIFY AND MAXIMIZE SUCCESS. AB - The selection of a DNA barcode in plants has been impeded in part due to the relatively low rates of nucleotide substitution observed at the most accessible plastid markers. However, the absence of consensus also reflects a lack of standards for comparing potential barcode markers. While many publications have suggested a host of plant DNA barcodes, the studies cannot be readily compared with each other through any quantitative or statistical parameter, partly because they put forward no single compelling rationale relevant to the adoption of a DNA barcode in plants. Here, we argue that the efficacy of any particular plant DNA barcode selection should reflect the anticipated performance of the resulting barcode database in assignment of a query sequence to species. While legitimate scientific disagreement exists over the criteria relevant to "database performance", the notion gives a unifying rationale for prioritizing selection criteria. Accordingly, we suggest a measure of barcode efficacy based on the rationale of database performance, "the probability of correct identification" (PCI). Moreover, the definition of PCI is left flexible enough to handle most of the scientific disagreement over how to best evaluate DNA barcodes. Finally, we consider how different types of barcodes might require different methods of analysis and database design and indicate how the analysis might affect the selection of the most broadly effective barcode for land plants. PMID- 19779571 TI - Real-Time Imaging of Protease Action on Substrates Covalently Immobilised to Polymer Supports. AB - We report for the first time single bead spatially resolved activity measurements of solid-phase biocatalytic systems followed in real-time. Trypsin cleavage of Bz Arg-OH and subtilisin cleavage of Z-Gly-Gly-Leu-OH each liberate a free amino group on aminocoumarin covalently immobilised to PEGA(1900) beads [a co-polymer of poly(ethylene glycol) with molecular mass of 1900 cross-linked with acrylamide]. This restores fluorescence which is imaged in optical sections by two-photon microscopy. For trypsin cleavage, fluorescence is restricted initially to surface regions, with more than 1 hour needed before reaction is fully underway in the bead centre, presumably reflecting slow enzyme diffusion. In contrast, for subtilisin cleavage fluorescence develops throughout the bead more quickly. PMID- 19779572 TI - Agency-Based Male Sex Work: A Descriptive Focus on Physical, Personal, and Social Space. AB - Thirty male sex workers (MSWs) from a single agency participated in a qualitative interview about social and occupational aspects of their lives. MSWs established physical (defined areas where clients were not invited) and psychological (limitations of relationship with clients, other escorts, and the agency manager) boundaries to construct personal and professional space regarding sex work. Physical and psychological boundaries often were blended (e.g., bringing friends/family to the agency, utilizing the agency as a "drop-in community center"). The agency further mitigated negative aspects of sex work by providing job training, social support, stigma management, and dual-use space. Actors co created a context wherein business could be conducted while meeting MSWs' psychosocial needs. PMID- 19779573 TI - Adolescent Satisfaction with Computer-Assisted Behavioural Risk Screening in Primary Care. AB - BACKGROUND: This study measures patient satisfaction with a computerised mental health and risk-behaviour screening tool and predictors of satisfaction. METHOD: Youth, aged 11-20, were recruited to use a laptop-based screening system in nine primary care clinics. The study assessed correlations between satisfaction with the system and selected predictors. RESULTS: Most users were satisfied with their experience. Multivariate logistic regression found perceived ease of use, perceived usefulness, and trust to be significantly associated with high satisfaction. Satisfaction was not related to computer experience or risk behaviour status. CONCLUSIONS: Adolescent patients, even those at risk, accept computer-assisted screening in primary care. KEY PRACTITIONER MESSAGE: Screening adolescents for behavioural and mental health issues in the primary care setting is time consuming. Computer assisted screening has the potential to improve screening. This study finds that youth will accept computerised screening if the system is perceived to be useful and easy to use. PMID- 19779574 TI - An electrophysiological investigation of early effects of masked morphological priming. AB - This experiment examined event-related responses to targets preceded by semantically transparent morphologically related primes (e.g., farmer-farm), semantically opaque primes with an apparent morphological relation (cornercorn), and orthographically, but not morphologically, related primes (scandalscan) using the masked priming technique combined with a semantic categorisation task. In order to provide information about possible early effects of morphology we focused our analysis on the N250 ERP component. Priming effects for transparent and opaque items patterned together in the early phase of the N250 (200-250 ms), whereas the transparent and orthographic items patterned together in the latter phase of this component (250-300 ms). These results provide further evidence in support of the rapid extraction of morphemes from morphologically complex stimuli independently of the semantic relatedness of the whole and its parts. PMID- 19779575 TI - Coupling Pd-Catalyzed Alcohol Oxidation to Olefin Functionalization: Hydrohalogenation/Hydroalkoxylation of Styrenes. AB - A hydrochlorination reaction of styrenes catalyzed by Pd(II) in combination with Cu(II) was developed, which was followed by an in situ conversion of electron rich products to an ether in the presence of an alcohol. Mechanistic experiments indicate that olefin functionalization is coupled to an alcohol oxidation, wherein a Pd hydride formed in the beta-hydride elimination step of the alcohol oxidation was incorporated into the product. PMID- 19779576 TI - Stem cell platforms for regenerative medicine. AB - The pandemic of chronic degenerative diseases associated with aging demographics mandates development of effective approaches for tissue repair. As diverse stem cells directly contribute to innate healing, the capacity for de novo tissue reconstruction harbors a promising role for regenerative medicine. Indeed, a spectrum of natural stem cell sources ranging from embryonic to adult progenitors has been recently identified with unique characteristics for regeneration. The accessibility and applicability of the regenerative armamentarium has been further expanded with stem cells engineered by nuclear reprogramming. Through strategies of replacement to implant functional tissues, regeneration to transplant progenitor cells or rejuvenation to activate endogenous self-repair mechanisms, the overarching goal of regenerative medicine is to translate stem cell platforms into practice and achieve cures for diseases limited to palliative interventions. Harnessing the full potential of each platform will optimize matching stem cell-based biologics with the disease-specific niche environment of individual patients to maximize the quality of long-term management, while minimizing the needs for adjunctive therapy. Emerging discovery science with feedback from clinical translation is therefore poised to transform medicine offering safe and effective stem cell biotherapeutics to enable personalized solutions for incurable diseases. PMID- 19779577 TI - Mechanisms of Gene-Environment Interaction Effects in the Development of Conduct Disorder. AB - The gene-environment interaction effect in the development of conduct disorder is one of the most important discoveries of the past decade, but the mechanisms through which this effect operates remain elusive. I propose a model of these processes that focuses on the individual's response to a threatening stimulus in ongoing social interaction. The individual's response coordinates three interrelated systems: neural, autonomic, and information-processing. In each system, adaptive, evolutionarily selected response patterns characterize normal responding, but in psychopathology these patterns have gone awry. Antecedents of individual differences in these response patterns arise from genetic polymorphisms, adverse environmental experiences early in life, and their interaction. Programs of research are proposed to test hypotheses in the model through longitudinal, experimental, and clinical intervention methods. This model can serve as a template for inquiry in other forms of developmental psychopathology. PMID- 19779579 TI - Mixtures of Polya trees for flexible spatial frailty survival modelling. AB - Mixtures of Polya trees offer a very flexible nonparametric approach for modelling time-to-event data. Many such settings also feature spatial association that requires further sophistication, either at the point level or at the lattice level. In this paper, we combine these two aspects within three competing survival models, obtaining a data analytic approach that remains computationally feasible in a fully hierarchical Bayesian framework using Markov chain Monte Carlo methods. We illustrate our proposed methods with an analysis of spatially oriented breast cancer survival data from the Surveillance, Epidemiology and End Results program of the National Cancer Institute. Our results indicate appreciable advantages for our approach over competing methods that impose unrealistic parametric assumptions, ignore spatial association or both. PMID- 19779580 TI - An academic-community outreach partnership: building relationships and capacity to address childhood lead poisoning. AB - BACKGROUND: Although academic institutions are rich resources for improving public health, academic partnerships with community organizations can be challenging. We describe a successful academic-community partnership composed of the Dartmouth Toxic Metals Research Program, the Manchester (New Hampshire) Health Department, and the Greater Manchester Partners Against Lead Poisoning (GMPALP). OBJECTIVE: Partners collaborated to translate science and best practices into social action and policy change to address childhood lead poisoning. METHODS: Using the evolution of a childhood lead poisoning prevention initiative, we discuss how an academic-community relationship can be created and sustained. LESSONS LEARNED: Our experience demonstrates that broad-based partnerships are enhanced by the attributes of community-based participatory research (CBPR). We observe that engaging in community collaborations that are not driven by research eliminates potential conflicts for academic and community partners. CONCLUSION: We identify four core values, namely, (1) adaptability, (2) consistency, (3) shared authority, and (4) trust, as being constructive when working in such partnerships. PMID- 19779581 TI - Properties of Calcium Phosphate Cements With Different Tetracalcium Phosphate and Dicalcium Phosphate Anhydrous Molar Ratios. AB - Calcium phosphate cements (CPCs) were prepared using mixtures of tetracalcium phosphate (TTCP) and dicalcium phosphate anhydrous (DCPA), with TTCP/DCPA molar ratios of 1/1, 1/2, or 1/3, with the powder and water as the liquid. Diametral tensile strength (DTS), porosity, and phase composition (powder x-ray diffraction) were determined after the set specimens have been immersed in a physiological-like solution (PLS) for 1 d, 5 d, and 10 d. Cement dissolution rates in an acidified PLS were measured using a dual constant composition method. Setting times ((30 +/- 1) min) were the same for all cements. DTS decreased with decreasing TTCP/DCPA ratio and, in some cases, also decreased with PLS immersion time. Porosity and hydroxyapatite (HA) formation increased with PLS immersion time. Cements with TTCP/DCPA ratios of 1/2 and 1/3, which formed calcium deficient HA, dissolved more rapidly than the cement with a ratio of 1/1. In conclusion, cements may be prepared with a range of TTCP/DCPA ratios, and those with lower ratio had lower strengths but dissolved more rapidly in acidified PLS. PMID- 19779578 TI - Mechanisms of non-opioid analgesics beyond cyclooxygenase enzyme inhibition. AB - Non-opioid analgesics including both selective and non-selective cyclooxygenase (COX) inhibitors and acetaminophen are the most widely used treatments for pain. Inhibition of COX is thought to be largely responsible for both the therapeutic and adverse effects of this class of drugs. Accumulating evidence over the past two decades has demonstrated effects of non-opioids beyond the inhibition of COX and prostaglandin synthesis that might also explain their therapeutic and adverse effects. These include their interaction with endocannabinoids, nitric oxide, monoaminergic, and cholinergic systems. Moreover, the recent development of microarray technology that allows the study of human gene expression suggests multiple pathways that may be related to the analgesic and anti-inflammatory effects of non-opioids. The present review will discuss the multiple actions of non-opioids and their interactions with these systems during inflammation and pain, suggesting that COX inhibition is an incomplete explanation for the actions of non-opioids and proposes the involvement of multiple selective targets for their analgesic, as well as, their adverse effects. PMID- 19779582 TI - Exploring Mothers' and Fathers' Relationships with Sons Versus Daughters: Links to Adolescent Adjustment in Mexican Immigrant Families. AB - Drawing on ecological and gender socialization perspectives, this study examined mothers' and fathers' relationships with young adolescents, exploring differences between mothers and fathers, for sons versus daughters, and as a function of parents' division of paid labor. Mexican immigrant families (N = 162) participated in home interviews and seven nightly phone calls. Findings revealed that mothers reported higher levels of acceptance toward adolescents and greater knowledge of adolescents' daily activities than did fathers, and mothers spent more time with daughters than with sons. Linkages between parent-adolescent relationship qualities and youth adjustment were moderated by adolescent gender and parents' division of paid labor. Findings revealed, for example, stronger associations between parent-adolescent relationship qualities and youth adjustment for girls than for boys. PMID- 19779583 TI - Exceptions to High School Dropout Predictions in a Low-Income Sample: Do Adults Make a Difference? AB - Adult-child relationship factors were examined to determine whether they differentiated between individuals who follow expected versus unexpected educational pathways. Low-income participants (96 men, 83 women) in the United States were followed from birth through age 23. Individuals were identified who followed expected versus unexpected pathways to high school graduation or dropping out based on academic achievement and behavioral problems. Patterns of parental involvement in school were significantly different between expected dropouts and unexpected graduates in middle childhood. In contrast, expected graduates had higher levels of parent involvement in middle childhood, more supportive parent-child relationships in early adolescence, and higher levels of social competence with adults than unexpected dropouts. PMID- 19779584 TI - Informal Hospice Caregiving: The Toll on Quality of Life. PMID- 19779586 TI - Improved spatial resolution in PET scanners using sampling techniques. AB - Increased focus towards improved detector spatial resolution in PET has led to the use of smaller crystals in some form of light sharing detector design. In this work we evaluate two sampling techniques that can be applied during calibrations for pixelated detector designs in order to improve the reconstructed spatial resolution. The inter-crystal positioning technique utilizes sub-sampling in the crystal flood map to better sample the Compton scatter events in the detector. The Compton scatter rejection technique, on the other hand, rejects those events that are located further from individual crystal centers in the flood map. We performed Monte Carlo simulations followed by measurements on two whole-body scanners for point source data. The simulations and measurements were performed for scanners using scintillators with Z(eff) ranging from 46.9 to 63 for LaBr(3) and LYSO, respectively. Our results show that near the center of the scanner, inter-crystal positioning technique leads to a gain of about 0.5-mm in reconstructed spatial resolution (FWHM) for both scanner designs. In a small animal LYSO scanner the resolution improves from 1.9-mm to 1.6-mm with the inter crystal technique. The Compton scatter rejection technique shows higher gains in spatial resolution but at the cost of reduction in scanner sensitivity. The inter crystal positioning technique represents a modest acquisition software modification for an improvement in spatial resolution, but at a cost of potentially longer data correction and reconstruction times. The Compton scatter rejection technique, while also requiring a modest acquisition software change with no increased data correction and reconstruction times, will be useful in applications where the scanner sensitivity is very high and larger improvements in spatial resolution are desirable. PMID- 19779585 TI - NEURODEVELOPMENTAL IMPAIRMENT: PREDICTORS OF ITS IMPACT ON THE FAMILIES OF EXTREMELY LOW BIRTH WEIGHT INFANTS AT 18 MONTHS. AB - Effects on a family of a child with chronic illness have been described. The Impact on Family Scale (IOF) was developed to measure these effects. The impact of extremely low birth weight (ELBW) infants with neurodevelopmental impairment on families is unknown. This study determined IOF scores for families of ELBW infants with increasing degree of impairment at 18 months and identified factors that increase vulnerability to impact. A total of 3,849 ELBW infant survivors born at the 16 centers of the National Institute of Child Health and Human Development Neonatal Research Network between January 1993 and February 2001 were assessed at 18 to 22 months. Infants were divided into four groups by degree of impairment. IOF scores were analyzed by impairment group. Multivariate analyses assessed effects of impairment, social/demographic factors, unmet service needs, and resource utilization on the IOF. A total of 1,624 (42.2%) infants had moderate/severe impairment. Increasing severity of impairment was associated with higher IOF scores. Severity of impairment contributed 6% of variance to the IOF scores. Twenty-one percent of variance was contributed by additional medical needs, low socioeconomic status (SES), and lack of social support. Although increasing severity of impairment impacts families of ELBW infants, significantly more impact is contributed by additional medical needs, low SES, and lack of social support. PMID- 19779588 TI - The mechanical properties of a surface-modified layer on poly(dimethylsiloxane). AB - Surface-modification of the elastomer poly(dimethylsiloxane) by exposure to oxygen plasma for four minutes creates a thin, stiff film. In this study, the thickness and mechanical properties of this surface-modified layer were determined. Using the phase image capabilities of a tapping-mode atomic-force microscope, the surface-modified region was distinguished from the bulk PDMS; specifically, it suggested a graded surface layer to a depth of about 200 nm. Load-displacement data for elastic indentation using a compliant AFM cantilever was analyzed as a plate bending on an elastic foundation to determine the elastic modulus of the surface (37 MPa). An applied uniaxial strain generated a series of parallel nano-cracks with spacing on the order of a few microns. Numerical analyses of this cracking phenomenon showed that the depth of these cracks was in the range of 300-600 nm and that the surface layer was extremely brittle, with its toughness in the range of 0.1-0.3 J/m(2). PMID- 19779587 TI - Therapeutic Robotics: A Technology Push: Stroke rehabilitation is being aided by robots that guide movement of shoulders and elbows, wrists, hands, arms and ankles to significantly improve recovery of patients. AB - In this paper, we present a retrospective and chronological review of our efforts to revolutionize the way physical medicine is practiced by developing and deploying therapeutic robots. We present a sample of our clinical results with well over 300 stroke patients, both inpatients and outpatients, proving that movement therapy has a measurable and significant impact on recovery following brain injury. Bolstered by this result, we embarked on a two-pronged approach: 1) to determine what constitutes best therapy practice and 2) to develop additional therapeutic robots. We review our robots developed over the past 15 years and their unique characteristics. All are configured both to deliver reproducible therapy but also to measure outcomes with minimal encumbrance, thus providing critical measurement tools to help unravel the key question posed under the first prong: what constitutes "best practice"? We believe that a "gym" of robots like these will become a central feature of physical medicine and the rehabilitation clinic within the next ten years. PMID- 19779589 TI - Evaluation of a Culturally Tailored Skills Intervention for Latinos with Persistent Psychotic Disorders. AB - Fifty-nine Latino participants diagnosed with persistent psychotic disorders were assigned to either a culturally tailored skills-training intervention (n = 21), an equivalent non-tailored intervention (n = 15), or a community-based support group (n = 23). Participants completed a number of skills-based performance assessments (e.g., UCSD performance-based skills assessment; UPSA) and a well being measure prior to and immediately post-treatment. Compared to those in the non-tailored intervention, participants receiving the tailored intervention showed significant improvement in several outcomes. These results indicate that Latino individuals with persistent psychotic disorders benefit from interventions which consider cultural values and mores. PMID- 19779590 TI - A Diastereoselective Intramolecular Pauson-Khand Approach to the Construction of the BC Ring System in Tuberostemoninol. AB - Herein we describe an asymmetric approach to the synthesis of a BC-ring synthon in tuberostemoninol via an intramolecular Pauson-Khand reaction stereocontrolled by a commercially available chiral glycinate. PMID- 19779592 TI - An Appropriate Response to the Black-Box Warning: Corrective, Barrier Repair Therapy in Atopic Dermatitis. AB - Due to years of sophisticated research on T cell function, many dermatologists have viewed atopic dermatitis (AD) largely as an inflammatory disorder of TH1/TH2 imbalance. Hence, therapy has largely consisted of topical immunomodulators and/or steroids. The imposition of "black box" warnings about the potential toxicity associated with prolonged use of the immunosuppressive drugs, tacrolimus 0.1% or 0.3% ointment (Protopic((R)), Astellas Pharma U.S., Inc., Deerfield, IL) and pimecrolimus 1% cream (Elidel((R)), Novartis, Basel, Switzerland), as well as legitimate concerns about the adverse side effects of potent topical steroids, has stimulated a search for alternate forms of therapy. Recent genetic studies point to the primary role of a defective barrier to water loss and microbial invasion in the provocation of AD, creating a rationale for 'barrier repair' therapy. This approach utilizes topical applications of specific combination of the three (3) epidermal lipids that comprise the epidermal permeability barrier in a ratio (ceramide-dominant) that corrects the biochemical abnormality in AD.1,2 We review here both recent concerns about the topical immunomodulators, as well as the rationale for barrier repair therapy. PMID- 19779591 TI - Soluble Epoxide Hydrolase Inhibition: Targeting Multiple Mechanisms of Ischemic Brain Injury with a Single Agent. AB - Soluble epoxide hydrolase (sEH) is a key enzyme in the metabolic conversion and degradation of P450 eicosanoids called epoxyeicosatrienoic acids (EETs). Genetic variations in the sEH gene, designated EPHX2, are associated with ischemic stroke risk. In experimental studies, sEH inhibition and gene deletion reduce infarct size after focal cerebral ischemia in mice. Although the precise mechanism of protection afforded by sEH inhibition remains under investigation, EETs exhibit a wide array of potentially beneficial actions in stroke, including vasodilation, neuroprotection, promotion of angiogenesis and suppression of platelet aggregation, oxidative stress and post-ischemic inflammation. Herein we argue that by capitalizing on this broad protective profile, sEH inhibition represents a prototype "combination therapy" targeting multiple mechanisms of stroke injury with a single agent. PMID- 19779594 TI - Choosing anatomical-prior strength for MAP SPECT reconstruction to maximize lesion detectability. AB - With the widespread availability of SPECT/CT systems it has become feasible to incorporate prior knowledge about anatomical boundaries into the SPECT reconstruction process, thus improving observer performance on tasks of clinical interest. We determine the optimal anatomical-prior strength for lesion search by measuring area under the LROC curve using human observers. We conclude that prior strength should be chosen assuming that only organ boundaries are available, even if lesion boundaries will also be known some of the time. We also test whether or not the presence of anatomical priors affects the observer's strategy, and conclude that mixing images with and without priors does not hurt reader performance when priors are not available. Finally, we examine whether using an anatomical prior in SPECT reconstruction helps observer performance when the observer already knows the possible lesion location, and conclude for this task anatomical priors do not provide the same improvement seen in search tasks. PMID- 19779593 TI - Genetics of PTSD: Fear Conditioning as a Model for Future Research. AB - In the last decade, the number of publications in psychiatric genetics has nearly tripled but little attention has been paid to the role of genetic factors in the etiology of posttraumatic stress disorder (PTSD). The present review summarizes the current state of genetic research on PTSD. First, we outline information regarding genetic influences provided by family investigations and by twin studies. Second, we propose the fear-conditioning model of PTSD as a framework for the nomination of candidate genes that may be related to the disorder. Third, we review lines of evidence from three neurobiological systems involved in fear conditioning, and we summarize published investigations of genetic variants studied in association with PTSD in these three systems. Finally, we review gene by-environment interaction research, a promising novel approach to genetic research in PTSD. PMID- 19779595 TI - Applying the Lorenz curve to disease risk to optimize health benefits under cost constraints. AB - This paper shows how the Lorenz curve can be used, together with models of disease risk, to allocate scarce resources so as to optimize a health benefit. Consider the example of breast cancer mortality. If there were sufficient resources to provide all women with mammograms, a certain maximal number of lives could be saved. Suppose, however, that only a fraction of that amount of money is available for prevention activities. Suppose that a questionnaire could be given to assess a woman's risk of dying of breast cancer. Depending on the amount of money available, on the ratio of the cost of a questionnaire to the cost of a mammogram, and on the Lorenz curve of the distribution of risks of breast cancer mortality, I calculate the proportion of women who should be given questionnaires, the proportion of women given the questionnaires who should be given mammograms because they have high risks, and the proportion of women not given questionnaires who should be assigned to receive mammograms at random so as to maximize the number of lives saved. PMID- 19779596 TI - Optimization of the Use of Consensus Methods for the Detection and Putative Identification of Peptides via Mass Spectrometry Using Protein Standard Mixtures. AB - Correct identification of peptides and proteins in complex biological samples from proteomic mass-spectra is a challenging problem in bioinformatics. The sensitivity and specificity of identification algorithms depend on underlying scoring methods, some being more sensitive, and others more specific. For high throughput, automated peptide identification, control over the algorithms' performance in terms of trade-off between sensitivity and specificity is desirable. Combinations of algorithms, called 'consensus methods', have been shown to provide more accurate results than individual algorithms. However, due to the proliferation of algorithms and their varied internal settings, a systematic understanding of relative performance of individual and consensus methods are lacking. We performed an in-depth analysis of various approaches to consensus scoring using known protein mixtures, and evaluated the performance of 2310 settings generated from consensus of three different search algorithms: Mascot, Sequest, and X!Tandem. Our findings indicate that the union of Mascot, Sequest, and X!Tandem performed well (considering overall accuracy), and methods using 80-99.9% protein probability and/or minimum 2 peptides and/or 0-50% minimum peptide probability for protein identification performed better (on average) among all consensus methods tested in terms of overall accuracy. The results also suggest method selection strategies to provide direct control over sensitivity and specificity. PMID- 19779597 TI - Children with chronic complex medical illnesses: Is inpatient care family centered? AB - BACKGROUND: Families of children with complex chronic medical illnesses (CCMI) benefit from coordinated, family-centered healthcare. OBJECTIVE: Compare parental perceptions of inpatient family-centered care for children with CCMI in structured clinical programs (SCPs) with those who are not in SCPs. DESIGN/METHODS: Cross-sectional mail survey of parents of children with CCMIs using the 56-item Measure of Processes of Care (MPOC) to rate perceptions of family-centered healthcare. We compared responses of SCP to non-SCP children. RESULTS: 215 (36.6%) of 588 surveys were returned. Response rates were 40.0% for SCP and 33.8% for non-SCP children. The proportion of favorable (6-7) ratings was higher for the SCP group than for the non-SCP group (52.4% vs. 48.3%, p < 0.035). The proportion of unfavorable ratings was also different (5.4% vs. 12.3%, p =< 0.001). SCP families felt care was directed at the whole child and consistent. Non-SCP families reported more unmet needs and less recognition of their role. CONCLUSIONS: Parents of children with CCMI perceive inpatient care as more family centered when provided in conjunction with a SCP. Children receiving non-SCP care may benefit from inclusion in SCPs dedicated to their needs. Further studies to determine the best way to provide this care are needed. PMID- 19779598 TI - Transient signals per se do not disrupt the flash-lag effect. AB - Nijhawan's theory rests on the assumption that transient signals compete with predictive signals to generate the visual percept. We describe experiments that show that this assumption is incorrect. Our results are consistent with an alternative theory that proposes that vision is instead postdictive, in that the perception of an event is influenced by occurrences after the event. PMID- 19779599 TI - AN APPLICATION OF PRINCIPAL STRATIFICATION TO CONTROL FOR INSTITUTIONALIZATION AT FOLLOW-UP IN STUDIES OF SUBSTANCE ABUSE TREATMENT PROGRAMS. AB - Participants in longitudinal studies on the effects of drug treatment and criminal justice system interventions are at high risk for institutionalization (e.g., spending time in an environment where their freedom to use drugs, commit crimes, or engage in risky behavior may be circumscribed). Methods used for estimating treatment effects in the presence of institutionalization during follow-up can be highly sensitive to assumptions that are unlikely to be met in applications and thus likely to yield misleading inferences. In this paper, we consider the use of principal stratification to control for institutionalization at follow-up. Principal stratification has been suggested for similar problems where outcomes are unobservable for samples of study participants because of dropout, death, or other forms of censoring. The method identifies principal strata within which causal effects are well defined and potentially estimable. We extend the method of principal stratification to model institutionalization at follow-up and estimate the effect of residential substance abuse treatment versus outpatient services in a large scale study of adolescent substance abuse treatment programs. Additionally, we discuss practical issues in applying the principal stratification model to data. We show via simulation studies that the model can only recover true effects provided the data meet strenuous demands and that there must be caution taken when implementing principal stratification as a technique to control for post-treatment confounders such as institutionalization. PMID- 19779600 TI - Sexual Behavior, Mental Health, Substance Use, and HIV Risk Among Agency-Based Male Escorts in a Small U.S. City. AB - Relatively little research has examined the personal sex lives of indoor male sex workers (MSWs) or possible connections in this group between sexual behavior and factors related to HIV risk. As part of a larger project, this study collected data from 30 agency-based indoor MSWs (mean = 22.4 years) about their sexual behavior, mental health, and substance use. Few HIV risk behaviors with clients occurred. Drug use and mental health problems were relatively frequent, but not related to increased risk behavior. Instead, MSWs appeared to employ rational decision-making and harm-reduction strategies. Conceptualization of MSW sexual behavior may be required where HIV risk is not attributed to sex work per se, but to other influences such as economic and relational factors. PMID- 19779601 TI - Beyond Patents and Royalties: Perception and Reality of Doing Business with the NIH. AB - Young, and mid size biotech companies can benefit hugely from the US National Institutes of Health (NIH), not least because of the agency's non-dilutive funding, guidance, and opportunities for collaboration. Increasingly, however, there is a fair bit of misunderstanding about what the NIH can and cannot do for a biotech entrepreneur. PMID- 19779602 TI - The PhysioNet / Computers in Cardiology Challenge 2008: T-Wave Alternans. AB - The 9th annual PhysioNet/Computers in Cardiology challenge invited participants to measure T-wave alternans (TWA) in a set of 100 two-minute electrocardiograms that included subjects with a variety of risk factors for sudden cardiac death (including ventricular tachyarrhythmias, transient myocardial ischemia, and acute myocardial infarctions), healthy controls, and synthetic ECGs with calibrated amounts of artificial TWA. The participants' TWA estimates were used to develop a ranking of the 100 test cases in order of TWA content, and the Kendall rank correlation coefficient between this reference ranking and each individual participant's ranking of the 100 cases was calculated as a score (between -1 and 1; actual scores were between 0.11 and 0.92). The challenge yielded insights into the strengths and weaknesses of classic and novel TWA analyses, open-source implementations of a variety of methods, and a set of freely available ECGs with reference rankings of TWA content. PMID- 19779603 TI - Lexical Studies of Filipino Person Descriptors: Adding Personality-Relevant Social and Physical Attributes. AB - Lexical studies have focused on traits. In the Filipino language, we investigated whether additional dimensions can be identified when personality-relevant terms for social roles, statuses, and effects, plus physical attributes, are included. Filipino students (N = 496) rated themselves on 268 such terms, plus 253 markers of trait and evaluative dimensions. We identified 10 dimensions of social and physical attributes-Prominence, Uselessness, Attractiveness, Respectability, Uniqueness, Destructiveness, Presentableness, Strength, Dangerousness, and Charisma. Most of these dimensions did not correspond in a one-to-one manner to Filipino or alternative trait models (Big Five, HEXACO, ML7). However, considerable redundancy was observed between the social and physical attribute dimensions and trait and evaluative dimensions. Thus, social and physical attributes communicate information about personality traits, and vice-versa. PMID- 19779604 TI - Molecular Imaging of Cancer: Applications of Magnetic Resonance Methods. AB - Cancer is a complex disease exhibiting a host of phenotypic diversities. Noninvasive multinuclear magnetic resonance imaging (MRI) and spectroscopic imaging (MRSI) provide an array of capabilities to characterize and understand several of the vascular, metabolic, and physiological characteristics unique to cancer. The availability of targeted contrast agents has widened the scope of MR techniques to include the detection of receptor and gene expression. In this paper, we have highlighted the application of several MR techniques in imaging and understanding cancer. PMID- 19779605 TI - SOCS2 influences LPS induced human monocyte-derived dendritic cell maturation. AB - Dendritic cells (DCs) are highly specific antigen presenting cells, which link innate and adaptive immune responses and participate in protecting hosts from invading pathogens. DCs can be generated in vitro by culturing human monocytes with GM-CSF and IL-4 followed by LPS induced DC maturation. We set out to study the suppressor of cytokine signaling (SOCS) proteins during maturation and activation of human monocyte-derived DCs from peripheral blood in vitro. We found that the expression of SOCS2 mRNA and protein is dramatically up-regulated during DC maturation. Silencing of SOCS2 using siRNA, inhibited DC maturation as evidenced by a decreased expression of maturation markers such as CD83, co stimulatory molecules CD40, CD86 and HLA-DR. Furthermore, silencing of SOCS2 decreased LPS induced activation of MAP kinases (SAKP/JNK, p38, ERK), IRF3, decreased the translocation of the NF-kappaB transcription factor and reduced downstream gene mRNA expression. These results suggest a role for SOCS2 in the MyD88-dependent and -independent TLR4 signaling pathways. In conclusion, our results demonstrate that SOCS2 is required for appropriate TLR4 signaling in maturating human DCs via both the MyD88-dependent and -independent signaling pathway. PMID- 19779606 TI - The pathogenic properties of a novel and conserved gene product, KerV, in proteobacteria. AB - Identification of novel virulence factors is essential for understanding bacterial pathogenesis and designing antibacterial strategies. In this study, we uncover such a factor, termed KerV, in Proteobacteria. Experiments carried out in a variety of eukaryotic host infection models revealed that the virulence of a Pseudomonas aeruginosa kerV null mutant was compromised when it interacted with amoebae, plants, flies, and mice. Bioinformatics analyses indicated that KerV is a hypothetical methyltransferase and is well-conserved across numerous Proteobacteria, including both well-known and emerging pathogens (e.g., virulent Burkholderia, Escherichia, Shigella, Vibrio, Salmonella, Yersinia and Brucella species). Furthermore, among the 197 kerV orthologs analyzed in this study, about 89% reside in a defined genomic neighborhood, which also possesses essential DNA replication and repair genes and detoxification gene. Finally, infection of Drosophila melanogaster with null mutants demonstrated that KerV orthologs are also crucial in Vibrio cholerae and Yersinia pseudotuberculosis pathogenesis. Our findings suggested that KerV has a novel and broad significance as a virulence factor in pathogenic Proteobacteria and it might serve as a new target for antibiotic drug design. PMID- 19779607 TI - Evidence for habitual and goal-directed behavior following devaluation of cocaine: a multifaceted interpretation of relapse. AB - BACKGROUND: Cocaine addiction is characterized as a chronically relapsing disorder. It is believed that cues present during self-administration become learned and increase the probability that relapse will occur when they are confronted during abstinence. However, the way in which relapse-inducing cues are interpreted by the user has remained elusive. Recent theories of addiction posit that relapse-inducing cues cause relapse habitually or automatically, bypassing processing information related to the consequences of relapse. Alternatively, other theories hypothesize that relapse-inducing cues produce an expectation of the drug's consequences, designated as goal-directed relapse. Discrete discriminative stimuli signaling the availability of cocaine produce robust cue induced responding after thirty days of abstinence. However, it is not known whether cue-induced responding is a goal-directed action or habit. METHODOLOGY/PRINCIPAL FINDINGS: We tested whether cue-induced responding is a goal-directed action or habit by explicitly pairing or unpairing cocaine with LiCl-induced sickness (n = 7/group), thereby decreasing or not altering the value of cocaine, respectively. Following thirty days of abstinence, no difference in responding between groups was found when animals were reintroduced to the self administration environment alone, indicating habitual behavior. However, upon discriminative stimulus presentations, cocaine-sickness paired animals exhibited decreased cue-induced responding relative to unpaired controls, indicating goal directed behavior. In spite of the difference between groups revealed during abstinent testing, no differences were found between groups when animals were under the influence of cocaine. CONCLUSIONS/SIGNIFICANCE: Unexpectedly, both habitual and goal-directed responding occurred during abstinent testing. Furthermore, habitual or goal-directed responding may have been induced by cues that differed in their correlation with the cocaine infusion. Non-discriminative stimulus cues were weak correlates of the infusion, which failed to evoke a representation of the value of cocaine and led to habitual behavior. However, the discriminative stimulus-nearly perfectly correlated with the infusion-likely evoked a representation of the value of the infusion and led to goal-directed behavior. These data indicate that abstinent cue-induced responding is multifaceted, dynamically engendering habitual or goal-directed behavior. Moreover, since goal-directed behavior terminated habitual behavior during testing, therapeutic approaches aimed at reducing the perceived value of cocaine in addicted individuals may reduce the capacity of cues to induce relapse. PMID- 19779608 TI - Panton-valentine leukocidin enhances the severity of community-associated methicillin-resistant Staphylococcus aureus rabbit osteomyelitis. AB - BACKGROUND: Extensive spread of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) in the United States, and the concomitant increase in severe invasive staphylococcal infections, including osteomyelitis, in healthy children, has led to renewed interest in Panton-Valentine leukocidin (PVL). However, the pathogenetic role of PVL in staphylococcal infections remains controversial, possibly because it depends on the site of infection. METHODOLOGY/PRINCIPAL FINDINGS: We compared the course of experimental rabbit osteomyelitis due to the PVL-positive CA-MRSA strain USA 300 (LAC) and its PVL negative isogenic derivative (LACDeltapvl), using a low and a high inoculum (8x10(5) and 4x10(8) CFU). With the low inoculum, bone infection was less frequent on day 7 (D7) and day 28 (D28) with LACDeltapvl than with LAC (respectively 12/19 and 18/19 animals, p = 0.042). With the high inoculum of both strains, all the animals were infected on D7 and the infection persisted on D28 in almost every case. However, tibial bacterial counts and the serum CRP concentration fell significantly between D7 and D28 with LACDeltapvl but not with LAC. Respectively 67% and 60% of LAC-infected rabbits had bone deformation and muscle/joint involvement on D7, compared to 0% and 7% of LACDeltapvl-infected rabbits (p = 0.001 and p = 0.005 respectively). Between D0 and D28, the anti-PVL antibody titer increased significantly only with the high inoculum of LAC. CONCLUSIONS/SIGNIFICANCE: PVL appears to play a role in the persistence and rapid local extension of rabbit osteomyelitis, in keeping with the greater severity of human bone infections due to PVL-positive S. aureus. The possible therapeutic implications of these findings are discussed. PMID- 19779609 TI - Repetitive immunization enhances the susceptibility of mice to peripherally administered prions. AB - The susceptibility of humans and animals to prion infections is determined by the virulence of the infectious agent, by genetic modifiers, and by hitherto unknown host and environmental risk factors. While little is known about the latter two, the activation state of the immune system was surmised to influence prion susceptibility. Here we administered prions to mice that were repeatedly immunized by two initial injections of CpG oligodeoxynucleotides followed by repeated injections of bovine serum albumin/alum. Immunization greatly reduced the required dosage of peripherally administered prion inoculum necessary to induce scrapie in 50% of mice. No difference in susceptibility was observed following intracerebral prion challenge. Due to its profound impact onto scrapie susceptibility, the host immune status may determine disease penetrance after low dose prion exposure, including those that may give rise to iatrogenic and variant Creutzfeldt-Jakob disease. PMID- 19779610 TI - Monocyte derived microvesicles deliver a cell death message via encapsulated caspase-1. AB - Apoptosis depends upon the activation of intracellular caspases which are classically induced by either an intrinsic (mitochondrial based) or extrinsic (cytokine) pathway. However, in the process of explaining how endotoxin activated monocytes are able to induce apoptosis of vascular smooth muscle cells when co cultured, we uncovered a transcellular apoptosis inducing pathway that utilizes caspase-1 containing microvesicles. Endotoxin stimulated monocytes induce the cell death of VSMCs but this activity is found in 100,000 g pellets of cell free supernatants of these monocytes. This activity is not a direct effect of endotoxin, and is inhibited by the caspase-1 inhibitor YVADcmk but not by inhibitors of Fas-L, IL-1beta and IL-18. Importantly, the apoptosis inducing activity co-purifies with 100 nm sized microvesicles as determined by TEM of the pellets. These microvesicles contain caspase-1 and caspase-1 encapsulation is required since disruption of microvesicular integrity destroys the apoptotic activity but not the caspase-1 enzymatic activity. Thus, monocytes are capable of delivering a cell death message which depends upon the release of microvesicles containing functional caspase-1. This transcellular apoptosis induction pathway describes a novel pathway for inflammation induced programmed cell death. PMID- 19779611 TI - Cost-effectiveness of a telephone-delivered intervention for physical activity and diet. AB - BACKGROUND: Given escalating rates of chronic disease, broad-reach and cost effective interventions to increase physical activity and improve dietary intake are needed. The cost-effectiveness of a Telephone Counselling intervention to improve physical activity and diet, targeting adults with established chronic diseases in a low socio-economic area of a major Australian city was examined. METHODOLOGY/PRINCIPAL FINDINGS: A cost-effectiveness modelling study using data collected between February 2005 and November 2007 from a cluster-randomised trial that compared Telephone Counselling with a "Usual Care" (brief intervention) alternative. Economic outcomes were assessed using a state-transition Markov model, which predicted the progress of participants through five health states relating to physical activity and dietary improvement, for ten years after recruitment. The costs and health benefits of Telephone Counselling, Usual Care and an existing practice (Real Control) group were compared. Telephone Counselling compared to Usual Care was not cost-effective ($78,489 per quality adjusted life year gained). However, the Usual Care group did not represent existing practice and is not a useful comparator for decision making. Comparing Telephone Counselling outcomes to existing practice (Real Control), the intervention was found to be cost-effective ($29,375 per quality adjusted life year gained). Usual Care (brief intervention) compared to existing practice (Real Control) was also cost-effective ($12,153 per quality adjusted life year gained). CONCLUSIONS/SIGNIFICANCE: This modelling study shows that a decision to adopt a Telephone Counselling program over existing practice (Real Control) is likely to be cost-effective. Choosing the 'Usual Care' brief intervention over existing practice (Real Control) shows a lower cost per quality adjusted life year, but the lack of supporting evidence for efficacy or sustainability is an important consideration for decision makers. The economics of behavioural approaches to improving health must be made explicit if decision makers are to be convinced that allocating resources toward such programs is worthwhile. TRIAL REGISTRATION: This paper uses data collected in a previous clinical trial registered at the Australian Clinical Trials Registry, Australian New Zealand Clinical Trials Registry: Anzcrt.org.au ACTRN012607000195459. PMID- 19779612 TI - Dysregulation of ribosome biogenesis and translational capacity is associated with tumor progression of human breast cancer cells. AB - Protein synthesis is a fundamental cell process and ribosomes - particularly through the ribosomal RNA that display ribozyme activity--are the main effectors of this process. Ribosome biogenesis is a very complex process involving transcriptional aswell as many post-transcriptional steps to produce functional ribosomes. It is now well demonstrated that ribosome production is enhanced in cancer cells and that ribosome biogenesis plays a crucial role in tumor progression. However, at present there is an important lack of data to determine whether the entire process of ribosome biogenesis and ribosome assembly is modified during tumor progression and what could be the potential impact on the dysregulation of translational control that is observed in cancer cells. In breast cancer cells displaying enhanced aggressivity, both in vitro and in vivo, we have analyzed the major steps of ribosome biogenesis and the translational capacity of the resulting ribosome. We show that increased tumorigenicity was associated with modifications of nucleolar morphology and profound quantitative and qualitative alterations in ribosomal biogenesis and function. Specifically cells with enhanced tumor aggressivity displayed increased synthesis of 45S pre rRNA, with activation of an alternative preRNA synthetic pathway containing a 43S precursor and enhanced post-transcriptional methylation of specifc sites located in the 28S rRNA. While the global translational activity was not modified, IRES initiated translation, notably that of p53 mRNA, was less efficient and the control of translational fidelity was importantly reduced in cells with increased aggressivity. These results suggest that acquisition of enhanced tumor aggressivity can be associated with profound qualitative alterations in ribosomal control, leading to reduced quality control of translation in cancer cells. PMID- 19779613 TI - Postmortem analyses unveil the poor efficacy of decontamination, anti inflammatory and immunosuppressive therapies in paraquat human intoxications. AB - BACKGROUND: Fatalities resulting from paraquat (PQ) self-poisonings represent a major burden of this herbicide. Specific therapeutic approaches have been followed to interrupt its toxic pathway, namely decontamination measures to prevent PQ absorption and to increase its excretion from organism, as well as the administration of anti-inflammatory and immunosuppressive drugs. Until now, none of the postmortem studies resulting from human PQ poisonings have assessed the relationship of these therapeutic measures with PQ toxicokinetics and related histopathological lesions, these being the aims of the present study. METHODOLOGY/PRINCIPAL FINDINGS: For that purpose, during 2008, we collected human fluids and tissues from five forensic autopsies following fatal PQ poisonings. PQ levels were measured by gas chromatography-ion trap mass spectrometry. Structural inflammatory lesions were evaluated by histological and immunohistochemistry analysis. The samples of cardiac blood, urine, gastric and duodenal wall, liver, lung, kidney, heart and diaphragm, showed quantifiable levels of PQ even at 6 days post-intoxication. Structural analysis showed diffused necrotic areas, intense macrophage activation and leukocyte infiltration in all analyzed tissues. By immunohistochemistry it was possible to observe a strong nuclear factor kappa B (NF-kappaB) activation and excessive collagen deposition. CONCLUSIONS/SIGNIFICANCE: Considering the observed PQ levels in all analyzed tissues and the expressive inflammatory reaction that ultimately leads to fibrosis, we conclude that the therapeutic protocol usually performed needs to be reviewed, in order to increase the efficacy of PQ elimination from the body as well as to diminish the inflammatory process. PMID- 19779614 TI - Systems integration of biodefense omics data for analysis of pathogen-host interactions and identification of potential targets. AB - The NIAID (National Institute for Allergy and Infectious Diseases) Biodefense Proteomics program aims to identify targets for potential vaccines, therapeutics, and diagnostics for agents of concern in bioterrorism, including bacterial, parasitic, and viral pathogens. The program includes seven Proteomics Research Centers, generating diverse types of pathogen-host data, including mass spectrometry, microarray transcriptional profiles, protein interactions, protein structures and biological reagents. The Biodefense Resource Center (www.proteomicsresource.org) has developed a bioinformatics framework, employing a protein-centric approach to integrate and support mining and analysis of the large and heterogeneous data. Underlying this approach is a data warehouse with comprehensive protein + gene identifier and name mappings and annotations extracted from over 100 molecular databases. Value-added annotations are provided for key proteins from experimental findings using controlled vocabulary. The availability of pathogen and host omics data in an integrated framework allows global analysis of the data and comparisons across different experiments and organisms, as illustrated in several case studies presented here. (1) The identification of a hypothetical protein with differential gene and protein expressions in two host systems (mouse macrophage and human HeLa cells) infected by different bacterial (Bacillus anthracis and Salmonella typhimurium) and viral (orthopox) pathogens suggesting that this protein can be prioritized for additional analysis and functional characterization. (2) The analysis of a vaccinia-human protein interaction network supplemented with protein accumulation levels led to the identification of human Keratin, type II cytoskeletal 4 protein as a potential therapeutic target. (3) Comparison of complete genomes from pathogenic variants coupled with experimental information on complete proteomes allowed the identification and prioritization of ten potential diagnostic targets from Bacillus anthracis. The integrative analysis across data sets from multiple centers can reveal potential functional significance and hidden relationships between pathogen and host proteins, thereby providing a systems approach to basic understanding of pathogenicity and target identification. PMID- 19779615 TI - Stabilization of influenza vaccine enhances protection by microneedle delivery in the mouse skin. AB - BACKGROUND: Simple and effective vaccine administration is particularly important for annually recommended influenza vaccination. We hypothesized that vaccine delivery to the skin using a patch containing vaccine-coated microneedles could be an attractive approach to improve influenza vaccination compliance and efficacy. METHODOLOGY/PRINCIPAL FINDINGS: Solid microneedle arrays coated with inactivated influenza vaccine were prepared for simple vaccine delivery to the skin. However, the stability of the influenza vaccine, as measured by hemagglutination activity, was found to be significantly damaged during microneedle coating. The addition of trehalose to the microneedle coating formulation retained hemagglutination activity, indicating stabilization of the coated influenza vaccine. For both intramuscular and microneedle skin immunization, delivery of un-stabilized vaccine yielded weaker protective immune responses including viral neutralizing antibodies, protective efficacies, and recall immune responses to influenza virus. Immunization using un-stabilized vaccine also shifted the pattern of antibody isotypes compared to the stabilized vaccine. Importantly, a single microneedle-based vaccination using stabilized influenza vaccine was found to be superior to intramuscular immunization in controlling virus replication as well as in inducing rapid recall immune responses post challenge. CONCLUSIONS/SIGNIFICANCE: The functional integrity of hemagglutinin is associated with inducing improved protective immunity against influenza. Simple microneedle influenza vaccination in the skin produced superior protection compared to conventional intramuscular immunization. This approach is likely to be applicable to other vaccines too. PMID- 19779616 TI - Evolution of asthma severity in a cohort of young adults: is there any gender difference? AB - INTRODUCTION: Little is known about the distribution of asthma severity in men and women in the general population. The objective of our study was to describe asthma severity and change in severity according to gender in a cohort of adult asthmatics METHODS: Subjects with asthma were identified from random samples of the 22 to 44 year-olds from the general population, screened for asthma from 1991 to 1993 in 48 centers from 22 countries and followed-up during 1998-2002, as part of the European Community Respiratory Health Survey (ECRHS). All participants to follow-up with current asthma at baseline were eligible for the analysis. To assess change over the follow-up, asthma severity at the two surveys was defined using standardized data on respiratory symptoms, lung function and medication according to the Global Initiative for Asthma (GINA) Guidelines. Another quantitative score (Ronchetti) further considering hospitalizations was also analysed. RESULTS: The study included 685 subjects with asthma followed-up over a mean period of 8.65 yr (min 4.3-max 11.7). At baseline, asthma severity according to GINA was distributed as intermittent: 40.7%, 31.7% as mild persistent, 14% as moderate persistent, and 13.5% as severe persistent. Using the Ronchetti score derived classification, the distribution of asthma severity was 58% mild, (intermittent and mild persistent), 25.8% moderate, and 15.4% severe. Whatever the classification, there was no significant difference in the severity distribution between men and women. There was also no gender difference in the severity distribution among incident cases which developed asthma between the two surveys. Men with moderate-to-severe asthma at baseline were more likely than women to have moderate-to-severe asthma at follow-up. Using GINA, 69.2% of men vs. 53.1% of women (p = 0.09) with moderate-to-severe asthma at baseline were still moderate-to-severe at follow-up. Using Ronchetti score, 53.3% of men vs. 36.2% of women (p = 0.03) with moderate-to-severe asthma at baseline were still moderate-to-severe at follow-up. CONCLUSIONS: There was no gender difference in asthma severity at the two surveys. However, our findings suggest that asthma severity might be less stable in women than in men. PMID- 19779617 TI - Molecular phylogenetics of the genus Neoconocephalus (orthoptera, tettigoniidae) and the evolution of temperate life histories. AB - BACKGROUND: The katydid genus Neoconocephalus (25+ species) has a prominent acoustic communication system and occurs in large parts of the Neotropics and Nearctic. This group has been subject of numerous behavioral, physiological, and evolutionary studies of its acoustic communication system. Two distinct life histories occur in this group: The tropical life history incorporates multiple generations/year and direct egg development without environmental triggers. Temperate life history is characterized by overwintering in the egg stage, cold trigger of egg development, and one generation/year. This study reconstructs the phylogenetic relationships within the genus to (1) determine the evolutionary history of the temperate life history, and (2) to support comparative studies of evolutionary and physiological problems in this genus. METHODOLOGY/PRINCIPAL FINDINGS: We used Amplified Fragment Length Polymorphisms (AFLP), and sequences of two nuclear loci and one mitochondrial locus to reconstruct phylogenetic relationships. The analysis included 17 ingroup and two outgroup species. AFLP and mitochondrial data provided resolution at the species level while the two nuclear loci revealed only deeper nodes. The data sets were combined in a super matrix to estimate a total evidence tree. Seven of the temperate species form a monophyletic group; however, three more temperate species were placed as siblings of tropical species. CONCLUSIONS/SIGNIFICANCE: Our analyses support the reliability of the current taxonomic treatment of the Neoconocephalus fauna of Caribbean, Central, and North America. Ancestral state reconstruction of life history traits was not conclusive, however at least four transitions between life histories occurred among our sample of species. The proposed phylogeny will strengthen conclusions from comparative work in this group. PMID- 19779618 TI - Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. AB - BACKGROUND: At least four laboratories have shown that endogenous cardiac progenitor cells (CPCs) can be grown directly from adult heart tissue in primary culture, as cardiospheres or their progeny (cardiosphere-derived cells, CDCs). Indeed, CDCs are already being tested in a clinical trial for cardiac regeneration. Nevertheless, the validity of the cardiosphere strategy to generate CPCs has been called into question by reports based on variant methods. In those reports, cardiospheres are argued to be cardiomyogenic only because of retained cardiomyocytes, and stem cell activity has been proposed to reflect hematological contamination. We use a variety of approaches (including genetic lineage tracing) to show that neither artifact is applicable to cardiospheres and CDCs grown using established methods, and we further document the stem cell characteristics (namely, clonogenicity and multilineage potential) of CDCs. METHODOLOGY/PRINCIPAL FINDINGS: CPCs were expanded from human endomyocardial biopsies (n = 160), adult bi-transgenic MerCreMer-Z/EG mice (n = 6), adult C57BL/6 mice (n = 18), adult GFP(+) C57BL/6 transgenic mice (n = 3), Yucatan mini pigs (n = 67), adult SCID beige mice (n = 8), and adult Wistar-Kyoto rats (n = 80). Cellular yield was enhanced by collagenase digestion and process standardization; yield was reduced in altered media and in specific animal strains. Heparinization/retrograde organ perfusion did not alter the ability to generate outgrowth from myocardial sample. The initial outgrowth from myocardial samples was enriched for sub-populations of CPCs (c-Kit(+)), endothelial cells (CD31(+), CD34(+)), and mesenchymal cells (CD90(+)). Lineage tracing using MerCreMer-Z/EG transgenic mice revealed that the presence of cardiomyocytes in the cellular outgrowth is not required for the generation of CPCs. Rat CDCs are shown to be clonogenic, and cloned CDCs exhibit spontaneous multineage potential. CONCLUSIONS/SIGNIFICANCE: This study demonstrates that direct culture and expansion of CPCs from myocardial tissue is simple, straightforward, and reproducible when appropriate techniques are used. PMID- 19779619 TI - Impact of working memory load on FMRI resting state pattern in subsequent resting phases. AB - BACKGROUND: The default-mode network (DMN) is a functional network with increasing relevance for psychiatric research, characterized by increased activation at rest and decreased activation during task performance. The degree of DMN deactivation during a cognitively demanding task depends on its difficulty. However, the relation of hemodynamic responses in the resting phase after a preceding cognitive challenge remains relatively unexplored. We test the hypothesis that the degree of activation of the DMN following cognitive challenge is influenced by the cognitive load of a preceding working-memory task. METHODOLOGY/PRINCIPAL FINDINGS: Twenty-five healthy subjects were investigated with functional MRI at 3 Tesla while performing a working-memory task with embedded short resting phases. Data were decomposed into statistically independent spatio-temporal components using Tensor Independent Component Analysis (TICA). The DMN was selected using a template-matching procedure. The spatial map contained rest-related activations in the medial frontal cortex, ventral anterior and posterior cingulate cortex. The time course of the DMN revealed increased activation at rest after 1-back and 2-back blocks compared to the activation after a 0-back block. CONCLUSION/SIGNIFICANCE: We present evidence that a cognitively challenging working-memory task is followed by greater activation of the DMN than a simple letter-matching task. This might be interpreted as a functional correlate of self-evaluation and reflection of the preceding task or as relocation of cerebral resources representing recovery from high cognitive demands. This finding is highly relevant for neuroimaging studies which include resting phases in cognitive tasks as stable baseline conditions. Further studies investigating the DMN should take possible interactions of tasks and subsequent resting phases into account. PMID- 19779620 TI - Syndromic management and STI control in urban Peru. AB - BACKGROUND: Syndromic management is an inexpensive and effective method for the treatment of symptomatic sexually transmitted infections (STIs), but its effectiveness as a method of STI control in at-risk populations is questionable. We sought to determine the potential utility of syndromic management as a public health strategy to control STI transmission in high-risk populations in urban Peru. METHODOLOGY: We surveyed 3,285 at-risk men and women from three Peruvian cities from 2003-05. Participants were asked about the presence of genital ulcers, discharge, or dysuria in the preceding six months. Participants reporting symptoms were asked about subsequent health-seeking and partner notification behavior. Urine and vaginal swab samples were tested for Neisseria gonorrhoeae and Chlamydia trachomatis by nucleic acid testing. Serum was tested for syphilis and Herpes Simplex Virus-Type 2 antibodies. FINDINGS: Recent urogenital discharge or dysuria was reported by 42.1% of participants with gonorrhea or chlamydia versus 28.3% of participants without infection. Genital ulceration was reported by 6.2% of participants with, and 7.4% of participants without, recent syphilis. Many participants reporting symptoms continued sexual activity while symptomatic, and approximately half of all symptomatic participants sought treatment. The positive and negative predictive values of urogenital discharge or genital ulcer disease in detecting STIs that are common in the study population were 14.4% and 81.5% for chlamydia in women and 8.3% and 89.5% for syphilis among gay-identified men. CONCLUSIONS: In our study, STIs among high-risk men and women in urban Peru were frequently asymptomatic and symptomatic participants often remained sexually active without seeking treatment. Additional research is needed to assess the costs and benefits of targeted, laboratory-based STI screening as part of a comprehensive STI control program in developing countries. PMID- 19779621 TI - Investigating the targets of MIR-15a and MIR-16-1 in patients with chronic lymphocytic leukemia (CLL). AB - BACKGROUND: MicroRNAs (miRNAs) are short, noncoding RNAs that regulate the expression of multiple target genes. Deregulation of miRNAs is common in human tumorigenesis. The miRNAs, MIR-15a/16-1, at chromosome band 13q14 are down regulated in the majority of patients with chronic lymphocytic leukaemia (CLL). METHODOLOGY/PRINCIPAL FINDINGS: We have measured the expression of MIR-15a/16-1, and 92 computationally-predicted MIR-15a/16-1 target genes in CLL patients and in normal controls. We identified 35 genes that are deregulated in CLL patients, 5 of which appear to be specific targets of the MIR-15a/16-1 cluster. These targets included 2 genes (BAZ2A and RNF41) that were significantly up-regulated (p<0.05) and 3 genes (RASSF5, MKK3 and LRIG1) that were significantly down-regulated (p<0.05) in CLL patients with down-regulated MIR-15a/16-1 expression. SIGNIFICANCE: The genes identified here as being subject to MIR-15a/16-1 regulation could represent direct or indirect targets of these miRNAs. Many of these are good biological candidates for involvement in tumorigenesis and as such, may be important in the aetiology of CLL. PMID- 19779622 TI - No consistent effect of ADRB2 haplotypes on obesity, hypertension and quantitative traits of body fatness and blood pressure among 6,514 adult Danes. AB - BACKGROUND: Evidence regarding the association of variation within ADRB2, the gene encoding the beta-adrenergic receptor 2 (ADRB2) with obesity and hypertension is exceedingly ambiguous. Despite negative reports, functional impacts of individual genetic variants have been reported. Also, functional haplotypes as well as haplotype combinations affecting expression levels in vivo of ADRB2 mRNA and protein as well as receptor sensitivity have been reported. The aim of the present study was therefore to evaluate if variations within ADRB2 as haplotypes or as haplotype combinations confer an increased prevalence of obesity and hypertension among adults. METHODOLOGY/PRINCIPAL FINDINGS: We genotyped five variants required to capture common variation in a region including the ADRB2 locus in a population-based study of 6,514 unrelated, middle-aged Danes. Phases of the genotypes were estimated in silico. The variations were then investigated for their combined association with obesity, hypertension and related quantitative traits. The present study did not find consistent evidence for an association of ADRB2 variants with either obesity or hypertension when variations were analysed in a case-control study. The same lack of impact was also seen in the quantitative trait analyses, apart from nominal differences on waist-to-hip ratio and systolic blood pressure between specific haplotype combinations. CONCLUSIONS/SIGNIFICANCE: In a population-based sample of 6,514 Danes we found no consistent associations between five common variants which tag the ADRB2 locus and prevalence of obesity or hypertension neither when analysed as individual haplotypes nor as haplotype pairs. PMID- 19779623 TI - Human regulatory T cell suppressive function is independent of apoptosis induction in activated effector T cells. AB - BACKGROUND: CD4(+)CD25(+)FOXP3(+) Regulatory T cells (Treg) play a central role in the immune balance to prevent autoimmune disease. One outstanding question is how Tregs suppress effector immune responses in human. Experiments in mice demonstrated that Treg restrict effector T cell (Teff) responses by deprivation of the growth factor IL-2 through Treg consumption, resulting in apoptosis of Teff. PRINCIPAL FINDINGS: In this study we investigated the relevance of Teff apoptosis induction to human Treg function. To this end, we studied naturally occurring Treg (nTreg) from peripheral blood of healthy donors, and, to investigate Treg function in inflammation in vivo, Treg from synovial fluid of Juvenile Idiopathic Arthritis (JIA) patients (SF-Treg). Both nTreg and SF-Treg suppress Teff proliferation and cytokine production efficiently as predicted. However, in contrast with murine Treg, neither nTreg nor SF-Treg induce apoptosis in Teff. Furthermore, exogenously supplied IL-2 and IL-7 reverse suppression, but do not influence apoptosis of Teff. SIGNIFICANCE: Our functional data here support that Treg are excellent clinical targets to counteract autoimmune diseases. For optimal functional outcome in human clinical trials, future work should focus on the ability of Treg to suppress proliferation and cytokine production of Teff, rather than induction of Teff apoptosis. PMID- 19779624 TI - Early outcomes of MDR-TB treatment in a high HIV-prevalence setting in Southern Africa. AB - BACKGROUND: Little is known about treatment of multidrug-resistant tuberculosis (MDR-TB) in high HIV-prevalence settings such as sub-Saharan Africa. METHODOLOGY/PRINCIPAL FINDINGS: We did a retrospective analysis of early outcomes of the first cohort of patients registered in the Lesotho national MDR-TB program between July 21, 2007 and April 21, 2008. Seventy-six patients were included for analysis. Patient follow-up ended when an outcome was recorded, or on October 21, 2008 for those still on treatment. Fifty-six patients (74%) were infected with HIV; the median CD4 cell count was 184 cells/microl (range 5-824 cells/microl). By the end of the follow-up period, study patients had been followed for a median of 252 days (range 12-451 days). Twenty-two patients (29%) had died, and 52 patients (68%) were alive and in treatment. In patients who did not die, culture conversion was documented in 52/54 patients (96%). One patient had defaulted, and one patient had transferred out. Death occurred after a median of 66 days in treatment (range 12-374 days). CONCLUSIONS/SIGNIFICANCE: In a region where clinicians and program managers are increasingly confronted by drug-resistant tuberculosis, this report provides sobering evidence of the difficulty of MDR-TB treatment in high HIV-prevalence settings. In Lesotho, an innovative community based treatment model that involved social and nutritional support, twice-daily directly observed treatment and early empiric use of second-line TB drugs was successful in reducing mortality of MDR-TB patients. Further research is urgently needed to improve MDR-TB treatment outcomes in high HIV-prevalence settings. PMID- 19779625 TI - Can the error detection mechanism benefit from training the working memory? A comparison between dyslexics and controls--an ERP study. AB - BACKGROUND: Based on the relationship between working memory and error detection, we investigated the capacity of adult dyslexic readers' working memory to change as a result of training, and the impact of training on the error detection mechanism. METHODOLOGY: 27 dyslexics and 34 controls, all university students, participated in the study. ERP methodology and behavioral measures were employed prior to, immediately after, and 6 months after training. The CogniFit Personal Coach Program, which consists of 24 sessions of direct training of working memory skills, was used. FINDINGS: Both groups of readers gained from the training program but the dyslexic readers gained significantly more. In the dyslexic group, digit span increased from 9.84+/-3.15 to 10.79+/-3.03. Working memory training significantly increased the number of words per minute read correctly by 14.73%. Adult brain activity changed as a result of training, evidenced by an increase in both working memory capacity and the amplitude of the Error-related Negativity (ERN) component (24.71%). When ERN amplitudes increased, the percentage of errors on the Sternberg tests decreased. CONCLUSIONS: We suggest that by expanding the working memory capacity, larger units of information are retained in the system, enabling more effective error detection. The crucial functioning of the central-executive as a sub-component of the working memory is also discussed. PMID- 19779626 TI - galign: a tool for rapid genome polymorphism discovery. AB - BACKGROUND: Highly parallel sequencing technologies have become important tools in the analysis of sequence polymorphisms on a genomic scale. However, the development of customized software to analyze data produced by these methods has lagged behind. METHODS/PRINCIPAL FINDINGS: Here I describe a tool, 'galign', designed to identify polymorphisms between sequence reads obtained using Illumina/Solexa technology and a reference genome. The 'galign' alignment tool does not use Smith-Waterman matrices for sequence comparisons. Instead, a simple algorithm comparing parsed sequence reads to parsed reference genome sequences is used. 'galign' output is geared towards immediate user application, displaying polymorphism locations, nucleotide changes, and relevant predicted amino-acid changes for ease of information processing. To do so, 'galign' requires several accessory files easily derived from an annotated reference genome. Direct sequencing as well as in silico studies demonstrate that 'galign' provides lesion predictions comparable in accuracy to available prediction programs, accompanied by greater processing speed and more user-friendly output. We demonstrate the use of 'galign' to identify mutations leading to phenotypic consequences in C. elegans. CONCLUSION/SIGNIFICANCE: Our studies suggest that 'galign' is a useful tool for polymorphism discovery, and is of immediate utility for sequence mining in C. elegans. PMID- 19779627 TI - Look before you leap: is risk of injury a foraging cost? AB - Theory states that an optimal forager should exploit a patch so long as its harvest rate of resources from the patch exceeds its energetic, predation, and missed opportunity costs for foraging. However, for many foragers, predation is not the only source of danger they face while foraging. Foragers also face the risk of injuring themselves. To test whether risk of injury gives rise to a foraging cost, we offered red foxes pairs of depletable resource patches in which they experienced diminishing returns. The resource patches were identical in all respects, save for the risk of injury. In response, the foxes exploited the safe patches more intensively. They foraged for a longer time and also removed more food (i.e., had lower giving up densities) in the safe patches compared to the risky patches. Although they never sustained injury, video footage revealed that the foxes used greater care while foraging from the risky patches and removed food at a slower rate. Furthermore, an increase in their hunger state led foxes to allocate more time to foraging from the risky patches, thereby exposing themselves to higher risks. Our results suggest that foxes treat risk of injury as a foraging cost and use time allocation and daring-the willingness to risk injury-as tools for managing their risk of injury while foraging. This is the first study, to our knowledge, which explicitly tests and shows that risk of injury is indeed a foraging cost. While nearly all foragers may face an injury cost of foraging, we suggest that this cost will be largest and most important for predators. PMID- 19779629 TI - Cell cycle re-entry and mitochondrial defects in myc-mediated hypertrophic cardiomyopathy and heart failure. AB - While considerable evidence supports the causal relationship between increases in c-Myc (Myc) and cardiomyopathy as a part of a "fetal re-expression" pattern, the functional role of Myc in mechanisms of cardiomyopathy remains unclear. To address this, we developed a bitransgenic mouse that inducibly expresses Myc under the control of the cardiomyocyte-specific MHC promoter. In adult mice the induction of Myc expression in cardiomyocytes in the heart led to the development of severe hypertrophic cardiomyopathy followed by ventricular dysfunction and ultimately death from congestive heart failure. Mechanistically, following Myc activation, cell cycle markers and other indices of DNA replication were significantly increased suggesting that cell cycle-related events might be a primary mechanism of cardiac dysfunction. Furthermore, pathological alterations at the cellular level included alterations in mitochondrial function with dysregulation of mitochondrial biogenesis and defects in electron transport chain complexes I and III. These data are consistent with the known role of Myc in several different pathways including cell cycle activation, mitochondrial proliferation, and apoptosis, and indicate that Myc activation in cardiomyocytes is an important regulator of downstream pathological sequelae. Moreover, our findings indicate that the induction of Myc in cardiomyocytes is sufficient to cause cardiomyopathy and heart failure, and that sustained induction of Myc, leading to cell cycle re-entry in adult cardiomyocytes, represents a maladaptive response for the mature heart. PMID- 19779630 TI - Investigating neuromagnetic brain responses against chromatic flickering stimuli by wavelet entropies. AB - BACKGROUND: Photosensitive epilepsy is a type of reflexive epilepsy triggered by various visual stimuli including colourful ones. Despite the ubiquitous presence of colorful displays, brain responses against different colour combinations are not properly studied. METHODOLOGY/PRINCIPAL FINDINGS: Here, we studied the photosensitivity of the human brain against three types of chromatic flickering stimuli by recording neuromagnetic brain responses (magnetoencephalogram, MEG) from nine adult controls, an unmedicated patient, a medicated patient, and two controls age-matched with patients. Dynamical complexities of MEG signals were investigated by a family of wavelet entropies. Wavelet entropy is a newly proposed measure to characterize large scale brain responses, which quantifies the degree of order/disorder associated with a multi-frequency signal response. In particular, we found that as compared to the unmedicated patient, controls showed significantly larger wavelet entropy values. We also found that Renyi entropy is the most powerful feature for the participant classification. Finally, we also demonstrated the effect of combinational chromatic sensitivity on the underlying order/disorder in MEG signals. CONCLUSIONS/SIGNIFICANCE: Our results suggest that when perturbed by potentially epileptic-triggering stimulus, healthy human brain manages to maintain a non-deterministic, possibly nonlinear state, with high degree of disorder, but an epileptic brain represents a highly ordered state which making it prone to hyper-excitation. Further, certain colour combination was found to be more threatening than other combinations. PMID- 19779632 TI - A Tribute to Professor Van C. Mow: A Wonderful Scholar and Leader in Bioengineering. PMID- 19779631 TI - Human ghrelin ameliorates organ injury and improves survival after radiation injury combined with severe sepsis. AB - In the terrorist radiation exposure scenario, radiation victims are likely to suffer from additional injuries such as sepsis. Our previous studies have shown that ghrelin is protective in sepsis. However, it remains unknown whether ghrelin ameliorates sepsis-induced organ injury and mortality after radiation exposure. The purpose of this study is to determine whether human ghrelin attenuates organ injury and improves survival in a rat model of radiation combined injury (RCI) and, if so, the potential mechanism responsible for the benefit. To study this, adult male rats were exposed to 5-Gy whole body irradiation followed by cecal ligation and puncture (CLP, a model of sepsis) 48 h thereafter. Human ghrelin (30 nmol/rat) or vehicle (saline) was infused intravenously via an osmotic minipump immediately after radiation exposure. Blood and tissue samples were collected at 20 h after RCI (68 h after irradiation or 20 h after CLP) for various measurements. To determine the longterm effect of human ghrelin after RCI, the gangrenous cecum was removed at 5 h after CLP and 10-d survival was recorded. In addition, vagotomy or sham vagotomy was performed in sham and RCI animals immediately prior to ghrelin administration, and various measurements were performed at 20 h after RCI. Our results showed that serum levels of ghrelin and its gene expression in the stomach were decreased markedly at 20 h after RCI. Administration of human ghrelin attenuated tissue injury markedly, reduced proinflammatory cytokine levels, decreased tissue myeloperoxidase activity, and improved survival after RCI. Furthermore, elevated plasma levels of norepinephrine (NE) after RCI were reduced significantly by ghrelin. However, vagotomy prevented ghrelin's beneficial effects after RCI. In conclusion, human ghrelin is beneficial in a rat model of RCI. The protective effect of human ghrelin appears to be attributed to re-balancing the dysregulated sympathetic/parasympathetic nervous systems. PMID- 19779633 TI - Live Cells Exert 3-Dimensional Traction Forces on Their Substrata. AB - The traction forces exerted by an adherent cell on a substrate have been studied only in the two-dimensions (2D) tangential to substrate surface (Txy). We developed a novel technique to measure the three-dimensional (3D) traction forces exerted by live bovine aortic endothelial cells (BAECs) on polyacrylamide deformable substrate. On 3D images acquired by confocal microscopy, displacements were determined with image-processing programs, and traction forces in tangential (XY) and normal (Z) directions were computed by finite element method (FEM). BAECs generated traction force in normal direction (Tz) with an order of magnitude comparable to Txy. Tz is upward at the cell edge and downward under the nucleus, changing continuously with a sign reversal between cell edge and nucleus edge. The method was evaluated regarding accuracy and precision of displacement measurements, effects of FE mesh size, displacement noises, and simple bootstrapping. These results provide new insights into cell-matrix interactions in terms of spatial and temporal variations in traction forces in 3D. This technique can be applied to study live cells to assess their biomechanical dynamics in conjunction with biochemical and functional activities, for investigating cellular functions in health and disease. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12195-009-0082-6) contains supplementary material, which is available to authorized users. PMID- 19779638 TI - Electrodes for integral membrane enzymes. PMID- 19779639 TI - The aminocoumarins: biosynthesis and biology. PMID- 19779640 TI - An update on lignans: natural products and synthesis. PMID- 19779641 TI - Discovery, biological activity, synthesis and potential therapeutic utility of naturally occurring histone deacetylase inhibitors. PMID- 19779645 TI - Identification and characterization of an epididymis-specific gene, Ces7. AB - Carboxylesterases (CEs) represent a multigene family of serine-dependent enzymes. Male-dependent CEs are over-expressed in the male reproductive tract of different animal species (bivalve mollusks, fruit-flies, and mammals). Here, a novel rat epididymis-specific gene named Ces7 was cloned and characterized. It was a novel member of CE family, which was mainly expressed and secreted to the lumens of the corpus and cauda epididymis. CES7 protein was highly glycosylated as other mammalian CEs. Furthermore, Ces7 increased with age growth until sex maturation and then maintained at high level. CES7 might be one of the major CEs in male reproductive tract and contribute to the sperm fertilization. PMID- 19779646 TI - Identification of FANCA as a protein interacting with centromere-associated protein E. AB - This study sought to isolate and identify proteins that interact with centromere associated protein E (CENPE), provide new clues for exploring the function of CENP-E in cell cycle control and the pathogenesis of tumor. Yeast two-hybrid screen and regular molecular biologic techniques were undertaken to screen human HeLa cDNA library with the kinetochore binding domain of CENP-E. The bait from the C-terminus of CENP-E was created by subcloning methods to find out optimal candidate proteins that interact with the kinetochore binding domain of CENP-E. Eight novel CENP-E interacting proteins including Homo sapiens Fanconi anemia complementation group A (FANCA) were obtained. In yeast two-hybrid assay, the N terminal 260 amino acids of FANCA were found to be necessary and sufficient for the interaction with the C-terminus of CENP-E. The interaction was confirmed by in vitro glutathione S-transferase pull-down assay and in vivo coimmunoprecipitation assay. Our finding of the interaction of CENP-E with FANCA demonstrates that CENP-E and FANCA may play important roles in the functional regulation of the mitotic checkpoint signal pathway. PMID- 19779647 TI - A small functional intramolecular region of NodD was identified by mutation. AB - In Rhizobium leguminosarum bv. viciae, NodD, as a member of the LysR-type transcriptional regulators (LTTRs), exerts auto-regulation and activates transcription of other nod genes in the presence of naringenin. LTTRs were typically composed of N-terminal DNA-binding domain and C-terminal regulatory domain. In this study, by systematic insertion mutation, a region of 12 amino acids in length of NodD was identified as functional domain. Insertion mutants in this region appeared to acquire the ability of constitutively activating nodA gene and retained their auto-regulation properties. This identified region was shown to be a hinge of NodD as revealed through the model built using Swiss- PDB Viewer software. It is the first time to report that as a member of LysR family, NodD has been shown to contain a short intramolecular domain that influences its performance. PMID- 19779648 TI - Human Elongator complex is involved in cell cycle and suppresses cell growth in 293T human embryonic kidney cells. AB - Elongator complex has been associated with hyperphosphorylated RNA polymerase II and is known to play critical roles in transcriptional elongation, as well as in tRNA modification and exocytosis. However, the specific mechanism of how human Elongator complex regulates cell growth and cell cycle remains unclear. To investigate the composition of human Elongator complex and its effects on cell growth, 293T cells were established that stably overexpressed Flag-Elp3 and Flag Elp4. By using anti-Flag M2 antibody-bound resin, a core Elongator complex was purified from cells that stably overexpressed Flag-Elp3. No Elongator complex was purified from cells stably transfected with pFlagCMV4-Elp4. Interestingly, the cell growth was inhibited in 293T cells transfected with pFlagCMV4- Elp3. Flow cytometry analysis showed that most of the cells stably overexpressing Flag-Elp3 were found in G1 stage, indicating a role of the core Elongator in the G1 checkpoint for the regulation of cell cycle. We observed increased basal transcription and remarkably enhanced transcription stimulated by VP16 in 293T cells overexpressing Flag-Elp3. The transcription could also be synergistically activated by overexpressing both Elp3 and Elp4. Taken together, our results suggested that the core Elongator complex formed by Elp1, Elp2, and Elp3 was rather stable, whereas Elp4, Elp5, and Elp6 might loosely contact and work together with the core Elongator to regulate cell functions. PMID- 19779649 TI - Cortactin is involved in transforming growth factor-beta1-induced epithelial mesenchymal transition in AML-12 cells. AB - Cortactin is an F-actin binding protein, regulating cell movement and adhesive junction assembly. However, the function of cortactin in epithelial-mesenchymal transition (EMT) remains elusive. Here we found that during transforming growth factor-beta1 (TGF-beta1)- induced EMT in AML-12 murine hepatocytes, cortactin underwent tyrosine dephosphorylation. Inhibition of the dephosphorylation of cortactin by sodium vanadate blocked TGF-beta1-induced EMT. Knockdown of cortactin by RNAi led to decrease of intercellular junction proteins E-cadherin and Zonula occludens-1 and induced expression of mesenchymal protein fibronectin. Additionally, knockdown of cortactin further promoted TGF-beta1-induced EMT in AML-12 cells, as determined by EMT markers and cell morphological changes. Moreover, migration assay showed that cortactin knockdown promoted the migration of AML-12 cells, and also enhanced TGF-beta1-induced migration. Our study showed the involvement of cortactin in the TGFbeta1- induced EMT. PMID- 19779642 TI - Plant-derived triterpenoids and analogues as antitumor and anti-HIV agents. PMID- 19779650 TI - Regulation of membrane band 3 Tyr-phosphorylation by proteolysis of p72(Syk) and possible involvement in senescence process. AB - Erythrocyte senescence is characterized by exposure of cell surface epitopes on cell membrane proteins leading to immune mediated removal of red blood cells. One mechanism for antigen formation is tyrosine phosphorylation (Tyr-P) of the transmembrane protein band 3 by Syk kinase. Our aim was to test the hypothesis that proteolytic activation of Syk kinase by conversion from 72 kDa (p72(Syk)) to the 36 kDa (p36(Syk)) isoform enhances its phosphorylating activity independently of the association of Syk kinase with the cytoskeleton. Tyr-P assay was conducted using quantification of (32)P uptake into the cytoplasmic domain of band 3 after addition of p72(Syk) or p36(Syk). Effect of prephosphorylation of erythrocyte membrane band 3 protein by p36(Syk) on p72(Syk)-mediated phosphorylation and the effect of addition of a protease inhibitor (leupeptin) on p72(Syk)-mediated phosphorylation were studied by autoradiographic visualization of (32)P uptake. Tyr-P by Syk isoforms of membrane skeletal and soluble fractions of band 3 was visualized by immunoblotting. It was found that p36(Syk) had a higher band 3 tyrosine phosphorylating activity compared with p72(Syk). Pre-phosphorylation with p36(Syk) or p72(Syk) increased band 3 phosphorylating activity. Protease inhibition treatment reduced p72(Syk) but not p36(Syk) band 3 tyrosine phosphorylating activity significantly. Both soluble and membrane skeletal fractions of band 3 protein were equally tyrosine phosphorylated by each Syk isoform. In conclusion, we confirmed the hypothesis that proteolytic cleavage of p72(Syk) is an important regulatory step for band 3 Tyr-P and its independence of the association of band 3 with the cytoskeleton. PMID- 19779651 TI - Protein engineering of a fibroblast growth factor-1 fusion protein with cell adhesive activity. AB - Fibroblast growth factor-1 (FGF1) is one of the most potent angiogenic growth factors, and also plays an important role in regulating cellular functions including cell proliferation, motility, differentiation, survival, and tissue regeneration processes. Here we described a novel fusion protein that was designed by combining the cell adhesion sequence from fibronectin with FGF1. The F1-Fn fusion protein functions as a minimized protein that directs integrin dependent cell adhesion and stimulates cellular responses including cell proliferation and differentiation. Moreover, our results indicate that Fn mediated signaling synergizes with signals from FGF1 in promoting cellular adhesion, proliferation, and differentiation in MG63 cells. PMID- 19779652 TI - Characterization of a novel alpha4/4-conotoxin, Qc1.2, from vermivorous Conus quercinus. AB - As part of continuing studies of the identification of gene organization and cloning of novel alpha-conotoxins, the first alpha4/4-conotoxin identified in a vermivorous Conus species, designated Qc1.2, was originally obtained by cDNA and genomic DNA cloning from Conus quercinus collected in the South China Sea. The predicted mature toxin of Qc1.2 contains 14 amino acid residues with two disulfide bonds (I-III, II-IV connectivity) in a native globular configuration. The mature peptide of Qc1.2 is supposed to contain an N-terminal post translationally processed pyroglutamate residue and a free carboxyl C-terminus. This peptide was chemically synthesized and refolded for further characterization of its functional properties. The synthetic Qc1.2 has two interconvertible conformations in aqueous solution, which may be due to the cis-trans isomerization of the two successive Pro residues in its first Cys loop. Using the Xenopus oocyte heterologous expression system, Qc1.2 was shown to selectively inhibit both rat neuronal alpha3beta2 and alpha3beta4 subtypes of nicotinic acetylcholine receptors with low potency. A block of about 63% and 37% of the ACh evoked currents was observed, respectively, and the toxin dissociated rapidly from the receptors. Compared with other characterized alpha-conotoxin members, the unusual structural features in Qc1.2 that confer to its receptor recognition profile are addressed. PMID- 19779653 TI - Purification and characterization of phenoloxidase from Octopus ocellatus. AB - Phenoloxidase (PO) from ink sacs of Octopus ocellatus was purified by gel filtration and ion-exchange chromatography, and characterized in terms of its biochemical and enzymatic properties by using L-dihydroxyphenylalanine (L-DOPA) as the specific substrate. It was found that prophenoloxidase from O. ocellatus was isolated as a heterodimeric protein of 153.8 kDa, and two subunits of 75.6 and 73.0 kDa were often detected in preparations after SDS activation. The PO like activity showed optimal pH of 7.0, optimal temperature of 40 degrees C, and an apparent Km value of 3.1 mM on L-DOPA, and 6.3 mM on catechol, respectively. The PO-like activity was extremely sensitive to 1-phenyl-2-thiourea and sodium sulfite, and very sensitive to ascorbic acid, thiourea, citric acid, and benzoic acid. Together with its specific enzyme activity on catechol and L-DOPA, it can be concluded that the Octopus PO is most probably a typical o-diphenoloxidase. The PO-like activity was also strongly inhibited by Cu(2+), Zn(2+), ethylenediaminetetraacetic acid and diethyldithiocarbamate (DETC), and the DETC inhibited PO-like activity could be perfectly restored by Cu(2+). These results indicated that Octopus PO is most probably a copper-containing metalloenzyme. All these results implied that the PO from O. ocellatus has the properties of a catechol-type copper-containing o-diphenoloxidase which functions not only as a catalytic enzyme in melanin production in ink sacs but also as a humoral factor in host defense via melaninization as in other crustaceans. PMID- 19779654 TI - Identification of a novel negative regulatory element on the hepatitis B virus S (+)-strand. AB - In this study, we scanned the whole hepatitis B virus (HBV) genome for the identification of potential regulatory elements located on the S-(+)-strand. With pCDNA3.1-HBV1.3 as template which contains 1.3-fold HBV whole genome, HBV fragments were amplified by PCR methods, and then inserted into the upstream of a heterologous luciferase reporter vector (pGL3control) in antisense orientation, allowing the HBV expression from the S-(+)-strand. We found that the reporter plasmid containing nt 509-1(3182)-2639 of HBV inhibited luciferase gene transcription and expression in HepG2 cells. Our results strongly suggested that nt 453-250 of HBV may act as a novel negative regulatory element, which has not been reported before. Serial deletion analyses further indicated that nt 453-250 sequence of HBV genome would be the minimal sequence essential for the inhibitory effect of the novel negative regulatory element. PMID- 19779655 TI - Bioaccumulation of total and methyl mercury in three earthworm species (Drawida sp., Allolobophora sp., and Limnodrilus sp.). AB - We determined total and methyl mercury contents in soil, three earthworm species and their vomitus to study the species-specific differences of mercury bioconcentration in Huludao City, a heavily polluted region by chlor-alkali and nonferrous metal smelting industry in Liaoning Province, northeast China. Total and methyl mercury contents were 7.20 mg/kg and 6.94 ng/g in soil, 1.43 mg/kg and 43.03 ng/g in Drawida sp., 2.80 mg/kg and 336.52 ng/g in Alolobophora sp., respectively. Total mercury contents were 0.966 mg/kg in Drawida sp. vomitus and 4.979 mg/kg in Alolobophora sp. vomitus, respectively. Total mercury contents in earthworms and their vomitus were significantly species-specific different and were both in decreasing with earthworms body lengths, which might due to the growth dilution. Among the soil, earthworms and their vomitus, total mercury contents were in the order of soil > earthworms > earthworm vomitus. Methyl mercury was about 3.01% of total mercury in Drawida sp., 12.02% of total mercury in Alolobophora sp., respectively. It suggested that mercury was mostly in inorganic forms in earthworms. Bioaccumulation factors of methyl mercury from soil to earthworms were much higher than those of total mercury, which suggested that methyl mercury might be more easily absorbed by and accumulated in earthworms because of its lipid solubility. PMID- 19779656 TI - Arsenic resistant bacteria isolated from arsenic contaminated river in the Atacama Desert (Chile). AB - In this study, arsenic resistant bacteria were isolated from sediments of an arsenic contaminated river. Arsenic tolerance of bacteria isolated was carried out by serial dilution on agar plate. Redox abilities were investigated using KMnO4. arsC and aox genes were detected by PCR and RT-PCR, respectively. Bacterial populations were identified by RapID system. Forty nine bacterial strains were isolated, of these, 55 % corresponded to the reducing bacteria, 4% to oxidizing bacteria, 8% presented both activities and in 33% of the bacteria none activity was detected. arsC gene was detected in 11 strains and aox genes were not detected. The activity of arsenic transforming microorganisms in river sediment has significant implications for the behavior of the metalloid. PMID- 19779657 TI - Response to Wall and Brown: "Commercial pressures and professional ethics: troubling revisions to the recent ACOG Practice Bulletins on surgery for pelvic organ prolapse". PMID- 19779659 TI - Comments on Wall and Brown: "Commercial pressures and professional ethics: troubling revisions to the recent ACOG Practice Bulletins on surgery for pelvic organ prolapse". PMID- 19779661 TI - Meniscoligamentous band between the posterior horn of the lateral meniscus and the anterior cruciate ligament: arthroscopic, anatomical and histological observations. AB - BACKGROUND: Following the example of the anterior cruciate ligament reconstruction, the success of meniscus allograft transplantation relies on good position of the graft and firm anchorage. The anatomy of the intercondylar region and the connections between the cruciate ligament and the meniscal horns have been the subject of many surveys. However, as far as we know, there is only one description of meniscoligamentous band between the posterior horn of the lateral meniscus (PHLM) and the anterior cruciate ligament (ACL) (Lahlaidi in Rev Chir Orthop Reparatrice Appar Mot 57(8):593-600, 1971). METHODS: Fourteen cadaveric knees have been dissected to study the presence and variations of the band between the PHLM and the ACL. In addition, we undertook a histological study to ensure its ligamentous nature. RESULTS: This meniscoligamentous band was found 13 times amongst the 14 investigated knees, and its ligamentous intra-articular extra-synovial nature was proved. CONCLUSIONS: This study helps us to better understand the biomechanics of the menisci that are both stable and mobile structures. PMID- 19779662 TI - Localization of motor entry points and terminal intramuscular nerve endings of the musculocutaneous nerve to biceps and brachialis muscles. AB - To determine the 3D location of the intramuscular motor nerve endings of the biceps brachii and brachialis, we identified from 56 fresh cadaveric arms the regions where the intramuscular branches were most densely located in relation to a reference line connecting the medial epicondyle of humerus and the coracoid process. For the biceps, these points were most densely distributed at a length from 64.6 to 70.3% point of the reference line with the coracoid process as starting point, at a width of 21.6-32.6 mm lateral to the reference line. For the brachialis muscle, these points were located at a length of 75.4% point and width of 27.1-35.4 mm lateral to the reference line. At these points, the biceps was located at a depth of the upper two-third portion and the brachialis at the lower one-third portion of the upper arm, from skin to humeral bone. PMID- 19779663 TI - For which type of chronic pancreatitis is the "Hamburg procedure" indicated? AB - BACKGROUND: A pancreatic duct diameter (PDD) ranging from 4 to 5 mm is regarded as "normal". The "large duct" form of chronic pancreatitis (CP) with a PDD > 7 mm is considered a classical indication for drainage procedures. In contrast, in patients with so-called "small duct pancreatitis" (SDP) with a PDD < 3 mm, extended resectional procedures are suggested including, as an "ultima ratio", even total pancreatectomy. METHODS: Between 1992 and 2008, among a total of 978 patients who were treated for CP, 51 suffered from SDP and underwent longitudinal "V-shaped excision" of the anterior aspect of the pancreas. The interval between symptoms and surgery varied from 12 to 123 months. Median follow-up was 87 months (range 32-131 months). A pain score was used as well as a multidimensional psychometric quality-of-life questionnaire. RESULTS: Hospital mortality was 0%. The perioperative morbidity (30 days) was 19.1%. Median pain score decreased by 95.5%. Global quality of life index increased in median by 53.6% (range 37.5 80%). In 35 patients (75%), complete pain relief was achieved. The impairment of exocrine and endocrine pancreatic function after surgery was statistically not significant. CONCLUSIONS: Longitudinal "V-shaped excision" of the ventral pancreas is a secure and effective approach for SDP, achieving significant improvement in quality of life and pain relief. While sparing patients from unnecessary, extended resectional procedures, it appears not to result in substantial deterioration of exocrine and endocrine pancreatic function. PMID- 19779664 TI - Has the Partington procedure for chronic pancreatitis become a thing of the past? A review of the evidence. AB - INTRODUCTION: For the surgical management of chronic pancreatitis with an inflammatory pancreatic head mass, extended drainage operations such as Beger and Frey procedures were established in the 1980s as an alternative to resectional procedures like pancreaticoduodenectomy and as opposed to simple drainage operations such as lateral pancreaticojejunostomy, that is, the Partington procedure. With the relatively rapid adoption of the two procedures, it seems that the Partington procedure has become a thing of the past. MATERIALS AND METHODS: The Partington procedure was re-evaluated with regard to the historical aspects and its present status by a literature review. RESULTS: The results show that this procedure relieves chronic abdominal pain in 66-91% of patients with a mean follow-up of 3.5-9.1 years. It is important to note that this procedure is generally used for inflammatory disease left of the gastroduodenal artery and is specifically not used as the procedure of choice for inflammatory disease of the pancreatic head. CONCLUSION: For patients with a dilated main pancreatic duct but without an inflammatory pancreatic head mass, the Partington procedure is still the procedure of choice, since it is technically simple to perform with a minimum of morbidity and mortality, preserving pancreatic endocrine and exocrine function. Because it is a relatively simple technique, the laparoscopic approach will be justified as a treatment of appropriate patients in the near future. PMID- 19779665 TI - Pancreatic lithiasis and intraductal papillary-mucinous neoplasm with special reference to the pathogenesis of lithiasis. AB - In pancreatic lithiasis in elderly autopsy cases, the stones are small and the pancreatic duct is changed very slightly when viewed by simple X-ray film, pancreatic ductography and gross appearance. Histologically, a slight fibrous increase is seen very locally, but findings consistent with chronic pancreatitis are not found throughout the whole pancreas. However, marked, diffuse and irregular dilatation of the pancreatic duct is frequently found in operative cases with chronic pancreatitis and pancreatic stones. These findings show that the changes seen with aging and with chronic pancreatitis can be distinguished based on the findings of pancreatic ductography. Mucin production in epithelia in intraductal papillary-mucinous neoplasm (IPMN) may not be strongly associated with the pathogenesis of pancreatic lithiasis. Pancreatic lithiasis may be related to squamous cell metaplasia. IPMN and dilatation of the pancreatic duct are closely associated with mucin production. An increase in intraductal pressure of the pancreatic duct may be somewhat related to the mechanism of stone formation. The incidental co-existence of pancreatic epithelia with pancreatic lithiasis in patients with chronic pancreatitis and the development of IPMN may also be possible. IPMN and pancreatic lithiasis may be related through the mechanism(s) of their pathogenesis, their synergism and the pathogenesis of stone formation. The relation between mucinous metaplasia and stone formation is slight and, therefore, there may be only a weak correlation between IPMN and pancreatic stones. This may explain why there are few reports of the co-existence of IPMN and pancreatic stones (Kimura in Kan Tan Sui 58:485-492, 2009). PMID- 19779666 TI - Minimizing intraoperative bleeding using a vessel-sealing system and splenic hilum hanging maneuver in laparoscopic splenectomy. AB - BACKGROUND/PURPOSE: The most common cause of conversion to laparotomy (open splenectomy) during laparoscopic splenectomy (LS) is bleeding from the splenic hilar vessels. Recently, the efficacy of Ligasure (a vessel-sealing system) as a safety device for sealing vessels and reducing intraoperative blood loss has been reported with various laparoscopic procedures. The objective of this report was to describe our techniques for minimizing bleeding during LS, characterized by the application of Ligasure (which reduces the number of clips and staples, and reduces unnecessary bleeding) and a splenic hilum hanging maneuver with a Diamond Flex flexible retractor to obtain optimal exposure of the splenic hilum. METHODS: We have performed 87 LSs since February 1993, and have employed the Ligasure instead of metal clips and staplers since September 2003. We have also introduced the splenic hilum hanging maneuver paired with Ligasure use. We have performed this new LS in 30 consecutive adult patients presenting with idiopathic thrombocytopenic purpura (n = 14), benign splenic tumor (n = 5), lymphoma (n = 4), hereditary spherocytosis (n = 2), liver cirrhosis (n = 2), and other pathologies (n = 3). The splenic ligaments and vessels, including the splenic artery and vein, were divided using a 5-mm Ligasure instead of a clip or stapler. The splenic hilum was encircled and elevated, using a Diamond-Flex, to ensure better exposure in all patients. RESULTS: LS was successfully completed in 29 patients (97%), with only one conversion to open splenectomy. Mean blood loss for all patients with completed LS was only 21.6 ml (range 0-250 ml). Moreover, blood loss was not determinable (considered as 0 ml in this study) in 15 patients (52%). Mean spleen weight and operating time were 319.4 g (range 80-1605 g) and 143.4 min (range 90-180 min), respectively. No postoperative mortalities were encountered. Two patients experienced complications, including grade B pancreatic fistula and atelectasis, for an overall morbidity rate of 6.7%. Mean postoperative stay was 6.5 days (range 3-14 days). CONCLUSIONS: LS using a Ligasure in combination with the splenic hilum hanging maneuver may reduce intraoperative blood loss. PMID- 19779667 TI - Laparoscopic hand-assisted right hemihepatectomy by ultrasound-directed intrahepatic approach. AB - BACKGROUND/PURPOSE: Laparoscopic hepatectomy is a promising option for patients affected by a liver mass, and the procedure is gaining popularity. Minor laparoscopic resections have been widely reported. In contrast, major laparoscopic hepatectomy has been performed in only a limited number of cases. Hand-assisted laparoscopic liver surgery has been advocated in order to improve liver exposure and vascular control and increase the safety of the procedure. Transparenchymal en-bloc transection of the right portal triad has been reported to be safe and useful in open surgery. METHODS: We describe a personal technique for hand-assisted right hemihepatectomy. With ultrasound guidance, the right hepatic pedicle is isolated intrahepatically and transected en bloc with a single firing of an endostapler. Parenchymal transection is carried out with ultrasonically activated or vessel-sealing devices together with endostaplers. RESULTS: The procedure was successfully accomplished in three patients. The Pringle maneuver was never performed. No intraoperative or postoperative complications occurred. CONCLUSION: This study is the first to report a technique of right hemihepatectomy that combines hand-assisted laparoscopy and an ultrasound-guided intrahepatic approach. This technique may be a useful option to simplify the operation, reduce operative time, and increase the safety of the procedure. PMID- 19779668 TI - Vitamin E exhibits bone anabolic actions in normal male rats. AB - Recently, vitamin E has been found to promote the bone structure of nicotine treated rats well above their baseline values, thus suggesting that vitamin E may have some anabolic action. A bone anabolic agent acts by improving the bone structure leading to stronger bone. To assess the possible anabolic action vitamin E on bone, we supplemented alpha-tocopherol (ATF) or gamma-tocotrienol (GTT) at 60 mg/kg or vehicle [normal control (NC) group] for 4 months to normal male rats and measured their bone structure and biomechanical properties. Histomorphometric analysis revealed that vitamin E-supplemented rats have better trabecular volume, thickness, number, and separation than rats receiving vehicle only. For the first time we reported that GTT improves all the parameters of bone biomechanical strength, while ATF only improved some of the parameters compared to the NC group. Vitamin E supplementation, especially with the gamma isomer, improves bone structure, which contributed to stronger bone. Therefore, vitamin E has the potential to be used as an anabolic agent to treat osteoporosis or as bone supplements for young adults to prevent osteoporosis in later years. PMID- 19779669 TI - Meningiomas of the ventral foramen magnum and lower clivus: factors influencing surgical morbidity, the extent of tumour resection, and tumour recurrence. PMID- 19779670 TI - What makes Maurice Ravel's deadly craniotomy interesting? Concerns of one of the most famous craniotomies in history. AB - Maurice Ravel (1875-1937), the great impressionist-classicist composer of many popular compositions, such as the Bolero, suffered from a progressive disease and died following an exploratory craniotomy by Clovis Vincent. The history of his progressive dementia and the contribution of a car accident, following which he was unable to function, have received a certain amount of interest in the neurological literature previously, but his deadly craniotomy was not evaluated from a neurosurgery perspective. The car accident in 1932, with the probable consequence of a mild-to-moderate traumatic brain injury, could be the key event in his life, triggering the loss of his ability to compose. It is clear that he never recovered from his injury and within a year he became completely unable to function. His dementia progressed dramatically. This event needs to be kept in mind. In 1937, Ravel died after the craniotomy performed by Vincent, but only a speculative, retrospective diagnosis is possible since an autopsy was not undertaken. PMID- 19779671 TI - Primary intradural Ewing's sarcoma of the cauda equina presenting with acute bleeding. PMID- 19779672 TI - [Congress of the German Society of Internal Medicine 2009: evaluation of the poster exhibition]. AB - BACKGROUND AND PURPOSE: The presentation of scientific posters gives young scientists the opportunity to present their data in the setting of a medical congress. In preparation of the organization of the 116th Congress of the German Society of Internal Medicine (DGIM) 2010, the authors evaluated the poster rounds at the 115th Congress of the DGIM 2009 by using a questionnaire that was given to poster presenters, poster chairmen, and visitors. The authors sought to receive an instructive criticism for the organization in 2010. METHODS: Distribution of questionnaires containing ten questions with preformulated response options and an additional field for further comments to all presenters, chairmen, and visitors of the poster rounds during the 115th Congress of the DGIM (April 2009). RESULTS: 159 questionnaires were returned and evaluated. Almost all respondents quoted the poster presentation as being important for their scientific work (98%). In general, they were satisfied with the discussion at the poster rounds (83%). The amount of posters within one round was criticized by 41%, as was the inadequate adherence to time constraints and time frame and room conditions themselves. CONCLUSION: The poster exhibition of the 115th Congress of the DGIM 2009 was evaluated positively by most of the respondents to the survey. Nevertheless, helpful hints were retrieved as how to further improve poster rounds. They should be respected when planning the exhibition at the congress in 2010. PMID- 19779673 TI - [Rate of venous thromboembolism after total hip and total knee replacement in inpatient orthopedic rehabilitation]. AB - BACKGROUND AND PURPOSE: The current incidence of total hip and total knee replacements in Germany amounts to approximately 320,000 per year. A high rate of asymptomatic deep vein thromboses causes venous thromboembolisms which are the most common complications after these operations. Partly, these venous thromboembolisms occur during or even after rehabilitation. We try to reduce symptomatic venous thromboembolisms during/after inpatient rehabilitation by mandatory examination of all patients with total hip and total knee replacement by means of compression/duplex ultrasound and a structured prophylaxis and therapy regimen. PATIENTS AND METHODS: 572 patients after total knee replacement and 609 patients after total hip replacement were examined by compression/duplex ultrasound during postoperative inpatient rehabilitation in Medical Park St. Hubertus, Bad Wiessee, Germany. Prophylaxis and therapy of thrombo embolic complications were performed according to the current guidelines. 3 months after rehabilitation, patients were questioned as to whether a thrombo embolic event had occurred or not. RESULTS: Out of 572 patients with total knee replacement, a total of 127 developed a thrombosis or lung embolism (22.2%), namely muscle vein thrombosis in 44 (7.7%), proximal thrombosis in eleven (1.9%), and lung embolism in five cases (0.9%). Out of 609 patients after total hip replacement, 37 showed a thrombosis or lung embolism (6.1%), that is 15 cases of muscle vein thrombosis (2.5%), six cases of proximal thrombosis (1.0%), and four cases of lung embolism (0.7%). An extra three patients developed lung embolism after rehabilitation, two of them because of a proximal thrombosis in the contralateral leg (without surgery), and one patient because of a progressive muscle vein thrombosis that turned into a proximal thrombosis. In 15 cases (9.4% of all thromboses), the thrombosis occurred in the contralateral leg (without surgery) CONCLUSION: In spite of consistent prophylaxis, a high rate of thrombosis occurs, partly also in the contralateral leg. PMID- 19779674 TI - [Effect of enzyme replacement therapy (ERT) on renal function of patients with Fabry's disease]. AB - Fabry's disease is an inherited lysosomal storage disorder characterized by the lack of enzyme alpha-galactosidase A (alpha-Gal A) which degrades globotriaosylceramides (Gb3) into products with lower molecular weight. The accumulation of Gb3 in different cell types is responsible for the variety of clinical manifestations. The renal function, estimated via proteinuria, hematuria and reduction of glomerular filtration rate (GRF), is heavily affected. Currently, substitution of alpha-Gal A remains the only therapeutic option for patients with Fabry's disease. Two products are approved for the treatment of Fabry's disease: agalsidase alfa and agalsidase beta. Both of these enzymes have shown a stabilization of renal function in various studies when evaluated by the creatinine clearance, estimated GFR, and serum creatinine. The pro gnosis has proven to be significantly better in cases of mild or moderate renal insufficiency from the baseline. For this reason, an early substitution of the lacking enzyme is necessary. Furthermore, enzyme replacement therapy (ERT) has proven efficient in reducing the amount of intracellular Gb3 and Gb3 in urine. Without treatment, an eGFR reduction of approximately 12 ml/min/year has been reported. After diverse studies of ERT, no significant correlation between enzyme substitution and improvement of patients' proteinuria could be shown. Furthermore, renoprotective drugs have not been consistently applied so far in the ERT trials. In any case, further studies to evaluate the long-term effect of ERT on the morbidity and mortality of patients with Fabry's disease are necessary. PMID- 19779675 TI - [Prevention and law. The legal regulation of prevention in health care]. AB - BACKGROUND AND PURPOSE: Law has to make order. The more complex a subject matter is, the more intensive it is usually legally regulated. As such, in Germany health care is an intensively regulated area with an own social code. For prevention, no such code exists, even though it is often praised as the fourth pillar of health care. Two attempts to enact a Prevention Act have failed. Therefore, this study analyzes how prevention is currently regulated in Germany. METHODS: The study evaluates the existing laws that govern prevention and health promotion. For this purpose, the respective legal provisions are analyzed and, then, an overall view of the legal rules and their interplay is performed. RESULTS: The legal regulation of prevention is based on a number of different laws. Mainly, two groups of legal provisions can be differentiated. The first group ist attributable to the field of danger defense. The second group regulates the specific prevention in heath care and health promotion and is part of social law. Most social codes encompass detailed provisions on prevention governing and regulate nearly all stages of prevention. Prominent roles are played by the health and accident insurance laws and rehabilitation laws. CONCLUSION: Even in the absence of a specific Prevention Act, prevention is not practiced without a legal fundament. However, this legal regulation of prevention is structured heterogeneously and built by several laws that either stand parallel side by side or are interwoven. Further, this legal frame involves all social insurance carriers and several authorities. Prevention is a joint effort. Nevertheless, a stronger concentration of the regulation of prevention would be beneficial to strengthen prevention. This is even more so as from a health economic perspective the current coexistence and interaction of numerous laws and authorities is often inadequately expensive. Therefore, the cost-benefit ratio of the legal regulation of prevention seems improvable. PMID- 19779676 TI - [Differential diagnosis and therapy of gout]. PMID- 19779677 TI - [Malignant melanoma masquerading as a neurotrophic ulcer]. AB - CASE REPORT: A 77-year-old female patient with an ulceration of the heel is described, which was treated over a period of 2 years as a neurotrophic ulcer related to diabetes mellitus. After the initial examination in the outpatient wound healing clinic, a malignant melanoma already showing invasive growth with a penetration depth of 4.6 mm was detected in a biopsy. After diagnosis and exclusion of metastases, a phase-adapted complete excision was carried out. Furthermore, an adjuvant immunotherapy was introduced. CONCLUSION: Malignant melanoma is a primary cutaneous malignant tumor. Its thickness at the time of the initial diagnosis is crucial to the prognosis. Ulcerated and amelanotic melanomas still present a considerable clinical challenge due to the likelihood of being mistaken for benign diseases and the occurrence of filiae when diagnosis is made too late. This case report demonstrates the importance of differential diagnostic consideration of neoplasias, for example malignant melanoma, in cases of unclear, therapy-refractory wounds and discusses the relevant aspects in avoiding an unnecessary prolongation of diagnostics. PMID- 19779678 TI - [Rheumatoid arthritis: subclinical atherosclerosis of the coronary arteries- effect of age, sex and disease activity]. PMID- 19779680 TI - [Editorial on the main topic: acetabular fractures]. PMID- 19779681 TI - [Reconstruction of fractures of the anterior wall and the anterior column of the acetabulum using an ilioinguinal approach]. AB - OBJECTIVE: Restoration of the congruence of the hip joint. Correction of gaps or steps in the articular surface, especially in the main weight-bearing area of the acetabular dome. Correction of femoral head subluxation. Restoration of joint stability in order to enable early postoperative mobilization. INDICATIONS: Fractures of the anterior wall and/or column that are characterized by intraarticular gaps or steps of > 1 mm in the area of the main weight-bearing dome of the acetabulum. Fractures complicated by subluxation or dislocation of the femoral head. CONTRAINDICATIONS: Poor general physical condition and/or dementia. Critical soft-tissue conditions in the area near the surgical approach. Local soft-tissue infection. Preexisiting severe osteoarthritis of the hip joint. SURGICAL TECHNIQUE: Exposure of the fracture through an ilioinguinal approach. Reduction of a subluxated femoral head. Reduction of the anterior column and/or wall. Correction of articular gaps, steps and areas of joint impression. Internal fixation using small-fragment reconstruction plates, if required in combination with additional screws. POSTOPERATIVE MANAGEMENT: Postoperative radiographs for the documentation of the surgical result and implant position (exclusion of intraarticular implants). Postoperative computed tomography, if indicated. Active and passive exercises of the hip joint starting on day 1. Hip joint flexion limited to 90 degrees . Prophylaxis of thrombosis until full weight bearing, starting preoperatively. Mobilization without weight bearing or 15 kg partial weight bearing for 8-12 weeks. Progressive weight bearing over a time period of 4 6 weeks. Radiologic evaluation after 2, 6, and 12 weeks as well as after 6, 12, and 24 months. RESULTS: Excellent and good functional results are observed in 73 85% of the isolated anterior column fractures. The anterior wall fracture is a seldom injury. Functional results are worse in comparison to the other simple fracture types. Good or excellent results can only be observed in two thirds of cases. This observation is related to the fact that anterior wall fractures often occur in elderly patients with osteoporotic bone. PMID- 19779682 TI - [Operative treatment of T-type fractures of the acetabulum via surgical hip dislocation or Stoppa approach]. AB - OBJECTIVE: Anatomic reduction and stable fixation by means of tissue- preserving surgical approaches. INDICATIONS Displaced acetabular fractures. Surgical hip dislocation approach with larger displacement of the posterior column in comparison to the anterior column, transtectal fractures, additional intraarticular fragments, marginal impaction. Stoppa approach with larger displacement of the anterior column in comparison to the posterior column. A combined approach might be necessary with difficult reduction. CONTRAINDICATIONS Fractures > 15 days (then ilioinguinal or extended iliofemoral approaches). Suprapubic catheters and abdominal problems (e.g., previous laparotomy due to visceral injuries) with Stoppa approach (then switch to classic ilioinguinal approach). SURGICAL TECHNIQUE: Surgical hip dislocation: lateral decubitus position. Straight lateral incision centered over the greater trochanter. Entering of the Gibson interval. Digastric trochanteric osteotomy with protection of the medial circumflex femoral artery. Opening of the interval between the piriformis and the gluteus minimus muscle. Z-shaped capsulotomy. Dislocation of the femoral head. Reduction and fixation of the posterior column with plate and screws. Fixation of the anterior column with a lag screw in direction of the superior pubic ramus. Stoppa approach: supine position. Incision according to Pfannenstiel. Longitudinal splitting of the anterior portion of the rectus sheet and the rectus abdominis muscle. Blunt dissection of the space of Retzius. Ligation of the corona mortis, if present. Blunt dissection of the quadrilateral plate and the anterior column. Reduction of the anterior column and fixation with a reconstruction plate. Fixation of the posterior column with lag screws. If necessary, the first window of the ilioinguinal approach can be used for reduction and fixation of the posterior column. POSTOPERATIVE MANAGEMENT: During hospital stay, intensive mobilization of the hip joint using a continuous passive motion machine with a maximum flexion of 90 degrees . No active abduction and passive adduction over the body's midline, if a surgical dislocation was performed. Maximum weight bearing 10-15 kg for 8 weeks. Then, first clinical and radiographic follow-up. Deep venous thrombosis prophylaxis for 8 weeks postoperatively. RESULTS: 17 patients with a mean follow-up of 3.2 years. Ten patients were operated via surgical hip dislocation, two patients with a Stoppa approach, and five using a combined or alternative approach. Anatomic reduction was achieved in ten of the twelve patients (83%) without primary total hip arthroplasty. Mean operation time 3.3 h for surgical hip dislocation and 4.2 h for the Stoppa approach. Complications comprised one delayed trochanteric union, one heterotopic ossification, and one loss of reduction. There were no cases of avascular necrosis. In two patients, a total hip arthroplasty was performed due to the development of secondary hip osteoarthritis. PMID- 19779683 TI - [Internal fixation of acetabular both-column fractures via the ilioinguinal approach]. AB - OBJECTIVE: Open anatomic reduction and stable internal fixation of both-column acetabular fractures by screw and plate osteosynthesis via the ilioinguinal approach. INDICATIONS: Displaced both-column fractures of the acetabulum with incongruence of the hip joint, central femoral head displacement, unstable hip joint, and/or loss of hip joint congruence without the potential of a secondary congruence (near anatomic fragment orientation due to ligamentotaxis). CONTRAINDICATIONS: General contraindications. Displaced fracture of the posterior wall. Extension of the posterior column fracture to the apex of the greater sciatic notch. SURGICAL TECHNIQUE: Indirect open reduction of a both-column fracture of the acetabulum that is typically characterized by a multifragmentary anterior column fracture and a simple posterior column fragment using an ilioinguinal approach. Stepwise reduction and reconstruction of the anterior column according to the "proximal-to-distal" rule. Reduction and fixation of the posterior column fragment against the reconstructed anterior column. POSTOPERATIVE MANAGEMENT: Partial weight bearing for 8-12 weeks with 15 kg body weight, beginning on the 2nd postoperative day. Thereafter, pain-dependent weight bearing. Thrombosis prophylaxis. RESULTS: Analysis of 27 patients treated between 1991 and 2005. A high-velocity trauma was the cause of injury in 74.1% of cases. Most patients showed an isolated injury of the acetabulum. In 55.5%, an additional central hip joint displacement was observed. A primary injury to the sciatic nerve was present in 14.8% of cases. Mean fracture gap/step was 14.3 mm. 81.5% of these fractures were anatomically reduced and stabilized; all joints were congruent. At 2-year follow-up, 14 out of 17 patients had no signs of posttraumatic osteoarthritis. Excellent and good functional results according to the Merle d'Aubigne Score were observed in eleven and five cases, respectively. One patient had a moderate functional outcome. PMID- 19779684 TI - [Internal fixation of acetabular posterior wall fractures]. AB - OBJECTIVE: Open anatomic reduction and stable internal fixation of a posterior wall fracture of the acetabulum by screw and plate osteosynthesis via the Kocher Langenbeck appoach. INDICATIONS: Displaced fractures or fracture-dislocations of the posterior wall of the acetabulum in combination with an unstable hip joint, presence of an additional femoral head fracture or intraarticular fragments, reduction inability in fracture-dislocations or deterioration of an additional sciatic nerve injury. CONTRAINDICATIONS: Poor general condition (due to additional injuries or medical disease). Local soft-tissue damage. Presence of only small bony avulsion fragments of the posterior capsule with hip joint stability. SURGICAL TECHNIQUE: Open reduction of the posterior wall fracture with stable internal fixation by screw and plate osteosynthesis. Depending on their presence: reduction and fixation of marginal impaction zones. POSTOPERATIVE MANAGEMENT: Partial weight bearing of the injured side with 15 kg body weight for 6 weeks. Thereafter, pain-dependent weight bearing. In cases of marginal impaction partial weight bearing is extended to 12 weeks. RESULTS: Between January 1, 1972 and December 31, 2005, 137 patients with fractures of the posterior wall of the acetabulum were treated operatively. A high-velocity trauma was the cause of injury in 91.1% of cases. 94.1% of these patients had an additional hip dislocation, which was reduced within 6 h post injury in 83.7%. A primary sciatic nerve injury was present in 22.2%. Additional injuries to the acetabular cartilage were found in 43%, additional femoral head lesions in 27.4%, and Pipkin fractures in 14.1%. Anatomic joint reconstruction (0-1 mm) was observed in 96.3%, the other five patients had near anatomic reconstructions (2-5 mm). All hip joints were congruent on conventional radiography. The overall complication rate was 11.8%. Osteosynthesis-related complications were seen in 6.7%. 86 patients had follow-up results after a mean of 52 months. A perfect or good functional result (Merle d'Aubigne Score) was observed in 73.3% of cases, a posttraumatic arthrosis of the hip joint was present in 31.4%. PMID- 19779685 TI - [Angle-stable intramedullary nailing of proximal humerus fractures with the PHN (proximal humeral nail)]. AB - OBJECTIVE: Stable fixation of two- and three-part fractures of the proximal humerus through minimally invasive operative technique and rapid bone healing as well as restoration of original anatomy. Early functional training with the goal of restoration of former mobility and daily activities. INDICATIONS: Unstabile two- and three-part fractures of the proximal humerus (AO classification: 11-A2, 11-A3, 11-B1, 11-B2, 11-B3). Subcapital nonunion of the humerus. Pathologic fractures. CONTRAINDICATIONS: Pediatric fractures of the proximal humerus. Fractures of the proximal humerus types 11-C2 und 11-C3 according to the AO classification. Active local infection, e.g., after former operation. SURGICAL TECHNIQUE: Closed reduction. Anterior acromial incision, splitting of the deltoid muscle and the rotator cuff. Opening of the medullary canal with the awl. Nail introduction. Spiral blade introduction in cannulated technique through stab incision. Distal interlocking through aiming device, angle-stable blocking of nail and blade through end cap. POSTOPERATIVE MANAGEMENT: Postoperative fixation in Gilchrist sling until 2nd postoperative day; then physiotherapy respecting fracture type and stability, local swelling, patient's age and compliance, and concomitant injuries. RESULTS: 151 proximal humeral fractures were treated with a proximal humeral nail (PHN). 108 patients could be followed up 1 year postoperatively. Significant complications were perforation of the articular surface through bolts or blades (n = 8), implant-related pain (n = 10), fragment dislocation (n = 2), nonunion (n = 2), humeral head necrosis (n = 3), and superficial infection (n = 1). 1 year after the operation, the Constant-Murley Score showed a median value of 75.3 in the injured shoulder and of 89.9 in the uninjured shoulder. The DASH (Disability of the Arm, Shoulder and Hand) Score was 5.9 preoperatively and 9.3 at 1 year postoperatively. The worst results regarding the Constant-Murley Score as well as the DASH Score were found in C-type fractures. PMID- 19779686 TI - [Computer-assisted surgery-(CAS-) guided correction arthrodesis of the ankle joint]. AB - OBJECTIVE: Restoration of a stable and plantigrade foot in deformities at the ankle and concomitant degenerative changes at the ankle joint. INDICATIONS: Deformities at the ankle and concomitant degenerative changes at the ankle joint. CONTRAINDICATIONS: Active local infection or relevant vascular insufficiency. SURGICAL TECHNIQUE: Supine position and anterior approach to the ankle joint. Placement of dynamic reference bases (DRBs) in tibia and talus. Two-dimensional (2-D) image acquisition for navigation. Definition of axes of tibia and talus, and of the extent of correction. Exposition of the ankle joint and removal of remaining cartilage. Computer-assisted surgery-(CAS-) guided correction and transfixation of the corrected position with two 2.5-mm Kirschner wires. Transplantation of autologous cancellous and cortical bone, if necessary. 3-D image acquisition for analysis of the accuracy of the correction and planning of the drillings for the four screws (two parallel from anterolateral, one from posteromedial from the tibia, and one from lateral from the fibula). CAS-guided drilling and insertion of the screws. 3-D image acquisition for analysis of the accuracy of the correction and implant position. Layerwise closure. POSTOPERATIVE MANAGEMENT: Partial weight bearing with 15 kg in an orthosis for 6 weeks, followed by full weight bearing in a stable standard shoe. RESULTS: From September 1, 2006 to August 31, 2008, 24 correction ankle arthrodeses were performed. The accuracy was assessed by intraoperative 3-D imaging. All achieved angles/ translations were within a maximum deviation of 2 degrees /2 mm when compared to the planned correction. Complications that were associated with CAS were not observed. In all 20 patients that completed follow-up so far, a timely fusion was registered. PMID- 19779687 TI - Extended posterior circumferential approach to thoracic and thoracolumbar spine. AB - OBJECTIVE: Posterior spinal surgical approach to achieve a retropleural/ retroperitoneal corpectomy with circumferential spinal cord decompression following subtotal vertebrectomy, posterior instrumentation and interbody spacer placement under compression as well as kyphosis correction with spinal column shortening. INDICATIONS: Infective, traumatic or neoplastic lesions of the vertebral body that lead to vertebral body destruction, instability and neurologic deficit. Need for immediate postoperative loading stability to permit ambulation and rehabilitation. CONTRAINDICATIONS: Multiple contiguous vertebral disease. Instances where the graft bed preparation and stable interbody spacer placement may be suboptimal due to the limited access offered by this approach. SURGICAL TECHNIQUE: Posterior midline exposure two to three levels above and below lesion, dissection at level of lesion extended bilaterally exposing transverse processes, costotransverse articulations and medial 5-8 cm of ribs. Placement of pedicle screws at proximal and distal levels; in case of osteoporotic bone augment screws with cement. Bilateral costotransversectomy at one or more levels to drain prevertebral abscess and expose diseased vertebral bodies. After temporary stabilization, laminectomy and corpectomy are carried out from both sides to permit circumferential decompression. A temporary rod is placed on the contralateral side in the position of deformity to prevent any inadvertent translatory movements during the subsequent surgical step. After completion of the procedure an appropriately contoured rod is placed. The interbody spacer is positioned. Kyphosis correction by spinal column shortening and compression along the posterior implant is performed. POSTOPERATIVE MANAGEMENT: By day 3 ambulation and rehabilitation are initiated. RESULTS: 22 patients were operated in the last 8 years with tuberculosis (18 patients - twelve paraplegics), osteoporotic fractures (two patients), congenital kyphosis and Ewing's sarcoma (one patient each). All patients were followed up at 3, 6, 9, and 12 months and then annually. At each followup, clinical, hematologic and radiologic parameters were assessed. All interbody grafts and cages incorporated without significant loss of correction. Ten of twelve tuberculous paraplegics recovered. No patient had postoperative infection, interbody spacer- or implant related complications. PMID- 19779688 TI - [The standard implantation of a total hip prosthesis via two incisions (the Yale Technique)]. AB - OBJECTIVE: Implantation of a total hip endoprosthesis with minimal trauma to the soft tissue. The need for visual aids (e.g., navigation or X-rays) during the procedure is frequently avoided. INDICATIONS: All kinds of coxarthrosis for every age group, for every variation of bone construction, and even in obese patients. CONTRAINDICATIONS: Extremely dysplastic hip joints involving the development of a secondary socket and the necessity of reconstruction of the acetabular socket (e.g., in the Harris method). SURGICAL TECHNIQUE: Using a fixed lateral position, a small entry incision is made between the tensor fasciae latae and the sartorius muscles and the prosthesis socket is put into place. Via a second dorsal incision, after stripping the exterior rotators, the prosthesis stem and ball are implanted and the two parts of the prosthesis are attached. POSTOPERATIVE MANAGEMENT: Full weight bearing allowed immediately. A luxation prophylaxis, in the form of a self-developed hip bodice (the so-called Yale bandage), is used until the end of the 4th postoperative week. Discharge from hospital is possible after just a few days. Upon discharge, the patient is sent to a rehabilitation facility, either as a resident or as an outpatient, for approximately 3 weeks. Return to the workplace, with only light physical activity, is possible once the wound has healed completely; this could be as soon as 14 days after the operation. Checkups are made after 4 weeks, 6 months, 1 year and then every year; these checkups include a full examination, X-rays and laboratory tests. Full exposure to sport or heavy manual labor is usually approved after the 6-month checkup. RESULTS: Between October 2004 and April 2006, a total of 221 patients underwent surgery using this new technique (of these 15 patients underwent two stage bilateral hip joint replacements). Patients were followed up for a minimum of 12 months and a maximum of 30 months. The Harris Hip Score improved from an average of 45.25 preoperatively to 96.4 postoperatively. PMID- 19779689 TI - [Screw osteosynthesis of proximal femur fractures in children]. AB - OBJECTIVE: Optimal reposition and stable fixation of M/1 and M/2 fractures are necessary. Careful operation and urgent surgery prevent complications. INDICATIONS: M/1 and M/2 fractures of the proximal femur in children > 4 years. CONTRAINDICATIONS: E/1 fractures are fixed with Kirschner wires. M/3 fractures are fixed with elastic stable intramedullary nailing. Fractures up to the age of 4 are fixed with Kirschner wires. SURGICAL TECHNIQUE: Surgical approach via a lateral incision. Anatomic fixation of the fracture with two to three cannulated screws. POSTOPERATIVE MANAGEMENT: No weight bearing during the first 4-6 weeks. Physiotherapy is optional. Magnetic resonance imaging at least 1 year after the fracture or immediately in case of problems to control the vascular situation of the femoral head. RESULTS: Due to the rarity of these fractures, only few results from large series have been published. M/1 fractures show a higher complication rate than M/2 fractures. The risk of avascular necrosis has to be estimated at up to 40%. PMID- 19779690 TI - Histone modifications during DNA replication. AB - Faithful and accurate replication of the DNA molecule is essential for eukaryote organisms. Nonetheless, in the last few years it has become evident that inheritance of the chromatin states associated with different regions of the genome is as important as the faithful inheritance of the DNA sequence itself. Such chromatin states are determined by a multitude of factors that act to modify not only the DNA molecule, but also the histone proteins associated with it. For instance, histones can be posttranslationally modified, and it is well established that these posttranslational marks are involved in several essential nuclear processes such as transcription and DNA repair. However, recent evidence indicates that posttranslational modifications of histones might be relevant during DNA replication. Hence, the aim of this review is to describe the most recent publications related to the role of histone posttranslational modifications during DNA replication. PMID- 19779691 TI - [Minimally invasive plate osteosynthesis: current state. Part 1: General information]. AB - Minimally invasive techniques and developments of implants with angular stability have led to a renaissance of plate osteosynthesis for fracture stabilization in recent years. They represent a major source of success which has facilitated minimally invasive plate osteosynthesis (MIPO) or even made it feasible. For implants with LCP technology all current types of screws can be used and/or combined. However, the treating surgeon is still confronted with the decision which fixation mode, absolute or relative stability, is required for each individual fracture. Moreover, reduction techniques, intra-operative imaging and the biomechanical features of the selected implant require a more meticulous preoperative planning. Minimizing the surgical trauma has resulted in decreased complication rates of problematic fractures. However, the particular inherent risks of a closed procedure have to be evaluated for each body region to avoid severe complications. PMID- 19779692 TI - [Cancer pain therapy]. AB - Pain belongs to the most prevalent symptoms that require patients with urological tumours to seek medical help. The treatment of cancer pain requires standardized guidelines that are best reflected by the WHO's three-step ladder of cancer pain relief. This implies an individualized approach, a detailed history taking of underlying pain and thorough clinical examination, as well as a consistent and forceful therapy of constant and breakthrough pain episodes, using pharmacological substances and non-pharmacological techniques. This requires the choice of the correct drug, an application "by the clock", an individualized dose titration, and the use of co-analgesics. For constant "background" pain, slow release substances are needed, whilst fast acting pain medication is given on demand for breakthrough pain episodes. Besides symptomatic analgesic therapy, cancer pain therapy may also comprise tumor specific treatment modalities, whenever appropriate and requested by the patient. This comprises radiation therapy, e.g. for bone or soft tissue processes or brain metastases, as well as radionuclide techniques, surgical procedures, chemotherapy, new substances or antihormonal therapy. Furthermore, pain is considered a multimodal experience that requires the consideration of psychical and social factors. This chapter describes the different facets of cancer pain, its epidemiology, pathophysiology, diagnostics and therapeutic principles. PMID- 19779693 TI - The potato developer (D) locus encodes an R2R3 MYB transcription factor that regulates expression of multiple anthocyanin structural genes in tuber skin. AB - A dominant allele at the D locus (also known as I in diploid potato) is required for the synthesis of red and purple anthocyanin pigments in tuber skin. It has previously been reported that D maps to a region of chromosome 10 that harbors one or more homologs of Petunia an2, an R2R3 MYB transcription factor that coordinately regulates the expression of multiple anthocyanin biosynthetic genes in the floral limb. To test whether D acts similarly in tuber skin, RT-PCR was used to evaluate the expression of flavanone 3-hydroxylase (f3h), dihydroflavonol 4-reductase (dfr) and flavonoid 3',5'-hydroxylase (f3'5'h). All three genes were expressed in the periderm of red- and purple-skinned clones, while dfr and f3'5'h were not expressed, and f3h was only weakly expressed, in white-skinned clones. A potato cDNA clone with similarity to an2 was isolated from an expression library prepared from red tuber skin, and an assay developed to distinguish the two alleles of this gene in a diploid potato clone known to be heterozygous Dd. One allele was observed to cosegregate with pigmented skin in an F(1) population of 136 individuals. This allele was expressed in tuber skin of red- and purple colored progeny, but not in white tubers, while other parental alleles were not expressed in white or colored tubers. The allele was placed under the control of a doubled 35S promoter and transformed into the light red-colored cultivar Desiree, the white-skinned cultivar Bintje, and two white diploid clones known to lack the functional allele of D. Transformants accumulated pigment in tuber skin, as well as in other tissues, including young foliage, flower petals, and tuber flesh. PMID- 19779694 TI - Cognitive decline associated with dementia and type 2 diabetes: the interplay of risk factors. PMID- 19779695 TI - Influence of different blood flows through a pumpless lung assist system on transpulmonary thermodilution-derived variables. PMID- 19779696 TI - A novel adaptive control system for noisy pressure-controlled ventilation: a numerical simulation and bench test study. AB - PURPOSE: There is growing interest in the use of both variable and pressure controlled ventilation (PCV). The combination of these approaches as "noisy PCV" requires adaptation of the mechanical ventilator to the respiratory system mechanics. Thus, we developed and evaluated a new control system based on the least-mean-squares adaptive approach, which automatically and continuously adjusts the driving pressure during PCV to achieve the desired variability pattern of tidal volume (V (T)). METHODS: The controller was tested during numerical simulations and with a physical model reproducing the mechanical properties of the respiratory system. We applied step changes in respiratory system mechanics and mechanical ventilation settings. The time needed to converge to the desired V (T) variability pattern after each change (t (c)) and the difference in minute ventilation between the measured and target pattern of V (T) (DeltaMV) were determined. RESULTS: During numerical simulations, the control system for noisy PCV achieved the desired variable V (T) pattern in less than 30 respiratory cycles, with limited influence of the dynamic elastance (E*) on t (c), except when E* was underestimated by >25%. We also found that, during tests in the physical model, the control system converged in <60 respiratory cycles and was not influenced by airways resistance. In all measurements, the absolute value of DeltaMV was <25%. CONCLUSION: The new control system for noisy PCV can prove useful for controlled mechanical ventilation in the intensive care unit. PMID- 19779697 TI - Bronchoalveolar lavage fluid peptidomics suggests a possible matrix metalloproteinase-3 role in bronchopulmonary dysplasia. AB - BACKGROUND: Bronchoalveolar lavage fluid (BALF) is an important diagnostic source to investigate molecular changes occurring in lung disorders. The objective of this study was to assess and compare the peptidomic profiles of BALF from premature neonates with and without bronchopulmonary dysplasia (BPD). METHODS: Samples were obtained on the 3rd day of life from 34 neonates with gestational age 25% (p = 0.030 at log-rank test). Univariate and multivariate analysis for DFS confirmed the prognostic value of the CD4(+)CD45RA(+)CXCR4(+) lymphocytes. Although further studies are needed to better define the involved subpopulation, the detection of cellular subset CD4(+)CD45RA(+)CXCR4(+) is an easy and feasible evaluation of melanoma patients in concomitance with the established melanoma prognostic markers. PMID- 19779715 TI - Phase III, randomised, multicentre trial of maintenance immunotherapy with low dose interleukin-2 and interferon-alpha for metastatic renal cell cancer. AB - This is the first phase III randomised trial to evaluate maintenance immunotherapy in metastatic renal cell cancer (mRCC). Patients were randomised to receive treatment with a 4-week cycle of subcutaneous low doses IL-2 + IFN in months 1, 3 and 5, and then every 3 months until the first documented disease progression (arm A, suspension), or the same regimen, with chronic maintenance of immunotherapy, regardless of tumour response, until death or intolerable toxicity (arm B, maintenance). The primary endpoint was overall survival (OS); secondary endpoints were time from first progression to death (TFPTD) and tolerability. One hundred and eighty-three patients were enrolled between January 1998 and November 2003. After a median follow-up of 53.9 months, response rate, median OS and median TFPTD were 14.7% (6.3% CR) versus 11.3% (5.5% CR), 14 versus 14 months, 6 versus 5 months, in arms A and B, respectively with no significant differences between the groups. Cox regression analysis showed that the use of chemotherapy after first progression (HR 0.54; 95% CI 0.35-0.86; p = 0.008), PS = 0 (HR 0.53; 95% CI 0.35-0.81; p = 0.001) and female gender (HR 0.63; 95% CI 0.41-0.98; p = 0.038) were significantly associated with a longer TFPTD; treatment arm was not significant (HR 0.88; 95% CI 0.60-1.31; p = 0.54). Toxicity was mainly limited to WHO grades 1 or 2. Chronic maintenance immunotherapy after disease progression is feasible, but does not significantly increase OS or the TFPTD. PMID- 19779717 TI - High endoplasmic reticulum activity renders multiple myeloma cells hypersensitive to mitochondrial inhibitors. AB - Multiple myeloma (MM) cells continuously secrete large amounts of immunoglobulins that are folded in the endoplasmic reticulum (ER) whose function depend on the Ca(2+) concentration inside its lumen. Recently, it was shown that the ER membrane leaks Ca(2+) that is captured and delivered back by mitochondria in order to prevent its loss. Thus, we hypothesized that the highly active and abundant ER in MM cells results in greater Ca(2+)-regulation by mitochondria which would render them sensitive to mitochondrial inhibitors. Here, we indeed find that Ca(2+) leak is greater in 3 MM, when compared to 2 B-cell leukemia cell lines. Moreover, this greater leak in MM cells is associated with hypersensitivity to various mitochondrial inhibitors, including CCCP. Consistent with our hypothesis, CCCP is more potent in inducing the unfolded protein response marker, CHOP/GADD153 in MM versus B-cell leukemia lines. Additionally, MM cells are found to be significantly more sensitive to clinically used fenofibrate and troglitazone, both of which were recently shown to have inhibitory effects on mitochondrial function. Overall, our results demonstrate that the unusually high ER activity in MM cells may be exploited for therapeutic benefit through the use of mitochondrial inhibitors including troglitazone and fenofibrate. PMID- 19779718 TI - Improved therapeutic activity of folate-targeted liposomal doxorubicin in folate receptor-expressing tumor models. AB - PURPOSE: The folate receptor (FR) is overexpressed in a broad spectrum of malignant tumors and represents an attractive target for selective delivery of anti-cancer agents to FR-expressing tumors. Targeting liposomes to the FR has been proposed as a way to enhance the effects of liposome-based chemotherapy. METHODS: Folate-polyethylene glycol-distearoyl-phosphatidyl-ethanolamine conjugate was inserted into pegylated liposomal doxorubicin (PLD). The therapeutic activity of folate-targeted (FT-PLD) and non-targeted (PLD) pegylated liposomal doxorubicin was tested in two human tumor models (KB, KB-V) and in one mouse ascitic tumor model (FR-expressing J6456) by the i.v. systemic route in all models, and by the i.p. intracavitary route in the ascitic tumor model only. RESULTS: Consistent with previous studies, PLD was clearly superior to free doxorubicin in all tumor models. When targeted and non-targeted liposome formulations were compared, FT-PLD was more effective than PLD in the KB and KB-V xenograft models, and in the J6456 intra-cavitary therapy model. The therapeutic effect was dose-dependent in the KB model and schedule-dependent in the J6456 intra-cavitary therapy model. In some experiments, toxic deaths aggravated by folate-depleted diet were a major confounding factor. In a non-FR expressing J6456 model, FT-PLD was as active as PLD indicating that its activity is not limited to FR-expressing tumors. CONCLUSION: Folate-targeting confers a significant albeit modest therapeutic improvement to PLD in FR-expressing tumor models, which appears particularly valuable in intracavitary therapy. The potential clinical added value of this approach has yet to be determined. PMID- 19779721 TI - Variable association of anti-CCP positivity with serum ferritin may be corrected by APF test. PMID- 19779719 TI - The pathological spectrum of CNS inflammatory demyelinating diseases. AB - Inflammatory demyelinating diseases of the central nervous system (CNS) occur throughout the world and are the leading cause of nontraumatic neurological disability in young adults. They represent a broad spectrum of disorders that vary in their clinical course, regional distribution, and pathology. However, there can be a considerable overlap between at least some of these disorders, leading to misdiagnoses or diagnostic uncertainty. Multiple sclerosis (MS), the most common inflammatory demyelinating CNS disease affecting approximately one million adults, shares the basic pathological hallmark of CNS inflammatory demyelination. Advances based on recent systematic clinicopathologic-serologic correlative approaches have led to novel insights with respect to the classification of this disorder, the pathologic substrate of disability, a better understanding of the underlying pathogenic mechanisms involved in lesion formation, as well as the clinical relevance of cortical demyelination and normal appearing white matter pathology. In addition to prototypic MS, these diseases include Marburg variant of acute MS, Balo's concentric sclerosis, neuromyelitis optica, acute disseminated encephalomyelitis, and tumefactive MS. The last decade has seen a resurgence of interest in examining the lesions of these inflammatory demyelinating CNS disorders with newer and more sophisticated immunological and molecular tools. Herein, we review the clinicopathologic features of these CNS inflammatory demyelinating disorders and discuss recent advances in understanding their immunopathogenesis. PMID- 19779720 TI - The blood-brain and the blood-cerebrospinal fluid barriers: function and dysfunction. AB - The central nervous system (CNS) is tightly sealed from the changeable milieu of blood by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). While the BBB is considered to be localized at the level of the endothelial cells within CNS microvessels, the BCSFB is established by choroid plexus epithelial cells. The BBB inhibits the free paracellular diffusion of water-soluble molecules by an elaborate network of complex tight junctions (TJs) that interconnects the endothelial cells. Combined with the absence of fenestrae and an extremely low pinocytotic activity, which inhibit transcellular passage of molecules across the barrier, these morphological peculiarities establish the physical permeability barrier of the BBB. In addition, a functional BBB is manifested by a number of permanently active transport mechanisms, specifically expressed by brain capillary endothelial cells that ensure the transport of nutrients into the CNS and exclusion of blood-borne molecules that could be detrimental to the milieu required for neural transmission. Finally, while the endothelial cells constitute the physical and metabolic barrier per se, interactions with adjacent cellular and acellular layers are prerequisites for barrier function. The fully differentiated BBB consists of a complex system comprising the highly specialized endothelial cells and their underlying basement membrane in which a large number of pericytes are embedded, perivascular antigen presenting cells, and an ensheathment of astrocytic endfeet and associated parenchymal basement membrane. Endothelial cell morphology, biochemistry, and function thus make these brain microvascular endothelial cells unique and distinguishable from all other endothelial cells in the body. Similar to the endothelial barrier, the morphological correlate of the BCSFB is found at the level of unique apical tight junctions between the choroid plexus epithelial cells inhibiting paracellular diffusion of water-soluble molecules across this barrier. Besides its barrier function, choroid plexus epithelial cells have a secretory function and produce the CSF. The barrier and secretory function of the choroid plexus epithelial cells are maintained by the expression of numerous transport systems allowing the directed transport of ions and nutrients into the CSF and the removal of toxic agents out of the CSF. In the event of CNS pathology, barrier characteristics of the blood-CNS barriers are altered, leading to edema formation and recruitment of inflammatory cells into the CNS. In this review we will describe current knowledge on the cellular and molecular basis of the functional and dysfunctional blood-CNS barriers with focus on CNS autoimmune inflammation. PMID- 19779722 TI - Single-nucleotide polymorphisms p53 G72C and Mdm2 T309G in patients with psoriasis, psoriatic arthritis, and SAPHO syndrome. AB - Psoriasis (Ps), psoriatic arthritis (PsA), and SAPHO syndrome are diseases of unknown etiology that share common clinical features; however, family studies support the hypothesis of a genetic background for each of these diseases. To study the two common single-nucleotide polymorphisms (SNP) in the murine-double minute-2-(Mdm2) and p53 genes in patients with Ps, PsA, and SAPHO syndrome. Genomic DNA was obtained from 187 patients with Ps, 50 with PsA, and 36 with SAPHO as well as 478 healthy controls. Mdm2-gene SNP T309G and p53-gene SNP G72C genotypes were determined by the polymerase chain reaction. Genotype and allele frequencies were analyzed with chi(2)-tests. Among the patients with Ps and PsA, no differences in allele or genotype frequencies of the p53-gene SNP G72C and Mdm2-gene SNP T309G were detected. However, in the SAPHO patients group, the frequencies of the Mdm2 SNP309 G allele and the genotype SNP 309 GG were significantly increased compared with the controls (G allele: 51.4 vs. 38.7%, P = 0.034; genotype GG: 36.1 vs. 14.2%, P = 0.002). In addition, the frequencies of the p53 SNP72 C allele and the genotype SNP 72 CC were also increased in the SAPHO patients cohort (C allele: 36.1 vs. 25.6%, P = 0.05; genotype CC: 16.7 vs. 6.3%, P = 0.05). SAPHO syndrome may be linked to an imbalance between MDM2 and p53 regulation with a "weak" p53-response associated with the Mdm2 SNP 309 G allele. In contrast, the p53 network does not seem to play a major role in pathogenesis of Ps or PsA. PMID- 19779723 TI - Relationships between MMP-2, MMP-9, TIMP-1 and TIMP-2 levels and their pathogenesis in patients with lupus nephritis. AB - Recent evidence suggests that matrix metalloproteinases (MMPs) were involved with many kinds of kidney diseases. We investigated the roles of MMPs and its tissue inhibitors TIMPs in patients with lupus nephritis (LN). A total of 44 systemic lupus erythematosus patients and 31 healthy subjects were enrolled. The levels of total MMP-2, 9 (tMMP-2, tMMP-9) along with TIMP-1, 2 were measured in serum by ELISA. Serum tMMP-2, tMMP-9 was higher in LN patients than those non-LN patients and healthy controls. Serum tMMP-2 in patients without LN was higher than in healthy controls. TIMP-2 was higher in LN patients than healthy controls, and no significant difference in TIMP-2 was observed between LN and non-LN patients. TIMP-1 levels among LN, non-LN patients and healthy controls were comparable. The ratio of tMMP-9 to TIMP-1 in LN patients was higher than non-LN patients and healthy controls and no difference in ratio of tMMP-9 to TIMP-1 between non-LN patients and healthy subjects was observed. A negative correlation between the ratio of tMMP-9 to TIMP-1 in lupus patients and the titers of anti-dsDNA was found; whereas, no correlation between the ratio of tMMP-9 to TIMP-1 and the concentration of C3 as well 24 h urine protein was observed in LN patients. We suggest imbalance between tMMP-9 and TIMP-1 may contribute to the pathogenesis of LN. Measurement of MMPs and TIMPs may be helpful in the early identification of lupus patients with LN and may help gauge the response to treatment in patients with active LN undergoing treatment. PMID- 19779724 TI - Association of tumor necrosis factor alpha and IL-10 promoter polymorphisms with rheumatoid arthritis in North Indian population. AB - Rheumatoid arthritis is a chronic autoimmune disorder associated with altered expression of pro- and anti-inflammatory cytokines in the affected tissues. The aim of this study was to investigate the association between promoter polymorphisms of TNFalpha and IL-10 gene with susceptibility, age of disease onset and disease severity in North Indian patients with rheumatoid arthritis (RA). SNPs at position -308 and -863 of TNF gene and -819/-592 and -1082 position of IL-10 gene were determined in 222 patients and 208 healthy controls using RFLP or ARMS method. Polymorphism TNF -308A was less prevalent among the patients (1.7%) than controls (4.9%; p = 0.01, OR: 0.32, 95% CI: 0.13-0.76). Among female patients, IL-10 -592A allele associated with higher baseline disease activity scores (5.77 +/- 1.99) than -592C (5.57 +/- 1.19; p = 0.04). Female patients carrying allele A of TNFalpha -863 had earlier age of onset of RA (33.99 +/- 9.6 years) than those with allele C (36.15 +/- 11.21 years; p = 0.043). In conclusion, allele A at TNFalpha -308 locus provides protection against RA in North Indian population while another TNF allele A at -863 position had weak association with earlier onset of disease in female patients. On the other hand promoter polymorphisms of IL-10 did not affect susceptibility but polymorphism at -819/-592A was associated with higher disease activity scores at baseline. PMID- 19779725 TI - The Hebrew version of the FibroFatigue scale: validation of a questionnaire for assessment of fibromyalgia and chronic fatigue syndrome. AB - The objective of this study is to validate a translated Hebrew version of the FibroFatigue Scale (FFS). The Hebrew version of the FFS was administered to 100 patients fulfilling ACR criteria for classification of FM together with the validated Hebrew version of the Fibromyalgia Impact Questionnaire (FIQ), the validated Hebrew version of the Short Form-36 (SF-36) and a Visual Analogue Scale (VAS) measurement of pain, anxiety, depression, morning stiffness and global well being. Test-retest reliability was assessed using Spearman correlations. Internal consistency was evaluated with Cronbach's alpha of reliability. Construct validity of the FFS was evaluated by correlations among the FFS, the FIQ and the subscales of the SF-36. Mean duration of symptoms was 10.7 years, and mean age of participants was 53.5 years. Test-retest reliability was between 0.46 and 0.85 for the various FFS items. Internal consistency was 0.89 for the overall FFS. Significant correlations were obtained between the FFS items and the SF-36. These results support the reliability and validity of the data obtained with the Hebrew version of the FSS for detecting and measuring symptom severity in Hebrew speaking patients with FM. PMID- 19779727 TI - Neural response telemetry in patients with the double-array cochlear implant. AB - This study aimed to evaluate the neural response in double-array cochlear implant as well as to describe the refractory recovery and the spread of excitation functions. In a prospective study 11 patients were implanted with the double array cochlear implant. Neural response telemetry (NRT) was performed intra operatively. NRT threshold could be registered in 6 of the 11 patients, at least in one electrode. The remaining five patients did not show measurable neural response intra-operatively. It was noted that although recovery and spread of excitation functions could be recorded in all the tested electrodes with measurable neural responses, the responses were shown to be different from the usual register in patients with other etiologies. PMID- 19779726 TI - Differences in in vitro cerebellar neuronal responses to hypoxia in eider ducks, chicken and rats. AB - Ducks are well-known to be more tolerant to asphyxia than non-diving birds, but it is not known if their defences include enhanced neuronal hypoxia tolerance. To test this, we compared extracellular recordings of spontaneous activity in the Purkinje cell layer of 400 mum thick isolated cerebellar slices from eider ducks, chickens and rats, before, during and after 60 min hypoxia (95%N(2)-5%CO(2)) or chemical anoxia (hypoxia + 2 mM NaCN). Most slices rapidly lost activity in hypoxia, with or without recovery after rinse and return to normoxia (95%O(2) 5%CO(2)), but some maintained spontaneous activity throughout the insult. Proportions of 'surviving' (i.e. recovering or active) duck slices were significantly higher than for chickens in anoxia, and relative activity levels were higher for ducks than for chickens during hypoxia, anoxia and recovery. Survival of rat slices was significantly poorer than for birds under all conditions. Results suggest that (1) duck cerebellar neurons are intrinsically more hypoxia-tolerant than chicken neurons; (2) avian neurons are more hypoxia tolerant than rat neurons, and (3) the enhanced hypoxic tolerance of duck neurons largely depended on efficient anaerobiosis since it mainly manifested itself in chemical anoxia. Mechanisms underlying the observed differences in neuronal hypoxic responses remain to be elucidated. PMID- 19779729 TI - The use of hair as an indicator of occupational 14C contamination. AB - This paper presents a study in which the specific activity of (14)C in hair has been investigated as an easily determined bio-indicator of the integrated (14)C exposure (over several months). The study includes 28 Swedish workers handling (14)C-labelled compounds, or working in a (14)C-enriched environment. Hair samples from personnel at a Swedish nuclear power plant showed very low levels of (14)C contamination, if any. In contrast, personnel at the investigated research departments showed (14)C levels in hair of up to 60% above the natural specific activity of (14)C. Much higher levels, up to 80 times the natural specific activity of (14)C, were found in hair from individuals working at a pharmaceutical research laboratory. This contamination was, however, not solely an internal contamination. There were indications that most of the (14)C in the hair originated from airborne (14)C-compounds, which were adsorbed onto the hair. The difficulties in removing this external (14)C contamination prior to analysis are discussed, as are the possibilities of using accelerator mass spectrometry to analyse various types of samples for retrospective dose assessment. PMID- 19779730 TI - Cryotherapy of sclerotomy sites for prevention of late post-vitrectomy diabetic hemorrhage: a randomized clinical trial. AB - BACKGROUND: To evaluate the role of cryotherapy of sclerotomy sites in prevention of late (after 4 weeks) post-vitrectomy diabetic hemorrhage. METHODS: In a prospective randomized double-masked clinical trial, a total of 124 eyes of 119 patients underwent pars plana vitrectomy for complications of proliferative diabetic retinopathy. At the end of vitrectomy, the eyes were randomly assigned to two groups. The case group received two cryotherapy spots at each sclerotomy site, whereas the eyes in the control group received no further intervention. Evaluations were repeated at months 1, 2, 4, and 6. The primary outcome measure was occurrence of vitreous hemorrhage after the first month and up to the sixth month. Ultrasound biomicroscopy (UBM) examination of the sclerotomy sites was performed concurrent with the occurrence of vitreous hemorrhage or at the last follow-up. RESULTS: Thirty-six eyes were excluded mostly because of early postoperative vitreous hemorrhage. Finally, the data of 42 eyes of the cases and 46 eyes of the controls were used for analysis. Late vitreous hemorrhage occurred in 17 out of 88 eyes (19.3%). This rate was significantly higher in the cases compared to the controls, 28.6% (12 eyes) versus 10.9% (five eyes) within 6 months (P = 0.036). There was no statistically significant difference in the UBM findings of the sclerotomy sites between the two groups. No relationship was noticed between morphologic patterns detected by UBM and occurrence of late vitreous hemorrhage. CONCLUSIONS: Cryotherapy of the sclerotomy sites at the end of the operation is not helpful for prevention of late post-vitrectomy diabetic hemorrhage, and it may even increase this risk. PMID- 19779731 TI - Ovarian hormones regulate expression of the focal adhesion proteins, talin and paxillin, in rat uterine luminal but not glandular epithelial cells. AB - During early pregnancy in the rat, focal adhesions disassemble in uterine luminal epithelial cells at the time of implantation to facilitate their removal so that the implanting blastocyst can invade into the underlying endometrial decidual cells. This study investigated the effect of ovarian hormones on the distribution and protein expression of two focal adhesion proteins, talin and paxillin, in rat uterine luminal and glandular epithelial cells under various hormone regimes. Talin and paxillin showed a major distributional change between different hormone regimes. Talin and paxillin were highly concentrated along the basal cell surface of uterine luminal epithelial cells in response to oestrogen treatment. However, this prominent staining of talin and paxillin was absent and also a corresponding reduction of paxillin expression was demonstrated in response to progesterone alone or progesterone in combination with oestrogen, which is also observed at the time of implantation. In contrast, the distribution of talin and paxillin in uterine glandular epithelial cells was localised on the basal cell surface and remained unchanged in all hormone regimes. Thus, not all focal adhesions are hormonally dependent in the rat uterus; however, the dynamics of focal adhesion in uterine luminal epithelial cells is tightly regulated by ovarian hormones. In particular, focal adhesion disassembly in uterine luminal epithelial cells, a key component to establish successful implantation, is predominantly under the influence of progesterone. PMID- 19779732 TI - Chronic stress experience in young physicians: impact of person- and workplace related factors. AB - OBJECTIVES: The objectives of the present study are to investigate and compare the relative impact of workplace-related factors and personal characteristics on chronic psychosocial stress experience in young physicians. METHODS: In a prospective study, a cohort of Swiss medical school graduates was followed up, beginning in 2001. In their fourth and eighth year after graduation, 443 physicians assessed their workplace conditions, the experienced effort-reward imbalance, the received professional and emotional support as well as their personal characteristics. The chronic stress experience was measured by the Trier Inventory for the Assessment of Chronic Stress-Screening Subscale of Chronic Stress (TICS-SCSS), 7 years after graduation. The model of influencing factors on chronic stress experience was tested with a hierarchical regression analysis. RESULTS: The mean in chronic stress (TICS-SCSS) in our study sample is significantly higher (p < 0.001) compared to an age-matched population representative sample. In the prediction of chronic stress, the workplace-related factor effort-reward imbalance as well as the personal characteristic overcommitment turned out to be the most important risk factors. Stress protective are high satisfaction with career support, sense of coherence and occupational self-efficacy. The whole set of variables used in the regression model explains 51% of the variance of chronic stress experience. In the prediction of chronic stress, gender has no significant moderator effect. CONCLUSIONS: It is a matter of concern that young physicians report to feel chronically stressed early in their professional career. Actions have to be taken to reduce the stress level mainly in regard to re-establish reciprocity between perceived effort invested and rewards received, in the form of esteem, monetary gain and career opportunities including job security. PMID- 19779733 TI - Hydroxypyrene in urine of football players after playing on artificial sports field with tire crumb infill. AB - BACKGROUND: Artificial sports fields are increasingly being used for sports. Recycled rubber from automotive and truck scrap rubber tires are used as an infill material for football grounds. There are concerns that football players may be at risk due to exposure from released compounds from rubber infill. Compounds from crumb infill may be inhaled and dermal exposure may occur. A study was performed to assess the exposure of football players to polycyclic aromatic hydrocarbons due to sporting on synthetic ground with rubber crumb infill. METHODS: In this study, football players were trained and had a match on the artificial turf pitch during 2.5 h. They had an intensive skin contact with rubber infill. All urine of seven nonsmoking football players was collected over a 3-day period, the day before sporting, the day of sporting and the day after sporting. Urine samples were analyzed for 1-hydroxypyrene. Confounding exposure from environmental sources and diet was controlled for. RESULTS: The individual increase of the amount of excretion over time was used as a measure to assess the uptake of PAH. It appeared that the baseline of excreted 1-hydroxypyrene in 4 of 7 volunteers was sufficient stable and that 1 volunteer out of 4 showed after the 2.5-h period of training and match on the playground an increase in hydroxypyrene in urine. However, concomitant dietary uptake of PAH by this volunteer was observed. CONCLUSIONS: This study provides evidence that uptake of PAH by football players active on artificial grounds with rubber crumb infill is minimal. If there is any exposure, than the uptake is very limited and within the range of uptake of PAH from environmental sources and/or diet. PMID- 19779734 TI - Effects of two glucose ingestion rates on substrate utilization during moderate intensity shivering. AB - Although the importance of food consumption to survive in the cold is well established, most shivering studies have focused on fuel selection in fasting subjects. Therefore, the aim of the present study was to provide the first estimates of exogenous glucose as well as liver and muscle glycogen oxidation rates of non-cold acclimatized men (n = 6) ingesting glucose in trace amounts (Control; C), and at rates of 400 mg min(-1) (Low Glucose; LG), and 800 mg min( 1) (High Glucose; HG) during moderate-intensity shivering (~3 times resting metabolic rate or ~20% VO(2max)) using indirect calorimetry and stable isotope methodologies. Exogenous glucose oxidation peaked at ~200 mg min(-1) at the lowest glucose ingestion rate (~400 mg min(-1)). In addition, glucose ingestion increased the contribution of plasma glucose to total heat production by ~50% but did not change the role played by muscle glycogen (~27% of heat production for control condition and ~23-28% for LG and HG). Instead, the contribution of liver derived glucose to total heat production was reduced by 40-60% in LG and HG, respectively. In conclusion, glucose ingestion even at low rates contributes a significant proportion of total heat production during moderate intensity shivering and reduces the utilization of liver-derived glucose but not muscle glycogen. PMID- 19779735 TI - Do sessions of cryostimulation have influence on white blood cell count, level of IL6 and total oxidative and antioxidative status in healthy men? AB - The influence of extremely low temperatures on the human body and physiological reactions are not fully recognized. It has been postulated that cryostimulation could modify immunological reactions, leukocytes mobilization and levels of cytokines. The aim of this research was to estimate the influence of a ten sessions 3-min-long exposures to cryogenic temperature (-130 degrees C) on the white blood cell (WBC) count, level of IL6 and the total oxidative and antioxidative status in 15 young, clinically healthy men. Blood samples were obtained in the morning before cryostimulation, again 30 min after treatment and the next day in the morning, both during the first and tenth session. The WBC count, level of IL6 and total lipid peroxides as the total oxidative status and the total antioxidative status (TAS), were measured. After completing a total of ten whole-body therapy sessions a significant increase in WBC count, especially lymphocytes and monocytes was noted. There was an increase in level of IL6 after first and the last cryostimulation the most pronounced after tenth session. On the contrary the TAS level decreased significant after the treatment. It was concluded that repeated expositions to extremely low temperatures use in cryostimulation have mobilization effect on immunological system. PMID- 19779736 TI - Effect of 21 days of horizontal bed rest on behavioural thermoregulation. AB - The present study investigated the effect of 21 days of horizontal bed rest on cutaneous cold and warm sensitivity, and on behavioural temperature regulation. Healthy male subjects (N = 10) were accommodated in a hospital ward for the duration of the study and were under 24-h medical care. All activities (eating, drinking, hygiene, etc.) were conducted in the horizontal position. On the 1st and 22nd day of bed rest, cutaneous temperature sensitivity was tested by applying cold and warm stimuli of different magnitudes to the volar region of the forearm via a Peltier element thermode. Behavioural thermoregulation was assessed by having the subjects regulate the temperature of the water within a water perfused suit (T (wps)) they were wearing. A control unit established a sinusoidal change in T (wps), such that it varied from 27 to 42 degrees C. The subjects could alter the direction of the change of T (wps), when they perceived it as thermally uncomfortable. The magnitude of the oscillations towards the end of the trial was assumed to represent the upper and lower boundaries of the thermal comfort zone. The cutaneous threshold for detecting cold stimulus decreased (P < 0.05) from 1.6 (1.0) degrees C on day 1 to 1.0 (0.3) degrees C on day 22. No effect was observed on the ability to detect warm stimuli or on the regulated T (wps). We conclude that although cold sensitivity increased after bed rest, it was not of sufficient magnitude to cause any alteration in behavioural thermoregulatory responses. PMID- 19779737 TI - Modeling familial British and Danish dementia. AB - Familial British dementia (FBD) and familial Danish dementia (FDD) are two autosomal dominant neurodegenerative diseases caused by mutations in the BRI ( 2 ) gene. FBD and FDD are characterized by widespread cerebral amyloid angiopathy (CAA), parenchymal amyloid deposition, and neurofibrillary tangles. Transgenic mice expressing wild-type and mutant forms of the BRI(2) protein, Bri ( 2 ) knock in mutant mice, and Bri ( 2 ) gene knock-out mice have been developed. Transgenic mice expressing a human FDD-mutated form of the BRI ( 2 ) gene have partially reproduced the neuropathological lesions observed in FDD. These mice develop extensive CAA, parenchymal amyloid deposition, and neuroinflammation in the central nervous system. These animal models allow the study of the molecular mechanism(s) underlying the neuronal dysfunction in these diseases and allow the development of potential therapeutic approaches for these and related neurodegenerative conditions. In this review, a comprehensive account of the advances in the development of animal models for FBD and FDD and of their relevance to the study of Alzheimer disease is presented. PMID- 19779738 TI - Imaging the relationship between structure, function and behaviour in the human brain. PMID- 19779739 TI - Humoral immune responses and protective efficacy of sequential B- and T-cell epitopes of V antigen of Yersinia pestis by intranasal immunization in microparticles. AB - Capsular F1 and secretory V antigen are the putative vaccine candidates for plague, caused by Yersinia pestis. Contemplating this, we studied the immunogenicity and protective efficacy of collinearly synthesized B- and T-cell epitopes (B-T constructs) of V antigen entrapped in poly (DL-lactide-co glycolide) microparticles immunized intranasally using single dose immunization schedule in outbred, H-2(b) and H-2(d) mice. High antibody levels were observed in terms of IgG, IgA and SIgA peak titers in sera and mucosal washes to different B-T constructs. The constructs ai, bi and fi especially showed high peak antibody titers ranging from 51,200 to 204,000, which were maintained till day 120 post immunization. IgG/IgA Specific activity in sera and washes correlated well with the peak antibody titers. Moreover, all the B-T constructs showed mixed IgG1 and IgG2a/2b response, variable immunoreactivity as well as memory response with V antigen. B-T constructs, viz ai, ak, bi, fi, di and ik showed comparatively high isotype levels. These constructs showed high immunoreactivity, and good recall response with V antigen. Finally, in vivo protective study in BALB/c mice demonstrated the protective efficacy of three B-T constructs (ai, bi and fi) against lethal doses of Yersinia pestis till day 20 post challenge, while construct 'id' showed partial protection. PMID- 19779740 TI - Molecular characterization of Trichomonas vaginalis isolates from the Philippines. AB - Trichomonas vaginalis is a human urogenital pathogen that causes trichomoniasis, the most common nonviral parasitic sexually transmitted infection in the world. Presently, there are no reports on comparative sequence analysis as well as on the identification of phylogenetic positions of T. vaginalis isolates from the Philippines relative to known trichomonads. In this study, 5.8S rDNA and the flanking internal transcribed spacer (ITS) regions of 57 T. vaginalis isolates were sequenced. The phylogenetic positions of the isolates relative to known trichomonads were determined using the model-based (GTR+Gamma+I) neighbor joining, maximum likelihood, and Bayesian-inference analyses and the nonmodel based maximum parsimony analysis. Construction of a phylogenetic tree showed the clustering of all the sequences in one branch together with other T. vaginalis strains obtained through basic local alignment search tool search. Sequencing of the 5.8S rDNA gene and the flanking ITS1and ITS2 regions of T. vaginalis isolates from the Philippines demonstrated low genetic polymorphism. However, comparison of the ribosomal DNA sequences may have implications on some phenotypic characteristics of T. vaginalis. PMID- 19779741 TI - A salivary cystatin, HlSC-1, from the ixodid tick Haemaphysalis longicornis play roles in the blood-feeding processes. AB - Ticks feed exclusively on blood to obtain their nutrients, but the gene products that mediate blood-sucking processes in ticks are still unknown. We report here the molecular characterization and possible biological function of a cysteine protease inhibitor (HlSC-1) identified in the salivary gland of the ixodid tick Haemaphysalis longicornis. The HlSC-1 cDNA contains 423 bp that code for 140 amino acids with a predictable molecular weight of 12 kDa. The recombinant HlSC-1 expressed in Escherichia coli was shown to inhibit the activity of papain and cathepsin L, while cathepsin B activity was unaffected. Immunolocalization studies detected the endogenous enzyme in the salivary gland type II acini of an adult tick. Furthermore, quantitative RT-PCR analysis showed that the expression of HlSC-1 transcripts was associated with blood-feeding processes and was highly up-regulated in the early phase of feeding. Our results strongly suggest that HlSC-1 may play pivotal roles in the blood-feeding processes. PMID- 19779742 TI - Phenotypic and transcriptomic analyses of Plasmodium falciparum protein kinase A catalytic subunit inhibition. AB - The emergence and dissemination of drug-resistant malaria parasites represent one of the most important problems in malaria case management. Plasmodium falciparum is the causative agent of the most lethal form of human malaria. The molecular mechanisms that control the life cycle of the malaria parasite are still poorly understood. The published genome sequence (P. falciparum strain 3D7) reveals that several homologs of eukaryotic signaling proteins, such as protein kinases and phosphatases, are conserved in P. falciparum. Proteins kinases are now widely recognized as valuable drug targets in protozoan parasites. In this study, gene silencing with double-stranded RNA (dsRNA) and microarray techniques were used to study the biological function of the cAMP-dependent protein kinase catalytic subunit (PfPKAc) in the parasite erythrocytic life cycle. Treatment of parasites with PfPKAc dsRNA resulted in a marked reduction of endogenous PfPKAc mRNA associated with a compensatory decrease of PfPKAr mRNA followed by morphological changes in schizont stages and cell cycle arrest. The global effects of gene silencing were also investigated using a P. falciparum pan-genomic microarray. Transcriptomic analysis showed that the expression of 329 genes was altered in response to downregulation of PfPKAc mRNA particularly genes in specific metabolic pathways linked with merozoite invasion processes, the calcium/calmodulin signaling, and kinases network and mitochondrial functions. PMID- 19779743 TI - Dingoes (Canis dingo) can use human social cues to locate hidden food. AB - There is contention concerning the role that domestication plays in the responsiveness of canids to human social cues, with most studies investigating abilities of recognized domestic dog breeds or wolves. Valuable insight regarding the evolution of social communication with humans might be gained by investigating Australian dingoes, which have an early history of domestication, but have been free-ranging in Australia for approximately 3500-5000 years. Seven 'pure' dingoes were tested outdoors by a familiar experimenter using the object choice paradigm to determine whether they could follow nine human communicative gestures previously tested with domestic dogs and captive wolves. Dingoes passed all cues significantly above control, including the "benchmark" momentary distal pointing, with the exception of gaze only, gaze and point, and pointing from the incorrect location. Dingo performance appears to lie somewhere between wolves and dogs, which suggests that domestication may have played a role in their ability to comprehend human gestures. PMID- 19779744 TI - A relational differential outcomes effect: pigeons can classify outcomes as "good" and "better". AB - In a conditional discrimination each of two sample stimuli indicates which of two comparison stimuli is correct. When correct choice following each conditional stimulus is followed by a different outcome (one kind of food following one, a different kind of food following the other) it often facilitates acquisition and improves memory. In transfer designs, in which two different conditional discriminations are followed by the same two differential outcomes, outcome expectation can be shown to be sufficient for comparison choice. That is, the samples from one conditional discrimination are matched to comparisons from the other conditional discrimination based on the common outcomes alone. In the present study we asked if for pigeons the relative value of the differential outcomes (higher versus lower value) can serve as the basis for comparison choice, independent of other characteristics of the outcomes and of differential sample responding. That is, would different outcomes that could be described as "good" and "better" form two stimulus classes. For one conditional discrimination, the differential outcomes involved differential probability of reinforcement for choice of the correct comparison stimulus (0.80 vs. 0.20 for correct choice of the two comparisons, respectively). For the other conditional discrimination, the differential outcomes involved differential responding to the two comparison stimuli (5 pecks vs. 20 pecks to the correct comparisons, respectively). On test trials, when conditional stimuli from the two conditional discriminations were interchanged and the relative value of the differential outcomes could serve as the only basis for comparison choice, we found positive transfer. The results indicate that relational attributes of outcomes can serve as effective cues for comparison choice. PMID- 19779745 TI - First report on methicillin-resistant Staphylococcus aureus of Spa type T037, Sequence Type 239, SCCmec type III/IIIA in Malaysia. AB - Methicillin-resistant Staphylococcus aureus (MRSA) from Malaysia were shown to possess staphylococcal cassette chromosome mec (SCCmec)-III and IIIA. Spa sequencing and multi-locus sequence typing (MLST) documented t037 and ST 239 (CC8) for 83.3% of the isolates. This confirms observations in several other Far Eastern countries and corroborates the epidemicity of this clone. PMID- 19779746 TI - Universal species concept: pipe dream or a step toward unifying biology? AB - The Universal Tree of Life, which is based on phylogenetic analysis of the RNA sequence from the small ribosomal subunit, was a breakthrough in understanding the relatedness among all living organisms. The result has had a major impact on taxonomy by separating life into three domains: Eukarya, Bacteria, and Archaea. Indeed, microbiologists have used the 16S ribosomal RNA (rRNA) of the small ribosomal subunit to construct the hierarchical classification of Bacteria and Archaea from the level of domain to genus. However, the 16S rRNA of the Bacteria and Archaea and the corresponding 18S rRNA of the Eukarya are too highly conserved to be useful phylogenetically at the species level. For this reason, I propose that biologists adopt a phylogenomic species concept that utilizes both phylogenetic analyses of less highly conserved genes and proteins as well as genomic analyses for the circumscription of species. If biologists adopt a phylogenomic concept for species, the classification of all living organisms from domain to species could be completed. Furthermore, this universal species concept could help provide a more equitable circumscription among all species, as well as aid in the unification of biologists and biology. PMID- 19779748 TI - Abstracts of ESMRMB 2009, the 26th Annual Scientific Meeting of the European Society for Magnetic Resonance in Medicine and Biology. Antalya, Turkey. October: 1-3, 2009. PMID- 19779747 TI - Quantitative metabolic profiles of 2nd and 3rd trimester human amniotic fluid using (1)H HR-MAS spectroscopy. AB - OBJECT: To establish and compare normative metabolite concentrations in 2nd and 3rd trimester human amniotic fluid samples in an effort to reveal metabolic biomarkers of fetal health and development. MATERIALS AND METHODS: Twenty-one metabolite concentrations were compared between 2nd (15-27 weeks gestation, N = 23) and 3rd (29-39 weeks gestation, N = 27) trimester amniotic fluid samples using (1)H high resolution magic angle spinning (HR-MAS) spectroscopy. Data were acquired using the electronic reference to access in vivo concentrations method and quantified using a modified semi-parametric quantum estimation algorithm modified for high-resolution ex vivo data. RESULTS: Sixteen of 21 metabolite concentrations differed significantly between 2nd and 3rd trimester groups. Betaine (0.00846+/-0.00206 mmol/kg vs. 0.0133+/-0.0058 mmol/kg, P < 0.002) and creatinine (0.0124+/-0.0058 mmol/kg vs. 0.247+/-0.011 mmol/kg, P < 0.001) concentrations increased significantly, while glucose (5.96+/-1.66 mmol/kg vs. 2.41+/-1.69 mmol/kg, P < 0.001), citrate (0.740+/-0.217 mmol/kg vs. 0.399+/-0.137 mmol/kg, P < 0.001), pyruvate (0.0659+/-0.0103 mmol/kg vs. 0.0299+/-0.286 mmol/kg, P < 0.001), and numerous amino acid (e.g. alanine, glutamate, isoleucine, leucine, lysine, and valine) concentrations decreased significantly with advancing gestation. A stepwise multiple linear regression model applied to 50 samples showed that gestational age can be accurately predicted using combinations of alanine, glucose and creatinine concentrations. CONCLUSION: These results provide key normative data for 2nd and 3rd trimester amniotic fluid metabolite concentrations and provide the foundation for future development of magnetic resonance spectroscopy (MRS) biomarkers to evaluate fetal health and development. PMID- 19779753 TI - Polybrominated diphenyl ethers and their methoxylated metabolites in anchovy (Coilia sp.) from the Yangtze River Delta, China. AB - BACKGROUND, AIM, AND SCOPE: Polybrominated diphenyl ethers (PBDEs) and their metabolites are toxic to animals, and concentrations of the PBDEs metabolites can exceed those of the parent materials. But no information was available on concentrations of PBDEs metabolites in the lower Yangtze River in the region around Jiangsu Province of China, which is heavily urbanized and industrialized area. The aims of this study were to determine whether PBDEs and their methoxylated PBDEs (MeO-PBDEs) were accumulated in Coilia sp. in this area and to investigate the potential sources for these two kinds of brominated organic pollutants. MATERIALS AND METHODS: Samples of four species of anchovy were collected from eight sites in the lower Yangtze River, Taihu Lake, and Hongzehu Lake. Concentrations of 13 PBDEs congeners and eight methoxylated PBDEs were determined by use of organic solvent extraction, followed by gas chromatography and mass spectrometry. RESULTS AND DISCUSSION: The frequencies of detection for PBDEs and MeO-PBDEs were 92% and 53%, respectively. Concentrations of summation operatorPBDEs ranged from not detected (ND) to 77 ng/g lipids (ND-3.8 ng/g wet weight). Concentrations of summation operatorMeO-PBDEs in anchovy ranged from ND to 48 ng/g lipids (ND-8.2 ng/g wet weight). The PBDE concentrations in anchovy from the Yangtze River Delta were similar to or less than those reported for other species from other locations around the world, while the concentrations of MeO-PBDEs were comparable to or slightly less than those reported in other studies. This is the first report of MeO-PBDEs in biota of China. CONCLUSIONS: The results of this study as well as those of other studies suggest that PBDEs in anchovy are primarily of synthetic origin and released by human activities, while MeO-PBDEs in anchovy are primarily from nature as natural products from the sea instead of metabolism of PBDEs in anchovy. PMID- 19779755 TI - Comments on "Gene and genon concept" by K. Scherrer and J. Jost. PMID- 19779756 TI - [Scalp blocks. A useful technique for neurosurgery, dermatology, plastic surgery and pain therapy]. AB - Safe and effective cranial analgesia can be achieved by blocking the sensitive nerves of that region. These include the supraorbital nerve, the supratrochlear nerve, the zygomaticotemporal nerve, the auriculotemporal nerve and the greater and lesser occipital nerves which are accessible at typical and most proximal points. Preferably long acting local anesthetics such as ropivacaine 0.75% or levobupivacaine 0.5% are used supplemented with 5 microg/ml epinephrine to reduce systemic resorption and to elongate the duration. Scalp blocks are useful for intraoperative neurologic testing of the patient during awake craniotomy or for supplementation of general anesthesia for other forms of craniotomy. Other applications are minimally invasive and stereotactic neurosurgery including deep brain stimulation, photodynamic therapy of actinic ceratosis, cranial plastic surgery and pain therapy. PMID- 19779754 TI - Conjugated linoleic acid induces uncoupling protein 1 in white adipose tissue of ob/ob mice. AB - Conjugated linoleic acid (CLA) reduces body weight and adipose mass in a variety of species. The mechanisms by which CLA depletes adipose mass are unclear, but two independent microarray analyses indicate that in white adipose tissue (WAT), uncoupling protein 1 (UCP1) was among genes most changed by CLA. The objective of this study was to determine whether CLA induces ectopic expression of UCP1 in WAT, which may contribute to increased energy expenditure and weight loss. Six week old, male ob/ob mice were fed either a control diet (CON) or a diet supplemented with 1.5% mixed isomer CLA (CLA) for 4 weeks. A third group of mice (LEPTIN) was fed the control diet and received daily injections of recombinant leptin as a positive control for adipose depletion in ob/ob mice. CLA did not alter several mRNA markers of lipid oxidation in epididymal white adipose tissue (eWAT) , but significantly increased carnitine palmitoyltransferase-1b (CPT1b) and PPAR gamma coactivator-1alpha (PGC1alpha) expression. Notably, CLA increased both mRNA and protein expression of uncoupling protein-1 (UCP1). beta3 adrenoceptor mRNA and phosphorylated-p38 mitogen activated protein kinase (MAPK) protein levels were not affected by CLA, but were upregulated by LEPTIN. These data suggest the increased CPT1b, PGC1alpha, and UCP1, in WAT of CLA-fed mice may contribute to the depletion of adipose, and CLA does not appear to increase UCP1 through beta3-adrenergic signaling. Future studies will focus on understanding how CLA increases mitochondrial oxidation and energy dissipation in white adipose tissue. PMID- 19779757 TI - Is remodeling the dominant compensatory mechanism in both chronic heart failure with preserved and reduced left ventricular ejection fraction? AB - The mechanisms of heart failure are ill understood with multiple, heterogeneous hypotheses proposed to describe the condition. This study examines the individual effects of left ventricular hypertrophy, long-axis shortening and the effect of left ventricular remodeling on ejection fraction, end-diastolic volume and stroke volume using a mathematical model of left ventricular contraction. Reducing long axis shortening caused a decline in stroke volume independently of hypertrophy. Increasing concentric left ventricular hypertrophy resulted in an increase in ejection fraction secondary to augmented wall thickening. A decline in stroke volume occurred despite a preserved ejection fraction when concentric hypertrophy was present. Normalization of stroke volume by remodeling resulted in a marked increase in end-diastolic volume in the absence of hypertrophy and an end diastolic volume similar to normal in the presence of concentric hypertrophy. The model predicts that the dominant compensatory mechanism in chronic heart failure is remodeling with normalization of stroke volume. Observational data cited supports this conclusion. PMID- 19779759 TI - Strong attraction of the parasitoid Cotesia marginiventris towards minor volatile compounds of maize. AB - Plants infested with herbivorous arthropods emit complex blends of volatile compounds, which are used by several natural enemies as foraging cues. Despite detailed knowledge on the composition and amount of the emitted volatiles in many plant-herbivore systems, it remains largely unknown which compounds are essential for the attraction of natural enemies. In this study, we used a combination of different fractionation methods and olfactometer bioassays in order to examine the attractiveness of different compositions of volatile blends to females of the parasitoid Cotesia marginiventris. In a first step, we passed a volatile blend emitted by Spodoptera littoralis infested maize seedlings over a silica containing filter tube and subsequently desorbed the volatiles that were retained by the silica filter (silica extract). The volatiles that broke through the silica filter were collected on and subsequently desorbed from a SuperQ filter (breakthrough). The silica extract was highly attractive to the wasps, whereas the breakthrough volatiles were not attractive. The silica extract was even more attractive than the extract that contained all herbivore-induced maize volatiles. Subsequently, we fractioned the silica extract by preparative gas-chromatography (GC) and by separating more polar from less polar compounds. In general, C. marginiventris preferred polar over non-polar compounds, but several fractions were attractive to the wasp, including one that contained compounds emitted in quantities below the detection threshold of the GC analysis. These results imply that the attractiveness of the volatile blend emitted by Spodoptera-infested maize seedlings to C. marginiventris females is determined by a specific combination of attractive and repellent/masking compounds, including some that are emitted in very small amounts. Manipulating the emission of such minor compounds has the potential to greatly improve the attraction of certain parasitoids and enhance biological control of specific insect pests. PMID- 19779760 TI - Diagnostic medical radiation dose in patients after laparoscopic bariatric surgery. AB - BACKGROUND: The purpose of this study was to estimate the cumulative radiation dose from computed tomography (CT) scans and upper gastrointestinal fluoroscopic exams in the post-bariatric-surgery population and correlate these values with current concepts of potential radiation-induced cancer risk. METHODS: A retrospective study of 100 roux-en-y gastric bypass (RYGB) patients and 100 gastric band patients was performed. The cumulative estimated radiation doses from CT scans and fluoroscopic studies received by these patients over a 2.5-year postoperative interval were calculated. The rate of positive radiological studies was determined. Nonlinear regression analyses were used to identify potential independent predictors of higher radiation dose. RESULTS: Mean cumulative dose was 20 +/- 20 mSv for RYGB patients and 11 +/- 11 mSv for gastric band patients. The RYGB procedure and a higher preoperative body mass index were each significant predictors of higher cumulative radiation doses. Dose in the RYGB group ranged from 4 to 156 mSv. Dose in the gastric banding group ranged from 4 to 46 mSv. In the RYGB cohort, positive findings were present in 35% and 16% of CT and fluoroscopic studies, respectively, and 24% and 22% in the gastric band group. None of the fluoroscopic exams performed after the routine 24-h postoperative studies were positive. CONCLUSIONS: Allowing for uncertainties of cancer risk at doses less than 50 mSv, patients undergoing laparoscopic bariatric surgery may receive radiation doses from postoperative diagnostic imaging tests that increase their lifetime cancer risk. PMID- 19779762 TI - Bacterial dissimilatory MnO(2) reduction at extremely haloalkaline conditions. AB - A possibility of dissimilatory MnO(2) reduction at extremely high salt and pH was studied in sediments from hypersaline alkaline lakes in Kulunda Steppe (Altai, Russia). Experiments with anaerobic sediment slurries demonstrated a relatively rapid reduction of colloidal MnO(2) in the presence of acetate and formate as electron donor at in situ conditions (i.e., pH 10 and a salt content from 0.6 to 4 M total Na(+)). All reduced Mn at these conditions remained in the solid phase. A single, stable enrichment culture was obtained from the slurries consistently reducing MnO(2) at pH 10 and 0.6 M total Na(+) with formate. A pure culture of a haloalkaliphilic Mn-reducing bacterium obtained from the positive enrichment was phylogenetically closely related to the anaerobic haloalkaliphilic Bacillus arseniciselenatis isolated from Mono Lake (CA, USA). Bacillus sp. strain AMnr1 was obligately anaerobic, able to grow either by glucose fermentation, or respiring few nonfermentable substrates by using MnO(2) as the electron acceptor. Optimal growth by dissimilatory MnO(2) reduction was achieved with glycerol as electron donor at pH 9.5-10 and salt content between 0.4 and 0.8 M total Na(+). PMID- 19779763 TI - Usefulness and limitations of QuantiFERON-TB Gold in Japanese rheumatoid arthritis patients: proposal to decrease the lower cutoff level for assessing latent tuberculosis infection. AB - We aimed to determine the sensitivity and specificity of QuantiFERON-TB Gold (QFT G) in Japanese rheumatoid arthritis (RA) patients with a past history of tuberculosis (TB). We assessed whether it is possible to decrease the cutoff using receiver operating characteristic (ROC) analysis. We evaluated chest computed tomography (CT) findings, prior history of treatment, and contact with active TB in 370 RA patients. Forty-nine patients before initiation of treatment with tumor necrosis factor (TNF) inhibitors were divided into two groups: 22 with a past history of TB and 27 without. We estimated the efficacy of QFT-G compared with the tuberculin skin test and antituberculosis (anti-TB) glycolipid antigen antibody. QFT-G was positive (>or=0.35 IU/ml) in 13.6% with a past history of TB, increasing to 27.3% at the intermediate range cutoff of 0.1 IU/ml. The sensitivity and specificity of QFT-G was 0.27 and 1.00, respectively, at 0.1 IU/ml. Using ROC analysis, the area under the curve (AUC) of QFT-G but not for the other two tests was significantly large. QFT-G is a useful diagnostic method due to its superior specificity, but the use of a cutoff value of 0.35 IU/ml will likely result in an underestimate. We propose that a lower interferon-gamma (IFN gamma) titer of 0.1 IU/ml be adopted when deciding to administer anti-TB drugs before initiation of TNF inhibitors. PMID- 19779761 TI - Sarcopenia: etiology, clinical consequences, intervention, and assessment. AB - The aging process is associated with loss of muscle mass and strength and decline in physical functioning. The term sarcopenia is primarily defined as low level of muscle mass resulting from age-related muscle loss, but its definition is often broadened to include the underlying cellular processes involved in skeletal muscle loss as well as their clinical manifestations. The underlying cellular changes involve weakening of factors promoting muscle anabolism and increased expression of inflammatory factors and other agents which contribute to skeletal muscle catabolism. At the cellular level, these molecular processes are manifested in a loss of muscle fiber cross-sectional area, loss of innervation, and adaptive changes in the proportions of slow and fast motor units in muscle tissue. Ultimately, these alterations translate to bulk changes in muscle mass, strength, and function which lead to reduced physical performance, disability, increased risk of fall-related injury, and, often, frailty. In this review, we summarize current understanding of the mechanisms underlying sarcopenia and age related changes in muscle tissue morphology and function. We also discuss the resulting long-term outcomes in terms of loss of function, which causes increased risk of musculoskeletal injuries and other morbidities, leading to frailty and loss of independence. PMID- 19779764 TI - Lack of association between endothelial constitutive nitric oxide synthase (ecNOS 4 b/a) gene polymorphism and rheumatic heart disease. AB - Our aim in this work was to explore any possible association between ecNOS 4 b/a polymorphism and rheumatic heart disease (RHD). In this study, leukocyte DNA was extracted from 139 patients with RHD and 79 healthy control children. After amplification by PCR, the products were separated by electrophoresis in 6% polyacrylamide gel and visualized after ethidium bromide staining with UV light. PCR resulted in a 420-bp fragment (ecNOS4b) when five 27-bp repeats were present in intron 4 of the ecNOS gene, a 393-bp product (ecNOS4a)when only four repeats were present, and 420-bp and 393-bp fragments in heterozygous individuals (ecNOS4b/a). ecNOS4b/a genotyping in the control group gave the following results: b/b genotype (77.2%), b/a genotype(21.5%) and a/a genotype (1.3%). The frequencies in RHD group were as follows: b/b genotype (67.6%), b/a genotype (31.7%), and a/a genotype (0.7%). The b allele/a allele ratio was (88%/12%) in the control group and (83.5%/16.5%) in the RHD group. We found no statistical difference in genotype or allele frequency between these groups. The present study is the first to study the association between ecNOS 4b/a gene polymorphism and RHD, and to find a lack of any association between them. Further investigations of this gene polymorphism alone and in combination with other genes should be encouraged. PMID- 19779765 TI - The specificity of capillaroscopic pattern in connective autoimmune diseases. A comparison with microvascular changes in diseases of social importance: arterial hypertension and diabetes mellitus. AB - Capillaroscopy is a method with substantial value for diagnosis and differentiation of primary and secondary Raynaud's phenomenon in rheumatic diseases. The most specific finding is in systemic sclerosis--the so-called "scleroderma pattern." which is characterized by the presence of dilated capillaries, hemorrhages, avascular areas, and neoangiogenesis. Similar changes are found in patients with dermatomyositis, overlap syndromes, and others and are termed "scleroderma-like pattern." For the development of these patterns, the most specific finding in the early phase is appearance of dilated capillaries. Capillaroscopic changes in connective autoimmune diseases are specific and differ significantly from those of that can be found in other diseases. Diseases of social importance such as diabetes mellitus and arterial hypertension often present as comorbidity in patients with rheumatic diseases. In diabetes mellitus, the capillaroscopic examination does not show dilated capillaries until the advanced stages of the disease. In the late stages of connective tissue disease, a loss of capillaries is typical. In addition, in diabetes mellitus, the diabetic stiff-hand syndrome and sclerodactyly are common complications, which have to be differentiated from similar signs in rheumatic diseases, and capillaroscopic examination appears to be useful in these situations. In arterial hypertension, a reduced capillary density in different body regions has been observed in patients with established disease as well as in preclinical stages. Analogous phenomenon of reduction in the nail-fold area has also been observed in a group of patients with essential hypertension, none of whom previously received hypertensive drugs. PMID- 19779766 TI - Langerhans cell histiocytosis with multifocal bone lesions: comparative clinical features between single and multi-systems. AB - Langerhans cell histiocytosis (LCH) can be a single system or multi-system disease. Both disease types can be associated with multi-focal bone lesions, but their bone involvement patterns have not been compared systematically. Of the new pediatric LCH cases enrolled into the JLSG-02 study during 2002-2007, 67 cases of single system multifocal bone (SMFB) LCH and 97 cases of multi-system bone (MSB) LCH were analyzed to determine if the bone involvement patterns differ in these two types, and whether these differences correlate with outcome. Statistical analysis was performed with Mann-Whitney U test, Fisher's exact test, and other measures. Onset ages were higher for SMFB (P < 0.001), but the two types did not differ in the number of bone lesions per patient. The skull was most frequently affected in both types, followed by the spine. Lesions in the temporal bone (P = 0.002), ear-petrous bone (P < 0.001), orbita (P = 0.003), and zygomatic bone (P = 0.016) were significantly more common in MSB. The two types did not differ in response to treatment, but MSB was associated with a significantly higher incidence of diabetes insipidus (DI) (P < 0.001). Novel measures are required in preventing the development of DI in MSB-type LCH patients with "risk" bone lesions. PMID- 19779767 TI - Transforming growth factor beta inducible apoptotic cascade in epithelial cells during rat molar tooth eruptions. AB - In tooth eruptions, the presence of apoptotic epithelial cells at the eruption site has been reported, but the factors that induce apoptosis in these cells remain to be elucidated, as do the induction pathways. In this study, we focused our attention on transforming growth factor beta (TGF-beta), which is known to induce apoptosis during embryonic development. Oral epithelium and dental lamina of maxillary first molars in 8- and 15-day-old rats were used to investigate the induction pathway of apoptosis by performing the immunohistochemical tests outlined below and assessing the characteristics of cells that undergo apoptosis by transmission electron microscopy in rats 8 and 15 days after birth. We examined TGF-beta-receptor 1, TGF-beta inducible transcription factor 1 (TIEG1), NADPHoxidase 4 (Nox4), cytochrome c, caspase-3 (active form and pro-enzyme), apoptosis-inducing protein Daxx, apoptosis signal-regulating kinase 1 (ASK1), glycogen synthase kinase-3 beta phosphorylated on serine 9 (p-GSK-3beta), and beta-catenin. We also performed periodic acid Schiff (PAS) reaction and terminal deoxynucleotidyl transferase-mediated dUTD nick end labeling (TUNEL) staining. At eruption sites 8 days after birth, reactions to TGF-beta-receptor 1, TIEG1, Nox4, cytochrome c, caspase-3, p-GSK-3beta, and beta-catenin, and PAS-positive cells were observed in areas close to the basal layer of oral epithelium through to the center of the dental lamina, but no reaction to Daxx or ASK1 was noted at these sites. Electron microscopy revealed the accumulation of glycogen granules in the cells that showed reactions to the above-mentioned markers as well as in the spaces among them. In the rats 15 days after birth (immediately before tooth eruption), the PAS-positive cells that showed reactions to the above antibodies remained on the buccal side of the epithelium, and high-electron-density apoptotic bodies and TUNEL-positive bodies were noted. Therefore, during tooth eruption, TGF-beta may induce apoptosis of cells rich in glycogen granules, and cytochrome c and caspase-3 may function to induce apoptosis. In addition, reactive oxygen species may be involved in this induction pathway via TIEG1 and Nox4 without involvement of Daxx and ASK1. Moreover, overexpression of p-GSK 3beta and beta-catenin may also contribute to apoptosis of oral epithelium at the eruption site and dental lamina cells. Glycogen storage mediated by p-GSK-3beta and crosstalk between the TGF-beta and Wnt signaling pathways may participate in the formation of tooth eruption passage. PMID- 19779768 TI - Quality and safety initiatives in the future practice of surgery: meeting patient demands for enhanced professionalism. AB - This article is based on a speech that Thomas R. Russell, MD, FACS, Executive Director of the American College of Surgeons, delivered to the Japan Surgical Society in May 2008, which centered on quality of care and patient safety issues and their relationship to professionalism. The article provides a brief overview of the American and Japanese health care systems, outlines the quality and safety issues facing our health care systems, and addresses the changes that need to occur within surgery's professional culture in order to improve patient care. In addition, he explains what the American College of Surgeons is doing to advance quality, safety, and professionalism. PMID- 19779769 TI - Optimal utilization of extended hepatic grafts. AB - Orthotopic liver transplantation has emerged as the standard treatment for end stage liver disease. In the United States, the number of listed patients has tripled in the last two decades. Organ availability during the same period has plateaued at approximately 6000 grafts annually, resulting in a fivefold increase in wait-list mortality. The problem is not specific to the United States; European and Asian registries report similar shortages. Donor pool expansion strategies such as the use of living donors, cadaveric split livers, and "extended criteria donors"; (ECD) are being pursued. Used judiciously, ECD grafts provide an opportunity for addressing the shortage. Although there is no universally accepted definition of ECD, the term generally refers to donor factors predisposing recipients to poor initial graft function and/or increased long-term risk. These factors include advanced donor age, hypernatremia, prolonged warm ischemic time, pressor requirement, and donation after cardiac death. The transplant community is scrutinizing all factors to evaluate the degree of risk they impart on the recipient and the extent to which grafts can be "matched"; to maintain acceptable outcomes. We review the importance of selected factors and the impact of a "matching"; strategy to minimize recipient risk while optimizing graft use. PMID- 19779770 TI - Predictors of hypocalcemia occurring after a total/near total thyroidectomy. AB - PURPOSE: The aim of this study was to identify the predictors of early postoperative hypocalcemia after a total/near total thyroidectomy in order to select patients for prompt treatment to prevent symptomatic hypocalcemia. METHODS: Patients with hypocalcemia within 24 h of surgery were identified as Group I and normocalcemic patients as Group II. The perioperative serum total calcium (tCa, ionized calcium (iCa) and intact parathormone (iPTH) were measured perioperatively. Skin closure (SC) was accepted as the reference time point. Data are expressed as the mean +/- SEM. RESULTS: The study included 73 patients. Hypocalcemia (Group I) was detected in 40 patients (54%) within the first 24 h postoperatively. Symptomatic hypocalcemia was detected in 40% of the patients in Group I. Intact parathormone values at 10 min of SC were significantly lower in Group I (P = 0.001). IPTH measurement at 10 min of SC showing a >/=30% decrease had a 92.3% sensitivity and 92.6% specificity in predicting hypocalcemia after a total/near total thyroidectomy. The postoperative day 15 mean tCa, iCa, and iPTH values were similar in both groups of patients. The mean iPTH level was 16.79 +/- 2.5 pg/dl at 10 min after SC in patients who developed symptomatic hypocalcemia. CONCLUSIONS: Intact parathormone measurement 10 min after SC is helpful to predict early postoperative hypocalcemia. An IPTH decrease >/=30% at this time point estimates the risk of postoperative hypocalcemia. PMID- 19779771 TI - Travel of patients to distant hospitals for elective surgery in Japan: a cross sectional analysis of a nationally representative sample. AB - PURPOSE: The principles and methods of the geographical allocation of healthcare resources and their relationships with patient behavior have long been issues in the health policy research of many countries. This study aimed to investigate the associations between specific healthcare services such as surgical procedures and the behavior of patients in selecting hospitals that may be related to health service allocations under the relatively deregulated social health insurance settings in Japan. METHODS: A total of 520 976 discharge records were analyzed to examine the relationships between patient characteristics, primary diagnoses, interventions, distance to the hospitals of admission, and medical areas designated by local governments. RESULTS: Patients undergoing cardiac and orthopedic surgery were admitted to hospitals in distant medical areas more than twice as frequently and approximately 1.7 times as far from their residences compared to patients without such surgeries. In contrast, elderly patients and patients undergoing trauma or gastrointestinal surgery were admitted to nearby hospitals. CONCLUSIONS: Patients who needed nonemergency and relatively complicated surgical interventions tended to be admitted to distant hospitals, thus suggesting that patients may select better hospitals for elective, technically demanding surgeries. PMID- 19779772 TI - Clinical outcome of perioperative nonpermanent vena cava filter placement in patients with deep venous thrombosis or blood stasis of the vein. AB - PURPOSE: To evaluate the recent clinical experience with nonpermanent inferior vena cava (IVC) filter placement preoperatively, especially with regard to patients who had deep venous thrombosis (DVT) due to compression by a tumor or an aneurysm. METHODS: Preoperative prophylactic IVC filter placement was performed between October 2002 and March 2008 in 48 of 83 patients who underwent IVC filter placement. IVC filter placement was performed preoperatively in 35 of the 48 patients due to DVT located distally in an iliac vein or due to IVC compression by a tumor or aneurysm. This study examined the early and mid-term outcomes resulting from nonpermanent IVC filter placement. RESULTS: The mean implantation period was 11.1 +/- 9.3 days (range, 3-56 days). Three patients (8.6%) experienced minor complications during the IVC filter placement. A thrombus was captured in the filter in 4 patients (8.8%). One patient in whom the filter was left as a permanent filter died during the follow-up period. No patient experienced any pulmonary embolus during the follow-up period. CONCLUSION: Nonpermanent IVC filter insertion is perioperatively useful in surgical procedures that eliminate the compression of the vein by an excision of either the tumor or aneurysm compressing the vein. PMID- 19779773 TI - Should the extrahepatic bile duct be resected or preserved in R0 radical surgery for advanced gallbladder carcinoma? Results of a Japanese Society of Biliary Surgery Survey: a multicenter study. AB - PURPOSE: We assessed the significance of an extra bile duct resection by comparing the survival of patients with advanced gallbladder carcinoma who had resected bile ducts with those who had preserved bile ducts. A radical cholecystectomy that includes extra bile duct resections has been performed without any clear evidence of whether an extra bile duct resection is preventive or curative. METHODS: We conducted a questionnaire survey among clinicians who belonged to the 114 member institutions of the Japanese Society of Biliary Surgery. The questionnaires included questions on the preoperative diagnosis, complications, treatment, and surgical treatment, resection procedures, surgical results, pathological and histological findings, mode and site of recurrence, and the need for additional postoperative treatment. A total of 4243 patients who had gallbladder carcinoma and were treated from January 1, 1994 to December 31, 2003 were identified. The 838 R0 patients with pT2, pT3, and pT4 advanced carcinoma of the gallbladder for which there was no cancer invasion to the hepatoduodenal ligament or cystic duct in the final analysis. RESULTS: The 5-year cumulative survival, postoperative complications, postoperative lymph node metastasis, and local recurrence along the hepatoduodenal ligament were not substantially different between the resected bile duct and the preserved bile duct groups. CONCLUSIONS: Our retrospective questionnaire survey showed that an extrahepatic bile duct resection had no preventive value in some patients with advanced gallbladder carcinoma in comparison to similar patients who had no such bile duct resection. An extrahepatic bile duct resection may therefore be unnecessary in advanced gallbladder carcinoma without a direct infiltration of the hepatoduodenal ligament and the cystic duct. PMID- 19779774 TI - The effect of a total colectomy on the motor inhibition of the upper gut induced by intraileal stimuli in conscious dogs. AB - PURPOSE: The administration of stimuli to the ileum inhibits upper gastrointestinal motility. The aim of this study was to determine whether a total colectomy can alter this motor inhibitory effect. METHODS: Beagle dogs were each equipped with four strain gauge force transducers on the upper gastrointestinal tract. The infusion of nutrients (saline as placebo control, oleate, butyrate, and glucose) began 90 min after feeding and continued for 30 min via a silicone catheter placed in the ileal lumen. Capsaicin (10 mg) was injected into the ileum as a bolus. All of the dogs underwent a relaparotomy and a total colectomy, and the same experiments were performed on all dogs. RESULTS: Before performing a colectomy, the oleate, the glucose, and the capsaicin were each found to inhibit the postprandial upper gastrointestinal motility in comparison to the placebo control (P < 0.05). The butyrate had no inhibitory effect. After a total colectomy, the inhibition of upper gastrointestinal motility was observed after the intraileal infusion of the oleate and the capsaicin (P < 0.05). The motor inhibitory response to the intraileal glucose was delayed after a total colectomy, and a reduction of the motility index was not observed in the gastric antrum and the duodenum because of this delay. However, a significant reduction in the motility index was observed in the jejunum. CONCLUSION: The intraileal stimuli-induced motor inhibition decreased after a total colectomy after the administration of glucose, but not after the administration of either oleate or capsaicin. PMID- 19779775 TI - Superior vena cava reconstruction via a posterolateral thoracotomy without venous occlusion for locally advanced lung cancer: report of a case. AB - We performed a right upper lobectomy with prosthetic replacement of the superior vena cava (SVC) through a posterolateral thoracotomy in a 65-year-old man undergoing complete resection of a locally advanced non-small-cell lung cancer with invasion of the SVC. Instead of using a vascular shunt, the right atrium and a right brachiocephalic vein (BCV) were anastomosed using a ringed polytetrafluoroethylene (PTFE) graft. During the anastomosis, vascular flow was maintained through the left BCV. By using this technique, SVC resection and reconstruction during lung cancer surgery can be safely performed through a posterolateral thoracotomy without blood flow interruption. PMID- 19779776 TI - Concomitant aortic valve and internal mammary artery injuries in blunt chest trauma: report of a case. AB - We report a case of concomitant injury to the aortic valve and internal mammary artery (IMA) from nonpenetrating chest trauma. To our knowledge, this is the first such case to be reported. Transcatheter arterial embolization (TAE) following diagnostic angiography offers an effective and minimally invasive treatment for traumatic IMA injuries. Because there might be an asymptomatic interval after traumatic aortic valve injuries, serial physical examinations and repeated echocardiography should be mandatory for patients with de novo heart failure after blunt chest trauma. Transesophageal echocardiography can provide a clearer image of cardiac injuries than transthoracic echocardiography, particularly if there is extensive anterior mediastinal hematoma resulting from IMA trauma. PMID- 19779777 TI - A foreign body granuloma after gastric perforation mimicking peritoneal dissemination of gastric cancer: report of a case. AB - This report presents the case of a 58-year-old man who was found to have foreign body granulomas (FBGs) that mimicked disseminated gastric cancer. The patient presented with a severe attack of acute upper abdominal pain, was admitted to the hospital, and thereafter underwent an immediate laparotomy due to a diagnosis of an upper gastrointestinal perforation. Follow-up endoscopy revealed an ulcer scar measuring 2 cm in size in the anterior wall of the middle stomach. The pathological examination of biopsy specimens taken around the scar revealed well to poorly differentiated adenocarcinoma. At the time of reoperation performed 2 months after the first operation, many small white granulomas were observed which were thought to be the result of peritoneal dissemination of the gastric cancer. However, both the cytology of the Douglas washing and pathological examination of frozen section specimens were negative for carcinoma, and therefore a distal gastrectomy was performed. The pathological examination revealed the presence of FBGs. In this rare case, the FBGs formed shortly after surgery and were difficult to distinguish from disseminated cancer. PMID- 19779778 TI - Adenocarcinoma arising in a colonic interposition following a total gastrectomy: report of a case. AB - A segment of the transverse colon can be used for gastric reconstruction after a total gastrectomy. This report presents the case of a 68-year-old woman with primary adenocarcinoma of the colon in a segment used for reconstruction after a total gastrectomy. The interposed colon developed colon carcinoma 9 years after the gastric reconstruction. The possibility of a primary carcinoma arising in a gastric colon interposition must be considered when employing the transverse colon as a gastric substitute. PMID- 19779779 TI - Duodenal stenosis caused by cystic dystrophy in heterotopic pancreas: report of a case. AB - We herein describe the first reported case of duodenal stenosis caused by cystic dystrophy in heterotopic pancreas (CDHP) in Asia. A 63-year-old man was admitted to the hospital presenting with nausea and vomiting of 2 days' duration. Laboratory examinations showed an elevation in both the serum amylase level (275 IU/l) and white blood cell count (13 600/microl). A 3-cm-diameter tumor close against the duodenum was pointed out from the results of computed tomography (CT) and magnetic resonance cholangiopancreatography (MRCP); the tumor contained a cystic and solid component. Endoscopic examinations and an upper gastrointestinal series showed stenosis of the second portion of the duodenum without any mucosal change. The tumor was considered to be located at the submucosal layer of the second duodenum. The biopsy specimen of the duodenum revealed no malignancy. We strongly doubted the presence of a malignant submucosal tumor in the duodenum based on the findings of diagnostic imaging, and a pancreaticoduodenectomy was thus performed. Histopathologically, the lesion was diagnosed to be CDHP. The postoperative course was uneventful. The patient was symptomatic but was free of any symptoms after surgery. He continues to be regularly followed up on an outpatient basis and has had no recurrence of symptoms. This case demonstrates the need to consider CDHP in the differential diagnosis as a rare cause of duodenal stenosis. PMID- 19779780 TI - Successful perioperative management of patients with Parkinson's disease following gastrointestinal surgery: report of three cases. AB - Parkinson's disease is a chronic progressive disease with symptoms of tremors, rigidity, and akinesia. Parkinson's disease is a major risk factor for postoperative complications and it is difficult to manage patients with Parkinson's disease after gastrointestinal surgery. This report presents the cases of three patients with Parkinson's disease who underwent gastrointestinal surgery and had no serious postoperative complications. Antiparkinsonian medications were reduced before surgery and replaced by an intravenous infusion of levodopa until the patients could take oral antiparkinson drugs after surgery to prevent malignant syndrome or exacerbate parkinsonism. Prokinetics were also used for the prevention of paralytic ileus. These cases demonstrate an effective method to administer antiparkinson drugs during perioperative management of patients with Parkinson's disease and also indicate that sufficient doses of antiparkinson drugs can control the symptoms of parkinsonism and prevent complications in cases of surgery with parkinsonism. PMID- 19779781 TI - Reconstruction of an infected recurrent ventral hernia after a mesh repair using a pedicled tensor fascia lata flap: report of two cases. AB - Recently, the use of prosthetic mesh has revolutionized the repair of ventral hernias. However, the occurrence of infection related with the use of this prosthesis remains an important complication, which may result in occurrence of fistula formation of the skin or intestine, sepsis, or reoccurrence of ventral hernia. This report presents two cases where a pedicled musculocutaneous flap using the tensor fascia lata (pedicled TFL flap) was effective as a treatment for an infectious large abdominal hernia, and reviews the previous literature. Two Japanese men aged 61 and 78 years old underwent a ventral hernia repair using Composix Kugel mesh. They both developed a wound infection with methicillin resistant Staphylococcus aureus. Conservative therapy was not successful and the defect in the abdominal wall of two patients measured 12 x 21 cm and 7 x 10 cm in length, respectively. Reoperations were performed by removing the infectious mesh and then reconstructing the abdominal wall with the bilateral and left-side pedicled TFL flaps, respectively. No recurrence of the ventral hernia has been recognized for 50 months and 7 months after reoperation, respectively. A review of previous studies showed that no patients treated with a pedicled TFL flap experienced a recurrent hernia. Therefore, the pedicled TFL flap was considered to be effective for infectious large abdominal recurrent hernia. PMID- 19779782 TI - Hypersplenism caused by an accessory spleen mimicking an intra-abdominal neoplasm: report of a case. AB - Accessory spleens are usually asymptomatic, although they may cause hematological disorders associated with hypersplenism, usually after splenectomy. Moreover, cases of hypersplenism occurring secondary to enlargement of an accessory spleen with an unaltered normal spleen have been reported. An accessory spleen can also mimic an intra-abdominal neoplasm. We report a case of hypersplenism that occurred secondary to an increase in the size of the accessory spleen, which was located in the mesentery close to the cecum, mimicking recurrence of previously resected renal carcinoma. PMID- 19779783 TI - Impacted obturator hernia treated successfully with a Kugel repair: report of two cases. AB - Obturator hernia repair has traditionally been performed via an intra-abdominal approach, although laparoscopy is also emerging as a feasible alternative. On the other hand, the Kugel method is a minimally invasive and effective form of repair of groin hernia, but there have been few reports on its use for an incarcerated obturator hernia. We describe how we used the Kugel method to repair an obturator hernia in two patients. Both patients presented with acute intestinal obstruction, necessitating emergency surgery. Via a preperitoneal approach, the impacted obturator hernia was carefully released and the obturator canal defect was repaired with a Kugel patch. One patient recommenced oral intake on postoperative day (POD) 1, and was discharged on POD 5. The other patient's postoperative course was complicated by ileus, prolonging the hospital stay to 14 days. There has been no sign of recurrent disease for 6 and 21 months, respectively. The Kugel method offers several advantages, such as a short operative time (76-82 min), small scar (3 cm), and early postoperative ambulation (POD 1), thus minimizing the hospital stay. Further study is needed to confirm the usefulness of this procedure for an incarcerated obturator hernia. PMID- 19779784 TI - A hepatic lipoma mimicking angiomyolipoma of the liver: report of a case. AB - Lipoma of the liver is extremely rare. Since the current knowledge of such tumors is based primarily on individual case reports and small case series, little is so far known about this disease. This report presents a case of lipoma of the liver mimicking angiomyolipoma. The patient was a 38-year-old man, who was hospitalized without any symptoms after a medical check. Radiological examinations (computed tomography, ultrasonography, magnetic resonance imaging) showed a well-defined mass, which was finally diagnosed to be located in the left part of the caudate lobe of the liver, containing two spotty enhanced nodules within the tumor. These were diagnosed to be either lipoma or angiomyolipoma of the liver. The resected specimen measured 9 cm in diameter. The cut surface of the specimen showed an encapsulated, homogeneous, yellowish tumor consisting of mature adipose tissue, which was diagnosed as lipoma of the liver. The two nodules within the tumor were encapsulated hemorrhage. Histopathological examinations revealed the lipoma to be composed of mature lipocytes without angiomatous or myomatous elements. There was no immunoreactivity to homatropine methylbromide 45. Therefore, the final diagnosis was lipoma of the liver, which is an extremely rare benign liver tumor. PMID- 19779785 TI - High dorsal resection for recurrent hepatocellular carcinoma originating in the caudate lobe. AB - Standards that enable surgeons to balance radical operative procedures with functional preservation for recurrent hepatocellular carcinoma (HCC) in the caudate lobe have not yet been established. A 54-year-old man with recurrent HCC originating in the caudate lobe was readmitted to our hospital. The combined resection of the adjacent hepatic parenchyma may have carried a risk of postoperative liver failure. The anterior transhepatic approach may have caused massive bleeding due to the presence of scarring from the previous hepatectomy. Therefore, we performed an isolated total caudate lobectomy, i.e., a "high dorsal resection" as a second hepatectomy. The postoperative course of the patient was uneventful, and there has been no local recurrence 1 year after the repeat hepatectomy. Indeed a "high dorsal resection" is rarely required, but it is still ingenious, and this surgical modality can balance the curability with the hepatic functional reserve even for recurrent caudate HCC in patients with liver cirrhosis. PMID- 19779786 TI - Registry of the Japanese Society of Lung and Heart-Lung Transplantation: the official Japanese lung transplantation report 2008. AB - The year 2008 marked the 10th anniversary of the Japanese lung transplantation program started in accordance with the Japanese Organ Transplant Law, which took effect in 1997. A total of 105 lung transplantations, including 39 deceased-donor transplants and 66 living-related transplants, had been performed as of the end of 2007. This article is the 2008 official report of the Japanese Society of Lung and Heart-Lung Transplantation. It summarizes the data for clinical lung transplantation during the period 1998-2007 and discusses the current status of Japanese lung transplantation. The overall 5-year survival rate was 67.0%: including 53.4% and 74.6% for deceased-donor lung transplantation and living donor lobar lung transplantation groups, respectively. The total operation related and 1-month mortality rates after surgery were 3.8% and 10.4%, respectively. These data are better, or at least acceptable, in comparison with the international registry data. PMID- 19779787 TI - Clinical report on a computer-controlled hand-actuated stapling system for general lung surgery: the first application in Japan. AB - OBJECTIVE: Computer-controlled stapling systems can improve lung tissue approximation during thoracic surgery. We report our experience with a handy system with computer-controlled placement of staples for lung resection in Japan. METHODS: The iDrive system is the improved second version of the SurgAssist stapling system. It comprises a self-contained computer microprocessor and hand held control unit combined with a digital loading unit (a power linear cutter with a blue or green cartridge) for use in open and minimally invasive thoracic surgery. The mounted control unit has two uses: (1) controlling accurate placement of the cartridge by orientating the tip of the rigid and curved shaft and (2) controlling the closure of the stapler and the firing. Each cartridge contains a programmed electronic device that triggers activation of the appropriate program in the self-contained microprocessor. The compression level on lung tissue is determined by the computer. RESULTS: From March to October 2008, the iDrive system was used 53 times in a consecutive series of 39 patients during open thoracic lung surgery. There were 12 women and 27 men. The following procedures were performed: lobectomy, segmentectomy, and wedge resection. The power linear cutters were used for stapling lung parenchyma for wedge resection in 6 patients, bullectomy in 1, segmentectomy in 2, and fissure division in 33. There were no stapling failures and no complications related to the staplers. CONCLUSION: The new computer-controlled stapling system may be safe and efficient for lung parenchymal tissue resection during open thoracic surgery. PMID- 19779788 TI - Irradiation inhibits vascular anastomotic stenosis in a canine model. AB - OBJECTIVE: The graft patency rate after coronary artery bypass grafting (CABG) correlates with anastomotic stenosis. Intracoronary radiation therapy is effective for preventing restenosis after percutaneous coronary intervention (PCI). We postulated that intracoronary radiation therapy could prevent anastomotic stenosis and tested this hypothesis in an animal model. METHODS: Femoral arteries and veins of beagle dogs were harvested, and composite arterioarterial and arteriovenous grafts were prepared. After external irradiation of the anastomotic sites, these composite grafts were transplanted into femoral arteries. Histomorphometric and immunohistological analyses of the anastomotic sites were performed. The study groups consisted of controls and animals exposed to 10 Gy, 20 Gy, and 30 Gy (n = 5, in each group). RESULTS: In the artery graft model, the ratio of negative remodeling was significantly increased in all groups exposed to >or=10 Gy. The ratio of neointimal hyperplasia was significantly decreased in all groups exposed to >or=10 Gy. Cell density of anti-alpha-actin antibody-positive cells and anti-proliferating cell nuclear antigen (PCNA) antibody-positive cells was highest in the adventitial layer, and the density decreased as the dosage increased. Experimental results were almost the same in the vein graft models as in the artery graft models. With double immunohistostaining, the anti-PCNA antibody-positive cells expressed alpha-actin. CONCLUSION: Irradiation can inhibit anastomotic stenosis in a canine model. Adventitia is a factor in the creation of stenosis, and irradiation appears to target the adventitia. We speculate that there might be a possible role for intracoronary irradiation in the future to prevent anastomotic stenosis. PMID- 19779789 TI - In situ replacement of the thoracic aorta using an equine pericardial roll graft for an aortobronchial fistula due to aortic rupture. AB - A 74-year-old woman with massive hemoptysis and shock who had been diagnosed with thoracic aortic rupture underwent in situ replacement of the thoracic aorta using an equine pericardial roll graft. The lower lobe of the left lung was resected because of a massive hematoma and adhesion to the wall of the thoracic aorta. Intraoperative microscopic examination of the resected aortic wall revealed Gram positive bacteria (alpha-streptococcus in bacterial cultivation). Histology of the resected aorta revealed abscess formation in the media and adventitia of the aortic wall associated with disruption of the media (dissection). Postoperative computed tomography revealed no fluid collection around the graft 1 month after surgery, and magnetic resonance imaging showed no significant graft dilation 20 months after operation. The equine pericardium can be an option of alternative graft materials for in situ replacement of the thoracic aorta in patients with an aortobronchial fistula due to aortic rupture. PMID- 19779790 TI - Awake partial sternotomy pacemaker implantation under thoracic epidural anesthesia. AB - An 82-year-old man with symptomatic bradycardia had infective endocarditis with tricuspid vegetation. The patient also had severe obstructive pulmonary disease, and endotracheal general anesthesia was contraindicated. Under satisfactory epidural anesthesia with catheterization at the T5/6 level, lower partial sternotomy was performed, and dual pacing electrodes were placed on the heart. Throughout the surgery, spontaneous breathing was maintained with a sufficient level of oxygenation. The postoperative course was uneventful. Although awake cardiac surgery under thoracic epidural anesthesia is challenging, this less invasive technique was useful for epicardial pacemaker implantation in this patient with severe pulmonary dysfunction. PMID- 19779791 TI - Primary sarcoma of the right ventricle: surgical and adjuvant therapy. AB - We describe surgical and adjuvant therapeutic management of a right ventricular (RV) sarcoma and pulmonary artery occlusion. Echocardiographic evaluation of a 39 year-old man with exertional dyspnea revealed a tumor mass in the right ventricle, pulmonary trunk, and bilateral pulmonary arteries. The tumor was resected with concomitant pulmonary valvotomy, but the resection was incomplete. The RV outflow was reconstructed with an allograft patch, and a stentless valve was implanted for pulmonary valvular function. The pulmonary trunk and arteries were enlarged with allograft patches. The tumor was undifferentiated sarcoma and caused postoperative pulmonary artery restenosis. Radiotherapy improved pulmonary perfusion (reduction of RV pressure), but the patient died of brain metastasis. Undifferentiated cardiac sarcomas associated with pulmonary hypoperfusion should be resected even if incompletely, and radiation therapy could alleviate reduced pulmonary perfusion. PMID- 19779792 TI - Surgical repair of a sinus of a Valsalva aneurysm ruptured into the left ventricle. AB - A 47-year-old man presented with orthopnea. He had no infection or, in particular, infectious endocarditis. An echocardiogram and multislice computed tomography scan revealed a left sinus of Valsalva aneurysm (SVA) that had ruptured into the left ventricle, with severe aortic regurgitation. He was diagnosed with ruptured congenital SVA with severe aortic regurgitation and underwent closure of the aneurysmal mouth with a Dacron patch, and concomitant aortic valve replacement. The use of a Dacron patch to close the aneurysmal mouth of a ruptured congenital left SVA has not been reported previously in the medical literature. PMID- 19779793 TI - Delayed diagnosis of traumatic diaphragmatic rupture. AB - We report a case of late presentation of traumatic rupture of the diaphragm discovered incidentally on chest radiography (CXR) during an annual medical checkup. A 60-year-old man suffered severe blunt trauma from heavy steel frames collapsing against his back, resulting in pelvic and femoral fractures as well as pulmonary contusions. The patient recovered, but 10 months later CXR performed for lung cancer surveillance during an annual medical checkup revealed a traumatic rupture of the diaphragm. Video-assisted thoracic surgery was performed with reduction of the intestine and primary closure of the diaphragmatic defect. The patient recovered uneventfully. This report serves as a useful reminder that a medical history of severe blunt trauma should provoke a high index of suspicion for diaphragmatic rupture during annual medical surveillance. PMID- 19779794 TI - Organizing pneumonia with an enlarging tumor-like lesion: immunohistochemical study. AB - An 86-year-old woman was transferred to our department for investigation of an abnormal enlarging pulmonary shadow with vascular convergence. She had no respiratory symptoms or laboratory data suggesting inflammatory disease. A pulmonary wedge resection was performed under video-assisted thoracic surgery. Pathology examination revealed that the tumor was organizing pneumonia and was composed of fibroblast-like spindle cells, macrophages, lymphoplasma cells, and collagen fibers. Immunohistochemical study revealed that the lesion was in the proliferative state with the relatively more Ki-67-positive fibroblast-like spindle cells. When a surgical resection is necessary for an enlarging abnormal pulmonary mass without any systemic inflammatory reaction or respiratory symptoms, a less invasive approach should be selected. PMID- 19779795 TI - Acute esophageal necrosis after lung cancer surgery. PMID- 19779797 TI - Speech-induced blepharospasm. AB - Primary blepharospasm is an adult-onset dystonia typically present at rest and exacerbated by bright light, stress and voluntary movements of eyes and eyelids. Inconsistency or inducibility by activities involving muscles other than orbicularis oculi muscles are considered incongruous with typical primary blepharospasm, heralding the suspicion of psychogenicity. We report the clinical vignette of two patients manifesting an unusual presentation of primary blepharospasm, specifically triggered by voiced speech and associated with an otherwise 'typical' presentation of primary adult-onset dystonia in the lower face, larynx or upper limb. Speech-induced primary blepharospasm seems a rare occurrence, representing 1.3% of our clinic-based series of 149 patients with primary adult-onset primary blepharospasm. In these atypical patients, the feature of speech inducibility suggests that the abnormal surrounding inhibition between cortical subregions representing laryngeal and orbicularis oculi muscles might underlie dystonic overflow to the orbicularis oculi muscles following the voiced speech. PMID- 19779796 TI - Myocardial metastasis from squamous cell carcinoma of the esophagus. AB - A 62-year-old woman was admitted to our hospital because of cancer of the middle thoracic esophagus. We performed a right transthoracic subtotal esophagectomy with systemic three-field lymphadenectomy. Histopathological findings resulted in a diagnosis of well-differentiated squamous cell carcinoma staged as pT3N0M0, pStage IIA, with clear surgical margins. Although she had no clinical symptoms, solitary cardiac metastasis located in the ventricular septum close to the apex was detected on the follow-up computed tomography scans during postoperative month 6. Regardless of chemotherapy followed by radiotherapy, she died of the cancer 17 months after the initial operation. An autopsy revealed metastatic lesions to the heart, lungs, kidneys, and liver. There were two metastatic masses in the heart without direct invasion from the outside of the heart. In cases of esophageal cancer, tumor spread to the heart is usually caused by direct invasion; thus, solitary hematopoietic cardiac metastasis is quite rare. PMID- 19779798 TI - Progressive necrotic encephalopathy following tacrolimus therapy for liver transplantation. AB - Previously described neurologic damage induced by immunosuppressive treatments includes transient or reversible central nervous system involvement. We describe a 57-year-old man who underwent liver transplantation and was started on immunosuppressive therapy with tacrolimus (FK506). Six months later, he started complaining of a progressive motor and sensory impairment of the left side, together with cognitive impairment. Brain MRI showed an enlarging lesion of the white matter with peripheral contrast enhancement. PET study indicated severe hypometabolism in the right hemisphere and spectroscopic MRI showed a peak of choline and relative reduction of other metabolites. Findings of CSF examinations and cultures, serology, and molecular techniques were normal. Tacrolimus treatment was stopped. A cerebral biopsy of the lesion showed a sub acute necrotizing process. In the following months, cognitive status of the patient tended to improve although he remained hemiplegic, while serial MRI confirmed the tendency to the recovery of the lesion that was still present 1 year after. The present observation describes a progressive encephalopathy associated with immune suppression with an unusual feature and permanent brain damage. PMID- 19779799 TI - Dopamine transporter (DAT1) VNTR polymorphism in 12 Indian populations. AB - The dopamine transporter (DAT1) is a membrane spanning protein that binds the neurotransmitter dopamine and performs re-uptake of dopamine from the synapse into a neuron. The gene encoding DAT1 consists of 15 exons spanning 60 kb on chromosome 5p15.32. Several studies have investigated the possible associations between variants in DAT1 gene and psychiatric disorders. The present study aimed to determine the distribution of the variable number of tandem repeat (VNTR) polymorphism in the 3' untranslated region of DAT1 in 12 Indian populations. A total of 471 healthy unrelated individuals in 12 Indian populations from 3 linguistic groups were included in the present study. The analysis was carried out using PCR and electrophoresis. Overall, 4 alleles of the DAT1 40-bp VNTR, ranging from 7 to 11 repeats were detected. Heterozygosity indices were low and varied from 0.114 to 0.406. The results demonstrate the variability of the DAT1 40-bp VNTR polymorphism in Indian populations and revealed a high similarity with East Asian populations. PMID- 19779801 TI - HCV genotype 1b chimeric replicon with NS5B of JFH-1 exhibited resistance to cyclosporine A. AB - Cyclosporine A (CsA) is a well-characterized anti-HCV reagent. Recently it was reported that the genotype 2a JFH-1 strain was more resistant than genotype 1 HCV strains to CsA in a cell culture system. However, the JFH-1 responsible region for the resistance to CsA remains unclear. It was also demonstrated that in genotype 1b HCVs, NS5B interacts with cyclophilin (CyP). To clarify whether or not NS5B of JFH-1 is significant for CsA resistance, we developed a chimeric replicon with NS5B of JFH-1 in the genotype 1b backbone. The chimeric replicon was more resistant to CsA than the parental genotype 1b replicon. Furthermore, reduction of CyPA had a greater effect on HCV RNA replication and sensitivity to CsA than reduction of CyPB. Here, we demonstrated that NS5B of JFH-1 contributed to this strain's CsA-resistant phenotype. NS5B and CyPA are significant for determining HCV's sensitivity to CsA. PMID- 19779800 TI - Effects of extracellular pH reductions on [(3)H]D-aspartate and [(3)H]noradrenaline release by presynaptic nerve terminals isolated from rat cerebral cortex. AB - We analyzed the effects of extracellular pH reductions on the release of [(3)H]D: -aspartate ([(3)H]D: -ASP) and [(3)H]noradrenaline ([(3)H]NA) from cerebrocortical synaptosomes isolated from rats. Synaptosomes were superfused with standard medium at a physiologic pH of 7.4 and with acidified medium with a pH of 6.00, 5.50, or 5.0. Medium acidification produced pH-dependent stimulation of [(3)H]D: -ASP release. The increase amounted to 202 +/- 12.6% when the pH was reduced to 5.5. The [(3)H]D: -ASP release evoked by low pH (5.50) was still observed in the absence of Ca(2+) ions, but it was abolished by DL: -threo-beta benzyloxyaspartate (DL: -TBOA) (100 microM), which inhibits neuronal glutamate/aspartate transport. Exposure to 5-(N,N-hexamethylene)-amiloride (EIPA) (30-100 microM), a selective inhibitor of Na(+)/H(+) exchange, caused concentration-dependent stimulation of [(3)H]D: -ASP release; the increase observed with EIPA 30 microM was 160 +/- 12%. The EIPA-induced release was not dependent on the presence of Ca(2+) ions in the medium, but it was abolished when synaptosomes were pretreated with 100 microM DL: -TBOA. Reduction of the extracellular pH (5.50-5.0) also stimulated the release of [(3)H]NA from rat cortical synaptosomes. Exposure to medium with a pH of 5.50 increased basal release by 136 +/- 9.5%. The release-stimulating effect of this medium was calcium-independent and abolished by 3 muM desipramine (DMI). [(3)H]NA release was also stimulated by EIPA. The increase induced by a concentration of 30 muM amounted to 136 +/- 9.50%, and this effect was calcium-independent and abolished by pretreatment with DMI (3 muM). These findings suggest that reduction of the extracellular pH stimulates release of [(3)H]D-ASP and [(3)H]NA by reversing neurotransmitter transport in the nerve terminal. This reversal might be activated by increased cytosolic concentrations of the transmitters caused by reduction of the pH gradient between the cytoplasm and the synaptic vesicles that take up the transmitters. This hypothesis is confirmed by the results of experiments conducted with EIPA. Selective blockade of Na(+)/H(+) exchange with this compound induces accumulation of H(+) in the nerve terminals and intracellular acidification, which leads to calcium-independent, transporter mediated release of [(3)H]D: -ASP and [(3)H]NA. PMID- 19779802 TI - In vitro heat shock of human monocytes results in a proportional increase of inducible Hsp70 expression according to the basal content. AB - Heat shock proteins play an important role as molecular chaperones of the cell. Inducible heat shock protein 70 is rapidly synthesised in response to numerous stressors and monocytes are sensitive to changes in core temperature resulting in a circadian variation of Hsp70 expression. Monocytes were isolated via density centrifugation from nine healthy male volunteers at 5 am, 1 pm and 9 pm, representing the nadir (5 am), peak (9 pm) and intermediate (1 pm) of Hsp70 expression in the 24-h cycle. Analysis of freshly isolated monocytes for Hsp70 expression confirmed Hsp70 levels at the three selected time points. Monocytes were subjected to in vitro heat shock at 40 degrees C (+/-0.1) for 90 min with a 90 min 37 degrees C (+/-0.1) exposure acting as a control. A significant increase in Hsp70 was observed at 5 am (p < 0.001) and 1 pm (p = 0.028) at 40 degrees C when compared to 37 degrees C but not at 9 pm (p = 0.19). A significant increase was also observed from the basal levels of Hsp70, measured on freshly isolated monocytes and the levels detected after heat shock at 40 degrees C at 5 am (p < 0.001) and 1 pm (p = 0.001), which was not observed at 9 pm (p = 0.15). Furthermore, a significant correlation was observed in the heat shock response at 40 degrees C and that obtained at 37 degrees C (p < 0.001). In conclusion, the heat shock response in monocytes is directly proportional to the amount of Hsp70 present in the cells and the stress response may be much higher at different times of the day. PMID- 19779803 TI - Similar response in male and female B10.RIII mice in a murine model of allergic airway inflammation. AB - BACKGROUND: Several reports have been published on the gender differences associated with allergies in mice. GOAL: In the present study we investigate the influence of gender on allergy response using a strain of mice, B10.RIII, which is commonly used in the collagen-induced arthritis murine model. METHODS: Both male and female B10.RIII young mice were immunized with OVA and challenged four times with OVA intranasally. Samples were taken 24 h after the last challenge, and eosinophils in bronchoalveolar lavage (BAL) and parenchyma, Th-2 cytokines in BAL, total and antigen-specific IgE in sera, and antigen-specific T-cell proliferation were measured. RESULTS: Immunization in both male and female B10.RIII mice with OVA elicited a classical Th2-type response. Results showed no significant differences among male and female mice. Also a high eosinophilia in BAL fluid and parenchyma was produced in both genders without any significant differences. However, the deviation of both parameters was higher in young males compared to young females. CONCLUSIONS: Gender differences, classically associated with some strains of mice, are not reproducible in B10.RIII mice. Gender differences in murine models of allergic airway inflammation are probably strain-dependent. PMID- 19779804 TI - Reliability and validity of the Disability Assessment Structured Interview (DASI): a tool for assessing functional limitations in claimants. AB - OBJECTIVE: The aim of this study is to investigate the reliability and validity of the Disability Assessment Structured Interview (DASI). The DASI is a semi structured interview for assessing long-term functional limitations concerning the work disability assessment of claimants. METHODS: A randomized controlled trial was conducted. Patients applying for a work-disability pension after 21 months of sick leave were independently interviewed and examined either by two physicians who had completed a DASI training period (n = 32) or by two physicians from a control group (n = 30) without any DASI training. Agreement percentages within both groups of physicians, eligibility for a disability benefit, and differences between the groups in terms of the scores given on the work limitation items from the Functional Ability List (FAL) were measured to investigate reliability and concurrent validity. To determine the content validity, the insurance physicians who completed DASI training (n = 8) were asked to fill out a questionnaire concerning their opinion of the DASI. Additionally, patients filled out a questionnaire to measure their satisfaction as to the behavioral aspects of the physicians. RESULTS: The groups showed no important differences in agreement percentages (mean percentage about 80%) and eligibility for a disability benefit. In 9 out of 21 items the physicians of the control group indicated fewer work limitations compared to physicians using the DASI. All physicians agreed on the fact that the DASI was an acceptable tool in daily practice, one that provided a realistic picture of the patient and provided sufficient information to assess functional limitations. In addition, between the two groups, no differences were found as to the satisfaction of patients concerning the behavioral aspects of the physicians. CONCLUSION: The DASI is a tool with a reasonable to good inter-rater reliability and content validity, and it appears to be acceptable to both patients and physicians. It did not improve inter-observer agreement beyond that of usual interview procedures used in the Netherlands. The DASI would seem to be a worthwhile tool for collecting self reported information in order to assess functional limitations in claimants. PMID- 19779805 TI - Emotional and behavioral effects of romantic relationships in Chinese adolescents. AB - Adolescents' romantic relationships have been associated with higher levels of depression, although their links with externalizing behavioral problems remain unclear. The present study examined the impact of adolescent romantic relationships on depression and externalizing behaviors in a large sample of 10,509 Chinese secondary school students (ages 12-19, 54.5% female). The results showed that romantic involvement in adolescence, especially in early adolescence, was associated with more depressive symptoms and behavior problems. Breakups in romantic relationships were an important factor in producing the negative emotional and behavioral consequences. Romantically involved girls experienced higher levels of depressive symptoms, while romantically involved boys had higher levels of externalizing behaviors, compared to their non-dating peers. The results also indicated that the adverse impact was stronger for those involved in romantic relationships at younger ages. PMID- 19779807 TI - Linkages over time between adolescents' relationships with parents and friends. AB - This 5-wave longitudinal study examines linkages over time between adolescents' perceptions of relationships with parents and friends with respect to support, negative interaction, and power. A total of 575 early adolescents (54.1% boys) and 337 middle adolescents (43.3% boys) participated. Path analyses mainly showed bidirectional associations between adolescents' perceptions of parent-adolescent relationships and friendships with a predominantly stronger influence from parent adolescent relationships to friendships than vice versa in early to middle adolescence and an equal mutual influence in middle to late adolescence. The findings support the theoretical ideas that perceptions of relationships with parents generalize to perceptions of relationships with friends and that relationship skills and principles of adolescent friendships generalize to relationships with parents. Furthermore, the results indicate that the influence of parents decreases, whereas the influence of friends increases, and that both social worlds become equally important and overlapping towards late adolescence. PMID- 19779806 TI - The developmental significance of adolescent romantic relationships: parent and peer predictors of engagement and quality at age 15. AB - From a longitudinal sample (n = 957; 49.9% male; 77.3% White/non-Hispanic) of participants studied from infancy through age 15, adolescents' depth of engagement in, and quality of romantic relationships were predicted from early and contemporaneous parent-child interactive quality and peer social competence. High quality maternal parenting and peer experiences prior to and during adolescence tended to be negatively associated with the depth of engagement in this domain for the full sample, yet positively associated with the quality of adolescents' romantic relationships for the sub-set of individuals currently dating at age 15. Results reconcile contrasting views of the origins of romantic relationship engagement and quality and the positive versus negative developmental salience of romantic relationships in adolescence. PMID- 19779808 TI - Depressive symptoms and school burnout during adolescence: evidence from two cross-lagged longitudinal studies. AB - The main purpose of this study was to examine the extent to which middle and late adolescents' depressive symptoms predict their later school burnout and, in turn, the extent to which school burnout predicts depressive symptoms. Drawing on data gathered at ages 15-19 in two-three-wave longitudinal studies, we investigated cross-lagged paths between school burnout and depressive symptoms. In Study 1 the participants were 15-year-old adolescents (Time 1: N = 611, Time 2: N = 614, Time 3: N = 725) who completed the School Burnout Inventory and depressive symptoms twice during their final term of comprehensive school and once after the transition to upper secondary high school or vocational school. In Study 2 the participants were 17-year-old adolescents whose school burnout and depressive symptoms were measured three times annually (Time 1: N = 474, Time 2: N = 412, Time 3: N = 414) during their 3 years of secondary education. Results of both studies revealed moderate stability for both school burnout and depressive symptoms. They also showed that school burnout more strongly predicted subsequent depressive symptoms later on than vice versa. Lastly, they revealed cumulative cycles between school burnout and depressive symptoms. PMID- 19779809 TI - Perceptions of problem behavior in adolescents' families: perceiver, target, and family effects. AB - Considerable research has focused on the reliability and validity of informant reports of family behavior, especially maternal reports of adolescent problem behavior. None of these studies, however, has based their orientation on a theoretical model of interpersonal perception. In this study we used the social relations model (SRM) to examine family members' reports of each others' externalizing and internalizing problem behavior. Two parents and two adolescents in 69 families rated each others' behavior within a round-robin design. SRM analysis showed that within-family perceptions of externalizing and internalizing behaviors are consistently due to three sources of variance; perceiver, target, and family effects. A family/contextual effect on informant reports of problem behavior has not been previously reported. PMID- 19779810 TI - The quality of mentoring relationships and mentoring success. AB - The quality of the relationships that mentors forge with their proteges is assumed to significantly affect the success of mentoring interventions. Building on previous research, this study examined the association between relationship qualities and protege functioning. Multiple reporters (e.g., mentors, proteges and teachers) were used in a prospective research design spanning eight months in Israel's largest mentoring program-Perach. The sample consisted of 84 proteges ranging in age from 8 to 13 years (M = 10.75). Qualities in the mentoring relationship such as closeness, dependency and unrealistic expectations for the continuation and deepening of the relationship, beyond the planned period, were positively associated with the children's social and academic adjustment, and contributed to perceived academic competence, social support and wellbeing. Generalization of positive mentoring experiences to other relationships (such as the mother-child relationship) and the role of unrealistic expectations and dependency as key elements are considered. Implications of the findings for research and mentoring intervention are discussed. PMID- 19779811 TI - An ecological system approach to adolescent smoking behavior. AB - The aim of the present study was to simultaneously examine the effect of factors related to school, leisure, family and the individual on adolescent smoking. These determining factors occupy the micro- and mesosystems of Bronfenbrenner's Ecological Theory. Data were collected using questionnaires from a nationally representative sample of 15-year-olds (1404 pupils) and 73 staff members from 73 schools in Norway. Males formed 51% of the sample size. Consistent with previous studies, the various factors were linked to adolescent smoking when examined separately. However, in an ecological setting, factors related to the individual and leisure (i.e., attitudes towards smoking, perceived behavioural control and evenings with friends) emerged as the strongest predictors. School and family factors were completely mediated by individual and leisure factors, although when examined alone, they explained quite a substantial amount of the variance and a considerable amount of school difference in adolescent smoking. The implications are discussed. PMID- 19779812 TI - Associations between smoking and extreme dieting among adolescents. AB - This study examined the association between cigarette smoking and dieting behaviors and trends in that association among US adolescents in grades 9-12 between 1999 and 2007. Youth Risk Behavior Survey datasets were analyzed using the multivariable logistic regression method. The sample size of each survey year ranged from 13,554 to 15,273 with girls representing 49-51% of the sample (N = 71,854). About 62% of the entire study participants were whites and 14% were blacks. Prevalence estimates of current smoking and corresponding 95% confidence intervals were computed across four comparison groups formed by gender and body weight. Extreme dieting was an independent predictor of smoking. Extreme dieters showed a higher variability of smoking behavior than their peers. The magnitude of the association between smoking and extreme dieting became smaller in recent years among adolescents but remained unchanged among non-overweight girls over that same time period. When adolescent smoking behavior is examined, the intensity of dieting behavior should be considered within its association with other co-occurring unhealthy behaviors. PMID- 19779813 TI - School smoking policy characteristics and individual perceptions of the school tobacco context: are they linked to students' smoking status? AB - The purpose of this study was to explore individual- and school-level policy characteristics on student smoking behavior using an ecological perspective. Participants were 24,213 (51% female) Grade 10-11 students from 81 schools in five Canadian provinces. Data were collected using student self-report surveys, written policies collected from schools, interviews with school administrators, and school property observations to assess multiple dimensions of the school tobacco policy. The multi-level modeling results revealed that the school a student attended was associated with his/her smoking behavior. Individual-level variables that were associated with student smoking included lower school connectedness, a greater number of family and friends who smoked, higher perceptions of student smoking prevalence, lower perceptions of student smoking frequency, and stronger perceptions of the school tobacco context. School-level variables associated with student smoking included weaker policy intention indicating prohibition and assistance to overcome tobacco addiction, weaker policy implementation involving strategies for enforcement, and a higher number of students smoking on school property. These findings suggest that the school environment is important to tobacco control strategies, and that various policy dimensions have unique relationships to student smoking. School tobacco policies should be part of a comprehensive approach to adolescent tobacco use. PMID- 19779814 TI - Relationships of adolescents' perceptions of parental and peer behaviors with cigarette and alcohol use in different neighborhood contexts. AB - This study examined the relationships of adolescents' perceptions of parental and peer behaviors with cigarette and alcohol use in different neighborhood contexts. The sample included 924 adolescents (49% boys, 51% girls) 12-14 years of age whose addresses were matched with 1990 census block groups. Six neighborhood types were identified through a cluster analysis. The findings suggest that parental smoking was associated with increased adolescent smoking in suburban white middle socioeconomic status (SES) neighborhoods. Peer smoking was associated with increased adolescent smoking in rural neighborhoods. Parental monitoring was associated with decreased adolescent drinking in urban white high SES neighborhoods and parental drinking was associated with increased adolescent drinking in urban white middle-SES neighborhoods, respectively. Peer drinking was associated with increased adolescent drinking in urban neighborhoods. This study demonstrates the importance of examining parental and peer influences on adolescent smoking and drinking in different neighborhood contexts. PMID- 19779816 TI - Top quality embryos at day 2: a prerequisite for single blastocyst transfer? An observational cohort study in women under 36. AB - PURPOSE: While extended culture has been considerably improved, some questions remain regarding the application of Single Blastocyst Transfer (SBT). METHODS: An observational cohort study was undertaken with 456 women under 36 years old and assigned to SBT on a voluntary basis. The main outcome was the cumulative delivery rate per couple according to the number of Top Quality Embryos (TQE) on day 2 (Group 1= > or =2 TQE, Group 2= 1 TQE and Group 3= 0 TQE). RESULTS: Rate of transfer and mean number of frozen blastocyts were higher in Group 1 compared to Group 3. As a consequence, the cumulative delivery rate per couple was higher in Group 1 (47.9%) compared to Group 3 (34.9%). CONCLUSIONS: Single blastocyst transfer combining fresh and frozen cycles, might be a worthwhile strategy irrespective of embryo quality on day 2 providing good delivery rates while keeping the rate of multiple deliveries low. PMID- 19779817 TI - Evaluation of the histological size of the sentinel lymph node metastases using RT-PCR assay: a rapid tool to estimate the risk of non-sentinel lymph node invasion in patients with breast cancer. AB - A RT-PCR assay (GeneSearchTM, Veridex, LLC), FDA approved and CE marked to detect metastases > 0.2 mm in sentinel lymph nodes (SLNs) is used intra-operatively for the management of patients with breast cancer. The assay provides qualitative results by applying cut-off values to cycle times (Ct) for mammaglobin (MG) and cytokeratin-19 (CK19) genes. Aims of this study were to evaluate the performance of the quantitative Ct values to estimate the size of nodal metastases and the risk of additional disease in non-SLNs. SLNs from 367 patients were clinically processed using both BLN assay and post-operative histology. Complementary axillary lymph node dissection (ALND) was performed concurrently in case of BLN assay positivity or tumour size > 2 cm. BLN positivity was reported in 19.6% of the patients for a sensitivity of 89%. BLN specificity (94.5%) and negative predictive value (97.5%) clearly demonstrated its reliability to guide ALND decision. All, except one, residual axillary metastases were found in BLN positive patients. Considering the 78 patients with SLN positivity or discordant status according to both criteria, the metastases histological size was significantly correlated to the expression level of MG (rho = 0.62) and CK19 (rho = 0.64) genes (P < 10E-6). Moreover, ALND status positivity was significantly associated to Ct value of MG (z = 2.4; P = 0.018) and CK19 (z = 3.2; P = 0.001). The high intra-operative quality performance of the BLN assay minimizes the need for second surgeries for ALND. Results from this investigational study suggest that markers Ct value may provide, intra-operatively, valuable metastases size data and a risk prediction of additional disease in non-SLNs. PMID- 19779818 TI - Occurrence and distribution of steroids, hormones and selected pharmaceuticals in South Florida coastal environments. AB - The common occurrence of human derived contaminants like pharmaceuticals, steroids and hormones in surface waters has raised the awareness of the role played by the release of treated or untreated sewage in the water quality along sensitive coastal ecosystems. South Florida is home of many important protected environments ranging from wetlands to coral reefs which are in close proximity to large metropolitan cities. Because, large portions of South Florida and most of the Florida Keys population are not served by modern sewage treatment plants and rely heavily on the use of septic systems, a comprehensive survey of selected human waste contamination markers was conducted in three areas to assess water quality with respect to non-traditional micro-constituents. This study documents the occurrence and distribution of fifteen hormones and steroids and five commonly detected pharmaceuticals in surface water samples collected from different near shore environments along South Florida between 2004 and 2006. The compounds most frequently detected were: cholesterol, caffeine, estrone, DEET, coprostanol, biphenol-A, beta-estradiol, and triclosan. The concentration detected for estrone and beta-estradiol were up to 5.2 and 1.8 ng/L, respectively. Concentrations of caffeine (5.5-68 ng/L) and DEET (4.8-49 ng/L) were generally higher and more prevalent than were the steroids. Distribution of microconstituents was site specific likely reflecting a diversity of sources. In addition to chemical analysis, the yeast estrogen screen assay was used to screen the samples for estrogen equivalency. Overall, the results show that water collected from inland canals and restricted circulation water bodies adjacent to heavily populated areas had high concentrations of multiple steroids, pharmaceuticals, and personal care products while open bay waters were largely devoid of the target analytes. PMID- 19779819 TI - Research participant recruitment in Hispanic communities: lessons learned. AB - Hidden/special populations such as new immigrants are hard-to-reach due to issues such as stigma, discrimination, fear of immigration authorities, and cultural norms. Such factors can affect the recruitment of participants for behavioral research, especially research which addresses stigmatizing conditions such as HIV/AIDS. This research involved a qualitative approach and methods. The study identified contextual factors as well as attitudes, experiences and beliefs affecting HIV risk among recent Hispanic immigrants in New York. During the course of this research, challenges to participant recruitment were identified which were related to the environments, characteristics of the populations, and the sensitive nature of the topic to be studied. Strategies including exploratory fieldwork and sensitivity to participants' fear of "the system" were effective in recruiting individuals from this population. The authors discuss the strategies which facilitated recruitment of research subjects from these new Hispanic immigrant communities and the importance of behavioral research among these vulnerable communities. PMID- 19779821 TI - The orf virus inhibitor of apoptosis functions in a Bcl-2-like manner, binding and neutralizing a set of BH3-only proteins and active Bax. AB - We have previously shown that the Orf virus protein, ORFV125, is a potent inhibitor of the mitochondrial pathway of apoptosis and displays rudimentary sequence similarities to cellular anti-apoptotic Bcl-2 proteins. Here we investigate the proposal that ORFV125 acts in a Bcl-2-like manner to inhibit apoptosis. We show that the viral protein interacted with a range of BH3-only proteins (Bik, Puma, DP5, Noxa and all 3 isoforms of Bim) and neutralized their pro-apoptotic activity. In addition, ORFV125 bound to the active, but not the inactive, form of Bax, and reduced the formation of Bax dimers. Mutation of specific amino acids in ORFV125 that are conserved and functionally important in mammalian Bcl-2 family proteins led to loss of both binding and inhibitory functions. We conclude that ORFV125's mechanism of action is Bcl-2-like and propose that the viral protein's combined ability to bind to a range of BH3-only proteins as well as the active form of Bax provides significant protection against apoptosis. Furthermore, we demonstrate that the binding profile of ORFV125 is distinct to that of other poxviral Bcl-2-like proteins. PMID- 19779820 TI - Risk factors for type 2 diabetes among female Pakistani immigrants: the InvaDiab DEPLAN study on Pakistani immigrant women living in Oslo, Norway. AB - The risk for type 2 diabetes (T2D) in Pakistani immigrants is high. The aim of this study was to provide an update of the risk of T2D and the metabolic syndrome (MetS) in female Pakistani immigrants living in Oslo, Norway. Female Pakistani immigrants (n = 198, age 25-63) were interviewed, and data related to T2D, including anthropometric measurements, blood data, heart rate, and level of physical activity, were determined. Ninety-eight percentage had body mass index (BMI > 23 kg m(-2)) and 39% were obese (BMI >= 30). Impaired glucose tolerance (IGT) was found in 37%, MetS in 41%, and T2D in 13%, using fasting glucose. By score evaluation, approximately 90% had risk of T2D. The participants had low energy expenditure, despite acceptable number of steps walked during a day. The risk of T2D is very high in female Pakistani immigrants in Oslo. PMID- 19779823 TI - Thinning of the motor-cingulate-insular cortices in siblings concordant for Tourette syndrome. AB - Fraternal twin studies on normal subjects have demonstrated low heritability (intra-class correlation coefficient) estimates for frontal brain regions (r = 0.43). Here we aimed to investigate the relatedness/similarity estimates of the frontal brain regions in fraternal subjects concordant for Tourette syndrome (TS). We sought to identify regional brain similarities between siblings concordant for TS as an exploratory step towards the identification of potential brain structures involved in the TS phenotype. The identified brain structures may then serve in subsequent molecular genetic and linkage studies. In addition, we regressed cortical thickness and TS clinical severity scores to assess the relation between TS clinical symptoms and cortical structures. Sixteen sibling pairs concordant for TS were scanned using a 1.5 T magnetic resonance imaging scanner (age range 10-25, mean 17.19 +/- 4.1). Brain morphology was assessed using the fully automated Civet pipeline at the Montreal Neurological Institute. TS was assessed using the Children's Yale-Brown Obsessive Compulsive Scale (CY BOCS), Yale Global Tic Severity Scale (YGTSS) and the Goetz Tic Scale. We report high relatedness/similarity estimates for fraternal siblings concordant for TS (r = 0.86-0.60) in the middle frontal-motor/cingulate/insular cortices. Regression analysis revealed significant negative correlations in the right insula with the YGTSS (r = -0.41, F = 6.09, P < 0.02) and the left cingulated cortex with the (CY BOCS) (r = -0.35, F = 4.30, P < 0.05). Since previous findings have concluded that normal fraternal siblings are less alike in frontal cortices, the present findings may be attributed to TS. We speculate that the high ICC between siblings and the negative correlation between TS symptoms severity and cortical thickness measurements are related to the disturbances in the maturation of the motor cingulate-insular cortical neural system that mediate self-regulatory processes. Such delayed maturation may consequently contribute to the development of TS by releasing motor and vocal tics from regulatory control. These findings may have important genetic implications. PMID- 19779822 TI - Patterns of confidant use among patients and spouses in the year after breast cancer. AB - INTRODUCTION: We describe the frequency of, satisfaction with, and characteristics associated with confidant use among patients and their spouse in the year after diagnosis of non-metastatic breast cancer. METHODS: In a prospective study of 308 women diagnosed in 1996-97 in Quebec and their spouses, participants were interviewed about confidant use 2 weeks, 3 and 12 months after treatment start. Study completion among eligible individuals was high (patients, 86%; spouses, 84%). RESULTS: Compared to before diagnosis when 55% of patients reported confiding in >or=1 individuals, 84% reported confiding since diagnosis when interviewed 2 weeks after treatment start (prevalence ratio (PR(2 weeks)) = 1.43, p < 0.0001). Spouses reported a greater increase in confiding (PR(2 weeks) = 1.97, p < 0.0001). Nonetheless, spouses were significantly less likely to report confidant use at any given time (PRs comparing spouses to patients: range 0.43-0.61). The primary confidant types with increases were nurses (both couple members) and physicians (patients). Most patients and spouses (84% to 93%) were satisfied with their confidant situation. At 3 months, the woman's having >or=2 types of adjuvant therapy predicted greater confidant use in both partners. CONCLUSIONS: Judging from the relative differences in confidant use, the effect of diagnosis of non-metastatic breast cancer on natural support-seeking behaviour over time is at least as strong among spouses as among their wives. IMPLICATIONS FOR CANCER SURVIVORS: The majority of women and their spouses appear satisfied with their confidant situation, even in the first months after diagnosis when this type of support-seeking behaviour increased in both partners. PMID- 19779824 TI - Post-stroke cognitive impairments. PMID- 19779825 TI - Behavior and spatial learning in radial mazes in birds. AB - This review addresses studies of spatial memory and learning in birds performed using the radial maze method. Descriptions of different versions of this test (standard and "giant" tunnel-type mazes, as well as unstructured "analogs") are described and the methodological problems of testing birds are discussed. Behavioral measures from birds and laboratory rats, as the "standard" system for radial maze studies, are compared. The characteristics of spatial learning in birds of different systematic groups (pigeons, tits, corvids, chickens, etc.) are compared. Particular attention is paid to studies addressing spatial memory in closely related bird species with different ecological features, in terms of the ability to hoard food and finding their hoards after prolonged time periods, as well as to the few reports of results from experiments with migrant birds and homing pigeons. PMID- 19779826 TI - Cooperative activity of neurons in the nucleus accumbens and frontal cortex in cats trained to select reinforcements of different value. AB - Results obtained at the level of the organization of interneuronal interactions of cells in the nucleus accumbens and frontal cortex revealed the features of the involvement of this component in "impulsive" and "self-controlled" behavior, consisting of an increase in bidirectional interactions between the structures of interest, accompanied by simultaneous reductions in the regularity of interactions with increases in "impulsivity" and decreases in "self-control." Long-latency reactions appearing only in "impulsive" animals were associated with decreases in the control of frontal cortex cells by the nucleus accumbens during the signal period, which correlated with the low activity of the network activity of the nucleus accumbens in these animals. Comparison of the patterns of frontal accumbens interactions as the animals performed a single type of activity demonstrated that the connections in neuron pairs during the presignal and signal periods were similar, while significant differences in patterns were seen during the performance of different types of activity. PMID- 19779827 TI - Formation of spatial memory in rats with ischemic lesions to the prefrontal cortex; effects of a synthetic analog of ACTH(4-7). AB - Photochemically induced thrombosis of blood vessels in the prefrontal cortex in rats was shown to lead to ischemic infarcts in the lesion zone. Bilateral ischemic lesioning of the prefrontal cortex degraded measures of spatial memory when animals were tested in a Morris water maze with an invisible platform 20-24 days after surgery. Chronic intranasal administration of the peptide Met-Glu-His Phe-Pro-Gly-Pro (Semax), a synthetic analog of ACTH(4-7), at a dose of 250 microg/kg/day during the first six days after photothrombosis, led to recovery of the animals' learning ability. The long-term antiamnestic action of the peptide observed here may result from its neuroprotective activity and its ability to stimulate the synthesis of neurotrophic factors. PMID- 19779828 TI - Effects of chronic hypotension on the adrenergic nervous plexus of the saphenous artery in rats and its regeneration after femoral nerve injury. AB - The effects of chronic hypotension on the density and intensity of fluorescence (after treatment with glyoxylic acid) of the plexus of adrenergic fibers in the wall of the saphenous artery and on the reinnervation of this vessel were studied in Wistar rats. Regional hypotension in the vascular bed of the hind part of the rats' bodies was induced by stenosis of the abdominal part of the aorta distal to the renal arteries. After four weeks, the saphenous artery was denervated in one limb by resection of a segment of the femoral nerve. In the limb with the nerve lesion, chronic (6-7 weeks) hypotension led to a reduction in the intensity of nerve fiber fluorescence by 20% as compared with normotensive animals (controls), though the density of the nerve plexus did not change. Partial reinnervation of the vessel was observed 2-3 weeks after femoral nerve lesioning. Measures of reinnervation in normotensive and hypotensive rats were no different at two weeks, though at three weeks rats with hypotension showed more complete recovery of innervation. PMID- 19779829 TI - Origin and molecular evolution of ionotropic glutamate receptors. AB - This article provides a review of approaches to identification of the pathways of the molecular evolution of glutamate receptors. Extensive evidence has now accumulated on the homology of glutamate-binding proteins with the ability to function as ligand-activated channels. However, knowledge of the amino acid sequences of the polypeptides forming these channels is a necessary but insufficient condition for identifying their origin and changes during evolution. Natural selection of protein molecules appears to have identified and fixed their functional nature. Molecular and functional approaches should therefore complement each other in studies of protein evolution. Studies of glutamate receptor channels in vertebrates and invertebrates provide an example showing how knowledge of the spatial organization and the details of the mechanisms of operation allows relationships to be identified and possible pathways of the molecular evolution of receptors to be established. PMID- 19779830 TI - Differences in the activation of inhibitory motoneuron receptors in the frog Rana ridibunda by GABA and glycine and their interaction. AB - Intracellular recording of potentials was used in isolated spinal cord segments from the frog Rana ridibunda to compare the inhibitory effects of GABA and glycine on the motoneuron membrane. At equal concentrations, the response (a change in membrane potential) to application of glycine was 1.5-2 times greater than the response to GABA in terms of amplitude, and EC(50) values were 0.75 and 1.57 mM, respectively. The response to simultaneous application of GABA and glycine averaged 79.1 +/- 2.4% (n = 19) of the sum of the individual responses and 130.1 +/- 1.5% (n = 19) of the glycine response (partial occlusion). Preliminary application of glycine decreased the GABA response by 85.3 +/- 0.2% (n = 10), while preapplication of GABA decreased the glycine response by only 52.9 +/- 0.3% (n = 11). The glycine and GABA responses were specifically suppressed by strychnine and bicuculline. These results provide evidence that as in mammals, amphibian motoneurons have both glycine (predominantly) and GABA(A) receptors; they also show that asymmetrical cross inhibition can occur. PMID- 19779831 TI - From communication signals to human language and thought: evolution or revolution? AB - This article addresses a question which has in recent years been widely discussed: that of the specific features of mental functions and language in humans as compared with other higher biological species. The main hypotheses of the origin and evolution of humans and their language are discussed, along with studies identifying genes responsible for higher functions. The cognitive capacities of animals and their communication signals are addressed, as are the basic principles of brain functions. PMID- 19779832 TI - The prokaryotic origin and evolution of eukaryotic chemosignaling systems. AB - Analysis of our own results and data published over the last two decades supports the authors' hypothesis of the prokaryotic origin and endosymbiotic mechanism of appearance of chemosignaling systems in higher eukaryotes. Comparison of the structural-functional organization of these information systems and their component blocks (receptors, GTP-binding proteins, enzymes with cyclase activity, protein kinases, etc.) in bacteria and eukaryotes revealed a whole series of similar characteristics pointing to evolutionary relatedness. This led to the conclusion that eukaryotic signal systems have prokaryotic roots. In terms of their architecture and functional properties, the signal transduction systems seen in unicellular eukaryotes represent a transitional stage in the evolution of chemosignaling systems between prokaryotes and higher eukaryotes. The propagation of chemosignaling systems in three kingdoms - Bacteria, Archaea, and Eukarya - occurred by horizontal transfer of bacterial genes and the coevolution of the components of these systems. PMID- 19779833 TI - The dopaminergic system of the telencephalo-diencephalic areas of the vertebrate brain in the organization of the sleep-waking cycle. AB - The aim of the present work was to study the involvement of the dopaminergic system of the telencephalic and diencephalic areas of the vertebrate brain in the organization of the sleep-waking cycle in cold-blooded and warm-blooded vertebrates. Immunohistochemical studies of tyrosine hydroxylase content, this being the key enzyme in dopamine synthesis, in the striatum, supraoptic and arcuate nuclei, and zona incerta of the hypothalamus of sturgeon and mammals (rats) of three age groups (14 and 30 days and adults), in conditions of tactile and sleep-deprivation stressors. In fish, transient stress was followed by the detection of tyrosine hydroxylase-immunoreactive cells in all parts of the brain. In prolonged stress, tyrosine hydroxylase-immunoreactive cells and fibers were not found in the forebrain, though they were well represented in the hypothalamic nuclei. In 14-day-old rat pups, 2-h sleep deprivation increased the tyrosine hydroxylase content of fibers in the caudate nucleus and cells in the zona incerta of the hypothalamus, while 30-day-old animals subjected to 6-h sleep deprivation showed increases in tyrosine hydroxylaseimmunoreactive material contents in cells in the paraventricular nucleus and decreases in the quantity in fibers. In adult rats, the arcuate nucleus and zona incerta showed decreases in the content of tyrosine hydroxylase-immunoreactive material on the background of sleep deprivation, with increases during postdeprivation sleep. These data are discussed in the light of the phylo- and ontogenetic development of the neurosecretory and neurotransmitter functions of the dopaminergic system in the evolutionarily ancient diencephalic and evolutionarily young telencephalic areas of the vertebrate brain as major systems triggering and maintaining the functional states of the body during the sleep-waking cycle. PMID- 19779834 TI - Characterization of different water pools in solid-state NMR protein samples. AB - We observed and characterized two distinct signals originating from different pools of water protons in solid-state NMR protein samples, namely from crystal water which exchanges polarization with the protein (on the NMR timescale) and is located in the protein-rich fraction at the periphery of the magic-angle spinning (MAS) sample container, and supernatant water located close to the axis of the sample container. The polarization transfer between the water and the protein can be probed by two-dimensional exchange spectroscopy, and we show that the supernatant water does not interact with protein on the timescale of the experiments. The two water pools have different spectroscopic properties, including resonance frequency, longitudinal, transverse and rotating frame relaxation times. The supernatant water can be removed almost completely physically or can be frozen selectively. Both measures lead to an enhancement of the quality factor of the probe circuit, accompanied by an improvement of the experimental signal/noise, and greatly simplify solvent-suppression by substantially reducing the water signal. We also present a tool, which allows filling solid-state NMR sample containers in a more efficient manner, greatly reducing the amount of supernatant water and maximizing signal/noise. PMID- 19779835 TI - Cytotype-specific ISSR profiles and karyotypes in the Neotropical genus Eigenmannia (Teleostei: Gymnotiformes). AB - The genus Eigenmannia (Teleostei: Gymnotiformes), a widely distributed fish genus from the Neotropical region, presents very complex morphological patterns and many taxonomic problems. It is suggested that this genus harbors a species complex that is hard to differentiate using only morphological characteristics. As a result, many species of Eigenmannia may be currently gathered under a common name. With the objective of providing new tools for species characterization in this group, an analysis of the polymorphism of DNA inter-simple sequence repeats (ISSR), obtained by single primer amplification reaction (SPAR), combined with karyotype identification, was carried out in specimens sampled from populations of the Upper Parana, Sao Francisco and Amazon river basins (Brazil). Specific ISSR patterns generated by primers (AAGC)(4) and (GGAC)(4) were found to characterize the ten cytotypes analyzed, even though the cytotypes 2n = 38 and 2n = 38 XX:XY, from the Upper Parana basin, share some ISSR amplification patterns. The geographical distribution of all Eigenmannia specimens sampled was inferred, showing the cytotype 2n = 31/2n = 32 as the most frequent and largely distributed in the Upper Parana basin. The cytotype 2n = 34 was reported for the first time in the genus Eigenmania, restricted to the Sao Francisco basin. Polymorphic ISSR patterns were also detected for each cytotype. Considering our results and the data reported previously in the literature, it is suggested that many of the forms of Eigenmannia herein analyzed might be regarded as different species. This work reinforces the importance of employing diverse approaches, such as molecular and cytogenetic characterization, to address taxonomic and evolutionary issues. PMID- 19779836 TI - Potential fluoride contamination in the drinking water of Marks Nagar, Unnao district, Uttar Pradesh, India. AB - This study was conducted in the summer season (May, 2007). The fluoride concentration along with other physico-chemical parameters in ground water samples was determined in Marks Nagar of Unnao district, Uttar Pradesh (India), since it is the only source of drinking water for the villagers. The fluoride concentration in the water varied from 0.8 to 13.9 mgl(-1) with a mean of 4.02 mgl(-1). The correlation analysis revealed that fluoride had a positive correlation with pH, CO(3), HCO(3), and sodium adsorption ratio (SAR), whereas a negative correlation with Ca and Mg was found. A soil profile was also dug in the area to assess depth-wise fluoride content in the soil. The soil samples and underneath calcium carbonate (CaCO(3)) concretion were analyzed for fluoride content. The percent of soluble fluoride to total fluoride in the soil varied from 25.15 to 4.76% down the soil profile. The soluble fluoride was found to decrease with the increase in the clay content in the soil. The total leachable fluoride in CaCO(3) concretions was found to be 6.08%. It was inferred from this study that the soil and underneath layer of CaCO(3) concretions may be the potential source of fluoride contamination in the shallow drinking water sources of the area. PMID- 19779837 TI - Enrichment and exposure assessment of As, Cr and Pb of the soils in the vicinity of Stawell, Victoria, Australia. AB - Stawell Gold Mine in NW Victoria, Australia, mines ores that contain large concentrations of As and significant quantities of the metals Pb and Cr. The aim of this research was to understand the dispersion, enrichment and probable exposure of these potentially hazardous elements around the mine site. Fifty-five surface soil samples were collected near the mine (<15 km) and analysed by ICP MS/OES following bioavailable and four-acid extractions. Soils near the mine show greater concentrations of As, Cr and Pb than those near a regionally determined background. This is attributed to the combination of a natural geochemical halo around mineralization and anthropogenic dispersion due to mining and urbanization. Total As concentrations were between 16 and 946 mg kg(-1) near the mine in a regional background of 1-16 mg kg(-1). Total Cr concentrations were between 18 and 740 mg kg(-1) near the mine in a regional background of 26-143 mg kg(-1). Total Pb concentrations were between 12 and 430 mg kg(-1) near the mine in a regional background of 9-23 mg kg(-1). Dispersion of contaminant elements from the present ore processing is <500 m. The most enriched soils occur close to the town and are unrelated to present mining practices. The bioavailable As, Cr and Pb, soil ingestion rates and Risk Reference Doses were used to estimate health risks. An average toddler (12 kg) would need to consume at least 1.5 g, and most likely 12 g, of soil per day to show some symptoms of As toxicity. The maximum measured bioavailable As would pose a risk at average ingestion rates of 200 mg per day. Individuals with soil-eating disorders would exceed the safe daily consumption limits for As, and potentially Cr and Pb. Small children are not typically exposed to soil everyday, very few have soil eating disorders, and, therefore, the health risk from the soils around the mine is minimal. PMID- 19779838 TI - Marital status, educational level and household income explain part of the excess mortality of survey non-respondents. AB - Survey respondents and non-respondents differ in their demographic and socio economic position. Many of the health behaviours are also known to be associated with socio-economic differences. We aimed to investigate how much of the excess mortality of survey non-respondents can be explained by the socio-economic differences between respondents and non-respondents. Questionnaire-based adult health behaviour surveys have been conducted in Finland annually since 1978. Data from the 1978 to 2002 surveys, including non-respondents, were linked with mortality data from the Finnish National Cause of Death statistics and with demographic and socio-economic register data (marital status, education and household income) obtained from Statistics Finland. The mortality follow-up lasted until 2006, in which period there were 12,762 deaths (7,994 in men and 4,768 in women) during the follow-up. Total and cause-specific mortality were higher among non-respondents in both men and women. Adjusting results for marital status, educational level and average household income decreased the excess total and cause-specific mortality of non-respondents in both men and women. Of the total excess mortality of non-respondents, 41% in men and 20% in women can be accounted for demographic and socio-economic factors. A part of the excess mortality among non-respondents can be accounted for their demographic and socio economic characteristics. Based on these results we can assume that non respondents tend to have more severe health problems, acute illnesses and unhealthy behaviours, such as smoking and excess alcohol use. These can be reasons for persons not taking part in population surveys. PMID- 19779839 TI - Breastfeeding and risk of epithelial ovarian cancer. AB - OBJECTIVE: Several studies have found inverse associations between breastfeeding and ovarian cancer occurrence but there are inconsistencies. The relationship with breastfeeding duration is unclear, and it is uncertain whether the association varies according to histological subtype of ovarian cancer. We sought to clarify these issues. METHODS: Parous women who participated in an Australia wide population-based case-control study of epithelial ovarian cancer between 2001 and 2005 (1,092 cases and 1,288 controls) completed a reproductive/lifestyle questionnaire. Logistic regression was used to calculate odds ratios and 95% confidence intervals to investigate relations between breastfeeding and ovarian cancer. RESULTS: We found a strong inverse association between total duration of breastfeeding (all episodes combined) and ovarian cancer occurrence (OR = 0.986, 95% CI 0.978-0.994 per month of breastfeeding) that appeared to be independent of parity. However, individual episodes of lactation beyond 12 months conferred no appreciable additional benefit. The relation with breastfeeding appeared to vary by histological subtype such that we saw no association between duration of breastfeeding and borderline serous cancers or mucinous cancers, but inverse associations for the other subtypes, although these were not always statistically significant. CONCLUSIONS: A long total duration of breastfeeding appears to be associated with a substantial reduction in the overall risk of ovarian cancer, independent of the decrease in risk due to childbirth, but this may vary according to histological subtype. PMID- 19779840 TI - Low cancer incidence rates in Ohio Amish. AB - BACKGROUND: The Amish have not been previously studied for cancer incidence, yet they have the potential to help in the understanding of its environmental and genetic contributions. The purpose of this study was to estimate the incidence of cancer among the largest Amish population. METHODS: Adults from randomly selected households were interviewed and a detailed cancer family history was taken. Using both the household interview data and a search of the Ohio cancer registry data, a total of 191 cancer cases were identified between the years 1996 and 2003. RESULTS: The age-adjusted cancer incidence rate for all cancers among the Amish adults was 60% of the age-adjusted adult rate in Ohio (389.5/10(5) vs. 646.9/10(5); p < 0.0001). The incidence rate for tobacco-related cancers in the Amish was 37% of the rate for Ohio adults (p < 0.0001). The incidence rate for non-tobacco-related cancers in the Amish was 72% of the age-adjusted adult rate in Ohio (p = 0.0001). CONCLUSION: Cancer incidence is low in the Ohio Amish. These data strongly support reduction of cancer incidence by tobacco abstinence but cannot be explained solely on this basis. Understanding these contributions may help to identify additional important factors to target to reduce cancer among the non-Amish. PMID- 19779842 TI - Butyltin contamination in sediments and seawater from Kaohsiung Harbor, Taiwan. AB - The distribution of butyltin (BT) compounds in the sediments and seawater, at the river outfalls, fishing ports, shipyards, and industrial zone docks of Kaohsiung Harbor, Taiwan were investigated. Twenty sediment and seawater samples were collected from various locations in the Harbor in 2006 and analyzed for monobutyltin (MBT), dibutyltin (DBT), and tributyltin (TBT). Results showed that the concentration of total BTs varied from 1.5 to 151 ng/g in sediment samples, with TBT being the major component of the sediment samples. This suggests that sediments could be the most possible sink of TBT brought by the sorption mechanism. The concentrations of BTs ranged from 9.7 to 270 ng/L in seawater samples, whereas DBT and MBT, the degradation byproducts of TBT, were mainly the most abundant BT compounds of the seawater samples. This indicates that the abiotic or biotic degradation potential of TBT was significant. Spatially, the highest concentrations of BTs were observed in both water and sediment samples collected from the shipyard and fishing port areas. This indicates that the shipping-related activities (e.g., navigation, ship repair, and ship building) would contribute most of BTs in the environment. Results show that the concentrations of degradation products (DBT and MBT) were related closely to temperature, salinity, dissolved oxygen (DO), and chlorophyll-a of the seawater. This implies that seasonal changes of the water parameters controlled the degradation of TBT in seawater. The observed levels of BT compounds in both seawater and sediments were much higher than those required to induce toxic effects on marine organisms, suggesting that appropriate TBT control strategies should be taken in Kaohsiung Harbor. PMID- 19779841 TI - Dm nxf1/sbr gene affects the formation of meiotic spindle in female Drosophila melanogaster. AB - The small bristles (sbr) gene of Drosophila melanogaster belongs to the family of nuclear export factor (NXF) genes that participate in mRNA nuclear export. During meiosis, females of Drosophila melanogaster that carry various combinations of mutant alleles of the Dm nxf1/sbr gene exhibit disruption of the division spindle and misalignment of chromosomes at the metaphase plate. Meiosis of sbr ( 5 ) /+ females is characterized by the formation of tripolar spindles during the first cell division. According to the sequencing results, the sbr ( 5 ) (l(1)K4) lethal allele is a deletion of 492 nucleotides. In SBR(5) protein, 57 of the 146 amino acids that have been lost by deletion belong to the NTF2-like domain. PMID- 19779843 TI - Evidence that active transmission of porcine cysticercosis occurs in Venezuela. AB - There is a paucity of quantitative data on the status of porcine cysticercosis in Venezuela, information which is essential for understanding the level of disease transmission. This study was, therefore, conducted in a typical small rural community in Yaracuy State, Venezuela, where previous cases of human Taenia solium taeniasis/cysticercosis had been reported and where the free-ranging pig management practices and the lack of rudimentary sanitary facilities indicated an obvious risk for transmission of the disease. Serum samples from 52 village pigs were screened by enzyme-linked immunosorbent assays for anti-cysticercal antibodies (Ab-ELISA), using T. solium cyst fluid as the antigen and the HP10, monoclonal antibody-based, antigen trapping ELISA for parasite antigen (HP10 Ag ELISA). Significantly, a high proportion of the animals (65.4% for the Ab-ELISA and 42.3% for the HP10 Ag-ELISA) were sero-positive. Five of the pigs, which were selected on that basis of positive tongue palpation, were killed for autopsy, and large numbers of viable cysticerci were found in the carcases. This unequivocal documentation of porcine cysticercosis in Venezuelan pigs presents clear evidence that T. solium is actively transmitted in Venezuela. Further detailed studies and implementation of appropriate control measures are therefore indicated. PMID- 19779844 TI - Impaired renal function is associated with mortality in kidney-transplanted patients. AB - INTRODUCTION: To date, only a few, at times conflicting, reports suggested that renal function and mortality are associated in kidney-transplanted patients. In our prevalence cohort study, we tested the hypothesis that renal function is associated with mortality in transplanted patients. METHODS: Data from 985 transplanted patients were analyzed. Socio-demographic parameters, laboratory data, medical and transplant history, type of immunosuppression and estimated glomerular filtration rate were tabulated at baseline. Data on 5-year outcome were collected prospectively. RESULTS: In multivariate Cox proportional hazard models, the estimated glomerular filtration rate measured at baseline significantly predicted mortality [hazard ratio (HR)(for each 10 ml/min decrease) = 1.271; 95% confidence interval (CI): 1.121-1.440] after adjustment for several covariables. Additionally, in multivariate Cox proportional hazard models, chronic kidney disease stage 4-5 (HR = 2.678; 95% CI: 1.494-4.802) significantly increased the mortality hazard compared to chronic kidney disease stage 1-2. CONCLUSIONS: Renal function is significantly and independently associated with mortality over 5 years in kidney-transplanted patients among whom mycophenolate mofetil use was very prevalent. PMID- 19779845 TI - Rosiglitazone, peroxisome proliferator receptor-gamma agonist, ameliorates gentamicin-induced nephrotoxicity in rats. AB - Nephrotoxicity is a major complication of gentamicin (GEN), which is widely used in the treatment of severe gram-negative infections. Reactive oxygen spaces (ROS) are important mediators of gentamicin-induced nephrotoxicity. Peroxisome proliferator-activated receptors (PPARs) have different activities including antioxidant properties. This study was performed to investigate the protective role of PPAR-gamma agonist against GEN-induced nephrotoxicity. Male Wistar Albino rats were randomly divided into the following four groups, each of which consisted of six animals: (1) control; (2) intraperitoneally injected with GEN for 14 consecutive days (100 mg/kg/day); (3) treatment with rosiglitazone (RSG) via nasogastric gavage (10 mg/kg/daily for 14 days); (4) treatment with GEN + RSG combination for 14 day. Rats were decapitated on the 15th day and kidneys were removed. Urine was collected for every 24 h for the determination of daily urine volume. Urea, creatinine, Na(+) and K(+) levels were measured in blood. Malondialdehyde (MDA), reduced glutathione (GSH), and nitric oxide (NO) levels along with glutathione peroxidase (GSH-Px), catalase (CAT), and superoxide dismutase (SOD) activities were determined in the renal tissue. Changes in body weight were recorded. GEN treatment was found to cause nephrotoxicity as evidenced by elevation of serum urea and creatinine levels. Renal impairment was also assessed by the renal histology. The significant decrease in GSH and increases in MDA and NO levels as well as a decrease in GSH-Px, CAT, and SOD activities indicated that GEN-induced renal damage was mediated through oxidative reactions. On the other hand, RSG administration protected kidney tissue against GEN-induced and free radical-mediated oxidative renal damage in rats. PMID- 19779846 TI - Single and multiple CH (calponin homology) domain containing multidomain proteins in Dictyostelium discoideum: an inventory. AB - We present an inventory of single or multiple calponin homology (CH) domain containing proteins of Dictyostelium discoideum. A multiple alignment and a phylogenetic tree of all 60 CH domains found in 36 proteins showed that most CH domains can be assigned to one of 6 types. We have then distributed the proteins into several classes according to the type and arrangement of the CH domains. Most proteins belong to the class of ABD (actin-binding domain)-forming CH tandems (CH1-CH2) of the alpha-actinin and fimbrin families or to the class of CH3 domain-bearing proteins. There are a few examples of proteins with a single CH1 or CH2 domain, one with a CH1-CH1 doublet and a single representative of the CHe class of microtubule-binding proteins. A comparison with CH domain proteins in Homo sapiens suggests that while the individual domains are available in both species, the existence of identical multidomain proteins in toto is rare. Fimbrin 1, alpha-actinin and EB1 appear as perfect orthologs in both species, whereas filamin and interaptin may represent ancestral forms of human filamin and nesprins. In four more cases (NAV/Unc-53-, smoothelin-, transgelin- and Gas2 related proteins) functional data are needed in order to establish a potential relationship with a human counterpart. Although extensive data exist for a few of the D. discoideum CH proteins, most remain to be characterized and our analysis may help predicting some of their properties. PMID- 19779847 TI - Outcomes of nasopharyngeal carcinoma screening for high risk family members in Hong Kong. AB - We undertook a large retrospective study to evaluate the impact of screening family members of NPC patients with Epstein Barr Virus (EBV) serology. 1,199 asymptomatic family members of NPC patients were entered into the annual screening program with EBV serology and nasopharyngoscopy between 1994 and 2005. Eighteen participants of our screening program developed NPC; 17 of them were treated in our institute, of whom 16 were detected in screening. The sensitivity and specificity of EBV serology were 83.3 and 87.0%, respectively, and for the program they were 88.9 and 87.0%, respectively. Stage distributions and survival outcomes of the 17 cases were compared with that of 1,185 consecutive symptomatic patients diagnosed in the same period through general referral. It was found that the screening program resulted in early detection of cancer, with 59% presenting at early stage (stage I: 41%, stage II: 18%) compared to 24% (stage I: < 1%, stage II: 23%) of symptomatic cancers (P < 0.001), and a significant improvement in disease-free survival (P = 0.04). The cancer specific survival and overall survival rate at 5-year are also higher (92 vs. 77% and 92 vs. 70%, respectively), though they fail to reach statistical significance. In conclusion, screening asymptomatic family members of NPC patients annually leads to earlier detection of NPC and clinically valuable survival advantage among these family members. A larger sample size is needed to confirm its full potential in survival benefit. PMID- 19779848 TI - Matricellular proteins: an overview. PMID- 19779849 TI - Backbone resonance assignments of the 48 kDa dimeric putative 18S rRNA methyltransferase Nep1 from Methanocaldococcus jannaschii. AB - Nep1 from Methanocaldococcus jannaschii is a 48 kDa dimeric protein belonging to the SPOUT-class of S-adenosylmethionine dependent RNA-methyltransferases and acting as a ribosome assembly factor. Mutations in the human homolog are the cause of Bowen-Conradi syndrome. We report here 1H, 15N and 13C chemical shift assignments for the backbone of the protein in its apo state. PMID- 19779850 TI - The NF-kappaB/AKT-dependent Induction of Wnt Signaling in Colon Cancer Cells by Macrophages and IL-1beta. AB - Progression of colon cancer from microadenoma to macroscopic tumors is coupled to augmentation of canonical Wnt signaling. We recently reported that tumor associated macrophages, through interleukin 1beta (IL-1beta) dependent phosphorylation of GSK3beta, promote Wnt signaling in colon cancer cells, demonstrating that proinflammatory cytokines can enhance TCF4/beta-catenin transcriptional activity in tumor cells. Here we investigated the pathway whereby IL-1beta inactivates GSK3beta and promotes Wnt signaling in colon cancer cells. We showed that normal human monocytes, THP1 macrophages and IL-1 failed to induce Wnt signaling in tumor cells expressing dominant negative IkappaB (dnIkappaB), demonstrating that macrophages and IL-1 activate Wnt signaling in a NF-kappaB dependent manner. NF-kappaB activity was required for macrophages and IL-1 to activate PDK1 and AKT in tumor cells and thereby inhibit GSK3beta activity. Consistently, dominant negative AKT (dnAKT), or pharmacological inhibition of AKT in tumor cells, prevented macrophage/IL-1 mediated phosphorylation of GSK3beta, activation of Wnt signaling, and induction of c-jun and c-myc, confirming that macrophages and IL-1 promote Wnt signaling in an AKT dependent manner. Finally, we showed IL-1 and macrophages failed to promote growth of colon cancer cells with impaired NF-kappaB or AKT signaling, confirming the requirement for NF kappaB and AKT activation for the protumorigenic activity of tumor associated macrophages. Thus, we showed that IL-1 and tumor associated macrophages activate NF-kappaB-dependent PDK1/AKT signaling in tumor cells, and thereby inactivate GSK3beta, enhance Wnt signaling and promote growth of colon cancer cells, establishing a novel molecular link between inflammation and tumor growth. PMID- 19779851 TI - Special issue on neuron-glia interactions. PMID- 19779852 TI - Sperm quality in male Barbus barbus L. fed different diets during the spawning season. AB - Sperm quality of Barbus barbus L. was compared among the three following dietary regimes: Group A, fed 100% commercial diet (Karpico containing 33% crude protein and 6% fat), Group B, fed 78% commercial diet and 22% frozen chironomid (Chironomus plumosus) larvae, and Group C, fed 56% commercial diet and 44% frozen chironomid larvae. Concentrations of polyunsaturated fatty acids (PUFAs) in Group A, B, and C were 39.1, 42.0, and 44.6, respectively, as a percentage of total fatty acids. Sperm morphology, volume, concentration and motility, total number of spermatozoa, and osmolality of the seminal plasma were compared during the spawning season. Dietary regime did not influence sperm volume, concentration, or total number of spermatozoa, osmolality of seminal plasma, or the percentage of motile sperm, but significantly affected sperm morphology (except for anterior and posterior parts of the midpiece) and sperm velocity (P < 0.05). Groups B and C showed similar sperm characteristics during the spawning season compared to Group A. Almost all parameters changed either among or within groups during the spawning season, suggesting differences in terms of the optimal time for sperm collection. The best time for sperm collection was March for Group A, but April for Groups B and C, when the osmolality of the seminal plasma measured 289 mOsmol kg(-1) and sperm motility was maximal. Spermatogenesis, hydration, and cell decomposition were confirmed as the three major parameters controlling sperm characteristics during the spawning season. The possible correlation between sperm morphology and motility requires further study. PMID- 19779854 TI - Symptomatic unilateral submandibular gland aplasia associated with ipsilateral sublingual gland hypertrophy. PMID- 19779853 TI - Recombinant protein expression in Leishmania tarentolae. AB - A variety of recombinant protein expression systems have been developed for heterologous genes in both prokaryotic and eukaryotic systems such as bacteria, yeast, mammals, insects, transgenic animals, and plants. Recently Leishmania tarentolae, a trypanosomatid protozoan parasite of the white-spotted wall gecko (Tarentola annularis), has been suggested as candidate for heterologous genes expression. Trypanosomatidae are rich in glycoproteins, which can account for more than 10% of total protein; the oligosaccharide structures are similar to those of mammals with N-linked galactose, and fucose residues. To date several heterologous proteins have been expressed in L. tarentolae including both cytoplasmic enzymes and membrane receptors. Significant advances in the development of new strains and vectors, improved techniques, and the commercial availability of those tools coupled with a better understanding of the biology of Leishmania species will lead to value and power in commercial and research labs alike. PMID- 19779855 TI - Brief intervention in substance-use among adolescent psychiatric patients: a randomized controlled trial. AB - Objective of the study is to assess the efficacy of a brief motivational enhancement intervention in adolescents referred to psychiatric treatment who reported substance-use. In a sample of adolescents (n = 237) consecutively admitted to a psychiatry department, 143 were identified as users. Subjects were randomly allocated to one of two groups: an experimental group that received a brief intervention aimed at increasing their awareness of the risks of substance use, or a control group. All subjects received standard treatment according to the primary diagnosis. Structured questionnaires assessing knowledge, problems, perception of risks and intention of use of psychoactive substances were administered upon admission and 1 month later. Fifty-nine subjects entered the experimental group and 44 the control group. No significant differences between the two groups were identified in socio-demographic features or substance-use. Non-parametric analyses showed a significant increase across time in overall knowledge about drugs and perception of risk in the experimental group (P < 0.05). A significant increase in overall knowledge in the experimental group compared to controls was found (P < 0.05). No differences were observed for other variables such as intention of use or perception of risk. Brief intervention in adolescents entering psychiatric treatment led to a significant change in overall knowledge about psychoactive substances but not in other variables related to use. Our results point to the need of more intensive interventions. PMID- 19779856 TI - Overexpression and characterization of a thermostable trehalose synthase from Meiothermus ruber. AB - A thermostable trehalose synthase (TreS) gene from Meiothermus ruber CBS-01 was cloned and overexpressed in Escherichia coli. The purified recombinant TreS could utilize maltose to produce trehalose, and showed an optimum pH and temperature of 6.5 and 50 degrees C, respectively. Kinetic analysis showed that the enzyme had a twofold higher catalytic efficiency (k (cat)/K (m)) for maltose than for trehalose, indicating maltose as the preferred substrate. The TreS also had a weak hydrolytic property with glucose as the byproduct, and glucose was a strong competitive inhibitor of the enzyme. The maximum production of trehalose by the enzyme reached 65% at 20 degrees C. The most importantly the enzyme could maintain very high activity (above 90%) at pH 4.0-8.0 and 60 degrees C 5 h. These results provided that the stable TreS was suitable for the industrial production of trehalose from maltose in a one-step reaction. PMID- 19779857 TI - Perceptive aspects of visual aura. AB - Visual aura is the most common feature associated with migraine, though it can occur separately. In both cases it often represents a dramatic event, especially for patients who experience it for the first time. Besides, its subjective characteristics may illuminate on the functional architecture of the visual cortex. Repetitive events of migraine and visual aura have been suggested to affect the visual system in the long run, both on the cortical and precortical level. In effect, objective investigation of visual functions in patients support the idea that a selective damage does occur, so that more attention to visual examination seems to be justified. In this paper, subjective and psychophysical aspects of visual aura are examined, lastly highlighting and discussing the interesting correlations found between this condition and normal-tension glaucoma. PMID- 19779858 TI - Harmful effect of kainic acid on brain ischemic damage is not related to duration of status epilepticus. AB - Status epilepticus is common in infants and may have long-term consequences on the brain persisting into adulthood. Vascular ischemia is a common cause of stroke in adulthood. The extent of stroke in 15-day-old rats is larger when previously exposed to kainic acid-induced status epilepticus. In this paper, we assess whether shortening the duration of seizures modifies subsequent susceptibility to middle cerebral artery occlusion. We administered pentobarbital 50 mg/kg to abort seizures after 1 h. Although administration of pentobarbital aborted seizures, it had no effect on volume of infarction following ischemia. This study indicates that there is dissociation between stopping status epilepticus and modifying its long-term consequences. PMID- 19779859 TI - Tips and tricks: hemorrhoidectomy with LigaSure. PMID- 19779860 TI - Tips and tricks: haemorrhoidectomy with LigaSure. AB - Haemorrhoidectomy is frequently associated with significant postoperative pain and prolonged hospital stay. New techniques to reduce these problems are constantly under evaluation. Amongst these, LigaSure haemorrhoidectomy is a safe and fast technique that fulfils the requirements of low-complication rate, fast wound healing and quick return to work, reduction in postoperative pain and hospitalisation. The authors detail all the steps of the surgical procedure: operative position; haemorrhoids exposure; dissection, vascular pedicle legation and haemorrhoidal removal, final control. Besides this, the attention is focused on the technical features of LigaSure technology, given that understanding of technical background is a prerequisite for adequate handling of the LigaSure device. PMID- 19779862 TI - Dermacentor marginatus and Ixodes ricinus ticks versus L929 and Vero cell lines in Rickettsia slovaca life cycle evaluated by quantitative real time PCR. AB - Ticks transmit many different pathogens to animals, humans and their pets. Rickettsia slovaca, as a member of the spotted-fever-group rickettsiae is an agent of the human disease Tick-borne lymphadenopathy (TIBOLA), also called Dermacentor-borne necrosis erythema and lymphadenopathy (DEBONEL), which occurs from the Mediterranean to central Europe, transmitted by Dermacentor reticulatus and Dermacentor marginatus (Acari: Ixodidae). In this study, quantitative real time PCR was used to characterize the growth of R. slovaca, strain B in static (mammalian L929 and Vero cells without replacement of growth medium) and dynamic (D. marginatus and Ixodes ricinus ticks) cultivation systems. Curves of bacterial growth in static cultivations were modeled with exponential, stationary and death phases, whereas in dynamic systems the stationary phase was absent. The highest point of multiplication of R. slovaca was recorded on the 4th day post infection in both cell lines and the rickettsial DNA copy number in L929 and Vero cells at this point was 21 and 27 times greater than rickettsial DNA copy number of inoculum, respectively. In the dynamic system, the highest point of multiplication was on the 21th and 12th day after feeding of ticks and rickettsial DNA copy numbers were 7,482 and 865 times greater than the inoculum in D. marginatus and I. ricinus, respectively. Life cycle of R. slovaca in mammalian cell lines was shorter; supposedly, bacteria destroyed these cells and ticks, especially D. marginatus, were considered a more appropriate environment. PMID- 19779861 TI - Amplification and overexpression of KIT, PDGFRA, and VEGFR2 in medulloblastomas and primitive neuroectodermal tumors. AB - Medulloblastomas (MB) and primitive neuroectodermal tumors (PNET) are the most common malignant brain tumors in children. These two tumor types are histologically similar, but have different genetic backgrounds and clinical outcomes. Other brain tumors, such as gliomas, frequently have coamplification and overexpression of receptor tyrosine kinases KIT, platelet-derived growth factor receptor alpha (PDGFRA), and vascular endothelial growth factor receptor 2 (VEGFR2). We investigated protein expression and gene copy numbers of KIT, PDGFRA, and VEGFR2 in 41 MB and 11 PNET samples by immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH). KIT and PDGFRA expression was detected in both MBs and PNETs, whereas VEGFR2 expression was weak in these tumors. KIT, PDGFRA, and VEGFR2 amplifications were all present in 4% of MBs/PNETs, and KIT amplification was associated with concurrent PDGFRA and VEGFR2 amplifications (P 8 h) within each group. Six out of the 31 patients referred, were evaluated for vascular injury without an evidence-based protocol. These patients were significantly more likely to have had a delay in the diagnosis of their vascular injury beyond 8 h (P = 0.032) and were less likely to have been evaluated at a level I trauma center (P < 0.001). As expected, evidence based protocols are superior when compared to initial pedal pulse examination alone for identifying surgically significant vascular injury within 8 h. The consequences of a delay in diagnosis beyond 8 h can be catastrophic and one patient in this series required an above-knee amputation. This is not new information, however, a significant number of patients with knee dislocations continue to be evaluated solely by initial pedal pulse examination. Though effective protocols exist, orthopedic surgeons must work to facilitate the implementation of these protocols at their referring institutions. PMID- 19779892 TI - Portal safety and efficacy of anterior subtalar arthroscopy: a cadaveric study. AB - Anterior subtalar arthroscopy was performed in 14 feet of 7 cadaveric bodies using the primary visualization and working portals. The cartilage of the anterior/middle calcaneal facet that can be reached was marked. The feet were dissected and the distances between the portals and surrounding cutaneous nerves were measured. Any damage to the ligaments of the sinus tarsi was noted. The percentage area of the articular cartilage that was marked was measured. In all specimens, the primary visualization portal tract passed through the lateral root of the inferior extensor retinaculum. The primary working portal tract passed through the lateral root in nine specimens (64%). Cervical ligament was intact in all specimens. In three specimens (21%), the primary visualization portal tract passed through the posterior edge of the intermediate root of the inferior extensor retinaculum. The interosseous talocalcaneal ligament was intact in all specimens. The primary visualization portal tract passed through the medial root of the inferior extensor retinaculum in eight specimens (57%). The primary working portal tract passed through the medial root of the inferior extensor retinaculum in one specimen. The average working area on the calcaneal facet was 95% +/- 4% of the total articular surface. There was no case of nerve injury in all specimens. In conclusion, anterior subtalar arthroscopy is a minimally invasive approach to deal with pathologies of this joint without the need of extensive resection of the ligamentous structures of the sinus tarsi. PMID- 19779893 TI - Arthroscopic microfracture for osteochondral lesions of the talus. AB - The purpose of the present study was to evaluate the outcomes of arthroscopic microfracture for isolated osteochondral lesions of the talus without combined lesions, in patients of less than 50 years old with lesions of <1.5 cm(2). Thirty five patients (35 ankles) with isolated osteochondral lesions of the talus were treated by arthroscopic microfracture. There were 27 men and 8 women of average age 35 years (range 17-50) and mean body mass index (BMI) 25 kg/m(2) (range 20 34) at the time of surgery. Clinical outcome evaluations were performed at a mean follow-up of 33 months. Overall results, as determined using American Orthopaedic Foot and Ankle Society (AOFAS) Ankle-Hindfoot scores, were excellent in 16 (46%), good in 15 (43%), and fair in 4 (11%). Mean AOFAS scores improved from 63 points (range 52-77) preoperatively to 90 points (range 73-100) at final follow-up, median Ankle Activity Score (AAS) from 3 points (range 1-5) to 6 points (range 3 8), mean Visual Analogue Scale (VAS) scores from 7 points (range 5-8) to 2 points (range 0-5), and mean Short Form-36 scores showed improvements in physical function, role limitation, bodily pain, social function, and general health (P < 0.05). In terms of prognostic factors, a longer symptom duration was found to negatively affect outcome, as determined by AOFAS scores, AAS, and VAS scores. Arthroscopic microfracture for isolated osteochondral lesions of the talus is a safe and effective procedure, which provides good clinical outcomes in the majority of patients. PMID- 19779895 TI - Ochronosis: complicated tear of black meniscus. AB - We describe a case of a previously healthy 35-year-old man who presents with meniscal symptoms, and present the arthroscopic findings of a complicated tear of black lateral meniscus. Investigations revealed that he had underlying alkaptonuria, which was previously undiagnosed without any other findings. After the surgical treatment, the patient's complaints were alleviated and almost no complaints were registered, during the next follow-up. PMID- 19779894 TI - Osteointegration of soft tissue grafts within the bone tunnels in anterior cruciate ligament reconstruction can be enhanced. AB - Anterior cruciate ligament reconstruction with a soft tissue autograft (hamstring autograft) has grown in popularity in the last 10 years. However, the issues of a relatively long healing time and an inferior histological healing result in terms of Sharpey-like fibers connection in soft tissue grafts are still unsolved. To obtain a promising outcome in the long run, prompt osteointegration of the tendon graft within the bone tunnel is essential. In recent decades, numerous methods have been reported to enhance osteointegration of soft tissue graft in the bone tunnel. In this article, we review the current literature in this research area, mainly focusing on strategies applied to the local bone tunnel environment. Biological strategies such as stem cell and gene transfer technology, as well as the local application of specific growth factors have been reported to yield exciting results. The use of biological bone substitute and physical stimulation also obtained promising results. Artificially engineered tissue has promise as a solution to the problem of donor site morbidity. Despite these encouraging results, the current available evidence is still experimental. Further clinical studies in terms of randomized control trial in the future should be conducted to extrapolate these basic science study findings into clinical practice. PMID- 19779896 TI - Development and validation of a Monte Carlo simulation tool for multi-pinhole SPECT. AB - PURPOSE: In this work, we developed and validated a Monte Carlo simulation (MCS) tool for investigation and evaluation of multi-pinhole (MPH) SPECT imaging. PROCEDURES: This tool was based on a combination of the SimSET and MCNP codes. Photon attenuation and scatter in the object, as well as penetration and scatter through the collimator detector, are modeled in this tool. It allows accurate and efficient simulation of MPH SPECT with focused pinhole apertures and user specified photon energy, aperture material, and imaging geometry. The MCS method was validated by comparing the point response function (PRF), detection efficiency (DE), and image profiles obtained from point sources and phantom experiments. A prototype single-pinhole collimator and focused four- and five pinhole collimators fitted on a small animal imager were used for the experimental validations. We have also compared computational speed among various simulation tools for MPH SPECT, including SimSET-MCNP, MCNP, SimSET-GATE, and GATE for simulating projections of a hot sphere phantom. RESULTS: We found good agreement between the MCS and experimental results for PRF, DE, and image profiles, indicating the validity of the simulation method. The relative computational speeds for SimSET-MCNP, MCNP, SimSET-GATE, and GATE are 1: 2.73: 3.54: 7.34, respectively, for 120-view simulations. We also demonstrated the application of this MCS tool in small animal imaging by generating a set of low noise MPH projection data of a 3D digital mouse whole body phantom. CONCLUSIONS: The new method is useful for studying MPH collimator designs, data acquisition protocols, image reconstructions, and compensation techniques. It also has great potential to be applied for modeling the collimator-detector response with penetration and scatter effects for MPH in the quantitative reconstruction method. PMID- 19779926 TI - Pesticide extraction from table grapes and plums using ionic liquid based dispersive liquid-liquid microextraction. AB - Room temperature ionic liquids (RTILs) have been used as extraction solvents in dispersive liquid-liquid microextraction (DLLME) for the determination of eight multi-class pesticides (i.e. thiophanate-methyl, carbofuran, carbaryl, tebuconazole, iprodione, oxyfluorfen, hexythiazox, and fenazaquin) in table grapes and plums. The developed method involves the combination of DLLME and high performance liquid chromatography with diode array detection. Samples were first homogenized and extracted with acetonitrile. After evaporation and reconstitution of the extract in water containing sodium chloride, a quick DLLME procedure that used the ionic liquid 1-hexyl-3-methylimidazolium hexafluorophosphate ([C(6)MIM][PF(6)]) and methanol was developed. The RTIL dissolved in a very small volume of acetonitrile was directed injected in the chromatographic system. The comparison between the calibration curves obtained from standards and from spiked sample extracts (matrix-matched calibration) showed the existence of a strong matrix effect for most of the analyzed pesticides. A recovery study was also developed with five consecutive extractions of the two types of fruits spiked at three concentration levels. Mean recovery values were in the range of 72-100% for table grapes and 66-105% for plum samples (except for thiophanate-methyl and carbofuran, which were 64-75% and 58-66%, respectively). Limits of detection (LODs) were in the range 0.651-5.44 microg/kg for table grapes and 0.902-6.33 microg/kg for plums, representing LODs below the maximum residue limits (MRLs) established by the European Union in these fruits. The potential of the method was demonstrated by analyzing 12 commercial fruit samples (six of each type). PMID- 19779897 TI - 64Cu-labeled affibody molecules for imaging of HER2 expressing tumors. AB - INTRODUCTION: The development of molecular probes based on novel engineered protein constructs is under active investigation due to the great potential of this generalizable strategy for imaging a variety of tumor targets. DISCUSSION: In this report, human epidermal growth factor receptor type 2 (HER2)-binding Affibody molecules were radiolabeled with (64)Cu and their imaging ability was further evaluated in tumor mice models to understand the promise and limitations of such probes. The anti-HER2 Affibody molecules in monomeric (Z(HER2:477)) and dimeric [(Z(HER2:477))(2)] forms were site specifically modified with the maleimide-functionalized chelator, 1,4,7,10-tetraazacyclododecane-1,4,7 tris(acetic acid)-10-acetate mono (N-ethylmaleimide amide) (Mal-DOTA). The resulting DOTA-Affibody conjugates were radiolabeled with (64)Cu and evaluated in nude mice bearing subcutaneous SKOV3 tumors. Biodistribution experiments showed that tumor uptake values of (64)Cu-DOTA-Z(HER2:477) and (64)Cu-DOTA (Z(HER2:477))(2) were 6.12 +/- 1.44% and 1.46 +/- 0.50% ID/g, respectively, in nude mice (n = 3 each) at 4 h postinjection. Moreover, (64)Cu-labeled monomer exhibited significantly higher tumor/blood ratio than that of radiolabeled dimeric counterpart at all time points examined in this study. MicroPET imaging of (64)Cu-DOTA-Z(HER2:477) in SKOV3 tumor mice clearly showed good and specific tumor localization. This study demonstrates that (64)Cu-labeled Z(HER2:477) is a promising targeted molecular probe for imaging HER2 receptor expression in living mice. Further work is needed to improve the excretion properties, hence dosimetry and imaging efficacy, of the radiometal-based probe. PMID- 19779927 TI - Developmental aspects of amperometric ATP biosensors based on entrapped enzymes. AB - A novel concept for a dual-enzyme-based microbiosensor for the detection of adenosine-5'-triphosphate (ATP) was developed. The employed enzymes pyrroloquinoline quinone-dependent glucose dehydrogenase (PQQ-GDH) and hexokinase were entrapped, using pH-shift-induced precipitation of electrodeposition paint (EDP) at platinum microelectrodes (diameter of 25 microm). PQQ-GDH is known showing a superior activity for glucose conversion at the relevant conditions (low oxygen concentration) for ATP detection in targeted biomedical studies. For immobilizing the two enzymes PQQ-GDH and hexokinase, the deposition conditions of EDP Resydrol AY498w/35WA were adapted to ensure high immobilization rates. Prior to ATP sensing, the conversion of glucose, which is the co-substrate for both enzymatic reactions, was optimized. Optimization was targeted towards ATP measurements in biomedical environments by optimizing the PQQ-GDH sensor for glucose. Therefore, different mediators were tested regarding their electron transfer rate and their compatibility with the enzyme: free-diffusing N methylphenazonium methyl sulfate (PMS) and ferrocenemethanol, and an immobilized chromium hexacyanoferrate layer at platinum electrode. Free-diffusing ferrocenemethanol reveals high sensitivity towards glucose of 1.5 +/- 0.4 nA/mM. In a next step, hexokinase was co-entrapped in the polymer film resulting in a sensitivity of up to 290 pA/microM. PMID- 19779928 TI - Diffuse cavitary lung lesions. AB - An 11-year-old girl presented with a 2-month history of progressively worsening cough, daily fevers, and weight loss. A chest radiograph revealed multiple cystic cavitary lung lesions. An extensive infectious work-up was negative. Chest CT verified multiple cavitary lung lesions bilaterally, and [F-18]2-fluoro-2-deoxy-D glucose ((18)F-FDG) positron emission tomography with CT (PET/CT) showed increased uptake in the lung lesions as well as regional lymph nodes. Subsequent biopsy of an involved lymph node confirmed classical Hodgkin lymphoma, nodular sclerosis type. This case represents an unusual presentation for a child with Hodgkin lymphoma and demonstrates a role for (18)F-FDG PET/CT in evaluating a child with cavitary lung lesions. PMID- 19779929 TI - Response to "Total hip arthroplasty for active tuberculosis of the hip". PMID- 19779930 TI - Age dependence of otoacoustic emissions: the loss of amplitude is primarily caused by age-related hearing loss and not by aging alone. AB - The amplitude of otoacoustic emissions (OAE) is known to decrease with increasing age, but it is still unclear whether this is due to aging alone or to age-related hearing loss. This study describes the exploration of a large database (5,142 patients from 0.4 to 89.8 years) collected in a routine clinical testing. Reliable pure tone audiograms, transitory evoked otoacoustic emissions (TEOAE) and distortion product otoacoustic emissions (DPOAE) recordings were available from 5,424 ears without conductive loss, acute sudden deafness or retrocochlear disorder. From this database, group 1 with behavioral thresholds of 10 dB HL or better at all frequencies from 1 to 4 kHz and group 2 with age-accordant thresholds after ISO 7029 were formed. In both groups, the OAE amplitude decreased with increasing age, but in group 1, the effect was significant only for DPOAE recorded at 3 and 4 kHz. In group 2, the loss of amplitude was steeper and highly significant for TEOAE as well as DPOAE at all frequencies, but most pronounced at high frequencies. These findings support the hypothesis that the reduction of OAE amplitude with increasing age is primarily caused by age-linked hearing loss and not by aging alone. PMID- 19779931 TI - Dynamic changes in the air-tear film interface modulation transfer function. AB - PURPOSE: To determine objectively the changes in the optical quality of the air tear film interface by measuring the modulation transfer function (MTF) of the anterior surface of the film. METHODS: Air-tear film interface MTF was determined from the wavefront aberration obtained from corneal elevation maps and custom software. MTF and Strehl ratio were derived for 3 (photopic) and 7 (mesopic) mm pupils, in 14 healthy young subjects at various intervals after a blink (1 second up to 15 seconds). Fluorescein tear break-up times (TBUT) measured by a standard method were determined for clinical correlation purposes RESULTS: The MTF profile varies as a function of the time post-blink, showing the highest values at 6-7 seconds. Strehl ratio showed a similar dynamic pattern reaching its maximum level, on average, at 6.2 +/- 0.4 seconds after a blink. Minimum levels occur from 10 seconds after a blink, worsening with larger times. Strehl ratio values were correlated with clinical TBUT: minimum values were found to occur earlier for those subjects with shorter TBUT and vice versa. CONCLUSION: Air-tear film interface MTF and Strehl ratio estimation are useful metrics for optical quality analysis of tear film changes. PMID- 19779932 TI - Preoperative duration of retinal detachment and subretinal immunoreactive endothelin-1: repercussion on logarithmic visual acuity. AB - PURPOSE: To analyze whether preoperative duration of primary rhegmatogenous retinal detachment (RD) influences endothelin-1 (ET-1)--a vasoactive, mitogenic, and pro-apoptotic peptide- levels with repercussions on logarithmic (LogMAR) visual acuity (VA). METHODS: Prospective clinical cohort study on 66 healthy patients [33 with proliferative vitreoretinopathy (PVR) and 33 with no PVR] with unilateral RD candidates for scleral buckling (SB) surgery. Using radioimmunoassay, immunoreactive ET-1 (IR-ET-1) was tested in both plasma and subretinal fluid (SRF) of these RD patients. Pearson's correlations were evaluated between preoperative RD duration and each IR-ET-1 level (plasma, SRF and the difference SRF minus plasma) and also between both variables and the LogMAR VAs (preoperative, postoperative 8 months, and the difference: postoperative 8 months minus preoperative). RESULTS: PVR was associated with higher preoperative RD duration, higher LogMAR VA values (pre- and postoperative 8 months) and higher IR-ET-1 values (plasma, SRF and the difference: SRF minus plasma) than no-PVR IR-ET-1 levels (plasma and SRF) were only correlated (r = 0.462, p = 0.007; r = 0.397, p = 0.022 respectively) with preoperative RD duration in the no-PVR group. IR-ET-1 values (plasma, SRF and the difference:SRF minus plasma) showed statistically significant correlations with pre- and with postoperative 8 months LogMAR VAs in no-PVR and with postoperative 8 months LogMAR VA and LogMAR VA difference in PVR The highest correlation between IR-ET-1 levels and LogMAR VAs was found between SRF IR-ET-1 and postoperative 8 months LogMAR VA in PVR (cases with macula-on) (r = 0.956, p < 0.0001). CONCLUSIONS: Preoperative RD duration showed statistically significant positive correlations with pre- and with postoperative 8 months LogMAR VAs in both the no-PVR and the PVR groups and with IR-ET-1 measurements (plasma and SRF: lower correlations) only in the no-PVR group. These findings support the idea of doing primary and prompt vitrectomy for RD and perhaps using coadjutant pharmacologic therapy in order to improve visual results. PMID- 19779933 TI - Aberrant p16((INK4a)) methylation is a frequent event in colorectal cancers: prognostic value and relation to mRNA expression and immunoreactivity. AB - PURPOSE: Aberrant p16((INK4a)) promoter methylation is common in colorectal cancer (CRC), but its clinicopathological significance remains controversial. The present study was therefore conducted to analyze p16((INK4a)) methylation and its relationship to clinicopathological features, mRNA levels and immunoreactivity in a series of lesions. METHODS: p16((INK4a)) methylation was assessed for normal mucosa (n = 30) and CRC samples (n = 212) by methylation-specific real-time quantitative PCR, and p16((INK4a)) expression by immunostaining in formalin-fixed paraffin-embedded specimens. In addition, fresh DNA (n = 61) was analyzed for relationships to p16((INK4a)) mRNA by reverse-transcription PCR. RESULTS: The p16((INK4a)) methylation index of normal mucosa samples ranged from 0 to 2% (mean, 0.23%; median, 0.02%), while the values for tumor samples varied widely from 0 to 100% (mean, 25.7%; median, 7.1%), the difference being statistically significant (P < 0.001). Of 151 paraffin-embedded CRC tissue samples, 51 (34%), 54 (36%), and 46 (30%) were classified as low, intermediate, and high for aberrant methylation of p16((INK4a)). High p16((INK4a)) methylation was significantly associated with large tumor size (P = 0.025). Patients with higher methylation further showed more frequent recurrence as compared with the low methylation group, and shortened cancer-related survival (Hazard ratio [HR], 3.379; P < 0.001) and recurrence-free survival (HR, 3.962; P < 0.001 on multivariate analysis). A significant inverse relationship was apparent between the p16((INK4a)) methylation and immunoreactivity (P = 0.017). A similar tendency was also observed for the methylation status and the mRNA level (P = 0.195). CONCLUSIONS: We conclude that p16((INK4a)) methylation results in transcriptional silencing and defines a group of CRCs with a poor prognosis. PMID- 19779934 TI - Association of clinicopathological features with UbcH10 expression in colorectal cancer. AB - PURPOSE: UbcH10 is the cancer-related E2 ubiquitin-conjugating enzyme, and its overexpression has been demonstrated in a variety of malignancies. The aim of this study is to investigate the association of UbcH10 gene expression with the carcinogenesis and tumor progression of colorectal cancer. METHODS: The expression levels of UbcH10 in human malignant colorectal carcinoma tissues and their adjacent normal tissues were examined using real-time quantitative RT-PCR and immunohistochemical analysis. The correlations of UbcH10 expression to the clinicalpathologic characteristics of the colorectal cancer were analyzed. Cell proliferation and Matrigel invasion assays were performed in HT-29 cells transfected with UbcH10 expression plasmid pcDNA3.1-UbcH10, UbcH10 RNA interference vector pUbcH10-RNAi as well as their control vectors. RESULTS: Our study demonstrated that the expression of UbcH10 in colorectal carcinoma tissues was significantly higher than that in non-cancerous tissues (P < 0.01), and the UbcH10 overexpression was related to the degree of tumor differentiation and lymph node metastasis of colorectal cancer patients (P < 0.05). In vitro, the overexpression of UbcH10 promoted cell proliferation and tumor invasiveness, but the downregulation of UbcH10 expression significantly reduced the growth rate and the invasiveness activity of tumor cell line. CONCLUSIONS: Our study suggests that the overexpression of UbcH10 gene plays a critical role in the carcinogenesis and tumor progression of colorectal cancer. It may be a new marker in diagnosis and prognosis of colorectal cancer, and the inhibition of UbcH10 may be a therapeutic potential for the treatment of colorectal cancer. PMID- 19779935 TI - Mating order-dependent female mate choice in the polygynandrous common lizard Lacerta vivipara. AB - Recent studies indicate that directional female mate choice and order-dependent female mate choice importantly contribute to non-random mating patterns. In species where females prefer larger sized males, disentangling different hypotheses leading to non-random mating patterns is especially difficult, given that male size usually correlates with behaviours that may lead to non-random mating (e.g. size-dependent emergence from hibernation, male fighting ability). Here we investigate female mate choice and order-dependent female mate choice in the polygynandrous common lizard (Lacerta vivipara). By sequentially presenting males in random order to females, we exclude non-random mating patterns potentially arising due to intra-sexual selection (e.g. male-male competition), trait-dependent encounter probabilities, trait-dependent conspicuousness, or trait-dependent emergence from hibernation. To test for order-dependent female mate choice we investigate whether the previous mating history affects female choice. We show that body size and body condition of the male with which a female mated for the first time were bigger and better, respectively, than the average body size and body condition of the rejected males. There was a negative correlation between body sizes of first and second copulating males. This indicates that female mate choice is dependent on the previous mating history and it shows that the female's choice criteria are non-static, i.e. non-directional. Our study therefore suggests that context-dependent female mate choice may not only arise due to genotype-environment interactions, but also due to other female mating strategies, i.e. order-dependent mate choice. Thus context-dependent female mate choice might be more frequent than previously thought. PMID- 19779936 TI - Receptor based 3D-QSAR to identify putative binders of Mycobacterium tuberculosis Enoyl acyl carrier protein reductase. AB - In the current study, the applicability and scope of 3D-QSAR models (CoMFA and CoMSIA) to complement virtual screening using 3D pharmacophore and molecular docking is examined and applied to identify potential hits against Mycobacterium tuberculosis Enoyl acyl carrier protein reductase (MtENR). Initially CoMFA and CoMSIA models were developed using series of structurally related arylamides as MtENR inhibitors. Docking studies were employed to position the inhibitors into MtENR active site to derive receptor based 3D-QSAR models. Both CoMFA and CoMSIA yielded significant cross validated q(2) values of 0.663 and 0.639 and r(2) values of 0.989 and 0.963, respectively. The statistically significant models were validated by a test set of eight compounds with predictive r(2) value of 0.882 and 0.875 for CoMFA and CoMSIA. The contour maps from 3D-QSAR models in combination with docked binding structures help to better interpret the structure activity relationship. Integrated with CoMFA and CoMSIA predictive models structure based (3D-pharmacophore and molecular docking) virtual screening have been employed to explore potential hits against MtENR. A representative set of 20 compounds with high predicted IC(50) values were sorted out in the present study. PMID- 19779937 TI - Antioxidant mechanisms of Quercetin and Myricetin in the gas phase and in solution--a comparison and validation of semi-empirical methods. AB - Flavonoids have long been recognized for their general health-promoting properties, of which their antioxidant activity may play an important role. In this work we have studied the properties of two flavonols, quercetin and myricetin, using semi-empirical methods in order to validate the application of the recent Parametric Model 6 and to understand the fundamental difference between the two molecules. Their geometries have been optimized and important molecular properties have been calculated. The energetic of the possible antioxidant mechanisms have also been analyzed. The two studied flavonols do not differ significantly in their molecular properties, but the antioxidant mechanisms by which they may act in solution can be rather different. Moreover, we also show that the Parametric Model 6 can produce reliable information for this type of compounds. PMID- 19779938 TI - Submaximal exercise in patients with severe obstructive sleep apnea. AB - PURPOSE: Several studies have used the cardiopulmonary exercise test to assess patients with obstructive sleep apnea (OSA). However, no report has investigated the use of the 6-min walk test (6MWT) in this group of patients. METHODS: We studied consecutive, newly diagnosed, OSA patients (aged >18 years). The control group was composed of matched healthy subjects with no clinical history indicative of sleep breathing disorders. The study population was divided into three groups: an OSA group, a control obese group, and a control lean group. The obese controls were gender-, age- (+/-2 years), height- (+/-5 cm), and weight- (+/-2 kg) matched to the OSA patients, while the lean controls were matched in gender, age, and height, but not weight. All patients underwent sleep study at our Sleep Disorders Center. Each subject underwent a single 6MWT within 1 week of the sleep study. RESULTS: A total of 55 patients were recruited to the OSA group (age 36.7 +/- 7.9 years, body mass index 38.7 +/- 8.6 kg/m(2), and apnea hypopnea index 66.6 +/- 34.8/h), 32 subjects to the control obese group, and 30 to the control lean group. There was no difference in distance walked (6-min walk distance (6MWD)) between the OSA group (389 +/- 70 m) and the obese group (408 +/ 66 m). In the OSA group, the 6MWD results did not correlate with patient age, apnea hypopnea index, or other polysomnographic variables. At the end of the test, heart rate, systolic and diastolic blood pressure, and dyspnea perception were significantly increased in the OSA group compared with healthy subjects. CONCLUSIONS: The 6MWT is easy to perform and well tolerated by patients with OSA. There were no correlations between the 6MWD and the severity of OSA or other polysomnographic parameters. However, patients with OSA exhibited abnormal hemodynamic responses to submaximal exercise. PMID- 19779939 TI - Hill coefficients, dose-response curves and allosteric mechanisms. AB - Hill coefficients (n(H)) derived from four parameter logistic fits to dose response curves were compared to calculated realistic reaction schemes and related to experimental data: (1) Hill coefficients may give information on the number of interacting sites but cannot distinguish between competitive, non competitive or ortho-, iso-, or allosteric mechanisms. (2) For enzymatic dose inhibition curves, Hill coefficients smaller than one do not indicate anticooperative binding but show that at least one ternary complex has enzymatic activity. (3) Hill coefficients different from one are proof for multiple ligand binding. The large variations of reported Hill coefficients corresponds to multiple allosteric binding, where induced conformational changes cause loss of the active conformation. Such a denaturation mechanism is in stark contrast to the desired specificity of drugs. The discussion is open. PMID- 19779940 TI - An effective point-based registration tool for surgical navigation. AB - BACKGROUND: Surgical navigation assists in endoscopic surgeries by enabling surgeons to see concealed lesions and surrounding organs. Successful surgical navigation depends on accurate registration between a medical image and a patient. For accurate point-based registration, it is important to determine the matching order and positions of the markers correctly. It is particularly difficult to determine the order and positions when part of the markers cannot be located on the patient's body or when they cannot be identified in the images. METHODS: By using the automatic marker-matching option of the proposed tool, an optimum registration result can be obtained even with the partial loss of markers. In addition, this tool provides an intuitive marker selection interface that displays the registration error of each marker pair in different colors. RESULTS: The efficiency of the described tool in terms of the registration accuracy and time has been confirmed in more than 70 clinical applications. The fiducial registration errors were 1.28 + or - 1.09 mm in ear, nose, and throat surgery and 3.55 + or - 1.30 mm in liver tumor ablation therapy. CONCLUSIONS: The proposed automatic matching scheme with marker selection interface was particularly effective where the markers were partly lost or incorrectly identified. PMID- 19779942 TI - Synthetic grape volatiles attract mated Lobesia botrana females in laboratory and field bioassays. AB - In laboratory experiments, we identified and quantified volatiles emitted by inflorescences and berries of two grape varieties (Trebbiano and Sangiovese) and examined the effects of the volatiles on oviposition by the grapevine moth Lobesia botrana. Compared to Trebbiano, Sangiovese is relatively more susceptible to L. botrana infestations under natural conditions. Chemical and electrophysiological analysis indicated only quantitative differences between the volatiles released by the two varieties. In a dual-choice oviposition bioassay based only on volatile cues, females did not show any preference between the two varieties. The six major components of the odor profiles that were GC-EAD-active to female antennae included: limonene, 4,8-dimethyl-1,(E)-3,7-nonatriene, (+/-) linalool, (E)-caryophyllene, (E,E)-alpha-farnesene, and methyl salicylate. At the beginning of the berry touch phenological stage, their proportions were about 10:0.6:0.4:0.5:0.9:0.6 in Trebbiano and 10:1:0.4:1.5:0.4:0.3 in Sangiovese. A six component synthetic lure (with the proportion 10:1:1:1:1:1, which approximated the ratio of components released by both varieties) was used in further laboratory oviposition bioassays. Depending on its dosage, the synthetic lure either attracted or repelled oviposition. L. botrana females laid significantly more eggs in the presence of either the grape bunches or the synthetic lure at the attractive dosage. In a release-capture experiment conducted in a field cage that covered two grapevine rows, the synthetic lure was more attractive than a grape cluster or a blank control, and it stimulated oviposition on the vegetation near the lure. The results indicate that L. botrana uses olfactory cues to select oviposition sites and that an artificial lure, containing the major volatiles released by two grape varieties, may be useful in monitoring female activity in the field. PMID- 19779943 TI - The size of the esophageal hiatus in gastroesophageal reflux pathophysiology: outcome of intraoperative measurements. AB - OBJECTIVE: The aim of the study was to investigate the impact of the size of the esophageal hiatus on lower esophageal sphincter pressure (LESP) and acid reflux. METHODS: Patients with gastroesophageal reflux disease who underwent Nissen fundoplication in 2006-2008 were included. All underwent esophageal manometry and 22 had 24-h pH monitoring. The area of the esophageal hiatus was calculated from a photograph shot during surgery. A hiatal index was calculated via division of hiatal area with body mass index (BMI). Correlation and logistic regression analysis were performed. RESULTS: Twenty-eight patients (average age 44, 14 males) were enrolled. The mean BMI, LESP, DeMeester score, hiatal area, and hiatal index were 27 +/- 3.9 kg/m(2), 11.7 +/- 6.6 mmHg, 43 +/- 34, 3.83 +/- 1.24 cm(2), and 0.143 +/- 0.048, respectively. There was a significant negative correlation between hiatal area, hiatal index and LESP (-0.513, p = 0.005, r = 0.439, p = 0.019 respectively). Additionally there was a negative correlation between hiatal area and total LES length (r = -0.508, p = 0.013) and a significant positive correlation between hiatal area, hiatal index, and DeMeester scores (0.452, p = 0.035, 0.537, p = 0.01, respectively). Height and hiatal area were significant factors in multiple linear regression. CONCLUSIONS: The size of the esophageal hiatus significantly affects LESP and acid reflux, and hiatal index is a new value, which appears to reflect the amount of acid reflux. Total LES length is also shortened in patients with a large hiatus. PMID- 19779944 TI - Intestinal surgery for Crohn's disease: predictors of recovery, quality of life, and costs. AB - INTRODUCTION: The aim of this prospective study was to analyze the impact of different surgical techniques on patients undergoing intestinal surgery for Crohn's disease (CD) in terms of recovery, quality of life, and direct and indirect costs. PATIENTS AND METHODS: Forty-seven consecutive patients admitted for intestinal surgery for CD were enrolled in this prospective study. Surgical procedures were evaluated as possible predictors of outcome in terms of disability status (Barthel's Index), quality of life (Cleveland Global Quality of Life score), body image, disease activity (Harvey-Bradshaw Activity Index), and costs (calculated in 2008 Euros). Univariate and multivariate analyses were performed. RESULTS: Significant predictors of a long postoperative hospital stay were the creation of a stoma, postoperative complications, disability status on the third post-operative day, and surgical access (R (2) = 0.59, p < 0.01). Barthel's index at discharge was independently predicted by laparoscopic-assisted approach, ileal CD, and colonic CD (R (2) = 0.53, p < 0.01). The disability status at admission showed to be an independent predictor of quality of life score at follow-up. The overall cost for intestinal surgery for CD was 12,037 (10,117-15,795) euro per patient and stoma creation revealed to be its only predictor (p = 0.006). CONCLUSIONS: Laparoscopy was associated with a shorter postoperative length of stay; stoma creation was associated with a long and expensive postoperative hospital stay, and stricturoplasty was associated with a slower recovery of bowel function. PMID- 19779945 TI - The value of high-resolution manometry in the assessment of the resting characteristics of the lower esophageal sphincter. AB - INTRODUCTION: High-resolution manometry (HRM) is faster and easier to perform than conventional water perfused manometry. There is general acceptance of its usefulness in evaluating upper esophageal sphincter and esophageal body. There has been less emphasis on the use of HRM to evaluate the lower esophageal sphincter (LES) resting pressure and length, both factors important in LES barrier function. The aim of this study was to compare the resting characteristics of the LES determined by HRM and conventional manometry in the same patients. METHODS: We performed both HRM and conventional manometry including a slow motorized pull-through technique in 55 patients with foregut symptoms. The characteristics of the LES analyzed were: resting pressure, total length, and abdominal length. Four available modes of HRM analysis were used to assess resting characteristics of the LES: spatiotemporal mode using both abrupt color change and isobaric contour, line tracing, and pressure profile. The values obtained from these four HRM modes were then compared to the conventional manometry measurements. RESULTS: High-resolution manometry and conventional manometry did not differ in their measurement of LES resting pressure. LES overall and abdominal length were consistently overestimated by HRM. A variability up to 4 cm in overall length was observed and was greatest in patients with hiatal hernia (1.8 vs. 0.9 cm, p = 0.027). CONCLUSION: The current construction of the catheter and software analysis used in high-resolution manometry do not allow precise measurement of LES length. Errors in the identification of the upper border of the sphincter may compromise accurate positioning of a pH probe. PMID- 19779946 TI - Selective management of patients with acute biliary pancreatitis. AB - BACKGROUND: Detection of common bile duct (CBD) stones in patients with acute biliary pancreatitis (ABP) proves challenging. We hypothesized that grouping clinically significant predictors would increase reliability of detection. METHODS: A retrospective review was performed of 144 consecutive patients who presented to a single tertiary care institution from 2002 to 2007 with ABP. RESULTS: Of the 144 patients, 32 had a persistent CBD stone. Following multivariate analysis, admission CBD size on ultrasound, gamma glutamyl transferase (GGT), alkaline phosphatase (AP), total bilirubin (TB), and direct bilirubin (DB) significantly correlated with persistent CBD stone. Receiver operator curve analysis and linear regression were applied to obtain optimal and equitable predictive values, and variables combined. Optimal values were: CBD >or= 9 mm; AP >or= 250 U/l; GGT >or= 350 U/l; TB >or= 3 mg/dl; and DB >or= 2 mg/dl. Presence of five variables had an associated odds ratio (OR) of 53.1 (p < 0.001) and four variables an OR of 8.97 (p = 0.004) for presence of persistent CBD stone. Zero variables conferred a significantly decreased probability of CBD stone, OR 0.15 (p < 0.001). Presence of one to three variables did not predict presence of CBD stone. CONCLUSION: Presence of four or five variables significantly correlated with persistent CBD stone. Biliary evaluation by endoscopic retrograde cholangiopancreatography is suggested, as initial magnetic resonance cholangiopancreatography (MRCP) may only increase cost and delay time to intervention. In the absence of any variable, biliary evaluation by intraoperative cholangiogram may be sufficient. Decisions regarding patients with one to three variables should occur on a case-to-case basis. Initial biliary evaluation by MRCP is likely preferable, however, as no increased probability of CBD stone was identified, thus not warranting risks associated with intervention. PMID- 19779947 TI - Enhanced recovery after surgery (ERAS) versus conventional postoperative care in colorectal surgery. AB - BACKGROUND: Enhanced Recovery After Surgery (ERAS) programs are associated with reduced hospital morbidity and mortality. The aim of the present study was to evaluate whether the introduction of ERAS care improved the adverse events in colorectal surgery. In a cohort study, mortality, morbidity, and length of stay were compared between ERAS patients and carefully matched historical controls. METHODS: Patients were matched for their type of disease, the type of surgery, P Possum (Portsmouth-Possum), CR-Possum (Colorectal-Possum) Physiological and Operative Score for Enumeration of Mortality and Morbidity (POSSUM), gender, and American Society of Anesthesiologists (ASA) grade. The primary outcome measures of this study were mortality and morbidity. Secondary outcome measures were fluid intake, length of hospital stay, the number of relaparotomies, and the number of readmissions within 30 days. Data on the ERAS patients were collected prospectively. RESULTS: Sixty-one patients treated according to the ERAS program were compared with 122 patients who received conventional postoperative care. The two groups were comparable with respect to age, ASA grade, P-Possum (Portsmouth Possum), CR-Possum (Colorectal-Possum) score, type of surgery, stoma formation, type of disease, and gender. Morbidity was lower in the ERAS group compared to the control group (14.8% versus 33.6% respectively; P = <0.01). Patients in the ERAS group received significantly less fluid and spent fewer days in the hospital (median 6 days, range 3-50 vs. median 9 days, range 3-138; P = 0.032). There was no difference between the ERAS and the control group for mortality (0% vs. 1.6%; P = 0.55) and readmission rate (3.3% vs. 1.6%; P = 0.60). CONCLUSION: Enhanced Recovery After Surgery program reduces morbidity and the length of hospital stay for patients undergoing elective colonic or rectal surgery. PMID- 19779948 TI - Enucleation of pancreatic cystadenomas. AB - BACKGROUND: Optimal surgical treatment of pancreatic cystadenomas is controversial due to the rarity of the tumors and paucity of studies regarding long-term outcomes. This is especially true for large pancreatic cystadenomas. The objective of this study was to determine the safety and effectiveness of treating pancreatic cystadenomas by enucleation. METHODS: Eleven cases of pancreatic mucinous or serous cystadenomas were selected for enucleation according to the following criteria: (1) the benign nature of the tumors was ascertained preoperatively and intraoperatively, (2) small tumors or larger tumors no more than 6 cm in diameter growing outwardly with small tumor beds, and (3) the main pancreatic duct was not in jeopardy of damage by enucleation. The patients' demographics, tumor features, morbidity, and follow-up results were retrospectively reviewed and analyzed. RESULTS: Among 11 cases, three were serous cystadenomas and eight were mucinous cystadenomas; the average size of the neoplasms was 4.8 cm (ranging from 3 to 6 cm). Two cases were complicated by the development of fistulas postoperatively and one had an incision infection. All cases were followed up from 23 to 67 months, which revealed no neoplasm recurrence or new onset of diabetes mellitus; one patient developed a pseudocyst in the body 30 months after enucleation. CONCLUSIONS: It is safe and effective to perform enucleation for well-selected benign pancreatic cystadenomas even if the tumor size is as large as 6 cm, and the endocrine or exocrine function of the pancreas is maintained as much as possible. PMID- 19779949 TI - Outcomes of laparoscopic bariatric surgery after renal transplant. AB - Obesity has been associated with poor graft and patient survival after kidney transplantation, requiring functional increase of anti-rejection drugs. Weight loss surgery may be a good alternative in this clinical scenario. The aim of this report is to describe the outcomes of bariatric procedures performed in patients after kidney transplantation at our institution. A retrospective chart review of a prospectively collected database was conducted to analyze the outcomes of morbidly obese patients after kidney transplantation who underwent laparoscopic bariatric procedures between November 2004 and October 2007. Our series included five patients who underwent a bariatric procedure following kidney transplantation. All patients were females, with a mean age of 40.8 years (range 30-48) and mean body mass index (BMI) of 52.2 (range 48-69). Percent of excess weight loss (%EWL) at 2 years was over 50% for all patients; other comorbidities that might affect postoperative renal function were diabetes mellitus in 2/5 patients, hypertension in 5/5 patients, and chronic heart failure in 1/5 patients. Four patients had laparoscopic Roux-en-Y gastric bypass and one had laparoscopic sleeve gastrectomy. There were no postoperative complications in any patients, and no alteration to the dosages of the immunosuppressant drugs were recorded after bariatric surgery. Laparoscopic bariatric surgical techniques may be used safely and effectively to control obesity in renal transplant patients. PMID- 19779950 TI - The learning curve for adopting hip resurfacing among hip specialists. AB - Patient demand and surgeon interest in hip resurfacing has recently increased, but surgeons in the United States are relatively inexperienced with this procedure. We determined the learning curve associated with hip resurfacing and compared the rate of early complications of the first 650 hip resurfacings between five experienced hip surgeons and a national safety survey database study we previously published, which included 89 surgeons and 537 hip resurfacings. Patient demographics and adverse events were recorded. Specific features on pre- and postoperative radiographs were measured in a blinded fashion by a single observer. There were 13 major complications (2.0%), which is 3.7 times lower than our national safety survey complication rate of 7.4%. All fractures occurred in the first 25 cases performed. The complication rate was higher for the first 25 procedures (5.6%) compared with the second 25 procedures (1.6%). For experienced hip surgeons, the learning curve for avoiding early complications was short, 25 cases or less. The learning curve for achieving the desired component positioning radiographically was much longer, 75 to 100 cases or more. If achieving some ideal component position proves important for long-term function and implant survival, improved instrumentation and surgical techniques would be necessary to shorten the learning curve. LEVEL OF EVIDENCE: Level II, prognostic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 19779951 TI - Optimism in the world of cardiovascular imaging: nuclear cardiology remains the cornerstone of risk assessment for ischemic heart disease. PMID- 19779952 TI - Case report: Neurological deficit associated with intraneural needle placement without injection. AB - PURPOSE: Recent reports of painless intraneural injection of low volumes of local anesthetic without subsequent neurological deficit have led to the suggestion that deliberate subepineural injection may be a safe and therefore acceptable practice. CLINICAL FEATURES: This report describes a case where a venous cannulation needle inadvertently penetrated a patient's median nerve. Sudden onset severe lancinating pain occurred in the median nerve sensory distribution. A subsequent thorough ultrasound examination showed the median nerve to be located immediately posterior to the targeted median cubital vein. New onset sensory symptoms (numbness, tingling, pain, and altered sensation to touch) in the distribution of the penetrated median nerve persisted for >6 weeks. CONCLUSION: This report highlights the hazards of intraneural needle placement irrespective of an associated injection. PMID- 19779953 TI - Randomized non-inferiority trial of the vitalHEAT temperature management system vs the Bair Hugger warmer during total knee arthroplasty. AB - PURPOSE: Intraoperative and postoperative hypothermia occur commonly; mild hypothermia (34-36 degrees C) is associated with adverse events. The use of perioperative warming devices has become routine, but currently available active warming devices may be limited in certain circumstances. The vitalHEAT Temperature Management System provides conductive warming (circulating warm water) around a single extremity together with a vacuum that is applied to the limb. In this randomized trial, we tested the hypothesis that the vitalHEAT system is non-inferior to the Bair Hugger during unilateral total knee arthroplasty. METHODS: Physical status I-III patients who were >or=18 yr-old were eligible to participate. The patients were randomly assigned to the vitalHEAT system (n = 30) or to Bair Hugger (n = 25) warming. Intraoperative and first recovery room temperatures were recorded in both groups. RESULTS: The baseline characteristics of the groups were similar. In terms of the primary outcome measure, i.e., sublingual temperature measured within 10 min of recovery room arrival, the vitalHEAT system did not meet the criterion for non-inferiority. Specifically, the confidence interval for the difference between means included the non-inferiority margin (-0.5 degrees C). In terms of the secondary measures, i.e., intraoperative esophageal temperatures, the vitalHEAT system also underperformed compared with the Bair Hugger. CONCLUSIONS: The vitalHEAT system may have advantages over convective warming systems because it requires a much smaller body surface area; however, in this study of warming during total knee arthroplasty, it underperformed when compared with the Bair Hugger, especially around and after the time of tourniquet release. CLINICAL TRIAL REGISTRATION NUMBER: NCT00711867. PMID- 19779954 TI - The optimal dose of rocuronium for rapid sequence induction. PMID- 19779955 TI - Anesthetic drugs and sustained neuroprotection in acute cerebral ischemia: can we alter clinical outcomes? PMID- 19779957 TI - Efficacy of oxygen inhalation in sumatriptan refractory "high altitude" cluster headache attacks. AB - We describe the case of a 40-year-old woman, affected by episodic cluster headache, who presented with a cluster headache triggered by exposure to high altitude. Her attacks were refractory to sumatriptan, very effective at sea level, but responded to oxygen. A pathophysiological mechanism is proposed. PMID- 19779956 TI - Dysregulation of CREB activation and histone acetylation in 3-nitropropionic acid treated cortical neurons: prevention by BDNF and NGF. AB - 3-Nitropropionic acid (3-NP), an inhibitor of mitochondrial complex II, leads to metabolic impairment and neurodegeneration. In this study, we investigated the roles of brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in the dysregulation of transcription factors and histone modifying enzymes induced by 3-NP in primary cortical neurons. BDNF prevented the 3-NP-induced decrease in cAMP response-element binding protein (CREB) phosphorylation and CREB binding protein levels. Both NGF and BDNF counteracted the increase in the levels of histone H3 and H4 acetylations and reduced histone deacetylase (HDAC) activity induced by 3-NP. BDNF further led to hyperphosphorylation of HDAC2. Our results support an important role for neurotrophins, particularly BDNF, in preventing detrimental changes in transcription factors and histone acetylation states in cortical neurons that have been subjected to selective mitochondrial inhibition. PMID- 19779958 TI - Is there an inherent limit to the efficacy of calcitonin gene-related peptide receptor antagonists in the acute treatment of migraine? A comment. AB - Calcitonin gene-related peptide (CGRP) receptor antagonists are a new treatment principle in acute migraine attacks. Intravenous olcegepant 2.5 mg resulted in 66% headache relief after 2 h, whereas subcutaneous sumatriptan resulted in 81 92% headache relief after 2 h. The intrinsic activity of a parenteral triptan, a 5HT(1B/1D) receptor agonist, is thus higher than the maximum effect of the parenteral CGRP receptor antagonist olcegepant. For the orally bioavailable CGRP antagonist telcagepant 300 mg, the headache relief was only 55% in one phase III study. These results indicate that CGRP receptor antagonism results in success in the acute treatment of migraine in only a certain fraction of the patients. PMID- 19779959 TI - Genetic polymorphisms of glutathione S-transferase T1 and bladder cancer risk: a meta-analysis. AB - In recent years, there have been numerous papers emphasizing the relationship between Glutathione S-transferases polymorphisms and bladder cancer risk, but the findings have not reached a consensus. The relationship between glutathione S transferase T 1 null genotype and bladder cancer susceptibility is now even more disputable. Therefore, we present a meta-analysis of (nested) case-controlled, genotype-based studies (including 37 studies, 6,986 cases and 9,166 controls) examining this association. Using a fixed-effect model, statistically significant increase was observed between glutathione S-transferase T 1 deletion and bladder cancer risk for the overall studies (OR = 1.12; 95% confidence interval (CI): 1.04-1.21; P = 0.004 for Z test; I (2) = 47.43 for heterogeneity). After adjusting the result using trim-and-fill method, the outcome still had significant difference with little downgrade (OR = 1.10, 95% CI = 1.02-1.18). Three potential sources of heterogeneity including ethnicity, source of control and smoking status were also assessed. Minor increased correlation was found only in population-based studies (OR = 1.16; 95% CI = 1.03-1.30; I (2) = 47.16). Our analysis suggests that glutathione S-transferase T 1 null status is associated with a modest increase in the risk of bladder cancer and the difference exiting in source of control has been confirmed. Due to limited sample size, various confounding variables as well as discrepancy in study design, a valid conclusion still cannot be confirmed. PMID- 19779960 TI - Parathormone and 1,25(OH)2D3 but not 25(OH)D3 serum levels, in an inverse correlation, reveal an association with advanced stages of colorectal cancer. AB - Experimental, epidemiologic, and clinical trial data indicate the antineoplastic effects of calcium and vitamin D in large-bowel neoplasia. The aim of this study was to determine serum levels of vitamin D metabolites and parathormone (PTH) in patients with colorectal cancer (CRC) and to extract conclusions comparing their different levels in serum with healthy individuals. Group 1 (cancer patients) was consisted of 140 patients with CRC with clinical stages Duke's A: 12, B: 52, C: 62, and D: 14. Serum levels of 25(OH)D(3), 1,25(OH)(2)D(3), and PTH were determined in all patients. The findings are: (a) No significant difference was found in the serum levels of 25(OH)D(3) in each Duke's clinical stage in cancer patients, (b) serum 1,25(OH)(2)D(3) levels decreased with advanced cancer stages, and (c) serum levels of PTH showed a corresponding increase. Low serum levels of 1,25(OH)(2)D(3) on one hand and increased levels of PTH in patients with CRC on the other might be strongly related to the carcinogenetic process. PMID- 19779961 TI - Hedgehog signaling regulates proliferation of prostate cancer cells via stathmin1. AB - Hedgehog (Hh) signaling is an essential pathway in embryonic development of prostate. Hh also plays roles in the proliferation of progenitor cells and cancer cells of adult prostate. However, how Hh signaling contributes to carcinogenesis of prostate is poorly understood. Stathmin1 is a microtubule-regulating protein that plays an important role in the assembly and disassembly of the mitotic spindle. Stathmin1 is expressed in normal developing mouse prostate and in prostate cancer. The expression pattern of stathmin1 is similar to that of Shh in prostate development and cancer, suggesting a connection between these two proteins. In this study, we examined the relationship between stathmin1 and Hh signaling. Here, we show that stathmin1 expression is regulated by Hh signaling in prostate cancer cells. Cyclopamine, a specific inhibitor of Hh signaling, reduced the expression of stathmin1 in prostate cancer cells. However, the Shh peptide induced stathmin1 expression. Overexpression of Gli1 further confirmed the relationship. Co-expression of stathmin1 and Patched 1, a receptor for Hh signaling was observed in prostate cancer tissues. Cyclopamine and stathmin1 siRNA both decreased proliferation of prostate cancer cells but did not produce an additive effect, suggesting a common pathway. These results suggest that Hh signaling regulates proliferation of prostate cancer cells by controlling stathmin1 expression. PMID- 19779962 TI - Aberrant phenotypes in childhood and adult acute leukemia and its association with adverse prognostic factors and clinical outcome. AB - Occurrence of aberrant phenotypes in childhood and adult acute leukemia (AL) differs considerably in independent studies and their association with prognostic factors is still controversial. In the present study, 214 patients with AL (106 children and 108 adults) were evaluated for the aberrant expression of CD33 in ALL (B cell and T cell) and CD3, CD5, CD7, and CD19 in AML. In B-ALL, aberrant expression of CD33 was found in 39 and 23% cases of adult and children, respectively. In T-ALL, CD33 was seen in 33% cases of adults while in children CD33 was not observed. In AML, aberrant expression of CD19 was expressed in 52 and 32% while CD7 was expressed in 14 and 15% cases of childhood and adult AML, respectively. Among FAB subtypes, aberrant expression of CD19 and CD7 was more commonly seen in M5 subtype. One adult patient (AML-M5) showed expression of CD3, CD5, and CD19. In summary, aberrant phenotype was commonly seen in adults than childhood B-ALL while in AML, aberrant phenotype was more common in children than adults. CD19 was most commonly expressed antigen followed by CD7 in both childhood and adult AML. Interestingly, aberrant phenotype was not found in childhood T-ALL; however, it was seen in 33% cases of adults. We did not find any association of aberrant phenotype with adverse prognosis factors, CD34 marker, and clinical outcome except the absence of auer rod which was found to be significantly associated with aberrant phenotype of childhood AML (P = 0.01). PMID- 19779963 TI - The effects of staphylococcal bacteriophage lysates on cancer cells in vitro. AB - Bacteriophages constitute a serious alternative to antibiotic therapy of bacterial infections. They are also extremely numerous entities: phages can be found in almost all places on Earth and are constantly present in human and animal bodies. Observations of the effect of therapeutic staphylococcal phages and their bacterial hosts on melanoma migration in vitro are reported in this article. Together with bacteriophage preparations, disrupted Staphylococci (host strains) were investigated to compare the effects of bacteria with those of bacteriophages. Migration was decreased by all the investigated preparations in various ways and this was rather due to the activity of the bacterial components. Importantly, none of the investigated bacteriophage or bacterial preparations induced an increase in the migration activity of melanoma cells, which is important from the perspective of the therapeutic use of phage lysates. The possible presence of staphylococcal enterotoxins in the therapeutic bacteriophage preparations was also verified. All the studied therapeutic bacteriophage preparations were negative for the Staphylococcal enterotoxins A, B, C, D, and E (i.e., the enterotoxin content was less than 0.2-0.5 ng/ml). PMID- 19779964 TI - The mRNA and protein expression of A-kinase anchor proteins 13 in human colorectal cancer. AB - There was no literature reporting the relationship between AKAP13 and colorectal carcinoma. This study is aim to investigate the expression and role of AKAP13 in human colorectal cancers. This study investigated 94 pair-matched human colorectal cancers and adjacent normal mucosa, as well as 36 adenomas, of which mRNA expression of AKAP13 was detected by relative Quantitative-Real-Time RT-PCR and protein expression by immunohistochemical staining. AKAP13 gene was upregulated in colorectal cancer group by 2.259 times compared to control group without significant difference (P = 0.081), and no expression was detected in adenoma by RT-PCR. The positive expression rate of AKAP13 protein in colorectal carcinoma (52.3%) was significantly higher than those in adenoma (9.1%) and normal tissue (34.7%) (P = 0.006) by immunohistochemical staining. Either the mRNA or protein expressions of AKAP13 were correlated with histological types and differentiation grade (P < 0.05). Our results suggest AKAP13 protein may be related to the carcinogenesis of human colorectal cancer. However, more deeply and larger scale research are required to prove the correlation. PMID- 19779965 TI - Effects of exposure to hyperbaric oxygen on oxidative stress in rats with type II collagen-induced arthritis. AB - Arthritis was induced in 9-week-old female Dark Agouti rats by injecting type II collagen. Serum levels of the derivatives of reactive oxygen metabolites (dROMs), which are oxidative stress markers, and C-reactive protein (CRP) in arthritic rats that were exposed to a pressure of 1.25 atmospheres absolute and an oxygen concentration of 36% for 3 weeks (arthritis + HBO group) were compared to those of control rats (control group) and arthritic rats that were not exposed to hyperbaric oxygen (arthritis group). The body weights of the arthritis and arthritis + HBO groups were lower than that of the control group, whereas no difference in the body weight was observed between the arthritis and arthritis + HBO groups. The serum levels of dROMs and CRP in the arthritis group were higher than those in the control and arthritis + HBO groups. No difference in the serum level of CRP was observed between the control and arthritis + HBO groups. These results indicate that the conditions of hyperbaric oxygen exposure used in this study are effective for reducing the levels of reactive oxygen species, which are overproduced during arthritis. PMID- 19779966 TI - Stress-related Epstein-Barr virus reactivation. AB - Epstein-Barr virus (EBV) remains latent in 90% of the patients following primary infection. The infection might be reactivated due to various stress factors. We, therefore, examined the levels of stress hormones (epinephrine, norepinephrine and cortisol), viral capsid antigen (VCA) immunoglobulin Ig G, VCA IgM, EBV early antigen IgG, Epstein-Barr nuclear antigen (EBNA) IgG, EBNA IgM antibody screening tests and performed EBV polymerized chain reaction (PCR) test and EBV DNA PCR in 100 draftees on their first day of recruitment and at the end of 1 month. Examination of the initial samples revealed that 94 (94%) subjects previously had EBV infection and 6 (6%) were seronegative. Second samples obtained at the end of first month showed that 7 (7.4%) reactivations occurred in 94 subjects who previously had EBV infection (P < 0.001). Two out of six (33.3%) who were initially seronegative had acute infection (P = 0.289). There was no significant difference between the median values of the levels of stress hormones in the initial and second serum and plasma samples. There was a significant difference between the rates of acute infection and reactivation among subjects with elevated cortisol and epinephrine levels in the second samples compared to subjects with normal levels (P < 0.001). No significant difference was determined between the first and second sample hormone levels of all nine subjects whose EBV DNA turned positive. Routine examinations might not reveal any specific findings since EBV infection often has an asymptomatic course. EBV reactivations should always be kept in mind in patients subject to such stressful conditions. PMID- 19779967 TI - Evaluation of a 99mTc-labeled AnnexinA5 variant for non-invasive SPECT imaging of cell death in liver, spleen and prostate. AB - PURPOSE: We investigate radio-labeling and pharmacokinetics of a new AnnexinA5 variant (HYNIC-cys-AnxA5) and then assess its utility for the non-invasive detection of cell death in liver, spleen and prostate. METHODS: AnnexinA5 binds to phosphatidylserine expressed on the surface of apoptotic and necrotic cells. Contrary to other AnnexinA5 variants, the new cys-AnxA5 allows for site-specific conjugation of a hydrazinonicotinamide-maleimide moiety and subsequent radio labeling with (99m)Tc at a position not involved in the AnxA5-phosphatidylserine interaction. Distribution of (99m)Tc-HYNIC-cys-AnxA5 was studied in rats, both invasively and via SPECT/CT. Cycloheximide was used to induce cell death in liver and spleen, whereas apoptosis in the prostate was induced by castration. RESULTS: HYNIC-cys-AnxA5 was efficiently and reproducibly labeled with (99m)Tc. Blood clearance of radioactivity after iv-injection was adequately described by a two compartment model, the renal cortex representing the main site of accumulation. Cycloheximide treatment resulted in increased accumulation of intravenous injected (99m)Tc-HYNIC-cys-AnxA5 in liver and spleen over controls, which correlated well with TUNEL staining for cell death in corresponding tissue sections. However, the increase in TUNEL-positive prostate epithelial cells observed following castration was not paralleled by greater (99m)Tc-HYNIC-cys AnxA5 accumulation. CONCLUSION: (99m)Tc-HYNIC-cys-AnxA5 appears a suitable tracer for assessment of cell death in liver and spleen, but not prostate. PMID- 19779968 TI - Silibinin suppresses spontaneous tumorigenesis in APC min/+ mouse model by modulating beta-catenin pathway. AB - PURPOSE: Here we assessed whether silibinin, a nontoxic chemopreventive agent, inhibits spontaneous intestinal tumorigenesis in APC ( min/+) mouse model, a genetically predisposed animal model of human familial adenomatous polyposis (FAP). MATERIALS AND METHODS: Six-week-old APC (min/+) mice were divided into four groups and orally gavaged with 0.2 ml vehicle, or 250, 500 and 750 mg silibinin/kg body weight in 0.2 ml vehicle for five days/week. After 6 weeks, polyp burden was analyzed and tissues examined for molecular alterations. RESULTS: Silibinin treatments decreased total number of intestinal polyps by 34% (P < 0.01), 42% (P < 0.01) and 55% (P < 0.001), respectively. Immunohistochemical analysis showed that silibinin dose-dependently decreases (P < 0.001) proliferation and induces (P < 0.001) apoptosis only in intestinal polyps without any considerable effects on normal crypt-villi in APC (min/+) or wild-type mice. Further analysis of polyps showed that silibinin decreases beta-catenin, cyclin D1, c-Myc and phospho-glycogen synthase kinase-3beta expression. Silibinin treatment also decreased phospho-Akt, cyclooxygenase-2, inducible nitric oxide synthase, nitrotyrosine and nitrite levels in polyps, the well-known mediators of intestinal/colon carcinogenesis. CONCLUSION: Together, these results establish silibinin efficacy in a well-established genetic model of FAP, APC (min/+) mouse, and suggest that this natural agent modulates various molecular pathways including beta-catenin in its overall chemopreventive efficacy against intestinal carcinogenesis. PMID- 19779969 TI - Grandmothers as gems of genetic wisdom: exploring South African traditional beliefs about the causes of childhood genetic disorders. AB - With its diverse cultural and linguistic profile, South Africa provides a unique context to explore contextual influences on the process of genetic counseling. Prior research suggests intergenerational differences regarding models of causation which influence treatment-seeking paths. This pilot study therefore aimed to explore South African traditional beliefs regarding common childhood genetic disorders. Three focus groups were conducted with fifteen grandmothers from different cultural backgrounds in an urban community. Questions pertained to the role of the grandmother, traditional beliefs regarding causes of genetic disorders, explanations of heredity, and prevention and management of genetic disorders. Results indicate a variety of cultural explanations for causes of childhood genetic disorders. These causes can be classified into categories related to lifestyle, behavior, social issues, culture, religion, genetic, and familial causes. Prevention and treatment issues are also highlighted. These findings have implications for genetic counseling practice, which needs to include a greater focus on cultural issues. PMID- 19779971 TI - The DSM diagnostic criteria for paraphilia not otherwise specified. AB - The category of "Not Otherwise Specified" (NOS) for DSM-based psychiatric diagnosis has typically retained diagnoses whose rarity, empirical criterion validation or symptomatic expression has been insufficient to be codified. This article reviews the literature on Telephone Scatologia, Necrophilia, Zoophilia, Urophilia, Coprophilia, and Partialism. Based on extant data, no changes are suggested except for the status of Partialism. Partialism, sexual arousal characterized by "an exclusive focus on part of the body," had historically been subsumed as a type of Fetishism until the advent of DSM-III-R. The rationale for considering the removal of Partialism from Paraphilia NOS and its reintegration as a specifier for Fetishism is discussed here and in a companion review on the DSM diagnostic criteria for fetishism (Kafka, 2009). In the DSM-IV and DSM-IV-TR, the essential features of a Paraphilia are recurrent, intense sexually arousing fantasies, sexual urges or behaviors generally involving nonhuman objects, the suffering or humiliation of oneself or one's partner, or children or other nonconsenting persons that occur over a period of at least 6 months (Criterion A). Given consideration for the erotic focus of Partialism and Autoerotic Asphyxia, amending the operational criteria for Paraphilia should be considered to include an atypical focus involving human subjects (self or others). PMID- 19779970 TI - Perceptions of the concept of mutation among family members of patients receiving outpatient genetic services and university students. AB - Our objectives were to investigate: (1) relationships between perceptions of various terms regarding mutation and the depth of knowledge regarding mutation among family members of patients receiving genetic outpatient services, and (2) differences in perceptions of the term "gene mutation" for family members versus university students. Fifty-eight family members and 178 university students responded to two questionnaires: Impressions regarding the term, and Knowledge about the concept of mutation. Factor analyses were conducted to determine the factor structure of ratings of the terms, and two-way analyses of variance [(1)Term, (2)Group x Knowledge] were conducted to examine differences in perceptions of the terms as measured by scores for each extracted factor. Family members had a significantly more negative perception of the term "gene mutation" than "gene change" and a less negative perception of the term "gene mutation" than "gene lesion"; they had significantly more negative perceptions of the term "gene mutation" than did university students. PMID- 19779974 TI - Generativity and the U.S. Roman Catholic bishops' responses to priests' sexual abuse of minors. AB - In this article, Erik Erikson's and subsequent researchers' ideas on generativity are applied to "the clerical abuse crisis," in which 111 U.S. Roman Catholic bishops protected priests rather than safeguard children. The goal was to discover what psychological dispositions led bishops to act in the manner they did. A case is made that pre-existing tendencies coupled with an all-male, celibate environment and formation indoctrination led to deficits in psychological development, moral judgment and leadership capacity, revealing an Episcopal subculture characterized by pseudo-speciation and authoritism. PMID- 19779973 TI - Intestinal ischemic preconditioning after ischemia/reperfusion injury in rat intestine: profiling global gene expression patterns. AB - OBJECTIVE: Intestinal ischemia/reperfusion (IR) injury involves activation of inflammatory mediators, mucosal necrosis, ileus, and alteration in a variety of gene products. Ischemic preconditioning (IPC) reduced all the effects of intestinal injury seen in IR. In an effort to investigate the molecular mechanisms responsible for the protective effects afforded by IPC, we sought to characterize the global gene expression pattern in rats subjected to IPC in the setting of IR injury. METHODS: Rats were randomized into five groups: (1) Sham, (2) IPC only (3) IR, (4) Early IPC + IR (IPC --> IR), and (5) Late IPC + IR (IPC -> 24 h --> IR). At 6 h after reperfusion, ileum was harvested for total RNA isolation, pooled, and analyzed on complementary DNA (cDNA) microarrays with validation using real-time polymerase chain reaction (PCR). Significance Analysis of Microarray (SAM) software was used to determine statistically significant changes in gene expression. RESULTS: Early IPC + IR had 5,167 induced and 4 repressed genes compared with the other groups. SAM analysis revealed 474 out of 10,000 genes differentially expressed among the groups. Early and Late IPC + IR had more genes involved in redox hemostasis, the immune/inflammatory response, and apoptosis than either the IPC only or IR alone groups. CONCLUSION: The transcriptional profile suggests that IPC exerts its protective effects by regulating the gene response to injury in the intestine. PMID- 19779975 TI - Ethical dilemmas and ethical competence in the daily work of research nurses. AB - In spite of the growing interest in nursing ethics, few studies have focused on ethical dilemmas experienced by nurses working with clinical studies as 'research nurses'. The aim of the present study was to describe and explore ethical dilemmas that Swedish research nurses experience in their day-to-day work. In a qualitative study a purposeful sample of six research nurses from five wards of differing disciplines in four Swedish hospitals was interviewed. The analysis displayed several examples of ethical dilemmas, primarily tensions between the nurses' obligations to the study and to the patients involved. A guiding moral principle for the nurses was patient-centeredness, where the interest of research must not override the interest of the patient. In situations where tensions between research and patient interests occurred, and doctors and nurses disagreed upon the judgement, the nurses sometimes chose to follow the doctors' advice, and thus acted against their own moral judgment. Such situations seemed to create feelings of moral distress among the nurses. They described their profession as being 'invisible' and as lacking opportunities for ethical competence building. The conclusion is that research nurses frequently experience severe and difficult ethical dilemmas in their daily work. They need to be acknowledged as a particular profession in the health care organisation and encouraged to develop their specific ethical competence. PMID- 19779976 TI - Combined student ratings and self-assessment provide useful feedback for clinical teachers. AB - Many evaluation instruments have been developed to provide feedback to physicians on their clinical teaching but written feedback alone is not always effective. We explored whether feedback effectiveness improved when teachers' self-assessment was added to written feedback based on student ratings. 37 physicians (10 residents, 27 attending physicians) from different specialties (Internal Medicine, Surgery, Obstetrics/Gynecology, Pediatrics, Neurology, Dermatology, Ophthalmology, ENT, and Psychiatry) were invited to fill out a self-assessment questionnaire on their teaching skills. Students completed an almost identical questionnaire to evaluate the same teachers based on their experiences during clerkships. After receiving written feedback incorporating their self-assessment and the student ratings, the teachers indicated their perceptions of the self assessment exercise and the written feedback in a questionnaire (five-point Likert scale items) and next, in more detail, in semi-structured interviews with a purposive sample of 12 of the participating teachers. 25 physicians participated (67%). The results showed that self-assessment and student feedback were both perceived as useful (3.7, SD 1.0) but the latter was considered more effective. The physicians we interviewed considered the combination of self assessment with student ratings more effective than either self-assessment or written feedback alone. Notably, discrepancies between student ratings and self assessment were deemed a strong incentive for change. We conclude that self assessment can be a useful tool to stimulate improvement of clinical teaching when it is combined with written feedback based on student ratings. Future research among larger groups is needed to confirm our findings and examine whether these combined tools actually lead to improved teaching. PMID- 19779977 TI - Reproducibility and accuracy of automated measurement for dynamic arterial lumen area by cardiovascular magnetic resonance. AB - Bright blood cine images acquired using magnetic resonance imaging contain simple contrast that is tractable to automated analysis, which can be used to derive a measure of arterial compliance that is known to correlate with disease severity. The purpose of this work was to evaluate whether automated methods could be used reliably on a clinically relevant population, and to assess the precision of these measurements so that it could be compared with expert manual assessment. In this paper we apply an algorithm similar to that used by Krug et al., and the exact processing steps are described in detail to allowing easy reproduction of our methods. Phantoms of different sizes have been assessed and the MRI measurements are found to correlate well (r = 0.9998) with physical measurement. Reproducibility assessment was performed on 33 CAD subjects in three anatomical locations along the aorta. Six normal volunteers and ten patients with more severe aortic plaques were investigated to assess reproducibility and sensitivity to pathological changes, respectively. The performance was also assessed on carotid vessels in 40 patients with known arterial plaques. In the human aorta the method is found to be robust (failing in only 7% of cases, all due to clear errors with image acquisition), and to be quantifiably consistent with expert clinical measurement, but showing smaller errors than that approach [<1.21% (5.62 mm(2)) manual vs. <0.58% (2.71 mm(2)) automated, for the aortic area] and with reduced bias, and operated correctly in advanced disease. We have proved over a large number of subjects the superiority of this automated method for evaluating dynamic area changes over the Gold-standard manual approach. PMID- 19779978 TI - Actual status of adjuvant chemotherapy for non-small-cell lung cancer at one Japanese cancer center: the need for increased cooperation between medical oncologists and surgeons. AB - Adjuvant chemotherapy improves the prognosis of patients with non-small-cell lung cancer (NSCLC) treated by complete resection. At Shizuoka Cancer Center, thoracic surgeons evaluate the indications for adjuvant chemotherapy, and once a patient is judged as suitable for adjuvant chemotherapy, uracil-tegafur (UFT) is prescribed by them mainly in cases of stage IB, or the patient is referred to a medical oncologist for parenteral chemotherapy mainly in cases of stages IIA to IIIA. However, both the medical oncologists and the surgeons at our institute often encounter differences in attitudes toward adjuvant chemotherapy among them. One hundred and nine patients with NSCLC, of pathological stages IB to IIIA, who underwent complete resection at our institute, between April 2005 and June 2007, were recruited for this study. By reviewing medical charts of the patients and interviewing medical oncologists and surgeons at our institute, we mainly analyzed the differences in the judgment of the patients' suitability for adjuvant chemotherapy among surgeons and the differences in the proportion of patients who agreed to the adjuvant chemotherapy recommended by the medical oncologists. The proportion of patients judged as unsuitable for adjuvant chemotherapy by one surgeon was higher when compared with that by the other three surgeons. While all patients who were referred to two medical oncologists agreed to the adjuvant chemotherapy, few patients referred to the other medical oncologists agreed. This study revealed that there were considerable differences in whether patients consented to adjuvant chemotherapy depending on the medical oncologists that they were referred to, and suggested possible differences in the judgment of the patients' suitability for adjuvant chemotherapy among surgeons. PMID- 19779979 TI - Historical development and current status of emergency nursing in Turkey. AB - As the demand for high quality Accident and Emergency Departments and nursing staff increases throughout Turkey, the need for more specialized emergency nurse training has also increased. Although there have been a number of positive developments regarding emergency nursing standards, the general quality of emergency nurse training needs to be improved and job definitions amended to better reflect the specialist duties of emergency nurses. PMID- 19779980 TI - Effects of melatonin and phospholipid on adhesion formation and correlation with vascular endothelial growth factor expression in rats. AB - BACKGROUND: The aim of this experimental study was to investigate the effects of melatonin and phospholipid on adhesion formation and the correlation with vascular endothelial growth factor (VEGF) expression in rats. METHODS: Sixty Wistar-Albino rats were divided into four groups as sham, control and two study groups, each including 15 rats. In the sham group, laparotomy was the only procedure. Left lower parietal peritoneum was abraded after laparotomy and serosal defects formed on the cecum, ileum and right uterine horn in the study and control groups. Ringer lactate was then applied to the control group, while melatonin and phospholipid suspension were applied separately in the two study groups. Relaparotomy was performed in all groups on the 15th day to score and evaluate the adhesion formation. RESULTS: Adhesion formation was significantly lower in the sham, melatonin and phospholipid groups than in the control group (p<0.05). VEGF staining was significantly higher in the control group with adhesion areas compared to the other groups (p<0.05). When VEGF staining was compared, there was no significant difference between VEGF- stained and normal areas in the melatonin and phospholipid groups. CONCLUSION: Melatonin and phospholipid decreased the adhesion formation in an experimental adhesion model in rats. There is a correlation between adhesion severity and VEGF expression. PMID- 19779982 TI - Comparison of ePTFE graft repair with primary suturing in an experimental duodenal perforation model in rats. AB - BACKGROUND: In this experimental study, we treated peptic ulcer perforation in the first portion of the duodenum using an ePTFE (expanded polytetrafluoroethylene) soft tissue graft and compared results with primary suturing. METHODS: Wistar Albino rats were randomized into two groups. A duodenal defect of 3 mm was created in the first portion of the duodenum in all 24 rats. Macroscopic evaluation was done to determine presence of intraabdominal leakage, peritonitis, intraabdominal adhesions, and the level of adhesion, if present. The adhesion severity scoring system was used to score severity of adhesions. Histology section score criteria were used for scoring in microscopic evaluation. RESULTS: There was no statistically significant difference between the two groups in the adhesion severity scoring according to grades. However, when overall scoring was considered, a statistically significant difference was determined between the two groups (p=0.045). According to microscopic examination, there was no statistically significant difference between the two groups when classified into none to minimal cell accumulation, thin immature granulations and moderately thick granulation (p=0.089, p=0.178, p=0.755); however, there was a statistically significant difference between the two groups in the thick vascular granulation class (p=0.005). CONCLUSION: Use of the ePTFE graft method is easy, and results are comparable to those achieved with primary suturing. However, our results need further confirmation with larger series in animals and also with human studies. PMID- 19779981 TI - The renal effect of replacement fluids in controlled severe hemorrhagic shock: an experimental study. AB - BACKGROUND: This experimental study examined the effects of resuscitation with Ringer's lactate (RL), 6% hydroxyethyl starch (130/0.4-HES), and the combination of RL and HES on renal function in hemorrhagic shock (HS). METHODS: Twenty-four male New Zealand white rabbits weighing 2198-3435 g were divided at random into four groups. HS was constituted by maintaining the mean arterial blood pressure at 30 mmHg and blood lactate at >4 mM/L. Subsequently, Group 1 (control) was not resuscitated, while the study rabbits' resuscitation was initiated with RL (Group 2), HES (Group 3), or the combination of RL and HES (Group 4). RESULTS: In all groups, the serum creatinine and blood urea nitrogen (BUN) levels were observed to be within normal limits, while the lactate dehydrogenase and alpha-1 microglobulin levels statistically significantly increased when time points were compared with beginning values (p<0.05). Furthermore, cystatin-C levels were observed to be increased after the HS (p<0.05), but returned to the normal level after resuscitation in all the study groups. Interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha levels were increased in all the rabbits after HS (p<0.05), and there were no significant differences among the study groups after resuscitation (p>0.05). There were no differences in the histological imaging between the groups (p>0.05). CONCLUSION: The 6% HES (130/0.4) did not have any harmful effects on the kidney when it was used alone or in combination with crystalloid for resuscitation of HS in rabbits. PMID- 19779983 TI - The use of infection probability score and sequential organ failure assessment scoring systems in predicting mechanical ventilation requirement and duration. AB - BACKGROUND: This study examines the efficacy of two different scoring systems in predicting mechanical ventilation need (MVN) and duration (DMV) in a surgical intensive care unit (ICU). METHODS: This prospective observational study included 144 consecutive patients admitted to the ICU for more than 24 hours for whom the Sequential Organ Failure Assessment (SOFA) score and the Infection Probability Score (IPS) were calculated on admission and every 48 hours until discharge or death. Sensitivity and specificity of the two scoring systems were measured by the chi-square method. The Youden index and area under the Receiver Operating Characteristic (ROC) curve were also obtained. RESULTS: For prediction of MVN, the best cut-off points were 2.5, 3.5, 2.5 for SOFA and 10.5, 10.5, 9.5 for IPS on the day of admission (0) and days 2 and 4, respectively. For the prediction of MVN, SOFA on days 0, 2 and 4 yielded significantly better results in the area under the ROC curve and Youden index than those of IPS (p<0.05). Neither of the two scoring systems provided good discrimination in prediction of more than 3 days respiratory support under MV. CONCLUSION: For prediction of MVN, the SOFA scoring system on days 0, 2 and 4 has better accuracy than IPS. PMID- 19779984 TI - The role of the ankle brachial pressure index in the diagnosis of peripheral arterial injury. AB - BACKGROUND: Angiography is the "gold standard" diagnostic tool for patients presenting soft signs of arterial injury. To reduce the number of unnecessary angiographies, we aimed to evaluate the role of the ankle brachial pressure index (ABPI) in the diagnosis of peripheral arterial injury in extremity trauma with soft signs. METHODS: The data of 1772 patients with the suspicion of peripheral arterial injury was recorded prospectively. Two hundred eighty-three patients (16%) with any hard sign underwent immediate surgery. ABPI was calculated in 1489 patients with soft signs. Patients with ABPI <1 were evaluated by duplex ultrasonography and/or angiography, and if arterial injury was detected, the patients underwent surgery. Patients with an ABPI > or =1 were followed up conservatively. RESULTS: 1343 (90%) patients had ABPI > or =1; seven (0.5%) of them developed symptoms and signs of arterial injury and healed without morbidity. One hundred forty-six (10%) patients had ABPI <1; with DUS/angiography, arterial injury was detected in 39 of them (26.7%), and they underwent surgery. The sensitivity of ABPI <1 was 84.8%; specificity 92.6%; positive predictive value 26.7%; negative predictive value 99.5%; and overall accuracy 92.3%. CONCLUSION: ABPI excludes arterial injury in 99.5% of patients with soft signs of arterial injury and avoids unnecessary examinations in 90% of patients. In the management of extremities with soft signs, ABPI measurement should be the first-line diagnostic choice. PMID- 19779985 TI - The revised Acute Physiology and Chronic Health Evaluation System (APACHE II) is more effective than the Glasgow Coma Scale for prediction of mortality in head injured patients with systemic trauma. AB - BACKGROUND: The Glasgow Coma Scale (GCS) is popular, simple, and reliable, and provides information about the level of consciousness in trauma patients. Nevertheless, the necessity of using a more complex system than GCS has been questioned recently. The revised Acute Physiology and Chronic Health Evaluation system (APACHE II) is a physiologically based system including 12 physiological variables, and it also includes GCS. In addition, it is thought to be superior to GCS due to recognition of increasing age and significant chronic health problems, which adversely affect mortality. METHODS: This retrospective study included 266 patients (195 males, 71 females; mean age 60.5; range 14 to 87 years) with head injury associated with systemic trauma in 2003 and 2004. RESULTS: Mortality increased in the elderly group (p<0.001). Mean survival score in APACHE II was 38.0 and death score was 68.7 (p<0.001); these values in GCS were 10.4 and 6.3, respectively (p<0.001). APACHE II at the cut-off point was better than GCS in the prediction of death and survival in patients (p<0.01). The area under the receiver operating characteristic curve for sensitivity and specificity was larger in APACHE II (0.892+/-0.028) than GCS (0.862+/-0.029). CONCLUSION: For the assessment of mortality, the GCS score still provides simple, less-time consuming and effective information concerning head injury patients, especially in emergencies; however, for the prediction of mortality in multitrauma patients, APACHE II is superior to GCS since it includes the main physiologic parameters of patients. PMID- 19779986 TI - Comparison of operative and non operative management of acute appendicitis. AB - BACKGROUND: In this prospective study, operative and nonoperative management of acute appendicitis were evaluated regarding their safety and cost effectiveness. METHODS: Two hundred ninety patients presenting to our Emergency Department between March 2005 and March 2006 with acute appendicitis were included in this prospective study. Nonoperative medical therapy was performed in 107 patients (Group 1), and 183 patients were treated surgically (Group 2). Routine follow-up controls were done on the 10th day, at the 3rd and 6th months and at the first year after discharge in Group 1. Both groups were compared regarding age, gender, mean hospital stay, modified Alvarado score, morbidity, mortality, and cost effectiveness. RESULTS: The male/female ratio of Groups 1 and 2 were 65/42 (mean age: 30.98+/-1.30) and 125/58 (mean age: 26.25+/-0.79), respectively. In Group 1, 19 patients were operated. Operation indications were resistance to therapy, patient's request, and operation in another hospital. Although the mean hospital stay of Group 1 was statistically significantly longer than Group 2, the mean cost of the therapy was $559 in Group 2 and $433 in Group 1. Morbidity rates were similar, with no mortality in either group. CONCLUSION: With its high success rate and cost effectiveness, medical treatment seems to be a good alternative to the gold standard therapy of surgery in management of acute appendicitis. PMID- 19779987 TI - Outcome of traumatic hip dislocation. AB - BACKGROUND: This retrospective study was carried out to identify prognostic factors that can predict a better long-term outcome. METHODS: Between 1 January 1993 and 31 December 2004, 97 patients were treated at King Fahd University Hospital, AlKhobar. Fifty-eight patients were analyzed. Hips were evaluated on functional basis as per the classification of Merle d'Aubigne. RESULTS: There were 52 males and 6 females, with a mean age of 29.6+/-9.8 (18-57) years and follow-up of 59.5+/-18.8 (24-120) months. In 43 patients, the dislocations were due to road traffic accidents. In 57 patients, closed reduction was done, while one patient required open reduction. Traction was applied for 4.71+/-1.07 weeks on average. Forty-three patients had excellent results. Patients with only a three-week immobilization period fared badly. CONCLUSION: Our study indicates that good results in traumatic hip dislocation can be achieved with early reduction of dislocation and immobilization for at least four weeks. PMID- 19779988 TI - Management of duodenal injury: our experience and the value of tube duodenostomy. AB - BACKGROUND: The aim of this study was to report our experience with duodenal injuries and determine if primary repair and/or tube duodenostomy are valid options for definitive operative repair of severe duodenal injuries. METHODS: Sixty-seven patients who underwent surgery for duodenal injuries were evaluated. Management of duodenal injury was classified as primary repair and tube decompression. RESULTS: Fifty-nine patients were injured by a penetrating mechanism, and eight were injured by blunt mechanism. The most common injury site was in the second portion of the duodenum. There were no significant differences between the two groups with respect to morbidity and mortality rate. In 35 patients without morbidity, the mean length of hospital stay was 18.53+/-1.85 days in the tube duodenostomy group and 11.45+/-1.92 days in the primary repair group, and the difference was statistically significant. In the 32 patients with morbidity, the mean length of hospital stay was 47.05+/-10.46 days in the tube duodenostomy group and 49.86+/-10.86 days in primary repair group, but there was no statistically significant difference between the groups. CONCLUSION: Primary repair is suitable in the vast majority of duodenal injuries; tube duodenostomy increases the length of hospital stay and does not improve clinical outcome. PMID- 19779989 TI - [The needs of the critical patients' relatives in the emergency department and how they are met]. AB - BACKGROUND: This study was designed as a definitive study to determine the needs of the critical patient's family and whether or not these needs are met. METHODS: The study was conducted in the emergency departments (EDs) of a University and a state hospital between February-May 2007 with the families of 353 critical patients. The data was collected by face to face interview technique using the Needs of the Critically Ill Patients' Family Members in Emergency Department Scale and uestionnaires and a personal information form. RESULTS: It was determined that the patient's family valued their right and need to be informed of the patient's status and take part in their care more than their own personal needs. In a more general perspective, nine of the 10 most frequently stated needs regarded communication. It was also found that the needs to be provided by the ED staff were listed as the most important or important. CONCLUSION: Defining the needs of the family of critical patients in the ED may help raise awareness of the health care providers about this issue, thereby helping to improve the service. Support of patients' relatives in regards to their needs would increase satisfaction of the patients' relatives and the quality of care in the ED. PMID- 19779990 TI - Knowledge and attitude of Turkish parents regarding car safety seats for children. AB - BACKGROUND: One of the major causes of death among children younger than 15 years is vehicular injury. Car safety seats protect children in a crash if they are used correctly. The objective of this study was to assess the level of parental knowledge and their attitudes regarding car safety seats. METHODS: The survey was conducted in May and June 2007 at Bakirkoy Dr. Sadi Konuk Research-Training Hospital. Randomly selected parents were asked to complete an anonymous self administered questionnaire after providing informed consent. Five hundred thirty two Turkish parents were sampled. RESULTS: Twenty-eight percent of the parents did not know what a car safety seat was. While 20% of parents reported using a car safety seat, only 10% used them correctly. Car safety seat use was correlated with higher socioeconomic status. CONCLUSION: Increased education of parents regarding the proper use of child safety seats can protect children from potentially fatal injuries. Health care professionals are obligated to give information to parents regarding car safety seats and their proper use. This study should alert planners and policy makers regarding the need to implement educational prevention programs concerning car safety for children in Turkey. PMID- 19779991 TI - Experience with mass casualties in a subcontinent earthquake. AB - BACKGROUND: A massive earthquake struck North Pakistan on 8 October 2005. The objective of this study was to evaluate the types of injuries and the procedures carried out on the admitted casualties, and to present recommendations based on these experiences for improvement in disaster preparedness and management. This is a descriptive study conducted at the Military Hospital, Rawalpindi. METHODS: Inclusion criteria included all patients who required admission for treatment. Patients who had minor injuries not requiring indoor treatment and those who were dead on arrival were excluded from this study. The files of admitted patients were analyzed for type of injuries, procedures performed, complications, and causes of death. RESULTS: The total number of patients received was 1698, of which 862 (50.8%) were admitted. A total of 2289 operations were performed including 1046 (45.7%) major interventions. Sixteen (1.5%) amputations were necessary. Seventeen deaths (1.9%) occurred in hospital, while 76 dead bodies were received. CONCLUSION: After the initial days of life- and limb saving, it is important to quickly divide the manpower into teams with a major emphasis on plastic, orthopedics and spinal surgery, to start shifts and to utilize the volunteer manpower early and judiciously. Prevention of tetanus is essential. PMID- 19779992 TI - [Tracheobronchial foreign body aspirations]. AB - BACKGROUND: Determining and removing aspirated foreign bodies from the airways is important in preventing complications. Foreign body aspiration is usually seen in childhood but can occur at any age. Complete or partial obstruction of the main bronchial system produces different findings, and death can result if emergency treatment is not given. We analyzed patients treated for foreign body aspiration in our clinic. METHODS: In this report, 96 cases were examined in our clinic for aspiration of foreign bodies between 1995 and 2007. Patients were aged between 10 months and 70 years. Most cases were in the pediatric age group. Sixty-two (62%) patients were female and 34 (38%) were male. The period between aspiration and treatment varied from 1 hour to 10 years. RESULTS: Bronchoscopies were established with controlled ventilation under general anesthesia. The foreign bodies were seen and extracted in 83 patients (86.5%) using foreign body forceps. Thirteen (13.5%) cases underwent thoracotomy. In the late period, pulmonary resection was performed in 5 (5.2%) cases because of irreversible pathology. CONCLUSION: This study reports that foreign body aspiration is important in adults as well as in children, and suspicion and history are the most important diagnostic criteria. Radiologic findings with physical examination are of great importance in the evaluation of these patients. PMID- 19779993 TI - Water park injuries. AB - BACKGROUND: The purpose of this study was to identify water park injuries, particularly injuries related to waterslides. METHODS: This prospective observational study was carried out between May 2005 and September 2006 in a university hospital emergency clinic, which has 50,000 annual visits. The study form, including patient demographics, types and mechanisms of injuries and the final diagnoses, was completed for all patients. A total of 73 patients were enrolled into the study. The mean age of the patients was 23.92+/-15.05 and 48 patients (65.8%) were male. RESULTS: The mechanisms of injury were as follows: 23 patients (31.5%) were injured on waterslides, 16 (21.9%) were injured in pools and 34 (46.6%) were injured by slipping and falling on the wet surfaces. After the emergency department evaluations, 15 patients (20.5%) were diagnosed to have spinal trauma, 16 (21.9%) head trauma, 15 (20.5%) maxillofacial trauma, and 30 (41%) other injuries. CONCLUSION: In water park injuries, while children have especially head and maxillofacial trauma, extremity and spinal injuries are more frequent in the adult group. Unless sufficient and required safety precautions are maintained during water park activities, fatal injuries may occur. PMID- 19779994 TI - Tracheo-innominate artery fistula: two cases. AB - Tracheo-innominate artery fistula (TIF) is a rare but catastrophic and almost always fatal complication of tracheostomy. Two surgically intervened TIF cases are presented. In both cases, innominate artery ligation was performed. The first patient died due to respiratory failure 10 hours after operation. The second patient was discharged with normal neurologic examination on the 12th day of operation. Since the mechanism of injury leading to TIF is pressure necrosis, it is of vital importance to be aware of the predisposing factors and to take preventive measures. On the other hand, only patients treated with emergency surgery tend to survive. PMID- 19779995 TI - Torsion of an appendix epiploica present at the vermiform appendix: a rare cause of acute abdomen. AB - An extremely rare case of torsion of an appendix epiploica attached to the vermiform appendix is reported in a 57-year-old male who presented with acute abdominal pain and tender right inguinal fossa. An infarcted appendix epiploica was seen attached near the tip of an otherwise unremarkable vermiform appendix through a narrow stalk. The histological examination revealed lobulated fibrofatty tissue showing congestion, acute inflammation and fat necrosis. The appendix was otherwise unremarkable. PMID- 19779996 TI - [Soft tissue reconstruction of the foot with free rectus abdominis muscle flap: case report]. AB - Major soft tissue defects of the foot usually require free tissue transfer for successful reconstruction. A 29-year-old man who injured his left foot in a mine explosion was admitted to Sarikamis Military Hospital. Initial examination showed an extreme crush injury including soft tissue and bone structures of the lateral part of the foot. All necrotic tissues were extensively debrided and the soft tissue defect was reconstructed with a free rectus abdominis muscle flap and full thickness skin graft one week after the injury. The operation outcome was successful. After the rehabilitation period, the patient returned to a normal social life with minimal difficulties. The aims of this report were to alert reconstructive microsurgeons to the possible difficulties that can be encountered during free tissue transfer in small hospitals remote from city centers and to propose some possible solutions. PMID- 19779997 TI - Delayed presentation of a traumatic brachial artery pseudoaneurysm. AB - Delayed presentation of a brachial artery pseudoaneurysm following penetrating trauma is infrequently reported. We report the case of a 23-year-old male who presented three months following a penetrating trauma to his antecubital fossa with a sudden exacerbation of swelling and tenderness of his elbow. Doppler ultrasound and computed tomography arteriography confirmed the presence of a large pseudoaneurysm. Surgical reconstruction was performed using the long saphenous vein as an interposition vein graft, restoring normal arterial circulation. PMID- 19779998 TI - Intercondylar fracture of the distal humerus in youth: two case reports. AB - Intercondylar fracture of the distal humerus in youth is an extremely rare injury. Three cases have been reported in the literature to date. We describe two cases, aged 15 and 14 years, both of whom were boys. The stability in this injury allowed non-operative treatment and a favorable outcome. PMID- 19779999 TI - Etiology of temporomandibular disorder pain. AB - Pain in the masticatory muscles and temporomandibular joint is the main symptom of temporomandibular disorders. The etiology of temporomandibular disorder pain is multifactorial. Several studies have reported that there are predisposing, initiating and aggravating factors contributing to this disorder. Although factors such as trauma, occlusal discrepancies, stress, parafunctions, hypermobility, age, gender, and heredity have been implicated in the maintenance of temporomandibular disorder pain, there are still controversies regarding the actual etiology. This review will summarize the past and current concepts related to the etiology of arthrogenic- and myogenic-originated temporomandibular pain. PMID- 19780000 TI - The efficacy of topical thiocolchicoside (Muscoril) in the treatment of acute cervical myofascial pain syndrome: a single-blind, randomized, prospective, phase IV clinical study. AB - OBJECTIVES: Myofascial pain syndrome is a disorder characterized by hypersensitive sites called trigger points at one or more muscles and/or connective tissue, leading to pain, muscle spasm, sensitivity, rigor, limitation of movement, weakness, and rarely, autonomic dysfunction. Various treatment methods have been used in the treatment of myofascial pain syndrome. Among these, stretch and spray technique, trigger point injection, dry needling, pharmacological agents, and physical therapy modalities have been proven effective. METHODS: Sixty-five patients with acute myofascial pain syndrome were recruited into the study. Patients were randomized into three groups. The first group received thiocolchicoside ointment onto the trigger points, the second group received 8 mg thiocolchicoside intramuscular injection to the trigger points, and the third group received both treatments. Treatment was applied for 5 consecutive days. Algometric and goniometric measurements and pain severity assessments with visual analog scale (VAS) were repeated on the first, third, and fifth days of the treatment. RESULTS: Pain severity measured with VAS significantly improved after the first day in the mono-therapy groups and after the third day in all groups. While significant improvement was observed in all three groups in right lateral flexion measurements, no significant changes were observed in the combined treatment group in left lateral flexion measurements. CONCLUSION: Thiocolchicoside can be used in the treatment of myofascial pain syndrome. The ointment form may be a good alternative, particularly in patients who cannot receive injections. PMID- 19780001 TI - [Comparison of non-invasive and invasive techniques in the treatment of patients with myofascial pain syndrome]. AB - OBJECTIVES: We compared in this study the efficiency of non-invasive techniques including transcutaneous electrical nerve stimulation (TENS) and laser treatments with invasive techniques including lidocaine and botulinum toxin-A injection in patients with myofascial pain syndrome (MPS). METHODS: One hundred patients who admitted to Firat University Hospital Pain Department and who were diagnosed as MPS were included in the study. Patients were randomized into four groups of 25 patients each. Sixty sessions of TENS and 20 sessions of laser treatments were performed in the first and second groups, respectively. Lidocaine and botulinum toxin-A were injected in the third and fourth groups, respectively. 2 ml (20 mg) 1% lidocaine was injected in each patient twice a week for one month in Group III. 25 U (0.5 ml) of botulinum toxin-A was injected in each patient only once in Group IV. Pain was evaluated with visual analogue scale (VAS), palpable muscle spasm scoring (PMSS) and anesthesiometer at baseline, 15, 30 and 45 days. RESULTS: There were no statistically significant differences between the groups with respect to age, sex and education level. Pain control was statistically better in Group IV compared with the other groups with respect to VAS, PMSS and anesthesiometer scores. CONCLUSION: Botulinum toxin-A injection provided better pain control when compared to trigger point injection with lidocaine and non invasive techniques including TENS and laser treatments. PMID- 19780002 TI - Effects of preoperative lornoxicam versus tramadol on postoperative pain and adverse effects in adult tonsillectomy patients. AB - OBJECTIVES: This study assessed the efficacy and adverse effects of preoperatively administered lornoxicam versus tramadol in adults, for post tonsillectomy pain. METHODS: This prospective, double blind, randomized, clinical research was performed in the Ear, Nose and Throat Surgery Room in the Department of Anesthesia and Reanimation, Gazi University Faculty of Medicine. Forty American Society of Anesthesiologists (ASA) status I-II patients of both gender, aged 18-55 years, were included. RESULTS: Tonsillectomy patients were divided into two groups: Those in Group L received 8 mg lornoxicam and in Group T received 50 mg tramadol intravenously just before induction of general anesthesia. Induction and maintenance of anesthesia (propofol, atracurium, nitrous oxide and sevoflurane) were standardized. Heart rate and systolic and diastolic arterial pressure data were monitored during the anesthesia. Intra operative bleeding was scored by the same operator using a 5-point scale at the end of the surgery. Postoperative pain on swallowing was scored by a blinded anesthesiologist using Verbal Rating Scale (VRS) on arrival in the Post Anesthesia Care Unit (T(0)), at 30 min (T(1)), 1h (T(2)), 2h (T(3)), 3h (T(4)), 4h (T(5)), 5h (T(6)), and 6h (T(7)) thereafter. During the first postoperative 6 hours, when VRS >/=2, 1mg.kg(-1) im meperidine was used as a rescue analgesic. Adverse effects in the postoperative 6h period were noted. T(1) and T(2) pain scores in Group T were higher than in Group L (p=0.049, p=0.007, respectively). The number of patients requiring rescue analgesics during the first 6 hours in Group L was lower than in Group T. Nausea-vomiting, bleeding and postoperative hemorrhage values were similar between Group L and Group T. CONCLUSION: Preoperative 8 mg lornoxicam was more effective than 50 mg tramadol with respect to early postoperative tonsillectomy pain in adult patients, and side effects were similar. PMID- 19780003 TI - Spondylodiscitis caused by sudden onset back pain following transrectal ultrasonography-guided prostate biopsy: a case report. AB - Spondylodiscitis is a serious and important clinical problem that can occur after iatrogenic interventions and should be kept in mind. Spondylodiscitis after transrectal ultrasonography (TRUS)-guided prostate biopsy is an extremely rare complication. A 70-year-old patient who presented with severe back pain, intermittent high fever, loss of appetite, and fatigue following TRUS-guided prostate biopsy was diagnosed with thoracic spondylodiscitis (T6-7) after clinical, laboratory and radiological assessments and he was treated surgically. We present this case to remind medical professionals to keep spondylodiscitis in mind in the presence of sudden onset back and low-back pain, since TRUS-guided prostate biopsy is a frequently used procedure. PMID- 19780004 TI - Ultrasound-guided infraclavicular block supplementation is possible during hand surgery. PMID- 19780005 TI - [Chemonucleolysis and intradiscal electrothermal therapy: what is the current evidence?]. AB - We evaluated the efficacy and safety of chemonucleolysis and intradiscal electrothermal therapy (IDET) on the basis of the data presented in recently published papers with respect to pain relief, function, and complication rates. Detailed searches for English and German articles published between 2003 and 2008 were performed in a number of electronic databases. Further publications were identified by manual search. For summarizing the evidence, we considered only systematic reviews and controlled studies. The internal validity of reviews and studies was judged by two authors independently. Data extraction was performed by one author, and the extracted data was checked for completeness and correctness by a second author. The evidence of the efficacy of chemonucleolysis using chymopapain or collagenase is summarized in two recent, high-quality systematic reviews. We found 5 controlled studies evaluating nucleolysis using an oxygen ozone mixture (O (2)O (3)-nucleolysis). Some of those studies were of limited methodological quality, but all showed the efficacy of O (2)O (3)-nucleolysis in comparison to microdiscectomy or the use of alternative substances. There is hardly any data regarding O (2)O (3)-nucleolysis complications. Regarding IDET, the authors of the 6 identified systematic reviews come to different conclusions about the efficacy of the procedure. The results of the 3 included controlled IDET studies, of which 2 are of high methodological quality, are also conflicting. The complication rates range from 0 to 15 %. In summary, the evidence of efficacy is presently more compelling for chemonucleolysis than for IDET. This may also be because indications for chemonucleolysis are more firmly established. However, safety aspects should be better evaluated and presented in the literature. PMID- 19780006 TI - [Evaluation of a liquid embolization agent (Onyx) for transcatheter embolization for renal vascular lesions]. AB - PURPOSE: To evaluate the therapeutic outcome after endovascular treatment of renal vascular lesions using the liquid embolization agent, Onyx. MATERIALS AND METHODS: Between 2004 and 2008 nine patients with renal vascular lesions were treated with transcatheter arterial embolization using Onyx. The renal vascular lesions consisted of 4 AV-fistulas, a pseudoaneurysm, bleeding from a single subsegmental artery, diffuse parenchymal bleeding after trauma, septic embolizations and multiple aneurysms in endocarditis. All patients underwent selective angiography of the renal artery. A dimethyl sulfoxide (DMSO)-compatible microcatheter was used and Onyx was injected. The technical and clinical success rate, examination time and procedure-related complications were documented. RESULTS: The overall technical and clinical success rate was 100 %. One patient had to be treated twice due to recurrent bleeding after an accidental puncture with a drainage catheter. No loss of viable renal tissue occurred in 4 cases. In 4 patients mild to moderate parenchyma loss was noted. In one patient having diffuse renal bleeding, occlusion of the main renal artery was performed. No procedure-related complications were noted. The mean examination time was 16.17 min when treating with Onyx alone and 60 min when using a combination of Onyx and coils. Within an average follow-up period of 21 months, no recurrent renal bleeding or recurrent AV-fistulas occurred. CONCLUSION: Onyx is an effective embolization agent for the treatment of renal vascular lesions. It allows controlled and quick application with low complication rates and a short examination time as a standalone agent or in combination with coils. PMID- 19780007 TI - Prevalence of nuclear cataract in Swiss veal calves and its possible association with mobile telephone antenna base stations. AB - The purpose of this study was to valuate the prevalence of nuclear cataract in veal calves and to elucidate a possible impact by mobile phone base stations (MPBS). For this experiment a cohort study was conducted. A follow-up of the geographical location of each dam and its calf from conception through the fetal period up to slaughter was performed. The first trimester of gestation (organogenesis) was particularly emphasized. The activities of selected protective antioxidants (superoxide dismutase, catalase, glutathione peroxidase [GPx]) were assessed in aqueous humor of the eye to evaluate the redox status. Of 253 calves, 79 (32 %) had various degrees of nuclear cataract, but only 9 (3.6 %) calves had severe nuclear cataract. Results demonstrate a relation between the location of veals calves with nuclear cataracts in the first trimester of gestation and the strength of antennas. The number of antennas within 100 to 199 meters was associated with oxidative stress and there was an association between oxidative stress and the distance to the nearest MPBS. Oxidative stress was increased in eyes with cataract (OR per kilometer: 0.80, confidence interval 95 % 0.62,0.93). It has not been shown that the antennas actually affected stress. Hosmer-Lemeshow statistics showed an accuracy of 100 % in negative cases with low radiation, and only 11.11 % accuracy in positive cases with high radiation. This reflects, that there are a lot of other possibilities for nuclear cataract beside MPBS. Further studies on the influence of electromagnetic fields during embryonic development animal or person at risk are indicated. PMID- 19780008 TI - [The dilemma with Lyme borreliosis in the dog with particular consideration of "Lyme nephritis"]. AB - Lyme borreliosis is the most commonly reported tick-transmitted infectious disease in the northern hemisphere in humans. Certain diseases are associated with Lyme borreliosis in the dog as well, but only intermittent lameness with articular swelling, lymphadenomegaly, fever, and anorexia were experimentally documented. Lyme borreliosis is considered an over diagnosed disease. The term "Lyme nephritis" was introduced for dogs with characteristic renal lesions and typical clinical signs, in which antibodies against Borrelia burgdorferi were found. Different studies have been aimed at showing a relation between renal disease and B. burgdorferi infection; however, this was not possible until now. Reasons for the uncertainty of the effects of B. burgdorferi in the dog are the high prevalence of circulating antibodies, the unspecific clinical picture and the inaccuracy of serologic tests. PMID- 19780009 TI - [Occurrence of Trichinella spp. in wild boar in Switzerland]. AB - Trichinellosis is a worldwide occurring zoonosis caused by the intracellular nematode Trichinella spp. One of the main infection sources in Europe is raw or undercooked meat from wild boar. Trichinella britovi is prevalent in wild carnivores in Switzerland, thus a possible inclusion of wild boar in this wildlife cycle cannot be excluded. In order to assess the prevalence of Trichinella infection in wild boar, we tested 1,458 animals with both parasitological and serological methods. In none of the animals Trichinella larvae could be recovered by the artificial digestion method (prevalence of larvae: 0 %; 95 % CI 0.0 - 0.3). Antibodies in meat juice were detected in 57 animals using a standardized E/S-Ag-ELISA. However, in the confirmatory westernblot, only 3 animals remained seropositive (seroprevalence: 0.2 %; 95 % CI 0.07 %-0.60 %). The occurrence of wild boar positive for anti-Trichinella antibodies indicates that meat inspection for Trichinella-larvae in this species is important to prevent human infections. PMID- 19780010 TI - [Ultrasonographic findings and treatment in a cow with a haemangiosarcoma of the urinary bladder]. AB - A 4.5-year-old Swiss Braunvieh cow was presented to the Department of Farm Animals, University of Zurich, because of severe haematuria. All other clinical findings were within normal ranges. Transrectal ultrasonography revealed a 1 cm x 1 cm echogenic, irregularly-shaped, raised mass in the wall of the urinary bladder. Endoscopy identified the mass as a proliferation, approximately 0.5 cm in diameter, which was bleeding continuously. Thermocautery of the bleeding site was carried out twice five days apart via endoscopy. Clinical signs resolved for the remainder of the cow's life; she was slaughtered 15 months later because of infertility. Histological examination of the mass revealed a haemangiosarcoma. PMID- 19780011 TI - [Megaesophagus secondary to an esophageal leiomyoma and concurrent esophagitis]. AB - A 13-year-old male intact Golden Retriever was presented for chronic regurgitation and vomitus. The only clinical abnormality was halitosis, a neurological examination was normal. Thoracic radiography revealed a moderately distended, air-filled esophagus and a presumptive diagnosis of idiopathic megaesophagus was made. No other disorder causing abnormal esophageal motor function could be identified. As supportive and anticholinergic therapy failed to improve the dogs condition and ongoing regurgitation worsened, owners opted for euthanasia. Postmortem examination revealed a small (1.5 cm diameter) mass in the terminal esophagus. Microscopically a leio-myoma with mild multifocal mixed-cell esophagitis was diagnosed. This report illustrates how a potentially curable disease such as leiomyoma can clinically mimic acquired idiopathic megaesophagus and emphasizes that additional diagnostic procedures (contrast study, esophagoscopy) can be indicated in individual cases. PMID- 19780016 TI - ["What can I still do, what may I still do?"--ambivalent lived experiences and instruction need of patients in the early period after renal transplantation]. AB - With a share of approximately 27 % of renal replacement therapies renal transplantation (RTx) has by now become a well-established alternative to dialysis. However, little is known ab-out how patients experience their new situation shortly after the RTx and about their instruction and education needs. The purpose of this phenomenological study is to describe the patients' experiences after an RTx before being discharged from the inpatient ward or from hospital and to identify topics for patient instruction and education. The method included ten semi-structured interviews with patients after a first time allogenic renal transplantation, with stable transplant function, who still received in-patient treatment. Recorded, transcribed interviews were analyzed using Colaizzi's method. The essential structure of the experiences of patients after renal transplantation can be described as a "feeling of being torn". Within this overarching theme, six sub-themes were identified: 1) weighing dialysis against transplantation, 2) dealing with the organ, 3) the experience of positive changes, 4) the self-confidence resulting from it, 5) the experience of still existing impairments and worries, and finally 6) the ensuing need for support. As a conclusion for practice it is necessary to offer an actively approaching and realistic instruction and education in order to create everyday skills and a higher degree of self-determination in the patients. PMID- 19780017 TI - [Dealing with sensitive interview topics--insights into the research project "Everyday life of people with urinary incontinence"]. AB - This article has been written as part of a research project investigating the experiences of people with urinary incontinence. In this article a systematic literature analysis combined with excerpts from the study was used to describe and reflect on the best way to conduct interviews on sensitive topics. Ethical aspects are emphasised. These include informed and process consent, different types, places, and phases of such an interview, and reasons for people to participate in such interviews. It is shown that grappling with sensitive and shameful topics can promote recruitment of potential candidates and add depth to qualitative research. As such, sensitive interview topics constitute important quality indicators for qualitative research. PMID- 19780018 TI - [Eating in hospital--a challenge for the interdisciplinary team]. AB - Annually, the hospital Zollikerberg in Switzerland collects data about patient satisfaction. Among others, patients are asked to rate food preparation, variety, presentation, and temperature of the meals as well as the overall quality of the food. The study presented in this article explored what the aspect food quality means to patients. A total of 24 patients participated in 23 narrative interviews which were transcribed and analysed using the method of inductive content analysis. In general, patients were satisfied with the meals in the hospital, i. e., preparation, variety, presentation and temperature as well as the mealtimes. The staff was described as being friendly and helpful. Potential for improvement was identified with regard to information about food variety, and services for people whose appetite was limited. Patients experienced difficulties particularly in the first days of hospitalisation to identify their food options. Patients with a reduced appetite tried to choose meals they found most appealing. Given the widespread problem of malnutrition in hospitals this last point needs attention both from the nursing and the interdisciplinary team. PMID- 19780019 TI - [Ideas about a "good death" in Palliative Care Nursing]. AB - In the modern hospice movement and in Palliative Care, helping severely ill and dying patients to have a "good end of life" and a "good death" has high priority. The concept of a "good death" reflects the corresponding ideal of a "good dying". This concept analy-sis aimed at clarifying the current understanding of the characteristics of a "good death" as well as at presenting a coherent theoretical and ideational basis. The meaning of an ideal death as a point of reference and leitmotif in structuring palliative and hospice care, the theoretical background, and the components of a "good death" will be described in this article. PMID- 19780020 TI - Effectiveness of rosuvastatin compared to other statins for the prevention of cardiovascular events-a cohort study in 395 039 patients from clinical practice. AB - PURPOSE: This study compared the effectiveness of rosuvastatin (RSV) to other statins prescribed in clinical practice in prevention of cardiovascular (CV) events. METHODS: This longitudinal inception cohort study, using Thomson Healthcare's MarketScan databases, included patients aged > or = 18 starting statin therapy during August 2003-December 2005. Patients were followed until 90 days after index statin monotherapy exposure, start of another lipid-lowering therapy, an event, end of eligibility, or end of study. The primary endpoint was a composite of CV death (in-hospital only), myocardial infarction, unstable angina, coronary revascularization, stroke, and carotid revascularization. Adjusted time-to-event analyses incorporating a propensity score covariate were used, and analyses were stratified by duration of statin exposure. RESULTS: Among 395 039 patients who met inclusion/exclusion criteria, 12% initiated RSV, and 9622 (2.4%) of the total patient population experienced an outcome event. The median duration of statin treatment and follow-up was 100 days and 180 days, respectively. No statistically significant difference in CV event rates between RSV and other statins was observed after adjustment for demographics and medical/prescription history (HR = 0.99, 95%CI = 0.93-1.06). However, with longer exposure time, there was a suggestion of increased benefit with RSV compared to other statins. CONCLUSIONS: The primary analysis showed similar incidence rates of CV-related events between the statin cohorts over a median of 180 days of follow-up. PMID- 19780021 TI - Recorded incidents in a high-secure hospital: a descriptive analysis. AB - BACKGROUND: Incidents of violence, self-harm and security are of concern in psychiatric hospitals with regard to both patient and staff welfare. AIM: The purpose of this study was to examine the frequency and nature of incidents in all directorates in a high-security psychiatric hospital. METHODS: Data were collected from the hospital's incident recording forms for the period 1 June 2007 to 30 September 2008. RESULTS: In total, 5658 incidents were recorded, almost all patients (95%) having been involved in at least one incident. Most incidents, however, were in the categories of less serious violence and self-harm. The rate was 0.89 incidents per patient per month. The women's directorate had a significantly higher frequency of violent or self-harm incidents than the other directorates (male mental health, learning disability, personality disorder or dangerous and severe personality disorder). Violence was almost equally against fellow patients or staff. It was commonest in communal areas during day-time hours. Self-harm was most likely in a patient's own room. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: These findings can inform prevention and management of violence and self-harm. Dealing with such a large number of incidents is time consuming, even if they are not especially serious. Attention to environmental, as well as individual, issues is recommended. PMID- 19780022 TI - Moral cognitive correlates of empathy in juvenile delinquents. AB - INTRODUCTION: Numerous theories of anti-social behaviour have featured lack of empathy as an essential characteristic of the anti-social personality. AIM: To investigate the relationships between empathy and three theoretically related moral cognitive constructs: moral judgement maturity, moral identity and self serving cognitive distortion. METHODS: Seventy-eight adjudicated juvenile delinquents aged 13 to 21 years who had been directed by the court to attend a 10 week empathy training programme completed self-report measures as part of routine evaluation. Their anonymized scores were retrieved from programme records. RESULTS: Applying zero-order correlation, followed by regression analysis, we established that moral judgement maturity was associated with greater empathy, whereas extensive endorsement of self-serving cognitive distortions was associated with lower empathy. An observed association between moral identity and empathy was mediated or 'neutralised' by self-serving cognitive distortion. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Our results suggest that interventions designed to promote empathy and curtail anti-social behaviour should embrace strategies that facilitate moral judgement maturity and correct or counteract self-serving cognitive distortions. PMID- 19780024 TI - Bradykinin protects against brain microvascular endothelial cell death induced by pathophysiological stimuli. AB - The morphological and functional integrity of the microcirculation is compromised in many cardiovascular diseases such as hypertension, diabetes, stroke, and sepsis. Angiotensin converting enzyme inhibitors (ACEi), which are known to favor bradykinin (BK) bioactivity by reducing its metabolism, may have a positive impact on preventing the microvascular structural rarefaction that occurs in these diseases. Our study was designed to test the hypothesis that BK, via B2 receptors (B2R), protects the viability of the microvascular endothelium exposed to the necrotic and apoptotic cell death inducers H(2)O(2) and LPS independently of hemodynamics. Expression (RT-PCR and radioligand binding) and functional (calcium mobilization with fura-2AM, and p42/p44MAPK and Akt phosphorylation assays) experiments revealed the presence of functional B2R in pig cerebral microvascular endothelial cells (pCMVEC). In vitro results showed that the cytocidal effects of H(2)O(2) and LPS on pCMVEC were significantly decreased by a BK pretreatment (MTT and crystal violet tests, annexin-V staining/FACS analysis), which was countered by the B2R antagonist HOE 140. BK treatment coincided with enhanced expression of the cytoprotective proteins COX-2, Bcl-2, and (Cu/Zn)SOD. Ex vivo assays on rat brain explants showed that BK impeded (by approximately 40%) H(2)O(2)-induced microvascular degeneration (lectin-FITC staining). The present study proposes a novel role for BK in microvascular endothelial protection, which may be pertinent to the complex mechanism of action of ACEi explaining their long-term beneficial effects in maintaining vascular integrity. PMID- 19780023 TI - Changes in global gene expression during in vitro decidualization of rat endometrial stromal cells. AB - During the preimplantation phase of pregnancy the endometrial stroma differentiates into decidua, a process that implies numerous morphological changes and is an example of physiological transdifferentiation. Here we show that UIII rat endometrial stromal cells cultured in the presence of calf serum acquired morphological features of decidual cells and expressed decidual markers. To identify genes involved in decidualization we compared gene expression patterns of control and decidualized UIII cells using cDNA microarray. We found 322 annotated genes exhibiting significant differences in expression (>3-fold, fold discovery rate (FDR) >0.005), of which 312 have not been previously related to decidualization. Analysis of overrepresented functions revealed that protein synthesis, gene expression, and chromatin architecture and remodeling are the most relevant modified functions during decidualization. Relevant genes are also found in the functional terms differentiation, cell proliferation, signal transduction, and matrix/structural proteins. Several of these new genes involved in decidualization (Csdc2, Trim27, Eef1a1, Bmp1, Wt1, Aes, Gna12, and Men1) are shown to be also regulated in uterine decidua during normal pregnancy. Thus, the UIII cell culture model will allow future mechanistic studies to define the transcriptional network regulating reprogramming of stromal cells into decidual cells. PMID- 19780025 TI - Mutations in the external loops of BK virus VP1 and urine viral load in renal transplant recipients. AB - Polyomavirus-associated nephropathy (PVAN) is a major complication that occurs after renal transplantation and is induced by reactivation of the human polyomavirus BK (BKV). The structure of the viral capsid protein 1 (VP1) is characterized by the presence of external loops, BC, DE, EF, GH, and HI, which are involved in receptor binding. The pathogenesis of PVAN is not well understood, but viral risk factors are thought to play a crucial role in the onset of this pathology. In an attempt to better understand PVAN pathogenesis, the BKV-VP1 coding region was amplified, cloned, and sequenced from the urine of kidney transplant recipients who did, and did not, develop the pathology. Urine viral loads were determined by using real time quantitative PCR (Q-PCR). Amino acid substitutions were detected in 6/8 patients, and 6/7 controls. The BC and EF loop regions were most frequently affected by mutations, while no mutations were found within the GH and HI loops of both patients and controls. Some mutations, that were exclusively detected in the urine of PVAN patients, overlapped with previously reported mutations, although a correlation between changes in amino acids and the development of PVAN was not found. Urine viral loads were higher than that of the proposed cut-off loads for identification of patients that are at a high risk of developing PVAN (10(7) copies/ml), both in the PVAN and control groups, thus confirming that urine viral load is not a useful predictive marker for the development of PVAN. PMID- 19780026 TI - A contemporary review of AudioGene audioprofiling: a machine-based candidate gene prediction tool for autosomal dominant nonsyndromic hearing loss. PMID- 19780027 TI - Endoscopy-assisted surgery with topical mitomycin for a cholesterol granuloma in the petrous apex. AB - OBJECTIVES/HYPOTHESIS: We present the case of a 21-year-old woman who underwent endoscopy-assisted surgery with topical mitomycin for a large cholesterol granuloma in the petrous apex that involved the eustachian tube. STUDY DESIGN: Case report. METHODS: Minimally invasive surgery was performed on the cholesterol granuloma with endoscopic assistance, and topical mitomycin (0.4 mg/mL) was administered to prevent scarring of the newly created drainage/ventilation route. With the endoscopic approach, the drainage/ventilation route was secured not only from the tympanic cavity, but also using a guidewire inserted from the pharyngeal orifice of the eustachian tube. RESULTS: The drainage/ventilation route between the nasopharynx and middle ear cavity involving the cholesterol granuloma has been preserved more than for 9 months postoperatively. Her hearing has recovered. CONCLUSIONS: This less invasive technique is a surgical option for patients with a large cholesterol granuloma in the petrous apex involving the eustachian tube. PMID- 19780028 TI - Globular adiponectin inhibits angiotensin II-induced nuclear factor kappaB activation through AMP-activated protein kinase in cardiac hypertrophy. AB - Activation of nuclear factor kappaB (NF-kappaB) has been found necessary for cardiac hypertrophic growth in vivo and in vitro experiments. Adiponectin, an adipocyte-derived polypeptide, suppresses cardiac hypertrophy in response to pressure overload. Here we investigated the potential effect of adiponectin on NF kappaB activation in hypertrophic neonatal rat ventricular myocytes (NRVMs) and related signal transduction pathway. We treated NRVMs with globular adiponectin (gAd) before angiotensin II (AngII) stimulation. Pretreating cells with gAd reduced the increased incorporation of [(3)H]-leucine and the mRNA levels of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) stimulated by AngII, indicating gAd inhibited AngII-induced cardiac hypertrophic signaling. Moreover, gAd pretreatment suppressed inhibitory protein kappaB (I-kappaB) phosphorylation and decreased p65 nuclear translocation, DNA-binding and transcription activity of NF-kappaB. Meanwhile, gAd promoted AMP-activated protein kinase (AMPK) phosphorylation, which is a downstream signaling mediator of adiponectin. Pharmacological activator of AMPK could inhibit AngII-induced NF kappaB translocation, and inhibitor of AMPK or a dominant-negative AMPK adenovirus suppressed gAd-mediated inhibition of I-kappaB phosphorylation and NF kappaB activation. When AMPK was inhibited, the suppressive effect of gAd on ANP mRNA expression was reduced. Our data indicate that gAd inhibits cardiac hypertrophic signaling through AMPK mediated suppression of NF-kappaB activation. PMID- 19780029 TI - Radiotherapy for basal cell carcinoma of the medial canthus region. AB - OBJECTIVES/HYPOTHESIS: To report outcome for patients treated with radiotherapy (RT) for basal cell carcinoma of the medial canthus. STUDY DESIGN: Retrospective review. METHODS: Thirty-three patients treated with RT at the University of Florida between 1965 and 2005 for basal cell carcinoma of the medial canthus were retrospectively reviewed. RT was the primary treatment for gross disease in 70% of patients and for positive margin after resection in 30%. The prescribed dose was 50 to 60 Gy at 2.0 to 2.5 Gy per fraction. RESULTS: Surviving patients were followed for a median of 14 years. Tumor recurred at the primary site in 10%. There were no regional recurrences or distant metastases. The local control rate was 100% in patients treated with surgery followed by RT for positive margins. In patients treated with RT alone, the local control rate was 94% with de novo lesions and 67% if the lesion was recurrent after prior surgery. Cause-specific survival was 95% at 10 years; overall survival was 52% at 10 years. There were no severe complications. Chronic epiphora was present in 21% and chronic dry eye symptoms in 3%. CONCLUSIONS: With the proper technique, RT produces excellent results in several of these patients. Patients with recurrent tumors and gross disease at the time of RT have a suboptimal cure rate. Our plan is to increase the RT dose to 64.8 Gy at 1.8 Gy per fraction. PMID- 19780030 TI - A prospective study of paranasal sinus osteomas in 1,889 cases: changing patterns of localization. AB - OBJECTIVES/HYPOTHESIS: We developed the largest paranasal sinus computed tomography (CT) scan study so far by including 1,889 cases to investigate the prevalence, localization, age distribution, and the secondary complications of paranasal sinus osteomas. STUDY DESIGN: Prospective study. METHODS: A prospective study was performed on 1,889 consecutive adult individuals who underwent paranasal sinus CT examinations with suspected sinus disease. RESULTS: The prevalence of paranasal sinus osteomas was determined to be 3%. Osteomas were located most frequently in the ethmoid sinuses. The size of the osteomas varied from approximately from 2 to 30 mm. Of the osteomas found, 37%were accompanied by pathological sinonasal findings. CONCLUSIONS: The prevalence of sinonasal osteoma in the paranasal sinus region detected by CT scan is supporting the literature, whereas the localization pattern challenges it. PMID- 19780031 TI - Magnetic resonance imaging of facial nerve schwannoma. AB - OBJECTIVES/HYPOTHESIS: This study characterizes the magnetic resonance (MR) appearances of facial nerve schwannoma (FNS). We hypothesize that the extent of FNS demonstrated on MR will be greater compared to prior computed tomography studies, that geniculate involvement will be most common, and that cerebellar pontine angle (CPA) and internal auditory canal (IAC) involvement will more frequently result in sensorineural hearing loss (SNHL). STUDY DESIGN: Retrospective study. METHODS: Clinical, pathologic, and enhanced MR imaging records of 30 patients with FNS were analyzed. Morphologic characteristics and extent of segmental facial nerve involvement were documented. RESULTS: Median age at initial imaging was 51 years (range, 28-76 years). Pathologic confirmation was obtained in 14 patients (47%), and the diagnosis reached in the remainder by identification of a mass, thickening, and enhancement along the course of the facial nerve. All 30 lesions involved two or more contiguous segments of the facial nerve, with 28 (93%) involving three or more segments. The median segments involved per lesion was 4, mean of 3.83. Geniculate involvement was most common, in 29 patients (97%). CPA (P = .001) and IAC (P = .02) involvement was significantly related to SNHL. Seventeen patients (57%) presented with facial nerve dysfunction, manifesting in 12 patients as facial nerve weakness or paralysis, and/or in eight with involuntary movements of the facial musculature. CONCLUSIONS: This study highlights the morphologic heterogeneity and typical multisegment involvement of FNS. Enhanced MR is the imaging modality of choice for FNS. The neuroradiologist must accurately diagnose and characterize this lesion, and thus facilitate optimal preoperative planning and counseling. PMID- 19780032 TI - Long-term outcomes from the English national comparative audit of surgery for nasal polyposis and chronic rhinosinusitis. AB - OBJECTIVES/HYPOTHESIS: We present a large, prospective cohort study following patients who underwent surgery for chronic rhinosinusitis (CRS), with or without nasal polyps, in hospitals in England and Wales. Five-year outcomes will be reported, and we will revisit a previous analysis of the effectiveness of extensive surgery in the treatment of nasal polyposis. METHODS: Baseline clinical data was collected for 3,128 patients undergoing surgery for CRS (with or without nasal polyps). Outcomes are described in terms of the proportion of patients undergoing revision surgery and mean Sino-Nasal Outcome Test (SNOT-22) scores. RESULTS: A total of 1,459 (52.2%) patients responded to 5-year follow-up. Revision surgery rates increased at each time point. Of the patients responding, 279 patients (19.1%) had undergone further surgery during the 5 years since their original operation. Of the patients with polyps, 20.6% had undergone revision compared to 15.5% of patients with CRS alone. The mean SNOT-22 score for all patients was 28.2 (standard deviation [SD] = 22.4) at 5 years after surgery. This is remarkably similar to the results observed at 3 months (25.5), 12 months (27.7), and 36 months (27.7), and represents a 14-point improvement over the baseline score. Polyp patients report better SNOT-22 scores at 5 years (mean = 26.2; SD = 21.6) than patients with CRS alone (mean = 33.3; SD = 23.7). Of the patients who had originally received simple polypectomy, 21.2% had undergone revision surgery compared to 20.0% of patients who had also received additional sinus surgery. The difference in unadjusted revision surgery rates is not statistically significant (chi(2) = 0.22; P = .64). However, the difference becomes statistically significant when a multivariate logistic regression is used to adjust for baseline characteristics, with patients undergoing additional sinus surgery being less likely to undergo further surgery within the study period (adjusted odds ratio = 0.66; P = .04). CONCLUSIONS: We have shown sinonasal surgery to be safe and effective in reducing the symptoms associated with CRS over a 5-year period. The reduction in symptoms is large, with no significant decline in symptomatic improvement from 12 to 60 months postsurgery. However, revision surgery rates approach 20% over this time, and patients should be counseled accordingly prior to surgery. PMID- 19780033 TI - Association of a functional polymorphism of PTPN22 encoding a lymphoid protein phosphatase in bilateral Meniere's disease. AB - OBJECTIVES/HYPOTHESIS: Bilateral Meniere's disease (BMD) is a severe disease that usually results in bilateral severe or profound sensorineural hearing loss and chronic disequilibrium with loss of vestibular function. We examined single nucleotide polymorphisms (SNPs) in the PTPN22 and CTLA4 genes in Caucasian patients with BMD to assess the possible association between these polymorphism and the predisposition and clinical expression of this disease. STUDY DESIGN: A case control study. METHODS: The functional protein tyrosine phosphatase type 22 (PTPN22) SNP (rs2476601, 1858C/T) and CTLA4 SNP (rs231775, 49A/G) were analyzed in 52 patients with BMD and 348 healthy controls by a TaqMan 5' allelic discrimination assay. Data were analyzed by a chi(2) test with Fisher exact test. RESULTS: No association was found between the +49A/G CTLA4 genotype and BMD patients. However, the heterozygote PTPN22 1858C/T genotype was present at a significantly higher frequency in BMD patients than in controls (odds ratio = 2.25, 95% confidence interval: 1.09-4.62; P = .04). CONCLUSIONS: These results suggest that the PTPN22 1858C/T genotype may confer differential susceptibility to BMD in the Spanish population and support an autoimmune etiology for BMD. PMID- 19780034 TI - Reformation of concha bullosa following treatment by crushing surgical technique: implication for balloon sinuplasty. AB - OBJECTIVES/HYPOTHESIS: There are various surgical techniques designed to treat conchae bullosae (CB). These include partial or total resection and crushing. Frontal sinus balloon sinuplasty is thought to work by the crushing/remodeling of the agger nasi and frontal recess air cells. The long-term outcome of sinuplasty in the frontal/ethmoid air cell region is unknown. To date, no study has been done on the reformation of CB after crushing. We report on the long-term outcome of a series of patients who underwent crushing of their CB and suggest implications for frontal sinus balloon sinuplasty. STUDY DESIGN: Retrospective case series. METHODS: Retrospective review of 10 patients who re-presented with CB as a component of their nasal obstructive symptoms despite previously undergoing crushing of their CB. Data analyzed included paranasal sinus computed tomography (CT) scans and operative reports. RESULTS: These 10 patients re presented with recurrent rhinosinusitis and nasal obstructive symptoms. The patients had previously undergone septoplasty surgery with crushing of the CB and were noted to have reformed the CB on their most recent sinus CT. The previous surgeries were preformed from 2 to 15 years prior to their representation. CONCLUSIONS: CB can reform following crushing technique. One may extrapolate that agger nasi and frontal recess air cells may reform following balloon sinuplasty leading to recurrent obstruction of the frontal sinus outflow tract. PMID- 19780035 TI - Exploring a taxonomy for aggression against women: can it aid conceptual clarity? AB - The assessment of aggression against women is demanding primarily because assessment strategies do not share a common language to describe reliably the wide range of forms of aggression women experience. The lack of a common language impairs efforts to describe these experiences, understand causes and consequences of aggression against women, and develop effective intervention and prevention efforts. This review accomplishes two goals. First, it applies a theoretically and empirically based taxonomy to behaviors assessed by existing measurement instruments. Second, it evaluates whether the taxonomy provides a common language for the field. Strengths of the taxonomy include its ability to describe and categorize all forms of aggression found in existing quantitative measures. The taxonomy also classifies numerous examples of aggression discussed in the literature but notably absent from quantitative measures. Although we use existing quantitative measures as a starting place to evaluate the taxonomy, its use is not limited to quantitative methods. Implications for theory, research, and practice are discussed. PMID- 19780036 TI - Generation of neural crest progenitors from human embryonic stem cells. AB - The neural crest (NC) is a transient population of multipotent progenitors arising at the lateral edge of the neural plate in vertebrate embryos, which then migrate throughout the body to generate diverse array of tissues such as the peripheral nervous system, skin melanocytes, and craniofacial cartilage, bone and teeth. The transient nature of neural crest stem cells make extremely challenging to study the biology of these important cells. In humans induction and differentiation of embryonic NC occurs very early, within a few weeks of fertilization giving rise to technical and ethical issues surrounding isolation of early embryonic tissues and therefore severely limiting the study of human NC cells. For that reason our current knowledge of the biology of NC mostly derives from the studies of lower organisms. Recent progress in human embryonic stem cell research provides a unique opportunity for generation of a useful source of cells for basic developmental studies. The development of cost-effective, time and labor efficient improved differentiation protocols for the production of human NC cells is a critical step toward a better understanding of NC biology. PMID- 19780037 TI - Do aggression and rule-breaking have different interpersonal correlates? A study of antisocial behavior subtypes, negative affect, and hostile perceptions of others. AB - There is mounting evidence that physical aggression and nonaggressive, rule breaking delinquency constitute two separable though correlated subtypes of antisocial behavior. Even so, it remains unclear whether these behavioral subtypes have meaningfully different interpersonal correlates, particularly as they are subsumed within the same broad domain of antisocial behavior. To evaluate this, we examined whether hostile perceptions of others (assessed via exposure to a series of neutral unknown faces) were linked to level and type of antisocial behavior aggression vs. rule-breaking, and moreover, whether this association persisted even when also considering the common association with negative affect (as manipulated via written recollection of one's best and worst life experiences). Analyses revealed that aggression, but not rule-breaking, was uniquely tied to hostile perceptions of others. Furthermore, this association persisted over and above the common association of both hostile perceptions and aggression with negative affect (at both trait and state levels). Such results provide additional support for clinically meaningful differences between the behavioral subtypes of aggression and nonaggressive rule-breaking and for the independent role of hostile perceptions in aggressive behavior. PMID- 19780039 TI - Expression of estrogen receptor beta increases integrin alpha1 and integrin beta1 levels and enhances adhesion of breast cancer cells. AB - Estrogen effects on mammary gland development and differentiation are mediated by two receptors (ERalpha and ERbeta). Estrogen-bound ERalpha induces proliferation of mammary epithelial and cancer cells, while ERbeta is important for maintenance of the differentiated epithelium and inhibits proliferation in different cell systems. In addition, the normal breast contains higher ERbeta levels compared to the early stage breast cancers, suggesting that loss of ERbeta could be important in cancer development. Analysis of ERbeta-/- mice has consistently revealed reduced expression of cell adhesion proteins. As such, ERbeta is a candidate modulator of epithelial homeostasis and metastasis. Consequently, the aim of this study was to analyze estrogenic effects on adhesion of breast cancer cells expressing ERalpha and ERbeta. As ERbeta is widely found in breast cancer but not in cell lines, we used ERalpha positive T47-D and MCF-7 human breast cancer cells to generate cells with inducible ERbeta expression. Furthermore, the colon cancer cell lines SW480 and HT-29 were also used. Integrin alpha1 mRNA and protein levels increased following ERbeta expression. Integrin beta1-the unique partner for integrin alpha1-increased only at the protein level. ERbeta expression enhanced the formation of vinculin containing focal complexes and actin filaments, indicating a more adhesive potential. This was confirmed by adhesion assays where ERbeta increased adhesion to different extracellular matrix proteins, mostly laminin. In addition, ERbeta expression was associated to less cell migration. These results indicate that ERbeta affects integrin expression and clustering and consequently modulates adhesion and migration of breast cancer cells. PMID- 19780038 TI - Calcium-stimulated mitogen-activated protein kinase activation elicits Bcl-xL downregulation and Bak upregulation in notexin-treated human neuroblastoma SK-N SH cells. AB - Notechis scutatus scutatus notexin induced apoptotic death of SK-N-SH cells accompanied with downregulation of Bcl-xL, upregulation of Bak, mitochondrial depolarization, and ROS generation. Upon exposure to notexin, Ca(2+)-mediated JNK and p38 MAPK activation were observed in SK-N-SH cells. Production of ROS was a downstream event followed by Ca(2+)-mediated mitochondrial alteration. Notexin induced cell death, mitochondrial depolarization, and ROS generation were suppressed by SB202190 (p38 MAPK inhibitor) and SP600125 (JNK inhibitor). Moreover, phospho-p38 MAPK and phospho-JNK were proved to be involved in Bcl-xL degradation, and overexpression of Bcl-xL attenuated the cytotoxic effect of notexin. Bak upregulation was elicited by p38 MAPK-mediated ATF-2 activation and JNK-mediated c-Jun activation. Suppression of Bak upregulation by ATF-2 siRNA or c-Jun siRNA attenuated notexin-evoked mitochondrial depolarization and rescued viability of notexin-treated cells. Taken together, our data indicate that notexin-induced apoptotic death of SK-N-SH cells is mediated through mitochondrial alteration triggering by Ca(2+)-evoked p38 MAPK/ATF-2 and JNK/c-Jun signaling pathways. PMID- 19780040 TI - Primary and multisensory cortical activity is correlated with audiovisual percepts. AB - Incongruent auditory and visual stimuli can elicit audiovisual illusions such as the McGurk effect where visual /ka/ and auditory /pa/ fuse into another percept such as/ta/. In the present study, human brain activity was measured with adaptation functional magnetic resonance imaging to investigate which brain areas support such audiovisual illusions. Subjects viewed trains of four movies beginning with three congruent /pa/ stimuli to induce adaptation. The fourth stimulus could be (i) another congruent /pa/, (ii) a congruent /ka/, (iii) an incongruent stimulus that evokes the McGurk effect in susceptible individuals (lips /ka/ voice /pa/), or (iv) the converse combination that does not cause the McGurk effect (lips /pa/ voice/ ka/). This paradigm was predicted to show increased release from adaptation (i.e. stronger brain activation) when the fourth movie and the related percept was increasingly different from the three previous movies. A stimulus change in either the auditory or the visual stimulus from /pa/ to /ka/ (iii, iv) produced within-modality and cross-modal responses in primary auditory and visual areas. A greater release from adaptation was observed for incongruent non-McGurk (iv) compared to incongruent McGurk (iii) trials. A network including the primary auditory and visual cortices, nonprimary auditory cortex, and several multisensory areas (superior temporal sulcus, intraparietal sulcus, insula, and pre-central cortex) showed a correlation between perceiving the McGurk effect and the fMRI signal, suggesting that these areas support the audiovisual illusion. PMID- 19780041 TI - Evidence for modulation of opioidergic activity in central vestibular processing: A [(18)F] diprenorphine PET study. AB - Animal and functional imaging studies had identified cortical structures such as the parieto-insular vestibular cortex, the retro-insular cortex, or the anterior cingulate cortex belonging to a vestibular cortical network. Basic animal studies revealed that endorphins might be important transmitters involved in cerebral vestibular processing. The aim of the present study was therefore to analyse whether the opioid system is involved in vestibular neurotransmission of humans or not. Changes in opioid receptor availability during caloric air stimulation of the right ear were studied with [(18)F] Fluoroethyl-diprenorphine ([(18)F]FEDPN) PET scans in 10 right-handed healthy volunteers and compared to a control condition. Decrease in receptor availability to [(18)F]FEDPN during vestibular stimulation in comparison to the control condition was significant at the right posterior insular cortex and the postcentral region indicating more endogenous opioidergic binding in these regions during stimulation. These data give evidence that the opioidergic system plays a role in the right hemispheric dominance of the vestibular cortical system in right-handers. PMID- 19780042 TI - Sensory-motor brain network connectivity for speech comprehension. AB - The act of listening to speech activates a large network of brain areas. In the present work, a novel data-driven technique (the combination of independent component analysis and Granger causality) was used to extract brain network dynamics from an fMRI study of passive listening to Words, Pseudo-Words, and Reverse-played words. Using this method we show the functional connectivity modulations among classical language regions (Broca's and Wernicke's areas) and inferior parietal, somatosensory, and motor areas and right cerebellum. Word listening elicited a compact pattern of connectivity within a parieto-somato motor network and between the superior temporal and inferior frontal gyri. Pseudo Word stimuli induced activities similar to the Word condition, which were characterized by a highly recurrent connectivity pattern, mostly driven by the temporal lobe activity. Also the Reversed-Word condition revealed an important influence of temporal cortices, but no integrated activity of the parieto-somato motor network. In parallel, the right cerebellum lost its functional connection with motor areas, present in both Word and Pseudo-Word listening. The inability of the participant to produce the Reversed-Word stimuli also evidenced two separate networks: the first was driven by frontal areas and the right cerebellum toward somatosensory cortices; the second was triggered by temporal and parietal sites towards motor areas. Summing up, our results suggest that semantic content modulates the general compactness of network dynamics as well as the balance between frontal and temporal language areas in driving those dynamics. The degree of reproducibility of auditory speech material modulates the connectivity pattern within and toward somatosensory and motor areas. PMID- 19780043 TI - Functional 5-HT1a receptor polymorphism selectively modulates error-specific subprocesses of performance monitoring. AB - Our study investigates the dependence of response monitoring and error detection on genetic influences modulating the serotonergic system. This was done using the event-related potentials (ERPs) after error (Ne/ERN) and correct trials (Nc/CRN). To induce a sufficient amount of errors, a standard flanker task was used. The subjects (N = 94) were genotyped for the functional 5-HT1A C(-1019)G polymorphism. The results show that the 5-HT1A C(-1019)G polymorphism specifically modulates error detection. Neurophysiological modulations on error detection were paralleled by a similar modulation of response slowing after an error, reflecting the behavioral adaptation. The 5-HT1A -1019 CC genotype group showed a larger Ne and stronger posterror slowing than the CG and GG genotype groups. More general processes of performance monitoring, as reflected in the Nc/CRN, were not affected. The finding that error-specific processes, but not general response monitoring processes, are modulated by the 5-HT1A C(-1019)G polymorphism is underlined by a wavelet analysis. In summary, the results suggest a specific effect of the 5-HT1A C(-1019)G polymorphism on error monitoring, as reflected in the Ne, and suggest a neurobiological dissociation between processes of error monitoring and general response monitoring at the level of the serotonin 1A receptor system. PMID- 19780045 TI - Candida famata modulates toll-like receptor, beta-defensin, and proinflammatory cytokine expression by normal human epithelial cells. AB - Candida albicans is no longer the only yeast involved in infectious disorders, as others, such as C. famata, commonly associated with foods as well as terrestrial and marine environments, are being recognized as potential emerging pathogens that cause human candidiasis. We investigated the interaction between C. famata and human epithelial cells using monolayer cultures and an engineered human oral mucosa (EHOM). C. famata was able to adhere to gingival epithelial cells but failed to adopt the hyphal form in the presence/absence of proteins. Interestingly, when cultured onto the engineered human oral mucosa (EHOM), C. famata formed a biofilm and invaded the connective tissue. When normal human gingival epithelial cells were put in contact with C. famata, they expressed high levels of Toll-like receptors (TLR)-2, -4, and -6, but not TLR-9 mARN. The upregulation of TLRs was paralleled by an increase of IL-1beta and TNFalpha, but not IFNgamma mARN expression, suggesting the involvement of specific pro inflammatory cytokines (IL-1beta and TNFalpha) in the defense against infection with C. famata. The active role of epithelial cells in the innate immunity against C. famata infection was enhanced by their capacity to express high levels of human beta-defensin (HBD)-1, -2, and -3. The upregulation of pro-inflammatory cytokines and antimicrobial peptide expression may explain the growth inhibition of C. famata by the gingival epithelial cells. Overall results provide additional evidence of the involvement of C. famata in the activation of innate immunity and the contribution of human epithelial cells in local defenses against such exogenous stimulations as C. famata infections. PMID- 19780046 TI - Mixed volume sample preparation method for intact cell mass spectrometry of Fusarium spores. PMID- 19780044 TI - Comparing 3 T and 1.5 T MRI for tracking Alzheimer's disease progression with tensor-based morphometry. AB - A key question in designing MRI-based clinical trials is how the main magnetic field strength of the scanner affects the power to detect disease effects. In 110 subjects scanned longitudinally at both 3.0 and 1.5 T, including 24 patients with Alzheimer's Disease (AD) [74.8 +/- 9.2 years, MMSE: 22.6 +/- 2.0 at baseline], 51 individuals with mild cognitive impairment (MCI) [74.1 +/- 8.0 years, MMSE: 26.6 +/- 2.0], and 35 controls [75.9 +/- 4.6 years, MMSE: 29.3 +/- 0.8], we assessed whether higher-field MR imaging offers higher or lower power to detect longitudinal changes in the brain, using tensor-based morphometry (TBM) to reveal the location of progressive atrophy. As expected, at both field strengths, progressive atrophy was widespread in AD and more spatially restricted in MCI. Power analysis revealed that, to detect a 25% slowing of atrophy (with 80% power), 37 AD and 108 MCI subjects would be needed at 1.5 T versus 49 AD and 166 MCI subjects at 3 T; however, the increased power at 1.5 T was not statistically significant (alpha = 0.05) either for TBM, or for SIENA, a related method for computing volume loss rates. Analysis of cumulative distribution functions and false discovery rates showed that, at both field strengths, temporal lobe atrophy rates were correlated with interval decline in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog), mini-mental status exam (MMSE), and Clinical Dementia Rating sum-of-boxes (CDR-SB) scores. Overall, 1.5 and 3 T scans did not significantly differ in their power to detect neurodegenerative changes over a year. Hum Brain Mapp, 2010. (c) 2009 Wiley-Liss, Inc. PMID- 19780047 TI - Saturated fatty acid-induced insulin resistance is associated with mitochondrial dysfunction in skeletal muscle cells. AB - Increased plasma levels of free fatty acids (FFA) occur in states of insulin resistance such as obesity and type 2 diabetes mellitus. These high levels of plasma FFA are proposed to play an important role for the development of insulin resistance but the mechanisms involved are still unclear. This study investigated the effects of saturated and unsaturated FFA on insulin sensitivity in parallel with mitochondrial function. C2C12 myotubes were treated for 24 h with 0.1 mM of saturated (palmitic and stearic) and unsaturated (oleic, linoleic, eicosapentaenoic, and docosahexaenoic) FFA. After this period, basal and insulin stimulated glucose metabolism and mitochondrial function were evaluated. Saturated palmitic and stearic acids decreased insulin-induced glycogen synthesis, glucose oxidation, and lactate production. Basal glucose oxidation was also reduced. Palmitic and stearic acids impaired mitochondrial function as demonstrated by decrease of both mitochondrial hyperpolarization and ATP generation. These FFA also decreased Akt activation by insulin. As opposed to saturated FFA, unsaturated FFA did not impair glucose metabolism and mitochondrial function. Primary cultures of rat skeletal muscle cells exhibited similar responses to saturated FFA as compared to C2C12 cells. These results show that in muscle cells saturated FFA-induced mitochondrial dysfunction associated with impaired insulin-induced glucose metabolism. PMID- 19780049 TI - Publications of Lelio Mazzarella (1963-2008). PMID- 19780048 TI - Influence of the H-site residue 108 on human glutathione transferase P1-1 ligand binding: structure-thermodynamic relationships and thermal stability. AB - The effect of the Y108V mutation of human glutathione S-transferase P1-1 (hGST P1 1) on the binding of the diuretic drug ethacrynic acid (EA) and its glutathione conjugate (EASG) was investigated by calorimetric, spectrofluorimetric, and crystallographic studies. The mutation Tyr 108 --> Val resulted in a 3D-structure very similar to the wild type (wt) enzyme, where both the hydrophobic ligand binding site (H-site) and glutathione binding site (G-site) are unchanged except for the mutation itself. However, due to a slight increase in the hydrophobicity of the H-site, as a consequence of the mutation, an increase in the entropy was observed. The Y108V mutation does not affect the affinity of EASG for the enzyme, which has a higher affinity (K(d) approximately 0.5 microM) when compared with those of the parent compounds, K(d) (EA) approximately 13 microM, K(d) (GSH) approximately 25 microM. The EA moiety of the conjugate binds in the H-site of Y108V mutant in a fashion completely different to those observed in the crystal structures of the EA or EASG wt complex structures. We further demonstrate that the Delta C(p) values of binding can also be correlated with the potential stacking interactions between ligand and residues located in the binding sites as predicted from crystal structures. Moreover, the mutation does not significantly affect the global stability of the enzyme. Our results demonstrate that calorimetric measurements maybe useful in determining the preference of binding (the binding mode) for a drug to a specific site of the enzyme, even in the absence of structural information. PMID- 19780053 TI - Gene expression analysis identifies over-expression of CXCL1, SPARC, SPP1, and SULF1 in gastric cancer. AB - To elucidate gene expression signatures associated with gastric carcinogenesis, we performed a genome-wide expression analysis of 46 Finnish and 20 Japanese gastric tissues. Comparative analysis between Finnish and Japanese datasets identified 58 common genes that were differentially expressed between cancerous and non-neoplastic gastric tissues. Twenty-six of these genes were up-regulated in cancer and 32 down-regulated. Of these genes, 64% were also differentially expressed in another unrelated publicly available dataset. The expression levels of four of the up-regulated genes, CXCL1, SPARC, SPP1 and SULF, were further analyzed in 82 gastric tissues using quantitative real-time RT-PCR. This analysis validated the results from the microarray analysis as the expression of these four genes was significantly higher in the cancerous tissue compared with the normal tissue (fold change 3.4-8.9). Over-expression of CXCL1 also positively correlated with improved survival. To conclude, irrespective of the microarray platform or patient population, a common gastric cancer gene expression signature of 58 genes, including CXCL1, SPARC, SPP1, and SULF, was identified. These genes represent potential biomarkers for gastric cancer. PMID- 19780054 TI - Prediction of hypocalcemia after using 1- to 6-hour postoperative parathyroid hormone and calcium levels: an analysis of pooled individual patient data from 3 observational studies. AB - BACKGROUND: Parathyroid hormone (PTH) levels up to 6 hours postthyroidectomy have been shown to have excellent predictive power in determining hypocalcemia. In this study, we investigate the usefulness of combining calcium and PTH to increase the predictive power. METHODS: Individual patient data were obtained from 3 studies (152 patients) that fulfilled our criteria (using PTH assay within hours postthyroidectomy to predict symptomatic hypocalcemia). RESULTS: Changes in combined PTH and calcium threshold levels checked 1 to 6 hours after thyroidectomy were excellent in predicting postoperative hypocalcemia. A decrease in PTH of 60%, coupled with a simultaneous decrease in calcium of 10%, 5 to 6 hours postoperatively resulted in a sensitivity and specificity of 100%. However, combined PTH and calcium threshold changes were not significantly better than using PTH threshold changes alone. CONCLUSIONS: Threshold changes in serum calcium and PTH, checked hours after surgery, can be used together to accurately predict whether a patient will become hypocalcemic after thyroidectomy. PMID- 19780055 TI - Unintentional parathyroidectomy and hypoparathyroidism in secondary central compartment surgery for thyroid cancer. AB - BACKGROUND: Unintentional parathyroidectomy is a complication of thyroid surgery. To our knowledge, no study has specifically examined the incidence of inadvertent parathyroidectomy exclusively in patients undergoing secondary central compartment surgery for recurrent or persistent thyroid cancer. METHODS: The records of 40 patients who underwent 42 secondary central compartment surgeries for thyroid cancer were reviewed to determine the incidence of inadvertent parathyroidectomy. RESULTS: Parathyroid tissue was present on permanent pathology in 31% of SCCSs. Unintentional parathyroidectomy did not have an effect on hypoparathyroidism. Concomitant lateral neck dissection did not have an effect on the incidence of hypoparathyroidism, but did have a statistically significant effect on inadvertent parathyroidectomy. CONCLUSION: Accidental resection of parathyroid tissue is relatively common in secondary central compartment surgery compared with primary thyroid surgery, but does not appear to correlate with postoperative hypoparathyroidism. PMID- 19780056 TI - Respiratory-swallow phase patterns and their relationship to swallowing impairment in patients treated for oropharyngeal cancer. AB - BACKGROUND: Unstable respiratory-swallowing coordination has been associated with disorders and disease. The goals of this study were (1) to describe respiratory swallow patterns in patients with dysphagia consequent to treatments for cancers of the oropharynx and (2) to determine the association between respiratory swallow patterns, airway invasion, and overall severity of swallowing impairment. METHODS: This prospective, cross-sectional design compared respiratory-swallow patterns in 20 patients treated for oropharyngeal cancer and 20 healthy, age matched control participants. Nasal airflow direction was synchronously recorded with videofluoroscopic imaging in participants who swallowed 5-mL thin liquid barium boluses. RESULTS: Respiratory-swallow patterns differed between groups. Most control participants initiated and completed swallowing bracketed by expiratory airflow. Swallowing in patients often interrupted inspiratory flow and was associated with penetration or aspiration of the bolus. CONCLUSIONS: We suggest nonexpiratory bracketed respiratory-swallowing phase patterns in patients with oropharyngeal cancer may place patients at greater risk of airway penetration or aspiration during swallowing. PMID- 19780057 TI - Bone loss induced by Runx2 over-expression in mice is blunted by osteoblastic over-expression of TIMP-1. AB - The Runx2 gene is essential for osteoblast differentiation and function. In vivo over-expression of Runx2 in osteoblasts increases bone resorption, and blocks terminal osteoblast differentiation. Several lines of evidence suggest that osteoblastic matrix metalloproteinases (MMPs) could contribute to the increased bone resorption observed in mice over-expressing Runx2 (Runx2 mice). The goal of our study was to use a transgenic approach to find out whether the inhibition of osteoblastic MMPs can reduce the bone loss induced by the over-expression of Runx2. We analyzed the effect of the in vivo over-expression of the TIMP-1 in osteoblasts on the severe osteopenic phenotype in Runx2 mice. Females with the different genotypes (WT, Runx2, TIMP-1 and TIMP-1/Runx2) were analyzed for bone density, architecture, osteoblastic and osteoclastic activity and gene expression using qPCR. TIMP-1 over-expression reduces the bone loss in adult Runx2 mice. The prevention of the bone loss in TIMP-1/Runx2 mice was due to a combination of reduced bone resorption and sustained bone formation. We present evidence that the ability of osteoblastic cells to induce osteoclastic differentiation is lower in TIMP-1/Runx2 mice than in Runx2 mice, probably due to a reduction in the expression of RANK-L and of the Runx2 transgene. Osteoblast primary cells from TIMP-1/Runx2 mice, but not from Runx2 mice, were able to differentiate into fully mature osteoblasts producing high osteocalcin levels. In conclusion, our findings suggest that osteoblastic MMPs can affect osteoblast differentiation. Our work also indicates that osteoblastic MMPs are partly responsible for the bone loss observed in Runx2 transgenic mice. PMID- 19780059 TI - Nickel allergy and device closure of the patent foramen ovale, now that we were told should we care? PMID- 19780058 TI - Selective control of gene expression by CDK9 in human cells. AB - CDK9 associates with T-type cyclins and positively regulates transcriptional elongation by phosphorylating RNA polymerase II (RNAPII) and negative elongation factors. However, it is unclear whether CDK9 is required for transcription of most genes by RNAPII or alternatively plays a role regulating the expression of restricted subsets of genes. We have investigated the direct effects of inhibiting cellular CDK9 activity in global gene expression in human cells by using a dominant-negative form of CDK9 (dnCDK9). We have also compared direct inhibition of cellular CDK9 activity to pharmacological inhibition with flavopiridol (FVP), a CDK inhibitor that potently inhibits CDK9 and cellular transcription. Because of its presumed selectivity for CDK9, FVP has been previously used as a tool to infer the role of CDK9 on global gene expression. DNA microarray analyses described here show that inhibition of gene expression by FVP is consistent with global inhibition of transcription. However, specific inhibition of CDK9 activity with dnCDK9 leads to a distinctive pattern of changes in gene expression, with more genes being specifically upregulated (122) than downregulated (84). Indeed, the expression of many short-lived transcripts downregulated by FVP is not modulated by dnCDK9. Nevertheless, consistently with FVP inhibiting CDK9 activity, a significant number of the genes downregulated/upregulated by dnCDK9 are modulated with a similar trend by FVP. Our data suggests that the potent effects of FVP on transcription are likely to involve inhibition of CTD kinases in addition to CDK9. Our data also suggest complex and gene-specific modulation of gene expression by CDK9. PMID- 19780060 TI - Fluoroscopy guided vascular access: asking the right question, but getting the wrong answer? PMID- 19780062 TI - A mass spectrometry based functional assay for the quantitative assessment of ABC transporter activity. AB - ATP-Binding Cassette (ABC) transporters are highly expressed in pharmacological barriers limiting the access of drugs to their targets. Since characterization of a compound as a transporter substrate or inhibitor bears significant consequences in drug development, there is a great need for reliable tools that enable the rapid analysis of the transport susceptibility of drugs. Here we describe a simple but very efficient high-performance liquid chromatography/mass spectrometry (HPLC/MS) assay for measuring the ABC transporter-dependent vesicular transport of compounds. In addition, we provide evidence that the requirement for sample preparation can be minimized using desorption electrospray ionization (DESI)-MS, paving the way for a direct, high-throughput investigation of drug-transporter interactions. PMID- 19780061 TI - Manipulation of electrostatic and saccharide linker interactions in the design of efficient glycopolypeptide-based cholera toxin inhibitors. AB - Multivalent, glycopolymer inhibitors designed for the treatment of disease and pathogen infection have shown improvements in binding correlated with general changes in glycopolymer architecture and composition. We have previously demonstrated that control of glycopolypeptide backbone extension and ligand spacing significantly impacts the inhibition of the cholera toxin B subunit pentamer (CT B(5)) by these polymers. In the studies reported here, we elucidate the role of backbone charge and linker length in modulating the inhibition event. Peptides of the sequence AXPXG (where X is a positive, neutral or negative amino acid), equipped with the alkyne functionality of propargyl glycine, were designed and synthesized via solid-phase peptide synthetic methods and glycosylated via Cu(I)-catalyzed alkyne-azide cycloaddition reactions. The capacity of the glycopeptides to inhibit the binding of the B(5) subunit of cholera toxin was evaluated. These studies indicated that glycopeptides with a negatively charged backbone show improved inhibition of the binding event relative to the other glycopeptides. In addition, variations in the length of the linker between the peptide and the saccharide ligand also affected the inhibition of CT by the glycopeptides. Our findings suggest that, apart from appropriate saccharide spacing and polypeptide chain extension, saccharide linker conformation and the systematic placement of charges on the polypeptide backbone are also significant variables that can be tuned to improve the inhibitory potencies of glycopolypeptide-based multivalent inhibitors. PMID- 19780063 TI - Improvements in quantification accuracy of inorganic time-of-flight secondary ion mass spectrometric analysis of silicate materials by using C60 primary ions. AB - Time-of-flight secondary ion mass spectrometry is a very useful tool for the comprehensive characterization of samples by in situ measurements. A pulsed primary ion beam is used to sputter secondary ions from the surface of a sample and these are then recorded by a time-of-flight mass spectrometer. The parallel detection of all elements leads to very efficient sample usage allowing the comprehensive analysis of sub-micrometre sized samples. An inherent problem is accurate quantification of elemental abundances which mainly stems from the so called matrix effect. This effect consists of changes in the sputtering and ionization efficiencies of the secondary neutrals and ions due to different sample compositions, different crystal structure or even different crystallographic orientations. Here we present results obtained using C60 molecules as a new primary ion species for inorganic analyses. The results show an improvement in quantification accuracy of elemental abundances, achieving relative errors as small as the certified uncertainties for the analyzed silicate standards. This improvement is probably due to the different sputter mechanism for C60+ primary ions from that for single atomic primary ions such as Ga+, Cs+ or Ar+. The C60+ cluster breaks up on impact, distributing the energy between its constituent carbon atoms. In this way it excavates nano-craters, rather than knocking out single atoms or molecules from the surface via a collision cascade, leading to a more reproducible sputter process and much improved quantification. PMID- 19780064 TI - Association between oxidized LDL, obesity and type 2 diabetes in a population based cohort, the Health, Aging and Body Composition Study. AB - BACKGROUND: Accumulating evidence suggests a cross-sectional association between oxidative stress and type 2 diabetes (T2D). Systemic oxidative stress, as measured by oxidized LDL (oxLDL), has been correlated with visceral fat. We examined the relationship between oxLDL, and T2D- and obesity-related traits in a bi-racial sample of 2985 subjects at baseline and after 7 years of follow-up. METHODS: We examined six T2D-related traits (T2D status, HbA(1c), fasting glucose, insulin, adiponectin and HOMA-IR) as well as six obesity-related traits (obesity status, BMI, leptin, % body fat, visceral and subcutaneous fat mass) using logistic and linear regression models. RESULTS: In all subjects at baseline, oxLDL was positively associated with T2D (OR = 1.3, 95% CI:1.1-1.5), fasting glucose (ss = 0.03 +/- 0.006), HbA(1c) (ss = 0.02 +/- 0.004), fasting insulin (ss = 0.12 +/- 0.02), HOMA-IR (ss = 0.13 +/- 0.02) and negatively with adiponectin (ss = -0.16 +/- 0.03), (all p < 0.001). The strength and magnitude of these associations did not differ much between blacks and whites. In both blacks and whites, oxLDL was also associated with obesity (OR = 1.3, 95% CI:1.1-1.4) and three of its related traits (ss = 0.60 +/- 0.14 for BMI, ss = 0.74 +/- 0.17 for % body fat, ss = 0.29 +/- 0.06 for visceral fat; all p < 0.001). Furthermore, of four traits measured after 7 years of follow-up (fasting glucose, HbA1c, BMI and % fat), their relationship with oxLDL was similar to baseline observations. No significant association was found between oxLDL and incident T2D. Interestingly, oxLDL was significantly associated with % change in T2D- and obesity-related traits in whites but not in blacks. CONCLUSION/INTERPRETATION: Our data suggest that systemic oxidative stress may be a novel risk factor for T2D and obesity. PMID- 19780065 TI - DRG prospective payment systems: refine or not refine? AB - We present a model of contracting between a purchaser of health services and a provider (a hospital). We assume that hospitals provide two alternative treatments for a given diagnosis: a less intensive one (for example, a medical treatment) and a more intensive one (a surgical treatment). We assume that prices are set equal to the average cost reported by the providers, as observed in many OECD countries (yardstick competition). The purchaser has two options: (1) to set one tariff based on the diagnosis only and (2) to differentiate the tariff between the surgical and the medical treatment (i.e. to refine the tariff). We show that when tariffs are refined, the provider has always an incentive to overprovide the surgical treatment. If the tariff is not refined, the hospital underprovides the surgical treatment (and overprovides the medical treatment) if the degree of altruism is sufficiently low compared with the opportunity cost of public funds. Our main result is that price refinement might not be optimal. PMID- 19780066 TI - Family history of myocardial infarction predicts incident coronary heart disease in postmenopausal women with diabetes: the Women's Health Initiative Observational Study. AB - BACKGROUND: Diabetes is a risk factor for coronary heart disease (CHD) but CHD does not occur in all diabetic individuals. The goal of this study was to assess the relationship between family history of myocardial infarction (MI) and incident CHD in diabetic postmenopausal women. METHODS: We conducted a prospective cohort study among 2642 diabetic postmenopausal women without CHD at baseline in the Women's Health Initiative Observational Study. Family history was defined as a proband report of MI in first-degree relatives. Incident CHD was defined as non-fatal MI, coronary revascularization, or CHD death. RESULTS: During 7.3 ( +/- 1.8) years of follow-up, 14.3% of the participants had incident CHD. The risk of incident CHD was 50% higher (HR = 1.50, 95% CI: 1.20-1.87, p = 0.0003) in those with a family history of an MI in at least one first-degree relative, and 79% higher (HR = 1.79, 95% CI: 1.36-2.35, P < 0.0001) if two or more first-degree relatives had an MI, compared to participants without a family history, after adjustment for covariates. The CHD risk increased with elevated systolic blood pressure (SBP) (HR = 1.01, 95% CI: 1.003-1.02, p = 0.001) but decreased with elevated diastolic BP (HR = 0.98, 95% CI: 0.97-0.999, p = 0.005) and with two or more episodes per week of physical activity (HR = 0.70, 95% CI: 0.52-0.93, p = 0.02). CONCLUSIONS: The results suggest that a family history of MI predicts CHD in diabetic postmenopausal women. Close attention should be paid to BP control and physical activity in these women. PMID- 19780067 TI - Twin-reversed arterial perfusion sequence: pre- and postoperative cardiovascular findings in the 'pump' twin. AB - OBJECTIVES: To assess cardiovascular findings in twin-reversed arterial perfusion (TRAP) sequence pre- and post-therapy and compare these findings to traditional obstetric markers, defined as acardius to pump twin weight ratio and presence of polyhydramnios. METHODS: This was a retrospective review of 27 cases of TRAP sequence diagnosed between 2004 and 2008. Echocardiographic data included indexed cardiac output and functional and anatomic parameters. Ultrasound reports were reviewed for acardius to pump twin weight ratio and polyhydramnios. We assessed the relationship between cardiac output and the remaining cardiac/obstetric variables obtained pre- and post-treatment. RESULTS: Twenty-three subjects had complete echocardiographic data sets at initial evaluation (mean gestational age, 20.4 +/- 2.5 weeks) and, of these, post-treatment echocardiographic evaluation was available in 10. Six of seven (86%) pump twins with elevated indexed cardiac output had significant cardiovascular compromise. Most fetuses with abnormal cardiac output or right ventricular dysfunction normalized post-therapy. There was no relationship between cardiac output and obstetric markers. CONCLUSIONS: Elevated indexed cardiac output is strongly associated with cardiovascular compromise. Traditional obstetric prognosticators do not correlate with cardiovascular derangements. In pump twins with cardiac compromise, postoperative cardiovascular status improves acutely. Given this analysis, we conclude that assessment of cardiovascular findings should be incorporated into the management and treatment of TRAP sequence. PMID- 19780069 TI - Co-delivery of doxorubicin and Bcl-2 siRNA by mesoporous silica nanoparticles enhances the efficacy of chemotherapy in multidrug-resistant cancer cells. PMID- 19780070 TI - Intracellular localization and cytotoxicity of spherical mesoporous silica nano- and microparticles. AB - This work evaluates the cytotoxicity of spherical mesoporous silica (MS) nano- and microparticles and investigates the effects of particle size, concentration, biodegradation products of MS, residual surfactant, and surfactant removal by extraction and calcination on the cytotoxicity. The results from the intracellular localization of spherical MS nano- and microparticles with different sizes reveal the mechanism for their cytotoxicity and that the smaller particles in nanoscale are more easily endocytosed and consequently located within lysosomes. PMID- 19780071 TI - Potential of (1)H MR spectroscopic imaging to segregate patients who are likely to show malignancy of the peripheral zone of the prostate on biopsy. AB - PURPOSE: To evaluate the potential of MR spectroscopic imaging (MRSI) to segregate patients who, upon prostate biopsy, are more likely to show a malignancy in the peripheral zone (PZ) of the prostate gland. MATERIALS AND METHODS: Before biopsy, MRSI was carried in 123 men with elevated prostate specific antigen level or an abnormal digital rectal examination. After the MRSI investigation, all patients underwent systematic transrectal ultrasound guided biopsy and were categorized using standard random number tables into the following two groups: (i) Group I, a 62 member training set; and (ii) Group II, a 61-member test set. The cutoff value for the [citrate/(choline+creatine)] ratio for patients in the training set was obtained using the receiver operating characteristic (ROC) curve method. This value was then applied to the test set of patients as well. RESULTS: The ROC method gave a cutoff value of 1.2 for the [Citrate/(Choline+Creatine)] ratio. When applied as a malignancy-predictor to the test group of patients (Group II), the ROC method generated the following results: sensitivity, 77%; specificity, 83%; negative predictive value, 93%; positive predictive value, 55% and accuracy, 82%. CONCLUSION: The results indicate that patients who are deemed as malignancy-positive in the PZ by MRSI using the ROC cutoff may be subjected to prostate biopsy to confirm the diagnosis of cancer. PMID- 19780072 TI - Pleural plaques in dentists from occupational asbestos exposure: a report of three cases. AB - BACKGROUND: White asbestos (chrysotile) has been used in dentistry since 1930 when it was introduced as a lining material for casting rings. METHODS: All three patients presented with pleural plaques on chest X-rays as well as on CT-scans. They were working as dentists for 35-45 years. Under the instructions of the first dentist we represented precisely the whole process of manipulating a kind of paper that contained asbestos. In order to measure asbestos fibers concentration we used the membrane filter method and phase contrast optical microscopy. Dry asbestos sheets were scanned with x-ray diffraction and electron microscope. RESULTS: Analysis of the filter demonstrated 0.008 fibers/cm(3) during the sampling period. X-ray diffraction analysis revealed that the material consisted of chrysotile exclusively. Electron microscope pictures confirmed the presence of chrysotile. CONCLUSION: Everyday occupational exposure for many years even to low asbestos levels, under poor ventilation conditions in a closed space, could cause pleural lesions. PMID- 19780074 TI - Development of new and selective Trypanosoma cruzi trans-sialidase inhibitors from sulfonamide chalcones and their derivatives. AB - A series of sulfonamide-containing hydroxylated chalcone (4-7) and quinolinone (8, 9) derivatives was synthesised and tested for inhibition of the trans sialidase from Trypanosoma cruzi (TcTS). IC(50) values for these inhibitors ranged from 0.6 to 7.3 microM, with the dihydroxylated (catechol) derivatives being the tightest binders. Full kinetic analyses of inhibition were performed for these catechol derivatives, both for the transglycosylation reaction in the presence of lactose and for the hydrolysis reaction in its absence. Competitive inhibition was seen in each case with K(i) values for 5, 7 and 9 of 2.0, 2.2 and 0.2 microM, respectively, in the absence of lactose, and 4.6, 3.7 and 0.4 microM in its presence. None of the compounds tested showed any significant inhibition of the human sialidase Neu2, at concentrations up to 200 microM. PMID- 19780073 TI - Structure and replication of yDNA: a novel genetic set widened by benzo homologation. AB - In a functioning genetic system, the information-encoding molecule must form a regular self-complementary complex (for example, the base-paired double helix of DNA) and it must be able to encode information and pass it on to new generations. Here we study a benzo-widened DNA-like molecule (yDNA) as a candidate for an alternative genetic set, and we explicitly test these two structural and functional requirements. The solution structure of a 10 bp yDNA duplex is measured by using 2D-NMR methods for a simple sequence composed of T-yA/yA-T pairs. The data confirm an antiparallel, right-handed, hydrogen-bonded helix resembling B-DNA but with a wider diameter and enlarged base-pair size. In addition to this, the abilities of two different polymerase enzymes (Klenow fragment of DNA pol I (Kf) and the repair enzyme Dpo4) to synthesize and extend the yDNA pairs T-yA, A-yT, and G-yC are measured by steady-state kinetics studies. Not surprisingly, insertion of complementary bases opposite yDNA bases is inefficient due to the larger base-pair size. We find that correct pairing occurs in several cases by both enzymes, but that common and relatively efficient mispairing involving T-yT and T-yC pairs interferes with fully correct formation and extension of pairs by these polymerases. Interestingly, the data show that extension of the large pairs is considerably more efficient with the flexible repair enzyme (Dpo4) than with the more rigid Kf enzyme. The results shed light on the properties of yDNA as a candidate for an alternative genetic information encoding molecule and as a tool for application in basic science and biomedicine. PMID- 19780075 TI - Identifying natural product biosynthetic genes from a soil metagenome by using T7 phage selection. PMID- 19780076 TI - Ultrahigh-throughput FACS-based screening for directed enzyme evolution. AB - Directed enzyme evolution has proven to be a powerful tool for improving a range of properties of enzymes through consecutive rounds of diversification and selection. However, its success depends heavily on the efficiency of the screening strategy employed. Fluorescence-activated cell sorting (FACS) has recently emerged as a powerful tool for screening enzyme libraries due to its high sensitivity and its ability to analyze as many as 10(8) mutants per day. Applications of FACS screening have allowed the isolation of enzyme variants with significantly improved activities, altered substrate specificities, or even novel functions. This review discusses FACS-based screening for enzymatic activity and its potential application for the directed evolution of enzymes, ribozymes, and catalytic antibodies. PMID- 19780077 TI - Eukaryotic DNA polymerases alpha, beta and epsilon incorporate guanine opposite 2,2,4-triamino-5(2H)-oxazolone. PMID- 19780078 TI - Biosynthesis and biological screening of a genetically encoded library based on the cyclotide MCoTI-I. PMID- 19780079 TI - Generation of surface-bound multicomponent protein gradients. PMID- 19780080 TI - Reactivity of cyclic (alkyl)(amino)carbenes (CAACs) and bis(amino)cyclopropenylidenes (BACs) with heteroallenes: comparisons with their N heterocyclic carbene (NHCs) counterparts. AB - Similarly to NHCs, CAAC(a) and BAC(a) react with CO2 to give the corresponding betaines. Based on the carbonyl stretching frequencies of cis-[RhCl(CO)2(L)] complexes, the order of electron donor ability was predicted to be CAAC(a) approximately BAC(a)>NHCs. When the betaines nu(asym)(CO2) values are used, the apparent ordering is BAC(a)>NHCs approximately CAAC(a) that indicates a limitation for the use of IR spectroscopy in the ranking of ligand sigma-donating ability. Although all carbenes react with carbon disulfide to give the corresponding betaines, a second equivalent of CS2 reacts with the BAC-CS2 leading to a bicyclic thieno[2,3-diamino]-1,3-dithiole-2-thione, which results from a novel ring expansion process. Surprisingly, in contrast to NHCs, CAAC(a) does not react with carbodiimide, whereas BAC(a) exclusively gives a ring expanded product, analogous to that obtained with CS2. The intermediate amidinate can be trapped, using the lithium tetrafluoroborate adduct of BAC(b) as a carbene surrogate. PMID- 19780081 TI - Room-temperature infrared spectroscopy combined with mass spectrometry distinguishes gas-phase protein isomers. PMID- 19780082 TI - Highly efficient and chemoselective peptide ubiquitylation. PMID- 19780083 TI - From the selective cleavage of the Si-O-Si bond in disiloxanes to zwitterionic, water-stable zinc silanolates. PMID- 19780084 TI - Breathing transitions in MIL-53(Al) metal-organic framework upon xenon adsorption. PMID- 19780085 TI - Evolution of ordered block copolymer serpentines into a macroscopic, hierarchically ordered web. PMID- 19780087 TI - Micelles and vesicles formed by polyoxometalate-block copolymer composites. PMID- 19780086 TI - Application of fragment growing and fragment linking to the discovery of inhibitors of Mycobacterium tuberculosis pantothenate synthetase. PMID- 19780088 TI - Naphthalene-mediated electronic communication in tetrakis(imino)pyracene complexes. PMID- 19780089 TI - Water-gas shift reaction on a highly active inverse CeOx/Cu111 catalyst: unique role of ceria nanoparticles. PMID- 19780090 TI - Niobium-catalyzed activation of aryl trifluoromethyl groups and functionalization of C-H bonds: an efficient and convergent approach to the synthesis of N heterocycles. PMID- 19780093 TI - Effects of pulsed magnetic field on the formation of magnetosomes in the Magnetospirillum sp. strain AMB-1. AB - Magnetotactic bacteria are a diverse group of microorganisms which possess one or more chains of magnetosomes and are endowed with the ability to use geomagnetic fields for direction sensing, thus providing a simple and excellent model for the study of magnetite-based magnetoreception. In this study, a 50 Hz, 2 mT pulsed magnetic field (PMF) was applied to study the effects on the formation of magnetosomes in Magnetospirillum sp. strain AMB-1. The results showed that the cellular magnetism (R(mag)) of AMB-1 culture significantly increased while the growth of cells remained unaffected after exposure. The number of magnetic particles per cell was enhanced by about 15% and slightly increased ratios of magnetic particles of superparamagnetic property (size <20 nm) and mature magnetosomes (size >50 nm) were observed after exposure to PMF. In addition, the intracellular iron accumulation slightly increased after PMF exposure. Therefore, it was concluded that 50 Hz, 2 mT PMF enhances the formation of magnetosomes in Magnetospirillum sp. strain AMB-1. Our results suggested that lower strength of PMF has no significant effects on the bacterial cell morphologies but could affect crystallization process of magnetosomes to some extent. PMID- 19780092 TI - Survey of electromagnetic field exposure in bedrooms of residences in lower Austria. AB - Previous investigations of exposure to electric, magnetic, or electromagnetic fields (EMF) in households were either about electricity supply EMFs or radio frequency EMFs (RF-EMFs). We report results from spot measurements at the bedside that comprise electrostatic fields, extremely low-frequency electric fields (ELF EFs), extremely low-frequency magnetic fields (ELF-MFs), and RF-EMFs. Measurements were taken in 226 households throughout Lower Austria. In addition, effects of simple reduction measures (e.g., removal of clock radios or increasing their distance from the bed, turning off Digital Enhanced Cordless Telecommunication (DECT) telephone base stations) were assessed. All measurements were well below International Commission on Non-Ionizing Radiation Protection (ICNIRP) guideline levels. Average night-time ELF-MFs (long-term measurement from 10 pm to 6 am, geometric mean over households) above 100 nT were obtained in 2.3%, and RF-EMFs above 1000 microW/m(2) in 7.1% of households. Highest ELF-EFs were primarily due to lamps beside the bed (max = 166 V/m), and highest ELF-MFs because of transformers of devices (max = 1030 nT) or high current of power lines (max = 380 nT). The highest values of RF-EMFs were caused by DECT telephone base stations (max = 28979 microW/m(2)) and mobile phone base stations (max = 4872 microW/m(2)). Simple reduction measures resulted in an average decrease of 23 nT for ELF-MFs, 23 V/m for ELF-EFs, and 246 microW/m(2) for RF-EMFs. A small but statistically significant correlation between ELF-MF exposure and overall RF-EMF levels of R = 0.16 (P = 0.008) was computed that was independent of type (flat, single family) and location (urban, rural) of houses. PMID- 19780094 TI - Pharmacokinetic behavior of huperzine A in plasma and cerebrospinal fluid after intranasal administration in rats. AB - The aim of this study was to investigate the pharmacokinetic behavior of huperzine A (Hup A) in plasma and cerebrospinal fluid (CSF) after intranasal administration (0.5 mg/kg) in male Sprague-Dawley rats. A pharmacokinetic study of intravenous Hup A (0.5 mg/kg) was also performed. The concentrations of Hup A in the biological samples were measured by high performance liquid chromatography mass spectrometry. Blood samples were taken from the tail vein and CSF was sampled by cisternal puncture using a stereotaxic frame. The contribution of the olfactory pathway to the uptake of Hup A into CSF was determined by comparing the AUC(CSF)/AUC(plasma) ratios after intranasal and intravenous administration. The AUC ratios of intranasal to intravenous administration in CSF and plasma were 104% and 118%, respectively. No significant difference was observed between the AUC(CSF)/AUC(plasma) ratios of Hup A after intranasal administration (20%) and after intravenous infusion (23%). This indicated that approximately 20% of the Hup A level in plasma reached the CSF after both nasal and intravenous administration, and that no direct transport of Hup A from nose to CSF was found in rats. PMID- 19780095 TI - Staging laparoscopy enhances the detection of occult metastases in patients with pancreatic adenocarcinoma. AB - BACKGROUND: The use of staging laparoscopy has been highly institutional dependent. We sought to assess the incidence of occult intra-abdominal metastases identified at the time of staging laparoscopy for patients with either potentially resectable or locally advanced pancreatic adenocarcinoma (LAPC). We also compared the rate of occult metastases in patients who underwent staging laparoscopy versus laparotomy. METHODS: Patients were confirmed to have potentially resectable or LAPC at a multidisciplinary hepatopancreaticobiliary conference. Patients with potentially resectable lesions were initially explored via staging laparoscopy or laparotomy, based on surgeon preference. RESULTS: Over a 4-year period, 25 patients with potentially resectable tumors and 33 patients with LAPC were staged with laparoscopy, with an equivalent prevalence of occult metastases found at laparoscopy (28% potentially resectable vs. 33% LAPC, P = 0.8). Fifty-two patients with potentially resectable lesions were explored initially via laparotomy. Occult peritoneal metastases were more likely to be detected in patients with potentially resectable tumors that were explored via laparoscopy than via laparotomy (32% vs. 10%, P = 0.018). CONCLUSIONS: Staging laparoscopy is more likely than open exploration to detect occult metastases. Current preoperative imaging inadequately identifies unresectable pancreatic adenocarcinoma; therefore, all patients with potentially resectable disease should undergo staging laparoscopy. PMID- 19780096 TI - UV polymerisation of surfactants adsorbed at the nematic liquid crystal-water interface produces an optical response. AB - We have investigated the changes in crossed polariser optical textures produced by adsorption and UV polymerisation of a range of polymerisable surfactants at the interface between a nematic liquid crystal and water. Similar to non polymerisable surfactants, the adsorption of polymerisable surfactants with sufficiently long hydrophobic tail groups produces a transition from planar to homeotropic anchoring. UV polymerisation of surfactants with a polymerisable group located in the hydrophobic tail region changes the anchoring from homeotropic back to planar. Polymerisation in the hydrophilic headgroup region does not produce an optical transition. We demonstrate that these systems can be used to "write with light" in the interfaces and that they form the basis of a UV sensor device in which the optical response is visible to the naked eye. PMID- 19780097 TI - Structural and viscoelastic properties of actin networks formed by espin or pathologically relevant espin mutants. AB - The structural organization of the cytoskeleton determines its viscoelastic response which is crucial for the correct functionality of living cells. Both the mechanical response and microstructure of the cytoskeleton are regulated on a microscopic level by the local activation of different actin binding and/or bundling proteins (ABPs). Misregulations in the expression of these ABPs or mutations in their sequence can entail severe cellular dysfunctions and diseases. Here, we study the structural and viscoelastic properties of reconstituted actin networks cross-linked by the ABP espin and compare the obtained network properties to those of other bundled actin networks. Moreover, we quantify the impact of pathologically relevant espin mutations on the viscoelastic properties of these cytoskeletal networks. PMID- 19780098 TI - The roles of 3' and 4' hydroxy groups in alpha-galactosylceramide stimulation of invariant natural killer T cells. PMID- 19780099 TI - Synthesis and evaluation of imidazo[2,1-b]thiazoles as iodide efflux inhibitors in thyrocytes. AB - The Na(+)/I(-) symporter (NIS) mediates iodide uptake in the thyroid gland as well as in other NIS-expressing cells. This transport is the basis for an emerging approach to selective cancer cell destruction by using radioiodide after targeted NIS gene transfer. Therapeutic efficacy requires that radioiodide retention be maximized in tumor cells. A first generation of forty imidazo[2,1 b]thiazole derivatives as iodide efflux inhibitors is described along with the evaluation of their biological properties. Structure-activity relationship studies by using radioiodide uptake in rat thyroid-derived cells (FRTL5) revealed that the 5,6-dihydroimidazo[2,1-b]thiazole heterocycle is required for activity. Introduction of electron-donor substituents on the 3-biphenyl moiety led to the discovery of novel potent compounds. A compound was identified with enhanced potency compared to reference 1. These molecules give the possibility to increase the cellular retention of radioiodide in NIS-expressing tumors, leading to higher absorbed doses and killing efficacy. PMID- 19780100 TI - Development of molecular and solid catalysts for the direct low-temperature oxidation of methane to methanol. AB - The direct low-temperature oxidation of methane to methanol is demonstrated on a highly active homogeneous molecular catalyst system and on heterogeneous molecular catalysts based on polymeric materials possessing ligand motifs within the material structure. The N-(2-methylpropyl)-4,5-diazacarbazolyl-dichloro platinum(II) complex reaches significantly higher activity compared to the well known Periana system and allows first conclusions on electronic and structural requirements for high catalytic activity in this reaction. Interestingly, comparable activities could be achieved utilizing a platinum modified poly(benzimidazole) material, which demonstrates for the first time a solid catalyst with superior activity compared to the Periana system. Although the material shows platinum leaching, improved activity and altered electronic properties, compared to the conventional Periana system, support the proposed conclusions on structure-activity relationships. In comparison, platinum modified triazine-based catalysts show lower catalytic activity, but rather stable platinum coordination even after several catalytic cycles. Based on these systems, further development of improved solid catalysts for the direct low temperature oxidation of methane to methanol is feasible. PMID- 19780101 TI - Sustainable chemistry metrics. AB - Green chemistry has developed mathematical parameters to describe the sustainability of chemical reactions and processes, in order to quantify their environmental impact. These parameters are related to mass and energy magnitudes, and enable analyses and numerical diagnoses of chemical reactions. The environmental impact factor (E factor), atom economy, and reaction mass efficiency have been the most influential metrics, and they are interconnected by mathematical equations. The ecodesign concept must also be considered for complex industrial syntheses, as a part of the sustainability of manufacturing processes. The aim of this Concept article is to identify the main parameters for evaluating undesirable environmental consequences. PMID- 19780102 TI - Recovery of gold with Japanese cedar wood powder. PMID- 19780103 TI - Immobilization of lipases onto magnetic Fe(3)O(4) nanoparticles for application in biodiesel production. PMID- 19780104 TI - Intramolecular spin alignment within mono-oxidized and photoexcited anthracene based pi radicals as prototypical photomagnetic molecular devices: relationships between electrochemical, photophysical, and photochemical control pathways. AB - AnOV is a pi-conjugated radical built from an anthracene (An) unit linked by a p phenylene to an oxoverdazyl (OV) moiety. The mono-oxidized (cationic) form of AnOV was generated both electrochemically and photochemically (in the presence of an electron acceptor). The triplet nature (S=1) of the electronic ground state of AnOV(+) was demonstrated by combining spectroelectrochemistry, electron-spin resonance (ESR) experiments, and ab initio molecular orbital (MO) calculations. The intramolecular spin alignment (ISA) within AnOV(+) results from the ferromagnetic coupling (J(electrochem)>0) of the two unpaired electrons located on the oxidized electron donor (An(+)) and on the pendant OV radical. The spin density distribution pattern of AnOV(+) is akin to that of AnOV when photopromoted (AnOV*) to its high-spin (HS) lowest excited quartet (S=3/2) state. This high-spin state results from the ferromagnetic coupling (J(photophys)>0) of the triplet locally excited state of An ((3)An*) with the doublet ground state of OV. As a shared salient feature, AnOV(+) and AnOV* (HS) show a spin delocalization within the domain of activated An in either An(+) or (3)An* (nexus states) forms. The present study essentially contributes to establish and clarify relationships between electrochemical, photophysical, and photochemical pathways to achieve ISA processes within AnOV. In particular, we discuss the impact of the spin polarization of the unpaired electron of OV on electronic features of the An electron-donating subunit. Close analysis of this polarizing interplay allows one to derive a novel functional paradigm to manipulate electron spins at the intramolecular level with light and under an external magnetic field. Indeed, two original functional elements are identified: light-triggered donors of spin polarized electrons and spin-selective electron acceptors, which are of potential interest for molecular spintronics. PMID- 19780105 TI - Polyketide building blocks via diastereoselective nitrile oxide cycloadditions with homoallylic alcohols and monoprotected homoallylic diols. AB - A modular approach to Delta(2)-isoxazolines, latent aldol adducts and polyketide building blocks, is reported. The magnesium-mediated, hydroxyl-directed method allows for the diastereoselective access to a wide variety of masked beta-hydroxy ketones, starting from readily available aliphatic and aromatic oximes, homoallylic alcohols and monoprotected homoallylic diols. The utility of the prepared Delta(2)-isoxazolines as polyketide building blocks is demonstrated by their ready conversion into the corresponding beta-hydroxy ketones. The anti diastereoselectivity of the reaction was established by derivatization, NOE studies and comparison of known compounds. A rationale for the observed diastereoselectivity is proposed. PMID- 19780106 TI - Reducing Ga-H and Ga-C bonds in close proximity to oxidizing peroxo groups: conflicting properties in single molecules. AB - Treatment of [Li(H(2)Ga{CH(SiMe(3))(2)}(2))]2 OEt(2) (12 OEt(2)) with two equivalents of tert-butyl hydrogen peroxide, H-O-O-CMe(3), afforded the organogallium peroxide [({(Me(3)Si)(2)HC}(2)Ga(OH)(OOCMe(3))Li)(2)] (3), which possesses oxidizing peroxo groups in close proximity to reducing Ga-C bonds. The lithium atoms of the dimeric formula units are coordinated by both oxygen atoms of the peroxides and by two hydroxo groups. The cleavage of the Ga--C bond was not observed, even when an excess of H-O-O-CMe(3) was applied. Instead, the adduct [{(Me(3)Si)(2)HC}(2)Ga(OH)(OOCMe(3))(2)Li(2)(HOOCMe(3))] (4) was isolated, which has an intact H-O-O-CMe(3) molecule terminally attached to lithium. A similar structural motif was found for the compound [(LiOOCMe(3))(2)(HOOCMe(3))(2)] (5). The trihydrido gallanate [Li(H(3)Ga {CH(SiMe(3))(2)})]OEt(2) (2) yielded the unique peroxide [({(Me(3)Si)(2)HC}- Ga(H)(OOCMe(3))(2)Li)(2)] (6) under similar conditions that possesses Ga-C and even more reactive Ga-H bonds beside peroxo groups. It decomposed at room temperature by the insertion of oxygen atoms into the Ga-H bonds and the formation of [({(Me(3)Si)(2)HC}-Ga(OH)(OCMe(3))(OOCMe(3))Li)(2)] (7), which was isolated in a low yield. Further decomposition gave the complete degradation of all peroxo groups with the formation of a relatively complicated Li(4)Ga(4)O(8) cage (8). PMID- 19780107 TI - Enantiopure aminopyrans by a Lewis acid promoted rearrangement of 1,2-oxazines: versatile building blocks for oligosaccharide and sugar amino acid mimetics. AB - 1,3-Dioxolanyl-substituted 1,2-oxazines, such as syn-1 and anti-1, rearrange under Lewis acidic conditions to provide bicyclic products 2-5. Subsequent reductive transformations afforded enantiopure 3-aminopyran derivatives such as 7 and 9 or their protected diastereomers 16 and 18, which can be regarded as carbohydrate mimetics. An alternative sequence of transformations including selective oxidation of the primary hydroxyl groups in 21 and 24 led to two protected beta-amino acid derivatives with carbohydrate-like backbone (sugar amino acids). Treatment of bicyclic ester 23 with samarium diiodide cleaved the N -O bond and furnished the unusual beta-lactam 27 in excellent yield. Alternatively, gamma-amino acid derivative 29 was efficiently prepared in a few steps. Fairly simple transformations gave azides 32 and 35 or alkyne 30 which are suitable substrates for the construction of oligosaccharide mimetics such as 34 by copper iodide catalyzed cycloadditions. With this report we demonstrate that enantiopure rearrangement products 2-5 are protected precursors of a variety of polyfunctionalized pyran derivatives with great potential for chemical biology. PMID- 19780108 TI - Synthesis and studies of the visible-light photocatalytic properties of near monodisperse bi-doped TiO(2) nanospheres. AB - Near-monodisperse Bi-doped anatase TiO(2) nanospheres with almost uniform diameters in the range of 117 to 87 nm were prepared simply by introducing different amounts of bismuth nitrate pentahydrate into the reaction system and subsequent calcinations. X-ray diffraction, UV-visible diffuse reflectance spectra, and X-ray photoelectron spectroscopy confirm that the doped ions substitute some of the lattice titanium atoms, and furthermore, Bi(3+) and Bi(4+) ions coexist. All the Bi-doped TiO(2) samples show much better photocatalytic activity than pure TiO(2) in the degradation of rhodamine B (RhB) under the irradiation of visible light (lambda>420 nm), and, interestingly, it was found that the degradation mechanism is different from the conventional one, which has already been reported elsewhere. The detailed mechanism is discussed in this article. PMID- 19780109 TI - Oxidative addition reactions of element-hydrogen bonds with different polarities to a gallium(I) compound. AB - The gallium(I) derivative [Ga({N(dipp)CMe}(2)CH)] (1; dipp = 2,6 diisopropylphenyl) undergoes facile oxidative addition reactions with various element-hydrogen bonds including N-H, P-H, O-H, Sn-H, and H-H bonds. This was demonstrated by its reaction with triphenyltin hydride, ethanol, water, diethylamine, diphenylphosphane, and dihydrogen. All products were characterized by means of single-crystal X-ray structure determination, NMR spectroscopy, IR spectroscopy, and mass spectrometry. PMID- 19780110 TI - Synthesis, structure and reactivity of disila- and distanna ansa half-sandwich complexes of molybdenum and tungsten. AB - We present the synthesis and characterization of disila- and distanna ansa half sandwich complexes of Group 6 transition metals. These compounds exhibit high ring strain within the ansa bridge, which is the key factor for the insertion of elemental chalcogens. PMID- 19780111 TI - Synthesis of early-transition-metal carbide and nitride nanoparticles through the urea route and their use as alkylation catalysts. AB - The use of urea as either a carbon or a nitrogen source enabled the synthesis of various early-transition-metal nitride and carbide nanoparticles (TiN, NbN, Mo(2)N, W(2)N, NbC(x)N(1-x), Mo(2)C and WC). The ability of these particles to promote alkylation reactions with alcohols was tested on benzyl alcohol and acetophenone at 150 degrees C for 20 h in xylene. Group IV and V ceramics proved to be able to catalyse the formation of 1,3-diphenyl propenone, whereas group VI ceramics showed a tendency to promote the Friedel-Crafts-type reaction of benzyl alcohol on xylene (the solvent). TiN featured the highest activity for the alkylation of ketones and was further tested for more difficult alkylations. Group VI ceramics were further investigated as catalysts for the Friedel-Crafts type alkylation of aromatics with activated alcohols. Interestingly, even hexanol could be effectively used for these reactions. PMID- 19780112 TI - Acid-catalyzed cyclization of terpenes under homogeneous and heterogeneous conditions as probed through stereoisotopic studies: a concerted process with competing preorganized chair and boat transition states. AB - Based on stereoisotopic studies and beta-secondary isotope effects, we propose that the acid-catalyzed cyclization of geranyl acetate proceeds through a concerted mechanism. Under heterogeneous conditions (zeolite Y confinement), a preorganized chairlike transition state predominates, whereas under homogeneous conditions the boat- and chairlike transition states are almost isoenergetic. For the case of farnesyl acetate, we propose that under homogeneous conditions a concerted dicyclization occurs with a preorganized boat-chair transition state competing with the chair-chair transition state. Under zeolite confinement conditions, the chair-chairlike dicyclization transition state is highly favorable. The preference of chairlike transition states within the cavities of zeolite Y is attributed to a transition state shape selectivity effect. PMID- 19780113 TI - Thermal homo- and heterolytic C-H bond activation of ethane and propane by bare [P(4)O(10)](*+): regioselectivities, kinetic isotope effects, and density functional theory based potential-energy surfaces. PMID- 19780114 TI - Soft-chemical exfoliation route to layered cobalt oxide monolayers and its application for film deposition and nanoparticle synthesis. AB - A colloidal suspension of exfoliated, layered cobalt oxide nanosheets has been synthesized through the intercalation of quaternary tetramethylammonium ions into protonated lithium cobalt oxide. According to atomic force microscopy, exfoliated nanosheets of layered cobalt oxide show a plateau-like height profile with nanometer-level height, underscoring the formation of unilamellar 2D nanosheets. The exfoliation of layered cobalt oxide was cross-confirmed by X-ray diffraction, UV/Vis spectroscopy, and transmission electron microscopy. The maintenance of the hexagonal in-plane structure of the cobalt oxide lattice after the exfoliation process was evidenced by selected-area electron diffraction and Co K-edge X-ray absorption near-edge structure analysis. The zeta-potential measurements clearly demonstrated the negative surface charge of cobalt oxide nanosheets. Adopting the nanosheets of layered cobalt oxide as a precursor, we were able to prepare the monodisperse CoO nanocrystals with a particle size of approximately 10 nm as well as the heterolayered film composed of cobalt oxide monolayer and polycation. PMID- 19780115 TI - Polyfluorophore labels on DNA: dramatic sequence dependence of quenching. AB - We describe studies carried out in the DNA context to test how a common fluorescence quencher, dabcyl, interacts with oligodeoxynucleoside fluorophores (ODFs)--a system of stacked, electronically interacting fluorophores built on a DNA scaffold. We tested twenty different tetrameric ODF sequences containing varied combinations and orderings of pyrene (Y), benzopyrene (B), perylene (E), dimethylaminostilbene (D), and spacer (S) monomers conjugated to the 3' end of a DNA oligomer. Hybridization of this probe sequence to a dabcyl-labeled complementary strand resulted in strong quenching of fluorescence in 85% of the twenty ODF sequences. The high efficiency of quenching was also established by their large Stern-Volmer constants (K(SV)) of between 2.1 x 10(4) and 4.3 x 10(5) M(-1), measured with a free dabcyl quencher. Interestingly, quenching of ODFs displayed strong sequence dependence. This was particularly evident in anagrams of ODF sequences; for example, the sequence BYDS had a K(SV) that was approximately two orders of magnitude greater than that of BSDY, which has the same dye composition. Other anagrams, for example EDSY and ESYD, also displayed different responses upon quenching by dabcyl. Analysis of spectra showed that apparent excimer and exciplex emission bands were quenched with much greater efficiency compared to monomer emission bands by at least an order of magnitude. This suggests an important role played by delocalized excited states of the pi stack of fluorophores in the amplified quenching of fluorescence. PMID- 19780116 TI - Application of asymmetric ylide cyclopropanation in the total synthesis of halicholactone. PMID- 19780117 TI - Bipyridinium array-type porous polymer displaying hydrogen storage, charge transfer-type guest inclusion, and tunable magnetic properties. AB - A multifunctional pillared-layer porous coordination polymer, {[Mn(2)(Bpybc)(ox)(2)]8 H(2)O}(n), has been constructed based on a flexible viologen derivative, 1,1'-bis(4-carboxybenzyl)-4,4'-bipyridinium dichloride (H(2)BpybcCl(2)), and an oxalate (ox) coligand. Single-crystal X-ray analysis reveals that the compound possesses multichannels with dimensions of about 6.1x6.6 A along the [110] and [-110] directions and 4.2x7.6 A along [100], and a void space of about 41.4 %. Hydrogen adsorption measurements at 77 K and 1 atm indicate that the compound exhibits a hydrogen uptake of 0.71 wt %. Owing to the incorporation of bipyridinium acceptor units, the compound can selectively accommodate aromatic donors into its nanosized pores based on charge-transfer interactions in an elastic way, and afford a specific color to different guests. Furthermore, the effect of perturbation exerted by the guest molecules on its magnetic properties has been investigated. The results indicate that the donor inclusion has little effect on its antiferromagnetic behavior, whereas dehydration of the compound decreases the strength of the magnetic exchange couplings and results in a change of the antiferromagnetic transition temperature from 14.7 to 9.8 K. PMID- 19780118 TI - Chemoselective boron-carbon bond cleavage by hydroboration of borirenes. AB - We report on the hydroboration of 1-[bis(trimethylsilyl)amino]-2,3 diethylborirene (3) with 9-borabicyclo[3.3.1]nonane (9-BBN), which led through ring-opening to an amino(vinyl)borane. The viscous borane was subsequently converted into a crystalline borate on treatment with MeLi. Both compounds were fully characterized by multinuclear NMR spectroscopy and in case of the latter by single-crystal X-ray diffraction analysis. To elucidate the reaction mechanism of the unexpected boron-carbon bond cleavage, DFT calculations of energy minima and transition states for the hydroboration were carried out. PMID- 19780119 TI - Regioselective arene functionalization: simple substitution of carboxylate by alkyl groups. AB - Arenes with various alkyl side-chains were synthesized in high yields and excellent regioselectivities. Starting from toluic and naphthoic acids, the carboxylate group was conveniently substituted by alkyl halides by Birch reduction and subsequent decarbonylation. The method is characterized by inexpensive starting materials and reagents, and methylation of arenes was realized. Besides simple alkyl substituents, the scope of arene functionalization was extended by benzyl, fluoro, amino, and ester groups. We were able to control the alkylation of 1-naphthoic acid during Birch reduction by the addition of tert butanol. This allowed the regioselective synthesis of mono and bis-substituted naphthalenes from the same starting material. PMID- 19780120 TI - Formal highly enantioselective organocatalytic addition of alkyl anions to alpha,beta-unsaturated aldehydes: application to the synthesis of isotope enantiomers. PMID- 19780121 TI - Low-molecular-weight analogues of the soluble methane monooxygenase (sMMO): from the structural mimicking of resting states and intermediates to functional models. AB - The active centre of sMMO contains a diiron core ligated by histidine and glutamate residues, which is capable of catalysing a remarkable reaction: the oxidation of methane with O(2) yielding methanol. This review describes the results of efforts to prepare low-molecular-weight analogues of this active site directing towards 1) the assignment of the spectroscopic signatures identified for certain intermediates of the sMMO catalytic cycle to structural features and 2) the synthesis of molecular compounds that can mimic the reactivity. The historical development of the model chemistry, which is subdivided into structural and functional mimicking, is illustrated and achievements reached so far are highlighted. PMID- 19780122 TI - Diastereoselective alkylation of glycinates by assistance of intramolecular potassium...fluorine interactions. PMID- 19780123 TI - Catalytic conjugate additions of geminal bis(sulfone)s: expanding the chemistry of sulfones as simple alkyl anion equivalents. AB - The value of cyclic gem-bis(sulfone) 4 as a simple alkyl nucleophile equivalent in catalytic C-C bond-forming reactions is demonstrated. The 1,4-type nucleophilic additions of bis(sulfone) 4 to alpha,beta-unsaturated ketones take place by assistance of catalytic guanidine base. On the other hand, pyrrolidines are able to catalyze the conjugate addition of 4 to both enones and enals, likely by means of iminium ion activation. Upon exploration of the best chiral pyrrolidine catalyst, it has been found that the addition of 4 to enals catalyzed by diphenylprolinol silyl ether 10 proceeds with very high enantioselectivity (beta-aryl-substituted enals >95% ee; beta-alkyl substituted enals up to 94% ee; ee = enantiomeric excess). Further reductive desulfonation of adducts gives rise to the corresponding beta-methyl aldehydes, as well as the derived alcohols, acetals, and methyl esters after simple (Mg, MeOH) well-established protocols. Application of the procedure to the synthesis of biologically relevant phenethyl building blocks is shown. Most interestingly, alpha-alkylation of initially obtained bis(sulfone) adducts can be done even with less reactive alkylating reagents, such as long linear-chain or branched-chain alkyl halides. Accordingly, upon the desulfonation process, a general, experimentally simple and highly enantioselective access to beta-branched aldehydes, alcohols, or esters is possible. Further exploration of the method includes the use of chiral alpha,beta unsaturated aldehydes derived from citronellal as the Michael acceptor partners. In these instances, the sense of the conjugate addition of 4 is controlled by the chirality of the pyrrolidine catalyst, thus allowing for a stereochemically predictable access to 1,3-dimethyl arrays, such as those present in deoxygenated polyketide-type natural products. The intramolecular variation of this technology by using doubly unsaturated aldehyde-ester 22 illustrated the site selectivity of the procedure and its potential for tandem processes leading to highly substituted polycyclic systems, such as 24. PMID- 19780124 TI - Spontaneously patterned ZnO nanoarrays. PMID- 19780125 TI - DSM-V PTSD diagnostic criteria for children and adolescents: a developmental perspective and recommendations. AB - The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-V) should ensure systematic attention to age-specific manifestations and selective modifications of the diagnostic criteria for posttraumatic stress disorder (PTSD) among children and adolescents. The authors propose developmental refinements to the conceptual framework for PTSD based on an appreciation of the different neurosignatures of danger and safety, and maturational processes that underlie symptom presentation. This includes preliminary evidence for the developmental salience of additional dimensions for PTSD (e.g., recklessness and thrill seeking). The authors provide conservative recommendations for DSM-V diagnostic criteria that primarily highlight age-related developmental manifestations that, if included in the accompanying text, would bring a richer appreciation of developmentally linked symptom presentations. PMID- 19780127 TI - Membrane interactions of antimicrobial beta-peptides: the role of amphipathicity versus secondary structure induction. AB - The membrane interaction of two beta peptides was studied using a surface plasmon resonance biosensor. The two peptides are beta-17, a novel beta-amino acid based antimicrobial peptide and the corresponding scrambled-beta17--a non-antimicrobial beta-peptide analogue. Membrane interaction studies were performed with a series of phospholipid mixtures which mimic either mammalian cells (high in phosphatidylcholine and cholesterol) or microbial cells (high in phosphatidylethanolamine and phosphatidylglycerol). The results were compared with the membrane binding of the well-characterized antimicrobial peptide magainin 2. The secondary structure of these peptides were also determined in each lipid mixture by circular dichroism and correlated with the membrane-binding properties. Both beta-17 and the scrambled peptide have the same peptide length, charge and showed a similar secondary structure in both aqueous buffer and in the presence of liposomes. Both peptides also bound to a similar level on each membrane mixture, showing that the dramatic difference in biological activity is not based on the amount of peptide bound but rather differences in the degree of insertion and rate of membrane dissociation. Although beta-17 and the scrambled beta-17 peptide exhibited similar binding properties on all membrane mimics, both beta-peptides bound more to all membranes compared with magainin 2. Overall, the results further reveal the significant interplay between peptide amphipathicity and secondary structure induction on membrane binding. PMID- 19780126 TI - Solid-state characterization of amorphous and mesomorphous calcium ketoprofen. AB - This article is concerned with exploring the application of pair distribution in pharmaceutical analysis. The solid-state characterization of amorphous and mesomorphous (liquid crystalline) calcium ketoprofen is used as an example and the structures of the amorphous and mesomorphous phases of calcium ketoprofen are compared to that of the crystalline phase. An approach to calculating the optimal experimental parameters in pair distribution function (PDF) analysis as well as a suggested method to help assign the many different peaks in a PDF diagram of an organic material are discussed. The studied salts were analyzed by X-ray powder diffraction (XRPD), single crystal X-ray diffraction, Raman spectroscopy, polarized light microscopy (PLM), solid-state NMR (SSNMR), variable-temperature SSNMR, and PDF. Raman and SSNMR were useful techniques in identifying and differentiating the crystalline phase from the other two phases but failed, alone, to differentiate between the amorphous and mesomorphous phases. The absence of significant changes in chemical shifts in SSNMR and peak shifts in Raman spectra suggested that the differences in the molecular environment of the major chemical groups in the amorphous and mesomorphous phases were minimal. However, the broadening of the Raman and SSNMR peaks in the noncrystalline phases indicated an increase in the disorder in these systems. PDF analysis of the disordered phases revealed that upon dehydration or quench cooling where the system transformed from crystalline to become disordered, the calcium-calcium and calcium-oxygen (oxygen of the carboxylic acid) distances remained intact meanwhile the rest of the molecule became disordered. The preliminary results from variable-temperature SSNMR showed two different T(1) relaxation time profiles for the amorphous and mesomorphous phases. This was consistent with the hypothesis that part of the molecule remained ordered while the rest of the molecule became disordered and the amorphous phase was more disordered than the mesomorphous phase. In conclusions, SSNMR and PDF supported the hypothesis that part of the anhydrous salt remained ordered while the rest of the molecule became disordered and the amorphous phase was more disordered than the mesomorphous phase. PMID- 19780128 TI - Small-molecule reductants inhibit multicatalytic activity of AA-NADase from Agkistrodon acutus venom by reducing the disulfide-bonds and Cu(II) of enzyme. AB - AA-NADase from Agkistrodon acutus venom is a unique multicatalytic enzyme with both NADase and AT(D)Pase activities. Among all identified NADases, only AA NADase contains Cu(II) and has disulfide-bond linkages between two peptide chains. The effects of the reduction of the disulfide-bonds and Cu(II) in AA NADase by small-molecule reductants on its NADase and ADPase activities have been investigated by polyacrylamide gel electrophoresis, high performance liquid chromatography, electron paramagnetic resonance spectroscopy and isothermal titration calorimetry. The results show that AA-NADase has six disulfide-bonds and fifteen free cysteine residues. L-ascorbate inhibits AA-NADase on both NADase and ADPase activities through the reduction of Cu(II) in AA-NADase to Cu(I), while other reductants, dithiothreitol, glutathione and tris(2 carboxyethyl)phosphine inhibit both NADase and ADPase activities through the reduction of Cu(II) to Cu(I) and the cleavage of disulfide-bonds in AA-NADase. Apo-AA-NADase can recover its NADase and ADPase activities in the presence of 1 mM Zn(II). However, apo-AA-NADase does not recover any NADase or ADPase activity in the presence of 1 mM Zn(II) and 2 mM TCEP. The multicatalytic activity relies on both disulfide-bonds and Cu(II), while Cu(I) can not activate the enzyme activities. AA-NADase is probably only active as a dimer. The inhibition curves for both ADPase and NADase activities by each reductant share a similar trend, suggesting both ADPase and NADase activities probably occur at the same site. In addition, we also find that glutathione and L-ascorbate are endogenous inhibitors to the multicatalytic activity of AA-NADase. PMID- 19780129 TI - Structural transition from dimeric to tetrameric i-motif, caused by the presence of TAA at the 3'-end of human telomeric C-rich sequence. AB - Widely dispersed in genomic DNA, the tandem C-rich repetitive stretches may fold below physiological pH, into i-motif structures, stabilized by C.C(+) pairing. Herein, structural status of a 9-mer stretch d(CCCTAACCC), [the truncated double repeat of human telomeric sequence], and its extended version, comprising of additional--TAA segment at the 3'-end, representing the complete double repeat d(CCCTAACCCTAA), has been investigated. The pH dependent monophasic UV-melting, Gel and CD data suggested that while the truncated version adopts a bimolecular i motif structure, its complete double repeat (12-mer) sequence exists in two (bimolecular and tetramolecular) forms. A model is proposed for the tetramolecular i-motif with conventional C.C(+) base pairs, additionally stabilized by asymmetric A.A base pairs at the -3' TAA flanking ends and Watson Crick A.T hydrogen bonding between intervening bases on antiparallel strands. Expanding the known topologies of DNA i-motifs, such atypical geometries of i motifs may have implications in their recognition by proteins. PMID- 19780130 TI - NSAID drugs release from injectable microspheres produced by supercritical fluid emulsion extraction. AB - Supercritical fluid emulsion extraction is an innovative technology that uses supercritical carbon dioxide (SC-CO(2)) to extract the dispersed oily phase of an emulsion. This technology was used to produce poly-lactic-co-glycolic acid (PLGA) microspheres charged with two common NSAIDs: piroxicam (PX) and diclophenac sodium (DF). Single (O/W) and double (W/O/W) emulsions were tested and a comparative study between the characteristics of the microspheres obtained by SC CO(2) extraction and the ones produced by conventional solvent evaporation (SE) is proposed. Varying the droplet dimensions, microspheres with mean diameters (MDs) of 1, 2, and 3 microm were obtained; however, the microspheres produced by SC-CO(2) gave always a better reproduction of the MD of original droplets because aggregation phenomena often modify the mean size and distribution of the microparticles produced by SE. Moreover, very efficient drug loadings (88% w/w of DF in PLGA using W/O/W emulsion and 97% of PX w/w in PLGA starting from O/W emulsion) were measured in the products obtained by SC-CO(2), respectively; whereas, the SE produced a drug loading of 30% in the case of double emulsion and of 70% for single emulsion. Solvent residue of 10 ppm was also measured by SC CO(2) technology against the 600 ppm of the SE products. The release profiles of the entrapped drugs were also monitored to check the structure of the microspheres produced by this new technology. PMID- 19780132 TI - Thermogravimetric investigation of the hydration behaviour of hydrophilic matrices. AB - This article proposes thermogravimetric analysis (TGA) as a useful method to investigate the hydration behaviour of hydrophilic matrix tablets containing hydroxypropylmethylcellulose (HPMC), sodium carboxymethylcellulose (NaCMC) or a mixture of these two polymers and four drugs with different solubility. The hydration behaviour of matrix systems was studied as a function of the formulation composition and of the dissolution medium pH. TGA results suggest that the hydration of matrices containing HPMC is pH-independent and not affected by the characteristics of the loaded drug; this confirms HPMC as a good polymer to formulate controlled drug delivery systems. On the other hand, the performances of NaCMC matrix tablets are significantly affected by the medium pH and the hydration and swelling of this ionic polymer is influenced by the loaded drug. For systems containing the two polymers, HPMC plays a dominant role in the hydration/dissolution process at acidic pH, while at near neutral pH both the cellulose derivatives exert a significant influence on the hydration performance of systems. The results of this work show that TGA is able to give quantitative highlights on the hydration behaviour of polymeric materials; thus this technique could be a helpful tool to support conventional hydration/swelling/dissolution studies. PMID- 19780131 TI - Plasma pharmacokinetics and tissue disposition of novel dextran methylprednisolone conjugates with peptide linkers in rats. AB - The plasma and tissue disposition of two novel dextran prodrugs of methylprednisolone (MP) containing one (DMP-1) or five (DMP-5) amino acids as linkers were studied in rats. Single 5-mg/kg doses (MP equivalent) of each prodrug or MP were administered intravenously, and blood and tissue samples were collected. Prodrug and drug concentrations were quantitated using HPLC, and noncompartmental pharmacokinetic parameters were estimated. Whereas conjugation of MP with dextran in both prodrugs substantially decreased the clearance of the drug by approximately 200-fold, the accumulations of the drug in the liver, spleen, and kidneys were significantly increased by conjugation. However, the extent of accumulation of DMP-1 in these tissues was substantially greater than that for DMP-5. Substantial amounts of MP were regenerated from both prodrugs in the liver and spleen, with the rate of release from DMP-5 being twice as fast as that from DMP-1. However, the AUCs of MP regenerated from DMP-1 in the liver and spleen were substantially higher than those after DMP-5. In contrast, in the kidneys, the AUC of MP regenerated from DMP-5 was higher than that after DMP-1 administration. These data suggest that DMP-1 may be more suitable than DMP-5 for targeting immunosuppression to the liver and spleen. PMID- 19780133 TI - Characterization of niosomes prepared with various nonionic surfactants for paclitaxel oral delivery. AB - Nonionic surfactant based vesicles (niosomes) are novel drug delivery systems formed from the self-assembly of nonionic amphiphiles in aqueous media. In the present study niosomal formulations of Paclitaxel (PCT), an antineoplastic agent, were prepared using different surfactants (Tween 20, 60, Span 20, 40, 60, Brij 76, 78, 72) by film hydration method. PCT was successfully entrapped in all of the formulations with encapsulation efficiencies ranging between 12.1 +/- 1.36% and 96.6 +/- 0.482%. Z-average sizes of the niosomes were between 229.3 and 588.2 nm. Depending on the addition of the negatively charged dicetyl phosphate to the formulations negative zeta potential values were obtained. High surface charges showed that niosomes can be suspended in water well and this is beneficial for their storage and administration. PCT released from niosomes by a diffusion controlled mechanism. The slow release observed from these formulations might be beneficial for reducing the toxic side effects of PCT. The niosome preparation method was found to be repeatable in terms of size distribution, zeta potential and % drug loading values. The efficiency of niosomes to protect PCT against gastrointestinal enzymes (trypsin, chymotrypsin, and pepsin) was also evaluated for PCT oral delivery. Among all formulations, gastrointestinal stability of PCT was well preserved with Span 40 niosomes. PMID- 19780134 TI - Granule size distribution of tablets. AB - The purpose of this study was to determine the variation in the granule size distribution in a die of an eccentric tableting machine. Theophylline anhydrate and alpha-lactose monohydrate were granulated with an aqueous solution of polyvinylpyrrolidone, using an instrumented fluid bed granulator. The granules were tabletted, using an instrumented eccentric tableting machine. Punch forces were recorded and tablets were collected in order during the tableting process. Powder samples, which had the same mass as the tablets, were also collected from the die for particle size determination. The particle size distribution was measured, using a spatial filtering technique. In addition, the segregation of microcrystalline cellulose pellets during tableting was analyzed. The particle size distribution changed dramatically during the tableting process, due to a segregation phenomenon. PMID- 19780135 TI - Evaluation of phospholipid and liposomal S-adenosyl methionine for the treatment of liver injury in a murine model. AB - We have used a murine model of Acetaminophen induced hepatoxicity to determine if S-adenosyl methionine 1,4 butanedisulfonate (SD4) in liposomes can prevent liver injury when administered immediately prior to acetaminophen, as judged by serum aspartate aminotransferase and alanine aminotransferase levels, and histological evidence of liver necrosis. No protection was observed when mice received 1 g/kg unencapsulated SD4. Partial protection was observed with 5 or 0.5 mg/kg SD4 in unextruded distearoylphosphatidylglycerol (DSPG) liposomes. Protection comparable to that seen in mice receiving encapsulated SD4 is achieved when mice received lipid alone in equivalent amounts, suggesting that the contribution of encapsulated SD4 to the efficacy of the liposomes may be minimal. Unextruded distearoylphosphatidylcholine (DSPC) liposomes show only slight effects even at 50 mg/kg SD4. This is likely caused by the size of unextruded DSPC lipsomes, because extruded DSPC liposomes, whose size is smaller, are of comparable efficacy to unextruded DSPG liposomes. PMID- 19780136 TI - High throughput thermostability screening of monoclonal antibody formulations. AB - Differential scanning fluorimetry (DSF) was employed to increase the throughput of the thermostability screening of monoclonal antibody (mAb) formulations. The method consists of measuring the fluorescence intensity of a polarity sensitive probe at gradually increasing temperatures, and obtaining the transition temperature of exposure of the hydrophobic regions of proteins (T(h)). The change in fluorescence intensity was directly related to protein unfolding levels and temperatures. The results from thermostability measurements were compared with the data acquired using differential scanning calorimetry (DSC), and a good correlation between T(h) and the temperature of protein unfolding or melting (T(m)) was observed. The method was applied to screen four mAb molecules in 84 different buffers. The studies revealed a good correlation of T(h) values with the known effects of pH and excipients on protein stability in solution. Specifically, the elevated aggregation levels induced by salt, low pH, and high protein concentrations could be successfully predicted by this thermal stability screening. This method is efficient, with high throughput capability, and could be widely applied in the biopharmaceutical industry for formulation and process development, and characterization. PMID- 19780137 TI - The intestinal absorption of a prodrug of the mGlu2/3 receptor agonist LY354740 is mediated by PEPT1: in situ rat intestinal perfusion studies. AB - LY354740 is a potent mGlu2/3 agonist with a limited oral bioavailability. Its alanyl prodrug, LY544344, showed high affinity to the intestinal peptide transporter PEPT1, and improved the oral bioavailability of LY354740 in various animal models. The aim of the present study was to investigate the mechanism of in vivo absorption of the dipeptidic prodrug LY544344. The permeabilities of LY544344 and LY354740 were examined in the rat in situ single-pass intestinal perfusion model. The intestinal absorptive flux of LY354740 was shown to be very low in comparison with LY544344. The absorptive flux of LY544344 could best be described by a Michaelis-Menten process in parallel with a linear process. The estimated parameters were: J(max) = 26.7 x 10(-5) micromol/(cm(2)-s), K(m) = 2.6 mM. The absorptive permeability of LY544344 was reduced to approximately 5% of control in the presence of excess Gly-Sar, a known PEPT1 substrate. Intracellular accumulation of LY354740 and LY544344, estimated postperfusion, showed high levels of LY354740 over LY544344 at all perfusate concentrations studied. However, there was a decline in the intracellular ratio of LY354740 to LY544344 at higher concentrations, suggesting that the metabolic activation to release LY354740 is saturable. PMID- 19780138 TI - Dielectric study of equimolar acetaminophen-aspirin, acetaminophen-quinidine, and benzoic acid-progesterone molecular alloys in the glass and ultraviscous states and their relevance to solubility and stability. AB - Equimolar mixtures of acetaminophen-aspirin, acetaminophen-quinidine, and benzoic acid-progesterone have been vitrified and dielectric properties of their glassy and ultraviscous alloys have been studied. For 20 K/min heating rate, their T(g)s are 266, 330, and 263 K, respectively. The relaxation has an asymmetric distribution of times, and the distribution parameter increases with increase in temperature. The dielectric relaxation time varies with T according to the Vogel Fulcher-Tammann equation, log(10)(tau(0)) = A(VFT) + [B(VFT)/(T - T(0))], where A(VFT), B(VFT), and T(0) are empirical constants. The equilibrium permittivity is highest for the aspirin-acetaminophen and lowest for the benzoic acid progesterone alloy, indicating a substantial interpharmaceutical hydrogen bonding that makes the alloy more stable against crystallization than the pure components. The benzoic acid-progesterone alloy is thermodynamically the most nonideal. It showed cold crystallization on heating, which is attributed to its relatively greater magnitude of the JG relaxation in relation to its alpha relaxation. It is argued that the difference between the free energy of an alloy and the pure components would have an effect on the solubility. Studies of solution thermodynamics of a glassy molecular alloy may be useful for optimizing choice of components and composition to form molecular alloys and to impact drug delivery. PMID- 19780143 TI - Abstracts of the 23rd Annual North American Cystic Fibrosis Conference, Minneapolis, Minnesota, USA, October 15-17, 2009. PMID- 19780139 TI - Calixarene-entrapped nanoemulsion for uranium extraction from contaminated solutions. AB - Accidental cutaneous contamination by actinides such as uranium occurring to nuclear power plant workers can lead to their dissemination in other tissues and induce severe damages. Until now, no specific emergency treatment for such contamination has been developed. The aim of the present work was to formulate a tricarboxylic calix[6]arene molecule, known to exhibit good affinity and selectivity for complexing uranium, within a topical delivery system for the treatment of skin contamination. Since calixarene was shown to reduce oil/water interfacial tension, we have designed an oil-in-water nanoemulsion, taking advantage of the small droplet size offering a high contact surface with the contaminated aqueous medium. Characterization of the calixarene nanoemulsion was performed by determination of the oily droplet size, zeta potential and pH, measured as a function of the calixarene concentration. The obtained results have confirmed the surface localization of calixarene molecules being potentially available to extract uranyl ions from an aqueous contaminated solution. In a preliminary experiments, the calixarene nanoemulsion was used for the removal of free uranium from an aqueous contaminated solution. Results showed that the calixarene nanoemulsion extracted up to 80 +/- 5% of uranium, which demonstrates the potential interest of this delivery system for uranium skin decontamination. PMID- 19780144 TI - Utilization of in vitro Caco-2 permeability and liver microsomal half-life screens in discovering BMS-488043, a novel HIV-1 attachment inhibitor with improved pharmacokinetic properties. AB - Optimizing pharmacokinetic properties to improve oral exposure is a common theme in modern drug discovery. In the present work, in vitro Caco-2 permeability and microsomal half-life screens were utilized in an effort to guide the structure activity relationship in order to improve the pharmacokinetic properties of novel HIV-1 attachment inhibitors. The relevance of the in vitro screens to in vivo pharmacokinetic properties was first demonstrated with a number of program compounds at the early stage of lead optimization. The Caco-2 permeability, tested at 200 microM, was quantitatively predictive of in vivo oral absorption, with complete absorption occurring at a Caco-2 permeability of 100 nm/s or higher. The liver microsomal half-life screen, conducted at 1 microM substrate concentration, can readily differentiate low-, intermediate-, and high-clearance compounds in rats, with a nearly 1:1 correlation in 12 out of 13 program compounds tested. Among the >100 compounds evaluated, BMS-488043 emerged as a lead, exhibiting a Caco-2 permeability of 178 nm/s and a microsomal half-life predictive of a low clearance (4 mL/min/kg) in humans. These in vitro characteristics translated well to the in vivo setting. The oral bioavailability of BMS-488043 in rats, dogs, and monkeys was 90%, 57%, and 60%, respectively. The clearance was low in all three species tested, with a terminal half-life ranging from 2.4 to 4.7 h. Furthermore, the oral exposure of BMS-488043 was significantly improved (6- to 12-fold in rats and monkeys) compared to the prototype compound BMS-378806 that had a suboptimal Caco-2 permeability (51 nm/s) and microsomal half-life. More importantly, the improvements in preclinical pharmacokinetics translated well to humans, leading to a >15-fold increase in the human oral exposure of BMS-488043 than BMS-378806 and enabling a clinical proof-of-concept for this novel class of anti-HIV agents. The current studies demonstrated the valuable role of in vitro ADME screens in improving oral pharmacokinetics at the lead optimization stage. PMID- 19780145 TI - Measurement of brain perfusion, blood volume, and blood-brain barrier permeability, using dynamic contrast-enhanced T(1)-weighted MRI at 3 tesla. AB - Assessment of vascular properties is essential to diagnosis and follow-up and basic understanding of pathogenesis in brain tumors. In this study, a procedure is presented that allows concurrent estimation of cerebral perfusion, blood volume, and blood-brain permeability from dynamic T(1)-weighted imaging of a bolus of a paramagnetic contrast agent passing through the brain. The methods are applied in patients with brain tumors and in healthy subjects. Perfusion was estimated by model-free deconvolution using Tikhonov's method (gray matter/white matter/tumor: 72 +/- 16/30 +/- 8/56 +/- 45 mL/100 g/min); blood volume (6 +/- 2/4 +/- 1/7 +/- 6 mL/100 g) and permeability (0.9 +/- 0.4/0.8 +/- 0.3/3 +/- 5 mL/100 g/min) were estimated by using Patlak's method and a two-compartment model. A corroboration of these results was achieved by using model simulation. In addition, it was possible to generate maps on a pixel-by-pixel basis of cerebral perfusion, cerebral blood volume, and blood-brain barrier permeability. PMID- 19780146 TI - Magnetic resonance elastography: Inversions in bounded media. AB - Magnetic resonance elastography is a noninvasive imaging technique capable of quantifying and spatially resolving the shear stiffness of soft tissues by visualization of synchronized mechanical wave displacement fields. However, magnetic resonance elastography inversions generally assume that the measured tissue motion consists primarily of shear waves propagating in a uniform, infinite medium. This assumption is not valid in organs such as the heart, eye, bladder, skin, fascia, bone and spinal cord, in which the shear wavelength approaches the geometric dimensions of the object. The aim of this study was to develop and test mathematical inversion algorithms capable of resolving shear stiffness from displacement maps of flexural waves propagating in bounded media such as beams, plates, and spherical shells, using geometry-specific equations of motion. Magnetic resonance elastography and finite element modeling of beam, plate, and spherical shell phantoms of various geometries were performed. Mechanical testing of the phantoms agreed with the stiffness values obtained from finite element modeling and magnetic resonance elastography data, and a linear correlation of r(2) >or= 0.99 was observed between the stiffness values obtained using magnetic resonance elastography and finite element modeling data. In conclusion, we have demonstrated new inversion methods for calculating shear stiffness that may be more appropriate for waves propagating in bounded media. PMID- 19780147 TI - Optimized MRI contrast for on-resonance proton exchange processes of PARACEST agents in biological systems. AB - Image contrast associated with paramagnetic chemical exchange saturation transfer agents can be generated by off-resonance irradiation of agent-bound water or amide protons or on-resonance irradiation of bulk water. Previously, a four-pool model was developed to describe an in vivo system. The model incorporated the magnetization transfer effect from macromolecules when using off-resonance irradiation. In the current study, this four-pool model is modified to describe the in vivo system when using on-resonance irradiation. The influences of pulse power, pulse duration, the chemical shift of bound water, the proton exchange rate between bulk water and bound water, and agent concentration on the on resonance paramagnetic agent chemical exchange effects were simulated using a WALTZ-16 pulse train in the absence and presence of the macromolecule pool. The results demonstrated that while contrast increases with pulse duration in aqueous solution, there is an optimal pulse duration that maximizes on-resonance paramagnetic agent chemical exchange effects contrast in vivo. This predication was verified by experimental spectroscopic and imaging results from aqueous solution, bovine serum albumin phantoms, and a tissue phantom containing thulium DOTAM (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetamide)-glycine-lysine. This model can be used to optimize sequence parameters to maximize in vivo on resonance paramagnetic agent chemical exchange effects contrast. PMID- 19780148 TI - Partial fourier reconstruction through data fitting and convolution in k-space. AB - A partial Fourier acquisition scheme has been widely adopted for fast imaging. There are two problems associated with the existing techniques. First, the majority of the existing techniques demodulate the phase information and cannot provide improved phase information over zero-padding. Second, serious artifacts can be observed in reconstruction when the phase changes rapidly because the low resolution phase estimate in the image space is prone to error. To tackle these two problems, a novel and robust method is introduced for partial Fourier reconstruction, using k-space convolution. In this method, the phase information is implicitly estimated in k-space through data fitting; the approximated phase information is applied to recover the unacquired k-space data through Hermitian operation and convolution in k-space. In both spin echo and gradient echo imaging experiments, the proposed method consistently produced images with the lowest error level when compared to Cuppen's algorithm, projection onto convex sets based iterative algorithm, and Homodyne algorithm. Significant improvements are observed in images with rapid phase change. Besides the improvement on magnitude, the phase map of the images reconstructed by the proposed method also has significantly lower error level than conventional methods. PMID- 19780149 TI - Teaching bovine abdominal anatomy: use of a haptic simulator. AB - Traditional methods of teaching anatomy to undergraduate medical and veterinary students are being challenged and need to adapt to modern concerns and requirements. There is a move away from the use of cadavers to new technologies as a way of complementing the traditional approaches and addressing resource and ethical problems. Haptic (touch) technology, which allows the student to feel a 3D computer-generated virtual environment, provides a novel way to address some of these challenges. To evaluate the practicalities and usefulness of a haptic simulator, first year veterinary students at the Royal Veterinary College, University of London, were taught basic bovine abdominal anatomy using a rectal palpation simulator: "The Haptic Cow." Over two days, 186 students were taught in small groups and 184 provided feedback via a questionnaire. The results were positive; the majority of students considered that the simulator had been useful for appreciating both the feel and location of key internal anatomical structures, had helped with their understanding of bovine abdominal anatomy and 3D visualization, and the tutorial had been enjoyable. The students were mostly in favor of the small group tutorial format, but some requested more time on the simulator. The findings indicate that the haptic simulator is an engaging way of teaching bovine abdominal anatomy to a large number of students in an efficient manner without using cadavers, thereby addressing some of the current challenges in anatomy teaching. PMID- 19780150 TI - Application of DENSE-MR-elastography to the human heart. AB - Typically, MR-elastography (MRE) encodes the propagation of monochromatic acoustic waves in the MR-phase images via sinusoidal gradients characterized by a detection frequency equal to the frequency of the mechanical vibration. Therefore, the echo time of a conventional MRE sequence is typically longer than the vibration period which is critical for heart tissue exhibiting a short T(2). Thus, fast acquisition techniques like the so-called fractional encoding of harmonic motions were developed for cardiac applications. However, fractional encoding of harmonic motions is limited since it is two orders of magnitude less sensitive to motion than conventional MRE sequences for low-frequency vibrations. Here, a new sequence is derived from the so-called displacement encoding with stimulated echoes (DENSE) sequence. This sequence is more sensitive to displacement than fractional encoding of harmonic motions, and its spectral specificity is equivalent to conventional MRE sequences. The theoretical spectral properties of this new motion-encoding technique are validated in a phantom and excised pork heart specimen. An excellent agreement is found for the measured displacement fields using classic MRE and displacement encoding with stimulated echoes MRE (8% maximum difference). In addition, initial in vivo results on a healthy volunteer clearly show propagating shear waves at 50 Hz. Thus, displacement encoding with stimulated echoes MRE is a promising technique for motion encoding within short T(2)* materials. PMID- 19780151 TI - Improved SNR efficiency in gradient echo coronary MRA with high temporal resolution using parallel imaging. AB - Contemporary coronary magnetic resonance angiography techniques suffer from signal-to-noise ratio (SNR) constraints. We propose a method to enhance SNR in gradient echo coronary magnetic resonance angiography by using sensitivity encoding (SENSE). While the use of sensitivity encoding to improve SNR seems counterintuitive, it can be exploited by reducing the number of radiofrequency excitations during the acquisition window while lowering the signal readout bandwidth, therefore improving the radiofrequency receive to radiofrequency transmit duty cycle. Under certain conditions, this leads to improved SNR. The use of sensitivity encoding for improved SNR in three-dimensional coronary magnetic resonance angiography is investigated using numerical simulations and an in vitro and an in vivo study. A maximum 55% SNR enhancement for coronary magnetic resonance angiography was found both in vitro and in vivo, which is well consistent with the numerical simulations. This method is most suitable for spoiled gradient echo coronary magnetic resonance angiography in which a high temporal and spatial resolution is required. PMID- 19780152 TI - Sources of hepatic glycogen synthesis during an oral glucose tolerance test: Effect of transaldolase exchange on flux estimates. AB - Sources of hepatic glycogen synthesis during an oral glucose tolerance test were evaluated in six healthy subjects by enrichment of a 75-g glucose load with 6.67% [U-(13)C]glucose and 3.33% [U-(2)H(7)]glucose and analysis of plasma glucose and hepatic uridine diphosphate-glucose enrichments (sampled as urinary menthol glucuronide) by (2)H and (13)C nuclear magnetic resonance. The direct pathway contribution, as estimated from the dilution of [U-(13)C]glucose between plasma glucose and glucuronide, was unexpectedly low (36 +/- 5%). With [U (2)H(7)]glucose, direct pathway estimates based on the dilution of position 3 (2)H-enrichment between plasma glucose and glucuronide were significantly higher (51 +/- 6%, P = 0.05). These differences reflect the exchange of the carbon 4, 5, and 6 moiety of fructose-6-phosphate and glyceraldehyde-3-phosphate catalyzed by transaldolase. As further evidence of this exchange, (2)H-enrichments in glucuronide positions 4 and 5 were inferior to those of position 3. From the difference in glucuronide positions 5 and 3 enrichments, the fraction of direct pathway carbons that experienced transaldolase exchange was estimated at 21 +/- 4%. In conclusion, the direct pathway contributes only half of hepatic glycogen synthesis during an oral glucose tolerance test. Glucose tracers labeled in positions 4, 5, or 6 will give significant underestimates of direct pathway activity because of transaldolase exchange. PMID- 19780154 TI - Early changes in the apparent diffusion coefficient (ADC) in a mouse model of Sandhoff's disease occur prior to disease symptoms and behavioral deficits. AB - Sandhoff's disease is a lysosomal storage disease in which the ganglioside GM2 accumulates in lysosomes. It has been reported that MRI cannot detect abnormalities in spin echo images in clinically presymptomatic Sandhoff's disease patients. Because one of the results of GM2 accumulation is cell swelling and lysosomal distension, our goal was to determine if changes in the diffusion of water is perturbed. We utilized the MRI imaging modality diffusion-weighted imaging to measure the apparent diffusion coefficient in a mouse models of Sandhoff's disease, the hexb-/- mouse, and determined if diffusion-weighted imaging could be utilized to detect early changes prior to behavioral or overt disease symptom onset. Here we report for the first time a comprehensive behavioral characterization of the hexb-/- mouse in conjunction with the apparent diffusion coefficient measurement. Our data indicate that the apparent diffusion coefficient decreases in the hexb-/- mouse in many but not all brain regions prior to disease symptoms (<3.5 to 4 months of age) and behavioral deficits (3 months of age). The magnitude of the decrease ranged from 4-18%. PMID- 19780153 TI - Tyrosine polyethylene glycol (PEG)-micelle magnetic resonance contrast agent for the detection of lipid rich areas in atherosclerotic plaque. AB - Vulnerable or high-risk atherosclerotic plaques often exhibit large lipid cores and thin fibrous caps that can lead to deadly vascular events when they rupture. In this study, polyethylene glycol (PEG)-micelles that incorporate a gadolinium diethylenetriamine pentaacetic acid (Gd-DTPA) amphiphile were used as an MR contrast agent. In an approach inspired by lipoproteins, the micelles were functionalized with tyrosine residues, an aromatic, lipophilic amino acid, to reach the lipid-rich areas of atherosclerotic plaque in a highly efficient manner. These micelles were applied to apolipoprotein E(-/-) (ApoE(-/-)) mice as a model of atherosclerosis. The abdominal aortas of the animals were imaged using T(1)-weighted (T(1)W) high-resolution MRI at 9.4T before and up to 48 h after the administration of the micelles. PEG-micelles modified with 15% tyrosine residues yielded a significant enhancement of the abdominal aortic wall at 6 and 24 h postinjection (pi) as compared to unmodified micelles. Fluorescence microscopy on histological sections of the abdominal aorta showed a correlation between lipid rich areas and the distribution of the functionalized contrast agent in plaque. Using a simple approach, we demonstrated that lipid-rich areas in atherosclerotic plaque of ApoE(-/-) mice can be detected by MRI using Gd-DTPA micelles. PMID- 19780156 TI - Independent slab-phase modulation combined with parallel imaging in bilateral breast MRI. AB - Independent slab-phase modulation allows three-dimensional imaging of multiple volumes without encoding the space between volumes, thus reducing scan time. Parallel imaging further accelerates data acquisition by exploiting coil sensitivity differences between volumes. This work compared bilateral breast image quality from self-calibrated parallel imaging reconstruction methods such as modified sensitivity encoding, generalized autocalibrating partially parallel acquisitions and autocalibrated reconstruction for Cartesian sampling (ARC) for data with and without slab-phase modulation. A study showed an improvement of image quality by incorporating slab-phase modulation. Geometry factors measured from phantom images were more homogenous and lower on average when slab-phase modulation was used for both mSENSE and GRAPPA reconstructions. The resulting improved signal-to-noise ratio (SNR) was validated for in vivo images as well using ARC instead of GRAPPA, illustrating average SNR efficiency increases in mSENSE by 5% and ARC by 8% based on region of interest analysis. Furthermore, aliasing artifacts from mSENSE reconstruction were reduced when slab-phase modulation was used. Overall, slab-phase modulation with parallel imaging improved image quality and efficiency for 3D bilateral breast imaging. PMID- 19780155 TI - High spatial and temporal resolution cardiac cine MRI from retrospective reconstruction of data acquired in real time using motion correction and resorting. AB - Cine MRI is used for assessing cardiac function and flow and is typically based on a breath-held, segmented data acquisition. Breath holding is particularly difficult for patients with congestive heart failure or in pediatric cases. Real time imaging may be used without breath holding or ECG triggering. However, despite the use of rapid imaging sequences and accelerated parallel imaging, real time imaging typically has compromised spatial and temporal resolution compared with gated, segmented breath-held studies. A new method is proposed that produces a cardiac cine across the full cycle, with both high spatial and temporal resolution from a retrospective reconstruction of data acquired over multiple heartbeats during free breathing. The proposed method was compared with conventional cine images in 10 subjects. The resultant image quality for the proposed method (4.2 +/- 0.4) without breath holding or gating was comparable to the conventional cine (4.4 +/- 0.5) on a five-point scale (P = n.s.). Motion corrected averaging of real-time acquired cardiac images provides a means of attaining high-quality cine images with many of the benefits of real-time imaging, such as free-breathing acquisition and tolerance to arrhythmias. PMID- 19780157 TI - Motion correction of single-voxel spectroscopy by independent component analysis applied to spectra from nonanesthetized pediatric subjects. AB - For single-voxel spectroscopy, the acquisition of the spectrum is typically repeated n times and then combined with a factor sqrt[n] in order to improve the signal-to-noise ratio. In practice, the acquisitions are not only affected by random noise but also by physiologic motion and subject movements. Since the influence of physiologic motion such as cardiac and respiratory motion on the data is limited, it can be compensated for without data loss. Individual acquisitions hampered by subject movements, on the other hand, need to be rejected if no correction or compensation is possible. If the individual acquisitions are stored, it is possible to identify and reject the motion disturbed acquisitions before averaging. Several automatic algorithms were investigated using a dataset of spectra from nonanesthetized infants with a gestational age of 40 weeks. Median filtering removed most subject movement artifacts, but at the cost of increased sensitivity to random noise. Neither independent component analysis nor outlier identification with multiple comparisons has this problem. These two algorithms are novel in this context. The peak height values of the metabolites were increased compared to the mean of all acquisitions for both methods, although primarily for the ICA method. PMID- 19780158 TI - Methods for metabolic evaluation of prostate cancer cells using proton and (13)C HR-MAS spectroscopy and [3-(13)C] pyruvate as a metabolic substrate. AB - Prostate cancer has been shown to undergo unique metabolic changes associated with neoplastic transformation, with associated changes in citrate, alanine, and lactate concentrations. (13)C high resolution-magic angle spinning (HR-MAS) spectroscopy provides an opportunity to simultaneously investigate the metabolic pathways implicated in these changes by using (13)C-labeled substrates as metabolic probes. In this work, a method to reproducibly interrogate metabolism in prostate cancer cells in primary culture was developed using HR-MAS spectroscopy. Optimization of cell culture protocols, labeling parameters, harvesting, storage, and transfer was performed. Using [3-(13)C] pyruvate as a metabolic probe, (1)H and (13)C HR-MAS spectroscopy was used to quantify the net amount and fractional enrichment of several labeled metabolites that evolved in multiple cell samples from each of five different prostate cancers. Average enrichment across all cancers was 32.4 +/- 5.4% for [3-(13)C] alanine, 24.5 +/- 5.4% for [4-(13)C] glutamate, 9.1 +/- 2.5% for [3-(13)C] glutamate, 25.2 +/- 5.7% for [3-(13)C] aspartate, and 4.2 +/- 1.0% for [3-(13)C] lactate. Cell samples from the same parent population demonstrated reproducible fractional enrichments of alanine, glutamate, and aspartate to within 12%, 10%, and 10%, respectively. Furthermore, the cells produced a significant amount of [4-(13)C] glutamate, which supports the bioenergetic theory for prostate cancer. These methods will allow further characterization of metabolic properties of prostate cancer cells in the future. Magn Reson Med, 2009. (c) 2009 Wiley-Liss, Inc. PMID- 19780159 TI - Whole-heart imaging using undersampled radial phase encoding (RPE) and iterative sensitivity encoding (SENSE) reconstruction. AB - Whole-heart isotropic nonangulated cardiac magnetic resonance (CMR) is becoming an important protocol in simplifying MRI, since it reduces the need of cumbersome planning of angulations. However the acquisition times of whole-heart MRI are prohibitive due to the large fields of view (FOVs) and the high spatial resolution required for depicting small structures and vessels. To address this problem, we propose a three-dimensional (3D) acquisition scheme that combines Cartesian sampling in the readout direction with an undersampled radial scheme in the phase-encoding plane. Different undersampling patterns were investigated in combination with an iterative sensitivity encoding (SENSE) reconstruction and a 32-channel cardiac coil. Noise amplification maps were calculated to compare the performance of the different patterns using iterative SENSE reconstruction. The radial phase-encoding (RPE) scheme was implemented on a clinical MR scanner and tested on phantoms and healthy volunteers. The proposed method exhibits better image quality even for high acceleration factors (up to 12) in comparison to Cartesian acquisitions. PMID- 19780160 TI - SSFP signal with finite RF pulses. AB - The theoretical description of steady state free precession (SSFP) sequences is generally well accepted and unquestioned, although it is based on instantaneously acting radiofrequency (RF) pulses. In practice, however, all excitation processes are finite, thereby questioning the overall validity of the common SSFP signal description for use with finite RF pulses. In this paper, finite RF pulse effects on balanced SSFP signal formation are analyzed as a function of the RF time, the pulse repetition time, the flip angle (alpha) and relaxation times (T(1,2)). The observed signal modulations from finite RF pulses (compared to infinitesimal ones) can range from only a few percent (for RF time/pulse repetition time << 1, alpha << 90 degrees, T(2)/T(1) approximately 1) to over 10% (for RF time/pulse repetition time << 1, alpha approximately 90 degrees, T(2)/T(1) << 1) and may even exceed 100% in the limit of RF time/pulse repetition time --> 1 (for alpha approximately 90 degrees, T(2)/T(1) << 1). As a result, a revision of SSFP signal theory is indicated not only for reasons of completeness but also seems advisable, e.g., for all quantitative SSFP methods. A simple modification for the common balanced SSFP equation is derived that provides an accurate framework for SSFP signal description over a wide variety of practical and physiologic parameters. PMID- 19780161 TI - In vivo proton MRS to quantify anesthetic effects of pentobarbital on cerebral metabolism and brain activity in rat. AB - To quantitatively investigate the effects of pentobarbital anesthesia on brain activity, brain metabolite concentrations and cerebral metabolic rate of glucose, in vivo proton MR spectra, and electroencephalography were measured in the rat brain with various doses of pentobarbital. The results show that (1) the resonances attributed to propylene glycol, a solvent in pentobarbital injection solution, can be robustly detected and quantified in the brain; (2) the concentration of most brain metabolites remained constant under the isoelectric state (silent electroencephalography) with a high dose of pentobarbital compared to mild isoflurane anesthesia condition, except for a reduction of 61% in the brain glucose level, which was associated with a 37% decrease in cerebral metabolic rate of glucose, suggesting a significant amount of "housekeeping" energy for maintaining brain cellular integrity under the isoelectric state; and (3) electroencephalography and cerebral metabolic activities were tightly coupled to the pentobarbital anesthesia depth and they can be indirectly quantified by the propylene glycol resonance signal at 1.13 ppm. This study indicates that in vivo proton MR spectroscopy can be used to measure changes in cerebral metabolite concentrations and cerebral metabolic rate of glucose under varied pentobarbital anesthesia states; moreover, the propylene glycol signal provides a sensitive biomarker for quantitatively monitoring these changes and anesthesia depth noninvasively. PMID- 19780162 TI - Sodium long-component T(2)(*) mapping in human brain at 7 Tesla. AB - Sodium ((23)Na) MRI may provide unique information about the cellular and metabolic integrity of the brain. The quantification of tissue sodium concentration from (23)Na images with nonzero echo time (TE) requires knowledge of tissue-specific parameters that influence the single-quantum sodium signal such as transverse (T(2)) relaxation times. We report the sodium ((23)Na) long component of the effective transverse relaxation time T(2) (*) values obtained at 7 T in several brain regions from six healthy volunteers. A two-point protocol based on a gradient-echo sequence optimized for the least error per given imaging time was used (TE(1) = 12 ms; TE(2) = 37 ms; averaged N(1) = 5; N(2) = 15 times; pulse repetition time = 130 ms). The results reveal that long T(2)(*) component of tissue sodium (mean +/- standard deviation) varied between cerebrospinal fluid (54 +/- 4 ms) and gray (28 +/- 2 ms) and white (29 +/- 2 ms) matter structures. The results also show that the long T(2)(*) component increases as a function of the main static field B(0), indicating that correlation time of sodium ion motion is smaller than the time-scale defined by the Larmor frequency. These results are a prerequisite for the quantification of tissue sodium concentration from (23)Na MRI scans with nonzero echo time, will contribute to the design of future measurements (such as triple-quantum imaging), and themselves may be of clinical utility. PMID- 19780163 TI - 4D retrospective black blood trueFISP imaging of mouse heart. AB - The purpose of this study was to demonstrate the feasibility of steady-state True fast imaging with steady precession (TrueFISP) four-dimensional imaging of mouse heart at high resolution and its efficiency for cardiac volumetry. Three dimensional cine-imaging of control and hypoxic mice was carried out at 4.7 T without magnetization preparation or ECG-triggering. The k-space lines were acquired with the TrueFISP sequence (pulse repetition time/echo time = 4/2 ms) in a repeated sequential manner. Retrospective reordering of raw data allowed the reconstruction of 10 three-dimensional images per cardiac cycle. The acquisition scheme used an alternating radiofrequency phase and sum-of-square reconstruction method. Black-blood three-dimensional images at around 200 mum resolution were produced without banding artifact throughout the cardiac cycle. High contrast to noise made it possible to estimate cavity volumes during diastole and systole. Right and left ventricular stroke volume was significantly higher in hypoxic mice vs controls (20.2 +/- 2 vs 15.1 +/- 2; P < 0.05, 24.9 +/- 2 vs 20.4 +/- 2; P < 0.05, respectively). In conclusion, four-dimensional black-blood TrueFISP imaging in living mice is a method of choice to investigate cardiac abnormalities in mouse models. PMID- 19780164 TI - Optimizing saturation-recovery measurements of the longitudinal relaxation rate under time constraints. AB - The saturation-recovery method using two and three recovery times is studied for conditions in which the sum of recovery times is 1.5T(1) to 3T(1), where T(1) is the longitudinal relaxation time. These conditions can reduce scan time considerably for long T(1) species and make longitudinal relaxation rate R(1) (R(1) = 1/T(1)) mapping for body fluids clinically feasible. Monte Carlo computer simulation is carried out to determine the ideal set of recovery times under various constraints of the sum of recovery times. The ideal set is found to be approximately invariant to the signal-to-noise ratio. For the three-point method, two of the recovery times should be set the same or approximately the same and should be shorter than the third one. Only marginal improvements in accuracy and precision can be achieved by the three-point method over the two-point method under a common constraint of the sum of recovery times. Three-dimensional, high resolution, whole-brain saturation-recovery scans on volunteers with a fast-spin echo technique (XETA) and completed in a scan time of 10 min generated R(1) measurements of cerebrospinal fluid (T(1) approximately 4 s) in agreement with the computer simulation and literature results, which demonstrates the clinical feasibility of applying the two-point saturation-recovery method for R(1) mapping for long relaxation components. PMID- 19780166 TI - Simplified (13)C metabolic modeling for simplified measurements of cerebral TCA cycle rate in vivo. AB - (13)C NMR spectroscopy is a unique tool to measure the cerebral tricarboxylic acid (TCA) cycle rate in vivo. The measurement relies on metabolic modeling of glutamate C3 and C4 enrichment time courses during a (13)C-glucose intravenous infusion. Usual metabolic models require the plasma glucose and (13)C-glucose time courses as input functions, as well as the knowledge of Michaelis-Menten kinetics parameters governing passage through the blood-brain barrier. It is shown in the present work that, when using an infusion protocol yielding a rapidly stable plasma glucose fractional enrichment, metabolic modeling can be simplified in such a manner that this additional information on input function and glucose transport is no longer required, significantly simplifying the measurement of cerebral TCA cycle rate in vivo. PMID- 19780165 TI - Proton MRS detects metabolic changes in hormone sensitive and resistant human prostate cancer models CWR22 and CWR22r. AB - 17-Allylamino, 17-demethoxygeldanamycin (17-AAG), an effective inhibitor of the heat shock protein hsp90, preferentially inhibiting tumor hsp90 compared to hsp90 from normal cells, has shown promising results against several cancers, including hormone-resistant prostate cancer. Levels of several oncogenic proteins critical to tumor growth and progression, such as androgen receptor and HER2/neu, were reduced 4 h post 17-allylamino, 17-demethoxygeldanamycin treatment. Posttreatment metabolic changes have also been observed in several tumor cell lines. In this study, total choline distributions in hormone sensitive CWR22 and hormone resistant CWR22r prostate cancer xenograft tumors in mice were measured before and at 4 h and 48 h after a single-bolus 17-allylamino, 17-demethoxygeldanamycin treatment at 100 mg/kg, using proton MR spectroscopy. Our results show that tumor total choline levels declined 4 h after the treatment for CWR22 (P = 0.001) and 48 h post treatment for CWR22r (P = 0.003). Metabolic changes, in particular of total choline intensity detected by proton magnetic resonance spectroscopic imaging (MRSI), are consistent with the observed immunohistochemistry changes, tumor growth inhibition for CWR22r (P = 0.01 at 14 days post treatment), and a constant prostate specific antigen level versus increasing prostate specific antigen for control CWR22 (P = 0.01). Metabolic changes in total choline by proton MRSI can be used as an early biomarker of response for advanced-stage prostate cancer in targeted therapy such as 17-allylamino, 17 demethoxygeldanamycin. PMID- 19780167 TI - Split gradient coils for simultaneous PET-MRI. AB - Combining positron emission tomography (PET) and MRI necessarily involves an engineering tradeoff as the equipment needed for the two modalities vies for the space closest to the region where the signals originate. In one recently described scanner configuration for simultaneous positron emission tomography MRI, the positron emission tomography detection scintillating crystals reside in an 80-mm gap between the 2 halves of a 1-T split-magnet cryostat. A novel set of gradient and shim coils has been specially designed for this split MRI scanner to include an 110-mm gap from which wires are excluded so as not to interfere with positron detection. An inverse boundary element method was necessarily employed to design the three orthogonal, shielded gradient coils and shielded Z0 shim coil. The coils have been constructed and tested in the hybrid positron emission tomography-MRI system and successfully used in simultaneous positron emission tomography-MRI experiments. PMID- 19780168 TI - In vivo assessments of mucus dynamics in the rat lung using a Gd-Cy5.5-bilabeled contrast agent for magnetic resonance and optical imaging. AB - Dysfunctions in mucociliary clearance are associated with the accelerated loss of lung function in several respiratory diseases. Approaches enabling the in vivo visualization of mucus dynamics in rodents at high resolution and sensitivity would be beneficial for experimental lung research. We describe the synthesis and characterization of two bilabeled amino dextran-based probes binding specifically to mucin. Labeling of secreted mucus and of mucin in goblet cells in the lungs of lipopolysaccharide-challenged rats has been demonstrated in vivo with near infrared fluorescence and MRI and confirmed by histology. The effects of uridine triphosphate were then studied in lipopolysaccharide-challenged rats by simultaneously administering the imaging probe and the compound. The data suggest that uridine triphosphate increased the mucociliary clearance, but at the same time induced a release of mucin from goblet cells, thus not contributing to the overall reduction of mucus in the lung. The approach outlined here enables one to derive information on mucus clearance, as well as secretion. Such a global view on mucus dynamics may prove invaluable when testing new pharmacological agents aimed at improving mucociliary clearance. PMID- 19780169 TI - Enhanced positive-contrast visualization of paramagnetic contrast agents using phase images. AB - Iron oxide-based MRI contrast agents are increasingly being used to noninvasively track cells, target molecular epitopes, and monitor gene expression in vivo. Detecting regions of contrast agent accumulation can be challenging if resulting contrast is subtle relative to endogenous tissue hypointensities. A postprocessing method is presented that yields enhanced positive-contrast images from the phase map associated with T(2)*-weighted MRI data. As examples, the method was applied to an agarose gel phantom doped with superparamagnetic iron oxide nanoparticles and in vivo and ex vivo mouse brains inoculated with recombinant viruses delivering transgenes that induce overexpression of paramagnetic ferritin. Overall, this approach generates images that exhibit a 1- to 8-fold improvement in contrast-to-noise ratio in regions where paramagnetic agents are present compared to conventional magnitude images. This approach can be used in conjunction with conventional T(2)* pulse sequences, requires no prescans or increased scan time, and can be applied retrospectively to previously acquired data. PMID- 19780170 TI - Inverse reconstruction method for segmented multishot diffusion-weighted MRI with multiple coils. AB - Each k-space segment in multishot diffusion-weighted MRI is affected by a different spatially varying phase which is caused by unavoidable motions and amplified by the diffusion-encoding gradients. A proper image reconstruction therefore requires phase maps for each segment. Such maps are commonly derived from two-dimensional navigators at relatively low resolution but do not offer robust solutions. For example, phase variations in diffusion-weighted MRI of the brain are often characterized by high spatial frequencies. To overcome this problem, an inverse reconstruction method for segmented multishot diffusion weighted MRI is described that takes advantage of the full k-space data acquired from multiple receiver coils. First, the individual coil sensitivities are determined from the non-diffusion-weighted acquisitions by regularized nonlinear inversion. These coil sensitivities are then used to estimate accurate motion associated phase maps for each segment by iterative linear inversion. Finally, the coil sensitivities and phase maps serve to reconstruct artifact-free images of the object by iterative linear inversion, taking advantage of the data of all segments. The efficiency of the new method is demonstrated for segmented diffusion-weighted stimulated echo acquisition mode MRI of the human brain. PMID- 19780172 TI - Estimation of brain iron concentration in vivo using a linear relationship between regional iron and apparent transverse relaxation rate of the tissue water at 4.7T. AB - Maps of the apparent transverse relaxation time (T(2) were collected on a transaxial plane across the basal ganglia in 54 healthy subjects at 4.7T using a multiecho adiabatic spin-echo (MASE) imaging sequence. We attempted to quantify the nonhemin iron concentration ([Fe]) in various brain regions in vivo based on the linear relationship between the apparent relaxation rate constant (R(2) = 1/T(2) and regional [Fe], as demonstrated previously in 12 subjects. The calculated [Fe] in five gray matter (GM) regions agreed well with the previously reported regional iron distribution as well as reproduced its age-dependent change. In particular, a decrease of iron in the thalamus region in subjects over 30 years of age was demonstrated while an upward trend was shown in other regions. Furthermore, the average R(2) in each GM region in subjects over 30 years of age showed a deviation from the regression line with [Fe] in an identical manner to that obtained in the previous 12 subjects. This strongly suggests that there is a systematic regional factor affecting R(2), in addition to iron. Interregional difference in the macromolecular mass fraction (f(M)) explained this systematic deviation well. When accounting for f(M) in the analysis, the apparent transverse relaxation rate seems to give a significantly better estimation of regional [Fe]. PMID- 19780174 TI - Improved signal spoiling in fast radial gradient-echo imaging: Applied to accurate T(1) mapping and flip angle correction. AB - In conventional spoiled gradient echo imaging utilizing quadratic radio frequency (RF) spoiling, nonideal signal intensities are often generated, particularly when repetition time is short and/or excitation flip angle (FA) becomes larger. This translates to significant errors in various quantitative applications based on T(1)-weighted image intensities. In this work, a novel spoiling scheme is proposed, based on random gradient moments and RF phases. This scheme results in a non-steady-state condition, but achieves ideal mean signal intensity. In order to suppress artifacts created by the inter-TR signal variations and at the same time attain the ideal signal intensity, radial data acquisition is utilized. The proposed method achieves ideal spoiling for a wide range of T(1), T(2), TR, and FAs. Phantom and in vivo experiments demonstrate improved performance for T(1) mapping and FA correction when compared with conventional RF spoiling methods. PMID- 19780173 TI - Assessment of intervertebral disc degeneration with magnetic resonance single voxel spectroscopy. AB - This study examined the feasibility of using short-echo water-suppressed point resolved spectroscopy (PRESS) on a clinical 3T magnetic resonance (MR) scanner for evaluating biochemical changes in degenerated bovine and cadaveric human intervertebral discs. In bovine discs (N = 17), degeneration was induced with papain injections. Degeneration of human cadaveric discs (N = 27) was assessed using the Pfirrmann grading on T(2)-weighted images. Chemicals in the carbohydrate region (Carb), the choline head group (Cho), the N-acetyl region (N acetyl), and the lipid and lactate region (Lac+Lip) were quantified using (1)H PRESS, and were compared between specimens with different degrees of degeneration. The correlation between the spectroscopic findings and glycosaminoglycan (GAG) quantification using biochemical assays was determined. Significant differences were found between the ratios (N-acetyl/Cho, N acetyl/Lac+Lip) acquired before and after papain injection in bovine discs. For human cadaveric discs, significant differences in the ratios (N-acetyl/Carb, N acetyl/Lac+Lip) were found between discs having high and low Pfirrmann scores. Significant correlations were found between N-acetyl/Lac+Lip and GAG content in bovine discs (R = 0.77, P = 0.0007) and cadaveric discs (R = 0.83, P < 0.0001). Significant correlation between N-acetyl/Cho and GAG content was also found in cadaver discs (R = 0.64, P = 0.0039). This study demonstrates for the first time that short-echo PRESS on a clinical 3T MR scanner can be used to noninvasively and can reproducibly quantify metabolic changes associated with degeneration of intervertebral discs. PMID- 19780175 TI - Measurement of glycine in human prefrontal brain by point-resolved spectroscopy at 7.0 tesla in vivo. AB - Measurement of glycine in human frontal brain by an optimized point-resolved spectroscopy sequence at 7 T is reported. Echo time dependencies of the overlapping coupled resonances of myo-inositol, free choline, and threonine were investigated with density matrix simulations, incorporating the slice-selective radiofrequency and gradient pulses. The numerical simulations indicated that the selectivity of the 3.55-ppm glycine singlet is maximized at (TE(1), TE(2)) = (101, 51) ms. Phantom experiments indicated that the myo-inositol peak amplitude between 3.5 and 3.6 ppm is reduced by a factor of 30 following the optimized point-resolved spectroscopy, as predicted by the simulation. From LCModel analyses, the glycine concentration in the medial prefrontal cortex in healthy adults was estimated, with a mean Cramer-Rao lower bound of 7 +/- 1% (mean +/- standard deviation; n = 7), to be 0.8 +/- 0.1 mM, with reference to total creatine at 8 mM. PMID- 19780176 TI - An internal reference model-based PRF temperature mapping method with Cramer-Rao lower bound noise performance analysis. AB - The conventional phase difference method for MR thermometry suffers from disturbances caused by the presence of lipid protons, motion-induced error, and field drift. A signal model is presented with multi-echo gradient echo (GRE) sequence using a fat signal as an internal reference to overcome these problems. The internal reference signal model is fit to the water and fat signals by the extended Prony algorithm and the Levenberg-Marquardt algorithm to estimate the chemical shifts between water and fat which contain temperature information. A noise analysis of the signal model was conducted using the Cramer-Rao lower bound to evaluate the noise performance of various algorithms, the effects of imaging parameters, and the influence of the water:fat signal ratio in a sample on the temperature estimate. Comparison of the calculated temperature map and thermocouple temperature measurements shows that the maximum temperature estimation error is 0.614 degrees C, with a standard deviation of 0.06 degrees C, confirming the feasibility of this model-based temperature mapping method. The influence of sample water:fat signal ratio on the accuracy of the temperature estimate is evaluated in a water-fat mixed phantom experiment with an optimal ratio of approximately 0.66:1. PMID- 19780177 TI - Maximum linear-phase spectral-spatial radiofrequency pulses for fat-suppressed proton resonance frequency-shift MR Thermometry. AB - Conventional spectral-spatial pulses used for water-selective excitation in proton resonance frequency-shift MR thermometry require increased sequence length compared to shorter wideband pulses. This is because spectral-spatial pulses are longer than wideband pulses, and the echo time period starts midway through them. Therefore, for a fixed echo time, one must increase sequence length to accommodate conventional spectral-spatial pulses in proton resonance frequency shift thermometry. We introduce improved water-selective spectral-spatial pulses for which the echo time period starts near the beginning of excitation. Instead of requiring increased sequence length, these pulses extend into the long echo time periods common to PRF sequences. The new pulses therefore alleviate the traditional tradeoff between sequence length and fat suppression. We experimentally demonstrate an 11% improvement in frame rate in a proton resonance frequency imaging sequence compared to conventional spectral-spatial excitation. We also introduce a novel spectral-spatial pulse design technique that is a hybrid of previous model- and filter-based techniques and that inherits advantages from both. We experimentally validate the pulses' performance in suppressing lipid signal and in reducing sequence length compared to conventional spectral-spatial pulses. PMID- 19780178 TI - Metabolite proton T(2) mapping in the healthy rhesus macaque brain at 3 T. AB - The structure and metabolism of the rhesus macaque brain, an advanced model for neurologic diseases and their treatment response, is often studied noninvasively with MRI and (1)H-MR spectroscopy. Due to the shorter transverse relaxation time (T(2)) at the higher magnetic fields these studies favor, the echo times used in (1)H-MR spectroscopy subject the metabolites to unknown T(2) weighting, decreasing the accuracy of quantification which is key for inter- and intra animal comparisons. To establish the "baseline" (healthy animal) T(2) values, we mapped them for the three main metabolites' T(2)s at 3 T in four healthy rhesus macaques and tested the hypotheses that their mean values are similar (i) among animals; and (ii) to analogs regions in the human brain. This was done with three dimensional multivoxel (1)H-MR spectroscopy at (0.6 x 0.6 x 0.5 cm)(3) = 180 microL spatial resolution over a 4.2 x 3.0 x 2.0 = 25 cm(3) ( approximately 30%) of the macaque brain in a two-point protocol that optimizes T(2) precision per unit time. The estimated T(2)s in several gray and white matter regions are all within 10% of those reported in the human brain (mean +/- standard error of the mean): N-acetylaspartate = 316 +/- 7, creatine = 177 +/- 3, and choline = 264 +/- 9 ms, with no statistically significant gray versus white matter differences. PMID- 19780179 TI - SENSE shimming (SSH): A fast approach for determining B(0) field inhomogeneities using sensitivity coding. AB - The pursuit of ever higher field strengths and faster data acquisitions has led to the construction of coil arrays with high numbers of elements. With the sensitivity encoding (SENSE) technique, it has been shown that the sensitivity of those elements can be used for spatial image encoding. Here, a proof-of-principle is presented of a method that can be considered an extreme case of the SENSE approach, completely abstaining from using encoding gradients. The resulting sensitivity encoded free-induction decay (FID) data are then not used for imaging, but for determining B(0) field inhomogeneity distribution. The method has therefore been termed "SENSE shimming" (SSH). In phantom experiments the method's ability to detect inhomogeneities of up to the second order is demonstrated. PMID- 19780180 TI - Quantification of non-water-suppressed MR spectra with correction for motion induced signal reduction. AB - Intrascan subject movement in clinical MR spectroscopic examinations may result in inconsistent water suppression that distorts the metabolite signals, frame-to frame variations in spectral phase and frequency, and consequent reductions in the signal-to-noise ratio due to destructive averaging. Frame-to-frame phase/frequency corrections, although reported to be successful in achieving constructive averaging, rely on consistent water suppression, which may be difficult in the presence of intrascan motion. In this study, motion correction using non-water-suppressed data acquisition is proposed to overcome the above difficulties. The time-domain matrix-pencil postprocessing method was used to extract water signals from the non-water-suppressed spectroscopic data, followed by phase and frequency corrections of the metabolite signals based on information obtained from the water signals. From in vivo experiments on seven healthy subjects at 3.0 T, quantification of metabolites using the unsuppressed water signal as a reference showed improved correlation with water-suppressed data acquired in the absence of motion (R(2) = 0.9669; slope = 0.94). The metabolite concentrations derived using the proposed approach were in good agreement with literature values. Computer simulations under various degrees of frequency and phase variations further demonstrated robust performance of the time-domain postprocessing approach. PMID- 19780181 TI - Quantitative (19)F imaging of nmol-level F-nucleotides/-sides from 5-FU with T(2) mapping in mice at 9.4T. AB - A unique acquisition method is proposed for quantitative, high-sensitivity (19)F MR spectroscopic imaging for the study of drug distribution aiming at nmol-level metabolite information in mice. The use of fast spin echo (FSE) at 9.4T allowed us to obtain whole-body images with minimal effect of magnetic susceptibility and to acquire several metabolite signals simultaneously by the method of interleaved multifrequency selection. Modified 2-shot FSE was designed for simultaneous, high sensitivity (19)F imaging and T(2) mapping. A time course study including all the main metabolites at 10-minute resolution was attained with an oral dose of 1-2 mmol 5-fluorouracil (5-FU) (130-260 mg)/kg in mice. With acquisition parameters optimized for in vivo T(2) of 40 ms, images of F-nucleotides/-sides, effective anabolites of the anticancer drug 5-FU, were obtained at the level of 200 nmol in the tumor for all the mice studied with a linear correlation (R = 0.96) between image intensity and the quantity determined in the excised tissue. The method exhibits potential capability of molecular imaging with a variety of (19)F labeled compounds and drug evaluation. PMID- 19780183 TI - Hyperpolarized (13)C magnetic resonance detection of carboxypeptidase G2 activity. AB - Carboxypeptidase G2 (CPG2) is a bacterial enzyme that is currently employed in a range of targeted cancer chemotherapy strategies such as gene-directed enzyme prodrug therapy (GDEPT). Employing dynamic nuclear polarization (DNP) and natural abundance (13)C magnetic resonance spectroscopy (MRS), we observed the CPG2 mediated conversion of a novel hyperpolarized reporter probe 3,5-difluorobenzoyl L-glutamic acid (3,5-DFBGlu) to 3,5-difluorobenzoic acid (3,5-DFBA) and L glutamic acid (L-Glu) in vitro. Isotopic labeling of the relevant nuclei with (13)C in 3,5-DFBGlu or related substrates will yield a further factor of 100 increase in the signal-to-noise. We discuss the feasibility of translating these experiments to generate metabolic images of CPG2 activity in vivo. PMID- 19780184 TI - Quantitative assessment of myocardial T2 relaxation times in cardiac amyloidosis. AB - PURPOSE: To evaluate cardiac MRI (CMR) in the diagnosis of cardiac amyloidosis by comparing the T2 relaxation times of left ventricular myocardium in a pilot patient group to a normal range established in healthy controls. MATERIALS AND METHODS: Forty-nine patients with suspected amyloidosis-related cardiomyopathy underwent comprehensive CMR examination, which included assessment of myocardial T2 relaxation times, ventricular function, resting myocardial perfusion, and late gadolinium enhancement (LGE) imaging. T2-weighted basal, mid, and apical left ventricular slices were acquired in each patient using a multislice T2 magnetization preparation spiral sequence. Slice averaged T2 relaxation times were subsequently calculated offline and compared to the previously established normal range. RESULTS: Twelve of the 49 patients were confirmed to have cardiac amyloidosis by biopsy. There was no difference in mean T2 relaxation times between the amyloid cases and normal controls (51.3 +/- 8.1 vs. 52.1 +/- 3.1 msec, P = 0.63). Eleven of the 12 amyloid patients had abnormal findings by CMR, eight having LGE involving either ventricles or atria and four demonstrating resting subendocardial perfusion defects. CONCLUSION: CMR is a potentially valuable tool in the diagnosis of cardiac amyloidosis. However, calculation of myocardial T2 relaxation times does not appear useful in distinguishing areas of amyloid deposition from normal myocardium. PMID- 19780185 TI - Proximal femur bone marrow blood perfusion indices are reduced in hypertensive rats: a dynamic contrast-enhanced MRI study. AB - PURPOSE: To investigate the differences in proximal femoral bone marrow blood perfusion indices between hypertensive and normotensive rats using perfusion magnetic resonance imaging (MRI). MATERIALS AND METHODS: Six-month-old male spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were used (12 of each). Dynamic contrast-enhanced MRI of the right hip was performed after bolus injection of Gd-DOTA administered through a tail vein cannula. In all, 800 images were acquired at 0.6 sec/image. Regions of interest (ROIs) were drawn comprising the medullary component of proximal femoral shaft and femoral head. MRI maximum enhancement (E(max)) and enhancement slope (E(slope)) were analyzed. RESULTS: The E(max) and E(slope) of proximal femoral shaft and femoral head of SHR were significantly lower than those of WKY (E(max): 107.4 +/- 18.2% vs. 130.6 +/- 21.5%, P = 0.009, and 76.0 +/- 12.5% vs. 97.9 +/- 6.9%, P < 0.001, respectively; E(slope): 3.01 +/- 0.63%/sec vs. 3.75 +/- 0.74%/sec, P = 0.016, and 1.95 +/- 0.33%/sec vs. 2.28 +/- 0.28%/sec, P = 0.012, respectively). The E(max) and E(slope) of femoral head were significantly lower than those of proximal femoral shaft in both SHR and WKY (P < 0.001). In both SHR and WKY, proximal femoral shaft and femoral head had a rather different contrast enhancement pattern. CONCLUSION: Proximal femoral shaft and femoral head bone marrow blood perfusion indices were significantly lower in hypertensive rats than in normotensive rats. Femoral head bone marrow was less perfused than proximal femoral shaft in both rats. PMID- 19780186 TI - Assessment of lipids in skeletal muscle by LCModel and AMARES. AB - PURPOSE: To process single voxel spectra of the human skeletal muscle by using an advanced method for accurate, robust, and efficient spectral fitting (AMARES) and by linear combination of model spectra (LCModel). To determine absolute concentrations of extra- (EMCL) and intramyocellular lipids (IMCL). MATERIALS AND METHODS: Single-voxel proton magnetic resonance spectroscopy (PRESS) was used to obtain the spectra of the calf muscles. Unsuppressed water line was used as a concentration reference. A new prior knowledge for AMARES was proposed to estimate the concentrations of EMCL and IMCL. The prior knowledge was derived from the spectrum of vegetable oil. The results were compared with the values estimated by LCModel. Absolute concentrations of total lipid content in millimoles per kilogram wet weight were used for the comparisons. RESULTS: Absolute concentrations of total lipid content in skeletal muscle were estimated by AMARES and LCModel. Very good correlation of the total fat (EMCL + IMCL) and IMCL concentrations was achieved between both data processing approaches. CONCLUSION: Assessment the absolute concentrations of muscular lipids by AMARES and LCModel can be performed with comparable accuracy. PMID- 19780187 TI - Improvements in carotid plaque imaging using a new eight-element phased array coil at 3T. AB - PURPOSE: To design and compare an eight-channel phased array (PA) coil for carotid imaging to an established four-channel PA design at 3T. MATERIALS AND METHODS: An eight-channel PA (8PA) coil was designed specifically for imaging the carotid bifurcation and compared with the existing four-channel (4PA) design using a phantom and by in vivo black-blood magnetic resonance imaging (MRI). The 8PA and 4PA were compared in terms of coverage, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). RESULTS: The 8PA showed up to 1.7-fold improvement in SNR at a depth of 3.5 cm and greater longitudinal coverage at a given SNR on a phantom. The 8PA showed improved vessel wall SNR for high spatial resolution (0.63 mm(2)) PD, T1, and T2 (1.7, 1.7, 1.6 times, respectively; P 130mg/dl) were observed in 20% of rural subjects and 47% of urban diabetics. High TG levels (34%) were seen in rural diabetics. 54% of urban diabetics were centrally obese and 57% were obese from the rural study site. From this study, it was seen that, illiteracy percentage was found to be higher in rural subjects. Also, greater number of people (70%) were in inadequate status for the needed patient awareness. 77% of patients belonging to the rural study area were found to be unaware for the hypoglycaemia. Low patient compliance was seen in urban diabetics as compared to their rural counterparts, and 34% of patients belonging to both study sites were found to have no knowledge for diabetic complications. High total cholesterol was found to be the commonest lipid profile abnormality in this study. Second commonest lipid abnormality was high LDL levels. Low HDL cholesterol was found to be more commonly in patients of age > 60 years than <60 years (21.42% vs. 18.18%). More female patients were overweight and obese as compared to male (33.33% vs. 19.23%). A Large population of diabetics was found to have a sedentary lifestyle. Rural patients were progressing towards more coronary risk factors as compared to the urban ones, mainly with the lipid profile abnormalities. Although our type 2 diabetic patients share similar coronary risk factors as compared to diabetic patients from different countries, our type 2 patients have got high prevalence of hypertension. Male diabetics had high prevalence of smoking habits. PMID- 19780286 TI - Drug prescribing pattern and disease pattern in KMC Duwakot Health Center. AB - OBJECTIVE: To ascertain the disease pattern and drug prescribing pattern of the patients attending Kathmandu Medical College Health Center, Duwakot. METHODS: It is a cross sectional study conducted at Kathmandu Medical College (KMC) health Center, Duwakot during the month of Ashad to Mangshir, 2060. The sample size included was 292 patients attending the Health Center during this period. Prescription details were used as study tools to acquire information regarding patient's name, age, complaints for which consultation was sought, investigations, diagnosis, name of the drug which is prescribed and instruction for diet. RESULTS: Age of patients in this study ranged from 0-80 years. A total of 165 (56.50%) were male and 127 (43.49%) were female. Out of 165 male of different age group ranging from 0-80 years, most of the patient i.e. 25(15.15%) were suffering from viral fever followed by cut/injury, allergy, diarrhoea, abdomen pain, fungal infection, HTN (hypertension), cold/cough/sore throat, sinusitis, muscular skeletal pain, joint pain, contact dermatitis, acute peptic disease (APD), headache, worm infestation, tonsillitis, pharyngitis, dizziness, eye infection, chest infection, calf and backache, viral rashes, hypo pigmentation, tension/depression, Urinary tract infection (UTI), coliolilethis, diabetes, p/r bleeding and insect bite poisoning. Out of 127 female of different age group ranging from 0-80 years 21 (16.54%) patients were suffering from viral fever, followed by backache, cold/cough/sore throat, allergy, weakness, acne, diarrhoea, sinusitis, flue, pneumonia, headache, acid peptic disease, dysmenorrhoea, Lower Respiratory Tract Infection and Upper Respiratory Tract Infection, muscular skeletal pain, joint pain, eye infection, Urinary Tract Infection, hypertension, abdomen pain, tonsillitis, tinea corporis, rhinitis, ear problems, insect bite poisoning, CSOM, trichiasis, uteric colic, otitis media, entropion and epiphora, worm infestation and pharyngitis. All together 384 drugs (23 category) were distributed to the different patient of different age group ranging from 0-80 years, to cure the different types of diseases. Among the different categories of drugs prescribed antipyretic (31.8%), antibiotics (17.2%) and (Non steroid Antiinflammatory Drugs (NSAIDs) (11.2%) were the most common. CONCLUSION: The assessment of the existing prescribing practices in a health facility helps to identify the specific drug use problems, which need to be understood before any meaningful intervention can take place. A prescription provides an insight into a prescriber's attitude to the disease being treated and the nature of health care delivery system in the community. The average number of drugs per prescription is an important index of a prescription audit. It is preferable to keep the number of drugs per prescription as low as possible to minimize the risk of drug interactions, development of bacterial resistance and hospital costs. PMID- 19780287 TI - Effect of lead on male gonadal activity in albino rats. AB - Lead poisoning often prevails in children and industrial workers. The present study was undertaken to evaluate the effects of lead acetate on steroidogenic functions of testis, serum levels of gonadotrophins and testosterone in albino rats. Testicular steroidogenic activity was evaluated by measuring the activities of two steroidogenic key enzymes, Delta5-3beta hydroxysteroid dehydrogenase (Delta5-3beta-HSD) and 17beta-hydroxysteroid dehydrogenase (17beta-HSD). Administration of lead acetate at a dose of 8mg/kg body weight for 14 days lowered the weights of testes and accessory sex organs, and decreased testicular Delta5-3beta-HSD and 17beta-HSD activities and serum levels of FSH, LH and testosterone but 7 days of lead acetate administration showed no effect on the above parameters. This report is perhaps the first evidence to show that lead exerts some deleterious effects on testicular steroidogenesis indirectly by decreasing serum levels of gonadotropins. PMID- 19780288 TI - In vitro activity of cefazolin and ampicillin. AB - An in vitro antimicrobial sensitivity of Cefazolin and Ampicillin towards 85 strains of Staphylococcus aureus and 52 strains of Esch. Coli was carried out by Kirby-Baurer's Technique at Microbiology Dept. Nepalgunj Medical College, Nepal. 47% Staphylococcus aureus and 25% Esch. coli. were found sensitive to Cefazolin where as sensitivity pattern of Ampicillin was 19% and 7.74% respectively. PMID- 19780289 TI - Variations in termination of brachial artery--a case report. AB - Normally the brachial artery divides at the neck of the radius 2 to 3 cms below the crease of the elbow into two terminal branches namely ulnar and radial arteries .Common interrosseous artery arises from ulnar artery. In the present study there was difference in the terminations of brachial arteries in two limbs of the same body. In the left upper limb, the artery terminated into ulnar and radial arteries and the common interrosseous artery. In the right upper limb, the artery terminated into ulnar and radial arteries and the common interrosseous arteries were arising from the radial artery but not from ulnar artery. In both limbs radial and ulnar arteries were present anterior (superficial) to flexor group of muscles. There were also difference in the calibre of the above vessels. Hence the study was done on the terminations of the brachial artery and reported. PMID- 19780290 TI - Reproductive rights of Nepalese women: current status and future directions. PMID- 19780291 TI - Early management of acute ischemic stroke: review of literature and proposed guidelines. PMID- 19780292 TI - Preventive cardiology: a brief review from developing country viewpoint. PMID- 19780293 TI - An overview of undergraduate and postgraduate medical education in Nepal and elsewhere. AB - Though Health Sciences education started in the country as far back as 1934, it was only in 1978 that the MBBS course was started. The first postgraduate (PG) course, which was started, was the MD in general practice, which was started in 1982. It is over the course of the last 22 years, and more specifically after 1993, that there has been a spurt in postgraduate (PG) education. The rapid increase of medical schools/colleges within the country during the last decade, has been the main reason for fulfilling the demand of doctors with postgraduate degrees required for different faculty positions at the newly established medical colleges, This article also looks at the role of foreign qualifications vis-a-vis the local degree for the development of PG programmes within the country. PMID- 19780294 TI - An elective in KMC. PMID- 19780295 TI - Oncologic science on the move: cervical cancer screening. PMID- 19780296 TI - Patients and clinical practice guidelines development. PMID- 19780297 TI - Ovarian cancer clinical practice guidelines. PMID- 19780299 TI - Counterpoint: Intraperitoneal chemotherapy: an investigational treatment in ovarian cancer. AB - Intraperitoneal (IP) chemotherapy in ovarian cancer has been studied since 1978. Numerous phase II trials have been performed, which have shown that higher levels can be obtained in the peritoneal cavity compared with systemic circulation after administration of cytoxic agents in a large volume via a semi-permanent catheter. Three randomized trials have been performed in patients with ovarian cancer comparing different IP regimens to standard therapy with intravenous agents. The last two trials from the Gynecologic Oncology Group (GOG) and the Southwest Oncology Group (SWOG) compared two different IP regimens versus standard therapy with intravenous cisplatin plus paclitaxel. Although an improvement in progression-free survival was reported for the IP regimens, they have been associated with unacceptable toxicity, and no IP regimen can be considered standard therapy. Maintenance therapy with IP cisplatin also failed to improve survival in patients who obtained complete remission after intravenous chemotherapy. The GOG is considering another phase III trial of IP therapy that will compare a carboplatin-based regimen versus standard therapy with intravenous paclitaxel plus carboplatin. Unless such a trial shows an improvement in clinical outcome, intravenous carboplatin plus paclitaxel remains the standard of care and IP chemotherapy should not be used outside of a clinical trial. PMID- 19780298 TI - Point: Intraperitoneal chemotherapy in the management of ovarian cancer. AB - Both preclinical considerations and results of phase I safety and pharmacokinetic studies provided support for the argument that intraperitoneal antineoplastic drug delivery should be a rational approach to the management of ovarian cancer. Subsequently conducted phase II trials exploring regional treatment revealed surgically documented objective responses when the approach was employed as a second-line therapy. Recently, the results of three randomized phase III trials have shown that the use of primary cisplatin-based intraperitoneal therapy leads to superior survival compared with intravenous cisplatin-based treatment in patients with small-volume residual advanced ovarian cancer after initial surgical cytoreduction. Further exploration of this unique management strategy is indicated to develop an optimal approach that maintains the demonstrated enhanced efficacy while reducing the toxicity (principally because of cisplatin) of treatment. PMID- 19780300 TI - Surgery for ovarian cancer: rationale and guidelines. AB - Ovarian cancer is the second most common gynecologic cancer in women and the leading cause of death caused by gynecologic malignancy. Surgery plays a fundamental role in treating this challenging disease. Goals of primary surgery for ovarian cancer are to establish diagnosis, proper staging, determination of prognosis, and optimal cytoreduction of gross disease before chemotherapy for improved outcome. In addition to standard removal of the ovaries, uterus, omentum, and pelvic and para-aortic lymph nodes for early disease, extended surgical techniques used to debulk advanced disease include bowel resection, splenectomy, partial liver resection, peritoneal or diaphragmatic stripping, and use of laser or ultrasound (CUSA). Secondary surgery is used in a variety of situations. Second-look procedures were performed historically to determine response to chemotherapy to delineate duration of treatment, but now are best used in a research setting with the advent of improved chemotherapeutic agents. As a high percentage of patients have a gynecologic malignancy recurrence after primary treatment, many practitioners perform secondary cytoreductive procedures for recurrent disease. Additionally, in the recurrent setting, surgery may be necessary for relief of bowel obstruction and palliation of symptoms. Surgical management of ovarian cancer must be performed by surgeons, such as gynecologic oncologists, who have a firm understanding of the disease process, display good clinical judgment, and are adequately trained to perform the complex surgery that commonly is required for appropriate care. PMID- 19780301 TI - Cervical cancer screening clinical practice guidelines in oncology. PMID- 19780302 TI - High risk human papillomavirus testing: guidelines for use in screening, triage, and follow-up for the prevention and early detection of cervical cancer. AB - The changes in cervical cytology characterization agreed on by the Bethesda committee meeting in 2001 created a category of atypical findings that has caused some management confusion. By description, the characterization of cervical cytology as only atypical implies a less worrisome prognosis. However, more than 40% of high-grade (CIN II or III or cancer) will be discovered within this category. The development and Food and Drug Administration approval of the Hybrid Capture 2 (HC-2; Digene Corporation, Gaithersburg, MD) for detecting high-risk human papillomavirus (HR-HPV) subtypes and the subsequent level I evidence supporting use of this test in the triage of women with atypical cytology has revolutionized the management of this cytology. With this success has come numerous additional uses for HR-HPV testing in the treatment and follow-up of women with a variety of cytologic abnormalities. This article reviews the literature on uses of HR-HPV testing in this population, with reference to currently accepted guidelines. PMID- 19780303 TI - Liquid-based cytology: evaluation of effectiveness, cost-effectiveness, and application to present practice. AB - This article reviews the data available as of 2004 on the effectiveness and cost effectiveness of cervical screening with the two available cytologic methods, the conventional Papanicolaou (Pap; CP) smear and liquid-based cytology (LBC), and discusses the application of LBC to current practice. The majority of LBC studies are on the ThinPrep Pap Test (CYTYC, Boxsborough, MA) and the remainder are on SurePath (TriPath, Burlington, NC), which was previously known as AutoCyte Prep. LBC identified more low-grade squamous intraepithelial lesion (LSIL) Pap test results compared with paired conventional cytology in 17 of 21 ThinPrep and 9 of 12 SurePath "split-sample" studies considered to fulfill the criteria for inclusion in the British NHS Health Technology Assessment (HTA) evaluation of cervical cytology. In four of the six recent ThinPrep and one of two SurePath split-sample studies, more high-grade squamous intraepithelial lesion-positive (HSIL+) results were identified by LBC than by CP. All 15 "direct-to vial studies" meeting HTA criteria reported more LSIL+ results for LBC compared with CP, and all eight of the direct-to-vial studies reporting HSIL+ results separately showed increased detection of high-grade cytology interpretations. Fifteen studies met the criteria for evaluating sensitivity and specificity. Aggregate sensitivity for the CP was 71.5% and for LBC was 80.1%. Indirect comparisons of the two LBC methods did not detect a difference in sensitivity, and a meta-analysis of the six studies comparing specificity between CP and LBC found no difference. Other capabilities of LBC are improved specimen adequacy and the ability to do ancillary testing out of the liquid-based vial. In cost effective analyses based on models of disease natural history and/or the clinical effectiveness of each screening modality, screening with CP was always dominated by screening with LBC. Primary cervical screening guidelines issued by the American Cancer Society in 2002 recommend repeating the cytology biannually if liquid-based and annually if conventional. The gain in sensitivity, apparent cost effectiveness, and advantage of having a representative specimen for ancillary testing, support the use of LBC. PMID- 19780304 TI - Cervical cancer guidelines. Clinical practice guidelines in oncology. PMID- 19780305 TI - Combined chemotherapy and radiation therapy for cervical cancer. AB - More than 50% of patients with newly diagnosed cervical cancer will undergo radiation therapy as a primary treatment modality. Results from five phase III trials conducted by National Cancer Institute (NCI)-sponsored cooperative groups showed significant survival advantages from the addition of cisplatin-based chemotherapy to primary radiation therapy, changing the standard of care for patients with bulky or locally advanced cervical carcinoma. The majority of patients for whom treatment fails, however, have persistent pelvic disease. Other agents (alone or in combination with cisplatin) with potential synergy with radiation therapy should be studied. Future trials should investigate potential interrelationships between anemia, tumor hypoxia, angiogenesis, and the effectiveness of radiation therapy. Therapies specific to tumor hypoxia (tirapazamine) or strategies to maintain higher nadir hemoglobin levels during treatment (aggressive transfusion policies; erythropoietin) should also be studied. PMID- 19780306 TI - Introduction: Characterization of nonconductive materials. PMID- 19780307 TI - About the mechanisms of charging in EPMA, SEM, and ESEM with their time evolution. AB - The physical mechanisms involved in electron irradiation of insulating specimens are investigated by combining some simple considerations of solid-state physics (trapping mechanisms of electrons and secondary electron emission) with basic equations of electrostatics. To facilitate the understanding of the involved mechanisms only widely irradiated samples having a uniform distribution of trapping sites are considered. This starting hypothesis allows development of simple models for the trapped charge distributions in ground-coated specimens as investigated in electron probe microanalysis (EPMA) as well as for the bare specimens investigated in scanning electron microscopy (SEM) and environmental SEM (ESEM). Governed by self-regulation processes, the evolution of the electric parameters during the irradiation are also considered for the first time and practical consequences in EPMA, SEM, and ESEM are deduced. In particular, the widespread idea that the noncharging condition of SEM is obtained at a critical energy E2 (where delta + eta = 1 with delta and eta yields obtained in noncharging experiments) is critically discussed. PMID- 19780308 TI - Static and dynamic charges: changing perspectives and aims in electron microscopy. AB - In the context of electron microscopists' changing attitudes to charging effects, some basic aspects of these phenomenona are surveyed. Methods of mapping internal charge distributions such as doping levels in semiconductors, trap distributions, or internal electric fields in insulators are discussed. PMID- 19780309 TI - Charge trapping in dielectrics. AB - When a dielectric is irradiated by electrons with energy E of several kiloelectron volts, a large number of processes take place: backscattering of incident electrons, excitation and ionization of the electrons in the dielectric with binding energies lower than E, creation of excitons, radiative and nonradiative decays of the excited and ionized states, slowing down of the primary and secondary electrons, and thermalization in the conduction band. The thermalized electrons can move freely in the unoccupied conduction states of the material. If electric connection exists between the dielectric and the apparatus, then the charges normally flow out. Thermalized electrons can also be trapped in excited levels localized in the band gap of the dielectric and nonradiative and radiative recombinations from these levels can be observed. The number of the trapped electrons varies with the structural characteristics of the dielectric. In a monocrystal, this number is weak because the number of the defect states in the band gap is small, making the localization of the charges restricted. In contrast, in a polycrystal or amorphous material, the number of the trapped electrons can be large and increases with the disorder. Information on the charge effects suffered by the sample during its irradiation can be deduced by studying the trapping of electrons in localized states and, consequently, by analyzing radiations emitted from these states in the visible and X-ray ranges. In the case of oxides, F+ centers (oxygen-ion vacancy having trapped one electron) and F centers (F+ center having trapped a second electron) are generally present. We will show that the F+ <--> F conversion can be used to study the dynamic of the trapping in the oxides. Application to various samples of crystallized and amorphous alumina will be presented. PMID- 19780310 TI - Charge implantation measurement on electron-irradiated insulating materials by means of an SEM technique. AB - The goal of this article is first to review the charging effects occurring when an insulating material is subjected to electron irradiation in a scanning electron microscope (SEM) and next their consequences from both scanning electron microscopy and electron probe microanalysis (EPMA) points of view. When bare insulators are observed, the so-called pseudo mirror effect leads to an anomalous contrast and also to an erroneous surface potential, V(S), measurement when a Duane-Hunt limit (DHL) method is used. An alternative possibility is to use an electron toroidal spectrometer (ETS), specially adapted to a SEM, which directly gives the V(S) value. In the case of a bulk specimen coated with a grounded layer, although the layer prevents external effects of the trapped charge, the electric field beneath the coating is reinforced and leads to loss of ionizations that reduces the number of generated X-ray photons. To take into account both effects mentioned above, whether the studied insulator is coated or not, a method is proposed to deduce the trapped charge inside the insulator and the corresponding internal or external electric field. PMID- 19780311 TI - Charging processes in low vacuum scanning electron microscopy. AB - A framework is presented for understanding charging processes in low vacuum scanning electron microscopy. We consider the effects of electric fields generated above and below the specimen surface and their effects on various processes taking place in the system. These processes include the formation of an ionic space charge, field-enhanced electron emission, charge trapping and dissipation, and electron-ion recombination. The physical mechanisms behind each of these processes are discussed, as are the microscope operating conditions under which each process is most effective. Readily observable effects on gas gain curves, secondary electron images, and X-ray spectra are discussed. PMID- 19780312 TI - Charge contrast imaging of gibbsite using the variable pressure SEM. AB - The variable pressure scanning electron microscope (VP-SEM) allows imaging of insulators without the need for a conductive coating, due to charge neutralization at the surface from recombination of positive ions and surface electrons. Varying certain parameters such as pressure, bias, and working distance creates incomplete neutralization, and localized charging develops called charge contrast. Although the exact mechanism creating charge contrast imaging (CCI) is unknown, it is agreed that it is related to an optimum charge compensation. The behavior of the CCI is still vague, which presents a problem for determining the mechanisms. This article provides user-friendly methods of finding the optimum levels of charge contrast in the VP-SEM. We show that the CCI is obtained at optimum operating conditions where the specimen current is between 2.5 nA and 3.5 nA. The specimen current is a function of secondary electrons (SE) emission and ionization potential, producing an ion flux. Therefore an optimum specimen current represents the balanced conditions of SE emission and ion flux. Controlling the pressure, working distance, bias, scan rate, and beam current allows the microscopist to set the specimen current at this optimum level for charge contrast imaging. All the work was performed on gibbsite using the S3000N VP-SEM from Hitachi. PMID- 19780313 TI - Quantitative electron probe microanalysis of nonconducting specimens: science or art? AB - The influence of a lack of sufficient electrical conductivity on the results of quantitative electron probe microanalysis has been investigated on a number of oxides. The effect of surface charging and the way it alters the emitted X-ray signals has been studied. It is shown that the presence of conducting coatings, such as carbon or copper, will affect the interelement X-ray intensity ratios, whatever the thickness of the coating may be. Although the effects for heavier elements may be acceptable, they cannot be ignored for a light element such as oxygen, where strong variations with coating thickness were observed. Quantitative analyses of oxygen, on uncoated well-conducting oxide specimens, using uncoated well-conducting hematite (Fe2O3) as a standard yielded excellent results in the range between 4 and 40 kV with the phi (pz) software used. As soon as coated nonconducting specimens were examined, using the same hematite standard, coated under exactly the same conditions, widely scattering and noncoherent results were obtained. These discrepancies can only be attributed to a lack of conductivity. PMID- 19780314 TI - Assessing charging effects on spectral quality for X-ray microanalysis in low voltage and variable pressure/environmental scanning electron microscopy. AB - Energy dispersive X-ray spectrometry of uncoated insulators performed at low beam energy (incident energy < or = 5 keV) and in the variable pressure scanning electron microscope and the environmental scanning electron microscope is subject to spectral artifacts. Charging decelerates the incident beam electrons and reduces the impact energy, lowering the available overvoltage to excite characteristic X-ray peaks. The Duane-Hunt limit of the X-ray bremsstrahlung continuum is commonly used as a diagnostic of charging. Dynamic charging effects can hide the true impact of charging on the X-ray spectrum. Careful examination of the behavior of the X-ray spectrum with time and other variables is needed to avoid spectral artifacts, particularly on relative X-ray intensities. PMID- 19780315 TI - Microanalysis of porous materials. AB - A signal loss is generally reported in electron probe microanalysis (EPMA) of porous, highly divided materials like heterogeneous catalysts. The hypothesis generally proposed to explain this signal loss refers to porosity, roughness, energy losses at interfaces, or charging effects. In this work we investigate by Monte Carlo simulation all these physical effects and compare the simulated results with measurements obtained on a mesoporous alumina. A program using the PENELOPE package and taking into account these four physical phenomena has been written. Simulation results show clearly that neither porosity nor roughness, nor specific energy losses at interfaces, nor charging effects are responsible for the observed signal loss. Measurements performed with analysis of carbon and oxygen lead to a correct total of concentration. The signal loss is thus explained by a composition effect due to a carbon contamination brought by the sample preparation and to a lesser extent by a stoichiometry of the porous alumina different from a massive alumina. For this kind of high specific surface porous sample, a little surface contamination layer becomes an important volume contamination that can produce large quantification errors if the contaminant is not analyzed. PMID- 19780316 TI - Charge neutralization in the ESEM for quantitative X-ray microanalysis. AB - Quantitative chemical analysis by energy-dispersive X-ray spectrometry (EDS) in the environmental scanning electron microscope (ESEM) is difficult. This analysis is complicated by the spread of the electron beam by chamber gas molecules and the necessity for surface charge neutralization. Without charge neutralization, errors in quantitative analysis can range up to 15-20% relative. It is possible to achieve the error expected of traditional EDS, +/- 5% relative error, using a newly developed surface charge neutralization scheme for the ESEM. Estimates of accuracy and precision are based on studies of the National Bureau of Standards (now National Institutes for Science and Technology) Standard Reference Material 482, a series of certified copper-gold alloys. The scheme for charge neutralization requires an independent path to ground at or near the surface of the specimen. The current through the ground path must be maintained at zero by adjusting the voltage on the Gaseous Secondary Electron Detector when the sample chamber is at a gas pressure of 1-2 torr. This procedure forms the exact number of chamber gas positive ions to neutralize negative electrical charge on the specimen surface from electron bombardment. PMID- 19780317 TI - Monte Carlo modeling of electron scattering in nonconductive specimens. AB - Very low energy electrons in a solid should behave like Bloch electrons and will interact with perturbations of the atomic lattice, that is, with phonons. So we use the acoustic phonon scattering for replacing the elastic binary encounter approximation of the Mott scattering for electrons with low energies E < 100 eV. For ballistic electrons (1 eV < E < Eg) and higher energies up to 1 keV we determined the acoustic phonon scattering and the impact ionization rate by means of the "backscattering-versus-range" proof and respective eta(E0) - R(E0) diagrams. Electron trajectories demonstrate the relatively short range of primary electrons (PE) with energies E > 50 eV due to strong impact ionization losses (cascading) and the much greater range of secondary electrons (SE) with E < 50 eV, finally as a consequence of less effective phonon losses. The field-dependent transport parameters allow us to model the self-consistent charge transport and charging-up of insulating SiO2 layers during electron bombardment maintained by the current components of primary electrons jPE, secondary electrons jSE, and associated ballistic holes jBH, as well as by Fowler-Nordheim field injection jFN from the substrate. The resulting distributions of currents j(x, t), charges p(x, t), electric fields F(x, t), and the potential V(x, t) across the dielectric layer explain the phenomena of field-enhanced and field-blocked secondary electron emission with rates delta >or 0.05). CONCLUSION: Femur's length increasing also produces increasing of absolute anatomical parametars of distal femur which can produce rupture of anterior cruciate ligament, while relative dimensions do not show femur's length increasing. PMID- 19780333 TI - [Quality of life in patients with surgical treatment of hip fractures, preliminary study]. AB - INTRODUCTION: Fractures of the proximal segment of the femur occurring most commonly in elderly patients are a serious, both medical (orthopaedic) and socioeconomic, problem. MATERIAL AND METHODS: 46 patients (14 male and 32 female) operated for hip fracture in the January-June 2008 period, who were available for analysis (as 24 patients were not) were investigated. In addition to descriptive analysis, general health status-quality of life was assessed by means of SF-36 questionnaire comprising eight groups of questions determining the physical, psychological and social status of the patients within the 0 to 100 (problem) points range. RESULTS: The findings were that the average patient age was 74 years (76.9 for male patients and 74.06 fro female ones). The values of all eight parameters were lower by up to 89% in comparison to the pre-injury values, but improved by as much as 50% after six months (for physical functioning and the role of physical functioning) or by 30% for the role of emotions. The values never return to their pre-injury levels. In foreign studies, the parameters are higher, especially post-treatment values for vitality and role of emotions. CONCLUSION: In patients treated for hip fractures, it is necessary to carry out an assessment of general, physical, mental and social functioning of the patient in addition to the assessment of their clinical and radiological findings, so as to get a more realistic insight in the status of the treated and operated patients. The SF-36 questionnaire is widely used in such investigations along with other questionnaires. It is also necessary to investigate the general health status-quality of life of the entire healthy population in our country. PMID- 19780334 TI - [Evaluation of pulmonary and metabolic function in classic and laparoscopic cholecystectomy in patients with ASA I and ASA II scores]. AB - This is a prospective study of patients treated at the Center for Urgent Surgery, Clinical Center of Serbia. The patients were divided into two groups; i.e., the controls consisted of 30 subjects, who underwent conventional cholecystectomy, and studied group with 30 patients who had laparoscopic cholecystectomy. The patients were homogenized by ASA score (ASA I and ASA II) and on population basis. Hemodynamic parameters and 4 time-point pulmonary function tests were monitored in both groups. Peritoneal insufflation resulted in significant increase of systemic arterial pressure (23%), mean arterial pressure (23.8%), systemic vascular resistance (65%), pulmonary vascular resistance (90%), and significant reduction of cardiac output (24%) and cardiac index (51%). Pneumoperitoneum caused transient restriction of pulmonary function by reducing the thoracic and lung compliance. Fall of pH concentration, increase of PaCO2 and ET CO2 without any changes of PaO2, SO2, base excess and bicarbonate ions concentrations were the sequelae of CO2 absorption from peritoneal cavity. Postoperative "hypothermi", i.e. lowering of body temperature for 0.3 degrees C was the consequence of sudden gas expansion (Joule-Thompson phenomenon), which implies continuous flow of dry gas under pressure over peritoneal surface. Tissue damage factors (D-dimer, C-reactive protein, Protein C) were significantly lower in laparoscopic group, meaning that such mode of treatment resulted in minor postoperative pain and shorter period of recovery. Laparoscopy is a revolution in surgery. Definite success of any laparoscopic intervention depends on anesthesia as its crucial factor, at the same time meeting the patient's wish and expectations to be free from pain and discharged in no time from hospital. PMID- 19780335 TI - [Etiology of surgical site infections at the orthopaedic trauma units]. AB - OBJECTIVES: The aim of the study was to analyze the epidemiological and microbiological analysis of surgical site infections in the orthopedic wards. MATERIALS AND METHODS: A 6-month prospective cohort study was conducted at the major teaching hospital in Belgrade. Patient's basic demographic data and data about surgical site infections were collected. Bacteria cultured from the surgical site were also analyzed. RESULTS: A total of 277 patients operated in the Institute of Orthopedics and trauma surgery, Clinical Center of Serbia. Sixty three cases of SSI were detected, and the overall incidence rate was 22.7% (95% IP = 17.8-27.6). Fifty-three (84.1%) SSIs had microbiological confirmation and overall 82 bacterial strains were isolated. The most frequent isolated bacteria were Staphylococcus aureus, Acinetobacter sp, Klebsiella pp, Pseudomonas sp and Enterococcus sp. Nineteen (79.2%) strains of Staphylococcus aureus isolated from infected surgical sites were meticillin- resistant. CONCLUSION: This study suggests that it is necessary to maintain continuous surveillance of surgical site infections. It is important to emphasize the need for implementation the measures of contact isolation in order to prevent the nosocomial transmission of resistant bacteria. PMID- 19780336 TI - [Laparoscopic cholecystectomy in elderly patients]. AB - Laparoscopic cholecystectomy (LC) is the method of choice of surgical treatment of gallbladder diseases. Operations in elderly people over 65 years because of chronic diseases, are often associated with high operative and postoperative morbidity and mortality. The aim of this study was to analyze the outcome of LC in the treatment of cholelithiasis in patients older than 65 years. For evaluation of LC effectiveness and security in old patients, we did this prospective analysis of 81 patients surgically treated because of symptomatic cholelithiasis. We had analyzed associated diseases, operative and postoperative complications, the reasons of conversion to open cholecystectomy. The research points to the small percentage of operative and postoperative complications, short hospital stay, less postoperative pain, quick recovery and savings in treatment. The age can not be contraindication for LC in older patients. In uncomplicated symptomatic cholelithiasis in elderly people, LC is a successful and safe procedure. Complicated symptomatic cholelithiasis, because of longer duration of operations is looking for a good assessment of general condition and associated diseases for LC. PMID- 19780337 TI - [Biochemical and antropometric monitoring of growth in preterm infants]. AB - Enriched human milk may stimulate gain weight in preterm infants during neonatal period. Aim is biochemical assessment of preterm infants, feed by mother's milk fortificated with special domestic formula (pre)Impamil during the first month of life. 80 preterm infants (45 male and 35 female), up to 36 weeks of gestation. BW less than 2500 g, which started enteral intake in the first three day of life. Total volume intake was in range from 70 ml/kg first day, to 170-200 ml/kg, after 10th day of life. Mother's milk fortification was prepared as 5% mixture solution of (pre)Impamil. The dynamics of biochemical analyses started on the first day of study and was repeated once weekly. We analysed levels of: total protein, albumin, prealbumin, transferin, urea, Ca ionised, P and alkaline phosphatase using standard biochemical methods. Statistical analyses completed by ANOVA test, one factorial analyses of variance. During monitoring total protein level increased in the second week of life (p < 0.03), as well as albumin (p < 0.03). Prealbumin level increased, as well as transferin (p-NS). Initial level of ionised fraction of Ca was significantly lower (p < 0.03) at the beginning of the study, compared to the rest. Serum level of P increased, as well as level of alkaline phosphatase at the end of first and second week (p < 0.01). Conclusion is that biochemical parameters as level of protein and albumin are important at the assessement growth in preterm infants on special feeding regimes. PMID- 19780338 TI - [Rare case of quadricuspid aortic valve]. AB - Quadricuspid aortic valve is rare congenital anomaly. There are only 197 cases published in literature so far. That includes clinical and autopsy reports. This congenital anomaly occurs more often in pulmonary valve but function stays normal in 10 of lies. On the other side, in aortic position valve is malfunctioning in 50% of cases. Valve regurgitation is more likely to occur than stenosis In this kind of malformation, valves are prone to early dysfunction and endocarditis due to different valve architecture and unequal distribution of mechanical stress along valve cusps. Aortic valve replacement is indicated in younger population of these patients. This is a case report of rare congenital anomaly of big blood vessels--aortic valve with four cusps. This anomaly produced significant aortic regurgitation so this patient was indicated for aortic valve replacement. PMID- 19780339 TI - Penile metastasis from invasive bladder cancer. AB - OBJECTIVE: To present the rare case of penile metastasis from bladder cancer. PATIENT REPORT: A 68-year-old man with invasive bladder cancer disseminated in penile shaft and the pelvic lymph nodes is presented. The patient underwent cystoprostatectomy, total penectomy and adjuvant chemotherapy. RESULTS: Ten months after surgery, patient is in complete remission. CONCLUSION: Despite the fact that secondary penile tumors usually require palliative therapy, in selected cases surgical treatment of primary tumor and penectomy, followed with chemotherapy, can improve survival. PMID- 19780340 TI - [Successful treatment of second hepatoblastoma relapse--case report]. AB - INTRODUCTION: The prognosis of hepatoblastoma has changed since effective adjuvant chemotherapy had been introduced in 1980's. There is a general agreement that complete resection is the cornerstone of treatment for children with hepapatoblastoma and the only way for eventual cure. CASE REPORT: We describe a boy with relapsed hepatoblastoma presenting with elevated -fetoprotein (AFP) and no visible tumor by ultrasound and computed tomography (CT). The relapse was treated with chemotherapy. Second relapse occurred shortly after therapy was completed, but this time we waited for tumor mass to appear. Combined surgery and chemotherapy resulted in remission status with 48 months of follow up. CONCLUSION: Hepatoblastoma relapse without evidence of tumor is not unusual but its treatment remains controversial. Radiological investigations should be repeated until site of relapse is identified. Based on our experience it seems of no benefit to treat isolated elevation of AFP. PMID- 19780341 TI - Falls prevention: new ways of thinking about a continuing challenge. PMID- 19780342 TI - The interictal spike: what does it mean? PMID- 19780343 TI - Epileptiform EEG spikes and their functional significance. AB - Field potentials detected in the space surrounding cellular elements of the nervous system are essential in the diagnosis of epileptic seizures. This article describes the elementary mechanisms underlying the generation of field potentials and the special functional conditions leading to epileptiform field potentials. Primary transmembranous currents generate secondary ional currents along the cell membranes in intra- and extracellular compartments. The portion of these currents that flows through the brain tissue to the cortical surface can be detected as field potentials. A high synchronization of these field potentials is needed to induce brain signals. Field potentials recorded during epileptic activity are based on alterations in neuronal membrane potentials. Paroxysmal depolarization shift has proved to be characteristic in the epileptiform activity of individual neurons. Epileptiform field potentials are generated in functionally different structures with different elementary mechanisms. In focal convulsive activity limited to the cortex, the surface potential does not necessarily reflect the bioelectrical events in deeper cortical laminae and can be interrupted in different ways. The discrepancy between superficial EEG potentials and neocortical output may be the basis for dissociation between EEG signals and clinical signs. PMID- 19780344 TI - An animal model to study the clinical significance of interictal spiking. AB - Interictal spikes (IIS) are paroxysmal discharges commonly observed in patients with epilepsy which represent an abnormally-synchronized population of hyperexcitable neurons firing as an aggregate. Due to conflicting studies on the clinical significance of IIS, research focusing on IIS has been sparse. However, recent attention on IIS has increased for patients undergoing surgery for intractable epilepsy as a means to identify epileptic foci for surgical resection. There is growing evidence that IIS are not asymptomatic as has been commonly accepted. Other than epilepsy, IIS have been associated with a wide range of behavioral and psychiatric disorders, including attention deficit disorder, anxiety disorders and psychoses. For these reasons, a well characterized animal model of interictal spiking which accurately mimics the human phenomenon would be a valuable tool to gain, insights both into the pathophysiology of epilepsy as well as a broad variety of human neuropsychiatric diseases. Here, we review the literature on the clinical significance of IIS in humans and on animal models where IIS has been observed. We then demonstrate the utility of using tetanus toxin to generate a reproducible pattem of progressive IIS for future studies into their clinical significance. PMID- 19780345 TI - Epileptiform discharges in psychiatric patients: a controversy in need of resurrection. AB - The current view of the psychiatric significance of inter-ictal spike discharges (IIS) in nonepileptic, psychiatric patients is that the discharges are "incidental" and are of no clinical significance. Hence, despite a voluminous literature suggestive that such discharges may have clinical relevance, electroencephalograms are hardly ever recorded in nonepileptic psychiatric patients. This literature is briefly summarized, and one detailed example of a disorder (i.e., autistic spectrum disorders) where such discharges are particularly common is provided. The argument is made that this is an area of psychiatry that is under-investigated and that research devoted to elucidating the mechanisms of development of IIS, their possible clinical relevance, and the role of anticonvulsants in managing such patients, could be very profitable. PMID- 19780346 TI - "All that spikes is not fits", mistaking the woods for the trees: the interictal spikes--an "EEG chameleon" in the interface disorders of brain and mind: a critical review. AB - Recent research into mammalian cortical neurophysiology, after 6 decades of Berger's seminal work on electroencephalography, has shifted the older concept of interictal epileptiform activity (IEA) away from that of a mere electrographic graphoelement of relevance to diagnostic implications in epilepsy. Instead, accumulating information has stressed the neuropsychological implications, cognitive and/or behavioral consequence of these electrophysiological events, which are the phenotypic expression of aberrations of actual biophysical cellular function. We feel that this review is germane to neuropsychiatry, however, a rather neglected area of research. There is a great scope for brain-behavior-EEG research in the future that can be complimented by other techniques of "neurobehavioral electrophysiology". This review does not address the "pearls, perils and pitfalls" in the use of EEG in epilepsy, but critically and systematically reappraises the published electroencephalographic correlates of human behavior. We reiterate that epileptiform and other paroxysmal EEG dysrhythmias unrelated to clinical seizures do have neuropsychological, cognitive and/or behavioral implications as seen in the various neuropsychiatric and neurobehavioral disorders discussed in this article. IEA and EEG dysrhythmias should neither be ignored as irrelevant nor automatically attributed to epilepsy. The relevance of these EEG aberrations in the disorders of the brain-mind interface extend beyond epilepsy, and may be an electrophysiological endophenotype of aberrant neuronal behavior indicative of underlying morpho functional brain abnormalities. Magnetoencephalography (MEG), data fusion models (EEG-fMRI-BOLD), transcranial magnetic stimulation (TMS), evoked potentials (EP); intracranial electrophysiology, and EEG neurofeedback complemented by current functional neuroimaging techniques (fMRI and PET) would certainly help in further understanding the broader relationship between brain and behavior. PMID- 19780347 TI - Automatic EEG spike detection. AB - Since the 1970s advances in science and technology during each succeeding decade have renewed the expectation of efficient, reliable automatic epileptiform spike detection (AESD). But even when reinforced with better, faster tools, clinically reliable unsupervised spike detection remains beyond our reach. Expert-selected spike parameters were the first and still most widely used for AESD. Thresholds for amplitude, duration, sharpness, rise-time, fall-time, after-coming slow waves, background frequency, and more have been used. It is still unclear which of these wave parameters are essential, beyond peak-peak amplitude and duration. Wavelet parameters are very appropriate to AESD but need to be combined with other parameters to achieve desired levels of spike detection efficiency. Artificial Neural Network (ANN) and expert-system methods may have reached peak efficiency. Support Vector Machine (SVM) technology focuses on outliers rather than centroids of spike and nonspike data clusters and should improve AESD efficiency. An exemplary spike/nonspike database is suggested as a tool for assessing parameters and methods for AESD and is available in CSV or Matlab formats from the author at brainvue@gmail.com. Exploratory Data Analysis (EDA) is presented as a graphic method for finding better spike parameters and for the step-wise evaluation of the spike detection process. PMID- 19780348 TI - Magnetoencephalography and magnetic source imaging in epilepsy. AB - Magnetoencephalograpy (MEG) and Electroencephalography (EEG) provide physicians with complementary data and should not be regarded as mutually exclusive evaluative methods of cerebral activity. Relevant to this edition, MEG applications related to the surgical treatment of epilepsy will be discussed exclusively. Combined MEG/EEG data collection and analysis should be a routine diagnostic practice for patients who are still suffering seizures due to the failure of drug therapy. Clinicians in the field of epilepsy agree that a greater number of patients would benefit from surgery than are currently referred for pre surgical evaluation. Regardless of age or presumed epilepsy syndrome, all patients deserve the possibility of living seizure-free through surgery. Technological advances in superconducting elements as well as the digital revolution were necessary for the development of MEG into a clinically valuable diagnostic tool. Compared to the examination of electrical activity of the brain, investigation into its magnetic concomitant is a more recent development. In MEG, cerebral magnetic activity is recorded using magnetometer or gradiometer whole head systems. MEG spikes usually have a shorter duration and a steeper ascending slope than EEG spikes, and variable phase relationships to EEG. When co registered spikes are compared, it is apparent that EEG and MEG spikes differ. There is agreement among investigators that more interictal epileptiform spikes are seen in MEG than EEG. When MEG is co-registered with invasive intracranial EEG data, the detection rate of interictal epileptiform discharges depends on the number of electrocorticographic channels that record a spike. When patients have a non-localizing video-EEG recording, MEG pinpoints the resected area in 58-72% of the cases. PMID- 19780349 TI - Advances in spike localization with EEG dipole modeling. AB - EEG interpretation by visual inspection of waveforms, using the assumption that activity at a given electrode is a representation of only the activity of the cortex immediately beneath it, has been the traditional form of EEG analysis since its inception. The relatively recent advent of digital EEG has allowed more advanced analysis of EEG data and has shown that the simple visual inspection described above is a simplistic form of analysis. This is especially true when one is attempting to localize an epileptogenic focus using EEG spikes or seizure onset data. Spatiotemporal analysis of scalp voltage fields has allowed for improved localization of likely cerebral origins of such waveforms. Equivalent dipole source modeling is one such technique and, although not perfect, provides improved characterization of spike and seizure sources as compared to previous methods when properly interpreted. The use of other modern techniques, such as 3D MRI reconstructions and realistic head models, can further improve accuracy of dipole localization and allow for the synthesis of EEG and imaging data, which may be invaluable, especially in cases of pre-surgical epilepsy evaluation. PMID- 19780350 TI - Spikes and epilepsy. AB - Digital EEG analysis provides significantly more information to the clinical electroencephalographer (EEGer) for scalp as well as for intracranial monitoring than is currently being routinely utilized. When modern data analysis software is used, interictal spikes contain considerably more information than had previously been ascribed to them. To optimize the diagnostic value of the EEG, sleep recordings after sleep deprivation is valuable because focal spikes, unless abundant, are relatively rare in the waking state. Recording time should also be sufficiently long to allow spikes to emerge. Spikes are always pathologic and can be associated with impaired cerebral perfusion, metabolic changes and concomitant behavioral changes. They can also be separated into simple and complex forms which may allow prognostic statements. The simplest way to accomplish this is by placing a cursor on the peak of the spike and see whether or not other channels show latency differences. More precise methods are: comparisons of voltage maps with current source density maps, principal component analysis and distinctions between stationary versus moving dipoles. Averaging of spikes is valuable but care must be taken that only those spikes which have the same distribution are averaged, and when the average is obtained only from the spike peak, propagation may already have occurred. It has been recommended that the midpoint of the ascending negative phase be used as the point for averaging. In intracranial recordings the frequencies above the gamma range should also be assessed. Their small electrical field allows a differentiation between locally generated events from those which are volume conducted and can thereby more accurately reflect the epileptogenic zone(s). High frequency activity can also be recorded from foramen ovale electrodes which enhances their diagnostic utility. It is emphasized that for centers which perform pre-surgical evaluations the software supplied by instrument manufacturers is inadequate and needs to be supplemented by additional commercially available programs. Furthermore, archived data should be used for retrospective investigations and follow-up studies of patients who have undergone either excisions, resections, or multiple subpial transections to evaluate the success rates by taking into account all the properties of interictal and ictal recordings which are mentioned in this article. PMID- 19780351 TI - The contributions of Edward H. Angle to dental public health. AB - The genius of Edward Hartley Angle, (1855-1930), the founder of the dental specialty of orthodontics, to create order from chaos in the study and treatment of positional discrepancies of the teeth, jaws and face advanced greatly the cause of dental public health. Angle's innovations that had the most public health impact were (1) his identification of dental occlusion, not simply tooth irregularity, as a prime concern, (2) his development of an uncomplicated classification system for occlusal conditions, (3) his introduction of prefabricated orthodontic appliances and (4) his framing of orthodontics as a dental specialty by organizing the world's first educational program to train orthodontists. PMID- 19780352 TI - The fractional urinary fluoride excretion of adults consuming naturally and artificially fluoridated water and the influence of water hardness: a randomized trial. AB - AIMS: To assess whether there was any significant difference in the average fractional urinary fluoride excretion (FUFE) values among adults consuming (NaF) fluoridated Ca-free water (reference water), naturally fluoridated hard water and an artificially (H2SiF6) fluoridated soft water. DESIGN: Sixty adult females (N=20 for each treatment) participated in this randomized, double-blind trial. The experimental design of this study provided an indirect estimation of the fluoride absorption in different types of water through the assessment of the fractional urinary fluoride excretion of volunteers. RESULTS: Average daily FUFE values (daily amount of fluoride excreted in urine/daily total fluoride intake) were not significantly different between the three treatments (Kruskal-Wallis; p = 0.62). The average 24-hour FUFE value (n=60) was 0.69; 95% C.I. 0.65-0.73. CONCLUSIONS: The results of this study suggest that the absorption of fluoride is not affected by water hardness. PMID- 19780353 TI - The prevalence and severity of dental fluorosis in the high and low altitude parts of Central Plateau, Nigeria. AB - OBJECTIVE: To compare the prevalence and severity of dental fluorosis in the high and low altitude parts of the Central Senatorial District of Plateau State. BASIC RESEARCH DESIGN: The study was cross-sectional and descriptive. SETTING: The community based study was carried out in Central Plateau Nigeria, in 2005. PARTICIPANTS: The study subjects were 12-15 year old life long residents selected using the multistage sampling technique. One Local Government Area each was randomly selected from the high and low altitude parts of the district and from each selected Local Government Area two health districts were randomly selected with probability proportional to size. From each of the selected health Districts two major settlements were selected again with probability proportional to size. 12-15 year old life long residents of the selected settlements were studied. Each respondent completed an interviewer administered questionnaire after which he/she was clinically examined to ascertain his/her fluorosis status. Samples of water were collected from water sources consumed by the respondents in each settlement. MAIN OUTCOME MEASURES: The main outcome measures were presence and severity of dental fluorosis as measured by the Thylstrup and Fejerskov index. (TF score). RESULTS: One thousand one hundred children were studied, 554 (50.4%) from the high altitude part of the district and 546 (49.6%) from the low altitude part. Fluorosis prevalence was 12.9% in the district, but significantly higher (22.2%) in the high altitude areas compared to the low altitude ones (3.5%). The severest form of fluorosis in the district was TF 6 for tooth 14 and TF 5 for tooth 11. CONCLUSION: The prevalence and severity of dental fluorosis is significantly higher in the high altitude parts of the District compared to the low altitude ones. Efforts are needed to further investigate and control the problem. PMID- 19780354 TI - Prevalence of enamel defects related to pre-, peri- and postnatal factors in a Brazilian population. AB - OBJECTIVES: The aim of this paper is to evaluate the prevalence of enamel defects in infants from a socially and economically poor population and the possible association of these defects with disturbances occurring in the pre-, peri- and postnatal periods of human development. PARTICIPANTS: 117 infants aged between 16 and 18 months old were included in four groups based on gestational age and whether part or full term pregnancy. METHOD: The data were collected in two stages: hospital-based, where gestational and birth records were examined, and home-based, where dental examinations and nutrition were evaluated. The teeth were cleaned and dried with gauze and examined in the open air, avoding direct sunlight in the knee-to-knee position. The enamel defects were coded according to the modified Developmental Defects of Enamel Index. Besides this, body weight and height were considered as anthropometric measures for the evaluation of nutritional status by the National Center for Health Statistics standards. MAIN OUTCOME MEASURES: The data were analyzed using the chi-square and Fisher Exact tests. Besides these tests, logistic regression models were used. RESULTS: The prevalence of enamel defects was 49.6%, higher in the group of male infants (p<0.001). The most frequent type of defect and the most affected surface were, respectively, diffuse opacity (9.5%) and the buccal surface (83.3%), located in the gingival half (6.7%). The logistic regression model showed that educational level, gestational age and intrauterine growth retardation (IUGR), besides a lack of breastfeeding, increased the probability of enamel defects up to level of 5%. CONCLUSIONS: The association between enamel defects and the etiologic factors shown in this study suggest the existence of social influences regarding oral health and teeth development. PMID- 19780355 TI - Development of a psychometric scale to assess satisfaction with dental care among Sri Lankans. AB - OBJECTIVE: To develop and validate a psychometric scale to assess dental satisfaction among Sri Lankans. DESIGN: A population based cross sectional study, where the data were collected by a postal questionnaire. A 22-item scale was developed to measure dental satisfaction. PARTICIPANTS: 1,000 Sri Lankans aged 18 75 years, selected by cluster sampling with probability proportionate to size technique, using National Voters' register. OUTCOME MEASURES: Reliability of the scale was assessed by internal consistency using Cronbach's alpha and corrected item-total correlations. Construct validity was determined by factor analysis and acceptability was assessed by percentage of item-specific non-response. RESULTS: The overall response rate was 30.9%. Among respondents, analysis was limited to dental care users within two years (n=117). Item-specific non-response was low, ranging from 3.4% to 9.4%. Four (negatively worded) items were removed from the scale due to poor internal consistency (corrected item-total correlations <0.2). After removal, corrected item-total correlations of remaining 18 items were improved, ranging from 0.23 to 0.76. Factor analysis revealed a four factor solution, interpreted as: "outcome of care/clinic context" (8-items), 'factors related to treatment process" (7-items), "convenience" (2-items) and "cost of care" (single item). Identified factors explained 64.56% of the variance of the scale. The Cronbach's alpha values for the first three dimensions were 0.90, 0.87 and 0.60 respectively and for the overall construct it was 0.91. CONCLUSIONS: The present scale appeared to be a valid and reliable instrument for measuring dental satisfaction among Sri Lankans, but merits further refinements to explore detailed aspects of it. PMID- 19780356 TI - Consent of older children participating in BASCD coordinated dental epidemiology surveys in Wales. AB - New guidance on consent for England and Wales, which has positive consent at its core, has implications for the UK-wide BASCD coordinated dental epidemiology programme. This paper describes a method used in Wales for obtaining consent from older children which is believed to comply with the new guidance. OBJECTIVE: The objective was to establish a more robust approach to gaining consent from 12 and 14 year olds taking part in the surveys, by building on existing "negative consent" practice and supplementing it with Gillick competent child consent. DESIGN AND SETTING: Questionnaire data from the 2002-03 survey of 6,393 13-14 year-old children and the 2004-05 survey of 6,749 11-12 year olds were used in this analysis. Questions specifically designed to establish competency to consent were asked of participating children. These ascertained whether children were happy to proceed and if so, whether they understood the nature and the purpose of the survey and whether they were happy with the outcome. RESULTS: Ninety-nine percent of those taking part in both survey years were happy to proceed with the examination and questionnaire. Whilst the majority of children, agreeing to take part, indicated that they had understood what was proposed and were happy with the outcome, approximately 15% of these age groups gave answers after the event which indicated that they had not understood either the nature or purpose of the survey. CONCLUSION: Use of "Gillick competent" consent in Wales did not affect participation rates adversely. The authors would suggest that indication of assent as used in Wales in these two surveys is appropriate and would only exclude 1% of children. The alternative, of examining only those children who answered questions on whether they understood the nature and purpose of what is proposed prior to assenting, would exclude 15% of children. PMID- 19780357 TI - Predicting relative need for urgent dental care. AB - OBJECTIVE: To develop prediction models of the relative need for care to differentiate between urgent and not urgent individuals presenting for emergency dental care. DESIGN AND METHODS: Data were collected from 839 adults presenting to public dental clinics across South Australia (SA) and New South Wales (NSW) for emergency dental care. Prediction of the urgency of emergency dental care was based on the assessment of two binary logistic regression models - Model 1: urgency of care=<48 hours vs. 2+ days, Model 2: urgency of care=2-7 days vs. 8+ days. Subsequently predictive equations for urgency of emergency dental care were developed using binary logistic regression analysis. The models incorporated subjective oral health indicators (i.e., experience of pain or other oral symptoms) and measures of psychosocial impact of oral disorders (i.e., difficulty sleeping and being worried about the appearance/health of one's teeth or mouth). RESULTS: The cut-off point for the prediction of urgency was defined as a probability value > or =0.40 and > or =0.50 for Model 1 and Model 2 respectively. These cut-off values were chosen as they produced test results that were consistent with the proportions of patients falling into various urgency categories derived from dentist's assessment of urgency. Model 1's sensitivity was 58%, specificity 77% and positive predictive value (PPV) 59%. Model 2's sensitivity was 75%, specificity 65% and PPV 71%. CONCLUSIONS: These models of relative need may be useful tools for the screening of urgent dental care and for allocating priority among patients presenting for emergency dental care. PMID- 19780358 TI - A comparison of Personal Dental Service (PDS) and General Dental Service (GDS) patients in terms of reported interventions, oral health and dentists' perceptions. AB - AIMS: The aim of the study was to investigate the reported working patterns, dentist perceptions and patient oral health for dentists in a Personal Dental Services (PDS) pilot and compare this with that of matched dentists working in the General Dental Services (GDS) arrangements in the same part of England. METHOD: Ten dentists were recruited, five each from PDS and GDS practices in Warwickshire, UK. The number of interventions carried out for adult patients in the year to April 2003 was obtained from the Dental Practice Board (DPB) for the two groups and compared. An Oral Health Index (OHX) (Burke and Wilson, 1995) was used to determine the oral health of a selection of patients from the two groups of dentists in the study. The final stage of the study involved semi-structured interviews with the dentists. RESULTS: The average age of dentists was similar, in the early to mid 40's (p>0.05). Both groups were, on average, around 20 years post qualification. The GDS dentists made an average of 3,507 activity reports to the Dental Practice Board in the year examined, compared with 3,441 from the PDS dentists. PDS dentists provided fewer simple periodontal treatments than GDS dentists, but otherwise the pattern of reported activity was similar. Both PDS and GDS dentists suggested that GDS dentists carried out more fillings because of a perverse incentive to provide fillings compared with PDS arrangements. PDS dentists believed that their treatment profiles had not changed significantly since changing to PDS, and suggested that their prescribing was based on clinical need only and was not influenced by the remuneration system. A total of 225 OHX scores were obtained for patients attending PDS dentists and a further 214 from patients attending GDS dentists. Overall, the mean OHX score was lower in the GDS patients than for PDS patients. CONCLUSIONS: PDS dentists provided fewer simple periodontal treatments than their GDS counterparts. There was no difference in the oral health of patients treated under either system. Although there was some evidence of a difference in attitude between GDS and PDS dentists towards charging and claiming for simple periodontal treatment, there was no uniformity of opinion within either group. There would appear to be a number of complex factors impacting upon decisions to treat or monitor dental conditions. PMID- 19780359 TI - Hopelessness, depression and oral health concerns reported by community dwelling older Australians. AB - OBJECTIVES: The purpose of this analysis was to explore whether, and if so to what extent, there is an association between self-reported oral and mental health problems, and if this association exists after controlling for self-rated physical health and age. RESEARCH DESIGN: A large cross-sectional population based telephone health survey with participants selected using random stratified sampling. The response rate was 71%. Survey weights were used for estimating proportions and for all statistical inferences. SETTING AND PARTICIPANTS: Participants (n=8,881) were community-dwelling older people (65+ years) living independently in New South Wales, Australia. MEASURES AND ANALYSIS: The following measures were used in the analysis: physical health (1 item); oral health (5 items), mental health (2 items). Trends in prevalences across groups were analysed using the Cochrane-Armitage trend test. Logistic regression modelling was conducted to account for the main confounders of age and self-rated physical health, and attributable fractions calculated. RESULTS: Both measures of mental health, feeling hopeless and feeling depressed, were significantly and positively associated with increased reporting of oral health concerns in both males and females. Logistic regression modelling showed that most of the oral health items remained strongly associated with mental health after controlling for self-rated physical health and age. The attributable fractions demonstrated that a proportion of the mental health problems identified in older people would be reduced if oral health concerns were adequately addressed. CONCLUSIONS: The findings highlight the association between oral and mental health, and provide evidence to support the expansion of publicly funded dental health services. PMID- 19780360 TI - Higher-order exploratory factor analysis of the Dental Subscale of Children's Fear Survey Schedule in a Taiwanese population. AB - OBJECTIVES: The Dental Subscale of the Children's Fear Survey Schedule (CFSS-DS) is extensively used to assess the level of child dental anxiety. The present study aimed to explore the higher-order factor structure of the parental Chinese version of the CFSS-DS with a large sample of young children in Taiwan. DESIGN: The parental CFSS-DS was used as a screening tool to survey the dental anxiety levels of 5 to 8- year-old children at kindergartens and elementary schools in Kaohsiung city, Taiwan. Subjects were selected by stratified random sampling. The stratification was done by geographic district, age group, and gender. PARTICIPANTS: The sample was 1,819 children aged 5 to 8 years old. MAIN OUTCOME MEASURES: A first-order factor analysis was performed using the principal components method with promax rotation, and a second-order factor was obtained by applying the Schmid-Leiman solution (SLS). RESULTS: The present study found three first-order factors, defined as: (1) fear of dental aspects, (2) fear of medical aspects, and (3) fear of potential victimization. The second-order factor defined as "dental fear" accounted for most of the variance in the second-order factor structure. The results of higher-order factor analysis according to different gender or age levels were identical. CONCLUSIONS: A higher-order factor structure consisting of a single second-order factor and three first-order factors was extracted, giving a fuller understanding of the CFSS-DS. The second-order factor structure of Chinese version CFSS-DS was stable and reliable. PMID- 19780361 TI - Opportunities and challenges to promoting oral health in primary schools. AB - Inequalities in oral health in areas of socio-economic disadvantage are well recognised. As children spend a considerable proportion of their lives in education, schools can play a significant role in promoting children's health and oral health. However, to what extent schools are able to do this is unclear. The aim of this study was therefore to investigate opportunities and challenges to promoting oral health in primary schools. METHODS: A purposive sample of 20 primary schools from socially and economically disadvantaged areas of Cardiff, UK were selected to participate in this qualitative study. Data were collected through semi-structured interviews conducted with head teachers or their nominated deputies. RESULTS: General awareness of health and oral health was good, with all schools promoting the consumption of fruit, water and milk and discouraging products such as carbonated drinks and confectionaries. Health promotion schemes wereimplemented primarily to improve the health of the children, although schools felt they also offered the potential to improve classroom behaviour and attendance. However, oral health was viewed as a separate entity to general health and perceived to be inadequately promoted. Successful health promotion schemes were also influenced by the attitudes of headteachers. Most schools had no or limited links with local dental services and, or oral health educators, although such input, when it occurred, was welcomed and highly valued. Knowledge of how to handle dental emergencies was limited and only two schools operated toothbrushing schemes, although all expressed an interest in such programmes. CONCLUSION: This study identified a positive predisposition to promoting health in primary schools. The challenge for the dental team, however, is to promote and integrate oral health into mainstream health promotion activities in schools. The paper also makes recommendations for further research. PMID- 19780362 TI - The U.S. military wartime pediatric trauma mission: how surgeons and pediatricians are adapting the system to address the need. AB - PURPOSE: Over 3,500 infants and children, many critically ill and injured, have been admitted to military combat support hospitals (CSH) in Afghanistan and Iraq, which are not doctrinally staffed or equipped to provide their care. This report details how the military medical system is adapting to create a data driven and comprehensive response to optimize the medical and surgical pediatric care being provided. METHODS: Information from multiple sources was used over time to craft the military medical response to the pediatric wartime mission. Pediatric data from both the Joint Theater Trauma Registry (JTTR) and the Patient Administration Systems and Biostatistics Activity (PASBA) database were utilized extensively. The resulting educational, supply, and personnel adaptations implemented by the U.S. military will be highlighted, and innovations currently under development will also be described on the basis of this demonstrated need. RESULTS: This information helped drive pediatric-specific, just-in-time education for CSH personnel, modified CSH equipment and supply lists, inspired the 24/7 pediatric critical care teleconsultation service, and resulted in new initiatives in the predeployment training for CSH personnel. CONCLUSION: Military physicians are routinely asked to perform outside their traditional scopes of practice while deployed. Given this reality, military pediatric specialists in medicine and surgery have initiated several successful multidisciplinary programs designed to improve in-theater care of injured children. These innovative efforts include drafting a pediatric addendum to the Army's "Emergency War Surgery" manual, development of instructional compact discs, augmenting and refining the pediatric portion of the Joint Forces Combat Trauma Management course, formation of a pediatric augmentation team to the CSH, and a comprehensive hyperlinked Web-based pediatric critical care and trauma educational platform. PMID- 19780363 TI - Illness and injury risk and healthcare utilization, United States Air Force battlefield airmen and security forces, 2000-2005. AB - OBJECTIVE: To study the illness and injury risk and healthcare utilization of male U.S. Air Force (USAF) battlefield airmen in comparison to male USAF security forces. METHODS: Using data in electronic format, battlefield airmen (n = 2,089) and security forces personnel (n = 19,416) were identified and matched to data from the Military Health System, with analyses conducted to explore hospitalization risks and healthcare utilization differences. RESULTS: Battlefield airmen were at an increased risk for hospitalizations for illnesses (HR = 1.35, 95% CI 1.03, 1.77), musculoskeletal conditions (HR = 2.28, 95% CI 1.47, 3.52), and injuries (HR = 3.34, 95% CI 2.38, 4.69) compared with security forces. Differences in the mean number of hospitalization days per person and mean outpatient medical costs also existed across the groups. CONCLUSIONS: Battlefield airmen are significantly more likely to be hospitalized for a number of illnesses and injuries in comparison to security forces. A surveillance study has been implemented to further explore these findings. PMID- 19780364 TI - Association of bacterial colonization at the time of presentation to a combat support hospital in a combat zone with subsequent 30-day colonization or infection. AB - U.S. casualties have developed multidrug-resistant (MDR) bacterial infections. A surveillance project to evaluate U.S. military patients for the presence of MDR pathogens from wounding through the first 30 days of care in the military healthcare system (MHS) was performed. U.S. military patients admitted to a single combat support hospital in Iraq during June-July of 2007 had screening swabs obtained for the detection of MDR bacteria and a subsequent retrospective electronic medical records review for presence of colonization or infection in the subsequent 30 days. Screening of 74 U.S. military patients in Iraq found one colonized with methicillin-resistant Staphylococcus aureus. Fifty-six patients of these were screened for Acinetobacter in Germany and one found colonized. Of patients evacuated to the U.S., 9 developed infections. Carefully obtained screening cultures immediately after injury combined with look-back monitoring supports the role of nosocomial transmission. Consistent infection control strategies are needed for the entire MHS. PMID- 19780365 TI - Use of vector diagnostics during military deployments: recent experience in Iraq and Afghanistan. AB - Vector-borne diseases such as malaria, dengue, and leishmaniasis are a threat to military forces deployed outside of the United States. The availability of specific information on the vector-borne disease threat (e.g., presence or absence of a specific disease agent, temporal and geographic distribution of competent vectors, and vector infection rates) allows for effective implementation of appropriate measures to protect our deployed military forces. Vector diagnostics can provide critical, real-time information crucial to establishing effective vector prevention/control programs. In this article we provide an overview of current vector diagnostic capabilities, evaluate the use of vector diagnostics in Operation Enduring Freedom and Operation Iraqi Freedom, and discuss the concept of operations under which vector diagnostics are employed. PMID- 19780367 TI - Organizational commitment of military physicians. AB - An individual's loyalty or bond to his or her employing organization, referred to as organizational commitment, influences various organizational outcomes such as employee motivation, job satisfaction, performance, accomplishment of organizational goals, employee turnover, and absenteeism. Therefore, as in other sectors, employee commitment is crucial also in the healthcare market. This study investigates the effects of organizational factors and personal characteristics on organizational commitment of military physicians using structural equation modeling (SEM) on a self-report, cross-sectional survey that consisted of 635 physicians working in the 2 biggest military hospitals in Turkey. The results of this study indicate that professional commitment and organizational incentives contribute positively to organizational commitment, whereas conflict with organizational goals makes a significantly negative contribution to it. These results might help develop strategies to increase employee commitment, especially in healthcare organizations, because job-related factors have been found to possess greater impact on organizational commitment than personal characteristics. PMID- 19780366 TI - Operational impact of health problems observed during a four-month military deployment in Ivory Coast. AB - Diseases always have a significant impact during military deployments. We evaluated the operational impact of health problems observed in a French infantry battalion (n = 690) during a 4-month assignment in Ivory Coast. In all, 55.7% of soldiers consulted at least once and sought care for 608 health problems. A total operational incapacity was observed in 22.2% of cases (7.6/1,000 person-days). The 5 diseases causing the greatest operational incapacity were diarrhea (2.1 days lost/1,000 person-days), musculoskeletal diseases and injuries (53.7 days), malaria (29 days), dental diseases (30.9 days), and fevers of undetermined origin (7 days). The incidence of diarrhea and skin infections was higher in rank-and file troops than among noncommissioned officers. It was also higher during the mission's first month, when individual susceptibility to infections is suspected to be highest. Some diseases that are not serious nonetheless have a significant operational impact and should be better studied to determine preventive measures. PMID- 19780368 TI - A four-system comparison of patients with chronic illness: the Military Health System, Veterans Health Administration, Medicaid, and commercial plans. AB - We compared chronic care utilization in four major health systems in the U.S.: the military health system (TRICARE), the Department of Veterans Affairs (VA), Medicaid, and employer-sponsored commercial plans. Prevalence rates and key performance indicators were constructed from administrative data in federal fiscal year 2003 for eight chronic conditions: hypertension, major depression, diabetes, tobacco dependence, ischemic heart disease, severe mental illness, persistent asthma, and stroke. Continuously enrolled beneficiaries under 65 years old were studied: TRICARE (N = 2,963,987), VA (N = 2,114,739), Medicaid enrollees in five states (N = 5,554,974), and commercial insurance (N = 5,212,833). Condition-specific adjusted prevalence rates and measures were compared using the standardized rate ratio. For the majority of the conditions, the estimated prevalence rates were highest in the VA and Medicaid populations. Prevalence rates were generally lower in TRICARE and commercial plans. Medicaid beneficiaries had the highest hospitalization rates in four of the six conditions where hospitalization rates were measured. These results provide empirical evidence of differences in chronically ill patient populations in several of the major U.S. health insurance systems. PMID- 19780369 TI - One surgeon's Army experience with "wound shock" from Pearl Harbor to the present. AB - The Army has had extensive experience in the study and treatment of shock, beginning with the American Civil War and continuing to the present. This is the story of one Army surgeon's experience, both in research and treatment of shock, from Pearl Harbor to the present. PMID- 19780370 TI - Is poor sleep in veterans a function of post-traumatic stress disorder? AB - Substantial research has demonstrated an association between post-traumatic stress disorder (PTSD) and quality of sleep, particularly in veteran populations. The exact nature of this relationship, however, is not clear. The possibility that poor sleep is a more general experience among veterans has not been explored to date, with most studies focusing only on veteran populations with PTSD. This pilot study aimed to explore whether sleep disturbance is common to veterans generally or simply those with PTSD. Data were collected from a community sample of 152 Australian Vietnam war veterans, 87 of whom did not meet criteria for PTSD. All those with PTSD and 90% of those without PTSD reported clinically significant sleep disturbance, indicating that serious sleep problems are common across the veteran population. Despite the limitations of this initial study, these results highlight the importance of ensuring that research into sleep disorders in veterans with PTSD pays attention to the potential etiological role of other military factors, including deployments. PMID- 19780371 TI - Musculoskeletal disorders in main battle tank personnel. AB - PURPOSE: To compare the prevalence of musculoskeletal disorders of personnel in the main battle tank (MBT) units in the Danish army with those of personnel in other types of army units, and to investigate associations between job function in the tank, military rank, and musculoskeletal problems. METHOD: An epidemiologic cross-sectional questionnaire-based examination of an exposed group (MBT personnel) and a reference group (army personnel from other units than MBT units) was conducted. Outcome measures were 1-year prevalence of pain in the anatomical locations of neck, shoulder, low back, knee, and ankle. RESULTS AND CONCLUSIONS: There were only 4 women in the MBT group; as a consequence, female personnel were excluded from the study. The participation rate was 58.0% (n = 184) in the MBT group and 56.3% (n = 333) in the reference group. The pattern of musculoskeletal disorders among personnel in the main battle tank units of the Danish army was not significantly different from that in other types of units (infantry, signal, combat service support, engineers, and artillery). Working as a gunner less than 2 years increased the risk of reporting neck pain (p = 0.011) and working as a loader increased the risk of reporting shoulder pain (p = 0.017). PMID- 19780372 TI - Trends in prescription drug utilization and spending for the Department of Defense, 2002-2007. AB - OBJECTIVE: Examine trends in U.S. Department of Defense (DoD) outpatient drug spending and utilization between 2002 and 2007. METHODS: We analyzed pharmacy claims data from the U.S. Military Health System (MHS), using a cross-sectional analysis at the prescription and patient-year level and measuring utilization in 30-day equivalent prescriptions and expenditures in dollars. RESULTS: Pharmaceutical spending more than doubled in DoD, from $3 billion in FY02 to $6.5 billion in FY07. The largest increase occurred in the DoD community pharmacy network, where utilization grew from 6 million 30-day equivalent prescriptions in the first quarter of FY02 to more than 16 million in the last quarter of FY07. The smallest increase in annual spending occurred in FY07 (5.5%), down from a high of 27.5% in FY03. CONCLUSIONS: The MHS has experienced rapid growth in pharmaceutical spending since FY02. However, there are signs that growth in pharmaceutical spending may be slowing. PMID- 19780374 TI - Promoting oral hygiene behavior in recruits in the Dutch Army. AB - OBJECTIVES: To make practical recommendations for improving oral hygiene behavior (OHB) potential predictors based on the Theory of Planned Behavior (TPB) were assessed. Measurements of oral health knowledge (OHK) and the expected social effect for having healthy teeth were included. METHODS: 216 recruits in the Dutch Army ground forces completed a questionnaire about oral hygiene behavior, attitudes, social norms, perceived behavioral control (PBC), intention to perform optimal OHB, OHK, and expected social outcomes. RESULTS: The multivariate regression analysis revealed that attitude and PBC explained 37.2% of the variance in intention to perform optimal oral hygiene behavior, which is a substantial proportion. Furthermore, actual oral hygiene behavior was only predicted by attitude, explaining 7.1% of the variance. CONCLUSION: The present findings suggest that recruits' oral hygiene behavior may be improved by promoting a more positive attitude and especially by enhancing perceived behavior control. PMID- 19780373 TI - Short half-life hypnotics preserve physical fitness and altitude tolerance during military mountainous training. AB - OBJECTIVE: We study the effect of short half-life hypnotics (zaleplon or zolpidem against placebo) on altitude tolerance in 12 nonacclimated male soldiers (age, 22.1 +/- 0.8 years; height, 177.8 +/- 1.7 cm; weight, 69.8 +/- 1.7 kg). METHODS: Soldiers were trained to practice mountaineering at high altitude (2,533-4,810 meters) during 3 periods (one per medication tested) of 4 days (D1-D4). In each period the nights were spent in a hut (3,613 m). Administration of hypnotics or placebo was then implemented at 9:45 p.m. Nocturnal arterial oxygen saturation (SaO2) and heart rate variability (HRV) were monitored. At 5:00 a.m. and 9:00 p.m. physical fitness was assessed using acute mountain sickness (AMS) score. At 5:00 p.m., a posteffort stand test was carried out to evaluate the orthoparasympathetic imbalance with fatigue. RESULTS: Nocturnal SaO2 correlated negatively with morning AMS scores (R = -0.820, p < 0.02) and HRV analysis favored the sympathetic modulation. Posteffort stand tests revealed that sympathetic modulation attenuated from D2 to D3 in treated groups. CONCLUSION: The present study provides evidence that zolpidem or zaleplon improves sleep and subsequent physical fitness at altitude. PMID- 19780375 TI - Does respiratory muscle training increase physical performance? AB - Special force units and military personnel undergo demanding physical exercise and might benefit from high-intensity respiratory muscle training (RMT) by increasing their endurance performance. This study examined the effects of a 6 week high-intensity RMT on running performance and oxygen uptake (VO2max) in a group of German Special Force Squad members. METHODS: 17 participants were randomly assigned to a training or control group. Baseline and post-testing included a ramp test, as well as an incremental test on a treadmill, performed to physical exhaustion. VO2, respiratory exchange ratio, and heart rate were measured breath by breath. Furthermore, maximum running speed (V(max)), 4 mmol x 1(-1) lactate threshold (V4) and perception of respiratory effort were determined. During pulmonary testing, sustained maximum inspiratory and expiratory pressure (PI(max) and PE(max)) were obtained. RMT was performed daily at approximately 90% PI(max) for 6 weeks with 2 x 30 breath cycles using an Ultrabreathe lung trainer. RESULTS: No statistical differences were detected between the groups for any parameter after RMT. CONCLUSION: High-intensity RMT did not show any benefits on VO2max and endurance performance and are unlikely to be of benefit to military or paramilitary training programs for an increase in endurance performance. PMID- 19780376 TI - Real-time FRET PCR assay for Salmonella enterica serotype detection in food. AB - Salmonella enterica subsp. enterica serotypes are leading etiological agents of food-borne gastroenteritis. Traditional identification is laborious and time intensive. Faster molecular methods may allow early identification in contaminated food products. We developed a real-time, fluorescence resonance energy transfer hybridization probe polymerase chain reaction (PCR) assay for S. enterica serotypes on the basis of the exclusive presence of the apeE gene in Salmonella Typhimurium. Assay sensitivity for 12 S. enterica serotypes was as low as 1.87 x 10(2) genomic equivalents per milliliter. PCR efficiency was 94% and the dynamic range was linear over six orders of magnitude from 10(0) to 10(6) copies. The lower limit of detection for 12 different food matrices was between 1.5 x 10(2) and 1.5 x 10(5) CFU/mL without pre-enrichment. When combined with high-throughput automated DNA extraction, 32 food specimens were processed and assayed in less than 2 hours, allowing rapid, specific, sensitive detection of S. enterica serotypes in food products. PMID- 19780377 TI - Wireless capsule endoscopy in Israeli Defense Force: two years of experience. AB - OBJECTIVES: Evaluate outcome and diagnostic yield of capsule endoscopy (CE) in soldiers with suspected small bowel disease, in comparison to traditional diagnostic procedures. METHODS: 27 consecutive soldiers who underwent CE between June 2002 and February 2004 were enrolled. Results of CE were compared to standard techniques. RESULTS: CE was normal in 16 patients (59.3%). Findings could not explain any signs or symptoms were observed in 11.1%. Definite diagnosis of Crohn's disease was obtained in 11.1%. Patients (62.5%) with a triad of symptoms (abdominal pain, changed bowel habits, and gastrointestinal bleeding) versus 15.8% without that triad, had either diagnostic or suspicious CE (p = 0.015). Diagnostic yield of CE was higher in gastrointestinal bleeding (25%) in comparison to suspected Crohn's disease (15.8%). Three out of 6 patients (50%) with suggestive findings of Crohn's disease in the preliminary workup were diagnosed as definite Crohn's by capsule endoscopy. CE allowed the physician to conclude workup in 71% patients. CONCLUSION: CE should be used when obscure gastrointestinal bleeding or Crohn's disease is suspected without a conclusive diagnosis. Furthermore, when a triad of symptoms exists CE should be considered as first line examination. PMID- 19780378 TI - Corneal hysteresis: a useful tool in the diagnosis and management of primary open angle glaucoma. AB - PURPOSE: To describe a case of primary open angle glaucoma (POAG) and to illustrate a new principle in detecting and managing the disease using intraocular pressure (IOP) corneal hysteresis as a clinical guide. METHOD: A case report is reviewed of a white 87-year-old male who was detected with ocular hypertension (OHTN) with bilateral asymmetrical corneal stiffness and POAG. CONCLUSION: A new indicator and alternative approach to determine and manage POAG is presented using evidence-based technology for clinical care and facilitating positive outcomes for one of the leading causes of blindness in the world. PMID- 19780379 TI - Psychosis following mycoplasma pneumonia. AB - Extrapulmonary manifestations of Mycoplasma pneumoniae are well described, including a subset of central nervous system (CNS)-associated syndromes. In pediatric populations, frequencies of CNS sequelae occur in 0.1% to 7% of patients. Neurologic illness associated with M. pneumoniae, such as meningitis, encephalitis, polyradiculitis, Guillain-Barre, and stroke have been reported; however, the incidence of M. pneumoniae-associated organic brain syndrome is rare. We present the case of a 20-year-old midshipman with acute psychosis following resolution of M. pneumoniae pneumonia and review 6 other adult cases found in the literature. M. pneumoniae remains one of the most common causes of respiratory illnesses in the military recruit setting and therefore should always be suspected as an organic cause of mental status changes in young persons such as recruits, cadets, and midshipmen particularly with antecedent respiratory illnesses. PMID- 19780381 TI - Are you on Angie's List--yet? PMID- 19780380 TI - Radiology corner. Venous fragment embolism to the pulmonary artery. PMID- 19780383 TI - Time to take better care of our own. PMID- 19780382 TI - Physician leadership is key to creating a safer, more reliable health care system. PMID- 19780384 TI - Wisconsin health system targets employee health. PMID- 19780385 TI - The documentation management program: a concerto for typically unaccompanied physician executives. PMID- 19780386 TI - Financial impact of concurrent coding. PMID- 19780387 TI - The savvy communicator: three ways to connect your information to their reality. PMID- 19780388 TI - Establishing patient-and family-centered care in a non-academic pediatric intensive care unit. PMID- 19780389 TI - Peer review: a new tool for quality improvement. PMID- 19780390 TI - The chief medical officer: a critical success factor. PMID- 19780391 TI - Knocking down your organization's barriers to efficiency and effectiveness. PMID- 19780392 TI - Coaching the abrasive personality. PMID- 19780393 TI - Dealing with difficult people. PMID- 19780394 TI - Bunches, groups and teams working together. PMID- 19780395 TI - Crossing the leadership bridge. PMID- 19780396 TI - The ethics of exclusivity: should doctors practice concierge medicine? PMID- 19780397 TI - 8 insights for physicians joining the life science industry. PMID- 19780398 TI - Magnesium in subarachnoid haemorrhage: proven beneficial? AB - Subarachnoid haemorrhage (SAH) caused by a ruptured aneurysm accounts for only 5% of strokes, but occurs at a fairly young age and carries a worse prognosis. Delayed cerebral ischaemia (DCI) is an important cause of death and dependence after aneurysmal subarachnoid haemorrhage. The current mainstay of preventing DCI is nimodipine and maintenance of normovolemia, but even with this strategy DCI occurs in a considerable proportion of patients. Magnesium is an inexpensive, easily available neuroprotective agent and has been shown to reduce cerebral vasospasm and infarct volume after experimental SAH. In a subgroup analysis in the Cochrane review of all randomized clinical trials of calcium antagonists in SAH, magnesium reduced the occurrence of DCI and that of poor outcome. Magnesium is a promising agent to prevent the occurrence of secondary ischemia and to improve outcome in patients with SAH. Currently two large phase Il trials are being conducted that will hopefully provide definite evidence whether magnesium treatment is beneficial in SAH patients. PMID- 19780399 TI - Epithelial Mg2+ channel TRPM6: insight into the molecular regulation. AB - Our understanding of the molecular mechanisms of renal magnesium (Mg2+) handling has greatly enhanced over recent years. This review highlights the regulatory factors controlling Mg2+ homeostasis through its effects on the epithelial Mg2+ channel TRPM6 (Transient Receptor Potential Melastatin subtype 6), the gatekeeper of the body's Mg2+ balance. Drug treatment, acid-base status, and several hormones have been shown to regulate TRPM6 expression, while its channel activity is modified by intracellular Mg2+, pH, and ATP. Recently, epidermal growth factor (EGF) and estrogen have been implicated as magnesiotropic hormones. The stimulation of the EGF receptor (EGFR) leads to an intracellular cascade involving Rac1 that promotes trafficking of TRPM6 to the plasma membrane. Furthermore, long-term EGF treatment upregulates the expression of TRPM6. Estrogen has also been shown to stimulate TRPM6 activity upon short-term treatment, next to its long-term regulatory effect on TRPM6 transcription. TRPM6, and its closest homologue TRPM7, are composed of a Mg2+ -permeable channel fused to an alpha-kinase domain. In the intracellular compartment, the receptor for activated C-kinase (RACK1), the repressor for estrogen receptor activity (REA), and ATP were identified as negative modulators of TRPM6 activity through its alpha-kinase domain. Therefore, the a-kinase domain acts as an indirect player involved in Mg2+ homeostasis by its feedback function in the TRPM6-mediated Mg2+ influx. PMID- 19780400 TI - Rumen epithelial cells adapt magnesium transport to high and low extracellular magnesium conditions. AB - A protein of approximately 70-kDa was identified as a candidate Na+/Mg2+ exchanger in rumen epithelial cells (REC). Melastatin-related Transient Receptor Potential 7 (TRPM7) and Magnesium Transporter 1 (MagT1) transcripts and, from them, encoded proteins were also detected. The regulation of these Mg transport pathways by extracellular [Mg] changes was the main focus of this study. Therefore, a 24-h pre-incubation of ovine REC in control (1.2 mM), low (0.12 mM) Mg, and high (5 mM)-Mg medium was performed. Na+/Mg2+ exchangers, TRPM7 and MagT1 abundance and activity were investigated by Western blot analysis, flow cytometry, immunocytochemistry and fluorescence spectroscopic measurements of [Mg2+]i changes. Inhibitors were employed to differentiate Na+/Mg2+ exchanger mediated (imipramine) and channel-mediated (cobalt(III)hexaammine, nitrendipine) Mg transport. Basal [Mg2+]i (0.40 +/- 0.02 mM) was not influenced by pre incubation in low- or high-Mg medium. However, compared with control REC (4.1 +/- 0.7 microM/min), such cells showed reduced (2.8 +/- 0.6 microM/min) or elevated (6.4 +/- 0.9 microM/min) Mg extrusion rates that correlated with a decreased (25%) and increased (38%) expression of the putative Na+/Mg2+ exchanger protein, respectively. Low- and high-Mg pre-incubated REC were both characterized by an increased (30-40%) influx capacity. In low-Mg REC, the latter resulted mainly from a strong activation of the TRPM7-related transport component. The data thus clearly demonstrate the intrinsic regulation of REC transmembrane Mg transport. PMID- 19780401 TI - Failure of beta-cell function for compensate variation in insulin sensitivity in hypomagnesemic subjects. AB - To evaluate if decreased insulin sensitivity is appropriately compensated by beta cell function in subjects with hypomagnesemia, 165 individuals, 20 to 65 years of age, were randomly enrolled in a cross-sectional study. Subjects were allocated into groups with and without hypomagnesemia, matched by age, gender, waist circumference, and body mass index. Pregnancy, smoking, alcohol consumption, high blood pressure, type 2 diabetes, chronic diarrhea, renal disease, malignancy, and heavy physical activity were exclusion criteria. Hypomagnesemia was defined by a serum magnesium concentration of < 1.8 mg/dL. As a surrogate of the hyperbolic model of beta-cell function, the relation between Belfiore's index {2/[1 + (Fasting insulin pmol/L x Fasting glucose mmol/L)]} and the HOMA-beta index {20 X Fasting insulin microU/mL /(Fasting glucose mmol/L - 3.5)} was used. The mean Area Under Curve (AUC) was calculated for each group. Although the Belfiore index was significantly lower (0.041 +/- 0.021 and 0.053 +/- 0.030, p = 0.005) and fasting plasma glucose higher (113.6 +/- 23.0 and 106.8 +/- 18.4 mg/dL, p = 0.04) in the subjects with hypomagnesemia, the HOMA-beta index (82.5 +/- 48.5 and 91.2 +/- 79.9, p = 0.32) and insulin levels (8.6 +/- 5.4 and 9.6 +/- 4.8 mciroU/mL, p = 0.17) were similar between the groups studied. The AUC which evaluates the adaptation of beta-cell function to variation in insulin sensitivity was significantly higher in the normo-magnesemic than the hypomagnesemic group (proportion 1:2.5). Results of this study show that the decrease in insulin sensitivity is not appropriately compensated by beta-cell function in individuals with hypomagnesemia; our finding suggests that hypomagnesemia could be linked to inadequate beta-cell compensation. PMID- 19780402 TI - Magnesium in acute and chronic brain injury: an update. AB - While brain free magnesium levels have been shown to decline in a number of acute and chronic brain pathologies, the mechanisms of such decline and the potential for magnesium administration as a therapeutic intervention are still unclear. In acute brain injury, magnesium therapy has failed in recent clinical trials of trauma, presumably because of an intact blood brain barrier at the time of administration reducing central penetration. Under such conditions, magnesium's peripheral effects on cardiovascular parameters may dominate over the central, and potentially neuroprotective, effects of the compound. In contrast, magnesium has been demonstrated to be beneficial in lacunar strokes, albeit that recent animal studies indicate that this effect is without any significant reduction of lesion size. Postnatal magnesium has also been shown to improve neurological outcome in term neonates with perinatal asphyxia, although this may be limited to cases of mild to moderate brain injury; no effect is observed following severe brain injury. Prenatal magnesium has been reported to be beneficial for outcome in very preterm infants, although this may only be at low doses. Combination therapies are also showing promise in experimental studies, with combined magnesium and mild hypothermia as well as magnesium and polyethylene glycol proving effective in ischemic stroke and in spinal cord injury, respectively. With respect to chronic brain injury, recent results indicate that magnesium deficient mice are susceptible to developing Parkinson's disease, which is consistent with earlier findings that magnesium deficiency over a number of generations is associated with the development of Parkinson's disease. The latter was associated with the appearance of variants of the TRPM channels. Our recent studies have shown that Parkinson's disease is associated with reduced TRPM2 and TRPM7 channel mRNA expression. Taken together, a more complete picture is emerging of the role of magnesium in brain injury, its therapeutic potential as well the mechanisms associated with its decline. PMID- 19780403 TI - Magnesium in major depression. AB - There are contradictory data regarding the levels of magnesium in patients with major depression (MD) and how antidepressants influence their concentration. Our results show erythrocyte magnesium in patients with MD (44.39 +/- 2.7 mg/L vs. 59.1 +/- 3.2 mg/L in control group, p < 0.05) and only in patients with severe MD (Hamilton score > 23) was a moderate decrease in plasmatic magnesium observed (17.7 +/- 1.5 mg/L vs. 22.9 +/- 3.3 mg/L in control group). Therapy with antidepressants from different groups and with different mechanisms of action, such as amytriptiline (25 mg x 3/day per os, 4 weeks) and sertraline (50 mg x 3/day per os, 4 weeks) leads to a significant increase of magnesium concentration in erythrocytes (57.6 +/- 4.5 mg/L after amytriptiline, respectively 56.9 +/- 3.2 mg/L after sertraline, p < 0.05 vs. before therapy). At the same time, in patients with MD, plasmatic levels of zinc were significantly decreased before therapy and increased after treatment with amytriptiline and sertraline (0.68 +/- 0.09 mg/L before treatment vs. 0.9 +/- 0.07 after amytriptiline). There is a positive correlation between concentrations of magnesium in erythrocytes and the clinical evolution of patients with MD. We consider that increasing intracellular concentration is a component of the antidepressant mechanism of sertraline and amytriptiline and maybe of other antidepressants. Anhedonia and autolytic tendencies are important elements of MD symptomatology. We tested the influence of MgCl2 0.2 mM/kg/day on a reward system using conditioned place preference (Panlab) in rats. Our data show a moderate stimulation of the reward system by magnesium (290.6 +/- 27 s time spent in a conditioned compartment before magnesium treatment and 363.3 +/- 16 s after magnesium treatment) that reflects a stimulation of the reward system (RS). We consider that a magnesium-induced stimulation of the RS is an important issue for treating anhedonia in patients with MD. An increase of intracellular magnesium may be part of the mechanism of action of antidepressants. PMID- 19780404 TI - Neutral endopeptidase inhibition enhances substance P mediated inflammation due to hypomagnesemia. AB - During dietary deficiency of magnesium neurogenic inflammation is mediated, primarily, by elevated levels of substance P (SP). The enzyme most specific for degrading this neuropeptide is neutral endopeptidase (NEP). In recent studies we found that pharmacological inhibition of NEP by phosphoramidon resulted in elevated plasma levels of SP and greater oxidative stress. We also observed that hypomagnesemia reduced cardiac and intestinal expression of NEP. In these magnesium-deficient rats increased intestinal permeability and impaired cardiac contractility occurred. In our colony of genetically-engineered NEP knockout mice that have reduced ability to degrade SP, we found increased oxidative stress that was prevented by SP (neurokinin-1) receptor blockade. Thus, we submit that inhibition of NEP by pharmacological, genetic and dietary approaches (magnesium restriction), causes greater neurogenic inflammation that may result in increased intestinal and cardiac dysfunction. PMID- 19780406 TI - No more excuses. PMID- 19780405 TI - Effect of Mg2+ on neural activity of rat cortical and hippocampal neurons in vitro. AB - Mg2+ plays an important role in biological functions, similar to that of Ca2+. In terms of neural activity, it is well known that Mg2+ blocks the NMDA receptor. However, the relationship between Mg2+ and neural function has not been well understood. We have investigated the effect of low extracellular Mg2+ concentration ([Mg2+]o) on neural activity in rat cortical and hippocampal neurons by using microelectrode array (MEA) measurements and glutamate measurements, with an enzyme modified MEA-based multi-array sensor. In this study, we investigated the effects of low [Mg2+]o on intracellular Ca2+ concentration ([Ca2+]i) using a confocal laser microscope and a flow cytometer with a fluorescence probe. The results indicate that low [Mg2+]o has an effect on neural activity. The responses of cortical and hippocampal neurons to low [Mg2+]o differed in the developmental period. The results suggest that hippocampal neurons are more sensitive to [Mg2+ than cortical neurons. The glutamate receptor distributions in the cortex and hippocampus may be different. Further investigation is required to understand the mechanisms of the Mg2+ effect on neural activity. PMID- 19780407 TI - Open source will help drive EHR costs down. The use of open source in healthcare will break down many barriers, from high cost and lack of interoperability, to inaccessibility and complexity. PMID- 19780408 TI - Laboratory systems: outlook for the '80s. 1981. PMID- 19780409 TI - Choose your shift. PMID- 19780410 TI - Outsourced billing service saves $2M annually. The service provides industry specific business intelligence, allowing staff to effectively data mine, drill down, chart and analyze data. PMID- 19780411 TI - Software verifies reimbursement accuracy. Contract-management system helps centralized billing office recover $2.7 million in contractual underpayments. PMID- 19780412 TI - Charge capture upgrade improves cash flow. While the Kentucky Medical Services Foundation was successful in converting users to the new platform, there were surprises along the way. PMID- 19780413 TI - [A Jubilee deserving of respect: 170 years of existence of the Serbian Armed Forces Medical Services]. PMID- 19780414 TI - [Malignant tumors of auricula and periauricular area]. AB - BACKGROUND/AIM: Malignant tumors of auricula and periauricular area represent seven percent of all cutaneous tumors. They appear mostly in the sixth and seventh decade. According to histological type they are basocellular and planocellular carcinomas. The most frequent etiology is the sun exposition. The aim of this study was to analyze clinical and histological characteristics and therapy of malignant tumors of auricular and periauricular area. METHODS: Totally 155 patients were treated in ORL Clinic, Clinical Center Nis during the period 1990-2006. The patients were treated surgically (59.35%), by radiotherapy (1.94%) and by combination of the two methods (38.71%). RESULTS: Since the majority of tumors were small and presented on the helix, wedge excision and primary reconstruction were performed (136), while total (9) or partial (10) auriculectomy were done in a small number of the patients. For larger lesions (T4 -when lesion is greater than 4.0 cm) and neck metastasis invading cartilage or bone, parotidectomy (15), radical neck dissection (25) and temporal bone resection (9) were performed. CONCLUSION: Carcinoma of auricular and periauricular area should be confirmed by biopsy and histopathologic evaluation. In all cases an adequate excision, margin examination and observation of appropriate lymph node draining regions should be provided. PMID- 19780415 TI - [The c.-1639g > A polymorphism of the VKORC1 gene and his influence on the therapeutic response during oral anticoagulants use]. AB - BACKGROUND/AIM: A single nucleotide polymorphism c.-1639G > A in the promoter region of vitamin K-epoxide reductase (VKORC1) gene has been found to account for most of the variability in response to oral anticoagulants (OA). The aim of the study was to determine the incidence and the effect of c.-1639G > A polymorphism on the acenocoumarol dosage requirements in the group of patients under stable anticoagulation, and to estimate the variability in response to OA. METHODS: Our study included 200 consecutive patients requiring low (n = 43), medium (n = 127) and high (n = 30) acenocoumarol dose. RESULTS: Out of 43 low dose patients, 40 (93%) carried the A allele. The A allele was less frequent in the group of 30 patients requiring high dose: among these patients 13 (43.3%) carried the A allele in the heterozygous form and none of them carried AA genotype. The patients with GG genotype required 2.6 times higher dose than the patients carriers of AA genotype (p < 0.0001). In 33 patients (16.5%) the overdose occurred during the initiation of anticoagulant therapy and in 11 patients (5.5%) it was associated with bleeding. Out of the group of 33 overdosed patients, 27 and 6 patients carried AA and GA genotype, respectively (p < 0.000001). CONCLUSION: VKORC1 significantly influenced OA dose and predicted individuals predisposed to unstable anticoagulation. The carriers of AA genotype required 2.6 time lower doses of OA than the carriares of GG genotype. Pharmacogenetic testing could predict a high risk of overdose among 28.5% of our patients--carriers of AA genotype, before anticoagulation therapy initiation. PMID- 19780416 TI - [Role of mucinohistochemical analysis in verification of malignant potential of colorectal adenoma]. AB - BACKGROUND/AIM: It is a general opinion that the biggest number of colorectal carcinoma (CRC) develops with the malignant alteration of colorectal adenomas (adenoma carcinoma sequence). Malignant potential of adenoma is in the function of its size, histological structure and the grade of dysplasia. An adequate analysis of colorectal adenomas helps their definition and timely removal, which significantly decreases carcinoma incidence. Mucin analysis can provide results which support the adenoma carcinoma sequence theory. The aim of the study was to present histochemical characteristics of adenomas and emphasize the significance of these analyses for the precise adenoma definition. METHODS: This prospective study included analysis of 117 colorectal adenomas obtained by transcolonoscopic biopsy or polipectomy in 82 patients. The biopsy samples and the removed polyps were coloured by hematoxilin-eozin (HE) staining and histochemical stainings by Periodic Acid Schiff (AB-PAS) and High Iron Diamine/Alcian blue (HID-AB; pH = 2.5) to prove mucins. RESULTS: Sulphomucins are more often found in adenomas of the left colon than of the right one (p < 0.001). Sialomucins are more reactive in adenomas of the right colon (p < 0.001). Sulphomucins are more reactive in adenomas of < 10 mm diameter (p < 0.05). The reactivity of all mucins is in negative correlation with the degree of dysplasia (p < 0.001). There is a significant difference in the reactivity of sialomucins in adenomas of the same histological type but different degree of dysplasia (chi2 = 25,743, df = 6, p < 0.001). CONCLUSION: The difference in the presence of mucins between adenomas of the left and right colons supports the theory of adenoma carcinoma sequence, since adenomas of the right colon are more protected by sialomucins and therefore less malignantly altered, which is consistent with CRC topography. Histochemical analysis of colorectum is significant for more accurate gradation of dysplasia and confirmation of malignant alteration. The negative correlation between the degree of dysplasia and the production of mucin indicates the significance of the degree of dysplasia in malignant potential of colorectal adenomas. PMID- 19780417 TI - Systemic manifestations in the course of meningococcal disease. AB - BACKGROUND/AIM: Meningococcal disease most often manifests itself as meningitis or sepsis. During the course of these diseases, other clinical events sometimes develop such as pneumonia, pericarditis, arthritis, and they are referred to as extrameningeal or systemic manifestations of the meningococcal disease. The aim of this study was to investigate the type and the incidence of particular extrameningeal/systemic manifestations among patients with meningococcal meningitis and sepsis, including time of their onset and the influence on the disease outcome. METHODS: The retrospective study of the medical records of 246 patients treated for meningococcal disease over the 25-year period in the Institute for Infectious and Tropical Diseases, Belgrade was conducted. The patients, aged 3 months to 82 years both sexes, were divided into two groups. RESULTS: Out of 246 patients extrameningeal/systemic manifestations were found in 42 (17.1%) patients: 35 (14.2%) occurred during meningitis, and seven (2.8%) during sepsis. Pulmonary manifestations (mostly pneumonia) were the most prevalent, found in 12 (4.9%) patients, followed by heart involvement in nine (3.6%) patients (mostly pericarditis, in seven or 2.8% patients). Various ophthalmic manifestations occurred in seven (2.8%), arthritis in 4 (1.6%) and sinusitis in six (2.4%) patients. Otitis, multiple renal embolisms with hematuria, osteomyelitis and thrombophlebitis were evidenced in one patient, each. Most of the systemic manifestations (30 patients or 71.4%), developed within the initial three days of the disease (p < 0.01), suggesting direct pathogenic mechanism induced by meningococci per se, while only three (7.1%) developed after seven days, when immune-mediated disease was more likely. Even though these manifestations complicate and prolong treatment of the meningococcal disease, they had no major influence on the disease outcome. Lethal outcome occurred in 2 (4.76%) patients, both with the meningococcal type of the disease. CONCLUSION: Extrameningeal or systemic manifestations are uncommon complications during the course of both meningococcal meningitis and sepsis. The onset of pneumonia, pericarditis, eye involvement, and arthritis, within the initial seven days of the disease, were most prevalent in the course of meningitis. They had no major influence on the disease outcome. PMID- 19780418 TI - [Frequency of uterine rupture at delivery and accompanying risks for the mother and the newborn]. AB - BACKGROUND/AIM: Uterine rupture at delivery is a severe lifethreatening complication for both mather and the newborn. The aim of the study was to determine the frequency of total number uterine rupture within the deliveries, to perceive circumstances and causes that lead to rupture, to establish perinatal and maternal mortality and to present our therapeutic procedure. METHODS: In the group of 37 ruptures at 59 660 deliveries from the period 1991-2000 included in this retrospective study we analyzed age, level of education, gestational age, parity, previous caesarian section and other operations on uterus, time of diagnosing rupture, grade and place of rupture, use of Syntocinon and Prostaglandin at delivery, perinatal and maternal mortality, as well as therapeutic procedures at rupture that occurred. RESULTS: The highest influence on uterine rupture in our group had been exerted by previous caesarian section and myomectomy in relation 33 : 4. Incomplete uterine ruptures were more frequent, 26 (70.27%), in relation to complete ones, 11 (29.75%). The most frequent place of uterine rupture was the front wall, 34 (91.89%), two ruptures occurred on the fundus and one on the back wall. The most frequently applied therapeutic procedures were rupture suture in 31 (83.78%) cases, and in six (16.22%) cases hysterectomy. Perinatal mortality was three times higher than average (17.78%) in that period and was 51.28%. CONCLUSION: We emphasize that rupture frequency in the total number of deliveries was one rupture at 1 612 deliveries, whereas rupture frequency on the intact uterus was 1 : 17 269, and frequency of uterine rupture after caesarian section was one rupture at 245 deliveries. Our research as well as researches of other authors, showed that a previous caesarian section is the most frequent cause for the occurrence of uterine rupture. Therefore, caesarian section should be avoided whenever possible, not just because of a potential rupture, but also because of more frequent hysterectomy that interrupts woman's reproductive ability. PMID- 19780419 TI - Renal transplantation vs hemodialysis: cost-effectiveness analysis. AB - BACKGROUND/AIM: Chronic renal insufficiency (CRI), diabetes, hypertension, autosomal dominant polycystic kidney disease (ADPKD) are the main reasons for starting dialysis treatment in patients having kidney function failure. At present, dialysis treatments are performed in about 4,100 patients at 46 institutions in Serbia, out of which 90% are hemodialyses. At end-stage renal disease (ESRD) the only correct selection is kidney transplantation. The basic aim of the planned research was to compare ratio of costs and effects (Cost Effectiveness Analysis - CEA) of hemodialysis and kidney transplantation in patients at ESRD. METHODS: As the main issue of treatment in patients from both groups the life quality measured by the validated McGill Questionary, was used. The study included 150 patients totally, divided into two groups. The study group consisted of 50 patients with kidney transplantation performed at the Clinical Center of Serbia and the control group consisted of 100 patients on hemodialysis at Clinical Center of Serbia, Clinical Hospital Center Zemun, Clinical Hospital Center "Zvezdara", Clinical Center Kragujevac and Health Center "Studenica", Kraljevo, comparable with respect to sex, age and length of treatment with the study group. RESULTS: Effect of kidney transplantation in relation to hemodialysis being selection of treatment is expressed in the form of incremental ratio of costs and effects (Incremental Cost-Effectiveness Ratio - ICER). It is clear from the enclosed tables that the strategy of kidney transplantation is far more profitable considering the fact that it represents saving of EUR 132,256.25 per one year of contribution Quality Adjusted Life Years (QALY) within the period of 10 years. According to all aspects of live quality (physical symptoms and problems, physical well-being, phychological symptoms, existential well-being and support), difference is statistically important in favour of transplant patents. CONCLUSION: The costs of patient therapy by hemodialysis at end-stage renal disease is far greater than by performing therapy of transplantation and maintenance, by almost three and a half times. Difference in total quality aspects of human life (physical, emotional, social, spiritual and financial) between dialysed and transplant patients is statistically significant and by 18.12% greater in transplant patients than in patients on hemodialysis. PMID- 19780420 TI - [Quality of life assessment in patients with multiple sclerosis]. AB - BACKGROUND/AIM: Multiple sclerosis (MS) is a chronic inflammatory disease of central nervous system. The main physiopatological feature of MS is demyelination. Multiple sclerosis is one of three most common causes of severe disability in youngest people. In patients with MS, apart from complete psychophysical status and objective neurologic status, a subjective perception of symptoms and signs, known as quality of life, must be considered, too. The aim of this study was to estimate a health related quality of life (HRQoL) in patients with multiple sclerosis (MS) and to investigate the correlations between scores of HRQoL and selected demographic and clinical parameters. METHODS: A cross sectional study was performed in patients meeting following inclusion criteria: MS diagnosis (McDonald's criteria), age 18-60 years, the Expanded Disability Status Scale (EDSS) < 8, and written informed consent. Exclusion criteria were exacerbation of MS in the last month, any preexisting major chronic illness and/or psychiatric disorders and antidepressive and/or corticosteroid therapy in the last month. The quality of life was measured by a disease specific instrument, MSQoL-54 (The Multiple Sclerosis Quality of Life). The neurological impairment was assessed using the Expended Disability Status Scale (EDSS) and Mini Mental Scale (MMS). The presence and severity of depression was estimated by the Hamilton Depression Rating Scale (HDRS). The presence and severity of fatigue was assessed by the Fatigue Severity Scale (FSS). Statistical analysis included descriptive statistics and correlation analysis. RESULTS: The higher HRQoL score was registered for mental health (56.3 +/- 19.5) than for physical one (51.3 +/- 17.9), which means that physical disability had more important influence on quality of life deterioration comparing to mental health. The highest values of HRQoL were observed in domains of Cognitive Functioning (77.4 +/- 22.5) and Pain (75.7 +/- 25.5). The lowest scores of HRQoL were registered in domains of Role Limitations due to Physical Problems (32.5 +/- 42.0) and Role Limitations due to Emotional Problems (44.6 +/- 47.8). HRQoL scores statistically significantly correlated with natural history of MS, duration of diseases, employment and marriage status of participants. Deterioration in quality of life scores in the most of MSQoL-54 scales and subscales statistically significantly correlated with the presence and severity of physical disability, depression status and fatigue in patients with MS. CONCLUSION: This study showed that different demographic and clinical parameters had a major influence on HRQoL impairment in the sample of patients with MS. PMID- 19780421 TI - [The role of colposcopy and typization of human papillomavirus in further diagnostic proceedings in patients with ASC-US cytological finding of the uterine cervix]. AB - BACKGROUND/AIM: Bethesda system of classification of cytological findings was introduced in 2001 two subcategories in the category of atypical squamous cells (ASC) findings: ASC of undetermined significance (ASC-US) and ASC which cannot exlude high-grade intraepithelial lesions (ASC-H). The aim of our study was to assess a possible association of these two subcategories with pathologic biopsy finding and to find out the best further diagnostic proceedings. METHODS: At the Clinic of Gynecology and Obstetrics, Nis 130 patients with ASC findings were analyzed. Colposcopy was performed in all study participants. Patients with pathological colposcopic findings underwent cervical biopsy. In 10 patients with pathologic histologic and 15 with benign findings human papilloma virus (HPV) typization was done using the Hybrid Capture method. RESULTS: Patients with ASC-H finding had significantly more pathologic biopsies compared with patients with ASC-US finding (57.84: 20.72). CONCLUSION: Colposcopy was exhibited somewhat higher sensitivity compared to HPV typization (94.7 : 90), but lower sensitivity (79.27 : 86.6). The usage of HPV typization in the triage of patients with ASC cytologic smear induces statistically significant reduction of unnecessary percentage of cervical biopsies. PMID- 19780423 TI - [Modem visualisation techniques in brain functions estimation]. PMID- 19780422 TI - Sentinel node biopsy for skin melanoma. AB - BACKGROUND/AIM: Skin melanoma is one of the most malignant diseases with increasing incidence rate. Sentinel node biopsy (SNB) is very important for early detection of metastatic spread. The aim of the study was to analyze the first 40 patients with skin melanoma of 1 to 4 mm Breslow thickness when SNB was indicated. METHODS: The patient characteristics, localization of the primary melanoma as well as histology grade were analyzed. SNB with intraoperative radiocolloid and methylene blue dye detection was performed. RESULTS: Complication rate after SNB was analyzed and seroma was found in 5% of the patients. The therapeutic node dissection was performed in 10 patients with positive sentinel biopsy. The follow-up lasted two years. In five patients the false negative SNB was defined after the mean time of 11 months and the therapeutic dissection was performed. CONCLUSION: SNB in melanoma patients is a useful diagnostic procedure. It is advised for melanoma of 1 to 4 mm Breslow thickness. PMID- 19780424 TI - [Brugada syndrome--a brand new case]. AB - BACKGROUND: Brugada syndrome (BS) is a disorder characterized by syncope or sudden death associated with one of several electrocardiographic (ECG) patterns characterized by incomplete right bundle branch block and ST elevation in the anterior precordial leads. Patients with BS are prone to develop ventricular tachyarrhythmias that may lead to syncope, cardiac arrest, or sudden cardiac death. CASE REPORT: A 58-year-old woman is the first described case of Brugada syndrome in Serbia with intermittent typical changes in basic electrocardiography (ECG): ST segment elevation in the precordial chest leads like dome or coved- major form or type I. For the last 27 years the patient had suffered of palpitations and dizziness, without syncopal events. Her sister had died suddenly during the night in sleep. During 24-hour Holter monitoring the patient had ventricular premature beats during the night with R/T phenomenon and during the recovery phase of exercise testing had rare premature ventricular beats as the consequence of parasympatethic stimulation. Late potentials were positive. Echocardiography revealed left ventricular ejection fraction of 60%. We performed coronary angiography and epicardial coronary arteries were without significant stenosis and structural heart disease was excluded. In the bigining of the electrophysiological study ECG was normal, and after administration of Propaphenon i.v. Brugada syndrome unmasked with appearance of type I ECG pattern. A programed ventricular stimulation induced non sustained ventricular tachycardia. One-chamber implantable cardioverter defibrillator was implanted and the patient was treated with a combination od amiodarone and metoprolol per os. After one-year folow-up, there were no episodes of ventricular tachycardia and ventricular fibrillation. CONCLUSION: Brugada syndrome is a myocardial disorder which prognosis and therapy are related to presence of ventricular fibrillation or ventricular tachycardia. Electrophysiologicaly induced malignant ventricular disorders class I are indication for implantation of cardioverter defibrilator, as also occurred in presented patient. PMID- 19780425 TI - Oropharyngeal dysphagia as dominant and life-threatening symptom in dermatomyositis. AB - BACKGROUND: Dysphagia can be a serious problem in patients with inflammatory myopathies. It may be associated with nutritional deficit, aspiration pneumonia, and poor prognosis. CASE REPORT: We presented a 60-year-old male, suffering from difficulty in swallowing, pain and weaknes in the proximal parts of his extremities, and skin manifestation. Laboratory findings showed increased creatine kinase and aldolase. Antinuclear antibodies to HEP-2 subtrate revealed titer of 1:40. Electromyoneurography demonstrated evidence of a proximal myopathy. A muscle biopsy revealed myositis. The baruim swallow test was remarkable for regurgitation, and nasal emerging of barium. Nuclear magnetic resonance images of cranium was normal. Tumor markers CEA, and Ca 19-9 were increased. A dose of 1 mg daily prednisolone was administered and percutaneous enteral feeding was performed. Two months later, the patient developed febrile state, aspiration pneumonia, and died due to respiratory failure. CONCLUSION: In cases of dermatomyositis with the serious dysphagia, percutaneous endoscopic gastrostomy should be performed as soon as possible. Overall survival rate is low, even with an adequate therapy administration. Inflammatory myopathies should be considered in any patient with oropharyngeal dysphagia. PMID- 19780426 TI - [Developing of preventive medicine in the town of Nis and the south Serbia with the specific role of Royal Military Pasteur Institute, the first in Balkan]. PMID- 19780427 TI - Occlusal tooth surface treatment plans and their possible effects on oral health care costs. AB - PURPOSE: The aim of this study was to evaluate decision making with regard to detection and treatment of carious lesions on occlusal tooth surfaces and to evaluate the possible costs related to the different treatment plans of a group of clinicians in private practice. MATERIALS AND METHODS: Forty extracted permanent teeth with no fillings or macroscopic carious cavitations were selected and radiographed, using a standard method similar to bitewing and then mounted in two models. A sample of 130 clinicians in private practice in Piracicaba, Brazil were asked to carry out combined visual-radiographic caries examination of the occlusal surfaces and to recommend possible treatment plans for each surface. Teeth were sectioned bucco-lingually and caries was assessed using a stereomicroscope and classified as either enamel or dentine lesions. The costs of treatments suggested by each examiner were calculated, using a fee scale reported by the Brazilian Federal Council of Dentistry. RESULTS: Most teeth (53.7%) that were found to be sound on histological examination were considered to have enamel lesions. In 85.7% of these cases, the clinicians recommended restorative treatments. There was about 14-fold difference among clinicians concerning the costs related to decision making. CONCLUSION: Not only did the clinicians overestimate the presence and depth of carious lesions, but they also tended to treat enamel lesions using invasive therapeutic procedures. Great disparities were observed with regard to treatment costs related to decision making. Assuming an in vivo situation, the clinicians may be performing overtreatments and consequently interfering in the quality of patients' oral health. PMID- 19780428 TI - Prevalence of malocclusions in 10- to 12-year-old schoolchildren in Ceara, Brazil. AB - PURPOSE: The aim of the present study was to determine the prevalence of malocclusions and dental characteristics of schoolchildren aged between 10 and 12 years in the city of Fortaleza, Ceara in northeastern Brazil. MATERIALS AND METHODS: Two hundred and sixty-four children (107 boys and 157 girls) were examined using the Angle classification system. The occlusal characteristics studied were the measurements for overbite, overjet, crowding and midline diastema. The children who were selected had not had prior orthodontic treatment and were born in Ceara, as were their parents and grandparents. RESULTS: Of the schoolchildren who were studied, 25.8% had normal occlusion, 47.7% had Class I malocclusion, 22.3% had Class II malocclusion and 4.2% had Class III malocclusion. There was no statistically significant difference between age and gender; 30.3% of the individuals had a normal overbite and 36.7% and 19.7% had increased and reduced overbites, respectively. A normal overjet was found in 33.7% of the subjects and increased and reduced overjet was found in 50% and 3.4%, respectively. Dental crowding was observed in 62.5% and the presence of midline diastema was observed in 14.8% of the schoolchildren. CONCLUSIONS: The most prevalent occlusal status was Class I malocclusion, with no distinction between age and gender. Increased overbite and overjet were predominant. There was a high occurrence of dental crowding among the subjects in contrast to the few cases of midline diastema. PMID- 19780429 TI - The importance of psychological factors in the maintenance of oral health: a study of Swedish university students. AB - PURPOSE: The aim of this study was to investigate the predictive value of the traditional multidimensional health locus of control (MHLC) scale, a corresponding dental health locus of control (DHLC) scale and dental health values (DHVs) regarding students' dental health before and after a video programme that presented information about dental diseases and instructions on oral hygiene. MATERIALS AND METHODS: A group of 217 university students participated in this study. Before the video programme was presented, assessments were made of MHLC, DHLC and DHVs. Plaque and gingival indices were obtained in a clinical examination conducted before (plaque index [PLI] 1 and gingival index [GI] 1) and 10 weeks after (PLI 2 and GI 2) the presentation of the programme. RESULTS: The percentage of tooth surfaces exhibiting plaque and of sites involving gingivitis decreased and was statistically significant between baseline and re-examination for both males and females. The females exhibited statistically significant better PLI 1 and GI 1 values and stronger DHVs than males. Also, better GI 1 values were found to be statistically significant and related to stronger DHVs for females. A stronger trust in the dental health personnel regarding the dental health was related to more gingivitis at the initial examination (GI 1). For males, stronger internal DHLC was related to more plaque at the final examination (PLI 2). CONCLUSION: The only psychological scales that showed some relationship to the measures of dental health were DHLC and DHVs. Gender was the strongest related variable to dental health. PMID- 19780430 TI - Orthodontic treatment complexity and need with associated oral health-related quality of life in Nigerian adolescents. AB - PURPOSE: The aim of this study was to assess the orthodontic treatment complexity and need in Nigerian adolescents as well as to ascertain the relationship between these professionally assessed facets of orthodontic provision and the oral health related quality of life in the adolescents. MATERIALS AND METHODS: The orthodontic treatment complexity and need in 274 adolescents who were drawn from four secondary schools in Ibadan, Nigeria aged 12 to 17 years (142 (51.8%) females and 132 (48.2%) males) were examined using the index of complexity, outcome and need. The oral health-related impacts of the same subjects were assessed using the shortened version of the oral health impacts profile. In addition to the descriptive statistics, the Pearson chi-square test was used in the analysis of data. RESULTS: Cases that were considered to belong to the easy complexity grade accounted for 20.1% while difficult/very difficult complexity grades accounted for 9.8%. Boys had significantly fewer complexity grades that were in the easy grade (P < 0.05). Of the subjects, 42% would need orthodontic treatment and 62.4% had some oral health-related impacts, with boys suffering significantly more impacts than girls. The relationship between oral health related impacts and treatment need was significant (P < 0.05) unlike with complexity (P > 0.05). CONCLUSIONS: The orthodontic treatment complexity and need in these Nigerian adolescents was comparable to Caucasians including the association with oral health-related impacts on daily activities. PMID- 19780431 TI - Evaluation of procedures employed for the maintenance of removable dentures in elderly individuals. AB - PURPOSE: The objective of the present study was to evaluate the behaviour of the wearers of removable dentures in relation to cleaning and maintaining the prosthesis. MATERIALS AND METHODS: Two hundred and thirty-one people were interviewed, most of whom were females, over 60 years of age and participants in the Center for Integrated Study and Support to the Elderly. RESULTS: After analysing the responses, it was verified that most people brush their dentures three times a day using dentifrice and only go to the clinician when they have a complaint. They do not receive follow-up appointments for checkups, do not use immersion cleaners for their dentures and do not remove their dentures during the night. CONCLUSIONS: It was concluded that the study sample did not receive proper orientation for the conservation of removable dentures, which may consequently reduce the useful life of dentures and cause social and functional problems. PMID- 19780432 TI - Self-reported oral health status, oral health-related behaviours, resilience and hope in Romania. AB - PURPOSE: The aim of the present study was to investigate whether resilience, hope, perceived oral health status and oral health-related behaviours were associated. MATERIALS AND METHODS: The study sample consisted of 198 first-year medical students in Romania. The questionnaire included information about sociodemographic factors, behavioural variables, perceived oral health status, resilience and hope. RESULTS: Women had more resilience and 'personal competence' than men (P < 0.05). Resilience and hope were correlated with perceived dental health (P < 0.01). Perceived dental health was related to current non-treated caries, satisfaction with the appearance of one's own teeth, toothache last time and resilience (P < 0.001). Age, gender, current extracted teeth, perceived gingival bleeding and hope were not independent distinguishing variables after adjustment for internal heterogeneity. When oral health behaviours (toothbrushing, flossing, mouthrinse frequency and pattern of dental visit) were evaluated, it was demonstrated that flossing frequency was correlated with resilience and hope (P < 0.01). CONCLUSIONS: The results suggested that resilience and hope might be a psychosocial risk marker that influences perceived oral health status and behaviours. PMID- 19780433 TI - Effect of providing outreach oral health care to institutionalised elders in Hong Kong. AB - PURPOSE: The aim of the present study was to evaluate the effect of providing outreach oral health care services on the oral health status and oral health related quality of life to institutionalised elders in Hong Kong. MATERIALS AND METHODS: At baseline, 232 Chinese adults aged 65 to 80 years living in 14 elderly homes participated in a free oral health examination and completed a validated Chinese version of general oral health assessment index (GOHAI) in a face-to-face interview. Afterwards, free dental treatments, including extractions, scaling and fillings, were offered to the subjects every year according to their needs. On the third year, the subjects were examined and interviewed again at least 6 months after the last treatment. RESULTS: A total of 144 elders (62.1%) were examined and interviewed at the time of evaluation. Their oral health status had improved greatly compared with that found at baseline. They had fewer decayed teeth (1.3 versus 2.0, P < 0.001), and a lower proportion of the dentate subjects had periodontal pockets (60.9% versus 28.9%, P < 0.001). However, no significant change in their mean GOHAI score between baseline and the time of evaluation was detected. Despite this, a higher proportion of the elders were satisfied with their own oral health at the time of evaluation compared with baseline (66.2% versus 75.7%, P = 0.047). CONCLUSIONS: The provision of outreach oral health care services can lead to an improvement in both the assessed and the perceived oral health status of institutionalised elders. PMID- 19780434 TI - Oral health status of dialysis patients based on their renal dialysis history in Kerman, Iran. AB - PURPOSE: Maintaining a high level of periodontal and oral health in patients undergoing renal dialysis is of paramount importance because of the inherent compromised host defence mechanisms. The aim of the present study was to determine the periodontal status and the level of dental caries in renal dialysis patients in Kerman, Iran. MATERIALS AND METHODS: A cross-sectional study was conducted on two groups of patients: one including 68 renal dialysis patients (test) and the other including 30 healthy subjects (control). Half-mouth measurements of Gingival Index (GI), Plaque Index (PI), probing pocket depth (PPD), gingival recession (GR), clinical attachment level (CAL) and bleeding on probing (BOP) as well as decayed, missing or filled teeth (DMFT) index were recorded. RESULTS: The GI, BOP, PPD, CAL and GR were significantly greater among the test group as compared with the control group; however, the DMFT did not differ significantly among the groups. There was no relationship between the duration of the dialysis and the periodontal indices. CONCLUSIONS: It seems that patients with chronic renal failure have less favourable periodontal health than normal patients. The present study showed that oral home care practices were inadequate. Thus, preventive programmes to promote the oral health status of haemodialysis patients are needed. PMID- 19780435 TI - Perceived oral health in patients with Crohn's disease. AB - PURPOSE: The aim of the present study was to investigate perceived oral health in patients with Crohn's disease (CD) in comparison with a control group without CD. MATERIALS AND METHODS: The study population comprised 1943 patients with CD recruited from the Swedish National Patients Organisation of inflammatory bowel disease and 1000 randomly selected controls. All participants received a questionnaire with questions concerning socioeconomic variables, education, civil status, income, dental care habits, oral health and tobacco use. RESULTS: Eighty eight per cent of the patients and 75% of the controls answered the questionnaire. Patients with CD perceived their oral health to be worse than controls. The odds ratio (OR) for the patients to estimate their oral health as much worse than others in the same age group was 9.7 (95% CI, 5.8 to 16.4) after adjustment for age, smoking habit, gender and education. The patients also reported a significantly greater need for dental treatment than the controls, with an OR of 5.7 (95% CI, 4.2 to 7.9) after taking into account the age, smoking habit, gender and education. Furthermore, the patients with CD reported significantly more mouth-related problems than controls (OR 3.2), such as significantly more caries and more gingival bleeding. Of note, there were significantly more smokers in the patient group. CONCLUSIONS: The results of the present study show that patients with CD perceived their oral health to be worse and have a greater need for dental treatment compared with the control group. PMID- 19780436 TI - Artificial plaque removal from interproximal tooth surfaces (maxillary premolar and molar) of a jaw model. AB - PURPOSE: The aim of this study was to compare the ability of the bristles of newly developed toothbrushes in removing artificial plaque deposits from the interproximal areas of a jaw model. MATERIALS AND METHODS: Four toothbrushes were evaluated in this study: A, two differences in level patterns, combination of flat and extremely high-tapered filaments; B, one difference in level pattern, combination of flat and extremely high-tapered filaments; C, rippled pattern and high-tapered filaments; and D, rippled pattern and tapered filaments. The brushing simulator was adjusted to provide a horizontal brushing stroke of 20 mm at a rate of 190 strokes per minute for a duration of 1 min. A 200-g force was applied to the brush head. A plaque-like substrate was placed in the facial and the interproximal sides of the artificial teeth that had the cross-sectional dimensions of mesial face in the maxillary right first molar and distal face in the second premolar. The results were photographed, and the area of penetration and the cleaning effectiveness were calculated for each picture by computer digital image analysis. This test was repeated five times for the toothbrush for each design that was evaluated. The resulting data were analysed using ANOVA and the Scheffe test. RESULTS: The rate of plaque removal was the highest with toothbrush A that gave a significantly greater removal of the artificial plaque than the other three toothbrushes on the maxillary right first molar mesial surface (P < 0.05). CONCLUSION: These results suggest that toothbrush A was more effective in plaque removal in this in vitro model used for determining the interproximal penetration of the four bristle designs. PMID- 19780437 TI - Fluoride intake from meals served in daycare centres in municipalities with different fluoride concentrations in the water supply. AB - PURPOSE: The aim of this study was (1) to determine the fluoride content in the meals served to children aged up to 36 months in daycare centres of two municipalities with different levels of fluoride in the water supply, (2) to calculate the mean fluoride ingested daily by the children when consuming those meals and (3) to analyse the contribution of this consumption to the development of dental fluorosis. MATERIALS AND METHODS: Samples of the meals served to the children were collected during a whole week. The fluoride content of the samples of solid foods and milk was analysed using an ion-specific electrode combined with reference electrode after diffusion facilitated by hexamethyldisiloxane. Samples of beverages were buffered with an equal volume of total ionic strength adjustment buffer and analysed using a combined electrode. The results were compared using the Mann-Whitney test. RESULTS: Mean fluoride contents of the meals were of 0.204 +/- 0.179 and 0.322 +/- 0.242 microg F/mL (P < 0.05), respectively, in the municipalities with low and adequate fluoride content. Daily fluoride intake in the former was 0.013 +/- 0.003 mg/kg body weight/day and in the latter was 0.012 +/- 0.001 mg/kg body weight/day (P > 0.05). CONCLUSIONS: The children were not exposed to dental fluorosis in the daycare centres. However, the risk cannot be ignored, considering the meals and the use of fluoridated dentifrices at home may also contribute to fluoride intake. PMID- 19780438 TI - Evaluating knowledge and attitudes of elementary school teachers on emergency management of traumatic dental injuries: a study in an Iranian urban area. AB - PURPOSE: The aim of this survey was to evaluate the knowledge and attitudes of Iranian elementary school teachers with regard to emergency management of dental trauma, in a northwestern urban area. MATERIALS AND METHODS: A total of 160 teachers from 40 schools, all selected randomly, were included in the study. A three-part self-administered questionnaire surveying teachers' background, knowledge of the growth patterns of children's dentition, general dental trauma, fractured and avulsed teeth, as well as attitudes regarding dental trauma was used. Chi-square analysis was performed to examine the effect of educational background, gender, length of service and topics they teach on their knowledge and attitudes on the management of dental trauma. RESULTS: A majority of the participants had received tertiary education. Regarding the management of tooth fracture, 52.4% provided appropriate answers. A similar proportion (50.6%) realised that they should replant a permanent avulsed tooth. However, they had little knowledge on the correct procedures; less than a fifth were acquainted with the urgent need for action. Only 38% knew about appropriate washing mediums and about a third were familiar with proper storage media. Health teachers and those with higher educational background (16 years of education) were significantly more knowledgeable regarding the disciplines of avulsion management. Teachers with a high level of experience (third decade) were also more knowledgeable in terms of prevalence of dental trauma accidents. CONCLUSIONS: The current survey indicated a substantial lack of knowledge regarding dental trauma management among elementary school teachers. Educational campaigns to improve their knowledge and awareness seem crucial for this group of adults who are usually the first to respond in cases of dental trauma accidents in schools. PMID- 19780439 TI - Return of a problem child. PMID- 19780440 TI - Nuclear architecture. PMID- 19780441 TI - Tasting the light. PMID- 19780442 TI - Going with Golgi. PMID- 19780444 TI - Not set in stone (or ice). PMID- 19780443 TI - Hunting a croc killer. PMID- 19780445 TI - The way the wind blows. PMID- 19780446 TI - Shifting gears. PMID- 19780447 TI - Too little, too late. PMID- 19780448 TI - The crisis of public management. PMID- 19780449 TI - Captain Hook meets Adam Smith. PMID- 19780450 TI - Space, the final frontier? PMID- 19780451 TI - Black stars, not holes. PMID- 19780453 TI - Squeezing more oil from the ground. PMID- 19780452 TI - Turbocharging the brain. PMID- 19780454 TI - Lost cities of the Amazon. PMID- 19780455 TI - Boosting vaccine power. PMID- 19780456 TI - Privacy and the quantum internet. PMID- 19780457 TI - Biotech's plans to sustain agriculture. PMID- 19780458 TI - Why do whales beach themselves? Are strandings increasing? PMID- 19780459 TI - The end of a decade: challenges for a changing world. PMID- 19780460 TI - New practice model for Latinos in need of social work services. AB - The practice model described in this article represents a new synthesis of some of the best and most pragmatic models and concepts in the cultural competence literature. The article begins by infusing the ecosystems perspective with Latino relevant theories and research for enhancing cultural sensitivity, both heightened awareness of the Latino experience and understanding of problem patterns in their historical, social, and cultural contexts. The article builds to a description of the practice model by selectively reviewing and synthesizing state-of-the-art models and methods of culturally competence practice. The resulting 2 x 4 matrix describes four major dimensions of culturally competent practice, across generalist and domain-specific levels of practice, considered essential to practice with U.S. Latinos: (1) increasing service availability and access, often through outreach; (2) assessment in social and cultural context, emphasizing basic grounding in the nature of oppression and social justice oriented services; (3) selecting interventions acceptable to Latinos on the basis of their social and cultural experience and diverse subgroup memberships; and (4) institutionalizing multiple forms of social work service accountability to Latino clients and communities. PMID- 19780461 TI - Consumer-driven health care: answer to global competition or threat to social justice? AB - Health planning in the United States is rapidly approaching a fork in the policy road, with one direction leading the nation toward a universal plan with strong government involvement and the other direction strengthening existing market based reforms and preserving a commercial health insurance industry. "Consumer driven health care," a slogan that captures a range of market-based approaches to preserving patient choice and increasing cost savings, is most commonly implemented in the form of individual health savings accounts. These accounts are offered to employees as a means of increasing the cost sharing ofpersonal health care expenses. The author provides an overview of health insurance history and discusses some implications of abandoning earlier practices of risk pooling health care expenses across a wider community. Access and affordability issues connected with the adoption of a consumer-driven health care system in the United States are addressed. Parallels are drawn between the expansion of community based insurance in the United States following World War II and social work's historic commitment to social justice and economic inclusion. Suggestions are made for social workers'involvement in health policy discourse and activism during this critical time ofnational reflection on universal versus market-based reforms for the U.S. health care system. PMID- 19780463 TI - Civilian social work: serving the military and veteran populations. AB - This article discusses social work practice areas for civilian social workers who provide services to military service members,veterans, and their families. These practice areas include education, child welfare, domestic violence, mental health, health care, substance abuse, and criminal justice. The authors examine the impact of the contemporary military lifestyle and current military operations on service members and their families in the context of these practice areas, with the goal of compelling civilian social workers to acknowledge their responsibility to competently serve military and veteran clients. PMID- 19780462 TI - The big picture: how social work can effectively utilize photographs. AB - Social work has struggled with image problems and misperceptions of the profession and the types of services it provides. Photography is a medium that has been used effectively by other professions to change attitudes and perceptions. The present study examined the potential of photographs to change the image of available social services--namely, an adult day care program. Participants were divided into two groups: (1) a control group that only completed a survey on attitudes about adult day care services and (2) an experimental group that viewed photographs showing positive images of clients engaged in program activities before taking the survey. A multivariate regression demonstrated that those who saw the photographs before taking the survey had more positive attitudes about adult day care services. In fact, the variable representing the presentation of the photographs had the strongest effect on attitudes. Such findings suggest that photography is a potentially powerful tool to promote positive attitudes about social services programs. The implications of these results are discussed. PMID- 19780464 TI - Treating female perpetrators: state standards for batterer intervention services. AB - Although domestic violence has historically been considered primarily a crime perpetrated by men, increasing numbers ofwomen are being arrested and mandated into batterer intervention programs. This study examined existing state policies to explore the degree to which they address the unique needs of women in batterer intervention programs. Nearly all existing standards were designed primarily to address the needs of heterosexual male clients.The goal of the study was to examine existing standards as they relate to female perpetrators and to make recommendations for future development of state standards. PMID- 19780465 TI - Results from a national study of social workers sanctioned by state licensing boards. AB - This article presents the results of a descriptive study, synthesizing the reports of 27 state regulatory boards about their actions against certified and licensed social workers (N = 874) during the period of 1999 to 2004. The purpose of this study was to examine the unprofessional behavior of certified and licensed social workers, the results of which can inform the education and training of social workers and help protect the public. The most frequent violations were dual relationships, license-related problems, problems with basic practice, crimes, and practice below specific standards of care. State regulatory boards typically sanctioned social workers with letters of reprimand, revoked certificates or licenses, imposed probation or instituted the supervision of practice, and accepted the social workers' surrender of their licenses. PMID- 19780466 TI - Child welfare worker caseload: what's just right? AB - This study was designed to establish a caseload standard for child welfare workers. Understanding reasonable workload expectations for child welfare workers is a cornerstone of quality service provision and the recruitment and retention of qualified workers. Because of the analytic complexity of this question, qualitative and quantitative methods were used.The mixed methods included focus group sessions involving 60 Children, Youth and Families (CYF) workers, analysis of more than 16,000 CYF cases maintained by the CYF information management system, and job shadowing of 34 randomly selected CYF workers for an aggregate of 5,600 work hours. The study was conducted on the CYF located in Pittsburgh. Results indicated that, on average, some CYF workers had been assigned twice as many cases as the 16 to 17 per month suggested as reasonable by the present findings. PMID- 19780467 TI - Making difficult decisions. PMID- 19780468 TI - Tribute to Professor E.E Zijlstra: a decade in the College of Medicine. PMID- 19780469 TI - Malawi's health publication productivity--a response and where do we go from here? PMID- 19780470 TI - Malawi's new magnetic resonance imaging (MRI) centre. PMID- 19780471 TI - Perceptions towards private medical practitioners' attachments for undergraduate medical students in Malawi. AB - OBJECTIVE: To describe perceptions of medical students, recent medical graduates, faculty of the College of Medicine, University of Malawi and private medical practitioners (PMPs) towards an attachment of undergraduate medical students in private medical doctors' offices. METHOD: Qualitative cross sectional study conducted in Blantyre, Malawi in 2004 using in-depth key informant interviews and content analysis. RESULTS: In general, private medical practitioners were favourable to the idea of having medical students within their consulting offices while the majority of students, recent graduates and faculty opposed, fearing compromising teaching standards. The lack of formal post-graduate qualifications by most private medical practitioners, and nationally-approved continued medical education programs were mentioned as reasons to suspect that private medical practitioners (PMPs) could be outdated in skills and knowledge. Private medical practitioners however reported participation in credible continued professional development (CPD) programs although these were not necessary for re-registration. Students and faculty suggested that the need for privacy in private institutions unlike in the public teaching hospitals as one reason why patients may not be willing to participate in the teaching in PMPs facilities. The fact that the patients profiles with regard to disease presentation (mostly ambulatory) and higher socio-economic status may be different from patients attending the public, free for service teaching hospital was not seen as a desirable attribute to allocate students to PMPs clinics. CONCLUSION: Faculty, medical students and recent graduates of the Malawi College of Medicine do not perceive PMPs as a resource to be tapped for the training of medical students. PMID- 19780472 TI - Impact of iron supplementation on schistosomiasis control in Zambian school children in a highly endemic area. AB - AIM: To study impact of once weekly iron supplementation on praziquantel cure rate, Schistosoma haematobium reinfection, and haematological parameters in pupils aged between 9 and 15 years of age in Nchelenge district, Zambia. METHODS: Pupils in the intervention group received once weekly dose of ferrous sulphate at 200 mg while those in the control received once weekly vitamin C at 100 mg for up to 9 months. Both study groups received a single dose of praziquantel at baseline. RESULTS: S haematobium reinfection intensity was significantly lower in boys in the intervention group than in boys in the control group at 6 months (P < 0.001) and 9 months (P < 0.001) of supplementation. Significantly lower S haematobium reinfection intensity was found in girls in the intervention group than in girls in the control group only at 6 months of supplementation (P = 0.018). Boys in the intervention group were 42% (Adjusted Risk Ratio = 0.58, 95% confidence interval 0.39, 0.86) less likely to be reinfected with S haematobium than in the control group at 6 months follow up. CONCLUSION: Once weekly iron supplementation can decrease S haematobium reinfection after 6 months and should be incorporated into school based schistosomiasis control programs in highly endemic areas. PMID- 19780473 TI - Perceived effects of rotating shift work on nurses' sleep quality and duration. AB - The aim of this longitudinal study was to assess the effect of rotating shift work on perceived sleep quality and sleep duration of nurses at Queen Elizabeth Central Hospital, Blantyre, Malawi. Twenty four female nurses were recruited at random from among personnel engaged in rotating shift work. The nurses worked a three-phase schedule: five day shifts (7.00 - 17.00) followed by three night shifts (17.00 - 7.00) and five days off. Controls were 22 female nurses who did not perform night duties. Sleep quality and duration was assessed using standardized and validated questionnaires on sleep duration and subjective sleep quality (SSQ). One-way analysis of variance revealed a significant effect of shift phase on total sleep duration (F = 36.8, d.f. = 8, P < 0.000) and perceived sleep quality (F = 8.81, d.f. = 3, P < 0.000). Night shift work was associated with reduction of sleep quality and duration. The after effects of night shifts persisted during days of the recovery period indicating accumulation of fatigue. PMID- 19780474 TI - The epidemiology of trypanosomiasis in Rumphi district, Malawi: a ten year retrospective study. AB - BACKGROUND: Human African Trypanosomiasis (HAT) is caused by two species of the tsetse fly vectored protozoan hemoflagellates belonging to Trypanosma brucei, namely T.b gambiense which predominates in Western Africa and follows a chronic disease course and T.b rhodensiense which is more prevalent in Southern and Eastern Africa, Malawi included, and follows a more acute and aggressive disease course. Previous studies in the Democratic Republic of Congo, Angola, Uganda and Sudan have demonstrated that the prevalence rates of T.b rhodensiense infection have reached epidemic proportions. OBJECTIVES: To describe the epidemiology of Trypanosomiasis in Rumphi District over the past ten years. METHODOLOGY: A total of 163 records from January 2000 to December 2006 were retrospectively studied. RESULTS: There were more males than females (121 vs. 40) with the 20 - 29 years age bracket having the highest number of cases (26.3%, n = 160). Stage 2 HAT was the commonest stage at presentation (58.2%, n = 158) with the patients in the same being 3.5 times more likely to die than those with stage 1 HAT. Case fatality rates for late and early stage disease were 21.5% (n = 92) and 7.2% (n = 66) respectively with 84.6% having been cured (n = 162). Convulsions were associated with fatal disease outcome and the majority of cases (97.2%, n = 103) lived within 5 kilometres of the Vwaza game reserve boundary. CONCLUSION: More men have been infected than women, with a high involvement in the 20 - 29 age brackets. A dramatic increase with active case finding indicates a high under detection of the disease with late stage HAT being predominant at presentation. Though it has been found that cases with late stage disease have an increased likelihood of dying compared to those in early stage HAT, the high proportion of successful treatment indicates that the disease still carries a high degree of favourable outcome with treatment. It has also been demonstrated in this study that more than 95% of trypanosomiasis cases live within 5 km of game reserve boundary. Disease interventions should be implemented in areas within 5 km of marshland game reserve boundary as priority areas. PMID- 19780475 TI - Ward round--sudden increase of breathlessness in a patient with pneumocystis pneumonia (PCP) and haematemesis. PMID- 19780476 TI - Ward round--crocodile bites in Malawi: microbiology and surgical management. AB - We present a case series of 5 patients admitted over 5 months to Queen Elizabeth Central Hospital who had sustained injuries from a crocodile bite. Three patients required amputation of a limb. The severe soft tissue injury associated with a crocodile bite and the unusual normal oral flora of the crocodile create challenges in treatment. Progressive tissue destruction and haemolysis are complications of such infected wounds. An antibiotic regime is recommended that covers gram negative rods, anaerobes and may include doxycycline, as well as the need to have a low threshold for early amputation. PMID- 19780477 TI - Opinions on the church's stand against condom use by the youth. PMID- 19780479 TI - Swine flu: the second wave. PMID- 19780480 TI - Ethics of healthcare technology. PMID- 19780481 TI - Compassion in care. PMID- 19780482 TI - How productive wards can improve patient care. AB - In this article, the progress made by the Productive Ward programme since its introduction just over a year ago is reviewed and a guide to its implementation and three case studies outlining what it has achieved are offered. PMID- 19780483 TI - Technological innovations: from bench to bedside. AB - The NHS is perceived to be slower than other healthcare systems in adopting innovative technologies that can deliver patient benefits. This article summarises what is known about the role of nurses in assimilating such innovations into clinical care, and outlines the challenges facing nurse leaders. PMID- 19780484 TI - Clinical simulation: a better way of learning? AB - This article describes the practice of clinical simulation, in which real-world experiences are replicated in learning environments. It also describes how education programmes can be adapted to accommodate this practice so that students can participate actively in their education. PMID- 19780485 TI - Public sector scorecard. AB - This article identifies how performance measurement can achieve the greatest number of benefits with the smallest number of drawbacks. PMID- 19780486 TI - Using a performance management framework to improve quality. AB - In light of Lord Darzi's NHS Next Stage Review final report, which emphasises the need for clinical services to be effective and good quality, this article describes how a directorate in a mental health trust used a performance management framework to focus more closely on the quality of services. PMID- 19780487 TI - New perspectives. PMID- 19780488 TI - [Relatedness of methicillin-resistant coagulase-negative staphylococci]. AB - Many identification and relatedness studies methods had been commonly used for epidemiological studies in microbiological laboratories. Apart from phenotypic methods, genotypic are also often used. The aim of this study was to compare, obtained by PFGE chromosomal DNA patterns of methicillin-resistant S. epidermidis strains isolated from clinical material. 46 methicillin-resistant S. epidermidis strains were included in this study. Most of them were isolated from wound swabs (65.2%) and catheters (19.6%) from different surgical clinics (76.1%). To identify strains and receive biochemical profiles, ID 32 Staph tests and GPI cards of Vitek 1 system were used. Pulsed-field gel electrophoresis and Tenover et al. interpretation were used to compare chromosomal DNA patterns of examined strains. 44 and 42 PFGE patterns of chromosomal DNA were received, using visual interpretation classifying two pairs of strains as the same, two pairs as closely related and three pairs as probably related. Strains classified as identical and similar in visual evaluation were indistinguishable in Molecular Analyst DST interpretation, probably due to tolerance in bands location pattern. Strains probably related in visual interpretation represent at least 96% similarity in Molecular Analyst DST but different susceptibility and biochemical profiles obtained by ID 32 Staph and Vitek 1. PFGE analysis had foremost capacity to distinguish methicillin-resistant S. epidermidis strains using visual interpretation and Molecular Analyst DST (Bio-Rad) program and seems to be useful method in epidemiological studies. Strains with the same PFGE pattern, had different susceptibility and biochemical profiles. PMID- 19780489 TI - [Influence of ciprofloxacin on the ability of production of staphylococcin T in Staphylococcus cohnii (StT)]. AB - The aim of this study was to evaluate the influence of ciprofloxacin in a concentration of 0.25 microg/ml on the ability of synthesis of staphylococcin T (StT) Staphylococcus cohnii at 37 degrees C after 24 and 48 hours incubation. Ciprofloxacin in concentration of 0.25 microg/ml after 24 hours incubation inhibits antistaphylococcal activity StT produced by S. cohnii, while after 48 hour incubation, S. cohnii StT is excreted on the same level, in the presence and in the absence of ciprofloxacin. PMID- 19780490 TI - [Occurrence of virulence genes among Enterococcus faecalis strains isolated from patients and hospital environment]. AB - The aim of this study was to evaluate occurrence of virulence genes among Enterococcus faecalis strains isolated from two hospitals in Lodz, during 2005 2006. The second goal was to determine possible relationship between presence of those genes, resistance to ampicillin and sources of isolation. Enterococcal strains were identified to the species by PCR with ddl primers. All 161 isolates were tested for the presence of aggregation substance gene (agg), cytolisine genes (cyl-L, cyl-S), esp protein gene, gelatinase gene (gelE), serine protease gene (sprE). Susceptibility to ampicillin was tested by microdillution method. Both cyl-L and cyl-S genes were found in 52,2% of strains, agg gene was present in 62,73% isolates, esp gene--in 71.2%. Most frequently found genes were gelE (85.1%) and sprE (82.6%). The presence of esp gene in isolates resistant to ampicillin was statistically higher than in susceptible strains, what might suggest appearance of epidemic strains. Besides, strains possessing both, cyl-L/S and esp genes, were found to be statistically more often isolated strains than those possessing only single genes. PMID- 19780491 TI - [Assessment of new restriction enzymes: SfaAI and SmiI for the differentiation of Y enterocolitica bioserotype 4/O3 and 1B/O8 clinical isolates by pulsed-field gel electrophoresis (PFGE)]. AB - Endonucleases SfaAI and SmiI have not been yet applied for Y enterocolitica genotyping. Our goal was to evaluate usefulness of these endonucleases and two other rarely used (SfiI and SmaI) ones for the differentiation of Y enterocoilitica clinical isolates by PFGE. Reference strains used in this study belong to the major agents of human yersiniosis in Poland, the bioserotype 4/O3 (n=5), and to the highly pathogenic bioserotype 1B/08 (n=5) that has recently emerged in Poland. Our data indicated that all the tested enzymes are useful for distinguishing Y enterocolitica strains of bioserotypes 4/O3 and 1B/O8 which are the most common representatives of the two Y enterocolitica subspecies: palearctica and enterocolitica, respectively. Hovewer, only two enzymes: SfaAI and SfiI completely differentiated strains belonging to the same bioserotype. The discrimination power of these two enzymes varied depending on the bioserotype. SfaAI and SfiI were found to be the most discriminatory for Y enterocolitica 1B/O8 and 4/O3, respectively. In conclusion, SfaAI and SfiI appear to be useful for the PFGE-subtyping of Y enetrocolitica isolates to aid epidemiological investigations of food-poisoning or dispersed-outbreaks. PMID- 19780492 TI - [Epidemiologic analysis of increased frequency of isolation of multidrug resistant Acinetobacter sp. using PFGE technique]. AB - From November 2007 to November 2008, 25 multidrug resistant Acinetobacter baumanii/haemolyticus strains were isolated from 21 patients treated in the Pulmonary Diseases and Tuberculosis Hospital in Bystra. Seven cases were regarded as nosocomial infections. Most of the patients were hospitalized several times and/or admitted from other hospitals. The aim of this study was to find the reason for increasing colonization and infections with this microorganism. PFGE analysis showed high, exceeding 90% relationship among tested strains suggesting their clonal spread among patients in several hospitals in our region. Despite excessive search, no environmental reservoir of Acinetobacter was found, so cross contamination via staff's hands was suspected the most likely source of this spread. Therefore, hand hygiene and contact isolation seemed the most relevant infection control measures. PMID- 19780493 TI - [Microorganisms isolated from healthy newborns in the first and third twenty-four hours]. AB - From forty healthy newborns of The Neonatology Ward of H.Jordan Hospital in Lodz, skin and nasal septum-swabs have been sampled immediately after the delivery. Whereas, in the third twenty-four hours of their lives, apart from skin and nasal septum-swabs, it has been sampled also faeces-swabs. The aim of the examination was to establish time of bacterial colonization and kinds of microorganisms responsible for that colonization after children's delivery. Two hundred clinic samples have been entirely taken to microbiological examination. It has been received 119 positive inoculations; 186 Gram-positive bacteria strains as well as 38 strains belonging to Enterobacteriaceae family have been cultured from healthy newborns. Eleven strains of methicillin resistant Staphylococcus aureus have been isolated--each from the skin and the nasal septum, during the first twenty-four hours, eight strains from skin in the third twenty-four hours as well as one from the nasal septum in the third twenty four hours. The results gathered on the basis of the study, allow to conclude that healthy newborns as early as in their first twenty four hours are influenced both by the physiological bacterial flora and pathogenic microorganism that can be an ethiological factor of hospital infection. PMID- 19780494 TI - [Influence of antibiotic-therapy on the selection of multi-drug resistant pathogens]. AB - In this paper, relations between the number of nosocomial infections caused by multi-drug resistant pathogens and antibiotic-therapy were investigated. It was found that the number of MRSA infections is directly proportional to the amount of CAZ (ceftazidime) used in the therapy. It was also stated that CAZ, Amc (amoxicillin-clavulan acid) and IPM (imipenem) are strong inductors of ESBL. A good correlation between the number of infections caused by ESBL(+) strains and the total consumption of these antibiotics was found. A growing number of infections generated by Ps. aeruginosa and Acinetobacter spp. strains resistant to carbapenems as a result of IPM therapy is also an anxiety-provoking fact. In this case, the changes in the number of isolated IPM-R streins occur only after approx. half an year from the changes in the IPM consumption. PMID- 19780495 TI - [Evaluation of chromogenic media in microbiological diagnostics]. AB - The aim of the study was the evaluation ofchromogenic agars as a screening media in the routine microbiological diagnostics. 627 clinical samples were cultured on the chromogenic media: chromID S. aureus, chromID MRSA, chromID CPS3 and chromID ESBL from bioMerieux. The results of presumptive identification and detection of selected resistance mechanisms by chromogenic media were compared with results obtained with the conventional methods. Our studies revealed the highest sensitivities of chromID MRSA and chromID CPS3 (> 90%). The sensivities for chromID ESBL and chromID S. aureus were > 70%. All media were also highly specific (97%). This specificity for chromID S.aureus and chromID CPS3 was 100%. We conclude, that all tested media showed good performance in presumptive identification and detection of resistance mechanisms. PMID- 19780497 TI - [Evaluation of the effectiveness of serodiagnosis of Mycoplasma pneumoniae infections by ELISA in Poland in 2006-2008]. AB - This study analyses the results of over 15 thousand patients tested by ELISA against the presence of antibodies to Mycoplasma pneumoniae in Poland in 2006 2008. Most of the tested patients were hospital-treated children with lower respiratory tract infections or pneumonia. The positive results of ELISA were obtained in 4.513 (29.6%) patients. Among them IgG and IgM antibodies were diagnosed in 24.0%, antibodies only class IgG in 44.0% and only IgM in 32.0% of cases. The results of our study showed the oversensitivity of serodiagnosis of mycoplasmosis based only on the presence in the tested sera of IgG antibodies. PMID- 19780496 TI - [Evaluation of the usefulness of selected antigens of Mycoplasma pneumoniae for the serodiagnosis of mycoplasmosis]. AB - A panel of 33 different antigens, among them lipoproteins, glicolipids and proteins, of Mycoplasma pneumoniae used in commercial western-blotting (Virotech) were assessed for reactivity with sera of patients with mycoplasmosis and other bacterial infections of variable etiology. In addition, commercial ELISA (Virotech) with recombinant proteins as antigen and complement fixation test (CFT) with in-house prepared glicolipid-protein antigen were also assessed for comparison. The proteins with molecular weight of 170 kDa (P1) and 90 kDa (P90) were most recognized by the serum samples of patients with mycoplasmosis. The reactions of proteins P50, P47 and Fts monomer with positive sera were not such often and the response was usually weak. The other proteins of M. pneumoniae, particularly P88, Repet. Prot. or P20, were recognized occasionally or at all. We observed also the often reactions ofglicolipids of M. pneumoniae with IgM antibodies. The result of the study showed that the commercial ELISA (Virotech) was equivalent in sensitivity and specificity to the CFT in the case of sera obtained in the acute phase of mycoplasmosis (90.7% of agreement of results in the class IgA, 85.6% in the class IgG and 100% in the class IgM). Analytical specificity studied by screening serum samples from patients with different bacterial infections and blood donors have shown lower specificity of ELISA in compared to western-blotting. The present study confirmed the earlier observations of the high usefulness of P1 protein and P90 protein for reliable serologic diagnosis of acute M. pneumoniae infection. PMID- 19780498 TI - [The occurrence of human papillomavirus--HPV in the biopsies from colon polyps and cancer]. AB - Human papillomaviruses (HPV) infection can be associated with benign (warts) and malignant (precancer and cancer) genital, perianal and oral lesions. The role of HPV in the pathogenesis of colonorectal cancer and adenomas is still undetermined. We investigated the occurrence of nononcogenic HPV 6/11 and oncogenic 16/18 DNA in colon cancer, polyps and normal tissue using PCR. HPV 16/18 were detected more frequently in colon cancers (67%) and adenomas (56%) than in normal colon mucosa (28%). In case of HPV 6/11 the differences were not significant. The results suggest the possible role of HPV 16/18 in pathogenesis of colon cancers and polyps. PMID- 19780500 TI - Charitable care: an example. PMID- 19780499 TI - [The influence of Namalwa cells on inhibition of HSV-1 replication]. AB - The main immunological elements that control infection with herpes simplex virus type 1 include interferon, NK cells, and specific T and B cells. The aim of this study was to determine the influence of Namalwa cells (B cell immortalized by EBV) which produce IFN alpha in large amount on inhibition of HSV-1 replication in CV-1 and MDBK cells. Inhibition of HSV-1 replication was measured by MTT assay. Addition Namalwa cells to CV-1 or MDBK cells infected HSV-1 inhibited virus replication. Degree of inhibition was connected with amount of added cells and with time of addition (before infection or after infection). The highest inhibition of HSV-1 replication showed Namalwa cells added one hour before infection (72% for CV-1 infected HSV-1 and 68% for MDBK infected HSV-1). PMID- 19780501 TI - Patient's page. Diet and oral health. PMID- 19780502 TI - A model for access to free community medical and dental care. PMID- 19780503 TI - Donated dental services. PMID- 19780504 TI - Matthew 25 Health and Dental Clinic: part of the fabric of the community. PMID- 19780505 TI - Oral health is an achievement, not an entitlement. PMID- 19780506 TI - Nurse blows whistle on EMT's dereliction of duty. Baybridge v. City of Ortonville, 2009-MN-0408.128 (4/7/2009)-MN. PMID- 19780507 TI - Is contraction of hepatitis B occupational hazard? Case on point: Fidelity and Guaranty Ins. Co.v. Polk County, 2009-FL-3377 (7/14/2009)-FL. PMID- 19780508 TI - NY: Rn's opinion key in denying Dr.'s Motion: Pt. died from bowel obstruction & no consults. Secondo v. KRNH, Inc, NY-31810-( 9/14/2009)-NY. PMID- 19780509 TI - Texas court overturns motion granting new trial Case on point: In Re Columbia Med. Ctr. of Las Colinas, Subsidiary, L.R-0707.1263(7/3/2009)-TX. PMID- 19780510 TI - H1N1 (swine) flu bears watching. PMID- 19780511 TI - Assessing the size of the pill: health care reform. PMID- 19780512 TI - A theoretical model for understanding mental health, substance use, and work performance among Asian immigrants. AB - Mental illness and substance use disorders are prevalent among workers. Each year businesses lose billions of dollars to decreased work performance associated with these issues. This article discusses a theoretical model that depicts relationships between social discrimination, job concerns, and social support and workers' mental health problems and substance use and work performance. The focus is Asian immigrant workers, a population underrepresented in the literature. This model serves to assist occupational health nurses in the practice and research arenas better understand the complexities of mental health problems and substance use among Asian immigrant workers. Occupational health nurses are in a prime position to recognize, identify, and respond to at-risk workers. Examples of areas that might be considered by occupational health nurses when using this model are included. PMID- 19780514 TI - Health and gender comparisons in the long-haul trucking industry: a pilot study. AB - This descriptive pilot study was conducted to determine whether health conditions and health care access differ between male and female long-haul truck drivers. Data indicated that 54% of men and 66% of women had a health care provider, but 21% of men and 35% of women had no health insurance. Male and female drivers both reported common health problems (e.g., back pain, sinus problems, hypertension, headaches, and arthritis). While working, drivers of each gender often waited until returning home to seek treatment for health problems. Approximately half of the drivers expressed dissatisfaction with health care while "on the road." Occupational and environmental health nurses could address the health needs of drivers by conducting examinations and distributing wellness information at truck stop clinics and from mobile health vans, posting health information within truck stop driver lounges, creating interactive websites with real-time health care information, attending trucker trade shows to conduct health screening, or providing health information through occupational or trade magazines and newsletters. PMID- 19780515 TI - PCR-free quantification of multiple splice variants in a cancer gene by surface enhanced Raman spectroscopy. AB - We demonstrate a surface-enhanced Raman spectroscopy (SERS) based array platform to monitor gene expression in cancer cells in a multiplex and quantitative format without amplification steps. A strategy comprising DNA/RNA hybridization, S1 nuclease digestion, and alkaline hydrolysis was adopted to obtain DNA targets specific to two splice junction variants, Delta(9,10) and Delta(5), of the breast cancer susceptibility gene 1 from MCF-7 and MDA-MB-231 breast cancer cell lines. These two targets were identified simultaneously, and their absolute quantities were estimated by a SERS strategy utilizing the inherent plasmon-phonon Raman mode of gold nanoparticle probes as a self-referencing standard to correct for the variability in surface enhancement. The results were then validated by reverse-transcription polymerase chain reaction. Our proposed methodology could be expanded to a higher level of multiplexing for quantitative gene expression analysis of any gene without any amplification steps. PMID- 19780517 TI - Nanosecond to submillisecond dynamics in dye-labeled single-stranded DNA, as revealed by ensemble measurements and photon statistics at single-molecule level. AB - Single-molecule and ensemble time-resolved fluorescence measurements were applied for the investigation of the conformational dynamics of single-stranded DNA, ssDNA, connected with a fluorescein dye by a C6 linker, where the motions both of DNA and the C6 linker affect the geometry of the system. From the ensemble measurement of the fluorescence quenching via photoinduced electron transfer with a guanine base in the DNA sequence, three main conformations were found in aqueous solution: a conformation unaffected by the guanine base in the excited state lifetime of fluorescein, a conformation in which the fluorescence is dynamically quenched in the excited-state lifetime, and a conformation leading to rapid quenching via nonfluorescent complex. The analysis by using the parameters acquired from the ensemble measurements for interphoton time distribution histograms and FCS autocorrelations by the single-molecule measurement revealed that interconversion in these three conformations took place with two characteristic time constants of several hundreds of nanoseconds and tens of microseconds. The advantage of the combination use of the ensemble measurements with the single-molecule detections for rather complex dynamic motions is discussed by integrating the experimental results with those obtained by molecular dynamics simulation. PMID- 19780518 TI - Diffusion dynamics of water molecules in a LiCl solution: a low-temperature crossover. AB - A quasielastic neutron scattering experiment probing the dynamics of water molecules on the pico- to nanosecond time scale in an aqueous solution of lithium chloride has detected a crossover at about 220-230 K between the high-temperature non-Arrhenius and low-temperature Arrhenius behavior. This is the first experiment where the crossover in the dynamics of water molecules is detected in bulk rather than in confinement. The results suggest that the dynamic crossover observed in the current and many recent experiments is not linked to the specific properties of water; instead, it may represent a more general dynamic transition. PMID- 19780516 TI - Conformational heterogeneity of a leucine enkephalin analogue in aqueous solution and sodium dodecyl sulfate micelles: comparison of time-resolved FRET and molecular dynamics simulations. AB - We have undertaken time-resolved Forster resonance energy transfer (FRET) and molecular dynamics simulations to analyze conformations and conformational heterogeneity of an analogue of leucine enkephalin in solution and in the presence of sodium dodecyl sulfate (SDS) micelles. Enkephalins are opioid pentapeptides that interact with opioid receptors in the central nervous system. We used time-correlated single-photon counting to detect energy transfer between the N-terminal tyrosine and a tryptophan residue substituted for phenylalanine at the 4 position. FRET from Tyr to Trp was measured over a temperature range from 5 to 55 degrees C in aqueous solution. By taking into account Tyr rotamer interconversion rates measured previously, we determined average distances between Tyr and Trp for the two populated rotameric conformations of Tyr. Molecular dynamics simulations (100 ns) support this analysis and indicate extensive conformational heterogeneity. The simulations also predict that the FRET orientational factor is correlated with the Tyr-Trp separation. Failure to account for the correlation between orientation and distance results in errors that appear to be largely offset in the leucine enkephalin analogue (YGGWL) by a weighting bias inherent in the R(-6) dependence of the energy-transfer rate. The Tyr lifetimes decrease upon titration of the peptides with SDS, indicating formation of compact conformations of the peptide in the micelle environment. This result is consistent with the conjecture that the lipid environment may induce formation of bioactive conformations of the peptide. PMID- 19780519 TI - Quantum dynamics of the ultrafast pi pi*/n pi* population transfer in uracil and 5-fluoro-uracil in water and acetonitrile. AB - We present the first fully quantum-mechanical dynamical study of the pi pi* --> n pi* decay in photoexcited uracil derivatives in solution. The dynamics of this process for uracil (U) and 5-fluoro-uracil (5FU) in acetonitrile and aqueous solution is investigated, by treating both electrons and nuclei at the quantum mechanical level, and solving the time-dependent Schrodinger equation for the evolution of the photoexcited system. The potential energy surfaces along the most relevant nuclear degrees of freedom have been obtained at the time-dependent density functional theory level, accounting for the solvent effect by mixed atomistic/continuum models. The obtained results nicely agree with experimental evidence. For U, we predict an ultrafast (<50 fs) pi pi* --> n pi* decay with 10 25% yields, weakly dependent on the solvent. This finding strongly indicates that the npi* state is responsible for the decay channel observed in experiments for U in polar solvents, yielding to a final recovery of the ground state in tens of picoseconds. At variance, our dynamical calculations predict a remarkable solvent effect for 5FU, showing that the pi pi* --> n pi* decay channel is open in acetonitrile and closed in water, in agreement with the much faster decay observed in experiments in the first solvent. The analysis of our theoretical simulations, also including explicitly the laser excitation step, allows us to point out a number of interesting features for the decay dynamics of photoexcited molecules with close-lying electronic states, whose general interest goes beyond the specific system under investigation. PMID- 19780520 TI - Challenges in pKa predictions for proteins: the case of Asp213 in human proteinase 3. AB - Knowledge of the protonation states of the ionizable residues in an enzyme is a prerequisite to an accurate description of its structure and mechanism. In practice, the use of the inappropriate protonation state for an amino acid in a molecular modeling computation (e.g., molecular dynamics simulation) is likely to lead to unrealistic results. Although methods using solvers of the linearized Poisson-Boltzmann equation have proven to yield accurate pK(a) predictions, they bear a number of limitations. They are quite demanding in terms of computational power and are sensitive to representation of the charges and their position (force field and protein conformation). Moreover they depend on the choice of a dielectric constant for the protein interior. In this manuscript, we describe the difficulties met when trying to predict the protonation state of a buried amino acid, located in a protein for which very little biochemical data is available. Such a case is highly representative of the challenges faced in theoretical biology studies. Proteinase 3 (PR3) is an enzyme involved in proteolytic events associated with inflammation. It is a potential target in the development of new anti-inflammatory therapeutic strategies. We report the results of pK(a) predictions of the aspartic acid 213 of PR3 with a FDPB solver. We probed the influence of the choice of the dielectric constant for the protein interior epsilon(p) and the benefits of conformational sampling by molecular dynamics (MD) on the pK(a) prediction of this carboxylate group. Using only the FDPB calculations, we could not conclude on the protonation state of Asp213. MD simulations confronted to knowledge of the ligand-binding and reaction mechanism led us to decide on a protonated form of this aspartic acid. We also demonstrate that the use of the wrong protonation state leads to an unreliable structural model for PR3. pK(a) prediction with a fast empirical method yielded a pK(a) of 8.4 for Asp213, which is in agreement with our choice of protonation state based on MD simulations. PMID- 19780521 TI - Reaction of protonated tyrosine with electronically excited singlet molecular oxygen (a1Delta(g)): an experimental and trajectory study. AB - Reaction of protonated tyrosine with the lowest electronically excited singlet state of molecular oxygen, (1)O(2) (a(1)Delta(g)), is reported over the center-of mass collision energy (E(col)) range from 0.1 to 3.0 eV, using an electrospray ionization, guided-ion-beam scattering instrument, in conjunction with ab initio electronic structure calculations and direct dynamics trajectory simulations. Only one product channel is observed, corresponding to generation of hydrogen peroxide via transfer of two hydrogen atoms from protonated tyrosine. Despite being exoergic, the reaction is in competition with physical quenching of (1)O(2) and is very inefficient. At low E(col), the reaction may be mediated by intermediate complexes and shows strong inhibition by collision energy. At high E(col), the reaction efficiency drops to approximately 1% and starts to have contribution from a direct mechanism. Quasi-classical trajectory simulations were performed to probe the mechanism at high collision energies. Analysis of trajectories shows that, at E(col) of 3.0 eV, a small fraction of hydrogen peroxide (25%) is produced via a direct, concerted mechanism where two hydrogen atoms are transferred simultaneously, but most hydrogen peroxide (75%) is formed by dissociation of hydroperoxide intermediates. According to ab initio calculations and trajectory simulations, collisions also lead to formation of various endoperoxides, and dissociation of endoperoxides may play a role in physical quenching of (1)O(2). The apparatus and experimental techniques are described in detail. PMID- 19780522 TI - H/Br exchange in BBr3 by HSiR3 (R = H, CH3, C2H5): origin of DFT failures to describe a seemingly innocuous reaction barrier. AB - We investigate the suitability of density functional theory (DFT) and second order Moller-Plesset perturbation theory (MP2) for the title reaction, which serves as a model to represent the key step in a recently developed B-C bond formation reaction. CBS-QB3 is employed as a reference throughout this study. The classical barrier height associated with the concerted transition state for the H/Br exchange reaction poses a serious challenge to most standard GGAs or hybrid functionals. In particular the popular B3LYP hybrid functional shows dramatically overestimated reaction barriers (by 12 kcal mol(-1)) for the largest system with R = C(2)H(5). We find that a proper description of intramolecular dispersion interactions arising in the transition state is crucial for a correct assessment of this reaction and that the inclusion of Grimme's empirical dispersion correction effectively compensates for most of the errors to a large extent. In conclusion we find a pleasing performance of the dispersion corrected functionals B2PLYP-D or B3LYP-D for the present set of systems if used in combination with basis sets of triple-zeta quality, which we recommend for future quantum chemical studies on related systems. Also the recently devised M05-2X hybrid meta-GGA shows an excellent performance, in particular if used in combination with the small SVP basis. PMID- 19780523 TI - Mechanism of the Ni(0)-catalyzed vinylcyclopropane-cyclopentene rearrangement. AB - A combination of physical organic experiments and quantum chemical calculations were used to construct a detailed mechanistic model for the Ni(0)-N-heterocyclic carbene-catalyzed vinylcyclopropane-cyclopentene rearrangement that involves a mutistep oxidative addition/haptotropic shift/reductive elimination pathway. No evidence for the intermediacy of radicals or zwitterions was found. The roles of substituents on the vinylcyclopropane substrate and variations in the ligands on Ni were evaluated. It is postulated that bulky carbene ligands facilitate formation of the active catalyst species. PMID- 19780524 TI - Precise site-selective termination of DNA replication by caging the 3-position of thymidine and its application to polymerase chain reaction. AB - A new caged thymidine, 3-N-(2-(2-nitrophenyl)propyloxymethyl)thymidine (T(NPPOM)) was synthesized and used as a site-selective terminator of DNA-polymerase reaction in light-assisted cohesive-ending PCR (LACE-PCR), which directly gives sticky-ended PCR products after brief UVA irradiation. Primer-extension experiments using a template involving T(NPPOM) have shown that this caged nucleotide efficiently and site-selectively blocks reactions of a variety of polymerases commonly used in PCR. Misincorporation of nucleobases, observed with the use of other previously reported caged thymidines, scarcely occurred. It has turned out that a slight structural difference of caging groups can significantly improve the termination yield of polymerase reactions. A LACE-PCR product coding GFP gene was prepared by using primers containing T(NPPOM) and was ligated with a vector fragment prepared using restriction enzymes. The resulting recombinant vector successfully transformed E. coli. PMID- 19780525 TI - Metal loading capacity of Abeta N-terminus: a combined potentiometric and spectroscopic study of zinc(II) complexes with Abeta(1-16), its short or mutated peptide fragments and its polyethylene glycol-ylated analogue. AB - Aggregation of the amyloid beta-peptide (Abeta) into insoluble fibrils is a key pathological event in Alzheimer's Disease (AD). There is now compelling evidence that metal binding to Abeta is involved in AD pathogenesis. The amino acid region 1-16 is widely considered as the metal binding domain of Abeta. In this work, we used a combined potentiometric, NMR, and electrospray ionization mass spectrometry (ESI-MS) approach to study the zinc(II) binding to a new polyethylene glycol (PEG)-conjugated peptide fragment encompassing the 1-16 amino acid sequence of Abeta (Abeta(1-16)PEG). Our results demonstrate for the first time that the Abeta(1-16) is able to coordinate up to three zinc ions, all the histidyl residues acting as independent anchor sites. The study was complemented by systematically investigating the zinc(II) complexes of a series of shorter peptide fragments related to the Abeta(1-16) sequence, namely, Abeta(1-4), Abeta(1-6), AcAbeta(1-6), AcAbeta(8-16)Y10A. The comparison of the whole results allowed the identification of the zinc(II) preferred binding sites within the longer Abeta(1-16) amino acid sequence. Unlike copper(II) that prefers the N terminal amino group as the main binding site, the zinc(II) is preferentially placed in the 8-16 amino acidic region of Abeta(1-16). PMID- 19780526 TI - Luminescence vapochromism of a platinum(II) complex for detection of low molecular weight halohydrocarbon. AB - Platinum(II) complex [Pt(Me(3)SiC[triple bond]CbpyC[triple bond]CSiMe(3))(C[triple bond]CPh)(2)] (1) with 5,5-bis(trimethylsilylethynyl) 2,2'-bipyridine (Me(3)SiC[triple bond]CbpyC[triple bond]CSiMe(3)) and phenylacetylene (PhC[triple bond]CH) exhibits unusual luminescence vapochromism to volatile organic compounds (VOCs) including CH(2)Cl(2), CHCl(3), and CH(3)I, which is useful for detection of volatile halohydrocarbon with one carbon atom and molecular weight less of than 150. Crystal structural determination of 1, 1 x CHCl(3), 1 x 1/2(CH(2)ClCH(2)Cl), and 1 x 1/2(toluene) revealed a staggered packing for 1 x CHCl(3) whereas there was an antiparallel packing for other three structures in stacking of planar platinum(II) moieties. The Pt...Pt distance is 3.302(1) A in 1 x CHCl(3), whereas it is >4.0 A in the other three structures. Complex 1 displays bright orange luminescence in dichloromethane solution, arising from pi(phenylacetylide)-->pi*(Me(3)SiC[triple bond]CbpyC[triple bond]CSiMe(3)) (3)LLCT and d(Pt)-->pi*(Me(3)SiC[triple bond]CbpyC[triple bond]CSiMe(3)) (3)MLCT triplet states which are supported by DFT calculation. The solid-state emission occurs at approximately 762 nm for 1 x VOC (VOC = CH(2)Cl(2), CHCl(3), and CH(3)I), whereas it was at approximately 562 (603sh) or 603 (562sh) nm for 1 and other 1 x VOC, corresponding to a vapochromic response shift of approximately 160-200 nm. The dramatic vapochromism and vapoluminescence of 1 to the vapor of CH(2)Cl(2), CHCl(3), or CH(3)I are induced by a reversible conversion of the emissive state from (3)MLCT/(3)LLCT character to (3)MMLCT/(3)LLCT state. PMID- 19780527 TI - Elucidation of the structure of a highly active catalytic system for CO2/epoxide copolymerization: a salen-cobaltate complex of an unusual binding mode. AB - Salen-type ligands comprised of ethylenediamine or 1,2-cyclohexenediamine, along with an salicylaldehyde bearing a methyl substituent on its 3-position and a [CR(CH(2)CH(2)CH(2)N(+)Bu(3))(2)] (R = H or Me) on its 5-position, unexpectedly afford cobalt(III) complexes with uncoordinated imines. In these complexes, two salen-phenoxys and two 2,4-dinitrophenolates (DNPs), which counter the quaternary ammonium cations, coordinate persistently with cobalt, while two other DNPs are fluxional between a coordinated and an uncoordinated state in THF at room temperature. The complexes of this binding mode show excellent activities in carbon dioxide/propylene oxide copolymerization (TOF, 8300-13,000 h(-1)) but with some fluctuation in induction times (1-10 h), depending on how dry the system is. The induction time is shortened (<1.0 h) and activity is increased approximately 1.5 times upon the replacement of the two fluxional DNPs with 2,4-dinitrophenol 2,4-dinitrophenolate homoconjugation ([DNP...H...DNP](-)). Imposing steric congestion either by replacing the methyl substituent on the salicylaldehyde with tert-butyl or by employing H(2)NCMe(2)CMe(2)NH(2) instead of ethylenediamine or 1,2-cyclohexenediamine results in conventional imine-coordinating complexes, which show lower activities than uncoordinated imine complexes. PMID- 19780528 TI - Solution phase production of graphene with controlled thickness via density differentiation. AB - Graphene flakes with controlled thicknesses are isolated in solution using density gradient ultracentrifugation. These stable graphene dispersions are produced using the bile salt sodium cholate, which promotes graphite exfoliation and results in graphene-surfactant complexes having buoyant densities that vary with graphene thickness. The sorted graphene flakes are characterized using atomic force microscopy and Raman spectroscopy. Graphene dispersions produced using density differentiation offer superior performance in transparent conductors than those produced using conventional sedimentation-based centrifugation techniques. PMID- 19780530 TI - Size-dependent optical properties of colloidal PbS quantum dots. AB - We quantitatively investigate the size-dependent optical properties of colloidal PbS nanocrystals or quantum dots (Qdots), by combining the Qdot absorbance spectra with detailed elemental analysis of the Qdot suspensions. At high energies, the molar extinction coefficient epsilon increases with the Qdot volume d(3) and agrees with theoretical calculations using the Maxwell-Garnett effective medium theory and bulk values for the Qdot dielectric function. This demonstrates that quantum confinement has no influence on epsilon in this spectral range, and it provides an accurate method to calculate the Qdot concentration. Around the band gap, epsilon only increases with d(1.3), and values are comparable to the epsilon of PbSe Qdots. The data are related to the oscillator strength f(if) of the band gap transition and results agree well with theoretical tight-binding calculations, predicting a linear dependence of f(if) on d. For both PbS and PbSe Qdots, the exciton lifetime tau is calculated from f(if). We find values ranging between 1 and 3 mus, in agreement with experimental literature data from time resolved luminescence spectroscopy. Our results provide a thorough general framework to calculate and understand the optical properties of suspended colloidal quantum dots. Most importantly, it highlights the significance of the local field factor in these systems. PMID- 19780529 TI - Magnetic and nonmagnetic nanoparticles from a group of uniform materials based on organic salts. AB - The size and uniformity of magnetic nanoparticles developed from a group of uniform materials based on organic salts (GUMBOS) were controlled using an in situ ion exchange, water-in-oil (w/o) microemulsion preparation. Most of these nanoGUMBOS are in fact ionic liquids (i.e., melting points less than 100 degrees C), while others have melting points above the conventional 100 degrees C demarcation. Simple variations in the reagent concentrations following a w/o approach allowed us to smoothly and predictably vary nanoparticle dimensions across a significant size regime with excellent uniformity. Average sizes of GUMBOS particles ranging from 14 to 198 nm were achieved by manipulation of the reagent concentration, for example. Controllable formation of this new breed of nanoparticles is important for numerous potential applications and will open up interesting new opportunities in drug delivery, magnetic resonance imaging, and protein separations, among other areas. PMID- 19780531 TI - Insight into CH(4) formation in iron-catalyzed Fischer-Tropsch synthesis. AB - Spin-polarized density functional theory calculations have been performed to investigate the carbon pathways and hydrogenation mechanism for CH(4) formation on Fe(2)C(011), Fe(5)C(2)(010), Fe(3)C(001), and Fe(4)C(100). We find that the surface C atom occupied sites are more active toward CH(4) formation. In Fischer Tropsch synthesis (FTS), CO direct dissociation is very difficult on perfect Fe(x)C(y) surfaces, while surface C atom hydrogenation could occur easily. With the formation of vacancy sites by C atoms escaping from the Fe(x)C(y) surface, the CO dissociation barrier decreases largely. As a consequence, the active carburized surface is maintained. Based on the calculated reaction energies and effective barriers, CH(4) formation is more favorable on Fe(5)C(2)(010) and Fe(2)C(011), while Fe(4)C(100) and Fe(3)C(001) are inactive toward CH(4) formation. More importantly, it is revealed that the reaction energy and effective barrier of CH(4) formation have a linear relationship with the charge of the surface C atom and the d-band center of the surface, respectively. On the basis of these correlations, one can predict the reactivity of all active surfaces by analyzing their surface properties and further give guides for catalyst design in FTS. PMID- 19780532 TI - Cationic gold(I)-mediated intramolecular cyclization of 3-alkyne-1,2-diols and 1 amino-3-alkyn-2-ols: a practical route to furans and pyrroles. AB - The intramolecular cyclizations of the 3-alkyne-1,2-diols and the 1-amino-3-alkyn 2-ols with a low catalyst loading (0.05-0.5 mol %) of (Ph(3)P)AuCl-AgNTf(2) or (Ph(3)P)AuCl-AgOTf proceeded at room temperature to provide a variety of substituted furans and pyrroles in excellent yields (85-98% yields). This method is also fully applicable to the conversion of several dozen grams of the substrate using only 0.05 mol % each of the Au and Ag catalysts. PMID- 19780534 TI - The effects of chemical substitution and polymerization on the pKa values of sulfonic acids. AB - The effects of ring substitution on the pK(a) value of benzenesulfonic acid (BSA) were investigated using a combined quantum mechanical and classical approach. Ring substitution with strong electron-withdrawing elements such as F, Cl, and Br is found to enhance the acidity of the BSA. More importantly, ring substitution with -NO(2) groups which form an extended conjugated pi-system with the benzene ring exhibits the strongest enhancement of the acidity. The effects of polymerization on the styrenesulfonic acid (SSA) were also investigated by solving the classical Poisson-Boltzmann equation. It is found that polymerization significantly decreases the acidity of SSA due to the alteration of the electrostatic environment surrounding the acid group upon polymerization. The average pK(a) value converges to 2.9 from the corresponding monomer value of 0.53 at a degree of polymerization of 8-12. These results shed significant light on how to design sulfonic-acid-based solid acid catalysts to achieve desired catalytic properties. PMID- 19780533 TI - Organo-ruthenium supported heteropolytungstates: synthesis, structure, electrochemistry, and oxidation catalysis. AB - The reaction of [Ru(arene)Cl(2)](2) (arene = benzene, p-cymene) with [X(2)W(22)O(74)(OH)(2)](12-) (X = Sb(III), Bi(III)) in buffer medium resulted in four organo-ruthenium supported heteropolytungstates, [Sb(2)W(20)O(70)(RuC(6)H(6))(2)](10-) (1), [Bi(2)W(20)O(70)(RuC(6)H(6))(2)](10-) (2), [Sb(2)W(20)O(70)(RuC(10)H(14))(2)](10-) (3), and [Bi(2)W(20)O(70)(RuC(10)H(14))(2)](10-) (4), which have been characterized in solution by multinuclear ((183)W, (13)C, (1)H) NMR, UV-vis spectroscopy, electrochemistry, and in the solid state by single-crystal X-ray diffraction, IR spectroscopy, thermogravimetric analysis, and elemental analysis. Polyanions 1, 2, and 4 crystallize in the triclinic system, space group P1 with the following unit cell parameters: K(5)Na(5)[Sb(2)W(20)O(70)(RuC(6)H(6))(2)] x 22 H(2)O (KNa 1), a = 12.1625(2) A, b = 13.1677(2) A, c = 16.0141(3) A, alpha = 78.9201(7) degrees, beta = 74.4442(8) degrees, gamma = 78.9019(8) degrees, and Z = 1; Cs(2)Na(8)[Bi(2)W(20)O(70)(RuC(6)H(6))(2)] x 30 H(2)O (CsNa-2), a = 11.6353(7) A, b = 13.3638(7) A, c = 16.7067(8) A, alpha = 79.568(2) degrees, beta = 71.103(2) degrees, gamma = 80.331(2) degrees, and Z = 1; Na(10)[Bi(2)W(20)O(70)(RuC(10)H(14))(2)].35H(2)O (Na-4), a = 15.7376(12) A, b = 15.9806(13) A, c = 24.2909(19) A, alpha = 92.109(4) degrees, beta = 101.354(4) degrees, gamma = 97.365(3) degrees, and Z = 2. Polyanions 1-4 consist of two (L)Ru(2+) (L = benzene or p-cymene) units linked to a [X(2)W(20)O(70)](14-) (X = Sb(III), Bi(III)) fragment via Ru-O(W) bonds resulting in an assembly with idealized C(2h) symmetry. Polyanions 1-4 are stable in solution as indicated by the expected (183)W, (13)C, and (1)H NMR spectra. The electrochemistry of 1-4 is described by considering the reduction and the oxidation processes. The nature of the arene in Ru(arene) has practically no influence on the formal potentials of the W-centers, which are more sensitive to the Sb or Bi hetero atoms. The results suggest that the respective Sb- and Bi derivatives have very different pK(a) values, with the reduced form of 1 being the most basic, thus permitting the observation of two well-developed voltammetric waves at pH 6. In contrast, the identity of the arene influences the oxidation processes, thus permitting to distinguish them. A strong electrocatalytic water oxidation peak is observed that is more positive than the one corresponding to the Ru(arene) oxidation process. Also a stepwise oxidation of the Ru(benzene) group could be observed at pH 3. The catalytic efficiency, on the other hand, of 1-4 toward the oxidation of n hexadecane and p-xylene illustrated the effect of ruthenium substitution on the polyanion catalytic performance. PMID- 19780535 TI - Evaluation of the total content and the operationally defined species of copper in beers and wines. AB - A two-column solid phase extraction was used to determine the operationally defined speciation of Cu in lager beers and red wines. Applying a nonionic macroreticular adsorbing resin Amberlite XAD-16 and a gel type strong cation exchange resin Dowex 50Wx8-200, three different groupings of the chemical forms of Cu, including the hydrophobic, the cationic, and the residual species fractions, were separated and determined. The total content of Cu in the analyzed samples and its concentrations in the distinguished fractions were measured using flame atomic absorption spectrometry without any special preparation of the sample solutions. It was found that the residual species (72-82% of the total content), being polar and noncationic forms of Cu, are the most abundant fraction of Cu in the analyzed beers. In the case of wines, the fraction of the hydrophobic species was established to have the highest share in the total Cu content, that is, 27-77%. This fraction was presumed to contain relatively strong complexes of Cu with various flavonoids and other polyphenols. PMID- 19780536 TI - Rational prediction of the herbicidal activities of novel protoporphyrinogen oxidase inhibitors by quantitative structure-activity relationship model based on docking-guided active conformation. AB - Molecular docking-guided active conformation selection was used in a quantitative structure-activity relationship (QSAR) study of a series of novel protoporphyrinogen oxidase (PPO) inhibitors with herbicidal activities. The developed model can be used for the rational and accurate prediction of herbicidal activities of these inhibitors from their molecular structures. Molecular docking study was carried out to dock the inhibitors into the PPO active site and to obtain the rational active conformations. Based on the conformations generated from molecular docking, satisfactory predictive results were obtained by a genetic algorithm-multiple linear regression (GA-MLR) model according to the internal and external validations. The model gave a correlation coefficient R(2) of 0.972 and 0.953 and an absolute average relative deviation AARD of 2.24% and 2.75% for the training set and test set, respectively. The results from this work demonstrate that the molecular docking-guided active conformation selection strategy is rational and useful in the QSAR study of these PPO inhibitors and for the quantitative prediction of their herbicidal activities. The results obtained could be helpful to the design of new derivatives with potential herbicidal activities. PMID- 19780537 TI - Morphology and melting behavior of ionic liquids inside single-walled carbon nanotubes. AB - We report the synthesis and characterization of single-walled carbon nanotubes (SWNTs) filled with a zinc-containing quaternary ammonium based ionic liquid (ChZnCl(3)) inside. The threshold SWNT diameter for efficient encapsulation was determined to be ca. 0.97 nm. Different morphologies of the encapsulated ChZnCl(3) such as single-chain, double-helix, zigzag tubes, and random tubes were observed. The melting of ChZnCl(3) ionic liquid into "nanofluid" inside SWNTs was investigated by in situ TEM electron beam irradiation and compared with a high temperature heat treatment. The thermal-decomposition temperature of the ChZnCl(3) ionic liquid confined in the SWNTs was much higher than in the bulk system. Furthermore, the doping effect of the encapsulated ChZnCl(3) on the host SWNTs can be varied (from p-type to n-type) by gradually reducing the filling ratio. The versatility of ionic liquids and the unique phase transition observed inside the SWNTs provide a new opportunity for modulating the electronic properties of carbon nanotubes. PMID- 19780538 TI - Effects of glyphosate application on seed iron and root ferric (III) reductase in soybean cultivars. AB - Previous research demonstrated that plant nutrient assimilation was reduced by glyphosate (Gly). A 2 year field experiment investigated the effects of Gly at drift rate (12.5% of commercial use rate) on Fe concentrations in leaves and seeds of Gly-sensitive (GS) soybean, and a greenhouse experiment evaluated Gly effects on Fe assimilation using root in vivo ferric reductase activity (FRA) in two GS and one Gly-resistant (GR) soybean cultivars. Field studies showed that Gly drift rates resulted in a significant decrease in the Fe concentration in seeds and leaves compared to the nontreated plants. In greenhouse studies, leaf Fe and FRA were inhibited in GS cultivars Hutcheson and DP 5110 and the GR cultivar AG 4604RR and leaf Fe was positively correlated with root FRA (p < 0.0001). These results indicate that Gly can interfere with Fe assimilation in both GS and GR soybean. Understanding the implication of Gly on Fe nutrition in soybean seed would help soybean agronomists and breeders seeking to improve seed mineral nutrition qualities. PMID- 19780539 TI - Influence of chocolate matrix composition on cocoa flavan-3-ol bioaccessibility in vitro and bioavailability in humans. AB - Conflicting data exist regarding the influence of chocolate matrices on the bioavailability of epicatechin (EC) from cocoa. The objective of this study was to assess the bioavailability of EC from matrices varying in macronutrient composition and physical form. EC bioavailability was assessed from chocolate confections [reference dark chocolate (CDK), high sucrose (CHS), high milk protein (CMP)] and cocoa beverages [sucrose milk protein (BSMP), non-nutritive sweetener milk protein (BNMP)], in humans and in vitro. Six subjects consumed each product in a randomized crossover design, with serum EC concentrations monitored over 6 h post consumption. Areas under the serum concentration-time curve (AUC) were similar among chocolate matrices. However, AUCs were significantly increased for BSMP and BNMP (132 and 143 nM h) versus CMP (101 nM h). Peak serum concentrations (C(MAX)) were also increased for BSMP and BNMP (43 and 42 nM) compared to CDK and CMP (32 and 25 nM). Mean T(MAX) values were lower, although not statistically different, for beverages (0.9-1.1 h) versus confections (1.8-2.3 h), reflecting distinct shapes of the pharmacokinetic curves for beverages and confections. In vitro bioaccessibility and Caco-2 accumulation did not differ between treatments. These data suggest that bioavailability of cocoa flavan-3-ols is likely similar from typical commercial cocoa based foods and beverages, but that the physical form and sucrose content may influence T(MAX) and C(MAX). PMID- 19780540 TI - Ab initio nonadiabatic molecular dynamics of wet-electrons on the TiO(2) surface. AB - The electron transfer (ET) dynamics of wet-electrons on a TiO(2) surface is investigated using state-of-the-art ab initio nonadiabatic (NA) molecular dynamics (MD). The simulations directly mimic the time-resolved experiments [Science 2005, 308, 1154] and reveal the nature of ET in the wet-electron system. Focusing on the partially hydroxylated TiO(2) surface with 1-monolayer water coverage, and including electronic evolution, phonon motions, and electron-phonon coupling, the simulations indicate that the ET is sub-10 fs, in agreement with the experiment. Despite the large role played by low frequency vibrational modes, the ET is fast due to the strong coupling between the TiO(2) surface and water. The average ET for the system has equal contributions from the adiabatic and NA mechanisms, even though a very broad range of individual ET events is seen in the simulated ensemble. Thermal phonon motions induce a large fluctuation of the wet electron state energy, generate frequent crossings of the donor and acceptor states, and drive the adiabatic mechanism. The rapid phonon-assisted NA tunneling from the wet-electron state to the TiO(2) surface is facilitated by the strong water-TiO(2) electronic interaction. The motions of molecular water have a greater effect on the ET dynamics than the hydroxyl vibrations. The former contribute to both the wet-electron state energy and the water-TiO(2) electronic coupling, while the latter changes only the energy and not the coupling. Delocalized over both water and TiO(2), wet-electrons are supported by a new type of state that is created at the interface due to the strong water-TiO(2) interaction and that cannot exist separately in either material. Similar states are present in a number of other systems with strong interfacial coupling, including certain dye-sensitized semiconductors and metal-liquid interfaces. The ET dynamics involving such interfacial states share many universal features, such as an ultrashort time scale and weak-dependence on temperature, surface defects, and other system details. PMID- 19780541 TI - Electroreductive coupling of phthalimides with alpha,beta-unsaturated esters: unusual rearrangement of resulting silyl ketene acetals. AB - The electroreductive intramolecular coupling of phthalimides with alpha,beta unsaturated esters in the presence of chlorotrimethylsilane and subsequent desilylation of resulting silyl ketene acetals with TBAF gave five- and six membered trans-cyclized products stereospecifically. The silyl ketene acetals were readily rearranged to benzoindole and tetrahydrobenzoquinoline by standing or treatment with a Lewis acid under open-air conditions. The electroreductive intermolecular coupling of N-methylphthalimide with methyl acrylate also proceeded. PMID- 19780542 TI - Chloro and azido diruthenium complexes bearing electron-rich N,N',N'' triphenylguanidinate ligands. AB - The reaction of Ru(2)(OAc)(4)Cl with N,N',N''-triphenylguanidine (HTPG) produces one of two different compounds depending on the reaction conditions. In acetone in the presence of triethyl amine, the reaction produces tri-substituted Ru(2)(TPG)(3)(OAc)Cl, and in refluxing xylene, the tetra-substituted Ru(2)(TPG)(4)Cl is produced. Both of these new complexes can be cleanly converted into their corresponding azido analogues by reaction with sodium azide in methanol. The X-ray crystal structures of Ru(2)(TPG)(3)(OAc)Cl, Ru(2)(TPG)(3)(OAc)N(3), and Ru(2)(TPG)(4)Cl are presented, along with magnetic, electrochemical, and spectral measurements for each compound. Studies in solution show that, in contrast to Ru(2)(TPG)(3)(OAc)Cl, Ru(2)(TPG)(4)Cl is sterically hindered at the axial positions, and readily dissociates a chloride ion at high ionic strength. Equilibrium constants for chloride association and dissociation have been estimated. Mass spectrometric data suggest that the two azido complexes are precursors to new diruthenium nitrido species. PMID- 19780544 TI - Expression of recombinant antibacterial lactoferricin-related peptides from Pichia pastoris expression system. AB - Four recombinant antimicrobial peptide (rAMP) cDNAs, constructed from two goat lactoferricin-related peptide cDNAs (GLFcin and GLFcin II) with/without (His)(6) Tag, were cloned into pPICZalphaC and transformed into Pichia pastoris SMD1168H. After methanol induction, these rAMPs were expressed and secreted into broth. They were purified after CM-Sepharose (without His-tg), HisTrap (with His-tg) and Sephadex G-25 chromatographies. The yield of purified rAMP was 0.15 mg/mL of broth. These 4 rAMPs were thermal-stable and with high antibacterial activity against Escherichia coli BCRC 11549, Pseudomonas aeruginosa BCRC 12450, Bacillus cereus BCRC 10603, Staphylococcus aureus BCRC 25923, Propioni bacterium acnes BCRC 10723, and Listera monocytogenes BCRC 14845. The minimum inhibitory concentration (MIC) of rAMPs against these indicators ranged from 4.07 to 16.00 mg/mL. PMID- 19780543 TI - On the impact of steric and electronic properties of ligands on gold(I)-catalyzed cycloaddition reactions. AB - It is shown that [4 + 3] and [4 + 2] cycloaddition pathways are accessible in the Au(I) catalysis of allene-dienes. Seven-membered ring gold-stabilized carbenes, originating from the [4 + 3] cycloaddition process, are unstable and can rearrange via a 1,2-H or a 1,2-alkyl shift to yield six- and seven-membered products. Both steric and electronic properties of the AuL(+) catalyst affect the electronic structure of the intermediate gold-stabilized carbene and its subsequent reactivity. PMID- 19780546 TI - Proteome analysis of Lactobacillus rhamnosus GG using 2-D DIGE and mass spectrometry shows differential protein production in laboratory and industrial type growth media. AB - Lactobacillus rhamnosus GG (LGG) is one of the most extensively studied and widely used probiotic bacteria. While the benefits of LGG treatment in gastrointestinal disorders and immunomodulation are well-documented, functional genomics research of this bacterium has only recently been initiated. In the present study, a 2-D DIGE approach was used for the quantitative analysis of growth media-dependent changes in LGG protein abundance. Proteins were isolated from cells grown in industrial-type whey-based medium or in rich laboratory medium for subsequent 2-D DIGE. The analysis revealed patterns of protein abundance unique to each growth condition. In total, 196 quantitatively altered protein spots (at least 1.5-fold change in relative abundance, p < 0.05) representing approximately 13% of all protein spots in the gel were detected. From these protein spots, 157 were identified by mass spectrometry and were found to represent 100 distinct gene products. Collectively, these data show that growth of LGG in whey medium increased the relative abundance of proteins involved in purine biosynthesis, galactose metabolism, and fatty acid biosynthesis. In comparison, growth of LGG in laboratory medium resulted in an increase in the amount of proteins involved in translation and the general stress response, as well as pyrimidine and exopolysaccharide biosynthesis. Moreover, several enzymes of the proteolytic system of LGG demonstrated growth medium dependent production. The present study demonstrates the fundamental effects of culture conditions on the proteome of LGG, which are likely to affect the functionality and characteristics of its use as a probiotic. PMID- 19780547 TI - Effect of oxidation and mutation on the conformational dynamics and fibril assembly of amyloidogenic peptides derived from apolipoprotein C-II. AB - The oxidation of methionine residues in proteins can inhibit the self-assembly of proteins to form amyloid fibrils. For human apolipoprotein (apo) C-II the oxidation of methionine at position 60 inhibits fibril formation by the mature protein and by the core peptides apoC-II(56-76) and apoC-II(60-70). To investigate the molecular nature of these effects, we carried out fully solvated, all-atom molecular dynamics simulations of the structural changes in apoC-II(56 76) associated with substitutions of oxidized methionine (Met ox) at position 60. The results with apoC-II(56-76) (Met ox) showed less flexibility in structure, leading to a perturbation of the hydrophobic core. Valine substitution at position 60 showed an increased tendency to explore a wide range of conformational space, whereas the behavior of the Gln substitution mutant was similar to the wild-type peptide. These simulations are consistent with kinetic measurements which showed that a Met60Gln substitution within apoC-II(56-76) had little effect on the rate of fibril formation whereas substitution of Met ox or Val at position 60 lead to significant inhibition of peptide fibril formation. The effects of amino acid modification and substitutions on the kinetics of peptide fibril formation differ from the effects observed with full-length apoC II inferring that additional mechanisms are involved in fibril formation by mature apoC-II. PMID- 19780548 TI - Single polymer photosensitizer for Tb3+ and Eu3+ ions: an approach for white light emission based on carboxylic-functionalized poly(m-phenylenevinylene)s. AB - Here, we have demonstrated a facile molecular approach to generate white light emission by combining carboxylic functionalized poly(m-phenylenevinylene)s polymeric architectures with lanthanide beta-diketonate complexes. The new class of carboxylic functional conjugated polymeric materials was custom-designed from phenyl propanoic and acetic acids and structurally characterized by NMR, FT-IR, and MALDI-TOF spectroscopic techniques. The designed conjugated polymers were employed for the synthesis of lanthanide complexes in the presence of acetyl acetone (acac) as coligand and investigated their photophysical properties. For comparison, carboxylic-anchored oligo-phenylenevinylene (OPV) was also designed, characterized, and utilized for the synthesis of lanthanide complexes in the presence of acetyl acetone as coligand. Investigations revealed that carboxylic functionalized polymeric material with Eu(3+)-beta-diketonate complex exhibits unique magenta emission when excited at 310 nm. On the other hand, carboxylic functionalized polymeric material with Tb(3+)-beta-diketonate complex shows bright sky-blue emission. Interestingly, when Eu(3+) and Tb(3+) were incorporated into polymer backbone in equimolar ratio along with acetyl acetone as coligand, exhibited a white emission with CIE 1976 color coordinates x = 0.28, y = 0.34. The intrinsic quantum yield and lifetime of Ln(3+) complexes have been evaluated. The singlet and triplet energy levels of the antenna chromophore ligands have been calculated and the probable energy transfer mechanisms in Ln(3+) complexes have also been discussed. The effect of polymer structure and spacer effect on the photosensitizing of Tb(3+) and Eu(3+) ions was also investigated. PMID- 19780549 TI - Molecular mobility in self-assembled dendritic chromophore glasses. AB - Increasing complexity in bottom-up molecular designs of amorphous structures with multiple relaxation modes demands an integrated and cognitive design approach, where chemical synthesis is guided by both analytical tools and theoretical simulations. In particular, this is apparent for novel organic second-order nonlinear optical materials of self-assembling molecular glasses involving dendritic arene stabilization moieties (phenyl, naphthyl, and anthryl) with electro-optical activities above 300 pm/V. In this study, nanoscale thermo mechanical analyses yield direct insight into the molecular enthalpic and entropic relaxation modes. Arene-perfluoroarene interactions for coarse self assembly are found to impose three phase relaxation regimes, with intermediate regimes of 8-15 degrees C in width and apparent activation energies between 40 and 60 kcal/mol to be the most effective for poling. Energetic analyses based on intrinsic friction microscopy (IFA) identify increasing temporal stability with increasing arene size for the low-temperature regime. Electric field poling efficiency is found to be inversely proportional to entropic cooperative contributions that can make up 80% of the overall apparent relaxation energy for the high-temperature regime. The origin for the activation energies below the incipient glass transition temperature, based on complementary molecular dynamic simulations, is tied primarily to noncovalent interactions between chromophore (dipole), dendritic (quadrupole) moieties, and combinations thereof. PMID- 19780550 TI - Use of model Pt(111) single crystal electrodes under HMRDE configuration to study the redox mechanism for charge injection at aromatic/metal interfaces. AB - The electrochemical reactivity of hydroquinone-derived, catechol-derived and benzene-derived adlayers is compared at Pt(111) single-crystal surfaces (i) under stagnant hanging meniscus (HM) configuration and (ii) under hydrodynamic conditions imposed by combining the HM configuration with the rotating disk electrode (RDE) that merge in the so-called HMRDE technique. For the three cases studied, the results suggest that reductive desorption of the adlayers can be accomplished in aqueous 0.5 M H(2)SO(4) solutions within the time frame of a single cathodic scan, i.e. the first half of a single CV experiment. The results highlight the simplicity of exploiting the hydrodynamic conditions imposed by RDE as a convenient electroanalytical strategy to elucidate controversies regarding whether desorption takes place or not during electrode processes studied under the HM configuration. PMID- 19780551 TI - Observation of the membrane binding activity and domain structure of gpV, which comprises the tail spike of bacteriophage P2. AB - The P2 phage virion has tail spike proteins beneath the baseplate and uses them to adsorb to the outer membrane of Escherichia coli during the infection process. Previous immunoelectron microscopic studies suggested that the tail spikes are composed of the gene V product (gpV); however, experimental evidence of its membrane binding activity has yet to be reported. In this study, we purified and characterized recombinant full-length gpV and its C-terminal domain. Limited chymotrypsin proteolysis of gpV produced a C-terminal domain composed of Ser86 Leu211. Our experiments demonstrated that the N- and C-terminal domains have very different melting temperatures: 50 and 74 degrees C, respectively. We also found that gpV binds the E. coli membrane via its C-terminal domain. We conclude that the C-terminal domain of gpV is a stable trimer and serves as the receptor binding domain for the second step in the phage adsorption process. PMID- 19780552 TI - Gold nanoparticles supported on passivated silica: access to an efficient aerobic epoxidation catalyst and the intrinsic oxidation activity of gold. AB - Well-defined and perfectly dispersed [( identical withSiO)Au(I)] surface species supported on silica have been obtained via surface organometallic chemistry and transformed upon mild reduction (H(2), 300 degrees C) into small (1.8 +/- 0.6 nm) Au particles supported on silica passivated with SiMe(3) functionalities. Improved performance in liquid-phase aerobic epoxidation has been achieved, and the intrinsic activity of gold in oxidation is revealed. PMID- 19780553 TI - Short-range coherence of internal protein dynamics revealed by high-precision in silico study. AB - Correlated internal dynamics of proteins, which is believed to be important for their function, is analyzed at unprecedented precision using explicit-solvent submicrosecond molecular dynamics simulations of ubiquitin and calbindin D(9k). Without exception, all of the mobile dihedral angle pairs in ubiquitin with sizable dynamics correlations (R(2) >or= 0.1) are at short-range distance. In rare cases, they involve sequentially remote dihedral angles that form sparse clusters, suggesting a structural-dynamic propagation mechanism via soft torsional couplings that act over short distances with a rapid loss of coherence over longer distances. PMID- 19780554 TI - Regioselective synthesis of 4,6,7-trisubstituted benzofurans from furfural imines and nonheteroatom stabilized alkynylcarbene complexes. AB - Nonheteroatom stabilized chromium alkynylcarbene complexes 3,6, generated in situ from Fischer cabene complexes 1, smoothly react with furan-2-ylmethanimines 4 to provide substituted 7-aminobenzofurans 5 in moderate to good yields. The procedure involves the construction of the arene ring by a regioselective [3+3] carbocyclization reaction. PMID- 19780556 TI - Surface-mediated visible-light photo-oxidation on pure TiO(2)(001). AB - We used STM to observe visible light photo-oxidation reactions of formic acid on the ordered lattice-work structure of a TiO(2)(001) surface for the first time. The nanostructured surface makes the band gap significantly smaller than 3.0 eV only at the surface layer, and the surface state of the crystal enables a visible light response. PMID- 19780555 TI - An enzymatic cyclopentyl[b]indole formation involved in scytonemin biosynthesis. AB - Previous studies of the biosynthetic enzymes involved in the assembly of scytonemin (1), a cyanobacterial sunscreen, have identified beta-ketoacid 2 as an important intermediate that is produced by ThDP-dependent enzyme ScyA. We now report that ScyC, previously annotated as a hypothetical protein, catalyzes cyclization and decarboxylation of 2 to generate ketone 5. Assembly of the cyclopentyl[b]indole structure in this manner has little precedent in the chemical literature. Additional mechanistic experiments have revealed that cyclization likely precedes decarboxylation and that the latter event may provide a driving force for cyclopentane formation. PMID- 19780557 TI - Homopolymer induced aggregation of poly(ethylene oxide)n-b-poly(butylene oxide)m polymersomes. AB - We have studied the addition of poly(ethylene oxide) homopolymer (PEO) to a range of polymersome dispersions composed of amphiphilic di- and triblock copolymers. A number of E(n)B(m) E(n)B(m)E(n) and B(m)E(n)B(m) (E = poly(ethylene oxide) B = poly(butylene oxide)) block copolymers of varying molecular weights that spontaneously form polymersomes in water were investigated. This resulted in the aggregation of the dispersed polymersomes by two mechanisms, PEO adsorption or depletion interactions, and is shown to be dependent on PEO concentration. The aggregation kinetics and the resultant structures were analyzed by dynamic light scattering (DLS), small-angle X-ray scattering (SAXS) and scanning electron microscopy (SEM). There is a critical relationship between the polymersome corona thickness t and the PEO radius of gyration R(g), where R(g) must equal t to induce aggregation. This phenomenon has been reported with small self-assembling surfactants such as sodium dodecyl sulfate, but here we show an insight into how this transposes into much larger block copolymer systems which show great promise as biomimetic delivery vectors for controlled release. PMID- 19780558 TI - Headgroup effects on the unusual lamellar-lamellar coexistence and vesicle-to micelle transition of salt-free catanionic amphiphiles. AB - Salt-free ion-paired catanionic amphiphiles of the C(m)(+)C(n)(-) type, with a high solubility mismatch (n >> m or m >> n) display a remarkable phase behavior in water. A temperature-driven vesicle-to-micelle transition in the dilute side together with a coexistence of two lamellar phases on the concentrated side is one of the peculiar effects that have been reported for the hexadecyltrimethylammonium octylsulfonate surfactant, C(16)C(8) or TA(16)So(8) (extensive to C(14)C(8) and C(12)C(8)). In this work, with TA(16)So(8) as a reference, the cationic trimethylammonium (TA(+)) and pyridinium (P(+)) headgroups are combined with the anionic sulfate (S(-)) and sulfonate (So(-)) headgroups to yield other C(16)C(8) compounds: hexadecyltrimethylammonium octylsulfate (TA(16)S(8)), 1-hexadecylpyridinium octylsulfonate (P(16)So(8)), and 1-hexadecylpyridinium octylsulfate (P(16)S(8)). We show that, if the asymmetry of the chain lengths is kept constant at C(16)C(8) and the headgroup chemistry is changed, most of the unusual self-assembly properties are still observed, indicating that they are not system-specific but extensive to other combinations of headgroups and mainly dictated by the ion-pair solubility mismatch. Thus, all the compounds in water quite remarkably show a lamellar-lamellar phase coexistence and spontaneously form vesicles upon solubilization. Moreover, P(16)So(8) undergoes a temperature-driven vesicle-to-micelle transition that involves an intermediate planar lamellar state, similar to TA(16)So(8). Some interesting effects on the global phase behavior, however, do arise when the headgroups are changed. Geometric packing effects are shown to be important, but the differences in phase behavior seem to be mainly dictated by (i) the charge density of the headgroups, which tunes the solubility mismatch of the ion-pair, and (ii) specific interactions between headgroups, which affect the short-range repulsive force that controls the swelling of the concentrated lamellar phase. PMID- 19780559 TI - Synthesis of the louisianin alkaloid family via a 1,2,4-triazine inverse-electron demand Diels-Alder approach. AB - Isolated in 1995, the four members of the louisianin family (A, B, C and D) are simple pyridine and 2-pyridone alkaloids that display both antibacterial and anticancer activity. Herein we describe the synthesis of all four members of the louisianin family, from a conveniently prepared 1,2,4-triazine and via a common tetrasubstituted pyridine intermediate. This study includes the synthesis of louisianin B in both racemic form and as the (-)-enantiomer. PMID- 19780560 TI - Increasing hydrogen storage capacity using tetrahydrofuran. AB - Hydrogen hydrates with tetrahydrofuran (THF) as a promoter molecule are investigated to probe critical unresolved observations regarding cage occupancy and storage capacity. We adopted a new preparation method, mixing solid powdered THF with ice and pressurizing with hydrogen at 70 MPa and 255 +/- 2 K (these formation conditions are insufficient to form pure hydrogen hydrates). All results from Raman microprobe spectroscopy, powder X-ray diffraction, and gas volumetric analysis show a strong dependence of hydrogen storage capacity on THF composition. Contrary to numerous recent reports that claim it is impossible to store H(2) in large cages with promoters, this work shows that, below a THF mole fraction of 0.01, H(2) molecules can occupy the large cages of the THF+H(2) structure II hydrate. As a result, by manipulating the promoter THF content, the hydrogen storage capacity was increased to approximately 3.4 wt % in the THF+H(2) hydrate system. This study shows the tuning effect may be used and developed for future science and practical applications. PMID- 19780562 TI - Solid-state NMR study of dehydration of layered alpha-niobium phosphate. AB - The dehydration of a representative layered alpha-niobium phosphate (alpha-NbP) was studied by (93)Nb solid state wide-line NMR in combination with several other techniques including X-ray diffraction, thermogravimetric analysis, and (31)P MAS NMR. Four niobium phosphate species associated with dehydration including tri-, di-, and monohydrate phases, as well as a completely dehydrated phase, are identified by (93)Nb NMR. The tri- and dihydrate phases coexist in the as-made alpha-NbP sample. The monohydrate phase formed after heating the sample at 70 degrees C, and an additional anhydrous phase was produced when further dehydrated at 140 degrees C. The dehydration at 250 degrees C resulted in a completely anhydrous phase. The (93)Nb NMR parameters extracted from the wide-line NMR spectra acquired at different magnetic fields are highly sensitive to the dehydration process. PMID- 19780563 TI - Structural anomalies associated with antiferromagnetic transition of single component molecular metal [Au(tmdt)2]. AB - The crystal structure of the single-component molecular metal [Au(tmdt)(2)] was examined by performing powder X-ray diffraction experiments in the temperature range of 9-300 K using a synchrotron radiation source installed at SPring-8. The structural anomalies associated with antiferromagnetic transition were observed around the transition temperature (T(N) = 110 K). The continuous temperature dependence of the unit cell volume and the discontinuous change in the thermal expansion coefficient at T(N) suggested that the antiferromagnetic transition of [Au(tmdt)(2)] is a second-order transition. Au(tmdt)(2) molecules are closely packed in the (021) plane with two-dimensional lattice vectors of a and l (= 2a + b + 2c). The shortest intermolecular S...S distance along the a axis shows a sharp decrease at around T(N), while the temperature dependence of l exhibits a characteristic peak in the same temperature region. A distinct structure anomaly was not observed along the direction perpendicular to the (021) plane. These results suggest that the molecular arrangement in only the (021) plane changes significantly at T(N). Thus, the intermolecular spacing shows anomalous temperature dependence at around T(N) only along that direction where the neighboring tmdt ligands have opposite spins in the antiferromagnetic spin structure model recently derived from ab initio band structure calculations. The results of single-crystal four-probe resistance measurements on extremely small crystals (approximately 25 microm) did not show a distinct resistance anomaly at T(N). The resistance anomaly associated with antiferromagnetic transition, if at all present, is very small. The Au-S bond length decreases sharply at around 110 K; this is consistent with the proposed antiferromagnetic spin distribution model, where the left and right ligands of the same molecule possess opposite spin polarizations. The tendency of the Au-S bond to elongate with decreasing temperature is ascribed to the small energy gap between the pd sigma(-) (or SOMO + 1) and the asym-Lpi(d) (or SOMO) states of the Au(tmdt)(2) molecule. PMID- 19780564 TI - A hydrogen-bond facilitated cycle for oxygen reduction by an acid- and base compatible iron platform. AB - We report a hydrogen-bond functionalized N4Py ligand platform (N,N-bis(2-R-6 pyridylmethyl)-N-bis(2-pyridyl)methylamine; R = neopentyl-NH, N4Py(2NpNH), 9; R = phenyl-NH, N4Py(2PhNH), 10) and the ability of its iron(II)-triflate [N4Py(2R)Fe(II)(OTf)][OTf] complexes (R = NpNH, 11; R = PhNH, 12) to activate and reduce dioxygen in a synthetic cycle by coupled proton and electron transfer. A pair of iron(III)-hydroxide [N4Py(2R)Fe(III)(OH)][OTf](2) complexes (R = NpNH, 13; R = PhNH, 14) are isolated and structurally and spectroscopically characterized after exposure of the iron(II)-triflate precursors to 1 atm of O(2) at ambient temperature. The stability of this system to acids and bases allows regeneration of the labile iron(II)-triflate starting materials by sequential electron and proton transfer with cobaltocene and triflic acid, respectively, or through direct proton-coupled reduction with ascorbic acid. In the stepwise process, reduction of the iron(III)-hydroxide complexes with cobaltocene gives structurally homologous iron(II)-hydroxide [N4Py(2R)Fe(II)(OH)][OTf] congeners (R = NpNH, 15; R = PhNH, 16) that can be prepared independently from 11 and 12 with 20% aq. NaOH. Additions of triflic acid to complexes 15 and 16 furnish the starting compounds 11 and 12, respectively, to complete the synthetic cycle. The combined data establish a synthetic cycle for O(2) reduction by an iron platform that manages proton and electron transfer through its first and second coordination spheres. PMID- 19780565 TI - Valence-tautomeric ionic liquid composed of a cobalt bis(dioxolene) complex dianion. AB - We successfully synthesized a room-temperature ionic liquid showing valence tautomeric behavior, by combining a cobalt bis(dioxolene) complex dianion with a bulky trihexyl(tetradecyl)phosphonium cation. Its magnetic moment exhibits a gradual increase up to ca. 280 K through the glass transition (262 K) and then has an abrupt upturn at around 300 K. The valence-tautomeric behavior was confirmed by the temperature dependence of the electronic absorption spectra. This successful implementation allowed the "smart" ionic liquid, whose magnetic behavior responds evidently to temperature change. PMID- 19780566 TI - Macrocycle-based spin-crossover materials. AB - New iron(II) complexes of formula [Fe(L1)](BF(4))(2) (1) and [Fe(L2)](BF(4))(2) x H(2)O (2) (L1 = 1,7-bis(2'-pyridylmethyl)-1,4,7,10-tetraazacyclododecane; L2 = 1,8-bis(2'-pyridylmethyl)-1,4,8,11-tetraazacyclotetradecane) have been synthesized and characterized by infrared spectroscopy, variable-temperature single-crystal X-ray diffraction, and variable-temperature magnetic susceptibility measurements. The crystal structure determinations of 1 and 2 reveal in both cases discrete iron(II) monomeric structures in which the two functionalized tetraazamacrocycles (L1 and L2) act as hexadentate ligands; the iron(II) ions are coordinated with six nitrogen atoms: four from the macrocycle and two from two pyridine groups occupying two cis positions around the metal ion. In 1, the N-Fe-N bond angles indicate that the Fe(II) ion adopts an unusual distorted trigonal prismatic geometry. In agreement with the observed paramagnetic behavior, the average of the six Fe-N distances at 293 K (2.218(6) A) and at 90 K (2.209(2) A) correspond well with distances observed for high-spin (HS) Fe(II) complexes with a coordination index of 6. For 2, the Fe(II) ion adopts a distorted octahedral geometry for which the six Fe-N distances (average 2.197(4) A) at room temperature are in the range expected for HS Fe(II) complexes. The crystal structure solved at 90 K showed a strong modification of the iron coordination sphere, suggesting the presence of a spin-crossover transition from HS to low spin (LS). Surprisingly, the averaged Fe-N value (2.077(4) A) at this temperature is not in agreement with the magnetic measurements since the chi(m)T product versus T showed a full LS state at 90 K. This may be explained by the presence of important distortions arising from the macrocycle constraints. To understand how the crystal and the lattice parameters were affected by the magnetic transition, the temperature dependence of the lattice parameters of 2 was determined in the range 293-90 K: the a and b parameters show essentially linear and gradual decreases, while the c and beta parameters show dramatic decreases nearly similar to that observed in the magnetic behavior. PMID- 19780567 TI - Effect of counterions on the structure and stability of aqueous uranyl(VI) complexes. A first-principles molecular dynamics study. AB - The inclusion of NH(4)(+) as counterions in Car-Parrinello molecular dynamics (CPMD) simulations of anionic uranyl(VI) complexes is proposed as a viable approach to modeling "real" aqueous solutions. For [UO(2)F(4)(H(2)O)](2-) in water, it is shown that the inclusion of two NH(4)(+) ions strengthens the bond between uranyl and the water ligand by ca. 2 kcal/mol, improving the accordance with experiment. According to CPMD simulations for [UO(2)X(5)][NH(4)](3) (X = F, OH) in water, the fifth fluoride is bound much stronger than the fifth OH(-). Implications for a recently proposed model for oxygen exchange in uranyl hydroxide are discussed. PMID- 19780568 TI - Twofold coordinated ground-state and eightfold high-pressure phases of heavy transition metal nitrides MN(2) (M = Os, Ir, Ru, and Rh). AB - Using ab initio evolutionary methodology for crystal structure prediction, a twofold coordinated ground-state hexagonal structure (P6/mmm, 1 f.u./cell) with peculiar double N horizontal lineN bonded N(2) units was uncovered for MN(2) (M = Os, Ir, Ru, and Rh) compounds. This structure exhibits an unusual incompressibility along the c axis, higher than that of diamond. At much higher pressures, an eightfold coordinated tetragonal structure (P4/mbm, 2 f.u./cell) containing MN(8) cuboids was unraveled and possesses also orientational ultra incompressibility. A unified phase transition diagram for these nitrides was thus derived to reveal the intriguing chemistry of nitrogen at extreme conditions. Formation energy calculations demonstrate that the ground state phase is synthesizable at low pressure ( approximately 40 GPa) while the eightfold phase can be achieved through the phase transformation via the marcasite structure. PMID- 19780569 TI - Mapping active dopants in single silicon nanowires using off-axis electron holography. AB - We demonstrate that state-of-the-art off-axis electron holography can be used to map active dopants in silicon nanowires as thin as 60 nm with 10 nm spatial resolution. Experiment and simulation demonstrate that doping concentrations of 10(19) and 10(20) cm(-3) can be measured with a detection threshold of 10(18) cm( 3) with respect to intrinsic silicon. Comparison of experimental data and simulations allows an estimation of the charge density at the wire-oxide interface of -1 x 10(12) electron charges cm(-2). Off-axis electron holography thus offers unique capabilities for a detailed analysis of active dopant concentrations in nanostructures. PMID- 19780570 TI - Tuning the properties of polymer bulk heterojunction solar cells by adjusting fullerene size to control intercalation. AB - We demonstrate that intercalation of fullerene derivatives between the side chains of conjugated polymers can be controlled by adjusting the fullerene size and compare the properties of intercalated and nonintercalated poly(2,5-bis(3 hexadecylthiophen-2-yl)thieno[3,2-b]thiophene (pBTTT):fullerene blends. The intercalated blends, which exhibit optimal solar-cell performance at 1:4 polymer:fullerene by weight, have better photoluminescence quenching and lower absorption than the nonintercalated blends, which optimize at 1:1. Understanding how intercalation affects performance will enable more effective design of polymer:fullerene solar cells. PMID- 19780571 TI - Straightforward synthesis of the near-infrared fluorescent voltage-sensitive dye RH1691 and analogues thereof. AB - A highly straightforward synthesis of the near-infrared voltage-sensitive dye RH1691 is reported featuring two sequential anionic additions of C-nucleophilic heterocycles on a cyanine. This convergent approach led to the synthesis of four new probes, which also exhibit fluorescence in the near-infrared region. PMID- 19780572 TI - Benchmarking second order methods for the calculation of vertical electronic excitation energies: valence and Rydberg states in polycyclic aromatic hydrocarbons. AB - The performance of the six second order linear response methods RPA(D), SOPPA, SOPPA(CCSD), CIS(D), CC2, and CCSD, which include either noniterative or iterative doubles contributions, has been studied in calculations of vertical excitation energies. The benchmark set consisted of 39 valence and 76 Rydberg states of benzene and five polycyclic aromatic hydrocarbons. As reference values we have used the results of the corresponding calculations with the third order method CCSDR(3), which includes noniterative triples contributions. In addition we have also carried out equivalent calculations at the level of the random phase approximation as well as with the configuration interaction singles and multireference configuration interaction singles and doubles methods. PMID- 19780573 TI - Tuning selectivity of anionic cyclizations: competition between 5-exo and 6-endo dig closures of hydrazides of o-acetylenyl benzoic acids and based-catalyzed fragmentation/recyclization of the initial 5-exo-dig products. AB - Depending on the reaction conditions and the nature of substituents at the triple bond, anionic cyclizations of hydrazides of o-acetylenyl benzoic acids can be selectively directed along three alternative paths, each of which provides efficient access to a different class of nitrogen heterocycles. The competition between 5-exo and 6-endo cyclizations of the "internal" nitrogen nucleophile is controlled by the nature of alkyne substituents under the kinetic control conditions. In the presence of KOH, the initially formed 5-exo products undergo a new rearrangement that involves a ring-opening followed by recyclization to the formal 6-exo-products and rendered irreversible by a prototropic isomerization. DFT computations provide insight into the nature of factors controlling relative rates of 5-exo, 6-endo, and 6-exo cyclization paths, ascertain the feasibility of direct 6-exo closure and relative stability for the anionic precursor for this process, provide, for the first time, the benchmark data for several classes of anionic nitrogen cyclizations, and dissect stereoelectronic effects controlling relative stability of cyclic anionic intermediates and influencing reaction stereoselectivity. We show that the stability gain due transformation of a weak pi-bond into a stronger sigma-bond (the usual driving force for the cyclizations of alkynes) is offset in this case by the transformation of a stable nitrogen anion into an inherently less stable carbanionic center. As a result, the cyclizations are much more sensitive to external conditions and substituents than similar cyclizations of neutral species. However, the exothermicity of such anionic cyclizations is increased dramatically upon prototropic isomerization of the initially formed carbanions into the more stable N-anions. Such tautomerizations are likely to play the key role in driving such cyclizations to completion but may also prevent future applications of such processes as the first step in domino cyclization processes. PMID- 19780574 TI - Bronsted acid-promoted glycosylations of disaccharide glycal substructures of the saccharomicins. AB - An acid-promoted glycosylation and alkynol cycloisomerization sequence provided direct access to the 2-deoxytrisaccharide corresponding to the fucose saccharosamine-digitoxose substructure of saccharomicin B. In the course of this work, the absolute stereochemistry of the repeating fucose-saccharosamine disaccharide of saccharomicins was also confirmed. PMID- 19780575 TI - Multipole model for the electron group functions method. AB - Electron groups provide a natural way to introduce local concepts into quantum chemistry, and the wave functions based on the group products can be considered as a framework for constructing efficient computational methods in terms of "observable" parts of molecular systems. The elements of the group wave functions (electronic structure variables) can be optimized by requiring the number of operations proportional to the size of the molecule. This directly leads to computational methods linearly scaling for large molecular systems. In the present work we consider a particular case of such a wave function implemented for the semiempirical NDDO Hamiltonian. The electron groups are expressed in terms of optimized atomic (hybrid) orbitals with chemical bonds described by geminals and the delocalized groups described by Slater determinants (with or without spin restriction). This scheme is very fast by itself but its speed is considerably limited by the computations of the interatomic Coulomb interactions. Here we develop a consistent method based on group functions which uses the multipole scheme for interatomic interactions. The explicit usage of the atomic multipoles makes the method extremely fast, although the numerical efficiency is largely achieved due to the local character of the electron groups involved. We discuss numerical characteristics of the new method as well as its possible parametrization. We apply this method to study dodecahedral water clusters with hydrogen fluoride substitution and base the analysis on the exhaustive calculation of all symmetry-independent hydrogen-bond networks. PMID- 19780576 TI - Ligand prediction for orphan targets using support vector machines and various target-ligand kernels is dominated by nearest neighbor effects. AB - Support vector machine (SVM) calculations combining protein and small molecule information have been applied to identify ligands for simulated orphan targets (i.e., targets for which no ligands were available). The combination of protein and ligand information was facilitated through the design of target-ligand kernel functions that account for pairwise ligand and target similarity. The design and biological information content of such kernel functions was expected to play a major role for target-directed ligand prediction. Therefore, a variety of target ligand kernels were implemented to capture different types of target information including sequence, secondary structure, tertiary structure, biophysical properties, ontologies, or structural taxonomy. These kernels were tested in ligand predictions for simulated orphan targets in two target protein systems characterized by the presence of different intertarget relationships. Surprisingly, although there were target- and set-specific differences in prediction rates for alternative target-ligand kernels, the performance of these kernels was overall similar and also similar to SVM linear combinations. Test calculations designed to better understand possible reasons for these observations revealed that ligand information provided by nearest neighbors of orphan targets significantly influenced SVM performance, much more so than the inclusion of protein information. As long as ligands of closely related neighbors of orphan targets were available for SVM learning, orphan target ligands could be well predicted, regardless of the type and sophistication of the kernel function that was used. These findings suggest simplified strategies for SVM-based ligand prediction for orphan targets. PMID- 19780577 TI - Heats of formation of the H1,2OmSn (m, n = 0-3) molecules from electronic structure calculations. AB - Atomization energies at 0 K and heats of formation at 0 and 298 K are predicted from high level ab initio electronic structure calculations using the coupled cluster CCSD(T) method with augmented correlation-consistent basis sets extrapolated to the complete basis set (CBS) limit for the H(1,2)O(m)S(n) (m, n = 0-3) compounds, as well as various radicals involved in different bond breaking processes. To achieve near chemical accuracy (+/-1.0 kcal/mol), additional corrections were added to the CBS binding energies based on the frozen core CCSD(T) energies including corrections for core-valence, scalar relativistic, and first-order atomic spin-orbit effects. Geometries were optimized up through the CCSD(T)/aV(T+d)Z level. Vibrational zero point energies were computed at the MP2/aV(T+d)Z level. The calculated heats of formation are in excellent agreement with the available experimental data and allow the prediction of adiabatic bond dissociation energies (BDEs) to within +/-1.0 kcal/mol. The decomposition mechanisms were largely determined by a preference to maintain a strong S=O bond in the dissociated products as opposed to O=O and S=S bonds, exactly matching the ordering of the BDEs in the diatomics. For the H(2)X(2) and H(2)X(3) systems, as well as the HX(3) radicals, the energetically favorable decomposition pathway leads to the formation of XH radicals and breaking the X-X bond as opposed to breaking the X-H bond. For the HX(2) radicals, however, the more thermodynamically favorable pathway leads to a breaking of the H-X bond and forming X(2) molecules. PMID- 19780578 TI - Ibuprofen loading in surfactant-templated silica: role of the solvent according to the polarizable continuum model. AB - Ibuprofen (an anti-inflammatory drug) has been loaded onto two different surfactant-templated silicas (SBA-15 and MCM-48). To evaluate the effect of the drug-solvent combination on the loading capacity of the silica, we have performed ibuprofen adsorption experiments using 10 different solvents; we have interpreted our experimental results assuming a chemical equilibrium between the ibuprofen adsorbed on the silica and that remaining in solution. To estimate the equilibrium constant for different solvents, we have calculated the free energy in solution for the ibuprofen molecule using the polarizable continuum model (PCM) to take the solvent into account. The results have been analyzed statistically to eliminate the effects of the dispersion of experimental data; results reveal a statistically significant (95-99%) linear relationship between the ibuprofen loading capacity and its free energy in solution calculated with the PCM solvation model. In addition, useful relationships between loading capacity and dielectric constant and molecular size of the solvents are established. PMID- 19780579 TI - Improved surface-patterned platinum microelectrodes for the study of exocytotic events. AB - Surface-patterned platinum microelectrodes insulated with 300 nm thick fused silica were fabricated using contact photolithography. These electrodes exhibit low noise and were used for monitoring single vesicle exocytosis from chromaffin cells by constant potential amperometry as well as fast-scan cyclic voltammetry. Amperometric spike parameters were consistent with those obtained with conventional carbon fiber electrodes. Catecholamine voltammograms acquired with platinum electrodes exhibited redox peaks with full width at half-maximum of approximately 45 mV, much sharper than those of carbon fiber electrode recordings. The time course of voltammetrically measured release events was similar for platinum and carbon fiber electrodes. The fused-silica-insulated platinum electrodes could be cleaned and reused repetitively and allowed incorporation of micrometer precision surface-patterned poly-D-lysine. Poly-D lysine-functionalized devices were applied to stimulate mast cells and record single release events without serotonin preloading. Microfabricated platinum electrodes are thus able to record single exocytotic events with high resolution and should be suitable for highly parallel electrode arrays allowing simultaneous measurements of single events from multiple cells. PMID- 19780580 TI - Potential of human saliva for nuclear magnetic resonance-based metabolomics and for health-related biomarker identification. AB - In the present study, the ability of (1)H nuclear magnetic resonance (NMR) for metabolic profiling of human saliva samples was investigated. High-resolution (1)H NMR spectra were obtained, and signals were assigned to various metabolites mainly representing small organic acids and amino acids. In addition, the use of human saliva for metabolomic studies was evaluated, and multivariate data analysis revealed that the 92 morning and night samples from 46 subjects could be discriminated with a predictability of 85%. The diurnal effect on the salivary metabolite profile were ascribed to changes in intensities of several metabolites including trimethylamine oxide (TMAO), choline, propionate, alanine, methanol, and N-acetyl groups. No effects of gender and body mass index (BMI) on the salivary metabolite profile were detected. The relationships between the salivary metabolome and glycated hemoglobin, systolic and diastolic blood pressure were investigated; however, no significant correlations could be established. PMID- 19780582 TI - One-dimensional homochiral cyano-bridged heterometallic chain coordination polymers with metamagnetic or ferroelectric properties. AB - Two couples of enantiomerically pure chiral cyano-bridged heterobimetallic chain coordination polymers, [Mn((R,R)-Salcy)Fe(Tp)(CN)(3) x H(2)O x 1/2 CH(3)CN](n) (1), [Mn((S,S)-Salcy)Fe(Tp)(CN)(3) x H(2)O x 1/2 CH(3)CN](n) (2), [Mn((R,R) Salcy)Fe(bpca)(CN)(3) x H(2)O](n) (3), and [Mn((S,S)-Salcy)Fe(bpca)(CN)(3) x H(2)O](n) (4) [(R,R)-Salcy or (S,S)-Salcy = (R,R)- or (S,S)-N,N'-(1,2 cyclohexanediylethylene)bis(salicylideneiminato) dianion, Tp = tris(pyrazolyl)hydroborate, bpca = bis(2-pyridylcarbonyl)amidate anion], were synthesized using the modified cyanometalate building blocks [Fe(L)(CN)(3)](-) (L = Tp, bpca) and the chiral polydentate Schiff base manganese(III) complex fragments. The circular dichroism measurements showed Cotton effects of the opposite sign at the same wavelength for each pair of enantiomers. Magnetic property studies indicated that complexes 1 and 2 show not only intrachain but also interchain field-induced metamagnetic transitions from an antiferromagnetic to a ferromagnetic state and exhibit an antiferromagnetic long-range ordering with a T(N) of 3.2 K, while enantiomers 3 and 4 are typical antiferromagnetic coupling compounds. Furthermore, complex 3 exhibits a ferroelectric behavior that relates to the polar point group C(2), in which it crystallizes. PMID- 19780581 TI - Hybrid separation and detection device for analysis of benzene, toluene, ethylbenzene, and xylenes in complex samples. AB - We present a hybrid system for rapid detection and analysis of benzene, toluene, ethylbenzene, and xylenes (BTEX). The system combines selective and sensitive sensing elements with a fast and miniaturized chromatographic separation method. The sensing elements are an array of microfabricated quartz crystal tuning forks modified with selective molecularly imprinted polymers, and the separation method uses optimized short columns. The high sensitivity and selectivity of the sensing elements together with the help of the separation provides fast detection and analysis of BTEX in real samples containing highly concentrated interfering agents without preconcentration or heating of columns. The low cost, low power consumption, and small size of the hybrid device are particularly suitable for occupational health, industrial safety, and epidemiological applications. PMID- 19780583 TI - Spin transport of excitons. AB - We report on observation of the spin transport of spatially indirect excitons in GaAs/AlGaAs coupled quantum wells (CQW). Exciton spin transport over substantial distances, up to several micrometers in the present work, is achieved due to orders of magnitude enhancement of the exciton spin relaxation time in CQW with respect to conventional quantum wells. PMID- 19780584 TI - Interactions of the acidic domain and SRF interacting motifs with the NKX3.1 homeodomain. AB - NKX3.1 is a prostate tumor suppressor belonging to the NK-2 family of homeodomain (HD) transcription factors. NK-2 family members often possess a stretch of 10-15 residues enriched in acidic amino acids, the acidic domain (AD), in the flexible, disordered region N-terminal to the HD. Interactions between the N-terminal region of NKX3.1 and its homeodomain affect protein stability and DNA binding. CD spectroscopy measuring the thermal unfolding of NKX3.1 constructs showed a 2 degrees C intramolecular stabilization of the HD by the N-terminal region containing the acidic domain (residues 85-96). CD of mixtures of various N terminal peptides with a construct containing just the HD showed that the acidic domain and the following region, the SRF interacting (SI) motif (residues 99 105), was necessary for this stabilization. Phosphorylation of the acidic domain is known to slow proteasomal degradation of NKX3.1 in prostate cells, and NMR spectroscopy was used to measure and map the interaction of the HD with phosphorylated and nonphosphorylated forms of the AD peptide. The interaction with the phosphorylated AD peptide was considerably stronger (K(d) = 0.5 +/- 0.2 mM), resulting in large chemical shift perturbations for residues Ser150 and Arg175 in the HD, as well as a 2 degrees C increase in the HD thermal stability compared to that of the nonphosphorylated form. NKX3.1 constructs with AD phosphorylation site threonine residues (89 and 93) mutated to glutamate were 4 degrees C more stable than HD alone. Using polymer theory, effective concentrations for interactions between domains connected by flexible linkers are predicted to be in the millimolar range, and thus, the weak intramolecular interactions observed here could conceivably modulate or compete with stronger, intermolecular interactions with the NKX3.1 HD. PMID- 19780585 TI - Growth of metal oxide nanowires from supercooled liquid nanodroplets. AB - Nanometer-sized liquid droplets formed at temperatures below the bulk melting point become supercooled as they grow through Ostwald ripening or coalescence and can be exploited to grow nanowires without any catalyst. We used this simple approach to synthesize a number of highly crystalline metal oxide nanowires in a chemical or physical vapor deposition apparatus. Examples of nanowires made in this way include VO(2), V(2)O(5), RuO(2), MoO(2), MoO(3), and Fe(3)O(4), some of which have not been previously reported. Direct evidence of this new mechanism of nanowire growth is found from in situ 2-dimensional GISAXS (grazing incidence small angle X-ray scattering) measurements of VO(2) nanowire growth, which provides quantitative information on the shapes and sizes of growing nanowires as well as direct evidence of the presence of supercooled liquid droplets. We observe dramatic changes in nanowire growth by varying the choice of substrate, reflecting the influence of wetting forces on the supercooled nanodroplet shape and mobility as well as substrate-nanowire lattice matching on the definition of nanowire orientation. Surfaces with defects can also be used to pattern the growth of the nanowires. The simplicity of this synthesis concept suggests it may be rather general in its application. PMID- 19780586 TI - Simulations of the BM2 proton channel transmembrane domain from influenza virus B. AB - BM2 is a small integral membrane protein from influenza B virus which forms proton-permeable channels. Coarse-grained (CG) molecular dynamics simulations have been used to produce a model of the BM2 channel by self-assembly of a tetrameric bundle of BM2 transmembrane helices in a lipid bilayer. The BM2 channel model is conformationally stable on a 5 mus time scale. This CG model was converted to atomistic resolution to refine interhelix and channel-water interactions. Atomistic molecular dynamics simulations indicate that the BM2 channel is closed when no more than two of the four His19 residues are protonated. Protonating a third His19 side chain initiates a conformational change that opens the channel. In summary, our simulations suggest a common mechanism for BM2 and A/M2, whereby changes in helix packing play a functional role in channel gating. PMID- 19780587 TI - Electrophoretic force on a protein-coated DNA molecule in a solid-state nanopore. AB - Using solid-state nanopores with optical tweezers, we perform force spectroscopy on DNA molecules that are coated with RecA proteins. We observe that the electrophoretic force is 2-4 times larger for RecA-DNA filaments than for uncoated DNA molecules and that this force increases at lower salt concentrations. The data demonstrate the efficacy of solid-state nanopores for locally probing the forces on DNA-bound proteins. Our results are described quantitatively by a model that treats the electrophoretic and hydrodynamic forces. The conductance steps that occur when RecA-DNA enters the nanopore change from conductance decreases at high salt to conductance increases at low salt, which allows the apparent charge of the RecA-DNA filament to be extracted. The combination of conductance measurements with local force spectroscopy increases the potential for future solid-state nanopore screening devices. PMID- 19780588 TI - The membrane topography of the diphtheria toxin T domain linked to the a chain reveals a transient transmembrane hairpin and potential translocation mechanisms. AB - The diphtheria toxin T domain helps translocate the A chain of the toxin across membranes. To gain insight into translocation, the membrane topography of key residues in T domain attached to the A chain (AT protein) was compared to that in the isolated T domain using fluorescence techniques. This study demonstrates that residues in T domain hydrophobic helices (TH5-TH9) tended to be less exposed to aqueous solution in the AT protein than in the isolated T domain. Under conditions in which the loop connecting TH5 to TH6/7 is located stably on the cis (insertion) side of the membrane in the isolated T domain, it moves between the cis and trans sides of the membrane in the AT protein. This is indicative of the formation of a dynamic, transient transmembrane hairpin topography by TH5-TH7 in the AT protein. Since TH8 and TH9 also form a transmembrane hairpin, this means that TH5-TH9 may form a cluster of transmembrane helices. These helices have a nonpolar surface likely to face the lipid bilayer in a helix cluster and a surface rich in uncharged hydrophilic residues which in a helix cluster would likely be facing inward (and perhaps be pore-lining). This uncharged hydrophilic surface could play a crucial role in translocation, interacting transiently with the translocating A chain. A similar motif can be found in, and may be important for, other protein translocation systems. PMID- 19780589 TI - The periplasmic chaperone Skp facilitates targeting, insertion, and folding of OmpA into lipid membranes with a negative membrane surface potential. AB - The basic biochemical and biophysical principles by which chaperone-bound membrane proteins are targeted to the outer membrane of Gram-negative bacteria for insertion and folding are unknown. Here we compare spontaneous folding of outer membrane protein A (OmpA) of Escherichia coli from its urea-unfolded form and from the complex with its periplasmic chaperone Skp into lipid bilayers. Skp facilitated folding of OmpA into negatively charged membranes containing dioleoylphosphatidylglycerol (DOPG). In contrast, Skp strongly inhibited folding of OmpA when bilayers were composed of dioleoylphosphatidylethanolamine and dioleoylphosphatidylcholine (DOPC). These results indicate that the positively charged Skp targets OmpA to a negatively charged membrane, which facilitates the release of OmpA from its complex with Skp for subsequent folding and membrane insertion. The dual functionality of Skp as a chaperone and as a targeting protein is ideal to mediate the transport of OmpA and other outer membrane proteins across the periplasm in a folding-competent form to the outer membrane, which is negatively charged on its periplasmic side. OmpA (pI 5.5) folded most efficiently above its isoelectric point. In the absence of Skp and in contrast to folding into DOPC bilayers, insertion and folding of OmpA were retarded for membranes containing DOPG at neutral or basic pH because of electrostatic repulsion. When folding of OmpA was performed near its isoelectric point, urea dilution led to a more compact aqueous form of OmpA previously characterized by fluorescence, which folded at a much slower rate. Under conditions where two different aqueous conformations of OmpA coexisted, e.g., in the titration region of OmpA, the last step of OmpA folding could be well described by two parallel pseudo-first-order kinetic phases. In this kinetic model, the contribution of the faster folding process, but not the changes in the rate constants, determined the folding yields obtained at different pH. The faster phase dominated when the experimental conditions favored the less compact form of aqueous OmpA. PMID- 19780590 TI - Cytotoxic diterpenoids from Croton argyrophylloides. AB - Two new diterpenes, 1 and 2, together with the known ent-15-oxo-kaur-16-en-18-oic acid (3), were isolated from the bark of Croton argyrophylloides. The structural characterization of 1 and 2 was determined on the basis of spectroscopic data interpretation. The cytotoxicity of each compound was evaluated against HL-60 (leukemia), MDAMB-435 (melanoma), SF-295 (glioblastoma), and HCT-8 (colon carcinoma) human tumor cell lines and against human peripheral blood mononuclear cells. The hemolytic potential in mouse erythrocytes was also tested for 1-3. PMID- 19780591 TI - Dibenzo[f,h]thieno[3,4-b] quinoxaline-based small molecules for efficient bulk heterojunction solar cells. AB - Two isomeric compounds (1 and 2) containing a dibenzo[f,h]thieno[3,4 b]quinoxaline core and two peripheral arylamines were synthesized. Solution processed bulk heterojunction (BHJ) solar cells based on these sensitizers and [6,6]-phenyl-C61-butyric acid methyl ester (PCBM) are reported. The cell fabricated from 1/67 wt % of PCBM exhibited a high power conversion efficiency of 1.70% and an external quantum yield of 55%. The film of the cell was found to have balanced electron and hole mobility and good film morphology. PMID- 19780592 TI - When T. rex is part of a day's work. AB - John Asara's journey into analytical chemistry and proteomics leads him to dinosaurs. PMID- 19780593 TI - Aptamer-DNAzyme hairpins for amplified biosensing. AB - Engineered nucleic acid hairpin structures are used for the amplified analysis of low-molecular-weight substrates (adenosine monophosphate, AMP) or proteins (lysozyme). The hairpin structures consist of the anti-AMP or antilysozyme aptamer units linked to the horseradish peroxidase (HRP)-mimicking DNAzyme sequence. The HRP-mimicking DNAzyme sequence is protected in a "caged", inactive structure in the stem regions of the respective hairpins, whereas the loop regions include a part of the respective aptamer sequence. The opening of the hairpins by the analytes, AMP or lysozyme, through the formation of the respective analyte-aptamer complexes, results in the self-assembly of the active HRP-mimicking DNAzyme. The DNAzyme catalyzes the H(2)O(2)-mediated oxidation of 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS(2-)) to the colored ABTS(*-), thus providing the amplified optical detection of the respective analytes. The engineered aptamer-DNAzyme hairpin structures reveal significantly improved analytical performance, as compared to analogous fluorophore-quencher labeled hairpins. PMID- 19780594 TI - The rate of intramolecular loop formation in DNA and polypeptides: the absence of the diffusion-controlled limit and fractional power-law viscosity dependence. AB - The problem of determining the rate of end-to-end collisions for polymer chains has attracted the attention of theorists and experimentalists for more than three decades. The typical theoretical approach to this problem has focused on the case where a collision is defined as any instantaneous fluctuation that brings the chain ends to within a specific capture distance. In this paper, we study the more experimentally relevant case, where the end-to-end collision dynamics are probed by measuring the excited state lifetime of a fluorophore (or other lumiphore) attached to one chain end and quenched by a quencher group attached to the other end. Under this regime, a "contact" is defined not by the chain ends approach to within some sharp cutoff but, instead, typically by an exponentially distance-dependent process. Previous theoretical models predict that, if quenching is sufficiently rapid, a diffusion-controlled limit is attained, where such measurements report on the probe-independent, intrinsic end-to-end collision rate. In contrast, our theoretical considerations, simulations, and an analysis of experimental measurements of loop closure rates in single-stranded DNA molecules all indicate that no such limit exists, and that the measured effective collision rate has a nontrivial, fractional power-law dependence on both the intrinsic quenching rate of the fluorophore and the solvent viscosity. We propose a simple scaling formula describing the effective loop closure rate and its dependence on the viscosity, chain length, and properties of the probes. Previous theoretical results are limiting cases of this more general formula. PMID- 19780595 TI - Logic gates using nanofluidic diodes based on conical nanopores functionalized with polyprotic acid chains. AB - Single-track conical nanopores functionalized with polyprotic acid chains have pH sensitive fixed charge groups and show three levels of conductance that allow integrating several functions on a single nanofluidic diode. Nanometer-scaled pores have previously been employed in separation and sensing but not in logic devices, despite the fact that biological ion channels with pH-dependent fixed charges are known to be responsible for information processing in biophysical structures. As a preliminary application, we propose a logic gate scheme where binary and multivalued logical functions are implemented. PMID- 19780596 TI - PdCl2-promoted electrophilic annulation of 2-alkynylphenol derivatives with disulfides or diselenides in the presence of iodine. AB - An efficient synthesis of 3-chalcogen-benzo[b]furans via palladium-promoted annulation reactions of 2-alkynylphenol derivatives with disulfides or diselenides and iodide has been developed. In the presence of I(2) and PdCl(2), both 3-sulfenylbenzofurans and 3-selenenylbenzofurans were selectively prepared from the cyclization of 2-alkynyanisoles with disulfides or diselenides in moderate to excellent yields. PMID- 19780597 TI - Dynamic behavior of avian influenza A virus neuraminidase subtype H5N1 in complex with oseltamivir, zanamivir, peramivir, and their phosphonate analogues. AB - The outbreak of avian influenza A subtype H5N1 virus has raised a global concern for both animal as well as human health. Recently, drug resistance in H5N1 infections has been widely reported due to neuraminidase mutations. Consequently, the understanding of inhibitor-neuraminidase interactions at the molecular level represents the main goal of our study. Molecular dynamics simulations were carried out for the neuraminidase N1 in complex with six inhibitors--oseltamivir, zanamivir, peramivir, and their phosphonate analogues. Molecular dynamics trajectories were extensively analyzed in terms of important interactions between inhibitors and the enzyme target. Results show that open and closed forms (defined by the relative position of the flexible 150-loop) of neuraminidase N1 interchange during the course of 20 ns molecular dynamics simulation of the protein-inhibitor complexes. Reported free energies of closing indicate that the carboxylate inhibitors prefer the closed form more than their phosphonate analogues. This can be understood in view of the negative total charge (-1 e0) of the phosphonate inhibitors, which repels the Asp151 residue of the loop away from the inhibitor and drives the complex into the open form. Obtained results constitute new valuable information to assist further drug development of inhibitors against the H5N1 avian influenza A virus and could also inspire similar studies for other systems of the influenza family such as the 2009 influenza A (H1N1) virus. PMID- 19780598 TI - Sonication-induced molecular gels based on mono-cholesterol substituted quinacridone derivatives. AB - A series of monocholesterol substituted quinacridone derivatives MCC(n) (n = 4, 6, 8) has been designed and synthesized. Compounds MCC(6) and MCC(8) can gelate a wide range of organic solvents upon ultrasound irradiation and afford intriguing well-defined nanostructures composed of three-dimensional sponge-like superstructures or fibrous networks. Interestingly, the gel produced from MCC(6) is sensitive to thermo-, aniline, and formic acid stimulus, giving obviously different aggregation behaviors as well as physical properties. Time-dependent spectroscopic data and theoretical calculation results provided explanation for the possible molecular aggregation mode during the formation of the gels. PMID- 19780599 TI - Propagation and beam geometry effects on two-dimensional fourier transform spectra of multilevel systems. AB - Four-level two-dimensional (2D) Fourier transform relaxation spectra are simulated with response functions for a chromophore pair in the exponential relaxation (optical Bloch model) limit. The parameters in this study are chosen to model coupled carbonyl stretching vibrations. As long as coherence persists, every peak in the real 2D spectra has a partially mixed absorptive/dispersive ("phase-twisted") shape because the nonlinear signals are not symmetric with respect to interchange of the first two pulses. This asymmetry in 2D relaxation spectra arises from coherence between singly excited states and a red shift of the doubly excited state. Coherence between the singly excited states causes oscillation of the 2D spectra and the associated spectrally resolved pump-probe (SRPP) transients at the quantum beat frequency. Projecting the phase-twisted nature of the 2D peaks onto the detection frequency axis, the SRPP peaks are also asymmetric about their maximum when not at maximum or minimum amplitude. Three dimensional Fourier transform (3DFT) methods are used to simulate absorption/dispersion and beam geometry distortions of the multilevel 2D spectra with cross peaks. The distortions can be understood by consideration of their effects on individual coherence pathways that contribute to peaks in the 2D spectra. The beam geometry distortion explains some unequal cross peak amplitudes previously observed experimentally by Khalil et al. (J. Chem. Phys. 2004, 121, 362). A representation of 2D spectra that reduces beam geometry distortion is presented. If the transformation to correct for beam geometry distortion is combined with the transformations that correct absorptive/dispersive propagation distortions (J. Chem. Phys. 2007, 126, 044511), the recovered 2D spectrum matches the ideal 2D spectrum after all coherence is destroyed. In the presence of coherence, the new representation reduces the error in the distorted 2D spectrum by a factor of 4 for practical 2D-IR experimental conditions. PMID- 19780600 TI - Water vapor effect on the HNO3 yield in the HO2 + NO reaction: experimental and theoretical evidence. AB - The influence of water vapor on the production of nitric acid in the gas-phase HO(2) + NO reaction was determined at 298 K and 200 Torr using a high-pressure turbulent flow reactor coupled with a chemical ionization mass spectrometer. The yield of HNO(3) was found to increase linearly with the increase of water concentration reaching an enhancement factor of about 8 at [H(2)O] = 4 x 10(17) molecules cm(-3) ( approximately 50% relative humidity). A rate constant value k(1bw) = 6 x 10(-13) cm(3) molecule(-1) s(-1) was derived for the reaction involving the HO(2)xH(2)O complex: HO(2)xH(2)O + NO --> HNO(3) (1bw), assuming that the water enhancement is due to this reaction. k(1bw) is approximately 40 times higher than the rate constant of the reaction HO(2) + NO --> HNO(3) (1b), at the same temperature and pressure. The experimental findings are corroborated by density functional theory (DFT) calculations performed on the H(2)O/HO(2)/NO system. The significance of this result for atmospheric chemistry and chemical amplifier instruments is briefly discussed. An appendix containing a detailed consideration of the possible contribution from the surface reactions in our previous studies of the title reaction and in the present one is included. PMID- 19780601 TI - Comprehensive DFT and MP2 level investigations of reaction of 2,3-dihydro-1,5 benzodiazepine-2-thiones with hydrazine. AB - Density functional theory approach was used for the 4-phenyl-2,3-dihydro-1,5 benzodiazepine-2-thione compound to determine the mechanism of hydrazinolysis of 4-substituted 2,3-dihydro-1,5-benzodiazepine-2-thiones. Single-point calculations at the MP2/6-311+G(d,p)//B3LYP/6-311+G(d,p) level were performed for the more accurate energy prediction. The solvent effect was taken into account by carrying out single-point calculations using the PCM methodology. The obtained results show that in the investigating mechanism the first step consists of the hydrazine molecule addition to the thiocarbonyl bond of the 4-phenyl-2,3-dihydro-1,5 benzodiazepine-2-thione following removal of H(2)S. Further addition of another hydrazine molecule to the azomethyne bond and cyclization with pyrazole ring formation occur, and then the diazepine ring-opening and the removal of hydrazine molecule proceed. Finally, imine-enamine tautomerization leads to 5-N-(2 aminophenyl-1-amino)-3-phenylpyrazole as a main product that is in agreement with the experimental observation. The cyclization step is a rate-determining step of this reaction. PMID- 19780602 TI - Structural transformations of sVI tert-butylamine hydrates to sII binary hydrates with methane. AB - Binary clathrate hydrates with methane (CH(4), 4.36 A) and tert-butylamine (t BuNH(2), 6.72 A) as guest molecules were synthesized at different molar concentrations of t-BuNH(2) (1.00-9.31 mol %) with methane at 7.0 MPa and 250 K, and were characterized by powder X-ray diffraction (PXRD) and Raman microscopy. A structural transformation from sVI to sII of t-BuNH(2) hydrate was clearly observed on pressurizing with methane. The PXRD showed sII signatures and the remnant sVI signatures were insignificant, implying the metastable nature of sVI binary hydrates. Raman spectroscopic data on these binary hydrates suggest that the methane molecules occupy the small cages and vacant large cages. The methane storage capacity in this system was nearly doubled to approximately 6.86 wt % for 5.56 mol % > t-BuNH(2) > 1.0 mol %. PMID- 19780603 TI - CuO(x)-TiO2 photocatalysts for H2 production from ethanol and glycerol solutions. AB - Hydrogen production by photocatalytic reforming of aqueous solutions of ethanol and glycerol was studied with the use of impregnated and embedded CuO(x)/TiO(2) photocatalysts. Embedded CuO(x)@TiO(2) was prepared by a water-in-oil microemulsion method, which consists in the formation of Cu nanoparticles in the microemulsion followed by controlled hydrolysis and condensation of tetraisopropyl orthotitanate with the aim of covering the protected metal particles with a surrounding layer of porous titanium oxyhydroxide. Mild calcination leads to the complete removal of the organic residues, the crystallization of TiO(2), and an unavoidable oxidation of copper. Two reference samples were prepared by classical wet impregnation of preformed TiO(2) with different ratios of anatase, rutile, and brookite polymorphs. The two supports were prepared by sol-gel (TiO(2)-SG) and microemulsion (TiO(2)-ME) methods. Superior performances have been observed for the embedded system, which shows higher hydrogen production rates with respect to the impregnated systems using either ethanol or glycerol as sacrificial molecules. Deep structural characterization of the materials has been performed by coupling high resolution transmission electron microscopy (HRTEM), high angle annular dark field-scanning transmission electron microscopy (HAADF-STEM), X-ray absorption fine structure (XAFS), and electron paramagnetic resonance (EPR) techniques. Correlation between copper oxidation state and its dispersion and reactivity has been attempted. Finally, the stability of the CuO(x)/TiO(2) catalysts was also studied with respect to carbonaceous deposits and copper leaching. PMID- 19780604 TI - Molecular mechanism of the Z/E-photoisomerization of hemithioindigo hemistilbene. AB - Hemithioindigo hemistilbene (HTI) can be selectively photoisomerized from the Z isomer into the E-isomer and vice versa. Using quantum chemical calculations, we have investigated the mechanism of the photoisomerization in detail. Our calculations demonstrate that two Z- and E-isomers exist in the electronic ground state as well as on the S(1) surface. The S(1) isomers are separated by small energy barriers along the dihedral twisting coordinate, but also a conical intersection with the electronic ground state is present at about 90 degrees twisting angle. Comparison with previously published experimental data reveals that most excited molecules, however, do not isomerize but instead relax to the equilibrium structure of the Z-isomer on the S(1) surface and return back to the ground state via regular fluorescence. Only a small fraction of the excited state population decays via the identified conical intersection and forms ground state E-isomers. This explains the comparably long lifetime of 38 ps of the excited HTI molecules and the observed low quantum yield of photoswitching. PMID- 19780605 TI - New type of dual solid-state thermochromism: modulation of intramolecular charge transfer by intermolecular pi-pi interactions, kinetic trapping of the aci-nitro group, and reversible molecular locking. AB - When heated above room temperature, some crystalline polymorphs of the 1,3 bis(hydroxyalkylamino)-4,6-dinitrobenzenes (BDBn, n = 2-5), bis(hydroxyalkyl) analogues of the intramolecular charge-transfer molecule 1,3-diamino-4,6 dinitrobenzene, exhibit "dual" thermochromism: gradual color change from yellow to orange at lower temperatures, and sharp color change from orange to red at higher temperatures. These two thermochromic changes are related to different solid-state processes. When allowed to cool to room temperature, the yellow color of the thermochromic molecules with different alkyl length (n) is recovered with unexpectedly different kinetics, the order of the respective rate constants ranging from 10(-7)-10(-6) s(-1) for BDB2 to about 0.1 s(-1) in the case of BDB3. The thermochromic mechanism and the reasons behind the different kinetics were clarified on the basis of detailed crystallographic characterization, kinetic thermoanalysis, and spectroscopic study of eight crystalline forms (seven polymorphs and one solvate). It was found that the polymorphism is due to the possibility of "locking" and "unlocking" of the alkyl arms by formation of a strong intramolecular hydrogen bond between the hydroxyl groups at their hydroxyl termini. The locking of BDB2, with shortest alkyl arms, is reversible and it can be controlled thermally; either of the two conformations can be obtained in the solid state by proper thermal treatment. By use of high temperature in situ single crystal X-ray diffraction analysis of BDB3, direct evidence was obtained that the gradual thermochromic change is related to increased distance and weakened pi-pi interactions between the stacked benzene rings: the lattice expands preferably in the stacking direction, causing enhanced oscillator strength and red shift of the absorption edge of the intramolecular charge transfer transition. The second, sharp thermochromic change had been assigned previously to solid-solid phase transition triggered by intramolecular proton transfer of one amino proton to the nitro group, whereupon an aci-nitro form is thermally populated. Contrary to the numerous examples of solid thermochromic molecules based on either pericyclic reactions or keto-enol tautomerism, this system appears to be the first organic thermochromic family where the thermochromic change appears as an effect of intermolecular pi-pi interactions and thermal intramolecular proton transfer to aromatic nitro group. PMID- 19780606 TI - Biomineralization and superhydrophobicity of BaCO3 complex nanostructures. AB - In this paper, we report on biomineralization of BaCO(3) hierarchical architectures with self-cleaning ability. The phase structures of the obtained samples were characterized by X-ray diffraction (XRD). All of these complex nanostructures, including dendrite-like nanostructures, dumbbell-like nanostructures, and spherical nanostructures of BaCO(3), were obtained by tuning the experimental parameters, such as the concentration of glucosan and Ba(2+) cations. The morphology and structures were studied by scanning electron microscopy (SEM), transmission electron microscopy (TEM), high resolution TEM (HRTEM), and Fourier transform infrared (FT-IR) spectrum. The formation of dendrite-like, dumbbell-like, and spherical complex nanostructures can be explained by a rod-dumbbell-sphere (RDS) self-assembly growth mechanism. To our knowledge, this is the first demonstration of the biomimetic synthesis of BaCO(3) hierarchical architectures which uniquely display the characteristic of superhydrophobicity. A water contact angle of >150 degrees and sliding angle of 1 degree of the BaCO(3) hierarchical architectures can be adjusted, which opens up a wide range of new potential applications of bioinspired complex nanostructures in environmental chemistry. PMID- 19780607 TI - Gas-phase geometry optimization of biological molecules as a reasonable alternative to a continuum environment description: fact, myth, or fiction? AB - Gas-phase optimization of single biological molecules and of small active-site biological models has become a standard approach in first principles computational enzymology. The important role played by the surrounding environment (solvent, enzyme, both) is normally only accounted for through higher level single point energy calculations performed using a polarizable continuum model (PCM) and an appropriate dielectric constant with the gas-phase-optimized geometries. In this study we analyze this widely used approximation, by comparing gas-phase-optimized geometries with geometries optimized with different PCM approaches (and considering different dielectric constants) for a representative data set of 20 very important biological molecules--the 20 natural amino acids. A total of 323 chemical bonds and 469 angles present in standard amino acid residues were evaluated. The results show that the use of gas-phase-optimized geometries can in fact be quite a reasonable alternative to the use of the more computationally intensive continuum optimizations, providing a good description of bond lengths and angles for typical biological molecules, even for charged amino acids, such as Asp, Glu, Lys, and Arg. This approximation is particularly successful if the protonation state of the biological molecule could be reasonably described in vacuum, a requirement that was already necessary in first principles computational enzymology. PMID- 19780608 TI - Facile preparation of 3,4-diarylpyrroles and hydrogen by a platinum(II) terpyridyl complex. AB - With visible-light irradiation of the platinum(II) terpyridyl complex 1 (lambda > 450 nm), an effective photocatalytic conversion from readily available 3,4-diaryl 2,5-dihydropyrroles (2a-2e) to 3,4-diarylpyrroles (3a-3e) and hydrogen (H(2)) is achieved with high efficiency and large catalytic turnover in a homogeneous solution. PMID- 19780609 TI - H2 activation by a (PNP)Ir(C6H5) complex via the dearomatization/aromatization process of the PNP ligand: a computational study. AB - Density functional theory calculations have been carried out to explore the mechanism of the H(2) activation by the (PNP)Ir(C(6)H(5)) complex. Our calculations show that the reaction is most likely to go though three steps. The first step (also the rate-determining step) involves the proton transfer from the benzylic position of the PNP ligand to the metal center to form an Ir(III) hydride intermediate, accompanied by the dearomatization of the PNP ligand. Second, H(2) is coordinated to the metal of this Ir(III) intermediate to form a molecular hydrogen complex. Finally, the H-H bond is heterolytically cleaved to produce the final trans-dihydride product, in which the benzylic carbon is protonated, and the PNP ligand is rearomatized. Thus, the H(2) activation by the Ir(I) complex actually involves an Ir(III) hydride complex as a key intermediate. The Ir center and the PNP ligand cooperate in a synergistic manner in the H(2) activation process. The above molecular mechanism could provide reasonable explanations for known experimental facts. PMID- 19780610 TI - Sulfonamide-supported group 4 catalysts for the ring-opening polymerization of epsilon-caprolactone and rac-lactide. AB - Reaction of RCH(2)N(CH(2)CH(2)NHSO(2)Tol)(2) (R = 2-NC(5)H(4) (8, H(2)L(py)) or MeOCH(2) (9, H(2)L(OMe))) with Ti(NMe(2))(4) at room temperature afforded Ti(L(py))(NMe(2))(2) (10) or Ti(L(OMe))(NMe(2))(2) (11), respectively, which contain tetradentate bis(sulfonamide)amine ligands. The corresponding reactions with Ti(O(i)Pr)(4) or Zr(O(i)Pr)(4) x HO(i)Pr required more forcing conditions to form the homologous bis(isopropoxide) analogues, M(L(R))(O(i)Pr)(2) (M = Ti, R = py (12) or OMe (14); M = Zr, R = py (13) or OMe (15)). Reaction of Ti(NMe(2))(2)(O(i)Pr)(2) with H(2)L(R) formed 12 or 14 under milder conditions. The X-ray structures of 10-15 have been determined revealing C(s) symmetric, 6 coordinate complexes except for 13 which is 7-coordinate with one kappa(2)(N,O) bound sulfonamide donor. Compounds 10-15 are all catalysts for the ring-opening polymerization (ROP) of epsilon-caprolactone, with the isopropoxide compounds being the fastest and best controlled, especially in the case of zirconium. In addition, Zr(L(OMe))(O(i)Pr) (2) (15) was an efficient catalyst for the well controlled ROP of rac-lactide both in toluene at 100 degrees C and in the melt at 130 degrees C, giving atactic poly(rac-lactide). The polymerization rates and control achieved for 13 and 15 are comparable to those of the well-established bis(phenolate)amine-supported Group 4 systems reported recently. PMID- 19780611 TI - Metal-organic framework assembled from T-shaped and octahedral nodes: a mixed linker strategy to create a rare anatase TiO2 topology. AB - A novel porphyrin paddlewheel framework (PPF-25), assembled from a zinc paddlewheel cluster and mixed linkers (4,4'-bipyridyl; zinc 5,15-di(4 carboxyphenyl)-10,20-diphenylporphyrin), has been synthesized and structurally characterized. T-shaped organometallic nodes are generated, and the resulting structure is closely related to anatase, a polymorph of TiO(2). PMID- 19780612 TI - Template-free hydrothermal synthesis and photocatalytic performances of novel Bi2SiO5 nanosheets. AB - Orthorhombic Bi(2)SiO(5) nanosheets with thicknesses of 10-20 nm were first synthesized by a template-free hydrothermal synthesis process using Bi(NO(3))(3) and different Si sources as raw materials. The as-prepared samples were characterized by X-ray diffraction, Brunauer-Emmett-Teller (BET) surface area analysis, UV-vis diffuse reflectance spectroscopy, scanning electron microscopy, high-resolution transmission electron microscopy, and a photoluminescence technique with terephthalic acid. The results showed that different precursors led to samples with different morphologies, particle sizes, and BET surface areas. As a novel photocatalyst, the photocatalytic performances of Bi(2)SiO(5) samples were evaluated by the photocatalytic degradation of salicylic acid and gaseous benzene. The results revealed that the sample obtained from Na(2)SiO(3) as a precursor exhibited higher activity than that from (C(2)H(5)O)(4)Si due to its biscuit-like morphology, a smaller particle size, and a higher BET surface areas. PMID- 19780613 TI - Mixed-ligand copper(II) maltolate complexes: synthesis, characterization, DNA binding and cleavage, and cytotoxicity. AB - The mixed-ligand complexes [Cu(L)(maltol)] where L = 2,2'-bipyridine (bpy; 1), 1,10-phenanthroline (phen; 2), 1,10-phenanthroline-5,6-dione (phendione; 3), dipyrido[3,2-a:2',3'-c]phenazine (dppz; 4), and 4b,5,7,7a-tetrahydro-4b,7a epiminomethanoimino-6H-imidazo[4,5-f][1,10]-phenanthroline-6,13-dione (bipyridylglycoluril; bpg; 5) have been synthesized and characterized by structural, analytical, and spectral methods. The single-crystal X-ray structures of 1, 2, and 5 exhibit a distorted square-pyramidal structure, with the polypyridyl ligands and maltol occupying equatorial positions and either a water or nitrate anion at the axial position. The N,N-dimethylformamide glass as well as the single-crystal electron paramagnetic resonance of the complexes confirms the distorted square-pyramidal structure. The DNA binding investigated using different techniques (absorption titration, viscosity, thermal melting, and fluorescence quenching) indicates the partial intercalation of the planar polypyridyl ligands into DNA. The complexes cleave plasmid pBR322 DNA by a hydrolytic mechanism. The kinetic aspects of DNA cleavage under pseudo-Michaelis Menten and true Michaelis-Menten conditions as well as the phosphodiesterase activity using model 4-nitrophenylphosphate are also detailed. The cytotoxicity of the complexes against HeLa (cervical) cancer cell lines shows that synergy between the metal and ligands results in a significant enhancement in the cell death with IC(50) of approximately 150-270 microg mL(-1). PMID- 19780614 TI - Investigation of the new P'3-Na0.60VO2 phase: structural and physical properties. AB - A new layered phase Na(0.60)VO(2) was synthesized by chemical deintercalation of sodium from the pristine compound O3-NaVO(2). The Na(0.60)VO(2) compound exhibits a distorted P'3-type oxygen stacking (AABBCC) with an average monoclinic unit cell containing a = 4.9862(14) A, b = 2.8708(8) A, c = 5.917(2) A, and beta = 104.36(3) degrees. A modulated structure was observed by transmission electron microscopy and X-ray diffraction (XRD) measurements. Indexation of the XRD pattern was achieved by using the q vector equal to 0.44b*, and the 4D superspace group C2/m (0 beta 0) s0 was then deduced. The specific heat measurement showed a strong correlated system with a gamma value of around 20 mJ x mol(-1) x K(-2). The electrical conductivity shows a semiconductor-like behavior with an activation energy of 0.52 eV. A paramagnetic behavior of the susceptibility is observed below room temperature with a Curie constant equal to C = 0.076 emu x K( 1) x mol(-1) x Oe(-1). To explain this small value, a model of pseudotriangular clusters of vanadium with a random distribution of V(3+) and V(4+) was considered. PMID- 19780616 TI - Investigation in the binary system Yb-Ga: crystal structure of the Ga-rich compound YbGa3.34. AB - Compounds within the Yb-Ga binary system were prepared by direct melting of the elements, and their crystal structure was solved from single crystal X-ray diffraction. YbGa(2) crystallizes in the hexagonal system, P6(3)/mmc, a = 4.4527(2), c = 7.1969(3) A, and YbGa(4) is monoclinic, C2/m, a = 6.129(2), b = 6.1096(14), c = 6.097(2) A, beta = 119.05(5) degrees . A new compound of formula YbGa(3.34) was identified in this system, and its crystal structure determined in the orthorhombic Immm space group, a = 4.2049(4), b = 4.3320(5), c = 25.691(3) A. While atoms are fully ordered in YbGa(2) and YbGa(4), partial atomic disorder occurs in YbGa(3.34) where gallium triangular units are found to substitute for some Yb atoms. The electronic structures have been calculated by first principles density functional theory methods using ordered models in supercells. Crystal structures and bonding therein are analyzed on the basis of gallium three dimensional (3D) anionic networks and are compared with similar compounds. YbGa(3.34) marks the boundary between layered and 3D intergrown gallium frameworks. PMID- 19780615 TI - Density functional theory calculations on Mossbauer parameters of nonheme iron nitrosyls. AB - Density Functional Theory (DFT) calculations on transition metal nitrosyls often reveal unusual spin density profiles, involving substantial spatial separation of majority and minority spin densities. Against this context, there is a significant lack of studies where DFT calculations have been quantitatively calibrated against experimental spectroscopic properties. Reported herein are DFT calculations of Mossbauer isomer shifts and quadrupole splittings for 21 nonheme iron complexes (26 distinct iron sites) including 9 iron nitrosyls. Low- (S = 1/2) and high-spin (S = 3/2) {FeNO}(7) complexes, S = 1/2 {Fe(NO)(2)}(9) species, and polynuclear iron nitrosyls are all represented within the set of compounds examined. The general conclusion with respect to isomer shifts is that DFT (OLYP/STO-TZP) performs comparably well for iron nitrosyls and for iron complexes in general. However, quadrupole splittings are less accurately reproduced for nitrosyl complexes. PMID- 19780618 TI - Structural and NMR characterization of Sm(III), Eu(III), and Yb(III) complexes of an amide based polydentate ligand exhibiting paramagnetic chemical exchange saturation transfer abilities. AB - Complexes of Sm(III), Eu(III), and Yb(III) with a new polydentate ether ligand with amide arms were synthesized. Solid state X-ray structures of the complexes reveal all three complexes crystallize in monoclinic unit cells. The mononuclear complexes have nine coordinate tricapped trigonal prismatic geometries with coordination of all four amide carbonyl oxygen and all three of the backbone ether oxygen atoms. The molecules possess a pseudo C(2) symmetry axis. The complexes were characterized by solution and solid state emission spectroscopy and IR spectroscopy. Solution state behavior of the complexes was further explored using NMR. The (1)H NMR spectra show 16 peaks suggesting the complexes are slow in exchanging on the NMR time scale and that the C(2) symmetry axis is maintained. The NMR spectra were assigned using (1)H, (13)C, COSY, and HMQC experiments. The Eu(III) complex was tested for the recently explored Magnetic Resonance Imaging phenomenon called paramagnetic chemical exchange saturation transfer (PARACEST). At physiological pH and temperature two CEST peaks were observed that caused a decrease in the bulk water molecule signal intensity of 10 and 16%. PMID- 19780617 TI - Identification of the minimal copper(II)-binding alpha-synuclein sequence. AB - Parkinson's disease has been long linked to environmental factors, such as transition metals and recently to alpha-synuclein, a presynaptic protein. Using tryptophan-containing peptides, we identified the minimal Cu(II)-binding sequence to be within the first four residues, MDV(F/W), anchored by the alpha-amino terminus. In addition, mutant peptide 1-10 (Lys --> Arg) verified that neither Lys6 nor Lys10 are necessary for Cu(II) binding. Interestingly, Trp4 excited state decay kinetics measured for peptides and proteins reveal two quenching modes, possibly arising from two distinct Cu(II)-polypeptide structures. PMID- 19780619 TI - Toward unidirectional rotary motion in nickelacarboranes: characterization of diastereomeric nickel bis(dicarbollide) complexes derived from the [nido-7-CH3 7,8-C2B9H11]- anion. AB - Two diastereomeric pairs of nickel bis(C-monomethyldicarbollide) complexes, derived from the racemic [nido-7-CH(3)-7,8-C(2)B(9)H(11)](-) anion, have been synthesized and characterized by NMR spectroscopy and single-crystal X-ray diffraction analysis. Neutral (dd/ll) [1(2),1'(2')-Me(2)-closo-3,1,2 Ni(IV)C(2)B(9)H(10)-{3:3'}-closo-3',1',2'-Ni(IV)C(2)B(9)H(10)] 1 and (meso) [1,2' Me(2)-closo-3,1,2-Ni(IV)C(2)B(9)H(10)-{3:3'}-closo-3',1',2'-Ni(IV)C(2)B(9)H(10)] 2 adopt typical cisoid conformations in the solid state. The temperature dependent (11)B and (1)H NMR spectra of 2 indicate that the energy barrier to the interconversion of racemic rotational isomers is 66.5 +/- 2 kJ/mol. In the solid state, the [NMe(4)](+) salts of the (dd/ll) [1(2),1'(2')-Me(2)-closo-3,1,2 Ni(III)C(2)B(9)H(10)-{3:3'}-closo-3',1',2'-Ni(III)C(2)B(9)H(10)](-) anion NMe(4) x 3 and the (meso) [1,2'-Me(2)-closo-3,1,2-Ni(III)C(2)B(9)H(10)-{3:3'}-closo 3',1',2'-Ni(III)C(2)B(9)H(10)](-) anion NMe(4) x 4 adopt gauche and transoid configurations, respectively, with transoid methyl substituents in both cases. PMID- 19780620 TI - Structural, magnetic, and Mossbauer spectral study of the electronic spin-state transition in [Fe{HC(3-Mepz)2(5-Mepz)}2](BF4)2. AB - The complex [Fe{HC(3-Mepz)(2)(5-Mepz)}(2)](BF(4))(2) (pz = pyrazolyl ring) has been prepared by the reaction of HC(3-Mepz)(2)(5-Mepz) with Fe(BF(4))(2) x 6 H(2)O. The solid state structures obtained at 294 and 150 K show a distorted iron(II) octahedral N(6) coordination environment with the largest deviations arising from the restrictions imposed by the chelate rings. At 294 K the complex is predominately high-spin with Fe-N bond distances averaging 2.14 A, distances that are somewhat shorter than expected for a purely high-spin iron(II) complex because of the presence of an admixture of about 80% high-spin and 20% low-spin iron(II). At 294 K the twisting of the pyrazolyl rings from the ideal C(3v) symmetry averages only 2.2 degrees, a much smaller twist than has been observed previously in similar complexes. At 150 K the Fe-N bond distances average 1.99 A, indicative of an almost fully low-spin iron(II) complex; the twist angle is only 1.3 degrees, as expected for a complex with these Fe-N bond distances. The magnetic properties show that the complex undergoes a gradual change from low spin iron(II) below 85 K to high-spin iron(II) at 400 K. The 4.2 to 60 K Mossbauer spectra correspond to a fully low-spin iron(II) complex but, upon further warming above 85 K, the iron(II) begins to undergo spin-state relaxation between the low- and high-spin forms on the Mossbauer time scale. At 155 and 315 K the complex exhibits spin-state relaxation rates of 0.36 and 7.38 MHz, respectively, and an Arrhenius plot of the logarithm of the relaxation rate yields an activation energy of 670 +/- 40 cm(-1) for the spin-state relaxation. PMID- 19780621 TI - Ruthenium(II) arene anticancer complexes with redox-active diamine ligands. AB - The synthesis and characterization of ruthenium(II) arene complexes of the general formula [(eta(6)-arene)Ru(XY)Z](+), where arene = p-cymene (p-cym), hexamethylbenzene (hmb), or biphenyl (bip), XY = o-phenylenediamine (o-pda), o benzoquinonediimine (o-bqdi), or 4,5-dimethyl-o-phenylenediamine (dmpda), and Z = Cl, Br, or I, are reported (complexes 1-6). In addition, the X-ray crystal structures of [(eta(6)-p-cym)Ru(o-pda)Cl]PF(6) (1) and [(eta(6)-hmb)Ru(o bqdi)Cl]PF(6) (3PF(6)) are described. The Ru-N distances in 3PF(6) are significantly shorter [2.033(4) and 2.025(4) A] compared to those in 1 [2.141(2) and 2.156(2) A]. All of the imine complexes (3-5) exhibit a characteristic broad (1)H NMR NH resonance at ca. delta 14-15. Complex 1 undergoes concomitant ligand based oxidation and hydrolysis (38% after 24 h) in water. The oxidation also occurs in methanol. The iodido complex [(eta(6)-p-cym)Ru(o-bqdi)I]I (4) did not undergo hydrolysis, whereas the chlorido complex 3 showed relatively fast hydrolysis (t(1/2) = 7.5 min). Density functional theory calculations showed that the total bonding energy of 9-EtG in [(eta(6)-p-cym)Ru(o-pda)(9-EtG-N7)](2+) (1EtG) is 23.8 kJ/mol lower than that in [(eta(6)-p-cym)Ru(o-bqdi)(9-EtG-N7)](2+) (3EtG). The greater bonding energy is related to the contribution from strong hydrogen bonding between the NH proton of the chelating ligand and O6 of 9-EtG (1.69 A). A loss of cytotoxic activity was observed upon oxidation of the amine ligand to an imine (e.g., IC(50) = 11 microM for 1 and IC(50) > 100 microM for 3, against A2780 ovarian cancer cells). The relationship between the cytotoxic activity and the solution and solid state structures of the imine and amine complexes is discussed. PMID- 19780622 TI - Bioreduction of U(VI)-phthalate to a polymeric U(IV)-phthalate colloid. AB - Phthalic acid, a ubiquitous organic ligand, formed soluble mono- and biligand complexes with a uranyl ion that was then reduced to a U(IV)-phthalate by a Clostridium species under anaerobic conditions. We confirmed the reduction of the hexavalent uranium to the tetravalent oxidation state by UV-vis absorption and X ray absorption near edge structure spectroscopy. Sequential micro- and ultrafiltration of the solution revealed that the bioreduced uranium was present as a colloid with particles between 0.03 and 0.45 microm. Analysis with extended X-ray absorption fine structure revealed the association of the reduced uranium with the phthalic acid as a repeating biligand 1:2 U(IV):phthalic acid polymer. This is the first report of the formation of a U(IV) complexed to two phthalic acid molecules in the form of a polymeric colloid. Although it was proposed that the bioreduction and the precipitation of uranium might be an invaluable strategy to immobilize uranium in contaminated environments, our results suggest that the organic ligands present there might hinder the precipitation of the bioreduced uranium under anaerobic conditions and, thereby, enhance its environmental mobility as uranium organic complexes or colloids. PMID- 19780623 TI - Synthesis, synchrotron X-ray diffraction, and kinetic studies on the formation of a novel thiolatocobalamin of captopril: evidence for cis-trans isomerization in the beta-axial ligand. AB - The orally administered therapeutic captopril is widely used for treating hypertension, congestive heart failure, and cardiovascular disease. However, a number of undesirable side effects are associated with high doses of captopril. By coordinating a therapeutic to the upper (= beta) axial site of the naturally occurring macrocycle cobalamin (vitamin B(12)), the absorption and cellular uptake of the therapeutic can be significantly enhanced. We report the synthesis of captopril-cobalamin, a derivative of vitamin B(12) in which captopril is bound via its thiol group at the beta-axial site of cobalamin. Characterization of captopril-cobalamin by (1)H NMR spectroscopy and X-ray diffraction shows that captopril-cobalamin exists in both solution and the solid state as a mixture of geometric isomers. Kinetic studies on the formation of captopril-cobalamin have been carried out, and the data fits a model in which the thiol form (RSH, k(1) = 40.9 +/- 1.2 M(-1) s(-1)) and the thiolate form of captopril (RS(-), k(2) = 660 +/- 170 M(-1) s(-1)) react rapidly with aquacobalamin. PMID- 19780624 TI - Di- and tri-zinc catalysts for the low-pressure copolymerization of CO2 and cyclohexene oxide. AB - The syntheses and characterization of three new macrocyclic proligands, with variation of the para aryl ring substituent, are reported. Dizinc and trizinc acetate complexes are prepared using these ligands and are characterized using infrared and nuclear magnetic resonance spectroscopies, mass spectrometry, elemental analysis, and, for the three trizinc complexes, single-crystal X-ray diffraction. The X-ray crystallographic and spectroscopic data indicate bridging and terminal acetate coordination modes, both in the solid state and in solution, for the trizinc complexes. All of the complexes show good turnover numbers and frequencies, under 1 atm of pressure of carbon dioxide, for the copolymerization of CO(2) and cyclohexene oxide to produce poly(cyclohexene carbonate). The electronic nature of the ancillary ligands' substituents influences the catalytic activity of the complex, with the electron-donating substituent reducing the activity. The dizinc catalysts show markedly higher activities than the trizinc analogues, suggesting that the coordination environment within the macrocycle is crucial to controlling the catalytic activity. PMID- 19780625 TI - Tetrazole-5-carboxylic acid based salts of earth alkali and transition metal cations. AB - The tetrazole-5-carboxylate anion was investigated as ligand for earth alkali metal and transition metal complexes. Therefore, the strontium 4a (*3 H(2)O, *2.75 H(2)O, *2.5 H(2)O), barium 4b (*3 H(2)O), copper 4c (*3.5 H(2)O, *4 H(2)O), manganese 4d (*4 H(2)O, *5 H(2)O), and silver tetrazol-5-carboxylate 4e (*1.56 H(2)O) were synthesized and characterized by vibrational spectroscopy (IR), and the crystal structures of 4a (*2.75 H(2)O, *2.5 H(2)O), 4b*3 H(2)O, 4c*4 H(2)O, and 4d*5 H(2)O were determined using single crystal X-ray diffraction. The thermal stability was investigated by DSC-measurements, and the sensitivity toward impact and friction was determined by BAM-standards. The copper, strontium, and barium tetrazole-5-carboxyate proved to be suitable thermal and physical stable colorants for pyrotechnic compositions. The crystal structure of the tetragonal modification of strontium tetrazole-5-carboxyate possesses channels along the c-axis, leading to a porous material. PMID- 19780626 TI - A modified KESTREL search reveals a basophilic substrate consensus for the Saccharomyces cerevisiae Npr1 protein kinase. AB - The Saccharomyces cerevisiae nitrogen permease reactivator Npr1 is a hyperphosphorylated protein that belongs to a family of Ser/Thr protein kinases dedicated to the regulation of plasma membrane transporters. Its activity is regulated by the Tor (target of rapamycin) signaling pathway. Inhibition of the Tor proteins by treating yeast cells with the immunosuppressant drug rapamycin promotes rapid dephosphorylation of Npr1. As an alternative to peptide arrays, the substrate requirement of Npr1 was probed with a peptide library that was generated by cleaving yeast cell extracts with CNBr, and after reverse-phase chromatography, the individual fractions were phosphorylated in vitro with recombinant Npr1. In this way, the ribosomal protein Rpl24a was found to be an excellent in vitro substrate for Npr1. Synthetic peptides tailored around the phosphorylation site of Rpl24a show that Npr1 is a Ser/Thr protein kinase with an absolute requirement for a basic residue at the P-3 position and a strong preference for basic P + 1 residues, whereas proline at P + 1 is strongly disfavored. The results obtained with synthetic peptides suggest a (K/R)-X-X-S (K/R) consensus sequence for Npr1. The availability of a consensus sequence allows a targeted search for physiologically relevant Npr1 substrates involved in the regulation of yeast amino acid permeases. PMID- 19780627 TI - Simultaneous isolation of DNA, RNA, and proteins for genetic, epigenetic, transcriptomic, and proteomic analysis. AB - Analysis of DNA, RNA, and proteins for downstream genetic, epigenetic, transcriptomic, and proteomic analysis holds an important place in the field of medical care and life science. This is often hampered by the limited availability of sample material. For this reason, there exists an increasing interest for simultaneous isolation of DNA, RNA and proteins from a single sample aliquot. Several kit-systems allowing such a procedure have been introduced to the market. We present an approach using the AllPrep method for simultaneous isolation of DNA, RNA and proteins from several human specimens, such as whole blood, buffy coat, serum, plasma and tissue samples. The quantification and qualification of the isolated molecular species were assessed by different downstream methods: NanoDrop for measuring concentration and purity of all molecular species; DNA and RNA LabChip for fractionation analysis of nucleic acids; quantitative PCR for quantification analysis of DNA and RNA; thymidine-specific cleavage mass array on MALDI-TOF silico-chip for epigenetic analysis; Protein LabChip and two dimensional (2D) gel electrophoresis for proteomic analysis. With our modified method, we can simultaneously isolate DNA, RNA and/or proteins from one single sample aliquot. We could overcome to some method limitations like low quality or DNA fragmentation using reamplification strategy for performing high-throughput downstream assays. Fast and easy performance of the procedure makes this method interesting for all fields of downstream analysis, especially when using limited sample resources. The cost-effectiveness of the procedure when material is abundantly available has not been addressed. This methodological improvement enables to execute such experiments that were not performable with standard procedure, and ensures reproducible outcome. PMID- 19780628 TI - Presidential address: Parasites on a shrinking planet. PMID- 19780630 TI - Photodynamic therapy in planktonic and biofilm cultures of Aggregatibacter actinomycetemcomitans. AB - OBJECTIVE: To evaluate the inactivation of Aggregatibacter actinomycetemcomitans (A. actinomycetemcomitans), responsible for causing aggressive periodontitis, using photodynamic therapy (PDT) by rose bengal (RB) as a model of a reactive oxygen species (ROS) generator, in planktonic and biofilm cultures. MATERIALS AND METHODS: A. actinomycetemcomitans was grown in planktonic and biofilm cultures using tryptic soy broth medium. The sensibility (dark toxicity) to RB was determined, and its ideal concentration for PDT was established. Concentrations in the range from 0.01 to 50.0 micromol L(-1) RB, with different light potencies and incubation times, were used. An odontological resin photopolymerizer that emits the adequate wavelength for absorption of the RB dye was applied. Bacterial viability was determined by colony- forming units (CFU). RESULTS: RB photosensitizer dye in concentrations up to 0.1 micromol L(-1) did not show toxicity per se toward A. actinomycetemcomitans cells. In a PDT study with photoirradiation (1 min) at 0.1 micromol L(-1), a 55% reduction of A. actinomycetemcomitans viability was obtained in planktonic cultures. Preincubation (30 min) of the bacteria with the dye resulted in a 90% reduction of its viability. It is important to note that, for dye concentrations up to 1 micromol L(-1), in the same experimental conditions, no death effect on gingival fibroblasts was observed. The A. actinomycetemcomitans biofilm was not affected by RB or light alone. After PDT, the reduction in the biofilm (about 45%) is significantly dependant on RB concentration and irradiation time when this dye was used as a ROS generator. CONCLUSION: Photodynamic therapy-generated ROS inactivates A. actinomycetemcomitans both in planktonic and biofilm cultures, even in small concentrations of the photosensitizing agent, and it does not cause damage to fibroblast cells under the same conditions. PMID- 19780631 TI - Root surface biomodification with an Er:YAG laser for the treatment of gingival recession with subepithelial connective tissue grafts. AB - BACKGROUND/AIM: Root surface biomodification has been used to treat gingival recession and periodontitis. The principle for this procedure is that removing the smear layer from the root surfaces exposes collagen fibers, which leads to improved healing. Clinical studies generally have failed to find any improvement in clinical parameters when using such agents. The aim of this study was to evaluate and compare the outcome of gingival recession therapy using the subepithelial connective tissue graft (SCTG) with or without Er:YAG laser application for root surface biomodification. MATERIALS AND METHODS: Twenty-four teeth in 12 patients with Miller class I and II recession were treated with SCTG with (test group) or without (control group) the application of an Er:YAG laser (2 Hz, 60 mJ/pulse, 40 s, with air spray). Clinical attachment level (CAL), recession depth (RD), recession width (RW), and probing depth (PD) were measured at baseline and 6 months postsurgery. RESULTS: There were no significant differences between test and control groups (p > 0.05). Postoperatively, significant root coverage, gains in CAL, and highly significant increases in the RW were observed in both groups. For test and control groups, the average root coverage was 80% and 86%, respectively (p > 0.05), and complete root coverage was 75% and 67%, respectively. CONCLUSIONS: The present study showed that root surface conditioning with an Er:YAG laser does not enhance the results achieved when SCTG was performed alone. PMID- 19780632 TI - Influence of aluminum oxide sandblasting associated with Nd:YAG or Er:YAG lasers on shear bond strength of a feldspathic ceramic to resin cements. AB - OBJECTIVE: This in vitro study evaluated the influence of the surface pretreatment of a feldspathic ceramic on the shear bond strength of two different resin cements. BACKGROUND DATA: Although several conventional surface treatments have been used on feldspathic ceramic, few studies have investigated the effects of an alternative surface treatment, the association of aluminum oxide sandblasting with Nd:YAG and Er: YAG lasers. METHODS: Sixty samples made of a feldspathic ceramic were divided into three groups (n = 20) and treated with (1) controlled-air abrasion with Al(2)O(3) + 10% hydrofluoric acid (HF), (2) Al(2)O(3) + Er:YAG laser, and (3) Al(2)O(3) +Nd:YAG laser. Afterward, silane (Dentsply) was applied on each treated surface. Each of the three main groups was divided into two subgroups (n = 10), where a different resin cement was employed for each subgroup. It was built a cylinder with resin cement (RelyX Arc) in subgroup (A) and with self-adhesive cement (RelyX U100) in subgroup (B). After 24 h at 37 degrees C, the prepared specimens were submitted to shear bond strength test and stereoscopic evaluation to determine the type of failure. RESULTS: Bond strength mean values were not statistically significant for the surface treatment methods or resin cements. CONCLUSION: The null surface treatment proposed with aluminum oxide sandblasting associated with the Er:YAG or Nd:YAG laser and using cementation with self-adhesive cement can be an alternative bonding technique for feldspathic ceramic, since it was as effective as the conventional treatment with aluminum oxide sandblasting and hydrofluoric acid using the conventional resin cement. PMID- 19780633 TI - Anti-inflammatory effect of low-level laser and light-emitting diode in zymosan induced arthritis. AB - OBJECTIVE: The aim of this work was to investigate the effect of low-level laser therapy (LLLT) and light-emitting diode (LED) on formation of edema, increase in vascular permeability, and articular joint hyperalgesia in zymosan-induced arthritis. BACKGROUND DATA: It has been suggested that low-level laser and LED irradiation can modulate inflammatory processes. MATERIAL AND METHODS: Arthritis was induced in male Wistar rats (250-280 g) by intra-articular injection of zymosan (1 mg in 50 microL of a sterile saline solution) into one rear knee joint. Animals were irradiated immediately, 1 h, and 2 h after zymosan administration with a semiconductor laser (685 nm and 830 nm) and an LED at 628 nm, with the same dose (2.5 J/cm(2)) for laser and LED. In the positive control group, animals were injected with the anti-inflammatory drug dexamethasone 1 h prior to the zymosan administration. Edema was measured by the wet/dry weight difference of the articular tissue, the increase in vascular permeability was assessed by the extravasation of Evans blue dye, and joint hyperalgesia was measured using the rat knee-joint articular incapacitation test. RESULTS: Irradiation with 685 nm and 830 nm laser wavelengths significantly inhibited edema formation, vascular permeability, and hyperalgesia. Laser irradiation, averaged over the two wavelengths, reduced the vascular permeability by 24%, edema formation by 23%, and articular incapacitation by 59%. Treatment with LED (628 nm), with the same fluence as the laser, had no effect in zymosan-induced arthritis. CONCLUSION: LLLT reduces inflammatory signs more effectively than LED irradiation with similar irradiation times (100 sec), average outputs (20 mW), and energy doses (2 J) in an animal model of zymosan-induced arthritis. The anti inflammatory effects of LLLT appear to be a class effect, which is not wavelength specific in the red and infrared parts of the optical spectrum. PMID- 19780635 TI - Preparation of liposomes containing zedoary turmeric oil using freeze-drying of liposomes via TBA/water cosolvent systems and evaluation of the bioavailability of the oil. AB - The purpose of this study was to enhance the absorption of zedoary turmeric oil (ZTO) in vivo and develop new formulations of a water-insoluble oily drug. This study described a method for preparing ZTO liposomes, which involved freeze drying (FD) of liposomes with TBA/water cosolvent systems. The TBA/water cosolvent systems were used to investigate a feasible method of liposomes manufacture; the two factors, sugar/lipid mass ratio and TBA content (concentration), of the preparation process were evaluated in this study. The results showed that the addition of TBA content could significantly enhance the sublimation of ice resulting in short FD cycles time, and reduce the entrapment efficiency of liposomes. In addition, the residual TBA solvents levels were determined to be less than 0.37% under all optimum formulations and processing conditions. Several physical properties of liposomes were examined by H-600 transmission electron microscope (TEM) and zetamaster analyser system. The results revealed that the liposomes were smooth and spherical with an average particle size of 457 +/- 7.8 nm and the zeta potential was more than 3.65 Mv. The bioavailability of the liposomes was evaluated in rabbits, compared with the conventional self-emulsifying formulation for oral administration. Compared with the conventional self-emulsifying formulation, the plasma concentration-time profiles with improved sustained-release characteristics were achieved after oral administration of the liposomes with a bioavailability of 257.7% (a good strategy for improving the bioavailability of an oily drug). In conclusion, the present experimental findings clearly demonstrated the usefulness of ZTO liposome vesicles in improving therapeutic efficacy by enhancing oral bioavailability. Our study offered an alternative method for designing sustained-release preparations of oily drugs. PMID- 19780637 TI - A semi-quantitative approach to compare high-sensitivity power Doppler sonography and conventional power Doppler sonography in the assessment of thyroid vascularity. AB - BACKGROUND: Ultrasound is a useful imaging tool in the assessment of thyroid glands, and Doppler ultrasound helps in the evaluation of thyroid vascularity. This study was undertaken to evaluate the difference in the thyroid vascularity demonstrated on the state-of-the-art high-sensitivity power Doppler sonography (HSPDS) and the conventional power Doppler sonography (PDS), and to investigate the feasibility of using a customized algorithm with image-processing software for semi-quantitative assessment of thyroid vascularity. METHODS: A total of 25 healthy volunteers were included in the study, and each subject had two thyroid ultrasound examinations with HSPDS and PDS, respectively. High sensitivity and conventional power Doppler sonograms of the thyroid glands were taken and recorded. To evaluate the vascularity of thyroid lobes quantitatively, a customized algorithm using the software Matlab was developed and used to analyze the ultrasound images. The vascularity of thyroid lobe (i.e., region of interest, ROI) was expressed as the vascular index (VI), which is the ratio of the number of color pixels to the total number of pixels within the ROI. RESULTS: Results showed that thyroid vascularity was detected in all thyroid lobes on both HSPDS and PDS. The mean VI of the thyroid lobes on HSPDS (right lobe, 0.31 +/- 0.08; left lobe, 0.32 +/- 0.07) was significantly higher than on PDS (right lobe, 0.18 +/- 0.09; left lobe, 0.16 +/- 0.08) (p < 0.05). There was no significant difference in the VI between the right and left thyroid lobes (p >0.05). On HSPDS, 96% of the thyroid lobes showed a VI <0.5, while 96% of thyroid lobes had a VI <0.3 on PDS. CONCLUSIONS: HSPDS is more sensitive than PDS in the detection of thyroid vascularity. The developed algorithm can quantify the color pixels on power Doppler sonograms, which is useful for objective assessment of thyroid vascularity. PMID- 19780640 TI - Structural biology of MCM helicases. AB - The eukaryotic MCM2-7 complex is recruited onto origins of replication during the G1 phase of the cell cycle and acts as the main helicase at the replication fork during the S phase. Over the last few years a number of structural reports on MCM proteins using both electron microscopy and protein crystallography have been published. The crystal structures of two (almost) full-length archaeal homologs provide the first atomic pictures of a MCM helicase. However one of the structures is at low resolution and the other is of an inactive MCM. Moreover, both proteins are monomeric in the crystal, whereas the activity of the complex is critically dependent on oligomerization. Lower resolution structures derived from electron microscopy studies are therefore crucial to complement the crystallographic analysis and to assemble the multimeric complex that is active in the cell. A critical analysis of all the structural results elucidates the potential conformational changes and dynamic behavior of MCM helicase to provide a first insight into the gamut of molecular configurations adopted during the processes of DNA melting and unwinding. PMID- 19780638 TI - The ins and outs of phospholipid asymmetry in the plasma membrane: roles in health and disease. AB - A common feature of all eukaryotic membranes is the non-random distribution of different lipid species in the lipid bilayer (lipid asymmetry). Lipid asymmetry provides the two sides of the plasma membrane with different biophysical properties and influences numerous cellular functions. Alteration of lipid asymmetry plays a prominent role during cell fusion, activation of the coagulation cascade, and recognition and removal of apoptotic cell corpses by macrophages (programmed cell clearance). Here we discuss the origin and maintenance of phospholipid asymmetry, based on recent studies in mammalian systems as well as in Caenhorhabditis elegans and other model organisms, along with emerging evidence for a conserved role of mitochondria in the loss of lipid asymmetry during apoptosis. The functional significance of lipid asymmetry and its disruption during health and disease is also discussed. PMID- 19780641 TI - Temporal regulation of DNA replication in mammalian cells. AB - Eukaryotic cells follow a temporal program to duplicate their genomes. Chromosomes are divided into domains with a specific DNA replication timing (RT), not dictated by DNA sequence alone, which is conserved from one cell cycle to the next. Timing of replication correlates with gene density, transcriptional activity, chromatin structure and nuclear position, making it an intriguing epigenetic mark. The differentiation from embryonic stem cells to specialized cell types is accompanied by global changes in the RT program. This review covers our current understanding of the mechanisms that determine RT in mammalian cells, its possible biological significance and how unscheduled alterations of the RT program may predispose to human disease. PMID- 19780642 TI - Correlation of protein-protein interactions as assessed by affinity chromatography with colloidal protein stability: a case study with lysozyme. AB - Lysozyme-lysozyme interactions were assessed in the native state at 25 degrees C as well in the denatured state at 80 degrees C by affinity chromatography in order to measure the osmotic second virial coefficient (B). This parameter allows us to better understand protein aggregation pathways and colloidal protein stability. Repulsive interactions (B > 0) were weakened for both protein states by increasing salt concentration and by increasing the pH value toward lysozyme pI. This decrease was more pronounced in the denatured state, most likely caused by changes in electrostatic interactions and the formation of hydrophobic clusters. The lysozyme formulations presenting the more repulsive conditions (B > 0), as derived from the osmotic second virial coefficient, showed better colloidal stability under mechanical and thermal stresses. As expected, B values are much more negative for the interactions in the denatured state compared to the data obtained for the native state, reflecting a strong tendency of denatured lysozyme to aggregate. Thus, measurement of protein interactions by affinity chromatography allows us to gain information on protein interactions in both native and denatured states as well as to predict solution conditions prone for improving protein colloidal stability. PMID- 19780643 TI - A systems biology approach to understanding elevated serum alanine transaminase levels in a clinical trial with ximelagatran. AB - Ximelagatran was developed for the prevention and treatment of thromboembolic conditions. However, in long-term clinical trials with ximelagatran, the liver injury marker, alanine aminotransferase (ALT) increased in some patients. Analysis of plasma samples from 134 patients was carried out using proteomic and metabolomic platforms, with the aim of finding predictive biomarkers to explain the ALT elevation. Analytes that were changed after ximelagatran treatment included 3-hydroxybutyrate, pyruvic acid, CSF1R, Gc-globulin, L-glutamine, protein S and alanine, etc. Two of these analytes (pyruvic acid and CSF1R) were studied further in human cell cultures in vitro with ximelagatran. A systems biology approach applied in this study proved to be successful in generating new hypotheses for an unknown mechanism of toxicity. PMID- 19780639 TI - Membrane-bending proteins. AB - Cellular membranes can assume a number of highly dynamic shapes. Many cellular processes also require transient membrane deformations. Membrane shape is determined by the complex interactions of proteins and lipids. A number of families of proteins that directly bend membranes have been identified. Most associate transiently with membranes and deform them. These proteins work by one or more of three types of mechanisms. First, some bend membranes by inserting amphipathic domains into one of the leaflets of the bilayer; increasing the area of only one leaflet causes the membrane to bend. Second, some proteins form a rigid scaffold that deforms the underlying membrane or stabilizes an already bent membrane. Third, some proteins may deform membranes by clustering lipids or by affecting lipid ordering in membranes. Still other proteins may use novel but poorly understood mechanisms. In this review, we summarize what is known about how different families of proteins bend membranes. PMID- 19780644 TI - Outcomes following single-treatment Gamma Knife surgery for trigeminal neuralgia with a minimum 3-year follow-up. AB - OBJECT: Gamma Knife surgery (GKS) has been shown to be effective in treating trigeminal neuralgia (TN). Existing studies have demonstrated success rates of 69.1-85% with median follow-up intervals of 19-60 months. However, series with uniform long-term follow-up data for all patients have been lacking. In the present study the authors examined outcomes in a series of patients with TN who underwent a single GKS treatment followed by a minimum follow-up of 36 months. They used a clinical scale that simplifies the reporting of outcome data for patients with TN. METHODS: Fifty-three consecutive patients with typical, intractable TN received a median maximum radiation dose of 80 Gy applied with a single 4-mm isocenter to the affected trigeminal nerve. Follow-up data were obtained by clinical examination and questionnaire. Outcome results were categorized into the following classes (in order of decreasing success): Class 1A, complete pain relief without medications; 1B, complete pain relief with either a decrease or no change in medications; 1C, > or = 50% pain relief without medications; 1D, > or = 50% pain relief with either a decrease or no change in medications; and Class 2, < 50% pain relief and/or increase in medications. Patients with Class 1A-1D outcome (equivalent to Barrow Neurological Institute Grades I-IIIb) were considered to have a good treatment outcome, whereas in patients with Class 2 outcome (equivalent to Barrow Neurological Institute Grades IV and V) treatment was considered to have failed. RESULTS: A good treatment outcome from initial GKS was achieved in 31 (58.5%) patients for whom the mean follow-up period was 48 months (range 36-66 months). Outcomes at last follow-up were reflected by class status: Class 1A, 32.1% of patients; 1B, 1.9%; 1C, 3.8%; 1D, 20.8%; and Class 2, 41.5%. Statistical analysis showed no difference in outcomes between patients previously treated with microvascular decompression or rhizotomy compared with patients with no previous surgical treatments. Thirty-six percent of patients reported some degree of posttreatment facial numbness. Anesthesia dolorosa did not develop in any patient. CONCLUSIONS: Despite a time dependent deterioration in the success rate of GKS for medically intractable TN, the authors' study showed that > 50% of patients can be expected to have a good outcome based on their scoring system, with approximately 33% having an ideal outcome (pain free with no need for medications). Long-term data, as those presented here, are important when counseling patients on their treatment options. PMID- 19780645 TI - Novel technique to improve vessel mismatch when using saphenous vein bypass grafts for intracranial revascularization procedures. AB - Cerebral bypass procedures in the posterior circulation are difficult to perform and are considered to be high-risk surgery. Venous grafts, like that formed using the saphenous vein (SV), are simple to obtain without posing a high risk of morbidity. The main disadvantage of these high-flow grafts is the mismatch in vessel diameter between donor and recipient vessels in the posterior circulation. The authors performed a retrospective case study based of data from intraoperative video, patient charts, axial images, and cerebral angiograms. They treated a 66-year-old man who presented with a giant aneurysm of the vertebrobasilar junction and another large aneurysm of the basilar tip. They chose to create a vertebral artery (VA)-superior cerebellar artery anastomosis with a tapered-down SV graft. It was necessary to reengineer the SV graft to include a gentle taper that would allow for this anastomosis. The vein was incised for a distance of 2.5 cm. A triangular section of the vein, 2 mm at the base and 20 mm high, was then excised from the opened end of the SV. The 2.5-cm long venotomy was then closed with interrupted 9-0 Prolene sutures creating a gentle taper to the vein down to ~ 2.5 mm in diameter. Thereafter, the authors created a standard end-to-side anastomosis of the VA to the SV with 8-0 Prolene. Postoperatively both VAs were obliterated with coils just proximal to the vertebrobasilar aneurysm. The bypass was patent; after a prolonged stay in the intensive care unit, the patient recovered gradually. This technique of linear venotomy along the distal 2.5 cm of the vein and subsequent tapering down of the diameter diminishes the circumference of the distal end of the graft, facilitating bypass to smaller vessels. This is a novel and feasible technique to eliminate vessel mismatch in cerebral bypass procedures in the difficult accessible vessels of the posterior circulation. PMID- 19780646 TI - Long-term outcome following ilioinguinal neurectomy for chronic pain. AB - OBJECT: Ilioinguinal neuralgia is one cause of chronic groin pain following inguinal hernia repair, and it affects approximately 10% of patients. Selective ilioinguinal neurectomy is one proposed treatment option for carefully selected patients. The goal of this study was to determine the long-term outcome of patients who underwent selective ilioinguinal neurectomy for chronic post-hernia pain. METHODS: The authors retrospectively reviewed the clinical assessment, surgical treatment, and long-term outcome in 26 patients with ilioinguinal neuralgia who underwent selective ilioinguinal neurectomy performed by the senior author (K.J.B.) at Oregon Health & Science University between 1998 and 2008. Data were collected from patient charts and a follow-up telephone questionnaire. RESULTS: Twenty-six patients (14 men and 12 women) had a clinical diagnosis of ilioinguinal neuralgia based on a history of radiating neuropathic groin, medial thigh, and genitalia pain. One patient had bilateral disease (therefore there were 27 surgical cases). A selective nerve block was performed in 21 (81%) of 26 patients and was positive in 20 (77%) of the 26. In all but 2 patients, pain onset followed abdominal surgery (for hernia repair in 18 patients), and was immediate in 16 (67%) of 24 patients. The mean patient age was 48.7 years, and the mean duration of pain prior to neurosurgical consultation was 3.9 years. Surgery was performed after induction of local or general anesthesia in 17 and 10 cases, respectively. The ilioinguinal nerve was identified in 25 cases, and the genitofemoral nerve in 2, either entrapped in mesh, scar, or with obvious neuroma (22 of 27 cases). The identified nerve was doubly ligated, cut, and buried in muscle at its most proximal point. At the 2-week follow-up evaluations, 14 (74%) of 19 patients noted definite pain improvement. Nineteen (73%) of the 26 patients were contacted by telephone and agreed to participate in completing long-term follow-up questionnaires. The mean follow-up duration was 34.78 months. Return of pain was reported by 13 (68%) of 19 patients. Using a verbal numerical rating scale (0-10), pain was completely relieved in 27.8%, better in 38.9%, no better in 16.7%, and worse in 16.7% of patients. CONCLUSIONS: Ilioinguinal neurectomy is an effective and appropriate treatment for selected patients with iatrogenic ilioinguinal neuralgia following abdominal surgery. Although a high proportion of patients reported some long-term recurrence of pain, complete or partial pain relief was achieved in 66.7% of the patients observed. PMID- 19780647 TI - The genetics of sporadic ruptured and unruptured intracranial aneurysms: a genetic meta-analysis of 8 genes and 13 polymorphisms in approximately 20,000 individuals. AB - OBJECT: Intracranial aneurysms (IAs) are thought to have a multifactorial origin. The authors undertook a comprehensive meta-analysis on all genes investigated using a case-control model in ruptured (subarachnoid hemorrhage) and unruptured aneurysms. METHODS: Electronic databases were searched until and including July 2008 for any candidate gene studied in IA or subarachnoid hemorrhage using a case control model. The ORs and 95% CIs were determined for each gene-disease association using fixed and random effect models. RESULTS: Thirty studies of 8 genes and 13 polymorphisms were analyzed among 19,961 individuals (6622 cases and 13,339 controls). Two genes and 3 polymorphisms were associated with IA. The eNOS gene T786C polymorphism (OR 1.24, 95% CI 1.0-1.54; p = 0.05) and IL-6 gene G572C polymorphism (OR 7.08, 95% CI 2.85-17.57; p < 0.0001) both showed a significant association with ruptured/unruptured IA. The IL-6/G174C polymorphism exerted a significant protective effect against IA (OR 0.49, 95% CI 0.25-0.95; p = 0.04). The other candidate genes investigated (ACE, endoglin, APOE, elastin, MMP-3, and SERPINA3) showed no significant associations. CONCLUSIONS: There is a likely genetic basis to sporadic IAs. However, the evidence base is small when compared against other complex disorders. PMID- 19780648 TI - Jean Baptiste Paulin Trolard (1842-1910): his life and contributions to neuroanatomy. AB - One hundred years after his death, Jean Baptiste Paulin Trolard's name endures in the medical literature primarily because of his work on the anastomotic veins of the cerebral circulation. Specifically, and known to all neurosurgeons, the great anastomotic vein, or the vein of Trolard, underscores a portion of Trolard's contribution to neuroanatomy. The country of Algeria has also remembered this influential colonist because of his life's work as a physician, professor, humanitarian, environmentalist, and French nationalist. Trolard fought deforestation, injustice, epidemics, and bureaucracy in northern Africa and tragically died in the midst of these struggles. In this historical vignette, the authors review the life and contributions of this pioneer of early neuroanatomy. PMID- 19780649 TI - Acellular cardiac extracellular matrix as a scaffold for tissue engineering: in vitro cell support, remodeling, and biocompatibility. AB - We have developed an efficient decellularization process for the isolation of extracellular matrix (ECM) from native cardiac tissue. The isolated ECM exhibited desirable mechanical properties in terms of elasticity, strength and durability properties required from scaffolds used for cardiac tissue repair. This study further investigates the potential use of this scaffold for cardiac tissue engineering in terms of interactions with seeded cells and biocompatibility. We used the commonly studied fibroblasts, cardiomyocytes, and mesenchymal stem cells, which were isolated and seeded onto the scaffold. Cell density and distribution were followed by 3,3'-dioctadecyloxacarbocyanine perchlorate staining, and their proliferation and viability were assessed by AlamarBlue assay and fluorecein-diacetate/propidium iodide staining. Fibroblast-seeded scaffolds shrank to 1-2 mm(3) spheroids, and their glycosaminoglycans significantly increased by 23%. The expression of ECM remodeling-related mRNAs of collagens I and III, matrix metalloproteinase 2, and type 1 tissue inhibitor of metalloproteinases was quantified by real-time polymerase chain reaction, and was found significantly elevated in fibroblast-seeded scaffold, compared with the control cells on plates. Fibroblast-seeded scaffolds lost some flexibility, yet gained strength compared with the acellular scaffolds, as shown by mechanical testing. Scaffold seeded with cardiomyocyte began to beat in concert few days after seeding, and the myocytes expressed typical functional cardiac markers such as alpha-actinin, troponin I, and connexin43. The cells revealed aligned elongated morphology, as presented by immunofluorescent staining and scanning electron microscopy. Mesenchymal stem cell-seeded scaffolds maintained viability over 24 days in culture. These findings further strengthen the potential use of acellular cardiac ECM as a biomaterial for heart regeneration. PMID- 19780650 TI - Mechanisms influencing the timing and success of reproductive migration in a capital breeding semelparous fish species, the sockeye salmon. AB - Two populations of homing sockeye salmon (Oncorhynchus nerka; Adams and Chilko) were intercepted in the marine approaches around the northern and southern ends of Vancouver Island (British Columbia, Canada) en route to a natal river. More than 500 salmon were nonlethally biopsied for blood plasma, gill filament tips, and gross somatic energy (GSE) and were released with either acoustic or radio transmitters. At the time of capture, GSE, body length, and circulating testosterone ([T]) differed between populations, differences that reflected known life-history variations. Within-population analyses showed that in Adams sockeye salmon, plasma glucose ([glu]), lactate ([lactate]), and ion concentrations were higher in the northern approach than in the southern approach, suggesting that the former was more stressful. GSE, [T], and gill Na(+),K(+)-ATPase activities also differed between the two locales, and each varied significantly with Julian date, suggesting seasonality. Despite these relative geographic differences, the timing of river entry and the ability to reach spawning areas were strongly correlated with energetic, reproductive, and osmoregulatory state. Salmon that delayed river entry and reached spawning areas had relatively high GSE and low [T] and gill ATPase. In contrast, salmon that entered the river directly but that ultimately failed to reach spawning areas had lower GSE and higher [T] and gill ATPase, and they also swam at significantly faster rates (failed fish approximately 20.0 km d(-1) vs. successful fish approximately 15.5 km d(-1)). Physiologically, salmon that did not enter the river at all but that presumably died in the marine environment exhibited high stress (plasma [glu] and [lactate]) and ionoregulatory measures (plasma [Na(+)], [Cl(-)], osmolality). PMID- 19780651 TI - Maternal effects mediated by antioxidants and the evolution of carotenoid-based signals in birds. AB - Bright yellow to red signals used in mate choice or intrasexual competition are based on carotenoid pigments that are hypothesized to be traded between physiological functions and coloration. These signals have recently been shown to be influenced by maternal effects. Indeed, yolk-derived carotenoids are essential for embryos to develop efficient carotenoid metabolism in posthatching life. Maternal effects facilitate adaptation to environmental variability and influence the evolution of phenotypic traits such as secondary sexual signals. Here we propose that maternal investment in yolk carotenoids promotes the evolution of carotenoid-based ornaments. We conducted a comparative analysis of lipid-soluble antioxidants (carotenoids and vitamins A and E) in the eggs of 112 species of bird. Species with large clutch sizes deposited higher yolk concentrations of the three antioxidants. There was a significant positive relationship between yolk carotenoids and the expression of male carotenoid-based signals, but not between yolk carotenoids and sexual dichromatism in these signals. These relationships were specific to carotenoids, as they were not found for vitamins A and E. This provides evidence consistent with the hypothesis that maternal effects mediated by yolk carotenoids play a role in the evolution of carotenoid-based signals as a response to sexual selection, likely based on organizational effects of carotenoids during embryo development. PMID- 19780653 TI - Chemokines and their receptors: orchestrating a fine balance between health and disease. AB - Chemokines are a family of small, structurally related proteins that may participate in immune and inflammatory responses through the chemoattraction and activation of leukocytes. These chemotactic cytokines mediate their effects by binding to the seven transmembrane domain superfamily of receptor proteins. Besides their role in leukocyte trafficking, chemokines and their receptors have been found to be implicated in a number of inflammatory and infectious diseases. Chemokines also appear to have beneficial effects involving tissue repair or tumor progression, angiogenesis, hematopoiesis, and antimicrobial mechanisms. These have recently been found to be involved in coordinating the cellular communication in the central nervous system as well. Based on these findings, chemokines agonists and antagonists targeted against chemokines and their receptors have the potential to become therapeutically important in the treatment of various diseases. This review explores the role of the chemokine system in the pathophysiology of diseases and their potential as targets for therapy. PMID- 19780654 TI - Renal UDP-glucuronosyltransferases and the glucuronidation of xenobiotics and endogenous mediators. AB - The role of the kidney in drug and chemical disposition has traditionally focused on the excretion of polar xenobiotics and metabolites. However, there is increasing evidence demonstrating that renal UGTs are integral to the "local" intrarenal, and, possibly, systemic, metabolic clearance of numerous drugs and nondrug xenobiotics, as well as to the maintenance of renal homeostasis through limiting the biological activity of endogenous renal mediators that control electrolyte balance and renal blood flow. The common involvement of UGT1A9 and UGT2B7 in the metabolism of both endogenous and exogenous compounds in kidney predicates significant renal drug-endobiotic interactions that may explain, in part, the adverse renal effects of some drugs. PMID- 19780659 TI - Molecular epidemiology of Clostridium difficile over the course of 10 years in a tertiary care hospital. AB - BACKGROUND: The molecular epidemiology of endemic and outbreak Clostridium difficile strains across time is not well known. METHODS: HindIII restriction endonuclease analysis (REA) typing was performed on available clinical C. difficile isolates from 1982 to 1991. RESULTS: The annual incidence of C. difficile infection (CDI) ranged from 3.2 to 9.9 cases per 1000 discharges and was significantly higher in 1982, 1983, 1985, and 1991 (high-incidence years) than in other years (mean standard deviation number of cases for the high- vs the low-incidence years, 121.8 +/-20.4 and 70.0 +/-15.0; P =.002). A total of 696 (76.6%) of 908 C. difficile isolates were available for REA typing over the 10 year period. Large clusters (>or=10 CDI cases in consecutive months) were caused by REA types B1 and B2 in 1982 and 1983, F2 and B1 in 1985, and K1 in 1991 (high incidence years). Small clusters of 4-9 CDI cases in consecutive months were caused by REA types G1 (1984), Y4 and Y6 (1987), Y2 (1988), L1 (1989), Y1 (1990), and K1 (1991). Current epidemic REA group BI (unrelated to type B1) was isolated 6 times, twice in 1984, 1988, and 1990. CONCLUSIONS: Years with a high incidence of CDI were associated with large clusters of specific REA types that changed yearly. The molecular epidemiology of CDI in this hospital was characterized by a wide diversity of C. difficile types and an ever-changing dominance of specific C. difficile types over time. The current epidemic BI group was found sporadically on 6 occasions. A changing CDI molecular epidemiology should be expected in the future. PMID- 19780660 TI - The A, B, BI, and Cs of Clostridium difficile. PMID- 19780661 TI - Management of the catheter in documented catheter-related coagulase-negative staphylococcal bacteremia: remove or retain? AB - BACKGROUND: Studies and guidelines recommending the retention of the central venous catheter (CVC) in patients with coagulase-negative staphylococcal bacteremia were based on loose definitions of bacteremia and/or did not evaluate the risk of recurrence. In this study, we used strict definitions of coagulase negative staphylococcal bacteremia to determine the impact of CVC retention on response to and recurrence of infection. METHODS: During the period from July 2005 through December 2007, we retrospectively evaluated 188 patients with coagulase-negative staphylococcal bacteremia. Bacteremia was defined using the strict Centers for Disease Control and Prevention criteria of 2 positive blood culture results. Catheter-related bacteremia was confirmed by differential quantitative blood cultures (>or=3:1) or time to positivity (>2 h). RESULTS: Resolution of infection within 48 h after commencement of antimicrobial therapy was not influenced by CVC removal or exchange versus retention and occurred in 175 patients (93%). Multiple logistic regression analysis showed that infection was 7.0 times (95% confidence interval [CI], 1.5-32.6 times) more likely to fail to resolve in patients with an intensive care unit stay prior to infection ( P = .013 ) and 3.8 times (95% CI, 1.1-13.3 times) more likely to fail to resolve in patients who had other concurrent sites of infection (P = .041 ). Duration of therapy did not affect recurrence. Multiple logistic regression analysis revealed that patients with catheter retention were 6.6 times (95% CI, 1.8-23.9 times) more likely to have a recurrence than were those whose catheter was removed or exchanged (P = .004). CONCLUSIONS: CVC retention does not have an impact on the resolution of coagulase-negative staphylococcal bacteremia but is a significant risk factor of recurrence. PMID- 19780662 TI - Poor agreement between 2 assays for measuring low levels of HIV-1 viral load. PMID- 19780663 TI - Wider range for parasites that cause eosinophilic meningitis. PMID- 19780664 TI - Repeated bacteremia with subsequent septic arthritis caused by Klebsiella pneumoniae capsular serotype K57 in a patient with diabetes. PMID- 19780665 TI - Development of daptomycin-susceptible, methicillin-resistant Staphylococcus aureus pneumonia during high-dose daptomycin therapy. PMID- 19780666 TI - Time for a worldwide shift from oral polio vaccine to inactivated polio vaccine. PMID- 19780667 TI - Surveillance definitions for urinary tract infections. PMID- 19780672 TI - Common features of gammadelta T cells and CD8(+) alphabeta T cells responding to human cytomegalovirus infection in kidney transplant recipients. AB - BACKGROUND: Kidney transplant recipients infected with cytomegalovirus (CMV) undergo a persistent gammadelta T cell expansion in their peripheral blood. The anti-CMV function of these cells was previously demonstrated by their ability to kill CMV-infected cells in vitro. METHODS: To gain insight into the role of gammadelta T cells within the antiviral immune network, we compared the expansion kinetics of these T cells with that of CMV pp65-specific CD8(+) alphabeta T cells in the peripheral blood of twenty-one kidney transplant recipients. RESULTS: Both the percentage and the absolute number of pp65-specific CD8(+) T cells and gammadelta T cells showed a concomitant increase and persistence in most of the kidney transplant recipients with CMV infection. Both cell subsets exhibited an effector/memory phenotype (CD28(-), CD27(-), and CD45RA(+)) that predominated for the entire follow-up period. CONCLUSIONS: In conclusion, CMV-specific CD8(+) alphabeta T cells and gammadelta T cells share common expansion kinetics and a common effector phenotype, suggesting that these cell types act similarly in response to CMV infection. PMID- 19780673 TI - The HLA-E(R)/HLA-E(R) genotype affects the natural course of hepatitis C virus (HCV) infection and is associated with HLA-E-restricted recognition of an HCV derived peptide by interferon-gamma-secreting human CD8(+) T cells. AB - Recently, we showed chronic hepatitis C to be associated with increased expression of HLA-E and identified peptide hepatitis C virus (HCV) core amino acids 35-44 as a ligand for HLA-E that stabilizes HLA-E expression, favoring inhibition of natural killer cell cytotoxicity. Here we describe HLA-E-restricted recognition of peptide HCV core amino acids 35-44 by CD8(+) T cells. Frequency of HLA-E-restricted responses was significantly higher in patients homozygous for the HLA-E(R) allele (60% vs 38%; P = .038). Moreover, we found that the HLA-E(R) allelic variant confers protection against chronic infection with HCV genotypes 2 and 3. Taken together, our data indicate an important immunomodulating function of HLA-E in hepatitis C. PMID- 19780674 TI - Usefulness of weekly methicillin-resistant Staphylococcus aureus screening. AB - We evaluated the usefulness of adding weekly methicillin-resistant Staphylococcus aureus (MRSA) screening to our established admission screening and clinical sampling in 4 acute care units of a university hospital. Our results suggest that weekly MRSA screening allows the detection of 56.1% of all cases of hospital acquired MRSA carriage. These cases would have remained undetected had admission screening and clinical sampling been the only types of surveillance in place. PMID- 19780675 TI - Incidence of and risk factors for nosocomial bloodstream infections in adults in the United States, 2003. AB - BACKGROUND: Although many studies have examined nosocomial bloodstream infection (BSI), US national estimates of incidence and case-fatality rates have seldom been reported. OBJECTIVE: The purposes of this study were to generate US national estimates of the incidence and severity of nosocomial BSI and to identify risk factors for nosocomial BSI among adults hospitalized in the United States on the basis of a national probability sample. METHODS: This cross-sectional study used the US Nationwide Inpatient Sample for the year 2003 to estimate the incidence and case-fatality rate associated with nosocomial BSI in the total US population. Cases of nosocomial BSI were defined by using 1 or more International Classification of Diseases, 9th Revision, Clinical Modification codes in the secondary field(s) that corresponded to BSIs that occurred at least 48 hours after admission. The comparison group consisted of all patients without BSI codes in their NIS records. Weighted data were used to generate US national estimates of nosocomial BSIs. Logistic regression was used to identify independent risk factors for nosocomial BSI. RESULTS: The US national estimated incidence of nosocomial BSI was 21.6 cases per 1,000 admissions, while the estimated case fatality rate was 20.6%. Seven of the 10 leading causes of hospital admissions associated with nosocomial BSI were infection related. We estimate that 541,081 patients would have acquired a nosocomial BSI in 2003, and of these, 111,427 would have died. The final multivariate model consisted of the following risk factors: central venous catheter use (odds ratio [OR], 4.76), other infections (OR, 4.61), receipt of mechanical ventilation (OR, 4.97), trauma (OR, 1.98), hemodialysis (OR, 4.83), and malnutrition (OR, 2.50). The total maximum rescaled R(2) was 0.22. CONCLUSIONS: The Nationwide Inpatient Sample was useful for estimating national incidence and case-fatality rates, as well as examining independent predictors of nosocomial BSI. PMID- 19780676 TI - Surgical site infection as a surrogate marker of physician impairment. AB - Our report details an implant-associated outbreak of surgical site infections related to the adverse effects of treatment for hepatitis C virus infection administered to surgeon X. During the 12-month period of this outbreak, 14 (9.5%) of 148 of surgeon X's patients developed a surgical site infection, a rate of SSI that was 8-fold higher than the rate during the 14-month baseline period or the 14-month follow-up period (P = .001), and higher than the rate among peer surgeons (P = .02). PMID- 19780681 TI - Management of infectious complications in percutaneous nephrolithotomy. AB - Infectious complications are one of the most frequent and feared adverse medical events in percutaneous nephrolithotomy. They represent a dangerous and life threatening condition, especially when postoperative septicemia or severe sepsis develops. In order to limit morbidity and mortality it is crucial to recognize preoperative and intraoperative risk factors that could be clear contributors to an adverse infectious event; those factors are mainly immunosuppression caused by some comorbidities, presence of urinary infection or colonization, stone characteristics, obstruction, long-lasting operation, and high intrapelvic pressure during nephrolithotomy. Close observation during the immediate and early postoperative period must be established and a high index of suspicion must be maintained to identify a major complication. The early recognition and prompt multidisciplinary management of sepsis is mandatory to optimize the final outcome. Appropriate therapy is a continuum of management of infection, ranging from adequate drainage and broad-spectrum antibiotics to aggressive fluid resuscitation and invasive monitoring with medical management in the intensive care setting until the causative agent is found and eradicated. PMID- 19780682 TI - Influence prediction of tissue injury on frequency variations of the lumbar spine under vibration. AB - A three-dimensional finite element model of the spine T12-S1 segment was developed and used to investigate biodynamics characteristics of the human lumbar spine. The T12-S1 model was carefully built including spinal vertebrae, intervertebral discs, and ligaments so as to approach the real human spine. Finite element modal analysis was carried out to obtain vibration modes and resonant frequencies of the spine. The analytical results indicate that the vertical resonant frequency of the spinal T12-S1 segment with a mass of 40 kg on the top vertebra is 7.68 Hz. The vertical resonant frequencies of spine motion segments decrease with the number of spine motion segments increasing. The tissue injury, such as disc denucleation and removal both of facet articulations and their capsular ligaments may decrease the resonant frequencies of spine in different extent. The denucleation makes larger influence on vertical resonant frequencies than facetectomy does. The denucleation is more harmful to the facet articulations under whole body vibration. The dynamic characteristics of the T12 S1 model accords with the actual human spine, and it is useful for the relative studies of the human spine, such as biomechanical characteristics, vibration related injury mechanism of the human spine, and development of vibration-related mechanical products. PMID- 19780685 TI - Telehealth for managing COPD. PMID- 19780683 TI - Regulation of hepatic microRNA expression in response to ischemic preconditioning following ischemia/reperfusion injury in mice. AB - MicroRNAs play important regulatory roles in many physiological processes. This study investigated potential involvement of microRNAs in hepatic ischemia/reperfusion injury and ischemic preconditioning in mice. MicroRNAs with significant changes in expression in the livers upon ischemic preconditioning following ischemia/reperfusion injury were detected by microRNA microarrays. Seventy-eight microRNAs (40 down/38 up) exhibiting more than twofold differences were identified in the livers upon ischemia/reperfusion injury. Among these microRNAs, four microRNAs were further significantly downregulated by ischemic preconditioning in comparison to nonpreconditioned controls. These included mmu miR-23a, mmu-miR-326, mmu-miR-346_MM1, and mmu-miR-370, all of which were positively correlated with the severity of ischemic injury. The expression of mmu miR-326 was further confirmed by quantitative real-time RT-PCR, and CCAAT/enhancer binding protein alpha was predicted by computer-aided algorithms to be a downstream target of this microRNA. In summary, our study showed a distinctive miRNA expression pattern in mouse livers in response to ischemic preconditioning following ischemia/reperfusion injury. Further studies on the miRNAs identified herein may enhance the understanding of miRNA-based mechanisms of hepatic ischemia/reperfusion injury and ischemic preconditioning. PMID- 19780687 TI - Telemedicine is green!! PMID- 19780688 TI - Experiences of telemedicine-aided hypertension control in the follow-up of Finnish hypertensive patients. AB - The prevalence of hypertension is high in Finland. Only one fourth of the drug treated hypertensive patients reach their target pressure. We evaluated a commercially available telemedicine system for impact in reaching better blood pressure control among Finnish hypertensive patients. A telemedicine system, the Doc@home, was used to assist blood pressure treatment in 19 Finnish hypertensive patients. Blood pressure control improved during the 3-month follow-up. Patient to-Doc@home compliance was good, but study physicians found the system time consuming in the beginning. According to our results, the Doc@home telemedicine system showed a promising approach in hypertension treatment but needs some further development and trained staff to become a still more practical alternative. PMID- 19780689 TI - A comparison of different survey periods in online surveys of persons with eating disorders and their relatives. AB - Evaluations of Internet-based interventions offered to patients with mental or psychosomatic illnesses are mostly carried out in the form of online surveys. This study tested whether modifying this time interval brings about changes in the respondents' response behavior and the make-up of the sample. Two survey strategies were compared: a postblock survey (with a variable time interval between the Internet-based intervention and the online survey) and a postspot survey (time interval standardized to 90 days). In the postspot survey, it was possible to prove a higher response rate (39.9%) than in the postblock survey (28.0%) as well as a higher number of questionnaires completed correctly and in full. No differences were identified in the basic characteristics of the random samples. It was possible to demonstrate that the quality of the online survey could be improved by standardizing the length of time. Standardization of the time difference implies a controllable degree of influence on the quality of the evaluations. PMID- 19780690 TI - A Web services-based distributed system with browser-client architecture to promote tele-audiology assessment. AB - The purpose of this research was to extend applications of the Internet and other telecommunication means to the assessment of hearing. The newly developed distributed system consists primarily of an application server and its database, and Web services under browser-server architecture to support remote hearing assessment. A pilot study was conducted: three independent audiologists assessed hearing of 25 subjects using testing approaches with different data communication configurations. Analysis of the results demonstrated the feasibility of replacing conventional "face-to-face" tests with the remote hearing tests using the distributed system. Because of its distributed architecture, the present system supports a new service model and separates technical maintenance and clinical services. Consequently, the system shows great potential to benefit the clinical hearing care profession. Future research is planned to apply this system to medical facilities and for distance applications. PMID- 19780691 TI - A qualitative study of the experiences and satisfaction of direct telemedicine providers in diabetes case management. AB - Telehealth interventions are feasible and efficacious. While patients are the focus of both quantitative and qualitative studies that assess their response to telehealth, little is known about the view of providers of telehealth services. The purpose of this study was to better understand the experiences of providers and the factors that they perceive to contribute to the success of telehealth interventions as well as to their own satisfaction. Face-to-face or telephone interviews were conducted with 10 diabetes educators (nurses and dietitians) who served as providers of a telemedicine case management intervention for older adults who have diabetes. Qualitative analyses revealed that providers were very satisfied with their experience and felt their efforts with patients were generally successful. Providers also identified a number of unique benefits to telehealth interventions. These included opportunities for more frequent contact with patients, greater relaxation and information due to the ability to interact with the patients in their own homes, increased ability to reach the underserved, more timely and accurate medical monitoring, and improved management of data. The primary disadvantages of telehealth they identified were technology problems and a concern about the lack of physical contact with patients. Findings illustrate providers' perspectives on the unique advantages of telehealth and offer insight as to how to make telehealth interventions more effective, as well as more satisfying for those who do the day-to-day work of providing the interventions. PMID- 19780693 TI - Telehealth ethics. AB - The ethical implications of telehealth go well beyond providers' obligations to ensure privacy and confidentiality. The ethical conundrum of telehealth realizes the uniquely positive impact that telehealth can have on patients, providers, and clinical outcomes, as well as the potential for harm and abuse that may ensue. This article explores telehealth as one of many evolving information technologies that have ethical questions extending well beyond the confines of privacy and confidentiality. Providers and systems who utilize telehealth should also consider how it influences relationships with patients, access to healthcare, capacity for equitable treatment, cost, and quality of life. The ability to respond to these concerns will be important to the future development and deployment of this important technology as one means by which to improve access and quality of healthcare for all members of our society. PMID- 19780692 TI - A study of medication-taking and unobtrusive, intelligent reminding. AB - Poor medication adherence is one of the major causes of illness and of treatment failure in the United States. The objective of this study was to conduct an initial evaluation of a context-aware reminder system, which generated reminders at an opportune time to take the medication. Ten participants aged 65 or older, living alone and managing their own medications, participated in the study. Participants took a low-dose vitamin C tablet twice daily at times that they specified. Participants were considered adherent if they took the vitamin within 90 minutes (before or after) of the prescribed time. Adherence and activity in the home was measured using a system of sensors, including an instrumented pillbox. There were three phases of the study: baseline, in which there was no prompting; time-based, in which there was prompting at the prescribed times for pill-taking; and context-aware, in which participants were only prompted if they forgot to take their pills and were likely able to take their pills. The context based prompting resulted in significantly better adherence (92.3%) as compared to time-based (73.5%) or no prompting (68.1%) conditions (p < 0.0002, chi(2) = 17.0). In addition, subjects had better adherence in the morning than in the evening. We have shown in this study that a system that generates reminders at an opportune time to take the medication significantly improves adherence. This study indicates that context-aware prompting may provide improved adherence over standard time-based reminders. PMID- 19780694 TI - Traveling an audiologist to provide otolaryngology care using store-and-forward telemedicine. AB - This project increased access to otolaryngology services by having an audiologist travel to remote Alaska and communicate with an otolaryngologist using store-and forward electronic consultation. The audiologist was instructed to effectively image appropriate parts of the otolaryngology exam and create telemedicine cases that included clinical histories, images, audiograms, tympanograms, otoacoustic emission testing and/or other documents. The otolaryngology consultants reviewed new referrals as well as follow up cases and made treatment and triage recommendations. Over a 57 month period, 54 trips were made to 14 villages providing 197 clinic service days. The 1,458 patient encounters resulted in referral for surgery or special diagnostic testing 26%, referral for monitoring 23%, starting of medications 19%, referral to regional ENT clinic 15%, and referral to another specialty 5%. Approximately 27% patients did not need to see the otolaryngologist and were triaged out of the specialty clinic. The total cost to run this project was $141,114. Travel was prevented for 85% encounters, resulting in travel cost avoidance in airfare of $496,420. These services were provided at a significantly lower cost and with fewer burdens to the patients when compared to the standard referral system. An audiologist that travels to remote locations and uses store-and-forward telemedicine can rapidly deliver otolaryngology services. This model is a proven mechanism of efficient healthcare delivery that may be expanded to other specialties. PMID- 19780695 TI - Fates of donor and recipient mitochondrial DNA during generation of interspecies SCNT-derived human ES-like cells. AB - To investigate nuclear donor and cytoplast recipient mitochondria fate and their effects on generation of interspecies somatic cell nuclear transfer (iSCNT) derived human embryonic stem (ES)-like cells, iSCNT embryos were reconstructed between enucleated goat oocytes and human neural stem cells (hNSCs). A total of 10.74% cleaved embryos (13/121) developed to blastocyst stage. One typical primary ES-like (tpES-like) colony and two nontypical primary ES-like (non-tpES like) colonies designated as non-tpES-like cell-1 and non-tpES-like cell-2, respectively, were obtained from the inner cell masses of iSCNT blastocysts. The tpES-like cells expressed ESC markers. Both human and goat mtDNA could be detected in the embryos at 2-8-, 16-32-cell, and blastocyst stages, and in tpES like colony and two non-tpES-like colonies. Human mtDNA copies per cell from embryos at two- to eight-cell stage to the three colonies maintain almost its original level, whereas 2.88 x 10(5) goat mtDNA copies per oocyte decreased to 10.8 copies per tpES-like cell, 493 copies per non-tpES-like cell-1, and 77.6 copies per non-tpES-like cell-2, resulting in 43.75% (8.4/19.2), 1.24% (6.2/499), and 14.63% (13.3/90.9) mtDNA content in tpES-like cell, non-tpES-like cell-1, and non-tpES-like cell-2 was that of nuclear donor, respectively. Human-specific Tfam and Polg mRNA could be detected in cells of the three colonies. However, tpES like colony failed to be passaged. The mRNA level of CoxIV encoded by nuclear donor in tpES-like cell was higher than that in non-tpES-like cell, but significantly lower than that of human ESC, suggesting proper nuclear-cytoplasmic communication would not be established in tpES-like cells. Thus, the data suggest that (1) goat oocytes could reprogram human neural stem cells (hNSCs) into embryonic state and further support the inner cell mass (ICM) of iSCNT blastocyst to form tpES-like colony; (2) nuclear donor mtDNA could be replicated and maintain its original level during the reduction of recipient mitochondrial DNA copies, (3) nuclear-cytoplasmic communication and recipient mtDNA copies might affect the derivation of iSCNT-derived ES-like cells. PMID- 19780696 TI - Calcium release and development of heat-shocked porcine oocytes after nucleus ooplasm reconstruction. AB - We determined the effect of heat shock (HS) on the alterations of development and calcium releasing capacity of nuclear-ooplasmic reconstructed porcine oocytes stimulated by thimerosal. The non-HS (39 degrees C) and the HS2h (41.5 degrees C for 2 h) matured oocytes were enucleated and their spindles/chromosomes were exchanged between these two groups followed by parthenogenetic activation. In the Control group (Csp-Coop), the non-HS spindle (Csp) was transferred to the non-HS ooplasm (Coop). Blastocyst and cleavage rates were higher in both Csp-HSoop (non HS spindle transferred to the HS ooplasm) and HSsp-Coop (HS spindle transferred to non-HS ooplasm) reconstructed oocytes, but no difference was detected in the average cell number per blastocyst. However, intracellular calcium concentrations ([Ca(2+)](i)) generally declined (p < 0.05) in the reconstructed HS oocytes, with a greater blastocyst rate after parthenogenetic activation. In the present study, time for the completion of spindle transfer in these oocytes was 1-2 h, during which some physiological remodeling or adaptation might have been occurred in the oocytes. Therefore, changes in heat-shock protein70 (HSP70) expression and developmental competence of the HS2h oocytes with 1 or 2 h of recovery time under normal culture temperature (39 degrees C) were examined. The results showed that the expression of HSP70 in the HS2h oocytes was higher (p < 0.05) than those had recovery incubation for 1 h (HC1h) after HS, but the cleavage and blastocyst rates were greater (p < 0.05) in the HC1h group. We demonstrated that a recovery period prior to activation of porcine oocytes and reconstructed oocytes is beneficial to further development. Heat shock to either the karyoplast or the ooplasm enhances embryonic development but reduces intracellular calcium release in the cloned porcine oocytes. PMID- 19780697 TI - Serum-starved apoptotic fibroblasts reduce blastocyst production but enable development to term after SCNT in cattle. AB - Cell cycle synchronization by serum starvation (SS) induces apoptosis in somatic cells. This side effect of SS is hypothesized to negatively affect the outcome of somatic cell nuclear transfer (SCNT). We determined whether apoptotic fibroblasts affect SCNT yields. Serum-starved, adult, bovine fibroblasts were stained with annexin V-FITC/propidium iodide to allow apoptosis detection by flow cytometry. Positive and negative cells sorted by fluorescence activated cell sorting (FACS) and an unsorted control group were used as nuclear donors for SCNT. Reconstructed embryos were cultured in vitro and transferred to synchronized recipients. Apoptosis had no effect on fusion and cleavage rates; however, it resulted in reductions in blastocyst production and quality measured by apoptotic index. However, reconstructed embryos with apoptotic cells resulted in pregnancy rates similar to that of the control on day 30, and generated one live female calf. In conclusion, we showed that apoptotic cells present in serum-starved cultures negatively affect embryo production after SCNT without compromising full-term development. Further studies will evaluate the ability of the oocyte to reprogram cells in specific phases of apoptosis. PMID- 19780698 TI - Cytochalasin B and trichostatin a treatment postactivation improves in vitro development of porcine somatic cell nuclear transfer embryos. AB - Somatic cell nuclear transfer (SCNT) is a useful technique for the production of transgenic pigs that can be used for biomedical research. However, the efficiency of SCNT in pigs is low. In this study, we examined the effect of two postactivation treatments, cytochalasin B (CB) and trichostatin A (TSA), on the in vitro development of porcine SCNT embryos. Treating porcine parthenotes with 7.5 microg/mL CB for 3 h after electrical activation was effective in preventing the extrusion of the second polar body in 65% of the oocytes compared to 17% in the control group. Treating SCNT embryos with CB for 3 h after electrical activation significantly increased the average blastocyst cell number compared to the control group (CB treatment 51, Control 34, p < 0.05). Treatment of porcine SCNT embryos with CB for 3 h and 50 nM TSA for 24 h after electrical activation resulted in a threefold increase in blastocyst rate (CB + TSA 64%, CB 20%, p < 0.05) and an increase in the average blastocyst cell number (CB + TSA 63, CB 46, p < 0.05), compared to CB treatment alone. These results show that treatment with TSA and CB significantly improves the in vitro morphological development and quality of porcine SCNT embryos. PMID- 19780699 TI - Changes in the DNA methylation status of bovine embryos from the blastocyst to elongated stage derived from somatic cell nuclear transfer. AB - The epigenetic reprogramming of the donor cell nucleus is an important factor in the development of embryos and production of normal offspring derived by somatic cell nuclear transfer (NT-SC). During early development, a dramatic reduction in methylation levels occurs in mouse. In early embryos, this process makes it possible to erase gamete-specific methylation patterns and induce de novo methylation at defined developmental time-points. To clarify changes in DNA methylation in bovine NT-SC embryos, we examined satellite I sequences in bovine embryos derived in vivo (Vivo) and by NT-SC at the blastocyst (BC) and elongated (EL) stages. Because the EL stage embryo consists of the embryo disc (ED) and trophectoderm (TE), the methylation status of each part was analyzed with respect to the progress of differentiation. DNA methylation levels in Vivo embryos were increased during the elongation stage. In contrast, DNA methylation levels in NT SC embryos remained unchanged in the ED and significantly decreased in the TE. Real-time PCR analysis showed that Dnmt-1 expression in BC embryos derived by NT SC was significantly lower than that in Vivo embryos; thus, differences in the DNA methylation status may reflect transcript levels of Dnmt-1. Our results suggest that the aberrant methylation level of bovine NT-SC embryos in the satellite I region is corrected as a result of demethylation and retention of methylation as the embryo develops and differentiates. PMID- 19780700 TI - GPR119 agonists for the treatment of type 2 diabetes. AB - BACKGROUND: Diabetes is a chronic disease that occurs when the pancreas does not produce enough insulin, or when the body cannot effectively use the insulin it produces. Hyperglycemia, or raised blood sugar, is a common effect of uncontrolled diabetes and over time leads to serious damage to many of the body's systems, especially nerves and blood vessels. Diabetes causes about 5% of all deaths globally each year and is likely to increase by > 50% in the next 10 years without urgent action. In light of these alarming statistics, the pharmaceutical industry has been on a quest to characterize more promising molecular targets to satisfy stringent new criteria for anti-hyperglycemic agents introduced by the American Diabetes Association. On to this stage, G-protein-coupled receptor 119 (GPR119) has emerged as arguably one of the most exciting targets for the treatment of type 2 diabetes mellitus in the new millennium. OBJECTIVE: In this review, we outline the current clinical trial landscape and paint a detailed illustration of the key structural information realized from GPR119 agonist campaigns that have recently emerged in the Patent Cooperation Treaty literature. CONCLUSION: GPR119 agonists mediate a unique nutrient-dependent dual elevation of both insulin and glucagon like peptide 1/glucose-dependent insulinotropic peptide levels in vivo. As a stand-alone therapy or in tandem with approved DPP-IV inhibitors, they could herald a brand new treatment paradigm for type 2 diabetes mellitus. With the passage of the first GPR119 agonist clinical candidates into Phase I trials (Arena/Ortho McNeil APD597; Metabolex MBX-2982; Prosidion/OSI PSN821) and confirmatory reports of clinical proof of concept with respect to glycemic control and incretin release, the spotlight has been set for this new class of therapeutic. PMID- 19780701 TI - Biological activities of guanidine compounds. AB - BACKGROUND: The guanidine group defines chemical and physicochemical properties of many compounds of medical interest and guanidine-containing derivatives constitute a very important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. OBJECTIVE: To review the most important pharmacological properties, mechanisms of action and therapeutic uses of simple guanidine derivatives, cyclic analogues of guanidines as well as peptides, peptidomimetics and peptoids incorporating arginine. METHODS: The review presents both the recent patent literature and original papers dealing with guanidine derivatives that show interesting biological activity and emphasizes the newest developing drugs. CONCLUSION: Recent achievements in the synthesis of guanidine containing molecules with diverse chemical, biochemical and pharmacological properties make them of great importance to the design and development of novel drugs acting at CNS, anti-inflammatory agents, inhibitors of Na(+)/H(+) exchanger, inhibitors of NO synthase, antithrombotic, antidiabetic and chemotherapeutic agents as well as guanidinium-based transporters and vectors. PMID- 19780703 TI - Diazepane-acetamide derivatives as selective 11beta-hydroxysteroid dehydrogenase type 1 inhibitors. AB - WO2008052638 describes the identification and synthesis of diazepane- acetamide derivatives as a novel class of selective small molecule inhibitors of 11beta hydroxysteroid dehydrogenase type 1 (11beta-HSD1) for the treatment of metabolic syndrome. The generic structure of the disclosed diazepane-acetamide derivatives offers considerable possibilities for modifications that allow optimizing compound properties. Further studies to assess target selectivity, species specificity, modulation of tissue-specific functions of 11beta-HSD1 as well as interference with alternative functions of this enzyme are needed to explore the therapeutic potential of these chemicals. PMID- 19780705 TI - Lurasidone: a new drug in development for schizophrenia. AB - BACKGROUND: Lurasidone is a novel psychotropic agent in development for the treatment of schizophrenia and bipolar disorder. OBJECTIVES: This paper describes the development of lurasidone, including its receptor binding affinities, pharmacokinetics, CNS activity in rodent models and results of early clinical efficacy and safety studies in humans. METHODS: The available literature on lurasidone was reviewed, including abstracts from medical congresses supplemented by data on file with the sponsor. RESULTS/CONCLUSIONS: Lurasidone has a high affinity for dopamine D(2) and serotonin 5-HT(2A) receptors as well as for receptors implicated in enhancement of cognitive function (e.g., 5-HT(7,) 5 HT(1A), alpha(2c)). Lurasidone has no affinity for muscarinic M(1) and histamine H(1) receptors and minimal affinity for alpha(1) adrenoceptors, dopamine D(1) and D(3) receptors, serotonin 5-HT(2C) receptors and alpha(2A) adrenoceptors. Phase II efficacy data indicate that lurasidone doses from 40 to 120 mg/day are effective in the treatment of schizophrenia, with positive symptom reduction exceeding that for negative symptoms, as seen with other antipsychotics. Preclinical data indicate that lurasidone reverses MK-801 induced learning and memory impairment in rodents, and active comparator data from a Phase Ib study of lurasidone 120 mg/day versus ziprasidone 160 mg/day also found a signal for effects on cognition. Phase II studies suggest that lurasidone has no significant QTc prolongation and a benign metabolic profile. PMID- 19780704 TI - Darinaparsin: a novel organic arsenical with promising anticancer activity. AB - Darinaparsin is an organic arsenical composed of dimethylated arsenic linked to glutathione, and is being investigated for antitumor properties in vitro and in vivo. While other arsenicals, including arsenic trioxide, have been used clinically, none have shown significant activity in malignancies outside of acute promyelocytic leukemia. Darinaparsin has significant activity in a broad spectrum of hematologic and solid tumors in preclinical models. Here, we review the literature describing the signaling pathways and mechanisms of action of darinaparsin and compare them to mechanisms of cell death induced by arsenic trioxide. Darinaparsin has overlapping, but distinct, signaling mechanisms. We also review the current results of clinical trials with darinaparsin (both intravenous and oral formulations) that demonstrate significant antitumor activity. PMID- 19780706 TI - Neratinib: an oral, irreversible dual EGFR/HER2 inhibitor for breast and non small cell lung cancer. AB - BACKGROUND: The revolutionary success of imatinib, a specific inhibitor of the BCR-ABL tyrosine kinase (TK) in the treatment of chronic myelogenous leukemia ushered in the era of targeted therapies in cancer. The erythroblastic leukemia viral oncogene homolog family of receptor TKs, to which EGFR (HER1) and human epidermal growth factor receptor 2 (HER2)/neu TKs belong, has been implicated in a variety of cancers, and several agents that inhibit these TKs are in clinical use, with many more in various stages of development. OBJECTIVES: To summarize current knowledge about neratinib (HKI-272), an oral, irreversible dual inhibitor of EGFR and HER2 and to define its future clinical role, especially in the context of related agents that are either available or in the pipeline. METHODS: A Medline search using Pubmed was conducted using the keywords neratinib, HKI 272, EGFR, HER2, lapatinib, trastuzumab, erlotinib, gefitinib, cetuximab and panitumumab. Relevant abstracts presented at the American Society of Clinical Oncology and San Antonio Breast Cancer Symposium meetings were also reviewed. CONCLUSIONS: Both preclinical and human studies have shown that neratinib has promising activity in both advanced breast cancer and NSCLC with an acceptable safety profile. The data support its continued clinical development. PMID- 19780707 TI - Targeting of HDAC8 and investigational inhibitors in neuroblastoma. AB - Histone deacetylase (HDAC) inhibitors are an emerging class of promising novel anticancer drugs. However, little is known which one of the 11 classical HDAC family members is the most relevant drug target for therapy. The first Phase I/II trials show that unselective inhibition of HDACs causes a variety of side effects. Therefore, identification and selective targeting of the most critical tumor entity-relevant HDAC family member may reduce unspecific effects and increase antitumor efficacy in the future. Here, we review the clinical relevance of a particular HDAC family member, HDAC8, in neuroblastoma biology, a highly malignant embryonal childhood cancer. HDAC8 expression correlates with poor outcome in neuroblastoma and selective HDAC8 inhibition induces differentiation. In contrast, the targeting of other HDAC family members results in a completely different phenotype. Because HDAC8-selective inhibitors are available, HDAC8 may be a potential drug target for neuroblastoma differentiation therapy using selective inhibitors, avoiding unspecific side effects. PMID- 19780708 TI - Oxaliplatin induces apoptosis in hepatocellular carcinoma cells and inhibits tumor growth. AB - OBJECTIVE: The platinum-based chemotherapeutic agent oxaliplatin displays a wide range of antitumor activities. To date, no detailed data are available about the effects of oxaliplatin on hepatocellular carcinoma (HCC) cells. Herein, the anti proliferation effects of oxaliplatin on HCCLM3 and Hep3B cells in vitro and in vivo are studied. RESEARCH METHODS: Cell viability was assessed by an MTT assay and apoptosis by flow cytometry and transmission electron microscopy. Apoptosis related proteins in HCCLM3 cells were evaluated by microarray analysis, quantitative reverse transcriptase-PCR assay and western blotting. The effect of oxaliplatin was also studied in vivo using a xenograft model. RESULTS: Oxaliplatin inhibited the growth of HCCLM3 and Hep3B cells. Using flow cytometry, transmission electron microscopy and the terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay, we found that apoptosis was the main mechanism by which oxaliplatin inhibited tumor progression. Microarray analysis, quantitative reverse transcriptase-PCR and western blot analysis further demonstrated downregulation of the anti-apoptotic proteins Bcl-2 and Bcl-xL and upregulation of the pro-apoptotic protein Bax during oxaliplatin-induced apoptosis. CONCLUSIONS: The anti-proliferation effect of oxaliplatin in HCC cells is due to induction of apoptosis. Therefore, oxaliplatin may be an effective treatment for HCC and its use merits further in-depth investigation. PMID- 19780709 TI - Investigational drugs in sickle cell anemia. AB - Sickle cell anemia is one of the most common autosomal recessive diseases in the world. Patients with sickle cell anemia have variable penetrance and it is hard to predict the risk and timing of complications. It is characterized by a point mutation in the beta-globin gene (GAG --> GTG) and the production of hemoglobin S. The latter leads to decreased deformability of the red blood cells (RBCs) that adhere to endothelia cells culminating in vascular occlusion and its sequelae of tissue ischemia and organ damage. Moreover, sickled RBCs undergo intravascular hemolysis and accelerated erythropoesis. The hallmarks of this disease are shortened RBC survival and vaso-occlusive crises. For the past ten years, the pathophysiology of this disease has been better elucidated and has led to significant improvements in the standard of care. Vaso-occlusion is now understood to be a complex event that involves abnormal interactions between RBCs, leukocytes, endothelial cells and the coagulation pathways. The field of translational research in sickle cell anemia has expanded greatly and has led to new clinical trials with new therapeutic agents and strategies. In this paper, we review the drugs that are now being investigated in the treatment of sickle cell anemia. PMID- 19780710 TI - The biological routes of gene delivery mediated by lipid-based non-viral vectors. AB - Cationic lipid/DNA complexes (lipoplexes) represent an attractive alternative to viral vectors for cell transfection in vitro and in vivo but still suffer from relatively low efficiency. Comprehension of the interactions between vectors and DNA as well as cellular pathways and mechanisms in DNA entry into cells and ultimately nuclei will lead to the design of better adapted non-viral vectors for gene therapy applications. Here, some recent developments in the field on the pathways and mechanisms involved in lipoplex-mediated transfection are discussed. The techniques that are widely used to study the mechanism of gene delivery are also discussed. PMID- 19780711 TI - Recent advances in tumor vasculature targeting using liposomal drug delivery systems. AB - Tumor vessels possess unique physiological features that might be exploited for improved drug delivery. The targeting of liposomal anticancer drugs to tumor vasculature is increasingly recognized as an effective strategy to obtain superior therapeutic efficacy with limited host toxicity compared with conventional treatments. This review introduces recent advances in the field of liposomal targeting of tumor vasculature, along with new approaches that can be used in the design and optimization of liposomal delivery systems. In addition, cationic liposome is focused on as a promising carrier for achieving efficient vascular targeting. The clinical implications are discussed of several approaches using a single liposomal anticancer drug formulation: dual targeting, vascular targeting (targeting tumor endothelial cells) and tumor targeting (targeting tumor cells). PMID- 19780712 TI - Non-viral gene delivery using nanoparticles. AB - Although the potential benefits of gene therapy for the treatment of acquired and inherited genetic diseases have been demonstrated through preclinical studies, the results of human gene therapy trials have been disappointing. Recombinant viruses are the primary vectors of choice because of their ability to protect genetic materials, cross cellular membranes, escape from endosomes and transport their genetic materials into the nucleus. Unfortunately, viral vectors have been unable to gain widespread clinical application because of their toxicity and immunogenicity. Consequently, the need for safer alternatives has led to the development of liposomes, cationic polyplexes, microparticles and nanoparticles. Although these alternative vectors have shown promise, degradable nanoparticles are the only non-viral vectors that can provide a targeted intracellular delivery with controlled release properties. Furthermore, the potential advantage of degradable nanoparticles over their non-degradable counterparts is the reduced toxicity and the avoidance of accumulation within the target tissue after repeated administration. In this article, current non-viral gene delivery devices are reviewed with a special emphasis on nanoparticle gene delivery systems. Also, the authors highlight their philosophy and efforts on the development of l tyrosine-based polyphosphate nanoparticle-based non-viral gene delivery systems and assess the potential benefits and shortcomings of their approach. PMID- 19780713 TI - Responses of adipose-derived stem cells during hypoxia: enhanced skin regenerative potential. AB - Mesenchymal stem cells within the stromal-vascular fraction of subcutaneous adipose tissue (i.e., adipose-derived stem cells (ASCs)), have been used for tissue engineering. In addition to serving a building-block function, ASCs are reported to secrete growth factors that are essential for their function. Increasing evidence indicates that ASCs play a significant role in skin regeneration, a function that is enhanced by hypoxia through upregulating secretion of growth factors. Although the anatomical sites of ASCs in the body are relatively oxygen-deficient, ASCs are usually cultured under normoxic conditions (i.e., atmospheric oxygen levels). Culturing ASCs under physiologically relevant low-oxygen-tension conditions may uniquely benefit the expansion, differentiation, adhesion, growth factor secretion and regenerative potential of ASCs. Therefore, understanding the response and adaptation of ASCs to hypoxia may be invaluable for developing novel cell- and cyto-therapy strategies. This review highlights our current understanding of cellular and molecular responses of ASCs to hypoxia, focusing on the enhancement of ASC function and secretory activity by hypoxic culture conditions. PMID- 19780714 TI - Overcoming pre-existing adenovirus immunity by genetic engineering of adenovirus based vectors. AB - Adenovirus (Ad)-based vectors offer several benefits showing their potential for use in a variety of vaccine applications. Recombinant Ad-based vaccines possess potent immunogenic potential, capable of generating humoral and cellular immune responses to a variety of pathogen-specific antigens expressed by the vectors. Ad5 vectors can be readily produced, allowing for usage in thousands of clinical trial subjects. This is now coupled with a history of safe clinical use in the vaccine setting. However, traditional Ad5-based vaccines may not be generating optimal antigen-specific immune responses, and generate diminished antigen specific immune responses when pre-existing Ad5 immunity is present. These limitations have driven initiation of several approaches to improve the efficacy of Ad-based vaccines, and/or allow modified vaccines to overcome pre-existing Ad immunity. These include: generation of chemically modified Ad5 capsids; generation of chimeric Ads; complete replacement of Ad5-based vaccine platforms with alternative (human and non-human origin) Ad serotypes, and Ad5 genome modification approaches that attempt to retain the native Ad5 capsid, while simultaneously improving the efficacy of the platform as well as minimizing the effect of pre-existing Ad immunity. Here we discuss recent advances in- and limitations of each of these approaches, relative to their abilities to overcome pre-existing Ad immunity. PMID- 19780715 TI - Human adipose tissue precursor cells: a new factor linking regulation of fat mass to obesity and type 2 diabetes? AB - The current epidemic of obesity has caused a surge of interest in the study of the mechanisms regulating adipose tissue formation. It has been observed that adipose tissue contains a pool of adult stem cells with multipotent properties, which provide for the physiological cell turnover, and can be isolated and potentially utilized for tissue engineering and regenerative medical applications. These "stromal" cells exhibit pre-adipocyte characteristics, can be isolated from adipose tissue of adult subjects, propagated in vitro, and induced to differentiate into adipocytes. Different populations of multi-potent precursor cells can be isolated from human fat fragments. Thus, adipose precursors cells are a heterogeneous cells population, consisting of fibroblast-like multi potential stem cells generally termed adipose-derived stem cells (ASCs). In this review, we discuss some aspects of ASCs basic biology, the methodology involved in ASCs isolation and culture, and some implications of ASCs availability for the understanding of metabolic diseases in humans. PMID- 19780716 TI - MicroRNA mir-346 targets the 5'-untranslated region of receptor-interacting protein 140 (RIP140) mRNA and up-regulates its protein expression. AB - RIP140 (receptor-interacting protein 140) is a transcriptional co-repressor that regulates diverse genes such as those responsive to hormones and involved in metabolic processes. The expression of RIP140 is regulated by multiple hormonal activities in adipose tissue and cancer cell lines. However, it is unclear whether and how RIP140 is regulated post-transcriptionally. Using 5'RACE (rapid amplification of 5' cDNA ends), we have identified a novel 5' splice variant of RIP140 mRNA in mouse brain and P19 cells. A target sequence for miRNA (microRNA) mir-346 was found in the 5'UTR (5'-untranslated region) of RIP140 mRNA; this miRNA is also expressed endogenously in mouse brain and P19 cells. Gain- and loss of-function studies demonstrated that mir-346 elevates RIP140 protein levels by facilitating association of its mRNA with the polysome fraction. Furthermore, the activity of mir346 does not require Ago-2 (Argonaute 2). The expression of mir 346 enhances the gene repressive activity of RIP140. This is the first report demonstrating post-transcriptional regulation of RIP140 mRNA, involving the enhancing effect of a specific miRNA that targets RIP140's 5'UTR. PMID- 19780717 TI - Hereditary tubular transport disorders: implications for renal handling of Ca2+ and Mg2+. AB - The kidney plays an important role in maintaining the systemic Ca2+ and Mg2+ balance. Thus the renal reabsorptive capacity of these cations can be amended to adapt to disturbances in plasma Ca2+ and Mg2+ concentrations. The reabsorption of Ca2+ and Mg2+ is driven by transport of other electrolytes, sometimes through selective channels and often supported by hormonal stimuli. It is, therefore, not surprising that monogenic disorders affecting such renal processes may impose a shift in, or even completely blunt, the reabsorptive capacity of these divalent cations within the kidney. Accordingly, in Dent's disease, a disorder with defective proximal tubular transport, hypercalciuria is frequently observed. Dysfunctional thick ascending limb transport in Bartter's syndrome, familial hypomagnesaemia with hypercalciuria and nephrocalcinosis, and diseases associated with Ca2+-sensing receptor defects, markedly change tubular transport of Ca2+ and Mg2+. In the distal convolutions, several proteins involved in Mg2+ transport have been identified [TRPM6 (transient receptor potential melastatin 6), proEGF (pro-epidermal growth factor) and FXYD2 (Na+/K+-ATPase gamma-subunit)]. In addition, conditions such as Gitelman's syndrome, distal renal tubular acidosis and pseudohypoaldosteronism type II, as well as a mitochondrial defect associated with hypomagnesaemia, all change the renal handling of divalent cations. These hereditary disorders have, in many cases, substantially increased our understanding of the complex transport processes in the kidney and their contribution to the regulation of overall Ca2+ and Mg2+ balance. PMID- 19780718 TI - Endoplasmic reticulum stress in disease: mechanisms and therapeutic opportunities. AB - Various stresses, which impair ER (endoplasmic reticulum) function, lead to an accumulation of unfolded or misfolded proteins. ER stress triggers many rescuer responses, including a UPR (unfolded protein response). Increasing evidence has suggested that ER stress is involved in neurodegenerative diseases (Alzheimer's disease, Parkinson's disease and cerebral ischaemic insults), cancer, obesity and diabetes. In the present review, we consider the importance of ER stress under pathological conditions in mammals. Furthermore, we discuss the therapeutic potential for treatment targeting ER stress. PMID- 19780719 TI - Inhibitor selectivity in the clinical application of dipeptidyl peptidase-4 inhibition. AB - DPP-4 (dipeptidyl peptidase-4) degrades the incretin hormones GLP-1 (glucagon like peptide-1) and GIP (gastric inhibitory polypeptide), decreasing their stimulatory effects on beta-cell insulin secretion. In patients with Type 2 diabetes, meal-related GLP-1 secretion is reduced. DPP-4 inhibitors (alogliptin, saxagliptin, sitagliptin and vildagliptin) correct the GLP-1 deficiency by blocking this degradation, prolonging the incretin effect and enhancing glucose homoeostasis. DPP-4 is a member of a family of ubiquitous atypical serine proteases with many physiological functions beyond incretin degradation, including effects on the endocrine and immune systems. The role of DPP-4 on the immune system relates to its extra-enzymatic activities. The intracytosolic enzymes DPP-8 and DPP-9 are recently discovered DPP-4 family members. Although specific functions of DPP-8 and DPP-9 are unclear, a potential for adverse effects associated with DPP-8 and DPP-9 inhibition by non-selective DPP inhibitors has been posed based on a single adverse preclinical study. However, the preponderance of data suggests that such DPP-8 and DPP-9 enzyme inhibition is probably without clinical consequence. This review examines the structure and function of the DPP-4 family, associated DPP-4 inhibitor selectivity and the implications of DPP-4 inhibition in the treatment of Type 2 diabetes. PMID- 19780720 TI - Ambient temperature influences aging in an annual fish (Nothobranchius rachovii). AB - Extending lifespan by lowering ambient temperature in the habitat has been shown in a variety of organisms. Its mechanism, however, remains elusive. In this study, we examined the survivorship and the aging process of the annual fish (Nothobranchius rachovii) reared under high (30 degrees C), moderate (25 degrees C) and low (20 degrees C) ambient temperatures. The results showed that low ambient temperatures prolong survivorship, whereas high ambient temperatures shorten survivorship. At low ambient temperature, expression of senescence associated beta-galactosidase, lipofuscin, reactive oxygen species, lipid peroxidation, protein oxidation, mitochondrial density and ADP/ATP ratio were reduced compared with those reared at high and moderate temperatures, whereas catalase activity, Mn-superoxide dismutase activities, mitochondrial membrane potential and the levels of ATP, ADP, Sirt1 and Forkhead box O expression were elevated. The expression levels of Hsp70 and CIRP showed no significant difference under any of the ambient temperatures tested. We concluded that cellular metabolism, energy utilization and gene expression are altered at lower ambient temperature, which is associated with the extension of lifespan of the annual fish. PMID- 19780721 TI - Mapping of quantitative trait loci affecting eggshell quality on chromosome 9 in an F(2) intercross between two chicken lines divergently selected for eggshell strength. AB - Broken and cracked eggshells are major causes of significant economic losses to the egg production industry. The quantitative trait loci (QTL) on chromosome 9 influencing the quality of eggshells were identified by analysing an intercross between two parent lines developed from the same founder population by a two-way selection for eggshell strength with non-destructive deformation conducted over 14 generations. Chromosome-wide highly significant (P < 0.01) QTL associated with egg weight (EW), short length of egg (SLE), long length of egg (LLE) and eggshell weight were mapped to the distal region of chromosome 9. Among the QTL affecting EW, SLE and LLE, ovocalyxin-32 was identified as a potential candidate gene influencing eggshell traits. Marker-assisted selection based on these QTL could be used to develop strategies for reducing the breakage and cracking of eggs in commercial layer houses. PMID- 19780722 TI - Ovarian cancer screening: still waiting for the right answer. PMID- 19780723 TI - Population screening and early detection of ovarian cancer in asymptomatic women. AB - The National Breast and Ovarian Cancer Centre position statement: 'Population screening and early detection of ovarian cancer in asymptomatic women', was developed and agreed following a Forum in February 2009 attended by key Australian stakeholders. The final position statement and supporting background information have been endorsed by key Australian colleges and agencies. Position statement on population screening and early detection of ovarian cancer in asymptomatic women: 1) There is currently no evidence that any test, including pelvic examination, CA125 or other biomarkers, ultrasound (including transvaginal ultrasound), or combination of tests, results in reduced mortality from ovarian cancer. 2) There is no evidence to support the use of any test, including pelvic examination, CA125 or other biomarkers, ultrasound (including transvaginal ultrasound), or combination of tests, for routine population-based screening for ovarian cancer. 3) Further validation in large clinical trials is required before current or new biomarkers could be recommended for routine use in a population screening setting. PMID- 19780724 TI - Caesarean scar ectopic pregnancy: a single centre case series. AB - OBJECTIVE: To examine the characteristics, management and outcomes of 13 caesarean scar pregnancies (CSPs) at a single tertiary obstetric centre over a five-year period. METHODS: Retrospective cohort study. Cases were identified from interrogation of the institutional database with patient characteristics, management and outcome data extracted from the medical record chart and ultrasound image review. RESULTS: Thirteen cases of CSP were identified from 2002 2007. Median maternal age was 34 years (interquartile range (IQR) 32.2, 35.2) with a median parity of 2 (IQR 1, 3). In nine of 13 (69%) cases there was one prior caesarean section and > or = 2 in four of 13 (31%). The median gestation at diagnosis was 6.8 weeks (range 5.5-11.5). Vaginal bleeding was the most common presenting symptom (nine of 13 cases). The final diagnosis was made by ultrasound in 11 of 13 cases (84.6%) but the diagnosis was delayed in seven of 13 cases, including four that had an earlier ultrasound assessment. Treatment was with systemic methotrexate in seven cases with five (71.4%) requiring no further intervention. One case received intragestational sac and systemic methotrexate with a delayed hysterectomy as a result of molar complications. Two cases were treated with uncomplicated curettage and three by hysterectomy. Four women are known to have had pregnancies following the CSP. CONCLUSIONS: The diagnosis of CSP can be challenging, and awareness of this condition is needed, particularly as the incidence is increasing. There does not appear to be a clear association between number of prior caesarean deliveries and CSPs. No consistent management strategy was evident in our series, being based predominantly on patient factors and consultant resources rather than CSP features. PMID- 19780725 TI - Term breech singletons and caesarean section: a population study, Australia 1991 2005. AB - OBJECTIVE: To describe the method of birth of term breech singletons in Australia. DESIGN, SETTING AND PARTICIPANTS: A retrospective population-based study of women who gave birth to term breech singletons in Australia between 1 January 1991 and 31 December 2005 using data from the National Perinatal Data Collection. MAIN OUTCOME MEASURES: Caesarean section, vaginal breech birth. RESULTS: Method of birth changed for term breech singletons from 1991 (vaginal breech birth 23.1% versus caesarean (no labour 55.6%, labour 21.2%)) to 2005 (vaginal breech birth 3.7% versus caesarean (no labour 76.6%, labour 19.7%)). Overall, the population attributable risk percentage of term breech singletons for all caesarean sections declined from 10.2% in 1991 to 6.9% in 2005. CONCLUSION: Planned caesarean section is the standard method of birth for term breech singletons in Australia. Active measures including external cephalic version should be supported to reduce the rate of caesarean section where clinically indicated. Retention of a skilled clinical workforce is essential in the provision of the latter and to assist the minority of women having vaginal breech births. Breech presentation is not a major factor in the overall rise in caesarean section experienced by Australia since 1996. PMID- 19780726 TI - Twin deliveries and place of birth in NSW 2001-2005. AB - BACKGROUND: Twin pregnancies have an elevated risk of adverse outcomes, particularly preterm twins. AIMS: Describe the distribution of twin deliveries by hospital level, the associated perinatal and maternal morbidity, and determine predictors of perinatal morbidity and urgent transfer to a neonatal intensive care unit. METHODS: Longitudinally linked New South Wales delivery and hospital records for the years 2001-2005 were used to identify perinatal and maternal morbidity/mortality in twin pregnancies. Regression analysis was used to examine predictive factors, including birth hospital volume. RESULTS: At < or = 32 weeks, 88.1% of twins were delivered in tertiary referral hospitals. By 34-35 weeks, only 39.7% of twins were delivered in tertiary units. Gestational age was the primary predictor of perinatal morbidity/mortality. Perinatal morbidity/mortality and maternal morbidity were lowest for deliveries at 38 weeks. There was no evidence that planned caesarean section at < or = 38 weeks was protective against perinatal morbidity/mortality. There was an increased risk of perinatal morbidity/mortality (odds ratio (OR) = 2.22) for twins delivered at 33-35 weeks gestation at hospitals with < 500 deliveries per annum, and an increased risk of urgent neonatal transfer (OR = 2.06). Twin pairs for whom there was a > or = 20% discordance in birthweight had an increased risk of morbidity/mortality at 36-38 weeks (OR = 1.79). CONCLUSIONS: Both infant and maternal morbidity increase from 39 weeks gestation. Delivery of twins before 36 weeks at smaller hospitals (< 500 deliveries per annum) should be avoided. A twin pregnancy where there is a > or = 20% difference in estimated fetal weights should be considered for referral to a tertiary obstetric unit. PMID- 19780727 TI - A comparison of the Perinatal Society of Australia and New Zealand-Perinatal Death Classification system and relevant condition at death stillbirth classification systems. AB - BACKGROUND: Stillbirths comprise two-thirds of all perinatal mortality. A classification system with low 'unexplained' stillbirth rates is important when developing prevention strategies. AIMS: This study aims to (i) determine whether the proportion of stillbirths classified as 'unexplained' is reduced, by using the relevant condition at death (ReCoDe) stillbirth classification system, compared with the Perinatal Society of Australia and New Zealand - Perinatal Death Classification (PSANZ-PDC) system; and (ii) compare the proportion of stillbirths attributed to fetal growth restriction and other causes by each system. METHODS: The ReCoDe stillbirth classification system was applied to the National Women's Health's stillbirth database for years 2004-2007. The proportion of stillbirths classified as 'unexplained' and as a result of fetal growth restriction was compared between the ReCoDe and the PSANZ-PDC systems using the chi(2) test. RESULTS: The proportion of stillbirths classified as unexplained was less with ReCoDe compared with PSANZ-PDC (8.5% (n = 26) vs 14.1% (n = 43) P = 0.04). The proportion with the primary cause attributed to fetal growth restriction was increased with ReCoDe compared with PSANZ-PDC (23.2% (n = 71) vs 8.2% (n = 25) P < 0.0001). However, 44.8% (n = 137) of all stillbirths were small for gestational age (birthweight < 10th customised centile). The most common primary cause or condition at death by both systems was congenital abnormalities. CONCLUSION: The proportion of stillbirths classified as unexplained was less with ReCoDe compared with PSANZ-PDC but rates with either method were low compared with earlier classification systems. Fetal growth restriction was listed as the primary condition more commonly with ReCoDe compared with PSANZ-PDC because of different definitions. PMID- 19780728 TI - Systematic multidisciplinary approach to reporting perinatal mortality: lessons from a five-year regional review. AB - BACKGROUND: Because of differences in reporting criteria throughout the world, comparing perinatal mortality rates and identifying areas of concern can be complicated and imprecise. AIMS: To detail the systematic approach to reporting perinatal deaths and to identify any significant differences in outcomes in the Australian Capital Territory (ACT). METHODS: Review of perinatal deaths from 2001 to 2005 in the ACT using the Australian and New Zealand Antecedent Classification of Perinatal Mortality (ANZACPM) and the Australian and New Zealand Neonatal Death Classification (ANZNDC) systems. RESULTS: ACT residents' perinatal mortality rate was 10.6 per 1000 total births, fetal death rate 7.5 per 1000 total births and neonatal death rate 3.2 per 1000 live births. The three leading antecedent causes of perinatal death were congenital anomalies, spontaneous preterm birth and unexplained antepartum death. The three leading causes of neonatal death were extreme prematurity, cardiorespiratory disorders and congenital anomalies. Multiple births attributed to 20% (65 of 321) of perinatal deaths. Perinatal autopsy was performed in 50% of cases, but in only 64% of unexplained antepartum deaths. CONCLUSIONS: Causes of perinatal death for the ACT and surrounding New South Wales region are similar to other states using this classification system. The following are considered important lessons to promote accurate perinatal mortality reporting: (i) a universal reporting system for Australia utilising a multidisciplinary team; (ii) a high perinatal autopsy rate, especially in the critical area of antepartum death with no identifiable cause; and (iii) standardised definitions for avoidability. Attention to these areas may prompt further research and changes in practice to further reduce perinatal mortality. PMID- 19780729 TI - Prospective randomised multicentre trial with the birth trainer EPI-NO for the prevention of perineal trauma. AB - BACKGROUND: In several non-randomised trials training with EPI-NO increased the rate of intact perineum and decreased episiotomy rates, shortened the second stage of labour and lowered use of pain killers. AIMS: To verify the preliminary results with EPI-NO in a prospective randomised trial. METHODS: Randomised, single-blind multicentre trial in four university hospitals in Germany including 276 primigravidae. RESULTS: After training with EPI-NO we observed a significant increase in the incidence of intact perineum (37.4% vs 25.7%; P = 0.05) and a tendency towards lower episiotomy rates (41.9% vs 50.5%; P = 0.11). We found no significant differences between the two groups regarding incidence of perineal tears, duration of second stage of labour, use of pain relief and rate of vaginal infection. CONCLUSIONS: Training with EPI-NO increases significantly the likelihood of having an intact perineum and reduces the episiotomy rate. PMID- 19780730 TI - Population-based carrier screening for cystic fibrosis in Victoria: the first three years experience. AB - BACKGROUND: Cystic fibrosis (CF) is the most common inherited, life-shortening condition affecting Australian children. The carrier frequency is one per 25 and most babies with CF are born to parents with no family history. Carrier testing is possible before a couple has an affected infant. AIMS: To report the outcomes of a carrier screening program for CF. METHOD: Carrier screening was offered to women and couples planning a pregnancy, or in early pregnancy, through obstetricians and general practitioners in Victoria, Australia. Samples were collected by cheek swab and posted to the laboratory. Twelve CFTR gene mutations were tested. Carriers were offered genetic counselling and partner testing. Carrier couples were offered prenatal testing by chorionic villous sampling (CVS) if pregnant. The number of people tested, carriers detected and pregnancy outcomes were recorded from January 2006 to December 2008. RESULTS: A total of 3200 individuals were screened (3000 females). One hundred and six carriers were identified (one per 30, 95% confidence interval one per 25, one per 36). All carrier partners were screened, and nine carrier couples identified (total carriers 115). Ninety-six individuals (83%) were carriers of the p.508del mutation. Of the nine carrier couples, six were pregnant at the time of screening (five natural conception and one in vitro fertilisation) and all had CVS (mean gestation 12.5 weeks). Two fetuses were affected, three were carriers and one was not a carrier. Termination of pregnancy was undertaken for the affected fetuses. CONCLUSION: Carrier screening for CF by obstetricians and general practitioners by cheek swab sample can be successfully undertaken prior to pregnancy or in the early stages of pregnancy. PMID- 19780731 TI - Incidence and risk factors predicting blood transfusion in caesarean section. AB - BACKGROUND: Routine preoperative evaluation for caesarean section (CS) has commonly included a blood type and screen evaluation due to risk of blood transfusion. However, there have been no objective local data to support such practices. AIMS: To evaluate the cost-effectiveness of blood type and screen testing for CS. METHODS: This retrospective study reviewed all singleton CS at a tertiary hospital using data from Blood Bank Registry and Obstetric Database, from 1 January 2004 to 31 December 2005. Clinical variables including demographic characteristics, estimated blood loss, indications for CS, preoperative haemoglobin and indications for transfusions were gathered. All patients who had blood transfusion recorded in Obstetric Database or in Blood Bank Registry had their medical records reviewed by two reviewers to confirm accuracy and identify risk factors for haemorrhage. RESULTS: Of 2212 patients with singleton pregnancy who underwent CS, 14 (0.63%) required a blood transfusion. The risk of blood transfusion for elective and emergency CS are 3.9 per 1000 and 9.8 per 1000, respectively. In the absence of risk factors identified in this study, no women (of a total of 1293 elective CS) required blood transfusion. CONCLUSION: In the absence of significant risk factors for haemorrhage at CS in a tertiary setting, routine blood type and screen testing does not enhance patient care. In the rare event that a patient without previously identifiable risk factors requires an urgent blood transfusion, O negative blood could be given in the interim pending formal determination of type and cross-match. PMID- 19780732 TI - Postnatal testing for diabetes in Australian women following gestational diabetes mellitus. AB - BACKGROUND: Postnatal blood glucose testing is recommended for reclassification of glucose tolerance following a pregnancy affected by gestational diabetes mellitus (GDM); however, there are limited data on the postnatal follow-up sought by Australian women. AIMS: To describe postnatal diabetes testing patterns in Australian women following a pregnancy affected by GDM and identify factors associated with return for follow-up testing in accordance with the Australasian Diabetes in Pregnancy Society (ADIPS) guidelines. METHODS: A cross-sectional self administered survey of 1372 women diagnosed with GDM between 2003 and 2005, sampled from the National Diabetes Services Scheme database. RESULTS: Postnatal diabetes testing was reported by 73.2% of survey respondents with 27.4% returning for an oral glucose test tolerance at six to eight weeks post-GDM pregnancy. Using logistic regression analysis, factors associated with appropriate postnatal testing were receiving individualised risk reduction advice (odds ratio (OR) 1.41 (1.08,1.84)) or written information (OR 1.35 (1.03,1.76)) and in two-way interactions, being under the care of an endocrinologist and not tertiary educated (OR 2.09 (1.49,2.93)) as well as seeing an obstetrician and diabetes educator during pregnancy (OR 1.72 (1.19,2.48)). Every five years increase in age reduced the likelihood of a woman returning for testing by 17%. CONCLUSIONS: Specialist diabetes care in non-tertiary educated women, or a team approach to management with diabetes education and obstetric care may act to reinforce the need for postnatal diabetes testing in accordance with the ADIPS guidelines. Individualised follow up from a health professional and provision of written information following a GDM pregnancy may also encourage return for postnatal testing in this high-risk group. PMID- 19780733 TI - Castor oil for induction of labour: not harmful, not helpful. AB - BACKGROUND: Castor oil is one of the most popular drugs for induction of labour in a non-medical setting; however, published data on safety and effectiveness of this compound to induce labour remain sparse. AIM: To assess the safety and effectiveness of castor oil for induction of labour in pregnancies with an ultrasound estimated gestational at birth of more than 40 weeks. METHODS: Data were extracted from hospital-based records of all pregnant women who attended antenatal clinics on the Thai-Burmese border and who were more than 40 weeks pregnant. The effectiveness of castor oil to induce labour was expressed as time to birth and analysed with a Cox proportional hazards regression model. Measures associated with safety were fetal distress, meconium-stained amniotic fluid, tachysystole of the uterus, uterine rupture, abnormal maternal blood pressure during labour, Apgar scores, neonatal resuscitation, stillbirth, post-partum haemorrhage, severe diarrhoea and maternal death. Proportions were compared using Fisher's exact test. RESULTS: Of 612 women with a gestation of more than 40 weeks, 205 received castor oil for induction and 407 did not. The time to birth was not significantly different between the two groups (hazard ratio 0.99 (95% confidence interval: 0.81 to 1.20; n = 509)). Castor oil use was not associated with any harmful effects on the mother or fetus. CONCLUSIONS: Castor oil for induction of labour had no effect on time to birth nor were there any harmful effects observed in this large series. Our findings leave no justification for recommending castor oil for this purpose. PMID- 19780734 TI - Fetal macrosomia and pregnancy outcomes. AB - BACKGROUND: Pregnancies with a macrosomic fetus comprise a subgroup of high-risk pregnancies. There is uncertainty in the clinical management and outcomes of such pregnancies. AIM: We sought to examine clinical management and maternal and fetal outcomes in pregnancies with macrosomic infants at Royal Brisbane and Women's Hospital (RBWH). METHODS: Data from 276 macrosomic births (weighing > or = 4500 g) and 294 controls (weighing 3250-3750 g) delivered during 2002-2004 at RBWH were collected from the hospital database. Univariate and logistic regression analyses were performed for maternal risk factors and maternal and neonatal outcomes that were associated with fetal macrosomia. RESULTS: Macrosomia was more than two times likely in women with body mass index (BMI) of > 30 kg/m(2) (odds ratio (OR) 2.41, 95% confidence interval (CI) 1.26-4.61) and in male infant sex (OR 2.05, 95% CI 1.35-3.12), and four times more likely in gestation of > 40 weeks (OR 3.93, 95% CI 1.99-7.74). Maternal smoking reduced the risk of fetal macrosomia (OR 0.27, 95% CI 0.14-0.51). Macrosomia was associated with nearly two times higher risk of emergency caesarean section (OR 1.75, 95% CI 1.02-2.97) and maternal hospital stay of > 3 days (OR 1.66, 95% CI 1.11-2.50), and four times higher risk of shoulder dystocia (OR 4.08, 95% CI 1.62-10.29). Macrosomic infants were twice as likely to have resuscitation (OR 2.21, 95% CI 1.46-3.34) and intensive care nursery admission (OR 1.89, 95% CI 1.03-3.46). CONCLUSION: Macrosomia was associated with an increased risk of adverse maternal and neonatal health outcomes. Optimal management strategies of macrosomic pregnancies need evaluation. PMID- 19780735 TI - Kjelland's forceps in the new millennium. Maternal and neonatal outcomes of attempted rotational forceps delivery. AB - BACKGROUND: The use of Kjelland's forceps is now uncommon, and published maternal and neonatal outcome data are from deliveries conducted more than a decade ago. The role of Kjelland's rotational delivery in the 'modern era' of high caesarean section rates is unclear. AIMS: To compare the results of attempted Kjelland's forceps rotational delivery with other methods of instrumental delivery in a tertiary hospital. METHODS: Retrospective review of all instrumental deliveries for singleton pregnancies 34 or more weeks gestation in a four-year birth cohort, with reference to adverse maternal and neonatal outcomes. RESULTS: The outcomes of 1067 attempted instrumental deliveries were analysed. Kjelland's forceps were successful in 95% of attempts. Kjelland's forceps deliveries had a rate of adverse maternal outcomes indistinguishable from non-rotational ventouse, and lower than all other forms of instrumental delivery. Kjelland's forceps also had a lower rate of adverse neonatal outcomes than all other forms of instrumental delivery. CONCLUSIONS: Prudent use of Kjelland's forceps by experienced operators is associated with a very low rate of adverse maternal and neonatal outcomes. Training in this important obstetric skill should be reconsidered urgently, before it is lost forever. PMID- 19780736 TI - An anonymous survey of registrar training in the use of Kjelland's forceps in Australia. AB - Large series suggest that, when used with appropriate care and skill, rotational deliveries with Kjelland's forceps are a safe and useful procedure. We surveyed obstetric trainees in Australia to assess their experience with, and intentions to use, Kjelland's forceps. The response rate was 65%, and it was uncommon for even senior trainees to have performed more than ten Kjelland's forceps rotations during their training. Ninety-four per cent of final-year trainees stated they did not intend to use Kjelland's forceps in their consultant practice. PMID- 19780737 TI - Cryotherapy as the treatment modality of postcoital bleeding: a randomised clinical trial of efficacy and safety. AB - BACKGROUND: Postcoital bleeding is a common gynaecological problem that impacts on a woman's quality of life and sexual function. There is little systematic research into its management. AIMS: To assess the efficacy and side-effects of cryotherapy as treatment for postcoital bleeding. METHODS: A prospective randomised controlled trial was conducted in a tertiary referral hospital in Hong Kong. A total of 85 women who presented with postcoital bleeding were recruited, and randomised to cryotherapy or no treatment. The treatment group received cryotherapy with compressed carbon dioxide through a cryoprobe placed on the cervix, and controls had cryoprobe on the cervix without compressed carbon dioxide flow. All recruited women were followed up two weeks, three months and six months to review their symptoms and response to the treatment. RESULTS: The treatment group had a significantly better long-term cure rate and improvement rate. At six months, the cryotherapy group reported a cure rate of 72.1% while that in the control group the cure rate was 50.0% (P = 0.04). The number needed to treat was 5. The mean improvement rate of the cryotherapy group was 82.88% +/- 35.87 but was only 61.62% +/- 55.30 in the control group (P = 0.04). The results were more significant in women with the defined pathological cervix. Apart from the vaginal discharge at second week follow up in the treatment group, there was no statistical significant difference in side-effects and complications among two groups. CONCLUSION: Our study demonstrated that cryotherapy is a safe and an effective treatment for postcoital bleeding. PMID- 19780738 TI - Randomised double-blind trial of the effect of vitamin C on dyspareunia and vaginal discharge in women receiving doxycycline and triple sulfa for chlamydial cervicitis. AB - BACKGROUND: Chlamydia trachomatis is the most common bacterial cause of cervicitis. AIM: The aim of this randomised, double-blind trial was to compare the effect of vitamin C on dyspareunia and vaginal discharge in women receiving doxycycline and triple sulfa for chlamydial cervicitis. METHODS: Eighty women with increased anti-C. trachomatis IgM, reporting abnormal vaginal discharge and dyspareunia, demonstrating signs of cervical oedema and erythema and friability of cervix were included. Thirty-nine women received doxycycline capsules 100 mg twice daily plus triple sulfa vaginal cream once daily for ten days, and 41 received doxycycline capsules 100 mg twice-daily and triple sulfa vaginal cream once daily plus vitamin C tablets 250 mg once daily for ten days. Women were evaluated at follow-up visit, eleventh day, following completion of intervention. ANALYSIS: The effect of treatment was assessed regarding clinical criteria (presence of endocervical mucopus and cervical severity score) and presence of dyspareunia. Statistical analysis was carried out using spss version 11.5. RESULTS: The mean age of women was 30.6 +/- 8.4 years. There was no relationship between demographics and dyspareunia and discharge (P > 0.05). There was statistically significant difference between the effect of 'doxycycline plus triple sulfa' and 'doxycycline, triple sulfa plus vitamin C' on discharge and dyspareunia (P = 0.005, P < 0.001, respectively). Most frequently reported drug related adverse event in both groups was heartburn. CONCLUSION: Adding vitamin C to doxycycline and triple sulfa was more efficient than standard regimen (doxycycline and triple sulfa without vitamin C) in treating chlamydial cervicitis. PMID- 19780739 TI - A pilot survey of the impact of menstrual cycles on adolescent health. AB - BACKGROUND: The experience of menstruation and reproductive health by adolescent girls has been poorly studied in New Zealand. AIMS: To develop and pilot a Web based survey of 16-year-olds' experience of menstruation and reproductive health with the eventual objective of conducting a larger population-based survey. A secondary aim was to report on the experience of menstrual and reproductive health in a group of 16-year-old girls in an urban setting. METHODS: A Web-based survey was developed and tested in 2006 with assistance of a multidisciplinary advisory group. The final version of the questionnaire had 146 questions in 11 sections and the topics were menstrual history, general health including use of medications, access to medical care or health information, sexual health, family history and personal information including smoking, height, weight, ethnicity, paid employment of parents, drug and alcohol use and exercise patterns. RESULTS: Seventy-five 16-year-old students completed the survey. Twenty-five per cent considered that their periods were quite a bit or a lot of trouble and 10% avoided certain activities during their menstrual periods, nearly 50% of girls always experienced some pain with every period, and 30% had seen a health professional about their period pains. Thirty-three stated that menstruation was moderately to severely painful and that daily activity was affected. Fifty per cent of girls were sexually active and of these 80% described it as painful. CONCLUSIONS: The Web-based survey was a successful approach to collecting information and could be used in a larger study. PMID- 19780740 TI - Magnetic resonance imaging for assessment of deep endometrial invasion for patients with endometrial carcinoma. AB - AIMS: To evaluate the value of magnetic resonance imaging (MRI) for the detection of deep myometrial invasion. METHODS: The patient group consisted of 53 women with endometrial cancer who underwent preoperative workup, including MRI, and surgical staging between August 1999 and August 2008 at Korea University Medical Center, Seoul, South Korea. The pathological data from surgical staging were compared with the preoperative MRI results. RESULTS: The mean age of the patients was 51 years and most patients had endometrioid cancer. On pathological evaluation of the myometrium, 20.8% had a deep myometrial invasion. The sensitivity, specificity, accuracy, positive predictive value and negative predictive value of MRI in detecting deep myometrial invasion were 50.0%, 89.7%, 79.2%, 63.6% and 83.3%, respectively. Evaluation of MRI findings and tumour grades by preoperative biopsy had a sensitivity and specificity of 88.9% and 87.5%, respectively, with a kappa of 0.764. CONCLUSION: In patients with endometrial cancer, MRI is limited in its ability to detect deep myometrial invasion. The combination of MRI findings and tumour histology or grade can be helpful in determining if lymphadenectomy is necessary. PMID- 19780741 TI - Discrepancies between clinical staging and pathological findings of operable cervical carcinoma with stage IB-IIB: a retrospective analysis of 818 patients. AB - INTRODUCTION AND OBJECTIVES: Cervical cancer is the only gynaecological cancer that is staged clinically. The clinical stage of cervical cancer relies largely on the pelvic examination. The aim of this study is to analyse the discrepancy between clinical stage and pathological results, and to explore the accuracy of pelvic examination. METHODS: We collected retrospective data from 818 patients with cervical carcinoma staged IB-IIB, who were treated with primary surgery from January 1999 to June 2007. Clinical stages of those patients were determined by pelvic examination without anaesthesia. After surgery, all the patients were assigned to pT category according to the pathological findings. Comparisons were made between these two stages. RESULTS: The total concordance between clinical stage and pT category for stage IB-IIB was 53.1%, with an overestimation of 37.3% and an underestimation of 9.7%. The concordance in stage IB1, stage IB2, stage IIA and stage IIB were 85.4%, 77.4%, 35.3% and 20.5%, respectively. The most significant discrepancy was caused by the failure to detect the parametrial invasion accurately in stage IIB. The accuracy of pelvic examination to determine vaginal and parametrial disease was 70.2% and 74.0%, respectively. CONCLUSIONS: There are significant discrepancies between clinical stage and pathological results. Pelvic examination has its limitations in staging determination. Thus for operable cervical cancer, clinical stage alone is not reliable for selecting postoperative therapies and surgical staging system may be considered. PMID- 19780742 TI - The effect of elevated serum estradiol levels on the day of human chorionic gonadotropin injection on pregnancy outcomes in an assisted reproduction program. AB - BACKGROUND: Women who have a high estradiol level on the day of human chorionic gonadotropin injection are considered to have their in vitro fertilisation treatments compromised. How this really affects the pregnancy rates needs to be questioned. AIM: To determine if elevated serum estradiol levels on the day of human chorionic gonadotropin injection have a deleterious effect on clinical and ongoing pregnancy rates in an assisted reproduction program. METHODS: A retrospective analysis was done of women with estradiol levels higher than 10,000 pmol/L and women with estradiol levels between 8000-10,000 pmol/L on the day of ovulation trigger undergoing in vitro fertilisation treatment at the Fertility Unit of the Royal Prince Alfred Hospital, University of Sydney, Australia. Pregnancy rates were compared for those having fresh embryo transfers and those having frozen thawed embryo transfers in subsequent cycles. RESULTS: There was no difference between the groups in terms of clinical and ongoing pregnancy rates. CONCLUSION: Frozen thawed embryos obtained from controlled ovarian hyperstimulation cycles resulted in similar clinical and ongoing pregnancy rates as those obtained in previous fresh embryo transfer cycles. PMID- 19780743 TI - Treatment of suction termination of pregnancy-retained products with misoprostol markedly reduces the repeat operation rate. AB - A six-year audit of clinical outcomes following the treatment of suction termination of pregnancy-retained products of conception symptoms with 200 microg of misoprostol orally or sublingually three times a day for six doses showed that it was 93% effective and it reduced the repeat dilation and curettage rate by 79.6% (P < 0.001). PMID- 19780744 TI - The obstructed hemivagina, ipsilateral renal anomaly, uterus didelphys triad. AB - The triad of obstructed hemivagina, renal anomaly and uterus didelphys is an uncommon cause of abdominal pain and menstrual discomfort in adolescent girls. Accurate diagnosis and surgical treatment can be delayed for several months or even years. Adolescent girls presenting with these symptoms should have a baseline pelvic ultrasound scan to establish uterine anatomy. In those with ultrasound findings of Mullerian anomalies appropriate follow up would include a magnetic resonance imaging, preferably at a tertiary centre with expertise in interpretation of Mullerian anatomy, as well as early consultation and referral to a centre with experience in the management of these rare conditions. Appropriate surgery would be a single stage procedure to either excise or completely divide the obstructing septum. There is currently no consensus on concurrent laparoscopy. We present a case series of four patients with the triad of uterus didelphys, obstructed hemivagina and ipsilateral renal agenesis managed between 2005-2009 at a tertiary centre for paediatric and adolescent gynaecology. PMID- 19780745 TI - Primary aldosteronism and pregnancy: a case report. PMID- 19780746 TI - Uterine perfusion following laparoscopic clipping of uterine arteries at myomectomy. AB - Laparoscopic clipping of uterine arteries facilitates laparoscopic myomectomy with minimal blood loss. This paper shows the return to normal myometrial perfusion following this procedure with literary evidence of the safety and efficacy of this technique. PMID- 19780747 TI - Post-partum pneumoperitoneum: not a surgical emergency. PMID- 19780749 TI - Comment on: The early pregnancy assessment project: The effect of cooperative care in the emergency department for management of early pregnancy complications. Aust N Z J Obstet Gynaecol 2009; 49: 110-114. PMID- 19780750 TI - Preventing repeat abortions. PMID- 19780751 TI - Comment on: Association of maternal pre-pregnancy weight with birth defects: Evidence from a case-control study in Western Australia. Aust N Z J Obstet Gynaecol 2009; 49: 11-15. PMID- 19780755 TI - Pseudocatalase and narrowband ultraviolet B for vitiligo: clearing the picture. PMID- 19780757 TI - Distinctive cell properties of B cells carrying the BCL2 translocation and their potential roles in the development of lymphoma of germinal center type. AB - The BCL2/IGH translocation is a hallmark of follicular lymphoma and germinal center B-cell type diffuse large B-cell lymphoma. Although a strong determinant of these histological subtypes, this translocation is insufficient by itself for lymphomagenesis, so that other genetic alterations are required. To clarify how the BCL2 translocation contributes to the development of specific lymphoma subtypes, we used chimeric mouse models and a bone marrow transplantation system to examine the biological features of BCL2-overexpressing B cells. These cells showed a cell-autonomous differentiation preference for follicular B cells. Their cell cycle progression was enhanced in wild-type but not in Emu-BCL2 transgenic mice, indicating that the low proliferative activity of B cells in Emu-BCL2 transgenic mice is partly due to their specific microenvironment, which is caused by the abnormal B cells themselves. Moreover, in vitro experiments demonstrated that Emu-BCL2(+) B cells have reduced responsiveness to terminal differentiation stimulation. According to these results, we hypothesize that B cells that have undergone BCL2/IGH translocation might possibly be forced to localize in follicles, and accumulate genetic abnormalities by being subjected to recurrent stimulation. Our findings lead us to propose that B cells carrying the BCL2/IGH translocation comprise a distinctive cell population that leads to the development of germinal center B-cell type lymphoma. PMID- 19780758 TI - Identification of transforming activity of free fatty acid receptor 2 by retroviral expression screening. AB - Gallbladder cancer (GBC) is a highly fatal malignancy in humans. Genetic alterations in KRAS or TP53 as well as overexpression of ERBB2 have been shown to contribute to the development of certain types of GBC. However, many cases of GBC do not harbor such genetic changes, with other transforming events awaiting discovery. We here tried to identify novel cancer-promoting genes in GBC, with the use of a retroviral cDNA expression library. A retroviral cDNA expression library was constructed from a surgically resected clinical specimen of GBC, and was used to infect 3T3 fibroblasts in a focus formation assay. cDNA incorporated into the transformed foci was rescued by PCR. One such cDNA was found to encode free fatty acid receptor 2 (FFAR2), a G protein-coupled receptor for short-chain fatty acids. The oncogenic potential of FFAR2 was confirmed both in vitro with the focus formation assay and by evaluation of cell growth in soft agar as well as in vivo with a tumorigenicity assay in nude mice. The isolated FFAR2 cDNA had no sequence alterations, suggesting that upregulation of FFAR2 expression may contribute to malignant transformation. Indeed, all of quantitative RT-PCR, in situ hybridization, and immunohistochemical analyses showed that the amount of FFAR2 mRNA and its protein product was increased in digestive tract cancer specimens. Furthermore, short-chain fatty acids potentiated the mitogenic action of FFAR2 in 3T3 cells. Our data thus, for the first time, implicate FFAR2 in carcinogenesis of the digestive tract. PMID- 19780759 TI - Pharmacokinetic and pharmacodynamic modelling of the novel human granulocyte colony-stimulating factor derivative Maxy-G34 and pegfilgrastim in rats. AB - OBJECTIVES: This study aims to compare pharmacokinetics and pharmacodynamics of pegfilgrastim, a pharmaceutical recombinant human granulocyte colony-stimulating factor (rhG-CSF), with that of a newly developed reagent, Maxy-G34. This comparison was performed using rat experiments and biomathematical modelling of granulopoiesis. METHODS: Healthy rats and those with cyclophosphamide-induced neutropenia were treated with either pegfilgrastim or Maxy-G34 under various schedules. Time courses of absolute neutrophil count (ANC) and G-CSF serum level were measured and we constructed a combined pharmacokinetic/pharmacodynamic model of both drugs. Neutropenic episodes were assessed by experimental data and model simulations. RESULTS: Both Pegfilgrastim and Maxy-G34 showed strong dose dependent efficacy in reducing neutropenic episodes. However, time courses of ANC and G-CSF serum levels were markedly different. The biomathematical model showed good agreement with these data. We estimated that differences between the two drugs could be explained by lower bioavailability and reduced elimination of Maxy G34. Based on the data and model interpolations, we estimated that Maxy-G34 is superior in reducing neutropenic episodes. Also, we predicted that G-CSF administration 48 h after cyclophosphamide would be superior to its administration after 2 or 24 h, for both derivatives. CONCLUSION: Maxy-G34 is a highly potent drug for stimulation of neutrophil production in rats. By our modelling approach, we quantified differences between Maxy-G34 and pegfilgrastim, related to pharmacokinetic parameters. Model simulations can be used to estimate optimal dosing and timing options in the present preclinical rat model. PMID- 19780760 TI - Dimethylthiazolidine carboxylic acid as a rigid p3 unit in inhibitors of serine proteases: application to two targets. AB - Serine proteases are a very large class of enzymes, many of which represent important targets for therapeutic agents against a wide variety of disease states. The similarity in active site architecture for these proteases has often allowed inhibitor design strategies for a particular target to be successfully applied to other enzymes in the class. In many cases, the presence of a bulky P3 amino acid residue in peptide-based inhibitors is central to conferring an extended peptide conformation, critical to binding of the ligands to serine protease active sites. The dimethylthiazolidine carboxylic acid 'residue' was found to be effective as a novel P3 replacement in peptidomimetic inhibitors of two distinct serine proteases, the hepatitis C NS3 protease and the human cytomegalovirus maturational protease. An array of NMR methods was used to confirm that the dimethylthiazolidine carboxylic acid unit indeed confers conformational and dynamic properties very similar to that of the rigidified parent structures. PMID- 19780761 TI - Bacteriology of external ocular infections in Aba, South Eastern Nigeria. AB - BACKGROUND: Bacteria are microbial agents that frequently cause infections of the eye and possible loss of vision. METHOD: The common isolates were studied in 298 bacterial infections of the anterior eye, consisting of 35 blepharitis, 208 conjunctivitis and 55 keratitis. Isolates were cultured in blood agar and chocolate agar. Each strain's susceptibility to the antibiotics was determined using a standard table of antibiotic susceptibility. RESULTS: In decreasing order of frequency, the implicated bacteria were Staphylococcus aureus 80 (23.7 per cent), Staphylococcus albus 65 (19.2 per cent), Pseudomonas aeruginosa 34 (10.1 per cent), Streptococcus pneumoniae 29 (8.6 per cent), Haemophilus influenzae 26 (7.7 per cent), Streptococcus pyogene 20 (6.2 per cent), Klebsiella pneumoniae 18 (6.2 per cent), Escherichia coli 15 (4.4 per cent), Neisseria gonorrhoeae 13 (3.9 per cent), Streptococcus viridans 11 (3.5 per cent), Moraxella catarrhalis 10 (3.0 per cent), Streptococcus faecalis 5 (1.5 per cent), Proteus mirabilis 5 (1.5 per cent) and Neisseria meningitides 1 (0.3 per cent). Bacteria were isolated most frequently from infections of the conjunctiva (222, 66.7 per cent), then the cornea (65, 20.1 per cent) and least from the eyelids (44, 13.2 per cent). Bacterial isolates varied in their clinical features (p < 0.01). The age distribution showed isolations of 77 (23.2 per cent) and 79 (23.7 per cent) in the age groups of newborn to under three years and three to under 12 years, respectively. This was comparable to 66 (19.8 per cent) for the 12 to under 18 years, 61 (18.3 per cent) for the 18 to under 40 years age group and 50 (15 per cent) for those 40 years and above. Bacterial isolates had no predilection for the age of patients (p < 0.95). Conjunctivitis was diagnosed more in children, 60 (28.8 per cent) in the newborn to under three years and 53 (25.5 per cent) in the three to under 12 years age groups. Blepharitis was diagnosed most frequently (15, 42.8 per cent) in adolescents 12 to under 18 years, while keratitis was more in adults (20, 36.4 per cent) in the 18 to under 40 years and (15, 27.3 per cent) in the 40 years and above. Diagnosis varied among age groups but there was no relationship between sex and diagnosis (p < 0.75). Klebsiella pneumoniae was the most resistant to all the anti-bacterial preparations. The bacterial isolates were more susceptible to the second generation quinolones than the first. CONCLUSION: The study recommends that quinolones be available as ophthalmic preparations to be prescribed by the qualified practitioners to avoid development of resistance from indiscriminate use. PMID- 19780762 TI - Analysis of human myocardial dynamics using virtual markers based on magnetic resonance imaging. AB - SUMMARY BACKGROUND: Myocardial dynamics are three-dimensional (3D) and time varying. Cineradiography of surgically implanted makers in animals or patients is accurate for assessing these events, but this invasive method potentially alters myocardial motion. The aim of the study was to quantify myocardial motion using magnetic resonance imaging (MRI) and hence to provide a non-invasive approach to characterize 3D myocardial dynamics. METHODS: Myocardial motion was quantified in ten normal volunteers by tracking the Lagrangian motion of individual points (i.e. virtual markers), based on time-resolved 3D phase-contrast MRI data and Fourier tracking. Nine points in the myocardium were tracked over the entire cardiac cycle, allowing a wire frame model to be generated and systolic and diastolic events identified. RESULTS: Radius of curvature of the left ventricular (LV) wall was calculated from the virtual markers; the ratio between the anterior posterior (AP) and septal-lateral (SL) walls in the LV shows an oval shape of the apical short axis plane at end systole (ES) and more circular at end diastole (ED). The AP/SL ratio for the basal plane shows an oval shape at ES and ED. We found that the rotation of the basal plane in ES was less compared to the apical plane [-2.0 +/- 2.2 versus 4.1 +/- 2.6 degrees (P<0.005)]. The apical plane rotated counter clock wise as viewed from the apex. CONCLUSION: This new non invasive tool, despite current limitations in temporal and spatial resolution, may provide a comprehensive set of virtual myocardial markers throughout the entire LV without the confounding effects introduced by surgical implantation. PMID- 19780763 TI - Genotype-phenotype studies in infantile spinal muscular atrophy (SMA) type I in Germany: implications for clinical trials and genetic counselling. AB - We reviewed the natural history and assessed the SMN2 copy number of 66 patients with infantile spinal muscular atrophy (SMA) type I born between 2000 and 2005 in Germany whose diagnosis was confirmed by a homozygous SMN1 deletion in the first 6 months of life. After excluding patients who had received valproic acid, the median/mean age at disease endpoint was 6.1/7.3 months (range 0.0-34.0). Four (6.1%) patients with one SMN2 copy had severe SMA type '0' with joint contractures and respiratory distress from birth. Median/mean age at onset (months) in 57 (86.3%) patients with two SMN2 copies was 1.2/1.3, and 3.5/3.4 in 5 (7.6%) patients with three SMN2 copies. Median/mean age at disease endpoint was 6.5/7.8 months (range 0.5-30) in patients with two SMN2 copies. All patients with three SMN2 copies were still alive at 10-55 months, two of them under permanent ventilation. Our data are relevant for prognostication and genetic counselling. The observed clinical variability, especially in the group with two SMN2 copies, might be important for clinical trials in SMA I where a possible control group could be defined as follows: age at onset within 4-5 months, age at genetic diagnosis <6 months, two SMN2 copies present, head control in less than 10%, no respiratory distress from birth, disease endpoint either age at death or age at permanent ventilation. PMID- 19780764 TI - Dissection of biochemical borderline phenotypes in carriers and genetic variants of medium-chain acyl-CoA dehyrogenase deficiency: implications for newborn screening [corrected]. AB - Medium-chain acyl-CoA dehydrogenase deficiency (MCADD) represents a potentially fatal fatty acid beta-oxidation disorder. Newborn screening (NBS) by tandem mass spectrometry (MS/MS) has been implemented worldwide, but is associated with unresolved questions regarding population heterogeneity, burden on healthy carriers, cut-off policies, false-positive and negative rates. In a retrospective case-control study, 333 NBS samples showing borderline acylcarnitine patterns but not reaching recall criteria were genotyped for the two most common mutations (c.985A>G/c.199C>T) and compared with genotypes and acylcarnitines of 333 controls, 68 false-positives, and 34 patients. c.985A>G was more frequently identified in the study group and false-positives compared to controls (1:4.3/1:2.3 vs. 1:42), whereas c.199C>T was found more frequently only within the false-positives (1:23). Biochemical criteria were devised to differentiate homozygous (c.985A>G), compound heterozygous (c.985A>G/c.199C>T), and heterozygous individuals. Four false-negatives were identified because our initial algorithm required an elevation of octanoylcarnitine (C(8)) and three secondary markers in the initial and follow-up sample. The new approach allowed a reduction of false-positives (by defining high cut-offs: 1.4 micromol/l for C(8); 7 for C(8)/C(12)) and false-negatives (by sequencing the ACADM gene of few suspicious samples). Our validation strategy is able to differentiate healthy carriers from patients doubling the positive predictive value (42-->88%) and to target NBS to MCADD-subsets with potentially higher risk of adverse outcome. It remains controversial, if NBS programs should aim at identifying all subsets of all diseases included. Because the natural course of milder variants cannot be assessed by observational studies, our strategy could serve as a general model for evaluation of MS/MS-based NBS. PMID- 19780765 TI - Mutations in the mitochondrial glutamate carrier SLC25A22 in neonatal epileptic encephalopathy with suppression bursts. AB - Neonatal epileptic encephalopathies with suppression bursts (SBs) are very severe and relatively rare diseases characterized by neonatal onset of seizures, interictal electroencephalogram (EEG) with SB pattern and very poor neurological outcome or death. Their etiology remains elusive but they are occasionally caused by metabolic diseases or malformations. Studying an Arab Muslim Israeli consanguineous family, with four affected children presenting a severe neonatal epileptic encephalopathy, we have previously identified a mutation in the SLC25A22 gene encoding a mitochondrial glutamate transporter. In this report, we describe a novel SLC25A22 mutation in an unrelated patient born from first cousin Algerian parents and presenting severe epileptic encephalopathy characterized by an EEG with SB, hypotonia, microcephaly and abnormal electroretinogram. We showed that this patient carried a homozygous p.G236W SLC25A22 mutation which alters a highly conserved amino acid and completely abolishes the glutamate carrier's activity in vitro. Comparison of the clinical features of patients from both families suggests that SLC25A22 mutations are responsible for a novel clinically recognizable epileptic encephalopathy with SB. PMID- 19780766 TI - SURF1 missense mutations promote a mild Leigh phenotype. AB - SURF1 gene mutations are the most common cause of Leigh syndrome (LS), a rare progressive neurodegenerative disorder of infancy, characterized by symmetric necrotizing lesions and hypervascularity in the brainstem and basal ganglia, leading to death before the age of 4 years. Most of the reported mutations create premature termination codons, whereas missense mutations are rare. The aim of the study was to characterize the natural history of LS patients carrying at least one missense mutation in the SURF1 gene. Nineteen such patients (8 own cases and 11 reported in the literature) were compared with a reference group of 20 own c.845_846delCT homozygous patients, and with other LS(SURF-) cases described in the literature. Disease onset in the studied group was delayed. Acute failure to thrive and hyperventilation episodes were rare, respiratory failure did not appear before the age of 4 years. Dystonia, motor regression and eye movement dissociation developed slowly. The number of patients who survived 7 years of life totaled 9 out of 15 (60%) in the 'missense group' and 1 out of 26 (4%) patients with mutations leading to truncated proteins. IN CONCLUSION: (i) The presence of a missense mutation in the SURF1 gene may correlate with a milder course and longer survival of Leigh patients, (ii) normal magnetic resonance imaging (MRI) findings, normal blood lactate value, and only mild decrease of cytochrome c oxidase (COX) activity are not sufficient reasons to forego SURF1 mutation analysis in differential diagnosis. PMID- 19780767 TI - Day surgery visits for dental problems. AB - OBJECTIVES: To fill an information gap for dental care policy stakeholders in Canada, this pilot study explored the nature of day surgery (DS) visits for dental problems in Ontario, the country's largest province. METHODS: The Canadian Institute for Health Information's National Ambulatory Care Reporting System was used, which contains demographic, diagnostic, procedural and administrative information for ambulatory care settings across Ontario. Fiscal years 2003/2004 to 2005/2006 data were included for DS visits that had a main problem coded with an International Classification of Diseases code in the range K00-K14, representing diseases of the oral cavity, salivary glands and jaws. RESULTS: During this period, approximately 75 791 persons made 79 133 DS visits for dental problems in Ontario. Proportionally, children under 5 years of age with dental caries represent the majority of DS visits. Restorations and extractions were the most frequently performed DS care procedure. CONCLUSIONS: This is the first study of its kind in Canada, and confirms many of the assumptions held about DS care for dental problems. The study also acts as a baseline for ongoing quality improvement and planning within the province of Ontario. PMID- 19780769 TI - Body weight and serum albumin change after prosthodontic treatment among institutionalized elderly in a long-term care geriatric hospital. AB - OBJECTIVES: An important purpose of denture treatment is the improvement of nutritional intake. This is especially important for the dependent elderly who have a high risk of protein-energy malnutrition. To evaluate the impact of denture treatment on such a population, we compared body weight as an indicator of nutritional status before and 6 months after prosthodontic treatment. METHODS: This study was conducted in a long-term care geriatric hospital in Hiroshima, Japan from October 2004 to September 2006. One hundred and four patients received complete or partial denture treatment in both jaws. Nineteen patients were lost to the study because of the development of severe physical conditions or death. Among the remaining 85 patients, 66 used their new prostheses and 19 did not. Body weight and serum albumin levels were examined at prosthesis insertion and 6 months after treatment. RESULTS: Six months after prosthodontic treatment body weight changes were significantly different between users and non-users regardless of denture type and, in addition, serum albumin level were significantly increased among individuals using partial denture in either or both jaws (P < 0.05). CONCLUSION: It can be concluded that prosthodontic treatment may improve the nutritional status of institutionalized elderly. PMID- 19780768 TI - Oral health inequalities between young Aboriginal and non-Aboriginal children living in Ontario, Canada. AB - OBJECTIVES: To investigate (i) oral health inequalities between off-reserve Aboriginal and non-Aboriginal children entering junior kindergarten (JK) in the Thunder Bay District, Northwest Ontario, Canada, (ii) oral health inequalities between kindergarten-aged (4 years old) Aboriginal children living on reserves in the Sioux Lookout Zone (SLZ), Northwest Ontario and those living off-reserve in the Thunder Bay District and (iii) early childhood caries (ECC) trends among SLZ children between 2001 and 2005. METHODS: Cross-sectional oral health data (dmft/s Indices) for 416 (2003/2004), 687 (2004/2005) and 544 (2005/2006) 3- to 5-year olds attending JK in the Thunder Bay District were collected by calibrated dental hygienists with the District's Health Unit. Secondary analysis of oral health status data from two studies conducted in the SLZ between 2001 and 2005 provided the dmft of random samples of children younger than 6 years of age living in 16 20 First Nations communities. RESULTS: When compared with non-Aboriginal children aged 3-5 years attending the same schools in the Thunder Bay District between 2003 and 2006, off-reserve Aboriginal children had 1.9 to 2.3 times the risk of having ECC (dmft > 0), 2.9 to 3.5 times the risk of a dmft > 3 and 1.8 to 2.5 times the risk of untreated decayed teeth after adjusting the prevalence ratios for child's age and sex, school's risk level and clustered-correlated data. The mean dmft of on-reserve Aboriginal 4-year olds in 2005 was 11.2 and 5.9 for their off-reserve Aboriginal counterparts. In 2001, the mean dmft scores (95% confidence interval) of 2-, 3- and 4-year-old Aboriginal children in the SLZ were: 9.1 (8.3-9.9), 12.4 (11.8-13.1), 13.1 (12.1-14.2). In 2005, similarly aged SLZ children had a mean dmft of: 6.2 (5.2-7.1), 8.9 (8.2-9.6), 11.2 (10.5-11.9), representing significant reductions in caries severity (32%, 28% and 14.5%, respectively). CONCLUSIONS: Significant disparities in caries experience exist between off-reserve Aboriginal and non-Aboriginal children living in the same locales and between Aboriginal children living on- and off-reserve in northwestern Ontario. The study showed decreased trends in the severity of ECC for children in the SLZ occurring over the 5-year period. Despite this progress, the oral health of young Aboriginal children in Ontario continues to lag far behind that of non-Aboriginal children, demanding further programs and policies to tackle the social determinants of oral health and resolve these inequalities. PMID- 19780770 TI - A review of the materials and allergens in protective gloves. AB - The ingredients previously reported to cause protective glove allergy are presented and evaluated for strength of evidence. Allergens that have caused both delayed hypersensitivity and contact urticaria are considered for rubber, plastic, leather, and textile gloves. The current guidelines regarding glove manufacture are described. A list of materials confirmed by the industry to be used in glove production is presented together with a suggested series for investigating patients with delayed type hypersensitivity and contact urticaria secondary to glove use. PMID- 19780771 TI - Usefulness of skin testing in cutaneous drug eruptions in routine practice. AB - BACKGROUND: Cutaneous drug eruptions are common side-effects. The imputation score combining intrinsic (chronology, clinical and paraclinical signs) and extrinsic criteria used in Pharmacovigilance Centres is insufficient alone to identify with certainty a responsible drug. OBJECTIVE: To evaluate the imputation score before and after performing skin testing in patients with cutaneous drug eruptions. PATIENTS/METHODS: A single-centre retrospective study was performed on 339 patients tested between 2001-2006. Imputation scores were calculated before and after skin tests for each cutaneous drug eruption according to the clinical type of skin eruption and the type of drug. RESULTS: Among 121 patients meeting inclusion criteria, 46% showed an increase of the imputation score as shown by 25/41 cases of maculo-papular exanthema, 4/11 cases of acute generalized exanthematous pustulosis and 17/41 cases of urticaria/anaphylaxis. The imputation score increased in 25/70 cases of the tested antibiotic drugs, in 14/56 cases of cardiovascular drugs, and it increased in 19 patients (34%) with I1 or I2 imputation scores before skin testing and in 29 (52%) with an I3 imputation score before skin testing. CONCLUSIONS: Drug skin testing appeared useful in investigating cutaneous drug eruptions in routine practice, including not only drugs with a high imputation score (I3) but also those with a lower score (I1, I2). Drug skin testing should lead to oral rechallenge of drugs with negative tests in order to determine which drugs may be used safely. PMID- 19780772 TI - Health-related quality of life in health care workers with work-related skin diseases. AB - BACKGROUND: Occupational skin diseases (OSDs) are common among health care workers (HCWs). Little is known about how OSD impacts on health-related quality of life (HRQoL) in HCWs with suspected OSD and associated factors. OBJECTIVES: To describe HRQoL in 278 HCWs with suspected OSD, compare data with the general and populations with skin diseases and analyse HRQoL's associations with clinical and demographic variables. METHODS: HCWs with suspected OSD completed a generic (SF 36) and specific (Skindex-29) instrument. RESULTS: Seven of 8 SF-36 dimensions were significantly lower in HCWs than the general population. Compared with norms for patients with skin disease and cleaning and kitchen employees (CKEs) with suspected OSD, physical functioning (PF) and general health perception were less impaired in HCWs. Skindex-29 scores were similar to CKEs' while they appeared better than patients' norms. Multivariate analysis found severity unrelated to SF 36, apart from pain but associated with all Skindex-29 scales. CONCLUSIONS: Although HCWs with suspected OSD display considerable HRQoL impairments, (general) PF and general health perception appear less affected than expected. Severity appears to affect specific and to a lesser extent general HRQoL. Clinical and demographic variables contributed moderately to the prediction of specific and little to the prediction of general HRQoL. PMID- 19780774 TI - Delayed hypersensitivity to corticosteroids in a series of 315 patients: clinical data and patch test results. AB - BACKGROUND: Corticosteroids may cause immediate or delayed hypersensitivity. In 1989, based on structural and clinical characteristics, we put forward a classification of corticosteroids into four cross-reacting groups, namely group A, B, C, and D, the latter later subdivided into two subgroups, i.e. D1 and D2. The constituents on the D-ring of the corticosteroid-molecule are considered to have a central role for binding to skin proteins and for cross-reactions patterns; however, halogenation of the molecules is also interfering. OBJECTIVE: To study the clinical data and analyse simultaneous positive reactions obtained in a large group of corticosteroid-allergic patients. METHODS: Patch tests were performed with the baseline series, to which hydrocortisone butyrate and prednisolone caproate were added, as well as with the corticosteroids to which the patients had been exposed. Three hundred and forty subjects with a presumed or proven corticosteroid allergy were further investigated with an extended series containing 72 molecules. RESULTS: Out of 11 596 patients investigated, 315 subjects reacted positively to at least 1 corticosteroid-molecule, with most of them presenting with multiple positive reactions. CONCLUSION: A prevalence of corticosteroid allergy of 2.7% was found. Despite validity of the ABCD (sub)classification in many cases, possible adjustments may have to be considered. PMID- 19780773 TI - Quantitative patch and repeated open application testing in hydroxyisohexyl 3 cyclohexene carboxaldehyde sensitive-patients. AB - OBJECTIVE: To identify the concentration of the fragrance compound hydroxyisohexyl 3-cyclohexene carboxaldehyde (INCI) (HICC) that is sufficiently low not to cause an allergic reaction in patients with proven sensitization. METHODS: Repeated open application testing (ROAT) in 64 subjects with 2 preparations (perfume and cream) in different concentration (0.005-2.5%). Confirmatory patch testing with four preparations in two different concentrations (2.5% and 5%). RESULTS: The concentrations of HICC being tolerated by 90% of those sensitized to HICC are estimated as <88.2 ppm (cream) and <270 ppm (perfume) equivalent to 1.2 microg/cm(2) (perfume) and 4.9 microg/cm(2) (cream). Patch test preparations differed with regard to sensitivity (88.5-98.1%) and specificity (37.5-87.5%) against the ROAT result as external criterion. ROAT concentrations and the reaction strength in patch testing were inversely correlated (Kendall's tau-b: 0.69), both indicating the existence of different degrees of susceptibility. CONCLUSION: To protect 90% (50%) of people sensitized, the use concentration should be in the range of 0.009-0.027% (0.18-0.34%), depending on the product type. Taking into account these results, excessive concentrations should be avoided, as this would continue to sensitize people. Close monitoring is indispensable to prove the efficacy of any recommendations aiming to prevent induction. PMID- 19780775 TI - Occupational contact urticaria caused by donepezil. PMID- 19780776 TI - Contact dermatitis to captopril. PMID- 19780777 TI - Erythema multiforme-like generalized contact dermatitis to l-menthol contained in anti-inflammatory medical compresses as an ingredient. PMID- 19780778 TI - Systemic allergic dermatitis reaction to nickel released from an eyelet in an intravenous catheter. PMID- 19780779 TI - Allergic contact dermatitis to ethylhexylglycerin and pentylene glycol. PMID- 19780780 TI - Irritant contact dermatitis from shower cream applied as a moisturizing cream: a review of three cases*. PMID- 19780781 TI - Allergic contact dermatitis to 1,2-benzisothiazolin-3-one in the water softener manufacturing industry. PMID- 19780782 TI - Allergic contact dermatitis from incense. PMID- 19780783 TI - Contact urticaria and asthma from Sarcophaga carnaria. PMID- 19780785 TI - Duplicated zebrafish relaxin-3 gene shows a different expression pattern from that of the co-orthologue gene. AB - Relaxin-3 (Rln3) is thought to function as a neurotransmitter mainly produced in the mammalian nucleus incertus and is involved in different neural processes; among them, the stress response and food intake. Here, we report the expression pattern of the duplicated zebrafish rln3b gene and compare it to the previously analyszd spatial expression pattern of the rln3a gene. Both genes, during the embryogenesis and in the adult fish, are active and show relevant differences in their expression patterns. rln3b is diffusely expressed in the brain until the pharyngula period, when, at 48 h postfertilization (hpf), the expression becomes restricted to the periaqueductal gray, where it persists also at later developmental stages. No expression was observed in the nucleus incertus cells that express the rln3a gene from 72 hpf. In the adult, both genes are expressed in brain, but only rln3b transcript is revealed in testis at the similar expression level, whereas in the other analyzed tissues the transcript levels are lower or absent. Both the putative mature protein sequences are highly conserved, this feature and their differential expression patterns might indicate a sub functionalization during evolution with the consequent retention of the two paralogues genes. PMID- 19780786 TI - Generation of a second eye by embryonic transplantation of the antero-ventral hemicephalon. AB - Vertebrate ocular morphogenesis requires proper dorso-ventral polarity within the optic vesicle, and loss of dorso-ventral polarity results in failure of optic cup formation and domain specification, as shown by a reverse transplantation of the optic vesicle. We have shown previously that the ocular development depends not only on the signal within the antero-ventral optic vesicle but also on the extraocular signals. In the present study, using embryonic transplantation of a discrete portion of the embryonic chick brain, we demonstrate formation of a second eye from the antero-ventral hemicephalon when it was transplanted in the antero-dorsal hemicephalon of the host embryo. The transplant consists of an antero-ventral quadrant of the optic vesicle and the surrounding part of the anterior cephalon. The original dorso-ventral polarity of the transplant was once cancelled and re-established in accordance with that of the host embryo. Neither dorsal nor ventral cephalic halves in isolation did not develop into entire eye structures under the culture condition; the dorsal halves developed merely into the retinal pigmented epithelium and the ventral halves into the neural retina alone. The present study clearly suggests that extraocular dorsal and ventral signals counterbalance each other to specify the polarity of the optic vesicle. PMID- 19780787 TI - The evolution of intermediate castration virulence and ant coexistence in a spatially structured environment. AB - Theory suggests that spatial structuring should select for intermediate levels of virulence in parasites, but empirical tests are rare and have never been conducted with castration (sterilizing) parasites. To test this theory in a natural landscape, we construct a spatially explicit model of the symbiosis between the ant-plant Cordia nodosa and its two, protecting ant symbionts, Allomerus and Azteca. Allomerus is also a castration parasite, preventing fruiting to increase colony fecundity. Limiting the dispersal of Allomerus and host plant selects for intermediate castration virulence. Increasing the frequency of the mutualist, Azteca, selects for higher castration virulence in Allomerus, because seeds from Azteca-inhabited plants are a public good that Allomerus exploits. These results are consistent with field observations and, to our knowledge, provide the first empirical evidence supporting the hypothesis that spatial structure can reduce castration virulence and the first such evidence in a natural landscape for either mortality or castration virulence. PMID- 19780788 TI - Experimental warming transforms multiple predator effects in a grassland food web. AB - This experimental study tests new theory for multiple predator effects on communities by using warming to alter predator habitat use and hence direct and indirect interactions in a grassland food web containing two dominant spider predator species, a dominant grasshopper herbivore and grass and herb plants. Experimental warming further offers insight into how climate change might alter direct and indirect effects. Under ambient environmental conditions, spiders used habitat in spatially complementary locations. Consistent with predictions, the multiple predator effect on grasshoppers and on plants was the average of the individual predator effects. Warming strengthened the single predator effects. It also caused the spider species to overlap lower in the vegetation canopy. Consistent with predictions, the system was transformed into an intraguild predation system with the consequent extinction of one spider species. The results portend climate caused loss of predator diversity with important consequences for food web structure and function. PMID- 19780789 TI - Predatory senescence in ageing wolves. AB - It is well established that ageing handicaps the ability of prey to escape predators, yet surprisingly little is known about how ageing affects the ability of predators to catch prey. Research into long-lived predators has assumed that adults have uniform impacts on prey regardless of age. Here we use longitudinal data from repeated observations of individually-known wolves (Canis lupus) hunting elk (Cervus elaphus) in Yellowstone National Park to demonstrate that adult predatory performance declines with age and that an increasing ratio of senescent individuals in the wolf population depresses the rate of prey offtake. Because this ratio fluctuates independently of population size, predatory senescence may cause wolf populations of equal size but different age structure to have different impacts on prey populations. These findings suggest that predatory senescence is an important, though overlooked, factor affecting predator-prey dynamics. PMID- 19780790 TI - Voxel-based morphometry of sporadic epileptic patients with mesiotemporal sclerosis. AB - PURPOSE: In refractory temporal lobe epilepsy (rTLE), gray matter (GM) abnormalities are not confined to the hippocampus but also are found in extrahippocampal structures. Very recently we observed in mild TLE (mTLE) with or without mesiotemporal sclerosis (MTS), GM reductions in regions outside the presumed epileptogenic focus. To date, there are no studies that directly investigate whether whole-brain GM volume differs between rTLE and mTLE. Herein, we used optimized voxel-based morphometry (VBM) to identify GM abnormalities beyond the hippocampus in both rTLE and mTLE with evidence of MTS. METHODS: Brain magnetic resonance imaging (MRI) and optimized VBM were performed in 19 unrelated patients with mTLE, 19 patients with rTLE, and 37 healthy controls. MRI diagnosis of MTS was based on the atrophy of the hippocampal formation and/or mesiotemporal hyperintensity on fluid-attenuated inversion recovery (FLAIR) or T(2) images, or both. RESULTS: No patients (rTLE and mTLE) had generalized tonic-clonic or complex partial seizures for at least 3 weeks before scanning. Both mTLE and rTLE patients showed GM volume reduction of the bilateral thalamus, left hippocampus, and sensorimotor cortex compared with controls. No significant GM difference was found between rTLE and mTLE groups. DISCUSSION: In both rTLE and mTLE, VBM shows GM reductions not confined to the hippocampus involving mainly the thalamus bilaterally. This finding together with the lack of significant GM differences between the two TLE groups supports the hypothesis that mTLE and rTLE might lie along a biologic continuum, suggesting a pathophysiologic role of the thalamus in partial epilepsy. PMID- 19780791 TI - Mutations in LGI1 gene in Japanese families with autosomal dominant lateral temporal lobe epilepsy: the first report from Asian families. AB - Autosomal dominant lateral temporal lobe epilepsy (ADLTE) caused by LGI1 (leucine rich gene, glioma-inactivated-1) mutations is a rare familial epileptic syndrome characterized by the auditory ictal manifestation and rare nocturnal generalized seizures. We have examined the sequence of the LGI1 gene in four Japanese families with lateral temporal lobe epilepsy having characteristic auditory features, and identified one novel (1421G>A), and one reported (1418C>T) point mutation each in two families. These two mutations were 3 bp apart in the LGI1 gene and caused adjoining amino acid substitutions. The two families presented different clinical phenotypes and seizure control to drug treatment. These findings suggest that LGI1 mutations in Japanese ADLTE families may not be uncommon, and that diverse clinical phenotypes make adequate diagnosis of ADLTE difficult when only based on clinical information. PMID- 19780792 TI - Xp22.3 genomic deletions involving the CDKL5 gene in girls with early onset epileptic encephalopathy. AB - PURPOSE: Mutations of the X-linked gene cyclin-dependent kinase-like 5 (CDKL5) cause an X-linked encephalopathy with early onset intractable epilepsy, including infantile spasms and other seizure types, and a Rett syndrome (RTT)-like phenotype. Very limited information is available on the frequency and phenotypic spectrum associated with CDKL5 deletions/duplications. We investigated the role of CDKL5 deletions/duplications in causing early onset intractable epilepsy of unknown etiology in girls. METHODS: We studied 49 girls with early onset intractable epilepsy, with or without infantile spasms, and developmental impairment, for whom no etiologic factors were obvious after clinical examination, brain magnetic resonance imaging (MRI) and expanded screening for inborn errors of metabolism. We performed CDKL5 gene mutation analysis in all and multiplex ligation dependent probe amplification assay (MLPA) in those who were mutation negative. Custom Array-comparative genomic hybridization (CGH), breakpoint polymerase chain reaction (PCR) analysis, and X-inactivation studies were performed in patients in whom MLPA uncovered a genomic alteration. RESULTS: We found CDKL5 mutations in 8.2% (4 of 49) of patients and genomic deletions in 8.2% (4 of 49). Overall, abnormalities of the CDKL5 gene accounted for 16.3% (8 of 49) of patients. DISCUSSION: CDKL5 gene deletions are an under-ascertained cause of early onset intractable epilepsy in girls. Genetic testing of CDKL5, including both mutation and deletion/duplication analysis, should be considered in this clinical subgroup. PMID- 19780793 TI - Ghrelin levels are reduced in prepubertal epileptic children under treatment with carbamazepine or valproic acid. AB - A relationship between ghrelin and epilepsy has been already shown in humans, although the results are controversial. Ghrelin levels are reduced in obesity. Epileptic patients progressively develop a therapy-linked weight gain; however, the mechanisms for this have not been fully explained. The aim of our study is to evaluate if ghrelin secretion is modulated by treatment with carbamazepine or valproic acid in young prepubertal epileptic children. Ghrelin levels were reduced in normal-weight young epileptic prepubertal children under treatment with carbamazepine (p < 0.0001) or valproic acid (p < 0.006) compared to healthy age- and weight-matched subjects. Ghrelin was also lower in children under carbamazepine when compared to those under valproic acid (p < 0.01). A derangement in ghrelin secretion in epilepsy during specific pharmacologic therapies and independent of weight gain could be hypothesized. PMID- 19780794 TI - Interictal EEG spikes identify the region of electrographic seizure onset in some, but not all, pediatric epilepsy patients. AB - PURPOSE: The role of sharps and spikes, interictal epileptiform discharges (IEDs), in guiding epilepsy surgery in children remains controversial, particularly with intracranial electroencephalography (IEEG). Although ictal recording is the mainstay of localizing epileptic networks for surgical resection, current practice dictates removing regions generating frequent IEDs if they are near the ictal onset zone. Indeed, past studies suggest an inconsistent relationship between IED and seizure-onset location, although these studies were based upon relatively short EEG epochs. METHODS: We employ a previously validated, computerized spike detector to measure and localize IED activity over prolonged, representative segments of IEEG recorded from 19 children with intractable, mostly extratemporal lobe epilepsy. Approximately 8 h of IEEG, randomly selected 30-min segments of continuous interictal IEEG per patient, were analyzed over all intracranial electrode contacts. RESULTS: When spike frequency was averaged over the 16-time segments, electrodes with the highest mean spike frequency were found to be within the seizure-onset region in 11 of 19 patients. There was significant variability between individual 30-min segments in these patients, indicating that large statistical samples of interictal activity were required for improved localization. Low-voltage fast EEG at seizure onset was the only clinical factor predicting IED localization to the seizure-onset region. CONCLUSIONS: Our data suggest that automated IED detection over multiple representative samples of IEEG may be of utility in planning epilepsy surgery for children with intractable epilepsy. Further research is required to better determine which patients may benefit from this technique a priori. PMID- 19780795 TI - Vigabatrin but not valproate prevents development of age-specific flexion seizures induced by N-methyl-D-aspartate (NMDA) in immature rats. AB - In immature rats, N-methyl-D-aspartate (NMDA) induces several seizure types: flexion seizures (FS; in rats younger than 3 weeks), clonic seizures (in animals older than 3 weeks), and clonic-tonic seizures (CTS; in rats of all ages). FS represent a model of human infantile spasms. Effects of vigabatrin and valproate against all types of NMDA-induced seizures were studied in rats at postnatal days 12 (P12) and 25 (P25). NMDA (60 or 300 mg/kg) was injected to animals pretreated with vigabatrin (300-1,200 mg/kg; 24 h before NMDA) or valproate (100-400 mg/kg; 15 min before NMDA). Vigabatrin suppressed FS in P12 rats, but was ineffective against CTS in both age groups. Valproate suppressed CTS in P12, but not in P25 rats. Clonic seizures were rare in NMDA-treated P25 rats, but valproate pretreatment increased their incidence significantly. Neither drug decreased NMDA induced mortality, which occurred within approximately 15 min after NMDA administration and reached almost 100% in all groups. PMID- 19780796 TI - Medically intractable epilepsy in Sturge-Weber syndrome is associated with cortical malformation: implications for surgical therapy. AB - PURPOSE: Anecdotal reports have described cortical malformations in epileptic patients with Sturge-Weber syndrome (SWS). No data are available regarding the prevalence and significance of this association. METHODS: We reviewed retrospectively the clinical profile, preoperative magnetic resonance imaging (MRI) studies, and pathology reports of all patients with SWS and medically intractable epilepsy evaluated in our epilepsy surgery program between 1979 and 2006. RESULTS: Twelve patients (male/female = 7/5) were identified. Mean age at seizure onset was 11.1 +/- 16.7 months. Seizures occurred daily in seven patients and weekly in five patients. A facial port-wine stain was noted in 10 cases. Eleven patients evidenced developmental delay and eight were hemiparetic. Eight patients underwent excisional surgery for epilepsy (mean age 10.3 +/- 6.5 year), including hemispherectomy (n = 4) and focal cortical resection (n = 4). Tissue was available for neuropathology in six operated cases and revealed polymicrogyria (n = 3) and cortical dysplasia (n = 4). Polymicrogyria was associated with cortical dysplasia in one child. Brain MRIs were reviewed in 10 of 12 patients and were consistent with cortical malformations in all cases. CONCLUSIONS: We conclude that cortical malformations are frequent in patients with medically intractable epilepsy and Sturge-Weber-syndrome and may be the primary cause of epilepsy. PMID- 19780797 TI - Hyperhomocysteinemia in epileptic patients on new antiepileptic drugs. AB - PURPOSE: Older enzyme-inducing antiepileptic drugs (AEDs) may induce supraphysiologic plasma concentrations of total (t) homocysteine (Hcy). The aim of the present study was to investigate the effect of new AEDs on plasma tHcy levels. METHODS: Patients 18-50 years of age, on AEDs monotherapy, with no other known cause of hyper-tHcy were enrolled. Plasma tHcy, folate, vitamin B(12), and AEDs levels were determined by standard high-performance liquid chromatography (HPLC) methods. Methylenetetrahydrofolate-reductase (MTHFR) polymorphisms were checked using Puregene genomic DNA purification system (Gentra, Celbio, Italy). A group of healthy volunteers matched for age and sex was taken as control. RESULTS: Two hundred fifty-nine patients (151 on newer and 108 on older AEDs) and 231 controls were enrolled. Plasma tHcy levels were significantly higher [mean values, standard error (SE) 16.8, 0.4 vs. 9.1, 0.2 microm; physiologic range 5-13 microm] and folate lower (6.3, 0.1 vs. 9.3, 0.1 nm; normal > 6.8 nm) in patients compared to controls. Patients treated with oxcarbazepine, topiramate, carbamazepine, and phenobarbital exhibited mean plasma tHcy levels above the physiologic range [mean values (SE) 16 (0.8), 19.1 (0.8), 20.5 (1.0), and 18.5 (1.5) microm, respectively]. Conversely, normal tHcy concentrations were observed in the lamotrigine and levetiracetam groups [both 11.1 (0.5) microm]. DISCUSSION: Oxcarbazepine and topiramate might cause hyper-tHcy, most likely because of the capacity of these agents to induce the hepatic enzymes. Because literature data suggest that hyper-tHcy may contribute to the development of cerebrovascular diseases and brain atrophy, a supplement of folate can be considered in these patients to normalize plasma tHcy. PMID- 19780798 TI - Adult-onset drug-refractory seizure disorder associated with anti-voltage-gated potassium-channel antibody. AB - Voltage-gated potassium channels are widely expressed throughout the entire nervous system. These channels play a critical role in establishing the resting membrane potential and generation of neuronal action potentials. There is mounting evidence that autoantibodies reactive to neuronal cell surface antigens, such as voltage-gated potassium channels, play a pathogenic role in a wide spectrum of central and peripheral nervous system disorders. We report a case of new-onset drug-refractory seizure disorder associated with the presence of high levels of serum anti-voltage-gated potassium channel antibodies that responded only to immunotherapy. As demonstrated by this case report, anti-voltage-gated potassium channel antibody associated drug-refractory seizure disorder, although rare, should be considered in patients with unexplained adult-onset seizure activity. Once the diagnosis has been established the initiation of immunotherapy should be undertaken without delay. PMID- 19780799 TI - Vagus nerve stimulation might have a unique effect in reflex eating seizures. AB - We studied the effects of vagus nerve stimulation (VNS) on eating seizures, which theoretically would be triggered by neural activity and signaling from organs innervated by the vagus nerve. Three adult patients with daily nonreflex and reflex eating seizures were studied; one patient also had hot-water seizures. One patient had bilateral polymicrogyria and two had normal magnetic resonance imaging (MRI) findings. All patients were submitted to VNS implantation and had at least 2 years of postimplantation follow-up. Final stimulation parameters were 2.0-2.5 mA, 500 micros, and 30 Hz. Eating seizures decreased 70-95% and nonreflex seizures decreased 0-40% after VNS. There was no improvement in hot-water seizures. VNS seems to be an especially useful treatment modality in patients with reflex eating seizures not amenable to resective surgery. PMID- 19780800 TI - Nonmanipulative proximal upper extremity automatisms lateralize contralaterally in temporal lobe epilepsy. AB - PURPOSE: Upper extremity automatisms are considered to be an ipsilateral seizure lateralizing sign in temporal lobe epilepsy (TLE). Herein we describe different types of contralateral upper extremity automatisms (CUEAs). METHODS: One hundred ninety-three video-(electroencephalography) EEG recordings of 59 patients were reviewed. Other than two patients who refused surgery, all patients underwent standardized temporal lobectomy with favorable postoperative outcome. Fifty-seven seizures of 21 patients were selected with CUEAs. We evaluated their electroclinical characteristics and their relation to other lateralizing motor symptoms. RESULTS: Two types of CUEAs were observed. Nonmanipulative, proximal upper extremity automatisms were seen unilaterally and contralaterally to the operated side. These automatisms were rhythmic; repetitive; and often occurred with a circulatory component resembling waving, flaunting, circling, or stirring movements. They occurred in 29 seizures (15%) of 11 patients (19%), in most seizures in the first half of the seizure, and never postictally, in various time sequences and combined with dystonic/tonic posturing or limb immobility. Manipulative/distal type of CUEAs occurred in 11 seizures (6%) of 7 patients (12%) on the unexpected contralateral side. These CUEAs were seen in all phases of the seizures, including in the postictal state. DISCUSSION: Nonmanipulative unilateral proximal upper extremity automatism is a reliable lateralizing sign to the contralateral hemisphere in TLE. This sign may be pathophysiologically related to dystonic/tonic posturing. Manipulative distal automatisms have less lateralizing value. PMID- 19780801 TI - Neurostimulation in ischaemic stroke - down with the healthy hemisphere! PMID- 19780802 TI - Role of 1 and 3 Hz repetitive transcranial magnetic stimulation on motor function recovery after acute ischaemic stroke. AB - BACKGROUND AND PURPOSE: The purpose of this study was to compare the long-term effect of five daily sessions of 1 vs. 3 Hz repetitive transcranial magnetic stimulation (rTMS) on motor recovery in acute stroke. METHODS: A total of 36 patients with acute ischaemic stroke participated in the study. The patients were randomly assigned into one of three groups; the first and second groups received real rTMS; 1 and 3 Hz and third group received sham stimulation, daily for 5 days. Motor disability was assessed before and after the last session, and then after first, second and third month. Cortical excitability was assessed before and after the second and fifth session. The outcome measure was clinical disability at 3 months post-rTMS. RESULTS: No significant differences were found in basal rating scales between the three groups. At the 3-month time point, both of the real rTMS groups had improved significantly more in different rating scales than the sham group; in addition, the 1 Hz group performed better than the 3 Hz group. Measures of cortical excitability immediately after the last session showed that the 1 Hz group had reduced excitability of the non-stroke hemisphere and increased excitability of the stroke hemisphere, whereas the 3 Hz group only showed increased excitability of the stroke hemisphere. CONCLUSION: These results confirm that five daily sessions of rTMS over motor cortex using either 1 Hz over the unaffected hemisphere or 3 Hz over the affected hemisphere can enhance recovery. At 3 months, the improvement was more pronounced in 1 Hz group. PMID- 19780805 TI - Impact of stroke units on mortality: a Bayesian analysis. AB - BACKGROUND: Observational studies of the impact of care delivered in stroke units on mortality after acute stroke have been difficult to interpret because of bias. METHODS: This study used Bayesian methodology to (i) sequentially update current knowledge based on a systematic review of observational studies, (ii) adjust for the likely effect of observational bias in a conservative, scenario-based approach and (iii) evaluate the likely impact of further studies. The data were interpreted both unmodified and adjusted for bias by explicitly correcting for point estimate and precision bias. RESULTS: As of 2007, the total evidence base was almost 47 000 patients. The unadjusted data yielded a current 95% posterior credible interval (Cr.I.) for the odds ratio of death within 1 year after stroke unit versus alternative models of stroke care of (0.77, 0.85). Given the adjusted data, the current 95% Cr. I. is (0.79, 0.93). CONCLUSIONS: The current estimates are robust, with demonstrable stability despite the addition of recent large studies. Further studies are very unlikely to alter current knowledge but may have a role in ensuring regional stability of outcome. PMID- 19780807 TI - Management of mitochondrial stroke-like-episodes. AB - Aim of this review is to discuss recent findings concerning the management of stroke-like episodes (SLEs) in patients with mitochondrial disorders (MIDs). Various databases were searched for appropriate literature. SLEs are a dominant feature of MIDs and occur most frequently in MELAS-syndrome, less frequently in MERRF-syndrome, Kearns-Sayre-syndrome, or Leigh-syndrome. SLEs occur at all ages and are frequently accompanied by other cerebral abnormalities. Clinically, SLEs mimic ischemic stroke but not on imaging studies and concerning the management. The morphological equivalent on MRI is the stroke-like-lesion, representing a vasogenic edema (hyperintensity on T2, diffusion-weighted imaging and apparent diffusion coefficient in the acute and subacute or chronic stage, most frequently in the parieto-occipital region, surpassing vascular territories). For diagnostic and therapeutic reasons SLEs need to be clearly delineated from ischemic stroke and cerebral bleeding. Though there is no causal therapy available, symptomatic and general measures can help to resolve the clinical manifestations. In conclusion this review shows that SLEs are a dominant feature of some syndromic or non-syndromic MIDs. The most effective strategy for the treatment of SLEs appears to be the application of L-arginine, coenzyme-Q, steroids, edaravone, creatine-monohydrate, or dichloracetate. PMID- 19780806 TI - Decision-making in Parkinson's disease patients with and without pathological gambling. AB - BACKGROUND AND PURPOSE: Pathological gambling (PG) in Parkinson's disease (PD) is a frequent impulse control disorder associated mainly with dopamine replacement therapy. As impairments in decision-making were described independently in PG and PD, the objective of this study was to assess decision-making processes in PD patients with and without PG. METHODS: Seven PD patients with PG and 13 age, sex, education and disease severity matched PD patients without gambling behavior were enrolled in the study. All patients were assessed with a comprehensive neuropsychiatric and cognitive evaluation, including tasks used to assess decision-making abilities under ambiguous or risky situations, like the Iowa Gambling Task (IGT), the Game of Dice Task and the Investment Task. RESULTS: Compared to PD patients without gambling behavior, those with PG obtained poorer scores in the IGT and in a rating scale of social behavior, but not in other decision-making and cognitive tasks. CONCLUSIONS: Low performance in decision making under ambiguity and abnormal social behavior distinguished PD patients with PG from those without this disorder. Dopamine replacement therapy may induce dysfunction of the ventromedial prefrontal cortex and amygdala-ventral striatum system, thus increasing the risk for developing PG. PMID- 19780808 TI - Independent validation of the scales for outcomes in Parkinson's disease autonomic (SCOPA-AUT). AB - BACKGROUND AND PURPOSE: Autonomic dysfunction is common in Parkinson's disease (PD) and causes a great impact in health-related quality of life (HRQL) and functional status of patients. This study is the first independent validation of the Scales for Outcomes in PD-Autonomic (SCOPA-AUT). METHODS: In an observational, cross-sectional study (ELEP Study), 387 PD patients were assessed using, in addition to the SCOPA-AUT, the Hoehn and Yahr staging, SCOPA-Motor, SCOPA-Cognition, Cumulative Illness Rating Scale-Geriatrics, modified Parkinson Psychosis Rating Scale, Clinical Impression of Severity Index for PD, Hospital Anxiety and Depression Scale, SCOPA-Sleep, SCOPA-Psychosocial, pain and fatigue visual analogue scales, and EQ-5D. SCOPA-AUT acceptability, internal consistency, construct validity, and precision were explored. RESULTS: Data quality was satisfactory (97%). SCOPA-AUT total score did not show floor or ceiling effect, and skewness was 0.40. Cronbach's alpha coefficients ranged from 0.64 (Cardiovascular and Thermorregulatory subscales) to 0.95 (Sexual dysfunction, women). Item homogeneity index was low (0.24) for Gastrointestinal subscale. Factor analysis identified eight factors for men (68% of the variance) and seven factors for women (65% of the variance). SCOPA-AUT correlated at a high level with specific HRQL and functional measures (r(S) = 0.52-0.56). SCOPA-AUT scores were higher for older patients, for more advanced disease, and for patients treated only with levodopa (Kruskal-Wallis test, P < 0.01). Standard error of measurement for SCOPA-AUT subscales was 0.81 (sexual, men) - 2.26 (gastrointestinal). CONCLUSIONS: Despite its heterogeneous content, which determines some weaknesses in the psychometric attributes of its subscales, SCOPA AUT is an acceptable, consistent, valid and precise scale. PMID- 19780809 TI - Autobiographical memory in progressive supranuclear palsy. AB - BACKGROUND: We aimed to investigate recall of autobiographical memories across lifetime periods in patients with progressive supranuclear palsy (PSP). METHOD: Patients with PSP (n = 10) were given a test of autobiographical and personal semantic information and the Addenbrooke's Cognitive Examination (ACE). The result was compared to 30 matched neurologically intact participants. RESULT: A mild autobiographical memory impairment was observed in PSP without a temporal gradient for the recall of autobiographical or personal semantic information. Performance correlated with verbal fluency in ACE. CONCLUSION: Patients with PSP show mild deficits in autobiographical memory, which is likely to reflect a frontal retrieval deficit. PMID- 19780810 TI - Are species real? The shape of the species boundary with exponential failure, reinforcement, and the "missing snowball". AB - Under simple assumptions, the evolution of epistatic "Dobzhansky-Muller" incompatibilities between a pair of species should yield an accelerating decline of log overall reproductive compatibility--a "snowball" effect that might rapidly provide new species with "reality." Possible alternatives include: (1) simple exponential failure, giving a linear rate of log compatibility loss, and (2) "slowdown," likely during reinforcement in which mate choice evolves to prevent deleterious hybridization, yielding a decelerating log compatibility loss. In analyses of multiple datasets, we find little support for the snowball effect, except possibly in Lepidoptera hybrid viability. The snowball predicts a slow initial rate of incompatibility acquisition, with low initial variance; instead, highly variable compatibility is almost universally observed at low genetic distances. Another deviation from predictions is that reproductive isolation usually remains incomplete until long after speciation. These results do not disprove snowball compatibility decay, but can result if large deleterious effects are due to relatively few genetic changes, or if different types of incompatibility evolve at very different rates. On the other hand, data on Bacillus and Saccharomyces, as well as theories of chromosomal evolution, suggest that some kinds of incompatibility accumulate approximately linearly, without Dobzhansky-Muller effects. In microorganisms, linearity can result from direct negative effects of DNA sequence divergence on compatibility. Finally, a decelerating slowdown model is supported for sympatric Leptasterias starfish, and in Drosophila prezygotic isolation in sympatry but not allopatry, providing novel comparative evidence for reinforcement. PMID- 19780812 TI - Greenbeards. AB - Greenbeards are genes that can identify the presence of copies of themselves in other individuals, and cause their bearer to behave nepotistically toward those individuals. In recent years, a number of examples have been discovered, and it has been suggested that greenbeards represent one of the fundamental routes to social behaviors such as cooperation. However, despite their possible theoretical and empirical importance, many basic aspects of greenbeard biology are commonly misunderstood. Here, we distinguish between four different types of greenbeard, which differ in their evolutionary dynamics. We show that all four types exist, and that they differ in the ease with which they can be empirically detected. We clarify the inclusive fitness explanation of greenbeards, and show that they are not intragenomic outlaws. Finally, we argue that although greenbeards are likely to be most common and easiest to detect in microorganisms, they are unlikely to important in organisms such as humans. PMID- 19780813 TI - The combined effects of rivers and refugia generate extreme cryptic fragmentation within the common ground skink (scincella lateralis). AB - Rivers can act as both islands of mesic refugia for terrestrial organisms during times of aridification and barriers to gene flow, though evidence for long-term isolation by rivers is mixed. Understanding the extent to which riverine barrier effects can be heightened for populations trapped in mesic refugia can help explain maintenance and generation of diversity in the face of Pleistocene climate change. Herein, we implement phylogenetic and population genetic approaches to investigate the phylogeographic structure and history of the ground skink, Scincella lateralis, using mtDNA and eight nuclear loci. We then test several predictions of a river-refugia model of diversification. We recover 14 well-resolved mtDNA lineages distributed east-west along the Gulf Coast with a subset of lineages extending northward. In contrast, ncDNA exhibits limited phylogenetic structure or congruence among loci. However, multilocus population structure is broadly congruent with mtDNA patterns and suggests that deep coalescence rather than differential gene flow is responsible for mtDNA-ncDNA discordance. The observed patterns suggest that most lineages originated from population vicariance due to riverine barriers strengthened during the Plio Pleistocene by a climate-induced coastal distribution. Diversification due to rivers is likely a special case, contingent upon other environmental or biological factors that reinforce riverine barrier effects. PMID- 19780814 TI - Evolution of dominance under frequency-dependent intraspecific competition in an assortatively mating population. AB - We study the evolution of higher levels of dominance as a response to negative frequency-dependent selection. In contrast to previous studies, we focus on the effect of assortative mating on the evolution of dominance under frequency dependent intraspecific competition. We analyze a two-locus two-allele model, in which the primary locus has a major effect on a quantitative trait that is under a mixture of frequency-independent stabilizing selection, density-dependent selection, and frequency-dependent selection caused by intraspecific competition for a continuum of resources. The second (modifier) locus determines the degree of dominance at the trait level. Additionally, the population mates assortatively with respect to similarities in the ecological trait. Our analysis shows that the parameter region in which dominance can be established decreases if small levels of assortment are introduced. In addition, the degree of dominance that can be established also decreases. In contrast, if assortment is intermediate, sexual selection for extreme types can be established, which leads to evolution of higher levels of dominance than under random mating. For modifiers with large effects, intermediate levels of assortative mating are most favorable for the evolution of dominance. For large modifiers, the speed of fixation can even be higher for intermediate levels of assortative mating than for random mating. PMID- 19780815 TI - Assortative mating and spatial structure in hybrid zones. AB - The spatial genetic composition of hybrid zones exhibits a range of possible patterns, with many characterized by patchy distributions. While several hypothetical explanations exist for the maintenance of these "mosaic" hybrid zones, they remain virtually unexplored theoretically. Using computer simulations we investigate the roles of dispersal and assortative mating in the formation and persistence of hybrid zone structure. To quantify mosaic structure we develop a likelihood method, which we apply to simulation and empirical data. We find that long distance dispersal can lead to a patchy distribution that assortative mating can then reinforce, ultimately producing a mosaic capable of persisting over evolutionarily significant periods of time. By reducing the mating success of rare males, assortative mating creates a positive within-patch frequency dependent selective pressure. Selection against heterozygotes can similarly create a rare-type disadvantage and we show that it can also preserve structure. We find that mosaic structure is maintained across a range of assumptions regarding the form and strength of assortative mating. Interestingly, we find that higher levels of mosaic structure are sometimes observed for intermediate assortment strengths. The high incidence of assortment documented in hybrid zones suggests that it may play a key role in stabilizing their form and structure. PMID- 19780816 TI - The role of keratinocyte growth factor in melanogenesis: a possible mechanism for the initiation of solar lentigines. AB - Solar lentigines (SLs) are hyperpigmentary lesions presented on sun-exposed areas of the skin and associated with ageing. The molecular mechanism of SL initiation is not completely understood. Ultraviolet B (UVB) stimulates keratinocytes to produce interlukin-1 alpha (IL-1alpha), which then induces keratinocyte growth factor (KGF) secretion; therefore, we examined their possible roles in the induction of SLs. We found that KGF increases pigment production in both pigmented epidermal equivalents and human skin explants. In addition, UVB exposure increases KGF expression, and KGF treatment induces tyrosinase (TYR) expression in primary melanocytes. The KGF-induced pigmentary changes were confirmed using pigmented Yucatan swine, and human skins grafted onto immuno deficient mice. In both model systems, the topical treatment with KGF, alone or in combination with IL-1alpha, resulted in the in vivo formation of hyperpigmentary lesions with increased pigment deposition and elongated rete ridges, which resemble the histological features of human SLs. Preliminary immunohistochemical analysis of human skins showed a moderate increase in KGF, and a strong induction in KGF receptor (KGFR) in SL lesions. In summary, KGF increases pigment production and deposition in vitro and in vivo. Moreover, we show for the first time the in vivo generation of hyperpigmentary lesions with histological resemblance to human SLs and indicate the involvement of KGF/KGFR in the molecular pathology of human SLs. PMID- 19780817 TI - Essential role of the C-terminus in Melanocarpus albomyces laccase for enzyme production, catalytic properties and structure. AB - The C-terminus of the fungal laccase from Melanocarpus albomyces (MaL) is processed during secretion at a processing site conserved among the ascomycete laccases. The three-dimensional structure of MaL has been solved as one of the first complete laccase structures. According to the crystal structure of MaL, the four C-terminal amino acids of the mature protein penetrate into a tunnel leading towards the trinuclear site. The C-terminal carboxylate group forms a hydrogen bond with a side chain of His140, which also coordinates to the type 3 copper. In order to analyze the role of the processed C-terminus, site-directed mutagenesis of the MaL cDNA was performed, and the mutated proteins were expressed in Trichoderma reesei and Saccharomyces cerevisiae. Changes in the C-terminus of MaL caused major defects in protein production in both expression hosts. The deletion of the last four amino acids dramatically affected the activity of the enzyme, as the deletion mutant delDSGL(559) was practically inactive. Detailed characterization of the purified L559A mutant expressed in S. cerevisiae showed the importance of the C-terminal plug for laccase activity, stability, and kinetics. Moreover, the crystal structure of the L559A mutant expressed in S. cerevisiae showed that the C-terminal mutation had clearly affected the trinuclear site geometry. The results in this study clearly confirm the critical role of the last amino acids in the C-terminus of MaL. PMID- 19780818 TI - The potassium channel subunit Kvbeta3 interacts with pannexin 1 and attenuates its sensitivity to changes in redox potentials. AB - Pannexin 1 (Panx1), a member of the second gap junction protein family identified in vertebrates, appears to preferentially form non-junctional membrane channels. A candidate regulatory protein of Panx1 is the potassium channel subunit Kvbeta3, previously identified by bacterial two-hybrid strategies. Here, we report on the physical association of Panx1 with Kvbeta3 by immunoprecipitation when co expressed in a neuroblastoma cell line (Neuro2A). Furthermore, in vivo co expression of Panx1 and Kvbeta3 was shown to occur in murine hippocampus and cerebellum. Kvbeta3 is known to accelerate inactivation of otherwise slowly inactivating potassium channels under reducing conditions. We subsequently found that Panx1 channel currents exhibit a significant reduction when exposed to reducing agents, and that this effect is attenuated in the presence of Kvbeta3. Apparently, Kvbeta3 is involved in regulating the susceptibility of Panx1 channels to redox potential. Furthermore, the Panx1 channel blockers carbenoxolone and Probenecid were less effective in inhibiting Panx1 currents when Kvbeta3 was co-expressed. The influence of Kvbeta3 on Panx1 is the first example of modulation of Panx1 channel function(s) by interacting proteins, and suggests the physiological importance of sensing changes in redox potentials. PMID- 19780819 TI - The mode of antistaphylococcal action of Eleutherine americana. AB - The anti-methicillin-resistant Staphylococcus aureus (anti-MRSA) activity and the possible mechanism of action of a crude extract from red bulbs of Eleutherine americana Merr. were investigated. The crude ethanolic extract from E. americana produced minimum inhibitory concentrations (MICs) of 62.5-1000 and 250 microg mL( 1) against MRSA isolates and the reference strains, respectively. Treatment of S. aureus ATCC 27664 with a crude extract at 2MIC reduced the inoculum size by 5 log at 24 h compared with the control. The combined effect of the extract and 7.5% NaCl on the enterotoxin-producing ATCC strain resulted in no detection of organisms within 24 h compared with the control. The release of cell materials after extract treatment was determined by measuring OD(260 nm), the treatment resulted in cytoplasmic leakage. Determination of OD(620 nm) showed that the extract did not cause gross cell wall damage. However, observation of S. aureus cells under an electron microscope after treatment with 2MIC and 4MIC of the crude extract revealed that the extract caused damage to membrane morphology. A knowledge of the mechanism of action of the E. americana extract may offer useful hints in the search for novel antibacterial substance. PMID- 19780820 TI - Cysteine peptidases from Phytomonas serpens: biochemical and immunological approaches. AB - Phytomonas serpens, a phytoflagellate trypanosomatid, shares common antigens with Trypanosoma cruzi. In the present work, we compared the hydrolytic capability of cysteine peptidases in both trypanosomatids. Trypanosoma cruzi epimastigotes presented a 10-fold higher efficiency in hydrolyzing the cysteine peptidase substrate Z-Phe-Arg-AMC than P. serpens promastigotes. Moreover, two weak cysteine-type gelatinolytic activities were detected in P. serpens, while a strong 50-kDa cysteine peptidase was observed in T. cruzi. Cysteine peptidase activities were detected at twofold higher levels in the cytoplasmic fraction when compared with the membrane-rich or the content released from P. serpens. The cysteine peptidase secreted by P. serpens cleaved several proteinaceous substrates. Corroborating these findings, the cellular distribution of the cruzipain-like molecules in P. serpens was attested through immunocytochemistry analysis. Gold particles were observed in all cellular compartments, including the cytoplasm, plasma membrane, flagellum, flagellar membrane and flagellar pocket. Interestingly, some gold particles were visualized free in the flagellar pocket, suggesting the release of the cruzipain-like molecule. The antigenic properties of the cruzipain-like molecules of P. serpens were also analyzed. Interestingly, sera from chagasic patients recognized both cellular and extracellular antigens of P. serpens, including the cruzipain-like molecule. These results point to the use of P. serpens antigens, especially the cruzipain like cysteine-peptidases, as an alternative vaccination approach to T. cruzi infection. PMID- 19780821 TI - Erythema nodosum caused by ascariasis and Chlamydophila pneumoniae pulmonary infection--a case report. AB - Erythema nodosum belongs to a group of relatively common hypodermal inflammations. It occurs mainly among women, particularly young women. The etiology of the disease is not clear. Most frequently, changes appear on the surface of the frontal part of the shins. Initially, red nodules change in color to dark brown and then to yellow and green. There is neither dissolution nor cicatrization of the exanthema. Regression is frequent. We present a case of erythema nodosum caused by Ascaris lumbricoides infection as well as by an early Chlamydophila pneumoniae infection, whose etiology has rarely been described in the literature. We were not able to confirm which factor was responsible for the occurrence of the skin changes as treatment of both infections was effective and all skin changes later disappeared completely. Particular attention should be paid to the fact that precise diagnosis of a patient and the search for etiologic factors, even rare ones, are crucial to obtain good results with treatment of erythema nodosum. PMID- 19780822 TI - Past, present and future directions in human genetic susceptibility to tuberculosis. AB - The historical impression that tuberculosis was an inherited disorder has come full circle and substantial evidence now exists of the human genetic contribution to susceptibility to tuberculosis. This evidence has come from several whole genome linkage scans, and numerous case-control association studies where the candidate genes were derived from the genome screens, animal models and hypotheses pertaining to the disease pathways. Although many of the associated genes have not been validated in all studies, the list of those that have been is growing, and includes NRAMP1, IFNG, NOS2A, MBL, VDR and some TLR. Certain of these genes have consistently been associated with tuberculosis in diverse populations. The future investigation of susceptibility to tuberculosis is almost certain to include genome-wide association studies, admixture mapping and the search for rare variants and epigenetic mechanisms. The genetic identification of more vulnerable individuals is expected to inform personalized treatment and perhaps vaccination strategies. PMID- 19780823 TI - Microarray-based analysis of microbial functional diversity along an oil contamination gradient in oil field. AB - To understand better the in situ microbial functional diversity under oil contamination stress, soils were sampled along a contamination gradient at an oil field in north-east China. Microbial community functional structure was examined with a functional gene array, termed GeoChip. Multivariate statistical analysis and meta-analysis were conducted to study the functional gene responses to oil concentrations. The total functional gene abundance and diversity decreased along the gradient of increasing contamination. The overall abundance of soil bacteria, archaea and fungi decreased to 10%, 40% and 80% of those in the pristine soil. Several functional genes in the families pgl, rbcL, nifH and nor and those encoding cellulase, laccase, chitinase, urease and key enzymes in metabolizing organic compounds were significantly decreased with oil contamination, especially under high contamination stress. However, a few genes encoding key enzymes for catechol, protocatechuate, and biphenyl degradation and in the gene families of nir, rbcL and pgl showed a significant increase at a medium level of oil contamination. Oil content and soil available nitrogen were found to be important factors influencing the microbial community structure. The results provide an insight into microbial functional diversity in oil-contaminated soils, providing potential information for on-site management and remediation measures. PMID- 19780824 TI - Sympatric soil communities of Bacillus cereus sensu lato: population structure and potential plasmid dynamics of pXO1- and pXO2-like elements. AB - Eighty soil-borne Bacillus cereus group isolates were collected from two neighbouring geographical sites in Belgium. Their genetic relationships and population structure were assessed using Multilocus sequence typing analysis of five chromosomal genes, while the contribution of extrachromosomal elements to the population dynamics was gauged by the presence, diversity and transfer capacity of pXO1- and pXO2-like plasmids. Globally, the bacterial population displayed a broad diversity, including an important subpopulation of psychrotolerant isolates related to Bacillus weihenstephanensis. pXO1- and pXO2 like replicons were present in 12% and 21% of the isolates, but no Bacillus anthracis-related toxin genes were found. Furthermore, only one of the isolates containing a pXO2-related plasmid was shown to be able to mobilize small non-self conjugative plasmids. Interestingly, several B. cereus sensu lato isolates displaying the same sequence type were observed to have different plasmid contents, suggesting the occurrence of horizontal gene exchange. Similarly, a number of pXO2-like replicons with identical sequences were found in distinct bacterial isolates, therefore strongly arguing for lateral transfers among sympatric bacteria. PMID- 19780825 TI - Vibrio sp. as a potentially important member of the Black Band Disease (BBD) consortium in Favia sp. corals. AB - Black Band Disease (BBD) is a well-described disease plaguing corals worldwide. It has been established that ecological and environmental stress factors contribute to the appearance and progression of the disease, believed to be caused by a diverse microbial consortium. We have identified and characterized Vibrio sp. associated with BBD in Eilat reef corals using both culture-dependent and -independent methods. Direct sampling using 16S rRNA gene clone libraries showed seasonal dynamics in the diversity of BBD-associated Vibrios. In the two sampling periods, BBD-associated Vibrio clones showed similarities to different groups: October samples were similar to known pathogens, while December samples were similar to general aquatic Vibrio sp. Cultured bacterial isolates of Vibrio sp. were highly homologous (>or=99%) to previously documented BBD-associated bacteria from the Caribbean, Bahamas and Red Seas, and were similar to several known coral pathogens, such as Vibrio coralliilyticus. The proteolytic activity of Vibrio sp., as measured using casein- and azocasein-based assays, directly correlated with temperature elevation and peaked at 26-28 degrees C, with the microorganisms producing more proteases per bacterial cell or increasing the rate of proteolytic activity of the same proteases (potentially metalloproteases). This activity may promote coral tissue necrosis and aid in ensuing progression of the coral BBD. PMID- 19780826 TI - Community dynamics within a bacterial consortium during growth on toluene under sulfate-reducing conditions. AB - A sulfate-reducing bacterial consortium was enriched from an anoxic aquifer contaminated with BTEX compounds, using toluene as a growth substrate. Total cell counts, protein contents and sulfide production were determined to follow growth at the in situ temperature (14 degrees C) and at 25 degrees C, respectively. Community members were identified by 16S rRNA gene cloning and sequencing. Phylogenetic analysis revealed 12 sequence types belonging to Deltaproteobacteria (several groups), Epsilonproteobacteria, Bacteroidetes, Spirochaetaceae and an unclassified bacterial clade. The most prominent phylotype comprising 34% of all clones was affiliated to the Desulfobulbaceae and closely related to environmental clones retrieved from hydrocarbon-contaminated aquifers. Flow cytometric methods were applied to analyze the community dynamics and to identify key organisms involved in toluene assimilation. Flow-cytometric measurement of DNA contents and scatter behavior served to detect and quantify dominant and newly emerging clusters of subcommunities. Up to seven subcommunities, two of them dominant, were distinguished. Cell sorting was used to facilitate the analysis of conspicuous clusters for phylogenetic identity by terminal restriction fragment length polymorphism profiling of the 16S rRNA genes. The Desulfobulbaceae phylotype accounted for up to 87% in proliferating subcommunities, indicating that it represents the key organism of toluene degradation within this complex anaerobic consortium. PMID- 19780827 TI - Patterns of Fusarium community structure and abundance in relation to spatial, abiotic and biotic factors in soil. AB - Members of the Fusarium genus are important components of many plant-soil systems worldwide and are responsible for many crop diseases. Knowledge of the relative influence of biotic and abiotic factors on this genus is therefore of broad economic and ecological importance. In order to address this issue, we examined Fusarium communities in soils nearby apparently healthy and symptomatic asparagus plants in 50 fields scattered in four agricultural regions of Quebec, Canada. Fusarium community structure and abundance were assessed using genus-specific PCR denaturing gradient gel electrophoresis and CFU counts, respectively. Multivariate statistical analyses were used to detect community patterns related to spatial, abiotic and biotic factors. Results suggested that Fusarium community structure (i.e. the presence and absence of the different Fusarium sequence variants in the samples) in soil is mainly related to biotic factors (arbuscular mycorrhizal fungi and bacterial community structure), whereas Fusarium abundance is more closely related to abiotic factors (mainly clay, organic matter, NH(4), Na and Cu). Some degree of influence of spatial patterns was also observed on both Fusarium community structure and abundance with, for instance, a large regional variation in Fusarium community structure. However, Fusarium community structure was not directly related to the disease status of nearby asparagus plants. PMID- 19780828 TI - Altitude ammonia-oxidizing bacteria and archaea in soils of Mount Everest. AB - To determine the abundance and distribution of bacterial and archaeal ammonia oxidizers in alpine and permafrost soils, 12 soils at altitudes of 4000-6550 m above sea level (m a.s.l.) were collected from the northern slope of the Mount Everest (Tibetan Plateau), where the permanent snow line is at 5800-6000 m a.s.l. Communities were characterized by real-time PCR and clone sequencing by targeting on amoA genes, which putatively encode ammonia monooxygenase subunit A. Archaeal amoA abundance was greater than bacterial amoA abundance in lower altitude soils (or=5700 m a.s.l.). Both archaeal and bacterial amoA abundance decreased abruptly in higher altitude soils. Communities shifted from a Nitrosospira amoA cluster 3a-dominated ammonia-oxidizing bacteria community in lower altitude soils to communities dominated by a newly designated Nitrosospira ME and cluster 2 related groups and Nitrosomonas cluster 6 in higher altitude soils. All archaeal amoA sequences fell within soil and sediment clusters, and the proportions of the major archaeal amoA clusters changed between the lower altitude and the higher altitude soils. These findings imply that the shift in the relative abundance and community structure of archaeal and bacterial ammonia oxidizers may result from selection of organisms adapted to altitude-dependent environmental factors in elevated soils. PMID- 19780829 TI - Bacterial diversity of water and sediment in the Changjiang estuary and coastal area of the East China Sea. AB - The Changjiang estuary and the coastal area of the East China Sea (ECS) represent important interfaces of terrestrial and marine environments. This study included analyses of water and sediments collected during different seasons in these regions to determine the composition of microbial assemblages by means of 16S rRNA gene clone libraries. We retrieved 1946 sequences and 779 distinct operational taxonomic units from 36 clone libraries. Shannon-Weaver diversity index values and rarefaction analysis indicated that bacterial diversity in the sediment samples was much higher than in the water samples. Proteobacteria (72.9%) was the most abundant phylum, followed by Firmicutes (6.4%), Bacteroidetes (4.6%) and Actinobacteria (4.1%). In the water, clone sequences related to Alphaproteobacteria were the most abundant, whereas in the sediment samples, sequences affiliated with Gammaproteobacteria were predominant. Principal coordinate analysis showed that water samples collected from the Changjiang estuary and the ECS clustered separately. However, this spatial pattern could not be observed in sediment samples, which were mainly distinguished from one another by the season. Bacterial diversity in the Changjiang estuary was higher than that in the ECS, which may be the result of the mixing of bacterial communities from the Changjiang River, the estuary and the coastal ocean. PMID- 19780830 TI - Soil analysis reveals the presence of an extended mycelial network in a Tuber magnatum truffle-ground. AB - Truffles are hypogeous ectomycorrhizal fungi. They belong to the genus Tuber and are currently considered a hot spot in fungal biology due to their ecological and economic relevance. Among all the species, Tuber magnatum is the most appreciated because of its special taste and aroma. The aim of this work was to set up a protocol to detect T. magnatum in soil and to assess its distribution in a natural truffle-ground. We used the beta-tubulin gene as a marker to identify T. magnatum in the soil. This gene allowed us to trace the distribution of the fungus over the entire truffle-ground. Tuber magnatum was found, in one case, 100 m from the productive host plant. This study highlights that T. magnatum mycelium is more widespread than can be inferred from the distribution of truffles and ectomycorrhizas. Interestingly, a new haplotype - never described from fruiting body material - was identified. The specific detection of T. magnatum in the soil will allow to unravel the ecology of this fungus, following its mycelial network. Moreover, this new tool may have practical importance in projects aimed to increase large-scale truffle production, checking for T. magnatum persistence in plantations. PMID- 19780831 TI - Molecular analysis of intestinal microbiota of rainbow trout (Oncorhynchus mykiss). AB - The aim of this study was to evaluate different molecular tools based on the 16S rRNA gene, internal transcribed spacer, and the rpoB gene to examine the bacterial populations present in juvenile rainbow trout intestines. DNA was extracted from both pooled intestinal samples and bacterial strains. Genes were PCR-amplified and analysed using both temporal temperature gradient gel electrophoresis (TTGE) and restriction fragment length polymorphism methods. Because of the high cultivability of the samples, representative bacterial strains were retrieved and we compared the profiles obtained from isolated bacteria with the profile of total bacteria from intestinal contents. Direct analysis based on rpoB-TTGE revealed a simple bacterial composition with two to four bands per sample, while the 16S rRNA gene-TTGE showed multiple bands and comigration for a few species. Sequencing of the 16S rRNA gene- and rpoB-TTGE bands revealed that the intestinal microbiota was dominated by Lactococcus lactis, Citrobacter gillenii, Kluyvera intermedia, Obesumbacterium proteus, and Shewanella marinus. In contrast to 16S rRNA gene-TTGE, rpoB-TTGE profiles derived from bacterial strains produced one band per species. Because the single-copy state of rpoB leads to a single band in TTGE, the rpoB gene is a promising molecular marker for investigating the bacterial community of the rainbow trout intestinal microbiota. PMID- 19780832 TI - Bacterioplankton composition of the coastal upwelling system of 'Ria de Vigo', NW Spain. AB - Catalysed reported deposition-FISH and clone libraries indicated that Roseobacter, followed by Bacteroidetes, and some gammaproteobacterial groups such as SAR86, dominated the composition of bacterioplankton in Ria de Vigo, NW Spain, in detriment to SAR11 (almost absent in this upwelling ecosystem). Since we sampled four times during the year, we observed pronounced changes in the structure of each bacterioplankton component, particularly for the Roseobacter lineage. We suggest that such variations in the coastal upwelling ecosystem of Ria de Vigo were associated with the characteristic phytoplankton communities of the four different hydrographical situations: winter mixing, spring bloom, summer stratification, and autumn upwelling. We retrieved new sequences among the major marine bacterial lineages, particularly among Roseobacter, SAR11, and especially SAR86. The spring community was dominated by two Roseobacter clades that had previously been related to phytoplankton blooms. In the other seasons, communities with higher diversity than the spring one were detected. PMID- 19780833 TI - Simultaneous improvement of catalytic activity and thermal stability of tyrosine phenol-lyase by directed evolution. AB - The tyrosine phenol-lyase from Symbiobacterium toebii was engineered to improve both its stability and catalytic activity by the application of random mutagenesis and subsequent reassembly of the acquired mutations. Activity screening of the random library produced four mutants with a two-fold improved activity, whereas parallel screening after heat treatment at 65 degrees C identified three mutants with half-inactivation temperatures improved by up to 5.6 degrees C. The selected mutants were then reassembled using the staggered extension PCR method, and subsequent screening of the library produced seven mutants with up to three-fold improved activity and half-inactivation temperatures improved by up to 11.2 degrees C. Sequence analyses revealed that the stability-improved hits included A13V, E83K and T407A mutations, whereas the activity-improved hits included the additional T129I or T451A mutation. In particular, the A13V mutation was propagated in the hits with improved stability during the reassembly-screening process, indicating the critical nature of the N terminal moiety for enzyme stability. Furthermore, homology modeling of the enzyme structure revealed that most of the stability mutations were located around the dimer-dimer interface, including the N-terminus, whereas the activity improving mutations were located further away, thereby minimizing any interference that would be detrimental to the co-improvement of the stability and catalytic activity of the enzyme. PMID- 19780834 TI - Membrane type-1 matrix metalloprotease-independent activation of pro-matrix metalloprotease-2 by proprotein convertases. AB - Matrix metalloprotease-2 is implicated in many biological processes and degrades extracellular and non-extracellular matrix molecules. Matrix metalloprotease-2 maintains a latent state through a cysteine-zinc ion pairing which, when disrupted, results in full enzyme activation. This pairing can be disrupted by a conformational change or cleavage within the propeptide. The best known activation mechanism for pro-matrix metalloprotease-2 occurs via cleavage of the propeptide by membrane type-1 matrix metalloprotease. However, significant residual activation of pro-matrix metalloprotease-2 is seen in membrane type-1 matrix metalloprotease knockout mice and in fibroblasts treated with metalloprotease inhibitors. These findings indicate the presence of a membrane type-1 matrix metalloprotease-independent activation mechanism for pro-matrix metalloprotease-2 in vivo, which prompted us to explore an alternative activation mechanism for pro-matrix metalloprotese-2. In this study, we demonstrate membrane type-1 matrix metalloprotease-independent propeptide processing of matrix metalloprotease-2 in HEK293F and various tumor cell lines, and show that proprotein convertases can mediate the processing intracellularly as well as extracellularly. Furthermore, processed matrix metalloprotease-2 exhibits enzymatic activity that is enhanced by intermolecular autolytic cleavage. Thus, our experimental data, taken together with the broad expression of proprotein convertases, suggest that the proprotein convertase-mediated processing may be a general activation mechanism for pro-matrix metalloprotease-2 in vivo. PMID- 19780835 TI - The tetralogy of Fallot-associated G274D mutation impairs folding of the second epidermal growth factor repeat in Jagged-1. AB - Notch signaling controls spatial patterning and cell-fate decisions in all metazoans. Mutations in JAG1, one of the five Notch ligands in man, have been associated with Alagille syndrome and with a familial form of tetralogy of Fallot. A specific G274D mutation in the second epidermal growth factor repeat of the Jagged-1 was found to correlate with tetralogy of Fallot symptoms but not with usual Alagille syndrome phenotypes. To investigate the effects of this mutation, we studied the in vitro oxidative folding of the wild-type and mutant peptides encompassing the second epidermal growth factor. We found that the G274D mutation strongly impairs the correct folding of the epidermal growth factor module, and folding cannot be rescued by compensative mutations. The 274 position displays very low tolerance to substitution because neither the G274S nor the G274A mutants could be refolded in vitro. A sequence comparison of epidermal growth factor repeats found in human proteins revealed that the pattern displayed by the second epidermal growth factor is exclusively found in Notch ligands and that G274 is absolutely conserved within this group. We carried out a systematic and comprehensive analysis of mutations found in epidermal growth factor repeats and show that specific residue requirements for folding, structural integrity and correct post-translational processing may provide a rationale for most of the disease-associated mutations. PMID- 19780836 TI - An engineered right-handed coiled coil domain imparts extreme thermostability to the KcsA channel. AB - KcsA, a potassium channel from Streptomyces lividans, was the first ion channel to have its transmembrane domain structure determined by crystallography. Previously we have shown that its C-terminal cytoplasmic domain is crucial for the thermostability and the expression of the channel. Expression was almost abolished in its absence, but could be rescued by the presence of an artificial left-handed coiled coil tetramerization domain GCN4. In this study, we noticed that the handedness of GCN4 is not the same as the bundle crossing of KcsA. Therefore, a compatible right-handed coiled coil structure was identified from the Protein Data Bank and used to replace the C-terminal domain of KcsA. The hybrid channel exhibited a higher expression level than the wild-type and is extremely thermostable. Surprisingly, this stable hybrid channel is equally active as the wild-type channel in conducting potassium ions through a lipid bilayer at an acidic pH. We suggest that a similar engineering strategy could be applied to other ion channels for both functional and structural studies. PMID- 19780837 TI - Structural and mutational analysis of TenA protein (HP1287) from the Helicobacter pylori thiamin salvage pathway - evidence of a different substrate specificity. AB - HP1287 (tenA) from Helicobacter pylori is included among the genes that play a relevant role in bacterium colonization and persistence. The gene has been cloned and its product, protein TenA, has been expressed and purified. The crystal structures of the wild-type protein and the mutant F47Y have been determined at resolutions of 2.7 and 2.4 A, respectively. The molecular model, a homotetramer with 222 symmetry, shows that the H. pylori TenA structure belongs to the thiaminase II class of proteins. These enzymes were recently found to be involved in a salvage pathway for the synthesis of the thiamin precursor hydroxypyrimidine, which constitutes a building block in thiamin biosynthesis, in particular in bacteria living in the soil. By contrast, enzymatic measurements on TenA from H. pylori indicate that the activity on the putative substrate 4-amino 5-aminomethyl-2-methylpyrimidine is very modest. Moreover, in the present study, we demonstrate that the mutation at residue 47, a position where a phenylalanine occurs in all the strains of H. pylori sequenced to date, is not sufficient to explain the very low catalytic activity toward the expected substrate. As a result of differences in the colonization environment of H. pylori as well as the TenA structural and catalytic peculiar features, we suggest a possible pivotal role for the H. pylori enzyme in the thiamin biosynthetic route, which is in agreement with the relevance of this protein in the stomach colonization process. PMID- 19780838 TI - Nanoparticles can induce changes in the intracellular metabolism of lipids without compromising cellular viability. AB - There is growing concern about the safety of engineered nanoparticles, which are produced for various industrial applications. Quantum dots are colloidal semiconductor nanoparticles that have unique luminescence characteristics and the potential to become attractive tools for medical imaging. However, some of these particles can cause oxidative stress and induce cell death. The objective of this study was to explore quantum dot-induced metabolic changes, which could occur without any apparent cellular damage. We provide evidence that both uncoated and ZnS-coated quantum dots can induce the accumulation of lipids (increase in cytoplasmic lipid droplet formation) in two cell culture models: glial cells in primary mouse hypothalamic cultures and rat pheochromocytoma PC12 cells. Glial cells treated with CdTe quantum dots accumulated newly synthesized lipids in a phosphoinositide 3-kinase-dependent manner, which was consistent with the growth factor-dependent accumulation of lipids in PC12 cells treated with CdTe and CdSe/ZnS quantum dots. In PC12 cells, quantum dots, as well as the hypoxia mimetic CoCl(2), induced the up-regulation of hypoxia-inducible transcription factor-1alpha and the down-regulation of the beta-oxidation of fatty acids, both of which could contribute to the accumulation of lipids. On the basis of our results, we propose a model illustrating how nanoparticles, such as quantum dots, could trigger the formation of intracellular lipid droplets, and we suggest that metabolic measurements, such as the determination of fat oxidation in tissues, which are known sites of nanoparticle accumulation, could provide useful measures of nanoparticle safety. Such assays would expand the current platform of tests for the determination of the biocompatibility of nanomaterials. PMID- 19780839 TI - Spectroscopic investigation of the reaction mechanism of CopB-B, the catalytic fragment from an archaeal thermophilic ATP-driven heavy metal transporter. AB - The mechanism of ATP hydrolysis of a shortened variant of the heavy metal translocating P-type ATPase CopB of Sulfolobus solfataricus was studied. The catalytic fragment, named CopB-B, comprises the nucleotide binding and phosphorylation domains. We demonstrated stoichiometric high-affinity binding of one nucleotide to the protein (K(diss) 1-20 microm). Mg is not necessary for nucleotide association but is essential for the phosphatase activity. Binding and hydrolysis of ATP released photolytically from the caged precursor nitrophenylethyl-ATP was measured at 30 degrees C by infrared spectroscopy, demonstrating that phosphate groups are not involved in nucleotide binding. The hydrolytic kinetics was biphasic, and provides evidence for at least one reaction intermediate. Modelling of the forward reaction gave rise to three kinetic states connected by two intrinsic rate constants. The lower kinetic constant (k(1) = 4.7 x 10(-3) s(-1) at 30 degrees C) represents the first and rate-limiting reaction, probably reflecting the transition between the open and closed conformations of the domain pair. The subsequent step has a faster rate (k(2) = 17 x 10(-3) s(-1) at 30 degrees C), leading to product formation. Although the latter appears to be a single step, it probably comprises several reactions with presently unresolved intermediates. Based on these data, we suggest a model of the hydrolytic mechanism. PMID- 19780840 TI - Identification of a new promoter for the response regulator rcsB expression in Salmonella enterica serovar Typhimurium. AB - The RcsCDB (Rcs) phosphorelay system regulates capsule synthesis, flagella production and other cellular activities in several enteric bacteria. This system consists of three proteins: the sensor RcsC, the cognate response regulator RcsB and the histidine-containing phosphotransfer protein RcsD (YojN), which is hypothesized to act as an intermediary in the phosphotransfer from RcsC to RcsB. The rcsC gene is convergently transcribed toward rcsB, which follows rcsD in what appears to be a two-gene operon. Here, it is reported that the overproduction of the rcsB gene represses rcsD transcription, but has a weak effect on its own expression. We demonstrated that the differential rcsD and rcsB expression is due to the activity of two promoters to transcribe the rcsB gene: (1) P(rcsDB) located upstream of rcsD and (2) P(rcsB) located within the rcsD coding region. In addition, here it was demonstrated that in Salmonella typhimurium, P(rcsB) is important to activate the rcsB expression during the stationary growth phase. PMID- 19780841 TI - Molecular analysis of Leptospira spp. isolated from humans by restriction fragment length polymorphism, real-time PCR and pulsed-field gel electrophoresis. AB - A total of 17 Leptospira clinical strains isolated from humans in Croatia were serologically and genetically analysed. For serovar identification, the microscopic agglutination test (MAT) and pulsed-field gel electrophoresis (PFGE) were used. To identify isolates on genomic species level, PCR-based restriction fragment length polymorphism (RFLP) and real-time PCR were performed. MAT revealed the following serogroup affinities: Grippotyphosa (seven isolates), Icterohaemorrhagiae (eight isolates) and Javanica (two isolates). RFLP of PCR products from a 331-bp-long fragment of rrs (16S rRNA gene) digested with endonucleases MnlI and DdeI and real-time PCR revealed three Leptospira genomic species. Grippotyphosa isolates belonged to Leptospira kirschneri, Icterohaemorrhagiae isolates to Leptospira interrogans and Javanica isolates to Leptospira borgpetersenii. Genomic DNA from 17 leptospiral isolates was digested with NotI and SgrAI restriction enzymes and analysed by PFGE. Results showed that seven isolates have the same binding pattern to serovar Grippotyphosa, eight isolates to serovar Icterohaemorrhagiae and two isolates to serovar Poi. Results demonstrate the diversity of leptospires circulating in Croatia. We point out the usefulness of a combination of PFGE, RFLP and real-time PCR as appropriate molecular methods in molecular analysis of leptospires. PMID- 19780842 TI - Oral health-related quality of life in patients receiving home-care nursing: associations with aspects of dental status and xerostomia. AB - OBJECTIVE: To explore the differences in oral status, dental attendance and dry mouth problems between patients with long-term disease with high and low scores on Oral Health Impact Profile 14 (OHIP 14) and how patients cope with oral problems such as xerostomia and a reduced ability to brush their teeth. BACKGROUND: There has been a lack of studies of oral health and oral health related quality of life in the frail elderly within the community services. MATERIALS AND METHODS: A cross-sectional questionnaire study was conducted with 137 patients receiving home-care nursing. Structured interviews were conducted by student nurses using OHIP-14, items from the Xerostomia Inventory and questions concerning dental visit habits, brushing of teeth and data from medical records. RESULTS: Eighty-three per cent of patients had natural teeth and 60% had only natural teeth. 'Natural teeth only' indicated a low score on OHIP-14. Problems with brushing and items concerning xerostomia indicated a high score on OHIP-14. Contrasts in the assessments concerning brushing of teeth and xerostomia indicated low priority from the patients themselves and the nursing staff. CONCLUSION: Community health services should focus upon oral health. Both patients and nurses should assess the need for regular brushing of teeth carried out by home-care nurses. Assessment and treatment of dry mouth problems should have higher priority. PMID- 19780843 TI - Effect of a denture cleanser on the concentration of volatile sulphur compounds and denture biofilm in institutionalised elderly. AB - OBJECTIVE: To determine the effectiveness of a denture cleanser in reducing the concentration of volatile sulphur compounds (VSC) and its antimicrobial action. BACKGROUND: Micro-organisms from the denture biofilm can cause local and systemic disease and halitosis. Denture cleansers are important adjuncts in oral care, but there is limited investigation on their effect in malodour compounds. MATERIAL AND METHODS: Nineteen institutionalised elderly who wore at least an upper denture were selected; their VSC concentrations were measured and the denture biofilm was collected. In phase 1, the subjects wore their old denture and data were collected before (B0) and after 7(A1), 14(A2), 28(A3) days of continuous daily use of the denture cleanser. In phase 2, new dentures were inserted and measurements were made at 30(A1.1), 60(A2.2), 90(A3.3) days of treatment. RESULTS: The VSC concentration increased from B0 to A1 (p<0.05), but no differences were found for the others intervals of times. Total micro-organism data did not show a statistical difference between times in Phase I, but in Phase II, there was a statistical difference (p<0.05) and a progressive re-colonisation was observed. CONCLUSION: Within the limits of this study, it was concluded that the denture cleanser had no antimicrobial effect and VSC levels were not reduced. PMID- 19780844 TI - In vivo assessment of the effect of an adhesive for complete dentures on colonisation of Candida species. AB - OBJECTIVE: Denture adhesives have long been recognised by denture wearers as a useful adjunct to denture retention and stability. The objective of the present study was to evaluate, in vivo, the effect of a denture adhesive on oral quantities of Candida species by determination of absolute counts of colony forming units (CFU) per ml of saliva of individuals who use this denture adhesive for a period of 14 days. MATERIALS AND METHODS: Twenty-four individuals were randomised in two equal groups of 12 (test and control), with the individuals of the test group using the adhesive for 14 days. Samples of saliva were collected from all individuals on days 0 (initial), 7 and 14. Aliquots of saliva were diluted and plated in duplicate on Sabouraud dextrose agar with chloramphenicol and incubated for 37 degrees C for 48 h, the CFU/ml were counted in the individuals of each group and the data of each group were compared at the different time periods and analysed statistically by the non-parametric Mann Whitney U-test (alpha <= 5%). RESULTS: There were no statistically significant differences between the test and control groups during the test periods. CONCLUSION: Within of the limitations of this study, the data suggested that the denture adhesive tested did not significantly alter the oral microbiota during the 14-day trial period. PMID- 19780846 TI - Haemophilia care in India: innovations and integrations by various chapters of Haemophilia Federation of India (HFI). AB - Care of persons with haemophilia (PWH) in western countries is the responsibility of the government of those countries with or without funding from health insurers. Haemophilia societies in western countries work as pressure groups to ensure better care, and they disseminate information on the disease and some of the societies even support medical research for haemophilia care. In India, Haemophilia Federation of India (HFI) was established in 1982 with few haemophilia families and sympathizers of their cause; subsequently more than 65 chapters involving more than 12 500 PWH came up under HFI. HFI and its constituent chapters are unique in the world in the sense that they are not only trying to involve state and federal government to take responsibility for delivering haemophilia care, but they are also using various innovative and integrative techniques to deliver haemophilia care to PWH themselves, till the time federal and state governments of the country make suitable arrangement for their care. In this study, several of these approaches are discussed with the understanding that 80% of worlds' haemophilia population needs similar help, and the national haemophilia organizations (NMO) of various developing countries will find some of the approaches useful and adaptable to their own circumstances. PMID- 19780845 TI - FEIBA prophylaxis in haemophilia patients: a clinical update and treatment recommendations. AB - In patients with severe haemophilia and inhibitors, regular factor VIII inhibitor bypassing activity (FEIBA) prophylaxis has been shown to reduce the frequency of bleeding by up to 85% and to improve patient quality of life. FEIBA is well tolerated; the incidence of thrombotic events and of allergic reactions is extremely low. The concept of prophylaxis in haemophilia patients with inhibitors is relatively new and some clinicians may be unsure of how to use FEIBA in this context. These treatment recommendations, based on published evidence plus the collective experience of a group of haematologists (with practical knowledge of managing inhibitor patients with FEIBA prophylaxis), are intended to provide guidance to clinicians considering initiating and maintaining patients on FEIBA prophylaxis with specific focus on practical aspects of patient selection, dosing, monitoring and stop criteria. PMID- 19780847 TI - Mycophenolate in the remission induction of a patient with acquired haemophilia A. PMID- 19780848 TI - Organizational characteristics and cancer care for nursing home residents. AB - OBJECTIVE: We evaluate whether organization, market, policy, and resident characteristics are related to cancer care processes and outcomes for dually eligible residents of Michigan nursing homes who entered facilities without a cancer diagnosis but subsequently developed the disease. DATA SOURCES/STUDY DESIGN/DATA COLLECTION: Using data from the Michigan Tumor Registry (1997-2000), Medicare claims, Medicaid cost reports, and the Area Resource File, we estimate logistic regression models of diagnosis at or during the month of death and receipt of pain medication during the month of or month after diagnosis. PRINCIPAL FINDINGS: Approximately 25 percent of the residents were diagnosed at or near death. Only 61 percent of residents diagnosed with late or unstaged cancer received pain medication during the diagnosis month or the following month. Residents in nursing homes with lower staffing and in counties with fewer hospital beds were more likely to be diagnosed at death. After the Balanced Budget Act (BBA), residents were more likely to be diagnosed at death. CONCLUSIONS: Nursing home characteristics and community resources are significantly related to the cancer care residents receive. The BBA was associated with an increased likelihood of later diagnosis of cancer. PMID- 19780849 TI - The influence of targeted education on medication persistence and generic substitution among consumer-directed health care enrollees. AB - OBJECTIVE: To evaluate an educational outreach among consumer-directed health plan (CDHP) enrollees on medication persistence and lower-cost generic substitution within four chronic medication therapies. STUDY SETTING: A cross sectional analysis using pharmacy claims data from a national employer group that began offering a CDHP in 2006 and implemented an educational outreach to some CDHP enrollees in 2007 was used. METHODS: The intervention group was comprised of CDHP enrollees who received education outreach and was compared with CDHP enrollees without the educational outreach. Adjusted and unadjusted medication persistence and lower-cost generic substitutions were compared between groups. PRINCIPAL FINDINGS: There was no difference in medication persistence between groups. CDHP enrollees with the educational outreach were more likely to have converted to lower-cost generic alternative antihypertensive medication compared with CDHP enrollees without the educational outreach (OR(adj)=29.82, 95 percent CI=4.41-201.93). CONCLUSION: Educational outreach directed to CDHP enrollees was associated with increases in lower-cost generic alternatives with no change in patients' chronic medication use. However, considerable opportunity exists to assist CDHP enrollees in making sound health care decisions. PMID- 19780851 TI - The role of monetary and nonmonetary incentives on the choice of practice establishment: a stated preference study of young physicians in Germany. AB - INTRODUCTION: The study aimed to quantify the preferences of young physicians for different attributes relevant to practice establishment in Germany. METHODS: Qualitative in-depth interviews of 22 physicians were conducted to identify relevant practice attributes. Based on this information, a questionnaire was developed containing a discrete choice experiment comprised of a "best-worst scaling" (BWS) task. It was mailed to a representative sample of 14,939 young physicians who were close to making a decision regarding practice establishment. Regression analysis was used to estimate utility weights quantifying physicians' preferences for practice attributes. RESULTS: Qualitative interviews identified six attributes: "professional cooperation,""income,""career opportunities of the partner,""availability of child care,""leisure activities," and "on-call duties." For the BWS task, 5,026 returned questionnaires were analyzed. Results indicated that a change in income led to the largest utility change compared with changes in other attributes. Additional net income to compensate the disutility of a rural practice as compared with an urban practice was 9,044euro/months (U.S.$ 11,938). Yet, nonmonetary attributes such as on-site availability of childcare and fewer on-call duties would decrease the additional income required to compensate the disutility of a rural practice. DISCUSSION: The results offer quantifiable information about young physicians' preferences in establishing a practice. It can assist health policy makers in developing tailored incentive based interventions addressing urban-rural inequalities in physician coverage. PMID- 19780850 TI - Do physicians attend to base rates? Prevalence data and statistical discrimination in the diagnosis of coronary heart disease. AB - OBJECTIVE: To examine whether physicians attend to gender prevalence data in diagnostic decision making for coronary heart disease (CHD) and to test the hypothesis that previously reported gender differences in CHD diagnostic certainty are due to discrimination arising from reliance on prevalence data ("statistical discrimination"). DATA SOURCES: A vignette-based experiment of 256 randomly sampled primary care physicians conducted from 2006 to 2007. STUDY DESIGN: Factorial experiment. Physicians observed patient presentations of cardinal CHD symptoms, standardized across design factors (gender, race, age, socioeconomic status). DATA COLLECTION: Structured interview. PRINCIPAL FINDINGS: Most physicians perceived the U.S. population CHD prevalence as higher in men (48.4 percent) or similar by gender (44.9 percent). For the observed patient, 52 percent did not change their CHD diagnostic certainty based on patient gender. Forty-eight percent of physicians were inconsistent in their population-level and individual-level CHD assessments. Physicians' assessments of CHD prevalence did not attenuate the observed gender effect in diagnostic certainty for the individual patient. CONCLUSIONS: Given an adequate presentation of CHD symptoms, physicians may deviate from their prevalence data during diagnostic decision making. Physicians' priors on CHD prevalence did not explain the gender effect in CHD certainty. Future research should examine personal stereotypes as an explanation for gender differences. PMID- 19780852 TI - Spatial implications associated with using Euclidean distance measurements and geographic centroid imputation in health care research. AB - OBJECTIVE: To determine the effect of using Euclidean measurements and zip-code centroid geo-imputation versus more precise spatial analytical techniques in health care research. DATA SOURCES: Commercially insured members from a southeastern managed care organization. STUDY DESIGN: Distance from admitting inpatient facility to member's home and zip-code centroid (geographic placement) was compared using Euclidean straight-line and shortest-path drive distances (measurement technique). DATA COLLECTION: Administrative claims from October 2005 to September 2006. PRINCIPAL FINDINGS: Measurement technique had a greater impact on distance values compared with geographic placement. Drive distance from the geocoded address was highly correlated (r=0.99) with the Euclidean distance from the zip-code centroid. CONCLUSIONS: Actual differences were relatively small. Researchers without capabilities to produce drive distance measurements and/or address geocoding techniques could rely on simple linear regressions to estimate correction factors with a high degree of confidence. PMID- 19780854 TI - Role and involvement of life end information forum physicians in euthanasia and other end-of-life care decisions in Flanders, Belgium. AB - OBJECTIVE: To describe role and involvement of Life End Information Forum (LEIF) physicians in end-of-life care decisions and euthanasia in Flanders. STUDY DESIGN: All 132 LEIF physicians in Belgium received a questionnaire inquiring about their activities in the past year, and their end-of-life care training and experience. PRINCIPAL FINDINGS: Response rate was 75 percent. Most respondents followed substantive training in end-of-life care. In 1 year, LEIF physicians were contacted 612 times for consultations in end-of-life decisions, of which 355 concerned euthanasia requests eventually resulting in 221 euthanasia cases. LEIF physicians also gave information about various end-of-life issues (including palliative care) to patients and colleagues. CONCLUSIONS: LEIF physicians provide a forum for information and advice for physicians and patients. A similar health service providing support to physicians for all end-of-life decisions could also be beneficial for countries without a euthanasia law. PMID- 19780853 TI - The role of outpatient facilities in explaining variations in risk-adjusted readmission rates between hospitals. AB - OBJECTIVE: Validate risk-adjusted readmission rates as a measure of inpatient quality of care after accounting for outpatient facilities, using premature infants as a test case. STUDY SETTING: Surviving infants born between January 1, 1998 and December 12, 2001 at five Northern California Kaiser Permanente neonatal intensive care units (NICU) with 1-year follow-up at 32 outpatient facilities. STUDY DESIGN: Using a retrospective cohort of premature infants (N=898), Poisson's regression models determined the risk-adjusted variation in unplanned readmissions between 0-1 month, 0-3 months, 3-6 months, and 3-12 months after discharge attributable to patient factors, NICUs, and outpatient facilities. DATA COLLECTION: Prospectively collected maternal and infant hospital data were linked to inpatient, outpatient, and pharmacy databases. PRINCIPAL RESULTS: Medical and sociodemographic factors explained the largest amount of variation in risk adjusted readmission rates. NICU facilities were significantly associated with readmission rates up to 1 year after discharge, but the outpatient facility where patients received outpatient care can explain much of this variation. Characteristics of outpatient facilities, not the NICUs, were associated with variations in readmission rates. CONCLUSION: Ignoring outpatient facilities leads to an overstatement of the effect of NICUs on readmissions and ignores a significant cause of variations in readmissions. PMID- 19780855 TI - Racial and ethnic disparities in the treatment of a Medicaid population with schizophrenia. AB - OBJECTIVE: To assess health care disparities among black and Latino adults with schizophrenia receiving services during the period July 1994-June 2006, and to evaluate trends in observed disparities. DATA SOURCES: Administrative claims data from the Florida Medicaid program. Data sources included membership files (demographic information), medical claims (diagnostic, service, and expenditure information), and pharmacy claims (prescriptions used and expenditures). STUDY DESIGN: We identified adults with at least two schizophrenia claims during a fiscal year. We used generalized estimating equation models to estimate disparities in spending on psychotropic drugs, psychiatric inpatient services, all mental health services, and all health services. PRINCIPAL FINDINGS: Spending on psychotropic drugs, mental health, and all health was 0.9-70 percent lower for blacks and Latinos than for whites. With the exception of blacks with substance use disorder comorbidity, minorities were less likely than whites to use psychiatric inpatient services. Psychiatric inpatient spending among users did not differ by race/ethnicity. With the exception of psychiatric inpatient utilization/spending, trend analyses showed no change or modest reductions in disparities. CONCLUSIONS: Black and Latino Medicaid recipients diagnosed with schizophrenia experience health care disparities. Some but not all disparities narrowed modestly over the study period. PMID- 19780856 TI - The impact of CHIP on children's insurance coverage: an analysis using the National Survey of America's Families. AB - OBJECTIVE: To assess the impact of the Children's Health Insurance Program (CHIP) on the distribution of health insurance coverage for low-income children. DATA SOURCE: The primary data for the study were from the 1997, 1999, and 2002 National Survey of America's Families (NSAF), which includes a total sample of 62,497 children across all 3 years, supplemented with data from other data sources. STUDY DESIGN: The study uses quasi-experimental designs and tests the sensitivity of the results to using instrumental variable and difference-in difference approaches. A detailed Medicaid and CHIP eligibility model was developed for this study. Balanced repeated replicate weights were used to account for the complex sample of the NSAF. Descriptive and multivariate analyses were conducted. PRINCIPLE FINDINGS: The results varied depending on the approach utilized but indicated that the CHIP program led to significant increases in public coverage (14-20 percentage points); and declines in employer-sponsored coverage (6-7 percentage points) and in uninsurance (7-12 percentage points). The estimated share of CHIP enrollment attributable to crowd-out ranged from 33 to 44 percent. Smaller crowd-out effects were found for Medicaid-eligible children. CONCLUSIONS: Implementation of the CHIP program resulted in large increases in public coverage with estimates of crowd-out consistent with initial projections made by the Congressional Budget Office. This paper demonstrates that public health insurance expansions can lead to substantial reductions in uninsurance without causing a large-scale erosion of employer coverage. PMID- 19780857 TI - Preventive HIV vaccine acceptability and behavioral risk compensation among a random sample of high-risk adults in Los Angeles (LA VOICES). AB - OBJECTIVE: To assess HIV vaccine acceptability among high-risk adults in Los Angeles. STUDY SETTING: Sexually transmitted disease clinics, needle/syringe exchange programs, Latino community health/HIV prevention programs. STUDY DESIGN: Cross-sectional survey using conjoint analysis. Participants were randomly selected using three-stage probability sampling. DATA COLLECTION: Sixty-minute structured interviews. Participants rated acceptability of eight hypothetical vaccines, each with seven dichotomous attributes, and reported post-vaccination risk behavior intentions. PRINCIPAL FINDINGS: Participants (n=1164; 55.7 percent male, 82.4 percent ethnic minority, mean age=37.4 years) rated HIV vaccine acceptability from 28.4 to 88.6; mean=54.5 (SD=18.8; 100-point scale). Efficacy had the greatest impact on acceptability, followed by side effects and out-of pocket cost. Ten percent would decrease condom use after vaccination. CONCLUSIONS: Findings support development of social marketing interventions to increase acceptability of "partial efficacy" vaccines, behavioral interventions to mitigate risk compensation, and targeted cost subsidies. PMID- 19780858 TI - Does cyclin D1 discriminate between BRCA2 and BRCAX breast cancers? PMID- 19780859 TI - CD81 expression in peripheral blood lymphocytes before and after treatment with interferon and ribavirin in HIV/HCV coinfected patients. AB - BACKGROUND: CD81 is expressed on lymphocytes and confers HCV viral infectivity support. The aim of our study was to quantify CD81 expression in peripheral blood B- and T-cells of HCV/HIV-coinfected patients and healthy subjects to examine its association with several HCV virological characteristics and the therapeutic responsiveness to HCV antiviral treatment. METHODS: We carried out a cross sectional study on 122 naive patients. For a duration of 48 weeks, 24 out of 122 patients underwent HCV antiviral therapy with interferon (IFN)-alpha and ribavirin. T- and B-cell subsets were analysed by flow cytometry. RESULTS: We found that HIV/HCV coinfected patients with HCV-RNA > or =850 000 IU/mL had lower values of %CD19+CD81-CD62L+ and %CD19+CD62L+; and higher values of CD19+CD81+CD62L- and CD19+CD81+ percentages and absolute counts than patients with HCV-RNA <850 000 IU/mL. Similarly, HIV/HCV coinfected patients with the genotype 1 had lower values of %CD19+CD81-CD62L+ and higher values of CD3+CD81+CD62L- and CD3+CD81+ percentages and absolute counts than patients without genotype 1. Moreover, we found that HIV/HCV coinfected patients had higher values of %CD19+HLA-DR+CD25+, %CD19+CD40+CD25+ and %CD19+CD25+ than healthy control patients. When we studied the B- and T-cell subset kinetics of 24 HIV/HCV coinfected patients on HCV antiviral therapy, we found a significant decrease in CD3+CD81+and CD3+CD81+CD62L- subsets and a significant increase in CD3+CD62L+ and CD3+CD81+CD62L+ percentages and absolute counts, but the variation in these markers disappeared several months after stopping the treatment. CONCLUSIONS: We observed a different pattern of CD81 T-cell and B-cell levels in naive HIV/HCV coinfected patients according to HCV virological status and their subsequent variations during HCV antiviral treatment. CD81 expression might influence HCV pathogenesis and response to HCV antiviral treatment. PMID- 19780860 TI - Prospective epidemiological study of the prevalence of human leukocyte antigen (HLA)-B*5701 in HIV-1-infected UK subjects. AB - OBJECTIVES: Human leukocyte antigen (HLA)-B(*)5701 is strongly associated with developing a hypersensitivity reaction to abacavir (ABC) in White and Hispanic subjects. Across the UK, limited data exist on HLA-B(*)5701 prevalence in HIV-1 infected subjects. We determined HLA-B(*)5701 prevalence in the general HIV-1 infected population and in specific ethnic groups, particularly Black Africans who, in general, exhibit greater genetic diversity. We also compared HLA-B(*)5701 results obtained from local laboratories with those from a central provider. DESIGN AND METHODS: Multi-centre, observational study. All HIV-1-infected adult individuals receiving care at participating centres were eligible, irrespective of treatment status or prior exposure to ABC. Subjects provided samples for HLA B(*)5701 assessment by both local (blood) and central laboratories (buccal swabs). HLA-B(*)5701 prevalence was adjusted to represent the ethnic group composition of the general UK population, and by main ethnic group. RESULTS; From eight UK centres, 1494 subjects [618 (41%) White, 770 (52%) Black] were recruited. Eighty-nine per cent of Black subjects reported an immediate country of origin in Africa. Overall adjusted HLA-B(*)5701 prevalence was 4.55% [95% confidence interval (CI) 3.49% to 5.60%]. Among White subjects, prevalence was 7.93% (CI 5.80% to 10.06%). Among Black subjects, only two (both Ugandan) were HLA-B(*)5701 positive giving a rate of 0.26% (CI 0.07% to 0.94%). CONCLUSIONS: HLA-B(*)5701 prevalence was similar to previously reported rates in White HIV infected subjects but considerably lower than that reported in Black HIV-1 infected subjects, as a result of the large proportion of Black African subjects. PMID- 19780861 TI - Large particle hyaluronic acid for the treatment of facial lipoatrophy in HIV positive patients: 3-year follow-up study. AB - OBJECTIVES: Facial lipoatrophy can be a stigmatizing side effect of antiretroviral (AVR) treatment for HIV-infected patients. We sought to evaluate the long-term efficacy and safety of a new formulation of hyaluronic acid that can be injected in larger amounts and into deeper skin layers during 3 years of follow-up. METHODS: Twenty patients received injections of Restylane SubQ(). Refill treatment was offered at 12 and 24 months. Treatment effects were evaluated using ultrasound, the Global Aesthetic Improvement Scale, visual analogue scale (VAS) and the Rosenberg self-esteem scale. RESULTS: Seventeen patients remained at 36 months. Mean (+/- standard deviation) total cutaneous thickness increased from 6 +/- 1 mm at baseline to 12 +/- 1 mm (P<0.001) at 36 months. Response rate (total cutaneous thickness >10 mm) was 70%. Fifteen patients classified their facial appearance as very much or moderately improved. VAS increased from 39 +/- 25 to 70 +/- 20 (P<0.05) and higher self-esteem scores were reported. Local swelling and tenderness after treatment was common. Persistent papules found in several patients after treatment were removed effectively with hyaluronidase injections. Three patients, treated only at baseline, still had higher total cutaneous thickness scores at 36 months. CONCLUSIONS: Our results indicate that a large particle hyaluronic acid formulation is a durable and well-tolerated dermal filler for treating HIV positive patients with facial lipoatrophy. PMID- 19780862 TI - Risk factors for HIV transmission among heterosexual discordant couples in South India. AB - OBJECTIVE: To assess the risk factors associated with heterosexual HIV transmission among South Indian discordant couples enrolled in clinical care. METHODS: A nested matched case-control study of serodiscordant couples in which the HIV-infected partner (index case) was enrolled in care. Demographic and clinical characteristics, sexual behaviours, CD4 cell count and plasma HIV-1 RNA loads were measured at enrollment and longitudinally over 12 months of follow-up. The study included 70 cases who seroconverted during study follow-up and 167 matched controls who remained persistently serodiscordant. RESULTS: The incidence of HIV infection among the initially seronegative partners was 6.52 per 100 person-years. Persistently discordant patients were more likely to have initiated highly active antiretroviral therapy (HAART) than patients in seroconverting relationships (62.9%vs. 42.9%) (P=0.001). Patients in seroconverting relationships had significantly higher plasma viral loads (PVLs) than patients in discordant relationships at enrolment, at 6 months and at 12 months (P<0.05). Patients in seroconverting relationships were less likely to use condoms with their primary partners than patients in discordant relationships (P<0.05). Patients in relationships that seroconverted between 6 and 12 months were diagnosed more often with genital Herpes simplex than patients in discordant relationships (P=0.001). In the univariate and multivariate logistic regression, the following variables were associated with seroconversion: PVL >100,000 [odds ratio (OR): 1.82; 95% confidence interval (CI): 1.1-2.8], non-disclosure of HIV status (OR: 5.5; 95% CI: 4.3-6.2) and not using condoms (OR: 2.8; 95% CI: 2.4 3.6). CONCLUSIONS: Couples-based intervention models are crucial in preventing HIV transmission to seronegative spouses. Providing early treatment for sexually transmitted infections, HAART and enhancing condom use and disclosure could potentially decrease the risk of HIV transmission within Indian married couples. PMID- 19780863 TI - Lipoprotein lipase and endothelial lipase in human testis and in germ cell neoplasms. AB - The aim of this study was to investigate endothelial lipase (EL, LIPG) and lipoprotein lipase (LPL) mRNA and protein expression in normal human testis and testicular germ cell tumours (GCT). Both EL and LPL were expressed in normal seminiferous tubules and in the interstitial compartment. EL mRNA and protein were found in all germ cells as well as in Sertoli and Leydig cells. EL mRNA was abundant in pre-invasive carcinoma in situ (CIS) cells and GCTs, and EL protein was present in the cytoplasm of these cells. LPL mRNA was also relatively abundant in germ cells, Sertoli cells, CIS cells and GCTs. The LPL protein, however, was restricted to the cell membranes of pachytene spermatocytes and spermatids in normal tubules, absent from CIS cells and scarcely represented in tumours. The distribution of LPL protein in non-seminomas resembled the distribution of OCT3/4, a marker of embryonal carcinoma. The results suggest that both EL and LPL participate in the supply of nutrients and steroidogenesis in the testes, and that especially EL may be important for the supply of cholesterol for testosterone production in the Leydig cells. The partial cellular separation of the expression of the two lipases in normal testis suggests the existence of distinct biological roles, perhaps developmentally regulated, as indicated by the LPL expression in GCTs with embryonic features. A high expression of EL and abundance of lipid in tubules with CIS may have a diagnostic value. PMID- 19780864 TI - Country-specific chemical signatures of persistent environmental compounds in breast milk. AB - Recent reports have confirmed a worldwide increasing trend of testicular cancer incidence, and a conspicuously high prevalence of this disease and other male reproductive disorders, including cryptorchidism and hypospadias, in Denmark. In contrast, Finland, a similarly industrialized Nordic country, exhibits much lower incidences of these disorders. The reasons behind the observed trends are unexplained, but environmental endocrine disrupting chemicals (EDCs) that affect foetal testis development are probably involved. Levels of persistent chemicals in breast milk can be considered a proxy for exposure of the foetus to such agents. Therefore, we undertook a comprehensive ecological study of 121 EDCs, including the persistent compounds dioxins, polychlorinated biphenyls (PCBs), pesticides and flame retardants, and non-persistent phthalates, in 68 breast milk samples from Denmark and Finland to compare exposure of mothers to this environmental mixture of EDCs. Using sophisticated, bioinformatic tools in our analysis, we reveal, for the first time, distinct country-specific chemical signatures of EDCs with Danes having generally higher exposure than Finns to persistent bioaccumulative chemicals, whereas there was no country-specific pattern with regard to the non-persistent phthalates. Importantly, EDC levels, including some dioxins, PCBs and some pesticides (hexachlorobenzene and dieldrin) were significantly higher in Denmark than in Finland. As these classes of EDCs have been implicated in testicular cancer or in adversely affecting development of the foetal testis in humans and animals, our findings reinforce the view that environmental exposure to EDCs may explain some of the temporal and between country differences in incidence of male reproductive disorders. PMID- 19780865 TI - Sexual dysfunction in subjects with Klinefelter's syndrome. AB - While the association of Klinefelter's Syndrome (KS) with infertility is well known, very few investigations have evaluated the prevalence of sexual dysfunction in KS. The aim of the present study was to systematically analyse the prevalence of KS in a consecutive series of adult male patients consulting for sexual problems and to investigate its specific correlates. Among a consecutive series of 1386 men (mean age 48.9 +/- 12.7 years old), 23 (1.7%) subjects with KS were found. Patients with KS were younger and more often hypogonadal when compared with the rest of the sample. Among patients with KS, five (22.7%) subjects reported severe erectile dysfunction, 14 (60.9%) hypoactive sexual desire (HSD), two (9.5%) premature and two (9.5%) delayed ejaculation. Only the association between KS and HSD was confirmed after adjustment for age [HR = 3.2 (1.37-7.5)], however, when patients with KS were compared with age, smoking habit, and testosterone matched controls, even the association between KS with HSD disappeared. In comparison to matched hypogonadal controls, subjects with KS had lower levels of education, a higher frequency of cryptorchidism and poorer pubertal progression. In conclusion, our results indicate that sexual dysfunction present in KS is not specifically associated with the syndrome but is caused by the underlying hypogonadal state. Further studies are needed to evaluate the efficacy of testosterone substitution in ameliorating the hypoactive sexual desire often reported in subjects with KS. PMID- 19780866 TI - Practical guidance on intensification of insulin therapy with BIAsp 30: a consensus statement. AB - BACKGROUND: Basal insulin and premix insulin are commonly prescribed first-line insulin therapies for patients failing to maintain glycaemic control on oral therapy. When control on these insulins starts to drift, premix analogues, such as biphasic insulin aspart 30/70 (BIAsp 30), are a simple and effective tool for intensification as they can be injected up to three-times daily (TID). However, at present, international recommendations for intensification of insulin therapy using premix analogues are limited and specific guidance on dosing is not available for many scenarios. METHODS: In October 2008, an international expert panel met to review the current guidelines for insulin intensification with BIAsp 30 in patients with type 2 diabetes, with the aim of developing practical guidance for general and specialist practitioners. RESULTS: Simple treatment algorithms have been developed for (i) patients on basal insulin (human or analogue) once daily or twice daily (BID) who need intensification to BIAsp 30 BID, and (ii) patients on BIAsp 30 once daily or BID who can be intensified to BIAsp 30 BID or TID. As well as these algorithms, specific guidance has been provided on dose transfer (from basal insulin to BIAsp 30), dose split (when intensifying from once daily to BID), and combination oral therapies. In addition, a guide to dose titration is included. CONCLUSIONS: The guidelines presented here should enable general or specialist practitioners to use BIAsp 30 to intensify the insulin therapy of patients failing on basal insulin or BIAsp 30 once or twice daily. PMID- 19780867 TI - Worldwide-Schizophrenia Outpatient Health Outcomes (W-SOHO): baseline characteristics of pan-regional observational data from more than 17,000 patients. AB - OBJECTIVE: To describe the Worldwide-Schizophrenia Outpatient Health Outcomes (W SOHO) patient population at study entry, focusing on illness burden and prescribing practices across regions. METHODS: The SOHO study was a 3-year, prospective, observational study designed to assess costs and outcomes associated with antipsychotic use in outpatients initiating or changing antipsychotic (with an emphasis on olanzapine compared with other antipsychotics). SOHO was conducted in 10 European countries and 27 other countries as Intercontinental SOHO (IC SOHO). Data from all countries have been pooled to produce the W-SOHO dataset. MAIN OUTCOMES MEASURES: Clinical Global Impression-Schizophrenia (CGI-SCH) severity scores, psychotropic medication use, adverse events, social interaction, housing and employment status, self-perceived health state (EuroQoL EQ-5D scale and Visual Analogue Scale, EQ-VAS), and reasons for initiation/change of antipsychotic. RESULTS: The W-SOHO database comprises 17,384 patients from six regions; East Asia (n = 1223), Central and Eastern Europe (n = 2175), Northern Europe (n = 4291), Southern Europe (n = 5788), Latin America (n = 2566), North Africa and the Middle East (n = 1341). Overall, patients were 38 +/- 13 years old (mean +/- SD), moderately ill (mean CGI-SCH overall score of 4.4 +/- 1.0) with a median duration of illness of 7 years (interquartile range 1-16 years); 43% were female, 10% were receiving antipsychotic medication for the first time. Adverse events were prevalent across all regions; on average, 50% (range 41-59%) of patients taking antipsychotics exhibited extrapyramidal symptoms at baseline, and 62% (34-67%) of patients reported sexual dysfunction in the previous month. On average, only 19% (16-23%) of patients were in paid employment and as many as 69% were living in dependent housing. CONCLUSIONS: Despite inherent diversity in these patients and the health care systems supporting them, there are striking cross-regional similarities in baseline characteristics for most measures. Not all countries are represented; regional comparisons may not be valid outside of the countries studied. PMID- 19780868 TI - Nerve injury-related erectile dysfunction following nerve-sparing radical prostatectomy: a novel experimental dissection model. AB - OBJECTIVES: To establish a new experimental rat model in order to define the mechanisms of erectile dysfunction (ED) and to evaluate the changes of neuronal nitric oxide synthase (nNOS) in the pelvic ganglia following nerve-sparing radical prostatectomy. METHODS: Sprague-Dawley rats were randomized to sham operation, bilateral cavernous nerve dissection (BCND) and bilateral cavernous nerve resection (BCNR) groups. In the BCND group, the cavernous nerves were only dissected bilaterally from the major pelvic ganglion (MPG) to the apex of the prostate without crushing or cutting. At 1, 2, 4 and 8 weeks after surgery, we examined intracavernous pressure along with arterial pressure (ICP/AP), retrograde dye tracing using Fluorogold (FG) and expression of nNOS in the MPG. RESULTS: Intracavernous pressure and arterial pressure in the BCND group was significantly decreased at 2 and 4 weeks after surgery compared with the sham group, and improved at 8 weeks. The number of FG-positive cells in the MPG also recovered at 8 weeks. ICP/AP and FG-positive cells in the BCNR group were greatly decreased until 8 weeks. The percentage of nNOS-positive cells per total cells was not different between the sham and BCND groups during the experimental period, whereas that in the BCNR group gradually decreased with time. CONCLUSIONS: We established a novel rat model, in which cavernous nerve dissection alone caused nerve injury-related ED. We believe that this cavernous nerve dissection model might help clarify the mechanism of nerve injury-related ED and the recovery from ED after nerve-sparing radical prostatectomy. PMID- 19780869 TI - Oral analgesia by non-steroidal anti-inflammatory drug zaltoprofen to manage cystoscopy-related pain: a prospective study. AB - OBJECTIVES: To examine the pre-emptive analgesic effect of the non-steroidal anti inflammatory drug zaltoprofen against rigid cystoscopy-associated pain, and compare it with the effect of an anesthetic gel. METHODS: Forty men periodically undergoing follow-up office cystoscopy were enrolled in this prospective study. The effects of lidocaine gel alone or in combination with zaltoprofen, were examined. The following parameters were assessed using an 11-point numerical rating scale: pain during injection of gel into the urethra, insertion of rigid cystoscope, and the endoscopic examination of the urinary bladder, pain at the first urination after cystoscopy, and at the first urination in the following morning at home. RESULTS: Pain scores with pre-emptive zaltoprofen plus lidocaine gel were significantly lower than the ones with lidocaine gel alone at the time points of inserting rigid cystoscope into the urethra, viewing inside the urinary bladder and the first urination after cystoscopy. The efficacy of zaltoprofen was more significant in the patients with higher baseline pain score. There was no correlation between pain scores and bladder cancer grading, number of tumors, and time from surgery. CONCLUSIONS: Pre-emptive zaltoprofen is able to control cystoscopy-associated pain, which translates into better quality of life for patients. Thus, its use is recommended in the management of these patients. PMID- 19780870 TI - Enhanced neointimal hyperplasia and carotid artery remodelling in sequestosome 1 deficient mice. AB - Deficiency in the signal adaptor protein sequestosome 1 (SQSTM1/A170/p62) in mice is associated with mature-onset obesity, accompanied by insulin and leptin resistance. We previously established that redox sensitive transcription factor Nrf2 up-regulates SQSTM1 expression in response to atherogenic stimuli or laminar shear stress in vascular cells, and here examine the role of SQSTM1 in neointimal hyperplasia and vascular remodelling in vivo following carotid artery ligation. Neointimal hyperplasia was markedly enhanced at ligation sites after 3 weeks in SQSTM1(-/-) compared with wild-type (WT) mice. The intimal area and stenotic ratio were, respectively, 2.1- and 1.7-fold higher in SQSTM1(-/-) mice, indicating enhanced proliferation of vascular smooth muscle cells (SMCs). When aortic SMCs were isolated from WT and SQSTM1(-/-) mice and cultured in vitro, we found that SQSTM1(-/-) SMCs proliferated more rapidly in response to foetal calf serum (FCS) and attained 2-3-fold higher cell densities compared to WT SMCs. Moreover, migration of SQSTM1(-/-) SMCs was enhanced compared to WT SMCs. Early and late phases of p38(MAPK) activation in response to FCS stimulation were also more enhanced in SQSTM1(-/-) SMCs, and inhibitors of p38 and ERK1/2 signalling pathways significantly attenuated SMC proliferation. In summary, SQSTM1(-/-) mice exhibit enhanced neointimal hyperplasia and vascular remodelling following arterial ligation in vivo. The enhanced proliferation of SQSTM1(-/-) aortic SMCs in vitro highlights a novel role for SQSTM1 in suppressing smooth muscle proliferation following vascular injury. PMID- 19780871 TI - Recruitment of endogenous bone marrow mesenchymal stem cells towards injured liver. AB - Recent studies suggest that mesenchymal stem cells (MSCs) possess a greater differentiation potential than once thought and that they have the capacity to regenerate damaged tissues/organs. However, the evidence is insufficient, and the mechanism governing the recruitment and homing of MSCs to these injured sites is not well understood. We first examined the MSCs circulating in peripheral blood and then performed chemotaxis, wound healing and tubule-formation assays to investigate the migration capability of mouse bone marrow MSCs (mBM-MSCs) in response to liver-injury signals. In addition, BM-MSCs from donor enhanced green fluorescent protein transgenic male mice were transplanted into liver-injured co isogenic female recipients, either by intra-bone marrow injection or through the caudal vein, to allow in vivo tracking analysis of the cell fate after transplantation. Donor-derived cells were analysed by in vivo imaging analysis, PCR, flow cytometry and frozen sections. Microarray and real-time PCR were used for chemokine/cytokine and receptor analyses. We successfully isolated circulating MSCs in peripheral blood of liver-injured mice and provided direct evidence that mBM-MSCs could be mobilized into the circulation and recruited into the liver after stimulation of liver injury. CCR9, CXCR4 and c-MET were essential for directing cellular migration towards the injured liver. The recruited mBM MSCs may play different roles, including hepatic fate specification and down regulation of the activity of hepatic stellate cells which inhibits over accumulation of collagen and development of liver fibrosis. Our results provide new insights into liver repair involving endogenous BM-MSCs and add new information for consideration when developing clinical protocols involving the MSCs. PMID- 19780873 TI - Cutaneous leiomyosarcoma originating in a symplastic pilar leiomyoma: a rare occurrence and potential diagnostic pitfall. AB - A case of cutaneous leiomyosarcoma originating in a symplastic pilar leiomyoma is described. The patient was a 60-year-old man who presented with a painless nodule on his chest. Thorough clinical examination did not reveal any evidence of tumor elsewhere. A punch biopsy was performed which showed a benign spindle cell neoplasm with focal cellular pleomorphism that had smooth muscle differentiation and was clearly originating from the arrector pili muscle, consistent with a cutaneous symplastic pilar leiomyoma. Immunohistochemical studies were performed and the tumor cells were strongly positive for smooth muscle actin (SMA) and desmin. Given the clinical information of a mass on the chest, clinical evaluation was recommended and a re-excision was performed. Histologically, the re-excision showed two distinct populations of cells. The upper portion of the tumor mirrored the initial biopsy; however, the base of the tumor showed hypercellular areas composed of spindle cells with marked pleomorphism and increased number of mitoses. The diagnosis of a cutaneous leiomyosarcoma originating in a symplastic pilar leiomyoma was given. This is the first report of this association of such occurrence reported in the literature. PMID- 19780872 TI - Ovarian cancer cytoreduction induces changes in T cell population subsets reducing immunosuppression. AB - Surgery is the primary therapeutic strategy for most solid tumours; however, modern oncology has established that neoplasms are frequently systemic diseases. Being however a local treatment, the mechanisms through which surgery plays its systemic role remain unknown. We have investigated the influence of cytoreduction on the immune system of primary and recurrent ovarian cancer. All ovarian cancer patients show an increase in CD4+ CD25+ FOXP3+ circulating cells (CD4 T(reg) ). CD4/CD8 ratio is increased in primary tumours, but not in recurrent neoplasms. Primary cytoreduction is able to increase circulating CD4 and CD8 effector cells and decrease CD4 naive T cells. CD4+ T(reg) cells rapidly decreased after primary tumour debulking, while CD8+ CD25+ FOXP3+ (CD8 T(reg) ) cells are not detectable in peripheral blood. Similar results on CD4 T(reg) were observed with chemical debulking in women subjected to neoadjuvant chemotherapy. CD4 and CD8 T(reg) cells are both present in neoplastic tissue. Interleukin (IL)-10 serum levels decrease after surgery, while no changes are observed in transforming growth factor-beta1 and IL-6 levels. Surgically induced reduction of the immunosuppressive environment results in an increased capacity of CD8+ T cells to respond to the recall antigens. None of these changes was observed in patients previously subjected to chemotherapy or affected by recurrent disease. In conclusion, we demonstrate in ovarian cancer that primary debulking is associated with a reduction of circulating T(reg) and an increase in CD8 T-cell function. Debulking plays a beneficial systemic effect by reverting immunosuppression and restoring immunological fitness. PMID- 19780874 TI - Strong morphological support for the molecular evolutionary tree of placental mammals. AB - The emerging molecular evolutionary tree for placental mammals differs greatly from morphological trees, leading to repeated suggestions that morphology is uninformative at this level. This view is here refuted empirically, using an extensive morphological and molecular dataset totalling 17 431 characters. When analysed alone, morphology indeed is highly misleading, contradicting nearly every clade in the preferred tree (obtained from the molecular or the combined data). Widespread homoplasy overrides historical signal. However, when added to the molecular data, morphology surprisingly increases support for most clades in the preferred tree. The homoplasy in the morphology is incongruent with all aspects of the molecular signal, while the historical signal in the morphology is congruent with (and amplifies) the historical signal in the molecular data. Thus, morphology remains relevant in the genomic age, providing vital independent corroboration of the molecular tree of mammals. PMID- 19780875 TI - Adefovir plus lamivudine are more effective than adefovir alone in lamivudine resistant HBeAg- chronic hepatitis B patients: a 4-year study. AB - BACKGROUND AND AIM: Adefovir dipivoxil (ADV) is effective in lamivudine (LAM) resistant hepatitis B e antigen-negative (HBeAg(-)) chronic hepatitis B (CHB). However, it is unclear whether LAM treatment should be continued in these patients. We aimed to compare the long-term efficacy of adding ADV to ongoing LAM treatment versus switching to ADV monotherapy in LAM-resistant HBeAg(-) CHB. METHODS: Sixty LAM-resistant patients with HBeAg(-) CHB were randomly assigned (3:1) to combination therapy (10 mg ADV once daily plus ongoing LAM at 100 mg once daily [n = 45]) or 10 mg ADV monotherapy once daily (n = 15). Virological and biochemical responses were defined as hepatitis B virus (HBV)-DNA <400 copies/mL and as normalization of alanine aminotransferase levels, respectively. RESULTS: The median follow-up time was 53 months (range 20-60 months). A virological response was observed in 38/45 (84.4%) and 11/15 (73.3%) patients in the ADV/LAM and ADV monotherapy groups, respectively (P = 0.56). Biochemical response rates were higher in the ADV/LAM group than in the ADV monotherapy group (90.9% vs 57.1%, respectively; P = 0.01). In the ADV/LAM group, serum HBV-DNA remained undetectable in all patients who achieved a virological response (n = 38). In the ADV monotherapy group, virological breakthrough occurred in four of the 11 patients who achieved a virological response (36.4%; P < 0.001 vs the ADV/LAM group, log-rank test). In addition, two patients in each group who did not achieve a virological response eventually developed ADV resistance. CONCLUSIONS: Adding ADV to LAM is more effective than switching to ADV monotherapy in LAM-resistant patients with HBeAg(-) CHB. PMID- 19780876 TI - Effect of miRNA-10b in regulating cellular steatosis level by targeting PPAR alpha expression, a novel mechanism for the pathogenesis of NAFLD. AB - BACKGROUND AND AIM: Accumulating evidence supports the effects of miRNA in lipid metabolism, providing a potential linkage between certain miRNA and non-alcoholic fatty liver disease (NAFLD). We aimed to investigate the miRNA expression pattern in a steatotic L02 cell model and explore the function of certain miRNA target pairs. METHODS: The cell model was established by culturing L02 cells with a high concentration of free fatty acid. Micro-array and stem-loop reverse transcription polymerase chain reaction (RT-PCR) were utilized to detect dysregulated miRNA, whereas computational algorithms were used for target prediction. Real time RT PCR, Western blot, luciferase activity measurement, and other techniques were employed for target verification. RESULTS: Seventeen upregulated and 15 downregulated miRNA were found in steatotic L02 cells, while miRNA-10b was proven to regulate the steatosis level. Peroxisome proliferator-activated receptor-alpha (PPAR-alpha) was also found to participate in steatosis, as its protein level was decreased in steatotic L02 cells and its overexpression by transfection into the PPAR-alpha-pcDNA 3.1 vector could partially alleviate steatosis. We further found that PPAR-alpha is the direct target of miRNA-10b as it showed significantly changed protein expression, but a relatively unchanged mRNA level in steatotic L02 cells transfected with pre-miRNA-10b and anti-miRNA-10b. Moreover, the action of miRNA-10b on PPAR-alpha depends on the presence of a single miRNA-10b binding site, as the activity of a luciferase reporter carrying the mutant PPAR-alpha 3' untranslated region was not reduced by the expression of miRNA-10b. CONCLUSION: The established miRNA profile of the steatotic L02 cell model and the novel effect of miRNA-10b in regulating hepatocyte steatosis may provide a new explanation of the pathogenesis of NAFLD. PMID- 19780877 TI - N-Acetylcysteine improves disturbed ileal contractility following partial hepatectomy in rats. AB - BACKGROUND AND AIMS: It is well known that disturbed intestinal motility and bacterial overgrowth may occur following partial hepatectomy. These events have been followed by the translocation of enteric bacteria that play a major role in the development of infections. We designed the present study to evaluate the effect of N-acetylcysteine (NAC) on ileal muscle contractility as an indication of intestinal motility. METHODS: Sprague-Dawley rats were divided into four groups (n = 6): sham, sham plus preoperative intraperitoneal NAC injection, hepatectomy, and hepatectomy plus preoperative intraperitoneal NAC injection. Contractile and relaxant responses in isolated ileal smooth muscle strips were determined using an in vitro muscle technique. Statistical analyses were performed by Kruskal-Wallis and Mann-Whitney U-tests. RESULTS: Contractile responses to KCl and carbachol were significantly decreased in the ileal strips of the hepatectomy group when compared to the sham-operated control group. The impaired contraction of strips was markedly improved by preoperative NAC treatment. However, neither the electrical field stimulation nor the sodium nitroprusside-mediated relaxant responses changed in any of the groups. CONCLUSIONS: Our data indicated that disturbed ileal contractility after partial hepatectomy was remedied by preoperative NAC treatment, which in turn might cause attenuation of bacterial translocation. PMID- 19780878 TI - Guidewire cannulation increases the success rate of needle-knife fistulotomy for difficult bile duct access. AB - BACKGROUND AND AIM: Selective bile duct cannulation is a prerequisite for performing therapeutic endoscopic biliary intervention. This study aimed to evaluate if using a soft-tipped guidewire to cannulate the bile duct would increase the success rate of needle-knife fistulotomy for difficult bile duct access. METHODS: We reviewed sixty 60 patients with difficult bile duct access who underwent conventional cannulation with radiocontrast dye (29) or guidewire cannulation (31) after needle-knife fistulotomy. RESULTS: There were no significant differences in the demographic data between the two groups. The initial success rate of selective bile duct cannulation was significantly higher in the guidewire cannulation group compared with the conventional cannulation group: 100% versus 79.3%, P = 0.009. The success rate of selective biliary cannulation in the patients with non-dilated common bile duct (< 8 mm) was significantly higher in the guidewire cannulation group compared with the conventional cannulation group: 100% versus 68.4%, P = 0.003. The incidence of post-endoscopic retrograde cholangiopancreatography pancreatitis was not significantly different between the two groups. No serious complications occurred in either group. CONCLUSIONS: In this retrospective and small case series, guidewire cannulation after needle-knife fistulotomy increased the success rate of selective bile duct cannulation in patients with difficult bile duct access. PMID- 19780879 TI - Feasibility of individualized treatment for hepatitis C patients in the real world. AB - BACKGROUND AND AIM: Individualized treatment with a combination of peg-interferon and ribavirin for patients with hepatitis C virus (HCV) infection has been validated in randomized controlled clinical trials, but its usefulness in the real world is unknown. The aim of the present study was to assess the feasibility of individualized treatment for HCV patients compared with standard therapy in a real-life clinical setting. METHODS: A total of 253 naive patients with HCV infection who received peg-interferon and ribavirin combination treatment were analyzed and grouped into one of three clinical settings: (i) infection with genotype non-1 (HCV non-1) and treatment for standard 24 weeks (n = 105; none received an abbreviated therapy); (ii) genotype 1 (HCV-1) and standard therapy for either 24 weeks (n = 71) or 48 weeks (n = 21); and (iii) HCV-1 and individualized treatment (n = 56). The individualized therapy used was an abbreviated 24-week treatment for HCV-1 patients who achieved a rapid virological response, otherwise patients received a 48-week course of treatment. Early termination of treatment at week 16 was recommended for non-responders. RESULTS: A sustained virological response (SVR) was achieved in 83.8% of patients with HCV non-1 infection. Among the HCV-1-infected patients, 53.5% of patients who underwent standard 24-week treatment, 66.7% of patients who underwent standard 48 week treatment, and 64.3% of patients treated by individualized therapy achieved SVR. Patients infected with HCV-1 and treated by individualized therapy had a similar efficacy response compared with the standard 48-week therapy (adjusted odds ratio [OR] 0.765, 95% confidence interval [CI], 0.220-2.659, P = 0.673). Both individualized therapy (adjusted OR 2.855, 95% CI 1.189-6.855, P = 0.019) or standard 48-week treatment (adjusted OR 3.733, 95% CI 1.073-12.986, P = 0.038) had significantly higher odds of SVR compared with HCV-1 patients treated by standard 24-week course. CONCLUSION: Individualized therapy is feasible in the real world, especially for patients with HCV-1 infection. PMID- 19780880 TI - Intraductal ultrasonography combined with percutaneous transhepatic cholangioscopy for the preoperative evaluation of longitudinal tumor extent in hilar cholangiocarcinoma. AB - BACKGROUND AND AIM: In hilar cholangiocarcinoma, an accurate assessment of preoperative resectability is important to optimize surgical resection. We investigated the accuracy of the combination of intraductal ultrasonography (IDUS) and percutaneous transhepatic cholangioscopy (PTCS) for evaluating longitudinal extent in hilar cholangiocarcinoma. METHODS: Patients diagnosed with hilar cholangiocarcinoma underwent multidetector computed tomography (MDCT) and magnetic resonance cholangiography (MRC) for tumor staging and Bismuth type. Percutaneous transhepatic biliary drainage was performed at the left or right bile duct of the liver section that was anticipated to be preserved in the surgical treatment. After tract dilation, PTCS with cholangioscope-directed biopsy and IDUS were sequentially performed to evaluate Bismuth type. Surgical treatment was executed according to tumor staging and longitudinal tumor extent. Postoperative histological Bismuth types were compared to preoperative Bismuth types based on MDCT, MRC, PTCS with biopsy, and IDUS. RESULTS: From June 2006 to November 2008, 25 patients with hilar cholangiocarcinoma were enrolled, with 20 of these patients evaluable. The accuracy of MDCT, MRC, PTCS with biopsy, and IDUS for the evaluation of Bismuth type was 80%, 84.2%, 90%, and 85.0%, respectively, in 20 patients, and 82.4%, 82.4%, 94.1%, and 88.2%, respectively, in 18 patients with Bismuth type IIIa, IIIb, or IV cancer. The accuracy of the combination of IDUS and PTCS with biopsy was 95% in 20 patients, and 100% in 18 with Bismuth type IIIa, IIIb, or IV cancer. CONCLUSIONS: The combination of IDUS and PTCS with biopsy was highly accurate for assessing Bismuth type and may help in the identification of an optimal surgical plan for the treatment of hilar cholangiocarcinoma, especially in Bismuth type IIIa, IIIb, or IV. PMID- 19780881 TI - Prevalence of irritable bowel syndrome and its relationship with psychological stress status in Chinese university students. AB - BACKGROUND AND AIMS: Although irritable bowel syndrome (IBS) is a common disorder in the West, information on the prevalence of IBS in university students is relatively scant, especially in Asia. The aims of the present study were to investigate the prevalence and pattern of symptoms of IBS and its relationship with psychological stress status in Chinese university students. METHODS: Basic demographic data and IBS symptoms were sought using the Rome II criteria and a validated bowel symptom questionnaire. Another questionnaire used related to psychosomatic symptoms of depression and anxiety. RESULTS: In total, 491 of the 530 students in the trial met the selected criteria, which included 241 men. The participants were medical college students (313/491) and non-medical college students (178/491). The apparent prevalence of IBS was 15.7%, with a prevalence of 14.5% in men and 16.8% in women. The most common symptom was abdominal pain associated with change in the consistency of stool (36.9%), followed by altered stool frequency (16.3%), and abdominal pain relieved by defecation (12.4%), predominantly in women. The self-reported psychological and psychosomatic symptoms of anxiety (P < 0.001) and depression (P < 0.001) were encountered more frequently in participants with IBS. The depression (P = 0.03) and anxiety measures (P = 0.02) significantly predicted IBS status. CONCLUSION: The prevalence of IBS in Chinese university students is often compared with university students in developed countries and the general Chinese population. Depression and anxiety could potentially induce IBS. Medical education should be considered when aiming to reduce stress of university students who are susceptible to IBS. PMID- 19780882 TI - Evaluation of visualization of squamous cell carcinoma of esophagus and pharynx using an autofluorescence imaging videoendoscope system. AB - BACKGROUND AND AIM: An autofluorescence imaging (AFI) videoendoscope system produces pseudo-color images combining autofluorescence and green reflectance, with the utility of this system previously confirmed for the diagnosis of bronchial squamous cell carcinoma (SCC). Our aim was to evaluate visualization of esophageal and pharyngeal SCC comparing AFI with white light endoscopy (WLE). METHODS: Thirty-two patients with superficial esophageal SCC and 11 patients with superficial pharyngeal SCC diagnosed in other hospitals were enrolled in this prospective study. We observed the esophagus and pharynx with WLE followed by AFI and took both WLE and AFI images of the esophageal and pharyngeal SCC. Three experienced endoscopists subsequently evaluated the visualization quality of images from both systems on a three-tier scale: visible, illegible and invisible. RESULTS: A total of 39 superficial esophageal SCC were diagnosed with 20, 11 and eight lesions classified as visible, illegible and invisible, respectively, by WLE compared to 31, three and five lesions, respectively, using AFI. Using AFI, 79% of superficial esophageal SCC lesions were visible, compared to only 51% with WLE (P < 0.05). In addition, 12 superficial pharyngeal SCC were diagnosed with four, five and three lesions considered as visible, illegible and invisible, respectively, using WLE in contrast to nine, three and 0 lesions, respectively, by AFI. Thus, using AFI, 75% of superficial pharyngeal SCC lesions were visible compared with only 33% with WLE (P = 0.13). CONCLUSION: The AFI system appears to be more useful than WLE for early diagnosis of SCC of the esophagus and pharynx. PMID- 19780883 TI - Hydroxyoctadecadienoic acid as a potential biomarker for oxidative stress in patients with chronic hepatitis C. AB - BACKGROUND AND AIM: The possible involvement of oxidative stress in hepatitis C virus (HCV)-induced liver damage and hepatocarcinogenesis has been reported. We have recently developed a novel method to measure total hydroxyoctadecadienoic acid (tHODE) and have proposed its usefulness as a biomarker for lipid peroxidation. The present study was undertaken to evaluate oxidative stress in HCV-infected liver diseases by several potential oxidative stress markers including tHODE and further to validate the biomarkers for evaluating the efficacy of iron reduction therapy. METHODS: Total hydroxyoctadecadienoic acid, total 8-iso-prostagrandin F(2alpha) (t8-iso-PGF(2alpha)), selenoprotein P and other antioxidant compounds were measured in the plasma and erythrocytes obtained from 42 healthy controls and 78 HCV patients. Plasma levels of biomarkers and antioxidants were also assessed during the iron reduction therapy for 16 weeks in 12 HCV patients. RESULTS: The concentrations of tHODE in the plasma and erythrocytes and t8-iso-PGF(2alpha) in the plasma of chronic HCV-infected patients were significantly higher than those of healthy controls. Plasma levels of vitamin E and vitamin C of HCV-infected patients were lower than those of the controls. Furthermore, the plasma tHODE significantly correlated with serum aminotransferases and type IV collagen-7S domain in chronic HCV-infected patients. During the iron reduction therapy, the plasma levels of tHODE but not t8-iso-PGF(2alpha) decreased and inversely its stereo-isomer ratio (ZE/EE) increased in parallel with the decreases of serum alanine aminotransferase, ferritin and alpha-fetoprotein. CONCLUSION: The levels of tHODE in chronic HCV infected patients can be a useful biomarker for the evaluation of oxidative stress in chronic hepatitis C. PMID- 19780884 TI - Protective effects of resveratrol on small intestines against intestinal ischemia reperfusion injury in rats. AB - BACKGROUND AND AIM: The aim of this study was to determine whether resveratrol could prevent intestinal tissue injury induced by ischemia-reperfusion (I/R). METHODS: Intestinal I/R was induced in rats' intestines by 60-min occlusion of the superior mesenteric artery, followed by a 60-min reperfusion. Thirty rats were divided into three groups as follows: sham (group 1), control (group 2), and the treatment groups (group 3). The rats in the treatment group received resveratrol both before ischemia and before reperfusion. In all groups, serum aspartate aminotransferase, alanine aminotransferase, and lactate dehydrogenase levels were determined. Total antioxidant capacity (TAC), catalase, total oxidative status (TOS), oxidative stress index (OSI), and myeloperoxidase (MPO) in the intestinal tissue were measured. Intestinal tissue histopathology was also evaluated by light microscopy. RESULTS: The levels of liver enzymes in group 3 were significantly lower than those in group 2 (P < 0.05). TAC in the intestinal tissue was significantly higher in group 3 than in group 2 (P < 0.05). TOS, OSI, and MPO in the intestinal tissue were significantly lower in group 3 than in group 2 (P < 0.05 for all). Histological tissue damage was milder in the resveratrol treatment group than in the control group. CONCLUSIONS: The results of this study indicated that resveratrol treatment limits the oxidative injury of the small intestine induced by I/R in rats. However, more precise investigations are required to evaluate the antioxidative effect of resveratrol on small intestine tissue damage in clinical and experimental models. PMID- 19780885 TI - Biliary drainage, photodynamic therapy and chemotherapy for unresectable cholangiocarcinoma with jaundice. AB - BACKGROUND AND AIM: The combination of photodynamic therapy and biliary stenting seems to be beneficial in the palliative treatment of unresectable cholangiocarcinoma. We aimed to assess the accuracy of photodynamic therapy in a single centre. METHODS: Fourteen selected patients, with jaundice related to unresectable cholangiocarcinoma, underwent photodynamic therapy and biliary stenting (with or without chemotherapy). Photofrin was injected intravenously (2 mg/kg) 2 days before intraluminal photoactivation. In case of malignant progression, photodynamic therapy was repeated. The outcome parameters were overall survival and quality of life. RESULTS: There were eight men and six women (median age: 67 [42-81]). Unresectability was related to a low Karnofski index (n = 2), peritoneal carcinomatosis (n = 4), vascular involvement (n = 3), invasion of the hepatoduodenal ligament (n = 2) and an under-sized liver remnant (n = 3). Biliary stenting was efficient (> or = 50% total bilirubin) in 78.5% of cases. Eight patients developed cholangitis. The mean number of photodynamic therapy procedures was two (1-4). Six (43%) patients needed > or = 2 procedures. No severe toxicity was noted. Photodynamic therapy improved the Karnofski index in 64% of cases. Six (42.8%) patients received concomitant chemotherapy (gemcitabine). The median survival time was 13.8 [0.7-29.2] months. The 3-, 6- and 12-month survival rates were 85%, 77% and 77%, respectively. CONCLUSION: These results confirm the beneficial effect of biliary drainage, photodynamic therapy and chemotherapy for unresectable cholangiocarcinoma in selected patients with jaundice. PMID- 19780887 TI - Pilot study on confocal endomicroscopy for determination of the depth of squamous cell esophageal cancer in vivo. AB - BACKGROUND AND AIM: Confocal endomicroscopy is ultra-high-magnification endoscopy with histological observation during ongoing endoscopy. We planned a pilot study of the diagnosis of the depth of esophageal cancer using confocal endomicroscopy for treatment strategies. METHODS: Patients had 14 superficial esophageal cancers and one dysplasia. The depth of neoplasms in 15 lesions was confirmed by endoscopic mucosal resection or surgery. We examined the rate of delineation and compared results of confocal imaging with histological findings. We classified two cellular and three microvascular patterns on confocal endomicroscopic images: CP-N for normal squamous mucosa and CP-Ca for cancerous lesion; VP-type A for normal squamous mucosa; VP-type B for T1a-EP and T1a-LPM cancers; and VP-type C for T1a-MM or a more invasive cancer pattern. We measured diameters of microvessels for the three patterns of confocal endomicroscopic images and histological specimens. RESULTS: The rate of delineation was 73.3% (11/15) for esophageal cancer. The results of confocal imaging coincided well with microvessel distribution on horizontal histology. Two endoscopists blindly diagnosed the two types by cellular pattern and the three types by vascular pattern: their overall accuracies were 96% and 89% for the cellular pattern and 85% and 85% for the vascular pattern, respectively. The k value of the cellular pattern and the vascular pattern diagnosis was 0.84 and 0.75, respectively. CONCLUSION: Scoring and quantification of confocal endomicroscopic images may be useful for the differential diagnosis and diagnosis of superficial invasion by squamous cell carcinoma. PMID- 19780886 TI - Effect of baicalin and octreotide on the expression levels of P-selectin protein in multiple organs of rats with severe acute pancreatitis. AB - AIM: To investigate the effect of baicalin and octreotide on the expression levels of P-selectin protein in multiple organs of rats with severe acute pancreatitis and explore the underlying mechanism. METHODS: Rats were randomly divided into sham-operated, model control, baicalin-treated and octreotide treated groups. At 3, 6 and 12 h after operation, the mortality rates of rats, the contents of plasma endotoxin as well as serum NO and ET-1, the pathological changes in multiple organs, and the expression levels of P-selectin protein in each group were observed. RESULTS: At 12 h after operation, the mortality rates of rats in treated groups were significantly lower than that in the model control group (P < 0.05), and the pathological severity scores in multiple organs in treated groups were also significantly lower than those in the model control group (P < 0.05). The contents of plasma endotoxin, serum PLA(2) (at 6 and 12 h after operation), ET-1 and NO (at 3 and 12 h after operation) in treated groups were significantly lower than those in the model control group (P < 0.05, P < 0.01 or P < 0.001). In the baicalin-treated group, the expression levels of P selectin protein in liver (at 3 h after operation), kidney (at 3 and 6 h after operation), pancreas, lung and spleen were significantly lower than those in the model control group (P < 0.01). In the octreotide-treated group, the expression levels of this protein in lung, intestinal mucosa (at 6 and 12 h after operation), lymph nodes (at 3 and 6 h after operation), spleen and thymus were significantly lower than those in the model control group (P < 0.05). Additionally, the products of the staining intensity and positive rate of P selectin protein in pancreas, spleen (at 3 h after operation), intestinal mucosa (at 6 h after operation), thymus (at 6 h after operation) and lung (at 6 h after operation) in treated groups were significantly lower than those in the model control group (P < 0.05). CONCLUSION: Both baicalin and octreotide can exert some protective effects on multiple organs and the former is superior to the latter in protecting pancreas. Furthermore, decreasing the expression levels of P-selectin protein in these organs is one of the possible mechanisms. PMID- 19780888 TI - Extrinsic left main compression: review of the literature. PMID- 19780889 TI - Predictors of mortality in patients with lower extremity peripheral arterial disease: 5-year follow-up. AB - BACKGROUND: Peripheral arterial disease (PAD) is associated with increased mortality. Lower extremity (LE) revascularization improves symptoms, but less is known about long-term survival benefits of LE arterial revascularization. METHODS: Two hundred and eighty-three patients with an ankle brachial index (ABI) or=65 years (HR 2.42 [95% CI 1.52 3.85], P < 0.001), history of coronary artery disease (HR 1.67 [95% CI 1.13 2.46], P = 0.010), chronic kidney disease (HR 1.75 [95% CI 1.15-2.67], P = 0.010), and an ABI 0.05) for color change. For roughness, polymerization cycle was significant for the results. GIII (0.23 +/- 0.06) presented the highest roughness difference (before and after AAA), statistically significant (p < 0.05) from GII. No statistically significant difference could be found among groups when considering the porosity test. CONCLUSION: It may be concluded that irrespective of the type of heat used for polymerization, there was an intense color alteration, to clinically unacceptable levels, when the specimens were submitted to AAA. For the other properties, alterations were less intense. PMID- 19780908 TI - Relationship between oral health-related quality of life, satisfaction, and personality in patients with prosthetic rehabilitations. AB - PURPOSE: This study investigated the relationship between oral health-related quality of life, satisfaction with dentition, and personality profiles among patients with fixed and/or removable prosthetic rehabilitations. MATERIALS AND METHODS: Thirty-seven patients (13 males, 24 females; mean age 37.6 +/- 13.3 years) with fitted prosthetic rehabilitations and 37 controls who matched the patients by age and gender were recruited into the study. The Dental Impact on Daily Living (DIDL) questionnaire was used to assess dental impacts on daily living and satisfaction with the dentition. The Oral Health Impact Profile (OHIP) was used to measure self-reported discomfort, disability, and dysfunction caused by oral conditions. Oral health-related quality of life was assessed by the United Kingdom Oral Health-Related Quality of Life (OHQoL-UK) measure. Moreover, the NEO five-factor inventory was used to assess participants' personality profiles. RESULTS: Prosthetic factors had no relationship to the DIDL, OHIP, and OHQoL-UK scores. Patients with the least oral health impacts had better oral health-related quality of life (p= 0.023, r =-0.37), higher levels of total satisfaction, and satisfaction with appearance, pain, oral comfort, general performance, and eating (p < 0.05, r =-0.79, -0.35, -0.59, -0.56, -0.58, and 0.50, respectively). Patients with better oral health-related quality of life (QoL) had higher total satisfaction, satisfaction with oral comfort, general performance, and eating (p < 0.05, r = 0.34, 0.39, 0.33, and 0.37, respectively). Patients with lower neuroticism scores had less oral health impact (p= 0.006, r = 0.44), better oral health-related QoL (p= 0.032, r =-0.35), higher total satisfaction, satisfaction with appearance, pain, oral comfort, and eating (p < 0.05, r =-0.58, -0.35, -0.33, -0.39, and -0.35, respectively). CONCLUSION: Patients' satisfaction with their dentition and prosthetic rehabilitations has positive effects on oral health-related QoL and oral health impacts and improves patients' daily living and dental perceptions. Neuroticism might influence and predict patients' satisfaction with their dentition, oral health impacts, and oral health-related QoL. Satisfaction with the dentition might predict a patient's level of neuroticism. PMID- 19780909 TI - Risk factors for impaired oral health among 18- to 34-year-old Australians. AB - OBJECTIVES: The objective of this study was to determine risk factors for a summary measure of oral health impairment among 18- to 34-year-olds in Australia. METHODS: Data were from Australia's National Survey of Adult Oral Health, a representative survey that utilized a three-stage, stratified, clustered sampling design. Oral health impairment was defined as reported experience of toothache, poor dental appearance, or food avoidance in the last 12 months. Multivariate Poisson regression models were used to evaluate effects of sociodemographic characteristics, self-perceived oral health, dental service utilization, and clinical oral disease indicators on oral health impairments. Effects were quantified as prevalence ratios (PR). RESULTS: The estimated percent of 18- to 34 year-olds with oral health impairment was 42.4 [95 percent confidence interval (CI) 37.7-47.2]. In the multivariate model, oral health impairment was associated with untreated dental decay (PR 1.38, 95 percent CI 1.13-1.68) and presence of periodontal pockets 4 mm+ (PR 1.29, 95 percent CI 1.03-1.61). In addition to those clinical indicators, greater prevalence of oral health impairment was associated with trouble paying a $100 dental bill (PR 1.37, 95 percent CI 1.12 1.68), usually visiting a dentist because of a dental problem (PR 1.46, 95 percent CI 1.15-1.86), reported cost barriers to dental care (PR 1.46, 95 percent CI 1.16-1.85), and dental fear (PR 1.43, 95 percent CI 1.18-1.73). CONCLUSIONS: Oral health impairment was highly prevalent in this population. The findings suggest that treatment of dental disease, reduction of financial barriers to dental care, and control of dental fear are needed to reduce oral health impairment among Australian young adults. PMID- 19780910 TI - Relationship between dental status and Oral Impacts on Daily Performances in older Southern Chinese people. AB - OBJECTIVE: The objective of this study was to assess the relationship between different clinical indicators of dental status and an Oral Health-Related Quality of Life (OHRQoL) measure, the Oral Impacts on Daily Performances (OIDP) index, using different scoring formats, among older Southern Chinese people. METHODS: A total of 1,196 dentate people aged 55 years and older, attending routine annual health checkups at Guangxi Medical University Hospital Health Centre in Guangxi, China, participated in the study. They had a face-to-face structured interview and a clinical dental examination. The OIDP index was used to assess the impacts of oral conditions on quality of life. Spearman and Pearson as well as partial correlation coefficients were used to assess, respectively, the unadjusted and adjusted associations of 14 clinical indicators with the overall OIDP score, OIDP intensity, and OIDP extent. RESULTS: All clinical indicators, except number of filled teeth, were significantly correlated with the OIDP index, after controlling for covariates. However, correlations were weak, ranging between 0.07 and 0.26. The strongest correlation was for the relationship between the number of natural plus replaced teeth and the OIDP index, irrespective of whether the overall OIDP score, OIDP intensity, or OIDP extent was used to measure OHRQoL. CONCLUSIONS: Clinical dental status indicators were related to OIDP, regardless of the scoring format used to calculate the OIDP index. Clinical indicators that included natural plus replaced teeth were more strongly associated with the OIDP index than their corresponding indicators that included only natural teeth. PMID- 19780912 TI - Differential neonatal and postneonatal infant mortality rates across US counties: the role of socioeconomic conditions and rurality. AB - PURPOSE: To examine differences in correlates of neonatal and postneonatal infant mortality rates, across counties, by degree of rurality. METHODS: Neonatal and postneonatal mortality rates were calculated from the 1998 to 2002 Compressed Mortality Files from the National Center for Health Statistics. Bivariate analyses assessed the relationship between neonatal and postneonatal mortality by Urban Influence (UI) codes. Multivariable, weighted least-squares regression models included measures of county socioeconomic conditions, health services and environmental risks. FINDINGS: The bivariate analysis indicated neonatal and postneonatal mortality was significantly higher in the most nonmetropolitan counties compared to the most metropolitan counties. However the relationship was not linear across the Urban Influence codes. In the multivariable models, a nonmetropolitan advantage was observed for counties not adjacent to metropolitan areas for neonatal mortality. However, postneonatal mortality rates were higher in the most rural nonmetropolitan counties. CONCLUSIONS: Certain characteristics of nonmetropolitan counties not adjacent to metropolitan counties and with an urban area of 2,500 population or more are protective against neonatal mortality (UI = 7, UI = 8). This may indicate that just having access to health services is more important to creating a protective effect for these nonmetropolitan counties than having a high concentration of medical facilities. The nonmetropolitan, not adjacent (UI = 9) disadvantage observed for postneonatal mortality supports the idea that the isolation of these areas combined with the combination of risk factors across the most nonmetropolitan counties leads to poorer postneonatal health outcomes in these areas. PMID- 19780913 TI - The association between rural-urban continuum, maternal education and adverse birth outcomes in Quebec, Canada. AB - CONTEXT: Rural relative to urban area and low socioeconomic status (SES) are associated with adverse birth outcomes. Whether a graded association of increasing magnitude is present across the urban-rural continuum, accounting for SES, is unclear. We examined the association between rural-urban continuum, SES and adverse birth outcomes. METHODS: Singleton births from 1999 to 2003 (n = 356,147) were linked to Quebec municipalities ranked on a continuum of 3 urban and 4 rural areas based on population and economic base. Maternal education was used to represent SES. Odds ratios (OR) were calculated for preterm birth (PTB), low birth weight (LBW), and small-for-gestational-age (SGA) birth, accounting for municipality and individual-level covariates. We used stratified analyses to examine interaction between SES and rural-urban continuum. FINDINGS: Relative to metropolitan area residence, living in small urban or rural areas was associated with adverse birth outcomes. Living in rural areas was associated with SGA birth (OR 1.11, 95% CI 1.05-1.17) and LBW (OR 1.15, 95% CI 1.05-1.26), and living in small urban areas was associated with PTB (OR 1.14, 95% CI 1.08-1.20). Upon stratification by education, living in remote rural relative to metropolitan areas was associated with adverse birth outcomes among university educated mothers only, and living in small urban areas was associated with adverse birth outcomes among mothers with lesser but not higher education. An SES gradient was present in all rural-urban areas, particularly for SGA birth. CONCLUSION: Differences in perinatal health exist across the rural-urban continuum, and maternal education has a modifying influence. PMID- 19780914 TI - Implementing patient safety initiatives in rural hospitals. AB - Implementation of patient safety initiatives can be costly in time and energy. Because of small volumes and limited resources, rural hospitals often are not included in nationally driven patient safety initiatives. This article describes the Tennessee Rural Hospital Patient Safety Demonstration project, whose goal was to strengthen capacity for patient safety initiatives in 8 small Tennessee rural hospitals using a multi-organizational collaborative model. The demonstration identified and facilitated implementation of 3 patient safety interventions: the Agency for Healthcare Research and Quality (AHRQ) patient safety culture survey, use of personal digital assistants (PDAs), and sharing of emergency room protocols. The experience suggested that a collaborative model between rural hospitals, a payer, a hospital association, a quality improvement organization, and academic institutions can effectively support patient safety activities in rural hospitals. Successful implementation of the 3 patient safety interventions depended on leadership provided by nursing and patient safety/quality managers and open, trusting communications within the hospitals. PMID- 19780915 TI - Rurality and other determinants of early colorectal cancer diagnosis in Nebraska: a 6-year cancer registry study, 1998-2003. AB - BACKGROUND: There are no studies of rurality, and other determinants of colorectal cancer (CRC) stage at diagnosis with population-based data from the Midwest. METHODS: This retrospective study identified, incident CRC patients, aged 19 years and older, from 1998-2003 Nebraska Cancer Registry (NCR) data. Using federal Office of Management and Budget classifications, we grouped patients by residence in metropolitan, micropolitan nonmetropolitan, or rural nonmetropolitan counties (non-core based statistical areas). In univariate and multivariate logistic regression analyses, we examined the association of the county classification and of other determinants with early (in situ/local) versus late (regional/distant) stage at CRC diagnosis. RESULTS: Of the 6,561 CRC patients identified, 45% were from metropolitan counties, 24% from micropolitan nonmetropolitan counties and 31% from rural nonmetropolitan counties, with 32%, 38%, and 33%, respectively, being diagnosed at an early stage. Multivariate analysis showed micropolitan nonmetropolitan residents were significantly more likely than rural nonmetropolitan residents to be diagnosed at an early stage (adjusted OR, 1.22; 95% CI: 1.05-1.42, P < .05). However, rural nonmetropolitan and metropolitan residents did not significantly differ in the likelihood of early diagnosis. Residents with Medicare rather than those with private insurance (P < .0001), married rather than unmarried residents (P < .01), and residents with rectal cancer rather than those with colon cancer (P < .0001) were more likely to be diagnosed at an early stage. CONCLUSIONS: Early CRC diagnosis needs to be increased in rural (non-core) non-metropolitan residents, unmarried residents, and those with private insurance. PMID- 19780916 TI - Does distance matter? Distance to mammography facilities and stage at diagnosis of breast cancer in Kentucky. AB - BACKGROUND: National and regional data indicate that breast cancer early detection is low in Kentucky, especially rural regions, perhaps because access to mammography services can be problematic. OBJECTIVE: This study examined the distance between residences of women diagnosed with breast cancer and the nearest mammography facility, as a risk factor for advanced stage diagnosis in rural populations. METHODS: 1999-2003 Kentucky Cancer Registry data were used for this study. A total of 12,322 women, aged 40 and older at diagnosis, with no previous history of cancer, and with known cancer stage were included. Travel distance was obtained using a geographic information system (GIS). Hierarchical logistic regression models were used to analyze the relationship between travel distance and advanced stage diagnosis. RESULTS: Advanced diagnoses had longer average travel distances than early stage diagnoses (P < 0.01). After adjusting for age, race, insurance, and education at census tract level, the odds of advanced diagnosis were significantly greater for women residing over 15 miles from a facility, compared to those living within 5 miles (adjusted OR = 1.50, 95% CI = 1.25-1.80). CONCLUSION: Although socioeconomic status, race, and age may help explain advanced diagnoses, longer travel distance also adversely affects early detection for rural populations. Accurate measurement of spatial accessibility indicators, such as travel distance, facilitates identification of at-risk groups so that interventions can be developed to reduce this disease. PMID- 19780918 TI - Changes in cancer incidence patterns among a northeastern American Indian population: 1955-1969 versus 1990-2004. AB - PURPOSE: This manuscript examines shifts in patterns of cancer incidence among the Seneca Nation of Indians (SNI) for the interval 1955-1969 compared to 1990 2004. METHODS: A retrospective cohort design was used to examine cancer incidence among the SNI during 2 time intervals: 1955-1969 and 1990-2004. Person-years at risk were multiplied by cancer incidence rates for New York State, exclusive of New York City, over 5-year intervals. A computer-aided match with the New York State Cancer Registry was used to identify incident cancers. Overall and site specific standardized incidence ratios (SIRs = observed/expected x 100), and 95% confidence intervals (CIs), were calculated for both time periods. RESULTS: During the earlier interval, deficits in overall cancer incidence were noted among males (SIR = 56, CI 36-82) and females (SIR = 71, CI 50-98), and for female breast cancers (SIR = 21, CI 4-62). During the more recent intervals, deficits in overall cancer incidence persisted among both genders (males SIR = 63, CI 52-77; females SIR = 67, CI 55-80). Deficits were also noted among males for cancers of the lung (SIR = 60, CI 33-98), prostate (SIR = 51, CI = 33-76) and bladder (SIR = 17, CI = 2-61) and among females for breast (SIR = 33, CI = 20-53) and uterus (SIR = 36, CI = 10-92). No cancer sites demonstrated increased incidence. Persons ages 60-69 years, 70-79 years, and ages 80+ years tended to exhibit deficits in overall incidence. CONCLUSIONS: Despite marked changes over time, deficits in overall cancer incidence have persisted between the time intervals studied. Tribal-specific cancer data are important for the development and implementation of comprehensive cancer control plans which align with local needs. PMID- 19780917 TI - Cancer risk assessment by rural and Appalachian family medicine physicians. AB - CONTEXT: Challenges to the identification of hereditary cancer in primary care may be more pronounced in rural Appalachia, a medically underserved region. PURPOSE: To examine primary care physicians' identification of hereditary cancers. METHODS: A cross-sectional survey was mailed to family physicians in the midwestern and southeastern United States, stratified by rural/non-rural and Appalachian/non-Appalachian practice location (n = 176). Identification of hereditary breast-ovarian cancer (BRCA1/2), hereditary non-polyposis colon cancer (HNPCC), and other hereditary cancers was assessed. FINDINGS: Less than half of physicians (45%) reported having patients with cancer genetic testing. Most (70%) correctly identified the BRCA1/2-relevant scenario; 49% correctly identified the HNPCC-relevant scenario. Factor analysis of psychosocial variables revealed 2 factors: Confidence (knowledge, comfort, confidence) and importance (responsible, important, effective, need) of identifying hereditary cancer. Greater confidence was associated with use of 3 generation pedigree in taking family history. Greater knowledge and access to genetic services were associated with use of genetic testing. More recent graduation year, greater knowledge, and greater confidence were associated with identifying the BRCA1/2-relevant scenario. Greater knowledge and confidence were associated with identifying the HNPCC relevant scenario. CONCLUSIONS: Though rural Appalachian physicians do not differ in ability to identify high risk individuals, access barriers may exist for genetic testing. Interventions are needed to boost physician confidence in identifying hereditary cancer and to improve availability and awareness of availability of genetic services. PMID- 19780920 TI - Exercise preference patterns, resources, and environment among rural breast cancer survivors. AB - CONTEXT: Rural breast cancer survivors may be at increased risk for inadequate exercise participation. PURPOSE: To determine for rural breast cancer survivors: (1) exercise preference "patterns," (2) exercise resources and associated factors, and (3) exercise environment. METHODS: A mail survey was sent to rural breast cancer survivors identified through a state cancer registry, and 483 (30%) responded. FINDINGS: The majority (96%) were white, with mean education of 13 (+/ 2.5) years and mean 39.0 (+/-21.5) months since diagnosis. Most participants (67%) preferred face-to-face counseling from an exercise specialist (27%) or other individual (40%). A third (31%) preferred home-based exercise with non face to-face counseling from someone other than an exercise specialist. Participants preferring face-to-face counseling were more apt to prefer supervised exercise (38% vs 9%, P < 0.001) at a health club (32% vs 8%, P < 0.001). Home exercise equipment was reported by 63%, with 97% reporting home telephone and 67% reporting Internet access. Age, education, self-efficacy, treatment status, and exercise behavior were associated with exercise resources. The physical environment was often not conducive to exercise but a low crime rate and high trust in neighbors was reported. CONCLUSIONS: Rural health education programs encouraging exercise should offer multiple programming options while considering the physical environment and capitalizing on available resources and beneficial social environmental characteristics. PMID- 19780919 TI - Adaptation of consultation planning for Native American and Latina women with breast cancer. AB - CONTEXT: Resource centers in rural, underserved areas are implementing Consultation Planning (CP) to help women with breast cancer create a question list before a doctor visit. PURPOSE: To identify changes needed for acceptable delivery of CP to rural Native Americans and Latinas. METHODS: We interviewed and surveyed 27 Native American and Latino key informants. We coded interviews thematically, and calculated summary statistics for the survey data. FINDINGS: Native American and Latino respondents endorsed CP as culturally acceptable to their communities, while suggesting changes. Respondents also raised the topic of how to further support patients once they have successfully prepared a question list using CP. CONCLUSIONS: The resource centers implemented the requested changes. PMID- 19780921 TI - Designated medical directors for emergency medical services: recruitment and roles. AB - CONTEXT: Emergency medical services (EMS) agencies rely on medical oversight to support Emergency Medical Technicians (EMTs) in the provision of prehospital care. Most states require EMS agencies to have a designated medical director (DMD), who typically is responsible for the many activities of medical oversight. PURPOSE: To assess rural-urban differences in obtaining a DMD and in their responsibilities. METHODS: A national survey of 1,425 local EMS directors, conducted in 2007. FINDINGS: Rural EMS directors were more likely than urban ones to report DMD recruitment problems, but recruitment barriers were similar, with the most commonly reported barrier being an unwillingness of local physicians to serve. Rural EMS directors reported that their DMDs were less likely to be trained in Emergency Medicine, and were less likely to provide educational support functions such as continuing education. Rural agencies were more likely to get on-line medical direction from their DMD, but were less likely to always get the on-line support they needed. Common barriers to on-line support were typical of rural communication barriers. CONCLUSIONS: Existing recommendations for DMD qualifications may be difficult to attain in rural communities. To develop programs that will support medical direction for rural EMS agencies, it is important to learn what physicians identify as the barriers to serving as DMDs, and whether there are alternative and innovative ways to provide an optimal level of medical oversight. Solutions will likely be multi-faceted, as EMS activities and organizational structures are diverse and the responsibilities of the DMD are broad. PMID- 19780922 TI - Double whammy? Rural youth with serious emotional disturbance and the transition to adulthood. AB - CONTEXT: All youth, especially those with serious emotional disturbances (SED), face challenges as they transition to adulthood. Little is known about rural youth at risk for transition problems. PURPOSE: To examine transition-age youth who use publicly funded services in rural and urban/suburban locations in Tennessee in order to describe youth at risk for transition difficulties who need policy and service planning. METHODS: Using Medicaid enrollment and claims/encounter data, youth at high risk for transition difficulties were identified in the following groups: SED, at risk of or in foster care/state custody, intensive or frequent mental health services users, or diagnosed with major mental disorders, behavior disorders, mental retardation, or substance use. Membership in these groups was compared between youth living in rural and urban/suburban counties. Multivariate regression was used to examine factors related to multiple group membership. FINDINGS: Rural youth were more likely to be in groups at high risk for problems transitioning to adulthood, and enrolled in Medicaid as uninsured/uninsurable, compared to their urban counterparts. The strongest factors associated with multiple risk group membership were being in state custody/foster care and receiving Supplemental Security Income (SSI). CONCLUSIONS: Services are needed to support the transition to adulthood for youth at high risk of behavioral and adjustment problems. Systems to support coordinated planning and accountability are needed, including data on populations and services, and research on transition-age youth. PMID- 19780923 TI - Physician assistants and nurse practitioners as a usual source of care. AB - PURPOSE: To identify characteristics and outcomes of patients who use physician assistants and nurse practitioners (PA/NPs) as a usual source of care. METHODS: Cross sectional analysis using the telephone and mail surveys of the Wisconsin Longitudinal Study (WLS), a prospective cohort study of Wisconsin high school graduates and selected siblings (n = 6,803). FINDINGS: Individuals from metropolitan (OR = 0.40, 95% CI = 0.29-0.54) and micropolitan (OR = 0.65, 95% CI = 0.44-0.95) areas were less likely to utilize PA/NPs than participants from rural locations. Participants without insurance or with public insurance other than Medicare were more likely than those with private insurance to utilize PA/NPs (OR = 1.71, 95% CI = 1.02-2.86). Patients of PA/NPs were more likely to be women (OR = 1.77, 95% CI = 1.34-2.34), younger (OR = 0.95, 95% CI = 0.92-0.98) and have lower extroversion scores (OR = 0.81, 95% CI = 0.68-0.96). Participants utilizing PA/NPs reported lower perceived access (beta=-0.22, 95% CI =-0.35-0.09) than those utilizing doctors. PA/NP utilization was associated with an increased likelihood of chiropractor visits (OR = 1.57, 95% CI = 1.15-2.15) and decreased likelihood of a complete health exams (OR = 0.74, 95% CI = 0.55-0.99) or mammograms (OR = 0.65, 95% CI = 0.45-0.93). There were no significant differences in self-rated health or difficulties/delays in receiving care. CONCLUSIONS: Populations served by PA/NPs and doctors differ demographically but not in complexity. Though perceived access to care was lower for patients of PA/NPs, there were few differences in utilization and no differences in difficulties/delays in care or outcomes. This suggests that PA/NPs are acting as primary care providers to underserved patients with a range of disease severity, findings which have important implications for policy, including clinician workforce and reimbursement issues. PMID- 19780924 TI - Resilience in rural community-dwelling older adults. AB - CONTEXT: Identifying ways to meet the health care needs of older adults is important because their numbers are increasing and they often have more health care issues. High resilience level may be one factor that helps older adults adjust to the hardships associated with aging. Rural community-dwelling older adults often face unique challenges such as limited access to health care resources. PURPOSE: To determine the resilience level of rural community-dwelling older adults and to determine if socio-demographic factors, social networks, and health status are associated with resilience. METHODS: Data were collected from 106 registered voters, aged 65 years or over from a rural area in New York State using a cross- sectional design. The instruments used in the study include the Resiliency Scale, the SF-12v2, and the Lubben Social Network Scale-Revised. FINDINGS: The mean resilience level of the sample was high. Resilience was not correlated with any of the socio-demographic factors which included gender, age, income, education, marital, and employment status. There was a weak positive correlation between social networks and resilience levels of rural older adults. Both physical and mental health status were positively correlated with resilience. In a regression model, mental health status was the strongest predictor of resilience levels. CONCLUSION: If low resilience levels are identified in rural community-dwelling older adults, interventions to build resilience may be helpful in promoting independence; however, further research is needed to determine this. PMID- 19780925 TI - Horse-related injuries among agricultural household members: Regional Rural Injury Study II (RRIS-II). AB - PURPOSE: To determine the incidence, associated consequences, and potential risk factors for horse-related injuries among youth and adults residing in Midwestern agricultural households. METHODS: Demographic, injury, and exposure data were collected for 1999 and 2001 among randomly selected agricultural households within a 5-state region. A causal model facilitated survey design, data analysis, and interpretation of results; directed acyclic graphs guided multivariate modeling. FINDINGS: From 7,420 households (84% response of eligible), involving 32,601 persons, 5,045 total injury events were reported; 1,016 were animal related injuries, of which 215 (21%) were horse-related (rate, 6.7 events per 1,000 persons per year). Seventy-seven percent (77%) required health care; comparing those under age 20 and those 20 and older, 49% and 54%, respectively, lost work time on their operation (28% and 26%, one week or more), as a result of injuries largely associated with horse riding activities (70% and 56%). Multivariate analysis for youths under age 20 indicated: increased risks in North and South Dakota, for >0 hours worked, and for having a history of prior agriculture-related injury; and decreased risks for males. For those 20 and older, increased risks were identified for a prior injury history and less than high school education. CONCLUSIONS: Horse-related injuries, primarily associated with riding activities, are a significant problem among agricultural communities, and greatly impact their operations. PMID- 19780926 TI - Mortality of life-insured Swedish cats during 1999-2006: age, breed, sex, and diagnosis. AB - BACKGROUND: A cat life insurance database can potentially be used to study feline mortality. HYPOTHESIS: The aim was to describe patterns of mortality in life insured Swedish cats. Cats: All cats (<13 years of age) with life insurance during the period 1999-2006 were included. METHODS: Age-standardized mortality rates (MR) were calculated with respect to sex (males and females), age, breed, and diagnosis. Survival to various ages is presented by time period and breed. RESULTS: The total number of cats insured was 49,450 and the number of cat-years at risk (CYAR) was 142,049. During the period, 6,491 cats died and of these 4,591 cats (71%) had a diagnosis, ie, were claimed for life insurance. The average annual MR was 462 deaths per 10,000 CYAR (95% confidence interval, 431-493). Sex specific rates did not differ significantly. The overall mortality of the Persian and the Siamese groups was higher than that of several other breeds. Overall and breed-specific (for most breeds) survival increased with time when analyzed by 2 year periods. The 6 most common diagnostic categories (ignoring cats recorded as dead with no diagnosis) were urinary, traumatic, neoplastic, infectious, cardiovascular, and gastrointestinal. The MR within diagnostic categories varied by age and breed. CONCLUSIONS AND CLINICAL IMPORTANCE: In this mainly purebred, insured cat population, the overall mortality varied with age and breed but not with sex. The increase in survival over time is likely a reflection of willingness to keep pet cats longer and increased access to and sophistication of veterinary care. PMID- 19780927 TI - Association between hyperglycemia and survival in 228 horses with acute gastrointestinal disease. AB - BACKGROUND: Glucose homeostasis is dysregulated in critically ill humans resulting in hyperglycemia and decreased survival. Hyperglycemia is common in horses presenting with abdominal crisis, and this might be associated with a worse prognosis for survival. OBJECTIVE: To determine if hyperglycemia in horses with acute abdominal disease is associated with increased odds of failure to survive to hospital discharge. ANIMALS: Two hundred and twenty-eight adult horses with acute gastrointestinal disease. METHODS: Observational retrospective study. Records of horses > 1 year of age presenting for treatment of colic over a 3-year period were reviewed. Data collected included age, duration of colic, glucose, heart rate, PCV, total protein, anion gap, cost of hospitalization, breed, sex, pain at admission, diagnosis, whether surgery was performed, and life status at hospital discharge. Potential risk factors for nonsurvival were screened by univariable logistic regression and the best-fitting univariable model was used as the basis for multivariable regression modeling. RESULTS: Mean blood glucose was 155 mg/dL (8.5 mM) with 45% of the population above the reference range; 16.7% (38 of 228) of horses had severe hyperglycemia (>195 mg/dL; 10.7 mM). Factors associated with increased odds of failure to survive included glucose, severity of pain at admission, heart rate, PCV, anion gap, and diagnosis. The best-fitting multivariable model included glucose and diagnosis, with age included as a confounding variable. The model correctly classified outcome for 92.5% of horses. CONCLUSIONS AND CLINICAL IMPORTANCE: This study has confirmed prior reports that hyperglycemia is common in horses with colic and is associated with a worse prognosis for survival to hospital discharge. PMID- 19780928 TI - Magnetic resonance imaging in dogs with neurologic impairment due to acute thoracic and lumbar intervertebral disk herniation. AB - BACKGROUND: Magnetic resonance imaging (MRI) is a correlate to physical examination in various myelopathies and a predictor of functional outcome. OBJECTIVES: To describe associations among MRI features, neurological dysfunction before MRI, and functional outcome in dogs with disk herniation. ANIMALS: One hundred and fifty-nine dogs with acute thoracolumbar disk herniation. METHODS: Retrospective case series. Signalment, initial neurological function as assessed by a modified Frankel score (MFS), and ambulatory outcome at hospital discharge and >3 months (long-term) follow-up were recorded from medical records and telephone interview of owners. Associations were estimated between these parameters and MRI signal and morphometric data. RESULTS: Dogs with intramedullary T2W hyperintensity had more severe pre-MRI MFS (median 2, range 0 4) and lower ambulatory proportion at long-term follow-up (0.76) than those dogs lacking hyperintensity (median MFS 3, range 0-5; ambulatory proportion, 0.93) (P=.001 and .013, respectively). Each unit of T2W length ratio was associated with a 1.9 times lower odds of long-term ambulation when adjusted for pre-MRI MFS (95% confidence interval 1.0-3.52, P=.05). Dogs with a compressive length ratio >1.31 (which was the median ratio within this population) had more severe pre-MRI MFS (median 3, range 0-5) compared with those with ratios < or =1.31 (median MFS 3, range 0-4; P=.006). CONCLUSIONS AND CLINICAL IMPORTANCE: MRI features were associated with initial injury severity in dogs with thoracolumbar disk herniation. Based on results of this study, the T2W length ratio and presence of T2W intramedullary hyperintensity appear to be predictive of long-term ambulatory status. PMID- 19780929 TI - Guidelines for the diagnosis and treatment of canine chronic valvular heart disease. PMID- 19780930 TI - Lymphoma-associated polymyositis in dogs. PMID- 19780932 TI - Porcine circovirus type 2 and porcine circovirus-associated disease. AB - Porcine circovirus type 2 (PCV2) belongs to the viral family Circoviridae and to the genus Circovirus. Circoviruses are small, single-stranded nonenveloped DNA viruses that have an unsegmented circular genome. PCV2 is the primary causative agent of several syndromes collectively known as porcine circovirus-associated disease (PCVAD). Many of the syndromes associated with PCVAD are a result of coinfection with PCV2 virus and other agents such as Mycoplasma and porcine reproductive and respiratory syndrome virus. PCV2 infection is present in every major swine-producing country in the world, and the number of identified cases of PCVAD is rapidly increasing. In the United States, the disease has cost producers an average of 3-4 dollars per pig with peak losses ranging up to 20 dollars per pig. The importance of this disease has stimulated investigations aimed at identifying risk factors associated with infection and minimizing these risks through modified management practices and development of vaccination strategies. This paper provides an overview of current knowledge relating to PCV2 and PCVAD with an emphasis on information relevant to the swine veterinarian. PMID- 19780933 TI - Vitamin K deficiency bleeding in a Standardbred colt. PMID- 19780931 TI - Evaluation of pimobendan and N-terminal probrain natriuretic peptide in the treatment of pulmonary hypertension secondary to degenerative mitral valve disease in dogs. AB - BACKGROUND: Pimobendan is a positive inotrope and vasodilator that may be useful in the treatment of pulmonary hypertension (PHT) secondary to degenerative mitral valve disease. HYPOTHESIS: Pimobendan decreases the severity of PHT measured echocardiographically and improves quality-of-life scores. Changes in N-terminal probrain natriuretic peptide (NT-proBNP) concentrations will reflect improvement in severity of PHT. ANIMALS: Ten client-owned dogs with peak tricuspid regurgitant flow velocity (TRFV) > or =3.5 m/s. METHODS: Prospective short-term, double-blinded, crossover design, with a long-term, open-label component. Short term, dogs were randomly allocated to receive either placebo or pimobendan (0.18 0.3 mg/kg PO q12 h) for 14 days. After a 1-week washout, they received the alternative treatment for 14 days, followed by pimobendan open-label for 8 weeks. RESULTS: Short-term comparison: peak TRFV decreased in all dogs on pimobendan compared with placebo from a median of 4.40 (range, 3.2-5.6) to 3.75 (range, 2.4 4.8) m/s (P < .0001). NT-proBNP concentration decreased after treatment with pimobendan from a median of 2,143 (range, 450-3,981) to 1,329 (range, 123-2,411) pmol/L (P= .0009). All dogs improved their quality-of-life score (P= .006). In the long-term comparisons, peak TRFV decreased in all dogs from a median of 4.28 (range, 3.5-5.7) to 3.52 (range, 2.4-5.0) m/s (P < .0001). No significant changes in NT-proBNP or quality-of-life scores were detected. CONCLUSIONS AND CLINICAL IMPORTANCE: Pimobendan lowered severity of measurable PHT, improved quality-of life scores, and decreased NT-proBNP concentrations short-term. Long term, only the reduction in TRFV was maintained. PMID- 19780934 TI - A survey of evidence in the Journal of Veterinary Internal Medicine oncology manuscripts from 1999 to 2007. AB - OBJECTIVES: To survey and monitor trends in evidence for oncology manuscripts published in the Journal of Veterinary Internal Medicine (JVIM) between 1999 and 2007 based on an evidence-based medicine (EBM) standard. METHODS: All veterinary oncology-related articles published in JVIM and 7 other high-impact journals from 1999 to 2007 were collected by database searches. Relevant manuscripts then were characterized including investigator affiliation, subject matter investigated, retrospective or prospective study design, manuscript type, and classifications of manuscripts using an EBM standard. RESULTS: A total of 172 relevant veterinary oncology manuscripts were identified in JVIM between 1999 and 2007. The proportion of oncology manuscripts published each year rose with the total number of manuscripts published in JVIM (mean, 13%; range, 8-15%). The author affiliations and subject matter were similar during this evaluation period. Case series represented the most common manuscript type (40%). With the exception of a progressive increase in prospective manuscripts and a reduction in case reports, no significant changes in the classification of manuscripts using EBM standards were seen. During this same period, veterinary oncology manuscripts published in 7 high-impact journals were associated with higher standards of evidence including prospective studies and randomized trials. CONCLUSIONS: The standards of evidence for veterinary oncology manuscripts published in JVIM have remained static between 1999 and 2007. This survey provides an informative benchmark for the state of evidence in previous JVIM oncology manuscripts and may be useful in identifying specific opportunities that may raise the standards of evidence in future publications in JVIM. PMID- 19780935 TI - Pancreatic islet cell tumor secreting insulin-like growth factor type-II in a dog. PMID- 19780937 TI - Hepatitis D outbreak among children in a hepatitis B hyper-endemic settlement in Greenland. AB - Hepatitis B virus (HBV) infection is endemic in Greenland with 5-10% of the population being HBsAg-positive (chronic carriers). Surprisingly, despite of the high prevalence of HBV infection, acute and chronic hepatitis B, liver cirrhosis and primary hepatocellular carcinoma appear much less frequently than expected. The reasons for the low frequencies are unknown, but as a consequence implementation of a childhood HBV vaccination programme, though debated for years, has never been instituted. We describe an outbreak of hepatitis D (HDV) infection among children in a hepatitis B hyper-endemic settlement of 133 inhabitants on the west coast of Greenland. In 2006 a total of 27% of the inhabitants were HBsAg-positive (chronic carriers) and 83% were HBcAb-positive (previously exposed). Forty-six percent of the HBsAg-positive persons were below 20 years of age. On follow-up 1 year later a total of 68% of the HBsAg-positive persons were HDV-IgG positive. Five children, who were HBsAg-positive in 2006, had HDV-seroconverted from 2006 to 2007, indicating a HDV-super-infection. Most of the HDV-IgG positive children had markedly elevated liver enzymes. In the multivariate analysis, among the HBV and HDV markers, presence of HDV-IgG was most strongly associated with elevation of liver enzymes. In conclusion, the HBV HDV super-infection and presumed HDV outbreak in this settlement challenges the notion that HBV infection may not be as harmless in Greenland as previously anticipated. The findings strongly suggest that HBV vaccination should be included in the child-immunization program in Greenland. PMID- 19780936 TI - The impact of the prevention programme of hepatitis C over more than a decade: the French experience. AB - To assess the impact of the French national hepatitis C prevention programme initiated in 1999, we analysed trends in hepatitis C virus (HCV) prevalence, testing and characteristics of HCV-infected patient at first referral from 1994 to 2006. We used four data sources: Two national population-based sero-prevalence surveys carried out in 1994 and 2004; two surveillance networks, one based on public and private laboratories throughout France and the other on hepatology reference centres, which aim to monitor, respectively, trends of anti-HCV screening and of epidemiological-clinical characteristics of HCV patients at first referral. Between 1994 and 2004, the anti-HCV prevalence for adults aged 20 59 years decreased from 1.05 (95% confidence interval 0.75-1.34) to 0.71 (0.52 0.97). During the same period, those anti-HCV positive with detectable HCV RNA decreased from 81 to 57%, whereas, the proportion of anti-HCV positive persons aware of their status evolved from 24 to 56%. Anti-HCV screening activity increased by 45% from 2000 to 2005, but decreased in 2006 (-10%), while HCV positivity among those tested decreased from 4.3 to 2.9%. The proportion of cirrhosis at first referral remains around 10% between 2001 and 2006, with many patients with excessive alcohol consumption (34.7% among males) or viral co infections (HIV seropositivity for 5.2% patients). Our analysis indicates that the national programme had a positive impact at the population level through improved prevention, screening and management. There is still a need to identify timely those at risk for earlier interventions, to assess co-morbidities better and for a multidisciplinary approach to HCV management. PMID- 19780938 TI - Putative association of transforming growth factor-alpha polymorphisms with clearance of hepatitis B virus and occurrence of hepatocellular carcinoma in patients with chronic hepatitis B virus infection. AB - Previous studies showed that several genetic polymorphisms might influence the clinical outcome of chronic hepatitis B virus (HBV) infection, including HBV clearance or development of hepatocellular carcinoma (HCC). The aim of this study was to determine whether polymorphisms of the transforming growth factor-alpha (TGF-alpha) gene are associated with clinical outcome of HBV infection. A total of 1096 Korean subjects having either present or past evidence of HBV infection were prospectively enrolled between January 2001 and August 2003. Among 16 genetic variants in TGFA gene, nine variants were genotyped using TaqMan assay and the genetic association with HBV clearance and HCC occurrence was analysed. Statistical analyses revealed that TGFA+103461T>C, TGFA+106151C>G and TGFA-ht2 were marginally associated with clearance of HBV infection. However, only TGFA ht2 retained significance after multiple correction (OR = 0.39, P(corr) = 0.007 in recessive model). Although no variants were significant after multiple correction, TGFA+88344G>A and TGFA+103461T>C were weakly associated in recessive model in the analysis of HCC occurrence. In addition, Cox relative hazards model also revealed that TGFA+88344G>A was associated with onset age of HCC occurrence in subjects (RH = 1.46, P(corr) = 0.04). TGF-alpha polymorphisms might be an important factor in immunity, progression of inflammatory process and carcinogenesis, which explains the variable outcome of HBV infection at least in part. Further biological evidence is warranted in the future to support these suggestive associations. PMID- 19780940 TI - Fibrosis staging in chronic hepatitis C: analysis of discordance between transient elastography and liver biopsy. AB - In chronic hepatitis C, transient elastography (TE) accurately identifies cirrhosis, but its ability to assess significant fibrosis (Metavir > or = F2) is variable. Constitutional and liver disease-related factors may influence TE and here we examined the variables associated with differences. Three hundred consecutive hepatitis C virus (HCV)-RNA positive patients had biochemical tests, TE and a biopsy performed on the same day. The Dale model was used to identify the variables associated with discordance between biopsy and elastography results. In 97 patients (34.2%), TE and histological assessment were discordant. Seventy-six of 286 (26.6%) had stage > or =F2 and TE < 7.1 kPa (false negative); 21 of 286 (7.3%) had stage or = 7.1 kPa (false positive). No patient with discordant results had cirrhosis. By Dale model, aspartate aminotransferase (AST) was found to be the unique variable significantly related (P = 0.046) with discordance between biopsy and TE. Discordance rate was 43.4% (82 patients) with AST < 1.5 x UNL vs 25.8% (25 patients) with AST > or = 1.5 x UNL (P = 0.004). False negative rate was 43.4 (82 patients) with AST < 1.5 x UNL vs 17.1% (13 patients) with AST > or = 1.5 x UNL (P < 0.001). Areas under the receiver operating characteristic (AUROC) for F > or = 2, according to AST < 1.5 x UNL vs > or = 1.5 x UNL were 0.738 (95% CI: 0.683-0.812) and 0.854(95% CI: 0.754-0.907). Transient elastography is not adequate on its own to rule out or to rule in significant fibrosis, as it is influenced by major variations in biochemical activity of liver disease. Liver stiffness, at low levels of AST, can underestimate fibrosis. PMID- 19780939 TI - Retrospective, observational, multicentre study on an Italian population affected by chronic hepatitis C who failed to clear HCV-RNA after the combined therapy (PEG-IFN and ribavirin): NADIR study. AB - There is a lack of information on the characteristics of patients with chronic hepatitis C virus infection (HCV) who fail to respond to antiviral treatment. We studied HCV-positive subjects with chronic liver diseases treated with pegylated interferon (PEG-IFN) and ribavirin (RBV) who failed to clear HCV in routine clinical practice. A total of 2150 consecutive adult patients treated with PEG IFN plus RBV therapy in 46 Italian centres between 1 July 2004, and 30 June 2005, were studied. Of the 2150 patients, 923 (42.9%) (M/F 585/335, mean age 54.8 years) failed to achieve a serum HCV-RNA clearance. Of these 923 patients, 429 (46.5%) were nonresponders, 298 (32.3%) relapsers, 168 (18.2%) drop-outs for noncompliance or adverse events and 28 (3.0%) were lost during follow-up. Overall, 642 (70.6%) patients received adequate therapy (defined as more than 80% of the drug doses for >80% of the time). Genotypes 1-4 were observed in 76.9% of cases; genotypes 2-3 in 21.2% and mixed in 1.9%, respectively. Multiple logistic regression analysis identified genotypes 1 and 4 as the sole independent predictors of the likelihood of nonresponse to therapy compared with relapse (OR: 4.38; 95% CI = 2.28-8.4). Age older than 65 years was the sole independent factor associated with no adherence to therapy (OR: 2.22; 95% CI = 1.36-3.62). Patients who fail to respond to treatment are a nonhomogeneous population with different features, and the sole factor that discriminates nonresponse from relapse is the distribution of genotypes 1-4. Co-morbidities are unable to determine the type of treatment failure and inadequate adherence to therapy mostly affects patients older than 65 years of age. PMID- 19780941 TI - Response to Madejon et al.: are HIV-infected patients at risk of HEV infection? PMID- 19780942 TI - Autoantibodies are commonly detected by the AIT test in patients with chronic hepatitis C virus infection. PMID- 19780943 TI - Factors affecting the changes in molecular epidemiology of acute hepatitis B in a Southern Italian area. AB - To explore changes in molecular epidemiology of acute viral hepatitis B (AVH-B), hepatitis B virus (HBV) genotypes were determined by direct sequencing of the Pre S-S region in 123 consecutive patients, with AVH-B observed in Naples or its surroundings in the last decade (group AVH-B) and in 123 HBV chronic carriers [chronic carrier of HBV (CC-B) group] from the same areas, who had been hepatitis B surface antigen-positive for more than 10 years. Genotype D was less frequently detected in patients with AVH-B than in those in the CC-B group (76.4%vs 97.5%, P < 0.0001). In the AVH-B group, intravenous drug addiction (IVDA) was the prevalent risk factor (55.3%) for acquiring HBV in the 94 patients with HBV genotype D, but it was rarely recorded (6.9%) in the 29 patients with genotypes non-D (P < 0.0001); unsafe sexual intercourse was prevalent in patients with genotype non-D (72.3%) and less frequent in those with genotype D (28.8%, P < 0.005). In the AVH-B group, the prevalence of non-D genotypes increased during the observation period from 11.1% in 1999-2003 to 41.1% in 2004-2008 (P < 0.0005), paralleling the increase in the prevalence of patients with unsafe sexual intercourse; similarly, the progressive decrease in IVDA paralleled the decrease in the prevalence of genotype D (from 88.3% in 1999-2003 to 11.7% in 2004-2008). The prevalence of HBV non-D genotypes recorded in the last 10 years in AVH-B in this area shows a progressive increase, most probably because of recent changes in HBV epidemiology, namely, the HBV mass vaccination campaign and increased immigration from areas with high HBV endemicity. PMID- 19780944 TI - Does acute hepatitis C infection affect the central nervous system in HIV-1 infected individuals? AB - Central nervous system (CNS) manifestations of chronic hepatitis C virus (HCV) and chronic human immune deficiency virus-1 (HIV-1) infections have been reported, but the impact of acute HCV infection on the CNS is unknown. A total of 10 individuals with chronic stable HIV-1 with documented acute HCV (HCV-RNA polymerase chain reaction positive and HCV antibody negative, group 1) underwent cerebral proton magnetic resonance spectroscopy (MRS) using acquisition parameters to quantify myo-inositol/creatine (mI/Cr) ratio in the right basal ganglia (RBG). Two matched control groups also underwent MRS; group 2: ten with chronic HIV-1 and no evidence of HCV, and group 3: ten with no evidence of HIV or HCV. Subjects also underwent computerized neurocognitive assessments (CogState). RBG mI/Cr ratio in group 1 (acute HCV in a background of HIV) was significantly lower than that in groups 2 and 3 [2.90 (+/-0.7) vs 3.34 (+/-0.4) and 3.43 (+/ 0.4), mean (SD) for group 1 vs 2 and 3 respectively, P = 0.049], with 50% of subjects in group 1 having a mI/Cr ratio below the lowest observed ratio in either of the other groups. On neurocognitive testing, significant defects in the monitoring domain were observed in group-1, compared with matched controls (P = 0.021). Acute HCV in HIV-1 infected subjects is associated with CNS involvement. Clinicians should be vigilant of early CNS involvement when assessing subjects with acute HCV. PMID- 19780945 TI - HIV-HCV co-infected patients with low CD4+ cell nadirs are at risk for faster fibrosis progression and portal hypertension. AB - Patients co-infected with the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) are fraught with a rapid fibrosis progression rate and with complications of portal hypertension (PHT) We aimed to assess the influence of immune function [Centers of Disease Control and Prevention (CDC) stage] on development of PHT and disease progression in HIV-HCV co-infection. Data of 74 interferon-naive HIV-HCV co-infected patients undergoing liver biopsy, measurement of portal pressure and of liver stiffness and routine laboratory tests (including CD4+ cell count, HIV and HCV viral load) were analysed. Time of initial exposure (risk behaviour) was used to assess fibrosis progression. Fibrosis progression, time to cirrhosis and portal pressure were correlated with HIV status (CDC stage). HIV-HCV patients had rapid progression of fibrosis [0.201 +/- 0.088 METAVIR fibrosis units/year (FU/y)] and accelerated time to cirrhosis (24 +/- 13 years), high HCV viral loads (4.83 x 10(6) IU/mL) and a mean HVPG at the upper limit of normal (5 mmHg). With moderate or severe immunodeficiency, fibrosis progression was even higher (CDC-2 = 0.177 FU/y; CDC-3 = 0.248 FU/y) compared with patients with higher CD4+ nadirs (CDC-1 = 0.120 FU/y; P = 0.0001). An indirect correlation between CD4+ cell count and rate of fibrosis progression (R = -0.6654; P < 0.001) could be demonstrated. Hepatic venous pressure gradient (HVPG) showed early elevation of portal pressure with median values of 4, 8 and 12 mmHg after 10, 15 and 20 years of HCV infection for CDC-3 patients. Patients treated with highly active anti-retroviral therapy (HAART) had similar rates of progression and portal pressure values than patients without HAART. Progression of HCV disease is accelerated in HIV-HCV co-infection, being more pronounced in patients with low CD4+ cell count. A history of a CD4+ cell nadir <200/microL is a risk factor for rapid development of cirrhosis and PHT. Thus, HCV treatment should be considered early in patients with HIV-HCV co-infection and largely preserved CD4+ cell counts. PMID- 19780946 TI - Implications of the relationship between maternal age and parity with hepatitis B carrier status in a high endemicity area. AB - This study aimed to examine the prevalence of maternal hepatitis B virus (HBV) infection in the past 10 years and the age- and parity-specific incidences for evidence of control of HBV infection in the female reproductive population. We conducted a retrospective cohort study on 58 736 consecutive pregnant women delivered from July 1998 to June 2008. Maternal HBV status and demographic data were retrieved from a computerized database for analysis by year, age, year of birth and parity. A total of 5788 (10.1%) women had HBV infection, and the annual prevalence was around 10% throughout. When categorized by maternal age into six 5 year cohorts, the incidence increased from 6.8% in the <20 years cohort to 10.8% in the 20-24 and 25-29 year cohorts, then declined to 9.3% in the > or =40 years cohort (P < 0.001). When categorized by year of birth into 5-year cohorts, the incidence varied from 9.2% for the 1965-1969 cohort to 11.3% in the 1980-1984 cohort, which then declined to 7.3% in the > or =1985 cohort (P < 0.001). Multiparas had higher incidence when compared with nulliparas overall (10.5% vs 9.6%, P = 0.001), and significantly higher incidences for the 25-29 year (P = 0.009), 30-34 year (P < 0.001) and 35-39 year (P = 0.032) cohorts when analysed by age. In conclusion, the prevalence of maternal HBV infection remained constant at 10% for the past decade. The changes in relation to age and parity suggested that horizontal transmission, probably by sexual contact, had played an important role in maintaining the same prevalence as reported from Hong Kong 20 years ago. PMID- 19780947 TI - Prediction of nonSVR to therapy with pegylated interferon-alpha2a and ribavirin in chronic hepatitis C genotype 1 patients after 4, 8 and 12 weeks of treatment. AB - In patients with chronic hepatitis C genotype 1, the current algorithm for treatment discontinuation is based on no early virological response (<2 log decline in hepatitis C virus (HCV)-RNA) at 12 weeks. It is important to determine whether prediction of nonsustained virological response (NR) before 12 weeks can be robustly obtained by statistical methods. We used longitudinal discriminant analysis (LDA) to build and cross-validate models including baseline patient characteristics and measurements of serum HCV-RNA in the first 4, 8 or 12 weeks of treatment. The performance of each model was evaluated by the partial AUC (PA) index, exploring the accuracy of prediction in the range of high negative predictive values. Models were compared by computing 95% confidence intervals for the difference in PA indices. NR was best predicted before week 12 by a single HCV-RNA measurement at week 8 taken together with gender, BMI and age (W8 model, PA index = 0.857). This model was not inferior to models that included a measurement at week 12 (PA index = 0.831). The best model obtained with LDA within the first 4 weeks, which included measurements at days 4, 8 and at week 4, was found to be inferior to the week 8 model (PA index = 0.796). These results indicate that lack of sustained viral response is best predicted after 8 weeks of treatment and that waiting until 12 weeks does not improve the prediction. PMID- 19780949 TI - Heterologous production of the Piromyces equi cinnamoyl esterase in Trichoderma reesei for biotechnological applications. AB - AIMS: The objective of the study was to produce and characterize the cinnamoyl esterase EstA from the anaerobic fungus Piromyces equi for potential industrial applications. METHODS AND RESULTS: The catalytic domain EstA was produced in Trichoderma reesei. Because the two fungi displayed different genome features, including different codon usage and GC content, a synthetic gene was designed and expressed, leading to the production of the corresponding protein at around 33 mg per litre in the T. reesei culture medium. After the recombinant protein was purified, biochemical characterization showed that EstA presents peak activity at pH 6.5 and at 50-60 degrees C. Furthermore, EstA remained stable at pH 6-8 and below 50 degrees C. EstA was compared to cinnamoyl esterases FaeA and FaeB from Aspergillus niger in terms of ferulic acid (FA) release from wheat bran (WB), maize bran (MB) and sugar beet pulp (SBP). CONCLUSION: The synthetic gene was successfully cloned and overexpressed in T. reesei. EstA from P. equi was demonstrated to efficiently release FA from various natural substrates. SIGNIFICANCE AND IMPACT OF THE STUDY: Recombinant EstA produced in an industrial enzyme producer, T. reesei, was biochemically characterized, and its capacity to release an aromatic compound (FA) for biotechnological applications was demonstrated. PMID- 19780948 TI - Molecular and serological characterization of hepatitis B virus genotype A and D infected blood donors in Poland. AB - Hepatitis B virus (HBV) genotypes have distinct geographical distributions and influence severity of clinical outcome and response to antiviral therapies. HBV polymorphism in HBV surface antigen (HBsAg) positive first time blood donors from Poland was examined. HBV serological markers and HBV DNA were tested in 170 samples. Whole genome (n = 53) or specific region sequences: pre-S/S and basic core promoter/precore (BCP/PC) region (91 and 154 samples, respectively) were phylogenetically analyzed. The median age of infected donors was 21 years. Anti HBs, anti-HBe and hepatitis B e antigen were detected in 5%, 92.4% and 10.5% of tested donors, respectively. The HBV DNA load ranged between unquantifiable and 3.1 x 10(10) IU/mL (median: 4.10 x 10(3) IU/mL). Genotypes A2 (81.2%) and D (18.8%) co-circulated. Phylogenetic analyses revealed differences between the genotypes. Viral load and level of HBsAg tended to be lower in genotype D. The median HBsAg/HBV DNA ratio expressed in IU/mL was one for both genotypes, but very low or very high ratios appeared more frequent in genotype D infections. Higher amino acid variability in the surface proteins (median: 4%vs 1.5%; P = 0.01) and in the major hydrophilic region was observed in genotype D (P = 0.01). BCP/PC region analysis revealed the double mutation 1762T/1764A in 49/125 (39.2%) genotype A2 and 6/29 (20.7%) genotype D strains (P = 0.08). Mutations in PC and BCP regions correlated neither with HBsAg nor HBV DNA levels. HBV genotype A2 is dominant in HBsAg positive donors in Poland. Minority genotype D strains are significantly more substituted than genotype A2 strains potentially affecting the course of infection. PMID- 19780950 TI - Effects of yeast probiotic formulation on viability, revival and protection against infection with Salmonella enterica ssp. enterica serovar Typhimurium in mice. AB - AIMS: To compare the effects of five yeast probiotic formulations on viability, revival and washout kinetic in the digestive tract of mice, and the protection against an experimental infection with Salmonella enterica serovar Typhimurium. METHODS AND RESULTS: The number of viable cells in five commercial probiotic products codified as A, B, C and D (Saccharomyces boulardii- lyophilized) and E (Saccharomyces cerevisiae- aqueous suspension) was determined, as well as revival and washout kinetic in mouse intestine. Protective capacity was evaluated by survival rate and histopathology of liver and intestine of mice treated with each product and then challenged with Salm. Typhimurium. CONCLUSIONS: Product A contained the highest number of viable cells and, fed to mice, gave the highest counts of viable yeasts and the longest persistence in faeces. Probably as a consequence, the highest survival and protection of intestinal and hepatic tissues were observed when product A was used for mouse treatment. Product E showed low counts in the formulation and was not recovered from mouse intestine. SIGNIFICANCE AND IMPACT OF THE STUDY: Formulation (lyophilization or aqueous suspension) is an important factor for revival and survival of a probiotic product in vivo and consequently for its protective properties. PMID- 19780951 TI - Induction of production and secretion beta(1-->4) glucanase with Saccharomyces cerevesiae by replacing the MET10 gene with egl1 gene from Trichoderma reesei. AB - AIMS: To construct novel brewer's yeast strains with the ability to degrade beta glucan and increase sulfite levels in beer brewing by genetic manipulation. METHODS AND RESULTS: The recombinant plasmid pA15ME containing P(met10)-egl1 T(met10) expression cassette was constructed. BamHI-linearized target plasmid pA15ME was transformed into the industrial brewer's yeast strain Z0103 to replace the MET10 locus through one-step gene replacement. The recombinants Z8, Z7 and Z3 with the ability to secrete active endo-beta-1,4-glucanase I into the culture medium were isolated by Congo red dyeing. The enzymatic activities of EG I of Z8, Z7 and Z3 were 3.3, 1.5, 1.3 U l(-1), and the hydrolysing degrees of beta-glucans in wort were increased 11.9%, 8.6% and 6.9%, respectively, than that of original strain Z0103. The MET10 gene deletions were confirmed by real-time PCR, and the sulfite levels of the culture mediums inoculated with Z8, Z7 and Z3 were increased 26%, 16% and 17%, respectively, compared to that of Z0103. CONCLUSIONS: The novel endoglucanase-producing brewer's yeast strains with inserted endoglucanase gene and deficient MET10 gene led to reduced content of barley beta glucans, enhanced filterability and increased sulfur dioxide in fermenting wort. Thus, the cost for addition of microbial beta-glucanase enzyme and sulfite preparations in normal beer brewing processes could be reduced. SIGNIFICANCE AND IMPACT OF THE STUDY: These results suggested that genetic engineering approach is a powerful tool to construct the novel recombinant brewer's yeast strains with different properties to reduce the cost of beer brewing and improve the flavour of a beer, and the strains obtained have potential application value in beer brewing. PMID- 19780952 TI - Effects of moderately high pressure plus heat on the germination and inactivation of Bacillus cereus spores lacking proteins involved in germination. AB - AIMS: To determine the germination and inactivation of Bacillus cereus spores lacking various germination proteins using moderately high pressure (MHP) and heat. METHODS: The inactivation and germination of wild-type B. cereus spores in buffer by MHP (150 MPa) at various temperatures, as well as the MHP inactivation and germination of B. cereus spores lacking individual germinant receptors and monovalent cation antiporters, was determined. RESULTS: Loss of individual germinant receptors had no large effects on spore inactivation or germination, although germination of receptor-deficient spores was generally slightly decreased. Loss of the GerN in particular the GerN and GerT antiporters also decreased spore germination by MHP, especially at 40 and 50 degrees C. CONCLUSIONS: Both inactivation and germination of B. cereus spores by MHP increased with rise of temperature; however, mutant strains lacking individual germinant receptor had similar levels of germination as compared to wild-type spores. To evaluate the role of germinant receptors in MHP, a strain lacking a large number of germinant receptors is needed. SIGNIFICANCE AND IMPACT OF THE STUDY: The results of this work may lead to a better understanding of how MHP causes germination of spores of B. cereus. PMID- 19780953 TI - Production of tylosin in solid-state fermentation by Streptomyces fradiae NRRL 2702 and its gamma-irradiated mutant (gamma-1). AB - AIMS: To develop solid-state fermentation system (SSF) for hyper production of tylosin from a mutant gamma-1 of Streptomyces fradiae NRRL-2702 and its parent strain. METHODS AND RESULTS: Various agro-industrial wastes were screened to study their effect on tylosin production in SSF. Wheat bran as solid substrate gave the highest production of 2500 microg of tylosin g(-1) substrate by mutant gamma-1 against parent strain (300 microg tylosin g(-1) substrate). The tylosin yield was further improved to 4500 microg g(-1) substrate [70% moisture, 10% inoculum (v/w), pH 9.2, 30 degrees C, supplemental lactose and sodium glutamate on day 9]. Wild-type strain displayed less production of tylosin (655 microg of tylosin g(-1) substrate) in SSF even after optimization of process parameters. CONCLUSION: The study has shown that solid-state fermentation system significantly enhanced the tylosin yield by mutant gamma-1. SIGNIFICANCE AND IMPACT OF THE STUDY: This study proved to be very useful and resulted in 6.87 +/- 0.30-fold increase in tylosin yield by this mutant when compared to that of wild type strain. PMID- 19780954 TI - Detection of genogroup IV norovirus in wastewater and river water in Japan. AB - AIMS: To test wastewater and river water in Japan for genogroup IV norovirus (GIV NoV). METHODS AND RESULTS: Influent and effluent samples from a wastewater treatment plant and the Tamagawa River water samples were collected monthly for a year. The water samples were concentrated by the adsorption-elution method, using an HA electronegative filter with acid rinse procedure, followed by quantitative detection of GIV NoV using TaqMan-based real-time RT-PCR. Both wastewater and river water samples showed a high positive ratio of GIV NoV during winter and spring. The highest concentration in wastewater and river water was 6.9 x 10(4) and 1.5 x 10(4) copies l(-1), respectively. CONCLUSIONS: Presence of GIV NoV in the environments demonstrates that not only GI and GII NoVs but also GIV strains are circulating and that routine monitoring of GIV NoV in water environments is recommended to understand its epidemics, environmental distribution and potential health risks. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first study providing quantitative data on the occurrence of GIV NoV in environmental water over a 1-year period. PMID- 19780955 TI - Multiple displacement amplification as a pre-polymerase chain reaction (pre-PCR) to detect ultra low population of Ralstonia solanacearum (Smith 1896) Yabuchi et al. (1996). AB - AIMS: To develop a reliable and sensitive protocol for detection of Ralstonia solanacearum using MDA-PCR (Multiple displacement amplification-PCR amplification). METHODS AND RESULTS: MDA-PCR technique was performed on pure cell lysates as well as soil samples. Pure cell lysate as well as that of soil DNA was used as template in MDA reaction. MDA of template DNA was carried out in the presence of sample buffer, reaction buffer and enzyme mix (Phi 29 DNA polymerase and random hexamers). The MDA amplified DNA was used for PCR amplification using R. solanacearum -specific PCR primers. MDA-PCR could detect as low as 1 colony forming unit (CFU ml(-1)) of bacteria within 8 h including DNA isolation. CONCLUSION: MDA followed by standard PCR facilitated the detection of pathogen from very low count samples. The method is of great importance in managing the brown rot disease of potato. SIGNIFICANCE AND IMPACT OF STUDY: The ultrasensitive detection technique developed in the present study is sensitive and speedy enough to be included into integrated wilt disease control programmes. PMID- 19780957 TI - Vasoactive mediators in patients with acute liver failure treated with albumin dialysis. PMID- 19780956 TI - Synergism of hydroxyapatite nanoparticles and recombinant mutant human tumour necrosis factor-alpha in chemotherapy of multidrug-resistant hepatocellular carcinoma. AB - BACKGROUND/AIMS: Locoregional chemotherapy continues to be the mainstay for the treatment of unresectable hepatocellular carcinoma (HCC). One of the principal obstacles implicated in its unsuccessful therapy is multidrug resistance (MDR). Former studies have identified the multidrug-resistant nature and possible mechanisms of hepatoma cells both in vitro and in vivo. This work aimed to develop an effective strategy for the treatment of HCC with MDR. METHODS: The treatment was exploited to inhibit the MDR cells by co-administration of the recombinant mutant human tumour necrosis factor-alpha (rmhTNF-alpha), a sublethal dose of chemicals [adriamycin (ADM), mitomycin and 5-FU] and hydroxyapatite nanoparticles (nHAPs). Real-time quantitative reverse transcriptase-polymerase chain reaction and electrochemiluminescence Western blot were used to detect the expression of several related genes. RESULTS: The chemicals acted synergistically with rmhTNF-alpha and nHAP in suppressing the growth of hepatoma cells and inducing apoptosis of the cells, with the MDR phenotype reversed, as measured by intracellular ADM retention. Analysis of mRNA and protein revealed that rmhTNF alpha inhibited the gene expression of XIAP, survivin, Ki67, PCNA, MDR1 and BCRP to some extent. Moreover, the inhibitory effects mentioned above could be as good or better than when nHAP is incorporated into the regimens. CONCLUSIONS: rmhTNF alpha was not only able to restore the chemotherapeutic sensitivity to HepG2/ADM, its xenograft model and clinical samples but also further inhibited the growth of these tumours by a combination of nHAP. These results strongly suggested that chemicals in combination with rmhTNF-alpha and nHAP may be beneficial for the local treatment of advanced HCC. PMID- 19780958 TI - Optimization of medium constituents for improved chitinase production by Paenibacillus sp. D1 using statistical approach. AB - AIMS: Statistical optimization of medium components for improved chitinase production by Paenibacillus sp. D1. METHODS AND RESULTS: Urea, K(2)HPO(4), chitin and yeast extract were identified as significant components influencing chitinase production by Paenibacillus sp. D1 using Plackett-Burman method. Response surface methodology (central composite design) was applied for further optimization. The concentrations of medium components for improved chitinase production were as follows (g l(-1)): urea, 0.33; K(2)HPO(4), 1.17; MgSO(4), 0.3; yeast extract, 0.65 and chitin, 3.75. This statistical optimization approach led to the production of 93.2 +/- 0.58 U ml(-1) of chitinase. CONCLUSIONS: The important factors controlling the production of chitinase by Paenibacillus sp. D1 were identified as urea, K(2)HPO(4), chitin and yeast extract. Statistical approach was found to be very effective in optimizing the medium components in manageable number of experimental runs with overall 2.56-fold increase in chitinase production. SIGNIFICANCE AND IMPACT OF THE STUDY: The present investigation provides a report on statistical optimization of medium components for improved chitinase production by Paenibacillus sp. D1. Paenibacillus species are gram positive, spore-forming bacteria with several PGPR and biocontrol potentials. However, only few reports concerning mycolytic enzyme production especially chitinases are available. Chitinase produced by Paenibacillus sp. D1 represents new source for biotechnological and agricultural use. PMID- 19780959 TI - Effects of carotenoids from Deinococcus radiodurans on protein oxidation. AB - AIMS: To evaluate the antioxidant effect of carotenoids from Deinococcus radiodurans on protein. METHODS AND RESULTS: Deinococcus radiodurans strain R1 (ATCC 13939) and its mutant strain R1DeltacrtB were used for this study. The total carotenoids (R1ex) from D. radiodurans were obtained by extraction with acetone/methanol (7 : 2, by vol), and their antioxidant activity was measured using the DPPH (2,2-diphenyl-1-picrylhydrazyl) system. The protein oxidation level, in vitro and in the cell, was measured using the DNPH (2,4-dinitrophenyl hydrazine) method. The carotenoid extract R1ex scavenged 40.2% DPPH radicals compared to beta-carotene (31.7%) at a concentration of 0.5 mg ml(-1). The intracellular level of protein oxidation in mutant R1DeltacrtB, which does not contain carotenoid, was 0.0212 mmol mg(-1) protein which is significantly greater than that in the wild type (0.0169 mmol mg(-1) protein) following the treatment with H(2)O(2). The purified major carotenoid product (deinoxanthin) from the wild type showed a greater inhibition of oxidative damage in bovine serum albumin than lycopene or lutein. CONCLUSIONS: Carotenoids prevent protein oxidation and contribute to the resistance to cell damage in D. radiodurans. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results provide the evidence that carotenoids can protect proteins in D. radiodurans against oxidative stress. PMID- 19780960 TI - Epitope mapping of pathogenic Leptospira LipL32. AB - AIMS: To identify LipL32 epitopes and to evaluate their capability to recognize specific antibodies using ELISA. METHODS AND RESULTS: Epitope mapping by means of a library of overlapping peptide fragments prepared by simultaneous and parallel solid phase peptide synthesis on derivatized cellulose membranes (SPOT synthesis) was carried out. Eighty-seven overlapping decapentapeptides corresponding to the complete sequence of LipL32 were synthesized. According to spot-image intensities, the most reactive sequences were localized in regions 151-177 (sequence AAKAKPVQKLDDDDDGDDTYKEERHNK) and 181-204 (sequence LTRIKIPNPPKSFDDLKNIDTKKL). Two peptides (P1 and P2) corresponding to these sequences were synthesized, and their reactivity evaluated using ELISA test. CONCLUSIONS: Epitope identification and analysis suggested the existence of two antigenic regions within LipL32. These LipL32 reactive regions were highly conserved among antigenically variants of Leptospira spp. isolates. Peptides containing these regions (P1 and P2) showed a good capability for anti leptospiral antibody recognition. SIGNIFICANCE AND IMPACT OF THE STUDY: This finding could have potential relevance not only for serodiagnosis but also as a starting point for the characterization of targets for vaccine design. PMID- 19780961 TI - Identification of Oxalobacter formigenes in the faeces of healthy cats. AB - AIMS: Oxalobacter formigenes is an oxalate-degrading intestinal bacterium that has been found in humans, cattle, sheep, rats and dogs. Its presence in the intestinal tract may be a protective factor against calcium oxalate urolithiasis because of its ability to degrade oxalate. The objective of this study was to determine whether O. formigenes could be detected in the faeces of healthy cats. METHODS AND RESULTS: A convenience sample of 28 cats was enrolled. Faecal samples were tested for oxc, a gene specific for O. formigenes, by real-time PCR. This gene was detected in 5/28 (18%) cats; however, the prevalence increased to 86% (24/28) with a modification of the methodology. CONCLUSIONS: Demonstrating the presence of O. formigenes in the faeces of healthy cats for the first time in this study. SIGNIFICANCE AND IMPACT OF THE STUDY: Future investigation of the role of this organism in the pathophysiology of calcium oxalate urolithiasis in cats is indicated. PMID- 19780962 TI - Distribution of integron-associated trimethoprim-sulfamethoxazole resistance determinants among Escherichia coli from humans and food-producing animals. AB - AIMS: To compare the distribution of integrons and trimethoprim-sulfamethoxazole resistance genes among Escherichia coli isolates from humans and food-producing animals. METHODS AND RESULTS: A collection of 174 multidrug-resistant E. coli isolates obtained from faecal samples of food-producing animals (n = 64) and humans (n = 59), and patients with urinary tract infections (n = 51) in Hong Kong during 2002-2004 were studied. The strains were analysed for their phylogenetic groups, the presence of sul genes (sul1 and sul2), integrons (intl1 and intl2) and class 1 integron-associated dfr cassette genes by PCR, restriction enzyme analysis and sequencing. Integrons were identified in 110 (63.2%) isolates. The prevalence of integrons was significantly different according to the specimen sources (animal faecal 84.4%, human faecal 67.8% and human urinary 31.4%) and phylogenetic groups (B1 80.8%, A 77.6%, D 54.1% and B2 11.5%). Faecal isolates (both human and animal) are more likely to belong to group A and B1. In contrast, most urinary isolates were either groups B2 and D. Among dfr containing isolates, dfrA1 and dfrA12 were almost exclusively found in strains of phylogenetic groups A and B1; and were present in animal and human faecal isolates. In contrast, dfrA17 was found in both faecal and urinary isolates and comprised strains from all phylogenetic groups. The sul1 and sul2 genes were equally prevalent among the isolates irrespective of the specimen source and phylogenetic group status. Pulsed-field gel electrophoresis analysis of isolates with identical cassette genes showed that they were genetically diverse. CONCLUSIONS: More animal faecal isolates carry class 1 integrons than human faecal and human urinary isolates, and the distribution of phylogenetic groups is common across animal and human faecal isolates but different from human urinary isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: Commensal isolates from food-producing animals are an important reservoir for integrons carrying antibiotic resistance genes. PMID- 19780963 TI - Surface motility and associated surfactant production in Agrobacterium vitis. AB - AIMS: Agrobacterium vitis is the causal agent of crown gall of grapevine. Surface motility (swarming), an important mechanism for bacterial colonization of new environments and a previously unknown behaviour of Ag. vitis, was demonstrated. METHODS: Surface motility assays were performed on half-strength potato dextrose agar (Difco) containing 0.75% agar. To test for surfactant production, a drop collapse test was used. Quorum-sensing (QS) negative and complemented mutants were tested for swarming activity. RESULTS: Ninety-one Agrobacterium strains representing -Agrobacterium tumefaciens (17 strains), Agrobacterium rhizogenes (14 strains) and Ag. vitis (60 strains) were tested for swarming and production of surfactant. All Ag. vitis strains expressed a surface-related motility. In contrast, none of 17 strains of Ag. tumefaciens or 14 strains of Ag. rhizogenes exhibited this behaviour. Surface motility in Ag. vitis was associated with surfactant secretion; both of which are regulated by a QS system previously associated with induction of a hypersensitive response on tobacco and necrosis on grape. An aviR (belongs to luxR family) mutant was surface motility negative and did not produce surfactant. An avsI mutant (autoinducer synthase) was also surface motility negative and was complemented with an Ag. tumefaciens clone expressing avsI. CONCLUSIONS: Agrobacterium vitis is able to produce a characteristic swarming phenotype that is regulated by a complex QS system. SIGNIFICANCE AND IMPACT OF THE STUDY: Swarming activity is unique to Ag. vitis among Agrobacterium sp. and may be associated with the ability of the pathogen to colonize grapevines. PMID- 19780964 TI - An intact soil-core microcosm method to evaluate the survival and vertical dispersal of Trichoderma atroviride SC1. AB - AIM: To develop an intact soil-core microcosm method to study the survival and vertical dispersal of an experimental biocontrol agent (Trichoderma atroviride SC1) applied to the soil surface. METHODS AND RESULTS: The soil for the microcosms was collected using iron pipes with perforations corresponding to different soil layers. The tool was inserted into the soil and gently removed with the soil core inside. Trichoderma atroviride SC1 was mixed with the top layer of soil in the pipe. The experiment was performed in 2006 and 2007, and data from the microcosms were compared with results obtained under field conditions in the locations in which, the microcosms were collected, in the same periods. The concentrations of T. atroviride SC1 in the soil were estimated immediately after treatment, and 1, 5, 9 and 18 weeks after treatment at both the soil surface and the above-mentioned depths. The development of T. atroviride SC1 populations in the microcosms during the 18 weeks of monitoring was similar to that observed under field conditions. The dispersal of conidia was affected by the application of water to the soil. CONCLUSIONS: Results demonstrate that this microcosm prototype can be used to model the behaviour of T. atroviride SC1 in soil. SIGNIFICANCE AND IMPACT OF THE STUDY: The intact soil-core microcosm is a reliable, easy-to-use, fast and cheap method that could also be used in studies of similar filamentous fungi to study their probable fate in the soil prior to their being introduced into the environment. PMID- 19780965 TI - Eight enrichment broths for the isolation of Campylobacter jejuni from inoculated suspensions and ground pork. AB - AIMS: The efficiency of eight enrichment broths for the selective isolation of Campylobacter jejuni was compared to identify an optimal enrichment broth. METHODS AND RESULTS: Brucella-FBP, Preston, Doyle and Roman, modified CCD (mCCD), Park and Sanders, Bolton, Hunt and Radle and Hunt broths were compared for their recovery of (i) Camp. jejuni in suspension, (ii) Camp. jejuni from inoculated ground pork, (iii) heat-injured Camp. jejuni (55 degrees C for 20 min) in suspension and (iv) heat-injured Camp. jejuni from inoculated ground pork. Hunt broth and Bolton broth showed the highest and most rapid enrichment efficacy for the cell suspensions and ground pork, respectively. Preston, Park and Sanders and mCCD broths had relatively high enrichment efficiencies, while Brucella-FBP broth was significantly inferior to the other broths (P < 0.05). CONCLUSIONS: Cell recovery from the eight enrichment broths was dependent on the sample type and the state of the cells. The use of the appropriate broth is important for the rapid and efficacious enrichment of Camp. jejuni. In particular, heat-injured Camp. jejuni require a longer cultivation time and a suitable enrichment broth. SIGNIFICANCE AND IMPACT OF THE STUDY: The results from the present study provide information for selecting the most appropriate enrichment broth for Camp. jejuni and may contribute to improved detection methods for the organism. PMID- 19780967 TI - A novel DNA vaccine containing multiple TB-specific epitopes cast in a natural structure elicits enhanced Th1 immunity compared with BCG. AB - Vaccination is expected to make a major contribution to the goal of eliminating tuberculosis worldwide by 2050. Because the protection afforded by the currently available tuberculosis vaccine, BCG, is insufficient, new vaccine strategies are urgently needed. Protective immunity against MTB depends on generation of a Th1 type cellular immune response characterized by secretion of IFN-gamma from antigen-specific T cells. Epitope-driven vaccines are created from sub-sequences of proteins (epitopes) derived by scanning the protein sequences of pathogens and selecting epitopes with patterns of amino acids which permit binding to human MHC molecules. Guided by the crystal structure of HSP65 and its characteristics, four functional T cell epitopes elaborately elicited from ESAT-6, Ag85A, CFP-10 and Ag85B were cast into the intermediate domain of HSP65. A panel of a novel chimeric vaccine, ECANS, expressing HSP65 and combined T cell epitopes was created. Gene cloning and sequencing, DNA vaccination and humoral and cellular responses were studied. After being immunized with DNA vaccine three times, all mice injected with ECANS had specific cellular immune responses. In addition, lymphocytes obtained from the spleen of ECANS immunized mice at week eight exhibited significantly greater specific lymphocyte proliferation, IFN-gamma secretion and CTL activity than those of mice that had been immunized with BCG. DNA vaccine with ECANS can successfully induce enhanced specific cellular immune response to PPD, and further study of its protective effects against Mycobacterium tuberculosis in vivo is needed. PMID- 19780966 TI - Aromatic hydrocarbon degradation genes from chronically polluted Subantarctic marine sediments. AB - AIM: The goal of this study was to identify functional targets to detect polycyclic aromatic hydrocarbon (PAH)-degrading bacterial populations in cold marine ecosystems. METHODS AND RESULTS: We designed a degenerate primer set targeting genes encoding the alpha subunit of PAH-dioxygenases from Gram-positive bacteria. This primer set was used to amplify gene fragments from metagenomic DNA isolated from Subantarctic marine sediments (Ushuaia Bay, Argentina). These gene fragments were cloned and sequenced. We identified 14 distinct groups of genes, most of them showing significant relatedness with dioxygenases from Gram-positive bacteria of the genera Rhodococcus, Mycobacterium, Nocardioides, Terrabacter and Bacillus. The level of identity with these genes, however, was low to moderate (33-62% at the amino acid level). CONCLUSION: These results indicate the presence of a high diversity of hitherto unidentified dioxygenase genes in this cold polluted environment. SIGNIFICANCE AND IMPACT OF THE STUDY: Subantarctic marine ecosystems are particularly vulnerable to hydrocarbon pollution, and the development of environmental restoration strategies for these environments is pressing. The information obtained in this work will be the starting point for the design of quantitative molecular tools to analyse the abundance and dynamics of these aromatic hydrocarbon-degrading bacterial populations in the marine environment. PMID- 19780968 TI - A host-vector system for molecular study of the intracellular growth of Mycobacterium tuberculosis in phagocytic cells. AB - The mechanisms by which Mycobacterium tuberculosis survives and persists in phagocytic cells remain poorly understood. To study the question, a convenient and safe host-vector system is indispensable. In this study it has been shown that, in contrast with M. smegmatis strain mc(2)155 which has been widely used for molecular analysis, M. smegmatis strain J15cs is able to survive even at day 6 post-infection in a murine macrophage cell line, J774. The survivability of J15cs was found to depend on the culture medium used for the bacteria prior to infection. Bacteria precultured on nutrient agar medium showed a high survivability and a characteristic cell wall ultrastructure. A plasmid vector, pYT923hyg, was developed from an Escherichia coli- mycobacterium shuttle vector pYT923 (previously constructed in our laboratory) to obtain three drug resistant genes (amp-, hyg- and km-resistant gene) and cloning sites in the km resistant gene. The vector pYT923hyg exerted no influence on in vitro growth of J15cs and intracellular survival in J774 cells, and was stably retained in J15cs after serial subculturing (three subcultures) in Luria-Bertani broth and at day 5 post infection into J774 cells. Furthermore, using this system, the possibility of a relationship between some seemingly essential genes of M. tuberculosis and intracellular growth was demonstrated. In this study, M. smegmatis strain J15cs and pYT923hyg were found to be capable of serving as an appropriate host-vector system for molecular study of the intracellular growth of M. tuberculosis in phagocytic cells; this system may be useful as a screening tool for M. tuberculosis genes. PMID- 19780969 TI - Isolation and characterization of bacteriophages specific for Campylobacter jejuni. AB - Human infection by Campylobacter jejuni is mainly through the consumption of contaminated poultry products, which results in gastroenteritis and, rarely, bacteremia and polyneuropathies. In this study, six C. jejuni-specific bacteriophages (CPS1-6) were isolated by the spot-on-the-lawn technique from chicken samples in Korea and characterized for potential use as biocontrol agents. All isolated bacteriophages exhibited a high specificity, being able to lyse only C. jejuni, but not other Gram-negative bacteria, including C. coli, Escherichia coli, Salmonella spp., and Gram-positive bacteria. Bacteriophages contain an icosahedral head and a contractile tail sheath in transmission electron microscopy, and possess ds-DNA with an average genome size of approximately 145 kb; therefore, all bacteriophages are categorized into the Myoviridae family. Bacterial lysis studies in liquid media revealed that CPS2 could be used to control the growth of C. jejuni. PMID- 19780970 TI - Antiviral treatments reduce severity of diabetes in Ljungan virus-infected CD-1 mice and delay onset in diabetes-prone BB rats. AB - The effects of LV in two different species, CD-1 mice, without a genetic disposition for diabetes, and BB rats prone to T1D were examined. Male CD-1 mice that had been exposed to LV in utero developed a type 2-like diabetes with increased blood glucose, insulin levels and epididymal fat at the age of 10-15 weeks. Combination therapy including LV-antiserum and an antiviral drug, Pleconaril, significantly reduced the levels of blood glucose and insulin and the amount of abdominal fat. In BB rats, LV has been found in both prediabetic- and diabetic diabetes-prone rats, as well as in diabetes-resistant rats. To evaluate whether the presence of LV has any influence on the onset of T1D, prediabetic BB rats were treated with an antiserum against LV or a combination of the antiviral drugs Pleconaril and Ribavirin. In the group treated with antiviral drugs, the onset was significantly delayed. These results indicate that the presence of LV can be involved in the pathogenesis of diabetes in these animal models. PMID- 19780971 TI - Adrenomedullin treatment reduces intestinal inflammation and maintains epithelial barrier function in mice administered dextran sulphate sodium. AB - Hyperactivation and hyperpermeability of the intestinal epithelium is a hallmark of IBD. AM has been shown to reduce the severity of colitis in the acetic acid and TNBS-induced colitis model, however the mechanism of the therapeutic effect of AM against the colitis has not been clarified. Here, we show that the protective capability of AM is associated with suppression of inflammation and maintenance of the intestinal epithelial barrier function. In the DSS-induced colitis model, intra-rectal AM-treated mice showed a reduction in loss of body weight and severity of colitis. AM-treatment suppressed phosphorylation of STAT1 and STAT3 in the colonic epithelium, and altered the cytokine balance in the intestinal T cells, with lower levels of IFN-gamma and TNF-alpha but higher levels of TGF-beta. Expression of the epithelial intercellular junctions such as tight and adherence junctions were sustained in the AM-treated mice. In contrast, the epithelial junctions were down-regulated in the control mice, leading to loss of epithelial barrier integrity and enhanced permeability. Collectively, these data indicate a broad spectrum of AM-induced effects with respect to protection against DSS-induced colitis, and suggest a potential therapeutic value of this treatment for IBD. PMID- 19780972 TI - Differential response of Vibrio cholerae planktonic and biofilm cells to autoinducer 2 deficiency. AB - The formation of biofilm communities enhances the persistence of Vibrio cholerae in aquatic environments. Biofilm production is repressed by the quorum-sensing regulator HapR in response to the accumulation of CAI-1 and AI-2. CAI-1 is the strongest input signal activating HapR, whereas the role of AI-2 remains ill defined. In the present study, we show that a V. cholerae luxS (AI-2-defective) mutant made increased biofilm. Interestingly, cells in the biofilm were more responsive to AI-2 deficiency than cells from the planktonic population. PMID- 19780973 TI - Genetic relatedness in wintering groups of house sparrows (Passer domesticus). AB - Social behaviour of group-living animals is often influenced by the relatedness of individuals, thus understanding the genetic structure of groups is important for the interpretation of costs and benefits of social interactions. In this study, we investigated genetic relatedness in feeding aggregations of free-living house sparrows (Passer domesticus) during the nonbreeding season. This species is a frequent model system for studies of social behaviour (e.g. aggression, social foraging), but we lack adequate information on the kin structure of sparrow flocks. During two winters, we ringed and observed sparrows at feeding stations, and used resightings to identify stable flock-members and to calculate association indices between birds. We genotyped the birds using seven highly polymorphic microsatellite loci, and estimated pairwise relatedness coefficients and relatedness categories (close kin vs. unrelated) by maximum likelihood method. We found that most birds were unrelated to each other in the flocks (mean +/- SE relatedness coefficient: 0.06 +/- 0.002), although most individuals had at least a few close relatives in their home flock (14.3 +/- 0.6% of flock-mates). Pairwise association between individuals was not significantly related to their genetic relatedness. Furthermore, there was no difference between within-flock vs. between-flock relatedness, and birds had similar proportions of close kin within and outside their home flock. Finally, relatedness among members of different flocks was unrelated to the distance between their flocks. Thus, sparrow flocks were not characterized by association of relatives, nevertheless the presence of some close kin may provide opportunity for kin-biased behaviours to evolve. PMID- 19780974 TI - Efficiency of selection, as measured by single nucleotide polymorphism variation, is dependent on inbreeding rate in Drosophila melanogaster. AB - It is often hypothesized that slow inbreeding causes less inbreeding depression than fast inbreeding at the same absolute level of inbreeding. Possible explanations for this phenomenon include the more efficient purging of deleterious alleles and more efficient selection for heterozygote individuals during slow, when compared with fast, inbreeding. We studied the impact of inbreeding rate on the loss of heterozygosity and on morphological traits in Drosophila melanogaster. We analysed five noninbred control lines, 10 fast inbred lines and 10 slow inbred lines; the inbred lines all had an expected inbreeding coefficient of approximately 0.25. Forty single nucleotide polymorphisms in DNA coding regions were genotyped, and we measured the size and shape of wings and counted the number of sternopleural bristles on the genotyped individuals. We found a significantly higher level of genetic variation in the slow inbred lines than in the fast inbred lines. This higher genetic variation was resulting from a large contribution from a few loci and a smaller effect from several loci. We attributed the increased heterozygosity in the slow inbred lines to the favouring of heterozygous individuals over homozygous individuals by natural selection, either by associative over-dominance or balancing selection, or a combination of both. Furthermore, we found a significant polynomial correlation between genetic variance and wing size and shape in the fast inbred lines. This was caused by a greater number of homozygous individuals among the fast inbred lines with small, narrow wings, which indicated inbreeding depression. Our results demonstrated that the same amount of inbreeding can have different effects on genetic variance depending on the inbreeding rate, with slow inbreeding leading to higher genetic variance than fast inbreeding. These results increase our understanding of the genetic basis of the common observation that slow inbred lines express less inbreeding depression than fast inbred lines. In addition, this has more general implications for the importance of selection in maintaining genetic variation. PMID- 19780975 TI - Complete mitochondrial DNA replacement in a Lake Tanganyika cichlid fish. AB - We used nuclear and mitochondrial DNA (mtDNA) sequences from specimens collected throughout Lake Tanganyika to clarify the evolutionary relationship between Lamprologus callipterus and Neolamprologus fasciatus. The nuclear data support the reciprocal monophyly of these two shell-breeding lamprologine cichlids. However, mtDNA sequences show that (i) L. callipterus includes two divergent and geographically disjunct (North-South) mtDNA lineages; and that (ii) N. fasciatus individuals cluster in a lineage sister group to the northern lineage of L. callipterus. The two mtDNA lineages of L. callipterus diverged c. 684 kya to 1.2 Ma, coinciding with a major water level low stand in Lake Tanganyika, which divided the lake into isolated sub-lakes. This suggests that the two mtDNA lineages originated as the result of the separation of L. callipterus populations in different sub-basins. The incongruent phylogenetic position of N. fasciatus can best be explained by an ancient unidirectional introgression from L. callipterus into N. fasciatus. Remarkably, our data indicate that this event resulted in the complete mtDNA replacement in N. fasciatus. Our data suggest that hybridization occurred soon after the divergence of the two L. callipterus mtDNA lineages, probably still during the water level low stand, and that subsequently the invading mtDNA lineage spread throughout the lake. PMID- 19780976 TI - Rapid reversal of hyperpigmentation in pityriasis versicolor upon short-term topical cycloserine application. AB - The clinical phenomena of pityriasis versicolor (PV), a common Malassezia associated skin disease, such as hyperpigmentation, depigmentation and fluorescence of the lesions may at least partly be explained by the generation of Trp-derived indole pigments through the action of transaminase 1 (TAM 1). Cycloserine, a TAM inhibitor, was able to completely inhibit pigment production in M. furfur in vitro in a dose-dependent manner. Application of a 0.2-mol l(-1) aqueous cycloserine solution b.i.d. for 5 days in three patients with hyperpigmented PV resulted in complete healing within 3-5 days without side effects. Topically applied TAM inhibitors may therefore represent a new therapeutic principle for prophylaxis and therapy of PV, thus underlining the importance of the TAM pathway for the pathogenesis of the disease. PMID- 19780978 TI - Tinea corporis purpurica and onychomycosis caused by Trichophyton violaceum. AB - We report two cases of tinea corporis purpurica of the legs, presumably caused by self-inoculation of the mycete from the toenails, in two elderly women (80 and 78 years). Trichophyton violaceum was isolated from the skin and nails. Histological examination of a biopsy specimen from the leg lesions confirmed the diagnosis. The source of infection was an Ethiopian carer who had tinea capitis in the first case, and was undiagnosed in the second patient. Cases of purpuric variants of tinea corporis are rare and this is the first report of probable self-inoculation of T. violaceum from onychomycosis. PMID- 19780977 TI - In vitro interactions between amphotericin B and other antifungal agents and rifampin against Fusarium spp. AB - Fusarium species are common hyaline soil saprophytes and plant pathogens that are opportunistic fungal pathogens of immunocompromised patients. The treatment for fusariosis remains uncertain with an unfavourable prognosis; new possibilities for treatment, such as various synergistic drug interactions, must be uncovered. In this study, we evaluated the in vitro interactions of amphotericin B with caspofungin, ketoconazole, 5-flucytosine, itraconazole, miconazole, rifampin, fluconazole, terbinafine and voriconazole against isolates of Fusarium spp. using the chequerboard method with interactions evaluated by fractional inhibitory concentration indices. The highest percentages of synergistic interactions were observed for the combinations of amphotericin B and caspofungin (68.7%), amphotericin B and rifampin (68.7%), amphotericin B plus 5-flucytosine (59.3%) and amphotericin B with voriconazole (37.5%). The pattern of susceptibility to antifungal agents among Fusarium species and their consequence on the effects of drug combinations are also discussed. PMID- 19780979 TI - Self-elimination of risk factors for recurrent vaginal candidosis. AB - Women suffering from recurrent vulvo-vaginal candidosis (RVC) often follow medical and non-medical advices to diminish the severity and frequency of the recurrences, but the impact of such interventions is unclear. The aim of this study was to identify differences in life style habits of women with RVC compared with normal women and to define which changes have influenced the frequency of recurrences in these women. Fifty-one women with RVC and 51 age-matched control women without a history of RVC were sent a questionnaire. History of allergic disease (OR 2.8) and use of corticoids (OR 5) were more frequent in patients with RVC than controls. When interrogated about beneficial changes introduced in their life style habits, lowering the intake of sugars, preventing perineum humidity and stopping contraceptive pills were factors offering substantial improvement. Apart from an increased risk of having an allergic constitution, no differences in the medical history or life style habits were evident between women with RVC and healthy women. However, women with RVC have introduced several changes in life style habits that proved beneficial to them. Among these changes, lowering intake of sugars, preventing perineum humidity and stopping oral contraceptives were the most important. PMID- 19780980 TI - Trichophyton rubrum suppurative tinea of the bald area of the scalp. AB - An 83-year-old man presented with an approximately 1-year history of an extensive inflammatory purulent crusted lesion in the bald area of the scalp diagnosed as tinea caused by Trichophyton rubrum. The scalp biopsy specimen showed suppurative folliculitis with perifollicular abscesses in upper dermis, and periodic acid Schiff-positive fungal elements within the hair follicles and in the hyperkeratotic horny layer. The infection probably spread from diseased fingernails. A cure of the scalp lesion was achieved 2 months after starting daily oral treatment with 250 mg terbinafine. To our knowledge, the case presented is the first in which a suppurative abscess-forming T. rubrum infection of the bald area of the scalp in an immunocompetent man has been described. PMID- 19780981 TI - Alzheimer's disease: report of two autopsy cases with a clinical diagnosis of corticobasal degeneration. AB - Alzheimer's disease (AD) is the most common cause of dementia in the elderly. Corticobasal degeneration (CBD) is a rare neurodegenerative disease affecting adults, being characterized clinically by a combination of extrapyramidal signs and focal cortical syndromes. In both diseases, tau deposits are a characteristic neuropathological feature. We report two new patients with autopsy-proven AD, in whom clinical diagnoses of CBD were made during life. The ages of the patients at onset were 52 and 67 years, and the disease durations were 9 and 15 years, respectively. At autopsy, both cases exhibited marked cortical atrophy with evident neuronal loss in the convex areas of the frontal and parietal lobes. Immunohistochemically, AT8-positive neurofibrillary tangles (NFTs) and Abeta positive senile plaques (SPs) were widespread and abundant in the cerebral cortex (Alzheimer pathology stage VI/C of Braak and Braak), leading us to the final pathological diagnosis of AD. No tau lesions suggestive of CBD were observed, and the deep gray matter areas, including the substantia nigra, were unremarkable (exceptionally, only mild neuronal loss was noted in the putamen in case 2). These findings further strengthen the idea that in AD, neurodegeneration with tau and Abeta deposits may begin in the fronto-parietal neocortical areas, which are often preferentially affected in CBD, earlier than, or as early as the medial temporal lobe, and that extrapyramidal signs, such as rigidity and tremor, can occur in the absence of neuronal loss in the basal ganglia and substantia nigra. PMID- 19780982 TI - The expression and activity of brain lipoprotein lipase is increased after acute cerebral ischemia-reperfusion in rats. AB - Lipoprotein lipase (LPL) is a key enzyme involved in lipid metabolism. Previous studies have shown that the levels of brain LPL mRNA, protein and activity are up regulated after brain and nerve injury. The aim of this study was to determine the response of expression and activity of brain LPL following acute cerebral ischemia-reperfusion. Adult male Sprague-Dawley rats were subjected to surgical occlusion of the middle cerebral artery. The expression of brain LPL was assessed by immunohistochemical staining and the enzyme activity of brain LPL was evaluated by colorimetric method. Increase of LPL immunopositive cells in the cerebral cortex around the infarction area was observed at 4, 6, 12 h ischemia, 2 h ischemia 2 h reperfusion, and 4 h ischemia 2 h reperfusion. LPL activity was significantly decreased in the ischemic side cortex at 2 h ischemia, and then significantly increased at 4 and 6 h ischemia. Our results showed that LPL immunopositive cells were increased in the cortex around the infarction area, and activity of LPL first decreased and then increased following acute cerebral ischemia-reperfusion. These results may suggest that LPL plays a potential role in the pathophysiological response of the brain to cerebral ischemia-reperfusion. PMID- 19780983 TI - Anaplastic meningioma: progression from atypical and chordoid morphotype with morphologic spectral variation at recurrence. AB - The current WHO 2007 classification divides meningiomas into a 3-grade prognostic hierarchy. Recent literature evokes two pathways to disease progression in meningiomas akin to a comparable paradigm in gliomas, but without similar prognostic connotation: de novo anaplastic meningioma (better prognosis), and transformed meningioma (worse prognosis). We present two adult cases of transformed meningiomas that display a spectrum of morphologic progression. Case 1 at presentation showed a random admixture of meningothelial, atypical and anaplastic meningioma. The tumor recurred as anaplastic meningioma. Case 2 presented as a chordoid meningioma, but recurred as anaplastic meningioma mainly at the invasive front in transition with residual chordoid pattern. Of interest, portions of tumor also showed papillary configuration. In accordance with the dire prognosis for anaplastic meningioma, both patients succumbed to their disease within 2 months of recurrence. The present study highlights two main points: First, that proper recognition of focal high-grade areas in a heterogeneous low-grade meningioma (case 1) provides critical morphologic clues to spatial histologic progression and predicts aggressive biologic behavior, as evidenced by progression to frankly anaplastic meningioma at recurrence. Second, the presence of papillary in addition to anaplastic areas, in the recurrence of a previously diagnosed chordoid meningioma supports the ostensibly heightened transforming potential of grade II meningiomas, but also reflects on the morphologic heterogeneity of high-grade meningiomas, and their potentially diverse pathways of progression. We propose that grading of meningiomas as outlined by WHO is of more critical prognostic import than histologic sub-typing, and must include a thorough survey of the tumor-brain interface. Future molecular genetic correlates, akin to those characterized in gliomas, could help stratify prognostic subcategories to refine meningioma grading, and govern optimal therapeutic strategies. PMID- 19780984 TI - Clinical entity of frontotemporal dementia with motor neuron disease. AB - Non-Alzheimer-type dementias occur in association with a variety of pathological conditions that include a group of diseases characterized by atrophy of the frontal and temporal lobes. Frontotemporal dementia (FTD) is a clinical entity that comprises at least two distinct diseases: Pick's disease with Pick bodies and frontotemporal lobar degeneration with ubiquitin-positive inclusions (FTLD U). The vast majority of FTLD-U is now referred to as FTLD-TDP, following the recent discovery of TAR DNA-binding protein of 43 kDa (TDP-43) as the major constituent of the ubiquitin-positive inclusions. FTLD-TDP, but not Pick's disease with Pick bodies, is often associated with motor neuron disease (MND). MND is a group of diseases in which the central nervous system lesions were long believed to be confined to the motor neuron system. In other words, MND was not considered to be associated with other neurological symptoms such as dementia. Nevertheless, more than 200 FTD cases associated with clinical MND have been reported in Japan since 1964. Neuropathologically, MND in such FTD cases was essentially similar to MND in cases without dementia. The combination of FTD and MND was so characteristic that we considered these cases comprise a unique clinicopathological subgroup of FTD. FTD with MND and the classical MND without dementia share the occurrence of ubiquitinated TDP-43-positive inclusions, a finding that could be a key to unlock the pathological backgrounds of both diseases. PMID- 19780985 TI - Evolutionary-thinking in agricultural weed management. AB - Agricultural weeds evolve in response to crop cultivation. Nevertheless, the central importance of evolutionary ecology for understanding weed invasion, persistence and management in agroecosystems is not widely acknowledged. This paper calls for more evolutionarily-enlightened weed management, in which management principles are informed by evolutionary biology to prevent or minimize weed adaptation and spread. As a first step, a greater knowledge of the extent, structure and significance of genetic variation within and between weed populations is required to fully assess the potential for weed adaptation. The evolution of resistance to herbicides is a classic example of weed adaptation. Even here, most research focuses on describing the physiological and molecular basis of resistance, rather than conducting studies to better understand the evolutionary dynamics of selection for resistance. We suggest approaches to increase the application of evolutionary-thinking to herbicide resistance research. Weed population dynamics models are increasingly important tools in weed management, yet these models often ignore intrapopulation and interpopulation variability, neglecting the potential for weed adaptation in response to management. Future agricultural weed management can benefit from greater integration of ecological and evolutionary principles to predict the long term responses of weed populations to changing weed management, agricultural environments and global climate. PMID- 19780986 TI - Studying global change through investigation of the plastic responses of xylem anatomy in tree rings. AB - Variability in xylem anatomy is of interest to plant scientists because of the role water transport plays in plant performance and survival. Insights into plant adjustments to changing environmental conditions have mainly been obtained through structural and functional comparative studies between taxa or within taxa on contrasting sites or along environmental gradients. Yet, a gap exists regarding the study of hydraulic adjustments in response to environmental changes over the lifetimes of plants. In trees, dated tree-ring series are often exploited to reconstruct dynamics in ecological conditions, and recent work in which wood-anatomical variables have been used in dendrochronology has produced promising results. Environmental signals identified in water-conducting cells carry novel information reflecting changes in regional conditions and are mostly related to short, sub-annual intervals. Although the idea of investigating environmental signals through wood anatomical time series goes back to the 1960s, it is only recently that low-cost computerized image-analysis systems have enabled increased scientific output in this field. We believe that the study of tree-ring anatomy is emerging as a promising approach in tree biology and climate change research, particularly if complemented by physiological and ecological studies. This contribution presents the rationale, the potential, and the methodological challenges of this innovative approach. PMID- 19780987 TI - Rapid structural and epigenetic reorganization near transposable elements in hybrid and allopolyploid genomes in Spartina. AB - *Transposable elements (TE) induce structural and epigenetic alterations in their host genome, with major evolutionary implications. These alterations are examined here in the context of allopolyploid speciation, on the recently formed invasive species Spartina anglica, which represents an excellent model to contrast plant genome dynamics following hybridization and genome doubling in natural conditions. *Methyl-sensitive transposon display was used to investigate the structural and epigenetic dynamics of TE insertion sites for several elements, and to contrast it with comparable genome-wide methyl-sensitive amplified polymorphism analyses. *While no transposition burst was detected, we found evidence of major structural and CpG methylation changes in the vicinity of TE insertions accompanying hybridization, and to a lesser extent, genome doubling. Genomic alteration appeared preferentially in the maternal subgenome, and the environment of TEs was specifically affected by large maternal-specific methylation changes, demonstrating that TEs fuel epigenetic alterations at the merging of diverged genomes. *Such genome changes indicate that nuclear incompatibilities in Spartina trigger immediate alterations, which are TE specific with an important epigenetic component. Since most of this reorganization is conserved after genome doubling that produced a fertile invasive species, TEs certainly play a central role in the shock-induced dynamics of the genome during allopolyploid speciation. PMID- 19780988 TI - Poplar defense against insects: genome analysis, full-length cDNA cloning, and transcriptome and protein analysis of the poplar Kunitz-type protease inhibitor family. AB - *Kunitz protease inhibitors (KPIs) feature prominently in poplar defense responses against insects. The increasing availability of genomics resources enabled a comprehensive analysis of the poplar (p)KPI family. *Using genome analysis, expressed sequence tag (EST) mining and full-length (FL)cDNA cloning we established an inventory and phylogeny of pKPIs. Microarray and real-time PCR analyses were used to profile pKPI gene expression following real or simulated insect attack. Proteomics of insect midgut content was used to monitor stability of pKPI protein. *We identified 31 pKPIs in the genome and validated gene models by EST mining and cloning of 41 unique FLcDNAs. Genome organization of the pKPI family, with six poplar-specific subfamilies, suggests that tandem duplications have played a major role in its expansion. pKPIs are expressed throughout the plant and many are strongly induced by insect attack, although insect-specific signals seem initially to suppress the tree pKPI response. We found substantial peptide coverage for a potentially intact pKPI protein in insect midgut after eating poplar leaves. *These results highlight the complexity of an important defense gene family in poplar with regard to gene family size, differential constitutive and insect-induced gene expression, and resilience of at least one pKPI protein to digestion by herbivores. PMID- 19780989 TI - Parental perceptions regarding healthy behaviours for preventing overweight and obesity in young children: a systematic review of qualitative studies. AB - Evidence is increasingly pointing towards the importance of early life strategies to prevent childhood overweight and obesity. This systematic review synthesizes qualitative research concerning parental perceptions regarding behaviours for preventing overweight and obesity in young children. During May and June 2008, a range of electronic databases were searched and together with lateral searching techniques 21 studies were identified for review. Data extraction and synthesis using thematic content analysis revealed six organizing and 32 finer level themes. These related to child factors, family dynamics, parenting, knowledge and beliefs, extra-familial influences and resources and environment. Themes were mapped to a socioecological model which illustrated how factors at individual, interpersonal, community, organizational and societal levels interact in complex ways to impact on parental perceptions about healthy behaviours for preventing child overweight. Although parents suggested several ideas to promote healthy child weight-related behaviours, many of their views concerned perceived barriers, some of which may be amenable to practical intervention. Furthermore, intergenerational influences on parental health beliefs and knowledge suggest that health promotion strategies may be more effective if directed at the wider family, rather than parents alone. Significantly, many parents believed strategies to promote healthy weight should start early in a child's life. PMID- 19780990 TI - Intelligence in relation to obesity: a systematic review and meta-analysis. AB - We performed a systematic review describing obesity/intelligent quotient (IQ) association, particularly childhood IQ in relation to adulthood obesity. After screening 883 citations from five electronic databases, we included 26 studies, most of medium quality. The weighted mean difference (WMD) of the full IQ (FIQ)/obesity association in the pre-school children was -15.1 (P > 0.05). Compared with controls, the WMD of FIQ and performance IQ of obese children were 2.8 and -10.0, respectively (P < 0.05), and the WMD of verbal IQ was -7.01 (P > 0.05). With increasing obesity, the FIQ in pre-school children declined, with a significant difference for severely obese children and FIQ. In pubertal children, a slightly different effect of FIQ and obesity emerged. Two studies reported an inverse FIQ/obesity association in adults, but it was non-significant after adjusting for educational attainment. Four papers found that childhood FIQ was inversely associated with adult body mass index, but after adjusting for education, became null. Overall there was an inverse FIQ/obesity association, except in pre-school children. However, after adjusting for educational attainment, FIQ/obesity association was not significantly different. A lower FIQ in childhood was associated with obesity in later adulthood perhaps with educational level mediating the persistence of obesity in later life. PMID- 19780991 TI - Lack of association between IRF6 polymorphisms (rs2235371 and rs642961) and non syndromic cleft lip and/or palate in a Brazilian population. AB - BACKGROUND: Interferon regulatory factor 6 (IRF6) gene has emerged as a potential susceptibility gene for non-syndromic cleft lip and/or palate (NSCL/P) in different populations. The aim of this study was to determine the association of IRF6 rs2235371 and rs642961 polymorphisms with NSCL/P in a Brazilian population. METHODS: Two hundred and twenty-eight patients affected by NSCL/P and 126 healthy individuals were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. RESULTS: Overall genotype distributions of rs2235371 and rs642961 polymorphisms were as expected by Hardy-Weinberg equilibrium test. The rs2235371 polymorphic genotype GA was identified in 10.1% of the patients with NSCL/P and in 10.3% of the control group, revealing no statistical difference. Similarly, the frequency of rs642961 minor genotypes (GA and AA) was quite similar between control group (28.6%) and NSCL/P group (25.4%), without significant difference. CONCLUSION: Our findings are consistent with a lack of involvement of IRF6 rs2235371 and rs642961 polymorphisms in the NSCL/P pathogenesis in the Brazilian population. PMID- 19780993 TI - Aortic elastic properties of patients with neurocardiogenic syncope. AB - OBJECTIVE: Neurocardiogenic syncope (NCS) is a common clinical problem; however, hemodynamic mechanism is not clearly understood. Aim of the present study was to investigate aortic elastic parameters of patients with NCS provoked by head-up tilt test. MATERIAL AND METHOD: We conducted a prospective study of 40 cases referred to our institution for head-up tilt testing. Group I constituted as 22 patients who developed mixed response and were enrolled for analysis. Hemodynamic data were compared with subjects of negative head-up tilt test (Group II). Aorta diastolic and aorta-systolic diameters, aortic strain, aortic distensibility, aortic elastic modulus, and aortic stiffness index were calculated from transthoracic echocardiographically derived diameters of thoracic aorta. RESULTS: Aortic distensibility (mean+/-SD; 2.7+/-1.2 cm2xdyn(-1)x10(-6) vs 4.0+/-1.2 cm2xdyn(-1)x10(-6), P=0.003) and aortic strain index (mean+/-SD; 7.0+/-1.8% vs 8.7+/-2.9%, P=0.042) were lower, and aortic stiffness index (mean+/-SD; 27.6+/ 10.9 vs 20.9+/-6.18, P=0.035) and aortic elastic modulus (mean+/-SD; 0.94+/-0.7 cm2xdyn(-1)x10(-6) vs 0.49+/-0.1 cm2xdyn(-1)x10(-6), P=0.009) were higher in patients in Group I compared with those in Group II. There was no difference between two groups for following clinical variables: aorta-diastolic and aorta systolic diameters, systolic and diastolic blood pressure, pulse pressure, E/A, weight, height, and body mass index. CONCLUSIONS: Findings of this study have shown that elastic properties of aorta are impaired in patients with NCS. The data suggest that increase in aortic stiffness might be one of the determinants responsible for NCS. This proposal of novel link should be confirmed in further studies. PMID- 19780995 TI - Device monitoring: remote and not so remote responsibilities: a call to the professional societies. PMID- 19780997 TI - Postdeployment, self-reporting of mental health problems, and barriers to care. AB - PURPOSE. This study explored the relationship between self-reported mental health symptoms and help-seeking behaviors of active-duty Air Force members. DESIGN AND METHODS. Mixed-methods approach reviewed 200 postdeployment surveys from active duty members assigned to Eglin Air Force Base, Florida, USA. Chi-square analysis examined significance between self-reporting mental health problems and accessing treatment. FINDINGS. As the rate of self-reported mental health symptoms increased, active-duty members were less inclined to seek help. There were inconsistencies among gender for self-reporting and accessing services. PRACTICE IMPLICATIONS. Air Force psychiatric nurses need to be at the forefront of outreach services when treating combat-stressed troops. PMID- 19780998 TI - Effective interaction with patients with schizophrenia: qualitative evaluation of the interaction skills training programme. AB - PURPOSE. The purpose of this study was to describe experiences of caregivers with the Interaction Skills Training Programme, and to evaluate the training effects observed by caregivers. DESIGN AND METHODS. A qualitative research design was applied. Semistructured interviews were conducted with 17 caregivers who had followed the training program. FINDINGS. The research findings clearly confirm the value of the program. Positive effects of the training were reported in terms of: (a) awareness and insightfulness; (b) the attitude of caregivers; (c) the quality of the therapeutic alliance; and (d) job perception. PRACTICE IMPLICATIONS. Training interactive skills may contribute to a better quality of care for chronic psychiatric patients. Based on the qualitative study, implementation of the skills training program can be recommended. PMID- 19780999 TI - PTSD is associated with an excess of inflammatory immune activities. AB - PURPOSE. Post-traumatic stress disorder (PTSD) is associated with inflammatory related medical conditions. This review examines studies of immune function in individuals with PTSD to determine if excessive inflammation is associated with PTSD. CONCLUSIONS. Current studies suggest an excess of inflammatory actions of the immune system in individuals with chronic PTSD. High levels of inflammatory cytokines have also been linked to PTSD vulnerability in traumatized individuals. There is also evidence that excessive inflammation is in part due to insufficient regulation by cortisol. PRACTICE IMPLICATIONS. An excess of inflammatory immune activity may contribute to health declines in individuals with PTSD, and treating PTSD symptoms may reduce these risks. PMID- 19781000 TI - Forever changed: posttraumatic stress disorder in female military veterans, a case report. AB - PURPOSE. This paper examines the experience of posttraumatic stress disorder (PTSD) in a female veteran of Operation Iraqi Freedom, including the barriers to treatment she encountered in an outpatient psychiatry clinic. DESIGN AND METHODS. Case report data were obtained through review of records and interviews with a veteran combat nurse diagnosed with chronic PTSD. CONCLUSIONS. Sex differences in PTSD are controversial, but PTSD in female military veterans is a significant problem. Gender may complicate diagnosis and treatment. This case report discusses these issues and invites further research. PRACTICE IMPLICATIONS. Advanced practice psychiatric nurses increasingly will see female veterans with PTSD in their practices. PMID- 19781001 TI - Calcium and its implications for psychiatric nursing. PMID- 19781002 TI - Aox gene structure, transcript variation and expression in plants. AB - Alternative oxidase (Aox) has been proposed as a functional marker for breeding stress tolerant plant varieties. This requires presence of polymorphic Aox allele sequences in plants that affect plant phenotype in a recognizable way. In this review, we examine the hypothesis that organization of genomic Aox sequences and gene expression patterns are highly variable in relation to the possibility that such a variation may allow development of Aox functional markers in plants. Aox is encoded by a small multigene family, typically with four to five members in higher plants. The predominant structure of genomic Aox sequences is that of four exons interrupted by three introns at well conserved positions. Evolutionary intron loss and gain has resulted in the variation of intron numbers in some Aox members that may harbor two to four introns and three to five exons in their sequence. Accumulating evidence suggests that Aox gene structure is polymorphic enough to allow development of Aox markers in many plant species. However, the functional significance of Aox structural variation has not been examined exhaustively. Aox expression patterns display variability and typically Aox genes fall into two discrete subfamilies, Aox1 and Aox2, the former being present in all plants and the latter restricted in eudicot species. Typically, although not exclusively, the Aox1-type genes are induced by many different kinds of stress, whereas Aox2-type genes are expressed in a constitutive or developmentally regulated way. Specific Aox alleles are among the first and most intensively stress-induced genes in several experimental systems involving oxidative stress. Differential response of Aox genes to stress may provide a flexible plan of plant defense where an energy-dissipating system in mitochondria is involved. Evidence to link structural variation and differential allele expression patterns is scarce. Much research is still required to understand the significance of polymorphisms within AOX gene sequences for gene regulation and its potential for breeding on important agronomic traits. Association studies and mapping approaches will be helpful to advance future perspectives for application more efficiently. PMID- 19781003 TI - Identification of regulatory elements involved in expression and induction by sucrose and UV-B light of the Arabidopsis thaliana COX5b-2 gene, encoding an isoform of cytochrome c oxidase subunit 5b. AB - The promoter sequences required for expression of the Arabidopsis thaliana COX5b 2 gene, encoding an isoform of cytochrome c oxidase subunit 5b, were analyzed using plants transformed with deleted and mutagenized forms of the promoter fused to gus. A 1000-bp promoter fragment produces expression in root and shoot meristems, leaf and cotyledon tips, and anthers. Deletion analysis indicated the presence of positive and negative regulatory elements. A regulatory element located between -660 and -620 from the translation start site was identified as a G-box by mutagenic analysis. Mutation of the G-box, that is present within the coding region of the preceding gene in the genome, increases expression of COX5b 2 in cotyledon and leaf lamina and abolishes induction by ultraviolet-B (UV-B) light, which presumably acts through the removal of an inhibitory factor. Identified positive regulatory elements include a site II element (TGGGCC), a related element with the sequence TGGGTC and four initiator elements (YTCANTYY) that completely abolish expression when mutated in combination. Site II elements are also involved in the response to sucrose. The results imply that the COX5b-2 gene has retained expression characteristics presented by most respiratory chain component genes, but its expression mechanisms have diverged from those employed by COX5b-1, the other gene encoding cytochrome c oxidase subunit 5b in Arabidopsis. PMID- 19781004 TI - Water translocation between ramets of strawberry during soil drying and its effects on photosynthetic performance. AB - To explore the mechanisms underlying water regulation in clonal plants and its effects on carbon assimilation under water stress, we studied the responses of water status, gas exchange and abscisic acid (ABA) contents to water stress in leaves of pairs of strawberry ramets that consist of mother and daughter ramets. There was a greater decrease in photosynthetic rates (P(n)) and stomatal conductance (G(s)) in the disconnected mother ramets than the connected mother ramets upon exposure to water stress, indicating that water stress in mother ramets was alleviated by water translocation from the well-watered daughter ramets. Conversely, the connected mother ramets displayed enhanced symptoms of water stress when the connected daughter ramets were exposed to water deficit. The mother ramets had lower water potential (psi(w)) due to their stronger osmotic adjustment than in well-watered daughter ramets; this resulted in water flow from the connected daughter ramets to mother ramets, thus alleviating water stress of mother ramets. During soil drying, there was a striking increase in ABA concentrations in leaves of the disconnected mother ramets, whereas leaf bulk ABA was much lower in the connected and water-stressed mother ramets than that in the drought-affected mother ramets in the disconnected group. In this study, though G(s) was linearly correlated with leaf bulk ABA and psi(w), G(s) in water stressed mother ramets in disconnected group exhibited less sensitivity to the variation in leaf bulk ABA and psi(w) than that in connected and water-stressed mother ramets. Taken together, these results indicate that: (1) the flux of water translocation between the connected ramets is determined by a water potential gradient; (2) water translocation between connected ramets helps to keep sensitivity of G(s) to ABA and psi(w) in drought-affected ramets, thereby benefit to effectively maintain the homeostasis of leaf water status and (3) the improvements in P(n) in water-stressed ramets due to water translocation from well-watered ramets suggest the advantages of physiological integration in clonal plants in environments with heterogeneous water distribution. PMID- 19781005 TI - Intron-mediated enhancement as a method for increasing transgene expression levels in barley. AB - It is desirable to produce transgenic plants which have optimized and stable levels of transgene expression. Low levels of transgene expression may lead to an insufficient quantity of transgenic protein being produced for a particular purpose. This report demonstrates a means of enhancing transgene expression in barley beyond that conferred by the Ubi1 promoter, via the inclusion of an intron at a specific position within the transgene coding sequence. We independently cloned two different introns (RpoT-i4 from maize and UBQ10-i1 from Arabidopsis) into the same position within the firefly luciferase (luc) coding sequence. The constructs produced were transformed into barley (Hordeum vulgare) via Agrobacterium-mediated transformation, and the resulting transformant populations (of between 119 and 123 independent plants for each construct) were assayed for luciferase activity. Both introns significantly increased luciferase activity, and a quantitative reverse-transcription polymerase chain reaction assay revealed that the introns increased the accumulation of luciferase mRNA transcripts. The enhanced transgene expression levels were maintained in the T(1) and T(2) progenies. These findings show that intron-mediated enhancement is a valuable additional tool for achieving high and stable levels of transgene expression in crop plants. PMID- 19781006 TI - The LP2 leucine-rich repeat receptor kinase gene promoter directs organ-specific, light-responsive expression in transgenic rice. AB - Biotechnologists seeking to limit gene expression to nonseed tissues of genetically engineered cereal crops have only a few choices of well characterized organ-specific promoters. We have isolated and characterized the promoter of the rice Leaf Panicle 2 gene (LP2, Os02g40240). The LP2 gene encodes a leucine-rich repeat-receptor kinase-like protein that is strongly expressed in leaves and other photosynthetic tissues. Transgenic rice plants containing an LP2 promoter GUS::GFP bifunctional reporter gene displayed an organ-specific pattern of expression. This expression corresponded to transcript levels observed on RNA blots of various rice organs and microarray gene expression data. The strongest beta-glucuronidase activity was observed in histochemically stained mesophyll cells, but other green tissues and leaf cell types including epidermal cells also exhibited expression. Low or undetectable levels of LP2 transcript and LP2 mediated reporter gene expression were observed in roots, mature seeds, and reproductive tissues. The LP2 promoter is highly responsive to light and only weak expression was detected in etiolated rice seedlings. The specificity and strength of the LP2 promoter suggests that this promoter will be a useful control element for green tissue-specific expression in rice and potentially other plants. Organ-specific promoters like LP2 will enable precise, localized expression of transgenes in biotechnology-derived crops and limit the potential of unintended impacts on plant physiology and the environment. PMID- 19781007 TI - Production and characterization of an orally immunogenic Plasmodium antigen in plants using a virus-based expression system. AB - Increasing numbers of plant-made vaccines and pharmaceuticals are entering the late stage of product development and commercialization. Despite the theoretical benefits of such production, expression of parasite antigens in plants, particularly those from Plasmodium, the causative parasites for malaria, have achieved only limited success. We have previously shown that stable transformation of tobacco plants with a plant-codon optimized form of the Plasmodium yoelii merozoite surface protein 4/5 (PyMSP4/5) gene resulted in PyMSP4/5 expression of up to approximately 0.25% of total soluble protein. In this report, we describe the rapid expression of PyMSP4/5 in Nicotiana benthamiana leaves using the deconstructed tobacco mosaic virus-based magnICON expression system. PyMSP4/5 yields of up to 10% TSP or 1-2 mg/g of fresh weight were consistently achieved. Characterization of the recombinant plant-made PyMSP4/5 indicates that it is structurally similar to PyMSP4/5 expressed by Escherichia coli. It is notable that the plant-made PyMSP4/5 protein retained its immunogenicity following long-term storage at ambient temperature within freeze dried leaves. With assistance from a mucosal adjuvant the PyMSP4/5-containing leaves induced PyMSP4/5-specific antibodies when delivered orally to naive mice or mice primed by a DNA vaccine. This study provides evidence that immunogenic Plasmodium antigens can be produced in large quantities in plants using the magnICON viral vector system. PMID- 19781008 TI - Post-transcriptional gene regulation of salinity and drought responses by plant microRNAs. AB - In the past few years, factors involved in abscisic acid signalling have been isolated and recognized as elements related to RNA metabolism, suggesting that post-transcriptional regulation of gene expression is required for abiotic stress responses. Some of these factors can be linked to the biogenesis of microRNAs (miRNAs), small RNA molecules that are important regulators of gene expression at the posttranscriptional level by repressing mRNA expression. Here, we review the role of miRNAs in stress responses, highlighting recent advances in elucidating the role of individual miRNAs and efforts to identify stress-responsive miRNAs at a genome-wide level in different model plants. Complete understanding of miRNA action depends on the identification of its target transcripts, and recent developments in miRNA research indicate that they will be uncovered in the near future. PMID- 19781009 TI - Mining for robust transcriptional and metabolic responses to long-term salt stress: a case study on the model legume Lotus japonicus. AB - Translational genomics, the use of model species to generate knowledge about biological processes and the functions of genes, offers great promise to biotechnologists. Few studies have sought robust responses of model plants to environmental stresses, such as salinity, by altering the stress dosage or by repeating experiments in consecutive years and/or different seasons. We mined our published and unpublished data on legume salt acclimation for robust system features at the ionomic, transcriptomic and metabolomic levels. We analysed data from the model legume Lotus japonicus, obtained through six independent, long term, non-lethal salt stress experiments which were carried out over two consecutive years. Best possible controlled greenhouse conditions were applied and two main questions asked: how reproducible are results obtained from physiologically meaningful salinity experiments, and what degree of bias may be expected if conclusions are drawn from less well-repeated sampling? A surprisingly large fraction of the transcriptional and metabolic responses to salt stress were not reproducible between experiments. A core set of robust changes was found that was shared between experiments. Many of these robust responses were qualitatively and quantitatively conserved between different accessions of the same species, indicating that the robust responses may be a sound starting point for translational genomics. PMID- 19781010 TI - Optimization of ammonium acquisition and metabolism by potassium in rice (Oryza sativa L. cv. IR-72). AB - ABSTRACT We present the first characterization of K(+) optimization of N uptake and metabolism in an NH(4)(+)-tolerant species, tropical lowland rice (cv. IR 72). (13)N radiotracing showed that increased K(+) supply reduces futile NH(4)(+) cycling at the plasma membrane, diminishing the excessive rates of both unidirectional influx and efflux. Pharmacological testing showed that low affinity NH(4)(+) influx may be mediated by both K(+) and non-selective cation channels. Suppression of NH(4)(+) influx by K(+) occurred within minutes of increasing K(+) supply. Increased K(+) reduced free [NH(4)(+)] in roots and shoots by 50-75%. Plant biomass was maximized on 10 mm NH(4)(+) and 5 mm K(+), with growth 160% higher than 10 mm NO(3)(-)-grown plants, and 220% higher than plants grown at 10 mm NH(4)(+) and 0.1 mm K(+). Unlike in NH(4)(+)-sensitive barley, growth optimization was not attributed to a reduced energy cost of futile NH(4)(+) cycling at the plasma membrane. Activities of the key enzymes glutamine synthetase and phosphoenolpyruvate carboxylase (PEPC) were strongly stimulated by elevated K(+), mirroring plant growth and protein content. Improved plant performance through optimization of K(+) and NH(4)(+) is likely to be of substantial agronomic significance in the world's foremost crop species. PMID- 19781011 TI - Genome-wide analyses of the transcriptomes of salicylic acid-deficient versus wild-type plants uncover Pathogen and Circadian Controlled 1 (PCC1) as a regulator of flowering time in Arabidopsis. AB - Salicylic acid (SA) has been characterized as an activator of pathogen-triggered resistance of plants. SA also regulates developmental processes such as thermogenesis in floral organs and stress-induced flowering. To deepen our knowledge of the mechanism underlying SA regulation of flowering time in Arabidopsis, we compared the transcriptomes of SA-deficient late flowering genotypes with wild-type plants. Down- or up-regulated genes in SA-deficient plants were screened for responsiveness to ultraviolet (UV)-C light, which accelerates flowering in Arabidopsis. Among them, only Pathogen and Circadian Controlled 1 (PCC1) was up-regulated by UV-C light through a SA-dependent process. Moreover, UV-C light-activated expression of PCC1 was also dependent on the flowering activator CONSTANS (CO). PCC1 gene has a circadian-regulated developmental pattern of expression with low transcript levels after germination that increased abruptly by day 10. RNAi plants with very low expression of PCC1 gene were late flowering, defective in UV-C light acceleration of flowering and contained FLOWERING LOCUS T (FT) transcript levels below 5% of that detected in wild-type plants. Although PCC1 seems to function between CO and FT in the photoperiod-dependent flowering pathway, transgenic plants overexpressing a Glucocorticoid Receptor (GR)-fused version of CO strongly activated FT but not PCC1 after dexamethasone treatment. PMID- 19781012 TI - Abscisic acid is involved in the response of grape (Vitis vinifera L.) cv. Malbec leaf tissues to ultraviolet-B radiation by enhancing ultraviolet-absorbing compounds, antioxidant enzymes and membrane sterols. AB - We investigated the interactions of abscisic acid (ABA) in the responses of grape leaf tissues to contrasting ultraviolet (UV)-B treatments. One-year-old field grown plants of Vitis vinifera L. were exposed to photosynthetically active radiation (PAR) where solar UV-B was eliminated by using polyester filters, or where PAR was supplemented with UV-B irradiation. Treatments combinations included weekly foliar sprays of ABA or a water control. The levels of UV-B absorbing flavonols, quercetin and kaempferol were significantly decreased by filtering out UV-B, while applied ABA increased their content. Concentration of two hydroxycinnamic acids, caffeic and ferulic acids, were also increased by ABA, but not affected by plus UV-B (+UV-B) treatments. Levels of carotenoids and activities of the antioxidant enzymes, catalase, ascorbate peroxidase and peroxidase were elevated by +ABA treatments, but only if +UV-B was given. Cell membrane beta-sitosterol was enhanced by ABA independently of +UV-B. Changes in photoprotective compounds, antioxidant enzymatic activities and sterols were correlated with lessened membrane harm by UV-B, as assessed by ion leakage. Oxidative damage expressed as malondialdehyde content was increased under +UV-B treatments. Our results suggest that the defence system of grape leaf tissues against UV-B is activated by UV-B irradiation with ABA acting downstream in the signalling pathway. PMID- 19781013 TI - Identification of high-risk dementia cohorts in a community sample of Japanese elderly. AB - AIM: The aim of this study was to develop a simple diagnostic procedure for subjects at high risk of developing dementia using the Clinical Dementia Rating (CDR), which is applicable to community-based activities. METHODS: This study divided 252 community-dwelling elderly with a CDR score of 0.5 into two groups based on the presence or absence of cognitive decline within the previous one year of the baseline, as assessed by a semi-structured interview. One hundred subjects were in the 'previously progressive group' (PP group) and 152 subjects were in the 'previously stable group' (PS group). After 6 years of observation, a total of 111 subjects were assessed in the follow-up investigation. RESULTS: Among the 39 subjects from the PP group (82.9 +/- 6.8 years old, 11 male, 28 female), 34 developed dementia (87%). Among the 72 subjects from the PS group (84.4 +/- 6.0 years old, 22 male, 50 female), 44 developed dementia (61%). The relative risk of developing dementia for the PP group versus the PS group was 1.43. The rate of conversion to dementia was 12.9% per 100 person-years in the PP group, and 9.8% in the PS group. In the PP group, the Mini-Mental State Examination score was significantly lower and the CDR score was significantly higher than in the PS group. CONCLUSION: Although there have been many attempts to identify subjects with high risk of dementia, this preliminary study suggests that information about temporal changes in cognitive function is useful when performing community-based surveys. PMID- 19781014 TI - Zarit Caregiver Burden Interview: development, reliability and validity of the Chinese version. AB - AIMS: To develop a specific scale used in measuring caregiver burden in China, and to evaluate its reliability and validity. METHODS: Participants from the First and Second Affiliated Hospital of China Medical University and the Hospital of Tiefa Coal Industry Group completed the Chinese version of the Zarit Caregiver Burden Interview. RESULTS: A total of 523 caregivers were included. The internal consistency of the Zarit Caregiver Burden Interview was high (Cronbach's alpha 0.875). The item-total correlations were all statistically significant (P < 0.01). Confirmatory factor analysis confirmed the five factors of the Zarit Caregiver Burden Interview in this study, and the goodness-of-fit indices reported for this 5-factor model all fell within the acceptable range. CONCLUSIONS: The Chinese version of the Zarit Caregiver Burden Interview is reliable and valid for use. This study has important implications for burden measurement in Chinese caregivers. PMID- 19781015 TI - Low level of parental bonding might be a risk factor among women with prolonged depression: a preliminary investigation. AB - AIMS: The aim of the present study was to determine whether or not the effect of parenting by the father and mother on outcomes for depression may be different between male and female subjects. METHODS: A total of 115 patients were involved in this investigation: 74 had states of depression that continued for more than 2 years, and 41 had symptoms that remitted within 4 months. The Parental Bonding Instrument (PBI) was used to test for gender differences in the PBI score, the level of education, and the age at which the depression began, using an unpaired t-test. RESULTS: It is suggested that female patients with low paternal care and low levels of education have a higher likelihood of showing symptoms of prolonged depression in a primary episode. No relationship was found among prolongation of depression, educational level, and parental care in male patients. Furthermore, comparing the PBI quadrants established by Parker showed that female patients who were exposed to paternal care as 'Affectionless Control', had a tendency towards a higher risk of prolonged depression than female patients who received 'Optimal Parenting'. CONCLUSION: Especially in female patients, the prolongation of depression is likely a result of low levels of paternal care and low education. PMID- 19781016 TI - Stress-coping strategies of patients with gender identity disorder. AB - AIMS: Previous research has not addressed gender differences in coping strategies among patients with gender identity disorder (GID). Nor has the relationship of coping strategies to other demographic characteristics ever been clarified in GID. In this study, we tried to clarify the relationship between stress-coping strategies and demographic characteristics among patients with GID. METHODS: The coping strategies of 344 patients with GID [227 female-to-male (FTM) and 117 male to-female (MTF)] were assessed using the Japanese version of the Ways of Coping Questionnaires, Lazarus Stress-coping Inventory. RESULTS: Comparison of the stress-coping inventory between MTF and FTM GID patients revealed that FTM GID patients were significantly more reliant on positive reappraisal strategies in stressful situations than MTF GID patients (P = 0.007). CONCLUSIONS: The difference in the usage of positive reappraisal strategies between MTF and FTM type GID patients was not explained by other demographic characteristics, and we suppose that the gender difference in GID patients might influence the usage of positive reappraisal strategies. The ratio of FTM GID patients might be higher at our center because MTF GID patients can obtain vaginoplasty easily, whereas phalloplasty surgery for FTM GID patients is performed at only a few centers, including our clinic, in Japan. As a result, more FTM GID patients come to our clinic with a clear intention to undergo sexual rearrangement surgery, which might influence the gender difference in using positive reappraisal. PMID- 19781017 TI - How the psychiatrists of a mental health department managed their patients before an attempted suicide. AB - AIMS: The aim of this survey was to describe patients in care at a large mental health department in northern Italy who attempted suicide, and the clinical management adopted by their psychiatrists before the event. METHODS: Data collection was based on a questionnaire administered to the reference psychiatrists. RESULTS: Over a period of 12 months, 166 catchment area residents attempted suicide. Sixty-six (40%) had contacted the mental health department in the previous two years and completed data were obtained on 63. Twenty-nine (46%) suffered from mood, 26 (41%) from personality and 11 (18%) from schizophrenic disorders. Thirty-four attempts occurred within one year of psychiatric ward discharge, mostly in the first quarter. The reference psychiatrists reported that, at the last evaluation, 38 of 63 patients (60%) presented no change in clinical conditions, and 41 of 63 (68%) were considered at no immediate risk of suicide. Most of the attempted suicides in question (45, 72%) were judged to be unpreventable. In the two logistic regression analyses carried out, no independent variables were able to statistically significantly explain the variance in judged suicidal risk or the preventability of the index attempted suicide. CONCLUSIONS: According to the psychiatrists' descriptions of their last contact with the patients, most attempted suicides have not been preceded by a change in clinical conditions. Moreover, psychiatrists, irrespective of their age and gender, and of patient diagnosis, frequently judged the attempts to have been unpreventable. PMID- 19781018 TI - Point-of-use water filtration reduces healthcare-associated infections in bone marrow transplant recipients. AB - Outbreaks of infection with gram-negative bacteria (GNB) have been linked to hospital water. We sought to determine whether point-of-use (POU) water filtration might result in decreased risk of infection in hospitalized bone marrow transplant (BMT) recipients in the absence of any recognized outbreak. Unfiltered water was sampled from taps in the BMT unit of a major US teaching hospital, and cultured at a reference laboratory. POU bacterial-retentive filters (0.2 mum) were installed throughout the unit, and replaced every 14 days. Infection rates were tracked over a 9-month period, and compared with rates for a 16-month period before POU filtration. Unfiltered water samples from 50% (2 of 4) outlets sampled grew P. aeruginosa (2 of 4) and Stenotrophomonas maltophilia (1 of 4). Clinical infection rates in the unit were significantly reduced from 1.4 total and 0.4 GNB infections per 100 patient days in the period before POU filtration to 0.18 total and 0.09 GNB infections per 100 patient days (P=0.0068 and 0.0431, respectively) in the 9-month period for which filters were in place. Infections during the POU filtration period were due to non-waterborne organisms. Point-of-use (POU) water filtration may significantly reduce infection rates in BMT recipients in the absence of any recognized outbreak. PMID- 19781019 TI - Mycoplasma hominis pericarditis in a lung transplant recipient: review of the literature about an uncommon but important cardiothoracic pathogen. AB - Purulent pericarditis due to Mycoplasma hominis is rare, and is usually associated with mediastinitis or pleuritis following cardiothoracic surgery. We report the first case to our knowledge of isolated purulent pericarditis caused by M. hominis in a lung transplant recipient and review previously reported cases of this disease. PMID- 19781020 TI - Endoscope-guided balloon sinuplasty of the equine nasomaxillary opening. AB - OBJECTIVE: To describe and evaluate an endoscope-guided balloon sinuplasty technique for dilation of the equine nasomaxillary opening (NMO). STUDY DESIGN: Experimental study. ANIMALS: Equine cadaver heads (n=5); Quarter Horses (n=4). METHODS: A custom rigid balloon introducer was passed into position within the NMO at the caudal recess of the middle meatus. Under endoscopic guidance, a balloon catheter was passed via the introducer into the NMO and inflated to 6 atmospheres, for 30 seconds 3 times, to dilate the NMO. Drainage rates after sinuplasty were evaluated for the caudal maxillary sinus in 5 cadaver heads and balloon sinuplasty was performed in 4 live horses. All skulls were examined to assess the efficacy of NMO dilation. RESULTS: Positioning of the balloon catheter was readily achieved in all heads. Dilation was observed endoscopically and confirmed on necropsy in all heads. Drainage rates from the caudal maxillary sinus increased significantly (approximately 1.5 x) in all 5 cadaver heads after sinuplasty (P=.001). CONCLUSIONS: Dilation of the NMO improved sinus drainage in all 5 cadaver heads. Endoscopic evaluation of the ostium revealed marked dilation of the NMO in live horses and indicates potential clinical use in standing horses. CLINICAL RELEVANCE: Balloon sinuplasty of the NMO opening is an easily performed, clinically applicable technique for use in standing horses. Clinical studies will be necessary to evaluate the efficacy of this technique in diseased sinuses. PMID- 19781021 TI - Cytologic and histopathologic evaluation of extruded canine degenerate disks. AB - OBJECTIVE: To describe the cytologic and histopathologic appearance of degenerate disk material in dogs with Hansen type I intervertebral disk disease (IVDD). STUDY DESIGN: Case series. ANIMALS: Dogs (n=45) that had surgical intervention for Hansen type I IVDD (January-November 2007). METHODS: Impression smears and histopathologic sections were prepared from surgically removed degenerate disk material. All slides were evaluated for overall cellularity, quantity and attributes of extracellular matrix, types of cells present, and their cytomorphology. Histopathologic sections were also examined for presence of neovascularization and hemorrhage. RESULTS: Cytologically, 11 of 45 samples consisted of only extracellular matrix, 30 had evidence of inflammation, and 20 contained dysplastic spindloid cells. Histologically, hyaline cartilage predominated in 35 of 45 samples, fibrocartilage in 4, and spindloid cells in 6; 37 of 45 were inflamed, 37 were hemorrhagic, and 13 had neovascularization. CONCLUSIONS: The cytologic and histopathologic appearance of extruded degenerate disk material in dogs is variable and can include dysplastic spindloid cells. CLINICAL RELEVANCE: The variability in cytologic findings and frequent presence of dysplastic spindloid cells suggest that cytology alone may not be a reliable tool to differentiate degenerate canine disk material from a mesenchymal neoplasm. PMID- 19781022 TI - Contact mechanics of simulated meniscal tears in cadaveric canine stifles. AB - OBJECTIVE: To evaluate the biomechanical effects of 5 types of meniscal lesions on contact mechanics in the canine stifle. STUDY DESIGN: Experimental study. ANIMALS: Cadaveric canine stifles (n=12 pair). METHODS: Medial meniscal lesions (radial, vertical longitudinal, nonreducible bucket handle, flap, and complex tears) were simulated in cadaveric stifles. A contact map was recorded from each tear type and contact area (CA) and peak contact pressure (PCP) from each tear type were compared. RESULTS: A significant difference in PCP was detected between control and nonreducible bucket handle, flap, and complex tears. PCP increased by >45% in nonreducible bucket handle, flap, and complex meniscal tears when compared with control. No significant difference was found in PCP between control and radial and vertical longitudinal tears. No significant difference was found in CA between any of the meniscal conditions. CONCLUSIONS: Nonreducible bucket handle, flap, and complex tears cause a significant increase in PCP. Radial and vertical longitudinal tears had a minimal impact on the contact pressures of the medial compartment of the stifle. CLINICAL RELEVANCE: Based on this ex vivo model, we support the clinical recommendation of debriding nonreducible bucket handle, flap, and complex tears because the injured portion of the meniscus no longer contributes significantly to the function of the meniscus. Radial and vertical longitudinal tears do not cause a change in contact mechanics allowing consideration of nonsurgical treatment and meniscal repair, respectively. Future experimental and clinical studies should aim to refine the treatment of specific meniscal injuries. PMID- 19781023 TI - The effect of laparoscopic versus open ovariectomy on postsurgical activity in small dogs. AB - OBJECTIVE: To describe a technique for laparoscopic ovariectomy (LapOVE) in small dogs, and compare the surgical time, complications, and postoperative activity of dogs undergoing LapOVE to those undergoing conventional traditional open ovariectomy (OOVE). STUDY DESIGN: A randomized, controlled clinical trial. ANIMALS: Intact small breed (<10 kg) female dogs (n=20). METHODS: Ventral median celiotomy was performed for OOVE. A 2-midline portal technique using a 3.5 mm laparoscope port and a 6 mm instrument portal was used for LapOVE. An accelerometer was attached to the collar of each dog to record 24-hour preoperative and 48-hour postoperative activity. Total activity counts recorded before surgery were compared with total counts recorded after surgery. The percent change in counts after surgery was compared between OOVE- and LapOVE treated dogs. RESULTS: No major complications occurred and surgical time for LapOVE was significantly longer than for OOVE cases (P=.005). Dogs in the LapOVE group had a 25% decrease in total activity counts after surgery (95% confidence interval [CI]: 11-38%), whereas dogs in the OOVE group had a 62% decrease in total activity counts after surgery (95% CI: 48-76%). CONCLUSIONS: Both procedures were performed with reasonable surgical times and without major complication. Postoperative activity, as measured by accelerometry, was significantly different between the 2 groups. CLINICAL RELEVANCE: Laparoscopy is a safe method for ovariectomy in small dogs and results in increased postoperative activity counts when compared with an open technique. PMID- 19781024 TI - Laparoscopic ovariectomy in dogs: comparison between single portal and two-portal access. AB - OBJECTIVE: To compare surgical times and perioperative complication rates of single portal access and 2-portal laparoscopic ovariectomy (LapOVE) in dogs using a bipolar vessel sealer/divider device, and to evaluate the performance of novice laparoscopists for right ovariectomy. STUDY DESIGN: Controlled clinical trial. ANIMALS: Female dogs (n=42). METHODS: Dogs were divided into groups: 1=single portal and 2=2 portal. LapOVE was performed using a 5 mm vessel sealer/divider device and a 10 mm operating laparoscope (Group 1) or a 5 mm laparoscope (Group 2). Dog characteristics (weight, body condition score, ovarian ligament fat score), operative time, and perioperative complication rate were compared between groups. Right ovariectomy duration was evaluated for 2 novice laparoscopists. RESULTS: No significant difference was found in mean total surgical time between group 1 (21.07 min/s) and group 2 (19.06 min/s). Factors significantly affecting times included body condition scores, ovarian ligament fat score, ovarian bleeding, and surgeon expertise. Minor complications (bleeding from ovaries or after splenic trauma) occurred and were similar in both groups. Bleeding was correlated to body condition score and ovarian ligament fat score. Interindividual differences were found among surgeons for right ovariectomy time. CONCLUSIONS: Single portal access LapOVE using vessel sealer/divider device is feasible, safe, and does not significantly increase total surgical time in comparison with 2-portal approach. Laparoscopic skills may play a role in ability to perform single portal LapOVE. CLINICAL RELEVANCE: LapOVE can be performed using single portal access. PMID- 19781025 TI - Biceps brachii and brachialis tendon of insertion injuries in eleven racing greyhounds. AB - OBJECTIVE: To report injuries of the biceps brachii (BTI) or brachialis (BrTI) tendons of insertion in 11 racing Greyhounds. STUDY DESIGN: Case series. ANIMALS: Greyhounds (n=11). METHODS: Medical records (1990-2006) of racing Greyhound dogs with BTI injuries were reviewed. Preinjury, injury, and posttreatment information was obtained via trainer telephone questionnaire and individual greyhound race data. Outcomes between surgical and conservative management were compared. RESULTS: Dogs had elbow hyperextension, positive biceps test, and forelimb circumduction and 82% were male, whereas Queensland's male to female ratio of racing Greyhounds was almost equal. Eight dogs had right BTI injuries. Nine dogs had surgically confirmed tendon injuries: 5 combined BTI and BrTI, 2 mid-body BTI, 1 musculotendinous BTI, and 1 ulnar tuberosity avulsion fracture. Seven dogs were treated surgically (3 loop pulley sutures, single radial screw and washer, suture screws or fracture fixation in lag fashion), 2 dogs were euthanatized at surgery, 2 were rehomed and hence managed conservatively. All surgically treated dogs returned to near preinjury performance; 6 returned to racing and at least 4 won races in the same or higher grade. One conservatively managed dog returned to "pet" function. No dog reinjured its BTI or BrTI. CONCLUSION: BTI and BrTI avulsions are rare acute traumatic performance injuries of racing Greyhounds. CLINICAL RELEVANCE: Preinjury racing performance can be achieved with early surgical repair of BTI and BrTI and optimal postoperative management. PMID- 19781026 TI - Biomechanical comparison of four soft tissue replacement materials: an in vitro evaluation of single and multilaminate porcine small intestinal submucosa, canine fascia lata, and polypropylene mesh. AB - OBJECTIVE: To compare mechanical performance of 4 soft tissue replacement materials. STUDY DESIGN: Experimental. SAMPLE POPULATION: Polypropylene mesh (PM), single-layer porcine small intestinal submucosa (SIS), multilaminate (4 layer) porcine small intestinal submucosa (MLSIS), and canine fascia lata (FL). METHODS: The mechanical properties of each material were determined by testing to failure on a materials testing machine. Samples of each material (n=10) were tested in 3 different modes: resistance to suture pullout, tensile testing, and push-through testing. PM was tested both parallel (PMa) to and perpendicular (PMb) to its longitudinal cord orientation. SIS and FL were similarly tested in 2 orthogonal directions. RESULTS: With some exceptions, the following generalizations can be made regarding the mechanical performance of the materials tested: Suture pullout-FL>PMa=PMb>MLSIS>SIS (P< or =.04). Tensile testing FL>PMa>PMb>MLSIS>SIS (P< or =.02). Push-through testing-FL>PM>MLSIS>SIS (P< or =.003). CONCLUSIONS: PM accommodated a significantly higher load and energy to yield when its longitudinal cords were oriented parallel with the tension axis (PMa). FL performed similarly to the PM, with the exception of limited elongation in tension. MLSIS had biomechanical characteristics that were inferior to FL and PM but superior to SIS. CLINICAL RELEVANCE: PM's orientation may need to be considered when used clinically. FL is a biomechanically suitable soft tissue replacement material but its use may be limited by currently available sizes. SIS cannot be recommended in high-strain environments. PMID- 19781027 TI - In vitro biomechanical comparison of polypropylene mesh, modified three-loop pulley suture pattern, and a combination for repair of distal canine achilles' tendon injuries. AB - OBJECTIVE: To compare mechanical stability between a novel polypropylene mesh repair (Mesh), a modified 3-loop pulley suture (Suture), and a combination of the techniques (Suture+Mesh) for the repair of distal canine Achilles' tendon ruptures. STUDY DESIGN: In vitro mechanical evaluation. SAMPLE POPULATION: Cadaveric canine Achilles' tendon/calcaneus units (n=34). METHODS: Constructs were loaded under tension to failure in a materials testing machine with synchronized kinematic analysis. Ultimate load to failure, global construct stiffness, and force required to reach 1 and 3 mm gap formation was recorded. RESULTS: Ultimate load to failure was greatest for the Suture+Mesh group and lowest for the Suture group. The Suture+Mesh technique afforded a significantly greater global stiffness than the Suture or Mesh treatments. Force to generate 1 and 3 mm gap formation was greatest with the Suture group. CONCLUSIONS: The Suture+Mesh group had the highest ultimate load to failure and afforded the greatest global stiffness though it had no added benefit to resist local gap formation at the repair. CLINICAL RELEVANCE: Achilles' ruptures repaired with suture can be augmented with mesh to increase the ultimate load to failure, but as currently tested, there was a decrease in resistance to gap formation At this time we cannot recommend Mesh or the Suture+Mesh techniques without further testing. PMID- 19781028 TI - Clinical evaluation of pancarpal arthrodesis using a CastLess plate in 11 dogs. AB - OBJECTIVE: To describe the use of a 3.5/2.7 mm CastLess Plate (CLP) for pancarpal arthrodesis (PCA) in dogs. STUDY DESIGN: Case series. ANIMALS: Dogs with traumatic/degenerative carpal disease (n=11). METHODS: Records (September 2006 July 2007) of dogs that had PCA using a 3.5/2.7 mm CLP were reviewed to determine intra- and postoperative complications and use of external coaptation. Follow-up (> or =12 months) was obtained by telephone interview of owners. RESULTS: Thirteen PCA procedures were performed; 5 intraoperative complications occurred in 4 procedures and included iatrogenic metacarpal fissure fracture (2), inability to remove an alignment pin (1), and poor distal plate position (2). External coaptation was used in 4 dogs: concomitant or iatrogenic injuries (3), bilateral PCA (1), for 3-6 weeks. Clinical evaluation 6-24 weeks postoperatively revealed iatrogenic metacarpal fractures to have healed and that 1 postoperative complication (infection) developed. Telephone follow-up for 10 dogs (mean, 14 months; range, 12-20 months) revealed no further problems. CONCLUSION: PCA using a 3.5/2.7 mm CLP reduces the need for external coaptation and seemingly reduces postoperative morbidity associated with other internal fixation techniques. CLINICAL RELEVANCE: PCA can be performed safely and successfully using a 3.5/2.7 mm CLP, with low postoperative morbidity compared with other PCA techniques. Particular attention should be taken when applying the distal component of the plate. PMID- 19781029 TI - Arthrodesis of the equine proximal interphalangeal joint: a biomechanical comparison of two parallel headless, tapered, variable-pitched, titanium compression screws and two parallel 5.5 mm stainless-steel cortical screws. AB - OBJECTIVE: To compare the biomechanical characteristics, failure mode, and effects of side (left or right limb) and end (forelimb or hindlimb) of different screws in 2-screw, parallel-screw proximal interphalangeal joint arthrodesis constructs in horses. STUDY DESIGN: In vitro experimental study. SAMPLE POPULATION: Twenty limbs from 6 cadavers (4 complete limb sets, 2 partial sets total of 4 forelimb and 6 hindlimb pairs). METHODS: Two parallel 5.5 mm cortical (AO) screws were inserted in lag fashion in 1 randomly allocated limb of a pair, and 2 parallel headless, tapered, variable-pitched, titanium compression screws (Acutrak-Plus) were inserted in the contralateral limb. Constructs were tested in 3-point bending in a dorsopalmar (plantar) direction using a materials-testing machine at a loading rate of 5.83 mm/s. Maximal bending moment at failure and composite stiffness were calculated from data generated on load-displacement curves. Data were analyzed using a Friedman 2-way analysis of variance and Wilcoxon's signed-rank tests. RESULTS: No significant difference was detected for bending moment or stiffness values in proximal interphalangeal joint arthrodesis constructs using 2 parallel Acutrak-Plus or AO screws for fixation. Mean stiffness values were significantly different between forelimb and hindlimb constructs. CONCLUSIONS: Performance of 2 parallel Acutrak-Plus screws was biomechanically comparable with 2 parallel AO 5.5 mm cortical screws in in vitro pastern arthrodesis constructs. CLINICAL RELEVANCE: Acutrak-Plus screws may provide an alternative means of fixation for proximal interphalangeal joint arthrodesis. PMID- 19781030 TI - Potential iatrogenic medial meniscal damage during tibial plateau leveling osteotomy. AB - OBJECTIVE: To evaluate potential iatrogenic medial meniscal (MM) damage during tibial plateau leveling osteotomy (TPLO) and to establish a safe zone (SZ) for hypodermic needle (HN) identification of the medial aspect of the stifle joint. STUDY DESIGN: Prospective cohort. ANIMALS: Cadaveric canine stifles (n=40). METHODS: HN (20 or 25 G) were inserted through the medial collateral ligament (MCL) of the femorotibial joint and through the SZ insertion points. The medial meniscus was inspected for iatrogenic damage. Statistical comparison of MM damage caused by different needle sizes and insertion sites was performed using Fisher's exact test with significance at P< .05. RESULTS: Twenty-gauge group: 65% of stifles had minor MM damage with MCL insertion compared with 35% of stifles with SZ insertion (P=.0049). Severe MM damage occurred in 25% of stifles with MCL insertion compared with 0% of stifles with SZ insertion (P=.0014). Twenty-five gauge group: 85% of stifles had minor MM damage with MCL insertion compared with 30% after SZ insertion (P=.0011); however, no severe MM injury was noted. CONCLUSIONS: HN insertion though the MCL can produce iatrogenic damage to the MM. Use of a 25 G HN and SZ site for insertion reduced the frequency and severity of MM damage. CLINICAL RELEVANCE: HN insertion into the medial aspect of the femorotibial joint during TPLO can cause gross iatrogenic MM damage, which may contribute to the incidence and misdiagnosis of latent MM injuries after TPLO. PMID- 19781031 TI - Biomechanical analysis of torsion and shear forces in lumbar and lumbosacral spine segments of nonchondrodystrophic dogs. AB - OBJECTIVE: To determine stiffness and load-displacement curves as a biomechanical response to applied torsion and shear forces in cadaveric canine lumbar and lumbosacral specimens. STUDY DESIGN: Biomechanical study. ANIMALS: Caudal lumbar and lumbosacral functional spine units (FSU) of nonchondrodystrophic large-breed dogs (n=31) with radiographically normal spines. METHODS: FSU from dogs without musculoskeletal disease were tested in torsion in a custom-built spine loading simulator with 6 degrees of freedom, which uses orthogonally mounted electric motors to apply pure axial rotation. For shear tests, specimens were mounted to a custom-made shear-testing device, driven by a servo hydraulic testing machine. Load-displacement curves were recorded for torsion and shear. RESULTS: Left and right torsion stiffness was not different within each FSU level; however, torsional stiffness of L7-S1 was significantly smaller compared with lumbar FSU (L4-5-L6-7). Ventral/dorsal stiffness was significantly different from lateral stiffness within an individual FSU level for L5-6, L6-7, and L7-S1 but not for L4 5. When the data from 4 tested shear directions from the same specimen were pooled, level L5-6 was significantly stiffer than L7-S1. CONCLUSIONS: Increased range of motion of the lumbosacral joint is reflected by an overall decreased shear and rotational stiffness at the lumbosacral FSU. CLINICAL RELEVANCE: Data from dogs with disc degeneration have to be collected, analyzed, and compared with results from our chondrodystrophic large-breed dogs with radiographically normal spines. PMID- 19781032 TI - In vitro evaluation of the effect of fracture configuration on the mechanical properties of standard and novel interlocking nail systems in bending. AB - OBJECTIVE: To investigate the effect of fracture configuration on the mechanical properties of standard interlocking nails (ILNs) and a novel angle-stable ILN (ILNn) in bending. STUDY DESIGN: In vitro experimental study. SAMPLE POPULATION: Synthetic tibial gap fracture bone models. METHODS: Bone models, featuring a 5 or 120 mm central defect, respectively, mimicking a simple diaphyseal and a comminuted fracture involving both metaphyses, were implanted with 6 or 8 mm screwed or bolted standard ILNs (ILN6s, ILN6b, ILN8s, ILN8b, respectively) or an ILNn. Specimens were tested in 4-point bending. Construct angular deformation (AD) and slack were statistically compared (P<.05). RESULTS: With increasing gap size, standard ILN construct AD increased significantly by approximately 27% in ILN8b and by up to 105% in ILN6s. Similarly, standard ILN construct slack significantly increased by approximately 33% in ILN8b (from approximately 4.2 degrees to approximately 5.6 degrees) and by up to approximately 130% in ILN6s (from approximately 7 degrees to approximately 16 degrees). Conversely, there was no difference in the ILNn construct AD (approximately 4 degrees) regardless of gap size. ILNn AD was the lowest of all groups and occurred without slack. CONCLUSIONS: This study demonstrated that the angle-stable ILNn provided construct stability regardless of fracture configuration, whereas the intrinsic slack of standard ILNs could jeopardize construct stability in a fracture configuration involving the metaphyses. CLINICAL RELEVANCE: Use of standard ILNs may be optimal in diaphyseal fractures where circumferential nail/cortical contact could augment repair stability. Conversely, the angle-stable ILNn may represent a reliable fracture stabilization method for diaphyseal fractures as well as fractures involving the metaphyseal regions. PMID- 19781033 TI - Percutaneous cementoplasty in the palliative, multimodal treatment of primary bone tumors of the distal aspect of the radius in four dogs. AB - OBJECTIVE: To (1) evaluate the analgesic effect of percutaneous cementoplasty (PC) in dogs with primary bone tumor (PBT) of the distal aspect of the radius and (2) evaluate the impact on the course of disease by adding PC to a palliative, multimodal treatment protocol in these dogs. STUDY DESIGN: Prospective pilot study. ANIMALS: Dogs (n=4) with PBT of the distal aspect of the radius. METHODS: Tumor lesions were filled percutaneously with polymethylmethacrylate under fluoroscopic guidance. Pamidronate was administered once in a week before PC. Radiotherapy and chemotherapy were initiated 2 and 6 weeks after PC, respectively. Force plate analysis was performed immediately before 2, and 6 weeks after PC. Survival time was defined from PC to euthanasia. RESULTS: Two dogs had a significant increase in peak vertical force 2 weeks after PC (P=.043) and remained free of lameness for 18 and 20 weeks, respectively. One dog had an acute relapse after an initially lame-free period of 10 days. The remaining dog failed to improve (P=.686). Three dogs developed at least 2 complications including transient worsening of the lameness after PC, cement leakage, wound infection and suspected thromboembolism in combination with cough and anemia. Median survival was 4.8 months (range, 1-5.7 months). CONCLUSIONS: PC in combination with pamidronate significantly improved lameness in 2 dogs; however, PC is not risk-free. Deep wound infection, intraarticular cement leakage, and venous thrombosis were the main complications. CLINICAL RELEVANCE: PC might be a useful addition to established palliative, multimodal treatment protocols in dogs with PBT; however, because of the complications encountered PC warrants further study before routine use can be considered. PMID- 19781034 TI - Challenging the current paradigm of equine castration. PMID- 19781035 TI - Liver gene expression in relation to hepatic steatosis and lipid secretion in two duck species. AB - The susceptibility to development of hepatic steatosis is known to differ between Muscovy and Pekin ducks. Although some experiments were conducted to decipher these differences, few data have been produced to analyse the role of specific genes in this process. For this purpose, expression levels of genes involved in lipid (ATP citrate lyase, malic enzyme 1, fatty acid synthase, stearoyl-CoA desaturase 1, diacylglycerol O-acyl transferase 2, microsomal triglyceride transfer protein, apolipoprotein A1, apolipoprotein B, sterol regulatory element binding factor 1, hepatocyte nuclear factor 4, choline/ethanolamine phosphotransferase 1, carnitine palmitoyl transferase 1A, peroxisome proliferator activated receptor alpha and sterol O-acyltransferase) and carbohydrate (activating transcription factor 4 or cAMP-response element binding protein, mitochondrial malate dehydrogenase 2 and carbohydrate responsive element binding protein) metabolism and in other functions were analysed in the liver of Pekin and Muscovy ducks fed ad libitum or overfed. A specific positive effect of feeding was observed on the expression of genes involved mainly in fatty acids and TG synthesis and glycolysis, and negative effect on genes involved in beta oxidation. Interestingly, a strong species effect was also observed on stearoyl CoA desaturase 1 and to a lesser extent on diacylglycerol O-acyl transferase 2 expression, leading to large differences in expression levels between Pekin and Muscovy overfed ducks, which could explain the difference in lipid metabolism and steatosis ability observed between the two duck species. These results should shed light on gene expression that might underlie susceptibility to hepatic steatosis in humans. PMID- 19781036 TI - Postnatal transcription profile and polymorphism of the ADIPOR1 gene in five pig breeds. AB - As a result of its role in energy homeostasis regulation, the ADIPOR1 gene is a candidate for fat deposition, an important production trait, in the pig. The aim of the study was to conduct a comparative analysis of the ADIPOR1 postnatal transcript level, in order to establish its promoter and 5'UTR sequences and to search the gene for polymorphisms. The transcription level was examined in longissimus dorsi and semimembranosus muscles collected from 180 pigs at 60-210 days of age, representing five pig breeds: Duroc, Polish Large White, Polish Landrace, Pietrain and Pulawska. We calculated highly significant breed by age by muscle interaction (P < 0.0001) and breed by muscle interactions (P < 0.01). The 5'UTR and promoter region of the porcine ADIPOR1 gene were amplified for the first time and their sequences were deposited in the GenBank database. In total, 21 novel and two previously described polymorphisms were found in the ADIPOR1 promoter, coding, intronic, 5' and 3' untranslated regions. The only SNP detected in the coding region was a synonymous substitution. Two polymorphisms in 3'UTR (c.*129A>C and c.*536A>G) showed no significant effect on the transcript level. Our results showed a high polymorphism of the ADIPOR1 and a complexity in its transcription level in the studied muscles. This complexity indicates that conclusions based on such studies should be carefully gradated. PMID- 19781037 TI - Comparison of PERV genomic locations between Asian and European pigs. AB - Xenotransplantation from pigs provides a possible solution to the shortage of human organs for allotransplantation. Porcine endogenous retroviruses (PERVs) are a possible obstacle to using porcine organs in addition to the immunological barriers. Three main types of PERVs (A, B and C) have been previously investigated in diverse pig breeds. To examine the copy numbers of PERVs and their genomic locations in the Korean native pig genome, we screened a BAC (Bacterial Artificial Chromosome) library with PERV-specific protease primers for initial recognition of PERV-positive clones and three sets of envelope-specific primers for the identification of PERV types. A total of 45 PERV-positive clones, nine PERV-A and 36 PERV-B, have been identified from the library screening and the BAC contigs were constructed using the primers designed from BAC end sequences (BESs). These primers were also used for SCH (Somatic Cell Hybrid) and RH (Radiation Hybrid) mapping of the PERV-positive clones. The results indicate that 45 PERV-positive BAC clones belong to nine contigs and a singleton. SCH and IMpRH (INRA-Minnesota Porcine Radiation Hybrid) mapping results indicated that there are at least eight separate PERV genomic locations, consisting of three PERV-A and five PERV-B. One contig could not be mapped, and two contigs are closely located on SSC7. Southern blotting indicates there may be up to 15 additional sites. Further investigation of these clones will contribute to a general strategy to generate PERV-free lines of pigs suitable for xenotransplantation. PMID- 19781038 TI - Across-line SNP association study of innate and adaptive immune response in laying hens. AB - The aim of the present study was to detect quantitative trait loci (QTL) for innate and adaptive immunity in laying hens. For this purpose, the associations between 1022 single nucleotide polymorphism (SNP) markers and immune traits were studied in 583 hens from nine different layer lines. Immune traits were natural antibodies for keyhole limpet haemocyanin (KLH) and lipopolysaccharide (LPS) at 20, 40 and 65 weeks, acquired antibodies to the vaccinal virus of Newcastle disease at 20 weeks, and complement activity measured on sheep and bovine red blood cells at 20, 40 and 65 weeks. We adopted a novel approach based on across line analysis and testing of the SNP-by-line interaction. Among lines, linkage disequilibrium is conserved at shorter distances than in individual lines; therefore, SNPs significantly associated with immune traits across lines are expected to be near the functional mutations. In the analysis, the SNPs that had a significant across-line effect but did not show significant SNP-by-line interaction were identified to test whether the association was consistent in the individual lines. Ultimately, 59 significant associations between SNPs and immune traits were detected. Our results confirmed some previously identified QTL and identified new QTL potentially involved in the immune function. We found evidence for a role of IL17A (chromosome 3) in natural and acquired antibody titres and in the classical and alternative pathways of complement activation. The major histocompatibility genes on chromosome 16 showed significant association with natural and acquired antibody titres and classical complement activity. The IL12B gene on chromosome 13 was associated with natural antibody titres. PMID- 19781039 TI - Identification of a 3.7-Mb region for a marbling QTL on bovine chromosome 4 by identical-by-descent and association analysis. AB - QTL mapping for growth and carcass traits was performed using a paternal half-sib family composed of 325 Japanese Black cattle offspring. Nine QTL were detected at the 1% chromosome-wise significance level at a false discovery rate of less than 0.1. These included two QTL for marbling on BTA 4 and 18, two QTL for carcass weight on BTA 14 and 24, two QTL for longissimus muscle area on BTA 1 and 4, two QTL for subcutaneous fat thickness on BTA 1 and 15 and one QTL for rib thickness on BTA 6. Although the marbling QTL on BTA 4 has been replicated with significant linkages in two Japanese Black cattle sires, the three Q (more marbling) haplotypes, each inherited maternally, were apparently different. To compare the three Q haplotypes in more detail, high-density microsatellite markers for the overlapping regions were developed within the 95% CIs (65 markers in 44-78 cM). A detailed haplotype comparison indicated that a small region (<3.7 Mb) around 46 cM was shared between the Qs of the two sires, whose dams were related. An association of this region with marbling was shown by a regression analysis using the local population, in which the two sires were produced and this was confirmed by an association study using a population collected throughout Japan. These results strongly suggest that the marbling QTL on BTA 4 is located in the 3.7-Mb region at around 46 cM. PMID- 19781040 TI - Effects of DGAT1 and GHR on milk yield and milk composition in the Chinese dairy population. AB - Previous studies have demonstrated that the p.Lys232Ala substitution in the acylCoA: diacylglycerol acyltransferase (DGAT1) gene and the p.Phe279Tyr mutation in the growth hormone receptor (GHR) gene are the causative quantitative trait loci underlying milk yield and composition on BTA14 and BTA20 respectively. To examine their applications in the genetic improvement of Chinese dairy cattle productivity, we herein investigated the effects of the DGAT1 p.Lys232Ala and GHR p.Phe279Tyr mutations on milk, fat and protein yield, as well as fat and protein percentage in the milk of 1222 Holstein cows. Genotyping was performed using PCR RFLP for DGAT1 or primer-introduced restriction analysis (PCR-PIRA) for GHR. With a mixed animal model, the significant associations of the DGAT1 p.Lys232Ala substitution with 305-day milk, fat and protein yield were identified (P = 0.0001). The DGAT1 allele that encode lysine at position 232 was associated with increased 305-day milk fat yield, but with decreased 305-day milk and protein yield, whereas the GHR p.Phe279Tyr mutation was found to be significantly associated with protein percentage (P = 0.0014). The allele substitution effect of p.279Phe by p.279Tyr may lead to a significant increase in protein percentage. Our findings indicate that DGAT1 p.232Ala and GHR p.279Phe could be used to increase milk yield and protein yield of Chinese Holstein cows. PMID- 19781041 TI - Preterm premature rupture of membranes, chorioamnion inflammatory scores and neonatal respiratory outcome. AB - OBJECTIVE: To evaluate whether histological chorioamnionitis (HCA), in the setting of preterm premature rupture of membranes (PPROM), affects infant respiratory outcome. DESIGN: A prospective histological study on 287 consecutive placentas was performed in preterm infants (or=15) quartiles (test for trend, P = 0.01). When adjusted for height, body mass index, marital status, smoking status, induction of labour, week of gestation of delivery and birthweight percentile; the odds ratio for operative delivery associated with a 5-year increase in age at menarche (0.78, 95% CI 0.61-0.99) was very similar to the odds ratio for a 5-year decrease in age at delivery (0.73, 95% CI 0.67-0.79). There was no association between age at menarche and the risk of operative delivery following adjustment for the interval between menarche and the first birth (adjusted odds ratio 0.98, 95% CI 0.77-1.25). CONCLUSION: Later menarche is associated with a decreased risk of operative delivery by decreasing the interval between menarche and first birth. The observation is consistent with the hypothesis that prolonged hormonal stimulation of the uterus prior to the first birth has a deleterious effect on uterine function. PMID- 19781051 TI - A grapevine Shaker inward K(+) channel activated by the calcineurin B-like calcium sensor 1-protein kinase CIPK23 network is expressed in grape berries under drought stress conditions. AB - Grapevine (Vitis vinifera), the genome sequence of which has recently been reported, is considered as a model species to study fleshy fruit development and acid fruit physiology. Grape berry acidity is quantitatively and qualitatively affected upon increased K(+) accumulation, resulting in deleterious effects on fruit (and wine) quality. Aiming at identifying molecular determinants of K(+) transport in grapevine, we have identified a K(+) channel, named VvK1.1, from the Shaker family. In silico analyses indicated that VvK1.1 is the grapevine counterpart of the Arabidopsis AKT1 channel, known to dominate the plasma membrane inward conductance to K(+) in root periphery cells, and to play a major role in K(+) uptake from the soil solution. VvK1.1 shares common functional properties with AKT1, such as inward rectification (resulting from voltage sensitivity) or regulation by calcineurin B-like (CBL)-interacting protein kinase (CIPK) and Ca(2+)-sensing CBL partners (shown upon heterologous expression in Xenopus oocytes). It also displays distinctive features such as activation at much more negative membrane voltages or expression strongly sensitive to drought stress and ABA (upregulation in aerial parts, downregulation in roots). In roots, VvK1.1 is mainly expressed in cortical cells, like AKT1. In aerial parts, VvK1.1 transcripts were detected in most organs, with expression levels being the highest in the berries. VvK1.1 expression in the berry is localized in the phloem vasculature and pip teguments, and displays strong upregulation upon drought stress, by about 10-fold.VvK1.1 could thus play a major role in K(+) loading into berry tissues, especially upon drought stress. PMID- 19781052 TI - Cellular transport of anti-inflammatory pro-drugs originated from a herbal formulation of Zingiber cassumunar and Nigella sativa. AB - BACKGROUND: The rhizome of Zingiber cassumunar and the seed of Nigella sativa are two ingredients in Thai traditional medicine to relieve dysmenorrhea and adjust the menstrual cycle. Mixture of these two herbs produces three esters, namely (E) 4-(3,4-dimethoxyphenyl)but-3-en-1-yl linoleate (1), (E)-4-(3,4 dimethoxyphenyl)but-3-en-1-yl oleate (2) and (E)-4-(3,4-dimethoxyphenyl)but-3-en 1-yl palmitate (3). The aim of this study is to examine in vitro absorption of these esters and evaluate their transport across the membrane. METHODS: In vitro transport of these three esters was observed in Caco-2 cell monolayers. The ester compounds 1, 2 and 3 at a concentration of 10 microM were hydrolyzed by porcine liver esterase. RESULTS: All esters transported across the Caco-2 cell without enzymatic hydrolysis. The apparent permeability coefficients P(app) of compound 1 at 53 microM and 106 microM were 13.94 (0.60) x 10(-6) and 14.33 (0.17) x 10(-6) cm/s respectively, while those of compound 2 were 9.45 (0.29) x 10(-6) and 10.08 (0.32) x 10(-6) cm/s, respectively. Papp values of compound 3 were 7.48 (0.31) x 10(-6) cm/s at 53 microM and 8.60 (0.55) x 10(-6) cm/s at 106 microM. P(app) values of the parent compound (compound D), i.e. (E)-4-(3,4-dimethoxyphenyl)but-3 en-1-ol were 8.53 (0.83) x 10(-6) cm/s at 53 microM and 16.38 (0.61) x 10(-6) cm/s at 106 microM. The ester hydrolysis of compounds 1, 2 and 3 by porcine liver esterase was monitored by HPLC and the hydrolysis reactions were completed within 10 minutes. CONCLUSION: Using the Caco-2 cell monolayer model, the present study finds that compounds (E)-4-(3,4-dimethoxyphenyl)but-3-en-1-yl linoleate (1), (E) 4-(3,4-dimethoxyphenyl)but-3-en-1-yl oleate (2) and (E)-4-(3,4 dimethoxyphenyl)but-3-en-1-yl palmitate (3) originated from Prasaplai preparation (a Thai herbal formula) may be transported through a facilitated mechanism and serve as pro-drugs to increase the compound D level in the blood. PMID- 19781053 TI - Effects of a training program after surgically treated ankle fracture: a prospective randomised controlled trial. AB - BACKGROUND: Despite conflicting results after surgically treated ankle fractures few studies have evaluated the effects of different types of training programs performed after plaster removal. The aim of this study was to evaluate the effects of a 12-week standardised but individually suited training program (training group) versus usual care (control group) after plaster removal in adults with surgically treated ankle fractures. METHODS: In total, 110 men and women, 18-64 years of age, with surgically treated ankle fracture were included and randomised to either a 12-week training program or to a control group. Six and twelve months after the injury the subjects were examined by the same physiotherapist who was blinded to the treatment group. The main outcome measure was the Olerud-Molander Ankle Score (OMAS) which rates symptoms and subjectively scored function. Secondary outcome measures were: quality of life (SF-36), timed walking tests, ankle mobility tests, muscle strength tests and radiological status. RESULTS: 52 patients were randomised to the training group and 58 to the control group. Five patients dropped out before the six-month follow-up resulting in 50 patients in the training group and 55 in the control group. Nine patients dropped out between the six- and twelve-month follow-up resulting in 48 patients in both groups. When analysing the results in a mixed model analysis on repeated measures including interaction between age-group and treatment effect the training group demonstrated significantly improved results compared to the control group in subjects younger than 40 years of age regarding OMAS (p = 0.028), muscle strength in the plantar flexors (p = 0.029) and dorsiflexors (p = 0.030). CONCLUSION: The results of this study suggest that when adjusting for interaction between age-group and treatment effect the training model employed in this study was superior to usual care in patients under the age of 40. However, as only three out of nine outcome measures showed a difference, the beneficial effect from an additional standardised individually suited training program can be expected to be limited. There is need for further studies to elucidate how a training program should be designed to increase and optimise function in patients middle-aged or older. TRIAL REGISTRATION: Current Controlled Trials ACTRN12609000327280. PMID- 19781054 TI - Health services utilization by school going Omani adolescents and youths with DSM IV mental disorders and barriers to service use. AB - BACKGROUND: Recent corpus of research suggests that psychiatric disorders amongst adolescents and youths are an emerging global challenge, but there is paucity of studies exploring health services utilization by this age group in Arab region. AIM: This study focus on the health services utilization and the barriers among school going adolescents and youths with DSM IV disorders in the country Oman, whose population is predominantly youthful. METHODS: Representative sample of secondary school Omani adolescents and youths were concurrently interviewed for the (i) presence of DSM IV mental disorders using the face-to-face interview, World Mental Health-Composite International Diagnostic Interview (WMH-CIDI), (ii) tendency for health care utilization and (iii) predictors of utilization with clinical and demographic background. RESULTS: The proportions of lifetime cases having ever made treatment contact are low, being 5.2% for any anxiety disorder and 13.2% for any mood disorder category. None of these anxiety cases made treatment contact in the year of onset of the disorder, and the median delay when they eventually made treatment contact is about 14 years. In any mood disorders category only 3.6% made contact within the 1st year of onset with the median delay in initial treatment contact is two years for the Bipolar disorder (broad), four years for Any Mood disorder and nine years for the Major Depressive Disorder group. Male gender is significantly associated with less likelihood of making treatment contact when suffering from Social phobia (p = 0.000), Major Depressive Disorder (p = 0.000) and Bipolar Disorder (p = 0.000). The younger cohorts of 14 16 years and 17-18 years of Social phobic made significantly less lifetime any treatment contact (p = 0.000). The 14-16 year olds were significantly less likely to make lifetime any treatment contact for Bipolar Mood disorder (p = 0.000), while the 17-18 group were 1.5 times more likely to do so. Over past 12 months only between 6 to 12% of those having some form of mental disorder avail of any treatment facility with utilization pattern nearly equal between the any healthcare and any non healthcare facilities. In the any healthcare services, more of those with anxiety disorders seek help from general medical doctors while those with Major Depressive Disorder and any Mood disorders are comparatively treated more by non allopathic services. Females were 13.5 times more likely to avail treatment(chi sq 7.1) as also those cases with increased severity of illness were 7 times more likely(chi sq 9.6). In the any treatment category for any 12 month disorder in general, the younger cohort of 14-16 years is 2.2 times more likely to receive any treatment over past 12 months (p = 0.042) while the situation shows marked reversal in the 17-18 age groups. Having any mood disorder is a significant predictor for the same (p = 0.040). DISCUSSION: Present findings confer with other studies from elsewhere suggesting under utilization of health care services for those with mental illness. Since cultural teaching and traditional coping with mental illness are contributing significantly in furnishing mental health need for many in Oman, the findings are discussed within social-cultural context that forms the basis of the complex health care utilization in Oman. This could foster policies that help bridge the gap between allopathic and non-allopathic care services. PMID- 19781055 TI - Psychological factors that promote behavior modification by obese patients. AB - BACKGROUND: The weight-loss effect of team medical care in which counseling is provided by clinical psychologists was investigated in an university hospital obesity (OB) clinic. Nutritional and exercise therapy were also studied. In our previous study, we conducted a randomized, controlled trial with obese patients and confirmed that subjects who received counseling lost significantly more weight than those in a non-counseling group. The purpose of this study was to identify the psychological characteristics assessed by ego states that promote behavior modification by obese patients. METHODS: 147 obese patients (116 females, 31 males; mean age: 45.9 +/- 15.4 years) participated in a 6-month weight-loss program in our OB clinic. Their psychosocial characteristics were assessed using the Tokyo University Egogram (TEG) before and after intervention. The Wilcoxon signed rank test was used to compare weight and psychological factors before and after intervention. Multiple regression analysis was used to identify factors affecting weight loss. RESULTS: Overall, 101 subjects (68.7%) completed the program, and their data was analyzed. The subjects mean weight loss was 6.2 +/- 7.3 kg (Z = 7.72, p < 0.01), and their mean BMI decreased by 2.4 +/- 2.7 kg/m2 (Z = 7.65, p < 0.01). Significant differences were observed for the Adult (A) ego state (0.68 +/- 3.56, Z = 1.95, p < 0.05) and the Free Child (FC) ego state (0.59 +/- 2.74, Z = 2.46, p < 0.01). The pre-FC ego state had a significant effect on weight loss (beta = 0.33, p < 0.01), and a tendency for changes in the A ego state scores to affect weight loss (beta = - 0.20, p = 0.06) was observed. CONCLUSION: This study of a 6-month weight-loss program that included counseling by clinical psychologists confirmed that the A ego state of obese patients, which is related to their self-monitoring skill, and the FC ego state of them, which is related to their autonomy, were increased. Furthermore, the negative aspects of the FC ego state related to optimistic and instinctive characteristics inhibited the behavior modification, while the A ego state represented objective self-monitoring skills that may have contributed to weight loss. PMID- 19781056 TI - Diabetes prevalence and diagnosis in US states: analysis of health surveys. AB - BACKGROUND: Current US surveillance data provide estimates of diabetes using laboratory tests at the national level as well as self-reported data at the state level. Self-reported diabetes prevalence may be biased because respondents may not be aware of their risk status. Our objective was to estimate the prevalence of diagnosed and undiagnosed diabetes by state. METHODS: We estimated undiagnosed diabetes prevalence as a function of a set of health system and sociodemographic variables using a logistic regression in the National Health and Nutrition Examination Survey (2003-2006). We applied this relationship to identical variables from the Behavioral Risk Factor Surveillance System (2003-2007) to estimate state-level prevalence of undiagnosed diabetes by age group and sex. We assumed that those who report being diagnosed with diabetes in both surveys are truly diabetic. RESULTS: The prevalence of diabetes in the U.S. was 13.7% among men and 11.7% among women >/= 30 years. Age-standardized diabetes prevalence was highest in Mississippi, West Virginia, Louisiana, Texas, South Carolina, Alabama, and Georgia (15.8 to 16.6% for men and 12.4 to 14.8% for women). Vermont, Minnesota, Montana, and Colorado had the lowest prevalence (11.0 to 12.2% for men and 7.3 to 8.4% for women). Men in all states had higher diabetes prevalence than women. The absolute prevalence of undiagnosed diabetes, as a percent of total population, was highest in New Mexico, Texas, Florida, and California (3.5 to 3.7 percentage points) and lowest in Montana, Oklahoma, Oregon, Alaska, Vermont, Utah, Washington, and Hawaii (2.1 to 3 percentage points). Among those with no established diabetes diagnosis, being obese, being Hispanic, not having insurance and being >/= 60 years old were significantly associated with a higher risk of having undiagnosed diabetes. CONCLUSION: Diabetes prevalence is highest in the Southern and Appalachian states and lowest in the Midwest and the Northeast. Better diabetes diagnosis is needed in a number of states. PMID- 19781058 TI - Parallel changes in gene expression in peripheral blood mononuclear cells and the brain after maternal separation in the mouse. AB - BACKGROUND: The functional integration of the neuro-, endocrine- and immune systems suggests that the transcriptome of white blood cells may reflect neuropsychiatric states, and be used as a non-invasive diagnostic indicator. We used a mouse maternal separation model, a paradigm of early adversity, to test the hypothesis that transcriptional changes in peripheral blood mononuclear cells (PBMCs) are paralleled by specific gene expression changes in prefrontal cortex (PFC), hippocampus (Hic) and hypothalamus (Hyp). Furthermore, we evaluated whether gene expression profiles of PBMCs could be used to predict the separation status of individual animals. FINDINGS: Microarray gene expression profiles of all three brain regions provided substantial evidence of stress-related neural differences between maternally separated and control animals. For example, changes in expression of genes involved in the glutamatergic and GABAergic systems were identified in the PFC and Hic, supporting a stress-related hyperglutamatergic state within the separated group. The expression of 50 genes selected from the PBMC microarray data provided sufficient information to predict treatment classes with 95% accuracy. Importantly, stress-related transcriptome differences in PBMC populations were paralleled by stress-related gene expression changes in CNS target tissues. CONCLUSION: These results confirm that the transcriptional profiles of peripheral immune tissues occur in parallel to changes in the brain and contain sufficient information for the efficient diagnostic prediction of stress-related neural states in mice. Future studies will need to evaluate the relevance of the predictor set of 50 genes within clinical settings, specifically within a context of stress-related disorders. PMID- 19781057 TI - Immature and mature species of the human Prostacyclin Receptor are ubiquitinated and targeted to the 26S proteasomal or lysosomal degradation pathways, respectively. AB - BACKGROUND: The human prostacyclin receptor (hIP) undergoes agonist-induced phosphorylation, desensitisation and internalisation and may be recycled to the plasma membrane or targeted for degradation by, as yet, unknown mechanism(s). RESULTS: Herein it was sought to investigate the turnover of the hIP under basal conditions and in response to cicaprost stimulation. It was established that the hIP is subject to low-level basal degradation but, following agonist stimulation, degradation is substantially enhanced. Inhibition of the lysosomal pathway prevented basal and agonist-induced degradation of the mature species of the hIP (46-66 kDa). Conversely, inhibition of the proteasomal pathway had no effect on levels of the mature hIP but led to time-dependent accumulation of four newly synthesised immature species (38-44 kDa). It was established that both the mature and immature species of the hIP may be polyubiquitinated and this modification may be required for lysosomal sorting of the mature, internalised receptors and for degradation of the immature receptors by the 26S proteasomes through the ER associated degradation (ERAD) process, respectively. Moreover, these data substantially advance knowledge of the factors regulating processing and maturation of the hIP, a complex receptor subject to multiple post-translational modifications including N-glycosylation, phosphorylation, isoprenylation, palmitoylation, in addition to polyubiquitination, as determined herein. CONCLUSION: These findings indicate that the hIP is post-translationally modified by ubiquitination, which targets the immature species to the 26S proteasomal degradation pathway and the mature species to the lysosomal degradation pathway. PMID- 19781059 TI - Development of a neuro-fuzzy technique for automated parameter optimization of inverse treatment planning. AB - BACKGROUND: Parameter optimization in the process of inverse treatment planning for intensity modulated radiation therapy (IMRT) is mainly conducted by human planners in order to create a plan with the desired dose distribution. To automate this tedious process, an artificial intelligence (AI) guided system was developed and examined. METHODS: The AI system can automatically accomplish the optimization process based on prior knowledge operated by several fuzzy inference systems (FIS). Prior knowledge, which was collected from human planners during their routine trial-and-error process of inverse planning, has first to be "translated" to a set of "if-then rules" for driving the FISs. To minimize subjective error which could be costly during this knowledge acquisition process, it is necessary to find a quantitative method to automatically accomplish this task. A well-developed machine learning technique, based on an adaptive neuro fuzzy inference system (ANFIS), was introduced in this study. Based on this approach, prior knowledge of a fuzzy inference system can be quickly collected from observation data (clinically used constraints). The learning capability and the accuracy of such a system were analyzed by generating multiple FIS from data collected from an AI system with known settings and rules. RESULTS: Multiple analyses showed good agreements of FIS and ANFIS according to rules (error of the output values of ANFIS based on the training data from FIS of 7.77 +/- 0.02%) and membership functions (3.9%), thus suggesting that the "behavior" of an FIS can be propagated to another, based on this process. The initial experimental results on a clinical case showed that ANFIS is an effective way to build FIS from practical data, and analysis of ANFIS and FIS with clinical cases showed good planning results provided by ANFIS. OAR volumes encompassed by characteristic percentages of isodoses were reduced by a mean of between 0 and 28%. CONCLUSION: The study demonstrated a feasible way to automatically perform parameter optimization of inverse treatment planning under guidance of prior knowledge without human intervention other than providing a set of constraints that have proven clinically useful in a given setting. PMID- 19781060 TI - A modified echocardiographic protocol with intrinsic plausibility control to determine intraventricular asynchrony based on TDI and TSI. AB - BACKGROUND: Established methods to determine asynchrony suffer from high intra- and interobserver variability and failed to improve patient selection for cardiac resynchronization therapy (CRT). Thus, there is a need for easy and robust approaches to reliably assess cardiac asynchrony. METHODS AND RESULTS: We performed echocardiography in 100 healthy subjects and 33 patients with left bundle branch block (LBBB). To detect intraventricular asynchrony, we combined two established methods, i.e., tissue synchronization imaging (TSI) and tissue Doppler imaging (TDI). The time intervals from the onset of aortic valve opening (AVO) to the peak systolic velocity (S') were measured separately in six basal segments in the apical four-, two-, and three-chamber view. Color-coded TSI served as an intrinsic plausibility control and helped to identify the correct S' measuring point in the TDI curves. Next, we identified the segment with the shortest AVO-S' interval. Since this segment most likely represents vital and intact myocardium it served as a reference for other segments. Segments were considered asynchronous when the delay between the segment in question and the reference segment was above the upper limit of normal delays derived from the control population. Intra- and interobserver variability were 7.0% and 7.7%, respectively. CONCLUSION: Our results suggest that combination of TDI and TSI with intrinsic plausibility control improves intra- and interobserver variability and allows easy and reliable assessment of cardiac asynchrony. PMID- 19781062 TI - Applied public health research -- falling through the cracks? AB - BACKGROUND: There is a degree of dissonance between the types of evaluative research required by organisations providing or commissioning health care, those recommended by organisations developing evidence-based guidance, and those which research funding bodies are prepared to support. METHODS: We present a case study of efforts to establish a pragmatic but robust evaluation of local exercise referral schemes. We considered the epidemiological, ethical and practical advantages and disadvantages of a number of study designs and applied for research funding based on an uncontrolled design, outlining the difficulties of carrying out a randomised controlled trial to evaluate an existing service. RESULTS: Our proposal was praised for its relevance and clear patient outcomes, but the application was twice rejected because both funders and reviewers insisted on a randomised controlled trial design, which we had found to be impractical, unacceptable to service users and potentially unethical. CONCLUSION: The case study highlights continuing challenges for applied public health research in the current funding climate. PMID- 19781061 TI - Comparative genome and phenotypic analysis of Clostridium difficile 027 strains provides insight into the evolution of a hypervirulent bacterium. AB - BACKGROUND: The continued rise of Clostridium difficile infections worldwide has been accompanied by the rapid emergence of a highly virulent clone designated PCR ribotype 027. To understand more about the evolution of this virulent clone, we made a three-way genomic and phenotypic comparison of an 'historic' non-epidemic 027 C. difficile (CD196), a recent epidemic and hypervirulent 027 (R20291) and a previously sequenced PCR-ribotype 012 strain (630). RESULTS: Although the genomes are highly conserved, the 027 genomes have 234 additional genes compared to 630, which may contribute to the distinct phenotypic differences we observe between these strains relating to motility, antibiotic resistance and toxicity. The epidemic 027 strain has five unique genetic regions, absent from both the non epidemic 027 and strain 630, which include a novel phage island, a two component regulatory system and transcriptional regulators. CONCLUSIONS: A comparison of a series of 027 isolates showed that some of these genes appeared to have been gained by 027 strains over the past two decades. This study provides genetic markers for the identification of 027 strains and offers a unique opportunity to explain the recent emergence of a hypervirulent bacterium. PMID- 19781063 TI - Environmental surveillance of Non-Polio Enteroviruses in Iran. AB - BACKGROUND: Enteroviruses can shed in feces for several weeks, so many excrete viruses can remain infectious for a long time in environment. Therefore, by detecting enteroviruses in environmental specimens and sewage, we can understand this virus circulation, the approximate ratio of contaminated persons in society and they are suitable indicators for environmental surveillance. METHODS: Since March 2006 to February 2007, 86 specimens from Sistan & Balouchestan, 63 specimens from Tehran and 48 samples from Fars sewage disposal systems and surface water were collected by Grab Sample method and tested for enteroviruses directly by using two concentration methods: Pellet and Two-phase. Then Non-Polio Enteroviruses (NPEV) were serotyped by microneutralization method. RESULTS: Enteroviruses were isolated from 49(56.98%) of specimens in Sistan & Baluchestan,38(60.32%) in Tehran and 11(22.92%) in Fars. Besides, the majority of Non-Polio Enteroviruses related to Non-typable Enteroviruses (N.T.E.V), E11 (31.52%), COX-B (27.58%), E7 (17.73%) and E4 (21.67%). CONCLUSION: Environmental surveillance has been used successfully in monitoring enteric virus circulation and assessing the extent or duration of epidemic non polioviruses in specific populations. The results of this research show the seasonal circulation of enteroviruses in different parts of Iran. PMID- 19781064 TI - Hepatic wound repair. AB - BACKGROUND: Human chronic liver diseases (CLDs) with different aetiologies rely on chronic activation of wound healing that represents the driving force for fibrogenesis progression (throughout defined patterns of fibrosis) to the end stage of cirrhosis and liver failure. ISSUES: Fibrogenesis progression has a major worldwide clinical impact due to the high number of patients affected by CLDs, increasing mortality rate, incidence of hepatocellular carcinoma and shortage of organ donors for liver transplantation. BASIC SCIENCE ADVANCES: Liver fibrogenesis is sustained by a heterogeneous population of profibrogenic hepatic myofibroblasts (MFs), the majority being positive for alpha smooth muscle actin (alphaSMA), that may originate from hepatic stellate cells and portal fibroblasts following a process of activation or from bone marrow-derived cells recruited to damaged liver and, in a method still disputed, by a process of epithelial to mesenchymal transition (EMT) involving cholangiocytes and hepatocytes. Recent experimental and clinical data have identified, at tissue, cellular and molecular level major profibrogenic mechanisms: (a) chronic activation of the wound-healing reaction, (b) oxidative stress and related reactive intermediates, and (c) derangement of epithelial-mesenchymal interactions. CLINICAL CARE RELEVANCE: Liver fibrosis may regress following specific therapeutic interventions able to downstage or, at least, stabilise fibrosis. In cirrhotic patients, this would lead to a reduction of portal hypertension and of the consequent clinical complications and to an overall improvement of liver function, thus extending the complication-free patient survival time and reducing the need for liver transplantation. CONCLUSION: Emerging mechanisms and concepts related to liver fibrogenesis may significantly contribute to clinical management of patients affected by CLDs. PMID- 19781065 TI - Selective activation of tumor growth-promoting Ca2+ channel MS4A12 in colon cancer by caudal type homeobox transcription factor CDX2. AB - Colon cancer-associated MS4A12 is a novel colon-specific component of store operated Ca2+ (SOC) entry sensitizing cells for epidermal growth factor (EGF) mediated effects on proliferation and chemotaxis. In the present study, we investigated regulation of the MS4A12 promoter to understand the mechanisms responsible for strict transcriptional restriction of this gene to the colonic epithelial cell lineage. DNA-binding assays and luciferase reporter assays showed that MS4A12 promoter activity is governed by a single CDX homeobox transcription factor binding element. RNA interference (RNAi)-mediated silencing of intestine specific transcription factors CDX1 and CDX2 and chromatin immunoprecipitation (ChIP) in LoVo and SW48 colon cancer cells revealed that MS4A12 transcript and protein expression is essentially dependent on the presence of endogenous CDX2. In summary, our findings provide a rationale for colon-specific expression of MS4A12. Moreover, this is the first report establishing CDX2 as transactivator of tumor growth-promoting gene expression in colon cancer, adding to untangle the complex and conflicting biological functions of CDX2 in colon cancer and supporting MS4A12 as important factor for normal colonic development as well as for the biology and treatment of colon cancer. PMID- 19781066 TI - Characterisation of a GII-4 norovirus variant-specific surface-exposed site involved in antibody binding. AB - BACKGROUND: The human noroviruses are a highly diverse group of viruses with a single-stranded RNA genome encoding a single major structural protein (VP1), which has a hypervariable domain (P2 domain) as the most exposed part of the virion. The noroviruses are classified on the basis of nucleotide sequence diversity in the VP1-encoding ORF2 gene, which divides the majority of human noroviruses into two genogroups (GI and GII). GII-4 noroviruses are the major aetiological agent of outbreaks of gastroenteritis around the world. During a winter season the diversity among the GII-4 noroviruses has been shown to fluctuate, driving the appearance of new virus variants in the population. We have previously shown that sequence data and in silico modelling experiments suggest there are two surface-exposed sites (site A and site B) in the hypervariable P2 domain. We predict these sites may form a functional variant specific epitope that evolves under selective pressure from the host immune response and gives rise to antibody escape mutants. RESULTS: In this paper, we describe the construction of recombinant baculoviruses to express VLPs representing one pre-epidemic and one epidemic variant of GII-4 noroviruses, and the production of monoclonal antibodies against them. We use these novel reagents to provide evidence that site A and site B form a conformational, variant specific, surface-exposed site on the GII-4 norovirus capsid that is involved in antibody binding. CONCLUSION: As predicted by our earlier study, significant amino acid changes at site A and site B give rise to GII-4 norovirus epidemic variants that are antibody escape mutants. PMID- 19781068 TI - Changes in health-related quality of life and clinical implications in Chinese patients with chronic cough. AB - BACKGROUND: Chronic cough has negative effects on quality of life. However, the changes in health-related quality of life and clinical implications remain unclear in Chinese patients with chronic cough. METHODS: A standard Chinese version of Leicester cough questionnaire (LCQ) was developed by an established translation procedure and its repeatability was assessed in a preliminary study involving 20 untreated patients with stable chronic cough. The quality of life was measured with the Short form-36 health survey and compared between 110 patients with chronic cough and 90 healthy volunteers. The changes in health related quality of life were evaluated in the patients with chronic cough with the LCQ just before the specific treatment was initiated and a week after the cough had resolved completely. Cough threshold with inhaled capsaicin, expressed as the lowest concentration of capsaicin required for the induction of > or = 5 coughs, was also measured. RESULTS: The repeatability of the Chinese version of the LCQ was validated at a four day interval with the intraclass correlation coefficients of 0.89-0.94 for total and domain score (n = 20). The scores of the Short form-36 health survey were significantly lower in patients with chronic cough than those in healthy volunteers. In general, there was no significant difference in overall quality of life between different causes of chronic cough or genders although embarrassment, frustration and sleep disturbance were more common in female patients, as indicated by the LCQ. However, the successful treatment of cough obviously increased the total scores of the LCQ from 14.2 +/- 2.7 to 19.5 +/- 1.9 (t = 13.7, P < 0.0001). There was a significant correlation between the total score of the LCQ and physical (r = 0.39, P < 0.0001) or mental (r = 0.30, P < 0.001) component summary of the Short form-36 health survey but not between the LCQ and capsaicin cough threshold. CONCLUSION: The quality of life is significantly impaired in Chinese patients with chronic cough. The Chinese version of the LCQ is a valid measure of cough related quality of life and is repeatable and responsive. PMID- 19781067 TI - Preclinical characterization of DEKAVIL (F8-IL10), a novel clinical-stage immunocytokine which inhibits the progression of collagen-induced arthritis. AB - INTRODUCTION: In this article, we present a comparative immunohistochemical evaluation of four clinical-stage antibodies (L19, F16, G11 and F8) directed against splice isoforms of fibronectin and of tenascin-C for their ability to stain synovial tissue alterations in rheumatoid arthritis patients. Furthermore we have evaluated the therapeutic potential of the most promising antibody, F8, fused to the anti-inflammatory cytokine interleukin (IL) 10. METHODS: F8-IL10 was produced and purified to homogeneity in CHO cells and shown to comprise biological active antibody and cytokine moieties by binding assays on recombinant antigen and by MC/9 cell proliferation assays. We have also characterized the ability of F8-IL10 to inhibit arthritis progression in the collagen-induced arthritis mouse model. RESULTS: The human antibody F8, specific to the extra domain A of fibronectin, exhibited the strongest and most homogenous staining pattern in synovial biopsies and was thus selected for the development of a fully human fusion protein with IL10 (F8-IL10, also named DEKAVIL). Following radioiodination, F8-IL10 was able to selectively target arthritic lesions and tumor neo-vascular structures in mice, as evidenced by autoradiographic analysis and quantitative biodistribution studies. The subcutaneous administration route led to equivalent targeting results when compared with intravenous administration and was thus selected for the clinical development of the product. F8-IL10 potently inhibited progression of established arthritis in the collagen-induced mouse model when tested alone and in combination with methotrexate. In preparation for clinical trials in patients with rheumatoid arthritis, F8-IL10 was studied in rodents and in cynomolgus monkeys, revealing an excellent safety profile at doses tenfold higher than the planned starting dose for clinical phase I trials. CONCLUSIONS: Following the encouraging preclinical results presented in this paper, clinical trials with F8-IL10 will now elucidate the therapeutic potential of this product and whether the targeted delivery of IL10 potentiates the anti-arthritic action of the cytokine in rheumatoid arthritis patients. PMID- 19781069 TI - The Tilburg double blind randomised controlled trial comparing inguinal hernia repair according to Lichtenstein and the transinguinal preperitoneal technique. AB - BACKGROUND: Anterior open treatment of the inguinal hernia with a tension free mesh has reduced the incidence of recurrence and direct postoperative pain. The Lichtenstein procedure rules nowadays as reference technique for hernia treatment. Not recurrences but chronic pain is the main postoperative complication in inguinal hernia repair after Lichtenstein's technique. Preliminary experiences with a soft mesh placed in the preperitoneal space showed good results and less chronic pain. METHODS: The TULIP is a double-blind randomised controlled trial in which 300 patients will be randomly allocated to anterior inguinal hernia repair according to Lichtenstein or the transinguinal preperitoneal technique with soft mesh. All unilateral primary inguinal hernia patients eligible for operation who meet inclusion criteria will be invited to participate in this trial. The primary endpoint will be direct postoperative- and chronic pain. Secondary endpoints are operation time, postoperative complications, hospital stay, costs, return to daily activities (e.g. work) and recurrence. Both groups will be evaluated.Success rate of hernia repair and complications will be measured as safeguard for quality.To demonstrate that inguinal hernia repair according to the transinguinal preperitoneal (TIPP) technique reduces postoperative pain to <10%, with alpha = 0,05 and power 80%, a total sample size of 300 patients was calculated. DISCUSSION: The TULIP trial is aimed to show a reduction in postoperative chronic pain after anterior hernia repair according to the transinguinal preperitoneal (TIPP) technique, compared to Lichtenstein.In our hypothesis the TIPP technique reduces chronic pain compared to Lichtenstein. TRIAL REGISTRATION: ISRCTN 93798494. PMID- 19781070 TI - Impact of GnRH analogues on oocyte/embryo quality and embryo development in in vitro fertilization/intracytoplasmic sperm injection cycles: a case control study. AB - BACKGROUND: Despite the clinical outcomes of ovarian stimulation with either GnRH agonist or GnRH-antagonist analogues for in vitro fertilization (IVF) being well analysed, the effect of analogues on oocyte/embryo quality and embryo development is still not known in detail. The aim of this case-control study was to compare the efficacy of a multiple-dose GnRH antagonist protocol with that of the GnRH agonist long protocol with a view to oocyte and embryo quality, embryo development and IVF treatment outcome. METHODS: Between October 2001 and December 2008, 100 patients were stimulated with human menopausal gonadotrophin (HMG) and GnRH antagonist in their first treatment cycle for IVF or intracytoplasmic sperm injection (ICSI). One hundred combined GnRH agonist + HMG (long protocol) cycles were matched to the GnRH antagonist + HMG cycles by age, BMI, baseline FSH levels and by cause of infertility. We determined the number and quality of retrieved oocytes, the rate of early-cleavage embryos, the morphology and development of embryos, as well as clinical pregnancy rates. Statistical analysis was performed using Wilcoxon's matched pairs rank sum test and McNemar's chi-square test. P < 0.05 was considered statistically significant. RESULTS: The rate of cytoplasmic abnormalities in retrieved oocytes was significantly higher with the use of GnRH antagonist than in GnRH agonist cycles (62.1% vs. 49.9%; P < 0.01). We observed lower rate of zygotes showing normal pronuclear morphology (49.3% vs. 58.0%; P < 0.01), and higher cell-number of preembryos on day 2 after fertilization (4.28 vs. 4.03; P < 0.01) with the use of GnRH antagonist analogues. The rate of mature oocytes, rate of presence of multinucleated blastomers, amount of fragmentation in embryos and rate of early-cleaved embryos was similar in the two groups. Clinical pregnancy rate per embryo transfer was lower in the antagonist group than in the agonist group (30.8% vs. 40.4%) although this difference did not reach statistical significance (P = 0.17). CONCLUSION: Antagonist seemed to influence favourably some parameters of early embryo development dynamics, while other morphological parameters seemed not to be altered according to GnRH analogue used for ovarian stimulation in IVF cycles. PMID- 19781071 TI - Endosperm and whole grain rye breads are characterized by low post-prandial insulin response and a beneficial blood glucose profile. AB - BACKGROUND: Rye products have previously been shown to induce comparatively low post-prandial insulin responses; irrespectively of their glycaemic indices (GI). However, the mechanism behind this lowered insulin demand remains unknown. An improved insulin economy might contribute to the benefits seen in epidemiological studies with whole grain diets on metabolic risk factors and weight regulation. The objective of this study was to explore the mechanism for a reduced post prandial insulin demand with rye products. METHODS: 12 healthy subjects were given flour based rye products made from endosperm, whole grain or bran, produced with different methods (baking, simulated sour-dough baking and boiling) as breakfasts in random order in a cross-over design. White wheat bread (WWB) was used as a reference. Blood glucose, serum insulin, plasma ghrelin and subjective satiety were measured during 180 minutes. To evaluate the course of post-meal glycaemia, a measure of the glycaemic profile (GP) was introduced defined as the duration for the incremental post-prandial blood glucose response divided with the blood glucose incremental peak (min/mM). RESULTS: The study shows that whole grain rye breads and endosperm rye products induced significantly (p < 0.05) lower insulinaemic indices (II's) than WWB. Rye bran bread (RBB) produced significantly higher II compared with all the other rye products. Furthermore, the acute insulin response showed better correlations with the GP than with the GI of the products. The endosperm rye bread and the whole grain rye bread with lactic acid induced a significantly higher GP than RBB, WWB, white wheat- and whole grain rye porridge, respectively. A low insulin incremental peak was associated with less severe late post-prandial hypoglycaemia (r = 0.38, p < 0.001), and hypoglycaemia was negatively correlated to subjective satiety at 180 min (r = -0.28, p < 0.05). A low insulin incremental peak was also associated with a milder recovery of plasma ghrelin in the late post-prandial phase (180 min, r = 0.34, p < 0.01). CONCLUSION: Our study shows that endosperm and whole grain rye products induce low acute insulinaemic responses and improved glycaemic profiles. The results also suggest that the rye products possess beneficial appetite regulating properties. Further studies are needed to identify the unknown property or bioactive component(s) responsible for these beneficial metabolic features of rye. PMID- 19781072 TI - Systemic T-helper and T-regulatory cell type cytokine responses in rhinovirus vs. respiratory syncytial virus induced early wheezing: an observational study. AB - BACKGROUND: Rhinovirus (RV) associated early wheezing has been recognized as an independent risk factor for asthma. The risk is more important than that associated with respiratory syncytial virus (RSV) disease. No comparative data are available on the immune responses of these diseases. OBJECTIVE: To compare T helper1 (Th1), Th2 and T-regulatory (Treg) cell type cytokine responses between RV and RSV induced early wheezing. METHODS: Systemic Th1-type (interferon [IFN] gamma, interleukin [IL] -2, IL-12), Th2-type (IL-4, IL-5, IL-13) and Treg-type (IL-10) cytokine responses were studied from acute and convalescence phase serum samples of sole RV (n = 23) and RSV affected hospitalized wheezing children (n = 27). The pre-defined inclusion criteria were age of 3-35 months and first or second wheezing episode. Analysis was adjusted for baseline differences. Asymptomatic children with comparable demographics (n = 11) served as controls for RV-group. RESULTS: RV-group was older and had more atopic characteristics than RSV-group. At acute phase, RV-group had higher (fold change) IL-13 (39 fold), IL-12 (7.5-fold), IFN-gamma (6.0-fold) and IL-5 (2.8-fold) concentrations than RSV-group and higher IFN-gamma (27-fold), IL-2 (8.9-fold), IL-5 (5.6-fold) and IL-10 (2.6-fold) than the controls. 2-3 weeks later, RV-group had higher IFN gamma (>100-fold), IL-13 (33-fold) and IL-10 (6.5-fold) concentrations than RSV group and higher IFN-gamma (15-fold) and IL-2 (9.4-fold) than the controls. IL-10 levels were higher in acute phase compared to convalescence phase in both infections (p < 0.05 for all). CONCLUSION: Our results support a hypothesis that RV is likely to trigger wheezing mainly in children with a predisposition. IL-10 may have important regulatory function in acute viral wheeze. PMID- 19781073 TI - Can we prevent drug related deaths by training opioid users to recognise and manage overdoses? AB - BACKGROUND: Naloxone has been evidenced widely as a means of reducing mortality resulting from opiate overdose, yet its distribution to drug users remains limited. However, it is drug users who are most likely to be available to administer naloxone at the scene and who have been shown to be willing and motivated to deliver this intervention. The current study builds on a national training evaluation in England by assessing 6-month outcome data collected primarily in one of the participating centres. METHODS: Seventy patients with opioid dependence syndrome were trained in the recognition and management of overdoses in Birmingham (n = 66) and London (n = 4), and followed up six months after receiving naloxone. After successful completion of the training, participants received a supply of 400 micrograms of naloxone (in the form of a preloaded syringe) to take home. The study focused on whether participating users still had their naloxone, whether they retained the information, whether they had witnessed an overdose and whether they had naloxone available and were still willing to use it in the event of overdose. RESULTS & DISCUSSION: The results were mixed - although the majority of drug users had retained the naloxone prescribed to them, and retention of knowledge was very strong in relation to overdose recognition and intervention, most participants did not carry the naloxone with them consistently and consequently it was generally not available if they witnessed an overdose. The paper discusses the reasons for the reluctance to carry naloxone and potential opportunities for how this might be overcome. Future issues around training and support around peer dissemination are also addressed. CONCLUSION: Our findings confirm that training of drug users constitutes a valuable resource in the management of opiate overdoses and growth of peer interventions that may not otherwise be recognised or addressed. Obstacles have been identified at individual (transportability, stigma) and at a systems level (police involvement, prescription laws). Training individuals does not seem to be sufficient for these programmes to succeed and a coherent implementation model is necessary. PMID- 19781074 TI - Complications associated with transobturator sling procedures: analysis of 233 consecutive cases with a 27 months follow-up. AB - BACKGROUND: The transobturator tape procedure (TOT) is an effective surgical treatment of female stress urinary incontinence. However data concerning safety are rare, follow-up is often less than two years, and complications are probably underreported. The aim of this study was to describe early and late complications associated with TOT procedures and identify risk factors for erosions. METHODS: It was a 27 months follow-up of a cohort of 233 women who underwent TOT with three different types of slings (Aris, Obtape, TVT-O). Follow-up information was available for 225 (96.6%) women. RESULTS: There were few per operative complications. Forty-eight women (21.3%) reported late complications including de novo or worsening of preexisting urgencies (10.2%), perineal pain (2.2%), de novo dyspareunia (9%), and vaginal erosion (7.6%). The risk of erosion significantly differed between the three types of slings and was 4%, 17% and 0% for Aris, Obtape and TVT-O respectively (P = 0.001). The overall proportion of women satisfied by the procedure was 72.1%. The percentage of women satisfied was significantly lower in women who experienced erosion (29.4%) compared to women who did not (78.4%) (RR 0.14, 95% CI 0.05-0.38, P < 0.001). CONCLUSION: Late post operative complications are relatively frequent after TOT and can impair patient's satisfaction. Women should be informed of these potential complications preoperatively and require careful follow-up after the procedure. Choice of the safest sling material is crucial as it is a risk factor for erosion. PMID- 19781075 TI - Improving outpatient safety through effective electronic communication: a study protocol. AB - BACKGROUND: Health information technology and electronic medical records (EMRs) are potentially powerful systems-based interventions to facilitate diagnosis and treatment because they ensure the delivery of key new findings and other health related information to the practitioner. However, effective communication involves more than just information transfer; despite a state of the art EMR system, communication breakdowns can still occur. [1-3] In this project, we will adapt a model developed by the Systems Engineering Initiative for Patient Safety (SEIPS) to understand and improve the relationship between work systems and processes of care involved with electronic communication in EMRs. We plan to study three communication activities in the Veterans Health Administration's (VA) EMR: electronic communication of abnormal imaging and laboratory test results via automated notifications (i.e., alerts); electronic referral requests; and provider-to-pharmacy communication via computerized provider order entry (CPOE). AIM: Our specific aim is to propose a protocol to evaluate the systems and processes affecting outcomes of electronic communication in the computerized patient record system (related to diagnostic test results, electronic referral requests, and CPOE prescriptions) using a human factors engineering approach, and hence guide the development of interventions for work system redesign. DESIGN: This research will consist of multiple qualitative methods of task analysis to identify potential sources of error related to diagnostic test result alerts, electronic referral requests, and CPOE; this will be followed by a series of focus groups to identify barriers, facilitators, and suggestions for improving the electronic communication system. Transcripts from all task analyses and focus groups will be analyzed using methods adapted from grounded theory and content analysis. PMID- 19781076 TI - Arterial tortuosity syndrome in two Italian paediatric patients. AB - BACKGROUND: Arterial tortuosity syndrome (ATS) (OMIM #208050) is a rare autosomal recessive connective tissue disorder characterized by tortuosity and elongation of the large and medium-sized arteries, propensity to aneurysms formation, vascular dissection, and pulmonary arteries stenosis. ATS is caused by mutations in SLC2A10 gene, encoding for the facilitative glucose transporter 10 (GLUT10). So far, 17 SLC2A10 mutations have been reported in 32 families, two of which were Italian with a total of five patients. Here we present the clinical and molecular characterization of two novel Italian paediatric ATS patients. METHODS: The exons and intronic flanking regions of SLC2A10 gene were amplified and direct sequencing was performed. RESULTS: In both patients, the involvement of major- and medium-sized arteries was characteristic; the nonvascular connective tissue manifestations were mild and not pathognomic of the disorder. Both patients, born from non-consanguineous parents, were heterozygous for two different SLC2A10 mutations, three of which were recurrent and one was novel (p.Arg231Trp). This mutation is localized at the endofacial loop between the transmembrane domains 6 and 7 of GLUT10. CONCLUSION: Two novel ATS patients were characterized at clinical and molecular level. Overall, four ATS unrelated families are known in Italy so far. Though ATS clinical delineation improved in the last years, further works in the comprehension of disease presentation and complications onset, particularly in paediatric age, and on ATS molecular basis are needed to add new insights for diagnosis and prevention strategies for related complications. PMID- 19781077 TI - Frontotemporal dementia and amyotrophic lateral sclerosis-associated disease protein TDP-43 promotes dendritic branching. AB - BACKGROUND: TDP-43 is an evolutionarily conserved RNA-binding protein implicated in the pathogenesis of frontotemporal dementia (FTD), sporadic and familial amyotrophic lateral sclerosis (ALS), and possibly other neurodegenerative diseases. In diseased neurons, TDP-43 is depleted in the nucleus, suggesting a loss-of-function pathogenic mechanism. However, the normal function of TDP-43 in postmitotic neurons is largely unknown. RESULTS: Here we demonstrate that overexpression of Drosophila TDP-43 (dTDP-43) in vivo significantly increases dendritic branching of sensory neurons in Drosophila larvae. Loss of dTDP-43 function, either in a genetic null mutant or through RNAi knockdown, decreased dendritic branching. Further genetic analysis demonstrated a cell-autonomous role for dTDP-43 in dendrite formation. Moreover, human TDP-43 (hTDP-43) promoted dendritic branching in Drosophila neurons, and this function was attenuated by mutations associated with ALS. CONCLUSION: These findings reveal an essential role for TDP-43 in dendritic structural integrity, supporting the notion that loss of normal TDP-43 function in diseased neurons may compromise neuronal connectivity before neuronal cell loss in FTD and ALS. PMID- 19781078 TI - Evaluating the forced oscillation technique in the detection of early smoking induced respiratory changes. AB - BACKGROUND: Early detection of the effects of smoking is of the utmost importance in the prevention of chronic obstructive pulmonary disease (COPD). The forced oscillation technique (FOT) is easy to perform since it requires only tidal breathing and offers a detailed approach to investigate the mechanical properties of the respiratory system. The FOT was recently suggested as an attractive alternative for diagnosing initial obstruction in COPD, which may be helpful in detecting COPD in its initial phases. Thus, the purpose of this study was twofold: (1) to evaluate the ability of FOT to detect early smoking-induced respiratory alterations; and (2) to compare the sensitivity of FOT with spirometry in a sample of low tobacco-dose subjects. METHODS: Results from a group of 28 smokers with a tobacco consumption of 11.2 +/- 7.3 pack-years were compared with a control group formed by 28 healthy subjects using receiver operating characteristic (ROC) curves and a questionnaire as a gold standard. The early adverse effects of smoking were adequately detected by the absolute value of the respiratory impedance (Z4Hz), the intercept resistance (R0), and the respiratory system dynamic compliance (Crs, dyn). Z4Hz was the most accurate parameter (Se = 75%, Sp = 75%), followed by R0 and Crs, dyn. The performances of the FOT parameters in the detection of the early effects of smoking were higher than that of spirometry (p < 0.05). CONCLUSION: This study shows that FOT can be used to detect early smoking-induced respiratory changes while these pathologic changes are still potentially reversible. These findings support the use of FOT as a versatile clinical diagnostic tool in aiding COPD prevention and treatment. PMID- 19781079 TI - Actomyosin contractility controls cell surface area of oligodendrocytes. AB - BACKGROUND: To form myelin oligodendrocytes expand and wrap their plasma membrane multiple times around an axon. How is this expansion controlled? RESULTS: Here we show that cell surface area depends on actomyosin contractility and is regulated by physical properties of the supporting matrix. Moreover, we find that chondroitin sulfate proteoglycans (CSPG), molecules associated with non permissive growth properties within the central nervous system (CNS), block cell surface spreading. Most importantly, the inhibitory effects of CSPG on plasma membrane extension were completely prevented by treatment with inhibitors of actomyosin contractility and by RNAi mediated knockdown of myosin II. In addition, we found that reductions of plasma membrane area were accompanied by changes in the rate of fluid-phase endocytosis. CONCLUSION: In summary, our results establish a novel connection between endocytosis, cell surface extension and actomyosin contractility. These findings open up new possibilities of how to promote the morphological differentiation of oligodendrocytes in a non-permissive growth environment. See related minireview by Bauer and ffrench-Constant: http://www.jbiol.com/content/8/8/78. PMID- 19781080 TI - Identification of a bacteriocin and its cognate immunity factor expressed by Moraxella catarrhalis. AB - BACKGROUND: Bacteriocins are antimicrobial proteins and peptides ribosomally synthesized by some bacteria which can effect both intraspecies and interspecies killing. RESULTS: Moraxella catarrhalis strain E22 containing plasmid pLQ510 was shown to inhibit the growth of M. catarrhalis strain O35E. Two genes (mcbA and mcbB) in pLQ510 encoded proteins predicted to be involved in the secretion of a bacteriocin. Immediately downstream from these two genes, a very short ORF (mcbC) encoded a protein which had some homology to double-glycine bacteriocins produced by other bacteria. A second very short ORF (mcbI) immediately downstream from mcbC encoded a protein which had no significant similarity to other proteins in the databases. Cloning and expression of the mcbI gene in M. catarrhalis O35E indicated that this gene encoded the cognate immunity factor. Reverse transcriptase-PCR was used to show that the mcbA, mcbB, mcbC, and mcbI ORFs were transcriptionally linked. This four-gene cluster was subsequently shown to be present in the chromosome of several M. catarrhalis strains including O12E. Inactivation of the mcbA, mcbB, or mcbC ORFs in M. catarrhalis O12E eliminated the ability of this strain to inhibit the growth of M. catarrhalis O35E. In co culture experiments involving a M. catarrhalis strain containing the mcbABCI locus and one which lacked this locus, the former strain became the predominant member of the culture after overnight growth in broth. CONCLUSION: This is the first description of a bacteriocin and its cognate immunity factor produced by M. catarrhalis. The killing activity of the McbC protein raises the possibility that it might serve to lyse other M. catarrhalis strains that lack the mcbABCI locus, thereby making their DNA available for lateral gene transfer. PMID- 19781082 TI - Social tagging in the life sciences: characterizing a new metadata resource for bioinformatics. AB - BACKGROUND: Academic social tagging systems, such as Connotea and CiteULike, provide researchers with a means to organize personal collections of online references with keywords (tags) and to share these collections with others. One of the side-effects of the operation of these systems is the generation of large, publicly accessible metadata repositories describing the resources in the collections. In light of the well-known expansion of information in the life sciences and the need for metadata to enhance its value, these repositories present a potentially valuable new resource for application developers. Here we characterize the current contents of two scientifically relevant metadata repositories created through social tagging. This investigation helps to establish how such socially constructed metadata might be used as it stands currently and to suggest ways that new social tagging systems might be designed that would yield better aggregate products. RESULTS: We assessed the metadata that users of CiteULike and Connotea associated with citations in PubMed with the following metrics: coverage of the document space, density of metadata (tags) per document, rates of inter-annotator agreement, and rates of agreement with MeSH indexing. CiteULike and Connotea were very similar on all of the measurements. In comparison to PubMed, document coverage and per-document metadata density were much lower for the social tagging systems. Inter-annotator agreement within the social tagging systems and the agreement between the aggregated social tagging metadata and MeSH indexing was low though the latter could be increased through voting. CONCLUSION: The most promising uses of metadata from current academic social tagging repositories will be those that find ways to utilize the novel relationships between users, tags, and documents exposed through these systems. For more traditional kinds of indexing-based applications (such as keyword-based search) to benefit substantially from socially generated metadata in the life sciences, more documents need to be tagged and more tags are needed for each document. These issues may be addressed both by finding ways to attract more users to current systems and by creating new user interfaces that encourage more collectively useful individual tagging behaviour. PMID- 19781081 TI - Gene promoter methylation assayed in exhaled breath, with differences in smokers and lung cancer patients. AB - BACKGROUND: There is a need for new, noninvasive risk assessment tools for use in lung cancer population screening and prevention programs. METHODS: To investigate the technical feasibility of determining DNA methylation in exhaled breath condensate, we applied our previously-developed method for tag-adapted bisulfite genomic DNA sequencing (tBGS) for mapping of DNA methylation, and adapted it to exhaled breath condensate (EBC) from lung cancer cases and non-cancer controls. Promoter methylation patterns were analyzed in DAPK, RASSF1A and PAX5beta promoters in EBC samples from 54 individuals, comprised of 37 controls [current- (n = 19), former- (n = 10), and never-smokers (n = 8)] and 17 lung cancer cases [current- (n = 5), former- (n = 11), and never-smokers (n = 1)]. RESULTS: We found: (1) Wide inter-individual variability in methylation density and spatial distribution for DAPK, PAX5beta and RASSF1A. (2) Methylation patterns from paired exhaled breath condensate and mouth rinse specimens were completely divergent. (3) For smoking status, the methylation density of RASSF1A was statistically different (p = 0.0285); pair-wise comparisons showed that the former smokers had higher methylation density versus never smokers and current smokers (p = 0.019 and p = 0.031). For DAPK and PAX5beta, there was no such significant smoking related difference. Underlying lung disease did not impact on methylation density for this geneset. (4) In case-control comparisons, CpG at -63 of DAPK promoter and +52 of PAX5beta promoter were significantly associated with lung cancer status (p = 0.0042 and 0.0093, respectively). After adjusting for multiple testing, both loci were of borderline significance (p(adj) = 0.054 and 0.031). (5) The DAPK gene had a regional methylation pattern with two blocks (1) approximately -215--113 and (2) -84-+26; while similar in block 1, there was a significant case-control difference in methylation density in block 2 (p = 0.045); (6)Tumor stage and histology did not impact on the methylation density among the cases. (7) The results of qMSP applied to EBC correlated with the corresponding tBGS sequencing map loci. CONCLUSION: Our results show that DNA methylation in exhaled breath condensate is detectable and is likely of lung origin. Suggestive correlations with smoking and lung cancer case-control status depend on individual gene and CpG site examined. PMID- 19781083 TI - Collagenofibrotic glomerulopathy: three case reports in Brazil. AB - BACKGROUND: We are reporting the first collagenofibrotic glomerulopathy (CG) in South America. So, this collagen type III glomerulopathy is not limited to Japan but may be found throughout the world. CASE REPORTS: We describe three patients that presented some factors in common, such as sex, age and the presence of non nephrotic proteinuria associated with microscopic hematuria. The findings with the immunofluorescence microscopy, of immunoglobulins, and components of the complement were usually negative. The picrosyrius staining showed the presence of reddish material in the mesangium, when it was seen under standard microscopy; however, when it was seen with birefringence, it became greenish under polarized light, showed the collagen found in this area of the glomerulus. The identification of CG was made through electronic microscopic scanning, and curved and disorganized fibers were found. CONCLUSION: These cases are the first from South America to be reported, and they are about an idiopathic renal disease that is not related to any specific races or locations. The reports contribute to a better understanding of this disease, which although not so prevalent, should be considered as an importantly differential diagnostic of cases of proteinuria. PMID- 19781085 TI - Colorectal cancer screening, perceived discrimination, and low-income and trust in doctors: a survey of minority patients. AB - BACKGROUND: Completion of colorectal cancer (CRC) screening testing is lower among low-income and minority groups than the population as a whole. Given the multiple cancer screening health disparities known to exist within the U.S., this study investigated the relationship between perceived discrimination, trust in most doctors, and completion of Fecal Occult Blood Testing (FOBT) among a low income, minority primary care population in an urban setting. METHODS: We recruited a convenience sample of adults over age 40 (n = 282) from a federally qualified community health center (70% African American). Participants completed a survey which included measures of trust in most doctors, perceived discrimination, demographics and report of cancer screening. RESULTS: Participants reported high levels of trust in most doctors, regardless of sex, race, education or income. High trust was associated with low perceived discrimination (p < 0.01). The trend was for older participants to express more trust (p = 0.09) and less perceived discrimination (p < 0.01). Neither trust nor discrimination was associated with race or education. Trust was higher among participants over 50 who were up-to-date on FOBT screening vs. those who were not (31 vs. 29 (median), p < 0.05 by T-test). Among those over 50, up-to-date FOBT screening was nearly associated with high trust (p < 0.06; 95% CI 0.99, 1.28) and low perceived discrimination (p < 0.01; 95% CI 0.76, 0.96). Nevertheless, in multivariate-modeling, age and income explained FOBT completion better than race, trust and discrimination. CONCLUSION: Perceived discrimination was related to income, but not race, suggesting that discrimination is not unique to minorities, but common to those in poverty. Since trust in most doctors trended toward being related to age, FOBT screening could be negatively influenced by low trust and perceived discrimination in health care settings. A failure to address these issues in middle-aged, low income individuals could exacerbate future disparities in CRC screening. PMID- 19781084 TI - An EST screen from the annelid Pomatoceros lamarckii reveals patterns of gene loss and gain in animals. AB - BACKGROUND: Since the drastic reorganisation of the phylogeny of the animal kingdom into three major clades of bilaterians; Ecdysozoa, Lophotrochozoa and Deuterostomia, it became glaringly obvious that the selection of model systems with extensive molecular resources was heavily biased towards only two of these three clades, namely the Ecdysozoa and Deuterostomia. Increasing efforts have been put towards redressing this imbalance in recent years, and one of the principal phyla in the vanguard of this endeavour is the Annelida. RESULTS: In the context of this effort we here report our characterisation of an Expressed Sequence Tag (EST) screen in the serpulid annelid, Pomatoceros lamarckii. We have sequenced over 5,000 ESTs which consolidate into over 2,000 sequences (clusters and singletons). These sequences are used to build phylogenetic trees to estimate relative branch lengths amongst different taxa and, by comparison to genomic data from other animals, patterns of gene retention and loss are deduced. CONCLUSION: The molecular phylogenetic trees including the P. lamarckii sequences extend early observations that polychaetes tend to have relatively short branches in such trees, and hence are useful taxa with which to reconstruct gene family evolution. Also, with the availability of lophotrochozoan data such as that of P. lamarckii, it is now possible to make much more accurate reconstructions of the gene complement of the ancestor of the bilaterians than was previously possible from comparisons of ecdysozoan and deuterostome genomes to non-bilaterian outgroups. It is clear that the traditional molecular model systems for protostomes (e.g. Drosophila melanogaster and Caenorhabditis elegans), which are restricted to the Ecdysozoa, have undergone extensive gene loss during evolution. These ecdysozoan systems, in terms of gene content, are thus more derived from the bilaterian ancestral condition than lophotrochozoan systems like the polychaetes, and thus cannot be used as good, general representatives of protostome genomes. Currently sequenced insect and nematode genomes are less suitable models for deducing bilaterian ancestral states than lophotrochozoan genomes, despite the array of powerful genetic and mechanistic manipulation techniques in these ecdysozoans. A distinct category of genes that includes those present in non-bilaterians and lophotrochozoans, but which are absent from ecdysozoans and deuterostomes, highlights the need for further lophotrochozoan data to gain a more complete understanding of the gene complement of the bilaterian ancestor. PMID- 19781086 TI - Visualization of ribosomal RNA operon copy number distribution. AB - BACKGROUND: Results of microbial ecology studies using 16S rRNA sequence information can be deceiving due to differences in rRNA operon copy number and genome size of the detected organisms. It therefore will be useful for investigators to have a better understanding of how these two parameters differ in various organism types. In this study, the number of ribosomal operons and genome size were separately mapped onto a Bacterial phylogenetic tree. RESULTS: A representative Bacterial tree was constructed using 31 marker genes found in 578 bacterial genome sequences. Organism names are displayed on the trees using graduations of color such that similar colors indicate similar numbers of operons or genome size. The resulting images provide an intuitive understanding of how copy number and genome size vary in different Bacterial phyla. CONCLUSION: Once the phylogenetic position of a novel organism is known the number of rRNA operons, and to a lesser extent the genome size, can be estimated by examination of the colored maps. Further detail can then be obtained for members of relevant taxa from the rrnDB database. PMID- 19781087 TI - Meteorologically estimated exposure but not distance predicts asthma symptoms in schoolchildren in the environs of a petrochemical refinery: a cross-sectional study. AB - BACKGROUND: Community concern about asthma prompted an epidemiological study of children living near a petrochemical refinery in Cape Town, South Africa. Because of resource constraints and the complexity of refinery emissions, neither direct environmental measurements nor modelling of airborne pollutants was possible. Instead a meteorologically derived exposure metric was calculated with the refinery as the putative point source. The study aimed to determine whether (1) asthma symptom prevalences were elevated compared to comparable areas in Cape Town and (2) whether there was an association between asthma symptom prevalences and the derived exposure metric. METHODS: A cross-sectional study was carried out of all consenting school children aged 11 to 14 years attending schools in a defined area, utilizing the International Study of Asthma and Allergy in Childhood (ISAAC) written and video questionnaires. Information was collected on potential confounders, e.g. parental history of atopic disease, active and passive smoking by the participant, birth order, number of children in the home and distance from a major road. The exposure metric combined residential distance of each child from the refinery with a wind vector in the form of wind speed, wind direction and proportion of the year blown. RESULTS: A total of 2,361 children from 17 schools met the criteria for inclusion. In multivariate analysis, meteorologically estimated exposure (MEE), but not simple distance from the refinery, was positively associated with having to take an inhaler to school [odds ratio per interquartile range (OR) 1.22, 95% confidence interval (CI) 1.06 1.40], and with a number of video elicited asthma symptoms, including recent waking with wheezing (OR 1.33, 95% CI 1.06-1.66) and frequent wheezing at rest (OR 1.27, 95% CI 1.05 - 1.54). Symptom prevalences were higher than in other areas of the city, with frequent waking with wheezing being in great excess (OR 8.92, 95% CI 4.79-16.63). CONCLUSION: The results support the hypothesis of an increased prevalence of asthma symptoms among children in the area as a result of refinery emissions and provide a substantive basis for community concern. The methodology also provides a low cost means of testing hypotheses about point source pollutant effects on surrounding populations of children. PMID- 19781088 TI - Association of common variants in mismatch repair genes and breast cancer susceptibility: a multigene study. AB - BACKGROUND: MMR is responsible for the repair of base-base mismatches and insertion/deletion loops. Besides this, MMR is also associated with an anti recombination function, suppressing homologous recombination. Losses of heterozygosity and/or microsatellite instability have been detected in a large number of skin samples from breast cancer patients, suggesting a potential role of MMR in breast cancer susceptibility. METHODS: We carried out a hospital-based case-control study in a Caucasian Portuguese population (287 cases and 547 controls) to estimate the susceptibility to non-familial breast cancer associated with some polymorphisms in mismatch repair genes (MSH3, MSH4, MSH6, MLH1, MLH3, PMS1 and MUTYH). RESULTS: Using unconditional logistic regression we found that MLH3 (L844P, G>A) polymorphism GA (Leu/Pro) and AA (Pro/Pro) genotypes were associated with a decreased risk: OR = 0.65 (0.45-0.95) (p = 0.03) and OR = 0.62 (0.41-0.94) (p = 0.03), respectively.Analysis of two-way SNP interaction effects on breast cancer revealed two potential associations to breast cancer susceptibility: MSH3 Ala1045Thr/MSH6 Gly39Glu - AA/TC [OR = 0.43 (0.21-0.83), p = 0.01] associated with a decreased risk; and MSH4 Ala97Thr/MLH3 Leu844Pro - AG/AA [OR = 2.35 (1.23-4.49), p = 0.01], GG/AA [OR = 2.11 (1.12-3,98), p = 0.02], and GG/AG [adjusted OR = 1.88 (1.12-3.15), p = 0.02] all associated with an increased risk for breast cancer. CONCLUSION: It is possible that some of these common variants in MMR genes contribute significantly to breast cancer susceptibility. However, further studies with a large sample size will be needed to support our results. PMID- 19781089 TI - Prevalence of the metabolic syndrome in Latin America and its association with sub-clinical carotid atherosclerosis: the CARMELA cross sectional study. AB - BACKGROUND: Metabolic syndrome increases cardiovascular risk. Limited information on its prevalence in Latin America is available. The Cardiovascular Risk Factor Multiple Evaluation in Latin America (CARMELA) study included assessment of metabolic syndrome in 7 urban Latin American populations. METHODS: CARMELA was a cross-sectional, population-based, observational study conducted in Barquisimeto, Venezuela; Bogota, Colombia; Buenos Aires, Argentina; Lima, Peru; Mexico City, Mexico; Quito, Ecuador; and Santiago, Chile. The prevalence of metabolic syndrome, defined according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III), and associated carotid atherosclerosis were investigated in 11,502 participants aged 25 to 64 years. RESULTS: Across CARMELA cities, metabolic syndrome was most prevalent in Mexico City (27%) and Barquisimeto (26%), followed by Santiago (21%), Bogota (20%), Lima (18%), Buenos Aires (17%), and Quito (14%). In nondiabetic participants, prevalence was slightly lower but followed a comparable ranking. Overall, 59%, 59%, and 73% of women with high triglycerides, hypertension, or glucose abnormalities, respectively, and 64%, 48% and 71% of men with abdominal obesity, hypertension, or glucose abnormalities, respectively, had the full metabolic syndrome. Prevalence of metabolic syndrome increased with age, markedly so in women. Mean common carotid artery intima-media thickness (CCAIMT) and prevalence of carotid plaque increased steeply with increasing numbers of metabolic syndrome components; mean CCAIMT was higher and plaque more prevalent in participants with metabolic syndrome than without. CONCLUSION: The prevalence of metabolic syndrome and its components by NCEP ATP III criteria was substantial across cities, ranging from 14% to 27%. CARMELA findings, including evidence of the association of metabolic syndrome and carotid atherosclerosis, should inform appropriate clinical and public health interventions. PMID- 19781090 TI - Homocysteine-induced macrophage inflammatory protein-2 production by glomerular mesangial cells is mediated by PI3 Kinase and p38 MAPK. AB - BACKGROUND: Homocysteine (Hcy) and inflammatory cytokines have been linked to adverse outcomes in persons with cardiovascular and kidney diseases and recent reports suggest that cytokine-mediated inflammatory infiltrates may be an important contributor to the pathogenesis the aforementioned diseases. Although some reports suggest that Hcy directly influences inflammatory cytokine production, this proposition has not been supported by data from other studies. The objective of the current study was to a) utilize an in vitro cellular model to identify cytokines that may be affected by Hcy and b) examine the role of mitogen activated protein kinase (MAPK) and phosphatidyl inositol 3- (PI3) Kinase in Hcy modulated cytokine production. METHODS: Primary rat glomerular mesangial cells (MC, passage 8 to 15), isolated by standard sieving methodology, were exposed to Hcy (15, 50 or 100 muM) with L-cysteine (L-Cys; 100 muM) serving as a control. An antibody array was used to identify cytokines that were modulated when MCs were exposed to Hcy. Gene expression was assessed by quantitative RT PCR, while western blotting analysis was used to assess cellular protein levels in the presence and absence of inhibitors of MAPK and PI3 Kinase. Finally, leukocyte adhesion assay was used to examine the effect of Hcy on leukocyte adhesion to glomerular MCs that were maintained in media without, and with, kinase inhibitors. RESULTS: We identified macrophage inflammatory protein 2 (MIP 2) as a key cytokine that manifested increases in both protein and mRNA following exposure of glomerular MC to pathophysiologic Hcy levels (50 muM). Further analyses revealed that Hcy-induced MIP-2 was dependent on activation of p38 MAPK and PI3 kinase. MIP-2 enhanced leukocyte adhesion to MC and this MIP-2-enhanced leukocyte adhesion was also dependent on activation of p38 MAPK and PI3K. Finally, we demonstrate that leukocyte adhesion to MC is specifically inhibited by anit-MIP2 antibody. CONCLUSION: The data suggest that Hcy participates in inflammatory cytokines production by glomerular MC and that Hcy-induced MIP-2 mediates leukocyte adhesion to MC. PMID- 19781092 TI - Short-term effects of air pollution: a panel study of blood markers in patients with chronic pulmonary disease. AB - BACKGROUND: Growing evidence indicates that ambient air pollution is associated with exacerbation of chronic diseases like chronic pulmonary disease. A prospective panel study was conducted to investigate short-term changes of blood markers of inflammation and coagulation in response to daily changes in air pollution in Erfurt, Germany. 12 clinical visits were scheduled and blood parameters were measured in 38 male patients with chronic pulmonary disease during winter 2001/2002. Additive mixed models with random patient intercept were applied, adjusting for trend, weekday, and meteorological parameters. Hourly data on ultrafine particles (UFP, 0.01-0.1 mum), accumulation mode particles (ACP, 0.1 1.0 mum), PM10 (particulate matter <10 mum in diameter), elemental (EC) and organic carbon (OC), gaseous pollutants (nitrogen monoxide [NO], nitrogen dioxide [NO2], carbon monoxide [CO], and sulphur dioxide [SO2]) were collected at a central monitoring site and meteorological data were received from an official network. For each person and visit the individual 24-hour average of pollutants immediately preceding the blood withdrawal (lag 0) up to day 5 (lag1-4) and 5-day running means were calculated. RESULTS: Increased levels of fibrinogen were observed for an increase in one interquartile range of UFP, PM10, EC, OC, CO, and NO revealing the strongest effect for lag 3. E-selectin increased in association with ACP and PM10 with a delay of one day. The ACP effect was also seen with the 5-day-mean. The pattern found for D-dimer was inconsistent. Prothrombin fragment 1+2 decreased with lag 4 consistently for all particulate pollutants. Von Willebrand factor antigen (vWF) showed a consistent decrease in association with almost all air pollutants with all lags except for lag 0. No associations were found for C-reactive protein, soluble intercellular adhesion molecule 1, serum amyloid A and factor VII. CONCLUSION: These results suggest that elevated concentrations of air pollution are associated with changes in some blood markers of inflammation and coagulation in patients with chronic pulmonary disease. The clinical implications of these findings need further investigation. PMID- 19781091 TI - Di-(2 ethylhexyl) phthalate and flutamide alter gene expression in the testis of immature male rats. AB - We previously demonstrated that the androgenic and anti-androgenic effects of endocrine disruptors (EDs) alter reproductive function and exert distinct effects on developing male reproductive organs. To further investigate these effects, we used an immature rat model to examine the effects of di-(2 ethylhexyl) phthalate (DEHP) and flutamide (Flu) on the male reproductive system. Immature male SD rats were treated daily with DEHP and Flu on postnatal days (PNDs) 21 to 35, in a dose dependent manner. As results, the weights of the testes, prostate, and seminal vesicle and anogenital distances (AGD) decreased significantly in response to high doses of DEHP or Flu. Testosterone (T) levels significantly decreased in all DEHP- treated groups, whereas luteinizing hormone (LH) plasma levels were not altered by any of the two treatments at PND 36. However, treatment with DEHP or Flu induced histopathological changes in the testes, wherein degeneration and disorders of Leydig cells, germ cells and dilatation of tubular lumen were observed in a dose-dependent manner. Conversely, hyperplasia and denseness of Leydig, Sertoli and germ cells were observed in rats given with high doses of Flu. The results by cDNA microarray analysis indicated that 1,272 genes were up regulated by more than two-fold, and 1,969 genes were down-regulated in response to DEHP, Flu or both EDs. These genes were selected based on their markedly increased or decreased expression levels. These genes have been also classified on the basis of gene ontology (e.g., steroid hormone biosynthetic process, regulation of transcription, signal transduction, metabolic process, biosynthetic process...). Significant decreases in gene expression were observed in steroidogenic genes (i.e., Star, Cyp11a1 and Hsd3b). In addition, the expression of a common set of target genes, including CaBP1, Vav2, Plcd1, Lhx1 and Isoc1, was altered following exposure to EDs, suggesting that they may be marker genes to screen for the anti-androgenic or androgenic effects of EDs. Overall, our results demonstrated that exposure to DEHP, Flu or both EDs resulted in a alteration of gene expression in the testes of immature male rats. Furthermore, the toxicological effects of these EDs on the male reproductive system resulted from their anti-androgenic effects. Taken together, these results provide a new insight into the molecular mechanisms underlying the detrimental impacts of EDs, in regards to anti-androgenic effects in humans and wildlife. PMID- 19781093 TI - Leadership is the essential non-technical skill in the trauma team--results of a qualitative study. AB - BACKGROUND: Trauma is the leading cause of death for young people in Norway. Studies indicate that several of these deaths are avoidable if the patient receives correct initial treatment. The trauma team is responsible for initial hospital treatment of traumatized patients, and team members have previously reported that non-technical skills as communication, leadership and cooperation are the major challenges. Better team function could improve patient outcome. The aim of this study was to obtain a deeper understanding of which non-technical skills are important to members of the trauma team during initial examination and treatment of trauma patients. METHODS: Twelve semi-structured interviews were conducted at four different hospitals of various sizes and with different trauma load. At each hospital a nurse, an anaesthesiologist and a team leader (surgeon) were interviewed. The conversations were transcribed and analyzed using systematic text condensation according to the principles of Giorgi's phenomenological analysis as modified by Malterud. RESULTS AND CONCLUSION: Leadership was perceived as an essential component in trauma management. The ideal leader should be an experienced surgeon, have extensive knowledge of trauma care, communicate clearly and radiate confidence. Team leaders were reported to have little trauma experience, and the team leaders interviewed requested more guidance and supervision. The need for better training of trauma teams and especially team leaders requires further investigation and action. PMID- 19781094 TI - Improving clinical research and cancer care delivery in community settings: evaluating the NCI community cancer centers program. AB - BACKGROUND: In this article, we describe the National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) pilot and the evaluation designed to assess its role, function, and relevance to the NCI's research mission. In doing so, we describe the evolution of and rationale for the NCCCP concept, participating sites' characteristics, its multi-faceted aims to enhance clinical research and quality of care in community settings, and the role of strategic partnerships, both within and outside of the NCCCP network, in achieving program objectives. DISCUSSION: The evaluation of the NCCCP is conceptualized as a mixed method multi-layered assessment of organizational innovation and performance which includes mapping the evolution of site development as a means of understanding the inter- and intra-organizational change in the pilot, and the application of specific evaluation metrics for assessing the implementation, operations, and performance of the NCCCP pilot. The assessment of the cost of the pilot as an additional means of informing the longer-term feasibility and sustainability of the program is also discussed. SUMMARY: The NCCCP is a major systems-level set of organizational innovations to enhance clinical research and care delivery in diverse communities across the United States. Assessment of the extent to which the program achieves its aims will depend on a full understanding of how individual, organizational, and environmental factors align (or fail to align) to achieve these improvements, and at what cost. PMID- 19781095 TI - Self-efficacy instruments for patients with chronic diseases suffer from methodological limitations--a systematic review. AB - BACKGROUND: Measurement of self-efficacy requires carefully developed and validated instruments. It is currently unclear whether available self-efficacy instruments for chronic diseases fulfill these requirements. Our aim was to systematically identify all existing self-efficacy scales for five major chronic diseases and to assess their development and validation process. METHODS: We conducted a systematic literature search in electronic databases (MEDLINE, PSYCHINFO, and EMBASE) to identify studies describing the development and/or validation process of self-efficacy instruments for the five chronic diseases diabetes, chronic obstructive pulmonary disease (COPD), asthma, arthritis, and heart failure. Two members of the review team independently selected articles meeting inclusion criteria. The self-efficacy instruments were evaluated in terms of their development (aim of instrument, a priori considerations, identification of items, selection of items, development of domains, answer options) and validation (test-retest reliability, internal consistency reliability, validity, responsiveness) process. RESULTS: Of 584 potentially eligible papers we included 25 (13 for diabetes, 5 for asthma, 4 for arthritis, 3 for COPD, 0 for heart failure) which covered 26 different self-efficacy instrument versions. For 8 instruments (30.8%), the authors described the aim before the scales were developed whereas for the other instruments the aim was unclear. In one study (3.8%) a priori considerations were specified. In none of the studies a systematic literature search was carried out to identify items. The item selection process was often not clearly described (38.5%). Test-retest reliability was assessed for 9 instruments (34.6%), validity using a correlational approach for 18 (69.2%), and responsiveness to change for 3 (11.5%) instruments. CONCLUSION: The development and validation process of the majority of the self-efficacy instruments had major limitations. The aim of the instruments was often not specified and for most instruments, not all measurement properties that are important to support the specific aim of the instrument (for example responsiveness for evaluative instruments) were assessed. Researchers who develop and validate self-efficacy instruments should adhere more closely to important methodological concepts for development and validation of patient reported outcomes and report their methods more transparently. We propose a systematic five step approach for the development and validation of self-efficacy instruments. PMID- 19781097 TI - Micro-scaled high-throughput digestion of plant tissue samples for multi elemental analysis. AB - BACKGROUND: Quantitative multi-elemental analysis by inductively coupled plasma (ICP) spectrometry depends on a complete digestion of solid samples. However, fast and thorough sample digestion is a challenging analytical task which constitutes a bottleneck in modern multi-elemental analysis. Additional obstacles may be that sample quantities are limited and elemental concentrations low. In such cases, digestion in small volumes with minimum dilution and contamination is required in order to obtain high accuracy data. RESULTS: We have developed a micro-scaled microwave digestion procedure and optimized it for accurate elemental profiling of plant materials (1-20 mg dry weight). A commercially available 64-position rotor with 5 ml disposable glass vials, originally designed for microwave-based parallel organic synthesis, was used as a platform for the digestion. The novel micro-scaled method was successfully validated by the use of various certified reference materials (CRM) with matrices rich in starch, lipid or protein. When the micro-scaled digestion procedure was applied on single rice grains or small batches of Arabidopsis seeds (1 mg, corresponding to approximately 50 seeds), the obtained elemental profiles closely matched those obtained by conventional analysis using digestion in large volume vessels. Accumulated elemental contents derived from separate analyses of rice grain fractions (aleurone, embryo and endosperm) closely matched the total content obtained by analysis of the whole rice grain. CONCLUSION: A high-throughput micro scaled method has been developed which enables digestion of small quantities of plant samples for subsequent elemental profiling by ICP-spectrometry. The method constitutes a valuable tool for screening of mutants and transformants. In addition, the method facilitates studies of the distribution of essential trace elements between and within plant organs which is relevant for, e.g., breeding programmes aiming at improvement of the micronutrient density in edible plant parts. Compared to existing vial-in-vial systems, the new method developed here represents a significant methodological advancement in terms of higher capacity, reduced labour consumption, lower material costs, less contamination and, as a consequence, improved analytical accuracy following micro-scaled digestion of plant samples. PMID- 19781096 TI - A randomized controlled multicenter trial of post-suicide attempt case management for the prevention of further attempts in Japan (ACTION-J). AB - BACKGROUND: A previous suicide attempt is a potent risk factor for suicide later on. Crisis intervention, psychiatric and psychosocial evaluation at emergency medical facilities, and follow-up care for suicide attempters are considered important components for suicide prevention. The Japanese Multimodal Intervention Trials for Suicide Prevention (J-MISP) includes a randomized, controlled, multicenter trial of post-suicide attempt case management for the prevention of further attempts (ACTION-J) to address the continuing increase in suicides in Japan. The primary aim of ACTION-J is to examine the effectiveness of an extensive intervention for suicide attempters in prevention of recurrent suicidal behavior, as compared with standard intervention. This paper describes the rationale and protocol of the ACTION-J trial. METHODS/DESIGN: In this clinical trial, case management intervention will be provided at 19 emergency medical facilities in Japan. After crisis intervention including psychiatric evaluation, psychosocial assessment, and psychological education, subjects will be randomly assigned to either a group receiving continuous case management or a control group receiving standard care. Suicidal ideation, depressive symptoms, and general health condition will be evaluated as secondary measures. The intervention was initiated in July 2006. By December, 2009, 842 subjects will be randomized. Subject follow-up will continue for 1.5 to 5 years. DISCUSSION: Suicide is a complex phenomenon that encompasses multiple factors. Case management by multi-sector collaboration is needed. ACTION-J may provide valuable information on suicide attempters and may develop effective case management to reduce future risk for suicide attempters. TRIAL REGISTRATION: UMIN Clinical Trials Registry number, UMIN000000444. ClinicalTrials.gov number, NCT00736918. PMID- 19781098 TI - Prevalence and age-of-onset distributions of DSM IV mental disorders and their severity among school going Omani adolescents and youths: WMH-CIDI findings. AB - BACKGROUND: There is a dearth of studies exploring the magnitude of mental disorders amongst adolescents and youths in the Arab world. To our knowledge, this phase 2 survey in Oman is the first nationally representative school-based study to determine the prevalence of DSM-IV mental disorders (lifetime and over the preceding 12 months), their age-of-onset distributions and determine their severity over the past 12 months using the World Mental Health-Composite International Diagnostic Interview, the WMH-CIDI, used for international comparison. METHODS: A total of 1,682 (91.61%) students out of 1836 students who formed the phase 2 random sub-sample of a multi-stage, stratified, random sampling design (phase 1), participated in the face-to-face structured interview using the Arabic-version of WMH-CIDI 3.0. RESULTS: The phase 1 results using the General Health Questionnaire (GHQ-12) and Child Depression Inventory (CDI) showed depressive symptoms to be 17% prevalent in the larger sample of 5409 adolescents and youths. Amongst the phase 2 respondents from this sample, 13.9% had at least one DSM IV diagnostic label. The lifetime prevalence of Major Depressive Disorder (MDD) was 3.0%; Bipolar Mood Disorder (BMD) was 1%, Specific phobia 5.8% and Social phobia 1.6%. The female gender was a strong predictor of a lifetime risk of MDD (OR 3.3, 95% CI 1.7-6.3, p = 0.000); Any Mood Disorders (OR 2.5, 95% CI 1.4-4.3, p = 0.002) and Specific Phobia (OR 1.5, 95% CI 1.0-2.4, p = 0.047). The severity of illness for cases diagnosed with 12 month DSM IV disorders was found to be 80% lower in females (OR 0.2, 95%CI 0.0-0.8). The estimates over the previous 12 month period when compared with the lifetime prevalence showed a 25% to 40% lower prevalence for MDD, Specific phobia, Social phobia, Any Anxiety Disorders (AAD) and Any Mood disorders (AMD) while the rate was 80% lower for Separation Anxiety Disorder/Adult Separation Anxiety (SAD/ASA). Mood disorders were significantly lower in the 14-16 age groups (70% lower) in comparison to the older age groups and AMD showed a linear increase in prevalence across increasing age groups (p = 0.035). CONCLUSION: The implications of the present findings are not clear cut, however this study endorses the adult CIDI studies findings that mental disorders do begin earlier in life. The relatively lower prevalence of DSM IV depressive disorders cautions against any conclusive interpretation of the inflated results based on the exclusive study of the depressive symptoms alone in the same sample in the same time period. The female gender proved to be a strong predictor of lifetime risk of MDD, any mood disorder and specific phobia. Under reporting by males or some other gender-specific factors may have contributed to such a discrepancy. The odds of the severity of illness for cases with 12 month DSM IV disorders were significantly lower in females. PMID- 19781099 TI - Incremental cardiovascular costs and resource use associated with diabetes: an assessment of 29,863 patients in the US managed-care setting. AB - BACKGROUND: Patients with type 2 diabetes are at increased risk of cardiovascular events, and there is an associated economic burden attached to this risk. We conducted a retrospective claims database analysis to evaluate incremental cardiovascular costs in diabetic versus non-diabetic patients hospitalized for a cardiovascular event. METHODS: Patients hospitalized for a cardiovascular event between January 1, 2001 and June 30, 2005 were identified from a large US managed care population. Diabetic patients were identified by evidence of type 2 diabetes in the 12 months prior to the index hospitalization. Direct medical costs and resource use - including inpatient expenditures (for the index and first recurrent hospitalizations), as well as outpatient, laboratory, and pharmacy expenditures (during the 3-year follow-up period) - were determined for patients with or without diabetes. RESULTS: Of the 29,863 patients identified with a cardiovascular hospitalization, 5,501 patients (18.4%) had a history of diabetes in the pre-index period (mean age, 57.8 years; 42.1% female). The overall mean follow-up period was 22.8 months. The incidence of subsequent cardiovascular events in the first year of follow-up was significantly higher for patients with diabetes compared with non-diabetic patients for all types of cardiovascular events except angina. Compared with non-diabetic patients, patients with diabetes had similar mean direct medical costs per patient for the index cardiovascular hospitalization ($17,435 versus $16,917; P = 0.09), and the first recurrent cardiovascular hospitalization ($18,488 versus $17,481; P = 0.2), yet higher mean total direct medical costs per patient for cardiovascular events during follow-up years (Year 1: $8,805 versus $6,982; Year 2: $13,860 versus $10,056; Year 3: $16,149 versus $12,163; all P < or = 0.0002). The cost difference between diabetic and non-diabetic patients remained significant after adjusting for age, gender and other potential confounders in multivariate regression analysis. The mean (SD) total period of inpatient cardiovascular hospitalization after 3 years of follow-up was 3.3 (12.4) days for patients with diabetes compared with 1.8 (5.8) days for non-diabetic patients (P < 0.0001). CONCLUSION: Diabetic patients hospitalized for a cardiovascular event incur higher costs for cardiovascular care than their non-diabetic counterparts. This analysis of the incremental cardiovascular cost and resource use provides the basis for greater accuracy and precision when modeling the economic value of initiatives aimed at reducing cardiovascular morbidity in patients with diabetes mellitus. PMID- 19781100 TI - Candidate metastasis suppressor genes uncovered by array comparative genomic hybridization in a mouse allograft model of prostate cancer. AB - BACKGROUND: The purpose of this study was to identify candidate metastasis suppressor genes from a mouse allograft model of prostate cancer (NE-10). This allograft model originally developed metastases by twelve weeks after implantation in male athymic nude mice, but lost the ability to metastasize after a number of in vivo passages. We performed high resolution array comparative genomic hybridization on the metastasizing and non-metastasizing allografts to identify chromosome imbalances that differed between the two groups of tumors. RESULTS: This analysis uncovered a deletion on chromosome 2 that differed between the metastasizing and non-metastasizing tumors. Bioinformatics filters were employed to mine this region of the genome for candidate metastasis suppressor genes. Of the 146 known genes that reside within the region of interest on mouse chromosome 2, four candidate metastasis suppressor genes (Slc27a2, Mall, Snrpb, and Rassf2) were identified. Quantitative expression analysis confirmed decreased expression of these genes in the metastasizing compared to non-metastasizing tumors. CONCLUSION: This study presents combined genomics and bioinformatics approaches for identifying potential metastasis suppressor genes. The genes identified here are candidates for further studies to determine their functional role in inhibiting metastases in the NE-10 allograft model and human prostate cancer. PMID- 19781101 TI - Quantitative data management in quality improvement collaboratives. AB - BACKGROUND: Collaborative approaches in quality improvement have been promoted since the introduction of the Breakthrough method. The effectiveness of this method is inconclusive and further independent evaluation of the method has been called for. For any evaluation to succeed, data collection on interventions performed within the collaborative and outcomes of those interventions is crucial. Getting enough data from Quality Improvement Collaboratives (QICs) for evaluation purposes, however, has proved to be difficult. This paper provides a retrospective analysis on the process of data management in a Dutch Quality Improvement Collaborative. From this analysis general failure and success factors are identified. DISCUSSION: This paper discusses complications and dilemma's observed in the set-up of data management for QICs. An overview is presented of signals that were picked up by the data management team. These signals were used to improve the strategies for data management during the program and have, as far as possible, been translated into practical solutions that have been successfully implemented.The recommendations coming from this study are: From our experience it is clear that quality improvement programs deviate from experimental research in many ways. It is not only impossible, but also undesirable to control processes and standardize data streams. QIC's need to be clear of data protocols that do not allow for change. It is therefore minimally important that when quantitative results are gathered, these results are accompanied by qualitative results that can be used to correctly interpret them.Monitoring and data acquisition interfere with routine. This makes a database collecting data in a QIC an intervention in itself. It is very important to be aware of this in reporting the results. Using existing databases when possible can overcome some of these problems but is often not possible given the change objective of QICs. Introducing a standardized spreadsheet to the teams is a very practical and helpful tool in collecting standardized data within a QIC. It is vital that the spreadsheets are handed out before baseline measurements start. PMID- 19781102 TI - Blockage of transdifferentiation from fibroblast to myofibroblast in experimental ovarian cancer models. AB - BACKGROUND: Tumour stromal myofibroblasts can promote tumour invasion. As these cells are genetically more stable than cancer cells, there has been enormous interest in developing targeted molecular therapies against them. Chloride intracellular channel 4 (CLIC4) and reactive oxygen species (ROS) have been linked with promoting stromal cell transdifferentiation in various cancers, but little is known of their roles in ovarian cancer. In this study, we examined the functional roles that both CLIC4 and ROS play in the process of ovarian cancer cell-stimulated or TGF-beta1 induced fibroblast-to-myofibroblast transdifferentiation. We also examine whether it is possible to reverse such a process, with the aim of developing novel therapies against ovarian cancer by targeting activated transdifferentiated myofibroblasts. RESULTS: We demonstrate that TGF-beta1 induced or CM(SKOV3) activate transdifferentiated myofibroblasts (fibroblasts). These fibroblasts mimic "reactive" stromal myofibroblasts and demonstrate significant up-regulation of CLIC4 expression and increased level of ROS production. Blocking the production of ROS with an antioxidant consequently reduces the expression of CLIC4, and is accompanied by disappearance of alpha smooth-muscle actin (alpha-SMA), a myofibroblast marker, suggesting ROS acts as a signalling molecule that promotes and enhances CLIC4 activities in the myofibroblast transdifferentiaton process. Down-regulation of CLIC4 with a generic agent or specific siRNA both significantly reduces the expression of factors related to the phenotypes and functions of myofibroblasts, such as alpha SMA, hepatocyte growth factor (HGF) and vascular endothelial growth factor (VEGF), thus reversing the myofibroblast phenotype back to fibroblasts. These results convincingly show that ROS and CLIC4 are responsible for TGF-beta1 induced fibroblast-to-myofibroblast transdifferentiaton and down-regulation of both is sufficient to block transdifferentiated myofibroblasts. CONCLUSION: Molecular targeting of ROS and CLIC4 has the potential to develop novel therapies for ovarian cancer. PMID- 19781103 TI - Adjuvant concurrent chemoradiation therapy (CCRT) alone versus CCRT followed by adjuvant chemotherapy: which is better in patients with radically resected extrahepatic biliary tract cancer?: a non-randomized, single center study. AB - BACKGROUND: There is currently no standard adjuvant therapy for patients with curatively resected extrahepatic biliary tract cancer (EHBTC). The aim of this study was to analyze the clinical features and outcomes between patients undergoing adjuvant concurrent chemoradiation therapy (CCRT) alone and those undergoing CCRT followed by adjuvant chemotherapy after curative resection. METHODS: We included 120 patients with EHBTC who underwent radical resection and then received adjuvant CCRT with or without further adjuvant chemotherapy between 2000 and 2006 at Seoul National University Hospital. RESULTS: Out of 120 patients, 30 received CCRT alone, and 90 received CCRT followed by adjuvant chemotherapy. Baseline characteristics were comparable between the two groups. Three-year disease-free survival (DFS) rates for CCRT alone and CCRT followed by adjuvant chemotherapy were 26.6% and 45.2% (p = 0.04), respectively, and 3-year overall survival (OS) rates were 30.8% and 62.6% (p < 0.01), respectively. CCRT followed by adjuvant chemotherapy showed longer survival than did CCRT alone, especially in R1 resection (microscopically positive margins) or negative lymph node. CONCLUSION: Adjuvant CCRT followed by adjuvant chemotherapy prolonged DFS and OS, compared with CCRT alone in patients with curatively resected EHBTC. Adjuvant chemotherapy deserves to consider after adjuvant CCRT. In the future, a randomized prospective study will be needed, with the objective of investigating the role of adjuvant chemotherapy. PMID- 19781104 TI - Chromosome territories, X;Y translocation and Premature Ovarian Failure: is there a relationship? AB - BACKGROUND: Premature ovarian failure (POF) is a secondary hypergonadotrophic amenorrhea occurring before the age of 40 and affecting 1-3% of females. Chromosome anomalies account for 6-8% of POF cases, but only few cases are associated with translocations involving X and Y chromosomes.This study shows the cytogenetic and molecular analysis of a POF patient came to our attention as she developed a left ovary choriocarcinoma at the age of 10 and at 14 years of age she presented secondary amenorrhea with elevated levels of gonadotropins. RESULTS: Breakpoint position on X and Y chromosomes was investigated using Fluorescent In Situ Hybridisation (FISH) with a panel of specific BAC probes, microsatellite analysis and evaluation of copy number changes and loss of heterozigosity by Affymetrix(R) GeneChip platform (Santa Clara, CA, USA). Patient's karyotype resulted 46, X, der(Y)t(X;Y)(q13.1;q11.223). X inactivation study was assessed by RBA banding and showed preferential inactivation of derivative chromosome. The reciprocal spatial disposition of sexual chromosome territories was investigated using whole chromosome painting and centromeres probes: patient's results didn't show a significant difference in comparison to normal controls. CONCLUSION: The peculiar clinical case come to our attention highlighted the complexity of POF aetiology and of the translocation event, even if our results seem to exclude any effect on nuclear organisation. POF phenotype could be partially explained by skewed X chromosome inactivation that influences gene expression. PMID- 19781105 TI - IL-6 predicts organ dysfunction and mortality in patients with multiple injuries. AB - BACKGROUND: Although therapeutic concepts of patients with major trauma have improved during recent years, organ dysfunction still remains a frequent complication during clinical course in intensive care units. It has previously been shown that cytokines are upregulated under stress conditions such as trauma or sepsis. However, it is still debatable if cytokines are adequate parameters to describe the current state of trauma patients. To elucidate the relevance of cytokines, we investigated if cytokines predict development of multiple organ dysfunction syndrome (MODS) or outcome. METHODS: A total of 143 patients with an injury severity score >or= 16, between 16 and 65 years, admitted to the Hannover Medical School Level 1 Trauma Center between January 1997 and December 2001 were prospectively included in this study. Marshall Score for MODS was calculated for at least 14 days and plasma levels of TNF-alpha, IL-1beta, IL-6, IL-8 and IL-10 were measured. To determine the association between cytokine levels and development of MODS the Spearman rank correlation coefficient was calculated and logistic regression and analysis were performed. RESULTS AND DISCUSSION: Patients with MODS had increased plasma levels of IL-6, IL-8 and IL-10. IL-6 predicted development of MODS with an overall accuracy of 84.7% (specificity: 98.3%, sensitivity: 16.7%). The threshold value for development of MODS was 761.7 pg/ml and 2176.0 pg/ml for mortality during the in patient time. CONCLUSION: We conclude that plasma IL-6 levels predict mortality and that they are a useful tool to identify patients who are at risk for development of MODS. PMID- 19781106 TI - Early responses of insulin signaling to high-carbohydrate and high-fat overfeeding. AB - BACKGROUND: Early molecular changes of nutritionally-induced insulin resistance are still enigmatic. It is also unclear if acute overnutrition alone can alter insulin signaling in humans or if the macronutrient composition of the diet can modulate such effects. METHODS: To investigate the molecular correlates of metabolic adaptation to either high-carbohydrate (HC) or high-fat (HF) overfeeding, we conducted overfeeding studies in 21 healthy lean (BMI < 25) individuals (10 women, 11 men), age 20-45, with normal glucose metabolism and no family history of diabetes. Subjects were studied first following a 5-day eucaloric (EC) diet (30% fat, 50% CHO, 20% protein) and then in a counter balanced manner after 5 days of 40% overfeeding of both a HC (20% fat, 60% CHO) diet and a HF (50% fat, 30% CHO) diet. At the end of each diet phase, in vivo insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp technique. Ex vivo insulin action was measured from skeletal muscle tissue samples obtained 15 minutes after insulin infusion was initiated. RESULTS: Overall there was no change in whole-body insulin sensitivity as measured by glucose disposal rate (GDR, EC: 12.1 +/- 4.7; HC: 10.9 +/- 2.7; HF: 10.8 +/- 3.4). Assessment of skeletal muscle insulin signaling demonstrated increased tyrosine phosphorylation of IRS-1 (p < 0.001) and increased IRS-1-associated phosphatidylinositol 3 (PI 3)-kinase activity (p < 0.001) following HC overfeeding. In contrast, HF overfeeding increased skeletal muscle serine phosophorylation of IRS-1 (p < 0.001) and increased total expression of p85alpha (P < 0.001). CONCLUSION: We conclude that acute bouts of overnutrition lead to changes at the cellular level before whole-body insulin sensitivity is altered. On a signaling level, HC overfeeding resulted in changes compatible with increased insulin sensitivity. In contrast, molecular changes in HF overfeeding were compatible with a reduced insulin sensitivity. PMID- 19781107 TI - Ovarian cancer mouse models: a summary of current models and their limitations. AB - Development of mouse models representing human spontaneous ovarian cancer has been hampered by the lack of understanding of the etiology of this very complex disease. Mouse models representing the different types of ovarian cancer are needed to understand how epithelial ovarian cancer differs from granulosa cell tumors. Many different methods have been used to generate a viable genetic model with limited success. This review focuses on the methods of various investigators and the limitations of each model in establishing a reproducible and inheritable line to study this disease. PMID- 19781109 TI - Protection from late life depression. PMID- 19781110 TI - Top cited papers in International Psychogeriatrics: 6b. Behavioral disorders and caregivers' reaction in Taiwanese patients with Alzheimer's disease. PMID- 19781108 TI - Sarcoglycanopathies: molecular pathogenesis and therapeutic prospects. AB - Sarcoglycanopathies are a group of autosomal recessive muscle-wasting disorders caused by genetic defects in one of four cell membrane glycoproteins, alpha-, beta-, gamma- or delta-sarcoglycan. These four sarcoglycans form a subcomplex that is closely linked to the major dystrophin-associated protein complex, which is essential for membrane integrity during muscle contraction and provides a scaffold for important signalling molecules. Proper assembly, trafficking and targeting of the sarcoglycan complex is of vital importance, and mutations that severely perturb tetramer formation and localisation result in sarcoglycanopathy. Gene defects in one sarcoglycan cause the absence or reduced concentration of the other subunits. Most genetic defects generate mutated proteins that are degraded through the cell's quality control system; however, in many cases, conformational modifications do not affect the function of the protein, yet it is recognised as misfolded and prematurely degraded. Recent evidence shows that misfolded sarcoglycans could be rescued to the cell membrane by assisting their maturation along the ER secretory pathway. This review summarises the etiopathogenesis of sarcoglycanopathies and highlights the quality control machinery as a potential pharmacological target for therapy of these genetic disorders. PMID- 19781111 TI - Predictors of change in health-related quality of life among older people with depression: a longitudinal study. AB - BACKGROUND: Depression is a common psychological problem among older people. Health-related quality of life (HRQoL) is now recognized by healthcare providers as an important treatment goal for people with depression. This study aimed to identify predictors of change in HRQoL among older people with depression. METHODS: In a longitudinal study, data were collected when participants were newly diagnosed with a depressive disorder at a regional outpatient department in Hong Kong and 12 months later. Seventy-seven Chinese participants aged 65 years or older completed the study. Measures included the Physical Health Condition Checklist (PHCC), Geriatric Depression Scale (GDS), Modified Barthel Index (MBI), Instrumental Activities of Daily Living (IADL) scale, Social Support Questionnaire (SSQ), and World Health Organization Quality of Life Scale-Brief Version (WHOQOL). RESULTS: Significant improvements between the first and second assessments were noted in the total WHOQOL scores, GDS scores, and the number of the social support. The results of linear regression models showed that the increases in the IADL scores and decreases in the PHCC and GDS scores were significantly associated with higher final WHOQOL scores. DISCUSSION: Treatment for depression was effective in improving the participants' overall condition and their perceived HRQoL. The results suggest that interventions to alleviate older people's level of depression, manage their physical ill health and enhance their instrumental activities of daily living ability could help improve their perceived HRQoL. PMID- 19781112 TI - Trajectories of cognitive decline in Alzheimer's disease. AB - BACKGROUND: Late-onset Alzheimer disease (LOAD) is a clinically heterogeneous complex disease defined by progressively disabling cognitive impairment. Psychotic symptoms which affect approximately one-half of LOAD subjects have been associated with more rapid cognitive decline. However, the variety of cognitive trajectories in LOAD, and their correlates, have not been well defined. We therefore used latent class modeling to characterize trajectories of cognitive and behavioral decline in a cohort of AD subjects. METHODS: 201 Caucasian subjects with possible or probable Alzheimer's disease (AD) were evaluated for cognitive and psychotic symptoms at regular intervals for up to 13.5 years. Cognitive symptoms were evaluated serially with the Mini-mental State Examination (MMSE), and psychotic symptoms were rated using the CERAD behavioral rating scale (CBRS). Analyses undertaken were latent class mixture models of quadratic trajectories including a random intercept with initial MMSE score, age, gender, education, and APOE 4 count modeled as concomitant variables. In a secondary analysis, psychosis status was also included. RESULTS: AD subjects showed six trajectories with significantly different courses and rates of cognitive decline. The concomitant variables included in the best latent class trajectory model were initial MMSE and age. Greater burden of psychotic symptoms increased the probability of following a trajectory of more rapid cognitive decline in all age and initial MMSE groups. APOE 4 was not associated with any trajectory. CONCLUSION: Trajectory modeling of longitudinal cognitive and behavioral data may provide enhanced resolution of phenotypic variation in AD. PMID- 19781113 TI - Effects of Bacillus thuringiensis Cry1Ab and Cry3Aa endotoxins on predatory Coleoptera tested through artificial diet-incorporation bioassays. AB - Traditional approaches to studying the effects of genetically modified (GM) crops on beneficial insects involve either field assays, comparing insect population levels between control and GM crops or tritrophic bioassays with contaminated insects - usually larvae or eggs of Lepidoptera - as preys. Here, we report the results of a bioassay using an artificial diet, suitable for predatory Coleoptera, to supply Bacillus thuringiensis (Bt) solubilized Cry1Ab and Cry3Aa as well as trypsin-activated Cry1Ab to Atheta coriaria and Cryptolaemus montrouzieri adults and young larvae of Adalia bipunctata. Water, solubilization buffer and trypsin-treated solubilization buffer were used as controls. In total, 1600 insects were assayed. Assays showed a relatively low mortality rate in the controls, ranging from as low as 7% after 15 days (C. montrouzieri) to about 15 20% after five days (A. bipunctata) or 15 days (A. coriaria). For all three predators, there were no statistical differences between the mortality recorded in any of the treatment groups and the corresponding controls. These results indicate a lack of short- (A. bipunctata) and long-term (A. coriaria and C. montrouzieri) mortality associated with oral ingestion of Cry1Ab and Cry3Aa at the high dose tested (50 microg ml-1). We discuss the relevance of these findings for the ecology of beneficial Coleoptera and compatibility with Bt and GM Bt crops. PMID- 19781114 TI - Case-control study on Puumala virus infection: smoking is a risk factor. AB - Puumala hantavirus (PUUV) is apparently transmitted to humans by inhalation of aerosolized secretions of carrier rodents (bank voles). The means of transmission and the associated risk factors are poorly defined. An epidemiological study during the peak of an epidemic season in Finland was conducted based on 282 acute clinical PUUV infections and 204 controls without PUUV infection or immunity. The main risk factors adjusted by age, sex and living environment were cigarette smoking [odds ratio (OR) 3.6, 95% confidence interval (CI) 2.1-5.9, P<0.0001] and buildings with holes allowing rodents to enter (OR 3.3, 95% CI 2.0-5.6); these results were similar in two subsets. Further, use of rodent traps (OR3.5, 95% CI 2.2-5.7) and handling firewood (OR 2.7, 95% CI 1.6-4.4) were associated with a risk. The risk attributed to smoking also remained high using simulated population controls with average smoking habits. The results suggest that hantavirus transmission occurs by inhalation mainly indoors and is dependent on the condition of the respiratory tract. PMID- 19781115 TI - An outbreak of Pontiac fever due to Legionella longbeachae serogroup 2 found in potting mix in a horticultural nursery in New Zealand. AB - Previous outbreaks of Pontiac fever have invariably been associated with water droplet spread of Legionella spp. In January 2007 three workers from a horticultural nursery were admitted to hospital with non-pneumonic legionellosis. Investigations showed that a working party of ten people had been exposed to aerosolized potting mix; nine of these workers met the case definition for Pontiac fever. The presence of genetically indistinguishable Legionella longbeachae serogroup 2 was demonstrated in clinical specimens from two hospitalized workers and in the potting mix to which they had been exposed. A further seven cases were diagnosed by serological tests. This is the first documented outbreak of Pontiac fever from L. longbeachae serogroup 2 confirmed from inhalation of potting mix. Pontiac fever is likely to be under-diagnosed. We advocate the introduction of an industry standard that ensures the use of face masks when handling potting mix and attaching masks and warning labels to potting mix bags sold to the public. PMID- 19781116 TI - Modelling the impact of one-dose vs. two-dose vaccination regimens on the epidemiology of varicella zoster virus in Australia. AB - We examined the impact of one-dose vs. two-dose vaccination strategies on the epidemiology of varicella zoster virus (VZV) in Australia, using a mathematical model. Strategies were assessed in terms of varicella (natural and breakthrough) and zoster incidence, morbidity, average age of infection and vaccine effectiveness (VE). Our modelling results suggest that compared to a one-dose vaccination strategy (Australia's current vaccination schedule), a two-dose strategy is expected to not only produce less natural varicella cases (5% vs. 13% of pre-vaccination state, respectively) but also considerably fewer breakthrough varicella cases (only 11.4% of one-dose strategy). Therefore a two-dose infant vaccination programme would be a better long-term strategy for Australia. PMID- 19781117 TI - Epidemiology of group B streptococcus in Korean pregnant women. AB - Between January 2006 and May 2008, 2624 pregnant S. Korean women between 35-37 weeks gestation were screened for group B streptococcus (GBS). Resistance to antimicrobials was tested by disk diffusion and serotype determined using co agglutination assays and microarray methods. Overall, 8% of pregnant women were colonized. Serotype III was the predominant serotype (43.8%), followed by serotypes V (20.3%), Ia (12.1%), and Ib (9.5%). GBS was frequently resistant to clindamycin (54.0%) and erythromycin (25.6%); 3.7% were resistant to cefazolin. More than three-quarters of serotype V were resistant to clindamycin or erythromycin or both, and 71% of serotype III were resistant to clindamycin but only 12% were resistant to erythromycin. GBS prevalence exceeded earlier reports by one-third. This is the first report of cefazolin resistance in Korea. These results underscore the need to establish screening measures and chemoprophylaxis guidelines regarding GBS infections in Korea. PMID- 19781119 TI - Association between habitual coffee consumption and normal or increased estimated glomerular filtration rate in apparently healthy adults. AB - Habitual coffee consumption is associated with the prevention of type 2 diabetes, which often accompanies diabetic nephropathy. However, the relationship between coffee consumption and kidney function is unclear. Therefore, we investigated the associations between habitual coffee consumption and kidney function and damage assessed by the estimated glomerular filtration rate (eGFR) and proteinuria using dipstick urinalysis, respectively, in a cross-sectional study of 342 apparently healthy adults. Habitual coffee consumption was defined as drinking one or more cups of coffee per d. eGFR in coffee consumers (n 182; 80.1 (sd 15.0) ml/min per 1.73 m(2)) was significantly higher than that in non-coffee consumers (n 160; 76.9 (sd 12.6) ml/min per 1.73 m(2)) (P < 0.05). Multivariate logistic analysis showed that, compared with non-coffee consumption, coffee consumption was significantly associated with normal or increased eGFR (NIGFR) ( >or= 90 ml/min per 1.73 m(2)), but not proteinuria, which was not attenuated, even after adjustment for age, sex, smoking, tea consumption and other cardiovascular risks (OR 2.91; 95 % CI 1.51, 5.61; P = 0.001). When we took into account eGFR measured 1 year before in a subgroup of the subjects (n 262), coffee consumption (n 142) had a significant relationship with eGFR, which was consistently higher with a difference of 4.0 ml/min per 1.73 m(2) compared with non-coffee consumption (P = 0.01; two-way repeated ANOVA). Similar associations were observed in both sexes when data were reanalysed according to sex. In conclusion, our findings suggest that habitual coffee consumption is associated with NIGFR independently of clinical confounders. Further studies are needed to confirm this association and to explore whether the effect of coffee consumption on eGFR is beneficial for the kidney. PMID- 19781118 TI - Enteric calicivirus and rotavirus infections in domestic pigs. AB - We report the prevalence of rotavirus and calicivirus infections, along with their respective association with diarrhoea in the porcine population of the region of northern Spain. A total of 221 samples were collected at random from different farms in the region and from the main slaughterhouse facility in the city of Zaragoza. Faecal samples were scored as diarrhoeic or normal and grouped into five groups to match general farm management and age criteria: group I (suckling 0-4 weeks), group II (weaning >4-8 weeks), group III (transition >8-16 weeks), group IV (fattening >16-24 weeks) and group V (adults >24 weeks). Group A rotavirus detection and caliciviruses were investigated by reverse transcription polymerase chain reaction (RT-PCR). Conventional RT-PCR was performed using primers designed to detect rotavirus group A, caliciviruses and/or human noroviruses. A real-time RT-PCR was carried out using TaqMan probes for genogroups GI and GII of noroviruses. Rotaviruses and caliciviruses were detected with an overall prevalence of 16.7% and 12.2%, respectively. Rotavirus detection in faecal samples was associated with both age and faecal consistency, being more frequent in piglets aged <8 weeks with odds ratios (ORs) equal to 4.3 and 4.9, respectively. Calicivirus shedding in faecal samples was homogenously distributed in all ages, showing no significant association with age or faecal consistency (OR 0.87 and 0.99, respectively). A selection of rotavirus-positive stools were genotyped by multiplex nested PCR. G10, P[6], G12 P[8], G9 [p8] and G4 P[23] genotype combinations were found. Three isolates showed a G3 genotype, but their VP4 gene could not be amplified. It should be noted that the G9 genotype was the major G genotype circulating during that period in Spain. None of the porcine samples was positive for norovirus by real-time RT-PCR, despite the ability of this technique to detect at least 18 human norovirus genotypes. Our data indicate that human noroviruses are unlikely to be circulating in the porcine population; however, sapoviruses have been found. Contrary to rotavirus infection, Calicivirus infection is asymptomatic. Specific primers to detect porcine noroviruses are needed. PMID- 19781120 TI - A controlled study of consumption of beta-glucan-enriched soups for 2 months by type 2 diabetic free-living subjects. AB - Type 2 diabetes is associated with a higher cardiovascular risk and there has been a growing interest in using dietary intervention to improve lipid profile and glucose control. The present work aims at analysing the effects of the enrichment of a normal diet with beta-glucan (3.5 g/d) in free-living type 2 diabetic subjects for 2 months, using a palatable soup. This trial was a parallel, placebo-controlled, double-blinded randomised study performed in fifty three type 2 diabetic subjects. During a 3-week run-in period, subjects daily consumed a ready meal control soup (without beta-glucan). For the following 8 weeks, subjects were randomly assigned to consume daily either a control soup or a beta-glucan soup. Changes in lipid profile (total cholesterol (TC), HDL- and LDL-cholesterol (HDLc and LDLc), apo B and TAG) and in glucose control (HbA1c and fasting glucose) were measured. There was no significant alteration in lipid profile in the two groups (TC, HDLc, LDLc and apo B). TAG decreased significantly in the beta-glucan group compared with the control group ( - 0.12 (SD 0.38) v. 0.12 (SD 0.44) mmol/l, P = 0.03). HbA1c and fasting glucose were not reduced in any group. A single daily ingestion of 3.5 g beta-glucan, as required by official dietary recommendations, for 8 weeks did not change the lipid profile and HbA1c in type 2 diabetic subjects. To improve the metabolic profile of type 2 diabetic subjects in the long term, the quantity, the food vectors and the tolerability of beta-glucan products may be re-evaluated. PMID- 19781121 TI - Glycaemic index and glycaemic load values of a selection of popular foods consumed in Hong Kong. AB - The objective of the present paper is to provide glycaemic index (GI) and glycaemic load (GL) values for a variety of foods that are commonly consumed in Hong Kong and expand on the international GI table of Chinese foods. Fasted healthy subjects were given 50 g of available carbohydrate servings of a glucose reference, which was tested twice, and test foods of various brands of noodles (n 5), instant cereals (n 3) and breads (n 2), which were tested once, on separate occasions. For each test food, tests were repeated in ten healthy subjects. Capillary blood glucose was measured via finger-prick samples in fasting subjects ( - 5, 0 min) and at 15, 30, 45, 60, 90 and 120 min after the consumption of each test food. The GI of each test food was calculated geometrically by expressing the incremental area under the blood glucose response curve (IAUC) of each test food as a percentage of each subject's average IAUC for the reference food. GL was calculated as the product of the test food's GI and the amount of available carbohydrate in a reference serving size. The majority of GI values of foods tested were medium (a GI value of 56-69) to high (a GI value of 70 or more) and compared well with previously published values. More importantly, our dataset provides GI values of ten foods previously untested and presents values for foods commonly consumed in Hong Kong. PMID- 19781122 TI - Dietary vitamin D and risk of non-Hodgkin lymphoma: the multiethnic cohort. AB - The present study explored the association between dietary vitamin D and non Hodgkin's lymphoma (NHL) risk. The multiethnic cohort (MEC) includes more than 215 000 Caucasians, African Americans, Native Hawaiians, Japanese Americans and Latinos, aged 45-75. After 10 years of follow-up, 939 incident NHL cases were identified. Risk was estimated using proportional hazards' models adjusted for possible confounders. Vitamin D intake was not associated with NHL risk in the entire cohort (P(trend) = 0.72 for men and P(trend) = 0.83 for women), but significantly lowered disease risk in African American women (hazard ratio (HR) = 0.50, 95 % CI: 0.28, 0.90, P(trend) = 0.03) and was borderline protective in African American men (HR = 0.68; 95 % CI: 0.39, 1.19; P(trend) = 0.31) when the highest to the lowest tertile was compared. In NHL subtype analyses, a 19, 36 and 32 % lowered risk, although not significant, was observed for diffuse large B cell lymphoma, follicular lymphoma and small lymphocytic lymphoma/chronic lymphocytic leukemia in women, respectively. High dietary intake of vitamin D did not show a protective effect against NHL within the MEC except among African Americans, possibly because vitamin D production due to sun exposure is limited in this population. PMID- 19781123 TI - Low calcium:phosphorus ratio in habitual diets affects serum parathyroid hormone concentration and calcium metabolism in healthy women with adequate calcium intake. AB - Excessive dietary P intake alone can be deleterious to bone through increased parathyroid hormone (PTH) secretion, but adverse effects on bone increase when dietary Ca intake is low. In many countries, P intake is abundant, whereas Ca intake fails to meet recommendations; an optimal dietary Ca:P ratio is therefore difficult to achieve. Our objective was to investigate how habitual dietary Ca:P ratio affects serum PTH (S-PTH) concentration and other Ca metabolism markers in a population with generally adequate Ca intake. In this cross-sectional analysis of 147 healthy women aged 31-43 years, fasting blood samples and three separate 24-h urinary samples were collected. Participants kept a 4-d food record and were divided into quartiles according to their dietary Ca:P ratios. The 1st quartile with Ca:P molar ratio < or = 0.50 differed significantly from the 2nd (Ca:P molar ratio 0.51-0.57), 3rd (Ca:P molar ratio 0.58-0.64) and 4th (Ca:P molar ratio > or = 0.65) quartiles by interfering with Ca metabolism. In the 1st quartile, mean S PTH concentration (P = 0.021) and mean urinary Ca (U-Ca) excretion were higher (P = 0.051) than in all other quartiles. These findings suggest that in habitual diets low Ca:P ratios may interfere with homoeostasis of Ca metabolism and increase bone resorption, as indicated by higher S-PTH and U-Ca levels. Because low habitual dietary Ca:P ratios are common in Western diets, more attention should be focused on decreasing excessively high dietary P intake and increasing Ca intake to the recommended level. PMID- 19781124 TI - The key to life nutrition program: results from a community-based dietary sodium reduction trial. AB - OBJECTIVE: Evaluation of a dietary Na reduction trial in a community setting. DESIGN: Community-based randomized trial. Ten-week nutrition intervention activities focused on lifestyle modification to decrease dietary Na intake, under the supervision of a registered dietitian. Twenty-four hour urine specimens were collected at baseline and follow-up visits to determine 24 h urinary Na excretion. SETTING: The University of Pittsburgh Center for Healthy Aging, Key to Life Nutrition Program. SUBJECTS: Hypertensive adults at least 65 years of age. RESULTS: Mean age of participants was 75 years. Twenty-four hour mean urinary Na excretion at baseline was 3174 mg/d. This reduced to 2944 mg/d (P = 0.30) and 2875 mg/d (P or=1000 ml, baseline to 12 months), mean urinary Na excretion decreased from 3220 mg/d to 2875 mg/d (P or=2 (presence of two or more metabolic syndrome components except for waist circumference) and at least one risk factor (diabetes, hypertension or dyslipidaemia) were categorical outcome variables. Receiver-operating characteristic (ROC) curves were prepared by plotting 1 - specificity on the x axis and sensitivity on the y-axis. The WHtR value that had the highest Youden index was selected as the optimal cut-off point for each cardiometabolic risk factor (Youden index = sensitivity + specificity - 1). SETTING: Turkey, 2003. SUBJECTS: Adults (1121 women and 571 men) aged 18 years and over were examined. RESULTS: Analysis of ROC coordinate tables showed that the optimal cut-off value ranged between 0.55 and 0.60 and was almost equal between men and women. The sensitivities of the identified cut-offs were between 0.63 and 0.81, the specificities were between 0.42 and 0.71 and the accuracies were between 0.65 and 0.73, for men and women. The cut-off point of 0.59 was the most frequently identified value for discrimination of the studied cardiometabolic risk factors. Subjects classified as having WHtR >or= 0.59 had significantly higher age and sociodemographic multivariable-adjusted odds ratios for cardiometabolic risk factors than subjects with WHtR < 0.59, except for diabetes in men. CONCLUSIONS: We show that the optimal WHtR cut-off point to discriminate cardiometabolic risk factors is 0.59 in Turkish adults. PMID- 19781127 TI - Evaluation of a nutrition intervention in adolescents of an urban area in Greece: short- and long-term effects of the VYRONAS study. AB - OBJECTIVE: To assess the short-term (15-d) and long-term (12-month) effects of a school-based health and nutrition education intervention on diet, nutrition intake and BMI. DESIGN: The 12-week teacher-implemented intervention in combination with seminars organized for parents was aimed at improving children's diet and nutrition knowledge. The intervention took place between September 2007 and January 2008. The participants were randomized to two study groups, the intervention group (IG) and control group (CG), and were examined prior to the intervention on a variety of health knowledge, dietary, behavioural and anthropometric indices. The same measurements were collected 15 d and 1 year after the intervention. SETTING: All high schools in Vyronas, a densely populated district of Athens, Greece. SUBJECTS: The sample consisted of 191 students aged 12-13 years. RESULTS: Twelve months after the intervention, the programme was effective in reducing various indices in the IG compared with baseline findings (BMI: 23.3 (sd 2.8) v. 24.0 (sd 3.1) kg/m2, P < 0.001; daily energy intake: 8112.4 (sd 1412.4) v. 8503.3 (sd 1419.3) kJ/d, P < 0.001; total fat intake: 31.3 (sd 4.4) v. 35.4 (sd 4.7) % of daily energy, P < 0.001). Except for BMI, decreases in the aforementioned indices were also observed 15 d after the intervention. In addition, students of the IG reduced their weekly consumption of red meat and non-home-made meals and increased their frequency of fruit and breakfast cereal consumption. CONCLUSIONS: The beneficial effects of this nutrition education intervention among adolescents may highlight the potential of such programmes in the prevention of obesity. PMID- 19781129 TI - Development of larval Contracaecum rudolphii Hartwich, 1964 (Ascaridida: Anisakidae) in experimentally infected goldfish (Carassius auratus L., 1758). AB - Laboratory-bred goldfish were experimentally infected with Contracaecum rudolphii, either directly (with nematode larvae) or indirectly via infected zooplankton. Intensity and prevalence of infection were markedly higher in fish exposed to the infected zooplankton than in goldfish exposed to nematode larvae. When transmitted to fish via the zooplankton, larvae developed much faster and, after 8 weeks, became firmly encysted in the intestine wall. The digestive tract of larvae isolated from the intestine wall showed a well-developed ventriculus, ventricular appendix and intestinal caecum. The mouth was surrounded by three lips. When free-living larvae induced infection, they rapidly penetrated the intestine wall and migrated to internal organs (e.g. liver). The primordial lips of those larvae were poorly visible, the ventricular appendix was short, and the intestinal caecum was absent. During the 10-week experiment, no encysted larvae were found in fish infected with free-living larvae. PMID- 19781130 TI - Relative expression of antigen B coding gene of bubaline isolates of Echinococcus granulosus in fertile and sterile cysts. AB - This article communicates the relative quantification of five isoforms of antigen B (AgB) of Echinococcus granulosus. Relative expression of the AgB was quantified in active and inactive cysts. Cysts with germinal membrane, clear cyst fluid and protoscoleces showed uniform expression of the five isoforms and were utilized as control. Relative expression of AgB1 was the highest in cysts, where calcification has initiated. AgB2 and AgB4 were expressed more in fertile cysts irrespective of the condition of germinal membrane. The lowest expression of AgB3 was seen in calcified cysts. The relative expression of AgB5 could not be correlated with respect to the condition of the cyst because AgB5 is typically expressed by the adult stage of the parasite. PMID- 19781131 TI - Vitamin D supplementation reduces insulin resistance in South Asian women living in New Zealand who are insulin resistant and vitamin D deficient - a randomised, placebo-controlled trial. AB - Low serum 25-hydroxyvitamin D (25(OH)D) has been shown to correlate with increased risk of type 2 diabetes. Small, observational studies suggest an action for vitamin D in improving insulin sensitivity and/or insulin secretion. The objective of the present study was to investigate the effect of improved vitamin D status on insulin resistance (IR), utilising randomised, controlled, double blind intervention administering 100 microg (4000 IU) vitamin D(3) (n 42) or placebo (n 39) daily for 6 months to South Asian women, aged 23-68 years, living in Auckland, New Zealand. Subjects were insulin resistant - homeostasis model assessment 1 (HOMA1)>1.93 and had serum 25(OH)D concentration < 50 nmol/l. Exclusion criteria included diabetes medication and vitamin D supplementation >25 microg (1000 IU)/d. The HOMA2 computer model was used to calculate outcomes. Median (25th, 75th percentiles) serum 25(OH)D(3) increased significantly from 21 (11, 40) to 75 (55, 84) nmol/l with supplementation. Significant improvements were seen in insulin sensitivity and IR (P = 0.003 and 0.02, respectively), and fasting insulin decreased (P = 0.02) with supplementation compared with placebo. There was no change in C-peptide with supplementation. IR was most improved when endpoint serum 25(OH)D reached > or = 80 nmol/l. Secondary outcome variables (lipid profile and high sensitivity C-reactive protein) were not affected by supplementation. In conclusion, improving vitamin D status in insulin resistant women resulted in improved IR and sensitivity, but no change in insulin secretion. Optimal vitamin D concentrations for reducing IR were shown to be 80 119 nmol/l, providing further evidence for an increase in the recommended adequate levels. Registered Trial No. ACTRN12607000642482. PMID- 19781132 TI - Assessing physical activity in general practice: a disconnect between clinical practice and public health? AB - BACKGROUND: GPs comply poorly to public health recommendations to routinely assess their patients' physical activity. The reasons for this disconnect between recommended practice and GPs' actual practice are unclear. AIM: To investigate GPs' perceptions of assessing physical activity, and to explore how GPs assess their patients' physical activity. DESIGN OF THE STUDY: Qualitative study. SETTING: General practice. METHOD: Semi-structured interviews were performed with 15 randomly selected southern Tasmanian GPs, with stratification to include GPs with a range of demographic characteristics. Each interview was recorded, transcribed in full, and analysed using an iterative thematic approach to identify major themes. RESULTS: GPs recognised the importance of assessing physical activity, but rather than assessing every patient, they target at-risk patients and those with conditions likely to benefit from increased physical activity. Depth of assessment and GPs' definition of sufficient physical activity varied according to the clinical and social context of each patient. Major barriers were the time needed to perform an adequate assessment and lack of time to deal with physical inactivity in patients once it was identified. CONCLUSION: GPs' assessment of physical activity is a complex and highly individualised process that cannot be divorced from the issue of managing physical inactivity once it is identified. Expectations that GPs will assess physical activity levels in all their patients are unlikely to be met. This must be taken into account when developing strategies to improve physical activity assessment in general practice, and should be considered in policy decisions about approaches to take to improve physical activity levels at a population level. PMID- 19781135 TI - Nonlinear detrended fluctuation analysis of sitting center-of-pressure data as an early measure of motor development pathology in infants. AB - Upright sitting is one of the first motor skills an infant learns, and thus sitting postural control provides an early window into the infant's motor development. Early identification of infants with motor developmental delay, such as infants with cerebral palsy, allows for early therapeutic intervention by physical therapists. Early intervention is thought to produce better outcomes, due to greater neural plasticity in younger infants. Postural sway, as measured by a force plate, can be used to objectively and quantitatively characterize infant motor control during sitting. Pathology, such as cerebral palsy, may alter the fractal properties of motor function. Often physiologic time series data, including infant sitting postural sway data, is mathematically non-stationary. Detrended Fluctuation Analysis (DFA) is useful to characterize the fractal nature of time series data because it is does not assume stationarity of the data. In this study we found that suitable selection of the order of the detrending function improves the performance of the DFA algorithm, with a higher order polynomial detrending better able to distinguish infant sitting posture time series data from Brown noise (random walk), and first order detrending better able to distinguish infants with motor delay (cerebral palsy) from infants with typical development. PMID- 19781136 TI - Target dimension affects 1/f noise in aiming. AB - The present study tested for 1/f noise to examine how timing and target constraints affect cognitive processes in aiming. Participants pointed to targets of varied height and width at preferred speed (Experiment 1) and as quickly as possible (Experiment 2). Results show greater intensity of 1/f noise, or long range correlation in variability, at preferred speed and with increased accuracy demands perpendicular to the target (i.e., related to height). Prior research suggests that increased 1/f noise in movement reflects increased coordination of processes at different timescales (e.g., planning and control), particularly when there is more time to complete the movement. Previous studies also suggest that target height constraints promote more reliance on both predictive and reactive control, as more time is spent during initial aiming and adjustment. Thus, present results expand on what we know about aiming movements in two ways: (a) by further suggesting a non-orthogonal relation between planning (coarse aiming) and control (fine tuning) that is time dependent; and (b) by demonstrating that such an integration of processes, reflected in distinct patterns of 1/f noise, may be modulated by multiple environmental characteristics (i.e., target shape). PMID- 19781137 TI - Interdisciplinary matrix in economics: two applications to the transition from socialism to capitalism. AB - The 7-fold interdisciplinary matrix is introduced. This integrated methodological point of view is original, although it is based on ideas of others in various ways. The name for this new approach draws on the Kuhnian notion of a disciplinary matrix. There are four components of the Kuhnian matrix on which the existence of scientific communities hinges: symbolic generalizations, models, values, and exemplars. In this context the term "paradigm" should refer to exemplars. The interdisciplinary matrix is composed of seven elements: cybernetics, catastrophe theory, fractal geometry, deterministic chaos, artificial intelligence, theory of complexity, and humanistic values. Scientific developments have recently brought substantial changes in the structure of scientific communities. Transferability of ideas and thoughts contributed to the creation of scientific communities, which unite representatives of various professions. When researching into certain phenomena we no longer need to develop theories for them from scratch, as we can draw on the achievements in other disciplines. Two examples of the employment of the interdisciplinary matrix in macroeconomics are elaborated here: the investment cycle model in socialist economy, and the model of economic transformation based on chaotic hysteresis. PMID- 19781138 TI - Turning points in nonlinear business cycle theories, financial crisis and the 2007-2008 downturn. AB - This paper reviews three nonlinear dynamical business cycle theories of which only one (The Goodwin model) reflects the stylized facts of observed business cycles and has a plausible turning point mechanism. The paper then examines the US (and now global) financial crisis of 2008 and the accompanying downturn in the US. The paper argues that a skewed income distribution could not sustain effective demand and that over the 2001-2006 expansion demand was maintained through massive amounts of credit, with more than 50 percent of sales in the US being maintained through credit. A vector autoregression model confirms the crucial role played by credit. However legislative changes that dismantled the restrictions placed on the financial sector after the crash of 1929 and the consequent structural changes in the financial sector after 1980 enabled the growth of new debt instruments and credit. But overexpansion of credit when profits and house prices were declining in 2005/06 led to a nonlinear shift due to a new realization of the poor quality of some of this debt, namely mortgage backed securities. Bankruptcies, followed by retrenchment at the banks, then led to the bursting of the credit bubble, with the possibility of a severe recession. PMID- 19781139 TI - Unemployment and inflation dynamics prior to the economic downturn of 2007-2008. AB - This article revisits a long-standing theoretical issue as to whether a "natural rate" of unemployment exists in the sense of an exogenously driven fixed-point Walrasian equilibrium or attractor, or whether more complex dynamics such as hysteresis or chaos characterize an endogenous dynamical process instead. The same questions are posed regarding a possible natural rate of inflation along with an investigation of the actual relationship between inflation and unemployment for which extent theories differ. Time series of unemployment and inflation for US data - were analyzed using the exponential model series and nonlinear regression for capturing Lyapunov exponents and transfer effects from other variables. The best explanation for unemployment was that it is a chaotic variable that is driven in part by inflation. The best explanation for inflation is that it is also a chaotic variable driven in part by unemployment and the prices of treasury bills. Estimates of attractors' epicenters were calculated in lieu of classical natural rates. PMID- 19781140 TI - [To promote the appropriate use of beta-adrenergic receptor blocker following Chinese expert consensus document.]. PMID- 19781141 TI - [Expert consensus document on appropriate use of beta-adrenergic receptor blocker in patients with cardiovascular diseases.]. PMID- 19781142 TI - [Inflammation may play a key role in in-stent restenosis.]. PMID- 19781143 TI - [Current clinical practice patterns and outcome for acute coronary syndromes in China: results of BRIG project.]. AB - OBJECTIVE: To analyze current clinical management patterns and outcome of inpatients with ST segment elevation acute coronary syndromes (ACS) in China. METHODS: Totally 1304 in-patients with ST segment elevation ACS from 64 hospitals across China were recruited and a standard questionnaire was used to get information of the patients including demographic, treatments and in-hospital outcomes. RESULTS: (1) There were no significant differences in baseline characteristics between the patients from tertiary hospitals and that from the secondary hospitals. (2) Reperfusion therapy was applied more often in tertiary hospitals (57.9%) than in secondary hospitals (42.3%). Thrombolysis was more often used in secondary hospitals than that in tertiary hospitals (37.4% vs. 14.5%). The median time from pain onset to hospital was 240 min, the median time from admission to reperfusion was 60 min for thrombolysis and 110 min for PCI. (3) Statins and glycoprotein IIb/IIIa antagonists were given more frequently in tertiary hospitals. (4) Major in-hospital events and death rates were significantly higher in secondary hospitals than in tertiary hospitals. Multivariate logistic regression analysis showed that age >/= 75 years, hypertension, diabetes, reperfusion, aspirin, beta-blocker and ACE/ARB inhibitor use were associated independently with in-hospital mortality. CONCLUSIONS: There is a big gap between guidelines and current management of ST segment elevation ACS in China, especially in secondary hospitals. PMID- 19781144 TI - [The relationship between plasma BNP level and the left ventricular dysfunction parameters in patients with acute myocardial infarction and it's value in diagonosing heart failure.]. AB - OBJECTIVE: To explore the correlation between plasma BNP level and left ventricular dysfunction parameters in patients with acute myocardial infarction (AMI). METHODS: Plasma BNP level was determined in 230 consecutive inpatients with AMI and 111 normal controls. Patients were grouped according Killip grades, LVEF and LVEDd, respectively. BNP was transformed into lnBNP for the normal distribution. The receiver operator characteristic curve (ROC curve) was drawn to determine the best threshold and criteria for diagnosing heart failure. RESULTS: After AMI, lnBNP levels increased significantly in proportion with increasing Killip grades (I-III), and decreasing LVEF (all P < 0.05). lnBNP level was significantly higher in LVEDd > 55 mm group than in the LVEDd < 55 mm group (P < 0.01). lnBNP, LVEDd and LVEF all linearly correlated with Killip grades (P < 0.05) and the best correlation was shown between lnBNP and Killip grades (r = 0.53, P < 0.05). lnBNP also positively correlated with LVEDd (r = 0.17, P < 0.05) and negatively correlated with LVEF (r = -0.41, P < 0.01). Among the parameters, lnBNP level presented the largest AUC in their ROC curves (P < 0.01) for diagnosing decompensated heart failure and cardiogenic shock. The sensitivity, specifiticity and accuracy rates for diagnosing decompensated heart failure were 84.9%, 45.0% and 70.0% respectively by lnBNP at the cut point of 140 ng/L. The sensitivity, negative predicting value and accuracy rate for diagnosing cardiac shock were 82.8%, 66.7% and 67.4% respectively by BNP at the cut point of 400 ng/L. CONCLUSION: lnBNP level in hospitalized patients with AMI was positively correlated with Killip grades and LVEDd, negatively correlated with LVEF and could serve as a parameter for diagnosing the decompensated heart failure and excluding the cardiac shock. PMID- 19781145 TI - [Low-dose adenosine echocardiography for detection of myocardial viability in patients with acute myocardial infarction.]. AB - OBJECTIVE: To evaluate the value of low-dose adenosine echocardiography (LDAE) for detection of myocardial viability in patients with acute myocardial infarction (MI). METHODS: Thirty-six patients underwent LDAE within 3 - 10 days after onset of first acute MI before (n = 4) or after (n = 32) percutaneous coronary intervention. A 17-segment semi-quantitative scoring model was adopted. Wall motion improvement derived from two dimensional images at follow-up (2 - 3 months after acute MI) comparing baseline before adenosine infusion was used as gold criteria for myocardial viability. RESULTS: Low-dose adenosine slightly increased heart rates [(70.7 +/- 10.8) beats/min vs. (78.1 +/- 10.9) beats /min, P < 0.01] and also significantly reduced left ventricular endsystolic volume [(30.4 +/- 1.9) ml vs. (20.1 +/- 9.3) ml, P < 0.01] and increased ejection fraction (62.6% +/- 10.4% vs. 74.7% +/- 9.8%, P < 0.01). The sensitivity, specificity, diagnostic accuracy, positive and negative prective values of LDAE for identification of viable myocardium were 90.3%, 80.8%, 86.0%, 84.8% and 87.5%, respectively. Incidence of mild adverse reaction during LDAE was 38.9% (14/36). LDAE at dose of 100 microgxkg(-1)xmin(-1) was ideal in terms of balanced sensitivity and specificity for detecting viable myocardium without increasing the adverse effects compared to lower doses. CONCLUSIONS: LDAE (100 microgxkg( 1)xmin(-1)) has excellent sensitivity and specificity for detecting viable myocardium in acute MI with only minimal adverse effects. PMID- 19781146 TI - [The protective role of transient receptor potential vanilloid subtype 1 in post myocardial infarction inflammation process.]. AB - OBJECTIVE: To investigate the protective role of transient receptor potential vanilloid subtype 1 (TRPV1) in inflammatory process after myocardial infarction. METHODS: The survival rate, infarct size, the levels of plasma cardiac troponin I, infiltration of inflammatory cells, the levels of cytokines and chemokines, and cardiac function were monitored 3 and 7 days post-myocardial infarction in TRPV1 gene knockout (TRPV1(-/-)) and wild type (WT) mice. RESULTS: The survival rate was significantly lower in TRPV1(-/-) mice than that in WT mice (62.5% vs. 82.1%, P < 0.05). The infarct size on day 3 after MI was significantly larger in TRPV1(-/-) mice than that in WT mice (INF/AAR: 69.5% +/- 3.1% vs. 40.1% +/- 2.6%, P < 0.05). Plasma cardiac troponin I level, number of infiltrated inflammatory cells including neutrophils and macrophages were significant increased in TRPV1( /-) mice compared to WT mice. Expressions of cytokines including TNF-alpha, IL 1beta, and IL-6, chemokines including MCP-1 and MIP-2 in the infarct area at 3 and 7 days after MI were significantly higher in TRPV1(-/-) mice than those in WT mice (all P < 0.05). Furthermore, end-systolic and -diastolic diameters were significantly increased and contractile function of the heart significantly reduced in TRPV1(-/-) mice compared to WT mice. CONCLUSION: TRPV1 gene deletion results in reduced survival rate, excessive inflammation, deteriorated cardiac function and aggravated left ventricular remodelling after MI, indicating that TRPV1 may prevent infarct expansion and cardiac injury by inhibiting inflammation and reservation cardiac function. PMID- 19781147 TI - [Gelatin microspheres containing vascular endothelial growth factor enhances the efficacy of bone marrow mesenchymal stem cells transplantation in a swine model of myocardial infarction.]. AB - OBJECTIVE: To investigate the efficacy of transplantation of mesenchymal stem cells (MSC) with gelatin microspheres containing vascular endothelial growth factor in ischemic regions in infracted swine hearts. METHODS: Twelve Chinese mini swines with infarction were randomized to receive autogenetic MSC injection to the peri-infarction area of left ventricular wall (MSC group, n = 6) or MSC transplantation with gelatin hydrogel microspheres incorporating vascular endothelial growth factor (VEGF-MSC group, n = 6). Three weeks later, left ventricular function was assessed by magnetic resonance imaging (MRI). The contrast of the MSC hypointense lesion was determined using the difference in signal intensity between the hypointense and normal myocardium divided by signal intensity of the normal region. Myocardial capillary density, the number of DAPI positive MSC and the apoptotic MSC were also determined. RESULTS: The diameter of the microspheres averaged (104.0 +/- 22.6) microm. At 24 hours after transplantation, MSC were identified by MRI as large intramyocardial signal voids at injection sites which persisted up to 3 weeks. There was no significant difference in the contrast of the lesions and in the size of the lesions at 24 hours between two groups. At 3 weeks after injection, the size of the lesions and the contrast of the lesion were decreased (P < 0.05) in both groups. The capillary density of the injection site was significantly more in the MSC-VEGF microsphere group than that in MSC group [(15.2 +/- 5.4)/HPF vs. (10.2 +/- 5.0)/HPF, t = 2.43, P < 0.05], and there were more dense DAPI labeled MSC per high power fields in injection sites of MSC-VEGF microsphere group than that in MSC group [(354 +/- 83)/HPF vs. (278 +/- 97)/HPF, t = 3.14, P < 0.05]. Moreover, the apoptosis rate of MSCs of MSCs-VEGF microsphere group was less than that of MSC group [(6.4 +/- 4.1)% vs. (11.9 +/- 4.8)%, t = 2.97, P < 0.05]. CONCLUSIONS: MSC transplantation with gelatin hydrogel microspheres incorporating VEGF enhanced the efficacy of MSC in this swine model of myocardial infarction. MRI tracking of MSC is feasible and represents a preferred method for studying the engraftment of MSCs in infracted tissue. PMID- 19781148 TI - [Report of a case of fatal side effect of captopril.]. PMID- 19781149 TI - [The Chinese coronary artery bypass grafting registry report: 2004-2005.]. AB - OBJECTIVE: Number of coronary artery bypass grafting (CABG) increased steadily during the past decade as a result of a higher incidence of coronary artery disease in China. However, little is known about the current status of CABG surgery in contemporary China. This study was to get exact information on CABG in China. METHODS: A national multicentre database of patients undergoing CABG with the name of the Chinese CABG Registry Study was established at Fuwai hospital, Beijing, China which is the biggest cardiac centre of China in 2006 and 32 centers of cardiac surgery all over China (mainland) participated in the study. Registry forms were used to collect related information of patients undergoing CABG in these centers for statistical analysis. RESULTS: From January 2004 to December 2005, CABG was performed in 9247 consecutive patients with coronary artery disease. Mean age was (62.1 +/- 9.1) years and 21.5% patients were female, 76.7% patients had triple vessel disease, and 25.8% patients had left main disease. Overall in-hospital mortality was 3.3%. The in-hospital mortality of isolated CABG was 2.2%. CONCLUSION: The in-hospital mortality and the incidences of major accidents of surgery were low in these patients underwent CABG. The operative risk evaluating system for the Chinese CABG patients should be established to improve the survival of CABG operation in China. PMID- 19781150 TI - [Relationship between serum resistin level and large arterial elasticity in patients with essential hypertension.]. AB - OBJECTIVE: To investigate the association between serum resistin concentration and large arterial elasticity in patients with essential hypertension (EH). METHODS: 271 recruited subjects were divided into the control group (n = 134) and EH group (n = 137). Blood pressure, waist circumference, hip, body mass index (BMI) were measured. Serum resistin concentration was assessed by enzyme immunoassay, fasting serum insulin and TNF-alpha were measured using radioimmunity kits. Insulin resistance was evaluated by insulin resistance index (HOMA-IR). Brachial ankle pulse wave velocity (baPWV) was tested by the full automatic arteriosclerosis diagnostic instrument. RESULTS: (1) The serum resistin concentration, baPWV and TNF-alpha were significantly increased in EH group compared to the control group [(0.65 +/- 0.12) microg/L vs (0.59 +/- 0.13) microg/L; (1513.24 +/- 182.30) cm/s vs (1301.69 +/- 151.15) cm/s; (5.69 +/- 1.98) microg/L vs (3.83 +/- 2.38) microg/L; all P < 0.01]. (2) Pearson correlation analysis showed that resistin was positively correlated with baPWV, TNF-alpha. and HOMA-IR in EH group (r = 0.219, r = 0.212, r = 0.183, P < 0.05 respectively); partial correlation analysis revealed that resistin was positively correlated with baPWV and TNF-alpha (r = 0.238, P < 0.01; r = 0.207, P < 0.05), but not with HOMA-IR. (3) Multivariate regression analysis showed that SBP, age, TNF-alpha, resistin were risk factors of impaired baPWV in EH group (R(2) = 0.368, P < 0.01). CONCLUSION: Large arterial elasticity was decreased in proportion to increasing serum resistin level in hypertensive patients. PMID- 19781151 TI - [Clinical characteristics and treatment of a Chinese family with congenital short QT syndrome.]. AB - OBJECTIVE: To observe the clinical characteristics and therapeutic efficacy of a Chinese family with congenital short QT Syndrome (SQTs). METHODS: Fourteen family members including the proband were screened with routine clinical examination, serum electrolyte, serum myocardial enzymes, electrocardiography (ECG), Holter recording, treadmill exercise test, echocardiography and chest radiograph. High risk patient received intracardiac electrophysiological study (EPS). RESULTS: Among the fourteen family members, 4 members died of sudden cardiac death at young ages, 4 members including the proband and his two daughters and one son were diagnosed as SQTs with structurally intact hearts. Initial ECG in these subjects revealed sinus rhythm with a high peaked T wave, QTc interval 150 and < 450. In TWP group, subjects received TWP tablets (1.0 - 1.5 mg x kg(-1) x d(-1)) with uncontrolled diets; while in the group of combination therapy, the patients were given total enteral nutrition (TEN) through tube feeding in addition to TWP tablets. Clinical response was defined by a decrease of at least 70 points in the CDAI from baseline after treatment, and clinical remission was defined as the absolute value of CDAI (less than 150). Patients' nutritional and disease activity index, such as CDAI score, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), were determined at 0, 4, and 12 weeks after treatment. RESULTS: The ratio of clinical response (78.6% vs. 40.0%, P = 0.003) and clinical remission (69.1% vs. 30.0%, P = 0.004) were both significantly higher in the combined treatment group than in those the TWP group at week 4. At week 12, the clinical response ratio was significantly higher in the combined treatment group (90.5% vs. 65.0%, P = 0.014); the remission ratio was also higher in the combined treatment group (76.2% vs. 55.0%, P = 0.091). The nutritional parameters improved from baseline at week 4 and 12 in the combined treatment group but not in TWP group. At week 4, blood albumin, prealbumin, and transferrin levels was higher in the combined treatment group than those in TWP group (P < 0.05); at week 12, patients in combined treatment group also had significantly higher body mass index (BMI), blood albumin, prealbumin, transferrin and hemoglobin levels (P < 0.05). CONCLUSIONS: Treatment with enteral nutrition and TWP in combination are superior to TWP alone for induction of clinical response and remission in adult Crohn's Disease. This strategy also improves patient's nutritional status and avoids the adverse effects of traditional therapy. PMID- 19781165 TI - [Feasibility of small size graft following living donor liver transplantation]. AB - OBJECTIVE: To analyze the complication rate and survival rate of the patients whose graft-recipient weight ratio (GRWR) less than 0.8% following living donor liver transplantation (LDLT). METHODS: There were 92 consecutive LDLT patients from January 2001 to December 2007 in West China Hospital, Sichuan University. There were 85 males and 7 females aged from 18 to 65 years old (averaged, 42 years old) and among which 89 patients were involved in the study. There were 15 patients whose GRWR less than 0.8% (group 1), while other 74 recipients were in group 2. Comparing the two groups' complication rates and survival rates and finding out the potential influencing factor of small-size-graft recipients' survival rate. RESULTS: The survival rates of group 1 and group 2 were 73.3% (11/15) and 71.6% (53/74), respectively. The grade II-V complication rates of group 1 and group 2 were 46.7% (7/15) and 48.6% (36/74), respectively. There were no difference in survival rates (chi(2) = 0.058, P = 0.811) and complication rates (chi(2) = 0.000, P = 1.000) between the two groups. Ascites volume of group 1 and group 2 were (1532 +/- 322) ml and (1466 +/- 110) ml, respectively (t = 0.234, P = 0.815). The condition of the graft's middle hepatic vein had significant influence on small-size-liver recipients' survival rates (chi(2) = 6.821, P = 0.009). CONCLUSIONS: GRWR < 0.8% is not the limitation of the living donor liver transplantation but the outflow tract of the graft must be unobstructed. PMID- 19781166 TI - [Characteristics of hemoglobin changes and its significance in critically ill patients]. AB - OBJECTIVES: To investigate characteristics of hemoglobin changes in surgical critically ill patients. METHODS: One hundred and ten consecutive critically ill patients admitted to the surgical ICU of Shanghai Ruijin Hospital were prospectively included in the clinical trial from January 2004 to December 2006. And changes of hemoglobin and prognosis were retrospectively analyzed. The inclusion criteria were surgical critical illness, APACHE II > or = 8 points, and admission to ICU within 48 hours after onset of critical illness, except for patients with bleeding. According to hemoglobin level before transfusion, 110 patients divide into the low level hemoglobin group (< or = 100 g/L) and the high level hemoglobin group (> 100 g/L). Time interval for valley value of hemoglobin within 28 days and incidence of hypo-hemoglobin (< or = 100 g/L) were investigated; the mean hemoglobin level, mean APACHE II scores, amount of concentrated red blood cells and rate of mechanical ventilation as well as duration of ventilation within 28 days were calculated. ICU survival rate was observed. RESULTS: Level of hemoglobin in low level group was decreased significantly compared to high level group [(86.3 +/- 23.8) g/L vs. (112.9 +/- 20.4) g/L, P < 0.01]; and time of its valley values was shorter than that of high level group [(3 +/- 1) d vs. (5 +/- 2) d, P < 0.01]; the responding level of hemoglobin was (89.3 +/- 11.3) g/L and (110.0 +/- 12.5) g/L (P = 0.001), respectively. Incidence of hypo-hemoglobin was 92.9% in low level group and 0 in high level group within 28 days (P < 0.01). Hemoglobin level of high level group was significantly higher than that of low level group within 28 days [(120.2 +/- 12.5) g/L vs. (89.3 +/- 11.3) g/L, P < 0.05], and the total amount of blood transfusion in high level group was less significantly than that of low level group [(12.4 +/- 10.1) U vs. (24.0 +/- 15.6) U, P = 0.042]; mean APACHE II score in high level group was significantly lower than that of low level group [(8.7 +/ 2.4) vs. (13.2 +/- 4.3), P < 0.001]; rate of mechanical ventilation was no difference (56.4% vs. 52.7%, P = 0.765); but duration of mechanical ventilation was shorter than that of low level group [(12 +/- 5) d vs. (25 +/- 7) d, P < 0.001]. Survival rate in high level group in ICU was significantly higher than that of low level group (80.0% vs. 61.8%, P = 0.036). CONCLUSION: Prolonged hypo hemoglobin level (< or = 100 g/L) and valley value in advance suggest bad prognosis. PMID- 19781167 TI - [The surgical management of sacral chordoma]. AB - OBJECTIVE: To analyze the surgical treatment results and experience of sacral chordoma. METHODS: The data of 51 cases of sacral chordoma surgically treated from July 1997 to July 2007 was retrospectively studied. The age of patients ranged from 21 to 75 years (mean 57 years), including 32 males and 19 females. Forty patients had the first surgery, while other 11 patients were referred to our hospital because of local recurrence from other hospital. Wide resection for all 17 S(3-5) tumors, and wide resection plus piece-meal excision for 34 tumors which involved S(3) above. Reconstruction was performed using pedicle screw and rod device to achieve the continuity between the lumbar spine and the pelvis. The oncologic and functional outcomes of 51 patients were reviewed. RESULTS: After a mean duration of follow-up of 3.5 years (range from 15 to 108 months), 5 of 51 patients died of disease. Seventeen of 40 (42.5%) patients who underwent first surgery recurred during follow-up, 18 of 28 patients (64.3%) got re-relapse after second or third surgeries. Postoperative wound complications were as high as 31.6%. CONCLUSIONS: Chordoma is a biologically aggressive low-grade malignant tumor. Wide resection is a prerequisite for curative treatment of sacrococcygeal chordoma, intralesional curettage causes the risk of high local recurrence for which curative resection in a second or third procedure is more difficult to achieve. In order to preserve near normal bowel and bladder function for the tumor which involves S(3) above, wide en-bloc resection plus piece-meal excision in the cephalad is performed. PMID- 19781169 TI - [Analysis of change in length of glenohumeral ligaments in vivo during shoulder abduction]. AB - OBJECTIVE: To investigate the in vivo and three-dimensional (3D) length changes of the glenohumeral ligaments during shoulder abduction using open magnetic resonance imaging (MRI). METHODS: From 2007 to 2008 3D attachment points of the glenohumeral ligaments were obtained by anatomical study and computed tomographic scanning of 10 embalmed cadaveric shoulders, including the superior glenohumeral ligament (SGHL), middle glenohumeral ligament (MGHL), the anterior band of the inferior glenohumeral ligament (AIGHL), axillary pouch and the posterior band of the inferior glenohumeral ligament (PIGHL). Then an in vivo study was conducted, in which 14 right shoulder joints of 14 healthy volunteers were evaluated in 7 isometric abduction positions (0 degrees , 30 degrees , 60 degrees , 90 degrees , 120 degrees , 150 degrees and 180 degrees ) using a noninvasive 3D motion analysis system. 3D models of the shoulders and located the attachment points of the ligaments were created. Ligament lengths were based on the shortest calculated paths between each origin and insertion in 3D space along the 3D bone surface for each abduction position. RESULTS: During shoulder abduction, the 3D distance of SGHL was found to elongated and attained maximal length at 30 degrees abduction (P = 0.2). MGHL and AIGHL attained maximal length at 60 degrees (P < 0.05) and 120 degrees (P < 0.05) abduction, respectively. Pouch and PIGHL reached the maximal length at 180 degrees abduction (P < 0.05). CONCLUSIONS: The SGHL limits inferior translation of the humeral head at 30 degrees of abduction. MGHL maintains maximum anterior stability at 60 degrees of abduction. AIGHL prevents anterior dislocation of the humeral head at 120 degrees of abduction. In 180 degrees abduction, pouch provided anterior stability and PIGHL has the contribution to the inferior stability. PMID- 19781170 TI - [The diagnosis and treatment of rotational unstable nonunion of femoral shaft fracture after interlocking nailing]. AB - OBJECTIVE: To evaluate the principle and treatment of rotational unstable nonunion of the femoral shaft fracture after interlocking nailing. METHODS: From April 2003 to June 2007, 18 cases of rotational unstable nonunion of femoral shaft fractures after interlocking nailing were treated with exchanged reamed nailing and/or LCP fixation and iliac bone graft. The average age was 40 years old (from 22 to 52). RESULTS: All patients were followed up for an average time of 28 months (from 12 to 58). All the fractures were united in an average time of 7 months (from 6 to 8). There were no perioperative complications occurred and no wound infection were observed. No loosening was found around the implant till the last follow-up. CONCLUSIONS: Rotational instability is one of the reasons of nonunion of femoral shaft fracture after interlocking nailing. Reaming and nail exchanging or LCP fixation with iliac bone graft are the appropriate methods which can achieve a great clinic results. PMID- 19781171 TI - [Clinical outcome of mitral valve repair in primary infective endocarditis with mitral insufficiency]. AB - OBJECTIVE: To study the clinical results of mitral valve repair in patients of primary infective endocarditis with mitral insufficiency. METHODS: From January 2004 to July 2007, 40 patients who had undergone valve repair procedure for infective endocarditis with mitral insufficiency were analyzed retrospectively. There were 26 male and 14 female patients, with an average age of (34.0 +/- 3.5) years old, including 6 patients of underlying heart disease, 34 patients of no previously underlying heart disease. There were 12 patients in NYHA functional class II, 19 patients in class III, 9 patients in class IV preoperatively. Preoperative echocardiography showed moderate to severe MR in all patients. The surgery was performed under extracorporeal circulation and moderate hypothermia. The distribution of anatomical lesion according to surgical findings were vegetation in 32 patients, leaflet prolapsed in 34 patients, leaflet perforation in 16 patients, chordal rupture in 32 patients, and annular abscess in 2 patients. The vegetations and infected tissues were debrided. The surgery consisted of complex methods to repair mitral valve, including direction leaflet closure in 5 patients, pericardial patch closure of leaflet perforation in 18 patients, chords reimplantation in 4 patients and chords transference in 6 patients, quadrangular resection in 12 patients, double orifice method in 17, closure of the commissure in 8, rings annuloplasty in 28 cases, and so on. There were 28 selective surgeries and 12 emergent ones. Patients were evaluated for early and long-term clinic and echocardiographic outcome before and after operation. RESULTS: There were no early postoperative death. Mitral valve repair was feasible in 39 patients, one patient was transformed to mitral valve replacement during the operation. Postoperative echocardiography demonstrated no (n = 24) or mild (n = 15) mitral regurgitation at the discharge examination and observed significant reductions in left ventricular end diastolic [from (62 +/- 7) mm to (51 +/- 6) mm, P < 0.05] and end systolic dimensions [from (45 +/- 3) mm to (40 +/- 4) mm, P < 0.05] and left atrial dimensions [from (49 +/- 4) mm to (42 +/- 6) mm, P < 0.05]. Mean follow-up (25.6 +/- 3.2) months, freedom from recurrent moderate to severe MR, freedom from repeat operation or infective endocarditis, revealed patients were 36 cases in NYHY class I, 3 cases in class II. CONCLUSION: Mitral valve repair for mitral valve endocarditis is feasible with a satisfied clinical outcome, maintains valve competency with significant reductions in left atrial and left ventricular dimensions after surgery. PMID- 19781172 TI - [Diagnosis and treatment for the corticomedullary mixed tumor of adrenal gland]. AB - OBJECTIVE: To study and summarize the diagnosis and treatment for the corticomedullary mixed tumor of adrenal gland. METHODS: The clinical data of 25 cases of adrenal corticomedullary mixed tumor from January 2000 to April 2008 were analyzed retrospectively, which including 9 males and 16 females. The ages were from 25 to 60 years old, and the average age was 39 years old. Thirteen cases had paroxysmal hypertension and 11 cases had central obesity, as well as 8 cases with hypokalemia. There were different degree abnormalities in plasma endocrine hormones in laboratory examination. Every case underwent b-ultrasound and CT normal plus extensive scan to make the diagnosis. RESULTS: Adrenalectomy was performed in the 25 cases, which contain 9 cases of open operations and 16 cases of endoscopic adrenalectomies. All of the cases had blood pressure fluctuation during dissection of the adrenal tumors, with the highest blood pressure reached to 230/140 mm Hg (1 mm Hg = 0.133 kPa). Postoperative histopathological study revealed that the pathological changes was corticomedullary mixed tumor of adrenal gland, which was supported by immunohistochemical study. CONCLUSIONS: In cases with complex phenomenon that can't explain with single cortical or medullary changes, it must beware of the mixed pathological changes in adrenal gland. PMID- 19781173 TI - [Robot-assisted laparoscopic radical cystectomy with extracorporeal urinary diversion]. AB - OBJECTIVE: To present the technique and experience of robotic-assisted laparoscopic radical cystectomy (RARC) by da Vinci surgical system. METHODS: From December 2007 to September 2008, 4 patients underwent RARC and urinary diversion. The age of patients was 44 to 63 years old. The body mass index was 22.8 to 27.7. All their clinical stages were lower than T2N0M0. The technique for RARC involving ureters dissection, posterior dissection, lateral pedicle control, anterior dissection, dorsal vein complex control, neurovascular bundles sparing, lymphadenectomy, ureter-ileal anastomosis, urethra-neobladder anastomosis to either ileal conduit urinary diversion or neobladder reconstruction performed extracorporeally. RESULTS: All the operations were accomplished successfully. The urinary diversion of 2 case was ileal conduit and others was ileal orthophoria neobladder. The operation time was 300 to 450 min. The time of radical cystectomy was 150 to 180 min. The estimated blood loss was 100 to 500 ml. The postoperative hospital stay was 9 to 35 d. The bed rest time was 4 to 9 d. There was 1 patients who had incomplete intestinal obstruction at 8th postoperative day cured by conservative therapy. The patients were followed up for 3 to 12 months, all patients survived without tumor recurrence. The patients have satisfied urinary continence and normal renal functions without hydronephrosis after the operation. CONCLUSIONS: RARC is small incision and safe, the results are definite. It is one of the direction of minimally invasive urologic surgery. PMID- 19781174 TI - [The correlation of the fetal cytokeratin expressing in epidermal cells and the different outcomes of wound repairing]. AB - OBJECTIVE: To investigate the changing regular of specific cytokeratin (CK) markers expressing in human pseudoepitheliomatous hyperplasia (PEH), keloids (Ke) and hypertrophic scar (HS) lesion, and to explore the correlation between such changes and the different outcomes of wound repair. METHODS: Histopathology and immunohistochemistry (IHC) double staining methods were used in samples of human PEH, Ke, HS and NS to determine the distribution characteristics and changing regularity of CKs in epidermal tissues. RESULTS: No CK8&18 and CK17 expressed in epidermis of NS group, while CK8&18(+) cells and CK17(+) cells were detected in epidermis of active-stage Ke, HS and PEH. The quantities of CK8&18(+) cells and CK17(+) cells ranked as follows: PEH > Ke > HS and HS > Ke > PEH (P < 0.05). CK19(+) cells and CK5&6(+) cells expressed similar changing trend, while reverse trend of CK10(+) cells was detected in epidermal cells, with local epidermal hyperplasia, cells morphological changes and sub-epidermal inflammatory reaction. CONCLUSION: Different degree of de-differentiation and terminal differentiation imbalance are found in epidermal cells of active-stage PEH, Ke and HS, which hint the correlation between the abnormal proliferation and differentiation of epidermal cells and the different outcomes of wound repair. PMID- 19781175 TI - [Protective effect of heme oxygenase-1 induction in vivo to pancreas islet xenograft]. AB - OBJECTIVE: To study the protective effect of islet xenograft and its possible mechanism of high expression of heme oxygenase-1 (HO-1) in donor pancreas islet induced by cobalt protoporphyrin (CoPP). METHODS: Male SD rats and C57BL/6 mouse were used as donors and recipients respectively. Donors were divided into 3 groups according to different pretreatment 24 hours before donation: control group (injected intraperitoneally with NaCl), induce group [injected intraperitoneally with cobalt-protoporphyrin (CoPP)], block group (injected intraperitoneally with CoPP and zinc protoporphyrin simultaneously). A modified approach was used for islet isolation.Recipients were rendered diabetic by intraperitoneal injection of streptozotocin. Islets were transplanted into mouse subrenal capsule. Postoperative mouse glycemia were monitored daily and normoglycemia time was compared among each group. The receptor mouse serum IL-10 was detected by ELISA approach, and real-time PCR was used to check the expression of IL-10 mRNA in islet graft tissues. The graft tissues were observed for the lymphocyte infiltration after HE staining. RESULTS: Diabetes mice accepted islets untreated, induced or blocked maintained the euglycemia for (9.3 +/- 1.4), (16.3 +/- 1.5) and (9.7 +/- 1.0) d respectively. The xeno-islets presented HO-1 over-expression survived much longer than that absent (P < 0.05), it was no significance between control group and block group (P > 0.05). The mouse islet serum IL-10 content after induction was (73.0 +/- 9.7) pg/ml, significantly higher than (30.6 +/- 3.9) pg/ml of the untreated group and (32.1 +/- 5.9) pg/ml of the blocked group (P < 0.05), there was no difference between control group and block group (P > 0.05). Moreover, the IL-10 mRNA expression up regulated statistic significantly in HO-1 induced islet xeno-graft. Pathological examination showed that the graft lymphocyte infiltration of the induced group was obviously less serious than the other two groups. CONCLUSIONS: The higher expression of HO-1 induced by CoPP in vivo would significantly prolong graft survival time and its mechanism could be related to immune modulation of IL-10. PMID- 19781176 TI - [Allografted olfactory mucosa gliacytes repair Wistar rats' sciatic nerve long defect]. AB - OBJECTIVE: To investigate whether or not allografted olfactory mucosa gliacytes could repair peripheral nerve injure. METHODS: Olfactory mucosa gliacytes had been cultured in vitro for 2 weeks, then purified and condensed for later transplantation.Sixty adult female Wistar rats were randomized into 2 groups of 30 rats each, A (control) and B (test). Rats' left sciatic nerves were excised 25 mm long axons and retained epineurium lumen anastomosed to proximal ends. Culture mediums, and olfactory mucosa gliacytes were transplanted into epineurium lumen of A and B groups respectively. At 3 months postoperatively, the regenerations of injured sciatic nerves were evaluated by methods of macroscopy, photomicroscopy, transmission electron microscopy, retro-marked fluorescence red, the condensation of glial fibre acid protein (GFAP) and nerve growth factors (NF) assayed by immunofluorescence, and the concentration of myelin basic protein (MBP) and neurofilament protein (NF) assayed by enzyme linked immunosorbent assay. RESULTS: The regenerations of injured sciatic nerves were superior in B group to in A group; the transportation distance of retro-marked fluorescence red were longer in B group than in A group (P < 0.01). The condensations of GFAP and NGF were more dense in B group than in A group. The concentrations of MBP and NF were more high in B group than in A group (P < 0.01). The function scores of injured limbs were superior in B group to in A group (P < 0.01). The quantifications of nerve fibers and myelin fibers of injured sciatic nerve were larger in B group than in A group (P < 0.01). CONCLUSION: Allografted olfactory mucosa gliacytes could repair injured nerve defect. PMID- 19781177 TI - [Nuclear factor kappa B impairs insulin signaling pathway in skeletal muscle cells of rat with sepsis]. AB - OBJECTIVE: To investigate the effects of nuclear factor kappa B (NF-kappaB) on insulin signaling in skeletal muscle cells of rat with sepsis. METHODS: SD rats were randomly divided into two groups: control group and sepsis group.Sepsis model was reproduced by cecal ligation and puncture in sepsis group. At 8, 16, 24, 48 and 72 h after operation, the gastrocnemius was harvested. Conventional HE staining was used to observe the morphology of skeletal muscle cells. IRS-1 protein and tyrosine phosphorylation of IRS-1 and Ser(307) phosphorylation of IRS 1 were detected by Western Blotting and immuno-precipitation. Activities of NF kappaB in skeletal muscle cells were detected by electrophoretic mobility shift assay. RESULTS: Tyrosine phosphorylation of IRS-1 in sepsis group was significantly lower than in control group (P < 0.01), while Ser(307) phosphorylation of IRS-1 in sepsis group was significantly higher than in control group (P < 0.01). In sepsis group, NF-kappaB activity in skeletal muscle cells was significantly higher than in control group (P < 0.01). There was significant negative correlation between activity of NF-kappaB and tyrosine phosphorylation of IRS-1 (r = 0.972, P < 0.01). There was significant positive correlation between activities of NF-kappaB and Ser(307) phosphorylation of IRS-1 (r = 0.969, P < 0.01). CONCLUSIONS: There is no inflammatory cell infiltrate in skeletal muscle cells with sepsis. But the activity of NF-kappaB in skeletal muscle cells is obviously enhanced, and it is closely related with disorder of insulin signaling in skeletal muscle cells of rat with sepsis. PMID- 19781178 TI - [Changes in proliferative activity of myoblasts and expression of Akt in skeletal muscle of rats after severe burn injury]. AB - OBJECTIVE: To investigate changes in proliferative activity of myoblasts in skeletal muscle and potential role of phosphorylated Akt on it, so that a better understanding in mechanisms of skeletal muscle atrophy after burn injury will be got. METHODS: One hundred and twenty Wistar rats were randomly divided into 2 groups: control and severe thermal injury group. Rats in severe thermal injury group were subjected to a 40% total body surface area full-thickness scald injury, and Tibialis Anterior (TA) muscles were collected on 0, 1, 4, 7, 10, 14 days post-injury. After muscle mass determined, immunohistochemical double staining was used for detection of Proliferative Cell Nuclear Antigen (PCNA) of myoblasts. Protein expression of total Akt and phosphorylated Akt was determined by Western Blot. RESULTS: Burn injury induced significant reduction of TA muscle mass and maximal reduction of it appeared by 4 days after injury (P < 0.01). Proliferative activity of myoblasts decreased significantly from the first day post-injury (P < 0.01) and increased slowly to basal level of controls after 7 days post-injury. The phosphorylated Akt was undetectable in both of controls and injured samples before 4 days but increased significantly after 7 days post injury (P < 0.01), though total Akt expression had no significant alteration at any time points (P > 0.05). CONCLUSIONS: Decrease in proliferative activity of myoblasts may be one of the contributors of significant atrophy of skeletal muscle after burn injury. Effect of phosphorylated Akt on proliferation attenuated in early stage and increased significantly in later stage after burn injury may partly explain the changes in proliferative activity of myoblasts. PMID- 19781187 TI - [Conceptual and technical issues in pathologic diagnosis of prostate cancer]. PMID- 19781188 TI - [Clinicopathologic analysis of mixed epithelial and stromal tumor of kidney and adult cystic nephroma]. AB - OBJECTIVE: To study the clinicopathologic features, immunophenotype and differential diagnosis of mixed epithelial and stromal tumor of kidney (MEST) and adult cystic nephroma (CN). METHODS: Five cases of MEST and 4 cases of CN were retrospectively analyzed. Immunohistochemical study was carried out and the literature was reviewed. RESULTS: All of the five patients with MEST were females. Their median age was 45 years. For CN, there were 3 males and 1 female and their median age was 41 years. All patients presented with loin pain and hematuria. On gross examination, MEST was well-circumscribed but non encapsulated. There was no evidence of haemorrhage or necrosis. Three of the cases were solid in nature. One was composed of a mixture of solid and cystic elements, while the remaining case showed a multicystic cut surface bridged by thick fibrous septa. On the other hand, CN were well-circumscribed and encapsulated. They were multiloculated cystic in nature. The cystic spaces were separated by thin septa and there was no significant solid or necrotic component. Histologically, MEST consisted of proliferation of cystically dilated glands admixed with spindly stromal cells with various cellularity and growth patterns. Both the glandular and stromal elements were well-differentiated with no cytologic atypia identified. The glandular structures in 2 of the cases were partially lined by endometrial or tubal epithelium. In contrast, the thin-walled cystic spaces in CN were lined by a single layer of epithelium.Immunohistochemical study showed that the epithelial cells were positive for pan-cytokeratin and epithelial membrane antigen. The spindle cells in MEST expressed vimentin (5/5), smooth muscle actin (3/5), desmin (4/5), CD10 (5/5), estrogen receptor (4/5) and progesterone receptor (4/5). They were negative for HMB45, CD34, CD117 and S-100 protein. On the other hand, the spindle cells in CN were variably positive for vimentin (4/4), smooth muscle actin (4/4), desmin (1/4), estrogen receptor (3/4) and progesterone receptor (1/4). They were negative for CD10, HMB45, CD34, CD117 and S-100 protein. CONCLUSIONS: Both MEST and CN are uncommon renal neoplasm. Most of them run a benign clinical course. The stromal cells in MEST show smooth muscle or myofibroblastic differentiation. Areas demonstrating Mullerian features also existed in some cases. MEST and CN share overlapping histological and immunohistochemical features, and may represent spectrum of the same group of lesions. PMID- 19781189 TI - [Quantity and distribution of CD44+/CD24- cells in breast cancer tissue and the cell lines]. AB - OBJECTIVE: To study the distribution and quantity of CD44+/CD24- cells in breast cancer tissue and the cell lines, and as well as its correlation with the expression of various breast cancer markers and molecular subtyping of breast carcinoma. METHODS: The expression of CD44/CD24, estrogen receptor, progesterone receptor, HER2, human estrogen-induced protein PS2, bcl-2 and nm23 in 60 cases of invasive ductal carcinoma of breast were studied by either single or double immunohistochemical staining. The co-expression of CD44 and CD24 in 3 breast cancer cell lines (MCF-7, MDA-MB-468, and MDA-MB-231) was also examined. RESULTS: The quantity and distribution of CD44+/CD24- cells varied greatly and no specific patterns were identified. The percentage of CD44+/CD24- in breast cancer was 65%. The amount of CD44+/CD24- cells did not correlate with the age of patients, lymph node metastasis, tumor size, molecular subtypes and expression of various breast cancer markers in breast carcinoma. The proportion of CD44+/CD24- cells in MCF-7, MDA-MB-468, and MDA-MB-231 cell lines was <1%, 5% and >80%, respectively. CONCLUSIONS: CD44+/CD24- cells are demonstrated in certain breast cancer tissues and cell lines. However, there is no relationship obtained between the quantity or the distribution of these cells and the molecular subtyping or the clinicopathologic parameters in breast cancer. PMID- 19781190 TI - [Loss of heterozygosity of chromosome 1p/19q and p53 protein expression in oligodendroglioma]. AB - OBJECTIVE: To study the status of loss of heterozygosity (LOH) of chromosome 1p/19q and p53 protein expression in oligodendroglioma, as compared to astrocytoma. METHODS: One hundred and ninety-one cases of glioma of different histologic types and grades, including 116 cases of low-grade of oligodendroglioma (86 paraffin-embedded and 30 fresh tissues), 45 cases of anaplastic oligodendroglioma (all paraffin-embedded tissues) and 30 cases of astrocytoma of various grades (all paraffin-embedded tissues), were enrolled into the study. The LOH of chromosome 1p/19q was investigated by polymerase chain reaction (PCR)-based microsatellite analysis. The p53 protein expression was demonstrated by immunohistochemical staining. RESULTS: The rates of 1p loss, 19q loss and 1p/19q loss were 69.8%, 64%, and 57.0% respectively in the 86 paraffin embedded low-grade oligodendroglioma samples, as compared to 71.1%, 60.0% and 55.6% respectively in the 45 paraffin-embedded anaplastic oligodendroglioma samples. There was no difference of LOH of 1p/19q between low-grade oligodendroglioma and anaplastic oligodendroglioma (P>0.05). In the 30 cases of low-grade oligodendroglioma with fresh tissues available, the rates of 1p loss, 19q loss and 1p/19q loss were 70.0%, 63.3% and 60.0% respectively. The LOH of 1p/19q between paraffin-embedded and fresh samples was not statistically significant (P>0.05). In the 30 cases of astrocytoma, the rates of 1p loss, 19q loss and 1p/19q loss were 23.3%, 33.3% and 20.0% respectively, which were significantly less than those in oligodendroglioma (P<0.05). The expression of p53 protein was significantly lower in low-grade oligodendroglioma (8.1%) than in anaplastic oligodendroglioma (31.1%, P=0.007). The expression of p53 protein in oligodendroglioma was also lower than in astrocytoma (P=0.001). Furthermore, p53 protein expression negatively correlated with 1p/19q loss in anaplastic oligodendroglioma (P<0.05). CONCLUSIONS: Both paraffin-embedded and fresh tissues are suitable for analysis of LOH of chromosome 1p/19q. Oligodendroglioma demonstrates a higher frequency of LOH of chromosome 1p/19q and lower expression of p53 protein than astrocytoma. The LOH of chromosome 1p/19q negatively correlates with the expression of p53 protein. These parameters have both diagnostic and prognostic values. PMID- 19781191 TI - [Prognostic significance and grading of stromal invasion in pT1 adenocarcinoma of lung]. AB - OBJECTIVE: To study the prognostic significance of grading system for stromal invasion in pathologic tumor stage T1 (pT1) adenocarcinoma of lung. METHODS: Eighty-five cases of surgically resected pT1 lung adenocarcinoma with clinicopathologic and follow-up data were retrospectively reviewed. The degree of invasive growth was classified into three grades according to its location in the tumor. The clinicopathologic characteristics and prognostic significance were analyzed. RESULTS: Amongst the 85 cases studied, 17 cases (20%) were in grade 1, 12 (14%) in grade 2 and 56 (66%) in grade 3. The tumor size was smaller and lymphovascular permeation was less frequently encountered in cases with grade 1 stromal invasion than in those with grade 3 (P=0.005 for tumor size and P=0.018 for occurrence of lymphovascular permeation). The rate of lymph node metastasis and pathologic staging in cases with grade 1 and grade 2 were similar and were significantly lower than those with grade 3 (P=0.007 for rate of lymph node metastasis in grade 1 versus grade 3 tumors, P=0.002 for pathologic stage in grade 1 versus grade 3 tumors, P=0.027 for rate of lymph node metastasis in grade 2 versus grade 3 tumors and P=0.021 for pathologic stage in grade 2 versus grade 3 tumors). There was no statistically significant difference with respect to age, gender and smoking history of the patients, amongst cases in different grades. The overall five-year survival rate was 63%. The five-year survival rates for cases with grade 1, grade 2 and grade 3 were 100%, 83.3% and 46.6%, respectively. The difference between cases with grade 2 and grade 3 was statistically significant (P=0.027). The death rate during follow-up for cases with grade 1, grade 2 and grade 3 were 0, 16.7% and 42.9%, respectively. The difference between cases with grade 1 and grade 3 was statistically significant (P=0.001). Univariate analysis showed that grade of stromal invasion (P=0.001), pathologic stage (P<0.001), presence of lymphovascular permeation (P<0.001) and lymph node involvement (P<0.001) represented important prognostic factors. Multivariate analysis also showed that pathologic stage (P<0.001) was an independent prognostic factor. CONCLUSIONS: The grading system of stromal invasion in pulmonary adenocarcinoma correlates with tumor prognosis and other prognostic factors. It represents a useful criterion in prognostic categorization of pT1 adenocarcinoma of lung. PMID- 19781193 TI - [Inducing of epithelial mesenchymal transition of HK-2 cells by connective tissue growth factor in vitro]. AB - OBJECTIVE: To investigate the role of connective tissue growth factor (CTGF) in epithelial mesenchymal transition of HK-2 cells in vitro. METHODS: HK-2 cells were randomly divided into two groups: (1) control group including cells cultured in DMEM medium supplemented with 10% fetal bovine serum only; and (2) experimental group including cells cultured in DMEM medium supplemented with 10% fetal bovine serum and recombinant CTGF at a final concentration of 5 microg/L. The cells were collected at 72 h time points. Direct immunofluorescence staining and immunohistochemistry were used to evaluate the E-cadherin, Vimentin, alpha SMA and ERK2 in cells. Western-blotting was used to detect the E-cadherin, Vimentin and ERK2 protein expression. Boyden Chamber was used to detect the migration of tubular endothelium at 1 d, 3 d and 5 d. RESULTS: There were less E cadherin but more Vimentin expressed in cells of the experimental group. The presence of alpha-SMA was detected at 48 h with peak at 72 h in the cells of the experimental group. On the first day, the cellular migration in the two groups showed no difference. However, after 3 days, the transformed cells migrated surpassed the control group with peak at the 5th day [(45.0+/-1.1):(14.0+/-1.2), P<0.05)]. CONCLUSION: Connective tissue growth factor induces mesenchymal transformation of HK-2 cells, in which the ERK2 signaling pathway may play an important role. PMID- 19781192 TI - [NADPH oxidase-derived reactive oxygen species involved in angiotensin II-induced monocyte chemoattractant protein-1 expression in mesangial cells]. AB - OBJECTIVE: To investigate the origin of oxidative stress induced by angiotensin II (AngII) in human mesangial cells and the role of reactive oxygen species (ROS) in AngII-induced monocyte chemoattractant protein-1 (MCP-1) expression. METHODS: MCP-1 expression was determined by real time RT-PCR. ROS production was measured by DCFDA fluorescence. Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity was examined by lucigenin chemiluminescence. p47phox and p67phox translocation was assayed by Western blot. Twenty-four male mice were randomly divided into three groups: the control, the AngIIinfusion [AngII 400 ng/(kg.min)], and the apocynin treatment. AngII was infused by subcutaneously osmotic minipump for 14 days. Urinary albumin and 8-isoprostane excretion were measured by ELISA. RESULTS: In cultured human mesangial cells, AngII induced the MCP-1 expression in a dose-dependent manner with 3.56 fold increase as compared with the control. AngII increased intracellular ROS production as early as 3 min with the peak at 60 min and was in a time and dose-dependent. Incubation with different dosages of AngII (1 nmol/L, 10 nmol/L, and 100 nmol/L AngII) for 60 min, ROS production increased at 1.82, 2.92, and 4.08 folds respectively. AngII induced ROS generation was sensitive to diphenyleneiodonium sulfate (DPI, 10 micromol/L) and apocynin (500 micromol/L), two structurally distinct NADPH oxidase inhibitors. In contrast, inhibitors of other oxidant-producing enzymes, including the mitochondrial complex Iinhibitor rotenone, the xanthine oxidase inhibitor allopurinol, the cyclooxygenase inhibitor indomethacin, the lipoxygenase inhibitor nordihydroguiaretic acid, the cytochrome P450 oxygenase inhibitor ketoconazole and the nitric oxide synthase inhibitor G-nitro-L-arginine methyl ester were without an effect. AngII-induced ROS generation was inhibited by the AT1 antagonist losartan (10 micromol/L) but not the AT2 antagonist PD123319 (10 micromol/L). AngII treatment induced translocation of cytosolic of p47phox and p67phox to the membrane. The antioxidants almost abolished AngII induced MCP-1 expression. AngII infusion increased urinary and p67 translocation by 2.69-, 2.97-, and 2.67-fold, respectively. CONCLUSIONS: NADPH oxidase-derived ROS is involved in AngII-induced MCP-1 expression. Inhibition of NADPH oxidase alleviates AngII-induced renal injury. PMID- 19781194 TI - [Role of angiotensin II and JAK2 signal pathway in transdifferentation of renal tubular cells in mice after acute ischemic followed by reperfusion]. AB - OBJECTIVE: To investigate the effect of angiotensin (Ang)II and its Janns activated kinase-2 (JAK2) signal pathway in transdifferentiation of renal tubular cells under the challenge of acute ischemic reperfusion injury. METHODS: Models of acute ischemic reperfusion injury were established and the level of local AngII, a key element of renin-angiotensin system (RAS), in kidney was measured using radioimmunity technique. The expression of alpha-smooth muscle actin (alpha SMA), a phenotype of mesenchymal cells, was detected by RT-PCR and immunohistochemistry methods. Renal tubule cells (NRK-52E) were cultured with various concentration of AngII, followed by blocking of PD123319, AngII receptor 2 antagonist, and AG490, an inhibitor of JAK2 signal pathway. RESULTS: AngII of kidney tissue increased immediately after acute ischemic-reperfusion injury, in time dependent fashion. Expression of alpha-SMA in renal tubule cells was found at 48 hours after ischemic-reperfusion injury and in NRK-52E cells treated by high concentration of AngII and was dose and time dependent. The peak of alpha SMA expression was seen after 30 minute treatment at the dose of 10(-9) mol/L, which was interrupted by both of PD123319 and AG490. CONCLUSIONS: Transdifferentiation of renal tubular epithelial cells occurs under acute ischemic-reperfusion injury. Local renin-angiotensin system may play a role in the transdifferentiation of TEC through AT2 receptor and its JAK2 signal pathway. PMID- 19781195 TI - [Role of short haipin RNA targeting vascular endothelial growth factor-C on biological characteristics of human breast cancer cell MCF-7]. AB - OBJECTIVE: To study the effect of short haipin RNA (shRNA) on expression of vascular endothelial growth factor C (VEGF-C) and proliferation and invasion behavior of human breast cancer cell MCF-7. METHODS: The recombinant vector (pSIREN-VEGF-C) was transfected into the human breast cancer cell MCF-7 by liposome and the positive transfected cell clones were screened with puromycin. Expression of VEGF-C in MCF-7 cells after gene transfer was detected by real-time quantitative PCR and Western blot assay, respectively. Proliferation and invasion ability of transfected cells were analyzed by MTT and Transwell filter. RESULTS: The expressions of VEGF-C mRNA and protein were decreased markedly compared with the control group after the transfection and the inhibitive ratio was 95% and 100% respectively (P<0.05). The proliferation of MCF-7 cells transfected by pSIREN-VEGF-C, measured with MTT assays, was significantly decended (P<0.05). The invasion ability of passing through the Transwell filter of MCF-7 cells transfected by pSIREN-VEGF-C were declined evidently (P<0.05). CONCLUSION: The recombinant vector (pSIREN-VEGF-C) have been proved not only to be effective and specific for down-regulation of VEGF-C, but also can inhibit the proliferation and invasion of MCF-7 cells significantly. PMID- 19781196 TI - [Basal cell carcinoma of prostate: clinicopathologic analysis of two cases]. PMID- 19781197 TI - [Clinicopathologic analysis of primary synovial sarcoma of prostate]. PMID- 19781198 TI - [Expression of core components of Wnt2 signaling pathway in gliomas]. PMID- 19781199 TI - [Basicranial sellar tumor]. PMID- 19781200 TI - [Invasive urothelial carcinoma in bladder associated with bilateral benign ovarian Brenner tumor: report of a case]. PMID- 19781201 TI - [Renal medullary carcinoma in child: report of a case]. PMID- 19781202 TI - [Intravascular large B-cell lymphoma: report of a case]. PMID- 19781203 TI - [Desmoplastic non-infantile ganglioglioma: report of a case]. PMID- 19781204 TI - [Epigastric heteropagus twins: report of a case]. PMID- 19781205 TI - [Rectal metastases from carcinoma of breast: report of a case]. PMID- 19781206 TI - [Hepatoid adenocarcinoma of duodenal papilla: report of a case]. PMID- 19781207 TI - [Histologic variants of prostate cancer]. PMID- 19781208 TI - [Eosinophils and related diseases]. PMID- 19781209 TI - [Role of probucol in preventing contrast induced acute kidney injury after coronary interventional procedure: a randomized trial]. AB - OBJECTIVE: Contrast induced acute kidney injury (CIAKI) is a significant clinical problem. We, therefore, performed a prospective, randomized trial to investigate the role of probucol in the prevention of CIAKI in patients with unstable angina pectoris (UAP) undergoing percutaneous coronary angiography (CAG) and interventions (PCI). METHODS: We studied 205 patients with UAP, who underwent CAG or PCI prospectively. Patients were randomly assigned to probucol group (n = 102) and control group (n = 103). In the probucol group, the patients received probucol tablets 500 mg b.i.d for 3 days before and after intervention. All the patients, after intervention, underwent hydration with intravenous saline at a rate of 1 ml per kilogram of body weight per hour for 12 hours. RESULTS: Patients were well-matched with no significant difference at baseline in majority measured parameters between two groups. CIAKI occurred in 23 of the 205 (11.22%) patients. Multivariate logistic regression was used to identify correlates of CIAKI and clinical data. CIAKI was most strongly associated with Scr > or = 132.6 micromol/L (OR = 21.11, 95%CI 1.95 - 56.06, P < 0.001), Ccr < 60 ml/min (OR = 4.19, 95%CI 1.94 - 9.05, P < 0.001), heart function > class II (OR = 6.23, 95%CI 2.73 - 14.21, P < 0.001), Diabetes (OR = 2.049, 95%CI 1.19 - 5.25, P < 0.001), age > or = 70 yrs (OR = 3.52, 95%CI 1.66 - 7.43, P < 0.001), coronary artery calcification shown by CAG (OR = 4.29, 95%CI 1.99 - 9.24, P < 0.001). The rate of CIAKI in probucol groups was slightly lower compared with control group (7.84% vs. 14.56%), without significant difference. The post-procedure mean peak of Scr [(101.62 +/- 42.98) micromol/L vs. (117.67 +/- 68.77) micromol/L, P = 0.047] and the post-procedure increasing Scr from baseline (DeltaScr) [(13.49 +/- 19.61) micromol/L vs. (22.50 +/- 18.31) micromol/L, P = 0.001] in the probucol group decreased significantly compared with that of control group. CONCLUSION: Prophylactic treatment with probucol 500 mg b.i.d during periprocedural stage in patients with UAP has preventing role against CIAKI after cardiac catheterization. PMID- 19781210 TI - [Atorvastatin attenuated contrast induced renal function damage]. AB - OBJECTIVE: To study the effects of atorvastatin on contrast induced renal function change and plasma hsCRP in patients undergoing coronary angiography. METHODS: 120 patients who underwent coronary angiography were randomized to receive atorvastatin (20 mg/qn, n = 60) or no atorvastatin (n = 60) treatment 2 to 3 days before coronary angiography. Urinary alpha1-MG, TRF and mALB were checked for evidence of tubular or glomerular damage at start, 1 day and 2 days after the administration of a radiocontrast agent. Serum creatinine, BUN, cystatin C and hsCRP levels were also assessed at the same time. Ccr and GFR were calculated according to Cockcroft-Gault and GFR (ml/min) = 74.835/Cys C(1.333) formulas basing on serum creatinine or cystatin C concentration. RESULTS: (1) In control group, comparison with the value before coronary angiography, urinary alpha1-MG, TRF and mALB or serum cystatin C and hsCRP significantly increased at day 1 after angiography (P < 0.01). In comparison to the levels at day 1 after angiography, urinary alpha1-MG, TRF, mALB, serum cystatin C significantly decreased at day 2 after angiography (P < 0.01), but alpha1-MG, cystatin C still exceeded the values before coronary angiography, TRF and mALB levels at day 2 after angiography had no significant change compared to baseline (P > 0.05), hsCRP level at day 2 after angiography had no significant change compared to that at day 1 after angiography (P > 0.05) too. (2) In comparison with the value before coronary angiography in atorvastatin-treated group, the levels of urinary alpha1-MG, TRF and mALB or serum cystatin C at day 1 and day 2 after angiography had no significant change compared to baseline (P > 0.05).Serum hsCRP significantly increased at day 1 after angiography compared to baseline (P < 0.01), but it had no significant change compared to day 2 after angiography (P > 0.05). (3) To compare to the atorvastatin-treated group, the values of urinary alpha1-MG, TRF and mALB or Cys C and hsCRP significantly increased at day 1 after angiography in control group (P < 0.01), the values of urinary alpha1-MG, cystatin C and hsCRP still significantly increased at day 2 (P < 0.01)too, but those of TRF and mALB had no significantly change at day 1 or day 2 after angiography between the two groups (P > 0.05). There was no significant change in BUN, Cr, Ccr levels before and after angiography between the two groups. CONCLUSIONS: Low dose contrast induces light renal function damage. Pretreatment with atorvastatin 20 mg/qn for 2 to 3 days could significantly reduce procedural inflammatory reaction, attenuate urinary protein and the effect of degrading GFR in coronary angiography patients. PMID- 19781211 TI - [Efficacy of high dose atorvastatin on preventing contrast induced nephropathy in patients underwent coronary angiography]. AB - OBJECTIVE: To compare the efficacy of high and low dose atorvastatin on preventing contrast induced nephropathy (CIN) in patients underwent diagnostic and therapeutic coronary intervention. METHODS: All patients received atorvastatin 10 mg/d on the basis of hydrated therapy (n = 100) and high dose group received additional atorvastatin 80 mg at 12 to 24 hours before procedure (n = 50). Scr, Ccr, blood beta(2)-M, urine NAG/Cr, and urine osmolality before and after the procedure were compared between the groups. RESULTS: Baseline demographic characteristics and nephropathy risk factors were similar between groups. Ccr was significantly reduced while blood beta(2)-M and uric NAG/Cr were significantly increased in low dose group (all P < 0.05). Blood beta(2)-M in the high dose group was significantly lower than that in the low dose group at day 1 [(2.35 +/- 0.52) mg/L vs. (2.67 +/- 0.64) mg/L, P = 0.008], day 3 [(2.49 +/- 0.55) mg/L vs. (2.80 +/- 0.64) mg/L, P = 0.011] and day 5 [(2.29 +/- 0.53) mg/L vs. (2.56 +/- 0.66) mg/L, P = 0.026] post-procedure respectively;urine NAG/Cr in the high dose group was also significantly lower than that in the low dose group at day 1 [(1.19 +/- 0.30) U/mmol vs. (1.46 +/- 0.34) U/mmol, P < 0.001], day 3 [(1.30 +/- 0.30) U/mmol vs. (1.59 +/- 0.33) U/mmol, P < 0.001], and day 5 [(1.10 +/- 0.30) U/mmol vs. (1.34 +/- 0.35) U/mmol, P = 0.001] post-procedure respectively;Ccr in the high dose group was significantly higher than that in the low dose group at day 1 [(73.69 +/- 20.99) ml/min vs. (65.19 +/- 18.72) ml/min, P = 0.035], day 3 [(64.04 +/- 15.82) ml/min vs. (56.79 +/- 14.50) ml/min, P = 0.019]post-procedure respectively. CONCLUSION: High dose atorvastatin use before angiography is superior than low dose atorvastatin on attenuating contrast induced renal dysfunction. PMID- 19781212 TI - [Intravascular ultrasound assessment of sirolimus-eluting stent restenosis or thrombosis after stent implantation]. AB - OBJECTIVE: To identify underlying mechanical risk factors of that developed in stent restenosis (ISR) or early stent thrombosis in sirolimus-eluting stent (SES) treated lesions using intravascular ultrasound (IVUS). METHODS: IVUS were performed in 60 (ISR, n = 43; early stent thrombosis, n = 17) patients (event group) and in 34 patients without ISR and early stent thrombosis (no-event group) underwent SES implantations. RESULTS: Compared with the no-event group, minimum stent area [MSA, (4.6 +/- 1.6) mm(2) vs. (5.8 +/- 1.6) mm(2), P < 0.01], minimum stent diameter [(2.2 +/- 0.5) mm vs. (2.5 +/- 0.4) mm, P < 0.01], and stent expansion [(69.2 +/- 20.7)% vs. (80.6 +/- 17.2)%, P < 0.01] were significantly smaller, and longitudinal stent symmetry index (MSA/maximum stent area, 2.0 +/- 0.6 vs. 1.7 +/- 0.6, P < 0.05) was significantly larger in the event group. Incidence of MSA < 4.0 mm(2) (43.3% vs. 14.7%, P < 0.01) and stent expansion < 60% (40.7% vs. 11.8%, P < 0.01) were more frequent in the event group than that in no-event group. Furthermore, proximal residual plaque burden was significantly higher compared to the no-event group [(49.0 +/- 15.5)% vs. (38.4 +/- 17.6)%, P < 0.01]. Independent predictors of post SES ISR or early thrombosis were MSA (OR:0.7, 95%CI:0.5 - 0.8, P < 0.01) and proximal residual plaque burden (OR: 280.7, 95%CI: 17.2 - 40 583.6, P < 0.01). CONCLUSION: Smaller MSA and higher proximal residual plaque burden are independent predictors of ISR or early thrombosis post SES implantations. PMID- 19781213 TI - [Angiographic characteristics and long term clinical outcomes post coronary stenting in non-diabetic and type 2 diabetic patients with coronary artery disease]. AB - OBJECTIVE: To observe the angiographic characteristics and the long-term clinical outcomes following coronary stenting in non-diabetic (non-DM) and type 2 diabetic (DM) patients with coronary artery disease. METHODS: This cohort study enrolled 1172 consecutive patients with coronary heart disease underwent elective coronary stenting (249 type 2 DM and 923 non-DM). The angiographic characteristics and the long-term clinical follow-up results were compared between non-DM and DM patients. RESULTS: The follow-up period was (39.2 +/- 6.4) months (6 - 83 months), follow-up rate was 90.3% in DM and 91.0% in non-DM group (P > 0.05). Compared with non-diabetic patients, there were significantly higher incidences of 2-vessel (P = 0.029) and 3-vessel (P = 0.013) diseases of coronary artery, severe stenosis lesion (P = 0.012), chronic total obstructive lesion (P = 0.044) and long lesion (P = 0.001), in-stent restenosis (ISR, P = 0.000) and revascularization (P = 0.000) and MACE (P = 0.000) in DM patients. COX multiple factorial analysis showed that DM is independent risk factor for ISR (P = 0.000), revascularization (P = 0.001) and MACE (P = 0.003). CONCLUSIONS: CHD patients with type 2 DM are associated with multi- and more severe vessel lesions. Type 2 DM is also an independent risk factor for increased ISR, revascularization and MACE post stenting. PMID- 19781214 TI - [Transradial coronary intervention registration investigation in China]. AB - OBJECTIVE: To assess the application status of transradial coronary angiography (TRA) and transradial coronary intervention (TRI) in China in 2007. METHODS: From Feb 10th to Apr 30th 2008, investigating questionnaires of this study were sent to 450 hospitals in China to collect information on application of percutaneous coronary intervention (PCI) and TRI in these centers. RESULTS: One hundred and twelve questionnaires were received. A total of 115 142 coronary angiography (CAG) and 48 379 PCI were performed in these centers including 69 354 TRA (60.24%) and 27 227 TRI (56.28%). A total of 77 488 stents were implanted from 47 160 PCI (1.64 stents per PCI) and 93.98% implanted stents were drug-eluting stent. Total 9290 stents (86.95% drug-eluting stent) were implanted in 7140 primary PCI (1.30 stents per PCI). CONCLUSION: TRA and TRI have become the major approaches of CAG and PCI in China in 2007. PMID- 19781215 TI - [Association between GATA-4 mutations and congenital cardiac septal defects in Han Chinese patients]. AB - OBJECTIVE: To elucidate the association between GATA-4 gene mutations and congenital cardiac septal defects in Han Chinese patients. METHODS: Fifty Han Chinese patients with congenital cardiac septal defects and 100 normal subjects with the same ethnical background were studied. Total six exons and the intron exon boundaries of GATA-4 were amplified by the polymerase chain reaction. The polymerase chain reaction products were purified and directly sequenced with automatic sequencer. RESULTS: Two novel heterozygous mutations were discovered in the GATA-4 gene of patients with congenital cardiac septal defects, His28Tyr in exon 2 and His436Tyr in exon 7 respectively, which were absent in the control population and not reported in the SNP database (http://www.ncbi.nlm.nih.gov/SNP). CONCLUSION: Our finding suggests that the mutations in the transcription factor GATA-4 may be related to congenital cardiac septal defects in Han Chinese patients. PMID- 19781216 TI - [Prevalence of Epsilon wave in patients with arrhythmogenic right ventricular cardiomyopathy]. AB - OBJECTIVE: To investigate the prevalence of Epsilon wave in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC). METHODS: The epsilon wave was detected in 32 patients [24 men, mean age (42.3 +/- 13.3) years] with ARVC using three different electrocardiography (ECG) recording methods: standard twelve leads ECG (S-ECG), right precordial leads ECG (R-ECG) and Fontaine bipolar precordial leads ECG (F-ECG). The Epsilon wave was defined as wiggler, small spike wave and smooth potential between the end of the QRS complex and the beginning of the ST segment. RESULTS: Epsilon wave was detected in 37.5%, 37.5% and 50.0% patients with ARVC by S-ECG, R-ECG and F-ECG respectively. The detection rates derived from the three recording methods were similar (P > 0.05). The Epsilon wave was only detectable by S-ECG in one case, by R-ECG in three cases, and by F-ECG in five cases. The detection rate of Epsilon wave was 50.0% by combined use of S-ECG and R-ECG (SR-ECG), 56.3% by combined use of S-ECG and F ECG (SF-ECG), and 65.6% by combined use of the three recording methods (SRF-ECG). The detection rate was significantly higher by SF-ECG (56.3%) and SRF-ECG (65.6%) than by S-ECG alone (37.5%, all P < 0.05). Most Epsilon waves detected by the S ECG, R-ECG and F-ECG were small spiked waves. CONCLUSION: Combined use of S-ECG, F-ECG and R-ECG could increase the detection rate of Epsilon wave in patients with ARVC. PMID- 19781218 TI - [Characterization of atherosclerotic plaque in patients with unstable angina pectoris and stable angina pectoris by optical coherence tomography]. AB - OBJECTIVE: To compare the characterization of coronary atherosclerotic plaques in patients with unstable angina pectoris (UAP) and stable angina pectoris (SAP) by optical coherence tomography (OCT). METHODS: OCT was performed in 47 patients (23 UAP and 24 SAP) undergoing coronary angiography. Lipid-rich plaque (defined by > or = 2 quadrants of the cross-section area), thin cap fibroatheroma (TCFA), thickness of fibrous cap, plaque rupture, calcification and thrombus visualized by OCT were compared between UAP and SAP patients. RESULTS: OCT imaging was successfully in 44 out of 47 patients (22 UAP, 22 SAP). Proportion of lipid-rich plaques was similar between UAP and SAP groups [91% (20/22) vs. 73% (16/22), P = 0.741]. The minimum thickness of fibrous cap in the UAP group was significantly thinner than that in SAP group [(69.5 +/- 34.7) microm vs. (141.1 +/- 68.5) microm, P = 0.000] and the rate of fibrous cap erosion in the UAP group was significantly higher than that in the SAP group [59% (13/22) vs. 9% (2/22), P = 0.000]. Percents of TCFA [73% (16/22) vs. 14% (3/22), P = 0.000] and plaque rupture [50% (11/22) vs. 9% (2/22), P = 0.003] were significantly higher in UAP group compared those in SAP group. Incidence of thrombus and calcification were similar between two groups. CONCLUSIONS: OCT imaging can clearly define plaque characterization of coronary atherosclerosis. UAP patients have thinner fibrous cap, higher incidences of fibrous cap erosion, plaque rupture and TCFA compared patients with SAP. PMID- 19781217 TI - [Effects of different statin regimens on lipid profile and serum metalloproteinases in patients with coronary heart disease]. AB - OBJECTIVE: Patients with coronary artery disease (CAD, stenosis between 50% - 70% evidenced by coronary angiography) were treated with atorvastatin 40 mg (n = 19) or atorvastatin 10 mg in combination with ezetimibe 10 mg (n = 23). Blood lipid profile and metalloproteinases were monitored up to 3 months. METHODS: Cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL C), high-density lipoprotein cholesterol (HDL-C), liver function, renal function, creatine kinase, MMP-2, MMP-9, TIMP-1 were measured at baseline and at 1 month and 3 months post therapy. RESULTS: (1) At 3 months, LDL-C was similarly reduced in monotherapy group [(1.94 +/- 0.49) mmol/L, 37.82% reduction compared to baseline] and in combined therapy group [(1.92 +/- 0.54) mmol/L, 38.26% reduction compared to baseline]. (2) AST, ALT, renal function and creatine kinase remained unchanged post various therapy (all P > 0.05). (3) MMP-2, MMP-9 significantly decreased and TIMP-1 significantly increased at 3 months compared to baseline in monotherapy group but these parameters remained unchanged in combined therapy group. CONCLUSION: Both therapy regimens were well tolerated and similarly effectively reduced blood lipids and 40 mg atorvastatin monotherapy regimen is superior to atorvastatin 10 mg plus ezetimibe 10 mg regimen in improving metalloproteinases parameters. PMID- 19781219 TI - [Clinical and angiographic characteristics of left coronaroventricular microfistula]. AB - OBJECTIVE: To investigate the clinical and angiographic characteristics of left coronaroventricular microfistula. METHODS: In his retrospective review, clinical, electrocardiogram, echocardiography and coronary angiography data were analyzed for patients with left coronaroventricular microfistula. RESULTS: Left coronaroventricular microfistula was identified in 9 out of 8300 patients underwent coronary angiographies from 1998 to 2008 in our center. Seven patients were female (77.8%) and the average age was 71.5 years. All 9 patients had presenting symptoms of chest distress or dyspnea, coronary artery disease was documented in 5 (55.6%), hypertension in 2 (22.2%), valve disease in 1 (11.1%)and cardiomyopathy in 1 (11.1%) patient. Microfistula originated from one single coronary artery was seen in 1 patient (11.1%), from two coronary arteries in 6 patients (66.7%), from three coronary arteries in 2 patients (22.2%). The diagonal artery was involved in all patients. The characteristic sign of microfistula from CAG was intracavitary staining. CONCLUSION: Microfistula between coronary arteries and left ventricle is a rare disease, often originates from two coronary vessels and diagonal artery is involved in most cases. PMID- 19781220 TI - [Chlamydia pneumoniae induces THP-1-derived foam cell formation by up-regulating the expression of acyl-coenzyme A: cholesterol acyltransferase 1]. AB - OBJECTIVE: To investigate the expression changes of acyl-coenzyme A: cholesterol acyltransferase 1 (ACAT1) on Chlamydia pneumoniae (C.pn) induced foam cell formation. METHODS: Human monocytic cell line (THP-1) was induced into macrophages by 160 nmol/L phorbol myristate acetate (PMA) for 48 h, and were randomly allocated into four groups: negative control group (50 microg/ml LDL for 48 h); positive control group (50 microg/ml ox-LDL for 48 h); C.pn infection group (50 microg/ml LDL plus 1 x 10(5), 4 x 10(5), 5 x 10(5) and 1 x 10(6) IFU C.pn for 48 h or 1 x 10(6) IFU C.pn for 0, 24, 48 and 72 h); ACAT inhibitor 58 035 plus C.pn infection group (1, 5, 10 microg/ml ACAT inhibitor 58-035 pretreatment for 1 h, 50 microg/ml LDL and 1 x 10(6) IFU C.pn for 48 h). The mRNA and protein expressions of ACAT1 were determined by RT-PCR and Western blot, respectively. Lipid droplets in cytoplasm were observed by oil red O staining. The contents of intracellular cholesteryl esters were detected by enzyme fluorescence. RESULTS: The mRNA and protein expressions of ACAT1 were significantly up-regulated in positive control cells compared those in negative control cells and further upregulated by C.pn infection in a time-dependent and concentration-dependent manner (all P < 0.05). There were significantly increases in the accumulation of lipid droplets and the ratio of cholesteryl ester to total cholesterol in positive control cells as compared with negative control cells and these were further aggravated by C.pn (at the concentrations of 5 x 10(5) and 1 x 10(6) IFU for 48 h) and C.pn infection induced increases in the accumulation of lipid droplets and the ratio of cholesteryl ester to total cholesterol could be significantly attenuated by ACAT inhibitor 58-035 (all P < 0.05). CONCLUSION: Chlamydia pneumoniae induces THP-1-derived foam cell formation by up-regulating the expression of ACAT1. PMID- 19781221 TI - [Erythropoietin inhibits angiotensin II induced cardiomyocyte hypertrophy in vitro via activating PI3K/Akt-eNOS pathway]. AB - OBJECTIVE: To explore the effect of erythropoietin (EPO) on angiotensin II (AngII) induced neonatal rat cardiomyocyte hypertrophy and the association with PI3K/Akt-eNOS signaling pathway. METHODS: Cardiomyocytes were isolated from new born Sprague-Dawley rats and stimulated by AngII in vitro. The cell surface area and mRNA expression of atrial natriuretic factor (ANF) of cardiomyocytes were determined in the presence and absence of various concentrations of EPO, phosphatidylinositol 3'-kinase (PI3K) inhibitor LY294002 and nitric oxide synthase (NOS) inhibitor L-NAME. Intracellular signal molecules, such as Akt, phosphorylated Akt, eNOS and phosphorylated eNOS protein expressions were detected by western blot. Nitric oxide (NO) level in the supernatant of cultured cardiomyocytes was assayed by NO assay kit. RESULTS: EPO (20 U/ml) significantly inhibited AngII induced cardiomyocyte hypertrophy as shown by decreased cell surface area and ANF mRNA expression (all P < 0.05). EPO also activated Akt and enhanced the expression of eNOS and its phosphorylation (all P < 0.05), increased the NO production (P < 0.01). These effects could be partially abolished by cotreatment with LY294002 or L-NAME (all P < 0.05). CONCLUSION: EPO attenuates AngII induced cardiomyocytes hypertrophy via activating PI3K-Akt-eNOS pathway and promoting NO production. PMID- 19781222 TI - [rhG-CSF promotes re-endothelialization and attenuates intima hyperplasia in carotid artery of rabbits post balloon catheter injury]. AB - OBJECTIVE: To investigate the effect of rhG-CSF on mobilizing bone marrow-MSCs, re-endothelialization and intima hyperplasia in carotid artery of rabbits post balloon catheter injury. METHODS: Rabbits were treated with rhG-CSF (25 microg/kg, twice daily, i.p, n = 35) or saline (n = 32) for 5 days, then, carotid arteries of rabbits were injured by balloon catheter. The number of peripheral MSCs was detected with FACS. The morphology of injured artery was examined with hematoxylin and eosin stain, PCNA was determined with immunohistochemistry. RESULTS: (1) Number of peripheral MSCs was similar at baseline and significantly increased at 24 hours and peaked at 7 days and remained increased till 14 days post rhG-CSF. (2) Significant endothelial cell deletion was evidenced in the control group, while scatter endothelial cells was observed in the rhG-CSF group at 1 week post injury. Two weeks after injury, new endothelial area was significantly higher in rhG-CSF group compared to control group. At 4 weeks post injury, endothelial connection was evidenced and regularly displayed in rhG-CSF treated group. (3) PCNA-positive cells in the tunica intima were significantly lower in rhG-CSF treated rabbits at 7, 14 and 28 days compared that in control rabbits (all P < 0.01). CONCLUSION: rhG-CSF could mobilize the bone marrow-MSCs and promote re-endothelialization and attenuate intima hyperplasia post balloon catheter injury in carotid arteries of rabbits. PMID- 19781223 TI - [Effects of hydrogen sulfide on the K ATP current in isolated rat ventricular myocytes]. AB - OBJECTIVE: To investigate the effects of endogenous and exogenous hydrogen sulfide (H(2)S) on the K(ATP) current in isolated rat ventricular myocytes. METHODS: Ventricular myocytes were isolated from rat heart by modified Langendorff perfusion with collagenase. K(ATP) current of single rat ventricular myocytes was recorded by whole-cell patch-clamp technique. RESULTS: The density of K(ATP) current was significantly reduced by 200 micromol/L DL-propargylglycine (PPG, an irreversible inhibitor of the H(2)S) [(5.3258 +/- 0.7556) pA/pF vs. (3.7856 +/- 0.4312) pA/pF, P < 0.01] in a time-dependent way. The density of K(ATP) current could be significantly increased by NaHS (a H(2)S donor, 9.375, 18.75, 37.5, 75, 150 micromol/L) in a concentration-dependent manner [(6.6310 +/- 0.6092) pA/pF vs. (9.0949 +/- 1.0259) pA/pF at 150 micromol/L, P < 0.01]. CONCLUSION: Both endogenous and exogenous H(2)S could open K(ATP) channels and enhance the K(ATP) current in rat ventricular myocytes. PMID- 19781224 TI - [Prevalence, awareness, and treatment of hypercholesterolemia among inpatients with acute coronary syndrome in China]. AB - OBJECTIVE: To estimate the current prevalence, awareness and treatment status of hypercholesterolemia among inpatients with acute coronary syndrome (ACS) in China. METHODS: Sixty-four hospitals across China, including 32 secondary hospitals and 32 tertiary hospitals were selected for baseline survey. Fifty inpatients diagnosed with ACS were recruited consecutively in each participated hospitals. Retrospective information for 2751 patients were collected, and the prevalence, awareness, and treatment status of hypercholesterolemia among the patients were analyzed. RESULTS: (1) Mean age of the patients was 65 +/- 11. Sixty-nine percent of the patients were males and 31.2% were females. Among them, 39.4% were diagnosed as ST-segment elevation MI, 8.8% as non-ST-segment elevation MI and 51.8% as unstable angina. Twenty-seven percent of them had previous ACS history. (2) Hypercholesterolemia was found in 19.6% ACS patients. Among 7 geographic districts (north China, east China, south China, middle China, northeast, northwest and southwest), the prevalence rate of hypercholesterolemia was highest (24.7%) in east China and lowest (10.0%) in middle China. Significant difference was observed among these areas. (3) Awareness rate of hypercholesterolemia was 12.2% among patients with hypercholesterolemia, with significant difference among various areas. Treatment rate was 66.7% among patients with known hypercholesterolemia, with the highest (83.3%) seen in south China and lowest (0%) in southwest area. (4) The prevalence, awareness rate and treatment rate of hypercholesterolemia were higher in recurrent ACS patients than in those without ACS history. CONCLUSIONS: Nearly 20% ACS inpatients have hypercholesterolemia.It is essential to pay more attention on the treatment of hypercholesterolemia for the purpose of secondary prevention of cardiovascular disease. PMID- 19781225 TI - [Association between job stress and blood lipids among university staff in Yunnan province]. AB - OBJECTIVE: To observe the association between job stress (effort-reward imbalance model)and blood lipids among university staff in Yunnan province. METHODS: A cross-sectional survey was conducted among 1244 university staff in Yunnan province. The job stress was measured by the validated Chinese self-reported Effort-Reward Imbalance Questionnaire (ERI). Blood lipids were measured in all participated staff members. RESULTS: After adjustment for relevant confounding factors, it was found that the risk of increased serum triglyceride was 3.5 folds higher in male staffs with high extrinsic effort compared those with low extrinsic effort (OR = 3.45, 95%CI: 1.32 - 9.04) while the risk of increased serum low density lipoprotein-cholesterol was 2.9 folds higher in male staffs with high overcommitment compared those with low overcommitment (OR = 2.86, 95%CI: 1.03 - 7.96). The risk of elevated serum triglyceride increased in proportion to increasing job stress: 3.5 folds increase in male staffs with moderate job stress (OR = 3.43, 95%CI: 1.24 - 9.53) and 4 folds increase in male staffs with high job stress (OR = 4.16, 95%CI: 1.42 - 12.17) compared those with low job stress. However, there was no significant association between job stress and lipid profile in female staffs. CONCLUSION: Our results show that job stress (effort-reward imbalance) is positively associated with abnormal blood lipids in male university staffs. PMID- 19781226 TI - [Effect of the valved stent on closure of patent ductus arteriosus in a miniswine model]. AB - OBJECTIVE: To evaluate the feasibility of a valved stent on closure patent ductus arteriosus in a Chinese miniswine model. METHODS: Self-expandable nitinol stents were made of Ni-Ti shape memory alloy (9 mm in diameter). Bovine pericardium was shaped and sutured onto the stents. Fluid passing test, pre-releasing test and static test of pressure in tube were performed in all devices before use. In eight Chinese miniswine, vascular grafts (PTFE vascular prosthesis) were surgically inserted between the descending thoracic aorta and pulmonary artery for establishment of patent ductus arteriosus model. Valved stents were deployed to occlude the patent ductus arteriosus. Echocardiography was performed two hours post operation. Aortic angiography was made 30 days post operation in survived animals. Animals were then sacrificed for autopsy and electron microscopy examinations. RESULTS: In vitro testing showed that the closure of the valved stent leaflets was satisfactory and fluid flows were not restricted in the opposite direction. The valved stents could be released through catheter, expanded completely, rapidly fixed in the tube. Closure of patent ductus arteriosus was succeeded in 6 out of 8 animals. One animal died of respiratory failure 2 hours post operation, another one died of pulmonary embolism due to valved stent displacement. Resident shunt was not evidenced by echocardiography, aortic angiography and dissection examinations in the remaining 6 animals. The new endothelial tissue fully covered the pulmonary and aortic sides of patent ductus arteriosus in 4 and 3 animals respectively. The electron microscopic observation revealed endothelial coverage of dives. CONCLUSION: The valved stent could effectively close artificial patent ductus arteriosus in vivo with satisfactory new intima covering on both sides of patent ductus arteriosus. PMID- 19781227 TI - [A case report of left and right coronary artery fistula to the left ventricle in an elderly patient]. PMID- 19781228 TI - [A case report of young male benign myocarditis]. PMID- 19781229 TI - [Report of a case of hemolysis induced by transcatheter device closure of postoperative residual ventricular septal defect]. PMID- 19781230 TI - [Hemorrhagic fever with renal syndrome combined with severe heart complications: a case report]. PMID- 19781233 TI - [Efficacy and safety of new generation drug eluting stent on preventing restenosis]. PMID- 19781234 TI - [Progress of minimally invasive radiofrequency ablation for atrial fibrillation treatment]. PMID- 19781236 TI - [Some problems in the treatment of elbow joint injury]. PMID- 19781237 TI - [Semi-constrained total elbow arthroplasty for the treatment of the elbow disorders]. AB - OBJECTIVE: To retrospectively review the results of Coonrad-Morrey semi constrained total elbow arthroplasty (TEA) for the treatment of different elbow disorders. METHODS: Between December 2003 and April 2008, 30 patients with different kinds of elbow disorders including elbow fracture, non-healing elbow fracture, rheumatoid arthritis and osteoarthritis were treated with TEA using the semi-constrained Coonrad-Morrey elbow replacement prostheses. One patient had bilateral total elbow replacements. There were 22 females and 8 males, with a mean age of 66 years (47 to 78). RESULTS: Twenty patients (21 elbows) were available for review. The average length of follow-up was 35 months (from 12 to 52 months). The mean Mayo elbow performance score was 84 points. Excellent results were achieved in 6 elbows (28%), 11 elbows had good outcome (52%), 2 elbows had improvement (10%), while the other 2 elbows had no improvement (10%). The 2 elbows with distal humeral fractures, had no pain after treatment but developed heterotopic ossification, which caused stiffness and lower the Mayo elbow performance score. One delayed healing of the wound, one patient experienced temporary radial nerve hypesthesia and one elbow showed transparent region around the implant without radiological sign of loosening in the implanted prostheses. CONCLUSIONS: This study reveals good to excellent outcome with the use of semi-constrained TEA for the treatment of rheumatoid arthritis, elbow fracture, osteoarthritis and non-healing elbow fractures in elder patients. The non-healing elbow fractures in elder patients would accompany with severe osteoporosis and comminuted fracture, which would affect the result of open reduction internal fixation. So TEA may be one optimal treatment for these patients. PMID- 19781238 TI - [A randomized comparison of open and arthroscopic Nirschl debridement for refractory lateral epicondylitis]. AB - OBJECTIVE: To compare open and arthroscopic methods for treatment of recalcitrant lateral epicondylitis. METHODS: A prospective trial of 26 patients (28 elbows) with recalcitrant lateral epicondylitis were treated between May 2006 and September 2008. The mean duration of conservative care was 23. 0 months (4 - 60 months). The mean follow-up was 17.4 months (4 - 32 months). The patients were randomized divided into two groups, 13 elbows with an open Nirschl procedure and 15 with an arthroscopic Nirschl procedure. All patients had pre- and post operative assessment using VAS (visual analog scale) scores, Mayo 12 points elbow scores, time of return to work or sports, satisfaction, and so on. RESULTS: There were no significant differences in VAS scores at rest and activities of daily living, time of return to work or sports and satisfaction between the two groups. But there was a statistically significant difference in VAS scores at work and sports and Mayo 12 points elbow scores between the two groups. 100% of the patients had excellent or good results in the open group and 93.3% in arthroscopic group. There were no severe complications in this series. CONCLUSIONS: Both open and arthroscopic Nirschl procedures are valid and reliable treatments for patients with refractory lateral epicondylitis. The patients in the open group have a better function in the return-to work and sports postoperatively than the arthroscopic group. PMID- 19781239 TI - [Treatment of type C intercondylar fractures of distal humerus using dual plating]. AB - OBJECTIVE: To evaluate the clinical outcome of dual plating in the treatment of humeral intercondylar type-C fractures in adults. METHODS: From June 2004 to October 2007, 38 cases of type-C distal humeral fractures were stabilised with dual plating. There were 21 males and 17 females. The average age was 43 years with a range from 21 to 71 years. According to the AO classification, 9 cases were of type C1, 17 of C2 and 12 of C3. The posterior midline approach was selected. Twenty-one cases were exposed through the trans-olecranon osteotomy, 11 through the Campbell (Van Gorder) approach, 6 through triceps sparing approach. Autogenous bone graft was performed in 5 cases because of severe comminution. RESULTS: Thirty-five patients were followed-up for 14-30 months (mean 24.2 months). At the latest follow-up, the elbow flexion averaged 119 degrees (range 90 degrees - 135 degrees ), and the loss of extension averaged 16.2 degrees (range 5 degrees - 25 degrees ). All the patients got bony healing, the average healing period was 14 weeks. The patients were evaluated using the criteria of Aitken and Rorabeek and the scores were 13 excellent, 16 good, 6 fair. Twenty nine patients (82.9%) had a good or excellent results. Complications included 4 cases of traumatic osteoarthritis, 2 heterotopic ossification, 1 ulnar neuropathy. Infection as well as loosening or breakage of the implant was not found. CONCLUSIONS: The dual plating is able to provide rigid fixation for the humeral intercondylar fractures. In addition, it can allow early functional exercise after operation, decrease the related complications significantly, and improve the functional results. PMID- 19781240 TI - [Clinical observation on the different treatments targeted at different types of radial head fracture and radial neck fracture]. AB - OBJECTIVE: To assess the effect of the different treatments targeted at different types of radial head fracture and radial neck fracture. METHODS: A retrospective study was performed in 87 patients from February 2006 to March 2007. Fifty-four patients with radial head fractures included 36 males and 18 females, aged from 18 to 65 years (the average age was 33); Forty of them resulted from crashing, 8 from traffic injury and 6 from falling injury. According to Mason classification system, there were 15 type I, 23 type II and 16 type III. Thirty-three patients with radial neck fractures included 21 males and 12 females, aged from 9 to 17 years (the average age was 13), 29 of them resulted from crashing, 1 from traffic injury and 3 from falling injury. According to O'Brien classification system, there were 8 type I, 14 type II and 11 type III. Type I of radial head fractures and radial neck fractures were immobilization with cast, the patients with type II of radial head fractures were treated with open reduction and micro-screw or T trapezoid and bridge-shaped plate fixation and type III had operations to fix with bridge-shaped locked plate and repair the broken annular ligament, or replace heads with prosthesis. All patients with type II and type III of radial neck fractures were treated with closed reduction by leverage and percutaneous intra-medullary nailing. RESULTS: The patients were followed up for 4-12 months (mean 7.2 months). The functional recovery degrees were evaluated with Wheeler's evaluation system. In group of radial head fractures, the results were excellent in 26 patients, good in 20, fair in 6 and poor in 2, the excellent and good rate was 85.2%. In group of radial neck fractures, the results were excellent in 20 patients, good in 9, fair in 4 and poor in no patient, and the excellent and good rate was 87.9%. CONCLUSIONS: Different types of fractures should choose different surgical methods according to their characters. The excellent functional recovery depend on anatomical reduction, retaining the head of radius, early repairing and protecting the broken annular ligament of radius, and early functional training. PMID- 19781241 TI - [Posterior monteggia fracture-dislocations of proximal ulna]. AB - OBJECTIVES: To discuss the diagnosis and differential diagnosis, and to establish an effective protocol to treat the posterior Monteggia fracture-dislocations of proximal ulna in adult according to our experience. METHODS: Between April 2004 and December 2007, 16 patients with posterior Monteggia fracture-dislocations were treated surgically, 13 were followed up at a mean of 28 months (range, 12 - 58 months). All the operations were through the posterior midline approach. The fractures of radial head and coronoid process were reduced and fixed, if possible. The proximal ulna fractures were fixed with a single plate in 7 cases, plate combined with K-wires in 2, plate combined with K-wires tension band in 3, and K-wires tension band combined with screws in 1. RESULTS: No elbow was painful or unstable at the last follow up examination. They had an average of 100 degrees (range, 0 degrees to 145 degrees ) of flexion-extension of elbow. The average motion of forearm rotation was 119 degrees (range, 0 degrees to 170 degrees ). The mean Mayo Elbow Performance Score (MEPS) was 93.1 points (67 - 100 points), excellent and good results were achieved in 92.3%. The mean system of Broberg and Morrey score was 88.8 points (53 - 100 points), excellent and good results were achieved in 76.9%. CONCLUSIONS: Attention should be paid to the diagnosis and differential diagnosis of the posterior Monteggia fracture-dislocation of proximal ulna. Anatomically reduction and stable fixation of proximal ulna is the keystone for the surgical treatment. PMID- 19781242 TI - [Advances in treatment of humeral intercondylar fractures]. PMID- 19781243 TI - [Summary of total elbow replacement arthroplasty]. PMID- 19781244 TI - [Study on the applied value of digital medical technology in diagnosis and treatment of the hepatolithiasis]. AB - OBJECTIVE: To study the value of digital medical technology in diagnosis and treatment of the hepatolithiasis. METHODS: 64-slice spiral computer tomography (CT) scan data of 14 cases (11 female, 3 male; median age, 48 years) with hepatolithiasis admitted from February to September 2008 were collected. The data were imported into medical image proceeding system (MIPS) for sequence segmenting and three-dimensional (3D) reconstruction. The reconstructed models were imported into FreeForm Modeling System for performing simulation surgery with simulation surgical instruments. According to the results of 3D reconstruction and simulation surgery, reasonable operation strategies were chosen. Finally, the value of clinical application of simulation surgery was evaluated according to the findings of clinical operation on hepatolithiasis patients and postoperative T-tube angiography. RESULTS: The 3D reconstructed models of 14 cases with hepatolithiasis revealed 7 cases of left liver hepatolithiasis, 2 cases of right liver hepatolithiasis, 5 cases of bilateral hepatolithiasis, including 6 cases of hepatolithiasis with common bile duct calculi, 6 cases of biliary system models with absolute stricture, 8 cases with relative stricture. The results were of agreement with clinical diagnosis. A variety of operation plans were simulated before operation. Simulation equipment used in process of simulation surgery was a powerful sense of feedback. CONCLUSIONS: Digital medical technology is helpful to understand the calculi distribution, bile ducts stricture and deformity. Through preoperative training, simulation surgery are able to guide for choosing operative strategies. It reduces the operation risks. PMID- 19781245 TI - [Study on the tectology change of rectum wall above the hemorrhoids]. AB - OBJECTIVE: To investigate the histomorphological characteristics and its significance of rectum wall above hemorrhoids. METHODS: Tissues of rectum wall above hemorrhoids were obtained after stapled hemorrhoidopexy from 21 patients with grade III-IV internal hemorrhoids. Seven macroscopically normal rectal tissues collected from upper rectal cancer patients without a history of hemorrhoids served as control. Masson trichrome staining was performed for detecting smooth muscles and collagen in the tissues. The expression of type III collagen was detected by using immunohistochemical staining in the two groups. RESULTS: Morphological abnormalities, such as fragment, rupture, disorganization were found in smooth muscle of proximal rectal tissues above the piles, and it was statistically different from the distal rectal tissues above the piles and control tissues (all P < 0.05). Moreover, hyperplasia of type III collagen in both muscularis mucosa and rectum wall in tissues above hemorrhoids were observed, no such changes was found in the control tissues. CONCLUSIONS: The range of pathological changes in hemorrhoids is beyond the anal cushions. The pathological changes of the smooth muscle and the type III collagen in the tissues above the piles are the pathological basis of hemorrhoids. PMID- 19781246 TI - [The treatment of dorsally displaced intra-articular fractures of the distal radius via palmar approach]. AB - OBJECTIVE: To treat dorsally displaced intra-articular fractures of the distal radius, and to assess the integrity of radiocarpal joint and the reliability of stable fixation fracture. METHODS: Sixty-three cases (65 sides) patients with dorsally displaced intra-articular fractures of the distal radius were performed operatively with the open reduction and internal fixation via palmar approach between August 2003 and May 2008. The series included 20 males (21 sides) and 43 females (44 sides). The mean age of patients was 52.4 years ranging from 18 to 82 years. According to the Frykman classification, 6 sides were of type III, 8 of type IV, 5 of type V, 4 of type VI, 13 of type VII and 29 of type VIII. With the exception of the radiocarpal arthrography and the standard antero-posterior and lateral views of the wrist joint, two new tangential antero-posterior and lateral views of the wrist joint were intraoperatively described so as to observe the relation of the distal screws with the articular surface. RESULTS: The 53 cases (54 sides) of the 63 cases (65 sides) were followed up, and the follow-up time was averagely 16.4 months ranging from 4 to 47 months. According to Gartland and Werley criteria, 32 sides were rated as excellent (59.3%), 14 sides as good (25.9%), 7 fair (13.0%) and 1 poor (1.8%), and the excellent-good rate was 85.2%. Observing the new tangential antero-posterior and lateral views of the wrist joint, it showed that screws appeared penetrating into the radiocarpal joint in 26 of the 42 sides by standard antero-posterior view and in 31 of the 42 sides by standard lateral view. CONCLUSION: This palmar approach represents a simple and valuable treatment methodology for the most frequent types of unstable fractures of the distal radius in young and elderly patients. PMID- 19781247 TI - [Reconstruction of acetabular bone deficiency in total hip arthroplasty]. AB - OBJECTIVE: To discuss the characteristics and reconstruction strategies of acetabular bone deficiency in total hip arthroplasty in order to find the optimal resolution for this clinical puzzle. METHODS: Clinical and radiological materials of 37 patients (37 hips) with acetabular deficiency who underwent primary or revision total hip arthroplasty were analyzed retrospectively from May 1998 to August 2008. According to the common classification system for acetabular bone deficiency-the AAOS classification system, the acetabular bone defect was reconstructed using morselized or structural bone grafting, accessory acetabular hardware (ring, cup or cage) together with cemented or cementless acetabular component respectively. All patients were followed up regularly to assess their hip function improvement by measuring the Harris hip score and to find out the grafting bone healing, absorption and position of the prosthesis by plain radiographic examination. RESULTS: There were 11 primary and 26 revision total hip arthroplasty. There were 9 hips of AAOS-type I defect, 13 of type II and 15 of type III. Morselized bone grafting was used in 24 cases, bulk structural bone grafting in 6 cases and mixed bone grafting in 7 cases. Twenty-one patients used cementless prosthesis and 16 used cemented prosthesis. The average follow-up period was 53.7 months (6.5 to 130.5 months), the average preoperative Harris hip score was 42 +/- 8 with contrast to 87 +/- 5 of post-operation. Statistically significant difference was found according to t-test with P value less than 0.05. Major or complete healing of grafting bone was obtained at the latest follow-up. CONCLUSIONS: Acetabular bone defect during primary or revision total hip arthroplasty should be reconstructed according to its characteristics and severity. For relatively simple AAOS type I and type II cases, morselized or bulk structural bone grafting together with cementless prosthesis could achieve favorable initial stability, but for more severe AAOS type III cases, bulk structural bone grafting with accessory reinforcement hardware would be necessary. Though the early and mid-term results of the above strategies are satisfied, the long term outcome still require further study. PMID- 19781248 TI - [Structural and functional changes of postoperative small left ventricle patients]. AB - OBJECTIVE: To explore the perioperative features of surgical treatment in valvular patients with small left ventricle, and investigate the postoperative early structural changes of left ventricle and its correlation with cardiac function. METHODS: A total of 51 patients with small left ventricle underwent mitral valve replacement from January 2003 to August 2008. There were 7 males and 44 females with mean age of (48 +/- 5) years old. The mean pathologic course was (18 +/- 9) years old. The concomitant procedures included aortic valve replacement in 6 cases, coronary artery bypass grafting in 1 case, tricuspid valvular plasty in 48 cases, left atrial thrombi scavenging in 36 cases, and left atrium folding in 42 cases. RESULTS: The perioperative mortality was 3.9% (2/51). Fourteen patients (27.5%) suffered from severe low-output syndrome in the earlier period postoperatively. Among them, 5 patients needed secondary cardiopulmonary bypass (CPB) to assist circulation, with the result of 1 patient died of weaning off CPB unsuccessfully, 1 patient revived with intra-aortic balloon pump assisted for another 2 d after termination of CPB and another 1 patient died of multiple organ failure (MOF) 10 d later. Eleven cases complicated with MOF. Five patients complicated with ventricular arrhythmia. The echocardiographic examinations showed that the left ventricular dimensions didn't expand significantly postoperatively at 7 to 14 d postoperatively. Left ventricular end-diastolic diameter (LVEDD) was (36.5 +/- 3.2) mm preoperatively and (38.6 +/- 5.3) mm postoperatively (P > 0.05). Preoperative LVEDD index (LVEDDI) was (45.9 +/- 3.8) ml/m(2) and postoperative LVEDDI was (48.2 +/- 7.4) ml/m(2) (P > 0.05). The contract function of left ventricle was improved postoperatively but with no statistical significance. Ejection fraction was 48.6% +/- 6.7% preoperatively and 52.8% +/- 8.3% postoperatively. Left ventricular fraction shortness was 25.5% +/- 3.3% preoperatively and 27.1% +/- 1.3% postoperatively. CONCLUSIONS: For the patients with small left ventricle usually, the postoperative emphases should be put on the management of low output syndrome. The decreased dimension of left ventricle doesn't expand in the early period after valvular operation. PMID- 19781249 TI - [Comparison study of pelvic floor muscle tension and neuropeptide level in different level of spinal cord injury]. AB - OBJECTIVE: To find more evidence for mechanism and treatment of pelvic floor dysfunction (PFD), we observed muscle tension and neuropeptide of pelvic floor muscle in rats after spinal cord injury (SCI). METHODS: 30 SD adult female rats were randomly divided into suprasacral cord injury group (SS), spinal cord injury at or below the sacral level group (SC) and normal group; 4 weeks after transection of spinal cord, muscle tension including compliance and excitability, and neuropeptide were observed. RESULTS: Compliances in SC group, SS group and normal group were (16.23 +/- 4.46) g, (13.44 +/- 4.15) g and (14.46 +/- 5.61) g respectively, there were no difference among them (P > 0.05), but their excitability under best initial length were (0.35 +/- 0.19) g, (2.80 +/- 2.12) g and (7.75 +/- 2.98) g according to SC, SS and normal group, excitability under prolonged length were (2.61 +/- 0.73) g, (4.67 +/- 1.16) g, (14.86 +/- 3.79) g respectively. SC and SS group were both lower than normal group (P < 0.05), meanwhile SC group was much lower than SS group (P < 0.05); neuropeptide Y and vasoactive intestinal peptide in SS and SC group were significant lower than normal group, and these two neuropeptides in SC were much lower than SS group (P < 0.05). CONCLUSIONS: Muscular excitability and neuropeptide in pelvic floor muscle are decreased obviously at both below and above sacral cord injury, SCI below sacral cord makes much lower level excitability and neuropeptide. The abnormality in pelvic floor muscle after SCI should be emphasized. PMID- 19781250 TI - [Preliminary study on cardiac allograft rejection in mice by Extractum trametes robiniophila murr]. AB - OBJECTIVE: To study the effect of Extractum trametes robiniophila murr on cardiac allograft rejection in mice. METHODS: All abdominal heterotopic heart transplantation models were divided into three groups as follows: (A) Extractum trametes robiniophila murr group. (B) Rejection group. (C) Isograft group. In each group, mean survival times (MST) of transplanted hearts and their pathologic histological changes at postoperative fifth day were observed. With fluoroimmunoassay, granzyme B and CD8(+) expressions were examined. RESULTS: The MST of heart allografts in group A were (6.38 +/- 0.69) d, significantly shorter than that of group B [(8.31 +/- 0.59) d] (P < 0.01). In group A, acute rejection was present in advance; transplanted hearts were seriously damaged into acute rejection pathological grade 3, and CD8(+) T lymphocytes infiltrated diffusely and the expression of granzyme B increased significantly as compared with other groups. CONCLUSIONS: Exclusive application of Extractum trametes robiniophila murr can promote the acute rejection of graft in early phase of postoperation, and the mechanism may be the promoted proliferation and infiltration of CD8(+) T lymphocytes and the increased expression of granzyme B. PMID- 19781251 TI - [Local X-irradiation promotes regeneration of spinal cord central nervous system in a rat model]. AB - OBJECTIVE: To evaluate the effect of local X-irradiation on spinal cord injury by using physiology, kinology, electrophysiology and histology method. METHODS: 46 female Sprague-Dawley rats were subjected to spinal cord injury by weight dropping on T(11-12). All animals were divided into 3 groups randomly. One of the animal groups was irradiated with 10 Gy at the lesion site; another was irradiated with 20 Gy, the other without irradiation is regarded as sham-group. The animals were euthanized at different time points at 4 and 12 weeks after irradiation. Spinal cord callus was assessed by using physiology, kinology, and electrophysiology and histology method. RESULTS: In all the groups, the NF at 14 weeks were found higher than that of 6 weeks. Both 10 Gy irradiated and 20 Gy irradiated groups were higher than those of group at each time point (P < 0.05). The MBP decreased at 14 weeks in irradiated groups (P < 0.05), but increased at 14 weeks in sham-group (P < 0.05), the MBP of irradiated groups was lower than that sham-group at 14 weeks (P < 0.05). The GFAP and Nogo-A at 14 weeks were higher than that in 6 weeks in all the groups (P < 0.05), and there was no statistical significance with physiology, kinology, electrophysiology test in all groups. CONCLUSION: A self-repair mechanism exists after SCI, which will last at least 14 weeks. Local irradiation promotes the regeneration of spinal cord system after injury to some extent. PMID- 19781252 TI - [Adenovirus-mediated CTLA4 immunoglobulin based conditioning for non myeloablative allogeneic hematopoietic cell transplantation to induce tolerance to hind limb allografts in rats]. AB - OBJECTIVE: To investigate a non-toxic AdCTLA4-Ig-based protocol for non myeloablative allogeneic hematopoietic cell transplantation to induce donor specific tolerance to hind limb allografts in rats. METHODS: Fully mismatched, 4 to 8 week old Brown Norway (RT1(n)) and Lewis (RT1(1)) rats were used as cell/organ donors and recipients, respectively. Recipients were treated with AdCTLA4-Ig (5 x 10(9) PFU, day -30, 0, 30), standard immunosuppressive therapy (MP: 10 mg x kg(-1) x d(-1), MMF: 20 mg x kg(-1) x d(-1), RAPA: 0.2 mg x kg(-1) x d(-1);day -33 - 100), soon after total body irradiation (3 Gy, day -30) and donor bone marrow (100 x 10(6), day -30) transplantation (BMT). Thirty days after BMT, chimeric animals received hind limb transplantations. And 100 days after hind limb transplantations, immunosuppressive therapy was changed for low-dosed CsA (8 mg x kg(-1) x d(-1), day 100-), until the allografts were rejected. RESULTS: In Group C, hematopoietic chimerism was (38.8 +/- 10.6)% at day 0, and was stable (29.3 +/- 11.9)% at 330 days post-BMT. There was no graft versus host disease in both Group C and Group D. When the standard immunosuppressive therapy was stopped and changed for low-dosed CsA, chimeric recipients (Lewis, RT1(1)) permanently accepted (> 200 days) donor specific (Brown Norway, RT1(n)) hind limb allografts in Group C, yet rapidly rejected in Group A (8 +/- 2) d, Group B (18 +/- 3) d and in Group C (20 +/- 2) d. Lymphocytes of graft tolerant animals' demonstrated hyporesponsiveness in mixed lymphocyte cultures in a donor-specific manner in Group C. Tolerant graft histology showed no obliterative arteriopathy or chronic rejection. CONCLUSION: The AdCTLA4-Ig based conditioning regimen with donor BMT produce stable mixed chimerism and induce donor-specific tolerance to hind limb allografts. PMID- 19781263 TI - [New concepts of intestinal failure]. PMID- 19781253 TI - [Expression of Smads in keloid scarring]. AB - OBJECTIVE: To investigate the differential expression of different types of Smads in keloids, normal scars and normal skins and its possible clinicopathological significance. METHODS: RT-PCR and Western blot methods were used to examine the expression of Smads mRNA and proteins level in 10 cases of keloid, in 10 cases of normal scar and in 10 cases of normal skin tissues and fibroblasts. Fibroblasts of keloid, normal scar and normal skin were cultured in vitro. The expression difference were compared and analyzed by t-test, there was statistical difference when P < 0.05. RESULTS: The mRNA and protein expression of inhibitory Smad7 were significantly down regulated in keloid compared with normal scar (P < 0.05) and normal skin (P < 0.05). However, no significant difference of the mRNA and protein expression of Smad2, 3 and the protein expression of phosphorylation of Smad2, 3 in keloid, normal scar, normal skin tissues and fibroblasts. CONCLUSIONS: The decreased expression of Smad7 in keloid might play a significant role in the increased TGF-beta1/Smads signal transduction, which can not be terminated by autologous negative feedback cycle. PMID- 19781264 TI - [Surgical procedures for esophageal cancer with postoperative recurrence]. PMID- 19781266 TI - [Surgical treatment of ipsilateral multi-focal non-small cell lung cancer]. AB - OBJECTIVES: The staging and treatment of multi-focal non-small cell lung cancer (NSCLC) are controversial. This study evaluated the effectiveness of surgical treatment for the ipsilateral multi-focal NSCLC. METHODS: Sixty-eight patients with multi-focal NSCLC underwent complete resection from December 1999 to December 2006. This series included 44 males and 24 females, with a mean age of 60.3 years old (range from 33 to 81 years old). Fifty-four patients had multiple nodules in primary lobe (T4) and 13 patients had additional nodules in non primary lobe (M1), and a patient was proved to have synchronous primary NSCLC lesions. Surgical treatments included lobectomy in 53 cases, bilobectomy in 4 cases, pneumonectomy in 2 cases, and lobectomy combined with wedge resection in 9 cases. RESULTS: The median overall survival time of this series was 30 months. Prognostic study demonstrated that mediastinal lymph node metastasis and bronchioloalveolar carcinoma histology had significant impact on overall survival. The median survival times were 39 months for patients with N0 and N1, and 14 months for patients with N2, respectively, and there was significant difference between the groups (P < 0.01). The difference in survival was significant between patients with bronchioloalveolar carcinoma components and other NSCLC histologic types (P < 0.01), and the median survival times were 46 months and 20 months, respectively. CONCLUSION: Surgery could provide choice for multi-focal NSCLC patients (T4 and M1), especially for patients with bronchioloalveolar carcinoma components and without mediastinal lymph node metastasis. PMID- 19781265 TI - [Optimized perioperative management helps improve the results of thoracotomy in elderly patients]. AB - OBJECTIVES: To optimize perioperative respiratory and circulatory management so as to improve the surgical results of thoracotomy in elderly patients. METHODS: Respiratory and circulatory status was prospectively monitored and postoperative complications were documented in 58 elderly patients aged over 65 years underwent thoracotomy. The results were compared with those from 56 young patients aged under 65 years in the same time period. Based on the study results, the original perioperative management model was modified and prospectively studied in the following 179 elderly patients. Again the results were compared with 477 younger patients concomitantly treated. RESULTS: Through optimized perioperative management, the in-hospital mortality (4.9% vs. 1.1%, P = 0.033) and overall morbidity (58.6% vs. 21.8%, P < 0.01) were significantly decreased. This was most significant in the decrease of functional complications (51.7% vs. 14.5%, P < 0.01), especially the cardiovascular (22.4% vs. 7.3%, P = 0.001) and respiratory complications (20.7% vs. 7.3%, P = 0.004). There was no difference in technical complications between the two time periods. Comparing with the original model, the optimized perioperative management strategy resulted in significant decrease in acute lung injury (17.2% vs. 6.7%, P = 0.016), respiratory failure (6.9% vs. 1.7%, P = 0.041), as well as cardiac arrhythmia (20.7% vs. 7.3%, P = 0.004) in the early postoperative period. CONCLUSIONS: Optimization of perioperative management through careful preoperative functional evaluation, intraoperative protective ventilation, postoperative close monitoring of water balance, and timely intervention, may help improve surgical results in the elderly. PMID- 19781267 TI - [The long-term outcome and prognostic analysis of surgically treated patients with trachea tumors]. AB - OBJECTIVE: To investigate and evaluate the clinical features, diagnostic methods, surgical management of trachea tumors in order to improve patients outcome. METHODS: Clinical data of 32 patients with trachea tumors surgically treated from June 1986 to June 2005 were retrospectively analyzed. There were 22 male and 10 female patients. The age ranged from 14 to 63 years old with a median of 48 years old. The surgical procedures performed were resection and reconstruction of trachea in 10 cases, right or left pneumonectomy and carinal resection and reconstruction in 8 cases, right sleeve upper lobectomy, carinal resection and reconstruction of trachea and carina in 8 cases, and carina resection and reconstruction with tumor removal through tracheal windows 6 cases. The tracheal defect was repaired with a Teflon flap in two patients. Cardiopulmonary bypass was used in 2 patients during surgery. RESULTS: The histological examination of resected lesions revealed squamous cell carcinoma in 19 cases, adenoid cystic carcinoma in 8 cases, adenocarcinoma in 2 cases, carcinoid in 2 cases, leiomyosarcoma in 1 case and adenoma in 1 case. One case had infection of thoracic cavity and 3 cases experienced temporary cardiac arrhythmia. There was no operative death. The follow-up periods were from 5 months to 3 years. The 1, 2 and 3 year survival rates were 93.7%, 59.4% and 50.0% respectively. CONCLUSIONS: Squamous cell carcinoma adenoid cystic carcinoma are the most common in trachea tumors. Preoperative bronchoscope examination and chest CT scan can provide valuable diagnostic data. Proper choice of surgical procedure is important for improved patients' outcome. PMID- 19781268 TI - [Prognostic analysis of N2 non-small cell lung cancer]. AB - OBJECTIVE: To evaluate the surgical therapeutic strategy and prognostic factors for non-small cell lung cancer (NSCLC) with mediastinal lymph node metastasis (N2). METHODS: The survival rate of 117 patients with N2 NSCLC treated surgically from January 1999 to May 2003 were analyzed. There were 88 male cases and 29 female cases, aged from 29 to 79 years. The procedure of operation (lobectomy, pneumonectomy and palliative resection), histological classification (squamous cell carcinoma, adenocarcinoma, mixed carcinoma, and large cell carcinoma and others), T primary tumor status, and adjuvant therapy were analyzed to determine their impact on the 5-year survival rate. RESULTS: The median survival time was 22 months, and the over-all 3- and 5-year survival rate was 28.1% and 19.0%. Survival was higher in patients with lobectomy than with palliative resection, with T1 and T2 than with T4. The 5-year survival rate had no deference in age, sex and different histological classification. The 5-year survival rates of lobectomy and pneumonectomy (22.2% and 25.0% respectively) was higher than palliative resection (9.1%). CONCLUSIONS: Surgical procedures (especially lobectomy) is the best choice for N2 NSCLC patients with T1 or T2. But it can not prolong T4 patients' life significantly. PMID- 19781269 TI - [The expression of galectin-3 and osteopontin in occult metastasis of non-small cell lung cancer]. AB - OBJECTIVE: To study the relationship between expression of galectin-3 (Gal-3) and osteopontin (OPN) in occult metastasis in non-small cell lung cancer. METHODS: Forty-six patients of non-small cell lung cancer (NSCLC) from January 2006 to October 2007 were selected. There were 28 males and 18 females, aged from 33 to 77 years old. The levels of lung tissues Gal-3 and OPN were detected by RT-PCR, and the levels of blood plasma's were measured by ELISA. RESULTS: There were 12 patients who had metastasized. In un-metastasis group the Gal-3 and OPN mRNA expression levels were significantly lower than that in metastasis group: mean value were 0.07 +/- 0.17 and 0.17 +/- 0.25 in un-metastasis group, while 0.73 +/- 0.23 and 0.79 +/- 0.24 in metastasis group. Blood plasma levels of Gal-3 (18.8 +/ 7.9) microg/L and OPN (153.5 +/- 63.5) microg/L in NSCLC which were detected from metastasis group were higher than un-metastasis group of (9.2 +/- 5.6) microg/L and (89.2 +/- 24.0) microg/L. CONCLUSIONS: High serum levels of Gal-3 and OPN and high expression of Gal-3 and OPN mRNA in NSCLC are closely related to the occurrence and metastasis of NSCLC. They may be indexes of evaluating the occult metastasis in NSCLC. PMID- 19781270 TI - [Two-dose steroid combined with two-dose daclizumab and tacrolimus regimen in liver transplant recipients]. AB - OBJECTIVE: To investigate the efficiency and safety of two-dose steroid combined with two-dose daclizumab and tacrolimus (FK506) regimen in liver transplant recipients. METHODS: There were 74 patients who treated in the First Affiliated Hospital of Sun Yat-Sen University from September 2006 to March 2008. Expect for 7 patients who didn't measure up, 67 adult liver transplant recipients were randomized into two groups: conventional protocol group (n = 35) in which steroid was withdrawn in 3 months after operation, and two-dose steroid group (n = 32). Comparison of rejection, infection (bacteria, fungal and cytomegalovirus) and metabolic complications rates were studied between two groups. RESULTS: There were significant differences between two groups in the rate of early postoperation hyperglycemia, the average dosage of insulin consumption among hyperglycemia recipients as well as the rate of diabetes mellitus, hypertension and infection during the follow-up period (P < 0.05). The rate of hypertension in early postoperation period, hyperlipemia and rejection rate during the follow-up period were similar in two groups (P > 0.05). CONCLUSIONS: Two-dose steroid combined with two-dose daclizumab and tacrolimus would be a safe and efficient immunosuppression strategy without increase the acute rejection rate hazard, that could reduce post-transplant infection and other complications from side-effect of long-term usage of steroid. PMID- 19781271 TI - [Endoscopic thyroidectomy via the areola of breast approach]. AB - OBJECTIVE: To investigate the feasibility and safety of endoscopic thyroidectomy via the areola of breast approach. METHODS: Between April 2005 to September 2008, endoscopic thyroidectomy via the areola of breast approach was performed in 28 female patients. Of the patients, 25 cases presented with nodular goiter, 2 cases with Grave's disease and 1 case with minimum papillary carcinoma. The average age was 22.5 years (range, 18-38 years). A 10 mm trocar was placed on the medial border of the areola of the right breast for the video-endoscopy and removing specimens, and a 5 mm trocar was placed on the lateral border of the areola of the same breast as the assisted operation hole. Another 5 mm trocar was placed on the medial border of the areola of left breast as the main operation hole. The operation data was recorded and analyzed. RESULTS: All the 28 operations were successful. The procedures included one lobe total thyroidectomy in 5 cases, one lobe subtotal thyroidectomy in 15 cases, subtotal thyroidectomy in 3 cases, one lobe near total thyroidectomy + the other lobe subtotal thyroidectomy in 4 cases, and one lobe total thyroidectomy + the central group lymph node resection + the other lobe subtotal thyroidectomy in 1 case. The average operation time was 60.7 minutes (range, 40-125 minutes), the average operation blood loss was 5.8 ml (range, 2-15 ml), the average length of post-operative hospital stay was 3.1 days (range, 2-5 days). No adverse effects was found after the operation, such as damage to the parathyroid gland and the laryngeal nerve. The patients were followed-up for 1 to 40 months with satisfactory results. All 28 patients were satisfied with the cosmetic effects of the operation. CONCLUSIONS: Endoscopic thyroidectomy via the areola of breast approach produces an outstanding cosmetic effect, it is safe and feasible. PMID- 19781273 TI - [Surgical treatment for the giant aneurysms of middle cerebral artery]. AB - OBJECTIVE: To discuss the surgical treatment of the giant aneurysms of middle cerebral artery. METHODS: Clinical data, surgical methods and outcomes were analyzed in 17 giant aneurysms of middle cerebral artery treated from January 2001 to March 2008. CT scan, CTA, MRA, DSA and 3D-DSA were performed before operations so that we could comprehend the location, size, and shape of aneurysms and compensatory circulation of collateral branches to design the individualized treatment options. All patients had been surgically treated mostly by modified pterional approach, of which, direct clipping of the aneurysms was accomplished in 4 patients, aneurysms trapping or removal after trapping in 4, aneurysms excision or trapping combined with vessels reconstruction in 7, and aneurysms wrapping in 2 cases. RESULTS: CT and MRI revealed the shape and size of aneurysms clearly, while DSA and 3D-DSA could demonstrate the aneurysm's neck and relationship with the adjacent structure. Postoperative neurological function was evaluated according to Glasgow Outcome Scale when patients were discharged. Twelve patients had excellent neurological outcomes. However 4 patients were moderately disabled and one were severely disabled. No patient was dead postoperatively. CONCLUSIONS: It is necessary to perform elaborate imaging before operations for individualized surgical planning. The temporary occlusion of the parent artery and elimination of intra-aneurysmal thrombus are helpful to clipping the aneurysmal neck. Vessels reconstruction is a new and effective method of treating the giant aneurysms of middle cerebral artery. PMID- 19781272 TI - [Correlation between major histocompatibility complex class I-related chain A gene alleles and graft rejection in small intestine, liver and kidney transplantation]. AB - OBJECTIVE: To investigate the correlation between major histocompatibility complex (MHC) class I chain-related gene A (MICA) gene alleles matching rates and graft rejection in small intestine, liver and kidney transplantation. METHODS: Genome DNA were extracted from blood samples or pathological sections collected from donors and recipients of living-related transplantation, included 4 cases of small bowel transplantation, 5 cases of liver transplantation and 6 cases of kidney transplantation. The correlation between MICA alleles matching rates and acute graft rejection was analyzed following 13 MICA alleles determination by polymerase chain reaction based on sequence-specific primers (PCR-SSP). RESULTS: HLA zygosity of all donors and recipients was confirmed to be half-matching. The recipients displaying higher matching rates of MICA alleles with donors showed lighter clinical and pathological rejection and longer survival time. On the contrary, recipients with lower matching rates of MICA alleles with donors showed severer clinical and pathological rejection and shorter survival time relatively. CONCLUSION: Matching rates of MICA alleles has negative relevance to acute rejection, and positive relevance to survival time of recipients in small bowel, liver, and kidney transplantation. PMID- 19781274 TI - [Long-term result of fibula grafting for reconstruction of the distal radius after giant cell tumor excision]. AB - OBJECTIVE: To observe the long-term result of fibula grafting for reconstruction of the distal radius after giant cell tumor excision. METHODS: From March 1994 to November 2004, 31 cases of fibula grafting for reconstruction of the distal radius for giant cell tumors performed were analysed. There were 12 males and 19 females. The patients were from 19 to 48 years old, and the mean age was 31 years. Twenty-four patients had Campanacci grade 3 lesions, and 7 patients had Campanacci grade 2 lesions. There were 6 cases of vascularized fibular grafting and 25 cases of non-vascularized fibular grafting. All cases were evaluated by clinical and radiologic examinations; the movement of the wrist and the grip strength was measured; the MSTS score and Mayo Wrist scores were calculated. RESULTS: Clinical follow-up time after reconstruction averaged 86.3 months, range from 41 to 169 months. The mean time for bone union at the host-graft junctions was 5.1 months range from 3 to 9 months in vascularized group and 10.3 months range from 7 to 15 months in non-vascularized group. One patient who had non vascularized fibula grafting developed non-union at the host-graft junction, and one patient had local recurrence (3.2%). Five patients developed an wrist dislocation after surgery. The average movements of the wrist were: 67.3 +/- 9.4 degrees of extension, 31.2 +/- 5.1 degrees of flexion, 14.1 +/- 4.7 degrees of radial deviation, 19.4 +/- 3.9 degrees of ulnar deviation, 33.8 +/- 6.6 degrees of pronation, 15.3 +/- 4.0 degrees of supination. Average grip strength was 33.1 kg range from 15.5 to 52.1 kg. Compared with the contralateral side, there were accounted for 73%. MSTS score averaged 25.5 from 23 to 29, Mayo wrist score averaged 56 from 40 to 65. CONCLUSIONS: En bloc resection of giant cell tumor of the distal radius followed by reconstruction with a fibula graft is proved to be an effective method and results in a good functional outcome at long term follow up evaluation. The stability of wrist is achieved by reconstruction of the capsule. PMID- 19781275 TI - [Protective effects of affiliating portasystemic shunt on graft injury in small for-size liver transplantation in miniature pigs]. AB - OBJECTIVES: To evaluate the protective effects of affiliating portasystemic shunt on small-for-size graft in liver transplantation. METHODS: Fifteen Chinese Bama miniature pigs were divided into three groups: group A (small-for-size liver transplantation), group B (distal splenorenal shunt + small-for-size liver transplantation), and group C (mesocaval H-shape shunt + small-for-size liver transplantation). Animals were followed up for 7 days with survival, dynamical liver function biochemical parameters, liver biopsies, portal venous pressure (PVP) and portal blood flow (PBF). RESULTS: Animal survivals were as follows: group A, 1/5, group B, 3/5 and group C, 5/5.Group A resulted in abnormal liver function parameters that were significantly ameliorated in group B and C. The histological examination of graft in group A displayed severe pathologic changes including hepatocyte vacuolar change or necrosis, sinusoidal congestion, parenchymal hemorrhage. Affiliating portasystemic shunt significantly alleviated graft injuries in group B and C. PVP rose and peaked up to 28.6 mm Hg (1 mm Hg = 0.133 kPa), PBF fluctuated after reperfusion in group A, but group B and C with affiliating portasystemic shunt showed significantly lower PVP and maintained rather stable PBF after reperfusion. There were also statistical differences in PVP or PBF between group B and C. CONCLUSIONS: Affiliating portasystemic shunt effectively might protect small-for-size graft from injuries after reperfusion. PMID- 19781276 TI - [Application of intraoperative electrophysiological monitoring in lumbosacral selective posterior rhizotomy for spastic cerebral palsy]. AB - OBJECTIVE: To evaluate the clinical application of intraoperative electrophysiological monitoring in lumbosacral selective posterior rhizotomy for spastic cerebral palsy. METHODS: Total 372 dorsal roots of 89 patients underwent selective posterior rhizotomy at a single medical center. The dorsal roots from L3 to S1 were divided into rootlets and stimulated with a 1-second 50 Hz train. Motor responses were recorded by electromyography. Rootlets were assigned according to the extent of abnormal electrophysiological propagation, and grades of 3+ to 4+ were cut. If no electrical response was observed, the second criterion is the behavioral response (that is, muscle contraction in the legs or toes) assessed by the physical therapist, when rootlets were stimulated at the lowest threshold with a 1-second 50 Hz train. RESULTS: The rootlets of 340 dorsal roots were assigned according to the extent of abnormal electrophysiological propagation, 324 (83.5%) roots were assigned the maximally abnormal response of grade 3+ (76, 22.4%) or 4+ (248, 72.9%) in EMG monitoring and were cut. For no electrical response was observed, according to the second criterion, 48 roots were partially cut. It was also be found that free running EMG occurred earlier than stimulus triggered EMG, and identified "abnormal" rootlets on free running EMG monitoring was more easily and quickly than on stimulus triggered EMG. During the postoperative 2 weeks in hospital, there was a significant decrease in lower limb spasticity and an increase in range of movement in all patients, and no one case occurred obvious loss of muscle strength, abnormity of sensory, or deterioration of bladder/bowel control. CONCLUSIONS: The spread of electromyography response to the contra lateral limb and/or upper extremity remains a valid criterion to define a "abnormal" posterior nerve rootlet that feeds into a disinhibited spinal circuit involved in uncontrolled spasticity. Intraoperative electrophysiological monitoring is reproducible and reliable for selection of "abnormal" rootlets. PMID- 19781277 TI - [Establishment of red fluorescent protein orthotopic transplantation nude mice metastasis model of pancreatic cancer and whole-body fluorescent imaging]. AB - OBJECTIVE: To establish a stable high red fluorescent protein (RFP)-expressing orthotopic transplantation nude mice spontaneous metastasis model of pancreatic cancer. METHODS: Stable high RFP-expressing cells SW1990-RFP were injected subcutaneously into mice to establish subcutaneous implantation model. Fluorescent tumor piece from subcutaneous was transplanted into the body of the pancreas to establish surgical orthotopic implantation model. The growth of primary tumor, metastasis and micrometastasis were assessed by whole-body fluorescence imaging system. RESULTS: Twelve RFP orthotopic transplantation nude mice metastasis models of pancreatic cancer were established successfully, the percentage of success rate was 100%. RFP-labeled pancreatic cancer growth could be monitored in real time way. The micrometastasis of primary lesions were detected in early stage with whole-body fluorescence imaging system. CONCLUSIONS: The RFP orthotopic transplantation nude mice metastasis model of pancreatic cancer is stable and reliable, and can be observed dynamically in vitro in a noninvasive way, with much higher sensitivity and specificity. PMID- 19781278 TI - [The role of capsaicin-sensitive primary afferents in experimental sciatic pain]. AB - OBJECTIVES: To determine the effect of destroying capsaicin-sensitive primary afferents (CSPA) fibers on paw withdrawal mechanical threshold (PWMT) induced by the direct compression of L5 nerve root with autologous disc. METHODS: The procedure used autologous disc of the rats from the coccygeal intervertebral discs to apply direct pressure to the L5 dorsal root. PWMT was measured at the different time points post-surgery and pre-surgery. The changes in spatial expression pattern of c-fos protein in the spinal cord were also determined at 3 weeks when PWMT decreased to the peak. RESULTS: The pretreatment with capsaicin produced a complete prevention of mechanical hyperalgesia induced by disc compression. The direct compression of L5 nerve root produced an obvious expression of fos-like immunoreactivity neurons in the dorsal horn of the spinal cord, which was significantly decreased by pretreatment with capsaicin. CONCLUSIONS: The study shows that CSPA fibers, which mainly terminated in superficial layers of dorsal horn, may play a key role in mechanical hyperalgesia in the new sciatica model. PMID- 19781279 TI - [The anatomic study and clinical significance of the modified transforaminal lumbar interbody fusion]. AB - OBJECTIVE: To put some improvements to the traditional transforaminal lumbar interbody fusion (TLIF) and discuss its clinical significance. METHODS: Completed the traditional posterior lumbar interbody fusion (PLIF) and TLIF procedure in 12 fresh cadavers, dissect further to expose the surrounding anatomical structures, and put the modified TLIF surgery according to the anatomical findings. And simulated the operation in 12 fresh cadavers, analyzed its feasibility and potential advantages. RESULTS: The early anatomical study found that the related nerve root was in a state of high tension and certain risk of injury when completed the traditional PLIF and TLIF surgery, and found certain operational area between the superior articular process and the midline structures of the spinous processes and interspinous ligaments. Put the modified TLIF surgical approach according to the anatomical findings, which the operating area is located in PLIF outside and TLIF inside. As the following words: Take a posterior middle incision, preserve the supraspinous and interspinous ligaments, and the spinous processes, dissect the bilateral paravertebral muscle, expose lamina and facet joints, not including transverse process, and remove unilateral inferior two third lamina, inferior articular process and expose the articular surface of the superior articular process, then dispose the intervertebral space for interbody fusion obliquely in the unilateral approach. Successfully completed the modified TLIF procedure in 12 fresh cadavers, the results showed that the technique has the following advantages. (1) Only remove unilateral inferior two third lamina and inferior articular process, preserve the supraspinous and interspinous ligaments, and the spinous processes, not expose the transverse process. (2) Both central canal, and lateral recess and nerve root canal of the operative side can be decompressed effectively simultaneously. (3) Avoid excessive traction to the thecal sac and traversing nerve roots and decrease the injury rate due to the reservation of the midline structures and the oblique manipulation, and less injury rate of the exiting nerve root, because of not necessary to expose it routinely. CONCLUSIONS: The modified TLIF is safe and feasible, could effectively reduce the nerve roots injuries. Maybe it's a better choice for most of the Chinese patients at present. PMID- 19781288 TI - Technical refinement for treatment of coronary bifurcation lesion is still demanding. PMID- 19781289 TI - Mechanisms and clinical significance of quality of final kissing balloon inflation in patients with true bifurcation lesions treated by crush stenting technique. AB - BACKGROUND: The mechanisms responsible for the occurrence of a kissing unsatisfied (KUS) result after classical crush stenting remain unclear. The present study aimed at analyzing the mechanisms and clinical significance of KUS. METHODS: Two hundred and thirteen patients with true bifurcation lesions treated with classical crush stenting and final kissing balloon inflation (FKBI) were assigned to upper, middle, and lower groups according to the position of the side branch re-wiring assessed by visual estimation, quantitative coronary analysis (QCA) and intravascular ultrasound (IVUS). Angiographic follow-up was indexed at 12 months. RESULTS: The upper group was characterized by a larger bifurcation angle of 55.53 degrees +/- 25.25 degrees (P = 0.030) and a longer procedural time (42.43 +/- 23.92) minutes (P = 0.015). The overall rate of KUS by visual estimation was 10.48%, with 5.4% in the upper group, 3.9% in middle group, and 36.1% in lower group (P < 0.001). For the diagnosis of KUS, visual inspection demonstrated a good correlation with both QCA and IVUS. Smaller stent diameter was the main reason for KUS in the upper group, while extra-stent side wire location, or re-wire in a low position was the main mechanism attributed to KUS in the lower group. The Lower group had more restenosis, with most restenotic lesions at a lower position of the side branch ostium. KUS (HR 1.652, 95% CI 1.332 - 2.088, P < 0.001) and re-wiring position (HR 2.341, 95% CI 1.780 - 4.329, P < 0.001) were two independent predictors of side branch restenosis. Re-wiring position (OR 0.458, 95%CI 0.336 - 0.874, P = 0.001) and side stent expansion (OR 3.122, 95%CI 2.883 - 5.061, P = 0.014) were factors predicting the findings of KUS. CONCLUSIONS: Side wire outside side stents resulted in more KUS and restenosis. Different restenotic lesion types reflected individual mechanisms contributing to the development of plaque proliferation. PMID- 19781290 TI - Novel side branch ostial stent (BIGUARD): first-in-man study. AB - BACKGROUND: Stenting a bifurcation lesion is technically challenging. No study has reported the clinical outcome of a dedicated bifurcation stent in China. We aimed to analyze the safety and clinical outcome of a novel side branch ostial stent (BIGUARD) stent in treating coronary bifurcation lesions. METHODS: Forty seven patients were enrolled in this first-in-man study, with 61.7% true bifurcation lesions (0,1,1 and 1,1,1) and 26.7% diabetes. A two-stent technique was used in 27.6% of the patients, and 64.7% of patients crossed from the one stent technique to the two-stent arm. Clinical and angiographic follow-up data at 12 months were available in all the 47 patients and in 43 patients (91.9%), respectively. The study endpoint was the occurrence of major adverse cardiac events (MACE) at 12 months. RESULTS: Only one patient had a non-ST segment elevation myocardial infarction, which led to 2% of the in-hospital composite MACE. Notably, the target lesion revascularization at 12 months was 8.6%, with a 10.6% composite MACE at 12 months. Neither cardiac death nor stent thrombosis was seen during the follow-up. By quantitative coronary analysis, the restenosis rate at the main vessel and ostium of the side branch was 9.4% and 2.1%, respectively. Four of 12 patients (33.3%) treated with one-stent and kissing balloon inflation had restenosis in the main vessel. CONCLUSION: BIGUARD stent was safe and feasible in treatment of bifurcation lesions. PMID- 19781291 TI - Clinical study of arterial anatomic variations for transradial coronary procedure in Chinese population. AB - BACKGROUND: The radial artery is currently regarded as a useful approach for coronary intervention procedures. Adequate anatomical information of the radial artery should be helpful in performing transradial coronary procedures. Few data about the Chinese population have been obtained in this field. Therefore, we tried to evaluate the incidence and clinical significance of anomalous patterns, and their influence on the intervention procedure. METHODS: In an estimated sample of 3000 cases, radial artery and subclavical artery angiography were performed after insertion of the sheath and coronary angiography (CA). The evaluable data including branch anomaly, tortuosity of the radial artery and procedural characteristics were analyzed. The procedure success was defined as CA or percutaneous coronary intervention (PCI) completed with the initial radial artery approach without changing to other routes. RESULTS: In this study, 1897 cases of CA was undertaken and 1103 cases of CA combined with PCI were performed. The success rate of transradial intervention (TRI) was 96.6% (2899/3000). The approach in 44 cases was changed to the contralateral radial artery and 57 cases were changed to the brachial artery or femoral artery due to failure with the initial radial artery approach. The angiography of the upper limb artery was performed in all cases. Anatomic variations of upper limb arteries were noted in 610 patients (20.3%), which included tortuous configurations of the radial artery (5.0%), hypoplasias (2.2%), radioulnar loop (1.1%), abnormal origin of the radial artery (7.7%), stenosis of radial artery (1.4%), a tortuous configuration of the brachial artery (0.9%), a tortuous configurations of the subclavian artery (1.9%), lusoria subclavian artery (0.1%), and subclavian artery occlusion (0.03%). The procedural success rate in the normal population was higher than in the variation group (97.6% vs 93.0%, P < 0.001). In addition, other procedural outcomes and incidence of complications except radial artery occlusion were also significantly superior to variation group. CONCLUSIONS: Anatomic variations of the radial artery were common, making up an important limitation in the trans radial approach. Selection of appropriate instruments and understanding some tips and tricks were helpful to overcome the obstacles and effectively reduce the learning curve. PMID- 19781292 TI - Reference values of brachial-ankle pulse wave velocity for Northern Chinese. AB - BACKGROUND: Brachial-ankle pulse wave velocity (baPWV) is a reliable method for measuring arterial elasticity, but the absence of reference value for baPWV has limited its wide use. We conducted an epidemical study in north China to investigate the reference value of baPWV for Chinese people and its influential factors. METHODS: A total of 974 identified healthy subjects were recruited in this study. The values of baPWV were evaluated noninvasively with an automatic device. RESULTS: For healthy population, the mean value of baPWV was higher for male (P < 0.001). Multiple regression analysis demonstrated that both age and systolic blood pressure were positively associated with baPWV for male and female (P < 0.001). BaPWV value was higher in male than in female in younger group (< 50 years) but not in older group (P 0.05). On the contrary, no significant difference of plasma free warfarin concentration between genotypes was observed in each dosage group. It took 96 hours for the INR value and 144 hours for the free warfarin plasma concentration to come back to baselines after the last dose. No significant difference among genotypes and dosing groups was detected in the elimination phase (P > 0.05). CONCLUSION: VKORC1 polymorphisms are associated with differences in the initial response to warfarin when given at fixed doses, without affecting, as expected, its plasma concentration. PMID- 19781296 TI - Decreased expression of complement regulatory proteins, CD55 and CD59, on peripheral blood leucocytes in patients with type 2 diabetes and macrovascular diseases. AB - BACKGROUND: Macro- and microvascular diseases are the leading cause of morbidity and mortality in diabetic patients, but their mechanisms remain unclear. Recent reports provide evidence that the levels of CD55 and CD59 are decreased in diabetic microvascular diseases. However, very little is known about the levels of CD55 and CD59, the relationship between them and carotid artery intima-media thickness, and the effects of statins on CD55 and CD59 in diabetic macrovascular diseases. METHODS: The mean fluorescence intensity (MFI) of CD55 and CD59 expression on peripheral blood leucocyte subsets (lymphocytes, monocytes and neutrophils) was studied using flow cytometry, and carotid artery intima-media thickness was measured using B-mode ultrasonography in 23 healthy subjects (controls), 19 patients with type 2 diabetes (T2DM), and 43 patients with type 2 diabetes and macrovascular diseases (T2DM-M). The patients with T2DM-M were assigned to two subgroups based on whether statins were used: group with statins (n = 23) and group without statins (n = 20). RESULTS: Compared with the controls and T2DM, the MFI of CD55 positive neutrophils was significantly lower in T2DM-M (P = 0.049 vs controls and P = 0.033 vs T2DM); similarly, the MFI of CD59 positive monocytes was also lower in T2DM-M (P = 0.038 vs controls and P = 0.043 vs T2DM). The MFI of CD59 positive neutrophils in T2DM-M was lower than in T2DM (P = 0.032). The levels of CD55 and CD59 were negatively associated with age and blood pressure (r = -0.245 - -0.352, P = 0.041 - 0.003), but not acute-phase reactants and carotid artery intima-media thickness. The levels of CD55 and CD59 increased after treatment with statins, but the results were not significantly different (P > 0.05). CONCLUSIONS: CD55 and CD59 expressions on peripheral blood leucocytes are decreased in T2DM patients with macrovascular diseases. The results suggest that the decreased levels of complement regulatory proteins might play an important role in diabetic macrovascular diseases. PMID- 19781297 TI - Relationship between serum HBV DNA level and HBV-specific, nonspecific cytotoxic T lymphocytes and natural killer cells in patients with chronic hepatitis B. AB - BACKGROUND: The response of patients with chronic hepatitis B (CHB) to antiviral therapy against hepatitis B virus (HBV) is related to the base line level of HBV DNA, but the mechanism is not clear. The present study aimed to understand the possible relationship between the level of HBV DNA and HBV-specific, nonspecific cytotoxic T lymphocytes (CTL) and natural killer (NK) cells of CHB patients and the mechanism how the HBV DNA level influences the antiviral therapeutic effect. METHODS: Totally 100 adult patients with CHB who were positive for HBV DNA, HBeAg and (HLA)-A2 were enrolled into this study. HBV DNA was tested by real time fluorescence quantitative polymerase chain reaction (PCR). HBV specific and nonspecific CTL and NK cells were tested by flowcytometry. Serum alanine aminotransferase (ALT) and total bilirubin (TBil) were determined for each patient using routine biochemical tests. The 100 cases were assigned to two groups based on their HBV DNA level: group A had 48 cases, their HBV DNA level was 10(4) - 10(5) copies/ml, group B had 52 cases, their HBV DNA level was 10(6) 10(7) copies/ml. HBV specific CTL, nonspecific CTL, NK cells, ALT and TBil of the two groups were compared. RESULTS: HBV DNA level of groups A and B was (4.81 +/- 0.39) log(10) copies/ml and (6.81 +/- 0.40) log(10) copies/ml, respectively (t = 25.32, P < 0.001). HBV specific CTL and NK cells of group A were significantly higher than those of group B (P < 0.001 for both). Nonspecific CTL of group A was significantly lower than that of group B (P < 0.01). ALT and TBil of group A were significantly lower than those of group B (P < 0.01 and P < 0.05, respectively). CONCLUSIONS: Serum HBV DNA level of patients with CHB is related to HBV specific CTL, nonspecific CTL and NK cells, which might result in inflammatory reaction of liver and cause more damage to liver function. Mechanism of HBV DNA level affecting the efficacy of anti-viral treatment may be related to the levels of HBV specific CTL and NK cells. PMID- 19781298 TI - An alternative approach in the treatment of thumb web contracture skin defects: lateral tarsal artery flap. AB - BACKGROUND: Thumb web contracture is a common complication after hand injury, and can markedly affect whole hand function. Therefore, surgery involving thumb web reconstruction is often necessary to restore normal function of the involved hand. In this study, we present the application of the lateral tarsal artery (LTA) flap in first web reconstruction. METHODS: From November 1, 2005 to October 31, 2007, seven patients with severe post trauma or burn contractures around the first web space were treated with a LTA flap. All the patients were followed up. RESULTS: All flaps survived, with an average size of 6.7 cm x 4.8 cm. There were no complications or recurrent contractures during follow-up. All patients were satisfied with the esthetic appearance and functional outcome of the reconstruction. CONCLUSION: The LTA flap could be an excellent option for covering various defects in the thumb web space, serving as an excellent alternative for the thumb web space reconstruction. PMID- 19781299 TI - Prospective study of reconstructing pelvic floor with GORE-TEX Dual Mesh in abdominoperineal resection. AB - BACKGROUND: Mesh reconstruction has been proved to be an effective method in incisional hernia repairment. This study was designed to evaluate the effect of reconstructing the pelvic floor with the high-inlay expanded polytetrafluoroethylene (ePTFE) GORE-TEX Dual Mesh (WLGore And Associates, Flagstuff, USA) in abdominoperineal resection. METHODS: Sixty patients who underwent abdominoperineal resection for rectal cancer were assigned to 2 groups. The pelvic peritoneum was closed by routine sutures in group 1 and reconstructed with ePTFE in group 2. Postoperative complications and related items were evaluated and the patients were followed up. RESULTS: Time of confining to bed, bowel function recovery, fasting, and detaining drainage were significantly different between two groups (P < 0.05). In group 1, three patients developed bowel obstruction (10%), while no bowel obstruction was observed in group 2. CONCLUSION: Reconstruction of the pelvic floor using ePTFE results in quicker postoperative recovery and could decrease the risk of postoperative intestinal obstruction. PMID- 19781300 TI - Diagnostic imaging, preautopsy imaging and autopsy findings of. AB - BACKGROUND: Aquired immune deficiency syndrome (AIDS) presents a challenge to medical researchers because of its unique pathological and clinical picture. The clinical data, particularly autopsy evidence, from China have failed to provide enough pathological and etiological evidence for AIDS diagnosis, which impairs the reliability of the diagnosis and our full understanding of the occurrence and development of AIDS complications. The purpose of this study was to investigate the imaging and pathologic characteristics of AIDS. METHODS: Autopsy, imaging and pathological data from 8 cases of AIDS were retrospectively analyzed. Routine CT scanning of different body parts was performed during their periods of hospitalization. Transverse CT scanning was conducted from the skull to the pelvis immediately after the occurrence of death. After routine formalin fixing, 7 cardevers were cross sectioned for autopsy in freezing state and 1 for gross autopsy. Tissues were obtained from each section and organs for pathological examinations. RESULTS: The autopsy data indicated the presence of parasitic infections, bacterial infections, fungal infections, and virus infections in AIDS patients. Pneumocystis pneumonia, pulmonary tuberculosis, coccobacteria pneumonia, Aspergillus pneumonia, cytomegalovirus pneumonia, toxoplasma encephalitis, lymphoma and cerebrovascular diseases were found in these patients. CONCLUSIONS: During the course of AIDS progression, the concurrent multiple infections as well as tumor development may result in multiple organ pathological changes and clinically complex symptoms that further complicate the imaging and pathological manifestations, thus resulting in difficult differential diagnosis. A combination of imaging data and autopsy data can help to clarify the diagnosis. PMID- 19781301 TI - Role of interleukin-10 and transforming growth factor beta 1 in otitis media with effusion. AB - BACKGROUND: Otitis media with effusion (OME) is a disease with complicated pathogeneses which are not clearly known. Increasing interest has been focused on immunological cells, cytokines and their roles in chronic inflammatory states. This study was designed to disclose the existence and roles of interleukin-10 (IL 10) and transforming growth factor beta1 (TGF-beta1) in the cause of OME in adults, and to investigate the probable role of Foxp3(+)CD4(+)CD25(+) T cells in OME. METHODS: The concentrations of IL-10 and TGF-beta1 in the middle ear effusions (MEEs) and plasmas of 36 adults (45 ears) with OME were measured by means of enzyme linked immunosorbent assay (ELISA). As contrast, the concentrations of IL-10 and TGF-beta1 in the plasma of 30 normal volunteers were measured using the same method. Furthermore, the proportion of Foxp3(+)CD4(+)CD25(+) T cells in CD4(+) T cells of blood was tested by flow cytometry. RESULTS: (1) The concentrations of IL-10 in all MEEs and plasmas of the chronic OME patients were higher than those in patients with acute OME (both P < 0.05), so was TGF-beta1 (both P < 0.01). The concentration of IL-10 in MEEs was significantly higher than that in plasmas, not only in acute OME (P < 0.01), but also in chronic OME (P < 0.01). In chronic OME, the concentration of TGF beta1 in MEEs had no statistical difference with those in plasmas of the same patients. However, the concentration of TGF-beta1 in plasmas of patients with chronic OME was significantly higher than that in plasmas of normal volunteers (P < 0.01). (2) The concentrations of IL-10 and TGF-beta1 in MEEs of the patients who had been treated more than once were higher than those MEEs of the patients who were treated for the first time, respectively (P < 0.05, P < 0.01). The level of TGF-beta1 in plasmas of the patients who had been treated more than once was higher than in those of the patients who were treated firstly (P < 0.05), while the level of IL-10 in plasmas had no difference. The concentration of IL-10 in mucoid MEEs was higher than those in serous ones (P < 0.05), while TGF-beta1 had no statistical difference between mucoid and serous MEEs (P > 0.05). The concentration of IL-10 in MEEs had a strong correlation with the duration of the illness (r = 0.547, P < 0.01). The same correlation was also found between the concentration of TGF-beta1 in MEEs and the times patients being treated (r = 0.579, P < 0.01). (3) The proportion of Foxp3(+)CD4(+)CD25(+)T/CD4(+) T cells in the blood of chronic OME was not only significantly higher than that in the acute OME (P < 0.01), but also higher than that in normal volunteers (P < 0.01). In chronic OME, there was a correlation between the proportion of Foxp3(+)CD4(+)CD25(+) T/CD4(+) T cells in the blood and the concentration of IL 10 in the plasmas (r = 0.602, P < 0.05). CONCLUSIONS: IL-10 and TGF-beta1, as two important immunoregulatory mediators, participate in middle ear inflammatory response, especially in chronic course of OME in adults. Foxp3(+)CD4(+)CD25(+) T cells may play some immunoregulatory roles in the course of this disease. PMID- 19781302 TI - Piggyback liver transplant techniques in the surgical management of urological tumors with inferior vena cava tumor thrombus. AB - BACKGROUND: An important characteristic of renal cell carcinomas and adrenal tumors is that these tumors may expand into the renal vein and inferior vena cava, and transform into tumor thrombi. This study was to evaluate the use of piggyback liver transplant techniques for surgical management of urological tumors with inferior vena cava tumor thrombus. METHODS: Nineteen patients with renal cell carcinomas or adrenal tumors with inferior vena cava tumor thrombus were treated from November 1995 to April 2008. Their ages ranged from 29 years to 76 years (mean 54 years). The extent of tumor thrombus was infrahepatic (level I) in 2, retrohepatic (level II) in 7, suprahepatic (level III) in 6, and intra atrial (level IV) in 4 patients. We used cardiopulmonary bypass with deep hypothermic circulatory arrest to remove the thrombi in 3 cases of level IV and in 2 cases of level III. In all level II, 4 level III, and 2 level IV cases, we used piggyback liver transplant techniques to mobilize the liver off of the inferior vena cava and to separate the inferior vena cava from the posterior abdominal wall. RESULTS: Mean operative time was 5.1 hours, mean estimated blood loss was 2289 ml and mean blood transfusion was 12.84 U. One patient with adrenal cortical carcinoma and level IV thrombus died in the immediate postoperative period. Three patients were lost to follow up, and the other 15 survivors were followed from 5 months to 56 months. Eight of these 15 patients died due to metastasis; however 7 were still alive at the last follow-up. CONCLUSIONS: An aggressive surgical approach is the only hope for curing patients diagnosed with urological tumors combined with inferior vena cava tumor thrombus. The use of piggyback liver transplant techniques to mobilize the liver off of the inferior vena cava provides excellent exposure of the inferior vena cava. Patients with a level II or level III inferior vena cava thrombus may be treated without using cardiopulmonary bypass. PMID- 19781303 TI - Prevention of beta cell dysfunction and apoptosis by adenoviral gene transfer of rat insulin-like growth factor 1. AB - BACKGROUND: Islet beta-cells are almost completely destroyed when patients with type 1 diabete are diagnosed. To date, insulin substitute therapy is still one of the main treatments. The cure of type 1 diabetes requires beta-cell regeneration from islet cell precursors and prevention of recurring autoimmunity. Therefore, beta-cell regeneration and proliferation emerge as a new research focus on therapy for type 1 diabetes. Islet beta-cell regeneration and development are controlled by many growth factors, especially insulin-like growth factor-1 (IGF 1). METHODS: Recombinant adenovirus encoding rat IGF-1 (rIGF-1) was constructed and transduced into rat beta-cells, RINm5F cells. Western blotting analysis and ELISA were used to detect rIGF-1 protein. Streptozotocin (STZ) was used to induce RINm5F cell destruction. The level of nitric oxide (NO) was detected in cell culture supernatants by the Griess reaction. Islet cell function was evaluated by glucose-stimulated insulin production. Flow cytometry analysis was further used to investigate the apoptosis of RINm5F cells. Thiaoollyl blue viability assay was applied to determine cell viability. RESULTS: The recombined adenovirus-rIGF-1 was successfully constructed and the titer was 4.0 x 10(8) pfu/ml. The rIGF-1 protein was effectively expressed in the RINm5F cells and cell culture supernatants. rIGF-1 expression remarkably inhibited STZ-induced islet cell apoptosis and significantly decreased the level of NO. Furthermore, IGF-1 expression also significantly protected insulin secretion and cell proliferation in a time-dependent manner. CONCLUSIONS: Our study suggests that locally produced rIGF-I from RINm5F cells may be beneficial in maintaining beta-cell function, protecting beta-cells from the destruction of apoptosis factors and promoting beta-cell survival and proliferation. IGF-I might be considered as a candidate gene in gene therapy for type 1 diabetes. In addition, it appears that the apoptosis induced by STZ may be NO-dependent. PMID- 19781304 TI - Penetrability of interleukin-1beta and its effect on the concentration of tumor necrosis factor-alpha and interleukin-6 in the aqueous humor of rabbits treated with interleukin-1beta. AB - BACKGROUND: Interleukin (IL)-1beta may effectively decrease introcular pressure (IOP) when administered by subconjunctival injection in normal rabbit. However, IL-1beta is a large molecular agent and an inflammation factor. The aim of this study was to evaluate the penetrability of IL-1beta, and the concentrations of both tumor necrosis factor (TNF)-alpha and IL-6 in the aqueous humor of normal rabbits treated with IL-1beta. METHODS: A total of 170 rabbits were used in the study and were assigned to several different treatment groups as follows: 125 of the rabbits were assigned to two groups. In one group, 33 rabbits were injected subconjunctivally with IL-1beta and 39 were injected with saline alone. In the other group, 27 rabbits were given eye drops containing IL-1beta (400 ng/ml) and 26 were given saline alone. Aqueous humor (AH) was drawn and the concentration of IL-1beta within the fluid measured. The IOP was measured in another six rabbits after administration of eye drops containing IL-1beta (400 ng/ml). A further 20 rabbits were assigned to 3 groups as follows: eight untreated normal controls; six injected subconjunctivally with IL-1beta; and six injected subconjunctivally with saline alone. AH was drawn and the concentration of TNF-alpha in the fluid was measured. Another 19 rabbits were assigned to 3 groups as follows: seven untreated normal controls; and six injected subconjunctivally with IL-1beta; and six injected subconjunctivally with saline alone. AH was drawn and the concentration of IL-6 in the fluid measured. Measurement of cytokine concentration was by radio-immunoassay in all cases. RESULTS: The IL-1beta concentration in the AH was higher in those animals in which it had been administered subconjunctivally (P < 0.01). The IL-1beta concentration in the AH of the animals given eye drops was almost the same as that in the controls (P > 0.05). The administration of IL-1beta in the form of eye drops had little effect upon IOP reduction. Lower TNF-alpha concentrations were seen in the AH after the subconjunctival administration of IL-1beta, but the concentration of IL-6 was the same as in the normal controls. CONCLUSIONS: IL-1beta shows good corneal penetrability after subconjunctival injection into normal rabbit eyes. The IOP reduction induced by IL-1beta is unlikely be associated with an inflammatory response. PMID- 19781305 TI - Purification and characterization of anti-clotting protein component (ACPF-7221) from venom of Agkistrodon acutus. AB - BACKGROUND: Snake venom contains a number of components with different pharmacological and biological activities, especially in cancer therapy, and has increasingly become a research focus. This study was designed to isolate and purify a novel anti-clotting protein component from the venom of Agkistrodon acutus, and to explore its physico-chemical properties and biological activity. METHODS: The venom of Agkistrodon was isolated and purified by ion-exchange chromatography on diethylaminoethyl (DEAE)-Sepharose Fast Flow, molecular sieve filtration through Sephadex G75, SP-Sepharose Fast Flow and molecular sieve filtration through Sephadex G50. We detected the activated partial thromboplastin time (APTT) of the eluant to select the anti-clotting protein component of interest. The molecular weight was determined by sodium dodecyl sulfate polyacrylamid gel electrphoresis (SDS-PAGE) and liquid chromatography. Its protein content was detected by bicinchoninic acid (BCA). RESULTS: SDS-PAGE vertical gel electrophoresis showed that the anticoagulant factor is a tripolymer composed of three proteins whose molecular weights are 25 KDa, 30 KDa and 50 KDa. The factor contains about 65% percent protein. CONCLUSIONS: A novel anti-clotting protein component was purified by ion-exchange chromatography and molecular sieve filtration from the venom of Agkistrodon acutus and was found to be composed of three kinds of proteins. PMID- 19781306 TI - Vascular brachytherapy revisited for in-stent restenosis in the drug-eluting stent era: current status and future perspective. PMID- 19781307 TI - Effects of trimetazidine on atrial structural remodeling and platelet activation in dogs with atrial fibrillation. PMID- 19781308 TI - Multiple aortico-cameral tunnels associated with bicuspid aortic valve in aged: a case report. PMID- 19781309 TI - Triple antiplatelet therapy for clopidogrel resistance with stent malapposition: a case report. PMID- 19781310 TI - Heart-lung transplantation for end-stage heart disease with Eisenmenger's syndrome: report of two cases. PMID- 19781311 TI - Spontaneous intraperitoneal bleeding caused by adrenal pheochromocytoma. PMID- 19781312 TI - Isolated non-compaction of ventricular myocardium in a victim of the Wenchuan earthquake with crush syndrome and acute renal failure. PMID- 19781313 TI - Nonvisual ganglion cells, circuits and nonvisual pigments. PMID- 19781314 TI - Value of percutanous catheter fragmentation in the management of massive pulmonary embolism. AB - BACKGROUND: Acute massive pulmonary embolism (PE) is a clinical emergency requiring rapid and supportive measures. Percutanous mechanical thrombectomy is considered as a treatment option. The purpose of this study was to evaluate the clinical efficacy and safety of peructaneous mechanical catheter fragmentation in the management of acute massive PE. METHODS: From January 2003 to June 2007, 28 patients (20 men, 8 women; mean age 64 years) with acute massive PE initially diagnosed by computed tomography and confirmed by pulmonary angiography were treated with inferior vena caval filter placement and percutaneous catheter fragmentation. Twenty-six patients received thrombolytic agents after embolus fragmentation. RESULTS: Technical success was achieved in all patients. The improvement of clinical status and restoration of blood flow in the main branches of the pulmonary artery were seen in 27 patients. Only one case did not benefit from the percutaneous therapy and died from the failure of the surgery. Oxygen saturation increased from (86.2 +/- 4.5)% to (96.1 +/- 3.2)% (P < 0.001) after the interventional procedure. The post-procedure mean pulmonary artery pressure decreased from (34.2 +/- 4.8) mmHg to (25.2 +/- 5.1) mmHg (P < 0.001). During clinical follow-up (range, 1 - 5 years), no patients had recurrence of PE. CONCLUSION: Percutaneous catheter fragmentation combined with thrombolysis is an effective and safe therapy in the clinical management of acute massive PE. PMID- 19781315 TI - Endovascular repair: alternative treatment of ruptured abdominal aortic aneurysm. AB - BACKGROUND: As an alternative to open aneurysm repair, endovascular aortic repair (EVAR) has been applied to ruptured abdominal aortic aneurysm (rAAA). The aim of this study was to evaluate the immediate and long-term outcomes of EVAR for rAAA. METHODS: From July 1997 to September 2007, 20 men and six women with rAAA (median age, 68 years) were treated with EVAR. Most patients with suspected rAAA underwent emergency computed tomographic angiography (CTA). The procedure was performed under general or local anesthesia. Endovascular clamping was attempted in hemodynamically unstable patients. Bifurcated endografts and aorto-uni-iliac (AUI) endografts with crossover bypass were used. Patients had CT scan prior to discharge, 3, 6, 12 months after discharge, and annually thereafter. RESULTS: Time between diagnosis and EVAR ranged from 1 hour to 5 days. EVAR was performed under general anesthesia in 21 patients, and under local anesthesia in five patients. Endovascular aortic clamping was performed in four patients. There was no conversion to open surgery during EVAR. Stent-graft insertion was successful in all patients. One patient died during EVAR from acute myocardial infarction. Ten patients had systolic blood pressure < 80 mm Hg. Eleven patients received a blood transfusion. Mean aneurysm size was (47 +/- 12) mm. Mean ICU stay was (8 +/ 3) days, mean hospital stay (18+/- 6) days, and mean procedure time (120 +/- 32) minutes. The 30-day mortality was 23% (6/26 patients), and major morbidity 35% (9/26 patients). Early endoleak occurred in 8/26 patients (31%). The mean follow up was (18 +/- 7) months. No patient demonstrated migration of the stent-graft. CONCLUSIONS: EVAR is a safe and effective option for treatment of acute rAAA, independent of the patient's general condition. Immediate and mid-term outcomes are favorable, but long-term outcome is unknown. Multi-center studies are necessary to establish the role of EVAR for rAAA. PMID- 19781316 TI - Effects of upstream tirofiban versus downstream tirofiban on myocardial damage and 180-day clinical outcomes in high-risk acute coronary syndromes patients undergoing percutaneous coronary interventions. AB - BACKGROUND: For patients with moderate to high-risk acute coronary syndromes (ACS) who undergo early, invasive treatment strategies, current guidelines recommend the usage of glycoprotein (GP) IIb/IIIa inhibitors as an upstream treatment for a coronary care unit or as an downstream provisional treatment for selected patients who are undergoing percutaneous coronary intervention (PCI). The relative advantage of either strategy is unknown. The purpose of this study was to evaluate the effects of upstream tirofiban versus the effects of downstream tirofiban on myocardial damage and 180-day major adverse cardiovascular events (MACE) after PCI in high-risk non-ST-segment elevation ACS (NSTE-ACS) undergoing PCI. METHODS: From July 2006 to July 2007, 160 high-risk NSTE-ACS undergoing PCI were randomized to receive upstream (within 4 - 6 hours before coronary angiography) tirofiban or downstream (the guidewire crossing the lesion) tirofiban, to evaluate the extent of myocardial damage after PCI by quantitatively and qualitatively analyzing the value of cardiac troponin I (cTnI) as well as MB isoenzyme of creatine kinase (CK-MB) before and after PCI. The incidences of 24-hour, 3-day, 7-day, 30-day and 180-day MACE after PCI were followed up and the rates of bleeding complications and thrombocytopenia during tirofiban administration were recorded. RESULTS: The peak release and cumulative release of cTnI levels within 48 hours after PCI were significantly lower with upstream tirofiban than downstream tirofiban (0.45 vs 0.63 and 0.32 vs 0.43, respectively; P < 0.05). Post-procedural cTnI elevation within 48 hours was significantly less frequent among patients who received the upstream tirofiban than those who received the downstream tirofiban (66.3% vs 87.5%, P < 0.05). The peak and cumulative release of CK-MB levels as well as post-procedural CK-MB elevation within 48 hours after PCI were not significantly different between the two groups (16 vs 14 , 5 vs 3 and 26.3% vs 36.3%, respectively; P > 0.05). The incidences of 24-hour, 3-day, and 7-day MACE after PCI were the same between the two groups (0 vs 0, 0 vs 0 and 1.25% vs 1.25%, respectively). Although the incidences of 30-day and 180-day MACE after PCI were not statistically different between the two groups, the incidences were consistently lower with upstream tirofiban (3.75% vs 6.25% and 12.99% vs 16.67%; P > 0.05). Aging (OR = 1.164, P < 0.001), hypertension (OR = 4.165, P = 0.037) and type 2 diabetes (OR = 13.628, P < 0.001) were independent risk factors of MACE. The timing of administrating the tirofiban (OR = 2.416, P = 0.153) plays an extensive role in the incidence of MACE. The incidences of major and minor bleeding complications as well as mild thrombocytopenia during the administration of tirofiban were similar between the two groups (2.50% vs 1.25%, 1.25% vs 1.25% and 1.25% vs 1.25%, respectively; P > 0.05). CONCLUSIONS: Based on the pretreatment with aspirin and clopidogrel, upstream tirofiban was associated with attenuated minor myocardial damage and the tendency of reducing incidences of 180-day MACE after PCI among high-risk NSTE ACS patients undergoing PCI. Aging, hypertension and type 2 diabetes were independent risk factors of MACE in high-risk NSTE-ACS patients undergoing PCI associated with tirofiban. PMID- 19781317 TI - Association between inflammatory mediators and angiographic morphologic features indicating thrombus formation in patients with acute myocardial infarction. AB - BACKGROUND: Inflammatory mechanisms had played an important role in the occurrence and prognosis of acute myocardial infarction, inflammatory mediators was associated with adverse outcomes of acute myocardial infarction. This study tested the hypothesis that in the acute phase of myocardial infarction with ST segment elevation, neutrophil count and high-sensitivity C-reactive protein are predictive of angiographic morphologic features that indicate thrombus formation in the infarct-related artery. METHODS: This retrospective study included 182 consecutive patients with acute myocardial infarction and ST-segment elevation. Patients were assigned to a thrombus-formation group (n = 77) and a non-thrombus formation group (n = 106). All patients had a Killip's classification 0.05). Time for return of bowel function was significantly shortened in BAR group than that in suture group (P < 0.05). CONCLUSION: The BAR appears to be a standard, easy, safe and effective alternative either in elective or emergent intraperitoneal intestinal anastomotic surgery. PMID- 19781321 TI - Recent changes in the prevalence of Helicobacter pylori infection among children and adults in high- or low-incidence regions of gastric cancer in China. AB - BACKGROUND: The prevalence of Helicobacter pylori (H. pylori) infection varies by geographic locations. Studies indicate that the infection rate of H. pylori was previously high in China but that rates had been declining worldwide over recent decades. THE AIMS OF OUR STUDY WERE: (1) to determine the current prevalence of H. pylori infection among children and adults residing in areas with high (Muping County, Shandong) and low (Yanqing County, Beijing) incidences of gastric cancer in China, and (2) to compare the prevalence for 2006 with the prevalence for the early 1990s. METHODS: Using Warthin-Starry silver staining of gastric mucosal biopsy specimens and H. pylori stool antigen tests (HpSA), we tested a total of 2065 asymptomatic children aged 8 - 15 years and adults aged 40 - 79 years in the above two regions from May to July 2006. We evaluated 520 children and 526 adults from Muping, and 516 children and 503 adults from Yanqing. Subjects were selected randomly and H. pylori status was determined by HpSA in children and either HpSA or histology of gastric biopsies in adults. Data obtained in the early 1990s in the same two areas of China were also collected and studied. RESULTS: For children, the prevalence of H. pylori infection was significantly higher in Muping (37.69%) than it was in Yanqing (25.58%, P < 0.001). In both regions, the prevalence of H. pylori increased with age but was not related to gender. A significant difference was observed between 8 - 9-years old and 10 - 11-years old (P < 0.05), but not between other adjoining age groups (P > 0.05). From 1991 to 2006 H. pylori prevalence among 8 - 10-year-old children decreased in Muping (60.00% vs 32.07%, P < 0.001), but not Yanqing (24.06% vs 19.10%, P > 0.05). In the adult group, H. pylori prevalence was 50.95% in Muping, which was significantly higher than the 41.35% positive rate in Yanqing (P < 0.01). But there were no statistically significant differences between different age groups of 40 - 49, 50 - 59, and 60 - 79 years, or between males and females. A significant decrease in H. pylori prevalence in both regions was observed when the results of 2006 were compared with the data obtained in 1990 in Muping (50.95% vs 73.78%, P < 0.001) and in 1992 in Yanqing (41.35% vs 55.35%, P < 0.01). CONCLUSIONS: After fifteen years, the prevalence of H. pylori infection among both children and adults remained significantly higher in areas with a high incidence of gastric cancer in China compared with that in areas with a low incidence of gastric cancer. H. pylori infection rates have decreased in the general Chinese population during recent years. PMID- 19781322 TI - Nuclear corepressor 1 expression predicts response to first-line endocrine therapy for breast cancer patients on relapse. AB - BACKGROUND: Estrogen receptor alpha (ER alpha) is the most important endocrine therapy responsiveness predictor for women with breast cancer. The accuracy of the prediction of the response to endocrine therapy was thought to be affected by involving the estrogen receptor coregulatory proteins and cross-talk between ER and other growth factor-signaling networks. Nuclear corepressor 1 (NCOR1) is one of the ER a transcription repressor. The objective of the study is to investigate the expression of NCOR1 at the protein level and pursue its predictive value for breast cancer endocrine therapy. METHODS: In the present study, the level of expression of NCOR1 protein has been assessed by immunohistochemistry in 104 cases of invasive carcinoma of the breast. Associations between NCOR1 protein expression and different clinicopathological factors and survival were sought. RESULTS: It was found that NCOR1 was expressed at significantly higher levels in responsive patients treated with endocrine therapy as first-line treatment on relapse. Responsive patients also had a significantly longer post-relapse survival and overall survival. No NCOR1 expression difference was found between patient by age, tumor size, lymph node status, different histological grade groups and human epidermal growth factor receptor 2 (HER2) status. Multivariate analysis showed that NCOR1 is an independent prognostic factor for over-all survival. CONCLUSIONS: In breast cancer, NCOR1 protein expression level predicts response to endocrine therapy as first-line treatment for breast cancer patients on relapse and NCOR1 protein level assay may increase the accuracy in the endocrine treatment determination and, therefore, improving the patients survival. PMID- 19781323 TI - Long-term P300 in hemispherectomized patients. AB - BACKGROUND: In the years around 1990, in Beijing Tiantan Hospital Affiliated to Capital Medical University many children with infantile hemiplegia and intractable epilepsy were treated with further modified anatomical hemispherectomy. We report the follow up of the first six cases. To make good use of these precious clinical data and make clear their neuropsychological state, we performed neuropsychological and neurophysiological measurements in these patients, who were at a median of 17.8 years after hemispherectomy. METHODS: Oddball task was given to the patients and to a normal control group to collect the peak latency (PL) and peak amplitude (PA) of event-related potentials (ERPs) P300. The P300 data of the two groups were analyzed and the P300 patterns of the six patients are presented. The baseline characteristics and long-term follow-up of the six hemispherectomized patients, especially the long-term seizure control and cognitive function after surgery, are described. RESULTS: Five patients had no seizures and one was almost seizure-free during the years after surgery. Clear P300 was obtained from every electrode in the patients. Differences of P300 between patients and normal control group had no statistical significance. And the maximum PA was at the site of electrode Pz or Cz which was consistent with that of the control group and with previous findings. CONCLUSIONS: Further modified anatomical hemispherectomy has preferable long-term antiepileptic effects. The P300 results of the patients mean that the basic cognitive function of the patients has no difference from the control group. This reflects the plasticity of the hemisphere to some extent and increases the affirmation of the long-term curative effects of further modified anatomical hemispherectomy from both neuropsychological and neurophysiological aspects. PMID- 19781324 TI - Effect of estrogen on gene expression of fatty acid synthase in periosteum. AB - BACKGROUND: Estrogen deficiency contributes to postmenopausal osteoporosis. Periosteum might be a potential target of estrogen, but the underlying mechanism at gene level is far from being elucidated. The objective of this study was to investigate the correlation between estrogen and fatty acid synthase (FAS) expression in periosteum. METHODS: Human periosteum cells were cultured in vitro. Expressed genes in the substrated cDNA library were verified using semi quantitative PCR and real-time PCR. The expression of FAS in periosteum of ovarectomized (OVX) SD rats was investigated. RESULTS: FAS gene was most significantly expressed in the subtracted cDNA library of periosteal cells screened by semi-quantitative PCR. Low FAS expression was verified by real-time PCR in the estrogen exposed human periosteum rather than in the control. The estradiol levels were (20.81 +/- 12.62) pg/ml, (19.64 +/- 4.35) pg/ml and (13.47 +/- 1.84) pg/ml in the sham group, the control, and the OVX group, respectively. The estradiol levels in the OVX group was significantly lower (P = 0.0386). The FAS gene expression in periosteum in the OVX group, sham group, and control group was 3.09 +/- 1.97, 1.33 +/- 0.47 and 1.51 +/- 1.32, respectively. The gene expression in the OVX group was significantly higher (P = 0.0372). CONCLUSION: Estrogen modulates FAS gene expression in in vitro human perisoteum as well as in in vivo rat periosteum. PMID- 19781325 TI - Hyperoxygenated solution for improved oxygen supply in patients undergoing lung lavage for pulmonary alveolar proteinosis. AB - BACKGROUND: At present, the most effective treatment for pulmonary alveolar proteinosis (PAP) remains whole-lung lavage in spite of the usually accompanying severe hypoxemia, which is expected to be prevented by hyperoxygenated solution improving oxygen supply during lavage. In this study, the efficacy and safety of the effect of hyperoxygenated solution were evaluated. METHODS: Five patients underwent whole-lung lavage over a 28-month period. Each lung was lavaged with hyperoxygenated (HO) and normal saline solution (plain lactated Ringer's solution, NO) randomly and alternatively until the reclaimed fluid was clear. Random number was generated by computer before every cycle of lavage. If the number was odd, the patient was assigned to receive a lavage cycle with hyperoxygenated solution (HO group, n = 109); if the number was even, normal saline solution was used (NO group, n = 115). Data of saturation of peripheral oxygen (SPO(2)), mean arterial pressure (MAP), central venous pressure (CVP), heart rate (HR) and end-tidal carbon dioxide tension (P(ET)CO(2)) were taken down at 0, 30, 60, 90, 120, 150, 180, 210 and 240 seconds from the beginning of the instillation of solution, and frequency and volume of unilateral lung lavage were also recorded. Time interval between the left and the right lung lavage was 1 week. RESULTS: No patient was withdrawn from the study due to low SPO(2) or leakage. Oxygen pressure was (730.21 +/- 7.43) mmHg in the hyperoxygenated solution against (175.73 +/- 5.92) mmHg in the normal saline solution (P < 0.01). Compared with baseline, SPO(2) increased significantly as the instillation of solution began (P < 0.01), leveled for about 30 seconds (P > 0.05), and then decreased significantly to the lowest at the time of drainage (compared with 120 seconds or peak, P < 0.01). SPO2 was higher in HO group than in NO group (P < 0.01). There were no significant differences in MAP, HR, CVP and P(ET)CO(2) between HO group and NO group (P > 0.05) and also among different time points (P > 0.05). CONCLUSION: During the lung lavage for pulmonary alveolar proteinosis, hyperoxygenated solution could significantly improve oxygen supply in comparison with normal saline solution without obvious side effects. PMID- 19781326 TI - Value of the peripheral blood B-cells subsets in patients with ankylosing spondylitis. AB - BACKGROUND: The role of B-cell remains an enigma in the pathogenesis of ankylosing spondylitis (AS). This study aimed to investigate the distributions of B-cells and subsets in peripheral blood of AS patients and observe their changes in etanercept-treated AS patents. METHODS: We detected the proportions of CD19(+) B-cell, naive B-cell (CD19(+)CD27-), memory B-cell (CD19(+)CD27dim) and plasmablast (CD19(+)CD27high) in peripheral blood of 66 patients with AS (39 at active stage, 27 at stable stage; 35 patients with peripheral joint involvement, 31 patients with axial involvement alone), 30 patients with rheumatoid arthritis (RA) and 30 healthy volunteers using flow cytometry. And then we observed the changes of the above indexes of 39 active AS patients treated with etanercept in a randomized, double-blind, placebo-controlled trial. RESULTS: (1) Percentages of CD19(+) B-cells in active or peripheral joint involvement AS patients increased more obviously than those in stable or axial involvement alone AS patients (both P = 0.001), and percentage of CD19(+)CD27high B-cells in AS patients with peripheral joint involvement was significantly higher than that in cases with axial involvement alone or healthy volunteers (P = 0.005 and 0.006, respectively); (2) The percentage of CD19(+) B-cells in AS patients was positively correlated with Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores, Patient's Global Assessment (PGA) scores, total back pain scores and nocturnal back pain scores (r = 0.270, 0.255, 0.251 and 0.266, P = 0.029, 0.039, 0.042 and 0.031, respectively); (3) At week 6 and week 12, there were no statistical differences of the percentages of B-cells and subsets between etanercept group and placebo group of AS patients (P > 0.05); the percentage of CD19(+) B-cells in etanercept group was higher than that in healthy volunteers at week 12 (t = 3.320, P = 0.003). CONCLUSIONS: Misbalance is present in B-cells and some subsets in peripheral blood of active AS patients with peripheral joint involved. B-cells might play an important role in the pathogenesis of AS patients. The high percentage of CD19(+) B-cells in active AS patients cannot be down-regulated after 12-week etanercept treatment. PMID- 19781327 TI - Differential diagnosis and laparoscopic treatment of adrenal pheochromocytoma and ganglioneuroma. AB - BACKGROUND: Adrenal ganglioneuroma is a rare adrenal pathogenic disease with difficult differential diagnosis from adrenal pheochromocytoma. Currently, very limited literature is available to allow a differential diagnosis of these two conditions from each other. This study aimed to evaluate the clinical profile, differential diagnosis and surgical treatments of both conditions. METHODS: Clinical characteristics of 36 patients with adrenal pheocheomocytoma and 18 patients with adrenal ganglioneuroma were analyzed. Data from CT scans and surgical treatments from 1999 to 2007 were collected. Endocrine hormone tests and (131)I-metaiodobenzylguanidine (MIBG) were performed. Neither (131)I-MIBG nor endocrine hormone tests were available in 9 cases of asymptomatic adrenal ganglioneuroma with tumor size less than 4 cm and there were negative findings from contrast enhanced CT scans. The level of urine catecholamine of patients was compared by one-way analysis of variance. RESULTS: Te mean age of patients in the adrenal ganglioneuroma group was 41.2 years (16 - 67 year) and in the adrenal pheochromocytoma patients 38 years (17 - 74 year). Contrast enhanced CT showed that the foci were intensified in 5 cases (27.8%) of adrenal ganglioneuroma and there were obvious contrast indications in 30 (83.3%) of the pheochromocytoma. Catecholamine levels in a 24-hour urine sample were normal in 4 patients with adrenal ganglioneuroma and increased in 36 (100%) cases with adrenal pheochromocytoma. (131)I-MIBG nuclear scan showed negative results in 4 patients (100%) with adrenal ganglioneuroma and positive results in 25 (96.2%) with adrenal pheochromocytom. Laparoscopy for adrenal tumors was performed through a transperitoneal or retroperitoneal approach during a follow-up period of (43 +/- 6) months, and all cases survived well. CONCLUSIONS: CT, urinary catecholamine and (131)I-MIBG are standard and efficient tools for differential diagnosis of adrenal ganglioneuroma from pheochromocytoma. Laparoscopic surgery can be performed through a transperitoneal or retroperitoneal approach depending on the finding of CT scans. Open surgery is necessary for patients with blood loss of more than 800 ml and violent fluctuation of intraoperative blood pressure. PMID- 19781328 TI - Endoplasmic reticulum stress is involved in acetylated low-density lipoprotein induced apoptosis in THP-1 differentiated macrophages. AB - BACKGROUND: Cardiovascular disease is a major cause of mortality and morbidity in patients with chronic kidney disease. Macrophage death in advanced atherosclerosis promotes necrosis and plaque destabilization. In vitro data from peritoneal macrophages show apoptosis triggered through endoplasmic reticulum (ER) stress caused by free cholesterol accumulation plays an important role. Here we used THP-1 cells differentiated by 100 ng/ml of phorbol 12-myristate 13 acetate (PMA) for five days as an in vitro model, to investigate if acetylated low-density lipoprotein (AcLDL) loading could also induce apoptosis and its underlying mechanisms. METHODS: Oil red O staining was used to examine the lipid droplets. Confocal microscopy was used to visualize the uptake of AcLDL. Hoechst 33258 stain and the caspase 3,7 assay were used to detect apoptosis. High performance liquid chromatography was used in the intracellular free cholesterol (FC) and cholesterol ester (CE) assay. Western blotting was used to demonstrate the protein level. Real-time PCR was used to detect the changes of mRNAs. ER free cholesterol was also assayed. RESULTS: Confocal microscopy showed THP-1 cells differentiated by 100 ng/ml of PMA for five days uptake more AcLDL than differentiated for two days. Hoechst 33258 stain showed AcLDL could induce apoptosis in THP-1 macrophages in a time and dose dependent manner. Exposure of THP-1 macrophages to 100 microg/ml of AcLDL for 24 hours resulted in a significant increase in caspase 3,7 activity, a significant increase in FC and CE mass of 1.5 and 2.4-fold, meanwhile, a significant increase in transcription factor C/EBP homologous protein and a decrease in Bcl-2 both in protein and mRNA levels were observed with an 8-fold rise of free cholesterol in the ER. CONCLUSION: ER stress is involved in AcLDL induced apoptosis in THP-1 macrophages with free cholesterol accumulation in the ER. PMID- 19781329 TI - Cloning and bioinformatic analysis of lovastatin biosynthesis regulatory gene lovE. AB - BACKGROUND: Lovastatin is an effective drug for treatment of hyperlipidemia. This study aimed to clone lovastatin biosynthesis regulatory gene lovE and analyze the structure and function of its encoding protein. METHODS: According to the lovastatin synthase gene sequence from genebank, primers were designed to amplify and clone the lovastatin biosynthesis regulatory gene lovE from Aspergillus terrus genomic DNA. Bioinformatic analysis of lovE and its encoding animo acid sequence was performed through internet resources and software like DNAMAN. RESULTS: Target fragment lovE, almost 1500 bp in length, was amplified from Aspergillus terrus genomic DNA and the secondary and three-dimensional structures of LovE protein were predicted. CONCLUSION: In the lovastatin biosynthesis process lovE is a regulatory gene and LovE protein is a GAL4-like transcriptional factor. PMID- 19781330 TI - Uncommon characteristics of the structure and development of Trichosporon asahii. AB - BACKGROUND: Trichosporon asahii (T. asahii) is one of the most important pathogenic fungus in the genus of trichosporon. Although the species identification of T. asahii was based upon the complicated results of morphologic, biochemical and biologic examination, the morphology characteristic is still the first clue to the species. Some common structures of T. asahii had been described such as arthrofilaments and arthroconidia, but other important structures of T. asahii were unclear. METHODS: Six strains of T. asahii were incubated on the slant and micro culture of Sabouraud's dextrose agar at 30 degrees C for 7 days. Samples were fixed using 2% paraformaldehyde and 2.5% glutaraldehyde. T. asahii was observed under scanning electron microscope and transmission electron microscope. RESULTS: The detailed characteristics of the diverse sites of germination, as well as some uncommon structures such as giant cell, sarcinate, and club-shaped macroconidia, were presented. The pseudohyphae of T. asahii were noted to produce true hyphae, either along the longitude axis or on the flank. T. asahii was noted to have blastic and thallic conidiation. Digitated branches, trichoid structures and septa inside the spores were detected. CONCLUSION: These results may add our knowledge to the structure and development of T. asahii. PMID- 19781331 TI - Current state of myocardial tissue engineering. PMID- 19781332 TI - Modulating protein kinase D1 signal transduction. PMID- 19781333 TI - Effect and intracellular uptake of pure magnetic Fe3O4 nanoparticles in the cells and organs of lung and liver. PMID- 19781334 TI - Chromophobe renal cell carcinoma: clinicopathologic features and outcomes of 16 cases. PMID- 19781335 TI - Intracerebellar meningioma with peritumoral cyst in an adult: case report. PMID- 19781336 TI - Concurrence of Bartter syndrome and minimal change nephrotic syndrome. PMID- 19781337 TI - Malignant priapism secondary to testicular tumor. PMID- 19781338 TI - [Autopsy on medical dispute cases]. PMID- 19781339 TI - [Reappraisal of invasive lobular carcinoma]. PMID- 19781340 TI - [Analysis of discrepancies between clinical and autopsy diagnoses in 188 cases]. AB - OBJECTIVE: To analyze the discrepancies between clinical and autopsy diagnoses in hospitals of different grades and with respect to duration of hospitalization. METHODS: A total of 188 autopsy cases collected from hospitals of different grades were retrospectively reviewed and the discrepancies between clinical and autopsy diagnoses were analyzed. RESULTS: The overall rate of misdiagnosis was 48.9% (92/188). The misdiagnosis rate in grade I hospitals (75.8%, 25/33) was significantly higher than that in grade III (39.6%, 38/96; chi(2) = 12.861, P = 0.000) and grade II hospitals (49.2%, 29/59; chi(2) = 6.179, P = 0.016 ). The misdiagnosis rate of patients beyond 24 hours of admission was lower than that admitted within 24 hours (chi(2) = 20.991, P = 0.000). The overall rate of missed diagnosis was 34.6% (65/188). The rate of missed diagnosis in grade I hospitals was remarkably higher than that of the grade III hospitals (chi(2) = 8.241, P = 0.006). There was no difference between grades I and III hospitals on the rate of missed diagnosis within 24 hours of admission, however, this rate was lower in grade III hospitals in comparing with that of grade I hospitals in patients admitted beyond 24 hours (chi(2) = 5.181, P = 0.047). The distribution of disease entities commonly encountered in patients of both misdiagnosis and missed diagnosis were heart problems, infections, arterial diseases and pulmonary embolism. CONCLUSIONS: The rate of discrepancies between clinical and autopsy diagnoses is relatively high. The misdiagnosis and missed diagnosis rate in grade I hospitals was significantly higher than that in grade III hospitals and was closely related with the duration of hospitalization. Autopsy study thus still remains an important measure in clinical audit. PMID- 19781341 TI - [Autopsy study of 275 medical dispute cases]. AB - OBJECTIVE: To study the characteristics of autopsies in medical dispute cases, with respect to class of hospitals, clinical units concerned, age of deceased and cause of death. METHODS: Two hundred and seventy-five autopsies performed on medical dispute cases during the period from January 1, 2002 to September 30, 2008 at the Department of Pathology, Health Science Center, Peking University, China were retrospectively reviewed. RESULTS: During the period of study, the number of autopsies performed on medical dispute cases gradually increased. Medical dispute cases happened more often in surgical, obstetric and gynecology departments of grade II and III hospitals, as well as emergency departments of grade I hospitals. Perinatal death in infants of less than 1 year old more frequently caused medical dispute than death occurring in other age groups. According to the International Classification of Diseases (ICD10), disorders of the circulatory system, perinatal illnesses, external injury or iatrogenic conditions represented the major categories of cause of death. In general, the vast majority was due to natural causes and only 13.5% were related to iatrogenic reasons or medical negligence. Pathologic diagnosis of sudden coronary death, myocardial infarction and viral myocarditis should only be made with strict diagnostic criteria. CONCLUSIONS: Autopsies for medical dispute cases can help to delineate the cause of death and provide evidence for further clarification. Meticulous autopsy techniques, application of strict diagnostic criteria and detailed analysis of cause of death are key steps in achieving a high quality service in this area. PMID- 19781342 TI - [Expression of COX-2 and pregnancy associate plasma protein A in coronary arteries and their relationship with acute coronary syndrome: an autopsy study of 42 cases]. AB - OBJECTIVE: To study the expression of COX-2 and pregnancy associate plasma protein A (PAPP-A) in coronary arteries and their relationship with acute coronary syndrome. METHODS: Twenty-one autopsy cases with acute coronary syndrome encountered during the period from 2002 to 2007 were enrolled into the study. Another 21 autopsy cases without evidence of acute coronary syndrome were used as the controls. The right and left coronary arteries of each group were dissected, embedded and processed as paraffin sections. Immunohistochemical study for CD68 and alpha-actin was performed to highlight the presence of macrophages and smooth muscle cells, respectively. The expression of COX-2 and PAPP-A was evaluated. RESULTS: In the acute coronary syndrome group, COX-2 was localized mainly in the cytoplasm of endothelial cells, macrophages and smooth muscle cells. COX-2 expression in the cytoplasm of smooth muscle cells (28.60%) was significantly higher than that in the control group (4.76%, chi(2) = 14.13, P< 0.05). There was a positive correlation on COX-2 and PAPP-A expression in smooth muscle cells of the media layer of coronary arteries in acute coronary syndrome group (r = 0.88, P < 0.05). The expression of PAPP-A in smooth muscle cells of the media layer in coronary arteries not associated with plaque formation, was higher than that when there were atherosclerotic plaques (chi(2) = 10.36, P < 0.05). CONCLUSION: In coronary arteries, COX-2 and PAPP-A play certain roles in the pathogenesis of acute coronary syndrome. PMID- 19781343 TI - [Pathology of accidental electrocution: an autopsy study of 16 cases]. AB - OBJECTIVE: To study the pathologic findings seen in lethal cases due to accidental electrocution. METHODS: The macroscopic and microscopic findings in 16 autopsy cases died of electrocution encountered during the period from January, 2001 to July, 2008 were retrospectively reviewed. RESULTS: Typical electric marks were found on gross examination in 5 of the 16 cases studied. Histologically, 11 of the 16 cases showed evidence of electric burn. The morphologic features of atypical electric marks varied. Simple epidermal exfoliation and color changes were relatively common. Pathologic changes in internal viscera included disarray of myocardial fibers. Rupture of myocardial fibers was readily identified than in non-electrocution death. Sometimes, focal interstitial hemorrhage and polarization of endothelial cells were seen. CONCLUSIONS: The electric marks on the skin, as confirmed by histologic examination, remain important sequelae of electrocution. The pathologic changes seen in myocardium provide additional clues to the diagnosis. PMID- 19781344 TI - [Clinicopathological significance of cytotoxic lymphocytes in breast cancer and draining lymph nodes]. AB - OBJECTIVE: To analyze retrospectively the quantity and activation status of the tumor infiltrating cytotoxic lymphocytes in breast cancer and the draining lymph nodes, and its relation to the clinical pathological significance. METHODS: Seventy-four breast cancer samples with their corresponding axillary lymph nodes were histologically typed and staged. Cytotxic lymphocytes were analyzed by immunohistochemistry with the monoclonal antibodies against CD8, CD56, granzyme B and perforin. RESULTS: The number of infiltrating CD8(+) T cells in the cancerous interstitial tissue were much higher than that in the tumor parenchyma. Compared with the metastatic tumor samples, the CD8(+) T cells were more intensive in the primary tumors (35.7 +/- 16.0 vs. 23.7 +/- 9.6). The tumor infiltrating CD8(+) T cells of patients with 5 years survivals were more than that of the dead cases in this follow-up series death (32.9 +/- 14.1 vs. 20.1 +/- 9.9). There was no significant difference of activated tumor infiltrating cytotoxic T cell analyzed by using the activation marker granzyme B(+) and there was also no significant correlation between the intensity of CD8(+), CD56(+) cells and the clinicopathological stages. However, percentages of the activated cytotoxic lymphocytes in Stage I groups were significantly higher than those in stage III and IV. Moreover, the number of perforin(+) cells was significantly less than that of granzyme B(+) cells, particularly in the cancerous tissue, indicating a dysfunctional status of tumor infiltrating cytotoxic lymphocytes. CONCLUSIONS: Activated cytotoxic lymphocytes may play a significant role against the tumor progression and is associated with a favorable prognosis to some extent. However, a putative dysfunctional status of cytotoxic lymphocytes at tumor site may compromise the host immunity against cancer. PMID- 19781345 TI - [Pathologic diagnosis of specific infections in upper aerodigestive tract]. AB - OBJECTIVE: To find a fast and simple method for detection of specific pathogens in upper aerodigestive tract. METHODS: Sixty-one cases of specific infections in upper aerodigestive tract encountered during a 10-year period in Beijing Tongren Hospital were retrospectively studied. Six histochemical stains, including PAS, Giemsa, Gram, methylene blue, modified Warthin-Starry and acid-fast stains were applied. The morphology of different pathogens was studied and the staining patterns were compared. RESULTS: There were 23 cases of pharyngeal treponemal infection, 10 cases of short treponemal infection, 4 cases of mycobacterial infection, 4 cases of infection by rhinoscleroma bacilli, 1 case of sinonasal fungal infection, 1 case of combined infection of bacteria and Oidium albicans, 2 cases of tonsillar Actinomycetes and 16 cases of non-specific bacterial infections. Both pharyngeal treponemal infection and infection by rhinoscleroma bacilli could be detected by modified Warthin-Starry stain. As for sinonasal fungal infection, PAS, Giemsa and modified Warthin-Starry stains were useful in differentiating different types of fungi. Mycobacteria were best demonstrated by conventional acid-fast stain. CONCLUSIONS: Special histochemical stains performed on histologic sections are useful for diagnosing specific infections in upper aerodigestive tract. PMID- 19781346 TI - [Morphological diagnosis of endometrial intraepithelial neoplasia and expression of PTEN]. AB - OBJECTIVE: To investigate the diagnostic applications of endometrial intraepithelial neoplasia (EIN), and the expression of PTEN in endometrial lesions. METHODS: Fifty-one cases of endometrial lesions were enrolled in this study. Using diagnostic criteria of EIN, the diagnosis were made and compared with the original results. Immunohistochemistry for PTEN was performed in all cases. RESULTS: Two cases of simple hyperplasia originally diagnosed were reclassified as EIN. Three cases with atypia originally diagnosed showed no EIN pattern. PTEN deletion rates were 50.0%, 50.0%, 66.7% and 81.8% in proliferative endometrium, benign hyperplasia, EIN and endometrial carcinoma, respectively. CONCLUSIONS: Diagnosis of EIN is applicable and its morphology and diagnostic criteria are different from the classical one (WHO94) for endometrial hyperplasia. Detection of PTEN deletion by immunohistochemistry is useful in identifying EIN, but cannot be used as an ultimate confirming factor. PMID- 19781347 TI - [Mutation and protein expression of PTEN gene in cervical adenocarcinoma and glandular intraepithelial neoplasia]. AB - OBJECTIVE: To investigate PTEN expression and mutation status in the development of cervical adenocarcinoma. METHODS: Immunohistochemistry study of PTEN protein was performed on 42 cases of cervical adenocarcinoma, 20 cases of cervical glandular intraepithelial neoplasia and 28 cases of normal cervix tissue samples. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) was used to detect the presence of mutation of exons 5 and 8 of PTEN gene. RESULTS: Positive expression rates of PTEN protein were 54.8% (23/42), 25.0% (5/20) and 100% (28/28) in cervical adenocarcinoma, cervical glandular intraepithelial neoplasia and normal cervix tissues, respectively. There were significant differences among the 3 groups (P < 0.05). Positive expression rates of PTEN protein were 47.4% (9/19), 20.0% (2/10) and 92.3% (12/13) in mucinous, endometrioid and the other variants of cervical adenocarcinoma, respectively. Mutation rates at exon 5 and exon 8 of PTEN gene were 19.0% (8/42), 45.0% (9/20) and 0 in cervical adenocarcinoma, cervical glandular intraepithelial neoplasia and normal cervix tissue, respectively. There were significant differences among 3 groups (chi(2) = 4.29, chi(2) = 12.70; P < 0.05). The mutation rates were 21.1% (4/19) and 40.0% (4/10) in mucinous and endometrioid variants of cervical adenocarcinoma, respectively. There was no mutation at exons 5 and 8 of PTEN gene detected in other variants of cervical adenocarcinoma. CONCLUSION: The development of cervical adenocarcionomas is correlated with the mutation and absence of the protein expression of PTEN, likely in the early phase of their carcinogenesis. PMID- 19781348 TI - [Pilot study of differentiation of bone marrow derived mesenchymal stem cells into endothelial cells induced by B16 melanoma cells in vitro]. AB - OBJECTIVE: Bone-marrow derived mesenchymal stem cells (BMSC) have the potential to differentiate into endothelial cells. The aim of the study was to investigate the induction process of BMSC by B16 melanoma cells in vitro and to analyze the role of VEGF-a in the process. METHODS: A co-culture system containing BMSC and B16 melanoma cells based on transwell indirect model was established, and the induction process of BMSC by B16 melanoma cells was studied in vitro. RESULTS: BMSC were isolated from the bone marrow of C57 mice. BMSC expressed CD105, CD90, CD73, CD44 and CD166, and acquired expressin of endothelial phenotype markers including VEGFR-1, VEGFR-2 and Factor VIII after co-culture with B16 melanoma cells for 48 hours. The expression level of VEGFR-2 would be double and Factor VIII threefold more by extending the co-culture time to 72 hours. In the co culture system, B16 melanoma cells also up-regulated the expression of VEGF-a. CONCLUSIONS: VEGF-a plays a significant role in the differentiation of BMSC into cells of endothelial phenotype, therefore, is important to tumor angiogenesis. PMID- 19781349 TI - [Study of the relationship between early growth response gene 1 activity in p38 mitogen-activated protein kinase pathway and epirubicin resistance of human breast carcinoma cells]. AB - OBJECTIVE: To investigate the relationship between activities of early growth response gene 1 (EGR-1) of p38 mitogen-activated protein kinase (MAPK) pathway and in the epirubicin resistance of breast carcinoma cells. METHODS: Protein expression of phosphorylated p38MAPK was detected by confocal spectral microscopy. Using specific inhibitor SB203580, the effect of p38MAPK on cell apoptosis was analyzed by FITC-Annexin-V/PI double staining. The concentration of epirubicin was detected by flow cytometry (FCM). The 50% inhibition concentration (IC50) of epirubicin on MCF-7/Adr cells was determined by MTT method. Electrophoretic motility shift assay (EMSA) was performed to examine the affinity of EGR-1. EGR-1 mRNA was assessed by RT-PCR. The expression levels of p glycoprotein, phosphorylated p53 and p38 were detected by Western blot. RESULTS: After treatment with SB203580 (15 micromol/L) 24 h and 48 h, (1) the early and late apoptosis of MCF-7/Adr cells expressing the phosphorylated p38MAPK protein was (25.36 +/- 1.17)% and (38.21 +/- 1.25)%, respectively, P < 0.05. And the tendency was in a time-dependent manner. (2) The average fluorescence intensity of MCF-7/Adr cells expressing the phosphorylated p38MAPK protein was (32.45 +/- 2.36) and (41.66 +/- 3.12), higher than the blank group (14.17 +/- 1.45) and DMSO group (16.28 +/- 0.63), P < 0.01. The epirubicin resistance of MCF-7/Adr cells significantly decreased. (3) SB203580 demonstrated a significantly higher level of EGR-1 activity. The IC50 was (21.53 +/- 2.17) and (8.77 +/- 1.02), lower than the DMSO group (40.74 +/- 2.56). MCF-7/Adr cells treated with SB203580 down regulated the p38MAPK pathway activity, but up-regulated the EGR-1 mRNA expression. SB203580 significantly increased the cellular phosphorylated p53 protein level, but decreased the p-glycoprotein level in MCF-7/Adr cells. CONCLUSIONS: There is a close relationship between p38MAPK pathway activity and the epirubicin resistance of breast carcinoma cells. The activation of EGR-1 mediated by p38MAPK pathway plays a critical role in epirubicin resistance. PMID- 19781350 TI - [Differential proteomics in glioblastoma]. AB - OBJECTIVE: To establish differential proteomics profiles of glioblastoma cell lines from Chinese, and to provide reference for future basic studies. METHODS: Total protein was extracted from 3 glioblastoma cell lines, CHG-5, TJ899 and TJ905. After normalization, the total protein was presented by two-dimensional (2D) electrophoresis, scanned and analyzed. Some of the identified protein spots were verified by immunocytochemistry of cell lines and immunohistochemistry of solid tumors. The glia cells were used as the control throughout the study. RESULTS: A total of 13 differential protein spots were selected, and eventually 10 were identified as unique proteins. These 10 proteins were involved in cytoskeleton forming, cellular metabolism, tumor migration, stress and inflammatory reaction. Immunocytochemistry and immunohistochemistry further confirmed these proteins present in the solid tumors. CONCLUSION: Distinct differential proteomics profiles exist in glioblastoma cell lines and normal glia cells, likely related to the transformation of normal glia to glioma. PMID- 19781351 TI - [Clinicopathologic analysis of ovarian gonadoblastoma]. PMID- 19781352 TI - [Double-labelling immunofluorescence study by quantum dots for simultaneous detection of two different antigens in paraffin embedded tissues]. PMID- 19781353 TI - [Endolymphatic sac papillary tumor: report of a case]. PMID- 19781354 TI - [Recent advances of pathologic diagnosis and research on sudden cardiac death]. PMID- 19781357 TI - Accuracy of tumor grade by preoperative curettage and associated clinicopathologic factors in clinical stage I endometriod adenocarcinoma. AB - BACKGROUND: Preoperative tumor grading becomes one of the most important predictors for lymphadenectomy at primary surgery for clinical stage I endometriod adenocarcinoma. However, there is an inconsistency of tumor grade between preoperative curettage and final hysterectomy specimens, and its associated factors are poorly understood. This study aimed to evaluate the accuracy of tumor grade by preoperative curettage so as to achieve a better stratified management for clinical stage I endometriod adenocarcinoma. METHODS: Clinical data of totally 687 patients with clinical stage I endometriod adenocarcinoma who underwent preoperative curettage and primary surgery were retrospectively collected. Compared with final hysterectomy specimens, the sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of tumor grade by preoperative curettage were calculated and their associations with clinicopathologic parameters, including age, status of menopause, position of uterus, location and size of lesion, histological grade, depth of myometrial invasion, cervical invasion, extrauterine spread, peritoneal cytology, metastasis to retroperitoneal lymph node, serum CA125 level, and hormone receptor status, were analyzed. RESULTS: In final hysterectomy specimens, 139 of 259 grade 1 patients by curettage were upgraded to grade 1 or 2; 31 of 296 grade 2 were upgraded to grade 3, with a significantly discrepant rate of 40.9% (281/687) and an upgraded rate of 24.7% (170/687). The specificity and negative predictive value for grade 3 were 90.7% and 89.9%, while the sensitivity and positive predictive value for grade 1 were 67.1% and 40.9%, respectively. CONCLUSIONS: Preoperative tumor grade by curettage does not accurately predict final histological results, especially in those classified as grade 1. Complete surgical staging seems to be necessary for clinical stage I endometriod adenocarcinoma. PMID- 19781358 TI - Brain metastasis treated with Cyberknife. AB - BACKGROUND: Cyberknife can greatly raise the fractional dose of stereotactic radiosurgery, thus improving its clinical efficacy. We retrospectively analyzed clinical outcomes of brain metastasis treated with Cyberknife. METHODS: We analyzed 40 cases of brain metastases treated with Cyberknife in the Tianjin Cancer Hospital from August 1, 2006 to August 1, 2007, for a total of 68 lesions with maximal diameter of 0.4 - 7.5 cm (average 1.88 cm). Total hypofractional radiated dosage was 18 - 36 Gy (5 - 25 Gy/F, 1 - 5 F) by Cyberknife. We evaluated the remission rate of clinical symptoms, correlation factors to new foci, 3-month local control rates, and 3-month and 1-year survival rates. All patients were followed up for more than 14 months. RESULTS: After 1 week, clinical remission was 90.0% (36/40). After 3 months, the local control rate and therapeutic effective rate were 77.9% (53/68) and 94.1% (64/68), respectively, as observed by cranium augmentation CT or MRI. The three-month, six-month and 1-year survival rates were 97.5% (39/40), 82.5% (33/40) and 67.5% (27/40), respectively. Fourteen patients had neopathy outside the original lesion after 3 months. Neopathy was not correlated with age, whole-brain radiotherapy, number of original lesions, maximum diameter of the original lesion, therapeutic dose per fraction, therapeutic frequency or total therapeutic dose. CONCLUSIONS: Cyberknife got perfect clinical outcomes by higher dosage per fraction. It is an appropriate and valid treatment shortcut for brain metastasis. PMID- 19781359 TI - Embolization of brain arteriovenous malformations with ethylene vinyl alcohol copolymer: technical aspects. AB - BACKGROUND: Endovascular therapy plays an important role in the treatment of brain arteriovenous malformations (BAVMs). Ethylene vinyl alcohol copolymer (Onyx) is a novel liquid embolic material. This study aimed to summarize our experience of using Onyx for embolization of BAVMs with the focus on embolization technique. METHODS: From September 2003 to November 2007, 115 patients (43 women and 72 men, with a mean age of 29 years) with BAVMs were endovascularly treated with Onyx in our department. The following features of all AVMs were evaluated prior to treatment: type of nidus and shunt, draining veins, and feeding arteries. A total of 196 endovascular procedures were performed. RESULTS: The course of endovascular treatment was completed in 88 patients. Additional sessions were planned in 27 patients. Of the 88 patients, total occlusion was obtained in 23 patients (26.1%), near-total (> 80% of the original volume) occlusion was obtained in 35 patients (39.8%) and partial occlusion (< 80% of the original volume) was obtained in 30 patients (34.1%) using embolization as the sole therapeutic technique. Mean volume reduction was 72% (range 30% - 100%) in 115 patients. Thirty four patients (38.6%, 34/88) underwent radiosurgical treatment. Additional embolization sessions were planned in 27 patients. Complications occurred in 19 patients (16.5%, 19/115), leading to death in one patient (mortality 0.9%) and permanent disabling in 3 patients (morbidity 2.6%). CONCLUSIONS: Onyx was shown to be feasible and safe for embolization of BAVMs. Proper use of the Onyx injection technique largely improved the endovascular treatment of BAVMs. Large AVMs can be adequately reduced in size through the use of additional treatment. PMID- 19781360 TI - Optimal microsurgical treatment of dorsum sellae meningioma. AB - BACKGROUND: There are few reports of microsurgical treatment of dorsum sellae meningiomas-which, because of location, size, and differences in growth direction, clinical presentations, degree of surgical difficulty, have varied posttreatment sequelae. In pursuit of an optimal microsurgical treatment option for dorsum sellae meningioma patients, we performed a retrospective analysis of eight microsurgery-treated patients in our set up. METHODS: Clinical data of eight microsurgery-treated dorsum sellae meningioma patients were analyzed. Dorsum sellae meningiomas were classified into 2 types based on tumor location, size, and direction of growth. Type I tumors (dorsum sellae-inferior third ventricle type, four cases) were resected by craniotomy via the frontotemporal or orbitozygomatic approach. Type II tumors (dorsum sellae-third ventricle type, 4 cases) were resected by frontal craniotomy via the transcallosal-interforniceal approach. RESULTS: Complete tumor resection was achieved in all the eight patients. In Type I tumor patients, the only postoperative complication was oculomotor nerve palsy. In Type II tumor patients, the postoperative complications included hyperthermia, electrolyte imbalances, endocrinologic disturbances, and hydrocephalus. The mean follow-up was 2.1 years. Four patients returned to normal life and found a job, two were able to live independently, one required assistance, while one died. CONCLUSIONS: Dorsum sellae meningioma surgery is challenging, and resection of Type II tumors is more difficult than Type I tumors. The selection of a suitable microsurgical approach based on tumor type, and the active treatment of postoperative complications are important means of increasing therapeutic efficacy. PMID- 19781361 TI - Eighty-six cases of laparoscopic vaginoplasty using an ileal segment. AB - BACKGROUND: The surgical management of the absence of the vagina is a complex problem and constitutes a significant technical challenge. As the laparoscopy has been an important tool for the treatment of uterovaginal anomalies, we evaluated the feasibility of laparoscopic vaginoplasty using an ileal segment retrospectively. METHODS: Totally 86 patients who underwent laparoscopic vaginoplasty using an ileal segment in Beijing Anzhen Hospital during February 2004 to July 2007 were enrolled in this study. Of the 86 patients, 70 (81.4%) underwent primary operations and 16 (18.6%) secondary operations. Nineteen (22.1%) patients underwent total laparoscopic vaginoplasty and 67 (77.9%) patients underwent laparoscope-assisted vaginoplasty. The operation time, cost of hospitalization, and hospital duration were compared between the two laparoscopic groups. The Student's t test and the Mann-Whitney test were used to examine the differences. RESULTS: All the surgeries were successfully completed with no any intraoperative complication. There were three major surgical complications in the postoperative period: one case of intra-abdominal hemorrhage, one case of meatal stenosis, and one case of intestinal obstruction. The mean follow-up period of this series was 18 months. Seventy-eight patients were satisfied with their sexual lives after the surgeries except 5 women complaining of vaginal stenosis and 3 with no sexual partner during the follow-up. Significant differences were obtained between total laparoscopic and laparoscope-assisted vaginoplasty groups, such as the operation time, cost of hospitalization, and hospital duration (P < 0.01). There were no significant differences in sexual function between the two groups. CONCLUSIONS: The laparoscopic vaginoplasty using an ileal segment is satisfactory for cosmetic, functional, and anatomic results. Vaginoplasty with an ileal segment, performed by either total laparoscopic or laparoscope-assisted techniques, has a high success rate for a functional vagina. PMID- 19781362 TI - Mutation analysis of p63 gene in the first Chinese family with ADULT syndrome. AB - BACKGROUND: ADULT syndrome (acro-dermato-ungual-lacrimal-tooth syndrome) is a rare ectodermal dysplasia disorder known as autosomal dominant inheritance. Recent studies have linked p63 gene mutation to the development of this disease. However, the genetic characteristics of ADULT syndrome were still not well understood. METHODS: Mutation analysis of p63 gene in the first Chinese ADULT syndrome family was performed using direct DNA sequencing. RESULTS: The sequence analysis of exon 8 of p63 gene disclosed a heterozygous G>A substitution at nucleotide 893 (R298Q) in the proband. In addition, a single nucleotide polymorphism (SNP) rs16864880 in the downstream flanking region (DFR) of p63 exon 8 was also identified in this family. The proband and the paternal side including her father exhibited the C/G genotype at this position. The C/G variant frequency in the paternal was significantly higher as compared with the maternal (6/10 vs 0/6, P = 0.034). CONCLUSIONS: ADULT syndrome may be caused by the p63 gene mutation, and it might have closer genetic association with the paternal side in this family. PMID- 19781363 TI - Ultrasonic appearance of rhabdomyolysis in patients with crush injury in the Wenchuan earthquake. AB - BACKGROUND: On May 12, 2008, a major earthquake hit Wenchuan County in Sichuan Province of China. The number of cases of crush injury following this event was high. Ultrasonic appearance of rhabdomyolysis (RM) caused by crush injury in the Wenchuan earthquake was observed to evaluate the diagnostic value of ultrasound for detection of rhabdomyolysis. METHODS: We analyzed clinical and ultrasonic manifestations of 50 cases of RM and 18 cases of RM with osteofascial compartment syndrome (OCS). All cases were caused by crush injury in the Wenchuan earthquake. For these RM patients, we also evaluated the correlations between creatine kinase (CK) and the scope of the muscle lesions as observed by ultrasound. RESULTS: There were differences in clinical symptoms, physical signs and ultrasonic appearance between the two groups of patients. The ultrasonic characteristics of the RM were as follows: the striated muscle in the lesions thickened with good overall continuity, and the muscle texture was vague; the strength of the echo was uneven and the echo was cloudy or ground glass-like. Liquid dark zones appeared between muscles and were spindle-like or irregular in shape. There were no blood flow signals in the liquid dark areas. The volume of the striated muscle increased in patients with OCS; the fascia wrapping the muscle showed arched protrusions and significant displacement. The flow velocity of the distal arteries decreased and the spectrum was abnormal. The muscle lesion scope of RM group and RM and OCS group was (7.8 +/- 2.0) cm and (13.6 +/- 3.1) cm, respectively. The correlation coefficient (r) between the muscle lesion scope and the CK was 0.681 for the RM group (P < 0.05) and 0.516 for the RM and OCS group (P < 0.05). CONCLUSIONS: The ultrasonogram of RM has characteristic manifestations and can provide important information for clinical diagnosis and treatment of rhabdomyolysis. PMID- 19781364 TI - Clinical features and follow-up of Chinese patients with symptomatic hypogammaglobulinemia in infancy. AB - BACKGROUND: Hypogammaglobulinemia is common in infant humoral immunodeficiencies and has complicated causes and outcomes. We aimed to determine the clinical manifestations, immunological changes and outcomes of Shanghai infants with hypogammaglobulinemia. METHODS: Patients under 2 years old, having one or more warning signs of primary immunodeficiency disorders, serum immunoglobulin levels below the lower limit of reference range per age, and with normal numbers for lymphocyte subsets, were analyzed and followed up for 2 to 3 years. RESULTS: A total of 91 children (male-to-female ratio: 2.25: 1) participated in the study. Initial clinical presentation was recurrent upper respiratory tract infection (46%), invasive infection (3%), atopic disease (32%). IgA reduction (77%) was prevalent; 34% patients had more than one isotype reduced. During follow-up, 51 of 62 patients (82.25%) had immunoglobulins normalized at the age between 12 - 48 months; these were diagnosed as transient hypogammaglobulinemia of infancy (THI). Long-term follow-up may reveal a diagnosis for the remaining 11 infants with persistent lower immunoglobulin levels, who did not have antibody titers measured. Earlier onset was correlated with higher rates of normalization. More patients were diagnosed with isolated hypogammaglobulinemia in 2006 compared with the previous 4 years (2002 - 2005). CONCLUSIONS: The awareness of immunodeficiency among pediatricians has been greatly improved. Recurrent otitis media was not a major infection in our patients. THI is a relatively common condition associated with infant hypogammaglobulinemia. In the absence of specific antibody titers, the diagnosis of THI can be confirmed retrospectively with Ig levels normalized in follow-up visits. Therefore, long-term follow-up and frequent re-evaluation of these patients are necessary to distinguish them from true primary immunodeficiency. PMID- 19781365 TI - Effect of topical application of terbinafine on fungal keratitis. AB - BACKGROUND: Fungal keratitis is a rare but serious corneal disease that may result in loss of vision. The poor prognosis might be due to limited treatment option. This study aimed to evaluate the clinical efficacy of 0.25% terbinafine eye drops comparing with 5% natamycin suspension on fungal keratitis. METHODS: A retrospective clinical trial was performed on 90 patients presenting with direct smear and/or culture positive fungal keratitis at Beijing Tongren Hospital, Beijing, China from January 2006 to May 2008. Corneal ulcers were categorized as mild or severe. Forty-five patients were treated with topical terbinafine and the next 45 cases received topical natamycin hourly. RESULTS: Filamentous fungi were found in corneal scrapings among all 90 cases. Fungal cultures were positive in 64 patients (71%). Species of Fusarium and Aspergillus were the principal isolates. Forty (89%) patients showed favorable response to terbinafine, while forty-two (93%) patients exhibited favorable response to natamycin (P > 0.05). The mean course of treatment was significantly showed in the terbinafine treatment group than natamycin group ((26.5 +/- 11.2) days versus (19.3 +/- 6.4) days; P < 0.05). In terbinafine group, twenty patients with ulcers smaller than 4 mm had favorable outcome, while 20 of 25 patients with ulcers more than 4 mm in diameter had favorable response (P < 0.05). Twenty-seven patients with depth of infiltration less than half of stroma thickness had favorable response to terbinafine, while 13 of 18 patients with depth of infiltration more than half of stroma responded to terbinafine. This difference was statistically significant (P < 0.05). CONCLUSIONS: Our findings suggest that topical terbinafine is an effective antifungal drug for the management of filamentous mycotic keratitis, particularly in cases with smaller and shallower ulcers. Its mean duration of treatment was longer than natamycin. PMID- 19781366 TI - Modern use of Chinese herbal formulae from Shang-Han Lun. AB - BACKGROUND: The Chinese medical archive, Shang-Han Lun, is said to be written by ZHANG Zhong-jing (150 - 219 A.D.). This great influential work introduced the specific symptoms of six-channel disorders (Tai-Yang, Yang-Ming, Shao-Yang, Tai Yin, Shao-Yin, and Jue-Yin) and their corresponding treatments, the combined syndromes, deterioration due to malpractice, and the concept of six-channel transitions. The concept of Shang-Han Lun is widely accepted by Chinese herbal doctors. However, no clinical data about Shang-Han symptoms are described in oriental or western medical reports. METHODS: The clinical prescription data of traditional Chinese medicine visits were extracted under the National Health Insurance in Taiwan. The application rate of 42 Shang-Han formulae in clinical practice was analyzed in detail with the software SPSS. RESULTS: Between 1999 and 2002, the prescription rate of Shang-Han formula was only 5.22% among a total of 528 889 576 Chinese herbal formula prescriptions. The most frequently used formula was Tai-Yang formulae (71.31%), followed by Shao-Yang formulae (17.49%) and the most commonly prescribed individual Shang-Han formulae were Ge-Gen Tang (16.11%), Shao-Yao-Gan-Cao Tang (12.97%), Xiao-Qing-Long Tang (11.79%), Ban-Xia Xie-Xin Tang (10.24%), and Xiao-Chai-Hu Tang (9.11%), which comprised 60.22% of the utilization rate of total Shang-Han formulae. CONCLUSIONS: From the prescription patterns of Shang-Han formulae, there was no evidence of transitions among the six channels. Despite the fundamental role of Shang-Han Lun in traditional Chinese medicine, prescription of Shang-Han formulae was limited in clinical practice. PMID- 19781367 TI - Clinical and histopathological alterations of lymphangioleiomyomatosis in 14 Chinese patients. AB - BACKGROUND: Lymphangioleiomyomatosis (LAM) is a rare disease that predominantly affects young females. It is considered as an "orphan" life-threatening disease of unknown etiology, with uncertain clinical prognosis, and no effective treatment. LAM can arise sporadically or in association with tuberous sclerosis complex (TSC), an autosomal inherited syndrome characterized by hamartoma-like tumor growth and pathologic features that are distinct from manifestations of pulmonary LAM. The clinical course of LAM is characterized by progressive dyspnea on exertion, recurrent pneumothorax, and chylous fluid collections. METHODS: Fourteen cases of LAM from Zhongshan Hospital, Fudan University are reviewed, twelve were confirmed by lung biopsy, one by retroperitoneal lymphangioleiomyoma resection, and one by autopsy. RESULTS: All 14 patients were women, aged 18 to 69 years (mean 43.3 years, median 46.5 years). Haemoptysis (57.1%) and chylothorax (35.7%) were more frequent than those described in previous case series. Extrapulmonary findings such as renal angiomyolipoma (AML), enlarged abdominal lymph nodes, liver AML and retroperitoneal lymphangioleiomyoma were seen in 21.4%, 14.3%, 7.14% and 7.14% in 14 cases respectively, which is remarkably lower than in the previously reported. Abnormal smooth muscle cells (LAM cells) were found to line the airways, bronchioles, lymphatics and blood vessels leading to airflow obstruction and replacement of the lung parenchyma by cysts. There were some surprises in the autopsy case as several LAM cell emboli were found in the veins of mediastinum lymph nodes; LAM cells were found to be disseminated in soft tissues adjacent to the ilium. CONCLUSIONS: Women with unexplained recurrent pneumothorax, tuberous sclerosis, or a diagnosis of primary spontaneous pneumothorax or emphysema in the setting of limited or absent tobacco use should undergo high-resolution computed tomography (HRCT) scan screening for LAM. Routine abdominal and pelvic imaging examinations should be performed to detect extrapulmonary involvement. The autopsy studies histologically suggested that LAM could be a multisystemic disease and LAM cells might possess metastatic potential. PMID- 19781368 TI - Chinese word processing in nonfluent aphasic patients. AB - BACKGROUND: Chinese nonfluent aphasic patients experience apparent speech production deficit, but it remains less known in which part of Chinese speech production this deficit occurs. The present study aimed to examine the ability of nonfluent aphasic patients in Chinese orthography, phonological and semantic processing via two experiments. Experiment I disclosed the general pattern of deficit of Chinese nonfluent aphasic patients in speech production. Experiment II tested whether this deficit occurs in orthography, phonological or semantic processing. METHODS: The present study adopted neuropsychological testing methods to compare speech production and Chinese word processing between nonfluent aphasic patients (the patient group) and normal individuals (the control group). Character reading and word reading tasks were used to test speech production. Chinese radical decision, rhyme decision and semantic decision tasks were used to examine word processing. Reaction time and the correct answer rate were collected. RESULTS: The patient group had a longer reaction time and was more prone to errors in both character reading and word reading tasks than was the control group. For the patient group, there was no difference between the reaction time of character reading and word reading, the error rate of the former was higher than the latter. In radical decision task the reaction time and error rate to the radical "mu " were higher in the patient group than in the control group. In the rhyme decision task, the reaction time and error rate to the rhyme "ang" were higher for the aphasic patients. In the semantic decision task the reaction time to characters in the category of animals was higher for the aphasic patients, yet the error rate was not significantly different between the two groups. CONCLUSIONS: Nonfluent aphasic patients seemingly have decreased speed of speech production and an increased error rate. There is a deficit in phonological processing of aphasic patients while their semantic processing may remain intact. PMID- 19781369 TI - Experimental studies on imaging of infected site with (99m)Tc-labeled ciprofloxacin in mice. AB - BACKGROUND: Bacterial infection can pose a substantial diagnostic dilemma. (99m)Tc-labeled ciprofloxacin (CPF) was developed as a biologically active radiopharmaceutical to diagnose infection. In the present research, we studied the biodistribution and imaging properties of infection tracer (99m)Tc-CPF in a mouse model of infection. METHODS: CPF was labeled with (99m)Tc and the radiochemical purity and labeling rate were measured. A mouse model of infection was established. We then determined the biodistribution of (99m)Tc-CPF and conducted the whole body scintigraphy of the animal model. RESULTS: (99m)Tc Ciprotech was stable for at least 6 hours at room temperature. The labeling rate of CPF by (99m)Tc was over 90%. Clearance of radioactivity mainly occurred in the liver and kidney, and the clearance from blood was rapid. Both biodistribution and imaging results showed higher uptake of (99m)Tc-CPF at sites of infection. The infectious tissue/normal tissue ratio peak was 4.30 at 4 hours after injection. CONCLUSIONS: (99m)Tc-CPF is a sensitive radiopharmaceutical for scintigraphy of infectious lesions and it is easy to prepare. PMID- 19781370 TI - Effect of antimicrobial agents on the toll-like receptors and inflammatory cytokines in liver tissue of the alcohol-induced liver disease in rats with Vibrio vulnificus sepsis. AB - BACKGROUND: Septicemia and inflammation-mediated septic shock caused by Vibrio vulnificus (VV) is strongly associated with chronic liver disease. This study examined the effects of antimicrobial therapy on expression of hepatic toll-like receptors and inflammatory cytokines in rats with alcohol-induced liver disease complicated by VV sepsis. METHODS: Male Sprague-Dawley rats were assigned to the following treatment groups: normal control (N), alcoholic liver disease control (A), antimicrobial-treated alcoholic liver disease control (AA), alcoholic liver disease with VV sepsis (AV), and antimicrobial-treated alcoholic liver disease with VV sepsis (AVA). Alcohol-induced liver disease was observed in all groups except N. Expression of mRNAs encoding hepatic toll-like receptors 2 and 4, myeloid differentiation protein-2, tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6 and IL-10 was determined by RT-PCR. RESULTS: mRNAs encoding toll-like receptors 2 and 4 and myeloid differentiation protein-2 were significantly up-regulated in group AV as compared to control groups at 2 - 24 hours of sepsis; peak expression occurred at 12 hours. These mRNAs were also up regulated in group AVA but to lesser degrees than in group AV at comparable time post-infection. mRNAs encoding TNF-alpha, IL-1beta and IL-6 were significantly elevated in group AV as a function of infection. In group AVA as compared to AV, expression of TNF-alpha and IL-1beta mRNAs was lower at 12 - 24 hours post infection and expression of IL-6 mRNA was lower at 24 hours post-infection. Compared with control groups, IL-10 mRNA expression in group AV was markedly higher at 12 - 24 hours of sepsis. Expression of IL-10 mRNA was lower in group AVA as compared to AV at 24 hours of sepsis. CONCLUSIONS: Antimicrobial therapy reduces expression of toll-like receptors and cytokines in rats with alcohol induced liver disease complicated by VV sepsis. Monitoring hepatic toll-like receptor and cytokine expression during antibiotic therapy may be valuable for determining the course of VV sepsis in subjects with liver disease. PMID- 19781371 TI - Expression of chemokine receptors CCR3, CCR5 and CXCR3 on CD4(+) T cells in CBA/JxDBA/2 mouse model, selectively induced by IL-4 and IL-10, regulates the embryo resorption rate. AB - BACKGROUND: Chemokines and their receptors have been a research focus in transplantation immunology. Chemokines and their receptors play a role in lymphocyte recruitment and differentiation process. This study aimed to observe whether IL-4 and IL-10 may regulate the expression of chemokine receptors CCR3, CCR5 and CXCR3 on CD4(+) T cells in CBA/JxDBA/2 mouse model and to explore the role of CCR3, CCR5, CXCR3 in immune tolerance in pregnancy. METHODS: The mouse model of spontaneous abortion (CBA/JxDBA/2) and the normal pregnant mouse model (CBA/JxBALB/c) were used. CBA/JxDBA/2 mice were injected with IL-4 (CBA/JxDBA/2 IL-4), IL-4 and IL-10 (CBA/JxDBA/2-IL-4+IL-10), or normal saline (CBA/JxDBA/2-NS) as a control. The expression of CCR3, CCR5 and CXCR3 on CD4(+) T cells from mouse peripheral blood was measured by the double-labelled FCM method, and the embryo resorption rate was also examined. RESULTS: The embryo resorption rate in the CBA/JxDBA/2 group without any treatment was significantly higher than that in the CBA/JxBALB/c group (17.9% vs 3.7%, P < 0.01). The embryo resorption rate in the CBA/JxDBA/2 group immunized with IL-4 or IL-4 together with IL-10 was significantly decreased, compared with that in the control and NS groups respectively. CCR3 expression on CD4(+) T cells in the CBA/JxDBA/2 group without any treatment was significantly lower than that in the CBA/JxBALB/c group (0.3738 +/- 0.3575 vs 1.2190 +/- 0.2772, P < 0.01); both CCR5 (3.0900 +/- 1.5603 vs 1.2390 +/- 0.6361, P < 0.01) and CXCR3 (2.4715 +/- 0.9074 vs 0.9200 +/- 0.5585, P < 0.01) expressions on CD4(+) T cells of the CBA/JxDBA/2 group without any treatment were significantly higher than those of the CBA/JxBALB/c group. Significant up-regulation of CCR3 and down-regulation of CXCR3 were found in the CBA/JxDBA/2 group treated with IL-4 (CCR3: 2.0360 +/- 0.6944, CXCR3: 1.3510 +/- 0.5263, P < 0.01) or IL-4 and IL-10 (CCR3: 1.8160 +/- 1.0947, CXCR3:1.0940 +/- 0.7168, P < 0.01). Because of the CCR5, IL-4 and IL-10 (1.9400 +/- 0.8504 vs 3.0900 +/- 1.5603, P < 0.05), but IL-4 alone (2.5310 +/- 1.3595 vs 3.0900 +/- 1.5603, P > 0.05) treatment significantly decreased the expression of CCR5 in CBA/JxDBA/2. CONCLUSIONS: The abnormal expression of CCR3, CCR5 and CXCR3 on CD4(+) T cells may play an important role in the pathogenesis of spontaneous abortion. The pregnancy immune tolerance may be induced through selective induction of CCR3, CCR5 and CXCR3 expressions by IL-4 together with IL-10. PMID- 19781372 TI - C-reactive protein decreases interleukin-8 production in human endothelial progenitor cells by inhibition of p38 MAPK pathway. AB - BACKGROUND: C-reactive protein (CRP) has been reported to damage the vascular wall by inducing endothelial dysfunction and inflammation, and it is also speculated to have a role in attenuating angiogenic functions of human endothelial progenitor cells (EPCs). Interleukin-8 (IL-8) is an important mediator of the paracrine mitogenic effect of EPCs, which has direct angiogenic effects on mature endothelial cells. We, herein, investigated the direct effect of CRP on IL-8 production and gene expression in cultured human EPCs. METHODS: EPCs were isolated from the peripheral venous blood of healthy male volunteers. Cells were cultured in EndoCult liquid medium in the absence and presence of CRP at clinically relevant concentrations (5 to 25 microg/ml) for different durations (3 to 48 hours). IL-8 protein and mRNA of cultured EPCs were evaluated using ELISA and real-time PCR. RESULTS: The results showed that CRP at a concentration of 10 microg/ml significantly reduced IL-8 secretion of cultured EPCs with a peak at 25 microg/ml, and also decreased mRNA expression in EPCs with a peak at 12 hours. In addition, preincubation of EPCs with SB203580, an inhibitor of p38 mitogen-activated protein kinase (MAPK) decreased CRP inhibition of IL-8 mRNA expression at 12 hours in EPCs. CONCLUSIONS: Our study, for the first time, demonstrates that CRP directly inhibits EPCs IL-8 secretion, a key cytokine player of angiogenesis induced by EPCs. Inhibition occurred in part via an effect of CRP to active the p38 MAPK signal transduction pathway in EPC. The ability of CRP to inhibit EPCs IL-8 secretion may represent an important mechanism that further links inflammation to cardiovascular disease. PMID- 19781373 TI - Basic research of the relationship between irradiation dose and volume in radiation-induced pulmonary injury. AB - BACKGROUND: Irradiation dose and volume are the major physical factors of radiation-induced lung injury. The study investigated the relationships between the irradiation dose and volume in radiation-induced lung injury by setting up a model of graded volume irradiation of the rat lung. METHODS: Animals were randomly assigned to three groups. The ELEKTA precise 2.03 treatment plan system was applied to calculate the irradiation dose and volume. The treatment plan for the three groups was: group 1 received a "high dose to a small volume" (25% volume group) with the mean irradiation volume being 1.748 cm(3) (25% lung volume); the total dose and mean lung dose (MLD) were 4610 cGy and 2006 cGy, respectively (bilateral AP-PA fields, source to axis distance (SAD) = 100 cm, 6MVX, single irradiation); Group 2 received a "low dose to a large volume" (100% volume group) with the mean irradiation volume being 6.99 cm(3) (100% lung volume); the total dose was 1153 cGy. MLD was 2006 cGy, which was the same as that of group 1 (bilateral AP-PA fields, SAD = 100 cm, 6MVX, single irradiation); Group 3 was a control group. With the exception of receiving no irradiation, group 3 had rest steps that were the same as those of the experimental groups. After irradiation, functional, histopathological, and CT changes were compared every two weeks till the 16th week. RESULTS: Functionally, after irradiation breath rate (BR) increases were observed in both group 1 and group 2, especially during the period of 6th - 8th weeks. The changes of BR in the 100% volume group were earlier and faster. For the 25% volume group, although pathology was more severe, hardly any obvious increase in BR was observed. Radiographic changes were observed during the early period (the 4th week) and the most obvious changes manifested during the mediated period (the 8th week). The extensiveness of high density and the decreased lung permeability were presented in the 100% volume group, and ground glass opacity and patchy consolidation were presented in the 25% volume group without pleural effusion, pleural thickening, and lung shrinking. Morphologically, the 100% volume group mainly presented signs of vascular damage, including signs of vascular wall edemas, hypertrophy, and sclerosis. The 25% volume group mainly presented with erythrocyte cell exudation, inflammation, and parenchymal damage. CONCLUSIONS: The delivery of a small dose of radiation to a large volume is not safe. A low dose smeared out over large volumes, albeit reversible, may lead to fatal respiratory dysfunction. Damage to the lung may be more dependent on the volume of irradiation than on the radiation dose. Clinically, the safest approach is to limit both the volume of the irradiated normal lung and the amount of received radiation. PMID- 19781374 TI - Neuroprotective effects of edaravone on early brain injury in rats after subarachnoid hemorrhage. AB - BACKGROUND: The underlying mechanism of early neurobiological impairment after subarachnoid hemorrhage (SAH) is not well understood, but the system of reactive oxygen superoxide (ROS) might be involved. Edaravone (MCI-186), a potent free radical scavenger that prevents apoptosis of neurons, was thus used in this study to see its possible therapeutic effect in early brain injury due to SAH in a rat model. METHODS: One hundred and twenty male Sprague-Dawley rats were randomly assigned to four groups: group 1, control rats receiving sham operation only; group 2, rats with SAH treated by saline; group 3, rats with SAH treated with 1 mg/kg MCI-186 injected intraperitoneally; and group 4, rats with SAH treated with 3 mg/kg MCI-186. Treated with either saline or MCI-186 twice daily for two consecutive days after SAH, the rats were sacrificed for measurements of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) and histological analysis of caspase-3 protein by Western blotting and immunohistochemical staining. In addition, mortality and neurological scores were statistically analyzed by the chi-square test and Dunn's procedure respectively for each group. One-way analysis of variance followed by the Tukey's procedure was also used in data analysis. RESULTS: The rats in group 2 that received saline only showed neurological impairment as well as elevated mortality, and were found to have significantly increased levels of MDA and caspase-3, but reduced SOD activities in brain tissues (P < 0.05). When treated with MCI-186 at two different dosages, the rats in groups 3 and 4 had markedly decreased levels of MDA and caspase-3 but increased SOD activities in the brain tissue (P < 0.05), along with improved scores of neurological evaluation (P < 0.05). CONCLUSIONS: This study sheds some lights on the therapy of SAH-induced early brain injury by providing the promising data indicating that MCI-186, a radical scavenger, can efficiently diminish apoptosis of neurons and thus prevent the function loss of the brain in rats with SAH. PMID- 19781375 TI - Expression of programmed death 1 and its ligands in the liver of autoimmune hepatitis C57BL/6 mice. AB - BACKGROUND: Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease with unknown etiology. Programmed death 1 (PD-1) and its ligands (PD-L1 and PD L2), B7-H1/PD-L1 and B7-DC/PD-L2, are new CD28-B7 family members that are involved in the regulation of immune responses. Previous observation suggests that PD-1 system plays an inhibitory role in regulating peripheral blood T cells, B cells and myeloid cells, thus their abnormality may be related to autoimmune diseases. This study aimed to explore the role of PD-1/PD-L1, L2 system in the pathogenesis of AIH. METHODS: The mice model of experimental autoimmune hepatitis (EAH) was established in C57BL/6 mice and the expression levels of PD-1 and PD L1, L2 in the murine liver and the cytokines, including interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha and interleukin (IL)-4 in the spleen were detected using reverse transcription-polymerase chain reaction (RT-PCR), and the results were compared with those of normal controls. RESULTS: The expression levels of PD-1, PD-L1, PD-L2 mRNA were higher in EAH compared with normal controls (P < 0.05), the PD-L2/PD-1 ratio was relatively lower in EAH (EAH -0.08 +/- 0.35, normal controls 0.52 +/- 0.07, P = 0.009). In the EAH, the expression of the three cytokines were all upregulated compared with normal controls. PD-L1 had a positive correlation with the expression of IFN-gamma (r = 0.289, P < 0.05), while PD-L2 showed a positive correlation with both expressions of IL-4 (r = 0.378, P< 0.01) and IFN-gamma (r = 0.261, P < 0.05). While TNF-alpha showed no correlation with PD-L1 (r = 0.044, P = 0.736) or PD-L2 (r = 0.127, P = 0.335). CONCLUSIONS: The expression of PD-1/PD-L1, L2 is upregulated in EAH and regulated by IFN-gamma and IL-4. PD-1 system may play an important role in the pathogenesis of AIH. PMID- 19781376 TI - Endostatin derivative angiogenesis inhibitors. AB - OBJECTIVE: To throw light on the superiority of the anti-angiogenesis activity of endostatin (ES) derivatives by reviewing the recent progress in the field of ES molecular structure modification. DATA SOURCES: The data used in this article were mainly from PubMed with relevant English articles published from 1971 to May 2008. The search terms were "endostatin" and "angiothesis". STUDY SELECTION: Articles involved in the ES molecular structure modification and the original milestone articles were selected. RESULTS: A number of ES derivatives were designed and studied to improve its clinical relevance. The modified ES with polyethylene glycol (PEG), low molecular weight heparin (LMWH) and IgG Fc domain extended the circulation half-life. Meanwhile the recombinant ESs showed more potent anti-tumor activity than native ES in mouse xenografts. Mutated ES also changed its anti-angiogenesis activity. CONCLUSIONS: The anti-angiogenesis treatment remains a promising tumor therapeutic strategy. New ES derivatives would be a good choice to meet the future challenge on clinical application of ES. PMID- 19781377 TI - Anesthetic management of a child with relapsing polychondritis: a case report. PMID- 19781378 TI - Repair of left ventricular aneurysm: ten-year experience in Chinese patients. AB - BACKGROUND: A large transmural myocardial infarction often results in a dyskinetic or akinetic left ventricular aneurysm (LVA). This study aimed to explore the early and long-term clinical outcomes and to identify predictors for survivals and hospital re-admission after the repair of left ventricular aneurysm. METHODS: We followed up 497 patients who had undergone LVA repair from a single center in China between 1995 and 2005. The perioperative parameters were recorded. Risk factors for early mortality and long-term results were analyzed by multivariate Logistic regression. Cox's proportional hazard model was used to calculate risk factors for major adverse cardiac and cerebrovascular events, cause of death and re-admission. Kaplan-Meier curve was employed to analyze long term survival. RESULTS: The operative mortality was 2.0%. The long-term mortality was 11.1% and cardiac causes contributed to 61.8% of the overall long-term mortality. Four hundred and thirty-two patients survived during the follow-up period and 37.5% of them had been re-admitted at least one time. One hundred and five patients experienced major adverse cardiac and cerebrovascular events. Survival analysis exhibited that the probability of survival at 1 and 5 years after operation was 96% and 86% respectively. Previous atrial fibrillation was the independent risk factor for early mortality. Independent risk factors for long-term mortality were poor left ventricular ejection fraction and stroke,and risk factors for cardiac mortality were intraventricular block, stroke and poor left ventricular ejection fraction. Stroke, intraventricular block and advanced age were independent risk factors for major adverse cardiac and cerebrovascular events, and New York Heart Association (NYHA) class III-IV was the only risk factor for hospital re-admission. CONCLUSIONS: Postinfarction LVA can be repaired and satisfying early and long-term clinical outcome can be obtained. Endoventricular circular plasty technique is the better choice than linear repair in patients with large LVA. Survival is affected in patients with poor heart function, intraventricular block and stroke. PMID- 19781380 TI - A frozen-thawed embryo transfer program improves the embryo utilization rate. AB - BACKGROUND: Frozen-thawed embryo transfer (FET) is the most common way to prevent serious late ovarian hyperstimulation syndrome and increase the cumulative pregnancy rate. We evaluated the effectiveness of an FET program for improving the embryo implantation and clinical pregnancy rates, and ultimate embryo utilization rate in infertility treatment. METHODS: Patients undergoing in vitro fertilisation (IVF) cycles from January 2006 to June 2008 were enrolled, including 179 patients who had undergone the first FET cycle after controlled ovarian hyperstimulation (COH) in which all embryos were frozen (group C1) and 1306 patients who had COH with fresh embryo transfer (ET) (group T1). Logistic regression was used to model the embryo implantation and clinical pregnancy rates based on the mother's age, numbers of oocytes retrieved, embryos transferred and high-quality embryos transferred. The embryo implantation and clinical pregnancy rates were also compared between two groups after adjusting for age, the numbers of oocytes retrieved and the numbers of embryos transferred. RESULTS: Logistic regression analysis confirmed that embryo implantation and clinical pregnancy rates in group C1 were both significantly higher than those in group T1 after adjusting for confounding factors (43.6% vs 29.0%, 63.1% vs 47.0%, respectively; P < 0.01). The embryo implantation and clinical pregnancy rates were consistently higher in group C1 by comparing the age groups >or= 35 or < 35 years. The clinical pregnancy rates for the numbers of oocytes retrieved per cycle being >or= 15 or < 15 were higher in group C1, as was the embryo implantation rate. These differences were statistically significant for oocyte numbers >or= 15 (P < 0.05). The embryo implantation and clinical pregnancy rates in group C1 were both significantly higher than in group T1 when two or three embryos were transferred (P < 0.05). CONCLUSION: A program of freezing all embryos and performing FET improved the rates of embryo implantation and clinical pregnancy, and ultimately enhanced the embryo utilization rate. PMID- 19781379 TI - Arsenic trioxide downregulates the expression of annexin II in bone marrow cells from patients with acute myelogenous leukemia. AB - BACKGROUND: Most patients with acute myelogenous leukemia (AML) suffer from disordered hemostasis. We have previously shown that annexin II (Ann II), a high affinity co-receptor for plasminogen/tissue plasminogen activator, plays a central role in primary hyperfibrinolysis in patients with acute promyelocytic leukemia (APL). The expression of Ann II in cells from patients with major subtypes of AML and the effect of arsenic trioxide (As2O3) on Ann II expression in AML cells were investigated to determine whether As2O3-mediated downregulation of Ann II could restore hemostatic stability. METHODS: A total of 103 patients (48 females and 55 males; age, 19 - 58 years) were included. Plasma samples were collected before and after treatment as well as after complete remission. Ann II and plasminogen activation were measured in leukemic cells during treatment with 1 micromol/L As2O3. RESULTS: Before As2O3 treatment, Ann II mRNA expression (real time PCR) was the highest in M3 cells (P < 0.05), higher in M5 cells than that in M1, M2, M4, and M6 cells (P < 0.001), and positively correlated with Ann II protein expression (flow cytometry) (r = 0.752, P < 0.01). Exposure for up to 120 hours to As2O3 (1 micromol/L) had no significant effect on Ann II protein in M1 and M2 leukemic cells, but decreased Ann II protein expression twofold within 48 hours of exposure in M3 cells (P < 0.05) and twofold within 96 hours in M5 cells (P < 0.05). The rate of plasmin generation was higher in APL, M5, and M4 cells than in M1, M2, and M6 cells. CONCLUSIONS: As2O3 may reduce hyperfibrinolysis in AML by downregulation of Ann II. Furthermore, As2O3 affects more than one form of AML (APL, M4 and M5), suggesting its potential role in their management. PMID- 19781381 TI - Two-stage analysis of pharmacokinetics of sufentanil administered by target controlled infusion in Chinese patients. AB - BACKGROUND: Sufentanil is a suitable choice for target-controlled infusion (TCI) because of its shorter context-sensitive half-time. The current study was to estimate the pharmacokinetics of sufentanil TCI in Chinese patients using the two stage analysis. METHODS: Twelve adult patients with American Society of Anesthesiologists (ASA) physical status I or II undergoing elective surgery under general anesthesia were included. Anesthesia was induced with propofol, rocuronium and sufentanil administered by TCI lasting for 30 minutes, with target effect-site concentration of sufentanil 4 or 6 ng/ml. Frequent arterial blood samples (1.5 ml) were taken during and up to 24 hours after sufentanil TCI. Before the end of surgery, another arterial blood sample (1.0 ml) was drawn for the blood-gas analysis. Plasma sufentanil concentrations were determined by liquid chromatography-tandem mass spectrometry (limit of quantitation was 5 pg/ml). The data were analyzed with the two-stage approach, linear regression and correlation analysis. RESULTS: The pharmacokinetics of sufentanil TCI were adequately described by a three-compartment model. The variables were derived as follows: the volume of central compartment (V(1)) was 5.4 L, volume of distribution at steady-state (Vdss) was 222.6 L, metabolic clearance (Cl(1)) was 0.84 L/min and elimination half-life (t(1/2Y)) was 389 minutes. Patients' age, gender and PaCO2 correlated significantly with the pharmacokinetic parameters. The Vdss, volume of slowly equilibrating compartment (V(3)) and t(1/2Y) increased, and rapid distribution clearance (Cl(2)) decreased with increasing patient age. Male patients had larger values of Vdss, volume of rapidly equilibrating compartment (V(2)) and V(3) than female patients. The Vdss and V(3) increased with higher PaCO2 values. There were no significant correlations between the pharmacokinetic variables and body weight, height, lean body mass, plasma albumin, sufentanil dose, duration of surgery, pH or base excess of blood (BE-B). CONCLUSIONS: The pharmacokinetics of sufentanil TCI in Chinese patients can be optimally described by a three-compartment model. The pharmacokinetic analysis technique may affect the pharmacokinetic parameters and correlations. PMID- 19781382 TI - Pedicle screw fixation for cervical spine instability: clinical efficacy and safety analysis. AB - BACKGROUND: Reports of applying cervical pedicle screw (CPS) system in the posterior cervical spine surgeries are limited because of its inherent risk of neurovascular injury. The clinical results of cervical spine instability treated with CPS system were retrospectively analyzed, and the clinical efficacy and safety of this management were evaluated. METHODS: Twenty-five patients with cervical spine instability undergoing posterior C3 - C7 single/double door laminoplasty and free-hand CPS fixation as well as graft fusion were investigated; of whom, 3 were due to trauma, and 22 degenerative cervical pathogenesis. One hundred and fifty in total, CPSs were implanted in 5 cervical segments for 1 patient, 4 for 2, 3 for 18, and 2 for 4. Japanese Orthopaedic Association (JOA) score and its improvement rate, neck disability index (NDI), segmental stability, pedicle cortex perforation rate and other complication associated parameters were assessed. RESULTS: The average follow-up was 16.6 (6 - 30) months. Compared with pre-operative values, JOA score improved by 4.10 +/- 0.84 points on average (P < 0.05) at 6 months post operation, with a mean improvement rate of 61%. While the pre-operative and 6-month post-operative NDI were 32.96 +/- 6.13 and 16.84 +/- 4.40 (P < 0.05), respectively. At 6-month post operation and the final follow-up, fused segments were stable. Pedicle cortex perforation rate was 8.0%, with no neurovascular complications observed. CONCLUSIONS: Anatomizing the pre-operative radiographic data facilitates the precise operative design prior to surgery; and CPS system is capable of offering safe and satisfying outcomes in the management of cervical spine instability. PMID- 19781383 TI - Prognostic analysis of transarterial chemoembolization combined with a traditional Chinese herbal medicine formula for treatment of unresectable hepatocellular carcinoma. AB - BACKGROUND: Transarterial chemoembolization (TACE) is the most widely used primary treatment for unresectable hepatocellular carcinoma (HCC) due to its survival benefit, though its clinical effect is still far from satisfactory. Jiedufang (JDF) granule preparation is a commonly used Chinese herbal medicine formula for HCC. The aim of this study was to evaluate the effect of combined therapy with TACE and JDF granule preparation in treatment of unresectable HCC on survival. METHODS: A retrospective study of TACE was performed in 165 patients with unresectable HCC who were admitted between January 2002 and December 2007 in Changhai Hospital, Shanghai, China. Of the 165 patients, 80 patients (study group) received combined therapy consisting of TACE and a long-term maintenance treatment with oral JDF granule preparation, and the remaining 85 patients (control group) received TACE alone. The survival rates of both groups were calculated by the Kaplan-Meier method. Factors possibly affecting survival were assessed by multivariate analysis in the Cox proportional hazard model, such as maximum tumor size, number of lesions, portal vein invasion, and etc. RESULTS: The median overall survival was 9.2 months (95% CI: 6.94 - 11.46) in the study group versus 5.87 months (95% CI: 4.21 - 7.52) in the control group. In the study group,survival rates of the 1-, 2- and 3-year follow-up were 41.2%, 18.4%, and 9.6%, respectively. Significant independent prognostic factors identified by the Cox regression analysis were as follows: serum hepatitis B surface antigen (HBsAg) (P = 0.014), maximum tumor size (P = 0.027), number of lesions (P < 0.001), portal vein invasion (P < 0.001), and the therapy model (P = 0.006). CONCLUSION: Combination therapy of TACE and JDF granule preparation may significantly prolong survival of patients with unresectable HCC. PMID- 19781384 TI - Dynamic expression of glucose transporters 1 and 3 in the brain of diabetic rats with cerebral ischemia reperfusion. AB - BACKGROUND: Blood glucose control improves the outcome of diabetic patients with stroke, but the target range of blood glucose control remains controversial. The functional recruitment of ischemia penumbra is extremely important to the recovery after stroke. The present study aimed to explore the expression of brain type glucose transporters (GLUT1 and GLUT3) in cerebral ischemic penumbra at different blood glucose levels and different ischemic-reperfusion time in diabetic hypoxia-ischemia rats. The results might provide an experimental basis for clinical treatment of diabetic patients with stroke. METHODS: The Wistar rats included in this study were randomly assigned to 4 groups (50 rats each): normal control group (NC), uncontrolled diabetic group (DM1), poorly-controlled diabetic group (DM2), and well-controlled diabetic group (DM3). Diabetic rats were induced by single intraperitoneal injection of streptozotocin, and the focal ischemic rat model of middle artery occlusion (MCAO) was made by insertion of fishing thread in 6 weeks after the establishment of the diabetic model. Each group was divided into 5 subgroups (10 rats each): four focal ischemic subgroups at different ischemic-reperfusion time (at 3,12, 24 and 72 hours after reperfusion, respectively) and one sham-operated subgroup. The mRNA and protein expression of GLUT1 and GLUT3 was assessed by RT-PCR and Western blotting, respectively. RESULTS: There was significant difference in the mRNA expression of GLUT1 and GLUT3 between the four focal ischemic subgroups and the sham-operated subgroup at different reperfusion time in each group. The mRNA expression of GLUT1 and GLUT3 in the 4 ischemic groups began to increase at 3 hours, peaked at 24 hours after reperfusion and maintained at a higher level even at 72 hours compared with that of the sham-operated subgroup. The mRNA expression of GLUT1 increased more significantly than that of GLUT3. The mRNA expression of GLUT1 and GLUT3 was significantly different between the diabetic groups and normal control group. The mRNA expression of GLUT1 and GLUT3 was increased more significantly in the diabetic groups than that in the normal control group. There was a significant difference in the mRNA expression in the groups with different blood glucose levels. The mRNA expression tended to decrease with increased blood glucose levels. The expression trend of GLUT1 and GLUT3 protein was similar to that of GLUT1 and GLUT3 mRNA. CONCLUSIONS: GLUT1 and GLUT3 expression was notably up regulated in the penumbra region after cerebral ischemia in this study. But the up-regulated amplitude of GLUT1 and GLUT3 in the diabetic rats with cerebral ischemic injury became smaller than that of the normal controls. In the treatment of diabetic patients with cerebral embolism, blood glucose control should not be too strict, otherwise the up-regulation of GLUT1 and GLUT3 induced by cerebral ischemic injury might not be able to meet the needs of energy metabolism in cells. PMID- 19781385 TI - Comparison of adenosine stress and dobutamine stress by real-time myocardial contrast echocardiography in detecting myocardium ischemia in dogs. AB - BACKGROUND: Real-time perfusion imaging (RTPI) using ultrasound contrast agents has shown good "accuracy" in detecting myocardial infarction, however its accuracy in the assessment of peri-infarct ischemia and stress echocardiography are not known. The aim of this study was to determine the accuracy of RTPI in assessment of peri-infarct ischemia during dobutamine and adenosine stress. METHODS: We employed the RTPI modality (Agilent and ATL Philips) in a canine model (18 dogs) of distal coronary occlusion and proximal coronary stenosis. Using coronary flow probe recordings, the physiologic significance of proximal coronary stenosis was established by confirming abolition of the coronary reserve. The contrast agent Optison was given as a slow bolus injection at baseline, during prolonged distal coronary occlusion, during adenosine bolus stress and during dobutamine stress. Triphenyltetrazolium chloride (TTC) staining was used to verify a distal infarction. RTPI recordings at baseline, the distal coronary occlusion and stress protocols were randomly mixed and reviewed blindly. RESULTS: In all but one dog, RTPI detected a distal infarct as small as 9% of the left ventricle. The sensitivity, specificity and overall diagnostic accuracy of RTPI in the detection of distal infarcts were: 94%, 89% and 92%, respectively. The sensitivity, specificity, and overall diagnostic accuracy of RTPI in the assessment of peri-infarction ischemia were 83%, 92% and 88% for adenosine stress and 95%, 86% and 91% for dobutamine stress, respectively. CONCLUSIONS: Even small distal infarcts can be detected by RTPI; peri-infarct ischemia can be accurately recognized by RTPI during stress; adenosine and dobutamine stress appear equally reliable in the RTPI evaluation of peri-infarct ischemia. PMID- 19781386 TI - Neuroprotective effect of recombinant human erythropoietin on optic nerve injury in rats. AB - BACKGROUND: Optic nerve injury, caused by retinal and optic nerve diseases, can eventually result in vision loss. To date, few effective treatments have been discovered to restore visual function. Previous studies showed that recombinant human erythropoietin (rhEPO) has a neuroprotective effect on the central nervous system, particularly in nerve injury. In this study, we investigated the effects of rhEPO on axonal regeneration and functional restoration following optic nerve injury. This was done by measuring the expression of growth associated protein 43 (GAP-43), a marker for neuronal regeneration, on the retina and flash-visual evoked potential (F-VEP). METHODS: Adult Wistar rats were randomly assigned to rhEPO and control (saline) groups. Optic nerve crush injury models were established and rhEPO or saline were immediately injected into the vitreous cavity. The expression of GAP-43 was detected by immunohistochemistry and the F VEP was measured pre-injury, immediately after injury, 1 week and 2 weeks post injury. RESULTS: No detectable staining for GAP-43 was observed in normal retina. In the control group, the level of GAP-43 expression was higher at 1 week post injury, but decreased at 2 weeks. In the rhEPO group, the level of GAP-43 expression was notably higher at both 1 week and 2 weeks. At each time point post injury, the expression of GAP-43 in rhEPO group was significantly higher than the control group (P < 0.05). Obvious changes in F-VEP examination were detected immediately after optic nerve injury, including significantly prolonged latency and decreased amplitude of the P1 wave. In the control group, the changes were still obvious at 1 week. The latency was decreased and the amplitude had slightly recovered to 28.23% of the normal value at 2 weeks. In rhEPO group, there was significantly more recovery than the control group at 1 week and 2 weeks post injury (P < 0.05). The latency most close to the normal level and the amplitude had recovered to 65.51% of the normal value at 2 weeks. CONCLUSIONS: rhEPO can prolong the expression of GAP-43 and increase its intensity after optic nerve injury, thereby promoting neural repair and axonal regeneration. Under the protection of rhEPO, the conduction velocity of the optic nerve recovered significantly. Therefore, rhEPO has neuroprotective effects on the optic nerve and promotes functional restoration of the optic nerve. PMID- 19781387 TI - Effect of epidermal growth factor and dexamethasone on fetal rat lung development. AB - BACKGROUND: Epidermal growth factor (EGF), a mitogenic polypeptide that binds to cell surface receptors, is an important regulator of cell differentiation and fetal lung surfactant synthesis. We investigated the preventive and therapeutic effects of EGF in respiratory distress syndrome, by administering EGF and dexamethasone (Dex) to mother rat before delivery. METHODS: Six female Sprague Dawley (SD) rats were assigned to three groups (2 rats each); EGF or Dex was given to pregnant rats (EGF group and Dex group, respectively) from gestational day 16 to day 18 by intraperitoneal injection, while the group with normal saline injection was used as negative controls. Fetal rats were taken out of womb by hysterotomy on day 19 of pregnancy, then 24 fetal rats were randomly chosen from each group. Their body weights were measured, and pulmonary surfactant protein-A and -B (SP-A and SP-B) antigens were determined by immunohistochemical staining in each group. The histologic structure was examined under a light microscope, a light microscopic image system or an electron microscope. RESULTS: The expressions of SP-A and SP-B could be detected in each group. A significant difference was observed for SP-A and SP-B in the EGF and Dex groups compared with the control group (P < 0.01). Image analysis showed that the relative values of air space area and interalveolar septa area in the EGF and Dex groups were significantly greater than those in the control group (P < 0.01), while no significant difference was found between the two groups (P > 0.05). The ultrastructural features of fetal lungs showed that the number of alveolar type II cells containing lamellar bodies in the EGF and Dex groups was apparently increased compared with that in the control group. The mean body weight of fetus from the Dex group was smaller than that from the control group ((1.3192 +/- 0.0533) g, (1.3863 +/- 0.0373) g), but there was no significant difference between the EGF group and the control group ((1.3986 +/- 0.0730) g, (1.3863 +/- 0.0373) g). CONCLUSIONS: Maternal treatment with EGF and Dex on days 16 - 18 of gestation could promote morphogenesis and increase the surfactant levels in premature fetal lung. However, maternal treatment with Dex, not EGF, decreased the body weight. PMID- 19781388 TI - Different expression of dectin-1 and Toll-like receptor 2 in the lungs of different immune status mice infected with Aspergillus fumigatus. AB - BACKGROUND: Invasive pulmonary aspergillosis (IPA) is a severe and frequently fatal disease in patients receiving treatment with immunosuppressive agents such as cyclophosphamide. Aspergillus fumigatus (A. fumigatus) now is a leading cause of IPA. Dectin-1 and Toll-like receptor 2 (TLR2) are important pattern recognition receptors involved in immune responses to A. fumigatus in vitro. However, the expression of the two receptors during the infection of A. fumigatus in vivo is not completely understood. The effects of cyclophosphamide treatment on the expression of the receptors need to be further studied. METHODS: We established different immune status in mice models with or without A. fumigatus infection. On days 1, 3 and 5 post inoculation, pulmonary tissues from mice of the different groups were harvested. Dectin-1 and TLR2 mRNA expression in the lungs of the mice were investigated by real-time PCR. The pulmonary fungal burden in the mice with A. fumigatus infection was also evaluated. RESULTS: In the immunocompetent mice, three days after A. fumigatus inoculation, dectin-1 and TLR2 expression increased markedly compared with the normal control group. Cyclophosphamide inhibited the clearance of pathogens and the expression of dectin-1 with or without A. fumigatus infection in the lungs as well. There was no statistical difference in TLR2 expression between the different immune status groups. CONCLUSIONS: Our results suggest that in vivo, dectin-1 and TLR2 are activated during the experimental period which would provide a broad range of possibilities for a specific and effective inflammatory response to kill A. fumigatus. Inhibition of dectin-1 expression may be one of the mechanisms of cyclophosphamide in the development of IPA. PMID- 19781389 TI - Construction of cholecystokinin transgenic mouse and its effects on food intake. AB - BACKGROUND: Cholecystokinin (CCK) is one of the richest neuropeptides in the mammalian brain, which is mainly distributed in the cerebral cortex, hippocampus, thalamus and caudate-putamen. CCK is implicated in a variety of behavioral functions such as food intake, learning, memory, anxiety, pain and neuroprotection. The current research results for CCK are obtained mainly through injection of CCK peptide into the body. The key issues of whether CCK can regulate diet by a central pathway and whether there are long-term regulation effects on diet are still unresolved. In this study, the effects of CCK on food intake in transgenic mice were investigated. METHODS: Transgenic mice were created by microinjection of the PDGF-CCK construct into male pronucleus of the zygotes. The genomic phonetype of transgenic mice were identified by PCR. The expression of PDGF-CCK was analyzed by Western blotting. Body weight, plasma glucose, cholesterol and triglycerides were assayed and analyzed. RESULTS: Two PDGF-CCK transgenic independent lines were established and exhibited a high levels brain-specific transgene expression compared with that of nontransgenic littermate controls. The food intake of male CCK transgenic mice was decreased by 5% - 10% with the same levels of water consumed compared with wild type mice. The food intake in female mice was not obviously changed. In the transgenic mice the bodyweight was lower and plasma glucose was higher compared with the nontransgenic littermate controls. CONCLUSIONS: The high expression of the CCK gene in the brain can decrease body weight and increase plasma glucose. The differences in food intake between the males and females require further study. PMID- 19781391 TI - Mechanisms of treatment of cancer pain with a topical Chinese herbal formula in rats. AB - BACKGROUND: Pain has a substantial impact on patients' activities and overall quality of life, but current conventional drugs have debilitating side effects, including gastrointestinal disorders. Thus there is a pressing need for new therapies with fewer side effects to alleviate cancer pain. We recently developed a topical herbal formula Xiaotan Tongluo analgesic gel (XTTL gel) based on the principles of traditional Chinese herbalism, and we have received positive feedback from bone cancer pain patients. The aim of this study was to determine the analgesic effects and explore the mechanisms of XTTL gel in a rat model of bone cancer pain. METHODS: The rat model of bone cancer pain was established by inoculating Walker-256 rat carcinoma cells directly into the right tibial medullary cavity of Wistar rats. The rats were randomly assigned to three groups (n = 10 per group): (1) sham bone cancer control (sham group): vehicle (PBS) inoculation without carcinoma cells plus topical administration of blank gel; (2) Sham treatment control (vehicle group): Walker-256 cell inoculation plus topical administration of blank gel; (3) XTTL gel treatment (treatment group): Walker-256 cell inoculation plus topical administration of XTTL gel. XTTL gel treatments were applied daily for 7 days starting on day 14 following inoculation. Outcomes were assessed 21 days after inoculation by mechanical allodynia, histological staining, and by measuring concentrations of type I collagen carboxy-terminal telopeptide (ICTP) and bone-specific alkaline phosphatase (BAP) in serum. RESULTS: Fourteen days after cancer cell incubation, significant mechanical allodynia in the ipsilateral hind paw and tumor growth in proximal end of the tibia were observed in the vehicle and treatment groups but not in the sham group. At day 21, mechanical withdrawal thresholds in treatment group rats were significantly higher ((4.8557 +/- 0.8336) g) compared with those of the vehicle group ((1.8630 +/- 1.4369) g, P < 0.05). ICTP and BAP levels increased significantly in vehicle group rats ((101.5176+/- 11.0694) U/L and (370.7838 +/- 12.8273) U/L, respectively) compared with those of the sham group ((11.7553 +/- 1.1885) U/L and (185.7338 +/- 3.6761) U/L, respectively; P < 0.05). XTTL gel decreased the level of blood serum ICTP ((41.8998 +/- 6.4970) U/L, P < 0.05) but had little effect on blood serum BAP ((365.5338 +/- 18.5361) U/L, P > 0.05). CONCLUSION: Topical use of XTTL gel may have an analgesic effect on bone cancer pain, an effect mediated by lowering of ICTP levels and inhibiting bone resorption. PMID- 19781392 TI - A novel biosynthetic hybrid scaffold seeded with olfactory ensheathing cells for treatment of spinal cord injuries. AB - BACKGROUND: Implantation of tissue-engineered scaffolds is one of the most promising therapeutic strategies for inducing nerve regenerations following spinal cord injuries. In this paper, we report a novel bioengineered hybrid scaffold comprised of three major extracellular matrix (ECM) proteins. METHODS: ECM-scaffolds (ECM-S) were prepared by gelling fibrinogen, fibronectin and laminin using fresh rat plasma. Olfactory ensheathing cells (OECs) were isolated from fresh rat olfactory mucosa, purified under differential adhesion, and assessed by immunofluorescent staining. OECs were seeded onto ECM-S and cultured. The effects of the scaffolds on the seeded cells were detected using the immunofluorescent staining, Western blotting, scanning electron microscopy and transmission electron microscopy. RESULTS: Tissue-engineered ECM-S could be easily molded into mat-like or cylindrical shapes and gelled by addition of fresh plasma. Observations by electron microscopy show that the ECM-S forms a stable three-dimensional porous network. Studies on the effects of the ECM-S on the biological behaviors of OECs in vitro indicate that the scaffold can promote OEC adhesion, proliferation and process extensions. Additionally, OECs seeded on the scaffold maintained the expression of nerve growth factor, matrix metalloproteinase-3 and matrix metalloproteinase-9. CONCLUSION: We developed a biosynthetic hybrid gel which could be used as a scaffold for OEC transplantation; this gel can promote nerve regeneration following spinal cord injuries. PMID- 19781393 TI - Evaluation of damage to trabecular bone of the osteoporotic human acetabulum at small strains using nonlinear micro-finite element analyses. AB - BACKGROUND: With advance of age, alterations in bone quality, quantity and microarchitecture render osteoporotic trabecular bone become more sensitive to local failure. The aims of the present study were to clarify the extent to which the distribution of tissue-level stresses and strains was affected by structural changes and the extent to which osteoporotic acetabular trabecular bone was damaged at small strains. METHODS: Using a DAWING 4000A supercomputer, nonlinear micro-finite element (microFE) analyses were performed to calculate the tissue level strains and stresses for each element in the trabecular bone of one osteoporotic acetabulum at small strains to quantify the tissue-level damage accumulation and mechanical properties. RESULTS: In contour plots of the tissue, maximum principal logarithmic strains, high tissue-level strains, both compressive and tensile, were observed in the osteoporotic trabecular bone at small apparent strains from 0.2% to 0.5% strain. The compressive apparent stress strain curve showed typical nonlinear behavior and tangent modulus reduction with increasing strains. The microdamage curve suggested that microdamage began at 0.2% apparent strain in the osteoporotic trabecular bone and increased sharply, although very few microfractures occurred. The quartiles of the maximum principal logarithmic strains, minimum principal logarithmic strains and Von Mises stresses increased nonlinearly. For the inter-quartile range of the Von Mises stresses, a leap occurred at small strains ranging from 0.2% to 0.3% while microdamage commenced. CONCLUSIONS: Extensive microdamage was primarily responsible for the large loss in apparent mechanical properties that occurred in the trabecular bone of the osteoporotic acetabulum at small strains. With increasing apparent strains, continuous nonlinear increments of tissue-level strains and stresses resulted in microdamage that propagated throughout the specimen with very few microfractures. PMID- 19781394 TI - Kidney disease in China: recent progress and prospects. PMID- 19781395 TI - Major advances in respiratory medicine in China. PMID- 19781396 TI - Non-ablative controlled local hyperthermia for common warts. PMID- 19781397 TI - Receptor expression-enhancing protein 1 gene (SPG31) mutations are rare in Chinese Han patients with hereditary spastic paraplegia. PMID- 19781398 TI - Repeated radiofrequency ablation as both salvage solution and curative treatment for spontaneous rupture of giant medial lobe hepatocellular carcinoma. PMID- 19781399 TI - Detection of CD59-deficient granulocytes in a patient with advanced myelodysplastic syndrome. PMID- 19781400 TI - Five patients in a Chinese family with multiple epiphyseal dysplasia. PMID- 19781401 TI - A gastric duplication cyst at the splenic hilum mimicking endometriosis clinically in a female adult. PMID- 19781402 TI - Benefits of drug-eluting stents as compared to bare metal stent in ST-segment elevation myocardial infarction: four year results of the PaclitAxel or Sirolimus Eluting stent vs bare metal stent in primary angiOplasty (PASEO) randomized trial. AB - BACKGROUND: Drug-eluting stent (DES) may offer benefits in terms of repeat revascularization, which may be counterbalanced by a potential higher risk of stent thrombosis, especially among patients with STEMI. No data have been reported so far on the long-term benefits and safety of DES in STEMI. The aim of the current study was to evaluate the short- and long-term benefits of sirolimus eluting stent (SES) and paclitaxel-eluting stent (PES) as compared to bare-metal stent (BMS) in patients undergoing primary angioplasty. METHODS: Consecutive patients with STEMI admitted within 12 hours of symptom onset and undergoing primary angioplasty and stent implantation at a tertiary center with 24-hour primary percutaneous coronary intervention capability were randomly assigned to BMS, PES, and SES. All patients received upstream glycoprotein IIb-IIIa inhibitors. Primary end point was target-lesion revascularization at 1-year follow-up. Secondary end points were (1) cumulative combined incidence of death and/or reinfarction; (2) cumulative incidence of in-stent thrombosis; and (3) major adverse cardiac events (MACE) (combined death and/or reinfarction and/or target lesion revascularization [TLR]) at long-term follow-up (up to 4 years). No patient was lost to follow-up. RESULTS: From October 1, 2003, to December 2005, 270 patients with STEMI were randomized to BMS (n = 90), PES (n = 90), or SES (n = 90). Procedural success was obtained in 93% to 95% of patients. Follow-up data were available for all patients. As compared to BMS (14.4%), both PES (4.4%, hazard ratio [HR] 0.29, 95% CI 0.095-0.89, P = .023) and SES (3.3%, HR 0.21, 95% CI 0.06-0.75, P = .016) were associated with a significant reduction in TLR at 1 year follow-up (primary study end point). At long-term follow-up (1,233 +/- 215 days), no difference was observed in terms of death, reinfarction, and combined death and/or reinfarction, but as compared to BMS (21.1%), both PES (6.7%, HR 0.29, 95% CI 0.12-0.73, P = .008) and SES (5.6%, HR 0.24, 95% CI 0.09-0.63, P = .002), respectively, were associated with a significant reduction in TLR. CONCLUSIONS: This study shows that among patients with STEMI undergoing primary angioplasty, both SES and PES are safe and associated with significant benefits in terms of TLR up to 4 years' follow-up, as compared to BMS. Thus, until the results of further large randomized trials with long-term follow-up become available, DES may be considered among patients with STEMI undergoing primary angioplasty. PMID- 19781404 TI - Are we sure we have taken the best from clopidogrel? PMID- 19781403 TI - Treatment of stable angina pectoris by ivabradine in every day practice: the REDUCTION study. AB - BACKGROUND: The antianginal efficacy of ivabradine was studied in controlled clinical trials. Strict patient selection criteria may cause a discrepancy between the results of highly controlled clinical trials and everyday routine practice. The objective of this study was to evaluate the efficacy and safety of ivabradine in everyday routine practice. METHODS: In this multicenter study, 4,954 patients with stable angina pectoris received ivabradine in everyday routine practice and underwent follow-up for 4 months. The heart rate (HR), angina pectoris attacks, nitrate consumption, overall efficacy, and tolerance were evaluated. RESULTS: Within 4 months of treatment with ivabradine, HR was reduced by 12.4 +/- 12.2 beat/min from 82.9 +/- 15.3 to 70.4 +/- 9.2 beat/min (P < .0001). Angina pectoris attacks were reduced from 2.4 +/- 3.1 to 0.4 +/- 1.5 per week (P < .0001). Consumption of short-acting nitrates was reduced from 3.3 +/- 4.4 to 0.6 +/- 1.6 U/wk (P < .0001). Seventy-eight cases of adverse drug reactions were reported. The most common adverse drug reactions were nausea (n = 11, 0.22%) and dizziness (n = 9, 0.18%). Efficacy and tolerance were graded by physicians as being "excellent/very good" for 97% and 98% of the patients treated. CONCLUSION: Ivabradine reduces the HR and is highly effective and well tolerated in the treatment of patients with symptomatic coronary artery disease. The results confirm the findings of controlled clinical trials in a broad patient population in everyday routine practice. PMID- 19781405 TI - Learning from history: a commentary on the American Heart Association Science Advisory on depression screening. PMID- 19781406 TI - The high cost of nonadherence after percutaneous coronary intervention--can health care reform solve this problem? PMID- 19781407 TI - Rationale and design of China intensive lipid lowering with statins in acute coronary syndrome: the CHILLAS study. AB - BACKGROUND: Current guidelines recommended intensive low-density lipoprotein cholesterol lowering with statins, aiming at the target of 70 mg/dL (1.81 mmol/L) of low-density lipoprotein cholesterol for those with very high risk of coronary artery events. However, there is no multicenter study assessing the effect of intensive lipid lowering therapy with statins on acute coronary syndrome (ACS) in Chinese population. METHODS: An open-label multicenter study is planned to evaluate whether intensive treatment with statins for 2 to 5 years results in more reduction of cardiovascular events in patients with ACS compared to the standard statin therapy. A total of 1,600 patients will be randomly assigned to receive intensive statin therapy (atorvastatin, 20 or 40 mg/d, or equivalent dose of other statins) or standard statin therapy (atorvastatin, 10 mg/d, or equivalent dose of other statins). Both groups will receive dietary counseling. Over the follow-up period, the primary outcome measure is the time to occurrence of cardiac death, nonfatal acute myocardial infarction, revascularization with either percutaneous coronary intervention or coronary-artery bypass grafting, documented unstable angina or severe heart failure requiring emergency hospitalization, and stroke. The planned duration for enrollment is between December 2006 and December 2009. CONCLUSIONS: The CHILLAS study will be the first multicenter study in a Chinese population using a patient-level analysis to compare the effects and safety of intensive statin therapy with that of standard dose statin therapy, which may provide new evidence and therapeutic standards for the treatment of ACS. PMID- 19781409 TI - SPIRIT IV trial design: a large-scale randomized comparison of everolimus-eluting stents and paclitaxel-eluting stents in patients with coronary artery disease. AB - BACKGROUND: In the 300-patient SPIRIT II and 1002-patient SPIRIT III randomized trials, the everolimus-eluting stent (EES) compared to the paclitaxel-eluting stent (PES) resulted in reduced angiographic late loss (a primary end point in both trials), noninferior rates of 9-month target vessel failure (a primary end point in SPIRIT III), and reduced rates of target lesion revascularization and major adverse cardiac events (secondary end points). However, neither trial was powered for superiority for clinical end points, and the routine performance of angiographic follow-up may have artificially exaggerated the absolute benefits of EES. The relative efficacy of these 2 stents in patients with diabetes mellitus also remains controversial. We therefore designed a large-scale randomized trial without angiographic follow-up to further assess the differences between these 2 stent platforms. STUDY DESIGN: SPIRIT IV is an ongoing prospective, active controlled, single-blinded, multicenter clinical trial in which 3690 patients with native coronary artery disease have been randomized 2:1 to EES versus PES. Patients with up to 3 de novo native coronary artery lesions (maximum 2 lesions per epicardial vessel) with length or=2.5 to 3-fold increase odds of having any plaque (adjusted odds ratio [OR] 3.6, P = .047) and an increase of 2.5 segments of plaque (P < .001) as compared to those without AVC. When stratified by plaque composition, AVC was associated most with calcified plaque (OR 5.2, P = .004), then mixed plaque (OR 3.2, P = .02), but not with noncalcified plaque (P = .96). CONCLUSION: Aortic valve calcification is associated with the presence and greater extent of coronary artery plaque burden and may be part of the later stages of the atherosclerosis process, as its relation is strongest with calcified plaque, less with mixed plaque, and nonsignificant with noncalcified plaque. If AVC is present, consideration for aggressive medical therapy may be warranted. PMID- 19781416 TI - Early abciximab administration before transfer for primary percutaneous coronary interventions for ST-elevation myocardial infarction reduces 1-year mortality in patients with high-risk profile. Results from EUROTRANSFER registry. AB - BACKGROUND: There are conflicting data on the clinical benefit from early administration of abciximab from a large randomized trial and a registry. However, both sources suggest that a benefit may depend on the baseline risk profile of the patients. We evaluated the role of early abciximab administration in patients with ST-segment-elevation myocardial infarction (STEMI) referred for primary percutaneous coronary intervention stratified by the STEMI Thrombolysis In Myocardial Infarction (TIMI) risk score. METHODS: A total of 1,650 patients were enrolled into the EUROTRANSFER Registry. One thousand eighty-six patients received abciximab (66%). Abciximab was administered early in 727 patients (EA) and late in 359 patients (LA). We used the TIMI risk score for risk stratification. Patients with scores >or=3 constituted the high-risk group of 616 patients (56.7%), whereas 470 patients formed the low-risk cohort. Factoring in the timing of the abciximab administration resulted in 4 groups of patients who were compared for mortality at 1 year: EA/high-risk (n = 413); LA/high-risk (n = 203); EA/low-risk (n = 314); LA/low-risk (n = 156). Baseline difference was accounted for by means of propensity score. RESULTS: In high-risk patients, 1 year mortality was significantly lower with early abcximab compared to late administration (8.7% vs 15.8%; odds ratio 0.51, CI 0.31-0.85, P = .01). In multivariable Cox regression analysis, both early abciximab administration and patients' risk profile (TIMI score >or=3) were identified as independent predictors of 1-year mortality. CONCLUSIONS: Early abciximab administration before transfer for percutaneous coronary intervention in STEMI shows lower mortality at 1-year follow-up. This effect is confined to patients with higher risk profile as defined by TIMI risk score >or=3. PMID- 19781414 TI - Cardiovascular events with absent or minimal coronary calcification: the Multi Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Elevated coronary artery calcium (CAC) is a marker for increase risk of coronary heart disease (CHD). Although most CHD events occur among individuals with advanced CAC, CHD can also occur in individuals with little or no calcified plaque. In this study, we sought to evaluate the characteristics associated with incident CHD events in the setting of minimal (score 3 x upper limit of normal; any periprocedural increase of creatine kinase-MB, troponin-I, or myoglobin above upper limit of normal; Thrombolysis in Myocardial Infarction flow <3 after PCI; thrombocytopenia with platelet count of <70,000/mL; major bleeding defined according to the Thrombolysis in Myocardial Infarction criteria; and elevation of high-sensitivity C-reactive protein and soluble P selectin. RESULTS: Primary end point occurred in 12.6% ad hoc group versus 15.6% delayed group patients (P = .34). High-sensitivity C-reactive protein increased in both groups post-PCI (analysis of variance P < .0001) without difference between groups (P = .5). Major bleeding occurred in 2.9% ad hoc group versus 3.1% delayed group patients (P = .9). No significant difference was observed in any other secondary end point. CONCLUSIONS: In clopidogrel-naive patients, a strategy of delaying PCI for 2 hours after high-dose clopidogrel loading does not seem to confer any benefit compared to ad hoc PCI. PMID- 19781419 TI - Patterns of use of thienopyridine therapy after percutaneous coronary interventions with drug-eluting stents and bare-metal stents. AB - BACKGROUND: Twelve months of uninterrupted thienopyridine therapy after drug eluting stents (DES) implantation was recently recommended, but limited data are available regarding long-term use in clinical practice. The objective of the study was to determine the adherence to thienopyridine therapy after stent implantation, factors associated with suboptimal adherence, and association of suboptimal adherence with mortality. METHODS: We evaluated 5,263 older patients (>65 years) who received DES and 6,081 older patients who received bare-metal stents (BMS) from December 1, 2003, to March 31, 2006, in Ontario, Canada, who were eligible to receive 12 months of thienopyridine at minimal cost. RESULTS: Primary nonadherence was observed among 6.9% in the DES group and 7.1% in the BMS group that did not fill a single prescription of thienopyridine within 1 year of stent implantation. Premature discontinuation occurred in a progressive manner, with 28% in the DES group and 34% in the BMS group discontinuing therapy by 6 months. Low-income patients eligible for a waiver of deductible and dispensing fee were almost 70% more likely to fill their first prescription. For DES patients, primary nonadherence (hazard ratio [HR] 2.68, 95% CI 1.77-4.07), 12 months proportional days covered <80% (HR 2.39, 95% CI 1.67-3.43), and prematurely discontinuing therapy within 6 months (HR 2.64, 95% 1.60-4.35) were associated with an increased risk of death. CONCLUSIONS: We found suboptimal patterns of adherence to thienopyridine therapy after DES implantation that was strongly associated with an increased mortality risk. Eliminating any costs for thienopyridine therapy may be an effective strategy to increase medication adherence. PMID- 19781420 TI - Practice patterns, outcomes, and end-organ dysfunction for patients with acute severe hypertension: the Studying the Treatment of Acute hyperTension (STAT) registry. AB - BACKGROUND: Limited data are available on the care of patients with acute severe hypertension requiring hospitalization. We characterized contemporary practice patterns and outcomes for this population. METHODS: STAT is a 25-institution, US registry of consecutive patients with acute severe hypertension (>180 mm Hg systolic and/or >110 mm Hg diastolic; >140 and/or >90 for subarachnoid hemorrhage) treated with intravenous therapy in a critical care setting. RESULTS: One thousand five hundred eighty-eight patients were enrolled (January 2007 to April 2008). Median age was 58 years (interquartile range 49-70 years), 779 (49%) were women, and 892 (56%) were African American; 27% (n = 425) had a prior admission for acute hypertension and 486 (31%) had chronic kidney disease. Median qualifying blood pressure (BP) was 200 (186, 220) systolic and 110 (93, 123) mm Hg diastolic. Initial intravenous antihypertensive therapies used to control BP varied, with 1,009 (64%) patients requiring multiple drugs. Median time to achieve a systolic BP <160 mm Hg (<140 mm Hg for subarachnoid hemorrhage) was 4.0 (0.8, 12) hours; 893 (60%) had reelevation to >180 (>140 for subarachnoid hemorrhage) after initial control; and 63 (4.0%) developed iatrogenic hypotension. Hospital mortality was 6.9% (n = 109) with an aggregate 90-day mortality rate of 11% (174/1,588); 59% (n = 943) had acute/worsening end-organ dysfunction during hospitalization. The 90-day readmission rate was 37% (523/1,415), of which one quarter (132/523) was due to recurrent acute severe hypertension. CONCLUSION: This study highlights heterogeneity in care, BP control, and outcomes of patients hospitalized with acute severe hypertension. PMID- 19781421 TI - Cardiac amyloidosis in African Americans: comparison of clinical and laboratory features of transthyretin V122I amyloidosis and immunoglobulin light chain amyloidosis. AB - BACKGROUND: Transthyretin (TTR) mutations known to cause cardiac amyloidosis include V122I, found almost exclusively in African Americans at a prevalence of 3 3.9%. This retrospective study describes TTR V122I-associated cardiac amyloid disease (ATTR) in a major amyloid referral clinic population. METHODS: Self identified African Americans with amyloidosis (n = 156) were screened for TTR V122I by serum isoelectric focusing; mutant TTR was confirmed by DNA sequencing or mass spectrometry. Cardiac findings in ATTR V122I and immunoglobulin light chain (AL) amyloidoses were compared. RESULTS: TTR V122I was identified in 36/156 (23.1%) of evaluated patients and included 5 homozygotes; the allele frequency was 0.013. One compound heterozygote (F44L/V122I) and 4 patients who had AL and the mutant TTR allele were characterized. In patients negative for V122I, AL was the most frequent diagnosis (86/120). Cardiomyopathy was present in 100% of patients with ATTR and 84% of patients with AL (P = .01). In patients with dominant cardiac involvement, better survival occurred in ATTR (n = 30) compared to AL (n = 31), (27 vs 5 months, P < .01) although the mean age in ATTR was higher (70.3 vs 56.2 years, P < .01). Congestive heart failure symptoms and electrocardiographic findings were similar in ATTR and AL, but significant differences in echocardiographic measurements were observed. CONCLUSIONS: ATTR V122I and AL are equally prevalent as the cause of cardiomyopathy in African Americans referred for a diagnosis of amyloidosis. Available therapy for AL underscores the need for early and accurate determination of amyloid type. PMID- 19781422 TI - Insertion/deletion polymorphism in alpha2-adrenergic receptor gene is a genetic risk factor for sudden cardiac death. AB - BACKGROUND: Adrenoceptors mediate contraction of vascular smooth muscle and induce coronary vasoconstriction in humans. A deletion variant of the human alpha(2B)-adrenoreseptor of glutamic acid residues has been associated with impaired receptor desensitization. This receptor variant could, therefore, be involved in cardiovascular diseases associated with enhanced vasoconstriction. Our aim was to study whether an insertion/deletion (I/D) polymorphism in the alpha(2B)-adrenoceptor gene is associated with the risk for sudden cardiac death. METHODS: This was a prospective population-based study investigating risk factors for cardiovascular diseases in middle-aged men from 42 to 60 years from eastern Finland. The study is based on 1,606 men with complete data on DNA observed for an average time of 17 years. RESULTS: In this study population, 338 men (21%) had the D/D genotype, 467 (29%) had the I/I genotype, and 801 (50%) had a heterozygous genotype. There were 76 sudden cardiac deaths during follow-up (0.81 deaths/1,000 persons per year). In a Cox model adjusting for other coronary risk factors (age, systolic blood pressure, smoking, diabetes, serum low-density lipoprotein and high-density lipoprotein cholesterol, body mass index, and exercise-induced myocardial ischemia), men with the D/D or I/D genotype had 1.97 times (95% CI 1.08-3.59, P = .026) higher risk to experience sudden cardiac death (20 events for D/D genotype, 13 events for I/I genotype, and 43 events for I/D genotype) compared with men carrying the I/I genotype. In addition, the alpha(2B) adrenoceptor D/D genotype was associated with the risk of coronary heart disease death and acute coronary events, after adjusting for risk factors. CONCLUSIONS: The genetic polymorphism of the alpha(2B)-adrenoreceptor is genetic risk predictor for sudden cardiac death. PMID- 19781423 TI - Electrocardiographic predictors of atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is the most prevalent arrhythmia in the United States and accounts for more than 750,000 strokes per year. Noninvasive predictors of AF may help identify patients at risk of developing AF. Our objective was to identify the electrocardiographic characteristics associated with onset of AF. METHODS: This was a retrospective cohort analysis of 42,751 patients with electrocardiograms (ECGs) ordered by physician's discretion and analyzed using a computerized system. The population was followed for detection of AF on subsequent ECGs. Cox proportional hazard regression analysis was performed to test the association between these ECG characteristics and development of AF. RESULTS: For a mean follow-up of 5.3 years, 1,050 (2.4%) patients were found to have AF on subsequent ECG recordings. Several ECG characteristics, such as P-wave dispersion (the difference between the widest and narrowest P waves), premature atrial contractions, and an abnormal P axis, were predictive of AF with hazard ratio of approximately 2 after correcting for age and sex. P-wave index, the SD of P-wave duration across all leads, was one of the strongest predictors of AF with a concordance index of 0.62 and a hazard ratio of 2.7 (95% CI 2.1-3.3) for a P-wave index >35. These were among the several independently predictive markers identified on multivariate analysis. CONCLUSIONS: Several ECG markers are independently predictive of future onset of AF. The P index, a measurement of disorganized atrial depolarization, is one of the strongest predictors of AF. The ECG contains valuable prognostic information that can identify patients at risk of AF. PMID- 19781424 TI - Close bidirectional relationship between chronic kidney disease and atrial fibrillation: the Niigata preventive medicine study. AB - BACKGROUND: Atrial fibrillation (AF) and chronic kidney disease share risk factors and pathophysiologic mechanisms, suggesting that two conditions have close relationships. METHODS: This is a prospective community-based observational cohort study including 235,818 subjects based upon a voluntary annual health check-up program in Japan. We studied the association of kidney dysfunction at entry with subsequent new-onset AF and the association of AF at entry with the development of kidney disease. RESULTS: During a follow-up of 5.9 +/- 2.4 years, AF developed in 2947 subjects (1.3%). Baseline serum creatinine and estimated glomerular filtration rate (GFR) were associated with risk of subsequent AF. The HRs (95% CI) for AF were 1.32 (1.08-1.62) and 1.57 (0.89-2.77) for GFR 30 to 59 and <30 mL/min per 1.73 m(2), respectively. The effect of kidney disease on risk of new-onset AF remained significant in subjects without treated hypertension or diabetes. During the follow-up, 7791 subjects (3.3%) developed kidney dysfunction (GFR <60 mL/min per 1.73 m(2)), and 11 307 subjects (4.9%) developed proteinuria. Atrial fibrillation at entry was associated with development of kidney dysfunction (HRs [95% CI], 1.77 [1.50-2.10]) and proteinuria (HR [95% CI], 2.20 [1.92-2.52]). The association persisted in subjects without treated hypertension or diabetes. CONCLUSIONS: Kidney dysfunction increased the risk of new onset of AF, and AF increased the risk of development of kidney disease. This finding supports the concept that the two conditions share common abnormal molecular signaling pathways contributing to their pathogenesis. PMID- 19781425 TI - Drug-eluting versus bare-metal stents for treating saphenous vein grafts. AB - BACKGROUND: Current data show conflicting results regarding safety and efficacy of drug-eluting stents (DES) versus bare-metal stents (BMS) for treating saphenous vein grafts (SVG). Our objective was to compare DES with BMS for SVG intervention. METHODS: Patients undergoing stenting with DES or BMS to SVG from January 2000 to June 2007 were included. To eliminate any unobserved bias regarding stent selection, the BMS cohort was divided into pre- and post-2003 when DES became available. Adjusted Cox analysis compared DES with pre- and post 2003 BMS patients. The primary end point was a composite of all-cause mortality, myocardial infarction, or target lesion revascularization. RESULTS: Of the total 566 patients, 217 (38%) received DES, 110 (20%) received BMS post-2003, and 239 (42%) received BMS pre-2003. Median follow-up was 2.9 years (interquartile range 1.4-4.9 years). There was a trend toward lower primary end point with DES compared to post-2003 BMS (91 events, adjusted hazard ratio 0.61, 95% CI 0.35 1.07, P = .08). However, despite 179 events, DES use was not associated with lower primary end point compared with pre-2003 BMS (adjusted hazard ratio 0.61, 95% CI 0.28-1.35, P = .23). CONCLUSIONS: Although DES showed a trend toward a lower primary end point when compared with BMS post-2003, this association was no longer present when DES was compared to pre-2003 BMS. These results are consistent with the preponderance of available data and indicate that unobserved bias in observational registries may explain the reported benefit of DES over BMS for treating SVG. PMID- 19781426 TI - Characteristics and in-hospital outcomes for nonadherent patients with heart failure: findings from Get With The Guidelines-Heart Failure (GWTG-HF). AB - BACKGROUND: Medication and dietary nonadherence are precipitating factors for heart failure (HF) hospitalization; however, the characteristics, outcomes, and quality of care of patients with nonadherence are unknown. Recognizing features of nonadherent patients may provide a means to reduce rehospitalization for this population. METHODS: GWTG-HF registry data were collected from 236 hospitals and 54,322 patients from January 1, 2005 to December 30, 2007. Demographics, clinical characteristics, in-hospital outcomes, and quality of care were stratified by precipitating factor for HF admission. Multivariate logistic regression analysis was used to determine the association of nonadherence with length of stay (LOS) and in-hospital mortality. RESULTS: Clinicians documented dietary and/or medication nonadherence as the reason for admission in 5576 (10.3%) of HF hospitalizations. Nonadherent patients were younger and more likely to be male, minority, uninsured, and have nonischemic HF. These patients had lower ejection fractions (34.9% vs 39.6%, P < .0001), more frequent previous HF hospitalizations, higher brain natriuretic peptide levels (1813 vs 1371 pg/mL, P < .0001), and presented with greater signs of congestion. Despite this, nonadherent patients had shorter LOS (odds ratio 0.94, 95% CI 0.92-0.97) and lower in-hospital mortality (odds ratio 0.65, 95% CI 0.51-0.83) in multivariate analysis. Although nonadherent patients received high rates of Joint Commission core measures, rates of other evidence-based treatments were less optimal. CONCLUSIONS: Nonadherence is a common precipitant for HF admission. Despite a higher risk profile, nonadherent patients had lower in-hospital mortality and LOS, suggesting that it may be easier to stabilize nonadherent patients by reinstituting sodium and/or fluid restriction and resuming medical therapy. PMID- 19781427 TI - Blood transfusion for acute decompensated heart failure--friend or foe? AB - BACKGROUND: In acute coronary syndromes (ACSs), blood transfusion (BT) has been associated with worse outcomes. The impact of BT among patients with acute decompensated heart failure (ADHF) remains unknown. METHODS: Propensity score analysis of patients with ADHF with and without BT in a national heart failure (HF) survey was used in this study. RESULTS: Of the 4,102 enrolled patients, 2,335 had ADHF, of whom 166 (7.1%) received BT. These patients were older (75.6% vs 73.6%, P = .04), more likely to be females (54.8% vs 43.9%, P = .007), more likely to have diabetes (59.0% vs 51.1%, P = .04) and renal dysfunction (59.0% vs 40.2%, P < .001), and more likely to receive inotropes (16.9% vs 8.0%, P < .001), but they had similar rates of ACS (41.0% vs 39.4%, P = .69) and prior HF (64.5% vs 70.0%, P = .23). Nadir hemoglobin levels were commonly <10 g/dL in BT patients (92.7% vs 8.0%); 15 BT patients had bleeding complications, of which 10 are major bleeding. Major predictors for BT were ACS (OR 1.85, 95% CI 1.15-2.96), inotropes use (OR 2.36, 95% CI 1.22-4.55), and nadir hemoglobin (OR 0.18 per 1 g/dL increase, 95% CI 0.14-0.22). In-hospital, 30-day, 1-year, and 4-year unadjusted mortality rates were higher for BT patients (10.8% vs 5.2%, P = .02; 11.0% vs 8.5%, P = .27; 39.6% vs 28.5%, P = .03; 69.5% vs 59.5%, P = .01, respectively). However, in 103 propensity-matched pairs (c-statistic 0.97), short-term mortality tended to be lower with BT (8.7% vs 14.6%, P = .20; 9.7% vs 18.4%, P = .08; 38.8% vs 42.7%, P = .59; and 72.8% vs 76.7%, P = .52, respectively). CONCLUSIONS: Acute decompensated HF patients receiving BT had worse clinical features and unadjusted outcomes, but BT per se seemed to be safe and perhaps even beneficial. PMID- 19781428 TI - Red cell distribution width in heart failure: prediction of clinical events and relationship with markers of ineffective erythropoiesis, inflammation, renal function, and nutritional state. AB - OBJECTIVES: The goal of this study was to independently validate the recent observations on the predictive role of red cell distribution width (RDW) for outcomes in chronic heart failure and to provide epidemiologic data on the biological correlates of RDW in heart failure (HF). Understanding the mechanism underlying this observation is unclear, largely hampered by the lack of epidemiologic studies demonstrating factors that are associated with anisocytosis in cardiovascular diseases. METHODS: One hundred ninety-five patients (145 men, 50 women) with systolic HF were enrolled and followed up for a median of 14.5 months. Primary end points were all-cause mortality and hospital readmission due to worsening HF symptoms. A total of 19 clinical chemistry, hematology, and biochemical variables were considered for analysis together with clinical parameters in Cox proportional hazards and multiple regression models. RESULTS: Red cell distribution width was found to be an N-terminal pro-brain natriuretic peptide independent predictor of all-cause mortality (adjusted HR 1.61 per 1 SD increase) in our study. Multiple correlations between biomarkers of ineffective erythropoiesis (serum iron, ferritin, and soluble transferrin receptor levels), inflammation and acute-phase reaction (interleukin-6, soluble tumor necrosis factor (TNF) receptor I and soluble TNF receptor II, C-reactive protein, and prealbumin concentrations), undernutrition (total cholesterol and albumin levels), and renal function were observed. In the multiple regression model, the strongest relationship for RDW was obtained with soluble transferrin receptor, soluble TNF receptor I, soluble TNF receptor II, and total cholesterol. CONCLUSIONS: Here we validate the strong, independent prediction of morbidity and mortality in HF by RDW. The described correlations between RDW and inflammation, ineffective erythropoiesis, undernutrition, and impaired renal function may facilitate the understanding why this marker is associated with adverse outcomes in HF. PMID- 19781429 TI - Coffee consumption and risk of heart failure in men: an analysis from the Cohort of Swedish Men. AB - BACKGROUND: A previous study found that consuming 5 or more cups of coffee per day was associated with increased incidence of heart failure (HF). We sought to evaluate this association in a larger population. METHODS: We measured coffee consumption using food frequency questionnaires among 37,315 men without history of myocardial infarction, diabetes, or HF. They were observed for HF hospitalization or mortality from January 1, 1998, until December 31, 2006, using record linkage to the Swedish inpatient and cause of death registries. Cox proportional hazards models adjusted for age, dietary, and demographic factors were used to calculate incidence rate ratios (RR) and 95% confidence intervals (CIs). RESULTS: For 9 years of follow-up, 784 men experienced an HF event. Compared to men who drank or=5 cups/d (P for trend in RR = .61). CONCLUSIONS: This study did not support the hypothesis that high coffee consumption is associated with increased rates of HF hospitalization or mortality. PMID- 19781430 TI - Prevalence and prognostic significance of incidental cardiac troponin T elevation in ambulatory patients with stable coronary artery disease: data from the Heart and Soul study. AB - BACKGROUND: The significance of troponin elevation and clinical utility of troponin testing in ambulatory patients with coronary artery disease (CAD) have not been examined. We sought to investigate the prevalence and prognostic value of cardiac troponin T (cTnT) elevation in a population with stable CAD. METHODS: We studied 987 patients with stable CAD enrolled in the Heart & Soul study who had plasma cTnT measurements before performing exercise treadmill testing. RESULTS: Of the studied population, 58 patients or 6.2% had detectable cTnT levels, >or=0.01 ng/mL (0.01-0.72 ng/mL). During a mean follow-up period of 4.3 (0.1-6.5) years, 58.6% of participants with detectable cTnT had cardiovascular events compared with 22.5% of those without detectable cTnT (hazard ratio [HR] 3.8, 95% CI 2.6-5.4, P < .001). This association remained strong after adjustment for traditional risk factors and C-reactive protein (HR 2.0, 95% CI 1.3-3.1, P = .002). However, after further adjustment for N-terminal pro-B-type natriuretic peptide and echocardiographic parameters of left ventricular function, cTnT elevation was not an independent predictor of cardiovascular events (HR 1.3, 95% CI, 0.8-2.3, P = .28). CONCLUSIONS: In ambulatory patients with stable CAD, the prevalence of cTnT elevation was 6.2%. Cardiac troponin T elevation detected using the conventional troponin assay was associated with increased risk of adverse cardiovascular outcomes, but its prognostic value was not incremental over N-terminal pro-B-type natriuretic peptide and echocardiographic evidence of cardiac abnormalities. PMID- 19781431 TI - Predictors of 30-day mortality in patients with refractory cardiogenic shock following acute myocardial infarction despite a patent infarct artery. AB - BACKGROUND: Little is known about predictors of survival in patients with persistent shock following acute myocardial infarction (MI) despite a patent infarct artery. METHODS: We examined data from TRIUMPH, a multicenter randomized clinical trial of the nitric oxide synthase inhibitor, L-N(G)-monomethyl arginine, in patients with persistent vasopressor-dependent cardiogenic shock complicating acute MI at least 1 hour after established infarct-related artery patency. Patients who died within 30 days were compared with those who survived. Continuous variables were assessed using the Wilcoxon rank sum and categorical variables using the chi(2) test. Prespecified baseline variables were included in a multivariable logistic regression model to predict mortality. A second model incorporating baseline vasopressors and dosages and a third model including change in systolic blood pressure at 2 hours were also developed. Bootstrapping was used to assess the stability of model variables. RESULTS: Of 396 patients, 180 (45.5%) died within 30 days. Systolic blood pressure (SBP), measured on vasopressor support, and creatinine clearance were significant predictors of mortality in all models. The number of vasopressors and norepinephrine dose were also predictors of mortality in the second model, but the latter was no longer significant when change in SBP at 2 hours was added as a covariate in the third model. CONCLUSIONS: The SBP, creatinine clearance, and number of vasopressors are significant predictors of mortality in patients with persistent vasopressor dependent cardiogenic shock following acute MI despite a patent infarct artery. These prognostic variables may be useful for risk-stratification and in selecting patients for investigation of additional therapies. PMID- 19781432 TI - Characterization and outcomes of women and men with non-ST-segment elevation myocardial infarction and nonobstructive coronary artery disease: results from the Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) quality improvement initiative. AB - BACKGROUND: Women with non-ST-segment elevation myocardial infarction (NSTEMI) who undergo coronary angiography have no obstructive coronary lesions more often than men. Sex-specific characteristics and outcomes of patients without obstructive coronary artery disease (CAD) have not been described previously. METHODS: Using data from NSTEMI patients enrolled in CRUSADE from 2001 to 2005, we evaluated differences in clinical features and in-hospital outcomes between men and women with no obstructive CAD. RESULTS: After excluding patients with missing catheterization and sex data (n = 1,494), previous coronary artery bypass grafting or percutaneous coronary intervention (47,907), catheterization contraindications (n = 6,588), and missing obstructive CAD status (n = 1,565), there were 55,514 patients (68.4%) with NSTE acute coronary syndromes (ACS) who underwent angiography (among women, 62.1% [21,294/34,290], and among men, 73% [34,220/46,875]; P < .001). Among these, a total of 5,538 patients (10.0%) had nonnonobstructive CAD-15.1% (3,221/21,294) of women and 6.8% (2,317/34,220) of men (P < .0001). In patients without obstructive CAD, women were as likely as men to have MI (troponin elevation in 89% vs 87%, P = .37). Women and men were equally likely to have larger troponin elevations (58.9% vs 58.6% with troponin >5x upper limit of normal, P = .69, respectively). In NSTEMI patients without obstructive CAD, in-hospital death (0.6% women vs 0.7% men) and cardiogenic shock (1.0% women vs 0.7% men) were infrequent. CONCLUSIONS: Among NSTE ACS patients undergoing coronary angiography, absence of obstructive CAD is more common in women than men. Although nonobstructive CAD was twice as common among women with NSTEMI, sex differences in characteristics and outcomes were similar to those found with obstructive CAD. Unadjusted in-hospital outcomes of NSTEMI patients with nonobstructive CAD are favorable in both sexes. Whether the underlying pathophysiology of NSTE ACS without documentation of obstructive CAD is different between women and men requires further study. PMID- 19781433 TI - Effectiveness and tolerability of pharmacologic and combined interventions for reducing injection pain during routine childhood immunizations: systematic review and meta-analyses. AB - BACKGROUND: Immunization is the most common cause of iatrogenic pain in childhood. Despite the availability of various analgesics to manage vaccine injection pain, they have not been incorporated into clinical practice. To date, no systematic review has been published on the effectiveness of pharmacologic and combined interventions for reducing injection pain. OBJECTIVES: The objectives of this article were to assess the effectiveness and tolerability of various pharmacologic and combined interventions for reducing the pain experienced by children during immunization. METHODS: MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials were searched to identify randomized controlled trials (RCTs) and quasi-RCTs pertaining to pharmacologic and combined interventions to reduce injection pain in children 0 to 18 years of age using validated child self-reported pain or observer-reported assessments of child pain and distress. We included trials that (1) investigated the effects of pharmacologic interventions (ie, topical local anesthetics, sweet-tasting solutions, vapocoolants, and oral analgesics [acetaminophen or ibuprofen]); (2) compared 2 different analgesic interventions; and (3) evaluated combinations of >or= 2 analgesic interventions, including breastfeeding. Meta-analyses were performed using a fixed-effects model. RESULTS: Thirty-two studies, involving 3856 infants and children 2 weeks to 15 years of age, were included in this systematic review; 23 of these trials were included in meta-analyses. Ten trials, including 1156 infants and children, evaluated topical local anesthetics. In a meta-analysis of 2 trials, including 276 children, child self-reported pain ratings were lower in children who received topical local anesthetics than in those who received a placebo. The standardized mean difference (SMD) was -0.25 (95% CI, -0.49 to -0.01; P = 0.04). The use of topical local anesthetics was associated with less pain than was placebo in 4 trials (527 infants) based on the difference between Modified Behavioral Pain Scale scores (range, 0-10) before and after vaccination: the weighted mean difference (WMD) was -0.79 (95% CI, -1.10 to -0.48; P < 0.001) and the SMD was -0.43 (95% CI, -0.60 to -0.26; P = 0.001). Observer-rated pain, using visual analog scale (VAS) scores (range, 0-100 mm), was significantly lower (WMD, -16.56 mm; 95% CI, -22.11 to -11.01; P < 0.001; and SMD, -0.75; 95% CI, -1.00 to -0.49; P < 0.001). The number needed to treat (NNT) to prevent 1 child from having clinically significant pain, measured using the Faces Pain Scale (FPS; score, >-3), was 3.7 (95% CI, 2.5 to 7.7) from 1 study. Eleven trials (1452 infants and children) evaluated sweet-tasting solutions. In a meta-analysis of 6 studies (665 infants), administration of sucrose with or without non-nutritive sucking (NNS; use of a pacifier) was associated with less pain than no intervention or sterile water with or without NNS; the SMD was -0.56 (95% CI, -0.72 to -0.40; P < 0.001). Total cry duration was lower in infants who received sucrose than in those who received sterile water (WMD, -9.41 sec; 95% CI, -13.18 to -5.64; P < 0.001; and SMD, -0.43; 95% CI, -0.61 to -0.25; P < 0.001). The NNT to prevent 1 child from having clinically significant pain, using the Neonatal Infant Pain Scale (score, >3), was 1.4 (95% CI, 1.0 to 2.5). In 3 trials that evaluated sweet-tasting solutions longitudinally, administration of sucrose or glucose (vs sterile water, with or without NNS) was associated with reduced pain based on cry duration or the University of Wisconsin Children's Hospital Pain Scale (all, P < 0.05). Data were pooled for 2 studies conducted in 100 children who received a spray with a vapocoolant or placebo at the injection site before the procedure. Child self-rated pain (4-point scale) was lower in the group treated with the vapo-coolant (SMD, -0.43; 95% CI, -0.83 to -0.02; P = 0.04); significant heterogeneity was reported for this outcome (chi(2) = 5.51; P = 0.02; I(2) = 82%). In 2 studies (117 children), no significant difference was found between vapocoolants and typical care (no treatment) based on child self reports; significant heterogeneity was reported for this outcome (chi(2) = 9.89; P = 0.02; I(2) = 90%). None of the studies identified in the literature search evaluated oral analgesics (acetaminophen or ibuprofen). Four studies (318 infants and children) compared 2 different analgesic interventions; there was insufficient evidence to suggest superiority of 1 intervention over another. Combinations of >or=2 analgesic interventions were more effective than the individual interventions used alone. Child self-reported pain ratings were combined for 4 studies (350 children); the SMD was -0.52 (95% CI, -0.73 to -0.30; P = 0.001). Data on cry duration were pooled for 3 studies (229 infants and children); the WMD was -18.87 seconds (95% CI, -32.05 to -5.69; P = 0.005). Parent-rated child pain (VAS) scores were combined for 3 studies (365 infants and children); the WMD was -15.66 mm (95% CI, -19.74 to -11.57; P < 0.001). Nurse- or physician-rated child pain (VAS) scores were combined for 3 studies (368 infants and children); the WMD was -17.85 mm (95% CI, -21.43 to -14.28; P < 0.001). In a meta-analysis of 4 studies (474 infants), infants who were breastfed before, during, and after the procedure had less pain than did those who were not breastfed (SMD, -2.03; 95% CI, -2.26 to -1.80; P < 0.001). A meta-analysis of 3 studies (344 infants) found a shorter cry duration for infants who were breastfed than for those who were not breastfed (WMD, -38.00 sec; 95% CI, -42.27 to -33.73; P < 0.001; and SMD, -2.00; 95% CI, -2.27 to -1.73; P < 0.001). The NNT to prevent 1 infant from having clinically significant pain, using the Facial Pain Rating Scale (pain vs no pain), was 7.7 (95% CI, 4.5 to 25.0) from 1 study. CONCLUSION: Topical local anesthetics, sweet-tasting solutions, and combined analgesic interventions, including breastfeeding, were associated with reduced pain during childhood immunizations and should be recommended for use in clinical practice. PMID- 19781434 TI - Inadequate pain management during routine childhood immunizations: the nerve of it. AB - BACKGROUND: Immunization is regarded as one of the most significant medical achievements of all time. Recently, increasing attention has been paid to the pain resulting from routine childhood immunizations. OBJECTIVE: This narrative review summarizes existing knowledge about: (1) the epidemiology of childhood immunization pain; (2) the pain experience of children undergoing immunization; (3) current analgesic practices; (4) barriers to practicing pain management in children; and (5) recommendations for improvements in pain management during immunization. METHODS: We conducted a search of MEDLINE, PsycINFO, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials for primary research and review articles published from inception of the databases through October 2008. Key search terms included immunization, pain, child/infant, vaccine, and intervention. Additional studies were identified through searches of the reference lists in the retrieved articles. No language restrictions were imposed regarding the type of article (eg, full article, abstract) or language. RESULTS: Vaccine injections are the most common iatrogenic procedure performed in childhood and a major source of distress for children (of all ages), their parents, and the participating health care professionals, as well as a direct cause of vaccine nonadherence. In addition, lack of adequate pain management during immunization exposes children to unnecessary suffering and the potential for long-term consequences, such as fear of needles. Numerous pain management strategies are available to reduce vaccine injection pain, including: (1) physical interventions and injection techniques; (2) psychological interventions; and (3) phar-macologic and combined interventions. However, adoption of pain relieving techniques into clinical practice has been suboptimal. The underutilization of pain management strategies can be attributed to a lack of knowledge about pain and effective pain prevention strategies, and the persistence of attitudes about pain that interfere with optimal clinical practices. Current analgesic practices could be improved substantially if all stakeholders involved in immunization (eg, policy makers, practitioners, consumers) participate in efforts to reduce pain. Treating pain during childhood immunization has the potential to reduce distress during the procedure and greatly improve satisfaction with the immunization experience through more positive experiences for children and their families. Other potential benefits include improved adherence to immunization schedules and reduced sequelae of untreated pain. CONCLUSION: Immunization is a global health priority. Medical care can be improved if pain management becomes a routine aspect of the delivery of vaccine injections. PMID- 19781435 TI - Foreword. Conquering pain: the hidden cost of immunization. PMID- 19781436 TI - Physical interventions and injection techniques for reducing injection pain during routine childhood immunizations: systematic review of randomized controlled trials and quasi-randomized controlled trials. AB - BACKGROUND: Vaccine injections are the most common reason for iatrogenic pain in childhood. With the steadily increasing number of recommended vaccinations, there has been a concomitant increase in concern regarding the adequacy of pain management. Physical interventions and injection techniques that minimize pain during vaccine injection offer an advantage over other techniques because they can be easily incorporated into clinical practice without added cost or time. Their effectiveness, however, has not previously been studied using a systematic approach. OBJECTIVE: The purpose of this review was to determine the effectiveness of physical interventions and injection techniques for reducing pain during vaccine injection in children. METHODS: MEDLINE, EMBASE, CINAHL, and the Cochrane Central Register of Controlled Trials databases were searched to identify randomized controlled trials (RCTs) and quasi-RCTs that determined the effect of physical interventions and injection techniques on pain during injection of vaccines in children 0 to 18 years of age, using validated child self-reported pain or assessments of child distress or pain made by others (parent, nurse, physician, observer). We sought to determine the effects of: (1) different formulations of the same vaccine; (2) position of the child during injection; (3) intramuscular versus subcutaneous injection; (4) cooling of the skin at the injection site with ice before injection; (5) stroking the skin or applying pressure close to the injection site before and during injection; (6) order of vaccine injection when 2 vaccines were administered sequentially; (7) simultaneous versus sequential injection of 2 vaccines; (8) vaccine temperature; (9) aspiration before injection; (10) anatomic location of injection; (11) aspects of the needle (gauge, length, angle of insertion, speed of injection); and (12) combinations of these interventions. All meta-analyses were performed using a fixed-effects model. RESULTS: Nineteen RCTs involving 2814 infants and children (0-18 years of age) were included in the systematic review. One study included children >or=16 years and adults (n = 150). Interventions with positive findings are summarized here. In 2 trials that used child self-reports of pain during administration of measles-mumps-rubella vaccine (total, 680 children with complete data), the Priorix vaccine caused less pain than the M-M-R(II) vaccine (standardized mean difference [SMD], -0.66; 95% CI, -0.81 to -0.50; P < 0.001). In 3 trials (404 children), the number needed to treat (NNT) with Priorix to prevent 1 child from crying was 3.2 (95% CI, 2.6-4.2). In 4 trials (281 infants and children), sitting children up or having parents hold infants appeared to cause less pain than the supine position, but the difference was not statistically significant; however, significant heterogeneity was found among the studies, and a qualitative approach was used for data analysis. A benefit was observed for 3 of the 4 studies; the SMD ranged from -0.4 to -0.8 (P < 0.05 for all analyses). The negative findings observed for the remaining study may have been the result of methodologic heterogeneity. Stroking the skin close to the injection site before and during injection reduced pain in 1 trial (66 children; SMD, -0.53; P = 0.03). One study (120 children) found that when diphtheria-polio tetanus-acellular pertussis-Haemophilus influenzae type b (DPTaP-Hib; Pentacel) and pneumococcus (Prevnar) were injected sequentially during the same office visit, observer- and parent-reported pain scores were lower when DPTaP-Hib was injected first (SMD, -0.40 and -0.57, respectively; P .05). Aspiration time was statistically significantly shorter in the torsional mode than in the longitudinal mode for nucleus grades III and IV (P<.05). Total energy was significantly lower in the torsional mode for all nucleus densities (P<.05). The effective coefficient was significantly lower in the longitudinal mode except for nucleus grade I (P<.05). CONCLUSIONS: Torsional phacoemulsification was more effective than longitudinal phacoemulsification in the amount of applied fluid and the quantity of US energy expended. With the torsional method, it was possible to maintain a constant ratio of amount of fluid flow to quantity of US energy used, regardless of nucleus density. PMID- 19781467 TI - Feasibility of spherical aberration correction with aspheric intraocular lenses in cataract surgery based on individual pupil diameter. AB - PURPOSE: To evaluate the feasibility of correcting spherical aberration with aspheric intraocular lenses (IOLs) in cataract surgery based on individual pupil diameter. SETTING: Keio University Hospital, Tokyo, Japan. METHODS: In this prospective study, eyes having cataract surgery were divided into 4 groups based on IOL type: aspheric SN (AcrySof SN60WF), aspheric ZA (Tecnis ZA9003), aspheric PY (Hoya PY-60 AD), and spherical (AcrySof Natural SN60AT). Postoperative higher order aberrations (HOAs) of the cornea and whole eye and the pupil diameter under photopic and mesopic conditions were measured. The HOA was calculated using the individual pupil diameter. The correlation between corneal and ocular spherical aberrations and pupil diameter was evaluated. RESULTS: Each group comprised 30 eyes. Ocular spherical aberrations were significantly lower than corneal spherical aberrations under mesopic conditions in the aspheric SN group, the aspheric ZA group, and the aspheric PY group (P<.05); there was no significant difference between the aberrations in the spherical group. Linear regression showed significant correlations between postoperative corneal and ocular spherical aberrations (beta = 0.39, aspheric SN; beta = 0.38, aspheric ZA; beta = 0.58, aspheric PY; beta = 0.79, spherical). The differences in corneal and ocular spherical aberrations were significantly correlated with pupil diameter in the aspheric IOL groups but not in the spherical IOL group. CONCLUSIONS: The amount of spherical aberration correction by aspheric IOLs varied depending on IOL type and individual pupil diameter. The linear regression equation in this study may make it possible to customize postoperative ocular spherical aberration after cataract surgery. PMID- 19781468 TI - Intraocular lens power requirements for humanitarian missions. AB - PURPOSE: To develop a generalized method to determine an optimum set of intraocular lens (IOL) powers for humanitarian missions. SETTING: Humanitarian missions to Central America, South America, and Southeast Asia. METHODS: Biometric data of adults who had cataract surgery on 2 humanitarian missions were reviewed, and the ideal emmetropic IOL power for each eye was calculated. Using statistical modeling, the number of extra IOLs required at each power to account for natural variation inherent in random population samples was calculated. To limit the total number of IOLs and maximize availability of suitable IOLs for each patient, a tolerance strategy for choosing IOL powers was developed and the ideal proportion of extra IOLs required at each power was empirically determined. RESULTS: Data of 103 patients were reviewed. The mean IOL power was 20.38 diopters (D) +/- 2.32 (SD). Applying a tolerance strategy to accept IOLs with powers 0.5 D below or 1.0 D above the emmetropic IOL power, the number of extra IOLs required at each power was decreased to a fraction of the fourth root of the number of eyes anticipated to require that IOL power. The model predicted that with this strategy, fewer than 2% of all patients would be rejected due to lack of an IOL with a suitable power. CONCLUSIONS: The spreadsheet-based IOL power prediction model calculated an ideal distribution of IOLs to order for humanitarian cataract surgery. It is generalizable to missions of any size and should help planners minimize costs while ensuring excellent refractive outcomes. PMID- 19781469 TI - Impact of written and photographic instruction sheets on patient behavior after cataract surgery. AB - PURPOSE: To evaluate the extent to which patients unnecessarily restrict activities of daily living after routine cataract surgery and to test interventions to increase activity. SETTING: Day treatment center, London, United Kingdom. METHODS: In this nonrandomized interventional clinical study, consecutive patients having routine first-eye sutureless small-incision cataract surgery received 1 of 3 of the following postoperative instructions: standard discharge instructions informing patients that they could continue all activities of daily living (standard group), an additional written sheet specifying 9 activities of daily living that are safe to perform (written group), or an additional sheet with photographs of people performing safe activities of daily living (photo group). Three weeks postoperatively, patients answered a questionnaire on whether they had avoided the activities of daily living and if so, why. RESULTS: Each group comprised 50 patients. Sixty-four percent in the standard group reported avoiding 1 or more activities of daily living. The percentage was 44% in the written group (P = .07) and 30% in the photo group (P = .0013). In all groups, the decision to avoid activities was self-directed more than 50% of the time; it was based on the advice of a nurse in 17% of cases and of a doctor in 4% of cases. CONCLUSIONS: Many patients unnecessarily avoided activities of daily living after cataract surgery. Providing an additional written sheet did not significantly improve this, whereas a photograph sheet did. Better awareness of the safety and rapid rehabilitation after modern cataract surgery is needed in hospitals and primary care centers. PMID- 19781470 TI - Refractive lens exchange with spherical diffractive intraocular lens implantation after hyperopic laser in situ keratomileusis. AB - PURPOSE: To assess the safety, efficacy, and predictability in eyes that had refractive lens exchange (RLE) with implantation of a spherical diffractive intraocular lens (IOL) after previous hyperopic laser in situ keratomileusis (LASIK). SETTING: Fernandez-Vega Ophthalmological Institute, Oviedo, Spain. METHODS: This prospective study evaluated eyes that had RLE and implantation of an AcrySof ReSTOR SN60D3 IOL after hyperopic LASIK. Uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), uncorrected near visual acuity (UNVA), distance-corrected near visual acuity (DCNVA), and residual refractive errors were analyzed using vector analysis and recorded preoperatively and 6 months postoperatively. RESULTS: The study evaluated 41 eyes of 23 patients. The mean UDVA was 0.189 logMAR +/- 0.175 (SD) preoperatively and 0.113 +/- 0.101 logMAR 6 months postoperatively (P = .009) and the mean CDVA, 0.049 +/- 0.071 logMAR and 0.046 +/- 0.063 logMAR, respectively (P = .44). At 6 months, the efficacy index was 0.87 and the safety index, 1.00. The mean UNVA was 0.014 +/- 0.026 logMAR, with an efficacy index of 1.00. There were no differences in corrected near visual acuity between preoperatively (with spectacle addition) and postoperatively (P = .3); the safety index was 1.01. All eyes were within +/-1.25 diopters (D) of the targeted refraction and 73.17% were within +/-0.50 D. The mean postoperative spherical equivalent was -0.064 +/- 0.513 D. CONCLUSION: Implantation of a spherical multifocal IOL after hyperopic LASIK was safe, effective, and predictable. PMID- 19781471 TI - Postoperative rotation of a 3-piece loop-haptic acrylic intraocular lens. AB - PURPOSE: To assess the rotational stability of the AcrySof MA60BM acrylic intraocular lens (IOL) with and without aspiration of residual lens epithelial cells (LECs). SETTING: Stoke Mandeville Hospital, Aylesbury, United Kingdom. METHODS: Routine phacoemulsification was performed with (Group A) or without (Group B) aspiration of residual LECs (random allocation). The baseline position of the IOL was determined from a video frame acquired at the conclusion of surgery. Postoperative IOL position was documented using digital retroillumination images at 2 weeks and 3 months. Early IOL rotation (surgery to 2 weeks postoperatively) was graded as mild (<10 degrees), moderate (10 to 30 degrees), or severe (>30 degrees) by semiobjective comparison of the images. Late IOL rotation (2 weeks to 3 months) was measured more precisely using purpose designed software. RESULTS: Group A had incomplete aspiration of residual LECs. The only between-group demographic difference was significantly more men in Group A than in Group B (P<.05). There were no cases of severe early IOL rotation. Mild and moderate early rotation occurred in 91.5% of eyes and 8.5% of eyes, respectively. The mean late rotation was 0.03 degrees +/- 3.06 (SD) (range 7.8 to -8.7 degrees). Aspiration of residual LECs made no statistical difference in early or late rotation (P>.05). Between 2 weeks and 3 months, counterclockwise rotation occurred in 50% of all cases. CONCLUSIONS: Postoperative rotation of the loop-haptic IOL was stable; LEC clearance did not adversely affect performance. The tendency toward counterclockwise rotation would not preclude good performance of a toric model of the IOL. PMID- 19781472 TI - Dry eye associated with laser in situ keratomileusis: Mechanical microkeratome versus femtosecond laser. AB - PURPOSE: To compare the incidence of laser in situ keratomileusis (LASIK) associated dry eye and the need for postoperative cyclosporine A treatment after flap creation with a femtosecond laser and a mechanical microkeratome. SETTING: Cole Eye Institute, Cleveland, Ohio, USA. METHODS: Eyes were randomized to flap creation with an IntraLase femtosecond laser (30 or 60 kHz) or a Hansatome microkeratome. No patient had signs, symptoms, or treatment of dry eye preoperatively. Flap thickness was determined by intraoperative ultrasonic pachymetry. Slitlamp assessments of the cornea and need for postoperative dry-eye treatment were evaluated preoperatively and 1 month postoperatively. RESULTS: The flap was created with the femtosecond laser in 113 eyes and with the microkeratome in 70 eyes. The difference in mean central flap thickness between the femtosecond group (111 mum +/- 14 [SD]) and the microkeratome group (131 +/- 25 mum) was statistically significant (P<.001). The incidence of LASIK-associated dry eye was statistically significantly higher in the microkeratome group (46%) than in the femtosecond group (8%) (P<.0001), as was the need for postoperative cyclosporine A treatment (24% and 7%, respectively) (P<.01). In the microkeratome group, there was no correlation between thick flaps and a higher incidence of LASIK-induced dry eye. CONCLUSIONS: Eyes with femtosecond flaps had a lower incidence of LASIK-associated dry eye and required less treatment for the disorder. In addition to neurotrophic effects from corneal nerve cutting, other factors may be important because no correlation was found between flap thickness (or ablation depth) and the incidence of LASIK-induced dry eye. PMID- 19781473 TI - Biomechanical and morphological corneal response to placement of intrastromal corneal ring segments for keratoconus. AB - PURPOSE: To evaluate the biomechanical and morphological changes in keratoconic corneas after Intacs intrastromal corneal ring segment (ICRS) implantation. SETTING: Department of Ophthalmology, National Reference Center for Keratoconus, Bordeaux University, Bordeaux, France. METHODS: Keratoconic eyes were retrospectively analyzed after ICRS implantation; preoperative and 6-month postoperative evaluation were done using the Ocular Response Analyzer (ORA) and the Orbscan II topographer. Biomechanical parameters included corneal hysteresis (CH), the corneal resistance factor (CRF), and other parameters extracted from the signal curves. Morphological parameters included simulated keratometry and the cone location magnitude index from the axial map (aCLMI) and tangential map (tCLMI). Parameters were extracted using software designed to read and process topographic maps. RESULTS: There were no significant differences between preoperatively and postoperatively in mean CH (7.7 mm Hg +/- 1.4 [SD] versus 7.4 +/- 1.4 mm Hg) or mean CRF (6.6 +/- 1.8 mm Hg versus 6.1 +/- 1.4 mm Hg). Only 2 ORA signal parameters were significantly different. Topographic parameters with significant decreases were minimum central keratometry (K) (mean change -5.8 +/- 2.9 diopters [D]) (P<.001), minimum central K (mean change -5.8 +/- 2.3 D) (P<.001), mean aCLMI (9.6 +/- 2.7 preoperatively versus 7.7 +/- 2.5 postoperatively) (P<.009), and mean tCLMI (18.9 +/- 2.8 versus 12.9 +/- 4.4) (P<.002). The only significant correlation between biomechanical and topographic parameters was postoperative ORA infrared signal peak 1 and postoperative aCLMI. CONCLUSIONS: Intrastromal corneal ring implantation significantly decreased corneal curvature, with preoperative values predicting magnitude of change. However, it did not alter the viscoelastic biomechanical parameters of CH and CRF. PMID- 19781474 TI - Long-term follow-up of intrastromal corneal ring segments in keratoconus. AB - PURPOSE: To report the long-term follow-up of Ferrara intrastromal corneal ring segment (ICRS) implantation for the management of keratoconus. SETTING: Private clinic, Belo Horizonte, Brazil. METHODS: This study comprised patients with keratoconus who completed at least 5 years of follow-up. One or 2 ICRS were inserted in the cornea, embracing the keratoconus area. Statistical analysis included preoperative and postoperative uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), and keratometry (K) values. RESULTS: Thirty-five eyes of 28 patients were evaluated. The mean UDVA improved from 0.15 preoperatively to 0.31 postoperatively and the mean CDVA, from 0.41 to 0.62, respectively; the increases were statistically significant (P = .003 and P = .002, respectively). Corneal topography showed corneal flattening in all eyes. The mean minimum K value decreased from 48.99 D preoperatively to 44.45 D postoperatively and the mean maximum K value, from 54.07 D to 48.09 D, respectively; the decreases were statistically significant (both P = .000). CONCLUSIONS: Five years after ICRS implantation, the UDVA and CDVA were improved in eyes with keratoconus. There was significant postoperative corneal flattening that remained stable over the follow-up period. PMID- 19781475 TI - Postoperative changes in intraocular pressure and corneal biomechanical metrics Laser in situ keratomileusis versus laser-assisted subepithelial keratectomy. AB - PURPOSE: To compare intraocular pressure (IOP) and corneal biomechanical metric changes after myopic laser in situ keratomileusis and laser-assisted subepithelial keratectomy (LASEK). SETTING: Private practice, St. Louis, Missouri, USA. METHODS: The IOP, corneal biomechanical markers, and Ocular Response Analyzer (ORA) waveform parameters were prospectively measured preoperatively and after 6 months in ablation-matched myopic LASIK eyes (mLASIK group) and LASEK eyes (mLASEK group). A retrospectively identified cohort of low myopia LASIK eyes (lmLASIK group) and fellow unoperated eyes (control) were tested at a single postoperative visit. Statistical analysis compared the percentage change in parameters between groups. RESULTS: The mean postoperative Goldmann tonometry and Goldmann-correlated IOPs were statistically significant reduced in the mLASIK and mLASEK groups (P<.03). Corneal-compensated IOP, but not Pascal dynamic contour tonometry, was significantly reduced in the mLASIK group. The percentage change in corneal hysteresis (CH) and the corneal resistance factor (CRF) was greater in the mLASIK and mLASEK groups than in the lmLASIK group. The greatest percentage change in ORA signal parameters was in the mLASIK group and the smallest change, in the mLASEK group. On multivariate linear regression, the residual stromal bed was predictive of the percentage change in CH and CRF (P<.001). CONCLUSIONS: Microkeratome flap creation combined with deeper stromal ablation had the greatest effect on the ORA applanation signal, indicating corneas that are more readily deformable. The smallest change in the signal was in the group without a stromal flap (LASEK). There was a complex interaction between ablation location and depth that affected corneal biomechanical properties. PMID- 19781476 TI - Excimer laser correction of moderate to high astigmatism with a non-wavefront guided aberration-free ablation profile: Six-month results. AB - PURPOSE: To evaluate the postoperative clinical outcomes and higher-order aberrations (HOAs) in eyes with astigmatism greater than 2.00 diopters (D) that had laser in situ keratomileusis (LASIK) using a non-wavefront-guided aberration free ablation profile. SETTINGS: Private practice. METHODS: This retrospective study evaluated the 6-month results of LASIK for astigmatism greater than 2.00 D. Standard examinations and preoperative and postoperative wavefront analyses were performed. Aspheric treatments with a non-wavefront-guided ablation profile were planned using software integrated into the Amaris flying-spot excimer laser system, which was used to perform the ablations. The LASIK flaps were created using an LDV femtosecond laser. Clinical outcomes were predictability, refractive outcomes, safety, efficacy, and wavefront aberration. RESULTS: At 6 months, 84% of the 50 eyes evaluated achieved 20/20 or better uncorrected distance visual acuity (UDVA) and 40% achieved 20/16 or better UDVA. Forty-four percent of eyes were within +/-0.25 D of the attempted astigmatic correction, and 78% were within +/-0.50 D. The mean SE was -0.12 D +/- 0.25 (SD) and the mean astigmatism, 0.50 +/- 0.26 D. Corrected distance visual acuity (CDVA) improved in 36% of eyes; 4% of eyes lost 1 line of CDVA. The predictability slope for astigmatism was 0.97 and the intercept, -0.15 D. There were no clinically relevant changes in any aberration metric from preoperatively to postoperatively. CONCLUSIONS: Excimer laser LASIK using a non-wavefront-guided aberration-free ablation profile yielded excellent visual outcomes. The preoperative astigmatism was reduced to subclinical values with no clinically relevant induction of HOA. PMID- 19781477 TI - Heat production: Longitudinal versus torsional phacoemulsification. AB - PURPOSE: To compare the heat production of longitudinal versus torsional phacoemulsification under strict laboratory test conditions. SETTING: Department of Ophthalmology, David Geffen School of Medicine at UCLA, and Jules Stein Eye Institute, Los Angeles, California, USA. METHODS: Two Infiniti phacoemulsification handpieces were inserted into silicone test chambers filled with a balanced salt solution and imaged serially using a thermal camera. Incision compression was simulated by suspending 25.3 g weights from the silicone chambers. To simulate occlusion of the phacoemulsification tip, the aspiration line was clamped. Peak temperatures were measured 0, 10, 30, 60, and 120 seconds after the commencement of continuous ultrasound power. The 2 handpieces, operating exclusively in longitudinal or torsional modes, were compared 3 ways: (1) using the same power displayed on the instrument console, (2) using identical stroke lengths, and (3) using the same applied energy, a product of stroke length and frequency. RESULTS: For all 3 comparisons, torsional phacoemulsification resulted in lower temperatures at each time point. At the same displayed power setting, the scenario most familiar to cataract surgeons, longitudinal phacoemulsification elevated temperatures up to 41.5 degrees C more than torsional phacoemulsification. CONCLUSIONS: Torsional phacoemulsification generated less heat than longitudinal phacoemulsification in all 3 comparison tests. Lower operating temperatures indicate lower heat generation within the same volume of fluid, and this may provide additional thermal protection during cataract surgery. PMID- 19781478 TI - Experimental setup to determine the pulse energies and radiant exposures for excimer lasers with repetition rates ranging from 100 to 1050 Hz. AB - PURPOSE: To evaluate the feasibility of surface profiling for central ablation depth measurements and determine experimentally the required single-pulse energies and radiant exposures to achieve equivalent central ablation depths on bovine corneas for a myopic correction of -6.00 diopters (optical zone 6.5 mm) performed with laser repetition rates ranging from 100 to 1050 Hz. SETTING: Institute for Refractive and Ophthalmic Surgery, Zurich, Switzerland, and WaveLight AG, Erlangen, Germany. METHODS: Freshly enucleated bovine corneas and poly(methyl methacrylate) (PMMA) plates were photoablated. The shot pattern for the myopic correction was maintained during all experiments; the pulse laser energy was adjusted to achieve equal ablation depths for all repetition rates. Pulse energy, radiant exposure, and pulse duration were monitored to determine the required laser parameter. RESULTS: The variations (standard deviation) of the profile measurements were +/-0.45 microm or less for PMMA and +/-1.50 microm or less for bovine corneas. Measurements with bovine corneas should be performed within 3 minutes or less to avoid larger variations in profile measurements. Increasing the repetition rate from 100 Hz to 1050 Hz required an increase in peak radiant exposure from 400 mJ/cm(2) to 530 mJ/cm(2) to achieve equal ablation for the myopic correction. The required increase in the mean radiant exposure ranged from 190 to 260 mJ/cm(2). CONCLUSIONS: Higher-repetition-rate excimer lasers require increased radiant exposure. Further experimental studies should be performed to determine the relevance of spatial and temporal spot positioning, ablation-plume dynamics, and temperature increases during high-repetition-rate laser treatments. PMID- 19781479 TI - Perioperative management of anticoagulated patients having cataract surgery: National audit of current practice of members of the Royal College of Ophthalmologists. AB - An 11-item questionnaire was mailed to 891 consultant members of the Royal College of Ophthalmologists (RCOphth) to audit compliance with RCOphth guidelines for perioperative management of anticoagulated patients having cataract surgery. Four hundred ninety-nine questionnaires were analyzed. The results showed that 29.5% of respondents adhered to all aspects of RCOphth guidelines; that is, they checked the international normalized ratio (INR) preoperatively, continued warfarin, operated within the desired therapeutic INR range for the condition that warfarin was being used to treat (as set by the treating physician), and considered sub-Tenon or topical anesthesia in anticoagulated patients. PMID- 19781480 TI - Primary anterior chamber intraocular lens for the treatment of severe crystalline lens subluxation. AB - Subluxated cataractous and clear lenses are commonly treated by limbal or pars plana lensectomy followed by primary or secondary intraocular lens (IOL) implantation. Adjunctive capsular prosthetic devices have facilitated lens removal and IOL centration in these challenging cases but have also added complexity and potential complications to the procedure. Although crystalline lens extraction may be required to clear the visual axis in mild to moderate lens subluxations, we propose insertion of a primary anterior chamber IOL without lens extraction in severe subluxations when the eye is optically aphakic or can be made functionally aphakic following neodymium:YAG laser zonulysis. Two cases demonstrating this approach are presented. PMID- 19781481 TI - Culture-positive endophthalmitis after implantation of intraocular Collamer lens. AB - We report a case of culture-positive bacterial endophthalmitis following implantation of a Staar intraocular Collamer lens (ICL). The patient presented 4 days after uneventful sutureless surgery with decreased visual acuity, redness, and photosensitivity. Inflammation increased over the next 24 hours, which prompted a tap for culture and intravitreal injection of antibiotic agents. Vitreous culture was positive for coagulase-negative Staphylococcus epidermidis. One year postoperatively, the uncorrected distance visual acuity was 20/20; persistent anterior vitreous opacities were the only observable sequelae. Bacterial endophthalmitis is a potential complication of ICL implantation. It can be successfully diagnosed and treated if a high degree of suspicion is maintained and if appropriate diagnostic and treatment modalities are used. PMID- 19781482 TI - Straylight measurements before and after removal of epithelial ingrowth. AB - In 3 eyes with epithelial ingrowth after laser in situ keratomileusis, straylight was measured before and after the ingrowth was removed. In 2 eyes of 1 patient, epithelial ingrowth reached the pupillary axis. Straylight decreased (improved) significantly after ingrowth removal: a 3.6-fold decrease in the right eye and a 10-fold decrease in the left eye. The uncorrected distance visual acuity (UDVA) improved from 0.25 (20/80) in both eyes to 1.0 (20/20) and 0.8 (20/25), respectively. In 1 eye of another patient, from which epithelial ingrowth was removed to prevent flap melting and distortion, the pupillary opening was not obscured and no significant change in straylight was found. The UDVA improved from 0.32 (20/60) to 1.0 (20/20) after the ingrowth was removed. An increase in straylight can be a significant complication of epithelial ingrowth. After the interlamellar space is cleared, the improvement in straylight is several factors larger than the gain in UDVA. PMID- 19781483 TI - Overcorrection after femtosecond-assisted astigmatic keratotomy in a post Descemet-stripping automated endothelial keratoplasty patient. PMID- 19781484 TI - Toric intraocular lens versus opposite clear corneal incisions to correct astigmatism in eyes having cataract surgery. PMID- 19781485 TI - Consultation section. Cataract surgical problem. PMID- 19781495 TI - Cataract surgery in infant eyes with microphthalmos. PMID- 19781497 TI - Effectiveness of daily use of brimonidine as antimydriatic agent. PMID- 19781499 TI - The dysvascular and diabetic patient: Update in diagnosis, treatment and rehabilitation. Foreword. PMID- 19781500 TI - The dysvascular and diabetic patient: Update in diagnosis, treatment and rehabilitation. Preface. PMID- 19781501 TI - The prevention of foot ulceration in diabetic patients. AB - Diabetic foot ulcerations are a costly and common public health challenge. Although several organizations have emphasized the need to increase awareness of this problem and called health care providers to action to decrease the incidence of ulceration and amputation, there is limited evidence regarding what interventions are best suited to accomplish this goal. This article reviews the pathogenesis, risk factors, and current interventions that have been studied for the prevention of foot ulceration. Preventive measures with evidence for decreasing incidence of ulceration include patient education, offloading abnormal pressures with foot orthotics, and thermal monitoring. PMID- 19781502 TI - Update in diagnosis and treatment of diabetic foot infections. AB - Foot infections are a major cause of morbidity and mortality in diabetics. Evaluation of diabetic foot infections often requires clinical, radiologic, laboratory, and microbiologic assessment. Osteomyelitis has a profound impact on the prognosis and management of these infections, and diagnosis can be difficult; the gold standard remains bone biopsy. Despite a panoply of studies, the optimal management of diabetic foot infections remains poorly understood. Antibiotics, surgery, rehabilitation and/or off-loading, and glycemic control remain the cornerstones of treatment; alternative therapies remain largely unproven. PMID- 19781503 TI - Update on peripheral arterial disease and claudication rehabilitation. AB - The prevalence of peripheral arterial disease is high and will continue to grow with our aging population. It is often under diagnosed and under treated due to a general lack of awareness on the part of the patient and the practitioner. The evidence-base is growing for the optimal medical management of the patient with peripheral arterial disease; in parallel, endovascular revascularization options continue to improve. Exercise training for claudication rehabilitation plays a critical role. Comprehensive care of the peripheral arterial disease patient focuses on the ultimate goals of improving quality of life and reducing cardiovascular morbidity and mortality. PMID- 19781504 TI - Clinical features and electrodiagnosis of diabetic peripheral neuropathy in the dysvascular patient. AB - Diabetic peripheral neuropathy (DPN) is a common disorder that can lead to limb loss and death. Up to 50% of DPN patients can be asymptomatic. This fact contributes to making DPN the leading cause of lower limb amputation. The degree of heterogeneity in the clinical manifestations of DPN makes diagnosing this condition difficult. This article reviews the characteristics, diagnosis, electrodiagnosis, classification, pathogenesis, and treatment of DPN. PMID- 19781505 TI - Pre-operative rehabilitation evaluation of the dysvascular patient prior to amputation. AB - Lower-extremity amputation secondary to dysvascular disease, including diabetes and peripheral vascular disease, is a major health problem in the United States. Due to the increased comorbidities in this patient population, pre-operative rehabilitation evaluation by a multidisciplinary team is crucial to ensure optimal patient outcomes. This article discusses the key factors that may affect functional outcomes in this patient population and outlines important history and physical examination components that should be evaluated pre-operatively. PMID- 19781506 TI - Prosthetic rehabilitation issues in the diabetic and dysvascular amputee. AB - Evaluation and management of diabetic and dysvascular patients with lower limb amputation begins with a thorough history and physical examination. A pre prosthetic and prosthetic program of physical therapy, pain management, psychological assessment, and education helps patients resume functional mobility and gain acceptance of the limb loss. Physicians and prosthetic teams work together to design and prescribe the most appropriate prosthetic device for patients to reach maximal functional level. Careful monitoring of patients and a full understanding of patients' medical conditions help avoid complications and falls during rehabilitation. Long-term follow-up is necessary to assess fit and function of prosthetic devices. PMID- 19781507 TI - Psychosocial factors in chronic pain in the dysvascular and diabetic patient. AB - Dysvascular and diabetic patients are faced with high rates of chronic pain as a consequence of numerous secondary sequelae, including diabetic neuropathy and limb loss. Researchers and scientists have put forth a tremendous amount of effort to understand the complex nature of pain in this population of individuals, as well as others with chronic pain secondary to illness and injury. The emergent understanding of anatomy and sensory physiology within the past century has fueled an initial focus of understanding pain from a purely neurologic and biochemical perspective. Over the past few decades, the field has moved toward an understanding of pain as a process involving the dynamic interaction of biologic, psychological, behavioral, and social variables. This article provides a brief overview of several psychosocial processes, cognitive, affective, and behavioral, that have emerged as influential to the experience, impact, and treatment of pain. PMID- 19781508 TI - Updates in cardiac rehabilitation. AB - Cardiac rehabilitation is one of the most effective treatments for secondary prevention for patients with heart disease. In particular, exercise training confers a variety of clinical benefits that leads to an increase in functional ability and a decrease in mortality in patients with a variety of cardiac diagnoses. Although they require a long-term commitment, standard training programs are safe and cost-effective. Despite its proven benefit, however, cardiac rehabilitation is underused in the United States. PMID- 19781509 TI - Cardiovascular disease in persons with spinal cord dysfunction-an update on select topics. AB - Cardiovascular disease (CVD) is a leading cause of death in people with spinal cord injury (SCI), yet little is known about the prevalence of the disorder and how risk factors for CVD, such as dyslipidemia, diabetes, and obesity, differ compared with the able-bodied population. Additionally, limb loss, an underappreciated topic in the setting of SCI, is a frequent complication of SCI, and may be related to CVD, either directly, as undiagnosed peripheral vascular disease, or indirectly, as a consequence of diabetes or obesity. This article briefly reviews the topics of dyslipidemia, diabetes, and obesity in SCI and discusses the management of limb loss for individuals with SCI. PMID- 19781510 TI - Introduction. PMID- 19781511 TI - From the page to the clinic: Implementing new National Asthma Education and Prevention Program guidelines. AB - The National Asthma Education and Prevention Program's (NAEPP) revised guidelines, the Expert Panel Report 3 (EPR-3), published in 2007, represents a shift in the approach to asthma: the EPR-3 recommends that clinicians think of asthma as a chronic disease with an inflammatory basis. EPR-3 guidelines also represent a shift in the treatment paradigm for asthma in line with the shift in approach: although symptomatic relief is still necessary, the primary goal of asthma treatment is now long-term control, with the aim of minimizing exacerbation frequency and severity and limiting possible permanent airway damage that can result from frequent asthma exacerbations. To help clinicians implement the new EPR-3 guidelines into daily practice, the NAEPP's Guidelines Implementation Panel has identified 6 key action-focused recommendations. This article describes those recommendations and the evidence supporting them. PMID- 19781512 TI - Clinical importance of identifying immunoglobulin E-mediated disease in patients with asthma. AB - The strong association between allergy and asthma is well documented; however, few practitioners-even asthma specialists-accurately estimate the percentage of patients with asthma who have clinically relevant allergies. Because allergen exposure can prompt airway inflammation, trigger asthma exacerbations, and possibly lead to negative health outcomes for patients with asthma, identifying allergies and immunoglobulin E (IgE)-mediated disease in patients with persistent asthma is crucial. Updated Expert Panel 3 asthma guidelines from the National Asthma Education and Prevention Program reinforce the need for clinicians to identify allergic sensitivities in patients with persistent asthma and determine their clinical relevance. Allergy testing can be useful in educating the patient with IgE-mediated asthma about the need for allergic trigger avoidance and can help determine optimal therapy for patients with concomitant asthma and allergy. Implementing this guideline recommendation, however, requires active clinical engagement. Data from a recent observational study indicate that there may be a substantial gap between guideline recommendations and actual clinical practice. These data also suggest that when clinicians participate in education about the role of IgE in asthma and begin testing their patients for allergy, the recognition of allergies among patients with asthma dramatically increases. PMID- 19781513 TI - A 12-year-old student athlete with exercise-induced bronchospasm: Getting Jenny B. back on track: A case 360 degrees patient presentation. AB - Jenny B. is an active 12-year-old white female who recently stopped participating in junior high school track because of respiratory symptoms she experiences while running. On presentation to her pediatrician's office for a consultation, it immediately became apparent that she was anxious to rejoin her team to compete. This article will navigate through a patient case and explore multiple clinical approaches to exercise-induced broncho-spasm from diagnosis to treatment. As clinicians, our goal is to partner with all patients who experience asthma or respiratory symptoms, enabling them to have a life without limitations. Let us review Jenny B.'s case and examine what might be the best approach to get her back on track. PMID- 19781514 TI - Using long-acting beta2-agonists safely: What will be the impact of the US Food and Drug Administration's panel recommendations? AB - The US Food and Drug Administration (FDA) has launched an investigation into the safety of long-acting beta(2)-agonists (LABAs). While the impact of this investigation is yet to be seen, clinicians should be circumspect in the use of these agents and prescribe them according to the recommendations of current asthma guidelines, informing patients and their caretakers about potential risks. As clinical trials attempt to address the question of whether LABAs are safe for use in pediatric and adult populations, current data provide no clear answers. A special hearing of the FDA's Pulmonary-Allergy Drugs Advisory Committee, Drug Safety and Risk Management Advisory Committee, and Pediatric Advisory Committee attempted to seek consensus on the matter as it reviewed the results of controlled clinical trials and conducted a benefit:risk assessment of LABAs to make recommendations on their safety. PMID- 19781515 TI - Inhaled anticholinergics and the long-term treatment of chronic obstructive pulmonary disease: Weighing benefits and risks. AB - A meta-analysis recently published in the Journal of the American Medical Association found an increased risk of nonfatal myocardial infarction, stroke, and cardiovascular death associated with inhaled anticholinergic use in patients with chronic obstructive pulmonary disease (COPD); however, inherent limitations in the meta-analysis and contradictory results from other studies cast uncertainty onto its conclusions. For example, the Understanding Potential Long term Impacts on Function with Tiotropium trial, a large, prospective, 4-year outcome study in nearly 6000 patients with COPD, did not demonstrate an increase in cardiovascular events with anticholinergic therapy. Until more data are available, clinicians should always carefully weigh safety and efficacy data and help patients make informed decisions about their COPD care. PMID- 19781516 TI - Hydrofluoroalkane mandate in effect January 1, 2009: Switch from chlorofluorocarbon- to hydrofluoroalkane-propelled inhalers requires active transition. AB - The manufacture, sale, and distribution of chlorofluorocarbon-propelled albuterol metered-dose inhalers ceased as of December 31, 2008. Clinicians should actively transition patients to currently available hydrofluoroalkane-propelled devices, providing concise education and instruction for using the newer devices. PMID- 19781517 TI - Should clinicians routinely determine rhinitis subtype on initial diagnosis and evaluation? A debate among experts. AB - Rhinitis is one of the most prevalent conditions affecting Americans today. Twenty to 40 million Americans (10%-30% of adults and up to 40% of children) are estimated to have allergic rhinitis. In recent decades, its prevalence in Western societies has increased dramatically, and studies from around the world are reporting similar trends. Although studies have traditionally reported a 3:1 ratio of allergic to nonallergic rhinitis, recent data suggest that as many as 87% of patients with rhinitis may have mixed rhinitis, a combination of both allergic and nonallergic rhinitis. Untreated or inappropriately managed rhinitis can significantly affect a patient's quality of life and ability to perform activities of daily living. It is often associated with concomitant conditions, such as fatigue, headache, sleep disturbance, cognitive impairment, and respiratory conditions, complicated by rhinitis, including asthma and sinusitis. It is a significant cause of morbidity, health care expenditure, reduced work productivity, and absences from school. According to the recently released updated practice parameters, The Diagnosis & Management of Rhinitis, rhinitis is characterized by the presence of one or more of the following nasal symptoms: Congestion, Rhinorrhea (anterior and posterior), Sneezing, Itching. Inflammation is normally associated with rhinitis, but certain subtypes of the disease, such as vasomotor (increasingly known as chronic idiopathic rhinitis) or nonallergic rhinitis and atrophic rhinitis, are not predominantly inflammatory. The diagnosis of rhinitis may appear to be a fairly straightforward undertaking; however, rhinitis is composed of numerous subtypes and etiologies, and differentiating them can be a challenge for primary care practitioners. Further complicating matters is the fact that many patients have both an allergic and a nonallergic component to their rhinitis. Whether or not identification of rhinitis subtype should be an integral component of initial diagnosis remains an area of controversy. While standard treatment for allergic and nonallergic rhinitis is often the same, certain subtypes of the disease do not respond well to the usual first-line treatments for allergic rhinitis. Identification of subtype, therefore, can potentially have important implications for treatment choice. In the following section, we present a discussion between 2 members of the Respiratory & Allergic Disease (RAD) Foundation, Thomas B. Casale, MD, and Michael S. Blaiss, MD. Drs. Casale and Blaiss debate the question, "Should clinicians routinely determine rhinitis subtype on initial diagnosis and evaluation?" Each expert was randomly assigned a position to take: Dr. Casale's views represent the "pro" argument while Dr. Blaiss was asked to speak to the "con" argument. The debate concludes with a synthesis of their arguments and final points, including important takeaway messages for the primary care practitioner. PMID- 19781518 TI - Slight activation of nuclear factor kappa-B is associated with increased hepatic stellate cell apoptosis in human schistosomal fibrosis. AB - To investigate the relationship between NF-kappaB activation and hepatic stellate cell (HSC) apoptosis in hepatosplenic schistosomiasis, hepatic biopsies from patients with Schistosoma mansoni-induced periportal fibrosis, hepatitis C virus induced cirrhosis, and normal liver were submitted to alpha-smooth muscle actin (alpha-SMA) and NF-kappaB p65 immunohistochemistry, as well as to NF-kappaB Southwestern histochemistry and TUNEL assay. The numbers of alpha-SMA-positive cells and NF-kappaB- and NF-kappaB p65-positive HSC nuclei were reduced in schistosomal fibrosis relative to liver cirrhosis. In addition, increased HSC NF kappaB p65 and TUNEL labeling was observed in schistosomiasis when compared to cirrhosis.These results suggest a possible relationship between the slight activation of the NF-kappaB complex and the increase of apoptotic HSC number in schistosome-induced fibrosis, taking place to a reduced HSC number in schistosomiasis in relation to liver cirrhosis. Therefore, the NF-kappaB pathway may constitute an important down-regulatory mechanism in the pathogenesis of human schistosomiasis mansoni, although further studies are needed to refine the understanding of this process. PMID- 19781519 TI - Purification and characterization of a stable oxygen-evolving Photosystem II complex from a marine centric diatom, Chaetoceros gracilis. AB - Oxygen-evolving Photosystem II particles (crude PSII) retaining a high oxygen evolving activity have been prepared from a marine centric diatom, Chaetoceros gracilis (Nagao et al., 2007). The crude PSII, however, contained a large amount of fucoxanthin chlorophyll a/c-binding proteins (FCP). In this study, a purified PSII complex which was deprived of major components of FCP was isolated by one step of anion exchange chromatography from the crude PSII treated with Triton X 100. The purified PSII was still associated with the five extrinsic proteins of PsbO, PsbQ', PsbV, Psb31 and PsbU, and showed a high oxygen-evolving activity of 2135 micromol O2 (mg Chl a)(-1) h(-1) in the presence of phenyl-p-benzoquinone which was virtually independent of the addition of CaCl2. This activity is more than 2.5-fold higher than the activity of the crude PSII. The activity was completely inhibited by 3-(3,4)-dichlorophenyl-(1,1)-dimethylurea (DCMU). The purified PSII contained 42 molecules of Chl a, 2 molecules of diadinoxanthin and 2 molecules of Chl c on the basis of two molecules of pheophytin a, and showed typical absorption and fluorescence spectra similar to those of purified PSIIs from the other organisms. In this study, we also found that the crude PSII was significantly labile, as a significant inactivation of oxygen evolution, chlorophyll bleaching and degradation of PSII subunits were observed during incubation at 25 degrees C in the dark. In contrast, these inactivation, bleaching and degradation were scarcely detected in the purified PSII. Thus, we succeeded for the first time in preparation of a stable PSII from diatom cells. PMID- 19781520 TI - NMR structure of the transmembrane and cytoplasmic domains of human CD4 in micelles. AB - The human cluster determinant 4 (CD4) is a type I transmembrane glycoprotein involved in T-cell signalling. It is expressed primarily on the surface of T helper cells but also on subsets of memory and regulatory T lymphocytes (CD4(+) cells). It serves as a coreceptor in T-cell receptor recognition of MHC II antigen complexes. Besides its cellular functions, CD4 serves as the main receptor for human immunodeficiency virus type I (HIV-1). During T-cell infection, the CD4 extracellular domain is bound by HIV-1 gp120, the viral surface glycoprotein, which triggers a number of conformational changes ultimately resulting in virion entry of the cell. Subsequently, CD4 is downregulated in infected cells by multiple strategies that involve direct interactions of the HIV-1 proteins VpU and Nef with the cytoplasmic part of CD4. In the present work, we describe the NOE-based solution structure of the transmembrane and cytoplasmic domains of the cystein-free variant of CD4 (CD4mut) in dodecylphosphocholine (DPC) micelles. Furthermore, we have characterized micelle-inserted CD4mut by paramagentic relaxation enhancement (PRE) agents and (1)H-(15)N heteronuclear NOE data. CD4mut features a stable and well-defined transmembrane helix from M372 to V395 buried in the micellar core and a cytoplasmic helix ranging from A404 to L413. Experimental data suggest the amphipathic cytoplasmic helix to be in close contact with the micellar surface. The role of the amphipathic helix and its interaction with the micellar surface is discussed with respect to the biological function of the full-length CD4 protein. PMID- 19781521 TI - Probing excited states and activation energy for the integral membrane protein phospholamban by NMR CPMG relaxation dispersion experiments. AB - Phospholamban (PLN) is a dynamic single-pass membrane protein that inhibits the flow of Ca(2+) ions into the sarcoplasmic reticulum (SR) of heart muscle by directly binding to and inhibiting the SR Ca(2+)ATPase (SERCA). The PLN monomer is the functionally active form that exists in equilibrium between ordered (T state) and disordered (R state) states. While the T state has been fully characterized using a hybrid solution/solid-state NMR approach, the R state structure has not been fully portrayed. It has, however, been detected by both NMR and EPR experiments in detergent micelles and lipid bilayers. In this work, we quantitatively probed the mus to ms dynamics of the PLN excited states by observing the T state in DPC micelles using CPMG relaxation dispersion NMR spectroscopy under functional conditions for SERCA. The (15)N backbone and (13)C(delta1) Ile-methyl dispersion curves were fit using a two-state equilibrium model, and indicate that residues within domain Ia (residues 1-16), the loop (17 22), and domain Ib (23-30) of PLN undergo mus-ms dynamics (k(ex)=6100+/-800 s(-1) at 17 degrees C). We measured k(ex) at additional temperatures, which allowed for a calculation of activation energy equal to approximately 5 kcal/mol. This energy barrier probably does not correspond to the detachment of the amphipathic domain Ia, but rather the energy needed to unwind domain Ib on the membrane surface, likely an important mechanism by which PLN converts between high and low affinity states for its binding partners. PMID- 19781522 TI - Membrane cholesterol depletion enhances ligand binding function of human serotonin1A receptors in neuronal cells. AB - Membrane lipid composition of cells in the nervous system is unique and displays remarkable diversity. Cholesterol metabolism and homeostasis in the central nervous system and their role in neuronal function represent important determinants in neuropathogenesis. The serotonin(1A) receptor is an important member of the G-protein coupled receptor superfamily, and is involved in a variety of cognitive, behavioral, and developmental functions. We report here, for the first time, that the ligand binding function of human serotonin(1A) receptors exhibits an increase in membranes isolated from cholesterol-depleted neuronal cells. Our results gain pharmacological significance in view of the recently described structural evidence of specific cholesterol binding site(s) in GPCRs, and could be useful in designing better therapeutic strategies for neurodegenerative diseases associated with GPCRs. PMID- 19781523 TI - Protein kinase A-dependent phosphorylation of ryanodine receptors increases Ca2+ leak in mouse heart. AB - In heart failure, chronic catecholaminergic stimulation increases diastolic Ca(2+) leak from ryanodine receptors (RyRs) of sarcoplasmic reticulum (SR), possibly due to the phosphorylation of RyRs through the activation of protein kinase A (PKA) or Ca(2+)/calmodulin-dependent protein kinase II (CaMKII). In the present study, we attempted to identify which activated kinase is responsible for the enhanced Ca(2+) leak caused by beta-adrenergic stimulation. Trabeculae obtained from the hearts of adult male C57BL/6J mice were treated with isoproterenol and then permeabilized with saponin. To examine SR functions, Ca(2+) in SR was released with caffeine and measured with fluo-3. The Ca(2+) leak in isoproterenol-treated preparations was significantly increased when the PKA dependent phosphorylation of RyR was increased without the involvement of CaMKII dependent phosphorylation. Both the increase in Ca(2+) leak and the phosphorylation of RyR were blocked by a PKA inhibitor. Our results show that beta-adrenergic stimulation increases Ca(2+) leak from SR through PKA-dependent phosphorylation of RyR. PMID- 19781524 TI - Metabotropic glutamate receptor 4 interacts with microtubule-associated protein 1B. AB - The metabotropic glutamate receptor 4 (mGluR4) is a G-protein-coupled receptor that mediates inhibition of neurotransmitter release. Here, we used a proteomic approach to identify novel interaction partners of mGluR4 and report that the cytoplasmic C-terminal tail of mGluR4 interacts with microtubule-associated protein 1B (MAP1B). Binding of MAP1B to mGluR4 is inhibited by Ca(2+)/calmodulin, and MAP1B and mGluR4 colocalize at excitatory synapses in cultured hippocampal neurons. Thus, MAP1B might be implicated in the synaptic trafficking and/or regulation of mGluR4. PMID- 19781525 TI - An advanced blue-white screening method for construction of shRNA expression vectors. AB - Short hairpin RNA (shRNA) encoded within an expression vector is an effective tool for exploration of gene function in mammalian cells. Many of the current methods for constructing shRNA expression vectors require cumbersome and time consuming procedures for identification of the desired recombinants. We have developed a highly efficient and less labor-intensive cloning method that allows the construction of shRNA expression vectors in one day and with minimal effort. This advanced blue-white screening technique was developed by combining the reconstitution of ideal lacO with TA cloning. The DNAs are simply ligated into the destination vectors and, following transformation, a desired recombinant event will give a typical blue colony. In addition, we have used this cloning method for the construction of targeting reporter expression vectors to measure the efficacy of the corresponding shRNA. We constructed 122 functional shRNA expression vectors and sequencing of the positive cloning vectors confirmed a high degree of accuracy. Only three short DNA primers are needed for constructing both shRNA and targeting reporter expression vectors. This advanced blue-white screening system is a powerful tool for the high-throughput assay of RNAi libraries. PMID- 19781526 TI - The role of short-range Cys171-Cys178 disulfide bond in maintaining cutinase active site integrity: a molecular dynamics simulation. AB - Understanding structural determinants in enzyme active site integrity can provide a good knowledge to design efficient novel catalytic machineries. Fusarium solani pisi cutinase with classic triad Ser-His-Asp is a promising enzyme to scrutinize these structural determinants. We performed two MD simulations: one, with the native structure, and the other with the broken Cys171-Cys178 disulfide bond. This disulfide bond stabilizes a turn in active site on which catalytic Asp175 is located. Functionally important H-bonds and atomic fluctuations in catalytic pocket have been changed. We proposed that this disulfide bond within active site can be considered as an important determinant of cutinase active site structural integrity. PMID- 19781527 TI - Heat shock protein 27 upregulation and phosphorylation in rat experimental autoimmune encephalomyelitis. AB - Following stress or inflammation, the 27-kDa heat shock protein (HSP27) is induced in various cell types, where it promotes cell survival and inhibits inflammatory reactions. We examined the expression of HSP27 and phosphorylated HSP27 (p-HSP27) in the spinal cords of Lewis rats with experimental autoimmune encephalomyelitis (EAE). Western blotting analysis revealed low levels of HSP27 and p-HSP27 in the normal spinal cords and significantly higher levels in EAE affected spinal cords. Immunohistochemistry revealed that HSP27 was expressed constitutively in the neurons and some fibrous astrocytes of the spinal cords of normal rats. However, in EAE-affected spinal cords, HSP27 immunoreactivity was higher and located primarily in the fibrous astrocytes of the white matter, whereas few of the inflammatory cells were immunopositive for HSP27. Immunoreactivity for p-HSP27 was detected predominantly in the fibrous astrocytes of the normal controls and was markedly increased in EAE-affected spinal cords. Therefore, the levels of HSP27 expression and phosphorylation of HSP27 were increased primarily during reactive astrogliosis of spinal white matter affected by EAE. These observations suggest that in rat EAE, the increased expression and elevated activation of HSP27 modulate host cell activity, survival, and inflammation to counter the autoimmune inflammatory injury. Our results also suggest that HSP27 plays a role in spontaneous recovery from EAE-induced paralysis. PMID- 19781528 TI - Xanthine oxidase is one of the major sources of superoxide anion radicals in blood after reperfusion in rats with forebrain ischemia/reperfusion. AB - We recently reported that excessive superoxide anion radical (O(2)(-)) was generated in the jugular vein during reperfusion in rats with forebrain ischemia/reperfusion using a novel electrochemical sensor and excessive O(2)(-) generation was associated with oxidative stress, early inflammation, and endothelial injury. However, the source of O(2)(-) was still unclear. Therefore, we used allopurinol, a potent inhibitor of xanthine oxidase (XO), to clarify the source of O(2)(-) generated in rats with forebrain ischemia/reperfusion. The increased O(2)(-) current and the quantified partial value of electricity (Q), which was calculated by the integration of the current, were significantly attenuated after reperfusion by pretreatment with allopurinol. Malondialdehyde (MDA) in the brain and plasma, high-mobility group box 1 (HMGB1) in plasma, and intercellular adhesion molecule-1 (ICAM-1) in the brain and plasma were significantly attenuated in rats pretreated with allopurinol with dose-dependency in comparison to those in control rats. There were significant correlations between total Q and MDA, HMGB, or ICAM-1 in the brain and plasma. Allopurinol pretreatment suppressed O(2)(-) generation in the brain-perfused blood in the jugular vein, and oxidative stress, early inflammation, and endothelial injury in the acute phase of forebrain ischemia/reperfusion. Thus, XO is one of the major sources of O(2)(-)- in blood after reperfusion in rats with forebrain ischemia/reperfusion. PMID- 19781529 TI - Glycine receptor expression in the forebrain of male AA/ANA rats. AB - Ethanol is known to directly interact with the glycine receptor (GlyR). GlyRs are membrane proteins and are constituted as either alpha-homomers or alpha-beta heteromers with a subunit stoichiometry of 2 alpha 3 beta. Previous studies by our group have suggested a role for GlyRs and its endogenous ligands glycine and taurine in the mesolimbic dopamine activating and reinforcing effects of ethanol. Here we use quantitative PCR (qPCR) to compare the relative GlyR expression in Alko Alcohol/Non-Alcohol (AA/ANA) rats. These animals have been selectively bred to create distinct populations regarding alcohol consumption and preference, presumably mainly due to genetic differences. The aim of this study was to examine the relative gene expression of GlyR subunits (alpha1-3 and beta) in different brain areas and relate it to alcohol consumption. The hypothesis was that AA/ANA rats are differently disposed to ethanol consumption due to their GlyR set-ups and/or compositions. Results from the present study indicate that alpha2 is the most widely expressed alpha-subunit in the forebrain regions and that the alpha 2 beta-heteromer seems to be the most common subunit composition in this part of the CNS. Despite displaying different drinking behaviours the anticipated differences in mRNA expression were few. However, correlations found between alcohol consumption and/or preference and GlyR expression support a role for GlyRs in alcohol consumption. Tentative differences between AA and ANA animals related to GlyR transmission could therefore lie in, for example, the regulation of the levels of the endogenous ligand(s) for the receptor or in mechanisms downstream to GlyR activation. PMID- 19781530 TI - K(v) channel interacting protein 3 expression and regulation by haloperidol in midbrain dopaminergic neurons. AB - Antipsychotic drugs are the main treatment for schizophrenia, despite their adverse side effects and uncertain mode of action. Gene expression studies in the brains of rodents treated with antipsychotic drugs aim to uncover this mechanism and elucidate more specific targets for schizophrenia treatment. Previous expression profiling analyses showed that K(v) channel interacting protein 3 (KChIP3) was down-regulated in the mouse brain following treatment with multiple antipsychotic drugs. In this study, we used in situ hybridization to anatomically define the expression of KChIP3 mRNA in the mouse brain and to quantify its regulation by 7-day haloperidol treatment. We used immunohistochemistry to localize KChIP3 protein expression in the midbrain, dorsal and ventral striatum and the prefrontal cortex. We found KChIP3 mRNA throughout the grey matter of the brain, with high expression in the hippocampus, specific thalamic nuclei, deeper cortical layers and in the midbrain. KChIP3 mRNA was significantly down-regulated in the dorsal striatum and the ventral tegmental area following haloperidol treatment. KChIP3 protein is expressed in the neuropil in the cortex and striatum, as well as in the soma of deeper layer cortical and striatal neurons. This study, for the first time, also localized KChIP3 protein in the cell bodies and processes of dopaminergic neurons in the midbrain. These findings indicate that regulation of KChIP3, particularly in mesocortical dopamine neurons, may be part of the action of antipsychotic drugs and that prolonged and more specific targeting of ion channel subunits may enhance the therapeutic effects of antipsychotic drugs. PMID- 19781532 TI - The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor simvastatin reduces thrombolytic-induced intracerebral hemorrhage in embolized rabbits. AB - Statins were designed as cholesterol-lowering drugs for the prevention of coronary artery disease. It is estimated that there are currently 33.5 million U.S. patients on chronic statin treatment regimens. Recently, statins have been shown to have pleiotropic including anti-inflammatory and neuroprotective effects. In this study, we assessed the pharmacological effects of simvastatin administered alone and in combination with tissue plasminogen activator (tPA) on measures of ischemia and hemorrhage in large clot embolized New Zealand white rabbits. For these studies, simvastatin (20 mg/kg, SC in DMSO) was administered 24 and 4 h prior to large clot embolization in order to achieve a "loading dose" pretreatment with the drug. In combination studies, tPA (3.3 mg/kg, IV) was administered 1 h following embolization. Intravenous tPA administration significantly increased hemorrhage volume by 175% (p=0.015) and hemorrhage incidence by 60% (p>0.05) compared to control, but did not affect infarct incidence or volume. Simvastatin treatment significantly decreased tPA-induced hemorrhage incidence (p=0.022) and volume (p=0.0001) following embolization. The study suggests that simvastatin treatment blocks or attenuates mechanisms involved in tPA-induced hemorrhage. Based upon our results, patients on simvastatin treatment may have significantly reduced tPA-induced side effects should they require tPA administration following an embolic stroke. PMID- 19781531 TI - Insulin and IGF-I prevent brain atrophy and DNA loss in diabetes. AB - The aim of this study was to identify factors that regulate the bulk of adult brain mass, and test the hypothesis that concomitantly reduced insulin and insulin-like growth factor (IGF) levels are pathogenic for brain atrophy associated with impaired learning and memory in diabetes. Doses of insulin, or insulin plus IGF-I that were too small to prevent hyperglycemia were infused for 12 weeks into the brain lateral ventricles of streptozotocin-diabetic adult rats. Brain wet, water and dry weights were significantly decreased in diabetic rats; insulin prevented these decreases. The decrease in brain DNA and protein contents in diabetic rats was prevented by the combination treatment, but not by insulin alone. Levels of several glia- and neuron-associated proteins were reduced in diabetes; these reductions were also prevented by the combination treatment. Although hyperglycemia was not prevented in plasma or cerebrospinal fluid, insulin prevented brain atrophy but not bulk DNA loss in diabetes, whereas the combination prevented both. Insulin actively prevented the loss of brain water content as well. Brain atrophy is associated with concomitantly reduced levels of insulin and IGF in other disorders such as Alzheimer's disease. PMID- 19781534 TI - The effects of hypertonic saline and nicotinamide on sensorimotor and cognitive function following cortical contusion injury in the rat. AB - Hypertonic saline (HTS) is an accepted treatment for traumatic brain injury (TBI). However, the behavioral and cognitive consequences following HTS administration have not thoroughly been examined. Recent preclinical evidence has suggested that nicotinamide (NAM) is beneficial for recovery of function following TBI. The current study compared the behavioral and cognitive consequences of HTS and NAM as competitive therapeutic agents for the treatment of TBI. Following controlled cortical impact (CCI), bolus administrations of NAM (500 mg/kg), 7.5% HTS, or 0.9% saline Vehicle (1.0 mL/kg) were given at 2, 24, and 48 h post-CCI. Behavioral results revealed that animals treated with NAM and HTS showed significant improvements in beam walk and locomotor placing compared to the Vehicle group. The Morris water maze (MWM) retrograde amnesia test was conducted on day 12 post-CCI and showed that all groups had significant retention of memory compared to injured, Vehicle-treated animals. Working memory was also assessed on days 8-20 using the MWM. The NAM and Vehicle groups quickly acquired the task; however, HTS animals showed no acquisition of this task. Histological examinations revealed that the HTS-treated animals lost significantly more cortical tissue than either the NAM or Vehicle-treated animals. HTS-treated animals showed a greater loss of hippocampal tissue compared to the other groups. In general, NAM showed a faster rate of recovery than HTS without this associated tissue loss. The results of this study reiterate the strengths of NAM following injury and show concerns with bolus administrations of HTS due to the differential effects on cognitive performance and apparent tissue loss. PMID- 19781533 TI - Adverse early life experience and social stress during adulthood interact to increase serotonin transporter mRNA expression. AB - Anxiety disorders, depression and animal models of vulnerability to a depression like syndrome have been associated with dysregulation of serotonergic systems in the brain. To evaluate the effects of early life experience, adverse experiences during adulthood, and potential interactions between these factors on serotonin transporter (slc6a4) mRNA expression, we investigated in rats the effects of maternal separation (180 min/day from days 2 to 14 of life; MS180), neonatal handing (15 min/day from days 2 to 14 of life; MS15), or normal animal facility rearing (AFR) control conditions with or without subsequent exposure to adult social defeat on slc6a4 mRNA expression in the dorsal raphe nucleus (DR) and caudal linear nucleus. At the level of specific subdivisions of the DR, there were no differences in slc6a4 mRNA expression between MS15 and AFR rats. Among rats exposed to a novel cage control condition, increased slc6a4 mRNA expression was observed in the dorsal part of the DR in MS180 rats, relative to AFR control rats. In contrast, MS180 rats exposed to social defeat as adults had increased slc6a4 mRNA expression throughout the DR compared to both MS15 and AFR controls. Social defeat increased slc6a4 mRNA expression, but only in MS180 rats and only in the "lateral wings" of the DR. Overall these data demonstrate that early life experience and stressful experience during adulthood interact to determine slc6a4 mRNA expression. These data support the hypothesis that early life experience and major stressful life events contribute to dysregulation of serotonergic systems in stress-related neuropsychiatric disorders. PMID- 19781536 TI - Nickel induces intracellular calcium mobilization and pathophysiological responses in human cultured airway epithelial cells. AB - Environmental exposure to nickel is associated to respiratory disorders and potential toxicity in the lung but molecular mechanisms remain incompletely explored. The extracellular Ca(2+)-sensing receptor (CaSR) is widely distributed and may be activated by divalent cations. In this study, we investigated the presence of CaSR in human cultured airway epithelial cells and its activation by nickel. Nickel transiently increased intracellular calcium (-logEC(50)=4.67+/ 0.06) in A549 and human bronchial epithelial cells as measured by epifluorescence microscopy. Nickel (20muM)-induced calcium responses were reduced after thapsigargin or ryanodine exposure but not by Ca(2+)-free medium. Inhibition of phospholipase-C or inositol trisphosphate release reduced intracellular calcium responses to nickel indicating activation of G(q)-signaling. CaSR mRNA and protein expression in epithelial cells was demonstrated by RT-PCR, western blot and immunofluorescence. Transfection of specific siRNA inhibited CaSR expression and suppressed nickel-induced intracellular calcium responses in A549 cells thus confirming nickel-CaSR activation. NPS2390, a CaSR antagonist, abolished the calcium response to nickel. Nickel-induced contraction, proliferation, alpha(1)(I)collagen production and inflammatory cytokines mRNA expression by epithelial cells as measured by traction microscopy, BrdU assay and RT-PCR, respectively. These responses were blocked by NPS2390. In conclusion, micromolar nickel concentrations, relevant to nickel found in the lung tissue of humans exposed to high environmental nickel, trigger intracellular Ca(2+) mobilization in human airway epithelial cells through the activation of CaSR which translates into pathophysiological outputs potentially related to pulmonary disease. PMID- 19781535 TI - Role of adenosine A(1) receptor in the perifornical-lateral hypothalamic area in sleep-wake regulation in rats. AB - The perifornical-lateral hypothalamic area (PF-LHA) has been implicated in the regulation of arousal. The PF-LHA contains wake-active neurons that are quiescent during non-REM sleep and in the case of neurons expressing the peptide hypocretin (HCRT), quiescent during both non-REM and REM sleep. Adenosine is an endogenous sleep factor and recent evidence suggests that adenosine via A(1) receptors may act on PF-LHA neurons to promote sleep. We examined the effects of bilateral activation as well as blockade of A(1) receptors in the PF-LHA on sleep wakefulness in freely behaving rats. The sleep-wake profiles of male Wistar rats were recorded during reverse microdialysis perfusion of artificial cerebrospinal fluid (aCSF) and two doses of adenosine A(1) receptor antagonist, 1,3-dipropyl-8 phenylxanthine (CPDX; 5 microM and 50 microM) or A(1) receptor agonist, N(6) cyclopentyladenosine (CPA; 5 microM and 50 microM) into the PF-LHA for 2 h followed by 4 h of aCSF perfusion. CPDX perfused into the PF-LHA during lights-on phase produced arousal (F=7.035, p<0.001) and concomitantly decreased both non REM (F=7.295, p<0.001) and REM sleep (F=3.456, p<0.004). In contrast, CPA perfused into the PF-LHA during lights-off phase significantly suppressed arousal (F=7.891, p<0.001) and increased non-REM (F=8.18, p <0.001) and REM sleep (F=30.036, p<0.001). These results suggest that PF-LHA is one of the sites where adenosine, acting via A(1) receptors, inhibits PF-LHA neurons to promote sleep. PMID- 19781537 TI - Synergistic mitosis-arresting effects of arsenic trioxide and paclitaxel on human malignant lymphocytes. AB - The treatment outcome of acute lymphoblastic leukemia (ALL) has improved steadily over the last 50 years. However, the cure rates are unlikely to be raised further with current therapies. Since increasing the dosage of chemotherapeutic agents could also elevate toxicity, a solution to how one could achieve maximum therapeutic effect with the minimum dosage possible is imminent. One possibility is the employment of combination drug therapies. Arsenic trioxide (ATO) is a widely used drug for acute promyelocytic leukemia (APL). Its combination with other drugs presented therapeutic activities in malignant cancers other than APL. Considering the fact that ATO induces mitotic arrest prior to apoptosis induction, we attempted to investigate the potential anti-cancer effects of ATO in combination with the microtubule-stabilizing agent, paclitaxel (PTX), using malignant lymphocytes as in vitro models. Three malignant lymphocytic cell lines and primary cells were treated with ATO and/or PTX. Using the Chou-Talalay analysis for evaluation of combined effect of ATO and PTX, we found a synergistic effect of the two drugs in the inhibition of cell growth. We also found that the combination of ATO and PTX at low concentrations synergistically induced mitotic arrest followed by apoptosis in malignant lymphocytes, which increased phosphorylated cyclin-dependent kinase 1 (Cdk1) on Thr(161) and promoted the dysregulated activation of Cdk1. The ATO/PTX combination also significantly enhanced the activation of spindle checkpoint by inducing the formation of the inhibitory checkpoint complex BubR1/Cdc20. Our study provided the first in vitro demonstration that low concentrations of ATO and PTX synergistically induce mitotic arrest in malignant lymphocytes. PMID- 19781539 TI - New aspects of the regulation of glycosphingolipid receptor function. AB - We propose that the fatty acid heterogeneity of glycosphingolipids may compensate for the relative few and simple glycosphingolipid structures found in mammalian cells. Variation in GSL fatty acid composition may mediate aglycone regulation of GSL membrane receptor function by a differential interaction with cholesterol and other membrane components which may be differentially organized within plasma membrane lipid domains. These concepts are specifically illustrated in model membrane studies and in relation to the role of the glycolipid, globotriaosyl ceramide (Gb(3)) in verotoxin-induced renal pathology and gp120 binding in HIV infection. PMID- 19781538 TI - Effect of alpha tocopherol acetate in Walker 256/B cells-induced oxidative damage in a rat model of breast cancer skeletal metastases. AB - The pathophysiological changes and the oxidative-antioxidative status were evaluated in the bone microenvironment of rat inoculated with Walker 256/B mammary gland carcinoma cells, and used alpha-tocopherol acetate (ATA) as a countermeasure. Walker 256/B cells were injected into the right femora of aged male rats. Animals were randomized into three groups: 12 rats were injected with saline (control group); 14 rats were injected with Walker 256/B cells (5x10(4)) in the medullar cavity (W256 group); 14 rats were inoculated with Walker 256/B cells and treated with ATA (45mg/kg BW) (W256+ATA group). After 20 days, rats were euthanized and the femurs were radiographed. Micro architectural parameters were measured by microcomputed tomography and histology. Serum, bone and bone marrow were evaluated for oxidative damage. In parallel, cell cultures were done in the presence of ATA and ROS were measured by fluorescence; apoptotic cells were determined in parallel. W256 groups had osteolytic damages with marked resorption of cortical and trabecular bone. W256+ATA animals presented marked osteosclerotic areas associated with tumor necrosis areas inside the bone cavity. Levels of lipid peroxidation and protein oxidation were found to increase in W256 rats; a significant reduction in SOD and GSH-p activities was also observed. W256+ATA group had significantly reduced oxidative damage, but not reversed back to the control levels. The present study shows that Walker 256/B cells induce skeletal metastases associated with oxidative damage in the bone microenvironment. ATA reduced the oxidative stress damage, enhanced osteosclerosis and tumor cell apoptosis both in vitro and in vivo. PMID- 19781540 TI - Close relationship between serum concentrations of 1,5-anhydroglucitol and uric acid in non-diabetic male subjects implies common renal transport system. AB - BACKGROUND: 1,5-Anhydroglucitol is found in food. We determined factors other than glucosuria that affect serum 1,5-anhydroglucitol (1,5-AG) concentration. METHODS: The relationships between serum 1,5-AG concentration and metabolic parameters were investigated in 158 males with normal glucose tolerance verified by an oral glucose tolerance test. RESULTS: Serum uric acid was positively correlated to 2-h plasma glucose and serum 1,5-AG concentrations. Serum 1,5-AG levels were not different between hyperuricemic and normouricemic subjects, though those with normouricemia had lower 2-h plasma glucose concentrations than subjects with hyperuricemia. The association between 1,5-AG and uric acid in serum was still evident after adjustment with 2-h plasma glucose concentration. Multivariate regression analyses demonstrated that serum uric acid was an independent variable related to serum 1,5-AG and vice versa. CONCLUSIONS: 1,5-AG and uric acid may share in part a common renal tubular transport system, independent of glucose excretion. PMID- 19781541 TI - Expression profiling of the AT2R mRNA in affected tissue from children with CAKUT. AB - OBJECTIVES: Congenital anomalies of the kidney and urinary tract (CAKUT) are common causes of chronic renal failure in children. The angiotensin II receptor type 2 (AT2R) is one of proposed candidate genes for CAKUT, but the expression was never explored in humans. The aim was to establish the AT2R gene expression in human CAKUT concerning -1332A/G polymorphism, which might affect alternative splicing. DESIGN AND METHODS: Forty-eight patients with CAKUT constitute the basis of this study. Genotyping for -1332A/G, RT-PCR for AT2R gene expression and confirmation sequencing were performed. RESULTS: The expression of Ex 1/2/3 and Ex 1/3 transcript splice variants of the AT2R mRNA were detected in human CAKUT tissue. The pattern was observed independently of A to G transition. CONCLUSIONS: The expression of AT2R mRNA in human CAKUT was established for the first time and was not affected by -1332A/G polymorphism in children with CAKUT. PMID- 19781542 TI - Measurement of selected ions related to oxidative stress and energy metabolism in Saudi autistic children. AB - OBJECTIVES: Autism is a developmental disorder characterized by social and emotional deficits, language impairments and stereotyped behaviors that manifest in early postnatal life. This study aims to clarify the role of selected ions related to energy metabolism as a consequence of oxidative stress in the deterioration accompanied autism. MATERIALS AND METHODS: Malonaldehyde as measure of lipid peroxidation, Na(+)/K(+) ion pump (ATPase), together with the concentrations of Na(+), K(+), Mg(2+), Ca(2+) and Pb(2+) were determined in plasma of 30 Saudi autistic patients and compared to 30 age-matching control samples. RESULTS: The obtained data recorded that Saudi autistic patients have a remarkable higher activities of Na(+)/K(+) ATPase and high levels of lipid peroxidation compared to control. In addition, they have significantly elevated levels of K(+) and Pb(2+) while Ca(2+) recorded a significantly lower level compared to age-matching control subjects. On the other hand both Mg(2+) and Na(+) were non-significantly changed in autistic patients. CONCLUSION: Alteration of the selected measured ions confirms that oxidative stress and defective mitochondrial energy production could represent the primary causative factor in the pathogenesis of autism. PMID- 19781543 TI - Activation of Six1 target genes is required for sensory placode formation. AB - In vertebrates, cranial placodes form crucial parts of the sensory nervous system in the head. All cranial placodes arise from a common territory, the preplacodal region, and are identified by the expression of Six1/4 and Eya1/2 genes, which control different aspects of sensory development in invertebrates as well as vertebrates. While So and Eya can induce ectopic eyes in Drosophila, the ability of their vertebrate homologues to induce placodes in non-placodal ectoderm has not been explored. Here we show that Six1 and Eya2 are involved in ectodermal patterning and cooperate to induce preplacodal gene expression, while repressing neural plate and neural crest fates. However, they are not sufficient to induce ectopic sensory placodes in future epidermis. Activation of Six1 target genes is required for expression of preplacodal genes, for normal placode morphology and for placode-specific Pax protein expression. These findings suggest that unlike in the fly where the Pax6 homologue Eyeless acts upstream of Six and Eya, the regulatory relationships between these genes are reversed in early vertebrate placode development. PMID- 19781544 TI - Advances in imaging and technology of pre-invasive neoplasia: the big (and small) picture. PMID- 19781545 TI - Temporal mRNA expression of transforming growth factor-beta superfamily members and inhibitors in the developing rainbow trout ovary. AB - During mammalian ovarian development transforming growth factor-beta (TGFbeta) superfamily members and their inhibitors are critical paracrine regulators, yet the intraovarian functions of these proteins have received less attention in fish. Using quantitative real-time RT-PCR, changes in ovarian mRNA expression of six TGFbeta members and two inhibitors were investigated in rainbow trout across a wide range of fish ovarian stages (i.e., early perinucleous stage through acquisition of maturational competence). Transcript changes for insulin-like growth factor 1 and 2, and five enzymes associated with steroidogenesis, as well as plasma levels of three sex steroids were also measured to provide a framework of established intraovarian regulators in trout. Expression of bone morphogenetic protein 4 (bmp4), bone morphogenetic protein7 (bmp7), and growth differentiation factor 9 (gdf9) peaked during pre-vitellogenic stages and steadily decreased through advancing stages implicating these genes in early ovarian development. A dramatic increase in inhibin beta(A) and decrease in follistatin expression occurred during early to mid-vitellogenic stages, which corresponded with increased 17beta-estradiol plasma levels suggesting a vitellogenic role for ovarian activin A. Follicles that were competent to respond to the maturation inducing hormone had decreased levels of inhibin beta(B) and increased expression of bambi (bmp and activin membrane-bound inhibitor) suggesting their roles in maturation processes. Furthermore, bmp4, bmp7 and gdf9 are primarily expressed in the oocyte whereas the inhibin subunits, follistatin, and bambi are primarily expressed in the somatic follicle cells. These results support TGFbeta superfamily members and their inhibitors have wide-ranging and disparate roles in regulating ovarian development in fish. PMID- 19781546 TI - Comparison of three assays for the detection of GAD65Ab-specific anti-idiotypic antibodies. AB - Anti-idiotypic antibodies (anti-Id) to autoantibodies are present in several autoimmune diseases and are hypothesized to have regulatory function. Recently we reported the presence of anti-Id to a major type 1 diabetes-associated autoantibody (GAD65Ab) in sera of healthy individuals. Our current assay for the detection of GAD65Ab-specific anti-Id requires the initial removal of anti-Id from the sera using immobilized monoclonal GAD65Ab, followed by detection of the now exposed GAD65Ab. However, anti-Id in samples that are GAD65Ab-negative cannot be detected in this assay. Furthermore, we cannot distinguish between serum GAD65Ab and the monoclonal GAD65Ab used in the absorption of anti-Id. In this study we evaluated two novel detection assays for GAD65Ab-specific anti-Id. The biotin/streptavidin based absorption assay utilizes the strong interaction of biotin and streptavidin to prevent possible leakage of the immobilized antibody. Moreover, this assay format allows to identify the origin of the detected GAD65Ab. The ECL-based assay allows the direct detection of anti-Id independent of the presence of GAD65Ab. We analyzed new-onset type 1 diabetes patients (n=133) and matched healthy controls (n=178) for the presence of GAD65Ab-specific anti-Id using both new detection assays and the original absorption assay. We found that all three assays can distinguish between the type 1 diabetes cohort and the healthy control samples. The biotin/streptavidin assay allowed us to positively exclude the monoclonal GAD65Ab as the source of the detected GAD65Ab. While the original absorption assay showed the highest sensitivity and specificity, the ECL format showed the highest peak signal-to-noise ratio and excellent linear correlation, making this assay our first choice for quantification of anti-Id. PMID- 19781547 TI - A nutritional profile of the social wasp Polistes metricus: differences in nutrient levels between castes and changes within castes during the annual life cycle. AB - In wasps, nutrition plays a vital role for colony cohesion and caste determination. However, there is no baseline data set for the nutritional levels of wasps during the different stages of the colony cycle. Here we examined the levels of carbohydrates, lipids, protein, Ca, Cu, Fe, K, Mg, Mn, Na, and Zn in the wasp Polistes metricus at different stages of the wasp's lifecycle. Individuals were collected at the following stages (1) spring gynes, (2) foundress colonies, (3) early worker colonies, (4) late worker colonies, (5) emerging reproductives (gynes and males), (6) early fall reproductives, and (7) late fall reproductives. All eggs, larvae, pupae and adults were analyzed for their nutritional content to determine if there were any differences between the nutrient levels in the different castes and how these nutrients changed within a caste during its lifetime. The results show there are differences in macro and micronutrient levels between the reproductive females and workers during development. Gynes showed changes in nutrient levels during their lifetime especially as they changed roles from a solitary individual to a nesting queen. Males also showed distinct nutritional changes during their lifetime. The implications for these nutritional differences are discussed. PMID- 19781548 TI - Understanding the role of the extracellular matrix in cardiovascular development and disease: where do we go from here? PMID- 19781549 TI - The higher structure of chromatin in the LCR of the beta-globin locus changes during development. AB - The beta-globin locus control region (LCR) is able to enhance the expression of all globin genes throughout the course of development. However, the chromatin structure of the LCR at the different developmental stages is not well defined. We report DNase I and micrococcal nuclease hypersensitivity, chromatin immunoprecipitation analyses for histones H2A, H2B, H3, and H4, and 3C (chromatin conformation capture) assays of the normal and mutant beta-globin loci, which demonstrate that nucleosomes at the DNase I hypersensitive sites of the LCR could be either depleted or retained depending on the stages of development. Furthermore, MNase sensitivity and 3C assays suggest that the LCR chromatin is more open in embryonic erythroblasts than in definitive erythroblasts at the primary- and secondary-structure levels; however, the LCR chromatin is packaged more tightly in embryonic erythroblasts than in definitive erythroblasts at the tertiary chromatin level. Our study provides the first evidence that the occupancy of nucleosomes at a DNase I hypersensitive site is a developmental stage-related event and that embryonic and adult cells possess distinct chromatin structures of the LCR. PMID- 19781550 TI - PhhR binds to target sequences at different distances with respect to RNA polymerase in order to activate transcription. AB - The NtrC-family PhhR protein of Pseudomonas putida is involved in the control of the metabolism of aromatic amino acids, and it is a dual regulatory protein. When PhhR acts as an activator, it stimulates transcription from its cognate promoters with RNA polymerase/sigma(70) rather than with sigma(54), as is the case for most members of the family. The target binding sites in repressed and activated promoters are defined by the 5'-TGTAAAN(6)TTTACA-3' consensus sequence. PhhR binds to target sites as a dimer with affinity in the range of 0.03 to 6.6 microM, as shown by isothermal titration calorimetry. PhhR activates transcription from both the PP2827 and PP2078 promoters regardless of the absence or presence of aromatic amino acids, whereas PhhR stimulates transcription from certain positively regulated promoters (P(phhA), P(PP3122), P(PP3434), and P(hmg)) only in the presence of phenylalanine and tyrosine or their corresponding keto acids (i.e., phenylpyruvate and p-hydroxyphenylpyruvate). A surprising feature of PhhR-mediated transcriptional activation is that PhhR may bind to one or two upstream target sequences that are located at different distances from the RNA polymerase binding site. This allows PhhR to function as a class I regulator (target sites at -66/-83), a class II regulator (target sites around -40), as well as an enhancer protein (target sites >-128). When functioning as an enhancer protein, PhhR-mediated transcription is modulated by the integration host factor protein. PhhR represses transcription from its own promoter and the promoter of the paaY gene by steric hindrance. PMID- 19781551 TI - Residues gating the periplasmic pathway of LacY. AB - X-ray crystal structures of LacY (lactose permease of Escherichia coli) exhibit a large cytoplasmic cavity containing the residues involved in sugar binding and H(+) translocation at the apex and a tightly packed side facing the periplasm. However, biochemical and biophysical evidence provide a strong indication that a hydrophilic pathway opens on the external surface of LacY with closing of the cytoplasmic side upon sugar binding. Thus, an alternating-access mechanism in which sugar- and H(+)-binding sites at the approximate middle of the molecule are alternatively exposed to either side of the membrane is likely to underlie LacY catalyzed sugar/H(+) symport. To further investigate periplasmic opening, we replaced paired residues on the tightly packed periplasmic side of LacY with Cys, and the effect of cross-linking was studied by testing the accessibility/reactivity of Cys148 with the elongated ( approximately 29 A), impermeant hydrophilic reagent maleimide-PEG2-biotin. When the paired-Cys mutant Ile40-->Cys/Asn245-->Cys containing native Cys148 is oxidized to form a disulfide bond, the reactivity of Cys148 is markedly inhibited. Moreover, the reactivity of Cys148 in this mutant increases with the length of the cross-linking agent. In contrast, maleimide-PEG2-biotin reactivity of Cys148 is unaffected by oxidation of two other paired-Cys mutants at the mouth of the periplasmic cavity. The data indicate that residues Ile40 and Asn245 play a primary role in gating the periplasmic cavity and provide further support for the alternating-access model. PMID- 19781552 TI - The 20S proteasome as an assembly platform for the 19S regulatory complex. AB - 26S proteasomes consist of cylindrical 20S proteasomes with 19S regulatory complexes attached to the ends. Treatment with high concentrations of salt causes the regulatory complexes to separate into two sub-complexes, the base, which is in contact with the 20S proteasome, and the lid, which is the distal part of the 19S complex. Here, we describe two assembly intermediates of the human regulatory complex. One is a dimer of the two ATPase subunits, Rpt3 and Rpt6. The other is a complex of nascent Rpn2, Rpn10, Rpn11, Rpn13, and Txnl1, attached to preexisting 20S proteasomes. This early assembly complex does not yet contain Rpn1 or any of the ATPase subunits of the base. Thus, assembly of 19S regulatory complexes takes place on preexisting 20S proteasomes, and part of the lid is assembled before the base. PMID- 19781553 TI - Binding to PCNA in Euryarchaeal DNA Replication requires two PIP motifs for DNA polymerase D and one PIP motif for DNA polymerase B. AB - Replicative DNA polymerases possess a canonical C-terminal proliferating cell nuclear antigen (PCNA)-binding motif termed the PCNA-interacting protein (PIP) box. We investigated the role of the PIP box on the functional interactions of the two DNA polymerases, PabPol B (family B) and PabPol D (family D), from the hyperthermophilic euryarchaeon Pyrococcus abyssi, with its cognate PCNA. The PIP box was essential for interactions of PabPol B with PCNA, as shown by surface plasmon resonance and primer extension studies. In contrast, binding of PabPol D to PCNA was affected only partially by removing the PIP motif. We identified a second palindromic PIP box motif at the N-terminus of the large subunit of PabPol D that was required for the interactions of PabPol D with PCNA. Thus, two PIP motifs were needed for PabPol D for binding to PabPCNA. Moreover, the C-terminus of PabPCNA was essential for stimulation of PabPol D activity but not for stimulation of PabPol B activity. Neither DNA polymerase interacted with the PabPCNA interdomain connecting loop. Our data suggest that distinct processes are involved in PabPol D and PabPol B binding to PCNA, raising the possibility that Archaea require two mechanisms for recruiting replicative DNA polymerases at the replication fork. PMID- 19781554 TI - Binding of rabies virus polymerase cofactor to recombinant circular nucleoprotein RNA complexes. AB - In rabies virus, the attachment of the L polymerase (L) to the viral nucleocapsids (NCs)-a nucleoprotein (N)-RNA complex that serves as template for RNA transcription and replication-is mediated by the polymerase cofactor, the phosphoprotein (P). P forms dimers (P(2)) that bind through their C-terminal domains (P(CTD)) to the C-terminal region of the N. Recombinant circular N(m)-RNA complexes containing 9 to 12 protomers of N (hereafter, the subscript m denotes the number of N protomers) served here as model systems for studying the binding of P to NC-like N(m)-RNA complexes. Titration experiments show that there are only two equivalent and independent binding sites for P dimers on the N(m)-RNA rings and that each P dimer binds through a single P(CTD). A dissociation constant in the nanomolar range (160+/-20 nM) was measured by surface plasmon resonance, indicating a strong interaction between the two partners. Small-angle X-ray scattering (SAXS) data and small-angle neutron scattering data showed that binding of two P(CTD) had almost no effect on the size and shape of the N(m)-RNA rings, whereas binding of two P(2) significantly increased the size of the complexes. SAXS data and molecular modeling were used to add flexible loops (N(NTD) loop, amino acids 105-118; N(CTD) loop, amino acids 376-397) missing in the recently solved crystal structure of the circular N(11)-RNA complex and to build a model for the N(10)-RNA complex. Structural models for the N(m)-RNA (P(CTD))(2) complexes were then built by docking the known P(CTD) structure onto the completed structures of the circular N(10)-RNA and N(11)-RNA complexes. A multiple-stage flexible docking procedure was used to generate decoys, and SAXS and biochemical data were used for filtering the models. In the refined model, the P(CTD) is bound to the C-terminal top of one N protomer (N(i)), with the C terminal helix (alpha(6)) of P(CTD) lying on helix alpha(14) of N(i). By an induced-fit mechanism, the N(CTD) loop of the same protomer (N(i)) and that of the adjacent one (N(i)(-1)) mold around the P(CTD), making extensive protein protein contacts that could explain the strong affinity of P for its template. The structural model is in agreement with available biochemical data and provides new insights on the mechanism of attachment of the polymerase complex to the NC template. PMID- 19781555 TI - HIV-1 Nef dimerization is required for Nef-mediated receptor downregulation and viral replication. AB - Nef, a human immunodeficiency virus type 1 (HIV-1) accessory factor capable of interaction with a diverse array of host cell signaling molecules, is essential for high-titer HIV replication and AIDS progression. Previous biochemical and structural studies have suggested that Nef may form homodimers and higher-order oligomers in HIV-infected cells, which may be required for both immune and viral receptor downregulation as well as viral replication. Using bimolecular fluorescence complementation, we provide the first direct evidence for Nef dimers within HIV host cells and identify the structural requirements for dimerization in vivo. Bimolecular fluorescence complementation analysis shows that the multiple hydrophobic and electrostatic interactions found within the dimerization interface of the Nef X-ray crystal structure are essential for dimerization in cells. Nef dimers localized to the plasma membrane as well as the trans-Golgi network, two subcellular localizations essential for Nef function. Mutations in the Nef dimerization interface dramatically reduced both Nef-induced CD4 downregulation and HIV replication. Viruses expressing dimerization-defective Nef mutants were disabled to the same extent as HIV that fails to express Nef in terms of replication. These results identify the Nef dimerization region as a potential molecular target for antiretroviral drug discovery. PMID- 19781556 TI - Crystal structures of Leishmania mexicana phosphoglycerate mutase suggest a one metal mechanism and a new enzyme subclass. AB - The structures of Leishmania mexicana cofactor-independent phosphoglycerate mutase (Lm iPGAM) crystallised with the substrate 3-phosphoglycerate at high and low cobalt concentrations have been solved at 2.00- and 1.90-A resolutions. Both structures are very similar and the active site contains both 3-phosphoglycerate and 2-phosphoglycerate at equal occupancies (50%). Lm iPGAM co-crystallised with the product 2-phosphoglycerate yields the same structure. Two Co(2+) are coordinated within the active site with different geometries and affinities. The cobalt at the M1 site has a distorted octahedral geometry and is present at 100% occupancy. The M2-site Co(2+) binds with distorted tetrahedral geometry, with only partial occupancy, and coordinates with Ser75, the residue involved in phosphotransfer. When the M2 site is occupied, the side chain of Ser75 adopts a position that is unfavourable for catalysis, indicating that this site may not be occupied under physiological conditions and that catalysis may occur via a one metal mechanism. The geometry of the M2 site suggests that it is possible for Ser75 to be activated for phosphotransfer by H-bonding to nearby residues rather than by metal coordination. The 16 active-site residues of Lm iPGAM are conserved in the Mn-dependent iPGAM from Bacillus stearothermophilus (33% overall sequence identity). However, Lm iPGAM has an inserted tyrosine (Tyr210) that causes the M2 site to diminish in size, consistent with its reduced metal affinity. Tyr210 is present in trypanosomatid and plant iPGAMs, but not in the enzymes from other organisms, indicating that there are two subclasses of iPGAMs. PMID- 19781557 TI - The common architecture of cross-beta amyloid. AB - Amyloid fibril deposition is central to the pathology of more than 30 unrelated diseases including Alzheimer's disease and Type 2 diabetes. It is generally accepted that amyloid fibrils share common structural features despite each disease being characterised by the deposition of an unrelated protein or peptide. The structure of amyloid fibrils has been studied using X-ray fibre diffraction and crystallography, solid-state NMR and electron paramagnetic resonance, and many different, sometimes opposing, models have been suggested. Many of these models are based on the original interpretation of the cross-beta diffraction pattern for cross-beta silk in which beta-strands run perpendicular to the fibre axis, although alternative models include beta-helices and natively structured proteins. Here, we have analysed opposing model structures and examined the necessary structural elements within the amyloid core structure, as well as producing idealised models to test the limits of the core conformation. Our work supports the view that amyloid fibrils share a number of common structural features, resulting in characteristic diffraction patterns. This pattern may be satisfied by structures in which the strands align close to perpendicular to the fibre axis and are regularly arranged to form beta-sheet ribbons. Furthermore, the fibril structure contains several beta-sheets that associate via side-chain packing to form the final protofilament structure. PMID- 19781558 TI - Necrotic core in EMT6/Ro tumour spheroids: Is it caused by an ATP deficit? AB - Although commonly related to nutrient deprivation, the cause of the formation of the necrotic core in the multicellular tumour spheroids is still a controversial issue. We propose a simple model for the cell ATP production that assumes glucose and lactate as the only fuel substrates, and describes the main reactions occurring in the glycolytic and the oxidative pathways. Under the key assumption that cell death occurs when ATP production falls to a critical level, we formulate a multiscale model that integrates the energy metabolism at the cellular level with the diffusive transport of the metabolites in the spheroid mass. The model has been tested by predicting the measurements of the necrotic radius obtained by Freyer and Sutherland (1986a) in EMT6/Ro spheroids under different concentrations of glucose and oxygen in the culture medium. The results appear to be in agreement with the hypothesis that necrosis is caused by ATP deficit. PMID- 19781559 TI - Global mutations and local mutations have very different effects on evolution, illustrated by mixed strategies of asymmetric binary games. AB - We study the evolutionary effect of rare mutations causing global changes in traits. We consider asymmetric binary games between two players. The first player takes two alternative options with probability x and 1-x; and the second player takes options with probability y and 1-y. Due to natural selection and recurrent mutation, the population evolves to have broad distributions of x and y. We analyze three cases showing qualitatively different dynamics, exemplified by (1) vigilance-intrusion game, (2) asymmetric hawk-dove game and (3) cleaner-client game. We found that the evolutionary outcome is strongly dependent upon the distribution of mutants' traits, more than the mutation rates. For example in the vigilance-intrusion game, the evolutionary dynamics show a perpetual stable oscillation if mutants are always close to the parent (local-mutation mode), whilst the population converges to a stable equilibrium distribution if mutants can be quite different from the parent (global-mutation mode), even for extremely low mutation rate. When common local mutations and rare global mutations occur simultaneously, the evolutionary outcome is controlled by the latter. PMID- 19781560 TI - Gender moderates the association between 5-HTTLPR and decision-making under ambiguity but not under risk. AB - Decisions made under ambiguity may involve a different genetic architecture than those made under risk. Because gender moderates the effect of genetic polymorphisms on serotonin function and because there are gender differences in decision-making, the present study examined potential gender moderation of associations between polymorphisms in important serotonin system candidate genes (serotonin transporter [SLC6A4] and tryptophan hydroxylase-2 [TPH2]) and performance on a decision-making task (Iowa Gambling Task, IGT) in healthy, adults (N = 188; 62% women). Subjects were genotyped for the well-studied SLC6A4 promoter variant 5-HTTLPR and a TPH2 single nucleotide polymorphism in intron-8 (rs1386438). Genotype at rs1386438 was not associated with performance on the IGT. A significant gender by 5-HTTLPR genotype interaction effect was detected when decision-making was under ambiguity (i.e. the first block of 20 choices), but not under risk (blocks 2-5). Performance on the first block of 20 choices was not correlated with performance on subsequent blocks, supporting the interpretation that early performance on the IGT indexes decision-making under ambiguity, while performance on blocks 2-5 indexes decision-making under risk. These findings suggest that decision-making under ambiguity and risk may have different genetic architectures and that individual differences in decision making under ambiguity are associated with genetic variation in SLC6A4. PMID- 19781561 TI - Efficient maximum likelihood pedigree reconstruction. AB - A simple and efficient algorithm is presented for finding a maximum likelihood pedigree using microsatellite (STR) genotype information on a complete sample of related individuals. The computational complexity of the algorithm is at worst (O(n(3)2(n))), where n is the number of individuals. Thus it is possible to exhaustively search the space of all pedigrees of up to thirty individuals for one that maximizes the likelihood. A priori age and sex information can be used if available, but is not essential. The algorithm is applied in a simulation study, and to some real data on humans. PMID- 19781562 TI - Sprague-Dawley rats display sex-linked differences in the pharmacokinetics of 3,4 methylenedioxymethamphetamine (MDMA) and its metabolite 3,4 methylenedioxyamphetamine (MDA). AB - The use of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) has increased in recent years; it can lead to life-threatening hyperthermia and serotonin syndrome. Human and rodent males appear to be more sensitive to acute toxicity than are females. MDMA is metabolized to five main metabolites by the enzymes CYP1A2, CYP2D and COMT. Little is presently known about sex-dependent differences in the pharmacokinetics of MDMA and its metabolites. We therefore analyzed MDMA disposition in male and female rats by measuring the plasma and urine concentrations of MDMA and its metabolites using a validated LC-MS method. MDA AUC(last) and C(max) were 1.6- to 1.7-fold higher in males than in females given MDMA (5 mg/kg sc), while HMMA C(max) and AUC(last) were 3.2- and 3.5-fold higher, respectively. MDMA renal clearance was 1.26-fold higher in males, and that of MDA was 2.2-fold higher. MDMA AUC(last) and t(1/2) were 50% higher in females given MDMA (1 mg/kg iv). MDA C(max) and AUC(last) were 75-82% higher in males, with a 2.8-fold higher metabolic index. Finally, the AUC(last) of MDA was 0.73-fold lower in males given 1 mg/kg iv MDA. The volumes of distribution of MDMA and MDA at steady-state were similar in the two sexes. These data strongly suggest that differences in the N-demethylation of MDMA to MDA are major influences on the MDMA and MDA pharmacokinetics in male and female rats. Hence, males are exposed to significantly more toxic MDA, which could explain previously reported sexual dysmorphism in the acute effects and toxicity of MDMA in rats. PMID- 19781563 TI - Ginsenoside Rb1 protects against 6-hydroxydopamine-induced oxidative stress by increasing heme oxygenase-1 expression through an estrogen receptor-related PI3K/Akt/Nrf2-dependent pathway in human dopaminergic cells. AB - Phytoestrogens are polyphenolic non-steroidal plant compounds with estrogen-like biological activity. Ginseng, the root of Panax ginseng C.A. Meyer (Araliaceae), is a popular traditional herbal medicine. Ginsenoside Rb1 (Rb1), an active component commonly found in ginseng root, is a phytoestrogen that exerts estrogen like activity. In this study, we demonstrate that the phytoestrogen Rb1 inhibits 6-hydroxydopamine (6-OHDA)-induced oxidative injury via an ER-dependent Gbeta1/PI3K/Akt and heme oxygenase-1 (HO-1) pathway. Pretreatment of SH-SY5Y cells with Rb1 significantly reduced 6-OHDA-induced caspase-3 activation and subsequent cell death. Rb1 also up-regulated HO-1 expression, which conferred cytoprotection against 6-OHDA-induced oxidative injury. Moreover, Rb1 induced both Nrf2 nuclear translocation, which is upstream of HO-1 expression and PI3K activation, a pathway that is involved in induced Nrf2 nuclear translocation, HO 1 expression and cytoprotection. Also, Rb1-mediated increases in PI3K activation and HO-1 induction were reversed by co-treatment with ICI 182,780 and pertussis toxin. Taken together, these results suggest that Rb1 augments the cellular antioxidant defenses through ER-dependent HO-1 induction via the Gbeta1/PI3K/Akt Nrf2 signaling pathway, thereby protecting cells from oxidative stress. Thus our study indicates that Rb1 has a partial cytoprotective role in dopaminergic cell culture systems. PMID- 19781564 TI - Characterization of ricin toxin family members from Ricinus communis. AB - Ricin inhibits translation by removal of a specific adenine from 28S RNA. The Ricinus communis genome encodes seven full-length ricin family members. All encoded proteins have the ability of hydrolyzing adenine in 28S rRNA. As expected, these proteins also inhibited an in vitro transcription/translation system. These data show that the ricin gene family contains at least seven members that have the ability to inhibit translation and that may contribute to the toxicity of R. communis. PMID- 19781565 TI - Quantification of potency of neutralizing antibodies to botulinum toxin using compound muscle action potential (CMAP). AB - We evaluated a method for quantifying botulinum toxin-neutralizing antibodies which utilizes the CMAP. This method can be used just one day after administration, and the detection sensitivity was higher than that of the mouse neutralization test. The CMAP neutralization test detected neutralizing antibodies in patients who were resistant to treatment with the botulinum LL toxin. These results indicate that the CMAP neutralization test is useful for detecting low levels of antitoxin. PMID- 19781566 TI - Oculomotor and linguistic determinants of reading development: a longitudinal study. AB - We longitudinally assessed the development of oculomotor control in reading from second to fourth grade by having children read sentences with embedded target words of varying length and frequency. Additionally, participants completed oculomotor (pro-/anti-saccades) and linguistic tasks (word/picture naming), the latter containing the same item material as the reading task. Results revealed a 36% increase of reading efficiency. Younger readers utilized a global refixation strategy to gain more time for word decoding. Linguistic rather than oculomotor skills determined the development of reading abilities, although naming latencies of fourth graders did not reliably reflect word decoding processes in normal sentence reading. PMID- 19781567 TI - Sustained convergence induced changes in phoria and divergence dynamics. AB - PURPOSE: The purpose of this study was to investigate how sustained convergence induces phoria adaptation and changes divergence dynamics. METHODS: Near dissociated phoria and divergence step responses were recorded using an infrared eye movement monitor on four binocularly normal subjects. We tested three different adapting vergence positions (16 degrees , 6 degrees , and 0.5 degrees ) and measured 4 degrees divergence step responses for two different initial vergence positions (16 degrees and 4.5 degrees ). Dynamics were quantified by measuring peak velocities of the divergence responses. RESULTS: Phoria was significantly adapted after subjects fixated on a sustained convergent target at near (16 degrees ) and at far (0.5 degrees ). As a result of sustained convergence, divergence peak velocity from a 4 degrees step stimulus significantly changed. A regression analysis showed that when the phoria became more esophoric (near adapted) the peak velocity for the divergence steps with an initial position of 16 degrees decreased (R=0.54, p=0.04). A trend was observed between the change vergence velocity and the change in phoria. Change was defined as the post-adapted data minus the pre-adapted data for vergence steps with an initial position of 16 degrees (R=0.65) and 4.5 degrees (R=0.66). Furthermore, the modification of divergence dynamics was dependent on the initial position of those divergence steps (initial position of 16 degrees versus 4.5 degrees ). CONCLUSION: As a result of sustained convergence, phoria and divergence dynamics changed in a correlated manner. Such correlated changes in phoria and divergence dynamics are not explained by current models of disparity vergence eye movements. PMID- 19781569 TI - The pleiotropy of dioxin toxicity--xenobiotic misappropriation of the aryl hydrocarbon receptor's alternative physiological roles. AB - The aryl hydrocarbon receptor is a signal regulated transcription factor that has best been characterised as regulating the xenobiotic response to a variety of planar aromatic hydrocarbons. There is compelling evidence that it mediates most, if not all, of the toxic effects of dioxin (2,3,7,8-tetrachlorodibenzo-p-dioxin). Dioxin exposure results in a wide variety of toxic outcomes including severe wasting syndrome, chloracne, thymic involution, severe immune suppression, reduced fertility, hepatotoxicity, teratogenicity, tumour promotion and death. The pleiotropy of toxic outcomes implies the disruption of a wide range of normal physiological functions. The aryl hydrocarbon receptor has developmentally restricted expression as well as developmental defects in gene-targeted mice. It has a wide range of target genes that do not fit into the classical xenobiotic metabolising gene battery and has recently been shown to interact with NF-kappa B and the estrogen receptor. There is also evidence for its activation in the absence of exogenous ligand, all of which point to various roles outside xenobiotic metabolism. Ligands so far identified display differential activation potential with respect to receptor activity. This article addresses activities of the aryl hydrocarbon receptor that are outside the xenobiotic response. Known physiological roles are discussed as well as how their disruption contributes to the pleiotropic toxicity of TCDD. PMID- 19781568 TI - Expression changes of dopaminergic system-related genes in PC12 cells induced by manganese, silver, or copper nanoparticles. AB - Nanoparticles have received a great deal of attention for producing new engineering applications due to their novel physicochemical characteristics. However, the broad application of nanomaterials has also produced concern for nanoparticle toxicity due to increased exposure from large-scale industry production. This study was conducted to investigate the potential neurotoxicity of manganese (Mn), silver (Ag), and copper (Cu) nanoparticles using the dopaminergic neuronal cell line, PC12. Selective genes associated with the dopaminergic system were investigated for expression changes and their correlation with dopamine depletion. PC12 cells were treated with 10 microg/ml Mn 40 nm, Ag-15 nm, or Cu-90 nm nanoparticles for 24 h. Cu-90 nanoparticles induced dopamine depletion in PC12 cells, which is similar to the effect induced by Mn-40 shown in a previous study. The expression of 11 genes associated with the dopaminergic system was examined using real-time RT-PCR. The expression of Txnrd1 was up-regulated after the Cu-90 treatment and the expression of Gpx1 was down regulated after Ag-15 or Cu-90 treatment. These alterations are consistent with the oxidative stress induced by metal nanoparticles. Mn-40 induced a down regulation of the expression of Th; Cu-90 induced an up-regulation of the expression of Maoa. This indicates that besides the oxidation mechanism, enzymatic alterations may also play important roles in the induced dopamine depletion. Mn-40 also induced a down-regulation of the expression of Park2; while the expression of Snca was up-regulated after Mn-40 or Cu-90 treatment. These data suggest that Mn and Cu nanoparticles-induced dopaminergic neurotoxicity may share some common mechanisms associated with neurodegeneration. PMID- 19781571 TI - Comparison of the usefulness of the CACO-2 cell line with standard substrates for isolation of swine influenza A viruses. AB - Influenza A virus isolation is undertaken routinely in embryonated chicken eggs, but to improve virus detection various cell lines can be used. The CACO-2 cell line was compared to the MDCK cell line and embryonated chicken eggs for the isolation of H1N1, H1N2, H3N2 swine influenza A virus subtypes from clinical specimens. From 2006 to 2008, 104 influenza A samples found positive by PCR from 42 respiratory outbreaks in Italian swine farms were examined by virus isolation. Sixty swine influenza A viruses were isolated (16 H1N1, 28 H1N2 and 16 H3N2) and their growth behaviour on the different substrates was examined. 16/16 H1N1, 28/28 H1N2 and 8/16 of H3N2 viruses were isolated from the CACO-2 cell line, while 7/16 H1N1, 3/28 H1N2 and 16/16 H3N2 viruses were isolated using embryonated chicken eggs. Only 9/16 H1N1, 1/28 H1N2 and 6/16 H3N2 viruses replicated in MDCK cells. A link was found between viral hemagglutinin and the isolation rate on the various substrates. The CACO-2 line was statistically more sensitive (Fisher's exact test, p<0.01) compared to the MDCK cells and embryonated chicken eggs for the isolation of H1N1 and H1N2 subtypes. In contrast influenza A H3N2 virus was isolated more readily in embryonated chicken eggs than in cultured cells (Fisher's exact test, p<0.01). PMID- 19781572 TI - Development of a real-time TaqMan RT-PCR assay for the detection of infectious bronchitis virus in chickens, and comparison of RT-PCR and virus isolation. AB - A sensitive and specific method for the diagnosis of infectious bronchitis virus (IBV) is of great importance. In this study the development of a real-time TaqMan RT-PCR targeting the highly conserved nucleocapsid (N) gene of IBV and including an internal PCR control is described. The assay was specific for IBV and did not detect other avian pathogens, including turkey coronaviruses. A comparative limit of detection was determined for M41, an embryo-adapted strain, and IS/885/00, a poorly embryo-adapted variant. For M41 real-time RT-PCR and virus isolation were one or two times more sensitive than RT-PCR targeting the N or spike glycoprotein (S1) genes, respectively. For IS/885/00, real-time RT-PCR was more sensitive by tenfold than virus isolation and 30- or 40-fold than by N gene or S1 gene RT-PCR, respectively. Real-time RT-PCR and virus isolation were 17-75% more sensitive than RT-PCR targeting the S1 gene for testing tracheal swabs directly from experimentally infected chicks. When tracheal and cloacal swabs from clinical specimens were tested directly, 50% more samples were positive by real-time RT PCR than by the S1 gene RT-PCR. Real-time RT-PCR targeting the N gene is more sensitive than common diagnostic assays, allowing rapid and accurate IBV detection directly from clinical specimens, facilitating differential diagnosis. PMID- 19781570 TI - The regulation of neuronal gene expression by alcohol. AB - In recent years there has been an explosion of interest in how genes regulate alcohol drinking and contribute to alcoholism. This work has been stimulated by the completion of the human and mouse genome projects and the resulting availability of gene microarrays. Most of this work has been performed in drinking animals, and has utilized the extensive genetic variation among different mouse strains. At the same time, a much smaller amount of effort has gone into the in vitro study of the mechanisms underlying the regulation of individual genes by alcohol. These studies at the cellular and sub-cellular level are beginning to reveal the ways in which alcohol can interact with the transcriptional, translational and post-translational events inside the cell. Detailed studies of the promoter regions within several individual alcohol responsive genes (ARGs) have been performed and this work has uncovered intricate signaling pathways that may be generalized to larger groups of ARGs. In the last few years several distinct ARGs have been identified from 35,000 mouse genes, by both the "top-down" approach (ex vivo gene arrays) and the "bottom-up" methods (in vitro promoter analysis). These divergent methodologies have converged on a surprisingly small number of genes encoding ion channels, receptors, transcription factors and proteins involved in synaptic function and remodeling. In this review we will describe some of the most interesting cellular and microarray work in the field, and will outline specific examples of genes for which the mechanisms of regulation by alcohol are now somewhat understood. PMID- 19781573 TI - Development of an antibody-dependent enhancement assay for dengue virus using stable BHK-21 cell lines expressing Fc gammaRIIA. AB - Dengue virus (DENV) causes a wide range of symptoms, from mild febrile illness, dengue fever (DF), to severe life threatening illness, dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS). Subneutralizing concentrations of antibody to DENV enhance DENV infection in Fc gammaR positive cells. This phenomenon is known as antibody-dependent enhancement (ADE). ADE is considered to be a risk factor for DHF and DSS. To develop an ADE assay for DENV, two stable BHK-21 cell lines were established that express Fc gammaRIIA (BHK-Fc gammaRIIA). The BHK-Fc gammaRIIA cell lines were used in an ADE assay with monoclonal antibody (4G2) to DENV, and DENV antibody-positive human sera. Virus growth was quantified directly in BHK-Fc gammaRIIA cells with a standard plaque assay procedure. ADE was detected with monoclonal antibody (4G2) to DENV. ADE was also detected with DENV antibody-positive human sera, but not with DENV antibody-negative human sera. The new ADE assay using BHK-Fc gammaRIIA cells is simple and practical, and is useful for defining the role of ADE in the pathogenesis of DENV infection. PMID- 19781574 TI - Characterization of the hemagglutinin gene of subtype H9 avian influenza viruses isolated in 2007-2009 in China. AB - Subtype H9 avian influenza viruses (AIVs) circulating in China have aroused concerns for their impact on poultry and risk to public health. In this report, three surveys of the viruses were reported, and the hemagglutinin gene of 55 strains of the viruses isolated in China in 2007-2009 was sequenced and analyzed. The results indicated that the prevalence of the viruses was rising in China, and most of the H9 AIVs circulating in the past decade in China belonged to sublineage h9.4.2. The viruses isolated in China in 2007-2009 were a little different from previous strains (genetic distances >7.1%). Meanwhile, a presumably predominant clade of the viruses circulating in China in 2007-2009 was identified. Mutation analysis suggested that the viruses have become of greater risk to public health in recent years. PMID- 19781575 TI - Detection of human mammary tumor virus proteins in human breast cancer cells. AB - Mouse mammary tumor virus (MMTV) has been proven to induce mammary cancer in mice. MMTV-like env gene sequences have been detected in one-third of the human breast tumors studied. The whole proviral structure with 95% homology to MMTV was found in two human breast tumors and was designated as human mammary tumor virus (HMTV). HMTV viral particles with betaretroviral features have been isolated. In addition, a retrovirus called human betaretrovirus (HBRV), homologous to the mentioned retroviruses, has been isolated from tissues of patients with primary biliary cirrhosis. In this report, the expression of HMTV envelope (Env) and capsid (Ca) was detected in 10 primary cultures of human breast cancer containing HMTV sequences (MSSM) by Western blot and fluorescence activated cell sorting (FACS), using a panel of antibodies against HMTV Env, HBRV Env and Ca and the MMTV Env Gp36 and Ca P27 proteins. By contrast, HMTV proteins did not react with antibody against the MMTV Env Gp52 protein. All the antibodies detected MMTV proteins with exception of two out of four monoclonal antibodies against HMTV Env. Approximately 13% of the MSSM cells showed HMTV protein expression by FACS analysis. This report shows the expression of HMTV proteins for the first time in human breast cancer cells using a panel of antibodies against HMTV, HBRV and MMTV proteins. This should be taken into consideration when MMTV antibodies are used to detect HMTV proteins in human tissues. PMID- 19781576 TI - Strategy of the use of 28S rRNA as a housekeeping gene in real-time quantitative PCR analysis of gene transcription in insect cells infected by viruses. AB - Quantitative real-time reverse transcription-PCR (qRT-PCR) has been used widely to measure gene transcription regulation in cells. qRT-PCR must include one or more internal housekeeping genes to normalize data collection. A strategy to use the host cell 28S rRNA as a housekeeping gene in qRT-PCR analysis of gene transcription of insect cells infected by baculovirus and ascovirus was developed. It has been found that the 28S rRNA reverse primer can be incorporated in the oligo-dT-primed cDNA synthesis reaction. In such a way, amplification of 28S cDNA showed lower and less variable cycle thresholds in cells infected by viruses than by using only oligo-dT and other published housekeeping genes such as the TATA box binding protein (TBP) gene, the peptidyl prolyl isomerase A (PPI) gene and the ribosomal protein 13 (L13) gene. Incorporation of the 28S reverse primer in oligo-dT-primed cDNA synthesis also does not interfere with the detection of other polymerase II transcribed genes. PMID- 19781577 TI - In silico screening of small molecule libraries using the dengue virus envelope E protein has identified compounds with antiviral activity against multiple flaviviruses. AB - The flaviviruses comprise a large group of related viruses, many of which pose a significant global human health threat, most notably the dengue viruses (DENV), West Nile virus (WNV) and yellow fever virus (YFV). Flaviviruses enter host cells via fusion of the viral and cellular membranes, a process mediated by the major viral envelope protein E as it undergoes a low pH induced conformational change in the endosomal compartment of the host cell. This essential entry stage in the flavivirus life cycle provides an attractive target for the development of antiviral agents. We performed an in silico docking screen of the Maybridge chemical database within a previously described ligand binding pocket in the dengue E protein structure that is thought to play a key role in the conformational transitions that lead to membrane fusion. The biological activity of selected compounds identified from this screen revealed low micromolar antiviral potency against dengue virus for two of the compounds. Our results also provide the first evidence that compounds selected to bind to this ligand binding site on the flavivirus E protein abrogate fusion activity. Interestingly, one of these compounds also has antiviral activity against both WNV (kunjin strain) and YFV. PMID- 19781578 TI - Non-nucleoside reverse transcriptase inhibitors (NNRTIs), their discovery, development, and use in the treatment of HIV-1 infection: a review of the last 20 years (1989-2009). AB - It is almost 20 years since NNRTIs were identified as a new class of antiretroviral drugs for the treatment of HIV-1 infection. Although they belong to different and diverse chemical families, they share a common and unique mechanism of action: their interaction with HIV-1 reverse transcriptase induces conformational changes that inhibit the catalytic activities of the enzyme. They are characterized by their specificity for HIV-1, which makes them very selective inhibitors of the virus. First generation NNRTIs nevirapine and efavirenz, in combination with other antiretroviral drugs, have become a cornerstone for the treatment of HIV-1 infection, in patients initiating antiretroviral therapy. Further research has led to the discovery and development of next generation NNRTIs with an increased genetic barrier to the development of resistance. Etravirine is the first NNRTI to show sustained virologic efficacy in patients with NNRTI resistant HIV-1. This review covers the NNRTI class of anti-HIV-1 drugs, from the initial discovery of the class in 1990 to the current compounds in clinical development, i.e. around 20 years of research and development efforts. It describes the characteristics of the NNRTIs, their mechanisms of action, HIV-1 resistance to the inhibitors, and the drugs that have been approved for the treatment of HIV-1 infection, or are currently in clinical development. The role of NNRTIs in prevention of HIV transmission is also addressed. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, vol. 85, issue 1, 2010. PMID- 19781579 TI - Brain activation evoked by erotic films varies with different menstrual phases: an fMRI study. AB - In humans, fluctuating hormone levels throughout the menstrual cycle are believed to regulate many cyclical sexual behaviors and motivational processes. However, there is a dearth of research investigating the neural correlates of this phenomenon. We used functional magnetic resonance imaging to identify brain regions involved in sexual arousal's regulatory process. Fifteen female participants were scanned while viewing erotic film excerpts at three time points during a single menstrual cycle: ovulation, menstruation, and at one additional time point. Tripled two-group differences analysis revealed that significant activation in the comparison was observed in non-ovulatory phases of the menstrual cycle in parts of the right inferior frontal gyrus, right lateral occipital cortex, and left postcentral gyrus, as well as in the bilateral superior parietal lobule. Thus, our results indicate that brain activity differs in the ovulatory phase of the menstrual cycle compared to during other menstrual phases. This finding provides neurological evidence for the ovulatory cycle's modulation of the processing of the sexual arousal in female human brain. PMID- 19781580 TI - Studies on wakefulness-promoting effect of memantine in rats. AB - We hypothesized that memantine, an anti-dementia drug, may be useful for the treatment of excessive daytime sleepiness. The effect of memantine on excessive sleepiness after 6 h sleep deprivation was studied in comparison with that of methylphenidate, and the involvement of the dopaminergic system in the wakefulness-promoting effect of memantine was also evaluated. Electrodes for electroencephalogram (EEG) and electromyogram (EMG) were chronically implanted into the cortex and dorsal neck muscle, respectively, of adult male rats. EEG and EMG were recorded with an electroencephalograph for 6 h (19:00-01:00). After sleep deprivation (13:00-19:00), compensatory excessive sleepiness (19:00-01:00) was observed in rats. Memantine (10 mg/kg, p.o.) and methylphenidate (10-30 mg/kg, p.o.) caused a significant increase of sleep latency compared with the control group. Furthermore, a significant increase in total awake time and significant decreases in total non-rapid eye movement (NREM) sleep and REM sleep times were observed by administration of memantine (3-10 mg/kg) and methylphenidate (3-30 mg/kg) compared with control in sleep deprivation rats. Although the effect of memantine was significantly suppressed by D1 receptor antagonist SCH 23390 (0.1 mg/kg, i.p.), D2 receptor antagonist raclopride had no antagonistic effect (1 mg/kg, i.p.). From these results, the effect of memantine on sleepiness after sleep deprivation was similar to that of methylphenidate, and D1 receptor may be involved in the effect of memantine. PMID- 19781581 TI - Calcium-dependent plasma membrane repair requires m- or mu-calpain, but not calpain-3, the proteasome, or caspases. AB - Mechanically damaged plasma membrane undergoes rapid calcium-dependent resealing that appears to depend, at least in part, on calpain-mediated cortical cytoskeletal remodeling. Cells null for Capns1, the non-catalytic small subunit present in both m- and mu-calpains, do not undergo calcium-mediated resealing. However, it is not known which of these calpains is needed for repair, or whether other major cytosolic proteinases may participate. Utilizing isozyme-selective siRNAs to decrease expression of Capn1 or Capn2, catalytic subunits of mu- and m calpains, respectively, in a mouse embryonic fibroblast cell line, we now show that substantial loss of both activities is required to compromise calcium mediated survival after cell scrape-damage. Using skeletal myotubes derived from Capn3-null mice, we were unable to demonstrate loss of sarcolemma resealing after needle scratch or laser damage. Isolated muscle fibers from Capn3 knockout mice also efficiently repaired laser damage. Employing either a cell line expressing a temperature sensitive E1 ubiquitin ligase, or lactacystin, a specific proteasome inhibitor, it was not possible to demonstrate an effect of the proteasome on calcium-mediated survival after injury. Moreover, several cell-permeant caspase inhibitors were incapable of significantly decreasing survival or inhibiting membrane repair. Taken together with previous studies, the results show that m- or mu-calpain can facilitate repair of damaged plasma membrane. While there was no evidence for the involvement of calpain-3, the proteasome or caspases in early events of plasma membrane repair, our studies do not rule out their participation in downstream events that may link plasma membrane repair to adaptive remodeling after injury. PMID- 19781582 TI - TI-VAMP/VAMP7 and VAMP3/cellubrevin: two v-SNARE proteins involved in specific steps of the autophagy/multivesicular body pathways. AB - During reticulocyte maturation, some membrane proteins and organelles that are not required in the mature red cell are lost. Several of these proteins are released into the extracellular medium associated with the internal vesicles present in multivesicular bodies (MVBs). Likewise, organelles such as mitochondria and endoplasmic reticulum are wrapped into double membrane vacuoles (i.e., autophagosomes) and degraded via autophagy. Morphological, molecular, and biochemical studies have shown that autophagosomes fuse with MVBs forming the so called amphisomes, a prelysosomal hybrid organelle. SNAREs are key molecules of the vesicle fusion machinery. TI-VAMP/VAMP7 and VAMP3/cellubrevin are two v-SNARE proteins involved in the endocytic and exocytic pathways. We have previously shown that in the human leukemic K562 cells, Rab11 decorates MVBs and it is necessary for fusion between autophagosomes with MVBs. In the present report, we present evidence indicating that VAMP3 is required for the fusion between MVBs with autophagosomes to generate the amphisome, allowing the maturation of the autophagosome, but it does not seem to be involved in the next step, i. e., fusion with the lysosome. On the other hand, we demonstrate that VAMP7 is necessary for this latter event, allowing the completion of the autophagic pathway. Furthermore, VAMP7 and ATPase NSF, a protein required for SNAREs disassembly, participate in the fusion between MVBs with the plasma membrane to release the internal vesicles (i.e., exosomes) into the extracellular medium. PMID- 19781583 TI - Identification of fengycin homologues from Bacillus subtilis with ESI-MS/CID. AB - Bacillus subtilis fmbJ (CGMCC no.0943) was used to produce lipopeptides antibiotics fengycin. The fengycin mixture was precipitated with 6N HCl and extracted by methanol. Electrospray ionization mass spectrometry/collision induced dissociation (ESI-MS/CID) were used to analyze the fengycin mixture. In the ESI-MS/CID spectra of fengycin molecular ions, production ions (m/z 1080, m/z 966, m/z 1108 and m/z 994) were always detected. Therefore, these production ions (m/z 1080, m/z 966, m/z 1108 and m/z 994) could be used as fingerprints to quickly detect fengycin A and fengycin B. By the method of ESI-MS/CID, six homologues of fengycin A with C14 to 19 and four homologues of fengycin B with C14 to 17 were characterized. The method will be useful for rapidly determining whether a strain produces fengycin homologues. PMID- 19781584 TI - PEI-DNA complexes with higher transfection efficiency and lower cytotoxicity. PMID- 19781585 TI - Tachykinin-related peptides and their receptors in invertebrates: a current view. AB - Members of the tachykinin peptide family have been well conserved during evolution and are mainly expressed in the central nervous system and in the intestine of both vertebrates and invertebrates. In these animals, they act as multifunctional messengers that exert their biological effects by specifically interacting with a subfamily of structurally related G protein-coupled receptors. Despite the identification of multiple tachykinin-related peptides (TKRPs) in species belonging to the insects, crustaceans, mollusks and echiuroid worms, only five invertebrate receptors harboring profound sequence similarities to mammalian receptors for tachykinins have been functionally characterized to date. Three of these have been cloned from dipteran insect species, i.e. NKD (neurokinin receptor from Drosophila), DTKR (Drosophila tachykinin receptor) and STKR (tachykinin-related peptide receptor from the stable fly, Stomoxys calcitrans). In addition, two receptors from non-insect species, present in echiuroid worms and mollusks, respectively have been identified as well. In this brief review, we will survey some recent findings and insights into the signaling properties of invertebrate tachykinin-related peptides via their respective receptors. In this context, we will also point out the necessity to take into account differences in signaling mechanisms induced by distinct TKRP isoforms in insects. PMID- 19781586 TI - Expression of NMS and NMU2R in the pig reproductive axis during the estrus cycle and the effect of NMS on the reproductive axis in vitro. AB - Evidence has revealed that neuromedin S (NMS) and neuromedin U-receptor type-2 (NMU2R) mRNAs are expressed in the central nervous system and reproductive organs. Previous data indicated that variation of NMS and NMU2R was due to the phases of the adult rat hypothalamus estrus cycle. However, the expression and function of NMS in the pig reproductive axis remains unexplored. In this study, 16 virginal gilts were classified into four groups: proestrus, estrus, diestrus 1, and diestrus 2; the expression of NMS and NMU2R in the cyclic pig hypothalamus pituitary-ovary axis was studied by reverse transcriptaion-polymerase chain reaction (RT-PCR), and the effect of NMS on the reproductive axis in vitro was detected by radioimmunoassay (RIA). The cloned pig NMS and NMU2R sequences were 82% and 90.2% identical to those of the corresponding human homologues, respectively. RT-PCR showed that NMS and NMU2R mRNA expression in the hypothalamus and pituitary changed with the estrus cycle, i.e., with the highest level in the proestrus group and the lowest in the estrus group. In the ovary, NMS and NMU2R expression was highest in the diestrus 2 group and the lowest in the proestrus group. In the in vitro study, different concentrations of NMS induced the release of gonadotropin-releasing hormone, luteinizing hormone, and estradiol at different levels of the reproductive axis. Taken together, the expression pattern of NMS during the estrus cycle and its role in reproductive hormones in vitro provide novel evidences of the potential roles of NMS in the regulation of pig reproduction. PMID- 19781587 TI - Cholinergic protection via alpha7 nicotinic acetylcholine receptors and PI3K-Akt pathway in LPS-induced neuroinflammation. AB - The present study was planned to investigate the effect of anti-cholinesterase drugs donepezil and neostigmine on neuroinflammation induced by intracerebroventricular administration of lipopolysaccharide (LPS, 50 microg) in rat. Proinflammatory cytokines (TNF-alpha and IL-1beta), expressions of iNOS and COX-2, acetylcholinesterase activity, malondialdehyde and reduced glutathione were studied in different brain regions at 24h of LPS injection. Donepezil was found to decrease the LPS-induced AChE activity and oxidative stress in all the brain regions. It also inhibited the LPS-induced proinflammatory cytokines and iNOS expression but did not affect the increased COX-2 expression whereas neostigmine treatment had no effect on LPS-induced proinflammatory cytokines. Methyllycaconitine (MLA), a alpha7 nicotinic acetylcholine receptor antagonist, significantly antagonized the donepezil mediated inhibition of LPS-induced proinflammatory cytokines, indicating that alpha7 nicotinic acetylcholine receptor subunit was playing a role in regulation of neuroinflammation. The phosphorylation of Akt, an effector of PI3K, increased with donepezil treatment. These results suggest that increased cholinergic activity in brain by donepezil prevents LPS-induced neuroinflammation via alpha7-nAChRs, followed by the PI3K Akt pathway and this system may form the basis for the development of novel agents for reversing neuroinflammation or provide new indications for existing drugs. PMID- 19781588 TI - Short-term effects of zinc on acetylcholine metabolism and viability of SN56 cholinergic neuroblastoma cells. AB - Excessive accumulation of zinc in the brain is one of putative factors involved in pathomechanism of cholinergic encephalopathies. The aim of this work was to investigate whether short-term increase of zinc concentration in the extracellular space may affect energy and acetylcholine metabolism in SN56 cholinergic cells of septal origin. Short 30 min exposition of SN56 cells to increasing zinc levels caused greater loss of viability of differentiated (DC, [EC(0.4)] 0.09 mM) than nondifferentiated cells (NC, [EC(0.4)] 0.14 mM). Concentration-dependent accumulation of zinc displayed exponential non-saturable kinetics. Zinc accumulation caused the decrease of calcium accumulation in mitochondria and its increase in cytoplasmic compartment of SN56 cells. Significant inverse and direct correlations were found between zinc accumulation and calcium levels in mitochondrial (r=-0.96, p=0.028) and cytoplasmic (r=0.97, p=0.028) compartments of DC, respectively. Zinc exerted similar inhibition of pyruvate dehydrogenase, aconitase and isocitrate dehydrogenase both in NC and DC homogenates, at Ki values equal to about 0.07, 0.08 and 0.005 mM, respectively. On the other hand, ketoglutarate dehydrogenase activity in DC was inhibited by zinc (Ki 0.0005 mM) 8 times stronger that in NC (Ki 0.004 mM). Also zinc-evoked decreases in acetylcholine content and its release were significantly greater in DC than in NC. Same conditions caused suppression of cytoplasmic and mitochondrial content of acetyl-CoA, that positively correlated with inhibition of transmitter functions (r=0.995, p=005) and loss of cell viability (r=0.990, p=0.0006), respectively. Significant correlations were also found in zinc challenged cells between pyruvate dehydrogenase activity and both mitochondrial acetyl-CoA content and cell viability. These data indicate that pyruvate dehydrogenase-dependent acetyl-CoA synthesis in neuronal mitochondria may be a primary target for short-term neurotoxic effects of zinc. In consequence, shortages of acetyl-CoA in the mitochondrial compartment would cause fast loss of functional and structural integrity of cholinergic neurons. PMID- 19781590 TI - Germicidal activity of antimicrobials and VIOlight Personal Travel Toothbrush sanitizer: an in vitro study. AB - OBJECTIVES: The study evaluated the antibacterial effect of VIOlight (VL) Personal Travel Toothbrush Sanitizer on biofilms after toothbrush exposure to human saliva compared to Listerine Antiseptic (LA), 3% hydrogen peroxide (3%HP) and water. METHODS: Twenty toothbrush heads (n=5/Gp) were immersed in saliva and to allow for bacterial growth and biofilm formation for 24h. VL sanitizer and antiseptic(s) were used for 7 min; after treatment, brush heads were rinsed and placed into 10 mL of 2x AOAC Letheen Broth, sonicated and vortexed for 10s. Tenfold serial dilutions were prepared and plated and incubated aerobically and anaerobically. Log(10)CFU/mL data were compared utilizing ANOVA (p<0.05). RESULTS: Results showed 3%HP with significantly lower counts than LA, VL and control for aerobic and anaerobic bacteria. LA had significantly lower counts than VL and control for both types of bacteria and VIOlight had significantly lower counts than the control for aerobic bacteria. 3%HP and LA were most effective in rapidly killing bacteria when compared to VIOlight. CONCLUSIONS: Results showed that 3% hydrogen peroxide was most effective in reducing the numbers of both aerobic and anaerobic bacteria present on the toothbrush heads. Under the same test conditions, Listerine Antiseptic was shown to be secondarily effective for the same bacteria while the VIOlight unit was the least effective when compared to the other treatment groups. PMID- 19781589 TI - Antioxidant, anti-microbial and antimutagenicity activities of pistachio (Pistachia vera) green hull extract. AB - Antioxidant, anti-microbial and antimutagenicity activities of pistachio (Ahmadaghaei variety) green hull extracts (crude and purified extracts) were studied. At first, different solvents were compared for determining of the best solvent for extraction of phenolic compounds from pistachio green hull. Water and acetonitrile with 49.32 and 6.22 (mg of gallic acid equivalents/g sample) were the best and the worst solvent in the extraction of phenolic compounds, respectively. The antioxidant capacity of crude and purified extracts were assessed through ABTS assay, DPPH assay and beta-carotene bleaching (BCB) method. A concentration-dependent antioxidative capacity was verified in ABTS, DPPH assays and BCB method. The anti-microbial capacity was screened against Gram positive and Gram negative bacteria, and fungi. Aqueous and purified extracts inhibited the growth of Gram positive bacteria; Bacillus cereus was the most susceptible one with MIC of 1mg/mL and 0.5mg/mL for the crude and purified extracts, respectively. The results of antimutagenicity test showed that phenolic compounds of pistachio green hull have antimutagenicity activity against direct mutagen of 2-nitrofluorene. The results obtained indicate that pistachio green hull may become important as a cheap and noticeable source of compounds with health protective potential and anti-microbial activity. PMID- 19781591 TI - Resin-dentine interfacial morphology following CPP-ACP treatment. AB - OBJECTIVES: To evaluate the quality of bonded resin-dentine interfaces produced by two self-etching primer adhesives after casein phosphopeptide-amorphous calcium phosphate (CPP-ACP) treatment, in comparison to untreated dentine. METHODS: Thirty-four adult molar teeth were sectioned to obtain dentine with tubule orientations parallel/oblique or perpendicular to the surface. The specimens were divided into 'smear layer' (1A, 1B) and 'no smear layer' groups, after treatment with 15% EDTA (2A, 2B). The specimens were then left either untreated (1A, 2A) or treated (1B, 2B) with CPP-ACP paste (Tooth Mousse, GC Corp.) for 60 min x 7 days. Each treatment group was divided into three subgroups and specimens etched/conditioned (no conditioning; 30-40% phosphoric acid (H(3)PO(4)); 20% polyacrylic acid) and bonded with either a 2-step self-etching primer adhesive (Clearfil SE Bond, Kuraray Medical) or an 'all-in-one' adhesive (G-Bond, GC Corp.) and a hybrid resin composite. After 24-h water storage, the bonded specimens were sectioned, polished up to 4000-grit abrasive silicon carbide paper and 0.25-microm diamond paste, prepared for FE-SEM using the acid base technique, critical point-dried, gold-coated and examined. Bonded and fractured dentine interfaces were also prepared and examined. RESULTS: The 2-step adhesive produced a similar appearance of bonded resin-dentine interface irrespective of smear layer group, treatment or etching/conditioning. After polyacrylic acid conditioning, the 'all-in-one' adhesive exhibited more areas with bond failures. The bond failures were within the hybrid layer and more pronounced following CPP-ACP treatment. CONCLUSION: The quality of the bonded resin-dentine interface produced after CPP-ACP treatment may depend on the adhesive system used. PMID- 19781592 TI - Morphological and chemical characterization of tooth enamel exposed to alkaline agents. AB - OBJECTIVES: In this study, morphological and chemical changes in teeth enamel exposed to alkaline agents, with or without surfactants, have been investigated. In addition, chemical effects of the organic surface layer, i.e. plaque and pellicle, were also investigated. METHODS: The present study was conducted using several techniques: Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), X-ray diffraction (XRD) and scanning electron microscopy (SEM). RESULTS: From XPS-measurements, it was found that exposure to alkaline solutions resulted in a massive removal of carbon from the tooth surface, and that the addition of surfactants increased the rate under present conditions. Based on the results from the FTIR-analysis, no substitution reactions between phosphate, carbonate and hydroxide ions in the enamel apatite could be detected. From a minor SEM-analysis, degradation and loss of substance of the enamel surface was found for the exposed samples. From XRD-analysis, no changes in crystallinity of the enamel apatite could be found between the samples. CONCLUSIONS: The findings in this study show that exposure to alkaline solutions results in a degradation of enamel surfaces very dissimilar from acidic erosion. No significant erosion or chemical substitution of the apatite crystals themselves could be discerned. However, significant loss of organic carbon at the enamel surface was found in all exposed samples. The degradation of the protective organic layer at the enamel surface may profoundly increase the risk for caries and dental erosion from acidic foods and beverages. PMID- 19781593 TI - In vitro evaluation of bonding effectiveness to dentin of all-in-one adhesives. AB - OBJECTIVES: The study was aimed at assessing the bonding potential of all-in-one adhesives to dentin. METHODS: The microtensile bond strength of the all-in-one adhesives Bond Force (Tokuyama), AdheSE One (Ivoclar-Vivadent), and Xeno V (Dentsply) was measured in comparison with the etch-and-rinse system XP Bond (Dentsply). The ultrastructural characteristics of dentin-adhesive interface were observed under scanning electron microscope (SEM). Twenty human extracted third molars had their mid-coronal dentin exposed and ground with wet 600-grit SiC paper in order to create a standardized smear layer. Bonding procedures were performed according to the manufacturers' instructions and microtensile beams were obtained with the "non-trimming" technique. The bond strengths in MPa were statistically analyzed including pre-test failures as "zero" values (Kolmogorov Smirnov test, Levene's test, One-Way ANOVA, Tukey's test p<0.05). RESULTS: The following bond strengths were recorded in MPa (mean+/-standard deviation): AdheSE One 31.7+/-21.3; Xeno V 42.8+/-26.4; Bond Force 43.3+/-22.1; XP Bond 51.9+/-18.6. The statistical analysis demonstrated that the bond strengths achieved by Bond Force and Xeno V were similar to that of the etch-and-rinse adhesive, whereas the bond strength of AdheSE One was significantly lower. A distinct hybrid layer with resin tags was seen only in XP Bond specimens. All-in-one adhesives demonstrated a rather superficial interaction with the dentin substrate. CONCLUSIONS: Although the strongest bond to dentin was established by the etch-and-rinse system, however the all-in-one adhesives containing organic solvents reached bond strength levels that were comparable from a statistical point of view. PMID- 19781594 TI - Spectrophotometric assessment of the effectiveness of Opalescence PF 10%: a 14 month clinical study. AB - OBJECTIVES: To evaluate the effectiveness of Opalescence PF 10% just after treatment, at 6-month follow-up and at a 14-month follow-up period. METHODS: Opalescence PF 10% was applied nightly for 14 days. The color of teeth 11 and 21 of 17 subjects were measured with a spectrophotometer (L*; a*; b*) before treatment, just after treatment (14 days), after 6 months and after 14 months. Subjects were instructed to take note of any tooth sensitivity. RESULTS: For all three components (L*, a* and b*) statistical significant differences (p<0.05) in the values between base-line, after treatment (14 days later), after 6 months and after 14 months were found (Wilcoxon Signed Rank Sum Test). The decrease in L* was about 20% after 6 months and about 50% after 14 months. The a* value decreased approximately 14% after 6 months but was worse after 14 months than at the beginning. The b* value decreased the least with about 9% after 6 months and about 8% after 14 months. The decrease in DeltaE(ab)(*) was approximately 20% after 14 months. Less than 20% of the subjects experienced mild tooth sensitivity just after treatment. CONCLUSION: Significantly whiter teeth were found after treatment as well as after a 6-month follow-up period. The whiteness/brightness (L*) decreased with approximately 50% after 14 months and the a* value with approximately 50% after 7 months, while the yellowness (b* value) remained even after 14 months. CLINICAL IMPLICATIONS: The product is an effective tooth whitener resulting in only low tooth sensitivity. Re-bleaching could be done at about 14 months. PMID- 19781596 TI - On prokaryotic intelligence: strategies for sensing the environment. AB - The adaptive relationship with the environment is a sine qua non condition for any intelligent system. Discussions on the nature of cellular intelligence, however, have not systematically pursued yet the question of whether there is a fundamental way of sensing the environment, which may characterize prokaryotic cells, or not. The molecular systems found in bacterial signaling are extremely diverse, ranging from very simple transcription regulators (single proteins comprising just two domains) to the multi-component, multi-pathway signaling cascades that regulate crucial stages of the cell cycle, such as sporulation, biofilm formation, dormancy, pathogenesis or flagellar biosynthesis. The combined complexity of the environment and of the cellular way of life is reflected as a whole in the aggregate of signaling elements: an interesting power-law relationship emerges in that regard. In a basic taxonomy of bacterial signaling systems, the first level of complexity corresponds to the simplest regulators, the "one-component systems" (OCSs), which are defined as proteins that contain known or predicted input and output domains but lack histidine kinase and receiver domains. They are evolutionary precursors of the "two-component systems" (TCSs), which include histidine protein-kinase receptors and an independent response regulator, and are considered as the central signaling paradigm within prokaryotic organisms. The addition of independent receptors begets further functional complexity: thus, "three-component systems" (ThCSs) should be applied to those two-component systems that incorporate an extra non-kinase receptor to activate the protein-kinase. Further, the combined information processing functions (cross-talk) and integrative dynamics that OCS, TCS and ThCS may achieve together in the prokaryotic cell have to be depicted, as well as the relationship of these informational functions with the life cycle organization and its checkpoints. Finally, the extent to which formal models would capture the ongoing relationship of the living cell with its medium has to be gauged, in the light of both the complexity of molecular recognition events and the impredicative nature of living systems. PMID- 19781595 TI - Molecular dynamics analysis of the wild type and dF508 mutant structures of the human CFTR-nucleotide binding domain 1. AB - Mutations of CFTR (Cystic Fibrosis transmembrane Conductance Regulator), a membrane protein expressed in the epithelium that forms a chloride channel, cause a chronic, developmental and hereditary disease, known as Cystic Fibrosis. The most common mutation is the deletion of F508, a residue present in the first nucleotide binding domain (NBD1). We studied the thermodynamic properties of NBD1 wild type (WT) and mutant (dF508), starting from the crystallographic structures in the Protein Data Bank using the techniques of Molecular Dynamics. The two structures were similarly stable at room temperature, showed no change enthalpy or entropy, maintaining the same dimensions and the same order of magnitude of atomic fluctuations; the only difference was the energy of interaction with the solvent, in which the mutant appears slightly disadvantaged; these differences between the two models are at microscopic level and relate to local variations (in residues at 8 A from F508) of the surface exposed to the solvent. We also found a decrease in the mutant of about 30 times of affinity for ATP compared to WT. PMID- 19781597 TI - Negative BOLD during tongue movement: a functional magnetic resonance imaging study. AB - The aim of this functional magnetic resonance imaging (fMRI) study was to evaluate negative blood oxygen level-dependent (BOLD) signals during voluntary tongue movement. Deactivated (Negative BOLD) regions included the posterior parietal cortex (PPC), precuneus, and middle temporal gyrus. Activated (Positive BOLD) regions included the primary somatosensory-motor area (SMI), inferior parietal lobule, medial frontal gyrus, superior temporal gyrus, insula, lentiform nucleus, and thalamus. The results were not consistent with previous studies involving unilateral hand and finger movements showing the deactivation of motor related cortical areas including the ipsilateral MI. The areas of Negative BOLD in the PPC and precuneus might reflect specific neural networks relating to voluntary tongue movement. PMID- 19781598 TI - Modulation of the masseteric monosynaptic reflex by stimulation of the vestibular nuclear complex in rats. AB - The effect of stimulation of the vestibular nuclear complex (VN) on the masseteric monosynaptic reflex (MMR) was studied in anesthetized rats. The MMR was evoked by electrical stimulation of the mesencephalic trigeminal nucleus and was recorded, bilaterally, as the electromyographic responses of the masseter muscles. Conditioning electrical stimulation of the medial vestibular nucleus (MVN) facilitated the MMR bilaterally, as did microinjection of monosodium glutamate into the MVN. In contrast, conditioning electrical stimulation of the inferior vestibular nucleus (IVN) inhibited the MMR bilaterally. Microinjection of monosodium glutamate into the IVN also inhibited the MMR bilaterally. Conditioning electrical stimulation of the lateral and superior vestibular nuclei did not modulate the MMR. These results suggest that the MVN and the IVN are involved in modulation of the MMR and plays an important role in controlling jaw movements. PMID- 19781599 TI - Investigation of Van Gogh-like 2 mRNA regulation and localisation in response to nociception in the brain of adult common carp (Cyprinus carpio). AB - The Van Gogh-like 2 (vangl2) gene is typically associated with planar cell polarity pathways, which is essential for correct orientation of epithelial cells during development. The encoded protein of this gene is a transmembrane protein and is highly conserved through evolution. Van Gogh-like 2 was selected for further study on the basis of consistent regulation after a nociceptive stimulus in adult common carp and rainbow trout in a microarray study. An in situ hybridisation was conducted in the brain of mature common carp (Cyprinus carpio), 1.5 and 3 h after a nociceptive stimulus comprising of an acetic acid injection to the lips of the fish and compared with a saline-injected control. The vangl2 gene was expressed in all brain regions, and particularly intensely in neurons of the telencephalon and in ependymal cells. In the cerebellum, a greater number (P=0.018) of Purkinje cells expressed vangl2 after nociception (n=7) compared with controls (n=5). This regulation opens the possibility that vangl2 is involved in nociceptive processing in the adult fish brain and may be a novel target for central nociception in vertebrates. PMID- 19781600 TI - Mitochondrial dysfunction enhances the migration of vascular smooth muscles cells via suppression of Akt phosphorylation. AB - BACKGROUND: Atherosclerosis is one of the major complications of diabetes, which may result from insulin resistance via mitochondrial dysfunction. Although a strong association between insulin resistance and cardiovascular disease has been suggested, it is not clear yet whether stress-inducing factors damage mitochondria and insulin signaling pathway in cardiovascular tissues. METHODS: We investigated whether stress-induced mitochondrial dysfunction might alter the insulin/Akt signaling pathway in A10 rat vascular smooth muscle cells (VSMC). RESULTS: The treatment of oxidized low density lipoprotein (oxLDL) decreased ATP contents, mitochondrial respiration activity, mRNA expressions of OXPHOS subunits and IRS-1/2 and insulin-mediated phosphorylations of Akt and AMP-activated protein kinase (AMPK). Similarly, dideoxycytidine (ddC), the mtDNA replication inhibitor, or rotenone, OXPHOS complex I inhibitor, inhibited the insulin mediated pAkt while increased pAMPK regardless of insulin. Reciprocally, an inhibitor of Akt, triciribine (TCN), decreased cellular ATP contents. Overexpression of Akt dominant positive reversed the oxLDL- or ddC-mediated ATP decrease but AMPK activator did not. Akt activation also normalized the aberrant VSMC migration induced by ddC. CONCLUSIONS: Defective insulin signaling and mitochondrial function may collectively contribute to developing cardiovascular disease. GENERAL SIGNIFICANCE: Akt may be a possible therapeutic target for treating insulin resistance-associated atherosclerosis. PMID- 19781601 TI - Pineal projections in the zebrafish (Danio rerio): overlap with retinal and cerebellar projections. AB - The pineal organ in fishes is a photoreceptive organ with dual outputs, neuroendocrine and neural. The neural projections of the zebrafish pineal were experimentally studied by means of tract-tracing with carbocyanine dyes (1,1' dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine perchlorate (DiI), 3,3' dioctadecyloxacarbocyanine perchlorate (DiO)). Double-labeling experiments were also performed in order to investigate the degree of overlapping of pineal, retinal or cerebellar projections in zebrafish. The pineal organ sends efferent fibers bilaterally to the rostral hypothalamus, thalamus, pretectum, posterior tubercle and the mesencephalic tegmentum. A few pinealofugal fibers could also be traced to the optic tectum. Most of the targets of the zebrafish pineal also receive retinal and/or cerebellar afferents, indicating a high degree of overlap with these projections. Since most of the targets of the pineal projections of zebrafish appear to be premotor and precerebellar centers, the neural output of the pineal organ is probably, because of its photoreceptive and circadian function, involved in photic and circadian modulation of these centers. PMID- 19781602 TI - Phonological activation in chinese reading: an event-related potential study using low-resolution electromagnetic tomography. AB - The aim of the present study was to examine the pattern of phonological activation during Chinese sentence reading. Terminal words in high cloze sentences were manipulated across six conditions defined by word frequency and ending types. The P200 was smaller for the congruent targets than for the unrelated control targets, while there were no differences between the homophonic and unrelated control targets. No frequency effect on the P200 was observed. More importantly, a reduced N400 to the homophonic words was observed independent of word frequency. Source analysis by low resolution electromagnetic tomography (LORETA) revealed that the highly activated areas for the P200 were located at bilateral superior frontal (BA 6) and occipital (BA 17, 18 and 19) areas, while the N400 was located at left medial frontal (BA 6) area. These findings suggest that phonology is activated automatically for both high- and low-frequency words during Chinese sentence reading, even when the task is not focused on pronunciation. PMID- 19781603 TI - Dammarane-type glycosides and long chain sesquiterpene glycosides from Gynostemma yixingense. AB - A new dammarane-type glycoside and a new long chain sesquiterpene glycoside, along with nine known compounds 20(S)-ginsenoside Rh1 (3), 20(R)-ginsenoside Rh1 (4), ginsenoside F1 (4), amarantholidoside IV (6), ginsenoside Rc (7), 20(S) ginsenoside Rg2 (8), 20(R)-ginsenoside Rg2 (9), ginsenoside Rd (10) and gypenoside XLVI (11) were isolated from Gynostemma yixingense. The structures of the new compounds were determined on the basis of spectroscopic analysis, including 1D-, 2D-NMR and ESI-MS techniques as well as by comparison of the spectral data with those of related compounds as 2 alpha,3beta,20(S) trihydroxydammar-24-ene-3-O-[beta-D-glucopyranosyl((1-->2)-beta-D-glucopyranosyl] 20-O-[beta-D-xylopyranosyl((1-->6)-beta-D-glucopyranoside] (1) (2E,6E)-10-beta-D glucopyranosyl-1,10,11-trihydroxy-3,7,11-trimethyldodeca-2,6-diene (2). PMID- 19781604 TI - Antituberculosis activity of alkylated mulinane diterpenoids. AB - Natural azorellane and mulinane diterpenoids show antituberculosis activity, which is increased by methylation of their free carboxyl group. We have systematically investigated the effect of alkylation in this class of diterpenoids and found that the profile of bioactivity is relatively unaffected by the introduction of short alkyl groups, both linear and branched. In this investigation, three semisynthetic diterpenoids, 13 hydroxy-mulin-11-en-20-oic acid n-propyl ester (3) and the n-propyl (19) and n-butyl (20) esters of isomulinic acid, showed the strongest antituberculosis activity (MIC=6.25 microg/mL) against a drug-resistant strain of Mycobacterium tuberculosis. PMID- 19781605 TI - Determination of poly(epsilon-caprolactone) solubility parameters: application to solvent substitution in a microencapsulation process. AB - The evolution of regulation on chemical substances (i.e. REACH regulation) calls for the progressive substitution of toxic chemicals in formulations when suitable alternatives have been identified. In this context, the method of Hansen solubility parameters was applied to identify an alternative solvent less toxic than methylene chloride used in a microencapsulation process. During the process based on a multiple emulsion (W/O/W) with solvent evaporation/extraction method, the solvent has to dissolve a polymer, poly(epsilon-caprolactone) (PCL), which forms a polymeric matrix encapsulating or entrapping a therapeutic protein as the solvent is extracted. Therefore the three partial solubility parameters of PCL have been determined by a group contribution method, swelling experiments and turbidimetric titration. The results obtained allowed us to find a solvent, anisole, able to solubilize PCL and to form a multiple emulsion with aqueous solutions. A feasibility test was conducted under standard operating conditions and allowed the production of PCL microspheres. PMID- 19781606 TI - Fabrication of drug nanoparticles by evaporative precipitation of nanosuspension. AB - Evaporative precipitation of nanosuspension (EPN) was used to fabricate nanoparticles of a poorly water-soluble antimalarial drug, artemisinin (ART), with the aim of enhancing its dissolution rate. We investigated the nanoparticle fabrication of ART via a full factorial experimental design considering the effects of drug concentration and solvent to antisolvent ratio on the physical, morphological and dissolution properties of ART. Characterization of the original ART powder and EPN prepared ART nanoparticles was carried out by scanning electron microscopy, differential scanning calorimetry (DSC), X-ray diffraction (XRD) and dissolution tester. DSC and XRD studies suggested that the crystallinity of EPN prepared ART nanoparticles decreased with increasing drug concentration and ratio of solvent to antisolvent. The particle diameters of EPN prepared ART nanoparticles were found to be 100-360 nm. The dissolution of EPN prepared ART nanoparticles markedly increased as compared to the original ART powder. A percent dissolution surface-response model was used to elucidate the significant and direct relationships between drug concentration and solvent to antisolvent ratio on one hand and percent dissolution on the other hand. The best dissolution percent was found to be 75.9%, at the drug concentration of 15 mg/mL and solvent to antisolvent ratio (by volume) of 1:20. PMID- 19781607 TI - Wistar rat skin as surrogate for human skin in nortriptyline hydrochloride patch studies. AB - Six different matrices were prepared containing nortriptyline hydrochloride (NTH) with hydroxypropyl-methyl-cellulose as polymer. A mixture of transdermal enhancers was included as part of the vehicle. Diffusion studies were carried out through Wistar rat full thickness skin using Franz cells. They were compared with previously determined human heat separated epidermis in order to test if this animal can be used as model for in vivo assays. A linear correlation was obtained between NTH diffusion coefficients through both skin types (r2=0.996). PMID- 19781608 TI - Enhancement of solubility and dissolution of coenzyme Q10 using solid dispersion formulation. AB - This study aimed to develop a stable solid dispersion of Coenzyme Q(10) (CoQ(10)) with high aqueous solubility and dissolution rate. Among various carriers screened, poloxamer 407 was most effective to form a superior solid dispersion of CoQ(10) having significantly enhanced solubility. Particularly, solid dispersion of CoQ(10) with poloxamer 407 in the weight ratio of 1:5 prepared by melting method enhanced the solubility of CoQ(10) to the greatest extent. However, it exhibited poor stability and hence Aerosil 200 (colloidal silicon dioxide) was incorporated into the solid dispersion as an adsorbent to inhibit the recrystallization process. The solid dispersion of CoQ(10), poloxamer 407 and Aerosil 200 in the weight ratio of 1:5:6 exhibited improved stability with no significant change in solubility during the 1-month stability test. Moreover, the solid dispersion formulation containing Aerosil 200 significantly enhanced the extent of drug release (approx. 75% release) as well as the dissolution rate of CoQ(10). In conclusion, the present study has developed the stable solid dispersion formulation of CoQ(10) with poloxamer 407 and Aerosil 200 for the enhanced solubility and dissolution of CoQ(10), which could also offer some additional advantages including ease of preparation, good flowability and cost effectiveness. PMID- 19781609 TI - Preparation of nanobubbles for ultrasound imaging and intracelluar drug delivery. AB - Echogenic bubble formulations have wide applications in both disease diagnosis and therapy. In the current study, nanobubbles were prepared and the contrast agent function was evaluated in order to study the nanosized bubble's property for ultrasonic imaging. Coumarin-6 as a model drug was loaded into nanobubbles to investigate the drug delivery potential to cells. The results showed that the nanobubbles composed of 1% of Tween 80, and 3 mg/ml of lipid worked well as an ultrasonic contrast agent by presenting a contrast effect in the liver region in vivo. The drug-loaded nanobubbles could enhance drug delivery to cells significantly, and the process was analyzed by sigmoidally fitting the pharmacokinetic curve. It can be concluded that the nanobubble formulation is a promising approach for both ultrasound imaging and drug delivery enhancing. PMID- 19781610 TI - The menopause triggers hearing decline in healthy women. AB - BACKGROUND: Epidemiological studies have shown that women have better high frequency thresholds than men in virtually all age groups, and that age-related hearing decline starts after 30 in men but not until after the age of 50 in women. This coincides with the menopausal transition in most women, thus leading us to hypothesize that the menopause triggers auditory deterioration, possibly due to reduced levels of endogenous estrogens, which are known to have protective effects on the auditory system. METHODS: 104 women with a mean age 51.2 at baseline, were tested with pure tone audiometry twice with an average interval of 7.5 years. The age at the final menstrual period (FMP) was reported by all women. Hearing decline at individual frequencies was calculated. RESULTS: Women with a FMP 0-4 years ago, had a rate of high frequency hearing decline of 0.9-1.5dB/year in the left ear, those with 5-7 years since the FMP had a corresponding rate of 1.1-1.5dB/year in the right ear, and 8-13 years after the FMP the decline was more subtle, 0.7-1.1dB/year in both ears. CONCLUSION: The menopause appears to act as a trigger of a relatively rapid age-related hearing decline in healthy women, starting in the left ear. PMID- 19781611 TI - Cytotoxic and antibacterial triterpenoids derivatives from Clematis ganpiniana. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The roots and rhizomes of Clematis are commonly used as an analgesic, abirritative, antibacterial, antiphlogistic, anticancer and diuretic agent. The Naxi people traditionally used Clematis ganpiniana's (Levl. Et Vant.) as a diuretic agent, an anti-inflammatory and anticancer remedy. AIM OF STUDY: To investigate the cytotoxic and antibacterial components from Clematis ganpiniana. MATERIALS AND METHODS: The aboveground part of Clematis ganpiniana was isolated by chromatographic techniques. Structures of isolated compounds were identified by spectroscopic methods and comparison with published data. Their cytotoxic, apoptosis and antibacterial activities of purified components were also performed. RESULTS: By bioassay-guided fractionation techniques and chemical characterization, four triterpene glycosides were isolated and their cytotoxicity against cancer cells and antibacterial activity were tested. They showed significant inhibitory activities against MCF-7, MDA-MB-231 with IC50 value of 0.7-16.5 microg/ml, and significant apoptosis for MCF-7 and MDA-MB-231. Moreover, compound 4 showed weak wide-spectrum antibacterial activity. CONCLUSION: These results provide promising baseline information for the potential use of Clematis ganpiniana as well as some of the isolated compounds in the treatment of cancer and infectious disease. PMID- 19781612 TI - Study on liver targeting effect of vinegar-baked Radix Bupleuri on resveratrol in mice. AB - BACKGROUND AND PURPOSE: Site-direct delivery is a desirable and elusive goal. In Traditional Chinese Medicine, this goal is usually met by coadministration with a kind of meridian guide drug (MGD). Vinegar-baked Radix Bupleuri (VBRB) is usually used to focus other drugs pharmacological effect on liver in Traditional Chinese Medicine (TCM). However, the scientific data for this effect are not available. In this paper, the liver targeting enhancing effect of VBRB on resveratrol was investigated. EXPERIMENTAL APPROACH: Mice, 144, were divided into four groups by random, resveratrol group as control and resveratrol coadministered with three different doses of VBRB peroral. Concentrations of resveratrol in different tissues were determined by HPLC and the target efficiency was evaluated by relative uptake efficiency (RUE) and relative targeting efficiency (RTE). KEY RESULTS: Compared to the control group, medium dose VBRB enhanced the targeting efficiency of resveratrol significantly, and the RUE and RTE were 1.79 and 46.9%, respectively. Meanwhile, it considerably reduced the distribution of resveratrol in lung and blood, the RUE and RTE in blood were 1.1, -22.6%, and were 0.88, 55.0% in lung, respectively. VBRB reduced the Cmax of resveratrol in almost all the tissues except for liver, heart and kidney, with the extent in the range of 26-61%. In addition, VBRB prolonged the retention time of resveratrol in liver, and shortened the retention time in other tissues. CONCLUSIONS AND IMPLICATIONS: VBRB could enhance the distribution of resveratrol in liver, and reduce the distribution in other tissues, implying that VBRB might be a potential drug for achieving target therapy. PMID- 19781613 TI - Expression of the psoriasis-associated antigen, Pso p27, is inhibited by traditional Chinese medicine. AB - AIM OF THE STUDY: Pso p27 is shown to be an autoantigen in psoriasis and the objective of the present study was to investigate whether Traditional Chinese Medicine (TCM) would influence the expression of Pso p27. MATERIALS AND METHODS: Skin biopsies obtained from psoriatic patients before and after treatment with TCM were analyzed for the presence of Pso p27 antigen by indirect immunofluorescence using murine monoclonal antibodies against Pso p27. RESULTS: A significant reduction in the amount of Pso p27 in the psoriatic skin was obtained after treatment with TCM for 3 months. CONCLUSIONS: The presence of Pso p27 in psoriatic skin is reduced when psoriatic patients are treated with TCM. PMID- 19781614 TI - Mast cell stabilization and antihistaminic potentials of Curculigo orchioides rhizomes. AB - AIM OF THE STUDY: To investigate the mast cell stabilization and antihistaminic activities of the rhizomes of Curculigo orchioides (COR). Extract of Curculigo orchioides Gaertn. (Fam. Amaryllidaceae) has been reported to possess immunostimulant, and anti-inflammatory potentials. In Indian traditional system of medicine it is also used as anti-asthmatic and anti-inflammatory. MATERIALS AND METHODS: Estimation of histamine release is key parameter for evaluating any target for its anti-allergic potential. The stabilization potential of the alcoholic extract of COR (100-400mg/kg) against mast cell degranulation was studied on isolated mice peritoneal mast cells. The antihistaminic activity was performed by determining the mortality rate of mice upon exposure to compound 48/80 and effect on inhibition of histamine release upon degranulation. RESULTS: The raised number of intact mast cells intimates that the COR stabilized the mast cell degranulation (60.96+/-1.96%) and percentage antihistaminic potential of the extract (63.58+/-1.8 inhibition at dose of 400mg/kg) and it virtues further work towards the isolation of phytoconstituents from this plant. CONCLUSION: This finding provides evidence that COR inhibits mast cell-derived immediate-type allergic reactions and mast cell degranulation. PMID- 19781615 TI - Determination of the wound healing effect of Calendula extracts using the scratch assay with 3T3 fibroblasts. AB - PHARMACOLOGICAL RELEVANCE: Presentation of the scratch assay as a convenient and inexpensive in vitro tool to gain first insights in the wound healing potential of plant extracts and natural compounds. AIM OF THE STUDY: The present study deals with the optimization of the scratch assay which can be used as an in vitro model for quantification of fibroblast migration to and proliferation into the wounded area. It is suitable for the first evaluation of the wound re epithelialization potential of crude herbal extracts, isolated compounds and pharmaceutical preparations. As a proof of concept three preparations from traditional medicinal plants were investigated. MATERIALS AND METHODS: Swiss 3T3 albino mouse fibroblasts were used in monolayers and platelet derived growth factor as positive control. Hexane and ethanolic extracts from Calendula officinalis and Matricaria recutita, Hypericum oil as well as the triterpenoids faradiol myristate and palmitate were studied. To differentiate between proliferation and migration antimitotic mitomycin C was added. RESULTS: Both extracts of Calendula officinalis stimulated proliferation and migration of fibroblasts at low concentrations, e.g. 10 microg/ml enhanced cell numbers by 64.35% and 70.53%, respectively. Inhibition of proliferation showed that this effect is mainly due to stimulation of migration. Faradiol myristate and palmitate gave comparable stimulation rates at an almost 50 microg/ml concentration, indicating that they contribute partially, but not most significantly to the wound healing effects of Calendula preparations. Extracts from Matricaria recutita were only moderately active. Hypericum oil was cytotoxic at concentrations higher than 0.5 microg/ml. CONCLUSIONS: The scratch assay in the present form can be used as a promising scientific approach and platform to differentiate between plant extracts known for their wound healing and their anti inflammatory properties. PMID- 19781616 TI - Acute and subacute toxicity of Schinus terebinthifolius bark extract. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schinus terebinthifolius Raddi (Anacardiaceae) has long been used in traditional Brazilian medicine, especially to treat inflammatory and haemostatic diseases. AIM OF THE STUDY: The objective of this study was to evaluate the acute and subacute toxicity (45 days) of Schinus terebinthifolius via the oral route in Wistar rats of both sexes. MATERIALS AND METHODS: For the acute toxicity test, the dried extract of Schinus terebinthifolius bark was administered in doses from 0.625 to 5.0 g/kg (n=5/group/sex) and in the subacute toxicity test the following doses were used: 0.25, 0.625 and 1.5625 g/kg/day (n=13/group/sex), for 45 consecutive days. RESULTS: In the acute toxicity test, Schinus terebinthifolius did not produce any toxic signs or deaths. The subacute treatment with Schinus terebinthifolius did not alter either the body weight gain or the food and water consumption. The hematological and biochemical analysis did not show significant differences in any of the parameters examined in female or male groups, except in two male groups, in which the treatment with Schinus terebinthifolius (0.25 and 0.625 g/kg) induced an increase of mean corpuscular volume values (2.9 and 2.6%, respectively). These variations are within the physiological limits described for the specie and does not have clinical relevance. CONCLUSION: The acute and subacute administration of the dried extract of Schinus terebinthifolius bark did not produced toxic effects in Wistar rats. PMID- 19781617 TI - Anti-spasmodic effects of Zizyphus lotus (L.) Desf. extracts on isolated rat duodenum. AB - AIM OF THE STUDY: The present study deals with the anti-spasmodic activity of the aqueous and the methanolic extracts of the leaves and the root barks of Zizyphus lotus (L.) Desf. on male rats. MATERIALS AND METHODS: This activity was assessed on contractions of isolated rat duodenum, induced by acetylcholine, KCl, and BaCl(2) and compared with the effect of atropine and papaverine. RESULTS: Both extracts of leaves and root barks caused significant relaxation of spontaneous contractions and produced a concentration-dependent inhibition (P<0.01-0.001) of contraction induced by spasmogenic agents. CONCLUSION: These results indicate that Zizyphus lotus extracts contain anti-spasmodic constituents mediating their effect through cholinergic receptors and blockade Ca(2+) influx. This could explain the traditional use of Zizyphus lotus in the treatment of the intestinal diseases. PMID- 19781618 TI - Quantitative analysis of chemical constituents in different commercial parts of Notopterygium incisum by HPLC-DAD-MS. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Notopterygium incisum used as an antirheumatic and analgesic medicine for the treatment of rheumatism, headache, cold, etc., is not only a traditional Qiang medicine, but also a traditional Tibetan remedy for thousands of years. AIM OF THE STUDY: In order to use this herbal medicine in a more effective way, in the present investigation, we analyzed the main chemical constituents of different commercial parts as well as fibrous roots of Notopterygium incisum. MATERIALS AND METHODS: All crude Notopterygium incisum samples used in this study were collected in Sichuan province of China. We used HPLC-DAD-MS to analyze quantitatively the main chemical constituents of different commercial parts as well as fibrous roots of Notopterygium incisum. RESULTS: According to different commercial parts, 10 Notopterygium incisum samples collected from two main production areas have been investigated, and four main constituents have been quantitatively analyzed. CONCLUSION: The quality of rhizomes is better than that of main roots. Unexpectedly, the content of two main constituents, notopterol and isoimperaorin, in fibrous roots is higher than any other parts of Notopterygium incisum. This result implied that the fibrous root may also have value, and we should study it to explore its potential. PMID- 19781619 TI - In vivo efficacy of Trachyspermum ammi anticalcifying protein in urolithiatic rat model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Many medicinal plants have been employed during ages to treat urinary stones though the rationale behind their use is not well established. Recently, we have successfully purified an anticalcifying protein from the seeds of Trachyspermum ammi (L.) Sprague ex Turril (Umbelliferae) using oxalate depletion assay and deciphered its inhibitory activity against calcium oxalate crystal growth. AIM: In this report, the antilithiatic activity of Trachyspermum ammi anticalcifying protein (TAP) was studied in urolithiatic rat model. METHODOLOGY: Urolithiasis was induced by exposure of 0.4% ethylene glycol (EG) and 1.0% ammonium chloride (NH(4)Cl) for 9 days. The efficacy of TAP was studied in another group given same dose of EG and NH(4)Cl in addition to 2mg/kg body weight of TAP. Further, we evaluated ability of TAP to inhibit the attachment of calcium oxalate (CaO(x)) crystal in kidney tissue and studied the consequences of CaO(x) adhesion on renal functioning and tissue integrity. RESULTS: The antilithiatic potential of TAP was confirmed by its ability to maintain renal functioning, reduce renal injury and decrease crystal excretion in urine and retention in renal tissues. CONCLUSIONS: Thus, the present investigation suggests the potential of TAP in preventing calcium oxalate deposition and forms the basis for the development of antilithiatic drug interventions against urolithiasis. PMID- 19781620 TI - Involvement of the PI3K/AKT pathway in the hypoglycemic effects of saponins from Helicteres isora. AB - AIM OF THE STUDY: Saponins from Helicteres isora have previously been shown to exert antidiabetic effects. The present study explored the underlying mechanisms in C2C12 skeletal muscle cells. MATERIALS AND METHODS: C2C12 cells were incubated with saponins and sapogenin followed by Western blotting and immunofluorescence analysis. RESULTS: Western blotting revealed that incubation with saponins (100 microg/ml) and sapogenin (100 microg/ml) induced the phosphorylation of the phosphatidylinositol-3-kinase (PI3K) as well as of the downstream targets protein kinase B/Akt (at Ser473) and glycogen synthase kinase GSK-3 alpha/beta (at Ser21/9) in a time-dependent manner. In contrast, no phosphorylation of the AMP sensitive kinase AMPK (at Thr172) was observed. Within 48 h saponins/sapogenin treatment further increased the protein abundance of the insulin-sensitive glucose transporter Glut4. Confocal microscopy confirmed that saponins/sapogenin treatment stimulated Akt phosphorylation and revealed that the treatment was followed by translocation of Glut4 into the cell membrane of C2C12 muscle cells. CONCLUSIONS: Saponins and sapogenin activate the PI3K/Akt pathway thus leading to phosphorylation and inactivation of GSK-3 alpha/beta with subsequent stimulation of glycogen synthesis as well as increase of Glut4-dependent glucose transport across the cell membrane. PMID- 19781621 TI - Antisecretory activity from the flowers of Chiranthodendron pentadactylon and its flavonoids on intestinal fluid accumulation induced by Vibrio cholerae toxin in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The flowers of Chiranthodendron pentadactylon Larreat. (Sterculiaceae) has been traditionally used as folk medicine in Mexico for the treatment of gastrointestinal disorders such as diarrhea and dysentery. AIM OF THE STUDY: This study aimed to assess the antisecretory activity which supports the therapeutic use of Chiranthodendron pentadactylon and its flavonoids to treat diarrhea. MATERIALS AND METHODS: The methanol extract of Chiranthodendron pentadactylon, subsequent fractions, and flavonoids were evaluated on cholera toxin-induced intestinal secretion in rat jejunal loops model. RESULTS: Three antisecretory flavonoids were isolated by bioassay-guided purification, namely, isoquercitrin 3, (+)-catechin 4 and (-)-epicatechin 5. Among them, epicatechin exhibited the most potent antisecretory activity with ID(50) of 8.3 microM/kg. Its potency was close that of to loperamide (ID(50) 6.1 microM/kg), drug used as control. Isoquercitrin (ID(50) 19.2 microM/kg) and catechin (ID(50) 51.7 microM/kg) showed moderate and weak activity, respectively. CONCLUSION: The results of the present study lend some support to the anecdotal report for the traditional use of the flowers of Chiranthodendron pentadactylon in the control of dysentery. PMID- 19781622 TI - A pilot investigation into the effect of maca supplementation on physical activity and sexual desire in sportsmen. AB - AIMS OF THE STUDY: Maca (Lepidium meyenii Walp) is consumed both as a sports supplement by strength and endurance athletes, and as a natural stimulant to enhance sexual drive. However, whether or not the postulated benefits of maca consumption are of scientific merit is not yet known. The aim of the study was therefore to investigate the effect of 14 days maca supplementation on endurance performance and sexual desire in trained male cyclists. MATERIALS AND METHODS: Eight participants each completed a 40 km cycling time trial before and after 14 days supplementation with both maca extract (ME) and placebo, in a randomised cross-over design. Subjects also completed a sexual desire inventory during each visit. RESULTS: ME administration significantly improved 40 km cycling time performance compared to the baseline test (P=0.01), but not compared to the placebo trial after supplementation (P>0.05). ME administration significantly improved the self-rated sexual desire score compared to the baseline test (P=0.01), and compared to the placebo trial after supplementation (P=0.03). CONCLUSIONS: 14 days ME supplementation improved 40 km cycling time trial performance and sexual desire in trained male cyclists. These promising results encourage long-term clinical studies involving more volunteers, to further evaluate the efficacy of ME in athletes and normal individuals and also to explore its possible mechanisms of action. PMID- 19781623 TI - Anti-inflammatory effects of YeongyoSeungma-tang. AB - ETHNOPHARMACOLOGICAL RELEVANCE: YeongyoSeungma-tang which includes Fructus Forsythia, has been used in oriental traditional medicine for treatment of early smallpox and atopic dermatitis. AIM OF THE STUDY: YeongyoSeungma-tang was carried out to investigate for anti-inflammatory effects. MATERIALS AND METHODS: YeongyoSeungma-tang was tested for anti-inflammatory effects against lipopolysaccharide (LPS)-induced nitric oxide (NO), prostaglandin E(2) (PGE(2)), and tumor necrosis factor alpha (TNF-alpha) releases as well as nuclear factor kappa B (NF-kappaB) expression using RAW264.7 macrophage cells. RESULTS: YeongyoSeungma-tang significantly inhibited generation of NO (42% and 59% inhibition at doses of 5 microg/mL and 10 microg/mL, respectively), PGE(2) (46% and 80% inhibition at doses of 5 microg/mL and 10 microg/mL, respectively) and TNF-alpha (6% and 23% inhibition at doses of 5 microg/mL and 10 microg/mL, respectively) on LPS-stimulated RAW 264.7 cells in a concentration-dependent manner. Consistently in these observations, the expression of inducible NO synthase (iNOS) enzyme was also inhibited by YeongyoSeungma-tang. However, YeongyoSeungma-tang did not show any influence on the expression of cyclooxygenase-2. The cream containing 0.075% YeongyoSeungma-tang showed good skin moisturizing effect without any irritation. CONCLUSION: The present study may support the fact that YeongyoSeungma-tang can have the good possibility as an anti-inflammatory agent for troubled skins. PMID- 19781625 TI - Mechanism of potentiation of endosulfan cytotoxicity by thiram in Ehrlich ascites tumor cells. AB - Cytotoxicity of the two pesticides, thiram and endosulfan, have been studied in Ehrlich ascites tumor cells. Thiram cytotoxicity was much lower than that of endosulfan with LC(50) (1h exposure) of 4.02 and 1.12mM, respectively. The cytotoxic action of the pesticides on the cells were characterised by glutathione depletion, induction of reactive oxygen species (ROS). The cell death induced by the pesticides was of necrotic type as confirmed by lactate dehydrogenase (LDH) leakage. At non-cytotoxic concentration, thiram potentiated the cytotoxicity of endosulfan when cells were exposed to a mixture of both chemicals. The mechanisms involved in the potentiation of cytotoxicity include excessive glutathione depletion and induction ROS which were higher than the additive effects of individual chemicals. The study demonstrates the importance of pesticide interactions in toxicity risk assessment. PMID- 19781624 TI - Effects of Tribulus terrestris on endocrine sensitive organs in male and female Wistar rats. AB - AIM OF THE STUDY: Investigate the possible effects of Tribulus terrestris (TT) on endocrine sensitive organs in intact and castrated male rats as well as in a post menopausal rat model using ovariectomized females. MATERIALS AND METHODS: Three different dose levels of TT (11, 42 and 110 mg/kg/day) were administered to castrated males for 7 days and to intact males and castrated females for 28 days. In addition to TT treatment, all experiments also included a group of rats treated with dehydroepiandrosterone (DHEA). In experiments using castrated males and females we also used testosterone and 17 alpha-ethynylestradiol, respectively, as positive controls for androgenicity and estrogenicity. RESULTS: Neither DHEA nor TT was able to stimulate androgen sensitive tissues like the prostate and seminal vesicle in both intact and castrated male rats. In addition, administration of TT to intact male rats for 28 days did not change serum testosterone levels as well as did not produce any quantitative change in the fecal excretion of androgenic metabolites. However, a slight increase in the number of homogenization-resistant spermatids was observed in rats treated with 11 mg/kg/day of TT extract. In ovariectomized females, TT did not produce any stimulatory effects in uterine and vaginal epithelia. CONCLUSIONS: Tribulus terrestris was not able to stimulate endocrine sensitive tissues such as the prostate, seminal vesicle, uterus and vagina in Wistar rats, indicating lack of androgenic and estrogenic activity in vivo. We also showed a positive effect of TT administration on rat sperm production, associated with unchanged levels of circulating androgens. PMID- 19781626 TI - Repeated bouts of aerobic exercise enhance regulatory T cell responses in a murine asthma model. AB - We have reported previously that moderate intensity aerobic exercise training attenuates airway inflammation in a murine asthma model. Recent studies implicate regulatory T (Treg) cells in decreasing asthma-related airway inflammation; as such, the current study examined the effect of exercise on Treg cell function in a murine asthma model. Mice were sensitized with ovalbumin (OVA) prior to the start of exercise training at a moderate intensity 3x/week for 4weeks; exercise was performed as treadmill running (13.5m/min, 0% grade). Mice were OVA challenged repeatedly throughout the exercise protocol. At protocol completion, mice were analyzed for changes in the number and suppressive function of CD4(+)CD25(+)Foxp3(+) cells isolated from lungs, mediastinal lymph nodes, and spleens. Results show that exercise increased significantly the number of Foxp3(+) cells within the lungs and mediastinal lymph nodes, but not the spleens, of OVA-treated mice as compared with sedentary controls. Exercise also enhanced the suppression function of CD4(+)CD25(+)Foxp3(+) Treg cells derived from OVA treated mice as compared with sedentary controls. Specifically, Treg cells from exercised, OVA-treated mice more effectively suppressed CD4(+)CD25(-) cell proliferation and Th2 cytokine production in vitro. Enhanced suppression was associated with increased protein levels of TGF-beta and lesser amounts of IL-10 and IL-17; however, blocking TGF-beta had no effect on suppressive functions. These data demonstrate that exercise-mediated increases in Treg cell function may play a role in the attenuation of airway inflammation. Further, these results indicate that moderate intensity aerobic exercise training may alter the Treg cell function within the asthmatic airway. PMID- 19781627 TI - Loop mediated isothermal amplification combined with nucleic acid lateral flow strip for diagnosis of cyprinid herpes virus-3. AB - An improved loop mediated isothermal amplification (LAMP) assay for rapid, sensitive and specific detection of cyprinid herpes virus-3 (CyHV-3), also known as koi herpes virus (KHV), was developed. The lower detection limit of the CyHV-3 LAMP assay is 10 fg DNA which equivalent to 30 copies of CyHV-3 genome. Nucleic acid lateral flow assay was used for visual detection of the LAMP products. The LAMP- nucleic acid lateral flow assay relies on DNA hybridization technology and antigen-antibody reactions in combination with LAMP. For application of this assay, the biotinylated LAMP product was hybridized with a FITC-labelled specific probe for 5 min. The resulting DNA complex could be visualised as purple band at the strip test line within 5 min of sample exposure. The nucleic acid lateral flow analysis of the LAMP product was equivalent in sensitivity but more rapid than the conventional agarose gel electrophoresis. The combination of LAMP assay with the nucleic acid lateral flow analysis can simplify the diagnosis and screening of CyHV-3 as it is simple, requires very little training, does not require specialized equipment such as a thermal cycler, the results are read visually with no need to run a gel and has a high sensitivity and specificity. PMID- 19781629 TI - The cardioprotective effects of zileuton, a 5-lipoxygenase inhibitor, are mediated by COX-2 via activation of PKC delta. AB - Zileuton has been demonstrated to act as an anti-inflammatory agent by virtue of its well-known ability to inhibit 5-lipoxygenase (5-LO). However, the effects of zileuton on cardiovascular disease and cardiomyocyte apoptosis are unclear. Here, we investigated the effects of zileuton on apoptosis of cardiac myogenic H9c2 cells and neonatal rat cardiomyocytes (NRCMs), and examined the possible role of PKC delta-mediated induction of COX-2 in these effects. Treatment of H9c2 cells with zileuton efficiently induced COX-2 expression and PGE(2) biosynthesis in a time- and dose-dependent manner. Zileuton also exerted a profound protective effect against H(2)O(2)-induced oxidative stress, a mimic of reperfusion damage in vitro, and this protective effect was abolished by COX-2-selective inhibitor. When we investigated the signalling pathways involved in zileuton-induced COX-2 expression, we found that zileuton acts as a PKC delta activator, causing it to translocate from the cytosol to nucleus. Inhibition of PKC delta activation with rottlerlin, a PKC delta-specific inhibitor, abolished the zileuton-induced protection against H(2)O(2)-induced cell death and inhibited zileuton-induced COX 2 expression and PGE(2) production. The protective effect of zileuton was dramatically diminished by treatment with LY294002 or PD98059. Furthermore, zileuton-stimulated ERK1/2 and Akt phosphorylation was attenuated by rottlerin, indicating that PKC delta might act upstream of ERK1/2 and Akt. Moreover, inhibition of either ERK1/2 or Akt activation abolished zileuton-induced COX-2 expression. Knockdown of PKC delta with siRNA also reversed the protective effect of zileuton and blocked the induction of COX-2. These results suggest that zileuton-induced COX-2 expression is sequentially mediated through PKC delta dependent activation of ERK1/2 and Akt. Based on these findings, we propose that zileuton might provide a new therapeutic strategy for ischemia/reperfusion injury of the heart. PMID- 19781628 TI - Serine threonine receptor-associated protein (STRAP) plays a role in the maintenance of mesenchymal morphology. AB - The stromal tissue, made of extracellular matrix and mesenchymal cells, is vital for the functional design of all complex tissues. Fibroblasts are key components of stromal tissue and play a crucial role during organ development, wound repair, angiogenesis and fibrosis. We have previously reported the identification of a novel WD-domain protein, STRAP(1) that inhibits transforming growth factor-beta (TGF-beta) signaling and enhances tumorigenicity via TGF-beta-dependent and TGF beta-independent mechanisms. Here, we report, for the first time, that deletion of STRAP from Mouse Embryonic Fibroblasts (MEFs) results in a loss of mesenchymal morphology. These cells lose their spindle shape and exhibit features of an epithelial morphology. Gene expression profiling has confirmed that deletion of STRAP affects expression of sets of genes important for diverse functions including cell-cell adhesion and cell polarization, and upregulates E-cadherin expression leading to the formation of adherens junctions, subsequent localization of beta-catenin to the cell membrane and downregulation of the mesenchymal markers like LEF1 (lymphoid enhancer-binding factor 1). Upregulation of WT1 (Wilms tumor homolog 1) in STRAP null MEFs plays a role in E-cadherin induction. Finally, stable expression of STRAP in these cells results in a loss of WT1 and E-cadherin expressions, and a reversal from epithelial to the mesenchymal morphology. Thus, these results provide a novel TGF-beta-independent function of STRAP and describe a mechanism for the role of STRAP in the maintenance of mesenchymal morphology. PMID- 19781630 TI - UNC119 inhibits dynamin and dynamin-dependent endocytic processes. AB - Unc119 is an adapter signaling molecule, which regulates activation of tyrosine kinases in T cells, eosinophils and fibroblasts. It plays an important role in the photoreceptor synapses of the retina. Recently, we have shown that it inhibits bacterial uptake through macropinocytosis. In this paper we demonstrate a role for Unc119 in clathrin- and caveolae-based endocytosis as well as macropinocytosis. Depletion of Unc119 in fibroblasts increases, whereas overexpression inhibits uptake of transferrin, FM4-64, albumin, viruses, and ligand-coated beads. Physiological stimuli that upregulate the expression of Unc119 also inhibits endocytosis. Unc119 has the opposite effect on cholera toxin B uptake, which represents a clathrin- and dynamin-independent endocytic process. Unc119 interacts with dynamin, a key effector molecule of many endocytic processes. More importantly, Unc119 inhibits the GTPase activity of dynamin. Binding of Unc119 to dynamin decreases the association with its binding partner amphiphysin, a known regulator of dynamin activation. Thus, Unc119 regulates various endocytic pathways through dynamin and sets a threshold point for vesicular trafficking. PMID- 19781632 TI - Mathematical modelling of interferon-gamma signalling in pancreatic stellate cells reflects and predicts the dynamics of STAT1 pathway activity. AB - Signal transducer and activator of transcription (STAT) 1 is essentially involved in the mediation of antifibrotic interferon-gamma (IFN gamma) effects in pancreatic stellate cells (PSC). Here, we have further analysed the activation of the STAT1 pathway in a PSC line by combining quantitative data generation with mathematical modelling. At saturating concentrations of IFN gamma, a triphasic pattern of STAT1 activation was observed. An initial, rapid induction of phospho STAT1 was followed by a plateau phase and another, long-lasting phase of further increase. The late increase occurred despite enhanced expression of the feedback inhibitor (SOCS1), and corresponded to increased levels of total STAT1 protein. If IFN gamma was applied at non-saturating concentrations, phospho-STAT1 and SOCS1 levels peaked and declined again over a 12 hour period, while STAT1 protein levels remained high. The mathematical model, based on a system of ordinary differential equations, describes temporal changes of the network components as a function of interactions and transport processes. The model reproduced activation profiles of all components of the STAT1 pathway that were experimentally analysed. Furthermore, it successfully predicted the dynamics of network components in additional experimental studies. Based on experimental findings and the results obtained from modelling, we suggest exhaustion of applied IFN gamma and STAT1 dephosphorylation by tyrosine phosphatases as limiting factors of STAT1 activation in PSC. In contrast, we did not obtain compelling evidence that SOCS1 acts as an efficient feedback inhibitor in our experimental system. We believe that further investigations into mathematical modelling of the STAT1 pathway will improve the understanding of the antifibrotic interferon action. PMID- 19781631 TI - Proteinase-activated receptor-2 mediated inhibition of TNFalpha-stimulated JNK activation - A novel paradigm for G(q/11) linked GPCRs. AB - In this study we examined the potential for PAR(2) and TNFalpha to synergise at the level of MAP kinase signalling in PAR(2) expressing NCTC2544 cells. However, to our surprise we found that activation of PAR(2) by trypsin or the specific activating peptide SLIGKV-OH strongly inhibited both the phosphorylation and activity of JNK. In contrast neither p38 MAP kinase nor ERK activation was affected although TNFalpha stimulated IkappaBalpha loss was partially reversed. The inhibitory effect was not observed in parental cells nor in cells expressing PAR(4), however inhibition was reversed by pre-incubation with the novel PAR(2) antagonist K14585, suggesting that the effect is specific for PAR(2) activation. SLIGKV-OH was found to be more potent in inhibiting TNFalpha-induced JNK activation than in stimulating JNK alone, suggesting agonist-directed signalling. The PKC activator PMA, also mimicked the inhibitory effect of SLIGKV-OH, and the effects of both agents were reversed by pre-treatment with the PKC inhibitor, GF109203X. Furthermore, incubation with the novel G(q/11) inhibitor YM25480 also reversed PAR(2) mediated inhibition. Activation of PAR(2) was found to disrupt TNFR1 binding to RIP and TRADD and this was reversed by both GF109203X and YM25480. A similar mode of inhibition observed in HUVECs through PAR(2) or P2Y2 receptors demonstrates the potential of a novel paradigm for GPCRs linked to G(q/11), in mediating inhibition of TNFalpha-stimulated JNK activation. This has important implications in assessing the role of GPCRs in inflammation and other conditions. PMID- 19781633 TI - Suppression of DNA-PKcs enhances FGF-2 dependent human endothelial cell proliferation via negative regulation of Akt. AB - Angiogenesis initiation is crucially dependent on endothelial proliferation and can be stimulated by the fibroblast growth factor 2 (FGF-2). The DNA dependent protein kinase (DNA-PK), long known for its importance in repairing DNA double strand breaks, belongs to the phosphatidylinositol-3 kinase (PI3-K) super family and has recently been identified as one of the enzymes phosphorylating and activating Akt. Due to its similarity with PI3-K, we hypothesized that DNA-PK may have similar effects on endothelial angiogenic processes and signalling. We used primary endothelial cells (HUVEC and PAEC) and human microvascular endothelial cells (HMEC) to study the role of DNA-PK in endothelial proliferation and signalling. DNA-PKcs suppression with the compound NU7026 or with siRNA induced basal endothelial cell proliferation as well as enhanced FGF-2 dependent proliferation. This was associated with an increase in phosphorylated Akt. Tube formation was not affected by DNA-PKcs clearly showing that the role of DNA-PK in endothelial processes differs from that of PI3-K. Our findings indicate DNA-PK as an important enzyme maintaining the quiescent endothelial phenotype by actively inhibiting Akt thus restraining endothelial cell proliferation preventing excessive growth. PMID- 19781635 TI - Cellular BRET assay suggests a conformational rearrangement of preformed TrkB/Shc complexes following BDNF-dependent activation. AB - We developed a cellular Bioluminescent Resonance Energy Transfer (BRET) assay based on the interaction of TrkB fused to Renilla luciferase with the intracellular adaptor protein Shc fused to Enhanced Yellow Fluorescent Protein (EYFP). The TrkB agonist Brain Derived Neurotrophic Factor (BDNF) induced a maximum BRET signal as of 10 min with an EC(50) value of 1.4 nM, similar to the other endogenous agonists NT-3 and NT-4/5, 1.5 nM and 0.34 nM, respectively. Interestingly, measure of the BRET signal with increasing expression of Shc-EYFP, in the presence or absence of BDNF, suggested a conformational change of preformed TrkB/Shc complexes rather than Shc recruitment. Furthermore, the Y516F TrkB mutant deficient to bind Shc as well as the kinase-dead K572R TrkB mutant was unable to respond to BDNF and exhibited a lower basal BRET signal than that of the wild-type TrkB receptor, again suggesting a preformed complex with constitutive activity. The double YY706/707FF TrkB mutant in the kinase activation loop also showed reduced basal activity but surprisingly kept its capacity to enhance BDNF-induced interaction with Shc, though with less efficacy. The Trk selective kinase inhibitors K252a and BMS-9 blocked BDNF-induced BRET signal with similar potency (100-150 nM), the preferential c-Met inhibitor PF 2341006 being one order of magnitude less potent. Remarkably, in the absence of BDNF, K252a and BMS-9 also reduced basal activity to the level of the Y516F TrkB mutant, suggesting that these compounds were able to reduce the TrkB constitutive activity. BRET responses of mutants and to kinase inhibitors thus reveal a complex level of interaction between TrkB and Shc and suggest that this BRET assay could be of great utility to test blockers of TrkB signalling in a physiologically relevant context. PMID- 19781634 TI - Odorant-stimulated phosphoinositide signaling in mammalian olfactory receptor neurons. AB - Recent evidence has revived interest in the idea that phosphoinositides (PIs) may play a role in signal transduction in mammalian olfactory receptor neurons (ORNs). To provide direct evidence that odorants indeed activate PI signaling in ORNs, we used adenoviral vectors carrying two different fluorescently tagged probes, the pleckstrin homology (PH) domains of phospholipase C delta 1 (PLC delta 1) and the general receptor of phosphoinositides (GRP1), to monitor PI activity in the dendritic knobs of ORNs in vivo. Odorants mobilized PI(4,5)P(2)/IP(3) and PI(3,4,5)P(3), the substrates and products of PLC and PI3K. We then measured odorant activation of PLC and PI3K in olfactory ciliary-enriched membranes in vitro using a phospholipid overlay assay and ELISAs. Odorants activated both PLC and PI3K in the olfactory cilia within 2s of odorant stimulation. Odorant-dependent activation of PLC and PI3K in the olfactory epithelium could be blocked by enzyme-specific inhibitors. Odorants activated PLC and PI3K with partially overlapping specificity. These results provide direct evidence that odorants indeed activate PI signaling in mammalian ORNs in a manner that is consistent with the idea that PI signaling plays a role in olfactory transduction. PMID- 19781636 TI - Chaperone-protease systems in regulation and protein quality control in Bacillus subtilis. AB - The Gram-positive model organism Bacillus subtilis is extremely well adapted to changing environmental conditions. The chaperone-protease ClpCP and other AAA+ proteases constitute an important component of the B. subtilis protein quality control system that is essential for survival during stress. In this review, we discuss recent discoveries concerning the molecular mechanism, regulation and localization of proteases and chaperones in B. subtilis. PMID- 19781637 TI - Quantitative PCR of pmoA using a novel reverse primer correlates with potential methane oxidation in Finnish fen. AB - We report a new reverse primer (A621r) for use with A189f in PCR amplification of pmoA alleles in type II methanotrophs. The new primer combination was used to successfully amplify pmoA in peat monolith samples of various depths taken from fen-type peatlands in Finland. In quantitative PCR, pmoA amplicons produced from two sets of three replicate monoliths showed a significant Pearson correlation coefficient (r=0.77 and 0.61) with methane oxidation potential. The maximum methane oxidation potential and number of pmoA amplicons ranged between 8.8-40.5 micromol g (dry weight)(-1) d(-1) and 5.5 x 10(7)-18.7 x 10(7) g (wet weight)( 1), respectively, occurring in depths between 10 and 30 cm beneath the surface in the seven individual monoliths used in this study. PMID- 19781638 TI - The role of proteolysis in the Caulobacter crescentus cell cycle and development. AB - Caulobacter crescentus cell cycle progression is implemented by oscillating global transcriptional regulators that establish temporal and spatial control of modular genetic subsystems during the cell cycle. The hierarchy of this regulatory circuit is established through a combination of gene expression control and regulated proteolysis. Recent results highlight the importance of spatial organization for controlled proteolysis in C. crescentus. PMID- 19781639 TI - AAA proteases in mitochondria: diverse functions of membrane-bound proteolytic machines. AB - FtsH/AAA proteases comprise a distinct family of membrane-bound, ATP-dependent proteases present in eubacteria and eukaryotic cells, where they are confined to mitochondria and chloroplasts. Here, we will summarize versatile functions of AAA proteases within mitochondria, which ensure mitochondrial integrity and cell survival, acting both as quality control and processing enzymes. PMID- 19781640 TI - Principles of general and regulatory proteolysis by AAA+ proteases in Escherichia coli. AB - General and regulated proteolysis in bacteria is crucial for cellular homeostasis and relies on high substrate specificity of the executing AAA+ proteases. Here we summarize the various strategies that tightly control substrate degradation from both sides: the generation of accessible degrons and their specific recognition by AAA+ proteases and cognate adaptor proteins. PMID- 19781641 TI - The R1441C mutation alters the folding properties of the ROC domain of LRRK2. AB - LRRK2 is a 250 kDa multidomain protein, mutations in which cause familial Parkinson's disease. Previously, we have demonstrated that the R1441C mutation in the ROC domain decreases GTPase activity. Here we show that the R1441C alters the folding properties of the ROC domain, lowering its thermodynamic stability. Similar to small GTPases, binding of different guanosine nucleotides alters the stability of the ROC domain, suggesting that there is an alteration in conformation dependent on GDP or GTP occupying the active site. GTP/GDP bound state also alters the self-interaction of the ROC domain, accentuating the impact of the R1441C mutation on this property. These data suggest a mechanism whereby the R1441C mutation can reduce the GTPase activity of LRRK2, and highlights the possibility of targeting the stability of the ROC domain as a therapeutic avenue in LRRK2 disease. PMID- 19781642 TI - Purification and characterization of an exo-polygalacturonase from Pycnoporus sanguineus. AB - The present work describes the purification and characterization of a novel extracellular polygalacturonase, PGase I, produced by Pycnoporus sanguineus when grown on citrus fruit pectin. This substrate gave enhanced enzyme production as compared to sucrose and lactose. PGase I is an exocellular enzyme releasing galacturonic acid as its principal hydrolysis product as determined by TLC and orcinol-sulphuric acid staining. Its capacity to hydrolyze digalacturonate identified PGase I as an exo-polygalacturonase. SDS-PAGE showed that PGase I is an N-glycosidated monomer. The enzyme has a molecular mass of 42kDa, optimum pH 4.8 and stability between pH 3.8 and 8.0. A temperature optimum was observed at 50-60 degrees C, with some enzyme activity retained up to 80 degrees C. Its activation energy was 5.352calmol(-1). PGase I showed a higher affinity towards PGA than citric pectin (Km=0.55+/-0.02 and 0.72+/-0.02mgml(-1), respectively). Consequently, PGase I is an exo-PGase, EC 3.2.1.82. PMID- 19781643 TI - Characterization of the cell wall of the ubiquitous plant pathogen Botrytis cinerea. AB - The ascomycete Botrytis cinerea is a destructive and ubiquitous plant pathogen and represents a model organism for the study of necrotrophic fungal pathogens. Higher fungi possess a complex and dynamic multilayer cell wall involved in crucial aspects of fungal development, growth and pathogenicity. Plant resistance to microbial pathogens is determined often by the capacity of the plant to recognize molecular patterns associated with the surface of an interacting microbe. Here we report the chemical characterization of cell walls from B. cinerea during axenic growth. Neutral sugars and proteins constituted most of the mass of the B. cinerea cell walls, although chitin and uronic acids were detected. Glucose was the most abundant neutral sugar, but arabinose, galactose, xylose and mannose also were present. Changes in cell wall composition during culture were observed. As the culture developed, protein levels declined, while chitin and neutral sugars increased. Growth of B. cinerea was associated with a remarkable decline in the fraction of its cell wall material that was soluble in hot alkali. These results suggest that the cell wall of B. cinerea undergoes significant modifications during growth, possibly becoming more extensively covalently cross-linked, as a result of aging of mycelia or in response to decreasing nutrient supply or as a consequence of increasing culture density. PMID- 19781644 TI - Oxidative stress and cell death in cells expressing L-ferritin variants causing neuroferritinopathy. AB - Neuroferritinopathies are dominantly inherited movement disorders associated with nucleotide insertions in the L-ferritin gene that modify the protein's C terminus. The insertions alter physical and functional properties of the ferritins, causing an imbalance in brain iron homeostasis. We describe the effects produced by the over-expression in HeLa and neuroblastoma SH-SY5Y cells of two pathogenic L-ferritin variants, 460InsA and 498InsTC. Both peptides co assembled with endogenous ferritins, producing molecules with reduced iron incorporation capacity, acting in a dominant negative manner. The cells showed an increase in cell death and a decrease in proteasomal activity. The formation of iron-ferritin aggregates became evident after 10 days of variant expression and was not associated with increased cell death. The addition of iron chelators or antioxidants restored proteasomal activity and reduced aggregate formation. The data indicate that cellular iron imbalance and oxidative damage are primary causes of cell death, while aggregate formation is a secondary effect. PMID- 19781645 TI - Phosphorylation of Tau at S422 is enhanced by Abeta in TauPS2APP triple transgenic mice. AB - Amyloid beta peptides and microtubule-associated protein Tau are misfolded and form aggregates in brains of Alzheimer's disease patients. To examine their specific roles in the pathogenesis of Alzheimer's disease and their relevance in neurodegenerative processes, we have created TauPS2APP triple transgenic mice that express human mutated Amyloid Precursor Protein, presenilin 2 and Tau. We present a cross-sectional analysis of these mice at 4, 8, 12 and 16 months of age. By comparing with single transgenic Tau mice, we demonstrate that accumulation of Abeta in TauPS2APP triple transgenic mice impacts on Tau pathology by increasing the phosphorylation of Tau at serine 422, as determined by a novel immunodetection method that is able to reliably measure phospho-Tau species in transgenic mouse brains. The TauPS2APP triple transgenic mouse model will be very useful for studying the effect of new therapeutic paradigms on amyloid deposition and downstream neurofibrillary tangle development. PMID- 19781646 TI - Neuregulin-1 modulates the differentiation of neural stem cells in vitro through an interaction with the Swi/Snf complex. AB - The neuregulin-1 (Nrg-1) gene is translated into several protein isoforms, which are either secreted or membrane-anchored. In vitro, neural stem cells (NSC) express mainly the cystein-rich-domain NRG (CRD-NRG) isoform, a membrane-anchored type III form. This isoform exhibits a cystein-rich-domain, which constitutes a second transmembrane domain and can be cleaved to release both a signaling EGF containing domain (ECD) at the cell surface and an intracellular domain (ICD). The main goal of this paper was to determine the exact role of ECD and ICD in NSC survival and differentiation. Using an siRNA approach, we demonstrated that CRD NRG inhibition was followed by a decrease in NSC proliferation and of neuronal or oligodendroglial differentiation. Overexpression of ICD but not ECD was followed by a decrease in NSC proliferation and an increase in neuronal and oligodendroglial differentiation. Moreover, we showed that ICD physically interacted in cultured NSC with BRM and BAF57, two members of the Swi/Snf remodeling complex, and that ICD stimulation of neuronal cell differentiation is dependent on the presence of BAF57. PMID- 19781647 TI - Expression, purification, characterization and crystallization of non- and phosphorylated states of JAK2 and JAK3 kinase domain. AB - Janus-associated kinases (JAKs) play critical roles in cytokine signaling, and have emerged as viable therapeutic targets in inflammation and oncology related diseases. To date, targeting JAK proteins with highly selective inhibitor compounds have remained elusive. We have expressed the active kinase domains for both JAK2 and JAK3 and devised purification protocols to resolve the non-, mono- (Y1007) and diphosphorylated (Y1007 and Y1008) states of JAK2 and non- and monophosphorylated states of JAK3 (Y980). An optimal purified protein yield of 20, 29 and 69mg per 20L cell culture was obtained for the three JAK2 forms, respectively, and 12.2 and 2.3mg per 10L fermentation for the two JAK3 forms allowing detailed biochemical and biophysical studies. To monitor the purification process we developed a novel HPLC activity assay where a sequential order of phosphorylation was observed whereby the first tyrosine residue was completely phosphorylated prior to phosphorylation of the tandem tyrosine residue. A Caliper-based microfluidics assay was used to determine the kinetic parameters (K(m) and k(cat)) for each phosphorylated state, showing that monophosphorylated (Y1007) JAK2 enzyme activity increased 9-fold over that of the nonphosphorylated species, and increased an additional 6-fold for the diphosphorylated (Y1007/Y1008) species, while phosphorylation of JAK3 resulted in a negligible increase in activity. Moreover, crystal structures have been generated for each isolated state of JAK2 and JAK3 with resolutions better than 2.4A. The generation of these reagents has enabled kinetic and structural characterization to inform the design of potent and selective inhibitors of the JAK family. PMID- 19781648 TI - Unconsciously deciphering handwriting: subliminal invariance for handwritten words in the visual word form area. AB - Expert readers exhibit a remarkable ability to recognize handwriting, in spite of enormous variability in character shape-a competence whose cerebral underpinnings are unknown. Subliminal priming, combined with neuroimaging, can reveal which brain areas automatically compute an invariant representation of visual stimuli. Here, we used behavioral and fMRI priming to study the areas involved in invariant handwritten word recognition. Compared to printed words, easily readable handwritten words caused additional activity in ventral occipitotemporal cortex, particularly in the right hemisphere, while difficult handwriting also mobilized an attentional parietofrontal network. Remarkably, however, subliminal repetition effects were observed across printed and handwritten styles, whether easy or difficult to read, both behaviorally and in the activation of the left visual word form area (VWFA). These results indicate that the left inferotemporal VWFA possesses an unsuspected degree of fast and automatic visual invariance for handwritten words, although surprisingly this invariance can be reflected both as repetition suppression and as repetition enhancement. PMID- 19781649 TI - Cortical dynamics of selective attention to somatosensory events. AB - Recent studies have shown evidence of somatosensory deficits in individuals with attentional difficulties yet relatively little is known about the role of attention in the processing of somatosensory input. Neuromagnetic imaging studies have shown that rhythmic oscillations within the human somatosensory cortex are strongly modulated by somatosensory stimulation and may reflect the normal processing of such stimuli. However, few studies have examined how attention influences these cortical oscillations. We examined attentional effects on human somatosensory oscillations during median nerve stimulation by conducting time frequency analyses of neuromagnetic recordings in healthy adults. We found that selective attention modulated somatosensory oscillations in the alpha, beta, and gamma bands that were both phase-locked and non-phase-locked to the stimulus. In the primary somatosensory cortex (SI), directing the subject's attention toward the somatosensory stimulus resulted in increased gamma band power (30-55 Hz) that was phase-locked to stimulus onset. Directed attention also produced an initial suppression (desynchrony) followed by enhancement (synchrony) of beta band power (13-25 Hz) that was not phase-locked to the stimulus. In the secondary somatosensory cortex (SII), directing attention towards the stimulus increased phase-locked alpha (7-9 Hz) power approximately 30 ms after onset of phase-locked gamma in SI, followed by a non-phase-locked increase in alpha power. We suggest that earlier phase-locked oscillatory power may reflect the relay of input from SI to SII, whereas later non-phase-locked rhythms reflect stimulus-induced oscillations that are modulated by selective attention and may thus reflect enhanced processing of the stimulus underlying the perception of somatosensory events. PMID- 19781650 TI - A modified damped Richardson-Lucy algorithm to reduce isotropic background effects in spherical deconvolution. AB - Spherical deconvolution methods have been applied to diffusion MRI to improve diffusion tensor tractography results in brain regions with multiple fibre crossing. Recent developments, such as the introduction of non-negative constraints on the solution, allow a more accurate estimation of fibre orientations by reducing instability effects due to noise robustness. Standard convolution methods do not, however, adequately model the effects of partial volume from isotropic tissue, such as gray matter, or cerebrospinal fluid, which may degrade spherical deconvolution results. Here we use a newly developed spherical deconvolution algorithm based on an adaptive regularization (damped version of the Richardson-Lucy algorithm) to reduce isotropic partial volume effects. Results from both simulated and in vivo datasets show that, compared to a standard non-negative constrained algorithm, the damped Richardson-Lucy algorithm reduces spurious fibre orientations and preserves angular resolution of the main fibre orientations. These findings suggest that, in some brain regions, non-negative constraints alone may not be sufficient to reduce spurious fibre orientations. Considering both the speed of processing and the scan time required, this new method has the potential for better characterizing white matter anatomy and the integrity of pathological tissue. PMID- 19781651 TI - Individualized EEG source reconstruction of Stroop interference with masked color words. AB - A masked version of the classic color Stroop task was used to study interference effects with stimuli of variable visibility. Pattern masks with different stimulus onset asynchronies (SOAs) reduced the visibility in three steps. We took EEG recordings to measure neural correlates of Stroop interference and their relation to stimulus visibility. The analysis of event-related potentials indicated that N400 differences between congruent and incongruent trials varied with the degree of visibility, leaving no differences with stimuli near identification threshold. An equivalent current dipole model (ECD) was used to map source activity onto regions known to reflect interference-related activity. As expected, the anterior cingulate cortex (ACC) signaled the biggest differences between congruent and incongruent trials. As with event-related potentials, these differences disappeared with reduced stimulus visibility. In addition to equivalent current dipole modeling, Stroop-related neural sources were confirmed by means of current density reconstruction (SWARM) based on individualized boundary element models (BEMs) and a cortical constraint. PMID- 19781653 TI - Effect of CACNA1C rs1006737 on neural correlates of verbal fluency in healthy individuals. AB - BACKGROUND: Recent genetic studies found the A allele of the variant rs1006737 in the alpha 1C subunit of the L-type voltage-gated calcium channel (CACNA1C) gene to be overrepresented in patients suffering from bipolar disorder, schizophrenia or major depression. While the functions underlying the pathophysiology of these psychiatric disorders are yet unknown, impaired performance in verbal fluency tasks is an often replicated finding. We investigated the influence of the rs1006737 single nucleotide polymorphism (SNP) on verbal fluency and its neural correlates. METHODS: Brain activation was measured with functional magnetic resonance imaging (fMRI) during a semantic verbal fluency task in 63 healthy male individuals. They additionally performed more demanding verbal fluency tasks outside the scanner. All subjects were genotyped for CACNA1C rs1006737. RESULTS: For the behavioral measures outside the scanner, rs1006737genotype had an effect on semantic but not on lexical verbal fluency with decreased performance in risk allele carriers. In the fMRI experiment, while there were no differences in behavioural performance, increased activation in the left inferior frontal gyrus as well as the left precuneus was found in risk-allele carriers in the semantic verbal fluency task. CONCLUSIONS: The rs1006737 variant does influence language production on a semantic level in conjunction with the underlying neural systems. These findings are in line with results of studies in bipolar disorder, schizophrenia and major depression and may explain some of the cognitive and brain activation variation found in these disorders. PMID- 19781652 TI - Taking a gamble or playing by the rules: dissociable prefrontal systems implicated in probabilistic versus deterministic rule-based decisions. AB - A decision may be difficult because complex information processing is required to evaluate choices according to deterministic decision rules and/or because it is not certain which choice will lead to the best outcome in a probabilistic context. Factors that tax decision making such as decision rule complexity and low decision certainty should be disambiguated for a more complete understanding of the decision making process. Previous studies have examined the brain regions that are modulated by decision rule complexity or by decision certainty but have not examined these factors together in the context of a single task or study. In the present functional magnetic resonance imaging study, both decision rule complexity and decision certainty were varied in comparable decision tasks. Further, the level of certainty about which choice to make (choice certainty) was varied separately from certainty about the final outcome resulting from a choice (outcome certainty). Lateral prefrontal cortex, dorsal anterior cingulate cortex, and bilateral anterior insula were modulated by decision rule complexity. Anterior insula was engaged more strongly by low than high choice certainty decisions, whereas ventromedial prefrontal cortex showed the opposite pattern. These regions showed no effect of the independent manipulation of outcome certainty. The results disambiguate the influence of decision rule complexity, choice certainty, and outcome certainty on activity in diverse brain regions that have been implicated in decision making. Lateral prefrontal cortex plays a key role in implementing deterministic decision rules, ventromedial prefrontal cortex in probabilistic rules, and anterior insula in both. PMID- 19781654 TI - Decrease in anaerobe-related bacteraemias and increase in Bacteroides species isolation rate from 1998 to 2007: a retrospective study. AB - Conflicting data have accumulated in recent years regarding the incidence of anaerobic bacteraemias. The aim of this study was to determine the prevalence of bacteraemias due to anaerobic bacteria and evaluate the importance of anaerobic blood cultures in a university hospital in Israel. A retrospective survey which focused on anaerobic blood culture bottles was performed on blood cultures received in our laboratory during the decade from January 1998 to December 2007. Anaerobic-related bacteraemias decreased during that period, whereas a significant increase was observed in Bacteroides species isolated from the blood cultures (from 18% during 1998-2002 to 43% during 2003-2007). Comparison of the medical records of 54 patients with Bacteroides-related bacteraemia during the two end periods (1998-1999 and 2006-2007) revealed a marked increase in complex underlying diseases. Hypertension and diabetes mellitus type II were found in 29% of the patients in 1998-1999 and increased to 43-45% of the patients in 2006 2007. Ischemic heart disease also increased from 14% of the patients in 1998-1999 to 43% in 2006-2007. We conclude that although positive anaerobic blood cultures account for a small percentage of positive blood samples, the growing involvement of Bacteroides species-related bacteraemias together with an increase in complex underlying diseases in these patients emphasize the importance of anaerobic blood cultures, particularly in patients with co-morbidities. PMID- 19781655 TI - Influence of pretransplantation restrictive lung disease on allogeneic hematopoietic cell transplantation outcomes. AB - We conducted a 15-year retrospective cohort study to determine the prevalence of restrictive lung disease before allogeneic hematopoietic cell transplantation (HCT), and to assess whether this was a risk factor for poor outcomes. A total of 2545 patients were eligible for the analysis. Restrictive lung disease was defined as a total lung capacity (TLC) < 80% of predicted normal. Chest x-rays and /or computed tomography (CT) scans were reviewed for all restricted patients to determine whether lung parenchymal abnormalities were unlikely or highly likely to cause restriction. Multivariate Cox proportional hazard and sensitivity analyses were performed to assess the relationship between restriction and early respiratory failure and nonrelapse mortality. Restrictive lung disease was present in 194 subjects (7.6%) before HCT. Among these cases, radiographically apparent abnormalities were unlikely to be the cause of the restriction in 149 subjects (77%). In unadjusted and adjusted analyses, the presence of pulmonary restriction was significantly associated with a 2-fold increase in risk for early respiratory failure and nonrelapse mortality, suggesting that these outcomes occurring in the absence of radiographically apparent abnormalities may be related to respiratory muscle weakness. These findings suggest that pulmonary restriction should be considered a risk factor for poor outcomes after transplantation. PMID- 19781656 TI - Control of an outbreak of human parainfluenza virus 3 in hematopoietic stem cell transplant recipients. AB - Human parainfluenza virus 3 (HPIV3) infection can cause significant morbidity and mortality in patients undergoing hematopoietic stem cell transplantation (HSCT). There are no standard guidelines for the prevention and control of HPIV3 in the outpatient setting. After 2 HSCT inpatients diagnosed with HPIV3 were noted to have had multiple recent HSCT outpatient clinic (OPC) visits, an investigation of policy and procedures in the HSCT OPC was undertaken, and active surveillance for respiratory viral illness was instituted in the at-risk HSCT population. Between July 19 and August 30, 2005, 13 patients were diagnosed with HPIV3 infection. Morbidity in affected patients was significant, and mortality was high (38.5%) and not affected by antiviral therapy. Molecular typing identified several genetically distinct groups of the hemagglutinin-neuraminidase gene of the 11 available isolates. Based on sequence relatedness among the isolates and the demographic and exposure history of the patients, in many of these cases HPIV3 infection likely was acquired in the HSCT OPC. The major infection control interventions were introduced between August 20 and August 24. An epidemic curve revealed that HPIV3 infection frequency peaked between August 17 and August 26, with no cases identified after August 30. Prompt attention and focus on infection control interventions were associated with a rapid decrease in the number of incident cases. Policies and procedures regarding patients with respiratory viral illnesses in HSCT OPC populations should be formulated and universally reinforced with HSCT clinic staff to prevent the spread of these infections. PMID- 19781657 TI - The preventive health behaviors of long-term survivors of cancer and hematopoietic stem cell transplantation compared with matched controls. AB - Little is known about the health promotion, prevention, and disease screening behaviors of cancer survivors treated with hematopoietic cell transplantation (HCT), who undergo arduous treatment and may be at particular risk for late effects and secondary malignancies. The purposes of this study were to examine the current health and secondary prevention behaviors of long-term HCT survivors compared with matched controls without cancer, and to identify sociodemographic and clinical factors associated with appropriate preventive practices. HCT survivors (n = 662) were drawn from 40 North American transplantation centers. Peer-nominated acquaintances of survivors matched on sex, age, education, and marital status served as controls (n = 158). Data were collected a mean of 6.7 years post-HCT (range, 1.8-22.6 years). Despite a greater frequency of physical exams, the HCT survivors had similar health and screening behaviors as the matched controls. Sociodemographic factors were associated with health prevention behaviors in expected ways. Some differences between disease group and type of transplant were found, with survivors of acute leukemia less likely to report regular exercise, autologous transplant survivors more likely than allogeneic transplant survivors to report screenings for breast and cervical cancer, and allogeneic transplant survivors more likely than autologous transplant survivors to report undergoing a skin exam in the previous year. Despite higher levels of engagement with health care providers, HCT survivors had similar health behaviors as matched controls and comparable to those reported by cancer survivors who did not undergo HCT. There remains considerable room for improvement. These findings support the need for further education of both HCT survivors and health practitioners. PMID- 19781658 TI - Impending challenges in the hematopoietic stem cell transplantation physician workforce. AB - With increasing use of high dose chemotherapy with autologous and allogeneic transplants the need for the transplant physician workforce requires reassessment. The types of transplants and patients are also shifting toward transplants being done in patients with more comorbidities and more commonly these types of patients require more work effort per patient from the transplant physician. Additionally, HSCT survivors often require ongoing care at the transplant center due to the inability of the primary care workforce or the hematology/oncology workforce to absorb caring for post complex post transplant patients. The adult transplant workforce has had very few physicians join under age 40. Nearly 50% of adult transplant physicians are over age 50 whereas only 28% of pediatric transplant physicians are over age 50. By 2020, it is projected that we will need 1,264 new adult transplant physicians and 94 pediatric transplant physicians. Training time for a physician is approximately 15 years. The capping of both medical school slots and residency slots since the early '80s is now having a very big impact on supply, but other factors are also affecting supplies such as generational differences, lifestyle expectations, and the change of the medical workforce from being mostly men. Workforce shortages are being reported for many specialities. Workforce problems are also present for nurses, pharmacists and medical technologists. So increasing use of general internists and mid-level providers may not exist as a solution. Transplant physicians must be actively engaged in the medical education process to show young medical students and residents who are not committed to another sub specialty career the excitement and challenges of a career in bone marrow transplantation, so that our field will have providers for the future. PMID- 19781659 TI - Survival of secondary lethal systemic Francisella LVS challenge depends largely on interferon gamma. AB - Although survival of primary infection with the live vaccine strain (LVS) of Francisella tularensis depends on interferon gamma (IFN-gamma), the relative importance of IFN-gamma to secondary protective immunity in vivo has not been clearly established. Here we examine the role of IFN-gamma in T cell priming and expression of vaccine-induced protection against lethal intraperitoneal challenge of mice. Large amounts of IFN-gamma were detected between days 3 and 7 in the sera of LVS-immunized mice, while relatively small amounts were found transiently after secondary LVS challenge. Consistent with the production of this cytokine, mice lacking IFN-gamma (gamma interferon knockout, GKO, mice) could not be successfully vaccinated with LVS or an attenuated mglA mutant of F. novicida to withstand secondary Francisella LVS challenge. Further, splenocytes from such primed mice did not adoptively transfer protection to naive GKO recipient mice in vivo, nor control the intramacrophage growth of LVS in vitro. Finally, LVS-immune WT mice depleted of IFN-gamma prior to intraperitoneal challenge survived only the lowest doses of challenge. Thus successful priming of protective LVS-immune T cells, as well as complete expression of protection against Francisella during secondary challenge, depends heavily on IFN-gamma. PMID- 19781660 TI - Post-translational modification of CASK leads to its proteasome-dependent degradation. AB - CASK is a member of the membrane-associated guanylate kinase family. In mammals it is an essential protein, as CASK knockout mice die after birth and its deletion in humans has developmental consequences. CASK plays a role in the transcription of genes required for forebrain development, and in the nervous systems of Drosophila and C. elegans, it participates in receptor localization at the plasma membrane. This role in organizing supramolecular protein complexes to appropriate subcellular regions is shared in mammals and is regulated by phosphorylation. CASK is a kinase and regulator of cell proliferation and adhesion, which adds to an expanding list of roles. In this study we report for the first time that CASK is degraded in a characteristic fashion in mammalian cells. We found that CASK is a long-lived protein despite the fact that it contains three putative PEST sequences. Finally, we provide detailed evidence that CASK degradation is mediated through a ubiquitin-proteasome pathway and this is phosphorylation-dependent. Together, these results provide evidence that post translational modifications to CASK are major regulatory steps leading to its proteasomal degradation. This regulation not only has important implications on how CASK participates in its many disparate roles, but highlights how altering this regulation may contribute to the pathogenesis of human disease. PMID- 19781661 TI - Differential expression of alpha-2,3-sialyltransferases and alpha-1,3/4 fucosyltransferases regulates the levels of sialyl Lewis a and sialyl Lewis x in gastrointestinal carcinoma cells. AB - Sialyl Lewis x and sialyl Lewis a expression depends on sialyltransferases and fucosyltransferases. In this study, we screened for major variations of sialyltransferases and fucosyltransferases involved in the synthesis and regulation of sialyl Lewis x and sialyl Lewis a epitopes in gastrointestinal carcinoma cells. Our results show that expression of ST3Gal IV in several gastrointestinal cell lines is correlated with the expression of sialyl Lewis x at the cell surface. ST3Gal IV overexpressed in the gastric MKN45 cell line, showed exclusive enzymatic activity towards glycoproteins containing terminal Galbeta1-4GlcNAc structure. On the other hand, when ST3Gal III was overexpressed in MKN45, an increase in the expression levels of both sialyl Lewis epitopes was observed. ST3Gal III and ST3Gal IV lead to de novo synthesis of sialyl Lewis x determinant on different molecular weight glycoproteins of MKN45 cells suggesting that each enzyme used different substrates within the available glycoproteome. The final glycosylation step in sialyl Lewis x and sialyl Lewis a biosynthesis in MKN45 cell line was shown to be associated to FUT5, which efficiently fucosylated sialyl Lewis precursors on glycoproteins. Moreover we demonstrate that the expression of sialyl Lewis epitopes in the MKN45 was induced by cell confluence, which can be regarded as a model to study altered glycosylation during tumour progression. This increase was observed together with an increase in mRNA levels of ST3GAL3, FUT5 and FUT6, and a decrease in FUT4 transcript levels in MKN45 confluent cells, suggesting a possible control at the transcriptional level. PMID- 19781662 TI - Role of DNA methylation and methyl-DNA binding proteins in the repression of 5 lipoxygenase promoter activity. AB - Human 5-lipoxygenase (5-LO) is the key enzyme in the formation of inflammatory leukotrienes. 5-LO gene expression is mainly restricted to B cells and cells of myeloid origin. It is known that basal 5-lipoxygenase promoter activity is regulated by DNA methylation. In this study we investigated the impact of the DNA methylation status of the 5-LO promoter on its activity and the role of methyl DNA binding proteins (MBDs) in transcriptional silencing of the 5-LO promoter. Using ChIP assays, we found that the methyl-DNA binding proteins MBD1, MBD2 and MeCP2 bind to the methylated 5-LO core promoter in U937 cells. Knock down of each of the MBDs upregulates 5-LO mRNA expression in U937 cells indicating that these proteins are involved in silencing of the 5-LO gene. In reporter gene assays with in vitro methylated 5-LO promoter constructs, the extent of 5-LO promoter methylation inversely correlated with its activity. Furthermore, we found that MBD1 overexpression repressed 5-LO promoter activity when the CpG sites at the Sp1 binding site close to the transcriptional start site (GC4) were methylated. Gel shift data indicate that recruitment of Sp1 to this binding site is prevented by methylation. PMID- 19781663 TI - n-3 PUFA and lipotoxicity. AB - Excess lipid accumulation in nonadipose tissues may occur in the setting of high levels of plasma free fatty acids or triglycerides (TGs) in a process called "lipotoxicity". Evidence from human studies and animal models suggests that lipid accumulation in the heart, skeletal muscle, pancreas, and liver play an important role in the pathogenesis of heart failure, obesity, metabolic syndrome, and type 2 diabetes mellitus (T2DM). During the past few years, several studies have shown that n-3 polyunsaturated fatty acids (PUFA) have potentially cardioprotective effects, especially in high-risk patients with dyslipidemia, and might therefore be expected to be of benefit in T2DM. Moreover, new information has demonstrated the beneficial effects of consuming n-3 PUFA in preventing the complications of lipotoxicity. n-3 PUFA dietary intake thus had positive effects on fatty liver in patients with non-alcoholic fatty liver disease (NAFLD), with an improvement in liver echotexture and a significant regression of hepatic brightness, associated with improved liver hemodynamics. The n-3 PUFA also had beneficial effects on ectopic fat accumulation inside the heart, with stabilization of cardiac myocytes and antiarrhythmic effects. On the other hand, recent data from animal models suggest that oral dosing of eicosapentaenoic acid (EPA) could contribute to protect against beta-cell lipotoxicity. This review discusses the latest hypotheses regarding lipotoxicity, concentrating on the impact of the n-3 PUFA that contribute to ectopic lipid storage, affecting organ function. Further human studies are needed to test the evidence and elucidate the mechanisms involved in this process. PMID- 19781664 TI - Drosophila as a lipotoxicity model organism--more than a promise? AB - Looking back over the century long research career of the fruit fly, Drosophila melanogaster has frequently been in the scientific spotlight with respect to fundamental discoveries in biology. The last decade witnessed the increasing importance of the fly as a human disease model but studies on energy homeostasis and lipometabolism remain in their infancy. This perspective, addressing readers largely unfamiliar with the Drosophila model system, aims to highlight the starting points for which the fly could be employed to gain a deeper understanding of lipotoxicity and possibly contribute to strategies for the identification of novel drug targets relevant to type 2 diabetes mellitus and the metabolic syndrome. PMID- 19781666 TI - Anti-inflammatory effects of rhynchophylline and isorhynchophylline in mouse N9 microglial cells and the molecular mechanism. AB - Excessive production of nitric oxide (NO) and proinflammatory cytokines from activated microglia contributes to human neurodegenerative disorders. Our previous study demonstrated the potent inhibition of lipopolysaccharide (LPS) induced NO production in rat primary microglial cells by rhynchophylline (RIN) and isorhynchophylline (IRN), a pair of isomeric alkaloids of Uncaria rhynchophylla (Miq.) Jacks. that has been used in China for centuries as a "cognitive enhancer" as well as to treat strokes. We further investigated whether RIN and IRN effectively suppress release of proinflammatory cytokines in LPS activated microglial cells and the underling molecular mechanism for the inhibition of microglial activation. RIN and IRN concentration-dependently attenuated LPS-induced production of proinflammatory cytokines such as TNF-alpha and IL-1beta as well as NO in mouse N9 microglial cells, with IRN showing more potent inhibition of microglial activation. The western blotting analysis indicated that the potential molecular mechanism for RIN or IRN-mediated attenuation was implicated in suppressions of iNOS protein level, phosphorylation of ERK and p38 MAPKs, and degradation of IkappaBalpha. In addition, the differential regulation of the three signaling pathways by two isomers was shown. Our results suggest that RIN and IRN may be effective therapeutic candidates for use in the treatment of neurodegenerative diseases accompanied by microglial activation. PMID- 19781665 TI - Heart Healthy and Ethnically Relevant (HHER) Lifestyle trial for improving diet and physical activity in underserved African American women. AB - BACKGROUND: African American women are at increased risk for CVD morbidity and mortality relative to white women. Physical inactivity and poor dietary habits are modifiable health behaviors shown to reduce CVD risk. Community health centers have the potential to reach large numbers of African Americans to modify their risk for CVD, yet few lifestyle counseling interventions have been conducted in this setting. METHODS: The HHER Lifestyle trial is a randomized controlled trial to compare the effects of a standard care intervention (provider counseling, nurse goal setting, and educational materials) to a comprehensive intervention (standard care intervention plus 12 months of telephone counseling and tailored print materials) on changes in physical activity and dietary fat consumption in financially disadvantaged African American women at 6 and 12 months. Secondary outcomes are body mass index, central adiposity, and total cholesterol. Potential mediators of outcome are self-efficacy for overcoming barriers, social support, and decisional balance. RESULTS: African American women (N=266; 130 standard care, 136 comprehensive intervention) 35 years and older from nine clinics within two community health centers were enrolled. Most participants were overweight or obese with existing chronic health conditions. CONCLUSION: The HHER Lifestyle trial is unique in that it targets financially disadvantaged African American women from community health centers, incorporates a standard care intervention into a routine clinical appointment, and includes a comprehensive process evaluation. The design will permit further research examining the added effect of regular telephone counseling and tailored print materials to a primary care provider and nurse intervention. PMID- 19781667 TI - Personalized dementia care: proven effectiveness of psychosocial interventions in subgroups. AB - Many psychosocial intervention studies report effects in subgroups of people with dementia. Insight into the characteristics of these subgroups is important for care practice. This study reviews personal characteristics of people with dementia (living in the community or in an institution) that are related to positive outcomes of psychosocial interventions. Electronic databases and key articles were searched for effect studies published between January 1990 and February 2008. Outcome measures were clustered into categories such as cognitive functioning, behavioural functioning and mental health. Seventy-one studies showed positive outcomes on psychosocial interventions, such as decreased depression and less behavioural problems, related to personal characteristics of people with dementia, such as gender, type or severity of dementia, presence of behavioural or mental health problems, and living situation. For people with dementia living in the community positive effects were most frequently found in the persons with mild to severe dementia not otherwise specified and with mild to moderate Alzheimer's Disease. For people with dementia living in an institution positive effects were found most frequently in the subgroups moderate to severe dementia, severe to very severe dementia and in the subgroup with behavioural problems. This study provides a unique overview of characteristics that are related to effective intervention outcomes. It also suggests that more research will lead to a better understanding of which care and welfare interventions are effective for specific subgroups of people with dementia. PMID- 19781668 TI - Role of protein motions on proton transfer pathways in human carbonic anhydrase II. AB - We report here a theoretical study on the formation of long-range proton transfer pathways in proteins due to side chain conformational fluctuations of amino acid residues and reorganization of interior hydration positions. The proton transfer pathways in such systems may be modeled as fluctuating hydrogen-bonded networks with both short- and long-lived connections between the networked nodes, the latter being formed by polar protein atoms and water molecules. It is known that these fluctuations may extend over several decades of time ranging from a few femtoseconds to a few milliseconds. We have shown in this article how the use of a variety of theoretical methods may be utilized to detect a generic set of pathways and assess the feasibility of forming one or more transient connections. We demonstrate the application of these methods to the enzyme human carbonic anhydrase II and its mutants. Our results reveal several alternative pathways in addition to the one mediated by His-64. We also probe at length the mechanism of key conformational fluctuations contributing to the formation of the detected pathways. PMID- 19781669 TI - Proteomics and human proteome. From bench to bedside. PMID- 19781670 TI - Validation of serum protein profiles by a dual antibody array approach. AB - In recent years, affinity-based technologies have become important tools for serum profiling to uncover protein expression patterns linked to disease state or therapeutic effects. In this study, we describe a path towards the production of an antibody microarray to allow protein profiling of biotinylated human serum samples with reproducible sensitivity in the picomolar range. With the availability of growing numbers of affinity reagents, protein profiles are to be validated in efficient manners and we describe a cross-platform strategy based on data concordance with a suspension bead array to interrogate the identical set of antibodies with the same cohort of serum samples. Comparative analysis enabled to screen for high-performing antibodies, which were displaying consistent results across the two platforms and targeting known serum components. Moreover, data processing methods such as sample referencing and normalization were evaluated for their effects on inter-platform agreement. Our work suggests that mutual validation of protein expression profiles using alternative microarray platforms holds great potential in becoming an important and valuable component in affinity based high-throughput proteomic screenings as it allows to narrow down the number of discovered targets prior to orthogonal, uniplexed validation approaches. PMID- 19781671 TI - A proteomics approach to study in vivo protein N(alpha)-modifications. AB - In this article we present a simple method to enrich peptides containing in vivo N(alpha)-modified protein N-termini. We demonstrate that CNBr-activated Sepharose, a commercial amine reactive matrix, can selectively couple peptides via the alpha-NH(2) group under mild conditions. Following digestion by trypsin, a simple incubation step with the CNBr-activated Sepharose by which the free alpha-NH(2) containing peptides are coupled with matrix through a covalent bond, allows the separation of N(alpha)-modified peptides from massive free alpha-NH(2) containing peptides. The removal of contaminant peptides with artificial N(alpha) modifications, like cyclization of N-terminal S-carbamoylmethylcysteine and glutamine, are also discussed. Application of this method to tryptic digests of HeLa cell proteins resulted by a single LC-MS/MS analysis in the identification of 588 in vivo N(alpha)-modified peptides, of which 507 contain IPI (International Protein Index) annotated protein N-termini and 81 contain IPI unannotated protein N-termini. Most of the identified modifications are acetylations with only a few formylations and propionylations present. Furthermore, Lys-N digestion was also applied and resulted in the identification of 394 in vivo N(alpha)-modified peptides, of which 371 contain IPI annotated protein N-termini and 23 contain IPI unannotated protein N-termini. Combination of the two datasets leads to the identification of 675 N(alpha)-modified IPI annotated protein N-termini and 88 N(alpha)-modified IPI unannotated protein N termini. Our results suggest that N-terminal acetyltransferases (NATs) may function as N-terminal formyltransferases (NFTs) and N-terminal propionyltransferases (NPTs) in vivo. PMID- 19781672 TI - The maize HMGA protein is localized to the nucleolus and can be acetylated in vitro at its globular domain, and phosphorylation by CDK reduces its binding activity to AT-rich DNA. AB - The high mobility group (HMG) proteins are nonhistone chromosomal proteins that participate in diverse nuclear activities including chromatin structure and gene regulation. We previously studied the biochemistry of the maize HMGA protein and its role in transcriptional regulation during maize endosperm development. Here, we extended our study and showed that a strong binding of ZmHMGA to AT-rich DNA requires at least three AT-hook motifs; two motifs showed a significant reduction whereas a single motif was not sufficient for binding. CDK phosphorylation sites situated between AT-hook3 and AT-hook4 were strongly phosphorylated by a SUC1 associated kinase; no in vitro phosphorylation is evident for the AtHMGA protein. Phosphorylation of ZmHMGA reduced its binding to AT-rich DNA in vitro. The maize HMGA protein fused to GFP was localized in the nucleus of transgenic Arabidopsis plants tending to concentrate within the nucleolus. Localization to the nucleolus was conferred by the C-terminal portion of the protein containing the AT-hooks. ZmHMGA was acetylated in vitro on its N-terminal globular domain by the human PCAF acetyltransferase. Our results suggest that ZmHMGA participates in nucleolar function and that its role may be regulated posttranslationally by phosphorylation and acetylation. PMID- 19781673 TI - Structure and function of regulatory RNA elements: ribozymes that regulate gene expression. AB - Since their discovery in the 1980s, it has gradually become apparent that there are several functional classes of naturally occurring ribozymes. These include ribozymes that mediate RNA splicing (the Group I and Group II introns, and possibly the RNA components of the spliceosome), RNA processing ribozymes (RNase P, which cleaves precursor tRNAs and other structural RNA precursors), the peptidyl transferase center of the ribosome, and small, self-cleaving genomic ribozymes (including the hammerhead, hairpin, HDV and VS ribozymes). The most recently discovered functional class of ribozymes include those that are embedded in the untranslated regions of mature mRNAs that regulate the gene's translational expression. These include the prokaryotic glmS ribozyme, a bacterial riboswitch, and a variant of the hammerhead ribozyme, which has been found embedded in mammalian mRNAs. With the discovery of a mammalian riboswitch ribozyme, the question of how an embedded hammerhead ribozyme's switching mechanism works becomes a compelling question. Recent structural results suggest several possibilities. PMID- 19781675 TI - A microarray based identification of osteoporosis-related genes in primary culture of human osteoblasts. AB - Genetic factors influencing the pathogenesis of osteoporosis are still largely unknown. We employed genome-wide gene expression approach in order to discover novel genes involved in the pathogenesis of osteoporosis. To this end, primary cultures of osteoblasts isolated from osteoporotic and non-osteoporotic human bone tissue samples were prepared. One thousand six hundred six genes were found to be differentially expressed, indicating increased demand for protein synthesis and decreased cell proliferation rate in osteoblasts from osteoporotic tissue as compared to osteoblasts from non-osteoporotic tissue. At first, top four genes, based on the microarray data and potential role in bone metabolism, were further studied in bone tissue samples of 55 patients. PTN and COL15A1 were both downregulated in osteoporotic bone tissue (6.2- and 3.4-fold, respectively, both p<0.05), while IBSP and CXCL2 were both upregulated (5.7-fold, p<0.05, and 2.1 fold, p>0.05). Further biostatistical analysis of the microarray data by gene set enrichment analysis suggested oxidative stress may have an important part in the pathogenesis of osteoporosis. Thus, secondly, we tested it by an in vitro assay on human osteosarcoma cell line cells treated with hydrogen peroxide. After 72 h of treatment with 500 microM hydrogen peroxide, the upregulation of the same genes involved in the response to oxidative stress as on the microarrays was observed: MT1G (metallothionein 1G, 22.1-fold, p<0.05), TXNRD1 (thioredoxin reductase 1, 3.7-fold, p<0.05), AOX1 (aldehyde oxidase 1, 24.5-fold, p<0.05) and GSR (glutathione reductase, 4.7-fold, p<0.05). Our results present a novel list of genes and metabolic pathways that may be associated with the pathogenesis of osteoporosis. PTN, CXCL2, COL15A1, IBSP, AOX1, MT1G, GSR and TXNRD1 are candidate genes for further studies in the assessment of the genetic susceptibility to osteoporosis. In addition, differences in protein synthesis, cell proliferation rate and response to oxidative stress may also be involved in the pathogenesis of osteoporosis. PMID- 19781676 TI - Low-intensity pulsed ultrasound-dependent osteoblast proliferation occurs by via activation of the P2Y receptor: role of the P2Y1 receptor. AB - Low-intensity pulsed ultrasound (LIPUS) is commonly used in the treatment of fractures and nonunion-promoting acceleration of healing fractures. In this report, we investigated the implication of the P2 receptors in osteoblast proliferation induced with LIPUS treatment. We observed that ADP, ATP, UTP, and UDP promote osteoblast increase and an increase of intracellular Ca(2+), through activation of P2Y receptors. Osteoblasts' expression of the P2Y(1), P2Y(2), P2Y(4), P2Y(6), P2Y(11), P2Y(12), and P2Y(13) receptors was confirmed. In addition, the participation of the P2Y(1) receptor in osteoblast increase and the ADP-dependent increase of Ca(2+) concentration were shown. Furthermore, release of ATP/purines was induced by LIPUS treatment. Finally, LIPUS-dependent osteoblast increase was abolished in the presence of the Ca(2+) chelator (BAPTA), the inositol 1,4,5-trisphosphate receptor antagonist (2-APB), and the selective P2Y(1) receptor antagonist (MRS2179). In conclusion, LIPUS treatment induces osteoblastogenesis via the release of purines, such as ATP, activating P2Y receptors, mainly the P2Y(1) receptor. PMID- 19781678 TI - Intramuscular Matrix-M-adjuvanted virosomal H5N1 vaccine induces high frequencies of multifunctional Th1 CD4+ cells and strong antibody responses in mice. AB - Ideally, a candidate pandemic influenza vaccine should elicit rapid and strong cell-mediated and humoral immune responses, which are long-lasting and exhibit broad cross-reactivity against drifted strains. The present study investigated the detailed humoral and cellular immune responses in mice vaccinated intranasally or intramuscularly with inactivated influenza H5N1 (NIBRG-14) virosomal vaccine alone or formulated with Matrix-M adjuvant. The intramuscular Matrix-M-adjuvanted vaccine induced a strong immediate and long-term humoral immune response with high cross-reactivity against drifted H5N1 viruses and showed a dose-sparing potential. Additionally, the vaccine induced a balanced Th1/Th2 cytokine profile and most importantly high frequencies of multifunctional Th1 CD4(+) cells. Our results highlight that Matrix-M adjuvant is a promising parenteral adjuvant for formulating pandemic candidate vaccines. PMID- 19781677 TI - Treatment with a soluble receptor for activin improves bone mass and structure in the axial and appendicular skeleton of female cynomolgus macaques (Macaca fascicularis). AB - A recent study suggests that activin inhibits bone matrix mineralization, whereas treatment of mice with a soluble form of the activin type IIA receptor markedly increases bone mass and strength. To further extend these observations, we determined the skeletal effects of inhibiting activin signaling through the ActRIIA receptor in a large animal model with a hormonal profile and bone metabolism similar to humans. Ten female cynomolgus monkeys (Macaca fascicularis) were divided into two weight-matched groups and treated biweekly, for 3 months, with either a subcutaneous injection 10 mg/kg of a soluble form of the ActRIIA receptor fused with the Fc portion of human IgG(1) (ACE-011) or vehicle (VEH). Bone mineral density (BMD), micro-architecture, compressive mechanical properties, and ash fraction were assessed at the end of the treatment period. BMD was significantly higher in ACE-011 treated individuals compared to VEH: +13% (p=0.003) in the 5th lumbar vertebral body and +15% (p=0.05) in the distal femur. In addition, trabecular volumetric bone density at the distal femur was 72% (p=0.0004) higher than the VEH-treated group. Monkeys treated with ACE-011 also had a significantly higher L5 vertebral body trabecular bone volume (p=0.002) and compressive mechanical properties. Ash fraction of L4 trabecular bone cores did not differ between groups. These results demonstrate that treatment with a soluble form of ActRIIA (ACE-011) enhances bone mass and bone strength in cynomolgus monkeys, and provide strong rationale for exploring the use of ACE-011 to prevent and/or treat skeletal fragility. PMID- 19781674 TI - Cis-acting RNA elements in human and animal plus-strand RNA viruses. AB - The RNA genomes of plus-strand RNA viruses have the ability to form secondary and higher-order structures that contribute to their stability and to their participation in inter- and intramolecular interactions. Those structures that are functionally important are called cis-acting RNA elements because their functions cannot be complemented in trans. They can be involved not only in RNA/RNA interactions but also in binding of viral and cellular proteins during the complex processes of translation, RNA replication and encapsidation. Most viral cis-acting RNA elements are located in the highly structured 5'- and 3' nontranslated regions of the genomes but sometimes they also extend into the adjacent coding sequences. In addition, some cis-acting RNA elements are embedded within the coding sequences far away from the genomic ends. Although the functional importance of many of these structures has been confirmed by genetic and biochemical analyses, their precise roles are not yet fully understood. In this review we have summarized what is known about cis-acting RNA elements in nine families of human and animal plus-strand RNA viruses with an emphasis on the most thoroughly characterized virus families, the Picornaviridae and Flaviviridae. PMID- 19781679 TI - Gene gun administration of therapeutic HPV DNA vaccination restores the efficacy of prolonged defrosted viral based vaccine. AB - Freshly defrosted vaccines generate promising antitumor immunity by raising both robust CD8 and CD4 responses with a TC1/Th1-dominant cytokine profile. However, prolonged (overnight) defrosted Sindbis virus-E7/HSP70 priming and Vaccinia E7/HSP70 booster in mouse model only elicited 20% long-term tumor-free survival in comparison with the fresh vaccines. The present study is to search the possible cause of its potency loss, and to evaluate the ability of pcDNA-E7/HSP70 DNA vaccination via gene gun in restoring the efficacy of E7-specific immune responses and antitumor properties. We used prolonged defrosted SINrep5-E7/HSP70 prime and defrosted Vac-E7/HSP70 boost subcutaneously, and administered intradermally cluster (3-day interval) gene gun plasmid E7-HSP70DNA vaccine twice, and evaluated its ability to generate antigen-specific cytotoxic CD8+ T cell responses using flow cytometry as well as antitumor responses using animal positron-emission tomography (PET) imaging. The prolonged defrosted vaccines showed a significant reduction in the infectivity and a significant decrease of CD8+ and CD4+ T-cells immune responses. Administration of cluster gene gun plasmid E7-HSP70DNA twice was also found to lead to restoration of immunity that elicits a full recovery of the antitumor efficacy of the prolonged defrosted vaccines. Our study suggested that adding cluster gene gun plasmid E7-HSP70DNA vaccine twice offered a simple solution in restoring the efficacy of the prime boost vaccination with viral vectors and has potentially significant clinical applications. PMID- 19781680 TI - Parental attitude toward influenza A(H1N1)v vaccination in Italy. PMID- 19781681 TI - PPIB mutations cause severe osteogenesis imperfecta. AB - Deficiency of cartilage-associated protein (CRTAP) or prolyl 3-hydroxylase 1(P3H1) has been reported in autosomal-recessive lethal or severe osteogenesis imperfecta (OI). CRTAP, P3H1, and cyclophilin B (CyPB) form an intracellular collagen-modifying complex that 3-hydroxylates proline at position 986 (P986) in the alpha1 chains of collagen type I. This 3-prolyl hydroxylation is decreased in patients with CRTAP and P3H1 deficiency. It was suspected that mutations in the PPIB gene encoding CyPB would also cause OI with decreased collagen 3-prolyl hydroxylation. To our knowledge we present the first two families with recessive OI caused by PPIB gene mutations. The clinical phenotype is compatible with OI Sillence type II-B/III as seen with COL1A1/2, CRTAP, and LEPRE1 mutations. The percentage of 3-hydroxylated P986 residues in patients with PPIB mutations is decreased in comparison to normal, but it is higher than in patients with CRTAP and LEPRE1 mutations. This result and the fact that CyPB is demonstrable independent of CRTAP and P3H1, along with reported decreased 3-prolyl hydroxylation due to deficiency of CRTAP lacking the catalytic hydroxylation domain and the known function of CyPB as a cis-trans isomerase, suggest that recessive OI is caused by a dysfunctional P3H1/CRTAP/CyPB complex rather than by the lack of 3-prolyl hydroxylation of a single proline residue in the alpha1 chains of collagen type I. PMID- 19781684 TI - Economic appraisal of the Boston Ocular Surface Prosthesis. AB - PURPOSE: To perform an economic appraisal of the Boston Ocular Surface Prosthesis in patients with corneal ectasia, irregular astigmatism, or ocular surface disease. DESIGN: Cost, incremental cost-effectiveness, and benefit-cost analyses in a prospective observational study. METHODS: The effects of this scleral lens on visual functioning were measured in 69 patients who received the prosthesis in 2006 and were reassessed 6 months after fitting the prosthesis. Benefits, based on improvements in visual functioning, were converted to quality-adjusted life years (QALYs), and economic values were derived using results from published studies. Costs were estimated from the provider organization's 2006 operating financial statement with additions for donated resources and future scale-up. RESULTS: Mean scores on a 100-point visual functioning questionnaire (VFQ-25) improved from 57.0 to 77.8 (P < .0001). On average, each fitted patient cost $11,841 ($6001 for clinical services and $5840 to produce the prosthesis). Patients' quality of life improved by 0.10 QALYs per year. Assuming that benefits persist for an average of 5 years, the lifetime gain was 0.48 QALYs; the average cost-effectiveness of the prosthesis was $24,900 per QALY (95% confidence interval $19,100 to $29,600), and the average benefit-cost ratio was 4.0 to 1. In patients with the lowest baseline scores (average VFQ score 38.6), results were even more favorable: cost-effectiveness $17,100 per QALY and benefit-cost ratio 5.6 to 1. CONCLUSIONS: The Boston Ocular Surface Prosthesis is cost-effective and cost beneficial in patients with severely compromised visual function attributable to ectasia, irregular astigmatism, or ocular surface disease. PMID- 19781685 TI - Use of anterior segment optical coherence tomography to study corneal changes after collagen cross-linking. AB - PURPOSE: To investigate the stromal demarcation line after corneal cross-linking using anterior segment optical coherence tomography (AS-OCT) and its influence on the short-term results of cross-linking in patients with progressive keratoconus. DESIGN: Prospective, nonrandomized study. METHODS: Twenty-nine eyes of 29 patients with progressive keratoconus (n = 28) or after laser in situ keratomileusis ectasia (n = 1) were included and treated with corneal cross linking at our institution. Measurements at 1, 3, 6, and 12 months after corneal cross-linking were: refraction, best-corrected visual acuity (BCVA), tonometry, corneal topography, AS-OCT, specular microscopy, and aberrometry. Demarcation line depth was measured centrally, 2 mm temporally, and 2 mm nasally by two independent observers using AS-OCT and was correlated with clinical parameters. RESULTS: The stromal demarcation line was visible with AS-OCT at 1 month after surgery in 28 of 29 eyes. Pairwise comparisons between the two observers of the AS-OCT measurements did not show a statistically significant difference. After an initial steepening of maximal keratometry values and a decrease in BCVA at 1 month after surgery (both with P < .012), no significant changes were found at 3, 6, and 12 months after surgery compared with before surgery. Refractive cylinder, topographic astigmatism, aberration values, endothelial cell density, and intraocular pressure remained stable during all postoperative visits. A deeper demarcation line depth was associated with a larger decrease in corneal thickness (r = -0.506; P = .012). CONCLUSIONS: AS-OCT is a useful device to detect the stromal demarcation line after corneal cross-linking. At 3 to 12 months follow up, all clinical parameters remained stable, indicating stabilization of the keratoconic disease. PMID- 19781682 TI - Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer. AB - The susceptibility gene for ataxia telangiectasia, ATM, is also an intermediate risk breast-cancer-susceptibility gene. However, the spectrum and frequency distribution of ATM mutations that confer increased risk of breast cancer have been controversial. To assess the contribution of rare variants in this gene to risk of breast cancer, we pooled data from seven published ATM case-control mutation-screening studies, including a total of 1544 breast cancer cases and 1224 controls, with data from our own mutation screening of an additional 987 breast cancer cases and 1021 controls. Using an in silico missense-substitution analysis that provides a ranking of missense substitutions from evolutionarily most likely to least likely, we carried out analyses of protein-truncating variants, splice-junction variants, and rare missense variants. We found marginal evidence that the combination of ATM protein-truncating and splice-junction variants contribute to breast cancer risk. There was stronger evidence that a subset of rare, evolutionarily unlikely missense substitutions confer increased risk. On the basis of subset analyses, we hypothesize that rare missense substitutions falling in and around the FAT, kinase, and FATC domains of the protein may be disproportionately responsible for that risk and that a subset of these may confer higher risk than do protein-truncating variants. We conclude that a comparison between the graded distributions of missense substitutions in cases versus controls can complement analyses of truncating variants and help identify susceptibility genes and that this approach will aid interpretation of the data emerging from new sequencing technologies. PMID- 19781686 TI - Comparison between femtosecond laser-assisted sub-Bowman keratomileusis vs laser subepithelial keratectomy to correct myopia. AB - PURPOSE: To compare femtosecond laser sub-Bowman keratomileusis (FSBK) vs laser subepithelial keratectomy (LASEK) to correct myopia. DESIGN: Retrospective, nonrandomized, interventional, comparative case series. METHODS: Two thousand one hundred and eight eyes were included in the study. We compared 1,072 eyes treated with FSBK vs 1,036 eyes treated with LASEK with or without mitomycin C (MMC). Visual and refractive results were evaluated 1 day, 1 week, and 1 and 3 months postoperatively. RESULTS: Preoperative mean sphere and best spectacle-corrected visual acuity (BSCVA) were -3.93 diopters (D) vs -3.87 D (P = .5) and 1.12 vs 1.12 (P = .8) in FSBK and LASEK, respectively. Uncorrected visual acuity (UCVA) was 0.92 vs 0.62, 0.98 vs 0.78, 0.96 vs 0.91, and 1.06 vs 1.03 in FSBK and LASEK, respectively, at 1 day, 1 week, and 1 and 3 months after surgery (P < .01 for all comparisons). Three months postoperatively, BSCVA was 1.13 and 1.10, respectively (P = .001). At that moment, 20 eyes (1.93%) in the LASEK group vs 9 eyes (0.84%) in the FSBK group had lost 2 or more lines of BSCVA. Ten eyes (0.96%) in the LASEK group gained 2 or more lines of BSCVA, whereas 3 eyes (0.28%) in the FSBK group gained 2 lines. Six months postoperatively, only 2 LASEK eyes (0.19%) showed loss of 2 or more lines of BSCVA, compared to 3 FSBK-treated eyes (0.28%). CONCLUSION: Both FSBK and LASEK are safe and effective procedures to correct myopia. Slightly better visual and refractive results were observed in FSBK treated eyes in a 3-month follow-up. PMID- 19781687 TI - Fundus-based and electroretinographic strategies for stratification of late-stage Vogt-Koyanagi-Harada disease patients. AB - PURPOSE: To propose an analytic framework for ocular fundus alterations in late stage Vogt-Koyanagi-Harada (VKH) disease, to describe the characteristics of overall retinal function as measured with full-field electroretinography (ERG), and to correlate the intensity of the fundus changes with full-field ERG alterations and to stratify patients accordingly. DESIGN: Cross-sectional case series. METHODS: Forty-seven eyes of 26 patients with late-stage VKH disease (> 6 months past disease onset) followed-up at the University of Sao Paulo School of Medicine underwent fundus photography within 2 months of a full-field ERG examination, both according to predefined protocols. Fundus pictures were evaluated by two observers regarding diffuse fundus depigmentation, nummular lesions, pigment clumps, and subretinal fibrosis, and an overall analysis classified the fundus changes as mild, moderate, or severe. Full-field ERG results were analyzed according to fundus-based stratification and also were stratified into 3 groups solely on the basis of decreasing amplitudes (ERG based or cluster stratification). The concordance between fundus-based and full-field ERG-based stratification strategies was estimated. RESULTS: Overall fundus grading showed substantial interobserver concordance (kappa = 0.78). Comparison of full-field ERG parameters of the three fundus-based stratified groups showed diffusely diminished amplitudes with preservation of implicit times (P < .05). Fundus-based and full-field ERG-based stratification strategies also showed substantial concordance (kappa = 0.68). CONCLUSIONS: The analytic framework for fundus findings proposed in this study seems reproducible and useful, because the severity categories do correlate with retinal function as measured by full-field ERG. This system may allow more precise exchange of information between practitioners as well as researchers with regard to identifying patients with greater retinal compromise rapidly as well as in comparison of outcomes of different treatment regimens. PMID- 19781688 TI - Morphological characterization of rat incisor fluorotic lesions. AB - The morphological characterization of fluorotic rat incisor enamel was carried out. Experimental adult animals received drinking water with 45 mg F/L of fluoride, and the control group received distilled water. Fluoride concentrations found in the control and fluorosis groups were 0.04 and 0.09 microg/mL (plasma), 0.26 and 0.66 microg/mg (whole tibia), and 0.24 and 2.3 microg/mg (tibia surface), with P < or = 0.001 for all comparisons between the groups. A succession of white and pigmented bands was observed in the fluorotic rat incisors. Under polarizing light microscopy, cross-sections of superficial areas corresponding to the white bands (from the surface to approximately 20 microm) showed high positive birefringence. These fluorotic lesions also exhibited the lowest resistance to superficial acid etching. No morphological differences in inner enamel were seen under scanning electron microscopy. In fluorotic enamel, only the surface layer related to the white areas presented lower birefringence compared with the enamel of control teeth and the surface layer of the pigmented areas (normal ones) of fluorotic teeth. In conclusion, the white bands of fluorotic rat enamel represent hypomineralized superficial areas and are not subsurface lesions. The detailed description of these lesions is important to understand dental fluorosis. PMID- 19781689 TI - The time-course of attention to emotional faces in social phobia. AB - This study investigated the time-course of attentional bias in socially phobic (SP) and non-phobic (NP) adults. Participants viewed angry and happy faces paired with neutral faces (i.e., face-face pairs) and angry, happy and neutral faces paired with household objects (i.e., face-object pairs) for 5000ms. Eye movement (EM) was measured throughout to assess biases in early and sustained attention. Attentional bias occurred only for face-face pairs. SP adults were vigilant for angry faces relative to neutral faces in the first 500ms of the 5000ms exposure, relative to NP adults. SP adults were also vigilant for happy faces over 500ms, although there were no group-based differences in attention to happy-neutral face pairs. There were no group differences in attention to faces throughout the remainder of the exposure. Results suggest that social phobia is characterised by early vigilance for social cues with no bias in subsequent processing. PMID- 19781690 TI - Fear generalization in humans: impact of verbal instructions. AB - Fear generalization lies at the heart of many anxiety problems, but little is known about the factors that can influence this phenomenon. The present study investigated whether verbal instructions about specific stimulus features can influence conditioned fear generalization. All participants were fear conditioned to a yellow triangle, using an electric shock. Participants had received pre experimental instructions saying that the shapes (or colours) of the stimuli were informative for the occurrence of shock (group Shape and group Colour, respectively). Next, generalization was tested to presentations of a blue triangle (same shape) as well as a yellow square (same colour). Fear reactions were measured through skin conductance and online ratings of shock-expectancy. The results showed strongest generalization to the same shape stimulus in group Shape, versus the same colour stimulus in group Colour. Hence, the same learning experience can have opposite effects in terms of fear generalization, depending on verbally transmitted information about the relative importance of individual stimulus features. PMID- 19781691 TI - Components of attentional biases in contamination fear: evidence for difficulty in disengagement. AB - Attentional bias for threat has been implicated in the contamination fear (CF) subtype of obsessive-compulsive disorder, but the components of the bias (facilitated attention versus difficulty in disengagement) and the stage of processing during which the bias occurs (early versus late stage of processing) remains unclear. Further, it is unclear whether attentional biases in CF are towards fear or disgust-related stimuli. The present study examined attentional biases in a group of individuals selected to have elevated CF (n = 23) and a control group (n = 28) using the spatial cueing task. Stimuli were neutral, disgusting, or frightening pictures presented for either 100 or 500 ms. Results revealed evidence for delayed disengagement from both fear and disgust stimuli in the CF group, but not in the control group. The effect appeared to be greater at 500 ms stimulus presentation, but did not appear to differ between fear and disgust stimuli. The CF group was associated with delayed disengagement from threat even when controlling for generic response slowing. Theoretical and clinical implications are discussed. PMID- 19781692 TI - [Giant arteriovenous fistula resistant to embolization]. PMID- 19781693 TI - Episodic future thinking in 3- to 5-year-old children: the ability to think of what will be needed from a different point of view. AB - Assessing children's episodic future thinking by having them select items for future use may be assessing their functional reasoning about the future rather than their future episodic thinking. In an attempt to circumvent this problem, we capitalised on the fact that episodic cognition necessarily has a spatial format (Clayton & Russell, 2009; Hassabis & Maguire, 2007). Accordingly, we asked children of 3, 4, and 5 to chose items they would need to play a game (blow football) from the opposite side of the table on which they had never before played. The crucial item was the box that was needed by children to reach the table from the other side. Over four experiments, we demonstrated that, while children of 3 perform poorly on future questions and children of 5 generally perform quite well, children of 4 years find a question about what they themselves will need to play in the future harder to answer than a similar question posed about another child. We suggest that this result is due to the 'growth error' of over-applying newly-developed Level 2 perspective-taking skills (Flavell et al., 1981), which encourages the selection of non-functional items. The data are discussed in terms of perspective-taking abilities in children and of the neural correlates of episodic cognition, navigation, and theory of mind. PMID- 19781694 TI - Overgeneral autobiographical memory in Parkinson's disease. AB - Autobiographical memory (AM) concerns the ability to remember past events from one's own life and consists of autobiographical knowledge (personal facts) and autobiographical incidents (personal events). The novelty of this research was to assess both personal factual and personal event AM in Parkinson's disease (PD) for specified lifetime periods. An autobiographical fluency task was used in which participants were asked to recall personal events and personal facts from five separate lifetime periods. Previous findings as well the brain regions affected in PD lead to the hypothesis that Parkinson's patients would recall less autobiographical memories especially for the most recent lifetime periods. Sixteen non-demented and non-depressed Parkinson's patients and sixteen age education-matched controls participated. The results showed a temporal gradient for the recall of personal events in Parkinson's patients as they recalled fewer events for recent time periods. The PD group also had more difficulties in recalling autobiographical events rather than an autobiographical knowledge. The difficulty in recalling autobiographical events was characterized by overgenerality, with PD patients failing to generate specific episodic memories. PMID- 19781695 TI - Leukaemia incidence in people living close to an oil refinery. AB - OBJECTIVES: To assess the incidence of leukaemia in an area downwind of a large oil refinery emitting carcinogenic volatile organic compounds (VOCs) including benzene. METHODS: Using a dispersion model and the prevailing wind direction, two parishes with about 5000 inhabitants were a priori considered to be exposed to VOCs from the refinery. Numbers of observed and expected leukaemia cases in 1975 2004 were calculated using regional sex- and age-specific incidence rates. In addition, five nearby parishes (12000 inhabitants), considered unaffected by the emissions, served as a local reference area. Based on emission data, dispersion modelling and VOC measurements, the refinery's contribution to the population's exposure to carcinogenic VOCs was estimated. Published "unit risks" for carcinogenic VOCs were used to estimate the expected excess leukaemia risk. RESULTS: The incidence of leukaemia in the "exposed parishes" was significantly increased in 1975-2004 (33 cases v. 22 expected cases), owing to an increase in the last 10-year period, from 1995 to 2004 (19 cases v. 8.5 expected cases). The leukaemia incidence in the local control area was normal (50 cases v. 56 expected cases). The estimated contribution from the refinery to VOC concentrations was, however, only about 2 microg/m(3) (yearly average) for benzene, 2 microg/m(3) for ethylene, 0.5 microg/m(3) for 1,3-butadiene and 5 microg/m(3) for propene. Calculations of expected excess risk using published risk estimates would indicate a much lower excess risk in the exposed parishes. CONCLUSIONS: Using risk estimates extrapolated from high-level exposure, we would not expect an increase of leukaemia at low exposure to VOC emissions. Nevertheless, the clear elevation of leukaemia in the priori selected, exposed parishes was remarkable. Our finding may reflect a causal association due to emissions, but it could also be due to unknown confounding, or chance. PMID- 19781696 TI - Improvement in quality-of-life questionnaire measures in obese adolescent females with polycystic ovary syndrome treated with lifestyle changes and oral contraceptives, with or without metformin. AB - We studied the effect of metformin or placebo in a lifestyle modification program combined with oral contraceptives (OC) on quality-of-life parameters measured by the polycystic ovary syndrome (PCOS) questionnaire in obese adolescent women with validated PCOS. The quality-of-life indicators were measured at baseline and conclusion for five domains on the PCOS questionnaire, with equal improvement in scores in both placebo and metformin groups, suggesting that the addition of metformin does not add improvement to quality-of-life measures above those observed with lifestyle modification and OC treatment. PMID- 19781697 TI - The Homo sapiens 'hemibun': its developmental pattern and the problem of homology. AB - The occipital bun is widely considered a Neanderthal feature. Its homology to the 'hemibun' observed in some European Upper Palaeolithic anatomically modern humans is a current problem. This study quantitatively evaluates the degree of occipital plane convexity in African and Australian modern human crania to analyse a relationship between this feature and some neurocranial variables. Neanderthal and European Upper Palaeolithic Homo sapiens crania were included in the analysis as well. The results of this study indicated that there is a significant relationship between the degree of occipital plane convexity and the following two features in the examined crania of modern humans: the ratio of the maximum neurocranial height to the maximum width of the vault and the ratio of bregma lambda chord to bregma-lambda arc. The results also revealed that some H. sapiens crania (modern and fossil) show the Neanderthal shape of the occipital plane and that the neurocranial height and shape of parietal midsagittal profile has an influence on occipital plane convexity in the hominins included in this study. This study suggests that the occurrence of the great convexity of the occipital plane in the Neanderthals and H. sapiens is a "by-product" of the relationship between the same neurocranial features and there is no convincing evidence that the Neanderthal occipital bun and the similar structure in H. sapiens develop during ontogeny in the same way. PMID- 19781698 TI - Coordinating IMC-PID and adaptive SMC controllers for a PEMFC. AB - For a Proton Exchange Membrane Fuel Cell (PEMFC) power plant with a methanol reformer, the process parameters and power output are considered simultaneously to avoid violation of the constraints and to keep the fuel cell power plant safe and effective. In this paper, a novel coordinating scheme is proposed by combining an Internal Model Control (IMC) based PID Control and adaptive Sliding Mode Control (SMC). The IMC-PID controller is designed for the reformer of the fuel flow rate according to the expected first-order dynamic properties. The adaptive SMC controller of the fuel cell current has been designed using the constant plus proportional rate reaching law. The parameters of the SMC controller are adaptively tuned according to the response of the fuel flow rate control system. When the power output controller feeds back the current references to these two controllers, the coordinating controllers system works in a system-wide way. The simulation results of the PEMFC power plant demonstrate the effectiveness of the proposed method. PMID- 19781699 TI - Immune response deviation and enhanced expression of chemokine receptor CCR4 in TBI patients due to unknown serum factors. AB - BACKGROUND: Severe brain trauma leads to an activation of the immune system. To this date, neither the exact perturbation of the specific immune reaction induced by the traumatic brain injury (TBI), nor the interactions leading to the infiltration of peripheral immune cells into the brain are fully understood. PATIENTS AND METHODS: Serum was collected from 17 patients with TBI and a long bone fracture, 24 patients with an isolated long bone fracture and from healthy individuals. The effect of the serum on normal human monocytes and T-lymphocytes was tested in vitro by assessing proliferation and expression of surface markers, chemokine receptors and cytokines. RESULTS: Serum collected from patients with a TBI and a long bone fracture increased the expression of the chemokine receptor CCR4 in monocytes when compared to patients with an isolated long bone fracture. Extending this comparison to T-lymphocytes, the serum from TBI patients induced lower proliferation rates and decreased expression of the pro-inflammatory cytokine TNF-alpha, while simultaneously increasing the secretion of immune modulatory cytokines (IL-4, IL-10 and TGF-beta) (p<0.05). CONCLUSION: Patients with a TBI release currently unknown soluble factors into the circulating blood that up regulate expression of chemokine receptor CCR4 in peripheral blood monocytes whilst concurrently inducing expression of immunosuppressive cytokines by activated T-lymphocytes. PMID- 19781700 TI - Vaginal misoprostol for second-trimester pregnancy termination after one previous cesarean delivery. AB - OBJECTIVE: To determine the safety and efficacy of using misoprostol vaginally for second-trimester abortion in women with a single previous cesarean delivery. METHOD: This prospective observational study was carried out at a university hospital in Egypt with 50 pregnant women with 1 previous cesarean delivery; a gestation of at least 16 weeks but less than 20 weeks (group 1) or 20 or more weeks (group 2); and a need to terminate the pregnancy. The regimen was 4 doses of 200 microg of misoprostol applied vaginally every 4 hours daily, with a 12 hour nightly rest from misoprostol applications, until contractions appeared but not for more than 72 hours. The primary outcome was the induction-to-abortion interval. RESULTS: There were no cases of uterine rupture. Abortion within the study protocol occurred in 45 of the 50 women, for a 90% success rate. There was no significant difference in the induction-to-abortion interval between the 2 groups. CONCLUSION: Inducing abortion with lower misoprostol doses appear to be safe and effective throughout the second trimester in women with a single previous cesarean delivery. Larger randomized trials are needed to validate these results. PMID- 19781701 TI - Pressure ulcer prevention: development and psychometric validation of a knowledge assessment instrument. AB - BACKGROUND: Profound knowledge of pressure ulcers is important to enable good prevention. Validity and reliability of instruments assessing pressure ulcer knowledge are limited evaluated in previous research. AIMS AND OBJECTIVES: To develop a valid and reliable instrument to assess knowledge of pressure ulcer prevention. DESIGN: Prospective psychometric instrument validation study. METHODS: An extensive literature review was performed to develop an instrument to assess knowledge of pressure ulcer prevention. Face and content validity were evaluated in a double Delphi procedure by an expert panel of nine trustees of the European Pressure Ulcer Advisory Panel (EPUAP) who each have extensive experience in pressure ulcer care and research (PhD level). A convenience sample of 608 nurses and nursing students from Belgium and The Netherlands participated to evaluate validity of the multiple-choice test items (item difficulty, discriminating index, quality of the response alternatives), construct validity, internal consistency, and stability of the instrument. The data were collected between February and May 2008. RESULTS: A 26-item instrument was developed, reflecting 6 themes expressing the most relevant aspects of pressure ulcer prevention. The content validity was excellent (CVI=0.78-1.00). Group scores of nurses with a (theoretically expected) high level of expertise were found to be statistically significantly higher than those of participants with (theoretically expected) less expertise (P<0.001). The item difficulty index of the questions ranged from 0.27 to 0.87, while values for item discrimination ranged from 0.29 to 0.65. The quality of the response alternatives was found to be good. The overall internal consistency reliability (Cronbach's alpha) was 0.77. The 1-week test-retest intraclass correlation coefficient (stability) was 0.88. CONCLUSION: The instrument demonstrated acceptable psychometric properties and can be applied in both research and practice for evaluating knowledge about pressure ulcer prevention. PMID- 19781702 TI - Leadership styles and outcome patterns for the nursing workforce and work environment: a systematic review. AB - CONTEXT: Numerous policy and research reports call for leadership to build quality work environments, implement new models of care, and bring health and wellbeing to an exhausted and stretched nursing workforce. Rarely do they indicate how leadership should be enacted, or examine whether some forms of leadership may lead to negative outcomes. We aimed to examine the relationships between various styles of leadership and outcomes for the nursing workforce and their work environments. METHODS: The search strategy of this multidisciplinary systematic review included 10 electronic databases. Published, quantitative studies that examined leadership behaviours and outcomes for nurses and organizations were included. Quality assessments, data extractions and analysis were completed on all included studies. FINDINGS: 34,664 titles and abstracts were screened resulting in 53 included studies. Using content analysis, 64 outcomes were grouped into five categories: staffsatisfaction with work, role and pay, staff relationships with work, staff health and wellbeing, work environment factors, and productivity and effectiveness. Distinctive patterns between relational and task focused leadership styles and their outcomes for nurses and their work environments emerged from our analysis. For example, 24 studies reported that leadership styles focused on people and relationships (transformational, resonant, supportive, and consideration) were associated with higher nurse job satisfaction, whereas 10 studies found that leadership styles focused on tasks (dissonant, instrumental and management by exception) were associated with lower nurse job satisfaction. Similar trends were found for each category of outcomes. CONCLUSION: Our results document evidence of various forms of leadership and their differential effects on the nursing workforce and work environments. Leadership focused on task completion alone is not sufficient to achieve optimum outcomes for the nursing workforce. Efforts by organizations and individuals to encourage and develop transformational and relational leadership are needed to enhance nurse satisfaction, recruitment, retention, and healthy work environments, particularly in this current and worsening nursing shortage. PMID- 19781703 TI - Target organ damage in patients with rheumatoid arthritis: the role of blood pressure and heart rate. AB - BACKGROUND: Rheumatoid arthritis (RA) is characterised by increased cardiovascular morbidity and mortality. Even though hypertension (HT) is highly prevalent in RA, the extent of target organ damage (TOD) caused by it remains unknown. Inflammation and sympathetic overdrive may also associate with TOD. We investigated the prevalence and associations of TOD in RA. METHODS: In this cross sectional, observational study, 251 RA patients with no overt cardiovascular or renal disease had extensive clinical and laboratory evaluations, including a 12 lead electrocardiogram and urine albumin:creatinine ratio. Pulse pressure (PP) was used as a proxy of arterial stiffness and heart rate (HR) of autonomic activity. TOD was defined as described in the European guidelines for the management of arterial hypertension. Binary logistic regression analysis was used to evaluate the independence of the variables that associated with the presence of TOD. RESULTS: TOD prevalence was 23.5% (59/251). Of the 59 patients with TOD, 45.8% had suboptimally controlled HT, whereas 32.3% had undiagnosed HT. In univariable analysis, TOD was significantly associated with higher age (64.2+/ 11.7 years vs. 58.0+/-12.4 years, p=0.001), HT prevalence (89.8% vs. 60.4%, p<0.001), systolic blood pressure (SBP) (150.3+/-18.8mmHg vs. 139.7+/-20.7mmHg, p=0.001), PP (70.6+/-16.6mmHg vs. 60.3+/-17.3mmHg, p<0.001), HR (77.1+/-15.4bpm vs. 72.2+/-12.2bpm, p<0.001), serum uric acid (320.6+/-88.8mumol/l vs. 285.0+/ 74.9mumol/l, p=0.03) and type 2 diabetes mellitus prevalence (13.6% vs. 4.7%, p=0.019). Binary logistic regression analysis revealed that only hypertension indices and HR associated independently with TOD. CONCLUSIONS: TOD is highly prevalent in patients with RA and associates independently with hypertension, arterial stiffness and heart rate. Further prospective studies are needed to confirm these findings and examine the role of beta-blockers in this particular population. PMID- 19781704 TI - Coronary atherosclerosis detected by coronary CT angiography in asymptomatic subjects with early chronic kidney disease. AB - OBJECTIVES: The purpose of this study is to assess the independent association between early CKD (stages 1-3a) with coronary atherosclerosis and the feasibility of risk stratification of coronary atherosclerosis according to The Kidney Disease Outcomes Quality Initiative (K/DOQI) guidelines using non-invasive coronary angiography. METHODS: We consecutively enrolled 4297 asymptomatic subjects who underwent coronary CT angiography as part of a general health evaluation and had estimated glomerular filtration rates (eGFR) over 45 ml/min/1.73 m(2). Subjects were categorized from no CKD to stage 3a CKD, and multiple regression analyses for coronary atherosclerosis were performed. RESULTS: Early CKD was an independent risk factor for coronary artery disease (CAD) and obstructive CAD. However, neither the risk of CAD nor CACS >100 increased as stage of CKD advanced. The reason for unsuccessful stratification of coronary atherosclerosis risk was that the presence of proteinuria, which was used to define stages 1 and 2 CKD, was an independent risk factor for coronary atherosclerosis, but eGFR of 45-89 ml/min/1.73 m(2) was not associated with coronary atherosclerosis. CONCLUSIONS: Early CKD was an independent risk factor for coronary atherosclerosis, and the risk stratification for coronary atherosclerosis should be based on the presence of proteinuria rather than decreased eGFR within early CKD. PMID- 19781705 TI - Interrelationships of Factor VII activity and plasma leptin with insulin resistance in coronary heart disease. AB - OBJECTIVE: An increase of FVII activity (FVIIc) has been proposed to be an independent cardiovascular risk factor. Whether FVII is associated with insulin resistance in coronary heart disease (CHD) is still unknown. We tested the hypothesis that plasma FVII activity and leptin are associated with insulin resistance independently. METHODS: We studied 130 subjects, of which 65 were CHD subjects and 65 were non-CHD control subjects. Fasting plasma levels of leptin, insulin, glucose, FVIIc activity, fibrinogen, lipid parameters were estimated for all the subjects. Body mass index (BMI), waist circumference (WC) and blood pressure levels were also determined. RESULTS: We observed significantly raised plasma levels of FVIIc activity, leptin and insulin resistance among the CHD subjects compared to the non-CHD subjects. Raised FVIIc activity levels in CHD were significantly positively correlated with insulin resistance. Raised plasma leptin levels in CHD were correlated with insulin resistance, BMI and WC. Multivariate regression analysis showed that elevated levels of FVII activity in CHD was significantly associated with insulin resistance, independent of dyslipidemia, leptin, blood pressure levels, BMI, WC, gender and age. Furthermore, raised leptin levels in CHD subjects were significantly associated with insulin resistance and BMI, independently of each other and of dyslipidemia, FVIIc, blood pressure levels, WC, gender and age. CONCLUSION: Raised FVII and leptin levels in CHD patients were independently associated with insulin resistance, this was not observed among the non-CHD subjects. PMID- 19781707 TI - A new ultra-pressure liquid chromatography method for the determination of biogenic amines in cheese. AB - A fast and reliable ultra-performance liquid chromatography (UPLC) method for the determination of biogenic amines (ethanolamine, methylamine, agmatine, histamine, dimethylamine, ethylamine, octopamine, pyrrolidine, dopamine, isopropylamine, propylamine, tyramine, putrescine, butylamine, cadaverine, tryptamine, 2 phenylethylamine, 3-methylbutylamine, spermidine, spermine) in cheese was established. After pre-column derivatization with 6-aminoquinolyl-N-hydroxy succinimidyl carbamate (AQC), 20 primary and secondary biogenic amines were separated on an Acquity UPLC column (BEH C(18), 1.7 microm; 2.1 mm x 50 mm) within 9 min. Limits of detection (mg/100g cheese) ranged from 0.04 (ethanolamine) to 1.62 (spermine), and limits of quantification were between 0.16 (ethanolamine) and 6.09 (spermine). The UPLC method was applied to the analysis of 58 cheese samples as retailed in Austria. About 13.8% of samples had a histamine content above 10mg/100g, and 22.4% had a tyramine content above 10mg/100g. Moreover, 8.6% of samples had a putrescine or cadaverine content higher than 10mg/100g. The total concentration of biogenic amines in two cheese samples was about 194 mg/100g. Thus, obligatory monitoring of biogenic amines should be considered to ensure quality of cheese in future. PMID- 19781706 TI - Anti-inflammatory effects of nicotinic acid in adipocytes demonstrated by suppression of fractalkine, RANTES, and MCP-1 and upregulation of adiponectin. AB - OBJECTIVE: A major site of action for the atheroprotective drug nicotinic acid (NA) is adipose tissue, via the G-protein-coupled receptor, GPR109A. Since, adipose tissue is an active secretory organ that contributes both positively and negatively to systemic inflammatory processes associated with cardiovascular disease, we hypothesized that NA would act directly upon adipocytes to alter the expression of pro-inflammatory chemokines, and the anti-inflammatory adipokine adiponectin. METHODS AND RESULTS: TNF-alpha treatment (1.0ng/mL) of 3T3-L1 adipocytes resulted in an increase in gene expression of fractalkine (9+/-3.3 fold, P<0.01); monocyte chemoattractant protein-1 (MCP-1) (24+/-1.2-fold, P<0.001), 'regulated upon activation, normal T cell expressed and secreted' (RANTES) (500+/-55-fold, P<0.001) and inducible nitric oxide synthase (iNOS) (200+/-70-fold, P<0.05). The addition of NA (10(-4)M) to TNF-alpha-treated adipocytes attenuated expression of fractalkine (50+/-12%, P<0.01); MCP-1 (50+/ 6%, P<0.01), RANTES (70+/-3%, P<0.01) and iNOS (60+/-16%). This pattern was mirrored in protein released from the adipocytes into the surrounding media. The effect on gene expression was neutralised by pre-treatment with pertussis toxin. NA attenuated macrophage chemotaxis (by 27+/-3.5%, P<0.001) towards adipocyte conditioned media. By contrast, NA, (10(-6)-10(-3)M) increased, in a dose dependent manner, mRNA of the atheroprotective hormone adiponectin (3-5-fold n=6, P<0.01). CONCLUSIONS: NA suppresses pro-atherogenic chemokines and upregulates the atheroprotective adiponectin through a G-protein-coupled pathway. Since adipose tissue has the potential to contribute to both systemic and local (perivascular) inflammation associated with atherosclerosis our results suggest a new "pleiotropic" role for NA. PMID- 19781708 TI - Synthesis and characterization of fluorescent magneto polymeric nanoparticles (FMPNs) for bimodal imaging probes. AB - Novel bifunctional fluorescent magneto polymeric nanoprobes (FMPNs) were synthesized to provide simultaneous diagnostic information via magnetic resonance imaging (MRI) and optical imaging. FMPNs consist of ultra-sensitive magnetic nanocrystals that function as MR probes combined with Nile Red, which functions as a fluorescent probe. FMPNs were encapsulated by a nano-emulsion method in polyvinyl alcohol (PVA, 87-89% hydrolyzed) through a matrix of polymethyl methacrylate (PMMA). FMPNs exhibited excellent colloidal stability and monodispersity. The production of MR and optical images demonstrated that FMPNs have potential as dual-mode imaging agents. PMID- 19781709 TI - The kinetics of adsorption of tetracycline on chitosan particles. AB - Experiments to monitor and characterize the kinetics of adsorption of tetracycline on chitosan particles are reported in this work. The same pseudo order kinetics that has been widely used for describing the adsorption in systems related to wastewater purification and drug loading was used to treat the present data. As some unexpected results came out from the experiments, it was necessary a detailed deduction for this sort of kinetics to be carried out, so that approximations related to short and long times were obtained. Firstly it was shown that an apparently linear t/q(t) versus t relationship did not imply a pseudo-second-order sorption kinetics, differently of what has been repeatedly reported in the literature. It was found that this misinterpretation could be avoided by using non-linear regression. Finally, the adsorption of tetracycline on chitosan particles was analyzed, using the insights obtained from theoretical analysis, and the parameters generated were used to analyze to adsorption kinetics and to propose an adsorption mechanism. PMID- 19781710 TI - Thermally-responsive surfaces comprising grafted poly(N-isopropylacrylamide) chains: Surface characterisation and reversible capture of dispersed polymer particles. AB - In this study we investigate thermally-responsive surfaces prepared by grafting PNIPAm from a cationic macroinitiator (MI) that was adsorbed onto a range of anionic substrates. The substrates used were mica, glass, quartz and high surface area carbon foam. The carbon foam was rendered thermally responsive by first coating it with a layer of calcined laponite particles. PNIPAm brushes were grown from the substrates using surface-initiated atom transfer radical polymerisation. The thermally-responsive PNIPAm layers were characterised in detail at room temperature and 50 degrees C using atomic force microscopy (AFM) and contact angle measurements. The surfaces changed from being non-adhesive to adhesive when the temperature was increased to 50 degrees C. Young's modulus values and adhesive force values are reported. Particle capture experiments involving dispersed polystyrene or poly(BD/MAA) (butadiene and methacrylic acid) particles were conducted. High extents of particle capture were observed. It was shown that the highest extents of thermally-triggered particle capture at 50 degrees C occurred for surfaces that exhibited the largest increases in contact angle upon increasing the temperature. Importantly, thermally-triggered capture for both anionic polystyrene and poly(BD/MAA) particles was shown to be partially reversible with up to 30% of the captured particles released during cooling. This is the first time that significant reversibility of thermally-triggered capture of polymer particles has been reported. PMID- 19781711 TI - Fabrication of mesoporous SiO(2)-C-Fe(3)O(4)/gamma-Fe(2)O(3) and SiO(2)-C-Fe magnetic composites. AB - A synthetic method for the fabrication of silica-based mesoporous magnetic (Fe or iron oxide spinel) nanocomposites with enhanced adsorption and magnetic capabilities is presented. The successful in situ synthesis of magnetic nanoparticles is a consequence of the incorporation of a small amount of carbon into the pores of the silica, this step being essential for the generation of relatively large iron oxide magnetic nanocrystals ( approximately 10+/-3nm) and for the formation of iron nanoparticles. These composites combine good magnetic properties (superparamagnetic behaviour in the case of SiO(2)-C-Fe(3)O(4)/gamma Fe(2)O(3) samples) with a large and accessible porosity made up of wide mesopores (>9nm). In the present work, we have demonstrated the usefulness of this kind of composite for the adsorption of a globular protein (hemoglobin). The results obtained show that a significant amount of hemoglobin can be immobilized within the pores of these materials (up to 180mgg(-1) for some of the samples). Moreover, we have proved that the composite loaded with hemoglobin can be easily manipulated by means of an external magnetic field. PMID- 19781712 TI - Role of liquid crystal in the emulsification of a gel emulsion with high internal phase fraction. AB - A gel emulsion with high internal oil phase volume fraction was formed via an inversion process induced by a water-oil ratio change. The process involved the formation of intermediate multiple emulsions prior to inversion. The multiple emulsions contain a liquid crystal formed by the surfactant with water; this was both predicted by the equilibrium phase diagram as well as observed using polarization microscopy. These multiple emulsions were more stable compared to alternative multiple emulsions prepared in the same way with a surfactant that does not form liquid crystals. While the formation of a stable intermediate multiple emulsion may not be a necessary condition for the inversion to occur, the transitional presence of a liquid crystal proved to be a significant factor in the stabilization of the intermediate multiple emulsions. The resulting gel emulsion contained a small fraction of the liquid crystal according to the phase diagram, and it exhibited excellent stability. PMID- 19781713 TI - Synthesis of novel hybrid films of a layered silicate and alkylammonium cations on rough polymeric surfaces by Langmuir-Blodgett method. AB - Hybrid films of a layered silicate and an amphiphilic alkylammonium (hexadecyltrimethylammonium) cation have been prepared by Langmuir-Blodgett (LB) method and transferred onto a polyamide surface by dip coating. This is the first time that stable LB hybrid monolayer and multilayer films have been formed on rough polymeric surfaces. The films were characterized by X-ray diffraction (XRD), fourier transform infrared spectroscopy (FTIR), atomic force microscopy (AFM) and water contact angle measurements. XRD and FTIR showed that the hybrid multilayer was well-organized and the thickness of one layer was calculated to be 1.6nm. Furthermore, the layered silicate was determined to be on the substrate side and the amphiphilic molecule layer was exposed to the air side. This provides a novel methodology for the surface modification of polymers. PMID- 19781714 TI - Spectral parameters and Hamaker constants of silicon hydride compounds and organic solvents. AB - Cyclopentasilane (CPS) and polydihydrosilane, which consist of hydrogen and silicon only, are unique materials that can be used to produce intrinsic silicon film in a liquid process, such as spin coating or an ink-jet method. Wettability and solubility of general organic solvents including the above can be estimated by Hamaker constants, which are calculated according to the Lifshitz theory. In order to calculate a Hamaker constant by the simple spectral method (SSM), it is necessary to obtain absorption frequency and function of oscillator strength in the ultraviolet region. In this report, these physical quantities were obtained by means of an optical method. As a result of examination of the relation between molecular structures and ultraviolet absorption frequencies, which were obtained from various liquid materials, it was concluded that ultraviolet absorption frequencies became smaller as electrons were delocalized. In particular, the absorption frequencies were found to be very small for CPS and polydihydrosilane due to sigma-conjugate of their electrons. The Hamaker constants of CPS and polydihydrosilane were successfully calculated based on the obtained absorption frequency and function of oscillator strength. PMID- 19781715 TI - Osborn. PMID- 19781716 TI - Giant Inverted T waves in the emergency department: case report and review of differential diagnoses. AB - Inverted T waves are frequently seen in electrocardiograms (ECGs) and may represent a myriad of pathologies or nonspecific change. However, deep (giant) inverted T waves are only seen in a few clinical conditions. Presence of giant T waves should generally prompt investigations for apical (Yamaguchi) variant of hypertrophic cardiomyopathy, raised intracranial pressure, severe myocardial ischemia, posttachycardia syndrome, and others. This report describes an unusual case of moderate but not massive pulmonary embolism presenting with an ECG finding of giant inverted T waves. A review of the common conditions associated with such an ECG is also presented. PMID- 19781717 TI - Prostate specific antigen best practice statement: 2009 update. AB - PURPOSE: We provide current information on the use of PSA testing for the evaluation of men at risk for prostate cancer, and the risks and benefits of early detection. MATERIALS AND METHODS: The report is a summary of the American Urological Association PSA Best Practice Policy 2009. The summary statement is based on a review of the current professional literature, clinical experience and the expert opinions of a multispecialty panel. It is intended to serve as a resource for physicians, other health care professionals, and patients. It does not establish a fixed set of guidelines, define the legal standard of care or pre empt physician judgment in individual cases. RESULTS: There are two notable differences in the current policy. First, the age for obtaining a baseline PSA has been lowered to 40 years. Secondly, the current policy no longer recommends a single, threshold value of PSA, which should prompt prostate biopsy. Rather, the decision to proceed to prostate biopsy should be based primarily on PSA and DRE results, but should take into account multiple factors including free and total PSA, patient age, PSA velocity, PSA density, family history, ethnicity, prior biopsy history and comorbidities. CONCLUSIONS: Although recently published trials show different results regarding the impact of prostate cancer screening on mortality, both suggest that prostate cancer screening leads to overdetection and overtreatment of some patients. Therefore, men should be informed of the risks and benefits of prostate cancer screening before biopsy and the option of active surveillance in lieu of immediate treatment for certain men diagnosed with prostate cancer. PMID- 19781719 TI - Re: Urethral Stricture is Now an Open Surgical Disease A. Morey and H. Wessells J Urol 2009; 181: 953-955. PMID- 19781720 TI - Reliability of real-time ultrasound to detect pelvic floor muscle contraction in urinary incontinent women. AB - PURPOSE: We determined the reliability of real-time ultrasound for detecting involuntary or reflex pelvic floor muscle contraction. MATERIALS AND METHODS: A total of 118 women with the symptomatic and urodynamic evidence of stress urinary incontinence were recruited in a 3-year period from tertiary referral urogynecology clinics. Under the oral instruction of strong coughing involuntary pelvic floor muscle contraction was detected using introital ultrasound in real time and cine loop modes. Two dynamic imaging features were considered involuntary pelvic floor muscle contraction, including an inward clitoral motion and a superior-anterior anorectal lift before or during coughing. RESULTS: Real time ultrasound had good reliability to detect involuntary pelvic floor muscle contraction. For interobserver and intra-observer reliability Cohen's kappa was 0.645 to 0.679. Of the 118 women real-time ultrasound before or during coughing showed an inward clitoral motion in 100 (93%) and an anorectal lift in 108 (92%). Neither type of contraction during coughing was identified in 2 women. Although the 2 contraction patterns were synchronized in 88% of women, for this synchronization kappa was only 0.159, indicating poor coordination between these 2 involuntary activities. CONCLUSIONS: Real-time ultrasound is a reliable tool for detecting involuntary pelvic floor muscle contraction. PMID- 19781721 TI - [Relationship between C-telopeptides of type I collagen serum values with bone mineral density and antiosteoporotic drug intake in postmenopausal women. Preliminary data from the FRODOS study]. AB - BACKGROUND AND OBJECTIVE: Few studies have addressed the role of bone turnover markers (BTM) in Spanish postmenopausal women. The goal of the study was to analyse the relationship between crosslinked C-telopeptides of type I collagen (betaCTXs) serum values and bone mineral density (BMD) and antiosteoporotic drug intake in a large sample of postmenopausal women. PATIENTS AND METHOD: We have recruited 1495 women aged 59-70 years (15.7 years since menopause) randomly selected from the general population within the cross-sectional phase of a cohort study. All participants had undergone betaCTXs testing in fast state, BMD scan of spine and femur (WHO classification) and a clinic-epidemiological questionnaire with specific drug intake record. RESULTS: Twenty-six (26) % of the participants had osteoporosis and 18% took antiosteoporotic drugs. In women who did not receive antiosteoporotic drugs, betaCTXs was higher in participants with osteoporosis and osteopenia when compared with those with normal BMD (p < 0.05). In women under therapy, betaCTXs was significantly lower compared with women with no therapy and the mean values were similar to those of premenopausal women. CONCLUSIONS: In this group of unselected postmenopausal women, betaCTXs values are associated with BMD categories and showed a marked decrease in those taking antiosteoporotic drugs. PMID- 19781722 TI - [Cervical myelopathy by rheumatoid pannus as onset form of rheumatoid arthritis]. PMID- 19781723 TI - [Main features of the new influenza virus a pandemic (H1N1)]. AB - At the end of March 2009, a new influenza virus A (H1N1) of porcine origin was isolated in two children from California presenting flu-like clinical syndrome. This virus was initially disseminated in Mexico and US and then worldwide. Eight weeks later, it had reached 74 countries with almost 30,000 cases and had caused 145 deaths. The virus had also sustained community transmission in 6 countries. On June 11th, WHO stated the onset of a pandemic. The genetic combination of this virus is completely new, containing five segments of porcine origin, two avian, one human and a HA hemaglutinin adapted for human transmission, which is genetically and antigenically different compared with the H1N1 seasonal virus. Its transmissibility is slightly higher than the one observed in seasonal influenza and similar to previous pandemics. Its pathogenicity and virulence are low. Clinical manifestations are similar to seasonal influenza, with spontaneous resolution. Nevertheless, the variety of symptoms is large and range from asymptomatic to severe fatal pneumonia. The affected population is mainly young, aged under 30 years. Less than a half of the hospitalized patients in US and of the fatal cases in Mexico had concomitant chronic diseases or other baseline conditions. A specific monovalent vaccine against the virus is currently being produced in order to prevent and control the infection through the reduction of susceptible population. PMID- 19781724 TI - [Octreotide long acting release for severe obscure gastrointestinal haemorrhage in elderly patients with serious comorbidities]. AB - BACKGROUND AND OBJECTIVE: Octreotide LAR has shown preliminary promising results in the treatment of recurrent obscure gastrointestinal haemorrhage. PATIENTS AND METHODS: Eleven patients with severe comorbidities were treated with continuous octreotide LAR 20mg once a month. No changes were performed in concomitant drugs. Haemoglobin levels, blood transfusions, hospital admissions and adverse effects were recorded every three months. RESULTS: Median age and follow-up were 74 yr (65-86) and 15 months (5-48). Five patients were on acenocoumarol therapy and other five on antiplatelet drugs. Eight patients (72%) had diffuse small bowel angiodysplasia and 4 patients died during follow-up. Only two patients (18%) remained free of transfusions but it resulted for the first year in an outstanding decrease in the need of red cell packets (14 (9-49) vs 4 (0-9), p=0,002) and in admission days related to gastrointestinal bleeding (27 (10-99) vs 7(0-23), p=0,001). No side effects were reported. CONCLUSION: Octreotide LAR is an effective, safe and comfortable palliative therapy for severe obscure gastrointestinal bleeding. Medical resources saving and improved quality of life may warrant its use irrespective of comorbidities or life expectancy. PMID- 19781725 TI - Influence of Trypanosoma evansi in blood, plasma, and brain cholinesterase of experimentally infected cats. AB - Changes in blood, plasma and brain cholinesterase activities in Trypanosoma evansi-infected cats were investigated. Seven animals were infected with 10(8) trypomastigote forms each and six were used as control. Animals were monitored for 56 days by examining daily blood smears. Blood samples were collected at days 28 and 56 post-inoculation to determine the activity of acetylcholinesterase (AChE) in blood and the activity of butyrylcholinesterase (BChE) in plasma. AChE was also evaluated in total brain. The activity of AChE in blood and brain, and the activity of BChE in plasma significantly reduced in the infected cats. Therefore, the infection by T. evansi influenced cholinesterases of felines indicating changes in the responses of the cholinergic system. PMID- 19781726 TI - Antiviral efficacy of EICAR against canine distemper virus (CDV) in vitro. AB - Canine distemper virus (CDV) is a highly contagious pathogen of carnivores. In dogs, the disease is characterized by high lethality rates and no specific antiviral therapy is available. The aim of this study was to verify the in vitro antiviral activity of the 5-ethynyl-1-beta-d-ribofuranosylimidazole-4-carboxamide (EICAR) and to compare it with the 1-(beta-d-ribofuranosyl)-1,2,4-triazole-3 carboxamide (ribavirin, RBV). EICAR was more active than RBV against CDV replication, while both molecules exhibited low selectivity indexes. A reversal of their antiviral activity was observed after addition of guanosine, suggesting their involvement in the inhibition of the inosine monophosphate dehydrogenase enzyme (IMPDH). RBV and EICAR had a time- and concentration-dependent anti-CDV activity, mainly displayed during the first 10h post-infection. The involvement of the inhibition of the viral RNA-dependent RNA polymerase (vRdRp) is discussed, as well as the role of CDV as a model to study more potent and selective antiviral molecules active against other Paramyxoviridae. PMID- 19781727 TI - A pregnant pause. AB - A 23-year-old pregnant woman presented with a rapidly progressive unilateral optic neuropathy. The evaluation was complicated by her being pregnant and the issues surrounding the evaluation and management of the pregnant patient with a neuro-ophthalmic finding is discussed. Eventually an orbital apex lesion was found and proved to be an orbital schwannoma. Rapid growth of an orbital schwannoma should be included in the differential diagnosis of progressive visual loss in a pregnant patient. PMID- 19781728 TI - Cathepsin L is required for ecotropic murine leukemia virus infection in NIH3T3 cells. AB - Recently it has been reported that a cathepsin B inhibitor, CA-074Me, attenuates ecotropic murine leukemia virus (Eco-MLV) infection in NIH3T3 cells, suggesting that cathepsin B is required for the Eco-MLV infection. However, cathepsin B activity was negative or extremely low in NIH3T3 cells. How did CA-074Me attenuate the Eco-MLV infection? The CA-074Me treatment of NIH3T3 cells inhibited cathepsin L activity, and a cathepsin L specific inhibitor, CLIK148, attenuated the Eco-MLV vector infection. These results indicate that the suppression of cathepsin L activity by CA-074Me induces the inhibition of Eco-MLV infection, suggesting that cathepsin L is required for the Eco-MLV infection in NIH3T3 cells. The CA-074Me treatment inhibited the Eco-MLV infection in human cells expressing the exogenous mouse ecotropic receptor and endogenous cathepsins B and L, but the CLIK148 treatment did not, showing that only the cathepsin L suppression by CLIK148 is not enough to prevent the Eco-MLV infection in cells expressing both of cathepsins B and L, and CA-074Me inhibits the Eco-MLV infection by suppressing both of cathepsins B and L. These results suggest that either cathepsin B or L is sufficient for the Eco-MLV infection. PMID- 19781729 TI - The human papillomavirus 16 E2 protein is stabilised in S phase. AB - The human papillomavirus 16 E2 protein regulates transcription from, and replication of, the viral genome and is also required for segregation of the viral genome via interaction with mitotic bodies. To regulate DNA replication E2 interacts with sequences around the origin of replication and recruits the viral helicase E1 via a protein-protein interaction, which then initiates viral genome replication. The replication role of E2 must originally function in a host cell S phase. In this report, we demonstrate that E2 is stabilised in the S phase of the cell cycle and that this stabilisation is accompanied by an increase in phosphorylation of the protein. This increased phosphorylation and stability are likely required for optimum viral DNA replication and therefore identification of the enzymes involved in regulating these properties of E2 will provide targets for therapeutic intervention in the viral life cycle. Preliminary studies have identified E2 as a Cdk2 substrate demonstrating this enzyme as a candidate kinase for mediating the in vivo phosphorylation of HPV16 E2. PMID- 19781730 TI - Predicted environmental concentrations of cocaine and benzoylecgonine in a model environmental system. AB - A Mackay-type level II fugacity model has been used to predict the behaviour and final concentrations of cocaine (COC) and its main metabolite benzoylecgonine (BE) in a regional environmental system defined according to the European guidelines on Risk Assessment. The model takes into account the initial COC intake, partial degradation of the parent compound to BE, treatment of wastewater and environmental fate of these substances. Predicted environmental concentrations (PECs) lie in the ngL(-1) level, with the exception of the air compartment, where the concentrations are negligible. PECs in the water phase are in accordance with measured experimental concentrations in different European rivers. This case study shows that a simple level II fugacity model is suitable enough for modelling the environmental fate of high water soluble and low volatile organic compounds such as pharmaceuticals and personal care products. PMID- 19781731 TI - Restoration of the Golden Horn Estuary (Halic). AB - Restoration of the iconic Golden Horn Estuary in Istanbul, Turkey was a substantial political, logistical, ecological, and social challenge. Forty years of uncontrolled industrial and urban growth resulted in thick layers of anoxic sediment, toxic bacteria, strong hydrogen sulfide odor, and ecologically unlivable conditions. The major components of restoration, spanning two decades, have included (1) demolition and relocation of industries and homes along the shore, (2) creation of wastewater infrastructure, (3) removal of anoxic sludge from the estuary, (4) removal of a floating bridge that impeded circulation, and (5) creation of cultural and social facilities. Although Turkey is not known as an environmental leader in pollution control, the sum of these efforts was largely successful in revitalizing the area through dramatic water quality improvement. Consequently, the estuary is once again inhabitable for aquatic life as well as amenable to local resource users and foreign visitors, and Istanbul has regained a lost sense of cultural identity. This paper focuses on literature review and personal interviews to discuss the causes of degradation, solutions employed to rehabilitate the estuary, and subsequent physicochemical, ecological, and social changes. PMID- 19781732 TI - Citizen monitoring: Testing hypotheses about the interactive influences of eutrophication and mussel invasion on a cyanobacterial toxin in lakes. AB - An existing volunteer monitoring network in the state of Michigan was exploited to conduct a statewide survey of the cyanobacterial toxin, microcystin, and to test hypotheses about the interactive influences of eutrophication and dreissenid mussel invasion. A total of 77 lakes were sampled by citizen volunteers for microcystin, total phosphorus (TP) and chlorophyll a. Microcystin was measured in depth-integrated samples collected from the euphotic zone as well as in surface water samples collected along the shoreline. Average microcystin in samples collected by volunteers was not different from samples collected side-by-side by professionals. Euphotic-zone microcystin was positively related to TP in lakes without dreissenids (uninvaded) but not in lakes with dreissenids (invaded). Regression-tree analysis indicated that euphotic-zone microcystin was eight times higher in the presence of dreissenids for lakes with TP between 5 and 10microgL( 1). In contrast, euphotic-zone microcystin was almost identical in invaded and uninvaded lakes with TP between 10 and 26microgL(-1). Across all lakes, microcystin concentrations at the surface were on average more than double, and in some cases an order-of-magnitude greater than, concentrations in the euphotic zone. Given these results, it seems prudent to include dreissenid invasion status in forecasting models for microcystin, and to include shoreline sampling in monitoring programs aimed at assessing recreational exposure to cyanobacterial toxins. PMID- 19781733 TI - Differential effect of chlorine on the oxidative stress generation in dormant and active cells within colony biofilm. AB - In an effort to better control bacterial biofilm, we examined the effects of various oxidative antimicrobial chemicals including silver, paraquat, hydrogen peroxide, and chlorine depending on the physiological status of cells in biofilm. The metabolically heterogeneous cells within colony biofilm were physically fractionated and the oxidative stress generated in each fraction was monitored by soxS and oxyS promoter reporter systems. Chlorine induced soxS to a greater degree in the dormant cells than active cells of biofilm. In addition, chlorine dependent induction of soxS was more prominent in aerobically grown cells compared with anaerobically grown cells. On the contrary, the soxS induction by other chemicals such as paraquat and silver, and the oxyS induction by hydrogen peroxide were higher in active biofilm cells and aerobically grown cells. Our results suggest that chlorine might generate strong oxidative stress by direct modification of the 2Fe-2S cluster in an O(2)-independent manner, which provides the molecular basis of our previous report showing that chlorine has a more efficient killing effect on dormant cells in biofilm and cells grown under unaerobic conditions. This study shows that chlorine may be particularly promising for the control of anaerobic bacteria and biofilm where dormant cells are hard to control. PMID- 19781734 TI - Influence of operating parameters on the arsenic removal by nanofiltration. AB - Arsenic contamination of surface and groundwater is a worldwide problem in a large number of Countries (Bangladesh, Argentina, Italy, USA, New Zealand, etc.). In many contaminated areas a continuous investigation of the available arsenic removal technologies is essential to develop economical and effective methods for removing arsenic in order to meet the new Maximum Contaminant Level (MCL) standard (10microg/l) recommended by the World Health Organization (WHO). In this work the removal of pentavalent arsenic from synthetic water was studied on laboratory scale by using two commercial nanofiltration (NF) spiral-wound membrane modules (N30F by Microdyn-Nadir and NF90 by Dow Chemical). The influence of main operating parameters such as feed concentration, pH, pressure and temperature on the As rejection and permeate flux of both membranes, was investigated. An increase of pH and a decrease of operating temperature and As feed concentration led to higher As removal for both membranes, whereas higher transmembrane pressure (TMP) values slightly reduced the removal achievable with the N30F membrane. In both cases, the permeate flux increased with temperature and pressure and reached its maximum value at a pH of around 8. Among the parameters affecting the As rejection, feed concentration plays a key role for the production of a permeate stream respecting the limits imposed by WHO. PMID- 19781735 TI - Evaluation of the enterococci indicator in biosolids using culture-based and quantitative PCR assays. AB - The utility of the enterococci indicator for measuring biosolids quality was evaluated in biosolids from 22 U.S. wastewater treatment facilities. Enterococci were enumerated using 23S rRNA quantitative PCR (qPCR) and membrane filtration with mEI-agar culture analyses in biosolids collected after mesophilic anaerobic digestion (MAD, class B, 13 treatment plants), composting (class A, 10 treatment plants), and temperature-phased anaerobic digestion (TPAD, class A, six treatment plants). Enterococci qPCR and culture values were not significantly different for a given treatment (P>0.05, paired t-test) and both assays showed differences in biosolid treatment effectiveness-anaerobic digestion treatments averaged 5-5.5log genomic units (GU) and colony forming units (CFU)/dry g while composting decreased enterococci on average to 3.7logGU and 3.8logCFU/dry g. Only in class A TPAD biosolids dewatered with a belt-filter press were culture values significantly lower than qPCR values (1.7logCFU/dryg vs. 5GU/dryg). Further investigation of compost inactivation was compared for enterococci and other fecal indicators (n=5 treatment plants)-the enterococci indicator was more resistant to compost treatment than fecal coliforms, with reductions averaging only 1-2.5 logs for enterococci, male-specific coliphages, and sulfite-reducing Clostridia while 5-log reductions were observed for fecal coliforms. Lastly, biosolid isolates from culture-based methods were identified using DNA sequencing these results revealed that non-enterococci, including Bacillus spp. and Vagococcus spp., were commonly isolated from compost and TPAD biosolids using mEI agar. Given the equivalency of culture- and qPCR-based enterococci concentrations in biosolids and the more conservative inactivation noted for both assays during class A composting, the use of enterococci qPCR monitoring could bypass non specificity issues with culture-based methods while providing an improved description of pathogen fate in biosolids. PMID- 19781736 TI - Nitrate removal and biofilm characteristics in methanotrophic membrane biofilm reactors with various gas supply regimes. AB - Aerobic methanotrophs can contribute to nitrate removal from contaminated waters, wastewaters, or landfill leachate by assimilatory reduction and by producing soluble organics that can be utilized by coexisting denitrifiers. The goal of this study was to investigate nitrate removal and biofilm characteristics in membrane biofilm reactors (MBfR) with various supply regimes of oxygen and methane gas. Three MBfR configurations were developed and they achieved significantly higher nitrate removal efficiencies in terms of methane utilization (values ranging from 0.25 to 0.36molNmol(-1)CH(4)) than have previously been observed with suspended cultures. The biofilm characteristics were investigated in two MBfRs with varying modes of oxygen supply. The biofilms differed in structure, but both were dominated by Type I methanotrophs growing close to the membrane surface. Detection of the nitrite reductase genes, nirS and nirK, suggested genetic potential for denitrification was present in the mixed culture biofilms. PMID- 19781737 TI - Combined Bayesian statistics and load duration curve method for bacteria nonpoint source loading estimation. AB - Nonpoint source load estimation is an essential part of the development of the bacterial total maximum daily load (TMDL) mandated by the Clean Water Act. However, the currently widely used watershed-receiving water modeling approach is usually associated with a high level of uncertainty and requires long-term observational data and intensive training effort. The load duration curve (LDC) method recommended by the EPA provides a simpler way to estimate bacteria loading. This method, however, does not take into consideration the specific fate and transport mechanisms of the pollutant and cannot address the uncertainty. In this study, a Bayesian statistical approach is applied to the Escherichia coli TMDL development of a stream on the Eastern Shore of Virginia to inversely estimate watershed bacteria loads from the in-stream monitoring data. The mechanism of bacteria transport is incorporated. The effects of temperature, bottom slope, and flow on allowable and existing load calculations are discussed. The uncertainties associated with load estimation are also fully described. Our method combines the merits of LDC, mechanistic modeling, and Bayesian statistics, while overcoming some of the shortcomings associated with these methods. It is a cost-effective tool for bacteria TMDL development and can be modified and applied to multi-segment streams as well. PMID- 19781738 TI - Enhanced free-radical generation by shrinking microbubbles using a copper catalyst. AB - Free-radicals are generated by collapsing microbubbles in aqueous solutions; however, the concentration is too low to be of practical use. In this study, copper was found to enhance the generation of hydroxyl radicals from collapsing oxygen microbubbles under acidic conditions through electron-spin-resonance spectroscopy analysis. Moreover, the degradation of polyvinyl alcohol, which is not decomposed even by ozone, was also observed during the collapse of the air microbubbles. These findings greatly increase the potential of the microbubble collapse technique for use in the field of wastewater treatment. PMID- 19781739 TI - Bioremediation of weathered petroleum hydrocarbon soil contamination in the Canadian High Arctic: laboratory and field studies. AB - The bioremediation of weathered medium- to high-molecular weight petroleum hydrocarbons (HCs) in the High Arctic was investigated. The polar desert climate, contaminant characteristics, and logistical constraints can make bioremediation of persistent HCs in the High Arctic challenging. Landfarming (0.3 m(3) plots) was tested in the field for three consecutive years with plots receiving very little maintenance. Application of surfactant and fertilizers, and passive warming using a greenhouse were investigated. The field study was complemented by a laboratory experiment to better understand HC removal mechanisms and limiting factors affecting bioremediation on site. Significant reduction of total petroleum HCs (TPH) was observed in both experiments. Preferential removal of compounds nC16 occurred, whereas in the field, TPH reduction was mainly limited to removal of compounds nC16 was observed in the fertilized field plots only. The greenhouse increased average soil temperatures and extended the treatment season but did not enhance bioremediation. Findings suggest that temperature and low moisture content affected biodegradation of HCs in the field. Little volatilization was measured in the laboratory, but this process may have been predominant in the field. Low-maintenance landfarming may be best suited for remediation of HCs compounds or =1 week prior to a 600 mg clopidogrel loading dose. PPI treatment was based on physician preference. Residual platelet aggregation (RPA) was measured by optical aggregometry. To correct for potential selection bias, propensity score matching was applied. RESULTS: RPA was significantly higher in PPI-treated patients compared with non-PPI-users (final aggregation 34.0% vs. 29.8%, p<0.001). Low responder defined as RPA in the upper tertile were more often found in PPI-users. After adjustment for relevant confounders, PPI treatment was independently associated with higher RPA-levels. DISCUSSION: We demonstrated that peri-procedural co-administration of PPIs significantly decreases the effect of clopidogrel on RPA. To assess if clopidogrel-PPI interaction results in a higher susceptibility for cardiovascular events remains subject to further investigations. PMID- 19781744 TI - Percutaneous nephrolithotomy can be safely performed in the high-risk patient. AB - OBJECTIVES: To determine whether percutaneous nephrolithotomy (PCNL) can be safely performed in the high-risk patient. METHODS: The records of 84 patients undergoing 98 consecutive PCNL procedures from January 2005 to January 2007 at a single institution were examined. Patients were divided into a high-risk preoperative group, which comprised patients having American Society of Anesthesiologist scores of III or IV (n = 25) and a low-risk preoperative group of patients with an American Society of Anesthesiologist score of II or less (n = 59). RESULTS: A total of 33 and 65 procedures were performed in the high- and low risk groups, respectively. The high-risk group had significantly more comorbidities than the low-risk group (5.4 vs 1.5) (P <.001). No significant difference was noted in the mean cumulative stone size for single or multiple stones in either group. A significant difference was observed between the average anesthesia time (45 vs 25 minutes) and average length of hospital stay (4.0 +/- 3.5 vs 2.7 +/- 1.2 days) but no significant difference in estimated blood loss (132 vs 150 mL) or mean operative time (118 vs 100 minutes) between the high- and low-risk groups, respectively. The overall complication rate was similar between the high-risk (12.1%) and low-risk (12.3%) groups (P = .41). The stone-free rate for the high-risk group was 61% compared with 92% for the low-risk group (P = .028). CONCLUSIONS: PCNL can be safely performed in the high-risk preoperative patient population. PMID- 19781743 TI - Association between glomerular filtration rate, free, total, and percent free prostate-specific antigen. AB - OBJECTIVES: To determine the relationship between glomerular filtration rate (GFR) and free prostate-specific antigen (fPSA), percent-free PSA (%fPSA), and total PSA (tPSA) in patients with diminished kidney function not on dialysis, using nationally representative data. METHODS: A total of 3782 men aged >= 40 years who participated in the National Health and Nutrition Examination Survey 2001-2006, and who met eligibility criteria for PSA testing were included in the final study population. GFR (mL/min/1.73 m(2)) was calculated using the Modification of Diet in Renal Disease equation 7 and categorized as >= 90, 60 to < 90, and 15 to < 60. Distribution of tPSA, fPSA, and %fPSA were estimated by GFR category and by age and race. Multivariate linear regression models were fit to determine the adjusted relationship between GFR and tPSA and %fPSA after adjusting for age, race, and body mass index. RESULTS: The multivariate linear regression analysis showed that GFR had a linear relationship with tPSA that was of borderline significance. There was a significant nonlinear relationship between GFR and %fPSA (P < .001): increased GFR was associated with a decrease in %fPSA for GFR levels below 90 [eg, change in %fPSA = -2.67 (95% CI -3.56, -1.77) for a GFR of 85 as compared with 65; P < .001]. The decline in %fPSA with increasing GFR was nonsignificant for GFR levels above 90. CONCLUSIONS: Our finding that renal function as measured by GFR is negatively associated with %fPSA has potential implications for use of this test in men with renal disease. PMID- 19781746 TI - Proton magnetic resonance spectroscopy in prostate tuberculosis. AB - Prostate tuberculosis is an uncommon disease of the prostate, which usually involves the upper urinary tract. In the elderly patients, it may be mistaken for prostate carcinoma, both clinically and by conventional radiology. However, magnetic resonance spectroscopy can provide more information to differentiate prostate tuberculosis from prostate cancer. PMID- 19781745 TI - Limited prognostic value of tumor necrosis in patients with renal cell carcinoma. AB - OBJECTIVES: To test whether tumor necrosis (TN) could improve the prognostic ability of the predictors of 2 established prognostic renal cell carcinoma (RCC) models. Presence of TN within the nephrectomy specimen is considered an important prognostic marker in patients with RCC. However, its added prognostic value along with established cancer-specific mortality (CSM) predictors has never been formally tested. METHODS: We retrospectively analyzed data of 1526 patients with all stages of RCC, who were treated with radical or partial nephrectomy at 6 institutions between 1988 and 2004. Univariate and multivariate Cox-regression models tested the statistical significance of TN in CSM predictions. Covariates consisted of TNM stage, Fuhrman grade, tumor size, and symptom classification. The analyses first addressed the entire patient population (n=1526) and then repeated in patients with exclusive clear-cell histology (n=1320). RESULTS: TN was present in 476 patients (31.2%). TN was a statistically significant predictor of CSM (hazard ratio: 2.73; P<.001) but not an independent predictor of CSM (adjusted hazard ratio: 0.88; P=.4). Accuracy of TN ranked sixth among 7 examined predictors and TN failed to improve the accuracy of other variables. The same results were recorded in patients with exclusive clear-cell histology. CONCLUSIONS: TN does not improve the accuracy of established predictors of CSM that are used in 2 prognostic RCC models for patients with RCC of all stages. PMID- 19781747 TI - Tumor recurrence in prostatic urethra following simultaneous resection of bladder tumor and prostate: a comparative retrospective study. AB - OBJECTIVES: To evaluate the effect on the oncological outcomes and recurrences at the prostatic urethra of simultaneous transurethral resection of bladder tumor (TURBT) and benign prostatic hyperplasia (TURP). METHODS: The records of 85 men (group 1) who had undergone simultaneous TURBT and TURP at our clinic between 1986 and 2006 and fulfilled the inclusion criteria were retrospectively analyzed and compared with those of 85 men (group 2) who had undergone TURBT only during the same period. Clinicopathologic parameters, recurrence and progression rates, and recurrence rates in the bladder neck and prostatic urethra were determined and compared. RESULTS: There were no statistically significant differences in clinicopathologic parameters between the 2 groups. At a mean follow-up of 35.2 and 33.1 months in groups 1 and 2, respectively, only 1 patient developed recurrence in prostatic urethra or bladder neck in each group. There were no statistically significant differences between the 2 groups in follow-up time, recurrence, progression or recurrence in the prostatic urethra, and bladder neck. CONCLUSIONS: According to our results, simultaneous transurethral TURP and TURBT can be safely performed without increasing the risk of tumor recurrence in the prostatic urethra. PMID- 19781748 TI - Renal artery aneurysm treated with ex vivo reconstruction and autotransplantation. AB - A 64-year-old former heavy smoker with a history significant for hypertension was found to have a 2.2-cm left renal artery aneurysm. Computed tomographic arteriography with 3-dimensional reconstruction determined the management of this patient, who ultimately underwent successful ex vivo left renal artery aneurysm repair with autotransplantation. PMID- 19781749 TI - Radio-frequency ablation of solitary adrenal gland metastasis from renal cell carcinoma. AB - OBJECTIVES: To evaluate the early clinical experience associated with radio frequency (RF) ablation in patients with solitary adrenal gland metastasis of renal cell carcinoma (RCC). METHODS: A total of 5 patients were treated with RF ablation of adrenal gland metastasis from RCC under computed tomography (CT) guidance between 2006 and 2007. Radiotherapeutics generator (Boston Scientific, Natick, MA) and Radiotherapeutics RF ablation probe with "umbrella" array tip (Boston Scientific, Natick, MA) were used. These patients were contraindicated for surgery due to several associated morbidities. All patients underwent a tumor biopsy before RF. The access was percutaneous in all patients. Tumor control was defined as the absence of contrast enhancement in the tumor on CT. Data were collected in a retrospective manner. RESULTS: Five patients were treated with a RF ablation of the adrenal metastasis. The average age of the patients was 69.4 +/- 11.1 years (57-87), the average time between the radical nephrectomy and the onset of adrenal metastasis was 5.2 +/- 1.3 years (4-7), and average diameter of the tumor was 3.9 +/- 1.4 cm (2-6). A year after RF, four patients had a total necrosis of their tumor on CT and 1 had an active tumor for which the patient received a second course of RF. An abscess of the adrenal gland had occurred in 1 case requiring a percutaneous drainage. CONCLUSIONS: The treatment of metastatic adrenal gland with RF broadens the range of treatment of metastatic RCC. The efficacy of this therapeutic modality must be confirmed by larger series with the longest follow-up. PMID- 19781750 TI - Rigorous bicycling does not increase serum levels of total and free prostate specific antigen (PSA), the free/total PSA ratio, gonadotropin levels, or uroflowmetric parameters. AB - OBJECTIVES: To determine whether cycling has an effect on serum PSA, gonadotropins, and uroflowmetric parameters. METHODS: A total of 34 healthy male athletes from the National Cycling Team and 24 healthy male student volunteers from University and medical staff were prospectively enrolled in the study. Blood samples for serum total prostate-specific antigen (tPSA), free PSA (fPSA, fPSA/tPSA, follicle-stimulating hormone (FSH), luteinizing hormone (LH), and testosterone determinations were obtained before and after cyclists completed 300 km bicycle ride and with each cyclist seated without changing posture and with minimal movement for 10 minutes before blood collection. The cyclists also performed uroflowmetric and postvoid residual urine volume analysis before, and 1 hour after cycling course. Blood samples from the control group were drawn for serum hormones. They also underwent uroflowmetric and postvoid residual analysis. RESULTS: The athletes and the control group were well matched by age. There was no significant difference between the 2 groups in terms of serum tPSA, fPSA, f/t PSA values, FSH, LH, and testosterone levels and uroflowmetric parameters (P >.05). The differences between pre- and postcycling values for tPSA, fPSA, f/t PSA, FSH, LH, and uroflowmetric parameters were not statistically significant. The postcycling serum testosterone level was significantly lower than precycling levels (mean, 603.6 ng/dL [range, 300-949] vs 424.8 ng/dL [range, 193-723], P = .001]. There was no correlation between body mass index values, postcycling serum FSH, LH levels, age, and testosterone levels. CONCLUSIONS: There is no effect of professional bicycle riding on serum total and fPSA levels and uroflowmetric parameters. PMID- 19781751 TI - Intravesical migration and spontaneous expulsion of a Hem-o-lok polymer ligating clip after laparoscopic radical prostatectomy. AB - We present a rare postoperative complication occurring after a laparoscopic radical prostatectomy with nerve-sparing procedure carried out with the placement of 3 Weck Hem-o-lok-L clips in the right neurovascular bundle, in a patient with clinically localized prostate cancer. The procedure was completed without any complications and the urethral catheter was removal at 15 days. We report a case of intravesical migration and subsequent calculus formation with spontaneous expulsion of Hem-o-lok clip. To date, this is the only reported case of intravesical migration and subsequent calculus formation with a spontaneous expulsion. PMID- 19781753 TI - Effects of low versus physiologic plasma progesterone concentrations on ovarian follicular development and fertility in beef cattle. AB - The objective of this study was to determine the effects of low versus physiologic plasma progesterone concentrations during the ovulatory wave on fertility in cattle. Suckled beef cows (Bos taurus; n=129) and pubertal heifers (Bos taurus; n=150) at random stages of the estrous cycle were given a luteolytic dose of prostaglandin F(2 alpha) (500 microg cloprostenol; PGF) twice, 11 d apart. Ten days after the second PGF treatment, cattle were given estradiol benzoate im (1.5 and 1.0mg for cows and heifers, respectively) and a progesterone releasing intravaginal device (Cue-Mate) with a single pod containing 0.78 g progesterone (Day 0). Cattle in the low-progesterone group (n = 148) received a luteolytic dose of PGF on Day 0, whereas those in the high-progesterone (i.e., physiologic plasma concentrations) group (n=131) were allowed to retain their corpora lutea. On Day 8, the Cue-Mate was removed, and PGF was given to both groups. Fifty-four hours to 56 h later, cattle received 12.5mg of porcine LH (pLH) im and were concurrently artificially inseminated. The dominant follicle in the low-progesterone group was larger (P<0.001) than that in the high progesterone group on the day of insemination (14.9+/-0.3mm vs. 12.7+/-0.3mm, mean+/-SEM). At 7 d after ovulation, the low-progesterone group had a larger corpus luteum (24.5+/-0.54 mm vs. 21.9+/-0.64 mm, P<0.01) and higher plasma progesterone concentration (4.0+/-0.3 vs. 3.1+/-0.2, P<0.01) than that of the high-progesterone group. However, pregnancy rates did not differ (79 of 148, 53.4%, and 70 of 131, 53.4%) for low- and high-progesterone groups, respectively). In summary, low circulating progesterone concentrations during the growing phase of the ovulatory follicle resulted in a larger dominant follicle and a larger CL that produced more progesterone, with no significant effect on pregnancy rate. PMID- 19781752 TI - Condensins regulate meiotic DNA break distribution, thus crossover frequency, by controlling chromosome structure. AB - Meiotic crossover (CO) recombination facilitates evolution and accurate chromosome segregation. CO distribution is tightly regulated: homolog pairs receive at least one CO, CO spacing is nonrandom, and COs occur preferentially in short genomic intervals called hotspots. We show that CO number and distribution are controlled on a chromosome-wide basis at the level of DNA double-strand break (DSB) formation by a condensin complex composed of subunits from two known condensins: the C. elegans dosage compensation complex and mitotic condensin II. Disruption of any subunit of the CO-controlling condensin dominantly changes DSB distribution, and thereby COs, and extends meiotic chromosome axes. These phenotypes are cosuppressed by disruption of a chromosome axis element. Our data implicate higher-order chromosome structure in the regulation of CO recombination, provide a model for the rapid evolution of CO hotspots, and show that reshuffling of interchangeable molecular parts can create independent machines with similar architectures but distinct biological functions. PMID- 19781754 TI - Sperm quality evaluation in Solea senegalensis during the reproductive season at cellular level. AB - Sperm quality seems to be one of the reasons for the reproduction constraints faced by Senegalese sole (Solea senegalensis) aquaculturists. Previous studies in this species indicated that the sperm quality of individuals kept in culture varies throughout the year and that different sperm subpopulations can be identified in ejaculates according to the motility pattern of spermatozoa. Aiming to better understand factors affecting sole sperm quality in captivity, sperm of 11 males was assessed during the reproductive season using different parameters: motility characteristics using CASA analysis; cell plasma membrane resistance to seawater hyperosmolarity; DNA fragmentation with single-cell gel electrophoresis; and early apoptosis, labeled with Annexin-V FITC. Computer-assisted sperm analyses motility data were treated using multivariate analysis to identify the presence of different spermatozoa subpopulations according to their motility pattern. Four distinct sperm subpopulations were obtained: Subpop1, which includes fast linear spermatozoa; Subpop2, made up of fast nonlinear spermatozoa; Subpop3, which includes slow linear spermatozoa; and Subpop4, which contains slow nonlinear spermatozoa. The sperm subpopulation structure varied with time after activation and with male. Low cell resistance to the seawater hyperosmotic conditions was noticed. The Annexin-V assay allowed the identification of an apoptotic population ranging from 6% to 20%. A high percentage of cells (64.1%) showed a DNA fragmentation level below 30%, but these values varied significantly between males. DNA fragmentation appears to be related to cell membrane resistance to hyperosmotic conditions faced by the cells when in contact with seawater. This condition seems to modulate the composition of the motile sperm population and performance after activation. This phenomenon could be related to the spermatozoa maturation process. PMID- 19781756 TI - Differences in task demands influence the hemispheric lateralization and neural correlates of metaphor. AB - This study investigated metaphor comprehension in the broader context of task difference effects and manipulation of processing difficulty. We predicted that right hemisphere recruitment would show greater specificity to processing difficulty rather than metaphor comprehension. Previous metaphor processing studies have established that the left inferior frontal gyrus strongly correlates with metaphor comprehension but there has been controversy about whether right hemisphere (RH) involvement is specific for metaphor comprehension. Functional MRI data were recorded from healthy subjects who read novel metaphors, conventional metaphors, definition-like sentences, or literal sentences. We investigated metaphor processing in contexts where semantic judgment or imagery modulates linguistic judgment. Our findings support the position that the type of task rather than figurative language processing per se modulates the left inferior gyrus (LIFG). RH involvement was more influenced by processing difficulty and less by the novelty or figurativity of linguistic expressions. Our results suggest that figurative language processing depends upon the effects of task-type and processing difficulty on imaging results. PMID- 19781755 TI - Neural development of networks for audiovisual speech comprehension. AB - Everyday conversation is both an auditory and a visual phenomenon. While visual speech information enhances comprehension for the listener, evidence suggests that the ability to benefit from this information improves with development. A number of brain regions have been implicated in audiovisual speech comprehension, but the extent to which the neurobiological substrate in the child compares to the adult is unknown. In particular, developmental differences in the network for audiovisual speech comprehension could manifest through the incorporation of additional brain regions, or through different patterns of effective connectivity. In the present study we used functional magnetic resonance imaging and structural equation modeling (SEM) to characterize the developmental changes in network interactions for audiovisual speech comprehension. The brain response was recorded while children 8- to 11-years-old and adults passively listened to stories under audiovisual (AV) and auditory-only (A) conditions. Results showed that in children and adults, AV comprehension activated the same fronto-temporo parietal network of regions known for their contribution to speech production and perception. However, the SEM network analysis revealed age-related differences in the functional interactions among these regions. In particular, the influence of the posterior inferior frontal gyrus/ventral premotor cortex on supramarginal gyrus differed across age groups during AV, but not A speech. This functional pathway might be important for relating motor and sensory information used by the listener to identify speech sounds. Further, its development might reflect changes in the mechanisms that relate visual speech information to articulatory speech representations through experience producing and perceiving speech. PMID- 19781757 TI - Investigation of thiol-ene and thiol-ene-methacrylate based resins as dental restorative materials. AB - OBJECTIVES: The objective of this work was to evaluate thiol-norbornene and thiol ene-methacrylate systems as the resin phase of dental restorative materials and demonstrate their superior performance as compared to dimethacrylate materials. METHODS: Polymerization kinetics and overall functional group conversions were determined by Fourier transform infrared spectroscopy (FTIR). Flexural strength and modulus were determined with a 3-point flexural test. Polymerization-induced shrinkage stress was measured with a tensometer. RESULTS: Thiol-ene polymer systems were demonstrated to exhibit advantageous properties for dental restorative materials in regards to rapid curing kinetics, high conversion, and low shrinkage and stress. However, both the thiol-norbornene and thiol-allyl ether systems studied here exhibit significant reductions in flexural strength and modulus relative to BisGMA/TEGDMA. By utilizing the thiol-ene component as the reactive diluent in dimethacrylate systems, high flexural modulus and strength are achieved while dramatically reducing the polymerization shrinkage stress. The methacrylate-thiol-allyl ether and methacrylate-thiol-norbornene systems both exhibited equivalent flexural modulus (2.1+/-0.1 GPa) and slightly reduced flexural strength (95+/-1 and 101+/-3 MPa, respectively) relative to BisGMA/TEGDMA (flexural modulus; 2.2+0.1 GPa and flexural strength; 112+/-3 MPa). Both the methacrylate-thiol-allyl ether and methacrylate-thiol-norbornene systems exhibited dramatic reductions in shrinkage stress (1.1+/-0.1 and 1.1+/-0.2 MPa, respectively) relative to BisGMA/TEGDMA (2.6+/-0.2 MPa). SIGNIFICANCE: The improved polymerization kinetics and overall functional group conversion, coupled with reductions in shrinkage stress while maintaining equivalent flexural modulus, result in a superior overall dental restorative material as compared to traditional bulk dimethacrylate resins. PMID- 19781758 TI - Eluted substances from unpolymerized and polymerized dental restorative materials and their Nernst partition coefficient. AB - OBJECTIVES: Components released from resin-based dental materials are important factors in the assessment of the biocompatibility of these materials. The study was performed to investigate the elution of substances from unpolymerized and polymerized composites (Tetric=TET; Arabesk=ARA), ormoceres (Admira)=ADM; Definite=DEF) and the compomere (Hytac=HYT). METHODS: Specimens were polymerized and immersed in either water or methanol. Besides the unpolymerized specimens were dissolved in methanol. Eluted substances were detected by gas chromatography/mass spectroscopy. The Nernst partition coefficient (DC) of 64 substances, eluted from various resin-based dental materials was determined. RESULTS: Only in methanolic and aqueous eluates from unpolymerized and polymerized specimens of DEF and ADM, the comonomere 1,2/1,3-glycerol dimethacrylate was measured. Triethylene glycol dimethacrylate was eluted into the aqueous and methanolic phase from polymerized specimens from TET and ARA. 2 Hydroxyethyl methacrylate was eluted into the methanolic phase from polymerized specimen from TET and HYT. Residuals of monomer synthesis like triphenyl stibane were found in unpolymerized specimens of TET and ARA. Camphorquinone was eluted into the methanolic eluate from polymerized and unpolymerized specimens from all tested dental materials. Highest DC of 20.8 was found for 1/2-cyclohexene methacrylate. DC of urethane dimethacrylate and bisphenol-A glycidyldimethacrylate varies from different manufacturers. SIGNIFICANCE: Impurities from manufacturing process were found in some resin-based materials. Various well-known substances causing allergic reactions were found in aqueous or methanolic elutes. Patients, dental and manufacturing personnel are exposed to these substances. PMID- 19781759 TI - Canada 2010: what should global health expect? PMID- 19781760 TI - Exoskeletal deformities in Palaemonidae: are they a threat to survival? AB - Shrimps of the Palaemon genus have been affected for over 15 years by a problem of exoskeletal deformities, particularly in the Gironde estuary (France). Given the large numbers of individuals affected, this study focus on a better description of the phenomenon to estimate its impact on shrimps. This study, on Palaemon longirostris and Palaemon macrodactylus, is based on samples collected from 1992 to 2007 in the Gironde estuary with particular focus on the year 2007, and on a 4-month rearing of adult shrimps in experimental system. The different approaches reveal the relative persistence of the phenomenon since 1992 (with on average more than 58% of ovigerous females affected) and its persistence during shrimp life cycle, even after several moults. Important consequences associated with deformities at the individual level were demonstrated: a higher mortality, a lighter egg mass and a lower weight for a given size. The presence of exoskeletal deformities is now a major phenomenon, with profound effects on individual shrimps, and which may in turn have an important impact on the survival of the P. longirostris population in particular. PMID- 19781762 TI - Controlled presentation of recombinant proteins via a zinc-binding peptide-linker in two and three dimensional formats. AB - The presentation of proteins on surfaces is fundamental to numerous cell culture and tissue engineering applications. While a number of physisorption and cross linking methods exist to facilitate this process, few avoid denaturation of proteins or allow control over protein orientation, both of which are critical to the functionality of many signal proteins and ligands. Often recombinant protein sequences include a poly-histidine tag to facilitate purification. We utilize this sequence to anchor proteins to biosurfaces via a peptide bonded to the surface which conjugates with the poly-histidine tag in the presence of zinc rather than nickel, which is more traditionally used to conjugate poly-histidine tags to surfaces. We demonstrate that this strategy enables the display of proteins on 2D and 3D surfaces without compromising protein function through direct cross-linking or physisorption. PMID- 19781761 TI - The noninvasive, quantitative, in vivo assessment of adenoviral-mediated gene delivery in skin wound biomaterials. AB - Because there are few reports using gene delivery in clinically-approved synthetic matrices, we examined the feasibility of using a noninvasive imaging system to study the kinetics of luciferase gene expression when delivered in an adenoviral vector. Using a mouse model of full thickness injury, we quantified the kinetics of gene expression, determined the optimal dose of particle delivery, and established the temporal importance of drug delivery in obtaining optimal gene expression. Specifically, we found that the ideal time to deliver adenovirus to a graft is during the early phase of graft wound closure (days 0-3 post-operatively) for a peak of gene expression to occur 7 days after delivery. Under these conditions, there is a saturating dose of 6 x 10(8) adenoviral particles per graft. In light of these findings, we examined whether the efficacy of delivery could be increased by modulating the composition of the grafts. When a collagen gene-activated matrix (GAM) containing basic fibroblast growth factor (FGF2) was compared to matrix alone, a significant increase in gene expression is observed when identical amounts of vector are delivered (p<0.05). Taken together, these results show how a noninvasive and quantitative assessment of gene expression can be used to optimize gene delivery and that the composition of matrices can dramatically influence gene expression in the wound bed. PMID- 19781763 TI - The MRI assessment of intraurethrally--delivered muscle precursor cells using anionic magnetic nanoparticles. AB - Autografting of cultured myogenic precursor cells (MPC) is a therapeutic strategy for muscle disorders, including striated urethral sphincter insufficiency. Implantation of myofibers with their satellite cells into the urethra is a recently described method of MPC transfer aimed at generating a new sphincter in incontinent patients. In this study, we magnetically labeled muscle implants with dextran-free anionic iron oxide nanoparticles (AMNP). The aim was to evaluate the biocompatibility of the labeling procedure and its utility for non-invasive MRI follow-up of cell therapy in a female pig model. After adsorption of AMNP to the implant surface, various cell types, including MPC, were magnetically labeled within the implants. Magnetic labeling did not affect cell proliferation or differentiation. Autograft detection in vivo by 0.3-T MRI was possible for up to 1 month. Ex vivo, Perl's, anti-desmin and anti-myosin heavy chain staining confirmed the co-localization of AMNP and regenerated myofibers. AMNP labeling was thus useful for locating myofiber implant autografts in vivo and for ex vivo monitoring of the biology of this cell transfer method. PMID- 19781764 TI - On the effect of substrate curvature on cell mechanics. AB - Cell movement on a substrate or within the extracellular matrix is the phenomenological response to a biochemical signals' cascade transcripted into biophysical processes and viceversa. The process is complex in nature, including different length scales from the whole cell to organelle and protein levels, where substrate/ECM curvature has been shown to play an important role on cell's behavior. From a macroscopic perspective, the cytoskeleton may be modeled as a continuum body unbalanced by internal protein motors. In this work, we propose a cell constitutive model to simulate cell attachment on curved substrates, activated by contractile forces. We first analyze a single fiber bundle composed by microtubules, actin filaments and myosin machinery. Then, the model is macroscopically extended to the cytoskeletal level using homogenization. Substrate curvature has two implications in our model: (i) it forces fibers to work in a curved (bent) position and (ii) it eventually creates a pre-deformation state in the cytoskeleton. Interestingly, the model shows higher contractile force inhibition as curvature increases when implemented over different substrate morphologies, being this consistent with experimental results. The presented model may result useful in many new regenerative medicine techniques, miniaturized experimental tests, or to analyze cell behavior on manufactured nanoscaffolds for tissue engineering. PMID- 19781765 TI - Over-expression of receptor activator of nuclear factor-kappaB ligand (RANKL), inflammatory cytokines, and chemokines in periprosthetic osteolysis of loosened total hip arthroplasty. AB - Loosening of total hip arthroplasty (THA) caused by periprosthetic osteolysis induced by ultra-high molecular weight polyethylene (UHMWPE) particles is a major clinical problem. We investigated whether there are differences between loosened THA patients and primary THA patients in (1) receptor activator of nuclear factor kappaB ligand (RANKL) expression on periprosthetic bone marrow cells; (2) RANKL levels, osteoprotegerin (OPG)/RANKL ratios, the levels of inflammatory cytokines and chemokines in synovial fluid. We used flow cytometric analysis to detect RANKL expression on periprosthetic bone marrow cells. We used enzyme-linked immunoassay and multiplex microsphere-based immunoassay to measure RANKL, OPG, cytokines, and chemokines in synovial fluid. We found loosened THA patients had higher RANKL expression on osteoblastic stromal cells, higher levels of RANKL, interleukin (IL)-6, IL-8, IL-10, interferon-gamma-inducible protein (IP)-10, monocyte chemoattractant protein (MCP)-1, monokine induced by interferon-gamma (MIG), and lower OPG/RANKL ratios in synovial fluid than primary THA patients. There was positive correlation between the levels of IL-6, IL-8, IL-10, IP-10, MCP-1, or MIG and RANKL levels in synovial fluid or RANKL expression on osteoblastic stromal cells. These suggest that UHMWPE particles induce over expression of RANKL, IL-6, IL-8, IP-10, MCP-1, and MIG in human periprosthetic microenvironment. This results in periprosthetic osteolysis and loosening of THA. PMID- 19781766 TI - The use of a polyelectrolyte fibrous scaffold to deliver differentiated hMSCs to the liver. AB - Liver transplantation as a therapy for liver failure is often hampered by a shortage of donor tissue. The delivery of liver-differentiated human mesenchymal stem cells (hMSCs) is a potential therapy to aid in liver regeneration. In this study, an RGD-modified chitosan-alginate polyelectrolyte complex (PEC) fibrous non-woven scaffold was employed to deliver differentiated hMSCs in vivo. Bone marrow-derived hMSCs were differentiated in vitro by a combination of extracellular matrix (ECM) and conditioned medium and seeded onto the RGD modified chitosan-alginate fibrous scaffolds. The cell/scaffold construct was then implanted into the livers of a rat model, where 70% of the liver had been removed. Post-implantation analysis of the cell/scaffold constructs showed positive periodic acid-Schiff (PAS) staining for glycogen, and expression of the hepatic markers, AFP, CK19, CK18, albumin, HNF-3beta and MRP-2 by immunofluorescence labeling. In addition, human albumin was detectable in the rat serum by spot blot. These findings demonstrated that the RGD-modified chitosan alginate fibrous scaffold was useful for delivering transdifferentiated hMSCs into the liver and maintaining the differentiated phenotype of the cells. PMID- 19781767 TI - The correlation between human adipose-derived stem cells differentiation and cell adhesion mechanism. AB - In recent years, research in the areas of stem cells has dramatically increased, including studies of cellular adhesion to a substrate. We sought to determine the adhesive properties of human adipose-derived stem cells (hASCs) for extracellular matrix proteins. The adhesion of hASCs to collagens and laminin was completely inhibited by a monoclonal antibody, Mab 2253, which binds to the beta1 integrin subunit. These data indicate that hASC adhesion to collagens and laminin was exclusively mediated by an integrin. Cell adhesion on fibronectin (Fn) was inhibited by the heparin-binding peptide (HBP) in the presence of Mab 2253, but not by either Mab 2253 or HBP alone. These results indicate that both the beta1 subunit and the heparan sulfate proteoglycan participated in the cell adhesion to Fn. Microscopic views showed extensive spreading of hASCs cultured on Fn, whereas the cells maintained a round shape when cultured on a heparin-binding domain (HBD) substrate. hASCs differentiated into adipocytes, which stained positive for lipid vacuoles by Oil Red-O analysis, more readily on HBD substrate than on FN substrate. These results suggest that hASCs have an adhesion mechanism for the HBD of Fn and hASC morphology is controlled by the adhesion mechanism and strongly correlated with adipogenic differentiation. PMID- 19781768 TI - Opposite effects of nanocrystalline fullerene (C(60)) on tumour cell growth in vitro and in vivo and a possible role of immunosupression in the cancer-promoting activity of C(60). AB - In the present study, we compared the effects of nanocrystalline fullerene suspension (nanoC(60)) on tumour cell growth in vitro and in vivo. NanoC(60) suspension was prepared by solvent exchange using tetrahydrofuran to dissolve C(60). In vitro, nanoC(60) caused oxidative stress, mitochondrial depolarization and caspase activation, leading to apoptotic and necrotic death in mouse B16 melanoma cells. Biodistribution studies demonstrated that intraperitoneally injected radiolabeled (125I) nanoC(60) readily accumulated in the tumour tissue of mice subcutaneously inoculated with B16 cells. However, intraperitoneal administration of nanoC(60) over the course of two weeks starting from melanoma cell implantation not only failed to reduce, but significantly augmented tumour growth. The tumour-promoting effect of nanoC(60) was accompanied by a significant increase in splenocyte production of the immunoregulatory free radical nitric oxide (NO), as well as by a reduction in splenocyte proliferative responses to T- and B-cell mitogens ConcanavalinA and bacterial lipopolysaccharide, respectively. A negative correlation between NO production and splenocyte proliferation indicated a possible role of NO in reducing the proliferation of splenocytes from nanoC(60)-injected mice. These data demonstrate that nanoC(60), in contrast to its potent anticancer activity in vitro, can potentiate tumour growth in vivo, possibly by causing NO-dependent suppression of anticancer immune response. PMID- 19781769 TI - Preservation, sterilization and de-epithelialization of human amniotic membrane for use in ocular surface reconstruction. AB - In the past 20 years, human amniotic membrane (AM) has become widely used as an ophthalmic surgical patch as well as a substrate for stem cell tissue equivalents for ocular surface reconstruction. AM reduces ocular surface scarring and inflammation, and enhances epithelialization. In addition, it shows limited immunogenicity and some anti-microbial properties. Before being applied clinically, the donor of AM is required to undergo a thorough health screening and the membrane has to undergo an accepted processing routine, which includes preservation, sterilization and de-epithelialization. There have been various articles describing methods in preserving, sterilizing and de-epithelializing AM. Each preparation technique has been reported to have differential effects on the physical and biological properties of the AM. Therefore, it is difficult to establish a standardized procedure. In this review, we discuss the present techniques and several novel, new approaches in the preparation of AM for use in ocular surface reconstruction, and their impact on AM structure and biological activity. PMID- 19781770 TI - The use of PEGylated poly [2-(N,N-dimethylamino) ethyl methacrylate] as a mucosal DNA delivery vector and the activation of innate immunity and improvement of HIV 1-specific immune responses. AB - To minimize the cytotoxicity of poly (2-(dimethylamino) ethyl methacrylate) (PDMAEMA) as a gene delivery vector, we synthesized PEGylated PDMAEMA by atom transfer radical polymerization (ATRP). Here we report its effects on transfection efficiency in vitro delivered with a GFP expression plasmid and immunogenicity in vivo after complexed with a HIV gag gene DNA vaccine. mPEG(113) b-PDMAEMA(94) was efficient in condensing DNA and formed polyplexes with an average diameter of about 150 nm. The in vitro transfection experiments demonstrated that PEGylation dramatically decreased the cytotoxicity at the N/P ratios above 30, although the transfection efficiency in vitro was reduced. Interestingly, mice in vivo vaccination study clearly showed that PEGylated PDMAEMA used as DNA delivery vector significantly improved the prime effect of DNA vaccine through intranasal administration. Importantly, PEGylated PDMAEMA was further proved its ability to induce cytokines production by murine macrophages. Overall, mPEG-b-PDMAEMA can be used as an efficient DNA vaccine vector which enhances adaptive immune responses by activating innate immunity. PMID- 19781772 TI - Osteoclasts are involved in the maintenance of dormant leukemic cells. AB - Osteoclasts (OCs) are specialized cells for the resorption of bone matrix that have also been recently reported to be involved in the mobilization of hematopoietic progenitor cells. When Ba/F3 cells expressing wild-type bcr-abl were co-cultured with osteoblasts (OBs), OCs, and bone slices, their proliferation was significantly suppressed, and the Ki-67 negative population, which is believed to be in G(0) phase, was increased. The results of our in vitro experiments suggest that OCs could be involved in the maintenance of dormant leukemic cells in the bone marrow (BM) microenvironment through the release of soluble factors, one of which could be TGF-beta. PMID- 19781771 TI - Evidence from knockout mice for distinct implications of neuropeptide-Y Y2 and Y4 receptors in the circadian control of locomotion, exploration, water and food intake. AB - Members of the neuropeptide-Y (NPY) family acting via Y2 and/or Y4 receptors have been proposed to participate in the control of ingestive behaviour and energy homeostasis. Since these processes vary between day and night, we explored the circadian patterns of locomotor, exploratory and ingestive behaviour in mice with disrupted genes for Y2 (Y2-/-) or Y4 (Y4-/-) receptors. To this end, the LabMaster system was used and its utility for the analysis of changes in circadian activity and ingestion caused by gene knockout evaluated. Female animals, aged 27weeks on average, were housed singly in cages fitted with sensors for water and food intake and two infrared frames for recording ambulation and rearing under a 12h light/dark cycle for 4days. Relative to WT animals, diurnal locomotion, exploration, drinking and feeding were reduced, whereas nocturnal locomotion was enhanced in Y2-/- mice. In contrast, Y4-/- mice moved more but ate and drank less during the photophase, while they ate more and explored less during the scotophase. Both Y2-/- and Y4-/- mice weighed more than WT mice. These findings attest to a differential role of Y2 and Y4 receptor signalling in the circadian control of behaviours that balance energy intake and energy expenditure. These phenotypic traits can be sensitively and continuously recorded by the LabMaster system. PMID- 19781773 TI - Deguelin suppresses cell proliferation via the inhibition of survivin expression and STAT3 phosphorylation in HTLV-1-transformed T cells. AB - Adult T-cell leukemia (ATL) is an aggressive malignancy of peripheral T cells infected with human T-cell leukemia virus type 1 (HTLV-1). The prognosis of aggressive ATL patients remains poor because of its resistance to conventional chemotherapy. We examined the effect of deguelin, a naturally occurring rotenoid, on HTLV-1-transformed T-cell lines, KUT-1 and MT-2 cells. We found that deguelin suppressed cell proliferation and induced cell death in these cells. Immunoblot analysis showed the inhibition of survivin expression and signal transducers, and activators of transcription (STAT) 3 phosphorylation of both cells. We also observed the cleavage of caspase-3 and poly(ADP-ribose) polymerase (PARP) in deguelin-treated cells, indicating that deguelin induces caspase-dependent apoptosis in these cells. Furthermore, proteasome inhibitor MG132 prevented the down-regulation of survivin expression and STAT3 dephosphorylation by deguelin, suggesting that the action mechanism of deguelin involves the degradation of survivin and phosphorylated STAT3 through the ubiquitin/proteasome pathway. Our data indicate that deguelin presents a potent anti-proliferative effect in part via the down-regulation of survivin expression and STAT3 phosphorylation in HTLV 1-transformed cells. Deguelin merits further investigation as a potential chemotherapeutic agent for ATL. PMID- 19781774 TI - High levels of serum TIMP-1 correlate with advanced disease and predict for poor survival in patients with multiple myeloma treated with novel agents. AB - Tissue inhibitor of metalloproteinase-1 (TIMP-1) was evaluated in the pre treatment serum of 55 newly diagnosed patients with symptomatic myeloma. TIMP-1 was elevated in 47% of patients and correlated with lytic bone disease and increased bone resorption. Importantly, TIMP-1 correlated with ISS stage (p=0.005) and was an independent prognostic covariate for survival [HR: 1.003 (1 1.006), p=0.004] in these patients who were all treated with novel agents (bortezomib and/or IMiDs) during their disease course. Our study provides evidence that pre-treatment serum TIMP-1 is associated with advanced myeloma and suggests the further evaluation of this molecule to better determine its prognostic potential in MM. PMID- 19781775 TI - Immunophenotypic features of acute myeloid leukemia with inv(3)(q21q26.2)/t(3;3)(q21;q26.2). AB - Immunophenotypic identification of myeloid specific antigens is an important diagnostic tool in the management of patients with acute myeloid leukemia (AML). These antigens allow determination of cell of origin and degree of differentiation of leukemia blasts. AML with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) is a relatively rare subtype of AML. The immunophenotypic characteristics of inv(3) AML patients are somewhat limited. We identified 14 new cases of hematological disorders with increased myeloid blasts carrying inv(3)(q21q26.2)/t(3;3)(q21;q26.2). Also, we identified another 13 cases previously published in the literature, where the immunophenotype of inv(3)(q21q26.2) was documented. As a group, patients with AML with inv(3)(q21q26.2) had high levels of early myeloid (CD13, CD33, CD117 and MPO) and uncommitted markers (CD34, HLA-DR and CD56) and a high rate of monosomy 7 in addition to the inv(3)(q21q26.2). Differential karyotype and expression of certain antigens were noted in patients with de novo AML with inv(3)(q21q26.2) vs. those with inv(3)(q21q26.2)-containing blasts. PMID- 19781776 TI - Two further cases of myelodysplastic syndrome and acute myeloid leukemia with der(5;19)(p10;q10): association with abnormalities involving chromosomes 12 and 21. PMID- 19781777 TI - Toxic effects of heavy metals and their accumulation in vegetables grown in a saline soil. AB - A pot experiment was carried out to evaluate the effects of heavy metals on biomass, chlorophyll, and antioxidative enzyme activities of eight vegetables grown in a saline soil. The heavy metal accumulation in vegetables was also investigated. Results show that biomass and chlorophyll content of crops decreased with the increase of heavy metal concentration while peroxidase activity increased at low concentration and decreased at high concentration. The total translocation factor values in the eight vegetables are in order: water spinach>Chinese kale>pakchoi>edible amaranth>leaf mustard>Chinese flowering cabbage>green capsicum>tomato. Tomato, which is the most salt tolerant crop of the eight vegetables, also is the most heavy metals resistant studied in terms of growth, peroxidase activity and heavy metals translocation. Salt tolerant fruit vegetables such as tomato might be potential crops for the safe use of saline soils polluted with heavy metals. PMID- 19781778 TI - DNA vaccine encoding avian influenza virus H5 and Esat-6 of Mycobacterium tuberculosis improved antibody responses against AIV in chickens. AB - The H5 gene of avian influenza virus (AIV) strain A/chicken/Malaysia/5744/2004(H5N1) was cloned into pcDNA3.1 vector, and Esat-6 gene of Mycobacterium tuberculosis was fused into downstream of the H5 gene as a genetic adjuvant for DNA vaccine candidates. The antibody level against AIV was measured using enzyme-linked immunosorbent assay (ELISA) and haemagglutination inhibition (HI) test. Sera obtained from specific-pathogen-free chickens immunized with pcDNA3.1/H5 and pcDNA3.1/H5/Esat-6 demonstrated antibody responses as early as 2 weeks after the first immunization. Furthermore, the overall HI antibody titer in chickens immunized with pcDNA3.1/H5/Esat-6 was higher compared to the chickens immunized with pcDNA3.1/H5 (p<0.05). The results suggested that Esat-6 gene of M. tuberculosis is a potential genetic adjuvant for the development of effective H5 DNA vaccine in chickens. PMID- 19781779 TI - Improving social competence through character education. AB - Character education is supposed to meet early adolescents' need (i.e., eighth and ninth graders) for strengthening social competence. Moreover, adolescents' engagement in character education is integral to their learning from the education. The engagement and deficit in social competence are therefore plausible conditions for the effectiveness of character education in promoting social competence. Based on a quasi-experimental design, this study focuses on the prediction of social competence of 920 ninth graders in secondary schools of Hong Kong, China. To reduce bias from the selection process of the study and the character education program, the study adjusts for the propensity of enrolling in the program throughout the analysis. The results of the analysis show the contribution of the character education program to social competence. Moreover, engagement in the program and prior lower social competence are the adolescent's characteristics that are responsible for the contribution. PMID- 19781780 TI - Imaging appearance of primary bony tumors and pseudo-tumors of the spine. AB - We aim to review the imaging appearance of primary bony tumors of the spine and simulating lesions. Benign bone tumors commonly appear as well-circumscribed, slow-growing lesions with a calcified or sclerotic matrix. Malignancy is often aggressive permeative lesions with bone destruction, cortical invasion and associated soft-tissue mass. CT is an excellent imaging modality for characterization of the tumor matrix, exact location, extension and osseous changes, while MR imaging is superior for evaluation of the associated soft tissue mass, bone marrow infiltration and intraspinal extension. There is a spectrum of pseudotumors that may also involve the spine. The imaging appearance of primary spinal bone tumor in conjunction with the patient's age, gender and lesion location allows a high percentage of correct diagnosis. Imaging plays an important role in diagnosis, characterization and extension of bone tumors of the spine which will help guide therapy. PMID- 19781781 TI - Post-embolization perianeurysmal edema revealed by temporal lobe epilepsy in a case of unruptured internal carotid artery aneurysm treated with bare platinum coils. AB - We report the case of a patient with an unruptured internal carotid artery (ICA) aneurysm treated with bare platinum coils. The patient had seizures 1 month after treatment. Postoperative imaging showed perianeurysmal edema and enhancement of the aneurismal wall. After aneurysm coiling, perianeurysmal edema is an unusual complication that can be asymptomatic or cause symptoms depending on its location. Epilepsy as a clinical presentation of perianeurysmal edema has not previously been reported. Literature about post-embolization perianeurysmal edema is reviewed. PMID- 19781782 TI - Usefulness of functional MRI associated with PET scan and evoked potentials in the evaluation of brain functions after severe brain injury: preliminary results. AB - OBJECTIVE: To evaluate the feasability and the potential usefulness of functional MRI (fMRI) for the evaluation of brain functions after severe brain injury, when compared to a multimodal approach (evoked potentials [EP] and Positron Emission Tomography [PET] examinations). MATERIAL AND METHODS: Seven patients (mean age: 49 years [23-73], three males, four females) presenting with coma after acute severe brain injuries underwent fMRI (auditive, visual, somesthesic), (18)F-FDG PET and EP (auditive, visual, somesthesic) within a 3-day period of time in a mean of 120 days after initial brain injury. fMRI activations in somesthesic, visual and auditive cortical areas were compared to EP (28 possible comparisons) and to the metabolic activity on PET examination in the same anatomical areas (21 possible comparisons). RESULTS: In case of availability, results were concordant between fMRI and PET in 10 comparisons but not in one, and between fMRI and EP in 11 comparisons but not in four. CONCLUSIONS: In many patients, there is a good concordance between fMRI and brain functions suggested by EP and metabolic activity demonstrated with PET. In few others, fMRI can be integrated in the early evaluation of brain functions to further augment our capacity for a proper evaluation of brain functions in critically ill patients. PMID- 19781783 TI - Differentiation of tubercular infection and metastasis presenting as ring enhancing lesion by diffusion and perfusion magnetic resonance imaging. AB - BACKGROUND AND PURPOSE: As both tuberculoma and metastasis can manifest as solitary or multiple ring-enhancing intra-axial lesions that are difficult to differentiate by conventional magnetic resonance imaging (MRI), we hypothesized that the use of diffusion and perfusion MRI would make differentiation of these pathologies possible. MATERIALS AND METHODS: Diffusion and T2*-weighted dynamic contrast-enhanced perfusion MRI scans from 11 patients with histologically proven tuberculoma or metastasis were retrospectively reviewed by two radiologists who were blinded to the pathology. All patients had a ring-enhancing lesion on conventional MRI. Apparent diffusion coefficient (ADC) values and regional cerebral blood volume (rCBV) were calculated from the walls of the lesions. RESULTS: Lesions showed different perfusion characteristics depending on whether they were due to tuberculosis or metastasis. The mean rCBV ratio between the lesion periphery and normal white matter was inferior to one for tubercular lesions and greater than five for metastases. However, ADC values were similar. CONCLUSION: Measuring rCBV obtained by T2*-weighted dynamic contrast-enhanced perfusion MRI can help in differentiating intracranial tubercular mass lesions and metastases. PMID- 19781784 TI - Optimized time-resolved 3D contrast-enhanced MRA at 3T: appreciating the feasibility of assessing cervical paragangliomas. AB - OBJECTIVES: To describe an optimized 3D time-resolved contrast-enhanced MR angiography (3D TR-CE-MRA) at 3T in diagnosing head and neck paragangliomas and assessing their morphology and relation to neighboring vessels. METHODS: In a prospective study, eight consecutive patients presenting cranial cervical masses suspected to be 10 paragangliomas were examined with 3D TR-CE-MRA at 3T. Two neuroradiologists evaluated the overall image quality, the presence of a paraganglioma, the maximum diameter, as well as the vessel invasion. RESULTS: In all of the cases, the overall image quality was scored as good. The tumors (n=10) were all visualized and localized. The mean maximum diameter was 32.7mm [range 7 80]. Vessel invasion was assessed as uncertain in one case and improbable in nine cases. CONCLUSION: 3D TR-CE-MRA at 3T associated with conventional sequences facilitates a comprehensive investigation of paragangliomas, thus providing the anatomical and functional information. PMID- 19781785 TI - Overview of ecotoxicological studies performed in the Venice Lagoon (Italy). AB - This work reports on the state of the art of the bioindicators used to assess environmental quality (regarding chemical pollutant impacts) in the Venice lagoon. After a brief description of the roles, advantages and limitations of bioindicators in marine and transitional environments and a summary of the Venice lagoon characteristics, the ecotoxicological methods used during scientific studies and research projects in the Lagoon are reported. Since not all data are available and no database can be formulated, the main evidence from toxicity bioassays, biomarkers and bioaccumulation analyses since the end of the 1970s is spatially synthesized using maps and discussed according to the four Venice lagoon basins. The majority of indicators showed that the Lido basin (north central lagoon), affected by the presence of the industrial area and the city of Venice, is the one most highly impacted (particularly in the sites located within or in front of the industrial area, which showed very high sediment toxicity and high levels of DNA damage). The Malamocco basin (south-central lagoon) seems to be the least problematic. The southern basin (Chioggia basin) was shown to be impacted by urban contaminants from the town of Chioggia. The northern basin (Treporti basin) presented both impacted sites (high toxicity and high bioaccumulation factor) and relatively unpolluted sites (absence of toxicity, absence of imposex and low levels of bioaccumulation). This review can serve as a basis on which to select pragmatic, cost-effective biomonitoring techniques for environmental effects in lagoon ecosystems. PMID- 19781787 TI - Novel sequence of the porcine IGHA gene. AB - Two alleles of porcine IGHA have been reported previously. These have been detected by transcriptional length analysis and restriction fragment length polymorphism analysis. However, these methods may not be able to detect all polymorphism in porcine IGHA as they rely on the presence of either length variation or polymorphism in a restriction endonuclease recognition site respectively. Here we report a novel sequence occurring in the hinge region of the porcine IGHA gene that was detected using PCR-SSCP analysis. The novel sequence had two nucleotides that are missing at the splice-acceptor site relative to the previously reported IGHA-A sequence. Further identification of allelic variation in porcine IGHA may require an alternative typing system to be developed. PMID- 19781786 TI - Engagement of CD44 by hyaluronan suppresses TLR4 signaling and the septic response to LPS. AB - Fragments of hyaluronan released after injury bind and activate TLR4 in a complex with CD44. Here we investigated if the recognition of hyaluronan by CD44 and TLR4 alters lipopolysaccharide (LPS) responsiveness and thus could alter the septic response. In contrast to mice injected with LPS, mice exposed to hyaluronan prior to LPS had greatly decreased serum IL-6 and TNFalpha and were protected from symptoms of sepsis. The protective effect of HA was not seen in Cd44(-/-) mice. Consistent with our findings in vivo, addition of hyaluronan to macrophages before LPS exposure significantly decreased the release of IL-6 and TNFalpha and this effect was not seen in macrophages from Cd44(-/-) mice. Investigation of the mechanism responsible for inhibition of LPS activation showed hyaluronan treatment resulted in an increase in peritoneal macrophage A20 mRNA expression, and that this was significantly reduced in macrophages from Cd44(-/-) mice and Tlr4(-/-) mice. Suppression of the A20 response with siRNA inhibited the ability of hyaluronan to protect against the cytokine response to LPS. Therefore, our results show that hyaluronan acts through TLR4, CD44 and A20 to stimulate a unique cellular response that can protect against the septic response to LPS. PMID- 19781788 TI - Transcriptional analysis of Toll-like receptors expression in M cells. AB - M cells are located in the follicle associated epithelium (FAE) of Peyer's patches (PPs) in the small intestine, where they mediate the uptake and transcytosis of luminal antigens to the underlying lymphoid tissue. Toll-like receptors (TLRs) have emerged as key mediators in the innate immune response by recognising pathogen associated molecular patterns (PAMPs) expressed by microorganisms. TLRs have previously been shown to be differentially expressed in the gastrointestinal tract. In this study PP were harvested from BALB/c mice. Ulex europaeus agglutinin 1 (UAE-1) positive M cells were isolated from FAE and the expression of TLR1-9 transcripts in M cells, FAE and villus epithelium (VE) was compared by quantitative real-time PCR. Transcripts for TLR1, TLR2 and TLR4 were found to be expressed at a high level in M cells in comparison to VE, with no transcripts being detected in the FAE. TLR3 and TLR6 were not found to be expressed in M cells or in the FAE. TLR5 and TLR7 were found to be expressed at a higher level in FAE compared to M cells. TLR9, which recognises unmethylated CpG DNA of bacteria and viruses and TLR8, which recognises ssRNA, were found to be preferentially expressed in M cells compared to FAE and VE. PMID- 19781789 TI - Light chain somatic mutations change thermodynamics of binding and water coordination in the HyHEL-10 family of antibodies. AB - Thermodynamic and structural studies addressed the increased affinity due to L chain somatic mutations in the HyHEL-10 family of affinity matured IgG antibodies, using ITC, SPR with van't Hoff analysis, and X-ray crystallography. When compared to the parental antibody H26L26, the H26L10 and H26L8 chimeras binding to lysozyme showed an increase in favorable DeltaG(o) of -1.2+/-0.1 kcal mol(-1) and -1.3+/-0.1 kcal mol(-1), respectively. Increase in affinity of the H26L10 chimera was due to a net increase in favorable enthalpy change with little difference in change in entropy compared to H26L26. The H26L8 chimera exhibited the greatest increase in favorable enthalpy but also showed an increase in unfavorable entropy change, with the result being that the affinities of both chimeras were essentially equivalent. Site-directed L-chain mutants identified the shared somatic mutation S30G as the dominant contributor to increasing affinity to lysozyme. This mutation was not influenced by H-chain somatic mutations. Residue 30L is at the periphery of the binding interface and S30G effects an increase in hydrophobicity and decrease in H-bonding ability and size, but does not make any new energetically important antigen contacts. A new 1.2-A structure of the H10L10-HEL complex showed changes in the pattern of both inter- and intra-molecular water bridging with no other significant structural alterations near the binding interface compared to the H26L26-HEL complex. These results highlight the necessity for investigating both the structure and the thermodynamics associated with introduced mutations, in order to better assess and understand their impact on binding. Furthermore, it provides an important example of how backbone flexibility and water-bridging may favorably influence the thermodynamics of an antibody-antigen interaction. PMID- 19781790 TI - Suicide attempt by jumping: a study of gonadal axis hormones in male suicide attempters versus men who fell by accident. AB - Low plasma total testosterone (T) levels may influence the sense of well-being and produce depressive symptomatology, increasing the risk of suicide. In a previous study, we reported reduced serum T levels in male psychiatric patients after a suicide attempt. The reduction was more pronounced in subjects who used violent attempt methods, and we discussed the possible influence of stress of hospitalization, serious medical condition and treatment. In order to minimize the influence of such factors, we compared in this study the levels of plasma sex hormones of 15 psychiatric patients (10 suffering from schizophrenia and 5 from depression) who had attempted suicide by jumping with those of a group of 18 male subjects who were hospitalized after accidentally falling from a high height. Compared with a healthy control group of 40 males, both accident and attempt groups had lower T levels. The attempt group showed a trend toward lower T levels compared with levels in the accident group. In the accident group, luteinizing hormone (LH) levels were elevated compared with levels in healthy controls, indicating a normal function of the hypothalamic-pituitary-gonadal (HPG) axis. This was not the case for the attempt group, where low T levels were not accompanied by increases in LH. Cortisol and prolactin were similarly elevated in both patient groups, but were not related to the low T levels. The results indicate that male psychiatric patients who attempt suicide by violent methods may have low total plasma T levels, possibly due to a dysfunction of the HPG axis at the hypothalamic-pituitary level. Monitoring HPG axis function in future studies could prove to be a predictor of suicide at least for male psychiatric attempters, and could lead to preventive strategies. PMID- 19781791 TI - Expanded TCR Vbeta subsets of CD8(+) T-cells in late-onset myasthenia gravis: novel parallels with thymoma patients. AB - Little is known about pathogenesis -- and especially about involvement of CD8(+) T-cells -- in late-onset myasthenia gravis (LOMG). Remarkably, outstanding CD8(+) TCRVbeta-subset expansions were found in 64% and 72% of recent onset LOMG or thymoma-associated MG (vs. 16% with early-onset MG (p<0.0002); 21% in older controls (p<0.001)). In LOMG, ~25% of the expanded cells initially showed a naive CD62L(+hi)/CD45RA(+) recent thymic emigrant (RTE)-like phenotype. These expansions associated significantly with IgG antibodies against cytomegalovirus (p<0.036), IL-12 and/ or IFN-alpha2 (p<0.03). The CD8(+) TCRVbeta expansions were stable over 5years, but RTE markers declined. PMID- 19781792 TI - BK Channels: mediators and models for alcohol tolerance. AB - Enhanced acute tolerance predicts alcohol abuse. We describe work on the role of the calcium- and voltage-gated BK channel in alcohol tolerance, highlighting the lipid environment, BK protein isoform selection and auxiliary BK channel proteins. We show how ethanol, which had the reputation of a nonspecific membrane perturbant, is now being examined at realistic concentrations with cutting-edge techniques, providing novel molecular targets for therapeutic approaches to alcoholism. Addictive disorders impact our emotional, physical and financial status, and burden our healthcare system. Although alcohol is the focus of this review, it is highly probable, given the common neural and biochemical pathways used by drugs of abuse, that the findings described here will also apply to other drugs. PMID- 19781794 TI - Cingulate cortex: diverging data from humans and monkeys. AB - Cognitive neuroscience research relies, in part, on homologies between the brains of human and non-human primates. A quandary therefore arises when presumed anatomical homologues exhibit different functional properties. Such a situation has recently arisen in the case of the anterior cingulate cortex (ACC). In humans, numerous studies suggest a role for ACC in detecting conflicts in information processing. Studies of macaque monkey ACC, in contrast, have failed to find conflict-related responses. We consider several interpretations of this discrepancy, including differences in research methodology and cross-species differences in functional neuroanatomy. New directions for future research are outlined, emphasizing the importance of distinguishing illusory cross-species differences from the true evolutionary differences that make our species unique. PMID- 19781795 TI - Aquatic contaminants alter genes involved in neurotransmitter synthesis and gonadotropin release in largemouth bass. AB - Many aquatic contaminants potentially affect the central nervous system, however the underlying mechanisms of how toxicants alter normal brain function are not well understood. The objectives of this study were to compare the effects of emerging and prevalent environmental contaminants on the expression of brain transcripts with a role in neurotransmitter synthesis and reproduction. Adult male largemouth bass (Micropterus salmoides) were injected once for a 96 h duration with control (water or oil) or with one of two doses of a single chemical to achieve the following body burdens (microg/g): atrazine (0.3 and 3.0), toxaphene (10 and 100), cadmium (CdCl(2)) (0.000067 and 0.00067), polychlorinated biphenyl (PCB) 126 (0.25 and 2.5), and phenanthrene (5 and 50). Partial largemouth bass gene segments were cloned for enzymes involved in neurotransmitter (glutamic acid decarboxylase 65, GAD65; tyrosine hydroxylase) and estrogen (brain aromatase; CYP19b) synthesis for real-time PCR assays. In addition, neuropeptides regulating feeding (neuropeptide Y) and reproduction (chicken GnRH-II, cGnRH-II; salmon GnRH, sGnRH) were also investigated. Of the chemicals tested, only cadmium, PCB 126, and phenanthrene showed any significant effects on the genes tested, while atrazine and toxaphene did not. Cadmium (0.000067 microg/g) significantly increased cGnRH-II mRNA while PCB 126 (0.25 microg/g) decreased GAD65 mRNA. Phenanthrene decreased GAD65 and tyrosine hydroxylase mRNA levels at the highest dose (50 microg/g) but increased cGnRH-II mRNA at the lowest dose (5 microg/g). CYP19b, NPY, and sGnRH mRNA levels were unaffected by any of the treatments. A hierarchical clustering dendrogram grouped PCB 126 and phenanthrene more closely than other chemicals with respect to the genes tested. This study demonstrates that brain transcripts important for neurotransmitter synthesis neuroendocrine function are potential targets for emerging and prevalent aquatic contaminants. PMID- 19781793 TI - Critical role of nociceptor plasticity in chronic pain. AB - The transition from acute to chronic pain states might be the most important challenge in research to improve clinical treatment of debilitating pain. We describe a recently identified mechanism of neuronal plasticity in primary afferent nociceptive nerve fibers (nociceptors) by which an acute inflammatory insult or environmental stressor can trigger long-lasting hypersensitivity of nociceptors to inflammatory cytokines. This phenomenon, "hyperalgesic priming," depends on the epsilon isoform of protein kinase C (PKCepsilon) and a switch in intracellular signaling pathways that mediate cytokine-induced nociceptor hyperexcitability. We discuss the impact of this discovery on our understanding of, and ultimately our ability to treat, a variety of enigmatic and debilitating pain conditions, including those associated with repetitive injury, and generalized pain conditions, such as fibromyalgia. PMID- 19781796 TI - Population-specific incidence of testicular ovarian follicles in Xenopus laevis from South Africa: a potential issue in endocrine testing. AB - The African clawed frog (Xenopus laevis) has been identified as an appropriate sentinel for testing endocrine activity of existing chemicals in North America and Europe. Some reports suggest that the herbicide, atrazine (CAS Number [1912 24-9]) causes ovarian follicles to form in the testes of this frog. X. laevis collected from North East (NE) sites in South Africa had testicular ovarian follicles, irrespective of exposure to atrazine, while frogs from Southwest Western (SW) Cape region sites had none. Phylogenetic analysis of mitochondrial and nuclear genes indicates that frogs from the SW Cape are evolutionarily divergent from those from NE South Africa and the rest of sub-Saharan Africa. These findings provide a possible explanation for why conflicting results have been reported concerning the impact of atrazine on amphibian sexual differentiation and highlight the importance of understanding taxonomic status of the experimental animal. Even in common laboratory animals, there is a need for their correct taxonomic characterization before their use in tests for endocrine disruption. PMID- 19781797 TI - Ryanodine receptor (RyR2) mutations in sudden cardiac death: studies in extended pedigrees and phenotypic characterization in vitro. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia caused by mutations in the RyR2 gene manifests as severe arrhythmias, and may provide a candidate for sudden cardiac deaths. METHODS: We screened 19 victims of SCD for mutations in the RyR2 gene by direct sequencing, and analyzed DNAs from available family members and from 300 controls. Medico-legal investigations were conducted by experienced pathologists. We performed resting ECG, cardiac ultrasonography, exercise stress test, epinephrine test and 24-hour ambulatory ECG recording to related mutation carriers (n = 17). The single channel recordings of the mutant RyR2s were conducted in planar lipid bilayers, and the open probabilities were determined by sequential addition of CaCl(2) to the cis-side. RESULTS: We identified two novel RyR2 missense mutations (G2145R and R3570W) in three victims of SCD. The surviving carriers of these mutations exhibited only minor, if any structural abnormalities, and two carriers of R3570W showed ventricular arrhythmias predominantly at rest. Single channel recordings revealed a gain-of function defect in native unphosphorylated R3570W and a similar but milder defect in native G2145R. CONCLUSIONS: RyR2 mutations manifesting as a gain-of-function defect in vitro may be detectable in some cases of SCD. Not all RyR2 mutations lead to a uniform, highly penetrant CPVT phenotype. PMID- 19781798 TI - The role of veterinary epidemiology in combating infectious animal diseases on a global scale: the impact of training and outreach programs. AB - The effectiveness of detection and control of highly contagious animal diseases is dependent on a solid understanding of their nature and implementation of scientifically sound methods by people who are well trained. The implementation of specific detection methods and tools requires training and application in natural as well as field conditions. The aim of this paper is to present the design and implementation of training in disease investigation and basic veterinary epidemiology in selected countries using the Highly Pathogenic Avian Influenza (HPAI) H5N1 Asia strain as a disease detection model. Indonesia, Egypt, Nigeria, Turkey, and Vietnam were each identified as either a priority country where AI was spreading rapidly or a country at risk for infection. In each of these countries, a training program on epidemiological concepts, field investigation methodology, and detection of H5N1 Asia strain cases was conducted. This report includes the impact of these training sessions on national animal health programs, including follow-up activities of animal health officers who went through these training sessions. PMID- 19781799 TI - Preferences of cost factors for mastitis management among Dutch dairy farmers using adaptive conjoint analysis. AB - Although many control practices to improve the mastitis situation on a farm and to reduce the economic losses of mastitis are available, the adoption rate and level of compliance of these measures are generally low. Implementing new measures involves costs, which can be divided into costs for the milking parlour and other issues. These costs were subdivided into long term investments, short term investments, labour, and change of routines. In traditional cost-benefit analyses all costs belonging to the different factors are set on a comparable monetary value. Although in an economic way this is correct, farmers may value some costs in a different way because of certain preferences, influencing the adoption rate of the mastitis reducing measures. The objectives of this study were to explore differences between preferences of cost factors according to Dutch dairy farmers, and to distinguish different groups of farmers accordingly. 136 farmers were questioned by adaptive conjoint analysis about their individual preferences. A large difference between these preferences was found. Taking individual preferences together, overall, long term investments in issues other than milking parlour were preferred most and changing routines in issues other than milking parlour were preferred least. The results of this study show that, given the large variation in the valuations, to improve the adoption rate of management measures it is important to take the preference of cost factors into account in advice given. PMID- 19781800 TI - Diagnostic assessment without cut-offs: application of serology for the modelling of bovine digital dermatitis infection. AB - Bovine digital dermatitis (BDD) is an epidermitis which is a leading cause of infectious lameness. The only recognized diagnostic test is foot inspection, which is a labour-intensive procedure. There is no universally recognized, standardized lesion scoring system. As small lesions are easily missed, foot inspection has limited diagnostic sensitivity. Furthermore, interpretation is subjective, and prone to observer bias. Serology is more convenient to carry out and is potentially a more sensitive indicator of infection. By carrying out 20 serological assays using lesion-associated Treponema spp. isolates, three serogroups were identified. The reliability of the tests was established by assessing the level of agreement and the concordance correlation coefficient. Subsequently, an ELISA suitable for routine use was developed. The benchmark of diagnostic test validation is conventionally the determination of the key test parameters, sensitivity and specificity. This requires the imposition of a cut off point. For serological assays with outcomes on a continuous scale, the degree by which the test result differs from this cut-off is disregarded. Bayesian statistical methodology has been developed which enables the assay result also to be interpreted on a continuous scale, thereby optimizing the information inherent in the test. Using a cross-sectional study dataset carried out on 8 representative dairy farms in the UK, the probability of infection, P(I), of each individual animal was estimated in the absence of a 'Gold Standard' by modelling I as a latent variable which was determined by lesion status, L as well as serology, S. Covariate data (foot hygiene score and age) were utilized to estimate P(L) when no lesion inspection was performed. Informative prior distributions were elicited where possible. The model was utilized for predictive inference, by computing estimates of P(I) and P(L) independently of the data. A more detailed and informative analysis of the farm-level distribution of infection could thus be performed. Also, biases associated with the subjective interpretation of lesion status were minimized. Model outputs showed that young stock were unlikely to be infected, whereas cows tended to have high or low probabilities of being infected. Estimates of probability of infection were considerably higher for animals with lesions than for those without. Associations were identified between both covariates and probability of infection in cows, but not in the young stock. Under the condition that the model assumptions are valid for the larger population, the results of this work can be generalized by predictive inference. PMID- 19781801 TI - Multivariate analysis of management and biosecurity practices in smallholder pig farms in Madagascar. AB - A cross-sectional study was carried out in 2005 and 2006 in three geographical areas of Madagascar to investigate and differentiate swine farm management and biosecurity practices in smallholder farming communities. Questionnaire data from a total of 709 pig farms were analysed using multiple factor analysis (MFA) and hierarchical cluster analysis (HCA). Variables describing management and biosecurity practices were organised into five groups: structure of the farm, animal-contacts, person- and vehicle-contacts, feeding, and sanitary aspects. In general, few biosecurity measures were implemented in the pig farms included in the study. Regional differences in management and biosecurity practices emerged from the MFA and were mainly due to, in order of decreasing importance: structure of the farm, sanitary aspects, feeding and animal-contacts and, to a lesser extent, person- and vehicle-contacts. HCA resulted in the differentiation of four distinct types of farms in each of two study areas, Arivonimamo and Marovoay, while no grouping could be identified amongst farms in Ambatondrazaka area. The characterisation of the different types of smallholder pig farms will allow adapting recommendations on husbandry practices and control measures in pig farms of these regions of Madagascar. The development of tailored recommendations is essential for Malagasy smallholders who have limited resources and need to make evidence-based management changes to reduce the risk of contagious diseases in their herds. PMID- 19781802 TI - Hospital ownership and medical services: market mix, spillover effects, and nonprofit objectives. AB - Hospitals operate in markets with varied demographic, competitive, and ownership characteristics, yet research on ownership tends to examine hospitals in isolation. Here we examine three hospital ownership types -- nonprofit, for profit, and government -- and their spillover effects. We estimate the effects of for-profit market share in two ways, on the provision of medical services and on operating margins at the three types of hospitals. We find that nonprofit hospitals' medical service provision systematically varies by market mix. We find no significant effect of market mix on the operating margins of nonprofit hospitals, but find that for-profit hospitals have higher margins in markets with more for-profits. These results fit best with theories in which hospitals maximize their own output. PMID- 19781803 TI - MCP-1 gene A-2518G polymorphism and carotid artery atherosclerosis in patients with type 2 diabetes. AB - AIMS: Cardiovascular diseases are the major cause of mortality in patients with diabetes mellitus. Monocyte chemoattractant protein-1 (MCP-1) is a potent chemokine and plays an important role in cardiovascular diseases. The objective of this study was to evaluate the relation between the genotypes of the MCP-1 A 2518G polymorphism and the development of carotid atherosclerosis in patients with type 2 diabetes. METHODS: The subjects were 303 unrelated patients who were diagnosed with type 2 diabetes mellitus. To evaluate macroangiopathy, we measured carotid artery intima-media thickness (IMT) by ultrasonography. The MCP-1 A-2518G polymorphism was determined by TaqMan PCR method. RESULTS: IMT in patients with the MCP-1 -2518 AG or GG genotype was significantly greater than the AA-genotype (P=0.007). Simple regression analysis showed that age, systolic blood pressure, LDL-cholesterol, the MCP-1 -2518 AG+GG polymorphism, and HbA1c level were correlated with IMT (P<0.0001, <0.0001, 0.006, 0.007, 0.025, respectively). In multiple regression analysis, the MCP-1 -2518 AG+GG polymorphism was the third strongest independent determinant of IMT in patients with type 2 diabetes (P=0.021), subsequent to age and systolic blood pressure. CONCLUSION: Assessment of the MCP-1 A-2518G polymorphism would be useful in identifying the risk of developing carotid atherosclerosis in patients with type 2 diabetes. PMID- 19781804 TI - The long and winding road leading to the identification of the hepatitis C virus. AB - This review describes work conducted largely in my laboratory at the Chiron Corporation between 1982 and 1989 that led to the identification of the hepatitis C virus (HCV). Key colleagues included Dr. Qui-Lim Choo in my laboratory and Dr. George Kuo also of Chiron as well as my collaborator Dr. Daniel Bradley at the CDC who provided many biological samples from the NANBH chimpanzee model. Numerous molecular approaches were explored including the screening of tens of millions of bacterial cDNA clones derived from these materials. While this early genomics approach resulted in the identification of many host gene activities associated with NANBH, no genes of proven infectious etiology could be identified. A separate avenue of our research led to the molecular characterization of the complete hepatitis delta viral genome but unfortunately, this could not be used as a molecular handle for HCV. Largely following input from Dr. Kuo, I initiated a blind cDNA immunoscreening approach involving the large-scale screening of bacterial proteomic cDNA libraries derived from NANBH infectious chimpanzee materials (prior to the development of PCR technology) using sera from NANBH patients as a presumptive source of viral antibodies. Eventually, this novel approach to identifying agents of infectious etiology led to the isolation of a single small cDNA clone that was proven to be derived from the HCV genome using various molecular and serological criteria. This discovery has facilitated the development of effective diagnostics, blood screening tests and the elucidation of promising drug and vaccine targets to control this global pathogen. PMID- 19781805 TI - Methods toward in vivo measurement of zebrafish epithelial and deep cell proliferation. AB - We present a strategy for automatic classification and density estimation of epithelial enveloping layer (EVL) and deep layer (DEL) cells, throughout zebrafish early embryonic stages. Automatic cells classification provides the bases to measure the variability of relevant parameters, such as cells density, in different classes of cells and is finalized to the estimation of effectiveness and selectivity of anticancer drug in vivo. We aim at approaching these measurements through epithelial/deep cells classification, epithelial area and thickness measurement, and density estimation from scattered points. Our procedure is based on Minimal Surfaces, Otsu clustering, Delaunay Triangulation, and Within-R cloud of points density estimation approaches. In this paper, we investigated whether the distance between nuclei and epithelial surface is sufficient to discriminate epithelial cells from deep cells. Comparisons of different density estimators, experimental results, and extensively accuracy measurements are included. PMID- 19781806 TI - Quantitative helical dynamic contrast enhanced computed tomography assessment of the spatial variation in whole tumour blood volume with radiotherapy in lung cancer. AB - We aim to assess the spatial distribution of blood volume (BV) in whole lung tumours in patients undergoing radiotherapy using helical dynamic contrast enhanced computed tomography (DCE-CT), and to determine whether conventional single level, or whole tumour measurements is more representative of the vascular effects of radiotherapy. Following ethical approval and informed consent, 15 patients with histologically proven non-small cell lung cancer underwent paired helical DCE-CT studies at baseline to assess repeatability, and after two fractions of radiotherapy (9 Gy total dose). Tumour BV was calculated for individual contiguous 10mm axial slices, and for the entire tumour volume on a pixel-per-pixel basis. Baseline tumour BV was heterogeneous varying by 15.33%+/ 17.11 between adjacent 10mm axial slices. Within subject coefficient of variation was 36.72% with conventional single tumour level evaluation, and 13.62% with whole tumour measurements. Following radiotherapy, one patient had an increase in BV greater than baseline variation (derived from the 95% limits of change) using single level evaluation; in contrast, seven patients had an increase in BV when the whole tumour was assessed. As a group, following radiotherapy, mean BV increased by 17.27% (paired t-test, p=0.20) with single level evaluation and 19.26% (p=0.049) with whole tumour assessment. Tumour BV measured using DCE-CT is spatially heterogeneous. Given the slice-by-slice variation in blood volume, our results demonstrate that whole tumour DCE-CT measurements are more repeatable, and may be a better predictor of vascular changes following therapy, compared to conventional single tumour level evaluations. PMID- 19781807 TI - Specific surface area determinations on intact drillcores and evaluation of extrapolation methods for rock matrix surfaces. AB - Permanent storage of spent nuclear fuel in crystalline bedrock is investigated in several countries. For this storage scenario, the host rock is the third and final barrier for radionuclide migration. Sorption reactions in the crystalline rock matrix have strong retardative effects on the transport of radionuclides. To assess the barrier properties of the host rock it is important to have sorption data representative of the undisturbed host rock conditions. Sorption data is in the majority of reported cases determined using crushed rock. Crushing has been shown to increase a rock samples sorption capacity by creating additional surfaces. There are several problems with such an extrapolation. In studies where this problem is addressed, simple models relating the specific surface area to the particle size are used to extrapolate experimental data to a value representative of the host rock conditions. In this article, we report and compare surface area data of five size fractions of crushed granite and of 100 mm long drillcores as determined by the Brunauer Emmet Teller (BET)-method using N(2)-gas. Special sample holders that could hold large specimen were developed for the BET measurements. Surface area data on rock samples as large as the drillcore has not previously been published. An analysis of this data show that the extrapolated value for intact rock obtained from measurements on crushed material was larger than the determined specific surface area of the drillcores, in some cases with more than 1000%. Our results show that the use of data from crushed material and current models to extrapolate specific surface areas for host rock conditions can lead to over estimation interpretations of sorption ability. The shortcomings of the extrapolation model are discussed and possible explanations for the deviation from experimental data are proposed. PMID- 19781808 TI - Soft micropillar interfaces of distinct biomechanics govern behaviour of periodontal cells. AB - A soft micropillar extracellular environment of distinct biomechanics is established by fabricating polydimethylsiloxane (PDMS) interfaces with pillar distances of 5, 7, 9 and 11 microm and elasticity moduli of 0.6, 1.0 and 3.5 Mega Pascal. To allow for cell adhesion, the biomimetic concept of pillar head fibronectin (FN) biofunctionalisation is applied. This environmental set-up aims at the analysis of favourable conditions for cell behaviour of three periodontal cell-types, here reflected by the establishment of regular cell morphology and optimal collagen gene expression. Biomechanics of these predefined functionalized model surfaces reveal progressive deterioration of regular cell morphology with increasing pillar distance, independent from pillar elasticity and cell type. Analysis of collagen gene expression demonstrates interdependency to the elasticity and the micropattern of the extracellular environment in all cell types under study. The results suggest that biomechanics of the extracellular environment govern tissue-specific cell behaviour in different periodontal cell types. Moreover, they form the basis for the creation of new biomaterials which address distinct cell functions by specific biomechanical properties. PMID- 19781809 TI - TGF-beta1 down-regulates connexin 43 expression and gap junction intercellular communication in rat hepatic stellate cells. AB - Intercellular communication is an important tool used by the cells to effectively regulate concerted responses. Hepatic stellate cells (HSCs) communicate to each other through functional gap junctions composed of connexin 43 (Cx43) proteins. We show that exogenous human TGF-beta1 (hTGF-beta1), a pro-fibrotic stimulus, decreases Cx43 mRNA and protein in a rat HSC cell line and primary HSCs. Furthermore, hTGF-beta1 increases the phosphorylation of Cx43 at serine 368. These effects lead to a decrease in the gap junction intercellular communication between the HSCs, as shown by gap-FRAP analysis. We also observe the binding of Snai1, from the nuclear extract of HSCs, to a Snai1 consensus sequence in the Cx43 promoter. In the same context, Snai1 siRNA transfection results in an up regulation of Cx43 suggesting that TGF-beta1 may regulate Cx43 via Snai1. In addition, we demonstrate that the knockdown of Cx43 by siRNA transfection results in a slower proliferation of HSCs. These findings illuminate a new effect of TGF beta1 in HSCs, namely the regulation of intercellular communication by affecting the expression level and the phosphorylation state of Cx43 through Snai1 signaling. PMID- 19781810 TI - Metabolic acclimation to hypoxia revealed by metabolite gradients in melon fruit. AB - A metabolomics approach using (1)H NMR and GC-MS profiling of primary metabolites and quantification of adenine nucleotides with luciferin bioluminescence was employed to investigate the spatial changes of metabolism in melon fruit. Direct (1)H NMR profiling of juice collected from different locations in the fruit flesh revealed several gradients of metabolites, e.g. sucrose, alanine, valine, GABA or ethanol, with increase in concentrations from the periphery to the center of the fruit. GC-MS profiling of ground samples revealed gradients for metabolites not detected using (1)H NMR, including pyruvic and fumaric acids. The quantification of adenine nucleotides highlighted a strong decrease in both ATP and ADP ratios and the adenylate energy charge from the periphery to the center of the fruit. These concentration patterns are consistent with an increase in ethanol fermentation due to oxygen limitation and were confirmed by observed changes in alanine and GABA concentrations, as well as other markers of hypoxia in plants. Ethanol content in melon fruit can affect organoleptic properties and consumer acceptance. Understanding how and when fermentation occurred can help to manage the culture and limit ethanol production. PMID- 19781811 TI - Antimicrobial efficacy of copper touch surfaces in reducing environmental bioburden in a South African community healthcare facility. PMID- 19781812 TI - Survival of bacteria on uniforms in relation to risk management in dental clinics. PMID- 19781814 TI - Cortical thickness and voxel-based morphometry in posterior cortical atrophy and typical Alzheimer's disease. AB - A significant minority of Alzheimer's disease patients present with posterior cortical atrophy (PCA). PCA is characterized by visuospatial and visuoperceptual deficits, and relatively preserved memory, whereas patients with typical Alzheimer's disease (tAD) mostly present with early episodic memory deficits. We used two unbiased image analysis techniques to assess atrophy patterns in 48 PCA, 30 tAD, and 50 healthy controls. FreeSurfer was used to measure cortical thickness, and volumetric grey matter differences were assessed using voxel-based morphometry (VBM). Both PCA and tAD showed widespread reductions compared with controls using both techniques. Direct comparison of PCA and tAD revealed thinner cortex predominantly in the right superior parietal lobe in the PCA group compared with tAD, whereas the tAD group showed thinning in the left entorhinal cortex compared with PCA. Similar results were obtained in the VBM analysis. These distinct patterns of atrophy may have diagnostic utility. In a clinical context, a relatively spared medial temporal lobe in the presence of posterior parietal atrophy may imply PCA, and should not discount AD. PMID- 19781813 TI - The wake-promoting effects of hypocretin-1 are attenuated in old rats. AB - Disruption of sleep is a frequent complaint among elderly humans and is also evident in aged laboratory rodents. The neurobiological bases of age-related sleep/wake disruption are unknown. Given the critical role of the hypocretins in sleep/wake regulation, we sought to determine whether the wake-promoting effect of hypocretin changes with age in Wistar rats, a strain in which age-related changes in both sleep and hypocretin signaling have been reported. Intracerebroventricular infusions of hypocretin-1 (10 and 30 MUg) significantly increased wake time relative to vehicle in both young (3 mos) and old (25 mos) Wistar rats. However, the magnitude and duration of the wake-promoting effects were attenuated with age. An increase of parameters associated with homeostatic sleep recovery after sleep deprivation, including non-rapid eye movement (NR) sleep time, NR delta power, the ratio of NR to rapid eye movement (REM) sleep, and NR consolidation, occurred subsequent to Hcrt-induced waking in young but not old rats. ICV infusions of hypocretin-2 (10 and 30 MUg) produced fewer effects in both young and old rats. These data demonstrate that activation of a major sleep/wake regulatory pathway is attenuated in old rats. PMID- 19781815 TI - Reduced levels of IgM autoantibodies against N-truncated pyroglutamate Abeta in plasma of patients with Alzheimer's disease. AB - In the present work, we investigated the level of IgM autoantibodies directed against different Abeta epitopes as potential diagnostic biomarker for Alzheimer's disease (AD). Anti-Abeta autoantibody levels were measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age- and sex-matched controls (HC). To validate the presence of anti-Abeta IgMs, pooled plasma samples were subjected to gel-filtration analysis. The mean level of pGluAbeta-IgM (N-terminal truncated starting at position three with pyroglutamate) was significantly decreased in AD patients as compared to HC. In the group of MCI patients there was a significant positive correlation between pGluAbeta-IgM and cognitive decline analyzed by MMSE (rho = 0.58, d.f. = 13, p = 0.022). These observations indicate that the level of IgM autoantibodies against pGluAbeta is a promising plasma biomarker for AD and correlates with the cognitive status of individuals at risk to develop AD. PMID- 19781816 TI - [Evaluation of the patient centered clinical relationship: analysis of psychometric properties using the CICAA scale]. AB - OBJECTIVE: To analyse the psychometric properties by a scale for evaluating patient centered clinical communication. DESIGN: Validation and observational study of a measurement tool. SETTING: Health centres and hospital outpatient clinics. PARTICIPANTS: Three researchers independently evaluated video recorded interviews of different sub-samples: health professionals (family medicine medical residents, family doctors, specialist care physicians, and primary care nurses), actual patients who consulted for chronic or acute health problems, and standardised patients. PRIMARY MEASUREMENTS: Dimensionality (exploratory factor analysis), internal consistency (alpha de Cronbach), intra- and inter-observer agreement (Kappa index, intraclass correlation coefficient [ICC], generalisability), sensitivity to change (Student t test) and convergent validity with the GATHA questionnaire (Pearson correlation coefficient). RESULTS: Six factors have been identified that explain 66.0% of the variance. The overall internal consistency of the test was alpha=0.94. The overall intra-observer agreement, measured with the ICC, varied between 0.94 and 0.97, whilst the inter observer was between 0.82-0.90. The number of completed questionnaires required for the evaluator to obtain adequate reproducibility (generalisability) varied between 6 and 12. Statistical significance was not obtained when testing the sensitivity to change. The CICAA scale and the GATHA questionnaire had a correlation of 0.67. CONCLUSIONS: The CICAA scale is a generic patient centered clinical communication evaluation tool that may be used in different clinical contexts and situations, since it has shown to be reliable, valid and efficient. PMID- 19781817 TI - [Positive family medicine. More imagination and less memory]. PMID- 19781818 TI - [Efficacy of oral/buccal insulin in the treatment of diabetes mellitus.]. AB - OBJECTIVE: To evaluate the efficacy and safety of administering oral/buccal insulin. DESIGN: Systematic review. DATA SOURCES: Reference databases, MEDLINE, EMBASE, Scopus, Current Contents, Web of Science, and Cochrane Library, European Drugs Agency, Food and Drug Administration, International Network of Technological Evaluation Agencies, European Network for New and Emerging Technologies (EuroScan), and gravel research registers. SELECTION OF THE STUDIES: Two clinical trials were found. Those studies that did not compare oral/buccal insulin with the standard treatment with injected insulin in terms of clinical parameters in a population with diabetes were excluded. EXTRACTION OF DATA: Critical reading according to the method proposed by the CASPe program and the Jadad scale. RESULTS: Buccal insulin produced a greater and earlier reduction in post-prandial blood glucose at 30 min in the intervention group compared to the control group (decrease of 55 mg/dl) and a higher and more rapid peak blood insulin (98 compared to 65 microU/mL). The postprandial levels with oral insulin were similar to those obtained with injected insulin, and had a higher maximum insulin concentration (110+/-130 vs. 96.3+/-69.7 microU/mL). CONCLUSIONS: Oral/buccal insulin gives, at least, results similar to the standard treatment. However, the studies had methodological problems of internal and external validity. Studies of longer duration are required to evaluate the long-term efficacy and safety. PMID- 19781819 TI - [Now is the time to provide incentives to tutors, but how?]. PMID- 19781820 TI - [Primary care evaluation]. PMID- 19781821 TI - Synthesis, pharmacological and antiviral activity of 1,3-thiazepine derivatives. AB - The preparation of new fourteen thiourea and fourteen product of their condensation with 1,4-dibromobutane, viz. 1,3-thiazepine derivatives, of 10 isopropyl-8-methyl-4-aza-tricyclo[5.2.2.0(2,6)]undec-8-ene-3,5-dione and 1 isopropyl-7-methyl-4-aza-tricyclo[5.2.2.0(2,6)]undec-8-ene-3,5-dione is described. Elemental analysis, MS and (1)H NMR spectra confirmed the identity of the products. The molecular structure of linear disubstituted thiourea derivative and its cyclization product was determined by an X-ray crystal structure analysis. Two of new obtained compounds (6b' and 7a') were tested for their pharmacological activity on animal central nervous system (CNS) in behavioral animal tests. With relatively low acute toxicity (LD(50) lower than 2000 mg kg( 1) i.p.) they exhibited significant influence on spontaneous locomotor activity and body temperature. Additionally, compounds reduced number of the "head twitch" episodes after 5-hydroksytryptophan (5-HTP) administration. New compounds were evaluated in vitro against representatives of different virus classes, such as a HIV-1 (Retrovirus), a HBV (Hepadnavirus) and the single-stranded RNA(+) viruses Yellow fever virus (YFV) and Bovine viral diarrhea virus (BVDV), both belonging to Flaviridae. Three of new obtained compounds showed a modest activity against HIV-1 wt(IIIB), BVDV and YFV. PMID- 19781822 TI - Spectrophotometric and HPLC determinations of anti-diabetic drugs, rosiglitazone maleate and metformin hydrochloride, in pure form and in pharmaceutical preparations. AB - In this study, three spectrophotometric methods and one HPLC method were developed for analysis of anti-diabetic drugs in tablets. The two spectrophotometric methods were based on the reaction of rosiglitazone (RSG) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and bromocresol green (BCG). Linear relationship between the absorbance at lambda(max) and the drug concentration was found to be in the ranges 6.0-50.0 and 1.5-12 microg ml(-1) for DDQ and BCG methods, respectively. The third spectrophotometric method consists of a zero-crossing first-derivative spectrophotometric method for simultaneous analysis of RSG and metformin (MTF) in tablets. The calibration curves were linear within the concentration ranges of 5.0-50 microg ml(-1) for RSG and 1.0 10.0 microg ml(-1) for MTF. The fourth method is a rapid stability-indicating HPLC method developed for the determination of RSG. A linear response was observed within the concentration range of 0.25-2.5 microg ml(-1). The proposed methods have been successfully applied to the tablet analysis. PMID- 19781823 TI - Synthesis and anti-inflammatory evaluation of novel angularly or linearly fused coumarins. AB - Angular [7,8]-fused coumarins were obtained from the reaction of [2,3]-fused phenols with DMAD and PPh(3), while linear [6,7]-fused coumarins were formed from the analogous reaction of [3,4]-fused phenols with DMAD and PPh(3). These compounds were tested in vitro for antioxidant activity and they found to present significant scavenging activity. In parallel, these new compounds were evaluated in vivo for anti-inflammatory activity and they found to inhibit the carrageenin induced paw edema (34-65%). Although their interaction with the free stable radical DPPH was low, the methyl 2,2-dimethyl-8-oxo-3,8-dihydro-2H-furo[2,3 h]chromene-6-carboxylate was the most potent (65%) in the in vivo experiment. The later seems to be a potent soybean Lipoxygenase inhibitor and does not acquire gastrointestinal toxicity. PMID- 19781824 TI - L-proline-catalysed facile green protocol for the synthesis and antimycobacterial evaluation of [1,4]-thiazines. AB - A series of ethyl 6-(4-chlorobenzoyl)-1,1-dioxo-3,5-diaryl-1,4-thiazinane-2 carboxylates was prepared in good yields (72-90%) from the reaction of ethyl 2 [(2-oxo-2-arylethyl)sulfonyl]acetate, substituted aromatic aldehydes and amines in presence of green catalyst, L-proline. These compounds were evaluated for in vitro antimycobacterial activity against Mycobacterium tuberculosis H37Rv (MTB), multi-drug resistant M. tuberculosis (MDR-TB) and Mycobacterium smegmatis (MC(2)) using agar dilution method. Ethyl 6-(4-chlorobenzoyl)-3,5-di(4-nitrophenyl)-1,1 dioxo-1,4-thiazinane-2-carboxylate was found to be the most promising compound (MIC: 0.68 microM) active against MTB and MDR-TB. PMID- 19781825 TI - Stimulation of tetanus toxoid-specific immune responses by a traditional Chinese herbal medicine. AB - The immunomodulatory properties of botanical medicinals are well-documented. In this study, the capacity for the traditional Chinese herbal medicine, Rehmannia Six Formula (R6F), to stimulate anti-tetanus toxoid (TT) immunity following oral administration to mice was examined. A significant rise in serum anti-TT antibody levels were observed in R6F-treated mice immunized with a minimum immunogenic dose of 10 microg TT suggesting an oral adjuvant effect. No such enhancement was found for unimmunized mice treated with R6F. This anti-TT response was preferentially IgG and antigen-specific in relation to antibody reactivity to a panel of unrelated antigens. The R6F used was safe with no adverse effects on mouse weight or survival, providing evidence for the use of R6F as an oral adjuvant. PMID- 19781826 TI - Dealing with non-detect values in time-series measurements of radionuclide concentration in the marine environment. AB - The attention of scientists in the field of environmental radioactivity is drawn to statistical methods recommended by Dennis Helsel for dealing with datasets including measurements that fall below the detection limits, as often encountered in environmental monitoring programmes. The methods are described by Helsel in his book entitled "Nondetects and Data Analysis: Statistics for Censored Environmental Data" (John Wiley and Sons, New York, 2005, 250p). These methods are applied to a data subset (using data from France) of the Radioactive Substance Committee (OSPAR commission for the protection of the marine environment of the North-East Atlantic), corresponding to time-series measurements of Cs-137 concentration in seaweed in the vicinity of the Areva NC reprocessing plant at La Hague, which is used as an illustrative example. Despite the presence of 163 non-detect values out of 514 measurements, it is possible to estimate descriptive parameters and perform statistical tests to compare concentration levels between two periods of time. Finally, evidence is obtained for an overall decreasing trend with time. The benefits of these statistical methods for data analysis are discussed. PMID- 19781827 TI - An evaluation of the satisfaction of midwives' working in midwifery group practice. AB - OBJECTIVE: to examine changes in midwives' attitudes to their professional role following the introduction of midwifery group practice (MGP) (a caseload model of midwifery continuity of care provided to women of all risk levels) and to explore aspects of the model that were working well and those that were not working well. DESIGN: the questionnaire 'Attitudes to Professional Role' was used to measure midwives' satisfaction in terms of professional satisfaction, professional support, client interaction, and professional development. Open-ended questions were also included to offer an opportunity for midwives to expand on their experiences of working in the MGP model. The questionnaire was administered at five time points over the 18-month evaluation period. Round 1 was prior to the implementation of MGP, Rounds 2-4 were at three-month intervals, with Round 5 six months later. Analysis of the structured part of the questionnaire was undertaken by comparing mean scores of satisfaction ranging from -2 (very negative attitudes) to +2 (very positive attitudes), and the open-ended questions were analysed using qualitative content analysis. SETTING: the Women's and Children's Hospital, Adelaide, South Australia. PARTICIPANTS: questionnaires were distributed to all midwives (n=15) working in MGP in Rounds 1, 2 and 3, and to the 12 midwives remaining from the original sample in Rounds 4 and 5. Fourteen questionnaires were returned in Round 1, 12 in Round 2, 10 in Round 3, nine in Round 4, and 10 in Round 5. FINDINGS: overall, a positive change in attitudes to professional role was reflected in all sub-scales in the period between start-up and 18 months later; a reduction in scores occurred in Round 3. The mean increases were significant for all sub-scales apart from professional development. Five main themes were identified across the rounds in the content analysis: 'continuity of care', 'working pattern', 'working environment', 'collegiality' and 'issues relating to midwifery practice'. Midwives gained particular satisfaction from providing continuity of care and building relationships with women and their families, and through practising autonomously as a midwife. While there was a struggle to manage the hours worked and being on call, high levels of professional satisfaction were maintained. KEY CONCLUSIONS: while there were aspects of MGP that midwives were not satisfied with and wanted to change, overall they were satisfied with the model. IMPLICATIONS: there is a need for ongoing evaluation in order to monitor the short- and long-term impact on midwives of working in a caseload model of continuity of midwifery care. PMID- 19781828 TI - Xanthoria parietina as a monitor of ground-level ambient ammonia concentrations. AB - Total nitrogen in transplanted and in situ lichen thalli of Xanthoria parietina were related to ambient ammonia air concentrations measured with passive ALPHA (Adapted Low-cost Passive High Absorption) diffusion samplers in Denmark. Transplants and ALPHA samplers were exposed four months in a transect on heathland close to a pig farm. Monthly mean ammonia concentrations declined exponentially approaching background levels after 300m. Nitrogen content of the lichen transplants tended to decline with distance, though only a few stations were significantly different from each other. Where ammonia concentrations were high, maximum content of nitrogen was reached after one month of exposure. Conversely, at sites with background concentrations, it took several months to reach a statistically significant uptake. The correlation between ammonia concentration in the air and in situ X. parietina was significant. PMID- 19781829 TI - Excessive sulfur supply reduces cadmium accumulation in brown rice (Oryza sativa L.). AB - Human activities have resulted in cadmium (Cd) and sulfur (S) accumulation in paddy soils in parts of southern China. A combined soil-sand pot experiment was conducted to investigate the influence of excessive S supply on iron plaque formation and Cd accumulation in rice plants, using two Cd levels (0, 1.5 mg kg( 1)) combined with three S concentrations (0, 60, 120 mg kg(-1)). The results showed that excessive S supply significantly decreased Cd accumulation in brown rice due to the decrease of Cd availability and the increase of glutathione in rice leaves. But excessive S supply obviously increased Cd accumulation in roots due to the decrease of iron plaque formation on the root surface of rice. Therefore, excessive S supply may result in loss of rice yield, but it could effectively reduce Cd accumulation in brown rice exposed to Cd contaminated soils. PMID- 19781830 TI - Care of the undocumented immigrant in the United States with ESRD. AB - The growth of the undocumented immigrant population in the United States has been explosive. The absence of a uniform policy regarding health care for this population has created a unique problem for nephrologists. How should provision of care for undocumented immigrants with end-stage renal disease be delivered and compensated? This problem is exacerbated by the multiple complex laws that govern delivery of and payment for care, as well as that state regulations vary widely and are not easily understood. Furthermore, the ethical and moral commitments of providers to ensure adequate and appropriate care for any patient whose life is at stake, irrespective of his or her immigration status, place nephrologists in a difficult position. This review focuses on the scope of this problem, relevant case law and legislation, current care and payment models, the response of nephrology groups, and ethical dilemmas inherent in caring for this vulnerable population. Recommendations for further study, including convening of a consensus conference, are discussed. PMID- 19781832 TI - Imaging teaching case. Radiographic features of malpositioning of a hemodialysis catheter in the azygos vein. PMID- 19781831 TI - Computerized decision support for EPO dosing in hemodialysis patients. AB - BACKGROUND: Anemia management in hemodialysis patients poses significant challenges. The present study explored the hypothesis that computerized dosing of intravenous erythropoietin (EPO) would increase the percentage of hemoglobin (Hb) values within the target range and reduce staff time spent on anemia management. STUDY DESIGN: Retrospective cohort. SETTING & PARTICIPANTS: In-center hemodialysis patients who received EPO at Dialysis Clinic Inc dialysis units for at least 3 months between October 1, 2005, and April 30, 2006. QUALITY IMPROVEMENT PLAN: Computerized decision support (CDS) for EPO dosing is compared with manual physician-directed dosing. OUTCOMES: Achieved monthly Hb values, quantity of EPO administered, and time spent by dialysis unit personnel. MEASUREMENTS: Monthly Hb and quantity of EPO administered to 1,118 patients from 18 dialysis units treated using CDS and 7,823 patients from 125 dialysis units treated using manual dosing. RESULTS: There was no difference in the likelihood of a monthly Hb level of 11-12 or 10-12 g/dL using CDS compared with manual dosing. The likelihood of an Hb level > 12 g/dL decreased and the likelihood of an Hb level < 10 g/dL increased using CDS. EPO use was 4% lower using CDS, although the difference was not statistically significant. CDS was associated with a nearly 50% decrease (P < 0.001) in the time spent by dialysis unit staff on anemia management. LIMITATIONS: Retrospective and nonrandomized. CONCLUSION: The number of monthly Hb values in an 11- (and 10-) to 12-g/dL target range and EPO use did not differ with EPO dosing using CDS compared with manual dosing. Staff resources devoted to anemia management decreased significantly using CDS. PMID- 19781833 TI - Very low-molecular-mass fragments of albumin in the plasma of patients with focal segmental glomerulosclerosis. AB - BACKGROUND: Primary focal segmental glomerulosclerosis (FSGS) is a glomerular disease that frequently does not respond to treatment and progresses to kidney failure. FSGS can be of either genetic origin, caused by mutations in slit diaphragm proteins, such as podocin, or idiopathic origin of unknown cause. STUDY DESIGN: Case series. SETTING & PARTICIPANTS: Children with FSGS (aged 3-18 years); 15 with idiopathic and 11 with genetic forms of FSGS. PREDICTOR: Genetic versus idiopathic forms. OUTCOMES & MEASUREMENTS: Differentially expressed proteins in the plasma proteome, detected using 2-dimensional electrophoresis and identified using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, Western blot, and liquid chromatography electron spray ionization tandem mass spectrometry for fragmentation and identification of the peptides. RESULTS: We found 3 very low-molecular-mass (9.2, 6.9, and 4.7 kDa; isoelectric point, 5.7) spots that were present in pooled samples from patients with genetic FSGS, but missing in patients with idiopathic FSGS and healthy individuals. Spots were identified using mass spectrometry as fragments of albumin, 2 of them apparently containing peptides from both C- and N-terminal parts of the whole protein. Proteomic analyses were carried out on all genetic patients individually; of these, 10 of 11 patients had > or =1 albumin fragment detected in the pool. We did not find an evident relationship between type of mutation or clinical status of patients and albumin fragments observed. LIMITATIONS: Very low molecular-weight albumin fragments also can be produced by other diseases. CONCLUSIONS: We describe for the first time the presence of very low-molecular mass albumin fragments in plasma of patients with FSGS with podocyte protein mutations that are absent in patients with idiopathic FSGS or healthy individuals. Additional studies are necessary to determine whether these fragments could be potential biomarkers to distinguish between genetic and idiopathic forms of FSGS. PMID- 19781834 TI - A 42-year-old woman with flaccid paralysis. PMID- 19781835 TI - Association of LDL cholesterol and inflammation with cardiovascular events and mortality in hemodialysis patients with type 2 diabetes mellitus. AB - BACKGROUND: In the general population, C-reactive protein (CRP) in addition to low-density lipoprotein (LDL) cholesterol level is useful in predicting cardiovascular events. In hemodialysis patients, the additive value is unknown. The association between LDL cholesterol level and outcome previously was suggested to be inverse and confounded by inflammation. STUDY DESIGN: Prospective cohort study. SETTING & PARTICIPANTS: 1,255 hemodialysis patients with type 2 diabetes mellitus randomly assigned to atorvastatin versus placebo in the German Diabetes Dialysis Study. PREDICTORS: Baseline LDL cholesterol level. OUTCOMES & MEASUREMENTS: Combined vascular end point (cardiac death, myocardial infarction, and stroke), mortality, myocardial infarction, sudden death, and stroke. RESULTS: During 4 years, 465 combined vascular events, 612 deaths, 160 sudden deaths, 200 myocardial infarctions, and 99 strokes occurred. Median LDL cholesterol level was 123 mg/dL. LDL cholesterol level (millimoles per liter and quartiles) was not predictive of outcome. This was analyzed further in patients with and without inflammation. In patients with inflammation (CRP level > 5 mg/L), the adjusted relative risk of combined vascular events was 29% greater compared with those without inflammation and a low LDL cholesterol level (LDL cholesterol < or = 123 mg/dL). This was irrespective of whether LDL cholesterol level was low or high (hazard ratio [HR] for LDL < 123 mg/dL [HR (for LDL< or =123 mg/dL)], 1.29, with 95% confidence interval [CI], 0.98 to 1.70; HR(LDL>123 mg/dL), 1.29, with 95% CI, 0.99 to 1.69). Similar results were found for all-cause death (HR(LDL< or =123 mg/dL), 1.47 [95% CI, 1.16 to 1.86]; HR(LDL>123 mg/dL), 1.48 [95% CI, 1.16 to 1.88]), sudden death (HR(LDL< or =123 mg/dL), 1.98 [95% CI, 1.23 to 3.20]; HR(LDL>123 mg/dL), 1.66 [95% CI, 1.01 to 2.75]), and myocardial infarction (HR(LDL< or =123 mg/dL), 1.74 [95% CI, 1.14 to 2.66]; HR(LDL>123 mg/dL), 1.54 [95% CI, 0.99 to 2.38]). In patients without inflammation, the respective risks did not differ significantly between patients with varying LDL cholesterol levels. However, there was a trend toward an increased risk of myocardial infarction (HR(LDL>123 mg/dL), 1.45 [95% CI, 0.95 to 2.21]) in patients with high compared with low LDL cholesterol levels. P values for the interaction between CRP and LDL cholesterol levels were 0.9 (composite vascular end point), 0.5 (mortality), 0.9 (sudden death), 0.09 (stroke), and 0.2 (myocardial infarction). LIMITATIONS: Selected patient cohort, post hoc analysis. CONCLUSION: Because CRP level more than LDL cholesterol level determined outcome, the value of regular LDL cholesterol measurements in long-term hemodialysis patients with type 2 diabetes needs reassessment. PMID- 19781837 TI - Psychotherapy for chronic major depression and dysthymia: a meta-analysis. AB - Although several studies have examined the effects of psychotherapy on chronic depression and dysthymia, no meta-analysis has been conducted to integrate results of these studies. We conducted a meta-analysis of 16 randomized trials examining the effects of psychotherapy on chronic depression and dysthymia. We found that psychotherapy had a small but significant effect (d=0.23) on depression when compared to control groups. Psychotherapy was significantly less effective than pharmacotherapy in direct comparisons (d=-0.31), especially SSRIs, but that this finding was wholly attributable to dysthymic patients (the studies examining dysthymia patients were the same studies that examined SSRIs). Combined treatment was more effective than pharmacotherapy alone (d=0.23) but even more so with respect to psychotherapy alone (d=0.45), although again this difference may have reflected the greater proportion of dysthymic samples in the latter. No significant differences were found in drop-out rates between psychotherapy and the other conditions. We found indications that at least 18 treatment sessions are needed to realize optimal effects of psychotherapy. We conclude that psychotherapy is effective in the treatment of chronic depression and dysthymia but probably not as effective as pharmacotherapy (particularly the SSRIs). PMID- 19781836 TI - Military-related PTSD and intimate relationships: from description to theory driven research and intervention development. AB - Military operations in Iraq and Afghanistan have brought heightened awareness of military related PTSD, as well as the intimate relationship problems that accompany the disorder and can influence the course of veterans' trauma recovery. In this paper, we review recent research that documents the association between PTSD and intimate relationship problems in the most recent cohort of returning veterans and also synthesize research on prior eras of veterans and their intimate relationships in order to inform future research and treatment efforts with recently returned veterans and their families. We highlight the need for more theoretically-driven research that can account for the likely reciprocally causal association between PTSD and intimate relationship problems to advance understanding and inform prevention and treatment efforts for veterans and their families. Future research directions are offered to advance this field of study. PMID- 19781838 TI - Performance management in healthcare: performance indicator development, task uncertainty, and types of performance indicators. AB - In healthcare, performance indicators are increasingly used to measure and control quality and efficiency of care-providing teams. This article demonstrates that when controllability is emphasized during indicator development, the level of task uncertainty influences the type of resulting performance indicators. We report findings from a field study in a medical rehabilitation centre in The Netherlands, where four low task uncertain teams ('hand trauma', 'heart failure', 'amputation', 'chronic pain'), and four high task uncertain teams ('children with developmental coordination disorders (DCD)', 'parkinson's disease', 'young children (0-4 years) with developmental disorders', and 'acquired brain injuries') participated in the development of performance indicators using the Productivity Measurement and Enhancement System (ProMES) method. Results show that teams higher on task uncertainty developed relatively more process indicators compared to outcome indicators, whereas the reverse was true for teams lower on task uncertainty. Additionally, process indicators developed by high task uncertain teams were more of a problem solving nature than process indicators developed by low task uncertain teams, which had a more procedural character. The study expands existing knowledge by providing a framework which explicates the task processes to be executed under different levels of task uncertainty, and in line with that appropriate performance indicators for healthcare teams. PMID- 19781839 TI - Evidence-based policy-making: the implications of globally-applicable research for context-specific problem-solving in developing countries. AB - In the past 15 or so years, the "evidence-based medicine" (EBM) framework has become increasingly institutionalized, facilitating its transfer across the globe. In the late 1990s, the basic principles of EBM began to have a marked influence in a number of non-clinical public policy arenas. Policy-makers working in these areas are now being urged to move away from developing policies according to political ideologies to a more legitimate approach based on "scientific fact," a process termed "evidence-based policy-making" (EBPM). The conceptual diffusion of EBM to non-clinical arenas has exposed epistemologically destabilizing views regarding the definition of "science," particularly as it relates to the demands of global versus national/sub-national policy-making. Using the maternal and neonatal subfield as an ethnographic case-study, this paper explores the effects of these divergences on EBPM in 5 developing countries (Bangladesh, Burkina Faso, Ghana, Malawi and Nepal). In doing so, our analysis aims to explain why EBPM has thus far had a limited impact in the area of context specific programmatic policy-development and implementation at the national and sub-national levels. Results highlight that the political contexts in which EBPM is played out promote uniformity of methodological and policy approaches, despite the fact that disciplinary diversity is being called for repeatedly in the public health literature. Even in situations where national EBPM diverges from international priorities, national evidence-based policies are found to hold little weight in countering global policy interests, which some informants claim are themselves legitimated, rather than informed, by evidence. Informants also highlight the way interpretations of research findings are shaped by the broader political context within which donors set priorities and distribute limited resources - contexts that are driven by the need to provide generalisable research recommendations based on scientifically replicable methods. Added to this are clear rifts between senior and junior-level experts within countries that constrain national and sub-national research agendas from serving as tools for empowered knowledge production and problem-solving. We conclude by arguing for diverse forms of research that can more effectively address context-specific problems. While such diversity may render EBPM more conflict-ridden, debate is by no means an undesirable characteristic in any evolving system of knowledge, for it has the potential to foster critical insight and localized change. PMID- 19781840 TI - The estimation of mortality for ethnic groups at local scale within the United Kingdom. AB - As an input to projections of sub-national populations by ethnicity, this paper develops the first estimates of the mortality risks experienced by the UK ethnic groups. Two estimates were developed using alternative methods. In the first, UK 2001 Census data on limiting long-term illness to predict mortality levels and regression equations between local Standardized Illness and Mortality Ratios for all ethnicities are assumed to apply to individual ethnic groups. In the second, the geographical distribution of ethnic groups by local areas is combined with local mortality for all ethnicities to estimate national mortality rates by ethnicity, which are then employed to estimate local ethnic mortality. A comparison of the two estimates indicates that the method based on illness rates produces more plausible outcomes. The local SMRs produced for each ethnic group were used to generate ethnic group life tables for 432 UK local authority areas in 2001, which included estimates of survivorship probabilities by single year of age, gender and ethnic group for each local area for use in a projection model. PMID- 19781841 TI - Dynamic fearful gaze does not enhance attention orienting in individuals with Asperger's disorder. AB - Although impaired joint attention is one of the core clinical features of pervasive developmental disorder including autistic disorder and Asperger's disorder, experimental studies failed to report its impairment. This discrepancy might be the result of differences between real-life and experimental situations. The present study examined joint attention in 11 individuals with Asperger's disorder and 11 age-matched controls under naturalistic conditions using a target detection paradigm with dynamic emotional gaze cues. Although both groups showed gaze-triggered attention orienting as assessed by the differences in reaction time for invalid minus valid cues, enhancement of joint attention by fearful (vs. neutral) gaze was observed in the control, but not in the Asperger group. This suggests that the integration of emotion and gaze direction that elicits strong joint attention is impaired in individuals with Asperger's disorder. PMID- 19781842 TI - [Midface and its rejuvenation]. PMID- 19781843 TI - [Strategies for reducing risks in smoking: opportunity or threat]. AB - The smoking control policies recommended by the World Health Organisation have achieved a slight decrease in smoking prevalence in the developed countries, although associated mortality is still very high. The use of tobacco products other than cigarettes and even medicinal nicotine (known as nicotine replacement therapy (NRT)) has been proposed as a risk reduction strategy. Among the tobacco products with less individual risk than cigarettes would be any type of tobacco without smoke (smokeless) with a low content in nitrosamines and modified cigarettes; both forms included under the PREP (Potentially Reduced Exposure Products) concept. The idea would be to promote these products among those who cannot quit smoking or wish to reduce their risk without giving up nicotine intake. The possible effects of risk reduction strategies, including PREP, on the decreased prevalence and morbidity and mortality are reviewed, and the possible implications that this measure could have in our country are analysed. Tobacco control measures in Spain are recent and still insufficient. Therefore, the current priority in Spain is the development of policies of control that have shown to more than effective. The marketing and advertising of new tobacco products, even with reduced potential risk, seems more a serious threat than an opportunity for the development of smoking control policies. PMID- 19781844 TI - Internal noise-driven circadian oscillator in Drosophila. AB - An internal noise-driven oscillator was studied in a two-variable Drosophila model, where both positive feedback and negative feedback are crucial to the circadian oscillations. It is shown that internal noise could sustain reliable oscillations for the parameter which produces a stable steady state in the deterministic system. The noise-sustained oscillations are interpreted by using phase plane analysis. The period of such oscillations fluctuates slightly around the period of deterministic oscillations and the coherence of oscillations becomes the best at an optimal internal noise intensity, indicating the occurrence of intrinsic coherence resonance. In addition, in the oscillatory region, the coherence of noisy circadian oscillations is suppressed by the internal noise, but the period is hardly affected, demonstrating the robustness of the Drosophila model for circadian rhythms to the intrinsic noise. PMID- 19781845 TI - Investing in rangeland restoration in the Arid West, USA: countering the effects of an invasive weed on the long-term fire cycle. AB - In large areas of the arid western United States, much of which are federally managed, fire frequencies and associated management costs are escalating as flammable, invasive cheatgrass (Bromus tectorum) increases its stronghold. Cheatgrass invasion and the subsequent increase in fire frequency result in the loss of native vegetation, less predictable forage availability for livestock and wildlife, and increased costs and risk associated with firefighting. Revegetation following fire on land that is partially invaded by cheatgrass can reduce both the dominance of cheatgrass and its associated high fire rate. Thus restoration can be viewed as an investment in fire-prevention and, if native seed is used, an investment in maintaining native vegetation on the landscape. Here we develop and employ a Markov model of vegetation dynamics for the sagebrush steppe ecosystem to predict vegetation change and management costs under different intensities and types of post-fire revegetation. We use the results to estimate the minimum total cost curves for maintaining native vegetation on the landscape and for preventing cheatgrass dominance. Our results show that across a variety of model parameter possibilities, increased investment in post-fire revegetation reduces long-term fire management costs by more than enough to offset the costs of revegetation. These results support that a policy of intensive post-fire revegetation will reduce long-term management costs for this ecosystem, in addition to providing environmental benefits. This information may help justify costs associated with revegetation and raise the priority of restoration in federal land budgets. PMID- 19781846 TI - Flocculation performance of epichlorohydrin-dimethylamine polyamine in treating dyeing wastewater. AB - Epichlorohydrin-dimethylamine polymers with different intrinsic viscosity (eta) and cationicity (tau) were synthesized. The flocculation performance and mechanism of these polymers in the removal of the reactive and disperse dyes from synthetic wastewater was investigated in terms of flocculation dynamics and color removal efficiency. The polymer flocculation efficiency was compared with that of polyaluminum chloride (PAC) and a composite flocculant based on polyaluminum chloride-epichlorohydrin-dimethylamine polyamine. The results showed that epichlorohydrin-dimethylamine polymer was effective over a pH range of 2-10 for the reactive and disperse dye removal (Reactive Brilliant Red and Disperse Yellow dyes). Epichlorohydrin-dimethylamine polymer with the highest eta and tau gave the best reactive dye removal efficiency, and its adsorption-bridging and electric neutralization ability played important roles in the flocculation process. The higher the eta viscosity of the epichlorohydrin-dimethylamine polymer, the better the flocculation performance of epichlorohydrin-dimethylamine polyamine, and stronger adsorption-bridging ability was obtained for removing the disperse dye from dyeing wastewaters. Epichlorohydrin-dimethylamine polymer achieved better decolorization performance when used together with PAC. PMID- 19781847 TI - Platelet cyclic guanosine monophosphate as a biomarker of phosphodiesterase type 5 inhibitor efficacy in the treatment of erectile dysfunction: a randomized placebo-controlled study. AB - BACKGROUND: Phosphodiesterase 5 inhibitors (PDE5-Is) are a mainstay in the therapy of erectile dysfunction (ED). The primary end point of clinical efficacy, both in clinical studies and normal practice, is represented by the International Index of Erectile Function (IIEF). OBJECTIVE: To evaluate if platelet cyclic guanosine monophosphate (cGMP) could represent a valuable marker for PDE5-I activity in ED. DESIGN, SETTING, AND PARTICIPANTS: The study enrolled 46 patients with psychogenic, organic, and mixed ED (20-71 yr of age; IIEF score<26). Patients were randomized to 6 wk of vardenafil, 5 mg/d at bedtime, or placebo. INTERVENTION: All patients donated two blood samples, one before starting the protocol and the second after 6 wk of treatment. MEASUREMENTS: Platelet cGMP was measured in both placebo and vardenafil groups. All the patients completed the IIEF-Erectile Function (EF) domain and the sexual encounter profile (SEP) and underwent visual sexual stimulation (VSS) coupled with Rigiscan. All the measurements were performed prior to starting the protocol and after the 6 wk of treatment. RESULTS AND LIMITATIONS: Platelet cGMP production was significantly (p<0.05) elevated in patients taking 5mg vardenafil versus placebo. Vardenafil was not superior to placebo in improving IIEF-EF and SEP scores. Conversely, VSS Rigiscan revealed a significant amelioration (p<0.028) in the vardenafil group versus placebo. The changes in platelet cGMP level correlated well with VSS Rigiscan (p=0.0037) but not with IIEF-EF and SEP. CONCLUSIONS: Platelet cGMP could represent a relatively simple, reliable, and objective biomarker of PDE5-I activity in ED clinical studies. Larger clinical studies are needed to further validate the use, utility, and limits of this assay. PMID- 19781848 TI - Anatomic bladder neck preservation during robotic-assisted laparoscopic radical prostatectomy: description of technique and outcomes. AB - BACKGROUND: Robotic-assisted laparoscopic radical prostatectomy (RALP) has been rapidly adopted despite a daunting learning curve with bladder neck dissection as a challenging step for newcomers. OBJECTIVE: To describe an anatomic, reproducible technique of bladder neck preservation (BNP) and associated perioperative and long-term outcomes. DESIGN, SETTINGS, AND PARTICIPANTS: From September 2005 to May 2009, data from 619 consecutive RALP were prospectively collected and compared on the basis of bladder neck dissection technique with 348 BNP and 271 standard technique (ST). SURGICAL PROCEDURE: RALP with BNP. MEASUREMENTS: Tumor characteristics, perioperative complications, and post operative urinary control were evaluated at 4, 12 and 24 months using (1) the Expanded Prostate Cancer Index (EPIC) urinary function scale scored from 0-100; and (2) continence defined as zero pads per day. RESULTS AND LIMITATIONS: Mean age for BNP versus ST was 57.1+/-6.6 yr versus 58.9+/-6.7 yr (p=0.033), while complication rates did not vary significantly by technique. Estimated blood loss was 183.7+/-95.8 ml versus 224.6+/-108 ml (p=0.938) in men who underwent BNP versus ST. The overall positive margin rate was 12.8%, which did not differ at the prostate base for BNP versus ST (1.4% vs. 2.2%, p=0.547). Mean urinary function scores for BNP versus ST at 4, 12, and 24 mo were 64.6 versus 57.2 (p=0.037), 80.6 versus 79.0 (p=0.495), and 94.1 versus 86.8 (p<0.001). Similarly, BNP versus ST continence rates at 4, 12, and 24 mo were 65.6% versus 26.5% (p<0.001), 86.4% versus 81.4% (p=0.303), and 100% versus 96.1% (p=0.308). CONCLUSIONS: BNP versus ST is associated with quicker recovery of urinary function and similar cancer control. PMID- 19781849 TI - Primary hydatidosis of the central nervous system: a retrospective study of 39 Tunisian cases. AB - OBJECTIVE: To analyze epidemiological characteristics, clinical symptoms, radiological aspects, treatment and outcome of central nervous system hydatidosis and compare our results with those reported in literature. PATIENTS AND METHODS: In our retrospective study, we reviewed 39 cases of primary central nervous system hydatid cysts operated on in our hospital between 1998 and 2007. RESULTS: There were 20 male and 19 female patients (sex-ratio M/F=1.05) between 2 and 68 years of age (mean=26.5 years). Thirteen of the patients were children (33.3%) with a mean age of 6.8 years and 26 were adults (66.7%) with a mean age of 36.3 years. The location of hydatid cysts was intracranial in 27 cases (69.2%) and spinal in 12 cases (30.8%). Headache and motor deficits were the predominant symptoms in patients with intracranial hydatidosis whereas back pain and spinal cord compression syndrome were the most frequent clinical presentations in patients with spinal hydatidosis. All patients underwent surgical resection of the cyst. Pathologic findings were consistent with hydatid cyst in all cases. During the follow-up period which ranged between 12 months and 5 years, 12 patients had recurrence (30.7%). Only one patient with intracranial hydatid cyst died postoperatively due to anaphylactic shock. CONCLUSION: Despite all the advances in imaging techniques and therapeutic methods, central nervous system hydatidosis remains difficult to cure and patient outcomes are not satisfactory especially in case of spinal involvement due to the high incidence of recurrence. PMID- 19781850 TI - EGCG induces apoptosis in human laryngeal epidermoid carcinoma Hep2 cells via mitochondria with the release of apoptosis-inducing factor and endonuclease G. AB - (-)-Epigallocatechin-3-gallate (EGCG), a major green tea polyphenol, was tested for in vitro cytotoxicity against human laryngeal epidermoid carcinoma of the larynx Hep2 cells. EGCG-induced apoptotic cell death accompanied by a change in the cell cycle. However, EGCG did not result in caspase activation, nor did a caspase inhibitor block cell death. Furthermore, EGCG caused no change in the intracellular levels of reactive oxygen species (ROS). The levels of p53 were increased in the EGCG-treated cells, with a corresponding decrease in Bcl-2 and Bid protein levels as well as an increase in the Bax level. In addition, EGCG induced the cytoplasmic release of cytochrome c from the mitochondria accompanied by a decreased mitochondrial membrane potential, and subsequently upregulated translocation of apoptosis-inducing factor (AIF) and endonuclease G (EndoG) into the nucleus during the apoptotic process. Taken together, these findings indicate that the p53-mediated mitochondrial pathway and the nuclear translocation of AIF and EndoG play a crucial role in EGCG-induced apoptosis of human laryngeal epidermoid carcinoma Hep2 cells, which proceeds through a caspase-independent pathway. PMID- 19781851 TI - Effect of zinc on the transformation of haloacetic acids (HAAs) in drinking water. AB - Suspected carcinogen haloacetic acids (HAAs), as a major class of disinfection byproducts, are widespread in drinking water. Batch experiments were conducted to investigate the effect of zinc, a metal component of galvanized pipe in water distribution systems, on the fate of the HAAs. Results showed that zinc could induce sequential dehalogenation of HAAs. All brominated acetic acids were transformed to acetate ultimately, and chloroacetic acid (MCAA) was the final product for the dehalogenation of trichloroacetic acid (TCAA) and dichloroacetic acid (DCAA). The concentrations of the parent compounds as a function of time were fitted pseudo-first-order kinetic model with R(2)>0.904. Brominated acetic acids were more activated than chlorinated acetic acids in the reaction with zinc and the activity of HAAs decreased with the number of substituents reduced. While flowing through galvanized pipe, brominated and chlorinated acetic acids except MCAA would decrease to 1% of their initial concentrations in 2.11-6.34h, and the rates would not be affected obviously by the hydrodynamic or duct conditions. The health risk due to TCAA, DCAA in drinking water tends to be magnified, and that due to TBAA, DBAA tends to be first increased and then decreased, also that due to MBAA tends to be decreased. PMID- 19781852 TI - Thallium dynamics in contrasting light sandy soils--soil vulnerability assessment to anthropogenic contamination. AB - The influence of different soil conditions and the presence of LMWOA (Low Molecular Weight Organic Acids) on anthropogenic Tl dynamics were discussed in this study. A shift from the "labile" to the residual fraction during the ageing was identified, indicating Tl incorporation into stable phases (e.g., illite and/or amorphous silicates). The increased water-soluble Tl concentration (1.8 fold, in maximum) after the split application of LMWOA (simulating root exudation) was observed in all soils; partial dissolution of relatively "insoluble" Tl-bearing phases (silicates and eventually oxides) in the presence of LMWOA is suggested. Thermodynamic modeling showed that Tl mobilization in the presence of citric and oxalic acids was indirect and could be attributed to complexation of major elements (Ca, Mg, Al) originating from the dissolution of various soil phases. On the contrary, H(+)-promoted dissolution by acetic acid was assumed as the predominant mechanism of Tl mobilization. Manganese(III,IV) oxides, illite and probably amorphous silicates were evaluated as the dominant phases responsible for Tl retention in the soils. In carbonate-rich soils, Tl coprecipitation with the newly formed carbonates seems to be an important factor influencing Tl release. Therefore, we suggest data on CEC, pH(ZPC) and soil mineralogy to be critical for assessment of Tl behavior in soil systems. PMID- 19781853 TI - Brazil nut shells as a new biosorbent to remove methylene blue and indigo carmine from aqueous solutions. AB - The adsorption of methylene blue and indigo carmine, respectively a basic and an acid dye, was studied on raw Brazil nut shells. The dye removal from solution by BNS was governed by: (i) polarization effects between the colored ions and the surface sites, leading to physisorbed species due to weak electrostatic forces and (ii) diffusion limitations affecting the kinetic parameters. Thermodynamic studies showed that the adsorption of methylene blue and of indigo carmine was spontaneous and exothermic occurring with entropy decrease. H(0) values confirmed the physical nature of the adsorption processes. The adsorption followed the Langmuir model and pseudo-second order kinetics over the entire range of tested concentrations but the process was controlled by intraparticle diffusion. The maximal uptakes were 7.81 mg g(-1), for methylene blue, and 1.09 mg g(-1) for indigo carmine, at room temperature. These results indicate that Brazil nut shells may be useful as adsorbent either for basic or acid dyes. PMID- 19781854 TI - A systematic review of adverse events in placebo groups of anti-migraine clinical trials. AB - In analgesic clinical trials, adverse events are reported for the painkiller under evaluation and compared with adverse events in the placebo group. Interestingly, patients who receive the placebo often report a high frequency of adverse events, but little is understood about the nature of these negative effects. In the present study, we compared the rates of adverse events reported in the placebo arms of clinical trials for three classes of anti-migraine drugs: NSAIDs, triptans and anticonvulsants. We identified 73 clinical trials in 69 studies describing adverse events in placebo groups: 8 were clinical trials with NSAIDs, 56 were trials with triptans, and 9 were trials with anticonvulsants. Studies were selected of all Medline/PubMed or CENTRAL referenced trials published until 2007. Adverse event profiles of the three classes were compared using a systematic review approach. We found that the rate of adverse events in the placebo arms of trials with anti-migraine drugs was high. In addition, and most interestingly, the adverse events in the placebo arms corresponded to those of the anti-migraine medication against which the placebo was compared. For example, anorexia and memory difficulties, which are typical adverse events of anticonvulsants, were present only in the placebo arm of these trials. These results suggest that the adverse events in placebo arms of clinical trials of anti-migraine medications depend on the adverse events of the active medication against which the placebo is compared. These findings are in accordance with the expectation theory of placebo and nocebo effects. PMID- 19781855 TI - Hindpaw incision in early life increases the hyperalgesic response to repeat surgical injury: critical period and dependence on initial afferent activity. AB - Pain in early life can enhance the response to subsequent injury, but effects are influenced by both the nature and timing of neonatal injury. Using plantar hindpaw incision, we investigated how postnatal age influences the response to repeat surgical injury two weeks later. The degree and time course of behavioural changes in mechanical withdrawal threshold were measured, and injury-related hyperalgesia was further quantified by flexion reflex electromyographic responses to suprathreshold mechanical stimuli 24 h following incision. Plantar hindpaw incision produces acute mechanical hyperalgesia in neonatal and adult rats, but incision in neonatal pups has an additional effect on the response to subsequent injury. With initial incision at postnatal day (P) 3 or 6, the degree of hyperalgesia following repeat incision 2 weeks later was greater than in animals having a single incision at the same age. At older ages (initial incision at P10, P21 or P40) responses did not differ in repeat and single incision groups. To test the role of primary afferent activity, levobupivacaine sciatic block was performed prior to P6 plantar incision, and controls received saline or subcutaneous levobupivacaine. Repeat peri-operative, but not a single pre operative sciatic block, prevented the enhanced response to repeat incision two weeks later. Our results show that the first postnatal week represents a critical period when incision increases hyperalgesia following repeat surgery two weeks later, and effects are initiated by peripheral afferent activity. This has potential therapeutic implications for the type and duration of peri-operative analgesia used for neonatal surgery. PMID- 19781856 TI - Technical note: a tool for determining rotational tilt axis with or without fiducial markers. AB - Virtually all reliable TEM tomographic reconstructions in life science depend upon cross-correlating successive images in a tilt-stack, and then using gold nanobeads as fiducial markers for determining the relative image rotation axis. Although the rotational tilt angle is one of the essential parameters affecting the quality of tomographic reconstructions, little is discussed about its determination. We provide here a simple tool based on the property of Fast Fourier Transformation for determining this rotation axis offset angle. Our method uses two publicly-available software packages (IMOD and ImageJ), and can be used on any TEM-based image stack, which is useful for images with poor bead distribution or situations where such beads are not visible. We illustrate this procedure with two different biological samples, one of which is a plunge frozen cryo-sample with fiducials and the other an epon-embedded thin section without fiducials. Prior knowledge of the rotational tilt angle facilitates further processing tomograms. With cross-correlation and the FFT-obtained rotational tilt angle, we reconstructed tomograms, of which the cross-section did not show "arc" distortion. This tool could be easily incorporated into any software for the alignment with or without fiducials. PMID- 19781857 TI - Detection of cutaneous myiasis in sheep using an 'electronic nose'. AB - Cutaneous myiasis (flystrike), in Australia caused primarily by Lucilia cuprina [Diptera: Calliphoridae], is a debilitating, painful and potentially lethal disease of sheep. Early detection of flystrike is difficult and continual flock surveillance is required to enable timely treatment of struck sheep. Electronic nose technology offers the potential for early and automated detection of flystrike. An electronic nose consisting of six metal oxide semiconductor sensors and temperature and humidity sensors was used to measure odours collected by dynamic headspace sampling during flystrike development in four experiments and from urine- and faeces-stained fleece in one experiment. Non-linear signal measurement techniques and linear discriminant analysis (LDA) were used to extract signal features and process those features for analysis of categorical separation of odour groups. The results from LDA indicated that the electronic nose accurately distinguished flystrike odour on days 1, 2 and 3 of development from that of dry wool in all experiments (P<0.05). The electronic nose was also able to discriminate flystrike odour on the day of larval implantation (day 0) in three of the four studies. In the experiment with urine- and faeces-stained wool, these odours were accurately distinguished from both dry wool and flystrike (P<0.05). This study provides proof-of-concept for the detection of flystrike using electronic nose technology. Practical methods for collection of odour in the field and suitable detection algorithms will be required for development to commercial application. PMID- 19781858 TI - Pyoderma gangrenosum in burns: a report of 3 cases and review of the literature. PMID- 19781860 TI - The opposing roles of estradiol on synaptic protein expression in hippocampal cultures. AB - Estrogen-induced synaptic plasticity was frequently shown by an increase of spines at apical dendrites of CA1 pyramidal neurons after systemic application of estradiol to ovariectomized rats. Surprisingly, exogenous application of estradiol to hippocampal cultures had no effect on spines and on spine synapses, although quantitative immunohistochemistry revealed an upregulation of spinophilin and of synaptophysin, in these cultures. The role of synaptophysin as a presynaptic marker and of spinophilin as a postsynaptic marker, appears questionable from these discrepancies. In contrast, synaptopodin, a marker protein of "mature" mushroom-shaped spines, was downregulated after treatment of hippocampal cultures with estradiol. Synaptopodin is strongly associated to the spine apparatus, a spine-specific cell organelle, which is present in 80% of all mushroom-shaped spines. Consistently, we found a reduction in the number of spines, containing a spine apparatus in response to estradiol, suggesting that the presence of a spine apparatus in many but not all spines is very likely a result of their dynamic character. In summary, synaptic proteins appear to be regulated by estradiol, independent of its function on spine and spine synapse formation. PMID- 19781859 TI - A microarray analysis of temporal gene expression profiles in thermally injured human skin. AB - Partial-thickness burns incite a multitude of responses which eventually culminate in cutaneous wound repair. We hypothesized that these events would evoke extensive alterations in gene expression thereby orchestrating the complexity of spatial and temporal events that characterize "normal" human wound healing. In the present study, gene expression from partial-thickness areas at defined temporal periods (1-3 days, 4-6 days, and 7-18 days) after injury were compared to normal non-wounded skin. Gene alterations proved extensive (2286 genes). Statistically significant alterations were noted among increased and decreased genes expressed in the three different temporal groupings. Our foundational data (based on samples from 45 individuals) provide a comprehensive molecular gene expression portrait of the cutaneous reparative responses that are initiated during the first 17 days after injury. Our efforts also represent an initial endeavor to move beyond the historically defined "morphological phases" of wound repair toward reporting molecular clues that define the temporal sequence of healing in human subjects. Further analysis of genes that are either affected or remain not affected following injury to normal skin is expected to identify potential targets for therapeutic augmentation or silencing. PMID- 19781861 TI - Sexual and injecting risk behaviours among regular ecstasy users. AB - Substance users may be at a heightened risk for the transmission of HIV and other blood-borne viral infections (BBVI) through injecting drug use or risky sexual behaviours. The current study aimed to investigate the engagement in BBVI-risk behaviours among a sentinel group of regular ecstasy users in Australia, with a particular focus on sexual practices and describe the occurrence of BBVI testing among this group. Participants were regular ecstasy users recruited across Australia in 2007 who were administered a structured interview that contained questions regarding substance use, sexual behaviours and occurrence of BBVI testing. Results indicate high levels of unprotected sex in the past 6 months (77% reported inconsistent condom use with a regular partner; 54% with a casual partner). Half the sample reported never having an HIV test. Unprotected sex was associated with being heterosexual; despite this, heterosexuals were also less likely to report HIV testing status. These data suggest that targeted health promotion messages may be needed for this group of predominantly young, heterosexual substance users who may fall out of the reach of traditional messages. PMID- 19781862 TI - Factors associated with initiation of ecstasy use among US adolescents: findings from a national survey. AB - AIMS: To investigate adolescent pathways to ecstasy use by (1) examining how early onsets of smoking, drinking, and marijuana use are related to a child's risk of initiation of ecstasy use and (2) assessing the influence of other individual and parental factors on ecstasy use initiation. METHODS: Data on 6426 adolescents (12-17 years old at baseline) from the National Survey of Parents and Youth (NSPY), a longitudinal, nationally representative household survey of youth and their parents, were used in the analyses. Information on youth substance use, including ecstasy use, as well as familial and parental characteristics, was available. RESULTS: Initiation of ecstasy use is predicted by an adolescent's early initiation of smoking, drinking, or marijuana use. In particular, early initiation either of marijuana use, or of both smoking and drinking, increases a child's risk for ecstasy use initiation. Among the familial and parental variables, parent drug use emerged as significantly predictive of child initiation of ecstasy use; living with both parents and close parental monitoring, on the other hand, are negatively associated with ecstasy use initiation, and may be protective against it. At the individual level, sensation seeking tendencies and positive attitudes towards substance use, as well as close associations with deviant peers, are predictive of adolescent initiation of ecstasy use. CONCLUSION: Our findings on the risk and protective factors for initiation of ecstasy use, especially with regard to factors that are modifiable, will be useful for prevention programs targeting youth use not only of ecstasy, but also of other drugs. PMID- 19781863 TI - Seeing the forest through the trees: a comparison of different IAT variants measuring implicit alcohol associations. AB - Dual-process models propose that addictive behaviors are determined by an implicit, impulsive system and an explicit, reflective system. Consistent with these models, research has demonstrated implicit affective associations with alcohol, using the Implicit Association Test (IAT), that predict unique variance in drinking behavior above explicit cognitions. However, different IAT versions have been used to measure implicit affective associations with alcohol, and the present study sought to determine which of these IAT variants showed the highest validity and internal consistencies. In total, 4800 participants completed one of six IAT versions via the Internet: a bipolar IAT (i.e., positive vs. negative), a unipolar positive IAT (i.e., positive vs. neutral), or a unipolar negative IAT (i.e., negative vs. neutral) with general positive and negative stimuli or with positive and negative alcohol-related affective states. While the alcohol-related affective bipolar and unipolar positive IAT versions and the general affective bipolar and unipolar positive IAT versions showed comparable internal consistencies, somewhat lower internal consistencies were found for the unipolar negative IAT versions. Further, alcohol-related affective IAT variants were more strongly related to explicit measures than general affective IAT versions. Also, alcohol-related and general affective bipolar and unipolar positive IAT variants were related to drinking behavior, but not unipolar negative IAT variants. Finally, the bipolar alcohol-related affective IAT, the unipolar alcohol-related positive IAT and the unipolar general positive IAT predicted drinking behavior above explicit measures. Overall, the bipolar alcohol-related affective IAT outperformed all other IAT variants with respect to its relationship with explicit measures and drinking behavior. PMID- 19781864 TI - Evidence for a deficit in the salience attribution to errors in smokers. AB - The persisting use of substances despite of adverse consequences is one of the hallmarks of addictive behaviors such as cigarette smoking. In the present study we used event-related potentials (ERPs) to investigate one aspect of adverse consequences: responses to errors in smokers versus non-smokers. The aim of this study was to determine whether cigarette smokers display error-processing deficits as measured using error-related negativity (ERN) and error positivity (Pe). ERPs during an Eriksen flanker task were recorded from smokers and a non smoking control group. Smokers showed the same ERN response as controls after making an error. However, the later Pe response was reduced as compared to the control group. On the behavioral level, we observed a trend towards increased error rates of smokers on incongruent trials. The present findings reveal that cigarette smoking is associated with reduced error processing. More specifically, while initial error processing seem intact, brain systems reflecting the motivational significance of a performance error seem compromised. It is argued that these cognitive deficits may cause or contribute to the persistence of smoking behavior and addictive behaviors in general. PMID- 19781866 TI - DNA adenine methylase is involved in the pathogenesis of Edwardsiella tarda. AB - Edwardsiella tarda is a serious aquaculture pathogen that can infect many cultured fish species. The aim of this study was to investigate the potential importance of DNA adenine methylase (Dam) in E. tarda pathogenesis. The E. tarda dam gene (dam(Et)) was cloned from a pathogenic strain, TXD1, isolated from diseased fish. Dam(Et) shares high (70.2%) sequence identity with the Dam proteins of Yersinia enterocolitica and several other bacterial species. Recombinant Dam(Et) is able to complement a dam-deficient Escherichia coli strain and methylate the genomic DNA. Attenuation of dam(Et) expression by antisense RNA interference had no apparent effect on the growth of TXD1, but caused significant attenuation of overall bacterial virulence and altered several stress responses including spontaneous mutation, recovering from UV radiation and H(2)O(2) exposure, binding to host mucus, and dissemination in host blood and liver. In addition, attenuation of dam(Et) expression increased luxS expression and AI-2 activities in E. tarda. These results indicate that Dam(Et) is a virulence determinant and plays a role in the pathogenesis of TXD1, and that temporal expression of dam(Et) is essential for optimal bacterial infection. PMID- 19781865 TI - Evaluation of modafinil effects on cardiovascular, subjective, and reinforcing effects of methamphetamine in methamphetamine-dependent volunteers. AB - Methamphetamine is a highly addictive stimulant and long-term exposure leads to reductions in dopamine. One therapeutic strategy is to develop and test compounds that normalize dopamine. The primary aim of this study was to determine the safety of modafinil treatment during methamphetamine exposure in a controlled clinical setting. Methamphetamine-dependent volunteers (N=13), who were not seeking treatment, were randomized to receive either modafinil (200mg, PO) or matching placebo over three days (Days 1-3 or Days 8-10). On Day 1, subjects were randomized to modafinil or placebo in the morning, and then 3 and 6h later received infusions of methamphetamine (0 and 30 mg, i.v.), after which cardiovascular and subjective effects were assessed. On Day 3, participants completed i.v. self-administration sessions during which they made 10 choices for low doses of methamphetamine (3mg, i.v.) or saline. Days 4-7 were used as a washout period. On Day 8 participants were assigned to the alternate study medication (placebo or modafinil), and the same testing procedures were repeated through Day 10. The data reveal that modafinil treatment was well-tolerated and not associated with increased incidence of adverse events. In general, modafinil reduced by approximately 25% ratings of methamphetamine-induced "Any Drug Effect", "High", and "Want Methamphetamine", and reduced total number of choices for methamphetamine and monetary value of methamphetamine, though none of these measures reached statistical significance. Given these encouraging, though non significant trends, the primary conclusion is that it appears safe to proceed with modafinil in further clinical evaluations of therapeutic efficacy. PMID- 19781867 TI - Influence of a phytosphingosine-containing chlorhexidine shampoo on superficial bacterial counts and bacterial adherence to canine keratinocytes. PMID- 19781868 TI - Secreted and immunogenic proteins produced by the honeybee bacterial pathogen, Paenibacillus larvae. AB - American Foulbrood is a severe disease affecting larvae of honeybee Apis mellifera, causing significant decrease in the honeybee population, beekeeping industries and agricultural production. In spite of its importance, little is known about the virulence factors secreted by Paenibacillus larvae during larval infection. The aim of the present work was to perform a first approach to the identification and characterization of P. larvae secretome. P. larvae secreted proteins were analyzed by SDS-PAGE and identified by MALDI-TOF. Protein toxicity was evaluated using an experimental model based on feeding of A. mellifera larvae and immunogenicity was evaluated by Western blot, using an antiserum raised against cells and spores of P. larvae. Ten different proteins were identified among P. larvae secreted proteins, including proteins involved in transcription, metabolism, translation, cell envelope, transport, protein folding, degradation of polysaccharides and motility. Although most of these proteins are cytosolic, many of them have been previously detected in the extracellular medium of different Bacillus spp. cultures and have been related to virulence. The secreted proteins resulted highly toxic and immunogenic when larvae were exposed using an experimental model. This is the first description of proteins secreted by the honeybee pathogen P. larvae. This information may be relevant for the elucidation of bacterial pathogenesis mechanisms. PMID- 19781869 TI - Antigenic and genetic characterisation of border disease viruses isolated from UK cattle. AB - Available empirical data on the natural occurrence of ruminant pestiviruses has shown that in cattle, bovine viral diarrhoea virus (BVDV) is nearly exclusively found, whereas both border disease virus (BDV) and BVDV can be isolated from sheep. During routine genetic typing of pestivirus RNA from UK cattle diagnosed as BVDV positive between 2006 and 2008, five samples that were classified as BDV positive yielded positive virus isolates in cell cultures. The samples originated from animals that had shown signs typical for BVD. Phylogenetic analysis of the bovine BDVs showed that two belonged to the BDV-1a group and three to the BDV-1b group, thereby matching the genetic diversity seen for previously described UK ovine BDVs. Antigenic typing with a set of monoclonal antibodies (MABs) showed that all bovine BDVs lacked one or more epitopes conserved among ovine BDV-1 isolates, and that they had gained reactivity with at least one BVDV-1 specific MAB. Serial passaging of two of the virus isolates in ovine cell cultures did not change the epitope expression pattern. These findings suggest that the presumed natural resistance of cattle against infection with BDV no longer holds. A consequence of this is that BVD diagnostic assays should be checked for their ability to also detect BDV, and also highlights the need for monitoring of the BDV status in sheep that may be in contact with cattle in areas with organised BVD control programmes. PMID- 19781870 TI - Fusobacterium necrophorum variants present on the hooves of lame pigs. PMID- 19781871 TI - Bid cleavage, cytochrome c release and caspase activation in canine coronavirus induced apoptosis. AB - A previous study demonstrated that infection of a canine fibrosarcoma cell line (A-72 cells) by canine coronavirus (CCoV) resulted in apoptosis (Ruggieri et al., 2007). In this study, we investigated the cell death processes during infection and the underlying mechanisms. We found that CCoV-II triggers apoptosis in A-72 cells by activating initiator (caspase-8 and -9) and executioner (caspase-3 and 6) caspases. The proteolytic cleavage of poly(ADP-ribose) polymerases (PARPs) confirmed the activation of executioner caspases. Furthermore, CCoV-II infection resulted in truncated bid (tbid) translocation from the cytosolic to the mitochondrial fraction, the cytochrome c release from mitochondria, and alterations in the pro- and anti-apoptotic proteins of bcl-2 family. Our data indicated that, in this experimental model, both intrinsic and extrinsic pathways are involved. In addition, we demonstrated that the inhibition of apoptosis by caspase inhibitors did not affect CCoV replication, suggesting that apoptosis does not play a role in facilitating viral release. PMID- 19781872 TI - Zoonotic aspects of rotaviruses. AB - Rotaviruses are important enteric pathogens of humans and animals. Group A rotaviruses (GARVs) account for up to 1 million children deaths each year, chiefly in developing countries and human vaccines are now available in many countries. Rotavirus-associated enteritis is a major problem in livestock animals, notably in young calves and piglets. Early in the epidemiological GARV studies in humans, either sporadic cases or epidemics by atypical, animal-like GARV strains were described. Complete genome sequencing of human and animal GARV strains has revealed a striking genetic heterogeneity in the 11 double stranded RNA segments across different rotavirus strains and has provided evidence for frequent intersections between the evolution of human and animal rotaviruses, as a result of multiple, repeated events of interspecies transmission and subsequent adaptation. PMID- 19781873 TI - Effective communication in difficult situations: preventing stress and burnout in the NICU. AB - Stress and burnout, the human side of the health service and the quality of care, are touchy subjects experienced on an everyday basis. Caregivers in the health systems are constantly called upon to handle feelings and "strong emotions", both their own and those of others: rage, impatience, frustration, helplessness, fear and so on. Frustration and conflicts between oneself and others are a frequent event, and may undermine the professional skills of each health professional. This article summarises problems, skills and situations where caregivers, patients, family face the difficulty to communicate. The aim is to provide an overview in this area and to suggest possible tools to overcome the daily difficulties. PMID- 19781874 TI - Probiotics and prevention of necrotizing enterocolitis. AB - Necrotizing enterocolitis (NEC) is a devastating disease affecting primarily premature infants. Despite advances in neonatal care, the mortality rate following NEC has not changed significantly in the past 30 years. New preventative measures are needed. In this review, we will provide information to assess the possible role of probiotics, prebiotics and related agents in the prevention of this devastating disease. We will also discuss short and long term safety issues as well as potential alternatives. Although it is tempting to rebuild the intestinal microbiota using the agents such as pro and prebiotics during infancy, routine use is not yet warranted a cautious approach on the basis of sounds scientific data is needed. PMID- 19781875 TI - Dydrogesterone--a unique progestogen. PMID- 19781876 TI - Suspected black cohosh hepatotoxicity--causality assessment versus safety signal. PMID- 19781877 TI - When, why and for whom there is a relationship between physical activity and menopause symptoms. AB - OBJECTIVES: The relationship between enhanced physical activity and decreased menopause symptoms is equivocal. In this study we sought to better understand this relationship by examining the association of physical activity to different symptom domains and by examining mediating and moderating variables. STUDY DESIGN: Women participating in a randomized control trial on physical activity were given a menopause symptom measure (MENQOL) at follow-up. Of the 280 women participating, 113 (mean age=52) reported having symptoms they attributed to menopause. Regression analyses were run to examine if change in physical activity predicted fewer symptoms. Exercise self-efficacy was examined as a mediator and depressive symptoms as a moderator. RESULTS: An increase in physical activity from baseline was found to be related to reporting fewer total menopause symptoms (beta=-0.22, p=.02). When the total menopause symptoms score was examined by domain, increased physical activity was found to be related to reporting fewer general symptoms attributed to menopause (psychosocial (beta=-0.18, p=.05) and physical (beta=-0.23, p=.01)), but had no effect on specific symptoms of menopause (vasomotor and sexual). Exercise self-efficacy was found to mediate the relationship between increased physical activity and total, physical and psychosocial menopause symptoms. Finally, for individuals with high depressive symptoms, those who increased physical activity the most reported fewer sexual symptoms of menopause. CONCLUSION: This study suggests that physical activity participation is associated with lower general symptom reporting as opposed to specifically impacting menopause symptoms. Further, exercise self-efficacy mediates the relationship between physical activity and general menopause symptoms, suggesting a psychological pathway. PMID- 19781878 TI - Depressed mood but not fatigue mediate the relationship between physical activity and perceived stress in middle-aged women. AB - OBJECTIVE: To determine whether depressed mood and fatigue mediate the relationships between physical activity, body mass index, menopausal hot flashes, and perceived stress. METHOD: This study is a secondary analysis of data obtained from a sub-sample of peri- and postmenopausal women (N=212) from the TREMIN Research Program on Women's Health. RESULTS: The hypothesized mediational model was tested using path analysis within a structural equation modeling framework in Mplus Version 5.1. In unadjusted analysis, the relationships between physical activity, menopausal hot flashes, and perceived stress were mediated by depressed mood; fatigue mediated the relationships between hot flashes, body mass index, and perceived stress. When adjusting for age, insomnia, menopausal and hormone use status, the mediational effects of depressed mood on stress remained significant only for physical activity, and fatigue mediated the relationship between hot flashes and stress. The adjusted model explained 70% of variance in perceived stress, 82% of variance in depressed mood, and 81% of variance in fatigue. CONCLUSION: Depressed mood may partially explain the relationship between physical activity and perceived stress in middle-aged women, however further studies are needed to corroborate causality. PMID- 19781879 TI - Facial soft tissue thickness of Brazilian adults. AB - The auxiliary technique known as Facial Reconstruction enables one to reestablish the contours of the soft tissues over the skull, therefore producing a face and increasing the probability of a facial recognition. The reliability of this technique depends on the evaluation of the mean values of soft tissue thicknesses observed in a given population. Measurements were evaluated in autopsied corpses in "Section of Technical Verification of Deaths" in Guarulhos, Sao Paulo, Brazil. Thickness was measured manually by puncturing 10 midline craniometrical points and 11 bilateral points on a sample of 40 corpses of both sexes aged between 17 and 90 years, classified by skin color and the nutritional state. The results for the average thickness values are higher for males, variations related to the nutritional state are proportional to the increased fat on the face and age was not significant. The ethnic variable related to skin color when compared to studies with other populations showed differences, with the need for a reference table for a given population application of Facial Reconstruction technique in skulls of non-attributable identity. PMID- 19781880 TI - Efficiency evaluation of a DNA extraction and purification protocol on archival formalin-fixed and paraffin-embedded tissue. AB - Formalin-fixed and paraffin-embedded tissue (FF-PET) is an invaluable resource for retrospective molecular genetic studies, but the extraction of high-quality genomic DNA from FF-PET is still a problematic issue. Despite the range of DNA extraction methods currently in use, the association of phenol-chloroform extraction and silica-based purification protocols, reported in ancient DNA studies on archaeological bones, has, to our knowledge, not been used for DNA extraction from FF-PET yet. The present study compared the efficiency of three DNA extraction and purification protocols from two different FF-PET substrates, heart and liver, by using quantitative PCR and multiplex amplification. We showed that the method, using phenol-chloroform and the QIAamp DNA mini Kit (Qiagen), was the most effective DNA extraction and purification method and that the DNA quantity extracted from liver is statistically more important than that extracted from heart. Autosomal STR typing by multiplex amplifications gave partial allelic profiles with only small size products (less than 300 bases) amplified, suggesting that DNA extracted from FF-PET was degraded. In conclusion, the protocol presented here, previously described in studies on ancient bones, should find application in different molecular studies involving FF-PET material. PMID- 19781881 TI - [Posterior reversible encephalopathy related to tacrolimus in a liver transplanted HIV patient]. AB - Tacrolimus-related posterior reversible leukoencephalopathy (PRLE) is a rare complication which should be recognized by clinicians who regularly use immunosuppressive therapy. We report the case of an HIV-positive, hepatitis C positive liver transplant patient who presented with this complication. Immunosuppression with tacrolimus was started after postsurgery. On the 20th day, the patient suffered two tonic-clonic convulsive attacks against a background of hypertension. Cerebral magnetic resonance imaging and lumbar puncture led to diagnosis of tacrolimus-related PRLE after eliminating other possible diagnoses. Therapeutic management consisted of withdrawing tacrolimus and initiating treatment with antiepileptogenic and antihypertensive drugs, supplemented with magnesium sulphate. The symptoms regressed in the days following withdrawal of tacrolimus and the majority of lesions on magnetic resonance imaging disappeared within two weeks. The aim of which should be to identify patients at risk of developing this complication. This would enable targeted prevention involving magnesium supplementation, strict control of blood pressure and serial monitoring of tacrolimus blood concentrations. PMID- 19781883 TI - Imaging of cholangiolocellular carcinoma of the liver. AB - AIM: Cholangiolocellular carcinoma (CoCC) is currently considered to originate from hepatic progenitor cells. The purpose of this study was to evaluate the imaging features of cholangiolocellular carcinoma of the liver. MATERIALS AND METHODS: Five cases of surgically resected cases of CoCC from 4 institutions were retrospectively evaluated. All of the five patients underwent contrast-enhanced dynamic CT. MRI and angio-CT including CT during arterioportography (CTAP) and CT during hepatic arteriography were performed in 3 and 2 patients, respectively. Histological evaluation was also performed and was correlated with radiographic findings. RESULTS: On dynamic CT or MRI, the lesions presented hypervascular tumors with delayed washout in 2 cases and in the other 3 cases, the lesions showed peripheral enhancement with concentric delayed filling. On CTAP, the continued existence of portal veins or tiny spots of portal flow was identified in the tumors. Fibrous capsule or tumor necrosis was not observed. CONCLUSION: CoCC tumors have the dual imaging characteristics of hepatocellular carcinoma and cholangiocarcinoma. The absence of a fibrous capsule, the absence of tumor necrosis, peripheral location within the liver, and the presence of portal venous penetration within the tumor also appear to be characteristic features. PMID- 19781882 TI - Small colorectal liver metastases: detection with SPIO-enhanced MRI in comparison with gadobenate dimeglumine-enhanced MRI and CT imaging. AB - The aim of this prospective study was to compare the diagnostic role of superparamagnetic iron oxide (SPIO)-enhanced liver magnetic resonance imaging (MRI) versus gadobenate dimeglumine (GbD)-enhanced MRI and computed tomography (CT) investigations for detection of small (less than 1cm) colorectal liver metastases (LMs) of colorectal cancer. Seventy-eight LMs in 16 patients were evaluated with dynamic CT imaging, GbD-enhanced dynamic MR imaging and SPIO enhanced MR imaging. Two radiologists were reviewed the LMs separately. Agreement between the readers and three algorithms was analyzed. Differences between the lesion detection ratios of the methods were analyzed by two proportion z test. Sensitivity values of each modality were also calculated. Interobserver agreement values with kappa analysis were found to be the best for three modalities and kappa values were 0.866, 0.843, and 1.0 respectively. For all 78 LMs, SPIO enhanced MRI detected all lesions (100% sensitivity). This sensitivity value was higher than GbD-enhanced MRI, and there was a significant difference (p < 0.05). GbD-enhanced MRI depicted 71 lesions and this modality could not detected 7 lesions (91% sensitivity). This modality had moderate sensitivity, and this value is greater than CT imaging, so there was a significant difference also (p < 0.05). Dynamic triphasic CT imaging detected 64 (R1) and 65 (R2) LMs. This modality had the lowest sensitivity (R1: 0.82, R2: 0.83 respectively). Only SPIO enhanced MRI was able to detect all LMs less than 1cm. LMs were the best detected with SPIO-enhanced MRI. We recommend SPIO-enhanced MRI to be the primary alternative modality especially for diagnosis of small colorectal LMs. PMID- 19781884 TI - Whole-body MRI of neuroblastoma. AB - Whole-body MRI (WBMRI) is an emerging imaging method that has a great potential in pediatric oncologic imaging. It appears useful in staging and monitoring neuroblastoma although its clinical impact has not been thoroughly evaluated. Among various imaging techniques currently available for WBMRI, coronal and sagittal STIR imaging with a quadrature body coil at 1.5T MR system is recommended for a standard protocol. Nevertheless, further technical improvements are anticipated at 3.0T MR system and multi-channel surface coil system. Scan time of WBMRI is reasonably short ranging from 20 min to 60 min. In localized neuroblastoma, WBMRI may help in predicting surgical risks by evaluating image defined risk factors accurately. In addition, WBMRI is quite useful in detecting distant metastasis, assessing initial treatment responses, and identifying tumor recurrence of neuroblastoma. We should understand limitations of WBMRI in the evaluation of lymph node involvement, in the differentiation between viable tumor and non-viable residual lesion, and in the detection of calcified lesion. Diffusion-weighted imaging may improve diagnostic accuracy of WBMRI. Complementary use of WBMRI and other metabolic imaging method such as MIBG scintigraphy or PET probably increases diagnostic accuracy and, subsequently, improves clinical outcome of children with neuroblastoma. PMID- 19781885 TI - CT virtual intravascular endoscopy assessment of coronary artery plaques: a preliminary study. AB - PURPOSE: The purpose of this study was to investigate the potential value of CT virtual intravascular endoscopy (VIE) in the visualization and assessment of coronary plaques in patients suspected of coronary artery disease. MATERIALS AND METHODS: 20 (13 men, 7 women, mean age 54 years) consecutive patients with suspected coronary artery disease undergoing 64-slice CT angiography were included in the study. Four main coronary artery branches were assessed with regard to the presence of coronary plaques based on 2D axial, multiplanar reformation, 3D volume rendering and VIE visualizations. The coronary plaques were characterized into calcified, noncalcified and mixed plaques. The intraluminal appearances of these coronary plaques were demonstrated with VIE images and correlated with 2D and 3D images to determine the diagnostic value of VIE for the assessment of the plaques. RESULTS: VIE was able to identify and demonstrate the intraluminal appearances of coronary plaques in 18 patients involving 32 coronary artery branches which were shown as an irregularly intraluminal protruding sign in extensively calcified plaques and smooth protruding appearance in noncalcified or focally calcified plaques. An irregular intraluminal appearance was also noticed in the presence of mixed plaques due to variable components with different CT attenuations contained within the plaques. VIE accurately confirmed the degree of coronary stenosis or occlusion despite the presence of heavy calcification. CONCLUSION: VIE could be used as a complementary tool to conventional CT visualizations for the analysis of luminal changes and assessment of disease extent caused by the coronary plaques. PMID- 19781886 TI - The role of ultrasound imaging in the evaluation of peripheral nerve in systemic sclerosis (scleroderma). AB - BACKGROUND: Patients affected by scleroderma may complain of sensory disturbances especially in the hands. PURPOSE: To study the imaging features of upper limb nerves in patients affected by scleroderma (SSc). MATERIALS AND METHOD: Twenty five patients affected only by SSc were prospectively evaluated with high resolution US and magnetic resonance (MRI) or computer tomography (CT) when necessary (2 patients). Median and ulnar nerves were evaluated bilaterally. Nerve conduction studies were performed in the symptomatic patients (n = 10). Results of imaging studies were correlated with disease duration, autoimmunity and immunosuppression. Nerves of SSc patients were compared with a control group of 90 patients matched for age and body mass index. RESULTS: The prevalence of sensory disturbances revealed by clinical examination was 40%. In symptomatic SSc patients (n = 10) US evaluation revealed nerve abnormalities in 70% of cases (n = 7/10). n = 2 had a carpal tunnel syndrome. n = 5 had cubital tunnel syndrome. In two of them CT and MR were necessary to identify the compressed nerve at the level of the elbow due to the presence of calcifications. There was no association between the presence of an entrapment neuropathy and disease duration, autoantibodies and immunosuppression. CONCLUSION: Ultrasound, CT and MR may detect nerve abnormalities in 70% of SSc patients complaining of neurologic disturbances in the hands. The results of imaging studies support the hypothesis of a vascular dependent neuropathy in SSc. PMID- 19781887 TI - Time-resolved contrast-enhanced coronary magnetic resonance angiography with highly constrained projection reconstruction. AB - Contrast-enhanced magnetic resonance angiography (MRA) is a promising technique for coronary artery imaging. The blood signal changes during the contrast injection will result in image artifacts, blurring and relatively low signal-to noise ratio, when the k-space segments from different cardiac cycles are combined to reconstruct the final image as "time averaged." Thus, it is important to acquire data during maximal blood signal enhancement for first-pass, contrast enhanced MRA, and relatively high temporal resolution is required. This work demonstrated the feasibility of highly constrained backprojection reconstruction for time-resolved, contrast-enhanced coronary MRA. With this method, the temporal resolution can be increased. In addition, coronary artery images around blood signal enhancement peak have significantly improved contrast-to-noise ratio and suppressed artifacts compared to the composite images which were collected during a much longer acquisition time during substantial blood signal changes. PMID- 19781888 TI - A rapid, 2-well, multiplex real-time polymerase chain reaction assay for the detection of SCCmec types I to V in methicillin-resistant Staphylococcus aureus. AB - For us to assess the spread of methicillin-resistant Staphylococcus aureus (MRSA), typing of the staphylococcal cassette chromosome mec (SCCmec) is a valuable addition to existing typing methods, such as multilocus sequence typing (MLST). Traditional SCCmec typing assays, that is, that of Oliveira et al. and Ito et al., are polymerase chain reaction (PCR) based, requiring electrophoresis. We introduce a rapid, 2-well, multiplex real-time PCR assay that can be used directly on bacterial suspensions and is able to characterize SCCmec type I to V based on the detection of the ccr genes and the mec complex. The assay was evaluated on 212 clinical MRSA isolates from various countries, associated with MLST clonal complexes (CC) 1, 5, 8, 22, 30, and 45, as well as pig-associated CC398. When comparing the real-time PCR assay with traditional methods, the correct SCCmec element was identified in 209 (99%) of the 212 MRSA isolates. The new assay enables high-throughput analyses for SCCmec on large strain collections. PMID- 19781889 TI - Effects of a cognitive behavioral self-help program and a computerized structured writing intervention on depressed mood for HIV-infected people: a pilot randomized controlled trial. AB - OBJECTIVE: The aim of the present study was to examine whether low-resource, cost effective intervention programs can be effective in improving depressed mood in people with HIV. The efficacy of a cognitive-behavioral self-help program (CBS) and a computerized structured writing intervention (SWI) were tested in a pilot randomized controlled trial. METHODS: Participants were members of a patient organization. They completed a pretest and posttest. The questionnaire included the HADS. Participants were randomly allocated to CBS (n=24), SWI (n=25) or a waiting list condition (WLC, n=24). To evaluate changes in the continuous outcome measure, a 3 x 2 (group x time) repeated measures ANCOVA was performed. Also, an ANCOVA was performed using change scores. RESULTS: Respondents who followed the CBS improved significantly compared to the WLC. However, for people in the SWI condition no significant improvement on depression was found. CONCLUSION: This pilot study suggests that a low-resource, cost-effective CBS program seems to be effective in reducing depressed mood in people living with HIV. PRACTICE IMPLICATIONS: Because self-help programs can be delivered through regular mail or the internet, a high number of people could be reached while overcoming geographical and social barriers to treatment. PMID- 19781890 TI - Oral glucose leads to a differential response in glucose, insulin, and GLP-1 in lean versus obese cats. AB - The response to oral glucose was examined in 10 obese and 9 lean age-matched, neutered cats. In all cats, oral administration of 2g/kg glucose was followed by a prompt increase in glucose, insulin, and glucagon-like peptide (GLP)-1. There were significant differences between lean and obese cats in the areas under the curve for glucose, insulin, and GLP-1. However, the responses were variable, and a clear distinction between individual lean and obese cats was not possible. Therefore, this test cannot be recommended as a routine test to examine insulin resistance in individual cats as it is used in people. A further disadvantage for routine use is also the fact that this test requires gastric tubing for the correct administration of the glucose and associated tranquilization to minimize stress and that it was associated with development of diarrhea in 25% of the cats. GLP-1 concentrations were much lower in obese than lean cats. The low GLP-1 concentrations in obese cats might indicate a contribution of GLP-1 to the lower insulin sensitivity of obese cats, but this hypothesis needs to be further investigated. PMID- 19781891 TI - [Does anesthesia affect cerebral development]. AB - Several experimental studies have demonstrated the adverse effects of anesthetic agents on the developing brain. Most of these agents appear to induce apoptosis of immature neurons and could interfere with the development of dendritic arborization. Extrapolation of experimental data to clinical settings is uncertain because of the pharmacokinetic and pharmacodynamic differences between the diverse species. No prospective clinical studies deal with this question. Several recent epidemiologic studies nonetheless suggest a potential association between anesthesia and long-term damage to cognitive functions. In studying the potential effect of general anesthetics on the immature human brain, it is difficult to separate the effects of anesthesia from the effects of the surgery. Several prospective studies are currently underway to elucidate this important question. PMID- 19781892 TI - [PPS killed me]. PMID- 19781893 TI - [Use of rapid diagnostic tests of tonsillitis in medical practice. Survey conducted from November 2006 to January 2007 in Pays de la Loire (France)]. AB - INTRODUCTION: The use of the rapid diagnostic test (RDT) and the strategy of management of pharyngitis in medical practice are little known. METHODS: During the 2006-2007 winter, a survey was conducted in the Pays de la Loire Region to evaluate the use of the RDT. A focus group was also organised. RESULTS: Data were collected from 525 patients (patients who were consulting for a sore throat, angina or patients for whom a RDT was made). RDT were performed on 245 patients (46%). The sixty positive RDT patients systematically received an antibiotic. Twenty negative RDT patients received an antibiotic. More than 75% of GPs considered the RDT useful or very useful. DISCUSSION: The guidelines for the management of pharyngitis are known but they are partially followed by physicians. Many countries have national guidelines for the management of tonsillitis and they are also not unanimous. When patients had pharyngitis symptoms, the frequency of antibiotic prescription was lower when the RDT was used as recommended by the French Medicines Agency (AFSSAPS). The treatment must be short in order to improve the compliance of outpatients and reduce the inappropriate use of antibiotics. CONCLUSION: A decrease in antibiotics prescription was recorded in the community. It was attributed to the availability of the RDT provided by the CNAMTS (French National Health Service). Moreover, the RDT are still free for practitioners and their reimbursement could be extended to hospital. PMID- 19781894 TI - Practice variability in the assessment and treatment of critical illness-related corticosteroid insufficiency. AB - PURPOSE: Little is known about how published evidence regarding use of steroids in septic shock has been incorporated into clinical practice. MATERIALS AND METHODS: All patients admitted to an intensive care unit at a single, tertiary care, academic medical center from November 1, 2004, through February 28, 2005, were screened using the hospital's computerized pharmacy database to determine if they had received at least 1 qualifying medication: cosyntropin, fludrocortisone, hydrocortisone, or dopamine, epinephrine, or norepinephrine as a vasopressor infusion. RESULTS: Only 58% (95% confidence interval, 47%-69%) of the 81 patients who met criteria for vasopressor-dependent septic shock (VDSS) were evaluated for critical illness-related corticosteroid insufficiency. Forty-seven percent of the 81 patients who met the criteria for VDSS and 49% of the 47 patients who did not meet the criteria for VDSS were treated with corticosteroids. Nearly all (85%; 95% confidence interval, 72%-94%) patients who did not meet the criteria for VDSS received an adrenocorticotropic hormone test. CONCLUSIONS: Treatment and evaluation of critical illness-related corticosteroid insufficiency in critically ill patients at our institution are inconsistent. Many patients with VDSS do not receive either treatment or evaluation for critical illness-related corticosteroid insufficiency, and patients who do not meet the current criteria are being evaluated and/or treated for critical illness-related corticosteroid insufficiency. PMID- 19781895 TI - Acetaminophen has limited antipyretic activity in critically ill patients. AB - PURPOSE: Fever occurs commonly in the critically ill patients and may adversely affect outcome. Acetaminophen is one of the most commonly used antipyretic agents in the intensive care unit; however, there is little evidence that it is effective in this population. The objective of this study was to analyze the antipyretic activity of acetaminophen in critically ill patients. MATERIALS AND METHODS: We performed a retrospective study of medical intensive care unit and surgical intensive care unit patients with systemic inflammatory response syndrome and compared the resolution of fever in the presence and absence of acetaminophen treatment by comparing the absolute reduction in body temperature and the rate of cooling over comparable time frames in fevers that were untreated and those treated with acetaminophen. RESULTS: We analyzed 166 febrile episodes (body temperature, >38 degrees C) in 59 patients with systemic inflammatory response syndrome without cancer, neurologic disease, or liver disease. Acetaminophen was administered for 88 of 166 fevers. Febrile episodes in which other antipyretic drugs or external cooling were administered were excluded. The response to acetaminophen was variable, but the absolute temperature reduction was slightly higher (mean, 0.86 versus 0.56 degrees C; P = .0362), and the cooling rate was slightly more rapid (mean, 0.20 versus 0.13 degrees C per hour; P = .0152) in acetaminophen-treated versus untreated fevers. There were no obvious differences between the most and least responsive patients. CONCLUSIONS: We conclude that acetaminophen has significant albeit modest antipyretic activity in critically ill patients. PMID- 19781896 TI - High-flow nasal oxygen vs high-flow face mask: a randomized crossover trial in extubated patients. AB - PURPOSE: Oxygen delivery after extubation is critical to maintain adequate oxygenation and to avoid reintubation. The delivery of oxygen in such situations is usually by high-flow face mask (HFFM). Yet, this may be uncomfortable for some patients. A recent advance in oxygen delivery technology is high-flow nasal prongs (HFNP). There are no randomized trials comparing these 2 modes. METHODS: Patients were randomized to either protocol A (n = 25; HFFM followed by HFNP) or protocol B (n = 25; HFNP followed by HFFM) after a stabilization period of 30 minutes after extubation. The primary objective was to compare the efficacy of HFNP to HFFM in maintaining gas exchange as measured by arterial blood gas. Secondary objective was to compare the relative effects on heart rate, blood pressure, respiratory rate, comfort, and tolerance. RESULTS: Patients in both protocols were comparable in terms of age, demographic, and physiologic variables including arterial blood gas, blood pressure, heart rate, respiratory rate, Glasgow Coma Score, sedation, and Acute Physiology and Chronic Health Evaluation (APACHE) III scores. There was no significant difference in gas exchange, respiratory rate, or hemodynamics. There was a significant difference (P = .01) in tolerance, with nasal prongs being well tolerated. There was a trend (P = .09) toward better patient comfort with HFNP. CONCLUSIONS: High-flow nasal prongs are as effective as HFFM in delivering oxygen to extubated patients who require high flow oxygen. The tolerance of HFNP was significantly better than in HFFM. PMID- 19781897 TI - Best interests at end of life: a review of decisions made by the Consent and Capacity Board of Ontario. AB - PURPOSE: When patients are unable to communicate their own wishes, surrogates are commonly used to aid in decision making. Although each jurisdiction has its own rules or legislation governing how surrogates are to make health care decisions, many rely on the notion of "best interests" when no prior expressed wishes are known. METHODS: We purposively sampled written decisions of the Ontario Consent and Capacity Board that focused on the best interests of patients at the end of life. Interpretive content analysis was performed independently by 2 reviewers, and themes that were identified by consensus as describing best interests were construed, as well as the characteristics of an end-of-life dispute that may be most appropriately handled by an application to the Consent and Capacity Board. RESULTS: We found that many substitute decision makers rely on an appeal to religion or God in their interpretation of best interests, whereas physicians focused narrowly on the clinical condition of the patient in their interpretations. CONCLUSIONS: Several lessons are drawn for the benefit of health care teams engaged in end-of-life conflicts with substitute decision makers over the best interests of patients. PMID- 19781898 TI - Etiology of troponin elevation in critically ill patients. AB - PURPOSE: The aim of this study was to assess the etiology of cardiac troponin elevation among patients admitted to the intensive care unit (ICU) and to examine whether etiology affects mortality and length of stay. METHODS: All patients admitted over 2 months underwent screening with troponin measurements and were included if 1 or more measurements were elevated. Two adjudicators retrospectively reviewed patient charts to determine the likely cause of troponin elevation. RESULTS: Of 103 patient admissions, 52 (50.5%) had 1 or more elevated troponin measurements, and 49 (94.2%) had medical charts available for review. Troponin elevation was adjudicated as myocardial infarction (MI) in 53.1% of patients, sepsis in 18.4%, renal failure in 12.2%, and other causes in 16.3%. Overall ICU mortality was 16.0%; 2.0% for patients with no troponin elevation, 23.1% in patients with MI, and 39.1% in patients with troponin elevation not due to MI. Having an elevated troponin level not due to MI was significantly associated with increased hospital mortality compared with having no troponin elevation. CONCLUSIONS: The most common cause of troponin elevation among critically ill patients was MI. Patients with elevated troponin had worse outcomes compared with patients without troponin elevation, and troponin elevation not due to MI was predictive of increased hospital mortality. PMID- 19781899 TI - Safer glycemic control using isomaltulose-based enteral formula: a pilot randomized crossover trial. AB - PURPOSE: Preventing harmful hyperglycemia is important in critical illness. However, insulin therapy increases the risk of hypoglycemia. In patients with diabetes, isomaltulose-based enteral formula (IF) feeding has been shown to reduce glycemia. This randomized controlled crossover study was conducted to determine whether IF feeding improves glycemia in postoperative critically ill patients. MATERIAL AND METHODS: Eight patients who developed hyperglycemia (>150 mg/dL) after esophagectomy were included. Patients were randomized to either the IF or the standard feeding formula (SF) arm. After 16 hours of administration of randomized formula and 8 hours of washout, patients crossed over to the other formula for the next 16 hours. Continuous glucose measurement using STG-22 (Nikkiso, Tokyo, Japan) was performed during the trial. RESULTS: Maximum blood glucose concentration was 181 mg/dL with IF, significantly lower than the 206 mg/dL with SF (P = .001). Mean glycemia during feeding periods was 162 mg/dL with IF, significantly lower than the 176 mg/dL with SF (P = .0001). Seven (87.5%) patients taking SF exceeded 180 mg/dL compared with 3 (37.5%) patients taking IF (P = .005). This effect was seen without any risk of hypoglycemia and complication. CONCLUSIONS: Isomaltulose-based enteral formula might be useful for safer glycemic control in postoperative critically ill patients. Further study to determine clinical benefit of IF feeding is justified. PMID- 19781901 TI - Whole-body ultrasound in the intensive care unit: a new role for an aged technique. AB - Management of critically ill patients requires rapid and safe diagnostic techniques. Ultrasonography has become an indispensable tool that supplements physical examination in the intensive care unit. It enables early recognition of neurological emergencies, assists the diagnosis of abdominal and lung pathologies, and provides real-time information on the cardiac performance of critically ill patients. Furthermore, it detects possible infectious sites and renders therapeutic invasive procedures more convenient and less complicated. Whole-body ultrasound in the hands of adequately trained intensivists has the ability to reinvigorate the physical examination, without subjecting the patient to excessive irradiation and the risks of transport. PMID- 19781900 TI - Plasma neutrophil gelatinase-associated lipocalin is an early marker of acute kidney injury in adult critically ill patients: a prospective study. AB - PURPOSE: The aim of the study was to assess the ability of plasma neutrophil gelatinase-associated lipocalin (pNGAL) to predict acute kidney injury (AKI) in adult intensive care unit (ICU) patients. METHODS: All consecutives patients admitted to 3 ICUs were enrolled in this prospective-observational study. Plasma neutrophil gelatinase-associated lipocalin was analyzed at ICU admission. Risk, injury, failure, loss, and end-stage kidney (RIFLE) criteria were calculated at admission and for each day during the first week. Patients were classified according to whether they met the threshold for RIFLE criteria (RIFLE 0 or 1) at admission and during the first week. Four groups were identified: RIFLE (0-0), (1 1), (1-0), and (0-1). RESULTS: During this 1-month period, 88 patients were included in the study. Thirty-six patients met the criteria for RIFLE 0-0 with a mean pNGAL of 98 +/- 60 nmol/L, 22 for RIFLE 1-1 with a mean pNGAL of 516 +/- 221 nmol/L, and 20 patients had no AKI at admission but develop AKI at 48 hours (24 96 hours) (RIFLE 0-1) with a pNGAL of 342 +/- 183 nmol/L. Ten patients met the criteria for RIFLE 1-0 and had a mean pNGAL of 169 +/- 100 nmol/L. Using a cutoff of 155 nmol/L, sensitivity and specificity to predict AKI were 82% and 97%, respectively (area under the curve [AUC] = 0.92 [0.852-0.972]; P = .001). Looking at the patients without AKI at admission (n = 56) and who developed (n = 20) or did not develop (n = 36) AKI, receiver operating characteristic curve analysis was as follows: AUC = 0.956 (0.864-0.992). Sensitivity was 85% and specificity was 97%. Of the 7 patients who required renal replacement therapy, all of them had pNGAL of more than 303 nmol/L (AUC = 0.788 [0.687-0.868]). CONCLUSION: Plasma neutrophil gelatinase-associated lipocalin at ICU admission is an early biomarker of AKI in adult ICU patients. Plasma neutrophil gelatinase-associated lipocalin increased 48 hours before RIFLE criteria. PMID- 19781903 TI - Delirium in patients admitted to a step-down unit: analysis of incidence and risk factors. AB - BACKGROUND: Delirium is a rather common complication among patients admitted in intensive care units (ICUs), and rather than a single entity, it can be considered a spectrum of diseases where, besides overt cases, there are also many subsyndromal forms. Although there are many data about ICU delirium, there are few data concerning this complication in patients transferred from the ICU to a step-down unit (SDU) once clinically stable. OBJECTIVES: With the present study, we wanted to assess the incidence of and risk factors for delirium and subsyndromal forms and their impact on clinical outcome in a group of patients transferred from an ICU to an SDU. METHODS: All patients transferred from an ICU to our SDU over a 2-year period were screened for delirium and subsyndromal delirious forms using the Intensive Care Delirium Screening Checklist, a simple tool already validated in the ICU. The following data were also recorded: demographic data, severity score (SAPS II), reason for admission to the SDU, length of stay, death rate, use of sedatives, impact of delirium on weaning from mechanical ventilation (MV). RESULTS: Among the 234 patients, the incidence of delirium and subsyndromal forms was 7.6% and 20%, respectively. Subsyndromal forms diagnosed at admission represented a risk factor for the subsequent development of delirium (odds ratio [OR], P < .0001). A previous episode of brain failure during ICU stay and older age were risks factors for the development of subsyndromal forms, whereas not needing MV was a protective factor. Delirium significantly prolonged the stay in the SDU but did not influence survival and the process of weaning from MV. Overall, the percentage of patients with an abnormal Intensive Care Delirium Screening Checklist score at discharge (5%) was reduced compared with that recorded at admission (18%). CONCLUSIONS: Delirium may still occur after discharge from an ICU in patients who are transferred to an SDU. The strategy of care adopted in the SDU seems to positively affect the recovery from a delirious state. Patients with subsyndromal forms should be promptly recognized and treated because of the risk of developing delirium. Weaning from MV is not hindered by delirium. PMID- 19781902 TI - Reduced expression of systemic proinflammatory and myocardial biomarkers after off-pump versus on-pump coronary artery bypass surgery: a prospective randomized study. AB - BACKGROUND: The effects of off-pump (OffPCABG) and on-pump (OnPCABG) coronary artery bypass grafting (CABG) on myocardium and inflammation are unclear. OBJECTIVE: Compare the inflammatory response and myocardial injury from patients (pts) submitted to OffPCABG with those that undergo OnPCABG. METHODS: Patients with normal left ventricular function were assigned to OffPCABG (n = 40) and OnPCABG (n = 41). Blood samples were collected before and 24 hours after surgery for determination of creatine kinase (CK)-MB (CK-MB), troponin I (cTnI), interleukin (IL)-6, IL-8, P-selectin, intercellular adhesion molecule (ICAM)-1 and C-reactive protein (CRP). Mortalities were registered at 12 months. RESULTS: Preoperative CK-MB and cTnI levels were 3.1 +/- 0.6 IU and 1.2 +/- 0.5 ng/mL for OffPCABG and 3.0 +/- 0.5 IU and 1.0 +/- 0.2 ng/mL for OnPCABG pts. Postoperative CK-MB and cTnI levels were 13.9 +/- 6.5 IU and 19.0 +/- 9.0 ng/mL for OffPCABG vs 29.5 +/- 11.0 IU and 31.5 +/- 10.1 ng/mL for OnPCABG (P < .01). OffPCABG and OnPCABG pts had similar preoperative IL-6 (10 +/- 7 and 9 +/- 13 pg/mL), IL-8 (19 +/- 7 and 17 +/- 7 pg/mL), soluble P-selectin (70 +/- 21 and 76 +/- 23 pg/mL), soluble ICAM-1 (117 +/- 50 and 127 +/- 52 ng/mL), and CRP (0.09 +/- 0.05 and 0.11 +/- 0.07 mg/L). At 24 hours, for OffPCABG and OnPCABG: IL-6 was 37 +/- 38 and 42 +/- 41 g/mL; IL-8, 33 +/- 31 and 60 +/- 15 pg/mL; soluble P-selectin, 99 +/- 26 and 172 +/- 30 pg/mL; soluble ICAM-1, 227 +/- 47 and 236 +/- 87 ng/mL; and CRP, 10 +/- 11 and 14 +/- 13 mg/L (P < .01 vs preoperation; P < .01 vs OffPCABG). Increased 24-hour postoperative CRP levels was the only marker to have significant positive correlations with events and occurred just for the OnPCABG pts. In-hospital and 1-year mortalities for the OnPCABG and OffPCABG pts were 2.0% and 2.2% (P = .1) and 2.7% and 4.7% (P = .06), respectively. CONCLUSIONS: Thus, the absence of CPB during CABG preserves better the myocardium and attenuates inflammation-however, without improving survival. PMID- 19781904 TI - Hemodynamic effects of recombinant human activated protein C in patients with septic shock. AB - PURPOSE: The aim of this study is to examine the effects of recombinant human activated protein C (rhAPC) on hemodynamic parameters in patients with septic shock. METHODS: This is a retrospective study of 2 university-hospital critical care units. Patients with septic shock with pulmonary artery catheterization or transthoracic thermodilution monitoring were studied. We matched patients with septic shock with at least 2 organ failures (18 treated with rhAPC and 18 controls) on sex, age, sequential organ failure assessment (SOFA), Acute Physiology and Chronic Health Evaluation (APACHE) II, and sepsis etiology. We recorded norepinephrine dose and hemodynamic parameters at baseline and 24, 36, and 48 hours after the real or theoretical start of rhAPC treatment. RESULTS: Mean arterial pressure remained stable in both groups. In rhAPC patients, norepinephrine requirements, initially higher than in controls, were significantly lower at 48 hours, and stroke volume at 24 and 48 hours improved (P < .05). CONCLUSION: Recombinant human activated protein C use correlated with improved hemodynamic parameters and decreased norepinephrine requirements. The retrospective nature of the study limits the strength of these findings. PMID- 19781905 TI - Real-time monitoring of heart rate variability in critically ill patients. AB - PURPOSE: Heart rate variability (HRV) is widely used to evaluate autonomic nervous function; however, real-time monitoring of HRV has rarely been attempted in the intensive care unit (ICU). We report our experience in performing real time monitoring of HRV in our ICU. METHODS: We investigated 10 critically ill patients on total ventilatory support. Heart rate variability analysis was performed using the MemCalc system, which is a noninvasive, real-time analysis system. The low-frequency (LF) component of HRV reflects sympathetic and parasympathetic modulation, whereas the high-frequency (HF) component mainly reflects parasympathetic modulation. The LF/HF ratio represents a measure of sympathetic/parasympathetic balance. RESULTS: The HRV parameters for patients breathing spontaneously after extubation were significantly higher than those for patients on total ventilatory support. These findings suggest that mechanical ventilation under sedation may reduce autonomic nervous function in critically ill patients. In a representative case with septic shock, systolic blood pressure and LF/HF ratio showed a significant increase after intravenous infusion of epinephrine and then the HF component showed a significant increase due to vagal reflex. CONCLUSIONS: The MemCalc system is practicable for real-time monitoring of HRV in the ICU. Heart rate variability parameters may offer useful information in the management of critically ill patients. PMID- 19781906 TI - Risk factors and outcome of acute renal failure in patients with severe acute pancreatitis. AB - OBJECTIVE: Acute renal failure (ARF) is one of the most common causes of death in patients with severe acute pancreatitis (SAP). Here, we aimed to investigate the risk factors of ARF in patients with SAP, assess the prognosis of patients with SAP and ARF, and seek potential measures to prevent ARF. METHOD: A cross sectional study was performed to analyze the data from patients with SAP. Both univariate and multivariate logistic regression analyses were performed, including 15 indices such as age, history of renal disease, Acute Physiology and Chronic Health Evaluation II scores, hypoxemia, abdominal compartment syndrome (ACS), and others. Univariate analysis was also used to compare the prognosis between the groups of patients with SAP with and without ARF. RESULTS: There was a significant difference in age, history of renal disease, Acute Physiology and Chronic Health Evaluation II scores, hypoxemia, and ACS between the groups with and without ARF. Patients with SAP and ARF had significantly longer average length of stay and intensive care unit length of stay and higher infection rate of the pancreas and mortality rate. CONCLUSION: The significant risk factors for ARF in patients with SAP include history of renal disease, hypoxemia, and ACS. Measures that can prevent ARF include homeostasis maintenance, adequate perfusion of the kidneys, adequate oxygenation, and abdominal decompression to avoid ACS. PMID- 19781907 TI - Relevant risk factors affecting time of ventilation during early postoperative period after orthotopic liver transplantation. AB - PURPOSE: The aim of this study is to examine the relevant factors affecting the duration of mechanical ventilation after orthotopic liver transplantation. MATERIALS AND METHODS: The 96 patients who underwent liver transplantation were divided into 2 groups according to whether or not the duration of mechanical ventilation after operation was longer than 24 hours. Nineteen variables, including clinical and experimental variables, were analyzed by t test for continuous variables and chi(2) test for discrete variables. The variables with significance (P < .05) were then analyzed with stepwise logistic regression. RESULTS: Nine continuous preoperative clinical and experimental variables, including preoperative Child-Pugh stage, time of operation, volume of intraoperative liquid transfusion, volume of intraoperative blood loss, volume of intraoperative blood transfusion, volume of intraoperative urine, time of intraoperative hypotension, postoperative renal failure, and postoperative pulmonary edema revealed significant differences between the 2 groups. Stepwise logistic regression analysis for 9 variables indicated that volume of intraoperative blood loss, volume of intraoperative urine, and postoperative renal failure are relevant independent risk factors. CONCLUSION: The relevant risks affecting the time of ventilation in patients after orthotopic liver transplantation are multiple. The volume of intraoperative blood loss, volume of intraoperative urine, and postoperative renal failure are independent risk factors. PMID- 19781908 TI - Electroencephalogram for prognosis after cardiac arrest. AB - BACKGROUND: In assessing neurologic prognosis after cardiac arrest (CA), electroencephalogram (EEG) reactivity has not been specifically included with EEG classifications. Most studies have divided recordings into benign and malignant; however, some patterns within these groups may have greater prognostic significance than such broad classifications. We sought to explore reactivity, with broad classifications and subclassifications for their prognostic significance. METHODS: All consecutive adults in coma who had an EEG recording performed at least 1 day after CA or during normothermia after a 24-hour mild hypothermia protocol. Outcomes were dichotomous: recovery of awareness or no recovery of awareness during hospitalization. RESULTS: Twenty-nine patients met the inclusion criteria. Of the 18 patients with no reactivity, only 1 recovered awareness; of the 11 patients who demonstrated reactivity, 10 recovered awareness (sensitivity of 90% [95% confidence interval, or CI, 0.57-1] and specificity of 94% [95% CI, 0.7-1]). Of those with benign patterns, 7 recovered awareness and 1 did not; however, those patients demonstrating malignant patterns, 4 recovered and 17 did not (sensitivity of 94% [95% CI, 0.7-1] and a specificity of 63% [95% CI, 0.32-0.88]). None of the 15 patients with suppression or generalized spikes recovered consciousness, and none of these patients demonstrated reactivity. CONCLUSIONS: Electroencephalogram reactivity after CA is a relatively favorable EEG feature; generalized suppression or generalized epileptiform activity, without reactivity, is associated with lack of recovery of awareness. PMID- 19781909 TI - Increased synthetic phenotype behavior of smooth muscle cells in response to in vitro balloon angioplasty injury model. AB - Restenosis remains a common problem following balloon angioplasty, and it has been speculated that changes in the mechanical environment due to endovascular interventions are correlated with shifts in smooth muscle cell (SMC) phenotype. In order to study SMC response to forces similar to those exerted during balloon angioplasty, an in vitro concurrent shear and tensile forces simulator has been developed. After 24 hr of exposure to cyclic tension (5%) and shear (0.1-0.5 dynes/cm(2)) following simulated angioplasty injury (12% stretch), rat aortic SMCs exhibited significant synthetic behavior. These responses included increased cell proliferation, apoptosis, and cell hypertrophy compared to cells exposed to strain alone. While all SMCs exposed to dynamic stimuli (strain, strain+balloon injury, strain+balloon injury+shear) demonstrated a decrease in contractile protein expression, the injury group also exhibited significantly greater expression of the synthetic marker vimentin. These in vitro findings agree with in vivo events following balloon angioplasty and present a refined dynamic model to be implemented for better understanding of SMC activation and prevention of responses through pharmacological treatment. PMID- 19781910 TI - Acoustic and electroglottographic analyses of nonpathological, nonmodal phonation. AB - Languages where phonation type and tone are contrastive make use of extremely fine and controlled actions of laryngeal structures; hence, there is little opportunity to variation in either phonation or pitch. Nonetheless, many American Indian languages have contrastive nonmodal phonation, which, moreover, is subject to a great deal of variation. There are a few studies addressing the phonetics of nonmodal phonation in American Indian languages, and little is known about the phonetics/phonology interface of laryngeal features within the sound patterns of these languages. This article aims to contribute to the knowledge of nonmodal phonation through the detailed study of the phenomenon in Yalalag Zapotec (YZ) and American Indian language. A series of spectral and electrophysiological analyses contribute to the description of YZ nonmodal phonation and its variability across gender. It is argued that the temporal patterns in realization of laryngealization are a property of YZ speaker's grammar. PMID- 19781911 TI - The management of complications following displacement of oral implants in the paranasal sinuses: a multicenter clinical report and proposed treatment protocols. AB - This study retrospectively analyses paranasal sinus complications following displacement of oral implants in the maxillary sinus treated according to clinical situation by functional endoscopic sinus surgery (FESS), an intraoral approach, or a combination of both procedures. Over 5 years, 27 patients (13 male; 14 female), aged 27-73 years (mean 53.9 years), underwent treatment for postoperative complications involving the paranasal sinuses following displacement of oral implants in the maxillary sinuses. According to the complication (implant displacement, implant displacement with or without reactive sinusitis and/or with or without associated oro-antral communication), patients were treated with FESS, intraoral approach to the sinus, or FESS associated with an intraoral approach. Follow up lasted for at least 1 year with clinical and radiographic controls. 26 patients recovered completely; one patient underwent re intervention with FESS and an intraoral approach 2 years after implant removal, due to persistent signs and symptoms of maxillary sinusitis and oro-antral communication. Postoperative recovery after the second procedure was followed by complete recovery. The results demonstrate that a rational choice of surgical protocol for the treatment of complications involving the paranasal sinuses following displacement of implants in the maxillary sinuses may lead to reliable results. PMID- 19781912 TI - Effect of ethacrynic acid on the anticonvulsant activity of the second-generation antiepileptics against maximal electroshock-induced seizures in mice. AB - Recent experimental studies show that ethacrynic acid (ETA), a loop diuretic, exerts the anticonvulsant activity. Therefore, we tested the effect of ETA on the protective action of some second-generation antiepileptic drugs (oxcarbazepine [OXC], lamotrigine [LTG] and topiramate [TPM]) in the mouse maximal electroshock seizure (MES) model. ETA was administered acutely (50 and 100 mg/kg i.p.) or chronically, for 7 days (12.5 mg/kg i.p.). Both ETA acute (up to 100 mg/kg) and chronic (up to 12.5 mg/kg) treatment did not influence the threshold for electroconvulsions. In the MES test, ETA (100 mg/kg) potentiated the protective activity of TPM, decreasing its ED(50) value from 38.1 to 18.7 mg/kg (P<0.01). In contrast, ETA (100 mg/kg) remained without effect on the anticonvulsant action of the other antiepileptics (OXC and LTG) in mice. Chronic administration of ETA (12.5 mg/kg) did not affect the protective action of tested antiepileptics. The observed interaction between acute ETA and TPM was pharmacodynamic in nature because neither plasma nor total brain TPM concentrations were altered after injection of ETA.These results indicate existing interactions between ETA and TPM, which may have some clinical importance for epileptic patients treated with TPM and additionally ETA due to other medical causes. PMID- 19781913 TI - Maternal age and paternal age are associated with distinct childhood behavioural outcomes in a general population birth cohort. AB - BACKGROUND: Recent studies show that advanced paternal age (APA) is associated with an increased risk of neurodevelopmental disorders such as autism, bipolar disorder and schizophrenia. A body of evidence also suggests that individuals who develop schizophrenia show subtle deviations in a range of behavioural domains during their childhood. The aim of the study was to examine the relationship between paternal and maternal ages and selected behavioural measures in children using a large birth cohort. METHOD: Participants were singleton children (n=21,753) drawn from the US Collaborative Perinatal Project. The outcome measures were assessed at 7 years. The main analyses examined the relationship between parental age and behavioural measures when adjusted for a range of potentially confounding variables, including age of the other parent, maternal race, socio-economic measures, sex, gestation length, maternal marital status, parental mental illness, and child's age-at-testing. RESULTS: Advanced paternal age was associated with a significantly increased risk of adverse 'externalizing' behaviours at age seven years. For every five year increase in paternal age, the odds of higher 'externalizing' behaviours was increased by 12% (OR=1.12; 95% CI=1.03, 1.21, p<0.0001). The relationship persisted after adjusting for potential confounding factors. 'Internalizing' behavioural outcome was not associated with advanced paternal age. In contrast, advanced maternal age was significantly protective against adverse 'externalizing' behavioural outcomes, but associated with an increased risk of adverse 'internalizing' behavioural outcomes. DISCUSSION: The offspring of older fathers show a distinctly different pattern of behaviours compared to the offspring of older mothers. The diverse socio-cultural and biologically-mediated factors that underpin these findings remain to be clarified. In light of secular trends related to delayed parenthood, the mechanisms underlying these findings warrant closer scrutiny. PMID- 19781914 TI - DNA damage responses in skin biology--implications in tumor prevention and aging acceleration. AB - UV irradiation is the main etiological cause of most types of skin cancers and can accelerate skin photoaging. UV irradiation results in several types of DNA damage in eukaryotic cells, such as DNA single strand breaks, DNA interstrand cross-links, and nucleotide base modifications. In response to such DNA damages, mammalian cells exert DNA damage responses including cell cycle checkpoints, well developed DNA repair, apoptosis and premature senescence to prevent genomic instability. Cell cycle checkpoints are important surveillance systems to maintain genomic integrity. Once checkpoint systems sense the abnormal chromosomal DNA structures, they execute cell cycle arrest through inhibiting the activity of cell cycle regulators and coordinate it with the DNA repair process. Checkpoint responses also execute cellular senescence when cells sense unrepairable and extensive chromosomal abnormalities. Senescent cells are no longer able to divide despite remaining viable for long periods of time, metabolically active, but functionally impaired. Accumulation of senescent cells in skin results in harmful consequences such as skin aging. Therefore, skin photoaging is thought to be a phenotypic hallmark responsible for one of the major mechanisms against skin carcinogenesis. In this review, changes in chromatin modification in response to UV and the molecular mechanisms accelerating aging phenotypes are discussed. PMID- 19781915 TI - Emergence of a new mutation and its accumulation in the topoisomerase IV gene confers high levels of resistance to fluoroquinolones in Escherichia coli isolates. AB - Mutations in DNA gyrase and topoisomerase IV genes are the main mechanisms of resistance to quinolones. In this study, we determined mutations in gyrA, gyrB, parC and parE among 57 ciprofloxacin-resistant Escherichia coli isolates from a South Korean hospital and analysed the relationship between the minimal inhibitory concentrations (MICs) of fluoroquinolones and mutations in the topoisomerase IV gene. All ciprofloxacin-resistant E. coli isolates carried double mutations in gyrA and at least a single mutation in parC; some isolates also carried a single mutation in parE. The most common mutations were S83L and D87N in gyrA, S80I in parC and S458A in parE, which accounted for 25% of isolates. Single mutations in parE at L445I, S458P and S458W were identified for the first time. Double mutations in parC and a combination of single mutations in parC and parE significantly increased the MIC values of fluoroquinolones. In vitro induction of resistance to ciprofloxacin showed that double mutations in gyrA were a prerequisite to conferring a resistant phenotype to fluoroquinolones, and an additional mutation in the topoisomerase IV gene increased the MIC values of ciprofloxacin. In conclusion, emergence of a new mutation in parC and parE and its accumulation induces high levels of resistance to fluoroquinolones in E. coli. PMID- 19781916 TI - Adult-onset hippocampal-specific neuropeptide Y overexpression confers mild anxiolytic effect in mice. AB - The anticonvulsive properties of neuropeptide Y (NPY) are opening up opportunity for the development of NPY gene transfer as a therapy for epilepsy. In order to pursue the potential clinical translation of this approach, the effects of somatic NPY gene transfer on other hippocampal functions need to be assessed. The present study characterized the behavioral effects of recombinant adeno associated viral vector (rAAV)-mediated hippocampal NPY overexpression in adult male mice and also Y1 receptor knockout mice. In wild-type mice, there were no obvious adverse effects on the general health, motor function and cognition following rAAV-NPY treatment. Moreover, hippocampal NPY overexpression induced a moderate anxiolytic effect in the open field test and elevated plus maze. Intriguingly, the treatment also increased depressive-like behavior in the tail suspension test. Elevated hippocampal NPY levels in the absence of Y1 signalling had no effects on anxiety or cognition and actually improved the depressive-like phenotype observed in the wild-type mice treated with rAAV-NPY. PMID- 19781918 TI - High-resolution 2H MAS NMR applied to deuterium analogs of hydrido eta2 dihydrogen complexes. AB - (2)H solid-state, variable temperature magic angle spinning (MAS) NMR spectra of precipitated samples of the deutero dideuterium complexes Ru(D)(2)(eta(2) D(2))(2)(PCy(3))(2) and RuD(eta(2)-D(2))I(PCy(3))(2) [Cy=cyclohexyl] are presented. They show that even at moderate MAS speed, high resolution is achieved at 7 and 14T allowing (2)H chemical shifts and quadrupole couplings to be obtained and assigned to different solid and gaseous (2)H species. These two parameters allow identifying chemically different hydrogen species in the material. The analysis of these parameters in this study reveals the presence of three different species in the sample, namely the complexes RuD(eta(2) D(2))I(PCy(3))(2) and RuD(eta(2)-D(2))(2)I(PCy(3))(2), and highly mobile HD/D(2). These assignments are supported by (2)H T(1) relaxation times and (31)P MAS NMR spectra. Moreover, variable temperature MAS NMR spectra reveal temperature dependent line-shape changes, which are clear indications of intramolecular hydrogen exchange of the deutero and the dideuterium ligands and which give an estimate for the activation energy of this process. PMID- 19781917 TI - Corpus callosum volume in children with autism. AB - The corpus callosum (CC) is the main commissure connecting the cerebral hemispheres. Previous evidence suggests the involvement of the CC in the pathophysiology of autism. However, most studies examined the mid-sagittal area and investigations applying novel methods are warranted. The goal of this investigation is to apply a volumetric method to examine the size of the CC in autism and to identify any association with clinical features. An MRI-based morphometric study of the total CC volume and its seven subdivisions was conducted and involved 22 children with autism (age range 8.1-12.7 years) and 23 healthy, age-matched controls. Reductions in the total volume of the CC and several of its subdivisions were found in the autism sample. Associations were observed between CC structures and clinical features including social deficits, repetitive behaviors, and sensory abnormalities. Volumetric alterations of the CC observed in this investigation are consistent with midsagittal area tracings of decreased CC size in autism. These findings support the aberrant connectivity hypothesis with possible decrease in interhemispheric communications. PMID- 19781919 TI - Structure-function relationship of beta-lactoglobulin in the presence of dodecyltrimethyl ammonium bromide. AB - Bovine beta-lactoglobulin (beta-LG) present in milks has been found "in vivo" in complexes with lipids such as butyric and oleic acids. To elucidate the still unknown structure-function relationship in this protein, the structural changes of beta-lactoglobulin variant A (beta-LG A) in the presence of cationic surfactant such as dodecyltrimethyl ammonium bromide (DTAB) have been investigated using various experimental techniques such as UV-vis spectrophotometry, fluorimetry, isothermal titration calorimetry (ITC) and circular dichroism (CD). Subsequently, the retinol binding by beta-LG has been investigated in the presence of various amounts of this surfactant as its extrinsic functional binding fluorophore. Comparison of the results allowed to determine the binding of retinol by beta-LG in the presence of DTAB. The results of UV-vis and fluorescence studies showed a red shift in wavelength and an increase in absorbance and enhancement in the intensity of the quantum yield of protein during its interaction with DTAB. The results of UV-vis also showed two distinct conformational changes corresponding first to precipitation and second to solubilization of the precipitated beta-LG at pH 6.7 and 8.0. The results indicate the cooperative character of binding at pH 2.0. The results of fluorescence studies showed that the binding strength of beta-LG/DTAB complex increases with the increase of the pH. CD results showed the shifts in positions of the major minima and change in magnitude of ellipticity and subsequently signified two significant changes in structure of beta-LG between 10-30 and 50 100 molar ratio of [DTAB]/[beta-LG]. ITC measurements indicated the endothermic nature of beta-LG/DTAB interactions at pH 6.7 and the exothermic nature of beta LG/DTAB interactions at pH 8.0. The analysis of the binding data demonstrates the absence of significant changes in retinol-binding properties of beta-LG in the presence of various amounts of this surfactant. This implies that surfactant binding does not change the conformation of beta-LG in the regions defining retinol-binding site nor interferes with retinol binding by a competition for the same binding site(s). PMID- 19781920 TI - Adsorption behavior of ferritin and buffer components, buffer agents and salts, onto silane-coupled silicon substrate. AB - Fixation of ferritin using amino-silane modified substrates is effective, but salt and alkali ions of the buffer can contaminate substrates, inhibiting the sensing and fabrication of nano-electronic devices. To avoid adsorption of salts and alkali ions, buffer solutions have been replaced by pure water or alkali metal-ion-free buffer. However, proteins in such solutions are sometimes denatured. Therefore, we developed a substrate which adsorbs ferritin but does not adsorb contaminants such as salts and alkali metal-ions contained in the buffer. Adsorption of ferritin was achieved by using a buffer with a high ion strength, such as PBS buffer, because the Debye length becomes shorter with increased ion strength due to intermolecular force even when the substrate has no positive charge. The combination of high coverage methyltrimethoxysilane (MTMS) coupled silicon substrate and PBS buffer solution is effective for adsorption of ferritin while not adsorbing buffer components such as contaminants and/or salts on the silicon substrate. PMID- 19781921 TI - A new approach for the in vitro identification of the cytotoxicity of superparamagnetic iron oxide nanoparticles. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) are increasingly used in medical applications, such as targeting delivery and imaging. In the future, patients are more likely to be exposed to pharmaceutical products containing such particles. The study of toxicity of SPIONs has become of great importance in recent years, although the published data in this arena is limited. The aim of the present work is to investigate the cytotoxicity of SPIONs and the effect of the particles on the cell medium components. For this purpose, uncoated and polyvinyl alcohol (PVA) coated SPIONs with narrow size distribution were synthesized via a well-known coprecipitation method. The mouse fibroblast cell line L929 was exposed to SPIONs to probe the toxicity of magnetic nanoparticles during the bio application. Changes to the cell medium caused by SPIONs were analyzed with zeta potential measurements, ultraviolet visible spectroscopy (UV/vis) and the 3-[4,5-dimethylthiazol-2yl]-2,5-diphenyltetrazolium bromide (MTT) assay. It is observed that gas vesicles are formed in SPION-treated cells. Toxicity is conventionally explained by changes in the DMEM's pH and composition due to the tendency of SPIONs to interact with biomolecules. A new procedure is proposed to examine the in vitro toxicity of nanoparticles in a more rigorous manner, which gives an improvement in the relationship between in vivo and in vitro toxicity studies. PMID- 19781922 TI - Ferroelectric BaTiO3 nanoparticles: biosynthesis and characterization. AB - A new low-cost, green and reproducible Lactobacillus sp. assisted biosynthesis of BaTiO(3) nanoparticles is reported. X-ray and transmission electron microscopy analyses are performed to ascertain the formation of BaTiO(3) nanoparticles. The apparent crystallite size and lattice strain are estimated from Williamson-Hall approach. XRD analysis of the compound indicated the formation of a single-phase tetragonal structure. Individual nanoparticles as well as a few aggregate having the size of 20-80 nm are found. A possible involved mechanism for the biosynthesis of nano-BaTiO(3) has also been proposed in which ROS as well as partial pressure of gaseous hydrogen (rH(2)) of the culture solution seems to play an important role in the process. Remarkable enhancement in dielectric properties was observed in BaTiO(3)/polyvinylidene fluoride (PVDF) nanocomposite. PMID- 19781923 TI - Stage I germ cell tumours: achieving cure at minimal cost. PMID- 19781924 TI - Mechanism of subendocardial cell proliferation in the rat and relevance for understanding drug-induced valvular heart disease in humans. AB - A number of drugs and drug candidates, including fenfluramine and ergot derivatives, are associated with valvulopathy in humans; however, these responses are poorly predicted from animal studies. In vitro and in vivo evidence suggests that these compounds exert their pathological effect through activation of serotonin 2B receptor (5HT2BR) signaling. However, the variable effect of fenfluramine and other 5HT2BR agonists in rodents has cast doubt on the relevance of animal findings to predicting human risk. Herein, a candidate compound, RO3013, induced subendocardial cell proliferation in the mitral and tricuspid valves in rats after only 3 days of daily dosing. Additionally, there was a treatment-related increase in immunostaining of the proliferation marker Ki67, and phosphorylated Smad3 in the heart indicative of TGFbeta signaling co localized with 5HT2BR expression. To substantiate the hypothesis that RO3013 induced valvular proliferation is secondary to 5HT2BR activation, the compound was evaluated in vitro and found to bind to the human 5HT2BR with a K(i) of 3.8MUM; however, it was virtually devoid of agonist activity in a functional assay in human cells. By contrast, RO3013 bound to the rat 5HT2BR with a K(i) of 1.2MUM and activated the receptor with an EC50 of 0.5MUM. This agonist potency estimate is in good agreement with the free plasma concentrations of RO3013 at which valvular proliferation was observed. These results suggest that the rat may be susceptible to 5HT2BR-mediated valvular proliferation similar to humans; yet, the significant differences between binding and functional activities can be a possible explanation for the observed species-selective receptor responses. PMID- 19781925 TI - Effects of corticosteroid use on readmission in obstructive lung disease. AB - OBJECTIVE: Obstructive lung disease is a leading cause of morbidity and mortality worldwide. Some patients are readmitted, but currently predicting parameters for identifying these patients are lacking. The aim of this study was to quantify the incidence of readmission in chronic obstructive lung disease and to identify determinants for hospital readmission. METHODS: We conducted a cohort study using the PHARMO record linkage system, including demographic details and complete medication histories of more than two million community-dwelling residents in the Netherlands from 1985 onwards. Eligible patients were adult users of inhaled corticosteroids (ICS) with an admission for obstructive lung disease. The outcome parameter was readmission within a follow-up period of one year. RESULTS: We identified 605 ICS users with an admission for chronic obstructive lung disease, 132 of these patients were readmitted. Readmission was associated with a high Chronic Disease Score (adjusted HR 2.4; 95% CI 1.1-5.3). Patients using short courses of systemic corticosteroids only (adjusted HR 0.5; 95% CI 0.4-0.8) or combined with antibiotics (adjusted HR 0.4; 95% CI 0.2-0.6) were at decreased risk of readmission. The effect of high-dose ICS use varied over time. CONCLUSIONS: Treatment of exacerbations out of the hospital was associated with a decreased risk of readmission, while patients with multiple chronic diseases are at increased risk of readmission for obstructive lung disease. These patients should be educated and should be invited to consultation more often to be able to detect exacerbation in an early phase and start treatment as early as possible. PMID- 19781926 TI - Mitochondrial reactive oxygen species regulate hypoxic signaling. AB - Physiological hypoxia results in a host of responses that include increased ventilation, constriction of the pulmonary artery, and a cellular transcriptional program that promotes glycolysis, angiogenesis, and erythropoiesis. Mitochondria are the primary consumers of cellular oxygen and have thus been speculated for years to be the site of cellular oxygen sensing. Many of the cellular responses to hypoxia are now known to be mediated by the production of reactive oxygen species at mitochondrial complex III. While the mechanism by which cytosolic oxidant concentration is increased during hypoxia is unknown, the importance of the maintenance of cellular oxygen supply requires further investigation into the role of ROS as hypoxia signaling molecules. The following is a brief overview of the current understanding of the role of mitochondrial-produced ROS in cellular oxygen signaling. PMID- 19781929 TI - A mass transfer model of ammonia volatilization from anaerobic digestate. AB - Anaerobic digestion (AD) is becoming increasingly popular for treating organic waste. The methane produced can be burned to generate electricity and the digestate, which is high in mineral nitrogen, can be used as a fertiliser. In this paper we evaluate potential losses of ammonia via volatilization from food waste anaerobic digestate using a closed chamber system equipped with a sulphuric acid trap. Ammonia losses represent a pollution source and, over long periods could reduce the agronomic value of the digestate. Observed ammonia losses from the experimental system were linear with time. A simple non-steady-state partitioning model was developed to represent the process. After calibration, the model was able to describe the behaviour of ammonia in the digestate and in the trap very well. The average rate of volatilization was approximately 5.2 g Nm( 2)week(-1). The model was used to extrapolate the findings of the laboratory study to a number of AD storage scenarios. The simulations highlight that open storage of digestate could result in significant losses of ammonia to the atmosphere. Losses are predicted to be relatively minor from covered facilities, particularly if depth to surface area ratio is high. PMID- 19781928 TI - How to make beta cells? AB - Insulin-producing beta cells are lost or insufficient in diabetic patients, presenting the medical challenge for new beta cells. Currently, there are three strategies that offer promise. One involves the generation of beta cells de novo by directing the differentiation of either embryonic stem cells or induced pluripotent cells to the beta cell lineage. The second is based on the conversion of another terminally differentiated cell to beta cells in a process called reprogramming. The third approach is to promote the replication of existing beta cells either in vivo or in vitro. Significant progress is evident for each strategy, but it remains unclear which approach will ultimately prove successful. PMID- 19781927 TI - Cellular and nuclear degradation during apoptosis. AB - Apoptosis ensures quick death and quiet clearance of unwanted or damaged cells, without inducing much, if any, immunological responses from the organism. In metazoan organisms, apoptotic cells are swiftly engulfed by other cells. The degradation of cellular content is initiated in apoptotic cells and completed within engulfing cells. In apoptotic cells, caspase-mediated proteolysis cleaves protein substrates into fragments; nuclear DNA is partially degraded into nucleosomal units; and autophagy potentially contributes to apoptotic cell removal. In engulfing cells, specific signaling pathways promote the sequential fusion of intracellular vesicles with phagosomes and lead to the complete degradation of apoptotic cells in an acidic environment. Phagocytic receptors that initiate the engulfment of apoptotic cells play an additional and crucial role in initiating phagosome maturation through activating these signaling pathways. Here we highlight recent discoveries made in invertebrate models and mammalian systems, focusing on the molecular mechanisms that regulate the efficient degradation of apoptotic cells. PMID- 19781930 TI - CIELAB color variables as indicators of compost stability. AB - The composting process of different organic wastes both in laboratory and on a large-scale was characterized using CIELAB color variables to evaluate compost stability for the better application in agriculture. The time courses of the CIELAB variables of composting materials were determined directly from the bottom of a glass petri dish filled with dried and ground samples using a Minolta Color Reader (CR-13) calibrated with clean empty petri dishes placed on a white tile. To compare the proposed method with conventional methods, the same materials were also evaluated using commonly used compost stability evaluation indices. Most of the CIELAB variables of a compost made from a mixture of green tea waste and rice bran reached a plateau after 84 days of composting and showed strong relationships with the commonly used compost stability evaluation indices. The time needed for CIELAB variables, especially the L*and b* values, to stabilize at large-scale composting plants of cattle litter, farmyard manure, kitchen garbage and bark compost, were more or less similar to the times of maturation evaluated by the respective compost producers. The CIELAB color variable offers a new, simple, rapid and inexpensive means of evaluating compost stability and its quality prior to agricultural use. PMID- 19781931 TI - Label-free low-cost disposable DNA hybridization detection systems using organic TFTs. AB - Organic thin film transistors (OTFT) are potentially very attractive for making portable and disposable DNA hybridization detection toolkits because of their ultra-low-cost manufacturing and potentially high sensitivity. To make a self supported DNA sensor, we herein report an OTFT-based label-free DNA hybridization detection system integrating electrically read DNA hybridization sensors and microfluidic delivery channels. We previously reported DNA-doped OTFTs acting as electrically read DNA sensors. In this article, we first study physics of DNA sensitivity of OTFTs, clarifying the doping mechanism. The article also presents a method of verification of the immobilization and presence of DNA on the surface using TOF-SIMS analysis. As a further step, sources of variation of measured data and methods of minimization are discussed using a novel photolithography-based microfluidics fabrication method, directly enabling on-chip hybridization and self-supported DNA detection. By integrating the sensors with microfluidics, for the first time, we demonstrate necessary technologies required to realize disposable, rapid turn-around tools for field-deployable genetic diagnosis. PMID- 19781932 TI - A practical glucose biosensor based on Fe(3)O(4) nanoparticles and chitosan/nafion composite film. AB - A practical glucose biosensor was developed by combining the intrinsic peroxidase like activity of Fe(3)O(4) nanoparticles (Fe(3)O(4) NPs) and the anti interference ability of the nafion film. Glucose oxidase (GOD) was simply mixed with Fe(3)O(4) NPs and cross-linked on the Pt electrode with chitosan (Cs) medium by glutaraldehyde, and then covered with a thin nafion film. The biosensor showed high sensitivity (11.54 microAcm(-2)mM(-1)), low detection limit (6 x10(-6)M), and good storage stability. A linear calibration plot was obtained in the wide concentration range from 6 x10(-6) to 2.2 x10(-3)M. The modified electrode could virtually eliminate the interference during the detection of glucose. Furthermore, the biosensor was successfully applied to detect glucose in human serum sample. This fabrication of glucose biosensor was of considerable interest due to its promise for simple procedure and optimizing conditions in practical application. PMID- 19781933 TI - Covalently linked silica-multiwall carbon nanotube-polyaniline network: an electroactive matrix for ultrasensitive biosensor. AB - A three dimensional network comprising of covalently linked multi-walled carbon nanotubes (MWNT), silica and polyaniline chains (MWNT-Silica-PANI-NW) was prepared and used as the matrix for immobilization of an enzyme (horseradish peroxidase, HRP). MWNT-Silica-PANI-NW-HRP electrode showed superior performances over the individual components and their binary combinations, in terms of enzyme stability (minimum leaching to the medium), fast electron transfer from the enzyme to the electrode (2.11s(-1)), high sensitivity (58.1microAmM(-1)) and low detection limit (1pM) for the detection of hydrogen peroxide. The interconnected silica network provides open porous frame work for effective immobilization of the redox enzyme. The PANI units and MWNTs facilitate the electron transfer process and functions as molecular cable to "wire" the primary redox site of the enzyme (HRP) to the electrode. The improved performances for MWNT-Silica-PANI-NW arise from the synergistic contributions from conducting CNT, electron mediating PANI chains and porous silica network. PMID- 19781934 TI - Highly sensitive and reusable fluorescence microarrays based on hydrogenated amorphous silicon-carbon alloys. AB - We have designed a new architecture of fluorescent microarrays based on a thin layer of hydrogenated amorphous silicon-carbon alloy (a-Si(0.85)C(0.15):H) deposited on an aluminium-on-glass back reflector. These substrates are modified with an organic monolayer anchored through Si-C bonds and terminated with carboxyl groups, allowing for the covalent immobilization of biological probes. The fluorescence yield is maximized by optimization of the a-Si(0.85)C(0.15):H layer thickness. This approach is assessed for DNA recognition, demonstrating an increase in sensitivity by over one order of magnitude as compared to commercial slides, and the possibility of following in situ the molecular recognition event (hybridization). The immobilization chemistry provides these substrates with a superior chemical stability toward ageing or long-term exposure to physiological buffers, which allows for many successive hybridization/dehybridization cycles without measurable changes in performance. PMID- 19781936 TI - Semi-solid state fermentation of sweet sorghum for the biotechnological production of single cell oil. AB - A semi-solid fermentation process for the production of biodiesel from sweet sorghum is introduced. The microorganism used is the oleaginous fungus Mortierella isabellina, which is able to transform efficiently sugar to storage lipid. Kinetic experiments were performed at various water content percentages. The fungus consumed simultaneously sugars and nitrogen contained in sorghum and after nitrogen depletion the biomass growth was completed and oil accumulation began. Water content of 92% presented the highest oil efficiency of 11 g/100 g dry weight of substrate. The semi-solid process is shown to have certain advantages compared to liquid cultures or solid-state fermentation and gives oil of high quality. PMID- 19781935 TI - Genetic and optical targeting of neural circuits and behavior--zebrafish in the spotlight. AB - Methods to label neurons and to monitor their activity with genetically encoded fluorescent reporters have been a staple of neuroscience research for several years. The recent introduction of photoswitchable ion channels and pumps, such as channelrhodopsin (ChR2), halorhodopsin (NpHR), and light-gated glutamate receptor (LiGluR), is enabling remote optical manipulation of neuronal activity. The translucent brains of zebrafish offer superior experimental conditions for optogenetic approaches in vivo. Enhancer and gene trapping approaches have generated hundreds of Gal4 driver lines in which the expression of UAS-linked effectors can be targeted to subpopulations of neurons. Local photoactivation of genetically targeted LiGluR, ChR2, or NpHR has uncovered novel functions for specific areas and cell types in zebrafish behavior. Because the manipulation is restricted to times and places where genetics (cell types) and optics (beams of light) intersect, this method affords excellent resolving power for the functional analysis of neural circuitry. PMID- 19781937 TI - 3rd Annual Dysferlin Conference 2-5 June 2009, Boston, Massachusetts, USA. PMID- 19781939 TI - Deciphering cortical number coding from human brain activity patterns. AB - BACKGROUND: Neuropsychology and human functional neuroimaging have implicated human parietal cortex in numerical processing, and macaque electrophysiology has shown that intraparietal areas house neurons tuned to numerosity. Yet although the areas responding overall during numerical tasks have been well defined by neuroimaging, a direct demonstration of individual number coding by spatial patterns has thus far been elusive. RESULTS: We used multivariate pattern recognition on high-resolution functional imaging data to decode the information content of fine-scale signals evoked by different individual numbers. Parietal activation patterns for individual numerosities could be accurately discriminated and generalized across changes in low-level stimulus parameters. Distinct patterns were evoked by symbolic and nonsymbolic number formats, and individual digits were less accurately decoded (albeit still with significant accuracy) than numbers of dots. Interestingly, the numerosity of dot sets could be predicted above chance from the brain activation patterns evoked by digits, but not vice versa. Finally, number-evoked patterns changed in a gradual fashion as a function of numerical distance for the nonsymbolic notation, compatible with some degree of orderly layout of individual number representations. CONCLUSIONS: Our findings demonstrate partial format invariance of individual number codes that is compatible with more numerous but more broadly tuned populations for nonsymbolic than for symbolic numbers, as postulated by recent computational models. In more general terms, our results illustrate the potential of functional magnetic resonance imaging pattern recognition to understand the detailed format of representations within a single semantic category, and beyond sensory cortical areas for which columnar architectures are well established. PMID- 19781938 TI - Transcriptional and developmental functions of the H3.3 histone variant in Drosophila. AB - Changes in chromatin composition accompany cellular differentiation in eukaryotes. Although bulk chromatin is duplicated during DNA replication, replication-independent (RI) nucleosome replacement occurs in transcriptionally active chromatin and during specific developmental transitions where the genome is repackaged. In most animals, replacement uses the conserved H3.3 histone variant, but the functions of this variant have not been defined. Using mutations for the two H3.3 genes in Drosophila, we identify widespread transcriptional defects in H3.3-deficient animals. We show that mutant animals compensate for the lack of H3.3 in two ways: they upregulate the expression of the major histone H3 genes, and they maintain chromatin structure by using H3 protein for RI nucleosome replacement at active genes. Rescue experiments show that increased expression of H3 is sufficient to relieve transcriptional defects. In contrast, H3.3 is essential for male fertility, and germline cells specifically require the histone variant. Defects without H3.3 first occur around meiosis, resulting in a failure to condense, segregate, and reorganize chromatin. Rescue experiments with mutated transgenes demonstrate that H3.3-specific residues involved in RI nucleosome assembly-but not major histone modification sites-are required for male fertility. Our results imply that the H3.3 variant plays an essential role in chromatin transitions in the male germline. PMID- 19781941 TI - Ancient DNA reveals lack of continuity between neolithic hunter-gatherers and contemporary Scandinavians. AB - The driving force behind the transition from a foraging to a farming lifestyle in prehistoric Europe (Neolithization) has been debated for more than a century [1 3]. Of particular interest is whether population replacement or cultural exchange was responsible [3-5]. Scandinavia holds a unique place in this debate, for it maintained one of the last major hunter-gatherer complexes in Neolithic Europe, the Pitted Ware culture [6]. Intriguingly, these late hunter-gatherers existed in parallel to early farmers for more than a millennium before they vanished some 4,000 years ago [7, 8]. The prolonged coexistence of the two cultures in Scandinavia has been cited as an argument against population replacement between the Mesolithic and the present [7, 8]. Through analysis of DNA extracted from ancient Scandinavian human remains, we show that people of the Pitted Ware culture were not the direct ancestors of modern Scandinavians (including the Saami people of northern Scandinavia) but are more closely related to contemporary populations of the eastern Baltic region. Our findings support hypotheses arising from archaeological analyses that propose a Neolithic or post Neolithic population replacement in Scandinavia [7]. Furthermore, our data are consistent with the view that the eastern Baltic represents a genetic refugia for some of the European hunter-gatherer populations. PMID- 19781940 TI - An alternative pathway mediates the mouse and human cone visual cycle. AB - One of the fundamental mysteries of the human visual system is the continuous function of cone photoreceptors in bright daylight. As visual pigment is destroyed, or bleached, by light, cones require its rapid regeneration, which in turn involves rapid recycling of the pigment's chromophore. The canonical visual cycle for rod and cone pigments involves recycling of their chromophore from all trans retinol to 11-cis retinal in the pigment epithelium, adjacent to photoreceptors. However, shortcomings of this pathway indicate the function of a second, cone-specific, mechanism for chromophore recycling. Indeed, biochemical and physiological studies on lower species have described a cone-specific visual cycle in addition to the long-known pigment epithelium pathway. Two important questions remain, however: what is the role of this pathway in the function of mammalian cones, and is it present in higher mammals, including humans? Here, we show that mouse, primate, and human neural retinas promote pigment regeneration and dark adaptation selectively in cones, but not in rods. This pathway supports rapid dark adaptation of mammalian cones and extends their dynamic range in background light independently of the pigment epithelium. This pigment regeneration mechanism is essential for our daytime vision and appears to be evolutionarily conserved. PMID- 19781943 TI - Social facilitation of long-lasting memory retrieval in Drosophila. AB - Recent studies demonstrate that social interactions can have a profound influence on Drosophila melanogaster behavior and cuticular pheromone patterns. Olfactory memory performance has mostly been investigated in groups, and previous studies have reported that grouped flies do not interact with each other and behave in the same way as individual flies during short-term memory retrieval. However, the influence of social effects on the two known forms of Drosophila long-lasting associative memory, anesthesia-resistant memory (ARM) and long-term memory (LTM), has never been reported. We show here that ARM is displayed by individual flies but is socially facilitated; flies trained for ARM interact within a group to improve their conditioned performance. In contrast, testing shows LTM improvement in individual flies rather than in a group. We show that the social facilitation of ARM during group testing is independent of the social context of training and does not involve nonspecific aggregation. Furthermore, we demonstrate that social interactions facilitate ARM retrieval. We also show that social interactions necessary for this facilitation are specifically generated by trained flies: when single flies trained for ARM are mixed with groups of naive flies, they display poor retrieval, whereas mixing with groups trained either for ARM or LTM enhances performance. PMID- 19781942 TI - The CIL-1 PI 5-phosphatase localizes TRP Polycystins to cilia and activates sperm in C. elegans. AB - BACKGROUND: C. elegans male sexual behaviors include chemotaxis and response to hermaphrodites, backing, turning, vulva location, spicule insertion, and sperm transfer, culminating in cross-fertilization of hermaphrodite oocytes with male sperm. The LOV-1 and PKD-2 transient receptor potential polycystin (TRPP) complex localizes to ciliated endings of C. elegans male-specific sensory neurons and mediates several aspects of male mating behavior. TRPP complex ciliary localization and sensory function are evolutionarily conserved. A genetic screen for C. elegans mutants with PKD-2 ciliary localization (Cil) defects led to the isolation of a mutation in the cil-1 gene. RESULTS: Here, we report that a phosphoinositide (PI) 5-phosphatase, CIL-1, regulates TRPP complex ciliary receptor localization and sperm activation. cil-1 does not regulate the localization of other ciliary proteins, including intraflagellar transport (IFT) components, sensory receptors, or other TRP channels in different cell types. Rather, cil-1 specifically controls TRPP complex trafficking in male-specific sensory neurons and does so in a cell-autonomous fashion. In these cells, cil-1 is required for normal PI(3)P distribution, indicating that a balance between PI(3,5)P2 and PI(3)P is important for TRPP localization. cil-1 mutants are infertile because of sperm activation and motility defects. In sperm, the CIL-1 5 phosphatase and a wortmannin-sensitive PI 3-kinase act antagonistically to regulate the conversion of sessile spermatids into motile spermatozoa, implicating PI(3,4,5)P3 signaling in nematode sperm activation. CONCLUSION: Our studies identify the CIL-1 5-phosphatase as a key regulator of PI metabolism in cell types that are important in several aspects of male reproductive biology. PMID- 19781944 TI - Epigenetic resetting of a gene imprinted in plant embryos. AB - Genomic imprinting resulting in the differential expression of maternal and paternal alleles in the fertilization products has evolved independently in placental mammals and flowering plants. In most cases, silenced alleles carry DNA methylation. Whereas these methylation marks of imprinted genes are generally erased and reestablished in each generation in mammals, imprinting marks persist in endosperms, the sole tissue of reported imprinted gene expression in plants. Here we show that the maternally expressed in embryo 1 (mee1) gene of maize is imprinted in both the embryo and endosperm and that parent-of-origin-specific expression correlates with differential allelic methylation. This epigenetic asymmetry is maintained in the endosperm, whereas the embryonic maternal allele is demethylated on fertilization and remethylated later in embryogenesis. This report of imprinting in the plant embryo confirms that, as in mammals, epigenetic mechanisms operate to regulate allelic gene expression in both embryonic and extraembryonic structures. The embryonic methylation profile demonstrates that plants evolved a mechanism for resetting parent-specific imprinting marks, a necessary prerequisite for parent-of-origin-dependent gene expression in consecutive generations. The striking difference between the regulation of imprinting in the embryo and endosperm suggests that imprinting mechanisms might have evolved independently in both fertilization products of flowering plants. PMID- 19781945 TI - Medical countermeasures to protect humans from anthrax bioterrorism. AB - The deliberate dissemination of Bacillus anthracis spores via the US mail system in 2001 confirmed their potential use as a biological weapon for mass human casualties. This dramatically highlighted the need for specific medical countermeasures to enable the authorities to protect individuals from a future bioterrorism attack. Although vaccination appears to be the most effective and economical form of mass protection, current vaccines have significant drawbacks that justify the immense research effort to develop improved treatment modalities. After eight years and an expenditure of more than $50 billion, only marginal progress has been made in developing effective therapeutics. This article summarizes the most important medical countermeasures that have mostly been developed since the 2001 events, and highlights current problems and possible avenues for future research. PMID- 19781946 TI - Synovial plicae around the knee. AB - Synovial plicae around the knee are a relatively common occurrence but one that is rarely responsible for symptoms. The Plica syndrome has been well described but controversy still exists regarding its diagnosis and treatment. We have reviewed and studied the published literature both past and present in detail regarding synovial plicae around the knee to provide a comprehensive and up-to date review on the subject. The aim is to outline previous significant research into the embryology and pathology of synovial plicae as well as providing a review of the current thinking on treatment options available for the different synovial plicae with reference to the evidence available. PMID- 19781947 TI - Glucose-based spiro-isoxazolines: a new family of potent glycogen phosphorylase inhibitors. AB - A series of glucopyranosylidene-spiro-isoxazolines was prepared through regio- and stereoselective [3+2]-cycloaddition between the methylene acetylated exo glucal and aromatic nitrile oxides. The deprotected cycloadducts were evaluated as inhibitors of muscle glycogen phosphorylase b. The carbohydrate-based family of five inhibitors displays K(i) values ranging from 0.63 to 92.5 microM. The X ray structures of the enzyme-ligand complexes show that the inhibitors bind preferentially at the catalytic site of the enzyme retaining the less active T state conformation. Docking calculations with GLIDE in extra-precision (XP) mode yielded excellent agreement with experiment, as judged by comparison of the predicted binding modes of the five ligands with the crystallographic conformations and the good correlation between the docking scores and the experimental free binding energies. Use of docking constraints on the well defined positions of the glucopyranose moiety in the catalytic site and redocking of GLIDE-XP poses using electrostatic potential fit-determined ligand partial charges in quantum polarized ligand docking (QPLD) produced the best results in this regard. PMID- 19781948 TI - Structure-activity relationship of antiparasitic and cytotoxic indoloquinoline alkaloids, and their tricyclic and bicyclic analogues. AB - Based on the indoloquinoline alkaloids cryptolepine (1), neocryptolepine (2), isocryptolepine (3) and isoneocryptolepine (4), used as lead compounds for new antimalarial agents, a series of tricyclic and bicyclic analogues, including carbolines, azaindoles, pyrroloquinolines and pyrroloisoquinolines was synthesized and biologically evaluated. None of the bicyclic compounds was significantly active against the chloroquine-resistant strain Plasmodium falciparum K1, in contrast to the tricyclic derivatives. The tricyclic compound 2 methyl-2H-pyrido[3,4-b]indole (9), or 2-methyl-beta-carboline, showed the best in vitro activity, with an IC(50) value of 0.45 microM against P. falciparum K1, without apparent cytotoxicity against L6 cells (SI>1000). However, this compound was not active in the Plasmodium berghei mouse model. Structure-activity relationships are discussed and compared with related naturally occurring compounds. PMID- 19781949 TI - Synthesis and antioxidant properties of new chromone derivatives. AB - Nowadays, the recognition of the benefits of antioxidants is eliciting an increasingly interest in the search for new molecules with improved activity. The aim of the present work was to search for improved reactive oxygen species (ROS) and reactive nitrogen species (RNS) scavengers by testing new structures of 2 styrylchromones (2-SC) and 3-substituted flavones, which were synthesised by the Baker-Venkataraman approach. The new compounds were also tested for their metal chelating capacity and reducing activity. The obtained results showed that the methylation of hydroxyl groups decreases the scavenging of ROS and RNS by 2-SC. The decrease in the scavenging activities was, generally, more evident when the methylation occurred in B-ring, except for O2*- and (1)O(2). On the other hand, the introduction of a substituent, either hydroxyl or methoxyl, in position 8 was sometimes favourable and others unfavourable to the scavenging activities, depending on the reactive species. In conclusion, the study of the antioxidant properties of the new 2-SC and flavones allowed establishing new structure activity relationships and brought out, in some cases, pharmacophores with improved activity. PMID- 19781951 TI - Synthesis and evaluation of benzo[b]thiophene derivatives as inhibitors of alkaline phosphatases. AB - Presence of basic calcium phosphate in knee joints of osteoarthritis patients could be prevented by inhibiting tissue non-specific alkaline phosphatase (TNAP) activity. Levamisole or the L stereoisomer of tetramisole (a known TNAP inhibitor) has been used as a treatment for curing rheumatoid arthritis but its therapeutical use is limited due to side effects. We report the synthesis and the TNAP inhibition property of benzo[b]thiophene derivatives, among which benzothiopheno-tetramisole and benzothiopheno-2,3-dehydrotetramisole, which could be involved in a drug therapy for osteoarthritis. Two water soluble racemic benzothiopheno-tetramisole and -2,3-dehydrotetramisole with apparent inhibition constants K(i)=85+/-6 microM and 135+/-3 microM (n=3) comparable to that of enantiomeric levamisole 93+/-4 microM were found. Several novel derivatives showed more pronounced inhibition properties towards intestinal alkaline phosphatase than TNAP. PMID- 19781950 TI - Discovery and structure-activity relationship analysis of Staphylococcus aureus sortase A inhibitors. AB - Methicillin resistant Staphylococcus aureus (MRSA) is a major health problem that has created a pressing need for new antibiotics. Compounds that inhibit the S. aureus SrtA sortase may function as potent anti-infective agents as this enzyme attaches virulence factors to the cell wall. Using high-throughput screening, we have identified several compounds that inhibit the enzymatic activity of the SrtA. A structure-activity relationship (SAR) analysis led to the identification of several pyridazinone and pyrazolethione analogs that inhibit SrtA with IC(50) values in the sub-micromolar range. Many of these molecules also inhibit the sortase enzyme from Bacillus anthracis suggesting that they may be generalized sortase inhibitors. PMID- 19781952 TI - Comparison of chromosome preparation methods for the different developmental stages of the half-smooth tongue sole, Cynoglossus semilaevis. AB - Here we present a comparison of the different chromosome preparation methods, including the method of the single embryo or larva, the method of juvenile swimming and the method of phytohemagglutinin injection, used for the different developmental stages of the half-smooth tongue sole, Cynoglossus semilaevis. The mean index of mitosis for the three methods was 0.79%, 0.09% and 0.15%, respectively. From the well-spread metaphase chromosomes obtained, it was determined that C. semilaevis has a diploid chromosome number of 42 and heterotypic sex chromosomes. Also, the metaphase chromosomes produced could be used for karyotype preparation and banding studies. The three methods are also successfully used for chromosome preparation in Japanese flounder (Paralichthys olivaceus) and summer flounder (Paralichthys dentatus). PMID- 19781953 TI - Non-thoracoscopic extrapleural Nuss procedure for the correction of pectus excavatum in children. AB - OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of non thoracoscopic extrapleural approach of the Nuss procedure for the correction of pectus excavatum in children. METHODS: From October 2007 and January 2009, 42 patients with pectus excavatum were treated in the Tangdu Hospital, Xi'an, China, with surgical correction through the Nuss procedure. Among them, 20 underwent a Nuss procedure with thoracoscopic guidance, and the other 22 patients were treated with non-thoracoscopic extrapleural approach, in which a bilateral extrapleural tunnel to the edge of sternum was created using a blunt dissection through bilateral thoracic skin incisions. Without introducing the thoracoscopy into the thoracic cavity, a steel bar was inserted in the entirely extrapleural tunnel and turned as in the standard Nuss procedure. RESULTS: The operations were completed successfully in all patients treated. The operation time and postoperative hospitalisation time of the non-thoracoscopic extrapleural Nuss group were significantly less than those of the thoracoscopic group (P<0.05). There was no pneumothorax or hydrothorax in our series and no tube thoracostomy was further needed. All patients were followed up for more than 2 months, and the surgical outcomes were excellent. CONCLUSIONS: The non-thoracoscopic extrapleural approach of the Nuss procedure is a safe and less traumatic procedure for the correction of pectus excavatum. PMID- 19781954 TI - Intrathoracic hepatocarcinoma: when a thoracic mass is a fake. PMID- 19781955 TI - Prognostic significance of epithelial-mesenchymal transition in malignant pleural mesothelioma. AB - BACKGROUND: Epithelial-to-mesenchymal transition (EMT) is a morphologic transdifferentiation of carcinomas, conferring increased tumour invasiveness, but may also be applied to the epithelioid versus sarcomatoid histotype of malignant pleural mesothelioma (MPM). Herein, we correlated proteins of a putative MPM-EMT axis, including periostin, epidermal growth factor receptor (EGFR), integrin beta1, phosphatase and tensin homologue (PTEN), integrin-linked kinase (ILK), p21 and p27, with clinico-pathologic parameters, in particular overall survival (OS). PATIENTS AND METHODS: A retrospective cohort of 352 mostly untreated patients with MPM was investigated by immunohistochemistry of a tissue microarray. Protein expression intensities were semi-quantitatively scored from 0 to 3 in their respective compartments, including peritumoural stroma as well as tumour cell plasma membrane, cytoplasm or nucleus. Data were correlated with histotype and survival outcome. RESULTS: A total of 32% of the tumours were diagnosed as epithelioid, 13% as sarcomatoid and 55% as biphasic histotype. High expression of membranous EGFR and integrin beta1 as well as nuclear p27 correlated with the epithelioid and high expression of cytoplasmic tumoural and stromal periostin with the sarcomatoid histotype. The median survival time of the 128 patients with complete follow-up data was 11.7 months. Univariate survival analysis revealed age, epithelioid histotype and any therapy as prognosticators for better OS. High expression of cytoplasmic PTEN or ILK as well as high expression of nuclear p21 or p27 correlated with increased, whereas high expression of cytoplasmic periostin with decreased OS (all p values <0.05). Multivariate Cox regression revealed any treatment, low cytoplasmic periostin and high cytoplasmic PTEN as independent prognosticators for better OS. CONCLUSION: Activation of periostin triggered EMT is associated with the sarcomatoid histotype and has an impact on shorter survival of MPM patients. Finally, only the high expression of PTEN and the low expression of cytosolic periostin could be shown to be independent prognostic factors for longer OS. PMID- 19781956 TI - Singlet oxygen quenching by trolox C in aqueous micelle solutions. AB - Singlet oxygen ((1)O(2)) quenching by trolox C (TC, 6-hydroxy-2,5,7,8 tetramethylchroman-2-carboxylic acid), which is a water-soluble vitamin E analogue, in ethanol-water solutions and in aqueous SDS and CTAC micelles was studied by measuring the time-profiles of (1)O(2) phosphorescence at 1274 nm. The second-order rate-constant for (1)O(2) quenching by TC was determined in the ethanol-water solution to be 1.03 x 10(8), 6.22 x 10(7) and 6.23 x 10(7) M(-1) s( 1) at pH 2.0, 7.0, and 8.4, respectively. These values mean that the non dissociated form of TC under acidic conditions has superior activity to the mono anion form. In aqueous micelle systems, the decay rate of (1)O(2) at first decreased and then increased with increase of the concentration of TC. This behavior is explained in terms of the (1)O(2) quenching by TC in the bulk phase and in terms of shifting the environment surrounding (1)O(2) to lipophilic by dissolving TC in the hydrophobic region inside the micelle. The present investigation on (1)O(2) emission dynamics in inhomogeneous solutions made it possible to detect a little change in the solutions, which affects the environment around (1)O(2), such as the micelle formation and dissolving solute in the micelle. PMID- 19781957 TI - Treatment for metastatic malignant melanoma: old drugs and new strategies. AB - The number of melanoma cases worldwide is increasing faster than any other cancer and remains one of the most treatment-refractory malignancies. Despite decades of clinical trials testing chemotherapy and immunotherapy, a standard first-line treatment for metastatic melanoma has not yet been established; tough single agent dacarbazine represents the most common option. This review will focus on metastatic malignant melanoma treatment from single agent until new therapies. An overview of established chemotherapies and immunotherapies, followed by a summary of trials testing the potential combination and new agent are explored. PMID- 19781958 TI - Cyclization of peptide b9 ions. AB - The product ion mass spectra obtained by CID of the b(9) ions derived by loss of neutral alanine from the MH+ ion of the peptides Tyr(Ala)9, (Ala)4Tyr(Ala)5, and (Ala)8TyrAla are essentially identical, indicative of full cyclization reaction to a common intermediate before fragmentation. This leads to abundant nondirect sequence ions in the product ion mass spectra of the b9 ions. The product ion mass spectra of the b8 ions from the first two peptides also are essentially identical. The fragmentation of the MH+ ions also leads to low intensity nondirect sequence ions in the product ion mass spectra. N-terminal acetylation blocks the cyclization and eliminates nondirect sequence fragment ions in the product ion mass spectra. PMID- 19781959 TI - How chromatic phenomenality largely overflow its cognitive accessibility. AB - It has been suggested (Block, 2007) that the core neural bases for visual phenomenal consciousness and for access consciousness are located in anatomically separate regions. If this is correct, and if, as Block suggests, the core neural substrate of visual phenomenality is located early in the visual cortex where detailed chromatic information is available, then it would be reasonable to infer that our intuitions of chromatically rich visual phenomenality are plausible. It is furthermore suggested that during perception cognitive access to this chromatic cornucopia is mediated through mereologically superordinate (MS) concepts that regionally characterize both semantic and quantitative integrated properties within complex visual percepts. Such concepts contain much less information than do the particulars that they characterize, implying that the information represented in phenomenal consciousness greatly exceeds the information in the accompanying access consciousness. PMID- 19781960 TI - Concept paper: antihyperglycemic therapy and the diabetic heart--do we really know enough? AB - The purpose of this article is to provide reasons to start looking more critically at the existing glucose-lowering therapies in diabetes, from the point of their effect on cardiac metabolism. The presented arguments begin with the description of major differences between metabolism in myocardium and the skeletal muscle and of examples of myocardial metabolic inflexibility observed in heart failure and Type 2 diabetes. It is proposed that the metabolic inflexibility of diabetic myocardium should be taken into consideration as a factor to explain causes of unexpected cardiovascular mortality observed in the recently published outcome studies such as Action to Control Cardiovascular Risk in Diabetes (ACCORD) and Veterans Affairs Diabetes Feasibility Trial. The same reasoning was applied to challenge the "legacy effect" of the UK Prospective Diabetes Study and Steno-2 trials. A striking paucity of data on the effects of antihyperglycemic therapies on cardiac metabolism is brought to attention in spite of the fact that the technology to study human cardiac metabolism in vivo is available. It is hoped that increased focus on research in this area could contribute to improved cardiovascular safety monitoring of various antihyperglycemic regimens and thereby enhance our ability to save more lives of patients with Type 2 diabetes. PMID- 19781961 TI - Multi-voxel magnetic resonance spectroscopy of cerebral metabolites in healthy adults at 3 Tesla. AB - RATIONALE AND OBJECTIVES: The objective of this study was to determine how metabolite values (total N-acetyl aspartate [tNAA], glutamate plus glutamine [Glx], total choline [tCho], myoinositol [mI], and total creatine [tCr]) vary across brain regions in healthy subjects. This study was implemented to create an internal reference database for patients with psychiatric disorders and epilepsy. MATERIALS AND METHODS: Using the multivoxel technique with a voxelwise phantom calibration on a 3-T magnetic resonance imaging scanner, metabolite levels of 29 healthy controls (13 men, 16 women; average age, 29 years) were obtained from the hippocampi, basal ganglia, insula cortex, cingulum, and precuneus. Additionally, gray and white matter metabolite values were obtained from the frontal and parietal lobes. RESULTS: No significant effect of gender was noticed. The total magnitude of variation was greatest for Glx, followed by tNAA, mI, tCho, and tCr. Glx/tCr, Glx, and tCr were increased in gray matter, while tNAA/tCr, tCho/tCr, respectively tNAA and tCho, were elevated in white matter. These findings indicate (1) anterior-to-posterior increases of tNAA/tCr and Glx/tCr, respectively tNAA and Glx, along the midline in gray matter (cingulum); (2) increased tNAA/tCr, respectively tNAA, in white matter in the fiber tracts of the precentral region; (3) an accentuated anterior-to-posterior increase of tCr in the insula cortex; and (4) an anterior-to-posterior decrease of tCho/tCr and tCho in white matter. CONCLUSIONS: There are significant metabolic differences within tissue types and within tissue types at different locations; therefore, the spectra and metabolite values presented should provide a useful internal reference for both clinical and research studies. PMID- 19781962 TI - A novel ultrasound microbubble carrying gene and Tat peptide: preparation and characterization. AB - RATIONALE AND OBJECTIVES: Ultrasound-targeted microbubble destruction is a promising technology for the targeted gene delivery. The purpose of the present study is to prepare a novel lipid ultrasound microbubble-carrying gene and transactivating transcriptional activator (Tat) peptide and to investigate its transfection effect in vivo. METHODS AND MATERIALS: Lipid ultrasound microbubbles were prepared using mechanical vibration, and the appearance, distribution, concentration, diameter, and zeta potential of the lipid ultrasound microbubbles were measured. The efficiencies of the microbubble carrying gene and Tat peptide were investigated using the fluorospectrophotometer. Contrast-enhanced ultrasonography was performed on normal rabbits to observe the duration and intensity of enhancement in myocardium. Quantitative analysis was detected using the DFY Ultrasound Image Analyzer. Transfection in vivo was performed using the CGZZ ultrasound gene transfection instrument. The expression of enhanced green fluorescent protein in the organs was observed using confocal laser scanning microscope. RESULTS: The diameter of the lipid microbubbles carrying gene and Tat was (2.3 +/- 0.4) mum, the concentration was (3.1 +/- 0.4) x10(9)/mL, and Zeta potential was (2.0 +/- 0.1) mV. The gene encapsulation efficiency of the lipid ultrasound microbubbles was 32%, and the Tat encapsulation efficiency was 35%. In vivo experiment showed that lipid ultrasound microbubbles could enhance the echo intensity and transfection efficiency. CONCLUSION: Lipid microbubbles containing gene and Tat peptide can be used as a new vehicle for gene transfection. PMID- 19781963 TI - Identification of early interstitial lung disease in smokers from the COPDGene Study. AB - RATIONALE AND OBJECTIVES: The aim of this study is to compare two subjective methods for the identification of changes suggestive of early interstitial lung disease (ILD) on chest computed tomographic (CT) scans. MATERIALS AND METHODS: The CT scans of the first 100 subjects enrolled in the COPDGene Study from a single institution were examined using a sequential reader and a group consensus interpretation scheme. CT scans were evaluated for the presence of parenchymal changes consistent with ILD using the following scoring system: 0 = normal, 1 = equivocal for the presence of ILD, 2 = highly suspicious for ILD, and 3 = classic ILD changes. A statistical comparison of patients with early ILD to normal subjects was performed. RESULTS: There was a high degree of agreement between methods (kappa = 0.84; 95% confidence interval, 0.73-0.94; P < .0001 for the sequential and consensus methods). The sequential reading method had both high positive (1.0) and negative (0.97) predictive values for a consensus read despite a 58% reduction in the number of chest CT evaluations. Regardless of interpretation method, the prevalence of chest CT changes consistent with early ILD in this subset of smokers from COPDGene varied between 5% and 10%. Subjects with early ILD tended to have greater tobacco smoke exposure than subjects without early ILD (P = .053). CONCLUSIONS: A sequential CT interpretation scheme is an efficient method for the visual interpretation of CT data. Further investigation is required to independently confirm our findings and further characterize early ILD in smokers. PMID- 19781964 TI - Continuous intra-articular infusion of bupivacaine for post-operative pain relief after total hip arthroplasty: a randomized, placebo-controlled, double-blind study. AB - BACKGROUND: Instillation of local anesthetics into a surgical site has been gaining popularity in post-operative pain management. AIM: To determine whether continuous intra-articular infusion of bupivacaine via pain-control infusion pumps (PCIP) enhances and sustains analgesia after total hip arthroplasty (THA). METHODS: Ninety-two patients undergoing THA were randomized to receive continuous intra-articular infusion of either 0.5% bupivacaine or 0.9% normal saline at a flow rate of 2 mL/h via a PCIP for 48 h. The primary outcome measure was pain intensity on Visual Analogue Scale (VAS) scores in the first 72 h. Other measures included time to first rescue dose of narcotics, amount of narcotic use, presence of adverse events, length of hospital stay, and hip function evaluated with the Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index. RESULTS: Despite a longer time to first narcotic rescue (56 versus 21 min, p<0.0001) in patients receiving bupivacaine, the two groups did not differ significantly in overall pain relief (p=0.54). A lower VAS score was found only at time 0 and 2 h; no difference in VAS score was noted at any other time point. Additionally, no difference was found in terms of amount of narcotic use, incidence of adverse events, hospitalization days, and the WOMAC score. CONCLUSION: Continuous intra articular infusion of 0.5% bupivacaine at 2 mL/h via a PCIP does not provide sustained post-operative pain relief in patients undergoing THA. PMID- 19781965 TI - Dynamic nuclear polarization study of UV-irradiated butanol for hyperpolarized liquid NMR. AB - We have carried out a dynamic nuclear polarization (DNP) study of proton spins of UV-irradiated solid butanol containing phenol at 0.1-1%. By the aid of butyl free radicals produced by the photolysis, the butanol sample was dynamically polarized up to the polarization of 1.4+/-0.1% at 1.5 K and 1.2 T, which is about 4000 times larger than that at the thermal equilibrium at an ambient temperature. Unlike persistent free radicals such as nitroxy and trityl free radicals commonly used for DNP, the butyl free radicals immediately decay by melting. We propose that free radicals produced by UV-photolysis are applicable to the DNP-enhanced hyperpolarized liquid-state NMR (Ardenkjaer-Larsen et al. [6]). The hyperpolarization of the UV-irradiated samples should remain longer than that of the samples having persistent free radicals, because of the absence of the free radicals after the melting in the UV-irradiated samples. PMID- 19781966 TI - Labeling strategies for 13C-detected aligned-sample solid-state NMR of proteins. AB - (13)C-detected solid-state NMR experiments have substantially higher sensitivity than the corresponding (15)N-detected experiments on stationary, aligned samples of isotopically labeled proteins. Several methods for tailoring the isotopic labeling are described that result in spatially isolated (13)C sites so that dipole-dipole couplings among the (13)C are minimized, thus eliminating the need for homonuclear (13)C-(13)C decoupling in either indirect or direct dimensions of one- or multi-dimensional NMR experiments that employ (13)C detection. The optimal percentage for random fractional (13)C labeling is between 25% and 35%. Specifically labeled glycerol and glucose can be used at the carbon sources to tailor the isotopic labeling, and the choice depends on the resonances of interest for a particular study. For investigations of the protein backbone, growth of the bacteria on [2-(13)C]-glucose-containing media was found to be most effective. PMID- 19781967 TI - Molecular dynamics simulations of the conformational changes in signal transducers and activators of transcription, Stat1 and Stat3. AB - All signal transducers and activators of transcription (STAT) factors are a family of cytoplasmic transcription factors that mediate the signal response to cytokines, growth factors, and hormonal factors. The phosphorylation and subsequent activation of Stat3, a member of the STAT family, has been found to be elevated in a large number of diverse human cancers. Understanding of the dynamics of the Stat3 dimer interface is pertinent to designing small molecule inhibitors to activated Stat3 dimer. To this end, we have performed molecular dynamics simulations in explicit water of the activated Stat3 homodimer, and also its closely related member of the STAT family, activated Stat1 homodimer. We observed a large-scale domain motion in the Stat3 dimer while the structure of the monomer remains intact. The driving force for this conformational change is enhanced binding of the Stat3 dimer to the DNA, thereby regulating gene expression. Our model shows that the carboxy terminus of one monomer wraps around the core of the SH2 domain of the other monomer, and this region that makes up the dimer interface remains intact during the dynamics. Water diffuses into a cavity under this dimer interface, thus expanding a pre-existing cavity that gets gated and closed by the loops in the SH2 domain. This cavity could serve as a potential binding pocket for inhibitor design. PMID- 19781969 TI - Noninvasive prediction of vertebral body compressive strength using nonlinear finite element method and an image based technique. AB - Noninvasive prediction of vertebral body strength under compressive loading condition is a valuable tool for the assessment of clinical fractures. This paper presents an effective specimen-specific approach for noninvasive prediction of human vertebral strength using a nonlinear finite element (FE) model and an image based parameter based on the quantitative computed tomography (QCT). Nine thoracolumbar vertebrae excised from three cadavers with an average age of 42 years old were used as the samples. The samples were scanned using the QCT. Then, a segmentation technique was performed on each QCT sectional image. The segmented images were then converted into three-dimensional FE models for linear and nonlinear analyses. A new material model was implemented in our nonlinear model being more compatible with real mechanical behavior of trabecular bone. A new image based MOS (Mechanic of Solids) parameter named minimum sectional strength ((sigma(u)A)(min)) was used for the ultimate compressive strength prediction. Subsequently, the samples were destructively tested under uniaxial compression and their experimental ultimate compressive strengths were obtained. Results indicated that our new implemented FE model can predict ultimate compressive strength of human vertebra with a correlation coefficient (R(2)=0.94) better than usual linear and nonlinear FE models (R(2)=0.83 and 0.85 respectively). The image based parameter introduced in this study ((sigma(u)A)(min)) was also correlated well with the experimental results (R(2)=0.86). Although nonlinear FE method with new implemented material model predicts compressive strength better than the (sigma(u)A)(min), this parameter is clinically more feasible due to its simplicity and lower computational costs. This can make future applications of the (sigma(u)A)(min) more justified for human vertebral body compressive strength prediction. PMID- 19781968 TI - Identification of genetic variants of human cytochrome P450 2D6 with impaired mitochondrial targeting. AB - Human cytochrome P450 2D6 (CYP2D6) is responsible for the metabolism of approximately 20% of drugs in common clinical use. The CYP2D6 gene locus is highly polymorphic. Many of the polymorphisms have been shown to be clinically relevant and can account for inter-individual differences in the metabolism of specific drugs. In addition to the established sources of variability in CYP2D6 dependent drug metabolism, a recent study in our laboratory identified CYP2D6 in the mitochondria of human liver samples and found that it is metabolically active in this novel location. In the present study we show that mutations are present in the targeting signal region of CYP2D6 that may help to account for the inter individual variability that was observed previously in the level of the mitochondrial enzyme in human liver samples. These mutations were identified within the ER targeting domain, the proline-rich domain as well as the putative protein kinase A (PKA) and protein kinase C (PKC)-specific phosphorylation sites. In vitro studies demonstrate that the mutations identified in the targeting signals affect the efficiency of mitochondrial targeting of CYP2D6. Since the mitochondrial enzyme has been shown to be active in drug metabolism, this pharmacogenetic variation could play a role in modulating the response of an individual to drug therapy. PMID- 19781970 TI - [Paediatric one-stop surgery: a series of 75 cases]. AB - By one-stop surgery is meant the performing of both the pre-surgery assessment and the surgical procedure on the same day. We report our experience with a pilot study on one-stop surgery in the province of Bizkaia, with a population of 124,494 children aged 1 to 14 years old. Under the new scheme, the patient average of four visits to the hospital outpatient clinics was cut down to only one. Diagnosis and pre-surgery assessments were made by the children's Primary Care Paediatricians at their NHS clinics. Seventy-five children were treated over 10 months. They had abdominal wall, genital or soft tissue surgery. Only two developed minor complications. Families were generally satisfied with the quality of the medical care received as shown by a survey: 32.7% scored it as "excellent", 36.2% "very good", 24.1% "good" and 3.4% "medium". We think that one stop surgery is a breakthrough in ambulatory surgery. Not only does it dramatically lower the number of visits to hospital outpatient clinics, but also the waiting time for surgery, the costs, and the surgeon's workload, and helps streamline the Public Health Services and the quality of the medical care as perceived by both patients and families. Ensuring a close relationship between Paediatric Surgeons and Primary Care Paediatricians is paramount. PMID- 19781971 TI - Epidemics of severe cholera caused by El Tor Vibrio cholerae O1 Ogawa possessing the ctxB gene of the classical biotype in Orissa, India. AB - BACKGROUND: We investigated the epidemic of cholera that occurred in Kashipur and Dasmantpur blocks of Orissa, reported during July-September 2007. METHODS: Sixty two rectal swabs and 28 water samples collected from diarrhea patients at different hospitals and villages were bacteriologically analyzed for the identification, antibiogram, and detection of toxic genes of Vibrio cholerae. RESULTS: The cholera outbreaks were caused by V. cholerae O1 Ogawa biotype El Tor in both Kashipur and Dasmantpur blocks. All the V. cholerae isolates from the clinical and environmental samples were sensitive to tetracycline, gentamicin, azithromycin, and chloramphenicol, but were resistant to ampicillin, ciprofloxacin, norfloxacin, co-trimoxazole, nalidixic acid, neomycin, and furazolidone, except the water isolates, which were sensitive to ciprofloxacin and norfloxacin. The multiplex PCR assay revealed that all the clinical and environmental V. cholerae isolates were positive for the ctxA and tcpA genes, showing biotype El Tor. Interestingly, 88% of the clinical and environmental isolates of V. cholerae were El Tor biotype with mutation at the ctxB gene of the classical strain, as confirmed by mismatch amplification of mutation (MAMA)-PCR assay. CONCLUSIONS: This is the first report of the El Tor variant of V. cholerae O1 Ogawa having the ctxB gene of the classical strain with altered antibiogram causing epidemics of cholera in Orissa, India. PMID- 19781972 TI - [Crex and Orion analysis in radiation oncology: towards a mutualisation of corrective actions]. AB - After working on treatment organization in radiotherapy (bonnes pratiques organisationnelles en radiotherapie--action pilote MeaH 2003), the development of a security policy has become crucial. With the help of Air France consulting and the MeaH, three cancer centers in Angers, Lille et Villejuif worked together on the implantation of experience feed back committees (Crex) dedicated to the registration, analysis and correction of precursor events. This action has now been implemented in all the FNCLCC centers. It seems now important to have a program of mutualisation of corrective actions for all participants. This will allow to review the Orion method of events analysis. PMID- 19781973 TI - [Importance of skin graft in preventing recurrence of Dupuytren's contracture]. AB - OBJECTIVE: The aim of the study was to evaluate the ability of full thickness skin grafts to prevent recurrence of aggressive Dupuytren's contracture. PATIENTS AND METHODS: Eighteen patients presenting with bilateral recurrent Dupuytren's contracture were identified and retrospectively reviewed with a mean follow-up of 8.8 years after dermofasciectomy and skin grafting onto at least one hand. RESULTS: Only two patients presented with a complete diathesis of Dupuytren's contracture, such as defined by Hueston, thus confirming that recurrence is still not predictable. Each patient sustained 3.6 procedures on average. Thirteen patients were skin grafted on a single hand and five patients bilaterally. Recurrence occurred in three instances after skin grafting and in all instances when skin graft was not performed. Finally, three peroperative and five postoperative complications were reported. CONCLUSION: Skin grafting was able to prevent further recurrence of recurrent Dupuytren's contracture in 20 out of 23 hands with more than 8 years of follow-up. Since recurrence is still difficult to predict, primary skin grafting remains controversial. Indications for the procedure are more definite once recurrence has occurred. PMID- 19781974 TI - The Global Strategy for Plant Conservation: a challenge and opportunity for the international community. AB - In 2002, the United Nations Convention on Biological Diversity adopted a Global Strategy for Plant Conservation. This Strategy provided an important new opportunity to focus on the potential loss of tens of thousands of threatened plant species. Here, we briefly describe the development and implementation of the Strategy. PMID- 19781975 TI - Tropical botanical gardens: at the in situ ecosystem management frontier. AB - Tropical botanical gardens (TBGs) should have a leading role in in situ conservation by directly promoting several initiatives, including the reintroduction of important or valuable native species, focused habitat restoration, 'assisted migration' of species that are vulnerable to climate change, and creative local collaboration with governments, NGOs and indigenous peoples. Compared with temperate gardens, TBGs face heightened challenges for ex situ conservation, including greater absolute amounts of biodiversity, need for resource mobilization, risk of introducing invasive species and potential genetic introgression within living collections. Meanwhile, the ecosystems surrounding TBGs have undergone widespread and rapid conversion. Here, we provide several illustrations of the effectiveness of TBGs in achieving their mission of preserving tropical biodiversity at the frontier of in situ ecosystem management. PMID- 19781976 TI - Botanic gardens and the conservation of tree species. AB - The general role of botanic gardens in plant conservation has been widely accepted since the 1970s and many threatened plant species are now in well documented living collections and seed banks. Conserving tree species in ex situ collections still presents particular challenges. Many trees have so-called 'recalcitrant' seeds that cannot be stored in conventional seed banks and the sheer size of living trees restricts the number of individuals of a particular species that can be grown in a botanic garden. Even if space is available, is ex situ conservation a desirable option and how does this compare with conserving tree species in their natural habitats? In reality, conservation action for globally threatened tree species, by either in situ or ex situ means, remains inadequate and steps should be taken to combine approaches to prevent the urgent loss of tree species worldwide. PMID- 19781977 TI - Image intensity normalisation by maximising the Siddon line integral in the joint intensity distribution space. AB - This paper presents a novel data-driven method for image intensity normalisation, which is a prerequisite step for any kind of image comparison. The method involves a novel application of the Siddon algorithm that was developed initially for fast reconstruction of tomographic images and is based on a linear normalisation model with either one or two parameters. The latter are estimated by maximising the line integral, computed using the Siddon algorithm, in the 2D joint intensity distribution space of image pairs. The proposed normalisation method, referred to as Siddon Line Integral Maximisation (SLIM), was compared with three other methodologies, namely background ratio (BAR) scaling, linear fitting and proportional scaling, using a large number of synthesised datasets. SLIM was also compared with BAR normalisation when applied to phantom data and two clinical examples. The new method was found to be more accurate and less biased than its counterparts for the range of characteristics selected for the synthesised data. These findings were in agreement with the results from the analysis of the experimental and clinical data. PMID- 19781978 TI - Torturing the brain: on the folk psychology and folk neurobiology motivating 'enhanced and coercive interrogation techniques'. PMID- 19781980 TI - Environmental regulation of stomatal development. AB - Stomata are microscopic structures in the epidermis of the aerial parts of flowering plants formed by two specialized guard cells flanking a central pore. The role of stomata is to optimize gas exchange (the uptake of carbon dioxide and the loss of water vapor) to suit the prevailing environmental conditions. To do this plants open and close the stomatal pores and regulates the number of stomata that develop on the epidermes. Both these responses are controlled by integrating information from environmental cues and hormonal signals. Recent work has resulted in significant advances in our understanding of the underlying pathway controlling stomatal development. Here we shall discuss how environmental cues might modulate this pathway such that gas exchange is optimized to suit the prevailing environmental conditions. PMID- 19781981 TI - From functional genomics to systems (micro)biology. PMID- 19781979 TI - Recent progress and applications in glycosaminoglycan and heparin research. AB - Heparin, the focus of this review, is a crucially important anticoagulant drug produced from animal sources, which was contaminated last year leading to a number of adverse side effects, some resulting in death. Heparin is a highly acidic polysaccharide and a member of a family of biopolymers called glycosaminoglycans. The structure and activities of heparin are detailed along with recent advances in heparin structural analysis and biological evaluation. Current state-of-the-art chemical and chemoenzymatic synthesis of heparin and new approaches for its metabolic engineering are described. New technologies, including microarrays and digital microfluidics, are proposed for high-throughput synthesis and screening of heparin and for the fabrication of an artificial Golgi. PMID- 19781982 TI - Tunable fiber laser and fiber amplifier based photoacoustic spectrometer for trace gas detection. AB - A new wavelength modulated photoacoustic spectrometer based on a near-infrared tunable erbium doped fiber laser (TEDFL) and an erbium doped fiber amplifier (EDFA) is first developed for trace gas detection. This sensor has been applied to the detection of ammonia using a first longitudinal resonant photoacoustic cell with double absorption optical path (L=20cm) and lock-in harmonic detection technique. The minimum detectable limit of 3 parts-per-billion volume (signal-to noise ratio=1) and response time of approximately 1min is achieved at room temperature and atmospheric pressure with 100ms time constant and 500mW optical power at the 1531.7nm transition line. PMID- 19781983 TI - Spectrofluorimetric quantification of bromazepam using a highly selective optical probe based on Eu3+-bromazepam complex in pharmaceutical and serum samples. AB - A rapid, simple and sensitive spectrofluorimetric method for determination of trace amount of bromazepam is developed. In phosphate buffer of pH 7.4. The bromazepam enhance the luminescence intensity of the Eu(3+) ion in Eu(3+) bromazepam complex at lambda(ex)=390nm. The produced luminescence intensity of Eu(3+)-bromazepam complex is in proportion to the concentration of bromazepam. The working range for the determination of bromazepam is 2.3x10(-8) to 6.2x10( 7)M with detection limit (LoD) and quantitative detection limit (LoQ) of 3x10(-9) and 1.2x10(-8)M, respectively. While, the working range, detection limit (LoD) and quantitative detection limit (LoQ) in case of the quantum yield calculations are 3.7x10(-8) to 3.4x10(-7)M with of 3.4x10(-9) and 9.2x10(-8)M, respectively. The enhancement mechanism of the luminescence intensity in the Eu(3+)-bromazepam system has been also explained. PMID- 19781984 TI - Evaluation of DNA extraction methods for dried blood spots in the diagnosis of congenital cytomegalovirus infection. AB - BACKGROUND: Dried blood spots (DBS) may be valuable in the diagnosis of congenital cytomegalovirus (CMV) infection. However, the 2007 European Quality Control for Molecular Diagnostics (QCMD) proficiency testing programme showed that CMV DNA detection in DBS was lacking sensitivity in a considerable number of participating laboratories. OBJECTIVE: To compare DNA extraction methods for DBS for detecting CMV. Sensitivity and applicability of the methods for high throughput usage were assessed. STUDY DESIGN: Guthrie cards were spotted with CMV DNA-positive whole blood (n=15). DNA was extracted from the DBS using different extraction methods, followed by CMV amplification by means of real-time PCR. RESULTS: Significant differences between the extraction methods with respect to the sensitivity were found. Optimal sensitivity was achieved when samples were tested in triplicate, demonstrating that the methods in general operated around their detection limits. Triplicate testing using the protocol by Barbi et al. [Barbi M, et al. Cytomegalovirus DNA detection in Guthrie cards: a powerful tool for diagnosing congenital infection. J Clin Virol 2000;17:159-65], representing the most sensitive methods, resulted in sensitivities of 100%, 86%, and 50% for DBS with CMV DNA loads of 5-4, 4-3, and 3-2log(10)copies/ml, respectively. This indicates that sensitivity limitations apply in the clinically relevant concentration range. Few methods appeared suitable for 96-well format high throughput testing. DISCUSSION: When considering universal neonatal screening for congenital CMV infection, an assay which is both sensitive and applicable for high-throughput testing is required. The protocol by Barbi et al. and the BioRobot Universal System appear appropriate candidates currently available for 96-well format application in neonatal screening using DBS. PMID- 19781985 TI - Findings and conclusions from CMV hyperimmune globulin treatment trials. AB - A primary maternal infection with cytomegalovirus (CMV) either during or just before pregnancy accounts for the majority of congenital infections where the baby is symptomatic at birth. Following a primary maternal infection, depending on gestational age, between one quarter and three quarters of fetuses will become infected, and approximately one-third of infected fetuses will have symptoms at birth. Experiments using animal models of CMV infection and observational studies in humans indicate that administration of a CMV hyperimmune globulin (HIG) to the pregnant woman with a primary CMV infection should be effective for both the treatment and prevention of fetal infection. The HIG probably acts by reducing placental inflammation, neutralizing virus with high avidity antibodies, and perhaps by reducing cytokine mediated cellular immune responses. PMID- 19781986 TI - Spatial detection of multiple movement intentions from SAM-filtered single-trial MEG signals. AB - OBJECTIVE: To test whether human intentions to sustain or cease movements in right and left hands can be decoded reliably from spatially filtered single-trial magnetoencephalographic (MEG) signals for motor execution and motor imagery. METHODS: Seven healthy volunteers, naive to BCI technology, participated in this study. Signals were recorded from 275-channel MEG, and synthetic aperture magnetometry (SAM) was employed as the spatial filter. The four-class classification was performed offline. Genetic algorithm based Mahalanobis linear distance (GA-MLD) and direct-decision tree classifier (DTC) techniques were adopted for the classification through 10-fold cross-validation. RESULTS: Through SAM imaging, strong and distinct event-related desynchronization (ERD) associated with sustaining, and event-related synchronization (ERS) patterns associated with ceasing of right and left hand movements were observed in the beta band (15-30Hz) on the contralateral hemispheres for motor execution and motor imagery sessions. Virtual channels were selected from these areas of high activity for the corresponding events as per the paradigm of the study. Through a statistical comparison between SAM-filtered virtual channels from single-trial MEG signals and basic MEG sensors, it was found that SAM-filtered virtual channels significantly increased the classification accuracy for motor execution (GA-MLD: 96.51+/-2.43%) as well as motor imagery sessions (GA-MLD: 89.69+/-3.34%). CONCLUSION: Multiple movement intentions can be reliably detected from SAM-based spatially filtered single-trial MEG signals. SIGNIFICANCE: MEG signals associated with natural motor behavior may be utilized for a reliable high-performance brain computer interface (BCI) and may reduce long-term training compared with conventional BCI methods using rhythm control. PMID- 19781987 TI - Functional topography of the ventral striatum and anterior limb of the internal capsule determined by electrical stimulation of awake patients. AB - OBJECTIVE: To assess the behavioral and subjective effects of acute electrical stimulation along the anterior limb of the internal capsule (ALIC) and ventral striatum (VS). METHODS: Intraoperative awake electrical stimulation and postoperative programming was performed in a group of 6 patients with major depressive disorder (MDD) undergoing bilateral deep brain stimulation of the ALIC and VS areas. RESULTS: Electrical stimulation of the VS area acutely produced changes in mood as well as alertness, anxiety, dizziness, sensation of warmth and "flushing". Stimulation of the ventral capsule area just dorsal to the anterior commissure was associated with increments in mood, sensation of energy and alertness, laughing, calmness and talkative behavior. Behavioral effects were less commonly observed with stimulation of the dorsal region of the ALIC. CONCLUSION: Acute behavioral and subjective responses can be consistently obtained from stimulation in the ventral ALIC and VS region. Positive changes in mood and anxiety were reproducibly elicited in the ventral ALIC area. SIGNIFICANCE: Intraoperative awake stimulation and postoperative programming of patients undergoing DBS for MDD provide unique opportunities to explore the subjective responses and behavioral phenomena related to electrical stimulation of the area spanning from the dorsal ALIC to the ventral striatum. PMID- 19781988 TI - Immunomodulation by semi-mature dendritic cells: a novel role of Toll-like receptors and interleukin-6. AB - Dendritic cells (DCs) are key players in activation of the adaptive immune system by their ability of antigen presentation to and priming of T cells. An increasing body of evidence suggests that DCs may also play an important role in induction of tolerance, predominantly by induction of regulatory T cells (T(reg)). More recently, data have been published on how Toll-like receptor (TLR) ligands and cytokines affect DC differentiation, and how DC subsets might be involved in immunoregulation and tolerance rather than in T cell activation. The most important features of tolerance-inducing DCs appear to be their maturation state and their cytokine secretion pattern. The following types of tolerance-inducing DCs have been reported: immature DCs (DCs(im)) or DCs in the steady state (DCs(st)), DCs(IL-10), semi-mature DCs(TNF-alpha), semi-mature DCs(IL-6). With this review article we would like to discuss the aforementioned types of tolerogenic DCs with a focus on semi-mature DCs(IL-6) and discuss their potential role in maintenance of (hepatic or intestinal) immune homeostasis and inflammatory diseases such as inflammatory bowel disease. PMID- 19781989 TI - Role of NF-kappaB activation in intestinal immune homeostasis. AB - Inflammatory bowel diseases (IBD) are characterised by a disturbance of intestinal immune homeostasis, either caused by or followed by inappropriate responses to the resident commensal bacteria. Although the transcription factor NF-kappaB actively participates in the excessive inflammatory response observed in IBD, recent studies with mice defective in NF-kappaB activation have revealed that NF-kappaB also serves an essential protective function in the intestinal immune system. The enormous amount of commensal bacteria in the intestine might play a role in the distinct functions of NF-kappaB in the intestine, as they can initiate signalling to NF-kappaB through both Toll-like receptors and NOD-like receptors in intestinal epithelial cells as well as mucosal immune cells. However, the exact individual contributions of different NF-kappaB-activating stimuli as well as the target cells that mediate the detrimental or beneficial functions of NF-kappaB in the intestine are still elusive. In this review, I will summarise and discuss the current knowledge on the role of different NF-kappaB activating pathways in preserving intestinal immune homeostasis and the development of intestinal inflammation. PMID- 19781990 TI - Staphylococcus aureus host cell invasion and post-invasion events. AB - Staphylococcus aureus is now recognized as a facultative intracellular pathogen. The aim of this review is to discuss novel data regarding the invasion mechanism and post-invasion events with a focus on the fate of the infected phagosome in non-professional phagocytes and the role of S. aureus alpha-toxin. PMID- 19781991 TI - T cells, dendritic cells and epithelial cells in intestinal homeostasis. AB - The mucosal immune system of the intestinal tract is continuously exposed to both potential pathogens and beneficial commensal microorganism. A variety of mechanisms contribute to the ability of the gut to either react or remain tolerant to antigen present in the intestinal lumen. Antigens of the gut commensals are not simply ignored, but rather trigger an active immunosuppressive process, which prevents the outcome of immunopathology. The aim of this review is to provide an update on the mechanism of intestinal homeostasis, with particular focus on the complex crosstalk between T cells, dendritic cells and intestinal epithelial cells. PMID- 19781992 TI - Breast-milk levels of polybrominated diphenyl ether flame retardants in relation to women's age and pre-pregnant body mass index. AB - The aim of the present study was to determine associations between the occurrence of PBDEs in breast milk of women and their demographic parameters. Participants were randomly recruited from the general population in southern Taiwan. Thirty two breast milk samples were collected and subsequently 30 congeners of PBDEs were analyzed using a high resolution gas chromatograph with a high resolution mass spectrometer. The mean and median of SigmaPBDEs were 3.54 and 3.31 ng/g lipid, respectively. SigmaPBDE levels in breast milk were not significantly correlated with age and pre-pregnant BMI of Taiwanese mothers. We did find, however, that the higher hexaBDE level was significantly related to older age (>29 years). Higher levels of SigmaPBDEs and higher brominated PBDEs, such as nonaBDEs and decaBDE, had slightly but not significantly negative correlations with lower pre-pregnant BMI (< or =21 kg/m(2)). There were no significant differences in PBDE levels among parity and ethnic groups. SigmaPBDE levels in Taiwanese breast milk were lower than those reported from the United States or Canada. SigmaPBDE levels of the present study (2007-2008) are significantly lower than those found in our previous report (2000-2001). Although our results were limited by the sampling size, preliminary results suggest the exploratory relations to show positive associations of PBDE homologues (e.g. triBDEs and hexaBDEs) with maternal age. PBDEs pattern of breast milk may have changed after pentaBDEs were stopped to use in Taiwan. PMID- 19781993 TI - Psoriasis--as an autoimmune disease caused by molecular mimicry. AB - Psoriasis is strongly associated with streptococcal throat infection, and patients have increased occurrence of such infections. Psoriatic lesional T cells are oligoclonal, and T cells recognizing determinants common to streptococcal M protein and keratin have been detected in patients' blood. We propose that CD8(+) T cells in psoriatic epidermis respond mainly to such determinants, whereas CD4(+) T cells in the dermis preferentially recognize determinants on the streptococcal peptidoglycan that might itself act as an adjuvant. The streptococcal association might reflect the concurrence of superantigen production promoting skin-homing of tonsil T cells, M-protein mimicking keratin determinants, and adjuvant effects of the peptidoglycan. Accordingly, improvement of psoriasis after tonsillectomy should be associated with fewer T cells that recognize keratin and streptococcal determinants. PMID- 19781994 TI - Endotoxin tolerance: new mechanisms, molecules and clinical significance. AB - Prior exposure of innate immune cells like monocytes/macrophages to minute amounts of endotoxin cause them to become refractory to subsequent endotoxin challenge, a phenomenon called "endotoxin tolerance". Clinically, this state is associated with monocytes/macrophages in sepsis patients where they contribute to "immunosuppression" and mortality. The molecular mechanisms underlying endotoxin tolerance remain elusive. The recent appreciation of inflammation as a self regulating process, the relative contribution of MyD88 versus TRIF signaling pathways in inducing activation or tolerance, plasticity of NF-kappaB function and the role of chromatin modification and microRNAs in LPS-induced gene reprogramming urges a re-evaluation of endotoxin tolerance. This review integrates these new findings into an up-to-date account of endotoxin tolerance, its molecular basis and clinical implications in different pathologies. PMID- 19781995 TI - Thymic epithelial cells: the multi-tasking framework of the T cell "cradle". AB - The thymus provides the anatomical "cradle" that fosters developing thymocytes. Thymic epithelial cells (TECs) are specialized cellular components that may be viewed as a multifunctional "frame" to nurture distinct stages of thymopoiesis. A symbiotic relationship between TECs and thymocytes exists because reciprocal interactions are required to achieve complete maturation of both cell types. Here, we propose that crucial instructive signals delivered by developing thymocytes negatively regulate functional attributes of immature TECs (including the expression of Delta-like 4 (DLL4) and interleukin-7 (IL-7)) that are required during early stages of thymopoiesis, while promoting the diversification of more mature TEC subsets. Thus, the division of labour among TECs may be coordinated directly by local cellular feedback mechanisms operating within distinct thymic niches. PMID- 19781997 TI - The impact of podcasting on the learning and satisfaction of undergraduate nursing students. AB - Nursing education has evolved from traditional pedagogical models to current methods using technology for knowledge acquisition. Podcasting is one example of teaching methodology used in higher education. Studies demonstrate positive student satisfaction with podcasting, but there is limited data related to knowledge acquisition. The purpose of this study was to examine the impact of podcasting on nursing student learning and satisfaction. Two classes of junior baccalaureate nursing students had scores on selected exam questions compared. The 2007 class (n=63) had select content presented in traditional lecture format where the 2008 class (n=57) had the same content presented via podcast. Both methods used the same faculty and exam questions. The 2008 class completed a satisfaction survey. Results indicated no significant difference in correct responses on exam questions. Exam scores were better with the first podcast, equal for the second, and worse with the third podcast. Students were overall satisfied with the podcasting experience and commented positively on its portability and flexibility. This study contributes to the knowledge base of podcasting effectiveness and raises the question of evaluation of new teaching methodologies. Must an increase in learning occur for new methods to be considered effective, or is positive student satisfaction adequate to encourage the adoption of new technology methods? PMID- 19781998 TI - Illuminating blood components. PMID- 19781996 TI - Hemoglobin, nitric oxide and molecular mechanisms of hypoxic vasodilation. AB - The protected transport of nitric oxide (NO) by hemoglobin (Hb) links the metabolic activity of working tissue to the regulation of its local blood supply through hypoxic vasodilation. This physiologic mechanism is allosterically coupled to the O(2) saturation of Hb and involves the covalent binding of NO to a cysteine residue in the beta-chain of Hb (Cys beta93) to form S-nitrosohemoglobin (SNO-Hb). Subsequent S-transnitrosation, the transfer of NO groups to thiols on the RBC membrane and then in the plasma, preserves NO vasodilator activity for delivery to the vascular endothelium. This SNO-Hb paradigm provides insight into the respiratory cycle and a new therapeutic focus for diseases involving abnormal microcirculatory perfusion. In addition, the formation of S-nitrosothiols in other proteins may regulate an array of physiological functions. PMID- 19781999 TI - Dengue virus during blood donation: pre-screen using NS1 antigen. PMID- 19782000 TI - Motivators and barriers to blood donation in African American college students. AB - BACKGROUND: An adequate blood supply depends on volunteer non-remunerated blood donors. African Americans have lower blood donation rates than whites. To improve African American blood donation rates, the motivators and barriers to African Americans must be explored. This study investigated the differences in motivators and barriers to blood donation between donor and non-donor African American college students. METHODS: African Americans college students at two Historically Black Colleges and Universities completed a 41-item, self-administered questionnaire, which assessed participant's donation frequency, motivators and barriers toward donation, and knowledge and beliefs towards blood donation. RESULTS: Three hundred and sixty four primarily female college students (96% African Americans, 93% female) completed the questionnaire. Forty-nine percent reported prior blood donation experience (donors) and 51% were non-donors. The primary motivator for donors and non-donors was convenience (89% donor, 82% non donor). Donors were more likely than non-donors to disagree with statements regarding blood donation as being too painful (82% donor, 44% non-donor), resulting in feeling faint, dizzy, or nauseated (61% donor, 29% non-donor). Donors more often agreed that the blood supply is safe (77% donor, 58% non donor), less often concerned about receiving a transfusion (61% donor, 73% non donor), and more often aware of local blood shortages (50% donor, 35% non-donor). CONCLUSIONS: African Americans female college students are willing to donate blood given convenience and support from their university. Educational campaigns to increase knowledge regarding the safety of the blood donation process and the ongoing needs of an adequate blood supply might be effective methods to increase blood donation. PMID- 19782001 TI - Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: a systematic review and meta-analysis. AB - BACKGROUND: Reliable data on the prevalence and predictors of post-stroke dementia are needed to inform patients and carers, plan services and clinical trials, ascertain the overall burden of stroke, and understand its causes. However, published data on the prevalence and risk factors for pre-stroke and post-stroke dementia are conflicting. We undertook this systematic review to assess the heterogeneity in the reported rates and to identify risk factors for pre-stroke and post-stroke dementia. METHODS: Studies published between 1950 and May 1, 2009, were identified from bibliographic databases, reference lists, and journal contents pages. Studies were included if they were on patients with symptomatic stroke, were published in English, reported on a series of consecutive eligible patients or volunteers in prospective cohort studies, included all stroke or all ischaemic stroke, measured dementia by standard criteria, and followed up patients for at least 3 months after stroke. Pooled rates of dementia were stratified by study setting, inclusion or exclusion of pre stroke dementia, and by first, any, or recurrent stroke. Pooled odds ratios were calculated for factors associated with pre-stroke and post-stroke dementia. FINDINGS: We identified 22 hospital-based and eight population-based eligible cohorts (7511 patients) described in 73 papers. The pooled prevalence of pre stroke dementia was higher (14.4%, 95% CI 12.0-16.8) in hospital-based studies than in population-based studies (9.1%, 6.9-11.3). Although post-stroke ( or =34 weeks gestation, born between 2000 and 2008 with evidence of perinatal asphyxia and neonatal encephalopathy were identified. HIE was classified as mild, moderate or severe. Joinpoint regression model was used to identify changes in the trends of HIE incidences. RESULTS: A total of 90,963 live infants were born in La Paz Hospital between 2000 and 2008, and 23.3% of them (21.228) were admitted to the Neonatal Unit. In addition, 200 infants were referred from other centers. A total of 110 infants had HIE, of which 90% were inborn. The overall incidence of HIE was 1.088 per 1,000 live births, and the incidence of clinically significant HIE (moderate and severe grades) was 0.49 per 1,000 live births. The incidence of HIE showed a linear downward trend throughout the study period (slope=-5.37; P<0.05). Fifty-two neonates had moderate or severe HIE, this represents a prevalence of 2.42 per 1,000 infants admitted to the Neonatal Unit and means that 5-6 infants a year would have been candidates for therapeutic hypothermia. CONCLUSIONS: Neonatal HIE, and in particular significant HIE, is an infrequent condition. The low prevalence of HIE requires that these infants are referred to regional centers with sufficient experience in the use of therapeutic hypothermia, and in the management of all the medical problems associated with HIE. PMID- 19782013 TI - [Benign intracranial hypertension: experience over 18 years]. AB - INTRODUCTION: There are transient intracranial hypertension cases, recognizable by bulging fontanelle in infants and by papilloedema in children. We present our experience in benign intracranial hypertension (BIH) cases, excluding traumatic brain injuries, encephalitis and meningitis. RESULTS: Among the entire neuropaediatric database, with 10,720 children in 18 years, 31 cases had the diagnosis of BIH. Sixteen aged between 2.3 and 8.9 months (75% males), all of them with transient bulging fontanelle, and 15 aged between 4.4 and 13.7 years (73.3% females), all of them with papilloedema which was subsequently resolved. A total of 75% of infants had recently finished corticosteroid treatment for bronchitis. In the older children, there was 1 case associated with excessive vitamin A intake and 1 mastoiditis. Transfontanelle ultrasonography or CT was performed on all infants and CT or MRI in every child. Lumbar puncture was also performed on 7 infants and on 13 children. Infants developed favourably in a few days, and children did so between 1 week and 5 months, some with treatment. DISCUSSION: BIH usually has a favourable outcome, although it may take longer in children than in infants, but it can have serious visual repercussions, even blindness, so ophthalmological control is necessary. It is normally diagnosed by exclusion of other intracranial hypertension causes. MRI and lumbar puncture must be done on all children or infants who do not progress favourably. Acetazolamide and furosemide, corticosteroids, repeated lumbar punctures and optic nerve sheath fenestration should be considered in those who do not progress well. PMID- 19782014 TI - Prologue: advances in bronchopulmonary dysplasia. PMID- 19782015 TI - Striae ulceration in iatrogenic Cushing's syndrome. PMID- 19782016 TI - Hypoglycaemia: an overview. AB - Hypoglycaemia is a frequent side-effect of treatment with insulin and sulfonylureas for people with diabetes, threatening potentially serious morbidity and preventing optimal glycaemic control. Fear of hypoglycaemia and development of syndromes such as impaired awareness and counterregulatory deficiency provide additional hazards for intensification of treatment. Rapid lowering of HbA1c may be potentially dangerous in type 2 diabetes because of the adverse cardiovascular effects induced by hypoglycaemia. Hypoglycaemia can disrupt many everyday activities such as driving, work performance and recreational pursuits. Measures to reduce the risk of hypoglycaemia are labour-intensive and require substantial resources. PMID- 19782018 TI - How to choose a good scientific problem. AB - Choosing good problems is essential for being a good scientist. But what is a good problem, and how do you choose one? The subject is not usually discussed explicitly within our profession. Scientists are expected to be smart enough to figure it out on their own and through the observation of their teachers. This lack of explicit discussion leaves a vacuum that can lead to approaches such as choosing problems that can give results that merit publication in valued journals, resulting in a job and tenure. PMID- 19782019 TI - Linking the cell cycle to histone modifications: Dot1, G1/S, and cycling K79me2. AB - In a recent issue of Molecular Cell, Schulze et al. (2009) described distinct distributions and regulation of Dot1-dependent methylation states at lysine 79 on histone H3 and showed cell-cycle regulation of K79 dimethylation on genes expressed during the G1/S phase. PMID- 19782020 TI - Summon SUMO to wrestle with inflammation. AB - In this issue of Molecular Cell, Lee et al. (2009) report that SUMOylation of nuclear receptors LXRalpha and LXRbeta plays a critical role in the transrepression of IFN-gamma-induced STAT1-dependent inflammatory responses in brain astrocytes. PMID- 19782021 TI - A cut above the other caspases. AB - In this issue of Molecular Cell, Bouchier-Hayes et al. (2009) develop a novel approach to visualizing caspase-2 activation in real time, enabling resolution of several controversies surrounding the position of this enzyme in apoptotic signaling cascades. PMID- 19782022 TI - Destruction of RhoA CULtivates actin. AB - Cullin 3, the core subunit of the CRL3 ubiquitin ligase family, is essential for development, but its substrates remain poorly defined. Here, Chen et al. (2009) report that CRL3(BACURD) targets the RhoA GTPase for degradation, thereby maintaining actin cytoskeleton integrity. PMID- 19782023 TI - mir-210: a sensor for hypoxic stress during tumorigenesis. AB - In this issue of Molecular Cell, Huang et al. (2009) demonstrate that hypoxia inducible mir-210 acts as a rheostat for cellular adaptation and survival by inhibiting tumor initiation. PMID- 19782024 TI - The chicken or the egg: microRNA-mediated regulation of mRNA translation or mRNA stability. AB - In this issue of Molecular Cell, Fabian et al. (2009) demonstrate that in cell free extracts from mouse Krebs-2 ascites, microRNA-mediated translational repression precedes target mRNA deadenylation, and identify GW182, PABP, and deadenylase subunits CAF1 and CCR4 as factors required for deadenylation. PMID- 19782025 TI - Transcription dynamics. AB - All aspects of transcription and its regulation involve dynamic events. The basal transcription machinery and regulatory components are dynamically recruited to their target genes, and dynamic interactions of transcription factors with chromatin--and with each other--play a key role in RNA polymerase assembly, initiation, and elongation. These short-term binding dynamics of transcription factors are superimposed by long-term cyclical behavior of chromatin opening and transcription factor-binding events. Its dynamic nature is not only a fundamental property of the transcription machinery, but it is emerging as an important modulator of physiological processes, particularly in differentiation and development. PMID- 19782026 TI - Dynamic interactions and cooperative functions of PGC-1alpha and MED1 in TRalpha mediated activation of the brown-fat-specific UCP-1 gene. AB - PGC-1alpha is an inducible nuclear receptor coactivator with direct functions in both p300-mediated chromatin remodeling and Mediator-dependent transcription in vitro. Here, we have employed the PPARgamma- and TRalpha-activated brown adipose tissue-specific UCP-1 enhancer to investigate mechanistic aspects of PGC-1alpha function. We first demonstrate a cellular role for the PGC-1alpha-interacting MED1 subunit of Mediator in UCP-1 induction, as well as the accumulation of TRalpha, PPARgamma, PGC-1alpha, and MED1 on the UCP-1 enhancer in brown adipocytes. We then use biochemical assays to show that (i) PGC-1alpha is recruited to the TRalpha-RXRalpha-UCP-1 enhancer complex through interaction of an N-terminal LXXLL domain with TRalpha, (ii) MED1/Mediator displaces PGC-1alpha from TRalpha through LXXLL domain competition, and (iii) upon loss of PGC-1alpha TRalpha interactions, PGC-1alpha remains associated with the enhancer complex through an interaction between PGC-1alpha and MED1 C-terminal domains. These results indicate dynamic MED1-dependent PGC-1alpha interactions related to functions in both chromatin remodeling and the transition to subsequent transcription initiation. PMID- 19782027 TI - Reconstitution of heterochromatin-dependent transcriptional gene silencing. AB - Heterochromatin assembly in budding yeast requires the SIR complex, which contains the NAD-dependent deacetylase Sir2 and the Sir3 and Sir4 proteins. Sir3 binds to nucleosomes containing deacetylated histone H4 lysine 16 (H4K16) and, with Sir4, promotes spreading of Sir2 and deacetylation along the chromatin fiber. Combined action of histone modifying and binding activities is a conserved hallmark of heterochromatin, but the relative contribution of each activity to silencing has remained unclear. Here, we reconstitute SIR-chromatin complexes using purified components and show that the SIR complex efficiently deacetylates chromatin templates and promotes the assembly of altered structures that silence Gal4-VP16-activated transcription. Silencing requires all three Sir proteins, even with fully deacetylated chromatin, and involves the specific association of Sir3 with deacetylated H4K16. These results define a minimal set of components that mediate heterochromatic gene silencing and demonstrate distinct contributions for histone deacetylation and nucleosome binding in the silencing mechanism. PMID- 19782028 TI - Histone chaperones ASF1 and NAP1 differentially modulate removal of active histone marks by LID-RPD3 complexes during NOTCH silencing. AB - Histone chaperones are involved in a variety of chromatin transactions. By a proteomics survey, we identified the interaction networks of histone chaperones ASF1, CAF1, HIRA, and NAP1. Here, we analyzed the cooperation of H3/H4 chaperone ASF1 and H2A/H2B chaperone NAP1 with two closely related silencing complexes: LAF and RLAF. NAP1 binds RPD3 and LID-associated factors (RLAF) comprising histone deacetylase RPD3, histone H3K4 demethylase LID/KDM5, SIN3A, PF1, EMSY, and MRG15. ASF1 binds LAF, a similar complex lacking RPD3. ASF1 and NAP1 link, respectively, LAF and RLAF to the DNA-binding Su(H)/Hairless complex, which targets the E(spl) NOTCH-regulated genes. ASF1 facilitates gene-selective removal of the H3K4me3 mark by LAF but has no effect on H3 deacetylation. NAP1 directs high nucleosome density near E(spl) control elements and mediates both H3 deacetylation and H3K4me3 demethylation by RLAF. We conclude that histone chaperones ASF1 and NAP1 differentially modulate local chromatin structure during gene-selective silencing. PMID- 19782030 TI - Differential SUMOylation of LXRalpha and LXRbeta mediates transrepression of STAT1 inflammatory signaling in IFN-gamma-stimulated brain astrocytes. AB - To unravel the roles of LXRs in inflammation and immunity, we examined the function of LXRs in development of IFN-gamma-mediated inflammation using cultured rat brain astrocytes. LXR ligands inhibit neither STAT1 phosphorylation nor STAT1 translocation to the nucleus but, rather, inhibit STAT1 binding to promoters and the expression of IRF1, TNFalpha, and IL-6, downstream effectors of STAT1 action. Immunoprecipitation data revealed that LXRbeta formed a trimer with PIAS1-pSTAT1, whereas LXRalpha formed a trimer with HDAC4-pSTAT1, mediated by direct ligand binding to the LXR proteins. In line with the fact that both PIAS1 and HDAC4 belong to the SUMO E3 ligase family, LXRbeta and LXRalpha were SUMO-conjugated by PIAS1 or HDAC4, respectively, and SUMOylation was blocked by transient transfection of appropriate individual siRNAs, reversing LXR-induced suppression of IRF1 and TNFalpha expression. Together, our data show that SUMOylation is required for the suppression of STAT1-dependent inflammatory responses by LXRs in IFN-gamma-stimulated brain astrocytes. PMID- 19782029 TI - Cse4 is part of an octameric nucleosome in budding yeast. AB - The budding yeast CenH3 histone variant Cse4 localizes to centromeric nucleosomes and is required for kinetochore assembly and chromosome segregation. The exact composition of centromeric Cse4-containing nucleosomes is a subject of debate. Using unbiased biochemical, cell-biological, and genetic approaches, we have tested the composition of Cse4-containing nucleosomes. Using micrococcal nuclease treated chromatin, we find that Cse4 is associated with the histones H2A, H2B, and H4, but not H3 or the nonhistone protein Scm3. Overexpression of Cse4 rescues the lethality of a scm3 deletion, indicating that Scm3 is not essential for the formation of functional centromeric chromatin. We also find that octameric Cse4 nucleosomes can be reconstituted in vitro. Furthermore, Cse4-Cse4 dimerization occurs in vivo at the centromeric nucleosome, and this requires the predicted Cse4-Cse4 dimerization interface. Taken together, our experimental evidence supports the model that the Cse4 nucleosome is an octamer, containing two copies each of Cse4, H2A, H2B, and H4. PMID- 19782031 TI - Structure and activation mechanism of the CHK2 DNA damage checkpoint kinase. AB - The CHK2 protein kinase is an important transducer of DNA damage checkpoint signals, and its mutation contributes to hereditary and sporadic cancer. CHK2 activation is triggered by the phosphorylation of Thr68 by the DNA damage activated ATM kinase. This leads to transient CHK2 dimerization, in part through intermolecular phosphoThr68-FHA domain interactions. Dimerization promotes kinase activation through activation-loop autophosphorylation, but the mechanism of this process has not been clear. The dimeric crystal structure of CHK2, described here, in conjunction with biochemical and mutational data reveals that productive CHK2 dimerization additionally involves intermolecular FHA-kinase domain and FHA FHA interactions. Ile157, mutated in the Li-Fraumeni cancer-predisposition syndrome, plays a central role in the FHA-kinase domain interface, explaining the lack of dimerization and autophosphorylation of this mutant. In the dimer, the kinase active sites face each other in close proximity, indicating that dimerization may also serve to optimally position the kinase active sites for efficient activation loop transphosphorylation. PMID- 19782032 TI - Characterization of cytoplasmic caspase-2 activation by induced proximity. AB - Caspase-2 is an initiator caspase activated in response to heat shock and other stressors that induce apoptosis. Activation of caspase-2 requires induced proximity resulting after recruitment to caspase-2 activation complexes such as the PIDDosome. We have adapted bimolecular fluorescence complementation (BiFC) to measure caspase-2 induced proximity in real time in single cells. Nonfluorescent fragments of the fluorescent protein Venus that can associate to reform the fluorescent complex were fused to caspase-2, allowing visualization and kinetic measurements of caspase-2 induced proximity after heat shock and other stresses. This revealed that the caspase-2 activation platform occurred in the cytosol and not in the nucleus in response to heat shock, DNA damage, cytoskeletal disruption, and other treatments. Activation, as measured by this approach, in response to heat shock was RAIDD dependent and upstream of mitochondrial outer membrane permeabilization. Furthermore, we identify Hsp90alpha as a key negative regulator of heat shock-induced caspase-2 activation. PMID- 19782033 TI - Cullin mediates degradation of RhoA through evolutionarily conserved BTB adaptors to control actin cytoskeleton structure and cell movement. AB - Cul3, a Cullin family scaffold protein, is thought to mediate the assembly of a large number of SCF (Skp1-Cullin1-F-box protein)-like ubiquitin ligase complexes through BTB domain substrate-recruiting adaptors. Cul3 controls early embryonic development in several genetic models through mechanisms not understood. Very few functional substrate/adaptor pairs for Cul3 ubiquitin ligases have been identified. Here, we show that Cul3 knockdown in human cells results in abnormal actin stress fibers and distorted cell morphology, owing to impaired ubiquitination and degradation of small GTPase RhoA. We identify a family of RhoA binding BTB domain adaptors conserved from insects to mammals, designated BACURDs. BACURDs form ubiquitin ligase complexes, which selectively ubiquitinate RhoA, with Cul3. Dysfunction of the Cul3/BACURD complex decreases cell migration potential and impairs RhoA-mediated convergent extension movements during Xenopus gastrulation. Our studies reveal a previously unknown mechanism for controlling RhoA degradation and regulating RhoA function in various biological contexts, which involves a Cul3/BACURD ubiquitin ligase complex. PMID- 19782034 TI - Hypoxia-inducible mir-210 regulates normoxic gene expression involved in tumor initiation. AB - Previous studies have suggested that the HIF transcription factors can both activate and inhibit gene expression. Here we show that HIF1 regulates the expression of mir-210 in a variety of tumor types through a hypoxia-responsive element. Expression analysis in primary head and neck tumor samples indicates that mir-210 may serve as an in vivo marker for tumor hypoxia. By Argonaute protein immunoprecipitation, we identified 50 potential mir-210 targets and validated randomly selected ones. The majority of these 50 genes are not classical hypoxia-inducible genes, suggesting mir-210 represses genes expressed under normoxia that are no longer necessary to adapt and survive in a hypoxic environment. When human head and neck or pancreatic tumor cells ectopically expressing mir-210 were implanted into immunodeficient mice, mir-210 repressed initiation of tumor growth. Taken together, these data implicate an important role for mir-210 in regulating the hypoxic response of tumor cells and tumor growth. PMID- 19782035 TI - Drosophila miR2 primarily targets the m7GpppN cap structure for translational repression. AB - Understanding the molecular mechanism(s) of how miRNAs repress mRNA translation is a fundamental challenge in RNA biology. Here we use a validated cell-free system from Drosophila embryos to investigate how miR2 inhibits translation initiation. By screening a library of chemical m7GpppN cap structure analogs, we identified defined modifications of the triphosphate backbone that augment miRNA mediated inhibition of translation initiation but are "neutral" toward general cap-dependent translation. Interestingly, these caps also augment inhibition by 4E-BP. Kinetic dissection of translational repression and miR2-induced deadenylation shows that both processes proceed largely independently, with establishment of the repressed state involving a slow step. Our data demonstrate a primary role for the m7GpppN cap structure in miRNA-mediated translational inhibition, implicate structural determinants outside the core eIF4E-binding region in this process, and suggest that miRNAs may target cap-dependent translation through a mechanism related to the 4E-BP class of translational regulators. PMID- 19782037 TI - Rapid product analysis and increased sensitivity for quantitative determinations of botulinum neurotoxin proteolytic activity. AB - The ultimate molecular action of botulinum neurotoxin (BoNT) is a Zn-dependent endoproteolytic activity on one of the three SNARE (soluble N-ethylmaleimide sensitive factor attachment protein receptor) proteins. There are seven serotypes (A-G) of BoNT having distinct cleavage sites on the SNARE substrates. The proteolytic activity is located on the N-terminal light chain (Lc) domain and is used extensively as the primary target toward therapeutic development against botulism. Here we describe an improved method using ultra-performance liquid chromatography (UPLC) whereby quantitative data were obtained in 1/10th the time using 1/20th the sample and solvent volumes compared with a widely used high performance liquid chromatography (HPLC) method. We also synthesized a VAMP (vesicle-associated membrane protein)-based peptide containing an intact V1 motif that was efficiently used as a substrate by BoNT/D Lc. Although serotype C1 cleaves the serotype A substrate at a bond separated by only one residue, we were able to distinguish the two reactions by UPLC. The new method can accurately quantify as low as 7 pmol of the peptide substrates for BoNT serotypes A, B, C1, and D. We also report here that the catalytic efficiency of serotype A can be stimulated 35-fold by the addition of Triton X-100 to the reaction mixture. Combining the use of Triton X-100 with the newly introduced UPLC method, we were able to accurately detect very low levels of proteolytic activity in a very short time. Sensitivity of the assay and accuracy and rapidity of product analysis should greatly augment efforts in therapeutic development. PMID- 19782036 TI - Interaction of transcriptional regulators with specific nucleosomes across the Saccharomyces genome. AB - A canonical nucleosome architecture around promoters establishes the context in which proteins regulate gene expression. Whether gene regulatory proteins that interact with nucleosomes are selective for individual nucleosome positions across the genome is not known. Here, we examine on a genomic scale several protein-nucleosome interactions, including those that (1) bind histones (Bdf1/SWR1 and Srm1), (2) bind specific DNA sequences (Rap1 and Reb1), and (3) potentially collide with nucleosomes during transcription (RNA polymerase II). We find that the Bdf1/SWR1 complex forms a dinucleosome complex that is selective for the +1 and +2 nucleosomes of active genes. Rap1 selectively binds to its cognate site on the rotationally exposed first and second helical turn of nucleosomal DNA. We find that a transcribing RNA polymerase creates a delocalized state of resident nucleosomes. These findings suggest that nucleosomes around promoter regions have position-specific functions and that some gene regulators have position-specific nucleosomal interactions. PMID- 19782038 TI - A liquid chromatography-mass spectrometric assay for measuring activity of human 8-oxoguanine-DNA glycosylase. AB - A new assay for measuring glycosylase activity of human 8-oxoguanine-DNA glycosylase is described. The assay measures the amount of released 8-oxoguanine from synthetic oligonucleotides containing modified base in the middle of the sequence. After enzymatic release, the amount of base is quantified by liquid chromatography-mass spectrometry. Chromatographic separation is carried out on a reversed-phase C(18) column using 10% methanol/water. Quantitation of 8 oxoguanine is carried out by negative-ion electrospray on a single quadrupole mass spectrometer operated in selected-ion monitoring mode. The limit of quantitation was 6 nM and the assay was linear from 6 to 1000 nM. The method was evaluated by monitoring the kinetics of base excision of several substrates as well as by measuring stimulation of activity in the presence of APE1 endonuclease. The new assay provides much higher throughput compared to traditional gel-based assays, which is particularly important when large number of samples need to analyzed. PMID- 19782039 TI - Fluorescent homogeneous immunosensors for detecting pathogenic bacteria. AB - We developed a straightforward antibody-based assay for rapid homogeneous detection of bacteria. Our sensors utilize antibody recognizing cell-surface epitopes of the target cell. Two samples of the antibody are prepared, each labeled via nanometer size flexible linkers with short complementary oligonucleotides that are modified with fluorochromes that could participate in fluorescence resonance energy transfer (FRET). The length of the complementary oligonucleotide sequences was designed such that very little annealing occurred in the absence of the target cells. In the presence of the target cells the two labeled antibodies bind to the surface of the cell resulting in a large local concentration of the complementary oligonucleotides that are attached to the antibody. This in turn drives the annealing of the complementary oligonucleotides which brings the fluorescence probes to close proximity producing large FRET signals proportional to the amount of target cells. Long flexible linkers used to attach the oligonucleotides to the antibody enable target-induced oligonucleotide annealing even if the density of surface antigens is only modest. We used Escherichia coli 0157:H7 and Salmonella typhimurium to demonstrate that this design produced sensors exhibiting rapid response time, high specificity, and sensitivity in detecting the target bacteria. PMID- 19782040 TI - Precision of protein aggregation measurements by sedimentation velocity analytical ultracentrifugation in biopharmaceutical applications. AB - Sedimentation velocity analytical ultracentrifugation (SV-AUC) is routinely applied in biopharmaceutical development to measure levels of protein aggregation in protein products. SV-AUC is free from many limitations intrinsic to size exclusion chromatography (SEC) such as mobile phase and column interaction effects on protein self-association. Despite these clear advantages, SV-AUC exhibits lower precision measurements than corresponding measurements by SEC. The precision of SV-AUC is influenced by numerous factors, including sample characteristics, cell alignment, centerpiece quality, and data analysis approaches. In this study, we evaluate the precision of SV-AUC in its current practice utilizing a multilaboratory, multiproduct intermediate precision study. We then explore experimental approaches to improve SV-AUC measurement precision, with emphasis on utilization of high quality centerpieces. PMID- 19782041 TI - Immunoassay of low to moderately abundant anionic proteins utilizing selective immobilization to chitosan-coated plates. AB - The quantitation of low to moderately abundant serum proteins is a common problem encountered in biochemistry. A physical property of the antigen of interest needs to be exploited in the initial binding step of an immunoassay resulting in capture (purification). We describe a two-stage immunoassay utilizing chromogenic and chemiluminescent substrates which is applied to two serum anionic proteins. In this assay, anionic serum proteins are selectively bound to positively charged chitosan-coated polystyrene plates at pH 6.1, in the presence of detergent. The assay has a detection limit of 0.1 microg/mL and a 1000-fold range. PMID- 19782042 TI - Sphingosine kinase 1 localized to the plasma membrane lipid raft microdomain overcomes serum deprivation induced growth inhibition. AB - Several studies have demonstrated that sphingosine kinase 1 (SphK1) translocates to the plasma membrane (PM) upon its activation and further suggested the plasma membrane lipid raft microdomain (PMLRM) as a target for SphK1 relocalization. To date, however, direct evidence of SphK1 localization to the PMLRM has been lacking. In this report, using multiple biochemical and subcellular fractionation techniques we demonstrate that endogenous SphK1 protein and its substrate, D erythro-sphingosine, are present within the PMLRM. Additionally, we demonstrate that the PMA stimulation of SphK1 localized to the PMLRM results in production of sphingosine-1-phosphate as well as induction of cell growth under serum deprivation conditions. We further report that Ser225Ala and Thr54Cys mutations, reported to abrogate phosphatidylserine binding, block SphK1 targeting to the PMLRM and SphK1 induced cell growth. Together these findings provide direct evidence that the PMLRM is the major site of action for SphK1 to overcome serum deprived cell growth inhibition. PMID- 19782043 TI - Failure of apoptosis-inducing factor to act as neuroglobin reductase. AB - Neuroglobin (Ngb) is a hexacoordinate globin expressed in the nervous system of vertebrates, where it protects neurons against hypoxia. Ferrous Ngb has been proposed to favor cell survival by scavenging NO and/or reducing cytochrome c released into the cytosol during hypoxic stress. Both catalytic functions require an as yet unidentified Ngb-reductase activity. Such an activity was detected both in tissue homogenates of human brain and liver and in Escherichia coli extracts. Since NADH:flavorubredoxin oxidoreductase from E. coli, that was shown to reduce ferric Ngb, shares sequence similarity with the human apoptosis-inducing factor (AIF), AIF has been proposed by us as a candidate Ngb reductase. In this study, we tested this hypothesis and show that the Ngb-reductase activity of recombinant human AIF is negligible and hence incompatible with such a physiological function. PMID- 19782044 TI - bFGF expression mediated by a hypoxia-regulated adenoviral vector protects PC12 cell death induced by serum deprivation. AB - Basic fibroblast growth factor (bFGF) is a known neuroprotectant against a number of brain injury conditions such as cerebral ischemia. However, bFGF also regulates a plethora of brain developmental processes and functions as a strong mitogen. Therefore, unregulated long-term expression of bFGF in brain may potentially be tumorigenic, limiting its utility in brain therapy. Here, we report the successful construction of an adenoviral vector (Ad-5HRE-bFGF) expressing bFGF under the regulation of five hypoxia-responsive elements (5HRE) and a minimal cytomegalovirus promoter (CMVmp). Following hypoxia treatment in a hypoxic chamber with less than 1% of oxygen, Ad-5HRE-bFGF induced a significant and time-dependent expression of bFGF protein and the fluorescent tag, humanized GFP (hrGFP) protein, in infected PC12 cells. In contrast, normoxia treatment evoked extremely low level of bFGF and hrGFP expression, demonstrating that the 5HRE-CMVmp cassette was effective in regulating the expression of bFGF gene in response to hypoxia. More importantly, bFGF expressed by the Ad-5HRE-bFGF viral vector under the regulation of hypoxia was significantly neuroprotective against PC12 cell death evoked by serum deprivation. Taken together, these studies demonstrated the feasibility to express bFGF in a hypoxia-regulated fashion to provide neuroprotection. The Ad-5HRE-bFGF can be further developed as an effective tool to provide neuroprotection against hypoxia-induced brain diseases, such as cerebral ischemia. PMID- 19782045 TI - The nuclear pore complex protein ALADIN is anchored via NDC1 but not via POM121 and GP210 in the nuclear envelope. AB - The nuclear pore complex (NPC) consists of approximately 30 different proteins and provides the only sites for macromolecular transport between cytoplasm and nucleus. ALADIN was discovered as a new member of the NPC. Mutations in ALADIN are known to cause triple A syndrome, a rare autosomal recessive disorder characterized by adrenal insufficiency, alacrima, and achalasia. The function and exact location of the nucleoporin ALADIN within the NPC multiprotein complex is still unclear. Using a siRNA-based approach we downregulated the three known membrane integrated nucleoporins NDC1, GP210, and POM121 in stably expressing GFP ALADIN HeLa cells. We identified NDC1 but not GP210 and POM121 as the main anchor of ALADIN within the NPC. Solely the depletion of NDC1 caused mislocalization of ALADIN. Vice versa, the depletion of ALADIN led also to disappearance of NDC1 at the NPC. However, the downregulation of two further membrane-integral nucleoporins GP210 and POM121 had no effect on ALADIN localization. Furthermore, we could show a direct association of NDC1 and ALADIN in NPCs by fluorescence resonance energy transfer (FRET) measurements. Based on our findings we conclude that ALADIN is anchored in the nuclear envelope via NDC1 and that this interaction gets lost, if ALADIN is mutated. The loss of integration of ALADIN in the NPC is a main pathogenetic aspect for the development of the triple A syndrome and suggests that the interaction between ALADIN and NDC1 may be involved in the pathogenesis of the disease. PMID- 19782046 TI - Glucose is a key regulator of VEGFR2/KDR in human epithelial ovarian carcinoma cells. AB - Epithelial ovarian cancer (EOC) is a serious gynecological cancer and there may be an increased risk of developing EOC in women with metabolic disruptions such as diabetes-related hyperglycemia, obesity or high glycemic load. Upregulation of vascular endothelial growth factor (VEGF) in ischemic conditions (e.g. hypoxia, hypoglycemia) induces tumor angiogenesis. We previously showed that EOC cells employ an autocrine VEGF/VEGFR2 signaling loop. Here we demonstrate the influence of glucose levels on VEGF and its receptors in the human EOC lines OVCAR-3 and CAOV-3. Glucose (but not pyruvate) deprivation induced significant increase in VEGF transcription and secretion, but a rapid reduction in VEGFR2 protein synthesis and glycosylation, combined with a reduction in co-receptor neuropilin 1 (NRP-1) protein levels. In contrast, mRNA for KDR and NRP-1 was increased upon glucose depletion suggesting a mechanism of feed back upon protein reduction. The addition of the proteosome inhibitor epoxomycin restored VEGFR2 under glucose free conditions, suggesting degradation as the main mechanism of VEGFR2 reduction and transcriptional activation through the unfolded protein response (UPR) which was activated in glucose-starved cells through the upregulation of the Endoplasmic reticulum chaperon GRP-78. Our finding that glucose can regulate VEGF/VEGFR2 levels suggests that initiation and/or progression of ovarian surface epithelial cells towards a neoplastic phenotype might be modulated by dietary conditions, and that a patient's metabolic status may alter the effectiveness of the known anti-angiogenic therapies. This information provides opportunities to explore the biology of EOC progression and improve our understanding of the mechanistic insight of this interesting regulatory effect. PMID- 19782047 TI - Caldesmon inhibits the rotation of smooth actin subdomain-1 and alters its mobility during the ATP hydrolysis cycle. AB - Smooth muscle thin filaments have been reconstituted in muscle ghost fibers by incorporation of smooth muscle actin, tropomyosin and caldesmon. For the first time, rotation of subdomain-1 and changes of its mobility in IAEDANS-labeled actin during the ATP hydrolysis cycle simulated using nucleotides and non hydrolysable ATP analogs have been demonstrated directly. Binding of caldesmon altered the mobility and inhibited the rotation of actin subdomain-1 during the transition from AM * *.ADP.Pi to AM state, resulting in inhibition of both strong and weak-binding intermediate states. These new results imply that regulation of actomyosin interaction by caldesmon during the ATPase cycle is fulfilled via the inhibition of actin subdomain-1 rotation toward the periphery of the thin filament, which decreases the area of the specific binding between actin and myosin molecules and is likely to underlie at least in part the mechanism of caldesmon-induced contractility suppression. PMID- 19782048 TI - Demethylallosamidin, a chitinase inhibitor, suppresses airway inflammation and hyperresponsiveness. AB - Acidic mammalian chitinase is upregulated in response to allergen exposure in the lung. We investigated the effects of chitinase inhibitors, allosamidin (Allo) and demethylallosamidin (Dma), on asthmatic responses. Mice were subjected to IL-13 instillation into the airways or to ovalbumin sensitization plus exposure with or without treatment of Allo or Dma. Airway hyperresponsiveness (AHR) and inflammation were evaluated. Allo and Dma attenuated airway eosinophilia and the upregulation of eotaxin after IL-13 instillation, while Dma, but not Allo, suppressed AHR in IL-13-induced asthma. Allo or Dma suppressed the elevated chitinase activity in BAL fluids after IL-13 to similar levels. The bronchoprotective PGE(2) levels in BAL fluids were elevated after IL-13 instillation. Allo, but not Dma, suppressed the overproduction of PGE(2) and the expression of COX-2 and PGE synthase-1 induced by IL-13. In ovalbumin-induced asthma, Dma suppressed AHR more strongly than Allo. These findings suggest that Dma attenuates asthmatic responses induced by IL-13 without affecting PGE(2) synthesis. Dma may have potential as therapeutic agents for asthma. PMID- 19782049 TI - Sorting nexin 8 regulates endosome-to-Golgi transport. AB - Sorting nexin 8 (SNX8) belongs to the sorting nexin protein family, whose members are involved in endocytosis and endosomal sorting and signaling. The function of SNX8 has so far been unknown. Here, we have investigated the role of SNX8 in intracellular transport of the bacterial toxin Shiga toxin (Stx) and the plant toxin ricin. After being endocytosed, these toxins are transported retrogradely from endosomes, via the Golgi apparatus and the endoplasmic reticulum (ER), into the cytosol, where they exert their toxic effect. Interestingly, our experiments show that SNX8 regulates the transport of Stx and ricin differently; siRNA mediated knockdown of SNX8 significantly increased the Stx transport to the trans Golgi network (TGN), whereas ricin transport was slightly inhibited. We also found that SNX8 colocalizes with early endosome antigen 1 (EEA1) and with retromer components, suggesting an endosomal localization of SNX8 and supporting our finding that SNX8 is involved in endosomal sorting. PMID- 19782050 TI - Statins inhibit aminoglycoside accumulation and cytotoxicity to renal proximal tubule cells. AB - Nephrotoxicity due to renal proximal tubule accumulation of aminoglycoside (AG) antibiotics, such as gentamicin, represents a major clinical problem. Receptor mediated endocytosis via the multi-ligand receptor megalin is thought to be a key mechanism in the cellular uptake of AGs and nephrotoxicity. This process can be modulated by the intracellular concentration of isoprenoid pyrophosphates derived from the processing of mevalonate by 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Post-translation modifications by isoprenoid pyrophosphates are necessary for GTP-binding protein function. Given that statins inhibit HMG-CoA reductase and therefore affect the concentration of isoprenoid pyrophosphates, we have tested the hypothesis that statins will lead to a reduction in AG renal proximal tubule accumulation and cytotoxicity. Gentamicin accumulated within cultured proximal tubule derived opossum kidney (OK) cells and led to dose- and time-dependent cell death which was inhibited by non-toxic doses of simvastatin (IC(50) 1.3 microM), rosuvastatin (IC(50) 16.3 microM) and pravastatin (IC(50) 38.8 microM). The mechanism of inhibition was linked to the degree of cholesterol synthesis inhibition and GTP-binding protein unprenylation. Moreover, co incubation with mevalonate or geranyl-geranyl pyrophosphate, products of HMG-CoA reductase, reversed the inhibitory effect of statins on cellular accumulation and cytotoxicity of gentamicin. In summary, our data suggest that the inhibition of the mevalonate pathway by statins may provide a potential therapeutic strategy to prevent AG-induced nephrotoxicity. PMID- 19782051 TI - Oleanane triterpenoid CDDO-Me inhibits growth and induces apoptosis in prostate cancer cells through a ROS-dependent mechanism. AB - CDDO-Me, a synthetic triterpenoid derived from oleanolic acid, is a promising anticancer agent that has shown strong activity against a wide variety of cancer types in vitro and in vivo. We have previously shown that CDDO-Me induces apoptosis in prostate cancer cells irrespective of their hormonal status. To further understand the proapoptotic mechanism of CDDO-Me, we investigated the role of reactive oxygen species (ROS) in mediating the apoptosis inducing activity of CDDO-Me in LNCaP and PC-3 prostate cancer cell lines. Here, we show that CDDO-Me induces ROS generation from both nonmitochondrial and mitochondrial sources, which is associated with the induction of apoptosis as characterized by increased annexin V-binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c. In addition, CDDO-Me inhibited cell survival Akt, NF-kappaB and mTOR signaling proteins. The inhibition of ROS generation by N-acetylcysteine (NAC) or by overexpression of antioxidant enzymes glutathione peroxidase (GPx) and superoxide dismutase-1 (SOD 1) prevented CDDO-Me-induced apoptosis. Pretreatment with NAC blocked annexin V binding, cleavage of PARP-1 and procaspases-3, -8, -9, loss of mitochondrial membrane potential and release of cytochrome c by CDDO-Me. NAC also prevented the inhibition of constitutively active Akt, NF-kappaB and mTOR by CDDO-Me. Together, these data indicate that ROS plays an essential role in the induction of apoptosis by CDDO-Me in prostate cancer cells. PMID- 19782052 TI - TCDD-induced cyclooxygenase-2 expression is mediated by the nongenomic pathway in mouse MMDD1 macula densa cells and kidneys. AB - Cyclooxygenase-2 (Cox-2) plays a critical role in TCDD-induced hydronephrosis in mouse neonates. In this study we found that induction of Cox-2 by TCDD in MMDD1, a mouse macula densa cell line, is accompanied with a rapid increase in the enzymatic activity of cytosolic phospholipase A2 (cPLA2) as well as activation of protein kinases. Calcium serves as a trigger for such an action of TCDD in this cell line. These observations indicate that the basic mode of action of TCDD to induce the rapid inflammatory response in MMDD1 is remarkably similar to those mediated by the nongenomic pathway of aryl hydrocarbon receptor (AhR) found in other types of cells. Such an action of TCDD to induce Cox-2 in MMDD1 was not affected by "DRE decoy oligonucleotides" treatment or by introduction of a mutation on the DRE site of Cox-2 promoter, suggesting that this route of action of TCDD is clearly different from that mediated by the classical genomic pathway. An in vivo study with Ahr(nls) mouse model has shown that TCDD-induces Cox-2 and renin expression in the kidneys of the Ahr(nls) mice as well as Ahr(+/-) mice, but not in the Ahr(-/-) mice, indicating that this initial action of TCDD in mouse kidney does not require the translocation of AhR into the nucleus, supporting our conclusion that induction of Cox-2 by TCDD in mouse kidney is largely mediated by the nongenomic pathway of TCDD-activated AhR. PMID- 19782053 TI - Transplanted olfactory mucosal cells restore paw reaching function without regeneration of severed corticospinal tract fibres across the lesion. AB - Previous studies from our laboratory reported that transplantation of a mixture of 50% p75+ olfactory ensheathing cells (OECs) and fibroblasts derived from the outer layers of the adult olfactory bulb into unilateral lesions of the rat corticospinal tract (CST) restore function in a directed fore-paw retrieval task and induce regeneration of severed CST axons across the lesion. For future clinical application it would be preferable to obtain reparative cells from an olfactory mucosal biopsy via intranasal endoscopy rather than requiring the more invasive intracranial approach to remove an olfactory bulb. With this purpose, we used our original CST lesion paradigm to examine whether mucosal OEC preparations can provide a similar repair to those from the bulb. We found that, as in the case of bulbar OEC preparations, the mucosal cells also restored directed fore paw retrieval. Surprisingly, however, there was no evidence of any of the severed CST axons crossing the lesion site, suggesting that the recovery of function is due to some other reaction, such as sprouting of damaged or undamaged fibres. Compared with the previous findings with bulbar cells, the mucosal cell cultures contained only 5% of OECs and a conversely much larger proportion of fibroblasts. These cell preparations showed minimal migratory ability and failed to form complete bridges across the lesions. PMID- 19782054 TI - Treatment with ketanserin produces opioid-mediated hypoalgesia in the late phase of carrageenan-induced inflammatory hyperalgesia in rats. AB - Both pro-nociceptive and antinociceptive mediators are released in the tissues during inflammation. Balance of these two types of mediators determines the induction and maintenance of pain or hypernociception. This study was designed to explore whether 5-HT(2A) receptors in the periphery contributed to the maintenance of carrageenan-evoked hyperalgesia. Intraplantar (i.pl.) injection of carrageenan evoked hyperalgesia detected by noxious heat stimulus. The 5-HT(2A) receptor antagonist ketanserin administered i.pl. 1 h after carrageenan dose dependently (2-20 microg) prolonged paw withdrawal latency (PWL) during the late phase (24 h) of carrageenan-evoked inflammation. Following treatments with carrageenan and ketanserin, i.pl. injection of formalin (1%) produced significantly fewer nocifensive behaviors and expression of c-Fos protein in the spinal dorsal horn, confirming the hypoalgesic status in the inflamed site. However, injection of ketanserin in naive site failed to produce hypoalgesia. The hypoalgesia was completely abolished by local or systemic injection of naloxone methiodide. The present study suggests that 5-HT(2A) receptors were involved in the maintenance of inflammatory pain, and that 5-HT suppressed inflammation associated endogenous opioid analgesia contributing to its pro-nociceptive actions in the periphery. It implied a possible therapeutic benefit of blockade of local 5-HT(2A) receptors in the treatment of inflammatory pain. PMID- 19782056 TI - From local inhibition to long-range integration: a functional dissociation of alpha-band synchronization across cortical scales in visuospatial attention. AB - When attention is allocated to one visual hemifield, increased alpha power is observed in ipsilateral visual cortex. This has been attributed to synchronization of alpha-band oscillations within cortical regions which reflects inhibitory processing. Recent results, however, indicate that synchronization of alpha oscillations between cortical regions is relevant for transient functional coupling. Such coupling is thought to be involved in orienting attention to a specific region of the visual field. We thus hypothesized that alpha-band synchronization between low-level visual cortex and higher-level visual brain regions would be increased in the hemisphere contralateral to an attended location. To test this hypothesis we calculated phase synchronization between attention-related EEG source activations occurring between predictive directional cues and expected visual targets. Alpha amplitude (understood as an index of local synchronization) within low-level visual cortex was increased ipsilateral to attended locations and decreased contralateral to attended locations, consistent with alpha-band scalp topography and previous research relating local alpha power to active inhibition. Increased long-range alpha-band synchronization between low-level visual cortex and parietal cortex, however, was observed contralateral to the attended visual hemifield, whereas decreased synchronization (phase scattering) was observed in the ipsilateral hemisphere. These results identify a potential mechanism for the enhanced processing of stimuli appearing at attended locations, as long-range synchronization is thought to increase the fidelity and effectiveness of communication between brain areas. Our observation of inhibitory amplitude changes, interpreted as increased local-area synchronization, and facilitatory long-range synchronization demonstrates a functional dissociation for alpha-band synchronization across cortical scales. PMID- 19782057 TI - Regulatory effect of epigallocatechin gallate on the expression of C-reactive protein and other inflammatory markers in an experimental model of atherosclerosis. AB - The present study sought to evaluate the regulatory effect of epigallocatechin gallate (EGCG) on C-reactive protein (CRP) and other inflammatory markers in rats fed an atherogenic diet. Male albino Wistar rats were divided into three groups of nine each. Group I (normal) rats on normal diet received an intraperitoneal (i.p.) injection of physiological saline; group II (atherosclerotic-untreated) rats received an atherogenic diet for 45 days and daily i.p. administration of saline from days 31 to 45; group III (atherosclerotic-treated) rats received an atherogenic diet for 45 days and daily i.p. administration of EGCG (100mg/kg BW) from days 31 to 45 and were then euthanized. The biochemical parameter, CRP, and haematological parameters of inflammation (erythrocyte sedimentation rate [ESR], total leucocyte count [WBC], differential leucocyte count, platelet count) were determined. Immunoblotting and RT-PCR were employed to elucidate the CRP protein and its mRNA expression. Group II rats showed a significant increase in the mean serum CRP level, ESR and total WBC, platelet and differential leucocyte counts, when compared with corresponding values in group I rats. Significantly lower mean levels/counts of inflammatory markers were noted in group III rats than corresponding values in group II rats. Group II rats exhibited significantly higher mean values of CRP protein expression and relative transcript levels of CRP than group I or group III rats. These results suggest that EGCG, a major component of green tea catechins, may decrease the risk of cardiovascular disease by reducing inflammatory markers in rats fed an atherogenic diet. PMID- 19782058 TI - Rapid genotyping of two common G6PD variants, African (A-) and Mediterranean, by high-resolution melting analysis. AB - OBJECTIVES: The Mediterranean and A(-) G6PD variants are particularly prevalent in Africa and Southern Europe. Our study was aimed to develop an assay for the rapid genotyping of these two variants by HRM. METHODS: After PCR reactions corresponding to the G6PD Mediterranean (exon 6), G6PD (A-) (exon 4) and G6PD (A ) (exon 5) mutations, amplicons were submitted to HRM. This protocol was applied to a cohort of 132 patients suffering from sickle cell disease. RESULTS: Wild, homozygous or hemizygous and heterozygous states were fully discriminated by HRM for all three mutations. HRM results were in total accordance with DNA sequencing for 22 patients of our cohort with a 'A' genotype: presence of the (A-) (exon 5) mutation but absence of the (A-) (exon 4) mutation. CONCLUSIONS: Our HRM protocols allow a rapid, simple and cost-effective screening of G6PD deficiency in patients originating from the Mediterranean and the African areas. PMID- 19782059 TI - Reference values for serum nitric oxide metabolites in an adult population. AB - OBJECTIVES: To determine reference values for serum nitric oxide metabolites (nitrite+nitrate=NO(x)) concentrations in adult subjects. DESIGN AND METHODS: Serum NO(x) concentration was measured, using the Griess method, in 694 non smoking apparently healthy subjects, randomly selected from a population-based study. The International Federation of Clinical Chemistry guidelines and the robust method were used for determining reference values. RESULTS: The 95% reference values for serum NO(x) concentration and serum NO(x)/creatinine ratio were 11.5 to 76.4 micromol/L and 0.111 to 0.729 in men and 10.1 to 65.6 micromol/L and 0.121 to 0.777 in women, respectively. With increasing body mass index, upper limits of serum NO(x) and the NO(x)/creatinine ratio increased in women and decreased in men. Serum NO(x) levels above upper limits predicted both diabetes and metabolic syndrome in women. CONCLUSIONS: This study reports the first set of reference values for serum NO(x) concentration and NO(x)/creatinine ratio in a relatively large healthy non-smoking population. PMID- 19782055 TI - Dynorphin, stress, and depression. AB - Stress is most often associated with aversive states. It rapidly induces the release of hormones and neuropeptides including dynorphin, which activates kappa opioid receptors (KORs) in the central and peripheral nervous systems. In animal models, many aversive effects of stress are mimicked or exacerbated by stimulation of KORs in limbic brain regions. Although KOR signaling during acute stress may increase physical ability (by producing analgesia) and motivation to escape a threat (by producing aversion), prolonged KOR signaling in response to chronic or uncontrollable stress can lead to persistent expression of behavioral signs that are characteristic of human depressive disorders (i.e., "prodepressive like" signs). Accumulating evidence suggests that KORs contribute to the progressive amplification (sensitization) of stress-induced behaviors that occurs with repeated exposure to stress. Many of the aversive effects of stress are blocked by KOR antagonists, suggesting that these agents may have potential as therapeutics for stress-related conditions such as depression and anxiety disorders. This review summarizes current data on how KOR systems contribute to the acute (rapid), delayed, and cumulative molecular and behavioral effects of stress. We focus on behavioral paradigms that provide insight on interactions between stress and KOR function within each of these temporal categories. Using a simplified model, we consider the time course and mechanism of KOR-mediated effects in stress and suggest future directions that may be useful in determining whether KOR antagonists exert their therapeutic effects by preventing the development of stress-induced behaviors, the expression of stress-induced behaviors, or both. PMID- 19782060 TI - The alpha-fetoprotein enhancer region activates the albumin and alpha-fetoprotein promoters during liver development. AB - The four members of the albumin gene family encode the serum transport proteins albumin, alpha-fetoprotein, alpha-albumin, and vitamin D-binding protein. These genes are transcribed primarily in the liver with each having a different pattern of developmental expression. The tight linkage of these genes, particularly that of albumin, alpha-fetoprotein and alpha-albumin, and their liver-specific expression, has led to the suggestion that these genes share common regulatory elements. To directly examine whether the alpha-fetoprotein enhancer region could regulate the albumin gene family, expression of these genes was monitored in mice in which this region was deleted by homologous recombination. Our data indicate that this enhancer region is required for alpha-fetoprotein and albumin activation early in liver development and alpha-fetoprotein reactivation during liver regeneration, but that albumin, alpha-albumin, and vitamin D-binding protein expression later in hepatic development is not affected by the absence of these enhancers. We also demonstrate that RNA polymerase II loading on the alpha fetoprotein and albumin promoters is reduced in the absence of this enhancer region, indicating a direct role for these enhancers in the assembly of the RNA Polymerase II complex during liver development. PMID- 19782061 TI - Icariin inhibits beta-amyloid peptide segment 25-35 induced expression of beta secretase in rat hippocampus. AB - The present study was undertaken to investigate the protective effects of icariin on the learning and memory abilities in Alzheimer's disease model rats and explore its protection mechanisms. Beta-amyloid peptide (Abeta) is a key etiology in Alzheimer's disease and targeting on Abeta production and assembly is a new therapeutic strategy. Six-month (400-600 g) Wistar rats were unilaterally injected with amyloid beta-protein fragment 25-35 (Abeta(25-35)) 10 microg (5 g/l, 2 microl) into the right hippocampus. The day following Abeta injection, icariin 30, 60 or 120 mg/kg was administered by gavage for 14 days. The ability of spatial learning and memory of the animals was tested by the Morris water maze. In place navigation test, icariin significantly decreased the mean escape latency and searching distance. In the space probing test, icariin increased remarkably the searching time and searching distance in the quadrant where the platform was originally located. All tests indicated icariin improved the ability of spatial learning and memory in Alzheimer's disease model rats. Furthermore, immunohistochemistry and real time RT-PCR analysis showed that icariin significantly reduced the contents of Abeta(1-40) and the mRNA levels of beta secretase in the hippocampus and increased the mRNA level of superoxide dismutase 2, but it had no apparent effects on the immunostain and mRNA level of amyloid protein precursor. These results demonstrate that icariin can improve the learning and memory abilities in Abeta(25-35)-induced Alzheimer's disease rats. The mechanisms appear to be due to the decreased production of insoluble fragments of Abeta through suppression of beta-secretase expression. PMID- 19782062 TI - Inhibition of P-glycoprotein activity by limonin and other secondary metabolites from Citrus species in human colon and leukaemia cell lines. AB - P-glycoprotein (P-gp), a membrane transporter encoded by the MDR1 gene in human cells, mediates drug efflux from cells and plays a major role in causing multidrug resistance; which is one of the most accepted mechanisms for failure of chemotherapy in cancer treatment. In this study, we investigated the effects of nine naturally occurring compounds isolated from Citrus jambhiri Lush and Citrus pyriformis Hassk (Rutaceae) for their potential to modulate the activity of P-gp in the multidrug-resistant human leukaemia cell line CEM/ADR5000. Limonin, deacetylnomilin, hesperidin, neohesperidin, stigmasterol and ss-sitosterol-O glucoside inhibited the efflux of the P-gp substrate rhodamine 123 in a concentration-dependent manner. Some of these compounds were more active than verapamil, which was used as a positive control. Treatment of drug-resistant Caco 2 cells with the most active C. jambhiri and C. pyriformis compounds increased their sensitivity to doxorubicin and completely reversed doxorubicin resistance, which agrees with a decreased P-gp activity. Limonin was the most potent P glycoprotein inhibitor - when it was applied at a non-toxic concentration of 20 microM, it significantly enhanced doxorubicin cytotoxicity 2.98-fold (P<0.001) and 2.2-fold (P<0.001) in Caco2 and CEM/ADR5000 cells, respectively. These isolated Citrus compounds could be considered as good candidates for the development of novel P-gp/MDR1 reversal agents which may enhance the accumulation and efficacy of chemotherapy agents. PMID- 19782063 TI - Diazoxide protects against hydrogen peroxide-induced toxicity in the osteoblastic MC3T3-E1 cells. AB - Treatment of various types of cells with the mitochondrial ATP-sensitive K+ channel (mK(ATP)) opener has been shown to precondition cells to subsequent injuries and inhibit apoptosis. We exposed cultured osteoblastic MC3T3-E1 cells to hydrogen peroxide (H2O2) with or without pretreatment with a mK(ATP) opener, diazoxide. A marked decrease in osteoblast viability was evident after 48 h exposure of 0.3mM H2O2, compared with vehicle-treated cells. Diazoxide (0.001 approximately 10 microM) treatment significantly (P<0.05) reversed the cytotoxic effect of H2O2 and this effect was blocked by a specific mK(ATP) blocker, glibenclamide. Pretreatment with diazoxide (0.01 approximately 1 microM) also decreased the release of reactive oxygen species and the increase in oxidative damage markers (protein carbonyl and malondialdehyde) induced by H2O2 in osteoblastic MC3T3-E1 cells. Moreover, H2O2-induced reduction of differentiation markers, such as alkaline phosphatase, collagen content and calcium deposition was significantly recovered in the presence of diazoxide. In addition, diazoxide (0.01 approximately 1 microM) decreased the H2O2-induced production of osteoclast differentiation-inducing factors, such as interleukin (IL)-6 and the receptor activator of nuclear factor-kB ligand (RANKL). These results suggest that diazoxide may be useful for the protection of H2O2-induced oxidative damage and dysfunction in osteoblastic cells. PMID- 19782065 TI - Opposing regulation of histamine-induced calcium signaling by sodium selenite and ebselen via alterations of thiol redox status. AB - Elevated blood histamine plays a role in the pathogenesis of atherosclerosis. Calcium signaling mediates histamine action in endothelial cells. Selenium (Se) is a dietary essential trace element for humans. Se compounds in different oxidation states were found to exhibit an opposing effect on the histamine induced calcium signaling in the ECV304 cell line. When Se in the form of sodium selenite was added in the cell culture, the reactivity of the histamine H(1) receptor was increased as reported in our previous paper. We here show that as a culture supplement, sodium selenite enhanced the activity of selenoprotein thioredoxin reductase (TrxR) and the calcium response to histamine stimulation, which were reversed by treating the cells with gold thioglucose, a nucleophilic drug that selectively modifies thiolate/selenolate groups. Sodium selenite most likely caused a reductive shift in the thiol/disulfide redox balance through increasing TrxR activity. In contrast, when the cells were treated with Se in the form of ebselen, a thiol oxidant with peroxidase-like activity, histamine-induced calcium release and calcium entry were significantly suppressed. This effect appeared related to the thiol-directed modification rather than the peroxidase like activity of ebselen, because this inhibitory effect was not replicated by increasing cellular peroxidase activity. Thus, the opposing effects of sodium selenite and ebselen on histamine-induced calcium signaling are achieved, at least in part, through their opposite actions in modulating the thiol/disulfide redox state. PMID- 19782064 TI - Translocator protein (18 kDa) mediates the pro-growth effects of diazepam on Ehrlich tumor cells in vivo. AB - The Translocator Protein (TSPO), previously known as the peripheral-type benzodiazepine receptor, is a ubiquitous drug- and cholesterol-binding protein that is up regulated in several types of cancer cells. TSPO drug ligands (e.g., diazepam) induce or inhibit tumor cell proliferation, depending on the dose and tissue origin. We have previously shown that TSPO is expressed in Ehrlich tumor cells and that diazepam increases proliferation of these cells in vitro. Here, we investigated the in vivo effects of diazepam on Ehrlich tumor growth and the role of TSPO in mediating this process. Oral administration of diazepam to mice (3.0mg/kg/day for 7 days) produced plasma and ascitic fluid drug concentrations of 83.83 and 54.12 nM, respectively. Diazepam increased Ehrlich tumor growth, likely due to its ability to increase tumor cell proliferation and Reactive Oxygen Species production. Radioligand binding assays and nucleotide sequencing revealed that Ehrlich tumor cell TSPO had the same pharmacological and biochemical properties as TSPO described in other tumor cells. The estimated K(d) for PK 11195 in Ehrlich tumor cells was 0.44 nM and 8.70 nM (low and high binding site, respectively). Structurally diverse TSPO drug ligands with exclusive affinity for TSPO (i.e., 4-chlordiazepam, Ro5-4864, and isoquinoline-carboxamide PK 11195) also increased Ehrlich tumor growth. However, clonazepam, a GABA(A) specific ligand with no affinity for TSPO, failed to do so. Taken together, these data suggest that diazepam induces in vivo Ehrlich tumor growth in a TSPO dependent manner. PMID- 19782066 TI - Cannabinoid CB(1) and adenosine A(1) receptors independently inhibit hippocampal synaptic transmission. AB - Adenosine A(1) and cannabinoid CB(1) receptors are affected by drugs widely consumed by humans, as it is the case for caffeine, an adenosine receptor antagonist, and tetrahydrocannabinol, a cannabinoid receptor agonist. These receptors are present in the hippocampus and inhibit neurotransmitter release by operating similar transduction mechanisms. We, therefore, evaluated if they cross talk to modulate synaptic transmission in the hippocampus. To do so, field excitatory postsynaptic potentials (fEPSPs) were recorded from the CA1 area of rat hippocampal slices and the consequences of activation or blockade of cannabinoid CB(1) or adenosine A(1) receptors upon neuromodulation exerted by the other receptor were assessed. The cannabinoid CB(1) receptor agonist, WIN55212-2 (300nM), slowly decreased ( congruent with40%) the fEPSP slope, while the adenosine A(1) receptor agonist, cyclopenthyladenosine (CPA, 15nM) rapidly decreased ( congruent with50%) it. Blockade of cannabinoid CB(1) receptors with AM251 (1microM) did not influence the adenosine A(1) receptor-mediated inhibition of synaptic transmission. Blockade of adenosine A(1) receptors with 1,3-dipropyl 8-cyclopentylxanthine (DPCPX, 50nM) did not affect the inhibition perpetrated by cannabinoid CB(1) receptor activation. When both receptors were simultaneously activated (5nM CPA plus 300nM WIN55212-2) the net inhibition of synaptic transmission was about the sum of the effect of each drug applied independently. These results indicate independent synaptic transmission modulation by adenosine A(1) and cannabinoid CB(1) receptors at the hippocampus, suggesting that availability of G-proteins coupled to each receptor and availability of other signalling molecules involved in their transducing pathways, are not limiting factors for their modulatory role. PMID- 19782068 TI - Comparison of different tissue sampling methods for protein extraction from formalin-fixed and paraffin-embedded tissue specimens. AB - AIMS: Protein extracts from formalin-fixed and paraffin-embedded (FFPE) tissue for proteomic analysis has recently gained attention. In this study, we explored the possibility to standardize tissue sampling from paraffin blocks and compared the protein extracts with those obtained from fresh frozen material. MATERIALS AND METHODS: Fresh frozen and FFPE material was obtained from five patients with pancreatic ductal adenocarcinoma either by cutting sections with a microtome or by stamping a cylinder with tissue micro-array technology. All samples were weighed, forwarded to protein extraction and analyzed by polyacrylamide gel electrophoresis and Western blotting. Immunohistochemistry allocated proteins in tissue sections. RESULTS: Sampling of tissue was highly reproducible, as assessed by sample weight. While protein concentrations were significantly higher in fresh frozen material compared to FFPE material, equal amounts of protein were extracted from FFPE using either paraffin sections or core cylinders in SDS-PAGE, all three procedures showed comparable protein patterns. In Western blotting, annexin I had the same molecular weight independent of the sample source and sampling procedure. CONCLUSIONS: The sampling of FFPE specimens for protein extraction and analysis can be standardized, uncovering equal amounts of tissue and protein. In addition, the proteins extracted from FFPE tissue seem to be the same compared with those extracted from fresh frozen tissue. PMID- 19782067 TI - Spinal astrocyte and microglial activation contributes to rat pain-related behaviors induced by the venom of scorpion Buthus martensi Karch. AB - The present study investigated whether spinal astrocyte and microglia were activated in Buthus martensi Karch (BmK) venom-induced rat pain-related behaviors. The results showed that glial fibrillary acidic protein (GFAP) immunoreactivity indicative astrocyte activation in bilateral spinal cord started to increase by day 3, peaked at day 7 and gradually reversed at day 14 following intraplantar injection of BmK venom. Western blotting analysis confirmed GFAP expression was up-regulated by BmK venom. In contrast, bilateral spinal increase of OX-42 immunoreactivity indicative of microglial activation began at 4h peaked at day 1 and gradually reversed by days 3 to 7 after the administration of BmK venom. Pretreatment with either intrathecal injection of fluorocitrate or intraperitonial injection of minocycline, and two glial activation inhibitors, suppressed the spontaneous nociceptive responses, and prevented the primary thermal and bilateral mechanical hyperalgesia induced by BmK venom. The post treatment with fluorocitrate or minocycline could not affect the mechanical hyperalgesia. Moreover, minocycline partially inhibited BmK venom-induced spinal c-Fos expression but lack of effects on BmK venom-induced paw edema. Taken together, the current study demonstrated that spinal astrocyte and microglial activation may contribute to BmK venom-induced rat pain-related behaviors. Thus, spinal glia may represent novel targets for effective treatment of pain syndrome associated with scorpion envenomation. PMID- 19782069 TI - RhoB enhances migration and MMP1 expression of prostate cancer DU145. AB - Rho family protein regulates variety of cellular functions as cytoskeletal organization, cell proliferation and apoptosis. In the present study, we demonstrate that RhoB-overexpressed prostate cancer cells showed an enhanced cell motility and the administration of the GSK-3 inhibitors inhibited this increase in migration. Among the extracellular matrix and adhesion-related molecules, MMP1 RNA expression was increased in RhoB-overexpressed cells, administration of MMP inhibitor suppressed the collagen gel invasion in these cells. This is the first report evaluating RhoB function and the downstream signaling events in prostate cancer cell. Our results indicate that RhoB promotes cell motility and invasion in a metastatic prostate cancer cell. PMID- 19782070 TI - Heparan sulfate deficiency in periocular mesenchyme causes microphthalmia and ciliary body dysgenesis. AB - The heparan sulfate (HS) is a component of proteoglycans in the extracellular matrix and on cell surfaces, modulating developmental processes. The aim of this study is to investigate whether the defect of HS in the periocular mesenchyme impairs ocular morphogenesis. First, using Protein 0-Cre transgenic mice, we ablated Ext1, which encodes an indispensable enzyme for HS synthesis, in the developing periocular mesenchyme. The expression of Ext1 messenger RNA (mRNA) and HS were observed by RT-PCR and immunohistochemistry, respectively. The phenotypes in the mutant were evaluated by light microscopy and immunohistochemistry for cellular makers. Second, the distribution of the mutant periocular mesenchymal cells was tracked using a Rosa26 Cre-reporter gene. No mutant embryos (Protein 0 Cre;Ext1(flox/flox)) were identified after embryonic day 14.5 (E14.5). RT-PCR showed that an intense band amplified from Ext1 was observed in cDNAs from the control periocular mesenchymal cells at E13.5; however, the band for Ext1 was hardly detectable in cDNA from the mutant embryo, indicating that the mRNA was missing in the mutant periocular mesenchyme at E13.5. The HS expression was disrupted in the periocular mesenchyme of the mutant ocular tissues. The HS deficiency resulted in microphthalmia with reduced axial lengths, lens diameters, and vitreous sizes compared with the littermate eyes. The mutant embryos showed agenesis of the anterior chamber, where cells expressing Cre recombinase were distributed. Moreover, the mutants showed phenotypic alterations in the neural ectoderm including dysgenesis of the presumptive ciliary body and agenesis of the optic nerve head. These findings demonstrate that HS in the periocular mesenchyme plays a critical role in normal ocular morphogenesis, indicating reciprocal interactions between the periocular mesenchyme and the neural ectoderm. PMID- 19782071 TI - Ocular hypotensive effects of topically administered agmatine in a chronic ocular hypertensive rat model. AB - Agmatine, a primary polyamine and potential neuromodulator, exhibits a high affinity to the alpha2-adrenergic receptor as well as imidazoline receptors. As alpha2-adrenergic receptor agonists display positive ocular hypotensive effects, we assessed whether agmatine effectively lowers intraocular pressure (IOP) using a chronic ocular hypertensive rat model. We raised IOP in unilateral eyes of Sprague-Dawley rats by cauterizing three episcleral veins per eye. Four weeks later, we topically administered 10(-3) M agmatine solution 4 times a day for 6 consecutive weeks. After confirming the recovery of IOP to pretreatment level at 13 weeks after cauterization, the retinal ganglion cells (RGCs) were retrogradely labeled and counted. Eyes subjected to episcleral vein cauterization (EVC) demonstrated significant increases in IOP (48.39% increase over baseline IOP), and the elevated IOP was well maintained until 12 weeks. Topically administered agmatine powerfully lowered IOP to 30.29% of its pretreatment level, and the associated washout period was about two weeks. EVC was associated with a 55.44% loss of RGCs in the control group, but agmatine appeared to attenuate this RGC loss to 18.65%. Overall, topically administered agmatine appeared to effectively lower IOP and rescue RGCs in a chronic ocular hypertensive rat model. Although the mechanism underlying these effects is not yet established, it is possible that agmatine offers a powerful new ocular hypotensive agent for eyes with chronic ocular hypertension and/or glaucoma. PMID- 19782073 TI - GSK3: a possible link between beta amyloid peptide and tau protein. AB - Tau is a neuronal microtubule-associated phosphoprotein that is highly phosphorylated by glycogen synthase kinase 3 (GSK3). Tau phosphorylation by GSK3 regulates tau binding to microtubules, tau degradation and tau aggregation. Tau phosphorylation is important in Alzheimer disease pathology and in other tauopathies. In Alzheimer disease, it has been proposed that the peptide beta amyloid promotes GSK3 activation, resulting in tau phosphorylation. In this work, we review the links between beta amyloid peptide, tau protein and GSK3 that occur in familial Alzheimer disease. We also discuss the possible links between GSK3 and sporadic Alzheimer disease. Finally, we include a brief review of the pathology of animal models overexpressing GSK3. PMID- 19782074 TI - The brain RAS and Alzheimer's disease. AB - Alzheimer's disease (AD) has become a major world-wide health problem with ever rising costs associated with the treatment and care of afflicted individuals. As life expectancy has increased the occurrence of dementia has also increased. Hypertension during middle adulthood is correlated with a significantly elevated risk of cognitive impairment later in life. Treatment with antihypertensive drugs, particularly angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs), has been reported to reduce the likelihood and slow the progression of AD; however, the use of ACE inhibitors may be accompanied by an increase in amyloid beta protein(1-42) accumulation. This review summarizes available information regarding the brain renin-angiotensin system (RAS), and specifically the efficacy of ACE inhibitors as anti-dementia agents, and considers the recently discovered AT(4) receptor and associated agonist drugs as potential new therapeutic targets to treat memory impairments associated with AD. We conclude with a description of recent efforts by members of our laboratory to develop blood-brain barrier penetrant angiotensin IV analogue drugs that facilitate cognition in animal models of AD. These efforts have resulted in a small molecule with desirable hydrophobicity characteristics that shows promise with respect to memory facilitation when peripherally administered. PMID- 19782072 TI - Autonomic drugs and the accommodative system in rhesus monkeys. AB - Accommodation and pupil constriction result from parasympathetic stimulation from the Edinger-Westphal (EW) nucleus of the midbrain resulting in release of acetylcholine at the neuromuscular junctions of the ciliary muscle and iris. Cholinergic and adrenergic drugs can be applied topically to evaluate the effects on the pupil and accommodative system without input from the EW nucleus. This study is directed at characterizing how topical low dose echothiophate, an anti cholinesterase inhibitor (i.e., an indirect cholinergic agonist), epinephrine, an adrenergic agonist, and timolol maleate, a beta adrenergic antagonist, affect pupil diameter, resting refraction and accommodative amplitude and dynamics in rhesus monkeys. The effects of 0.015% echothiophate, 2% epinephrine, 0.5% timolol maleate and saline on pupil diameter and resting refraction were measured in one eye each of four normal rhesus monkeys for 60-90 min following topical instillation. Pupil diameter was measured with infrared videography and refraction was measured with a Hartinger coincidence refractometer. Effects on static and dynamic EW stimulated accommodation were studied in three iridectomized monkeys (ages 5, 6 and 12 years) with permanent indwelling stimulating electrodes in the EW nucleus. Dynamic accommodative responses were measured with infrared photorefraction for increasing current amplitudes before and during the course of action of the pharmacological agents. Echothiophate caused a significant decrease in pupil diameter of 3.07 +/- 0.65 mm (mean +/- SEM, p < 0.01), and a myopic shift in resting refraction of 1.30 +/- 0.39 D (p < 0.05) 90 min after instillation. Epinephrine caused a 2.76 +/- 0.38 mm (p < 0.01) increase in pupil diameter with no change in resting refraction 60 min after instillation. Timolol maleate resulted in no significant change in either pupil diameter or resting refraction 60 min after instillation. There was no significant change in maximum EW stimulated accommodative amplitude after any agent tested. The amplitude vs. peak velocity relationship for accommodation was significantly different after echothiophate and timolol maleate, and for disaccommodation after echothiophate, epinephrine and timolol maleate. In conclusion, when tested objectively in anesthetized monkeys, epinephrine and timolol maleate did not alter resting refraction or accommodative amplitude, but did have small, significant affects on accommodative dynamics. This suggests that there is an adrenergic component to the accommodative system. Low dose echothiophate had significant effects on pupil diameter and resting refraction, with only small effects on the dynamics of the accommodative response. PMID- 19782075 TI - Abeta exacerbates the neuronal dysfunction caused by human tau expression in a Drosophila model of Alzheimer's disease. AB - Alzheimer's disease (AD) is characterised by neurofibrillary tangles composed of hyper-phosphorylated tau, and neuritic plaques composed of misfolded amyloid peptide (Abeta(42)). It is generally believed that the hyper-phosphorylated tau and oligomeric Abeta(42) are responsible for the neuronal dysfunction and cognitive impairments that underlie the early stages of AD, but the mechanism by which they interact in the pathogenic process is not clear. Mounting evidence suggests that Abeta(42) pathology lies upstream of hyper-phosphorylated tau pathology. Similarly much is being learnt about how each protein affects neuronal function. However, the impact that either pathological protein has on neuronal dysfunction caused by the other is not extensively studied. We have investigated this in a Drosophila model of AD in which we express both phosphorylated human tau (tau(wt)) and oligomeric Abeta(42). We find that expression of tau(wt) causes neuronal dysfunction by disrupting axonal transport and synaptic structure, and that this leads to behavioural impairments and reduced lifespan. Co-expression of Abeta(42) with tau(wt) increases tau phosphorylation and exacerbates all these tau-mediated phenotypes. Treatment of tau(wt)/Abeta(42) and flies with LiCl ameliorates the exacerbating effect of Abeta(42), suggesting that GSK-3beta may be involved in the mechanism by which Abeta(42) and tau(wt) interact to cause neuronal dysfunction. Conversely to the effect of Abeta(42), mimicking the wingless signalling pathway by co-expression of dishevelled with tau(wt) reduces tau phosphorylation and suppresses the tau-mediated phenotypes. It is therefore possible to speculate that the mechanism by which Abeta(42) interacts with tau in the pathogenesis of AD is by down-regulating endogenous wnt signalling. PMID- 19782076 TI - A scanning peptide array approach uncovers association sites within the JNK/beta arrestin signalling complex. AB - Beta arrestins are molecular scaffolds that can bring together three-component mitogen-activated protein kinase signalling modules to promote signal compartmentalisation. We use peptide array technology to define novel interfaces between components within the c-Jun N-terminal kinase (JNK)/beta arrestin signalling complex. We show that beta arrestin 1 and beta arrestin 2 associate with JNK3 via the kinase N-terminal domain in a region that, surprisingly, does not harbour a known 'common docking' motif. In the N-domain and C-terminus of beta arrestin 1 and beta arrestin 2 we identify two novel apoptosis signal regulating kinase 1 binding sites and in the N-domain of the beta arrestin 1 and beta arrestin 2 we identify a novel MKK4 docking site. PMID- 19782077 TI - 60th residues of ubiquitin and Nedd8 are located out of E2-binding surfaces, but are important for K48 ubiquitin-linkage. AB - Nedd8, a ubiquitin-like modifier, is covalently attached to various proteins. Although Nedd8 has higher sequence identity (57%) with ubiquitin, its conserved K48 residue cannot form covalent linkage with ubiquitin. To decipher the reason why Nedd8 cannot be an effective ubiquitin-acceptor, we compared the non-covalent interaction between Nedd8 and ubiquitin for various E2s using cross-saturation NMR technique. However, both Nedd8 and ubiquitin displayed almost identical non covalent E2-binding properties. The K60 of Nedd8 was not present at the E2 binding surface, but its mutation to Asn converted Nedd8 into a ubiquitin acceptor. The N60 ubiquitin mutants also displayed a decreased ubiquitin accepting activity. These results suggest the presence of an uncharacterized determinant for the K48 ubiquitin-linkage that is not related to non-covalent E2 bindings. PMID- 19782078 TI - Multiple proteins and phosphorylations regulate Saccharomyces cerevisiae Cdc24p localization. AB - Targeting of Saccharomyces cerevisiae Cdc24p to polarized growth sites is essential for its function. Localization of GFP-tagged Cdc24 proteins or fragments was assayed in deletion mutants of Cdc24p-interacting proteins. The boi2Delta, ent2Delta, and hua1Delta mutants showed localization defects. The tos2Delta skg6Delta double mutant displayed aberrant pre-anaphase localization to the mother-bud neck region. The same aberrant pattern was seen when potential phosphorylation sites Ser697, Thr704, and Tyr200 were mutated. The S697A mutation also resulted in phosphorylation defects in vivo. These data support roles for Boi2p, Ent2p, Hua1p, Tos2p, and for Cdc24p phosphorylation in targeting Cdc24p to growth sites. PMID- 19782079 TI - Modulation of hepatic fibrosis by c-Jun-N-terminal kinase inhibition. AB - BACKGROUND & AIMS: c-Jun N-terminal kinase (JNK) is activated by multiple profibrogenic mediators; JNK activation occurs during toxic, metabolic, and autoimmune liver injury. However, its role in hepatic fibrogenesis is unknown. METHODS: JNK phosphorylation was detected by immunoblot analysis and confocal immunofluorescent microscopy in fibrotic livers from mice after bile duct ligation (BDL) or CCl(4) administration and in liver samples from patients with chronic hepatitis C and non-alcoholic steatohepatitis. Fibrogenesis was investigated in mice given the JNK inhibitor SP600125 and in JNK1- and JNK2 deficient mice following BDL or CCl(4) administration. Hepatic stellate cell (HSC) activation was determined in primary mouse HSCs incubated with pan-JNK inhibitors SP600125 and VIII. RESULTS: JNK phosphorylation was strongly increased in livers of mice following BDL or CCl(4) administration as well as in human fibrotic livers, occurring predominantly in myofibroblasts. In vitro, pan-JNK inhibitors prevented transforming growth factor (TGF) beta-, platelet-derived growth factor-, and angiotensin II-induced murine HSC activation and decreased platelet-derived growth factor and TGF-beta signaling in human HSCs. In vivo, pan JNK inhibition did not affect liver injury but significantly reduced fibrosis after BDL or CCl(4). JNK1-deficient mice had decreased fibrosis after BDL or CCl(4), whereas JNK2-deficient mice displayed increased fibrosis after BDL but fibrosis was not changed after CCl(4). Moreover, patients with chronic hepatitis C who displayed decreased fibrosis in response to the angiotensin receptor type 1 blocker losartan showed decreased JNK phosphorylation. CONCLUSIONS: JNK is involved in HSC activation and fibrogenesis and represents a potential target for antifibrotic treatment approaches. PMID- 19782080 TI - Spontaneous control of primary hepatitis C virus infection and immunity against persistent reinfection. AB - BACKGROUND & AIMS: We followed patients with ongoing hepatitis C virus (HCV) exposure following control of an initial HCV infection to determine whether primary control conferred protection against future persistent infections. METHODS: Twenty-two active injection drug users (IDU) who had cleared a primary hepatitis C viremia for at least 60 days were monitored monthly. Reinfection was defined as the detection of a new HCV infection. Protection was assessed based on the magnitude and duration of viremia following reinfection and generation of T cell and neutralizing antibody (nAb) responses. RESULTS: Reinfection occurred in 11 IDU (50%) who previously spontaneously controlled primary HCV infection. Although viral clearance occurs in approximately 25% of patients with primary infections, spontaneous viral clearance was observed in 83% of reinfected patients. The duration and maximum level of viremia during subsequent episodes of reinfection were significantly decreased compared with those of the primary infection in the same subjects. In contrast to chronic infection, reinfection was associated with a significant increase in the breadth of T-cell responses. During acute infection, nAbs against heterologous viral pseudoparticles were detected in 60% of reinfected subjects; cross-reactive nAbs are rarely detected in patients who progress to chronic infection. CONCLUSIONS: HCV reinfection is associated with a reduction in the magnitude and duration of viremia (compared with the initial infection), broadened cellular immune responses, and generation of cross reactive humoral responses. These findings are consistent with development of adaptive immunity that is not sterilizing but protects against chronic disease. PMID- 19782081 TI - Release of 5-hydroxytryptamine from the mucosa is not required for the generation or propagation of colonic migrating motor complexes. AB - BACKGROUND & AIMS: The pacemaker mechanism that underlies the cyclic generation of colonic migrating motor complexes (CMMCs) is unknown, although studies have suggested that release of 5-hydroxytryptamine (5-HT) from enterochromaffin cells in the mucosa is essential. However, no recordings of 5-HT release from the colon have been made to support these suggestions. METHODS: We used real-time amperometry to record 5-HT release directly from the mucosa in mouse isolated colon to determine whether 5-HT release from enterochromaffin cells was required for CMMC generation. RESULTS: We found that 5-HT was released from mucosal enterochromaffin cells during many, but not all, CMMC contractions. However, spontaneous CMMCs still were recorded even after removal of the mucosa, and submucosa and submucosal plexus when all release of 5-HT had been abolished. CMMC pacemaker frequency was slower in the absence of the mucosa, an effect reversed by focal application of exogenous 5-HT onto the myenteric plexus. Despite the absence of the mucosa and all detectable release of 5-HT, ondansetron significantly reduced CMMC frequency, suggesting that 5-HT(3) receptor blockade slows the CMMC pacemaker via a mechanism independent of 5-HT release from enterochromaffin cells. CONCLUSIONS: Our results show that 5-HT can be released dynamically during CMMCs. However, the intrinsic pacemaker and pattern generator underlying CMMC generation lies within the myenteric plexus and/or muscularis externa and does not require any release of 5-HT from enterochromaffin cells. Endogenous release of 5-HT from enterochromaffin cells plays a modulatory role, not an essential role, in CMMC generation. PMID- 19782082 TI - A functional role for CCR6 on proallergic T cells in the gastrointestinal tract. AB - BACKGROUND & AIMS: CCL20 is a chemokine that regulates the homeostatic and inflammatory trafficking of leukocytes to the small intestine and regulates the development of the gastrointestinal lymphoid architecture. T cells expressing T helper cell (Th) 2 cytokines are critical for experimental food allergy, and we hypothesized that CCL20 is involved in the localization of these cells to the gut. METHODS: We evaluated the role of CCR6 in allergic diarrhea induced by sensitization and oral challenge with ovalbumin (OVA) using CCR6(+/+) and CCR6(-/ ) mice. RESULTS: CCR6(-/-) mice were protected from OVA-induced diarrhea but surprisingly were not impaired in mastocytosis or allergen-specific immunoglobulin E. CCR6(-/-) mice were also protected from T cell-mediated diarrhea induced by anti-CD3 antibody. Allergic diarrhea was associated with an increased expression of Th2 cytokines within the intestinal mucosa that was significantly reduced in CCR6(-/-) mice. Inhibition of lymphocyte homing by treatment with FTY720 did not impair allergic diarrhea, indicating that reactivation of T cells could occur locally within the small intestine. Finally, T-cell transfer studies demonstrated that CCR6 was required both on the transferred T cells and in the recipient mouse to manifest allergic disease in the gastrointestinal tract. CONCLUSIONS: These studies highlight a mast cell- and immunoglobulin E-independent role for CCR6-bearing T cells in the pathogenesis of gastrointestinal allergic disease. PMID- 19782083 TI - Silymarin inhibits in vitro T-cell proliferation and cytokine production in hepatitis C virus infection. AB - BACKGROUND & AIMS: Silymarin, an extract from the seeds of the milk thistle plant Silybum marianum, has been used for centuries for the treatment of chronic liver diseases. Despite common use by patients with hepatitis C in the United States, its clinical efficacy remains uncertain. The goal of this study was to determine whether silymarin has in vitro effects on immune function that might have implications for its potential effect on hepatitis C virus (HCV)-induced liver disease. METHODS: Freshly isolated peripheral blood mononuclear cells (PBMC) and T cells from HCV-infected and uninfected subjects were tested in vitro for responses to nonspecific and antigenic stimulation in the presence and absence of a standardized preparation of silymarin (MK001). RESULTS: Minimal MK001 toxicity on PBMC was found at concentrations between 5 and 40 microg/mL. MK001 dose dependently inhibited the proliferation and secretion of tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma, and interleukin (IL)-2 by PBMC stimulated with anti-CD3. In addition, MK001 inhibited proliferation by CD4(+) T cells to HCV, Candida, and tetanus protein antigens and by HLA-A2/HCV 1406-1415-specific CD8(+) T cells to allogeneic stimulation. MK001 inhibited T-cell TNF-alpha and IFN-gamma cytokine secretion to tetanus and Candida protein antigens. Finally, MK001 inhibited nuclear factor-kappaB transcriptional activation after T-cell receptor-mediated stimulation of Jurkat T cells, consistent with its ability to inhibit Jurkat T-cell proliferation and secretion of IL-2. CONCLUSIONS: Silymarin's ability to inhibit the proliferation and proinflammatory cytokine secretion of T cells, combined with its previously described antiviral effect, suggests a possible mechanism of action that could lead to clinical benefit during HCV infection. PMID- 19782084 TI - Serum levels of interleukin-10 and interleukin-12 predict early, spontaneous hepatitis B virus e antigen seroconversion. AB - BACKGROUND & AIMS: This prospective cohort study aimed to determine the effect of cytokines on spontaneous hepatitis B e antigen (HBeAg) seroconversion in patients with chronic hepatitis B virus (HBV) infection. METHODS: Polymorphisms in interleukin (IL)-2, IL-4, IL-10, IL-12beta, and interferon-gamma were evaluated in 288 HBeAg-positive chronic HBV patients (median initial age, 8.6 years; median follow-up duration, 19.3 years). Serum cytokine levels were determined in 154 subjects (53.5%) before and after HBeAg seroconversion by enzyme-linked immunosorbent assay analysis. Peripheral blood mononuclear cells (PBMC) were isolated from patients with chronic HBV infection and stimulated with HBV core antigen (HBcAg); data on cytokine genotypes and phenotypes were compared. RESULTS: The IL-10-1082 G/G and IL-12beta -10993C/G genotypes predicted early, spontaneous HBeAg seroconversion (hazard ratio [HRs] = 3.43 and 1.54; P < .001, and P < .004, respectively), based on multivariate survival analysis. The IL-10 1082 G/G genotype was associated with higher serum levels of IL-10 and IL-12; the IL-12beta -10993 C/G genotype predicted higher levels of IL-12 secretion by PBMC after in vitro HBcAg stimulation (P = .04). Higher levels of serum IL-12 (>45 pg/mL) and IL-10 (>70 pg/mL) were associated with early, spontaneous HBeAg seroconversion (HR = 1.52 and 1.48; P = .04 and .02, respectively). CONCLUSIONS: The IL-10-1082 G/G is associated with higher serum IL-10 and IL-12 levels and IL 12beta -10993 C/G is associated with increased secretion of IL-12 in response to HBcAg stimulation of PBMC. Both genotypes are associated with early, spontaneous HBeAg seroconversion. Higher serum levels of IL-10 and IL-12 in HBeAg-positive patients are correlated with early, spontaneous HBeAg seroconversion. PMID- 19782086 TI - Carbamylated darbepoetin derivative prevents endothelial progenitor cell damage with no effect on angiogenesis. AB - Erythropoietin (EPO) prevents cell apoptosis induced by oxidative stress. Carbamylated EPO maintains the tissue-protective activities of the unmodified EPO but does not stimulate erythropoiesis. This study evaluates whether carbamylated erythropoietin is as effective as recombinant human erythropoietin in protecting endothelial progenitor cells (EPCs) from apoptosis without stimulating erythropoiesis. Experiments were performed in an erythroid cell line (UT-7) and in human EPCs. Cell signals regulating proliferation and apoptosis (Jak-2, Akt, Erk1/2, NFkappaB and Stat-5) were measured by Western blotting. In human EPCs, cell senescence, apoptosis and proliferation were assessed by acidic beta-gal and measurement of telomere length, TUNEL and PCNA labeling, respectively. Angiogenesis was evaluated using the endothelial tube formation assay. In UT-7, carbamylated erythropoietin (C-darbe) induced phosphorylation of the anti apoptotic Jak-2/Akt signal and, as opposed to recombinant human erythropoietin (darbe), did not produce a significant activation of cell proliferating signals. Darbe increased the percent of proliferating EPCs and promoted angiogenesis. By contrast, C-darbe failed to stimulate proliferation of EPCs. Both C-darbe and darbe equally reduced apoptosis and senescence. Thus, C-darbe protects EPCs from apoptosis and does not increase erythropoiesis. PMID- 19782087 TI - Predicting ligand binding affinity with alchemical free energy methods in a polar model binding site. AB - We present a combined experimental and modeling study of organic ligand molecules binding to a slightly polar engineered cavity site in T4 lysozyme (L99A/M102Q). For modeling, we computed alchemical absolute binding free energies. These were blind tests performed prospectively on 13 diverse, previously untested candidate ligand molecules. We predicted that eight compounds would bind to the cavity and five would not; 11 of 13 predictions were correct at this level. The RMS error to the measurable absolute binding energies was 1.8 kcal/mol. In addition, we computed "relative" binding free energies for six phenol derivatives starting from two known ligands: phenol and catechol. The average RMS error in the relative free energy prediction was 2.5 kcal/mol (phenol) and 1.1 kcal/mol (catechol). To understand these results at atomic resolution, we obtained x-ray co-complex structures for nine of the diverse ligands and for all six phenol analogs. The average RMSD of the predicted pose to the experiment was 2.0 A (diverse set), 1.8 A (phenol-derived predictions), and 1.2 A (catechol-derived predictions). We found that predicting accurate affinities and rank-orderings required near-native starting orientations of the ligand in the binding site. Unanticipated binding modes, multiple ligand binding, and protein conformational change all proved challenging for the free energy methods. We believe that these results can help guide future improvements in physics-based absolute binding free energy methods. PMID- 19782088 TI - Projection structure of DtpD (YbgH), a prokaryotic member of the peptide transporter family. AB - Cellular uptake of di- and tripeptides has been characterized in numerous organisms, and various transporters have been identified. In contrast, structural information on peptide transporters is very sparse. Here, we have cloned, overexpressed, purified, and biochemically characterized DtpD (YbgH) from Escherichia coli, a prokaryotic member of the peptide transporter family. Its homologues in mammals, PEPT1 (SLC15A1) and PEPT2 (SLC15A2), not only transport peptides but also are of relevance for uptake of drugs as they accept a large spectrum of peptidomimetics such as beta-lactam antibiotics, antivirals, peptidase inhibitors, and others as substrates. Uptake experiments indicated that DtpD functions as a canonical peptide transporter and is, therefore, a valid model for structural studies of this family of proteins. Blue native polyacrylamide gel electrophoresis, gel filtration, and transmission electron microscopy of single-DtpD particles suggest that the transporter exists in a monomeric form when solubilized in detergent. Two-dimensional crystallization of DtpD yielded first tubular crystals that allowed the determination of a projection structure at better than 19 A resolution. This structure of DtpD represents the first structural view of a member of the peptide transporter family. PMID- 19782085 TI - Effective treatment of injecting drug users with recently acquired hepatitis C virus infection. AB - BACKGROUND & AIMS: Patients with acute hepatitis C virus (HCV) infection who receive treatment achieve high rates of sustained virologic response (SVR), but few studies have examined outcomes among injecting drug users (IDUs). We evaluated the efficacy of treatment of recent HCV infection in IDUs with acute and early chronic HCV. METHODS: We analyzed data from the Australian Trial in Acute Hepatitis C-a prospective study of the natural history and treatment outcomes of patients with recent HCV infection. Participants eligible for the study had their first anti-HCV antibody-positive test result within the past 6 months and either acute clinical HCV within the past 12 months or documented anti HCV seroconversion within 24 months. Participants with HCV received pegylated interferon-alfa-2a (180 microg/wk, n = 74); those with HCV/human immunodeficiency virus (HIV) co-infection received pegylated interferon-alfa-2a (180 microg/wk) with ribavirin (n = 35) for 24 weeks. RESULTS: From June 2004 to February 2008, 167 participants were enrolled in the Australian Trial in Acute Hepatitis C; 79% had injected drugs in the previous 6 months. Among 74 with only HCV, the SVRs were 55% and 72% by intention-to-treat and per-protocol analysis, respectively. In multivariate analyses, baseline factors independently associated with lower SVR included decreased social functioning and current opiate pharmacotherapy. Adherent participants had higher SVR rates (63% vs 29%; P = .025). Of the 35 participants with HCV/HIV co-infection, the SVRs were 74% and 75% by intention-to treat and per-protocol analysis, respectively. CONCLUSIONS: Treatment of recent HCV infection among IDUs, including those with HIV co-infection, is effective. Strategies to engage socially marginalized individuals and increase adherence should improve treatment outcomes in this population. PMID- 19782090 TI - A conserved unfoldase activity for the p97 AAA-ATPase in proteasomal degradation. AB - The multifunctional AAA-ATPase p97 is one of the most abundant and conserved proteins in eukaryotic cells. The p97/Npl4/Ufd1 complex dislocates proteins that fail the protein quality control in the endoplasmic reticulum to the cytosol where they are subject to degradation by the ubiquitin/proteasome system. Substrate dislocation depends on the unfoldase activity of p97. Interestingly, p97 is also involved in the degradation of specific soluble proteasome substrates but the exact mode of action of p97 in this process is unclear. Here, we show that both the central pore and ATPase activity of p97 are necessary for the degradation of cytosolic ubiquitin-fusion substrates. Addition of a flexible extended C-terminal peptide to the substrate relieves the requirement for p97. Deletion mapping reveals a conserved length dependency of 20 residues for the peptide, which allows p97-independent degradation to occur. Our results suggest that initiation of unfolding may be more complex than previously anticipated and that the 19S regulatory complex of the proteasome can require preprocessing of highly folded, ubiquitylated substrates by the p97(Ufd1/Npl4) complex. Our data provide an explanation for the observation that p97 is only essential for a subpopulation of soluble substrates and predict that a common characteristic of soluble p97-dependent substrates is the lack of an initiation site to facilitate unfolding by the 26S proteasome. PMID- 19782091 TI - Towards a correct description of zooplankton feeding in models: taking into account food-mediated unsynchronized vertical migration. AB - Complex nature of foraging behaviour of zooplankton makes it difficult to describe adequately zooplankton grazing in models with vertical space. In mean field models (based on systems of PDEs or coupled ODEs), zooplankton feeding at a given depth is normally computed as the product of the local functional response and the zooplankton density at this depth. Such simplification is often at odds with field observations which show the absence of clear relationship between intake rates of organisms and the ambient food density. The observed discrepancy is generic and is often caused by fast non-synchronous vertical migration of organisms with different nutrition status. In this paper, we suggest a simple way of incorporating unsynchronized short-term vertical migration of zooplankton into the mean-field modelling framework. We compute grazing of zooplankton in each layer depending on feeding activity of organisms in the layer. We take into account grazing impact of animals which are in the active phase of foraging cycle at the given moment of time but neglect the impact of animals which are in the non-active phase of the cycle (e.g. digesting food). Unsynchronized vertical migration determines the vertical distribution of actively feeding animals in layers depending on vertical distribution of food. In this paper, we compare two generic plankton models: (i) a model based on 'classical' grazing approach and (ii) a model incorporating food-mediated unsynchronized vertical migration of zooplankton. We show that including unsynchronized food-mediated migration would make the behaviour of a plankton model more realistic. This would imply a significant enhancement of ecosystem's stability and some additional mechanisms of regulation of algal blooms. In the system with food-mediated unsynchronized vertical migration, the control of phytoplankton by herbivorous becomes possible even for very large concentrations of nutrients in the water (formally, when the system's carrying capacity tends to infinity). PMID- 19782089 TI - Coronavirus N protein N-terminal domain (NTD) specifically binds the transcriptional regulatory sequence (TRS) and melts TRS-cTRS RNA duplexes. AB - All coronaviruses (CoVs), including the causative agent of severe acute respiratory syndrome (SARS), encode a nucleocapsid (N) protein that harbors two independent RNA binding domains of known structure, but poorly characterized RNA binding properties. We show here that the N-terminal domain (NTD) of N protein from mouse hepatitis virus (MHV), a virus most closely related to SARS-CoV, employs aromatic amino acid-nucleobase stacking interactions with a triple adenosine motif to mediate high-affinity binding to single-stranded RNAs containing the transcriptional regulatory sequence (TRS) or its complement (cTRS). Stoichiometric NTD fully unwinds a TRS-cTRS duplex that mimics a transiently formed transcription intermediate in viral subgenomic RNA synthesis. Mutation of the solvent-exposed Y127, positioned on the beta-platform surface of our 1.75 A structure, binds the TRS far less tightly and is severely crippled in its RNA unwinding activity. In contrast, the C-terminal domain (CTD) exhibits no RNA unwinding activity. Viruses harboring Y127A N mutation are strongly selected against and Y127A N does not support an accessory function in MHV replication. We propose that the helix melting activity of the coronavirus N protein NTD plays a critical accessory role in subgenomic RNA synthesis and other processes requiring RNA remodeling. PMID- 19782092 TI - Systematic biases in the tactile perception of the subjective vertical in patients with unilateral neglect and the influence of upright vs. supine posture. AB - Patients with right hemisphere lesions often show contralesional neglect. Recent research focused on deficits beyond the typical neglect symptoms observed in the horizontal plane. Studies investigating deficits in the frontal and sagittal plane revealed impairments in the judgment of the subjective vertical. Systematic deviations in the subjective vertical have been demonstrated in the visual and tactile modality, indicating a supramodal spatial orientation deficit. Further, the magnitude of deviations appears to be manipulable by modulations of body posture. The present study investigated the subjective tactile vertical (STV) in neglect patients in the frontal and sagittal plane and its dependence on posture. Neglect patients and healthy controls performed tactile-spatial judgments of axis orientations in supine and upright posture. Neglect patients displayed a marked variability as well as a systematic tilt in their STV judgments. The STV was tilted counterclockwise in the frontal and backward in the sagittal plane. This tilt was larger in severe compared to moderate neglect patients, while it was not evident in healthy subjects. Our results support previous evidence and indicate a multisensory spatial orientation deficit in neglect patients which is related to neglect severity. Further, we found that performance of neglect patients deteriorated in supine compared to upright posture. This finding conflicts with the suggestion of a performance benefit in supine posture due to reduced (asymmetric) gravitational input. The negative effect of supine posture on the spatial bias in neglect is discussed with respect to a presumably further reduced intrinsic alertness state in the typically hypo-aroused neglect patients. PMID- 19782093 TI - Response inhibition subprocesses and dopaminergic pathways: basal ganglia disease effects. AB - Response inhibition is a component of executive functions, which can be divided into distinct subprocesses by means of event-related potentials (ERPs). These subprocesses are (pre)-motor inhibition and inhibition monitoring, which are probably reflected by the Nogo-N2 and Nogo-P3, respectively. Here we ask, if these subprocesses may depend on distinct basal ganglia subsystems. We examined response inhibition processes in an extended sample of young and elderly subjects, patients with Parkinson's disease (PD) and Huntington' disease (HD). This combination of groups also allow us to study whether, and to what degree, pathological basal ganglia changes and healthy aging have similar and/or different effects on these processes. We show that subprocesses of response inhibition are differentially modulated by distinct basal ganglia circuits. Processes related to (pre)-motor inhibition appear to be modulated by the nigrostriatal system, and are sensitive to aging and age-related basal ganglia diseases (i.e. PD). Parkinson's disease induces additive effects of aging and pathology. In contrast, inhibition monitoring is most likely modulated by the mesocortico-limbic dopamine system. These processes are equally affected in healthy aging and both basal ganglia diseases (i.e. PD, HD). PMID- 19782094 TI - Body schematics: on the role of the body schema in embodied lexical-semantic representations. AB - Words denoting manipulable objects activate sensorimotor brain areas, likely reflecting action experience with the denoted objects. In particular, these sensorimotor lexical representations have been found to reflect the way in which an object is used. In the current paper we present data from two experiments (one behavioral and one neuroimaging) in which we investigate whether body schema information, putatively necessary for interacting with functional objects, is also recruited during lexical processing. To this end, we presented participants with words denoting objects that are typically brought towards or away from the body (e.g., cup or key, respectively). We hypothesized that objects typically brought to a location on the body (e.g., cup) are relatively more reliant on body schema representations, since the final goal location of the cup (i.e., the mouth) is represented primarily through posture and body co-ordinates. In contrast, objects typically brought to a location away from the body (e.g., key) are relatively more dependent on visuo-spatial representations, since the final goal location of the key (i.e., a keyhole) is perceived visually. The behavioral study showed that prior planning of a movement along an axis towards and away from the body facilitates processing of words with a congruent action semantic feature (i.e., preparation of movement towards the body facilitates processing of cup.). In an fMRI study we showed that words denoting objects brought towards the body engage the resources of brain areas involved in the processing information about human bodies (i.e., the extra-striate body area, middle occipital gyrus and inferior parietal lobe) relatively more than words denoting objects typically brought away from the body. The results provide converging evidence that body schema are implicitly activated in processing lexical information. PMID- 19782095 TI - Aldosterone as a renal growth factor. AB - Aldosterone regulates blood pressure through its effects on the cardiovascular system and kidney. Aldosterone can also contribute to the development of hypertension that leads to chronic pathologies such as nephropathy and renal fibrosis. Aldosterone directly modulates renal cell proliferation and differentiation as part of normal kidney development. The stimulation of rapidly activated protein kinase cascades is one facet of how aldosterone regulates renal cell growth. These cascades may also contribute to myofibroblastic transformation and cell proliferation observed in pathological conditions of the kidney. Polycystic kidney disease is a genetic disorder that is accelerated by hypertension. EGFR-dependent proliferation of the renal epithelium is a factor in cyst development and trans-activation of EGFR is a key feature in initiating aldosterone-induced signalling cascades. Delineating the components of aldosterone-induced signalling cascades may identify novel therapeutic targets for proliferative diseases of the kidney. PMID- 19782096 TI - Translational research on rapid steroid actions. AB - Translational research is a burgeoning science that shows potential to improve the transition of research from bench to bedside. This novel science explores all major aspects of preclinical and clinical issues which are relevant for the success of translational pharmaceutical or medical device/diagnostic innovations. This includes target risk assessment, biomarker evaluation and predictivity grading both for efficacy and toxicity, early human trial design adequate to guide stop/go decisions on grounds of biomarker panels, and biostatistical methods to analyze multiple readout situations and quantify risk projections. Representing a comparably novel science, rapid steroid actions have been recognized to carry potential clinical implications in various fields. Findings in this field have not yet been successfully translated into clinically relevant new medicines except for neurosteroids. A promising compound is the membrane estrogen receptor agonist STX, which may be applicable for estrogen withdrawal symptoms. Nongenomic vitamin D analogs may be useful as antiinflammatory, anticancer or diabetes preventing agents. Further the membrane thyroid receptor agonist tetrac may be useful in cancer treatment. Unfortunately lazaroids (membrane-only active glucocorticoids), which have been clinically tested as neuroprotective agents, had to be abandoned because of lacking clinical efficacy. Yet, the hierarchy of antirheumatic glucocorticoid action in regard to their clinical potency may better correlate with their membrane effects than their ability to bind to the classic glucocorticoid receptor. To improve the translational success of the rapid actions of steroids research, scientists should become familiar with major aspects of translational work and always seek for translational dimensions in their research. PMID- 19782097 TI - Low concentration of arsenic could induce caspase-3 mediated head kidney macrophage apoptosis with JNK-p38 activation in Clarias batrachus. AB - We had earlier demonstrated that chronic exposure (30 days) to micro-molar concentration (0.50 microM) of arsenic induced head kidney macrophage (HKM) death in Clarias batrachus. The purpose of the present study is to characterize the nature of HKM death induced by arsenic and elucidate the signal transduction pathways involved in the process. Arsenic-induced HKM death was apoptotic in nature as evident from DNA gel, Annexin V-propidium iodide, Hoechst 33342 staining and TdT-mediated dUTP nick end labeling (TUNEL) assays. Inhibitor studies and immunoblot analyses further demonstrated that arsenic-induced HKM apoptosis involved activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase, a well-characterized caspase-3 substrate. Preincubation with antioxidants N-acetyl-cysteine or dimethyl sulfoxide significantly lowered reactive oxygen species (ROS) levels in arsenic-treated HKM and prevented caspase activation, malondialdehyde formation and HKM apoptosis. Arsenic induced membrane translocation of the NADPH oxidase subunit p47(phox). Preincubation with apocynin and diphenyleneiodonium chloride, both selective inhibitors of NADPH oxidases, prevented p47(phox) translocation, ROS production and HKM death. Exposure of HKM to arsenic induced the activation of mitogen-activated protein kinase family (MAPK) proteins including c-Jun NH(2)-terminal protein kinase (JNK) and p38 mitogen-activated protein kinase (p38). Preincubation of HKM with p38 inhibitor SB203580 and JNK inhibitor SP600125 protected the HKM against arsenic-induced apoptosis. We conclude that exposure to micro-molar concentration of arsenic induces ROS generation through the activation of NADPH oxidases, which in turn causes caspase-3 mediated HKM apoptosis. In addition, the study also indicates a role of p38-JNK pathway in arsenic-induced HKM apoptosis in C. batrachus. PMID- 19782098 TI - Ciguatera: a public health perspective. AB - Ciguatera fish poisoning is a seafood-borne illness caused by consumption of fish that have accumulated lipid-soluble ciguatoxins. In the United States, ciguatera is responsible for the highest reported incidence of food-borne illness outbreaks attributed to finfish, and it is reported to hold this distinction globally. Ciguatoxins traverse the marine food web from primary producers, Gambierdiscus spp., to commonly consumed fish in tropical and subtropical regions of the world. Ciguatoxins comprise 12 known congeners among Caribbean and tropical Atlantic fish and 29 reported congeners among Pacific fish. Expanding trade in fisheries from ciguatera-endemic regions contributes to wider distribution and increasing frequency of disease among seafood consumers in non-endemic regions. Ciguatoxins produce a complex array of gastrointestinal, neurological and cardiological symptoms. Treatment options are very limited and supportive in nature. Information derived from the study of ciguatera outbreaks has improved clinical recognition, confirmation, and timely treatment. Such studies are equally important for the differentiation of ciguatoxin profiles in fish from one region to the next, the determination of toxicity thresholds in humans, and the formulation of safety limits. Analytical information from case and outbreak investigations was used to derive Pacific and Caribbean ciguatoxin threshold contamination rates for adverse effects in seafood consumers. To these threshold estimates 10-fold safety factors were applied to address individual human risk factors; uncertainty in the amount of fish consumed; and analytical accuracy. The studies may serve as the basis for industry and consumer advisory levels of 0.10ppb C-CTX-1 equivalent toxicity in fish from the tropical Atlantic, Gulf of Mexico, Caribbean, and 0.01ppb P-CTX-1 equivalent toxicity in fish from Pacific regions. PMID- 19782099 TI - The object and background hypothesis for vection. AB - Stimulus attributes effective in inducing vection can be generalized by the object and background hypothesis, that is, properties that belong to 'objects' weaken vection while those of the 'background' enhance vection. We presented a motion-defined Rubin's vase to induce vection. Results clearly indicated that the background dominantly induced vection. We further demonstrated that motion stimuli that had a property of an object could not induce vection efficiently. Investigating vection in the framework of the object and background hypothesis provides a unified point of view for understanding vection stimuli. PMID- 19782100 TI - Saliency does not account for fixations to eyes within social scenes. AB - We assessed the role of saliency in driving observers to fixate the eyes in social scenes. Saliency maps (Itti & Koch, 2000) were computed for the scenes from three previous studies. Saliency provided a poor account of the data. The saliency values for the first-fixated locations were extremely low and no greater than what would be expected by chance. In addition, the saliency values for the eye regions were low. Furthermore, whereas saliency was no better at predicting early saccades than late saccades, the average latency to fixate social areas of the scene (e.g., the eyes) was very fast (within 200 ms). Thus, visual saliency does not account for observers' bias to select the eyes within complex social scenes, nor does it account for fixation behavior in general. Instead, it appears that observers' fixations are driven largely by their default interest in social information. PMID- 19782101 TI - Characterization of arrangement and expression of the beta-2 microglobulin locus in the sandbar and nurse shark. AB - Beta 2 microglobulin (beta2m) is an essential subunit of major histocompatibility complex (MHC) type I molecules. In this report, beta2m cDNAs were identified and sequenced from sandbar shark spleen cDNA library. Sandbar shark beta2m gene encodes one amino acid less than most teleost beta2m genes, and 3 amino acids less than mammal beta2m genes. Although sandbar shark beta2m protein contains one beta sheet less than that of human in the predicted protein structure, the overall structure of beta2m proteins is conserved during evolution. Germline gene for the beta2m in sandbar and nurse shark is present as a single locus. It contains three exons and two introns. CpG sites are evenly distributed in the shark beta2m loci. Several DNA repeat elements were also identified in the shark beta2m loci. Sequence analysis suggests that the beta2m locus is not linked to the MHC I loci in the shark genome. PMID- 19782102 TI - Magnetic resonance imaging reveals that galantamine prevents structural brain damage induced by an acute exposure of guinea pigs to soman. AB - Galantamine, a drug used to treat Alzheimer's disease, has recently emerged as a potential medical countermeasure against the toxicity of organophosphorus (OP) compounds, including the nerve agent soman. Here, magnetic resonance imaging (MRI) was used to characterize the neurotoxic effects of soman and the ability of galantamine to prevent these effects in guinea pigs, the best non-primate model to predict the effectiveness of antidotes against OP toxicity in humans. The brains of treated and untreated guinea pigs were imaged using a clinical 3.0 Tesla MRI scanner at 48 h before and 6-7 h, 48 h and 7 days after their challenge with 1.0xLD50 soman (26.6 microg/kg, sc). Significant brain atrophy was observed among all untreated animals at 7 days after their challenge with soman. In mildly intoxicated animals, significant shortening of spin-spin relaxation times (T2) was observed in the thalamus and amygdala at 7h after the challenge. In severely intoxicated animals, T2 values and T2-weighted signal intensities increased significantly in the piriform cortex, hippocampus, thalamus and amygdala; in most regions, changes were long-lasting. Voxel-based morphometric analysis of the images revealed that other brain regions were also damaged in these animals. Neuronal loss was confirmed histopathologically. In animals that were treated with galantamine (8 mg/kg, im) 30 min prior to the exposure to soman, T2, T2 weighted signal intensities, and CSF volumes were largely unaffected. It is, therefore, concluded that galantamine can effectively prevent the structural brain damage induced by an acute exposure to soman. PMID- 19782104 TI - Infusions of anti-sense oligonucleotides for DARPP-32 to the ventral tegmental area reduce effects of progesterone- and a dopamine type 1-like receptor agonist to facilitate lordosis. AB - Manipulating dopamine and/or adenosine 3',5' monophosphate regulated phosphoprotein of 32 kDa (DARPP-32) can influence sexual behavior of rodents. The ventral tegmental area (VTA) is an important brain site for progestogens to facilitate sexual behavior of rodents. We hypothesized that, in the VTA, dopamine type 1-like receptor (D1)-mediated increases in progesterone (P4)-facilitated lordosis involve DARPP-32. To investigate this, ovariectomized hamsters and rats, primed with estradiol (E2; 10 microg), received infusions to the VTA of saline vehicle or sense or anti-sense oligonucleotides targeted against DARPP-32 (4 nM). Subjects were then administered P4 via subcutaneous injection (hamsters: 200 microg; rats: 0 or 100 microg). Hamsters and rats were pre-tested for lordosis 3.5 h post-P4 injections, and then infused with the D1 agonist SKF38393 (100 ng) or vehicle to the VTA, and re-tested for sexual behavior 30 min later. Anti-sense oligonucleotides targeted against DARPP-32, but not infusions of sense oligonucleotides, to the VTA blocked the ability of systemic P4 to enhance receptive behavior of hamsters and rats. Similarly, SKF38393-mediated increases in P4-facilitated sexual behaviors were blocked by DARPP-32 anti-sense oligonucleotides to the VTA. The same pattern of effects was not observed in rats that were primed with E2-alone. Together, these findings suggest that, in the midbrain VTA, P4's actions to facilitate sexual behavior of female rodents, involving D1 receptors, may require DARPP-32. PMID- 19782105 TI - Intermittent prenatal MDMA exposure alters physiological but not mood related parameters in adult rat offspring. AB - The recreational party drug "ecstasy" (3,4-methylenedioxymethamphetamine MDMA) is particularly popular among young adults who are in the childbearing age and thus there is a substantial risk of prenatal MDMA exposure. We applied an intermittent treatment protocol with an early first injection on pregnant Wistar rats (15 mg/kg MDMA s.c. on the E4, E11 and E18 days of gestation) to examine the potential physiological, endocrine and behavioral effects on adult male and female offspring. Prenatal MDMA-treatment provoked reduced body weight of offspring from the birth as far as the adulthood. Adult MDMA-offspring had a reduced blood-glucose concentration and hematocrit, altered relative spleen and thymus weight, had lower performance on wire suspension test and on the first trial of rotarod test. In contrast, no alteration in the locomotor activity was found. Anxiety and depression related behavioral parameters in elevated plus maze, sucrose preference or forced swimming tests were normal. MDMA-offspring had elevated concentration of the ACTH-precursor proopiomelanocortin and male MDMA offspring exhibited elevated blood corticosterone concentration. No significant alteration was detected in the serotonergic marker tryptophan-hydroxylase and the catcholaminergic marker tyrosine-hydroxylase immunoreactive fiber densities in MDMA-offspring. The mothers exhibited reduced densities of serotonergic but not catecholaminergic fibers after the MDMA treatment. Our findings suggest that an intermittent prenatal MDMA exposure with an early first injection and a relatively low cumulative dose provokes mild but significant alterations in physical-physiological parameters and reduces motor skill learning in adulthood. In contrast, these adult offspring do not produce anxiety or depression like behavior. PMID- 19782106 TI - Myristoyl-CoA:protein N-myristoyltransferase depletion in trypanosomes causes avirulence and endocytic defects. AB - The enzyme myristoyl-CoA:protein N-myristoyltransferase (NMT) catalyses the co translational covalent attachment of the fatty acid myristate to the N-terminus of target proteins. NMT is known to be essential for viability in Trypanosoma brucei and Leishmania major. Here we describe phenotypic analysis of T. brucei bloodstream form cells following knockdown of NMT expression by tetracycline inducible RNA interference. Cell death occurs from 72h post-induction, with approximately 50% of cells displaying a defect in endocytic uptake by this time. The majority of these induced cells do not have an enlarged flagellar pocket typical of a block in endocytosis but vesicle accumulation around the flagellar pocket indicates a defect in vesicular progression following endocytic fusion. Induced parasites have a wild-type or slightly enlarged Golgi apparatus, unlike the phenotype of cells with reduced expression of a major N-myristoylated protein, ARL1. Critically we show that following NMT knockdown, T. brucei bloodstream form cells are unable to establish an infection in a mouse model, therefore providing further validation of this enzyme as a target for drug development. PMID- 19782107 TI - GDF5 and BMP2 inhibit apoptosis via activation of BMPR2 and subsequent stabilization of XIAP. AB - GDF5 and BMP2, members of the TGF-beta superfamily of growth factors, are known to regulate apoptosis in different cell types either positively or negatively. We wanted to investigate the effects of GDF5 and BMP2 on vascular smooth muscle cells and mouse embryonic fibroblasts and disclose the mechanism by which GDF5 and BMP2 might exert anti-apoptotic effects. The effect of GDF5 and BMP2 on proliferation and/or programmed cells death was assessed in isolated human vascular smooth muscle cells and mouse embryonic fibroblasts. We demonstrate that GDF5 and BMP2 prevent apoptosis induced by serum starvation in mouse embryonic fibroblasts but not in smooth muscle cells via the BMP receptor 2 (BMPR2), which is often mutated in hereditary cases of primary pulmonary hypertension. GDF5 and BMP2 stimulate the interaction of BMPR-2 with XIAP thereby reducing the ubiquitination of XIAP, which results in enhanced protein stability. The increased concentration of XIAP counteracts apoptosis by binding and inactivating activated caspases. We conclude that the inhibition of apoptosis in mouse embryonic fibroblasts by BMP2 and GDF5 does not depend on more complex signal transduction pathways such as smad and MAPK signaling but on direct stabilization of XIAP by BMPR2. PMID- 19782108 TI - Glycosylation of classical swine fever virus E(rns) is essential for binding double-stranded RNA and preventing interferon-beta induction. AB - Host cells sense double-stranded RNA (dsRNA) produced during viral replication and initiate type I interferon (IFN-alpha/beta) production, leading to subsequent antiviral responses. Many viruses, including classical swine fever virus (CSFV), have developed strategies for counteracting the IFN-alpha/beta response. In this study, we explored the role of the CSFV E(rns) glycoprotein in the inhibition of IFN-beta production induced by dsRNA [poly(IC)]. Our results demonstrated that CSFV E(rns) could bind to exogenous dsRNA and inhibit dsRNA-induced IFN-beta production but failed to inhibit TRIF-triggered IFN-beta production. Our data suggest that the inhibition of IFN-beta induction occurred at the initial step of the TLR3 signaling pathway. We also showed that deglycosylation of E(rns) rendered it unable to bind to dsRNA, and thus unable to inhibit dsRNA-induced IFN beta production. Taken together, these results indicated that N-glycan of CSFV E(rns) is essential for E(rns) blocking of IFN-beta induction. PMID- 19782103 TI - Novel approaches to inhibiting HIV-1 replication. AB - Considerable success has been achieved in the treatment of HIV-1 infection, and more than two-dozen antiretroviral drugs are available targeting several distinct steps in the viral replication cycle. However, resistance to these compounds emerges readily, even in the context of combination therapy. Drug toxicity, adverse drug-drug interactions, and accompanying poor patient adherence can also lead to treatment failure. These considerations make continued development of novel antiretroviral therapeutics necessary. In this article, we highlight a number of steps in the HIV-1 replication cycle that represent promising targets for drug discovery. These include lipid raft microdomains, the RNase H activity of the viral enzyme reverse transcriptase, uncoating of the viral core, host cell machinery involved in the integration of the viral DNA into host cell chromatin, virus assembly, maturation, and budding, and the functions of several viral accessory proteins. We discuss the relevant molecular and cell biology, and describe progress to date in developing inhibitors against these novel targets. This article forms part of a special issue of Antiviral Research marking the 25th anniversary of antiretroviral drug discovery and development, Vol 85, issue 1, 2010. PMID- 19782109 TI - Constructing target product profiles (TPPs) to help vaccines overcome post approval obstacles. AB - As history has demonstrated, post-approval obstacles can impede a vaccine's use and potentially lead to its withdrawal. Addressing these potential obstacles when changes in a vaccine's technology can still be easily made may improve a vaccine's chances of success. Augmented vaccine target product profiles (TPPs) can help vaccine scientists better understand and anticipate these obstacles and galvanize conversations among various vaccine stakeholders (e.g., scientists, marketers, business development managers, policy makers, public health officials, health care workers, third party payors, etc.) earlier in a vaccine's development. PMID- 19782110 TI - Vaccination with recombinant Plasmodium vivax MSP-10 formulated in different adjuvants induces strong immunogenicity but no protection. AB - Although largely considered benign, Plasmodium vivax causes disease in nearly 75 million people each year and the available strategies are not sufficient to reduce the burden of disease, therefore pointing to vaccine development as a cost effective control measure. In this study, the P. vivax merozoite surface protein 10 (MSP-10) was expressed as a recombinant protein in Escherichia coli and purified by affinity chromatography. High antigenicity was observed since sera from P. vivax-infected patients strongly recognized rPvMSP10. The immunogenicity of rPvMSP10 was tested in Aotus monkeys, comparing responses induced by formulations with Freund's adjuvant, Montanide ISA720 or aluminum hydroxide. All formulations produced high antibody titers recognizing the native protein in late schizonts. Despite inducing strong antibody production, none of the formulations protected immunized Aotus monkeys upon experimental challenge. PMID- 19782111 TI - Construction of an unmarked recombinant BCG expressing a pertussis antigen by auxotrophic complementation: protection against Bordetella pertussis challenge in neonates. AB - Mycobacterium bovis BCG has long been investigated as a candidate for heterologous antigen presentation. We have previously described an rBCG-Pertussis that confers protection against challenge with Bordetella pertussis in neonate and adult mice. In order to obtain stable expression in vivo, we constructed an unmarked BCG lysine auxotrophic and a complementation vector containing the lysine and the genetically detoxified S1 pertussis toxin genes, both under control of the same promoter. Complemented BCG-Delta lysine growth and expression of the pertussis antigen were stable, without the use of an antibiotic marker. Our results show that the complemented rBCG-Delta lysA-S1PT-lysA(+)(kan(-)), which is now suitable to be evaluated in clinical trials, maintains similar characteristics of the original rBCG-pNL71S1PT strain, such as the antigen expression level, cellular immune response and protection against the same model challenge in neonatal-immunized mice. PMID- 19782112 TI - Evaluation of Echinococcus multilocularis tetraspanins as vaccine candidates against primary alveolar echinococcosis. AB - Echinococcus multilocularis causes an important zoonotic cestode disease. The metacestode stage proliferates in the liver of intermediate hosts including human and rodents and forms multiple cysts. Recently, members of a transmembrane protein tetraspanin (TSP) family have been used as vaccines against schistosomosis, or as diagnostic antigens for cysticercosis. In this study, seven tetraspanins of E. multilocularis, designated as TSP1 to TSP7, were evaluated for their protective potential against primary alveolar echinococcosis. The large extracellular loop (LEL) region of these tetraspanins was cloned from a full length enriched cDNA library of E. multilocularis metacestodes and expressed in Escherichia coli as a fusion protein with thioredoxin. Recombinant TSPs were applied as vaccines against an E. multilocularis primary experimental infection in BALB/c mice. Cyst lesions in the livers of vaccinated and non-vaccinated mice were counted. The cyst lesion reduction rates induced by the seven tetraspanins in vaccinated vis-a-vis non-vaccinated mice were: 87.9%, 65.8%, 85.1%, 66.9%, 73.7%, 72.9% and 37.6%. Vaccination conferred protective rates to mice ranging from 0% (TSP5, 6, 7) to maximally 33% (TSP1, 3). The results indicated that recombinant tetraspanins have varying protective effects against primary alveolar echinococcosis and could be used in vaccine development. PMID- 19782114 TI - Comparison of uptake and neuroprotective potential of seven zinc-salts. AB - Zinc plays an important role as an antioxidant in different cells treated with various kinds of oxidative stressors. Although intracellular Zn(2+) is important in many cellular events, little is known about the cellular uptake of this trace metal and the intracellular status that is required for its optimal function. Since previous reports usually employed only one type of zinc-salt, in this work was compared cellular uptake and antioxidative potential of seven zinc-salts in order to discriminate whether different counterions and ligands may influence its function. Oxidative stress was induced by peroxide or iron in neuronal PC12 cells. We compared uptake of zinc-salts into the labile Zn(2+) pool of PC12 cells as well as their effects on the prevention of cell death, glutathione depletion, lipid peroxidation and ROS production. Zinc-salts provided better protection against oxidative stress-induced in PC12 cultures by peroxide than by iron. Preincubations with zinc-salts displayed better neuroprotection in all cases than coincubations. Zinc-histidine complex was shown to be the most potent compound. Our results indicated that protective effect of zinc is not related to its uptake into PC12 cells, what is indicated by the rather low salt concentrations required for the cell protection and by the observation that despite a superior antioxidant effect of zinc-histidine, the uptake of this salt by PC12 cells was remarkably lower in comparison with other zinc-salts. Although zinc-sulfate exerted weak neuroprotective potential, accumulation of Zn(2+) from this salt within cells was significantly higher compared to other salts. The differences in accumulation of zinc-salts were not specific and unique to PC12 cells, since similar results were obtained in rat primary hepatocytes and endothelial HUVEC cells. PMID- 19782113 TI - Hypothalamic injection of non-opioid peptides increases gene expression of the opioid enkephalin in hypothalamic and mesolimbic nuclei: Possible mechanism underlying their behavioral effects. AB - The peptides galanin (GAL) and orexin (OX) share common features with the opioid enkephalin (ENK) in their relationship to ingestive behavior, stimulating consumption of a fat-rich diet and ethanol when injected into the hypothalamus. Since receptors for GAL and OX are dense in areas where ENK-expressing neurons are concentrated, these non-opioid peptides may exert their effects, in part, through the stimulation of endogenous ENK. This study was conducted to determine whether injection of GAL or OX affects the expression of ENK in hypothalamic and mesolimbic nuclei involved in consummatory behavior. Rats were injected with GAL (1 microg), OX-A (1 microg), or saline vehicle just dorsal to the hypothalamic paraventricular nucleus (PVN). They were sacrificed 1h later for analysis of ENK mRNA levels in the PVN, ventral tegmental area (VTA), central nucleus of the amygdala (CeA), and nucleus accumbens (NAc). Both GAL and OX had similar effects, significantly increasing ENK mRNA expression in each of these areas, except for the NAc. This enhanced ENK expression in the PVN, VTA and CeA was demonstrated with real-time quantitative polymerase chain reaction and confirmed in separate groups using radiolabeled and digoxigenin-labeled in situ hybridization. These findings demonstrate that the non-opioid peptides, GAL or OX, which have similar effects on consummatory behavior, are also similar in their effect on endogenous ENK. In light of published findings showing an opioid antagonist to block GAL- and OX-induced feeding, these results provide additional evidence that ENK is involved in mediating the common behavioral effects of these peptides. PMID- 19782115 TI - 3D-QSAR study of corticotropin-releasing factor 1 antagonists and pharmacophore based drug design. AB - Corticotropin-releasing factor (CRF) is a neuropeptide that falls into the broad spectrum of having neurotransmitter/neurohormonal/neuromodulator activities. The design and synthesis of low molecular weight non-peptide antagonists for the CRF receptors is a very important area of research as they can be employed in the treatment of a wide variety of disorders. To investigate the ligand-receptor binding mode and design novel CRF1 antagonists, both quantitative and qualitative 3D-QSAR analysis have been performed on a data set of CRF(1) antagonists by using HypoGen and HipHopRefine programs of Catalyst software. The training set of HypoGen study included twenty-five structurally diverse CRF(1) antagonists with Ki values ranging from 0.5 nM to 10 microM. The common feature-based 3D-QSAR study used eight highly potent CRF(1) antagonists and four poor antagonistic ligands to generate 3D-pharmacophore models with excluded volumes. The obtained 3D-pharmacophore models from each study served as queries for virtual screening with a 'focused compound library' for novel CRF(1) antagonist development. Pharmacophore models obtained for antagonist binding are useful for CRF related chemical biology and drug design. Strategies and methods employed in this paper are simple and practical for medicinal chemists in drug R&D. PMID- 19782116 TI - Caffeine and CSC, adenosine A2A antagonists, offer neuroprotection against 6-OHDA induced neurotoxicity in rat mesencephalic cells. AB - In this study, the cytoprotective effects of caffeine (CAF) and 8-(3 chlorostyryl)-caffeine (CSC), A(2A) receptor antagonists, were tested against 6 OHDA-induced cytotoxicity, in rat mesencephalic cells. Both drugs significantly increased the number of viable cells, after their exposure to 6-OHDA, as measured by the MTT assay. While nitrite levels in the cells were drastically increased by 6-OHDA, their concentrations were brought toward normality after CAF or CSC, indicating that both drugs block 6-OHDA-induced oxidative stress which leads to free radicals generation. A complete blockade of 6-OHDA-induced lipid peroxidation, considered as a major source of DNA damage, was observed after cells treatment with CAF or CSC. 6-OHDA decreased the number of normal cells while increasing the number of apoptotic cells. In the CAF plus 6-OHDA group, a significant recover in the number of viable cells and a decrease in the number of apoptotic cells were seen, as compared to the group treated with 6-OHDA alone. A similar effect was observed after cells exposure to CSC in the presence of 6 OHDA. Unexpectedly, while a significant lower number of activated microglia was observed after cells exposure to CAF plus 6-OHDA, this was not the case after cells exposure to CSC under the same conditions. While CAF lowered the percentage of reactive astrocytes increased by 6-OHDA, CSC presented no effect. The effects of these drugs were also examined on the releases of myeloperoxidase (MPO), an inflammatory marker, and lactate dehydrogenase (LDH), a marker for cytotoxicity, in human neutrophils, in vitro. CSC and CAF (0.1, 1 and 10 microg/ml) produced inhibitions of the MPO release from PMA-stimulated cells, ranging from 45 to 83%. In addition, CSC and CAF (5, 50 and 100 microg/ml) did not show any cytotoxicity in the range of concentrations used, as determined by the LDH assay. All together, our results showed a strong neuroptrotection afforded by caffeine or CSC, on rat mesencephalic cells exposed to 6-OHDA. Furthermore, CSC and caffeine actions, inhibiting MPO as well as LDH releases, would contribute to their possible benefit in the treatment of neurodegenerative diseases, including DP. These effects are partially due to the ability of these A(2A) antagonists to decrease the cells free radicals production and oxidative stress, that are major components of 6-OHDA-induced cytotoxicity. PMID- 19782117 TI - Current regulatory perspectives on genotoxicity testing for botanical drug product development in the U.S.A. AB - Genotoxicity testing is an important part of preclinical safety assessment of new drugs and is required prior to Phase I/II clinical trials. It is designed to detect genetic damage such as gene mutations and chromosomal aberration, which may be reflected in tumorigenic or heritable mutation potential of the drug. Botanical new drugs in the U.S. are entitled to a waiver for preclinical pharmacology/toxicology studies, including genotoxicity testing, in support of an initial clinical trial under IND, contingent on previous human experience. Recently, ethical concerns have been raised over conducting Phase I/II clinical trials of new drugs with positive genotoxicity findings in healthy volunteers. Although the relevance of this issue to patients, as opposed to healthy volunteers, depends on the drug's indication, duration of treatment, and specific findings related to the assays, the regulatory view is to avoid exposing patients to genotoxic compounds unnecessarily in clinical trials. This philosophy may impact on herbal supplement marketing and botanical drug development, in that genotoxicity data are often lacking while consumers are exposed to the herbal supplement, or healthy volunteers are tested in an initial Phase I/II clinical trial on the botanical drug. This paper presents results of a survey conducted on genotoxicity data in botanical INDs submitted to the Agency and discusses the significance of this information. The information presented indicates that the sponsors of botanical INDs have increasingly recognized the importance of genotoxicity information and may have prioritized its acquisition in their strategic drug development programs. PMID- 19782118 TI - Risk assessment of mixtures of pesticides. Current approaches and future strategies. AB - The risk assessment of pesticide residues in food is based on toxicological evaluation of the single compounds and no internationally accepted procedure exists for evaluation of cumulative exposure to multiple residues of pesticides in crops, except for a few groups of pesticides sharing a group ADI. However, several attempts have been suggested during the last decade. This paper gives an overview of the various approaches. It is of paramount importance to consider whether there will be either no interaction or interaction between the compounds in the mixture. When there are no interactions several approaches are available for the risk assessment of mixtures of pesticides. However, no single simple approach is available to judge upon potential interactions at the low doses that humans are exposed to from pesticide residues in food. In these cases, PBTK models could be useful as tools to assess combined tissue doses and to help predict potential interactions including thresholds for such effects. This would improve the quality of the risk assessment. PMID- 19782119 TI - EEG in 1-week, 1-month and 3-month-old infants of depressed and non-depressed mothers. AB - EEGs were examined in data collected from 348 1-week, 1-month and 3-month-old infants of depressed and non-depressed mothers across several studies. Both the percentage of infants exhibiting spectral peaks and the frequency in Hz at which those peaks were exhibited increased with age. Consistent with previous studies, infants of depressed mothers exhibited greater left frontal EEG power, suggesting greater relative right frontal EEG activity than infants of non-depressed mothers. This profile was apparent across a narrow frequency range, which shifted from 3-9Hz at 1 week of age to 4-9Hz by 3 months of age. PMID- 19782121 TI - APE1/Ref-1 in Alzheimer's disease: an immunohistochemical study. AB - The oxidative injury in Alzheimer's disease (AD), in which amyloid beta protein induces production of reactive oxygen species, may be cause of neurodegeneration. APE1/Ref-1 is a protein involved in DNA repair and in redox co-activating function over different transcription factors. We investigated by immunohistochemistry using a highly specific monoclonal antibody, the localization of APE1/Ref-1 in autoptic and bioptic AD brain tissues in comparison with brains with unrelated pathological or normal conditions. Reliable APE1/Ref-1 immunostaining was obtained in biopsies, but not in autoptic tissues. An increased nuclear expression of APE1/Ref-1 in AD cerebral cortex supports the view that the cellular adaptive response to the oxidative stress condition is involved in the pathogenesis of this disease. PMID- 19782120 TI - Bone marrow engraftment but limited expansion of hematopoietic cells from multipotent germline stem cells derived from neonatal mouse testis. AB - OBJECTIVE: Multipotent germline stem (mGS) cells derived from neonatal mouse testis, similar to embryonic stem (ES) cells, differentiate into various types of somatic cells in vitro and produce teratomas after inoculation into mice. In the present work, we examined mGS cells for hematopoietic progenitor potential in vitro and in vivo. MATERIALS AND METHODS: mGS cells were differentiated on OP9 stromal cells and induced into Flk1(+) cells. Flk1(+) cells were sorted and replated on OP9 stromal cells with various cytokines and emerging hematopoietic cells were analyzed for lineage marker expression by fluorescein-activated cell sorting, progenitor activity by colony assay, and stem cell transplantation assay. RESULTS: mGS cells, like ES cells, produce hematopoietic progenitors, including both primitive and definitive erythromyeloid, megakaryocyte, and B- and T-cell lineages via Flk1(+) progenitors. When transplanted into the bone marrow (BM) of nonobese diabetic/severe combined immunodeficient (NOD/SCID) gammac(null) mice directly, mGS-derived green fluorescent protein (GFP)-positive cells were detected 4 months later in the BM and spleen. GFP(+) donor cells were also identified in the Hoechst33342 side population, a feature of hematopoietic stem cells. However, these mGS-derived hematopoietic cells did not proliferate in vivo, even after exposure to hematopoietic stressors, such as 5-fluorouracil (5FU) injection or serial transplantation. CONCLUSION: mGS cells produced multipotent hematopoietic progenitor cells with myeloid and lymphoid lineage potential in vitro and localized in the BM after intra-BM injection but, like ES cells, failed to expand or show stem cell repopulating ability in vivo. PMID- 19782122 TI - Male specific association between the 5-HTR6 gene 267C/T SNP and suicide in the Portuguese population. AB - Serotonergic system dysfunction has been implicated in the etiology of suicide. A large number of genetic studies have focused on the potential involvement of genes coding for components of serotonergic system in suicidal behavior. However, other genes belonging to this system remain to be investigated or have been poorly studied, as is the case of the 5-HT6 receptor (5-HTR6) gene. In this study, we investigated the potential association between the 5-HTR6 gene 267C/T SNP and suicide in a Portuguese population. Blood samples were collected from 179 suicide victims and 189 controls. Genotypes for the 5-HTR6 gene 267C/T SNP were obtained with the restriction enzyme Rsa I. A tendency was found for genotype association between this polymorphism and suicide, but the differences were not statistically significant (chi(2)=5.374, df=2, p=0.068). However, a gender specific association was detected when comparing the genotype distribution between male suicide victims and male controls (chi(2)=6.988, df=2, p=0.030), suggesting that this SNP might have a role in the etiology of suicide in male subjects in the Portuguese population. PMID- 19782123 TI - Interferon-gamma deficiency modifies the motor and co-morbid behavioral pathology and neurochemical changes provoked by the pesticide paraquat. AB - In addition to nigrostriatal pathology and corresponding motor disturbances, Parkinson's disease (PD) is often characterized by co-morbid neuropsychiatric symptoms, most notably anxiety and depression. Separate lines of evidence indicate that inflammatory processes associated with microglial activation and cytokine release may be fundamental to the progression of both PD and its co morbid psychiatric pathology. Accordingly, we assessed the contribution of the pro-inflammatory cytokine, interferon-gamma (IFN-gamma), to a range of PD-like pathology provoked by the ecologically relevant herbicide and dopamine (DA) toxin, paraquat. To this end, paraquat provoked overt motor impairment (reduced home-cage activity and impaired vertical climbing) and signs of anxiety-like behavior (reduced open field exploration) in wild-type but not IFN-gamma deficient mice. Correspondingly, paraquat promoted somewhat divergent variations in neurochemical activity among wild-type and IFN-gamma null mice at brain sites important for both motor (striatum) and co-morbid affective pathologies (dorsal hippocampus, medial prefrontal cortex, and locus coeruleus). Specifically, the herbicide provoked a dosing regimen-dependent reduction in striatal DA levels that was prevented by IFN-gamma deficiency. In addition, the herbicide influenced serotonergic and noradrenergic activity within the dorsal hippocampus and medial prefrontal cortex; and elevated noradrenergic activity within the locus coeruleus. Although genetic ablation of IFN-gamma had relatively few effects on monoamine variations within the locus coeruleus and prefrontal cortex, loss of the pro-inflammatory cytokine did normalize the paraquat-induced noradrenergic alterations within the hippocampus. These findings further elucidate the functional implications of paraquat intoxication and suggest an important role for IFN-gamma in the striatal and motor pathology, as well as the co-morbid behavioral and hippocampal changes induced by paraquat. PMID- 19782124 TI - Blood-based biomarkers of microvascular pathology in Alzheimer's disease. AB - Sporadic Alzheimer's disease (AD) is a genetically complex and chronically progressive neurodegenerative disorder with molecular mechanisms and neuropathologies centering around the amyloidogenic pathway, hyperphosphorylation and aggregation of tau protein, and neurofibrillary degeneration. While cerebrovascular changes have not been traditionally considered to be a central part of AD pathology, a growing body of evidence demonstrates that they may, in fact, be a characteristic feature of the AD brain as well. In particular, microvascular abnormalities within the brain have been associated with pathological AD hallmarks and may precede neurodegeneration. In vivo assessment of microvascular pathology provides a promising approach to develop useful biological markers for early detection and pathological characterization of AD. This review focuses on established blood-based biological marker candidates of microvascular pathology in AD. These candidates include plasma concentration of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1) that are increased in AD. Measures of endothelial vasodilatory function including endothelin (ET-1), adrenomedullin (ADM), and atrial natriuretic peptide (ANP), as well as sphingolipids are significantly altered in mild AD or during the predementia stage of mild cognitive impairment (MCI), suggesting sensitivity of these biomarkers for early detection and diagnosis. In conclusion, the emerging clinical diagnostic evidence for the value of blood-based microvascular biomarkers in AD is promising, however, still requires validation in phase II and III diagnostic trials. Moreover, it is still unclear whether the described protein dysbalances are early or downstream pathological events and how the detected systemic microvascular alterations relate to cerebrovascular and neuronal pathologies in the AD brain. PMID- 19782125 TI - Repeated restraint stress and corticosterone injections during late pregnancy alter GAP-43 expression in the hippocampus and prefrontal cortex of rat pups. AB - In the offspring of prenatal stress animals, overactivity and impaired negative feedback regulation of the hypothalamic-pituitary-adrenal axis are consistent finding. However, little was known about how prenatal stress can permanently alter developmental trajectories of pup's brain. Growth-associated protein-43 (GAP-43) is a presynaptic membrane phosphoprotein whose expression increases during developmental events such as axonal outgrowth or remodeling and synaptogenesis. Phosphorylation of GAP-43 by protein kinase C was correlated with enhanced axonal growth and transmitter release. In adult animals, increase of GAP 43 correlated with monoaminergic deficit in neuropsychiatric disorders. The present study examines the effects of repeated maternal restraint stress on the level of GAP-43 in the brain of rat pups. The results showed that prenatal stress significantly increased GAP-43 level in the PFC of rat pup during PND 7-14 as compared to control but not significant difference when observed at PND 21. Increased GAP-43 expression was also observed in the pup's hippocampus during the same postnatal periods. However, when observed at PND 60, pups born from stressed mother showed a significant lower (p<0.001) GAP-43 expression as compare with control group. These changes indicate the direct effect of corticosteroid hormone, since repeated maternal injection with corticosterone (CORT, 40 mg/kg) during GD 14-21 also gave the same results. PND 7-14 is the peak period of synaptogenesis in these brain areas and abnormal axon sprouting and reorganization may lead to a defect in synaptic pruning at later stage of life. The results suggested that maternal stress is harmful to the developing brain and upregulation of GAP-43 indicated a protective mechanism against the toxicity of maternal stress hormone. Prenatal stress alter the normal developmental trajectories in the pup's brain may underlies the mechanism link between early life stress and neuropsychopathology in later life. PMID- 19782126 TI - Distribution of Mycoplasma haemofelis in blood and tissues following experimental infection. AB - The aim of the study was to describe blood and tissue copy number distribution during Mycoplasma haemofelis infection and determine if sequestration of organisms in body tissues could explain blood copy number cycling in infected cats. Thirteen domestic-shorthaired cats were used. Blood samples were regularly collected, and at a differing time point post-infection for each cat, tissue samples also collected, for quantitative PCR (qPCR). Absolute haemoplasma copy numbers were calculated for all blood and tissue samples, as well as an estimation of the ratio of tissue haemoplasma copy number to that expected in the tissue if a positive qPCR result arose due to tissue blood supply alone. Cats with high or moderate M. haemofelis blood copy numbers at the time of tissue collection had fewer M. haemofelis copies in most tissues than expected due to the tissue blood supply alone; only splenic and lung tissues consistently contained more M. haemofelis. However tissues collected from cats at a time of very low M. haemofelis blood copy numbers, when putative copy number cycling nadirs were occurring, were usually qPCR negative. Hence no evidence of significant tissue M. haemofelis sequestration was found in this study to explain the copy number cycling reported with this feline haemoplasma species. PMID- 19782127 TI - Mechanisms involved in ultrafine carbon black-induced release of IL-6 from primary rat epithelial lung cells. AB - The aims of the present study were to establish to what extent IL-1, and intracellular pathways involving mitogen-activated protein kinases (MAPKs) and nuclear factor-kappa B (NF-kappaB), play a role in ultrafine particle-induced release of IL-6 by primary rat epithelial lung cells. Ultrafine carbon black (Printex 90) induced a concentration- and time-dependent increase in the release of IL-1alpha, IL-1beta and IL-6. The ultrafine carbon black-induced release of IL 6 was completely eliminated by an IL-1 receptor antagonist (IL-1ra). Cellular release of IL-1alpha, IL-1beta and IL-6 was significantly attenuated by curcumin and by inhibitors of the MAPKs ERK1/2 (PD98069), p38 (SB202190) and JNK (SP600125), whereas pyrrolidine dithiocarbamate (PDTC) attenuated the release of IL-6, but not of IL-1alpha and IL-1beta. The effects of curcumin and PDTC may indicate an involvement of NF-kappaB. Furthermore, ultrafine carbon black induced degradation of IkappaBalpha, used as an indicator of NF-kappaB activation, and induced phosphorylation of ERK1/2, p38 and JNK1/2. This degradation and phosphorylation was attenuated by IL-1ra. The present findings provide more insight into the largely unknown mechanisms involved in ultrafine particle induced release of cytokines from lung cells. The findings suggest that ultrafine carbon black-induced release of IL-6 strongly depends on IL-1 and that activation of MAPKs and NF-kappaB is involved in this response. PMID- 19782128 TI - Nuclear translocation and calpain-dependent reduction of Bcl-2 after neonatal cerebral hypoxia-ischemia. AB - Apoptosis-related mechanisms are important in the pathophysiology of hypoxic ischemic injury in the neonatal brain. Caspases are the major executioners of apoptosis, but there are a number of upstream players that influence the cell death pathways. The Bcl-2 family proteins are important modulators of mitochondrial permeability, working either to promote or prevent apoptosis. In this study we focused on the anti-apoptotic Bcl-2 protein after neonatal cerebral hypoxia-ischemia (HI) in 8-day-old rats. Bcl-2 translocated to nuclei and accumulated there over the first 24h of reperfusion after HI, as judged by immunohistochemistry and immuno-electron microscopy. We also found that the total level of Bcl-2 decreased after HI in vivo and after ionophore challenge in cultured human neuroblastoma (IMR-32) cells in vitro. Furthermore, the Bcl-2 reduction was calpain-dependent, because it could be prevented by the calpain inhibitor CX295 both in vivo and in vitro, suggesting cross-talk between excitotoxic and apoptotic mechanisms. PMID- 19782129 TI - The dopamine D4 receptor activates intracellular platelet-derived growth factor receptor beta to stimulate ERK1/2. AB - Dopamine receptors are GPCRs that play important roles in locomotion, reward, and cognitive processes. Previously, we demonstrated that this receptor transactivates PDGFRbeta to modulate ERK1/2 and NMDA receptor activity. Downregulation of maturely glycosylated PDGFRbeta by prolonged exposure to PDGF BB eliminated PDGF-BB-mediated ERK1/2 activation. The DRD4-mediated ERK1/2 response was only partially blunted by PDGF-BB-mediated downregulation, but remained sensitive to the PDGFRbeta kinase inhibitor tyrphostin A9. Tunicamycin prevented the N-linked glycosylation and maturation of PDGFRbeta as well as its activation by PDGF-BB. However, upon tunicamycin treatment, DRD4 continued to signal to ERK1/2 in a tyrphostin A9-sensitive manner. Collectively, our observations indicate that DRD4, unlike PDGF-BB, can activate a pool of intracellularly located PDGFRbeta. PMID- 19782131 TI - Formulate-ability of ten compounds with different physicochemical profiles in SMEDDS. AB - In order to gain a better understanding of the reasons of successful self microemulsifying drug delivery systems (SMEDDS) formulation, ten poorly water soluble drugs, exhibiting different physicochemical properties, were selected. The solubility of the compounds was determined in various oils (long and medium chain) and surfactants (HLB>12 and HLB<10). The best performing excipients were selected for SMEDDS formulation. The droplet size and zeta potential of SMEDDS were measured in the absence and the presence of drug. Media, time and the presence of drug showed little or no influence on droplet size of most systems. Some systems displayed a different zeta potential in the presence of drugs. In vitro pharmaceutical performance of the SMEDDS formulations was investigated using the dialysis bag method in reverse mode next to conventional in vitro release methodology. The results suggested that the measured concentration of the compounds inside the dialysis bag corresponded to solubility of the compound in the release medium, which suggested that the formation of micelles inside the dialysis bag was delayed or disturbed. Conventional in vitro release methodology with pH change from acidic to neutral appeared as a simple method which gives valuable information about the dispersion and the solubilization ability of the SMEDDS formulation at different pHs. In general, formulate-ability in SMEDDS was found to depend on the solubility of the drugs in the excipients and log P of the compounds (the optimal log P was found between 2 and 4). PMID- 19782130 TI - Influence of natriuretic peptide receptor-1 on survival and cardiac hypertrophy during development. AB - The heart adapts to an increased workload through the activation of a hypertrophic response within the cardiac ventricles. This response is characterized by both an increase in the size of the individual cardiomyocytes and an induction of a panel of genes normally expressed in the embryonic and neonatal ventricle, such as atrial natriuretic peptide (ANP). ANP and brain natriuretic peptide (BNP) exert their biological actions through activation of the natriuretic peptide receptor-1 (Npr1). The current study examined mice lacking Npr1 (Npr1(-/-)) activity and investigated the effects of the absence of Npr1 signaling during cardiac development on embryo viability, cardiac structure and gene and protein expression. Npr1(-/-)embryos were collected at embryonic day (ED) 12.5, 15.5 and neonatal day 1 (ND 1). Npr1(-/-)embryos occurred at the expected Mendelian frequency at ED 12.5, but knockout numbers were significantly decreased at ED 15.5 and ND 1. There was no indication of cardiac structural abnormalities in surviving embryos. However, Npr1(-/-)embryos exhibited cardiac enlargement (without fibrosis) from ED 15.5 as well as significantly increased ANP mRNA and protein expression compared to wild-type (WT) mice, but no concomitant increase in expression of the hypertrophy-related transcription factors, Mef2A, Mef2C, GATA-4, GATA-6 or serum response factor (SRF). However, there was a significant decrease in Connexin-43 (Cx43) gene and protein expression at mid-gestation in Npr1(-/-)embryos. Our findings suggest that the mechanism by which natriuretic peptide signaling influences cardiac development in Npr1(-/-) mice is distinct from that seen during the development of pathological cardiac hypertrophy and fibrosis. The decreased viability of Npr1(-/ )embryos may result from a combination of cardiomegaly and dysregulated Cx43 protein affecting cardiac contractility. PMID- 19782132 TI - Solid state characterization of the anti-HIV drug TMC114: interconversion of amorphous TMC114, TMC114 ethanolate and hydrate. AB - The interconversion of the ethanolate, hydrate and amorphous form of TMC114 ((3 [(4-amino-benzenesulfonyl)-isobutyl-amino]-1-benzyl-2-hydroxypropyl)-carbamic acid hexahydrofuro-[2,3-b]furan-3-yl ester) in open conditions was characterized. TMC114 hydrate and ethanolate form isostructural channel solvates. The crystal structure of TMC114 was obtained from single crystal X-ray diffraction, confirming that it is a channel solvate. Ethanol and water can exchange with one another. TMC114 ethanolate converts into TMC114 hydrate at moderate or high relative humidity (RH) at 25 degrees C, and it converts back into the ethanolate in ethanol atmosphere. The hydration level of the hydrate is determined by the environmental humidity. TMC114 hydrate collapses to the amorphous product when water is removed by drying at low RH or increasing temperature. TMC114 ethanolate becomes amorphous at elevated temperature in a dry environment below the desolvation temperature. Amorphous TMC114 obtained by dehydrating the hydrate during storage at room temperature/<5% RH, by increasing the temperature, or via desolvating the ethanolate by heating, converts into the hydrate at moderate or high RH at ambient conditions, and into TMC114 ethanolate in an ethanol atmosphere. Under ambient conditions, TMC114 ethanolate may convert into the hydrate, whereas the opposite will not occur under these conditions. The amorphous form, prepared by melting-quenching shows a limited water uptake. Whereas TMC114 ethanolate is stable in the commercialized drug product, special conditions can trigger its conversion. PMID- 19782133 TI - Properties of melt extruded enteric matrix pellets. AB - The objective of this study was to investigate the properties of enteric matrix pellets that were prepared by hot-melt extrusion in a one-step, continuous process. Five polymers (Eudragit) L100-55, L100 and S100, Aqoat grades LF and HF) were investigated as possible matrix formers, and pellets prepared with Eudragit S100 demonstrated superior gastric protection and acceptable processibility. Extruded pellets containing Eudragit S100 and up to 40% theophylline released less than 10% drug over 2h in acid, however, the processibility and yields were compromised by the high amounts of the non-melting drug material in the formulation. Efficient plasticization of Eudragit S100 was necessary to reduce the polymer's glass transition temperature and melt viscosity. Five compounds including triethyl citrate, methylparaben, polyethylene glycol 8000, citric acid monohydrate and acetyltributyl citrate were investigated in terms of plasticization efficiency and preservation of the delayed drug release properties. The aqueous solubility of the plasticizer and its plasticization efficiency impacted the drug release rate from the matrix pellets. The use of water-soluble plasticizers resulted in a loss of gastric protection, whereas low drug release rates in acid were found for pellets containing insoluble plasticizers or no plasticizer, independent of the extent of Eudragit S100 plasticization. The release rate of theophylline in buffer pH 7.4 was faster for pellets that were prepared with efficient plasticizers. The microstructure and solid-state properties of plasticized pellets were further investigated by scanning electron microscopy and powder X-ray diffraction. Pellets prepared with efficient plasticizers (TEC, methylparaben, PEG 8000) exhibited matrices of low porosity, and the drug was homogeneously dispersed in its original polymorphic form. Pellets containing ATBC or citric acid monohydrate had to be extruded at elevated temperature and showed physical instabilities in the form of recrystallization at room temperature. Enteric matrix pellets with a diameter below 1mm and containing 30% theophylline could be successfully prepared by hot melt extrusion when Eudragit S100 plasticized with either TEC or methylparaben was employed as the matrix material. PMID- 19782134 TI - Characterization of the copolymer poly(ethyleneglycol-g-vinylalcohol) as a potential carrier in the formulation of solid dispersions. AB - In order to fully exploit the graft copolymer poly(ethyleneglycol-g-vinylalcohol) (EG/VA) in the formulation of solid dispersions, a characterization of its phase behavior before, during and after spray-drying and hot-melt extrusion is performed. Solid state characterization was performed using MDSC and XRPD. The effect of heating/cooling rate on the degree of crystallinity was studied using HPer DSC and ultra-fast chip calorimetry. EG/VA consists of two semi-crystalline fractions, one corresponding to the polyethyleneglycol (PEG) fraction (T(g)=-57 degrees C, T(m)=15 degrees C) and one corresponding to the polyvinylalcohol (PVA) fraction (T(g)=45 degrees C, T(m)=212 degrees C). XRPD analysis confirmed its semi-crystallinity, and EG/VA showed Bragg reflections comparable to those of PVA. Spray-drying at a temperature lower than 170 degrees C resulted in amorphization of the PVA fraction, while after hot-melt extrusion at different temperatures, the crystallinity of this fraction increases. In both cases, the PEG fraction is not influenced. Plasticization of the amorphous domains of the PEG or PVA fraction of the copolymer was dependent on the type and concentration of plasticizer, suggesting that also other small organic molecules like drugs may not homogeneously mix with both amorphous domains. A controlled cooling rate of 3000 degrees C/s was necessary to make the copolymer completely amorphous. PMID- 19782135 TI - Aromatase and in situ estrogen production in DCIS (ductal carcinoma in situ) of human breast. AB - Ductal carcinoma in situ or DCIS belongs to intraductal proliferative lesions, which are a group of cytologically and architecturally diverse ductal proliferations, typically originating from the terminal duct-lobular units. In these intraductal proliferative diseases, estrogens are considered to be involved in the progression of the disease especially from ductal non-neoplastic hyperplasia to DCIS and possibly development of invasive carcinoma from DCIS. Estrogen receptor (ER) alpha is abundantly expressed in atypical ductal hyperplasia and low grade DCIS. Suppression of estrogenic actions using tamoxifen resulted in inhibition of recurrence of DCIS and/or of progression into invasive carcinoma. Intratumoral estrogen concentration in DCIS determined by liquid chromatography/electrospray tandem mass spectrometry is significantly higher than that in non-neoplastic breast tissues with statistically not lower than that in invasive carcinoma. Aromatase mRNA expression in both stromal and parenchymal cells of DCIS determined by quantitative RT-PCR following laser capture microdissection was also much higher than that in non-neoplastic breast, although lower than that in invasive carcinoma. Immunohistochemistry of aromatase also revealed the similar patterns of immunolocalization as in invasive carcinoma. Aromatase is overexpressed in noninvasive breast malignancies including DCIS and results in elevated concentrations of intratumoral estradiol. These findings could provide the scientific rationale as to employing aromatase inhibitors in the management of ER positive DCIS patients. PMID- 19782136 TI - Long-term incubation with beta-amyloid peptides impairs endothelium-dependent vasodilatation in isolated rat basilar artery. AB - Alzheimer's disease is associated to a cerebral amyloid angiopathy with dysregulation of cerebral blood flow (CBF). In vitro studies have shown that short-term application of beta-amyloid (Abeta) peptides to isolated vessels affects vascular tone within 1h, but no studies have examined the effect of long term incubation with Abeta. Here we evaluate the effect of Abeta((1-40)) and Abeta((25-35)) in rat basilar artery for up to 24h. Basilar artery segments were incubated with 25microeta((1-40)) or Abeta((25-35)), for 6 or 24h. After treatment, arteries were mounted in a wire myograph, in physiological salt solution gassed with O(2)/CO(2), in the absence of Abeta, and challenged with vasoconstrictors and vasodilators. Vasomotor responses were not significantly changed by 6h treatment with Abeta peptides whereas 24h treatment with either Abeta((25-35)) or Abeta((1-40)) increased vasoconstriction to 5-hydroxytryptamine (5-HT) and reduced endothelium-dependent vasodilatation to acetylcholine (ACh). Analysis of endothelial cells did not show apoptotic changes associated to endothelial dysfunction, as assessed by TUNEL immunostaining and examination of nuclear morphology, but basal phosphorylation of endothelial nitric oxide synthase (at serine 1177) appeared reduced. These data suggest that long incubation with Abeta peptides induces an alteration of endothelial function in isolated basilar artery, involving eNOS activity without changing cell morphology. This endothelial dysfunction may play a role in the pathogenesis of CBF dysregulation occurring in cerebral amyloid angiopathy and Alzheimer's disease. PMID- 19782138 TI - Ligand-enhanced expression and in-cell assay of human peroxisome proliferator activated receptor alpha ligand binding domain. AB - A human peroxisome proliferator-activated receptor alpha ligand binding domain (PPAR alpha LBD)-maltose binding protein fusion construct was expressed in Escherichia coli. A codon optimized DNA sequence encoding human PPAR alpha LBD (aa196-468) was synthesized and ligated into the pDEST17 E. coli expression vector downstream of a MBP solubility fusion tag and an intermittent TEV protease cleavage site. Following auto-induction at 28 degrees C, PPAR alpha LBD protein was purified to electrophoretic homogeneity by a nickel affinity chromatographic step, on-column TEV protease cleavage followed by Sephacryl S200 size exclusion chromatography. The recombinant protein displayed cross-reactivity with goat anti (human PPAR alpha) polyclonal antibody and was identified as human PPAR alpha by trypic peptide mass finger-printing. The addition of a PPAR alpha specific ligand (fenofibric acid, GW7647 or GW590735) to the growth media significantly stabilized the PPAR alpha LBD structure and enhanced the expression of soluble protein. In-cell ligand binding was examined by monitoring the enhancement of PPAR alpha LBD expression as a function of the concentration of ligand in the growth media. The efficient expression and in-cell assay of the reported PPAR alpha LBD construct make it amenable to high through-put screening assays in drug discovery programs. PMID- 19782137 TI - Altered development of glutamatergic synapses in layer V pyramidal neurons in NR3A knockout mice. AB - Expression of the NMDA receptor (NMDAR) subunit NR3A reaches its highest level in layer V of the developing rodent cortex during the second postnatal week, a peak period of synaptogenesis. Incorporation of NR3A leads to the formation of non canonical, Mg2+-insensitive NMDARs, but it is not known whether they participate in synaptic transmission and maturation. Here we show that in the second postnatal week, layer V pyramidal neurons in the somatosensory cortex of wild type (WT) mice exhibited evoked excitatory postsynaptic currents (eEPSCs) with 3- to 6-fold lower Mg2+ sensitivity than NR3A knockout (KO) mice and their reversal potential was approximately 2 mV more negative compared to KO mice consistent with decreased P(Ca) of NMDARs. Surprisingly, ablation of NR3A also led to a 20 fold reduction of the ratio of AMPAR- to NMDAR-mediated eEPSC amplitudes in KO mice. Insertion of AMPARs at the synapses of layer V pyramidal neurons appears to be facilitated by the expression of Mg2+-insensitive NMDARs. The data indicate that NR3A plays a significant role in the development of excitatory synapses in layer V of the developing neocortex. PMID- 19782139 TI - Detailed assessment of X-ray induced structural perturbation in a crystalline state protein. AB - The positions of hydrogen atoms significantly define protein functions. However, such information from protein crystals is easily disturbed by X-rays. The damage can not be prevented completely even in the data collection at cryogenic temperatures. Therefore, the influence of X-rays should be precisely estimated in order to derive meaningful information from the crystallographic results. Diffraction data from a single crystal of the high-potential iron-sulfur protein (HiPIP) from Thermochromatium tepidum were collected at an undulator beamline of a third generation synchrotron facility, and were merged into three data sets according to X-ray dose. A series of structures analyzed at 0.70A shows detailed views of the X-ray induced perturbation, such as the positional changes of hydrogen atoms of a water molecule. Based on the results, we successfully collected a low perturbation data set using attenuated X-rays. There was no influence on the crystallographic statistics, such as the relative B factors, during the course of data collection. The electron densities for hydrogen atoms were more clear despite the slightly lower resolution. PMID- 19782140 TI - The immunoglobulin gene loci in the teleost Gasterosteus aculeatus. AB - In the present study, we have annotated both the immunoglobulin heavy (IgH) and light (IgL) chain genes in the stickleback (Gasterosteus aculeatus), based on the recently released genome data. The IgH gene locus is arranged in a configuration of (V(n)-D-J-C(zeta)-D(3)-J(4)-C(mu)-C(delta))(3)-V(6)-D-J-C(zeta), which is structurally different from any of the known teleost IgH loci. The mu genes consistently exhibit a 4-CH encoding structure and all the zeta genes encode only three CH domains (lacking the equivalent exon of the zebrafish zetaCH2). As in many other teleosts, the stickleback delta genes contain multiple CH exons, but exist as three copies. The members of four V(H) gene families, containing 47 segments, were interspersed in the germline. The stickleback IgL chain genes are also organized in multiple clusters and located in three chromosomes (10, 11, and 15). Sequence and phylogenetic analyses revealed that two isotypes, L1 (kappa, including two subgroups, 1A and 1B) and L2 (sigma) could be identified. The transcriptional orientations of the V(L) segments were found to be either the same (only in L2 isotype) or opposite to (in L1A, 1B and 2 isotypes) those of the J(L) and C(L) segments, indicating that these segments would undergo rearrangement by deletion or inversion when expressed. PMID- 19782141 TI - cDNA cloning, identification, tissue localisation, and transcription profile of a transglutaminase from white shrimp, Litopenaeus vannamei, after infection by Vibrio alginolyticus. AB - Complementary (c)DNA encoding transglutaminase (TG) messenger (m)RNA of white shrimp, Litopenaeus vannamei, was cloned from haemocytes by a reverse transcription polymerase chain reaction (RT-PCR) and rapid amplification of cDNA ends (RACE) using oligonucleotide primers based on the TG sequence of the horseshoe crab, Tachypleus tridentatus (accession no.: BAA02134); tiger shrimp, Penaeus monodon (AAL78166); and Pacifastacus leniusculus (AF336805). The 2638-bp cDNA contained an open reading frame (ORF) of 2172 bp, a 55-bp 5'-untranslated region (UTR), and a 411-bp 3'-UTR containing a poly A tail. The molecular mass of the deduced amino acid (aa) sequence (757 aa) was 84.9 kDa with an estimated pI of 5.2. The L. vannamei TG (abbreviated LvTG) contains a typical transglutaminase like homologue, a putative integrin-binding motif (RGD), and four calcium-binding sites; a catalytic triad is present as in arthropod TG. Sequence comparison and phylogenetic analysis revealed that shrimp TG can be separated into two subgroups, STGS1 and STGS2, and LvTG is more closely related to STGS1 than to STGS2. LvTG mRNA and TG activities were detected in all tested tissues of L. vannamei, with LvTG mainly being synthesised in haemocytes. However, the pattern of LvTG mRNA expression was not directly correlated with TG activity. The haemocytes of L. vannamei injected with Vibrio alginolyticus showed a significant decrease of TG activity at 3 h and a significant increase of LvTG mRNA expression at 6 h followed by a notable decrease from 12 to 24 h, which indicated that cloned LvTG was involved in the immune response of shrimp. The results also imply that more than one type of TG may be involved in the defense response in L. vannamei. PMID- 19782142 TI - Nonhuman primate event-related potentials associated with pro- and anti-saccades. AB - Non-invasive event-related potential (ERP) recordings have become a popular technique to study neural activity associated with saccades in humans. To date, it is not known whether nonhuman primates exhibit similar saccade-related ERPs. Here, we recorded ERPs associated with the performance of randomly interleaved pro- and anti-saccades in macaque monkeys. Stimulus-aligned ERPs showed short latency visual component with more negative P2 and N2 peak amplitudes on anti- than on pro-saccade trials. Saccade-aligned ERPs showed a larger presaccadic negativity on anti- than pro-saccade trials, and a presaccadic positivity on pro saccade trials, which was attenuated or absent on anti-saccade trials. This was followed by sharp negative spike potential immediately prior to the movement. Overall, these findings demonstrate that macaque monkeys, like humans, exhibit task-related differences of visual ERPs associated with pro- and anti-saccades and furthermore share presaccadic positivity as well as a spike potential prior to these tasks. We suggest that the presaccadic positivity on pro-saccade trials is generated by a source in the contralateral frontal eye fields and that the more negative voltage on anti-saccade trials is the result of additional sources of opposite polarity in neighboring frontal areas. PMID- 19782143 TI - The oscillating brain: complex and reliable. AB - The human brain is a complex dynamic system capable of generating a multitude of oscillatory waves in support of brain function. Using fMRI, we examined the amplitude of spontaneous low-frequency oscillations (LFO) observed in the human resting brain and the test-retest reliability of relevant amplitude measures. We confirmed prior reports that gray matter exhibits higher LFO amplitude than white matter. Within gray matter, the largest amplitudes appeared along mid-brain structures associated with the "default-mode" network. Additionally, we found that high-amplitude LFO activity in specific brain regions was reliable across time. Furthermore, parcellation-based results revealed significant and highly reliable ranking orders of LFO amplitudes among anatomical parcellation units. Detailed examination of individual low frequency bands showed distinct spatial profiles. Intriguingly, LFO amplitudes in the slow-4 (0.027-0.073 Hz) band, as defined by Buzsaki et al., were most robust in the basal ganglia, as has been found in spontaneous electrophysiological recordings in the awake rat. These results suggest that amplitude measures of LFO can contribute to further between group characterization of existing and future "resting-state" fMRI datasets. PMID- 19782144 TI - Aplastic anemia: pathophysiology and treatment. AB - An immune basis for most patients with aplastic anemia (AA) provides a rationale for immunosuppressive therapy (IST), using antithmyocyte globulin and cyclosporine as one therapeutic modality; hematologic response is observed in up to 75% of patients. Recent advances in understanding the pathogenesis of AA have identified defective telomere maintenance as an important explanation for the onset of marrow failure, relapse and clonal evolution after IST, in some patients with AA. The finding of inherited mutations in the telomerase gene complex in patients with apparent acquired AA has important implications for clinical management. Hematopoietic stem cell transplantation (HSCT) for acquired AA, whether from an HLA identical sibling or an unrelated donor, provides an excellent chance of long term cure. Current issues with HSCT include graft rejection, chronic GVHD and poor outcome in older patients. The lack of a suitable bone marrow donor for all patients who need a transplant, illustrates the need for novel transplant procedures, such as cord blood transplantation. PMID- 19782146 TI - Towards a functional understanding of cell growth dynamics in shoot meristem stem cell niche. AB - Shoot apical meristems (SAMs) harbor a set of stem-cells which supply cells for the development of all above-ground structures. A precise spatio-temporal control of growth patterns in stem-cells and the differentiating progeny is critical to maintain a stable set of stem-cells. In recent years, an array of approaches including molecular genetics, transient perturbations, live-imaging, image processing and mathematical modeling have been employed to study the cellular dynamics. In this article, we highlight recent studies that link cell-cell communication mechanisms to cell mechanics and overall growth control that govern stem-cell homeostasis and morphogenesis in SAMs. PMID- 19782147 TI - The influence of feeding and fasting on plasma metabolites in the dogfish shark (Squalus acanthias). AB - Dogfish sharks are opportunistic predators, eating large meals at irregular intervals. Here we present a synthesis of data from several previous studies on responses in plasma metabolites after natural feeding and during prolonged fasting (up to 56days), together with new data on changes in plasma concentrations of amino acids and non-esterified fatty acids. Post-prandial and long-term fasting responses were compared to control sharks fasted for 7days, a typical inter-meal interval. A feeding frenzy was created in which dogfish were allowed to feed naturally on dead teleosts at two consumed ration levels, 2.6% and 5.5% of body weight. Most responses were more pronounced at the higher ration level. These included increases in urea and TMAO concentrations at 20h, followed by stability through to 56days of fasting. Ammonia levels were low and exhibited little short-term response to feeding, but declined to very low values during the extended fast. Glucose and beta-hydroxybutyrate both fell after feeding, the latter to a greater and more prolonged extent (up to 60h), whereas acetoacetate did not change. During prolonged fasting, glucose concentrations were well regulated, but beta-hydroxybutyrate increased to 2-3-fold control levels. Total plasma amino acid concentrations increased in a biphasic fashion, with peaks at 6 20h, and 48-60h after the meal, followed by homeostasis during the extended fast. Essential and non-essential amino acids generally followed this same pattern, though some exhibited different trends after feeding: taurine, beta-alanine, and glycine (decreases or stability), alanine and glutamine (modest prolonged increases), and threonine, serine, asparagine, and valine (much larger short-term increases). Plasma non-esterified fatty acid concentrations declined markedly through 48h after the 2.6% meal. These data are interpreted in light of companion studies showing elevations in aerobic metabolic rate, urea production, rectal gland function, metabolic base excretion, and activation of ornithine-urea cycle and aerobic enzymes after the meal, and muscle N-depletion but maintenance of osmolality and urea production during long-term fasting. PMID- 19782145 TI - Long-term consequences of hematopoietic stem cell transplantation: current state of the science. PMID- 19782148 TI - Understanding plasmid effect on hyaluronic acid molecular weight produced by Streptococcus equi subsp. zooepidemicus. AB - Hyaluronic acid is a biopolymer with valuable applications in the pharmaceutical and cosmetic industries. Streptococcus equi subspecies zooepidemicus cells transformed with a nisin-inducible, empty plasmid control displayed higher molecular weight. This increase in molecular weight is independent of the nisin promoter or antibiotic resistance. Using 2D DIGE followed by mass spectrometry, we identified up-regulation of the last step in UDP-N-acetyl-glucosamine biosynthesis (GlmU) and down-regulation of the first step in peptidoglycan biosynthesis (MurA) as possible mechanism for the plasmid effect. Over-expression of GlmU to further increase activity had no effect on UDP-N-acetyl-glucosamine levels or molecular weight, while over-expression of MurA reduced UDP-N-acetyl glucosamine levels and molecular weight. Global transcriptional analysis revealed that differential regulation of GlmU and MurA activity was not reflected in transcription levels. This results, suggest that regulation is at a translational or post-translational level. Differential expression of two clp proteases may explain this effect as well as the small but significant changes in transcription levels of nearly 300 genes. PMID- 19782149 TI - Protection against nontypeable Haemophilus influenzae challenges by mucosal vaccination with a detoxified lipooligosaccharide conjugate in two chinchilla models. AB - Otitis media (OM) can occur following outset of upper respiratory tract infections. Inhibition of bacterial colonization in nasopharynx (NP) by mucosal vaccination may prevent OM by reducing bacterial invasion of the middle ears (MEs). In this study, 80 chinchillas were intranasally (i.n.) immunized with a detoxified lipooligosaccharide (dLOS)-tetanus toxoid conjugate vaccine of nontypeable Haemophilus influenzae (NTHi) mixed with cholera toxin (CT) or CT alone. All vaccinated animals responded with elevated levels of mucosal and serum anti-LOS antibodies. Two weeks after the last immunization, 40 chinchillas were challenged i.n. with NTHi to evaluate NP colonization and ME infection while the rest of the animals were challenged transbullarly (T.B.) to examine the development of OM. Compared to the control group, the vaccination inhibited not only bacterial colonization in NP and transmission to MEs in the i.n. challenge group but also bacterial colonization in NP and transmission to unchallenged ears in the T.B. challenge group. Though no difference was found in the challenged ears of either group right after the T.B. challenge, an early clearance of NTHi from NP and unchallenged ears as well as less severity of OM in the unchallenged ears were observed in vaccinated animals. Current results along with our previous data indicate that mucosal vaccination is capable of inhibiting NTHi NP colonization and preventing OM occurrence in chinchillas; the i.n. challenge model is preferable for testing the mucosal vaccines while the T.B. challenge model is superior for testing the systemic vaccines. PMID- 19782150 TI - Current applications and future potential for bioinorganic chemistry in the development of anticancer drugs. AB - This review illustrates notable recent progress in the field of medicinal bioinorganic chemistry as many new approaches to the design of innovative metal based anticancer drugs are emerging. Current research addressing the problems associated with platinum drugs has focused on other metal-based therapeutics that have different modes of action and on prodrug and targeting strategies in an effort to diminish the side-effects of cisplatin chemotherapy. PMID- 19782152 TI - Fine-tuning the lipogenic/lipolytic balance to optimize the metabolic requirements of cancer cell growth: molecular mechanisms and therapeutic perspectives. AB - Evolving evidence suggest that metabolic requirements for cell proliferation are identical in all normal and cancer cells. HER2 oncogene-overexpressors, a highly aggressive subtype of human cancer cells, constitute one of the best examples of how malignant cells maximize their ability to acquire and metabolize nutrients in a manner conductive to proliferation rather than efficient ATP production. HER2 overexpressors optimize their requirements of rapid cancer cell growth by fine tuning a double [lipogenic/lipolytic]-edged metabolic sword. On the one edge, HER2 oncogene overexpression triggers redundant signaling cascades to ensure that all the major enzymes involved in de novo fatty acid (FA) synthesis will facilitate aerobic glycolysis instead of oxidative phosphorylation for energy production (Warburg effect). HER2 also establishes a positive bidirectional relationship with the key lipogenic enzyme Fatty Acid Synthase (FASN) that rapidly senses and respond to any disturbance in the flux of lipogenic substrates (e.g. NADPH and acetyl-CoA) and lipogenesis end-products (i.e. palmitate). On the other edge, HER2 overexpression arranges detoxifying mechanisms by upregulating PPARgamma, a well established positive regulator role of adipogenesis and lipid storage in cell types with active lipid metabolism. PPARgamma establishes a lipogenesis/lipolysis joining-point that enables HER2-positive cancer cells to avoid endogenous palmitate toxicity while securing palmitate into fat stores to avoid palmitate feedback on FASN functioning. The ability of HER2 to supercharge lipogenesis (by activating regulatory circuits that activate and fuel the lipogenic enzyme FASN) while averting lipotoxicity (by promoting conversion and storage of excess FAs to triglycerides in a PPARgamma-dependent manner) supports the notion that best adapted cancer phenotypes are addicted to oncogenic lipid metabolism for cell proliferation and survival. It is conceptually attractive to assume that we can crash HER2-driven rapid cell proliferation by inhibiting "motor refueling" (upon blockade of lipogenic enzymes), by losing the "lipolytic brake" (upon blockade of PPARgamma) and/or by sticking the "lipogenic gas pedal" (upon supplementation with dietary FAs). PMID- 19782151 TI - Coordinated regulation of the metabolome and lipidome at the host-microbial interface. AB - The creative use of gnotobiotic animals, coupled with the development of modern metagenomic sequencing platforms and metabolomic profiling of biospecimens, has bestowed new insight into the remarkably intricate interface between the host mammal and its resident microbiota. As mutual benefactors, each partner exhibits evidence of adaptation: the host provides a hospitable habitat, giving consideration to its own species of origin, diet, genotype, geographical location, presence or absence of disease, and use of medications; the microbiota, in turn, configures its constituency, collective genome (microbiome), transcriptome, and metabolome to optimally suit its ecological niche. In this review, we discuss the mechanisms through which the gut microbiota and its host collaborate to regulate lipid metabolism, thereby influencing the metabolic response to nutrient intake and ultimately, the development of obesity and associated diseases such as lipotoxicity. These studies therefore demonstrate that the gut microbiota is an "environmental" influence whose synergistic interdependence with its host strongly suggests that we are in fact "supraorganisms." PMID- 19782153 TI - Mitochondrial dysfunction and lipotoxicity. AB - Mitochondrial dysfunction in skeletal muscle has been suggested to underlie the development of insulin resistance and type 2 diabetes mellitus. Reduced mitochondrial capacity will contribute to the accumulation of lipid intermediates, desensitizing insulin signaling and leading to insulin resistance. Why mitochondrial function is reduced in the (pre-)diabetic state is, however, so far unknown. Although it is tempting to suggest that skeletal muscle insulin resistance may result from an inherited or acquired reduction in mitochondrial function in the pre-diabetic state, it cannot be excluded that mitochondrial dysfunction may in fact be the consequence of the insulin-resistant/diabetic state. Lipotoxicity, the deleterious effects of accumulating fatty acids in skeletal muscle cells, may lie at the basis of mitochondrial dysfunction: next to producing energy, mitochondria are also the major source of reactive oxygen species (ROS). Fatty acids accumulating in the vicinity of mitochondria are vulnerable to ROS-induced lipid peroxidation. Subsequently, these lipid peroxides could have lipotoxic effects on mtDNA, RNA and proteins of the mitochondrial machinery, leading to mitochondrial dysfunction. Indeed, increased lipid peroxidation has been reported in insulin resistant skeletal muscle and the mitochondrial uncoupling protein-3, which has been suggested to prevent lipid induced mitochondrial damage, is reduced in subjects with an impaired glucose tolerance and in type 2 diabetic patients. These findings support the hypothesis that fat accumulation in skeletal muscle may precede the reduction in mitochondrial function that is observed in type 2 diabetes mellitus. PMID- 19782154 TI - The role of hydrophobic and negatively charged surface patches of lipid-free apolipoprotein A-I in lipid binding and ABCA1-mediated cholesterol efflux. AB - Recent models of lipid-free apolipoprotein A-I, including a cross-link/homology model and an X-ray crystal structure have identified two potential functionally relevant "patches" on the protein surface. The first is a hydrophobic surface patch composed of leucine residues 42, 44, 46, and 47 and the second a negatively charged patch composed of glutamic acid residues 179, 191, and 198. To determine if these domains play a functional role, these surface patches were disrupted by site-directed mutagenesis and the bacterially expressed mutants were compared with respect to their ability to bind lipid and stimulate ABCA1-mediated cholesterol efflux. It was found that neither patch plays a significant functional role in the ability of apoA-I to accept cholesterol in an ABCA1 dependent manner, but that the hydrophobic patch did affect the ability of apoA-I to clear DMPC liposomes. Interestingly, contrary to previous predictions, disruption of the hydrophobic surface patch enhanced the lipid binding ability of apoA-I. The hydrophobic surface patch may be important to the structural stability of lipid-free apoA-I or may be a necessary permissive structural element for lipid binding. PMID- 19782155 TI - Differential contributions of protein kinase C isoforms in the regulation of group IIA secreted phospholipase A2 expression in cytokine-stimulated rat fibroblasts. AB - Protein kinase C (PKC) is a family of serine/threonine kinases involved in various signal transduction pathways. We investigated the roles of PKC in the regulation of group IIA secreted phospholipase A(2) (sPLA(2)-IIA) expression in cytokine-stimulated rat fibroblastic 3Y1 cells. Here we show that the induction of sPLA(2)-IIA by proinflammatory cytokines was under the control of both classical cPKCalpha and atypical aPKClambda/iota pathways by using PKC inhibitors, a PKC activator, and PKC knockdowns. Treatment of 3Y1 cells with PKC selective inhibitors having broad specificity, such as chelerythrine chloride and GF109203X, blocked IL-1beta/TNFalpha-dependent induction of sPLA(2)-IIA protein in a dose-dependent manner. Treatment with the PKC activator phorbol 12-myristate 13-acetate (PMA), which activates cPKC and novel nPKC isoforms, markedly attenuated the cytokine-dependent induction of sPLA(2)-IIA expression. In comparison, 24-h pretreatment with PMA, which down-regulates these PKC isoforms, markedly enhanced sPLA(2)-IIA expression. Results with short hairpin RNA (shRNA) mediated knockdown of PKC isoforms revealed that the cytokine-induced sPLA(2)-IIA expression was markedly enhanced in cPKCalpha knockdown cells compared to those in replicate control cells. In contrast, knockdown of the aPKClambda/iota isoform reduced the cytokine-induced expression of sPLA(2)-IIA. These results suggest that the aPKClambda/iota pathway is required for the induction of sPLA(2)-IIA expression and that the cPKCalpha pathway acts as a negative regulator of sPLA(2) IIA expression in cytokine-stimulated rat fibroblasts. PMID- 19782156 TI - An electronic regulatory document management system for a clinical trial network. AB - A computerized regulatory document management system has been developed as a module in a comprehensive Clinical Trial Management System (CTMS) designed for an NIH-funded clinical trial network in order to more efficiently manage and track regulatory compliance. Within the network, several institutions and investigators are involved in multiple trials, and each trial has regulatory document requirements. Some of these documents are trial specific while others apply across multiple trials. The latter causes a possible redundancy in document collection and management. To address these and other related challenges, a central regulatory document management system was designed. This manuscript shares the design of the system as well as examples of it use in current studies. PMID- 19782157 TI - A new topology of ACBP from Moniliophthora perniciosa. AB - Acyl-CoA binding protein (ACBP) is a housekeeping protein and is an essential protein in human cell lines and in Trypanosoma brucei. The ACBP of Moniliophthora perniciosa is composed of 104 amino acids and is possibly a non-classic isoform exclusively from Basidiomycetes. The M. perniciosa acbp gene was cloned, and the protein was expressed and purified. Acyl-CoA ester binding was analyzed by isoelectric focusing, native gel electrophoresis and isothermal titration calorimetry. Our results suggest an increasing affinity of ACBP for longer acyl CoA esters, such as myristoyl-CoA to arachidoyl-CoA, and best fit modeling indicates two binding sites. ACBP undergoes a shift from a monomeric to a dimeric state, as shown by dynamic light scattering, fluorescence anisotropy and native gel electrophoresis in the absence and presence of the ligand. The protein's structure was determined at 1.6 A resolution and revealed a new topology for ACBP, containing five alpha-helices instead of four. alpha-helices 1, 2, 3 and 4 adopted a bundled arrangement that is unique from the previously determined four helix folds of ACBP, while alpha-helices 1, 2, 4 and 5 formed a classical four helix bundle. A MES molecule was found in the CoA binding site, suggesting that the CoA site could be a target for small compound screening. PMID- 19782159 TI - Blood proteomics and the dynamic range: some light at the end of the tunnel? PMID- 19782158 TI - Surgical approaches to the submandibular gland: a review of literature. AB - OBJECTIVES: Surgical excision of the submandibular gland (SMG) is commonly indicated in patients with neoplasms, and non-neoplastic conditions such as chronic sialadenitis, sialolithiasis, ranula and drooling. Traditional SMG surgery involves a direct transcervical approach. In the recent past, alternative approaches to SMG excision have been described in effort to offer minimally invasive options or better cosmetic results. The purpose of this article is to describe the surgical approaches to the SMG and present relevant surgical anatomy via cadaveric dissection and a systematic review of literature to compare and contrast each technique. STUDY DESIGN: Cadaveric dissection with fresh human cadaver heads followed by a review of the literature. METHODS: Cadaver heads were dissected via both the transcervical and transoral approaches to the submandibular gland with the use of endoscopic assistance when indicated. Key landmarks and anatomic relationships were recorded via photo documentation. A review of the literature was conducted using a Medline search for approaches to SMG excision, including indications, results and complications. RESULTS: While the traditional SMG excision remains a direct transcervical approach, many other methods of excision are described that include open, endoscopic, and robot assisted resections. The approaches vary from being transcervical, submental, transoral or retroauricular. CONCLUSIONS: Alternative approaches to the SMG are feasible but should be tailored to the individual patient based on factors such as pathology, patient preferences, availability of technology, and the experience and skill of the surgeon. PMID- 19782160 TI - Interaction of intestinal and pancreatic transcription factors in the regulation of CFTR gene expression. AB - The tissue-specific regulation of the cystic fibrosis transmembrane conductance regulator gene (CFTR) is coordinated by intronic and extragenic cis-acting elements that influence its transcriptional activity. The promoter apparently lacks sequences to drive cell type-specific expression. We previously identified a number of intronic elements that were associated with DNase I hypersensitive sites (DHS) and bound the hepatocyte nuclear factor 1 (HNF1) transcription factor. Moreover, we demonstrated the likely involvement of HNF1 in the regulation of CFTR expression in vivo. Here we investigate DHS in introns 16 and 17a of the CFTR gene, which are evident in intestinal and pancreatic cell lines, and determine the transcription factors that interact with these sites. Of particular interest were factors known to interact with HNF1 in coordinated expression of genes in the gastrointestinal tract. We demonstrate that though sequences within these DHS bind HNF1, CDX2, and PBX1 in vitro, only PBX1 show a robust in vivo interaction. These data contribute to our understanding of the complexity of cell-type-specific CFTR regulatory mechanisms. PMID- 19782161 TI - Cultural complexities in dietary assessment and treatment. PMID- 19782162 TI - Improving nutrition for older Americans. PMID- 19782163 TI - Staying passionate about dietetics. PMID- 19782164 TI - Navigating cultural competency: in preparation for an expected standard in 2010. PMID- 19782165 TI - Cutting costs in a clinical setting. PMID- 19782166 TI - All practice is local. PMID- 19782167 TI - Validating dietary intake with biochemical markers. PMID- 19782168 TI - Against the tide of change: diet and health in the Pacific islands. PMID- 19782169 TI - Markers for the validation of reported dietary intake in adults with cystic fibrosis. AB - OBJECTIVE: To identify different markers in order to validate the assessment of dietary intake in adults with cystic fibrosis (CF). DESIGN: Cross-sectional survey. SETTING: Tertiary care. SUBJECTS: We assessed 37 adults with CF whose nutritional and respiratory condition was stable and 37 healthy adults, matched for age, sex, and nutritional status. INTERVENTIONS: A consecutive, 7-day, prospective dietary survey was given to all the participants. Anthropometric variables were measured and a fasting blood sample was drawn to measure the composition of the serum phospholipid fatty acids by gas chromatography. We also measured fecal fat and nitrogen at 72 hours and 24-hour urine nitrogen. RESULTS: The ratio of energy intake to basal metabolic rate expenditure was significantly greater in the patients (2.1+/-0.4) than the controls (1.79+/-0.4) and the percentage of patients with the ratio of energy intake to basal metabolic rate lower than 1.55 was 24% in the controls (n=9) vs 8% in the patients (n=3). Fecal nitrogen correlated significantly with total energy and the intake of carbohydrates, lipids, and proteins. In the patients, total dietary energy and fat and protein intake correlated positively with fecal fat. The protein and fat intake and fecal nitrogen and fat correlated significantly with urine nitrogen. In the controls, significant correlations were seen between different parameters of intake and the percentage of certain serum phospholipid fatty acids. These correlations in the patients were either absent or less marked. CONCLUSIONS: Use in persons with CF of the energy intake to basal metabolic rate ratio, measurement of fecal fat and nitrogen at 72 hours and of urine nitrogen may be useful to validate dietary surveys. The serum phospholipid fatty acid profile, however, may be less useful for this purpose in these patients. PMID- 19782170 TI - US acculturation, food intake, and obesity among Asian-Pacific hotel workers. AB - BACKGROUND: Both obesity and immigration continue to increase in the United States. Studies suggest that a transition in lifestyle patterns, such as food intake, may mediate the relationship between immigration and obesity. OBJECTIVE: We examine obesity among hotel workers in relation to age, sex, race/ethnicity, and indicators of food intake, immigration, and acculturation. SUBJECTS/SETTING: Four thousand five hundred thirty hotel workers in 30 hotels were studied from the first year of the Work, Weight and Wellness program, before intervention (during 2005-2006). MAIN OUTCOME MEASURES: Weight and height were measured, whereas race/ethnicity, language, education, immigration, acculturation, and food intake variables were assessed by questionnaire. RESULTS: The study included 43% male and 57% female hotel workers (mean age 44.4+/-11.3 years; 42% Filipino, 32% other Asian, 13% Pacific Islander, 9% white, 1% black/African American, and 3% other race/ethnicity). On average (mean value), 55% of participants were born outside the United States; 57% were overweight or obese (body mass index [BMI] >25). The BMI of those born in the United States was 1.3 higher than that of those born in another country, adjusting for sex and race/ethnicity. Intake of sweet drinks and meat was positively associated with BMI while intake of fruit was negatively associated with BMI. Age at arrival in United States ("generation") was negatively associated with BMI, whereas greater acculturation was positively associated with BMI. CONCLUSIONS: Food intake behaviors are probably related to place of birth, generation of migration to the United States, and acculturation. Direct measures of food intake added explanatory power to models, suggesting the importance of food intake to obesity. Further study of the influence of immigration, acculturation, and food intake on obesity using longitudinal study designs is warranted. PMID- 19782171 TI - Rice consumption in the United States: recent evidence from food consumption surveys. AB - BACKGROUND: Little is known about rice consumption, related food intake patterns, and the nutritional contribution that rice provides in the diets of Americans. OBJECTIVE: To provide information about rice consumption in the United States and the diets of rice consumers. DESIGN: Data come from the Continuing Survey of Food Intakes by Individuals (1994-1996) and the National Health and Nutrition Examination Survey (2001-2002). Respondents report 24-hour recall dietary intakes. The amount of rice available in foods is estimated using the Food Commodity Intake Database. Consumers are classified based on the amount of rice they consume in foods. SUBJECTS: The analysis includes information from adult individuals: 9,318 from the Continuing Survey of Food Intakes by Individuals and 4,744 from National Health and Nutrition Examination Survey. STATISTICS: Weighted percentages and mean values show the food and nutrient intake amounts. Logistic regression analysis is used to examine relationships among economic, social, and demographic factors that affect rice consumption. RESULTS: Rice is consumed by a significant portion of the US adult population. Compared with others who did not consume rice, rice consumers consumed a smaller share of energy per day from fat and saturated fat; more iron and potassium; and more dietary fiber, meat, vegetables, and grains. Race/ethnicity and education are determinants of the probability of consuming rice, and more so than low-income status. CONCLUSIONS: Rice consumers choose a diet that includes more vegetables, a smaller share of energy from fat and saturated fat, more dietary fiber and more iron than those who do not consume rice; the differences have remained relatively stable over the last decade. Accounting for race/ethnicity and income levels is important for better understanding of factors that affect food choices and for effective design of dietary interventions. PMID- 19782172 TI - Publishing nutrition research: a review of epidemiologic methods. AB - The use of epidemiologic research designs and analytical methods is common in dietetics research. Food and nutrition professionals who seek to perform evidence based practice or participate in research design, analysis, and communication need skills in the essentials of epidemiology. This is one of a series of monographs on research methodology that addresses these needs and supports the goals of the Board of Editors of the Journal of the American Dietetic Association to further enhance competency and skills. This monograph focuses on statistical approaches for univariate analyses used with the primary observational study designs associated with epidemiology. Tables illustrating the presentation and interpretation of these results are included. PMID- 19782173 TI - White rice sold in Hawaii, Guam, and Saipan often lacks nutrient enrichment. AB - Rice is a commonly consumed food staple for many Asian and Pacific cultures thus, nutrient enrichment of rice has the potential to increase nutrient intakes for these populations. The objective of this study was to determine the levels of enrichment nutrients (ie, thiamin, niacin, iron, and folic acid) in white rice found in Guam, Saipan (Commonwealth of the Northern Mariana Islands), and Oahu (Hawaii). The proportion of white rice that was labeled "enriched" varied by type, bag size, and location. Most long-grain rice was labeled as enriched and most medium-grain rice was not. Bags of either type weighing >10 lb were seldom labeled as enriched in Hawaii or Saipan. Samples of various types of rice were collected on these three islands (n=19; 12 of which were labeled as enriched) and analyzed for their content of enrichment nutrients. Rice that was labeled as enriched in Hawaii and Guam seldom met the minimum enrichment standards for the United States. For comparison, three samples of enriched rice from California were also analyzed, and all met the enrichment standards. Food and nutrition professionals who are planning or evaluating diets of these Pacific island populations cannot assume that rice is enriched. PMID- 19782174 TI - Predictors of calcium intake at dinner meals of ethnically diverse mother-child dyads from families with limited incomes. AB - Diets adequate in calcium and other key nutrients early in life are critical for optimal growth. This study's objective was to determine associations between beverage and dairy food intakes of mothers and their young children and food/beverage contributions to calcium at dinner meals from ethnically diverse families with limited incomes. This was a secondary analysis of dietary data on mother-child dyads from a cross-sectional study. The sample was 465 children (4.4+/-0.6 years) and their mothers, 41% African American, 34% Hispanic, and 21% white. Dietary and anthropometric data were collected in 52 Head Start centers in Alabama and Texas during 1 year starting fall 2004. Associations between mother child intakes were examined by race/ethnicity using correlations. Calcium intake from dinners was predicted (stepwise regression) from four beverage categories milk, sweetened beverages, 100% fruit juices, and non-energy-containing beverages plus water-and from cheese and dairy desserts. Overall, the mother's dinnertime intake of milk did not predict that of her child. Mother-child intakes of cheese, dairy desserts, and sweetened beverages correlated more strongly than did milk. All the beverages and dairy groups demonstrated moderate correlations for dyads with those for cheese (r=0.56), dairy desserts (r=0.39), fruit juice (r=0.36), and sweetened beverages (r=0.31) higher than that for milk overall (r=0.29, P<0.01). Milk and cheese predicted the most variance in calcium intake for both mothers and children overall (R(2)=0.82), and for all race-ethnic groups, except African-American children, where the contribution from cheese predominated. Food and nutrition professionals should encourage replacing sweet beverages at dinner with low-fat milk or calcium-fortified beverages to improve the nutrient density of meals. PMID- 19782175 TI - The University of New Hampshire's Young Adult Health Risk Screening Initiative. AB - Few comprehensive studies exist that evaluate the nutrient intake and health indicators of college-aged students. This article describes the University of New Hampshire's Young Adult Health Risk Screening Initiative and examines results from participants evaluated from September 2005 through July 2007. This cross sectional study included 1,701 students who enrolled in an introductory nutrition course, met age requirements (18 to 24 years), agreed to participate, and completed related assessments. All evaluation components were built into the semester-long course design, thus minimizing participant burden. Anthropometric measurements, blood lipids, blood glucose, and blood pressure were measured directly by research staff. Online dietary intake was self-reported and evaluated using a software program. Health risk data indicate high rates of overweight (33%), elevated low-density lipoprotein cholesterol (53%), and elevated systolic (47%) and diastolic blood pressures (39%). Less than 30 minutes of physical activity per day was reported by 28% of respondents. The majority of males (94%) and females (73%) exceeded sodium guidelines. Although females were less likely to be overweight than males, few met recommended intakes for vitamin D (26%), calcium (25%), potassium (35%), iron (31%), and folate (32%). Undergraduate and graduate dietetics students assisted with biological assessments, data entry, and record maintenance. Data inclusion rates ranged between 84% and 94% for various measurements. The methods employed in this study could be modified by institutions interested in profiling the health status of students. Results have led to an enhanced understanding of the nutrition practices and health status of this population and will serve to inform university programs and policies. PMID- 19782176 TI - Confidence to cook vegetables and the buying habits of Australian households. AB - Cooking skills are emphasized in nutrition promotion but their distribution among population subgroups and relationship to dietary behavior is researched by few population-based studies. This study examined the relationships between confidence to cook, sociodemographic characteristics, and household vegetable purchasing. This cross-sectional study of 426 randomly selected households in Brisbane, Australia, used a validated questionnaire to assess household vegetable purchasing habits and the confidence to cook of the person who most often prepares food for these households. The mutually adjusted odds ratios (ORs) of lacking confidence to cook were assessed across a range of demographic subgroups using multiple logistic regression models. Similarly, mutually adjusted mean vegetable purchasing scores were calculated using multiple linear regression for different population groups and for respondents with varying confidence levels. Lacking confidence to cook using a variety of techniques was more common among respondents with less education (OR 3.30; 95% confidence interval [CI] 1.01 to 10.75) and was less common among respondents who lived with minors (OR 0.22; 95% CI 0.09 to 0.53) and other adults (OR 0.43; 95% CI 0.24 to 0.78). Lack of confidence to prepare vegetables was associated with being male (OR 2.25; 95% CI 1.24 to 4.08), low education (OR 6.60; 95% CI 2.08 to 20.91), lower household income (OR 2.98; 95% CI 1.02 to 8.72) and living with other adults (OR 0.53; 95% CI 0.29 to 0.98). Households bought a greater variety of vegetables on a regular basis when the main chef was confident to prepare them (difference: 18.60; 95% CI 14.66 to 22.54), older (difference: 8.69; 95% CI 4.92 to 12.47), lived with at least one other adult (difference: 5.47; 95% CI 2.82 to 8.12) or at least one minor (difference: 2.86; 95% CI 0.17 to 5.55). Cooking skills may contribute to socioeconomic dietary differences, and may be a useful strategy for promoting fruit and vegetable consumption, particularly among socioeconomically disadvantaged groups. PMID- 19782177 TI - Limited English proficiency is a barrier to receipt of advice about physical activity and diet among Hispanics with chronic diseases in the United States. AB - The prevalence of obesity, diabetes, and cardiovascular disease is reaching epidemic proportions among Hispanics in the United States. Health care providers play an important role in motivating patients to make healthful lifestyle changes to reduce the burden of such conditions. Data from the US 2000 National Health Interview Survey was analyzed to determine differences in report of physician provided physical activity and/or dietary advice by level of English proficiency among obese Hispanics or those who reported having diabetes or cardiovascular disease and who contacted a physician during the past year (n=1,186). Only one third of the sample reported receiving advice to increase their physical activity or to improve their dietary habits; one fifth reported receipt of advice about both. English-proficient Hispanics were about 50% more likely to report receiving advice on physical activity (adjusted odd ratio [AOR]=1.5; 95% confidence interval [CI]: 1.1 to 2.1), diet (AOR=1.5; 95% CI: 1.1 to 2.2) or both (AOR=1.6; 95% CI: 1.1 to 2.3), as compared with limited English-proficient Hispanics, after controlling for health insurance coverage and number of visits to a physician during the last year. Sex, age, region of residence, level of education, annual family income, and smoking status were not significantly associated with receiving physical activity and/or dietary advice. In order to address racial health disparities, and lower the burden of chronic illness, culturally sensitive strategies must be implemented to enhance delivery of effective health-promotion messages by physicians, particularly among at-risk communities. PMID- 19782178 TI - Prospective associations among cereal intake in childhood and adiposity, lipid levels, and physical activity during late adolescence. AB - Cereal consumption is a common dietary behavior that has been associated with positive health outcomes. The objective of this study was to examine prospective associations between cereal intake in childhood and percent body fat, waist-to hip ratio, lipid levels, and physical activity during late adolescence. In this longitudinal investigation (data collected 1987-1997), data were analyzed for the 2,379 girls who participated in the 10-year National Heart, Lung, and Blood Institute Growth and Health Study. The cumulative percent of days that each girl consumed cereal during childhood (based on 3-day food diaries collected during six study visits between ages 11.5 and 18.6 years) was examined in relation to percent body fat, waist-to-hip ratio, lipid levels, and physical activity measured at age 18.6 years. Results indicated that nearly all girls (90.1%) reported eating cereal and 18.7% reported eating cereal on half or more of the days reported in the food diaries. Girls who ate cereal on a greater percentage of days during childhood had lower percent body fat and total cholesterol, and were more likely to exhibit high levels of physical activity and less television viewing during Study Year 10 (P values<0.05). Further research should explore lifestyle issues related to cereal consumption. PMID- 19782179 TI - Psyllium as a substitute for gluten in bread. AB - Celiac disease is an antibody-mediated enteropathy that presents permanent intolerance to ingested gluten. Currently, only one kind of treatment is available: the complete dietary elimination of all sources of gluten. The aim of the present study was to evaluate the effect of replacing gluten with psyllium on sensory characteristics of bread dough and to compare the chemical, nutritional, technological, and sensory characteristics of the modified preparations. This study is experimental and was subdivided into five steps: selection and development of preparation, chemical analysis, sensory analysis, and statistical analysis. Modified samples of the bread dough achieved a 93.0% acceptance rate for individuals with celiac disease and up to 97.0% for individuals without celiac disease. The most affected characteristics were odor and texture. In terms of chemical composition of the bread dough, energy was reduced by 32.1% and the fat fraction was 42.3% before being cooked. Data obtained from sensory analysis of psyllium doughs indicate that the products had good acceptance by individuals with celiac disease as well as by individuals without celiac disease. This suggests that psyllium can replace gluten in preparations. Furthermore, in terms of chemical composition, products made with modified dough had less fat and fewer calories. PMID- 19782181 TI - Food insecurity is associated with overweight in children younger than 5 years of age. AB - Both household food insecurity and childhood overweight are serious public health problems that appear to be paradoxically correlated. This study examines the relationship between overweight and household food insecurity with/without hunger in low-income children participating in the Special Supplemental Nutrition Program for Women, Infants, and Children. Weight, height, and household food insecurity data were collected on 8,493 children ages 1 month to 5 years and analyzed by sex and age groups using logistic regression to model the odds of being overweight (weight for length or body mass index [calculated as kg/m(2)] for age > or =95th percentile) given household food insecurity status, controlling for race/ethnicity and maternal education. Analyses were stratified by age and sex because interaction terms with household food insecurity were significant (P<0.10). In this sample, prevalence of household food insecurity was 30.7% (8.3% with hunger) and 18.4% were overweight. Among girls younger than 2 years of age, household food insecurity was associated with reduced odds of overweight compared with food-secure households (odds ratio=0.65; 95% confidence interval: 0.47 to 0.88); hunger status did not alter this association. Among 2- to 5-year-old girls, there was no overall significant association between household food insecurity and overweight; however, household food insecurity with hunger was positively associated with overweight compared with those from food secure households (odds ratio=1.49; 95% confidence interval: 1.06 to 2.10). No association between household food insecurity and overweight was found among boys. These findings suggest an association between household food insecurity and overweight prevalence in this low-income population. However, sex and age appear to modify both the magnitude and direction of the association. PMID- 19782180 TI - Use of a brief food frequency questionnaire for estimating daily number of servings of fruits and vegetables in a minority adolescent population. AB - The validity of the 5 A Day for Better Health Program food frequency questionnaire (5 A Day FFQ) for estimating fruit and vegetable consumption was examined in a sample of 156 African-American adolescents aged 10 to 14 years. To determine validity, the correlation between 5 A Day FFQ fruit, juice, and vegetable intake and 3-day intake measured by direct observation was assessed. Correlations were calculated separately by food type (ie, fruits, juices, and vegetables) and sex and age to determine whether the accuracy of youths' recording differed based on these factors. Paired-samples t tests were used to test for differences between 5 A Day FFQ and observed intake estimates. The ability of the 5 A Day FFQ to correctly classify youths according to intake level (ie, intake of five or more daily servings) was also examined. The 5 A Day FFQ intake was significantly correlated with observed intake (r=0.39; P<0.01). Correlations were weaker by food type (r=0.15 to r=0.28) and did not differ based on youths' sex or age. Mean 5 A Day FFQ intake (6.74+/-6.00 servings) was considerably higher than mean observed intake (5.41+/-1.51 servings), and this was a result of the overestimation of vegetable intake. Sensitivity, specificity, and positive and negative predictive values of the 5 A Day FFQ were 67.1%, 68.6%, 63.5%, and 71.9%, respectively. Findings suggest that the 5 A Day FFQ may be more useful as a screening tool for identifying African-American adolescents most in need of intervention than for estimating youths' mean intake in dietary intervention programs. PMID- 19782182 TI - What impact does pH have on food and nutrition? PMID- 19782183 TI - [Relationships of the thoracic aorta above the oesophageal hiatus of the diaphragm]. PMID- 19782185 TI - Optimization by the simplex method of the separation of phenolic acids by high performance liquid chromatography in wastewater olive and sugar beet vinasse. AB - Optimization of a high-performance liquid chromatography separation has been developed for nine polyphenols by application of the simplex method. The nine polyphenols selected were mainly phenolic acids that can be present in wastewater and they can be removed by adsorption on activated carbon and resins. After the organic solvent (MeOH) had been chosen, a linear gradient in three stages and the furnace temperature were retained as parameters of optimization. The optimal conditions were determined by the super modified simplex and, in order to measure them a Chromatographic Response Function (CRF) was chosen. With the optimal conditions, the time of analysis was decreased from 69 to 40 min. The validation of the method was made on wastewater olive oil (WWOO) and sugar beet vinasse. PMID- 19782186 TI - Integration of electrochemistry in micro-total analysis systems for biochemical assays: recent developments. AB - Micro-total analysis systems (microTAS) integrate different analytical operations like sample preparation, separation and detection into a single microfabricated device. With the outstanding advantages of low cost, satisfactory analytical efficiency and flexibility in design, highly integrated and miniaturized devices from the concept of microTAS have gained widespread applications, especially in biochemical assays. Electrochemistry is shown to be quite compatible with microanalytical systems for biochemical assays, because of its attractive merits such as simplicity, rapidity, high sensitivity, reduced power consumption, and sample/reagent economy. This review presents recent developments in the integration of electrochemistry in microdevices for biochemical assays. Ingenious microelectrode design and fabrication methods, and versatility of electrochemical techniques are involved. Practical applications of such integrated microsystem in biochemical assays are focused on in situ analysis, point-of-care testing and portable devices. Electrochemical techniques are apparently suited to microsystems, since easy microfabrication of electrochemical elements and a high degree of integration with multi-analytical functions can be achieved at low cost. Such integrated microsystems will play an increasingly important role for analysis of small volume biochemical samples. Work is in progress toward new microdevice design and applications. PMID- 19782187 TI - Spectrofluorimetric method for measuring the activity of the enzyme alpha-L fucosidase using the ion associate of 2-chloro-4-nitro phenol-rhodamine-B. AB - A low cost and accurate method for the detection and analytical determination of the activity of the enzyme alpha-L-fucosidase (AFU) was developed. The method was based upon measuring the fluorescence intensity of the complex ion associate of the ion associate of rhodamine-B and the compound 2-chloro-4-nitrophenol (RB(+)CNP(-)) at 580 nm in phosphate buffer (pH 5) against the reagent blank. The influence of the different parameters, e.g. pH, incubation time, temperature, 2 chloro-4-nitrophenol concentration, foreign ions and surfactants that control the fluorescence intensity of the produced ion associate was critically investigated. The correlation between the fluorescence activity of the enzyme AFU by the developed procedures and the standard method was positive and highly significant in patients and controls (r(2)=0.99, p<0.001). The developed method is simple and proceeds without practical artifacts compared to the standard method. PMID- 19782188 TI - Fabrication of SU-8 based microchip electrophoresis with integrated electrochemical detection for neurotransmitters. AB - A new SU-8 based microchip capillary electrophoresis (MCE) device has been developed for the first time with integrated electrochemical detection. Embedded electrophoretic microchannels have been fabricated with a multilayer technology based on bonding and releasing steps of stacked SU-8 films. This technology has allowed the monolithic integration in the device of the electrochemical detection system based on platinum electrodes. The fabrication of the chips presented in this work is totally compatible with reel-to-reel techniques, which guarantee a low cost and high reliability production. The influence of relevant experimental variables, such as the separation voltage and detection potential, has been studied on the SU-8 microchip with an attractive analytical performance. Thus, the effective electrical isolation of the end-channel amperometric detector has been also demonstrated. The good performance of the SU-8 device has been proven for separation and detection of the neurotransmitters, dopamine (DA) and epinephrine (EP). High efficiency (30,000-80,000 N/m), excellent precision, good detection limit (450 nM) and resolution (0.90-1.30) has been achieved on the SU-8 microchip. These SU-8 devices have shown a better performance than commercial Topas (thermoplastic olefin polymer of amorphous structure) microchips. The low cost and versatile SU-8 microchip with integrated platinum film electrochemical detector holds great promise for high-volume production of disposable microfluidic analytical devices. PMID- 19782189 TI - Voltammetric studies of sumatriptan on the surface of pyrolytic graphite electrode modified with multi-walled carbon nanotubes decorated with silver nanoparticles. AB - Multi-walled carbon nanotube decorated with silver nanoparticles (AgNPs-MWCNT) is used as an effective strategy for modification of the surface of pyrolytic graphite electrode (PGE). This modification procedure improved colloidal dispersion of the decorated MWCNTs in water, affording uniform and stable thin films for altering the surface properties of the working electrode. Robust electrode for sensing applications is obtained in a simple solvent evaporation process. The electrochemical behavior of sumatriptan (Sum) at the bare PGE and AgNPs-MWCNT modified PGE is investigated. The results indicate that the AgNPs MWCNT modified PGE significantly enhanced the oxidation peak current of Sum. A remarkable enhancement in microscopic area of the electrode together with strong adsorption of Sum on the surface of the modified electrode resulted in a considerable increase in the peak current of Sum. Experimental parameters, such as scan rate, pH, accumulation conditions and amount of the modifier used on the PGE surface are optimized by monitoring the CV responses toward Sum. It is found that a maximum current response can be obtained at pH 7.4 after accumulation at open circuit for 150 s. Further experiments demonstrated that the oxidative peak currents increased linearly with Sum concentration in the range of 8.0 x 10(-8) 1.0 x 10(-4)mol L(-1) with a detection limit of 4.0 x 10(-8) mol L(-1). The modified electrode showed high sensitivity, selectivity, long-term stability and remarkable voltammetric reproducibility in response to Sum. These excellent properties make the prepared sensor suitable for the analysis in pharmaceutical and clinical preparations. The modified electrode was successfully applied for the accurate determination of trace amounts of Sum in pharmaceutical preparations. PMID- 19782190 TI - Fire impact on forest soils evaluated using near-infrared spectroscopy and multivariate calibration. AB - The assessment of physico-chemical properties in forest soils affected by fires was evaluated using near infrared reflectance (NIR) spectroscopy coupled with chemometric methods. In order to describe the soil properties, measurements were taken of the total organic carbon on solid phase, the total nitrogen content, the organic carbon and the specific absorbences at 254 and 280 nm of humic substances, organic carbon in humic and fulvic acids, concentrations of NH(4)(+), Ca(2+), Mg(2+), K(+) and phosphorus in addition to NIR spectra. Then, a fire recurrence index was defined and calculated according to the different fires extents affecting soils. This calculation includes the occurrence of fires as well as the time elapsed since the last fire. This study shows that NIR spectroscopy could be considered as a tool for soil monitoring, particularly for the quantitative prediction of the total organic carbon, total nitrogen content, organic carbon in humic substances, concentrations of phosphorus, Mg(2+), Ca(2+) and NH(4)(+) and humic substances UVSA(254). Further validation in this field is necessary however, to try and make successful predictions of K(+), organic carbon in humic and fulvic acids and the humic substances UVSA(280). Moreover, NIR coupled with PLS can also be useful to predict the fire recurrence index in order to determine the spatial variability. Also this method can be used to map more or less burned areas and possibly to apply adequate rehabilitation techniques, like soil litter reconstitution with organic enrichments (industrial composts) or reforestation. Finally, the proposed recurrence index can be considered representative of the state of the soils. PMID- 19782191 TI - A methodology based on NIR-microscopy for the detection of animal protein by products. AB - This study develops a methodology based on NIR-microscopy analysis and chemometric tools for the detection of animal protein by-products in mixtures, such as compound feeds and mixtures of ingredients, using a library of animal meal by-products only. The proposed methodology is a two-step strategy which worked better than the SIMCA approach it was compared with. In the first step, animal particles are identified using one of two methods, a global or a local distance measure. In the second, K-nearest-neighbours (KNN) is used to discriminate between terrestrial and fish particles. The models were developed using a training set comprising 11,727 spectra of pure terrestrial meals and 5843 of fish meals. KNN using second derivative spectra and five neighbours correctly classifies 98.5% of these samples under cross-validation. The procedure was validated using two external datasets, one made up of mixtures of species (fish and bovine), and a second of commercial compound feeds. The results obtained confirm that the procedure is able to reliably detect the presence of animal meals, although further work would be needed to develop it into an accurate quantitative method. PMID- 19782192 TI - Spectral library validation to identify ingredients of compound feedingstuffs by near infrared reflectance microscopy. AB - To guarantee feed quality and safety the development and improvement of analytical methods for feed authentication and detection of contaminants is fundamental. Near infrared reflectance microscopy (NIRM) has been investigated as an alternative method to contribute to control systems for feed materials. The major task is the need to build NIRM reference spectral libraries that must represent the variability in feed ingredients. The aim of the present work was to evaluate the performance of a NIRM reference spectral library on animal feed, with external samples of animal feed ingredients and possible contaminants such as processed animal proteins, and in particular to assess its ability to identify ingredients in mixtures. Three external sample sets were used: (A) artificial mixtures, (B) synthetic mixtures and (C) synthetic binary mixtures. The prediction and repeatability results for set A, in which the spectra are from pure ingredients, were very good for both animal and vegetable ingredients and confirm that the spectral library is very good at identifying spectra from pure ingredients. For sets B and C, in which the spectra were measured on mixtures, the prediction results were very disappointing compared with the artificial samples. This means that a strategy that tries to match the spectra taken from a mixture with those of pure ingredients is unlikely to meet with much success. It is possible that an interpolation between pure ingredients for suitably chosen spectral ranges may provide a way to extend this system to mixtures, including mixtures of several ingredients. PMID- 19782193 TI - A multi-analytical study of degradation of lignin in archaeological waterlogged wood. AB - Historical or archaeological wooden objects are generally better conserved in wet environments than in other contexts. Nevertheless, anaerobic erosion bacteria can slowly degrade waterlogged wood, causing a loss of cellulose and hemicellulose and leading to the formation of water-filled cavities. During this process, lignin can also be altered. The result is a porous and fragile structure, poor in polysaccharides and mainly composed of residual lignin, which can easily collapse during drying and needs specific consolidation treatments. For this reason, the chemical characterization of archaeological lignin is of primary importance in the diagnosis and conservation of waterlogged wood artifacts. Current knowledge of the lignin degradation processes in historical and archaeological wood is extremely inadequate. In this study lignin extracted from archaeological waterlogged wood was examined using both Py-GC/MS, NMR spectroscopy and GPC analysis. The samples were collected from the Site of the Ancient Ships of San Rossore (Pisa, Italy), where since 1998 31 shipwrecks, dating from 2nd century BC to 5th century AD, have been discovered. The results, integrated by GPC analysis, highlight the depolymerization of lignin with cleavage of ether bonds, leading to an higher amount of free phenol units in the lignin from archaeological waterlogged wood, compared to sound lignin from reference wood of the same species. PMID- 19782194 TI - Advanced combined application of micro-X-ray diffraction/micro-X-ray fluorescence with conventional techniques for the identification of pictorial materials from Baroque Andalusia paintings. AB - The process of investigating paintings includes the identification of materials to solve technical and historical art questions, to aid in the deduction of the original appearance, and in the establishment of the chemical and physical conditions for adequate restoration and conservation. In particular, we have focused on the identification of several samples taken from six famous canvases painted by Pedro Atanasio Bocanegra, who created a very special collection depicting the life of San Ignacio, which is located in the church of San Justo y Pastor of Granada, Spain. The characterization of the inorganic and organic compounds of the textiles, preparation layers, and pictorial layers have been carried out using an XRD diffractometer, SEM observations, EDX spectrometry, FT IR spectrometry (both in reflection and transmission mode), pyrolysis/gas chromatography/mass spectrometry and synchrotron-based micro-X-ray techniques. In this work, the advantages over conventional X-ray diffraction of using combined synchrotron-based micro-X-ray diffraction and micro-X-ray fluorescence in the identification of multi-layer paintings is demonstrated. PMID- 19782195 TI - Metabolism profile of scutellarin in urine following oral administration to rats by ultra performance liquid chromatography coupled to time-of-flight mass spectrometry. AB - Scutellarin, a flavone glucuronide of 5,6,4'-trihydroxyflavone-7-O-glucoronide, is the main active component of the traditional Chinese botanic drug Erigeron breviscapus (Vant.) Hand.-Mazz. In this study, a method based on ultra performance liquid chromatography coupled with a time-of-flight mass spectrometer (UPLC/TOF MS) was established and validated to profile the metabolites of scutellarin in Sprague-Dawley rat urine following oral administration of single dose of scutellarin at 80.8 mg/kg. The column utilized was an Acquity BEH C18 (150 mm x 2.1 mm, 1.7 microm). The mobile phase was 0.2% formic acid and acetonitrile with gradient condition. Two standard curves of scutellarin were obtained for the concentration range of 1.065-10.65 microg/mL and 10.65-63.92 microg/mL, respectively. By automating the data processing of the software Masslynx developed by Waters Ltd., 17 metabolites of scutellarin were found and determined in rat urine, with the corresponding reactions in vivo such as isomerism, reduction, methylation, glucuronide conjugation, hydroxylation, hydroxylation and methylation, etc., most of which were discovered for the first time. For most metabolites, the time (T(p)) of peak excretion was 8-12h. Calculated as scutellarin, the cumulative urine excretion rate of the metabolites was 1.93%. PMID- 19782196 TI - A ratiometric fluorescent probe for fluoride ion employing the excited-state intramolecular proton transfer. AB - A ratiometric fluorescent probe 1 for fluoride ion was developed based on modulation of the excited-state intramolecular proton transfer (ESIPT) process of 2-(2'-hydroxyphenyl)benzimidazole (HPBI) through the hydroxyl group protection/deprotection reaction. The probe 1 was readily prepared by the reaction of HPBI with tert-butyldimethylsilyl chloride (TBS-Cl) and shows only fluorescence emission maximum at 360 nm. Upon treatment with fluoride in aqueous DMF solution, the TBS protective group of probe 1 was removed readily and ESIPT of the probe was switched on, which resulted in a decrease of the emission band at 360 nm and an increase of a new fluorescence peak around 454 nm. The fluorescent intensity ratio at 454 and 360 nm (I(454)/I(360)) increases linearly with fluoride ion concentration in the range 0.3-8.0 micromol L(-1) and the detection limit is 0.19 micromol L(-1). The proposed probe shows excellent selectivity toward fluoride ion over other common anions. The method has been successfully applied to the fluoride determination in toothpaste and tap water samples. PMID- 19782197 TI - Preparation and characterization of an immunoaffinity chromatography column for the selective extraction of trace contraceptive drug levonorgestrel from water samples. AB - The preparation and characterization of an immunoaffinity chromatography (IAC) column for the specific extraction and enrichment of trace contraceptive drug levonorgestrel (LNG) from water samples were described. The IAC column was constructed by covalently coupling specific polyclonal antibody against LNG to CNBr-activated Sepharose 4B and packed into a common solid phase extraction (SPE) cartridge. The extraction conditions including loading, washing and eluting solutions, as well as the effect of flow rate on the extraction were carefully optimized. Pure water, 5% of methanol and 50% of methanol were respectively selected as loading, washing and eluting solutions, while the flow rates in the loading, washing and eluting steps were selected to be 1.0, 2.0 and 0.5 mL min( 1), respectively. Under optimal conditions, the IAC column was characterized in terms of maximum capacity, extraction recovery and stability. It was found that, for IAC column packed with 0.2g of solid support immobilized with antibody, the maximum capacity for LNG was about 260 ng. The extraction recoveries of the column for LNG at three different spiked concentrations were within 95.3-106.9%. After more than 35 times repeated usage, there was not significant loss of specific recognition. Using high performance liquid chromatography (HPLC) as an analytical tool, trace amount of LNG in the range of ng L(-1) was found in river water and wastewater samples after 600-fold enrichment, demonstrated the feasibility of the prepared IAC column for LNG extraction. PMID- 19782198 TI - Determination of aromatic compounds in eluates of pyrolysis solid residues using HS-GC-MS and DLLME-GC-MS. AB - A method for the determination of 15 aromatic hydrocarbons in eluates from solid residues produced during the co-pyrolysis of plastics and pine biomass was developed. In a first step, several sampling techniques (headspace solid phase microextraction (HS-SPME), static headspace sampling (HS), and dispersive liquid liquid microextraction (DLLME) were compared in order to evaluate their sensitivity towards these analytes. HS-SPME and HS sampling had the better performance, but DLLME was itself as a technique able to extract volatiles with a significant enrichment factor. HS sampling coupled with GC-MS was chosen for method validation for the analytes tested. Calibration curves were constructed for each analyte with correlation coefficients higher than 0.999. The limits of detection were in the range of 0.66-37.85 ng/L. The precision of the HS method was evaluated and good repeatability was achieved with relative standard deviations of 4.8-13.2%. The recoveries of the analytes were evaluated by analysing fortified real eluate samples and were in the range of 60.6-113.9%. The validated method was applied in real eluate samples. Benzene, toluene, ethylbenzene and xylenes (BTEX) were the compounds in higher concentrations. The DLLME technique coupled with GC-MS was used to investigate the presence of less volatile contaminants in eluate samples. This analysis revealed the presence of significant amounts of alkyl phenols and other aromatic compounds with appreciable water solubility. PMID- 19782199 TI - Ultrasound-assisted emulsification of cosmetic samples prior to elemental analysis by different atomic spectrometric techniques. AB - In this work, ultrasound-assisted emulsification with a probe system is proposed as a rapid and simple sample treatment for atomic spectrometric determinations (Electrothermal Atomic Absorption Spectrometry, Inductively Coupled Plasma Optical Emission Spectrometry, Flame Atomic Absorption Spectrometry and Cold Vapour Atomic Absorption Spectrometry) of trace elements (As, Cd, Cr, Cu, Hg, Mg, Mn, Ni, Sr and Zn) in cosmetic samples such as shampoos, gel (hair gel), cremes (body milk, hair conditioner) and oil (body oil). The type of dispersion medium, the sample mass-to-dispersion medium volume ratio, as well as the parameters related to the ultrasound-assisted emulsification (sonication amplitude and treatment time) were exhaustively studied. Only 1 min of ultrasonic shaking and a dispersion medium containing 0.5% (w/v) of SDS+3% (v/v) of HNO(3) or HCl allows obtaining a stable emulsion at least for 3 months. Thermal programs, nebulization of emulsions, speed of pumps and concentration of reagents used in cold vapour generation were optimized. Calibration using aqueous standards was feasible in all cases. Calibration by the standard addition method and recovery studies was also applied for validation. Microwave-assisted digestion and Inductively Coupled Plasma Mass Spectrometry were used for comparison purposes. Relative standard deviations from analysis of five independent emulsions were less than 9% in all cases. PMID- 19782200 TI - Simultaneous multiresponse optimization of an HPLC method to separate seven cephalosporins in plasma and amniotic fluid: application to validation and quantification of cefepime, cefixime and cefoperazone. AB - An HPLC method for the separation of seven cephalosporins [Cefepime (CEP), ceftazidime (CTA), ceftizaxime (CTI), ceftriaxone (CTR), cefotaxime (COT), cefixime (CIX) and cefoperazone (COP)] in human plasma and amniotic fluid has been developed. Optimization of the chromatographic method was performed in three steps: a series of initial experiments followed by two sets of experiments based on different experimental designs. The initial experiments were performed to decide the basic analytical requirements of the method. Then screening experiment fractional factorial design was used in order to decrease the number of parameters by eliminating parameters which having insignificant effect on responses. The parameters having significant effect were further optimized through a full factorial design. Having studied two responses (retention times and resolutions), a desirability function that assess the responses together, was used to find experimental conditions where the system generated desirable results. The desirable results were obtained with XTerra C18 (250 mm x 4.6mm, 5 microm i.d.) column, 40 mM phosphate buffer, pH 3.2, 18% MeOH, 0.85 mL min(-1) flow rate and 32 degrees C column temperature. Gradient elution with MeOH was applied. A simple and efficient solid-phase extraction was applied for the preparation of plasma and amniotic fluid samples. The validation parameters of the method were evaluated in accordance with ICH guideline. The method validated was applied to the analysis of CEP and COP in maternal venous, fetal venous and fetal arterial plasma, and to the analysis of CIX in maternal venous plasma and amniotic fluid. PMID- 19782201 TI - Determination and interference studies of bismuth by tungsten trap hydride generation atomic absorption spectrometry. AB - The determination of bismuth requires sufficiently sensitive procedures for detection at the microg L(-1) level or lower. W-coil was used for on-line trapping of volatile bismuth species using HGAAS (hydride generation atomic absorption spectrometry); atom trapping using a W-coil consists of three steps. Initially BiH(3) gas is formed by hydride generation procedure. The analyte species in vapor form are transported through the W-coil trap held at 289 degrees C where trapping takes place. Following the preconcentration step, the W-coil is heated to 1348 degrees C; analyte species are released and transported to flame heated quartz atom cell where the atomic signal is formed. In our study, interferences have been investigated in detail during Bi determination by hydride generation, both with and without trap in the same HGAAS system. Interferent/analyte (mass/mass) ratio was kept at 1, 10 and 100. Experiments were designed for carrier solutions having 1.0M HNO(3). Interferents such as Fe, Mn, Zn, Ni, Cu, As, Se, Cd, Pb, Au, Na, Mg, Ca, chloride, sulfate and phosphate were examined. The calibration plot for an 8.0 mL sampling volume was linear between 0.10 microg L(-1) and 10.0 microg L(-1) of Bi. The detection limit (3s/m) was 25 ng L(-1). The enhancement factor for the characteristic concentration (C(o)) was found to be 21 when compared with the regular system without trap, by using peak height values. The validation of the procedure was performed by the analysis of the certified water reference material and the result was found to be in good agreement with the certified values at the 95% confidence level. PMID- 19782202 TI - Molecularly imprinted solid-phase extraction for the selective determination of bromhexine in human serum and urine with high performance liquid chromatography. AB - In this work, a novel method is described for the determination of bromhexine in biological fluids using molecularly imprinted solid-phase extraction as the sample cleanup technique combined with high performance liquid chromatography (HPLC). The water-compatible molecularly imprinted polymers (MIPs) were prepared using methacrylic acid as functional monomer, ethylene glycol dimethacrylate as cross-linker, chloroform as porogen and bromhexine as the template molecule. The novel imprinted polymer was used as a solid-phase extraction sorbent for the extraction of bromhexine from human serum and urine. Various parameters affecting the extraction efficiency of the polymer have been evaluated. The optimal conditions for molecularly imprinted solid-phase extraction (MISPE) consisted of conditioning 1 mL methanol and 1 mL of deionized water at neutral pH, loading of 5 mL of the water sample (25 microg L(-1)) at pH 6.0, washing using 2 mL acetonitrile/acetone (1/4, v/v) and elution with 3x 1 mL methanol/acetic acid (10/1, v/v). The MIP selectivity was evaluated by checking several substances with similar molecular structures to that of bromhexine. Results from the HPLC analyses showed that the calibration curve of bromhexine using MIP from human serum and urine is linear in the ranges of 0.5-100 and 1.5-100 microg L(-1) with good precisions (3.3% and 2.8% for 5.0 microg L(-1)), respectively. The recoveries for serum and urine samples were higher than 92%. PMID- 19782203 TI - Determination of bismuth in solid samples by hydride generation atomic fluorescence spectrometry with a dielectric barrier discharge atomizer. AB - An atmospheric pressure dielectric barrier discharge (DBD) atomizer was investigated for bismuth (Bi) determination with hydride generation (HG) atomic fluorescence spectrometry (AFS). The characteristics of the atomizer and the effects of experimental parameters, including observation height, discharge power, flow rate of discharge gas and AFS carrier gas were optimized. The linear range of present method for Bi determination is 0.5-300.0 microg L(-1) with a detection limit of 0.07 microg L(-1) (3 sigma). The method was validated by the analysis of reference materials (GBW08517 and GSB-14) and the results agreed well with the reference values. The established method was applied to the determination of Bi in ore, soil and ash samples. PMID- 19782204 TI - Rapid determination of actinides in urine by inductively coupled plasma mass spectrometry and alpha spectrometry: a hybrid approach. AB - A new rapid separation method that allows separation and preconcentration of actinides in urine samples was developed for the measurement of longer lived actinides by inductively coupled plasma mass spectrometry (ICP-MS) and short lived actinides by alpha spectrometry; a hybrid approach. This method uses stacked extraction chromatography cartridges and vacuum box technology to facilitate rapid separations. Preconcentration, if required, is performed using a streamlined calcium phosphate precipitation. Similar technology has been applied to separate actinides prior to measurement by alpha spectrometry, but this new method has been developed with elution reagents now compatible with ICP-MS as well. Purified solutions are split between ICP-MS and alpha spectrometry so that long- and short-lived actinide isotopes can be measured successfully. The method allows for simultaneous extraction of 24 samples (including QC samples) in less than 3h. Simultaneous sample preparation can offer significant time savings over sequential sample preparation. For example, sequential sample preparation of 24 samples taking just 15 min each requires 6h to complete. The simplicity and speed of this new method makes it attractive for radiological emergency response. If preconcentration is applied, the method is applicable to larger sample aliquots for occupational exposures as well. The chemical recoveries are typically greater than 90%, in contrast to other reported methods using flow injection separation techniques for urine samples where plutonium yields were 70-80%. This method allows measurement of both long-lived and short-lived actinide isotopes. (239)Pu, (242)Pu, (237)Np, (243)Am, (234)U, (235)U and (238)U were measured by ICP-MS, while (236)Pu, (238)Pu, (239)Pu, (241)Am, (243)Am and (244)Cm were measured by alpha spectrometry. The method can also be adapted so that the separation of uranium isotopes for assay is not required, if uranium assay by direct dilution of the urine sample is preferred instead. Multiple vacuum box locations may be set-up to supply several ICP-MS units with purified sample fractions such that a high sample throughput may be achieved, while still allowing for rapid measurement of short-lived actinides by alpha spectrometry. PMID- 19782205 TI - Utility of certain sigma- and pi-acceptors for the spectrophotometric determination of ganciclovir in pharmaceutical formulations. AB - Studies were carried out, for the first time, to investigate the charge-transfer reactions of ganciclovir as n-electron donor with the sigma-acceptor iodine and various pi-acceptors: 7,7,8,8-tetracyanoquinodimethane; tetracyanoethylene; 2,3 dichloro-5,6-dicyano-1,4-benzoquinone; p-chloranilic acid; 2,3,5,6-tetrabromo-1,4 benzoquinone; 2,3,5,6-tetrachloro-1,4-benzoquinone and 2,4,7-trinitro-9 fluorenone. The formation of the colored charge-transfer complexes was utilized in the development of simple, rapid and accurate spectrophotometric methods for the analysis of ganciclovir in pure form as well as in its pharmaceutical formulation (capsules). Different variables affecting the reactions were studied and optimized. Under the optimum reaction conditions, linear relationships with good correlation coefficients (0.9993-0.9998) were found between the absorbance and the concentration of ganciclovir in the range of 2.0-240 microg mL(-1). For more accurate analysis, Ringbom optimum concentration range was found to be between 5.0 and 225 microg mL(-1). The limits of detection ranged from 0.36 to 2.45 microg mL(-1) and the limits of quantification ranged from 1.20 to 8.17 microg mL(-1). A Job's plot of the absorbance versus the molar ratio of ganciclovir to each of acceptors under consideration indicated (1:1) ratio. The proposed methods were applied successfully for simultaneous determination of ganciclovir in capsules with good accuracy and precision and without interferences from common additives. The recovery percentages ranged from 99.45+/ 0.73% to 100.35+/-1.40%. The results were compared favourably with the reported method. PMID- 19782206 TI - Separation and preconcentration of trace amounts of aluminum ions in surface water samples using different analytical techniques. AB - A separation/preconcentration of aluminum (III) (Al(3+)) has been developed to overcome the problem of high matrix species, which may interfere with the determination of trace quantity of Al(3+) in natural water samples. The separation of Al(3+) in water samples was carried out from interfering cations by complexing them with 2-methyle 8-hyroxyquinoline (quinaldine) on activated silica. Whereas the separated trace amounts of Al(3+) was preconcentrated by cloud point extraction (CPE), as prior step to its determination by spectrofluorimetry (SPF) and flame atomic absorption spectrometry (FAAS). The Al(3+) react with 8-hydroxyquinoline (oxine) and then entrapped in non-ionic surfactant Triton X-114. The main factors affecting CPE efficiency, such as pH of sample solution, concentration of oxine and Triton X-114, equilibration temperature and time period for shaking were investigated in detail. The validity of separation/preconcentration of Al(3+) was checked by certified reference material of water (SRM-1643e). After optimization of the complexation and extraction conditions, a preconcentration factor of 20 was obtained for Al(3+) in 10 mL of natural water samples. The relative standard deviation for 6 replicates containing 100 microg L(-1) of Al(3+) was 5.41 and 4.53% for SPF and FAAS, respectively. The proposed method has been applied for determination of trace amount of Al(3+) in natural water samples with satisfactory results. PMID- 19782207 TI - Voltammetric determination of sericin based on its interaction with carmine. AB - A simple yet sensitive method is developed for the determination of sericin using voltammetry based on the interaction between sericin and carmine for the first time. In the absence of sericin, carmine has a pair of well-defined redox peaks in a pH 1.81 Britton-Robinson buffer solution. Although no new redox peaks appear upon the addition of sericin into a carmine solution, the peak currents of the old peaks reduce while the peak potentials shift positively. This observation is attributed to the decrease in the diffusion coefficient and electrode reaction rate constant of carmine in the presence of sericin. A binding mechanism is proposed and discussed, and the binding constant and binding ratio are calculated as 2.32 x 10(6) L mol(-1) and 1:1, respectively. Furthermore, the decrease in the peak currents is found proportional to the sericin concentration in the range of 32.0-800.0 microg mL(-1) with a detection limit of 13.52 microg mL(-1). The method is further applied to the determination of sericin in degumming wastewater with satisfied average recoveries from 96.7 to 103.3%. The results are in good agreement with those obtained by the conventional Coomassie brilliant blue G-250 spectrophotometric method. PMID- 19782208 TI - Flame atomic absorption spectrometry for the determination of trace amount of rhodium after separation and preconcentration onto modified multiwalled carbon nanotubes as a new solid sorbent. AB - The present article reports on the application of modified multiwalled carbon nanotubes (MMWCNTs) as a new, easily prepared and stable solid sorbent for the preconcentration of trace rhodium ion in aqueous solution. Rhodium ions were complexed with 1-(2-pyridylazo)-2-naphthol (PAN) in the pH range of 3.2-4.7 and then the formed Rh-PAN complex was adsorbed on the oxidized MWCNTs. The adsorbed complex was eluted from MWCNTs sorbent with 5.0 mL of N,N-dimethylformamide (DMF). The rhodium in eluted solution was determined by flame atomic absorption spectrometry (FAAS). Linear range for the determination of rhodium was maintained between 0.16 ng mL(-1) and 25.0 microg mL(-1) in initial solution. Relative standard deviation for the 10 replicated determination of 4.0 microg mL(-1) of rhodium was +/-0.97%. Detection limit was 0.010 ng mL(-1) in initial solution (3S(bl), n=10) and preconcentration factor was 120. Sensitivity for 1% absorbance of rhodium (III) was 0.112 microg mL(-1). The sorption capacity of oxidized MWCNTs for Rh (III) was 6.6 mg g(-1). The effects of the experimental parameters, including the sample pH, flow rates of sample and eluent solution, eluent type, breakthrough volume and interference ions were studied for the preconcentration of Rh(3+). The proposed method was successfully applied to the extraction and determination of rhodium in different samples. PMID- 19782209 TI - A novel cloud point extraction approach using cationic surfactant for the separation and pre-concentration of chromium species in natural water prior to ICP-DRC-MS determination. AB - A novel cloud point phase separation of cationic surfactant, Aliquat-336 and capabilities of its reactive solubilizing sites for selective extraction of chromium species at ultra trace levels was examined in natural water. The phase separation behavior of Aliquat-336 is studied with various additives. The nonionic surfactant, Triton X-114 was found to induce the cloud point phase separation of Aliquat-336. The separation of anionic Cr(VI) was enabled by the formation of ion associate with quaternary ammonium head group of Aliquat-336 at pH 2, and the recovery of Cr(VI) and Cr(III) were 101.4+/-1.4% and 2.2+/-0.4%, respectively at 0.5-1 ng mL(-1), Total Cr was pre-concentrated as Cr-APDC species using the hydrophobic tail group at pH 6.5. The Cr(III) concentration was obtained by subtracting Cr(VI) from total Cr. The recovery of total Cr was 99.5+/ 1.2%. Parameters affecting extraction were assessed. The procedure was applied to NIST 1643c and NIST 1643d waters, and the sum of individual species obtained was compared with the certified chromium values. The method was also applied to various natural waters with limits of detection and pre-concentration factor of 0.010 and 0.025 ng mL(-1); 10 and 10, respectively, for Cr(VI) and Cr(III)-APDC using ICP-MS operated in DRC mode. PMID- 19782210 TI - Novel enzyme-linked immunosorbent assay for determination of fluvastatin in plasma at picogram level. AB - For the first time, an enzyme-linked immunosorbent assay (ELISA) has been developed and validated for the determination of fluvastatin (FLV) in plasma samples at picogram level. The assay employed a polyclonal antibody that specifically recognizes FLV with high affinity, and FLV conjugate of bovine serum albumin (FLV-BSA) immobilized onto microplate wells as a solid-phase. The assay involved a competitive binding reaction between FLV, in plasma sample, and the immobilized FLV-BSA for the binding sites on a limited amount of the anti-FLV antibody. The bound anti-FLV antibody was quantified with horseradish peroxidase labeled second anti-rabbit IgG antibody (HRP-IgG) and 3,3',5,5' tetramethylbenzidine (TMB) as a substrate for the peroxidase enzyme. The concentration of FLV in the sample was quantified by its ability to inhibit the binding of the anti-FLV antibody to the immobilized FLV-BSA and subsequently the color intensity in the assay wells. The conditions for the proposed ELISA were investigated and the optimum conditions were employed in the determination of FLV in plasma samples. The assay limit of detection was 10 pg mL(-1) and the effective working range at relative standard deviations (RSD) of or = 25% or > or = 0.5 mg/dl after contrast media exposure. Logistic regression analysis was performed to evaluate the important factors related to CIN using four variables: age, pravastatin, pre-procedure serum creatinine, and contrast volume. RESULTS: CIN was observed in 36 patients (8.4%). Patients without pravastatin (p<0.01), high level pre-procedure serum creatinine (p<0.01), and high contrast volume (p=0.034) had a significantly higher incidence of CIN. Logistic regression analysis revealed that pravastatin treatment (chi(2)=6.549, p=0.011, odds ratio=0.34), pre-procedure serum creatinine (chi(2)=6.294, p=0.009, odds ratio=2.78), and contrast volume (chi(2)=4.484, p=0.034, odds ratio=1.01) were independently related to the decreased risk of CIN. CONCLUSIONS: Chronic pravastatin treatment before contrast media exposure was important for preventing CIN in patients with renal insufficiency. Also, reducing the dose of contrast media was important for preventing CIN in patients with high-baseline serum creatinine levels. PMID- 19782256 TI - Left ventricular diastolic dysfunction in the early stage of chronic kidney disease. AB - BACKGROUND: The disadvantageous effect of kidney dysfunction on left ventricular (LV) diastolic function is still unknown. METHODS: Forty non-chronic kidney disease (CKD) patients and 202 CKD patients, aged 40-89, were examined by standard echocardiography and the new modality of tissue Doppler imaging. All subjects were divided into 5 groups depending on their estimated glomerular filtration rate (GFR: ml/min/BSA). Classifications by GFR were defined as follows: group 1 (more than 90: normal subjects), group 2 (60-89), group 3 (30 59), group 4 (15-29) and group 5 (less than 15). RESULTS: There were no significant differences in LV systolic function among the groups. Mitral E velocity was significantly lower in groups 1-4 (p<0.01-0.02) compared with group 5. Mitral A velocity was higher in groups 2-5 (p<0.01-0.04) compared with group 1. The ratio of mitral E and A velocities (E/A) was significantly higher in group 1 (p<0.02-0.05) compared with groups 2-5. Deceleration time was significantly shorter in groups 1 and 2 (p<0.01-0.02) compared with groups 4 and 5. Furthermore, it was significantly lower in group 5 (p<0.01) compared with group 4. Early diastole velocity of mitral annulus (Ea) by tissue Doppler was also higher in group 1 (9.1+/-2.5; p<0.01-0.04) compared with group 2 (7.9+/-1.7), group 3 (7.9+/-1.6), group 4 (7.5+/-2.1), and group 5 (7.6+/-2.0). Severity of the kidney dysfunction appears to parallel with the rise of E/Ea significantly (p<0.02). A, E/A and Ea could differentiate between groups 1 and 2 with early stage of CKD. CONCLUSIONS: These data suggest that LV diastolic dysfunction was observed even in patients with early stages of chronic kidney dysfunction. Doppler indices combined with conventional and tissue Doppler methods could detect the subtle changes of diastolic function due to kidney dysfunction. PMID- 19782257 TI - Relationship between plaque composition and no-reflow phenomenon following primary angioplasty in patients with ST-segment elevation myocardial infarction- analysis with virtual histology intravascular ultrasound. AB - BACKGROUND: The angiographic no-reflow phenomenon after primary percutaneous coronary intervention (PCI) carries a poor prognosis in patients with ST-segment elevation myocardial infarction (STEMI). However, the type of plaque composition that associates with the angiographic no-reflow phenomenon remains unclear. METHODS: A total of 44 patients with STEMI were enrolled in this study. After thrombectomy with an aspiration catheter, virtual histology intravascular ultrasound (VH-IVUS) of the infarct-related vessel was performed. Patients were divided into two groups according to final thrombolysis in myocardial infarction (TIMI) flow grade at the completion of PCI procedure. Complete reperfusion group (CR-group) was defined as final TIMI flow grade 3, and no-reflow group (NR-group) was defined as final TIMI flow < or = 2. The relationship between plaque composition and angiographic no-reflow phenomenon was analyzed. RESULTS: The angiographic no-reflow phenomenon was observed in 20 individuals. The summation of the percentage of fibrofatty+necrotic core and fibrofatty+dense calcium was significantly higher in the NR-group. Receiver-operating characteristics analysis revealed that the summation of the volume and percentage of fibrofatty+necrotic core (> 20.1 mm(3), 26.2%) and fibrofatty+dense calcium (> 20.0 mm(3), 22.6%) predict the angiographic no-flow phenomenon. CONCLUSION: The fibrofatty-rich component with necrotic core or dense calcium derived from VH-IVUS is closely related to the angiographic no-reflow phenomenon observed in primary PCI. PMID- 19782258 TI - Contrast medium volume to estimated glomerular filtration rate ratio as a predictor of contrast-induced nephropathy developing after elective percutaneous coronary intervention. AB - BACKGROUND: Contrast-induced nephropathy (CIN) has been recognized as a serious complication of diagnostic coronary angiography and percutaneous coronary intervention (PCI), and has been associated with prolonged hospitalization and adverse clinical outcomes. A key step to minimize the risk for developing CIN is to identify patients at risk for CIN. METHODS AND RESULTS: We retrospectively investigated clinical factors associated with the development of CIN in 60 stable angina patients who had undergone elective PCI. The frequency of CIN was 13% (8/60). There were neither any significant differences in age, gender, baseline serum creatinine or hemoglobin levels, nor in the rate of diabetes mellitus between the CIN and the non-CIN group. However, the estimated glomerular filtration rate (eGFR) was significantly lower (40.4+/-11.4 mL/min/1.73 m(2) vs. 57.4+/-22.6 mL/min/1.73 m(2), p=0.044), and number of treated vessels (1.5+/-0.8 vs. 1.2+/-0.4, p=0.039) and stents used (2.1+/-0.6 vs. 1.4+/-0.6, p=0.007) were significantly higher in the CIN group. In addition, the amount of contrast medium was significantly larger (272+/-37 mL vs. 201+/-62 mL, p=0.003) and the contrast medium volume (CMV) to eGFR ratio (CMV/eGFR) was significantly greater (7.4+/-2.9 vs. 4.0+/-2.0, p=0.0001) in the CIN group. Stepwise regression analysis showed that the CMV/eGFR ratio was a significant independent predictor of CIN (p=0.035). At a cut-off point of >5.1, the CMV/eGFR ratio exhibited 87.5% sensitivity and 74.5% specificity for detecting CIN. CONCLUSION: The CMV/eGFR ratio could be a useful predictor of CIN developing after elective PCI. PMID- 19782259 TI - In patients with heart failure and non-ischemic heart disease, cardiac troponin T is a reliable predictor of long-term echocardiographic changes and adverse cardiac events. AB - BACKGROUND: The relationships between (1) serum concentration of cardiac troponin T (cTnT) and clinical hemodynamic profiles, (2) cTnT versus B-type natriuretic peptide (BNP) and long-term echocardiographic changes, and (3) cTnT versus BNP and echocardiographic changes, and rates of adverse cardiac events, have not been well elucidated. METHODS: Retrospective analysis of 100 consecutive patients with heart failure, left ventricular ejection fraction < 50%, and non-ischemic heart disease was performed. RESULTS: Baseline cTnT was > or = 0.01 ng/ml in 30 patients. By multiple variable logistic regression analysis, diabetes mellitus [DM; odds ratio (OR) 7.5; p=0.014], serum creatinine (OR 25.9; p=0.0157), and pulmonary capillary wedge pressure (PCWP; OR 1.12; p=0.0214) were independent predictors of baseline elevation of cTnT. At a follow-up of 40.6+/-20.6 months, echocardiograms and cTnT and BNP measurements were available in 93 patients, of whom 23 experienced an adverse cardiac event. By multiple variable analyses, elevated cTnT at follow-up was negatively correlated with echocardiographic improvements in cardiac function (OR 0.10; p=0.019), and was a significant predictor of adverse cardiac events after adjustment for covariables, including follow-up BNP and echocardiographic changes (hazard ratio 5.6; p=0.0046). CONCLUSIONS: DM, serum creatinine, and PCWP were correlated with elevated baseline serum cTnT concentrations. cTnT concentration during follow-up might be a surrogate marker of heart failure. PMID- 19782260 TI - Relationship between weather and onset of acute myocardial infarction: can days of frequent onset be predicted? AB - BACKGROUND: The aim of this study was to clarify the relationship between onset of acute myocardial infarction (AMI) and weather conditions, to determine whether days in which AMI onset is likely can be predicted. METHODS AND RESULTS: Of the 929 patients admitted to our hospitals in Kagoshima prefecture with AMI, subjects comprised 611 patients. Days of frequent onset (F-days) were defined as days with > or = 3 patients/day admitted for AMI, with days of non-frequent onset (N-days) defined as days with < 3 patients/day. Meteorological factors were measured, and daily differences in all parameters and intraday temperature differences on the onset day, and 1 and 2 days before onset were calculated. F-days were significantly associated with intraday temperature differences on the onset day (10.3 degrees C vs. 7.9 degrees C, p=0.005), 1 day before onset (10.7 degrees C vs. 7.9 degrees C, p=0.002), and 2 days before onset (11.3 degrees C vs. 7.9 degrees C, p=0.0001). A cutoff intraday temperature difference of > or = 9.4 degrees C on 1 and 2 days before onset was predictive of F-days with 89% sensitivity and 87% specificity. CONCLUSIONS: Intraday temperature differences offer a powerful predictor of F-days. Onset of AMI can be predicted based on weather conditions over the preceding 1-2 days. PMID- 19782262 TI - Vascular endothelial growth factor broadens lentivector distribution in the heart after neonatal injection. AB - For some applications, the success of gene therapy depends on the efficiency of gene transfer into target organs, however, delivery to many tissues is limited. Efforts have been made to improve the efficiency of gene transfer into target organs such as the brain by using mannitol or vascular endothelial growth factor (VEGF) prior to gene delivery, since these treatments have been reported to increase vascular permeability in experimental animals. Here, we investigated the effect of VEGF pretreatment of neonatal mice on the ability of injected lentivirus (LV)--engineering expression of firefly luciferase (luc)--to enhance the transduction of various organs, including the brain and heart. LV/luc was delivered to VEGF-treated neonatal mice via the temporal vein. Whole-body bioluminescence imaging (WBLI) of luciferase expression showed that VEGF pretreatment does not diminish transgene expression over time since it remained steady for up to 12 weeks. Ex vivo imaging of the organs and assessments of organ luciferase activity showed that VEGF pretreatment resulted in significantly increased luciferase expression not only in the heart, but also in the brain, lung, and kidney. This study shows that VEGF may have therapeutic importance to enhance the efficiency of viral gene delivery to the heart, as well as to other target organs. PMID- 19782261 TI - Significantly lower incidence of early definite stent thrombosis of drug-eluting stents after unrestricted use in Japan using ticlopidine compared to western countries using clopidogrel: a retrospective comparison with western mega studies. AB - BACKGROUND AND OBJECTIVES: The incidence of definite stent thrombosis (ST) after use of drug-eluting stents (DES), as defined by the Academic Research Consortium, is known to be lower in Japan than in western countries. However, a statistical difference in the incidence of early definite ST (EDST) associated with the unrestricted use of DES has not yet been documented. Therefore, the incidence of EDST in our Japanese institute after unrestricted use of DES was retrospectively compared with those reported in western mega-studies. METHODS AND RESULTS: During the 40 months from August 2004 to November 2007 (before approval of clopidogrel in Japan), DES were implanted in 3605 lesions in 1885 patients in our institute; lesion- and patient-associated percentages of DES use were 95.2% and 94.7%, respectively. Mean stent length per lesion was 33.2 mm, emergent procedures and ST-elevation myocardial infarctions made up 33.7% and 16.4% of the procedures, respectively, intravascular ultrasonography was used 96.0% of the time, a distal protection device for acute coronary syndrome was used 68.7% of the time, and the mean maximum inflation pressure was 19.5 atm. EDST was observed in five lesions (0.139%) in four patients (0.212%). The incidence of patient-associated EDST at our center was significantly lower than in four western mega-studies (0.736%, 66 of 8970 patients; 0.634%, 149 of 23,500; 0.595%, 52 of 8402; 0.997%, 20 of 2006) (p<0.05, <0.01, <0.05, <0.01, respectively, using a chi(2)-test). CONCLUSION: Due to differences in procedural approaches in Japan, the incidence of EDST after unrestricted use of DES was significantly lower than in western countries. PMID- 19782263 TI - Left ventricular transient ischemic dilation during dobutamine stress echocardiography predicts multi-vessel coronary artery disease. AB - BACKGROUND: We sought to explore the value of stress-induced transient ischemic dilation (TID) of the left ventricle during dobutamine stress echocardiography, to predict the presence of multi-vessel coronary artery disease as seen by coronary angiography. METHODS: We enrolled 60 patients referred to our stress echocardiography labs with ischemic-type chest pain or other symptoms suggestive of myocardial ischemia. All patients underwent resting and stress echocardiography employing the standard dobutamine stress protocol. TID ratio was defined as the ratio of left ventricular end-diastolic volume or end-systolic volume measured at peak stress, to that measured at rest (EDV ratio and ESV ratio, respectively). We enrolled 20 consecutive patients with normal response (control group) who were subsequently evaluated to develop normal limits for TID ratio, and 40 patients with ischemic response (study group) that comprised 20 consecutive patients without TID (group A) and 20 consecutive patients with TID (group B). Patients then underwent coronary angiography. RESULTS: Both EDV ratio and ESV ratio were significantly higher in groups A and B as compared to the control group (P<0.01 for both). Analysis of the receiver operating characteristic (ROC) curves identified the 1.12 cutoff value as the optimal cutoff value of TID ratio that best predicts three-vessel disease. Using this cutoff value, the ESV ratio was able to predict three-vessel disease with a sensitivity of 90%, specificity 84%, positive and negative predictive values of 85% and 89%, respectively. The mean number of vessels affected by significant stenosis was 1.8+/-0.83 in group A in comparison with 2.45+/-0.69 in group B (P<0.05). Among group B, both EDV ratio and ESV ratio were higher in female patients as compared to male ones. CONCLUSIONS: In patients undergoing dobutamine stress echocardiography, the occurrence of TID is both sensitive and specific to predict underlying three-vessel coronary artery disease. PMID- 19782264 TI - Cardioprotective effect of an L/N-type calcium channel blocker in patients with hypertensive heart disease. AB - BACKGROUND: Left ventricular (LV) diastolic dysfunction is related to increased cardiac sympathetic activity. We investigated the effect of cilnidipine, an L/N type calcium channel blocker, on LV diastolic function and cardiac sympathetic activity in patients with hypertensive heart disease (HHD) using radionuclide myocardial imaging. METHODS AND RESULTS: Thirty-two frame electrocardiography (ECG) -gated (99m)Tc-sestamibi (MIBI) myocardial single photon emission computed tomography (SPECT), and (123)I-metaiodobenzylguanidine (MIBG) imaging were performed before and 6 months after drug administration in 32 outpatients with HHD. Sixteen of the patients were treated with cilnidipine and the other 16 were treated with nifedipine retard. The parameters for assessing LV diastolic function evaluated using ECG-gated (99m)Tc-MIBI SPECT were peak filling rate (PFR), first-third filling rate (1/3FR), and time to peak filling (TPF). Cardiac sympathetic activity was assessed as early and delayed heart to mediastinum (H/M) ratios and a washout rate (WR), using (123)I-MIBG imaging. The PFR and 1/3FR significantly increased after 6 months of treatment with cilnidipine (p<0.05 for both), but did not with nifedipine retard. The H/M ratios significantly increased (p<0.05 for both) in conjunction with a decreased WR (p<0.05) in the cilnidipine group. Moreover, a significant positive correlation was seen between the rate of change in PFR and the rate of change in early and delayed H/M ratios in the cilnidipine group (p<0.05 for both). The same results were obtained for the relationship between the rate of change in 1/3FR and the rate of change in H/M ratios (p<0.05 for both). However, no such relationship was seen in the nifedipine group. CONCLUSION: These data indicate that cilnidipine seems to suppress cardiac sympathetic overactivity via blockade of N-type calcium channels and improves LV diastolic function in patients with HHD. PMID- 19782265 TI - Relationship between exercise tolerance and muscle strength following cardiac rehabilitation: comparison of patients after cardiac surgery and patients with myocardial infarction. AB - BACKGROUND AND PURPOSE: Previous studies have demonstrated that cardiac rehabilitation (CR) improves exercise tolerance and muscle strength in patients with myocardial infarction (MI) and in patients after cardiac surgery. However, the association between exercise tolerance and muscular strength following CR and the comparison of relationships among various disease categories has not been fully examined. The purpose of the present study was to assess the relationship between exercise tolerance and muscle strength following CR in patients after cardiac surgery and patients with MI. METHODS AND RESULTS: One hundred and four patients who participated in CR for 6 months were enrolled [post-cardiac valve surgery (VALVE), n=28; post-coronary artery bypass grafting (CABG), n=42; post acute MI, n=34]. The exercise tolerance, thigh/calf circumferences, and muscle strength were measured before and after CR. At the baseline, the thigh circumference was significantly smaller in the VALVE group than in the MI group. There were significant positive correlations between peak VO(2) and muscle torques of the lower muscles in all groups. After 6 months, peak VO(2) and muscle torque were significantly increased in all groups (p<0.001). A positive significant correlation between percent increases in peak VO(2) and muscular strength was observed in the VALVE group (r=0.51, p<0.01), but not in the other groups. In addition, the changes in peak VO(2) and calf circumference after CR were significantly higher in the VALVE group than in the MI group. CONCLUSIONS: These data suggest that exercise intolerance in patients after heart valve surgery may in part depend on decreased muscular strength. Further studies are needed to assess whether the strategy of increasing muscular strength of lower limb by programmed resistance training could be effective for improving exercise intolerance in patients after heart valve surgery and symptomatic patients with heart failure. PMID- 19782266 TI - Impact of intraoperative transesophageal echocardiography in cardiac and thoracic aortic surgery: experience in 1011 cases. AB - BACKGROUND: Although intraoperative transesophageal echocardiography (IOTEE) has been widely used in cardiovascular surgery, the exact incidence of abnormalities detected by IOTEE in each type of surgical procedure is still unclear. The aim of this study was to review our experiences of IOTEE, in patients who underwent different types of cardiovascular surgery and to evaluate the clinical usefulness of IOTEE. METHODS AND RESULTS: Our database of 1011 consecutive patients, who underwent cardiovascular surgery and IOTEE monitoring was reviewed. The incidence of abnormal findings was 115 of 1011 patients (11.4%), and the highest incidence was the appearance of new wall motion abnormalities after cardiopulmonary bypass. These findings influenced surgical decision-making in 59 of the evaluated 1011 patients (5.8%). CONCLUSIONS: IOTEE provides important intraoperative and postoperative information that may influence surgical decision-making in various cardiovascular surgeries. PMID- 19782267 TI - Intravenous administration of adenosine triphosphate disodium during primary percutaneous coronary intervention attenuates the transient rapid improvement of myocardial wall motion, not myocardial stunning, shortly after recanalization in acute anterior myocardial infarction. AB - BACKGROUND AND PURPOSE: Administration of adenosine attenuates myocardial stunning after reperfusion in a canine experimental ischemic model. However, it is unknown whether administration of adenosine triphosphate disodium (ATP) during reperfusion can attenuate myocardial stunning after coronary recanalization in patients with acute myocardial infarction (MI). Therefore, we sought to elucidate the effects of ATP administration on serial changes of left ventricular systolic function before and after coronary recanalization. METHODS: In 27 patients with first ST-elevation acute anterior MI, in whom primary percutaneous coronary intervention (PCI) was completed within 10 h after symptom onset, ATP at a mean rate of 103 microg/kg/min (n=16) or normal saline (n=11) was intravenously administered for 1 h during reperfusion. Left ventricular regional wall motion within the initially severely ischemic region was serially analyzed using the standard wall motion score index (WMSI) by transthoracic echocardiography. RESULTS: Means of WMSIs were similar shortly before primary PCI in both groups (2.79 in ATP group and 2.69 in controls). They changed to 2.56 and 2.22 shortly after PCI, 2.49 and 2.39 on day 2, 2.34 and 2.30 on day 3, 2.19 and 2.25 on day 10, and 1.85 and 2.02, 6 months later, respectively. Transient improved regional wall motion within the initially severely ischemic region was observed shortly after PCI in controls (10.3% of observed segments); however, it was significantly suppressed in the ATP group (2.55%). The percent recovery of WMSI on day 10, which was defined as WMSI on day 10 normalized by improvement of WMSI for 6 months, was 63.8% in ATP group and 65.7% in controls, implying ATP administration could not reduce myocardial stunning by day 10 after primary PCI. CONCLUSIONS: The high-dose administration of ATP during primary PCI prevented transient improved wall motion shortly after coronary recanalization rather than preventing left ventricular stunning. These results suggest that ATP can prevent reperfusion injury during primary PCI. PMID- 19782268 TI - A novel clinical course of free-floating left atrial ball thrombus without mitral stenosis treated by anticoagulants. AB - Free-floating left atrial ball thrombus is rare. We describe a case of a 48-year old man who had free-floating left atrial ball thrombus that was not accompanied by mitral stenosis and that was treated aggressively with anticoagulants. Echocardiography revealed dramatic disappearance of the thrombus. PMID- 19782269 TI - Cough syncope induced by gastroesophageal reflux disease. AB - A 52-year-old Japanese man was admitted to our hospital for evaluation of syncope and convulsions. An electrocardiogram on admission revealed normal sinus rhythm. However, after repeated bouts of coughing, the heart rate showed bradycardia associated with convulsion. He was diagnosed with cough syncope secondary to laryngopharyngitis, which was caused by gastroesophageal reflux disease (GERD). Once the patient was administrated lansoprazole (Takeda Pharmaceutical Co., Osaka, Japan) for GERD, the syncope disappeared. The causes of syncope are diverse and may manifest in disorders of different organ systems in the body. Therefore, clinicians should perform a careful whole body examination to obtain the correct diagnosis. PMID- 19782270 TI - Free-floating thrombus in the right common carotid artery. AB - We report the case with type A acute aortic dissection that vascular echo disclosed a free-floating thrombus in the right common carotid artery. PMID- 19782271 TI - Thrombo-occlusion of inferior vena cava filter in a patient with polycythemia vera. AB - This is a case of a thrombo-occlusion occurring below an inferior vena cava (IVC) filter inserted in a patient with polycythemia vera and deep vein thrombosis. The patient was a 48-year-old man with polycythemia vera and a chief complaint of swelling, redness, and bursting pain in his right leg. After admission, contrast enhanced computed tomography scanning demonstrated a pulmonary artery thrombus and deep vein thrombosis. We inserted a Gunther tulip vena cava filter on day 1 for the prevention of pulmonary embolism (PE), and started anticoagulation therapy based on the guideline of the Japanese Circulation Society for DVT. In addition to intravenous anticoagulants, we started therapeutic phlebotomy to improve the hypercoagulability state. On day 4, our patient complained of back pain caused by thrombo-occlusion below the IVC filter, despite the anticoagulation therapy and two therapeutic phlebotomies. From this case, we concluded it is important to lower hemoglobin level and hematocrit as early as possible for IVC-filter-insertion in patients with polycythemia vera. PMID- 19782272 TI - Case of transient mid-ventricular ballooning syndrome with a rapid and uncommon recovery. AB - A 60-year-old woman presented with acute pulmonary edema followed by cardiopulmonary arrest due to idiopathic ventricular fibrillation. Owing to immediate cardioversion, her electrocardiogram showed sinus rhythm and echocardiography did not show any wall motion abnormalities. The next day, echocardiographic re-examination was characterized by akinesis of both apical and mid segments of the left ventricle. One hour later, subsequently performed coronary angiography revealed non-occlusive coronary artery disease, but left ventriculography demonstrated only akinesis of mid-ventricular segment with hypercontractile other segments. Further echocardiographic investigation on the following day showed total resolution of left ventricular wall motion abnormalities. The diagnosis of mid-ventricular ballooning syndrome was made according to the findings of left ventriculography. In this case, the time course changes of both patient's pathophysiological condition and echocardiographic wall motion from the onset to recovery are rapid and uncommon. PMID- 19782273 TI - Congenitally severe tortuous circumflex artery fistula draining into the coronary sinus: transcatheter closure with Guglielmi detachable coils via different delivery system. AB - Coronary artery fistulae are very rare congenital anomalies which constitute 0.2 0.4% of all congenital heart diseases. The right chambers of the heart are the most frequent communication site of the coronary fistulae and may cause hemodynamic impairment in the coronary circulation. The fistulae arise frequently from right coronary and left anterior descending arteries. Fistulae from left circumflex artery are very rare. We report a case in which transcatheter embolization was performed with 3-mm Guglielmi detachable coils in a young adult with a rare type of congenital fistula originating from the circumflex artery and draining into the coronary sinus. PMID- 19782274 TI - Percutaneous coronary intervention for a single coronary artery arising from the right sinus of Valsalva. AB - We describe a 67-year-old woman who presented with acute lateral myocardial infarction. Coronary angiography demonstrated a single coronary artery along with the left anterior descending and left circumflex arteries that originated from proximal branches of the right coronary artery, which arose from a normal ostium in the right sinus of Valsalva. Percutaneous coronary intervention (PCI) was performed to treat 99% stenosis with a filling defect in the midportion of the left circumflex artery. This extremely rare coronary anomaly was successfully treated by PCI. PMID- 19782275 TI - Giant mediastinal thymolipoma simulating cardiomegaly. AB - Thymolipomas are rare anterior mediastinal tumors composed of mature adipose tissue and benign thymic tissue and they may rarely simulate cardiomegaly on chest radiograph. We report an adult male who presented with progressive dyspnea of 2 months' duration. Clinical examination was unremarkable. Chest radiograph showed enlarged cardiac silhouette. Computed tomography of chest revealed a giant anterior mediastinal noncontrast enhancing mass partially wrapping around the heart. A needle biopsy obtained lymphomatous material that was diagnosed as thymolipoma. The tumor was successfully removed en bloc through a median sternotomy. Histopathological examination confirmed thymolipoma. We emphasize the importance of considering mediastinal tumors as a differential diagnosis in patients with progressive dyspnea without any obvious cause and chest radiograph showing enlarged cardiac silhouette. PMID- 19782276 TI - Fulminant fatal cardiotoxicity following cyclophosphamide therapy. AB - A 59-year-old male with an abdominal mass that showed a diffuse large B cell lymphoma underwent extirpation of the tumor and chemotherapy. He subsequently received high-dose chemotherapy containing cyclophosphamide (1.5 g/m(2)/day x 2 days), followed by autologous peripheral blood stem cell transplantation. He developed congestive heart failure 5 days after administration of cyclophosphamide. His electrocardiogram showed extremely low voltage with ST segment change and echocardiogram showed diffusely increased left ventricular wall thickness, an increase in myocardial echogenicity, pericardial effusion, and generally decreased systolic function. Congestive heart failure progressed rapidly and he died the following day. Post-mortem examination of the heart revealed myocardial hemorrhage, yellowish brown pericardial effusion, and fibrinous pericarditis. His liver was atrophic and focal necrosis was observed histologically. Cyclophosphamide-induced cardiotoxicity occurred, even though the patient had both shown normal cardiac function before high-dose chemotherapy and had received a lower dose of cyclophosphamide. Concomitant administration of cytarabine might have affected his liver function and there might have been interaction between the drugs. PMID- 19782277 TI - Extraordinary cause of ischemic chest pain in a young man: congenital ostial atresia of the right coronary artery. AB - Chest pain in a young person without cardiovascular risk factors is usually attributed to noncoronary causes; however, if the history suggests ischemic pain, the potential presence of unusual cardiovascular abnormalities should not be disregarded. The present case describes a young man with solitary congenital ostial atresia of right coronary artery, who to our knowledge is only the second case in the medical literature. Manifestation of ischemic symptoms in a relatively advanced age in patients with coronary artery atresia may mislead clinicians to interpret them as signs of atherosclerotic coronary artery disease. Therefore congenital coronary artery atresia should be a part of the differential diagnosis particularly in young patients with ischemic symptoms and no cardiovascular risk factors. PMID- 19782278 TI - Echocardiographic progression of a subepicardial aneurysm after inferior myocardial infarction. AB - A 62-year-old man presented to hospital with chest oppression. Coronary angiography revealed total occlusion of the right coronary artery and inferior myocardial infarction was diagnosed. He was treated by percutaneous coronary intervention with stenting for myocardial infarction. After four months, echocardiography revealed a huge aneurysm protruding below the inferior surface of the left ventricle. It was considered to be a pseudoaneurysm from the echocardiographic findings. The patient had no symptoms and he refused surgery, so progression of the aneurysm was monitored carefully. At seven months after revascularization, the aneurysm showed a marked increase in size, with a maximal diameter of 48 mm and orifice diameter of 22 mm. Accordingly, the patient agreed to undergo surgical excision. The aneurysm was resected and the defect was closed with a pericardial patch. Pathological examination revealed all of the myocardial elements in the aneurysm wall and thrombus in its lumen. In conclusion, this was a rare case of ventricular subepicardial aneurysm. PMID- 19782279 TI - Neopterin and coronary artery disease. PMID- 19782281 TI - Scientific Registry of the International Society for Heart and Lung Transplantation: introduction to the 2009 Annual Reports. PMID- 19782282 TI - Registry of the International Society for Heart and Lung Transplantation: Twelfth Official Pediatric Heart Transplantation Report-2009. PMID- 19782283 TI - Registry of the International Society for Heart and Lung Transplantation: Twenty sixth Official Adult Heart Transplant Report-2009. PMID- 19782284 TI - Registry of the International Society for Heart and Lung Transplantation: Twelfth Official Pediatric Lung and Heart/Lung Transplantation Report-2009. PMID- 19782285 TI - The Registry of the International Society for Heart and Lung Transplantation: Twenty-sixth Official Adult Lung and Heart-Lung Transplantation Report-2009. PMID- 19782286 TI - Cytomegalovirus immunoglobulin decreases the risk of cytomegalovirus infection but not disease after pediatric lung transplantation. AB - BACKGROUND: Cytomegalovirus (CMV) has been associated with morbidity, including chronic allograft rejection, in transplant recipients. Data from adult centers suggests that CMV hyperimmune globulin (CMVIG) and ganciclovir together are superior in preventing CMV viremia than ganciclovir alone. METHODS: A retrospective review of pediatric lung transplant recipients at 14 sites in North America and Europe was conducted to evaluate the effect of adding cytomegalovirus immunoglobulin (CMVIG) prophylaxis to at least 3 weeks of intravenous ganciclovir therapy in pediatric lung transplant recipients. Data were recorded for the first year after transplantation. Associations between time to CMV and risk factors, including CMVIG use, were assessed by multivariable Cox proportional hazards models. RESULTS: Of 599 patients whose records were reviewed, 329 received at least 3 weeks of ganciclovir, with 62 (19%) receiving CMVIG. CMVIG was administered more frequently with CMV donor-positive/recipient-negative serostatus (p < 0.05). In multivariable models, patients who did not receive CMVIG as part of their prophylaxis were 3 times more likely to develop CMV infection (hazard ratio, 3.4; 95% confidence interval, 1.2-9.5) independent of CMV serostatus. However, CMVIG administration was not associated with decreased risk of episodes of CMV disease. Receipt of CMVIG was not associated with decreased risks of post-transplant morbidities (acute rejection, respiratory viral infection or early bronchiolitis obliterans) or morbidity within the first year after pediatric lung transplantation. CONCLUSION: The use of CMVIG in addition to antiviral prophylaxis in pediatric lung transplantation requires further evaluation. PMID- 19782287 TI - Transforming growth factor-beta polymorphisms and cardiac allograft rejection. AB - BACKGROUND: Cytokine gene polymorphisms regulate cytokine expression. We analyzed transforming growth factor-beta (TGF-beta) allelic variation in codon 25 in susceptibility to acute rejection episodes in cardiac transplant recipients. METHODS: Between June 1997 and December 2001, 123 de novo heart transplants were performed at UAB with analysis based on 109 patients. Clinical and laboratory data were recorded at intervals up to 1 year post-transplant. Recipient genotypes for TGF-beta (codon 25) were determined using polymerase chain reaction (PCR) sequence-specific primers. Correlations between TGF-beta genotypes and acute rejection were made using Kaplan-Meier plots and parametric hazard models. RESULTS: Of the patients enrolled, 72% had at least one rejection and 46% had multiple rejections in the first year post-transplant. Among those > or =55 years of age at transplant, patients with the GG genotype had significantly fewer rejections as compared to those with the CC or GC genotype (1.25 vs 2.5, p < 0.01). There was no difference in risk of rejection between the genotype groups among patients <50 years of age at transplant (p = 0.43). Similar results were observed when we used time to cumulative Grade 2R or greater rejection as the outcome. CONCLUSION: The GG TGF-beta genotype may protect against acute rejection in older recipients during the first year after transplant. PMID- 19782288 TI - Impact of donor-recipient race matching on survival after lung transplantation: analysis of over 11,000 patients. AB - BACKGROUND: Few studies have examined the effect of race in lung transplantation (LTx). The United Network for Organ Sharing (UNOS) database provides an opportunity to examine outcomes of race matching for a large cohort of patients. METHODS: We retrospectively reviewed UNOS data for 11,323 adults receiving primary LTx (1997 to 2007). Patients were stratified by donor-recipient race matching and divided into groups of specific race. All-cause mortality was examined with Cox proportional hazards regression incorporating 19 covariates. Short-term mortality (30 days, 90 days, 1 year and 2 years) and rejection in the first year were examined. RESULTS: Of 11,323 patients, 7,414 (65%) were race matched, including 7,104 (71%) Caucasians, 184 (22%) African Americans, 117 (28%) Hispanics and 9 (11%) Asians. During the study, 4,862 (43%) patients died. Race matching decreased the 30-day, 90-day, 1-year and 2-year unadjusted mortality. Race matching decreased risk-adjusted cumulative mortality (hazard ratio 0.88, 95% confidence interval 0.80 to 0.96, p = 0.006). Kaplan-Meier modeling showed that race matching significantly improved survival. Race matching did not impact rejection in the year after LTx. When deaths in the first year were censored, race matching no longer affected cumulative survival. Donor African American race conferred an increased risk of death, regardless of recipient race. CONCLUSIONS: Our study represents the largest cohort evaluating the effect of race matching in LTx. Race matching resulted in an improvement in long-term survival. This improvement appears to manifest in the 2 years after LTx. PMID- 19782289 TI - Higher rate of comorbidities after cardiac retransplantation contributes to decreased survival. AB - BACKGROUND: Cardiac retransplantation is the definitive treatment for allograft failure despite decreased long-term survival in these patients. The cause of the poorer outcomes in cardiac retransplant patients is unclear. METHODS: This study was a retrospective analysis of 859 adult cardiac transplant patients. Of these, 45 (5.7%) underwent cardiac retransplantation at 8.2 +/- 5.3 (mean +/- SD) years after the first transplant, primarily for severe transplant vasculopathy (n = 42). RESULTS: One-year survival for retransplant patients was significantly lower compared with de novo transplant patients (75% vs 87%; p < 0.003). Twenty-three patients died due to either malignancy (n = 8), infection (n = 6), rejection (n = 3), sudden death (n = 2), recurrent transplant coronary artery disease (n = 2) or post-operative bleeding (n = 1). CONCLUSION: Although cardiac retransplantation has immediate life-saving benefits, survival is lower compared with de novo cardiac transplantation due to higher rates of malignancy and infection. PMID- 19782291 TI - Increased CD62e(+) endothelial microparticle levels predict poor outcome in pulmonary hypertension patients. AB - BACKGROUND: Endothelial and leukocytes-derived microparticles (EMPs and LMPs, respectively) are increased in patients with pulmonary hypertension (PH). We hypothesized that the levels of circulating EMPs and LMPs could predict outcome in these patients. METHODS: Patients undergoing right heart catheterization for untreated pre-capillary PH were eligible for the study. Baseline hemodynamics and biologic and clinical parameters were measured at the time of enrollment. Measurements of CD62e(+), CD144(+) and CD31(+)/CD41(-) EMPs and CD45(+) LMPs were performed using flow cytometry in venous platelet-free plasma samples. After inclusion, patients were treated at the discretion of the physician and prospectively followed for 12 months. The primary end-point was the combined occurrence of death and re-admission for right heart failure (RHF) or worsening of RHF symptoms. RESULTS: Seven of 21 patients (mean age 54.1 +/- 3.5 years, 62% female) experienced the primary end-point during the study period. These patients had higher baseline levels of CD62e(+) EMPs, LMPs and hsCRP (high sensitivity C reactive protein) compared to patients without events (p < 0.05), whereas no difference was observed for other microparticles and functional and hemodynamics parameters. Receiver operating curve analysis showed that baseline CD62e(+) EMPs levels of >353 events/microl predicted clinical complications. Kaplan-Meier analysis revealed that patients with baseline CD62e(+) EMPs above this cut-off value had a significantly worse prognosis compared with those subjects who had levels below this cut-off (p = 0.02, log-rank statistics). CONCLUSIONS: Elevated levels of circulating CD62e(+) EMPs but not LMPs in PH patients prior to treatment are associated with adverse clinical events. Assessment of CD62e(+) EMPs levels may represent a new tool for stratification of PH patients. PMID- 19782290 TI - Transfer of cholesterol and other lipids from a lipid nanoemulsion to high density lipoprotein in heart transplant patients. AB - BACKGROUND: Beyond the first year after a heart transplant (HT) procedure, patients often develop dyslipidemias, which may be implicated in the genesis of transplant coronary heart disease. High-density lipoprotein (HDL) has a several anti-atherogenic properties, but the status of HDL in HT patients is still controversial. Nonetheless, determination of HDL cholesterol concentration is not sufficient for evaluation of the overall HDL protective role. In this study, a fundamental functional property of HDL, the ability to simultaneously receive the major lipid classes, was tested in HT patients. METHODS: Twenty HT patients and 20 healthy normolipidemic subjects paired for gender, age and body mass index were studied. Blood samples were collected after 12-hour fasting for determination of plasma lipids, glucose, paraxonase 1 (PON 1) activity, HDL diameter and transfer of labeled lipids from an artificial nanoemulsion to HDL. RESULTS: Plasma triglycerides (159 +/- 63 vs 94 +/- 35 mg/dl) and glucose (104 +/ 20 vs 86 +/- 10 mg/dl) were greater in HT patients than in control subjects. HDL cholesterol was lower and HDL diameter was smaller in the HT group (HDL cholesterol: 44 +/- 11 vs 55 +/- 15 mg/dl; HDL diameter: 8.8 +/- 0.6 vs 9.0 +/- 1.2 nm). PON 1 activity did not differ (87 +/- 47 vs 75 +/- 37 nmol/min/ml). The transfer rates of free cholesterol and cholesteryl esters were diminished in HT patients (HT: 8.4 +/- 1.2% and 3.8 +/- 0.6%; controls: 9.7 +/- 1.9% and 4.7 +/- 1.2%, respectively). CONCLUSIONS: The transfer of free cholesterol and cholesteryl esters to HDL is diminished in HT patients; disturbance in the ability of HDL to receive lipids may affect the anti-atherogenic properties of the lipoprotein. PMID- 19782292 TI - Alteration of matrix metalloproteinases in selective left ventricular adriamycin induced cardiomyopathy in the pig. AB - INTRODUCTION: Anthracyclines are widely used in oncogenic therapy. Owing to their cardiotoxic side effects, their application is subdued to dose limitations. Many cardioprotective approaches have failed. This study examined the role of matrix metalloproteinases (MMP) in the remodeling process of extracellular matrix after treatment with doxorubicin (Adriamycin) as a toehold for a new therapeutic approach, for example, treatment with MMP inhibitors. METHODS: Severe heart failure was induced in 6 pigs by the repetitive intracoronary application of Adriamycin. Degree of dilatation and insufficiency were measured by echocardiography and hemodynamics. Before and after treatment, MMP activity (fluorogenic assay: MMP-1, MMP-2) and gene expression (reverse transcription polymerase chain reaction [RT-PCR]: MMP-1, -2, -9; membrane type-1 matrix metalloproteinase, [MT1MMP]; tissue inhibitor of metalloproteinase 1 [TIMP-1]) were measured. Spatial distribution of MMP-1, MMP-2, and collagen were visualized in antibody-stained frozen sections. One-way analysis of variance was used for data analysis. RESULTS: Severe myocardial insufficiency (ejection fractions < 50% of baseline values) developed in all animals. No severe side effects were encountered. We found a strong activation of MMP-1 and MMP-2 in fluorogenic and PCR assays. RT-PCR revealed a significant activation of MMP-9 and MT1-MMP and a weaker induction of TIMP-1. Histology showed typical signs of myocardial fibrosis, with myocardial cell loss, collagen disorder, and vacuoles. CONCLUSION: We showed a strong transcriptional activation for several specific MMPs in Adriamycin-induced cardiac remodeling. Contrary to published data on myocardial infarction, early inhibitory therapy before myocardial injury is possible in Adriamycin-treated patients. Local application by our catheter-based system would additionally help to avoid systemic side effects. PMID- 19782294 TI - A novel and knotless technique for heterotopic cardiac transplantation in mice. AB - BACKGROUND: The development of microsurgical techniques has facilitated the establishment of fully vascularized cardiac transplantation models in small mammals. Anastomotic stenosis and bleeding continue to hamper procedures and limit long-term graft survival. In this study we assess a novel technique to improve outcome after cardiac transplantation in mice. METHODS: Our novel technique of murine heterotopic cardiac transplantation consists of three critical steps: (i) a novel procedure for graft harvest; (ii) a modified method for recipient vessel preparation; and (iii) a novel suturing procedure for graft implantation. Importantly, a new knotless suturing technique for end-to-side vascular anastomosis was applied, which allows for adjustment of the anastomosis after transplantation, thus reducing the risk of anastomotic bleeding or stenosis. RESULTS: The recipient survival rate based on this novel technique was between 90% and 98%, depending on physician expertise. Graft implantation time varied between 20 and 25 minutes after the initial 200 training cases. In comparing the standard knot microvascular suturing technique to the new knotless technique carried out by an experienced surgeon, the latter was found to be more efficient by significantly reducing the rate of anastomotic stenosis (0% vs 8% with knot, p < 0.001, n = 200) and anastomotic bleeding (2% vs 7% with knot, p < 0.05, n = 200). CONCLUSIONS: This novel technique offers a rapid, easy and effective method for murine heterotopic cardiac transplantation. PMID- 19782293 TI - Role of large-conductance calcium-activated potassium channels of coronary arteries in heart preservation. AB - BACKGROUND: Large-conductance calcium-activated potassium channels (BK(Ca)) of vascular smooth muscle cells (VSMCs) play an important role in the regulation of vascular tone. We tested the hypotheses that the alteration of arterial relaxation after exposure to ischemia or hyperkalemia is attributable to the alteration in the activities of BK(Ca) by using the patch-clamp technique and force measurement. METHODS: VSMCs were enzymatically isolated from porcine coronary arteries, with the primary cultures used for patch-clamp study. BK(Ca) currents were recorded in a whole-cell configuration (n = 5 in each group). The BK(Ca) activator NS1619 (-7 to -4.5 logM)-induced relaxation was studied myographically in small porcine coronary arteries (n = 6 per group). The effects of global ischemia for 1 hour and hyperkalemia (20 to 120 mmol/liter) were tested. RESULTS: Ischemia for 1 hour markedly reduced the BK(Ca) current from 119.8 +/- 11.4 pA/pF to 86.0 +/- 3.7 pA/pF (p < 0.05). The rise of extracellular K(+) resulted in increased BK(Ca) currents in a concentration-dependent manner (5.4 mmol/liter: 31.6 +/- 3.4 pA/pF; 20 mmol/liter: 73.6 +/- 11.4 pA/pF; 60 mmol/liter: 108.6 +/- 20.6 pA/pF; 120 mmol/liter: 135.2 +/- 20.5 pA/pF; p < 0.05). NS1619-induced relaxation was suppressed by ischemia (71.4 +/- 2.2% vs 95.3 +/- 1.6%; p < 0.01) and was inferior in K(+) pre-contraction, as compared with U(46619) (a thromboxane A(2) mimetic) pre-contraction (p < 0.05). CONCLUSIONS: In coronary circulation: (1) the BK(Ca) current density and related vasorelaxation are reduced after ischemia; and (2) hyperkalemia induces dual effects; the depolarization obscures the compensatory increase of the BK(Ca) activity. These findings imply that BK(Ca) activators may be used in cardioplegia or heart preservation solutions to protect the function of this ion channel. PMID- 19782295 TI - Living-donor lobar lung transplantation and closure of atrial septal defect for adult Eisenmenger's syndrome. AB - A 38-year-old woman with Eisenmenger's syndrome underwent bilateral living-donor lobar lung transplantation and simultaneous closure of atrial septal defect. The grafts were a right lower lobe from her husband and a left lower lobe from her brother. Although only 2 lobes were implanted, the dramatic improvement in pulmonary hemodynamics has been well maintained for more than 5 years. Living donor lobar lung transplantation and simultaneous cardiac repair may be one of the therapeutic options for patients with adult Eisenmenger's syndrome with simple congenital heart disease. PMID- 19782296 TI - Congenital pulmonary artery stenoses masquerading as chronic thromboembolic disease. AB - Stenotic pulmonary vascular lesions, often amenable to balloon angioplasty, can erroneously appear to suggest chronic thromboembolic disease on ventilation/perfusion (V/Q) scan. We report a case of multiple peripheral pulmonary artery stenoses and describe radiologic findings and treatment options. PMID- 19782297 TI - Pancreatic gout masquerading as pancreatic cancer in a heart transplant candidate. AB - In this report, a case is presented of a patient with advanced heart failure who had asymptomatic pancreatic gout, which masqueraded as metastatic pancreatic cancer. This unusual presentation of gout was important to recognize, as the presence of a pancreatic cancer would have precluded cardiac transplantation in an otherwise suitable candidate. PMID- 19782298 TI - Heart transplantation for ventricular arrhythmia caused by a rare hamartoma. AB - Hamartoma of mature cardiac myocytes is a form of cardiac tumor that shares some features with hypertrophic cardiomyopathy and rhabdomyomas. Here we describe a patient with a ventricular hamartoma complicated with ventricular tachycardia. Resection was not practical because of difficulty in maintaining the ventricular geometry, so heart transplantation was done. PMID- 19782299 TI - Intermediate-term outcome in lung transplantation from a donor with glioblastoma multiforme. AB - A 19-year-old man with cystic fibrosis, who was on extracorporeal membrane oxygenation, underwent bilateral lung transplantation from a donor with glioblastoma multiforme. Because the risk of tumor transmission from donor related central nervous system malignancies remains unclear, the use of these extended donors remains controversial. In fact, there are few reports on the outcomes of lung transplantation from donors with central nervous system malignancy. This patient was critically ill with extracorporeal membrane oxygenation support before transplantation, but is well without any sign of malignancy 20 months after transplantation. PMID- 19782300 TI - Gastrointestinal motility disorders. Preface. PMID- 19782301 TI - Development of the enteric nervous system and its role in intestinal motility during fetal and early postnatal stages. AB - Motility patterns in the mature intestine require the coordinated interaction of enteric neurons, gastrointestinal smooth muscle, and interstitial cells of Cajal. In Hirschsprung's disease, the aganglionic segment causes functional obstruction, and thus the enteric nervous system (ENS) is essential for gastrointestinal motility after birth. Here we review the development of the ENS. We then focus on motility patterns in the small intestine and colon of fetal mice and larval zebrafish, where recent studies have shown that the first intestinal motility patterns are not neurally mediated. Finally, we review the development of gastrointestinal motility in humans. PMID- 19782302 TI - The histopathology of gastrointestinal motility disorders in children. AB - Gastrointestinal motility disorders and chronic constipation are common pediatric problems. Symptoms of abdominal discomfort are frequently encountered in the daily practice of pediatricians and pediatric surgeons. Normal peristalsis depends on the interaction between muscles, nerve cells, and tendinous connective tissue of muscularis propria. Malfunction of any of these components results in a motility disorder. Aganglionosis, typically of the left distal colon, is the cause of Hirschsprung disease. Hypoganglionosis constitutes another gastrointestinal motility disorder. In hypoplastic hypoganglionosis, the number of nerve cells and the size of ganglia of the enteric nervous system are reduced, resulting in symptoms similar to aganglionosis. In intestinal neuronal dysplasia type B, submucous plexus development is disturbed. Immaturity of the enteric nervous system, but also ganglioneuromatosis, can be the underlying cause of chronic constipation. Chronic constipation may be caused by a myopathy. Aplasia or atrophy of the tendinous connective tissue of muscularis propria may cause desmosis, which may result in an aperistaltic syndrome. In severe chronic constipation, a histopathological diagnosis of the underlying cause is useful. In the diagnostic approach for most of these causes of chronic constipation, enzyme histochemistry is an efficient tool to complement conventional immunohistochemical and selected molecular technologies. An interdisciplinary approach of a gastrointestinal working group is beneficial in the management of these difficult patients. PMID- 19782303 TI - Practical pathology and genetics of Hirschsprung's disease. AB - Diagnosis and management of Hirschsprung's disease (HSCR) requires understanding of the malformation's anatomic features and multigenic nature. Rectal biopsies, intraoperative frozen sections, and resection specimens provide invaluable information. Extraction of these data requires thoughtful biopsy technique, adequate histologic sections, histochemistry, and collaboration of surgeon and pathologist. Critical consideration of transition zone anatomy and published studies of "transition zone pull through" indicate that more research is needed to determine how much ganglionic bowel should be resected from HSCR patients. Many HSCR-susceptibility genes have been identified, but mutational analysis has limited practical value unless family history or clinical findings suggest syndromic HSCR. PMID- 19782304 TI - Clinical management of motility disorders in children. AB - We review the current clinical evaluation and management of the most common esophageal and gastrointestinal motility disorders in children based on the literature and our experience in a pediatric motility center in the United States. The disorders discussed include esophageal achalasia, pre- and post fundoplication motility disorders, gastroparesis, motility disorders occurring after repair of congenital atresias, motility disorders associated with gastroschisis, chronic intestinal pseudo-obstruction, motility after intestinal transplantation, motility disorders after colonic resection for Hirschsprung's disease, chronic functional constipation, and motility disorders associated with imperforate anus. PMID- 19782305 TI - Omega-3 lipids for intestinal failure associated liver disease. AB - Intestinal failure associated liver disease (IFALD) is one of the most common and devastating complications in infants with intestinal failure. Although multifactorial, its pathophysiology is clearly related to the administration of parenteral nutrition (PN), with a recent focus on the role of PN lipid emulsions. This paper will review the evidence for the use of omega-3 fatty acid PN lipid emulsions, which are proposed to have efficacy in the treatment of IFALD. Mechanisms explaining their effects will be considered as will future research directions. PMID- 19782306 TI - Internal anal sphincter achalasia. AB - Internal anal sphincter (IAS) achalasia is a clinical condition with presentation similar to Hirschsprung's disease, but with the presence of ganglion cells on rectal suction biopsy. The diagnosis is made by anorectal manometry, which demonstrates the absence of the rectosphincteric reflex on rectal balloon inflation. The IAS is regulated by several neurogenic mechanisms, and so its pathogenesis is thought to be multifactorial, including the absence of nitrergic innervations, defective innervation of the neuromuscular junction, and altered distribution of interstitial cells of Cajal. The recommended treatment of choice is posterior IAS myectomy. Recently, however, the use of intrasphincteric botulinum toxin has been used to treat this condition, but further long-term studies are needed to determine its effectiveness. PMID- 19782307 TI - The dilated bowel: a liability and an asset. AB - The gastrointestinal tract responds to significant mechanical or functional obstruction by dilatation and hypertrophy of the segment proximal to the obstruction. Excessive dilatation compromises motility, and absorption and is associated with considerable morbidity (intraluminal stasis, sepsis) such that bowel dilatation represents a major liability that predisposes the patient to intestinal failure. The dilated bowel proximal to an obstruction provides valuable autologous material for reconstruction with "tissue appropriate to the part." Bowel elongation and dilatation are integral to the natural intestinal adaptation response to loss of small bowel and can also be induced through a structured "Bowel Expansion" program. The additional absorptive tissue that is progressively generated is essential for reconstruction of the bowel (tailoring and lengthening), to restore gastrointestinal dynamics (effective propulsion and absorption), and to reduce morbidity (intraluminal stasis, sepsis). In enhancing the prospects for enteral autonomy, dilatation and elongation of the residual autologous bowel are crucial to long-term survival and good quality life, and represent a most welcome asset. This paper reviews the impact and management of bowel dilatation along the gastrointestinal tract. PMID- 19782308 TI - Intestinal transplantation for motility disorders. AB - Intestinal transplantation (ITx) has now become an accepted form of replacement therapy for intestinal failure (IF) and its complications. Disorders of bowel motility may represent up to 25% of patients on waiting lists for ITx. Some patients with short bowel as a cause for IF may also have dysmotile bowel. Underlying pathology of the intestine is heterogeneous and may be due to abnormalities in the nerve supply, intestinal smooth muscle, or may be regarded as idiopathic (chronic intestinal pseudo-obstruction). Outcome after ITx for dysmotility has previously been guarded, but providing the appropriate graft is used and taking into account the functional motility of residual bowel, it should not be different from other indications. The subject is reviewed emphasizing the potential pitfalls in case selection and management. The results of the ITx unit in Birmingham, UK are briefly reviewed. PMID- 19782309 TI - Potential of cell therapy to treat pediatric motility disorders. AB - Gut motility disorders represent a significant challenge in clinical management with current palliative approaches failing to overcome disease and treatment related morbidity. The recent progress with stem cells to restore missing or defective elements of the gut neuromusculature offers new hope for potential cure. Focusing on enteric neuropathies such as Hirschsprung's disease, the review discusses the progress that has been made in the sourcing of putative stem cells and the studies into their biology and therapeutic potential. It also explores the practical challenges that must be overcome before stem cell-based therapies can be applied in the clinical arena. Although many obstacles remain, the speed of advancement of the enteric stem cell field suggests that such therapies are on the horizon. PMID- 19782310 TI - New tools in the treatment of motility disorders in children. AB - Gastrointestinal motility disorders can develop in neurologically impaired children and those with congenital malformations of the gut. It is characterized by moderate to severe abdominal pain, vomiting, and failure to thrive. Antral dysmotility after fundoplication and increased sympathetic over activity are 2 factors associated with this condition that make it difficult to treat. This paper proposes a management strategy using metoclopramide, celiac plexus blockade, and thoracic splanchnectomy. It reviews our experience with 11 patients. PMID- 19782311 TI - The potential significance of elevated vitreous sodium levels at autopsy. AB - Elevated levels of sodium that may be detected in the analysis of post-mortem fluid samples may arise from a wide variety of organic illnesses and environmental factors that have caused either water depletion or solute gain. When hypernatraemia is suspected at autopsy a careful history is required with particular emphasis on pre-existing medical conditions such as renal or gastrointestinal disease. In addition, detailed information is required on the circumstances of death, including any clinical symptoms and signs that the deceased may have manifested, or medical procedures such as dialysis, colonoscopy or intravenous fluid replacement. Reduced intake of fluid may be associated with cognitive or physical impairment or may result from environmental depletion (the latter may be a manifestation of inflicted injury). Both central and nephrogenic diabetes insipidus may result in the loss of excessive amounts of hypotonic fluid. This may also occur following diuretic use, or be due to gastroenteritis or burns. Hypernatraemia may be a marker of excessive salt/saline ingestion and/or administration and may occur accidentally or as a manifestation of child abuse. Given the range of possible etiologies, hypernatraemia may be a significant autopsy finding that requires explanation. PMID- 19782312 TI - Stature estimation from the length of the sternum in South Indian males: a preliminary study. AB - Estimation of stature is one of the important initial steps during forensic analysis of human skeletal remains. The aim of the present study was to derive a linear regression formula for estimating stature of adult South Indian males from the length of the sternum. The study included 35 male sternums of South Indian origin dissected from cadavers during medico-legal autopsies. The linear regression equation [Stature=117.784 + (3.429 x Sternal length)] was derived to estimate the stature from the length of the sternum. The correlation coefficient was 0.638. The standard error of the estimate was 5.64 cm. This preliminary study concludes that the length of the sternum can be used as a tool for stature estimation in adult South Indian males. PMID- 19782313 TI - Alcohol and drugs in suspected impaired drivers in Ontario from 2001 to 2005. AB - INTRODUCTION: Blood samples from 733 drivers suspected of driving under the influence of alcohol in the province of Ontario from 2001 to 2005 were retrospectively examined. METHODS: Samples were analyzed for alcohol content by headspace gas chromatography with flame ionization detection. Drivers ranged in age from 15 to 83 years old with the majority of blood samples obtained from males (n=623, 85%). Of the 704 cases where quantifiable numerical values were obtained, blood alcohol concentrations ranged from 13 to 414 mg/100 mL (mean 172 mg/100 mL) for males and 10 to 425 mg/100 mL (mean 173 mg/100 mL) for females. The majority of these drivers (n=640/704, 90.9%) had blood alcohol concentrations of 80 mg/100 mL and greater at the time of sampling. Analysis for alcohol was undertaken in all cases. However, additional toxicological examinations for drugs was conducted on a case-by-case basis based on the submitted case history and/or where there were requests for additional drug analysis, or where such analysis would be probative in the absence of the detection of alcohol at a concentration that could cause impairment. RESULTS: Therefore, analyses for drugs were only performed in a small subset of 42 cases (6%). Thirty-four of these cases had positive drug findings, with Delta(9)-tetrahydrocannabinol being the most frequently encountered drug (n=18), followed by benzoylecgonine/cocaine (n=8), morphine (n=6), lorazepam (n=5) and diphenhydramine (n=4). The majority of individuals were involved in some type of motor vehicle accident (n=658, 89.8%), with single motor vehicle accidents (n=412, 56.2%) being the most common, followed by multiple motor vehicle accidents (n=169, 23%). Injuries (n=309, 42.1%) were the main cause of individuals not being able to provide breath samples with specific, non-life threatening injuries (n=178, 24.3%) representing the highest percentage of cases. The majority of incidents (n=449, 61.3%) occurred between Friday and Sunday reaching a peak on Saturday (n=174, 23.7%). Incidents occurred throughout the day, with the majority of events (n=449/705, 63.7%) for which a time was provided occurring between 6:01 pm and 3:00 am, and the peak number of incidents occurring between 9:01 pm and midnight (n=168/705, 23.8%). CONCLUSION: However, these data demonstrate that ''drugged driving" does occur and that further, comprehensive investigation is needed to determine the frequency and type of drug use by Ontario drivers. PMID- 19782315 TI - Sexual abuse of children. A comparative study of intra and extra-familial cases. AB - The existing data suggest that individuals experiencing intra-familial abuse are affected more significantly than those experiencing extra-familial abuse. This study aims to identify possible differences between these types of abuse. A retrospective study was performed based on medico-legal reports related to children suspected of being sexually abused (n=1054). The results revealed that 40.2% of the suspected abuses were intra-familial and were significantly different than extra-familial cases with respect to the following: (a) the complainants were younger; (b) their relationship to the alleged abuser was closer; (c) the alleged abusers had higher rates of previous sexual abuse; (d) the suspected abuses were less intrusive physically; (e) there was less physical but more psychological violence; (f) the delay between the last abuse and the medico-legal examination was greater; and (g) there were fewer physical signs and DNA evidence (none in the great majority of cases). These results highlight aspects of intra-familial abuse that have been identified as factors influencing the severity of its consequences - physically, these instances of abuse were less intrusive but psychologically they were more intrusive than extra-familial abuse. This justifies the use of different strategies in the diagnosis and support for victims within the family. PMID- 19782314 TI - Fire-related fatalities in Istanbul, Turkey: analysis of 320 forensic autopsy cases. AB - In this retrospective autopsy study fire-related deaths whose autopsies were carried out in the Council of Forensic Medicine in Istanbul, Turkey were analyzed in order to evaluate the relationship between the mode of the death and the laboratory and autopsy findings. There were 320 fire-related fatalities constituting the 2.07% of all autopsy cases of that period. Of the 320 cases 228 (71.3%) were males and 91 (28.4%) were females, average age in age-determined group was 36.6 (SD: 21.98) ranging from 8 months to 98 years. Carbon monoxide intoxication played role in death of 104 cases (32.5%) either directly or together with other factors such as burning and lack of oxygen. In 32 cases (10.0%) burning was the only cause of death and in 90 cases (28.1%) burning and related complications during treatment period caused death. In 35 cases (10.9%) traumatic factors other than those related to fire were responsible for death. There were 31 cases of homicide (9.7%) and 20 cases of suicide (6.3%). Accidents constituted the majority of the cases in our autopsy population with a frequency of 51.9%. The relationship between the presence of soot in trachea or esophagus and the mode of death and that of CO-Hb and the mode of death was statistically significant. The internal findings and laboratory data of the study population were discussed particularly on the basis of the decision of vitality in burned cases. PMID- 19782316 TI - Study of fingerprint classification and their gender distribution among South Indian population. AB - Identification of an individual plays a vital part of any medicolegal investigation. Fingerprint is considered to be the most accurate and reliable indicator in identification. The present study was conducted on 500 South Indian subjects to determine the individuality and the predominant fingerprint pattern among South Indian population. Two-hundred and fifty males and 250 females of South Indian origin were included for this study and rolled prints were taken from all the 10 digits and the same were stored on a proforma. The most frequent fingerprint pattern was ulnar loop in the total population, as well as in the sex wise distribution. PMID- 19782317 TI - Landmine associated injuries in children in Turkey. AB - This study aims to examine trends of injuries due to landmines and unexploded ordnance (UXO) and to determine problems during and after the treatment of children and adolescent victims in Turkey. Data from the records of 23 children injured from landmines and UXO were analyzed from April 2001 to October 2008. Cases consist of 21 (91.3%) males and two (8.7%) females with a mean age of 12.8 years. Cause of injury was landmine explosion in 20 (87.0%) and UXO in three (13.0%) cases. Injuries in upper and lower extremities were determined in eight (34.8%) children. Hand amputation was the result in 10 (43.5%) children where in two cases a leg, in one case an eye, in one case a hand and arm, in two cases a hand and leg, in one case an eye and a leg and in three cases a hand and eye were lost. One case of death was recorded from UXO with an autopsy performed. Contaminated areas in our region should be cleared according to international contracts to prevent injuries in children, centers providing rehabilitation services should be established and policies regarding social support for child victims should be ascertained. PMID- 19782318 TI - Allele frequencies for six miniSTR loci of Northwestern Chinese Han populations. AB - MiniSTR loci has demonstrated to be an effective approach to recover genetic information from degraded sample, due to the improved PCR efficiency of their reduced PCR product sizes. Allele frequencies and forensic parameters for the six miniSTR loci D10S1248, D2S441, D1S1677, D9S1122, D10S1435 and D17S1301 were investigated in 154 Northwestern Chinese Han populations. All loci showed a moderate degree of polymorphism with observed heterozygosity >0.6 and did not show departures from Hardy-Weinberg equilibrium for Northwestern Chinese Han populations. The accumulated powers of discrimination for the six loci were 0.999998. PMID- 19782319 TI - A rare case of myocardial infarction due to parathion poisoning. AB - Organophosphorus poisoning occurs very commonly in southern India where farmers form a significant proportion of the population who commonly use organophosphorus compounds like parathion as insecticides. Awareness of the complications caused by parathion poisoning is essential for proper monitoring and treatment. We report a case of suicidal parathion poisoning in a farmer who was treated with atropine and oximes. He subsequently developed myocardial infarction, to the treatment of which, he showed no response and succumbed. In conclusion, myocardial infarction is a rare complication of parathion poisoning. Awareness of this complication of parathion poisoning, proper monitoring and treatment could prevent fatalities. PMID- 19782320 TI - Early adipocere formation: a case report and review of literature. AB - Adipocere has a long history of frightening and fascinating mankind, from so called "incorruptible saints" to the famous "iceman" and its formation on human remains has long been known and feared. Adipocere formation replaces the putrefactive changes, when the body lies buried in shallow, moist, clay, soiled grave or it is thrown into cess pools or submerged in water. As the progression of putrefaction is arrested, the facial features and wounds are preserved without much alteration, thereby aiding the identification and to certain extent, the cause of death. The time required for the formation of adipocere is a subject of controversy. Here we present a case of early adipocere formation within 3 days and the review of literature pertaining to it. PMID- 19782321 TI - Lemierre syndrome and unexpected death in childhood. AB - Lemierre syndrome refers to necrotizing infections of the head due to Fusobacterium necrophorum and has been called the 'forgotten disease' due to its rarity in the antibiotic era. Recently, however, more cases have been documented in the literature suggesting that there has been an increase in incidence. A 10 year-old boy is reported who had a five-day history of ear infection, with the development of fever, drowsiness and ipsilateral neck swelling. Unexpected cardiac arrest occurred soon after medical assessment. At autopsy, right otitis media was demonstrated with extension of suppurative infection into subcutaneous tissues behind the ear and also into the extradural space at the lateral end of the petrous temporal bone. There was also septic thrombophlebitis of the adjacent sigmoid sinus, but no evidence of meningitis. This case demonstrates yet another infectious condition that may be associated with rapid deterioration and unexpected death in childhood. An autopsy approach to suspected sepsis in childhood is outlined. PMID- 19782322 TI - Paradoxical air embolism through patent foramen ovale during consensual intercourse in a non-pregnant young female. AB - Sudden vaginal bleeding and a cardiac arrest occurred in a 18-year-old female during consensual intercourse. Resuscitation procedures, applied at the arrival of a medical emergency team, restored the cardiac function allowing admission to hospital, where two vaginal mucosal lacerations were diagnosed and sutured. Cardiological investigations diagnosed a left ventricle myocardial infarction and a patent foramen ovale while a brain CT scan showed ischemic signs and intravascular air images. Death occurred after 48 h, due to heart failure, cerebral anoxia and multiorgan failure. Autopsy confirmed a patent foramen ovale considered as responsible for a paradoxical air embolism. Judicial Authority evaluated the fatal paradoxical air embolism as a consequence of an unpredictable accident occurred during consensual intercourse without sexual violence. PMID- 19782323 TI - Homicide of six family members using multiple methods in Sri Lanka. AB - A family of six members were murdered at their own residence. Four of the family members had been killed with large heavy sharp weapons which produced multiple deep cut injuries predominantly on the neck and face. In these victims, death occurred as a result of haemorrhage. Two family members were killed by ligature strangulation and hanging. The victim, who was hanged, was sexually abused before she was killed. An unusual finding was the presence of an alleged assailant to the murders with multiple blunt weapon trauma to his body, at the scene of crime. The homicides of the family were as a result of personal disputes between the perpetrators who were their neighbours. Three of the alleged assailants were charged for murder and rape. The fourth assailant was charged for rape. No conclusive evidence as to who caused the death of the alleged perpetrator was reached. PMID- 19782324 TI - Life threatening intracerebral hemorrhage with isometheptene mucate, dichlorophenazine and acetaminophen combination therapy. AB - A 45 year old female with no stroke risk factors suffered a massive intracerebral hemorrhage (ICH) after ingesting Midrin--a combination of isometheptene mucate, dichlorophenazine and acetaminophen. Neuroimaging revealed no evidence of structural disease or underlying vasculopathy. This is the first reported case of isometheptene induced ICH in the absence of underlying cerebrovascular disease. Physicians must be aware of the potential for this complication, and inquire about the use of isometheptene in unexplained cerebral hemorrhages. Neurological communities in countries with nonprescription isometheptene should discourage unsupervised or excessive use of the drug. PMID- 19782325 TI - "Atypical Suicidal" cut throat injury--a case report. AB - Suicide is one of the leading causes of death in the world. The incidence and pattern of suicide vary from country to country. Cultural, religious and social value plays a vital role. Hanging, poisoning, drowning are the common methods of committing suicide. Suicide by incising one's own throat without hesitation marks remains a rare, and only few cases have been reported in the forensic literature. We present here an unusual and rare case of self-inflicted cut throat injury of a 45-year old ex-military man without tentative cuts over the neck, which has resulted from a curved sharp weapon. PMID- 19782326 TI - Identification at autopsy of pulverized pills in lungs of a first-time methadone user. AB - We recently encountered a 25-year-old white man who died of substance abuse including methadone. The route of administration of the drug(s) appears to have been insufflation. He was found dead at home. There were bottles of prescribed medications and an empty bottle of non-prescribed methadone. There was a grinding device nearby. At autopsy, no needle tracts were identified. Microscopically, the bronchi had desquamated ciliated respiratory epithelium admixed with red-brown pigment, which was found under plane-polarized light to be comprised of birefringent finely-granular material consistent with pulverized pills. Blood toxicology was positive for tetrahydrocannabinol, sertraline, nicotine, and methadone. The cause of death was ruled drug interactions with cerebral and pulmonary edema, the manner of death accidental. The decedent fit a profile of a victim of prescription drug abuse, for whom the mode of administration of drugs may be altered from intended use in as many as 80% of cases. PMID- 19782327 TI - Ethanol-based hand cleansers. PMID- 19782328 TI - Post-mortem toxicology is not quackery when done by qualified practitioners. PMID- 19782331 TI - Spreading the word -- post-cardiac arrest syndrome. PMID- 19782329 TI - Response to postcard from Sweden. PMID- 19782332 TI - Thrombolysis administration by nurses: An evolving UK evidence base? AB - BACKGROUND: In the United Kingdom, an estimated 240,000 people suffer myocardial infarction yearly. Whilst primary angioplasty has emerged as the treatment of choice for many patients, thrombolytic agents are an effective class of medications which reduce myocardial damage, morbidity and mortality. They are most effective when given at the earliest opportunity, and United Kingdom government policy and professional standards aim to reduce these delays. This can be facilitated by nurse-led services. AIM: This systematic review of the literature charts the development of nurse thrombolysis in relation to UK government policy and assesses the research evidence since 2003. FINDINGS: Six papers met the inclusion criteria, and the following themes emerged: Thrombolysis is safely administered by nurses, Nurse-led thrombolysis improves door-to-drug time, Nurse-led thrombolysis is seen as a positive change in practice, Issues in Emergency Department thrombolysis administration. CONCLUSIONS: Although the evidence retrieved does not rate highly in the accepted hierarchy of evidence, nurses can be accurate and safe in diagnosis and treatment of acute myocardial infarction; nurse-led thrombolysis reduces door-to-drug times; and these services are supported by other professionals. Local clinical leadership and local thrombolysis protocols have provided the greatest improvements. Managing acute myocardial infarction including primary angioplasty facilities and administering early thrombolysis are clearly core elements of emergency care that need to be provided on a full 24 h, 7 days a week basis by appropriate frontline clinical staff. PMID- 19782333 TI - Post-cardiac arrest syndrome: Epidemiology, pathophysiology, treatment, and prognostication: A scientific statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke (Part 1). AB - AIM OF THE REVIEW: To review the epidemiology, pathophysiology, treatment and prognostication in relation to the post-cardiac arrest syndrome. METHODS: Relevant articles were identified using PubMed, EMBASE and an American Heart Association EndNote master resuscitation reference library, supplemented by hand searches of key papers. Writing groups comprising international experts were assigned to each section. Drafts of the document were circulated to all authors for comment and amendment. RESULTS: The 4 key components of post-cardiac arrest syndrome were identified as (1) post-cardiac arrest brain injury, (2) post cardiac arrest myocardial dysfunction, (3) systemic ischaemia/reperfusion response, and (4) persistent precipitating pathology. CONCLUSIONS: A growing body of knowledge suggests that the individual components of the postcardiac arrest syndrome are potentially treatable. PMID- 19782334 TI - Working with Manchester triage -- job satisfaction in nursing. AB - INTRODUCTION: This article covers nurses' job satisfaction during triage at emergency departments in Western Sweden. METHODS: Data was collected from 74 triage nurses using a questionnaire containing 37 short form open questions. The answers were analyzed descriptively and by measuring the covariance. The open questions were analyzed by content analysis. RESULTS: The results showed a high degree of job satisfaction (88%). Triage as a method, the interesting nature of the work, and a certain freedom in connection with the triage tasks contributed to job satisfaction (R(2) = 0.40). The nurses found their work interesting and stimulating, although some reported job dissatisfaction due to a heavy workload and lack of competence. Most of the nurses thought that Manchester triage (MTS) was a clear and straightforward method but in need of development. CONCLUSIONS: The rational modelling structure by which the triage method is constructed is unable to distinguish all the parameters that an experienced nurse takes into account. When the model is allowed to take precedence over experience, it can be of hindrance and contribute to certain estimates not corresponding with the patient's needs. The participants requested regular exercises solving and discussing patient scenarios. They also wanted to participate on a regular basis in the development of the instrument. PMID- 19782335 TI - Medial tibial stress syndrome--a case report. PMID- 19782336 TI - The effects of conformity on recognition judgements for emotional stimuli. AB - Exposure to another's account of a shared event can influence the content of an individual's memory report. We examine whether the emotionality of the to-be remembered information influences the likelihood that socially encountered post event information is accepted into memory. Participants were exposed to positive, negative or neutral emotional pictures. Subsequently, they had to discriminate these pictures from new pictures in a 'yes/no' recognition decision either before or subsequent to a confederate providing misinformation, accurate or no information. Post-event information influenced participants' responding in the recognition test. Effects were larger for participants viewing neutral items and persisted for these items on a subsequent private source monitoring test. These findings indicate that people rely more on information from others when encountering non-emotional compared to emotional items. We suggest that increased memory strength in conjunction with access to strong retrieval cues in the recognition test serves to shield emotional items from vulnerability to effects of memory conformity. PMID- 19782337 TI - Observations on the role of assisted laparoscopic surgery in patients with early stage endometrial cancer. PMID- 19782338 TI - Water should not be used for uterine distension. PMID- 19782339 TI - Traumatic pseudoaneurysm of superficial temporal artery. AB - An 83-year-old man reported falling and bumping his right lateral forehead on the ground 3 weeks previously. Physical examination revealed a soft, reddish swelling on the lateral forehead. Computed tomography confirmed a hematoma of the right lateral forehead. On the seventh hospital day, the swelling showed slight enlargement. Re-examination revealed a pulsatile mass with a palpable thrill and systolic bruit. Doppler echo showed pulsation of the swelling, which disappeared with compression of the anterior branch of the superficial temporal artery (STA). Surgical exploration was performed, and the pseudoaneurysm was resected. Pathological findings confirm a pseudoaneurysm. PMID- 19782340 TI - The evaluation of force exertions and muscle activities when operating a manual guided vehicle. AB - A manual guided vehicle (MGV) is used to handle heavy materials in thin film transistor-liquid crystal display (TFT-LCD) manufacturing clean rooms. This study focuses on evaluating the force exertions and muscle activities in MGV operations. The independent variables include gender, force direction, handle height, load handled and wheel diameter of the MGV. The results show the force direction, handle height and load handling effects are significant in most measures except for F(ending) (the peak force required to stop the MGV) and the EMG of the anterior deltoid. The wheel diameter had a significant effect on F(initial) (the peak force required to move the MGV) and F(ending) responses. Gender did not significantly effect any measures. Moreover, the pushing and pulling force is less at 115cm handle height than at 101.5cm and 88cm handle heights. Using 15.3cm (6 inch) diameter wheels requires less force than 20.3cm (8 inch) diameter wheels because the two front wheels are fixed and the two rear wheels are rotatable. The design implications are discussed. PMID- 19782341 TI - Effects of phytoestrogen genistein on genioglossus function and oestrogen receptors expression in ovariectomized rats. AB - OBJECTIVE: This study was designed to investigate the effects of genistein on genioglossal muscle function and the expression of oestrogen receptors (ERs) in the ovariectomized rats. DESIGN: Fifty female Sprague-Dawley rats were randomly divided into 5 groups: the control group (SHAM), the ovariectomized group (OVX), the ovariectomized rats receiving low genistein dosage (OVX+L), the moderate genistein dosage group (OVX+M) and the high genistein dosage group (OVX+H). Oestradiol level was detected by radioimmunity. The isometric twitch tension (P(t)) and tetanic tension (P(0)) of the GG muscle were measured in response to electrical field stimulation. The expression of ERs on the mRNA and protein levels was measured by real-time PCR and western blot respectively. RESULTS: Ovariectomy decreased muscle fatigue resistance and the expression of different ERs significantly. Genistein treatment resulted in a dose-dependent protective effect on muscle fatigability and a parallel dose-responsive increase in the expression of oestrogen receptors mRNA and protein levels in genioglossus, with larger effects on oestrogen receptor beta vs. alpha. In contrast to the improvements in fatigability, there was no treatment effect on isometric twitch or tetanic tensions. CONCLUSION: The results indicated that genistein increased muscle fatigue resistance in addition to effects on receptors, and the up regulation of receptors expression may be a possible mechanism by which genistein improved fatigue. PMID- 19782342 TI - Regional distribution of interglobular dentine in human teeth. AB - Interglobular dentine (IGD) is an area of poorly mineralized dentine matrix. It has been reported that there is an association between the retraction of odontoblast processes (OP) and the formation of IGD. A variation of the extent of OP has been described depending on the region of the tooth and age. This study aimed to find out the regional distribution of IGD in human teeth to observe any association between the extent of OP and the pattern of distribution of IGD. Ground sections were prepared from 52 extracted permanent teeth and the presence of IGD was observed in different regions of the crown and the root. The highest occurrence of IGD was found in the cervical and middle thirds followed by intercuspal, and coronal third in the crown. Statistical analysis of data depicted that the occurrence of IGD differed according to the region of the tooth. In roots, the highest occurrence of IGD was seen in the cervical third followed by the middle third. Previous reports have shown that OP extend up to the dentine-enamel junction in the coronal region and to the inner one-third of the cervical region. The varied pattern of distribution of IGD in the crown and root observed in our results corresponds to the above findings. Therefore, it is reasonable to surmise that there is an association between the distribution of IGD and the extent of OP. This allows us to confer that IGD tends to form in areas where OP do not extend to the dentine-enamel junction. PMID- 19782343 TI - A randomized controlled trial of Internet-based self-help training for recurrent headache in childhood and adolescence. AB - Two different self-help training programs (multimodal cognitive-behavioral training (CBT) and applied relaxation (AR)) presented via the Internet were compared with an educational intervention (EDU) in an RCT. Sixty-five children and adolescents (mean age: 12.7 years) with recurrent headache (at least 2 attacks per month) were each assigned to one of the three treatment conditions. The main outcome variables related to changes in headache frequency, intensity and duration as well as the responder rate (50% reduction of headache frequency) and NNTs. Secondary outcome variables were pain catastrophizing and general well being (depression, psychopathological symptoms and health-related quality of life). All groups showed significant reduction in headache frequency, duration and pain catastrophizing, but not in headache intensity, depression, psychopathological symptoms or health-related quality of life at post-assessment. NNTs were 2.0 for the comparison CBT and EDU; 5.2 for the comparison of AR and EDU at post-treatment. The highest responder rates at post were from CBT (63%), significantly different compared to AR (32%) and EDU (19%), whereas at follow-up no significant differences were found (CBT: 63%, AR: 56%, EDU: 55%) reflecting in the NNTs. The effects remain stable in headache frequency, pain catastrophizing and psychopathological symptoms across all groups at follow-up assessment. CBT showed the highest within-effect size in headache frequency, duration and pain catastrophizing. The results support the use of Internet programs for pediatric recurrent headache, especially given their accessibility and suitability for children and adolescents. Further studies are needed to improve their quality and efficacy. PMID- 19782344 TI - Reduced orbitofrontal and parietal gray matter in chronic insomnia: a voxel-based morphometric study. AB - BACKGROUND: Brain mechanisms of chronic insomnia, a highly prevalent condition, have barely been investigated. We demonstrate here a decrease in orbitofrontal gray matter (GM) volume that strongly correlates with the severity of complaints. METHODS: In a case-control study, optimized voxel-based morphometry was used to compare the regional brain volumes of 24 medication-free chronic primary insomnia patients (age range 52-74 years, 17 women), carefully selected to exclude psychiatric comorbidity, with those of 13 matched control subjects without sleep problems (age range 50-76 years, 9 women). Additionally, the correlation of regional volumes with insomnia severity was investigated. RESULTS: Patients had a smaller volume of GM in the left orbitofrontal cortex, strongly correlating (r = .71) with the subjective severity of insomnia. Furthermore, reduced GM volume was found in the anterior and posterior precuneus. Patients did not show increased GM volume in any area. No group differences were found for white matter volume. CONCLUSIONS: This is the first voxel-based morphometry study showing structural brain correlates of insomnia and their relation with insomnia severity. Functional roles of the affected areas in decision-making and stimulus processing might better guide future research into the poorly understood condition of insomnia. PMID- 19782345 TI - [Necrotizing fasciitis of the neck]. PMID- 19782346 TI - A prospective, randomized, controlled study to compare two doses of recombinant human chorionic gonadotropin in serum and follicular fluid in woman with high body mass index. AB - This prospective, randomized, controlled study compares the efficiency of 250 microg or 500 microg of recombinant hCG in serum and follicular fluid (FF) levels and pregnancy rates (PR) in women with high body mass index (BMI) (>or=26 kg/m(2)) undergoing assisted reproduction treatment (ART). Treatment outcomes are similar between the two groups. PMID- 19782347 TI - Serologic markers of autoimmunity in women with the polycystic ovary syndrome. PMID- 19782348 TI - Vitrification of isolated human blastomeres. AB - This article describes a new methodology for preserving and banking isolated human blastomeres, whose originality is based on packing the blastomere into an emptied zona pellucida before vitrification. After warming, 75.7% of blastomeres survived and developed at a rate comparable to that in noncryopreserved blastomeres (62.5% cleavage, 26.6% compaction, and 20.3% cavitation). PMID- 19782349 TI - Bridge-1 is expressed in human granulosa cells and is involved in the activin A signaling cascade. AB - The present study investigates the expression of the coactivator Bridge-1 in the human ovary and its role in activin A signaling in the human granulosa cell line HGL-5. Expression of Bridge-1 can be stimulated by activin A, an important factor for follicle maturation, matching the increase of Smad 2, 3, and 4; treatment with Bridge-1-small interfering RNA is decreasing not only the expression of Bridge-1 but also the expression of Smad2, 3, and 4 in HGL-5 cells. PMID- 19782351 TI - Different phenotypes of polycystic ovary syndrome by Rotterdam criteria are differently steroidogenic but similarly insulin resistant. AB - In traditional Chinese medicine, polycystic ovary syndrome (PCOS) is considered an anovulation disorder related to ovarian insulin resistance. The three phenotypes of PCOS, according to the Rotterdam criteria, are differently steroidogenic but similarly insulin resistant, suggesting a similar involvement of insulin resistance/hyperinsulinemia in different compartments of the PCOS ovary, namely, overactive theca and/or granulosa cells. PMID- 19782352 TI - Blockage of ghrelin-induced prolactin secretion in women by bromocriptine. AB - OBJECTIVE: To investigate the effect of bromocriptine on ghrelin-induced PRL secretion in women. DESIGN: Longitudinal study. SETTING: University hospital. PATIENT(S): Ten healthy, normally cycling women. INTERVENTION(S): The women were injected IV on day 3 of three cycles with a single dose of normal saline (cycle 1) or ghrelin (1 microg/kg) after pretreatment for 2 days either with placebo (cycle 2) or with bromocriptine (cycle 3) per os. Blood samples were taken before and frequently after drugs administration for 120 minutes. MAIN OUTCOME MEASURE(S): The PRL and GH responses to ghrelin were assessed. RESULT(S): Bromocriptine suppressed basal PRL levels significantly. The injection of ghrelin stimulated a significant increase in serum PRL levels in cycle 2 but not in cycle 3, in which PRL levels remained stable. The response of GH to gherlin was significantly attenuated in cycle 3 as compared with cycle 2. CONCLUSION(S): The present study demonstrates for the first time that bromocriptine blocked the stimulating effect of ghrelin on PRL release and attenuated the GH response to the same stimulus. The mechanism of these interactions needs to be clarified. PMID- 19782353 TI - Comparison of the effectiveness of single versus double intrauterine insemination with three different timing regimens. AB - OBJECTIVE: To compare double insemination with two different single insemination regimens. DESIGN: Prospective study. SETTING: Tertiary education and research hospital. PATIENT(S): Four hundred and fifty patients with unexplained infertility, male factor, and ovulatory dysfunction underwent controlled ovarian hyperstimulation with gonadotropin. INTERVENTION(S): The patients were divided randomly into three groups: patients in group 1 underwent a single preovulatory intrauterine insemination (IUI) performed 24 hours after hCG administration. Patients in group 2 underwent two IUIs performed 12 and 36 hours after hCG administration. Patients in group 3 underwent a single periovulatory IUI performed 36 hours after hCG administration. MAIN OUTCOME MEASURE(S): Pregnancy rate. RESULT(S): The total pregnancy rate per patient was 14.2 % (64 pregnancies in 450 patients). Group 1 had 17 pregnancies (11.3%), while groups 2 and 3 had 21 (14.0%) and 26 (17.2%) pregnancies, respectively. The difference between the three groups in regard to pregnancy rates was statistically not significant. CONCLUSION(S): Despite the 36th hour being the preferred timing for IUI, there was no difference regarding pregnancy rates between single 24th hour and double 12th- and 36th-hour inseminations. This finding suggests that the 24th-hour IUI might be preferred in demanding situations. PMID- 19782354 TI - The hidden infertile: infertile women without pregnancy intent in the United States. AB - A national probability sample reveals two relatively distinct groups of infertile women: those with intent, who have experienced a period of 12 or more months during which they tried to conceive but did not, and those without intent, who had a period of at least 12 months during which they could have conceived and did not but who do not describe themselves as having tried to become pregnant at that time. Those with intent are more likely to identify as having a fertility problem, to be distressed, and to pursue infertility treatment than those without intent, suggesting that many women do not realize that they meet the medical criteria for infertility and may wait longer to get help, therefore lowering their chances of conception. PMID- 19782355 TI - Reconstructive, organ-preserving microsurgery in tubal infertility: still an alternative to in vitro fertilization. AB - In this retrospective study, we observed a total of 553 patients with tubal infertility who underwent microsurgical reconstructive surgery of the fallopian tubes (including adhesiolysis, anastomosis, fimbrioplasty, salpingostomy, and refertilization after former sterilization). The pregnancy (43.4%) and birth (29.2%) rates after microsurgery for acquired tubal damages (abortion: 6.4%; ectopic pregnancy: 7.9%) were higher than after single in vitro fertilization (28.4% and <20%, respectively; data from German IVF register). The pregnancy (73%) and birth (50.6%) rates after the reversal of sterilization also were higher (abortion: 15.7%; ectopic pregnancy: 6.7%). The advantages of reconstructive microsurgery over in vitro fertilization include the ideally permanent restoration of a woman's ability to conceive naturally in every cycle that she ovulates, a high postoperative birth rate overall, and avoidance of multiple births. PMID- 19782356 TI - Relationship between interleukin-6 levels and ambulatory blood pressure in women with polycystic ovary syndrome. AB - OBJECTIVE: To determine 24-hour ambulatory blood pressures (ABP) in patients with polycystic ovary syndrome (PCOS) and its relationship with interleukin-6 (IL-6). DESIGN: Prospective controlled study. SETTING: University hospital. PATIENT(S): Fifty-four PCOS patients. INTERVENTION(S): Ambulatory blood pressure monitoring was conducted. Anthropometric, hormonal, metabolic, and inflammatory parameters, including plasma IL-6, C-reactive protein (CRP), fibrinogen, and nitric oxide (NO), were measured in each subject. MAIN OUTCOME MEASURE(S): Ambulatory blood pressure and plasma IL-6, CRP, fibrinogen, and NO. RESULT(S): Serum IL-6 levels of PCOS women in the highest systolic blood pressure (SBP) quartile were significantly higher than those of women in the lowest SBP quartile. The high serum IL-6 levels (serum IL-6 level>or=5.1 pg/mL) were associated with a higher probability of raised SBP (>/=126 mm Hg), with an odds ratio of 2.2 (95% confidence interval 0.8-7.9). The systolic and diastolic (DBP) blood pressures were significantly related to serum IL-6 levels. The IL-6 levels were positively and significantly correlated with serum CRP levels. Interleukin-6 and CRP were negatively and significantly correlated with serum NO levels. CONLUSION(S): The results suggest that raised plasma IL-6 levels may be related to ambulatory SBP and DBP in PCOS. PMID- 19782357 TI - Efficacy of a novel educational curriculum using a simulation laboratory on resident performance of hysteroscopic sterilization. AB - OBJECTIVE: To assess whether a novel educational curriculum using a simulation teaching laboratory improves resident knowledge, comfort with, and surgical performance of hysteroscopic sterilization. DESIGN: An educational prospective, pretest/posttest study. SETTING: The Montefiore Institute of Minimally Invasive Surgery Laboratory. PATIENT(S)/SUBJECT(S): Thirty-four OB/GYN residents in an academic medical center. INTERVENTION(S): Hysteroscopic sterilization simulation laboratory and a brief didactic lecture. MAIN OUTCOME MEASURE(S): Differences in scores on validated skill assessment tools: Task specific checklist, Global Rating Scale (GRS), pass fail assessment, and a multiple-choice examination to evaluate knowledge and attitude. RESULT(S): In the entire cohort improvements were observed on all evaluation tools after the simulation laboratory, with 31% points (SD+/-11.5, 95% confidence interval [CI] 27.3-35.3) higher score on the written evaluation; 63% points (SD+/-15.7, 95% CI 57.8-68.8) higher score on the task specific checklist; and 54% points (SD+/-13.6, 95% CI 48.8-58.3) higher score on the GRS. Higher PGY status was correlated with better pretest performance, but was not statistically significant in posttest scores. Residents reported an improvement in comfort performing the procedure after the laboratory. CONCLUSION(S): Simulation laboratory teaching significantly improved resident knowledge, comfort level, and technical skill performance of hysteroscopic sterilization. PMID- 19782358 TI - PID controller tuning for integrating processes. AB - Minimizing the integral squared error (ISE) criterion to get the optimal controller parameters results in a PD controller for integrating processes. The PD controller gives good servo response but fails to reject the load disturbances. In this paper, it is shown that satisfactory closed loop performances for a class of integrating processes are obtained if the ISE criterion is minimized with the constraint that the slope of the Nyquist curve has a specified value at the gain crossover frequency. Guidelines are provided for selecting the gain crossover frequency and the slope of the Nyquist curve. The proposed method is compared with some of the existing methods to control integrating plant transfer functions and in the examples taken it always gave better results for the load disturbance rejection whilst maintaining satisfactory setpoint response. For ease of use, analytical expressions correlating the controller parameters to plant model parameters are also given. PMID- 19782359 TI - Dorgan's lateral cross-wiring of supracondylar fractures of the humerus in children: A retrospective review. AB - INTRODUCTION: The currently accepted treatment for displaced supracondylar humeral fractures in children is closed reduction and fixation with percutaneous Kirschner wires. The purpose of this study was to retrospectively review a novel cross-wiring technique where the cross-wire configuration is achieved solely from the lateral side, thereby reducing the risk of ulnar nerve injury. METHODS: We retrospectively reviewed all children who had undergone this procedure at our centre over a 10-year period. The primary end points were a major loss of reduction as determined by radiological alignment and iatrogenic ulnar nerve injury. Secondary end points included clinical alignment, elbow range of motion and complications. RESULTS: A total of 43 patients, who underwent lateral cross wiring for displaced supracondylar fractures (Gartland type II and type III) of the humerus were reviewed with a mean follow-up time of 36 months. No major loss of reduction occurred. The mean change in Baumann's angle (4.2+/-1.6 degrees) between intra-operative and follow-up radiographs was not significant (p>0.05). No iatrogenic case of ulnar nerve injury occurred. The 'carrying angle' and 'return to function' in all children had returned to normal relative to the other side. Postoperative complications consisted of three patients developing pin-site infections, which were successfully treated. CONCLUSION: Dorgan's lateral cross wiring technique is an effective option in treating displaced supracondylar fractures of the humerus in children. It is as effective as the traditional cross wire technique in terms of fracture healing with a reduced risk of ulnar nerve injury. PMID- 19782360 TI - Flexible working and the contribution of nurses in mid-life to the workforce: a qualitative study. AB - BACKGROUND: With the changing demographic profile of the nursing workforce, retaining the skill and experience of nurses in mid-life is very important. Work life balance is a concept that is gaining increasing prominence in today's society. However, little is known about older nurses' experience of family friendly policies and flexible working. OBJECTIVES: This study explored the organisational, professional and personal factors that influence perceptions of commitment and participation in the workforce for nurses working in mid-life (aged 45 and over). DESIGN: A qualitative study using a range of methods including biographical methods, semi-structured face-to-face interviews, focus groups and telephone interviews. Data were analysed using constant comparative method. SETTINGS: A large inner city acute teaching hospital and an inner city mental health and social care trust providing both community and inpatient health and social care. PARTICIPANTS: 34 nurses and 3 health care assistants participated in individual interviews, 10 nurses participated in two focus groups and 17 managers participated in individual telephone interviews. RESULTS: Four themes emerged: the nature of nursing poses a challenge to the implementation of flexible working, differences in perceptions of the availability of flexible working, ward managers have a crucial role in the implementation of flexible working policies and the implementation of flexible working may be creating an inflexible workforce. CONCLUSIONS: The findings suggest that there are limits to the implementation of flexible working for nurses. In some areas there is evidence that the implementation of flexible working may be producing an inflexible workforce as older nurses are required to compensate for the flexible working patterns of their colleagues. Ward managers have a key role in the implementation of family friendly policies and require support to fulfil this role. There is a need for creative solutions to address implementation of flexible working for all nurses to ensure that workforce policy addresses the need to retain nurses in the workforce in a fair and equitable way. PMID- 19782361 TI - Low-dose atorvastatin improves dyslipidemia and vascular function in patients with primary biliary cirrhosis after one year of treatment. AB - OBJECTIVE: Primary biliary cirrhosis (PBC) is frequently associated with hypercholesterolemia and with an increased cardiovascular morbidity and mortality. Statins lower serum cholesterol levels and may thus improve the cardiovascular risk in PBC patients. The aim of our study was to prospectively examine the efficacy of low-dose atorvastatin on cholestasis as well as cardiovascular risk markers such as dyslipidemia and vascular function in patients with PBC. METHODS: Nineteen patients with early-stage (biopsy proven and AMA positive) PBC and low-density lipoprotein cholesterol (LDL-C) above 130mg/dL were included in this single-center study and treated with atorvastatin 10mg per day for one year. RESULTS: Concentrations of total cholesterol, LDL-C, LDL triglycerides, oxLDL, IgG and sVCAM-1 decreased significantly after 48 weeks of atorvastatin treatment. Flow-mediated dilation (FMD) of the brachial artery as an indicator of vascular function significantly increased, while carotid artery intima-media thickness and vascular wall stiffness did not progress under treatment. No statistical differences in liver enzymes were observed except a transient increase of alkaline phosphatase. CONCLUSION: Treatment with low-dose atorvastatin is safe in early-stage PBC, effectively reduces total cholesterol, LDL-C, LDL triglycerides, oxLDL and sVCAM-1 and improves vascular function as reflected by FMD, without affecting cholestasis progression. Therefore, statin therapy should be considered in PBC patients with additional risk factors for cardiovascular disease. PMID- 19782362 TI - Berberine and plant stanols synergistically inhibit cholesterol absorption in hamsters. AB - The present study was conducted to determine the efficacy and underlying mechanism of berberine (BBR), plant stanols (PS) and their combination on plasma lipids. Male Golden Syrian hamsters were randomly divided into 4 groups (n=15/group) and fed a cornstarch-casein-sucrose-based diet containing 0.15% cholesterol and 5% fat. Three treatment groups were supplemented with 0.17% (equivalent to 100mgkg(-1)d(-1)) BBR, 1% PS, or a combination of both (BBRPS) for 4wk. At the end of the study, plasma lipids were analyzed with enzymatic methods, cholesterol absorption and synthesis using stable isotope tracer methodology, and gene and protein expressions in the liver and small intestine using real-time PCR and Western blot, respectively. BBR and PS significantly lowered plasma total- and nonHDL-cholesterol levels, and BBRPS markedly improved cholesterol-lowering efficacy compared to BBR or PS alone. Further examinations revealed that BBR and PS both inhibited cholesterol absorption and by contrast, increased cholesterol synthesis, and exerted a synergistic action when they were combined. Plasma total or nonHDL-cholesterol levels were significantly correlated with cholesterol absorption rates. BBR upregulated sterol 27-hydroxlase gene expression and BBRPS increased both cholesterol-7alpha-hydroxylase and sterol 27-hydroxlase gene expressions. BBR and PS also synergistically decreased plasma triacylglycerides. These findings suggest that the cholesterol-lowering action of BBR might involve a combination of inhibition of cholesterol absorption and stimulation of bile acid synthesis. The combination of BBR and PS improves cholesterol-lowering efficacy through a synergistic action on cholesterol absorption, in addition to synergistically reducing plasma triacylglycerols in hamsters. PMID- 19782363 TI - Thoracic aorta calcification detected by electron beam tomography predicts all cause mortality. AB - BACKGROUND: The presence of coronary artery calcium (CAC) is an independent marker of increased risk of cardiovascular disease (CVD) events and mortality. However, the predictive value of thoracic aorta calcification (TAC), which can be additionally identified without further scanning during assessment of CAC, is unknown. METHODS: We followed a cohort of 8401 asymptomatic individuals (mean age: 53+/-10 years, 69% men) undergoing cardiac risk factor evaluation and TAC and CAC testing with electron beam computed tomography. Multivariable Cox proportional hazards models were developed to predict all-cause mortality based on the presence of TAC. RESULTS: During a median follow-up period of 5 years, 124 (1.5%) deaths were observed. Overall survival was 96.9% and 98.9% for those with and without detectable TAC, respectively (p<0.0001). Compared to those with no TAC, the hazard ratio for mortality in the presence of TAC was 3.25 (95% CI: 2.28 4.65, p<0.0001) in unadjusted analysis. After adjusting for age, gender, hypertension, dyslipidemia, diabetes mellitus, smoking and family history of premature coronary artery disease, and presence of CAC the relationship remained robust (HR 1.61, 95% CI: 1.10-2.27, p=0.015). Likelihood ratio chi(2) statistics demonstrated that the addition of TAC contributed significantly in predicting mortality to traditional risk factors alone (chi(2)=13.62, p=0.002) as well as risk factors+CAC (chi(2)=5.84, p=0.02) models. CONCLUSION: In conclusion, the presence of TAC was associated with all-cause mortality in our study; this relationship was independent of conventional CVD risk factors as well as the presence of CAC. PMID- 19782364 TI - Platelet activation and inflammatory response in patients with non-dipper hypertension. AB - OBJECTIVE: Non-dipper hypertensives had about three times the risk of atherosclerotic events than hypertensives whose blood pressure was >10% lower at night compared to daytime (dippers). Platelet activation and inflammatory response may derive from most atherosclerotic events. Mean platelet volume (MPV) is a determinant of platelet activation and high sensitive C-reactive protein (hs CRP) is the best candidate assay to identify and monitor the inflammatory response. We aimed to determine whether MPV and hs-CRP levels are elevated in non dipper patients compared to dippers and healthy controls. In addition, we tried to find out if MPV and CRP are related to each other or not in non-dipper hypertensives. METHOD: The total 126 patients study group included 86 patients with hypertension and 40 healthy subjects (16 male, mean age; 51+/-4) as control. Ambulatory blood pressure monitoring was performed for all patients. Hypertensive patients were divided into two groups; 46 dipper patients (18 male, mean age; 50+/-9) and 40 non-dipper patients (17 male, mean age; 53+/-11). Clinical baseline characteristics were similar between groups. We measured mean platelet volume in a blood sample collected in EDTA tubes and high-sensitive CRP was measured by using BN2 model nephlometer. RESULTS: Non-dipper patients demonstrated higher levels of MPV compared to dippers and normotensives (9.72+/ 0.52 fl vs 9.38+/-0.33 fl and 8.92+/-0.42 fl, p<0.05, respectively). High sensitive CRP levels were also significantly higher in non-dippers compared to dippers and normotensives (4.9+/-1.7mg/l vs 3.8+/-1.5mg/l and 2.7+/-0.8mg/l, p<0.05, respectively). There was significant positive correlation between MPV and CRP levels (p=0.002, r=0.482) in non-dipper hypertensives. CONCLUSION: Our results suggest that patients with non-dipping tend to have increased platelet activation and inflammatory response. Increased platelet activation and inflammatory response could contribute to increase the atherosclerotic risk in non-dipper patients compared to dippers. PMID- 19782365 TI - Improvements to Hoang et al.'s method for measuring passive length-tension properties of human gastrocnemius muscle in vivo. AB - While the passive mechanical properties of a musculo-articular complex can be determined using the relationship between the articular angle and the passive torque developed in resistance to motion, the properties of different structures of the musculo-articular complex cannot be easily assessed. Recently, an elegant method has been proposed to estimate the passive length-tension properties of gastrocnemius muscle-tendon unit (Hoang et al., 2005). In the present paper, two improvements of this method are proposed to decrease the number of parameters required to assess the passive length-tension relationship from 9 to 2. Furthermore, these two parameters have physical meaning as they represent a passive muscle-tendon stiffness index (alpha) and the muscle-tendon slack length (l(0)). alpha and l(0) are relevant clinical parameters to study the chronic effects of aging, training protocols or neuromuscular pathologies on the passive mechanical properties of the muscle-tendon unit. Eight healthy subjects performed passive loading/unloading cycles at 5 degrees /s with knee angle at 6 knee angles to assess the torque-angle relationships and to apply the modified method. Numerical optimization was used to minimize the squared error between the experimental and the modeled relationships. The experiment was performed twice to assess the reliability of alpha and l(0) across days. The results showed that the reliability of the two parameters was good (alpha: ICC=0.82, SEM=6.1m(-1), CV=6.3% and l(0): ICC=0.83, SEM=0.29 cm, CV=0.9%). Using a sensitivity analysis, it was shown that the numerical solution was unique. Overall, the findings may provide increased interest in the method proposed by Hoang et al. (2005). PMID- 19782366 TI - Force platform for rats measures fore and hind forces concurrently. AB - Animal models are commonly used to test the efficacy of impact loading regimens on bone strength. We designed an inexpensive force platform to concurrently measure the separate peak vertical impact forces produced by the fore and hindfeet of immature F-344 rats when dropped onto the platform. The force platform consisted of three load cells placed in a triangular pattern under a flat plate. Rats were dropped from heights of 30, 45 and 60 cm onto the platform so that they landed on all four feet concurrently. The peak vertical impact forces produced by the feet of the rats were measured using a sampling frequency of 100 kHz. The location of each foot at landing relative to the load cells, and the force received by each load cell were combined in a series of static equations to solve for the vertical impact forces produced by the fore and hindfeet. The forces produced by feet when rats stood on the single platform were similarly determined. The forces exerted separately by the fore and hindfeet of young rats when landing on the plate as a ratio to standing forces were then calculated. Rats when standing bore more weight on their hindfeet but landed with more weight on their forefeet, which provides rationale for the greater response to landing forces of bones in the forelimbs than those in the hindlimbs. This system provided a useful method to simultaneously measure peak vertical impact forces in fore and hindfeet in rats. PMID- 19782367 TI - Numerical study of ball behavior in side-foot soccer kick based on impact dynamic theory. AB - This study examined the factors affecting the ball velocity and rotation for side foot soccer kick using a numerical investigation. Five experienced male university soccer players performed side-foot kicks with various attack angles and impact points using a one-step approach. The kicking motions were captured three-dimensionally by two high-speed cameras at 2500 fps. The theoretical equations of the ball velocity and rotation were derived based on impact dynamic theory. Using the theoretical equations, the relationships of the ball velocity and rotation to the attack angle and impact point were obtained. The validity of the theoretical equations was verified by comparing the theoretical relationships with measurement values. Furthermore, simulations of the ball velocity and rotation were conducted using the theoretical equations. The theoretical relationships were in good agreement with the measurement values. The theoretical results confirmed the previously reported experimental results, and indicated that the impact point is more influential on the ball velocity than the attack angle and the attack angle is more influential on the ball rotation than the impact point. The simulation results indicated the following. The ball velocity produced by impact for all impact patterns is largely affected by the foot velocity immediately before impact but barely affected by the degree of slip between the foot and the ball. The ball rotation produced by an impact with a large attack angle is affected by the foot velocity immediately before impact and the degree of slip between the foot and the ball; however, these factors affect the ball rotation less than the attack angle. PMID- 19782368 TI - Development of a fast capillary electrophoresis method for the determination of propranolol-Total analysis time reduction strategies. AB - The aim of this study was to develop a fast capillary electrophoresis method for the determination of propranolol in pharmaceutical preparations. In the method development the pH and constituents of the background electrolyte were selected using the effective mobility versus pH curves. Benzylamine was used as the internal standard. The background electrolyte was composed of 60mmolL(-1) tris(hydroxymethyl)aminomethane and 30mmolL(-1) 2-hydroxyisobutyric acid, at pH 8.1. Separation was conducted in a fused-silica capillary (32cm total length and 8.5cm effective length, 50microm I.D.) with a short-end injection configuration and direct UV detection at 214nm. The run time was only 14s. Three different strategies were studied in order to develop a fast CE method with low total analysis time for propranolol analysis: low flush time (Lflush) 35runs/h, without flush (Wflush) 52runs/h, and Invert (switched polarity) 45runs/h. Since the three strategies developed are statistically equivalent, Wflush was selected due to the higher analytical frequency in comparison with the other methods. A few figures of merit of the proposed method include: good linearity (R(2)>0.9999); limit of detection of 0.5mgL(-1); inter-day precision better than 1.03% (n=9) and recovery in the range of 95.1-104.5%. PMID- 19782369 TI - Highlighting the possible secondary interactions in the role of balhimycin and its analogues for enantiorecognition in capillary electrophoresis. AB - It is believed that the enantiorecognition mechanism based on macrocyclic antibiotics involves multimodal interactions via hydrogen bonding, pi-pi interaction, steric hindrance, hydrophobic interaction and so on. A variety of enantiomeric N-benzoylated amino acids were separated using balhimycin (A) or its analogues bromobalhimycin (B) and dechlorobalhimycin (C) as chiral mobile phase additive using a CE method, which combined the partial filling technique with the dynamic coating technique and the co-EOF electrophoresis technique. The enantioresolution and the migration time were highly relevant to the structure of analytes, especially to the substitutions on the N-tagged benzoyl moiety of the amino acids. A steric effect and pi-pi interaction based mechanism is proposed in order to explain some observed enantioresolution differences between positional isomers. Notably dechlorobalhimycin exhibited the best enantioresolution for several N-benzoylated derivatives of leucine, which was rarely observed for N dansylated amino acid derivatives. The hydrophobicity difference of the aglycone pocket among three chiral selectors was assumed to account for this behaviour. PMID- 19782371 TI - Application of affinity capillary electrophoresis and density functional theory to the investigation of benzo-18-crown-6-ether complex with ammonium cation. AB - Affinity capillary electrophoresis (ACE) and quantum mechanical density functional theory (DFT) calculations have been employed for investigation of non covalent interactions between macrocyclic ligand, benzo-18-crown-6-ether (B18C6) and ammonium cation, NH(4)(+). Firstly, by means of ACE, the strength of the B18C6-NH(4)(+) complex in mixed binary hydro-organic solvent system, methanol water (50/50, v/v), was determined from the dependence of effective electrophoretic mobility of B18C6 (corrected to reference temperature 25 degrees C and constant ionic strength, 10mM) on the concentration of ammonium ion in the background electrolyte (BGE) using non-linear regression analysis. The logarithmic form of the apparent binding (stability) constant (logK(b)) of B18C6 NH(4)(+) complex in the above binary solvent system was found to be equal to logK(b)=1.63+/-0.10. Secondly, the structural characteristics of B18C6-NH(4)(+) complex were described by quantum mechanical density functional theory (DFT) calculations. According to these calculations, in the energetically most favoured form of the B18C6-NH(4)(+) complex, three strong hydrogen bonds are formed between central ammonium ion and B18C6 ligand, one of them is directed to aryl-O alkyl (Ar-O-CH(2)) ethereal oxygen and the other two hydrogen bonds are oriented to alkyl-O-alkyl (CH(2)-O-CH(2)) ethereal oxygen atoms of the macrocyclic crown ligand. PMID- 19782372 TI - Sol-gel coatings with covalently attached methyl, octyl, and octadecyl ligands for capillary microextraction. Effects of alkyl chain length and sol-gel precursor concentration on extraction behavior. AB - Fused silica capillaries with surface-bonded sol-gel coatings containing covalently attached octadecyl, octyl, and methyl groups were prepared for capillary microextraction (CME) hyphenated on-line with high-performance liquid chromatography (HPLC). For this, octadecyltrimethoxysilane (C(18)TMS), octyltrimethoxysilane (C(8)TMS), or methyltrimethoxysilane (MTMS) was used as the respective sol-gel precursor. Hydrolytic polycondensation of these precursors led to the formation of surface-bonded sol-gel sorbents with pendant alkyl groups ready to serve as the extraction medium; no additional surface derivatization reactions were needed to anchor these ligands to the surface. Extraction behaviors of two sets of microextraction capillaries with alkyl-bonded sol-gel coatings were investigated: (a) capillaries prepared with a constant molar concentration of these precursors in the sol solution, and (b) capillaries prepared with varied molar concentrations of C(8)TMS in the sol solution. Among the capillaries prepared using sol solutions with the same molar concentration of sol-gel precursor, the detection limits for nonpolar and polar analytes ranged from 0.3ng/L to 213.9ng/L. The sol-gel octadecyl-coated capillaries were found to be the most efficient at extracting these analytes, followed by the sol-gel octyl coated capillaries, followed by the sol-gel methyl-coated capillaries. The results of this study point to the possibility that polar analytes are extracted through synergistic molecular level interactions of the polar and nonpolar parts of the analyte molecules with the alkyl chains and silanol groups within the sol gel coatings. These coatings also demonstrated run-to-run and capillary-to capillary reproducibility, with HPLC peak area RSD values ranging from 1.1% to 9.6% and 1.3% to 10.0%, respectively. In the set of sol-gel octyl capillaries with varied molar concentrations, the capillaries prepared with 0.514M concentration of C(8)TMS in the sol solution were most efficient in extracting nonpolar and polar analytes. When higher or lower concentrations of C(8)TMS were used in the sol solution, the resulting sol-gel coated capillaries were less efficient in extracting nonpolar and polar analytes. PMID- 19782370 TI - The development of an integrated platform to identify breast cancer glycoproteome changes in human serum. AB - Protein glycosylation represents one of the major post-translational modifications and can have significant effects on protein function. Moreover, changes in the carbohydrate structure are increasingly being recognized as an important modification associated with cancer etiology. In this report, we describe the development of a proteomics approach to identify breast cancer related changes in either concentration and/or the carbohydrate structures of glycoprotein(s) present in blood samples. Diseased and healthy serum samples were processed by an optimized sample preparation protocol using multiple lectin affinity chromatography (M-LAC) that partitions serum proteins based on glycan characteristics. Subsequently, three separate procedures, 1D SDS-PAGE, isoelectric focusing and an antibody microarray, were applied to identify potential candidate markers for future study. The combination of these three platforms is illustrated in this report with the analysis of control and cancer glycoproteomic fractions. Firstly, a molecular weight based separation of glycoproteins by 1D SDS-PAGE was performed, followed by protein, glycoprotein staining, lectin blotting and LC-MS analysis. To refine or confirm the list of interesting glycoproteins, isoelectric focusing (targeting sialic acid changes) and an antibody microarray (used to detect neutral glycan shifts) were selected as the orthogonal methods. As a result, several glycoproteins including alpha-1B glycoprotein, complement C3, alpha-1-antitrypsin and transferrin were identified as potential candidates for further study. PMID- 19782373 TI - Determination of benzenic and halogenated volatile organic compounds in animal derived food products by one-dimensional and comprehensive two-dimensional gas chromatography-mass spectrometry. AB - Animal-derived products are particularly vulnerable to contamination by volatile organic compounds (VOCs). These lipophilic substances, which are generated by an increasing number of sources, are easily transferred to the atmosphere, water, soil, and plants. They are ingested by livestock and become trapped in the fat fraction of edible animal tissues. The aim of this work was to determine the occurrence, risk for human health and entryways of benzenic and halogenated VOCs (BHVOCs) in meat products, milks and sea foods using gas chromatography- mass spectrometry (GC-MS) techniques. In the first part, the occurrence and levels of the BHVOCs in animal products were studied. One muscle and three fat tissues were analysed by GC-Quad/MS in 16 lambs. Of 52 BHVOCs identified, 46 were found in the three fat tissues and 29 in all four tissues, confirming that VOCs are widely disseminated in the body. Twenty-six BHVOCs were quantified in fat tissues, and risk for consumer health was assessed for six of these compounds regulated by the US Environmental Protection Agency (EPA). The BHVOC content was found to be consistent with previous reports and was below the maximum contaminant levels set by the EPA. In the second part, the performance of GCxGC-TOF/MS for comprehensively detecting BHVOCs and showing their entryways in animal-derived food chains was assessed. Meat, milk and oysters were analysed by GC-Quad/MS and GCxGC-TOF/MS. For all these products, at least a 7-fold increase in the contaminants detected was achieved with the GCxGC-TOF/MS technique. The results showed that the production surroundings, through animal feeding or geographical location, were key determinants of BHVOC composition in the animal products. PMID- 19782374 TI - In situ synthesis of di-n-butyl l-tartrate-boric acid complex chiral selector and its application in chiral microemulsion electrokinetic chromatography. AB - A novel procedure for in situ assembling a complex chiral selector, di-n-butyl l tartrate-boric acid complex, by the reaction of di-n-butyl l-tartrate with boric acid in a running buffer was reported and its application in the enantioseparation of beta-blockers and structural related compounds by chiral microemulsion electrokinetic chromatography (MEEKC) has been demonstrated. In order to achieve a good enantioseparation, the effect of dibutyl l-tartrate and sodium tetraborate concentration, surfactant identity and concentration, cosurfactant, buffer pH and composition, organic modifiers, as well as applied voltage and capillary length were investigated. Ten pairs of enantiomers that could not be separated with only dibutyl l-tartrate, obtained good chiral separation using the complex chiral selector; among them, seven pairs could be baseline resolved under optimized experimental conditions. The fixation of chiral centers by the formation of five-membered rings, and being oppositely charged with basic analytes were thought to be the key factors giving the complex chiral selector a superior chiral recognition capability. The effect of the molecular structure of analytes on enantioseparation was discussed in terms of molecular interaction. PMID- 19782375 TI - Gas flow headspace liquid phase microextraction. AB - There is a trend towards the use of enrichment techniques such as microextraction in the analysis of trace chemicals. Based on the theory of ideal gases, theory of gas chromatography and the original headspace liquid phase microextraction (HS LPME) technique, a simple gas flow headspace liquid phase microextraction (GF-HS LPME) technique has been developed, where the extracting gas phase volume is increased using a gas flow. The system is an open system, where an inert gas containing the target compounds flows continuously through a special gas outlet channel (D=1.8mm), and the target compounds are trapped on a solvent microdrop (2.4 microL) hanging on the microsyringe tip, as a result, a high enrichment factor is obtained. The parameters affecting the enrichment factor, such as the gas flow rate, the position of the microdrop, the diameter of the gas outlet channel, the temperatures of the extracting solvent and of the sample, and the extraction time, were systematically optimized for four types of polycyclic aromatic hydrocarbons. The results were compared with results obtained from HS LPME. Under the optimized conditions (where the extraction time and the volume of the extracting sample vial were fixed at 20min and 10mL, respectively), detection limits (S/N=3) were approximately a factor of 4 lower than those for the original HS-LPME technique. The method was validated by comparison of the GF-HS-LPME and HS-LPME techniques using data for PAHs from environmental sediment samples. PMID- 19782376 TI - Suicide attempts among women during low estradiol/low progesterone states. AB - The relationship between the menstrual cycle and risk for suicidal behaviors is not clear. The aim of this study is to determine whether perimenstrual phases in fertile women are associated with acute risk for suicide attempt and explore whether risk is elevated during low estradiol/low progesterone states. Women (N=431) recruited within 24h of a suicide attempt were assessed for psychopathology, suicidal behavior and LH, FSH, estradiol and progesterone blood levels. Among fertile women (N=281/431), suicide attempts were more likely to occur during menses (26%, 72/281 observed vs. 15%, 43/281 expected attempts; p<0.001). Compared to women whose attempts occurred during other phases, women who attempted suicide during low estradiol/low progesterone states (menstrual phase, amenorrhea and menopause) reported severe suicide intent, a measure that may be predictive of eventual suicide death. Suicide attempts among women are more likely when estrogen and progesterone levels are low and attempts made under these conditions are associated with greater severity. Low gonadal hormone levels may constitute a key factor in the neurobiological basis of suicidal behavior among women, suggesting a novel, testable hypothesis regarding the underpinnings of suicidal acts. PMID- 19782377 TI - Small intestine submucosa (SIS) implants in experimental IPOM repair. AB - BACKGROUND: Synthetic meshes can cause adverse effects (e.g., adhesions, mesh infection) in intraperitoneal onlay mesh repair (IPOM). Although data for its biocompatibility as well as degradation behavior is still scarce, small intestine submucosa (SIS) implants have been suggested as a favorable alternative for IPOM repair. The aim of the study was to assess safety and efficacy of SIS used as allo- or xenograft in an experimental model of IPOM repair, with the purpose of creating a critical awareness for specific aspects of the biomesh concept among researchers and surgeons alike. Main outcome parameters were adhesion formation, tissue integration, shrinkage, and dislocation. MATERIALS AND METHODS: Open IPOM repair was performed in 16 Sprague Dawley rats and two minipigs. SIS implants were 2 x 2 cm in rats (one per animal) and 6 x 8 cm in pigs (four per animal). All implants were fixed with six nonresorbable sutures. Observation period was 17 and 28 d (n =8) in rats and 28 d in pigs. Outcome parameters were assessed macroscopically, and histologic samples (H and E staining) were obtained. RESULTS: Upon autopsy, SIS appeared to be only moderately integrated. Dislocation of five SIS implants in the rats and of two SIS implants in the pigs were observed although all sutures were still in place. No seroma formation or infection was detected macroscopically, but substantial shrinkage and adhesion formation at the margins of implants and suture sites were frequently observed. Histology confirmed the macroscopic finding of limited integration and substantial shrinkage. The pathomorphology was similar in both species. CONCLUSIONS: Small intestine submucosa implants are susceptible to shrinkage, dislocation, and adhesion formation in experimental IPOM repair in rats and pigs. These findings are in accordance with literature and warrant further investigations of SIS implants in hernia repair. PMID- 19782378 TI - European Charcot Foundation Lecture: the natural history of multiple sclerosis and gender. AB - The role of gender in the natural history of multiple sclerosis (MS) is multi faceted. Earliest debate on this topic was about the sex ratio (female:male) among affected individuals. It was only clearly shown within the last 4 decades that females are more often affected. The sex ratio continues to intrigue researchers. An observed increase in the sex ratio among more recently born MS patients has now been taken as a clear indication that the rate of MS is truly increasing in many geographical areas. This temporal increase in females has been relatively rapid, implicating environmental rather than genetic risk factors. Gender issues in MS expand beyond the scope of sex ratio. Gender has an impact on various aspects of MS, including age of onset, "parent-of-origin" effects (seen in half-siblings, twin sibships, avuncular pairs, transmission of HLA haplotype), recurrence risks for relatives of MS patients and the topic of reproduction when one parent has MS. Gender issues can also confound data collection and analyses with respect to studies on comorbidity, risk factors and family history. In fact, it has now been clearly validated and quantified that among persons with MS, there is a sex-specificity of recall and reporting bias as well a greater female awareness of medical history. PMID- 19782379 TI - Cerebrospinal fluid levels of chemokines in HIV infected patients with and without opportunistic infection of the central nervous system. AB - Chemokines are chemoattractant cytokines involved in the immune response of a wide variety of diseases. There are few studies assessing their role in opportunistic infections in HIV-infected patients. In this study, we measured CC and CXC chemokines in cerebrospinal fluid (CSF) samples obtained from 40 HIV infected patients with or without opportunistic infections of the central nervous system (CNS). CSF samples were also analyzed for quantification of total protein, cell count and HIV-1 RNA. HIV+ patients with cryptococcal meningitis had higher levels of CCL2, CCL3, CCL5, CXCL9 and CXCL10 when compared to patients without opportunistic neurological infections. Furthermore, HIV+ patients with associated cryptococcal meningitis had higher levels of CCL3, CXCL9 and CXCL10 when compared to HIV+ patients with associated toxoplasmic encephalitis. CCL3 and CXCL9 levels were positively correlated with CSF HIV-1 RNA levels, CSF protein concentration, and CSF cell count. CXCL10 level was correlated with the CSF viral load and the CSF cell count and CCL5 level was correlated with the CSF cell count. In conclusion, the profile of chemokines in CSF of HIV patients may differ according to the modality of the presented opportunistic infection and according to other biological markers, such as viral load in CSF. These differences are probably related to different patterns of neuroinflammatory responses displayed by patients with different opportunistic neurological infections. PMID- 19782380 TI - High levels of persistent organic pollutants measured in blubber of island associated false killer whales (Pseudorca crassidens) around the main Hawaiian Islands. PMID- 19782382 TI - BK virus has tropism for human salivary gland cells in vitro: implications for transmission. AB - BACKGROUND: In this study, it was determined that BKV is shed in saliva and an in vitro model system was developed whereby BKV can productively infect both submandibular (HSG) and parotid (HSY) salivary gland cell lines. RESULTS: BKV was detected in oral fluids using quantitative real-time PCR (QRTPCR). BKV infection was determined using quantitative RT-PCR, immunofluorescence and immunoblotting assays. The infectivity of BKV was inhibited by pre-incubation of the virus with gangliosides that saturated the major capsid protein, VP1, halting receptor mediated BKV entry into salivary gland cells. Examination of infected cultures by transmission electron microscopy revealed 45-50 nm BK virions clearly visible within the cells. Subsequent to infection, encapsidated BK virus was detected in the supernatant. CONCLUSION: We thus demonstrated that BKV was detected in oral fluids and that BK infection and replication occur in vitro in salivary gland cells. These data collectively suggest the potential for BKV oral route of transmission and oral pathogenesis. PMID- 19782384 TI - DDT residues in water, sediment, domestic and indigenous biota from a currently DDT-sprayed area. AB - DDT is used for indoor residual spraying (IRS) in Limpopo Province, northern South Africa to control malaria. Through IRS, DDT may reach the outdoor environment via dust and air and from possible spillages during application. In this area the local people consume domestic chickens, wild fish or birds. Fish from the river catchment and impoundments seem to be the major source of protein intake. Water, sediment and tissue samples from two such fish species, domestic chickens and wild birds (terrestrial and aquatic) from this DDT-sprayed area were analysed for DDT and metabolite residues. The samples contained p,p'-DDT, p,p' DDD and p,p'-DDE residues, with the latter the most ubiquitous and in the highest concentrations. These findings raise concern that both water and food may be major routes of human exposure to DDT and metabolites, thereby posing possible adverse human health implications to the local communities. PMID- 19782381 TI - Characteristics of alpha/beta interferon induction after infection of murine fibroblasts with wild-type and mutant alphaviruses. AB - We examined the characteristics of interferon alpha/beta (IFN-alpha/beta) induction after alphavirus or control Sendai virus (SeV) infection of murine fibroblasts (MEFs). As expected, SeV infection of wild-type (wt) MEFs resulted in strong dimerization of IRF3 and the production of high levels of IFN-alpha/beta. In contrast, infection of MEFs with multiple alphaviruses failed to elicit detectable IFN-alpha/beta. In more detailed studies, Sindbis virus (SINV) infection caused dimerization and nuclear migration of IRF3, but minimal IFN-beta promoter activity, although surprisingly, the infected cells were competent for IFN production by other stimuli early after infection. A SINV mutant defective in host macromolecular synthesis shutoff induced IFN-alpha/beta in the MEF cultures dependent upon the activities of the TBK1 IRF3 activating kinase and host pattern recognition receptors (PRRs) PKR and MDA5 but not RIG-I. These results suggest that wild-type alphaviruses antagonize IFN induction after IRF3 activation but also may avoid detection by host PRRs early after infection. PMID- 19782383 TI - Serotype 5 Adenovirus fiber (F7F41S) chimeric vectors incur packaging deficiencies when targeting peptides are inserted into Ad41 short fiber. AB - Adenovirus is a well-established viral gene transfer model system that presents two major hurdles when being considered for cell-specific targeting applications. First is the need to detarget the vector from inherent host binding mechanisms, and second is the need to establish a productive and stable method to retarget the vector to a desired cell receptor. In previous studies we had generated an adenovirus vector platform that lacks the normal targeting attributes derived from the fiber and penton capsid proteins. In the current study we characterized our detargeted Ad5-based vectors (Ad5.F7F41S and Ad5.F7F41SDeltaRGD) as platforms for novel retargeted viruses. The experimental strategy relied on incorporating small peptide ligands into several sites of the Ad 41short fiber knob domain (AB, CD, HI, G and Cterm). Reengineering of Ad41 short fiber resulted either in a bypass to fiber 7 usage, or in a dominant negative packaging/production deficiency phenotype. Under specific growth conditions we could remedy some of the capsid deficiencies and generate high titer viruses. However when examined by Western blot analysis, the resulting viruses were still defective in capsid content. The tandem fiber F7F41S platform has revealed an unanticipated sensitivity of Adenovirus packaging to fiber 41short structural modifications. These studies indicate fiber assembly into an intact virion or fiber influenced capsid stability as a bottleneck to efficient particle production. We also demonstrate that virus particles characterized as mature virions following CsCl banding can vary significantly in capsid protein content. Considering the complexity of virus entry into a target cell, modified "mature virions" may be compromised at the level of transduction not only through the intended modification, but also by virtue of secondary structural packaging conflicts. PMID- 19782385 TI - Polarity based fractionation of fulvic acids. AB - Fulvic acids from the soil of Peking University (PF) and a Nordic river (NF) were separated into well defined sub-fractions using sequential elution techniques based on eluent polarity. The chemical properties of the fractions including: PF1 and NF1 (eluted by 0.01 M HCl), PF2 and NF2 (eluted by 0.01 M HCl+20% methanol), PF3 and NF3 (eluted by 0.01 M HCl+40% methanol), and PF4 and NF4 (eluted by 100% methanol), were characterized using UV-Visible spectroscopy, elemental analysis and (13)C NMR. The results showed that the UV absorptions of the elution peaks at 280 nm (A280) increased from PF2 to PF4 and NF2 to NF4. No elution peaks were observed for PF1 and NF1. The carbon contents increased from 43.34% to 51.90% and 43.06% to 53.26% while the oxygen contents decreased from 46.39% to 36.76% and 49.76% to 40.03% for PF1-PF4 and NF1-NF4, respectively. As a polarity indicator, the (O+N)/C ratio for PF1-PF4 and NF1-NF4 decreased from 0.88 to 0.62 and 0.89 to 0.58, respectively. The aromatic carbon content increased from PF1 to PF4 and NF1 to NF4, suggesting an increase of the hydrophobicity of these fractions. The polarity was positively related to the ratio of UV absorption at 250 nm and 365 nm (E2/E3), and negatively related to the aromaticity. A high positive relationship between the aromaticity and E2/E3 of fulvic acid fractions was also obtained. The use of an eluent with a decreasing polarity allowed to providing simpler fractions of soil and aquatic fulvic acids. PMID- 19782386 TI - Leishmaniasis and biologic therapies for rheumatologic diseases. PMID- 19782387 TI - Survival, causes of death, and risk factors associated with mortality in Spanish systemic sclerosis patients: results from a single university hospital. AB - OBJECTIVE: To analyze the causes of death, survival, and risk factors for mortality in a large series of Spanish systemic sclerosis (SSc) patients followed over the last 25 years in a tertiary care university hospital. METHODS: Demographic, clinical, and outcome data from all SSc patients followed in the rheumatology department were included in a database created in 1989. ANOVA, Kruskal-Wallis, or chi(2) tests were used to identify differences among groups; Kaplan-Meier analysis was used to estimate survival, and Cox proportional hazards regression analysis was used to identify factors associated with mortality. RESULTS: A total of 204 patients were included, of whom 182 (89%) were women. Mean age at diagnosis was 49 +/- 17 years, and mean follow-up was 8 years. Over 1635 patient-years, 36 of 44 deaths were attributable to SSc: 28 related to cardiorespiratory involvement, 4 to peripheral vascular disease, 3 to gastrointestinal, and 1 to renal involvement. The main SSc-unrelated causes of death were malignancy (3 cases) and infections (2 cases). Survival rates from disease onset were 85, 75, and 55% at 5, 10, and 20 years, respectively, with poorer survival in patients with renal disease and pulmonary hypertension (PH). Independent prognostic factors for mortality were older age at diagnosis, diffuse skin involvement, proteinuria, PH, and elevated erythrocyte sedimentation rate. CONCLUSIONS: Ten-year survival is over 70% in Spanish SSc patients. The main causes of death are lung and cardiac involvement, and to a lesser extent, peripheral vascular disease and coexisting malignancy. Diffuse subset, proteinuria, PH, elevated erythrocyte sedimentation rate and older age at diagnosis are the main risk factors for mortality. PMID- 19782388 TI - Lupus Anticoagulant (LAC) testing in patients with inflammatory status: does C reactive protein interfere with LAC test results? PMID- 19782389 TI - Expert consensus for the treatment of disseminated intravascular coagulation in Japan. AB - The present report from The Japanese Society of Thrombosis and Hemostasis provides an expert consensus for the treatment of disseminated intravascular coagulation (DIC) in Japan. Disseminated intravascular coagulation (DIC) may be classified as follows: asymptomatic type, marked bleeding type, and organ failure type. Although treatment of DIC is important, adequate treatment differs according to type of DIC. In asymptomatic DIC, low molecular weight heparin (LMWH), synthetic protease inhibitor (SPI), and antithrombin (AT) are recommended, although these drugs have not yet been proved to have a high degree of effectiveness. Unfractionated heparin (UFH) and danaparoid sodium (DS) are sometimes administrated in this type, but their usefulness is not clear. In the marked bleeding type, LMWH, SPI, and AT are recommended although these drugs do not have high quality of evidence. LMWH, UFH, and DS are not recommended in case of life threatening bleeding. In case of severe bleeding, SPI is recommended since it does not cause a worsening of bleeding. Blood transfusions, such as fresh frozen plasma and platelet concentrate, are also required in cases of life threatening bleeding. In the organ failure type, including sepsis, AT has been recommended based on the findings of several clinical trials. DIC is frequently associated with thrombosis and may thus require strong anticoagulant therapy, such as LMWH, UFH, and DS. PMID- 19782390 TI - Right visual field advantage in parafoveal processing: evidence from eye-fixation related potentials. AB - Readers acquire information outside the current eye fixation. Previous research indicates that having only the fixated word available slows reading, but when the next word is visible, reading is almost as fast as when the whole line is seen. Parafoveal-on-foveal effects are interpreted to reflect that the characteristics of a parafoveal word can influence fixation on a current word. Prior studies also show that words presented to the right visual field (RVF) are processed faster and more accurately than words in the left visual field (LVF). This asymmetry results either from an attentional bias, reading direction, or the cerebral asymmetry of language processing. We used eye-fixation-related potentials (EFRP), a technique that combines eye-tracking and electroencephalography, to investigate visual field differences in parafoveal-on-foveal effects. After a central fixation, a prime word appeared in the middle of the screen together with a parafoveal target that was presented either to the LVF or to the RVF. Both hemifield presentations included three semantic conditions: the words were either semantically associated, non-associated, or the target was a non-word. The participants began reading from the prime and then made a saccade towards the target, subsequently they judged the semantic association. Between 200 and 280ms from the fixation onset, an occipital P2 EFRP-component differentiated between parafoveal word and non-word stimuli when the parafoveal word appeared in the RVF. The results suggest that the extraction of parafoveal information is affected by attention, which is oriented as a function of reading direction. PMID- 19782391 TI - Candida albicans adherence on silicone elastomers: effect of polymerisation duration and exposure to simulated saliva and nasal secretion. AB - OBJECTIVES: The surfaces of maxillo-facial prostheses made of silicone elastomers exposed to soft tissues may interact with saliva and nasal secretion. These body fluids may lead to colonisation of microorganisms on their surfaces leading to their degradation or infection. This study investigated Candida albicans adhesion onto commercial maxillo-facial silicone elastomers based on different polymerisation processes. METHODS: Room-temperature polymerised maxillo-facial silicone elastomers (N=48) (10 mm x 10 mm x 2 mm) processed at different durations [VerSilTal VST-30 (20 min), VST-50 (12h overnight), VST-50F (6h)] were studied. C. albicans was chosen as a model organism for this study. The specimens were randomly divided into two subgroups and incubated in either 1.5 ml simulated saliva or nasal secretion containing C. albicans (ATCC 60193, set to 0.5 OD, 540 nm in advance) for 2h. Candida assays and adherence assays were made by inoculating C. albicans into Mueller Hinton Broth, Fluka added 500 mmol sucrose overnight. After fixation, specimens were stained by using sterilised Methylene Blue stain (Merck) and evaluated under optical microscope and SEM. For each material, on each specimen 15 different areas (mm(2)) were counted. Data were analysed using one-way ANOVA, paired sample t-test and Tukey's HSD (alpha=0.05). RESULTS: Material type (p<0.05) and exposure media (p<0.05) showed a significant influence on the C. albicans adherence. VST-30 material showed the most C. albicans adherence in both saliva and nasal secretion (mean rank: 99.84 and 53.47, respectively) (p<0.05) and VST-50 had the least colonisation in both media (10.35 and 5.57, respectively). Microscopic evaluation showed clusters of blastospore cells of C. albicans being more spread out on VST-30 whereas cells were more localised on VST-50 and VST-50F. SIGNIFICANCE: Among the tested materials, 12h room-temperature polymerised silicone elastomer resulted in less C. albicans adherence in both artificial saliva and nasal secretion. PMID- 19782392 TI - Explanation of normative declines in parents' knowledge about their adolescent children. AB - This study aimed to explain why parental knowledge of adolescents' whereabouts declines with age. Such an investigation is important because previous studies have established an association between behavior problems and low levels of parental knowledge. A time-sequential sample comprising 2415 adolescents aged 13 18 years was investigated on five annual occasions. Each year, parental knowledge declined by .10 SD. Adolescents' establishment of a private sphere (less disclosure; defiance) was the most important mediator of age effects on knowledge. Taken together, declining parental control and the establishment of a private sphere explained 37.5% of the age-related decline in knowledge. Parental control was, however, not a significant predictor any longer when disclosure and defiance were controlled for. Results also revealed that some of the mediating variables were stronger in early-to-mid adolescence. Other variables appeared to slow the age-related decline, especially in mid-to-late adolescence. These variables are therefore interpreted as parents' and adolescents' attempts to balance autonomy development and connectedness. If this balancing fails, adolescent behavior problems might arise along with low levels of parental knowledge early on. PMID- 19782393 TI - Anti-inflammatory peptide-functionalized hydrogels for insulin-secreting cell encapsulation. AB - Pancreatic islet encapsulation within semi-permeable materials has been proposed for transplantation therapy of type I diabetes mellitus. Polymer hydrogel networks used for this purpose have been shown to provide protection from islet destruction by immunoreactive cells and antibodies. However, one of the fundamental deficiencies with current encapsulation methods is that the permselective barriers cannot protect islets from cytotoxic molecules of low molecular weight that are diffusible into the capsule material, which subsequently results in beta-cell destruction. Use of materials that can locally inhibit the interaction between the permeable small cytotoxic factors and islet cells may prolong the viability and function of encapsulated islet grafts. Here we report the design of anti-inflammatory hydrogels supporting islet cell survival in the presence of diffusible pro-inflammatory cytokines. We demonstrated that a poly(ethylene glycol)-containing hydrogel network, formed by native chemical ligation and presenting an inhibitory peptide for islet cell surface IL-1 receptor, was able to maintain the viability of encapsulated islet cells in the presence of a combination of cytokines including IL-1 beta, TNF alpha, and INF-gamma. In stark contrast, cells encapsulated in unmodified hydrogels were mostly destroyed by cytokines which diffused into the capsules. At the same time, these peptide-modified hydrogels were able to efficiently protect encapsulated cells against beta-cell specific T-lymphocytes and maintain glucose stimulated insulin release by islet cells. With further development, the approach of encapsulating cells and tissues within hydrogels presenting anti-inflammatory agents may represent a new strategy to improve cell and tissue graft function in transplantation and tissue engineering applications. PMID- 19782394 TI - Substantiating in vivo magnetic brain tumor targeting of cationic iron oxide nanocarriers via adsorptive surface masking. AB - Cationic magnetic nanoparticles are attractive as potential vehicles for tumor drug delivery due to their favorable interactions with both the tumor milieu and the therapeutic cargo. However, systemic delivery of these nanoparticles to the tumor site is compromised by their rapid plasma clearance. We developed a simple method for in vivo protection of cationic nanocarriers, using non-covalent surface masking with a conjugate of low molecular weight heparin and polyethylene glycol. Surface masking resulted in a 11-fold increase in plasma AUC and a 2-fold increase in the magnetic capture of systemically injected nanoparticles in orthotopic rodent brain tumors. Overall, the described methodology could expand the prospective applications for cationic magnetic nanoparticles in magnetically mediated gene/drug delivery. PMID- 19782395 TI - Synthesis and antitumor activity of doxorubicin conjugated stearic acid-g chitosan oligosaccharide polymeric micelles. AB - Doxorubicin conjugated stearic acid-g-chitosan oligosaccharide polymeric micelles (DOX-CSO-SA) was synthesized via cis-aconityl bond between the anticancer drug doxorubicin (DOX) and stearic acid grafted chitosan oligosaccharide (CSO-SA) in this paper. The CSO-SA micelles had been demonstrated faster internalization ability into tumor cells. Here, the CSO-SA with 6.47% amino substituted degree (SD%) was used to synthesize DOX-CSO-SA. The critical micelle concentration (CMC) was about 0.14 mg mL(-1). The micelles with 1 mg mL(-1) CSO-SA concentration had 32.7 nm number average diameter with a narrow size distribution and 51.5 mV surface potential. After conjugating with doxorubicin, CMC of DOX-CSO-SA descended; the micellar size increased; and the zeta potential decreased. The DOX CSO-SA micelles indicated pH-dependent DOX release behavior. The release rate of DOX from DOX-CSO-SA micelles increased significantly with the reductions of the pH for release medium from 7.2 to 5.0. In vitro antitumor activity tests of DOX CSO-SA micelles against human breast carcinoma (MCF-7) cells and their multi-drug resistant (MCF-7/Adr) cells presented the reversal activity against DOX resistance MCF-7 cells (MCF-7/Adr). The in vivo antitumor activity results showed that DOX-CSO-SA micelles treatments effectively suppressed the tumor growth and reduced the toxicity against animal body than commercial doxorubicin hydrochloride injection. PMID- 19782396 TI - Engineering human neo-tendon tissue in vitro with human dermal fibroblasts under static mechanical strain. AB - Proper cell source is one of the key issues for tendon engineering. Our previous study showed that dermal fibroblasts could be used to successfully engineer tendon in vivo and tenocytes could engineer neo-tendon in vitro with static strain. This study further investigated the possibility of engineering human neo tendon tissue in vitro using dermal fibroblasts. Human dermal fibroblasts were seeded on polyglycolic acid (PGA) fibers pre-fixed on a U-shape as a mechanical loading group, or simply cultured in a dish as a tension-free group. In addition, human tenocytes were also seeded on PGA fibers with tension as a comparison to human dermal fibroblasts. The results showed that human neo-tendon tissue could be generated using dermal fibroblasts during in vitro culture under static strain and the tissue structure became more mature with the increase of culture time. Longitudinally aligned collagen fibers and spindle shape cells were observed histologically and collagen fibril diameter and tensile strength increased with time and reached a peak at 14 weeks. In contrast, the dermal fibroblast-PGA constructs failed to form neo-tendon, but formed disorganized fibrous tissue in tension-free condition with significantly weaker strength and poor collagen fiber formation. Interestingly, neo-tendon tissues generated with human dermal fibroblasts were indistinguishable from the counterpart engineered with human tenocytes, which supports the viewpoint that human dermal fibroblasts is likely to replace tenocytes for future tendon graft development in vitro with dynamic mechanical loading in a bioreactor system. PMID- 19782397 TI - Controlled compaction with ruthenium-catalyzed photochemical cross-linking of fibrin-based engineered connective tissue. AB - Tissue engineering utilizing fibrin gel as a scaffold has the advantage of creating a completely biological replacement. Cells seeded in a fibrin gel can induce fibril alignment by traction forces when subjected to appropriate mechanical constraints. While gel compaction is key to successful tissue fabrication, excessive compaction can result due to low gel stiffness. This study investigated using ruthenium-catalyzed photo-cross-linking as a method to increase gel stiffness in order to minimize over-compaction. Cross-links between the abundant tyrosine molecules that comprise fibrin were created upon exposure to blue light. Cross-linking was effective in increasing the stiffness of the fibrin gel by 93% with no adverse effects on cell viability. Long-term culture of cross-linked tubular constructs revealed no detrimental effects on cell proliferation or collagen deposition due to cross-linking. After 4 weeks of cyclic distension, the cross-linked samples were more than twice as long as non cross-linked controls, with similar cell and collagen contents. However, the cross-linked samples required a longer incubation period to achieve a UTS and modulus comparable to controls. This study shows that photo-cross-linking is an attractive option to stiffen the initial fibrin gel and thereby reduce cell induced compaction, which can allow for longer incubation periods and thus more tissue growth without compaction below a useful size. PMID- 19782398 TI - p15INK4b methylation correlates with thrombocytopenia, blast percentage, and survival in myelodysplastic syndromes in a dose dependent manner: quantitation using pyrosequencing study. AB - We investigated how the quantity of p15INK4b methylation related to International Prognosic Scoring System variables and survival in 74 patients with de novo myelodysplastic syndrome (MDS). Pyrosequencing of 11 consecutive CpG sites of the p15INK4b promotor region was performed, with the extent of CpG cytosine methylation assessed in terms of methylation level (MtL). Patients with >5% bone marrow blasts had higher MtL than patients with <5% blasts (10.1% vs. 6.1%, p=0.030, respectively). Methylation was not associated with chromosomal aberrations. The MtL of patients with thrombocytopenia were higher than patients without thrombocytopenia (11.2% vs. 6.2%, p=0.036, respectively); they were higher in patients with cytopenias in > or =2 lineages than in patients with either unilineage or no cytopenia (9.8% vs. 4.1%, p=0.036, respectively). The survival of patients with >7% MtL was worse than patients with <7% MtL (p=0.031). Heavy p15INK4b methylation in MDS is associated with IPSS predictors of poor prognosis and adverse survival. PMID- 19782399 TI - Differential sensitivity of human leukemic cell lines to the histone deacetylase inhibitor, trichostatin A. AB - Histone deacetylase inhibitors (HDACIs) inhibit deacetylases and the accumulation of high levels of acetylation results in chromatin remodeling events which may lead to cell cycle arrest and apoptosis. This work investigates the sensitivity of four leukemic cell lines to the HDACI, trichostatin A (TSA) as compared to normal lymphocytes with respect to acetylation and apoptotic levels. Specifically, this study analyzes the time kinetics of histone H4 and alpha tubulin acetylation and associates these findings to the time course of TSA induced PARP cleavage and DFF45 proteolysis. The results of this study show (1) that a non-responsive leukemic cell line to the apoptotic effects of TSA does not have increased acetylation levels in contrast to the responsive leukemic cell lines that show a hyperacetylated profile. This indicates that acetylation levels may be of special importance in accessing the potential sensitivities of leukemic cells to HDACIs, (2) TSA induced apoptosis in lymphocytes but at lower levels and (3) the lack of PARP cleavage and DFF45 proteolysis found in lymphocytes clearly differentiates the final stages apoptosis of human peripheral blood lymphocytes from those of the TSA-sensitive leukemic cell lines. Of value is that the results of this study show that the evaluation of the acetylation levels of target proteins may possibly have the potential of being used as additional indicators of the responsiveness or sensitivity of different cancer cell types to this continuously growing class of anticancer agents. PMID- 19782400 TI - Toxicodynamics of subacute co-exposure to groundwater contaminant arsenic and analgesic-antipyretic drug acetaminophen in rats. AB - Arsenic is an environmental contaminant, while acetaminophen is an extensively used nonsteroidal analgesic-antipyretic drug. We evaluated whether subacute co exposure to arsenic and acetaminophen would produce more toxicity than that caused by exposure to either of the xenobiotics in rats. Toxicity was evaluated through changes in body weight, feed consumption, liver weight and microsomal drug-metabolizing enzymes, lipid peroxidation and antioxidants in liver. Arsenic had no effect on body weight and feed consumption. Acetaminophen-mediated decrease in body weight was attenuated in the co-exposed rats. Acetaminophen alone or its co-administration with arsenic decreased feed consumption. Arsenic reduced acetaminophen-mediated increase in the activities of drug-metabolizing enzymes. The co-exposure caused lesser lipid peroxidation than the individual exposure. Arsenic or acetaminophen given alone depleted GSH and decreased the activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glutathione-S-transferase and these effects remained mostly unaffected after co-exposure. The results suggest that co-exposure to arsenic and acetaminophen may be less hazardous than their independent exposure in rats. PMID- 19782401 TI - Chlamydia trachomatis evokes a relative anti-inflammatory response in a free Ca2+ dependent manner in human macrophages. AB - Chlamydia trachomatis infections manifest as unique, chronic inflammatory diseases, indicating a relative compromise in the capacity of early immune responders such as macrophages to resolve the infection. We decided to investigate whether or not the chronic inflammatory manifestations are influenced by a disturbance in the pattern of inflammatory:anti-inflammatory cytokine elaboration early in the infection cycle in macrophages and assess the possible modulatory role of Ca(2+) signals in the process. Although the basal and functional levels of IL-12 and IL-10 are not identical in concentration, chlamydia initiated a significant decline in IL-12. This led to a difference in the ratio of time-course decline in IL-12 compared with IL-10 in a Ca(2+)-poor medium, while there was significant increase in IL-10 in a Ca(2+)-rich medium. Also, when macrophages were infected after treatment with drugs that either facilitated Ca(2+) influx into cells or inhibited efflux from intracellular stores into cytosol, there was a significant enhancement of the elaboration of IL 10 compared with IL-12. The immobilization of cytosolic Ca(2+) by BAPTA-AM resulted in the decline of macrophage IL-12 and IL-10 in both infected and uninfected cases. There was evidence that infectivity and status of chlamydial elementary bodies harvested from macrophages during these experiments were consistent with chronic forms as assessed by HSP-60:MOMP ratio. The implication of these findings is that chlamydia infection of macrophages, together with its capacity to moderate macrophage intracellular Ca(2+) levels, may evoke a net anti inflammatory response that presumably favors chronic chlamydia infections. PMID- 19782402 TI - Usefulness of multislice computerized tomography angiography in preoperative diagnosis of ruptured cerebral aneurysms. AB - OBJECTIVE: Non-invasive imaging methods have become primordial in subarachnoid hemorrhage. The aim of our study was to evaluate the sensitivity and specificity of multislice computed tomographic angiography (MSCTA) for the diagnosis of cerebral aneurysm. METHODS: The 28 included consecutive patients with SAH underwent both MSCTA and digital subtraction angiography (DSA). The MSCTA studies were interpreted by two independent readers (A and B) for the presence, the location and size of the aneurysm comparatively to the DSA as reference examination. RESULTS: In 20 patients, 38 aneurysms were diagnosed and in eight no aneurysm was found. Per patient basis, the diagnostic sensitivity and specificity were excellent. Per aneurysm basis, the diagnostic sensitivity and specificity of MSCTA were, respectively, 97.4 and 100% for reader A, 100 and 100% for reader B. For aneurysms less than 3mm, sensitivity was 100% for both readers. Interobserver agreement was excellent for the detection of aneurysm (kappa=0.98, 95% CI [0.96 1]). Intertechnique and interobserver agreements were excellent for the measurement of aneurysms (slope=0.86, r=0.91 p=3.1x10(-7) and slope=1.04, r=0.99, p<10(-6), respectively). CONCLUSION: MSCTA was an accurate and reproducible non invasive imaging technique for preoperative diagnosis of ruptured cerebral aneurysm. The MSCTA may be proposed in first intention after the diagnosis of SAH was established, with special care regarding injection procedure and a strict reading method using native images and thin MPR. PMID- 19782403 TI - Stenting of a cerebral venous thrombosis. AB - Cerebral venous and sinus thrombosis (CVT) is a rare but potentially alarming condition, which remains a diagnostic and therapeutic challenge. Endovascular procedure may be a therapeutic option when evolution is unfavourable despite medical treatment, but the use of stenting is rarely reported in CVT treatment. We report the case of a man who presented a jugular vein thrombosis responsible for severe intracranial hypertension. Because of clinical worsening despite intravenous heparin and symptomatic treatment, endovascular procedure including the placement of five venous stents, thrombolysis and balloon angioplasty, was performed and led to venous recanalization with successful clinical outcome. The patient is still asymptomatic 3 years later. Our report shows that venous stenting could represent an efficient alternative in the management of decoagulation refractory CVT. PMID- 19782404 TI - Collecting true blue blood: a journey to the heart of 1960s biology. AB - Mabel Boyden was a biologist, active in the field of immunochemical research and also a custodian of the Serological Museum at Rutgers University between 1948 and 1974. Her recollection of a trip to obtain the blood of the horseshoe crab is revealing: it contains figures of speech that give a glimpse into the immunological discourse of the mid-1960s; it shows how her thinking was torn between different ways of doing biology; and it offers an insight into the transition of biology into the modern, molecular era. PMID- 19782405 TI - C/EBPzeta (CHOP/Gadd153) is a negative regulator of LPS-induced IL-6 expression in B cells. AB - C/EBPzeta was originally identified as a gene induced upon DNA damage and growth arrest. It has been shown to be involved in the cellular response to endoplasmic reticulum stress. Because of sequence divergence from other C/EBP family members in its DNA-binding domain and its consequent inability to bind the C/EBP consensus-binding motif, C/EBPzeta can act as a dominant negative inhibitor of other C/EBPs. C/EBP transactivators are essential to the expression of many proinflammatory cytokines and acute phase proteins, but a role for C/EBPzeta in regulating their expression has not been described. We found that expression of C/EBPzeta is induced in response to LPS treatment of B cells at both the mRNA and protein levels. Correlating with the highest levels of C/EBPzeta expression at 48 h after LPS treatment, there is an increased association of C/EBPzeta with C/EBPbeta, and both the abundance of C/EBP DNA-binding species and IL-6 expression are downregulated. Furthermore, ectopic expression of C/EBPzeta inhibited C/EBPbeta-dependent IL-6 expression from both the endogenous IL-6 gene and an IL-6 promoter-reporter. These results suggest that C/EBPzeta functions as negative regulator of IL-6 expression in B cells and that it contributes to the transitory expression of IL-6 that is observed after LPS treatment. PMID- 19782406 TI - Safety of a novel oxygen-coordinated niacin-bound chromium(III) complex (NBC): I. Two-generation reproduction toxicity study. AB - The objective of this study was to evaluate the effects of a novel oxygen coordinated niacin-bound chromium(III) complex (NBC) on the reproductive systems of male and female rats, the postnatal maturation and reproductive capacity of their offspring, and possible cumulative effects through multiple generations. Sprague-Dawley rats were maintained on feed containing NBC at dose levels of 0, 4, 15, or 60ppm for 10weeks prior to mating, during mating, and, for females through gestation and lactation, across two generations. For the parents (F(0) and F(1)) and the offspring (F(1) and F(2a)), reproductive parameters such as fertility and mating, gestation, parturition, litters, lactation, sexual maturity and development of offspring were assessed. Results from the current study indicated that dietary exposure of NBC to parental male and female rats of both (F(0) and F(1)) the generations during the premating and mating periods, for both sexes, and during gestation and lactation in case of female rats, did not cause any significant incidence of mortality or abnormal clinical signs. Compared to respective controls, NBC exposure did not affect reproductive performance as evaluated by sexual maturity, fertility and mating, gestation, parturition, litter properties, lactation and development of the offspring. Based on the findings of this study, the parental as well as the offspring no-observed-adverse effect level for NBC was determined to be greater than 60ppm in diet or equivalent to 7.80 and 8.31mg/kg body weight/day in male and female rats, respectively. PMID- 19782407 TI - Midline brain abnormalities in established bipolar affective disorder. AB - BACKGROUND: Morphologic changes of cortico-limbic regions have been reported in bipolar disorder, but it remains unclear whether midline brain abnormalities relevant to cortico-limbic connectivity are also present. METHODS: We used magnetic resonance imaging to investigate the size of the adhesio interthalamica (AI) and cavum septi pellucidi (CSP), as well as third ventricular volume, in 26 patients with bipolar I disorder and 24 matched controls. RESULTS: CSP length and prevalence of a large CSP did not differ between the groups, but bipolar patients had significantly shorter AI and larger third ventricles compared to controls. LIMITATIONS: A comprehensive investigation of medication effects was not possible due to incomplete medication data. CONCLUSIONS: These findings implicate a role for the AI and connected brain regions in the neurobiology of bipolar disorder. PMID- 19782408 TI - Analyses of cerebrospinal fluid in the diagnosis and monitoring of multiple sclerosis. AB - The laboratory evaluation of cerebrospinal fluid (CSF) has been routinely employed as a diagnostic test in the diagnosis of neuroimmunological disorders such as multiple sclerosis (MS). Recently, CSF analyses in MS have garnered renewed interest as a tool for monitoring disease activity and prognosis. With the identification of patients that are very early in their disease course, namely patients with a radiologically isolated (RIS) or a clinically isolated syndrome (CIS), the true value of these evaluations has yet to be fully explored. Ultimately, the hope is that biomarkers within this compartment will be identified that will identify etiologic factors of MS and other inflammatory disorders of the central nervous system. In this review we discuss the history of CSF diagnostic tests and the most recent methodological advances. We also outline the potentially important diagnostic role and possible limitations of these tests. PMID- 19782409 TI - Making a neuron: Cdk5 in embryonic and adult neurogenesis. AB - Cyclin-dependent kinase 5 (Cdk5) has been implicated in the migration, maturation and survival of neurons born during embryonic development. New evidence suggests that Cdk5 has comparable but also distinct functions in adult neurogenesis. Here we summarize accumulating evidence on the role of Cdk5 in regulation of the cell cycle, migration, survival, maturation and neuronal integration. We specifically highlight the many similarities and few tantalizing differences in the roles of Cdk5 in the embryonic and adult brain. We discuss the signaling pathways that might contribute to Cdk5 action in regulating embryonic and adult neurogenesis, highlighting future research directions that will help to clarify the mechanisms underlying lifelong neurogenesis in the mammalian brain. PMID- 19782410 TI - An evolutionarily adaptive neural architecture for social reasoning. AB - Recent progress in cognitive neuroscience highlights the involvement of the prefrontal cortex (PFC) in social cognition. Accumulating evidence demonstrates that representations within the lateral PFC enable people to coordinate their thoughts and actions with their intentions to support goal-directed social behavior. Despite the importance of this region in guiding social interactions, remarkably little is known about the functional organization and forms of social inference processed by the lateral PFC. Here, we introduce a cognitive neuroscience framework for understanding the inferential architecture of the lateral PFC, drawing upon recent theoretical developments in evolutionary psychology and emerging neuroscience evidence about how this region can orchestrate behavior on the basis of evolutionarily adaptive social norms for obligatory, prohibited and permissible courses of action. PMID- 19782412 TI - Accumulation and disposition of hexabromocyclododecane (HBCD) in juvenile rainbow trout (Oncorhynchus mykiss). AB - The brominated flame retardant hexabromocyclododecane (HBCD) has been reported in environmental samples worldwide. The three diastereomers, alpha-, beta- and gamma HBCD, behave differently in aquatic food webs; likely depending on different factors influencing assimilation efficiency and metabolism. In the present study, two oral exposure experiments with rainbow trout were performed to assess the role of selective uptake on diastereomer-specific accumulation and disposition of HBCD to liver, brain and muscle. In both experiments, juvenile rainbow trout (Oncorhynchus mykiss) were administrated a technical HBCD-mixture in commercial feed (10mgkg(-1)), followed by up to 21 days of food deprivation. Already 6h after exposure, the HBCD accumulation was significant, and the concentrations peaked 4-8 days after the exposure. The relative change in HBCD pattern during the accumulation process (0-8 days), suggested that there was a diastereomer selective uptake of alpha- and beta-HBCD in the rainbow trout. During the initial 48h, considerable amounts of all three diastereomers were distributed to liver, brain and muscle. A 70% reduction in SigmaHBCD levels after 21 days, indicated elimination of HBCD from brain and liver, but no clear elimination from the muscle was observed. Differences in HBCD pattern between organs at the end of the experiment support a proposal of an organ-specific diastereomer accumulation. PMID- 19782413 TI - DNA hypomethylation induced by tributyltin, triphenyltin, and a mixture of these in Sebastiscus marmoratus liver. AB - Tributyltin (TBT) and triphenyltin (TPT) coexist in freshwater and marine environments. However, the effects of TBT, TPT, and a mixture of the two on DNA methylation in marine fish livers and the mechanism involved remain to be elucidated. Previous study have proved that abnormal methylation patterns are induced by the balance of transmethylation reaction including the tissue level of S-adenosylmethionine (SAM), S-adenosylhomocysteine (SAH) or the activity of DNA (cytosine-5) methyltransferase 1 (DNMT1). Therefore, in the present study, we assessed their ability to cause hepatic DNA hypomethylation in Sebastiscus marmoratus liver and the related mechanism. The results showed that TBT, TPT, and a mixture of the two significantly induced DNA hypomethylation in the fish livers in a dose-dependent manner. Using Pearson correlation coefficient analysis, we identified strong linear correlations between S-adenosylhomocysteine, S adenosylmethionine, or the SAM to SAH ratio and the hepatic genome-wide 5 methylcytosine content of the DNA, but no correlation between the latter and the DNMT1 expression level. It is therefore proposed that the organotins hypomethylation induced in the marine fish livers was due to altering the balance of the substrate and the product in transmethylation reactions. PMID- 19782411 TI - Molecular dissection of reactive astrogliosis and glial scar formation. AB - Reactive astrogliosis, whereby astrocytes undergo varying molecular and morphological changes, is a ubiquitous but poorly understood hallmark of all central nervous system pathologies. Genetic tools are now enabling the molecular dissection of the functions and mechanisms of reactive astrogliosis in vivo. Recent studies provide compelling evidence that reactive astrogliosis can exert both beneficial and detrimental effects in a context-dependent manner determined by specific molecular signaling cascades. Reactive astrocytes can have both loss of normal functions and gain of abnormal effects that could feature prominently in a variety of disease processes. This article reviews developments in the signaling mechanisms that regulate specific aspects of reactive astrogliosis and highlights the potential to identify novel therapeutic molecular targets for diverse neurological disorders. PMID- 19782414 TI - Prevalence and associated risk factors for bovine tick infestation in two districts of lower Punjab, Pakistan. AB - Bovine tick infestation is still a serious nuisance to livestock and the dairy industry of Pakistan. The current paper reports the prevalence and associated risk factors for bovine tick infestation in the districts Layyah and Muzaffargarh of lower Punjab, Pakistan. A questionnaire-based survey was conducted to identify and to quantify variation in the prevalence of bovine tick infestation with respect to host (age, species, sex, and breed) and environmental (geographical area and climate) determinants. Multiple stage cluster random sampling was used and 3500 cattle and buffaloes from the two districts were selected. Prevalence of bovine tick infestation was significantly higher (OR=1.95; p<0.05) in cattle (1076/1475; 72.9%) than in buffaloes (957/2025; 47.3%). Hyalomma anatolicum anatolicum was the major tick species (33.5%; 1173/3500), followed by Rhipicephalus sanguineus (13%; 456/3500). The highest monthly prevalence in both the districts was found in July. Ticks were not found in Layyah from November to March and in Muzaffargarh from December to March. The average number of ticks was proportional to the prevalence of infestation. Also, tick infestation in a 7cmx7cm dewlap of the animal was proportional to that of the rest of body. Prevalence of tick infestation was associated (p<0.05) with district, host species and breed. In cattle, prevalence of tick infestation was associated (p<0.05) with age and sex of host. The results of this study provide better understanding of disease epidemiology in the study districts, which will help for planning of control strategies. PMID- 19782415 TI - Expert judgement in a risk assessment model for Salmonella spp. in pork: the performance of different weighting schemes. AB - A structured expert judgement study was carried out in order to obtain input parameters for a quantitative microbial risk assessment (QMRA) model. This model aimed to estimate the risk of human Salmonella infections associated with the consumption of minced pork meat. Judgements of 11 experts were used to derive subjective probability density functions (PDFs) to quantify the uncertainty on the model input parameters. The performance of experts as probability assessors was measured by the experts' ability to correctly and precisely provide estimates for a set of seed variables (=variables from the experts' area of expertise for which the true values were known to the analyst). Subsequently different weighting schemes or "decision makers" (DMs) were applied using Cooke's classical model in order to obtain combined PDFs as a weighted linear combination of the expert's individual PDFs. The aim of this study was to compare the performance of four DMs namely the equal weight DM (each expert's opinion received equal weight), the user weight DM (weights are determined by the expert's self perceived level of expertise) and two performance-based DMs: the global weight DM and the item weight DM. Weights in the performance-based DMs were calculated based on the expert's calibration and information performance as measured on the set of seed variables. The item weight DM obtained the highest performance with a calibration score of 0.62 and an information score of 0.52, as compared to the other DMs. The weights of the performance-based DMs outperformed those of the best expert in the panel. The correlation between the scores for self-rating of expertise and the weights based on the experts' performance on the calibration variables was low and not significant (r=0.37, p=0.13). The applied classical model provided a rational basis to use the combined distributions obtained by the item weight DM as input in the QMRA model since this DM yielded generally more informative distributions for the variables of interest than those obtained by the equal weight and user weight DM. Attention should be paid to find adequate and relevant seed variables, since this is important for the validation of the results of the weighting scheme. PMID- 19782416 TI - Trials, tricks and transparency: how disclosure rules affect clinical knowledge. AB - Scandals of selective reporting of clinical trial results by pharmaceutical firms have underlined the need for more transparency in clinical trials. We provide a theoretical framework which reproduces incentives for selective reporting and yields three key implications concerning regulation. First, a compulsory clinical trial registry complemented through a voluntary clinical trial results database can implement full transparency (the existence of all trials as well as their results is known). Second, full transparency comes at a price. It has a deterrence effect on the incentives to conduct clinical trials, as it reduces the firms' gains from trials. Third, in principle, a voluntary clinical trial results database without a compulsory registry is a superior regulatory tool; but we provide some qualified support for additional compulsory registries when medical decision-makers cannot anticipate correctly the drug companies' decisions whether to conduct trials. PMID- 19782417 TI - Recurrence pattern after [(18)F]fluoroethyltyrosine-positron emission tomography guided radiotherapy for high-grade glioma: a prospective study. AB - PURPOSE: To assess the failure pattern observed after (18)F fluoroethyltyrosine (FET) planning after chemo- and radiotherapy (RT) for high-grade glioma. METHODS: All patients underwent prospectively RT planning using morphological gross tumour volumes (GTVs) and biological tumour volumes (BTVs). The post-treatment recurrence tumour volumes (RTVs) of 10 patients were transferred on their CT planning. First, failure patterns were defined in terms of percentage of RTV located outside the GTV and BTV. Second, the location of the RTV with respect to the delivered dose distribution was assessed using the RTV's DVHs. Recurrences with >95% of their volume within 95% isodose line were considered as central recurrences. Finally, the relationship between survival and GTV/BTV mismatches was assessed. RESULTS: The median percentages of RTV outside the GTV and BTV were 41.8% (range, 10.5-92.4) and 62.8% (range, 34.2-81.1), respectively. The majority of recurrences (90%) were centrally located. Using a composite target volume planning formalism, the degree of GTV and BTV mismatch did not correlate with survivorship. CONCLUSIONS: The observed failure pattern after FET-PET planning and chemo-RT is primarily central. The target mismatch-survival data suggest that using FET-PET planning may counteract the possibility of BTV-related progression, which may have a detrimental effect on survival. PMID- 19782418 TI - 4D-CT-based target volume definition in stereotactic radiotherapy of lung tumours: comparison with a conventional technique using individual margins. AB - PURPOSE: To investigate the dosimetric benefit of integration of 4D-CT in the planning target volume (PTV) definition process compared to conventional PTV definition using individual margins in stereotactic body radiotherapy (SBRT) of lung tumours. MATERIAL AND METHODS: Two different PTVs were defined: PTV(conv) consisting of the helical-CT-based clinical target volume (CTV) enlarged isotropically for each spatial direction by the individually measured amount of motion in the 4D-CT, and PTV(4D) encompassing the CTVs defined in the 4D-CT phases displaying the extremes of the tumour position. Tumour motion as well as volumetric and dosimetric differences and relations of both PTVs were evaluated. RESULTS: Volumetric examinations revealed a significant reduction of the mean PTV by 4D-CT from 57.7 to 40.7 cm(3) (31%) (p<0.001). A significant inverse correlation was found for the motion vector and the amount of inclusion of PTV(4D) in PTV(conv) (r=-0.69, 90% confidence limits: -0.87 and -0.34, p=0.007). Mean lung dose (MLD) was decreased significantly by 17% (p<0.001). CONCLUSIONS: In SBRT of lung tumours the mere use of individual margins for target volume definition cannot compensate for the additional effects that the implementation of 4D-CT phases can offer. PMID- 19782419 TI - A randomized phase II study of CEOP with or without semustine as induction chemotherapy in patients with stage IE/IIE extranodal NK/T-cell lymphoma, nasal type in the upper aerodigestive tract. AB - PURPOSE: In this randomized phase II study, we evaluated the efficacy of semustine added to CEOP regimen as induction chemotherapy in patients with stage I(E)/II(E) extranodal NK/T-cell lymphoma, nasal type in the upper aerodigestive tract. PATIENTS AND METHODS: Seventy-five eligible patients were randomized to receive either CEOP or CEOP plus semustine followed by involved-field radiotherapy. RESULTS: The overall response rate of induction chemotherapy was 57.9% in CEOP arm compared with 62.2% in CEOP plus semustine arm (P=0.71). With a median follow-up of 30.1 months, 2-year overall survival was 73.3% and 62.2%, respectively (P=0.37). Toxicities in both arms were comparable and manageable. Through univariate and multivariate analysis, PS of 2, Stage II(E) and elevated LDH level were identified to be adverse prognostic factors. A new prognostic index categorized three groups of patients (low risk, no adverse factors; intermediate risk, one factor; and high risk, 2 or 3 factors) with highly significant difference of prognosis. Two-year overall survival was 87.5%, 60.6% and 30%, respectively (P=0.0002). CONCLUSIONS: The addition of semustine to CEOP regimen was not associated with improved efficacy. More effective treatment needs to be explored in patients with intermediate or high risk. PMID- 19782420 TI - The effect of planning algorithms in oesophageal radiotherapy in the context of the SCOPE 1 trial. AB - BACKGROUND AND PURPOSE: In radiotherapy clinical trials multiple centres contribute to patient recruitment. Depending on the calculation algorithm used, the reported dose distributions may differ significantly: broadly, the results for algorithms which do not model lateral electron transport (type a) give less accurate results than the more recently available algorithms that do (type b) when compared to Monte Carlo simulations and measurements. Clinical implementation studies for type b algorithms have yet to be reported for oesophageal radiotherapy. Furthermore, clinical trials must ensure an equivalent effect of the treatment regardless of calculation method. This retrospective planning study aims to define guidance for type b planning in a UK oesophageal clinical trial, to enable acceptable consistency of dose distributions regardless of algorithm, and allow for the improved calculation accuracy of type b to be incorporated into the optimization. MATERIALS AND METHODS: Fifteen patient data sets were planned using a single type a algorithm. Plans were recalculated using a single type b algorithm and subsequently re-optimized with the type b in accordance with optimization rules. The changes in absolute dose at the point of prescription for type a were compared to the recalculated type b. Dose-volume data for organs at risk (OARs), and target volumes were compared, and the volume of the planning target volume (PTV) receiving 95% of the prescribed dose (V95%) was compared to the percentage of PTV overlapping with lung. RESULTS: Dose at the prescription point decreased by 0.69% on average (SD=0.71), p=0.0021, for type b compared to that for type a. For the re-optimized type b, the OAR doses corresponding to the trial dose-volume constraints were maintained within 1.0% of the type a levels on average. Reductions in the mean PTV V95% of 9.3% and 3.8% were observed for the recalculated and re-optimized type b plans, respectively, when compared to the mean PTV V95% for type a. For the re-optimized type b there is a correlation between PTV V95% and the percentage of PTV overlapping lung (R(2)=0.4979). CONCLUSIONS: Plan optimization with the type b algorithm results in improved PTV V95%. Using our suggested optimization rules, equivalent OAR doses can be maintained with both types. For type b, this requires a measured level of compromise to PTV in low density tissue, quantified by the relationship between PTV V95% and the percentage of PTV in lung. PMID- 19782422 TI - A pooled analysis of 29 patients with fulminant type 1 diabetes in Korea: a comparison with a nationwide survey in Japan. AB - We performed a retrospective pooled analysis of 29 patients who had been diagnosed with fulminant type 1 diabetes in Korea and compared the results with 161 patients' data from a nationwide survey in Japan. Fulminant type 1 diabetic patients in Korea have a similar phenotype compared with Japanese patients. PMID- 19782423 TI - Variation in the perilipin gene (PLIN) affects glucose and lipid metabolism in non-Hispanic white women with and without polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women. It is characterized by chronic anovulation, hyperandrogenism, obesity and a predisposition to type 2 diabetes mellitus (T2DM). Since obesity plays an important role in the etiology of PCOS, we sought to determine if variants in the perilipin gene (PLIN), a gene previously implicated in the development of obesity, were also associated with PCOS. We typed six single nucleotide polymorphisms (haplotype tagging and/or previously associated with obesity or related metabolic traits) in PLIN in 305 unrelated non-Hispanic white women (185 with PCOS and 120 without PCOS). None of the variants was associated with PCOS (P<0.05). However, the variant rs1052700*A was associated with increased risk for glucose intolerance (impaired glucose tolerance or T2DM) in both non-PCOS (OR=1.75 [1.02-3.01], P=0.044) and PCOS subjects (OR=1.67 [1.08-2.59], P=0.022). It was also associated with increased LDL (P=0.007) and total cholesterol levels (P=0.042). These results suggest that genetic variation in PLIN may affect glucose and lipid metabolism in women both with and without PCOS. PMID- 19782424 TI - GPU-based cone beam computed tomography. AB - The use of cone beam computed tomography (CBCT) is growing in the clinical arena due to its ability to provide 3D information during interventions, its high diagnostic quality (sub-millimeter resolution), and its short scanning times (60 s). In many situations, the short scanning time of CBCT is followed by a time consuming 3D reconstruction. The standard reconstruction algorithm for CBCT data is the filtered backprojection, which for a volume of size 256(3) takes up to 25 min on a standard system. Recent developments in the area of Graphic Processing Units (GPUs) make it possible to have access to high-performance computing solutions at a low cost, allowing their use in many scientific problems. We have implemented an algorithm for 3D reconstruction of CBCT data using the Compute Unified Device Architecture (CUDA) provided by NVIDIA (NVIDIA Corporation, Santa Clara, California), which was executed on a NVIDIA GeForce GTX 280. Our implementation results in improved reconstruction times from minutes, and perhaps hours, to a matter of seconds, while also giving the clinician the ability to view 3D volumetric data at higher resolutions. We evaluated our implementation on ten clinical data sets and one phantom data set to observe if differences occur between CPU and GPU-based reconstructions. By using our approach, the computation time for 256(3) is reduced from 25 min on the CPU to 3.2 s on the GPU. The GPU reconstruction time for 512(3) volumes is 8.5 s. PMID- 19782425 TI - Disease spread, susceptibility and infection intensity: vicious circles? AB - Epidemiological models and studies of disease ecology typically ignore the role of host condition and immunocompetence when trying to explain the distribution and dynamics of infections and their impact on host dynamics. Recent research, however, indicates that host susceptibility should be considered carefully if we are to understand the mechanism by which parasite dynamics influence host dynamics and vice versa. Studies in insects, fish, amphibians and rodents show that infection occurrence and intensity are more probable and more severe in individuals with an underlying poor condition. Moreover, infection itself results in further deterioration of the host and a 'vicious circle' is created. We argue that this potential synergy between host susceptibility and infection should be more widely acknowledged in disease ecology research. PMID- 19782426 TI - Blood monocytes stimulate migration of human pancreatic carcinoma cells in vitro: the role of tumour necrosis factor - alpha. AB - In some types of cancers, tumour-infiltrating monocytes/macrophages (TIM) may be responsible for the formation of an invasive microenvironment in a manner dependent on the secretion of soluble mediators such as tumour necrosis factor alpha (TNF). Human pancreatic carcinoma (HPC-4) cells are able to induce TNF production by monocytes. Here, the effect of human peripheral blood monocytes, precursors of TIM, on the motility of co-cultured HPC-4 cells, was directly analysed in vitro. A phenotypic transition, i.e., the appearance of rear-front polarised HPC-4 cells paralleled by their increased motility, and increased motility of monocytes, were observed. This effect was attenuated when HPC-4 cells and monocytes were co-cultured in the presence of inhibitors of TNF production and anti-TNF monoclonal antibodies, indicating the specific role of this cytokine in determining paracrine loops between monocytes and cancer cells. Moreover, exogenous TNF induced HPC-4 cell motility concomitantly to the appearance of cellular features characteristic for epithelial-mesenchymal transition (EMT) such as rear-front polarisation, rearrangements of the actin cytoskeleton characteristic for motile cells and the induction of Snail-1 expression. Since cell movement is crucial for cancer invasion and the formation of metastases, these findings demonstrate an EMT-dependent mechanism of cancer progression which acts through the phenotypic transition of pancreatic cancer cells dependent on monocyte-derived TNF. PMID- 19782427 TI - Molecular mechanisms underlying the pro-inflammatory synergistic effect of tumor necrosis factor alpha and interferon gamma in human microvascular endothelium. AB - Tumor necrosis factor alpha (TNFalpha) and interferon gamma (IFNgamma) are among the most potent cytokines involved in orchestrating the inflammation response. The molecular mechanisms implicated in the synergism between cytokines are still poorly characterized. We demonstrate that both cytokines dose-dependently stimulate IFNgamma-inducible-protein-of-10-kDa (IP-10) secretion in human microvascular endothelial cells (HMEC-1), showing a potent synergism which is not restricted to IP-10, but is also evident for monokine-induced-by-IFNgamma (MIG) and IL-6 secretion. Immunofluorescence analysis reveals that TNFalpha and IFNgamma converge on a rapid phosphorylation of ERK, which however results in a different subcellular compartmentalization of the activated enzyme in response to the two cytokines. Differences in the subcellular recruitment of ERK in response to IFNgamma and TNFalpha are responsible for generating different ERK downstream signaling, which can thus synergize on the secretion of IP-10 as well as of other cytokines/chemokines. The importance of ERK activation in mediating the synergism of the two cytokines is further confirmed by the inhibitory effect of the anti diabetic drug rosiglitazone and ERK blockers on IP-10, MIG and IL-6 secretion. A further mechanism of synergism involving the reciprocal upregulation of TNFalpha RII and of IFNgamma-R, in response to IFNgamma and TNFalpha, respectively, was revealed by flow cytometry and quantitative real time RT-PCR analysis. PMID- 19782430 TI - Risk factors for nosocomial infection during extracorporeal membrane oxygenation. AB - An increasing number of patients receive extracorporeal membrane oxygenation (ECMO) for life support. This study aimed to investigate the incidence and risk factors for nosocomial infection in adult patients receiving ECMO. We reviewed the medical records of adult patients who received ECMO support for more than 72h at Far Eastern Memorial Hospital from 2001 to 2007. ECMO-related nosocomial infections were defined as infections occurring from 24h after ECMO initiation until 48h after ECMO discontinuation. There were 12 episodes of nosocomial infection identified in 10 of the 114 (8.77%) patients on ECMO, including four cases of pneumonia, three cases of bacteraemia, three surgical site infections and two urinary tract infections. The incidence of ECMO-related nosocomial infection was 11.92 per 1000 ECMO-days. The length of ECMO use and intensive care unit (ICU) stay were significantly different between patients with, and without, nosocomial infection (P<0.001). More than 10 days of ECMO use was associated with a significantly higher nosocomial infection rate (P=0.003). Gram-negative bacilli were responsible for 78% of the nosocomial infections. In the univariate analysis, the duration of ICU stay and duration of ECMO use were associated with nosocomial infection. In the multivariate analysis, only the duration of ECMO was independently associated with nosocomial infection (P=0.007). Overall, the only independent risk factor for ECMO-related nosocomial infection identified in this study was prolonged ECMO use. PMID- 19782428 TI - Cloning and expression of 1-deoxy-d-xylulose 5-phosphate synthase cDNA from Croton stellatopilosus and expression of 2C-methyl-d-erythritol 4-phosphate synthase and geranylgeranyl diphosphate synthase, key enzymes of plaunotol biosynthesis. AB - 1-Deoxy-d-xylulose 5-phosphate synthase (DXS, EC: 4.1.3.37), the first enzyme in the 2C-methyl-d-erythritol 4-phosphate (MEP) pathway, is known to be responsible for the rate-limiting step of isoprenoid biosynthesis in Escherichia coli and Arabidopsis thaliana. In this study, the dxs gene from Croton stellatopilosus, designated csdxs, was cloned from leaf tissue using the rapid amplification of cDNA ends (RACE) technique. Leaves of C. stellatopilosus contain plaunotol, an acyclic diterpene alcohol. The csdxs cDNA containing the open reading frame of 2163 base pairs appeared to encode a polypeptide of 720 amino acids. Analysis of the deduced amino acid sequence revealed that the NH(2)-terminus of CSDXS carried a chloroplast transit peptide, a thiamine diphosphate binding site, and a transketolase motif, which are the important characteristics of DXS enzymes in higher plants. Multiple alignments of CSDXS with other plant DXSs have indicated that CSDXS has identity ranging between 68% and 89%. Expression levels of csdxs and genes encoding key enzymes in the plaunotol biosynthetic pathway, namely 2C methyl-d-erythritol 4-phosphate synthase (meps) and geranylgeranyl diphosphate synthase (ggpps), were analysed by measuring transcript levels in leaves of different developmental stages. The results showed that dxs, meps, and ggpps are all active in young leaves prior to full expansion when plaunotol is synthesised from the DXP precursor in chloroplasts. The dense presence of chloroplasts and oil globules in the palisade cells of these leaves support the view that these genes are involved in plaunotol biosynthesis in chloroplast-containing tissues. PMID- 19782431 TI - De-escalation for amoxicillin-susceptible Escherichia coli: easier said than done. PMID- 19782432 TI - Clinical and molecular characteristics of nosocomial meticillin-resistant Staphylococcus aureus skin and soft tissue isolates from three Indian hospitals. AB - We analysed risk factors for nosocomial meticillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infections (SSTIs) in three Indian hospitals. We also determined antimicrobial resistance patterns and genotypic characteristics of MRSA isolates using pulsed-field gel electrophoresis (PFGE), multilocus sequence typing (MLST) and staphylococcal cassette chromosome (SCCmec) typing. Medical records of 709 patients admitted to three tertiary hospitals with nosocomial S. aureus SSTIs were clinically evaluated. Antimicrobial susceptibility testing of patient isolates was performed in accordance with Clinical and Laboratory Standards Institute guidelines, with meticillin and mupirocin resistance confirmed by multiplex polymerase chain reaction. PFGE analysis of 220 MRSA isolates was performed, followed by MLST and SCCmec typing of a selected number of isolates. MRSA was associated with 41%, 31% and 7.5% of infections at the three hospitals, respectively. Multiple logistic regression analysis identified longer duration of hospitalisation [odds ratio (OR): 1.78; OR: 2.83 for >or=20 days], intra-hospital transfer (OR: 1.91), non-infectious skin conditions (3.64), osteomyelitis (2.9), neurological disorders (2.22), aminoglycoside therapy (1.74) and clindamycin therapy (4.73) as independent predictors for MRSA SSTIs. MRSA isolates from all three hospitals were multidrug resistant, with fifteen clones (I-XV) recognised. A majority of the strains possessed type III cassette. The common sequence type (ST) 239 was considered the signature MLST sequence for PFGE clone III. This major MRSA clone III was closely related to the UK EMRSA-1 and was significantly more resistant to antibiotics. Dissemination of multidrug-resistant MRSA clones warrants continuous tracking of resistant genotypes in the Indian subcontinent. PMID- 19782433 TI - Thermostable adenylate kinase technology: a new process indicator and its use as a validation tool for the reprocessing of surgical instruments. AB - Adenylate kinase (tAK), a thermostable enzyme, was assessed as a possible means of providing a quantitative measure of cleaning efficacy suitable for validating the performance of an automated washer disinfector (AWD) during routine use. Two indicator formulations were developed using either a commercially available washer disinfector soil or a protein-based soil. Each indicator consisted of 100 microg (in test soil) of tAK dried on to a steel or plastic surface. These indicators were placed in each basket of a washer disinfector and processed alongside soiled surgical instruments during a standard day's operation. After processing, remaining tAK activity was detected using a rapid enzyme assay (2 min detection time) in a handheld hygiene monitor. The amount of tAK remaining on each indictor after a full AWD cycle was found to range from 0.1 to 0.4 ng, which represented a mean log(10) removal of 5.8+/-0.3. There was no statistical difference in the residual tAK activity between individual runs or the position of the indicator in the machine. The tAK indicator was also used to analyse the protein removal within each component of the wash cycle. These results demonstrated that all phases of the wash process contributed to the removal of the protein load, with the main wash alone being responsible for 3.6-4.0 log(10) reductions in protein activity. We propose that a quantitative cleaning index using such rapid readout indicator devices would provide a valuable addition to the methodologies for validating cleaning processes. PMID- 19782434 TI - Gigaxonin mutation analysis in patients with NIFID. AB - Neuronal intermediate filament inclusion disease (NIFID) is a frontotemporal lobar degeneration (FTLD) characterized by frontotemporal dementia (FTD), pyramidal and extrapyramidal signs. The disease is histologically characterized by the presence of abnormal neuronal cytoplasmic inclusions (NCIs) which contain alpha-internexin and other neuronal intermediate filament (IF) proteins. Gigaxonin (GAN) is a cytoskeletal regulating protein and the genetic cause of giant axonal neuropathy. Since the immunoreactive profile of NCIs in NIFID is similar to that observed in brain sections from Gan(Deltaex1/Deltaex1) mice, we speculated that GAN could be a candidate gene causing NIFID. Therefore, we performed a mutation analysis of GAN in NIFID patients. Although the NCIs of NIFID and Gan(Deltaex1/Deltaex1) mice were immunohistochemically similar, no GAN variant was identified in DNA obtained from well-characterized cases of NIFID. PMID- 19782435 TI - Age-related changes in the functional neuroanatomy of overt speech production. AB - Alterations of existing neural networks during healthy aging, resulting in behavioral deficits and changes in brain activity, have been described for cognitive, motor, and sensory functions. To investigate age-related changes in the neural circuitry underlying overt non-lexical speech production, functional MRI was performed in 14 healthy younger (21-32 years) and 14 healthy older individuals (62-84 years). The experimental task involved the acoustically cued overt production of the vowel /a/ and the polysyllabic utterance /pataka/. In younger and older individuals, overt speech production was associated with the activation of a widespread articulo-phonological network, including the primary motor cortex, the supplementary motor area, the cingulate motor areas, and the posterior superior temporal cortex, similar in the /a/ and /pataka/ condition. An analysis of variance with the factors age and condition revealed a significant main effect of age. Irrespective of the experimental condition, significantly greater activation was found in the bilateral posterior superior temporal cortex, the posterior temporal plane, and the transverse temporal gyri in younger compared to older individuals. Significantly greater activation was found in the bilateral middle temporal gyri, medial frontal gyri, middle frontal gyri, and inferior frontal gyri in older vs. younger individuals. The analysis of variance did not reveal a significant main effect of condition and no significant interaction of age and condition. These results suggest a complex reorganization of neural networks dedicated to the production of speech during healthy aging. PMID- 19782436 TI - [Dementia, end of life and geriatrics]. PMID- 19782437 TI - [Influence of the immigrant population in the variability of the rate of abortions among autonomous communities]. PMID- 19782438 TI - [Partisan versions, facts and truth]. PMID- 19782439 TI - Stereoselective synthesis and antimicrobial activity of benzofuran-based (1E)-1 (piperidin-1-yl)-N2-arylamidrazones. AB - The reaction of 2-oxo-N-arylpropanehydrazonoyl chlorides 3a-e with 3-methyl-2 benzofurancarboxylic acid hydrazide (7) furnished N-(aryl)propanehydrazonoyl chlorides 8a-e. X-Ray of 8c revealed the (1Z,2E) configuration of structure 8. Nucleophilic substitution reaction of 8a or 8d with piperidine resulted in the formation of 1-(piperidin-1-yl)-N(2)-arylamidrazones 9a, b. The X-ray diffraction of 9b showed its (1E,2E) configuration and it confirmed the stereoselectivity of the latter reaction. (1E,2Z,3E)-1-(Piperidin-1-yl)-1-(arylhydrazono)-2-[(3 methylbenzofuran-2-oyl)hydrazono]-4-arylbut-3-enes 11 were synthesized in stereoselective reaction from 8 or alternatively from 9. X-ray analysis of 11b showed a conversion of configuration respect to 8d or 9b. X-Ray analysis of 9b and 11b revealed the role of hydrogen interactions in the stereochemistry of their solid state structure. The in vitro antimicrobial activity of the newly synthesized compounds demonstrated an excellent growth inhibition of compounds 9 and 11 against clinically isolated strains of human fungal pathogens and exhibited a significant potency against gram-positive bacteria. Griseofulvin and Amoxicilline were used as references for antifungal and antibacterial screening. The effect of most potent antifungal compound 9b on morphological features of Aspergillus fumigatus and Candida albicans using image analyzer was studied. Furthermore, the effect of 9b on the ultra-structures of the latter fungi was occurred by transmission electron microscope. PMID- 19782440 TI - Known drug space as a metric in exploring the boundaries of drug-like chemical space. AB - In this work, marketed drug compounds (or known drug space) were used as a metric to test the principles of eliminating parent structures of the nitrenium ion (aryl-amine/nitro compounds) as well as sulphur and halogen containing molecules from screening compound collections. Molecules containing such moieties and/or atoms have biological and physiochemical properties, which possibly make them less attractive as leads in drug development. It was found that precursors to the nitrenium ion were relatively abundant in known drug space at 14%. Thus, their simple elimination from drug-like chemical space is not advisable. Interestingly, the mutagenic potential of the nitrenium ions is linked to their stability and quantum mechanical calculations can be used to estimate it. Furthermore, 24% of drugs investigated contained sulphur atoms and around 28% were halogenated. As some sulphur containing moieties were abundant whilst others were scarce, it was deduced that it would be more effective to eliminate specific molecular scaffolds rather than all sulphur containing molecules. In conclusion, it has been shown that by statistically analysing known drug space a better understanding of the boundaries of drug-like chemical space was established which can help medicinal chemists in finding rewarding regions of chemical space. PMID- 19782441 TI - [Liver involvement in sarcoidosis: study of seven cases]. AB - INTRODUCTION: Sarcoidosis is a systemic disorder of unknown aetiology that may involve many organs including the liver. METHODS: This is a monocentre retrospective and descriptive study over 12 years of patients with systemic sarcoidosis who presented with liver involvement. RESULTS: Amongst 21 patients with systemic sarcoidosis, seven presented a liver involvement (five males and two females; mean age 42.5 years). The liver involvement was the presenting manifestation in three. Liver enlargement was noted in five patients and abnormal liver function tests in four. In one patient, abdominal computed tomographic scan showed a nodular hepatomegaly. Liver histology demonstrated typical granulomatous lesions in six. One patient developed a Budd-Chiari syndrome that responded favourably to corticosteroids. Six out of the seven patients were treated with corticosteroids. CONCLUSION: Liver involvement in common in sarcoidosis and commonly asymptomatic. Treatment is not systematic. PMID- 19782442 TI - [Gaucher's disease in Rennes University hospital: a 10-year retrospective study]. AB - INTRODUCTION: Gaucher's disease (GD) remains rare and cohort studies are essential to improve our knowledge of this disease. METHODS: We performed a 10 year retrospective study of patients with GD followed-up in the Rennes University teaching hospital. RESULTS: Among a population of 1,500,000 inhabitants, 12 patients with GD were identified. Eight were men, and four were women. Mean age at diagnosis was 32.3 years and the first symptoms appeared around 31 years old. Main symptoms were: splenomegaly (82%), hepatomegaly (64%), thrombocytopenia (73%), anemia (64%), deterioration of general status (45%), bone pain (27%). Parkinsonism was noted in two patients, polyclonal gammopathy in two others, and monoclonal gammopathy was evidenced in four patients, with chronic lymphocytic lymphoma in one of them. Enzymatic activity dosage confirmed the diagnosis of GD for eight patients. For the remaining four patients, diagnosis was obtained by identification of Gaucher's cells on tissue examination. Substitutive enzymotherapy (SE) was performed for seven patients, with great improvement of initial symptoms. For two of these seven patients, SE is changed for miglustat with persistent improvement of clinical status. CONCLUSION: Association between GD and Parkinsonism or between GD and gammopathy was confirmed in our study. Other cohort studies are needed to improve the knowledge of GD. PMID- 19782443 TI - Nutritional and exercise-based interventions in the treatment of amyotrophic lateral sclerosis. AB - BACKGROUND & AIMS: Disease pathogenesis in amyotrophic lateral sclerosis (ALS) involves a number of interconnected mechanisms all resulting in the rapid deterioration of motor neurons. The main mechanisms include enhanced free radical production, protein misfolding, aberrant protein aggregation, excitotoxicity, mitochondrial dysfunction, neuroinflammation and apoptosis. The aim of this review is to assess the efficacy of using nutrition- and exercise-related interventions to improve disease outcomes in ALS. METHODS: Studies involving nutrition or exercise in human and animal models of ALS were reviewed. RESULTS: Treatments conducted in animal models of ALS have not consistently translated into beneficial results in clinical trials due to poor design, lack of power and short study duration, as well as differences in the genetic backgrounds, treatment dosages and disease pathology between animals and humans. However, vitamin E, folic acid, alpha lipoic acid, lyophilized red wine, coenzyme Q10, epigallocatechin gallate, Ginkgo biloba, melatonin, Cu chelators, and regular low and moderate intensity exercise, as well as treatments with catalase and l carnitine, hold promise to mitigating the effects of ALS, whereas caloric restriction, malnutrition and high-intensity exercise are contraindicated in this disease model. CONCLUSIONS: Improved nutritional status is of utmost importance in mitigating the detrimental effects of ALS. PMID- 19782444 TI - Radiological hazards of TENORM in the wasted petroleum pipes. AB - Disposal petroleum pipes containing sludge and scale as a technically enhanced natural occurring radioactive material (TENORM) leads to internal and external radiation hazards and then a significant radiation dose to the workers. In order to contribute to a future waste management policy related to the presence of TENORM in the disposal sites of wasted petroleum pipes, scale and sludge as TENORM wastes are collected form these disposal pipes for radiometric analysis. These pipes are imported from onshore oilfields at south Sinai governorate, Egypt. The highest mean (226)Ra and (228)Ra concentrations of 519 and 50 kBq/kg respectively, were measured in scale samples. Sludge lies within the normal range of radium concentration. The average absorbed dose caused by the exposure to the wasted pipes equal to 4.09 microGy h(-1) from sludge and 262 microGy h(-1) from scale. This is much higher than the acceptable level of 0.059 microGy h(-1). Due to radon inhalation, important radon related parameters are calculated which advantage in internal dose calculation. Fairly good correlation between real radium content and radon exhalation rate for sludge samples is obtained. The hazards from sludge come from its high emanation power for radon which equal to 3.83%. The obtained results demonstrate the need of screening oil residues for their radionuclide content in order to decide about their final disposal. PMID- 19782445 TI - Safety and efficacy of herbal remedies in obstetrics-review and clinical implications. AB - OBJECTIVE: to review the literature on safety and efficacy of the most commonly used herbs to enable midwives to give evidence-based information to pregnant women. DESIGN: survey and review of the scientific literature. SETTING: the survey was performed at the antenatal clinic at Norfolk and Norwich University Hospital between 26 November 2007 and 15 February 2008. PARTICIPANTS: a total of 578 expectant mothers at least 20-weeks pregnant. MEASUREMENTS AND FINDINGS: 57.8% of the participants used one or more herbal remedies. The most commonly used herbal preparations during pregnancy were ginger, cranberry, raspberry leaf, chamomile, peppermint and echinacea. Altogether, 14 studies focusing on the safety and/or efficacy of these herbals in human pregnancy were identified. Ten studies of ginger, one of cranberry, two of raspberry leaf and one of echinacea were located. KEY CONCLUSIONS: there is limited documentation on the safety and efficacy of many herbs commonly used during pregnancy. IMPLICATIONS FOR PRACTICE: midwives are important caregivers for pregnant women and should strive to give evidence-based advice on herbal use in pregnancy. If 'traditional use' is the only available information, the pregnant woman should be made aware of this to enable her to make an informed decision about the eventual use. PMID- 19782446 TI - Localization of hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX) and 2,4,6 trinitrotoluene (TNT) in poplar and switchgrass plants using phosphor imager autoradiography. AB - Phosphor imager autoradiography is a technique for rapid, sensitive analysis of the localization of xenobiotics in plant tissues. Use of this technique is relatively new to research in the field of plant science, and the potential for enhancing visualization and understanding of plant uptake and transport of xenobiotics remains largely untapped. Phosphor imager autoradiography is used to investigate the uptake and translocation of the explosives 1,3,5-trinitro-1,3,5 triazine (RDX) and 2,4,6-trinitrotoluene within Populus deltoides x nigra DN34 (poplar) and Panicum vigratum Alamo (switchgrass). In both plant types, TNT and/or TNT-metabolites remain predominantly in root tissues while RDX and/or RDX metabolites are readily translocated to leaf tissues. Phosphor imager autoradiography is further investigated for use in semi-quantitative analysis of uptake of TNT by switchgrass. PMID- 19782447 TI - Diet shifts during egg laying: Implications for measuring contaminants in bird eggs. AB - We combined stable isotope tracers of blood plasma, blood cells and egg contents with faecal analysis during pre-breeding and egg laying phases in two dipper species Cinclus cinclus and Cinclus mexicanus to determine the occurrence of dietary shifts during egg production and to assess consequences for egg contaminant loads. In both species, changes in delta(13)C (C. cinclus) or delta(15)N (C. mexicanus) in female plasma relative to red blood cells indicated a dietary shift during laying that was not observed in males. Eurasian dippers increased prey consumption as breeding approached, shifting from primarily trichopteran insect larvae to ephemeropterans and plecopterans. In American dippers, egg-laying females switched to feeding at a higher trophic level by consuming more fish. Eggs derived from higher trophic level diets contained more mercury (American dipper), polychlorinated biphenyls and some organochlorines, especially DDT metabolites. The results demonstrate how dietary changes during egg laying accompany the demands for egg production with consequences for contaminant deposition in avian eggs. PMID- 19782448 TI - Lichens as an integrating tool for monitoring PAH atmospheric deposition: a comparison with soil, air and pine needles. AB - The aim of this study was to validate lichens as biomonitors of PAH atmospheric deposition; for that, an inter-comparison between the PAH profile and concentrations intercepted in lichens with those of air, soil and pine needles was performed. The study was conducted in a petro-industrial area and the results showed that PAH profiles in lichens were similar to those of the air and pine needles, but completely different from those of soils. Lichens accumulated higher PAH concentrations when compared to the other environmental compartments and its concentrations were significantly and linearly correlated with concentrations of PAHs in soil; we showed that a translation of the lichen PAHs concentrations into regulatory standards is possible, fulfilling one of the most important requirements of using lichens as biomonitors. With lichens we were then able to characterize the air PAHs profile of urban, petro-industrial and background areas. PMID- 19782449 TI - Effects of wastewater discharge on formation of Fe plaque on root surface and radial oxygen loss of mangrove roots. AB - Effects of wastewater discharge on radial oxygen loss (ROL), formation of iron (Fe) plaque on root surface, and their correlations in Bruguiera gymnorrhiza (L.) Poir and Excoecaria agallocha L. were investigated. ROL along a lateral root increased more rapidly in control than that in strong wastewater (with pollutant concentrations ten times of that in municipal sewage, 10NW) treatment, but less Fe plaque was formed in control for both plants. For B. gymnorrhiza receiving 10NW, Fe plaque formation was more at basal and mature zones than at root tip, while opposite trend was shown in E. agallocha. At day 0, the correlation between ROL and Fe plaque was insignificant, but negative and positive correlations were found in 10NW and control, respectively, at day 105, suggesting that more ROL was induced leading to more Fe plaque. However, excess Fe plaque also served as a 'barrier' to prevent excessive ROL in 10NW plants. PMID- 19782450 TI - Nonlinear binding of phenanthrene to the extracted fulvic acid fraction in soil in comparison with other organic matter fractions and to the whole soil sample. AB - Fractions of soil organic matter in a natural soil were extracted and sorption (or binding) characteristics of phenanthrene on each fraction and to the whole sample were investigated. The organic carbon normalized single point sorption (or binding) coefficient followed lipid > humin (HM) > humic acid (HA) > fulvic acid (FA) > whole soil sample, while the nonlinear exponent exhibited lipid > FA > HA > whole soil sample > HM. FA showed nonlinear binding of phenanthrene as it often does with other fractions. HM and HA contributed the majority of organic carbon in the soil. The calculated sorption coefficients of the whole soil were about two times greater than the measured values at different equilibrium phenanthrene concentrations. As for phenanthrene, the sorption capacity and nonlinearity of the physically mixed HA-HM mixtures were stronger as compared to the chemically reconstituted HA-HM composite. This was attributed to (besides the conditioning effect of the organic solvents) interactions between HA and HM and acid-base additions during fractionation. PMID- 19782451 TI - Recurrent pauci-immune necrotizing crescentic glomerulonephritis in a kidney transplant patient. PMID- 19782452 TI - Development of encapsulating peritoneal sclerosis following bacterial peritonitis in a peritoneal dialysis patient. PMID- 19782453 TI - Is choice of antihypertensive agent important in improving cardiovascular outcomes in high-risk hypertensive patients? PMID- 19782454 TI - Obesity and change in estimated GFR among older adults. AB - BACKGROUND: The prevalence of chronic kidney disease is growing most rapidly among older adults; however, determinants of impaired kidney function in this population are not well understood. Obesity assessed in midlife has been associated with chronic kidney disease. STUDY DESIGN: Cohort study. SETTING & PARTICIPANTS: 4,295 participants in the community-based Cardiovascular Health Study, aged >or= 65 years. PREDICTORS: Body mass index, waist circumference, and fat mass measured using bioelectrical impedance. OUTCOME: Change in glomerular filtration rate (GFR) during 7 years of follow-up. MEASUREMENTS: Longitudinal estimates of GFR calculated using the 4-variable Modification of Diet in Renal Disease (MDRD) Study equation. RESULTS: Estimated GFR decreased by an average of 0.4 +/- 3.6 mL/min/1.73 m(2)/y, and rapid GFR loss (>3 mL/min/1.73 m(2)/y) occurred in 693 participants (16%). Baseline body mass index, waist circumference, and fat mass were each associated with increased risk of rapid GFR loss: ORs, 1.19 (95% CI, 1.09-1.30) per 5 kg/m(2), 1.25 (95% CI, 1.16-1.36) per 12 cm, and 1.14 (95% CI, 1.05-1.24) per 10 kg after adjustment for age, sex, race, and smoking. The magnitude of increased risk was larger for participants with estimated GFR < 60 mL/min/1.73 m(2) at baseline (P for interaction < 0.05). Associations were substantially attenuated by further adjustment for diabetes, hypertension, and C-reactive protein level. Obesity measurements were not associated with change in GFR estimated using serum cystatin C level. LIMITATIONS: Few participants with advanced chronic kidney disease at baseline, no direct GFR measurements. CONCLUSION: Obesity may be a modifiable risk factor for the development and progression of kidney disease in older adults. PMID- 19782456 TI - Is my mum going to hear this? Methodological and ethical challenges in qualitative health research with young people. AB - Ethical issues arise in all research settings. However, qualitative research with young people raises specific dilemmas that warrant special attention. In this paper we describe an ethical dilemma that arose during a qualitative project we carried out exploring self-management of chronic illness in adolescents. A participant disclosed details of poor adherence with medication, which had significant health implications. Prior to this disclosure he had been assured of confidentiality and thus we found ourselves unsure of how to proceed. Here, we analyse the case in detail, highlighting the ethically important moments, the options for action and the implications of these. We do this with the aim of facilitating ethical mindfulness and thus, ultimately, ethical research practice. As a backdrop to this case we consider the broader ethical context. We find that qualitative research is susceptible to ethical dilemmas because: (1) it is not always possible to predict all possible questions and responses; (2) the nature of the relationship between researchers and participants is amenable to sensitive disclosures; (3) the process of qualitative research can make it difficult for participants to voice concerns or withdraw; and (4) participants' identities are generally known to researchers, complicating boundary issues. Research with young people is susceptible to ethical dilemmas because: (1) young people have limited life experience; (2) consent is often required from both young people and parents; (3) issues of competence can complicate assumptions about informed consent; and (4) the power differential between researchers and participants is significant. When combining qualitative research methods and young participants, the scope for ethical risk is thus substantial. PMID- 19782455 TI - Association between achievement of hemodialysis quality-of-care indicators and quality-of-life scores. AB - BACKGROUND: Incremental achievement of quality indicator goals has been associated with progressive improvement in mortality and hospitalization risk in hemodialysis (HD) patients. STUDY DESIGN: Descriptive cross-sectional study. SETTING & PARTICIPANTS: All 33,879 HD patients treated at Fresenius Medical Care North America facilities for >90 days with scorable 36-Item Short Form Health Survey responses from January 1, 2006, to December 31, 2006. PREDICTOR: We hypothesized that achieving up to 5 HD goals before the survey (albumin >or= 4.0 g/dL, hemoglobin of 11-12 g/dL, equilibrated Kt/V >or= 1.2, phosphorus of 3.5-5.5 mg/L, and absence of HD catheter) results in better self-reported quality of life (QoL). OUTCOMES & MEASUREMENTS: Distributions of Physical and Mental Component Summary (PCS/MCS) scores within and across quality indicator categories determined during the prior 90 days from survey date (compared using analysis of covariance and linear regression models, with adjustment for case-mix and each of the quality indicators). RESULTS: Incremental achievement of up to 5 goals was associated with progressively higher PCS and MCS scores (both P for trend < 0.001). Compared with patients meeting all 5 goals (n = 4,208; reference group), case-mix-adjusted PCS score was lower by 1.8 point with only 4 goals met (n = 11,785), 3.4 points for 3 goals (n = 10,906), 4.9 points for 2 goals (n = 5,119), 5.9 points for 1 goal (n = 1,592), and 7.8 points in the 269 patients who failed to meet any goal (each P < 0.001 vs the reference group). The corresponding decreases in case-mix-adjusted MCS scores were 1.0 point for 4 goals met, 1.7 point for 3 goals, 2.3 points for 2 goals, 3.0 points for 1 goal, and 4.7 points with no goal met, with each P < 0.001 compared with the MCS score from patients who achieved all 5 goals. LIMITATIONS: Potential residual confounding from unmeasured covariates. CONCLUSION: Patients progressively meeting more quality goals report incrementally better QoL. Further studies are needed to determine whether prospective achievement of quality goals will result in improved QoL for HD patients. PMID- 19782457 TI - Racial and socioeconomic disparities in arterial stiffness and intima media thickness among adolescents. A commentary on Thurston and Matthews (68(5), 2009, 807-813). PMID- 19782458 TI - Prohibiting or 'managing' conflict of interest? A review of policies and procedures in three European drug regulation agencies. AB - In light of debates about the relationship between interests and scientific expert judgments, and the potential for declarations of conflict of interest (COI) to minimize corporate bias, we reviewed the approach to COI in 3 European drug regulatory bodies. These bodies were the Irish Medicines Board, the Medicines and Healthcare products Regulatory Agency in the United Kingdom and the European Medicines Agency in the European Union. Official statements about COI laws and codes of practice in the 3 contexts suggest that COIs are prohibited. In practice, the approaches to COI in the 3 drug regulatory agencies presuppose and promote the ideas that COIs cannot and need not be eliminated as the risk of bias can be managed. Because the evidence about if and how COI affects micro-level decision-making in drug regulatory authorities is neither complete nor comprehensive, we advocate a precautionary principle model. Under this model COI would be prohibited on the grounds that it might influence the outcome of regulatory decisions. PMID- 19782459 TI - A longitudinal 2-year follow-up of quality of life in women referred for colposcopy after an abnormal cervical smear. AB - OBJECTIVE: To evaluate the long-term impact on quality of life (QoL) in women referred for colposcopy after an abnormal cervical smear. STUDY DESIGN: One hundred consecutive women referred for colposcopy for the first time subsequent to receiving notification of an abnormal cervical smear. Women in the study group completed the Swedish Health Survey Short Form-36 (SF-36), the State/Trait Anxiety Inventory (STAI, Form Y), and the Montgomery Asberg Depression Rating Scale, Self-rate (MADRS-S). The women had follow-up visits at 6 months and 2 years. RESULTS: The baseline mean for the mental component summary score and for all mental subscale scores on the SF-36 were statistically significantly lower than Swedish normative data for women. At the end of 2 years, the mental component summary scale and vitality were still significantly lower than such data. There were no differences in QoL between women having had treatment with Large Loop Excision of the Transformation Zone (LLETZ) compared to those who did not. When studied separately, non-depressed women felt no impact on QoL whereas women with higher depression scores judged their mental health QoL worse. CONCLUSIONS: Women experienced long-lasting negative effects on their mental health, but not on their physical health after referral for colposcopy. LLETZ had no measurable influence on QoL at any of the visits. This indicates that it is not the severity of the lesions or the treatment itself that affects women but the fact of having had an abnormal cervical smear identified. Depressive mood may be a major variable for the perception of low QoL. PMID- 19782460 TI - Direct allowance for the effects of thermodynamic nonideality in the quantitative characterization of protein self-association by osmometry. AB - A procedure is described for the direct analysis of osmotic pressure data for reversibly dimerizing proteins that makes allowance for effects of thermodynamic nonideality on the statistical-mechanical basis of the potential-of-mean-force between molecules. Detailed consideration is also given to calculation of the magnitudes of the required virial coefficients. After illustration of the approach with analysis of simulated osmotic pressure data, the method is used to obtain dimerization constants from published osmotic pressure data for soybean proteinase inhibitor, hemoglobin and alpha-chymotrypsin. PMID- 19782461 TI - Canonical Wnt signaling regulates Foxc1/2 expression in P19 cells. AB - FOXC1 and FOXC2 are forkhead/winged-helix transcription factors expressed in paraxial mesoderm and somites. Emphasizing the importance of FOXC1/2 during embryonic development, double-knockout mice lacking the alleles for both Foxc1 and Foxc2 failed to form segmented somites and undergo myogenesis. The present study aims to determine upstream factors that regulate Foxc1/2 expression during the differentiation of P19 cells into skeletal muscle. Previous work had shown that dominant-negative forms of beta-catenin, Gli2, and Meox1 could inhibit distinct stages of skeletal myogenesis in P19 cells. In the presence of a dominant-negative beta-catenin fusion protein, Foxc1/2 transcripts were not upregulated and neither were markers of somitogenesis/myogenesis, including Meox1, Pax3 and MyoD. Conversely, inhibition of GSK3 by LiCl or overexpression of activated beta-catenin in aggregated P19 cells resulted in enhancement of Foxc1/2 expression, indicating that FOX transcription may be under the control of Wnt signaling. Supporting this hypothesis, beta-catenin bound to conserved regions upstream of Foxc1 during P19 cell differentiation and drove transcription from this region in a promoter assay. In addition, ectopic expression of a dominant negative Meox1 or Gli2 resulted in decreased Foxc1/2 transcript levels, correlating with inhibition of skeletal myogenesis. Overexpression of Gli2 was also sufficient to upregulate Foxc1/2 transcript levels and induce skeletal myogenesis. In summary, Foxc1/2 expression is dependent on a complex interplay from various signaling inputs from the Wnt and Shh pathways during early stages of in vitro skeletal myogenesis. PMID- 19782462 TI - Market governance for safe food in developing countries: the case of low pesticide vegetables in Vietnam. AB - In many developed countries private arrangements have emerged in food governance. Following limited successes of state regulation, market actors and mechanisms are increasingly included in the environmental and safety governance of domestic and global food chains and networks. But do such private governance arrangements also work in domestic markets in developing countries? Pesticide use in vegetable supply is taken as a case to explore the role of market actors and dynamics in food safety governance in Vietnam. The so-called safe vegetable production system in the Red River Delta, introduced 10 years ago as a domestic alternative to conventional vegetable production, is analyzed through detailed monitoring of farmers, surveys of retailers and consumers, and in-depth interviews with state officials and vegetable traders. The paper finds limited success of this low pesticide vegetable production, distribution and consumption system. This private arrangement in food governance lacked trust from market actors (especially consumers), and was short of an active state that organized transparency and got market actors involved. As such, market governance in food safety needs to be strong. PMID- 19782464 TI - Disulfiram/copper complex inhibiting NFkappaB activity and potentiating cytotoxic effect of gemcitabine on colon and breast cancer cell lines. AB - Most of the gemcitabine (dFdC) resistant cell lines manifested high NFkappaB activity. The NFkappaB activity can be induced by dFdC and 5-FU exposure. The chemosensitizing effect of disulfiram (DS), an anti-alcoholism drug and NFkappaB inhibitor, and copper (Cu) on the chemoresistant cell lines was examined. The DS/Cu complex significantly enhanced the cytotoxicity of dFdC (resistant cells: 12.2-1085-fold) and completely reversed the dFdC resistance in the resitant cell lines. The dFdC-induced NFkappaB activity was markedly inhibited by DS/Cu complex. The data from this study indicated that DS may be used in clinic to improve the therapeutic effect of dFdC in breast and colon cancer patients. PMID- 19782466 TI - Novel tannin-based adsorbent in removing cationic dye (Methylene Blue) from aqueous solution. Kinetics and equilibrium studies. AB - Natural tannin-based adsorbent has been prepared on the basis of the gelification of Quebracho bark extract. The resulting product, Quebracho Tannin Gel (QTG) was tested as cationic dye adsorbent with Methylene Blue (MB). Kinetics of adsorption process were studied out and a period of 15 days was determined for reaching equilibrium. The influences of pH and temperature were evaluated. As pH or temperature raise q capacity of QTG increases. Theoretical modelization of dye QTG adsorption was carried out by multiparametric adjustment according to Langmuir's hypothesis. Values of the k(l1), k(l2) and activation energies were calculated. PMID- 19782465 TI - Lithocholic acid upregulates uPAR and cell invasiveness via MAPK and AP-1 signaling in colon cancer cells. AB - The secondary bile acid lithocholic acid (LCA) induced expression of urokinase type plasminogen activator receptor (uPAR) and enhanced cell invasiveness in colon cancer cells. A dominant negative mutant or a specific inhibitor of MEK-1 suppressed LCA-induced uPAR expression. Deletions and site-directed mutagenesis revealed that the AP-1 site was required for LCA-induced uPAR transcription. LCA mediated enhanced cell invasiveness was partially abrogated by uPAR neutralizing antibody and inhibitors of both Erk-1/2 and AP-1. These results suggest that LCA induces uPAR expression via Erk-1/2 and AP-1 pathway and, in turn, stimulate invasiveness of human colon cancer cells. PMID- 19782467 TI - Innovative methodology for comprehensive utilization of iron ore tailings: part 1. The recovery of iron from iron ore tailings using magnetic separation after magnetizing roasting. AB - Iron ore tailings have become one kind of the most hazardous solid waste. In order to recycle iron in the tailings, we present a technique using magnetizing roasting process followed by magnetic separation. After analysis of chemical composition and crystalline phase, according to experimental mechanism, the effects of different parameters on recovery efficiency of iron were carried out. The optimum reaction parameters were proposed as the following: ratio of coal: iron ore tailings as 1:100, roasting at 800 degrees C for 30 min, and milling 15 min of roasted samples. With these optimum parameters, the grade of magnetic concentrate was 61.3% Fe and recovery rate of 88.2%. With this method, a great amount of iron can be reused. In addition, the microstructure and phase transformation of the process of magnetizing roasting were studied. PMID- 19782468 TI - Fabrication of a selective mercury sensor based on the adsorption of cold vapor of mercury on carbon nanotubes: determination of mercury in industrial wastewater. AB - A new sensor for the determination of mercury at microg ml(-1) levels is proposed based on the adsorption of mercury vapor on single-walled carbon nanotubes (SWCNTs). The changes in the impedance of SWCNTs were monitored upon adsorption of mercury vapor. The adsorption behaviour of mercury on SWCNTs was compared with that on multi-walled carbon nanotubes (MWCNTs) and carbon nanofibers (CNFs). Cold vapor of mercury was generated at 65 degrees C using Sn(II) solution as a reducing agent. The limit of detection was 0.64 microg ml(-1) for Hg(II) species. The calibration curve for Hg(II) was linear from 1.0 to 30.0 microg ml(-1). The relative standard deviation (RSD) of eight replicate analyses of 15 microg ml(-1) of Hg(II) was 2.7%. The results showed no interfering effects from many foreign species and hydride forming elements. The system was successfully applied to the determination of the mercury content of different types of wastewater samples. PMID- 19782469 TI - Sensitivity and selectivity determination of BPA in real water samples using PAMAM dendrimer and CoTe quantum dots modified glassy carbon electrode. AB - Bisphenol A (BPA) is an environmental pollutant to disrupt endocrine system or cause cancer, thus the detection of BPA is very important. Herein, an amperometric sensor was fabricated based on immobilized CoTe quantum dots (CoTe QDs) and PAMAM dendrimer (PAMAM) onto glassy carbon electrode (GCE) surface. The cyclic voltammogram of BPA on the sensor exhibited a well-defined anodic peak at 0.490V in 0.1M pH 8.0 PBS. The determination conditions were optimized and the kinetic parameters were calculated. The linear range was 1.3 x 10(-8) to 9.89 x 10(-6)M with the correlation coefficient of 0.9999. The limit of detection was estimated to be 1 x 10(-9)M. The current reached the steady-state current within about 5s. Furthermore, the fabricated sensor was successfully applied to determine BPA in real water samples. PMID- 19782470 TI - Denitrification of high nitrate concentration wastewater using alternative carbon sources. AB - The use of different organic carbon sources in the denitrification of wastewater containing 2500 mg nitrates/L in a SBR was studied. Three alternative sources of carbon were tested: wastewater from a sweet factory, a residue from a soft drinks factory and a residue from a dairy plant. The first two are sugar-rich, whereas the third presents a high content in lactic acid. Maximum specific denitrification rates of between 42 and 48 mg NO(3)-N/g VSS h were obtained. The effluents were nitrate-free and very low COD concentrations were obtained in 4-6h reaction time, especially with the sugar-rich carbon sources. The values of the denitrifier net yield coefficient were higher than when using methanol (0.93-1.75 g VSS(formed)/g NO(x)-N(reduced)). The lowest value was obtained using the lactic acid-rich residue. The optimum COD/N ratios varied between 4.6 for the lactic acid-rich carbon source and 5.5-6.5 for the sugar-rich carbon sources. PMID- 19782471 TI - Innovative methodology for comprehensive utilization of iron ore tailings: part 2: The residues after iron recovery from iron ore tailings to prepare cementitious material. AB - In order to comprehensive utilization of iron ore tailings, this experimental research was to investigate the possibility of using the residues after iron recovery from iron ore tailings as raw materials for the preparation of cementitious material, abbreviated as TSC, including analyses of its mechanical properties, physical properties and hydration products. The TSC1 was prepared by blending 30% the residues, 34% blast-furnace slag, 30% clinker and 6% gypsum. Meanwhile, the raw iron ore tailings (before iron recovery) with the same proportion of TSC1 were selected to compare the cementitious activity of raw tailings and the residues after magnetizing roasting, denoted by TSC0. The hydration products of them were mostly ettringite, calcium hydroxide and C-S-H gel, characterized by XRD, IR and SEM. It was found that ettringite and C-S-H gel were principally responsible for the strength development of TSC mortars with curing time. The results showed that the kaolinite of the tailings was decomposed completely after magnetizing roasting, which promoted the cementitious property of TSC1. Moreover, the mechanical properties of TSC1 are well comparable with those of 42.5 ordinary Portland cement according to Chinese GB175-2007 standard. PMID- 19782472 TI - Oxaliplatin-induced neuropathy in the rat: involvement of oxalate in cold hyperalgesia but not mechanical allodynia. AB - Oxaliplatin is a key drug in the treatment of advanced metastatic colorectal cancer, but it causes acute peripheral neuropathy (acral paresthesias triggered by exposure to cold) and chronic neuropathy (abnormal of sensory and motor dysfunction). Oxaliplatin is metabolized to oxalate and dichloro(1,2 diaminocyclohexane)platinum (Pt(dach)Cl(2)). Although the chelating of Ca(2+) with oxalate eliminated from oxaliplatin is thought as one of the reasons for the neuropathy, there is little behavioral evidence. In this study, we investigated the involvement of oxalate in the oxaliplatin-induced peripheral neuropathy in rats. Oxaliplatin (4mg/kg, i.p., twice a week) induced cold hyperalgesia/allodynia (cold-plate and acetone tests) in the early phase, and mechanical allodynia (von Frey test) in the late phase. Oxalate (1.3mg/kg, i.p., twice a week) induced the cold hyperalgesia/allodynia in the early phase, but did not induce the mechanical allodynia. On the other hand, Pt(dach)Cl(2) (3.8mg/kg, i.p., twice a week) induced the mechanical allodynia in the late phase, but did not induce the cold hyperalgesia/allodynia. The pre-administration of calcium or magnesium (0.5mmol/kg, i.v.) before oxaliplatin or oxalate prevented the cold hyperalgesia but not mechanical allodynia. However, the treatment with calcium or magnesium after the development of neuropathy could not attenuate the cold hyperalgesia or mechanical allodynia. These findings suggest the involvement of oxalate in oxaliplatin-induced cold hyperalgesia but not mechanical allodynia, and usefulness of prophylactic treatments with calcium and magnesium on the acute peripheral neuropathy. PMID- 19782473 TI - Glial inhibitors influence the mRNA and protein levels of mGlu2/3, 5 and 7 receptors and potentiate the analgesic effects of their ligands in a mouse model of neuropathic pain. AB - Metabotropic glutamate (mGlu) receptors, which are present on neurons and glial cells, have been shown to play a role in neuropathic pain. The present study sought to investigate how the glial inhibitors minocycline and pentoxifylline alter the effect that chronic constriction injury (CCI) has on the expression of mGlu receptors and on their associated ligands. RT-PCR analysis revealed that seven days after CCI, the mRNA levels of glial markers C1q and GFAP, as well as those of mGlu5 and mGlu3, but not mGlu7, were elevated in the lumbar spinal cord ipsilateral to the injury. The protein levels of the microglial marker OX42, the astroglial marker GFAP, and mGlu5 receptor protein were increased, whereas the levels of mGlu2/3 and mGlu7 receptor proteins were reduced. Preemptive and repeated intraperitoneal (i.p.) administration (16 and 1h before nerve injury and then twice daily for seven days) of minocycline (30mg/kg) and pentoxifylline (20mg/kg) prevented the injury-induced changes in the levels of mGlu3 and mGlu5 receptor mRNAs and the injury-induced changes in the protein levels of all the receptors. Repeated administration of minocycline and pentoxifylline significantly attenuated CCI-induced allodynia (von Frey test) and hyperalgesia (cold plate test) measured on day seven after injury and potentiated the antiallodynic and antihyperalgesic effects of single i.p. and intrathecal (i.t.) injections of mGlu receptor ligands: MPEP, LY379268 or AMN082. We conclude that attenuation of injury-induced glial activation can reduce glutamatergic activity, thereby contributing to regulation of pain sensation. PMID- 19782474 TI - Thelazia callipaeda (Spirurida, Thelaziidae) in wild animals: report of new host species and ecological implications. AB - Thelazia callipaeda infects the eyes of carnivores and humans in Far Eastern Asiatic and European countries. Studies have demonstrated the occurrence of T. callipaeda in foxes from areas where canine thelaziosis is endemic. However, there is little information on the role of wild carnivores as hosts of this nematode. From May 2003 to May 2009, a total of 130 carcasses of red foxes (Vulpes vulpes; n=75), wolves (Canis lupus; n=2), beech martens (Martes foina; n=22), brown hares (Lepus europaeus; n=13), Eurasian badgers (Meles meles; n=10), and wild cats (Felis silvestris; n=8) were examined in an area of southern Italy where canine thelaziosis is highly prevalent. At necropsy, animals were examined and nematodes were collected from the conjunctival sacs of both eyes. All nematodes were morphologically identified and at least five specimens from each of the five host species were molecularly processed by PCR amplification and sequencing of a partial mitochondrial cytochrome c oxidase subunit 1 gene (cox1). Five out of the six wild animal species examined were found to be infected with eyeworms. The overall infection rate, excluding the Eurasian badgers that were all negative, was 39.1%. All the 189 adult nematodes collected (intensity of infection=4+/-2.2) were morphologically identified as T. callipaeda. The molecular analysis confirmed that the only haplotype of T. callipaeda circulating in Europe (i.e., haplotype 1) is present in that area. The competence of red foxes, wolves, beech martens, brown hares, and wild cats as definitive hosts for T. callipaeda is discussed in relationship to their ecology and their likely exposure to the vector Phortica variegata in the study area. The role the wild fauna plays in maintaining and spreading eyeworm infection in humans and domestic animals is also discussed. PMID- 19782475 TI - Epidemiology of hospitalized burn patients in a tertiary care hospital in South India. AB - BACKGROUND: The epidemiological pattern of burns varies widely in different parts of the world. To suggest effective preventive measures, an insight into the pattern of injury is desirable. However, data on burn victims and outcome is limited from this part of the world. METHODS: This study was conducted in the Department of Surgery, from April 2006 to April 2007. All consecutive patients with major burns admitted for in-hospital treatment during the study period were included in the study. The data collected included age, gender, cause and mode of burns, presence or absence of inhalational injury, facial burns, time delay from burn injury to admission in the hospital, burns depth, total body surface area distribution of burns, associated injuries and co-morbid illness, microbiological profile and outcome. Inhalational injury was assessed by clinical examination as bronchoscopy was not available. RESULTS: A total of 222 consecutive patients admitted for in-hospital treatment of burn injury were included in the study. 177 patients were adults and 45 were <13 years of age. The female:male ratio was 1.7:1. In adults, 52.5% of burns were due to non-intentional injury and 43.9% were due to self-immolation. In patients <13 years of age, 95.6% of cases were due to non-intentional injury. The mean TBSA was 48.75% and 30.18% of patients had predominantly deep burns. The overall mortality was 60.8%. The predominant organisms colonizing the burn wound were Pseudomonas aeruginosa (81.1%) followed by Acinetobacter species and MRSA. Multivariate logistic regression analysis of factors predicting survival in patients with burn injury showed that TBSA>30%, age>20 years, female gender and presence of facial injury were statistically significant as predictors of risk of death. CONCLUSIONS: In patients with burns, total body surface area involvement more than 30%, age more than 20 years, female gender and presence of facial injury are statistically significant, as predictors of poor outcome and risk of death. The strongest association was seen with facial injury, which increased the risk of death by fourfold. PMID- 19782476 TI - Testosterone reduces amygdala-orbitofrontal cortex coupling. AB - Testosterone influences various aspects of affective behavior, which is mediated by different brain regions within the emotion circuitry. Previous neuroimaging studies have demonstrated that testosterone increases neural activity in the amygdala. To investigate whether this could be due to altered regulation of amygdala functioning which is thought to be mediated by the prefrontal cortex, we studied the effects of exogenous testosterone on the interaction between the amygdala and other brain regions. Healthy middle-aged women received a single nasal testosterone dose in a randomized, placebo-controlled, crossover manner, and performed an emotional face matching task while their brain activity was measured with functional MRI. The results show that testosterone rapidly reduced functional coupling of the amygdala with the orbitofrontal cortex, and enhanced amygdala coupling with the thalamus. This suggests that testosterone may reduce the regulatory control over the amygdala, or that testosterone shifts amygdala output away from the orbitofrontal cortex towards the thalamus. Testosterone also reduced functional coupling with the contralateral amygdala. Because interhemispheric amygdala coupling is lower in men than in women, this result suggests that circulating testosterone may contribute to this sexual dimorphism. PMID- 19782477 TI - Differential expression of glucocorticoid receptor transcripts in major depressive disorder is not epigenetically programmed. AB - Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is one of the most consistent findings in major depressive disorder (MDD). Impaired HPA feedback may be due to the lower glucocorticoid receptor (GR) or mineralocorticoid receptor (MR) levels in the forebrain. GR levels are transcriptionally controlled by multiple untranslated alternative first exons, each with its own promoter providing a mechanism for tissue-specific fine-tuning of GR levels. Recently epigenetic methylation of these GR promoters was shown to modulate hippocampal GR levels. Here we investigate in post-mortem brain tissues whether in MDD HPA axis hyperactivity may be due to epigenetic modulation of GR transcript variants. Levels of GRalpha, GRbeta and GR-P transcripts were homogeneous throughout the limbic system, with GRalpha being the most abundant (83%), followed by GR-P (5 6%) while GRbeta was barely detectable (0.02%). Among the alternative first exons, 1B and 1C were the most active, while 1E and 1J showed the lowest expression and transcript 1F expressed intermediate levels of about 1%. In MDD, total GR levels were unaltered, although GRalpha was decreased in the amygdala and cingulate gyrus (p<0.05); transcripts containing exons 1B, 1C and 1F were lower, and 1D and1J were increased in some regions. NGFI-A, a transcription factor of exon 1F was down-regulated in the hippocampus of MDD patients; concomitantly exon 1F expression was reduced. Bisulphite sequencing of the alternative promoters showed low methylation levels in both MDD and control brains. Promoter 1F was uniformly unmethylated, suggesting that reduced 1F transcript levels are not linked to promoter methylation but to the observed dearth of NGFI-A. Previous studies showed high methylation levels in the 1F promoter, associated with childhood abuse. Provided our donors were not abused, our results suggest that the pathomechanism of MDD is similar but nevertheless distinct from that of abuse victims, explaining the clinical similarity of both conditions and that susceptibility to depression may be either predisposed by early trauma or developed independent of such a condition. However, this should be further confirmed in dedicated studies in larger cohorts. PMID- 19782478 TI - Selective nodal irradiation on basis of (18)FDG-PET scans in limited-disease small-cell lung cancer: a prospective study. AB - PURPOSE: To evaluate the results of selective nodal irradiation on basis of (18)F deoxyglucose positron emission tomography (PET) scans in patients with limited disease small-cell lung cancer (LD-SCLC) on isolated nodal failure. METHODS AND MATERIALS: A prospective study was performed of 60 patients with LD-SCLC. Radiotherapy was given to a dose of 45 Gy in twice-daily fractions of 1.5 Gy, concurrent with carboplatin and etoposide chemotherapy. Only the primary tumor and the mediastinal lymph nodes involved on the pretreatment PET scan were irradiated. A chest computed tomography (CT) scan was performed 3 months after radiotherapy completion and every 6 months thereafter. RESULTS: A difference was seen in the involved nodal stations between the pretreatment (18)F-deoxyglucose PET scans and computed tomography scans in 30% of patients (95% confidence interval, 20-43%). Of the 60 patients, 39 (65%; 95% confidence interval [CI], 52 76%) developed a recurrence; 2 patients (3%, 95% CI, 1-11%) experienced isolated regional failure. The median actuarial overall survival was 19 months (95% CI, 17 21). The median actuarial progression-free survival was 14 months (95% CI, 12 16). 12% (95% CI, 6-22%) of patients experienced acute Grade 3 (Common Terminology Criteria for Adverse Events, version 3.0) esophagitis. CONCLUSION: PET-based selective nodal irradiation for LD-SCLC resulted in a low rate of isolated nodal failures (3%), with a low percentage of acute esophagitis. These findings are in contrast to those from our prospective study of CT-based selective nodal irradiation, which resulted in an unexpectedly high percentage of isolated nodal failures (11%). Because of the low rate of isolated nodal failures and toxicity, we believe that our data support the use of PET-based SNI for LD SCLC. PMID- 19782479 TI - Alcohol consumption and all-cause mortality among elderly in Finland. AB - AIMS: To estimate the gender-specific prevalences of alcohol consumption levels and to investigate the association between heavy drinking and all-cause mortality among elderly males. DESIGN: A cohort derived from a nationally representative sample of Finns aged >65 years was followed for six years. Number of subjects was 1569 (72.7% of the original sample, 65.3% females, weighted n=1357). MEASUREMENTS: Alcohol consumption was retrospectively measured by beverage specific quantity and frequency over a 12-month period. Mortality data were obtained from the official Cause-of-Death Register. Cox proportional hazards models were used to analyse the relative risks (RRs) of death. FINDINGS: The prevalence of heavy drinking (>8 standard drinks per week) was 20.3% in males and 1.2% in females. Over one-tenth (11.4%) of males reported drinking > or =15 standard drinks per week. Relative death risks suggested a J-curved relationship between alcohol consumption levels and mortality. However, significant curvilinear relationship was not found, when using alcohol consumption as continuous variable. The multivariate adjusted RR of death among moderate drinkers (1-7 drinks per week) vs. abstinent subjects was 0.41 (95% CI=.23-.72). Males drinking > or =15 standard drinks per week had a two-fold multivariate adjusted risk of death (RR=2.11, 95% CI=1.19-3.75) compared with abstinent males. The level of alcohol consumption by females was too low for analysis. CONCLUSIONS: Heavy drinking is common among Finnish elderly males but not among females. The present study shows an increased all-cause mortality risk for males drinking, on average, more than two standard drinks per day. PMID- 19782481 TI - A multidimensional assessment of the validity and utility of alcohol use disorder severity as determined by item response theory models. AB - BACKGROUND: The relative severity of the 11 DSM-IV alcohol use disorder (AUD) criteria are represented by their severity threshold scores, an item response theory (IRT) model parameter inversely proportional to their prevalence. These scores can be used to create a continuous severity measure comprising the total number of criteria endorsed, each weighted by its relative severity. METHODS: This paper assesses the validity of the severity ranking of the 11 criteria and the overall severity score with respect to known AUD correlates, including alcohol consumption, psychological functioning, family history, antisociality, and early initiation of drinking, in a representative population sample of U.S. past-year drinkers (n=26,946). RESULTS: The unadjusted mean values for all validating measures increased steadily with the severity threshold score, except that legal problems, the criterion with the highest score, was associated with lower values than expected. After adjusting for the total number of criteria endorsed, this direct relationship was no longer evident. The overall severity score was no more highly correlated with the validating measures than a simple count of criteria endorsed, nor did the two measures yield different risk curves. This reflects both within-criterion variation in severity and the fact that the number of criteria endorsed and their severity are so highly correlated that severity is essentially redundant. CONCLUSIONS: Attempts to formulate a scalar measure of AUD will do as well by relying on simple counts of criteria or symptom items as by using scales weighted by IRT measures of severity. PMID- 19782480 TI - Examining differential effects of psychosocial treatments for cocaine dependence: an application of latent trajectory analyses. AB - BACKGROUND: The NIDA Collaborative Cocaine Treatment Study yielded different efficacies for different psychosocial treatments for cocaine dependence. However, substantial heterogeneity of patient outcomes was evident. Longitudinal data analysis techniques can be helpful in examining differential effects of psychosocial interventions on specific subpopulations of patients. METHODS: Overall drug and cocaine use of 346 patients diagnosed with DSM-IV cocaine dependence and treated with one of four psychosocial interventions were assessed monthly during 6-month treatment. Growth mixture models were used to identify patient subgroups based on typical patterns of change in substance use during treatment and to evaluate differential treatment effects within these subgroups. RESULTS: Three patient subgroups following different change patterns in cocaine and overall drug use were identified irrespective of the treatment type: (a) those with moderate baseline severity of drug use and very rapid reduction of drug use during treatment, (b) those with moderate baseline severity of drug use and moderate reduction of drug use during treatment, and (c) those with severe levels of baseline drug use with moderate reduction of drug use during treatment. Patient baseline characteristics enabled discrimination between these subgroups. Individual drug counseling was most efficacious among those patients with moderate baseline severity and moderate treatment response. There were no differential treatment effects in the two other patient subgroups. CONCLUSIONS: The population of treatment-seeking cocaine dependent individuals is heterogeneous. Research on patient subgroups with different change patterns revealed its potential to enable classifications of patients that indicate which treatment is most effective for which type of patient. PMID- 19782482 TI - (Highly pathogenic) avian influenza as a zoonotic agent. AB - Zoonotic agents challenging the world every year afresh are influenza A viruses. In the past, human pandemics caused by influenza A viruses had been occurring periodically. Wild aquatic birds are carriers of the full variety of influenza virus A subtypes, and thus, most probably constitute the natural reservoir of all influenza A viruses. Whereas avian influenza viruses in their natural avian reservoir are generally of low pathogenicity (LPAIV), some have gained virulence by mutation after transmission and adaptation to susceptible gallinaceous poultry. Those so-called highly pathogenic avian influenza viruses (HPAIV) then cause mass die-offs in susceptible birds and lead to tremendous economical losses when poultry is affected. Besides a number of avian influenza virus subtypes that have sporadically infected mammals, the HPAIV H5N1 Asia shows strong zoonotic characteristics and it was transmitted from birds to different mammalian species including humans. Theoretically, pandemic viruses might derive directly from avian influenza viruses or arise after genetic reassortment between viruses of avian and mammalian origin. So far, HPAIV H5N1 already meets two conditions for a pandemic virus: as a new subtype it has been hitherto unseen in the human population and it has infected at least 438 people, and caused severe illness and high lethality in 262 humans to date (August 2009). The acquisition of efficient human-to-human transmission would complete the emergence of a new pandemic virus. Therefore, fighting H5N1 at its source is the prerequisite to reduce pandemic risks posed by this virus. Other influenza viruses regarded as pandemic candidates derive from subtypes H2, H7, and H9 all of which have infected humans in the past. Here, we will give a comprehensive overview on avian influenza viruses in concern to their zoonotic potential. PMID- 19782483 TI - Evaluation of Lactobacillus rhamnosus GG using an Escherichia coli K88 model of piglet diarrhoea: Effects on diarrhoea incidence, faecal microflora and immune responses. AB - Probiotic bacterium Lactobacillus rhamnosus GG (LGG) has been demonstrated to adhere to pig intestinal mucus, and is able to displace and inhibit pathogens, including Escherichia coli (E. coli), in vitro. However, currently there are few data concerning the effects of LGG on piglet health. The objectives of this study were to assess the effectiveness of LGG in reducing the incidence and severity of post-weaning diarrhoea in piglets, and to investigate its mechanisms of action. Eighteen weaned barrows were allocated to nonchallenged control (NCN), challenged control (CCN) and LGG treatment (LGG) groups. Diarrhoea incidence was significantly lower in group LGG than group CCN after E. coli challenge. Faecal coliform bacteria counts were significantly increased, while lactobacilli and bifidobacteria counts were decreased, in group CCN compared with the other groups after challenge. In the jejunum and ileum, secretory immunoglobin A (SIgA) concentrations were significantly higher in group LGG than in group CCN. In group LGG, administration of short-term LGG before E. coli infection attenuated the elevation of serum IL-6 induced by E. coli. Significantly higher concentrations of TNF-alpha were observed in group LGG than NCN and CCN at 6h. IL-1beta concentrations in group NCN were significantly higher than LGG at 6h and higher than CCN at 24h. In conclusion, LGG was effective in ameliorating diarrhoea in post-weaning piglets induced by E. coli K88, possibly via modulation of intestinal microflora, enhancement of intestinal antibody defence, and regulation of production of systemic inflammatory cytokines. PMID- 19782484 TI - Does the progesterone receptor genetic polymorphism +331G/A hPR influence the risk of venous thromboembolism among postmenopausal women using hormone therapy? The ESTHER Study. AB - Hormone therapy (HT) increases venous thromboembolism (VTE) risk among postmenopausal women. Data on the influence of steroids receptors polymorphisms on this association remain scarce. Since progesterone receptor (hPR) is expressed in human veins and specific progestogens increase VTE risk, we investigated the impact of the functional +331G/A hPR polymorphism on the association of VTE with HT. Using the data of the ESTHER study, we showed that ORs for VTE in current users of progesterone or progestins were not significantly different by hPR+331G/A genotype status. hPR polymorphism appears not to have a significant effect on VTE risk related to HT. PMID- 19782486 TI - [Surgery of aortic coarctation with aneurysm of the ascending aorta and aortic coronary fistula]. AB - Aortic coarctation is rarely associated with an aneurysm of the ascending aorta and an aortic coronary fistula. In this study, we report the case of a 52-year old man undergoing surgery for an isthmic coarctation who also had an aneurysm of the initial portion of the aorta and an aortic coronary fistula. The diagnosis was clinically suspected and confirmed by vascular catheterism. The first operative stage consisted of treating the coarctation. The second stage was performed two months later to remove the aneurysm and replace the ascending aorta and the aortic valve with a prosthesis. The coronary arteries were then reimplanted. The postoperative results were quite favourable. PMID- 19782485 TI - [Two cases of iatrogenic cutis and subcutis calcinosis after calcium-containing heparin injection]. AB - BACKGROUND: Subcutis calcinosis, characterized by abnormal calcium deposition in the skin, is a rare side effect of calcium containing heparins. PATIENTS AND METHODS: Two patients with renal failure presented skin lesions after receiving a calcium-containing heparin treatment. The first patient exhibited erythematous nodules on the abdomen and the second a large erythematous induration of the abdomen and nodules on the thighs. Both had normal blood analysis. The diagnosis of subcutis calcinosis was confirmed by the histological exam showing calcium deposit in the dermis and hypodermis. Outcome was unfavourable in one of the patients who developed a superinfection and skin necrosis lesion requiring surgery at 2 months. DISCUSSION: Subcutis calcinosis is a rare and probably underdiagnosed disease. To our knowledge, only 10 cases have been reported. The pathogenesis is not well-known, tissue damage and calcium disorders are considered as risk factors. The differential diagnoses that can be suspected include calciphylaxis, such as calcifying panniculitis and other local side effects of heparins. Outcome is usually favourable without treatment. CONCLUSION: We describe two cases of iatrogenic subcutis calcinosis after injections of calcium-containing heparins, including the second case of poor outcome. Clinicians should be aware of this adverse effect since other heparins such as fondaparinux or low-weight molecular heparins are contraindicated in patients with renal failure, leading to a large prescription of calcium-containing heparins in this population. PMID- 19782487 TI - [Evaluation of an education program for patients taking oral anticoagulants: Experience of the GRANTED network in Isere]. AB - BACKGROUND: The guidelines for good clinical practices issued by the French Agency for Health and Drug Safety and the Superior Health Authority are designed to improve management of oral anticoagulants which can be an important source of iatrogenic morbidity. These guidelines have focused on the need for special education. The GRANTED network in Isere developed an education program for patients taking oral anticoagulants. OBJECTIVE: The purpose of this study was to evaluate quantitatively the therapeutic education of these patients taking oral anticoagulation, irrespective of their risk factor(s). PATIENTS AND METHODS: This was a retrospective analysis of 100 randomly selected patients taking oral anticoagulants for at least three months who participated in the GRANTED education program in 2007. The evaluation criterion was the number of hemorrhagic and/or thromboembolic events. RESULTS: Among the 97 patients contacted, 3.1% had a serious hemorrhagic event and 1.03% a recurrent thromboembolic event. CONCLUSIONS: The quality of a scientific study depends on the quality of the methodology, leading to a preference for prospective studies. It would nevertheless be pertinent to determine whether or not official management recommendations are applied correctly in real life conditions. We report a first evaluation of a therapeutic education program designed for patients taking oral anticoagulants. The education program within the GRANTED network has enabled a reduction in the iatrogenic morbidity related to oral anticoagulation despite the selection bias of the probably high-risk population enrolled in the GRANTED network. PMID- 19782488 TI - Vulnerable plaque: detection of agreement between multi-detector-row CT angiography and US-ECD. AB - OBJECTIVES: The purpose of this work was to evaluate the agreement between ultra sound echo-color Doppler (US-ECD) and multi-detector-row CT angiography (MDCTA) in the characterization of vulnerable plaque. METHODS: From January 2004 to January 2007 658 patients who underwent both MDCTA and US-ECD for the study of carotid arteries, were retrospectively evaluated (453 males, 205 females). For all subjects the following parameters were analysed: plaque morphology (regular versus irregular), type of the plaque (fatty, mixed and calcified) and presence of ulcerations. Statistical analysis was performed to calculate concordance between the two techniques employed. RESULTS: In the definition of the type of plaque, the observed agreements were 77.2% and the kappa value was 0.657 (95% confidence interval: 0.615-0.699). The weighted kappa resulted 0.644. In the definition of ulceration plaque, the observed agreements were 88.4% but the kappa value was only 0.325 (95% confidence interval: 0.201-0.449). Agreement observed in the evaluation of plaque morphology was 78.3% with a kappa value of 0.513 (95% confidence interval: 0.452-0.574). CONCLUSION: We observed a good agreement between US-ECD and MDCTA in the assessment of plaque type whereas a poor agreement resulted in the evaluation of plaque ulceration. The use of US-ECD and MDCTA provides different results in the evaluation of plaque. Our results suggest that information deriving from US-ECD should be always critically compared with other diagnostic techniques. PMID- 19782489 TI - Characteristics of pulmonary cysts in Birt-Hogg-Dube syndrome: thin-section CT findings of the chest in 12 patients. AB - PURPOSE: To describe in detail the characteristic chest computed tomography (CT) findings of Birt-Hogg-Dube (BHD) syndrome. MATERIALS AND METHODS: Thin-section chest CT scans of consecutive 12 patients with genetically diagnosed BHD syndrome were retrospectively evaluated by two observers, especially about the characteristics (distribution, number, size, shape and relation to pleura) of pulmonary cysts. Interobserver agreement in the identification of abnormalities on the CT images was achieved using the kappa statistic, and the degree of interobserver correlation for the characterization of pulmonary cysts was assessed using the Spearman rank correlation coefficient. RESULTS: Multiple pulmonary cysts were seen in all patients. The number of cysts in each patient was various (range, 29-407), and cysts of various sizes (from a few mm to 2 cm or more) were seen in all patient. 76.6% (mean) of cysts were irregular-shaped, and 40.5% (mean) of cysts were located along the pleura. The mean extent score of cysts was 13% of the whole lung, and the distribution of cysts was predominantly in the lower medial zone. Finally, cysts abutting or including the proximal portions of lower pulmonary arteries or veins were also seen in all patients. CONCLUSION: Multiple, irregular-shaped cysts of various sizes with lower medial lung zone predominance are characteristic CT findings of BHD syndrome. Cysts abutting or including the proximal portions of lower pulmonary arteries or veins may also exist in this syndrome in a high probability. PMID- 19782490 TI - CT- and MRI-based volumetry of resected liver specimen: comparison to intraoperative volume and weight measurements and calculation of conversion factors. AB - OBJECTIVE: To compare virtual volume to intraoperative volume and weight measurements of resected liver specimen and calculate appropriate conversion factors to reach better correlation. METHODS: Preoperative (CT-group, n=30; MRI group, n=30) and postoperative MRI (n=60) imaging was performed in 60 patients undergoing partial liver resection. Intraoperative volume and weight of the resected liver specimen was measured. Virtual volume measurements were performed by two readers (R1,R2) using dedicated software. Conversion factors were calculated. RESULTS: Mean intraoperative resection weight/volume: CT: 855 g/852 mL; MRI: 872 g/860 mL. Virtual resection volume: CT: 960 mL(R1), 982 mL(R2); MRI: 1112 mL(R1), 1115 mL(R2). Strong positive correlation for both readers between intraoperative and virtual measurements, mean of both readers: CT: R=0.88(volume), R=0.89(weight); MRI: R=0.95(volume), R=0.92(weight). Conversion factors: 0.85(CT), 0.78(MRI). CONCLUSION: CT- or MRI-based volumetry of resected liver specimen is accurate and recommended for preoperative planning. A conversion of the result is necessary to improve intraoperative and virtual measurement correlation. We found 0.85 for CT- and 0.78 for MRI-based volumetry the most appropriate conversion factors. PMID- 19782491 TI - Screening method for ethylene glycol and diethylene glycol in glycerin-containing products. AB - This paper describes a capillary gas chromatographic method with flame ionization detection for the identification/quantification of ethylene glycol (EG) and diethylene glycol (DEG) in glycerin. The validation study shows that the proposed method is specific, sensitive, precise, and accurate. The linear range of the method was 0.013-0.031mg/mL for EG and 0.012-0.030mg/mL for DEG. Wider ranges may be achievable but were not investigated. The limit of detection of EG and DEG were determined as 0.0018% and 0.0036% (w/w) respectively, and at this concentration the signal-to-noise ratios for EG and DEG were approximately 3:1. The method was also used to determine EG and DEG in toothpaste. The results were compared to those obtained by thin-layer chromatography (TLC) and showed greater sensitivity and specificity. PMID- 19782492 TI - The identification of (-)-trans-tadalafil, tadalafil, and sildenafil in counterfeit Cialis and the optical purity of tadalafil stereoisomers. AB - Four blisters with suspect Cialis (tadalafil) 20mg tablets were screened for authenticity using near infrared spectroscopy (NIRS) and for the presence of phosphodiesterase 5 (PDE-5) inhibitors using LC-DAD-MS. All samples were identified as counterfeit Cialis and contained sildenafil or a combination of tadalafil and sildenafil. Although the tablets contained efficacious amounts of PDE-5 inhibitors, neither the active ingredient nor the dosage corresponded to the description on the blister. This is the first reported case of a diastereomeric mixture of tadalafil and trans-tadalafil (3:1) being identified in a counterfeit medicine. The LC-DAD-CD revealed that both diastereomers had a high optical purity. The optical rotation of the diastereomeric mixture was measured indicating the presence of (-)-trans-tadalafil, which is the only other stereoisomer with some PDE-5 inhibitory activity. As no safety profiles are known for the stereoisomers of tadalafil, there is a potential health risk. In addition, the optical purity of tadalafil needs to be taken into account when calculating the dosage in illegal medicines. PMID- 19782493 TI - Broadening of 1H NMR signals in the spectra of heparin and OSCS by paramagnetic transition metal ions. The use of EDTA to sharpen the signals. AB - Some signals in the (1)H NMR spectra of heparin and oversulphated chondroitin sulphate (OSCS) are occasionally broad or very broad owing to the presence of paramagnetic metal ions in those polysaccharides. The addition of very small amounts of EDTA to heparin or to OSCS contaminated heparin solutions was needed to obtain normal looking spectra. PMID- 19782494 TI - Treatment approaches to prosthetic joint infections: results of an Emerging Infections Network survey. AB - We report the results of an Emerging Infections Network survey of 994 infectious disease consultants (IDCs) regarding their participation in the medical management of prosthetic joint infections and observations of adverse effects associated with antibiotic-impregnated materials (response rate, 54.8%). There was general agreement about when a prosthesis can be retained, but substantial variability in the duration of suppressive antibiotics was recommended, with 36% supporting life-long suppression. For 2-stage procedures, 95% recommended a minimum of 4 weeks of systemic antibiotics after the first stage. However, there was little agreement regarding the duration of an antibiotic-free period before reimplantation. Eleven percent of IDCs reported adverse events related to antibiotic-impregnated materials, ranging from skin reactions to renal failure. Further studies to address the substantial variability in the duration of antibiotic suppressive therapy for retained joints and for the duration of antibiotic-free period before reimplantation are needed. PMID- 19782495 TI - Leishmania spp. identification by polymerase chain reaction-restriction fragment length polymorphism analysis and its applications in French Guiana. AB - Leishmania (Viannia) guyanensis was for many years the only species commonly identified in French Guiana, but precise species identifications were quite rare. We describe a new restriction fragment length polymorphism-polymerase chain reaction technique using a 615-bp fragment of the RNA polymerase II gene and 2 restriction enzymes, TspRI and HgaI. Seven reference strains (Leishmania (Leishmania) amazonensis, Leishmania (Viannia) lainsoni, Leishmania (Viannia) braziliensis, L. (V.) guyanensis, Leishmania (Viannia) naiffi, Leishmania (Leishmania) major, Leishmania (Leishmania) infantum) and 112 clinical samples from positive lesions were used for the development of the technique. The rates of positive species identification were 85.7% for punch skin biopsy specimens, 93.1% for positive Giemsa-stained smears, and 100% for positive culture supernatants. In the framework of cutaneous leishmaniasis species surveillance for the 2006 to 2008 period, parasite identification was carried out for 199 samples from different patients. The prevalence of the various Leishmania spp. was 84.4% for L. (V.) guyanensis, 8.0% for L. (V.) braziliensis, 5.0% for L. (L.) amazonensis, and 2.6% for L. (V.) lainsoni. L. (V.) braziliensis seems to be locally an emerging pathogen. PMID- 19782496 TI - Detection of domestic violence by a domestic violence advocate in the ED. AB - BACKGROUND: The current domestic violence (DV) literature has evaluated the incidence and prevalence of DV via written surveys and verbal questioning performed by a variety of health care professionals. OBJECTIVES: We sought to examine the prevalence of DV as obtained by a full-time, trained DV advocacy coordinator using direct patient interviewing in our emergency department (ED), and to compare our results with the published literature. METHODS: The DV advocacy coordinator randomly selected and interviewed female patients presenting to the ED with various complaints during daytime hours. Participation was voluntary, and patients were excluded if they were too ill or injured to answer questions. We performed a retrospective review of data obtained through our DV advocacy coordinator's screening interviews of female patients presenting to the ED over a period of 1 year. Acute incidence and lifetime prevalence of DV was determined and compared to results reported in the literature. RESULTS: The domestic violence advocacy coordinator screened a total of 1550 patients over the study period. Domestic violence incidence and lifetime prevalence as detected by the coordinator was determined to be 4.8% (95% confidence interval [CI] 3.9-6.0%) and 27.5% (95% CI 25.3-29.8%), respectively. CONCLUSIONS: Although the lifetime DV prevalence of 27.5% uncovered by our trained DV advocacy coordinator is similar to other reports, the acute incidence of 4.8% is higher than most other reported results using personal interviews. The use of a trained DV coordinator may improve detection rates of domestic violence in the ED. PMID- 19782497 TI - Active retropharyngeal hemorrhage from an acute thyrocervical artery injury: a rare complication of hyperextension cervical spine injury. AB - BACKGROUND: Acute vascular injury is uncommon after cervical spine injury. We describe a recent case of active retropharyngeal bleeding from the thyrocervical artery after an acute cervical spine injury. OBJECTIVES: The case illustrates an unusual vascular injury diagnosed by 64-slice multidetector computed tomography (MDCT) and managed successfully by emergency transcatheter embolization. CASE REPORT: A 65-year-old woman presented to the Emergency Department after a fall. MDCT scans of the cervical spine revealed a fracture of C5 and a large prevertebral hematoma. Subsequent MDCT carotid angiography revealed active bleeding from a branch of the right thyrocervical trunk. Superselective catheterization into the right thyrocervical trunk confirmed this as the source vessel. A 3-mm coil was deployed without complication. CONCLUSION: This case illustrates an unusual arterial injury in the context of cervical spine trauma and how, as endovascular services become more accessible out of hours, the management of patients with acute arterial injury is increasingly a multidisciplinary team effort. Early recognition by the emergency physician of potential vascular injury and prompt referral for appropriate imaging will expedite treatment and improve clinical outcome. PMID- 19782498 TI - Intragastric balloon. PMID- 19782499 TI - Typical bilateral putaminal lesions of methanol intoxication. PMID- 19782500 TI - A young man presenting with acute encephalopathy, hemiparesis, and headache. AB - BACKGROUND: Familial hemiplegic migraine (FHM) is a rare type of migraine. Correct diagnosis is challenging for emergency physicians (EPs) due to its variable clinical picture, as well as its lack of diagnostic biological markers. OBJECTIVES: To raise awareness among EPs regarding FHM's diverse clinical picture, and to highlight FHM's diagnostic criteria to facilitate an accurate and timely diagnosis of FHM in patients presenting to the emergency department (ED) with indicative symptomatology. CASE REPORT: A 24-year-old male student presented to the ED complaining of dizziness, general weakness, and blurred vision that had developed the previous night. The initial physical examination revealed drowsiness, slow speech production, and slight weakness with paresthesia in all limbs. Detailed communication with the patient's aunt revealed that he had experienced several similar attacks since the age of 12 years, and that there was also an extensive family history of the same symptoms. In addition, 2 h after arrival, the patient experienced severe throbbing headache, vomiting, severe dysphasia, and the weakness shifted to the right side. A computed tomography scan of the brain showed no anomalies. He was admitted with a tentative diagnosis of FHM. CONCLUSION: A diagnosis of FHM should be considered if the patient's clinical features include headache and weakness, with a family history of similar symptomatology. However, atypical symptoms of FHM may present as recurrent episodes of unexplained encephalopathy. Crucial elements for making an accurate and timely diagnosis of FHM include a detailed knowledge of weakness-related diseases and an ability to consider FHM in the differential diagnosis, as well as obtaining a thorough family history with repeated neurologic assessments. PMID- 19782501 TI - Risk factors for riding and crashing a motorcycle unhelmeted. AB - BACKGROUND: Currently, less than half of all U.S. states require helmets for motorcycle operators. Although research has demonstrated the effectiveness of helmets, less is known about the characteristics of individuals who choose to ride motorcycles unhelmeted. OBJECTIVES: The specific aims of this study were to identify risk factors leading to riding and crashing a motorcycle without a helmet and to compare outcomes of helmeted vs. unhelmeted motorcyclists involved in a motorcycle crash. METHODS: This 13-year (1994-2006) retrospective study of adult motorcycle crashes admitted to a Level II trauma center compares helmeted to unhelmeted motorcyclists. RESULTS: There were 1738 motorcyclists admitted, including 978 (56%) helmeted (38 years old, 87% male) and 760 (44%) unhelmeted (38 years old, 85% male). Unhelmeted riders had a higher Injury Severity Score (16 vs. 13, p < 0.001), lower Glasgow Coma Scale score (13 vs. 14, p < 0.001), and more hypotension (6% vs. 4%, p = 0.03). Unhelmeted riders had worse outcomes, including higher rate of severe disability (16% vs. 10%, p < 0.001), more days in the hospital (7 vs. 6, p < 0.001) and intensive care unit (2 vs. 1, p < 0.001), incurred higher hospital charges ($44,744 vs. $31,369, p < 0.001), and had higher mortality (6% vs. 2%, p < 0.001). Independent predictors of riding without a helmet included alcohol intoxication, riding as a passenger, and lack of health insurance. CONCLUSIONS: Unhelmeted motorcyclists sustain more severe injuries and adverse outcomes. Motorcyclists who are intoxicated, uninsured, or passengers are less likely to wear a helmet. Education and prevention strategies should be targeted at these high-risk populations. PMID- 19782502 TI - The beta-adrenergic system is involved in the regulation of the expression of avian uncoupling protein in the chicken. AB - Avian uncoupling protein (avUCP) is orthologous to UCP3, which is suggested to be involved in fatty acid metabolism and to limit the mitochondrial production of reactive oxygen species in mammals. In the chicken, the role and regulation of avUCP remain to be clarified. The aim of this study was to explore the control of avUCP expression by the beta-adrenergic system, known to be involved in avian thermoregulation and lipid utilization, and in UCP expression in mammals. Therefore, we measured the expression of avUCP mRNA and protein in the Pectoralis major muscle of chickens injected with the beta(2) agonist isoproterenol, and we investigated the potential pathways involved in the regulation of avUCP mRNA expression. Avian UCP mRNA expression was increased 7-fold 4h after isoproterenol injection, leading to a tendency to a 40% increase in avUCP protein 24h post injection. This increase was preceded, 30 min after isoproterenol injection, by changes in the chicken thyroid status and in the muscular expression of PPARalpha, PPARbeta/delta, and PPARgamma coactivator-1alpha (PGC-1alpha). Moreover, the analysis of the avUCP promoter sequence suggested potential binding sites for PPARs and for thyroid hormone receptors. We also detected the activation of AMP-activated protein kinase, which has recently been reported to be involved in UCP3 regulation in mammals. This study presents for the first time evidence of beta-adrenergic control on avUCP messenger expression in chicken muscle and suggests the potential involvement of AMPK and several transcription factors in this regulation. PMID- 19782503 TI - Evidence for a potential role of neuropeptide Y in ovine corpus luteum function. AB - Neuropeptide Y (NPY) is a neurohormone that is typically associated with food intake, but it has also been reported to affect the production of progesterone from luteal tissue in vitro. However, NPY has not been previously immunolocalized in the ovine ovary or in the corpus luteum (CL) of any species, and the effects of this neurohormone on luteal function in vivo are not known. Thus, we performed fluorescent immunohistochemistry (IHC) to localize NPY in the ovine ovary and used avidin-biotin immunocytochemistry (ICC) to further define the intracellular localization within follicles and the CL. We then infused NPY directly into the arterial supply of the autotransplanted ovaries of sheep to determine the in vivo effect of exogenous NPY on ovarian blood flow and on the luteal secretion rate of progesterone and oxytocin. Immunohistochemistry revealed that the NPY antigen was localized to cells within the follicles and CL, in the nerve fibers of the ovarian stroma, and in the vessels of the ovarian hilus. In the follicle, the NPY antigen was localized to nerves and vessels within the theca interna layer, and strong staining was observed in the granulosal cells of antral follicles. In the CL, NPY was localized in large luteal cells and in the vascular pericytes and/or endothelial cells of blood vessels, found dispersed throughout the gland and within the luteal capsule. In vivo incremental infusions of NPY at 1, 10, 100, and 1,000 ng/min, each for a 30-min period, into the arterial supply of the transplanted ovary of sheep bearing a CL 11 d of age increased (P< or =0.05) ovarian blood flow. The intra-arterial infusions of NPY also increased (P< or =0.05) in a dose-dependent manner the secretion rate of oxytocin, which was positively correlated (P< or =0.05) with the observed increase in ovarian blood flow. The infusions of NPY had a minimal effect on the secretion rate of progesterone, and similar intra-arterial infusions of NPY into sheep with ovarian transplants bearing a CL over 30 d of age had no significant effect on ovarian blood flow or on the secretion rate of progesterone. These results suggest that NPY acts on the luteal vascular system and the large luteal cells to rapidly stimulate blood flow and the secretion of oxytocin, respectively, which collectively implies a putative role for NPY during the process of luteolysis when increasing amounts of oxytocin are secreted from the ovine CL in response to uterine pulses of prostaglandin F2alpha. PMID- 19782506 TI - Brachial vein transposition arteriovenous fistulas for hemodialysis access. AB - BACKGROUND: An arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis, offering lower morbidity, mortality, and cost compared with grafts or catheters. Patients with a difficult access extremity have often lost all superficial veins, and even basilic veins may be obliterated. We have used brachial vein transposition AVFs (BVT-AVFs) in these challenging patients and review our experience in this report. METHODS: The study reviewed consecutive patients in whom BVT-AVFs were created from September 2006 to March 2009. Most BVT-AVFs were created in staged procedures, with the second-stage transposition operations completed 4 to 6 weeks after the first-stage AVF operation. A single stage BVT-AVF was created when the brachial vein diameter was > or =6 mm. RESULTS: We identified 58 BVT-AVF procedures, comprising 41 women (71.0%), 28 diabetic patients (48.3%), and 29 (50.0%) had previous access surgery. The operation was completed in two stages in 45 operations (77.6%) and was a primary transposition in 13 patients. However, five of these were secondary AVFs with previous distal AV grafts or AVFs placed elsewhere; effectively, late staged procedures. Follow-up was a mean of 11 months (range, 2.0-31.7 months). Primary patency, primary-assisted patency, and cumulative (secondary) patency were 52.0%, 84.9%, and 92.4% at 12 months and 46.2%, 75.5%, and 92.4% at 24 months, respectively. Harvesting the brachial vein was tedious and more difficult than harvesting other superficial veins. No prosthetic grafts were used. CONCLUSION: BVT-AVFs provide a suitable option for autogenous access when the basilic vein is absent in patients with difficult access extremities. Most patients required intervention for access maturation or maintenance. Most BVT-AVFs were created with staged procedures. Cumulative (secondary) patency was 92.4% at 24 months. PMID- 19782507 TI - Spontaneous recanalization of a middle cerebral artery occlusion with subsequent carotid endarterectomy. AB - We report the case of a 55-year-old man who presented with a left hemisphere stroke. The initial computed tomography scan demonstrated a cerebral infarct in association with a left middle cerebral artery occlusion. Carotid duplex ultrasound imaging revealed a surgical grade stenosis of the proximal left internal carotid artery; however, in view of the uncertain benefits of internal carotid endarterectomy in the face of ipsilateral middle cerebral artery occlusion, surgery was deferred. Subsequent surveillance by transcranial Doppler imaging and repeat computed tomography demonstrated spontaneous recanalization. The patient proceeded to carotid endarterectomy with no complications. PMID- 19782509 TI - Percutaneous transluminal angioplasty for treatment of critical hand ischemia with a novel endovascular approach: "the radial to ulnar artery loop technique". AB - A 44-year-old patient with type I diabetes with critical upper limb ischemia of the left hand was referred to our department with ischemic tissue loss and rest pain. After unsuccessful use of the endovascular antegrade approach, retrograde revascularization with percutaneous transluminal angioplasty (PTA) of the ulnar artery and the Palmar arch through the radial artery was successfully performed (the radial to ulnar artery loop technique). Relief of the patient's symptoms was immediate and ischemic lesions were healed at 6-month follow-up. This technique, which has been used for the first time in critical upper limb ischemia, may significantly increase the success rate of percutaneous angioplasty, especially when antegrade recanalization fails. PMID- 19782508 TI - Primary leiomyosarcoma of the inferior vena cava: reports of infrarenal and suprahepatic caval involvement. AB - We report two cases of primary inferior vena cava (IVC) leiomyosarcoma. The first patient was a 60-year-old female who presented with abdominal pain. The patient was initially diagnosed with a retroperitoneal sarcoma that may have involved the right renal vessels and the IVC. The Vascular Surgery Service was consulted intra operatively when it became evident that the IVC was primarily involved. The patient was treated with total en-bloc excision of the infrarenal IVC tumor with concomitant interposition polytetrafluoroethylene (PTFE) graft caval replacement. The second patient was a 58-year-old female who presented with general malaise and anemia. This tumor began in the distal infrarenal IVC and extended cephalad to the suprahepatic IVC, ending approximately 2 cm below the right atrium. Intrapericardial IVC clamping was required for cephalad control in this patient, who was then treated with excision of the tumor and concomitant interposition PTFE graft caval replacement with reimplantation of the right renal vein. A review of this rare tumor is presented. PMID- 19782510 TI - Endovascular treatment of spontaneous dissections of the superior mesenteric artery. AB - BACKGROUND: Spontaneous dissection of the superior mesenteric artery (SMA) is exceedingly rare. Treatment options range from observation to anticoagulation to open surgery or endovascular repair. We present our experience to date in the management of isolated SMA dissections. METHODS: A retrospective review of the vascular surgery and radiology databases from 1998 to 2008 was performed. In general, incidental radiologic findings of a dissection were managed expectantly. The decision to intervene was based on anatomic suitability, patient comorbidities and symptoms, and physician preference. Endovascular stents were placed using a brachial approach, with the choice of stent determined by physician preference. Patients who underwent endovascular stent placement (ESP) were maintained on antiplatelet therapy for 6 months postoperatively. Follow-up consisted of yearly office visits and adjunctive computerized tomography (CT) or magnetic resonance imaging (MRI) when clinically indicated. RESULTS: CT or MRI imaging identified nine patients (7 men, 2 women) with an isolated SMA dissection. One patient also had a concomitant celiac artery dissection. Median age was 70 years (range, 46-73 years). Median follow-up time was 32 months (range, 13.8-62.5 months). Presentations included an incidental radiologic finding in three patients and acute onset abdominal pain in six. Treatment included expectant management in four patients, anticoagulation in two, and ESP in three. ESP was performed primarily in two patients and in a third patient after initial management with anticoagulation failed. The reduction in the diameter of the true lumen was significantly greater in patients treated with ESP vs patients who were successfully managed expectantly or with anticoagulation (F = 15.59, P < .005). No procedural complications were associated with ESP. CONCLUSIONS: An isolated SMA dissection is a rare entity that may be managed successfully in a variety of ways based on clinical presentation. Endovascular stenting can be performed with good results and may be the preferred treatment in patients with symptomatic isolated SMA dissections. PMID- 19782511 TI - Testicular infarction: a rare complication of endovascular aneurysm repair treatment for aortoiliac aneurysm. AB - Endovascular aneurysm repair (EVAR) is an established therapy to prevent rupture in large infrarenal abdominal aortic aneurysms (AAA). As experience with this therapy has grown, treatment of more challenging anatomy has led to the identification of several new procedurally related complications. We report the case of a 67-year-old man with an asymptomatic, large infrarenal AAA with an associated left common iliac artery aneurysm. Endovascular therapy for an aortoiliac aneurysm involved prior coil embolization of his left internal iliac artery to allow conventional EVAR with extension to the external iliac artery of the left graft limb, thus excluding the left iliac aneurysm. He presented 6 weeks postoperatively with onset of left-sided scrotal pain and underwent emergency orchidectomy for ischemic infarction of his left testis. The histology report confirmed that the left testis was necrotic secondary to a thrombus in the testicular artery. To our knowledge, this is the first report of testicular infarction after EVAR. PMID- 19782512 TI - Carotid endarterectomy in female patients. AB - OBJECTIVES: To evaluate early and late results of carotid endarterectomy (CEA) in female patients in a large single center experience. METHODS: Over a 12-year period ending in December 2007, 4009 consecutive primary and secondary CEAs in 3324 patients were performed at our institution. All patients were prospectively enrolled in a dedicated database containing pre-, intra-, and postoperative parameters. Patients were female in 1200 cases (1020 patients; Group 1) and male in the remaining 2809 (2304 patients, Group 2). Early results in terms of intraoperative neurological events and 30-day stroke and death rates were analyzed and compared. Follow-up results were analyzed with Kaplan Meier curves and compared with log-rank test. RESULTS: Patients of Group 1 were more likely to have hyperlipemia, diabetes, and hypertension; patients of Group 2 were more likely to be smokers and to have concomitant coronary artery disease (CAD) and peripheral arterial disease (PAD). There were no differences in terms of clinical status or degree of stenosis. Patients of Group 2 had a significantly higher percentage of contralateral carotid artery occlusion than patients in Group 1 (6.9% and 3.9%, respectively; P < .001). Thirty-day stroke and death rates were similar in the two groups (1.2% for both groups). Univariate analysis demonstrated the presence of CAD, PAD, diabetes, and contralateral carotid artery occlusion to significantly affect 30-day stroke and death rate in female patients. At multivariate analysis, only diabetes (odds ratio [OR] 3.6, 95% confidence interval [CI] 0.1-0.9; P = .05) and contralateral occlusion (OR 7.4, 95% CI 0.03-0.6; P = .006) were independently associated with an increased perioperative risk of stroke and death. Median duration of follow-up was 27 months (range, 1-144 months). There were no overall differences between the two groups in terms of survival, freedom from ipsilateral stroke, freedom from any neurological symptom, and incidence of severe (>70%) restenosis. In contrast to male patients, univariate and multivariate analysis demonstrated that female patients with diabetes or contralateral occlusion had an increased risk of developing ipsilateral neurological events during follow-up. CONCLUSIONS: Female sex per se does not represent an adjunctive risk factor during CEA, with early and long term results comparable to those obtained in male patients. However, in our study we found subgroups of female patients at higher surgical risk, requiring careful intra- and postoperative management. PMID- 19782513 TI - Misplacement of a vena cava filter into the spinal canal. AB - We report the case of a 70-year-old male with a complication of misplacement of a vena cava filter into the spinal canal. This likely happened as a result of penetration of the wire and filter sheath through the iliac vein or vena cava into the retroperitoneum, vertebral foramina, and spinal canal at the level of L2 and L3. Due to the patient's condition, the filter was not removed and no neurologic symptoms have occurred. This represents the first reported case of a filter deployment into the spinal canal. Although placement of vena cava filters is a relatively safe procedure, complications are seen commonly due to the large number of procedures performed. Spinal complications, however, are rarely reported. This is the first reported case of the inadvertent placement of a vena cava filter into the spinal canal. PMID- 19782514 TI - Management of a nontraumatic extracranial internal carotid aneurysm with external carotid transposition. AB - Primary aneurysms of the extracranial internal carotid artery are exceptionally rare, with only a very few reports in the medical literature that are not related to known connective tissue disease or antecedent trauma. The natural history of these entities has not been precisely defined. Nevertheless, the embolic risk that an aneurysm at this location represents mandates prompt intervention when identified. We present the case of a 42-year-old female who was found to have a 3 cm aneurysm of the right extracranial internal carotid artery after seeing a physician for refractory headaches. In an austere environment with limited resources, this patient was successfully managed with the use of external carotid transposition to the distal internal carotid artery, cephalad to the aneurysm. PMID- 19782515 TI - Management of a thoracic endograft infection through an ascending to descending extra-anatomic aortic bypass and endograft explantation. AB - A 52-year-old man presented 33 months after thoracic aortic endovascular repair with hemoptysis and was found to have an aortobronchial fistula secondary to a mycotic aneurysm. The endograft infection was managed in a two-stage fashion. During the initial stage, the patient underwent an ascending-to-descending thoracic aortic bypass. Neither cardiopulmonary bypass, hypothermic circulatory arrest, nor aortic cross-clamping were used. During the same hospitalization, the patient underwent successful endograft explantation through a left thoracotomy. Imaging at 6 months demonstrated no anastomotic concerns and resolution of residual pulmonary inflammation. Thoracic aortic endograft infections necessitating endograft removal can potentially be successfully and safely managed without the need for cardiopulmonary bypass, hypothermic circulatory arrest, or interruption of aortic blood flow. PMID- 19782516 TI - Stroke following endovenous laser treatment of varicose veins. AB - This report describes an ischemic stroke following endovenous laser treatment of the great saphenous vein in a patient with a patent foramen ovale. No thrombophilic conditions or other possible sources of emboli could be demonstrated. PMID- 19782517 TI - A comparative analysis of open and endovascular repair for the ruptured descending thoracic aorta. AB - BACKGROUND: Successful repair of the ruptured (non-traumatic) descending thoracic aorta (rTA) remains a formidable clinical challenge. Although effective for rTA, traditional open repair (DTAR) has significant associated morbidity. With expanding indications for thoracic endovascular aortic repair (TEVAR), we describe our experience with TEVAR and DTAR in this high-risk setting to elucidate their evolving roles. METHODS: Since the inception of our thoracic aortic endovascular program in 1993, 69 patients underwent DTAR (34) or TEVAR (35) for rTA. Patients underwent TEVAR if they were considered nonoperative candidates because of extensive comorbidities (n = 31; 88.6%) or had extremely favorable anatomy for endovascular repair (eg, mid-descending saccular aneurysm, n = 4). Aortic pathology causing rupture was fusiform aneurysm (18), saccular aneurysm/ulcer (22), and dissection (29). Associated aortobronchial fistulae (12) and aortoesophageal (1) fistulae were also present in 18.8%. Arch repair was needed in 46; total descending repair was needed in 33. Follow-up was 100% complete (mean 37.4 months). RESULTS: Mean age was 65.9 years (DTAR 60.3 year vs TEVAR 71.3 years, P = .005). In-hospital or 30-day mortality was seen in 13 patients (TEVAR n = 4; 11.4% vs DTAR n = 9; 26.5%, P = .13). Median length of stay was shorter after TEVAR (8 days vs DTAR 15 days, P = .02). Mean Kaplan-Meier survival was similar between groups (TEVAR 67.4 months vs DTAR 65.0 months, P = .7). By multivariate analysis, independent predictors of a composite outcome of early mortality, stroke, permanent spinal cord ischemia, or need for dialysis or tracheostomy included the presentation with hemodynamic instability (P < .001) and treatment with conventional open repair (P = .02). CONCLUSION: An endovascular approach for the ruptured (non-traumatic) descending thoracic aorta reduces early morbidity, mortality, and duration of hospitalization, while providing equivalent late outcomes even in an older group largely considered high risk for open repair. These data support a paradigm shift, with TEVAR emerging as the preferred therapy for all patients presenting with descending aortic rupture. PMID- 19782518 TI - Comparison of the efficacy of upper arm transposed arteriovenous fistulae and upper arm prosthetic grafts. AB - PURPOSE: Direct comparison of transposed arteriovenous fistulas (tAVF) and arteriovenous grafts (AVG) has been hampered by inherent differences in patient characteristics between tAVF and AVG groups. In this study, using matching to control patient variables, we evaluated our outcomes with upper arm tAVF and upper arm prosthetic AVG. METHODS: A retrospective review of all newly created upper arm tAVF and AVG was performed. One hundred ninety upper arm tAVF were group matched for age, gender, race, diabetes, and history of previous failed access with 168 AVG chosen from a pool of 476 concurrently performed AVG procedures. Complication, patency, and intervention rates were compared using multivariate analysis. RESULTS: Mean follow up for our cohort was 29.1 months. Transposed fistulae consisted of 119 basilic vein and 71 cephalic vein transpositions, which were found to have similar demographic parameters, complication rates, and patency rates. There were no differences in 30 day mortality, 24 hour thrombosis, bleeding requiring exploration, or ischemic steal requiring intervention between the tAVF and AVG groups. More AVG developed infection requiring operative exploration than tAVF (7.9% vs 1.6%, respectively. P = .004). Primary patency for tAVF was higher than for AVG: 48% vs 14% at five years (P < .0001). Secondary patency rate for tAVF was also higher than for AVG: 57% vs 19% at five years (P < .0001). Nine percent of tAVF compared with 53% of AVG required one or more surgical and/or percutaneous revisions to maintain secondary patency (P < .0001). Multivariate analysis revealed that utilization of a tAVF was associated with a reduced risk of primary (Hazard Ratio [HR] 0.47, 95% Confidence Interval [CI] 0.35-0.64, P < .0001) and secondary failure (HR 0.59, 95% CI 0.42-0.81, P = .0001). CONCLUSIONS: Transposed arteriovenous fistulas have significantly higher primary and secondary patency rates, require fewer revisions, and are less likely to develop a significant infection than AVG. This study supports the contention that as long as a patient is a candidate for a tAVF based on anatomic criteria, a tAVF should be considered before an AVG. PMID- 19782519 TI - Multilocus analysis in candidate genes ACE, AGT, and AGTR1 and predisposition to peripheral arterial disease: role of ACE D/-240T haplotype. AB - OBJECTIVE: Peripheral arterial disease (PAD) is a common manifestation of systemic atherosclerosis. Apart from traditional cardiovascular risk factors, several novel biologic mediators and genetic predisposing factors appear relevant in determining the atherogenetic process leading to PAD. Genes encoding for renin angiotensin system (RAS) components have been proposed as candidate in atherosclerosis. This study investigated four polymorphisms in angiotensinogen (AGT), angiotensin converting enzyme (ACE), and angiotensin II receptor type 1 (AGTR1), genes of RAS, in both predicting PAD and modulating the severity of the disease. METHODS: The ACE I/D and -240A>T, AGT M235T, and AGTR1 1166A>C polymorphisms were analyzed in 281 PAD patients and in 485 controls comparable for age and sex. RESULTS: The ACE D and -240T alleles both significantly influenced the predisposition to PAD. The ACE D, but not -240 T, allele remained associated with PAD after Bonferroni correction (P = .004) and adjustment for cardiovascular risk factors (P = .03). The ACE D allele influenced PAD predisposition with a dose-dependent effect (odds ratio for ACE ID vs II genotype, 1.77; P = .006; ACE DD vs II genotype, 2.15; P = .001). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T haplotype significantly and independently influenced the predisposition to PAD (P = .02). In 190 PAD patients with no additional atherosclerotic localizations (isolated PAD), a significant association between ACE D and -240T alleles and PAD was observed. Only the ACE D allele remained associated with isolated PAD after Bonferroni correction (P = .02) and after adjustment for cardiovascular risk factors (P = .02). The haplotype reconstruction analysis for the ACE gene showed that the D/-240T, but not the D/-240A haplotype significantly influenced the predisposition to PAD (P = .0003). No influence of the polymorphisms analyzed on the severity of the disease, according to Rutherford categories, was found. CONCLUSIONS: The present study contributes data to highlight the role of the ACED/-240T haplotype in predisposing to PAD, also in the absence of other atherosclerotic comorbidities. PMID- 19782520 TI - Mandibular subluxation for distal internal carotid artery exposure in edentulous patients. AB - Four patients with high internal carotid artery (ICA) occlusive disease were indicated for surgical endarterectomy and needed additional exposure besides regular head rotation and extension. When indicated, in our clinic this is usually achieved by mandibular subluxation with interdental wiring. Due to dental wear and periodontal disease, all 4 patients were edentulous. As a consequence, the technique of interdental wiring could not be used. In this technical note we will explain a method for interarch fixation with the use of two ipsilateral monocortical miniscrews and wiring, and the use of patients' pre-existing mandibular implants and provisional overdenture. This method gives rise to an additional exposure of 15 to 20 mm of the ICA. PMID- 19782521 TI - Revenue cycle management. AB - With the widening gap between overhead expenses and reimbursement, management of the revenue cycle is a critical part of a successful vascular surgery practice. It is important to review the data on all the components of the revenue cycle: payer contracting, appointment scheduling, preregistration, registration process, coding and capturing charges, proper billing of patients and insurers, follow-up of accounts receivable, and finally using appropriate benchmarking. The industry benchmarks used should be those of peers in identical groups. Warning signs of poor performance are discussed enabling the practice to formulate a performance improvement plan. PMID- 19782522 TI - The influence of stents on the performance of an ultrasonic navigation system for endovascular procedures. AB - OBJECTIVE: Image-guided surgery provides a mechanism to accurately and quickly assess the location of surgical tools relative to a preoperative image. Traditional image-guided surgery relies on infrared or radiofrequency triangulation to determine an instrument location relative to a preoperative image and has been primarily used in head and neck procedures. Advances in ultrasonic tracking devices, designed for tracking catheters within vessels, may provide an opportunity for image-guided endovascular procedures. This study evaluates the positional accuracy of an ultrasonic navigation system for tracking an endovascular catheter when different stents and graft materials have been deployed in an in vitro system. METHODS: Stent and graft materials commonly used in endovascular procedures were used for this study in combination with a custom three-head ultrasonic transducer navigation system. The stents evaluated were composed of Dacron/nitinol, polytetrafluoroethylene (PTFE)/nitinol, and bare nitinol. They were deployed into excised porcine tissue cannulized with a rotary drill, and a catheter with a custom microtransducer probe was inserted. The distance from each ultrasonic tracking module to a probe mounted on an endovascular catheter was measured using time of flight techniques, and the catheter position in three-dimensions was calculated using triangulation. RESULTS: The measured position was compared to the actual catheter position determined by a precision translation stage. The PTFE/nitinol, bare nitinol, and Dacron/nitinol stent materials were evaluated and resulted in a maximum error of 1.7, 3.0, and 3.6 mm and an SD of 0.7, 1.2, and 1.4 mm, respectively. A reduction in signal intensity of up to 6x was observed during passage of the endovascular probe through the stent materials, but no reduction in the accuracy of the ultrasonic navigation system was evident. CONCLUSION: The use of an ultrasonic based navigation system is feasible in endovascular procedures, even in the presence of common stent materials. It may have promise as a navigational tool for endovascular procedures. PMID- 19782523 TI - Gene transduction into aortic wall using plasmid-loaded cationized gelatin hydrogel-coated polyester stent graft. AB - OBJECTIVE: Stent grafts are increasingly recognized as useful devices for endovascular repair of aortic aneurysms and other vascular diseases. Stent graft mediated gene delivery into the vascular wall is expected to improve their therapeutic effects. This study evaluated the efficacy of genetically engineered cationized gelatin (CG) hydrogel-coated partially-covered polyester stent grafts that facilitate delivery of an expression plasmid DNA in rabbit aortic wall. METHODS: Partially covered polyester stent grafts coated with CG hydrogel impregnated with 10.0 mg/mL of beta-galactosidase (LacZ)-expression plasmid vector (pCAGGS-LacZ) or empty vector (pCAGGS) solutions were implanted via the femoral artery in rabbit balloon-injured aortas. The aortic segments were removed at 1, 3, or 7 days (4 rabbits/each group) after implantation and evaluated for the transgene (LacZ) delivery and expression by real-time reverse transcriptase polymerase chain reaction (RT-PCR) and X-gal (5-bromo-4-chloro-3-indolyl-beta-D galactoside) staining. Partially-covered polyester stent grafts coated with CG hydrogel impregnated with various amounts (0.1 mg/mL, 1.0 mg/mL, and 10.0 mg/mL) of pCAGGS-LacZ or pCAGGS were also implanted in rabbits' balloon-injured aortas (4 rabbits/each group) to evaluate transgene delivery and expression in the aortic wall 3 days after implantation. The difference of transgene efficiency among each group was compared using one-way analysis of variance (ANOVA) and Newman-Keuls' test according to the result of quantitative RT-PCR. RESULTS: In all animals, LacZ gene transduction into the aortic wall was detected at the implantation site of pCAGGS-LacZ-loaded, but not pCAGGS-loaded, stent grafts. LacZ expression was not detected in aortic segments immediately proximal or distal to the implanted pCAGGS-LacZ-loaded stent graft or remote organs including the brain, heart, liver, and kidney by either RT-PCR or X-gal staining. The X-gal staining-positive cells were observed at or near the luminal surface in the aortic segments only in contact with the stent graft and the ingrowth tissues within stent grafts. Immunohistochemical studies suggested that the LacZ-positive cells were mainly the neointimal alpha-smooth-muscle actin-positive cells and macrophages. The extent of the transgene expression was dependent on the quantity of the plasmid DNA loaded onto the stent graft (10.0 mg/mL plasmid vs 1.0 mg/mL plasmid, P < .01 and 10.0 mg/mL plasmid vs 0.1 mg/mL plasmid, P < .05). LacZ mRNA expression was maximal at day 1 and declined at day 7 (P < .05) but was still detectable. CONCLUSION: Plasmid-loaded CG hydrogel-coated stent graft is a promising vehicle for local transgene delivery to the aortic wall and offers the possibility of transduction of therapeutic genes into the vascular wall. PMID- 19782524 TI - Does vascular surgery cost too much? PMID- 19782525 TI - Retroesophageal internal jugular-to-internal jugular vein bypass for venous occlusion in a patient with complex hemodialysis access. AB - This report describes a right-hand dominant, self-dialyzing patient whose left brachiocephalic autogenous access was previously rescued for left brachiocephalic vein thrombosis with a bypass to the right internal jugular vein (IJV). After 1 year, the left IJV thrombosed, resulting in painful edema and venous dilatation. A retroesophageal IJV-IJV bypass was created, preserving the left brachiocephalic autogenous access. PMID- 19782527 TI - Nitinol stenting improves primary patency of the superficial femoral artery after percutaneous transluminal angioplasty in hemodialysis patients: a propensity matched analysis. AB - BACKGROUND: Although percutaneous transluminal angioplasty (PTA) has become a common therapeutic standard for peripheral artery disease (PAD), high restenosis rates in the superficial femoral artery (SFA) remain a major problem. Nitinol stent implantation is reported to reduce restenosis in SFA after PTA in the general population; however, little is known about whether the nitinol stent improves primary patency after PTA in hemodialysis patients who are at higher risk of revascularization failure. The aim of this study was to clarify the effects of nitinol stent implantation for primary patency in SFA after PTA in hemodialysis patients with PAD. METHODS: Eighty consecutive hemodialysis patients (167 SFA lesions) who underwent PTA with nitinol stents from January 2006 to January 2008 were compared with 64 hemodialysis patients (128 SFA lesions) who received stainless steel stents in the preceding 2 years. In the follow-up study to 2 years, incidence of restenosis, amputation, and all-cause mortality were analyzed. End points between the groups were examined with the Kaplan-Meier and log-rank methods. Prognostic values for end points were calculated by a Cox univariate analysis and Cox multivariable regression models. To statistically minimize the differences in each stent group, a propensity-matched analysis was also performed using the model including male gender, age, diabetes, hypertension, hyperlipidemia, smoking, incidence of ulcer/gangrene, and TransAtlantic Inter-Society Consensus (TASC) type C+D. RESULTS: The 2-year primary patency rate was 58% in the nitinol group vs 42% in the stainless steel group (hazard ratio [HR], 0.58; 95% confidence interval [CI], 0.39-0.84; P = .0045), despite a higher prevalence of TASC C+D lesion in the nitinol group (68% vs 49%, P = .0014). In 108 lesions matched after propensity score analysis, the primary patency for 2 years was 64% in the nitinol group vs 42% in the stainless steel group (HR, 0.39; 95% CI, 0.24-0.65; P = .0003). Cox multivariate models showed nitinol stent (HR, 0.42; 95% CI, 0.25-0.73; P = .002), age (HR, 1.04; 95% CI, 1.01-1.08; P = .031), and incidence of ulcer/gangrene (HR, 2.35; 95% CI, 1.17 4.75; P = .017) were independent predictors of restenosis. CONCLUSION: These data suggest that nitinol stent implantation improves primary patency in SFA after PTA compared with the stainless steel stent, even in hemodialysis patients with PAD. PMID- 19782528 TI - Pharmacomechanical thrombectomy for iliofemoral deep vein thrombosis: an alternative in patients with contraindications to thrombolysis. AB - OBJECTIVE: Venous lysis is usually reserved for symptomatic patients with acute deep vein thrombosis (DVT) and low risk for bleeding. This study reports the use of pharmacomechanical thrombectomy (PMT) in patients with contraindications to thrombolysis. METHODS: A retrospective review of all patients with symptomatic DVT treated between 2007 and 2008 with PMT was performed. All patients were treated by a combination of local tissue plasminogen activator (tPA) with the Angiojet (Possis Medical, Minneapolis, Minn) or Trellis device (Bacchus Vascular, Santa Clara, Calif). Catheter-directed lysis was used sparingly. RESULTS: Forty three patients (mean age, 48.4 +/- 16.6 years) presented with symptoms averaging 13.6 +/- 9.6 days in duration. Nineteen (44%) had symptoms for >14 days, and 15 (35%) had a high risk for bleeding. Symptomatic subclavian thrombosis occurred in eight (19%), and 35 (81%) presented with disabling lower extremity DVT (4 phlegmasia) despite anticoagulation. Fifteen patients had a thrombosed indwelling permanent filter. Sixty-three percent were treated in one session, but 16 patients required a lytic infusion after suboptimal PMT. Iliac stenting was required in 35% of limbs treated. Successful lysis (>50%) was achieved in 95% of patients and symptom resolution in 93%. All patients became ambulatory with no or minimal limitation. There were no major systemic bleeding complications, but access site hematoma occurred in two patients and worsening of pre-existing rectus sheath hematoma requiring transfusion occurred in another two. Limb salvage was maintained in 100% of patients who presented with phlegmasia. Mean follow-up was 5.0 +/- 4.8 months. Freedom from DVT recurrence and reintervention was 95% at 9 months by life-table analysis. CONCLUSIONS: PMT can be safely and effectively used for subacute iliocaval and iliofemoral DVT and in patients with contraindications for lytic therapy, resulting in improved functional outcomes relative to their debilitated state before the procedure. PMID- 19782529 TI - [Yes, there is a syndrome of the great exclusion]. PMID- 19782526 TI - Defining high-risk patients for endovascular aneurysm repair. AB - BACKGROUND: Endovascular aneurysm repair (EVAR) is commonly used as a minimally invasive technique for repairing infrarenal aortic aneurysms. There have been recent concerns that a subset of high-risk patients experience unfavorable outcomes with this intervention. To determine whether such a high-risk cohort exists and to identify the characteristics of these patients, we analyzed the outcomes of Medicare patients treated with EVAR from 2000-2006. METHODS: We identified 66,943 patients who underwent EVAR from Inpatient Medicare database. The overall 30-day mortality was 1.6%. A risk model for perioperative mortality was developed by randomly selecting 44,630 patients; the other one third of the dataset was used to validate the model. The model was deemed reliable (Hosmer Lemeshow statistics were P = .25 for the development, P = .24 for the validation model) and accurate (c = 0.735 and c = 0.731 for the development and the validation model, respectively). RESULTS: In our scoring system, where scores ranged between 1 and 7, the following were identified as significant baseline factors that predict mortality: renal failure with dialysis (score = 7); renal failure without dialysis (score = 3); clinically significant lower extremity ischemia (score = 5); patient age >or=85 years (score = 3), 75-84 years (score = 2), 70-74 years (score = 1); heart failure (score = 3); chronic liver disease (score = 3); female gender (score = 2); neurological disorders (score = 2); chronic pulmonary disease (score = 2); surgeon experience in EVAR <3 procedures (score = 1); and hospital annual volume in EVAR <7 procedures (score = 1). The majority of Medicare patients who were treated (96.6%, n = 64,651) had a score of 9 or less, which correlated with a mortality <5%. Only 3.4% of patients had a mortality >or=5% and 0.8% of patients (n = 509) had a score of 13 or higher, which correlated with a mortality >10%. CONCLUSION: We conclude that there is a high-risk cohort of patients that should not be treated with EVAR because of prohibitively high mortality; however, this cohort is small. Our scoring system, which is based on patient and institutional factors, provides criteria that can be easily used by clinicians to quantify perioperative risk for EVAR candidates. PMID- 19782530 TI - The Quality of Dying and Death Questionnaire (QODD): empirical domains and theoretical perspectives. AB - We used exploratory factor analysis within the confirmatory analysis framework, and data provided by family members and friends of 205 decedents in Missoula, Montana, to construct a model of latent-variable domains underlying the Quality of Dying and Death questionnaire (QODD). We then used data from 182 surrogate respondents, who were survivors of Seattle decedents, to verify the latent variable structure. Results from the two samples suggested that survivors' retrospective ratings of 13 specific aspects of decedents' end-of-life experience served as indicators of four correlated, but distinct, latent-variable domains: Symptom Control, Preparation, Connectedness, and Transcendence. A model testing a unidimensional domain structure exhibited unsatisfactory fit to the data, implying that a single global quality measure of dying and death may provide insufficient evidence for guiding clinical practice, evaluating interventions to improve quality of care or assessing the status or trajectory of individual patients. In anticipation of possible future research tying the quality of dying and death to theoretical constructs, we linked the inferred domains to concepts from identity theory and existential psychology. We conclude that research based on the current version of the QODD might benefit from the use of composite measures representing the four identified domains, but that future expansion and modification of the questionnaire are in order. PMID- 19782532 TI - Exercise echocardiography in rheumatoid arthritis: a case-control study. AB - BACKGROUND: Rheumatoid arthritis (RA) is associated with increased cardiovascular risk. METHODS: To assess the role of exercise echocardiography (EE) in the evaluation of patients with RA, follow-up (mean, 6.7+/-3.7 years) was retrospectively obtained in 159 patients with RA who underwent EE. Patients were matched for age, gender, and cardiovascular risk factors with 454 controls who underwent EE. RESULTS: Patients with RA were more likely to have positive results for ischemia on EE (odds ratio, 2.32; 95% confidence interval, 1.48-3.64; P=.0003). Rest and exercise wall motion score indexes were higher in the RA group (1.14+/-0.33 and 1.22+/-0.39, respectively, vs 1.06+/-0.18 and 1.10+/-0.24 in controls; P < .005 for each). Logistic regression adjusted for age revealed an increased odds ratio for myocardial ischemia of 1.06 (95% confidence interval, 1.02-1.11; P=.005) per year of RA. Five-year all-cause mortality in subjects with RA with myocardial ischemia on EE was 14.9%, compared with 4.3% in RA subjects without ischemia (P=.028). CONCLUSION: RA was associated with a 2-fold increased risk for myocardial ischemia on EE; risk increased with the duration of RA. Mortality was increased in patients with RA with ischemia on EE. PMID- 19782531 TI - Late-stage HIV/AIDS patients' and their familial caregivers' agreement on the palliative care outcome scale. AB - This study compares the self-assessments of 67 late-stage HIV/AIDS patients regarding their symptomatology, sense of self-worth, and several other aspects of their health-care situation, to assessments of that situation provided by their informal caregivers. As part of a dyadic study of care preferences, the patients and caregivers independently completed nearly identical versions of the Palliative Care Outcome Scale, a short 10-item measure of the patient's current health, social, and psychological status. The participants in the study were recruited from inpatient and outpatient services at an urban medical center. Substantial or moderate agreement, assessed by weighted kappa, was found between patient and caregiver assessments with regard to only four items assessing physical or emotional states of the patient (pain, other symptoms, anxiety, and life worthwhile). Fair or slight agreement was found for the six remaining items, including those assessing the patient's sense of self-worth, family/friends' anxiety, interactions with family/friends, and practical matters. Mean ratings of self-worth were significantly different for patients and caregivers. These findings underscore the clinical need to assess patient care outcomes directly, and they suggest the importance of facilitating more effective communication about relevant health issues among seriously ill patients, caregivers, and health care providers. PMID- 19782533 TI - Medical image denoising using one-dimensional singularity function model. AB - A novel denoising approach is proposed that is based on a spectral data substitution mechanism through using a mathematical model of one-dimensional singularity function analysis (1-D SFA). The method consists in dividing the complete spectral domain of the noisy signal into two subsets: the preserved set where the spectral data are kept unchanged, and the substitution set where the original spectral data having lower signal-to-noise ratio (SNR) are replaced by those reconstructed using the 1-D SFA model. The preserved set containing original spectral data is determined according to the SNR of the spectrum. The singular points and singularity degrees in the 1-D SFA model are obtained through calculating finite difference of the noisy signal. The theoretical formulation and experimental results demonstrated that the proposed method allows more efficient denoising while introducing less distortion, and presents significant improvement over conventional denoising methods. PMID- 19782534 TI - Autogenous femoral head as grafting material for mandibular augmentation. AB - Bone grafting is commonly used for augmentation of the atrophic edentulous maxilla and mandible. Although bone substitutes and allogeneic frozen bone grafts have been applied successfully, fresh autogenous bone grafts remain the 'gold standard' in maxillofacial reconstructive surgery. A disadvantage of harvesting autogenous bone is the resulting donor-site morbidity. The authors present a case in which an autogenous femoral head, which was removed because of a prosthetic hip replacement, was used for augmentation of the extreme atrophic mandible. Using this procedure avoids donor-site morbidity. PMID- 19782535 TI - Sialolithiasis in a stump of Wharton's duct of an aplastic unilateral submandibular gland. PMID- 19782536 TI - Stigma and health-related quality of life in Asian adults with epilepsy. AB - This study aims to (1) review the impact of epilepsy on the health-related quality of life (HRQoL) of Asian adult persons with epilepsy (PWE), and (2) identify the extent of stigma they experience and the associated factors. The electronic databases Medline, PsycINFO, ISI Web of Science, and the International Pharmaceutical Abstracts were searched using a combination of keywords to identify relevant journal articles published before October 2007, and supplemental manual searches of article bibliographies and the journal Neurology Asia were conducted. Thirty-six articles that met the predetermined inclusion criteria were selected and reviewed. The HRQoL of Asian adult PWE was lower than that of the general population. These PWE had difficulties in both physical and psychosocial functioning. Psychosocial factors appeared to have a more significant impact on PWE's HRQoL than physical factors. Stigma and negative attitudes towards marriage and employment of PWE was prevalent in many Asian countries, and the stigma's associated factors were multifaceted. Given the prevalent negative attitudes towards epilepsy, public education campaigns targeting misconceptions and associated factors may help reduce stigma and, together with psychosocial support, the HRQoL of Asian adult PWE can be improved. PMID- 19782537 TI - Unique and shared validity of the "Wechsler logical memory test", the "California verbal learning test", and the "verbal learning and memory test" in patients with epilepsy. AB - RATIONALE: This study was set-up to evaluate the construct validity of three verbal memory tests in epilepsy patients. METHODS: Sixty-one consecutively evaluated patients with temporal lobe epilepsy (TLE) or extra-temporal epilepsy (E-TLE) underwent testing with the verbal learning and memory test (VLMT, the German equivalent of the Rey auditory verbal learning test, RAVLT); the California verbal learning test (CVLT); the logical memory and digit span subtests of the Wechsler memory scale, revised (WMS-R); and testing of intelligence, attention, speech and executive functions. RESULTS: Factor analysis of the memory tests resulted in test-specific rather than test over-spanning factors. Parameters of the CVLT and WMS-R, and to a much lesser degree of the VLMT, were highly correlated with attention, language function and vocabulary. Delayed recall measures of logical memory and the VLMT differentiated TLE from E TLE. Learning and memory scores off all three tests differentiated mesial temporal sclerosis from other pathologies. A lateralization of the epilepsy was possible only for a subsample of 15 patients with mesial TLE. CONCLUSION: Although the three tests provide overlapping indicators for a temporal lobe epilepsy or a mesial pathology, they can hardly be taken in exchange. The tests have different demands on semantic processing and memory organization, and they appear differentially sensitive to performance in non-memory domains. The tests capability to lateralize appears to be poor. The findings encourage the further discussion of the dependency of memory outcomes on test selection. PMID- 19782538 TI - Correlation between free and total vancomycin serum concentrations in patients treated for Gram-positive infections. AB - Routine therapeutic drug monitoring (TDM) reports only total vancomycin (VAN) concentrations, although protein binding varies and it is generally accepted that only free VAN is active. The aims of this study were to examine the correlation between free and total VAN concentrations in order to estimate whether free VAN levels can be predicted based on its total concentration. A high-performance liquid chromatography (HPLC) method was set up and validated (against routine laboratory immunoassays) for measurement of free [ultrafiltration (Centrifree); cut-off 30 kDa] and total [solid-phase extraction (Oasis MCX cartridge)] VAN in serum. Samples (n=65) from patients (n=15) treated by continuous infusion were analysed. There was a wide variation in free to total VAN ratios [range 12-100%; mean 63.6+/-25.8%, with 59 values falling outside the 95% confidence interval (57.3-69.9%); median 70.2%]. The correlation between free and total VAN was poor (R(2)=0.55). Artefacts such as pH variation of sera could be excluded. Both intrapatient and interpatient variabilities were large and no correlation could be made with patients' clinical conditions. Total VAN concentration is not predictive of free VAN concentration, suggesting that actual determination of free VAN might be recommended as an improved method of TDM. PMID- 19782539 TI - Effect of dosing interval on the efficacy of topical ophthalmic gatifloxacin against Enterococcus faecalis in an in vitro pharmacokinetic model simulating the local eye compartment. AB - Improved dosing regimens have been proposed for various antimicrobial agents by application of pharmacokinetic/pharmacodynamic (PK/PD) principles. However, for topical ophthalmic use there are several limitations to changing the dosing regimen, such as drug formulation and bioavailability. In this study, we investigated the relationship between dosing interval and antibacterial efficacy in an in vitro PK model mimicking post-operative endophthalmitis. The in vitro PK model simulated the aqueous humour concentration following topical application of 0.3% gatifloxacin ophthalmic solution to rabbit eyes. A clinical isolate of Enterococcus faecalis was exposed to gatifloxacin three times repeatedly at various intervals from 0 h to 8 h. The area between the control growth curve and the bacterial killing and re-growth curve for 24 h (ABBC) was used to evaluate efficacy. The ABBC showed bell-shaped dependence on the dosing interval with a peak at 3h. Under limited condition of total exposure amount, i.e. area under the concentration-time curve, the antimicrobial efficacy appears to be associated with the cumulative time of a 24-h period such that the concentration exceeds the minimum inhibitory concentration (T>MIC) rather than the peak concentration:MIC ratio. The length of intermission of T>MIC during repeated dosing appears to be proportional to the decrease in efficacy of gatifloxacin against E. faecalis. A longer dosing interval, as long as T>MIC is continuous, would likely be more efficient at preventing post-operative enterococcal endophthalmitis. However, further investigation is necessary to explore whether this model is applicable to a variety of pathogens and drugs. PMID- 19782540 TI - Higher diffusion in striatum and lower fractional anisotropy in white matter of methamphetamine users. AB - Methamphetamine (METH) users showed structural and chemical abnormalities on magnetic resonance (MRI) studies, particularly in the frontal and basal ganglia brain regions. Diffusion tensor imaging (DTI) may provide further insights regarding the microstructural changes in METH users. We investigated diffusion tensor measures in frontal white matter and basal ganglia of 30 adult METH users and 30 control subjects using a 3 T MR scanner. Compared with healthy control subjects, METH users showed lower fractional anisotropy (FA) in right frontal white matter, and higher apparent diffusion coefficient (ADC) in left caudate and bilateral putamen. Higher left putamen ADC was associated with earlier initiation of METH use, greater daily amounts, and a higher cumulative lifetime dose. Similarly, higher right putamen ADC was associated with greater daily amounts and a higher cumulative lifetime dose. The lower FA in the right frontal white matter suggests axonal injury in these METH users. The higher ADC in the basal ganglia suggests greater inflammation or less myelination in these brain regions of those with younger age of first METH use and greater METH usage. PMID- 19782541 TI - Physico-chemical studies of molecular interactions between non-ionic surfactants and bovine serum albumin. AB - Surfactants, particularly non-ionic types, are often added to prevent and/or minimize protein aggregation during fermentation, purification, freeze-drying, shipping, and/or storage. In this work we have investigated the interactions between two non-ionic surfactants (Tween 20 and Tween 80) and bovine serum albumin (BSA), as model protein, using surface tension, fluorescence measurements and computational analysis. The results showed that, in both cases, the surface tension profile of the surfactants curve is modified upon addition of the protein, and the CMC values of Tween 20 and Tween 80 in the presence of protein are higher than the CMC values of the pure surfactants. The results indicate that although Tween 20 and Tween 80 do not greatly differ in their chemical structures, their interactions with BSA are of different nature, with distinct binding sites. Measurements at different protein concentrations showed that the interactions are also dependent on the protein aggregation state in solution. It was found from fluorescence studies that changes observed in both the intensity and wavelength of the tryptophan emission are probably caused by modifications of tryptophan environment due to surfactant binding, rather than by direct interaction. Based on a computational analysis of a BSA three-dimensional model, we hypothesize about the binding mechanism of non-ionic surfactant to globular protein, which allowed us to explain surface tension profiles and fluorescence results. PMID- 19782542 TI - Biodegradable polymeric nanoparticles based drug delivery systems. AB - Biodegradable nanoparticles have been used frequently as drug delivery vehicles due to its grand bioavailability, better encapsulation, control release and less toxic properties. Various nanoparticulate systems, general synthesis and encapsulation process, control release and improvement of therapeutic value of nanoencapsulated drugs are covered in this review. We have highlighted the impact of nanoencapsulation of various disease related drugs on biodegradable nanoparticles such as PLGA, PLA, chitosan, gelatin, polycaprolactone and poly alkyl-cyanoacrylates. PMID- 19782543 TI - New sucrose cocoate based vesicles: Preparation, characterization and skin permeation studies. AB - A commercial sucrose cocoate surfactant was used to obtain a new vesicular system for transdermal drug delivery. The preparation, the dimensional and morphological characterizations and the skin permeation profile of these new niosomes were evaluated. Moreover we studied the possible employment of mixture of sucrose cocoate and cholesterol at different weigh ratios for the vesicles preparation and we analyzed the influence of cholesterol on niosomes properties. Diclofenac and Sulfadiazine were used as model drugs. Results suggest that sucrose cocoate was able to form vesicles in the presence or not of cholesterol and the addition of cholesterol leads to a variation of size: larger vesicles were obtained in the absence of cholesterol both in empty and drug-loaded niosomes. All vesicles were spherical and regular in shape. In vitro skin permeation profiles were significantly higher than the free drug solution, indicating the favourable relations between skin and niosomes. The faster release of the drug was found for niosomes with no cholesterol or with a reduced amount of this membrane additive, in particular the optimal formulation was that in which the cholesterol content was about 27 wt% of total lipid amount: probably this value is a good compromise between the membrane stability and its deformation capacity, allowing a higher drug permeation across the skin. PMID- 19782544 TI - Effect of a limited-enforcement intelligent tutoring system in dermatopathology on student errors, goals and solution paths. AB - OBJECTIVES: Determine effects of a limited-enforcement intelligent tutoring system in dermatopathology on student errors, goals and solution paths. Determine if limited enforcement in a medical tutoring system inhibits students from learning the optimal and most efficient solution path. Describe the type of deviations from the optimal solution path that occur during tutoring, and how these deviations change over time. Determine if the size of the problem-space (domain scope), has an effect on learning gains when using a tutor with limited enforcement. METHODS: Analyzed data mined from 44 pathology residents using SlideTutor-a Medical Intelligent Tutoring System in Dermatopathology that teaches histopathologic diagnosis and reporting skills based on commonly used diagnostic algorithms. Two subdomains were included in the study representing sub-algorithms of different sizes and complexities. Effects of the tutoring system on student errors, goal states and solution paths were determined. RESULTS: Students gradually increase the frequency of steps that match the tutoring system's expectation of expert performance. Frequency of errors gradually declines in all categories of error significance. Student performance frequently differs from the tutor-defined optimal path. However, as students continue to be tutored, they approach the optimal solution path. Performance in both subdomains was similar for both errors and goal differences. However, the rate at which students progress toward the optimal solution path differs between the two domains. Tutoring in superficial perivascular dermatitis, the larger and more complex domain was associated with a slower rate of approximation towards the optimal solution path. CONCLUSIONS: Students benefit from a limited-enforcement tutoring system that leverages diagnostic algorithms but does not prevent alternative strategies. Even with limited enforcement, students converge toward the optimal solution path. PMID- 19782545 TI - Immunohistochemical localisation of renal cyclooxygenase-1 expression in non steroidal anti-inflammatory drug-treated mice. AB - The utility of cyclooxygenase-inhibiting non-steroidal anti-inflammatory drugs is limited by unwanted side effects that include disturbances in renal function. In order to further understand the mechanisms that underlie these renal side effects, the expression of the prostaglandin-synthesizing enzyme cyclooxygenase (COX) was examined by immunohistochemical methods in murine kidneys after treatment with indomethacin, a non-selective inhibitor or nimesulide, an inhibitor that preferentially and selectively blocks the COX-2 isoform of the enzyme. In untreated control kidneys, COX-1 protein was expressed in the glomeruli and parietal cells of the glomerular capsule, epithelial cells of the proximal and distal convoluted tubules including the juxtaglomerular region, and the collecting ducts. At therapeutic doses, indomethacin (10mg/kg) did not alter renal COX-1 expression relative to immunoreactivity in untreated control kidney. By contrast, an equipotent therapeutic dose of nimesulide reduced renal COX-1 expression within the first 24h of treatment. Taken together with the reports of reduced COX-1 expression prior to renal tissue damage following high-dose indomethacin treatment, our findings suggest that effects of NSAIDs on renal COX expression are dependent on dose and may be related to isoform specificity. PMID- 19782546 TI - Cell biology of adhesive setae in gecko lizards. AB - Adhesive devices of digital pads of gecko lizards are formed by microscopic hair like structures termed setae that derive from the interaction between the oberhautchen and the clear layer of the epidermis. The two layers form the shedding complex and permit skin shedding in lizards. Setae consist of a resistant but flexible corneous material largely made of keratin-associated beta proteins (KA beta Ps, formerly called beta-keratins) of 8-22 kDa and of alpha keratins of 45-60 kDa. In Gekko gecko, 19 sauropsid keratin-associated beta proteins (sKAbetaPs) and at least two larger alpha-keratins are expressed in the setae. Some sKA beta Ps are rich in cysteine (111-114 amino acids), while others are rich in glycine (169-219 amino acids). In the entire genome of Anolis carolinensis 40 Ka beta Ps are present and participate in the formation of all types of scales, pad lamellae and claws. Nineteen sKA beta Ps comprise cysteine rich 9.2-14.4 kDa proteins of 89-142 amino acids, and 19 are glycine-rich 16.5 22.0 kDa proteins containing 162-225 amino acids, and only two types of sKA beta Ps are cysteine- and glycine-poor proteins. Genes coding for these proteins contain an intron in the 5'-non-coding region, a typical characteristic of most sauropsid Ka beta Ps. Gecko KA beta Ps show a central amino acid region of high homology and a beta-pleated conformation that is likely responsible for the polymerization of Ka beta Ps into long and resistant filaments. The association of numerous filaments, probably over a framework of alpha-keratins, permits the formation of bundles of corneous material for the elongation of setae, which may be over 100 microm long. The terminals branching off each seta may derive from the organization of the cytoskeleton and from the mechanical separation of keratin bundles located at the terminal apex of setae. PMID- 19782548 TI - Progress in understanding and exploiting the immune response in solid organ and hemopoietic stem cell transplantation. PMID- 19782547 TI - Altered lipid profile, oxidative status and hepatitis B virus interactions in human hepatocellular carcinoma. AB - Altered membrane integrity in hepatocellular carcinoma (HCC) tissue was indicated by an elevation in cholesterol and significant decrease in phosphatidylcholine (PC). The resultant decreased phosphatidylcholine/phosphatidylethanolamine (PC/PE) and increased cholesterol/phospholipid ratios are associated with decreased fluidity in the carcinoma tissue. The lower PC was associated with a decrease in the quantitative levels of the saturated (C16:0, C18:0), omega6 (C18:2, C20:4) and omega3 (C22:5, C22:6) fatty acids (FAs), resulting in reduced long-chain polyunsaturated fatty acids (LCPUFAs), total PUFA and an increase in omega6/omega3 FA ratio. In PE, the saturated and omega3 (C22:5, C22:6) FAs were reduced while the total omega6 FA level was not affected, leading to an increased omega6/omega3 FA ratio. Increased levels of C18:1omega9, C20:2omega6 and reduction of 22:6omega3 in PC and PE suggest a dysfunctional delta-6 desaturase. The reduced PC/PE ratio resulted in a decreased C20:4omega6 (PC/PE) ratio, implying a shift towards synthesis of the 2-series eicosanoids. Lipid peroxidation was reduced in both hepatitis B negative (HBV(-)) and positive (HBV(+)) HCC tissues. Glutathione (GSH) was decreased in HCC while HBV had no effect, suggesting an impairment of the GSH redox cycle. In contrast HBV infection enhanced GSH in the surrounding tissue possibly to counter oxidative stress as indicated by the increased level of conjugated dienes. Apart from the reduced LCPUFA, the low level of lipid peroxidation in the carcinoma tissue was associated with increased superoxide dismutase and glutathione peroxidase activity. The disruption of the redox balance, resulting in increased cellular antioxidant capacity, could create an environment for resistance to oxidative stress in the carcinoma tissue. Alterations in membrane cholesterol, phospholipids, FA parameters, C20:4omega6 membrane distribution and low lipid peroxidation are likely to be important determinants underlying the selective growth advantage of HCC cells. PMID- 19782549 TI - Novel genetic etiologies of severe congenital neutropenia. AB - Severe congenital neutropenia (SCN) comprises a heterogenous group of primary immunodeficiency disorders collectively characterized by paucity of mature neutrophils. In recent years, progress has been made with respect to the elucidation of genetic causes underlying syndromic and non-syndromic variants of SCN. Most cases of autosomal dominant SCN are associated with mutations in the neutrophil elastase (ELA-2/ELANE) gene, autosomal recessive forms of this disorder can be caused by mutations in the gene encoding the mitochondrial protein HAX-1. Rarely, SCN can be caused by mutations in the gene encoding the transcription factor GFI1 or activating mutations in the Wiskott-Aldrich syndrome (WAS) gene, respectively. More recently, a complex disorder associating SCN and developmental aberrations was identified, caused by mutations in the glucose-6 phosphatase catalytic subunit 3 (G6PC3) gene. Despite our increasing knowledge of the genetic etiologies of SCN, the molecular pathophysiology underlying these disorders remains only partially understood. PMID- 19782550 TI - Exercise induced dyspnea in the young. Larynx as the bottleneck of the airways. AB - BACKGROUND: Exercise induced asthma may symptomatically be difficult to differentiate from exercise related obstruction in the upper airways, sometimes leading to diagnostic confusion and inappropriate treatment. Larynx accounts for a significant fraction of total airway resistance, but its role as a limiting factor for airflow during exercise has been hampered by lack of diagnostic tools. We aimed to study laryngeal function in exercising humans by transnasal laryngoscopy. METHODS: Continuous video recording of the larynx was performed in parallel with continuous film recording of the upper part of the body and recording of breath sounds in subjects running to respiratory distress or exhaustion on a treadmill. RESULTS: A successful examination was obtained in 20 asymptomatic volunteers and 151 (91%) of 166 young patients with a history of inspiratory distress or stridor during exercise. At rest, six patients had abnormal laryngeal findings. During exercise, a moderate or severe adduction of laryngeal structures was observed in parallel with increasing inspiratory distress in 113 (75%) patients. In 109 of these, adduction started within supraglottic structures, followed by adduction of the vocal cords in 88. In four patients, laryngeal adduction started in the vocal cords, involving supraglottic structures secondarily in three. CONCLUSION: Larynx can safely be studied throughout a maximum intensity exercise treadmill test. A characteristic laryngeal response pattern to exercise was visualised in a large proportion of patients with suspected upper airway obstruction. Laryngoscopy during ongoing symptoms is recommended for proper assessment of these patients. PMID- 19782551 TI - Plasma leptin and adiponectin in COPD exacerbations: associations with inflammatory biomarkers. AB - BACKGROUND: Various systemic inflammatory markers have been evaluated for their value in acute exacerbations of chronic obstructive pulmonary disease (COPD). Leptin and adiponectin have been linked to acute exacerbations and stable COPD. OBJECTIVES: To assess plasma leptin, adiponectin and their ratio in acute exacerbations of COPD and to study possible associations with inflammatory biomarkers. METHODS: Plasma leptin, adiponectin and their ratio (L/A) and serum biomarkers of systemic inflammation C-reactive protein (CRP), Tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) were assessed at three time points (admission, resolution and stable phase - 8 weeks after resolution) in a selected cohort of 63 COPD patients hospitalized for acute exacerbations. Subjects with comorbidities related to adipose tissue hormones were meticulously excluded. MEASUREMENTS AND MAIN RESULTS: All systemic inflammatory biomarkers, leptin and L/A ratio were elevated during admission compared to resolution and stable phase (mean L/A ratio 2.6 vs. 1.57 vs. 1.22, respectively; p<0.0001), whereas adiponectin was elevated at resolution compared to admission. Log leptin, adiponectin and L/A ratio were significantly associated with variables of systemic inflammation, after proper adjustments, both on admission and in stable condition. In stepwise multiple linear regression models, IL-6 and TNF-alpha present the most significant associations with leptin, adiponectin and their ratio. CONCLUSIONS: Our data suggest that both leptin and adiponectin are associated with the systemic inflammatory process during exacerbations of COPD. The most significant associations seem to be those with IL-6 and TNF-alpha. PMID- 19782552 TI - Risk factors for idiopathic pulmonary fibrosis in a Mexican population. A case control study. AB - The etiology of idiopathic pulmonary fibrosis (IPF) remains poorly understood, but some studies have suggested that cigarette smoking or other occupational or environmental exposures, diabetes mellitus, or gastroesophageal reflux may play a role. In this study we evaluated the clinical records of a group of 97 consecutive patients with IPF, and 560 patients suffering 5 different respiratory disorders that were examined as controls: asthma (n=111), chronic obstructive pulmonary disease (n=132), squamous cell lung carcinoma (n=118), lung adenocarcinoma (n=101) and patients with otorhinolaryngology problems but without lung disease (n=98). In bivariate analyses male sex, diabetes mellitus and being former cigarette smoker were associated with IPF. After adjusting by these variables, multivariate analysis revealed that type 2 diabetes mellitus [11.3% in IPF patients vs 2.9% in controls, OR=4.3 (95% CI: 1.9-9.8), p<0.0001] was an independent risk factor associated to IPF. Our results provide additional evidence of a putative relationship between DM2 and idiopathic pulmonary fibrosis. Experimental research is necessary for thorough assessment of the pathogenic mechanisms involved in this association. PMID- 19782554 TI - A glance at the world: Recycling of packaging waste in Poland. PMID- 19782553 TI - Differences in alcohol-related mortality between foreign-born and native-born Spaniards. AB - BACKGROUND: Alcohol consumption is associated with high rates of mortality. This study aimed to analyse mortality attributable to alcohol consumption in foreign born and native-born Spaniards in 2004 and to determine whether differences existed between these groups. METHODS: The number of deaths attributable to alcohol consumption was calculated by means of the alcohol-attributable fractions devised by the Center for Disease Control and Prevention for calculating mortality rates in the USA. Alcohol-related mortality rates and age-adjusted mortality rates per 100,000 persons (using European standard population) were calculated by gender. RESULTS: The mortality rates attributable to alcohol per 100,000 inhabitants were lower among foreign-born Spaniards (7.0) than native born Spaniards (16.7). Chronic conditions accounted for only 23.6% of all alcohol related mortality for foreign-born Spaniards, but 60% for native-born Spaniards. The former were much more likely to suffer unintentional injuries, particularly road traffic accidents, while the latter showed high rates of alcohol-related death for digestive diseases, cardiovascular disorders, intentional injuries and malignant neoplasm. CONCLUSION: Alcohol consumption is an important cause of death among the native-born Spanish population. The observed differences in alcohol-related mortality between native and foreign-born Spaniards should be considered when developing targeted harm reduction policies. PMID- 19782555 TI - A glance at the world: Role of rag-pickers in the management of solid waste in Tiruchirappalli City, Tamil Nadu, India. PMID- 19782556 TI - Multiplexed immunoassay using the stabilized enzymes in mesoporous silica. AB - Multiplexed immunoassay system was developed using the enzyme-immobilized mesoporous silica in a form of nanoscale enzyme reactors (NERs), which improve the enzyme loading, activity, and stability. Glucose oxidase (GO) and trypsin (TR) were adsorbed into mesoporous silica and further crosslinked for the construction of NERs, and antibody-conjugated NERs were employed for the analysis of target antigens in a sandwich-type magnetic bead-based immunoassay. This approach, called as NER-LISA (NER-linked immunosorbent assay), generated signals out of enzyme reactions that correlated well with the concentration of target antigens. The detection limit of NER-LISA using NER-GO and anti-human IgG was 67pM human IgG, and the sensitivity was 20 times higher than that of the conventional ELISA using anti-human IgG conjugated GO. Antibody-conjugated NER-GO and NER-TR were successfully employed for the simultaneous detection of two target antigens (human IgG and chicken IgG) in a solution by taking advantage of signals at different wavelengths (absorbances at 570nm and 410nm, respectively) from the assays of GO and TR activities, demonstrating the potential of NER-LISA in multiplexed immunoassay. The NER-LISA approach also enabled the successful use of a protease (trypsin), because the NER approach can effectively retain the protease molecules within the mesoporous silica and prevent the digestion of antibodies and enzymes during the whole process of NER-LISA. PMID- 19782557 TI - Sensitivity enhancement in the colorimetric detection of lead(II) ion using gallic acid-capped gold nanoparticles: improving size distribution and minimizing interparticle repulsion. AB - We have developed a colorimetric assay for the highly sensitive and selective detection of Pb(2+) by narrowing the size distribution of gallic acid-capped gold nanoparticles (GA-AuNPs) and minimizing electrostatic repulsion between each GA AuNP. We unveil that the particle size and size distribution of GA-AuNPs could be controlled by varying the pH of HAuCl(4) with fixed concentrations of HAuCl(4) and GA. When the pH of the precursor solution (i.e., HAuCl(4)) was adjusted from 2.2 to 11.1, the average diameter of GA-AuNPs was decreased from 75.1 nm to 9.3 nm and their size distribution was reduced from 56.6-93.6 nm to 9.0-9.6 nm. The colorimetric sensitivity of the Pb(2+)-induced aggregation of GA-AuNPs could be improved using narrow size distribution of GA-AuNPs. Moreover, further enhancement of the colorimetric sensitivity of GA-AuNPs toward Pb(2+) could be achieved by adding NaClO(4) to minimize electrostatic repulsion between GA-AuNPs, which provide a small energy barrier for Pb(2+) to overcome. Under the optimum conditions (1.0 mM NaClO(4) and 20 mM formic acid at pH 4.5), the selectivity of 9.3 nm GA-AuNPs for Pb(2+) over other metal ions in aqueous solutions is remarkably high, and its minimum detectable concentration for Pb(2+) is 10nM. We demonstrate the practicality of 9.3 nm GA-AuNPs for the determination of Pb(2+) in drinking water. This approach offers several advantages, including simplicity (without temperature control), low cost (no enzyme or DNA), high sensitivity, high selectivity, and a large linear range (10.0-1000.0 nM). PMID- 19782558 TI - Detection of microorganisms using biosensors-a smarter way towards detection techniques. AB - Along with useful microorganisms, there are some that cause potential damage to the animals and plants. Detection and identification of these harmful organisms in a cost and time effective way is a challenge for the researchers. The future of detection methods for microorganisms shall be guided by biosensor, which has already contributed enormously in sensing and detection technology. Here, we aim to review the use of various biosensors, developed by integrating the biological and physicochemical/mechanical properties (of tranducers), which can have enormous implication in healthcare, food, agriculture and biodefence. We have also highlighted the ways to improve the functioning of the biosensor. PMID- 19782559 TI - Tissue-engineered skin substitutes in regenerative medicine. AB - Recent advance in cellular tissue-engineered skin constructs have refined the applications already commercially available, in particular, by the use of genetically modified cells to enhance their properties on the treatment of wounds and to ease the application of epidermis using sprayed keratinocytes. This approach lends itself to use of chimeric epidermis, cultured allogeneic cells, to provide short-term coverage, together with minimally cultured autologous cells for long-term repair. Experimental models of skin include pathological conditions, phenomena such as aging and organogenesis, as in the hair follicle grown from isolated cells in vitro. The recent development of induced pluripotent stem cells raises the possibility of realizing the dream of skin and even limb regeneration shown by animals such as the salamander. PMID- 19782560 TI - Mass spectrometry of large complexes. AB - Mass spectrometry is becoming a more and more powerful tool for investigating protein complexes. Recent developments, based on different ionization techniques, electrospray, desorption/ionization and others are contributing to the usefulness of MS to describe the organization and structure of large non-covalent assemblies. PMID- 19782561 TI - Tobacco smoking, alcohol consumption and pancreatic cancer risk: a case-control study in Italy. AB - In Italy, pancreatic cancer accounts for approximately 5% of cancer-related deaths. Tobacco smoking is the major established risk factor for this cancer, whereas the role of alcohol consumption is open to debate. Between 1991 and 2008, we conducted a hospital-based case-control study on pancreatic cancer in northern Italy. Cases were 326 patients (median age 63 years) with incident pancreatic cancer admitted to major general hospitals. Controls were 652 patients (median age 63 years) with acute non-neoplastic conditions admitted to the same hospital network of cases. Multiple logistic regression was used to estimate the odds ratios (OR) and the corresponding 95% confidence intervals (CI). Pancreatic cancer was associated to current smoking (OR=1.68; 95% CI: 1.13-2.48), and the risk rose with increasing number of cigarettes/day (OR=2.04; 95% CI: 1.14-3.66 for > or = 20 cigarettes/day). No association emerged for former smokers (OR=0.98; 95% CI: 0.66-1.45). Alcohol consumption was associated to increased pancreatic cancer risk, but ORs were significant only among heavy drinkers (ORs: 2.03 and 3.42 for 21-34 and > or = 35 drinks/week, respectively). Pancreatic cancer risk was 4.3-fold higher in heavy smokers (> or = 20 cigarettes/day) and heavy drinkers (> or = 21 drinks/week) in comparison with never smokers who drunk < 7 drinks/week, which is compatible with an additive effect of these exposures. In conclusion, we found that tobacco smoking and alcohol drinking are two independent risk factors for pancreatic cancer which may be responsible for approximately one third of these cancers in our population. PMID- 19782562 TI - Isolation of the protein tyrosine phosphatase 1B inhibitory metabolite from the marine-derived fungus Cosmospora sp. SF-5060. AB - In the course of bioassay-guided study on the EtOAc extract of a culture broth of the marine-derived fungus Cosmospora sp. SF-5060, aquastatin A (1) was isolated as a protein tyrosine phosphatase 1B (PTP1B) inhibitory component produced by the fungus. The compound was isolated by various chromatographic methods, and the structure was determined mainly by analysis of NMR spectroscopic data. Compound 1 exhibited potent inhibitory activity against PTP1B with IC(50) value of 0.19muM, and the kinetic analyses of PTP1B inhibition by compound 1 suggested that the compound is inhibiting PTP1B activity in a competitive manner. Aquastatin A (1) also showed modest but selective inhibitory activity toward PTP1B over other protein tyrosine phosphatases, such as TCPTP, SHP-2, LAR, and CD45. In addition, the result of hydrolyzing aquastatin A (1) suggested that the dihydroxypentadecyl benzoic acid moiety in the molecule is responsible for the inhibitory activity. PMID- 19782563 TI - Inhibition of ErbB2(Her2) expression with small molecule transcription factor mimics. AB - Small molecules that mimic the transcriptional activation domain of eukaryotic transcriptional activators have the potential to serve as effective inhibitors of transcriptional processes. Here we show that one class of transcriptional activation domain mimics, amphipathic isoxazolidines, can be converted into inhibitors of gene expression mediated by the transcriptional activator ESX through small structural modifications. Addition of the small molecules leads to decreased expression of the cell surface growth receptor ErbB2(Her2) in ErbB2 positive cancer cells and, correspondingly, decreased proliferation. PMID- 19782564 TI - Synthesis, antiproliferative, and pharmacokinetic properties of 3- and 17-double modified analogs of 2-methoxyestradiol. AB - The syntheses of 21 analogs of 2-methoxyestradiol are presented, including ENMD 1198 which was selected for advancement into Phase 1 clinical trials in oncology. These analogs were evaluated for antiproliferative activity using breast tumor MDA-MB-231 cells, for antiangiogenic activity in HUVEC proliferation assays, and for estrogenic activity in MCF-7 cell proliferation. The most active analogs were evaluated for iv and oral pharmacokinetic properties via cassette dosing in rat and in mice pharmacokinetic models. PMID- 19782565 TI - Hydrogen sulfide induces nitric oxide release from nitrite. AB - Hydrogen sulfide has recently been considered to have an important role as a gasotransmitter in the cardiovascular system as well as in the central nervous system, but its action seems directly related to the presence of nitric oxide/nitric oxide-derivatives. We report here chemical evidence that emphasizes a prominent role of the hydrogen sulfide as cofactor of NO-derivatives in inducing nitric oxide release. PMID- 19782566 TI - Optimising metabolic stability in lipophilic chemical space: the identification of a metabolically stable pyrazolopyrimidine CRF-1 receptor antagonist. AB - Balancing potency and metabolic stability in a target which favours lipophilic ligands is a considerable challenge. Here we describe two strategies employed to achieve this balance in a series of pyrazolopyrimidine CRF antagonists: moderation of lipophilicity, and incorporation of a metabolically stable lipophilic group. PMID- 19782567 TI - Phytochemical investigation of labdane diterpenes from the rhizomes of Hedychium spicatum and their cytotoxic activity. AB - A comprehensive reinvestigation of chemical constituents from the rhizomes of Hedychium spicatum led to the isolation of two new labdane-type diterpene (1, 2), together with six known compounds (3-8). Their structures were established on the basis of extensive spectroscopic (IR, MS, 2D NMR) data analysis and by comparison with the spectroscopic data reported in the literature. In addition, all the isolates were tested for their cytotoxicity against the THP-1 (human acute monocytic leukemia), HL-60 (human promyelocytic leukemia), A-375 (human malignant melanoma) and A-549 (human lung carcinoma) cancerous cell lines. PMID- 19782568 TI - Synthesis and antitumor activities of 3-modified 2-methoxyestradiol analogs. AB - The syntheses of 2-methoxyestradiol analogs with modifications at the 3-position are described. The analogs were assessed for their antiproliferative, antiangiogenic, and estrogenic activities. Several lead substituents were identified with similar or improved antitumor activities and reduced metabolic liability compared to 2-methoxyestradiol. PMID- 19782569 TI - Control of the upper body movements during level walking in patients with facioscapulohumeral dystrophy. AB - Facioscapulohumeral dystrophy (FSHD) is a muscular disease usually spreading from upper to lower body and characterised by asymmetric muscle weakness. Walking ability is compromised in these patients, with a consequent high risk of falls. A quantitative analysis of the upper body oscillations may unveil useful information about the capacity of these patients to stabilise the head, maintain balance, and compensate for lower limb muscle weakness during walking. This study involved 13 patients with FSHD and 13 healthy volunteers. The trajectories of three points located on the cranio-caudal axis, at head, shoulder, and pelvis levels, during level walking, were analysed. The range of motion of these three points and the attenuation of the relevant accelerations going from pelvis to head level were used to describe the upper body movements during walking. The patients had wider and less symmetrical oscillations than the healthy controls both in antero-posterior and medio-lateral directions. Furthermore, the capacity of the patients to attenuate the accelerations going from pelvis to head level was reduced. These features may be related not only to upper body muscle weakness, but also to a strategy functional to the compensation of proximal leg muscle weakness. In conclusion, this study highlighted that the control of upper body oscillations and of head stability is reduced in patients with FSHD, suggesting that the assessment of the upper body movements should be included in the treatment decision process. PMID- 19782570 TI - The search for the fungal tree of life. AB - The Fungi comprise a diverse kingdom of eukaryotes that are characterized by a typically filamentous but sometimes unicellular vegetative form, and heterotrophic, absorptive nutrition. Their simple morphologies and variable ecological strategies have confounded efforts to elucidate their limits, phylogenetic relationships, and diversity. Here we review progress in developing a phylogenetic classification of Fungi since Darwin's On the Origin of Species. Knowledge of phylogenetic relationships has been driven by the available characters that have ranged from morphological and ultrastructural to biochemical and genomic. With the availability of multiple gene phylogenies a well corroborated phylogenetic classification has now begun to emerge. In the process some fungus-like heterotrophs have been shown to belong elsewhere, and several groups of enigmatic eukaryotic microbes have been added to the Fungi. PMID- 19782571 TI - Arterial occlusion caused by a non-adsorbable bone graft after open wedge tibial osteotomy. AB - We report a case of a near fatal complication of an open wedge high tibial osteotomy held by a Puddu plate. CT-scan and lysis therapy revealed a compression of the popliteal artery by the implanted hydroxyapatite wedge resulting in ischaemia of the lower limb. Revision surgery was performed and the prominent part of the wedge was removed, however two toes had to be amputated due to the initial tissue damage. PMID- 19782572 TI - Design, synthesis, and preliminary studies of the activity of novel derivatives of N-cinnamoyl-L-aspartic acid as inhibitors of aminopeptidase N/CD13. AB - A series of novel derivatives of N-cinnamoyl-l-aspartic acid were designed, synthesized, and assayed for their inhibitory activities against aminopeptidase N. The preliminary biological assay showed that compound 8c has the most potent inhibitory activity against APN with an IC(50) of 11.1+/-0.9 microM, this could be used as the lead compound in future research on anticancer agents. PMID- 19782573 TI - Use of aprotinin in cardiac surgery: effectiveness and safety in a population based study. AB - OBJECTIVE: The effectiveness and safety of aprotinin use in cardiac surgery have been questioned. More data reflecting everyday clinical practice from large scale, unselected populations are needed. We compared the effectiveness and safety of aprotinin in cardiac surgery with those of tranexamic acid in a follow up study using the population-based Danish health-care databases. METHODS: We identified a total of 3535 patients who underwent cardiac surgery at the Aarhus University Hospital, Skejby, between 1 January 2003 and 31 December 2006; of these, 635 patients were treated with aprotinin and 2900 with tranexamic acid. We used propensity score matching to match aprotinin-treated patients with tranexamic-acid-treated patients in a 1:1 ratio, followed by Poisson regression analysis to compute relative risks (RRs). RESULTS: Patients treated with aprotinin had more severe preoperative risk profiles than the tranexamic-acid treated patients. The rates of postoperative drainage and transfusion of red blood cells were similar in the two groups, whereas the aprotinin group received plasma (adjusted RR=1.39; 95% confidence interval (CI): 1.15-1.68) and platelets (adjusted RR=1.47; 95% CI: 1.19-1.81) more frequently than the tranexamic acid group. There were no statistically significant differences in risks of re operation due to bleeding (adjusted RR=1.22; 95% CI: 0.84-1.78), 30-day mortality (adjusted RR=1.03; 95% CI: 0.69-1.54), acute myocardial infarction (adjusted RR=1.06; 95% CI: 0.69-1.64), stroke (adjusted RR=1.36; 95% CI: 0.75-2.44) or composite major event (adjusted RR=1.14; 95% CI: 0.87-1.50) between the two groups. However, patients who received aprotinin had an increased risk of postoperative dialysis (adjusted RR=1.76; 95% CI: 1.15-2.70). CONCLUSIONS: Aprotinin treatment was associated with an increased use of plasma and platelet transfusion and an increased risk for postoperative dialysis, but not with other adverse outcomes, including short-term mortality. PMID- 19782574 TI - Aprotinin in cardiac surgery patients: is the risk worth the benefit? AB - BACKGROUND: Aprotinin is the only Food and Drug Administration-approved agent to reduce haemorrhage related to cardiac surgery and its safety and efficacy has been extensively studied. Our study sought to compare the efficacy, early and late mortality and major morbidity associated with aprotinin compared with e aminocaproic acid (EACA) in cardiac surgery operations. METHODS: Between January 2002 and December 2006, 2101 patients underwent coronary artery bypass grafting (CABG), valve surgery or CABG and valve surgery in our institution with the use of aprotinin (1898 patients) or EACA (203 patients). Logistic regression and propensity score analysis were used to adjust for imbalances in the patients' preoperative characteristics. The propensity score-adjusted sample included 570 patients who received aprotinin and 114 who received EACA (1-5 matching). RESULTS: Operative mortality was higher in the aprotinin group in univariate (aprotinin 4.3% vs EACA 1%, p=0.023) but not propensity score-adjusted multivariate analysis (4% vs 0.9%, p=0.16). In propensity score-adjusted analysis, aprotinin was also associated with a lower rate of blood transfusion (38.8% vs 50%, p=0.04), a lower rate of haemorrhage-related re-exploration (3.7% vs 7.9%, p=0.04) and a higher risk of in-hospital cardiac arrest (3.7% vs 0%, p=0.03) and a marginally but not statistically significantly higher risk of acute renal failure (6.8% vs 2.6%, p=0.09). In Cox proportional hazards regression analysis, the risk of late death was higher in the aprotinin compared to EACA group (hazard ratio=4.33, 95% confidence interval (CI)=1.60-11.67, p=0.004). CONCLUSION: Aprotinin decreases the rate of postoperative blood transfusion and haemorrhage-related re-exploration, but increases the risk of in-hospital cardiac arrest and late mortality after cardiac surgery when compared to EACA. Cumulative evidence suggests that the risk associated with aprotinin may not be worth the haemostatic benefit. PMID- 19782575 TI - UVA and UVB radiation-induced oxidation products of quercetin. AB - The flavonol quercetin is believed to provide protection against ultraviolet (UV) radiation-induced damage in plants. As part of our investigations into the potential for quercetin to protect skin against UV radiation-induced damage we have investigated the products of quercetin exposed to UV radiation in vitro. UVA (740 microW cm(-2) at 365 nm) or UVB (1300 microW cm(-2) at 310 nm) irradiation of quercetin in methanol results in a small conversion (less than 20%) to C-ring breakdown products over 11 h. When the triplet sensitizer benzophenone is added, greater than 90% conversion by UVA or UVB occurs within 1h. The major photoproducts from either UVA or UVB radiation are 2,4,6-trihydroxybenzaldehyde (1), 2-(3',4'-dihydroxybenzoyloxy)-4,6-dihydroxybenzoic acid (2) and 3,4 dihydroxyphenylethanol (3). Product 2 has previously been observed as a product of oxidative metabolism of quercetin, however products 1 and 3 appear to be the result of a unique UV-dependent pathway. In conclusion we have determined that quercetin undergoes slow decomposition to a mixture of C-ring-opened products, two of which to our knowledge have not been previously observed for quercetin decomposition, and that the presence of a triplet sensitizer greatly increases UV radiation-mediated quercetin decomposition. The presence of endogenous photosensitizers in the skin could potentially affect the UV stability of quercetin, suggesting that further study of quercetin for both its photoprotective properties and photostabilty in skin are warranted. PMID- 19782576 TI - Pegylated liposomal doxorubicin combined with carboplatin: a rational treatment choice for advanced ovarian cancer. AB - OBJECTIVE: Many questions remain unanswered regarding the optimal treatment paradigm for ovarian cancer, and alternatives for both first- and second-line therapy are needed. METHODS: This review summarizes recent data with the combination of pegylated liposomal doxorubicin (PLD) and carboplatin in ovarian cancer. RESULTS: Anthracyclines are active in ovarian cancer and lack the neurotoxic effects of taxanes. PLD has reduced cardiotoxic potential vs non liposomal doxorubicin and is the only non-platinum monotherapy to demonstrate a significant survival advantage as second-line treatment of ovarian cancer. Replacing the taxane with PLD in platinum doublets for either first-line or recurrent ovarian cancer (ROC) has been or is being evaluated in more than 1600 patients. Studies evaluating PLD plus carboplatin in platinum-sensitive ROC have shown that the regimen is tolerable and active. CONCLUSION: PLD-carboplatin is a promising chemotherapy combination. Phase III trials will elucidate whether it represents a new standard of care in ovarian cancer. PMID- 19782577 TI - Modulation of Th1/Th2 cytokines and inflammatory mediators by hydroxychavicol in adjuvant induced arthritic tissues. AB - The present study was undertaken to investigate the anti-arthritic activity of hydroxychavicol (HC) a major phenolic compound isolated from the aqueous extract leaves of plant Piper betle (Piperaceae). The compound showed significant lowering of pro-inflammatory (Th1) cytokine levels in arthritic paw tissue homogenate supernatant viz. IL-2, IFN-gamma, and TNF-alpha with maximum inhibition at higher dose levels of 2 and 4 mg/kg p.o. and enhanced the production of anti-inflammatory (Th2) cytokines IL-4 and IL-5 estimated by cytometric bead array immunoassay. Cytometric bead array uses the sensitivity of amplified fluorescence detection by flowcytometer to measure soluble analytes in a particle based immune assay. This assay can accurately quantitate five cytokines in a 50-microl sample volume. The T-helper (Th1) deviated cells produce detectable level of tumor necrosis factor (TNF-alpha), interleukin-2 (IL-2), and interferon-gamma (IFN-gamma), while the Th2 deviated cells produce significant amount of interleukin-4 (IL-4) and interleukin-5 (IL-5). HC at graded doses also significantly decreased the expression of IL-1beta, PGE(2), LTB(4), and nitric oxide levels showing significant inhibition of these parameters. Elevated levels of CD4(+) T cell specific interferon-gamma (IFN-gamma) in splenocytes of arthritic animals was also inhibited in treated animals. The oral LD(0) in both mice and rats was more than 1000 mg/kg. PMID- 19782578 TI - Dose-dependent effect of radiation on angiogenic and angiostatic CXC chemokine expression in human endothelial cells. AB - Blood vessel growth is regulated by angiogenic and angiostatic CXC chemokines, and radiation is a vasculogenic stimulus. We investigated the effect of radiation on endothelial cell chemokine signaling, receptor expression, and migration and apoptosis. Human umbilical vein endothelial cells were exposed to a single fraction of 0, 5, or 20 Gy of ionizing radiation (IR). All vasculogenic chemokines (CXCL1-3/5-8) increased 3-13-fold after 5 or 20 Gy IR. 20 Gy induced a marked increase (1.6-4-fold) in angiostatic CXC chemokines. CXCR4 expression increased 3.5 and 7-fold at 48 h after 5 and 20 Gy, respectively. Bone marrow progenitor cell chemotaxis was augmented by conditioned media from cells treated with 5 Gy IR. Whereas 5 Gy markedly decreased intrinsic cell apoptosis (0 Gy=16%+/-3.6 vs. 5 Gy=4.5%+/-0.3), 20 Gy increased it (21.4%+/-1.2); a reflection of pro-survival angiogenic chemokine expression. Radiation induces a dose dependent increase in pro-angiogenic CXC chemokines and CXCR4. In contrast, angiostatic chemokines and apoptosis were induced at higher (20 Gy) radiation doses. Cell migration improved significantly following 5 Gy, but not 20 Gy IR. Collectively, these data suggest that lower doses of IR induce an angiogenic cascade while higher doses produce an angiostatic profile. PMID- 19782579 TI - Rapid torque development in older female fallers and nonfallers: a comparison across lower-extremity muscles. AB - The objective of this study was to compare reaction time, joint torque, rate of torque development, and magnitude of neuromuscular activation of lower-extremity muscles in elderly female fallers and nonfallers. Participants included 11, elderly, female fallers (71.3+/-5.4 years) and twelve nonfallers (71.3+/-6.2 years) who completed a fall risk questionnaire. Then, maximal, voluntary, isometric contractions of the knee and ankle muscles were performed in reaction to a visual cue to determine joint torque, rate of torque development, reaction time, and nervous activation of agonists and antagonists. Results indicated that significantly more fallers reported "dizziness upon rising", "use of balance altering medications", "stress or depression", "not enough sleep", "arthritis in lower body", "chronic pain in lower body", and "tiring easily while walking" (all P<0.05). Normalized dorsiflexion and plantarflexion strength scores (summation of peak torque, rate of torque development and impulse) were lower in fallers than in nonfallers (P<0.05). When summed across lower-extremity muscle groups, fallers demonstrated 19% lower peak torque and 29% longer motor time (P<0.05). In conclusion, comprehensive fall risk screening and prevention programs should address both neuromuscular and non-muscular factors, and, weakness of the ankle dorsiflexors and plantarflexors should be further studied as potential contributors to falls in older adults. PMID- 19782580 TI - Incidence and risk factors for mortality in infants awaiting heart transplantation in the USA. AB - BACKGROUND: Infants awaiting heart transplantation (HT) face the highest wait list mortality among all children and adults listed for HT in the USA. We sought to determine the risk of death for infants <12 months old while awaiting HT in the current era, and to identify the principle risk factors associated with wait list mortality. METHODS: We analyzed outcomes for all infants listed for HT in the USA from January 1999 to July 2006, using data reported to the U.S. Scientific Registry of Transplant Recipients. RESULTS: Of the 1,133 listed infants, 61% were <3 months of age, 80% were listed as Status 1A, 64% had a congenital heart disease (CHD) and 31% had cardiomyopathy. Of 724 infants with CHD, 25% were on prostaglandin (PG) and 27% had a history of prior surgery. By 6 months after listing, 23% died on the wait-list and 54% were transplanted. Multivariate factors associated with wait-list mortality were weight <3 kg (hazard ratio [HR] 1.4, 95% confidence interval [CI] 1.0 to 1.9), extracorporeal membrane oxygenation (ECMO) support (HR 5.6, CI 4.0 to 7.9), ventilator support (HR 2.1, 95% CI 1.6 to 2.8), CHD with PG support (HR 2.8, 95% CI 1.8 to 4.3), CHD without prior surgery (HR 2.8, 95% CI 1.9 to 3.9) and non-white race/ethnicity (HR 1.8, 95% CI 1.4 to 2.3). CONCLUSIONS: One in four infants listed for HT in the USA die before a donor heart can be identified. Wait-list mortality is associated with weight <3 kg, level of invasive support and CHD, but not listing status, which captures medical urgency poorly. Measures to expand infant organ donation, especially among neonates, are urgently needed. PMID- 19782581 TI - Impact of recipient body mass index on organ allocation and mortality in orthotopic heart transplantation. AB - BACKGROUND: It is unknown whether obesity affects organ allocation in orthotopic heart transplantation (OHT). The United Network for Organ Sharing (UNOS) database provides an opportunity to examine this issue. METHODS: We reviewed UNOS data to identify 27,002 OHT candidates placed on the heart transplantation wait list (1998 to 2007). Patients were stratified by body mass index (BMI) at listing. Multivariate Cox proportional hazards model estimated the chance of receiving OHT, adjusting for factors that might affect allocation. Mortality on the wait list and post-OHT mortality were estimated using the Kaplan-Meier method. RESULTS: Of 27,002 patients listed, the distribution of BMI was as follows: BMI 18.5 to 24.9, n = 9,734 (36.0%); BMI 25 to 29.9, n = 10,063 (37.2%); BMI 30 to 34.9, 5,500 (20.4%); and BMI > or =35, 1,705 (6.3%). BMI was strongly associated with a decrease in the likelihood of receiving OHT once on the wait list (hazard ratio [HR] 0.96, 95% confidence interval [CI] 0.95 to 0.96, p < 0.001). Patients with BMI > or =35 had a 46% lower likelihood of receiving a donor heart after risk adjustment (HR 0.54, 95% CI 0.49 to 0.60, p < 0.001). On the wait list, patients with extreme BMIs (> or =35) who were listed as UNOS Status 1 had the lowest cumulative survival (61% at 3 years). After OHT, patients with high BMI did not have increased short-term mortality at 30 days, 90 days or 1 year. CONCLUSIONS: Obese individuals wait longer and have a lower likelihood of receiving a donor heart after listing, despite similar short-term survival. The results of this study point to a potential provider bias for obese individuals in OHT. PMID- 19782583 TI - Routine performance of endomyocardial biopsy decreases the incidence of orthotopic heart transplant for myocarditis. AB - BACKGROUND: In critically ill children presenting with dilated cardiomyopathy (DCM), the presence of myocarditis predicts an improved chance of myocardial recovery. Noninvasive differentiation of myocarditis from other causes of DCM is difficult. However, sensitivity of endomyocardial biopsy has been questioned. METHODS: We reviewed clinical, echocardiographic, catheterization, and pathology data from all children admitted to the intensive care unit with DCM undergoing orthotopic heart transplantation since the inception of our transplant program in 1987 and all patients with definitively diagnosed myocarditis presenting since 1996. RESULTS: Thirty-six patients with DCM underwent orthotopic heart transplantation. Cellular infiltrate was present in 3 of 36 (8.3%) explanted specimens. Pre-transplant biopsy was performed in 81%. No explanted heart demonstrated infiltrates after a negative biopsy. One biopsy was positive with negative explant histology after transplant 6 months later. No patient with biopsy-proven myocarditis died while listed for transplantation. Eleven additional patients with myocarditis did not undergo transplant. Ten have survived and experienced complete (n = 9) or near complete (n = 1) recovery of myocardial function. One patient died shortly after presentation from fulminant myocarditis. The 10 transplant-free survivors could not be easily distinguished from our transplant cohort by clinical features at presentation. CONCLUSION: The incidence of cellular infiltrate in explanted hearts was significantly lower than that previously reported. Potentially, our aggressive myocarditis diagnostic protocol was useful in therapeutic stratification as a cohort of myocarditis patients avoided transplant and experienced complete recovery of myocardial function despite being difficult to distinguish clinically from our DCM transplant cohort at presentation. PMID- 19782582 TI - Effect of ABO-incompatible listing on infant heart transplant waitlist outcomes: analysis of the United Network for Organ Sharing (UNOS) database. AB - BACKGROUND: Midterm heart transplant outcomes of ABO-incompatible (ABO-I) organ use in infants are favorable. ABO-I transplantation has resulted in reduced waitlist mortality in some countries. This study assessed the effect of an ABO-I listing strategy on pre-transplant outcomes in the United States. METHODS: The Organ Procurement and Transplantation Network (OPTN)/United Network of Organ Sharing (UNOS) database was used to identify infants aged younger than 1 year listed as status 1 for heart transplantation between January 1, 2001, and May 20, 2008. The cohort was divided into 2 groups: eligible for ABO-compatible (ABO-C) transplant and eligible for ABO-I transplant. Baseline characteristics, waitlist times, and outcomes were compared in univariate analysis. Competing risks analysis evaluated differences in time to transplant in the presence of other outcomes. RESULTS: Of 1,029 infants listed for transplant, 277 (27%) were listed for an ABO-I transplant. Overall, 92% of transplant recipients received an ABO-C organ regardless of listing type. Among recipients eligible for ABO-I, only 27% received an ABO-I organ. The percentage that underwent transplant in each group did not differ. Although infants listed for an ABO-I organ had a shorter wait time for transplant, waitlist mortality was similar. CONCLUSIONS: Despite the intended merits of ABO-I heart transplantation, ABO-I listing and organ acceptance have not yielded lower waitlist mortality in the United States under the current UNOS allocation algorithm. Consideration should be given to altering the allocation system to one that gives less preference toward blood group compatibility in hopes of improving organ use and reducing waitlist mortality. PMID- 19782584 TI - Facilitated cardiac recovery in fulminant myocarditis: pediatric use of the Impella LP 5.0 pump. AB - We describe the successful use of the Impella LP 5.0 intracardiac microaxial pump (Abiomed, Danvers, MA) in a 13-year-old boy with fulminant biopsy-proven viral myocarditis. The patient, who previously was in refractory cardiogenic shock despite increasing inotropic and vasopressor support, immediately stabilized after Impella LP 5.0 implantation and was successfully bridged to a full recovery. Months later, he remains completely well, with no intracardiac or peripheral vascular sequelae of the procedure. In carefully selected pediatric patients the Impella may be a beneficial form of temporary mechanical circulatory support for fulminant cardiogenic shock. PMID- 19782586 TI - Pre-operative prediction of post-VAD implant mortality using easily accessible clinical parameters. AB - BACKGROUND: Mortality rates are high after implantation of a ventricular assist device (VAD), occurring mainly in the early phase post-implant during the time in the intensive care unit (ICU). Pre-operative selection criteria, which predict successful outcome, are difficult to evaluate. We implemented a pre-operative risk score to predict mortality in the ICU after VAD implantation by using easily obtained and quickly accessible clinical parameters. METHODS: In 241 VAD patients, 100 pre-operative markers were related to mortality in the ICU using univariate analysis and ROC curves, followed by multinomial logistic regression analyses. RESULTS: The mortality rate in the ICU was 32.0%. Univariate statistical analysis revealed 34 parameters that were significantly associated with mortality in the ICU. Of these, multinomial logistic regression identified 13 markers as significant risk factors. These included demographic data (age >50 years); clinically/procedurally relevant data (ischemic cardiomyopathy [ICM], re do surgery, on extracorporeal membrane oxygenation [ECMO], on intra-aortic balloon pump [IABP], previous cardiac surgery, ventilation, emergency implant, inotropic support, renal replacement therapy, pre-operative resuscitation, transfusion) and laboratory values (blood urea nitrogen [BUN] >40 mg/dl, creatinine >1.5 mg/dl, lactate >3 mg/dl, platelets <100 x 10(3)/microl, white blood cell [WBC] count >13 x 10(3)/microl, C-reactive protein [CRP] >8 mg/dl, hemoglobin <12 g/dl, hematocrit <35%, lactate dehydrogenase [LDH] >500 U/liter, creatine kinase [CK] >200 U/liter, troponin >20 ng/ml). A weighted risk score was implemented with a maximum of 50 points. The risk for mortality in the ICU was as follows: low (15.8%), <15 points; medium (48.2%), 16 to 30 points; and high (65.2%), >30 points. CONCLUSIONS: Easily obtained and quickly accessible clinical parameters can inform potential patients, relatives, and physicians pre operatively about the risk of death in the ICU after VAD implantation. PMID- 19782585 TI - Fungal infections in pediatric lung transplant recipients: colonization and invasive disease. AB - BACKGROUND: The purpose of this study was to evaluate the epidemiology and investigate the impact of colonization and pulmonary fungal infections (PFIs). METHODS: In this investigation we performed a retrospective analysis of 55 pediatric lung transplant recipients from 2002 to 2007 at a single institution. Associations between risk factors and time to post-transplant colonization, PFI, and other outcomes were assessed using Cox proportional hazard models. RESULTS: Although 29 patients had positive pre-transplant colonization, 33 (60%) were colonized post-transplant and 20% (11 subjects) developed proven or probable PFI. In a multivariate model, post-transplant fungal colonization was associated with older age (hazard ratio [HR] 2.9, 95% confidence interval [CI] 1.1 to 7.6), cytomegalovirus (CMV) prophylaxis (HR 5.6, 95% CI 1.3 to 24.6) and respiratory viral infection prior to fungal colonization (HR 2.9, 95% CI 1.0 to 8.3). CONCLUSION: Neither fungal colonization nor PFI was associated with the development of chronic allograft rejection or death. PMID- 19782587 TI - Hypoxia and myocardial remodeling in human cardiac allografts: a time-course study. AB - BACKGROUND: Cardiac allografts are known to develop myocardial fibrosis, which may be a cause of progressive cardiac dysfunction. Apart from the renin angiotensin and transforming growth factor-beta system, hypoxia has been proposed as an important player in the pathogenesis of fibrosis, but its significance remains unclear. This study examines the degree of myocardial fibrosis, cellular remodeling and hypoxic signaling over a time-course of 10 years after human cardiac allograft transplantation. METHODS: Serial right ventricular biopsies of 57 patients were collected in 6-month intervals after cardiac transplant surgery for a total of 10 years to allow a retrospective longitudinal analysis. Over this period, tissue remodeling, including interstitial fibrosis and cellular changes, were determined morphometrically. Immunohistochemistry (IHC) was used to analyze expression of the following hypoxia-related proteins: hypoxia-induced factor 1 alpha (HIF1alpha); the oxygen sensor prolyl hydroxylase 3 (PHD3); and vascular endothelial growth factor (VEGF). RESULTS: Fibrosis increased significantly from 12.6 +/- 6.5% at the point of transplantation throughout follow-up to 28.8 +/- 7.7% at 10 years. The DNA content and number of nuclei changed over the period of follow-up, displaying signs of cellular hypertrophy and a loss of myocytes. Whereas HIF1alpha expression revealed a U-shaped pattern with both early and late elevation during fibrogenesis, PHD3 and VEGF expression patterns showed a gradual increase with PHD3 decreasing again in later fibrogenesis. CONCLUSIONS: In cardiac allografts, extensive and progressive tissue remodeling is present. Hypoxia may play a role in this process by up-regulating HIF1alpha and leading to differential regulation of pro-angiogenic signals. PMID- 19782588 TI - Effects of the 2006 U.S. thoracic organ allocation change: analysis of local impact on organ procurement and heart transplantation. AB - BACKGROUND: The United Network for Organ Sharing (UNOS) implemented a thoracic organ allocation policy change (APC) in July 2006 that aimed to reduce death on the waiting list by expanding regional organ sharing. As such, organs would be allocated to the sickest recipients with highest listing status across the region. Our aim was to determine the impact of the new policy on the procurement and transplant process within our program. METHODS: We analyzed data supplied by UNOS as the contractor for the Organ Procurement and Transplantation Network and from the local organ procurement organization for 2 years before and 2 years after implementation of the APC. RESULTS: The APC resulted in an increase in the proportion of Status 1A patients transplanted (24% to 43%, p = 0.015) and a decrease in the proportion of Status 2 patients transplanted (56% to 24%, p = 0.001). Significant increases were observed in mean graft ischemic time (196 minutes to 223 minutes, p = 0.022), number of patients transplanted with ventricular assist devices (17% to 31%, p = 0.036), and procurement costs. There was no significant difference in waiting-list mortality (6% to 5%, p = 0.75) and short-term post-transplant survival. CONCLUSIONS: The 2006 change in UNOS organ allocation policy resulted in an increase in Status 1A transplants, graft ischemic time and procurement costs, and a decrease in Status 2 transplants, but no effect on mortality on the waiting list within our center. To assess the full effect of the APC on outcomes, the long-term impact of the increased graft ischemic time on survival should be quantified. PMID- 19782589 TI - Utility of virtual crossmatch in sensitized patients awaiting heart transplantation. AB - BACKGROUND: Organ transplant candidates with serum antibodies directed against human leukocyte antigens (HLA) face longer waiting times and higher mortality while awaiting transplantation. This study examined the accuracy of virtual crossmatch, in which recipient HLA-specific antibodies, identified by solid-phase assays, are compared to the prospective donor HLA-type in heart transplantation. METHODS: We examined the accuracy of virtual crossmatch in predicting immune compatibility of donors and recipients in heart transplantation and clinical outcomes in immunologically sensitized heart transplant recipients in whom virtual crossmatch was used in allograft allocation. RESULTS: Based on analysis of 257 T-cell antihuman immunoglobulin complement-dependent cytotoxic (AHG-CDC) crossmatch tests, the positive predictive value of virtual crossmatch (the likelihood of an incompatible virtual crossmatch resulting in an incompatible T cell CDC-AHG crossmatch) was 79%, and the negative predictive value of virtual crossmatch (the likelihood of a compatible virtual crossmatch resulting in a compatible T-cell CDC-AHG crossmatch) was 92%. When used in a cohort of 28 sensitized patients awaiting heart transplantation, 14 received allografts based on a compatible virtual crossmatch alone from donors in geographically distant locations. Compared with the other 14 sensitized patients who underwent transplant after a compatible prospective serologic crossmatch, the rejection rates and survival were similar. CONCLUSION: Our findings are evidence of the accuracy of virtual crossmatch and its utility in augmenting the opportunities for transplantation of sensitized patients. PMID- 19782590 TI - In vivo acute performance of the Cleveland Clinic self-regulating, continuous flow total artificial heart. AB - BACKGROUND: The purpose of this study was to evaluate the acute in vivo pump performance of a unique valveless, sensorless, pulsatile, continuous-flow total artificial heart (CFTAH) that passively self-balances left and right circulations without electronic intervention. METHODS: The CFTAH was implanted in two calves, with pump and hemodynamic data recorded at baseline over the full range of pump operational speeds (2,000 to 3,000 rpm) in 200-rpm increments, with pulsatility variance, and under a series of induced hemodynamic states created by varying circulating blood volume and systemic and pulmonary vascular resistance (SVR and PVR). RESULTS: Sixty of the 63 induced hemodynamic states in Case 1 and 73 of 78 states in Case 2 met our design goal of a balanced flow and maximum atrial pressure difference of 10 mm Hg. The correlation of calculated vs measured flow and SVR was high (R(2) = 0.857 and 0.832, respectively), allowing validation of an additional level of automatic active control. By varying the amplitude of sinusoidal modulation of the speed waveform, 9 mm Hg of induced pulmonary and 18 mm Hg of systemic arterial pressure pulsation were achieved. CONCLUSIONS: These results validated CFTAH self-balancing of left and right circulation, induced arterial flow and pressure pulsatility, accurate calculated flow and SVR parameters, and the performance of an automatic active control mode in an acute, in vivo setting in response to a wide range of imposed physiologic perturbations. PMID- 19782591 TI - Continuous assessment of cardiac function during rotary blood pump support: a contractility index derived from pump flow. AB - BACKGROUND: The clinical application of rotary blood pumps (RBPs) for bridge-to recovery and destination therapy has focused interest on the remaining contractile function of the heart and its course. This study reports a method to determine contractility that uses readily measured variables of the RBP. METHOD: The proposed index (I(Q)) is defined as the slope of a linear regression between the maximum derivative of the pump flow and its peak-to-peak value. I(Q) was compared with the maximal derivative of ventricular pressure (dP/dt(max)) vs end diastolic volume (EDV) and the pre-load-recruitable stroke work. All indices were evaluated using computer simulations and animal experiments. For in vivo studies, a MicroMed-DeBakey ventricular assist device (VAD) was implanted in 7 healthy sheep. Ventricular contractility was examined under normal conditions and after pharmacologic intervention. For the computer simulation, variations of ventricular contractility, ventricular pre-load and after-load, and pump speeds were studied. RESULTS: In vivo and computer simulations showed the I(Q) index to be sensitive to changes of cardiac contractility, similar to other classic indices. For reduced cardiac contractility, it decreased to 9.3 +/- 3.9 (s(-1)) vs 15.3 +/- 4.0 (s(-1)) in the control condition (in vivo experiments). The I(Q) index was only marginally influenced by pre-load and after-load changes: a variation of 7.0% +/- 8.9% and 1.3% +/- 7.1%, respectively, was observed in computer simulations. CONCLUSIONS: The I(Q) index, which can be derived from pump data only, is a useful parameter for continuous monitoring of the cardiac contractility in patients with RBP support. PMID- 19782592 TI - Outcomes of children with cardiomyopathy listed for transplant: a multi institutional study. AB - BACKGROUND: Dilated (DCM), restrictive (RCM), and hypertrophic (HCM) cardiomyopathies (CM) in children have varying clinical courses and therapeutic options. Heart transplantation (HTx) offers a chance for long-term survival; but outcomes after listing have not been well defined. METHODS: A multi-institutional registry of 3,147 patients listed for HTx (January 1993-December 2006) was used to compare outcomes of 1,320 children with CM (42%) and 1,827 with non-CM (58%) etiologies. Comparisons were made between sub-groups: 1,098 DCM (83%), 145 RCM (11%), and 77 HCM (6%). RESULTS: CM patients had a waitlist mortality of 17% vs 32% for non-CM patients (p < 0.0001), with no difference between the CM sub groups. Risk factors were younger age, black race (relative risk [RR], 1.65; p = 0.009), mechanical ventilation (RR, 3.17; p < 0.001), and extracorporeal membrane oxygenation (RR, 2.16; p < 0.001). Ten-year survival after listing was 66% for CM vs 53% for non-CM (p < 0.0001). HCM and RCM patients aged < 1 year at the time of listing had the highest waitlist mortality and the lowest overall survival. CM patients had a better 10-year survival after HTx (68% vs 61%, p < 0.0001). Risk factors for death early after HTx included mechanical ventilation at HTx (RR, 3.07; p < 0.001), longer ischemic time (RR, 1.27; p = 0.01), and earlier era (RR, 1.77; p = 0.002). Late risk factors included black race (RR, 3.01; p < 0.001), HCM or RCM (RR, 1.93; p = 0.007), and older age (RR, 1.9; p < 0.001). CONCLUSION: Children with CM have a lower waitlist mortality and better survival post-HTx than children with a non-CM diagnosis. DCM patients have the best and HCM or RCM patients aged younger than 1 year have the worst overall outcomes. PMID- 19782593 TI - Adverse family social circumstances and outcome in pediatric cardiac transplant recipients at a UK center. AB - BACKGROUND: Socioeconomic disadvantage is known to prejudice certain health related outcomes. METHODS: Our objective was to establish whether adverse social circumstances are linked to rejection events after pediatric cardiac transplant in a UK context. A retrospective observational cohort study was conducted including 78 of 85 children who underwent cardiac transplantation between 2001 and 2005. RESULTS: Family social circumstances included: 36 (46%) unemployed/manual occupation; 29 (37%) non-home owners; 16 (21%) single parents; income support in 31 (40%); and 2 or more further children in 34 (44%). Adverse social risk factors were evenly distributed throughout the cohort in terms of other demographic variables. The rate for a first rejection event was 0.10 (95% confidence interval [CI] 0.07 to 0.15) episode per patient per year, and for late rejection was 0.04 (95% CI 0.02 to 0.07) episode per patient per year. There was some evidence that children from non-home-owning families (hazard ratio [HR] 0.31, 95% CI 0.11 to 0.82, p = 0.02) and those on income support (HR 0.43, 95% CI 0.18 to 1.04, p = 0.06) had reduced risk of early/all first-time rejection episodes. Other social risk factors were unrelated to early rejection. No relationship was found between any social factor and late rejection episodes or low immunosuppression levels at clinic visits 3, 6 or 12 months post-transplant. CONCLUSIONS: Children from more adverse circumstances were not predisposed to rejection episodes. To date, there is no evidence to support a policy of declining children for transplantation on psychosocial grounds in the UK. PMID- 19782594 TI - Noninvasive assessment of left ventricular assist devices with cardiovascular computed tomography and impact on management. AB - BACKGROUND: Left ventricular assist devices (LVADs) provide a bridge to recovery or heart transplantation but require serial assessment. Echocardiographic approaches may be limited by device artifact and acoustic window. Cardiovascular computed tomography (CCT) may provide improved non-invasive imaging of LVADs. We evaluated the diagnostic findings and clinical impact of CCT for non-invasive assessment of patients with LVADs. METHODS: CCT examinations performed between 2005 and 2008 in patients with LVADs were identified. Acquisitions were completed on the identical 64-detector-row scanner with intravenous contrast administration. Electrocardiographic gating was used in patients with pulsatile devices, and peripheral pulse gating was used in patients with continuous-flow devices. Comparison was made between CCT results and 30-day outcomes, including echocardiographic and intraoperative findings. RESULTS: We reviewed 32 CCT examinations from 28 patients. Indications included evaluation of low cardiac output symptoms, assessment of cannula position, low flow reading on the LVAD, and surgical planning. CCT identified critical findings in 6 patients, including thrombosis and inlet cannula malposition, all confirmed intraoperatively. CCT missed 1 case of intra-LVAD thrombus. Using intraoperative findings as the gold standard, CCT's sensitivity was 85% and specificity was 100%. Echocardiographic LVAD evaluation did not correlate with findings on CCT (kappa = -0.29, 95% confidence interval, -0.73 to 0.13). CONCLUSIONS: This preliminary observational cohort study indicates that non-invasive imaging using CCT of LVADs is feasible and accurate. CCT warrants consideration in the initial evaluation of symptomatic patients with LVADs. PMID- 19782595 TI - Comparison between referral diagnosis of patients requiring transplantation and pathologic diagnosis of native lungs. AB - BACKGROUND: The donor organs available for lung transplantation remain far fewer than the number of recipients. Therefore, it is of primary importance to optimize this resource, especially by carefully selecting potential recipients. The diagnosis of end-stage diseases referred for transplantation is mainly based on clinical/radiologic assessment and rarely on histology. METHODS: A clinicopathologic study was performed on 175 patients who underwent lung transplantation over a 12-year period (1995 to 2007). Diagnoses on native lungs were compared with referral diagnoses to assess the presence of discrepancies. In particular, major discrepancies included complete mismatch between referral and pathologic diagnoses and other additional findings likely to affect patient management. RESULTS: Major discrepancies were found in 18 of 175 cases (10%). The highest percentage of discordance was found in diffuse parenchymal lung diseases, more frequently idiopathic pulmonary fibrosis (IPF). In the majority of IPF and other non-IPF idiopathic forms, there was often an imprecise nosographic definition of the diseases. Unsuspected additional findings included Aspergillus and mycobacterial infections, carcinomas and carcinoids. Short-term survival is significantly lower in patients with discrepancies than in those without. CONCLUSIONS: On the basis of the high rate and importance of discrepancies, more accurate and repeated clinicopathologic investigations should be planned in the waiting list period. PMID- 19782596 TI - Neurodevelopmental outcomes in pediatric heart transplant recipients. AB - BACKGROUND: Physical functioning is without restriction in most pediatric heart transplant survivors, but only limited data are available about neuropsychologic outcomes in these children. In this study we assess neurodevelopmental outcomes in transplant survivors in comparison to population norms. METHODS: Neuropsychologic evaluations were performed 12 to 24 months (mean 16 months) post transplant in 21 children ranging in age from 1 to 101 months (median 15 months) at time of transplant. Outcomes included verbal, non-verbal and overall intelligence; visual-motor integration skills; and adaptive functioning. RESULTS: Transplant recipients had a mean overall IQ of 86.7, verbal IQ of 88.4 and non verbal IQ of 87.5, all significantly below the normative population mean of 100 (p < 0.01). Thirty-eight to 43% of subjects had low IQ scores (i.e., <85), significantly more than the normative 16% base rate (p < 0.02). Children with an initial diagnosis of congenital heart disease (CHD) had lower overall IQ (mean 78.6) than those with cardiomyopathy (mean 91.7). The mean expressive language score was 88.1, significantly below norms (p < 0.01), with 46% having low scores (p = 0.01). Receptive language was normal in the same patients (mean 96.8). Finally, 63% of patients had visual-motor deficits and 48% had fine motor deficits (p < 0.005 compared with norms). CONCLUSIONS: Although many pediatric heart transplant recipients display normal neurodevelopmental functioning, this population is at increased risk for cognitive difficulties, especially in expressive language, visual-motor integration and fine motor skills. Children with CHD may be at especially high risk. Early identification and intervention are essential to promote optimal neuropsychologic outcomes and overall quality of life in pediatric heart transplant recipients. PMID- 19782597 TI - Era effect on post-transplant survival adjusted for baseline risk factors in pediatric heart transplant recipients. AB - BACKGROUND: Post-transplant survival in pediatric heart transplant (HT) recipients has improved for recent era recipients. However, the era effect has not been assessed after adjusting for baseline risk factors in HT recipients. METHODS: We compared baseline characteristics and 5-year survival in pediatric HT recipients in three eras (early: July 1994 to June 1997, n = 1,153; middle: July 1997 to June 2000, n = 1,085; recent: July 2000 to June 2003, n = 1,138) for all recipients <18 years of age who were reported to the registry of the International Society for Heart and Lung Transplantation (n = 3,376). We used a Cox proportional hazards model for determining risk-adjusted era effect on death or graft loss (retransplant). RESULTS: There were more retransplants and more recipients had pre-formed antibodies in the recent eras. Recent era recipients were more likely to be supported by inotropes, ventilator, mechanical support and dialysis at the time of transplant. Five-year survival was better for patients who underwent HT in the middle era (hazard ratio [HR] 0.79, 95% confidence interval [CI] 0.68 to 0.93, p = 0.003) and the recent era (HR 0.70, CI 0.60 to 0.82, p < 0.001) as compared with those in the early era, adjusted for baseline risk factors. The determinants of conditional 5-year survival in HT recipients who survived the first 6 months were recipient and donor age, recipient gender, retransplant, pre-formed antibodies and inotropes, but not transplant era. CONCLUSIONS: Despite the worse baseline risk profile of pediatric HT recipients in recent years, their risk-adjusted survival during the first 5 years after transplant has improved. The entire era effect appears to be due to improved survival during the first 6 months post-transplant. PMID- 19782598 TI - Successful left ventricular decompression following peripheral extracorporeal membrane oxygenation by percutaneous placement of a micro-axial flow pump. PMID- 19782599 TI - An innovative, sensorless, pulsatile, continuous-flow total artificial heart: device design and initial in vitro study. AB - BACKGROUND: We are developing a very small, innovative, continuous-flow total artificial heart (CFTAH) that passively self-balances left and right pump flows and atrial pressures without sensors. This report details the CFTAH design concept and our initial in vitro data. METHODS: System performance of the CFTAH was evaluated using a mock circulatory loop to determine the range of systemic and pulmonary vascular resistance (SVR and PVR) levels over which the design goal of a maximum absolute atrial pressure difference of 10 mm Hg is achieved for a steady-state flow condition. Pump speed was then modulated at 2,600 +/- 900 rpm to induce flow and arterial pressure pulsation to evaluate the effects of speed pulsations on the system performance. An automatic control mode was also evaluated. RESULTS: Using only passive self-regulation, pump flows were balanced and absolute atrial pressure differences were maintained at <10 mm Hg over a range of SVR (750 to 2,750 dyne.sec.cm(-5)) and PVR (135 to 600 dyne.sec.cm(-5)) values far exceeding normal levels. The magnitude of induced speed pulsatility affected relative left/right performance, allowing for an additional active control to improve balanced flow and pressure. The automatic control mode adjusted pump speed to achieve targeted pump flows based on sensorless calculations of SVR and CFTAH flow. CONCLUSIONS: The initial in vitro testing of the CFTAH with a single, valveless, continuous-flow pump demonstrated its passive self-regulation of flows and atrial pressures and a new automatic control mode. PMID- 19782600 TI - Stress echocardiography as a gatekeeper to donation in aged marginal donor hearts: anatomic and pathologic correlations of abnormal stress echocardiography results. AB - BACKGROUND: Owing to the shortage of donor hearts, the criteria for acceptance have been considerably expanded. Pharmacologic stress echocardiography is highly accurate in identifying prognostically significant coronary artery disease, but brain death and catecholamine storm in potential heart donors may substantially alter the cardiovascular response to stress. This study assessed correlates of an abnormal resting/stress echocardiography results in potential donors. METHODS: From April 2005 to December 2007, 18 marginal candidate donors (9 men) aged 58 +/ 5 years were initially enrolled. After legal declaration of brain death, all marginal donors underwent bedside echocardiography, with baseline and (when resting echocardiography was normal) dipyridamole (0.84 mg/kg in 6 min) or dobutamine (up to 40 microg/kg/min) stress echo. Non-eligible hearts (with abnormal rest or stress echo findings) were excluded and underwent cardioautoptic verification. RESULTS: Resting echocardiography showed wall motion abnormalities in 5 patients (excluded from donation). Stress echocardiography was performed in the remaining 13 (dipyridamole in 11; dobutamine in 2). Results were normal in 7, of which 6 were uneventfully transplanted in marginal recipients. Results were abnormal in 6, and autoptic verification performed showed coronary artery disease in 5, and initial cardiomyopathy in 1. CONCLUSIONS: Bedside pharmacologic stress echocardiography can safely be performed in candidate heart donors, is able to unmask occult coronary artery disease or cardiomyopathy, and shows potential to extend donor criteria in heart transplantation. Further experience with using marginal donors is needed before exact guidelines can be established. PMID- 19782601 TI - Outcome of pediatric patients with dilated cardiomyopathy listed for transplant: a multi-institutional study. AB - BACKGROUND: The course of dilated cardiomyopathy (DCM) leading to heart failure in children varies; survival with conventional treatment is 64% at 5 years. Heart transplantation (HTx) enables improved survival; however, outcomes from listing for transplant are not well described. This study reports survival of patients with DCM from listing with the availability of mechanical bridge to transplant. METHODS: Patients with a primary diagnosis of DCM (n = 1,098) were identified from a multi-institutional, prospective, registry of patients aged < 18 years listed for HTx from January 1, 1993, to December 31, 2006. RESULTS: Characteristics of DCM patients at listing included a mean age of 7.3 years; 51% male, 64% white ethnicity, 77% United Network for Organ Sharing status I, 66% on inotropic support, 28% mechanically ventilated, and 15% on mechanical support. Waitlist mortality was 11%, and 75% underwent HTx at 2 years after listing. Overall 10-year survival after listing was 72%, with higher risk of death associated with arrhythmias, mechanical ventilation, and extracorporeal membrane oxygenation (ECMO) support, but not ventricular assist device (VAD) support. Survival at 10 years post-HTx was 72%, with a higher risk of death associated with black race, older age, mechanical ventilation, longer ischemic time, and earlier era of transplant. CONCLUSIONS: Transplantation for DCM in the pediatric population offers enhanced survival compared with the natural history. Overall waitlist mortality for DCM is low, with the exception of patients on ECMO, mechanically ventilated, or with arrhythmias. DCM patients fared well after transplant, making HTx a key therapeutic intervention. PMID- 19782602 TI - Poor functional recovery after transplantation of diabetic bone marrow stem cells in ischemic myocardium. AB - BACKGROUND: Autologous bone marrow mononuclear cell (BMMC) therapy has shown promise for improving cardiac function after myocardial infarction. The efficiency of such therapy for diabetic patients remains unknown. METHODS: BMMCs were harvested from type 2 diabetic male BKS.Cg-m+/+Lepr(db)/J mice or C57BLKS/J (non-diabetic control) mice and were isolated using Ficoll-based separation. Cell characterization was performed by flow cytometry. Cell viability was determined by apoptosis and proliferation assays. Female BKS.Cg-m+/+Lepr(db)/J mice underwent left anterior descending artery ligation and were randomized into 3 groups receiving 2.5 x 10(6) diabetic BMMCs (n = 8), 2.5 x 10(6) control BMMCs (n = 8), or phosphate-buffered saline (n = 6). At Week 5, cardiac function was assessed with echocardiography and invasive hemodynamic measurements. Post-mortem cell survival was quantified by TaqMan real-time transcription polymerase chain reaction (RT-PCR) for the male Sry gene. RESULTS: BKS.Cg-m+/+Lepr(db)/J BMMCs showed a significantly lower mononuclear fraction and a significantly lower proliferation rate compared with C57BLKS/J BMMCs. Fractional shorting (40.1% +/- 1.2% vs 30.3% +/- 1.9%; p = 0.001) and cardiac output (4,166 +/- 393 vs 2,246 +/- 462 microl/min; p = 0.016) significantly improved for mice treated with control BMMCs injection compared with those treated with diabetic BMMCs, respectively. This difference could not be attributed to difference in cell engraftment because TaqMan RT-PCR showed no significant difference in cell survival in infarcted hearts between the 2 groups. CONCLUSIONS: Diabetic BMMCs are significantly impaired in their ability to improve cardiac function after myocardial infarction compared with control BMMCs. These findings could have significant clinical implication regarding autologous BMMC therapy in diabetic patients. PMID- 19782603 TI - Outcomes of pediatric patients with hypertrophic cardiomyopathy listed for transplant. AB - BACKGROUND: The course of pediatric hypertrophic cardiomyopathy (HCM) is variable, and the indications for heart transplantation (HTx) are ill defined. This study investigated outcomes and risk factors for adverse outcomes after listing for HTx. METHODS: A multicenter, event-driven data registry of patients aged < 18 years listed for HTx between January 1993 and December 2007 was used. RESULTS: During the study period, 3,147 children were listed for HTx (mean age, 7.6 +/- 0.8 years). Of l,320 with CM at listing, 77 (6%) had HCM (61% boys; 79% white); 59% were United Network of Organ Sharing (UNOS) status I, 30% were receiving inotropes, 27% were ventilated, and 8% required extracorporeal membrane oxygenation. Arrhythmia had occurred in 27%, and 14% had failure to thrive. Within 1 year, 65% underwent HTx. Overall, 25 patients died after listing: 11 (14%) while waiting and 14 of 49 (29%) after HTx. Pre-HTx survival was lower for those listed at age < 1 year (p = 0.0005). Risk factors for death after listing included UNOS status 1 (p = 0.01) and younger age (relative risk, 2.3; p = 0.001). Late (10-year) survival after HTx for HCM patients was 47% vs 63% for non CM patients within the database. CONCLUSIONS: Children with HCM listed for HTx age < 1 year and UNOS status 1 have the highest mortality awaiting HTx. A more rigorous identification of additional risk factors should be performed to better define timing of listing and which patient sub-group may derive optimal benefit from HTx. PMID- 19782604 TI - Reversal of secondary pulmonary hypertension by axial and pulsatile mechanical circulatory support. AB - BACKGROUND: Pulmonary hypertension associated with chronic congestive heart failure posses a significant risk of morbidity and death after heart transplantation. Isolated observations suggest that chronic ventricular unloading may lead to normalization of pulmonary pressures and thus render a patient likely to be a heart transplant candidate. METHODS: This study is a retrospective analysis of 9 heart failure patients with secondary pulmonary hypertension (transpulmonary gradient [TPG] > 15 mm/Hg). Two were treated with a pulsatile left ventricular assist device (LVAD) and 7 with an axial-flow LVAD. RESULTS: After LVAD support, mean pulmonary artery pressure decreased from 39 +/- 7 to 31 +/- 5 mm Hg, and the TPG decreased from 19 +/- 3 to 13 +/- 4 mm Hg (p < 0.01). The 1-year Kaplan-Meier survival curve for patients with pre-LVAD TPG > 15 mm Hg vs those with TPG < 15 mm Hg showed no difference in survival (p = 0.6). This finding was supported by analysis of a large multi-institutional cohort obtained from the Organ Procurement and Transplantation Network database, where no differences in survival were found in the same groups. CONCLUSIONS: Pulmonary hypertension that is secondary to congestive heart failure, as defined by a TPG > 15 mm Hg can be reversed by the use of pulsatile and axial-flow LVADs; furthermore, post-transplant survival for patients with secondary pulmonary hypertension treated with an LVAD was no different than for those without pulmonary hypertension who received LVAD support. PMID- 19782605 TI - PPARalpha ligand WY14643 reduced acute rejection after rat lung transplantation with the upregulation of IL-4, IL-10 and TGFbeta mRNA expression. AB - BACKGROUND: The peroxisome proliferators-activated receptor-alpha (PPARalpha) is important in lipid metabolism and regulation of inflammation. Recent studies have demonstrated the immunoregulatory effects of PPARalpha. This investigated the immunosuppressive effects of PPARalpha using its ligand, WY14643, on acute lung allograft rejection in a rat model and its mechanism of action. METHOD: The left lungs were transplanted orthotopically from Brown-Norway donors to F344 recipients. The recipients were then divided into control and WY14643 treatment groups. The allograft rejection was evaluated by daily chest X-ray imaging and was evaluated histologically on Day 7 after transplantation. The cytokine messenger RNA (mRNA) expression at Days 3 and 5 were also evaluated in allografts and recipient spleens. RESULTS: The radiologic and histologic findings indicated that treatment with the WY14643 reduced acute allograft rejection. WY14643 also significantly extended the allograft survival time. This amelioration of acute rejection by WY14643 was also associated with up-regulated interleukin (IL)-4, IL 10, and transforming growth factor-beta (TGFbeta) mRNA expression in the lung allografts and spleens. CONCLUSION: This study demonstrated that the administration of the PPARa ligand, WY14643, ameliorates acute lung allograft rejection in rats. Treatment with WY14643 reduced histopathologic scores, prolonged graft survival, and up-regulated the expression of anti-inflammatory cytokine IL-4, IL-10, and TGFbeta mRNA compared with the control. PMID- 19782606 TI - Fulminant hepatic failure due to varicella zoster in a heart transplant patient: successful liver transplant. AB - Fulminant hepatic failure is a rare complication of infection by varicella zoster virus that is favored by immunosuppression. Within 1 week, a 43-year-old male heart transplant recipient who was admitted with epigastric pain successively developed a generalized vesicular rash, hepatitis, and secondary multiorganic failure involving encephalopathy, despite treatment with acyclovir (since Day 2) and varicella zoster virus immunoglobulin (since Day 6). Emergency liver transplantation was performed on Day 9, and 36 months later, his heart and liver function are normal. PMID- 19782608 TI - B-type natriuretic peptide levels late after transplant predict graft survival in pediatric heart transplant patients. PMID- 19782607 TI - Myocardial and peripheral lymphocytic transcriptomic dissociation of beta adrenoceptors and G protein-coupled receptor kinases in heart transplantation. AB - BACKGROUND: The genetic expression of adrenergic receptors plays an important pathophysiologic role in heart failure. G protein-coupled receptor kinases (GRKs) desensitize the beta-receptor to catecholaminergic stimulation. It has been suggested that their mRNA expression in peripheral lymphocytes could mirror the changes in their myocardial expression in the failing heart, but this relationship between the myocyte and lymphocyte has not been studied in heart transplantation (HT). The objective of this study was to analyze adrenergic receptor and GRK mRNA expression in myocardium and lymphocytes and their correlation. METHODS: Twenty-three HT patients without evidence of acute rejection or echocardiographic dysfunction were assessed. Myocardial biopsy samples and peripheral blood lymphocytes were obtained, and alpha(1)- and beta adrenoceptor subtype and GRK subtype mRNA was analyzed using reverse transcript polymerase chain reaction (RT-PCR). RESULTS: Mean age was 45 +/- 15 years, with a median of time since HT of 205 (351) days. In biopsies, the beta(1)/beta(2) adrenoceptor ratio was 57%/42%, and GRK5 was the most commonly expressed, followed by GRK2. In lymphocytes, the beta(1)/beta(2) ratio was 3%/96%, whereas GRK2 mRNA expression was greater than that of other subtypes. There was no correlation between myocardial and lymphocyte parameters. There were no correlations with clinical variables, but lymphocyte beta(2) and GRK2 were increased with time since HT. CONCLUSIONS: In the transplanted heart, there is no correlation between mRNA expression of adrenoceptors and GRKs in myocardium and peripheral lymphocytes. With time since transplant, mRNA expression of lymphocyte but not myocardial beta(2)-adrenoceptor and GRK2 increases. Therefore, this dissociation between myocardial and lymphocyte mRNA expression limits the potential use of peripheral blood samples for diagnosis of graft dysfunction. PMID- 19782609 TI - Soluble CD30 levels in recipients undergoing heart transplantation do not predict post-transplant outcome. AB - BACKGROUND: The pre-transplant serum level of soluble CD30 (sCD30), a proteolytic derivative of the lymphocyte surface receptor CD30, has been suggested as a biomarker for immunologic risk after organ transplantation. METHODS: Pre transplant serum sCD30 levels were determined in 200 consecutive adult heart transplant recipients undertaken at a single center. Transplant outcome (acute rejection in the first 12 months and patient survival up to 5 years post transplant) was determined. RESULTS: Patients treated with a left ventricular assist device (LVAD) prior to transplantation (n = 28) had higher levels of sCD30 (median 64 U/ml, range 12 to 112 U/ml) than those (n = 172) with no LVAD (median 36 U/ml, range 1 to 158 U/ml, p < 0.0001). Recipients were categorized according to whether sCD30 levels were "low" (lower quartile, <24 U/ml, n = 50), "intermediate" (24 to 58 U/ml, n = 100) or "high" (upper quartile, >58 U/ml, n = 50). Neither acute rejection nor recipient survival differed according to sCD30 level, with values (mean +/- SEM) of 0.30 +/- 0.04, 0.23 +/- 0.03 and 0.30 +/- 0.05 acute rejection episodes per 100 days in the low, intermediate and high groups, respectively, with recipient survival rates at 1 year of 77.7%, 84.9% and 86% and at 5 years of 73.6%, 67.9% and 75.8%, respectively. CONCLUSIONS: Pre transplant serum sCD30 level does not predict acute allograft rejection or recipient survival after heart transplantation, although sCD30 levels are increased by LVAD, possibly as a result of biomaterial-host immune interaction. PMID- 19782610 TI - Socioeconomic status and pediatric heart transplantation--does it matter? PMID- 19782611 TI - Pre-operative determination of an individual's neutrophil response: a potential predictor of early cardiac transplant cellular rejection. AB - BACKGROUND: Success of heart transplantation is affected by allograft rejection, which is known as a lymphocyte-mediated process. Recent studies suggest that neutrophils contribute to this process. We hypothesized that the severity of cardiac rejection can be predicted by evaluating an individual's neutrophil transendothelial migration potential, which can be assessed through artificial stimulation of neutrophils. METHODS: Eleven patients were recruited from the active heart transplant list. Pre-operative blood samples were stained with neutrophil adhesion molecule (CD11b, CD62L, and PSGL-1) antibodies before and after in vitro stimulation with phorbol 12-myristate 13-acetate (PMA; 1 ng/ml) and lipopolysaccharide (LPS 1 microg/ml), and assessed using flow cytometry. Stimulated neutrophil responses were correlated with rejection grade of the first endomyocardial biopsy sampled 10 days post-operatively. RESULTS: Neutrophil adhesion molecules are upregulated after artificial stimulation. Pre-operative neutrophil surface CD11b expression after in vitro lipopolysaccharide stimulation correlated with rejection grade detected in the first endomyocardial biopsy sample (R = 0.677; p = 0.022). CONCLUSION: Pre-operative neutrophil response to in vitro stimuli predicted the rejection grade in the first post-transplant endomyocardial biopsy specimen, suggesting that neutrophils may contribute more to cardiac allograft rejection than previously thought. PMID- 19782612 TI - Activated protein C in ischemia-reperfusion injury after experimental lung transplantation. AB - BACKGROUND: Ischemia-reperfusion injury remains the major cause of early morbidity and mortality after lung transplantation. Activated protein C (APC) has been demonstrated to attenuate various acute inflammation-related injuries in the lung and other organs. METHODS: The effect of exogenous APC in lung transplantation was examined using a rat orthotopic lung transplantation model of ischemia-reperfusion injury with 24 hours of cold ischemia. APC was administered to the donor airway before cold pulmonary artery flush, or intravenously to the recipient before reperfusion. RESULTS: The levels of APC in the lung tissue were significantly higher in the intra-airway group compared with the intravenous group and the saline control group (p < 0.01). Transplanted lung oxygenation was significantly better in the intra-airway APC group at 2 hours after reperfusion compared with controls (Pao(2), mean +/- SD mm Hg: intra-airway APC, 350.9 +/- 85.5; intravenous APC, 241.1 +/- 59.3; control, 200.2 +/- 37.3; p < 0.05). No difference was detected in proinflammatory cytokines or thrombin-anti-thrombin complexes in the lung tissue. Histologic examination of the lung injury score or alveolar fibrin deposition did not demonstrate significant differences among groups. CONCLUSION: Exogenous APC administered to the donor airway attenuates ischemia-reperfusion injury after lung transplantation. This novel administration route sustains high levels of APC in the lung tissue, which should avoid frequent administration and potential systemic side effects of bleeding. Further investigation is necessary to determine the mechanism of the beneficial effect of APC in this setting. PMID- 19782613 TI - Methicillin-resistant Staphylococcus aureus infection after lung transplantation: 5-year review of clinical and molecular epidemiology. AB - BACKGROUND: Data on the epidemiology of MRSA infection in lung transplantation is limited. METHODS: We performed a 5-year retrospective study to assess the incidence and microbiologic and clinical characteristics of methicillin-resistant Staphylococcus aureus (MRSA) infection in a cohort of 163 lung transplant recipients. RESULTS: Seventeen patients with MRSA colonization and/or infection were identified, for a calculated incidence rate of 76.1 cases per 1,000 transplanted-years. Pulsed-field gel electrophoresis identified 3 different distinct MRSA profiles, all of them consistent with hospital-associated MRSA infection. CONCLUSION: Despite negative polymerase chain reaction (PCR) for the virulence factor Panton-Valentine leukocidin, MRSA infections resulted in significant disease and morbidity. PMID- 19782614 TI - Hypnotic induction decreases anterior default mode activity. AB - The 'default mode' network refers to cortical areas that are active in the absence of goal-directed activity. In previous studies, decreased activity in the 'default mode' has always been associated with increased activation in task relevant areas. We show that the induction of hypnosis can reduce anterior default mode activity during rest without increasing activity in other cortical regions. We assessed brain activation patterns of high and low suggestible people while resting in the fMRI scanner and while engaged in visual tasks, in and out of hypnosis. High suggestible participants in hypnosis showed decreased brain activity in the anterior parts of the default mode circuit. In low suggestible people, hypnotic induction produced no detectable changes in these regions, but instead deactivated areas involved in alertness. The findings indicate that hypnotic induction creates a distinctive and unique pattern of brain activation in highly suggestible subjects. PMID- 19782615 TI - Juvenile hyaline fibromatosis of the mandible with bone involvement: report of a rare case. AB - Juvenile hyaline fibromatosis (JHF) is a rare autosomal-recessive hereditary disease, characterized by gingival hypertrophy, flexion contractures of joints, bone lesions, hyaline deposition in the extracellular spaces of the dermis and soft tissues, stunted growth, and skin lesions such as multiple nodules, tumors and pink, pearly papules. No case of JHF with a mandibular bone involvement, exists in the literature. Bone involvement in JHF is an uncommon finding and distinct solitary lesions in the calvarial bones has been reported by some authors. A 21-year-old male patient was referred to Diyarbakir Military Hospital, Department of Dental Service. Clinical findings were consistent with a solid alveolar mass in the right mandibular premolar-molar region and displaced right mandibular molar teeth. Orthopantomographic examination showed impaction of all lower right molars in a mixed radioopaque/radiolucent area. Microscopically, increased nodular connective tissue was seen under the lobulated mucosal surfaces of the resected area. The case presented here had a localized fibrous proliferation that infiltrated bone trabeculae and caused displacement of teeth. Juvenile hyaline fibromatosis should be considered in the differential diagnosis with the other intraosseous radiolucent-patchy opaque lesions of jaw bones. Based on the clinical and histopathological findings, a diagnosis of JHF was made. PMID- 19782616 TI - Oral findings in patients with Nijmegen breakage syndrome: a preliminary study. AB - OBJECTIVE: The objective of this study was to assess the oral cavity status of patients with Nijmegen breakage syndrome (NBS), an inherited genetic disorder that belongs to the group of chromosome instability syndromes and is characterized by microcephaly, a distinct facial appearance, growth retardation, radiation sensitivity, and immunodeficiency. STUDY DESIGN: Oral examination was conducted and immunological status assessed in 21 NBS patients (1.7-20.7 years old) and 21 healthy controls (5-21 years old). The differences between the frequency and severity of clinical manifestations and their correlation with immune parameters were analyzed by Student t test, the chi-square test, and Spearman's rank order correlation. RESULTS: Lesions of the oral mucosa and gingivitis were diagnosed more frequently in NBS patients than in controls. The mean Gingival Index was significantly higher in NBS subjects (P = 0.00043). Candidiasis was detected in 6 patients (28.6%) and in none of the healthy controls. Immune deficiency (humoral and/or cellular) was detected in 20 of 21 (95.2%) NBS patients. There was a significant association between severity of gingival inflammation and reduced number of B- and/or CD3+/CD4+ T cells combined with IgA+IgG4 deficiency. CONCLUSION: Our study showed that oral manifestations diagnosed in NBS patients were associated with combined deficiencies of the humoral and cellular arms of the immune system. We postulate that periodical examination of the oral cavity is essential for early medical intervention. PMID- 19782618 TI - Ligneous periodontitis is an analog lesion of ligneous conjunctivitis and described 150 years later. PMID- 19782617 TI - Bone formation on apatite-coated titanium with incorporated BMP-2/heparin in vivo. AB - OBJECTIVE: The objective of this study was to investigate whether the in vivo osteoinductive activity of an implant material is enhanced by covering the surface of apatite with incorporated bone morphogenetic protein 2 (BMP-2) and heparin which maintains the activity of BMP-2. STUDY DESIGN: Titanium implants were alkaline treated, heat activated, and soaked in stimulated body fluid with or without BMP-2/heparin to coat the apatite around them. Treated implant bars were then implanted in rat tibiae. After 3 weeks, nondecalcified sections were prepared and the new bone formation around the implants was examined. RESULTS: A greater amount of bone formed on the apatite-coated implants containing BMP 2/heparin than on apatite-coated implants containing BMP, with >or=3 microg/mL heparin. Apatite-coated titanium implants with BMP-2/heparin had significantly enhanced new endosteal bone formation, with increases vertically (134%) and horizontally (124%). CONCLUSIONS: Bone formation was stimulated around the apatite-covered titanium coated with BMP-2/heparin, which may be useful in improving implant therapy. PMID- 19782619 TI - A trial of alveolar cleft bone regeneration by controlled release of bone morphogenetic protein: an experimental study in rabbits. AB - OBJECTIVE: Autologous bone grafting is a currently preferred method for alveolar cleft bone regeneration. However, there are some disadvantages to this technique, including the limited availability of donor sites. In this study, we introduce a novel graft material of gelatin hydrogel enabling the controlled release of bone morphogenetic protein 2 (BMP-2) for alveolar cleft bone regeneration. STUDY DESIGN: Gelatin hydrogels incorporating BMP-2 or BMP-2-free solution and BMP-2 solution were applied to experimental alveolar clefts prepared in the maxillary bone of rabbits. As an additional control, the alveolar clefts were left untreated. Bone regeneration at the alveolar clefts was evaluated by microfocus computerized tomographic, histologic, and histomorphometric examinations. RESULTS: Significant bone regeneration was observed in the alveolar clefts treated with gelatin hydrogels incorporating BMP-2 compared with other groups. CONCLUSION: Gelatin hydrogels incorporating BMP-2 is a promising material for the bone regeneration of alveolar clefts. PMID- 19782620 TI - Miniature pigs as an animal model for implant research: bone regeneration in critical-size defects. AB - OBJECTIVE: Standardized experimental investigations determining the critical-size defect (CSD) in the mandible of miniature pigs are still lacking. The aim of the present study was to obtain information about the new bone formation in created defects of varying sizes. STUDY DESIGN: Marginal resection of the alveolar crest of the lower jaw was performed in 3 female miniature pigs. The animals used in the study were 3 years of age and weighed approximately 55 kg. For histologic evaluation the dental implants were harvested with the surrounding bone tissue 10 weeks after implant placement. For this, bone segments including the implants were removed from each side of the mandible. The sizes of the resected bone blocks varied, showing the following volumes: 10.1 cm(3), 4.2 cm(3), and 1.9 cm(3). Periosteal coverage of the defects was performed. Computerized tomography (CT) of the skull of the miniature pig was performed immediately after the surgical procedure as well as 6 weeks later using a 64-channel mult-slice scanner. RESULTS: The CT showed that 6 weeks after obtaining the biopsies, the filling of the defects with new bone varied. The percentage of newly formed bone in relation to the size of the original defect was 57.4% for the small- and 87.2% for the middle-sized defect. The large-sized defect showed 75.5% newly formed bone compared with baseline. CONCLUSION: Considering the amount of new bone formation found within this study, it is questionable if the critical defect size of 5 cm(3) stated in the literature is valid. Further research concerning the mandibular model in minipigs is required and more refinement needed to assure a standardized CSD, allowing qualitative and quantitative evaluation of bone grafts and bone graft substitutes. PMID- 19782621 TI - Safety of coronectomy versus excision of wisdom teeth: a randomized controlled trial. AB - OBJECTIVE: The objective of this study was to compare the surgical complications and neurosensory disturbances of coronectomy and total excision of lower wisdom teeth with roots in close proximity to the inferior dental nerve (IDN). STUDY DESIGN: A randomized controlled trial was conducted to compare the surgical complications and IDN deficit of coronectomy and total removal of wisdom teeth. Patients with specific radiographic signs of close proximity of wisdom teeth roots to the IDN were randomized. RESULTS: A total of 231 patients underwent surgery for 349 lower wisdom teeth (171 coronectomies, 178 controls); 16 coronectomies failed and were removed in total. Nine patients in the control group presented with IDN deficit, compared with 1 in coronectomy group (P = .023). Pain and dry socket incidence was significantly lower in the coronectomy group, and there were no statistical differences in infection rate between the 2 groups. Reoperation of one coronectomy case was performed owing to persistent root exposure. CONCLUSION: There are fewer complications in terms of IDN deficit, pain, and dry socket after coronectomy, but the infection rate is similar to that of total excision. PMID- 19782622 TI - Management of temporomandibular joint ankylosis: 11 years' clinical experience. AB - OBJECTIVE: Many surgical techniques to manage temporomandibular joint (TMJ) ankylosis have been described in the literature. The purpose of this paper is to report one institution's experience using various management techniques and to evaluate the results of these surgical interventions. STUDY DESIGN: The records from our hospital of 42 patients treated for TMJ ankylosis between 1996 and 2007 were reviewed. Pre- and postoperative assessment included age, gender, etiology, ankylosis type/classification, existing facial asymmetry, maximal pre- and postoperative mouth opening, arthroplasty method (gap or interpositional arthroplasty), complications, and recurrence of ankylosis. RESULTS: The mean maximal incisal opening in the preoperative period was 7.51 +/- 6.48 mm and in the post operative period was 27.74 +/- 7.86 mm. All patients experienced significant reduction of pain during function and resumed eating a normal diet. There was no facial nerve paralysis. There was recurrence in 3 cases. CONCLUSION: Joint reconstruction with interpositional arthroplasty for the treatment of ankylosis proved to be effective regarding the prevention of recurrence and restoration of joint function and patient quality of life. Early postoperative exercises, appropriate physiotherapy, and close follow-up play an important role in the prevention of recurrence. PMID- 19782623 TI - Aplicability of TNT "super-Q detection" to multipulse sequences. AB - The use of high-Q probes to increase the sensitivity in NMR and NQR is a well known technique, however very high Q values are associated with several limitations. This paper explores the (14)N NQR multipulse detection of trinitrotoluene (TNT) signal-to-noise ratio as a function of the pickup coil Q factor, with a particular emphasis on the "super-Q" regime, where probe bandwidth becomes narrower than the NQR linewidths. We have used a mixed experimental theoretical approach to find the TNT Q-dependent signal-to-noise value which avoided the inconvenient construction of a probe at every Q. The process has been repeated for a range of excitation/detection frequencies and a 2D sensitivity map was obtained. Our analysis suggests, that sensitivity is maximum and practically Q-independent when 400261.4 and m/z 440.4-->259.3 for silodosin and IS, respectively. The standard curve was linear in the range of 0.50-50.0 ng/ml with intra- and inter day precision of 3.2-7.2% and 2.0-7.5%, respectively. The lower limit of quantification (LLOQ) for silodosin was 0.50 ng/ml using 500 microl plasma sample. This method was successfully applied to the pharmacokinetic study in healthy volunteers. PMID- 19782649 TI - NBS1 cooperates with homologous recombination to counteract chromosome breakage during replication. AB - Nijmegen breakage syndrome (NBS) is characterized by genome instability and cancer predisposition. NBS patients contain a mutation in the NBS1 gene, which encodes the NBS1 component of the DNA double-strand break (DSB) response complex MRE11/RAD50/NBS1. To investigate the NBS phenotype in more detail, we combined the mouse mimic of the most common patient mutation (Nbs1(Delta B/DeltaB)) with a Rad54 null mutation, which diminishes homologous recombination. Double mutant cells were particularly sensitive to treatments that cause single strand breaks (SSBs), presumably because these SSBs can be converted into detrimental DSBs upon passage of a replication fork. The persistent presence of nuclear RAD51 foci and increased levels of chromatid type breaks in metaphase spreads indicated that replication-associated DSBs are repaired inefficiently in the double mutant cells. We conclude that Nbs1 and Rad54 function cooperatively, but in separate pathways to counteract this type of DNA damage and discuss mechanistic implications of these findings. PMID- 19782651 TI - Bioanalytical method development and validation using incurred samples- simultaneous quantitation of ramipril and ramiprilat in human EDTA plasma by LC MS/MS. AB - A new method development and validation approach is proposed in order to develop a reliable method for the simultaneous quantitation of ramipril and ramiprilat in the presence of numerous labile metabolites. This new approach involves the usage of a synthesized labile acyl glucuronide of ramipril as well as individual and pooled incurred (study) samples in the development and validation process. Following the method validation and prior to its application to a large clinical study, a mini pilot study was performed to evaluate the performance of the method. When the samples from the mini pilot study were analyzed by two different scientists, 100% of the results from incurred sample reanalysis (ISR) matched within 8% of difference and the mean differences were 0.21% and 1.40% for ramipril and ramiprilat, respectively. The validated concentration range reported in this article is 0.2-80 ng/mL for both analytes. Various stabilities, such as bench-top, autosampler, freeze/thaw, and long-term, were also successfully evaluated. The key to the success were low sample processing temperature (4 degrees C), proper choice of sample extraction procedure, and adequate chromatographic conditions to obtain good peak shape without the need of derivatization and baseline separation between the analytes and their glucuronide metabolites. PMID- 19782652 TI - Characterization of Leishmania (Leishmania) tropica axenic amastigotes. AB - Optimum conditions for generating Leishmania (Leishmania) tropica axenic amastigotes (AxA) in culture were determined, pH 5.5/36 degrees C, and the parasites characterized by different techniques, including light microscopy, macrophage infection, stage specific antigen expression and differential display. AxA were morphologically similar to amastigotes and 15.5-fold more infective than stationary phase promastigotes for mouse peritoneal macrophages. Western blotting with promastigote stage specific monoclonal antibodies to either lipophosphoglycan (T2) or a 60 kDa flagella antigen (F3) showed a dramatic decrease in antigen expression when AxA were compared to promastigotes. Similarly F3 gave strong immune fluorescent staining of the promastigote flagellum, but no fluorescence was detected when AxA were examined. Conversely, Western blotting with the amastigote specific monoclonal antibody (T16) showed that this antigen is more highly expressed in AxA than promastigotes. Differential display-PCR was used to identify several parasite genes showing stage specific expression. One gene selectively expressed by AxA was partially sequenced and identified as Leishmania (L.) tropicaamastin. Amastigote specific expression of this gene was further confirmed by reverse transcriptase-PCR (RT-PCR) using AxA and infected macrophages. No amastin expression was observed with promastigotes. Expression of the cysteine protease B (cpb) and protein kinase A catalytic isoform 1 subunit (pkac1) in promastigotes and AxA was also examined by RT-PCR. Pkac1 was strongly expressed by promastigotes, while cpb expression was only seen with AxA or infected macrophages. L. (L.) tropica AxA will prove useful for further studies on parasite differentiation and gene regulation, as well as for drug screening. PMID- 19782653 TI - Enhanced detection of staphylococcal genomes in positive blood cultures using a polymeric enzyme complex. AB - This article describes a simple and inexpensive signal amplification method, termed polymeric enzyme detection (PED), which permits rapid and sensitive detection of conserved sequences in the tuf gene that identify Staphylococcus genus, conserved sequences in the femB gene that specifically detect Staphylococcus aureus species, and the methicillin resistance gene mecA directly from positive blood culture bottles. Microbe-specific capture probes were immobilized onto microtiter plates or silicon chips. Target sequences and biotin labeled, target-specific probes were hybridized to complementary capture probes to create a biotin-labeled, surface-immobilized tripartite complex. In a two-step process, signal was amplified by incubating the surface-immobilized biotin with streptavidin followed by the addition of a 500-kDa dextran polymer conjugated with approximately 80 biotins. Signal was then developed by binding of a streptavidin-horseradish peroxidase conjugate followed by incubation with the substrate tetramethylbenzidine. Use of the PED method improved the lower limit of detection 10- to 100-fold in model DNA hybridization assays with limits of detection as low as 1 fmol/L target DNA. This level of sensitivity permits detection of genomic DNA from methicillin-resistant S. aureus positive blood cultures within 25 to 35 min using either a thin film biosensor chip or a microtiter plate-based assay. PMID- 19782654 TI - Keeping the intracellular vitamin C at a physiologically relevant level in endothelial cell culture. AB - It is generally accepted that the addition of vitamin C to cell culture medium improves cell growth. However, once added, the vitamin C concentration declines rapidly. This situation differs from the in vivo environment where the endothelium is constantly supplied with ascorbate from the blood. With a focus on intracellular vitamin C, we simulated constant supply of ascorbate by the hourly addition of freshly prepared medium containing 75 microM ascorbate and subsequently compared it with more practical regimens using combinations of ascorbate and 2-phosphoascorbate. We found that a single supplement of ascorbate and 2-phosphoascorbate adequately maintains intracellular vitamin C at physiological levels for up to 72 h. PMID- 19782655 TI - Cytotoxicity, cellular uptake, glutathione and DNA interactions of an antitumor large-ring Pt II chelate complex incorporating the cis-1,4-diaminocyclohexane carrier ligand. AB - Earlier studies have described promising antitumor activity of a large-ring chelate complex [PtCl(2)(cis-1,4-DACH)] (DACH=diaminocyclohexane). Encouraging antitumor activity of this analogue of cisplatin prompted us to perform studies focused on the mechanistic basis of pharmacological effects of this complex. Four early steps in the mechanism of biological activity of cisplatin have been delineated: cell entry, reactions with sulfur-containing compounds, platinum-DNA binding along with processing platinated DNA by proteins (enzymes) and DNA repair. Here, we describe comparative experiments (involving also cisplatin) revealing: (i) improved cytotoxicity (3.4-5.4-fold) of [PtCl(2)(cis-1,4-DACH)] in human tumor ovarian cell lines; (ii) enhanced cellular uptake (approximately 1.5 fold) of [PtCl(2)(cis-1,4-DACH)]; (iii) somewhat enhanced rate of reactions of [PtCl(2)(cis-1,4-DACH)] with glutathione (approximately 1.5-fold), but a similar rate of reactions with metallothionenin-2; (iv) enhanced rate of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media (approximately 2-fold); (v) similar sequence preference of DNA binding of [PtCl(2)(cis-1,4-DACH)] in cell-free media; (vi) identical DNA interstrand cross-linking efficiency (6%); (vii) similar bending (32 degrees) and enhanced local unwinding (approximately 1.5-fold) induced in DNA by the major 1,2-GG-intrastrand cross-link; (viii) markedly enhanced inhibiting effects of DNA adducts of [PtCl(2)(cis-1,4-DACH)] on processivity of DNA polymerase; and (ix) a slightly lower efficiency of DNA repair systems to remove the adducts of [PtCl(2)(cis-1,4-DACH)] from DNA. PMID- 19782656 TI - Human DEAD-box protein 3 has multiple functions in gene regulation and cell cycle control and is a prime target for viral manipulation. AB - The human DEAD-box RNA helicase DDX3 has been implicated to play a role in the whole repertoire of processes regulating gene expression, including transcription, splicing, mRNA export and translation. It has also been suggested to be involved in cell cycle control and the regulation of apoptosis. In addition, DDX3 was recently shown to be part of innate immune signalling pathways and to contribute to the induction of anti-viral mediators, such as type I interferon. Interestingly, DDX3 appears to be a prime target for viral manipulation: at least four different viruses, namely Hepatitis C virus (HCV), Hepatitis B virus (HBV), Human Immunodeficiency Virus (HIV) and poxviruses, encode proteins that interact with DDX3 and modulate its function. HIV and HCV seem to co-opt DDX3 and require it for their replication. It has therefore been suggested that DDX3 could be a novel target for the development of drugs against these two viruses, both of which still pose major global health threats. However, in the light of the apparent multifunctionality of DDX3 in the cell, drug development strategies targeting DDX3 will have to be carefully evaluated. This review summarises the available data on the cellular functions of DDX3 and discusses their manipulation by the different viruses known to target DDX3. Understanding the viral strategies for manipulating or co-opting DDX3 in functional and molecular detail can provide valuable insights for the development of strategies to therapeutically target DDX3. PMID- 19782657 TI - Functional near-infrared spectroscopy to investigate hemodynamic responses to deception in the prefrontal cortex. AB - Deception involves complex neural processes and correlates in the brain. Functional brain imaging techniques have been used to study and understand brain mechanisms during deception. In this study, we utilized functional near-infrared spectroscopy (fNIRS) to investigate hemodynamic responses to deception in the prefrontal cortex (PFC) at the individual level. The protocol involved a mock theft scenario that was previously used in a functional MRI (fMRI) study of detecting deception. Subjects (N=11) were instructed to steal a ring or a watch and then conceal the item that they stole. Participants then responded to visually presented questions regarding which item they took. While the subjects were answering the questions, their PFC activity was measured using fNIRS. The brain activity associated with deceptive responses demonstrated significant changes in hemoglobin concentrations with respect to the baseline, while the response of truth telling was not statistically different from baseline. The regions of greater activation induced by deception identified by fNIRS were approximately consistent with those reported by the previous fMRI study using a similar protocol. This study demonstrates that fNIRS is a promising new technique to understand hemodynamic and neural correlates of deception and thus to detect deception with the added advantages of being compact, technically easier to implement, and inexpensive compared to functional MRI. PMID- 19782658 TI - The nociceptin system and hippocampal cognition in mice: a pharmacological and genetic analysis. AB - This study examines the effects of NOP agonists nociceptin/orphanin FQ (N/OFQ) and Ro 64-6198, NOP antagonists [Nphe(1)]N/OFQ(1-13)-NH(2) Nphe(1) and naloxone benzoylhydrazone (NalBzoH) on spatial memory in NMRI mice and pronociceptin (proNC) knockout (KO) mice using the water maze task. N/OFQ, administered i.c.v. (1, 5 and 10 nmol/mouse) and into hippocampal CA3 (1 nmol/mouse, bilaterally), impaired acquisition and retention in the maze. Impairments were blocked by pre treatment with Nphe(1) (10 nmol, i.c.v.). Ro 64-6198 (0.1-0.3-1 mg/kg i.p.) also dose-dependently impaired learning. However, pre-treatment with NalBzoH (1 mg/kg, s.c.) failed to modify the effects of Ro 64-6198. Nphe(1) (10 nmol/mouse i.c.v.) and NalBzoH (1 mg/kg, s.c.) by themselves failed to affect maze performance, despite a tendency for enhanced performance. Prepro N/OFQ knockout (ppN/OFQ -/-) showed evidence of improved learning, evident at retention trials and in reversal training. ppN/OFQ -/- mice were not impaired by N/OFQ (10 nmol i.c.v.) in the task, suggesting that changes in postsynaptic NOP receptors may occur in such KO mice. It is concluded that N/OFQ and NOP receptors have an important role in hippocampus-dependent spatial learning and memory, probably by modulation of glutamatergic functions. PMID- 19782659 TI - Damage to the central amygdala produces differential encephalic c-fos expression in the water deprivation-partial rehydration protocol. AB - We investigated the effects of electrolytic damage to the central nucleus of the amygdala on brain c-fos expression and 0.3 M NaCl intake of adult male rats (n = 6-12/group) submitted to a cycle of 36 h of water deprivation (WD) followed by 2 h water intake until satiety or partial rehydration (PR). The groups were divided into sham lesion (CEAs), bilateral lesion of the CEA (CEAX) and misplaced lesion with intact CEA (CEAm). The WD-PR produced a marked increase in c-fos expression in the medial parabrachial nucleus (MPBN) and some increase in the parvocelullar portion of the hypothalamic paraventricular nucleus (PVNp), compared to respective hydrated control (no water deprivation) state in CEAX, but not in CEAs or CEAm. The WD-PR induced similar c-fos expression in the lamina terminalis, supraoptic nucleus, magnocellular PVN and lateral parabrachial nucleus in both CEAX and CEAs. The CEAX showed the typical reduced daily need-free 0.3 M NaCl intake compared to CEAs. However, the 0.3 M NaCl intake of CEAX, unexpectedly, was not significantly different from CEAs or intact rats in the sodium appetite test that followed a cycle of WD-PR. The results do not allow associating the alterations in c-fos expression to the typical inhibition of sodium appetite well known in the literature to be produced by damage to the CEA. Nevertheless, the enhanced cell activation in the MPBN and PVNp suggests an inhibitory role for the CEA on the activity of these nuclei when water-deprived rats have quenched their thirst. PMID- 19782660 TI - Activity of prolidase isoenzymes in the rat brain: subcellular and regional distribution during development. AB - Prolidase deficiency is characterized by chronic ulcerative dermatitis, mental retardation, and frequent infections. In the present study we examined the characteristics of rat brain prolidase isoenzymes. Prolidase isoenzymes (PD I and PD II) were isolated from the rat brain using DEAE cellulose column chromatography. PD I showed higher activity against seryl-proline and alanyl proline, while PD II was particularly active against methionyl-proline. Prolidase activity in the whole brain and in the different brain regions showed higher activity against methionyl-proline and seryl-proline. PD II activity was highest in the hippocampus, followed by the cerebellum, cerebral cortex, caudatum, and the midbrain. The most rapid changes in the activities of PD I and PD II occurred perinatally, with a peak at three days before birth and a nadir at two days after birth, which then gradually increased until 21 days. N-benzyloxycarbonyl-l proline inhibited PD I activity against various substrates in a dose-dependent manner. In contrast, there was no inhibition of PD II activity against methionyl proline at low concentrations. In summary, these data suggest that maintenance of levels of proline, other amino acids and peptides containing proline in the rat brain is regulated by prolidase isoenzymes. The age-related alterations in PD I and PD II also may help to elucidate the fundation of prolidase isoenzymes in brain nervous system. PMID- 19782661 TI - Serotonin 2C receptor signaling in a diffuse neuronal network is necessary for LPS anorexia. AB - LPS, a potent activator of the innate immune system, is commonly used to investigate the acute phase response to infection, including anorexia. Serotonin 2C-receptor signaling has been shown to be involved in the mediation of LPS anorexia. Here we used the selective, potent and brain-penetrant serotonin 2C receptor antagonist SB 242084 to identify the brain sites involved in LPS anorexia. Male Long-Evans rats received 1 ml/kg intraperitoneal injections of 0 or 0.3 mg/kg SB 242084 and intraperitoneal injections of 0 or 100 microg/kg LPS 1 h later, at dark onset. Food intake was measured in one set of rats and c-Fos immunoreactivity in another, unfed, group 90 min after LPS injection. SB 242084 markedly attenuated the LPS-induced reduction in food intake, with no anorexia evident for the first 2 h after LPS. SB 242084 also completely blocked the LPS induced increases in c-Fos expression in the paraventricular nucleus, central nucleus of the amygdala, nucleus tractus solitarii, median raphe nucleus and dorsal raphe nucleus and partially blocked it in the A1 noradrenergic area of the ventrolateral medulla and the raphe pallidus nucleus. SB 242084 did not significantly alter the c-Fos response in the arcuate nucleus or the raphe magnus nucleus. These data indicate that 2C receptor signaling activates a diffuse neural network, presumably mediating anorexia and other responses to LPS; they also suggest that the arcuate and the raphe magnus neurons that express c-Fos after LPS are not necessary for LPS anorexia. PMID- 19782662 TI - A possible role of neuropeptide Y in depression and stress. AB - Neuropeptide Y (NPY) mediates its physiological effects through at least four receptors known as Y(1), Y(2), Y(4), and Y(5). This peptide is one of the most abundant peptides in the central nervous system and is highly conserved throughout evolution. The most abundant receptors of the NPY family, the Y(1) and Y(2) receptors, are densely expressed in the cortex, hippocampus, and amygdala. These brain regions are particularly associated with mood disorders, stress responses, and memory processing. With this in mind, researchers suggested the involvement of NPY as well as the Y(1) and Y(2) receptors in affective disorders. Earlier studies showed that NPY and the Y(1) and Y(2) receptors mediate some aspects of depression-like disorders and stress responses in rodents. Recent research also suggests the involvement of the Y(4) and Y(5) receptors in emotion related processes in rodents. In addition, human studies have consistently suggested a role for NPY in stress responses, whereas conflicting data have been obtained in relation to the role of NPY in depression-related illnesses. However, novel evidence from polymorphisms in the prepro-NPY gene has shed new light on the potential clinical relevance of NPY in depression. In this article, we review the literature from both animal and human studies regarding the contribution of NPY and its receptors in depression and stress. PMID- 19782663 TI - Allopregnanolone effects on astrogliosis induced by hypoxia in organotypic cultures of striatum, hippocampus, and neocortex. AB - Perinatal asphyxia occurs in approximately 0.3% full-term newborn babies, and this percentage has not decreased despite medical advances. There are now evidences indicating that neurosteroids are important in neurodevelopment showing neuroprotective effects. We studied the potential protective effect of allopregnanolone (Allo) in vitro using organotypic cultures from neocortex, striatum, and hippocampus. Immunocytochemistry and confocal microscopy showed an increase of the glial fibrillary acidic protein (GFAP) signal in the studied brain areas after hypoxia. Western blot studies supported these results (hippocampus, 193%; neocortex, 306%; and striatum, 231%). Twenty-four-hour pretreatment with Allo showed different effects at the brain areas studied. In the hippocampus and the neocortex, 24-h pretreatment with Allo 5x10(-6) M showed to be neuroprotective as there was a significant decrease of the GFAP signal compared to control cultures exposed to hypoxia. Pretreatment with 5x10(-8) M Allo attenuated the astrogliosis response in the hippocampus and the neocortex in a nonsignificant way. Allo pretreatment at all doses did not show to affect the astrogliosis triggered by hypoxia in the striatum. Cell survival was analyzed by measuring LDH. After 1 h of hypoxia, all cultures showed a nonsignificant increase of LDH, which was greater after 24 h of hypoxia (hippocampus, 180%; striatum-cortex co-cultures, 140%). LDH levels have no changes by Allo pretreatment before hypoxia. CONCLUSION: 24 h pretreatment with 5x10(-6) M of Allo does not change neuronal viability but it prevents astrogliosis induced by hypoxia in the hippocampus and the neocortex. PMID- 19782664 TI - Inhibitory effects of somatostatin on the substantia gelatinosa neurons of trigeminal subnucleus caudalis via somatostatin type 2 receptors in juvenile mice. AB - The substantia gelatinosa (SG) of the trigeminal subnucleus caudalis (Vc) receives many thin-myelinated Adelta-fiber and unmyelinated C primary afferent fibers and has been implicated in the processing of nociceptive information. Somatostatin (SST) is a neuromodulator in the brain and spinal cord. A number of studies have demonstrated that SST can play a key role in pain modulation at the spinal cord level. However, there is little information available on functional SST receptor expression in the SG neurons of the Vc in mice. This study examined the direct membrane effects of SST and SST receptor type 2 agonist, seglitide (SEG) on the SG neurons of Vc in gramicidin perforated current clamp mode. In addition, SSTR2 mRNA expression was detected on the SG neurons using single cell RT-PCR in juvenile mice. Most SG neurons (37/68, 54%) were hyperpolarized after a bath application of SST. When SST was applied in stages, the second responses (83% of the first response) were less intense than those after the first application suggesting that SSTRs are desensitized by repeated application. The SST-induced hyperpolarizing response was maintained in the presence of TTX (Na(+) channel blocker), AP-5 (NMDA receptor antagonist), CNQX (non-NMDA glutamate receptor antagonist), picrotoxin (GABA(A) receptor antagonist) and strychnine (glycine receptor antagonist), respectively, suggesting that SST has direct effects on the postsynaptic SG neurons. SSTR2 mRNA was detected in 11 out of 28 (39%) SG neurons tested. The SST-induced hyperpolarizing effects were mimicked by SEG, a SSTR2 agonist. These results suggest that functional SSTR2 receptors are expressed on the SG neurons of Vc in juvenile mice and can be a potential target for modulating orofacial pain. PMID- 19782665 TI - Carbogen inhalation increases oxygen transport to hypoperfused brain tissue in patients with occlusive carotid artery disease: increased oxygen transport to hypoperfused brain. AB - Hyperoxic therapy for cerebral ischemia reduces cerebral blood flow (CBF) principally from the vasoconstrictive effect of oxygen on cerebral arterioles. Based on a recent study in normal volunteers, we now claim that the vasodilatory effect of carbon dioxide predominates when 5% CO(2) is added to inhaled oxygen (the mixture known as carbogen). In the present study, we measured CBF by positron emission tomography (PET) during inhalation of test gases (O(2), carbogen, and atmospheric air) in healthy volunteers (n = 10) and in patients with occlusive carotid artery disease (n = 6). Statistical comparisons by an additive ANOVA model showed that carbogen significantly increased CBF by 7.51 + or - 1.62 ml/100 g/min while oxygen tended to reduce it by -3.22 + or - 1.62 ml/100 g/min. A separate analysis of the hemisphere contralateral to the hypoperfused hemisphere showed that carbogen significantly increased CBF by 8.90 + or - 2.81 ml/100 g/min whereas oxygen inhalation produced no reliable change in CBF (-1.15 + or - 2.81 ml/100 g/min). In both patients and controls, carbogen was as efficient as oxygen in increasing Sa(O2) or PaO(2) values. The study demonstrates that concomitant increases of CBF and Sa(O2) are readily obtained with carbogen, while oxygen increases only Sa(O2). Thus, carbogen improves oxygen transport to brain tissue more efficiently than oxygen alone. Further studies with more subjects are, however, needed to investigate the applicability of carbogen for long-term inhalation and to assess its therapeutic benefits in acute stroke patients. PMID- 19782666 TI - The expression and significance of HIF-1alpha and GLUT-3 in glioma. AB - HIF-1alpha plays an indispensable role in tumor formation and histogenesis. Target genes involved in glucose transport are acutely transactivated by HIF 1alpha. GLUT-3 protein is the rate-limiting factor related to glucose transport, which is classified as brain-type glucose transporter. This study was the initial one aiming to probe into the co-expression and clinical significance of HIF 1alpha and GLUT-3 in glioma. One hundred and twenty cases of glioma tissues and ten human normal cerebral tissues decompressed in glioma excision were examined using immunohistochemistry and Western blot. The expression of HIF-1alpha and GLUT-3 increased gradually with the increase of pathological grade of glioma, respectively. There was significant difference in the expression of HIF-1alpha and GLUT-3 in every two groups, respectively. There was a positive correlation between HIF-1alpha and GLUT-3. In conclusion, the expression of HIF-1alpha and GLUT-3 in glioma was correlated significantly with tumors' pathological grade, which can be taken as a pair of useful markers for predicting the biological behavior of glioma. PMID- 19782667 TI - Frontoparietal activity and its structural connectivity in binocular rivalry. AB - To understand the brain areas associated with visual awareness and their anatomical interconnections, we studied binocular rivalry with functional magnetic resonance imaging (fMRI) and diffusion tensor imaging (DTI). Binocular rivalry occurs when one image is viewed by one eye and a different image by the other; it is experienced as perceptual alternations between the two images. Our first experiment addressed problems with a popular comparison condition, namely permanent suppression, by comparing rivalry with binocular fusion instead. We found an increased fMRI signal in right frontal, parietal, and occipital regions during rivalry viewing. The pattern of neural activity differed from findings of permanent suppression comparisons, except for adjacent activity in the right superior parietal lobule. This location was near fMRI signal changes related to reported rivalry alternations in our second experiment, indicating that neighbouring areas in the right parietal cortex may be involved in different components of rivalry. In our second experiment, we used probabilistic tractography to detect white matter fibres between right-hemispheric areas that showed event-related fMRI signal changes time-locked to reported perceptual alternations during rivalry viewing. Most of these functionally defined areas were linked by probabilistic fibre tracts, some of which followed long-distance connections such as the inferior occipitofrontal fasciculus. Corresponding anatomical pathways might mediate communication within the functional network associated with changes in conscious perception during binocular rivalry. PMID- 19782668 TI - EEG study of the mirror neuron system in children with high functioning autism. AB - Individuals with Autism Spectrum Disorder (ASD) are characterised by an impaired imitation, thought to be critical for early affective, social and communicative development. One neurological system proposed to underlie this function is the mirror neuron system (MNS) and previous research has suggested a dysfunctional MNS in ASD. The EEG mu frequency, more precisely the reduction of the mu power, is considered to be an index for mirror neuron functioning. In this work, EEG registrations are used to evaluate the mirror neuron functioning of twenty children with high functioning autism (HFA) between 8 and 13 years. Their mu suppression to self-executed and observed movement is compared to typically developing peers and related to age, intelligence and symptom severity. Both groups show significant mu suppression to both self and observed hand movements. No group differences are found in either condition. These results do not support the hypothesis that HFA is associated with a dysfunctional MNS. The discrepancy with previous research is discussed in light of the heterogeneity of the ASD population. PMID- 19782669 TI - Dynamics of caspase-3-mediated apoptosis during spinal cord regeneration in the teleost fish, Apteronotus leptorhynchus. AB - In contrast to mammals, adult teleost fish exhibit a vast potential for central nervous system regeneration after injury. Among other mechanisms, this capacity is mediated by replacement of cells lost to injury by new neurons and glia. Here, we examined the spatio-temporal dynamics of apoptosis, and its relationship to the generation and the differentiation of new cells, during this cell replacement phase. As an experimental paradigm, caudal transection of the spinal cord in the teleost fish Apteronotus leptorhynchus was used. During the cell replacement phase, there was a rather constant percentage of new cells (identified by incorporation of 5-bromo-2'-deoxyuridine into newly synthesized DNA) that underwent apoptosis (identified by anti-active caspase-3 immunolabeling). Many of these cells were also immunopositive for the marker proteins Hu C/D or glial fibrillary acidic protein, indicating that a large portion of cells undergo apoptosis after differentiation into neurons or glia, respectively. The spatial distribution of apoptotic cells was uneven, displaying a radial peak in the mid parenchymal regions and a longitudinal peak at the site of the initial spinal transection. The latter persisted for over 100 days post-injury, indicating possible problems in the integration of new cells at the interface between the old, intact tissue and the regenerated portion of the spinal cord. Taken together, the results of the present study are consistent with the hypothesis that apoptosis plays a role in the development of the new tissue during the cell replacement phase of the regenerating teleostean spinal cord. PMID- 19782670 TI - Down-regulation of dicer expression in ovarian cancer tissues. AB - OBJECTIVES: Although numerous recent studies have focused on analyses of microRNA expression profiles in cancer cells, the expression patterns of the enzymes responsible for the generation of miRNAs remains largely unexplored. The purpose of this study was to investigate whether Dicer mRNA expression is altered during progression of ovarian cancer. DESIGN AND METHODS: Total RNA was extracted from ovarian tissue specimens (normal, benign and malignant tumors). The expression of Dicer was analyzed by semi-quantitative RT-PCR. RESULTS: We analyzed a total of 34 ovarian tissue samples and found that Dicer mRNA expression is down-regulated in the majority of ovarian tumors when compared to normal tissues. CONCLUSIONS: Our results suggest that the levels of Dicer mRNA should be evaluated as a potential new candidate biomarker for ovarian cancer. PMID- 19782671 TI - Epidermal expression of Hox1 is directly activated by retinoic acid in the Ciona intestinalis embryo. AB - Hox genes play important roles in the specification of spatial identity during development of vertebrate embryos. Retinoic acid regulates the transcription of Hox genes in vertebrates. We identified an epidermal enhancer in the 5' flanking region of an ortholog of Hox1 (Ci-Hox1) in the ascidian Ciona intestinalis. This enhancer element drives the transcription of a lacZ reporter gene in the epidermis in the posterior trunk and the anterior tail region of tailbud-stage embryos. Inhibition of retinoic acid synthesis resulted in inactivation of the expression of the reporter gene. The enhancer contains a putative retinoic acid response element. When this element was mutagenized, the expression of the reporter gene disappeared from the epidermis. This sequence was also required for the response to exogenously administered retinoic acid. A heterodimeric nuclear receptor, consisting of the retinoic acid receptor and retinoid X receptor, bound to this sequence. These results indicate that retinoic acid directly activates the epidermal enhancer of Ci-Hox1. This is the first demonstration that retinoic acid is necessary for endogenous gene expression in ascidian embryos. PMID- 19782672 TI - Cis-regulation and chromosomal rearrangement of the fgf8 locus after the teleost/tetrapod split. AB - The complex expression pattern of fibroblast growth factor 8 (Fgf8) and the cellular responses dependent on concentration of its mRNA in vertebrates suggest that Fgf8 should be tightly controlled at the transcriptional level. We found zebrafish conserved noncoding elements (CNEs) with pan-vertebrate as well as fish specific orthologous sequences from across 200 kb of the zebrafish fgf8a genomic regulatory block to direct reporter expression in patterns consistent with the expression pattern of fgf8a. These included elements from inside the introns of the skin-specific slc2a15a and the ubiquitously expressed fbxw4 bystander genes. The fgf8a/fbxw4 gene pair, which has remained joined throughout three whole genome duplications in chordate evolution, is inverted in teleost genomes, but CNEs across both evolutionary breakpoints showed specific activity. While some CNEs directed highly reproducible expression patterns, others were subject to variation but showed, in a subset of transgenes, expression in the apical ectodermal ridge, the anterior boundaries of somites and the midbrain-hindbrain boundary, specific Fgf8 signaling domains, suggesting that their activity may be context specific. A human element with tetrapod-specific orthologous sequences directed reporter expression to the vasculature, possibly corresponding to a tetrapod innovation. We conclude that fgf8a transcriptional regulation employs pan-vertebrate and teleost-specific enhancers dispersed over three genes in the zebrafish genome. PMID- 19782673 TI - Signaling integration in the rugae growth zone directs sequential SHH signaling center formation during the rostral outgrowth of the palate. AB - Evolution of facial morphology arises from variation in the activity of developmental regulatory networks that guide the formation of specific craniofacial elements. Importantly, the acquisition of novel morphology must be integrated with a phylogenetically inherited developmental program. We have identified a unique region of the secondary palate associated with the periodic formation of rugae during the rostral outgrowth of the face. Rugae function as SHH signaling centers to pattern the elongating palatal shelves. We have found that a network of signaling genes and transcription factors is spatially organized relative to palatal rugae. Additionally, the first formed ruga is strategically positioned at the presumptive junction of the future hard and soft palate that defines anterior-posterior differences in regional growth, mesenchymal gene expression, and cell fate. We propose a molecular circuit integrating FGF and BMP signaling to control proliferation and differentiation during the sequential formation of rugae and inter-rugae domains in the palatal epithelium. The loss of p63 and Sostdc1 expression and failed rugae differentiation highlight that coordinated epithelial-mesenchymal signaling is lost in the Fgf10 mutant palate. Our results establish a genetic program that reiteratively organizes signaling domains to coordinate the growth of the secondary palate with the elongating midfacial complex. PMID- 19782675 TI - A diverse and intricate signalling network regulates stem cell fate in the shoot apical meristem. AB - At the shoot apex of plants is a small region known as the shoot apical meristem (SAM) that maintains a population of undifferentiated (stem) cells whilst providing cells for developing lateral organs and the stem. All aerial structures of the plant develop from the SAM post-embryogenesis, enabling plants to grow in a characteristic modular fashion with great phenotypic and developmental plasticity throughout their lifetime. The maintenance of the stem cell population is intimately balanced with cell recruitment into differentiating tissues through intercellular communication involving a complex signalling network. Recent studies have shown that diverse regulators function in SAM maintenance, many of which converge on the WUSCHEL (WUS) gene. In this review the diverse regulatory modules that function in SAM maintenance are discussed: transcriptional and epigenetic control, hormonal regulation, and the balance with organogenesis. The central role of WUS as an integrator of multiple signals is highlighted; in addition, accessory feedback loops emerge as a feature enabling dynamic regulation of the stem cell niche. PMID- 19782674 TI - Robo2 is required for Slit-mediated intraretinal axon guidance. AB - The developing optic pathway has proven one of the most informative model systems for studying mechanisms of axon guidance. The first step in this process is the directed extension of retinal ganglion cell (RGC) axons within the optic fibre layer (OFL) of the retina towards their exit point from the eye, the optic disc. Previously, we have shown that the inhibitory guidance molecules, Slit1 and Slit2, regulate two distinct aspects of intraretinal axon guidance in a region specific manner. Using knockout mice, we have found that both of these guidance activities are mediated via Robo2. Of the four vertebrate Robos, only Robo1 and Robo2 are expressed by RGCs. In mice lacking robo1 intraretinal axon guidance occurs normally. However, in mice lacking robo2 RGC axons make qualitatively and quantitatively identical intraretinal pathfinding errors to those reported previously in Slit mutants. This demonstrates clearly that, as in other regions of the optic pathway, Robo2 is the major receptor required for intraretinal axon guidance. Furthermore, the results suggest strongly that redundancy with other guidance signals rather than different receptor utilisation is the most likely explanation for the regional specificity of Slit function during intraretinal axon pathfinding. PMID- 19782676 TI - Mammalian Merkel cells are descended from the epidermal lineage. AB - Merkel cells are specialized cells in the skin that are important for proper neural encoding of light touch stimuli. Conflicting evidence suggests that these cells are lineally descended from either the skin or the neural crest. To address this question, we used epidermal (Krt14(Cre)) and neural crest (Wnt1(Cre)) Cre driver lines to conditionally delete Atoh1 specifically from the skin or neural crest lineages, respectively, of mice. Deletion of Atoh1 from the skin lineage resulted in loss of Merkel cells from all regions of the skin, while deletion from the neural crest lineage had no effect on this cell population. Thus, mammalian Merkel cells are derived from the skin lineage. PMID- 19782677 TI - On the roles of Notch, Delta, kuzbanian, and inscuteable during the development of Drosophila embryonic neuroblast lineages. AB - The generation of cellular diversity in the nervous system involves the mechanism of asymmetric cell division. Besides an array of molecules, including the Par protein cassette, a heterotrimeric G protein signalling complex, Inscuteable plays a major role in controlling asymmetric cell division, which ultimately leads to differential activation of the Notch signalling pathway and correct specification of the two daughter cells. In this context, Notch is required to be active in one sibling and inactive in the other. Here, we investigated the requirement of genes previously known to play key roles in sibling cell fate specification such as members of the Notch signalling pathway, e.g., Notch (N), Delta (Dl), and kuzbanian (kuz) and a crucial regulator of asymmetric cell division, inscuteable (insc) throughout lineage progression of 4 neuroblasts (NB1 1, MP2, NB4-2, and NB7-1). Notch-mediated cell fate specification defects were cell-autonomous and were observed in all neuroblast lineages even in cells born from late ganglion mother cells (GMC) within the lineages. We also show that Dl functions non-autonomously during NB lineage progression and clonal cells do not require Dl from within the clone. This suggests that within a NB lineage Dl is dispensable for sibling cell fate specification. Furthermore, we provide evidence that kuz is involved in sibling cell fate specification in the central nervous system. It is cell-autonomously required in the same postmitotic cells which also depend on Notch function. This indicates that KUZ is required to facilitate a functional Notch signal in the Notch-dependent cell for correct cell fate specification. Finally, we show that three neuroblast lineages (NB1-1, NB4-2, and NB7-1) require insc function for sibling cell fate specification in cells born from early GMCs whereas insc is not required in cells born from later GMCs of the same lineages. Thus, there is differential requirement for insc for cell fate specification depending on the stage of lineage progression of NBs. PMID- 19782679 TI - Inhibition of recombinant Ca(v)3.1 (alpha(1G)) T-type calcium channels by the antipsychotic drug clozapine. AB - Low voltage-activated T-type calcium channels are involved in the regulation of the neuronal excitability, and could be subject to many antipsychotic drugs. The effects of clozapine, an atypical antipsychotic drug, on recombinant Ca(v)3.1 T type calcium channels heterologously expressed in human embryonic kidney 293 cells were examined using whole-cell patch-clamp recordings. At a standard holding potential of -100 mV, clozapine inhibited Ca(v)3.1 currents with an IC(50) value of 23.7+/-1.3 microM in a use-dependent manner. However, 10 microM clozapine inhibited more than 50% of the Ca(v)3.1 currents in recordings at a more physiologically relevant holding potential of -75 mV. Clozapine caused a significant hyperpolarizing shift in the steady-state inactivation curve of the Ca(v)3.1 channels, which is presumably the main mechanism accounting for the inhibition of the Ca(v)3.1 currents. In addition, clozapine slowed Ca(v)3.1 deactivation and inactivation kinetics but not activation kinetics. Clozapine induced changes in deactivation and inactivation rates of the Ca(v)3.1 channel gating would likely facilitate calcium influx via Ca(v)3.1 T-type calcium channels. Thus, clozapine may exert its therapeutic and/or side effects by altering cell's excitability and firing properties through actions on T-type calcium channels. PMID- 19782678 TI - The involvement of lethal giant larvae and Wnt signaling in bottle cell formation in Xenopus embryos. AB - Lethal giant larvae (Lgl) plays a critical role in establishment of cell polarity in epithelial cells. While Frizzled/Dsh signaling has been implicated in the regulation of the localization and activity of Lgl, it remains unclear whether specific Wnt ligands are involved. Here we show that Wnt5a triggers the release of Lgl from the cell cortex into the cytoplasm with the concomitant decrease in Lgl stability. The observed changes in Lgl localization were independent of atypical PKC (aPKC), which is known to influence Lgl distribution. In ectodermal cells, both Wnt5a and Lgl triggered morphological and molecular changes characteristic of apical constriction, whereas depletion of their functions prevented endogenous and ectopic bottle cell formation. Furthermore, Lgl RNA partially rescued bottle cell formation in embryos injected with a dominant negative Wnt5a construct. These results suggest a molecular link between Wnt5a and Lgl that is essential for apical constriction during vertebrate gastrulation. PMID- 19782680 TI - Neuroprotective effect of 5,7,3',4',5'-pentahydroxy dihydroflavanol-3-O-(2''-O galloyl)-beta-D-glucopyranoside, a polyphenolic compound in focal cerebral ischemia in rat. AB - Ischemia/reperfusion injury ends up in the cascade of excitotoxic stimulation of superoxide and nitric oxide formation leading to the generation of highly reactive products, including peroxinitrite and hydroxyl radical, which are capable of damaging lipids, proteins and DNA. Several polyphenolic compounds scavenge the radicals and protect from injury. 5,7,3',4',5'-pentahydroxy dihdroflavanol-3-O-(2''-O-galloyl)-beta-d-glucopyranoside (AP1), a polyphenolic compound, isolated from Anogeissus pendula Edgew was tested for its neuroprotective effect in transient focal cerebral ischemia in rats. Transient focal cerebral ischemia was produced by middle cerebral artery occlusion for 2h for studying infarct volume, brain edema, apoptosis and oxidative stress. AP1 was tested for in vitro protection from glutamate and hydrogen peroxide-induced damage to Neuro-2a cells by MTT assay. It was also tested for its in vitro antioxidant, lipid peroxidation inhibition, NO scavenging and cyclooxygenase inhibitory activities. AP1 treatment (30 mg/kg i.p.) before reperfusion injury (0 h) significantly reduced the infarct volume, cerebral edema, number of apoptotic cells in penumbra and neurobehavioural abnormality score and lipid peroxidation, protein carbonyl levels and total thiols in brain. Increased catalase activity and NOx levels in ischemic animals were significantly reduced by AP1 treatment. AP1 (3 microg/ml) protected Neuro-2a cells to H2O2 and glutamate-induced damage. In in vitro studies, AP1 was found to possess reducing and NO scavenging activities. It also reduced lipid peroxidation and inhibited cyclooxygenase activity (cyclooxygenase-1 and cyclooxygenase-2). AP1 can be used as a neuroprotective agent in stroke as it reduced apoptosis and found to be a good antioxidant and anti-inflammatory compound. PMID- 19782681 TI - Differences in TRAIL-induced changes of Mcl-1 expression among distinct human colon epithelial cell lines. AB - In addition to its ability to act as a promising inducer of tumor-specific cell death, TRAIL has also been shown to stimulate signaling pathways leading to cancer cell survival. We examined the changes of anti-apoptotic Mcl-1 protein level following TRAIL treatment of human cell lines representing different stages of colon carcinogenesis-adenocarcinoma (HT-29, HCT116) or secondary metastasis (SW620), together with cell line derived from human fetal colon (FHC). While TRAIL was capable of triggering an anti-apoptotic signaling leading to significant early ERK-mediated transcriptional up-regulation of Mcl-1 in selected colon adenocarcinoma cell lines, none or very limited effects were demonstrated in cell lines derived from colon lymph node metastasis or fetal colon, respectively. We demonstrated an immediate impact of Mcl-1 protein level manipulations on the course of early acute apoptotic response of colon adenocarcinoma cells to TRAIL. It is therefore essential to consider the dynamics of modulation of Mcl-1 level and the balance between TRAIL-induced pro- and anti apoptotic pathways when predicting the response of cells in different stages of cancer development, and designing the anticancer therapy using TRAIL. PMID- 19782682 TI - Cholesterol and statins in Alzheimer's disease: current controversies. AB - Alzheimer's disease (AD) is the principal cause of dementia in older people, and accumulation of amyloid-beta (Abeta) peptide is a crucial event in AD pathogenesis. Despite opposite results found in literature, increased evidence posits that high cholesterol levels enhance the risk to develop AD. In fact, cholesterol metabolism and catabolism are affected in this neurodegenerative disorder. Since amyloid precursor protein (APP) processing and subsequent Abeta production are dependent on membrane cholesterol content and on levels of isoprenoid intermediates in the cholesterol biosynthesis pathway, changes in cholesterol might have different consequences on Abeta formation. These pieces of evidence support that inhibitors of cholesterol synthesis, like statins, could have a therapeutic role in AD. Many studies about the effect of statins use in AD show conflicting results; however, some authors explain it by the differences in administrated doses. Recent studies demonstrate that statins can efficiently decrease Abeta formation from APP and be neuroprotective against the peptide toxicity. Because of the high number of pleiotropic effects of statins, novel molecular mechanisms that account for the beneficial effect of these drugs on AD might be discovered in a near future. PMID- 19782684 TI - A new side opening on prolyl oligopeptidase revealed by electron microscopy. AB - Prolyl oligopeptidase (POP) has gained importance as a target for the treatment of neuropsychiatric diseases and cognitive disturbances. Therefore, a variety of strategies are currently used to identify POP inhibitors. Here we performed electron microscopy (EM) studies of human POP. Our data reveal for the first time the presence of a new side opening in POP that was not observed in any of the crystallographic structures described to date. Finally, molecular dynamics, the relevant normal modes that contribute to the fluctuation of the catalytic triad residues and the algorithm CAVERN also support the existence of a new large side opening on POP. PMID- 19782683 TI - Impaired hippocampal plasticity and altered neurogenesis in adult Ube3a maternal deficient mouse model for Angelman syndrome. AB - Angelman syndrome (AS) is a severe neurodevelopmental disorder characterized by mental retardation, seizures and sleep disturbances. It results from lack of the functional maternal allele of UBE3A gene. Ube3a maternal-deficient mice (Ube3a m /p+), animal models for AS, are impaired in hippocampal-dependent learning tasks as compared with control (Ube3a m+/p+) mice. We first examined the basal expression of immediate early genes which expression is required for synaptic plasticity and memory formation. We found that basal expression of c-fos and Arc genes is reduced in the DG of Ube3a maternal deficient mice compared to their non transgenic littermates. We then examined whether adult hippocampal neurogenesis, which likely serves as a mechanism toward brain plasticity, is altered in these transgenic mice. Neurogenesis occurs throughout life in mammalian dentate gyrus (DG) and recent findings suggest that newborn granule cells are involved in some forms of learning and memory. Whether maternal Ube3a deletion is detrimental on hippocampal neurogenesis is unclear. Herein, we show, using the mitotic marker Ki67, the birthdating marker 5-bromo-2'-dexoyuridine (BrdU) and the marker doublecortin (DCX) to respectively label cell proliferation, cell survival or young neuron production, that the Ube3a maternal deletion does not affect the proliferation nor the survival of newborn cells in the hippocampus. In contrast, using the postmitotic neuronal marker (NeuN), we show that Ube3a maternal deletion is associated with a lower fraction of BrdU+/NeuN+ newborn neurons among the population of surviving new cells in the hippocampus. Collectively, these findings suggest that some aspects of adult neurogenesis and plasticity are affected by Ube3a deletion and may contribute to the hippocampal dysfunction observed in AS mice. PMID- 19782685 TI - Corticosterone in migrating songbirds during endurance flight. AB - The specific role of the glucocorticoid hormone corticosterone in regulating the migratory stages of flight and refueling in free-living migrants is as yet poorly studied, because these stages are difficult to identify in the field. Night migrating songbirds provide an excellent model to investigate how corticosterone correlates with behavior and physiology because they fly during the night and rest and forage during the day. We measured baseline corticosterone and the adrenocortical response to restraint in 9 free-ranging songbird species: 3 night migrating species, 3 day-migrating species, and 3 day-migrating irruptive species. Baseline corticosterone of night migrants was higher in birds caught out of nocturnal migration than in birds resting and foraging, and on the same level as in day migrants, suggesting that a rise in circulating corticosterone may facilitate the heightened metabolic processes of active flight, in particular protein breakdown. Stress-induced corticosterone levels increased in both actively flying birds and birds resting and foraging. The increase was highest in landing birds, which are possibly most sensitive to stress when arriving at an unfamiliar place. Migratory endurance flight is thus characterized by corticosterone concentrations that are lower than those associated with acute stressful and life-threatening episodes. In addition, the responsiveness to stress increased with decreasing fat score in a night-migrating species. Corticosterone approaches therefore stressful concentrations only when fat depots are nearly depleted, possibly to promote protein catabolism and to trigger a change in behavior, i.e., a switch to landing and searching for food. PMID- 19782687 TI - Heat shock proteins contribute to mosquito dehydration tolerance. AB - This study examines the responses of heat shock protein transcripts, Hsp70 and Hsp90, to dehydration stress in three mosquito species, Aedes aegypti, Anopheles gambiae and Culex pipiens. We first defined the water balance attributes of adult females of each species, monitored expression of the hsp transcripts in response to dehydration, and then knocked down expression of the transcripts using RNA interference (RNAi) to evaluate potential functions of the Hsps in maintenance of water balance. Fully hydrated females of all three species contained nearly the same amount of water (66-68%), but water loss rates differed among the species, with A. aegypti having the lowest water loss rate (2.6%/h), followed by C. pipiens (3.3%/h), and A. gambiae (5.1%/h). In all three species water could be replaced only by drinking water (or blood). Both A. aegypti and C. pipiens tolerated a loss of 36% of their body water, but A. gambiae was more vulnerable to water loss, tolerating a loss of only 29% of its body water. Dehydration elicited expression of hsp70 in all three species, but only C. pipiens continued to express this transcript during rehydration. Hsp90 was constitutively expressed and expression levels remained fairly constant during dehydration and rehydration, except expression was not noted during rehydration of C. pipiens. Injection of dsRNA to knock down expression of hsp70 (83% reduction) and hsp90 (46% reduction) in A. aegypti did not alter water content or water loss rates, but the dehydration tolerance was lower. Instead of surviving a 36% water loss, females were able to survive only a 28% water loss in response to RNAi directed against hsp70 and a 26% water loss when RNAi was directed against hsp90. These results indicate a critical function for these Hsps in mosquito dehydration tolerance. PMID- 19782688 TI - Use of maize pollen by adult Chrysoperla carnea (Neuroptera: Chrysopidae) and fate of Cry proteins in Bt-transgenic varieties. AB - We investigated the use of maize pollen as food by adult Chrysoperla carnea under laboratory and field conditions. Exposure of the insects to insecticidal Cry proteins from Bacillus thuringiensis (Bt) contained in pollen of transgenic maize was also assessed. Female C. carnea were most abundant in a maize field when the majority of plants were flowering and fresh pollen was abundant. Field-collected females contained an average of approximately 5000 maize pollen grains in their gut at the peak of pollen shedding. Comparable numbers were found in females fed ad libitum maize pollen in the laboratory. Maize pollen is readily used by C. carnea adults. When provided with a carbohydrate source, it allowed the insects to reach their full reproductive potential. Maize pollen was digested mainly in the insect's mid- and hindgut. When Bt maize pollen passed though the gut of C. carnea, 61% of Cry1Ab (event Bt176) and 79% of Cry3Bb1 (event MON 88017) was digested. The results demonstrate that maize pollen is a suitable food source for C. carnea. Even though the pollen grains are not fully digested, the insects are exposed to transgenic insecticidal proteins that are contained in the pollen. PMID- 19782686 TI - Hormone therapy does not modify emotion-induced brain activity in older women. AB - Sex hormones have actions in brain regions important for emotion, including the amygdala and prefrontal cortex. Previous studies have shown that cyclic sex hormones and hormone therapy after menopause modify responses to emotional events. Thus, this study examined whether hormone therapy modified emotion induced brain activity in older women. Functional magnetic resonance imaging (fMRI), behavioral ratings (valence and arousal), and recognition memory were used to assess responses to emotionally laden scenes in older women currently using hormone therapy (HT) and women not currently using hormone therapy (NONE). We hypothesized that hormones would affect the amount or persistence of emotion induced brain activity in the amygdala and ventrolateral prefrontal cortex (VLPFC). However, hormone therapy did not affect brain activity with the exception that NONE women showed a modest increase over time in amygdala activity to positive scenes. Hormone therapy did not affect behavioral ratings or memory for emotional scenes. The results were similar when women were regrouped based on whether they had ever used hormone therapy versus had never used hormone therapy. These results suggest that hormone therapy does not modify emotion-induced brain activity, or its persistence, in older women. PMID- 19782689 TI - Molecular characterization of heat shock protein 90, 70 and 70 cognate cDNAs and their expression patterns during thermal stress and pupal diapause in the corn earworm. AB - Three heat shock protein transcripts, hsp90, hsp70, hsc70, isolated from the corn earworm, Helicoverpa zea, were evaluated for their responsiveness to diapause and thermal stress. These Hsps showed high homology to their counterparts in other species. A phylogenetic analysis of the Hsp90 sequence was consistent with the known classification of insects. Northern blot hybridization indicated the presence of hsp90 transcripts in all tissues, but expression in the brain subesophageal complex was especially pronounced. The genomic organization of hsp90 examined by Southern blot suggested the presence of a single copy of hsp90 in the H. zea genome. The expression patterns after heat shock indicated that hsp70 and hsp90 were heat-inducible, although hsp70 was more strongly induced than hsp90, and hsc70 was indeed a constitutively expressed member of the hsp70 family. Expression of hsp70 and hsc70 were not altered by the diapause program, but hsp90 was down-regulated at this time. Low temperatures (0-4 degrees C) and recovery from low temperature elicited hsp70 and hsp90 responses, but not an hsc70 response. Thus, unlike several other species, H. zea does not up-regulate hsp70 during pupal diapause, but the down-regulation of hsp90 is consistent with the pattern observed in several other species during diapause. Our results also indicate that hsp90 and hsp70 are responsive to low temperature in both diapausing and nondiapausing pupae. PMID- 19782690 TI - Activation of the ghrelin receptor is described by a privileged collective motion: a model for constitutive and agonist-induced activation of a sub-class A G-protein coupled receptor (GPCR). AB - Three homology models of the human ghrelin receptor (GHS-R1a) have been generated from the available X-ray structures of rhodopsin (RHO model), opsin (OPS model) and beta-2 adrenergic receptor (B2 model). The latter was used as a starting point for combined molecular dynamics simulation (MDS) and full atom normal modes analysis (NMA). A low-frequency normal mode (mode 16) perfectly reproduced the intracellular motions observed between B2 and RHO models; in the opposite direction along the same mode, the generated structures are closer to the OPS model, suggesting a direct link with GHS-R1a activation. This was in agreement with motions of the seven transmembranous segments, increase of the solvent accessibility of the 140-ERY-142 sequence, and flip of the Trp276 (C WLP) residue, some features related to GPCRs activation. According to our model, His280 was proposed to stabilize Trp276 in the active state; this was verified by site-directed mutagenesis and biochemical characterization of the resulting H280A and H280S mutants, which were fully functional but sharing an important decrease of their basal activities. Docking performed with short ghrelin derivatives Gly Ser-Ser ([octa])-Phe-NH (2) and Gly-Ser-Ser ([octa])-Phe-Leu-NH (2) allowed the identification of a robust position of these peptides in the active site of the receptor. This model was refined by MDS and validated by docking experiments performed on a set of 55 ghrelin receptor ligands based on the 1,2,4- triazole scaffold. Finally, NMA performed on the obtained peptide-receptor complex suggested stabilization of the Trp276 residue and of the whole receptor in the active state, preventing the motion observed along mode 16 computed for the unbound receptor. Our results show that NMA offers a powerful approach to study the conformational diversity and the activation mechanism of GPCRs. PMID- 19782691 TI - Are bird song complexity and song sharing shaped by habitat structure? An information theory and statistical approach. AB - In songbirds, song complexity and song sharing are features of prime importance for territorial defence and mate attraction. These aspects of song may be strongly influenced by changes in social environment caused by habitat fragmentation. We tested the hypothesis that habitat fragmentation induced by human activities influences song complexity and song sharing in the skylark, a songbird with a very large repertoire and whose population recently underwent a large decline. We applied powerful mathematical and statistical tools to assess and compare song complexity and song sharing patterns of syllables and sequences of syllables in two populations: a declining population in a fragmented habitat, in which breeding areas are separated from each other by unsuitable surroundings, and a stable population in a continuous habitat. Our results show that the structure of the habitat influences song sharing, but not song complexity. Neighbouring birds shared more syllables and sequences of syllables in the fragmented habitat than in the continuous one. Habitat fragmentation seems thus to have an effect on the composition of elements in songs, but not on the number and complexity of these elements, which may be a fixed feature of song peculiar to skylarks. PMID- 19782692 TI - Theoretical investigation of the role of the RANK-RANKL-OPG system in bone remodeling. AB - The RANK-RANKL-OPG system is an essential signaling pathway involved in bone cell cell communication, with ample evidence that modification of the RANK-RANKL-OPG signaling pathway has major effects on bone remodeling. The first focus of this paper is to demonstrate that a theoretical model of bone cell-cell interactions is capable of qualitatively reproducing changes in bone associated with RANK RANKL-OPG signaling. To do this we consider either biological experiments or bone diseases related to receptor and/or ligand deficiencies, including RANKL over expression, ablation of OPG production and/or RANK receptor modifications. The second focus is to investigate a wide range of possible therapeutic strategies for re-establishing bone homeostasis for various pathologies of the RANK-RANKL OPG pathway. These simulations indicate that bone diseases associated with the RANK-RANKL-OPG pathway are very effective in triggering bone resorption compared to bone formation. These results align with Hofbauer's "convergence hypothesis", which states that catabolic bone diseases most effectively act through the RANK RANKL-OPG system. Additionally, we demonstrate that severity of catabolic bone diseases strongly depends on how many components of this pathway are affected. Using optimization algorithms and the theoretical model, we identify a variety of successful "virtual therapies" for different disease states using both single and dual therapies. PMID- 19782693 TI - Inhibition of glycogen synthase kinase-3beta attenuates glucocorticoid-induced bone loss. AB - AIMS: Long-term glucocorticoid administration is known to induce bone deterioration. Glycogen synthase kinase-3beta (GSK-3beta) signaling reportedly participates in bone remodeling. This study investigated whether GSK-3beta inhibitor could regulate glucocorticoid-induced inhibition of osteoblast differentiation in vitro or bone mass in vivo. MAIN METHODS: MC3T3-E1 osteoblasts were treated with kinase-inactive GSK-3beta mutant and 6-bromoindirubin-3'-oxim (BIO) and then exposed to 1microM dexamethasone. Survival and osteoblast differentiation of cell cultures were assessed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end-labeling, quantitative RT-PCR, and von Kossa staining. Mineral density, biomechanical properties and microenvironments of BIO- and glucocorticoid-treated rat bone tissues were analyzed using dual-energy X-ray absorptiometry, material testing, and histomorphometry, respectively. KEY FINDINGS: Glucocorticoid decreased levels of phosphorylated Ser9-GSK-3beta and beta-catenin in osteoblast cultures. Kinase inactive GSK-3beta mutant and BIO treatments attenuated dexamethasone-induced inhibition of beta-catenin, Runx2 abundance, and osteoblast differentiation but suppressed glucocorticoid-induced apoptosis of cell cultures. Exogenous BIO treatment alleviated methylprednisolone-induced impairment of mineral density, biomechanical strength, trabecular bone volume, osteoblast surface, and bone formation rate of rat bone tissue. BIO treatment also attenuated glucocorticoid induced promotion of osteoclast surface and marrow adipocyte volume in bone tissue. Bone cells adjacent to glucocorticoid-stressed bone tissue displayed strong phosphorylated Ser9-GSK-3beta and beta-catenin immunostaining following BIO treatment. SIGNIFICANCE: Inhibition of GSK-3beta abrogated glucocorticoid induced bone loss by increasing beta-catenin- and Runx2-mediated osteoblast differentiation. Controlling GSK-3beta signaling in bone cells may be a strategy for preventing glucocorticoid-induced osteopenia. PMID- 19782694 TI - Cortical transients preceding voluntary movement. AB - The process of initiating a voluntary muscular movement evidently involves a focusing of diffuse brain activity onto a highly specific location in the primary motor cortex. Even the very simple stereotypic movements used to study the 'contingent negative variation' and the 'readiness potential' begin with EEG indicative of widely distributed brain activity. In natural settings the involvement of diffuse cortical networks is undoubtedly even more important. Eventually, however, activity must coalesce onto specific neurons for the intended movement to ensue. Here we examine that focusing process from a mathematical point of view. Using a digital simulation, we solve the global equations for cortical dynamics and model the flow from diffuse onset to localized spike. From this perspective the interplay between global and local effects is seen as a necessary consequence of a basic cortical architecture which supports wave propagation. Watching the process evolve over time allows us to estimate some characteristic amplitudes and delays. PMID- 19782695 TI - Functional brain network abnormalities during verbal working memory performance in adolescents and young adults with dyslexia. AB - Behavioral and functional neuroimaging studies indicate deficits in verbal working memory (WM) and frontoparietal dysfunction in individuals with dyslexia. Additionally, structural brain abnormalities in dyslexics suggest a dysconnectivity of brain regions associated with phonological processing. However, little is known about the functional neuroanatomy underlying cognitive dysfunction in dyslexia. In this study, functional magnetic resonance imaging and multivariate analytic techniques were used to investigate patterns of functional connectivity during a verbal WM task in individuals with dyslexia (n=12) and control subjects (n=13). Dyslexics were not significantly slower than controls; however, they were less accurate with increasing WM demand. Independent component analysis identified 18 independent components (ICs) among which two ICs were selected for further analyses. These ICs included functional networks which were positively correlated with the delay period of the activation task in both healthy controls and dyslexics. Connectivity abnormalities in dyslexics were detected within both networks of interest: within a "phonological" left lateralized prefrontal network, increased functional connectivity was found in left prefrontal and inferior parietal regions. Within an "executive" bilateral frontoparietal network, dyslexics showed a decreased connectivity pattern comprising bilateral dorsolateral prefrontal and posterior parietal regions, while increased connectivity was found in the left angular gyrus, the left hippocampal cortex and the right thalamus. The functional connectivity strength in the latter regions was associated with WM task accuracy and with the numbers of errors during a spelling test. These data suggest functional connectivity abnormalities in two spatiotemporally dissociable brain networks underlying WM dysfunction in individuals with dyslexia. PMID- 19782696 TI - Social cues, mentalizing and the neural processing of speech accompanied by gestures. AB - Body orientation and eye gaze influence how information is conveyed during face to-face communication. However, the neural pathways underpinning the comprehension of social cues in everyday interaction are not known. In this study we investigated the influence of addressing vs. non-addressing body orientation on the neural processing of speech accompanied by gestures. While in an fMRI scanner, participants viewed short video clips of an actor speaking sentences with object- (O; e.g., shape) or person-related content (P; e.g., saying goodbye) accompanied by iconic (e.g., circle) or emblematic gestures (e.g., waving), respectively. The actor's body was oriented either toward the participant (frontal, F) or toward a third person (lateral, L) not visible. For frontal vs. lateral actor orientation (F>L), we observed activation of bilateral occipital, inferior frontal, medial frontal, right anterior temporal and left parietal brain regions. Additionally, we observed activity in the occipital and anterior temporal lobes due to an interaction effect between actor orientation and content of the communication (PF>PL)>(OF>OL). Our findings indicate that social cues influence the neural processing of speech-gesture utterances. Mentalizing (the process of inferring the mental state of another individual) could be responsible for these effects. In particular, socially relevant cues seem to activate regions of the anterior temporal lobes if abstract person-related content is communicated by speech and gesture. These new findings illustrate the complexity of interpersonal communication, as our data demonstrate that multisensory information pathways interact at both perceptual and semantic levels. PMID- 19782697 TI - Thioredoxin reductase 1 ablation sensitizes colon cancer cells to methylseleninate-mediated cytotoxicity. AB - The relationship between selenium and cancer is complex because individuals with low serum selenium levels benefit from selenium supplementation, but those with high serum selenium levels are at increased risk for other diseases. This suggests that the use of selenocompounds might be limited to particular circumstances, such as adjuvant therapy. A contributor to this dichotomy may be the activity of certain selenium containing enzymes like the cytosolic thioredoxin reductase (TR1). We evaluated the cellular response to select selenocompounds that have anticancer activity when TR1 was attenuated by siRNA in RKO colon cancer cells. Methylseleninic acid (MSA), which is a substrate for TR1, enhanced cytotoxicity to colon cancer cells when TR1 was attenuated. MSA induced stress in the endoplasmic reticulum, as measured by GRP78 protein levels. However, this pathway did not appear to account for the change in cytotoxicity when TR1 was attenuated. Instead, knockdown of the cytosolic TR plus incubation with MSA increased autophagy, as measured by LC3B cleavage, and apoptosis, as measured by Annexin V and mitochondrial dysfunction. Therefore, the use of selenocompounds with anticancer activity, like MSA, might be utilized most effectively with agents that targets TR1 in chemotherapeutic applications. PMID- 19782698 TI - Transplantation of quantum dot-labelled bone marrow-derived stem cells into the vitreous of mice with laser-induced retinal injury: survival, integration and differentiation. AB - Accidental laser exposure to the eyes may result in serious visual impairment due to retina degeneration. Currently limited treatment is available for laser eye injury. In the current study, we investigated the therapeutic potential of bone marrow-derived stem cells (BMSCs) for laser-induced retinal trauma. Lineage negative bone marrow cells (Lin(-) BMCs) were labelled with quantum dots (Qdots) to track the cells in vivo. Lin(-) BMCs survived well after intravitreal injection. In vivo bromodeoxyuridine (BrdU) labelling showed these cells continued to proliferate and integrate into injured retinas. Furthermore, they expressed markers that distinguished retinal pigment epithelium (RPE), endothelium, pericytes and photoreceptors. Our results suggest that BMSCs participate in the repair of retinal lesions by differentiating into retinal cells. Intravitreal transplantation of BMSCs is a potential treatment for laser induced retinal trauma. PMID- 19782700 TI - Swine leukocyte antigen (SLA) diversity in Sinclair and Hanford swine. AB - The swine leukocyte antigen (SLA) haplotype B is associated with increased penetrance of the tumor traits in Sinclair swine cutaneous melanoma (SSCM). We established a series of SinclairxHanford swine crosses to facilitate genetic mapping of the tumor-associated loci. In this study, the SLA diversity in the founding animals was characterized for effective selection of maximum tumor penetrance in the pedigrees. Using the sequence-based typing (SBT) method we identified a total of 29 alleles at five polymorphic SLA loci (SLA-1, SLA-3, SLA 2, DRB1 and DQB1) representing six class I and five class II haplotypes. We subsequently developed a rapid PCR-based typing assay using sequence-specific primers (PCR-SSP) to efficiently follow the SLA types of the crossbred progeny. In a total of 469 animals we identified three crossovers within the class I region and three between the class I and class II regions, which corresponded to recombination frequencies of 0.39% and 0.56%, respectively. We also confirmed the presence of two expressed SLA-1 loci in three of the class I haplotypes and were able to determine the relative chromosomal arrangement of the duplicated loci in two haplotypes. This study furthers our understanding of the allelic architecture and polymorphism of the SLA system and will facilitate the mapping of loci associated with the expression of SSCM. PMID- 19782699 TI - Alterations in microRNA expression in stress-induced cellular senescence. AB - We investigated miRNA expression changes associated with stress-induced premature senescence (SIPS) in primary cultures of human diploid fibroblast (HDF) and human trabecular meshwork (HTM) cells. Twenty-five miRNAs were identified by miRNA microarray analysis and their changes in expression were validated by TaqMan real time RT-PCR in three independent cell lines of HTM and HDF. SIPS in both HTM and HDF cell types was associated with significant down-regulation of four members of the miR-15 family and five miRNAs of the miR-106b family located in the oncogenic clusters miR-17-92, miR-106a-363, and miR-106b-25. SIPS was also associated with up-regulation of two miRNAs (182 and 183) from the miR-183-96-182 cluster. Transfection with miR-106a agomir inhibited the up-regulation of p21(CDKN1A) associated with SIPS while transfection with miR-106a antagomir led to increased p21(CDKN1A) expression in senescent cells. In addition, we identified retinoic acid receptor gamma (RARG) as a target of miR-182 and showed that this protein was down-regulated during SIPS in HDF and HTM cells. These results suggest that changes in miRNA expression might contribute to phenotypic alterations of senescent cells by modulating the expression of key regulatory proteins such as p21(CDKN1A) as well as by targeting genes that are down-regulated in senescent cells such as RARG. PMID- 19782701 TI - Cloning and characterisation of the chicken orthologue of dendritic cell lysosomal associated membrane protein (DC-LAMP). AB - A cDNA encoding the chicken orthologue of dendritic cell-lysosomal associated membrane protein (DC-LAMP)/CD208 was cloned by RT-PCR from RNA isolated from mature chicken bone marrow-derived dendritic cells (chBM-DCs). The cloned chicken DC-LAMP (chDC-LAMP) cDNA consists of 1281 nucleotides encoding an open reading frame of 426 amino acids (aa). Comparison of the deduced aa sequence of DC-LAMP with orthologous proteins from human and mouse revealed 27 and 24% identity, respectively. The predicted chDC-LAMP protein shares the characteristic features of LAMP family members. ChDC-LAMP mRNA, unlike its mammalian orthologues, was expressed in a wide range of tissues, at highest levels in the lung. Lymphoid tissues including thymus, spleen, bursa, ceacal tonsil and Meckel's diverticulum had high chDC-LAMP mRNA expression levels. ChDC-LAMP mRNA was expressed in all splenocyte subsets with the highest expression in Bu-1(+) B cells and KUL01(+) cells, which would include macrophages and DC. ChDC-LAMP mRNA was highly expressed in chBM-DC, whereas expression levels in chicken monocyte-derived macrophages (chMo-Mac) and the HD11 macrophage cell line were significantly lower. Following CD40L stimulation, chDC-LAMP mRNA expression levels were up regulated in mature chBM-DC, chMo-Mac and HD11 cells whereas lipopolysaccharide (LPS) only up-regulated chDC-LAMP mRNA expression levels in chBM-DC. ChDC-LAMP is not solely expressed on chicken DC but can be used as a marker to differentiate between immature and mature DC. PMID- 19782702 TI - Mild steel welding fume causes manganese accumulation and subtle neuroinflammatory changes but not overt neuronal damage in discrete brain regions of rats after short-term inhalation exposure. AB - Serious questions have been raised by occupational health investigators regarding a possible causal association between neurological effects in welders and the presence of manganese (Mn) in welding fume. Male Sprague-Dawley rats were exposed by inhalation to 40 mg/m(3) of gas metal arc-mild steel (MS) welding fume for 3 h/day for 10 days. Generated fume was collected in the animal chamber during exposure, and particle size, composition, and morphology were characterized. At 1 day after the last exposure, metal deposition in different organ systems and neurological responses in dopaminergic brain regions were assessed in exposed animals. The welding particles were composed primarily of a complex of iron (Fe) and Mn and were arranged as chain-like aggregates with a significant number of particles in the nanometer size range. Mn was observed to translocate from the lungs to the kidney and specific brain regions (olfactory bulb, cortex, and cerebellum) after MS fume inhalation. In terms of neurological responses, short term MS fume inhalation induced significant elevations in divalent metal ion transporter 1 (Dmt1) expression in striatum and midbrain and significant increases in expression of proinflammatory chemokines (Ccl2, Cxcl2) and cytokines (IL1beta, TNFalpha) in striatum. In addition, mRNA and protein expression of glial fibrillary acidic protein (GFAP) was significantly increased in striatum after MS fume exposure. However, the 10-day MS welding fume inhalation did not cause any changes in dopamine and its metabolites or GABA in dopaminergic brain regions nor did it produce overt neural cell damage as assessed by histopathology. In summary, short-term MS welding fume exposure led to translocation of Mn to specific brain regions and induced subtle changes in cell markers of neuroinflammatory and astrogliosis. The neurofunctional significance of these findings currently is being investigated in longer, more chronic welding fume exposure studies. PMID- 19782703 TI - Designing, optimizing, and implementing high-throughput siRNA genomic screening with glioma cells for the discovery of survival genes and novel drug targets. AB - A major challenge for the treatment of cancers, such as glioblastoma multiforme (GBM), has been resistance to radiation and cancer chemotherapeutics. Short interfering RNA (siRNA) based screening may facilitate the identification of genes and pathways essential for cancer cell survival and could enable a more targeted therapeutic approach for the treatment of GBM. Although the commercial availability of siRNA libraries has expanded greatly, detailed methods for the implementation and analysis of genome-scale screens are largely lacking. To annotate the essential genes and pathways for glioma cell survival, we designed, optimized, and implemented a high-throughput siRNA screen in the highly drug and radiation resistant T98G glioma cell line. We developed a rapid, readily available, and simple strategy to optimize siRNA transfection assays in a 384 well plate format based on immunofluorescence studies and inhibition of the non essential, endogenous gene lamin A/C. We used these transfection conditions to successfully screen a library of 1056 siRNAs targeting 352 unique human genes in a cell-based one gene per well format to identify the genes essential for glioma cell survival and assess the quality of the screening conditions prior to large scale screening. After developing and applying a median-based outlier detection algorithm for post-screen analysis, we identified the Ras oncogene family member RAN as an essential gene for glioma cell survival. Successful implementation and analysis of this siRNA screen validates our transfection optimization approach and provides guidance for the rapid development of high-throughput siRNA screens in human glioma cells. PMID- 19782704 TI - Modulation of behavioural profile and stress response by 5-HTT genotype and social experience in adulthood. AB - Behavioural profiles can be shaped by genotype and environmental factors during early phases of life. The aim of this study was to investigate whether anxiety like behaviour, exploration and adrenocortical stress responses can be modulated by genotype and social experiences in adulthood. Male mice lacking the serotonin transporter gene which is under scrutiny for anxiety disorders were compared with heterozygous and wildtype controls. Concerning social experiences, the males of all three genotypes were provided with a winner or a loser experience in a resident-intruder paradigm on three consecutive days. Anxiety-like behaviour and exploration were recorded in the dark-light, elevated plus-maze and open-field test. To non-invasively assess adrenocortical activity, corticosterone metabolites were determined from feces. The main findings were: Repeated social experience, irrespective of winning or losing, elevated levels of anxiety-like behaviour and decreased exploration. In losers a distinct effect of genotype occurred, with homozygous knockout males showing more anxiety-like behaviour and less exploration than the other genotypes. In winners no genotype-dependent variation was found. Genotypes did not differ in basal stress hormone secretion. There was, however, a main effect of social experience with higher activation of the stress hormone system in losers than in winners. This effect was strongest in the heterozygous genotype. In conclusion, our data show that anxiety circuits retain their plasticity throughout adulthood and can be shaped by genotype and social experiences during this phase of life. Moreover, responsiveness towards negative life experiences is influenced significantly by the 5-HTT genotype. PMID- 19782705 TI - Mixed lineage kinase 3 negatively regulates IKK activity and enhances etoposide induced cell death. AB - Mixed lineage kinase 3 (MLK3) is a mitogen activated protein kinase kinase kinase (MAP3K) that activates multiple MAPK signaling pathways. Nuclear factor kappa B (NF-kappaB) is a transcription factor that has important functions in inflammation, immunity and cell survival. We found that silencing mlk3 expression with RNA interference (RNAi) in SKOV3 human ovarian cancer epithelial cells and NIH-3T3 murine fibroblasts led to a reduction in the level of the inhibitor of kappa B alpha (IkappaBalpha) protein. In addition, we observed enhanced basal IkappaB kinase (IKK) activity in HEK293 cells transiently transfected with MLK3 siRNA and in NIH3T3 cells stably expressing MLK3 shRNA (shMLK3). Furthermore, the basal level of NF-kappaB-dependent gene transcription was elevated in shMLK3 cells. Silencing mlk3 expression conferred resistance of cells to etoposide induced apoptotic cell death and overexpression of wild type MLK3 (MLK3-WT) or kinase-dead MLK3 (MLK3-KD) promoted apoptotic cell death and cleavage of poly (ADP-ribose) polymerase (PARP). Overexpression of MLK3-WT or MLK3-KD enhanced etoposide-induced apoptotic cell death and cleavage of PARP. These data suggest that MLK3 functions to limit IKK activity, and depleting MLK3 helps protect cells from etoposide-induced cell death through activation of IKK-dependent signaling. PMID- 19782706 TI - Development and validation of a modified broad-range 16S rDNA PCR for diagnostic purposes in clinical microbiology. AB - Broad-range PCR followed by sequencing identifies bacterial pathogens, even in challenging settings such as patients receiving antibiotics or infected with fastidious or non-cultivable organisms. The major problem with broad-range PCR is the risk of sample contamination. Risk is present at every step of the procedure, starting from sample collection. Contaminating bacterial DNA may be present not only in laboratory reagents but also at the surface of plastic consumables and containers used for specimen drawing and transport to the diagnostic laboratory. Contaminating DNA is amplified efficiently, leading to false-positive results. Thus, high specificity depends on eliminating such spurious targets, an awkward problem given the abundance of such targets and a highly sensitive method that detects very small numbers of molecules. Several investigators have reported strategies for eliminating the amplification of contaminating DNA sequences. So far, none of these methods has been entirely effective and reproducible. Here we describe a method that uses Exonuclease III (ExoIII) to disable contaminating sequences from acting as templates, while maintaining the high sensitivity of PCR for pathogen DNA. We use this assay in 144 clinical specimens from normally sterile sites, identifying pathogens from 24 (17%). Conventional methods identified pathogens in only four of these specimens, all of which were positive for the same pathogen by PCR. Compared with conventional methods, broad-range PCR with ExoIII pre-treatment of reagents substantially improves the diagnostic yield of bacterial pathogen identification from normally sterile sites. PMID- 19782707 TI - Cardiac defense response as a predictor of fear learning. AB - Prior studies have demonstrated that differences in activation of the defensive motivational system - as indexed by cardiac responses to the CS+ during aversive conditioning - are related to differences in the acquisition of two-levels-of learning: cognitive (contingency learning) and emotional (fear learning). Here we further explored these differences using an independent psychophysiological test to assess cardiac reactivity - Cardiac Defense Response (CDR) - prior to the aversive conditioning task. Participants were then classified as accelerators or decelerators based on the CDR second accelerative component. Both groups showed contingency learning, as indexed by greater skin conductance changes to CS+ than to CS- during acquisition and by consistent contingency awareness ratings after the conditioning task. However, only accelerators showed affective fear learning, as indexed by greater blinks to CS+ than to CS- during (acquisition) and after (extinction) aversive conditioning. These results extend evidence about differences in the two-levels-of-learning in aversive conditioning as a function of defensive reactivity, and suggest that the CDR second accelerative component could be a reliable predictor of fear learning. PMID- 19782708 TI - Decision-making impairments in women with binge eating disorder. AB - Even though eating is frequently driven by overindulgence and reward rather than by energy balance, few studies so far have analyzed decision-making processes and disturbances in feedback processing in women with binge eating disorder (BED). In an experimental study, 17 women with BED (DSM-IV) and 18 overweight healthy controls (HC) were compared in the game of dice task (GDT). This task assesses decision-making under risk with explicit rules for gains and losses. Additionally, differences in dispositional activation of the behavior inhibition and behavior approach system as well as cognitive flexibility were measured. Main results revealed that women with BED make risky decisions significantly more often than HC. Moreover, they show impaired capacities to advantageously utilize feedback processing. Even though these deficits were not related to disease specific variables, they may be important for the daily decision-making behavior of women with BED, thus being relevant as a maintenance factor for the disorder. PMID- 19782709 TI - Variation in the gene TAS2R38 is associated with the eating behavior disinhibition in Old Order Amish women. AB - Insensitivity to the bitter-tasting compound 6-n-propylthiouracil (PROP) has been proposed as a marker for individual differences in taste perception that influence food preference and intake. The principal genetic determinants of phenotypic variation in PROP taste sensitivity are alleles of the TAS2R38 gene, which encodes a chemosensory receptor sensitive to thiourea compounds including PROP and phenylthiocarbamide. Members of the TAS2R family are expressed in the gustatory system, where they function as bitter taste receptors, and throughout the gut, where their physiological roles in prandial, gut-derived hormone release are beginning to be elucidated. To better understand the relationship between TAS2R function and ingestive behaviors, we asked if TAS2R38 variants are associated with one or more of three eating behaviors: restraint, disinhibition, and hunger. We genotyped a single nucleotide polymorphism (SNP) located within the TAS2R38 gene, rs1726866 (T785C, Val262Ala) in 729 nondiabetic individuals (381 females, 348 males) within the Amish Family Diabetes Study. Eating behaviors were assessed using the Three-Factor Eating Questionnaire. An association analysis between rs1726866 and these three traits revealed a significant association of the PROP-insensitive "T" allele with increased disinhibition (p=0.03). Because eating behaviors differ substantially between males and females, we subsequently performed sex-stratified analyses, which revealed a strong association in females (p=0.0002) but not in males. Analyses with other SNPs in close proximity to rs1726866 suggest that this locus is principally responsible for the association. Therefore, our results indicate that a polymorphism in TAS2R38 is associated with differences in ingestive behavior. PMID- 19782710 TI - State craving, food availability, and reactivity to preferred snack foods. AB - The startle response has been shown to be useful in studying reactivity to food cues. Following 6h of food deprivation and exposure to neutral and food cues, we examined the role of state craving combined with both a short and long delay of consumption on affect and startle reflex. Participants completed the PANAS, consumed a controlled early morning meal, and experienced 6h of food deprivation. They then reported back to the laboratory, completed a second baseline PANAS, and had their baseline eyeblink EMG startle responses to 100 dB(A) startle probe assessed. Prior to and following the presentation of cues, startle probes were presented and responses were recorded. The PANAS and state craving were also assessed after each cue. Food cues provoked higher levels of state craving than neutral cues and startle responses failed to habituate as quickly to food cues as they did to neutral cues. In addition, cue exposure created the highest NA among high state cravers in the long delay of consumption group. Startle responses differed from NA in that with long delay startle was high irrespective of state craving scores; in the short delay of consumption condition, startle increased linearly with state craving. These results illustrate that state craving and expectations of food availability are important variables in understanding food related cue reactivity. PMID- 19782711 TI - Flavors prime processing of affectively congruent food words and non-food words. AB - The aim of this study was to explore the use of oral flavor stimuli in an implicit measure of attitudes; the affective priming paradigm. Unpleasant (cold instant coffee) and pleasant (strawberry lemonade) chemosensory flavor stimuli were used as primes in an affective cross-modal priming paradigm. Target stimuli were food words and non-food words, that were either affectively positive or negative, thus creating affectively congruent and incongruent prime-target pairs. We observed priming for congruent flavor-word pairs, i.e. if prime and target are both positive or both negative, this led to faster evaluation of the target words than for incongruent flavor-word pairs. Furthermore, the size of the priming effect was similar for food and non-food target words, suggesting that the affective priming effect is not augmented by the use of words that are semantically related. These results provide proof of concept of indirectly measuring attitudes to flavors with the affective priming paradigm, which may provide information on attitudes in addition to explicit pleasantness ratings. PMID- 19782712 TI - Short-term exposure to human cytomegalovirus-infected fibroblasts induces a proportional increase of active CD94/NKG2A(+) natural killer cells. AB - Natural killer (NK) cells are essential components of the immune response against human cytomegalovirus (HCMV). As NK cells are part of the innate immune system providing an immediate defense against pathogens, short-term exposure to HCMV infected cells may induce changes in the phenotype and function of these cells. To identify immediate reactions of NK cells to HCMV, we co-cultured peripheral blood mononuclear cells with HCMV-infected fibroblasts for 24 and 72 hours. A distinct, HCMV-mediated, proportional enlargement of a subset of NK cells expressing CD94/NKG2A was sustained throughout the period of incubation. As preceding studies have shown that HCMV can cause an increase in CD94/NKG2C(+) NK cells, our results were surprising. The NK cells showed intense upregulation of the early activation marker CD69 in response to HCMV. The CD94/NKG2A(+) NK cells demonstrated the highest expression of CD69. Studies of HCMV-induced interferon gamma expression after 24 hours of co-culture showed that this cytokine was almost exclusively produced by the CD94/NKG2A(+) subset of NK cells. In summary, our data demonstrate that HCMV induces an immediate proportional enlargement of a functionally active CD94/NKG2A expressing subset of NK cells. PMID- 19782713 TI - Monocyte chemoattractant protein-1 -2518 A/G single nucleotide polymorphism in Chinese Han patients with ocular Behcet's disease. AB - Recent studies in Caucasian uveitis patients have shown an association with the 2518 A/G polymorphism of the monocyte chemoattractant protein (MCP)-1 gene. It is unknown whether this polymorphism is also associated with ocular Behcet's disease (BD) in Chinese populations. The aim of the current study was therefore to investigate the possible involvement of MCP-1 in the susceptibility to ocular BD in Chinese Han individuals. A case control association study was performed in 296 ocular BD patients and 319 geographically and age-matched healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Binary logistic regression analysis revealed a decreased frequency of the homozygous AA genotype and an increased frequency of AG genotype of the MCP-1 2518 polymorphism in ocular BD patients compared with healthy controls, when adjusted for gender (p = 0.048, p = 0.028, respectively). However, when segregated on the basis of several clinical findings, no any association was found between this polymorphism and ocular BD. In conclusion, the present study suggests that the MCP-1 -2518 AA genotype seems to display a protective association with ocular BD, whereas the -2518 AG genotype might be a susceptible factor for ocular BD in the Chinese Han population. PMID- 19782714 TI - Suppressive activity rather than frequency of FoxP3(+) regulatory T cells is essential for CA-125-specific T-cell activation after abagovomab treatment. AB - The results of several clinical trials have clearly demonstrated the potential of the anti-idiotype (anti-Id) vaccine abagovomab to induce cancer antigen 125 (CA 125)-specific immunity in ovarian cancer patients. Because of the central role of regulatory T cells (Tregs) in tumor immunology, we analyzed the frequency and suppressive activity of CD25(+)FoxP3(+) Tregs in 16 patients treated with abagovomab. During vaccination, mean frequencies of peripheral Treg with a CD4(+)CD25(+)FoxP3(+) CD127(-) phenotype were enhanced but returned to baseline levels in the follow-up phase. Despite increasing Treg counts, the suppressive activity of Tregs was diminished in a subset of patients treated with abagovomab. Reduced Treg activity was associated with increasing polyclonal and CA-125 specific T-cell proliferation in these patients. Interestingly, CA-125-specific T cell activation could not be further improved by Treg depletion in vitro, as CA 125 induced a suppressive CD4(+)CD25(+)FoxP3(+) CD127(-) T cell subset derived from the originally Treg-depleted T-cell fraction. These CA-125-induced Tregs (iTregs) efficiently blocked polyclonal and tumor-specific T-cell activation. Further elimination of iTregs resulted in detectable CA-125-specific T-cell responses in a subset of patients. Based on our results, the suppressive potential rather than the frequency of natural and CA-125-induced Tregs is an important issues to consider for refinement of current anti-Id vaccination. PMID- 19782715 TI - Adolescent development, hypothalamic-pituitary-adrenal function, and programming of adult learning and memory. AB - Chronic exposure to stress is known to affect learning and memory in adults through the release of glucocorticoid hormones by the hypothalamic-pituitary adrenal (HPA) axis. In adults, glucocorticoids alter synaptic structure and function in brain regions that express high levels of glucocorticoid receptors and that mediate goal-directed behaviour and learning and memory. In contrast to relatively transient effects of stress on cognitive function in adulthood, exposure to high levels of glucocorticoids in early life can produce enduring changes through substantial remodeling of the developing nervous system. Adolescence is another time of significant brain development and maturation of the HPA axis, thereby providing another opportunity for glucocorticoids to exert programming effects on neurocircuitry involved in learning and memory. These topics are reviewed, as is the emerging research evidence in rodent models highlighting that adolescence may be a period of increased vulnerability compared to adulthood in which exposure to high levels of glucocorticoids results in enduring changes in adult cognitive function. PMID- 19782716 TI - Antivenom efficacy or effectiveness: the Australian experience. AB - Despite widespread use of antivenoms, many questions remain about their effectiveness in the clinical setting. The almost universal acceptance of their value is based mainly on in vitro studies, animal studies and human observational studies. Numerous examples exist where they demonstrate clear benefit, such as consumption coagulopathy in viper envenoming, prevention of neurotoxicity in Australasian elapid bites, systemic effects in scorpion and funnel-web spider envenoming. There are also concerns about the quality and efficacy of some antivenoms. However, it is important not to confuse the efficacy of antivenom, defined as its ability to bind and neutralise venom-mediated effects under ideal conditions, and the effectiveness of antivenom, defined as its ability to reverse or prevent envenoming in human cases. There are numerous potential reasons for antivenom failure in human envenoming, of which antivenom inefficacy is only one. Other important reasons include venom-mediated effects being irreversible, antivenom being unable to reach the site of toxin-mediated injury, or the rapidity of onset of venom-mediated effects. A number of recent studies in Australia bring into question the effectiveness of some antivenoms, including snake antivenom for coagulopathy, redback spider and box jellyfish antivenoms. Despite brown snake antivenom being able to neutralise venom induced clotting in vitro, use of the antivenom in human envenoming does not appear to change the time course of coagulopathy. However, it is important that apparent antivenom ineffectiveness in specific cases is correctly interpreted and does not lead to a universal belief that antivenom is ineffective. It should rather encourage further studies to investigate the underlying pathophysiology of envenoming, the pharmacokinetics of venoms and antivenoms, and ultimately the effectiveness of antivenom based on snake type, clinical effects and timing of administration. PMID- 19782718 TI - Nandrolone decanoate administration elevates hippocampal prodynorphin mRNA expression and impairs Morris water maze performance in male rats. AB - The misuse of anabolic androgenic steroids has in several reports been associated with effects resulting in altered behavior. This study used the Morris water maze task to investigate the effect of high doses of the anabolic androgenic steroid nandrolone on spatial learning and memory in male rats. During the experiment, we observed a significantly impaired Morris water maze performance in the nandrolone treated rats compared with controls. The hippocampus, a brain region associated with cognitive function, was analyzed for mRNA expression of prodynorphin, the precursor of dynorphinergic peptides. The results indicated that the transcription levels of prodynorphin were significantly elevated in the animals treated with nandrolone compared with controls. Thus, the findings suggest that administration of nandrolone to male rats impairs memory function, possibly via dynorphinergic actions. PMID- 19782717 TI - Neonatal exposure of male rats to Bisphenol A impairs fertility and expression of sertoli cell junctional proteins in the testis. AB - BACKGROUND: Sertoli cell junctional proteins (SCJP) (viz. adhesion, gap and tight junctions) are important for spermatogenesis and perturbations in expression of these proteins are associated with impairments in process of sperm production. Bisphenol A (BPA) is an endocrine disrupter that has been associated with impaired spermatogenesis. However the mechanistic basis of impaired spermatogenesis is unknown, whether BPA is a Sertoli cell toxicant has not yet been fully investigated. OBJECTIVES: The present study was undertaken to decipher the effects of neonatal exposure of male rats to BPA on fertility and its effect on the testicular expression of SCJP during development. METHODS: Neonatal male rats were s.c. injected with BPA at doses ranging from 0.6 to 10 microg/rat (100 1600 microg/kg bw of BPA) on post-natal days (PNDs) 1-5, and controls received vehicle. Diethylstilbestrol (DES) was used as a positive control. Male fertility was assessed during adulthood and the lowest dose of BPA that was most effective at impairing fertility was determined. Immunohistochemical localization for Connexin 43 (Cx-43, gap junctional), Zona Occludin-1 (ZO-1, tight junctions) and N-cadherin (adherens junction) was carried out on testicular tissue sections obtained from PNDs 15, 30, 45 and 90 of rats exposed to lowest dose of BPA that impaired fertility. RESULTS: Females mated with male rats that were exposed neonatally to various concentrations of BPA showed a significant increase in post implantation loss and a decrease in litter size. There were significant changes in sperm count along with hormonal imbalances in the rats exposed neonatally to BPA. The 2.4 microg dose (400 microg/kg bw) of BPA was determined as the lowest dose that was capable of impairing male fertility. A significant reduction in the expression of Cx-43 (PND 45 and 90) and increases in the expression of N-cadherin (PND 45 and 90) and ZO-1 (PND 90) were observed in the testes of rats exposed neonatally to effective dose of BPA. Interestingly, there was an altered expression pattern of Cx43 amongst the sloughed cells in the testes of the experimental rats as compared to controls. CONCLUSION: Neonatal exposure of BPA to rats impairs their fertility and has the potential to induce perturbations in SCJP. These perturbations may be one of the contributing factors that lead to impairments in spermatogenesis in the exposed animals and can be used as potential biomarkers to study BPA-induced effects on testes. PMID- 19782719 TI - MicroRNAs in the tumor endothelium: novel controls on the angioregulatory switchboard. AB - Tumor angiogenesis facilitates tumor metastasis and allows malignant tissues to grow beyond a diffusion limited size. It is a complex process that requires endothelial cells to execute specific steps during different phases. miRNAs are small non-coding RNAs that act as molecular switches to redirect the expression profile of a cell. Evidence is emerging that miRNAs are important players in endothelial cell biology and tumor angiogenesis. In this review we summarize the available data of miRNA expression in the endothelium. In addition, we describe the current knowledge regarding the function of miRNAs in endothelial cell biology. Finally, we discuss the potential applications of miRNA based treatment strategies in angiostatic cancer therapy. PMID- 19782720 TI - Cell-penetrating peptides: application in vaccine delivery. AB - Recent years have seen a surge in interest in cell-penetrating peptides (CPP) as an efficient means for delivering therapeutic targets into cellular compartments. The cell membrane is impermeable to hydrophilic substances yet linking to CPP can facilitate delivery into cells. Thus the unique translocatory property of CPP ensures they remain an attractive carrier, with the capacity to deliver cargoes in an efficient manner having applications in drug delivery, gene transfer and DNA vaccination. Fundamental for an effective vaccine is the delivery of antigen epitopes to antigen-presenting cells, ensuing processing and presentation and induction of an immune response. Vaccination with proteins or synthetic peptides incorporating CTL epitopes have proven limited due to the failure for exogenous antigens to be presented efficiently to T cells. Linking of antigens to CPP overcomes such obstacles by facilitating cellular uptake, processing and presentation of exogenous antigen for the induction of potent immune responses. This review will encompass the various strategies for the delivery of whole proteins, T cell epitopes and preclinical studies utilizing CPP for cancer vaccines. PMID- 19782722 TI - Selective inhibitory effects of pregabalin on peripheral C but not A-delta fibers mediated nociception in intact and spinalized rats. AB - Effects of pregabalin (PGB, 20-80 mg/kg i.v. injection) on spinally-organized nociception were investigated in isoflurane-anesthetized intact and spinalized rats. Responses of single deep spinal dorsal horn (DH) (laminae IV-V) nociceptive specific (NS) neurons receiving peripheral inputs from A-delta and C fibers to repetitive electrical stimulation (intensity: 3-5 mA; frequency: 1 Hz; pulse duration: 1 ms), mechanical/heat stimulation were recorded extracellularly during physiological condition and s.c. bee venom (BV) induced inflammation. PGB significantly inhibited C-fiber mediated spinal NS neurons' late responses including phenomena of wind-up (temporal summation) and after-discharge. However, the antinociceptive effects of PGB on nociception were not observed until 30 min after its administration. In contrast, no significant inhibitory effect of PGB on A-delta fiber mediated early responses was observed during the experiments. Compared with intact rats, the inhibitory effects of PGB upon nociception vanished in the spinalized animals. This suggests that PGB-induced selective antinociceptive effect on C-fiber mediated nociception is mainly central effects involving supraspinal centers via descending inhibitory controls. Furthermore, pre-treatment, but not post-treatment, with PGB (80 mg/kg) markedly inhibited s.c. BV elicited spontaneous neuronal responses, and noxious mechanical/heat stimuli evoked hyperactivities of spinal NS neurons, indicating that PGB has efficacy of pre-emptive analgesia on pathological pain associated with central sensitization. PMID- 19782721 TI - Neurological functional recovery after thymosin beta4 treatment in mice with experimental auto encephalomyelitis. AB - In the present study, we hypothesized that thymosin beta 4 (Tbeta4) is a potential therapy of multiple sclerosis (MS). To test this hypothesis, SJL/J mice (n=21) were subjected to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. EAE mice were treated with saline or Tbeta4 (6 mg/kg, n=10) every 3 days starting on the day of myelin proteolipid protein (PLP) immunization for total five doses. Neurological function, inflammatory infiltration, oligodendrocyte progenitor cells (OPCs) and mature oligodendrocytes were measured in the brain of EAE mice. Double immunohistochemical staining was used to detect proliferation and differentiation of OPCs. Tbeta4 was used to treat N20.1 cells (premature oligodendrocyte cell line) in vitro, and proliferation of N20.1 cells was measured by bromodeoxyuridine (BrdU) immunostaining. Tbeta4 treatment improved functional recovery after EAE. Inflammatory infiltrates were significantly reduced in the Tbeta4 treatment group compared to the saline groups (3.6+/-0.3/slide vs 5+/-0.5/slide, P<0.05). NG2(+) OPCs (447.7+/-41.9 vs 195.2+/ 31/mm(2) in subventricular zone (SVZ), 75.1+/-4.7 vs 41.7+/-3.2/mm(2) in white matter), CNPase(+) mature oligodendrocytes (267.5+/-10.3 vs 141.4+/-22.9/mm(2)), BrdU(+) with NG2(+) OPCs (32.9+/-3.7 vs 17.9+/-3.6/mm(2)), BrdU(+) with CNPase(+) mature oligodendrocytes (18.2+/-1.7 vs 10.7+/-2.2/mm(2)) were significantly increased in the Tbeta4 treated mice compared to those of saline controls (P<0.05). These data indicate that Tbeta4 treatment improved functional recovery after EAE, possibly, via reducing inflammatory infiltrates, and stimulating oligodendrogenesis. PMID- 19782723 TI - Interaction between vision and neck proprioception in the control of stance. AB - Balance control depends on the interaction of multiple inputs originating from different sensory systems. Here, we investigated the effect on quiet human stance of changing the visual condition prior to a proprioceptive perturbation produced by vibration of dorsal neck muscles. In complete absence of visual references, the amplitude of the postural responses to neck vibration (forward shift of the centre of foot pressure) was the largest and became progressively larger as a function of the repetition of administered stimuli. The posture-destabilizing effect of vibration eyes-closed (EC) and the build-up effect were reduced if vibration was preceded by a period during which vision was allowed (EO). Similarly, the small destabilizing effect of vibration EO was increased if vibration was preceded by an EC period. The fore-period must last more than 3 s in order to affect the response to neck muscle vibration. The responsiveness to a proprioceptive disturbing input does not immediately change on adding or subtracting vision, but a finite time period must elapse before the postural "set" defined by vision is fully established. The findings underline the importance of time when vision is used in re-weighting the excitability of the postural control mechanisms. PMID- 19782724 TI - Neurogenesis and astrogenesis contribution to recovery of vestibular functions in the adult cat following unilateral vestibular neurectomy: cellular and behavioral evidence. AB - In physiological conditions, neurogenesis occurs in restricted regions of the adult mammalian brain, giving rise to integrated neurons into functional networks. In pathological or postlesional conditions neurogenesis and astrogenesis can also occur, as demonstrated in the deafferented vestibular nuclei after immediate unilateral vestibular neurectomy (UVN) in the adult cat. To determine whether the reactive cell proliferation and beyond neurogenesis and astrogenesis following UVN plays a functional role in the vestibular functions recovery, we examined the effects of an antimitotic drug: the cytosine-beta-d arabinofuranoside (AraC), infused in the fourth ventricle after UVN. Plasticity mechanisms were evidenced at the immunohistochemical level with bromodeoxyuridine, GAD67 and glial fibrillary acidic protein (GFAP) stainings. Consequences of immediate or delayed AraC infusion on the behavioral recovery processes were evaluated with oculomotor and posturo-locomotor tests. We reported that after UVN, immediate AraC infusion blocked the cell proliferation and decreased the number of GFAP-immunoreactive cells and GABAergic neurons observed in the vestibular nuclei of neurectomized cats. At the behavioral level, after UVN and immediate AraC infusion the time course of posturo-locomotor function recovery was drastically delayed, and no alteration of the horizontal spontaneous nystagmus was observed. In contrast, an infusion of AraC beginning 3 weeks after UVN had no influence neither on the time course of the behavioral recovery, nor on the reactive cell proliferation and its differentiation. We conclude that the first 3 weeks after UVN represent a possible critical period in which important neuroplasticity mechanisms take place for promoting vestibular function recovery: reactive neurogenesis and astrogenesis might contribute highly to vestibular compensation in the adult cat. PMID- 19782725 TI - Estimating intracellular Ca2+ concentrations and buffering in a dendritic inhibitory hippocampal interneuron. AB - Calcium is known to regulate several phenomena like neuronal excitability and plasticity. Interestingly, the spatiotemporal profile of dendritic calcium depends on several processes, specific to each neuronal type. In this study, we investigated Ca(2+) buffering and action potential (AP)-evoked Ca(2+) signaling in the dendrites of anatomically identified oriens lacunosum-moleculare (O-LM) cells, a major type of dendrite-targeting interneurons in the hippocampal CA1 region, using a combination of whole-cell patch-clamp recording and fast Ca(2+) imaging in acute rat brain slices. Cells were loaded with fluorescent Ca(2+) indicators fura-2 or Oregon Green BAPTA-1 (OGB-1) via patch-clamping electrode, and the effect of fura-2 on AP-evoked dendritic Ca(2+) transients was determined by ratiometric Ca(2+) imaging. To estimate intracellular Ca(2+) concentrations ([Ca(2+)](i)) and endogenous Ca(2+)-binding ratio (kappa(s)) in the proximal dendrite, fluorescence signals were converted into [Ca(2+)](i) using the ratioing method and were analyzed on the basis of the "single compartment model." Resting [Ca(2+)](i) was 22+/-5 nM and the build-up of [Ca(2+)](i) during a single AP was up to 656+/-226 nM. Analysis of Ca(2+) transients revealed that O-LM cells have a relatively low endogenous Ca(2+)-binding ratio (kappa(s)): the kappa(s) was 20+/ 8 estimated during fura-2 loading and 27 estimated under steady-state fura-2 concentrations, respectively. To further examine the spatial profile of dendritic Ca(2+) transients, we measured somatic AP-evoked Ca(2+) transients beyond proximal dendrites using OGB-1. Dendritic Ca(2+) transients evoked by single APs or AP trains are not limited to regions close to the soma. The amplitude and decay of [Ca(2+)](i) associated with backpropagating APs are relatively independent of the distance from the soma. In sum, O-LM cells exhibit low endogenous Ca(2+)-binding ratios and relatively distance-independent Ca(2+) dynamics in the dendrites. These special features of Ca(2+) signaling in O-LM cells may have important functional implications for both normal and pathological conditions. PMID- 19782726 TI - Endotoxin-mediated regulation of nuclear factor-kappaB nuclear translocation and activation in the hippocampus of the central nervous system: modulation by intracerebroventricular treatment with thymulin and the immunomodulatory role of the IkappaB-alpha/pIkappaB-alpha pathway. AB - The transcription factor nuclear factor kappaB (NF-kappaB) is one member of a ubiquitously expressed family of Rel-related transcription factors that serve as critical regulators of many proinflammatory genes and immunomodulators. Nevertheless, the immunomodulatory potential of thymulin and its effect on NF kappaB in vivo, and particularly in the central nervous system (CNS), is not well characterized. In this study, the role of endotoxin (ET/LPS) in regulating NF kappaB was deciphered in various compartments of the CNS. Stereotaxic localization reverberated specific intracerebroventricular (ICV) injection of ET into the CNS, with or without pretreatment with ICV thymulin. Treatment with ET (1 microg for 45 min; ICV) upregulated the expression and nuclear localization of NF-kappaB(1) (p50), NF-kappaB(2) (p52), RelA (p65), RelB (p68) and c-Rel (p75) in the hippocampus (HC), an effect abrogated, in a dose-dependent manner, by ICV pretreatment (30 min) with thymulin. Thymulin modulated the phosphorylation of IkappaB-alpha in the HC by upregulating the cytosolic accumulation of IkappaB alpha and downregulating its phosphorylation (pIkappaB-alpha). Further analysis of the DNA-binding activity revealed an upregulated activity in the HC relative to saline-constitutive expression of the RelA (p65) subunit, the specificity of which was determined by a mutant oligonucleotide of RelA and a cold, non-specific competitor. ET did not induce the DNA-binding activity of NF-kappaB in the diencephalon (DE) or substantia nigra (SN) at various time points, when compared with baseline levels of expression. Intraperitoneal (IP) injections of ET (25 microg for 15 min) in vivo upregulated the expression of NF-kappaB subunits in the liver and reduced the cytosolic accumulation of IkappaB-alpha by inducing pIkappaB-alpha. Furthermore, IP pretreatment with thymulin followed by ICV injection of ET attenuated and reduced the DNA-binding activity of NF-kappaB in the HC. These results indicate that ICV injection of ET regulates the nuclear translocation and activation of NF-kappaB subunits within specific compartments in the brain, an effect particularly localized to the hippocampus. Additionally, thymulin attenuated the ET-induced response, with particular involvement of the transduction pathway implicating IkappaB-alpha, the major cytosolic inhibitor of NF-kappaB. The in vivo molecular regulation of thymulin via the NF-kappaB pathway is critical to understanding the alleviating anti-inflammatory role of this nonapeptide and paving the way to unraveling pathways associated with neuroimmune interactions mediating proinflammatory signals in the CNS. PMID- 19782729 TI - Horizontal and vertical dimensions of visual extinction: a theta burst stimulation study. AB - After a lesion of the posterior parietal cortex (PPC), the perception of a contra lesional stimulus in presence of a simultaneous, ipsilesional stimulus may be impaired, a phenomenon referred to as visual extinction. In the present study, visual extinction was transiently induced in healthy subjects by interfering with the function of the right PPC by means of continuous theta burst stimulation (TBS). We investigated to which extent the horizontal and vertical position of visual stimuli influenced the extinction rate. A single TBS train over the right PPC induced a significant increase of left visual extinctions of at least 30 min. Left visual extinction rate was higher when the left sided visual stimulus was presented at a more eccentric position on the horizontal axis (irrespective of right sided visual stimulus position) and in the lower part of the visual field. The results are discussed within the framework of current explanatory models and of putative inter- and intrahemispheric mechanisms directing visuospatial attention. PMID- 19782727 TI - A novel peptide, colivelin, prevents alcohol-induced apoptosis in fetal brain of C57BL/6 mice: signaling pathway investigations. AB - Fetal alcohol exposure is known to induce cell death through apoptosis. We found that colivelin (CLN), a novel peptide with the sequence SALLRSIPAPAGASRLLLLTGEIDLP, prevents this apoptosis. Our initial experiment revealed that CLN enhanced the viability of primary cortical neurons exposed to alcohol. We then used a mouse model of fetal alcohol exposure to identify the intracellular mechanisms underlying these neuroprotective effects. On embryonic day 7 (E7), weight-matched pregnant females were assigned to the following groups: (1) ethanol liquid diet 25% (4.49% v/v) ethanol derived calories; (2) pair-fed control; (3) normal chow; (4) ethanol liquid diet combined with administration (i.p.) of CLN (20 microg/20 g body weight); and (5) pair-fed combined with administration (i.p.) of CLN (20 microg/20 g body weight). On E13, fetal brains were collected and assayed for TdT-mediated dUTP nick end labeling staining, caspase-3 colorimetric assay, enzyme-linked immunosorbent assay, and Meso scale discovery electrochemiluminescence. CLN blocked the alcohol-induced decline in brain weight and prevented alcohol-induced: apoptosis, activation of caspase-3 and increases of cytosolic cytochrome c, and decreases of mitochondrial cytochrome c Analysis of proteins in the upstream signaling pathway revealed that CLN down-regulated the phosphorylation of the c-Jun N-terminal kinase. Moreover, CLN prevented alcohol-induced reduction in phosphorylation of BAD protein. Thus, CLN appears to act directly on upstream signaling proteins to prevent alcohol induced apoptosis. Further assessment of these proteins and their signaling mechanisms is likely to enhance development of neuroprotective therapies. PMID- 19782728 TI - Unaltered neuronal and glial counts in animal models of magnetic seizure therapy and electroconvulsive therapy. AB - Anatomical evidence of brain damage from electroconvulsive therapy (ECT) is lacking; but there are no modern stereological studies in primates documenting its safety. Magnetic seizure therapy (MST) is under development as a less invasive form of convulsive therapy, and there is only one prior report on its anatomical effects. We discerned no histological lesions in the brains of higher mammals subjected to electroconvulsive shock (ECS) or MST, under conditions that model closely those used in humans. We sought to extend these findings by determining whether these interventions affected the number of neurons or glia in the frontal cortex or hippocampus. Twenty-four animals received 6 weeks of ECS, MST, or anesthesia alone, 4 days per week. After perfusion fixation, numbers of neurons and glia in frontal cortex and hippocampus were determined by unbiased stereological methods. We found no effect of either intervention on volumes or total number or numerical density of neurons or glia in hippocampus, frontal cortex, or subregions of these structures. Induction of seizures in a rigorous model of human ECT and MST therapy does not cause a change in the number of neurons or glia in potentially vulnerable regions of brain. This study, while limited to young, healthy, adult subjects, provides further evidence that ECT and MST, when appropriately applied, do not cause structural damage to the brain. PMID- 19782730 TI - Effects of granulocyte colony-stimulating factor on the proliferation and cell fate specification of neural stem cells. AB - Granulocyte-colony stimulating factor (G-CSF) is a growth factor that regulates proliferation, differentiation and survival of hematopoietic progenitor cells. There is growing evidence to suggest that G-CSF exerts a powerful neuroprotective effect in different neurological disorders. However, it has remained to be elucidated if G-CSF has a direct effect on neural stem cells (NSCs). Here, we show that G-CSF could stimulate the proliferation of NSCs and promote their differentiation in vitro. Additionally, we have shown that G-CSF-induced proliferation of NSCs is associated with phosphorylation of STAT3, and the differentiation is linked to altered expression of differentiation-related genes. Remarkably, G-CSF could not initiate the differentiation of NSCs. The added roles of G-CSF in regulating proliferation and differentiation of NSCs as shown in this study would serve as a useful reference in designing new stem cell therapy strategies for promoting brain recovery and repair. PMID- 19782731 TI - Axonal ligation induces transient redistribution of TDP-43 in brainstem motor neurons. AB - Nuclear exclusion of TAR DNA binding protein 43 (TDP-43) and formation of cytosolic aggregates are a pathological characteristic of amyotrophic lateral sclerosis (ALS). However, the molecular basis of the aberrant distribution of TDP 43 remains elusive. Here, we show evidence that axonal ligation induced transient nuclear exclusion and peripheral accumulation of TDP-43, without apparent cytosolic aggregates in hypoglossal neurons in mice. Immunohistochemistry showed marked loss of nuclear TDP-43 7-14 days after ligation, which was accompanied by reduction of choline acetyltransferase (ChAT). TDP-43 staining was restored in the nucleus on day 28 exclusively in the neurons with normalized ChAT expression. We also showed that importin beta, which was shown to mediate nuclear transport of TDP-43 was downregulated transiently by nerve ligation. The analysis of the peripheral nerves proximal to the ligation revealed that TDP-43 markedly accumulated with a concomitant decrease in active autophagosome. Moreover, we showed that TDP-43 was present in the microsome fraction containing endoplasmic reticulum (ER) or autophagosomes in the brainstem section, indicating that TDP-43 is axonally transported with vesicles. These results indicate that axonal damage is associated with redistribution of TDP-43 through the combination of defective axonal autophagy periphery and the impaired nuclear transport system in the soma. Moreover, it was also shown that transient redistribution of TDP-43 does not prevent motor neurons from axonal regeneration. Therefore, our data suggest that the subcellular distribution of TDP-43 correlates to the innervation status of motor neurons, which may be governed by unidentified cause of ALS. PMID- 19782732 TI - Fibroblast growth factor 2 requires complex formation with ATP for neuroprotective activity. AB - The neurotrophic and neuroprotective activity of fibroblast growth factor (FGF2) is well documented. In this study, we attempted to demonstrate that binding of ATP to FGF2 is essential for its neuroprotective effect. Incubation of primary cultures of rat embryonic (E18) cortical neurons with alkaline phosphatase decreased the ATP concentration in the culture medium from about 8 to 0.3 nM measured luminometrically. Reduction of ATP concentration below 1 nM abolished the neuroprotective effect of FGF2. However, when the more stable nucleotide triphosphate gammaS-ATP was used which could not be cleaved by alkaline phosphatase, FGF2 still protected the cultured cortical neurons against damage. In control experiments alkaline phosphatase alone did not influence neuroprotection. In addition, also ATPase and apyrase were used as ATP cleaving enzymes. Added to the culture medium, both enzymes were capable of decreasing ATP below the critical level of approximately 1 nM, and the neuroprotective activity of FGF2 was abolished. Thus, our results demonstrate for the first time that the FGF2/ATP complex but not FGF2 alone mediates neuroprotection. PMID- 19782734 TI - High divergence across the whole mitochondrial genome in the "pan-Antarctic" springtail Friesea grisea: evidence for cryptic species? AB - Collembola are one of the few hexapod groups adapted to live in the harsh environmental conditions of Antarctic terrestrial ecosystems. Diversity is limited to a few species that can be very abundant in coastal deglaciated sites. A remarkable lack of overlap in Collembola species composition is evident between Western and Eastern Antarctica, and Friesea grisea is currently the only species whose distribution is thought to span these two main regions of the continent. However, our analysis of the complete sequences of the mitochondrial genomes from specimens obtained from each of the two regions showed unexpected genetic divergence, well above the average levels observed between populations belonging to the same species, and so indicating that these are actually separate species, despite their lack of distinguishing morphology. Detailed analysis of the two genomes showed the presence of a non-coding region observed between trnS(uga) and nad1. Other features of these mitochondrial genomes, such as base compositional bias, secondary structure features of tRNAs and the presence of regulatory elements in the control region, are described and discussed from an evolutionary standpoint. PMID- 19782733 TI - Mutational analysis of Drosophila basigin function in the visual system. AB - Drosophila basigin is a cell-surface glycoprotein of the Ig superfamily and a member of a protein family that includes mammalian EMMPRIN/CD147/basigin, neuroplastin, and embigin. Our previous work on Drosophila basigin has shown that it is required for normal photoreceptor cell structure and normal neuron-glia interaction in the fly visual system. Specifically, the photoreceptor neurons of mosaic animals that are mutant in the eye for basigin show altered cell structure with nuclei, mitochondria and rER misplaced and variable axon diameter compared to wild-type. In addition, glia cells in the optic lamina that contact photoreceptor axons are misplaced and show altered structure. All these defects are rescued by expression of either transgenic fly basigin or transgenic mouse basigin in the photoreceptors demonstrating that mouse basigin can functionally replace fly basigin. To determine what regions of the basigin protein are required for each of these functions, we have created mutant basigin transgenes coding for proteins that are altered in conserved residues, introduced these into the fly genome, and tested them for their ability to rescue both photoreceptor cell structure defects and neuron-glia interaction defects of basigin. The results suggest that the highly conserved transmembrane domain and the extracellular domains are crucial for basigin function in the visual system while the short intracellular tail may not play a role in these functions. PMID- 19782736 TI - The roles of acidifiers in solid dispersions and physical mixtures. AB - The roles of acidifiers in polyvinylpyrrolidone-based solid dispersions and physical mixtures were originally investigated on dissolution rate of drug, acidifier release, structural crystallinity and micro-environmental pH. A poorly water-soluble and weakly basic isradipine was used as a model drug. The solid dispersion and physical mixtures were prepared with drug and polyvinylpyrrolidone without or with pH modifiers using the solvent evaporation method and then compressed into tablet. The dissolution rate of drug from solid dispersions containing acidifiers were more pronounced when compared to physical mixtures. The dissolution rate of isradipine from solid dispersion was ranked by acidifiers in a decreasing order: fumaric acid, citric acid, glycolic acid and malic acid. In contrast, the acidifiers in physical mixtures had no significant difference in drug dissolution rate. It was attributed by the rank of acidifiers leading to the decrease of micro-environmental pH and slower release rate of acidifier as well as the maintenance of structural amorphousness. The selection of acidifiers with optimal micro-environmental pH, retarded release rate and maintaining structural amorphousness of drug could maximize the dissolution rate of weakly basic drug in solid dispersion. PMID- 19782735 TI - Failure of a vaccine using immunogenic recombinant proteins rNcSAG4 and rNcGRA7 against neosporosis in mice. AB - The development of an effective vaccine against Neospora caninum infection in cattle is an important issue due to the significant economic impact of this parasitic disease worldwide. In this work, the immune response, safety and efficacy of different vaccine formulations using the N. caninum recombinant proteins rNcSAG4 (the first bradyzoite-specific protein assayed as a vaccine) and rNcGRA7 were evaluated in mouse models. The survival curves of pups from all vaccinated groups showed a slight delay in time to death compared to control groups; this difference was statistically significant for rNcSAG4+adjuvant group. Immune response of mice vaccinated with rNcSAG4 was characterized by reduced specific IgG and cytokine levels with an equilibrated IFN-gamma/IL-10 balance. Regarding mice vaccinated with rNcGRA7, a very strong humoral and cellular immune response was generated characterized by a hyper-production of IFN-gamma. This response was not accompanied by significant protection. Vaccination with a mixture of both recombinant proteins reduced infection in lung and brain during acute and chronic infection, respectively, although it was not statistically significant. In summary, no significant protection was obtained with these vaccine formulations in the present mouse models. However, the study reveals some positive results on immune response and efficacy for both recombinant proteins; these results are being discussed in order to suggest new approaches with new chronic infection mouse models and adjuvants. PMID- 19782737 TI - Three-layered microcapsules as a long-term sustained release injection preparation. AB - Three-layered milli-capsules (3LMC), diameter of 1.85+/-0.07 and 0.15+/-0.09 mm thickness, were designed for the long-term subcutaneous (sc) administration of drugs. 3LMCs composed of (1) surface membrane (release rate control membrane), (2) drug-carrying layer and (3) base membrane were prepared by dispensing each solution in series. As surface membrane, poly-(epsilon-caprolactone) having MW of 70 kDa (PCL70) was used in combination with plasticizer, polysorbate 60 (Tween60). Base membrane was prepared with PCL70. Fluorescein isothiocyanate labeled dextrans (FD-4, MW=4 kDa and FD-20, MW=20 kDa) were used as model drug and in vitro release experiment was performed with PCL70 surface membrane containing Tween60 with 0.3, 1.0 and 3.0% (w/w). As the amount of Tween60 increased, release rate of FD-4 was increased. PCL70+0.3% Tween60 membrane showed a good sustained release property for 5 weeks; 50.3+/-6.0% of FD-4 was released during 5 weeks. When FD-20 was encapsulated, long-term sustained release was not obtained, 10.7+/-3.6% was released during 5 weeks. However, when lower MW drug, leuprolide acetate, was encapsulated, 3LMC composed of PCL70+0.3% Tween60 showed a good sustained release property, 63.0+/-5.9% released for 5 weeks. Leuprolide acetate encapsulated 3LMC was evaluated in rat experiment. After sc administration to rats, 0.5 and 1.0 mg, plasma leuprolide concentration showed its maximum concentration at day 1, thereafter gradually decreased and maintained the effective concentration for 14 weeks. Plasma leuprolide concentration vs. time curve showed a good dose-dependency. When surface membrane prepared by blending PCL70 and poly(lactic acid) (PLA) in the molar ratio of 5:1 was used, long-term sustained release property was not obtained. Instead, lower MW PCL, PCL40, was blended with PLA (5:1) to prepare surface membrane, sustained release of leuprolide was observed for 5 weeks. Through those studies, 3LMC has been shown to be a long-term sustained release preparation by properly selecting the surface membrane. PMID- 19782738 TI - An investigation into the kinetic (sliding) friction of some tablets and capsules. AB - The kinetic (or sliding) friction of pharmaceutical tablets and capsules influences how they will behave during the conveying, coating, and packaging operations that are used for drug product manufacturing. In order to logically design equipment for manufacturing and packaging operations, and to simulate manufacturing and packaging performance (for example, using discrete or finite element modeling approaches), it is necessary to quantify the magnitude of the kinetic friction. In this work, the coefficient of kinetic friction of a range of pharmaceutical tablets and capsules has been measured for the first time using a pin-on-disk tribometer. Binary tablet-tablet contacts and the contacts between tablets or capsules and common equipment surfaces were studied. The range of the friction coefficients was large (between 0.00 and 0.74), and the values depended strongly on the identity of both contacting materials. Tablet-tablet contacts generally exhibited lower friction coefficients than tablet-polymer or tablet metal contacts. Polymeric surfaces were generally less frictional than metal surfaces, even those that were highly polished. Tablet coatings appeared to have a marked effect on the kinetic friction coefficient between tablets and equipment surfaces, with the hardest coatings tending to be the least frictional. The surface roughness of the tablets and contacting surfaces did not contribute to the coefficient of kinetic friction in a consistent manner. The implications of the results for the design of conveying, processing and packaging operations are discussed. PMID- 19782740 TI - Characterization and pharmacokinetic analysis of tacrolimus dispersion for nebulization in a lung transplanted rodent model. AB - Lung transplantation animal models have been well established and enabled the investigation of a variety of new pharmacotherapeutic strategies for prevention of lung allograft rejection. Direct administration of immunosuppressive agents to the lung is a commonly investigated approach; however, can prove challenging due to the poor solubility of the drug molecule, the tortuous pathways of the lung periphery, and the limited number of excipients approved for inhalation. In this study, we aimed to evaluate a solubility enhancing formulation of tacrolimus for localized therapy in a lung transplanted rat model and determine the extent of drug absorption into systemic circulation. Characterization of the nebulized tacrolimus dispersion for nebulization showed a fine particle fraction (FPF) of 46.1% and a mass median aerodynamic diameter (MMAD) of 4.06 microm. After single dose administration to transplanted and non-transplanted rats, a mean peak transplanted lung concentration of 399.8+/-29.2 ng/g and mean peak blood concentration of 4.88+/-1.6 ng/mL were achieved. It is theorized that enhanced lung retention of tacrolimus is due to lipophilic associations with bronchial tissue and phospholipid surfactants in lung fluid. These findings indicate that tacrolimus dispersion for nebulization can achieve highly localized therapy for lung transplant recipients. PMID- 19782741 TI - Nanoparticles formed from PNIPAM-g-PEO copolymers in the presence of indomethacin. AB - Biocompatible double-hydrophilic PNIPAM-g-PEO copolymers containing 0.3-3.2 mol% PEO grafts were synthesized and utilized to prepare indomethacin (IMC)-loaded core-shell nanoparticles by dialysis and nanoprecipitation methods. IMC loading was conducted at room temperature using the organic solvents ethanol and DMF, which induced phase separation in the copolymers aqueous solutions due to the cononsolvency of PNIPAM. In ethanol-water solutions, the cononsolvency-induced phase separation of the copolymers promoted effective drug incorporation into the formed micellar structures. In DMF-water system, the formation of the nanoparticles did not correspond to the cononsolvent region of PNIPAM-g-PEO. In this case, hydrophobic interactions between PNIPAM and IMC allowed the copolymer self-association and drug loading. Irrespective of the solvents or preparation methods applied, the drug loading content (DLC) depended on the drug-to-copolymer feed weight ratio. DLC was relatively low at the 0.5:1 ratio but it significantly increased at the ratios of 0.75:1 and 1:1 (DLC approximately 90%). The particle size was strongly affected by the different mechanisms of nanoparticles formation. The nanoprecipitation from ethanol produced significantly smaller particles (<150 nm) with narrow size distribution than the dialysis from DMF. The velocity of indomethacin release from the nanoparticles was influenced by the amount of encapsulated drug, the process being faster at lower DLC. PMID- 19782739 TI - MRP isoforms and BCRP mediate sulfate conjugate efflux out of BeWo cells. AB - The breast cancer resistance protein (BCRP) and the multidrug resistance associated proteins (MRPs) have the ability to eliminate sulfate conjugates but it is not known if this constitutes one of their roles in the placenta. To determine this, the BeWo cell line was used as a model of placental trophoblast cells and the mechanisms of elimination of sulfate metabolites of two common sulfotransferase substrates, 4-nitrophenol and acetaminophen were examined. At 0.5-200 microM, neither 4-nitrophenyl sulfate nor acetaminophen sulfate affected the accumulation of the BCRP substrates BODIPY FL prazosin or mitoxantrone in BeWo monolayers, indicating a lack of interaction of BCRP with the sulfates. Examination of the effect of BCRP/MRP inhibitors on the efflux of intracellularly generated 4-nitrophenyl sulfate and acetaminophen sulfate, indicated that one or more of the MRP isoforms play a major role in the elimination of 4-nitrophenyl sulfate and acetaminophen sulfate across the basolateral (fetal-facing) and apical (maternal-facing) membranes respectively. BCRP played a minor role in the elimination of these two sulfate conjugates across the apical membrane. This study demonstrates that a yet undetermined role of trophoblast efflux transporters is the elimination of sulfate conjugates. PMID- 19782742 TI - Identification and functional characterization of breast cancer resistance protein in human bronchial epithelial cells (Calu-3). AB - Breast cancer resistance protein (BCRP), a 72 kDa protein belongs to the subfamily G of the human ATP-binding cassette transporter superfamily. Overexpression of BCRP was found to play a major role in the development of resistance against various chemotherapeutic agents. BCRP plays an important role in absorption, distribution and elimination of several therapeutic agents. BCRP expression and functional activity across human bronchial epithelium and its impact on pulmonary drug accumulation has not been established. The objective of this study was to identify and characterize the BCRP efflux transporter across human bronchial epithelium. Calu-3, a human bronchial epithelial cell line was employed as a model for this study. Reverse transcription-polymerase chain reaction (RT-PCR), Western blot and immunocytochemical studies were performed to identify and characterize the expression of BCRP. RT-PCR studies detected ABCG2 mRNA levels in Calu-3 cells. A strong band for BCRP with a molecular weight of approximately 72 kDa was observed in Western blot analysis. Immunocytochemical studies confirmed the presence of BCRP on the apical membrane of human bronchial epithelium. Functional activity of BCRP was determined by performing uptake of radioactive substrate [3H]-mitoxantrone in the presence and absence of BCRP inhibitors. Uptake of [3H]-mitoxantrone was elevated significantly in the presence of GF120918 and fumitremorgin C. An increase in the accumulation of Hoechst 33342, a fluorescent dye was also detected in the presence of BCRP inhibitors when compared to control. In summary, this study provides evidence for the presence of an ATP dependent, membrane bound efflux transporter BCRP across human bronchial epithelial cell line, Calu-3. PMID- 19782743 TI - Characterization, stabilization and activity of uricase loaded in lipid vesicles. AB - Uricase-containing lipid vesicles (UOXLVs) were prepared by reverse-phase evaporation method with high efficiency and the characteristics of UOXLVs were described. The average size and zeta potential of UOXLVs obtained by the optimized formulation were 205.47 nm and -37.33 mV, respectively. Uricase was encapsulated in the alkaline aqueous phase of the lipid vesicle and the stability of its tetrameric structure was thus improved and its activity preserved. The storage stability of uricase in lipid vesicles was significantly increased compared to that of free uricase at 4 degrees C in borate buffer of pH 8.5. At 55 degrees C, free uricase was deactivated much more quickly especially at lower concentration predominantly due to enhanced dissociation of uricase into subunits. An intrinsic tryptophan of uricase recovered from the lipid vesicle thermally treated at 55 degrees C revealed that a partially denatured uricase molecule was stabilized through its hydrophobic interaction with lipid vesicle membrane. This interaction was depressed mainly by dissociation of uricase into subunits. At the physiological pH, significant increase of enzyme activity was found for the uricase entrapped in the lipid vesicles (1.8 times that of free uricase) at their respective optimum pH. The shift of optimum pH and increased uricolytic activity suggested the conformation change of the uricase during the entrapment process. The stability to proteolytic digestion was increased obviously by entrapping the uricase in the lipid vesicles. UOXLVs also showed relatively slower loss in activity compared with free uricase when treated with some chemical reagents. Lastly, in vitro study explicitly indicated that the uricase entrapped by UOXLVs possessed higher uricolytic activity than that of native uricase solution. PMID- 19782744 TI - Value of the ethnomedical information for the discovery of plants with antifungal properties. A survey among seven Latin American countries. AB - ETHNOPHARMACOLOGICAL RELEVANCE: This study reports the antifungal evaluation of 327 plant species (92 families and 251 genera) from seven Latin American countries which were selected on the basis of their reported ethnomedical uses and compared them with plants selected at random. AIM OF THE STUDY: (a) The main aim of this study was to investigate whether the probability of detecting antifungal plants is higher when plants have reports of ethnopharmacological uses related to fungal infections (PAU group) than when they are selected at random (PNAU group). (b) The second objective was to determine, within the PAU group, whether the probability of obtaining a positive result will be higher when the plants are tested against dermatophytes, than against yeasts or Aspergillus spp. (c) The third goal was to investigate, within all MICs0.05). (c) Within the detected antifungal plants from both groups, plants of the PAU group displayed higher activities (lower MICs) than those of PNAU group against dermatophytes (p<0.05) but not against yeasts or Aspergillus spp. CONCLUSIONS: Considering that dermatophytes are the cause of superficial fungal infections, which can be easily detected and followed by traditional healers, our findings suggest that the ethnopharmacological approach is useful in guiding the detection of antifungal plants in Latin America mainly for infections in which the pathological expression is obvious and, therefore, the cure can be clearly observed. PMID- 19782745 TI - Immediate and enduring effects of neonatal isolation on maternal behavior in rats. AB - Previously, we showed that neonatal isolation (1-hisolation/day from dam, litter, and nest on PND 2-9) facilitates cocaine self-administration and increases extracellular dopamine responses in ventral striatum after stimulant administration in adulthood. Recent studies suggest that enduring alterations in neurobehavioral responses associated with early life manipulations reflect changes in maternal behavior. Thus, we sought to determine if neonatal isolation alters maternal care and if dams with neonatal isolation experience as pups showed differential maternal care towards their pups. In Experiment 1, litters were assigned to one of three conditions: neonatal isolation, handled (5-min separation of dam from litter), or non-handled (no separation). Maternal behaviors were rated on PND 2-9 for 60-min immediately following reunion of mother and litter. In Experiment 2, female rats with or without neonatal isolation experience were assigned to either the neonatal isolation or non handled litter condition and maternal behaviors rated. Dams of isolated and handled litters spent more time licking pups and less time picking up pups to put outside the nest than dams of non-handled litters. Further, dams of isolated and handled vs. non-handled litters showed less non-maternal behaviors of burrowing and grooming. Neonatal isolation-experienced dams with isolated litters failed to increase pup-licking and decrease non-maternal behaviors. Rather, these dams picked up pups to place outside the nest more than non-handled-experienced dams. Neonatal isolation alters maternal behavior that, in turn, may shape neurobehavioral responses of offspring including effects on maternal care. Such changes may reflect epigenetic effects resulting from changes in maternal behavior. PMID- 19782747 TI - TNFalpha activation of PKCdelta, mediated by NFkappaB and ER stress, cross-talks with the insulin signaling cascade. AB - TNFalpha plays key roles in the regulation of inflammation, cell death, and proliferation and its signaling cascade cross-talks with the insulin signaling cascade. PKCdelta, a novel PKC isoform, is known to participate in proximal TNFalpha signaling events. However, it has remained unclear whether PKCdelta plays a role in distal TNFalpha signaling events. Here we demonstrate that PKCdelta is activated by TNFalpha in a delayed fashion that is temporally associated with JNK activation. To investigate the signaling pathways activating PKCdelta and JNK, we used pharmacological and genetic inhibitors of NFkappaB. We found that inhibition of NFkappaB attenuated PKCdelta and JNK activations. Further analysis revealed that ER stress contributes to TNFalpha-stimulated PKCdelta and JNK activations. To investigate the role of PKCdelta in TNFalpha action, we used 29-mer shRNAs to silence PKCdelta expression. A reduction of ~90% in PKCdelta protein levels reduced TNFalpha-stimulated stress kinase activation, including JNK. Further, PKCdelta was necessary for thapsigargin-stimulated JNK activation. Because thapsigargin is a potent inducer of ER stress, we determined whether PKCdelta was necessary for induction of the UPR. Indeed, a reduction in PKCdelta protein levels reduced thapsigargin-stimulated CHOP induction, a hallmark of the UPR, but not BiP/GRP78 induction, suggesting that PKCdelta does not globally regulate the UPR. Next, the role of PKCdelta in TNFalpha mediated cross-talk with the insulin signaling pathway was investigated in cells expressing human IRS-1 and a 29-mer shRNA to silence PKCdelta expression. We found that a reduction in PKCdelta protein levels reversed the TNFalpha-mediated reduction in insulin-stimulated IRS-1 Tyr phosphorylation, Akt activation, and glycogen synthesis. In addition, TNFalpha-stimulated IRS protein Ser/Thr phosphorylation and degradation were blocked. Our results indicate that: 1) NFkappaB and ER stress contribute in part to PKCdelta activation; 2) PKCdelta plays a key role in the propagation of the TNFalpha signal; and 3) PKCdelta contributes to TNFalpha-induced inhibition of insulin signaling events. PMID- 19782746 TI - Enduring consequences of early-life infection on glial and neural cell genesis within cognitive regions of the brain. AB - Systemic infection with Escherichia coli on postnatal day (P) 4 in rats results in significantly altered brain cytokine responses and behavioral changes in adulthood, but only in response to a subsequent immune challenge with lipopolysaccharide [LPS]. The basis for these changes may be long-term changes in glial cell function. We assessed glial and neural cell genesis in the hippocampus, parietal cortex (PAR), and prefrontal cortex (PFC), in neonates just after the infection, as well as in adulthood in response to LPS. E. coli increased the number of newborn microglia within the hippocampus and PAR compared to controls. The total number of microglia was also significantly increased in E. coli-treated pups, with a concomitant decrease in total proliferation. On P33, there were large decreases in numbers of cells coexpressing BrdU and NeuN in all brain regions of E. coli rats compared to controls. In adulthood, basal neurogenesis within the dentate gyrus (DG) did not differ between groups; however, in response to LPS, there was a decrease in neurogenesis in early infected rats, but an increase in controls to the same challenge. There were also significantly more microglia in the adult DG of early-infected rats, although microglial proliferation in response to LPS was increased in controls. Taken together, we have provided evidence that systemic infection with E. coli early in life has significant, enduring consequences for brain development and subsequent adult function. These changes include marked alterations in glia, as well as influences on neurogenesis in brain regions important for cognition. PMID- 19782748 TI - EP2 receptor mediated cAMP release is augmented by PGF 2 alpha activation of the FP receptor via the calcium-calmodulin pathway. AB - Prostaglandins exert their effects on target cells by coupling to specific G protein-coupled receptors (GPCRs) that are often co-expressed in the same cells and use alternate and in some cases opposing intracellular signaling pathways. This study investigated the cross-talk that influences intracellular signaling and gene expression profiling in response to co-activation of the EP2 and FP prostanoid receptors in Ishikawa cells stably expressing both receptors (FPEP2 cells). In this study we show that in FPEP2 cells, PGF alone does not alter adenosine 3',5'-cyclic monophosphate (cAMP) production, but in combination with Butaprost enhances EP2 receptor mediated cAMP release compared to treatment with Butaprost alone. PGF-mediated potentiation of cAMP release was abolished by antagonism of the FP receptor, inhibition of phospholipase C (PLC) and inositol phosphate receptor (IP3R) whereas inhibition of protein kinase C (PKC) had no effect. Moreover, inhibition of calcium effectors using calmodulin antagonist (W7) or Ca(2+)/calmodulin-dependent kinase II (CaMK-II) inhibitor (KN-93) abolished PGF potentiation of Butaprost-mediated cAMP release. Using siRNA molecules targeted against the adenylyl cyclase 3 (AC3) isoform, we show that AC3 is responsible for the cross-talk between the FP and EP2 receptors. Using gene array studies we have identified a candidate gene, Spermidine/N1 acetyltransferase (SAT1), which is regulated by this cAMP mediated cross-talk. In conclusion, this study demonstrates that co-activation of the FP and EP2 receptors results in enhanced release of cAMP via FP receptor-G alpha(q)-Ca(2+) calmodulin pathway by activating calcium sensitive AC3 isoform. PMID- 19782749 TI - Characterization of intestinal bacteria tightly bound to the human ileal epithelium. AB - In order to perform selective isolation of bacteria tightly bound to the human gut, ileal biopsies of healthy volunteers were treated to wash out the mucus layer and loosely bound bacterial cells. Rod-shaped anaerobic bacteria that had remained attached to the epithelial cells were isolated and identified at the species level. One isolate was identified as belonging to the Bifidobacterium breve species, while all the others were lactobacilli of only two species, Lactobacillus mucosae and Lactobacillus gasseri. Members of these species were found previously in intestinal samples, but their predominance among bacteria strictly associated with the epithelium was not suspected before and suggests that these species may represent a specific subpopulation of tissue-bound bacteria. Physiological analysis indicated that all isolates were able to produce antimicrobials, grow and form biofilm in simulated intestinal fluid after exposure to gastric conditions. Some isolates were able to degrade mucin while none showed cytotoxicity in vitro on HT29 cells. The tight association of the strains isolated with ileal epithelial cells is presumably indicative of a direct interaction with the host cells. For this reason and for the absence of cytotoxicity in vitro, those isolates can be proposed as potential probiotic strains for human use. PMID- 19782750 TI - Oxidation of elemental sulfur, tetrathionate and ferrous iron by the psychrotolerant Acidithiobacillus strain SS3. AB - Mesophilic iron and sulfur-oxidizing acidophiles are readily found in acid mine drainage sites and bioleaching operations, but relatively little is known about their activities at suboptimal temperatures and in cold environments. The purpose of this work was to characterize the oxidation of elemental sulfur (S(0)), tetrathionate (S4O6(2-)) and ferrous iron (Fe2+) by the psychrotolerant Acidithiobacillus strain SS3. The rates of elemental sulfur and tetrathionate oxidation had temperature optima of 20 degrees and 25 degrees C, respectively, determined using a temperature gradient incubator that involved narrow (1.1 degrees C) incremental increases from 5 degrees to 30 degrees C. Activation energies calculated from the Arrhenius plots were 61 and 89 kJ mol(-1) for tetrathionate and 110 kJ mol(-1) for S(0) oxidation. The oxidation of elemental sulfur produced sulfuric acid at 5 degrees C and decreased the pH to approximately 1. The low pH inhibited further oxidation of the substrate. In media with both S(0) and Fe2+, oxidation of elemental sulfur did not commence until all available ferrous iron was oxidized. These data on sequential oxidation of the two substrates are in keeping with upregulation and downregulation of several proteins previously noted in the literature. Ferric iron was reduced to Fe2+ in parallel with elemental sulfur oxidation, indicating the presence of a sulfur:ferric iron reductase system in this bacterium. PMID- 19782751 TI - GDAP1 mutations differ in their effects on mitochondrial dynamics and apoptosis depending on the mode of inheritance. AB - Mutations in the GDAP1 gene lead to recessively or dominantly inherited peripheral neuropathies (Charcot-Marie-Tooth disease; CMT). Here, we demonstrate that GDAP1 is a mitochondrial fission factor whose activity is dependent on the fission factors Drp1 and Fis1. Unlike other mitochondrial fission factors, GDAP1 overexpression or knockdown does not influence the susceptibility of cells to apoptotic stimuli. Recessively inherited CMT-associated forms of GDAP1 (rmGDAP1s) have reduced fission activity, whereas dominantly inherited forms (dmGDAP1s) interfere with mitochondrial fusion. Only the expression of dmGDAP1s increases the production of ROS, leads to uneven mitochondrial transmembrane potentials, and enhances the susceptibility to apoptotic stimuli. Taken together, our results indicate that wild-type GDAP1 promotes fission without increasing the risk of apoptosis. In CMT, recessive GDAP1 mutations are associated with reduced fission activity, while dominant mutations impair mitochondrial fusion and cause mitochondrial damage. Thus, different cellular mechanisms that disturb mitochondrial dynamics underlie the similar clinical manifestations caused by GDAP1 mutations, depending on the mode of inheritance. PMID- 19782752 TI - Involvement of phosphatidylcholine-phospholipase C and protein kinase C in peptidoglycan-induced nuclear factor-kappaB activation and cyclooxygenase-2 expression in RAW 264.7 macrophages. AB - In this study, we examined the role of phosphatidylcholine-phospholipase C (PC PLC) and protein kinase C (PKC) in peptidoglycan (PGN)-induced nuclear factor kappaB (NF-kappaB) activation and cyclooxygenase-2 (COX-2) expression in RAW 264.7 macrophages. PGN-induced COX-2 expression was attenuated by a PC-PLC inhibitor (D609) and by PKC inhibitors (Go 6976 and Ro 31-8220), but not by a phosphatidylinositol-PLC (PI-PLC) inhibitor (U-73122). PGN caused an increase in PKC activity, and this effect was inhibited by D609, Go 6976, and Ro 31-8220, but not by U-73122. Furthermore, the PGN-mediated increases in kappaB-luciferase activity were also inhibited by D609 and Ro 31-8220. Our data demonstrate that PGN activates PC-PLC which induces PKC activation; this in turn initiates NF kappaB activation, and ultimately induces COX-2 expression in RAW 264.7 macrophages. PMID- 19782753 TI - Combined inhibition of Cdk5 and ROCK additively increase cell survival, but not the regenerative response in regenerating retinal ganglion cells. AB - CNS regeneration is limited by lesion-induced neuronal apoptosis and an environment inhibiting axonal elongation. Inhibition of ROCK has been previously shown to promote regeneration in retinal ganglion cells (RGC) whereas Cdk5 inhibition mainly promoted survival. Therefore, we have evaluated the effects of combined treatment with inhibitors of ROCK and Cdk5. We show that in vitro, the co-application of the Cdk5 inhibitor, Indolinone A, and the ROCK inhibitor, Y 27632, potentiated the survival-promoting effect of either substance alone. However, neurite outgrowth in vitro was promoted only by the presence of Y-27632, not by Indolinone A alone. In the ex vivo explant and the in vivo optic nerve crush model the combination of both inhibitors significantly increased neurite outgrowth at small distances, but this effect leveled off for longer neurites. In summary, the combined treatment with the Cdk5 inhibitor Indolinone A and the ROCK inhibitor Y-27632 results in a strong additive effect on neuronal survival, but is not able to increase the regenerative response beyond the effect of the ROCK inhibitor. PMID- 19782754 TI - Large-scale expression in Escherichia coli and efficient purification of precursor and active caspase-7 by introduction of thrombin cleavage sites. AB - Caspases are a family of cysteine proteases that have critical roles in the apoptotic pathway. Caspase-7 is a well-known apoptotic effector that cleaves a variety of cellular substrates, and is known to be an important target in the treatment of many diseases. For efficient research, large amounts of the protein are required. However, it has been difficult to obtain sufficient quantities of either the precursor or active caspase-7 from Escherichia coli strain. In the present study, we constructed thrombin-activatable caspase-7 precursors by changing the auto-activation sites of the caspase-7 precursor into sequences susceptible to thrombin cleavage. These engineered precursors were highly expressed as soluble proteins in E. coli, and were easily purified by affinity chromatography (to levels of 10-15 mg per liter of E. coli culture), and were then readily activated by treatment with thrombin. In vitro cleavage assays and kinetic analyses revealed that the engineered active caspase-7 proteins had characteristics similar to those of wild-type caspase-7. This novel method is valuable for obtaining both precursor and active caspase-7, thereby contributing to the development of caspase-7-specific drugs to treat various diseases, including cancer and neurodegenerative conditions. PMID- 19782755 TI - Expression of the human soluble epoxide hydrolase in Escherichia coli by auto induction for the study of high-throughput inhibition assays. AB - Soluble epoxide hydrolase (sEH) is a key enzyme involved in the metabolism of epoxy fatty acid mediators such as epoxyeicosatrienoic acids with emerging roles in the regulations of hypertension and inflammation. Inhibitors of human sEH (hsEH) are effective drug candidates for the treatment of cardiovascular diseases. Preparation of hsEH for enzyme inhibition studies has been carried out by using baculovirus expression system. We herein explored the feasibility of expression of hsEH in Escherichia coli cells for the study of high-throughput screening assays of enzyme inhibitors, because the bacterial expression system is easier to handle and more cost-effective than the baculovirus expression system. The functional target enzyme was successfully produced in prokaryotic expression system by an auto-induction method and exhibited comparable enzyme activity to that yielded in baculovirus expression system. The bacterial-hsEH showed similar sensitivity to the baculovirus-hsEH against six reported inhibitors. Overalls indicate that bacterial expression of hsEH employed in the present study is useful for preparing enzymatically active hsEH, leading to effective performance of high-throughput screening assay of hsEH inhibitors and to rapid identification of novel drug candidates for the treatment of cardiovascular diseases. PMID- 19782757 TI - Dichotic pitch activates pitch processing centre in Heschl's gyrus. AB - Although several neuroimaging studies have reported pitch-evoked activations at the lateral end of Heschl's gyrus, it is still under debate whether these findings truly represent activity in relation to the perception of pitch or merely stimulus-related features of pitch-evoking sounds. We investigated this issue in a functional magnetic resonance imaging (fMRI) experiment using pure tones in noise and dichotic pitch sequences, which either contained a melody or a fixed pitch. Dichotic pitch evokes a sensation of pitch only in binaural listening conditions, while the monaural signal cannot be distinguished from random noise. Our data show similar neural activations for both tones in noise and dichotic pitch, which are perceptually similar, but physically different. Pitch-related activation was found at the lateral end of Heschl's gyrus in both hemispheres, providing new evidence for a general involvement of this region in pitch processing. In line with prior studies, we found melody-related activation in Planum temporale and Planum polare, but not in primary auditory areas. These results support the view of a general representation of pitch in auditory cortex, irrespective of the physical attributes of the pitch-evoking sound. PMID- 19782756 TI - Bimodal modulation and continuous stimulation in optical imaging to map direction selectivity. AB - In the visual system, neurons with similar functional properties such as orientation and direction selectivity are clustered together to form modules. Optical imaging recordings in combination with episodic paradigms have been previously used to estimate direction selectivity, a fundamental property of visual neurons. The major drawback of the episodic approach is that the extraction of the signal from various forms of physiological noise is difficult, leading to a poor estimation of direction. Recent work, based on periodic stimulation and Fourier decomposition improved the extraction of periodic stimulus responses from noise and thus, reduced the recording time considerably. Given the success of this new paradigm in mapping orientation, the present study evaluated its reliability to measure direction selectivity in the visual cortex of anesthetized cats. Here, a model that exploits the harmonics of the Fourier decomposition is proposed where the first harmonic is related to direction responses, and the second to orientation. As expected, the first harmonic was absent when a static stimulus was presented. Contrarily, the first harmonic was present when moving stimuli were presented and the amplitude was greater with random dots kinematograms than with drifting gratings. The phase of the first harmonic showed a good agreement with direction preference measured by episodic paradigm. The ratio of the first/the second harmonic amplitude, related to a direction index, was weaker in fracture. It was also weaker in areas of the ventral pathway (areas 17 and 21a) where direction selectivity is known to be reduced. These results indicate that a periodic paradigm can be easily used to measure specific parameters in optical signals, particularly in situations when short acquisition periods are needed. PMID- 19782758 TI - Age-related differences in white matter microstructure: region-specific patterns of diffusivity. AB - We collected MRI diffusion tensor imaging data from 80 younger (20-32 years) and 63 older (60-71 years) healthy adults. Tract-based spatial statistics (TBSS) analysis revealed that white matter integrity, as indicated by decreased fractional anisotropy (FA), was disrupted in numerous structures in older compared to younger adults. These regions displayed five distinct region-specific patterns of age-related differences in other diffusivity properties: (1) increases in both radial and mean diffusivity; (2) increases in radial diffusivity; (3) no differences in parameters other than FA; (4) a decrease in axial and an increase in radial diffusivity; and (5) a decrease in axial and mean diffusivity. These patterns suggest different biological underpinnings of age related decline in FA, such as demyelination, Wallerian degeneration, gliosis, and severe fiber loss, and may represent stages in a cascade of age-related degeneration in white matter microstructure. This first simultaneous description of age-related differences in FA, mean, axial, and radial diffusivity requires histological and functional validation as well as analyses of intermediate age groups and longitudinal samples. PMID- 19782759 TI - Annual sex steroid and other physiological profiles of Pacific lampreys (Entosphenus tridentatus). AB - We documented changes in plasma levels of estradiol 17-beta (E2), progesterone (P), 15alpha-hydroxytestosterone (15alpha-T), thyroxine (T4), triiodothyronine (T3), protein, triglycerides (TGs), and glucose in adult Pacific lampreys (Entosphenus tridentatus) held in the laboratory in two different years. Levels of E2 in both sexes ranged from 0.5 to 2 ng/mL from September to March, peaked in late April (2-4 ng/mL), and decreased in May, with levels higher in males than in females. Levels of P were low from September through April, but then increased substantially during May (2-4 ng/mL), with levels again highest in males. Levels of 15alpha-T in males were around 0.75 ng/mL through the winter before exceeding 1 ng/mL in April and decreasing thereafter, whereas females showed a gradual increase from 0.25 ng/mL in November to 0.5 ng/mL in April before decreasing. Thyroxine concentrations differed between fish in each year, with most having levels ranging from 0.75 to 2.5 ng/mL in the fall and winter, and only fish in 2003 showing distinct peaks (3-4 ng/mL) in early April or May. Plasma T3 was undetectable from November through mid-March before surging dramatically in April (ca. 150 ng/mL) and decreasing thereafter. Levels of protein, TGs, and glucose decreased or were stable during the fall and winter with TGs and glucose surging in late April to early May for some fish. Our study is the first to document long term physiological changes in Pacific lampreys during overwintering and sexual maturation and increases our understanding of the life history of this unique fish. PMID- 19782760 TI - Gastro-intestinal handling of water and solutes in three species of elasmobranch fish, the white-spotted bamboo shark, Chiloscyllium plagiosum, little skate, Leucoraja erinacea and the clear nose skate Raja eglanteria. AB - The present study reports aspects of GI tract physiology in the white-spotted bamboo shark, Chiloscyllium plagiosum, little skate, Leucoraja erinacea and the clear nose skate, Raja eglanteria. Plasma and stomach fluid osmolality and solute values were comparable between species, and stomach pH was low in all species (2.2 to 3.4) suggesting these elasmobranchs may maintain a consistently low stomach pH. Intestinal osmolality, pH and ion values were comparable between species, however, some differences in ion values were observed. In particular Ca(2+) (19.67+/-3.65mM) and Mg(2+) (43.99+/-5.11mM) were high in L. erinacea and Mg(2+) was high (130.0+/-39.8mM) in C. palgiosum which may be an indication of drinking. Furthermore, intestinal fluid HCO(3)(-) values were low (8.19+/-2.42 and 8.63+/-1.48mM) in both skates but very high in C. plagiosum (73.3+/-16.3mM) suggesting ingested seawater may be processed by species-specific mechanisms. Urea values from the intestine to the colon dropped precipitously in all species, with the greatest decrease seen in C. plagiosum (426.0+/-8.1 to 0mM). This led to the examination of the molecular expression of both a urea transporter and a Rhesus like ammonia transporter in the intestine, rectal gland and kidney in L. erinacea. Both these transporters were expressed in all tissues; however, expression levels of the Rhesus like ammonia transporter were orders of magnitude higher than the urea transporter in the same tissue. Intestinal flux rates of solutes in L. erinacea were, for the most part, in an inward direction with the notable exception of urea. Colon flux rates of solutes in L. erinacea were all in an outward direction, although absolute rates were considerably lower than the intestine, suggestive of a much tighter epithelia. Results are discussed in the context of the potential role of the GI tract in salt and water, and nitrogen, homeostasis in elasmobranchs. PMID- 19782761 TI - Interplay between influenza A virus and the innate immune signaling. AB - Pathogens such as influenza A viruses (IAV) have to overcome a number of barriers defined and maintained by the host, to successfully establish an infection. One of the initial barriers is collectively characterized as the innate immune system. This is a broad anti-pathogen defense program that ranges from the action of natural killer cells to the induction of an antiviral cytokine response. In this article we will focus on new developments and discoveries concerning the interaction of IAV with the cellular innate immune signaling. We discuss new mechanisms of interference of IAV with the pathogen recognition receptor RIG-I and the type I IFN antagonist NS1 in the background of already known and established concepts. Further we summarize progress related to recently identified IFN induced proteins and the role of RNA interference in the context of IAV infection. PMID- 19782762 TI - Mammalian Ste20-like protein kinase 3 induces a caspase-independent apoptotic pathway. AB - In this study, it was shown that the mammalian sterile 20-like serine/threonine protein kinase 3 (Mst3) plays an essential role in the staurosporine-induced apoptosis of HeLa cells. The staurosporine-induced apoptosis was reduced by around 65% by the selective knockdown of Mst3 in stable clones, HeLa(siMst3). Although caspases were shown to be involved in the Mst3-mediated apoptosis, only 15-20% of staurosporine-induced apoptosis was suppressed by the caspase inhibitor, z-DEVD-fmk. Accordingly, Mst3 was proposed to trigger a caspase independent apoptotic pathway in response to staurosporine. Interestingly, staurosporine greatly induced the mitochondrial membrane potential transition in HeLa cells, but had no effect in Hela(siMst3). The role of Mst3 in controlling the mitochondrial integrity was therefore proposed, presumably through the regulation of Bax. Furthermore, it was shown that staurosporine promoted the nuclear translocation of apoptosis-inducing factor and endonuclease G in HeLa cells. The nuclease activity associated with endonuclease G was also enhanced in response to staurosporine. However, both staurosporine-induced nuclear translocation of apoptosis-inducing factor and endonuclease G and the nuclease activity associated with endonuclease G were markedly reduced in Hela(siMst3). These results suggest that Mst3 may respond to staurosporine to trigger the caspase-independent apoptotic pathway by regulating the nuclear translocation of apoptosis-inducing factor and endonuclease G, and the nuclease activity associated with endonuclease G. PMID- 19782763 TI - Caspase-7: a protease involved in apoptosis and inflammation. AB - Caspase-7 was considered to be redundant with caspase-3 because these related cysteine proteases share an optimal peptide recognition sequence and have several endogenous protein substrates in common. In addition, both caspases are proteolytically activated by the initiator caspase-8 and -9 during death receptor and DNA-damage-induced apoptosis, respectively. However, a growing body of biochemical and physiological data indicate that caspase-7 also differs in significant ways from caspase-3. For instance, several substrates are specifically cleaved by caspase-7, but not caspase-3. Moreover, caspase-7 activation requires caspase-1 inflammasomes under inflammatory conditions, while caspase-3 processing proceeds independently of caspase-1. Finally, caspase-7 deficient mice are resistant to endotoxemia, whereas caspase-3 knockout mice are susceptible. These findings suggest that specifically interfering with caspase-7 activation may hold therapeutic value for the treatment of cancer and inflammatory ailments. PMID- 19782764 TI - Recruitment of brown fat and conversion of white into brown adipocytes: strategies to fight the metabolic complications of obesity? AB - The role of white and brown adipose tissues in energy metabolism is well established. However, the existence of brown fat in adult humans was until very recently a matter of debate, and the molecular mechanisms underlying brown adipocyte development remained largely unknown. In 2009, several studies brought direct evidence for functional brown adipose tissue in adults. New factors involved in brown fat cell differentiation have been identified. Moreover, work on the origin of fat cells took an unexpected path with the recognition of different populations of brown fat cell precursors according to the anatomical location of the fat depots: a precursor common to skeletal muscle cells and brown adipocytes from brown fat depots, and a progenitor cell common to white adipocytes and brown adipocytes that appear in certain conditions in white fat depots. There is also mounting evidence that mature white adipocytes, including human fat cells, can be converted into brown fat-like adipocytes, and that the typical fatty acid storage phenotype of white adipocyte can be altered towards a fat utilization phenotype. These data open up new opportunities for the development of drugs for obesity and its metabolic and cardiovascular complications. PMID- 19782765 TI - Role of fatty acid uptake and fatty acid beta-oxidation in mediating insulin resistance in heart and skeletal muscle. AB - Fatty acids are a major fuel source used to sustain contractile function in heart and oxidative skeletal muscle. To meet the energy demands of these muscles, the uptake and beta-oxidation of fatty acids must be coordinately regulated in order to ensure an adequate, but not excessive, supply for mitochondrial beta oxidation. However, imbalance between fatty acid uptake and beta-oxidation has the potential to contribute to muscle insulin resistance. The action of insulin is initiated by binding to its receptor and activation of the intrinsic protein tyrosine kinase activity of the receptor, resulting in the initiation of an intracellular signaling cascade that eventually leads to insulin-mediated alterations in a number of cellular processes, including an increase in glucose transport. Accumulation of fatty acids and lipid metabolites (such as long chain acyl CoA, diacylglycerol, triacylglycerol, and/or ceramide) can lead to alterations in this insulin signaling pathway. An imbalance between fatty acid uptake and oxidation is believed to be responsible for this lipid accumulation, and is thought to be a major cause of insulin resistance in obesity and diabetes, due to lipid accumulation and inhibition of one or more steps in the insulin signaling cascade. As a result, decreasing muscle fatty acid uptake can improve insulin sensitivity. However, the potential role of increasing fatty acid beta oxidation in the heart or skeletal muscle in order to prevent cytoplasmic lipid accumulation and decrease insulin resistance is controversial. While increased fatty acid beta-oxidation may lower cytoplasmic lipid accumulation, increasing fatty acid beta-oxidation can decrease muscle glucose metabolism, and incomplete fatty acid oxidation has the potential to also contribute to insulin resistance. In this review, we discuss the proposed mechanisms by which alterations in fatty acid uptake and oxidation contribute to insulin resistance, and how targeting fatty acid uptake and oxidation is a potential therapeutic approach to treat insulin resistance. PMID- 19782766 TI - Long-term outcome of pneumatic dilation in the treatment of achalasia. AB - BACKGROUND & AIMS: Achalasia is treated with pneumatic dilation or Heller myotomy, but studies suggest poor long-term outcomes. We analyzed long-term outcomes after initial pneumatic dilation and studied factors associated with failure. METHODS: A total of 209 patients (111 men; mean age, 51.2 +/- 1.4 years) with achalasia who were treated with pneumatic dilation between 1992 and 2002 were followed. Outcomes were correlated with demographics, presenting symptoms, manometric features, and treatment variables by using chi(2) and Student t tests. RESULTS: All patients were initially treated with consecutive esophageal dilations up to balloon diameters of 3.0 (26%), 3.5 (41%), or 4.0 cm (33%). After dilations, mean lower esophageal sphincter (LES) pressure had decreased from 31.3 +/- 1.3 to 14.0 +/- 0.7 mm Hg (P < .0001); dysphagia decreased from 96% to 26%; and 49% had gained an average of 4.6 +/- 0.5 kg (weight loss at presentation was 10.6 +/- 0.7 kg in 39%). During follow-up, 66% required no additional treatment, whereas 23% underwent repeat dilations after 79 +/- 8 months. Patients without recurrence were older (41.2 +/- 2.1 vs 56.6 +/- 1.6 years; P < .0001) and had lower post-treatment LES pressure (17.8 +/- 1.2 vs 12.9 +/- 0.6 mm Hg; P < .005). After 70-month follow-up, balloon dilation yielded good or excellent outcomes in 72% of patients. In nonresponders, rescue surgery yielded higher success rates than botulinum toxin therapy (84% vs 44%). Patient satisfaction ranged from good to excellent in 81% of patients. CONCLUSIONS: Treating achalasia with initial dilation and then surgery for short-term failures yielded good long-term results in more than 70% and treatment satisfaction in more than 80% of patients. Management of dilation failures is more problematic. PMID- 19782767 TI - Survival and recurrence in patients with splanchnic vein thromboses. AB - BACKGROUND & AIMS: Hepatic, splenic, portal, and mesenteric veins are confluent elements within the splanchnic system. It is therefore unclear whether thromboses of isolated segments represent unique entities. We compared etiologies, recurrence, and survival of patients with thromboses of different splanchnic venous segments. METHODS: An inception cohort of individuals was identified with first lifetime incident of splanchnic vein thrombosis between 1980 and 2000. We performed a case-controlled comparison of recurrent thrombosis and survival data with those of patients with deep venous thrombosis (DVT). RESULTS: The study (832 patients; mean age, 53 +/- 17 years; 42% women) included patients with isolated portal (n = 329), mesenteric (n = 76), splenic (n = 62), and hepatic (n = 45) vein thrombosis and patients with multisegment involvement (n = 320). Malignancy (27%) and cirrhosis (24%) were the most common etiologies. Recurrence-free survival 10 years after splanchnic vein thrombosis (76%) was comparable with that after DVT (68%) and not improved by anticoagulant therapy. Hormone therapy was the only independent predictor of recurrence (hazard ratio [HR], 2.2; 95% confidence interval [CI], 1.09-4.45; P = .03). Major bleeding was 6.9/100 patient years. Gastroesophageal varices (HR, 2.63; 95% CI, 1.72-4.03; P < .001) and warfarin therapy (HR, 1.91, 95% CI, 1.25-2.92; P = .003) were independent predictors of bleeding. The 10-year survival rate of patients with splanchnic vein thrombosis (60%) was lower than that of patients with DVT (68%, P < .05). Older age (HR, 1.03; 95% CI, 1.02-1.03), active cancer (HR, 2.23; 95% CI, 1.78 2.78), and myeloproliferative disorder (HR, 1.92; 95% CI, 1.41-2.61) were independent determinants of mortality (P < .001). CONCLUSIONS: Splanchnic vein thrombosis depends on the pathology of the organ supplied. On the basis of the low rate of recurrence and substantial rate of major hemorrhage, prolonged anticoagulant therapy does not appear to be justified. PMID- 19782768 TI - Fine tuning T lymphocytes: a role for the lipid phosphatase SHIP-1. AB - The phosphoinositide 3-kinase signaling pathway regulates a range of T lymphocyte cellular functions including growth, proliferation, cytokine secretion and survival. Aberrant regulation of phosphoinositide 3-kinase-dependent signaling in T lymphocytes has been implicated in inflammatory and autoimmune diseases. In common with much of the immune system, several mechanisms exist to ensure the pathway is tightly regulated to elicit appropriate responses. One level of control involves the Src homology 2 domain-containing inositol-5-phosphatase-1 (SHIP-1) that modulates phosphoinositide 3-kinase signaling by degrading the key signaling lipid PI(3,4,5)P(3) to PI(3,4)P(2), but also serves as a key scaffolding molecule in the formation of multi-protein complexes. Here we discuss the role of SHIP-1 in regulating T lymphocyte and immune function, as well as its potential as a therapeutic target. PMID- 19782769 TI - Concanavalin A aggregation and toxicity on cell cultures. AB - A number of neurodegenerative diseases are known to involve protein aggregation. Common mechanisms and structural properties of amyloids are thought to be involved in aggregation-related cytotoxicity. In this context we propose an experimental study on Concanavalin A (Con A) aggregation and use it as a model to study the relationship between cell toxicity and aggregation processes. Depending on solution conditions, Con A aggregation has been monitored by static and dynamic light scattering, Thioflavin T emission, and FTIR absorption. The morphology of different aggregate species was verified by means of Atomic Force Microscopy and Confocal Microscopy. During the aggregation pathway the native protein conformation is destabilized and as a consequence, the simultaneous occurrence of conformational changes and protein aggregation is observed in both conditions. The effects of the extracellular addition of native protein, oligomers and mature fibrils were tested on LAN5 neuroblastoma cells by MTS assay. Results showed the toxicity of the first two species while a negligible effect was detected for amyloid fibrils. Both native and oligomeric aggregates were found to be able to activate apoptosis exclusively by extrinsic pathway through caspase 8 activation. Those results suggest that cytotoxicity mechanisms arise from specific membrane interactions with reactive conformations of destabilized molecules occurring during the amyloidal aggregation pathway. Those conformations, populated when native or preformed oligomers are incubated, are unavailable to bind cell membrane proteins. This happens because they are recruited in the mature fibrillar structure which-as a consequence-turns out to be non-toxic. PMID- 19782770 TI - The two faces of PTP1B in cancer. AB - PTP1B is a classical non-transmembrane protein tyrosine phosphatase that plays a key role in metabolic signaling and is a promising drug target for type 2 diabetes and obesity. Accumulating evidence also indicates that PTP1B is involved in cancer, but contrasting findings suggest that it can exert both tumor suppressing and tumor promoting effects depending on the substrate involved and the cellular context. In this review, we will discuss the diverse mechanisms by which PTP1B may influence tumorigenesis as well as recent in vivo data on the impact of PTP1B deficiency in murine cancer models. Together, these results highlight not only the great potential of PTP1B inhibitors in cancer therapy but also the need for a better understanding of PTP1B function prior to use of these compounds in human patients. PMID- 19782771 TI - Motion characterization by self-distribution-function procedure. AB - In the present paper a procedure for the biomolecular motion characterization based on the evaluation of the Mean Square Displacement (MSD), through the Self Distribution Function (SDF), is presented. In particular it will be shown how the MSD, which represents a good observable for the characterization of the dynamical properties in disordered systems, can be decomposed into partial contributions associated to the system dynamical processes within a specific spatial scale. It will be shown how the SDF procedure allows to evaluate both the total MSD and the partial MSDs through the total SFD and the partial SDFs. As a result, the total MSD is the weighed sum of the partial MSD contributions in which the weights are obtained by the fitting procedure of measured EINS intensity data. We apply the SDF procedure at EINS data collected, by the IN13 backscattering spectrometer at the Institute Laue-Langevin, Grenoble, on aqueous mixtures of two homologous disaccharides (sucrose and trehalose) and on dry myoglobin in trehalose environment. It emerges that the hydrogen bond imposed network of the water trehalose mixture appears to be stronger with respect to that of the water sucrose mixture and this result can justify the highest bioprotectant effectiveness of trehalose in comparison with sucrose. Furthermore it emerges that, the partial MSD behaviours of sucrose and trehalose are equivalent in the low Q domain (0-1.7) A(-1) whereas they are different in the high Q domain (1.7 4) A(-)(1). This circumstance suggests that the higher structure sensitivity of sucrose in respect to trehalose should be related to the small spatial observation windows. PMID- 19782772 TI - Sirtuin regulation in calorie restriction. AB - The beneficial effects of calorie restriction diet in extending lifespan and preventing diseases have long been recognized. Recent genetic and molecular studies in model organisms began to uncover the molecular regulation of calorie restriction response, with the gene SIR2 playing an essential role. This article summarizes the latest development on how mammalian SIR2 homologs coordinately regulate the calorie restriction response. PMID- 19782773 TI - Time-resolved quasielastic neutron scattering studies of native photosystems. AB - The internal molecular dynamics of proteins plays an important role in a number of functional processes in native photosystems. Prominent examples include the photocycle of bacteriorhodopsin and electron transfer in the reaction center of plant photosystem II. In this regard, the recently developed technique of time resolved quasielastic neutron scattering with laser excitation opens up new perspectives for the study of protein/membrane dynamics in specific functional states of even complex systems. The first direct observation of a functionally modulated protein dynamics has just recently been reported for the model system bacteriorhodopsin (Pieper et al., Phys. Rev. Lett. 100, 2008, 228103.), where a transient softening of the protein was observed on a timescale of approximately 1 ms along with the large-scale structural change in the M-intermediate of bacteriorhodopsin. In contrast, photosystem II membrane fragments with inhibited electron transfer show a suppression of protein dynamics approximately 160 mus after the actinic laser flash (Pieper and Renger, Biochemistry 48, 2009, 6111). This effect may reflect aggregation-like conformational changes capable of dissipation of excess excitation energy to prevent photodamage in the absence of Q(A)-->Q(B) electron transfer. These findings indicate that proteins exhibit a remarkable flexibility to accommodate different functional processes. This contribution will discuss methodical aspects, challenges, and recent applications of laser-excited, time-resolved quasielastic neutron scattering. PMID- 19782774 TI - Differential proteomics of the plasma of individuals with sepsis caused by Acinetobacter baumannii. AB - This study examines alterations in the plasma proteome in ten adults affected by sepsis caused by Acinetobacter baumannii as compared to paired healthy controls. 2-DE profiles of plasma from patients and paired healthy donors, depleted of the six most abundant proteins, were analysed by the DIGE technique. Protein spot detection and quantification were performed with the Differential In-gel Analysis and Biological Variation Analysis modules of the DeCyder() software. Differentially expressed proteins were identified by mass spectrometry (MALDI TOF/TOF) after colloidal Coomassie blue staining. Almost 900 spots were detected on a unique 2-D gel by the DIGE technique. A total of 269 protein spots of differential abundance were shown to be statistically significant (2.5-fold) with p values of p< or =0.01 (135 spots) and p< or =0.05 (134 spots) as determined by the t test. Seventy-one spots were submitted to mass spectrometry and about 30% could be successfully identified. This multiplex approach significantly reduced experimental variability, allowing for the confident detection of small differences in protein levels. Results include differentially expressed lipoproteins as well as proteins belonging to inflammatory/coagulation pathways and the kallikrein-kinin system. These data improves the knowledge for future developments in sepsis diagnosis, staging and therapy. PMID- 19782775 TI - A centrifugal ultrafiltration strategy for isolating the low-molecular weight (50K, and recovery and enrichment of low-M(r) components from human plasma. This filter membrane device was further optimized with respect to plasma buffer composition, centrifugal force, duration and temperature. Optimal ultrafiltration conditions were obtained using 100 microL of normal plasma in 10% acetonitrile, and a centrifugation force of 4000x g for 35 min at 20 degrees C. In this LMF, 44 proteins (from 266 unique peptides) were identified using a combination of 1D-SDS PAGE / nano-LC-MS/MS and a stringent level of identification (FDR <1%). We report the identification of several proteins (e.g., protein KIAA0649 (Q9Y4D3), rheumatoid factor D5, serine protease inhibitor A3, and transmembrane adapter protein PAG) previously not reported in extant high-confidence Human Proteome Organization (HUPO) Plasma Proteome Project datasets. When compared with the low M(r) human plasma/serum proteome datasets of Zhou et al. (Electrophoresis, 2004. 25, 1289-98), Gundry et al. (Proteomics Clin. Appl., 2007. 1, 73-88) and Villanueva et al. (Anal Chem, 2004. 76, 1560-70), 64% of our identifications (28 proteins) were novel; these include cofilin-1, PPIase A, and the SH3 domain binding glutamic acid-rich-like protein 3. In addition to intact proteins, many peptide fragments from high-abundance proteins (e.g., fibrinogen, clusterin, Factor XIIIa, transferrin, kinogen-1, and inter-alpha-trypsin inhibitor), presumably derived by ex vivo proteolysis, were observed. PMID- 19782776 TI - Comparative proteomics and transcriptomics analyses of livers from two different Bos taurus breeds: "Chianina and Holstein Friesian". AB - The Holstein Friesian and Chianina cattle breeds are representative of extreme selection for milk and meat traits, respectively, with significant changes in metabolism resulting from human selection over the past centuries. In the present study, we wanted to assess whether selection for different purposes has had a measurable effect on liver metabolism through a comparison of the protein and gene expression profiles of the two breeds. We applied 2-DE in order to identify proteins which were differentially expressed in the livers of the two breeds and relate them to different liver functions. We expected to find that only a small number of proteins would be differentially expressed, due to the relatively short phylogenetic distance between these cattle breeds. Nonetheless, thirty nine differentially-expressed proteins were characterized between Chianina and Holstein Friesian, out of a total of 560+/-57 spots that matched. Microarray analyses evidenced the differential expression of 167 genes (148 for the Holstein Friesian and 19 for the Chianina). Despite being closely related at the genetic level, the disparity of the proteomic and transcriptomic profiles of these two breeds allows us to perform pathway analysis thus to pinpoint proteins whose expression might render the latter capable of greater milk production, or proteins involved in altered thermoregulatory ability or hormone production. On the other hand, we found proteins and gene transcripts in Chianina, not expressed in Holstein, which, upon interaction pathway analysis, were mainly involved in anabolic pathways. In brief, our integrated study provides molecular evidences to support the physiological differences between Holstein and Chianina cattle breeds. PMID- 19782777 TI - Proteomic analysis of sugar beet apomictic monosomic addition line M14. AB - Apomixis in plants holds great promise for agriculture because of its vigor associated with heterozygosity and superior genotype. Despite the significance of apomictic reproductive process, our knowledge of proteins and their functions in apomictic development is limited. Here we report a comparative proteomic and transcriptomic analysis of sexual and apomictic processes in sugar beet. A total of 71 differentially expressed protein spots were successfully identified in the course of apomictic reproductive development using high-resolution 2-DE and MS analysis. The differentially expressed proteins were involved in several processes that might work cooperatively to lead to apomictic reproduction. This study has generated potential protein markers important for apomictic development. PMID- 19782778 TI - Cancer-specific MALDI-TOF profiles of blood serum and plasma: biological meaning and perspectives. AB - MALDI-TOF mass-spectrometry has become a popular tool of cancer research during the last decade. High throughput and relative simplicity of this technology have made it attractive for biomarker discovery and validation across various platforms in blood serum/plasma. Many technical approaches have been developed for plasma/serum profiling including protein-chip based SELDI-TOF mass spectrometry, purification of serum on magnetic beads, analysis of carrier associated fraction and mass-spectrometric immunoassays. Extensive data about the identity of differential features detected on mass-spectra up to now makes it possible to draw conclusions about potency and perspectives of MALDI-TOF mass spectrometry in this field. A great majority of identified differentially expressed proteins are either house-keeping or inflammatory proteins as well as their modifications or fragments. Discriminating ability of mass-spectra is likely to be based on differential modification and fragmentation patterns of abundant serum proteins reflecting activity of enzymes including proteases and their inhibitors. PMID- 19782779 TI - The HTLV-1 Tax protein: revealing mechanisms of transcriptional activation through histone acetylation and nucleosome disassembly. AB - The human T-cell leukemia virus, type-1 (HTLV-1)-encoded Tax protein is required for high-level transcription of the virus. Tax function is strictly dependent upon the phosphorylated form of the cellular transcription factor CREB (pCREB), and together they bind novel cAMP response elements located within the viral promoter. The DNA-bound Tax/pCREB complex recruits the cellular coactivators CBP/p300, which are essential for viral gene expression. The coactivators, via their histone acetyltransferase activity, function to promote changes in chromatin architecture that are permissive to transcriptional activation. Tax expression in vivo recruits p300 to the HTLV-1 promoter and correlates with depletion of nucleosomes from the integrated provirus. We recently developed a novel in vitro, chromatin-based experimental system that recapitulates the eviction of nucleosomes from the HTLV-1 promoter observed in vivo. These assays establish the essential function of Tax/pCREB recruitment of CBP/p300, and concomitant histone acetylation, in the nucleosome disassembly process. These observations are of particular significance, as Tax mediates disassembly of the full nucleosome octamer independent of transcriptional activity and ATP utilization. Instead, nucleosome eviction is absolutely dependent upon acetyl CoA and the histone chaperone Nap1. In this review, we will discuss HTLV-1, Tax transactivation, and our recent findings that uncover the critical role of Tax in promoting chromatin transitions that accompany activation of viral transcription. We will describe the phenomenon of acetylation-dependent promoter nucleosome disassembly and the emerging view that the formation of nucleosome-free promoter regions may represent a general prerequisite for transcriptional activation in eukaryotes. PMID- 19782781 TI - Circadian rhythm affects the preventive role of pulsed electromagnetic fields on ovariectomy-induced osteoporosis in rats. AB - Pulsed electromagnetic fields (PEMF) have been proved effective in the prevention of osteoporosis both experimentally and clinically. Chronotherapy studies have shown that circadian rhythm (CR) played an important role in the occurrence, development and treatment of several diseases. CR has also been recognized as an essential feature of bone metabolism. Therefore, it is of therapeutic significance to investigate the impact of CR on the efficacy of PEMF in the prevention of osteoporosis. However, this issue has never been discussed previously. The objective of this study was to systematically evaluate the impact of CR on the preventive effect of PEMF on osteoporosis in rats. Thirty-two 3 month old female Sprague-Dawley rats were randomly divided into four different groups: sham-operated control (Sham), ovariectomy (OVX), OVX with PEMF stimulation in daytime (OVX+DPEMF) and OVX with PEMF stimulation in nighttime (OVX+NPEMF) groups. The OVX+DPEMF and OVX+NPEMF groups were subjected to daily PEMF exposure on the 2nd post-operative day, from 9:00 to 15:00, and 0:00 to 6:00, respectively. After 12 weeks, the OVX+DPEMF group presented better efficacy in prevention against OVX-induced bone loss and deterioration of trabecular bone architecture compared with the OVX+NPEMF group. This was evidenced by the increased levels of femoral bone mineral density, trabecular area percentage, trabecular thickness, trabecular number and decreased trabecular separation. Furthermore, the bone turnover biomarkers (serum alkaline phosphatase, serum bone Gla protein and urinary deoxypyridinoline) and the dynamic histomorphometric parameters reflecting the trabecular osteoblast and osteoclast activity (bone formation rate with bone volume as referent, osteoclast number, etc.) in the OVX+DPEMF group decreased to a larger extent compared with the OVX+NPEMF group. In conclusion, the results indicated that CR was an important factor determining the preventive effect of PEMF on osteoporosis and PEMF exposure in the daytime presented better stimulus efficacy in rats. The findings might be helpful for the efficacious use of PEMF mediations, evaluation of PEMF action and experimental design in the future studies of biological effect of electromagnetic fields. PMID- 19782780 TI - COMP-Ang1, a chimeric form of Angiopoietin 1, enhances BMP2-induced osteoblast differentiation and bone formation. AB - INTRODUCTION: Angiogenesis is closely associated with bone formation, especially endochondral ossification. Angiopoietin 1 (Ang1) is a specific growth factor functioning to generate a stable and matured vasculature through the Tie2 receptor/PI3K/AKT pathway. Recently cartilage oligomeric matrix protein (COMP) Ang1, an Ang1 variant which is more potent than native Ang1 in phosphorylating Tie2 receptor and AKT, was developed. This study was designed to examine the effects of angiogenic COMP-Ang1 on BMP2-induced osteoblast differentiation and bone formation. METHODS: Expression of endogenous Ang-1 and its binding receptor Tie 2 mRNA was examined in osteoblast-like cells and primary mouse calvarial cells by RT-PCR analysis, and was also monitored during osteoblast differentiation induced by BMP-2 and/or ascorbic acid and beta-glycerophosphate. Effects of COMP-Ang-1 on osteoblast differentiation and mineralization were evaluated by alkaline phosphatase (ALP) activity and osteocalcin (OC) production, and Alizarin red stain. For a molecular mechanism, Western blot and OG2 and 6xOSE promoter assays were done. For in vivo evaluation, adenoviral (Ad) vectors containing COMP-Ang-1 or BMP-2 gene were administered into thigh muscle of mice, and after 2 weeks bone formation was analyzed by micro-computed tomography and histology. Angiogenic event of COMP-Ang1 was confirmed by immunofluorescence analysis with anti-CD31 antibody. RESULTS: Expression of Tie2 receptor was significantly increased in the course of osteoblast differentiation. Treatment or overexpression of COMP-Ang1 enhanced BMP2-induced ALP activity, OC production, and mineral deposition in a dose-dependent manner. In addition, COMP-Ang1 synergistically increased OG2 and 6xOSE promoter activities of BMP2, and sustained p38, Smad and AKT phosphorylation of BMP2. Notably, in vivo intramuscular injection of COMP-Ang1 dose-dependently enhanced BMP2-induced ectopic bone formation with increases in CD31 reactivity. CONCLUSIONS: These results suggest that COMP-Ang1 synergistically enhanced osteoblast differentiation and bone formation through potentiating BMP2 signaling pathways and angiogenesis. Combination of BMP2 and COMP-Ang1 should be clinically useful for therapeutic application to fracture and destructive bone diseases. PMID- 19782782 TI - Three dimensional cancellous bone structure in hypoparathyroidism. AB - By conventional 2-dimensional histomorphometric analysis, we have shown that cancellous bone architecture is markedly altered in hypoparathyroidism. We have now extended these observations to a 3-dimensional analysis using microcomputed tomography. Percutaneous iliac crest bone biopsies were analyzed by high resolution microcomputed tomography from the following 25 subjects with hypoparathyroidism: 5 postmenopausal women, 13 premenopausal women and 7 men. Thirteen living premenopausal healthy controls and 12 cadaver subjects without bone disease served as matched controls. Hypoparathyroid subjects had significantly greater bone surface density (BS/TV: 5.74+/-4.7 vs. 3.73+/-1.01 mm(2)/mm(3) [mean+/-SD]; p=0.04), trabecular thickness (Tb.Th: 0.25+/-0.19 vs. 0.17+/-0.04 mm; p=0.04), trabecular number (Tb.N: 2.99+/-3.4 vs. 1.62+/-0.39 mm( 1); p=0.05) and connectivity density (Conn.D: 16.63+/-18.7 vs. 8.39+/-5.8 mm(3); p=0.04) in comparison to matched controls. When an additional 8 hypoparathyroid (total n=33) and 24 cadaver (total cadaver n=36) subjects were added to the groups for an unmatched analysis, hypoparathyroid subjects had significantly greater cancellous bone volume (BV/TV: 26.98+/-10 vs. 15.39+/-4%; p<0.001), while trabecular separation (Tb.Sp: 0.642+/-0.10 vs. 0.781+/-0.13 mm; p<0.001) and estimation of the plate-rod characteristic (SMI: -0.457+/-1.52 vs. 0.742+/-0.51; p<0.001) were significantly lower, the latter observation implying a more plate like trabecular structure. Variables of cancellous bone structure in the hypoparathyroid subjects, as assessed by microcomputed tomography, were highly correlated with those assessed by conventional histomorphometry. We conclude that cancellous bone in hypoparathyroidism is abnormal, suggesting that parathyroid hormone is required to maintain normal trabecular structure. The effect of these structural changes on bone strength remains to be determined. PMID- 19782783 TI - Understanding heart failure through the HF-ACTION baseline characteristics. PMID- 19782784 TI - Baseline differences in the HF-ACTION trial by sex. AB - BACKGROUND: In patients with heart failure (HF), assessment of functional capacity plays an important prognostic role. Both 6-minute walk and cardiopulmonary exercise testing have been used to determine physical function and to determine prognosis and even listing for transplantation. However, as in HF trials, the number of women reported has been small, and the cutoffs for transplantation have been representative of male populations and extrapolated to women. It is also well known that peak VO(2) as a determinant of fitness is inherently lower in women than in men and potentially much lower in the presence of HF. Values for a female population from which to draw for this important determination are lacking. METHODS: The HF-ACTION trial randomized 2,331 patients (28% women) with New York Heart Association class II-IV HF due to systolic dysfunction to either a formal exercise program in addition to optimal medical therapy or to optimal medical therapy alone without any formal exercise training. To characterize differences between men and women in the interpretation of final cardiopulmonary exercise testing models, the interaction of individual covariates with sex was investigated in the models of (1) VE/VCO(2), (2) VO(2) at ventilatory threshold (VT), (3) distance on the 6-minute walk, and (4) peak VO(2). RESULTS: The women were younger than the men and more likely to have a nonischemic etiology and a higher ejection fraction. Dose of angiotensin converting enzyme inhibitor (ACEI) was lower in the women, on average. The lower ACEI dose may reflect the higher use of angiotensin II receptor blocker (ARB) in women. Both the peak VO(2) and the 6-minute walk distance were significantly lower in the women than in the men. Perhaps the most significant finding in this dataset of baseline characteristics is that the peak VO(2) for women was significantly lower than that for men with similar ventricular function and health status. CONCLUSION: Therefore, in a well-medicated, stable, class II-IV HF cohort of patients who are able to exercise, women have statistically significantly lower peak VO(2) and 6-minute walk distance than men with similar health status and ventricular function. These data should prompt careful thought when considering prognostic markers for women and listing for cardiac transplant. PMID- 19782785 TI - New York Heart Association functional class predicts exercise parameters in the current era. AB - BACKGROUND: The New York Heart Association (NYHA) functional class is a subjective estimate of a patient's functional ability based on symptoms that do not always correlate with the objective estimate of functional capacity, peak oxygen consumption (peak V(O2)). In addition, relationships between these 2 measurements have not been examined in the current medical era when patients are using beta-blockers, aldosterone antagonists, and cardiac resynchronization therapy (CRT). Using baseline data from the HF-ACTION (Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing) study, we examined this relationship. METHODS: One thousand seven hundred fifty-eight patients underwent a symptom-limited metabolic stress test and stopped exercise due to dyspnea or fatigue. The relationship between NYHA functional class and peak V(O2) was examined. In addition, the effects of beta-blockers, aldosterone antagonists, and CRT therapy on these relationships were compared. RESULTS: The NYHA II patients have a significantly higher peak Vo(2) (16.1 +/- 4.6 vs 13.0 +/- 4.2 mL/kg per minute), a lower ventilation (Ve)/V(CO2) slope (32.8 +/- 7.7 vs 36.8 +/ 10.4), and a longer duration of exercise (11.0 +/- 3.9 vs 8.0 +/- 3.4 minutes) than NYHA III/IV patients. Within each functional class, there was no difference in any of the exercise parameters between patients on or off of beta-blockers, aldosterone antagonists, or CRT therapy. Finally, with increasing age, a significant difference in peak Vo(2), Ve/V(CO2) slope, and exercise time was found. CONCLUSION: For patients being treated with current medical therapy, there still is a difference in true functional capacity between NYHA functional class II and III/IV patients. However, within each NYHA functional class, the presence or absence or contemporary heart failure therapies does not alter exercise parameters. PMID- 19782787 TI - N-terminal pro-brain natriuretic peptide and exercise capacity in chronic heart failure: data from the Heart Failure and a Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION) study. AB - OBJECTIVES: To examine the relationship between N-terminal pro-brain natriuretic peptide (NT-proBNP) and exercise capacity in a large contemporary cohort of patients with chronic heart failure. BACKGROUND: Natriuretic peptides such as NT proBNP are important biomarkers in heart failure. The relationship between NT proBNP and exercise capacity has not been well studied. METHODS: We analyzed the relationship between baseline NT-proBNP and peak oxygen uptake (peak VO(2)) or distance in the 6-minute walk test in 1383 subjects enrolled in the HF-ACTION study. Linear regression models were used to analyze the relationship between NT proBNP and peak Vo(2) or distance in the 6-minute walk test in the context of other clinical variables. Receiver operator curve analysis was used to evaluate the ability of NT-proBNP to accurately predict a peak VO(2) <12 mL/kg per minute. RESULTS: NT-proBNP was the most powerful predictor of peak VO(2) (partial R(2) = 0.13, P < .0001) of 35 candidate variables. Although NT-proBNP was also a predictor of distance in the 6-minute walk test, this relationship was weaker than that for peak VO(2) (partial R(2) = 0.02, P < .0001). For both peak VO(2) and distance in the 6-minute walk test, much of the variability in exercise capacity remained unexplained by the variables tested. Receiver operator curve analysis suggested NT-proBNP had moderate ability to identify patients with peak VO(2) <12 mL/kg per minute (c-index, 0.69). CONCLUSIONS: In this analysis of baseline data from HF-ACTION, NT-proBNP was the strongest predictor of peak VO(2) and a significant predictor of distance in the 6-minute walk test. Despite these associations, NT-proBNP demonstrated only modest performance in identifying patients with a low peak VO(2) who might be considered for cardiac transplantation. These data suggest that, although hemodynamic factors are important determinants of exercise capacity, much of the variability in exercise performance in heart failure remains unexplained by traditional clinical and demographic variables. PMID- 19782786 TI - The relationship between body mass index and cardiopulmonary exercise testing in chronic systolic heart failure. AB - BACKGROUND: Cardiopulmonary exercise testing (CPX) in patients with systolic heart failure (HF) is important for determining HF prognosis and helping guide timing of heart transplantation. Although approximately 20% to 30% of patients with HF are obese (body mass index [BMI] >30 kg/m(2)), the impact of BMI on CPX results is not well established. The objective of this study was to assess the relationship between BMI and CPX variables, including peak oxygen uptake (VO(2)) at ventilatory threshold, oxygen pulse, and ventilation-carbon dioxide production ratio. METHODS: Consecutive patients with systolic HF (n = 2,324) enrolled in the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise Training trial who had baseline BMI recorded were included in this study. Subjects were divided into strata based on BMI: underweight (BMI <18.5 kg/m(2)), normal weight (BMI 18.5-24.9 kg/m(2)), overweight (BMI 25.0-29.9 kg/m(2)), obese I (BMI 30-34.9 kg/m(2)), obese II (BMI 35-39.9 kg/m(2)), and obese III (BMI > or = 40 kg/m(2)). RESULTS: Obese III, but not overweight; obese I; or obese II was associated with decreased peak VO(2) (mL kg(-1) min(-1)) compared to normal weight status. Increasing BMI category was inversely related to ventilation/carbon dioxide production (V(E)/V(CO2)) ratio (P < .0001). On multivariable analysis, BMI was a significant independent predictor of peak VO(2) (partial R(2) = 0.07, P < .0001) and V(E)/V(CO2) slope (partial R(2) = 0.03, P < .0001) in patients with chronic systolic HF. CONCLUSIONS: Body mass index is significantly associated with key CPX fitness variables in patients with HF. The influence of BMI on the prognostic value of CPX in HF requires further evaluation in longitudinal studies. PMID- 19782793 TI - Molecular genetics and the classification of the corneal dystrophies: what is next? PMID- 19782794 TI - Fuchs heterochromic iridocyclitis--syndrome, disease, or both? PMID- 19782795 TI - Thessaloniki eye study: the importance of recognizing pseudoexfoliation. PMID- 19782796 TI - Risk comparisons. PMID- 19782798 TI - Cerebrospinal fluid pressure may play a role in reversal of cupping after glaucoma surgery. PMID- 19782790 TI - Relationship of age and exercise performance in patients with heart failure: the HF-ACTION study. AB - BACKGROUND: More than three fourths of patients with heart failure (HF) are 65 years and older, and older age is associated with worse symptoms and prognoses than is younger age. Reduced exercise capacity is a chief HF complaint and indicates poorer prognosis, especially among elderly persons, but the mechanisms underlying functional decline in older patients with HF are largely unknown. METHODS: Baseline cardiopulmonary exercise testing data from the HF-ACTION trial were assessed to clarify age effects on peak oxygen consumption (VO(2)) and ventilation-carbon dioxide production (VE/VCO(2)) slope. RESULTS: Among 2,331 New York Heart Association class II-IV patients with HF, increased age corresponded to decreased peak VO(2) (-0.14 mL kg(-1) min(-1) per year >40 years; P < .0001) and increased VE/VCO(2) slope (0.30 U/y >70 years; P < .0001). In a multivariable model with 34 other potential determinants, age was the strongest independent predictor of peak VO(2) (partial R(2) 0.130, total R(2) 0.392; P < .001) and a significant but relatively weaker predictor of VE/VCO(2) slope (partial R(2) 0.037, total R(2) 0.199; P < .001). Blunted peak heart rate was also a strong predictor of peak VO(2). Although peak heart rate and age were strongly correlated, both were significant independent predictors of peak VO(2) when analyzed simultaneously in a model. Aggregate comorbidity increased significantly with age but did not account for age effects on peak VO(2). CONCLUSIONS: Age is the strongest predictor of peak VO(2) and a significant predictor of VE/VCO(2) slope in the HF-ACTION population. Age-dependent comorbidities do not explain changes in peak VO(2). Age-related changes in cardiovascular physiology, potentially magnified by the HF disease state, should be considered a contributor to the pathophysiology and a target for more effective therapy in older patients with HF. PMID- 19782799 TI - Recovery of corneal hysteresis after reduction of intraocular pressure in chronic primary angle-closure glaucoma. PMID- 19782788 TI - Relationship of Doppler-Echocardiographic left ventricular diastolic function to exercise performance in systolic heart failure: the HF-ACTION study. AB - INTRODUCTION: Patients with systolic heart failure often have concomitant left ventricular (LV) diastolic dysfunction. Although in animal models diastolic dysfunction is associated with worsening exercise capacity and prognosis, information regarding these relationships in patients with established systolic heart failure (HF) is sparse. METHODS: HF-ACTION was a large, multicenter National Institutes of Health-funded trial of exercise training in systolic HF (LV ejection fraction [LVEF] < or = 35%) and included detailed Doppler echocardiographic (echo) and cardiopulmonary exercise testing at baseline. We tested the hypothesis that echo measures of LV diastolic function predict key cardiopulmonary exercise outcomes, including aerobic exercise capacity (peak exercise oxygen consumption, VO(2)), distance in the 6-minute walk test (6MWD), and ventilatory efficiency (VE/VCO(2) slope) in patients with systolic HF. RESULTS: Overall, 2,331 patients (28% women, median age 59 years, median LVEF 25%) were enrolled. There were significant bivariate correlations between echo diastolic function variables and peak VO(2) (inverse) and VE/VCO(2) slope (direct) that were strongest for ratio of early diastolic peak transmitral (MV) to myocardial tissue velocity (E/E'), peak MV early-to-late diastolic velocity ratio (E/A), and left atrial dimension (range of absolute r = 0.16-0.28). Both MV E/A and E/E' were more strongly related to all 3 exercise variables than was LVEF. The relationships of E/A and E/E' with 6MWD were weaker than with peak VO(2) or VE/VCO(2) slope. A multivariable model with peak VO(2) as the dependent variable, which included MV E/A and 9 demographic predictors including age, sex, race, body mass index, and New York Heart Association class, explained 40% of the variation in peak VO(2), with MV E/A explaining 6% of the variation. Including LVEF in the model explained less than an additional 1% of the variance in peak VO(2). In a multivariable model for VE/VCO(2) slope, MV E/A was the strongest independent echo predictor, explaining 10% of the variance. The relationship of LV diastolic function variables with 6MWD was weaker than with peak VO(2) or VE/VCO(2) slope. CONCLUSION: In patients with systolic HF, LV early diastolic function is a modest independent predictor of aerobic exercise capacity and appears to be a better predictor than LVEF. PMID- 19782789 TI - Myocardial perfusion, function, and dyssynchrony in patients with heart failure: baseline results from the single-photon emission computed tomography imaging ancillary study of the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) Trial. AB - BACKGROUND: There are currently limited data on the relationships between resting perfusion abnormalities, left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class, and exercise capacity as defined by peak VO(2) and 6-minute walk test in patients with heart failure (HF) and reduced LVEF. Furthermore, the association between resting perfusion abnormalities and left ventricular dyssynchrony is currently unknown. This article addresses the Heart Failure and A Controlled Trial Investigating Outcomes of Exercise TraiNing (HF-ACTION) gated SPECT imaging (gSPECT) substudy baseline results. METHODS: HF ACTION was a multicenter, randomized controlled trial of aerobic exercise training versus usual care in 2,331 stable patients with LVEF of < or = 35% and NYHA class II to IV HF symptoms treated with optimal medical therapy. Subjects enrolled in the HF-ACTION substudy underwent resting Tc-99m tetrofosmin gSPECT at baseline (n = 240). Images were evaluated for extent and severity of perfusion abnormalities using a 17-segment and a 5-degree gradation severity score (summed rest score [SRS]). Left ventricular function and dyssynchrony were assessed using validated available commercial software. RESULTS: The average age of patients enrolled was 59, 69% were male, 63% were white, and 33% were African American. Of the 240 participants, 129 (54%) were ischemic and 111 (46%) were nonischemic in etiology. The median LVEF by gSPECT for the entire cohort was 26%. Among the nuclear variables, there was a modest correlation between LVEF and SRS (r = 0.31, P < .0001) and there were stronger correlations between phase SD and SRS (r = 0.66, P < .0001) as well as phase SD and LVEF (r = -0.50, P < .0001). Patients with NYHA class III symptoms had more severe and significant degrees of dyssynchrony (median phase SD 54 degrees ) than those with NYHA class II symptoms (median phase SD 39 degrees, P = .001). Patients with an ischemic etiology had a higher SRS (P < .0001) and significantly more dyssynchrony (P < .0001) than those who were nonischemic. However, there was no difference in LVEF or objective measures of exercise capacity between these groups. With respect to peak VO(2), there was a weak correlation with LVEF (r = 0.18, P = .006) and no correlation with SRS (r = -0.04, P = 0.59) or with dyssynchrony (r = -0.13, P = .09). A weak but statistically significant correlation between SRS and 6-minute walk was observed (r = -0.15, P = .047). CONCLUSIONS: Gated SPECT imaging can provide important information in patients with HF due to severe LV dysfunction including quantitative measures of global systolic function, perfusion, and dyssynchrony. These measurements are modestly but significantly related to symptom severity and objective measures of exercise capacity. PMID- 19782802 TI - Rates of non-arteritic ischemic optic neuropathy in male veterans prescribed phosphodiesterase-5 inhibitors. PMID- 19782803 TI - Current technologies for analysis of biomass thermochemical processing: a review. AB - Pyrolysis and gasification are two of the more promising utilization methods for the conversion of biomass toward a clean fuel source. To truly understand and model these processes requires detailed knowledge ranging from structural information of raw biomass, elemental composition, gas-phase reaction kinetics and mechanisms, and product distributions (both desired and undesired). The various analytical methods of biomass pyrolysis/gasification processing are discussed, including reactor types, analytical tools, and recent examples in the areas of (a) compositional analysis, (b) structural analysis, (c) reaction mechanisms, and (d) kinetic studies on biomass thermochemical processing. PMID- 19782792 TI - Safety of symptom-limited cardiopulmonary exercise testing in patients with chronic heart failure due to severe left ventricular systolic dysfunction. AB - BACKGROUND: To assess the safety of symptom-limited exercise testing in patients with New York Heart Association class II-IV heart failure symptoms due to left ventricular systolic dysfunction, we investigated the frequency of all-cause fatal and nonfatal major cardiovascular (CV) events among subjects enrolled in a prospective clinical trial (HF-ACTION). We hypothesized that exercise testing would be safe, as defined by a rate for all-cause death of <0.1 per 1,000 tests and a rate of nonfatal CV events <1.0 per 1,000 tests. METHODS: Before enrollment and at 3, 12, and 24 months after randomization, subjects were scheduled to complete a symptom-limited graded exercise test with open-circuit spirometry for analysis of expired gases. To ensure the accurate reporting of exercise test related events, we report deaths and nonfatal major CV events per 1,000 tests at months 3, 12, or 24 after randomization. RESULTS: A total of 2,331 subjects were randomized into HF-ACTION. After randomization, 2,037 subjects completed 4,411 exercise tests. There were no test-related deaths, exacerbation of heart failure or angina requiring hospitalization, myocardial infarctions, strokes, or transient ischemic attacks. There was one episode each of ventricular fibrillation and sustained ventricular tachycardia. There were no exercise test related implantable cardioverter defibrillator discharges requiring hospitalization. These findings correspond to zero deaths per 1,000 exercise tests and 0.45 nonfatal major CV events per 1,000 exercise tests (95% CI 0.11 1.81). CONCLUSIONS: In New York Heart Association class II-IV patients with severe left ventricular systolic dysfunction, we observed that symptom-limited exercise testing is safe based on no deaths and a rate of nonfatal major CV events that is <0.5 per 1,000 tests. PMID- 19782791 TI - Outcomes, health policy, and managed care: relationships between patient-reported outcome measures and clinical measures in outpatients with heart failure. AB - BACKGROUND: Patient-reported outcomes are increasingly used to assess the efficacy of new treatments. Understanding relationships between these and clinical measures can facilitate their interpretation. We examined associations between patient-reported measures of health-related quality of life and clinical indicators of disease severity in a large, heterogeneous sample of patients with heart failure. METHODS: Patient-reported measures, including the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the EuroQol Visual Analog Scale (VAS), and clinical measures, including peak VO(2), 6-minute walk distance, and New York Heart Association (NYHA) class, were assessed at baseline in 2331 patients with heart failure. We used general linear models to regress patient-reported measures on each clinical measure. Final models included for significant sociodemographic variables and 2-way interactions. RESULTS: The KCCQ was correlated with peak VO(2) (r = .21) and 6-minute walk distance (r = .27). The VAS was correlated with peak VO(2) (r = .09) and 6-minute walk distance (r = .11). Using the KCCQ as the response variable, a 1-SD difference in peak Vo(2) (4.7 mL/kg/min) was associated with a 2.86-point difference in the VAS (95% CI, 1.98-3.74) and a 4.75-point difference in the KCCQ (95% CI, 3.78-5.72). A 1-SD difference in 6-minute walk distance (105 m) was associated with a 2.78-point difference in the VAS (95% CI, 1.92-3.64) and a 5.92-point difference in the KCCQ (95% CI, 4.98-6.87); NYHA class III was associated with an 8.26-point lower VAS (95% CI, 6.59-9.93) and a 12.73-point lower KCCQ (95% CI, 10.92-14.53) than NYHA class II. CONCLUSIONS: These data may inform deliberations about how to best measure benefits of heart failure interventions, and they generally support the practice of considering a 5 point difference on the KCCQ and a 3-point difference on the VAS to be clinically meaningful. PMID- 19782804 TI - Chemical and statistical characterization of selected documents from the archives of the Palazzo Ducale (Venice, Italy). AB - Inks and paper are the main materials and components of library and archive collections. Since the beginning of paper and ink production empirical recipes have been followed, but in the 19th century with the transformation of Europe during the Industrial Revolution, the continent became the main leader for the discovery of new products and new industrial production processes. The aim of this study is to shed light on paper and ink production processes during this key historical period. In this study we have chosen some documents preserved in the archive of the Soprintendenza dei Beni Architettonici e Paesaggistici (B.A.P.) di Venezia e Laguna, held in the Palazzo Ducale (Ducal Palace) of Venice. Attenuated total reflection Fourier transform infrared spectroscopy (ATR-FT-IR), and inductively coupled plasma-mass spectrometry (ICP-MS) allowed us to obtain a qualitative and quantitative characterization of the organic and inorganic components in both paper and inks. Cluster analysis and principal component analysis (PCA) were employed for statistical analysis of the results. PMID- 19782805 TI - Study of robustness based on n-way models in the spectrofluorimetric determination of tetracyclines in milk when quenching exists. AB - An important step in the validation of an analytical procedure is the study of its robustness. In the case of spectrofluorimetric determinations, quenching introduces specific problems which are approached in this paper for the particular case of tetracyclines determination in milk. Quenching can be detected with excitation emission matrices (EEM) signals and a three-way Parallel Factor (PARAFAC) decomposition and modelled by means of a four-way PARAFAC decomposition which reproduces the physical model of this effect. The robustness of the method is evaluated by including changes in seven experimental variables: trichloroacetic acid (TCA) volume solution used in the precipitation of milk proteins, revolutions per minute, time and temperature in the centrifugation step, pH and emission-excitation slit width in the fluorimetric analyte determination and the analyst. The robustness analysis is carried out by means of a Plackett-Burman experimental design as it is suggested by European Decision 2002/657/EC (European Decision (EC) No. 2002/657/EC of 12 August 2002, implementing Council Directive 96/23/EC, concerning the performance of analytical methods and the interpretation of results, Off. J.L 221, 17/8/2002, 8). The analyte concentration will be taken as response in the Plackett-Burman experimental design instead of the signal as it is habitual in these cases. Therefore, a three-way Partial Least Squares (3-PLS) calibration models with EEM signal is needed. When an analogous study is carried out for tetracycline (TC) in the absence of chlorotetracycline (CTC) as interferent, univariate calibration is employed, being able to conclude that in the robustness analysis, different factors are significantly active when quenching exists. PMID- 19782806 TI - Multi-target spectral moment: QSAR for antiviral drugs vs. different viral species. AB - The antiviral QSAR models have an important limitation today. They predict the biological activity of drugs against only one viral species. This is determined by the fact that most of the current reported molecular descriptors encode only information about the molecular structure. As a result, predicting the probability with which a drug is active against different viral species with a single unifying model is a goal of major importance. In this work, we use Markov Chain theory to calculate new multi-target spectral moments to fit a QSAR model for drugs active against 40 viral species. The model is based on 500 drugs (including active and non-active compounds) tested as antiviral agents in the recent literature; not all drugs were predicted against all viruses, but only those with experimental values. The database also contains 207 well-known compounds (not as recent as the previous ones) reported in the Merck Index with other activities that do not include antiviral action against any virus species. We used Linear Discriminant Analysis (LDA) to classify all these drugs into two classes as active or non-active against the different viral species tested, whose data we processed. The model correctly classifies 5129 out of 5594 non-active compounds (91.69%) and 412 out of 422 active compounds (97.63%). Overall training predictability was 92.34%. The validation of the model was carried out by means of external predicting series, the model classifying, thus, 2568 out of 2779 non active compounds and 224 out of 229 active compounds. Overall training predictability was 92.82%. The present work reports the first attempts to calculate within a unified framework the probabilities of antiviral drugs against different virus species based on a spectral moment analysis. PMID- 19782807 TI - A novel second-order standard addition analytical method based on data processing with multidimensional partial least-squares and residual bilinearization. AB - In the presence of analyte-background interactions and a significant background signal, both second-order multivariate calibration and standard addition are required for successful analyte quantitation achieving the second-order advantage. This report discusses a modified second-order standard addition method, in which the test data matrix is subtracted from the standard addition matrices, and quantitation proceeds via the classical external calibration procedure. It is shown that this novel data processing method allows one to apply not only parallel factor analysis (PARAFAC) and multivariate curve resolution alternating least-squares (MCR-ALS), but also the recently introduced and more flexible partial least-squares (PLS) models coupled to residual bilinearization (RBL). In particular, the multidimensional variant N-PLS/RBL is shown to produce the best analytical results. The comparison is carried out with the aid of a set of simulated data, as well as two experimental data sets: one aimed at the determination of salicylate in human serum in the presence of naproxen as an additional interferent, and the second one devoted to the analysis of danofloxacin in human serum in the presence of salicylate. PMID- 19782808 TI - Metabolomics data exploration guided by prior knowledge. AB - In metabolomics research, it is often important to focus the data analysis to specific areas of interest within the metabolome. In this paper, we describe the application of consensus principal component analysis (CPCA) and canonical correlation analysis (CCA) as a means to explore the relation between metabolome data and (i) biochemically related metabolites and (ii) an amino acid biosynthesis pathway. CPCA searches for major trends in the behavior of metabolite concentrations that are in common for the metabolites of interest and the remainder of the metabolome. CCA identifies the strongest correlations between the metabolites of interest and the remainder of the metabolome. CPCA and CCA were applied to two different microbial metabolomics data sets. The first data set, derived from Pseudomonas putida S12, was relatively simple as it contained metabolomes obtained under four environmental conditions only. The second data set, obtained from Escherichia coli, was much more complex as it consisted of metabolomes obtained under 28 different environmental conditions. In case of the simple and coherent P. putida S12 data set, CCA and CPCA gave similar results as the variation in the subset of the selected metabolites and the remainder of the metabolome was similar. In contrast, CCA and CPCA yielded different results in case of the E. coli data set. With CPCA the trends in the selected subset--the phenylalanine biosynthesis pathway--dominated the results. The main trends were related to high and low phenylalanine productivity, and the metabolites showing a similar behavior in concentration were metabolites regulating the phenylalanine biosynthesis route in the subset and metabolites related to general amino acid metabolism in the remainder of the metabolome. With CCA, neither subset truly dominated the data analysis. CCA described the differences between the wild type and the overproducing strain and the differences between the succinate and glucose grown cells. For the difference between the wild type and the overproducing strain, metabolites from the beginning and the end of aromatic amino acid pathways like erythrose-4-phosphate, tryptophan, and phenylalanine were important for the selected metabolites. CCA and CPCA proved to be complementary data analysis tools that enable the focusing of the data analysis on groups of metabolites that are of specific interest in relation to the remainder of the metabolome. Compared to an ordinary PCA, focusing the data analysis on biologically relevant metabolites lead especially for the complex E. coli data to a better biological interpretation of the data. PMID- 19782809 TI - Applications of titania and zirconia hollow fibers in sorptive microextraction of N,N-dimethylacetamide from water sample. AB - The convenient fabrications of titania and zirconia hollow fiber with three dimensional porous structure using polypropylene hollow fibers as templates were developed. And an analytical method based on enrichment and extraction of analytes in the water sample, hollow fiber sorptive microextraction in combined with gas chromatography has been developed for the rapid analysis of N,N dimethylacetamide (DMA) in the environmental samples. The results showed that zirconia hollow fiber gave higher extraction performance of DMA than that of titania hollow fiber. The method validations, including linearity, limit of detection, limit of qualification, precision, and repeatability were investigated. Linearity for six-point calibration curve was excellent with zirconia hollow fiber having r2 value greater than 0.9993 at the linearity range of 0.001-1.0 mg mL(-1). In addition, it seems that hollow fiber sorptive extraction is a promising technique for the enrichment and purification of analytes extracted directly from liquid samples without any other pretreatment. PMID- 19782810 TI - On-line derivatization coupled to flow injection permanganate chemiluminescence detection of total carbonyl compounds in natural waters and drinking water. AB - This work describes the development of a fast assay for the determination of low molecular weight carbonyl compounds based on the oxidative chemiluminescence of 2,4-dinitrophenylhydrazine with acidic permanganate, which is enhanced during conversion to the corresponding phenylhydrazone-carbonyl derivatives. By exploiting the common derivatization pathway and oxidation mechanism of phenylhydrazones under kinetically controlled conditions in a flow configuration, a common light emission is produced which corresponds to the total aqueous concentration of carbonyl compounds. The experimental conditions that afford the optimum analytical features were optimized for acetone, acetaldehyde and formaldehyde which constitute the most abundant carbonyl compounds in environmental samples. The method was successfully applied to the determination of total carbonyl content in natural waters and drinking water at the low microg L(-1) levels with satisfactory recoveries (94.0-99.5%) and very good reproducibility (RSD=1.58-2.99%, n=8, C=2 microg L(-1)). Validation of the results was performed with gas chromatography suggesting that the proposed method provides a fast alternative to the routine screening of low molecular weight carbonyl compounds in natural waters. PMID- 19782811 TI - Validation of a confirmatory method for the determination of melamine in egg by gas chromatography-mass spectrometry and ultra-performance liquid chromatography tandem mass spectrometry. AB - A sensitive and reliable method was developed and validated for detection and confirmation of melamine in egg based on gas chromatography-mass spectrometry (GC MS) and ultra-performance liquid chromatography-tandem mass spectrometry (UPLC MS/MS). Trichloroacetic acid solution was used for sample extraction and precipitation of proteins. The aqueous extracts were subjected to solid-phase extraction by mixed-mode reversed-phase/strong cation-exchange cartridges. Using ultra-performance liquid chromatography and electrospray ionization in the positive ion mode, melamine was determined by LC-MS/MS, which was completed in 5 min for each injection. For the GC-MS analysis, extracted melamine was derivatized with N,O-bis(trimethylsilyl)trifluoracetamide prior to selected ion monitoring detection in electron impact mode. The average recovery of melamine from fortified samples ranged from 85.2% to 103.2%, with coefficients of variation lower than 12%. The limit of detection obtained by GC-MS and UPLC-MS/MS was 10 and 5 microg kg(-1), respectively. This validated method was successfully applied to the determination of melamine in real samples from market. PMID- 19782812 TI - Isotopomer analysis of lipid biosynthesis by high resolution mass spectrometry and NMR. AB - We have coupled 2D-NMR and infusion FT-ICR-MS with computer-assisted assignment to profile 13C-isotopologues of glycerophospholipids (GPL) directly in crude cell extracts, resulting in very high information throughput of >3000 isobaric molecules in a few minutes. A mass accuracy of better than 1 ppm combined with a resolution of 100,000 at the measured m/z was required to distinguish isotopomers from other GPL structures. Isotopologue analysis of GPLs extracted from LCC2 breast cancer cells grown on [U-13C]-glucose provided a rich trove of information about the biosynthesis and turnover of the GPLs. The isotopologue intensity ratios from the FT-ICR-MS were accurate to approximately 1% or better based on natural abundance background, and depended on the signal-to-nose ratio. The time course of incorporation of 13C from [U-13C]-glucose into a particular phosphatidylcholine was analyzed in detail, to provide a quantitative measure of the sizes of glycerol, acetyl CoA and total GPL pools in growing LCC2 cells. Independent and complementary analysis of the positional 13C enrichment in the glycerol and fatty acyl chains obtained from high resolution 2D NMR was used to verify key aspects of the model. This technology enables simple and rapid sample preparation, has rapid analysis, and is generally applicable to unfractionated GPLs of almost any head group, and to mixtures of other classes of metabolites. PMID- 19782814 TI - Synthetic receptors for selectively detecting erythrocyte ABO subgroups. AB - Surface imprinting techniques with erythrocytes as templates yield polymer coatings with selective recognition sites towards red blood cells. The resulting cavities in the respective surface exhibit selectivity between blood subgroups as shown by Quartz Crystal Microbalance (QCM) measurements. Mass sensitive effects in the kilohertz range could be observed for concentrations down to 0.5 x 10(8) cells/mL. Frequency response as well as recovery of the sensor took place within a few minutes, indicating that no covalent binding is involved. Linear concentration dependence over a defined region provides ideal conditions for cross selectivity measurements. A1 imprinted sensor coatings resulted in an effect of 40 kHz when exposed to the template blood group, while A2 erythrocytes yielded just 11% of that value on the same layer. Furthermore, A2 imprinted coatings incorporated only one third the amount of A1 erythrocytes as compared to A2 ones. Therefore, imprinted materials depict the entire cell surface and utilize it for recognition, whereas natural antibodies bind on the defined antigen position and thus usually cannot distinguish between cells carrying different amounts of them. PMID- 19782813 TI - Highly selective molecular recognition and high throughput detection of melamine based on molecularly imprinted sol-gel film. AB - Multimode reader has been generally applied in immunoassay, and in the proposed paper, the 96 well micro-plate was modified with molecularly imprinted melamine sol-gel film, based on which the highly selective and high throughput detection of melamine was achieved. Melamine was imprinted into silica sol-gel films directly using phenyltrimethoxysilane and methyltrimethoxysilane as functionalized organosilicon precursors. The binding characteristic of the imprinted film to melamine was evaluated by equilibrium binding experiments and the morphology was studied by scanning electronic microscope (SEM). Scatchard analysis was carried out to estimate the binding parameters of the imprinted film. The proposed method exhibited excellent selectivity because of specific recognition of MM by molecularly imprinted film. Under the optimum conditions, the chemiluminescence (CL) intensity had a linear relationship against the concentration of melamine over the range of 0.1-50 microg mL(-1) with a lower detection limit of 0.02 microg mL(-1). PMID- 19782815 TI - A novel cobalt hexacyanoferrate nanocomposite on CNT scaffold by seed medium and application for biosensor. AB - In this paper, for the first time, we introduced the seed-mediated method to the growth of cobalt hexacyanoferrate nanoparticles (CoNPs), using 3.5 nm gold nanoparticles as seeds and multiwalled carbon nanotubes (MWCNTs) as growth scaffold which would both show synergistic action toward the reduction of H2O2. Via gold seeds, the one-step fabrication of CoNPs on the glassy carbon electrode is simple without any linking reagents, which will ingeniously exert the electrochemical properties of cobalt hexacyanoferrate. Combined with glucose oxidase, the sensing surface is applied as a biosensor for glucose. The growth of CoNPs is a chemical deposition process around the small Au nanoseed particles. The nanoseeds bridge the CoNPs and CNTs to form a smart nanocomposite. Spherical CoNPs have a relatively moderate dispersion on the three-dimensional network of CNTs with relatively even diameter ca. 100 nm. Whereas, in the control experiments without gold seeds cobalt hexacyanoferrate can only form continuous films, of which the size is far from nanolevel and the catalytic ability is poor. The synthesis and fabrication/modification of CoNPs are simple and fast without prior preparation of CoNPs and lengthy process of cross-linking. The amount of the seeds and CNTs, growth time and concentration of growth solution were investigated. Scanning electron microscopy (SEM) and electrochemical method were used. PMID- 19782816 TI - Trace mercury (II) detection and separation in serum and water samples using a reusable bifunctional fluorescent sensor. AB - In this work, a reusable bifunctional fluorescent sensor for simultaneous detection and separation of trace Hg2+ in water and serum, which contains a naphthalimide derivative of 2,6-bis(aminomethyl)pyridine covalently grafted to the surface of silica particles, was developed. Meanwhile, the fluorescence characteristics and the adsorbent properties of the sensor were investigated in detail. This sensor showed a very good linearity (correlation coefficient of R2=0.9991) in the range 0.1-1 microM of Hg2+ with detection limits lower than 6.8 x 10(-9) M. It can also be used as an adsorbent for the removal of mercuric ions from the contaminated aqueous solution. The regeneration of this sensor is very simple, only by modulating the pH value of the aqueous solution. It can be reused at least four cycles. In addition, the present approach has the advantages of rapidity, simplicity, and low cost. We believe that this approach may serve as a foundation for the preparation of practical fluorescent sensor for the rapid detection of Hg2+ in aqueous biological and environmental samples. PMID- 19782817 TI - Investigation of 3,3',5,5'-tetramethylbenzidine as colorimetric substrate for a peroxidatic DNAzyme. AB - In this work, the suitability of 3,3',5,5'-tetramethylbenzidine sulfate (TMB) as the substrate of a DNAzyme catalytic system composed of a guanine-quadruplex DNA molecule and hemin was investigated. In the presence of H2O2, the hemin-DNA complex catalyzes the oxidation of TMB to produce two colored products, much like a peroxidase. The color-generating activity of this system could be influenced by several factors such as buffer type, pH value, DNA sequence, reaction time, and concentrations of both the hemin and H2O2. To illustrate the utility of this catalytic system, we designed a colorimetric assay, in which a synthetic oligonucleotide with a sequence complementary to the G-quadruplex DNA was used as the target. A detection limit of 1.86 nM was obtained. Our data have shown that TMB was an excellent colorimetric indicator that reported the peroxidase activities of the widely studied hemin-G-quadruplex DNAzyme system. PMID- 19782818 TI - Rapid quantification of total microcystins in cyanobacterial samples by periodate permanganate oxidation and reversed-phase liquid chromatography. AB - Microcystins (MCs) comprise a family of more than 80 related cyclic hepatotoxic heptapeptides. Oxidation of MCs causes cleavage of the chemically unique C20 beta amino acid (2S, 3S, 8S, 9S)-3-amino-9-methoxy-2,6,8-trimethyl-10-phenyldeca-4,6 dienoic acid (Adda) amino to form 2-methyl-3-methoxy-4-phenylbutanoic acid (MMPB), which has been exploited to enable analysis of the entire family. In the present study, the reaction conditions (e.g. concentration of the reactants, temperature and pH) used in the production of MMPB by oxidation of cyanobacterial samples with permanganate-periodate were optimized through a series of well controlled batch experiments. The oxidation product (MMPB) was then directly analyzed by high-performance liquid chromatography with diode array detection. The results of this study provided insight into the influence of reaction conditions on the yield of MMPB. Specifically, the optimal conditions, including a high dose of permanganate (> or = 50 mM) in saturated periodate solution at ambient temperature under alkaline conditions (pH approximately 9) over 1-4 h were proposed, as indicated by a MMPB yield of greater than 85%. The technique developed here was applied to determine the total concentration of MCs in cyanobacterial bloom samples, and indicated that the MMPB technique was a highly sensitive and accurate method of quantifying total MCs. Additionally, these results will aid in development of a highly effective analytical method for detection of MMPB as an oxidation product for evaluation of total MCs in a wide range of environmental sample matrices, including natural waters, soils (sediments) and animal tissues. PMID- 19782819 TI - Toxicity issues surrounding herbal use internationally and the U.S. Foreword. PMID- 19782820 TI - Herbal toxicity. PMID- 19782821 TI - Simulated tissue using a unique pontic design: a clinical report. AB - Unfavorable relationships between the residual edentulous ridge, pontic, and gingival papilla may compromise the definitive result of a restoration. Different procedures have been described and developed to improve the relationship between esthetics and functionally acceptable fixed partial dentures. This article describes a unique pontic design as well as the application of pressure during insertion of the pontic to achieve proper tissue displacement. Controlled pressure enhances the interdental papilla and creates the illusion of pontics emerging from the soft tissue, providing the restoration with a natural-looking effect. PMID- 19782822 TI - Immediate loading and customized restoration of a single implant in the maxillary esthetic zone: a clinical report. AB - The replacement of a single missing anterior tooth with an implant-supported crown is a demanding therapy. This report describes a treatment in which an anterior maxillary implant was immediately restored with a provisional restoration. During the provisional phase, an optimal emergence profile was created by adjusting the provisional restoration. An impression was made with an individually fabricated impression post for an accurate reproduction of the established emergence profile and, finally, a screw-retained all-ceramic crown was placed. By implementing this protocol, an optimal definitive result could be achieved, together with immediate patient satisfaction. However, cooperation among several disciplines and careful patient selection were required. PMID- 19782823 TI - Characterization of cast-to implant components from five manufacturers. AB - STATEMENT OF PROBLEM: Cast-to components are commonly used in screw-retained implant-supported restorations to produce precise fit. There is little information in the literature about the compositions and microstructures of commercially available products. PURPOSE: The purpose of this study was to characterize as-received cast-to components from 5 manufacturers (Dentsply Friadent CeraMed, Lifecore Biomedical, Inc, Nobel Biocare AB, Institut Straumann AG, and Zimmer Dental). MATERIAL AND METHODS: Two components from each manufacturer were mounted in metallographic resin, sectioned into quarters, remounted, wet polished with alumina abrasives, cleaned by ultrasonic agitation in distilled water, etched with aqua regia solutions, and carbon coated for scanning electron microscope (SEM) observation. Secondary (SE) and backscattered electron (BSE) images were collected to investigate the variations in surface topography and composition, respectively. Elemental analyses (EDS) were performed using an energy-dispersive x-ray spectrometer coupled to the SEM. Overall Vickers hardness (500-g load) and Vickers hardness of the 2 primary microstructural constituents (10-g load) were measured. Mean values and standard deviations were determined for the composition and Vickers hardness data. RESULTS: All implant components were composed of 2 distinctive parallel-band constituents containing gold, palladium, and platinum. Trace concentrations of iridium were also found. Elemental compositions of the darker bands observed by BSE differed by up to 20% for Au and Pt in the 5 products, whereas there was a minimal difference in Pd content. The lighter bands observed by BSE had nearly the same compositions in all 5 products, and contained much more Au and much less Pt than the darker bands. The gold-rich bands in each product were found to have much lower Vickers hardness. At high magnifications, each of the 2 bands appeared to contain 2 phases. CONCLUSIONS: The elemental compositions, microstructures, and Vickers hardness of the 5 as-received cast-to implant components were similar. Because both microstructural bands principally contain gold, palladium, and platinum, these noble cast-to implant components should be metallurgically compatible with noble metal casting alloys. PMID- 19782824 TI - Ring liner and burn-out temperature affect the clinical time required to fit a cast post. AB - STATEMENT OF PROBLEM: A cast post that is made with an unlined metal casting ring may exhibit anisotropic shrinkage which could result in distortion and consequently require more chair time for fitting in the root canal. PURPOSE: The purpose of this study was to investigate whether the presence of a ring liner and the burn-out temperature of the investment material affect the clinical time required to fit a cast post. MATERIAL AND METHODS: Sixty identical post patterns were fabricated from a customized stainless steel root form. They were divided into 3 groups (n=20) as follows: group LH used a cellulose ring liner and a final burn-out temperature of 815 degrees C; group NH used no liner with the same temperature; group NL used no liner with a final burn-out temperature of 600 degrees C. All groups were invested in stainless steel casting rings with the same phosphate-bonded investment (Hi Temp) and cast with same alloy (Protocol). Two blinded investigators, with different levels of experience, adjusted and placed the posts in the experimental root form until a subjective acceptable fit was achieved. Each investigator fit 10 cast posts for each group, and the time required to achieve a subjective acceptable fit was measured in seconds. Two-way ANOVA was used to test the significance of the investigator, group, and their interaction. One-way ANOVA and a post hoc Tukey HSD test were used to find significant differences among the groups (alpha=.05). RESULTS: The 2-way ANOVA showed a significant effect of the investigator (P=.001) and group (P<.001), but not interaction (P=.15). The 1-way ANOVA showed significant differences among the 3 groups (P<.001), and the Tukey HSD test showed significant differences between the following pairs: LH and NH (P=.009), and LH and NL (P<.001). NH and NL did not demonstrate a significant difference. CONCLUSIONS: Investing a post pattern without a ring liner and setting the final burn-out temperature at 600 degrees C allow the fabrication of cast posts that require significantly less adjustment time for clinical placement than those invested with a ring liner and burned out at 815 degrees C. PMID- 19782825 TI - Load fatigue of teeth with different ferrule lengths, restored with fiber posts, composite resin cores, and all-ceramic crowns. AB - STATEMENT OF PROBLEM: There is no evidence to suggest that the ferrule length needed for an all-ceramic crown is different from that needed for a cast metal or metal ceramic crown. PURPOSE: The purpose of this study was to relate different ferrule lengths with the number of fatigue cycles needed for failure of the crown cement for an all-ceramic crown cemented with a resin cement. MATERIAL AND METHODS: Fifteen maxillary central incisors were divided into 3 groups (n=5), with ferrules of 0.0 mm (no-ferrule group), 0.5 mm (0.5-mm ferrule group), and 1.0 mm (1.0-mm ferrule group), respectively. Each tooth was restored with a 0.050 inch glass-filled composite post (ParaPost FiberWhite) and a composite resin core (ParaCore). The posts were cemented with resin cement (ParaPost Cement), and the composite resin cores were bonded to dentin using a dentin bonding agent (ParaPost Cement, Conditioner A & B). Each specimen was prepared with a 7-mm total preparation height, a 1.5-mm lingual axial wall, and a 1.0-mm shoulder around the tooth. The crowns for all specimens were pressed with a pressable ceramic material (IPS Empress 2) and cemented with resin cement (Variolink II). A 6-kg cyclic test load was applied to each specimen at 135 degrees to the long axis of the tooth. The independent variable measured was the number of load fatigue cycles required for failure of the crown cement. The data were subjected to the Kruskal-Wallis test to detect overall significance and the Mann-Whitney U test for pairwise comparisons with Bonferroni correction (alpha=.017). RESULTS: The mean (SD) number of cycles to failure for each group was: no-ferrule group, 213 (317); 0.5-mm ferrule group, 155,137 (68,991); and 1.0-mm ferrule group, 262,872 (21,432). None of the specimens in the 1.0-mm ferrule group failed. Significant differences were found between the no-ferrule group and the 0.5-mm ferrule group, and the no-ferrule group and the 1.0-mm ferrule group (P<.017), but not between the 0.5-mm ferrule group and the 1.0-mm ferrule group (P>.017). CONCLUSIONS: Specimens with a 0.0-mm ferrule survived few fatigue cycles despite the fact that both the post and crown were bonded with resin cement. Teeth with a 0.5-mm ferrule showed a significant increase in the number of fatigue cycles over the 0.0-mm group, whereas teeth with the 1.0-mm ferrule exhibited a significantly higher fatigue cycle count over the 0.0-mm but not the 0.5-mm group. PMID- 19782826 TI - Microleakage of ceramic inlays luted with different resin cements and dentin adhesives. AB - STATEMENT OF PROBLEM: Despite recent advances in adhesive dentistry, resin cement/dentin adhesive combinations are not able to prevent microleakage in ceramic inlays. Marginal quality of tooth-colored restorations in large Class II cavities is satisfactory in enamel margins, but microleakage in dentin margins remains a concern. PURPOSE: The purpose of this study was to evaluate the microleakage of all-ceramic inlays luted with 2 dual-polymerizing resin cements or 1 autopolymerizing resin cement in combination with different dentin adhesives. MATERIAL AND METHODS: One hundred and twenty extracted human mandibular third molars were used in this study. Teeth were prepared to receive Class II MOD inlays with enamel gingival margins on 1 proximal surface and dentin gingival margins on the other surface. One hundred and twenty prepared teeth were divided into 3 groups of 40; 1 group for each resin cement: RelyX ARC, Variolink II, or Panavia 21. Each of the 3 groups were further divided into 4 dentin adhesive groups; Single Bond, ExciTE DSC, ED Primer, or Admira Bond. Each of the resin cements were used in combination with the 4 dentin adhesives, and IPS Empress ceramic inlays were placed with 12 different cement/adhesive combinations. After 1000 thermal cycles in a 5 degrees -55 degrees C water bath with a dwell time of 30 seconds, all specimens were subjected to cyclic axial mechanical loading. Then the restored teeth were stored in 0.5% basic fuchsin solution for 24 hours. The extent of dye penetration along the margins was measured with a stereomicroscope at x40 magnification. The data were evaluated statistically using repeated-measures ANOVA and Duncan tests (alpha=.05). RESULTS: Microleakage at dentin margins was greater than that at enamel margins (P<.05) for all groups. Variolink II and RelyX ARC resin cements showed significantly lower microleakage results than Panavia 21 with all dentin adhesives in enamel margins. For dentin margins, Variolink II/Admira Bond combination showed the lowest microleakage value in dentin (P<.05). CONCLUSIONS: The overall microleakage at the enamel margins was significantly less than at the dentin margins (P<.05). Panavia 21 showed higher microleakage values than Variolink II and RelyX ARC in enamel margins. PMID- 19782827 TI - Evaluation of shear and tensile bond strength between dentin and ceramics using dual-polymerizing resin cements. AB - STATEMENT OF PROBLEM: The applications of dual-polymerizing resin cements for all ceramic restorations have considerably increased. For a successful clinical outcome, the luting agent should have high bond strength, not only to the ceramic surface, but also to the tooth surface. PURPOSE: The purpose of this study was to examine shear (S) and tensile (T) bond strengths between 2 all-ceramic systems and human dentin using 3 dual-polymerizing resin cements. MATERIAL AND METHODS: The buccal surfaces of 120 freshly extracted human third molars were ground flat, parallel to the long axis. Sixty specimens were prepared from each of 2 all ceramic systems (IPS Empress 2 (E) and Cergo Pressable Ceramic (C)). Twenty specimens were luted with each of the following resin cements: Nexus 2 (N) with Self-Etch Primer, Duo-Link (D), and Variolink II (V), with their respective bonding systems. All specimens were immersed in water at 37 degrees C for 1 week, before being thermal cycled for 500 cycles in 5 degrees C and 55 degrees C water. Shear (S) and tensile (T) bond strength tests were applied to 10 specimens from each group. Fractured surfaces were inspected by scanning electron microscopy (SEM). Statistical analyses were performed using nonparametric 1-way ANOVA (Kruskal-Wallis) followed by Duncan's multiple range tests for post hoc comparison and Mann-Whitney U test for 2 ceramic systems (alpha=.05). RESULTS: Significant differences were observed in shear and tensile bond strength values of the adhesive systems used (P<.05). Duo-Link showed the highest mean bond strength values, whereas Nexus 2 revealed lower shear and tensile bond strength values. Fracture modes were hybrid at the dentin interface and/or cohesive in dentin. CONCLUSIONS: Cementing agents/adhesive systems may influence the bond to dental hard tissues. Dual-polymerizing activators may have a negative effect on polymerization of the bonding agent. PMID- 19782828 TI - Internal fit evaluation of crowns prepared using a new dental crown fabrication technique: laser-sintered Co-Cr crowns. AB - STATEMENT OF PROBLEM: Difficulties encountered during casting of base metal dental alloys limit their use. Application of these alloys might be enhanced if new techniques are used. PURPOSE: The purpose of this study was to compare the internal fit of laser-sintered Co-Cr alloy crowns with base metal restorations prepared from another Co-Cr alloy and a Ni-Cr alloy using conventional casting techniques. MATERIAL AND METHODS: Internal fit of laser-sintered Co-Cr crowns was compared with the fit of conventionally cast Ni-Cr and Co-Cr alloy crowns. Twelve crown-shaped specimens were prepared on a stainless steel die representing a prepared maxillary right central incisor for each group. Fit of crowns was evaluated using 2 different techniques: (1) weighing the light-body addition silicone that simulated a cement material, and (2) measuring the internal gap width on a die for longitudinally sectioned specimens. One-way ANOVA followed by Tukey multiple comparison test was used for statistical analysis (alpha=.05). RESULTS: Significantly higher mean (SD) light-body silicone weights (P<.001) were observed in the laser-sintered Co-Cr alloy group (14.34 (1.67) mg) compared to the conventionally cast Ni-Cr alloy group (9.36 (1.97) mg) and Co-Cr alloy group (7.85 (1.19) mg). Mean internal gap widths (SDs) were 58.21 (19.92) microm, 50.55 (25.1) microm, and 62.57 (21.62) microm, respectively, for the cast Ni-Cr and Co Cr alloy groups and the laser-sintered Co-Cr alloy group. No significant difference was observed between the 3 groups for internal gap widths (P=.42). CONCLUSIONS: Weighing the light-body addition silicone is a convenient method for evaluating the 3-dimensional internal fit of dental crowns. However, no significant difference was found among the 3 alloy groups evaluated for the internal gap width of sectioned crown specimens. PMID- 19782829 TI - Making multiple predictable single-unit provisional restorations using an indirect technique. AB - This article describes a method to fabricate single provisional restorations for multiple preparations using an indirect technique. Provisional restorations need to mimic the definitive restoration as closely as clinically possible. When multiple adjacent provisional restorations are fabricated, the ability to make each separately, with its own path of insertion and contour, aids in providing a predictable final result for the patient. Individual provisional restorations will also allow the patient to maintain better hygiene. PMID- 19782830 TI - Attaching a midfacial prosthesis to eyeglass frames using a precision attachment. PMID- 19782831 TI - Use of coffee straw for overdenture bar fabrication. PMID- 19782832 TI - The coral reef crisis: the critical importance of<350 ppm CO2. AB - Temperature-induced mass coral bleaching causing mortality on a wide geographic scale started when atmospheric CO(2) levels exceeded approximately 320 ppm. When CO(2) levels reached approximately 340 ppm, sporadic but highly destructive mass bleaching occurred in most reefs world-wide, often associated with El Nino events. Recovery was dependent on the vulnerability of individual reef areas and on the reef's previous history and resilience. At today's level of approximately 387 ppm, allowing a lag-time of 10 years for sea temperatures to respond, most reefs world-wide are committed to an irreversible decline. Mass bleaching will in future become annual, departing from the 4 to 7 years return-time of El Nino events. Bleaching will be exacerbated by the effects of degraded water-quality and increased severe weather events. In addition, the progressive onset of ocean acidification will cause reduction of coral growth and retardation of the growth of high magnesium calcite-secreting coralline algae. If CO(2) levels are allowed to reach 450 ppm (due to occur by 2030-2040 at the current rates), reefs will be in rapid and terminal decline world-wide from multiple synergies arising from mass bleaching, ocean acidification, and other environmental impacts. Damage to shallow reef communities will become extensive with consequent reduction of biodiversity followed by extinctions. Reefs will cease to be large-scale nursery grounds for fish and will cease to have most of their current value to humanity. There will be knock-on effects to ecosystems associated with reefs, and to other pelagic and benthic ecosystems. Should CO(2) levels reach 600 ppm reefs will be eroding geological structures with populations of surviving biota restricted to refuges. Domino effects will follow, affecting many other marine ecosystems. This is likely to have been the path of great mass extinctions of the past, adding to the case that anthropogenic CO(2) emissions could trigger the Earth's sixth mass extinction. PMID- 19782833 TI - Advances in cardiac and aortic surgery. Foreword. PMID- 19782834 TI - Advances in cardiac and aortic surgery. Preface. PMID- 19782835 TI - Cardiac screening before noncardiac surgery. AB - Cardiovascular complications are infrequent but can result in significant morbidity following noncardiac surgery, especially in patients with peripheral vascular disease or increased age. All patients require some level of preoperative screening to identify and minimize immediate and future risk, with a careful focus on known coronary artery disease or risks for coronary artery disease and functional capacity. The 2007 American College of Cardiology/American Heart Association Guidelines are clear that noninvasive and invasive testing should be limited to circumstances in which results will clearly affect patient management or in which testing would otherwise be indicated. beta-Blocker therapy has become controversial in light of recent publications but should be continued in patients already on therapy, and started in patients with high cardiac risk undergoing intermediate- or high-risk surgery. PMID- 19782837 TI - Cardiopulmonary bypass/extracorporeal membrane oxygenation/left heart bypass: indications, techniques, and complications. AB - Cardiopulmonary bypass has revolutionized the ability to provide cardiorespiratory support and has advanced the field of cardiac surgery. This invention has given surgeons the ability to perform many procedures that were not possible previously. The concept and development of cardiopulmonary bypass has been pioneered by numerous legendary surgeons. Cardiopulmonary bypass, extracorporeal membrane oxygenation, and left heart bypass have revolutionized our ability to operate on the heart, great vessels, and aorta in addition to providing means of short-term support for reversible causes of cardiac and/or respiratory failure. The success of these approaches is dependent upon excellent communication between the surgeon, perfusionist, and anesthesiologist as well as constant vigilance and troubleshooting by the caregivers. PMID- 19782836 TI - Noninvasive imaging of the heart and coronary arteries. AB - There are multiple imaging modalities currently available to noninvasively evaluate the heart and coronary arteries. Choosing the most appropriate modality depends on the pertinent clinical question and the underlying patient characteristics. This article provides an overview of the fields of echocardiography, myocardial perfusion imaging, cardiac computed tomography, and cardiac magnetic resonance imaging, with particular attention to specific clinical applications for cardiac surgery patients. PMID- 19782838 TI - Great vessel and cardiac trauma. AB - Thoracic great vessel and cardiac trauma are characterized by anatomic location and mechanism of injury: blunt or penetrating. Management strategies are also directed by the extent and mechanism of injury. Advances in imaging and catheter based technologies have allowed easier and more accurate diagnosis and less invasive treatments. Although the advantages of endovascular techniques are attractive, open surgical repair remains the definitive treatment for many of these thoracic injuries. Given the increasing sophistication of these technologies and the demonstrated usefulness of a disease-oriented approach toward patient management, trauma centers have adopted a multidisciplinary team model for management of multitrauma victims. In this review, the authors detail the diagnosis and management of blunt aortic, nonaortic great vessel, blunt cardiac, and penetrating cardiac injuries. PMID- 19782839 TI - Surgical treatment of great vessel occlusive disease. AB - Occlusive disease of the supra-aortic trunks remains a diagnostic and therapeutic challenge to the surgeon. Although most cases in Western series are attributable to atherosclerotic disease, other entities such as Takayasu arteritis and radiation arteritis account for a substantial subset of patients in whom choice of therapy and clinical response may be significantly affected by the peculiarities of the disease process involved. This article reviews the anatomy, causes, and diagnosis of occlusive disease of the supra-aortic trunks. The indications, techniques, and outcomes of reconstruction are also discussed. PMID- 19782840 TI - Valve-sparing aortic root reconstruction. AB - The aortic valve-sparing root reconstruction procedure remains an ideal concept, but it has not yet become an ideal operation. There is still great variation and evolution in techniques, which mirrors the increasing understanding of the aortic root's functional anatomy and the disease processes that affect it. These operations remain complex, and the surgeons who perform them well are often times best armed with an experienced eye for what looks right more than a mathematical model that can predetermine who will do well, with what repair type and with what percentage chance of long-term success. Because of this, it will likely still be a while before these operations are more routinely used by a broader group of surgeons, as compared with the very reproducible Bentall and De Bono repair. PMID- 19782841 TI - Indications for the treatment of thoracic aortic aneurysms. AB - In an era of increasingly common and detailed imaging of the thorax, thoracic aortic aneurysms are being discovered in their precomplicated state with increasing frequency. At the same time, the list of potential treatments for thoracic aneurysms is beginning to expand. Deciding which treatment method to employ and which aneurysm to treat is often difficult. The risk of aneurysm complications must be balanced against the risks of the treatment. This work explores the behavior of thoracic aneurysms, the state-of-the-art in treatment, and a rational approach to the treatment decision is proposed. PMID- 19782842 TI - Approach to the treatment of aortic dissection. AB - Acute aortic dissection is a fatal disease if early diagnosis and institution of appropriate therapy are delayed. Unfortunately, the presentation of a dissection can be diabolical, leading to an initial misdiagnosis in more than 25% of patients. For type A dissections, surgical repair is essential because mortality rates approach 50% at 48 hours with expectant therapy alone. For type B dissections, medical management is successful in most patients, although a subset with complications or early dilation may benefit from newer endovascular techniques. The goal of this review is to summarize the diagnostic algorithm, initial therapeutic options, and long-term management regimen that offer patients with an acute aortic dissection the best chance for short-term and long-term survival. There is an emphasis on the specific practical approach that is applied at Washington University to patients who present with an aortic dissection. PMID- 19782843 TI - Endovascular repair of the thoracic aorta. AB - The use of endovascular stent grafts for treatment of the descending thoracic aorta is reviewed. Currently, 3 devices have been approved by the US Food and Drug Administration for the treatment of descending thoracic aneurysms, and multiple studies are ongoing to investigate the efficacy of endovascular treatment in such pathologies as traumatic aortic injury and Stanford type B dissection. Outcomes are highly dependent on good case planning and patient selection and will likely continue to improve as newer-generation devices and delivery systems are designed and made available. PMID- 19782844 TI - Off-pump versus on-pump coronary artery bypass grafting. AB - Off-pump coronary artery bypass is a safe and effective method of coronary revascularization that avoids the use of cardiopulmonary bypass. Randomized trials, typically enrolling low-risk patients, have shown comparable mortality and reduced morbidity between off-pump and on-pump coronary artery bypass. Larger retrospective analyses suggest improved mortality and a lower incidence of adverse events in patients undergoing off-pump coronary artery bypass. This article reviews the available literature comparing outcomes of patients undergoing on- and off-pump coronary artery bypass surgery. PMID- 19782845 TI - Minimally invasive valve surgery. AB - Traditional cardiac valve replacement surgery is being rapidly supplanted by innovative, minimally invasive approaches toward the repair of these valves. Patients are experiencing benefits ranging from less bleeding and pain to faster recovery and greater satisfaction. These operations are proving to be safe, highly effective, and durable, and their use will likely continue to increase and become even more widely applicable. PMID- 19782846 TI - Transcatheter cardiac valve interventions. AB - Currently aortic valve replacement is performed for patients with severe aortic stenosis and symptoms or objective pathophysiologic consequences such as left ventricular dysfunction. For transcatheter mitral valve interventions, the complex pathophysiology of mitral regurgitation with varying causes along with challenging imaging and delivery issues has led to slower than anticipated clinical introduction. Transcatheter pulmonary valve intervention was primarily designed to treat the difficult problem of right ventricular to pulmonary artery conduit stenosis in the congenital population. These techniques are reviewed in this article. PMID- 19782847 TI - Surgical treatments for advanced heart failure. AB - Patients with heart failure represent a significantly ill cohort, and the survival of the most advanced heart failure patients is dismal with medical management alone. This cohort of advanced heart-failure patients benefits from several surgical treatments. Although several techniques for surgical ventricular restoration in the setting of left ventricular aneurysms have been described, the broader application of these techniques to patients with ischemic cardiomyopathy has occurred during the last decade. This review focuses on left ventricular aneurysm (LVA) repair and surgical ventricular restoration, ventricular assist devices, and cardiac allograft transplantation for the treatment of advanced heart failure. Indications for these procedures are addressed, as well as intraoperative technical features and postoperative management strategies. PMID- 19782849 TI - Congenital heart disease surgery in the adult. AB - As a result of improved treatment of congenital heart disease (CHD) over the last half century, the number of patients reaching adulthood continues to grow. With increased success a challenging group of adults with unique anatomy and physiology, in addition to the usual effects of aging, has been created. All of these patients present unique and fascinating challenges, and their best care requires bridging pediatric and adult medical and surgical care. This review is a discussion of some of the more common surgical issues that arise in this evolving group of patients. PMID- 19782850 TI - Surgical research: the reality and the IDEAL. PMID- 19782848 TI - The surgical treatment of atrial fibrillation. AB - Atrial fibrillation is a complex disease affecting a significant portion of the general population. Although medical therapy is the mainstay of treatment, intervention plays an important role in selected patients. The Cox-Maze procedure is the gold standard for the surgical treatment of atrial fibrillation and has more than 90% success in eliminating atrial fibrillation. Ablation technologies have played a key role in simplifying this technically demanding procedure and making it available to more patients. A myriad of new lesion sets and approaches were introduced over the last decade which has made the operative treatment of atrial fibrillation less invasive and more confusing. PMID- 19782851 TI - A new UN agency for women. PMID- 19782852 TI - Tobacco smoking: why start? PMID- 19782853 TI - Surgical research: act 3, answers. PMID- 19782854 TI - Chronic subdural haematoma--to drain or not to drain? PMID- 19782855 TI - Non-surgical treatment in carpal tunnel syndrome. PMID- 19782856 TI - Benchmarking in surgical research. PMID- 19782857 TI - To cement or not in hip fracture surgery? PMID- 19782858 TI - New surgical thermal management guidelines. PMID- 19782859 TI - Ara Darzi: an innovative surgeon who led reforms of UK's NHS. PMID- 19782860 TI - Probable fluoxetine-induced carotidynia. PMID- 19782861 TI - In-flight medical emergencies. PMID- 19782862 TI - In-flight medical emergencies. PMID- 19782864 TI - In-flight medical emergencies. PMID- 19782865 TI - Mental illness in China. PMID- 19782866 TI - Mental illness in China. PMID- 19782867 TI - Mental illness in China. PMID- 19782868 TI - Translating statistical findings into plain English. PMID- 19782871 TI - AIDS treatment in Brazil: what kind of evidence do we need? PMID- 19782872 TI - Use of drains versus no drains after burr-hole evacuation of chronic subdural haematoma: a randomised controlled trial. AB - BACKGROUND: Chronic subdural haematoma causes serious morbidity and mortality. It recurs after surgical evacuation in 5-30% of patients. Drains might reduce recurrence but are not used routinely. Our aim was to investigate the effect of drains on recurrence rates and clinical outcomes. METHODS: We did a randomised controlled trial at one UK centre between November, 2004, and November, 2007. 269 patients aged 18 years and older with a chronic subdural haematoma for burr-hole drainage were assessed for eligibility. 108 were randomly assigned by block randomisation to receive a drain inserted into the subdural space and 107 to no drain after evacuation. The primary endpoint was recurrence needing redrainage. The trial was stopped early because of a significant benefit in reduction of recurrence. Analyses were done on an intention-to-treat basis. This study is registered with the International Standard Randomised Controlled Trial Register (ISRCTN 97314294). FINDINGS: Recurrence occurred in ten of 108 (9.3%) people with a drain, and 26 of 107 (24%) without (p=0.003; 95% CI 0.14-0.70). At 6 months mortality was nine of 105 (8.6%) and 19 of 105 (18.1%), respectively (p=0.042; 95% CI 0.1-0.99). Medical and surgical complications were much the same between the study groups. INTERPRETATION: Use of a drain after burr-hole drainage of chronic subdural haematoma is safe and associated with reduced recurrence and mortality at 6 months. FUNDING: Academy of Medical Sciences, Health Foundation, and NIHR Biomedical Research Centre (Neurosciences Theme). PMID- 19782873 TI - Surgery versus non-surgical therapy for carpal tunnel syndrome: a randomised parallel-group trial. AB - BACKGROUND: A previous randomised controlled trial reported greater efficacy of surgery than of splinting for patients with carpal tunnel syndrome. Our aim was to compare surgical versus multi-modality, non-surgical treatment for patients with carpal tunnel syndrome without denervation. We hypothesised that surgery would result in improved functional and symptom outcomes. METHODS: In this parallel-group randomised controlled trial, we randomly assigned 116 patients from eight academic and private practice centres, using computer-generated random allocation stratified by site, to carpal tunnel surgery (n=57) or to a well defined, non-surgical treatment (including hand therapy and ultrasound; n=59). The primary outcome was hand function measured by the Carpal Tunnel Syndrome Assessment Questionnaire (CTSAQ) at 12 months assessed by research personnel unaware of group assignment. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00032227. FINDINGS: 44 (77%) patients assigned to surgery underwent surgery. At 12 months, 101 (87%) completed follow-up and were analysed (49 of 57 assigned to surgery and 52 of 59 assigned to non-surgical treatment). Analyses showed a significant 12-month adjusted advantage for surgery in function (CTSAQ function score: Delta -0.40, 95% CI 0.11 0.70, p=0.0081) and symptoms (CTSAQ symptom score: 0.34, 0.02-0.65, p=0.0357). There were no clinically important adverse events and no surgical complications. INTERPRETATION: Symptoms in both groups improved, but surgical treatment led to better outcome than did non-surgical treatment. However, the clinical relevance of this difference was modest. Overall, our study confirms that surgery is useful for patients with carpal tunnel syndrome without denervation. FUNDING: NIH/NIAMS 5P60AR048093 and the Intramural Research Program of the NIH Clinical Center. PMID- 19782874 TI - Evaluation and stages of surgical innovations. AB - Surgical innovation is an important part of surgical practice. Its assessment is complex because of idiosyncrasies related to surgical practice, but necessary so that introduction and adoption of surgical innovations can derive from evidence based principles rather than trial and error. A regulatory framework is also desirable to protect patients against the potential harms of any novel procedure. In this first of three Series papers on surgical innovation and evaluation, we propose a five-stage paradigm to describe the development of innovative surgical procedures. PMID- 19782875 TI - Challenges in evaluating surgical innovation. AB - Research on surgical interventions is associated with several methodological and practical challenges of which few, if any, apply only to surgery. However, surgical evaluation is especially demanding because many of these challenges coincide. In this report, the second of three on surgical innovation and evaluation, we discuss obstacles related to the study design of randomised controlled trials and non-randomised studies assessing surgical interventions. We also describe the issues related to the nature of surgical procedures-for example, their complexity, surgeon-related factors, and the range of outcomes. Although difficult, surgical evaluation is achievable and necessary. Solutions tailored to surgical research and a framework for generating evidence on which to base surgical practice are essential. PMID- 19782876 TI - No surgical innovation without evaluation: the IDEAL recommendations. AB - Surgery and other invasive therapies are complex interventions, the assessment of which is challenged by factors that depend on operator, team, and setting, such as learning curves, quality variations, and perception of equipoise. We propose recommendations for the assessment of surgery based on a five-stage description of the surgical development process. We also encourage the widespread use of prospective databases and registries. Reports of new techniques should be registered as a professional duty, anonymously if necessary when outcomes are adverse. Case series studies should be replaced by prospective development studies for early technical modifications and by prospective research databases for later pre-trial evaluation. Protocols for these studies should be registered publicly. Statistical process control techniques can be useful in both early and late assessment. Randomised trials should be used whenever possible to investigate efficacy, but adequate pre-trial data are essential to allow power calculations, clarify the definition and indications of the intervention, and develop quality measures. Difficulties in doing randomised clinical trials should be addressed by measures to evaluate learning curves and alleviate equipoise problems. Alternative prospective designs, such as interrupted time series studies, should be used when randomised trials are not feasible. Established procedures should be monitored with prospective databases to analyse outcome variations and to identify late and rare events. Achievement of improved design, conduct, and reporting of surgical research will need concerted action by editors, funders of health care and research, regulatory bodies, and professional societies. PMID- 19782878 TI - Serious postoperative syncope. PMID- 19782877 TI - Standardised metrics for global surgical surveillance. AB - Public health surveillance relies on standardised metrics to evaluate disease burden and health system performance. Such metrics have not been developed for surgical services despite increasing volume, substantial cost, and high rates of death and disability associated with surgery. The Safe Surgery Saves Lives initiative of WHO's Patient Safety Programme has developed standardised public health metrics for surgical care that are applicable worldwide. We assembled an international panel of experts to develop and define metrics for measuring the magnitude and effect of surgical care in a population, while taking into account economic feasibility and practicability. This panel recommended six measures for assessing surgical services at a national level: number of operating rooms, number of operations, number of accredited surgeons, number of accredited anaesthesia professionals, day-of-surgery death ratio, and postoperative in hospital death ratio. We assessed the feasibility of gathering such statistics at eight diverse hospitals in eight countries and incorporated them into the WHO Guidelines for Safe Surgery, in which methods for data collection, analysis, and reporting are outlined. PMID- 19782879 TI - Toll-like receptor-2 agonist functionalized biopolymer for mucosal vaccination. AB - The objective of this study was to provide a new water-soluble chitosan derivative being functionalized with a Toll-like receptor-2 (TLR-2) agonist. At first, we synthesized the water-soluble TLR-2 agonist omega-amido-[N(alpha) palmitoyl-oxy-S-[2,3-bis(palmitoyl-oxy)-(2R)-propyl]-[R]-cysteinyl]-alpha-amino poly(ethylene glycol) (Pam(3)Cys-PEG-NH(2)), which was characterized by (1)H and (13)C NMR as well as mass spectroscopy. Secondly, Pam(3)Cys-PEG-NH(2) was then successfully grafted to 6-O-carboxymethyl-N,N,N-trimethyl chitosan polymers (CM TMC) using EDC/NHS as condensing agents. The copolymer was analysed by means of (1)H and (13)C NMR and FTIR spectroscopy. (13)C NMR spectroscopy did not deliver evidence that an amide bond was formed between CM-TMC and Pam(3)Cys-PEG-NH(2). However, (1)H NMR and FTIR spectroscopy demonstrated clearly that successful grafting took place. Based upon these results, this new TLR-2 functionalized biopolymer merits further investigations as material for vaccine delivery systems. PMID- 19782880 TI - Pluripotent stem cells as new drugs? The example of Parkinson's disease. AB - Cell replacement therapy is a widely discussed novel concept of medical treatment. The increased knowledge in the stem cell field, particularly pluripotent stem cells, potentially provides powerful tools for this therapeutic concept. A large number of disease characterized by the loss of functional cells are potential candidates for cell replacement therapy and, in this regards, Parkinson's disease is of particular interest. It is one of the most prevalent neurodegenerative diseases caused by the loss of dopaminergic neurons in the Substantia nigra pars compacta. Pharmacological therapies are valuable but suffer from the progressive decline of efficacy as the disease progresses. Cell therapy application has emerged about two decades ago as a valid therapeutic alternative and recent advances in stem cell research suggest that pluripotent stem cell transplantation may be a promising approach to replace degenerated neurons in Parkinson's disease. Various sources of pluripotent stem cells (PSC) currently tested in animal models of Parkinson's disease have proven their efficacy in relieving symptoms and restoring damaged brain function. This review summarizes and discusses the important challenges that actually must be solved before the first studies of PSC transplantation can be undertaken into humans. PMID- 19782881 TI - Freeze-drying of squalenoylated nucleoside analogue nanoparticles. AB - Nucleoside analogues are potent anticancer or antiviral agents that however display some limitations (rapid metabolism, induction of resistance). In order to overcome these drawbacks, we recently proposed new prodrugs, in which nucleoside analogues were covalently coupled to squalene (SQ). The resulting amphiphilic compounds spontaneously formed nanoparticles (NPs) and displayed a promising efficacy both in vitro and in vivo. Since long-term stability is essential for further clinical development we needed to develop a laboratory-scale freeze drying protocol in order to improve the colloidal stability of those NPs. Squalenoylated gemcitabine (SQdFdC) has been successfully freeze-dried with trehalose (10%, w/w) as a cryoprotectant. Concentrations of SQdFdC up to 4mg/mL after freeze-drying and rehydration have been obtained, which is necessary for in vivo studies. Stability measurements by dynamic light scattering showed that trehalose had a stabilizing effect on SQdFdC NPs, and that freeze-dried SQdFdC NPs could be stored up to four months at room temperature before rehydration, without loss of stability. In vitro cytotoxicity studies on three murine cell lines showed that SQdFdC NPs retained their cytotoxic activity after freeze drying. We showed that this freeze-drying protocol could also be applied to squalenoylated didanosine (SQddI) and zalcitabine (SQddC). Overall, these results allow for the use of freeze-dried NPs in upcoming preclinical trials of the different squalenoylated compounds developed in our laboratory. PMID- 19782882 TI - Influence of the composition of glycerides on the solid-state behaviour and the dissolution profiles of solid lipid extrudates. AB - A monoacid triglyceride and a partial glyceride were extruded below their melting ranges alone and together in different mixture ratios to investigate the influence of the chemical composition of the lipid matrix on the solid-state properties and dissolution characteristics. The partial glyceride exhibits a faster release of the drug compared to the triglyceride due to its surfactant properties. The lipid mixtures show rather complex solid-state behaviour and hence unexpected dissolution characteristics. Adding 10% (w/w) partial glyceride to a triglyceride matrix led to increased incidence of the unstable alpha-form of the triglyceride leading to recrystallization of the stable beta-form over time which causes fractal structures on the extrudate surface which decrease the dissolution rate. Adding 50% (w/w) partial glyceride to the triglyceride matrix also results in tristearin alpha-formation subsequently followed by recrystallization to the beta-form. But as 50% of the matrix consists of the partial glyceride the dissolution rate was faster than the rate obtained by pure triglyceride or the 9+1 (w/w) mixture of triglyceride and partial glyceride. The results of this study help in understanding the complex solid-state behaviour of solid lipid extrudates with different composition and to manufacture suitable lipid-based oral dosage forms. PMID- 19782885 TI - Effectiveness of vertebroplasty: a recent controversy. PMID- 19782883 TI - Influence of luminal monosaccharides on secretion of glutathione conjugates from rat small intestine in vitro. AB - Intestinal efflux transporters can significantly reduce the absorption of the drug after peroral application. In this work we studied secretion of glutathione conjugates triggered by glucose at the luminal side of the intestine. Glucose stimulated secretion of DNPSG, NEMSG and CDNB. We used some different monosaccharides and determined that glucose, galactose and alpha methylglucopyranoside trigger the secretion, while mannitol and fructose do not. We concluded that interaction with SGLT transporter is the key process necessary for this triggering. To determine which of possible glutathione conjugate transporters (MRP2, MRP4, BCRP or RLIP76) is responsible for the secretion of glutathione conjugates, we used benzbromarone, a MRP inhibitor, and sulfanitran and furosemide, two allosteric MRP2 activators. Benzbromarone inhibited glucose stimulated DNPSG secretion, while allosteric activators additionally increased the secretion. We concluded that MRP2 transporter is related to glucose stimulated DNPSG secretion. Regarding the work of Kubitz et al. we tested the effect of changed medium osmolarity on DNPSG transport and determined that hypoosmolar conditions trigger secretion of DNPSG. These findings suggest that intestinal MRP2 activity has no basal level, but can be stimulated by hypoosmolarity and SGLT transport. PMID- 19782886 TI - Magnetic resonance imaging-guided vacuum-assisted breast biopsy: an initial experience in a community hospital. AB - OBJECTIVE: To evaluate the effectiveness in diagnosing mammographically and sonographically occult breast lesions by using magnetic resonance imaging (MRI) guided vacuum-assisted breast biopsy in patients who presented to a community based hospital with a newly established breast MRI program. METHODS: The records of 142 consecutive patients, median age of 55 years, who had undergone MRI-guided biopsy at our institution between July 2006 and July 2007 were reviewed. From these patients, 197 mammographically and sonographically occult lesions were biopsied at the time of discovery. The pathology was then reviewed and correlated with the MRI findings. RESULTS: Cancer was present and subsequently discovered in 8% of the previously occult lesions (16/197) or 11% of the women studied (16/142). Of the cancerous lesions, 56% were invasive carcinomas (9/16) and 44% were ductal carcinomas in situ (7/16). Fourteen percent of the discovered lesions (28/197) were defined as high risk and included atypical ductal hyperplasia, atypical lobular hyperplasia, lobular carcinoma in situ, and radial scar. In total, occult cancerous and high-risk lesions were discovered in 22% of the found lesions (44/197) or 31% of the women who underwent MRI-guided biopsy (44/142). CONCLUSIONS: This study demonstrated that detection of cancerous and high-risk lesions can be significantly increased when an MRI-guided biopsy program is introduced at a community-based hospital. We believe that as radiologists gain confidence in imaging and histologic correlation, community-based hospitals can achieve similar rates of occult lesion diagnosis as those found in data emerging from academic institutions. PMID- 19782887 TI - Answer to case of the month #153. Leontiasis ossea. PMID- 19782888 TI - Answer to case of the month #154. Osteoid osteoma. PMID- 19782889 TI - Answer to case of the month #155. Shock bowel. PMID- 19782890 TI - Answer to case of the month #156. Dermoid cyst presenting as congenital midline nasal mass in 6-month-old infant. PMID- 19782892 TI - The call for health care reform and the pediatric nursing shortage. PMID- 19782893 TI - Prevalence estimates of overweight in Head Start preschoolers. AB - This study estimates prevalence of overweight and at risk of overweight among low income predominately non-Hispanic Black Head Start Mississippi preschoolers. A two-stage stratified probability design produced a representative sample of 1,250 preschoolers aged 3 to 5 years. Height, weight, age, gender, and race data were obtained. The prevalence of overweight (20.6%) and at risk of overweight (17.9%) combined was 38.5%. Moreover, highest rates were found in boys, non-Hispanic Blacks, and 5-year-olds. The prevalence of overweight in Mississippi Head Start children exceeds national averages, reinforcing the need for early-childhood health promotion and prevention. PMID- 19782894 TI - Maternal substance abuse and children's exposure to violence. AB - This article focuses on exposure to violence and violence-related activities (i.e., crime and drug use) in 70 children whose mothers are addicted to alcohol or other drugs and explores maternal characteristics associated with violence exposure. Results suggest that exposure to violence is relatively common for these children, with many exposed to repeated violence in both the home and community. Findings also suggest higher levels of exposure to violence among children whose mothers reported fewer symptoms of posttraumatic stress disorder and held beliefs and attitudes about child rearing that have been associated with abusive and neglectful parenting. Levels of violence exposure were also higher when mothers reported more severe drug use in the recent past. These findings point to the need for assessment and treatment for children whose mothers abuse alcohol and other drugs. PMID- 19782895 TI - Correlates of negative and positive mood state in mothers of twins. AB - Relationships between parenting distress, social support, and sense of competence and negative and positive maternal mood were assessed in 162 mothers with twins younger than 2 years. Women with lower satisfaction scores on the sense of competence scale reported higher negative mood (adjusted R(2) = 21.7%, p < .001). Women with lower parenting distress and higher efficacy scores on the sense of competence scale reported higher positive mood (adjusted R(2) = 39.4%, p < .001). Neither instrumental nor subjective social support contributed to variance in maternal mood. Interventions should be aimed at decreasing parenting distress and increasing sense of competence for mothers of twins. PMID- 19782897 TI - Parenting: linking impacts of interpartner conflict to preschool children's social behavior. AB - Family conflict is known to have detrimental impacts on the social development of young children. An important issue in counseling parents and the development of intervention for children is the extent to which other family environmental conditions are the path through which conflict impacts children's development. This study examined two maternal parenting behaviors (harsh discipline and warmth) that may alter the impact of interpartner conflict on child social development and behavior in a large (n = 440 girls, n = 451 boys) sample of ethnically diverse, low-income families of preschool children. Interpartner conflict was associated with poorer child social development and behavior problems. This study found that interpartner conflict increased harsh discipline, which resulted in poorer child social development. This study, however, found no evidence that interpartner conflict impacted child development through its impact on maternal warmth in that mothers experiencing conflict did not alter the level of warm parenting practices. These findings suggest that, when encountering families experiencing interpartner conflict, clinicians should not only direct families to interventions to lessen family conflict but also counsel them on the mechanism (harsh discipline) by which children are impacted by the conflict. PMID- 19782896 TI - Stress and body mass index each contributes independently to tumor necrosis factor-alpha production in prepubescent Latino children. AB - This investigation extended prior work by determining if stress and body mass index (BMI) contributed independently to tumor necrosis factor-alpha (TNF-alpha) levels among prepubescent Latino children and if sex and family history of type 2 diabetes mellitus (T2DM) modified these relationships. Data were collected in South Florida from 112 nondiabetic school-aged Hispanic children, of whom 43.8% were obese (BMI >/= 95th percentile) and 51.8% presented with a family history of T2DM. Stressful life events were assessed via parental report using a life events scale. Plasma TNF-alpha levels were determined with enzyme-linked immunosorbent assay. The relative contributions of stress and BMI with TNF-alpha levels and the potential interaction effects of sex and family history of T2DM were analyzed with multiple linear regression analyses. Stress and BMI each accounted for a significant proportion of the unique variance associated with TNF-alpha. The association between stress and TNF-alpha was not modified by sex or family history of T2DM. These findings implicate BMI and stress as independent determinants of TNF-alpha (an inflammatory cytokine and adipocytokine) among Latino children. Future investigations should examine the potential roles of exercise, nutritional status, age, and growth hormone in explicating the relationship between TNF-alpha production and psychosocial distress and risk for infection among obese children. PMID- 19782898 TI - Substance abuse, chronic sorrow, and mothering loss: relapse triggers among female victims of child abuse. AB - The purpose of this qualitative study was to explore chronic sorrow as a relapse trigger among female victims of child abuse seeking treatment for substance abuse relapse. A purposive convenience sample of 12 women was interviewed using qualitative description to provide insight into their perceptions of relapse triggers. In addition to chronic sorrow, three common themes were interwoven in the narrative stories of these women: mothering loss, blocking feelings, and relapse triggers. Feelings described as relapse triggers included loneliness, sadness, anger, and frustration. The information gleaned from these women can be incorporated into the treatment of women and children in an effort to better prepare them for these recurrent feelings and triggers that could result in substance abuse and relapse. PMID- 19782899 TI - Victorian children in trouble. PMID- 19782900 TI - Quality of life of adolescent and young adult survivors of childhood cancer. AB - The purpose of this study was to assess the quality of life of Greek survivors of childhood cancer by addressing the physical, psychological, spiritual, and social dimensions of their functioning. The SF-36 Health Survey and the Quality of Life Questionnaire, which was designed for this study, were used. Survivors' scores on most subscales of SF-36 were similar to those of controls, despite some difficulties in their daily activities. They perceived self as more susceptible to health problems, but also more mature and grounded. Generally, they seem to adapt well and focus on the positive aspects of their cancer experience, which enhances the meaning and quality of their life. PMID- 19782901 TI - An everyday struggle-Swedish families' lived experiences during a child's cancer treatment. AB - The aim was to elucidate families' lived experience during a child's cancer treatment. Interviews were conducted with members of 11 affected families. A hermeneutical phenomenological approach was chosen. "Focus on the ill child-An everyday struggle" emerged as an essential theme. The families' lived experience of daily life was described as "feeling drained," "disrupting family life," "feeling locked up and isolated," "retaining normality," "becoming experts," and "changing perspectives." The result indicates that life during a child's cancer treatment is a taxing period and that the entire family is in need of support to ease their burdens. PMID- 19782902 TI - Uncertainties and anxieties about vaccination, answering parent's concerns. AB - Vaccination is one of the most significant public health interventions responsible for saving millions of lives and preventing significant morbidity. Despite this, there remain concerns about a number of vaccines. Although vaccines are extensively tested, there are genuine questions that many parents have about a number of vaccine-related issues. It is important that practitioners can discuss these concerns because denying or dismissing them may lead parents and patients to seek advice from uninformed sources. This article discusses some of the major concerns about vaccines, including their safety, immunogenicity, and the development of national immunization programs. It concludes that although vaccines are overwhelmingly safe, constant vigilance is required. PMID- 19782903 TI - Invasive aspergillosis in non-neutropenic patients. PMID- 19782904 TI - Fatal lactic acidosis after prolonged linezolid exposure for treatment of multidrug-resistant tuberculosis. PMID- 19782905 TI - A case of thyroid storm following radioiodine therapy underlying usefulness of cardiac MRI. PMID- 19782906 TI - Diagnostic and therapeutic opportunities in hypertension and prehypertension. PMID- 19782907 TI - Omalizumab administration in Churg-Strauss syndrome. PMID- 19782908 TI - RS3PE Syndrome: extending spectrum? PMID- 19782909 TI - Spontaneous bacterial peritonitis presenting with a very high leukocyte count in the ascitic fluid. PMID- 19782910 TI - Progressive multifocal leukoencephalopathy - experimental options. PMID- 19782911 TI - Are colorectal adenomas associated with iron deficiency in hospitalized older patients? PMID- 19782912 TI - The role of tubular injury in diabetic nephropathy. AB - Diabetic nephropathy is associated with increased mortality in diabetic patients and is a major cause of end-stage renal disease in most countries. Understanding its pathogenesis is important as it may equip us with novel ways in its prevention and in slowing its progression. To date, attempts to unravel the complex pathogenesis and pathophysiology of diabetic nephropathy have mostly focused on the glomerulus. However, recently a lot of data has accumulated that implicates the tubules as playing a key role. This article reviews these data and the light they throw on the role of renal tubules in the pathogenesis of diabetic nephropathy. PMID- 19782913 TI - Evaluation of proteinuria and GFR to diagnose and classify kidney disease: systematic review and proof of concept. AB - Chronic kidney disease is often not associated with significant symptoms or abnormalities in common laboratory test results. Diagnosis is supposedly facilitated by calculating the glomerular filtration rate (GFR) from serum creatinine. A reference range GFR, however, does not exclude renal disease, because renal disease causes the subsequent decrease of renal function. Thorough analysis of proteinuria, however, requires a profound knowledge of the renal handling of the different marker proteins of glomerular and tubular origin. This paper summarizes the scientific basis, explains the diagnostic rationale and proves the concept by analyzing 5669 samples, where GFR and proteinuria work-up were available. 63% (1446 of 2287) of the samples with a GFR above 60 showed either glomerular (37.8%, n=865) or tubular proteinuria (25.4%, n= 581). The quantity of proteinuria increased severely with decreasing kidney function. The rate of glomerular proteinuria remained nearly constant in the different GFR groups, while primarily tubular proteinuria increased from 23% to 63%. A proteinuria pattern indicating a good response to therapy was frequently combined with a high GFR (selective glomerular proteinuria/ incomplete tubular proteinuria), while the severe forms of unselective or complete tubular proteinuria associated with a severe GFR decrease. Regression analysis showed a better inverse correlation of GFR with tubular (r=-0.643) than glomerular markers (r=-0.360; combined r=-0.646). We believe that this complex interrelated laboratory information must be delivered most effectively, i.e. with the use of a knowledge based system in combination with improved, visual oriented laboratory output. PMID- 19782914 TI - A new era for anticoagulants. AB - Selective inhibitors of specific coagulation factors represent a new class of antithrombotic agents, designed to overcome the limitations of traditional anticoagulants. Available clinical studies indicate that the most promising new anticoagulants are those selectively targeting factor Xa and thrombin. Typically, the standard steps for clinical evaluation of new anticoagulants are thromboprophylaxis in high risk orthopedic surgery, followed by treatment of established venous thromboembolism, nonvalvular atrial fibrillation and acute coronary syndromes. These agents - that have the potential to be more effective and easier to use than conventional drugs such as heparins and vitamin K antagonists - will greatly expand our armamentarium for the prevention and treatment of arterial and venous thromboembolism. The current knowledge on these antithrombotic agents is summarized in this review, particularly focusing on the early results of clinical trials. PMID- 19782915 TI - Common ground: the overlap between Endocrinology and Rheumatology. AB - A number of medical specialities have witnessed a dramatic change in the provision of in patient care over the last decade. Work has moved into outpatient and Day Unit settings and, more recently, into the community. This has led to the amalgamation of speciality based beds with the perceived threat of loss of independence and potential reduction in training opportunities. In reality, our experience of a combined inpatient ward for Rheumatology and Endocrinology patients has been positive, with increased awareness of the coexistence of certain disorders and a resulting enhanced approach to the delivery of patient care, junior doctor education and clinical research. We would like to share our experience by describing some of the overlapping clinical conditions between these specialities that physicians might wish to consider. PMID- 19782916 TI - Placebo therapy in Crohn's disease. AB - The knowledge of the outcome among patients receiving placebo is important for evaluating the response to therapy, for evaluating the natural history of a disease and for calculating the sample size for future clinical trials. In Crohn's disease placebo has been used in therapeutic trials in every relevant setting: active disease, prevention of relapse after induced medical remission and after surgery and fistulising disease. The analysis of the placebo response shows that in every setting there is a high heterogeneity demonstrating mainly that the selection of patients is not often homogeneous and that the outcome criteria used in the trials is not highly reliable. Better selection of patients and more precise definition of outcome measures are warranted to reduce the heterogeneity among placebo response in clinical trials. PMID- 19782917 TI - Chlamydophila pneumoniae infection and COPD: more evidence for lack of evidence? AB - Chlamydophila pneumoniae has been recognized as a common cause of respiratory tract infections affecting all age groups. The organism has been implicated as an infectious trigger for acute exacerbations of COPD. Moreover, the intracellular existence of this pathogen and the ability to cause chronic respiratory infections have led to a number of studies that investigated its possible association with disease development. The present paper examines and discusses the possible association of acute C. pneumoniae infection in episodes of acute exacerbation of COPD. It also reviews the existing evidence of chronic C. pneumoniae infection with disease pathogenesis and severity. The significant interstudy variation of the choice of diagnostic methods and criteria applied is most likely responsible for the great diversity of results observed. The use of well-standardized, commercially available diagnostic tools, as well as the adoption of a more unified diagnostic approach is probably the key element missing in order to clarify the exact role of C. pneumoniae in COPD. PMID- 19782918 TI - Secondary stroke prevention in the elderly: new evidence in hypertension and hyperlipidemia. AB - Recurrent stroke is a major public health concern, occurring in approximately one third of stroke survivors within 5 years. Besides, the overall aging of the developed countries population and the improved survival of patients with stroke have created a large population of older adults in need of secondary stroke prevention. Thus, at present, more than 5% of individuals 65 to 74 years old and more than 10% of those 75 and older have had a prior stroke. An age bias exists in the prescription of important secondary-preventive therapies in the elderly. Knowledge of the evidence behind the secondary prevention strategies could be useful to practicing physicians caring for stroke elderly patients. Effective strategies for the secondary prevention of stroke include treatment of hypertension and hyperlipidaemia. Our review presents the most recent evidence on hypertension and lipid lowering therapy for stroke prevention in elderly patients with previous stroke or TIA. Basis for evidence (or the lack thereof), areas of controversy, and avenues of future focus for these treatments are also discussed in this paper. PMID- 19782919 TI - Implantable cardioverter defibrillator: what a hospital practitioner needs to know. AB - The implantable cardioverter defibrillator (ICD) has undergone a remarkable transformation in the last three decades, both in generator size and functionality. This, coupled with improvements in lead design, allows the simplicity of defibrillator implantation to approach that of pacemakers, with outpatient placement now feasible. Nowadays, the majority of new ICD implants are performed on primary prevention grounds with device longevity of more than 7 years. In this article, we will concisely explain the evolution of this treatment, the implantation technique, arrhythmia detection and patient follow up. In addition, we will review the relevant clinical trials as well as prescription guidelines. PMID- 19782920 TI - A prospective study of the management of non-massive pulmonary embolism in the home. AB - BACKGROUND: The objective of this study is to compare the characteristics, outcomes, and clinical complications of patients with pulmonary embolism (PE) who were treated at home as outpatients versus traditional hospitalization. METHODS: Prospective study from January 2006 to June 2007. Selected patients diagnosed at the Emergency Department with stable non-massive pulmonary embolism that met standard inclusion criteria of Hospital at Home (HH) were treated at home. Patients that did not meet these criteria were admitted to Conventional Hospitalization (CH). Major and minor bleeding, re-thrombosis, clinical course, unexpected returns to hospital, and need for hospital re-admission in the following 3 months were recorded. RESULTS: 61 patients with PE were included (30 HH and 31 CH). Mean age 66.8 and 66.7 years in HH and CH, respectively. A history of neoplasm was found to be present in 13.3% and 9.7% of HH and CH patients. In the CH group, 19.3% of patients had prior thromboembolic disease. Concomitant DVT was seen in 40% and 29% of HH and CH patient. Pulmonary embolism was bilateral in 30% and 38.7% of HH and CH patients. No major bleeding, re-thrombosis, or death occurred. The home treatment was successfully completed in 100% of the patients. Three patients in the CH group had hospital-acquired infections. CONCLUSIONS: Patients with stable non-massive pulmonary embolism may be safely treated under conditions of home hospitalization. PMID- 19782921 TI - Coronary risk estimates and decisions on lipid-lowering treatment in primary prevention: comparison between general practitioners, internists, and cardiologists. AB - BACKGROUND: Quantitative assessment of an individual's absolute cardiovascular risk is essential for primary prevention. Although risk-scoring tools have been developed for this task, risk estimates are usually made subjectively. We investigated whether general practitioners (GPs), internists and cardiologists differ in their quantitative estimates of cardiovascular risk and their recommendations about lipid-lowering treatment for the same set of patients. METHODS: Mail survey. Nine written clinical vignettes, four rated high-risk and five rated low-risk according to the Framingham equation, were mailed to 90 randomly selected GPs and to the same number of internists and cardiologists in Sicily. The doctors were then asked to estimate the 10-year coronary risk in each case and to decide whether they would recommend a lipid-lowering treatment. RESULTS: In the majority of the nine cases, the cardiologists' risk estimates were significantly lower than those of the other two groups. A higher proportion of internists (mean value 0.68) decided to start treatment than GPs (0.54) or cardiologists (0.57). In all three groups, the doctors' willingness to begin treatment was over 90% when their risk estimate was above 20%, and less than 50% when it fell below this level. Internists were more prone to treat than the other two groups even when their patients' estimated risk was below 20%. CONCLUSION: When presented with the same set of clinical cases, GPs, internists and cardiologists make different quantitative risk estimates and come to different conclusions about the need for lipid-lowering treatment. This may result in over- or under-prescription of lipid-lowering drugs and inconsistencies in the care provided by different categories of doctors. PMID- 19782922 TI - Coronary artery disease is common in asymptomatic patients with signs of myocardial ischemia. AB - BACKGROUND: The incidence of coronary artery disease (CAD) in totally asymptomatic patients with myocardial ischemia during stress testing is unknown. METHODS: 54 patients with asymptomatic myocardial ischemia participated in the Swiss Interventional Study on Silent Ischemia type I (SWISSI I). Asymptomatic myocardial ischemia was verified by bicycle ergometry and stress imaging (echocardiography or scintigraphy). Findings from coronary angiographies in the course of the study constituted the main outcome. RESULTS: Of the 54 study participants, 29 patients (53.7%) underwent coronary angiography. CAD was found in 27 of 29 patients (93.1%). In those 27 patients with CAD, 9 patients (33.3%) suffered from single vessel disease, 9 patients (33.3%) from two vessel disease, and 9 patients (33.3%) from triple vessel disease. Two patients showed left main coronary artery stenosis. CONCLUSION: This study shows a high incidence of relevant CAD among totally asymptomatic patients with myocardial ischemia during stress testing. Previously healthy subjects with exercise-induced ST-segment depression at check-up examinations, even if asymptomatic, should have further diagnostic evaluation. PMID- 19782923 TI - Correlation between the prevalence of type 1 diabetes with the daily insulin dose and the autoimmune process against glutamic acid decarboxylase in adults. AB - In this study, we compared the rate of insulin requirement among adults with type 1 diabetes (T1D) in 24 Ukrainian regions. The glutamic acid decaroxylase 65 antibody (GADA), insulin antibody (IA), and plasma c-peptide levels were investigated. The data included the prevalent cases of T1D in Ukraine at the end of 2006. Only persons aged over 14 years at the time of inclusion into the Ukrainian register and diagnosed with diabetes before 30 years of age were included in this study (n=26796). A total of 86 T1D patients (42 males; 44 females) with a mean age of 27.5 years (0.86) and a mean diabetes duration of 10.3 (0.72) years (SE), were randomly selected from four regional diabetes registers. The GADA, IA, and the plasma c-peptide levels were also determined. The logistic regression model was used, and the odds ratio (OR) and 95% confidence interval (CI) were calculated. Furthermore, the differences in the T1D prevalence among the 24 Ukrainian regions were obtained (p<0.001). In the "minimal" regional cluster (MIC), the prevalence rate was 6 (5-6), and in the "maximal" (MAC) regional cluster, it was -9 (8-9) per 10000 adults. For patients with a disease duration (DD) of up to 15 years (n=13677), the daily insulin dose (DID) was observed to increase linearly with DD (R=0.899, p<0.001). The median insulin doses were standardized according to DD, and the values were lowest in the MIC and highest in the MAC populations: 45.89 (45.28-47.19) and 56.59 (53.33 57.88) U/24 h, respectively (p<0.01). Furthermore, the level of HbA1c in the MAC of T1D patients was observed to be higher than that in the MIC (9.52+/-2.24%, n=240, and 8.57+/-3.29%, n=111, respectively; p<0.01). In addition, the GADA levels and persistence in the MAC patients (n=38) were higher than that in the MIC patients (n=48): 14.1+/-4.6 and 3.2+/-1.2 U/ml, respectively, mean+/-SE; p=0.028; OR=9.66 (3.31-28.17), p<0.001. Adjusting for age, gender, and duration of diabetes affected the results only slightly. Furthermore, the IA and c-peptide levels and their persistence were not observed to be associated with TD1 prevalence. PMID- 19782924 TI - Long-term outcomes after medical and interventional therapy of critical limb ischemia. AB - BACKGROUND: Recommendations of clinical guidelines for the treatment of critical limb ischemia (CLI) are based on randomized controlled trials. Recent data from clinical practice are however lacking. Therefore a prospective observational study in patients with critical limb ischemia (CLI) in 3 hospitals with a specialized vascular medicine department was conducted to document the clinical course and outcome of patients with critical limb ischemia (CLI) in clinical practice. METHODS: 155 patients were stratified: 56 received endovascular intervention, 82 prostanoids and 17 antibiotic treatment. Patients with surgical revascularisation and primary amputation were excluded. All patients received structured wound treatment, analgesia and vascular risk factor treatment during hospital stay. RESULTS: Age 72.0+/-12.7 years, hospitalisation 23.2+/-20.3 days. 56.1% had Diabetes, 9.7% multiresistant staphylococcus aureus infection. 40% patients had rest pain, 60% ischemic tissue loss. At discharge 40.0% had no ulcers, 48.4% ongoing trophic alterations, 10.3% received major amputation and 4.5% had stable necrosis. After 18 month rate of major amputation was 6.3% (prostanoids), 14.5% (endovascular treatment; p=n.s. vs. prostanoids) and 26.7% (antibiotics; p=0.0323 vs. prostanoids). Major amputations were not different in logistic regression analyses adjusting for baseline characteristics. Wound healing and mortality rate was not different between groups (26.8, 25.0 and 23.5%). CONCLUSION: Structured therapy at specialized vascular centres in combination with interventional or conservative treatment is beneficial in patients with critical limb ischemia. Survival without amputation is higher than expected over 18 months. PMID- 19782926 TI - The role of glutathione S- transferase M1 and T1 gene polymorphisms and oxidative stress-related parameters in Egyptian patients with essential hypertension. AB - BACKGROUND: Essential hypertension is a complex, multifactorial, polygenic disease in which the underlying genetic components remain unknown. Glutathione S transferase (GST) enzyme is involved in detoxification of reactive oxygen species. This study aimed to investigate GSTM1 and GSTT1 gene polymorphisms in Egyptian essential hypertensive patients and their relationship with oxidative stress-related parameters. METHODS: The study included 40 newly-diagnosed, untreated, essential hypertensive patients and 40 normotensive subjects. Plasma levels of malondialdehyde (MDA), and nitrate/nitrite and erythrocyte reduced glutathione (GSH), activities of catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), and glutathione S-transferase (GST) were measured. Genotyping for GSTM1 and GSTT1 was performed. RESULTS: The frequency of GSTM1+ve/GSTT1+ve in hypertensives (5%) was lower than in normotensives (37.5%).The frequency of GSTM1-ve/GSTT1-ve was elevated in hypertensives (35%) as compared to normotensives (7.5%). Plasma MDA was higher and nitrate/nitrite was lower in hypertensives than in normotensives. Erythrocyte GSH, activities of CAT, SOD, GSH-Px, and GST of hypertensives were lower than normotensives. Moreover, GST activity was lower in subjects with GSTM1-ve/GSTT1-ve than in those with GSTM1+ve/GSTT1+ve. In hypertensives, both systolic and diastolic blood pressures were negatively correlated with activities of CAT, GSH-Px, and GST. CONCLUSIONS: GSTM1-ve/GSTT1-ve is a potential genetic factor to predict development of essential hypertension and permit early therapeutic intervention. The significant association between blood pressure and oxidative stress-related parameters indicates the pathogenic role of oxidative stress in hypertension. Antioxidants could be useful in the management of essential hypertension to prevent progressive deterioration and target organ damage however, further studies involving long-term clinical trials may help to assess the efficacy of these therapeutic agents. PMID- 19782925 TI - The daily walking distance of young doctors and their body mass index. AB - CONTEXT: Non-exercise physical activity thermogenesis (NEAT) has been shown to differ in obese and non-obese subjects. OBJECTIVE: To explore whether NEAT is determined by the body mass index (BMI) even within the normal range, we hypothesized that the daily walking distance of young doctors in training at a teaching hospital is inversely correlated with the BMI. DESIGN: Prospective, single blind, controlled trial. SETTING: Identical wards of a 400 bed university based teaching hospital, highly standardized for patient number treated, the severity of disease, the clinical experience of the doctors and their time spent in the institution. INTERVENTION: The walking distance was measured daily by a pedometer over one week and standardized for the setting, workload, and insurance status. MAIN OUTCOME MEASURES: Mean daily walking distance as a measure of NEAT. RESULTS: The mean daily distance walked was 2323+/-627 m with a more than 4-fold difference between the daily maximum of 4310 m and the minimum of 1003 m. There was an inverse correlation of the walking distance with the BMI (Spearman rho=0.750, p=0.02), and with the time spent in the hospital (rho=-0.800, p=0.01), but not with the months of clinical experience, age, gender, number of patients, disease, severity nor with the insurance status of the patients cared for. There was no mean difference between the distance walked in the morning vs. in the afternoon nor was there a trend from Monday through Friday. CONCLUSION: The results of this pilot study indicate that NEAT is related to the BMI in the non obese stage. PMID- 19782927 TI - Comparison of in-hospital secondary prevention for different vascular diseases. AB - BACKGROUND: Secondary prevention of coronary artery disease is highly effective and implemented on a large scale. However, studies testing adherence to recommended secondary prevention of other vascular diseases are rare. Our goal was to evaluate whether the kind of vascular disease influences prescription practice of secondary drug prophylaxis at hospital discharge and to which extent secondary prevention is actually complete. METHODS: A 3-month prospective observational review of the hospital discharge information of all patients hospitalized because of a vascular disease diagnosis: coronary artery disease (i.e. acute myocardial infarction [AMI] and chronic stable angina [CSA]); peripheral artery disease [PAD] and cerebrovascular disease [CVD]. The analysis was done by board registered internists with a structured form that founded on internationally accepted recommendations. RESULTS: From 271 patients 191 had coronary artery disease (105 AMI and 86 CSA), 88 PAD and 72 CVD. Global prescription rate (mean; 95% CI) of indicated secondary prophylaxis drugs was 74.1% (69.9-78.2) for AMI, 72.4% (67.2-77.5) for CSA, 74.7% (68.8-80.7) for PAD and 72.1% (66.9-77.3) for CVD. The proportion of patients who were prescribed a complete bundle of recommended medications was globally 29.5% (24.1-35.0). CONCLUSIONS: We found similar global prescription rates of secondary prevention for the different vascular diseases. However, only one third of the studied collective gets a complete set of required prophylactic drugs. PMID- 19782928 TI - Ability of physiological parameters versus clinical categories to predict mortality on admission to an internal medicine ward. AB - BACKGROUND: The prediction of mortality in internal medicine departments may help in taking diagnostic and therapeutic decisions. We analyzed the usefulness of two mortality prediction models, one physiological and the other mainly clinical, and determined whether one approach is better than the other to predict mortality at admission. METHODS: This is a prospective observational cohort study in patients admitted to an acute internal medicine ward in a tertiary care, urban, university teaching hospital in Spain. Five hundred consecutive patients either electively admitted or coming from the emergency department from May to December 2008 were analyzed. Medical history, physical examination and routine clinical laboratory tests were performed on admission. At discharge, diagnosis and dead or survived status was recorded. Logistic regression analyses were used to test variables that emerged as independent predictors of mortality. The area under the curve was used to determine which model best predicted mortality. RESULTS: Mortality in the ward was 13.0%. Age, chronic respiratory failure, creatinine, mean arterial pressure, respiratory rate and Glasgow coma scale independently predicted mortality. ROC curves showed that the physiological model was superior to the clinical model, but differences were not statistically significant. The predictive capacity improved when the two models were combined but the improvement was not significant. CONCLUSIONS: Both models are satisfactory predictors of in-hospital mortality for management purposes but neither proved to be a useful tool for individual predictions. Complementary approaches need to be considered. PMID- 19782929 TI - How accurate are doctors, nurses and medical students at predicting life expectancy? AB - BACKGROUND: Predicted patient life expectancy, based on a patient's medical history, is an important component of medical decision making. This study therefore aimed to determine the consistency, accuracy and precision with which doctors, nurses and medical students predict life expectancy (LE). METHODS: 20 doctors, 20 nurses and 20 medical students (4th and 5th year) independently examined 70 hypothetical patient case scenarios containing age, sex and comorbidity; this included 13 duplicate scenarios. Accuracy and consistency of prediction was assessed by comparison with statistical LE estimates generated using evidence-based actuarial and life insurance industry methods in collaboration with a team of professional actuaries. RESULTS: Doctors, nurses and medical students underestimated LE by a mean (95% confidence interval) of -1.46 ( 0.31 to -2.61), -1.79 (-0.52 to -3.06) and -2.24 (-1.16 to -3.32) years with an equivalent root mean squared error (RMSE) of 4.74, 5.49 and 5.08 years respectively. LE predictions were equal to actuarial LE in less than 10% of cases and accurate to within 25% of actuarial LE in less than 45% of cases. Intra observer reliability was 91%, 85% and 87% for doctors, nurses and medical students respectively. Inter-observer reliability was 66%, 57% and 57% for the three groups. CONCLUSION: Doctors, nurses and medical students were inconsistent, inaccurate and imprecise in their prediction of LE with a tendency toward underestimation. This may lead to patients being managed inappropriately. There is a need for improved training and objective outcome prediction models. PMID- 19782930 TI - Determinants of continuous positive airway pressure compliance in a group of Greek patients with obstructive sleep apnea. AB - OBJECTIVE: The aim of the study was to investigate the patients' characteristics that correlate with greater compliance to CPAP use. METHODS: Patients diagnosed with OSAHS and treated with CPAP, who had at least one follow-up visit in the Sleep Clinic during one year, were included in the study. Demographic data, history of symptoms, comorbidities, Body Mass Index (BMI), Epworth Sleepiness Scale questionnaire (ESS), were obtained from patients before and under CPAP use. All variables were correlated with average daily CPAP use. Objective and subjective compliance were estimated and a cut off point of 4.5h/d was used to distinguish 'more compliant' from less 'compliant' patients. RESULTS: Ninety eight patients, with a mean age (+/-SD) of 55.5 (+/-11.1) years were examined. Patients' symptoms improved after CPAP use. The objective compliance was 5.3+/ 1.6h/d whereas the subjective compliance was higher. Only 25% of patients were characterized as 'more compliant'. Compliance was positively correlated in a significant way with age and female gender, and negatively correlated with neck circumference, preexisting nasal problems and minimum saturation during sleep. Patients with arterial hypertension showed a trend to better compliance. Weight gain was more frequently observed in 'less compliant' patients. CONCLUSION: To our knowledge this is the first study examining parameters of CPAP compliance in a Greek population of OSAHS patients. Age, gender and minimum saturation during sleep were related to better compliance whereas higher neck circumference and preexisting nasal problems were the parameters related to a worse adherence to treatment. PMID- 19782931 TI - "Strawberry like" gingivitis being the first sign of Wegener's granulomatosis. AB - Wegener's granulomatosis (WG) is a rare granulomatous necrotizing vasculitis of small vessels, affecting vascular structures having predilection for upper airways. If untreated WG can be lethal. WG is also known to cause oral mucosal lesions. We report a case of WG that was first diagnosed on oral gingival mucosa. A 51-year old woman was referred to a specialized dentist because of consistent irritative buccal gingival hyperplasia that did not react to conservative and microbial treatment. The lesion was biopsied and the diagnosis was suggestive for WG. Patient was further referred to the Department of Rheumatology and the diagnose of WG was confirmed and treated. The oral lesions cured totally. This case emphasizes the importance to recognize the oral manifestation of WG to get proper medication as soon as possible and avoid serious systemic tissue damage. PMID- 19782932 TI - Motilin concentrations in relation to gastro intestinal dysmotility in diabetes mellitus. AB - AIM: Dysmotility in the upper gastro intestinal (GI) tract are common problems in diabetics. Many peptides are involved in the regulation of the motility. The aim of this study was to examine whether plasma levels of motilin were related to dysfunction in the oesophagus and stomach in a well-defined diabetic patient group. METHODS: Nineteen patients with symptoms from the GI tract who had been examined with oesophageal manometry, gastric emptying scintigraphy and deep breathing test were included. They received a fat-rich meal, after which blood samples were collected and analysed for motilin concentrations. RESULTS: Symptoms of abdominal fullness and gastro oesophageal reflux significantly associated with delayed gastric emptying, whereas no symptom correlated to oesophageal dysmotility. Plasma levels of motilin were increased after the fat-rich meal (p=0.000), with no difference between the groups. Abnormal manometry was characterized by aperistalsis and/or simultaneous contractions. The percentage of simultaneous contractions correlated to basic and peak motilin values (r(s)=0.898, p=0.006 and r(s)=0.842, p=0.017, respectively). Gastric emptying did not influence motilin concentrations. CONCLUSION: Plasma motilin concentrations vary with abnormalities of oesophageal motility in diabetics, but not with abnormalities of gastric emptying. PMID- 19782933 TI - Venous and arterial thrombosis: two aspects of the same disease? PMID- 19782935 TI - The blessing and curse of RNA dynamics: past, present, and future. PMID- 19782936 TI - Dermoscopy and recently developed imaging techniques. Introduction. PMID- 19782937 TI - Dermoscopy--the ultimate tool for melanoma diagnosis. AB - "We are beginning to move away from clinicopathologic diagnosis into an era of clinicoimaging diagnosis." This vision became a fact, as the dermatoscope represents nowadays the dermatologist stethoscope. This is not only because dermoscopy reveals a new and fascinating morphologic dimension of pigmented and nonpigmented skin tumors, but also because it improves the recognition of a growing number of skin symptoms in general dermatology. Melanoma detection remains the most important indication of dermoscopy and in melanoma screening the aim of dermoscopy is to maximize early detection while minimizing the unnecessary excision of benign skin tumors. In the last few years, 3 meta-analyses and 2 randomized studies have definitely proven that dermoscopy allows improving sensitivity for melanoma as compared to the naked eye examination alone. This is the consequence of at least 3 issues: first, the presence of early dermoscopy signs that are visible in melanoma much before the appearance of the classical clinical features; second, an increased attitude of clinicians to check more closely clinically banal-looking lesions; third, an improved attitude of clinicians to monitor their patients. PMID- 19782938 TI - The morphologic universe of melanocytic nevi. AB - Different types of nevi do exist in relation to their epidemiology, morphology, evolution, and associated melanoma risk. The introduction of dermoscopy opened a new dimension of the morphologic universe of nevi and allowed clinicians to observe colors and structures within nevi that are otherwise not visible to the unaided eye. Because most of these colors and structures correspond to well defined histopathologic correlates, dermoscopy enables clinicians to date to more precisely predict the histopathology diagnosis and thereby improve on their clinical diagnostic accuracy. Besides the diagnostic impact, the in vivo observation of thousands of nevi using dermoscopy and digital dermoscopic follow up has opened new understanding about the evolution of nevi and factors influencing the nevus pattern. In consequence, a new nevus classification has been proposed, subdividing nevi into 7 categories, which are as follows: (1) globular/cobblestone nevi, (2) reticular nevi, (3) starburst nevi, (4) homogeneous blue nevi, (5) nevi on special body sites, (6) nevi with special features, and (7) and unclassifiable melanocytic proliferations. This article provides an overview on the morphologic classification of nevi and the factors influencing the nevus pattern. PMID- 19782939 TI - Dermoscopic-pathologic correlation: apropos of six equivocal cases. AB - The increasing use of dermoscopy in preoperative diagnosis of melanocytic skin neoplasms is impacting on routine histopathology to a relevant extent. We herein present the dermoscopic-pathologic features of 6 cases of histopathologically controversial melanocytic skin neoplasms. By illustrating these cases, we emphasize at least 3 different fields of interest for a combined (clinico )dermoscopic-pathologic diagnostic approach, namely, information about the evolution of lesions; detection of gross sampling errors; definition of peculiar clinicopathologic entities. The theoretic and practical aspects of a close interaction among dermoscopists and histopathologists are itemized in detail. PMID- 19782940 TI - Dermoscopy research--an update. AB - Dermoscopy increases the clinician's diagnostic accuracy by as much as 30% over that of unaided visual clinical inspection alone and has been confirmed in 3 separate evidence-based publications using a meta-analysis of the literature. It can be viewed as an in vivo bridge between clinical morphology and histopathology. This "bridge" has provided clinician researchers with many new insights into morphology and tumor biology. In this article, we provide the reader with an overview of the different aspects of dermoscopy as a research tool. We cover different aspects, such as the new equipment, new structures, the importance of blood vessels, etc. PMID- 19782941 TI - Reflectance confocal microscopy--state-of-art and research overview. AB - Reflectance confocal microscopy (RCM) enables in vivo imaging of human skin at a quasi histologic resolution. The black-and-white RCM images show horizontal sections of the skin, at a maximum depth of 350 microm. To date, the RCM features of a significant number of skin conditions have been described. The main focus of the research community investigating RCM, however, lies on describing and diagnosing melanocytic skin lesions. Taking into account all RCM studies dealing with diagnostic accuracy in melanocytic skin lesions, sensitivity and specificity of approximately 90% and 86% could be found. Improvement of diagnostic accuracy, improved assessment of dermoscopic-histologic correlation, in vivo biopsy side selection, surgical margin assessment, and response control of conservative therapies in skin diseases are some of the major advantages of this novel imaging method. Additionally, RCM holds inherent potential for teledermatologic application and automated image analyzing. This article describes morphologic features of diverse skin lesions and features of "normal skin," summarizes diagnostic advances of RCM, compares studies dealing with diagnostic applicability, and discusses further research goals of this exciting new imaging technique. PMID- 19782942 TI - Reflectance confocal microscopy in the daily practice. AB - Reflectance confocal microscopy (RCM) allows noninvasive imaging of the epidermis and superficial dermis. Like dermoscopy, RCM acquires images in the horizontal plane (en face), allowing assessment of tissue pathology underlying dermoscopic structures of interest at a cellular-level resolution. Thus, clinicians using dermoscopy may find RCM to be particularly useful. Our aim was to show the value of RCM for diagnosis and management decisions related to pigmented and nonpigmented skin neoplasms seen in daily practice. Six cases of clinically and dermoscopically equivocal skin lesions, for which RCM facilitated making the correct diagnosis, are presented. Final diagnoses were made based on histopathologic analysis. Three flat pigmented skin lesions with dermoscopic signs of regression showed distinct RCM features that allowed their correct classification as pigmented basal cell carcinoma, pigmented actinic keratosis, and melanoma on sun-damaged skin. A flat nonpigmented skin lesion on the face, which did not show distinct clinical or dermoscopic features, was correctly diagnosed as basal cell carcinoma based on RCM findings. In addition, the response of a pigmented actinic keratosis and a melanoma in situ on sun-damaged skin to noninvasive topical treatment was monitored using RCM. RCM is a promising and practical imaging tool for the diagnosis and follow-up of pigmented and nonpigmented skin lesions. PMID- 19782943 TI - Multiphoton laser scanning microscopy--a novel diagnostic method for superficial skin cancers. AB - The increasing incidence of skin cancer and the importance of early diagnosis is a challenge, which requires the development of reliable, cost-effective, noninvasive, diagnostic techniques. Several such methods based on optical imaging techniques are available and currently being investigated. A novel method in this field is multiphoton laser scanning microscopy (MPLSM). This technique is based on the nonlinear process of 2-photon excitation of endogenous fluorophores, which can be used to acquire horizontal optical sectioning of intact biological tissue samples. When studying human skin, MPLSM provides high-resolution fluorescence imaging, allowing visualization of cellular and subcellular structures of the epidermis and upper dermis. This review covers the application of MPLSM as a diagnostic tool for superficial skin cancers, such as basal cell carcinomas, squamous cell carcinoma in situ, and melanomas. MPLSM has also been applied in other research areas related to skin, which will be mentioned briefly. The morphologic features observed in MPLSM images of skin tumors are comparable to traditional histopathology. Safety issues, limitations, and further improvements are discussed. Although further investigations are required to make MPLSM a mainstream clinical diagnostic tool, MPLSM has the potential of becoming a noninvasive, bedside, histopathologic technique for the diagnosis of superficial skin cancers. PMID- 19782944 TI - Optical coherence tomography for imaging of skin and skin diseases. AB - Optical coherence tomography (OCT) is an emerging imaging technology based on light reflection. It provides real-time images with up to 2-mm penetration into the skin and a resolution of approximately 10 microm. It is routinely used in ophthalmology. The normal skin and its appendages have been studied, as have many diseases. The method can provide accurate measures of epidermal and nail changes in normal tissue. Skin cancer and other tumors, as well as inflammatory diseases, have been studied and good agreement found between OCT images and histopathological architecture. OCT also allows noninvasive monitoring of morphologic changes in skin diseases and may have a particular role in the monitoring of medical treatment of nonmelanoma skin cancer. The technology is however still evolving and continued technological development will necessitate an ongoing evaluation of its diagnostic accuracy. Several technical solutions are being pursued to further improve the quality of the images and the data provided, and OCT is being integrated in multimodal imaging devices that would potentially be able to provide a quantum leap to the imaging of skin in vivo. PMID- 19782945 TI - Mobile teledermoscopy--melanoma diagnosis by one click? AB - Mobile telemedicine integrates wireless communications for different telemedical applications, such as mobile phones and personal digital assistants, and with the implementation of modern wireless telecommunication, wireless local area network and satellite communication is a reality. New generation cellular phones or personal digital assistants have overcome limitations of image quality seen in older devices and, with dermatology being a visual profession, mobile teledermatology is perhaps the most recent development in this field. Mobile teledermatology may provide a triage service aimed toward management of patients with emergent skin disease or for follow-up with patients requiring systemic treatment. Teledermoscopy enables rapid transmission of dermoscopic images via e mail or specific web-application and studies have demonstrated a high, 91%, concordance between face-to-face diagnosis and remote diagnosis of such images. Further to this, telediagnosis of melanocytic skin neoplasms achieved a diagnostic accuracy of 83% versus the conventional histopathologic diagnosis. Mobile teledermoscopy is the combination of such approaches enabling transfer of images captured with cellular phones coupled with a pocket dermatoscope and preliminary studies have demonstrated the feasibility and potential of its use in triage of pigmented lesions. Such applications are of benefit to physicians in enabling easy storage of data for follow-up or referral of images for expert second opinion and may facilitate a "person-centered health system" for patients with numerous moles and pigmented skin lesions who could forward images for evaluation. The incidence of skin cancers has reached epidemic proportions among whites and the trend is still going upward. Mobile teledermatology and teledermoscopy may be implemented as a triage or screening tool for malignant tumors to facilitate early detection and diagnosis, which is crucial for improved patient outcomes. While the legal aspects concerning teleconsultations need to be evaluated, the communications technologies provide a unique opportunity for physicians and patients alike and we foresee a place for these tools in dermatology soon. PMID- 19782946 TI - Hepatic myofibroblasts: a heterogeneous population of multifunctional cells in liver fibrogenesis. AB - Hepatic myofibroblasts constitute a heterogeneous population of highly proliferative, pro-fibrogenic, pro-inflammatory, pro-angiogenic and contractile cells that sustain liver fibrogenesis and then fibrotic progression of chronic liver diseases of different aetiology to the common advanced-stage of cirrhosis. These alpha-smooth muscle actin-positive myofibroblast-like cells, according to current literature, mainly originate by a process of activation and trans differentiation that involves either hepatic stellate cells or fibroblasts of portal areas. Hepatic myofibroblasts can also originate from bone marrow-derived cells, including mesenchymal stem cells or circulating fibrocytes able to engraft chronically injured liver, as well as, in certain conditions, by a process of epithelial to mesenchymal transition involving hepatocytes and cholangiocytes. Hepatic myofibroblasts may have also additional crucial roles in modulating immune response and in the cross talk with hepatic progenitor (stem) cells as well as with malignant cells of either primary hepatocellular carcinomas or of metastatic cancers. PMID- 19782948 TI - Endothelial CD146 is required for in vitro tumor-induced angiogenesis: the role of a disulfide bond in signaling and dimerization. AB - Tumor angiogenesis, induced by tumor-secreted pro-angiogenic factors, is an essential process for cancer development and metastasis. CD146 is identified as an endothelial cell adhesion molecule and implicated in blood vessel formation, however, its exact role in angiogenesis, particularly tumor angiogenesis, and its potential function of mediating downstream signaling are still unclear. In present study, we evidenced that silencing endogenous endothelial CD146 by RNAi significantly impaired hepatocarcinoma cell secretions-promoted tubular morphogenesis and -enhanced motility of endothelial cells. Biochemical studies revealed that CD146 was required for the activation of p38/IKK/NF kappaB signaling cascade and up-regulation of NF kappaB downstream pro-angiogenic genes, notably IL-8, ICAM-1 and MMP9, in response to tumor secretions. Interestingly, specific anti-CD146 mAb AA98, which bound a conformational epitope depending on C452-C499 disulfide bond, could abrogate NF kappaB activation and tumor angiogenesis, whereas another anti-CD146 mAb AA1 recognizing a linear epitope containing aa50-54 did not have such effects. Further structure-function analysis identified that C452-C499 disulfide bond within the fifth extracellular Ig domain was indispensible for CD146-mediated signaling and tube formation. Moreover, dimerization of CD146, which was enhanced by tumor secretions and suppressed by AA98 but not AA1, also relied on C452 and C499. Together, this study for the first time uncovered the pro-angiogenic role of CD146 and also pinpointed the key structural basis responsible for its signaling function and dimerization. These findings also suggested that CD146 might serve as not just a cell adhesion molecule but also a membrane signal receptor in tumor-induced angiogenesis. PMID- 19782949 TI - Downregulation of protein tyrosine phosphatase PTP-BL represses adipogenesis. AB - The insulin/insulin-like growth factor 1 (IGF-1) signaling pathway is a major regulator of adipose tissue growth and differentiation. We recently demonstrated that human protein tyrosine phosphatase (PTP) L1, a large cytoplasmic phosphatase also known as PTP-BAS/PTPN13/PTP-1E, is a negative regulator of IGF-1R/IRS-1/Akt pathway in breast cancer cells. This triggered us to investigate the potential role of PTPL1 in adipogenesis. To evaluate the implication of PTP-BL, the mouse orthologue of PTPL1, in adipose tissue biology, we analyzed PTP-BL mRNA expression in adipose tissue in vivo and during proliferation and differentiation of 3T3-L1 pre-adipocytes. To elucidate the role of PTP-BL and of its catalytic activity during adipogenesis we use siRNA techniques in 3T3-L1 pre-adipocytes, and mouse embryonic fibroblasts that lack wildtype PTP-BL and instead express a variant without the PTP domain (Delta P/Delta P MEFs). Here we show that PTP-BL is strongly expressed in white adipose tissue and that PTP-BL transcript and protein levels increase during proliferation and differentiation of 3T3-L1 pre adipocytes. Strikingly, knockdown of PTP-BL expression in 3T3-L1 adipocytes caused a dramatic decrease in adipogenic gene expression levels (PPAR gamma, aP2) and lipid accumulation but did not interfere with the insulin/Akt pathway. Delta P/Delta P MEFs differentiate into the adipogenic lineage as efficiently as wildtype MEFs. However, when expression of either PTP-BL or PTP-BL Delta P was inhibited a dramatic reduction in the number of MEF-derived adipocytes was observed. These findings demonstrate a key role for PTP-BL in 3T3-L1 and MEF derived adipocyte differentiation that is independent of its enzymatic activity. PMID- 19782947 TI - O-GlcNAc cycling: implications for neurodegenerative disorders. AB - The dynamic post-translational modification of proteins by O-linked N acetylglucosamine (O-GlcNAc), termed O-GlcNAcylation, is an important mechanism for modulating cellular signaling pathways. O-GlcNAcylation impacts transcription, translation, organelle trafficking, proteasomal degradation and apoptosis. O-GlcNAcylation has been implicated in the etiology of several human diseases including type-2 diabetes and neurodegeneration. This review describes the pair of enzymes responsible for the cycling of this post-translational modification: O-GlcNAc transferase (OGT) and beta-N-acetylglucosaminidase (OGA), with a focus on the function of their structural domains. We will also highlight the important processes and substrates regulated by these enzymes, with an emphasis on the role of O-GlcNAc as a nutrient sensor impacting insulin signaling and the cellular stress response. Finally, we will focus attention on the many ways by which O-GlcNAc cycling may affect the cellular machinery in the neuroendocrine and central nervous systems. PMID- 19782951 TI - Wide hybridization: engineering the next leap in wheat yield. PMID- 19782950 TI - The role of phosphorylated glucocorticoid receptor in mitochondrial functions and apoptotic signalling in brain tissue of stressed Wistar rats. AB - Mitochondrial dysfunction is increasingly recognized as a key component in compromised neuroendocrine stress response and, among other etiological causes, it may also involve action of glucocorticoid hormones. In the current study we followed glucocorticoid receptor and identified its mitochondrial phosphoisophorms in hippocampus and prefrontal brain cortex of Wistar male rats subjected to acute, chronic and combined neuroendocrine stresses. In both brain structures chronic social isolation caused marked increase in mitochondrial glucocorticoid receptor that was preferentially phosphorylated at serine 232 compared to serine 246 or serine 171. This increase corresponded with the decreased expression of mitochondrially encoded cytochrome oxidase subunits 1 and 3 in hippocampus, and with their increased expression in prefrontal brain cortex. Prefrontal brain cortex appeared to be more sensitive to chronic stress, since it exibited higher levels of mitochondrial Bax and cytoplasmic Bcl2 compared to hippocampus. Chronic stress also altered the response of both brain structures to subsequent acute stress according to the studied parameters. Therefore, prolonged social isolation may cause susceptibility to mitochondria triggered proapototic signalling, which at least in part may be mediated by the glucocorticoid receptor dependent mechanism. PMID- 19782952 TI - Genome evolution in allopolyploid wheat--a revolutionary reprogramming followed by gradual changes. AB - Allopolyploidy accelerates genome evolution in wheat in two ways: 1) allopolyploidization triggers rapid genome alterations (revolutionary changes) through the instantaneous generation of a variety of cardinal genetic and epigenetic changes, and 2) the allopolyploid condition facilitates sporadic genomic changes during the life of the species (evolutionary changes) that are not attainable at the diploid level. The revolutionary alterations, occurring during the formation of the allopolyploid and leading to rapid cytological and genetic diploidization, facilitate the successful establishment of the newly formed allopolyploid in nature. On the other hand, the evolutionary changes, occurring during the life of the allopolyploids, increase the intra-specific genetic diversity, and consequently, increased fitness, adaptability and competitiveness. These phenomena, emphasizing the dynamic plasticity of the allopolyploid wheat genome with regards to both structure and function, are described and discussed in this review. PMID- 19782953 TI - Rapid genomic changes in polyploid wheat and related species: implications for genome evolution and genetic improvement. AB - A polyploid organism by possessing more than two sets of chromosomes from one species (autopolyploidy) or two or more species (allopolyploidy) is known to have evolutionary advantages. However, by what means a polyploid accommodates increased genetic dosage or divergent genomes (allopolyploidy) in one cell nucleus and cytoplasm constitutes an enormous challenge. Recent years have witnessed efforts and progress in exploring the possible mechanisms by which these seemingly intangible hurdles of polyploidy may be ameliorated or eventually overcome. In particular, the documentation of rapid and extensive non-Mendelian genetic and epigenetic changes that often accompany nascent polyploidy is revealing: the resulting non-additive and novel gene expression at global, regional and local levels, and timely restoration of meiotic chromosomal behavior towards bivalent pairing and disomic inheritance may ensure rapid establishment and stabilization as well as its long-term evolutionary success. Further elucidation on these novel mechanisms underpinning polyploidy will promote our understanding on fundamental issues in evolutionary biology and in our manipulation capacities in future genetic improvement of important crops that are currently polyploids in genomic constitution. This review is intended to provide an updated discussion on these interesting and important issues within the scope of a specific yet one of the most important plant groups-polyploid wheat and its related species. PMID- 19782954 TI - An overview of plant centromeres. AB - The centromere is a defining region that mediates chromosome attachment to kinetochore microtubules and proper segregation of the sister chromatids. Intriguingly, satellite DNA and centromeric retrotransposon as major DNA constituents of centromere showed baffling diversification and species-specific. However, the key kinetochore proteins are conserved in both plants and animals, particularly the centromere-specific histone H3-like protein (CENH3) in all functional centromeres. Recent studies have highlighted the importance of epigenetic mechanisms in the establishment and maintenance of centromere identity. Here, we review the progress and compendium of research on plant centromere in the light of recent data. PMID- 19782955 TI - Synthetic hexaploid wheat and its utilization for wheat genetic improvement in China. AB - Synthetic hexaploid wheat (Triticum turgidumxAegilops tauschii) was created to explore for novel genes from T. turgidum and Ae. tauschii that can be used for common wheat improvement. In the present paper, research advances on the utilization of synthetic hexaploid wheat for wheat genetic improvement in China are reviewed. Over 200 synthetic hexaploid wheat (SHW) accessions from the International Maize and Wheat Improvement Centre (CIMMYT) were introduced into China since 1995. Four cultivars derived from these, Chuanmai 38, Chuanmai 42, Chuanmai 43 and Chuanmai 47, have been released in China. Of these, Chuanmai 42, with large kernels and resistance to stripe rust, had the highest average yield (>6 t/ha) among all cultivars over two years in Sichuan provincial yield trials, outyielding the commercial check cultivar Chuanmai 107 by 22.7%. Meanwhile, by either artificial chromosome doubling via colchicine treatment or spontaneous chromosome doubling via a union of unreduced gametes (2n) from T. turgidum-Ae. tauschii hybrids, new SHW lines were produced in China. Mitotic-like meiosis might be the cytological mechanism of spontaneous chromosome doubling. SHW lines with genes for spontaneous chromosome doubling may be useful for producing new SHW-alien amphidiploids and double haploid in wheat genetic improvement. PMID- 19782956 TI - Progress of chromosome engineering mediated by asymmetric somatic hybridization. AB - Plant somatic hybridization has progressed steadily over the past 35 years. Many hybrid plants have been generated from fusion combinations of different phylogenetic species, some of which have been utilized in crop breeding programs. Among them, asymmetric hybrid, which usually contains a fraction of alien genome, has received more attention because of its importance in crop improvement. However, few studies have dealt with the heredity of the genome of somatic hybrid for a long time, which has limited the progress of this approach. Over recent ten years, along with the development of an effective cytogenetical tool "in situ hybridization (ISH)", asymmetric fusion of common wheat (Triticum aestivum L.) with different grasses or cereals has been greatly developed. Genetics, genomes, functional genes and agricultural traits of wheat asymmetric hybrids have been subject to systematic investigations using gene cloning, genomic in situ hybridization (GISH) and molecular makers. The future goal is to fully elucidate the functional relationships among improved agronomic traits, the genes and underlying molecular mechanisms, and the genome dynamics of somatic introgression lines. This will accelerate the development of elite germplasms via somatic hybridization and the application of these materials in the molecular improvement of crop plants. PMID- 19782957 TI - Thinopyrum ponticum and Th. intermedium: the promising source of resistance to fungal and viral diseases of wheat. AB - Thinopyrum ponticum and Th. intermedium provide superior resistance against various diseases in wheat (Ttricum aestivum). Because of their readily crossing with wheat, many genes for disease resistance have been introduced from the wheatgrasses into wheat. Genes for resistance to leaf rust, stem rust, powdery mildew, Barley yellow dwarf virus, Wheat streak mosaic virus, and its vector, the wheat curl mite, have been transferred into wheat by producing chromosome translocations. These genes offer an opportunity to improve resistance of wheat to the diseases; some of them have been extensively used in protecting wheat from damage of the diseases. Moreover, new resistance to diseases is continuously detected in the progenies of wheat-Thinopyrum derivatives. The present article summaries characterization and application of the genes for fungal and viral disease-resistance derived from Th. ponticum and Th. intermedium. PMID- 19782958 TI - Research progress in BYDV resistance genes derived from wheat and its wild relatives. AB - Barley yellow dwarf virus (BYDV) may cause a serious disease affecting wheat worldwide. True resistance to BYDV is not naturally found in wheat. BYDV resistance genes are found in more than 10 wild relative species belonging to the genera of Thinopyrum, Agropyron, Elymus, Leymus, Roegneria, and Psathyrostachy. Through wide crosses combining with cell culture, use of ph mutants, or irradiation, 3 BYDV resistance genes in Th. intermedium, including Bdv2, Bdv3 and Bdv4, were introgressed into common wheat background. Various wheat-Th. intermedium addition and substitution, translocation lines with BYDV-resistance were developed and characterized, such as 7D-7Ai#1 (bearing Bdv2), 7B-7Ai#1, 7D 7E (bearing Bdv3), and 2D-2Ai-2 (bearing Bdv4) translocations. Three wheat varieties with BYDV resistance from Th. intermedium were developed and released in Australia and China, respectively. In addition, wheat-Agropyron cristatum translocation lines, wheat-Ag. pulcherrimum addition and substitution lines, and a wheat-Leymus multicaulis addition line (line24) with different resistance genes were developed. Cytological analysis, morphological markers, biochemical markers, and molecular markers associated with the alien chromatin carrying BYDV resistance genes were identified and applied to determine the presence of alien, chromosomes or segments, size of alien chromosome segments, and compositions of the alien chromosomes. Furthermore, some resistance-related genes, such as RGA, P450, HSP70, protein kinases, centrin, and transducin, were identified, which expressed specifically in the resistance translocation lines with Bdv2. These studies lay the foundations for developing resistant wheat cultivars and unraveling the resistance mechanism against BYDV. PMID- 19782959 TI - Utilization of blue-grained character in wheat breeding derived from Thinopyrum poticum. AB - The blue grain trait in common wheat (Triticum aestivum L., 2n=6x=42, AABBDD), which is caused by blue pigments in the aleurone layer, was originally derived from the tall wheatgrass (Thinopyrum ponticum Liu & Wang=Agropyron elongatum, 2n=10x=70, StStStStEeEeEbEbExEx) during chromosome engineering research. Over the last few decades, there have been continued interests in the genetic mechanism of this blue coloration and the practical utilization of the blue aleurone character as a phenotypic marker. This article reviews the research history and the recent progress of the studies on blue-grained wheat, with emphases on genetic and biochemical analysis and practical applications of blue-grained wheat. PMID- 19782960 TI - Hereditary thrombophilia and recurrence of ischemic placental disease. AB - OBJECTIVE: We sought to evaluate whether testing for hereditary thrombophilia alone or in combination with second-trimester uterine artery Doppler (UAD) is useful in predicting recurrent complications in patients with previous preeclampsia, placental abruption, or stillbirth. STUDY DESIGN: Between 2001 and 2005, 110 consecutive women were included in the study and received 100 mg of aspirin daily. Adjustment was made for several maternal confounding factors using a logistic regression model. RESULTS: After multivariable logistic regression analyses, only abnormal UAD assessment was significantly associated with recurrent complications (odds ratio, 11.2; 95% confidence interval, 3.8-32.6) Combining the results of UAD and the presence of laboratory markers of thrombophilia failed to improve the accuracy of UAD to predict recurrent complications. CONCLUSION: Hereditary thrombophilia testing is not useful in predicting recurrent complications in subsequent pregnancy. PMID- 19782961 TI - Screening and treating for primary cytomegalovirus infection in pregnancy: where do we stand? A decision-analytic and economic analysis. AB - OBJECTIVE: To estimate which 1 of 3 screening strategies for primary maternal cytomegalovirus infection, with intention to treat with hyperimmune globulin, is most cost-effective. STUDY DESIGN: A decision-analytic and cost-effectiveness model was constructed for pregnant women, comparing 3 strategies screening for primary maternal cytomegalovirus infection with intention to treat with cytomegalovirus-intravenous immune globulin: (1) serum screen all pregnant women, (2) serum screen women with risk factors for primary cytomegalovirus, (3) serum screen women with suspicious sonographic findings. Probability, use (or value), and cost estimates were derived from published literature. RESULTS: Universal screening for primary maternal cytomegalovirus was the preferred and most cost effective strategy. However, if treatment with cytomegalovirus-intravenous immune globulin achieved less than a 47% reduction (relative risk, 0.53) in clinical disease, universal screening would no longer be cost-effective. CONCLUSION: Universal screening for primary maternal cytomegalovirus infection is cost effective based on available evidence, highlighting the urgent need for additional study evaluating the efficacy of cytomegalovirus-intravenous immune globulin to prevent congenital cytomegalovirus. PMID- 19782962 TI - [Petrous apex lesions]. PMID- 19782963 TI - Effect of nonsurgical periodontal therapy on crevicular fluid levels of Cathepsin K in periodontitis. AB - OBJECTIVES: Cathepsin K (CTSK), predominantly expressed in osteoclasts, is a potent extracellular matrix degrading enzyme that plays a critical role in osteoclast-mediated bone resorption. Its increased gingival crevicular fluid (GCF) levels in periodontal disease have been reported in a previous study. The present study has been carried out to assess the role of CTSK in periodontal disease and to determine the effect of periodontal treatment on CTSK concentration in GCF. DESIGN: 60 subjects were divided into three groups (n=20) based on gingival index (GI), probing pocket depth (PPD) and clinical attachment loss (CAL): healthy (group I), gingivitis (group II) and chronic periodontitis (group III). A fourth group (group IV) consisted of 20 subjects from group III, 6 8 weeks after nonsurgical periodontal therapy (scaling and root planing). GCF samples collected from each patient were quantified for CTSK using ELISA. RESULTS: The mean CTSK concentration in GCF was found to be the highest in group III, i.e. 55.55 pmol/l. The mean CTSK concentration in GCF in group I and group II was 5.95 pmol/l and 6.90 pmol/l respectively. The mean CTSK concentration in GCF in group IV decreased to 11.15 pmol/l, slightly more than that in groups I and II. CONCLUSIONS: GCF CTSK levels increased in periodontitis and correlated negatively with clinical parameters like GI, PPD and CAL. CTSK levels decreased after nonsurgical treatment of periodontitis. Thus, CTSK can be considered as a 'marker of osteoclastic activity' in periodontal disease and also deserves further consideration as a therapeutic target. PMID- 19782965 TI - D-cycloserine facilitates extinction of naloxone-induced conditioned place aversion in morphine-dependent rats. AB - BACKGROUND: Cues paired with drug administration trigger relapse to drug seeking by inducing conditioned drug craving and withdrawal. Because drug cues hinder abstinence in addicts, therapies that reduce responsiveness to drug cues might facilitate rehabilitation. Extinction is a means of reducing conditioned responses and involves exposure to the conditioned stimulus in the absence of the unconditioned stimulus with which it was paired previously. We examined conditioned withdrawal extinction using naloxone-induced conditioned place aversion (CPA) in morphine-dependent rats. METHODS: Morphine-dependent rats were trained to associate an environment with naloxone-precipitated withdrawal. Subsequently, they received extinction training in which they were confined in the previously naloxone-paired environment in the absence of acute withdrawal. In some rats, the N-methyl-D-aspartate (NMDA) receptor partial agonist D-cycloserine (DCS) was administered before extinction training. RESULTS: Morphine withdrawal induced CPA persists in the absence of extinction training. Administration of DCS before extinction training facilitates extinction. CONCLUSIONS: D-cycloserine facilitates extinction of morphine withdrawal-associated place aversion. This effect is qualitatively similar to the effect of DCS on extinction of conditioned fear, raising the possibility of common neural mechanisms. This work extends our understanding of drug cue responsivity and provides a rationale for the development of extinction-based treatments for addiction. PMID- 19782964 TI - Sensorimotor transformation deficits for smooth pursuit in first-episode affective psychoses and schizophrenia. AB - BACKGROUND: Smooth pursuit deficits are an intermediate phenotype for schizophrenia that may result from disturbances in visual motion perception, sensorimotor transformation, predictive mechanisms, or alterations in basic oculomotor control. Which of these components are the primary causes of smooth pursuit impairments and whether they are impaired similarly across psychotic disorders remain to be established. METHODS: First-episode psychotic patients with bipolar disorder (n = 34), unipolar depression (n = 24), or schizophrenia (n = 77) and matched healthy participants (n = 130) performed three smooth pursuit tasks designed to evaluate different components of pursuit tracking. RESULTS: On ramp tasks, maintenance pursuit velocity was reduced in all three patients groups with psychotic bipolar patients exhibiting the most severe impairments. Open loop pursuit velocity was reduced in psychotic bipolar and schizophrenia patients. Motion perception during pursuit initiation, as indicated by the accuracy of saccades to moving targets, was not impaired in any patient group. Analyses in 138 participants followed for 6 weeks, during which patients were treated and psychotic symptom severity decreased, and no significant change in performance in any group was revealed. CONCLUSIONS: Sensorimotor transformation deficits in all patient groups suggest a common alteration in frontostriatal networks that dynamically regulate gain control of pursuit responses using sensory input and feedback about performance. Predictive mechanisms appear to be sufficiently intact to compensate for this deficit across psychotic disorders. The absence of significant changes after acute treatment and symptom reduction suggests that these deficits appear to be stable over time. PMID- 19782968 TI - [Intestinal obstruction secondary to invagination of a Meckel's diverticulum]. PMID- 19782967 TI - Mixture model clustering of phenotype features reveals evidence for association of DTNBP1 to a specific subtype of schizophrenia. AB - BACKGROUND: While DTNBP1, DISC1, and NRG1 have been extensively studied as candidate genes of schizophrenia, results remain inconclusive. Possible explanations for this are that the genes might be relevant only to certain subtypes of the disease and/or only in certain populations. METHODS: We performed unsupervised clustering of individuals from Finnish schizophrenia families, based on extensive clinical and neuropsychological data, including Structured Clinical Interview for DSM-IV (SCID) information. Families with at least one affected member with DSM-IV diagnosis of a schizophrenia spectrum psychosis were included in a register-based ascertainment. Final sample consisted of 904 individuals from 288 families. We then used the cluster phenotypes in a genetic association study of candidate genes. RESULTS: A robust three-class clustering of individuals emerged: 1) psychotic disorder with mood symptoms (n = 172), 2) core schizophrenia (n = 223), and 3) absence of psychotic disorder (n = 509). One third of the individuals diagnosed with schizophrenia were assigned to cluster 1. These individuals had fewer negative and positive psychotic symptoms and cognitive deficits but more depressive symptoms than individuals in cluster 2. There was a significant association of cluster 2 cases with the DTNBP1 gene, while the DISC1 gene indicated a significant association with schizophrenia spectrum disorders based on the DSM-IV criteria. CONCLUSIONS: In the Finnish population, DTNBP1 gene is associated with a schizophrenia phenotype characterized by prominent negative symptoms, generalized cognitive impairment, and few mood symptoms. Identification of genes and pathways related to schizophrenia necessitates novel definitions of disease phenotypes associated more directly with underlying biology. PMID- 19782966 TI - Physiological and focal cerebellar substrates of abnormal postural sway and tremor in alcoholic women. AB - BACKGROUND: Posturography analysis of static balance reveals marked sway and tremor in sober alcoholic men related to anterior vermis volume but can be attenuated by simple visual or tactile cues or alterations in stance. Whether alcoholic women, whose ataxia can persist with prolonged sobriety, exhibit the same physiological signature of balance instability and relation to cerebellar vermian volume as alcoholic men or can benefit from stabilizing factors is unknown. METHODS: Groups comprised 15 alcohol-dependent women, alcohol-free (median 3 months) and 29 control women. Groups were matched in age, demographic features, and finger movement speed and underwent balance platform testing and magnetic resonance imaging scanning. RESULTS: Alcoholic women exhibited excessive sway path length (.6 SD), more dramatic in the anterior-posterior than medial lateral direction. Truncal tremor, measured as peak sway velocity frequency, was disproportionately great in the 5 Hz to 7 Hz band of alcoholics. Control subjects and alcoholics exhibited sway and tremor reduction with visual, tactile, or stance-stabilizing conditions, which aided both groups equally well; thus, alcoholic women never achieved normal stability. Smaller anterior vermian volumes selectively correlated with longer sway path and higher 5 Hz to 7 Hz peak sway velocity. CONCLUSIONS: Sway and tremor abnormalities and the selective relations between greater sway and 5 Hz to 7 Hz tremor and smaller volumes of the anterior vermis had not heretofore been described in abstinent alcoholic women. Reduction in sway and tremor with stabilizing factors indicate that adaptive mechanisms involving sensorimotor integration can be invoked to compensate for vermian related dysfunction. PMID- 19782969 TI - [Biliary ileum. Assisted laparoscopic approach]. PMID- 19782971 TI - The embodied nature of spatial perspective taking: embodied transformation versus sensorimotor interference. AB - Humans are able to mentally adopt the spatial perspective of others and understand the world from their point of view. We propose that spatial perspective taking (SPT) could have developed from the physical alignment of perspectives. This would support the notion that others have put forward claiming that SPT is an embodied cognitive process. We investigated this issue by contrasting several accounts in terms of the assumed processes and the nature of the embodiment. In a series of four experiments we found substantial evidence that the transformations during SPT comprise large parts of the body schema, which we did not observe for object rotation. We further conclude that the embodiment of SPT is best conceptualised as the self-initiated emulation of a body movement, supporting the notion of endogenous motoric embodiment. Overall our results are much more in agreement with an 'embodied' transformation account than with the notion of sensorimotor interference. Finally we discuss our findings in terms of SPT as a possible evolutionary stepping stone towards more complex alignments of socio-cognitive perspectives. PMID- 19782970 TI - Asymmetric cultural effects on perceptual expertise underlie an own-race bias for voices. AB - The own-race bias in memory for faces has been a rich source of empirical work on the mechanisms of person perception. This effect is thought to arise because the face-perception system differentially encodes the relevant structural dimensions of features and their configuration based on experiences with different groups of faces. However, the effects of sociocultural experiences on person perception abilities in other identity-conveying modalities like audition have not been explored. Investigating an own-race bias in the auditory domain provides a unique opportunity for studying whether person identification is a modality-independent construct and how it is sensitive to asymmetric cultural experiences. Here we show that an own-race bias in talker identification arises from asymmetric experience with different spoken dialects. When listeners categorized voices by race (White or Black), a subset of the Black voices were categorized as sounding White, while the opposite case was unattested. Acoustic analyses indicated listeners' perceptions about race were consistent with differences in specific phonetic and phonological features. In a subsequent person-identification experiment, the Black voices initially categorized as sounding White elicited an own-race bias from White listeners, but not from Black listeners. These effects are inconsistent with person-perception models that strictly analogize faces and voices based on recognition from only structural features. Our results demonstrate that asymmetric exposure to spoken dialect, independent from talkers' physical characteristics, affects auditory perceptual expertise for talker identification. Person perception thus additionally relies on socioculturally acquired dynamic information, which may be represented by different mechanisms in different sensory modalities. PMID- 19782972 TI - The closing-in phenomenon in the drawing performance of Alzheimer's disease patients: a compensation account. AB - INTRODUCTION: The closing-in phenomenon, first described by Mayer Gross (1935) as a tendency to close in on models while performing a constructional task, occurs with a relatively high frequency in patients with dementia. The phenomenon may appear in several tasks, but it is more usually observed in tests of copying drawings. In the present study we examined the hypothesis that in patients with Alzheimer's disease (AD) the phenomenon may be related to particularly severe visuo-spatial dysfunction. METHODS: Thirty-nine of an overall sample of 382 patients consecutively admitted to an AD unit exhibited closing-in in their copying drawings performance. The presence of closing-in was diagnosed when, in at least one of three drawings, the copy touched, in one or more parts, the model. RESULTS: With respect to another group of 39 AD patients with constructional apraxia but who showed no closing-in behaviour, patients with closing-in showed more severe impairment on several tests of visuo-spatial abilities. The two groups did not differ in the frequency of neurological primitive reflexes or performance on tests of executive functioning. CONCLUSIONS: The present study supports the interpretation that the closing-in phenomenon in patients with AD is a compensatory strategy to overcome basic visuo-spatial dysfunctions involved in the preliminary visuo-perceptual analysis and/or in the on-line maintenance of the visual representation of the model while performing a copying drawing task. Possible limits in the conclusions of the present study are related to the retrospective nature of the present study and to the choice of considering only overlap-type forms of closing behaviour. PMID- 19782973 TI - Mechanically expanding the zona pellucida of human frozen thawed embryos: a new method of assisted hatching. AB - OBJECTIVE: To determine whether a new assisted hatching (AH) method increases the implantation and clinical pregnancy rates of frozen-thawed day-3 (D3) embryos. DESIGN: Prospective study. SETTING: A university hospital in vitro fertilization (IVF) program. PATIENT(S): Patients who had their first IVF/intracytoplasmic sperm injection (ICSI) cycles between June 1, 2006, and December 31, 2008, with fresh IVF-embryo transfer failures or without fresh embryo transfer. INTERVENTION(S): The couples were randomized into thawed embryo transfer after AH versus no AH. In the AH group, the zona pellucida (ZP) of D3 frozen-thawed embryos was expanded by injected hydrostatic pressure after thawing. In the control group, embryos were pierced by ICSI needles without expanding the ZP. MAIN OUTCOME MEASURE(S): Clinical pregnancy and implantation rates. RESULT(S): The morphologic features of the blastomeres were carefully monitored and recorded. In the AH group, 244 embryos were thawed, and 178 (73.0%) survived; in the control group, 259 embryos were thawed, and 190 (73.4%) survived. Despite the transfer of a similar number of embryos, the AH group resulted in statistically significantly higher implantation and clinical pregnancy rates compared with the no AH group. CONCLUSION(S): Mechanically expanding the ZP of frozen-thawed D3 embryos with injected hydrostatic pressure after thawing increases the implantation rate compared with control embryos. PMID- 19782974 TI - Three-point index in predicting redisplacement of extra-articular distal radial fractures in adults. AB - INTRODUCTION: In distal radial fractures in adults, factors affecting instability have been investigated in many studies in an effort to shorten the preoperative waiting period for the fractures requiring surgery. Numerous factors, aside from the alignment-related indices, have been searched to predict redisplacement. Unlike as in paediatric counterparts, the casting technique and casting-related indices have not been appropriately considered in adults. The aim of this study was to determine the impact of the various previously investigated factors in addition to casting technique-related indices such as three-point index, cast index, padding index and gap index, in predicting the risk of redisplacement of extra-articular distal radial fractures in adults and the presence of the ulnar deviation of the cast. PATIENTS AND METHODS: Seventy-five patients over 18 years who were treated with a cast in our emergency department within 24h after a displaced distal radial fracture, were recruited into the study. Age, alignment related indices, cast-related indices, extent of the ulnar deviation of the cast, having a non-anatomical reduction, co-existing ulnar fracture, dorsal comminution and obliquity of the fracture line were investigated. Casting technique according to three-point index, obliquity of the fracture line, degree of the ulnar deviation of the cast, and reduction accuracy were the significant factors affecting redisplacement. RESULTS: The three-point index had a sensitivity of 95.8%, specificity of 96.1%, positive predictive value of 92%, and negative predictive value of 98% in predicting redisplacement. Logistic regression revealed that having an inadequate cast according to the three-point index (p<0.001), degree of obliquity of the fracture line (p=0.018), decreased ulnar deviation of the cast (p=0.002), and having a non-anatomical reduction (p=0.029) were the significant predictive factors in redisplacement. CONCLUSIONS: Our results suggest that the casting technique plays a major role in the success of conservative treatment, which can best be examined with the three-point index. Ulnar deviation of the cast and fracture obliquity are the other dominant factors affecting redisplacement. PMID- 19782975 TI - Preterm delivery and ultrasound measurement of cervical length in Gran Canaria, Spain. AB - OBJECTIVE: To study the relationship between cervical length measured by ultrasound and risk of preterm delivery. METHODS: We measured cervical length in 2351 women between the 18th and 22nd week of pregnancy. Preterm delivery was categorized as before 37 weeks, before 34 weeks, and before 30 weeks. RESULTS: Before the 37th week, the odds ratios (ORs) of spontaneous delivery for cervical lengths in the 3rd, 5th, and 10th percentiles were, respectively, 25.47 (95% confidence intervals [CI], 15.5-41.73); 16.98 (95% CI, 11.51-25.05); and 7.55 (95% CI, 5.44-10.5). Before the 34th week the ORs were 28.7 (95% CI, 14.54 41.73); 20.5 (95% CI, 11.51-25.05); and 10.3 (95% CI, 5.44-10.5). And before the 30th week they were 29.8 (95% CI, 15.54-41.73); 23.1 (95% CI, 11.51-25.05); and 19.1 (95% CI, 7.44-31.5). In predicting premature delivery, the sensitivity, specificity, positive predictive value, and negative predictive value of cervical length were 26%, 98%, 63.6%, and 93.57% for the 3rd percentile; 34%, 97%, 51%, and 94% for the 5th percentile; and 39%, 92%, 31%, and 94% for the 10th percentile. CONCLUSION: Transvaginal measurement of cervical length during routine fetal morphological examination between the 18th and 22nd week of pregnancy helps identify asymptomatic women at risk for preterm delivery. PMID- 19782976 TI - Acute postpartum paraplegia caused by spinal extradural capillary hemangioma. PMID- 19782977 TI - Cesarean delivery outcomes from the WHO global survey on maternal and perinatal health in Africa. AB - OBJECTIVE: To assess the association between cesarean delivery rates and pregnancy outcomes in African health facilities. METHODS: Data were obtained from all births over 2-3 months in 131 facilities. Outcomes included maternal deaths, severe maternal morbidity, fresh stillbirths, and neonatal deaths and morbidity. RESULTS: Median cesarean delivery rate was 8.8% among 83439 births. Cesarean deliveries were performed in only 95 (73%) facilities. Facility-specific cesarean delivery rates were influenced by previous cesarean, pre-eclampsia, induced labor, referral status, and higher health facility classification scores. Pre eclampsia increased the risks of maternal death, fresh stillbirths, and severe neonatal morbidity. Adjusted emergency cesarean delivery rate was associated with more fresh stillbirths, neonatal deaths, and severe neonatal morbidity--probably related to prolonged labor, asphyxia, and sepsis. Adjusted elective cesarean delivery rate was associated with fewer perinatal deaths. CONCLUSION: Use of cesarean delivery is limited in the African health facilities surveyed. Emergency cesareans, when performed, are often too late to reduce perinatal deaths. PMID- 19782978 TI - Insulin-like growth factor-1 and insulin-like growth factor-binding protein-1 in patients with polycystic ovary syndrome during clomiphene citrate therapy. PMID- 19782979 TI - Inequalities in cesarean delivery rates by ethnicity and hospital accessibility in Brazil. AB - OBJECTIVE: To investigate inequalities in cesarean delivery rates in Brazil according to ethnic group and level of access to hospital delivery. METHODS: Cross-sectional analysis of data for primiparous women with singleton deliveries between 2003 and 2004 from the National Information System of Live-Births (6,064,799 live births). Robust Poisson regression modeling was applied to estimate prevalence ratios of cesarean deliveries for ethnic group and level of access to hospital delivery according to residence. RESULTS: There were 2,438,180 primiparous deliveries and the cesarean rate was 45.8%. Ethnic inequalities in cesarean delivery rates showed lower rates for all ethnic groups compared with white women, with the lowest rates recorded for indigenous women. The association between ethnicity and cesarean delivery was higher in states with lower access to hospital (P<0.001). Multiple regression models showed that this association was, in part, explained by older maternal age and higher levels of education and prenatal care. CONCLUSIONS: Overuse of cesarean delivery and strong evidence of ethnic inequalities in cesarean rates exist in Brazil. The inequalities are greater in states with lower access to hospital and were partially explained by socioeconomic factors and prenatal care, suggesting a misuse of medical technology at birth. PMID- 19782980 TI - Resumption of sexual activity and regular menses after childbirth among women infected with HIV in Malawi. AB - OBJECTIVE: To determine the factors associated with resumption of sexual activity and regular menses after childbirth among women infected with HIV-1. METHODS: Information on sociodemographic, behavioral, and clinical factors was obtained from 2 HIV perinatal studies (NVAZ and PEPI trials) conducted in Malawi, 2000 2009. Factors associated with resumption of sexual activity and menses were analyzed using Cox proportional hazard models. RESULTS: A total of 1838 women from the NVAZ study and 2982 women from the PEPI study were included in the analysis. Resumption of sexual activity was primarily associated with sociodemographic factors (e.g. in the PEPI study, marital status [adjusted hazard ratio (aHR) 0.56, P<0.001], use of contraceptive method [aHR 8.0, P<0.001], and breastfeeding [aHR 0.52, P<0.001]), whereas resumption of regular menses in the PEPI study was primarily associated with biological factors (e.g. plasma viral load [aHR 0.89, P<0.006], and breastfeeding [aHR 0.23, P<0.001). CONCLUSION: HIV infected women need adequate counseling to take into account their HIV infection status before resuming sexual activity after childbirth. PMID- 19782981 TI - Primary squamous cell carcinoma of the ovary associated with endometriosis. AB - OBJECTIVE: To analyze the clinical, therapeutic, and pathologic features of published cases presenting primary squamous cell carcinoma (SCC) of the ovary associated with endometriosis. METHODS: A case report, 15 cases of infiltrating SCC of the ovary associated with or arising from endometriosis, and 1 case of synchronous carcinoma in situ in the cervix and ovary from a review of the literature were studied. RESULTS: Young age, advanced stage of the disease, and hypogastric pain were frequent at the time of diagnosis. There was no ascites, but infiltration of neighboring organs was common. The tumor was associated with 80% patient mortality in the first few months. Adjuvant chemotherapy with paclitaxel and carboplatin or cisplatin appeared to improve the results. CONCLUSION: Primary SCC of the ovary associated with endometriosis is extremely rare and has a poor prognosis. The best therapeutic results are obtained with paclitaxel and carboplatin or cisplatin after radical surgery. PMID- 19782982 TI - Factors associated with pathologic colposcopic and cytologic changes in 500 clinically asymptomatic women. AB - OBJECTIVE: To determine the role of cytologic and colposcopic diagnosis in the early detection of pathologic cervical changes and the effect of the number of births, a history of abortion, the number of sexual partners, and contraceptive use on pathologic colposcopic and cytologic changes. METHOD: The 500 study participants were seen at the Obstetric-Gynecologic Clinic of Prishtina, Kosovo, in 2006 and 2007. They were assigned to 5 groups of 100 according to number of births, a history of abortion (whether spontaneous or induced), and total number of sexual partners, but the use of contraceptives was also analyzed. All participants underwent cytologic and colposcopic evaluations. RESULTS: Colposcopic atypia was observed in 70 participants (14%) and 77 (15.4%) had other findings. The degree of colposcopic atypia increased with the number of sexual partners, as did the frequency of infections. Most (91.2%) of the women with positive cytologic results were from groups 1 and 2, and the remaining 8.8% of these women were from groups 3, 4, and 5. From 44 patients with positive pathology results, 29 (65.9%) had chronic cervicitis, 13 (29. 5%) had hyperplasia, and 2 (4.5%) had carcinoma in situ. CONCLUSION: Number of births, a history of abortion, number of sexual partners, and contraceptive use directly affected pathologic colposcopic and cytologic changes. PMID- 19782983 TI - Relationship between common carotid intima-media thickness and thoracic aortic calcification: the Multi-Ethnic Study of Atherosclerosis. AB - BACKGROUND: Mean maximum carotid intima-media thickness (CIMT) is associated with both coronary artery disease and cerebral thromboembolism. Thoracic aortic calcification (TAC) detected by computed tomography (CT) is also highly associated with vascular disease and cardiovascular risk. No previous study has examined the relationship between CIMT and TAC in a large patient cohort. We performed a cross-sectional study to determine whether, at baseline, there is a relationship between CIMT and CT-determined TAC score. METHODS: In the Multi Ethnic Study of Atherosclerosis, the study cohort included a population based sample of four ethnic groups (Chinese, White, Hispanic and African-American) of 6814 women and men ages 45-84 years. After exclusion of 198 persons due to incomplete information, we compared results of 6616 participants with both CIMT and TAC. TAC was measured from the lower edge of the pulmonary artery bifurcation to the cardiac apex. CIMT at the common carotid artery site was represented as the mean maximal CIMT of the right and left near and far walls, respectively. Multivariable relative risk regression analysis was used to evaluate relationships between TAC and CIMT. RESULTS: The prevalence of TAC was 28% (n=1846) and the mean maximum (+SD) CIMT was 0.87+/-0.19mm. A higher prevalence of TAC was noted across increasing CIMT quartiles (1st: 12%, 2nd: 21%, 3rd: 30%, 4th: 49%, p<0.0001). One standard deviation increase in CIMT was associated with a 16% higher likelihood for presence of TAC after adjusting for demographics and cardiovascular disease (CVD) risk factors (95% CI: 1.12-1.26). In addition, individuals with CIMT in the highest quartile, as compared to those with CIMT in the first quartile, had a 76% higher likelihood for presence of TAC (prevalence ratio [PR]: 1.76, 95% CI: 1.37-2.26). In race-ethnic stratified analyses, similar associations were seen in all groups. Among those with TAC>0, a higher CIMT was significantly associated with continuous TAC scores (log transformed) in the overall population as well as among all ethnic-racial groups. CONCLUSIONS: Our study demonstrates that TAC is associated with increasing severity of carotid atherosclerotic burden as measured by CIMT. The combined utility of these two noninvasive measures of subclinical atherosclerosis for CVD risk assessment needs to be determined in future studies. PMID- 19782984 TI - Palmitic acid enhances lectin-like oxidized LDL receptor (LOX-1) expression and promotes uptake of oxidized LDL in macrophage cells. AB - OBJECTIVE: Elevated levels of nonesterified fatty acids (NEFA) in obesity and type 2 diabetes may contribute to the development of atherosclerosis. Therefore, we examined whether NEFA could regulate expression of scavenger receptors responsible for uptake of oxidized LDL (oxLDL) in macrophages, a critical step in atherogenesis. METHODS AND RESULTS: Expression level of scavenger receptors in NEFA-treated macrophage-like THP-1 and Raw264.7 cells were analyzed by real-time PCR. Palmitic acid showed the greatest enhancement of expression of lectin-like oxidized LDL receptor (LOX-1) among 7 NEFA examined (4 saturated and 3 unsaturated fatty acids). Upregulation of LOX-1 was selective as increases in expression level of other scavenger receptors (CD36, SR-AI, SR-BI, and CD68) were not observed. Western blotting analysis indicated that upregulation of LOX-1 also occurred at the protein level. Uptake of oxLDL by Raw264.7 cells was promoted by palmitic acid, and the enhanced uptake was abrogated when the cells were transfected with siRNA against LOX-1. Downregulation of Toll-like receptor (TLR) 2, TLR4, or IRAK4 with siRNA did not prevent LOX-1 upregulation, whereas inhibitors of p38 MAPK (p38) and reactive oxygen species (ROS) signal inhibited the upregulation of LOX-1 induced by palmitic acid. CONCLUSIONS: These results suggest that elevated level of palmitic acid may contribute to development of atherosclerosis through enhanced uptake of oxLDL via upregulation of LOX-1 in macrophages. The effects of palmitic acid may be mediated by ROS-p38 pathway rather than TLRs. PMID- 19782985 TI - A study of the role of the Myocyte-specific Enhancer Factor-2A gene in coronary artery disease. AB - We evaluated the role of the MEF2A as a risk factor for coronary artery disease (CAD) in 1186 subjects with angiographically documented disease compared with 885 CAD-free individuals in the Saudi population. Screening the gene revealed exon 11 as the most polymorphic of all coding regions, harbouring several substitution polymorphisms and insertion/deletions (indels) at a locus containing an 11 CAG trinucleotide chain and a CCGCCGCCA sequence, which introduced frameshifts and premature stop codons at nt146637 and nt146647, nt146780 or nt146783. While these indels were not significantly associated with CAD, a causative relationship was established for rs1059759 G>C [1.21(1.02-1.43); p=0.029], and a borderline one for rs34851361 A>G [1.22(0.9-1.54); p=0.088]. Importantly, a haplotype 1A-2G-3G 4A-5C-6G-7G-8A constructed from the studied SNPs was also associated with CAD [6.39(0.93-43.75); p=0.0052]. These results identify MEF2A gene as a susceptibility gene for CAD. PMID- 19782986 TI - Inertial sensor-based knee flexion/extension angle estimation. AB - A new method for estimating knee joint flexion/extension angles from segment acceleration and angular velocity data is described. The approach uses a combination of Kalman filters and biomechanical constraints based on anatomical knowledge. In contrast to many recently published methods, the proposed approach does not make use of the earth's magnetic field and hence is insensitive to the complex field distortions commonly found in modern buildings. The method was validated experimentally by calculating knee angle from measurements taken from two IMUs placed on adjacent body segments. In contrast to many previous studies which have validated their approach during relatively slow activities or over short durations, the performance of the algorithm was evaluated during both walking and running over 5 minute periods. Seven healthy subjects were tested at various speeds from 1 to 5 mile/h. Errors were estimated by comparing the results against data obtained simultaneously from a 10 camera motion tracking system (Qualysis). The average measurement error ranged from 0.7 degrees for slow walking (1 mph) to 3.4 degrees for running (5 mph). The joint constraint used in the IMU analysis was derived from the Qualysis data. Limitations of the method, its clinical application and its possible extension are discussed. PMID- 19782987 TI - Simulation of vertebral trabecular bone loss using voxel finite element analysis. AB - Trabecular bone loss in human vertebral bone is characterised by thinning and eventual perforation of the horizontal trabeculae. Concurrently, vertical trabeculae are completely lost with no histological evidence of significant thinning. Such bone loss results in deterioration in apparent modulus and strength of the trabecular core. In this study, a voxel-based finite element program was used to model bone loss in three specimens of human vertebral trabecular bone. Three sets of analyses were completed. In Set 1, strain adaptive resorption was modelled, whereby elements which were subject to the lowest mechanical stimulus (principal strain) were removed. In Set 2, both strain adaptive and microdamage mechanisms of bone resorption were included. Perforation of vertical trabeculae occurred due to microdamage resorption of elements with strains that exceeded a damage threshold. This resulted in collapse of the trabecular network under compression loading for two of the specimens tested. In Set 3, the damage threshold strain was gradually increased as bone loss progressed, resulting in reduced levels of microdamage resorption. This mechanism resulted in trabecular architectures in which vertical trabeculae had been perforated and which exhibited similar apparent modulus properties compared to experimental values reported in the literature. Our results indicate that strain adaptive remodelling alone does not explain the deterioration in mechanical properties that have been observed experimentally. Our results also support the hypothesis that horizontal trabeculae are lost principally by strain adaptive resorption, while vertical trabeculae may be lost due to perforation from microdamage resorption followed by rapid strain adaptive resorption of the remaining unloaded trabeculae. PMID- 19782988 TI - Local bone formation due to combined mechanical loading and intermittent hPTH-(1 34) treatment and its correlation to mechanical signal distributions. AB - We evaluated the local response of cortical bone in the rat tibia due to combined treatment with synthetic parathyroid hormone, hPTH-(1-34), and mechanical stimulation by four-point bending. Forty-eight female retired breeder Sprague Dawley rats were divided into six groups. Mechanically stimulated animals included the following groups: (1) Bend+PTH, (2) Sham+PTH, (3) Bend+Vehicle, (4) Sham+Vehicle. Non-mechanically stimulated animals included a (5) Control group that received neither loading nor injections, and a (6) PTH group that received only hPTH-(1-34) injections. The right limbs of mechanically loaded animals were exposed to a peak force of 50 N for 36 cycles at 2 Hz, three days per week for four weeks, and PTH-treated animals received injections equivalent to 50 microg/kg BW. Fluorochrome labeling was used to measure local formation at 12 sectors about the endocortical periphery. The distributions of endocortical bone formation were compared to the local formation differences between treatment groups and to a variety of potential mechanical stimuli signals. Results indicated that hPTH-(1-34) exerted a potent anabolic effect with near-uniform formation about the endocortical surface, and that localized formation peaks due to bending were further augmented in the presence of hPTH-(1-34) treatment. Correlation of formation patterns to mechanical signal distributions highlighted several candidate signals including the mid-principal stress, the dilatational strain, and the radial gradient of the local radial strain. PMID- 19782989 TI - Daidzein-imprinted membranes using co-functional monomers. AB - Daidzein-imprinted poly(methacrylamide-co-acrylic acid) composite membranes with different ratios of methacrylamide (MAM) versus acrylic acid (AA) were prepared via UV initiated photo-copolymerization on the commercial filter paper with ethylene glycol dimethacrylate (EGDMA) as cross-linker and mixed cellulose ester as agglutinant. Infra-red (IR) spectroscopy and scanning electron microscope (SEM) were used to visualize the surface of the membranes. Binding and recognising properties of the imprinted composite membranes to daidzein and its analogues genistein were evaluated by static adsorption experiment. It was found that the daidzein-imprinted membranes showed high selectivity to daidzein, with the highest selectivity when the composite membrane with the ratio of MAM vs AA as 4:1. The results suggested that the molecularly imprinted composite membranes were potentially useful for daidzein enrichment. PMID- 19782990 TI - Optimization of some experimental parameters in the electro membrane extraction of chlorophenols from seawater. AB - An electro membrane extraction (EME) methodology was utilized to study the isolation of some environmentally important pollutants, such as chlorophenols, from aquatic media based upon the electrokinetic migration process. The analytes were transported by application of an electrical potential difference over a supported liquid membrane (SLM). A driving force of 10V was applied to extract the analytes through 1-octanol, used as the SLM, into a strongly alkaline solution. The alkaline acceptor solution was subsequently analyzed by high performance liquid chromatography-ultraviolet (HPLC-UV) detection. The parameters influencing electromigration, including volumes and pH of the donor and acceptor phases, the organic solvent used as the SLM, and the applied voltage and its duration, were investigated to find the most suitable extraction conditions. Since the developed method showed a rather high degree of selectivity towards pentachlorophenol (PCP), validation of the method was performed using this compound. An enrichment factor of 23 along with acceptable sample clean-up was obtained for PCP. The calibration curve showed linearity in the range of 0.5 1000ng/mL with a coefficient of estimation corresponding to 0.999. Limits of detection and quantification, based on signal-to-noise ratios of 3 and 10, were 0.1 and 0.4ng/mL, respectively. The relative standard deviation of the analysis at a PCP concentration of 0.5ng/mL was found to be 6.8% (n=6). The method was also applied to the extraction of this contaminant from seawater and an acceptable relative recovery of 74% was achieved at a concentration level of 1.0ng/mL. PMID- 19782991 TI - Editorial on "Plucking, pillaging and plundering proteomes with combinatorial peptide ligand libraries" by P.G. Righetti, E. Boschetti, A. Zanella, E. Fasoli and A. Citterio. PMID- 19782992 TI - Current trends in sample preparation for growth promoter and veterinary drug residue analysis. AB - A comprehensive review is presented on the current trends in sample preparation for the isolation of veterinary drugs and growth promoters from foods. The objective of the review is to firstly give an overview of the sample preparation techniques that are applied in field. The review will focus on new techniques and technologies, which improve efficiency and coverage of residues. The underlying theme to the paper is the developments that have been made in multi-residue methods and particularly multi-class methods for residues of licensed animal health products, which have been developed in the last couple of years. The role of multi-class methods is discussed and how they can be accommodated in future residue surveillance. PMID- 19782993 TI - Correlation between surface free energy of quartz and its wettability by aqueous solutions of nonionic, anionic and cationic surfactants. AB - The measurements of the advancing contact angle for water, glycerol, diiodomethane and aqueous solutions of Triton X-100 (TX-100), Triton X-165 (TX 165), sodium dodecyl sulfate (SDDS), sodium hexadecyl sulfonate (SHDS), cetyltrimethylammonium bromide (CTAB) and cetylpyridinium bromide (CPyB) on quartz surface were carried out. On the basis of the contact angles values obtained for water, glycerol and diiodomethane the values of the Lifshitz-van der Waals component and electron-acceptor and electron-donor parameters of the acid base component of the surface free energy of quartz were determined. The determined components and parameters of the quartz surface free energy were used for interpretation of the influence of nonionic, anionic and cationic surfactants on the wettability of the quartz. From obtained results it was appeared that the wettability of quartz by nonionic and anionic surfactants practically does not depend on the surfactants concentration in the range corresponding to their unsaturated monolayer at water-air interface and that there is linear dependence between adhesional and surface tension of aqueous solution of these surfactants. This dependence for TX-100, TX-165, SDDS and SHDS can be expressed by lines which slopes are positive. This slope and components of quartz surface free energy indicate that the interaction between the water molecules and quartz surface might be stronger than those between the quartz and surfactants molecules. So, the surface excess of surfactants concentration at the quartz-water interface is probably negative, and the possibility of surfactants to adsorb at the quartz/water film-water interface is higher than at the quartz-water interface. This conclusion is confirmed by the values of the adhesion work of "pure" surfactants, aqueous solutions of surfactants and water to quartz surface. In the case of the cationic surfactants the relationship between adhesional and surface tension is more complicated than that for nonionic and anionic surfactants and indicates that the relationship between the adsorption of the cationic surfactant at water-air and quartz-water interface depends on the concentration of the surfactants in the bulk phase. PMID- 19782994 TI - Surface characterization and catalytic evaluation of copper-promoted Al-MCM-41 toward hydroxylation of phenol. AB - The Mobil Composition of Matter No. 41 (MCM-41) containing Cu and Al with Si/Al ratios varying from 100 to 10 and 1 to 6wt.% of Cu was synthesized under hydrothermal and impregnation conditions, respectively. The samples were characterized by nitrogen adsorption-desorption measurements, X-ray powder diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), UV-Vis diffuse reflectance spectroscopy (UV-Vis DRS), temperature-programmed reduction (TPR), temperature-programmed desorption (TPD), and (29)Si and (27)Al magic-angle spinning-nuclear magnetic resonance (MAS-NMR) spectra. X-ray diffraction patterns indicate that the modified materials retain the standard MCM-41 structure. TPR patterns show the two-step reduction of Cu species. TPD study shows that Cu impregnated Al-MCM-41 samples are more acidic than Al-MCM-41. From the MAS-NMR it was confirmed that most of the Al atoms are present tetrahedrally within the framework and some are present octahedrally in extraframework position. Impregnation of Cu shifted Al to the extraframework position. The catalytic activity of the samples toward hydroxylation of phenol in aqueous medium was evaluated using H(2)O(2) as the oxidant at 80 degrees C. The effects of reaction parameters such as temperature, catalyst amount, amount of H(2)O(2), and solvent were also investigated. Sample containing 4wt.% copper-loaded Al-MCM-41-100 showed high phenol conversion (78%) with 68% catechol and 32% hydroquinone selectivity. PMID- 19782995 TI - Particle electrophoresis and dielectrophoresis in curved microchannels. AB - Studies of particle electrophoresis have so far been limited to primarily theoretical or numerical analyses in straight microchannels. Very little work has been done on particle electrophoretic motions in real microchannels that may have one or multiple turns for reducing the devices size or achieving other functions. This article presents an experimental and numerical study of particle electrophoresis in curved microchannels. Polystyrene microparticles are found to migrate across streamlines and flow out of a spiral microchannel in a focused stream near the outer wall. This transverse focusing effect arises from the dielectrophoretic particle motion induced by the nonuniform electric field intrinsic to curved channels. The experimental observations agree quantitatively with the numerical predictions. PMID- 19782996 TI - Langmuir monolayers and Langmuir-Blodgett films of 1-acyl-1,2,4-triazoles. AB - New 1-acyl-1,2,4-triazoles (ATs) with different n-alkyl chain lengths from C2 to C18 were synthesized. ATs with long n-alkyl chains (C12 and larger) are non charged amphiphilic molecules with a polar triazole head group. The Langmuir isotherms of ATs at the air-water interface with 12 (DoT-C12), 14 (MyT-C14), 16 (PaT-C16) and 18 (StT-C18) carbon atoms in their n-alkyl chains were studied using surface pressure-mean molecular area (pi-mmA) measurements. Characteristic for the Langmuir isotherms of PaT-C16 and StT-C-18 was the first sharp increase of the surface pressure at a mmA value of approximately 20A(2) marking a transition of the ATs from the gaseous state with n-alkyl chains already oriented perpendicular to the water surface to a condensed state. The collapse of the monolayers occurred between 20 and 36mNm(-1) with a typical 'spike' in the isotherms of MyT-C14, PaT-C16 and StT-C18 which can be assigned to the buckling and subsequent folding of the monolayer. After the collapse point a pseudo plateau region of slightly increasing surface pressure appeared for all ATs from C12 to C18 indicating a trilayer formation by the roll-over mechanism for MyT C14, PaT-C16 and StT-C18. Upon further compression the final collapse occurred at pi values between 59 and 67mNm(-1). From reversibility studies it was found that the Langmuir isotherms of the ATs were irreversible. The morphology of Langmuir Blodgett films of ATs transferred onto silicon wafers was studied by atomic force microscopy. PMID- 19782997 TI - Using death certificates to characterize sudden infant death syndrome (SIDS): opportunities and limitations. AB - OBJECTIVE: To examine cause-of-death terminology written on death certificates for sudden infant death syndrome (SIDS) and to determine the adequacy of this text data in more fully describing circumstances potentially contributing to SIDS deaths. STUDY DESIGN: With 2003 and 2004 US mortality files, we analyzed all deaths that were assigned the underlying cause-of-death code for SIDS (R95). With the terminology written on the death certificates, we grouped cases into SIDS related cause-of-death subcategories and then assessed the percentage of cases in each subcategory with contributory or possibly causal factors described on the certificate. RESULTS: Of the 4408 SIDS-coded deaths, we subcategorized 67.2% as "SIDS" and 11.0% as "sudden unexplained (or unexpected) infant death." The terms "probable SIDS" (2.8%) and "consistent with SIDS" (4.6%) were found less frequently. Of those death certificates that described additional factors, "bedsharing or unsafe sleep environment" was mentioned approximately 80% of the time. Most records (79.4%) did not mention any additional factors. CONCLUSION: Our death certificate analysis of the cause-of-death terminology provided a unique opportunity to more accurately characterize SIDS-coded deaths. However, the death certificate was still limited in its ability to more fully describe the circumstances leading to SIDS death, indicating the need for a more comprehensive source of SIDS data, such as a case registry. PMID- 19782998 TI - Association of human metapneumovirus with radiologically diagnosed community acquired alveolar pneumonia in young children. AB - OBJECTIVES: To determine the involvement of human metapneumovirus (HMPV) in childhood community-acquired alveolar pneumonia (CAAP) and compare the demographic, clinical, and laboratory features of HMPV-associated CAAP and CAAP associated with other respiratory viruses. STUDY DESIGN: Nasopharyngeal wash specimens obtained prospectively over a 4-year period from children age < 5 years evaluated in the emergency department with radiologically diagnosed CAAP and from healthy controls were tested for HMPV by reverse-transcriptase polymerase chain reaction and for respiratory syncytial virus (RSV), adenovirus, influenza and parainfluenza viruses by direct immunofluorescence and culture. RESULTS: HMPV was detected in 108 of 1296 patients (8.3%) versus RSV in 23.1%, adenovirus in 3.4%, influenza A virus in 2.9%, and parainfluenza viruse in 2.9%. During the period of peak activity (November to May), HMPV was detected in 95 of 1017 patients (9.3%) and in 3 of 136 controls (2.2%) (P = .005). The patients with HMPV were older than those with RSV (P < .001) with a more common history of acute otitis media requiring tympanocentesis (P = .032), wheezing (P = .001) and gastrointestinal symptoms (P < .001) and a lower hospitalization rate (P = .005). CONCLUSIONS: The high detection rate suggests an important role for HMPV in childhood CAAP. Our findings identify demographic and clinical features of HMPV-positive CAAP and its age-related impact on hospital admissions. PMID- 19782999 TI - Is acute lobar nephronia the midpoint in the spectrum of upper urinary tract infections between acute pyelonephritis and renal abscess? AB - OBJECTIVE: To examine acute lobar nephronia (ALN) in the spectrum of upper urinary tract infections between acute pyelonephritis (APN) and renal abscess. STUDY DESIGN: Medical records of 115 patients diagnosed with APN, ALN, or renal abscess with computed tomography (CT) were reviewed retrospectively. CT lesions and patterns of ALN were checked, and the volume of CT lesions was estimated in every patient. Then the correlation between clinical presentation and CT lesions was examined. RESULTS: The study included 21 patients with APN, 85 with ALN (63 simple ALN, 22 complicated ALN), and 9 with renal abscesses. The volume fraction of CT lesions correlated well with duration of fever before and after treatment in patients with APN or simple ALN, and only the correlation between fever duration after treatment and CT lesions was significant in patients with complicated ALN or renal abscess. CONCLUSIONS: We suggest that simple ALN be regarded clinically as the progression of APN. By contrast, complicated ALN is a distinct, more severe disease entity, and it may relate to or progress to renal abscess. ALN is probably not the midpoint in the traditional dynamic spectrum of upper urinary tract infections between APN and renal abscess. PMID- 19783000 TI - Colostrum ingested during the first day of life by exclusively breastfed healthy newborn infants. AB - OBJECTIVE: To determine the mass of colostrum ingested by exclusively breastfed newborn infants during the first 24 hours of extrauterine life. STUDY DESIGN: Milk ingested during the first 24 hours of life by 90 healthy newborn infants was evaluated by use of a scale with high sensitivity. The masses were measured during 8-hour periods. Associations of the mass measured with prenatal and postnatal variables were tested. RESULTS: The mass of colostrum ingested was evaluated in 307 feedings, with 3.4+/-1 feedings recorded per 8-hour period of observation. Mean gain per feeding was 1.5+/-1.1 g. The daily mass of milk ingested by newborn infants was estimated at 15+/-11 g. This volume did not show a tendency to increase during the first 24 postnatal hours, nor was it related to perinatal or postnatal factors or to breastfeeding time. CONCLUSIONS: During the first 24 hours of life newborns ingested 15+/-11 g of milk. PMID- 19783001 TI - Child mental health problems and obesity in early adulthood. AB - OBJECTIVE: To examine whether mental health problems in childhood increase the likelihood of overweight or obesity during early adulthood among male subjects. STUDY DESIGN: In a national prospective population-based study conducted in Finland, child mental health, including depression, emotional problems, conduct problems, and hyperactivity (determined on the basis of child, parent, and teacher information), was assessed at age 8 years. Body mass index (BMI) was obtained from military examination records (n = 2209) conducted in early adulthood (age range, 18-23 years). RESULTS: Both moderate (50th-90th percentile) and high (>90th percentile) levels of conduct problems at age 8 years were prospectively associated with a young adult being obese (BMI > or = 30; odds ratio [OR], 2.0; 95% CI, 1.2-3.2; and OR, 2.9; 95% Confidence interval [CI], 1.5 5.9; respectively). Conduct problems were also prospectively associated with a young adult being overweight (25 < or = BMI < 30; OR, 1.5; 95% CI, 1.1-1.9 for moderate levels of conduct problems, and OR, 1.9; 95% CI, 1.2-2.8 for high levels), after controlling for hyperactive problems and sociodemographic factors. CONCLUSIONS: Conduct problems in childhood are prospectively associated with overweight and obese in young adulthood. Future studies should address the potential for interventions to reduce obesity risk in young adulthood for boys who manifest conduct problems early in life. PMID- 19783002 TI - Intestinal microbial ecology in premature infants assessed with non-culture-based techniques. AB - OBJECTIVES: To use high throughput techniques to analyze intestinal microbial ecology in premature neonates, who are highly susceptible to perturbations of the luminal environment associated with necrotizing enterocolitis (NEC) and late onset sepsis. STUDY DESIGN: With non-culture-based techniques, we evaluated intestinal microbiota shortly after birth and during hospitalization in 23 neonates born at 23 to 32 weeks gestational age. Microbiota compositions were compared in 6 preterm infants in whom NEC, signs of systemic inflammation, or both developed with matched control subjects by using 16S ribosomal RNA pyrosequencing. RESULTS: Microbial DNA was detected in meconium, suggesting an intrauterine origin. Differences in diversity were detected in infants whose mothers intended to breast feed (P = .03), babies born to mothers with chorioamnionitis (P = .06), and in babies born at <30 weeks gestation (P = .03). A 16S ribosomal RNA sequence analysis detected Citrobacter-like sequences only in cases with NEC (3 of 4) and an increased frequency of Enterococcus-like sequences in cases and Klebsiella in control subjects (P = .06). The overall microbiota profiles in cases with NEC were not distinguishable from that in control subjects. CONCLUSIONS: Microbial DNA in meconium of premature infants suggests prenatal influences. PMID- 19783003 TI - Refrigerator storage of expressed human milk in the neonatal intensive care unit. AB - OBJECTIVE: To provide recommendations for refrigerator storage of human milk, the overall integrity (bacterial growth, cell counts, and component concentrations) of milk was examined during 96 hours of storage at 4 degrees C. STUDY DESIGN: Fresh milk samples (n = 36) were divided and stored at 4 degrees C for 0, 24, 48, 72, and 96 hours. At each time, pH, white cell count, and osmolality were measured and additional samples were stored at -80 degrees C until analyzed for bacteria and concentrations of lactoferrin, secretory (s)IgA, fat, fatty acids, and protein. RESULTS: There were no significant changes for osmolality, total and Gram-negative bacterial colony counts or concentrations of sIgA, lactoferrin, and fat. Gram-positive colony counts (2.9 to 1.6 x 10(5) colony-forming units per mL), pH (7.21 to 6.68), white blood cell counts (2.31 to 1.85 x 10(6) cells per mL), and total protein (17.5 to 16.7 g/L) declined, and free fatty acid concentrations increased (0.35 to 1.28 g/L) as storage duration increased, P < .001. CONCLUSIONS: Changes were minimal and the overall integrity of milk during refrigerator storage was preserved. Fresh mother's milk may be stored at refrigerator temperature for as long as 96 hours. PMID- 19783004 TI - Outcomes at age 2 years of infants < 28 weeks' gestational age born in Victoria in 2005. AB - OBJECTIVE: To determine the survival rates and neurosensory outcomes of infants born at gestational age 22-27 weeks in the state of Victoria in 2005 and compare theses data with those for similar infants born in the 1990s. STUDY DESIGN: This was a population-based study of all extremely preterm (22-27 weeks' gestational age) live births in Victoria in 2005 free of lethal anomalies and randomly selected term controls. Survival and quality-adjusted survival rates at age 2 years were determined relative to the controls, and results were compared with regional extremely preterm cohorts born in 1991-92 and 1997. RESULTS: Of 270 very preterm live births in 2005, 172 (63.7%) survived to 2 years, not significantly different from the survival rate of 69.6% for those born in 1997. Rates of severe developmental delay and severe disability were lower than in the very preterm survivors born in 1997. Quality-adjusted survival rates in the extremely preterm cohorts rose from 42.1% in 1991-92 to 55.1% in 1997, but did not increase in 2005 (53.4%). CONCLUSIONS: Survival rates for infants born at 22-27 weeks' gestational age have not increased since the late 1990s, but the neurosensory outcome in survivors has improved. PMID- 19783005 TI - Mechanical ventilation of newborns infant changes in plasma pro- and anti inflammatory cytokines. AB - OBJECTIVE: To evaluate plasma levels of interleukin (IL)-1beta, IL-6, IL-8, IL 10, and tumor necrosis factor (TNF)-alpha in newborn infants immediately before and after 2 hours of mechanical ventilation. STUDY DESIGN: Term and late preterm neonates with no history of mechanical ventilation and/or ventilatory support were studied prospectively. Exclusion criteria were congenital malformations, congenital infections, use of nitric oxide, resuscitation with positive-pressure ventilation, and any procedure in the delivery room or neonatal intensive care unit that resulted in tracheal intubation. Blood samples for IL-1beta, IL-6, IL 8, IL-10, and TNF-alpha levels were collected before intubation and mechanical ventilation and 2 hours later. RESULTS: Nineteen newborn infants with gestational age 35.8 +/- 1.9 weeks and birth weight 2280 +/- 370 g were included. Pro inflammatory cytokines increased: IL-8 (2.5-fold), IL-1beta (7.5-fold), and TNF alpha (10-fold), and the anti-inflammatory cytokine IL-10 decreased by 90%. Although median IL-6 levels were similar between before and after ventilation, IL 6 increased in 89.4% of infants. CONCLUSIONS: A short period of mechanical ventilation promotes an imbalance of plasma levels of pro-inflammatory and anti inflammatory cytokines. The systemic alteration of cytokines in response to mechanical ventilation may lead to ventilator-induced lung injury. PMID- 19783006 TI - Effect of bacterial exposure on acellular human dermis in a rat ventral hernia model. AB - BACKGROUND: Effectiveness of acellular human dermis (AHD) as an alternative to synthetic mesh in contaminated fields has been described. Cellular migration after implantation and corresponding strength of attachment is not well documented. Our aim is to correlate AHD vascularization, fibroblast migration, and strength of attachment with presence of inflammatory cells in clean and contaminated fields. MATERIALS AND METHODS: Lewis rats were randomized to a control and three experimental groups. AHD was placed as an onlay over the intact abdominal wall. Experimental groups (n=72) were exposed to Staphylococcus aureus at 1 x 10(4), 1 x 10(5), or 1 x 10(6) by direct application; controls (n=12) were not exposed. At 5 and 28 d, abdominal walls were explanted and tissue ingrowth assessed via tensiometry measuring energy (E) and max stress (MS) at the AHD tissue interface. Vascularity, fibroblast migration, and inflammatory cell migration were compared using light microscopy. RESULTS: Shear strength reported as energy and max stress were significantly greater at 28 versus 5 d in all experimental groups, remaining unchanged in controls. Plasma cells and histiocytes significantly increased in all groups; macrophages increased in experimental groups only. Vascular ingrowth increased significantly in all groups; fibroblast migration was greater in controls and 1 x 10(6) exposed group only. CONCLUSIONS: Contamination of AHD results in inflammatory cell influx and a surprising increase in shear strength. Interestingly, shear strength does not increase without contamination. Inflammation stimulates vascular ingrowth, but not equally significant fibroblast migration. Longer survivals are required to determine if energy and max stress of controls increase, and fibroblast migration follows vascular ingrowth. PMID- 19783007 TI - Clinical importance of lymph node density in predicting outcome of prostate cancer patients. AB - BACKGROUND: To evaluate the prognostic role of lymph node density (LND) in patients affected by prostate cancer (PCa) and treated with radical prostatectomy (RP), pelvic lymph node dissection (PLND), and adjuvant hormonal blockade. METHODS: A total of 124 consecutive patients with lymph node positive PCa formed the basis of this report. Clinical and pathological parameters were collected. All patients were stratified in two groups according to LND: Group A (LND <= 32%) and Group B (LND >= 33%). Time to the first biochemical recurrence (BCR) was the main measure of outcome. RESULTS: Mean number of lymph nodes removed was 5.2 (range 1-17). The mean number of positive lymph nodes was 1.6 (range 1-5). At a mean follow-up of 84.3 mo, 22 patients in Group A (43.1%) and 40 in Group B (54.7%) had BCR. The mean overall BCR-free survival was 46.2 mo (range 8-90). No significant correlation was found between the number of positive lymph nodes and BCR-free survival (P = 0.68). In addition, the patients with LND >= 33% had a poor prognosis with significantly decreased disease-specific and BCR-free survival rates (hazard ratio: 0.48; 95% CI, 0.28-0.78; P = 0.0039). At multivariate and artificial neural network (ANN) analyses, LND, Gleason score, and stage were identified as independent prognostic factors of BCR-free survival (P = 0.002; P = 0.003; P = 0.003). CONCLUSIONS: The current study highlights the role of LND in predicting BCR-free survival in patients with lymph node positive PCa after prostatectomy. It also reinforces the need for a stratification of patients with nodal metastasis. PMID- 19783008 TI - The prognostic analysis of lymph node-positive gastric cancer patients following curative resection. AB - BACKGROUND: The purpose of this study was to evaluate the appropriate prognostic indicators of lymph node-positive gastric cancer patients following curative resection. METHODS: A retrospective study of 196 lymph node-positive patients who underwent radical gastrectomy (R0) for gastric cancer from January 1997 to December 2000 was analyzed statistically to identify the intensive indictors of prognosis. RESULTS: In 196 evaluable patients, 5-year survival rate was 33.2%. A total of 4048 lymph nodes were examined (median, 20.6; range, 15-49), and 1661 lymph nodes were positive (median, 8.5; range, 1-37). The median survival was 29 months. With multivariate analysis, we found number and ratio of metastatic lymph nodes were associated with overall survival (OS) of lymph node-positive patients after curative surgery. However, we ultimately identified that ratio of metastatic lymph nodes was more appropriate to evaluate OS of lymph node-positive patients than number of metastatic lymph nodes by using the case-control matched fashion. One hundred forty-four (73.5%) patients had recurrence after curative surgery. The median disease-free time was 18 month, and the median survival after recurrence was 4 month. With multivariate analysis (logistic regression model), we found number of metastatic lymph nodes was associated with recurrence after curative surgery. CONCLUSION: Ratio and number of metastatic lymph nodes were important indicators of OS and recurrence of lymph node-positive gastric cancer patients following curative resection, respectively. PMID- 19783009 TI - Role of the Oral Glucose Tolerance Test (OGTT) in the idiopathic restless legs syndrome. AB - BACKGROUND: Restless legs syndrome (RLS) is a sensorimotor disorder characterised by a distressing urge to move the legs. Several clinical conditions have been associated with RLS, such as iron deficiency, uraemia, pregnancy, polyneuropathy and Diabetes Mellitus (DM). However the causes remain unknown in about 70-80% of cases. OBJECTIVE: To evaluate the role of glucose metabolism abnormalities in idiopathic RLS. METHODS: We enrolled 132 consecutive patients with idiopathic RLS associated with normal fasting glycaemia and 128 control subjects. We evaluated glucose and insulin levels after a 2-h oral glucose tolerance test (2h-OGTT) in patients and control subjects. In addition we determined Insulin Resistance (IR) by Homa-Index. RESULTS: After 2h-OGTT, the prevalence of glucose metabolism abnormalities was significantly higher in patients with RLS than in controls (P=.002). Impaired Glucose Tolerance (IGT) was found in 54 (41%) patients and in 23 (18%) controls, while a new-diagnosed DM (NDDM) was found in 25 (19%) patients and in 8 (6%) controls. The IR showed no significant differences between patients and controls. CONCLUSIONS: Our study suggests that IGT (prediabetes) is frequently associated with idiopathic RLS. We propose to perform a 2h-OGTT in idiopathic RLS patients with normal fasting glycaemia. PMID- 19783010 TI - Pulmonary complications after lung resection in the absence of chronic obstructive pulmonary disease: the predictive role of diffusing capacity. AB - OBJECTIVE: Diffusing capacity is not routinely used in assessing risk of lung resection, perhaps owing to uncertainty as to whether patients with normal spirometric results require additional evaluation. We determined whether diffusing capacity is predictive of pulmonary complications after lung resection in patients with normal spirometric results. METHODS: We reviewed outcomes of major lung resection in The Society of Thoracic Surgeons General Thoracic Surgery Database from 2002 to 2008 to determine the relationship of diffusing capacity (expressed as percent of predicted) to postoperative pulmonary complications stratified by chronic obstructive pulmonary disease status. RESULTS: Percent of predicted diffusing capacity was measured in 7891 (57%) patients. There were 3905 women and 3986 men with a mean age of 66.3 +/- 10.6 years who underwent lobectomy (6904; 87.5%), bilobectomy (463; 5.9%), and pneumonectomy (524; 6.6%). Chronic obstructive pulmonary disease was identified in 2711 (34.4%) patients. Pulmonary complications occurred in 13%, and the operative mortality was 1.9%. Percent of predicted diffusing capacity was strongly associated with the development of pulmonary complications (odds ratio, 1.12 per 10-point decrease; P < .0001). Decreasing percent of predicted diffusing capacity was incrementally related to an increased incidence of pulmonary complications regardless of chronic obstructive pulmonary disease status. There was no apparent interaction between percent of predicted diffusing capacity and chronic obstructive pulmonary disease status in the predictive model. CONCLUSIONS: Percent of predicted diffusing capacity predicts pulmonary complications after lung resection in patients without chronic obstructive pulmonary disease. We recommend measurement of diffusing capacity in lung resection candidates, regardless of chronic obstructive pulmonary disease, as an important element in the accurate assessment of operative risk. PMID- 19783011 TI - Balloon sizing in surgical ventricular restoration: what volume are we targeting? PMID- 19783013 TI - Use of a hybrid operating room to diagnose and treat delayed coronary spasm after mitral valve repair. PMID- 19783014 TI - Transcatheter valve-in-valve implantation for the treatment of stentless aortic valve dysfunction. PMID- 19783015 TI - Is pneumonectomy mandatory after transection of the left main pulmonary artery? PMID- 19783016 TI - [Anatomic bases of surgical approaches to the nerves of the upper limb: tips for young surgeons]. AB - Peripheral nerve surgery requires a certain level of specialization. Surgeons must have solid knowledge of morphological anatomy of the different segments to be explored, decompressed, repaired, or even neurotized. This paper describes the most common approaches to the peripheral nerves of the upper limb. PMID- 19783017 TI - [Review of the peripheral nerve]. AB - The peripheral nerve provides the pathway for motor, sensory, and vegetative axons belonging to the peripheral nervous system. It transmits information between these neurons and their peripheral effectors in both directions (sensory receptors, skeletal muscles, and viscera). The afferences to the periphery correspond to the nerve motor content, whereas efferences from the periphery, in charge of delivering information to the central integrators, correspond to nerve sensitive content. This information support depends on the intrinsic properties of the nerve itself. Peripheral nerve injuries are frequent and generate significant deficits. Their treatment sometimes leads to functional recovery but is mostly incomplete or unpredictable, despite the regular use of sophisticated repair techniques. The clinician must clearly understand the peripheral nervous system's responses to injury, which reveal surprising degenerating and spontaneous regenerating abilities. This potential recovery is a peripheral nervous system specificity and follows a relatively complex process. Peripheral neurons depend on glial cell structure and metabolism, inducing the global and dynamic response of the whole axon environment, even in cases of focal lesion, modulated by the initial type and mechanism of injury. Today's progress remains insufficient to improve functional prognosis significantly, but a better understanding of peripheral nerve regenerating processes obtained in cellular and molecular biology has opened the door to new medical and surgical advances. PMID- 19783018 TI - Isolation of a lectin and a galactoxyloglucan from Mucuna sloanei seeds. AB - A lectin and a galactoxyloglucan were characterized from Mucuna sloanei seed cotyledons. The galactoxyloglucan, isolated by water extraction and ethanol precipitation, had Glc:Xyl:Gal proportions in a molar ratio of 1.8:1.7:1.0 and a molar mass (M(w)) of 1.6x10(6)g mol(-1). The lectin (sloanin), isolated from the same seed by affinity chromatography on cross-linked Adenanthera pavonina galactomannan, gave two protein bands by SDS-PAGE (36 and 34 kDa) and one peak by gel filtration (63.6 kDa). Its N-terminal sequence indicated approximately 69% identity with soybean agglutinin to leguminous lectins. Circular dichroism (CD) spectra established that sloanin predominantly contains beta-sheet structures. Sloanin has approximately 5.5% carbohydrate and displayed hemagglutinating activity against rabbit and enzyme treated human erythrocytes, inhibited only by D-Gal containing sugars. The interaction between sloanin and storage cell-wall galactoxyloglucan was tested by affinity chromatography and fluorescence spectroscopy. PMID- 19783019 TI - Applying core principles to the design and evaluation of the 'Take Charge. Take the Test' campaign: what worked and lessons learned. AB - OBJECTIVES: To describe the application of seven core principles to the design and evaluation of a human immunodeficiency virus (HIV) testing social marketing campaign as a case study example. STUDY DESIGN: The Centers for Disease Control and Prevention (CDC) used a structured social marketing approach, informed by the Ecological Model, the Theory of Planned Behaviour and the Health Belief Model, to develop and evaluate a two-city campaign with print, radio and outdoor advertising; HIV telephone hotlines; an HIV website; community partnerships; and events to promote information seeking and HIV testing. METHODS: The CDC applied seven core principles to design and evaluate the campaign, including formative research, the use of behavioural theories, audience segmentation, message design and pretesting, channel selection, process evaluation and outcome evaluation. RESULTS: Over 200 partners in both cities contributed significantly to campaign efforts. Key informant interviews indicated that, due to increased coordination, city infrastructures for HIV testing improved. More than 9600 individuals attended campaign events in both cities, with 1492 rapid HIV tests administered and 14 newly-identified HIV individuals. Overall, event attendees responded positively to campaign materials and events, and free HIV testing opportunities. The campaign significantly increased information-seeking behaviours in the form of hotline calls and web searches. Audience reaction and receptivity to the final campaign materials was very high. Exposure to campaign messages was associated with increases in key knowledge items, intentions to get tested, and peer-to-peer communication. CONCLUSIONS: The seven core principles, including formative research, behavioural theories and extensive partnerships, acted synergistically to help a campaign reach its target audience with compelling, relevant messages and motivate them to seek information and get an HIV test. Rapid testing removes many barriers by providing a testing process that can be accessed and acted upon quickly in response to media exposure. Findings suggest that modifying the campaign in future implementations to encourage the target audience to attend and participate in rapid testing events, while expanding the number and reach of such events, may have considerable potential to measurably increase testing behaviours. PMID- 19783021 TI - Ludwik Zamenhof: a major contributor to world culture, on the 150(th) anniversary of his birth. AB - More than 200 universal languages have been proposed to replace the nearly 3,000 existing languages. Esperanto, developed by the Polish-Jewish ophthalmologist Ludwik Zamenhof in 1887, became the most widely used artificial language of the 20(th) century. It is estimated that between one million and 15 million people in the world can speak or read Esperanto. Zamenhof was nominated 14 times for the Nobel Peace Prize, and also received the French Legion of Honor, and the Medal of Isabelle of Spain the Catholic. Ludwik Zamenhof started his professional training in ophthalmology at the Jewish Hospital in Warsaw, later spent several months in Vienna, and finally started a private ophthalmology practice in Warsaw, where he remained for most of his life. His son Adam was an associate professor of ophthalmology at the University of Warsaw and head of ophthalmology in the Jewish Hospital in Czyste, the biggest and most modern hospital in Warsaw at that time. Some lesser known aspects of Zamenhof's life and work drawn from the original 19(th) century Russian and 20(th) century Esperanto documents are described. PMID- 19783022 TI - Epicorneal polypoidal lipodermoid: lack of association of central corneal lesions with goldenhar syndrome verified with a review of the literature. AB - It is remarkable to uncover a new aspect of congenital epibulbar solid dermoids and lipodermoids. We describe a dramatic central epicorneal polypoidal lipodermoid coloboma accompanied by an upper eyelid coloboma that was not associated with Goldenhar syndrome. Histopathologically the excised lesion displayed superficial layers of epidermis and a thin dermis with eccrine glands, vestigial hair structures, and bundles of arrector pili smooth muscle that extended from the undersurface of the epidermis to the bulge area of the primitive hairs. This last feature is not present in normal eyelid skin nor in the conjunctiva, and has not been previously documented to occur in epibulbar dermoids and lipodermoids. S-100-positive dendritic melanocytes and CD1a-positive Langerhans cells were both observed intraepidermally, indicating a complete complement of normal cells in this layer. Beneath the dermis was a massive collection of lobules of mature adipose tissue that fused with the corneal stroma. A virtually identical pedunculated limbal tumor has been previously reported that was associated with Goldenhar syndrome. Review of earlier published cases of epibulbar dermoids and lipodermoids establishes that central corneal lesions are not a stigma of Goldenhar syndrome, in contrast to limbal masses. Other epibulbar choristomas that can be confused with lipodermoids are described. PMID- 19783023 TI - Aqueous humor dynamics in historical perspective. AB - In antiquity the aqueous humor was seen as essential to moisten and nourish the lens- the actual organ of vision-and therefore any loss was believed to lead to blindness. The recuperation of the eye after some aqueous loss during cataract couching and experimental loss in animals slowly undermined this idea in the 16(th) and 17(th) centuries. In the 18(th) century production of aqueous from the ciliary region and its outflow from the anterior chamber, and thus its circulation, was generally accepted. Early in the 19(th) century the aqueous was thought to be encapsulated, but by the end of the century the general dynamic principles of aqueous flow as we know them today were experimentally and clinically confirmed. The controversy concerning its mode of production and circulation that took place early in the 20(th) century was resolved with the discovery of the aqueous veins and advances in molecular biology. PMID- 19783024 TI - Punta Toro virus (Bunyaviridae, Phlebovirus) infection in mice: strain differences in pathogenesis and host interferon response. AB - The Adames strain of Punta Toro virus (PTV-A, Bunyaviridae, Phlebovirus) causes an acute lethal disease in hamsters and mice. The Balliet strain of the virus (PTV-B) is generally considered to be avirulent. The difference in hamster susceptibility is likely due to the ability of PTV-A to suppress interferon (IFN) beta similarly to that described for Rift Valley fever virus. Here we investigated strain differences in PTV pathogenesis and the IFN response in mice. Although PTV-B infection in mice did not induce systemic IFN-beta release, primary macrophages produced dramatically higher levels when exposed to the virus in culture. The importance of IFN in resistance to PTV infection was borne out in studies employing STAT-1 knock-out mice. Also, a number of genes specific to IFN response pathways were upregulated in PTV-B-infected macrophages. Our findings provide new insights into the type I IFN response during PTV infection in the mouse model of phleboviral disease. PMID- 19783025 TI - Identification of a medicinal off-flavour in mineral water. AB - The aim of the present study was to identify the compounds responsible for a characteristic medicinal off-odour in mineral water. 2-Dimensional high resolution gas chromatography-mass spectrometry analysis, in combination with olfactometry (HRGC-MS/O), led to the identification of 2-iodophenol and 2-iodo-4 methylphenol as the two compounds exhibiting the medicinal odour notes in mineral water. Determination of odour thresholds of these two compounds in air and water, as well as investigation of their odour characteristics in specific structure odour activity assays, showed that 2-iodophenol and 2-iodo-4-methylphenol were both extremely potent odour substances with odour thresholds down to 0.03 and 0.0003ng/L air and 0.313 and 0.009mug/L water, respectively. The higher odour potency of 2-iodo-4-methylphenol suggests that this compound is primarily responsible for the medicinal off-odour. Furthermore, the same proportion of the panellists who were not able to detect the off-odour in mineral water exhibited drastically decreased sensibility to 2-iodo-4-methylphenol, but not to 2 iodophenol, which supports this hypothesis. PMID- 19783026 TI - Evaluating the operational utility of a Bacteroidales quantitative PCR-based MST approach in determining the source of faecal indicator organisms at a UK bathing water. AB - Microbial source tracking techniques are used in the UK to provide an evidence base to guide major expenditure decisions and/or regulatory action relating to sewage disposal. Consequently, it is imperative that the techniques used robustly index faecal indicator organisms (FIOs) that are the regulatory parameters for bathing and shellfish harvesting areas. This study reports a 'field-scale' test of microbial source tracking (MST) based on the quantitative PCR analyses of Bacteroidales 16S rRNA genetic marker sequences. The project acquired data to test the operational utility of quantitative Bacteroidales MST data, comparing it with FIO concentrations in streams, effluents and bathing waters. Overall, the data did not exhibit a consistent pattern of significant correlations between Bacteroidales MST parameters and FIOs within the different sample matrices (i.e. rivers, bathing waters and/or effluents). Consequently, there was little evidence from this study that reported concentrations and/or percentages of human and/or ruminant faecal loadings (that are based on Bacteroidales MST gene copy numbers) offer a credible evidence-base describing FIO contributions to receiving water 'non-compliance'. The study also showed (i) there was no significant attenuation of the Bacteroidales gene copy number 'signal' through the UV disinfection process; and (ii) single non-compliant samples submitted for Bacteroidales MST analysis, do not reliably characterise the balance of faecal loadings due to the high variability in the MST signal observed. At this stage in the development of the MST tool deployed, it would be imprudent to use the percentage human and/or ruminant contributions (i.e. as indicated by MST data acquired at a bathing water) as the sole or principal element in the evidence-base used to guide major expenditure decisions and/or regulatory action. PMID- 19783027 TI - Use of zero-valent iron nanoparticles in inactivating microbes. AB - Nanoscale zero-valent iron (NZVI) particles were investigated in inactivating gram-positive Bacillus subtilis var. niger and gram-negative Pseudomonas fluorescens bacteria, and the fungus Aspergillus versicolor. NZVI particles were synthesized using NaBH(4) and Fe(NO(3))(3).9H(2)O, and the microbial suspensions were subjected to the treatments of NZVI particle suspensions with concentrations of 0.1, 1 and 10mg/ml for 5min. Field emission scanning electron microscope (FE SEM) was used to characterize the synthesized NZVI particles, suspensions and the surface morphologies of the treated agents. FE-SEM images showed that the NZVI particles were spherical with a fairly uniform size of about 20-30nm, and the iron precipitates FeO(OH) appeared in needle-shape aggregates. When treated directly with NZVI particles under aerobic condition, the surfaces of microbes were quickly coated with needle-shape yellow-brown iron oxides. In this study, complete inactivation was achieved both for B. subtilis var. niger and P. fluorescens when treated with 10mg/ml NZVI particles with vigorous shaking under aerobic condition. When NZVI particle concentration decreased to 1, 0.1mg/ml, there was still a complete inactivation for P. fluorescens, while for B. subtilis var. niger the inactivation decreased to 95%, 80%, respectively. However, no inactivation was observed for the fungus A. versicolor when treated the same manner. Physical coating, disruption of membrane and generation of reactive oxygen species have played major roles in the inactivation observed. PMID- 19783028 TI - Previously uncultured beta-Proteobacteria dominate in biologically active granular activated carbon (BAC) filters. AB - Bacteria colonizing BAC filters used in drinking water purification from lake water were characterized by morphology, physiological tests, whole cell protein profiles and PLFA (phospholipid fatty acid) composition, and identified by partial 16S rRNA gene sequencing. Epifluorescence revealed prothecate bacteria to dominate in BAC. The majority of the isolates belonged to order Burkholderiales of beta-Proteobacteria, a few to Comamonadaceae but the majority to an undescribed family and the related sequences belonged mainly to uncultured bacteria. Among the less common alpha-Proteobacteria the genus Sphingomonas and the genera Afipia, Bosea or Bradyrhizobium of the Bradyrhizobiaceae family were detected. The majority of cultured bacteria persisting in the BAC biofilter were Burkholderiales, which according to ecological information are efficient in the mineralisation of dissolved organic matter in BAC. The biotechnical potential of the previously uncultured dominant bacteria warrants to be further studied. PMID- 19783029 TI - Kinematic parameters inferred from enamel microstructure: new insights into the diet of Australopithecus anamensis. AB - The dietary adaptations of Australopithecus anamensis are contentious, with suggestions that range from soft fruits to hard, brittle, tough, and abrasive foods. It is unlikely that all propositions are equally valid, however. Here we extend recent finite element (FE) analyses of enamel microstructure (Shimizu and Macho, 2008) to enquire about the range of loading directions (i.e., kinematics) to which A. anamensis enamel microstructure/molars could safely be subjected. The rationale underlying this study is the observation that hard brittle foods are broken down in crush, while tough foods require shear. The findings are compared with those of Pan and Gorilla. Eighteen detailed FE models of enamel microstructure were created and analysed. The results highlight the uniqueness of A. anamensis dental structure and imply that mastication in this species included a greater shear component than in Pan, as well as a wider range of loading directions; it is similar to that in Gorilla in this respect. These findings are in accord with microwear studies (Grine et al., 2006a). Unlike either of the great apes, however, enamel microstructure of A. anamensis was found to be poorly equipped to withstand loading parallel to the dentino-enamel junction; such loading regimes are associated with mastication of soft fleshy fruits. This, together with broader morphological considerations, raises doubts as to whether A. anamensis was essentially a frugivore that expanded its dietary niche as a result of fluctuations in environmental conditions, e.g., during seasonal food shortages. Instead, it is more parsimonious to conclude that the habitual diet of A. anamensis differed considerably from that of either of the extant African great apes. PMID- 19783030 TI - Biokinetics of Hg and Pb accumulation in the encapsulated egg of the common cuttlefish Sepia officinalis: radiotracer experiments. AB - Uptake and depuration kinetics of dissolved (203)Hg and (210)Pb were determined during the entire embryonic development of the eggs of the cuttlefish, Sepia officinalis (50d at 17 degrees C). (203)Hg and (210)Pb were accumulated continuously by the eggs all along the development time reaching load/concentration ratio (LCR) of 467+/-43 and 1301+/-126g, respectively. During the first month, most of the (203)Hg and (210)Pb remained associated with the eggshell indicating that the latter acted as an efficient shield against metal penetration. From this time onwards, (203)Hg accumulated in the embryo, indicating that it passed through the eggshell, whereas (210)Pb did not cross the chorion during the whole exposure time. It also demonstrated that translocation of Hg associated with the inner layers of the eggshell is a significant source of exposure for the embryo. This study highlighted that the maturing embryo could be subjected to the toxic effects of Hg in the coastal waters where the embryonic development is taking place. PMID- 19783031 TI - The effectiveness of conventional trickling filter treatment plants at reducing concentrations of copper in wastewaters. AB - Eight different sewage treatment works were sampled in the North West of England. The effectiveness of the conventional treatment processes (primary sedimentation and biological trickling filters) as well as various tertiary treatment units in terms of both total and dissolved copper removal was evaluated. The removal of total copper across primary sedimentation averaged 53% and were relatively consistent at all sites, however, at three sites the removal of dissolved copper also occurred at this stage of treatment. Removal of total copper by the biological trickling filters averaged 49%, however, substantial dissolution of copper occurred at two sites, which highlighted the unpredictability of this treatment process in the removal of dissolved copper. Copper removal during tertiary treatment varied considerably even for the same treatment processes installed at different sites, primarily due to the variability of insoluble copper removal, with little effect on copper in the dissolved form being observed. The proportion of dissolved copper increased significantly during treatment, from an average of 22% in crude sewages to 55% in the final effluents. There may be the potential to optimise existing, conventional treatment processes (primary or biological treatment) to enhance dissolved copper removal, possibly reducing the requirement for installing any tertiary processes specifically for the removal of copper. PMID- 19783032 TI - Effect of oxytocin and flunixin meglumine on uterine response to insemination in mares. AB - The most probable reason for persistent postbreeding endometritis in mares is weak myometrial contractility. The influence of oxytocin (OT; an ecbolic agent) and flunixin meglumine (FLU; a prostaglandin inhibitor serving as a model for mares with decreased uterine contractility) on uterine response to artificial insemination (AI) was studied in mares with no history of reproductive failure. The mares were treated intravenously with 10 mL saline (Group C, n=10) or 0.01 IU/kg OT (Group OT, n=10) 2, 4, 8, and 25 h after AI. Group FLU (n=11) was treated with 1.1mg/kg FLU 2h after AI and with saline thereafter. The mares received the same treatments in the first and third cycles but were sampled either at 8 or 25 h. The amount of intrauterine fluid (IUF) and edema and the number of uterine contractions were recorded before AI and 10 min after the treatments using transrectal ultrasonography. At 8h after AI, the mares were treated with human chorionic gonadotropin, and, after 8-h or 25-h scans, a 500-mL uterine lavage and a biopsy were performed. Ovulation was confirmed at 48 h and pregnancy 14 to 17 d after AI. No manipulations were done during the second estrus. At 8h after AI, Group FLU had more polymorphonuclear leukocytes (PMNs) in the uterine lavage fluid than did Group OT (P<0.05), but uterine contractions did not differ significantly. At 25 h, the PMN concentrations were low in all groups. Group OT rarely showed IUF. The uterine biopsy specimens of Group FLU showed less inflammation of the stroma but more PMNs in the uterine lumen 8h after AI than that of the control group (P<0.05). The pregnancy rates did not differ between the groups (63% C, 53% OT, and 50% FLU). Oxytocin rapidly and effectively removed IUF and PMNs after AI and thereby shortened the duration of postbreeding inflammation. PMID- 19783033 TI - Tritrichomonas fetus extracellular products decrease progressive motility of bull sperm. AB - Tritrichomonas fetus causes infertility and abortion in cattle; however, there is scarce information regarding the susceptibility of bovine sperm to this parasite. The objective of this study was to analyze in vitro the interaction between T. fetus and bovine sperm and to evaluate the effect of extracellular products secreted by the parasite on these reproductive cells. Sperm from five fertile bulls (Bos taurus taurus, Holstein-Friesian), selected through a Percoll gradient, adhered to T. fetus after 30min of interaction, resulting in agglutination between the two kinds of cells. Based on reverse transcription polymerase chain reaction (RT-PCR), T. fetus continuously expressed its gene for cysteine peptidase in the presence or absence of sperm. Computer-assisted semen analysis (CASA) revealed that, after 1h incubation of sperm in T. fetus culture extract, the extracellular products secreted by the parasite decreased sperm progressive motility (P<0.05). Although T. fetus extracellular products did not lead to loss of sperm viability (P<0.05) based on the Annexin-V/propidium iodide assay, the percentage of Annexin-V fluorescein isothiocyanate-positive and propidium iodide-positive cells increased (P<0.05) during incubation of sperm in T. fetus culture extract, consistent with cellular damage. In conclusion, extracellular products secreted by T. fetus were cytotoxic to bovine sperm, as they decreased sperm progressive motility; perhaps this contributes to the pathogenesis of T. fetus-induced infertility. PMID- 19783034 TI - Modulating cellular adhesion through nanotopography. AB - Cellular adhesion is a fundamental process in the development of scaffolds for tissue engineering; in the design of biosensors and in preparing antibacterial substrates. A theoretical model is presented for predicting the strength of cellular adhesion to originally inert surfaces as a function of the substrate topography, accounting for both specific (ligand-receptor) and non-specific interfacial interactions. Three regimes have been identified depending on the surface energy (gamma) of the substrate: for small gamma, any increase in roughness is detrimental to adhesion; for large gamma, an optimal roughness exists that maximizes adhesion; and for intermediate gamma, surface roughness has a minor effect on adhesion. The results presented are in qualitative agreement with several experimental observations and can capture the long-term equilibrium configuration of the system. The model proposed supports the notion for rationally designing substrates where topography and physico-chemical properties are tailored to favour cellular proliferation whilst repelling bacterial adhesion. PMID- 19783035 TI - The nanofibrous architecture of poly(L-lactic acid)-based functional copolymers. AB - It remains a challenge to synthesize functional materials that can develop advanced scaffolding architectures for tissue engineering. In this study, a series of biodegradable amphiphilic poly(hydroxyalkyl (meth)acrylate)-graft poly(l-lactic acid) (PHAA-g-PLLA) copolymers have been synthesized and fabricated into nano-fibrous scaffolds. These copolymers can be further functionalized, are more hydrophilic, and have faster degradation rates than the PLLA homopolymer, which are advantageous for certain tissue engineering applications. First, PLLA based macromonomers were prepared by using functional hydroxyalkyl (meth)acrylates (HAA) as initiators. The PHAA-g-PLLA copolymers were then synthesized using free radical copolymerization of PLLA-based macromonomers and HAA. Nano-fibrous architecture was created using a thermally induced phase separation technique from these functional PHAA-g-PLLA copolymers. The nano fibrous structure mimics the architecture of natural collagen matrix at the nanometer scale. The effects of the macromonomer composition, copolymer composition, blending ratio, and solvent selection on nano-scale structures were studied. In general, the nano-fibrous structure was created when the amount of HAA in the macromonomer was low. By increasing the amount of HAA in the macromonomer, microspheres with nano-fibrous surfaces were obtained. Further increasing the amount of HAA led to the creation of microspheres with leaf-like surfaces. These PLLA-based materials had much faster degradation rates than the PLLA, and could be completely degraded from several weeks to a few months depending on their composition and molecular weight. Furthermore, the PHAA-g-PLLA copolymers possess functional hydroxyl groups, which can be used to couple with bioactive molecules to control cell-material interactions. Therefore, these biodegradable functional copolymers have the design flexibility to fabricate various biomimetic materials for tissue engineering applications. PMID- 19783036 TI - Gelatin-fibrinogen cryogel dermal matrices for wound repair: preparation, optimisation and in vitro study. AB - Macroporous sponge-like gelatin-fibrinogen (Gl-Fg) scaffolds cross-linked with different concentrations (0.05-0.5%) of glutaraldehyde (GA) were produced using cryogelation technology, which allows for the preparation of highly porous scaffolds without compromising their mechanical properties, and is a more cost efficient process than freeze-drying. The produced Gl-Fg-GA(X) scaffolds had a uniform interconnected open porous structure with a porosity of up to 90-92% and a pore size distribution of 10-120 microm. All of the obtained cryogels were elastic and mechanically stable, except for the Gl-Fg-GA(0.05) scaffolds. Swelling kinetics and degradation rate, but not the porous structure of the cryogels, were strongly dependent on the degree of cross-linking. A ten-fold increase in the degree of cross-linking resulted in an almost 80-fold decrease in the rate of degradation in a solution of protease. Cryogels were seeded with primary dermal fibroblasts and the densities observed on the surface, plus the expression levels of collagen types I and III observed 5 days post-seeding, were similar to those observed on a control dermal substitute material, Integra. Fibroblast proliferation and migration within the scaffolds were relative to the GA content. Glucose consumption rate was 3-fold higher on Gl-Fg-GA(0.1) than on Gl-Fg-GA(0.5) cryogels 10 days post-seeding. An enhanced cell motility on cryogels with reducing GA crosslinking was obtained after long time culture. Particularly marked cell infiltration was seen in gels using 0.1% GA as a crosslinker. The scaffold started to disintegrate after 42 days of in vitro culturing. The described in vitro studies demonstrated good potential of Gl-Fg GA(0.1) scaffolds as matrices for wound healing. PMID- 19783037 TI - Self-assembled hyaluronic acid nanoparticles for active tumor targeting. AB - Hyaluronic acid nanoparticles (HA-NPs), which are formed by the self-assembly of hydrophobically modified HA derivatives, were prepared to investigate their physicochemical characteristics and fates in tumor-bearing mice after systemic administration. The particle sizes of HA-NPs were controlled in the range of 237 424 nm by varying the degree of substitution of the hydrophobic moiety. When SCC7 cancer cells over-expressing CD44 (the receptor for HA) were treated with fluorescently labeled Cy5.5-HA-NPs, strong fluorescence signals were observed in the cytosol of these cells, suggesting efficient intracellular uptake of HA-NPs by receptor-mediated endocytosis. In contrast, no significant fluorescence signals were observed when Cy5.5-labeled HA-NPs were incubated with normal fibroblast cells (CV-1) or with excess free-HA treated SCC7 cells. Following systemic administration of Cy5.5-labeled HA-NPs with different particle sizes into a tumor-bearing mouse, their biodistribution was monitored as a function of time using a non-invasive near-infrared fluorescence imaging system. Irrespective of the particle size, significant amounts of HA-NPs circulated for two days in the bloodstream and were selectively accumulated into the tumor site. The smaller HA-NPs were able to reach the tumor site more effectively than larger HA-NPs. Interestingly, the concentration of HA-NPs in the tumor site was dramatically reduced when mice were pretreated with an excess of free-HA. These results imply that HA-NPs can accumulate into the tumor site by a combination of passive and active targeting mechanisms. PMID- 19783038 TI - Osteoblastic differentiation of human mesenchymal stem cells with platelet lysate. AB - Culture of expanded mesenchymal stem cells (MSCs) seeded on biomaterials may represent a clinical alternative to autologous bone graft in bone regeneration. Foetal bovine serum (FBS) is currently used for MSC expansion, despite risks of infectious disease transmission and immunological reaction due to its xenogenic origin. This study aimed to compare the osteogenic capacities of clinical-grade human MSCs cultured with FBS or allogenic human platelet lysate (PL). In vitro, MSCs cultured in PL both accelerate the expansion rate over serial passages and spontaneously induce osteoblastic gene expression such as alkaline phosphatase (ALP), bone sialoprotein (BSP), osteopontin (Op) and bone morphogenetic protein-2 (BMP-2). In vivo, ectopic bone formation is only observed on ceramics seeded with MSCs grown in PL medium implanted under the skin of immunodeficient mice for 7 weeks. In conclusion, allogenic human PL accelerates MSC proliferation and enhances MSC osteogenic differentiation. PMID- 19783039 TI - Inhibition of beta 1-40 amyloid fibrillation with N-acetyl-L-cysteine capped quantum dots. AB - One of the primary factors that induce Alzheimer's disease (AD) is the deposition of beta-amyloid (Abeta). The Abeta molecules can self-assemble to form neurotoxic aggregates with various morphologies, such as dimers, oligomers, protofibrils and fibrils. For this aspect, we demonstrated that the amyloid fibrillation can be inhibited by quenching the nucleation and elongation processes with a low concentration of water dispersed N-acetyl-L-cysteine capped quantum dots (NAC QDs). Based on the concentration dependence of NAC-QDs on the seeded fibril growth, there is a remarkable inhibition effect when the NAC-QDs concentration is increased by 100-fold from 10(-9) to 10(-7) M. The NAC-QDs concentration required to show inhibition effect is much lower than that of the amyloid peptide concentration (50 microM). The step-like change suggests that the inhibition effect of NAC-QDs displays a threshold response. The inhibition is likely due to the intermolecular attractive interactions such as the hydrogen bonding between NAC-QDs and amyloid fibrils resulting in the blockage of the active elongation sites on the fibrils. PMID- 19783040 TI - Folic acid conjugated nanoparticles of mixed lipid monolayer shell and biodegradable polymer core for targeted delivery of Docetaxel. AB - A system of nanoparticles of mixed lipid monolayer shell and biodegradable polymer core was developed for targeted delivery of anticancer drugs with Docetaxel as a model drug, which provide targeting versatility with a quantitative control of the targeting effect by adjusting the lipid component ratio of the mixed lipid monolayer, and combine the advantages and avoid disadvantages of polymeric nanoparticles and liposomes in drug delivery. X-ray photoelectron spectroscopy (XPS) confirmed the coating of the mixed lipid monolayer on the polymeric core. Fluorescent microscopy proved the targeting efficacy of the folic acid conjugated on the mixed lipid monolayer for the cancer cells of over expression of folate receptors. The folic acid conjugated nanoparticles of mixed lipid monolayer shell and biodegradable polymer core were proved to possess sustainable, controlled and targeted delivery of anticancer drugs with Docetaxel as a model drug, which may provide a drug delivery system of precise control of the targeting effect. PMID- 19783041 TI - Biodegradable nanoparticles modified by branched polyethylenimine for plasmid DNA delivery. AB - The main objective of this work is to build a comparative account of two PLGA nanoparticle (NP)-based gene delivery systems namely, plasmid DNA (pDNA) encapsulated PLGA NPs (PLGA-E) and surface adsorbed pDNA on PLGA-BPEI NPs (PLGA BPEI), with respect to the extent of internalization and intracellular release of pDNA. Several formulations have also been evaluated systematically for determination of the optimal transfection efficiency. The zeta-potential, particle size measurements and DNase I protection assay established the importance of the BPEI chain length in regulating the effective loading and condensation of pDNA with PLGA-BPEI NPs and pDNA protection ability of PLGA-BPEI NPs. The colloidal stability of these formulations was also investigated as a function of serum concentration. The in vitro release of pDNA from both kind of formulations was studied at pH 7.4 and pH 5.0 by comparing the kinetics of pH triggered release of pDNA from PLGA-BPEI-25K(5) and PLGA-E. In vitro time dependent gene transfection efficiencies were studied in presence as well as in absence of serum for NIH3T3 and HEK293 cells. The cell viability and intracellular localization were also investigated using MTT assay and confocal microscopy study, respectively. PMID- 19783042 TI - Myoblast morphology and organization on biochemically micro-patterned hydrogel coatings under cyclic mechanical strain. AB - Mechanical forces and geometric constraints play critical roles in determining cell functionality and tissue development. Novel experimental methods are essential to explore the underlying biological mechanisms of cell response. We present a versatile method to culture cells on adhesive micro-patterned substrates while applying long-term cyclic tensile strain (CTS). A polydimethysiloxane (PDMS) mold is coated with a cell repulsive NCO-sP(EO-stat PO) hydrogel which in turn is covalently patterned by fibronectin using micro contact printing. This results in two-dimensional, highly selective cell-adhesive micro-patterns. The substrates allow application of CTS to adherent cells for more than 4 days under cell culture conditions without unspecific adhesion. The applicability of our system is demonstrated by studying the adaptive response of C2C12 skeletal myoblasts seeded on fibronectin lines with different orientations relative to the strain direction. After application of CTS (amplitude of 7%, frequency of 0.5 Hz) we find that actin fiber organization is dominantly controlled by CTS. Nuclei shape is predominantly affected by the constraint of the adhesive lines, resulting in significant elongation. Morphologically, myotube formation was incomplete after 4 days of culture, but actin striations were observed exclusively on the 45 degrees line patterns subjected to CTS, the direction of maximum shear strain. PMID- 19783043 TI - Thermosensitive injectable hyaluronic acid hydrogel for adipose tissue engineering. AB - A series of thermosensitive copolymer hydrogels, aminated hyaluronic acid-g poly(N-isopropylacrylamide) (AHA-g-PNIPAAm), were synthesized by coupling carboxylic end-capped PNIPAAm (PNIPAAm-COOH) to AHA through amide bond linkages. AHA was prepared by grafting adipic dihydrazide to the HA backbone and PNIPAAm COOH copolymer was synthesized via a facile thermo-radical polymerization technique by polymerization of NIPAAm using 4,4'-azobis(4-cyanovaleric acid) as an initiator, respectively. The structure of AHA and AHA-g-PNIPAAm copolymer was determined by (1)H NMR. Two AHA-g-PNIPAAm copolymers with different weight ratios of PNIPAAm on the applicability of injectable hydrogels were characterized. The lower critical solution temperature (LCST) of AHA-g-PNIPAAm copolymers in PBS were measured as approximately 30 degrees C by rheological analysis, regardless of the grafting degrees. Enzymatic resistance of AHA-g-PNIPAAm hydrogels with 28% and 53% of PNIPAAm in 100U/mL hyaluronidase/PBS at 37 degrees C was 12.3% and 37.6% over 28 days, respectively. Equilibrium swelling ratios of AHA-g-PNIPAAm hydrogels with 28% of PNIPAAm were 21.5, and significantly decreased to 13.3 with 53% of PNIPAAm in PBS at 37 degrees C. Results from SEM observations confirm a porous 3D AHA-g-PNIPAAm hydrogel structure with interconnected pores after freeze drying and the pore diameter depends on the weight ratios of PNIPAAm. Encapsulation of human adipose-derived stem cells (ASCs) within hydrogels showed the AHA-g-PNIPAAm copolymers were noncytotoxic and preserved the viability of the entrapped cells. A preliminary in vivo study demonstrated the usefulness of the AHA-g-PNIPAAm copolymer as an injectable hydrogel for adipose tissue engineering. This newly described thermoresponsive AHA-g-PNIPAAm copolymer demonstrated attractive properties to serve as cell or pharmaceutical delivery vehicles for a variety of tissue engineering applications. PMID- 19783044 TI - In vitro performance of an injectable hydrogel/microsphere based immunocyte delivery system for localised anti-tumour activity. AB - The current practice of cell immunotherapy against cancer has encountered a substantial challenge, that is, targeted delivery of therapeutic cells to tumour sites is not favourably managed. In this study, we aimed to provide an engineering solution to govern the cell targeting and actions, for which a biomaterial model is developed to mediate the conveyance and accommodation of activated immunocytes with anti-cancer potentials. We fabricated a dual-layered hydrogel/microsphere (GS) composite, which preserves all advantageous features of hydrogel such as injectability and favourable permeability, to achieve genuine localisation and physical immobilisation of the executing immunocytes macrophages. According to our presented in vitro investigations, the GS immunoconstruct exhibited effective elimination of carcinoma cells as well as high safety free of gene alteration or cell leakage. Notably, unwanted long-term proliferation of the delivered cells was restrained by physical encapsulation in the bio-inert 3D hydrogel frameworks. By these efforts, we have provided an immunocyte delivery platform with which cell-based immunotherapy can be initiated at a desired location and implemented in a controlled manner. PMID- 19783045 TI - Bestrophin and TMEM16-Ca(2+) activated Cl(-) channels with different functions. AB - In the past, a number of candidates have been proposed to form Ca(2+) activated Cl(-) currents, but it is only recently that two families of proteins, the bestrophins and the TMEM16-proteins, recapitulate reliably the properties of Ca(2+) activated Cl(-) currents. Bestrophin 1 is strongly expressed in the retinal pigment epithelium, but also at lower levels in other cell types. Bestrophin 1 may form Ca(2+) activated chloride channels and, at the same time, affect intracellular Ca(2+) signaling. In epithelial cells, bestrophin 1 probably controls receptor mediated Ca(2+) signaling. It may do so by facilitating Ca(2+) release from the endoplasmic reticulum, thereby indirectly activating membrane localized Ca(2+)-dependent Cl(-) channels. In contrast to bestrophin 1, the Ca(2+) activated Cl(-) channel TMEM16A (anoctamin 1, ANO1) shows most of the biophysical and pharmacological properties that have been attributed to Ca(2+) dependent Cl(-) channels in various tissues. TMEM16A is broadly expressed in both mouse and human tissues and is of particular importance in epithelial cells. Thus exocrine gland secretion as well as electrolyte transport by both respiratory and intestinal epithelia requires TMEM16A. Because of its role for Ca(2+)-dependent Cl(-) secretion in human airways, it is likely to become a prime target for the therapy of cystic fibrosis lung disease, caused by defective cAMP-dependent Cl(-) secretion. It will be very exciting to learn, how TMEM16A and other TMEM16 proteins are activated upon increase in intracellular Ca(2+), and whether the other nine members of the TMEM16 family also form Cl(-) channels with properties similar to TMEM16A. PMID- 19783046 TI - Structural and biophysical determinants of single Ca(V)3.1 and Ca(V)3.2 T-type calcium channel inhibition by N(2)O. AB - We investigated the biophysical mechanism of inhibition of recombinant T-type calcium channels Ca(V)3.1 and Ca(V)3.2 by nitrous oxide (N(2)O). To identify functionally important channel structures, chimeras with reciprocal exchange of the N-terminal domains I and II and C-terminal domains III and IV were examined. In whole-cell recordings N(2)O significantly inhibited Ca(V)3.2, and - less pronounced - Ca(V)3.1. A Ca(V)3.2-prevalent inhibition of peak currents was also detected in cell-attached multi-channel patches. In cell-attached patches containing < or = 3 channels N(2)O reduced average peak current of Ca(V)3.2 by decreasing open probability and open time duration. Effects on Ca(V)3.1 were smaller and mediated by a reduced fraction of sweeps containing channel activity. Without drug, single Ca(V)3.1 channels were significantly less active than Ca(V)3.2. Chimeras revealed that domains III and IV control basal gating properties. Domains I and II, in particular a histidine residue within Ca(V)3.2 (H191), are responsible for the subtype-prevalent N(2)O inhibition. Our study demonstrates the biophysical (open times, open probability) and structural (domains I and II) basis of action of N(2)O on Ca(V)3.2. Such a fingerprint of single channels can help identifying the molecular nature of native channels. This is exemplified by a characterization of single channels expressed in human hMTC cells as functional homologues of recombinant Ca(V)3.1. PMID- 19783047 TI - Right and left shifts for age in MDS. PMID- 19783048 TI - Toxicity of hexachloronaphthalene (HxCN) and induction of CYP 1A in rats. AB - The aim of the study was to investigate the toxicity of hexachloronaphthalene (HxCN) and its effect on cytochrome P-450 in rats and to make a comparison between HxCN and tetrachloronaphthalene (TeCN), an inactive congener. Our study provided evidence that the anorectic effect, with concurrent significant increase in relative liver mass was the most spectacular symptom of the toxic effect of hexachloronaphthalene in the rats after its single (250mg/kg) and repeated (1 and 10mg/kg) administration. Regardless of the kind of the experiment (acute or subacute toxicity), dose-dependent increase in lipid peroxidation in the liver was also observed, which may indicate that HxCN most probably generates oxidative stress in this organ. It was also observed that HxCN is a very strong inducer of cytochrome P-450, especially of CYP 1A, which is the most sensitive biomarker of exposure to this congener. In this study, LOAEL is 1mg HxCN/kgb.w. PMID- 19783049 TI - I. Effects of a dopamine receptor antagonist on fathead minnow, Pimephales promelas, reproduction. AB - Neurotransmitters such as dopamine play an important role in regulating fish reproduction. However, the potential for neuroendocrine active chemicals to disrupt fish reproduction has not been well studied, despite emerging evidence of their discharge into aquatic environments. This study is the first to apply the fathead minnow 21 d reproduction assay developed for the US Endocrine Disruptor Screening Program to evaluate the reproductive toxicity of a model neuroendocrine active chemical, the dopamine 2 receptor antagonist, haloperidol. Continuous exposure to up to 20 imcrog haloperidol/L had no significant effects on fathead minnow fecundity, secondary sex characteristics, gonad histology, or plasma steroid and vitellogenin concentrations. The only significant effect observed was an increase in gonadotropin-releasing hormone (cGnRH) transcripts in the male brain. Results suggest that non-lethal concentrations of haloperidol do not directly impair fish reproduction. Potential effects of haloperidol on reproductive behaviors and gene expression were examined in a companion study. PMID- 19783050 TI - Re-shaping models of E. coli population dynamics in livestock faeces: increased bacterial risk to humans? AB - Dung-pats excreted directly on pasture from grazing animals can contribute a significant burden of faecal microbes to agricultural land. The aim of this study was to use a combined field and modelling approach to determine the importance of Escherichia coli growth in dung-pats when predicting faecal bacteria accumulation on grazed grassland. To do this an empirical model was developed to predict the dynamics of an E. coli reservoir within 1ha plots each grazed by four beef steers for six months. Published first-order die-off coefficients were used within the model to describe the expected decline of E. coli in dung-pats. Modelled estimates using first-order kinetics led to an underestimation of the observed E. coli land reservoir, when using site-specific die-off coefficients. A simultaneous experiment determined the die-off profiles of E. coli within fresh faeces of beef cattle under field relevant conditions and suggested that faecal bacteria may experience growth and re-growth in the period post defecation when exposed to a complex interaction of environmental drivers such as variable temperature, UV radiation and moisture levels. This growth phase in dung-pats is not accounted for in models based on first-order die-off coefficients. When the model was amended to incorporate the growth of E. coli, equivalent to that observed in the field study, the prediction of the E. coli reservoir was improved with respect to the observed data and produced a previously unquantified step change improvement in model predictions of the accumulation of these faecal bacteria on grasslands. Results from this study suggest that the use of first order kinetic equations for determining land-based reservoirs of faecal bacteria should be approached with caution and greater emphasis placed on accounting for actual survival patterns observed under field relevant conditions. PMID- 19783051 TI - Role of early lectin pathway activation in the complement-mediated killing of Trypanosoma cruzi. AB - The complement system is the first line of defence against pathogen infection and can be activated by the classic, alternative and lectin pathways. Trypanosoma cruzi, the causative agent of Chagas disease, has to evade complement system killing and invade the host cells to progress in infection. T. cruzi infectious stages resist complement-mediated killing by expressing surface receptors, which dissociate or prevent C3 convertase formation. Here, we present the first evidence that T. cruzi activates the complement lectin pathway. We detected rapid binding of mannan-binding lectin, H-ficolin, and L-ficolin to the surface of T. cruzi, and found that serum depleted of these molecules failed to kill parasites. Furthermore, lectin pathway activation by T. cruzi required the MBL-associated serine protease 2 (MASP2) activity resulting in C2 factor cleavage. In addition, we demonstrate that the infectious stage of T. cruzi inhibits the lectin pathway activation and complement killing expressing the complement C2 receptor inhibitor trispanning (CRIT) protein. Transgenic parasites overexpressing CRIT were highly resistant to complement-mediated killing. CRIT-derived peptides inhibited both C2 binding to the surface of T. cruzi and parasite killing. Biochemical studies revealed that the CRIT extracellular domain 1 inhibits MASP2 cleavage of C2 factor and thereby impairs C3 convertase formation. Our findings establish that the complement lectin pathway recognizes T. cruzi and provide molecular insights into how the infectious stage inhibits this activation to resist complement system killing. PMID- 19783052 TI - Beta-arrestin 2 is required for complement C1q expression in macrophages and constrains factor-independent survival. AB - The beta-arrestins (ARRB1 and ARRB2) regulate G-protein coupled receptor (GPCR) dependent- and independent-signaling pathways and are ubiquitously expressed. Here we show that ARRB2 mRNA and protein expression is enriched in macrophages, and that it regulates complement C1q expression and cell survival. Basal and Toll like receptor (TLR) inducible expression of mRNAs encoding the complement subcomponents C1qa, C1qb and C1qc was greatly reduced in bone marrow-derived macrophages (BMM) from ARRB2-deficient, but not ARRB1-deficient mice, while factor-independent survival of ARRB2(-/-) BMM was enhanced compared to wildtype BMM. TatARRB2(23), a cell-permeable peptide that contains the MAPK JNK-binding motif from within the ARRB2 C-domain, impaired ARRB2 interaction with JNK3, down regulated C1q expression and permitted factor-independent survival in BMM, thus suggesting that this peptide antagonises ARRB2 function in macrophages. In addition, TatARRB2(23) transiently activated the phosphorylation of JNK and ERK, but not p38 in BMM. These data imply that ARRB2 acts to limit JNK/ERK activation and survival in macrophages, but is required for basal and TLR-inducible complement C1q expression. Given that loss of C1q function is strongly associated with the development of systemic lupus erythematosus, ARRB2 may act to limit the development of autoimmune disease. PMID- 19783053 TI - Nickel-quinolones interaction. Part 1 - Nickel(II) complexes with the antibacterial drug sparfloxacin: structure and biological properties. AB - The mononuclear nickel(II) complexes with the third-generation quinolone antibacterial agent sparfloxacin in the absence or presence of nitrogen donor heterocyclic ligands (1,10-phenanthroline or 2,2'-bipyridine) have been synthesized and characterized. The experimental data suggest that sparfloxacin acts as deprotonated bidentate ligand coordinated to Ni(II) ion through the ketone and carboxylato oxygens. The crystal structure of (1,10 phenanthroline)bis(sparfloxacinato) nickel(II), 2 has been determined by X-ray crystallography. The cyclic voltammograms of the complexes recorded in dmso solution and in 1/2 dmso/buffer (containing 150 mM NaCl and 15 mM trisodium citrate at pH 7.0) solution have shown that in the presence of CT DNA they can bind to CT DNA by the intercalative binding mode. UV study of the interaction of the complexes with calf-thymus DNA (CT DNA) has shown that the complexes can bind to CT DNA and 2 exhibits the highest binding constant to CT DNA. Competitive study with ethidium bromide (EB) has shown that the complexes can displace the DNA-bound EB indicating that they bind to DNA in strong competition with EB for the intercalative binding site. The antimicrobial activity of the complexes has been tested on three different microorganisms and has revealed that the inhibition provided by the complexes is slightly decreased in comparison to free sparfloxacin. The complexes exhibit good binding propensity to human and bovine serum albumin proteins having relatively high binding constant values. PMID- 19783054 TI - Psychiatric reactions to isotretinoin in patients with bipolar disorder. AB - BACKGROUND: Isotretinoin (Accutane(R)) has been available for the treatment of severe cystic acne for about twenty-five years. There have been several reports of adverse psychiatric reactions to isotretinoin, including depressive symptoms and suicide. However, there have been only three case reports of patients with bipolar disorder (BD) who experienced an untoward psychiatric side effect while receiving isotretinoin treatment. In this study, the psychiatric side effects from isotretinoin were assessed in a larger group of BD patients than has previously been reported. METHODS: A retrospective chart review of 300 BD outpatients identified ten patients treated with isotretinoin. RESULTS: Nine of these ten patients experienced a significant worsening of mood symptoms, and three developed suicidal ideation. Eight experienced a reversal of the relapsed mood symptoms when the isotretinoin was discontinued, whether prematurely or after a full course. LIMITATIONS: The limitations of this study include small sample size, retrospective data collection, absence of double-blind controlled design, and inability to control for spontaneous mood episodes in patients with BD. CONCLUSIONS: These results indicate that BD patients treated with isotretinoin for acne are at risk for clinically significant exacerbation of mood symptoms, including suicidal ideation, even with concurrent use of psychiatric medicines for BD. The clinical implications of this study are especially relevant to the treatment of patients with BD because acne usually occurs during adolescence, which is often the age of onset of BD and because a common side effect of lithium (a standard treatment for BD) is acne. PMID- 19783055 TI - Responses of white sucker (Catostomus commersoni) to 20 years of process and waste treatment changes at a bleached kraft pulp mill, and to mill shutdown. AB - The impacts of pulp mill effluents on white sucker (Catostomus commersoni) have been studied at Jackfish Bay, ON, Canada since the late 1980s. The site receives effluent from a large bleached kraft pulp mill which is the only source of chemical contamination in the area. Many laboratory studies have looked at the toxicological consequences of pulping process changes, but the benefit of these changes have not been looked at in wild fish. Jackfish Bay white sucker showed impacts on sexual maturity, gonad size, secondary sexual characteristics and circulating steroids hormone levels in the early years of the studies, and impacts were evaluated after installation of secondary treatment (1989), major pulping process changes (1995) and after the mill ceased pulp production and effluent release (2006). The addition of secondary treatment resulted in minor improvements in wild fish health, and the conversion to elemental chlorine free (ECF) bleaching at the mill was associated with more recovery in liver and gonad size. While some impacts persist at the exposure site, reproductive parameters showed further improvement during the mill shutdown period demonstrating that biologically active chemicals are still being discharged from modernized mills. PMID- 19783056 TI - Long-term safety and efficacy of sirolimus- vs. paclitaxel-eluting stent implantation for acute ST-elevation myocardial infarction: 3-year follow-up of the PROSIT trial. AB - BACKGROUND: Meta-analysis of randomized trials showed superior efficacy and similar safety of drug-eluting stent over bare-metal stent in acute ST-elevation myocardial infarction (STEMI) patients. However, long-term relative outcomes of sirolimus- (SES) vs. paclitaxel-eluting stent (PES) have not been fully evaluated in randomized studies. This study compared long-term safety and efficacy of these two stents in STEMI. METHODS: A total of 308 STEMI patients were randomly treated with SES (n = 154) or PES (n = 154). Three-year clinical outcomes were assessed. Primary outcome of interest was incidence of major adverse cardiac events (MACE) including death, myocardial infarction (MI), stent thrombosis or target vessel revascularization (TVR). Secondary outcome of interest was occurrence of very late stent thrombosis. RESULTS: Both groups had similar baseline characteristics. During follow-up, there was no difference between the two groups in terms of death (6.5% for SES and 10.4% for PES, p = 0.22), MI (2.6% vs. 3.9%, p = 0.75), stent thrombosis (1.9% vs. 3.2%, p = 0.72), TVR (3.9% vs. 8.4%, p = 0.15) and MACE (12.3% vs. 18.8%, p = 0.12). Eight patients in overall population had stent thrombosis: definite 3, probable 1, and possible 4. Cumulative incidence of stent thrombosis was gradually increased; 0.6% at 30 days, 0.6% at 1 year, 1.6% at 2 years, and 2.6% at 3 years. Very late stent thrombosis, definite or probable, occurred in 0.6% for both. CONCLUSION: Among non-selected STEMI patients who underwent primary angioplasty, both SES and PES might be safe and SES showed similar three-year clinical outcomes compared to PES. PMID- 19783057 TI - PrP genotype: a flock-level risk factor for scrapie? AB - Previous epidemiological studies of risk factors for classical scrapie at flock level have identified a variety of management and purchase related variables, along with increased flock size and, in some cases, breed effects. Although known as a risk factor at the individual animal level, PrP genotype frequencies at flock level have not yet been studied. In an unmatched case-control study, three measures of flock-level prion protein (PrP) frequency estimates were investigated with respect to the scrapie status of the flock in 293 British sheep flocks (195 control flocks and 98 case flocks). Flocks with positive frequencies (more than 0 per cent) of two genotypes (VRQ/VRQ and AHQ/VRQ), large frequencies (more than 10 per cent) of the ARR/VRQ genotype, and large frequencies (more than 5.2 per cent) of the VRQ allele were at increased odds of being affected with clinical classical scrapie. When adjusted for flock size, breed and sampling strategy the genotype and allele effects remained, except that for flocks with positive frequencies of VRQ/VRQ. The known effect of increased risk with increased flock size was confirmed. A measure of the flock PrP genotype frequency profile should thus be included in studies of risk factors for scrapie. It could also be integrated into risk-based surveillance strategies for identification of "at-risk of scrapie" flocks. PMID- 19783058 TI - Unintended exposure in radiotherapy: identification of prominent causes. AB - BACKGROUND AND PURPOSE: Unintended exposures in radiotherapy are likely to occur when certain conditions that favour such exposures exist. Based on the frequency of occurrence of various causes of 100 events of unintended exposures in radiotherapy as derived from the analysis of published reports, a checklist for assessing the vulnerability of radiotherapy facilities for potential accidents has been prepared. The list presents items to be considered for safety critical assessments of a radiotherapy department for the improvement of patient safety and the entire radiotherapy processes. MATERIALS AND METHODS: The resources used for this paper consist of 100 unintended radiotherapy exposures and were derived from existing published reports. The analysis was performed by forming two templates: one consisting of 10 initiating events and another of 35 contributing factors. RESULTS: Four most prominent initiating events were identified and together accounted for about 70% of all the unintended exposure events. Ten most prominent contributing factors were also identified and together accounted for about 70% of all the radiotherapy unintended exposure events covered under this study. CONCLUSION: With this knowledge of high frequency of occurrences, the identified four prominent initiating events and the 10 most prominent contributing factors must be checked and dealt with as a matter of priority when assessing the safety of a radiotherapy facility. A simple checklist for checking the quality assurance programmes of a radiotherapy department for every aspect of the design and delivery of radiation have been provided. PMID- 19783059 TI - Gaze behavior during locomotion through apertures: the effect of locomotion forms. AB - The present study investigated spatio-temporal patterns of gaze fixations for passing safely through apertures. We focused on whether fixation patterns changed in response to changes in locomotion forms. Eight participants approached and passed through a narrow doorway using the following locomotion forms: normal walking, walking while holding a 63-cm horizontal bar with or without shoulder rotations permitted, and wheelchair use (63 cm wide). All participants were naive to wheelchair use. The results showed that the fixation patterns were dependent on whether the locomotion form was walking or wheelchair use. In the three walking conditions, fixations were almost evenly directed toward the aperture and door edges at first; however, in the final phase, fixations were exclusively directed toward the center of the aperture. In contrast, in the wheelchair condition, fixations were directed more frequently toward the door edges throughout locomotion. These findings demonstrate that spatial-temporal patterns of fixation remain unchanged during walking through apertures, irrespective of the constraints on movement. The observed fixation patterns indicate that individuals appear to rely on optic flow to guide locomotion. However, the patterns of fixation are altered when they involve a completely novel task of locomotion, such as when using a wheelchair for the first time. PMID- 19783060 TI - Evaluation of lactic acid bacteria for sourdough fermentation of amaranth. AB - Spontaneous fermented sourdoughs prepared from five amaranth flours were investigated for the presence of lactic acid bacteria predominating the autochthonous microbiota and thus may be suitable as starter cultures. The doughs were fermented with daily back-slopping on a laboratory scale at 30 degrees C for 10 days. Each day, pH-values and total titratable acidity degrees were determined and samples were analyzed for lactic acid bacteria and yeasts by cultural methods. The identity of the strains was tracked with randomly amplified polymorphic DNA-PCR during fermentation. Taxonomic identity of the strains was revealed by sequence analysis of 16S rDNA. Sugar and organic acid profiles of fermented doughs were determined with HPLC. The strains Lactobacillus plantarum RTa12, L. sakei RTa14, and Pediococcus pentosaceus RTa11 were selected and applied as starters in laboratory scale fermentations. All strains were predominant in repeated experiments, both as single strains and in combination, regardless of the amaranth flour used. The competitiveness of the strains L. plantarum RTa12 and P. pentosaceus RTa11 was characterized in further growth experiments. Both strains facilitated fast declines of pH-values, overgrew the autochthonous microbiota, and allowed stable fermentation characteristics at different temperatures. Thus, the characterized strains may be considered as candidates for amaranth sourdough starter cultures. PMID- 19783061 TI - Utilization of Frontal Assessment Battery and Executive Interview 25 in assessing for dysexecutive syndrome and its association with diabetes self-care in elderly patients with type 2 diabetes mellitus. AB - AIMS: Executive function (EF) comprises a set of cognitive skills that controls the execution of complex activities. In the context of diabetes, this may include patients' self-monitoring and daily management of their condition. We compared two different measures of EF in a population of elderly patients with type 2 diabetes mellitus (T2DM) and studied its relationship with diabetes self-care. METHODS: Fifty patients (34 males) had EF assessed using Frontal Assessment Battery (FAB) and Executive Interview 25 (EXIT25). Diabetes self-care was assessed using the Summary of Diabetes Self-Care Activities (SDSCA) scale. Haemoglobin A1c (HbA1c), lipid levels, blood pressure and diabetes duration were recorded. RESULTS: The mean age of the patients was 67.0+/-7.5 years and mean duration of diabetes was 8.1+/-6.4 years. Mean HbA1c was 7.0+/-1.2%, and mean fasting plasma glucose, cholesterol and LDL-C were 7.0+/-1.7mM, 4.0+/-0.9mM and 2.1+/-0.7mM respectively. Mean EXIT25 score was 9.5+/-4.6 in the range of normal EF (14% had EXIT25 score>15, indicating impaired EF). Mean FAB score was 13.7+/ 3.3 (48% having scores<15, indicating impaired EF), suggesting a degree of dysexecutive syndrome involving frontal lobe functions. EXIT25 score was inversely correlated with SDSCA (r=-0.3, p<0.05) but no significant correlation between FAB and SDSCA or HbA1c, diabetes duration, lipid levels and blood pressure with EXIT25, FAB or SDCSA was found. CONCLUSION: A substantial proportion of elderly patients with T2DM may have dysexecutive syndrome and impairment in EF may impact on self-care in this group. PMID- 19783062 TI - Determinants of length of stay for psychiatric inpatients: analysis of a national database covering the entire Korean elderly population. AB - OBJECTIVE: In a rapidly aging society, inappropriately long geropsychiatric inpatient hospitalization is a challenging concern for mental health policy makers and researchers. This study aimed to investigate patient and institutional factors affecting geropsychiatric inpatient length of stay (LOS), providing an overview of current geropsychiatric health care system in South Korea. METHODS: This retrospective, population-based, cross-sectional study analysed nationwide reimbursement claim databases covering the entire elderly population of Korea between January 2005 and June 2006. Given the nested structure of the data, a multivariate multilevel regression analysis was performed. RESULTS: The average LOS was 128 days. Males, patients with schizophrenia, and those enrolled in a National Medical Care Aid program tended to have longer hospital stays. Patient age was negatively related to LOS. Institutional variables related to longer hospitalizations included a psychiatric hospital, a higher number of beds, fewer human resource employees, a higher proportion of male, oldest old, and patients with dementia. CONCLUSIONS: Our results suggest that policies targeting geropsychiatric patients diagnosed with schizophrenia, enrolled in National Medical Care Aid programs, and admitted to psychiatric hospitals could reduce LOS. Additionally, the impact of the patient composition of a medical institution on LOS needs to be closely investigated. PMID- 19783063 TI - Functional compensation by duplicated genes in mouse. PMID- 19783064 TI - Emerging profile of cetuximab in non-small cell lung cancer. AB - This paper summarizes the phase II and III clinical trial experience with cetuximab in the first-line treatment of advanced non-small cell lung cancer (NSCLC). Single-arm and randomized phase II studies show that adding cetuximab to platinum-based doublets has favorable efficacy compared to chemotherapy alone or historical control groups that did not receive cetuximab. Two phase III studies have been conducted with different primary endpoints: overall survival in the pivotal FLEX trial, and progression-free survival (PFS) as assessed by an independent radiologic review committee in the supportive BMS 099 trial. FLEX shows that adding cetuximab significantly prolongs survival compared to chemotherapy alone. BMS 099 did not meet its primary objective, but did show that adding cetuximab significantly prolongs PFS as assessed by investigators. Across all studies, the safety and tolerability of adding cetuximab was predictable and manageable, and did not exacerbate the toxicity associated with chemotherapy. These trials enrolled a broad population of NSCLC patients regardless of histological subtype or comorbid cardiovascular disease, populations that have been underrepresented in clinical trials of other biologics. Cetuximab does not carry restrictions in use due to safety, and therefore it may be a particularly valuable option for patients who are not eligible for other biologics. PMID- 19783065 TI - Paths reunited: Initiation of the classical and lectin pathways of complement activation. AB - Understanding the structural organisation and mode of action of the initiating complex of the classical pathway of complement activation (C1) has been a central goal in complement biology since its isolation almost 50 years ago. Nevertheless, knowledge is still incomplete, especially with regard to the interactions between its subcomponents C1q, C1r and C1s that trigger activation upon binding to a microbial target. Recent studies have provided new insights into these interactions, and have revealed unexpected parallels with initiating complexes of the lectin pathway of complement: MBL-MASP and ficolin-MASP. Here, we develop and expand these concepts and delineate their implications towards the key aspects of complement activation via the classical and lectin pathways. PMID- 19783066 TI - The analysis of an Arabidopsis triple knock-down mutant reveals functions for MBF1 genes under oxidative stress conditions. AB - Transcriptional co-activators of the multiprotein bridging factor 1 (MBF1) type belong to a small multigenic family that controls gene expression by connecting transcription factors and the basal transcription machinery. In this report, a triple knock-down mutant (abc-) for the Arabidopsis thaliana MBF1 genes AtMBF1a, AtMBF1b and AtMBF1c was generated. The phenotypic characterization using oxidative agents such as hydrogen peroxide and methyl viologen revealed that the abc- mutant was more sensitive to oxidative stress. The triple knock-down mutant, abc- was also sensitive to osmotic stress mediated by high concentrations of sorbitol. Furthermore, the abc- phenotype was partially or completely rescued by AtMBF1c cDNA over-expression (abc- +c) depending on physiological and developmental conditions. AtMBF1s regulate the expression of ABR1, which is a member of the ethylene-response factor family and acts as ABA repressor. Thus, we conclude that AtMBF1 gene family may function as a regulatory component of the cross-talk node between ethylene, ABA and stress signal pathways. Furthermore, higher levels of a HSP70 mRNA and an immunoreactive HSP70 protein were detected in the abc- mutant. The participation of MBF1c as a possible negative regulator of HSP genes was discussed. PMID- 19783067 TI - Carriage rate of carbapenem-resistant Klebsiella pneumoniae in hospitalised patients during a national outbreak. AB - During a national outbreak of carbapenem-resistant Klebsiella pneumoniae (CRKP) in Israel, we conducted a point prevalence survey to determine the extent of asymptomatic carriage. Subsequently, a retrospective case-control study was done, comparing carriers of CRKP with non-carriers, in order to detect risk factors for carriage. Oral, perianal and rectal swabs were obtained from all hospitalised eligible and consenting patients. Selective media for carbapenem-resistant Gram negative bacteria were used and pulsed-field gel electrophoresis (PFGE) helped to determine clonal source. Culture was obtained from 298 patients. Sixteen (5.4%) were carriers of CRKP, with a higher carriage rate in medical and surgical wards. Only 18% of carriers were treated with any carbapenem prior to the survey. Five of the 16 carriers had a positive clinical specimen for CRKP, hence a clinical infection versus asymptomatic carriage ratio of 1:3. The rectum was the most sensitive site sampled, detecting 15/16 carriers, and the overall sensitivity of the method was 94% with a negative predictive value of 99.6%. In a multivariate analysis of risk factors for CRKP carriage, three variables were significantly related to carriage state: diaper use, longer duration of hospital stay and vancomycin use. PFGE demonstrated that all 16 isolates were identical, confirming clonal origin. A point prevalence survey performed at a single medical centre during an outbreak of CRKP demonstrated a carriage rate of 5.4%. The clonal origin of these isolates suggests that strict adherence to isolation procedure may contain this outbreak. PMID- 19783068 TI - UK healthcare workers' knowledge of meticillin-resistant Staphylococcus aureus practice guidelines; a questionnaire study. AB - Effective infection control practice requires knowledge of and adherence to contemporary infection control guidelines. Utilising a novel questionnaire tool, we evaluated knowledge of recently published guidelines on meticillin-resistant Staphylococcus aureus (MRSA) precautions in a number of relevant healthcare worker (HCW) populations. The questionnaire was developed from national UK MRSA practice guidelines and consisted of 10 'true or false' statements. The questionnaire was utilised to assess knowledge in 293 participants from HCW and control populations. The participants included 188 doctors attending the British Medical Association's Annual Representatives Meeting, 52 trainee surgeons attending the Association of Surgeons in Training annual conference, 30 members of a non-clinical control population and 23 infection control nurses (ICNs). The mean (SD) score for knowledge levels obtained from doctors was 6.6 (1.68), for non-clinical control population was 4.7 (1.8) and for ICNs, 8.4 (1.12). There were significant differences in knowledge levels between different population groups (P<0.001), UK employment region of the participant (P=0.01) and the doctors' medical specialty (P=0.02). Career seniority and gender of the participant were not significantly associated with differences in levels of knowledge. This questionnaire study evaluates a novel discriminatory questionnaire tool which differentiates knowledge levels of MRSA practice guidelines among a non-clinical population, HCWs and specialist infection control staff, thus providing a means for the rapid assessment of MRSA educational interventions. We identify demographics within HCW target populations which are associated with low levels of such knowledge. Consideration towards revising current HCW educational programmes to improve knowledge and best practice in MRSA prevention is required. PMID- 19783069 TI - Headwear in laminar flow operating theatres. PMID- 19783070 TI - Hand hygiene and infection in hospitals: what do the public know; what should the public know? AB - Healthcare-associated infection (HCAI) is a topic of increasing public interest, particularly to users of health services. At the same time, there is a move towards greater openness and transparency across the whole healthcare sector. Thus we see public reporting of performance in relation to rates of HCAI and infection control practices is increasingly well established in the NHS in England. So does any of this make a difference? And how embedded is the 'public right to know'? In this paper it is argued that, although the public right to know about rates of HCAIs is well recognised, the evidence base about the impact of such information is limited. The paper suggests actions which can be taken by boards and senior leaders in healthcare organisations to increase impact. Furthermore the example of hand hygiene suggests that we have some way to go in creating an environment in which patients feel empowered to ask questions that may reduce their own vulnerability to infection. PMID- 19783071 TI - Do we need an ethical framework for hospital infection control? AB - Strategies for the control of the spread of infection in hospitals may lead to constraints on individual autonomy, freedom of movement, or contact with others. Codes of (ethical) practice for healthcare professionals tend to emphasise responsibilities to individual patients. Ethical frameworks for public health focus on groups of individuals (populations), the majority of whom are relatively healthy and empowered. Hospital infection control professionals must take account of both of these perspectives, sensitive to the care of infected and potentially infectious individuals, while protecting the vulnerable and relatively dependent population of hospital patients from further compromise to their health. A number of frameworks for an ethics of public health have been proposed over the last few years but there are sufficient differences in ethical considerations between collective interventions that aim to protect and promote the health of the public and interventions taken in the context of hospital infection control to justify a distinctive ethics of hospital infection control. Professional bodies may be best placed to lead the development of such a framework. PMID- 19783072 TI - Hospital adverse events and control charts: the need for a new paradigm. AB - Control charts are being increasingly used to summarise sequential rates of hospital adverse events (AEs). They are designed to detect departures from stable, predictable processes and are therefore appropriate when information about the mean value and variability of the relevant time-series data is available, from when the process is or has been in a stable, predictable state. This is often the case with binary data AEs such as surgical site infections and surgical mortality. However, it may not always be possible to determine the stable predictable rate at which events such as patient falls, pressure ulcers, medication errors or new isolates of a multiresistant organism (MRO) occur. Furthermore, such a rate may sometimes not exist, as is frequently the case with antibiotic usage and MRO prevalence data. It may then be better to employ time series methods to analyse and present the data. A convenient approach is to employ spline-regression or a generalised additive model. PMID- 19783073 TI - Co-ordinated approach to healthcare worker influenza vaccination in an area health service. AB - To increase local influenza vaccination uptake among healthcare workers (HCWs), a co-ordinated, area-wide influenza vaccination campaign was undertaken in 2008 for five hospitals in the South Metropolitan Area Health Service of Perth, Western Australia (WA). The programme included standardised marketing and data collection, with a consent form completed by each recipient. Denominator data were obtained from the WA Department of Health's staff database. Vaccination coverage at each hospital was calculated and compared with that of 2007, with predictors for vaccination determined using a follow-up cross-sectional survey. A total of 6387 influenza vaccinations were administered. The coverage rate was above 55% in all but one hospital (range: 48.8-76.5%) whereas in 2007 no hospital achieved 55% (range: 29-51%). Allied health professionals attained the highest coverage (57.7%), followed by doctors (51.9%), nurses (49.6%) and patient support staff (48.6%). Of HCWs who worked half-time or more, 58.8% were vaccinated. The main reasons for vaccination were to prevent influenza, limit spread, and the programme's availability. The survey revealed that HCWs who perceived that they were susceptible to influenza, that it was a serious disease and that immunisation was effective and important were significantly more likely to be vaccinated. An area-wide approach to HCW influenza vaccination can substantially improve uptake. Regular working party meetings, consistent marketing, standardised data collection and analysis, and senior management support were key elements and could be used by others to attain good vaccination coverage among HCWs. PMID- 19783074 TI - Resistance of Legionella pneumophila serotype 1 biofilms to chlorine-based disinfection. AB - The presence of Legionella spp. in potable water systems is a major concern to municipal water providers and consumers alike. Despite the inclusion of chlorine in potable supplies and frequent chlorination cycles, the bacterium is a recalcitrant human pathogen capable of causing incidents of Legionnaires' disease, Pontiac fever and community-acquired pneumonia in humans. Using two materials routinely employed for the delivery of potable water as a substratum, copper and stainless steel, the development of Legionella pneumophila biofilms and their response to chlorination was monitored over a three-day and a three month period, respectively. Preliminary in vitro studies using broth and sterile tap water as culture media indicated that the bacterium was capable of surviving in low numbers for 28 days in the presence of chlorine. Subsequently, biofilms were grown for three days, one month and two months, respectively, on stainless steel and copper sections, which are widely used for the conveyance of potable water. Immediately after exposure to 50mg/L chlorine for 1h, the biofilms yielded no recoverable colonies, but colonies did reappear in low numbers over the following days. Despite chlorination at 50mg/L for 1h, both one- and two-month old L. pneumophila biofilms were able to survive this treatment and to continue to grow, ultimately exceeding 1x10(6)cfu per disc. This research provides an insight into the resistance afforded to L. pneumophila against high levels of chlorine by the formation of biofilms and has implications for the delivery of potable water. PMID- 19783075 TI - [Adult-onset Still's disease with liver failure requiring liver transplantation]. AB - We present the case of a 23-year-old man with fever of unknown origin, who developed acute liver failure 2 months after symptom onset, requiring an urgent liver transplantation. The diagnosis of adult-onset Still's disease was established after the reappearance of symptoms after transplantation, and high doses of corticosteroids were used to control disease activity. Subsequently, given the impossibility of tapering the steroid dose, interleukin-1 receptor blocking treatment was started with satisfactory outcome. We also review the published literature. PMID- 19783076 TI - [Arthritis caused by Burkholderia cepacia]. PMID- 19783077 TI - [Differentiating clinical characteristics in bacteriemia caused by Enterococcus faecalis or Enterococcus faecium]. AB - INTRODUCTION: Enterococci are responsible for severe infections, such as endocarditis and bacteremia. During recent decades, enterococcal infections have grown in importance because of the increasing number of cases. Knowledge of the factors predisposing to acquisition of infection by E. faecalis or E. faecium may be useful to improve the empirical treatment. METHODS: Retrospective study of patients diagnosed with enterococcal bacteremia and hospitalized over a 7-year period (January 2000-December 2006), analyzing demographic data, clinical and microbiological characteristics, antibiotic exposure, treatment, and outcome. To identify the predisposing factors for isolation of E. faecalis or E. faecium in a clinical specimen, we performed univariate comparisons between the 2 groups, and subsequently, multivariate logistic regression analysis. RESULTS: A total of 228 episodes of bacteremia were recorded, 168 caused by E. faecalis and 60 by E. faecium. All E. faecalis isolates were susceptible to ampicillin, but only 25% of E. faecium were ampicillin-susceptible. There was only 1 vancomycin-resistant isolate. The variables independently associated with acquisition of E. faecium bacteriemia were surgical ward admission (odds ratio [OR], 4.223; P=.001), >5 days of previous treatment with cephalosporins (OR, 2.564; P=.013), >5 days of carbapenems (OR, 2.652; P=.027), previous administration of penicillins (OR, 2.008; P=0.044), SAPS score >30 at admission (OR, 3.530; P=0.001), and hepatobiliary disease as a comorbid condition (OR, 3.754; P<0.001), CONCLUSION: Because of the differing susceptibility patterns of the enterococcal species studied, it is essential to know the factors predisposing to acquisition of infection by one or the other species to initiate adequate empirical treatment. PMID- 19783078 TI - Effect of ruthenium complexation on trypanocidal activity of 5-nitrofuryl containing thiosemicarbazones. AB - In the search of new therapeutic tools for the treatment of American Trypanosomiasis, the largest parasitic disease burden in the American continent, three series of novel ruthenium complexes of the formula [RuCl(2)(HL)(2)], [RuCl(3)(dmso)(HL)] and [RuCl(PPh(3))(L)(2)] with bioactive 5-nitrofuryl containing thiosemicarbazones as ligands (HL neutral, L monoanionic) were synthesized and characterized. Their in vitro growth inhibition activity against Trypanosoma cruzi and the effect of co-ligands in related physicochemical properties i.e. nitro moiety redox potential, lipophilicity and free radical scavenger capacity were evaluated. Results show that although a loss of activity was observed as a consequence of ruthenium complexation, lipophilicity and free radical scavenger capacity of the obtained complexes could be correlated to their trypanocidal effect. PMID- 19783079 TI - [Side effects of glucocorticoids and specialist in internal medicine]. PMID- 19783080 TI - Effects of early enteral nutrition supplemented with arginine on intestinal mucosal immunity in severely burned mice. AB - BACKGROUND: To investigate the effects of early enteral nutrition (EN) supplemented with Arginine (Arg) on intestinal mucosal immunity in severely burned mice. METHODS: Forty-four mice were randomly assigned into four groups: a sham injury+EN group (n=10), a sham injury+EN+Arg group (n=10), a burn+EN group (n=12), and a burn+EN+Arg group (n=12) and the mice in two experimental groups received a 20% total body surface area (TBSA), full-thickness scald burn on the back. Then, the burned mice were given a 175 kcal/kg body wt/day of conventional enteral nutrition or an isonitrogenous and isocaloric enteral nutrition supplemented with Arg by gastric gavage for 7 days. There was isonitrogenous and isocaloric intake in two experimental groups. The mice in two control groups received the same procedures as above, except for burn injury. On day 7 after injury, all mice among four groups were euthanized and the entire intestine was harvested. Intestinal immunoglobulin A (IgA) levels, total lymphocyte yield, and lymphocyte subpopulations in Peyer's patches were analyzed. Levels of IFN-gamma, IL-2, IL-4 and IL-10 in gut homogenates were also measured by ELISA. RESULTS: Total lymphocyte yield, numbers of lymphocyte subpopulations, and intestinal IgA levels in the EN+ARG group were higher than those in the EN group (p<0.05). Levels of gut tissue cytokines were significantly altered with enteral Arg supplementation: levels of IL-4 and IL-10 were increased, and levels of IFN-gamma and IL-2 declined, when compared with the EN-fed mice (p<0.05). CONCLUSIONS: The results of this study suggested that enteral nutrition supplemented with Arg has changed the cytokine concentrations in intestinal homogenates from a pro- to an anti-inflammatory profile, increased sIgA levels and changed lymphocytes in severely burned mice. PMID- 19783081 TI - Home-based life saving skills in Matlab, Bangladesh: a process evaluation of a community-based maternal child health programme. AB - OBJECTIVE: to conduct and describe results from a process evaluation of home based life saving skills (HBLSS) one year post-implementation. DESIGN: a non experimental, descriptive design was utilised employing both qualitative and quantitative techniques for data collection including: (1) key informant interviews, (2) group discussions, (3) performance testing, and (4) review of programme data. SETTING: rural Matlab, Bangladesh in the sub-district of Chandpur. PARTICIPANTS: 41 community health research workers (CHRW), five pregnant women, 14 support persons and four programme co-ordinators. INTERVENTION: HBLSS is a family-centred approach to improving recognition of and referral for potentially life-threatening maternal and newborn complications. In June 2007, four HBLSS meetings were implemented in Matlab by 41 CHRW with all pregnant women in the study area. MEASUREMENTS: (1) knowledge retention among CHRW, (2) programme coverage, and (3) strengths and challenges in HBLSS implementation. FINDINGS: results revealed rapid integration of the programme into the Matlab community with nearly 4500 HBLSS contacts with 2409 pregnant women between 15 June 2007 and 31 March 2008. Over 51% of pregnant women attended all four HBLSS meetings. Knowledge testing of CHRW showed strong retention with an increase in mean scores between immediate post-training and one-year post training (from 78.7% to 92.7% and from 77.8% to 97.7% for two different HBLSS modules). Strengths of the HBLSS programme include high satisfaction among pregnant women, dedication of CHRW to the community, and strong organisation and supervision by programme staff. Challenges include lack of involvement of men, loss of two master trainers, and limited access to comprehensive emergency obstetric care at some referral sites. KEY CONCLUSIONS: the HBLSS programme was successfully implemented as a result of the high level of support and supervision by the maternal, newborn and child health staff at ICDDR,B. This evaluation highlights the value of community health workers in the fight against maternal and newborn mortality. Findings emphasise the strength of the HBLSS training approach in transferring knowledge from trainer to HBLSS guide. PMID- 19783082 TI - Lumbar extraforaminal ligaments act as a traction relief and prevent spinal nerve compression. AB - BACKGROUND: In a previous study, ligaments that connect the extraforaminal lumbar spinal nerves with the fibrous capsule of the facet joints and the dorsolateral side of the intervertebral disc were described. This anatomical configuration suggests a mechanical role in transferring extraforaminal spinal nerve traction. METHODS: One embalmed human lumbar spine was dissected from the twelfth thoracic vertebra to the first sacral vertebra to isolate the twelfth thoracic to the fourth lumbar spinal nerves. The spinal nerves from L1 to L4 were pulled at different angles with respect to the axis of the spine. Forces of 1-6N were applied. The displacements of reflective markers glued to the proximal and distal ends of the adjoining ligaments were recorded with a video system. FINDINGS: The spinal nerve proximal of the extraforaminal ligaments stays centred in the intervertebral foramen when pulling at an angle. At levels L1-L4 strain reduction by the extraforaminal ligaments was largest when pulling at a wider angle to the spinal axis in the sagittal plane. Proximal to the extraforaminal ligaments less displacement was seen compared to the displacement distal of the extraforaminal ligaments when pulling in longitudinal direction. A graded decrease in the displacement proximal to the extraforaminal ligaments was seen from the levels L1 L4. INTERPRETATION: Extraforaminal ligaments play an important role in the prevention of damage due to spinal nerve traction. The proximal attachments secure a spinal nerve position central in the intervertebral foramen and also reduce longitudinal tension. PMID- 19783083 TI - Bioaccumulation and depuration of metals in blue crabs (Callinectes sapidus Rathbun) from a contaminated and clean estuary. AB - Blue crabs from a contaminated estuary (Hackensack Meadowlands-HM) and a cleaner reference site (Tuckerton-TK) were analyzed for Cr, Cu, Hg, Pb, and Zn in muscle and hepatopancreas. Crabs from each site were taken into the laboratory and fed food from the other site, or in another experiment, transplanted to the other site for eight weeks. All crabs were analyzed for metals. Overall, tissue concentrations reflected environmental conditions. Tissue differences were found for Cu, Pb and Zn (all higher in hepatopancreas), and Hg (higher in muscle). HM muscle had more Hg than TK muscle, but did not decrease after transplanting or consuming clean food. HM crabs lost Cu, Pb and Zn in hepatopancreas after being fed clean food or transplanted. TK crabs increased Hg in muscle and Cr and Zn in hepatopancreas after transplantation or being fed contaminated (HM) food. Concentrations were variable, suggesting that blue crabs may not be fully reliable bioindicators of polluted systems. PMID- 19783084 TI - Immobilization of lead and cadmium from aqueous solution and contaminated sediment using nano-hydroxyapatite. AB - The effectiveness and mechanism of nano-hydroxyapatite particles (nHAp) in immobilizing Pb and Cd from aqueous solutions and contaminated sediment were investigated. The maximum sorption amount (Q(max)) of Pb and Cd in aqueous solution was 1.17 and 0.57 mmol/g. The X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS) surface and depth analysis indicated that dissolution-precipitation is the primary immobilization mechanism for Pb, while surface complexation and intraparticle diffusion account for Cd sequestration. Different amounts of nHAp (0-10% nHAp/dry weight) were added to the contaminated sediment. Sequential extraction showed that nHAp could effectively reduce the exchangeable fraction of Pb and Cd in the sediment and significantly reduce the concentration in porewater. The results in this study showed that nHAp can immobilize Pb and Cd in sediment effectively. PMID- 19783085 TI - A meta-synthesis of pregnant women's decision-making processes with regard to antenatal screening for Down syndrome. AB - The diffusion of antenatal screening programmes for Down syndrome has triggered much discussion about their powerful potential to enhance pregnant women's autonomy and reproductive choices. Simultaneously, considerable debate has been engendered by concerns that such programmes may directly contribute to the emergence of new and complex ethical, legal and social dilemmas for women. Given such discussion and debate, an examination of women's decision-making within the context of antenatal screening for Down syndrome is timely. This paper aims to undertake a meta-synthesis of qualitative studies examining the factors influencing pregnant women's decisions to accept or decline antenatal screening for Down syndrome. The meta-synthesis aims to create more comprehensive understandings and to develop theory which might enable midwives and other healthcare professionals to better meet the needs of pregnant women as they make their screening decisions. Ten electronic health and social science databases were searched together with a hand-search of eleven journals for papers published in English between 1999 and 2008, using predefined search terms, inclusion and exclusion criteria, and a quality appraisal framework. Nine papers met the criteria for this meta-synthesis, providing an international perspective on pregnant women's decision-making. Twelve themes were identified by consensus and combined into five core concepts. These core concepts were: destination unknown; to choose or not to choose; risk is rarely pure and never simple; treading on dreams, and betwixt and between. A conceptual framework is proposed which incorporates these themes and core concepts, and provides a new insight into pregnant women's complex decision-making processes with regard to antenatal screening for Down syndrome. However, further research is necessary to determine whether or not the development of a model of decision-making may empower pregnant women in making choices about screening. PMID- 19783086 TI - Are rural health professionals also social entrepreneurs? AB - Social entrepreneurs formally or informally generate community associations and networking that produces social outcomes. Social entrepreneurship is a relatively new and poorly understood concept. Policy promotes generating community activity, particularly in rural areas, for health and social benefits and 'community resilience'. Rural health professionals might be well placed to generate community activity due to their status and networks. This exploratory study, conducted in rural Tasmania and the Highlands and Islands of Scotland considered whether rural health professionals act as social entrepreneurs. We investigated activities generated and processes of production. Thirty-eight interviews were conducted with general practitioners, community nurses, primary healthcare managers and allied health professionals living and working rurally. Interviewees were self-selecting responders to an invitation for rural health professionals who were 'formally or informally generating community associations or networking that produced social outcomes'. We found that rural health professionals initiated many community activities with social outcomes, most related to health. Their identification of opportunities related to knowledge of health needs and examples of initiatives seen elsewhere. Health professionals described ready access to useful people and financial resources. In building activities, health professionals could simultaneously utilise skills and knowledge from professional, community member and personal dimensions. Outcomes included social and health benefits, personal 'buzz' and community capacity. Health professionals' actions could be described as social entrepreneurship: identifying opportunities, utilising resources and making 'deals'. They also align with community development. Health professionals use contextual knowledge to envisage and grow activities, indicating that, as social entrepreneurs, they do not explicitly choose a social mission, rather they act within their known world view. Policymakers could consider ways to engage rural health professionals as social entrepreneurs, in helping to produce resilient communities. PMID- 19783087 TI - [Lymphangioleiomyomatosis in a post-menopausal women]. AB - Lymphangioleiomyomatosis is a rare disease characterised by pulmonary cysts with abnormal proliferation in the lymphatic system. It occurs almost exclusively in women of fertile age due to a hormonal influence, for this reason it is extremely rare in post-menopausal patients. In these cases it is usually associated to hormone replacement therapies. It is known that this diseases is strongly associated with other conditions, such as tuberous sclerosis and renal angiomyolipomas. We present a case of a post-menopausal patient suffering from lymphangioleiomyomatosis, with no history of hormone therapy, in whom were also detected renal angiomyolipomas and clinical signs indicative of a probable tuberous sclerosis. PMID- 19783088 TI - Membrane-induced peptide structural changes monitored by infrared and circular dichroism spectroscopy. AB - As more peptide secondary structures deduced by infrared spectroscopy (IR) have been reported in the literature, there have been overlaps in assignments of elements of secondary structure to carbonyl vibrational frequencies. We have investigated this phenomenon with regards to the use of IR for monitoring membrane-induced structural changes using conformationally diverse peptides. These IR studies, complemented by circular dichroism (CD) experiments, revealed that peptide-solvent interactions can mask membrane-induced conformational changes monitored by IR. A structural transition from random coil to alpha-helix upon the binding of mastoparan X to a membrane was clearly observed by CD but obscured in the amide I region of the IR spectrum. In addition, unlike the buried helical peptides gramicidin D and P16 in micelles, the amide II peak for mastoparan X was absent, likely due to H-D exchange. This suggests information on the peptide's membrane-bound solvent accessibility could be obtained from this region of the spectrum. PMID- 19783089 TI - Thermally induced structural changes of intrinsically disordered small heat shock protein Hsp22. AB - We applied different methods (differential scanning calorimetry, circular dichroism, Fourier transform infrared spectroscopy, and intrinsic fluorescence) to investigate the thermal-induced changes in the structure of small heat shock protein Hsp22. It has been shown that this protein undergoes thermal-induced unfolding that occurs within a very broad temperature range (from 27 degrees C to 80 degrees C and above), and this is accompanied by complete disappearance of alpha-helices, significant decrease in beta-sheets content, and by pronounced changes in the intrinsic fluorescence. The results confirm predictions that Hsp22 belongs to the family of intrinsically disordered proteins (IDP) with certain parts of its molecule (presumably, in the alpha-crystallin domain) retaining folded structure and undergoing reversible thermal unfolding. The results are also discussed in terms of downhill folding scenario. PMID- 19783090 TI - Photoelectrochemical activity of liquid phase deposited TiO2 film for degradation of benzotriazole. AB - TiO(2) film deposited on glassy carbon electrode surface was prepared via the liquid phase deposition (LPD). The deposited TiO(2) film before and after calcination was characterized with scanning electron microscopy (SEM) and X-ray diffraction (XRD). Based on the high photoelectrochemical activity of calcined LPD TiO(2) film, the photoelectrocatalytic degradation of benzotriazole (BTA) was investigated. Compared with the electrochemical oxidation process, direct photolysis or photocatalysis for treatment of BTA, a synergetic photoelectrocatalytic degradation effect was observed using the LPD TiO(2) film coated electrode. Various factors influencing the photoelectrocatalytic degradation of BTA such as film calcination, applied bias potential, pH value, supporting electrolyte concentration and initial concentration of BTA were investigated. The COD removal for BTA solution was analyzed to evaluate the mineralization of the PEC process. Based on the degradation experimental results, a possible photoelectrocatalytic degradation mechanism for BTA was proposed. PMID- 19783091 TI - Developments in CO2 mineral carbonation of oil shale ash. AB - Solid waste and atmospheric emissions originating from power production are serious problems worldwide. In the Republic of Estonia, the energy sector is predominantly based on combustion of a low-grade carbonaceous fossil fuel: Estonian oil shale. Depending on the combustion technology, oil shale ash contains 10-25% free lime. To transport the ash to wet open-air deposits, a hydraulic system is used in which 10(7)-10(8) cubic meters of Ca(2+)-ion saturated alkaline water (pH level 12-13) is recycled between the plant and sedimentation ponds. The goals of the current work were to design an ash-water suspension carbonation process in a continuous mode laboratory-scale plant and to search for potential means of intensifying the water neutralization process. The carbonation process was optimized by cascading reactor columns in which the pH progressed from alkaline to almost neutral. The amount of CO(2) captured from flue gases can reach 1-1.2 million ton at the 2007 production level of the SC Narva Power Plants. Laboratory-scale neutralization experiments were carried out to compare two reactor designs. Sedimentation of PCC particles of rhombohedral crystalline structure was demonstrated and their main characteristics were determined. A new method providing 50x greater specific intensity is also discussed. PMID- 19783092 TI - Ethyl lactate enhances ethylenediaminedisuccinic acid solution removal of copper from contaminated soils. AB - A new approach using aqueous ethyl lactate-modified [S,S] ethylenediaminedisuccinic acid (EDDS) washing solutions for the removal of Cu from field-contaminated soils was examined in the laboratory. At pH 7 the maximum extraction efficiencies of Cu were about 41% by EDDS solution (EDDS:Cu molar ratio=8), and <2% by ethyl lactate solution. However, greater extraction efficiencies of up to 50% were achieved by amending the EDDS solution with ethyl lactate (EDDS:Cu molar ratio=2, ethyl lactate:Cu molar ratio=25). The pH of the extraction solution did not have a significant effect on the extraction of Cu. The washing agent could also be regenerated quite effectively for economy of use. Sequential extraction results showed that the two most bioavailable Cu fractions, i.e., the acid extractable and reducible fractions, were significantly reduced. The mechanism responsible for the enhanced extraction efficiency in the presence of ethyl lactate is the increased the stability constant of Cu-EDDS complexes in the presence of ethyl lactate, which enhanced desorption of Cu from soil. PMID- 19783093 TI - Heavy metal and persistent organic compound contamination in soil from Wenling: an emerging e-waste recycling city in Taizhou area, China. AB - The present study was conducted to investigate the levels and sources of heavy metals (Cu, Cr, Cd, Pb, Zn, Hg and As) and persistent organic compounds including polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) in soils taken from Wenling, an emerging e-waste recycling city in Taizhou, China. The results suggested that most heavy metals exceeded the respective Grade II value of soil quality standards from State Environmental Protection Administration of China and also exceeded the Dutch optimum values. Total PAHs in soil ranged from 371.8 to 1231.2 microg/kg, and relatively higher PAHs concentrations were found in soils taken from simple household workshops. PCBs were detectable in all samples with total concentrations ranging from 52.0 to 5789.5 microg/kg, which were 2.1-232.5 times higher than that from the reference site (24.9 microg/kg). Results of this study suggested soil in the Wenling e waste recycling area were heavily contaminated by heavy metals, PAHs and PCBs. Furthermore, compared with large-scale plants, simple household workshops contributed more heavy metals, PAHs and PCBs pollution to the soil environment, indicating that soil contamination from e-waste recycling in simple household workshops should be given more attention. PMID- 19783094 TI - Landfill leachate ingestion induces protein oxidation and DNA-protein crosslinks in mouse viscera. AB - In the present study, protein oxidation (PCO content) and DNA-protein crosslinks (DPC coefficient) were investigated in the viscera of mice exposed to a municipal landfill leachate at various concentrations for 7 days. The study was designed to investigate the injuries and a possible mechanism of landfill leachate-induced toxicity on mammals. The results indicate that the leachate sample changed the ratio of viscera to body weight in all organs tested, and the effect on the brain was more obvious than that on other organs. The leachate ingestion increased PCO levels in the brain, kidney, liver and spleen in a concentration-dependent manner, but did not affect the content in the heart. Also, the leachate sample enhanced DPC formation in the tested organs in a concentration-dependent manner, and the responses of the liver, kidney and spleen were more sensitive than that of the brain and heart. These findings provide further evidence that landfill leachate-induced toxicity on mammals might involve the formation of free radicals, either via autoxidation or by enzyme-catalyzed oxidation of pollutants in leachate, and then attack of proteins and nucleic acids via generated free radicals. PMID- 19783095 TI - Interaction of malathion, an organophosphorus pesticide with Rhizopus oryzae biomass. AB - Adsorption of malathion on Rhizopus oryzae biomass (ROB) with special reference to binding mechanism has been described. ROB has been found to adsorb approximately 85% of malathion from its aqueous solution as against 47-68% by other fungal biomasses. Hydrogen ion concentration does not influence the adsorption of malathion by ROB which follows Langmuir-Freundlich dual equilibrium isotherm model (r(2)=0.998). Both physical and chemical interactions are responsible for binding of malathion on ROB. Scanning electron micrographs and EDXA spectra exhibit adsorption of the pesticide on cell surface of ROB. Studies with cell surface polysaccharides show that chitosan through its amine groups contributes largely in the adsorption of malathion. Extraction of lipids from ROB decreases its adsorption capacity to the extent of 36.37-94.02%, depending on the polarity of the solvent. PMID- 19783096 TI - Distribution and sources of DDTs in urban soils with six types of land use in Beijing, China. AB - The concentrations of dichlorodiphenyltrichloroethanes (DDTs) were investigated for urban soil samples collected from business area (BU), classical garden (CL), culture and educational area (CU), large public green space (LA), residential area (RE), and roadside area (RO) in Beijing. The DDTs concentrations ranged from 0.03 to 1282.58 ng/g, with an average of 68.14+/-189.46 ng/g. The DDTs concentration in CL was much higher than that in the other five types of land use, which was due to the usage of DDTs to protect vegetation in CL, and the DDTs concentration was affected by both the usage history of DDTs and the age of the CL. Only 22% of the samples, mainly located in RO, manifested the application of technical DDTs recently. DDTs concentration showed a decreasing trend from the city center to the suburb, and it increased with the age of the urban area. DDTs were positively correlated with total organic carbon and black carbon in soils. About 81.7% of the samples met the grade I standard (50 ng/g soil) of the Chinese Environmental Quality Standard for Soils, and only 1.5% of the samples exceeded the grade III standard (1000 ng/g soil). PMID- 19783097 TI - Immobilization of oxime derivative on silica gel for the preparation of new adsorbent. AB - A new silica gel compound modified 4,4'-oxy-bis(chlorophenylglyoxime) (CPGO) was synthesized and characterized by infrared spectroscopy, elemental analysis and thermogravimetric analysis. The sorption capacity of such a matrix towards Co(II), Ni(II) and Cu(II) from aqueous solutions was studied. The optimum pH values for the separation of these divalent cations on the sorbent were 5.0, 6.0 and 6.0 for Cu, Co and Ni, respectively. The process of metal separation was followed by batch method, and fitted to a Langmuir and Freundlich sorption isotherms. The maximum sorption capacities (0.055, 0.042, and 0.034 mmol g(-1)) were found from the Langmuir equation and the enthalpies of binding were 44.96, 71.63, and 68.14 kJ mol(-1) for Cu, Co and Ni, respectively. The other thermodynamic parameters calculated from the adsorption results were used to explain the mechanism of the adsorption. For example, the Gibbs free energies of binding agree with the spontaneity of the proposed reaction between cations and basic centers. PMID- 19783098 TI - Association between OPRM1 gene polymorphisms and fentanyl sensitivity in patients undergoing painful cosmetic surgery. AB - Individual differences in sensitivity to fentanyl, a widely used opioid analgesic, can hamper effective pain treatment. Still controversial is whether the single nucleotide polymorphisms (SNPs) of the human OPRM1 gene encoding the mu-opioid receptor influence the analgesic effects of opioids. We examined associations between fentanyl sensitivity and the two SNPs, A118G and IVS3+A8449G, in the human OPRM1 gene in 280 Japanese patients undergoing painful orofacial cosmetic surgery, including bone dissection. Regarding the A118G SNP in exon 1, in a cold pressor-induced pain test before surgery, less analgesic effects of fentanyl were shown in subjects carrying the minor G allele of the A118G SNP (median of difference between pain perception latencies before and after fentanyl injection [PPLpost-PPLpre]: 12s) compared with subjects not carrying this allele (PPLpost-PPLpre: 15s, p=0.046). Furthermore, the IVS3+A8449G SNP in intron 3, which represents a complete linkage disequilibrium block with more than 30 SNPs from intron 3 to the 3' untranslated region, was associated with 24-h postoperative fentanyl requirements. Subjects carrying the minor G allele of the IVS3+A8449G SNP required significantly less fentanyl for 24-h postoperative pain control (median: 1.5microg/kg) compared with subjects not carrying this allele (median: 2.5microg/kg, p=0.010). Although further validation is needed, the present findings shed light on the involvement of OPRM1 3' untranslated region polymorphisms in fentanyl sensitivity in addition to the A118G SNP and open new avenues for personalized pain treatment with fentanyl. PMID- 19783099 TI - Incidence of facial pain in the general population. AB - Facial pain has a considerable impact on quality of life. Accurate incidence estimates in the general population are scant. The aim was therefore to estimate the incidence rate (IR) of trigeminal neuralgia (TGN), postherpetic neuralgia (PHN), cluster headache (CH), occipital neuralgia (ON), local neuralgia (LoN), atypical facial pain (AFP), glossopharyngeal neuralgia (GPN) and paroxysmal hemicrania (PH) in the Netherlands. In the population-based Integrated Primary Care Information (IPCI) medical record database potential facial pain cases were identified from codes and narratives. Two medical doctors reviewed medical records, questionnaires from general practitioners and specialist letters using criteria of the International Association for the Study of Pain. A pain specialist arbitrated if necessary and a random sample of all cases was evaluated by a neurologist. The date of onset was defined as date of first specific symptoms. The IR was calculated per 100,000PY. Three hundred and sixty-two incident cases were ascertained. The overall IR [95% confidence interval] was 38.7 [34.9-42.9]. It was more common among women compared to men. Trigeminal neuralgia and cluster headache were the most common forms among the studied diseases. Paroxysmal hemicrania and glossopharyngeal neuralgia were among the rarer syndromes. The IR increased with age for all diseases except CH and ON, peaking in the 4th and 7th decade, respectively. Postherpetic neuralgia, CH and LoN were more common in men than women. From this we can conclude that facial pain is relatively rare, although more common than estimated previously based on hospital data. PMID- 19783100 TI - 4D ultrafast electron microscopy: imaging of atomic motions, acoustic resonances, and moire fringe dynamics. AB - In four-dimensional (4D) ultrafast electron microscopy (UEM), timed-pulse electron imaging and selected-area diffraction are used to study structural dynamics with space- and time-resolutions that allow direct observation of transformations affecting the fundamental properties of materials. Only recently, the UEM studies have begun to reveal a variety of dynamic responses of nanoscale specimens to material excitation, on ultrafast time scales and up to microseconds. Here, we give an account of some of these results, including imaging and diffraction dynamics of gold and graphite single crystal films, revealing atomic motions and morphology change in the former and two forms of acoustic resonance in the latter. We also report, for the first time, dynamic changes upon lattice excitation of moire fringes in graphite, recorded in bright- and dark-field images. Oscillations that are seen in moire fringe spacing and other selected-area image properties have the same temporal period as observed in Bragg spot changes in diffraction patterns from the same specimen areas. This period is shown to vary linearly with the local thickness of the specimen, thus establishing that the oscillations are due to excitation of a resonant elastic modulation of the film thickness and allowing derivation of a value of the Young's modulus (c(33)) of 36 GPa for the c-axis strain. The second form of resonance dynamics observed in graphite, on much longer time scales, corresponds to an out-of-plane drumming vibration of the film consistent with a 0.94 TPa elastic modulus for in-plane (a-axis) stretching. For the latter, the nanoscale membrane motion appears complicated ("chaotic") at early time and builds up to a resonance at longer times. Finally, electron energy loss spectroscopy (EELS) in the UEM provides a unique domain of study of chemical bonding on the time scale of change (femtoseconds), and its application to graphite is discussed. PMID- 19783101 TI - Diagnosis of Sarcocystis spp. in cattle (Bos taurus) and water buffalo (Bubalus bubalis) in Northern Vietnam. AB - Our aim was to develop a method for species diagnosis and to obtain data on the prevalence of Sarcocystis infections in cattle and water buffalo in the Son La Province of Northern Vietnam. Meat samples of naturally infected animals were examined by light and electron microscopy as well as by molecular methods. A PCR of part of the 18S rDNA gene followed by RFLP analysis was modified to detect infections with different Sarcocystis spp. in cattle and water buffaloes slaughtered in the Son La Province. It showed to be an economical method to detect multiple infections with Sarcocystis spp. Sequence analysis of the PCR amplicons was performed with selected samples and the results were compared with published sequences. With these methods the following Sarcocystis spp. were identified in cattle: Sarcocystis hirsuta, Sarcocystis cruzi and Sarcocystis hominis. Water buffaloes were infected with Sarcocystis fusiformis, S. cruzi, S. hominis and S. hirsuta. The results indicate that Sarcocystis spp. infecting cattle are also able to infect water buffaloes. So the validity of certain Sarcocystis spp. of water buffalo is discussed. Bovine lifestock in Northern Vietnam were commonly infected with Sarcocystis spp. PMID- 19783102 TI - Effects of glutamine added to enteral nutrition on Peyer's patch apoptosis in severely burned mice. AB - BACKGROUND AND AIMS: This study aimed to investigate the influence of enteral glutamine (GLN) supplementation on Peyer's patch apoptosis in severely burned mice. METHODS: Thirty-four mice were randomly assigned to a normal group (n=10), an EN group (n=12) and an EN supplemented with GLN (EN+GLN) group (n=12) and the mice in the EN and EN+GLN groups received a full-thickness scald burn over 20% total body surface area (TBSA) on the back. The burned mice then were fed orally with a common EN or an isonitrogenous and isocaloric EN supplemented with GLN for 7 days. On day 7 after injury, all surviving mice were euthanised and the entire intestine was collected. The percentage of apoptotic cells and cell percentage of phenotype in Peyer's patches were determined by flow cytometry (FCM). The FasL expression in Peyer's patches was analysed by reverse transcription polymer chain reaction (RT-PCR) and FCM. Both TNF-alpha levels and caspase-3 activity in Peyer's patches were also assessed. RESULTS: The results revealed that the percentage of lymphocyte subsets in Peyer's patches after burn injury significantly altered: the percentage of CD4 and CD19 cells declined and the percentage of CD8 cells correspondingly increased, when compared with the normal control mice (p<0.05). On the other hand, the total apoptotic ratio and all lymphocytes subset apoptosis in Peyer's patches were markedly increased (p<0.05), which were consistent with up-regulation in the FasL expression at the levels of both mRNA and protein, TNF-alpha levels and caspase-3 activity in Peyer's patches. Enteral GLN supplementation partially reversed these changes: the total apoptotic ratio and all lymphocytes subpopulation apoptosis in Peyer's patches were markedly decreased when compared with the EN group (p<0.05). The percentage of lymphocyte subsets within Peyer's patches also restored the condition prior to injury. However, no significant differences in the FasL expression, including mRNA and protein, were observed between the EN and EN+GLN groups. Although, both TNF-alpha levels and caspase-3 activity in Peyer's patches were lower in the EN+GLN group than in the EN group (p<0.05). CONCLUSIONS: This study suggests that enteral GLN supplementation is superior to a common enteral nutrition with respect to attenuating apoptosis in Peyer's patches, which might be more effective in decreasing TNF-alpha levels and down-regulating caspase-3 activity in Peyer's patches. PMID- 19783103 TI - Medial prefrontal cortex damage affects physiological and psychological stress responses differently in men and women. AB - The ability to produce appropriate physiological and psychological responses to stressful situations depends on accurate recognition and appraisal of such situations. Such ability is also important for proper emotion regulation. A number of studies have suggested that the medial prefrontal cortex (mPFC) plays a significant role in emotion regulation, as well as in the control of physiological endpoints of emotion regulation such as the hypothalamic-pituitary adrenal (HPA) axis and autonomic nervous system (ANS). Further, recent work has suggested that men and women may differ in these mechanisms of neural control of emotion regulation. Here, we examined the role of the human mPFC in self-report, ANS, and HPA stress reactivity by testing a group of participants with damage to this region (9 women and 9 men), a brain damaged comparison group (6 women and 6 men), and healthy comparison participants (27 women and 27 men) on an orthostatic challenge and the Trier Social Stress Test (TSST). The mPFC participants showed heightened self-reported stress in response to the TSST. In women, mPFC damage led to an increased cortisol response to the TSST. By contrast, in men, greater volume of mPFC damage was correlated with a decreased cortisol response. Finally, men with mPFC damage showed altered autonomic control of the heart (higher heart rate and lower high frequency heart rate variability) during an orthostatic challenge. These findings support the idea that the mPFC is involved in the regulation of physiological and psychological responses to stress and that this regulation may differ between men and women. PMID- 19783104 TI - Glucocorticoid receptor gene and depression in patients with coronary heart disease: the Heart and Soul Study-2009 Curt Richter Award Winner. AB - Alterations of glucocorticoid receptor sensitivity have been associated with depression. Thus, variation in the glucocorticoid receptor gene that determines glucocorticoid sensitivity may influence risk for depression. In a cross sectional genetic association study of 526 white outpatients with chronic coronary heart disease, we examined whether haplotypes of the glucocorticoid receptor gene (NR3C1) are associated with depression. Participants were genotyped for four common glucocorticoid receptor gene polymorphisms (ER22/23EK, BclI C/G, N363S, and 9beta A/G) and haplotype analyses were conducted. Depression was assessed by an interview (Computerized Diagnostic Interview Schedule). Of the 526 participants, 355 (67.5%) were non-carriers, 153 (29.1%) had one copy, and 17 (3.2%) had 2 copies of the haplotype 3 allele, which includes the minor allele of the 9beta A/G polymorphism and which has been associated with reduced glucocorticoid sensitivity. The prevalence of depression ranged from 24.4% in the non-carriers to 34.4% in heterozygotes to 52.9% in participants homozygous for the haplotype 3 allele (p<0.01). In logistic regression analyses, carriers of one haplotype 3 allele had an odds ratio of 1.64 (95% CI 1.1-2.5, p=0.02) for depression, while the odds ratio of homozygous haplotype 3 carriers was 3.52 (95% CI 1.3-9.4, p=0.01). These associations persisted after adjusting for potentially confounding variables. A common GR haplotype was associated with depression in a gene-dosage dependent manner and might be a vulnerability factor for depression. PMID- 19783105 TI - Imaging the immediate non-genomic effects of stress hormone on brain activity. AB - The stress hormones, glucocorticoids, bind to intracellular receptor proteins and act as transcription factors affecting gene activity. These genomic effects occur over hours and even days producing long-term changes in synaptic plasticity and neural transmission. In addition to this classic genomic pathway, there is evidence that stress hormones can have immediate, non-genomic effects on brain function. Using non-invasive functional magnetic resonance imaging, awake, adrenalectomized rats were given intravenous doses of corticosterone mimicking blood levels of hormone achieved with modest and intense stress. The dose of corticosterone mimicking high stress caused a significant increase in functional activity in the hippocampus, forebrain cortex and lateral hypothalamus within minutes of administration. This finding shows that stress hormones can have non genomic effects on brain activity potentially affecting the immediate cognitive and behavioral response to a highly emotional experience. PMID- 19783107 TI - Identification of peripheral blood mononuclear cells targeted by Ovine herpesvirus-2 in sheep. AB - Sheep-associated malignant catarrhal fever (MCF), caused by Ovine herpesvirus 2 (OvHV-2), is usually a fatal disease of various ruminants and swine. In contrast, natural OvHV-2 infection in sheep, which are the main OvHV-2 reservoir, proceeds without any clinical symptoms. Since the range of targeted cells may be important for pathogenesis, we wanted to analyze the natural range of peripheral mononuclear blood cells (PBMC) targeted by OvHV-2. To this end, OvHV-2-free sheep were exposed to natural infection and blood samples were taken at intervals. Four different PBMC subpopulations were purified by fluorescence activated cell sorting (FACS) before being subjected to analysis for OvHV-2-DNA. After an incubation period of between 11 and 12 weeks, all exposed sheep became positive for OvHV-2. In most sheep, a first peak of OvHV-2-DNA was identified in the CD2 and CD4 double positive subpopulation. However, with time, the highest load of OvHV-2-DNA shifted to the CD2-positive and CD4-negative T-cells. Furthermore, low amounts of OvHV-2-DNA were occasionally detected also in the fractions that represented either CD14-positive monocytes or triple negative cells (CD2(-)/CD4( )/CD14(-)). We conclude from these experiments that OvHV-2 has a similar host cellular range in sheep and cattle, respectively. Our results may be relevant in the context of comparative analysis of OvHV-2 pathogenesis in animal species that are susceptible to MCF. PMID- 19783106 TI - Combined effects of alcohol and hepatitis C: a secondary analysis of alcohol use biomarkers and high-risk behaviors from two medication trials for alcohol dependence. AB - OBJECTIVES: The goal of this secondary analysis was to examine the combined effects of HCV infection and recent alcohol use on baseline biologic markers of alcohol consumption in two outpatient medication trials for alcohol dependence. In addition, the relationship between Hepatitis C virus (HCV) infection and behavioral risk factors for HCV infection in these clinical populations were examined. METHODS: Data (n=345) from two randomized, placebo-controlled trials of naltrexone and psychosocial treatment for alcohol dependence (Study I, n=212) and comorbid alcohol and cocaine dependence (Study II, n=133) were used to examine baseline measures of HCV risk behaviors (injection drug use, needle sharing), and biomarkers of alcohol use (AST, ALT, GGT and CDT) were compared by HCV serostatus first within each study and then across studies. RESULTS: Although groups had differing sociodemographic profiles (as indicated by race, marital status, level of education) subjects in Study I exhibited no statistically significant differences from the Study II cohort in HCV prevalence (12.7 vs. 20.0%, p=0.07), lifetime history of injection drug use (13.8 vs. 22.0%, p=0.74), lifetime history of needle sharing (9.1 vs. 18.0%, p=0.62). As such, the data from both studies were analyzed together. Regardless of drinking status, HCV infection was significantly associated with an upward shift in the baseline level of ALT, AST, and GGT (p<0.006 for all measures) and a downward shift in baseline CDT (p=0.002). When using standard laboratory cutoff values to determine clinically significant elevations, HCV seropositivity was significantly associated with elevations in ALT, AST, GGT (p<0.001), and with decreases in CDT (p=.002). CONCLUSIONS: These data emphasize the importance of evaluating HCV infection and HCV risk behaviors at intake in medication trials for alcohol dependence and also raise questions regarding the use of cutoff scores for ALT, AST, GGT and CDT levels as biologic markers of alcohol use in subjects when HCV status is unknown. PMID- 19783108 TI - Regenerative medicine: a primer for paediatricians. AB - Regenerative medicine is a multidisciplinary field concerned with the replacement, repair or restoration of injured tissues. Cell therapy and tissue engineering are part of the broader remit of regenerative medicine. The ultimate aim is to provide safe and efficient therapies for a large number of clinical conditions. Novel regenerative therapies are already in use in initial clinical trials. The main components of regenerative medicine are cells and specially designed materials. A vast variety of cells types are currently used including: adult and stem cells. Equally a large number of natural and man-made materials have been investigated. Despite of considerable advances many challenges lie ahead. These are summarised in this review article. The field is slowly maturing and the initial unhelpful hype has been replaced by a more measured, mature and realistic outlook. PMID- 19783109 TI - Predicting age at onset of menopause: testing the "adaptive onset" hypothesis. AB - This study tests the "adaptive onset" hypothesis (AOH) proposed by Kuhle and explores the potential adaptive origins of menopause (Kuhle (2007) [3]). The AOH posits that both menopause and the timing of its onset are adaptive, and that age at onset may be mediated according to the likelihood of successful continued reproduction. Twelve factors were hypothesized to predict whether continued reproduction would be successful. Eight factors were tested using data extracted from the NLS Mature Women cohort. Statistical analyses reveal no support for predictions of the AOH; in fact, a majority of analyses suggest trends opposite from those predicted. PMID- 19783110 TI - Thiamine-deficient encephalopathy due to excessive intake of isotonic drink or overstrict diet therapy in Japanese children. AB - AIM: To report on two children with encephalopathy caused by dietary thiamine deficiency due to newly developing nutritional problems in contemporary Japan. SUBJECTS: A 1-year-old boy who had consumed 1l of isotonic drinks per day for 4 months after an episode of diarrhea, and presented with ocular movement disorder, dystonia, and unconsciousness. The other subject was an 11-month-old boy who suffered from vomiting and somnolence; he and his mother had atopic dermatitis, and he had been on a low-allergen diet that strictly restricted intake of eggs, dairy products, meat, and fish since his early infancy. RESULTS: Both patients showed decreased blood thiamine levels and magnetic resonance imaging revealed striatal and thalamic lesions. Thiamine administration yielded prompt improvement of symptoms, but cavitiform lesions in the bilateral putamen persisted in the first patient, accompanied by residual generalized dystonia. Marked elevation of blood/cerebrospinal lactate levels and severe hyponatremia were present in this patient. CONCLUSION: Thiamine-deficient encephalopathy in Japanese children due to excessive intake of sports drink or overstrict diet therapy for atopic dermatitis has been increasingly reported during the last decade, but is still not broadly recognized. These children may visit hospitals due to persistent vomiting as a symptom of thiamine deficiency, but glucose infusion without thiamine supplementation can aggravate their condition. Knowledge of these facts in medical and public settings is necessary to correct the erroneous impression that nutritional options given to ill children are necessarily beneficial for health, and promote awareness that they can be harmful when consumed in excess. PMID- 19783111 TI - Central nervous system and muscle involvement in an adolescent patient with riboflavin-responsive multiple acyl-CoA dehydrogenase deficiency. AB - We report an adolescent case of late-onset riboflavin-responsive multiple acyl CoA dehydrogenase deficiency (MADD) characterized by intermittent nausea and depressive state as early symptoms. At the age of 12 years and 11 months, the patient experienced intermittent nausea and vomiting, and depressive state. She was on medication for depression for 5 months but it was ineffective. Brain magnetic resonance imaging showed disseminated high-intensity areas in the periventricular white matter and in the splenium of the corpus callosum on T2 weighted images and fluid-attenuated inversion-recovery images. Progressive muscle weakness occurred and blood creatine kinase level was found to be elevated. The muscle biopsy revealed lipid storage myopathy. Urine organic acid analysis and mutation analysis of the ETFDH gene confirmed the diagnosis of MADD. With oral supplements of riboflavin and l-carnitine, in addition to a high calorie and reduced-fat diet, her clinical symptoms improved dramatically. Early diagnosis is important because riboflavin treatment has been effective in a significant number of patients with MADD. PMID- 19783112 TI - [Pneumocystis jiroveci pneumonia in an immunocompetent female patient]. AB - Pneumocystis jirovecci is an opportunist fungal agent that usually causes pneumonia in immunocompromised patients, particularly those presenting with AIDS. In rare cases, this fungus can cause pneumonia in immunocompetent patients. The symptomatology in this case is acute and fulminant. We report the case of a Pneumocystis jirovecci pneumonia in a young patient initially admitted for acute respiratory distress. This case is unusual since all the exams performed to screen for immune deficit were negative. The diagnosis was made after identifying Pneumocystis jirovecci cysts in broncho-alveolar lavage. PMID- 19783113 TI - [Brucella bacteremia reactivation 70 years after the primary infection]. AB - After primary infection, some bacteria can remain in a latent state for several years before a new bacteremia, often due to a weakened immune status. This is common for Mycobacterium tuberculosis, less for other pathogens more difficult to have in mind when facing patients with fever. We report the case of an 84-year old female patient presenting with fever in the months following antilymphoma chemotherapy, due to bacteremic brucellosis (with a hemophagocytic syndrome) probably latent after primary infection as a child. PMID- 19783114 TI - [Acute, hyperintense, and febrile cervicalgia. Crowned dens syndrome, a monofocal microcrystalline arthritis sometimes doubly misleading]. AB - Microcrystalline arthritis sometimes have atypical localizations and presentations. The crowned dens syndrome, due to hydroxyapatite or calcium pyrophosphate deposits in peri-odontoid ligaments of the atlas, can provoke acute or chronic cervicalgia or misleading presentations such as meningitidis or fever of unknown origin. We present a particularly severe new case requesting urgent surgery, and a literature review to alert clinicians and prevent misdiagnosing this syndrome. Indeed, calcifications may be very discrete or just incidental and prevent a complete diagnostic approach. PMID- 19783115 TI - Qualitative and quantitative analysis of traditional Chinese medicine Niu Huang Jie Du Pill using ultra performance liquid chromatography coupled with tunable UV detector and rapid resolution liquid chromatography coupled with time-of-flight tandem mass spectrometry. AB - An ultra performance liquid chromatography coupled with tunable UV detector (UPLC TUV) and rapid resolution liquid chromatography coupled with time-of-flight tandem mass spectrometry (RRLC-Q-TOF) method was developed for the quality assessment of Niu Huang Jie Du Pill (NHJDP), a commonly used traditional Chinese medicine (TCM). Ten compounds were simultaneously identified by electrospray ion mass spectrometry (ESI/MS) and comparison with reference standards and literature data. All of them were quantified by UPLC method. Baseline separation was achieved on an ODS-140HTP C(18) column (2.3mum, 100mmx2.1mm I.D.) with linear gradient elution of acetonitrile-0.1% formic acid. This developed method provides good linearity (r(2)>0.9996), repeatability (RSD<3.63%), intra- and inter-day precisions (RSD<0.86%) with accuracies (97.88-101.56%) and recovery (98.88 101.92%) of 10 major constituents, namely baicalin, baicalein, wogonoside, wogonin, glycyrrhizic acid, liquiritin, rhein, emodin, chrysophanol and physcion. In addition, the principal component analysis (PCA) coupled with the UPLC fingerprint was applied to classify the NHJDP samples according to their manufacture corporation. This proposed method with high sensitivity and selectivity was successfully utilized to analyze 10 major bioactive compounds in 30 batches of NHJDPs, and the results demonstrate that this analytical method is simple and suitable for the original discrimination and quality control of this TCM. PMID- 19783116 TI - Effectively discussing complementary and alternative medicine in a conventional oncology setting: communication recommendations for clinicians. AB - OBJECTIVE: Justifiable concerns around the use of complementary and alternative medicines (CAM) amongst cancer patients are becoming increasingly prominent. The aim was to develop evidence-based guidelines to assist oncology health professionals (HP) to have respectful, balanced and useful discussions with patients about CAM. METHODS: A systematic review was conducted, covering relevant literature from 1997 to 2007. The level of evidence was rated using a standardized rating system. The evidence was qualitatively synthesised into structured recommendations by a multidisciplinary team including a consumer. RESULTS: The search identified 78 original papers; 36 directly related to discussing CAM. No randomized controlled trials specifically addressing the methods or benefits of discussing CAM were identified. Evidence based guidelines are presented as a sequence of recommended steps: (1) Elicit the person's understanding of their situation; (2) Respect cultural and linguistic diversity and different epistemological frameworks; (3) Ask questions about CAM use at critical points in the illness trajectory; (4) Explore details and actively listen; (5) Respond to the person's emotional state; (6) Discuss relevant concerns while respecting the person's beliefs; (7) Provide balanced, evidence based advice; (8) Summarize discussions; (9) Document the discussion; (10) Monitor and follow-up. CONCLUSION: This represents the first comprehensive guidelines for discussing CAM. PRACTICE IMPLICATIONS: Given the concerns surrounding CAM use, it is critical to encourage informed decision-making about CAM and ultimately, improve outcomes for patients. PMID- 19783117 TI - Endothelin-1, endothelin converting enzyme-1 and endothelin receptors in the porcine corpus luteum. AB - Porcine corpora lutea (CL) fail to show a luteolytic response to prostaglandin-F 2alpha (PGF-2alpha) (ie, luteolytic sensitivity [LS]) until about day 12-13 of the estrous cycle. Although little is known of the control of LS in any species, endothelin-1 (EDN1) is believed to play a role in LS control in ruminants. Therefore, we measured mRNA and protein expression and examined the cellular localization of EDN1 precursor (pre-pro EDN1, or ppEDN1), EDN-converting enzyme-1 (ECE1), and EDN receptors (A, EDNRA and B, EDNRB) in porcine CLs collected on days 4, 7, 10, 13, and 15 of the estrous cycle to look for differences between CLs displaying (days 13-15) versus those lacking (days 4-10) LS. Abundance of ppEDN1 mRNA was greatest (and significant vs all other days) on day 7 of the cycle, whereas EDN1 protein expression did not vary during the cycle and was localized exclusively to endothelial cells (EC). Abundance of ECE1 mRNA was also greatest on day 7 (vs all other days), but ECE1 protein was significantly elevated on day 10 (vs day 4) and was immunolocalized to ECs and large luteal cells (LLC). Abundance of EDNRA mRNA was also maximal on day 7 (vs all other days) of the cycle, whereas EDNRA protein expression was not significantly changed during the cycle and was observed in LLCs, ECs, and small luteal cells (SLC). On day 13, EDNRB mRNA was significantly decreased (versus day 7). Expression of EDNRB protein was decreased on day 10 (versus all other days), and on days 13-15 (vs day 4), and was primarily localized to ECs. In conclusion, the observed elevation in ECE1 protein concentrations on day 10 and the presence of EDNRA on LLC suggests a possible role for EDN1 (resulting from the actions of ECE1) acting via EDNRA in the control of LS in the pig. PMID- 19783118 TI - Metabolic adaptations to heat stress in growing cattle. AB - To differentiate between the effects of heat stress (HS) and decreased dry matter intake (DMI) on physiological and metabolic variables in growing beef cattle, we conducted an experiment in which a thermoneutral (TN) control group (n=6) was pair fed (PF) to match nutrient intake with heat-stressed Holstein bull calves (n=6). Bulls (4 to 5 mo old, 135 kg body weight [BW]) housed in climate controlled chambers were subjected to 2 experimental periods (P): (1) TN (18 degrees C to 20 degrees C) and ad libitum intake for 9 d, and (2) HS (cyclical daily temperatures ranging from 29.4 degrees C to 40.0 degrees C) and ad libitum intake or PF (in TN conditions) for 9 d. During each period, blood was collected daily and all calves were subjected to an intravenous insulin tolerance test (ITT) on day 7 and a glucose tolerance test (GTT) on day 8. Heat stress reduced (12%) DMI and by design, PF calves had similar nutrient intake reductions. During P1, BW gain was similar between environments and averaged 1.25 kg/d, and both HS and PF reduced (P<0.01) average daily gain (-0.09 kg/d) during P2. Compared to PF, HS decreased (P<0.05) basal circulating glucose concentrations (7%) and tended (P<0.07) to increase (30%) plasma insulin concentrations, but neither HS nor PF altered plasma nonesterified fatty acid concentrations. Although there were no treatment differences in P2, both HS and PF increased (P<0.05) plasma urea nitrogen concentrations (75%) compared with P1. In contrast to P1, both HS and PF had increased (16%) glucose disposal, but compared with PF, HS calves had a greater (67%; P<0.05) insulin response to the GTT. Neither period nor environment acutely affected insulin action, but during P2, calves in both environments tended (P=0.11) to have a blunted overall glucose response to the ITT. Independent of reduced nutrient intake, HS alters post-absorptive carbohydrate (basal and stimulated) metabolism, characterized primarily by increased basal insulin concentrations and insulin response to a GTT. However, HS induced reduction in feed intake appears to fully explain decreased average daily gain in Holstein bull calves. PMID- 19783119 TI - Semi-supervised learning for tree-structured ensembles of RBF networks with Co Training. AB - Supervised learning requires a large amount of labeled data, but the data labeling process can be expensive and time consuming, as it requires the efforts of human experts. Co-Training is a semi-supervised learning method that can reduce the amount of required labeled data through exploiting the available unlabeled data to improve the classification accuracy. It is assumed that the patterns are represented by two or more redundantly sufficient feature sets (views) and these views are independent given the class. On the other hand, most of the real-world pattern recognition tasks involve a large number of categories which may make the task difficult. The tree-structured approach is an output space decomposition method where a complex multi-class problem is decomposed into a set of binary sub-problems. In this paper, we propose two learning architectures to combine the merits of the tree-structured approach and Co Training. We show that our architectures are especially useful for classification tasks that involve a large number of classes and a small amount of labeled data where the single-view tree-structured approach does not perform well alone but when combined with Co-Training, it can exploit effectively the independent views and the unlabeled data to improve the recognition accuracy. PMID- 19783120 TI - Double mitral valve imaging. AB - Double-orifice mitral valve is an uncommon anomaly of the mitral valve with a single fibrous annulus with 2 orifices opening into the left ventricle. Three major types of this anomaly are recognized: (1) the eccentric or hole type (accounting for about 85%), (2) the central or bridge type (about 15%), and (3) duplicate mitral valve, which involves 2 mitral valve annuli and valves, each with its own set of leaflets, commissures, chordae, and papillary muscles. However, some echocardiographic artifacts also may lead to interesting appearances. The duplicating of cardiac valves by refraction of the ultrasound beam or mirror images has rarely been reported. The authors present the duplication of a moving mitral valve associated with an echocardiographic refraction artifact. PMID- 19783121 TI - Prognostic value of ventricular-arterial coupling and B-type natriuretic peptide in patients after myocardial infarction: a five-year follow-up study. AB - BACKGROUND: The aim of this study was to determine the prognostic role of ventricular-arterial coupling compared with B-type natriuretic peptide (BNP) in patients after myocardial infarctions. METHODS: Forty-one consecutive patients with history of myocardial infarctions were enrolled. Ventricular-arterial coupling was assessed as the ratio between arterial elastance (E(a)) and end systolic ventricular elastance (E(es)). E(a) and E(es) were calculated using systolic and diastolic blood pressure, echocardiographically derived stroke volume, left ventricular ejection fraction, and the ratio between aortic preejection time and total systolic time. Cardiovascular mortality was the prespecified endpoint, with 5-year follow-up. RESULTS: BNP was significantly correlated with New York Heart Association class and known echocardiographic parameters of systolic and diastolic left ventricular function and also with the E(a)/E(es) ratio (P = .001), which emerged as an independent correlate of BNP in multivariate analysis. The E(a)/E(es) ratio demonstrated good accuracy in predicting long-term cardiovascular mortality (area under the receiver operating characteristic curve, 0.73; P = .019), comparable with that of BNP in patients after myocardial infarctions. CONCLUSION: Ventricular-arterial coupling assessed using the E(a)/E(es) ratio is an independent echocardiographic correlate of BNP levels in patients with previous myocardial infarctions and has a significant role in predicting long-term cardiovascular mortality in this setting. PMID- 19783122 TI - Dietary total antioxidant capacity is negatively associated with some metabolic syndrome features in healthy young adults. AB - OBJECTIVE: Oxidative stress has been related to the development of obesity and other features accompanying chronic diseases. Furthermore, dietary antioxidant intake has been suggested to protect against oxidative damage and related clinical complications. Therefore, the aim of this study was to assess the potential associations among dietary total antioxidant capacity (TAC) and several early metabolic syndrome manifestations in healthy young adults. METHODS: Anthropometric variables and blood pressure from 153 healthy subjects (20.8+/-2.7 y old) were measured. Dietary intake was assessed by a validated food-frequency questionnaire and a 3-d record, which were also used to calculate TAC and to adjust by daily energy intake. Fasting blood samples were collected for measuring biochemical markers. RESULTS: Dietary TAC showed positive and significant associations with fiber, folic acid, vitamin A and C, magnesium, selenium, and zinc intakes, after adjusting by sex and daily energy intake. Interestingly, systolic blood pressure, serum glucose, and free fatty acids were also found to be negatively associated with dietary TAC independently of sex and daily energy intake. Also, a relevant relation was found between body mass index and TAC values. Interestingly, after adjusting by sex and daily energy intake, complement factor-3 circulating levels appeared to be negatively and significantly associated with dietary TAC, whereas blood plasminogen activator inhibitor-1 and homocysteine concentrations showed an inverse marginally statistical trend. CONCLUSIONS: These data suggest that dietary TAC may be also a potential early estimate of the risk to develop metabolic syndrome features and that dietary TAC could be a useful research tool in assessing antioxidant intake. PMID- 19783123 TI - Associations between electroencephalographic and magnetic resonance imaging findings in tuberous sclerosis complex. AB - Nearly 90% of patients with tuberous sclerosis complex (TSC) develop epilepsy; however the mechanisms of epileptogenesis remain unclear. Some cortical tubers are thought to be epileptogenic while others are not. This study aimed to evaluate whether tuber burden, size or type seen on magnetic resonance imaging (MRI) co-registers with interictal epileptiform discharges on electroencephalogram (EEG). EEG and MRI data from 69 patients with TSC were reviewed by dividing the cerebrum into four quadrants. Quadrants containing greatest tuber burden, largest tuber, calcified tubers, cyst-like tubers, and no tubers were identified on MRI. For EEG analysis, spikes and sharp waves were counted and averaged to a value per minute, and each quadrant was assigned a score. MRI and EEG findings were compared in each patient. The presence of a cyst like tuber in a quadrant correlated with a higher incidence of epileptiform activity in the same quadrant (p=0.002). This finding supports the notion that cyst-like cortical tubers may contribute to the more severe epilepsy profile seen in TSC patients with these lesions. Quadrants containing greatest tuber burden, largest tubers, and calcified tubers were not predictive of regional interictal epileptiform activity. Furthermore, quadrants without any apparent tuber co registered with interictal epileptiform discharges in two patients, suggesting a multifactorial component of epileptogenicity in TSC. PMID- 19783124 TI - Relationship between clinical and neuropsychological characteristics in child and adolescent first degree relatives of subjects with schizophrenia. AB - INTRODUCTION: Studies have shown higher rates of psychopathology and cognitive difficulties among relatives of schizophrenia patients than among the general population. This study aimed to analyze the relationship between clinical and neuropsychological characteristics in children and adolescents at high genetic risk for schizophrenia. METHODS: Participants were 26 children and adolescent first-degree relatives of subjects diagnosed with schizophrenia (high-risk [HR] group) and 20 controls whose parents and siblings did not meet DSM-IV criteria for any psychotic disorder. These two groups were matched by age, sex and socio economic status and clinical and neuropsychological assessments were completed by all participants. RESULTS: Among HR children 42.3% were diagnosed with one or more DSM-IV axis I psychiatric disorders. The most common diagnoses were attention deficit/hyperactivity disorder (ADHD) (34.6%) and generalized anxiety disorder (3.8%) There were significant differences between HR children and controls with respect to prodromal symptoms, behavioral problems and premorbid adjustment, as well as on the majority of intelligence subscales, working memory and logical memory. When differences between HR with ADD (HR-ADD), HR without ADD (HR-NADD) and controls were analyzed, significantly higher scores on clinical scales of prodromal symptoms, behavioral problems and premorbid adjustment were found in HR-ADD than in HR-NADD or controls. There were no significant differences in cognitive domains between HR-ADD and HR-NADD, but there were between HR-ADD and controls and between HR-NADD and controls on the Verbal Comprehension Index, Perceptual Reasoning Index, Working Memory Index and GAI. CONCLUSIONS: Compared to controls, HR children showed more clinical symptoms and cognitive abnormalities. HR children with ADD had worse clinical symptoms than did HR without ADD, although there were no differences in terms of cognitive abnormalities. Both HR groups seem to have similar deficits in neuropsychological performance. PMID- 19783125 TI - Apoptosis-like death in Leishmania donovani promastigotes induced by diospyrin and its ethanolamine derivative. AB - Previous studies have demonstrated that diospyrin (1), a quinonoid plant product, can inhibit the growth of Leishmania donovani parasites. Here, several derivatives of 1 were evaluated by the MTT assay and it was observed that the ethanolamine analogue (10) exhibited maximum cytotoxicity [50% inhibitory concentration (IC(50))=2.9 microM] against L. donovani promastigotes. Subsequently, the mode of cell death in promastigotes was investigated through externalisation of membrane-associated phosphatidylserine, mitochondrial membrane depolarisation, DNA laddering and in situ labelling of DNA fragmentation by terminal deoxyribonucleotidyl transferase-mediated dUTP nick-end labelling (TUNEL) methods. Whilst both 1 and 10 were found to induce apoptosis-like death in promastigotes, the effect of 10 was evidently stronger even at a lower concentration. Hence, the ethanolamine derivative (10) of diospyrin (1) may be a prospective 'lead' for the development of novel cytotoxic agents inducing apoptosis in L. donovani parasites. PMID- 19783126 TI - Prevalence and awareness of cardiovascular risk factors in patients with schizophrenia: a cross-sectional study in a low cardiovascular disease risk geographical area. AB - OBJECTIVE: Prevalence of cardiovascular disease is high in schizophrenia. Our aim is to estimate the prevalence of cardiovascular risk factors (CVRF) among schizophrenia patients. METHOD: National cross-sectional study in patients diagnosed with schizophrenia under treatment with second generation antipsychotics and admitted to short-stay hospitalisation units. RESULTS: A sample of 733 consecutively admitted patients was enrolled; the most prevalent CVRFs were smoking 71% (95% CI: 67-74%) and hypercholesterolemia 66% (61-70%) followed by hypertriglyceridemia 26% (26-32%), hypertension 18% (15-21%) and diabetes 5% (4-7%). Metabolic syndrome showed 19% (95% CI: 16-23%) prevalence or, according to updated definitions (Clin Cornerstone 7 [2005] 36-45), 24% (95% CI: 20-28%). The rate of patients within the high-risk range of a 10-year fatal cardiovascular event was 6.5%. CVRFs under routine management were diabetes (60%), hypertension (28%) and, to a lesser extent, dyslipemia (14%). Treatment for CVRFs was associated to gender, men for hypertension OR = 25.34, p < 0.03 and women for diabetes OR = 0.02, p < 0.03. CONCLUSION: We found that CVRFs in schizophrenia were prevalent and under-diagnosed, and thus with insufficient therapeutic management. PMID- 19783127 TI - Transdermal delivery of anticancer drug caffeine from water-in-oil nanoemulsions. AB - Recently caffeine has been investigated for the treatment of various types of cancers upon oral administration. There is also some evidence that dermally applied caffeine can protect the skin from skin cancer caused by sun exposure. Therefore nanoemulsion formulation of caffeine for transdermal drug delivery was developed and evaluated in the present investigation. Different w/o nanoemulsion formulations of caffeine were prepared by oil phase titration method. Thermodynamically stable nanoemulsions were characterized for morphology, droplet size, viscosity and refractive index. The in vitro skin permeation studies were performed on Franz diffusion cell using rat skin as permeation membrane. The in vitro skin permeation profile of optimized formulation was compared with aqueous solution of caffeine. Significant increase in permeability parameters was observed in nanoemulsion formulations (P<0.05) as compared to aqueous solution of caffeine. The steady-state flux (J(ss)) and permeability coefficient (K(p)) for optimized nanoemulsion formulation (C12) were found to be 147.55+/-8.21 microg/cm(2)/h and 1.475 x 10(-2)+/-0.031 x 10(-2)cm/h, respectively. Enhancement ratio (E(r)) was found to be 17.37 in optimized formulation C12 compared with other formulations. Overall these results suggested that w/o nanoemulsions are good carriers for transdermal delivery of caffeine. PMID- 19783128 TI - Using thiophilic magnetic beads in purification of antibodies from human serum. AB - The rapid progress of biotechnology, immunology and molecular biology are requiring antibodies with higher purity and stronger activity. Therefore, the development of efficient technology, which is suitable for large-scale purification of antibodies at low cost, becomes much more urgent. In this study, we presented a novel method to isolate immunoglobulin G from human serum based on the utilization of thiophilic magnetic polymer beads. Micron-sized magnetic beads with paramagnetic properties were synthesized by microsuspension polymerization in the presence of modified magnetite. After the thiophilic ligand of 2 mercaptonicotinic acid was modified on the surface, these magnetic beads exhibited a strong specificity towards immunoglobulin G in a salt-independent manner. Then, antibodies could be directly isolated from human serum in batch wise mode with the assistance of magnetic decantation. The purity of the isolated antibody exceeded 94%. Because isolation was performed in physiological conditions, bioactivity of the antibody was fully preserved (>99%). Prominent advantages of this method, such as strong specificity, rapid processing, mild conditions, conventional equipment and excellent reusability, make this non chromatographic technology embody great potentialities to isolate the antibodies on a large scale. PMID- 19783129 TI - Interaction of human mesenchymal stem cells with osteopontin coated hydroxyapatite surfaces. AB - In vitro studies of the initial attachment, spreading and motility of human bone mesenchymal stem cells have been carried out on bovine osteopontin (OPN) coated hydroxyapatite (HA) and gold (Au) model surfaces. The adsorption of OPN extracted from bovine milk was monitored by the quartz crystal microbalance with dissipation (QCM-D) and the ellipsometry techniques, and the OPN coated surfaces were further investigated by antigen-antibody interaction. It is shown that the OPN surface mass density is significantly lower and that the number of antibodies binding to the resulting OPN layers is significantly higher on the HA as compared to the Au surfaces. The initial attachment, spreading and motility of human mesenchymal stem cells show a larger cell area, a faster arrangement of vinculin in the basal cell membrane and more motile cells on the OPN coated HA surfaces as compared to the OPN coated Au surfaces and to the uncoated Au and HA surfaces. These in vitro results indicate that there may be great potential for OPN coated biomaterials, for instance as functional protein coatings or drug delivery systems on orthopaedic implants or scaffolds for tissue-engineering. PMID- 19783130 TI - Hyperplasia of the lymphoepithelium of NALT in rats but not in mice upon 28-day exposure to 15 ppm formaldehyde vapor. AB - To investigate if local lymphoid tissues are a target of FA, nasopharynx associated lymphoid tissues (NALT) and upper-respiratory tract-draining lymph nodes were examined in a 28-day inhalation study with FA vapor in Fischer-344 rats and B6C3F1 mice. Paraffin-embedded tissues were sectioned and stained with H&E or stained immunohistochemically for cell proliferation (BrdU incorporation). Light microscopy revealed simple hyperplasia of NALT lymphoepithelium of rats exposed to 15 ppm and an increased proliferation rate of the epithelial cells. Principal component (discriminant) analysis of rat NALT and lymph nodes data did not reveal other effects or effects at lower exposure levels. Mice tissues were not affected. It was concluded that hyperplasia of the lymphoepithelium of NALT of rats exposed to 15 ppm was the only distinct effect of FA vapor on local lymphoid tissues (NALT and lymph nodes) of Fischer-344 rats and B3C3F1 mice. PMID- 19783131 TI - Rapid deposition of glomerular IgA in BALB/c mice by nivalenol and its modifying effect on high IgA strain (HIGA) mice. AB - To clarify the underlying mechanisms of IgA nephropathy (IgAN) induced by nivalenol (NIV), a trichothecene mycotoxin, we examined the time and dose relationships of glomerular deposition of IgA by NIV in BALB/c mice (Experiment 1), and also evaluated the modification of NIV on spontaneous IgAN in an inbred murine model, a high IgA strain (HIGA), during its early stage of pathogenesis (Experiment 2). In Experiment 1, female BALB/c mice were given a diet containing 0, 12, or 24 ppm concentration of NIV for 4 or 8 weeks. An increase in serum IgA levels was found at 24 ppm from 4 weeks. At week 8 of treatment, dose-dependent increases in serum IgA levels and glomerular deposition of IgA and IgG were observed without accompanying histopathological glomerular changes. On the other hand, in Experiment 2, control HIGA mice exhibited rather high levels of serum IgA as compared with BALB/c mice from 4 weeks of experiment as well as glomerular deposition of IgA and IgG and mesangial proliferation as revealed at week 8. NIV at 24ppm further increased serum IgA in this strain; however, it did not enhance glomerular immunoglobulin deposition or histopathological lesion. These results suggest that NIV-induced increase of serum IgA levels may be primarily responsible for glomerular immunoglobulin deposition; however, NIV does not enhance glomerular IgA deposition that may lead to exacerbation of predisposed IgAN in the short term, irrespective of the further elevation of serum IgA from the high basal levels. PMID- 19783132 TI - Assessing evidence for a causal link between cannabis and psychosis: a review of cohort studies. AB - Over the past five years, the release of cohort studies assessing the link between cannabis and psychosis has increased attention on this relationship. Existing reviews generally conclude that these cohort studies show cannabis has a causal relationship to psychosis, or at least that one cannot be excluded. Few studies have evaluated the relative strengths and limitations of these methodologically heterogeneous cohort studies, and how their relative merits and weaknesses might influence the way the link between cannabis use and psychosis is interpreted. This paper reviews the methodological strengths and limitations of major cohort studies which have looked at the link between cannabis and psychosis, and considers research findings against criteria for causal inference. Cohort studies that assessed the link between cannabis and psychosis were identified through literature searches using relevant search terms and MEDline, PsycINFO and EMBASE. Reference lists of reviews and key studies were hand searched. Only prospective studies of general population cohorts were included. Findings were synthesised narratively. A total of 10 key studies from seven general population cohorts were identified by the search. Limitations were evident in the measurement of psychosis, consideration of the short-term effects of cannabis intoxication, control of potential confounders and the measurement of drug use during the follow-up period. Pre-existing vulnerability to psychosis emerged as an important factor that influences the link between cannabis use and psychosis. Whilst the criteria for causal association between cannabis and psychosis are supported by the studies reviewed, the contentious issue of whether cannabis use can cause serious psychotic disorders that would not otherwise have occurred cannot be answered from the existing data. Further methodologically robust cohort research is proposed and the implications of how evidence informs policy in the case of uncertainty is discussed. PMID- 19783133 TI - Poultry litter-based activated carbon for removing heavy metal ions in water. AB - Utilization of poultry litter as a precursor material to manufacture activated carbon for treating heavy metal-contaminated water is a value-added strategy for recycling the organic waste. Batch adsorption experiments were conducted to investigate kinetics, isotherms, and capacity of poultry litter-based activated carbon for removing heavy metal ions in water. It was revealed that poultry litter-based activated carbon possessed significantly higher adsorption affinity and capacity for heavy metals than commercial activated carbons derived from bituminous coal and coconut shell. Adsorption of metal ions onto poultry litter based carbon was rapid and followed Sigmoidal Chapman patterns as a function of contact time. Adsorption isotherms could be described by different models such as Langmuir and Freundlich equations, depending on the metal species and the coexistence of other metal ions. Potentially 404 mmol of Cu2+, 945 mmol of Pb2+, 236 mmol of Zn2+, and 250-300 mmol of Cd2+ would be adsorbed per kg of poultry litter-derived activated carbon. Releases of nutrients and metal ions from litter derived carbon did not pose secondary water contamination risks. The study suggests that poultry litter can be utilized as a precursor material for economically manufacturing granular activated carbon that is to be used in wastewater treatment for removing heavy metals. PMID- 19783134 TI - Protein technologies. PMID- 19783135 TI - Bringing together components of the fly renal system. AB - The function of all animal excretory systems is to rid the body of toxins and to maintain homeostatic balance. Although excretory organs in diverse animal species appear superficially different they are often built on two common principals: filtration and tubular secretion/reabsorbtion. The Drosophila excretory system is composed of filtration nephrocytes and Malpighian (renal) tubules. Here we review recent molecular genetic data on the development and differentiation of nephrocytes and renal tubules. We focus in particular on the molecular mechanisms that underpin key cell and tissue behaviours during morphogenesis, drawing parallels with other species where they exist. Finally we assess the implications of patterned tissue differentiation for the subsequent regulation of renal function. These studies highlight the continuing usefulness of the fly to provide fundamental insights into the complexities of organ formation. PMID- 19783136 TI - Sequential high-dose chemotherapy for children with metastatic rhabdomyosarcoma. AB - AIM: The RMS4.99 study was designed to explore the role of multiple sequential high-dose chemotherapy cycles administered early in the treatment of children with metastatic rhabdomyosarcoma. PATIENTS AND METHODS: Seventy patients were enrolled and received three cycles of initial standard chemotherapy, followed by a course of cyclophosphamide and etoposide to obtain peripheral blood stem cells (PBSC), then three consecutive high-dose combinations followed by PBSC rescue. This was followed by surgery and/or radiotherapy, after which a final maintenance treatment with six courses of vincristine, actinomycin D and cyclophosphamide was administered. RESULTS: Sixty-two patients underwent the high-dose chemotherapy phase. The 3-year overall survival (OS) and progression free survival (PFS) rates for the 70 patients were 42.3% (95% confidence interval [CI] 39.5-53.6) and 35.3% (95% CI, 24.3-46.5), respectively. By multivariate analysis survival correlated strongly with age > 10 years. In a subset of patients with only one or no unfavourable prognostic factors (age > 10 years, unfavourable site of primary tumour, bone or bone marrow involvement and number of metastatic sites >2) the PFS was significantly higher, i.e. 60.5% at 3 years. CONCLUSION: Our study confirms that patients with favourable prognostic characteristics have a better survival. The use of sequential cycles of high-dose chemotherapy did not appear of benefit for patients with metastatic rhabdomyosarcoma. PMID- 19783137 TI - Effect of rhamnolipid on the aerobic removal of polyaromatic hydrocarbons (PAHs) and COD components from petrochemical wastewater. AB - The removal efficiencies of 15 PAHs and some COD components (inert, readily degradable, slowly degradable and metabolic products) from a wastewater taken from a petrochemical industry treatment plant (Izmir, Turkey) have been determined using an aerobic completely stirred tank reactor (CSTR). Addition of rhamnolipid surfactant (15 mg l(-1)) increased the removal efficiencies of PAHs and soluble COD from 72% and 90% to 80% and 99%, respectively. The rhamnolipid treatment caused a significant increase of 5- and 6-ring PAH degradation. The soluble COD removal efficiency was 93%, in CSTR reactors with rhamnolipid added. The inert COD removal efficiency was 60% in a CSTR reactor containing rhamnolipid. Batch tests showed that removal arising from the adsorption of the PAHs was low (between 1.88% and 4.84%) while the removal of PAHs from the petrochemical industry wastewater via volatilization varied between 0.69% and 5.92%. Low sorption capacity (K(p)) values for refinery activated sludge (approximately 2.98 l g(-1)) confirmed that bio-sorption was not an important mechanism controlling the fate of PAHs in aerobic CSTR reactors. Models proposed to simulate the PAH removal indicated that 94% of the PAHs were removed via biodegradation. PMID- 19783138 TI - Influence of carbon sources and C/N ratio on EPS production in anaerobic sequencing batch biofilm reactors for wastewater treatment. AB - The objective of this work was to evaluate the influence of different carbon sources and the carbon/nitrogen ratio (C/N) on the production and main composition of insoluble extracellular polymers (EPS) produced in an anaerobic sequencing batch biofilm reactor (ASBBR) with immobilized biomass in polyurethane foam. The yield of EPS was 23.6 mg/g carbon, 13.3 mg/g carbon, 9.0 mg/g carbon and 1.4 mg/g carbon when the reactor was fed with glucose, soybean oil, fat acids, and meat extract, respectively. The yield of EPS decreased from 23.6 to 2.6 mg/g carbon as the C/N ratio was decreased from 13.6 to 3.4 gC/gN, using glucose as carbon source. EPS production was not observed under strict anaerobic conditions. The results suggest that the carbon source, microaerophilic conditions and high C/N ratio favor EPS production in the ASBBR used for wastewater treatment. Cellulose was the main exopolysaccharide observed in all experimental conditions. PMID- 19783139 TI - Discovery of 3-(2-cyano-4-pyridyl)-5-(4-pyridyl)-1,2,4-triazole, FYX-051 - a xanthine oxidoreductase inhibitor for the treatment of hyperuricemia [corrected]. AB - Our previous study identified 2-[2-(2-methoxyethoxy)ethoxy]-5-[5-(2-methyl-4 pyridyl)-1H-[1,2,4] triazol-3-yl]benzonitrile (2)[corrected]as a safe and potent xanthine oxidoreductase (XOR) inhibitor for the treatment of hyperuricemia. Here, we synthesized a series of 3,5-dipyridyl-1,2,4-triazole derivatives and, in particular, examined their in vivo activity in lowering the serum uric acid levels in rats. As a result, we identified 3-(2-cyano-4-pyridyl)-5-(4-pyridyl) 1,2,4-triazole (FYX-051, compound 39) [corrected] to be one of the most potent XOR inhibitors; it exhibited an extremely potent in vivo activity, weak CYP3A4 inhibitory activity and a better pharmacokinetic profile than compound 2. Compound 39 is currently being evaluated in a phase 2 clinical trial. PMID- 19783140 TI - A dynamic target-based pharmacophoric model mapping the CD4 binding site on HIV-1 gp120 to identify new inhibitors of gp120-CD4 protein-protein interactions. AB - A dynamic target-based pharmacophoric model mapping the CD4 binding site on HIV-1 gp120 was built and used to identify new hits able to inhibit gp120-CD4 protein protein interactions. Two compounds showed micromolar inhibition of HIV-1 replication in cells attributable to an interference with the entry step of infection, by direct interaction with gp120. Inactivity of compounds toward a M475I strain suggested specific contacts with the Phe43 cavity of gp120. PMID- 19783141 TI - Synthesis of (R,S)-[4-11C]baclofen via Michael addition of nitromethane labeled with short-lived 11C. AB - The synthesis of (R,S)-[4-11C]baclofen, the first 11C-labeled GABAB agonist, was demonstrated via Michael addition of nitro[11C]methane as a key step. A tetrabutylammonium fluoride promoted Michael addition of nitro[11C]methane to methyl p-chlorocinnamate, followed by the nitro-group reduction in the presence of NiCl2 and NaBH4 in aqueous MeOH and alkaline hydrolysis yielded (R,S)-[4 11C]baclofen in 36.4+/-1.8% radiochemical conversion in three steps within 20 min. PMID- 19783142 TI - Thiazolidinedione derivatives as PTP1B inhibitors with antihyperglycemic and antiobesity effects. AB - Benzylidene-2,4-thiazolidinedione derivatives with substitutions on the phenyl ring at the ortho or para positions of the thiazolidinedione (TZD) group were synthesized as PTP1B inhibitors with IC50 values in a low micromolar range. Compound 3e, the lowest, bore an IC50 of 5.0 microM. In vivo efficacy of 3e as an antiobesity and hypoglycemic agent was evaluated in a mouse model system. Significant improvement of glucose tolerance was observed. This compound also significantly suppressed weight gain and significantly improved blood parameters such as TG, total cholesterol and NEFA. Compound 3e was also found to activate peroxisome proliferator-activated receptors (PPARs) indicating multiple mechanisms of action. PMID- 19783143 TI - Special ergolines are highly selective, potent antagonists of the chemokine receptor CXCR3: discovery, characterization and preliminary SAR of a promising lead. AB - The special ergoline 1 is a highly potent, selective antagonist of the chemokine receptor CXCR3. The surprising selectivity of this LSD-related compound can be explained by different electronic and steric properties of the ergoline core structure caused by the urea portion of the molecule. Discovery, biopharmaceutical properties and first derivatives of this promising lead compound are discussed. PMID- 19783144 TI - Functional and biochemical analysis of a key series of ramoplanin analogues. AB - Ramoplanin is a potent lipoglycodepsipeptide antibiotic that is active against a wide range of Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococcus (VRE). It acts as an inhibitor of peptidoglycan (PG) biosynthesis that disrupts glycan chain polymerization by binding and sequestering Lipid II, a PG precursor. Herein, we report the functional antimicrobial activity (MIC, S. aureus) and fundamental biochemical assessments against a peptidoglycan glycosyltransferase (Escherichia coli PBP1b) of a set of key alanine scan analogues of ramoplanin that provide insight into the importance and role of each of its individual amino acid residues. PMID- 19783145 TI - Point mutations in Czech DMD/BMD patients and their phenotypic outcome. AB - Duchenne and Becker muscular dystrophies (DMD/BMD) are associated with mutations in the DMD gene. We determined the mutation status of 47 patients with dystrophinopathy without deletion or duplication in the DMD gene by screening performed by reverse transcription-PCR, protein truncation test, and DNA sequencing. We describe three patients with a mutation creating a premature termination codon (p.E55X, p.E1110X, and p.S3497PfsX2) but with a mild phenotype, which present three different ways of rescuing the DMD phenotype. In one patient we detected the insertion of a repetitive sequence AluYa5 in intron 56, which led to skipping of exon 57. Further, using quantitative analysis of DMD mRNA carrying various mutated alleles, we examine levels of mRNA degradation due to nonsense mediated mRNA decay. The quantity of dystrophin mRNA is different depending on the presence of a mutation leading to a premature termination codon, and position of the analysed mRNA region with respect to its 5' end or 3' end. Average relative amounts of DMD mRNAs carrying a premature termination codon is 48% and 17%, when using primers amplifying the 5' and 3' cDNA regions, respectively. PMID- 19783146 TI - Current advances in the development of therapies for neuromuscular disorders based on myostatin signalling, 3rd International Institute of Myology Workshop, Paris, September 12th, 2008. PMID- 19783147 TI - Bisphosphonate osteonecrosis of the jaws in cancer patients. PMID- 19783148 TI - Clinicoradiological presentation, management options and a review of sellar and suprasellar tuberculomas. AB - Clinicoradiological presentation and management of patients with sellar and suprasellar tuberculomas (SST) were reviewed. The SSTs of eight patients were divided into five radiological subgroups: a sellar-suprasellar mass (n=3); multiple coalescing ring enhancing granulomas (n=2); an intrasellar abscess (n=1); pachymeningitis with suprasellar extension (n=1); and skull-base lesion involving the sella (n=1). The predominant endocrinopathies were hypogonadism, hypothyroidism and diabetes insipidus. The management options included surgery utilizing the frontotemporal, transylvian approach (n=4) or the transsphenoidal approach (n=1), stereotactic biopsy and ventriculoperitoneal shunt (n=1); endoscopic transsphenoidal biopsy (n=1); and antituberculous therapy (ATT) without surgery (n=1). All patients received ATT for 15-18 months. Patients with rapid visual deterioration (n=2) or with associated intramedullary tuberculoma (n=2) also received steroids for 2 weeks. At follow-up (range 10 months to 5.5 years; mean 3.2 years), the radiological response to ATT was evaluated. MRI after ATT showed resolution of SST in all except two patients with solid lesions. However, these lesions were smaller and had reduced contrast enhancement on imaging. Thus, SST may present with five radiological subtypes. Surgery is useful in obtaining histology. Short-term steroid therapy with ATT may reduce edema and adhesions around the optic nerve when rapid visual deterioration occurs and relieve symptoms of raised intracranial pressure. The often-associated hypopituitarism indicates the requirement for preoperative hormonal evaluation. PMID- 19783149 TI - Synthesis and evaluation of functionalized isoindigos as antiproliferative agents. AB - A series of functionalized isoindigos structurally related to meisoindigo (1 methylisoindigo), a therapeutic agent used for the treatment of a form of leukemia, were synthesized and evaluated for antiproliferative activities on a panel of human cancer cells. Two promising compounds (1-phenpropylisoindigo and 1 (p-methoxy-phenethyl)-isoindigo) that were more potent than meisoindigo and comparable to 6-bromoindirubin-3'-oxime on leukemic K562 and liver HuH7 cells were identified. Structure-activity relationships showed the importance of keeping one of the lactam NH in an unsubstituted state. Substitution of the other lactam NH with aryl or arylalkyl side chains retained or improved activity in most instances. An intact exocyclic double bond was also essential, possibly to maintain planarity and rigidity of the isoindigo scaffold. None of the compounds were found to inhibit CDK2 in an in vitro assay, in spite of reports linking the antiproliferative activities of meisoindigo and other isoindigos to CDK2 inhibition. Hence, these functionalized isoindigos disrupted cell growth and proliferation by other mechanistic pathways that did not involve CDK2 inhibition. PMID- 19783150 TI - Synthesis of fluorine-18 labeled rhodamine B: A potential PET myocardial perfusion imaging agent. AB - There is considerable interest in developing an (18)F-labeled PET myocardial perfusion agent. Rhodamine dyes share several properties with (99m)Tc-MIBI, the most commonly used single-photon myocardial perfusion agent, suggesting that an (18)F-labeled rhodamine dye might prove useful for this application. In addition to being lipophilic cations, like (99m)Tc-MIBI, rhodamine dyes are known to accumulate in the myocardium and are substrates for Pgp, the protein implicated in MDR1 multidrug resistance. As the first step in determining whether (18)F labeled rhodamines might be useful as myocardial perfusion agents for PET, our objective was to develop synthetic methods for preparing the (18)F-labeled compounds so that they could be evaluated in vivo. Rhodamine B was chosen as the prototype compound for development of the synthesis because the ethyl substituents on the amine moieties of rhodamine B protect them from side reactions, thus eliminating the need to include (and subsequently remove) protecting groups. The 2'-[(18)F]fluoroethyl ester of rhodamine B was synthesized by heating rhodamine B lactone with [(18)F]fluoroethyltosylate in acetonitrile at 165 degrees C for 30min using [(18)F]fluoroethyl tosylate, which was prepared by the reaction of ethyleneglycol ditosylate with Kryptofix 2.2.2, K(2)CO(3), and [(18)F]NaF in acetonitrile for 10min at 90 degrees C. The product was purified by semi-preparative HPLC to produce the 2'-[(18)F]fluoroethylester in >97% radiochemical purity with a specific activity of 1.3GBq/mumol, an isolated decay corrected yield of 35%, and a total synthesis time of 90min. PMID- 19783152 TI - Technical modifications in bar removal in the Nuss procedure. PMID- 19783153 TI - Translation to success of surgical innovation. AB - Contemporary thoracic and cardiovascular surgery uses extensive equipment and devices to enable its performance. As the specialties develop and new frontiers are crossed, the technology needs to advance in a parallel fashion. Strokes of genius or problem-solving brain-storming may generate great ideas, but the metamorphosis of an idea into a physical functioning tool requires a lot more than just a thinking process. A modern surgical device is the end-point of a sophisticated, complicated and potentially treacherous route, which incorporates new skills and knowledge acquisition. Processes including technology transfer, commercialisation, corporate and product development, intellectual property and regulatory routes all play pivotal roles in this voyage. Many good ideas may fall by the wayside for a multitude of reasons as they may not be marketable or may be badly marketed. In this article, we attempt to illuminate the components required in the process of surgical innovation, which we believe must remain in the remit of the modern-day thoracic and cardiovascular surgeon. PMID- 19783154 TI - RAGE, glomerulosclerosis and proteinuria: roles in podocytes and endothelial cells. AB - The multi-ligand Receptor for Advanced Glycation Endproducts (RAGE) is expressed in podocytes and endothelial cells in the human and murine glomerulus. Although present at low levels in homeostasis, RAGE expression is increased during disease. Pharmacological antagonism of RAGE or its genetic deletion imparts marked protection from podocyte effacement, albuminuria and glomerular sclerosis in disease models. In human subjects, associations between specific genetic polymorphisms of RAGE and levels of soluble forms of RAGE are linked to disease states in the kidney. In this review, we summarize the evidence from mouse to man, linking RAGE to the pathogenesis of nephropathy. PMID- 19783155 TI - Mid-trimester maternal plasma cytokines and CRP as predictors of spontaneous preterm birth. AB - Most previous studies of maternal cytokines and preterm birth have analyzed immunologic biomarkers after the onset of labor or membrane rupture; fewer have examined the systemic (blood) immune response prior to labor onset. We carried out a case-control study nested in a large (n=5337) prospective, multi-center cohort. Cohort women had an interview, examination, and venipuncture at 24-26 weeks. Frozen plasma samples in women with spontaneous preterm birth (n=207) and approximately 2 term controls per case (n=444) were analyzed using Luminex multianalyte profiling technology. Fresh placentas were fixed, stained, and blindly assessed for histologic evidence of infection/inflammation, decidual vasculopathy, and infarction, and vaginal swabs were analyzed for bacterial vaginosis and fetal fibronectin concentration. High maternal matrix metalloproteinase-9 (MMP-9) concentration, but none of the other cytokines or C reactive protein (CRP), was significantly associated with spontaneous preterm birth [adjusted OR=1.7 (1.1-2.4)] and showed a dose-response relation across quartiles. No association was observed, however, between maternal MMP-9 and placental infection/inflammation, bacterial vaginosis, or vaginal fetal fibronectin concentration. Our results require confirmation in future studies but suggest that a systemic immune response implicating MMP-9 may have an etiologic role in spontaneous preterm birth. PMID- 19783157 TI - Ionic matrix for matrix-enhanced surface-assisted laser desorption ionization mass spectrometry imaging (ME-SALDI-MSI). AB - Matrix-enhanced surface-assisted laser desorption ionization mass spectrometry imaging (ME-SALDI MSI) has been previously demonstrated as a viable approach to improving MS imaging sensitivity. We describe here the employment of ionic matrices to replace conventional MALDI matrices as the coating layer with the aims of reducing analyte redistribution during sample preparation and improving matrix vacuum stability during imaging. In this study, CHCA/ANI (alpha-cyano-4 hydroxycinnamic acid/aniline) was deposited atop tissue samples through sublimation to eliminate redistribution of analytes of interest on the tissue surface. The resulting film was visually homogeneous under an optical microscope. Excellent vacuum stability of the ionic matrix was quantitatively compared with the conventional matrix. The subsequently improved ionization efficiency of the analytes over traditional MALDI was demonstrated. The benefits of using the ionic matrix in MS imaging were apparent in the analysis of garlic tissue sections in the ME-SALDI MSI mode. PMID- 19783156 TI - Rigorous determination of the stoichiometry of protein phosphorylation using mass spectrometry. AB - Quantification of the stoichiometry of phosphorylation is usually achieved using a mixture of phosphatase treatment and differential isotopic labeling. Here, we introduce a new approach to the concomitant determination of absolute protein concentration and the stoichiometry of phosphorylation at predefined sites. The method exploits QconCAT to quantify levels of phosphorylated and nonphosphorylated peptide sequences in a phosphoprotein. The nonphosphorylated sequence is used to determine the absolute protein quantity and serves as a reference to calculate the extent of phosphorylation at the second peptide. Thus, the stoichiometry of phosphorylation and the absolute protein concentration can be determined accurately in a single experiment. PMID- 19783158 TI - Stability evaluation of vaccines. PMID- 19783159 TI - A duplicate middle scallop of the anterior mitral leaflet: benign curiosity, imaging artifact, or important pathology? PMID- 19783160 TI - Surgical management of the calcified patent ductus arteriosus under hypotensive anesthesia. PMID- 19783161 TI - Which protein C after cardiac surgery? PMID- 19783162 TI - The evolution of cardiac assist device technology. PMID- 19783163 TI - Anti-thymocyte globulin as an adjunct to treatment of fulminant lymphocytic myocarditis. AB - There is much debate over the role of immunosuppression in the treatment of acute and fulminant myocarditis. The low incidence of the condition prevents large numbers of cases for study, and treatment protocols vary greatly between institutions. In this study we add our experience with anti-thymocyte globulin as an adjunct to standard medical therapy for 5 patients presenting with cardiogenic shock due to fulminant myocarditis. All cases were associated with rapid and dramatic improvement in hemodynamic and electrophysiologic abnormalities, returning patients to NYHA Class I and cardiac function to normal or near normal by discharge. PMID- 19783164 TI - Everolimus but not mycophenolate mofetil therapy is associated with soluble HLA-G expression in heart transplant patients. AB - BACKGROUND: Human leukocyte antigen-G (HLA-G), a protein primarily expressed during pregnancy, helps maintain maternal-fetal immune tolerance. Myocardial and/or soluble HLA-G (sHLA-G) expression confers protection against rejection and vasculopathy after heart transplantation. Although the precise mechanisms remain unclear, immunosuppressive therapy has been reported to influence this expression. METHODS: We compared sHLA-G expression in heart transplant recipients receiving two different anti-proliferative agents: mycophenolate mofetil (MMF) and everolimus (RAD). Twelve-hour pharmacokinetic (PK) studies were conducted in patients after cyclosporine (CsA) administration in conjunction with RAD or MMF, during which plasma HLA-G concentrations were measured by enzyme-linked immunoassay (ELISA). RESULTS: Among patients receiving RAD, 78% expressed detectable levels of plasma HLA-G (1,002 +/- 511 ng/ml) compared with 25% of patients receiving MMF (612 +/- 438 ng/ml, p = 0.03). In all sHLA-G(+) patients, expression remained constant, with no significant changes in HLA-G levels throughout the 12-hour PK study period. CsA did not appear to influence sHLA-G expression, as there was no correlation between HLA-G levels and CsA exposure (R(2) = 0.43, p = 0.08). CONCLUSIONS: These preliminary findings suggest a disproportionate expression of HLA-G in patients under two distinct immunosuppression strategies after heart transplantation. Although CsA administration does not influence sHLA-G levels, RAD but not MMF is associated with sHLA-G expression. Larger prospective clinical investigations are required to confirm whether RAD is independently associated with increased HLA-G expression. PMID- 19783165 TI - Cardiac hormones ANF and BNP modulate proliferation in the unidirectional mixed lymphocyte reaction. AB - BACKGROUND: Previous investigations have shown that the plasma levels of the cardiac hormone brain natriuretic peptide (BNP) increase during acute cardiac allograft rejection as diagnosed by endomyocardial biopsy. Successful immunosuppressant treatment decreased plasma BNP levels, suggesting a role for BNP in transplantation immunity. We tested a possible immunomodulatory effect of the natriuretic peptides (NPs) BNP, atrial natriuretic factor (ANF), and C-type NP (CNP) using the unidirectional mixed lymphocyte reaction (MLR). METHODS: Lymphocytes were isolated from the lymph nodes of Brown Norway (BN) and Lewis (L) rats. BN lymphocytes were gamma-irradiated to inhibit DNA synthesis. Lymphocytes at 2.5 x 10(6) cell/ml were mixed (at an L:BN ratio of 4:1) and incubated. On Days 2 and 3, ANF (10(-6) to 10(-11) mol/liter), BNP (10(-5) to 10(-11) mol/liter), or CNP (10(-6) to 10(-12) mol/liter) were added. Cell proliferation was measured on Day 4. RESULTS: Reverse transcript-polymerase chain reaction (RT PCR) analysis of BN and L lymphocytes detected NP receptor (NPR) mRNA amplicons of the expected size. MLR induced an increase in relative receptor abundance as follows: NPRA > NPRB > NPRC. ANF and BNP significantly inhibited up to approximately 50% lymphocyte proliferation in a dose-dependent manner in the range of 10(-11) to 10(-6) mol/liter, whereas CNP significantly decreased lymphocyte proliferation only modestly (approximately 20%) at 10(-8) mol/liter and at 10(-6) mol/liter. CONCLUSIONS: Both ANF and BNP have immunomodulatory functions, although the response to cardiac rejection observed clinically involves increases in plasma levels of BNP only. This is likely related to BNP gene promoter sequences previously reported to be responsive to specific cytokines and related substances. The modulation of the MLR by NP suggests a possible clinical use of these peptides in transplantation immunity. PMID- 19783166 TI - Artificial neural networks predict mortality after lung transplantation better than logistic regression. PMID- 19783167 TI - ABPA: does it really exist after lung transplantation? PMID- 19783168 TI - Dismal lung transplant outcomes in children with tetralogy of Fallot with pulmonary atresia compared to Eisenmenger syndrome or pulmonary vein stenosis. AB - BACKGROUND: Certain congenital heart lesions in children can lead to irreversible lung disease thus making lung transplantation a therapeutic option. We retrospectively analyzed our experience with lung transplantation in 32 children with three distinct underlying congenital heart defects: (1) Eisenmenger syndrome (EIS); (2) tetralogy of Fallot with pulmonary atresia (PA); and (3) pulmonary vein stenosis (PVS). METHODS: Pediatric patients <18 years of age with either EIS (n = 7), PA (n = 8) or PVS (n = 17), who underwent lung or heart-lung transplantation, were analyzed. We compared survival rates between the three groups. Pre- and peri-operative variables were also assessed for their effect on outcome. RESULTS: Compared with EIS and PA patients, PVS patients were younger and sicker at the time of transplantation. All EIS and PA patients required either additional intracardiac repairs or a heart transplant at the time of lung transplantation. PA patients had the highest rate of major post-operative complications and in-hospital deaths. Median survival was comparable between EIS (6.1 years) and PVS (6.5 years) patients. Outcomes for PA patients were dramatically worse, with a median survival of only 0.12 year ( approximately 47 days). Needing additional intracardiac surgery or a heart transplant at the time of lung transplantation did not impact survival. The diagnosis of PA itself correlated with a worse outcome. CONCLUSIONS: Outcomes in EIS and PVS patients undergoing lung transplantation compare favorably to that of all pediatric lung transplant recipients (median survival 4.3 years). For PA patients, their underlying pathology appears to make them high-risk candidates for lung transplantation. For the younger and acutely sicker PVS patients, lung transplantation is a viable therapeutic alternative. PMID- 19783169 TI - Carbon monoxide diffusing capacity and mortality in pulmonary arterial hypertension. AB - BACKGROUND: Abnormal carbon monoxide diffusing capacity (DLCO) is a marker of pulmonary vascular disease and predicts the presence of pulmonary arterial hypertension (PAH) and poor prognosis in diseases such as systemic sclerosis and idiopathic pulmonary fibrosis. Little is known of its prognostic utility in World Health Organization (WHO) Group I PAH. METHODS: We performed a cohort study of 408 patients with WHO Group I PAH from 1982 to 2006, with data on demographics, comorbidities, medications, functional class, laboratory tests, exercise testing, and hemodynamics. DLCO was determined upon entry into the study. We divided the cohort into tertiles based on DLCO and compared differences between groups. We used a Cox proportional hazards analysis to determine the association of DLCO with mortality, after adjusting for age, connective tissue disease etiology, functional class, pulmonary function testing variables, serum creatinine, albumin, hemoglobin, lung parenchymal abnormalities on chest computed tomography, oxygen use, and hemodynamic variables. RESULTS: The lowest tertile of DLCO was independently associated with an increased risk of death (univariate hazard ratio [HR] = 2.7, 95% confidence interval [CI] 1.9 to 3.9, p < 0.0001; multivariate HR = 2.4, 95% CI 1.1 to 5.0, p = 0.025). On receiving operator characteristic (ROC) curve analysis, the c-statistic for the multivariate model without DLCO was 0.75, whereas the c-statistic for the multivariate model with DLCO was 0.78 (p = 0.003 by likelihood ratio test). Importantly, a multivariate model with hemodynamic variables alone (c-statistic = 0.61) was quite inferior to the multivariate model, which included DLCO. CONCLUSION: DLCO is an independent predictor of death in patients with WHO Group I PAH. PMID- 19783170 TI - Olfactory performance before and after lung transplantation: quantitative assessment and impact on quality of life. AB - BACKGROUND: Although olfactory function significantly impacts quality of life (QoL) and factors that potentially interfere with the sense of smell are numerous in solid-organ recipients, no respective data exist for this population. In this study we investigate the olfactory function, QoL, and the accuracy of subjectively perceived olfactory dysfunction. METHODS: Olfactory performance was assessed with the aid of a validated test battery (Sniffin' Sticks) in 70 randomly selected lung transplant recipients and 22 patients on the lung transplant waiting list. In addition to assess QoL, the Questions on Life Satisfaction Module (FLZ(M)) and the Hospital Anxiety Depression Scale (HADS) were used. RESULTS: Waiting list patients and lung transplant recipients did not show differences in terms of demographic data and olfactory performance. Compared with a normative population, patients <55 years of age had a significantly lower olfactory performance both before and after lung transplantation. Scores for general life satisfaction, health life satisfaction, and depression were significantly better in lung transplant recipients. In the multivariate analysis, better olfactory performance was significantly associated with better QoL before and after lung transplantation. Self-estimation of olfactory performance had a sensitivity of 36% and a specificity of 78%, respectively, to detect hyposmia/anosmia in our population. CONCLUSIONS: Although lung transplantation does not seem to have an impact on olfactory performance, sense of smell is significantly below the average in lung transplant recipients and patients on the waiting list. In both groups, olfactory performance is significantly associated with QoL. Furthermore, self-estimation of olfactory function shows inadequately low sensitivity and specificity. PMID- 19783171 TI - Predicting recovery: successful explant of a ventricular assist device in a child with dilated cardiomyopathy. AB - A previously healthy, 13-year-old girl presented with new-onset dilated cardiomyopathy, and is placed on a left ventricular assist device (VAD). Herein we describe a unique VAD weaning protocol used to determine the timing and feasibility of a VAD explant. PMID- 19783172 TI - Exogenous surfactant in ischemia/reperfusion: effects on endogenous surfactant pools. AB - BACKGROUND: Pre-ischemic surfactant treatment attenuates ischemia/reperfusion (I/R) injury. In this study we investigate whether exogenous surfactant acts by influencing endogenous intra-alveolar and intracellular surfactant pools and subtype composition. METHODS: Rat lungs from control with (C + S) or without (C - S) surfactant treatment and I/R with (I/R + S) or without (I/R - S) surfactant treatment were analyzed. In I/R groups, lungs underwent ischemic storage for 4 hours at 4 degrees C and reperfusion for 60 minutes. The ultrastructure of intra alveolar and intracellular surfactant forms fixed in their natural localization and microorganization was investigated by light- and electron-microscopic stereology. RESULTS: Only slight differences in alveolar epithelial Type II cell number or volume and lamellar body parameters were observed. Intra-alveolar surfactant volume was significantly enhanced in C + S and I/R + S. I/R increased inactivated surfactant forms (unilamellar vesicles) in untreated [mean (SD): C - S: 26.0% (8.0%) vs I/R - S: 64.8% (5.5%); p < 0.01], but not in surfactant treated rats [I/R + S: 23.5% (11.5%); p < 0.01 vs I/R - S]. The increase in unilamellar vesicles was closely correlated with intra-alveolar edema and decreased perfusate oxygenation. CONCLUSIONS: Attenuation of I/R injury by pre ischemic exogenous surfactant treatment is mainly based on stabilizing and increasing the active endogenous intra-alveolar surfactant pool. PMID- 19783173 TI - Tachyarrhythmias after pediatric heart transplantation. AB - BACKGROUND: Tachyarrhythmias in pediatric post-heart transplant patients are not well defined. In this study we sought to further characterize these arrhythmias in terms of presentation, course, and outcome. METHODS: This investigation was a retrospective review of heart transplant recipients at St. Louis Children's Hospital during the period of 1991 to 2006. Patients were excluded if they were >18 years at transplantation or if follow-up information was unavailable. Patients with tachyarrhythmias beyond the first 2 weeks post-transplant were identified. RESULTS: Twenty-eight tachyarrhythmias occurred in 25 of 237 heart transplant recipients. Freedom from arrhythmia was 92% at 1-year post-transplant and 86% at 15 years post-transplant. Intra-atrial reentry tachycardia (12 patients) and ectopic atrial tachycardia (10 patients) were the most common arrhythmias. Rejection was found in 3 (12%) and previously unrecognized coronary disease was found in another 2 (8%) at the time of presentation with arrhythmia. Fifteen of 25 (60%) were asymptomatic at presentation, but 4 of 25 (16%) presented with heart failure, including 3 without evidence of rejection. No risk factors for developing arrhythmia were identified. Twenty-one arrhythmias resolved with brief pharmacologic or no therapy. Only 3 had a recurrence after the initial arrhythmia. Five patients underwent catheter ablation. CONCLUSIONS: Our experience suggests that the presence of tachyarrhythmias after pediatric heart transplantation is not rare and usually not associated with rejection. Pediatric heart transplant recipients have a higher incidence of ectopic atrial tachycardia (EAT) than their adult counterparts. Most tachyarrhythmias resolve after a relatively brief period of medical treatment and recurrence is uncommon. PMID- 19783174 TI - Infections in heart transplant recipients in Brazil: the challenge of Chagas' disease. AB - BACKGROUND: Despite the high incidence of infections after heart transplantation, there is limited information about its epidemiology in patients from countries where Chagas' disease is endemic. METHODS: We analyzed the occurrence of infections in 126 patients aged older than 18 years who underwent transplantation from 1986 through 2007 at a Brazilian University Hospital and who survived at least 48 hours. RESULTS: Heart failure diagnoses before transplantation were idiopathic dilated cardiomyopathy (38.6%), Chagas' disease (34.9%), coronary artery disease (19.8%), and others (6.3%). The respiratory tract was the most common site of infections (40.9%), followed by surgical wound site (18.1%). Trypanosoma cruzi reactivations occurred in 38.8% of Chagas' disease patients: 47.0% had myocarditis, 23.5% had skin lesions, and 29.4% had both. New-onset ventricular dysfunction was observed in 47.0%, with complete response after specific treatment, and 41.0% were asymptomatic cases, diagnosed by routine endomyocardial biopsies. No patient died from such events. No differences in survival were found after 5 years of follow-up between recipients with and without Chagas' disease (p = 0.231). CONCLUSIONS: In a heart transplant population from a developing country, infectious complications occurred at a high rate. Tropical illnesses were uncommon, except for the high rate of Chagas' disease reactivations. Despite that, the overall outcome of these patients was similar to that of recipients with other cardiomyopathies. PMID- 19783175 TI - Costs and reimbursement gaps after implementation of third-generation left ventricular assist devices. AB - BACKGROUND: The purpose of this study was to compare and contrast total hospital costs and subsequent reimbursement of implementing a new program using a third generation left ventricular assist device (LVAD) in Norway. METHODS: Between July 2005 and March 2008, the total costs of treatment for 9 patients were examined. Costs were calculated for three periods-the pre-implantation LVAD phase, the LVAD implantation phase and the post-implantation LVAD phase-as well as for total hospital care. Patient-specific costs were obtained prospectively from patient records and included personnel resources, medication, blood products, blood chemistry and microbiology, imaging, and procedure costs including operating room costs. Overhead costs were registered retrospectively and allocated to the specific patient by pre-defined allocation keys. Finally, patient-specific costs and overhead costs were aggregated into total patient costs. RESULTS: The average total patient cost in 2007 U.S. dollars was $735,342 and the median was $613,087 (range $342,581 to $1,256,026). The mean length of stay was 77 days (range 40 to 127 days). For the LVAD implantation phase, the mean cost was $457,795 and median cost was $458,611 (range $246,239 to $677,680). The mean length of stay for the LVAD implantation phase was 55 days (range 25 to 125 days). The diagnosis-related group (DRG) reimbursement (2007) was $143,192. CONCLUSIONS: There is significant discrepancy between actual hospital costs and the current Norwegian DRG reimbursement for the LVAD procedure. This discrepancy can be partly explained by excessive costs related to the introduction of a new program with new technology. Costly innovations should be considered in price setting of reimbursement for novel technology. PMID- 19783176 TI - Outcomes of children with restrictive cardiomyopathy listed for heart transplant: a multi-institutional study. AB - BACKGROUND: Restrictive cardiomyopathy (RCM) in children often has a progressive nature, with a high risk of clinical deterioration and death. Heart transplantation (HTx) is a widely accepted therapy that offers long-term survival, but criteria for and outcomes after listing have not been well defined. METHODS: A multi-institutional, prospective, event-driven data registry of 3,147 patients aged < 18 years listed for HTx from January 1993 to December 2006 was used to assess risk factors and survival of 145 listed RCM patients. RESULTS: Mean age at listing was 8.1 years, with 44% listed as United Network of Organ Sharing status 1, 33% on inotropic support, 10% on a ventilator, and 5% on mechanical support. At 1 year, 82% of these patients survived to HTx, whereas 9% died waiting. Univariate risk factors for death while waiting included younger age (p < 0.001), ventilator dependence (p < 0.001), status 1 (p < 0.001), and inotrope usage (p < 0.001). Use of multiple support devices at listing (ventilator, extracorporeal membrane oxygenation, ventricular assist device, intraaortic balloon pump) was also an important risk factor for early phase death while waiting (relative risk; 9.01, p < 0.0001). Survival after listing was 63% at 10 years and compared favorably with survival for non-cardiomyopathy patients (p = 0.01). CONCLUSIONS: Children with RCM awaiting HTx have a generally low waitlist mortality and reasonable overall survival. Children requiring mechanical support and infants had a significantly higher risk of death while waiting. Further study is warranted to identify factors important in determining the optimal timing of listing in children with RCM before the need for inotropic or mechanical support. PMID- 19783177 TI - Wasting or obesity at time of transplant does not predict pediatric heart transplant outcomes: analysis of ISHLT pediatric heart transplant registry. AB - BACKGROUND: Body mass index (BMI) both before and after heart transplant (HT) is used to risk stratify in adult HT. Single-center studies identify BMI as a potential predictor of outcome after HT in children; large-scale analyses in pediatric HT have not been performed. METHODS: The ISHLT pediatric heart transplant registry was queried for HT recipients >2 years old between 1996 and 2006 with data for BMI percentile (BMI%ile) at HT. Survival and morbidity rates post-HT were compared between BMI%ile cohorts defined as: wasted, <5th BMI%ile; normal, 5th to 95th BMI%ile; and obese, >95th BMI%ile at HT. RESULTS: Data from 2,333 pediatric HT patients were available for analysis. Incidence of abnormal BMI%ile at HT was: wasted = 23% and obese = 8%. Wasting and obesity were similar in patients with congenital or cardiomyopathic diagnoses. Wasted or obese patients at HT did not differ from patients with normal BMI in survival on Kaplan Meier or multivariate analyses. There were no significant differences in pre-, peri- or post-operative adverse events between patients with wasting or obesity and those with normal BMI%ile at HT. CONCLUSIONS: In contrast to adults, abnormal body mass at time of transplant was not associated with decreased survival in pediatric HT recipients. Potential pediatric transplant candidates should not be excluded based on the perception that wasting or obesity will increase the risk of adverse outcomes. PMID- 19783178 TI - Does cytomegalovirus serology impact outcome after pediatric heart transplantation? AB - BACKGROUND: Cytomegalovirus (CMV) infection has been implicated in a number of complications after heart transplantation. A recent study suggested that children with positive CMV serology (CMV(+)) before transplantation are at increased risk of developing coronary allograft vasculopathy (CAV) and death when compared with CMV(-) recipients. We analyzed data from the Pediatric Heart Transplant Study Group to determine the impact of recipient CMV status and CMV mismatching on outcome. In addition, the use and efficacy of CMV prophylaxis were studied. METHODS: Subjects <18 years of age who underwent heart transplantation during the period from 1993 to 2007 were analyzed. Those transplants in which either the recipient or donor were <6 months of age were excluded due to the confounding effects of maternal antibody. The primary outcome variable was freedom from CAV (mild or greater). Secondary outcomes included freedom from death and freedom from clinical CMV infection. Risk factors were assessed using parametric hazard regression. RESULTS: Of the 1,598 subjects included in the analysis, 637 (40%) were CMV(+) at the time of transplantation. Some form of CMV prophylaxis was administered to 67% of all recipients, most commonly with a CMV mismatch (donor CMV(+)/recipient CMV(-)). Freedom from clinical CMV infection at 5 years was 91%. Pre-transplant CMV serology was not associated with mortality (p = 0.40) or risk of developing CAV (p = 0.10). CMV mismatch was associated with increased risk of clinical CMV disease (p < 0.001). The use of CMV prophylaxis had no association with mortality or development of CAV. There was also no significant association between CMV prophylaxis and the development of clinical CMV infection. CONCLUSIONS: CMV(+) serology at time of pediatric heart transplantation had no demonstrable association with death or development of CAV. CMV(-) recipients who receive a CMV(+) organ are at increased risk of clinical CMV disease. CMV prophylaxis was commonly used, although further studies are needed to establish an optimal approach for prevention of CMV disease in this population. PMID- 19783179 TI - Planned extracorporeal membrane oxygenation technique for peri-transplantation support for heart allografts with known prolonged ischemic time. PMID- 19783180 TI - Why do we not perform routine endomyocardial biopsies in childhood cardiomyopathy? PMID- 19783181 TI - Quilty effect, acute cellular rejection, and transplant vasculopathy: still controversial. PMID- 19783182 TI - Indoleamine 2,3-dioxygenase in lung allograft tolerance. AB - BACKGROUND: Indoleamine 2,3-dioxygenase (IDO), an enzyme involved in the degradation of tryptophan (Try) to kynurenine (Kyn), is thought to suppress T cell activity. Although a few experimental studies have suggested a role for IDO in graft acceptance, human data are scarce and inconclusive. We sought to establish whether, in lung transplant recipients (LTRs), plasma IDO activity mirrors the level of graft acceptance. METHODS: We measured the plasma Kyn/Try ratio, reflecting IDO activity, by high-performance liquid chromatography (HPLC) in 90 LTRs, including 26 patients who were still functionally/clinically stable for >36 post-transplant months (stable LTRs) and 64 LTRs with bronchiolitis obliterans syndrome (BOS, Grades 0-p to 3). Twenty-four normal healthy controls (NHCs) were also included. RESULTS: The Kyn/Try ratio in stable LTRs resembled that observed in NHCs, whereas, unexpectedly, patients with BOS, who had lower counts of peripheral CD4(+) T-regulatory cells and tolerogenic plasmacytoid dendritic cells than stable LTRs, showed an increased plasma Kyn/Try ratio compared with both NHCs and stable LTRs. IDO expression by in vitro-stimulated peripheral blood mononuclear cells (PBMC) did not vary between BOS and stable LTRs. Furthermore, BOS patients displayed signs of chronic systemic inflammation (increased plasma levels of interleukin-8 and tumor necrosis factor-alpha) and higher T-cell activation (increased frequency of peripheral interferon-gamma producing clones). CONCLUSIONS: Our results suggest that, in vivo, in lung transplantation, plasma IDO activity does not reflect the degree of lung graft acceptance, but instead is correlated with the degree of chronic inflammation. PMID- 19783183 TI - EBV-associated hepatic smooth muscle tumor after lung transplantation: report of a case and review of the literature. AB - Post-transplant smooth muscle tumors (PTSMTs) are a rare and recently recognized neoplasm associated with Epstein-Barr virus (EBV). We describe the clinicopathologic, immunohistochemical and molecular features of a new case of EBV-associated PTSMT arising in the liver of a 55-year-old lung transplant recipient for lymphangioleiomyomatosis. To our knowledge, this is the third smooth muscle tumor (the second one proved to be associated with EBV) after lung transplantation. The 2 previous cases are reviewed and the differential diagnosis is also discussed. PMID- 19783185 TI - Developments in genomics to improve understanding, diagnosis and management of aneurysms and peripheral artery disease. AB - Genome-wide approaches, including microarray-based expression profiling, DNA linkage studies and genetic association studies, offer an unbiased way to identify genetic risk factors and biological processes leading to discoveries, which might help in the development of new diagnostic and therapeutic approaches for a wide range of diseases. Currently, the number of published genome-wide analyses for aneurysms and peripheral artery diseases is still limited, and it is difficult to generalise about the disease pathogenesis or genetic risk factors contributing to these diseases. Large multicentre studies are needed to provide sufficient statistical power, and replication studies are essential before these findings are used for defining clinical policies of diagnosis and treatment. The biggest future challenge will be to translate the genomic information to the clinical settings so that it will improve our understanding of the disease processes, help us to develop better diagnostic tools and lead to the design of new ways to manage aneurysms and peripheral artery disease in the era of personalised medicine. Characterisation of diseases at the molecular level is likely to lead to more accurate diagnoses and the use of 'genomic nosology' of diseases. PMID- 19783184 TI - Short-term mechanical unloading and reverse remodeling of failing hearts in children. AB - BACKGROUND: Mechanical support using a left ventricular assist device (LVAD) can lead to functional recovery of the myocardium in patients with end-stage heart failure (HF). Molecular remodeling, cytoskeletal disruption, and apoptosis activation are associated with abnormal gene expression in the failing ventricular myocardium of HF subjects and can normalize in response to medium- and long-term mechanical unloading in adults. However, there is little knowledge of the changes in gene expression after short-term mechanical support in children with HF. METHODS: We evaluated left ventricular biopsies from 4 children with HF. The children had implantation of a continuous- or a pulsatile-flow LVAD for 8 to 16 days before undergoing heart transplantation. At the time of LVAD insertion and removal, we performed quantitative real-time polymerase chain reaction (QPCR) to study the expression of 326 genes encoding for structural, transcriptional, and signaling pathways proteins, and immunoblot analysis on dystrophin and apoptotic factors. RESULTS: Short-term LVAD therapy significantly decreased brain natriuretic peptide (BNP) levels from pre-LVAD (3,584.5 +/- 378.3 pg/ml [95% CI]) to post-LVAD (447.5 +/- 52.7 pg/ml [95% CI]) in 2 patients in whom comparative BNP measurements were available. In addition, short-term LVAD therapy reduced HF and apoptosis markers, whereas it upregulated structural proteins, including dystrophin, as well as pro-hypertrophic and pro-inotropic markers. Furthermore, LVAD therapy normalized expression of genes involved in calcium homeostasis, cell growth, and differentiation. CONCLUSIONS: Our pilot study suggests that even short-term LVAD therapy in children with severe HF can reverse molecular remodeling. This favorable effect should be taken into consideration in eligible children with significant ventricular dysfunction. PMID- 19783187 TI - 1H-19F spin-lattice relaxation spectroscopy: proton tunnelling in the hydrogen bond studied by field-cycling NMR. AB - Proton tunnelling in the hydrogen bonds of two fluorine substituted benzoic acid dimers has been investigated using field-cycling NMR relaxometry. The close proximity of the (19)F nuclei to the hydrogen bond protons introduces heteronuclear (19)F-(1)H dipolar interactions into the spin-lattice relaxation processes. This renders the (1)H magnetisation-recovery biexponential and introduces multiple spectral density components into the relaxation matrix characterised by frequencies that are sums and differences of the (19)F and (1)H Larmor frequencies. Using field-cycling NMR pulse sequences that measure the spin lattice relaxation and cross-relaxation rates we demonstrate how some of these multiple spectral density components can be separately resolved. This leads to an accurate determination of the correlation times that characterise the proton tunnelling motion. A broad spectrum of relaxation behaviour is illustrated and explored in the chosen samples and the investigation is used to explore the theory and practise of field-cycling NMR relaxometry in cases where heteronuclear interactions are significant. PMID- 19783188 TI - Anthropometric data of 14 patients with mucopolysaccharidosis I: retrospective analysis and efficacy of recombinant human alpha-L-iduronidase (laronidase). AB - OBJECTIVES: Our goal was to evaluate growth patterns in terms of body height, weight, head and chest circumference in patients with mucopolysaccharidosis type I (MPS I) without treatment and after enzyme replacement therapy (ERT) with alpha l-iduronidase (laronidase). PATIENTS AND METHODS: Anthropometric features of 14 patients with MPS I were followed from birth until the introduction of ERT (group 1-1st year of life, group 2 3rd year of life), after 52-260 weeks of ERT and periodically during treatment. The data since birth until beginning of treatment was obtained by retrospective review of patients' charts. Patients received intravenous laronidase at 100 U/kg (0.58 mg/kg) weekly for 52-260 weeks. RESULTS: Patients from group 1 (n=7) and group 2 (n=7) had similar characteristics at the time of birth but showed significant difference when compared with healthy population. Growth patterns were associated significantly with the MPS I at birth. After 96-260 weeks of ERT, patients receiving laronidase (group 1) compared with group 2 did not show statistically significant improvement. CONCLUSIONS: Anthropometric features of patients with MPS I significantly differ from the healthy population. Children with MPS I grew considerably slower, and differences between healthy and affected children increased with age. In studied patients with MPS I, laronidase did not appear to alter the growth patterns. PMID- 19783189 TI - Contiguous gene deletion syndrome in a female with ornithine transcarbamylase deficiency. AB - OTC deficiency, a partially dominant X-linked trait, is the most frequent inborn error of the urea cycle. We describe a female patient with a contiguous gene deletion syndrome encompassing the OTC, DMD, RPGR, CYBB and XK genes, amongst others, only manifesting features of OTC deficiency. Molecular characterization was ascertained by MLPA and confirmed by CGH microarray, which revealed an 8.7 Mb deletion of the X-chromosome. Complete de novo deletion of the OTC gene led to a severe clinical phenotype in the proband. The application of high resolution molecular genetic techniques such as MLPA and array CGH, in mutation negative OTC cases allows the identification of chromosomal rearrangements, such as large deletions and provides information for accurate genetic counseling and prenatal diagnosis. PMID- 19783190 TI - Thyroid stimulation with recombinant human thyrotropin in healthy cats, cats with non-thyroidal illness and in cats with low serum thyroxin and azotaemia after treatment of hyperthyroidism. AB - This study investigated the recombinant human thyrotropin (rhTSH) stimulation test in healthy cats (group 1), cats with non-thyroidal illness (group 2) and cats with low serum total T(4) (TT(4)) and azotaemia after (131)I treatment (group 3). Serum TT(4) responses and thyroidal pertechnetate uptake after administration of 25 microg rhTSH IV were assessed. Baseline serum TT(4) was significantly lower in group 3 compared with group 1, but not between other group pairs. Serum TT(4) increased significantly in groups 1 and 2 but not in group 3 after rhTSH administration. Post-rhTSH serum TT(4) concentrations differed significantly between groups 1 and 3 and groups 2 and 3, but not between groups 1 and 2. Thyroid/salivary gland uptake ratio (T/S uptake ratio) differed only significantly between groups 1 and 3. Stimulation with rhTSH is valuable to differentiate euthyroidism from iatrogenic hypothyroidism in cats. PMID- 19783191 TI - [The transfusion center, the blood donor and the given blood in francophone African countries]. AB - In subsaharan Africa, knowledge of the organization and methods of transfusion centers, as well as blood donor characteristics, is essential in choosing strategies to improve transfusion practices and the security of blood products on this Continent. The present study was based on a analysis led in partnership with the transfusion of seven francophone African countries (Burkina-Faso, Cameroon, Congo, Ivory Cost, Mali, Niger, and Rwanda). The results showed that withstanding significant progress has been realized in the organization and safety, but much remains to be undertaken over the years to come in order to improve the organization of the centers, the providing of blood products and the infectious and immunohematologic safety. This evolution, for the moment, is limited by the financial resources, insufficient training of personnel and cultural obstacles, but will necessarily pass through the pursuit of conjugated efforts of the scientific, international and local communities. PMID- 19783192 TI - [Hodgkin's disease: treatment specificities in childhood]. AB - Paediatric Hodgkin disease presents some particularities when compared to Hodgkin in adults. In this article, we focus on the paediatric particularities, especially in term of current treatment strategy. The aim is to decrease the important rate of late effects while keeping the excellent survival. PMID- 19783193 TI - A new variant in the brachium musculature with reinforced innervation from a median-musculocutaneous nerve communication. AB - Neural variations of the brachium constitute an important anatomical and clinical entity. Although frequently reported, if accompanied by other anomalies, they deserve special mention in anatomical literature. The goal of this present study is to report a communication between the median (MN) and musculocutaneous nerve (MCN), concomitant with an accessory muscle belly. Interestingly, an important proximal connection between the lateral and medial roots of the MN was also observed. The MCN joined the MN at mid humeral level. The peculiarity of the current report arises due to the presence of a twig passing from the site of communication between the two nerves, to supply the coracobrachialis. Concomitantly, an accessory muscle measuring 5cm in length originating from the short head of biceps brachii, fusing with the coracobrachialis was seen in the mid brachium. The observations of the current study may cause a perplexing situation for anesthetists attempting brachial plexus blocks and for surgeons who operate on this vital anatomical arena. PMID- 19783194 TI - [Tenth anniversary of the Association of Obstetrics and Gynecology Residents]. PMID- 19783195 TI - Olfaction and apathy in Parkinson's disease. AB - BACKGROUND: Olfactory deficits are frequent among patients with idiopathic Parkinson's disease (PD). Additionally, apathy (as quantified by the Apathy Evaluation Scale), is more prevalent in PD patients compared to the general population. Olfactory impairment and apathy are associated with dysfunction in overlapping brain regions. Neuroimaging studies indicate that the anterior cingulate gyrus and medial orbitofrontal cortex are hypoactive in apathetic patients and are also involved in secondary olfactory processing. However, no study until this point has been published investigating whether there is any association between olfactory dysfunction and apathy in PD patients. METHODS: In our study seventy consecutive patients with PD took the Brief Smell Identification Test (B-SIT), completed the Apathy Evaluation Scale (AES) and were administered the Folstein Mini-Mental Status exam (MMSE). RESULTS: Apathetic PD patients performed poorly on the B-SIT compared with non-apathetic PD patients and olfactory impairment correlated with apathy. The simultaneous disruption of olfaction and emotion in Parkinson's could be the result of disease pathology in brain regions involved in both olfactory and emotional processing and reinforces the idea that this link between olfaction and emotions may have clinical consequences. PMID- 19783196 TI - Biodiversity informatics and the plant conservation baseline. AB - Primary baseline data on taxonomy and species distribution, and its integration with environmental variables, has a valuable role to play in achieving internationally recognised targets for plant diversity conservation, such as the Global Strategy for Plant Conservation. The importance of primary baseline data and the role of biodiversity informatics in linking these data to other environmental variables are discussed. The need to maintain digital resources and make them widely accessible is an additional requirement of institutions who already collect and maintain this baseline data. The lack of resources in many species-rich areas to gather these data and make them widely accessible needs to be addressed if the full benefit of biodiversity informatics on plant conservation is to be realised. PMID- 19783198 TI - The exploring root--root growth responses to local environmental conditions. AB - Because of their sessile lifestyle, the areas which plants can access to forage for resources are confined to those which can be explored by growth. High sensitivity to environmental conditions coupled to the appropriate readjustment of growth and developmental responses are thus critical to plant survival. In this review, we focus on how roots perceive physical cues such as soil water status and mechanical properties and translate them into physiological signals to redirect organ growth and modulate root system architecture. Because the precise molecular identity of most of the sensors used by the root to sample the soil environment remain to be determined, the mechanisms underlying similar processes in microbes are providing important models for how these receptor systems may be functioning in plants. PMID- 19783197 TI - HKT transporter-mediated salinity resistance mechanisms in Arabidopsis and monocot crop plants. AB - The salinization of irrigated lands is increasingly detrimental to plant biomass production and agricultural productivity, as most plant species are sensitive to high concentrations of sodium (Na(+)), which causes combined Na(+) toxicity and osmotic stress. Plants have multiple Na(+)-transport systems to circumvent Na(+) toxicity. Essential physiological functions of major Na(+) transporters and their mechanisms mediating salinity resistance have been identified in Arabidopsis , including the AtSOS1, AtNHX and AtHKT1;1 transporters. As we discuss here, recent studies have demonstrated that a class of xylem-parenchyma-expressed Na(+) permeable plant HKT transporters represent a primary mechanism mediating salt tolerance and Na(+) exclusion from leaves in Arabidopsis, and that major salt tolerance quantitative trait loci in monocot crop plants are also based on this HKT-mediated mechanism. PMID- 19783199 TI - Cell-to-cell communication in vascular morphogenesis. AB - The plant vascular system consists of two conductive cell types, xylem and phloem, which are both produced by procambial cells. Recently, several novel regulatory mechanisms that control the specification of vascular patterning and differentiation have been uncovered. The non-cell-autonomous TDIF/CLE signalling mediates phloem-xylem cross-talk and cambial maintenance; a flowering-related long-distance signal governs secondary development; and novel genetic players such as LHW regulate vascular morphogenesis. A future challenge is to conflate data on the various genetic, hormonal and other factors to understand the networks underlying vascular tissue formation. PMID- 19783200 TI - The cellular dynamics of plant aquaporin expression and functions. AB - Aquaporins are channel proteins that facilitate the transport of water and small neutral molecules, including gases, across cell membranes of most of the living organisms. Integrative studies have stressed the role of aquaporins in maintaining the whole plant water and nutrient status. Cellular aspects of plant aquaporin functions and regulations are also extensively investigated. The present review provides a glance at recent progresses in this area. One first direction concerns the mechanisms that determine aquaporin targeting to specific subcellular membranes and a dynamic and stimulus-dependent control of their density in these membranes. The regulation of aquaporin opening and closing and its links to cell signalling cascades are also discussed. Multiple cellular functions are now attributed to plant aquaporins. They include the dynamic equilibration and subcellular partitioning of their various substrates and a contribution to cell expansion and possibly cell division. PMID- 19783201 TI - Determination of trace amounts of mercury(II) in water samples using a novel kinetic catalytic ligand substitution reaction of hexacyanoruthenate(II). AB - A simple, sensitive, selective and rapid kinetic catalytic method has been developed for the determination of Hg(II) ions at micro-level. This method is based on the catalytic effect of Hg(II) ion on the rate of substitution of cyanide in hexacyanoruthenate(II) with nitroso-R-salt (NRS) in aqueous medium and provides good accuracy and precision. The concentration of Hg(II) catalyst varied from 4.0 to 10.0x10(-6)M and the progress of reaction was followed spectrophotometrically at 525nm (lambda(max) of purple-red complex [Ru(CN)(5)NRS](3-), epsilon=3.1x10(3)M(-1)s(-1)) under the optimized reaction conditions; 8.75x10(-5)M [Ru(CN)(6)(4-)], 3.50x10(-4)M [nitroso-R-salt], pH 7.00+/-0.02, ionic strength, I=0.1M (KCl), temp 45.0+/-0.1 degrees C. The linear calibration curves, i.e. calibration equations between the absorbance at fixed times (t=15, 20 and 25min) versus concentration of Hg(II) ions were established under the optimized experimental conditions. The detection limit was found to be 1.0x10(-7)M of Hg(II). The effect of various foreign ions on the proposed method has also been studied and discussed. The method has been applied to the determination of mercury(II) in aqueous solutions. PMID- 19783202 TI - 1H NMR, 13C NMR and mass spectral studies of some Schiff bases derived from 3 amino-1,2,4-triazole. AB - Heterocyclic Schiff bases derived from 3-amino-1,2,4-triazole and different substituted aromatic aldehydes are prepared and subjected to (1)H NMR, (13)C NMR and mass spectral analyses. (1)H NMR spectra in DMSO exhibit a sharp singlet within the 9.35-8.90ppm region which corresponds to the azomethine proton. The position of this signal is largely dependent on the nature of the substituents on the benzal moiety. It is observed that the shape, position and the integration value of the signal of the aromatic proton of the triazole ring ((5)C) are clearly affected by the rate of exchange, relaxation time, concentration of solution as well as the solvent used. (13)C NMR is taken as substantial support for the results reached from (1)H NMR studies. The mass spectral results are taken as a tool to confirm the structure of the investigated compounds. The base peak (100%), mostly the M-1 peak, indicates the facile loss of hydrogen radical. The fragmentation pattern of the unsubstituted Schiff base is taken as the general scheme. Differences in the other schemes result from the effect of the electronegativity of the substituents attached to the aromatic ring. PMID- 19783203 TI - The health information system security threat lifecycle: an informatics theory. AB - PURPOSE: This manuscript describes the health information system security threat lifecycle (HISSTL) theory. The theory is grounded in case study data analyzing clinicians' health information system (HIS) privacy and security (P&S) experiences in the practice context. METHODS: The 'questerview' technique was applied to this study of 26 clinicians situated in 3 large Australian (across Victoria) teaching hospitals. Questerviews rely on data collection that apply standardized questions and questionnaires during recorded interviews. Analysis (using Nvivo) involved the iterative scrutiny of interview transcripts to identify emergent themes. RESULTS: Issues including poor training, ambiguous legal frameworks containing punitive threats, productivity challenges, usability errors and the limitations of the natural hospital environment emerged from empirical data about the clinicians' HIS P&S practices. The natural hospital environment is defined by the permanence of electronic HISs (e-HISs), shared workspaces, outdated HIT infrastructure, constant interruption, a P&S regulatory environment that is not conducive to optimal training outcomes and budgetary constraints. The evidence also indicated the obtrusiveness, timeliness, and reliability of P&S implementations for clinical work affected participant attitudes to, and use of, e-HISs. CONCLUSION: The HISSTL emerged from the analysis of study evidence. The theory embodies elements such as the fiscal, regulatory and natural hospital environments which impede P&S implementations in practice settings. These elements conflict with improved patient care outcomes. Efforts by clinicians to avoid conflict and emphasize patient care above P&S tended to manifest as security breaches. These breaches entrench factors beyond clinician control and perpetuate those within clinician control. Security breaches of health information can progress through the HISSTL. Some preliminary suggestions for addressing these issues are proposed. STUDY LIMITATIONS: Legislative frameworks that are not related to direct patient care were excluded from this study. Other limitations included an exclusive focus on patient care tasks post-admission and pre-discharge from public hospital wards. Finally, the number of cases was limited by the number of participants who volunteered to participate in the study. It is reasonable to assume these participants were more interested in the P&S of patient care work than their counterparts, though the study was not intended to provide quantitative or statistical data. Nonetheless, additional case studies would strengthen the HISSTL theory if confirmatory, practice-based evidence were found. PMID- 19783204 TI - The impact of short message service text messages sent as appointment reminders to patients' cell phones at outpatient clinics in Sao Paulo, Brazil. AB - OBJECTIVE: Nonattendance for appointments remains a challenge to health care managers and providers. The objective of this article is to present the results of a study on the impact of appointment reminders sent as short message service text messages to patients' cell phones on nonattendance rates at outpatient clinics in Sao Paulo, Brazil. DESIGN: Data were collected on scheduled appointments in four medical clinics using Clinic Manager or Clinic Web systems that can send automated messages to patients. Data on appointment attendance were collected from these systems. MEASUREMENTS: More than 29,000 appointments were scheduled between July 1, 2007, and May 31, 2008, and for 7890 of them a text message reminder was sent to the patient's cell phone. The rates of nonattendance were compared between those who were sent and those who were not sent a text message as an appointment reminder. RESULTS: The nonattendance reduction rates for appointments at the four outpatient clinics studied were 0.82% (p= .590), 3.55% (p= .009), 5.75% (p= .022), and 14.49% (p= < .001). CONCLUSION: The study results indicate that sending appointment reminders as text messages to patients' cell phones is an effective strategy to reduce nonattendance rates. When patients attend their appointments, the facility providing care and the patients receiving uninterrupted care benefit. PMID- 19783205 TI - Newborn screening for congenital cytomegalovirus: Options for hospital-based and public health programs. AB - BACKGROUND: Congenital cytomegalovirus (CMV) infection is a leading cause of sensorineural hearing loss (SNHL) and developmental disability in children. Early identification of infected children through screening could allow for early intervention and improvement in functional outcomes among the subset who develop sequelae. OBJECTIVES: To outline potential options and strategies for screening newborns for congenital CMV infection and to discuss barriers to screening and data needs to inform future policy decisions. STUDY DESIGN: Commentary based on the literature and expert opinion on newborn dried blood spot screening, newborn hearing screening/Early Hearing Detection and Intervention (EHDI) programs, and congenital CMV. RESULTS: Although no population-based screening for congenital CMV is underway, pilot newborn screening studies using a variety of assays with urine or dried blood spot specimens are underway. Challenges to screening are both practical-uncertain sensitivity of blood spot assays suitable for large scale screening and lack of infrastructure for collection of urine specimens; and evidentiary-the need to demonstrate improved outcomes and value of screening to offset the expense and potential adverse psychosocial consequences for children and families whose children require periodic monitoring but never develop sequelae. CONCLUSIONS: Screening for congenital CMV infection is a potentially important intervention that merits additional research, including the logistical feasibility of different screening options and psychosocial consequences for families. PMID- 19783206 TI - An unusual case of cholelithiasis. PMID- 19783207 TI - Motoneuron excitability: the importance of neuromodulatory inputs. AB - The excitability of spinal motoneurons is both fundamental for motor behavior and essential in diagnosis of neural disorders. There are two mechanisms for altering this excitability. The classic mechanism is mediated by synaptic inputs that depolarize or hyperpolarize motoneurons by generating postsynaptic potentials. This "ionotropic" mechanism works via neurotransmitters that open ion channels in the cell membrane. In the second mechanism, neurotransmitters bind to receptors that activate intracellular signaling pathways. These pathways modulate the properties of the voltage-sensitive channels that determine the intrinsic input output properties of motoneurons. This "neuromodulatory" mechanism usually does not directly activate motoneurons but instead dramatically alters the neuron's response to ionotropic inputs. We present extensive evidence that neuromodulatory inputs exert a much more powerful effect on motoneuron excitability than ionotropic inputs. The most potent neuromodulators are probably serotonin and norepinephrine, which are released by axons originating in the brainstem and can increase motoneuron excitability fivefold or more. Thus, the standard tests of motoneuron excitability (H-reflexes, tendon taps, tendon vibration and stretch reflexes) are strongly influenced by the level of neuromodulatory input to motoneurons. This insight is likely to be profoundly important for clinical diagnosis and treatment. PMID- 19783208 TI - Cancer mortality in a surveillance cohort of German males formerly exposed to asbestos. AB - The objective of this analysis was the estimation of the cancer risks of asbestos and asbestosis in a surveillance cohort of high-exposed German workers. A group of 576 asbestos workers was selected for high-resolution computer tomography of the chest in 1993-1997. A mortality follow-up was conducted through 2007. Standardised mortality ratios (SMRs) were calculated and Poisson regression was performed to assess mesothelioma risks. A high risk was observed for pleural mesothelioma (SMR 28.10, 95% CI 15.73-46.36) that decreased after cessation of exposure (RR 0.1; 95% CI 0.0-0.6 for > or =30 vs. <30 years after last exposure). Asbestosis was a significant risk factor for mesothelioma (RR 6.0, 95% CI 2.4 14.7). Mesothelioma mortality was still in excess in former asbestos workers although decreasing after cessation of exposure. Fibrosis was associated with subsequent malignancy. PMID- 19783209 TI - Outbreaks of Serratia marcescens in neonatal and pediatric intensive care units: clinical aspects, risk factors and management. AB - The following recommendations are derived from a systematic analysis of 34 Serratia marcescens outbreaks described in 27 publications from neonatal and pediatric intensive care units (NICU, PICU), in which genotyping methods were used to confirm or exclude clonality. The clinical observation of two or more temporally related cases of nosocomial S. marcescens infection should raise the suspicion of an outbreak, particularly in the NICU or PICU setting. Since colonized or infected patients represent the most important reservoir for cross transmission, hygienic barrier precautions (contact isolation/cohortation, the use of gloves and gowns in addition to strictly performed hand disinfection, enhanced environmental disinfection) should immediately be implemented and staff education given. Well-planned sampling of potential environmental sources should only be performed when these supervised barrier precautions do not result in containment of the outbreak. The current strategy of empiric antibiotic treatment should be reevaluated by a medical microbiologist or an infectious disease specialist. Empiric treatment of colonized children should use combination therapy informed by in vitro susceptibility data; in this context the high propensity of S. marcescens to cause meningitis and intracerebral abscess formation should be considered. In vitro susceptibility patterns do not reliably prove or exclude the clonality of the outbreak isolate. Genotyping of the isolates by pulse-field gel electrophoresis or PCR-based methods should be performed, but any interventions to interrupt further nosocomial spread should be carried out without waiting for the results. PMID- 19783210 TI - Mild anaemia is associated with increased all-cause mortality in heart failure. AB - AIM: To evaluate the association of anaemia with increased long-term morbidity and mortality in hospitalised heart failure (HF) patients. METHODS AND RESULTS: We analysed medical records of a random sample of 1000 patients admitted to tertiary care hospitals from 1996 to 2006 with a principal diagnosis of HF. Anaemia (WHO criteria) on admission was present in 45.2% of HF patients. Multivariate analysis identified anaemia as an independent predictor of 5-year mortality with a hazard ratio (HR) of 1.44 (95%CI 1.20-1.73) compared to non anaemic patients, and a rate ratio of 1.85 (95%CI 1.72-2.02) for unplanned all cause readmission and 1.22 (95%CI 1.16-1.29) for HF readmission within 5 years. Compared to patients in the highest gender-specific Hb quartile, those with mild anaemia (Hb 11.3-13.0 g/dL in males, 11.0-12.4 g/dL in females) had an adjusted HR of 1.32 (95%CI 1.01-1.71) for 5-year mortality. Anaemia and chronic kidney disease were independent (additive) predictors of survival, whereas anaemia interacted with prevalent diabetes (p for interaction=0.006), such that patients with both conditions had an adjusted mortality HR of 2.18 (95%CI 1.48-3.22) compared to those with diabetes only. CONCLUSION: Mild anaemia is common in hospitalised HF patients and is an independent predictor of 5-year all-cause mortality in HF. PMID- 19783211 TI - Early experience with a simplified technique for transcatheter closure of the patent foramen ovale. AB - BACKGROUND: Although generally safe, transcatheter patent foramen ovale (PFO) closure typically involves catheter exchanges and manipulations within the left atrium (LA) that may result in complications. We describe the development of a simplified technique for PFO closure, further to modification of our earlier approaches. METHODS: Early in our experience, LA angiography and/or balloon sizing of the PFO was routine prior to device closure. Subsequently, the simplified technique described herein became our standard approach. We reviewed immediate and medium term results in 27 consecutive patients who underwent closure in a 24-month time frame. RESULTS: All procedures used general anaesthesia, TEE guidance and CardioSEAL septal occluder. Device delivery was successful in all patients. The median fluoroscopy time was significantly shorter with the simplified technique (median difference 6.7min, p<0.05) with a 98.3% median confidence interval (4.5, 19.9min). There were four complications, all occurring in the early group of patients. There have been no recurrent neurological events or device related adverse events on medium term follow-up. CONCLUSIONS: Successful transcatheter PFO closure is feasible without LA angiography or catheter-based balloon sizing, utilising echocardiographic guidance for device selection and placement. Simplification of PFO closure technique could potentially decrease complications and shorten fluoroscopy times. PMID- 19783212 TI - The relationship between pulmonary artery and pulmonary capillary wedge pressure for the diagnosis of pulmonary vascular disease. AB - BACKGROUND: Left heart disease and pulmonary vascular disease (PVD) both lead to raised pulmonary artery pressure (PAP) but differ in pathophysiology, prognosis and treatment. There are currently no criteria for diagnosing PVD in the presence of left heart disease. We therefore studied the relationship between PAP and pulmonary capillary wedge pressure (PCWP, a measure of left atrial pressure) to help define when PAP should be considered 'out-of-proportion' to PCWP, thus suggestive of PVD. METHODS: Retrospective analysis of 898 consecutive simultaneous left and right heart catheterisations. Of these, 684 patients (age 63+/-14 years) were classified according to presence of absence of left heart disease. Multilinear regression explored the relationship between mean PAP and PCWP, age, gender, systemic haemodynamics and left heart disease diagnosis. RESULTS: Increasing PCWP, age and heart rate and female gender were associated with higher PAP (p<0.0001, p=0.049, p<0.0001 and p=0.0015, respectively). Thus, in males: (mean PAP)=0.94+[1.15 x (mean PCWP)]+[0.03 x (age)]+[0.07 x (heart rate)] (for females add 1.38 mm Hg). This model accounted for 75% of variability in PAP, with PCWP alone accounting for 74%. CONCLUSIONS: A strong linear relationship exists between PAP and PCWP, which may help identify PAP 'out-of proportion' to PCWP, facilitating the diagnosis of PVD in patients with pulmonary hypertension and left heart disease. PMID- 19783213 TI - Cancer cell apoptotic pathways mediated by PEDF: prospects for therapy. AB - Pigment epithelium-derived factor (PEDF) has roles in antiangiogenesis and antitumourigenesis that are intimately entwined and is showing promise as a potential anticancer agent. However, the function of PEDF in the deregulated apoptotic pathways of malignant cells must first be fully characterized. Here, we review the currently known apoptotic pathways that are relevant to PEDF and cancer. Recently, a pathway that includes the PEDF receptor, PPARgamma and p53 has emerged. It is hoped that further characterization of this and other pathways involved in cancer will bring to light potential new therapeutic targets and approaches, which due to their specificity might be free of the morbidity associated with conventional chemotherapy. PMID- 19783214 TI - Antituberculosis activity of the molecular libraries screening center network library. AB - There is an urgent need for the discovery and development of new antitubercular agents that target novel biochemical pathways and treat drug-resistant forms of the disease. One approach to addressing this need is through high-throughput screening of drug-like small molecule libraries against the whole bacterium in order to identify a variety of new, active scaffolds that will stimulate additional biological research and drug discovery. Through the Molecular Libraries Screening Center Network, the NIAID Tuberculosis Antimicrobial Acquisition and Coordinating Facility tested a 215,110-compound library against Mycobacterium tuberculosis strain H37Rv. A medicinal chemistry survey of the results from the screening campaign is reported herein. PMID- 19783215 TI - Antiphospholipid antibodies: pinning risk on a moving target. PMID- 19783216 TI - Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. AB - BACKGROUND: Arterial thrombosis is a major clinical manifestation of the antiphospholipid syndrome, which is an autoimmune disease found mostly in young women. Although the presence of circulating antiphospholipid antibodies in individuals who have a thrombotic event is a prerequisite for the diagnosis of the antiphospholipid syndrome, the risk of arterial thrombosis associated with antiphospholipid antibodies in the general population is unclear. METHODS: In RATIO (Risk of Arterial Thrombosis In relation to Oral contraceptives), a large multicentre population-based case-control study, we enrolled women aged under 50 years who were admitted to hospital at 16 centres with first ischaemic stroke or myocardial infarction between January, 1990, and October, 1995. An additional 59 women who presented with ischaemic stroke at the University Medical Centre Utrecht between 1996 and 2001 were also enrolled. Information on cardiovascular risk factors (such as oral contraceptive use, smoking, and hypertension) were assessed with a standard questionnaire. During the second phase (1998-2002), blood samples were taken to measure antiphospholipid antibody profiles (lupus anticoagulant, anticardiolipin IgG, anti-beta(2)-glycoprotein I IgG, and antiprothrombin IgG) and to determine genetic prothrombotic risk factors (factor V G1691A variant, prothrombin G20210A variant, and factor XIII 204Phe allele). FINDINGS: 175 patients with ischaemic stroke, 203 patients with myocardial infarction, and 628 healthy controls were included. Patients were frequency matched with controls for age, residence area, and index year. Lupus anticoagulant was found in 30 (17%) patients with ischaemic stroke, six (3%) patients with myocardial infarction, and four (0.7%) in the control group. The odds ratio for myocardial infarction was 5.3 (95% CI 1.4-20.8), which increased to 21.6 (1.9-242.0) in women who used oral contraceptives and 33.7 (6.0-189.0) in those who smoked. The odds ratio for ischaemic stroke was 43.1 (12.2-152.0), which increased to 201.0 (22.1-1828.0) in women who used oral contraceptives and 87.0 (14.5-523.0) in those who smoked. In women who had anti-beta(2)-glycoprotein I antibodies, the risk of ischaemic stroke was 2.3 (1.4-3.7), but the risk of myocardial infarction was not increased (0.9, 0.5-1.6). Neither anticardiolipin nor antiprothrombin antibodies affected the risk of myocardial infarction or ischaemic stroke. INTERPRETATION: Our results suggest that lupus anticoagulant is a major risk factor for arterial thrombotic events in young women, and the presence of other cardiovascular risk factors increases the risk even further. FUNDING: Netherlands Heart Foundation and Leducq Foundation. PMID- 19783217 TI - Psychosocial treatment programs in epilepsy: a review. AB - Psychosocial problems are a major unmet treatment need in epilepsy. The purpose of this review was to describe published psychosocial treatment interventions in the English medical literature. Seventeen outcome studies for 15 treatments were found. Survival past proof of concept was a problem, with only four programs making it into current use. With important exceptions, treatments met with limited success. Several were successful with medical education, improving quality of life, social adjustment, and adjustment to seizures. A psychological intervention for seizure control for patients with refractory epilepsy was outstanding. Research problems included few control groups, a dependence on paper and-pencil measures, limited variables, and only one study with serum determination for compliance. Low cost-effectiveness was a problem. Only one approach showed economic promise. Low participation by patients was an unexpected barrier. Psychosocial treatments should be targeted for development and needs to be integrated into the treatment flow of specialty clinics. PMID- 19783218 TI - Real-time detection, quantification, warning, and control of epileptic seizures: the foundations for a scientific epileptology. AB - Substantive advances in clinical epileptology may be realized through the judicious use of real-time automated seizure detection, quantification, warning, and delivery of therapy in subjects with pharmacoresistant seizures. Materialization of these objectives is likely to elevate epileptology to the level of a mature clinical science. PMID- 19783219 TI - Clinical efficacy and cognitive and neuropsychological effects of levetiracetam in epilepsy: an open-label multicenter study. AB - The aim of this prospective, multicenter, open-label study was to investigate the efficacy of levetiracetam (LEV) and determine its effects on cognitive and neuropsychological function. Sixty-nine patients were evaluated for effects of LEV on seizure control, cognitive (Mini-Mental State Examination [MMSE]) and neuropsychological (Symptom Checklist-90 Revised [SCL-90-R]) functions, and quality of life (Quality of Life in Epilepsy--10 [QOLIE-10]) assessments at 3 and 12 months of follow-up. Thirty-nine percent of patients achieved seizure freedom, and 68% had a > or =50% seizure frequency reduction after 1 year of LEV (1235.5+/ 392.7 mg/day). There were also significant improvements in mean MMSE score and in the recall and language items of MMSE. There were modest improvements in interpersonal sensitivity and paranoid ideation scales of the SCL-90-R, and improvements in cognition and medication effect items of the QOLIE-10. The results demonstrate that LEV not only effectively reduces seizure frequency, but also possibly contributes to improvements in neuropsychological functions such as recall, language, interpersonal sensitivity, and paranoid ideation. PMID- 19783220 TI - Employment outcome and satisfaction after anterior temporal lobectomy for refractory epilepsy: a developing country's perspective. AB - We examined employment outcome and its determinants in 172 south Indian patients who had undergone anterior temporal lobectomy (ATL) for medically refractory epilepsy. Despite seizure-free outcome in the majority, a significant change in post-ATL employment status occurred only in those involved in skilled jobs. Although factors such as younger age at surgery, shorter duration of epilepsy, longer post-ATL follow-up duration, and lower income were associated with favorable employment outcome in univariate analysis, only shorter duration of epilepsy was independently predictive in the multivariate model. A majority of homemakers appreciated marked improvement in their own day-to-day activities. Our patients did not express their desire to work as a principal aim of epilepsy surgery. To enhance occupational attainment, patients require, before epilepsy surgery, occupational assessment to identify their individual abilities and limitations and counseling in formulating realistic goals. After surgery, they require continued support in vocational training and job seeking. PMID- 19783221 TI - Multi-modal examination of psychological and interpersonal distinctions among MPI coping clusters: a preliminary study. AB - The Multidimensional Pain Inventory (MPI) is a widely used instrument to characterize distinct psychosocial subgroups of patients with chronic pain: Adaptive (AC), Dysfunctional (DYS), and Interpersonally Distressed (ID). To date, several questions remain about the validity and distinctiveness of the patient clusters, and continued scientific attention has strongly been recommended. It is unclear if AC patients experience better adjustment or merely present themselves favorably. Moreover, differences in psychological distress and interpersonal relations between DYS and ID patients are equivocal. The present study is the first to utilize comprehensive informant ratings to extend prior validity research on the MPI. We employed a multimodal methodology consisting of patient self-report, parallel informant ratings, and behavioral measures. Ninety-nine patients with chronic pain, their partners, and providers participated. They completed measures of patients' psychological distress and social relations. We also systematically observed patients' pain behavior. Results provided strong support for the validity of the AC cluster in that patients' positive adaptation was reliably corroborated by informants. The differentiating characteristics between the 2 maladaptive clusters, however, remain elusive. We found evidence that DYS patients' distress appeared to be illness specific rather than generalized; however, both clusters were equally associated with social distress and partner/caregiver burden. PERSPECTIVE: An adaptive style of coping with chronic pain is reliably recognized by patients' partners and healthcare providers. Differences between a dysfunctional and an interpersonally distressed coping style, however, remain unclear. Patients with a dysfunctional style appear more distressed by their illness but both styles are characterized by social difficulties. PMID- 19783222 TI - Do past pain events systematically impact pain ratings of healthy subjects or fibromyalgia patients? AB - We previously reported that 3 different electronic visual analogue and numerical pain scales are useful in providing refined capacity to discriminate discrete levels of pain intensity. Using the same subjects and scales, we now investigated whether pain scaling is influenced by past pain events and by recalled memories of these events in the rating of pain. Normal control subjects (NC: 19 male, 30 female) and female fibromyalgia (FM) (n = 17) patients received 5-second suprathreshold heat stimuli (45-49 degrees C) to both forearms. The participants rated these experimental heat stimuli using the previously described electronic pain scales. Subsequently, they were asked to report whether they used any prior pain experiences during the process of rating their pain. Out of 49 NC, only 6 females (12.2%) and 7 males (14.3%), and out of 17 FM patients, only 3 females (17.6%) stated that they had used past pain experiences during scaling. Notably, pain ratings of experimental heat stimuli did not statistically differ between subjects who used past pain experiences during scaling as compared to those who did not. Furthermore, ratings of their most severe past pains were not significantly correlated with ratings of experimental pain stimuli. These results do not provide support for the strong assertion that pain rating scales are elastic, ie, being used differently depending on the severity of past pain events such as childbirth. PERSPECTIVE: Less than 25% of subjects used memories of past pain events during pain scaling. In addition, if they were used, these pain memories did not influence pain scaling with electronic eVAS and eNUM scales. Thus, use of these scales allows reliable comparisons of experimental and clinical pain ratings within and between subjects. PMID- 19783224 TI - Development of the autonomic nervous system: New perspectives and open questions. PMID- 19783223 TI - A single nitrous oxide (N2O) exposure leads to persistent alleviation of neuropathic pain in rats. AB - Using the rat chronic constriction injury (CCI) pain model, we evaluated whether nitrous oxide (N2O), a gas shown to have potent anti-hyperalgesic properties, may alleviate neuropathic pain. Mechanical nociceptive threshold was estimated using the paw pressure vocalization test. Thermal allodynia was challenged by measuring the struggle latency by immersion of the hind paw in a 10 degrees C water bath. A single 50% N2O exposure for 1 hour, 15 minutes not only induced potent anti nociception during N2O exposure but also provoked a delayed and sustained reduction (37% to 46%) of pain hypersensitivity of the injured hind paw and abolished pain hypersensitivity of the contralateral uninjured hind paw for at least 1 month. Thermal allodynia was completely prevented by a single N2O exposure. A preadministration of naltrexone, which markedly reduced acute N2O induced anti-nociception, did not affect the persistent reduction of hyperalgesia. The administration of naltrexone in N2O-treated rats, 1 week after the gas exposure, did not induce any effect. This suggests that the long-lasting effect of N2O was not due to its prior acute analgesic effect and was independent of endogenous opioid systems. These data suggest that 50% N2O exposure could be an efficient and safe strategy for alleviating neuropathic pain in a persistent manner. PERSPECTIVE: Because a single 50% N2O exposure induced a persistent reduction of hyperalgesia-allodynia in a rat neuropathic pain model, clinical trials must be developed for evaluating the N2O effects in patients with neuropathic pain. The ability of N2O to potentiate analgesic effects of other drugs also must be evaluated. PMID- 19783225 TI - Is resistance futile? Changing external resistance does not improve microbial fuel cell performance. AB - Microbial fuel cells (MFCs) show promise as an alternative to conventional batteries for point source electricity generation. A better understanding of the relationship between the microbiological and electrical aspects of fuels cells is needed prior to successful MFC application. Here, we observed the effects of external resistance on power production and the anodic biofilm community structure. Large differences in the external resistance affected both power production and microbial community structure. After the establishment of the anodic microbial community, change in external resistance (from low to high and vice versa) changed the anodic microbial community structure, but the resulting community did not resemble the communities established at that same external resistance. Different microbial community structures, established under different external resistances, resulted in similar power production, demonstrating the flexibility of the MFC system. PMID- 19783226 TI - A mediated polyphenol oxidase biosensor immobilized by electropolymerization of 1,2-diamino benzene. AB - A biosensor based on a partially purified polyphenol oxidase (PPO) enzyme was developed by using electropolymerization of [(2,2'-bipyridine)(chloro)(p cymene)rutenium(II)]chloride] mediator complex and 1,2-diamino benzene (DAB) on a screen printing Pt electrode (1mm diameter). The electropolymerization was carried out at +0.7V for 45min in phosphate buffer (50mM, pH 7.0) which contained 14.0U/10mL polyphenole oxidase, 200mM DAB and 2.5mM Ru-mediator complex solutions. Measurement is based on the detection of the oxidation current of the Ru-mediator complex that related to the enzymatic reaction catalyzed by PPO at +0.65V. The phosphate buffer (50mM, pH 7.0 containing 0.1M KCl) and 30 degrees C were established as being the optimum working conditions. Under the optimum experimental conditions a linear calibration curve was obtained between 5 and 100microM catechol concentration. The detection limit of the biosensor is 2.385microM. In the characterization studies of the biosensor some parameters such as effect of Ru-mediator types on the biosensor response, substrate specificity, reproducibility and storage stability were studied. From the experiments, the average value (x), standard deviation (SD) and coefficient of variation (CV%) were found to be 48.75microM,+/-1.56microM, and 3.2% respectively for 50microM catechol standard. PMID- 19783227 TI - The effects of the electric fields on hydrogels to achieve antitumoral drug release. AB - The achievement of electrochemotherapy was obtained using electrodes covered with guar gum (GG) hydrogel swollen in a sulfate bleomycin solution. The bleomycin delivery into the plasma membranes of cancer cells occurs only when field strength (V/cm) was applied, decreasing the drug contact with healthy tissues. The effect of the delivered bleomycin at different concentrations was examined on tumoral mouse fibroblast (NIH3T3) and human coronary artery endothelial cells. The GG hydrogel released the drug only when the field strength was applied and the amount depended on the electromotive force. Consequently, cellular survival depended on the field strength. Moreover in vitro results showed a bigger cellular mortality of the NIH3T3 compared with endothelial cells. The best parameters to be utilized in electrochemotherapy were ascertained. PMID- 19783228 TI - Enhanced electro-mediated gene delivery using carrier genes. AB - Low transfection and expression of target genes has been a problem in gene delivery for clinical therapy. In this study, we present a method for enhancing the transfection efficiency of target genes by electroporation using carrier genes. To evaluate the transfection efficiency, we transfected HeLa cells with luciferase genes (pGL3-control) and then measured the luciferase activity. In our experiments, the prokaryotic expression vector pCR2.1 was used as a carrier gene in the electro-mediated gene delivery. The result shows that the luciferase gene can be effectively transferred into the cell membrane with the aid of carrier genes. In the presence of carrier genes, luciferase activities increased two- to three-fold compared with that in the absence of carrier genes. We also investigated the effect of the weight ratio of luciferase genes to carrier genes on transfection efficiency and found no significant relationship between them. Consequently, we believe that carrier genes are potentially beneficial for promoting transfection and expression of target genes in biological applications. PMID- 19783229 TI - Mammalian polymerase zeta is essential for post-replication repair of UV-induced DNA lesions. AB - DNA polymerase zeta is believed to be an essential constituent of DNA damage tolerance, comprising several pathways that allow the replication of DNA templates containing unrepaired damage. We wanted to better define the role of polymerase zeta in DNA damage tolerance in mammalian cells. To this aim we have investigated replication of ultraviolet light-damaged DNA templates in mouse embryonic fibroblasts deficient for Rev3, the catalytic subunit of polymerase zeta. We found that Rev3 is important for a post-replication repair pathway of helix-distorting [6-4]pyrimidine-pyrimidone photoproducts and, to a lesser extent, of cyclobutane pyrimidine dimers. Unlike its partner Rev1, Rev3 appears not to be involved in an immediate translesion synthesis pathway at a stalled replication fork. The deficiency of Rev3(-/-) MEFs in post-replication repair of different photoproducts contributes to the extreme sensitivity of these cells to UV light. PMID- 19783231 TI - Determination of metformin in human plasma using hydrophilic interaction liquid chromatography-tandem mass spectrometry. AB - A sensitive, simple and rapid assay based on hydrophilic interaction liquid chromatography (HILIC) with tandem mass spectrometry was developed and validated for the quantitative analysis of metformin in human plasma using protein precipitation. Plasma samples were prepared using a protein precipitation solution containing acetonitrile, 0.5% formic acid and the internal standard, metformin-D(6). The analytes were separated on a GL Sciences Inertsil HILIC column using an isocratic mobile phase consisting of water/acetonitrile (30:70, v/v) and 0.1% formic acid. Metformin and internal standard were recorded using multiple reaction monitoring in positive ion electrospray mode with transitions of m/z 130-71 and m/z 136-77, respectively. No endogenous components in plasma were found to interfere with metformin measurements. The lower limit of quantification (LLOQ) was 0.5 ng/mL (0.1 pg on-column). The linear range was 0.5 500 ng/mL with an average correlation coefficient of 0.999 using weighted (1/x(2)) linear least-squares regression. Dilutional linearity was evaluated up to 5000-fold dilution and the results indicate no influence on the accuracy of analysis. The absolute extraction recovery was 81% for metformin. Intra-day and inter-day precision (CV, %) ranged from 0.73% to 7.18%, and accuracy within +/ 10.98% from nominal. The analyte was found to be stable for at least 38 days at 20 and -80 degrees C, 24 h at room temperature, and stable for four freeze-thaw cycles. The processed extracts were stable for 88 h at 4 degrees C. PMID- 19783230 TI - Polk mutant mice have a spontaneous mutator phenotype. AB - Mice defective for the Polk gene, which encodes DNA polymerase kappa, are viable and do not manifest obvious phenotypes. The present studies document a spontaneous mutator phenotype in Polk(-/-) mice. The initial indication of enhanced spontaneous mutations in these mice came from the serendipitous observation of a postulated founder mutation that manifested in multiple disease states among a cohort of mice comprising all three possible Polk genotypes. Polk( /-) and isogenic wild-type controls carrying a reporter transgene (the lambda phage cII gene) were used for subsequent quantitative and qualitative studies on mutagenesis in various tissues. We observed significantly increased mutation frequencies in the kidney, liver, and lung of Polk(-/-) mice, but not in the spleen or testis. G:C base pairs dominated the mutation spectra of the kidney, liver, and lung. These results are consistent with the notion that Pol kappa is required for accurate translesion DNA synthesis past naturally occurring polycyclic guanine adducts, possibly generated by cholesterol and/or its metabolites. PMID- 19783232 TI - On-line coupling of anion exchange and ion-pair chromatography for measurement of intracellular triphosphate metabolites of reverse transcriptase inhibitors. AB - We developed an automated on-line weak anion exchange (WAX) solid-phase extraction (SPE) method coupled with ion-pair (IP) chromatography-tandem mass spectrometry (MS/MS) detection for quantitatively measuring triphosphorylated metabolites of three reverse transcriptase inhibitors (RTI). The administered pro drugs were Tenofovir disoproxil fumarate (TDF), Emtricitabine (FTC) and Lamivudine (3TC). Their intracellular metabolites Tenofovir-diphosphate (TFV-DP), Emtricitabine-triphosphate (FTC-TP), and Lamivudine-triphosphate (3TC-TP) were measured in peripheral blood mononuclear cells (PBMC). We coupled the WAX and IP chromatography systems using a combination of 6-port and 10-port switching valves, and we mixed the WAX elute with 1,5-dimethyl-hexyl-amine before IP chromatography separation. Multiple waste outlets allowed for eliminating potential matrix components interfering with MS/MS detection. Limits of detection were 9, 200 and 75 pg per sample for TFV-DP (448/176 m/z), FTC-TP (488/130 m/z) and 3TC-TP (468/119 m/z), respectively. PMID- 19783233 TI - Quantitative determination of free glycerol and myo-inositol from plasma and tissue by high-performance liquid chromatography. AB - A high-performance liquid chromatographic method that accurately measures glycerol and myo-inositol from plasma and tissue is described. The method incorporates a pre-column derivatization reaction using aqueous extracts with benzoyl chloride as a modifying agent. The benzoylated derivatives are isolated by HPLC using reversed-phase gradient chromatography and quantified via absorbance detection at 231 nm. The benzoylated derivatives of glycerol and myo inositol are well resolved from other known carbohydrates, internal standard and other contaminants encountered within samples and during incubation. The benzoylation of these analytes reach a maximum between 3.5 and 6 h of incubation and are stable for at least 24 days at 4 degrees C. The limit of quantization (LOQ) of glycerol was equal to 2.5 nmol/ml plasma and 6.4 nmol/g tissue and the LOQ of myo-inositol was 1.8 nmol/ml plasma and 3.6 nmol/g tissue. Incubation of known standards and samples with benzoyl chloride at 40 degrees C for 4 h showed fully benzoylated products as determined by mass spectral analysis. Calibration curves were linear between 2.7 and 174 nmol for glycerol and 1.4-89 nmol for myo inositol. Comparison of tissue and plasma concentrations of glycerol and myo inositol found using this method are in good agreement with other reported values using other techniques. PMID- 19783234 TI - Determination of amphetamine and methamphetamine in umbilical cord using liquid chromatography-tandem mass spectrometry. AB - The use of meconium as a drug-screening matrix for newborns has been the gold standard of care for the past two decades. A recent study using matched pairs of meconium and umbilical cord demonstrated a high degree of agreement. The use of liquid chromatography-tandem mass spectrometry as a means to confirm amphetamines presumptive positive umbilical cord specimens for amphetamine and methamphetamine is described here for the first time. The limit of detection for both compounds was 0.2 ng/g. The limit of quantitation for both compounds was 0.6 ng/g. The assay was linear for both compounds up to 100 ng/g. PMID- 19783235 TI - Validation of an LC-MS/MS method for the determination of epirubicin in human serum of patients undergoing drug eluting microsphere-transarterial chemoembolization (DEM-TACE). AB - Drug Eluting Microsphere-Transarterial Chemoembolization (DEM-TACE) is a new delivery system to administrate drugs in a controlled manner useful for application in the chemoembolization of colorectal cancer metastases to the liver. DEM-TACE is focused to obtain higher concentrations of the drug to the tumor with lower systemic concentrations than traditional cancer chemotherapy. Therefore a specific, precise and sensitive LC-ESI-MS/MS assay procedure was properly designed to detect and quantify epirubicin at the concentrations expected from a transarterial chemoembolization with microspheres. Serum samples were kept acidic (pH approximately of 3.5) and sample preparation consisted of a solid phase extraction (SPE) procedure with HLB OASIS cartridges using a methylene chloride/2-propanol/methanol mixture solution to recover epirubicin. The analyses consisted of reversed-phase high-performance liquid chromatography (rp-HPLC) coupled with tandem mass spectrometry (MS/MS). Accuracy, precision and matrix effect of this procedure were carried out by analyzing four quality control samples (QCs) on five separate days. The validation parameters were assessed by recovery studies of spiked serum samples. Recoveries were found to vary between 92 and 98% at the QC levels (5, 40, 80 and 150 microg/L) with relative standard deviation (RSD) always less than 3.7%. The limit of detection (LOD) was set at 1 microg/L. The developed procedure has been also applied to investigate the different capability of two types of commercially available microspheres to release epirubicin into the human circulatory system. PMID- 19783236 TI - Simultaneous measurement of cortisol and cortisone in human saliva using liquid chromatography-tandem mass spectrometry: application in basal and stimulated conditions. AB - Immunoassays used for the measurement of salivary cortisol are limited by variable interference from cortisone. Salivary cortisone is a consequence of the salivary glands expressing 11beta-hydroxysteroid dehydrogenase type 2 (11beta HSD2) which converts cortisol to cortisone. We report a combined salivary cortisol and cortisone (SalF and SalE respectively) liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay to address the cortisone cross-reactivity in cortisol immunoassays and as a tool to study 11beta-HSD2 activity. The method was linear up to 400 nmol/L for SalF and 200 nmol/L for SalE and the lower limits of quantitation were 0.39 nmol/L (SalF) and 0.78 nmol/L (SalE). No evidence of ion suppression was found and precision, accuracy and recovery were within internationally accepted limits. No interference was identified from 13 structurally related steroids. SalF, SalE and SalF/SalE were significantly greater in the morning than at bed-time and following stimulation of the adrenal glands. As serum cortisol increased, an exponential rise was observed in SalF and a linear increase in SalE which reached a plateau at higher SalF concentrations. We have developed a novel, robust LC-MS/MS assay for the combined measurement of SalF and SalE. Our results confirm the 11beta-HSD2 activity of the salivary glands resulting in high SalE concentrations and the enzyme saturation at high substrate concentrations. This method can be used as a simple, non-invasive and highly specific tool to assess the value of salivary cortisol as a surrogate for free serum cortisol and as a potential novel way to assess 11beta-HSD2 activity. PMID- 19783237 TI - Perceived calorie intake and state body-image satisfaction in women attempting weight loss: a preliminary investigation. AB - State body-image satisfaction levels (BIS) can be predicted by appearance concerns, eating attitudes and body mass index (BMI). Determinants of state BIS and its variability were examined in women attempting weight loss. Little is known about contextual cues that influence state BIS; therefore the effect of eating on BIS was examined. Forty-six females attending a commercial weight loss group completed measures of shape and weight concerns, appearance beliefs and dietary restraint, followed by completion of a diary that assessed state BIS, mood and perceived calorie intake immediately following evening meals. Regression analysis indicated that after controlling for mood, state BIS was associated with higher BMI and dietary restraint. Greater variability in state BIS was associated with greater variability in perceived calorie intake. This relationship was fully mediated by greater variability in mood. The findings imply that state BIS warrants investigation as a process that may influence weight loss management. PMID- 19783238 TI - Epidemiology of bronchopulmonary dysplasia. AB - First described more than 40 years ago, bronchopulmonary dysplasia (BPD) remains one of the most serious and vexing challenges in the care of very preterm infants. Affecting approximately one-quarter of infants born <1500g birth weight, BPD is associated with prolonged neonatal intensive care unit hospitalization, greater risk of neonatal and post-neonatal mortality and a host of associated medical and neurodevelopmental sequelae. This seminar focuses on the epidemiology and definition of BPD as well as the current evidence pertaining to a number of potential preventive treatments for BPD: non-invasive respiratory support technologies, inhaled nitric oxide, vitamin A, and caffeine. PMID- 19783239 TI - The UK primary hypospadias surgery audit 2006-2007. AB - AIM: To find out what primary hypospadias surgery is being done in the United Kingdom and at what ages patients have surgery. METHODS: On behalf of the British Associations of Paediatric Urologists, Paediatric Surgeons and Plastic, Reconstructive and Aesthetic Surgeons, paediatric surgeons/urologists, plastic surgeons and urologists were asked to record prospectively their data for 12 months, October 2006-September 2007. RESULTS: There were 50 replies (response rate 50%, 79% of plastic surgeons and 40% of paediatric surgeons/urologists). Most patients had distal hypospadias. The total numbers of operations were 814 (paediatric surgeons/urologists), 436 (plastic surgeons) and 5 (one urologist). More than 20 operations a year were performed by 79% of paediatric surgeons/urologists and 35% of plastic surgeons. Both groups used a similar range of single-stage and two-stage operations. Patients' ages at surgery were less than two years for 68% of paediatric surgeons/urologists and two to four years for 60% of plastic surgeons. CONCLUSIONS: In the UK most primary hypospadias surgery in children is performed by paediatric surgeons/urologists and plastic surgeons. Both groups of surgeons use a range of procedures. Many plastic surgeons are low volume operators. Most plastic surgeons operate on children two or more years old. Plastic surgeons should change their hypospadias service. All hypospadias surgeons should contribute to future prospective outcome studies of hypospadias surgery. PMID- 19783240 TI - Elderly patient's mortality and morbidity following trochanteric fracture. A prospective study of 100 cases. AB - BACKGROUND: Trochanteric fractures are a major source of mortality, morbidity and functional impairment in the elderly. Morbidity is closely related to the degree of instability and comminution and is substantially influenced by the quality of reduction and internal fixation. Advanced age and associated co-morbidities are two decisive factors of mortality secondary to trochanteric fracture. OBJECTIVES: This prospective study examined the epidemiological profile of trochanteric fractures and assessed mortality and morbidity with the aim of establishing management guidelines and improving prevention strategies. MATERIAL AND METHODS: One hundred patients were included; 60% were male. Mean age was 76 years (range, 60-96 yrs). One, or more than one, co-morbidities were present in 68% of cases. The fractures were caused by a simple fall in 90% of cases. Fractures were classified according to the criteria of Ramadier and the ones of Ender. Sixty five percent of these fractures were unstable. A dynamic hip screw was systematically used as the standard means of internal fixation. RESULTS: Anatomic and functional results were analyzed in 82 patients (18 had died within the first year following fracture occurrence). Mean follow-up period was 24 months (range, 12-36 months). Bone healing was achieved in 96% of cases. There were numerous postoperative complications (four cases of thromboembolism, fourteen immobility related complications, two infections, six secondary displacement combined to loss of fixation, four non-unions, and nine malunions). At 2 years follow-up, 28 patients had died. Mortality was strongly correlated with older age (over 90 years), associated co-morbidity and fracture instability. Good functional outcomes (72%) correlated with younger age (60-74 years), fracture stability, adequate reduction and internal fixation. DISCUSSION: In stable trochanteric fractures, osteosynthesis by dynamic screw-plate is more effective than alternative techniques (blade-plate, nail-plate, Ender nail or even trochanteric nail). In unstable trochanteric fractures, delayed weight-bearing should be preferred to avoid mechanical complications. In fractures that are unstable or extend far below the lesser trochanter, trochanteric nailing is indicated since providing enhanced stability, but sometimes at the cost of insufficient reduction. The treatment objective should be the complete resumption of weight bearing as early as possible with the fewest possible complications. Prevention consists in detecting and treating osteoporosis and countering the causes of falls in elderly subjects (muscular reinforcement and correction of neurosensory deficit). LEVEL OF EVIDENCE: Level III: Prospective diagnostic study. PMID- 19783241 TI - A mild, efficient, and selective procedure for transprotection of acetonides to acetates catalyzed with HClO4-SiO2. AB - The transformation of acetonides into acetates is frequently required in synthetic chemistry. An efficient procedure for direct conversion of acetonides into acetates in the presence of HClO(4)-SiO(2) under mild conditions was developed. The acetonides of primary hydroxy groups are directly converted to diacetates, and the anomeric acetonides of furanosides are stereoselectively transformed into the corresponding acetyl beta-d-furanosides with a 2 acetoxyisopropyl group. PMID- 19783242 TI - [Laparoscopic radical antegrade modular pancreatosplenectomy]. PMID- 19783243 TI - [Improving safety in the operating room reduces hospital mortality]. PMID- 19783244 TI - [Usefulness of urokinase in intraabdominal abscesses]. PMID- 19783245 TI - Modeling schizophrenic-like neuronal patterns using nonlinear delayed differential equations. AB - We examined the simultaneous effect of altered dopamine and glutamate level on pyramidal cells using a mathematical model. The simulation results suggest that increased dopamine brings about irregular and aperiodic activity, interpreted as schizophrenic state. Hypoglutamatergic conditions have the same effect on the membrane potential of pyramidal cells. Increased glutamate level was able to neutralize the effects of the hyperdopamine state and normal periodic bursting behavior appeared. We suggest that glutamate receptor activation may have therapeutic results in schizophrenic patients. Surely, this hypothesis must be evaluated in the light of experimental studies on animal models or clinical trials. PMID- 19783246 TI - Increased micronuclei and bulky DNA adducts in cord blood after maternal exposures to traffic-related air pollution. AB - Exposure to traffic-related air pollution in urban environment is common and has been associated with adverse human health effects. In utero exposures that result in DNA damage may affect health later in life. Early effects of maternal and in utero exposures to traffic-related air pollution were assessed through the use of validated biomarkers in blood cells from mother-newborn pairs. A cross-sectional biomonitoring study with healthy pregnant women living in the Greater Copenhagen area, Denmark, was conducted. Bulky DNA adducts and micronuclei (MN) were measured in blood from 75 women and 69 umbilical cords, concurrently collected at the time of planned Caesarean section. Modeled residential traffic density, a proxy measure of traffic-related air pollution exposures, was validated by indoor levels of nitrogen dioxide and polycyclic aromatic hydrocarbons in 42 non-smoking homes. DNA adduct levels were similar and positively correlated in maternal and cord blood (1.40 vs. 1.37 n/10(8) nucleotides; r=0.99; p<0.01). Maternal MN frequencies were significantly associated with age (p<0.01), and higher than those of the newborns (7.0 vs. 3.2 MN per 1000 binucleated cells). Adduct levels were highest among mother-newborn pairs who lived near medium-traffic-density (>400-2500 vehicle km/24h; p<0.01) places. MN frequencies among newborns from women who lived at high-traffic-density homes (>2500 vehicle km/24h) were significantly increased (p=0.02). This trend remained after adjusting for potential confounders and effect modifiers. For the first time increased bulky DNA adducts and MN in cord blood after maternal exposures to traffic-related air pollution are found, demonstrating that these transplacental environmental exposures induce DNA damage in newborns. Given that increased DNA damage early in life indicate an increased risk for adverse health effects later in life, these findings justify intervention of pregnant women. PMID- 19783247 TI - A comparison of cortical bone thickness in the femoral midshaft of humans and two non-human mammals. AB - Fragments of bone shafts that lack diagnostic features can be difficult to identify as human or non-human-an important task in forensic science and archaeology. Some workers have found the thickness of cortical bone in the shaft to be a useful distinction, although the sparse literature in the field is contradictory in how this may be applied. The aim of the present study was to determine whether any difference is discernible between humans, kangaroos and sheep (mammals whose remains are commonly confused with those of humans in Australia) at the femoral midshaft, with a view to a larger-scale analysis if differences were discovered. Cross-sections at the midpoint of the shaft were measured to determine the diameter of the whole shaft and the medullary cavity on each bone; an index describing cortical thickness relative to shaft diameter was calculated. Statistically significant differences were found between all three groups, with humans showing the thickest cortical bone, and sheep the thinnest. These differences may be linked to a higher load on the human femur, due to a larger body mass carried on two legs, as opposed to the sheep's four. Further work now needs to be carried out to determine if differences are present when comparing multiple sites on the skeleton, and between non-human mammals of different sizes. PMID- 19783248 TI - Multi-loop PI controller design based on the direct synthesis for interacting multi-time delay processes. AB - In this article, a new analytical method based on the direct synthesis approach is proposed for the design of a multi-loop proportional-integral (PI) controller. The proposed design method is aimed at achieving the desired closed-loop response for multiple-input, multiple-output (MIMO) processes with multiple time delays. The ideal multi-loop controller is firstly designed in terms of the relative gain and desired closed-loop transfer function. Then, the standard multi-loop PI controller is obtained by approximating the ideal multi-loop controller using the Maclaurin series expansion. The simulation study demonstrates the effectiveness of the proposed method for the design of multi-loop PI controllers. The multi loop PI controller designed by the proposed method shows a fast, well-balanced, and robust response with the minimum integral absolute error (IAE). PMID- 19783249 TI - Surgical techniques: how I do it? The Reamer/Irrigator/Aspirator (RIA) system. AB - Although reamed intramedullary nailing has long been considered a safe procedure, pulmonary complications have been reported in some groups of patients. Concerns over fat embolisation, adult respiratory distress syndrome (ARDS), and sudden intraoperative death have prompted some authors to question whether the benefits of reaming are outweighed by its potential adverse effects to the patient. In response to these complications, recent evaluations have focused on alternative systems that reduce intramedullary pressure during reaming. The Reamer/Irrigator/Aspirator (RIA) system (Synthes, Inc., West Chester, PA) was developed as a simultaneous reaming and aspiration system to reduce the intramedullary pressure, heat generation, operating time, and systemic effects of reaming. It was designed with an aggressive one-pass reamer head which is connected to a hand-held reamer via a drive shaft, simultaneously irrigating and aspirating femoral canal contents during reaming, thus preventing thermal necrosis and fat embolisation. After its early use, investigators examined the "aspirate" captured by the RIA which appeared to be loaded with osteogenic substrates. This discovery revealed a second potential use for the RIA-a bone graft harvester. The different design characteristics and technicalities of the RIA system necessitate a deep and clear understanding of its technique, a meticulous preoperative planning and a strict adherence to its principles intraoperatively. We present our current approach to the use of the RIA system, including the preoperative planning, the details of the operative procedure, the pitfalls and the potential complications that could be encountered. PMID- 19783250 TI - [Purulent peritonitis caused by diverticular disease: treatment by laparocopic peritoneal lavage and drainage (without resection of the colon)]. PMID- 19783251 TI - Paraoxonase 1 (PON1) expression in hepatocytes is upregulated by pomegranate polyphenols: a role for PPAR-gamma pathway. AB - OBJECTIVE: Serum paraoxonase-1 (PON1) expression is regulated by polyphenols, shown to activate the peroxisome proliferator-activated receptor gamma (PPARgamma). Pomegranate juice (PJ) is a polyphenol-rich fruit. Because promoter sequence of PON1 gene indicates that it could be regulated by nuclear receptors, we investigated the effect of PJ polyphenols on PON1 gene expression in HuH7 hepatocytes. METHODS AND RESULTS: PON1 protein or mRNA expression, determined by immunocytochemistry, or quantitative PCR, respectively, as well as PON1 gene promoter activation, was significantly increased in hepatocytes incubated with PJ or with its major polyphenols punicalagin, or gallic acid (GA). Ellagic acid (EA) elicited only modest stimulatory effect. Accordingly, PJ, punicalagin, GA, and less so EA, dose-dependently increased cell-associated and hepatocyte-secreted PON1 arylesterase activity. Functionally, the secreted PON1 exhibited biological activity by protecting LDL and HDL from oxidation. Finally, PJ polyphenols upregulated the hepatocyte PON1 expression, at least in part, via the intracellular signaling cascade PPARgamma-PKA-cAMP. CONCLUSIONS: This study shows for the first time that PJ polyphenols have a specific transcriptional role in hepatocyte PON1 expression upregulation, and its secretion to the medium. We conclude that the anti-atherogenic characteristics of PJ polyphenols are modulated, at least in part, via hepatocyte PON1 upregulation and its subsequent release to the medium. PMID- 19783253 TI - Chemometric study and optimization of extraction parameters in single-drop microextraction for the determination of multiclass pesticide residues in grapes and apples by gas chromatography mass spectrometry. AB - A simple and rapid single-drop microextraction method coupled with gas chromatography and mass spectrometry (SDME-GC/MS) for the determination of 20 pesticides with different physicochemical properties in grapes and apples was optimized by the use of a multivariate strategy. Emphasis on the optimization study was given to the role of ionic strength, sugar concentration and pH of the donor sample solution prepared from the fruit samples. Since all three variables were found to affect negatively SDME (a lower extraction efficiency was observed as the values of variables were increased for most of the pesticides studied), donor sample solution was optimized using a central composite design to evaluate the optimum pH value and the optimum dilution of the sample extract. With some exceptions (chlorpyrifos ethyl, alpha-endosulfan, beta-endosulfan, pyriproxyfen, lambda-cyhalothrin and bifenthrin), the optimum method included the dilution of the analytical sample by 12.5-fold with a buffered acetone/water solution at pH=4 and exhibited good analytical characteristics for the majority of target analytes (pyrimethanil, pirimicarb, metribuzin, vinclozolin, fosthiazate, procymidone, fludioxonil, kresoxim methyl, endosulfan sulfate, fenhexamid, iprodione, phosalone, indoxacarb and azoxystrobin) by providing high enrichment factors (14 328), low limits of detection (0.0003-0.007 microg/g), and good precision (relative standard deviations below 15%). PMID- 19783252 TI - Shortening amplitude affects the incomplete force recovery after active shortening in mouse soleus muscle. AB - Compared to isometric contraction, the force producing capacity of muscle is reduced (force depression, FD) after a work producing shortening phase. It has been suggested that FD results from an inhibition of cross-bridge binding. Because the rate constants of the exponential force (re)development are thought to be primarily determined by cross-bridge attachment/detachment rate, we aimed to investigate the components of force redevelopment (REDEV) after 0.6, 1.2 and 2.4mm shortening, resulting in varying amounts of FD (from about 5% to about 16%), in mouse soleus muscle (n=11). Compared to isometric force development (DEV), the time to reach steady-state during REDEV was about 3 times longer (370 versus 1261ms) increasing with increasing amplitude. Contrary to a single, a double exponential function with one component set equal to the rate constant of DEV (14.3s(-1)), accurately described REDEV (RMS<0.8%). The rate constant of the additional slow component decreased with increasing shortening amplitude and was associated with work delivered during shortening (R(2)=0.75) and FD (R(2)=0.77). We concluded that a work related slow exponential component is induced to the trajectory of incomplete force recovery after shortening, causing FD. These results suggest that after shortening, aside from cross-bridges with normal attachment/detachment rate, cross-bridges with reduced cycling rate are active. PMID- 19783254 TI - IgG adsorption on a new protein A adsorbent based on macroporous hydrophilic polymers. I. Adsorption equilibrium and kinetics. AB - Experimental determination and modeling of IgG binding on a new protein A adsorbent based on a macroporous resin were performed. The new adsorbent consists of polymeric beads based on hydrophilic acrylamido and vinyl monomers with a pore structure optimized to allow favorable interactions of IgG with recombinant protein A coupled to the resin. The particles have average diameter of 57 microm and a narrow particle size distribution. The IgG adsorption equilibrium capacity is 46 mg/cm(3) and the effective pore diffusivity determined from pulse response experiments for non-binding conditions is 8.0 x 10(-8) cm(2)/s. The IgG adsorption kinetics can be described with the same effective diffusivity by taking into account a heterogeneous binding mechanism with fast binding sites, for which adsorption is completely diffusion controlled, and slow binding sites for which adsorption is controlled by the binding kinetics. As a result of this mechanism, the breakthrough curve exhibits a tailing behavior, which appears to be associated with the slow binding sites. A detailed rate model taking into account intraparticle diffusion and binding kinetics is developed and is found capable of predicting both batch adsorption and breakthrough behavior over an ample range of experimental conditions. The corresponding effective diffusivity is independent of protein concentration in solution over the range 0.2-2 mg/cm(3) and of protein binding as a result of the large pore size of the support matrix. Overall, the small particle size and low diffusional hindrance allow capture of IgG with short residence times while attaining substantial dynamic binding capacities. PMID- 19783255 TI - Simultaneous determination of several phytohormones in natural coconut juice by hollow fiber-based liquid-liquid-liquid microextraction-high performance liquid chromatography. AB - A simple, selective, sensitive and inexpensive method of hollow fiber-based liquid-liquid-liquid microextraction (HF-LLLME) combined with high performance liquid chromatography (HPLC)-ultraviolet (UV) detection was developed for the determination of four acidic phytohormones (salicylic acid (SA), indole-3-acetic acid (IAA), (+/-) abscisic acid (ABA) and (+/-) jasmonic acid (JA)) in natural coconut juice. To the best of our knowledge, this is the first report on the use of liquid phase microextraction (LPME) as a sample pretreatment technique for the simultaneous analysis of several phytohormones. Using phenetole to fill the pores of hollow fiber as the organic phase, 0.1molL(-1) NaOH solution in the lumen of hollow fiber as the acceptor phase and 1molL(-1) HCl as the donor phase, a simultaneous preconcentration of four target phytohormones was realized. The acceptor phase was finally withdrawn into the microsyringe and directly injected into HPLC for the separation and quantification of the target phytohormones. The factors affecting the extraction efficiency of four phytohormones by HF-LLLME were optimized with orthogonal design experiment, and the data was analyzed by Statistical Product and Service Solutions (SPSS) software. Under the optimized conditions, the enrichment factors for SA, IAA, ABA and JA were 243, 215, 52 and 48, with the detection limits (S/N=3) of 4.6, 1.3, 0.9ngmL(-1) and 8.8 microg mL( 1), respectively. The relative standard deviations (RSDs, n=7) were 7.9, 4.9, 6.8% at 50ngmL(-1) level for SA, IAA, ABA and 8.4% at 500 microg mL(-1) for JA, respectively. To evaluate the accuracy of the method, the developed method was applied for the simultaneous analysis of several phytohormones in five natural coconut juice samples, and the recoveries for the spiked samples were in the range of 88.3-119.1%. PMID- 19783256 TI - A facile synthesis of highly water-soluble, core-shell organo-silica nanoparticles with controllable size via sol-gel process. AB - A series of highly water-soluble organo-silica nanoparticles, ranging from 2 to 10nm in diameter, were synthesized by the cohydrolysis and copolycondensation reactions. omega-methoxy(polyethyleneoxy)propyltrimethoxysilane (PEG6-9) and hydroxymethyltriethoxysilane (HMTEOS) mixtures were catalyzed by sodium hydroxide in the presence of surfactant benzethonium chloride (BTC) with various ratios of PEG6-9/HMTEOS at room temperature. The synthesized organo-silica nanoparticles possess a core-shell structure with a core of organo-silica resulting from HMTEOS and a monolayer shell of PEG6-9. The chemo-physical characteristics of the particles were studied by gel permeation chromatography (GPC), Fourier transform infrared (FTIR) spectroscopy, (29)Si nuclear magnetic resonance (NMR), dynamic light scattering (DLS), transmission electron microscopy (TEM), and thermogravimetric analysis (TGA). The molecular weight and particle size of the particles increased with increasing HMTEOS molar ratios. The richest HMTEOS composition for the water-soluble particles was found to be HMTEOS:PEG6-9=80:20, where the particles had a 6nm diameter core and a 0.8nm thick shell. We propose that these water-soluble organo-silica nanoparticles will be suitable for biomedical applications. PMID- 19783257 TI - Olfactory system pathology as a model of Lewy neurodegenerative disease. AB - Olfactory dysfunction has gained recognition as an early and nearly universal feature of Lewy body Parkinson's disease (PD). Recently, research efforts have focused on the use of early non-motor symptoms of PD as early biomarkers and have suggested that investigating neurodegeneration in the aspects of the nervous system subserving these symptoms may offer important insights into the pathophysiology of Lewy body PD. Therefore, there has been interest in characterizing the pathology observed in the olfactory bulb and system of patients with PD, dementia with Lewy bodies and perhaps more importantly, in subjects with incidental Lewy pathology, defined as people with Lewy pathology without evidence of Parkinsonism or dementia during life. The olfactory bulb may be ideally suited to investigations into the pathophysiology of the Lewy body disorders as it is one of the few areas of the brain wherein the entirety of neurons susceptible to Lewy neurodegeneration, including the dendritic arborization, cell soma, axon and synaptic terminals, can be examined in the same preparation. Interestingly, there is a lack of Lewy neurodegeneration in the dopaminergic neurons of the olfactory bulb and paradoxically, an apparent increase in dopaminergic neurons in some PD patients compared to controls. In this report, the known neuropathology of the olfactory system in PD will be reviewed and the advantages of investigating degeneration of the olfactory bulb as a model of Lewy neurodegeneration will be discussed. PMID- 19783258 TI - Water quality of a port in NW Mexico and its rehabilitation with swell energy. AB - Ensenada Harbor is one of the most important ports of Mexico. Anthropogenic activities have affected the area over several decades, leading to the accumulation of contaminants in its sediments, which eventually are re-suspended into the water column. In spite of water treatment of the tributaries that discharge into the Ensenada Harbor, the water circulation patterns of the harbor, which consist of closed eddies in the northern and southeastern sector, favor the accumulation of those contaminants and hinder exchange with adjacent seawater. Samples collected in October of 2005 registered 63 microM total inorganic nitrogen and 280 mg/L of COD, confirming that this is a highly contaminated environment when compared with other water bodies of North America. Such concentrations can be lowered up to 80% by using a wave energy pumping system that demonstrates the possibility to gradually dilute these contaminants and rehabilitate the Ensenada Harbor. PMID- 19783259 TI - [Special features of ambulatory blood pressure monitoring in the elderly]. PMID- 19783260 TI - [Prognostic value of B-type natriuretic peptide in unstable angina and non-ST elevation myocardial infarction]. AB - BACKGROUND AND OBJECTIVE: The B-type natriuretic peptide (BNP) has recently emerged as a prognostic marker in acute coronary syndromes (ACS). This role is based on results from randomized trials and other high selected population studies. The aim of this study was to determine the prognostic value of BNP in unselected patients with non-ST-elevated-ACS. PATIENTS AND METHOD: BNP plasma concentrations were measured in 100 consecutive patients admitted in 2007 with non-ST-elevated-ACS, taking as cut-off value 80pg/ml (high BNP levels on 48% of patients). RESULTS: After one year-of follow-up, 21 major adverse cardiovascular events occurred: 12 ACS, 7 hospitalizations for heart failure and 2 sudden cardiac deaths. No relationship was found between BNP levels and events on follow up. BNP >80pg/ml was the only independent predictor of heart failure and death. No relationship was found between high levels of BNP and coronary events during the follow-up. CONCLUSIONS: BNP was an independent predictor of heart failure and mortality in unselected patients with non-ST-elevated-ACS. PMID- 19783261 TI - [Recurrent rash on the hands: multiforme erythema]. PMID- 19783262 TI - Pleural fluid mesothelin for the differential diagnosis of exudative pleural effusions. AB - BACKGROUND: Malignant mesothelioma (MM) is a highly aggressive tumor that can be difficult to diagnose, resulting in a delayed diagnosis in some cases. Recent studies have reported that determination of soluble mesothelin-related peptides (SMRP) in pleural fluid may be a promising marker for use in the diagnosis of MM. PATIENTS AND METHODS: Pleural fluid SMRP concentration was measured in 68 patients: 47 had malignant pleural effusions (18 MM and 29 metastatic effusion) and 21 had benign pleural effusion (8 infectious disease and 13 idiopathic effusion). Mann-Whitney analysis was used to compare SMRP values according to the etiology of the effusion. RESULTS: Pleural fluid SMRP concentration was significantly higher in patients with malignant pleural effusion than in those with benign effusion (P=0.02). When malignant pleural effusions were analyzed separately, MM patients had the highest median pleural fluid SMRP concentration, with significant differences as compared to patients with idiopathic pleural effusion. CONCLUSIONS: Soluble mesothelin-related peptide measurement in pleural fluid may aid in the diagnosis of patients presenting with pleural effusion. PMID- 19783263 TI - [Pleuropericarditis after triple viral vaccination]. PMID- 19783264 TI - [Therapeutic alternatives to epidural analgesia in labor pain of childbirth]. PMID- 19783265 TI - [Levetiracetam-associated hyponatremia]. PMID- 19783266 TI - Seasonal variation in self-reported health and health-related behaviour in Dutch adolescents. PMID- 19783267 TI - Iron delocalisation in the pathogenesis of malarial anaemia. AB - There is consensus that the pathophysiology of malaria-associated anaemia is multifactorial, but the precise mechanisms behind many of the haematological changes during malaria remain unclear. In this review, we attempt to build a composite picture of the pathophysiology of malarial anaemia using evidence from experimental, human and animal studies. We propose that cytokine- and hepcidin mediated iron delocalisation, a principal mechanism in the anaemia of inflammation, plays an important role in the aetiology of malarial anaemia, and can explain some of the clinical and laboratory findings. These mechanisms interact with other aetiological determinants, such as dietary iron and micronutrient supply, helminth load, other infections and genetic variation, in determining the severity and associated features of anaemia. We suggest that iron delocalisation as a mechanism for malarial anaemia could be exploited for the development of alternative therapeutic strategies for post-malaria anaemia. PMID- 19783268 TI - Baseline characteristics, response to and outcome of antiretroviral therapy among patients with HIV-1, HIV-2 and dual infection in Burkina Faso. AB - In an urban district hospital in Burkina Faso we investigated the relative proportions of HIV-1, HIV-2 and HIV-1/2 among those tested, the baseline sociodemographic and clinical characteristics, and the response to and outcome of antiretroviral therapy (ART). A total of 7368 individuals (male=32%; median age=34 years) were included in the analysis over a 6 year period (2002-2008). The proportions of HIV-1, HIV-2 and dual infection were 94%, 2.5% and 3.6%, respectively. HIV-1-infected individuals were younger, whereas HIV-2-infected individuals were more likely to be male, have higher CD4 counts and be asymptomatic on presentation. ART was started in 4255 adult patients who were followed up for a total of 8679 person-years, during which time 469 deaths occurred. Mortality differences by serotype were not statistically significant, but were generally worse for HIV-2 and HIV-1/2 after controlling for age, CD4 count and WHO stage. Among severely immune-deficient patients, mortality was higher for HIV-2 than HIV-1. CD4 count recovery was poorest for HIV-2. HIV-2 and dually infected patients appeared to do less well on ART than HIV-1 patients. Reasons may include differences in age at baseline, lower intrinsic immune recovery in HIV-2, use of ineffective ART regimens (inappropriate prescribing) by clinicians, and poor drug adherence. PMID- 19783269 TI - Infection control during filoviral hemorrhagic fever outbreaks: preferences of community members and health workers in Masindi, Uganda. AB - Interviews were conducted with health workers and community members in Masindi, Uganda on improving the acceptability of infection control measures used during an Ebola outbreak. Measures that promote cultural sensitivity and transparency of control activities were preferred and should be employed in future control efforts. We suggest assessing the practicality of body bags with viewing windows, and face shields with or without chin protectors, in future outbreaks. PMID- 19783270 TI - Solitary surface acoustic waves and bulk solitons in nanosecond and picosecond laser ultrasonics. AB - Recent achievements of nonlinear acoustics concerning the realization of solitons and solitary waves in crystals and their surfaces attained by nanosecond and picosecond laser ultrasonics are discussed and compared. The corresponding pump probe setups are described, which allow an all-optical contact-free excitation and detection of short strain pulses in the broad frequency range between 10 MHz and about 300 GHz. The formation of solitons in the propagating longitudinal strain pulses is investigated for nonlinear media with intrinsic lattice-based dispersion. The excitation of solitary surface acoustic waves is realized by a geometric film-based dispersion effect. Future developments and potential applications of nonlinear nanosecond and picosecond ultrasonics are discussed. PMID- 19783271 TI - A novel fusion protein domain III-capsid from dengue-2, in a highly aggregated form, induces a functional immune response and protection in mice. AB - Based on the immunogenicity of domain III from the Envelope protein of dengue virus as well as the proven protective capacity of the capsid antigen, we have designed a novel domain III-capsid chimeric protein with the goal of obtaining a molecule potentially able to induce both humoral and cell-mediated immunity (CMI). After expression of the recombinant gene in Escherichia coli, the domain III moiety retained its antigenicity as evaluated with anti-dengue sera. In order to explore alternatives for modulating the immunogenicity of the protein, it was mixed with oligodeoxynucleotides in order to obtain particulated aggregates and then immunologically evaluated in mice in comparison with non-aggregated controls. Although the humoral immune response induced by both forms of the protein was equivalent, the aggregated variant resulted in a much stronger CMI as measured by in vitro IFN-gamma secretion and protection experiments, mediated by CD4(+) and CD8(+) cells. The present work provides additional evidence in support for a crucial role of CMI in protection against dengue virus and describes a novel vaccine candidate against the disease based on a recombinant protein that can stimulate both arms of the acquired immune system. PMID- 19783272 TI - A novel interaction between the human papillomavirus type 16 E2 and E1--E4 proteins leads to stabilization of E2. AB - The E4 (also called E1--E4) and E2 proteins of human papillomavirus type 16 are thought to be expressed within the same cells of a lesion, and their open reading frames overlap, suggesting that they may have a functional relationship. We have examined the effect of co-expression of these two proteins and found that each enhances the level of the other. We also identified the N-terminus of E2 as the first example of a viral protein that directly binds the HPV16 E1--E4 protein. This appears to result in the E2 becoming less soluble and promotes its relocation from the nucleus to the cytoplasm. In addition, the turnover of the E2 protein is decreased in the presence of E1--E4. All this raises the possibility that E1--E4 acts to influence E2 activity by varying the amount of available E2 in the cell. PMID- 19783274 TI - Evaluation of multiple sewage-associated Bacteroides PCR markers for sewage pollution tracking. AB - The host specificity of the five published sewage-associated Bacteroides markers (i.e., HF183, BacHum, HuBac, BacH and Human-Bac) was evaluated in Southeast Queensland, Australia by testing fecal DNA samples (n=186) from 11 animal species including human fecal samples collected via influent to a sewage treatment plant (STP). All human fecal samples (n=50) were positive for all five markers indicating 100% sensitivity of these markers. The overall specificity of the HF183 markers to differentiate between humans and animals was 99%. The specificities of the BacHum and BacH markers were>94%, suggesting that these markers are suitable for the detection of sewage pollution in environmental waters in Australia. The HuBac (i.e., 63%) and Human-Bac (i.e., 79% specificity) markers performed poorly in distinguishing between the sources of human and animal fecal samples. It is recommended that the specificity of the sewage associated markers must be rigorously tested prior to its application to identify the sources of fecal pollution in environmental waters. PMID- 19783273 TI - Specificity and sensitivity evaluation of novel and existing Bacteroidales and Bifidobacteria-specific PCR assays on feces and sewage samples and their application for microbial source tracking in Ireland. AB - Three novel ruminant-specific PCR assays, an existing ruminant-specific PCR assay and five existing human-specific PCR assays, which target 16S rDNA from Bacteroidales or Bifidobacteria, were evaluated. The assays were tested on DNA extracted from ruminant (n=74), human (n=59) and non-ruminant animal (n=44) sewage/fecal samples collected in Ireland. The three novel PCR assays compared favourably to the existing ruminant-specific assay, exhibiting sensitivities of 91-100% and specificities of 95-100% as compared to a sensitivity of 95% and specificity of 94%, for the existing ruminant-specific assay. Of the five human specific PCR assays, the assay targeting the Bifidobacterium catenulatum group was the most promising, exhibiting a sensitivity of 100% (with human sewage samples) and a specificity of 87%. When tested on rural water samples that were naturally contaminated by ruminant feces, the three novel PCR assays tested positive with a much greater percentage (52-87%) of samples than the existing ruminant-specific assay (17%). These novel ruminant-specific assays show promise for microbial source tracking and merit further field testing and specificity evaluation. PMID- 19783275 TI - Roof-harvested rainwater for potable purposes: application of solar collector disinfection (SOCO-DIS). AB - The efficiency of solar disinfection (SODIS), recommended by the World Health Organization, has been determined for rainwater disinfection, and potential benefits and limitations discussed. The limitations of SODIS have now been overcome by the use of solar collector disinfection (SOCO-DIS), for potential use of rainwater as a small-scale potable water supply, especially in developing countries. Rainwater samples collected from the underground storage tanks of a rooftop rainwater harvesting (RWH) system were exposed to different conditions of sunlight radiation in 2-L polyethylene terephthalate bottles in a solar collector with rectangular base and reflective open wings. Total and fecal coliforms were used, together with Escherichia coli and heterotrophic plate counts, as basic microbial and indicator organisms of water quality for disinfection efficiency evaluation. In the SOCO-DIS system, disinfection improved by 20-30% compared with the SODIS system, and rainwater was fully disinfected even under moderate weather conditions, due to the effects of concentrated sunlight radiation and the synergistic effects of thermal and optical inactivation. The SOCO-DIS system was optimized based on the collector configuration and the reflective base: an inclined position led to an increased disinfection efficiency of 10-15%. Microbial inactivation increased by 10-20% simply by reducing the initial pH value of the rainwater to 5. High turbidities also affected the SOCO-DIS system; the disinfection efficiency decreased by 10-15%, which indicated that rainwater needed to be filtered before treatment. The problem of microbial regrowth was significantly reduced in the SOCO-DIS system compared with the SODIS system because of residual sunlight effects. Only total coliform regrowth was detected at higher turbidities. The SOCO-DIS system was ineffective only under poor weather conditions, when longer exposure times or other practical means of reducing the pH were required for the treatment of stored rainwater for potable purposes. PMID- 19783276 TI - Occurrence and fate of synthetic musk compounds in water environment. AB - Synthetic musk compounds (SMCs) occur widely in water environments. The aims of this paper were to investigate the occurrence and fate of SMCs in sewage treatment plants (STPs) and surface waters. Total SMC concentrations ranged from 3.69 to 7.33microg/L (influent) and from 0.96 to 2.69microg/L (effluent) in 10 STPs. The SMC concentrations varied with the input source and treatment volume of each STP. Biological treatment processes had a greater SMCs removal effect than chemical treatment, filtration and disinfection processes. The SMC concentrations in surface waters ranged from 0.15 to 16.72microg/L and exhibited similar SMCs occurrence patterns generally. The fate of SMCs in water environments depends on their physical-chemical properties and their concentrations can be predicted from other SMC concentrations due to their similar fates. PMID- 19783277 TI - Congener fingerprints of tetra- through octa-chlorinated dibenzo-p-dioxins and dibenzofurans in Baltic surface sediments and their relations to potential sources. AB - Comprehensive congener fingerprints of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs), including non-2,3,7,8-substituted congeners, in 142 surface sediment samples from the Baltic Sea were characterized by Principal Component Analysis (PCA). The pattern analysis revealed source specific indicators of chlorophenol use, high temperature processes, chlorine bleach/chloralkali production and a source signature suggested to originate from pulp/paper or related production. Congener patterns in sediments from offshore and pristine coastal areas showed strong resemblance to patterns of atmospheric deposition and flue gases, indicating that these sources have high impact in areas that are not affected by point sources. Prominent contributors to the patterns of hotspot areas along the Swedish coast included chlorophenol indicators and a source characterized by hexa-CDDs while the contribution of the traditional chlorine bleach pattern was weaker. This study demonstrates the importance of comprehensive PCDD/F congener analysis for identifying links to candidate sources. PMID- 19783278 TI - Corrosion and transport of depleted uranium in sand-rich environments. AB - The firing of depleted uranium (DU) weapons during conflicts and military testing has resulted in the deposition of DU in a variety of sand-rich environments. In this study, DU-amended dune sand microcosm and column experiments were carried out to investigate the corrosion of DU and the transport of corrosion products. Under field-moist conditions, DU corroded to metaschoepite ((UO(2))(8)O(2)(OH)(12).(H(2)O)(10)) at a rate of 0.10+/-0.012 g cm(-2)y(-1). This loosely bound corrosion product detached easily from the coupon and became distributed heterogeneously within the sand. The corrosion of DU caused significant changes in the geochemical environment, with NO(3)(-) and Fe(III) reduction observed. Column experiments showed that transport of metaschoepite was mainly dependent on its dissolution and the subsequent interaction of the resulting dissolved uranyl (UO(2)(2+)) species with sand particles. The modelling results predict that the transport of U released from metaschoepite dissolution is retarded, due to a slowly desorbing surface species (first order desorption rate constant=5.0 (+/-1.0)x10(-8)s(-1)). The concentrations of U eluting from the metaschoepite column were orders of magnitude higher than the World Health Organisation's recommended maximum admissible concentration for U in drinking water of 15 microg L(-1). Therefore, a relatively high level of mobile U contamination would be expected in the immediate proximity of a corroding penetrator in a sand-rich environment. PMID- 19783279 TI - Effects of cadmium on plant growth and physiological traits in contrast wheat recombinant inbred lines differing in cadmium tolerance. AB - Four wheat (Triticum aestivum L.) lines differing in cadmium (Cd) tolerance previously identified from a recombinant inbred line population were subjected to 50 microM CdCl2 from the three-leaf stage for 24 d, to investigate the responses of wheat seedlings to Cd toxicity. Under Cd stress, most growth parameters and root morphological traits were reduced, except for secondary root numbers and average root diameter. Cd enhanced leaf cell peroxidation due to increased malondialdehyde (MDA) content and reduced activities of superoxide dismutase (SOD) and catalase (CAT) in leaves. In addition, CAT activity decreased in the Cd sensitive lines while increased in the tolerant lines. Leaf photosystem II (PSII) was damaged, since the maximum efficiency of PSII photochemistry (Fv/Fm) and potential efficiency of PSII photochemistry under dark-adapted (Fv/Fo) decreased, while the initial fluorescence (Fo) increased in all lines under Cd stress. Then, total soluble sugar concentration decreased while free amino acids concentration increased in both shoot and root. We concluded that Cd-tolerant lines accumulated less Cd in plant and contained low Cd concentration in shoot (less translocation of Cd to shoot), maintained higher CAT activity in leaf and higher PS II function than the Cd-sensitive lines under Cd toxicity, thus could be related to their tolerant capacity to Cd in the present study. PMID- 19783280 TI - Response surface model for predicting chronic toxicity of cadmium to Paronychiurus kimi (Collembola), with a special emphasis on the importance of soil characteristics in the reproduction test. AB - A central composite design (CCD) was employed to investigate the effects of organic matter (OM) content and soil pH on the reproduction, and chronic toxicity (28-d EC(50-reproduction)) of cadmium for Paronychiurus kimi after 28days exposure in a standard artificial soil. Two statistical models were developed, one describing reproduction in control artificial soils as a function of OM content and pH, and the other describing cadmium toxicity to the same soil parameters. In the reproduction model, pH was the most important factor, followed by two quadratic factors of OM(2) and pH(2). The parameter pH alone could explain 75.5% of the response variation. The reproduction model will allow us to predict a mean reproduction in the non-treated control soils that contain various combinations of OM content and different pH values. In the chronic toxicity model, only the linear factor of the OM content and pH significantly (p<0.05) affect cadmium toxicity, which explains the 78.9% and 14.9% of total response variance, respectively. Therefore, the final polynomial regression describing the chronic toxicity of cadmium to P. kimi is as follows: predicted 28-d EC(50) of cadmium (mgkg(-1))=-21.231+2.794 x OM+4.874 x pH. The present study show that soil characteristics, which can alter the toxicity of cadmium, can also act as stressors themselves in regards to the reproduction of P. kimi. Based on the physico-chemical characteristics of the test media, the response surface model developed in this study can be used to provide initial toxicity information for cadmium within a region of interest in terms of OM content and pH, and may lead to more scientific based risk assessment for metals. PMID- 19783282 TI - Water quality in the Tibetan Plateau: major ions and trace elements in the headwaters of four major Asian rivers. AB - The Tibetan Plateau covers an area of about one fourth of Europe, has an average elevation over 4000m above sea level, and is the water sources for about 40% of world's population. In order to foresee future changes in water quality, it is important to understand what pressures are governing the spatial variation in water chemistry. In this paper the chemistry including major ions and trace elements in the headwaters of four major Asian rivers (i.e. the Salween, Mekong, Yangtze River and Yarlung Tsangpo) in the Tibetan Plateau was studied. The results showed that the content of dissolved salts in these Tibetan rivers was relatively high compared to waters from other parts of the world. The chemical composition of the four rivers were rather similar, with Ca(2+) and HCO(3)(-) being the dominating ions. The exception was the Yangtze River on the Plateau, which was enriched in Na(+), Cl(-), SO(4)(2-) and Li due to silicate weathering followed by strong evaporation caused by a negative water balance, dissolution of evaporites in the catchment and some drainage from saline lakes. The concentrations of heavy metals (Cu, Co, Cr, Ni, Cd, Pb, and Hg) and As, NH(4)(+) were generally low in all the rivers. Anthropogenic impacts on the quality of the rivers were identified at a few locations in the Mekong River and Yarlung Tsangpo basins. Generally, the main spatial variation in chemical compositions of these under studied rivers was found to be governed mainly by difference in geological variation and regional climatic-environment. Climate change is, therefore, one of main determining factors on the water chemical characteristics of these headwaters of Asian major rivers in the Tibetan Plateau. PMID- 19783283 TI - Use of recombinant activated factor VII in severe post-partum haemorrhage: data from the Italian Registry: a multicentric observational retrospective study. AB - PURPOSE: To report the Italian real experience in clinical practice about recombinant factor VII activated (rFVIIa) in Post-Partum Haemorrhage (PPH) treatment. METHODS: An Italian retrospective survey of severe primary PPH cases treated with rFVIIa was performed. Anamnestic, clinical and haemostatic data about thirty-five patients with PPH, from 2005 to 2007, were collected. Coagulative parameters and transfusion requirements before and after rFVIIa treatment were compared. RESULTS: After rFVIIa administration INR was significantly decreased, while fibrinogen levels were markedly increased. Median of packed red blood cells units, platelets units, fresh frozen plasma, crystalloids and colloids needed, before and after rFVIIa administration, were respectively 6 and 2 units (p<1.2exp-6), 1.5 and 0 units (p=0.001), 1250 and 0 mL (p<4.4exp-5), 3000 and 1250 mL (p<0,0042). Twenty-nine of 35 patients needed surgical intervention before rFVIIa administration, 9/35 after treatment. Hysterectomies have been performed respectively in 10/35 cases before and in 6/35 cases after rFVIIa infusion. No maternal deaths have been reported. No adverse events or thromboembolic complications were observed. CONCLUSIONS: Our clinical and haemostatic data suggest that recombinant activated factor VII may be a safe and helpful adjunctive therapy in the PPH management. PMID- 19783284 TI - Expression of Slit2 and Robo1 after traumatic lesions of the rat spinal cord. AB - We have used semi-quantitative RT-PCR, Western blot, and immunofluorescence imaging approaches to detect the expression levels of Slit2 and its receptor Robo1 in the rat spinal cord after traumatic lesions. Our results revealed that both the mRNA and protein levels of Slit2 were up-regulated in the injured spinal cord. The Slit2 expression level was increased at day 7 until day 14, and then returned to normal level at day 21 after injury. A double-immunolabelling study showed that Slit2 and neurofilament (NF) proteins were both localized in neurons of spinal corda cinerea. Slit2 immunopositivity was detected in neuronal plasma membranes but not in the axonal fibers. In contrast, the immunolabelling of Robo1 in the normal spinal cord was at a low level, mostly in the neurons of spinal corda cinerea, and remained unchanged at all time points following spinal cord injury (SCI). The regulation levels of Slit2 and Robo1 after traumatic lesions in the rat spinal cord are different. Our results indicate that Slit2-Robo1 might not be involved in the inhibitory environment after SCI. PMID- 19783285 TI - Perioperative outcomes comparing patient controlled epidural versus intravenous analgesia in gynecologic oncology surgery. AB - OBJECTIVES: Our aim was to compare perioperative patient controlled epidural analgesia (PCEA) versus patient controlled intravenous analgesia (PCA) after gynecologic oncology laparotomy. METHODS: This was a prospective cohort study where perioperative pain management was decided through patient-centered discussion by anesthesia and surgical teams. The study was designed to accrue 224 patients, to test for equivalence in pain control on postoperative day 1, defined as less than a 10% difference in the proportion of patients with a visual analog scale pain score of <2 (0-10 scale). RESULTS: Two hundred forty patients were enrolled, with 205 patients evaluable for outcomes: 98 received PCA, while 107 received a thoracic level PCEA. Utilization of PCEA was associated with longer anesthesia time pre-op (means: 60 vs. 44 min, p<0.0001), as well as more likely use of pressors during surgery (78% vs. 57%, p=0.002). Pain control was comparable between groups on postoperative day 1 (mean VAS: 2.4 vs. 2.5, p=0.56), but patients with PCEA tended to require more supplemental pain medications. Time to first ambulation was longer in the PCEA patients (means: 49 vs. 36 h post-op, p=0.03), with no difference in time to tolerating regular diet (means: 89 vs. 77 h post-op, 0.17) and no difference in readiness for discharge (means: 144 vs. 145 h post-op, p=0.95). CONCLUSIONS: In this nonrandomized prospective study, selection of a PCEA for perioperative pain management did not improve pain management for patients undergoing gynecologic oncology surgery. PMID- 19783286 TI - Postoperative concurrent nedaplatin-based chemoradiotherapy improves survival in early-stage cervical cancer patients with adverse risk factors. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of postoperative nedaplatin-based concurrent chemoradiotherapy (CCRT) in patients with FIGO stage IA2-IIB cervical cancer with adverse risk factors. METHODS: We retrospectively reviewed the medical records of 183 patients with early-stage cervical cancer who had undergone radical surgery between April 1997 and March 2006. Of these, 68 patients displayed high-risk prognostic factors such as positive pelvic lymph nodes, parametrial involvement, or a positive surgical margin. Fifty-seven patients demonstrated intermediate-risk prognostic factors including deep stromal invasion, capillary lymphatic space involvement, or large tumor diameter. These patients were treated postoperatively with CCRT or radiotherapy alone (RT). Fifty eight patients showed no risk factors and, therefore, received no adjuvant therapy after surgery. The 3-year recurrence rate, progression free survival (PFS), and overall survival (OS) were compared between the treatment groups. RESULTS: CCRT was significantly superior to RT alone with regard to recurrence rate, PFS, and OS in patients that displayed high-risk and intermediate-risk prognostic factors. The frequencies of acute grade 3-4 toxicities were significantly higher in patients treated with CCRT than in those treated with RT alone. However, no statistically significant difference was observed with regard to severe late toxicities. CONCLUSIONS: Postoperative nedaplatin-based CCRT was safely performed and improved the prognosis of FIGO stage IA2-IIB cervical cancer patients displaying high-risk or intermediate-risk prognostic factors. This treatment can be considered as an alternative to cisplatin-based chemoradiotherapy in this patient population. PMID- 19783287 TI - Inhibition of osteopontin suppresses in vitro and in vivo angiogenesis in endometrial cancer. AB - OBJECTIVE: Osteopontin (OPN) has been found to play an important role in tumor angiogenesis in recent years. Our previous studies have shown that OPN is overexpressed in tumor-associated human endometrial endothelial cells (HEECs) isolated from tissue samples of patients with endometrial cancer. In the present study, we aimed to further determine the role of OPN in endometrial cancer associated angiogenesis. METHODS: We knock down OPN expression in HEECs and human endometrial cancer Ishikawa (ISK) cells using the small interference RNA method, and then evaluate the effects of OPN on endometrial cancer-associated angiogenesis by in vivo mouse studies and in vitro assays. RESULTS: Our results revealed that proliferative activity of HEECs and ISK cells in vitro was not affected by transfection with the siOPN-RNA (P>0.05). Inhibition of OPN expression in HEECs reduced the cell migration, with the percentage of repaired area of 36.32+/-2.88 vs. 8.54+/-1.13 (P=0.007). HEEC/siOPN and ISK/siOPN demonstrated 67.4% and 51.2% decreased invasiveness compared with controls, respectively (P<0.05). The number of branched points per well was obviously lower in HEEC/siOPN than that in HEEC/Control (32.46+/-17.10 vs. 53.15+/-15.44, P=0.021). Furthermore, ISK cells transfected with OPN siRNA formed smaller tumor in mice and led to a lower microvessel density, i.e., angiogenesis, in transplanted tumors of mice than scrambled siRNA controls (12.88+/-7.14 vs. 28.42+/-9.69 vessels per HPF, P=0.019). CONCLUSION: These data confirm the positive role of OPN in endometrial cancer-associated angiogenesis and might be of great benefit for finding rational approach in endometrial cancer therapy. PMID- 19783288 TI - The effect of hormone treatments (hCG and cloprostenol) and season on the incidence of hemorrhagic anovulatory follicles in the mare: a field study. AB - The association between use of hormone treatments to induce estrus and ovulation and the incidence of hemorrhagic anovulatory follicles (HAFs) was studied in a mixed population of mares (Equus caballus) during two breeding seasons in a commercial breeding clinic. Mares treated with cloprostenol (CLO) were more likely to develop HAFs than were mares with spontaneous cycles (P<0.001) or those treated with human chorionic gonadotropin alone (P=0.08). There was no significant effect of season on the incidence of HAFs. The mean (+/-SEM) interval from CLO treatment to beginning of HAF development was 6.1+/-0.5 d. Age of mares with HAF cycles was not different (12+/-1.3 yr; P>0.05) from that of mares with ovulatory cycles (10.5+/-1.5 yr). PMID- 19783289 TI - Association between evaluation of the reproductive tract by various diagnostic tests and restoration of ovarian cyclicity in high-producing dairy cows. AB - The uterine condition of clinically normal postpartum Holstein-Friesian dairy cows (n = 45) was evaluated once weekly (Weeks 3 to 7) by endometrial cytology, vaginal mucus collection device (VMCD), vaginoscopy, and ultrasonography to establish a relationship with postpartum resumption of ovulatory cycles. The time of first detection of the corpus luteum (CL) by ultrasonography and plasma progesterone concentration >or=1 ng/mL was recorded. By 49 d postpartum, 78% of the cows (n=35) had resumed ovarian function (CL group), whereas the remainder (n=10) had no CL (NCL group). There was a positive correlation between VMCD score and presence of fluid in the uterus in cows with a CL (P<0.01) during Week 3 postpartum but no significant correlation in cows without a CL. Percentage of polymorphonuclear leukocytes (PMN%) was higher in the NCL group (mean+/-SEM, 24.6+/-9.4%) than in the CL group (11.7+/-2.2%) during Week 5 postpartum (P<0.05). The PMN% (4.5+/-6.5%) and VMCD (0.5+/-0.5) scores during Week 5 in cows ovulating by Day 28 were lower (P<0.01) than the PMN% (15.0+/-14.3%) and VMCD (1.1+/-0.9) scores in those ovulating by Day 49. In conclusion, higher PMN% at 5 wk postpartum was associated with delayed resumption of ovarian cyclicity in high producing dairy cows. PMID- 19783290 TI - Measuring fecal progestogens as a tool to monitor reproductive activity in captive female bottlenose dolphins (Tursiops truncatus). AB - The objective was to develop and test radioimmunoassays (RIAs) to measure fecal progestogens (P) and estrogens (E) to monitor ovarian activity in the bottlenose dolphin (Tursiops truncatus). Fecal samples were collected at least once a week for 20 mo from three peripubertal female bottlenose dolphins. Blood samples were collected at least once a month to compare serum and fecal steroid concentrations. Moreover, random fecal samples from three pregnant females, one lactating female, and one sexually mature female receiving oral altrenogest treatment were also collected. Fecal samples were collected behaviorally with a probe to avoid water contamination and extracted with petroleum ether (for P analysis) or diethyl ether (for E analysis). When possible, vaginal cytology and ovarian ultrasonography were used to monitor the estrous cycle. The RIA for fecal P had good reproducibility and negligible matrix effect. In addition, when fecal samples (N=25) were extracted with ethanol, the results with the two methods of extraction were highly correlated (r=0.923). Therefore, extraction of fecal samples with petroleum ether represented a valid alternative to other, more time consuming methods of determining fecal P concentrations. In the absence of luteal activity, fecal P concentrations were consistently < 10 pmol/g feces, although they never decreased below 10 pmol/g during pregnancy. Thus, the threshold to confirm the presence of an active corpus luteum was provisionally set at 10 pmol/g. Around the onset of puberty, luteal phases appeared shorter and irregular in the bottlenose dolphin, as in other mammalian species. Additional HPLC-MS studies should be performed to identify predominant P metabolites to be used as fecal indicators of luteal activity in this species. PMID- 19783291 TI - Estimation of potential effects of improved community-based drug provision, to augment health-facility strengthening, on maternal mortality due to post-partum haemorrhage and sepsis in sub-Saharan Africa: an equity-effectiveness model. AB - BACKGROUND: Maternal mortality in Africa has changed little since 1990. We developed a mathematical model with the aim to assess whether improved community based access to life-saving drugs, to augment a core programme of health-facility strengthening, could reduce maternal mortality due to post-partum haemorrhage or sepsis. METHODS: We developed a mathematical model by considering the key events leading to maternal death from post-partum haemorrhage or sepsis after delivery. With parameter estimates from published work of occurrence of post-partum haemorrhage and sepsis, case fatality, and the effectiveness of drugs, we used this model to estimate the effect of three potential packages of interventions: 1) health-facility strengthening; 2) health-facility strengthening combined with improved drug provision via antenatal-care appointments and community health workers; and 3) all interventions in package two combined with improved community based drug provision via female volunteers in villages. The model was applied to Malawi and sub-Saharan Africa. FINDINGS: In the implementation of the model, the lowest risk deliveries were those in health facilities. With the model we estimated that of 2860 maternal deaths from post-partum haemorrhage or sepsis per year in Malawi, intervention package one could prevent 210 (7%) deaths, package two 720 (25%) deaths, and package three 1020 (36%) deaths. In sub-Saharan Africa, we estimated that of 182 000 of such maternal deaths per year, these three packages could prevent 21 300 (12%), 43 800 (24%), and 59 000 (32%) deaths, respectively. The estimated effect of community-based drug provision was greatest for the poorest women. INTERPRETATION: Community provision of misoprostol and antibiotics to reduce maternal deaths from post-partum haemorrhage and sepsis could be a highly effective addition to health-facility strengthening in Africa. Investigation of such interventions is urgently needed to establish the risks, benefits, and challenges of widespread implementation. FUNDING: Institute of Child Health and Faculty of Mathematical and Physical Sciences, University College London, and a donation from John and Ann-Margaret Walton. PMID- 19783292 TI - What will it take to stop maternal deaths? PMID- 19783293 TI - Combined use of environmental data and biomarkers in fish (Liza aurata) inhabiting a eutrophic and metal-contaminated coastal system - Gills reflect environmental contamination. AB - An investigative biomonitoring study was carried out in a eutrophic coastal system with a moderate contamination by metals (Obidos lagoon, Portugal), combining the evaluation of exposure concentrations with metals accumulation and oxidative stress responses in gills of the golden grey mullet (Liza aurata). Two contrasting seasons (winter and summer) were considered at three sites: Barrosa (BB) and Bom-Sucesso (BS) branches; Middle lagoon (ML). Data on the water column pointed to a higher metals and nutrients availability at BB that was reflected in the higher metal concentrations in gills, particularly in winter. Similarly, oxidative stress responses demonstrated a pro-oxidant challenge at BB (winter and summer), which was corroborated by an integrated biomarker response index (IBR). Metal concentrations in gills were higher in summer than winter, reflecting the increased environmental concentrations in combination with elevated metabolic rates. Catalase (CAT), glutathione-S-transferase (GST), total glutathione (GSH(t)) and lipid peroxidation (LPO) increases observed in winter at BB were related with metal accumulation, while summer enhancement of glutathione peroxidase (GPx), glutathione reductase (GR), GST and GSH(t) was associated with other stressors. Inter-site differences on the basis of IBR were more accentuated in winter. Gills can be considered as an important route of entry for contaminants and were demonstrated to reflect water contamination and are therefore useful in the context of environmental assessment. PMID- 19783294 TI - Induction of notch signaling by immobilization of jagged-1 on self-assembled monolayers. AB - Notch signaling is a key mechanism during mammal development and stem cell regulation. This study aims to target and control Notch signaling by ligands immobilization using self-assembled monolayers (SAMs) as model surfaces. Non fouling substrates were prepared by immersion of gold substrates in (1-Mercapto 11-undecyl)tetra(ethylene glycol) thiol solutions. These surfaces were activated with N,N'-carbonyldiimidazole (CDI) at different concentrations (0, 0.03, 0.3, 3 and 30 mg/ml) and an anti-human IgG, Fc specific fragment antibody (Ab) was covalently bound to EG4-SAMs to guarantee the correct exposure of the Notch ligand Jagged-1/Fc chimera (Jag-1). The presence of Ab and Jag-1 was confirmed by radiolabeling, X-ray photoelectron spectroscopy (XPS), ellipsometry and ELISA. The biological activity of Jag-1-Ab-SAMs was assessed by real-time PCR for Hes-1 family gene expression, a Notch pathway target gene, in HL-60 cell line. Results have shown an increase of the amount of immobilized Ab with increasing surface activator concentrations. Jag-1 concentration also increases with Ab concentration. Interestingly, a higher Jagged-1 exposure and fold increase in Hes 1 expression were obtained for surfaces activated with the lowest concentration of CDI (0.03 mg/ml). These results illustrate the great importance of ligands orientation and exposure, when compared with density. This investigation brings new insights into Notch signaling mechanisms. In particular, Jag-1-Ab-SAMs have shown to be adequate model surfaces to study Notch pathway activation and may provide a basis to develop new interfaces in biomaterials to control Notch mechanism in different cell systems. PMID- 19783296 TI - Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. AB - In order to study the mechanisms underlying the effects of TiO(2) nanoparticles on the brain, ICR mice were injected with nanoparticulate anatase TiO(2) (5 nm) of various doses into the abdominal cavity daily for 14 days. We then examined the coefficient of the brain, the brain pathological changes and oxidative stress mediated responses, and the accumulation of nanoparticulate anatase TiO(2) and levels of neurochemicals in the brain. The results showed that high-dose nanoparticulate anatase TiO(2) could induce some neurons to turn into filamentous shapes and others into inflammatory cells. The concentration of nanoparticulate anatase TiO(2) in the brain was increased as increases in nanoparticulate anatase TiO(2) dosages used. The oxidative stress and injury of the brain occurred as nanoparticulate anatase TiO(2) appeared to trigger a cascade of reactions such as lipid peroxidation, the decreases of the total anti-oxidation capacity and activities of antioxidative enzymes, the excessive release of nitric oxide, the reduction of glutamic acid, and the downregulated level of acetylcholinesterase activities. We concluded that TiO(2) nanoparticles injected at the abdominal cavity could be translocated into the brain and in turn caused the brain injury. PMID- 19783295 TI - Iron oxide core oil-in-water emulsions as a multifunctional nanoparticle platform for tumor targeting and imaging. AB - Nanoemulsions are increasingly investigated for the delivery of hydrophobic drugs to improve their bioavailability or make their administration possible. In the current study, oil-in-water emulsions with three different mean diameters (30, 60, and 95 nm) were developed as a new multimodality nanoparticle platform for tumor targeting and imaging. To that aim, hydrophobically coated iron oxide particles were included in the soybean oil core of the nanoemulsions to enable their detection with magnetic resonance imaging (MRI), while the conjugation of a near infrared fluorophore allowed optical imaging. The accumulation of this novel nanocomposite in subcutaneous human tumors in nude mice was demonstrated with MRI and fluorescence imaging in vivo, and with Perl's staining of histological tumor sections ex vivo. PMID- 19783297 TI - Films based on human hair keratin as substrates for cell culture and tissue engineering. AB - Keratin from hair or wool has been proposed as an appropriate material for producing films or cell cultivation scaffolds. The current study was performed to characterize two different approaches involving substrate coating based on keratin from human hair. Our goal was to evaluate cell growth behavior in these systems in comparison with a standard polystyrene substrate. The coating was made in two different ways: (i) by trichloroacetic acid precipitation or (ii) by casting a keratin nanosuspension. The resulting films were characterized using SDS-PAGE, SEM, and X-ray studies. The growth behaviors of twelve cell lines on the keratin films and on polystyrene were estimated using proliferation studies. Furthermore, we assessed the cell detachment behavior during trypsinization and the seeding efficiency. For epithelial cell lines with tight junction proteins, the transepithelial electrical resistance was measured and compared with values achieved using common coating materials. Both of the keratin coatings exhibited similar protein patterns and X-ray diffraction profiles, but we also detected differences in the transparency and ultrastructural surface morphologies. Culture dishes coated with keratin nanoparticles were used to create a transparent substrate that supports cell adherence and improves cell growth as compared with uncoated polystyrene or coatings that use trichloroacetic acid precipitation. We conclude that this coating method may be a new promising substrate for standard cell cultivation. PMID- 19783298 TI - Temperature-tuned DNA condensation and gene transfection by PEI-g-(PMEO(2)MA-b PHEMA) copolymer-based nonviral vectors. AB - In this work, thermoresponsive diblock copolymers, poly[2-(2-methoxyethoxy) ethyl methacrylate]-b-poly(2-hydroxyethyl methacrylate) (PMEO(2)MA-b-PHEMA) with low polydispersity were synthesized by atomic transfer radical polymerization(ATRP). Low molecular weight (LWM) polyethylenimine (PEI, 1200Da) was then grafted to 1,1'-carbonyldiimidazole (CDI)-activated PMEO(2)MA-b-PHEMA to fabricate PEI-g (PMEO(2)MA-b-PHEMA) (PEIMH) copolymer vectors. The LCSTs of PEIMHs with 3 and 8 grafted PEI side chains, separately termed as PEIMH-1 and PEIMH-2, were 32.5 and 38.7 degrees C in PBS solution. Variable temperature agarose retardation, Zeta potential and time-resolved fluorescence assays were performed to elucidate the temperature sensitive DNA condensation. It showed that DNA was condensed more efficiently by PEIMH, and the collapse of PMEO(2)MA chains led to more exposure of surface positive charges of PEIMH-1/pDNA complexes while temperature was above LCST. Variable temperature time-resolved fluorescence measurement of lifetimes of bound and free ethidium bromide (EB) unveiled that the population of EB at different states was dependent on temperature. At a temperature above LCST, the collapsed PMEO(2)MA polymer chains squeezed the loosely bound EB out of complex to become free species; thereby DNA was more tightly packaged by PEIMH-1. Temporary cooling was shown to improve the transfection efficiency of PEIMH-1 in COS-7 and HEK293 cell lines. The variable temperature protocol is more efficient in improving gene expression level in HEK293 cells. The transfection efficiency was equivalent or superior to that of PEI25K at an optimal weight ratio of vector/DNA. Furthermore, the cytotoxicity of PEIMH-1 was considerably lower than that of control PEI25K. PMID- 19783299 TI - Distinctive regulation of contact activation by antithrombin and C1-inhibitor on activated platelets and material surfaces. AB - Activated human plate lets trigger FXII-mediated contact activation, which leads to the generation of FXIIa-antithrombin (AT) and FXIa-AT complexes. This suggests that contact activation takes place at different sites, on activated platelets and material surfaces, during therapeutic procedures involving biomaterials in contact with blood and is differentially regulated. Here we show that activation in platelet-poor plasma, platelet-rich plasma (PRP), and whole blood induced by glass, kaolin, and polyphosphate elicited high levels of FXIIa-C1-inhibitor (C1INH), low levels of FXIa-C1INH and KK-C1INH, and almost no AT complexes. Platelet activation, in both PRP and blood, led to the formation of FXIIa-AT, FXIa-AT, and kallikrein (KK)-AT but almost no C1INH complexes. In severe trauma patients, FXIIa-AT and FXIa-AT were correlated with the release of thrombospondin 1 (TSP-1) from activated platelets. In contrast, FXIIa-C1INH complexes were detected when the FXIIa-AT levels were low. No correlations were found between FXIIa-C1INH and FXIIa-AT or TSP-1. Inhibition of FXIIa on material surfaces was also shown to affect the function of aggregating platelets. In conclusion, formation of FXIIa-AT and FXIIa-C1INH complexes can help to distinguish between contact activation triggered by biomaterial surfaces and by activated platelets. Platelet aggregation studies also demonstrated that platelet function is influenced by material surface-mediated contact activation and that generation of FXIIa-AT complexes may serve as a new biomarker for thrombotic reactions during therapeutic procedures employing biomaterial devices. PMID- 19783300 TI - Photoinitiated polymerization of PEG-diacrylate with lithium phenyl-2,4,6 trimethylbenzoylphosphinate: polymerization rate and cytocompatibility. AB - Due to mild reaction conditions and temporal and spatial control over material formation, photopolymerization has become a valuable technique for the encapsulation of living cells in three dimensional, hydrated, biomimetic materials. For such applications, 2-hydroxy-1-[4-(2-hydroxyethoxy) phenyl]-2 methyl-1-propanone (I2959) is the most commonly used photoinitiator (by virtue of its moderate water solubility), yet this initiator has an absorption spectrum that is poorly matched with wavelengths of light generally regarded as benign to living cells, limiting the rate at which it may initiate polymerization in their presence. In contrast, acylphosphine oxide photoinitiators, generally exhibit absorption spectra at wavelengths suitable for cell encapsulation, yet commercially available initiators of this class have low water solubility. Here, a water soluble lithium acylphosphinate salt is evaluated for its ability to polymerize diacrylated poly(ethylene glycol) (PEGDA) monomers rapidly into hydrogels, while maintaining high viability during direct encapsulation of cells. Through rheometric measurements, the time to reach gelation of a PEGDA solution with the phosphinate initiator is one tenth the time for that using I2959 at similar concentrations, when exposed to 365 nm light. Further, polymerization with the phosphinate initiator at 405 nm visible light exposure is achieved with low initiator concentrations and light intensities, precluded in polymerizations initiated with I2959 by its absorbance profile. When examined 24h after encapsulation, survival rates of human neonatal fibroblasts encapsulated in hydrogels polymerized with the phosphinate initiator exceed 95%, demonstrating the cytocompatibility of this initiating system. PMID- 19783301 TI - Nilotinib: a second-generation tyrosine kinase inhibitor for chronic myeloid leukemia. AB - Imatinib mesylate is currently the standard of care for chronic myeloid leukemia (CML) patients in early chronic phase. However, the emergence of resistance and intolerance has dampened the enthusiasm for this drug. To overcome this phenomenon, different strategies have been developed, including novel targeted agents. Nilotinib, formerly known as AMN107, is a second-generation tyrosine kinase inhibitor 30-fold more potent than imatinib, with high affinity and selectivity on BCR/ABL, and also active against a wide range of mutant clones, except T315I mutation. Phase II trials of nilotinib showed high activity in imatinib-resistant or intolerant CML patients, whereas front-line treatment of the disease in chronic phase demonstrated rapid and stable cytogenetic responses and increasing molecular responses. We here review the development of nilotinib and the efficacy data in phase II and front-line trials. The aim of this review is to evaluate the pharmacology, pharmacokinetic and pharmacodynamic properties of the drug and the recent results of clinical trials performed in patients with CML and Ph+ acute lymphoblastic leukemia (ALL). PMID- 19783302 TI - Clarification on the categorization of comorbidities. PMID- 19783303 TI - Nitric oxide and lysozyme production as an impact to Clostridium perfringens mastitis. AB - The anaerobic mastitis incidence was used to study the bovine udder response in anaerobic bacterial mastitis caused by the Gram-positive bacterial strain of Clostridium perfringens. Milk samples positive for C. perfringens were assayed for NO and lysozyme. The model produced a strong NO and lysozyme response which correlated positively with the severity and outcome of the disease (subclinical and clinical stages). This study is, to our knowledge, the first to suggest a possible link between NO and lysozyme and bovine mastitis caused by C. perfringens. The results raise the possibility that interfering with NO production during mastitis may help to prevent tissue damage. PMID- 19783304 TI - Asymmetrical interhemispheric fiber tracts in patients with hemimegalencephaly on diffusion tensor magnetic resonance imaging. AB - OBJECTIVE: The internal structures of cerebral white matter in patients with hemimegalencephaly have not yet been investigated except for one, which evaluated aberrant fibers. We examined interhemispheric fiber tracts (FT) passing through the corpus callosum using magnetic resonance (MR) diffusion tensor imaging (DTI). METHODS: MR studies, including DTI, were performed in nine consecutive patients with hemimegalencephaly and in 11 patients with West syndrome as disease controls. The interhemispheric FT passing through the corpus callosum were evaluated in six regional geometric subdivisions in every hemimegalencephaly and West syndrome patient (54 and 66 subregions, respectively), and the distribution and volume differences between affected and unaffected hemispheres were all compared. RESULTS: In patients with hemimegalencephaly, interhemispheric FT were symmetrically distributed in 27 (50%) of the 54 corpus callosum subregions. However, the FT were distributed to different areas in the same lobes in 22 (40%) subregions, and to different lobes in five (9%) subregions. FT volumes were symmetrical in 35 (65%) subregions, while FT volumes on the affected side were greater, but less than those on the unaffected side, in 14 (26%) and five (9%) subregions, respectively. In contrast, in the West syndrome patients, interhemispheric FT showed symmetrical distributions and volumes in all regions. CONCLUSION: Asymmetrical interhemispheric FT are often observed in patients with hemimegalencephaly, and DTI was a useful means of elucidating the internal structures of white matter. PMID- 19783305 TI - [Bilateral Sturge-Weber syndrome]. PMID- 19783306 TI - Leptomeningeal Rosai-Dorfman disease. PMID- 19783307 TI - What is your diagnosis? Nocardia abscessus infection. PMID- 19783308 TI - Perfusion MR imaging and 1H spectroscopy: their role in the diagnosis of microcystic and lipomatous meningiomas. AB - Microcystic and lipomatous meningiomas represent two of the recognised rare subtypes of meningiomas. We describe the CT and MR findings in one adult case of each subtype with emphasis on the diagnostic benefits of perfusion-weighted MR imaging (PWI) and/or proton magnetic resonance spectroscopy (MRS). PMID- 19783309 TI - Structural determinants of GAD antigenicity. AB - Our aim was to ascertain structural determinants of autoantigenicity based on the model of the diabetes autoantigen glutamic acid decarboxylase 65 kDa isoform (GAD65) in comparison with that of the non-autoantigenic isoform GAD67. This difference exists despite the two isoforms having the same fold and high sequence identity. Autoantibodies to GAD65 precede the development of type 1 diabetes and are clinical markers of this and certain neural autoimmune diseases. To date, epitope mapping has been based on particular amino acid differences between the two isoforms, and there is no explanation as to why autoantibodies that react with GAD65 only infrequently cross-react with GAD67. To characterize each isoform of the enzyme and gain insights into their contrasting autoantigenic properties, we have used the recently determined crystal structures of GAD65 and GAD67 to compare their structure, hydrophobicity, electrostatics, flexibility and physiochemical properties. The results revealed striking differences which appear almost exclusively at the C-terminal domain of the isoforms. Whereas GAD65 displayed a highly charged and flexible C-terminal domain containing numerous patches of high electrostatic and solvation energies, these characteristics were absent in the GAD67 molecule. Additionally, analysis indicated potential N terminal and PLP domain binding sites surrounding the C-terminal domain of GAD65, a major region of autoantigenic activity, but not of GAD67. These features agree with good accuracy with published epitope-mapping data. Our analysis suggests that the high flexibility and charge of GAD65 in the C-terminal domain is coupled with the mobility of its catalytic loop, a property that is absolutely required for its enzymatic function. Thus, the structural features that distinguish GAD65 from GAD67 as a B cell autoantigen are related to functional requirements for its enzymatic mechanism. This could well apply to the various other enzyme autoantigens and, if so, these features could be used as the basis of future predictive strategies. PMID- 19783310 TI - Relevance of the leaving group for antitumor activity of new platinum(II) compounds containing anthracene derivatives as a carrier ligand. AB - A new anticancer-active platinum(II) compound [Pt(A9pyp)(dmso)(cbdca)], containing the E-1-(9-anthryl)-3-(2-pyridyl)-2-propenone ligand (abbreviated as A9pyp) has been synthesized by the replacement of the anionic chloride ligands in cis-[Pt(A9pyp)(dmso)Cl(2)] by the dianionic chelating cyclobutanedicarboxylate ligand (abbreviated as cbdca). The in vitro relevance of the leaving group of these new platinum(II) compounds has been investigated. Measurements of the time dependent intracellular accumulation of both compounds in human ovarian carcinoma cell lines show that the leaving group affects their cellular uptake. In addition, the leaving group also influences DNA platination, and, therefore, has an effect on the biological activity against a pair of human ovarian carcinoma cell lines, i.e. sensitive and resistant to cisplatin. PMID- 19783311 TI - Clinical evaluation and antibody responses in sheep after primary and secondary experimental challenges with the mange mite Sarcoptes scabiei var. ovis. AB - In this work the clinical evolution and the specific serum IgG and IgE antibody responses in sheep after primary (n=10) and secondary (n=4) experimental challenges with the mange mite Sarcoptes scabiei var. ovis were studied. The primary infection was characterized by the development of mange lesions in all sheep, a detection of live S. scabiei mites in 70% skin scrapings taken in week 10 post-challenge (PC), strongly raised and sustained specific IgG levels and a more moderate but continuous rise in specific IgE levels. Seroconversion was detected for IgG and IgE by ELISA in 90% and 60% of the sheep in week 8 PC, respectively. By Western-blotting (WB), ten IgG-reactive bands (36-120 kDa) and four IgE-reactive bands (90-180 kDa) were observed in week 8 PC. Following the secondary challenge the ewes developed a smaller area of mange lesion than that seen following primary challenge and live S. scabiei mites were not detected in skin scrapings collected in week 8 PC, suggesting that sheep had developed immunity to re-infection. Compared to primary infection, the specific IgG secondary antibody levels were transient, but in contrast there was an anamnestic IgE response, resulting in an elicitation of specific serum IgE levels in week 2 PC significantly higher than those demonstrated after primary infection. WB analysis revealed one additional IgG-reactive band (180 kDa) and no additional IgE-reactive bands. Determining the immunodiagnostic or vaccination value of the IgG-reactive antigens and IgE-reactive allergens detected requires further studies. PMID- 19783312 TI - Bona diagnosis, bona curatio! PMID- 19783313 TI - Patient education and the impact of new medical research. AB - We examine the impact that medical research published in peer-reviewed journals has on the practice of medicine. We exploit the release of a recent New England Journal of Medicine article which demonstrated that the risks of attempting a vaginal birth after having a previous C-section birth (VBAC) were higher than previously thought. We find that immediately following this article, the national VBAC rate dropped by 16% and this change was largest among more educated mothers, particularly those with a graduate degree. PMID- 19783314 TI - Microbial biofilms: a concept for industrial catalysis? AB - Biofilm reactors have long been commercially used in the treatment of wastewater and off-gas. New opportunities are arising with the rapid expansion of our understanding of biofilm biology over the last few years. Biofilms have great potential as industrial workhorses for the sustainable production of chemicals because of their inherent characteristics of self-immobilization, high resistance to reactants and long-term activity, which all facilitate continuous processing. A variety of biofilm reactor configurations have been explored for productive catalysis and some reactors have been operated continuously for months. Sectors that might particularly benefit from this biofilm approach include synthetic chemistry (ranging from specialty to bulk chemicals), bioenergy, biologics and the food industry. PMID- 19783315 TI - Transgenic plants as vital components of integrated pest management. AB - Although integrated pest management (IPM) strategies have been developed worldwide, further improvement of IPM effectiveness is required. The use of transgenic technology to create insect-resistant plants can offer a solution to the limited availability of highly insect-resistant cultivars. Commercially available insect-resistant transgenic crops show clear benefits for agriculture and there are many exciting new developments such as transgenic plants that enhance biological control. Effective evaluation tools are needed to ascertain that transgenic plants do not result in undesired non-target effects. If these conditions are met, there will be ample opportunities for transgenic plants to become key components of environmentally benign and durable pest management systems. Here we discuss the potential and challenges for incorporating transgenic plants in IPM. PMID- 19783316 TI - Improvements in life expectancy in type 1 diabetes patients in the last six decades. AB - AIMS: To investigate the survival with diabetes in patients treated with insulin from diagnosis. SUBJECTS AND METHODS: We analyzed 845 subjects, 55.9% males, registered at "I. Pavel" Bucharest Diabetes Centre, insulin-treated from diagnosis, aged <40 years and deceased between 1946 and 2005. We divided the subjects in two groups by age at diagnosis: group A <18 years and group B 18 39.99 years. We used 20 years time periods for year of death: 1946-1965, 1966 1985 and 1986-2005. RESULTS: The mean age at diabetes onset was 30.36+/-8.04 years, disease duration at death 20.98+/-11.62 years and age at death 51.34+/ 14.37 years. The mean increase in survival with diabetes was 19.3 years for group A and 15.9 years for group B. There was a significant decrease in infections in both groups. The increase in coronary heart diseases and stroke is evident only in group B. CONCLUSIONS: We found no changes in age at onset, which combined with an increase in survival with diabetes lead to a significant increase in age at death over the six decades analyzed. PMID- 19783317 TI - The influence of housing tenure and marital status on smoking in South Korea. AB - OBJECTIVE: This study aimed to identify the most influential socioeconomic indicator of smoking in South Korea. METHODS: This study analyzed a nationally representative sample (6141 men and 7133 women aged 20-65) from the 2001 and 2005 Korea National Health and Nutrition Surveys. Weighted estimates were computed, adjusting for a complex survey design using "surveyfreq" and "surveylogistic" procedures of SAS 9.1 software. RESULTS: The adjusted OR for smoking in renters compared to homeowners was 1.50 (95% CI: 1.32-1.71) in men and 3.21 (95% CI: 2.41 4.27) in women, and larger in the older than younger groups. For non-married versus married individuals, the OR was 1.37 (95% CI: 1.19-1.59) in men and 3.25 (95% CI: 2.48-4.25) in women; the OR in non-married renters compared married homeowners was 1.79 (95% CI: 1.45-2.22) in men and 10.63 (95% CI: 7.31-15.45) in women. CONCLUSION: Housing tenure was a strong predictor of smoking in South Korea and its significance was very pronounced in non-married individuals. Housing policies to encourage homeownership could be effective in reducing smoking in countries such as China, India, and Vietnam where house ownership is regarded as the ultimate financial safeguard, there are numerous, and traditional attitudes toward marriage are undergoing transition. PMID- 19783318 TI - A ligand predication tool based on modeling and reasoning with imprecise probabilistic knowledge. AB - Ligand prediction has been driven by a fundamental desire to understand more about how biomolecules recognize their ligands and by the commercial imperative to develop new drugs. Most of the current available software systems are very complex and time-consuming to use. Therefore, developing simple and efficient tools to perform initial screening of interesting compounds is an appealing idea. In this paper, we introduce our tool for very rapid screening for likely ligands (either substrates or inhibitors) based on reasoning with imprecise probabilistic knowledge elicited from past experiments. Probabilistic knowledge is input to the system via a user-friendly interface showing a base compound structure. A prediction of whether a particular compound is a substrate is queried against the acquired probabilistic knowledge base and a probability is returned as an indication of the prediction. This tool will be particularly useful in situations where a number of similar compounds have been screened experimentally, but information is not available for all possible members of that group of compounds. We use two case studies to demonstrate how to use the tool. PMID- 19783319 TI - Etoposide plus cisplatin followed by concurrent chemo-radiotherapy and irinotecan plus cisplatin for patients with limited-stage small cell lung cancer: A multicenter phase II study. AB - PURPOSE: The combination of irinotecan and cisplatin (IP) has shown at least comparable efficacy to that of etoposide/cisplatin (EP) in patients with extensive-stage small cell lung cancer. We conducted a phase II study to evaluate the efficacy and tolerance of EP regimen followed by thoracic radiotherapy (TRT) and IP consolidation chemotherapy in patients with limited-stage small cell lung cancer. PATIENTS AND METHODS: Thirty-three chemotherapy-naive patients with limited-stage small cell lung cancer (LS-SCLC) were treated with etoposide 100mg/m(2) on days 1-3 and cisplatin 80mg/m(2) on day 1. Radiotherapy was given 3 weeks after the first treatment cycle concurrently with weekly cisplatin 20mg/m(2) on day 1 and etoposide 50mg/m(2) on day 4 within 5-6 weeks, followed by three courses of irinotecan 60mg/m(2) on days 1, 8, and 15 and cisplatin 60mg/m(2) on day 1 of a 4-week cycle. RESULTS: There were no treatment-related deaths. Toxicities during chemo-radiotherapy were mild including grade 3/4 neutropenia (24%) and grade 2 esophagitis (6%). The major toxicity observed during consolidation chemotherapy was grades 3-4 neutropenia which affected 42% of patients. In an intention-to-treat analysis the overall response rate was 66% (CR: 30% and PR: 36%). After a median follow-up period of 35.7 months (range: 9.6 41.2 months), the median survival time was 19 months (95% CI: 14.5-23.5 months), the median time to tumor progression 8.3 months and the 1- and 2-year survival rates 72% and 27.5%, respectively. CONCLUSIONS: Consolidation chemotherapy with IP following concurrent EP plus TRT is a safe and with acceptable toxicity regimen and deserves further phase III testing in patients with LS-SCLC. PMID- 19783320 TI - Activity of pemetrexed on brain metastases from non-small cell lung cancer: what is the mechanism? PMID- 19783321 TI - Effect on germination and early growth characteristics in sunflower (Helianthus annuus) seeds exposed to static magnetic field. AB - Seeds of sunflower (Helianthus annuus) were exposed in batches to static magnetic fields of strength from 0 to 250mT in steps of 50mT for 1-4h in steps of 1h. Treatment of sunflower seeds in these magnetic fields increased the speed of germination, seedling length and seedling dry weight under laboratory germination tests. Of the various treatments, 50 and 200mT for 2h yielded the peak performance. Exposure of seeds to magnetic fields improved seed coat membrane integrity and reduced the cellular leakage and electrical conductivity. Treated seeds planted in soil resulted in statistically higher seedling dry weight, root length, root surface area and root volume in 1-month-old seedlings. In germinating seeds, enzyme activities of alpha-amylase, dehydrogenase and protease were significantly higher in treated seeds in contrast to controls. The higher enzyme activity in magnetic-field-treated sunflower seeds could be triggering the fast germination and early vigor of seedlings. PMID- 19783322 TI - Suffering from meticillin-resistant Staphylococcus aureus: experiences and understandings of colonisation. AB - The objective was to explore individuals' experiences and understandings of meticillin-resistant Staphylococcus aureus (MRSA) colonisation. Thirteen interviews were performed and processed using content analysis, resulting in the theme 'Invaded, insecure and alone'. The participants experienced fears and limitations in everyday life and expressed a need to protect others from contagion. Moreover, they experienced encounters with, and information from, healthcare workers differently: some were content, whereas others were discontent. The described fears, limitations and inadequate professional-patient relationship generated unacceptable distress for MRSA-colonised persons. Thus, the healthcare sector should assume responsibility for managing MRSA, and healthcare workers must improve their professionalism and information skills, so as to better meet MRSA-colonised persons' needs. PMID- 19783324 TI - Does end tidal CO2 monitoring during emergency department procedural sedation and analgesia with propofol decrease the incidence of hypoxic events? A randomized, controlled trial. AB - STUDY OBJECTIVE: We determine whether the use of capnography is associated with a decreased incidence of hypoxic events than standard monitoring alone during emergency department (ED) sedation with propofol. METHODS: Adults underwent ED propofol sedation with standard monitoring (pulse oximetry, cardiac and blood pressure) and capnography and were randomized into a group in which treating physicians had access to the capnography and a blinded group in which they did not. All patients received supplemental oxygen (3 L/minute) and opioids greater than 30 minutes before. Propofol was dosed at 1.0 mg/kg, followed by 0.5 mg/kg as needed. Capnographic and SpO2 data were recorded electronically every 5 seconds. Hypoxia was defined as SpO2 less than 93%; respiratory depression, as end tidal CO2 (ETCO2) greater than 50 mm Hg, ETCO2 change from baseline of 10%, or loss of the waveform. RESULTS: One hundred thirty-two subjects were evaluated and included in the final analysis. We observed hypoxia in 17 of 68 (25%) subjects with capnography and 27 of 64 (42%) with blinded capnography (P=.035; difference 17%; 95% confidence interval 1.3% to 33%). Capnography identified all cases of hypoxia before onset (sensitivity 100%; specificity 64%), with the median time from capnographic evidence of respiratory depression to hypoxia 60 seconds (range 5 to 240 seconds). CONCLUSION: In adults receiving ED propofol sedation, the addition of capnography to standard monitoring reduced hypoxia and provided advance warning for all hypoxic events. PMID- 19783325 TI - Antibiotic resistance determinants in Acinetobacter spp and clinical outcomes in patients from a major military treatment facility. AB - We explored the association of antibiotic-resistant phenotypes and genotypes in Acinetobacter spp with clinical outcomes and characteristics in 75 patients from a major military treatment facility. Amikacin resistance was associated with nosocomial acquisition of A baumannii, and carbapenem resistance and bla(OXA-23) were associated with the need for mechanical ventilation. The presence of bla(OXA 23) also correlated with longer hospital and ICU stay. Associations between bla(OXA-23) and complexity, duration, and changes made to antibiotic regimens also existed. PMID- 19783326 TI - No association between high temperature requirement 1 (HTRA1) gene polymorphisms and Alzheimer's disease. AB - High temperature requirement 1 (HTRA1) gene is a plausible risk factor in Alzheimer's disease (AD) as it encodes a protease known to degrade amyloid-beta peptide. Here we have studied whether single nucleotide polymorphisms (SNPs) in the HTRA1 gene or its nearby regions associated with AD in a large clinic-based case-control cohort originating from Finland. We did not observe significant association of the HTRA1 SNPs with AD among the whole case-control cohort or age at-onset risk effect among AD patients. PMID- 19783327 TI - [Christmas for our diabetic patients: a situation of added cardiovascular risk?]. PMID- 19783328 TI - Interferon gamma release assays: principles and practice. AB - The last decade has witnessed significant advances in mycobacterial genomics and cellular research which have resulted in the development of two new blood tests, the enzyme-linked immunospot assay (ELISpot) (TSPOT.TB, Oxford Immunotec, Oxford, UK) and the enzyme-linked immunosorbent assay (ELISA) (QuantiFERON-TB Gold In Tube, Cellestis, Carnegie, Australia). These tests, which are collectively known as interferon gamma release assays (IGRAs), detect latent tuberculosis infection (LTBI) by measuring interferon (IFN)-gamma release in response to antigens present in Mycobacterium tuberculosis, but not bacille Calmette-Guerin (BCG) vaccine and most nontuberculous mycobacteria. This is done through enumeration of IFN-gamma-secreting T cells (ELISpot) or by measurement of IFN-gamma concentration (ELISA). The evidence base for these tests has expanded rapidly and now demonstrates that IGRAs are more specific than the tuberculin skin test (TST) as they are not confounded by previous BCG vaccination. In addition, with active tuberculosis (TB) as a surrogate for LTBI, it appears that the ELISA has a similar sensitivity to the TST, whereas the ELISpot is more sensitive. Using degree of exposure to TB as a surrogate for LTBI, both assays correlate at least as well with TB exposure as the TST. Recent longitudinal data have now demonstrated the prognostic power of positive IGRA results in recent contacts for the subsequent progression to active TB. Deployment of IGRAs, driven by new guidelines internationally, will impact on clinical practice in several ways. Their high specificity means that BCG-vaccinated individuals with a false positive TST will not receive unnecessary preventive treatment, whereas improved sensitivity in individuals with weakened cellular immunity at highest risk of progressing to active TB (for example HIV-positive individuals) enables more reliable targeted testing and treatment of these vulnerable groups. The role of IGRAs in active TB is less clear but they may be useful as adjunctive tests in the diagnostic work-up of an individual with suspected TB. Finally, recent developments and future directions in IGRA development are reviewed. PMID- 19783329 TI - [Cardiac involvement in Wegener's granulomatosis: report of four cases and review of the literature]. AB - INTRODUCTION: Discordance exists between the results of post-mortem studies and the low number of clinical reported cases of cardiac involvements in Wegener's granulomatosis. CASE REPORTS: Data from four patients were studied retrospectively. Three patients had associated airway localization and three had kidney involvement. All patients had positive test for anti-PR3 antineutrophil antibodies. Two patients presented with dilated cardiomyopathy (one with terminal cardiac failure), another patient with complete atrioventricular block and pericarditis, and the remaining one with myopericarditis. One patient was asymptomatic. For three of these patients, the cardiac manifestations were contemporary of the diagnosis of Wegener's granulomatosis and had a severe disease course. CONCLUSION: Cardiac events in Wegener's granulomatosis are probably underestimated, given the various type of heart damage and the clinical presentation. Cardiac involvement seems to be associated with a poor prognosis. Thus, we recommend systematic and regular cardiac assessment in the follow-up of patients with Wegener's granulomatosis. PMID- 19783323 TI - Emergency medical services intervals and survival in trauma: assessment of the "golden hour" in a North American prospective cohort. AB - STUDY OBJECTIVE: The first hour after the onset of out-of-hospital traumatic injury is referred to as the "golden hour," yet the relationship between time and outcome remains unclear. We evaluate the association between emergency medical services (EMS) intervals and mortality among trauma patients with field-based physiologic abnormality. METHODS: This was a secondary analysis of an out-of hospital, prospective cohort registry of adult (aged > or =15 years) trauma patients transported by 146 EMS agencies to 51 Level I and II trauma hospitals in 10 sites across North America from December 1, 2005, through March 31, 2007. Inclusion criteria were systolic blood pressure less than or equal to 90 mm Hg, respiratory rate less than 10 or greater than 29 breaths/min, Glasgow Coma Scale score less than or equal to 12, or advanced airway intervention. The outcome was in-hospital mortality. We evaluated EMS intervals (activation, response, on scene, transport, and total time) with logistic regression and 2-step instrumental variable models, adjusted for field-based confounders. RESULTS: There were 3,656 trauma patients available for analysis, of whom 806 (22.0%) died. In multivariable analyses, there was no significant association between time and mortality for any EMS interval: activation (odds ratio [OR] 1.00; 95% confidence interval [CI] 0.95 to 1.05), response (OR 1.00; 95% CI 9.97 to 1.04), on-scene (OR 1.00; 95% CI 0.99 to 1.01), transport (OR 1.00; 95% CI 0.98 to 1.01), or total EMS time (OR 1.00; 95% CI 0.99 to 1.01). Subgroup and instrumental variable analyses did not qualitatively change these findings. CONCLUSION: In this North American sample, there was no association between EMS intervals and mortality among injured patients with physiologic abnormality in the field. PMID- 19783330 TI - Metabolic syndrome and its components after liver transplantation: incidence, prevalence, risk factors, and implications. AB - Metabolic syndrome is defined as the mutual existence of obesity, impaired fasting glucose levels, insulin resistance, hypertension, and dyslipidemia. After liver transplantation, patients typically develop these disorders, and even though there has been minimal research focused on the chronic impact of this syndrome on post-liver transplant patients, studies point to an association with major vascular events and fibrosis. The aim of the current work is to review data on the incidence, prevalence, risk factors, and implications of metabolic syndrome and its components in patients who have undergone liver transplantation. PMID- 19783331 TI - Validation of 131I ecological transfer models and thyroid dose assessments using Chernobyl fallout data from the Plavsk district, Russia. AB - Within the project "Environmental Modelling for Radiation Safety" (EMRAS) organized by the IAEA in 2003 experimental data of (131)I measurements following the Chernobyl accident in the Plavsk district of Tula region, Russia were used to validate the calculations of some radioecological transfer models. Nine models participated in the inter-comparison. Levels of (137)Cs soil contamination in all the settlements and (131)I/(137)Cs isotopic ratios in the depositions in some locations were used as the main input information. 370 measurements of (131)I content in thyroid of townspeople and villagers, and 90 measurements of (131)I concentration in milk were used for validation of the model predictions. A remarkable improvement in models performance comparing with previous inter comparison exercise was demonstrated. Predictions of the various models were within a factor of three relative to the observations, discrepancies between the estimates of average doses to thyroid produced by most participant not exceeded a factor of ten. PMID- 19783332 TI - Ameloblastoma in children and adolescents. AB - This study first reviewed the data of 37 patients aged 18 years and younger with ameloblastoma over a 16-year period and then reviewed the literature on this subject from 1970 to 2009. Of 37 patients with ameloblastoma, 23 were male and 14 were female, a ratio of 1.6:1. The mean age was 14.8 years. All lesions were in the mandible. Clinical typing included 28 solid type and 9 unicystic type. Ten cases were recurrent (27.0%). A series of literature review disclosed 233 well documented cases of ameloblastoma in children and adolescents. The ages ranged from 4 to 20 years with a mean age of 14.5 years. The distribution among males and females were almost identical: 53.6% (125/233) males and 46.4% (108/233) females (1.16:1). The mandible was affected in 225 (96.6%), the maxilla in 8 (3.4%). Histologically, solid type (63.1%) predominated over unicystic type (36.9%). Of 226, 123 (54.4%) patients were treated with radical resection, 103 (45.6%) underwent conservative method. Owing to a high recurrent rate of ameloblastoma, solid type of tumors should be approached with radical surgical treatment, while conservative measure can be applied selectively to unicystic type. Long-term follow-up is important because recurrence may appear years after tumor removal. PMID- 19783333 TI - Stressful events, social support and coping strategies of primiparous women during the postpartum period: a qualitative study. AB - OBJECTIVE: to identify problems and events perceived as stressful by primiparous mothers during the postpartum period, and to explore the social support and coping strategies they used to face these situations. DESIGN: a qualitative study. Data were collected via semi-structured interviews and analysed using a content-analysis method. SETTING: Geneva University Hospitals, Geneva, Switzerland from October 2006 to March 2007. PARTICIPANTS: 60 women interviewed six weeks after the birth at term of their first child. FINDINGS: during the early postpartum period, interaction with caregivers was an important source of perceived stress. Upon returning home, the partner was considered as the primary source of social support, but the first need expressed was for material support. Breast feeding was perceived negatively by the new mothers, and this may be due to the difference between the actual problems encountered and the idealised expectations conveyed by prenatal information. Educational information dispensed by medical staff during the prenatal period was not put into practice during the postpartum period. Mothers expressed the need to be accompanied and counselled when problems arose and regretted the lack of long-term postpartum support. KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: both the prenatal education and postpartum social support seem to mismatch women's needs and expectations. Concerted efforts are required by health professionals at the maternity unit and in the community to provide mothers with more adequate postpartum assistance. PMID- 19783334 TI - Support during labour: first-time fathers' descriptions of requested and received support during the birth of their child. AB - OBJECTIVE: to explore how first-time fathers describe requested and received support during a normal birth. DESIGN: qualitative research design. Ten first time fathers were interviewed during the first postpartum week. Individual open ended interviews were used to explore the fathers' descriptions, and the interviews were analysed using qualitative analysis. SETTING: a labour ward at one hospital in a south-western county of Sweden in November and December 2006. PARTICIPANTS: first-time fathers who had experienced a normal birth at the hospital during the study period. FINDINGS: the support described is presented as one main theme, 'being involved or being left out', which included four underlying categories: 'an allowing atmosphere', 'balancing involvement', 'being seen' and 'feeling left out'. KEY CONCLUSIONS: fathers perceived that they were given good support when they were allowed to ask questions during labour, when they had the opportunity to interact with the midwife and their partner, and when they could choose when to be involved or to step back. Fathers want to be seen as individuals who are part of the labouring couple. If fathers are left out, they tend to feel helpless; this can result in a feeling of panic and can put their supportive role of their partner at risk. IMPLICATIONS FOR PRACTICE: the results of this study could initiate discussions about how health-care professionals can develop support given to the labouring couple, with an interest in increasing paternal involvement. PMID- 19783335 TI - Midwives' use of the Internet: an Australian study. AB - OBJECTIVE: to report findings on midwives' use of the Internet drawn from a larger study that explored midwives' attitudes and experiences to online and computer-based learning. DESIGN AND SETTING: a descriptive, quantitative design using anonymous questionnaires was employed to obtain information from a sample of midwives in Victoria, Australia. PARTICIPANTS: questionnaires were forwarded by mail to a sample of 300 members of the Victorian branch of the Australian College of Midwives. A total of 169 questionnaires were returned by reply paid mail, representing a response rate of 56%. FINDINGS: around 92.3% of respondents reported that they used the Internet. However, 31.5% did not find navigating it to be easy, 34.7% reported that finding information was not easy, and 27.2% were not confident using the Internet. KEY CONCLUSIONS: many midwives have insufficient Internet competence to be able to access necessary evidence to support practice and to assist women with decision making. IMPLICATIONS FOR PRACTICE: ongoing education and training is needed to ensure that midwives have the skills to source evidence to support practice, and are able to effectively critique Internet information. PMID- 19783336 TI - Earthworm cast production as a new behavioural biomarker for toxicity testing. AB - There is currently a lack of ecotoxicity tests adapted to earthworm species of higher ecological relevance and whose endpoints could be directly related to their ecological role in the soil. We propose a new and relatively simple ecotoxicity test based on the estimation of cast production (CP) by Lumbricus terrestris under laboratory conditions. CP was found to be linearly correlated to earthworm biomass and to be greatly influenced by soil water content. Azinphos methyl had no effect on CP at all the concentrations tested. Significant decreases were observed at the normal application rate for other pesticides with (imidacloprid, carbaryl, methomyl) or without (ethyl-parathion and chlorpyrifos ethyl) a clear concentration-effect response. For the highest concentration tested, reduction in CP varied between 35 and 67%. CP is straightforward and rapidly measured and ecologically meaningful. We thus believe it to be of great use as an endpoint in ecotoxicity testing. PMID- 19783337 TI - Evaluating the cytotoxicity of palladium/magnetite nano-catalysts intended for wastewater treatment. AB - Palladium/magnetite nanoparticulate catalysts were developed for efficient elimination of halogenated organic pollutants from contaminated wastewater. Particle recovery from treated water can be ensured via magnetic separation. However, in worst-case scenarios, this catalyst removal step might fail, leading to particle release into the environment. Therefore, a toxicological study was conducted to investigate the impact of both pure magnetite and palladium/magnetite nanoparticle exposure upon human skin (HaCaT) and human colon (CaCo-2) cell lines and a cell line from rainbow trout gills (RTgill-W1). To quantify cell viability after particle exposure, three endpoints were examined for all tested cell lines. Additionally, the formation of reactive oxygen species was studied for the human cells. The results showed only minor effects of the particles on the tested cell systems and support the assumption that palladium/magnetite nano-catalysts can be implemented for a new wastewater treatment technology in which advantageous catalyst properties outweigh the risks. PMID- 19783338 TI - An approach for arsenic in a contaminated soil: speciation, fractionation, extraction and effluent decontamination. AB - The fractionation and speciation of As in a contaminated soil were investigated, and a remediation strategy was tested. Regarding speciation, we found that As(V) prevails over As(III) whereas more than 40% of total arsenic is in organic form. The fractionation of As was investigated with two sequential extraction methods: a low mobility was found. Then we tested the possibility of using phosphoric acid to extract As from the soil and cleaning the washing effluents by sorption onto montmorillonite. The efficiency of the extraction and of the adsorption onto the clay were also investigated for Cr, Cu, Fe, Mn, Ni, Pb and Zn, whose total concentrations and fractionation in the soil are reported here. The extraction percentages for As and metals ranged from 30 to 65%; the residual proportions in the soil are presumably in very unreactive forms. Montmorillonite showed a good uptake capacity towards the investigated pollutants. PMID- 19783339 TI - Effects of elevated atmospheric CO2 and tropospheric O3 on tree branch growth and implications for hydrologic budgeting. AB - The forest hydrologic budget may be impacted by increasing CO(2) and tropospheric O(3). Efficient means to quantify such effects are beneficial. We hypothesized that changes in the balance of canopy interception, stem flow, and through-fall in the presence of elevated CO(2) and O(3) could be discerned using image analysis of leafless branches. We compared annual stem flow to the results of a computerized analysis of all branches from the 2002, 2004, and 2006 annual growth whorls of 97 ten-year-old trees from the Aspen Free-Air CO(2) and O(3) Enrichment (Aspen FACE) experiment in Rhinelander, WI. We found significant effects of elevated CO(2) and O(3) on some branch metrics, and that the branch metrics were useful for predicting stem flow from birch, but not aspen. The results of this study should contribute to development of techniques for efficient characterization of effects on the forest hydrologic budget of increasing CO(2) and tropospheric O(3). PMID- 19783340 TI - Performance of some biotic indices in the real variable world: a case study at different spatial scales in North-Western Mediterranean Sea. AB - The aim of this study was to analyse the variability of four different benthic biotic indices (AMBI, BENTIX, H', M-AMBI) in two marine coastal areas of the North-Western Mediterranean Sea. In each coastal area, 36 replicates were randomly selected according to a hierarchical sampling design, which allowed estimating the variance components of the indices associated with four different spatial scales (ranging from metres to kilometres). All the analyses were performed at two different sampling periods in order to evaluate if the observed trends were consistent over the time. The variance components of the four indices revealed complex trends and different patterns in the two sampling periods. These results highlighted that independently from the employed index, a rigorous and appropriate sampling design taking into account different scales should always be used in order to avoid erroneous classifications and to develop effective monitoring programs. PMID- 19783342 TI - Ascorbic acid for anemia management in hemodialysis patients: a systematic review and meta-analysis. AB - BACKGROUND: Ascorbic acid is believed to improve anemia in patients with end stage renal disease, but its overall effectiveness is unclear. STUDY DESIGN: Systematic review and meta-analysis. SETTING & POPULATION: Adult hemodialysis patients. SELECTION CRITERIA FOR STUDIES: Randomized clinical trials of ascorbic acid use in addition to standard anemia management. INTERVENTION: Ascorbic acid. OUTCOMES: Weighted mean difference (WMD) for change in hemoglobin level, recombinant human erythropoietin (rHuEPO) dose, transferrin saturation and ferritin level and adverse events. RESULTS: Of 157 potentially relevant studies, 6 studies (n = 326 patients) met the inclusion criteria. Combining the 3 randomized clinical trials involving patients with baseline hemoglobin levels <11 g/dL, change in hemoglobin level was greater for ascorbic acid use compared with standard care (WMD, 0.9 g/dL; 95% CI, 0.5-1.2 g/dL). Compared with standard care, ascorbic acid use also was associated with a statistically significant decrease in rHuEPO dose (WMD, -17.1 U/kg/wk; 95% CI, -26.0 to -8.2 U/kg/wk) and improvement in transferrin saturation (WMD, 7.9%; 95% CI, 5.2-10.5%), with no change in ferritin concentration. Adverse events had questionable relevance to ascorbic acid use; no study reported oxalate levels or occurrence of oxalosis. LIMITATIONS: Small number of studies, heterogeneity between study populations, and study durations were short. Adverse events were poorly reported. CONCLUSIONS: Although the studies are limited by small numbers of subjects, short durations of follow-up, and variable quality, these results suggest that compared with standard care, ascorbic acid use may result in an increase in hemoglobin concentration and transferrin saturation and decrease in rHuEPO requirements. Longer term studies are required to confirm these results, provide information about adverse events, and determine whether these changes translate into improved patient outcomes and cost-effectiveness. PMID- 19783341 TI - Cardiovascular risk assessment among potential kidney transplant candidates: approaches and controversies. AB - Cardiovascular disease is the most common cause of death after kidney transplantation. However, uncertainties regarding the optimal assessment of cardiovascular risk in potential transplant candidates have produced controversy and inconsistency in pretransplantation cardiac evaluation practices. In this review, we consider the evidence supporting cardiac evaluation in kidney transplant candidates, generally focused on coronary artery disease, according to the World Health Organization principles for screening. The importance of pretransplant cardiac evaluation is supported by the high prevalence of coronary artery disease and the incidence and adverse consequences of acute coronary syndromes in this population. Testing for coronary artery disease may be performed noninvasively by using modalities that include nuclear myocardial perfusion studies and dobutamine stress echocardiography. These tests have prognostic value for mortality, but imperfect sensitivity and specificity for detecting angiographically defined coronary artery disease in patients with end stage renal disease. Associations of angiographically-defined coronary artery disease with subsequent survival also are inconsistent, likely because plaque instability is more critical for infarction risk than angiographic stenosis. The efficacy and best methods of myocardial revascularization have not been examined in large contemporary clinical trials in patients with end-stage renal disease. Biomarkers, such as cardiac troponin, have prognostic value in end-stage renal disease, but require further study to determine clinical applications in directing more expensive and invasive cardiac evaluation. PMID- 19783345 TI - Patch test in the diagnosis of food allergy. AB - Double-blind, placebo-controlled food challenges (DBPCFC) are the gold standard method for diagnosing food allergies. However, due to the difficulty of their performance on routine clinic, there is a need for laboratory tools in order to minimise the frequency of DBPCFC. Atopy patch test (APT) represents a promising manner of diagnosing delayed-type allergic reactions. The APT may identify patients with food allergies with negative specific IgE. However, the clinical relevance of positive APT reactions is still to be proven by standardised outcome definitions. PMID- 19783343 TI - Subclinical tubular injury in HIV-infected individuals on antiretroviral therapy: a cross-sectional analysis. AB - BACKGROUND: Randomized control studies have not shown an association between treatment with tenofovir (TDF) and clinically significant kidney toxicity. However, multiple cases of renal tubular toxicity have been described in patients with HIV treated with TDF. It is unclear whether spot urine protein- or albumin creatinine ratio is a sufficiently sensitive screening test to detect subclinical renal tubular toxicity in patients with HIV. STUDY DESIGN: Cross-sectional. SETTING & PARTICIPANTS: 99 patients with HIV with serum creatinine levels < 1.70 mg/dL and dipstick-negative proteinuria; 19 were antiretroviral treatment (ART) naive, 47 were on a TDF regimen, and 33 were on ART, but with no history of TDF exposure. PREDICTOR OR FACTOR: Exposure to TDF. OUTCOMES: Spot urine concentrations of retinol-binding protein (RBP; a low-molecular-weight protein normally reabsorbed by the proximal tubule), N-acetyl-beta-D-glucosaminidase (NAG; a proximal tubule lysosomal enzyme), albumin (A; a marker of glomerular disease), and protein (P; a standard clinical screening test for kidney pathological states) expressed as a ratio to creatinine (C; U(RBP/C), U(NAG/C), U(A/C), and U(P/C), respectively). RESULTS: There were no significant differences in median U(A/C) (ART-naive, 7.3 mg/g [range, 0-245.8 mg/g]; TDF, 9.0 mg/g [range, 0.1-184.1 mg/g]; and non-TDF, 10.5 mg/g [range, 2.6-261.6 mg/g]; P = 0.8). U(RBP/C) excretion was significantly higher in the TDF group (median, 214.2 microg/g [range, 26.8-17,454.5 microg/g]) than in the ART-naive group (92.5 microg/g [range, 21.3-3,969.0 microg/g]; P = 0.03); there was also a trend toward higher values than in the non-TDF group (111.6 microg/g [range, 31.0-6,136.3 microg/g]; P = 0.08). U(NAG/C) excretion was significantly higher in both the TDF (median, 394.7 micromol/h/g [range, 140.5-10,851.3 micromol/h/g]; P = 0.01) and non-TDF (406.8 micromol/h/g [range, 12.4-8,485.8 micromol/h/g]; P = 0.03) groups compared with the ART-naive group (218.6 micromol/h/g [range, 56.5-2,876.1 micromol/h/g]). U(P/C) was significantly higher in the TDF (median, 123.9 mg/g [range, 53.1-566.4 mg/g]) than the non-TDF group (97.3 mg/g [range, 0-451.3 mg/g]; P = 0.03). The proportion of patients with evidence of tubular dysfunction (increased U(RBP/C) and/or U(NAG/C)) was considerably higher than the proportion with an increase in U(A/C) or U(P/C) in all groups: for ART-naive, 52.6% vs 31.6% vs 25.0%; for TDF, 80.9% vs 29.8% vs 52.2%; and for non-TDF, 81.8% vs 39.4% vs 30.0%. The level of agreement among the different urinary test results was low. LIMITATIONS: Causality cannot be established from single measurements of urinary markers in a cross-sectional study. CONCLUSIONS: Patients with HIV had high rates of subclinical proteinuria, but neither U(P/C) nor U(A/C) is sufficiently sensitive alone to detect many of these cases. Patients using TDF have increased U(RBP/C) and U(P/C); the significance of this will need to be determined from longer-term outcome studies. PMID- 19783347 TI - Exercise-induced bronchospasm in obese adolescents. AB - BACKGROUND: Assess the frequency and severity of exercise-induced bronchospasm (EIB) in obese adolescents. METHODS: A cross-sectional descriptive study involving 80 adolescents of both genders, aged 10-16 years-old, divided into four groups according to clinical history of asthma and/or allergic rhinitis and body mass index as follows: asthmatic obese (n = 18); asthmatic non-obese (n = 21); obese non-asthmatic (n = 26); and healthy individuals (n = 15). An exercise bronchoprovocation test was used for EIB diagnosis, considered positive when the forced expiratory volume in one second (FEV(1)) decreased > or = 15% in relation to pre-exercise FEV(1). Maximum percent fall in FEV(1) (MF%FEV(1)) and area above the curve (AAC(0-30)) were calculated to evaluate EIB severity and recovery. RESULTS: No significant difference was found in EIB frequency between asthmatic obese (50.0%) and asthmatic non-obese (38.0%) individuals or between obese non asthmatics (11.5%) and healthy individuals (6.7%). However, the MF%FEV(1) and AAC(0-30) were significantly greater in the asthmatic obese group compared to the asthmatic non-obese (37.7% and 455 vs 24.5% and 214, p<0.03). CONCLUSIONS: Obesity did not contribute to increased EIB frequency in asthmatics and non asthmatics. However, obesity did contribute to increased EIB severity and recovery among asthmatics. PMID- 19783346 TI - Are we overtreating recurrent wheezing in infancy? PMID- 19783348 TI - Exercise-induced bronchospasm or dyspnoea in obese children? PMID- 19783349 TI - Down-regulation of endogenous hydrogen sulphide pathway in nasal mucosa of allergic rhinitis in guinea pigs. AB - BACKGROUND: The present study was designed to explore the possible changes in endogenous hydrogen sulphide (H(2)S), a novel gasotransmitter, on the pathogenesis of allergic rhinitis (AR). METHODS: AR guinea pig model was established by nasal ovalbumin sensitisation. Guinea pigs were divided into four groups: Saline control, AR sensitised, sodium hydrosulphide (NaHS) treated, and propargylglycine (PPG) treated group. The frequency of sneezing and nose rubbing was recorded. Leukocyte infiltration in nasal lavage fluid (NLF) and plasma H(2)S level were measured. Expression of Cystathionine-beta-synthase (CBS) and Cystathionine-gamma-lyase (CSE) mRNA as H(2)S-producing enzymes in nasal mucosa was determined by real time Reverse Transcriptase-Polymerase Chain Reaction (RT PCR). RESULTS: The frequency of sneezing and nose rubbing, and levels of leukocyte infiltration in NLF were higher than those of control (P<0.01), but plasma H(2)S in sensitised guinea pigs was lower than those of control (P<0.05). From the results of RT-PCR, it was found that the expression of CSE was higher than CBS in nasal mucosa, and in sensitised guinea pigs it was lower than that of control (P<0.05). NaHS successfully increased the level of H(2)S and alleviated the symptoms of AR accompanied by up-regulation of CSE as compared with AR group (P<0.05). PPG significantly suppressed the expression of CSE and decreased the H(2)S level, yet also aggravated the symptoms of AR. CONCLUSION: H(2)S level may be negatively correlated with the process of inflammation and positively correlated with expression of CSE in nasal mucosa. The endogenous H(2)S pathway is down-regulated in AR. PMID- 19783350 TI - Food allergy to Shiitake (Lentinus edodes) manifested as oesophageal symptoms in a patient with probable eosinophilic oesophagitis. PMID- 19783352 TI - Early weaning accelerates the differentiation of mucous neck cells in rat gastric mucosa: possible role of TGFalpha/EGFR. AB - The development of the gastric mucosa is controlled by hormones, growth factors and feeding behavior. Early weaning (EW), which means the abrupt interruption of suckling, increases proliferation and differentiation in the rat gastric epithelium. Transforming growth factor alpha (TGFalpha) is secreted in the stomach, binds to the epidermal growth factor receptor (EGFR) and may control cell proliferation, differentiation and migration. Here, we investigated the influence of suckling-weaning transition on the differentiation of mucous neck cells in the stomach and its association to the expression of TGFalpha and EGFR. Fifteen-day-old Wistar rats were divided into two groups: suckling (control), in which pups were kept with the dam, and early weaning (EW), in which rats were separated from their mother and fed with hydrated powdered chow. TGFalpha and EGFR levels were increased at 18 days in EW animals compared to control ones (p<0.05). Histochemical reactions with Periodic Acid-Schiff reagent+Alcian Blue or Bandeiraea simplicifolia II lectin were used to stain the mucous neck cells and showed an increase in this cell population throughout EW, which was more pronounced at 17 days when compared to suckling pups (p<0.05). These morphological results were confirmed by RT-PCR for mucin 6. The levels of mucin 6 mRNA were higher in EW animals from the 16th to the 18th day (1-3 days post weaning) when compared to the respective control group. Inhibition of EGFR through AG1478 administration to EW animals prevented the expansion of mucous neck cell population induced by EW (p<0.05). Therefore, early weaning up regulated TGFalpha/EGFR expression and induced differentiation of mucous neck cells. Moreover, we showed that EGFR takes part in the maturation of this cell population. We conclude that regular suckling-weaning transition is crucial to guarantee the development of the gastric mucosa. PMID- 19783351 TI - Quantitative assignment of reaction directionality in constraint-based models of metabolism: application to Escherichia coli. AB - Constraint-based modeling is an approach for quantitative prediction of net reaction flux in genome-scale biochemical networks. In vivo, the second law of thermodynamics requires that net macroscopic flux be forward, when the transformed reaction Gibbs energy is negative. We calculate the latter by using (i) group contribution estimates of metabolite species Gibbs energy, combined with (ii) experimentally measured equilibrium constants. In an application to a genome-scale stoichiometric model of Escherichia coli metabolism, iAF1260, we demonstrate that quantitative prediction of reaction directionality is increased in scope and accuracy by integration of both data sources, transformed appropriately to in vivo pH, temperature and ionic strength. Comparison of quantitative versus qualitative assignment of reaction directionality in iAF1260, assuming an accommodating reactant concentration range of 0.02-20mM, revealed that quantitative assignment leads to a low false positive, but high false negative, prediction of effectively irreversible reactions. The latter is partly due to the uncertainty associated with group contribution estimates. We also uncovered evidence that the high intracellular concentration of glutamate in E. coli may be essential to direct otherwise thermodynamically unfavorable essential reactions, such as the leucine transaminase reaction, in an anabolic direction. PMID- 19783353 TI - Tree-based intercropping systems increase growth and nutrient status of hybrid poplar: a case study from two Northeastern American experiments. AB - Tree-based intercropping is considered to be a potentially useful land use system for mitigating negative environmental impacts from intensive agriculture such as nutrient leaching and greenhouse gas emissions. Rapid early growth of trees is critical for rapidly accruing environmental benefits provided by the trees. We tested the hypothesis that intercropping increases the growth and nutrient status of young hybrid poplars (Populus spp.), compared to a harrowing alley treatment (i.e., no intercrop), in two experimental sites (St-Remi and St-Edouard) in southern Quebec, Canada. Three hybrid poplar clones (TD3230, Populus trichocarpa x deltoides; DN3308, P. deltoides x nigra; and NM3729, P. nigra x maximowiczii) were planted at St-Remi. Clones DN3333 and DN3570 were planted at St-Edouard. At St-Remi, intercropping comprised a 4-year succession of three crops of soybean (Glycine max (L.) Merr.) and barley (Hordeum vulgare L.). At St-Edouard, intercropping comprised a 3-year succession of buckwheat (Fagopyrum esculentum Moench), winter rye (Secale cereale L.), and winter wheat (Triticum aestivum L.). At St-Remi, four years after treatment began, leafless aboveground biomass of hybrid poplars in the intercropping treatment was 37% higher compared to that in the harrowing treatment. At St-Edouard, after the third growing season, leafless aboveground biomass of hybrid poplars in the intercropping treatment was significantly higher by 40%. Vector analysis of foliar nutrient concentrations and comparison with critical concentration values showed that N (both sites) and K (St-Edouard) were the most limiting nutrients. Hybrid poplar clones responded similarly to treatments, with no consistent differences in tree growth observed between clones. We conclude that tree-based intercropping systems may offer an effective means of improving the early growth of hybrid poplars planted to provide both environmental services and high-value timber. PMID- 19783354 TI - Risk-sharing policies in the context of the French Flood Prevention Action Programmes. AB - This article analyzes the consequences for risk distribution of the French Flood Prevention Action Programme (PAPI). By redirecting floods from the most vulnerable to the least vulnerable areas, PAPIs expose farmers to greater flood risks. This has led local water management institutions to introduce compensation payments. The article outlines the results of an exhaustive survey of all PAPIs in France, which examined the way the compensation policies are set up locally. Results of the survey showed that the proposed policies may be financially non viable. Several more viable risk-sharing solutions are then discussed, involving insurance schemes, state intervention and local institutions. PMID- 19783355 TI - Modeling potential herbicide loss to surface waters on the Swiss plateau. AB - Lack of sufficiently detailed data often limits the applicability of complex transport-reaction models for estimating potential herbicide loss to surface waters. Therefore, there is also a need for simple models that are easy to apply but still capture the main features of the underlying processes. In this study, a simple regression model was developed to assess the vulnerability of catchments in the Swiss Plateau to diffuse herbicide loss to surface waters. The model is designed as a screening tool to rank the catchments in a relative sense and not to calculate Predicted Environmental Concentrations (PEC) of pesticides. The main goal is to capture two dominating factors controlling diffuse herbicide transport into streams and rivers. These factors are herbicide application and fast flow processes that are mainly responsible for herbicide transport. In a first step vulnerability of sites to herbicide loss is estimated based on site-specific conditions irrespective of actual herbicide application. In the second step, this vulnerability assessment is combined with actual herbicide application data to estimate the potential herbicide loss. The fast flow index (FFI), derived from discharge data using a base flow separation method, was applied as a proxy for the amount of fast flow occurring. The influence of catchment attributes (including topographic, climatic and soil data) on the FFI was analyzed using a multiple regression approach based on data from 57 catchments of the Swiss Plateau. By combining regression analysis with mechanistic knowledge, a two factor non-linear model based on river density and soil permeability as dominant input factors was selected as the best model for FFI prediction given the available data. Higher dimensional models had to be excluded because the strong correlation between the potential input factors led to unrealistic dependences while only minimally improving the quality of the fit. The spatial pattern of the predicted FFI as a measure for the vulnerability to diffuse herbicide losses shows a clearly increasing trend from the western to the eastern part of the Swiss Plateau and towards the pre-alpine/alpine regions in the south. In general the pattern of herbicide use corresponds to site conditions typical of a low FFI. However, the spatial analysis revealed exceptions, namely areas in which high actual herbicide use coincides with a high FFI. Despite the uncertainties in the model, this simple approach seems to be useful for supporting site-adapted agricultural practice whenever the higher accuracy of more detailed models is not required or too expensive to achieve. In addition, in combination with data on actual herbicide application, it can support the design of monitoring strategies by identifying critical areas of actual herbicide loss. PMID- 19783356 TI - Limitations of an optimum sustainable population or potential biological removal approach for conserving marine mammals: Pacific walrus case study. AB - Decision rules are the agreed-upon points at which specific management interventions are initiated. For marine mammal management under the U.S. Marine Mammal Protection Act (MMPA), decision rules are usually based on either a numeric population or biological-removal approach. However, for walrus and other ice-associated pinnipeds, the inability to reliably assess population numbers or biological removals highlights a significant gap in the MMPA, particularly when the Arctic environment is rapidly changing. We describe the MMPA's ecosystem based management goals, and why managers have bypassed these goals in favor of an approach that depends upon numerical population assessment. We then revisit the statute's primary goals in light of current knowledge about the Pacific walrus ecosystem and new developments in environmental governance. We argue that to monitor and respond to changes in the walrus ecosystem, decision rules should be based on scientific criteria that depend less on the currently-impractical goal of accurately enumerating population size and trends, or removals from that population. Rather, managers should base decisions on ecological needs and observed ecological changes. To implement this approach would require an amendment to the MMPA that supports filling the gap in management with achievable decision rules. Alternatively, walrus and other ice-associated pinnipeds will remain largely unmanaged during a period of profound environmental change. PMID- 19783357 TI - In-stand scenic beauty of variable retention harvests and mature forests in the U.S. Pacific Northwest: the effects of basal area, density, retention pattern and down wood. AB - Tensions between amenity- and timber-based economies in the U.S. and Canadian Pacific Northwest motivated a study of scenic beauty inside mature forests and timber harvests. A diverse sample of regional forests, measures of forest structure, and large, representative samples of photographs and public judges were employed to measure scenic beauty inside un-harvested mature and old-growth forests, and timber harvests. The latter varied systematically in down wood levels and retention level and pattern. Scenic beauty tended to be optimized at a basal area of 110-155 m(3)/ha and/or 700-900 trees/ha. Older forests and those with larger trees were perceived to be more beautiful. In harvests, greater retention levels, less down wood, and dispersed rather than aggregated retention patterns contributed to aesthetic improvements. Green-tree retention harvests offer considerable potential gains in perceived scenic beauty compared to perceived very ugly clearcuts, particularly at higher retention levels. These gains are more reliable from dispersed retention patterns. The silvicultural parameters studied change strength in affecting scenic beauty with changes in retention level. These interactions are explored in relation to a range of scenic quality objectives as an aid to planners, visual impact analysts, and silviculturists. PMID- 19783358 TI - Energy and resource basis of an Italian coastal resort region integrated using emergy synthesis. AB - Sustainable development of coastal zones must balance economic development that encourages human visitation from a larger population with desires that differ from the local residents with the need to maintain opportunities for the local resident society and conserve ecological capital, which may serve as the basis for residents. We present a case study in which the sustainability level of a coastal zone (Riviera del Beigua), located along the Ligurian coast of north western Italy, was assessed through the lens of systems ecology using emergy synthesis to integrate across economic, social and environmental sub-systems. Our purposes were (1) to quantify the environmental sustainability level of this coastal zone, (2) to evaluate the role of tourism in affecting the economy, society and environment, and (3) to compare emergy synthesis to Butler's Tourism Area Life Cycle model (TALC). Results showed that 81% of the total emergy consumption in the coastal zone was derived from external sources, indicating that this tourist-heavy community was not sustainable. Tourism, as the dominant economic sub-system, consumed 42% of the total emergy budget, while local residents used the remaining 58%. The progressive stages of the TALC model were found to parallel the dynamic changes in the ratio of external emergy inputs to local emergy inputs, suggesting that emergy synthesis could be a useful tool for detecting a tourist region's TALC stage. Use of such a quantitative tool could expedite sustainability assessment to allow administrative managers to understand the complex relationship between a region's economy, environment and resident society so sound policies can be developed to improve overall sustainability. PMID- 19783360 TI - Endoscopy in the management of intra-ventricular lesions: preliminary experience in the Middle East. AB - OBJECTIVES: The study is aimed at evaluating neuroendoscopic procedures in the management of various intra-cranial intra-ventricular lesions. METHODS: We retrospectively review 24 consecutive patients harboring various intra ventricular lesions with or without associated hydrocephalus, operated and managed by the authors between December 2002 and December 2007. Depending on the preoperative imaging and working diagnosis, endoscopic biopsy or endoscopic resection/debulking, along with concomitant treatment of hydrocephalus via third ventriculostomy or fenestration of the septum pellucidum and ventriculo peritoneal shunting, were done. RESULTS: The single endoscopic procedure was successful in most of the patients (22/24), where the goals of surgery in attaining a diagnostic biopsy or resection, and simultaneous treatment of hydrocephalus, were attained helping guide further therapy. The endoscopic procedure was the only procedure needed in most of the patients. CONCLUSIONS: The endoscopic procedures carried a high success rate in the management of intra ventricular lesions, and were especially valuable in patients harboring chemo and/or radiosensitive deep seated tumors. PMID- 19783361 TI - Differential inhibition sensitivities of MET mutants to the small molecule inhibitor SU11274. AB - Point mutations emerge as one of the rate-limiting steps in tumor response to small molecule inhibitors of protein kinases. Here we characterized the response of the MET mutated variants, V1110I, V1238I, V1206L and H1112L to the small molecule SU11274. Our results reveal a distinct inhibition pattern of the four mutations with IC(50) values for autophosphorylation inhibition ranging between 0.15 and 1.5muM. Differences were further seen on the ability of SU11274 to inhibit phosphorylation of downstream MET transducers such as AKT, ERK, PLCgamma and STAT3 and a variety of MET-dependent biological endpoints. In all the assays, H1112L was the most sensitive to SU11274, while V1206L was less affected under the used concentration range. The differences in responses to SU11274 are discussed based on a structural model of the MET kinase domain. PMID- 19783363 TI - Surface-modified nanoscale carbon black used as sorbents for Cu(II) and Cd(II). AB - Commercial carbon blacks often have low adsorption capacity for metal ions. Surface modification of them by appropriate physical and chemical treatments could improve their absorption capacities, and hence extend their environmental application. A surface-modified nanoscale carbon black was prepared by oxidizing the carbon black with 65% HNO(3). Batch experiments showed that the adsorption quantities of Cu(II) or Cd(II) on this modified carbon black (MCB) were significantly increased compared with those on the parent one, and the maximum adsorption quantities of Cu(II) and Cd(II) on the MCB were 438 and 282 mmol kg( 1), respectively. The desorption percentages of Cu(II) or Cd(II) from the MCB increased with the increasing quantities initially adsorbed. In the binary system of Cu(II) and Cd(II), these two metal ions exhibited competition on the MCB, preferential for Cu(II). It could be concluded that the MCB had very good adsorption properties for the metal ions, and could be applied in the purification of wastewater containing such metal ions. PMID- 19783362 TI - Kinetics and metabolic versatility of highly tolerant phenol degrading Alcaligenes strain TW1. AB - A bacterium that could completely metabolize phenol in batch culture supplied with up to 1200 mg phenol l(-1) at room temperature (25 degrees C) was isolated from the activated sludge of the industrial wastewater treatment plant of a Coke company (Cairo, Egypt). Morphological and physiological characterization showed strain TW1 was a motile, strictly aerobic, gram negative and short-rod occurring singly or in clusters. Partial 16S rRNA gene sequence analysis revealed strain TW1 belonged to the beta group of Proteobacteria, showing 100% identity to Alcaligenes SCTI. Strain TW1 aerobically grew on a number of monocyclic aromatic compounds (hydroquinone, catechol and o-cresol) as well as polycyclic aromatic compounds (pyrene, phenanthrene and naphthalene). The growth of Alcaligenes TW1 on phenol as sole carbon and energy source (25 degrees C) was well described by the Haldane kinetics model with a maximal specific growth rate of 0.58 h(-1), a half-saturation constant of 10 mg l(-1), and a substrate inhibition constant of 152-550 mg l(-1). The biomass yield coefficient ranged from 0.55 to 0.64 mg dry cell mass/mg phenol. Due to its high tolerance to phenol and high metabolic versatility, Alcaligenes sp. TW1 is considered an excellent candidate for the biotreatment of high strength phenol-laden industrial wastewaters. PMID- 19783364 TI - Reduction of COD in refinery wastewater through adsorption on date-pit activated carbon. AB - Experiments were carried out to evaluate the batch adsorption of COD from petroleum refinery wastewater on a locally prepared date-pit activated carbon (DP AC), and its adsorption effectiveness was compared to that of commercially available BDH activated carbon (BDH-AC). Adsorption equilibrium and kinetic data were determined for both adsorbents and fitted to several adsorption isotherm and kinetics models, respectively. The Langmuir monolayer isotherm fitted well the equilibrium data of COD on both adsorbents; whereas, the kinetics data were best fitted by the pseudo-second order model. Modeling of the controlling mechanisms indicated that both intrinsic kinetics and mass transfer contributed to controlling the adsorption process. Mass transfer seemed to be the dominant mechanism at low COD content, while intrinsic kinetics dominates at high concentrations. In general, the adsorption effectiveness of locally prepared DP AC was proven to be comparable to that of BDH-AC. Therefore, DP-AC can be utilized as an effective and less expensive adsorbent for the reduction of COD in refinery wastewater. PMID- 19783365 TI - Effect of microwave irradiation on TATB explosive (II): temperature response and other risk. AB - TATB (1,3,5-triamino-2,4,6-trinitrobenzene) explosives were safely irradiated with microwave and showed no visible change according to XPS and XRD spectra. Temperature of TATB sample increased quickly at the beginning and gently during sequent continuous irradiation with temperature less than 140 degrees C after 60 min, 480 W irradiation, and increased more quickly in 300 g at 480 W than in 150 g at 480 W, both implied that heat dissipation was in the majority of microwave energy. Two major risk factors in microwave irradiation were concerned including overheating which should be avoidable with temperature monitor and microwave discharge which should be controllable experimentally though dielectric breakdown mechanism was not elucidated theoretically yet. PMID- 19783366 TI - Extension of the anaerobic digestion model No. 1 (ADM1) to include phenol compounds biodegradation processes for simulating the anaerobic co-digestion of olive mill wastes at mesophilic temperature. AB - The anaerobic digestion model No. 1 (ADM1) was extended and enhanced to describe the anaerobic degradation processes of phenol compounds and homologues in olive mill wastewater (OMW) and olive mill solid waste (OMSW) at mesophilic temperature (37 degrees C). The original ADM1 basic structure was extended by to the inclusion of phenolic compounds degradation processes into benzoate and then into acetate. The inhibitory effect of phenolic compounds on the fermenting process was accounted for by the use of non-competitive inhibition functions. New sensitive phenolic and benzoate parameters were calibrated and validated using updated experimental data from our previous study dealing with the mesophilic anaerobic co-digestion of OMW with OMSW in semi-continuous tubular digesters. The simulating results revealed that the extended ADM1 could predict with adequate accuracy the steady-state results of gas flow rate, effluent pH and soluble phenol concentrations of various influent concentrations at different hydraulic retention times (HRTs). PMID- 19783367 TI - Adsorption of transition metal ions from aqueous solutions onto a novel silica gel matrix inorganic-organic composite material. AB - A novel inorganic-organic composite material silica gel microspheres encapsulated by imidazole functionalized polystyrene (SG-PS-azo-IM) has been synthesized and characterized. This composite material was used to investigate the adsorption of Cr(III), Mn(II), Fe(III), Ni(II), Cu(II), Zn(II), Hg(II), Pb(II), Pd(II), Pt(II), Ag(I), and Au(III) from aqueous solutions, and the research results displayed that SG-PS-azo-IM has the highest adsorption capacity for Au(III). Langmuir and Freundlich isotherm models were applied to analyze the experimental data, the best interpretation for the experimental data was given by the Langmuir isotherm equation, and the maximum adsorption capacity for Au(III) is 1.700 mmol/g. The adsorption selectivity, the dynamic adsorption and desorption properties of SG-PS azo-IM for Au(III) have also been studied. The results showed that SG-PS-azo-IM had excellent adsorption for Au(III) in four binary ions system, especially in the systems of Au(III)-Zn(II) and Au(III)-Cu(II), and almost Au(III) could be desorbed with the eluent solution of 0.5% thiourea in 1 mol/L HCl. Moreover, this novel composite material was used to preconcentrate Au(III) before its determination by flame atomic adsorption spectrometry. In the initial concentration range of 0.10-0.20 microg/mL, multiple of enrichment could reach 5.28. Thus, silica gel encapsulated by polystyrene coupling with imidazole (SG-PS azo-IM) is favorable and useful for the removal of transition metal ions, and the high adsorption capacity makes it a good promising candidate material for Au(III) removal. PMID- 19783369 TI - Extraction and separation of Co(II) and Ni(II) from acidic sulfate solutions using Aliquat 336. AB - Extraction and separation of Co(II) and Ni(II) from acidic sulfate solutions by solvent extraction technique were studied using different forms of Aliquat 336 diluted with kerosene. The extraction percent of each metal ion was found to increase with increasing pH and extractant concentration. Co(II) was preferentially extracted by different forms of Aliquat 336 over Ni(II) under the same extraction conditions. From analysis of the experimental results, the extraction mechanism of R(4)N-forms was proposed with Co(II). It was found that the highest separation factor (S(Co/Ni)) value of 606.7 was obtained with 0.36 M R(4)N-SCN in kerosene from 2.0M H(2)SO(4) solution at pH 4.8 and shaking time of 20 min. Stripping of the two metal ions from the organic phase was also investigated. Based on the experimental results, a separation method was developed and tested to separate high purity Co(II), Ni(II) and Ln(III) from Ni MH batteries leached by 2.0M H(2)SO(4). Based on the experimental results, a flow sheet was developed and tested and 0.34 g Co, 1.39 g Ln and 5.2g Ni were obtained from the leaching process. PMID- 19783368 TI - Biosorption of Acid Yellow 17 from aqueous solution by non-living aerobic granular sludge. AB - Batch biosorption experiments were carried out for the removal of Acid Yellow 17 from aqueous solution using non-living aerobic granular sludge as an effective biosorbent. The effects of solution pH value, biosorbent dosage, initial Acid Yellow 17 concentration, NaCl concentration and temperature on the biosorption were investigated. The experimental results indicate that this process was highly dependent on pH value and the pH value of 2.0 was favorable. The Temkin isotherm was more applicable for describing the biosorption equilibrium at the whole concentration range than the Freundlich and Langmuir isotherm. The results of kinetics study show that the pseudo-second-order model fitted to the experimental data well. Both intraparticle diffusion and boundary layer diffusion might affect the biosorption rate. Thermodynamic studies demonstrate that the biosorption process was spontaneous and exothermic. The FTIR analysis before and after Acid Yellow 17 binding indicated that functional groups such as amine, hydroxyl, carboxyl and either on the non-living aerobic granular sludge would be the active binding sites for the biosorption of the studied dye. These results show that non living aerobic granular sludge could be effectively used as a low-cost and alternative biosorbent for the removal of Acid Yellow 17 dye from wastewater. PMID- 19783370 TI - Rhizofiltration using sunflower (Helianthus annuus L.) and bean (Phaseolus vulgaris L. var. vulgaris) to remediate uranium contaminated groundwater. AB - The uranium removal efficiencies of rhizofiltration in the remediation of groundwater were investigated in lab-scale experiments. Sunflower (Helianthus annuus L.) and bean (Phaseolus vulgaris L. var. vulgaris) were cultivated and an artificially uranium contaminated solution and three genuine groundwater samples were used in the experiments. More than 80% of the initial uranium in solution and genuine groundwater, respectively, was removed within 24h by using sunflower and the residual uranium concentration of the treated water was lower than 30 microg/L (USEPA drinking water limit). For bean, the uranium removal efficiency of the rhizofiltration was roughly 60-80%. The maximum uranium removal via rhizofiltration for the two plant cultivars occurred at pH 3-5 of solution and their uranium removal efficiencies exceeded 90%. The lab-scale continuous rhizofiltration clean-up system delivered over 99% uranium removal efficiency, and the results of SEM and EDS analyses indicated that most uranium accumulated in the roots of plants. The present results suggested that the uranium removal capacity of two plants evaluated in the clean-up system was about 25mg/kg of wet plant mass. Notably, the removal capacity of the root parts only was more than 500 mg/kg. PMID- 19783371 TI - Outpatient intravenous ketamine for the treatment of complex regional pain syndrome: a double-blind placebo controlled study. AB - Complex regional pain syndrome (CRPS) is a severe chronic pain condition that most often develops following trauma. The pathophysiology of CRPS is not known but both clinical and experimental evidence demonstrate the important of the NMDA receptor and glial activation in its induction and maintenance. Ketamine is the most potent clinically available safe NMDA antagonist that has a well established role in the treatment of acute and chronic pain. This randomized double-blind placebo controlled trial was designed to evaluate the effectiveness of intravenous ketamine in the treatment of CRPS. Before treatment, after informed consent was obtained, each subject was randomized into a ketamine or a placebo infusion group. Study subjects were evaluated for at least 2 weeks prior to treatment and for 3 months following treatment. All subjects were infused intravenously with normal saline with or without ketamine for 4h (25ml/h) daily for 10 days. The maximum ketamine infusion rate was 0.35mg/kg/h, not to exceed 25mg/h over a 4h period. Subjects in both the ketamine and placebo groups were administered clonidine and versed. This study showed that intravenous ketamine administered in an outpatient setting resulted in statistically significant (p<0.05) reductions in many pain parameters. It also showed that subjects in our placebo group demonstrated no treatment effect in any parameter. The results of this study warrant a larger randomized placebo controlled trial using higher doses of ketamine and a longer follow-up period. PMID- 19783372 TI - A cognitive model for the intergenerational transference of alcohol use behavior. AB - A family history of alcoholism has shown to be one of the greatest consistent risk factors in the intergenerational transference of alcohol problems. Whereas a large number of studies have attempted to identify the processes responsible for this interfamilial transfer, the mechanisms remain unclear. Family, twin and adoption studies, and environmental theories have resulted in a number of unanswered questions regarding the extent that these factors influence the transmission of alcohol behavior. Recently, cognitive theories have suggested that the observation of parental drinking habits contributes to the child's beliefs and expectations of alcohol's effects. A hypothesised cognitive model will be proposed suggesting that the mechanism for the transference of particular drinking styles from parent to offspring may be further explained by the transference of alcohol cognitions, in particular, alcohol expectancies and drinking refusal self-efficacy. This review focuses on research of bio/psycho/social factors that perpetuate alcohol misuse across generations, and will delineate the proposed cognitive mechanisms for the interfamilial transference of alcohol problems and discuss the implications of the proposed model. PMID- 19783373 TI - Repeat stereotactic radiosurgery for acoustic neuromas. AB - PURPOSE: To evaluate the outcome of repeat stereotactic radiosurgery (SRS) for acoustic neuromas, we assessed tumor control, clinical outcomes, and the risk of adverse radiation effects in patients whose tumors progressed after initial management. METHODS AND MATERIALS: During a 21-year experience at our center, 1,352 patients underwent SRS as management for their acoustic neuromas. We retrospectively identified 6 patients who underwent SRS twice for the same tumor. The median patient age was 47 years (range, 35-71 years). All patients had imaging evidence of tumor progression despite initial SRS. One patient also had incomplete surgical resection after initial SRS. All patients were deaf at the time of the second SRS. The median radiosurgery target volume at the time of the initial SRS was 0.5 cc and was 2.1 cc at the time of the second SRS. The median margin dose at the time of the initial SRS was 13 Gy and was 11 Gy at the time of the second SRS. The median interval between initial SRS and repeat SRS was 63 months (range, 25-169 months). RESULTS: At a median follow-up of 29 months after the second SRS (range, 13-71 months), tumor control or regression was achieved in all 6 patients. No patient developed symptomatic adverse radiation effects or new neurological symptoms after the second SRS. CONCLUSIONS: With this limited experience, we found that repeat SRS for a persistently enlarging acoustic neuroma can be performed safely and effectively. PMID- 19783374 TI - Irradiated volume as a predictor of brain radionecrosis after linear accelerator stereotactic radiosurgery. AB - PURPOSE: To investigate the correlation between volume of brain irradiated by stereotactic radiosurgery (SRS) and the incidence of symptomatic and asymptomatic brain radionecrosis (RN). METHODS AND MATERIALS: A retrospective analysis was performed of patients treated with single-fraction SRS for brain metastases at our institution. Patients with at least 6-month imaging follow-up were included and diagnosed with RN according to a combination of criteria, including appearance on serial imaging and histology. Univariate and multivariate analyses were performed to determine the predictive value of multiple variables, including volume of brain receiving a specific dose (V8 Gy-V18 Gy). RESULTS: Sixty-three patients were reviewed, with a total of 173 lesions. Most patients (63%) had received previous whole-brain irradiation. Mean prescribed SRS dose was 18 Gy. Symptomatic RN was observed in 10% and asymptomatic RN in 4% of lesions treated. Multivariate regression analysis showed V8 Gy-V16 Gy to be most predictive of symptomatic RN (p < 0.0001). Threshold volumes for significant rise in RN rates occurred between the 75th and 90th percentiles, with a midpoint volume of 10.45 cm(3) for V10 Gy and 7.85 cm(3) for V12 Gy. CONCLUSIONS: Analysis of patient and treatment variables revealed V8 Gy-V16 Gy to be the best predictors for RN using linear accelerator-based single-fraction SRS for brain metastases. We propose that patients with V10 Gy >10.5 cm(3) or V12 Gy >7.9 cm(3) be considered for hypofractionated rather than single-fraction treatment, to minimize the risk of symptomatic RN. PMID- 19783375 TI - Detection of local, regional, and distant recurrence in patients with psa relapse after external-beam radiotherapy using (11)C-choline positron emission tomography. AB - PURPOSE: An elevated serum prostate-specific antigen (PSA) level cannot distinguish between local-regional recurrences and the presence of distant metastases after treatment with curative intent for prostate cancer. With the advent of salvage treatment such as cryotherapy, it has become important to localize the site of recurrence (local or distant). In this study, the potential of (11)C-choline positron emission tomography (PET) to identify site of recurrence was investigated in patients with rising PSA after external-beam radiotherapy (EBRT). METHODS AND MATERIALS: Seventy patients with histologically proven prostate cancer treated with EBRT and showing biochemical recurrence as defined by American Society for Therapeutic Radiology and Oncology consensus statement and 10 patients without recurrence underwent a PET scan using 400 MBq (11)C-choline intravenously. Biopsy-proven histology from the site of suspicion, findings with other imaging modalities, clinical follow-up and/or response to adjuvant therapy were used as comparative references. RESULTS: None of the 10 patients without biochemical recurrence had a positive PET scan. Fifty-seven of 70 patients with biochemical recurrence (median PSA 9.1 ng/mL; mean PSA 12.3 ng/mL) showed an abnormal uptake pattern (sensitivity 81%). The site of recurrence was only local in 41 of 57 patients (mean PSA 11.1 ng/mL at scan), locoregionally and/or distant in 16 of 57 patients (mean PSA 17.7 ng/mL). Overall the positive predictive value and negative predictive value for (11)C-choline PET scan were 1.0 and 0.44 respectively. Accuracy was 84%. CONCLUSIONS: (11)C-choline PET scan is a sensitive technique to identify the site of recurrence in patients with PSA relapse after EBRT for prostate cancer. PMID- 19783376 TI - Investigating verbal and visual auditory learning after conformal radiation therapy for childhood ependymoma. AB - PURPOSE: The primary objective of this study was to determine whether children with localized ependymoma experience a decline in verbal or visual-auditory learning after conformal radiation therapy (CRT). The secondary objective was to investigate the impact of age and select clinical factors on learning before and after treatment. METHODS AND MATERIALS: Learning in a sample of 71 patients with localized ependymoma was assessed with the California Verbal Learning Test (CVLT C) and the Visual-Auditory Learning Test (VAL). Learning measures were administered before CRT, at 6 months, and then yearly for a total of 5 years. RESULTS: There was no significant decline on measures of verbal or visual auditory learning after CRT; however, younger age, more surgeries, and cerebrospinal fluid shunting did predict lower scores at baseline. There were significant longitudinal effects (improved learning scores after treatment) among older children on the CVLT-C and children that did not receive pre-CRT chemotherapy on the VAL. CONCLUSION: There was no evidence of global decline in learning after CRT in children with localized ependymoma. Several important implications from the findings include the following: (1) identification of and differentiation among variables with transient vs. long-term effects on learning, (2) demonstration that children treated with chemotherapy before CRT had greater risk of adverse visual-auditory learning performance, and (3) establishment of baseline and serial assessment as critical in ascertaining necessary sensitivity and specificity for the detection of modest effects. PMID- 19783377 TI - Cognition and quality of life after chemotherapy plus radiotherapy (RT) vs. RT for pure and mixed anaplastic oligodendrogliomas: radiation therapy oncology group trial 9402. AB - PURPOSE: Radiation Therapy Oncology Group 9402 compared procarbazine, lomustine, and vincristine (PCV) chemotherapy plus radiation therapy (PCV + RT) vs. RT alone for anaplastic oligodendroglioma. Here we report longitudinal changes in cognition and quality of life, effects of patient factors and treatments on cognition, quality of life and survival, and prognostic implications of cognition and quality of life. METHODS AND MATERIALS: Cognition was assessed by Mini Mental Status Examination (MMSE) and quality of life by Brain-Quality of Life (B-QOL). Scores were analyzed for survivors and within 5 years of death. Shared parameter models evaluated MMSE/B-QOL with survival. RESULTS: For survivors, MMSE and B-QOL scores were similar longitudinally and between treatments. For those who died, MMSE scores remained stable initially, whereas B-QOL slowly declined; both declined rapidly in the last year of life and similarly between arms. In the aggregate, scores decreased over time (p = 0.0413 for MMSE; p = 0.0016 for B-QOL) and were superior with age <50 years (p < 0.001 for MMSE; p = 0.0554 for B-QOL) and Karnofsky Performance Score (KPS) 80-100 (p < 0.001). Younger age and higher KPS were associated with longer survival. After adjusting for patient factors and drop-out, survival was longer after PCV + RT (HR = 0.66, 95% CI = 0.49-0.9, p = 0.0084; HR = 0.74, 95% CI = 0.54-1.01, p = 0.0592) in models with MMSE and B-QOL. In addition, there were no differences in MMSE and B-QOL scores between arms (p = 0.4752 and p = 0.2767, respectively); higher scores predicted longer survival. CONCLUSION: MMSE and B-QOL scores held steady in the upper range in both arms for survivors. Younger, fitter patients had better MMSE and B-QOL and longer survival. PMID- 19783378 TI - A cinematic magnetic resonance imaging study of milk of magnesia laxative and an antiflatulent diet to reduce intrafraction prostate motion. AB - PURPOSE: To determine the reduction of prostate motion during a typical radiotherapy (RT) fraction from a bowel regimen comprising an antiflatulent diet and daily milk of magnesia. METHODS AND MATERIALS: Forty-two patients with T1c T2c prostate cancer voided the bladder and rectum before three cinematic magnetic resonance imaging scans obtained every 9 s for 9 min in a vacuum immobilization device. The MRIs were at baseline without bowel regimen (MRI-BL), before CT planning with bowel regimen (MRI-CT), and before a randomly assigned RT fraction (1-42) with bowel regimen (MRI-RT). A single observer tracked displacement of the posterior midpoint (PM) of the prostate. The primary endpoints were comparisons of the proportion of time that the PM was displaced >3 mm (PTPM3) from its initial position, and the secondary endpoints were comparisons of the reduction of initial rectal area, with and without the bowel regimen. RESULTS: The mean rectal area was: 13.5 cm(2) at MRI-BL, 12.7 cm(2) at MRI-CT, and 12.3 cm(2) at MRI-RT (MRI-BL vs. MRI-CT, p = 0.11; MRI-BL vs. MRI-CT, p = 0.07). Moving rectal gas alone (56%) and moving gas and stool (18%) caused 74% of intrafraction prostate motion. The PTPM3 was 11.3% at MRI-BL, 4.8% at MRI-CT, and 12.0% at MRI RT (MRI-BL vs. MRI-CT, p = 0.12; MRI-BL vs. MRI-RT, p = 0.89). CONCLUSION: For subjects voiding their rectum before imaging, an antiflatulent diet and milk of magnesia laxative did not significantly reduce initial rectal area or intrafraction prostate motion. PMID- 19783379 TI - Stereotactic body radiation therapy boost in locally advanced pancreatic cancer. AB - PURPOSE: To investigate the clinical application of a stereotactic body radiation therapy (SBRT) boost in locally advanced pancreatic cancer patients with a focus on local efficacy and toxicity. METHODS AND MATERIALS: We retrospectively reviewed 30 patients with locally advanced and nonmetastatic pancreatic cancer who had been treated between 2004 and 2006. Follow-up duration ranged from 4 to 41 months (median, 14.5 months). A total dose of 40 Gy was delivered in 20 fractions using a conventional three-field technique, and then a single fraction of 14, 15, 16, or 17 Gy SBRT was administered as a boost without a break. Twenty one patients received chemotherapy. Overall and local progression-free survival were calculated and prognostic factors were evaluated. RESULTS: One-year overall survival and local progression-free survival rates were 60.0% and 70.2%, respectively. One patient (3%) developed Grade 4 toxicity. Carbohydrate antigen 19-9 response was found to be an independent prognostic factor for survival. CONCLUSIONS: Our findings indicate that a SBRT boost provides a safe means of increasing radiation dose. Based on the results of this study, we recommend that a well controlled Phase II study be conducted on locally advanced pancreatic cancer. PMID- 19783381 TI - Introduction to College on Problems of Drug Dependence special conference on risk management and post-marketing surveillance of CNS drugs. PMID- 19783382 TI - Cannabis withdrawal severity and short-term course among cannabis-dependent adolescent and young adult inpatients. AB - OBJECTIVE: While previous studies questioned the existence of a cannabis withdrawal syndrome (CWS), recent research provided increasing evidence of a number of clinical symptoms after cessation of frequent cannabis consumption. The aim of this study is to prospectively assess the course of CWS in a sample of cannabis-dependent inpatients and to provide an estimate of the proportion of subjects experiencing CWS. METHODS: 118 subjects, aged 16-36 years, diagnosed with a cannabis dependence (DSM-IV, assessed by SCID I) were enrolled in the study. CWS was assessed prospectively over 10 days using a modified version of the Marijuana Withdrawal Checklist. Personality dimensions were assessed with the NEO-FFI. RESULTS: 73 subjects (61.3%) completed all assessments over the observation period. Most symptoms peaked on day 1. Model-based analyses revealed a high and low intensity CWS group. Less than half of the patients belonged to the high intensity craving, psychological, or physical withdrawal symptoms group. Symptom intensity decreased almost linearly over time. Indicators of cannabis consumption intensity as well as personality dimensions, but not recalled withdrawal were related to membership in the high intensity CWS group. DISCUSSION: A clinically relevant CWS may only be expected in a subgroup of cannabis-dependent patients. Most subjects with an elevated CWS experience physical and psychological symptoms. The small to negligible associations between recalled and prospectively assessed symptoms raise questions about the validity of the former approach. PMID- 19783380 TI - Evaluating and reporting dysphagia in trials of chemoirradiation for head-and neck cancer. AB - PURPOSE: Reporting long-term toxicities in trials of chemoirradiation (CRT) of head-and-neck cancer (HNC) has mostly been limited to observer-rated maximal Grades >or=3. We evaluated this reporting approach for dysphagia by assessing patient-reported dysphagia (PRD) and objective swallowing dysfunction through videofluoroscopy (VF) in patients with various grades of maximal observer reported dysphagia (ORD). METHODS AND MATERIALS: A total of 62 HNC patients completed quality-of-life questionnaires periodically through 12 months post-CRT. Five PRD items were selected: three dysphagia-specific questions, an Eating Domain, and "Overall Bother." They underwent VF at 3 and 12 months, and ORD (Common Terminology Criteria for Adverse Events) scoring every 2 months. We classified patients into four groups (0-3) according to maximal ORD scores documented 3-12 months post-CRT, and assessed PRD and VF summary scores in each group. RESULTS: Differences in ORD scores among the groups were considerable throughout the observation period. In contrast, PRD scores were similar between Groups 2 and 3, and variable in Group 1. VF scores were worse in Group 3 compared with 2 at 3 months but similar at 12 months. In Group 1, PRD and VF scores from 3 through 12 months were close to Groups 2 and 3 if ORD score 1 persisted, but were similar to Group 0 in patients whose ORD scores improved by 12 months. CONCLUSIONS: Patients with lower maximal ORD grades, especially if persistent, had similar rates of PRD and objective dysphagia as patients with highest grades. Lower ORD grades should therefore be reported. These findings may have implications for reporting additional toxicities besides dysphagia. PMID- 19783383 TI - Risk management and post-marketing surveillance for the abuse of medications acting on the central nervous system: expert panel report. AB - The abuse and diversion of medications is a significant public health problem. This paper is part of a supplemental issue of Drug and Alcohol Dependence focused on the development of risk management plans and post-marketing surveillance related to minimizing this problem. The issue is based on a conference that was held in October 2008. An Expert Panel was formed to provide a summary of the conclusions and recommendations that emerged from the meeting involving drug abuse experts, regulators and other government agencies, pharmaceutical companies and professional and other non-governmental organizations. This paper provides a written report of this Expert Panel. Eleven conclusions and 11 recommendations emerged concerning the state of the art of this field of research, the regulatory and public health implications and recommendations for future directions. It is concluded that special surveillance tools are needed to detect the emergence of medication abuse in a timely manner and that risk management tools can be implemented to increase the benefit to risk ratio. The scientific basis for both the surveillance and risk management tools is in its infancy, yet progress needs to be made. It is also important that the unintended consequences of increased regulation and the imposition of risk management plans be minimized. PMID- 19783384 TI - Test of association between GABRA2 (SNP rs279871) and adolescent conduct/alcohol use disorders utilizing a sample of clinic referred youth with serious substance and conduct problems, controls and available first degree relatives. AB - Recent findings have linked the GABRA2 gene with antisocial personality disorder and alcohol dependence (AD) in adults and conduct disorder (CD), but not AD symptoms, in children and adolescents. We sought to replicate previous findings and test for an association between a single nucleotide polymorphism (SNP) in the GABRA2 gene (rs279871) and CD among adolescents. METHODS: Adolescent patients (n=371), 13-18 years old, were recruited from a university substance abuse treatment program. Patient siblings (n=245), parents of patients (n=355), adolescent controls (n=185), siblings of controls (n=163) and parents of controls (n=263) were included in these analyses (total sample n=1582). Case-control (using only Caucasian and Hispanic probands) and family-based association tests were completed to test for association between rs279871 and several a priori CD and AD phenotypes. RESULTS: For case-control association tests, rs279871 was significantly associated with CD (p=0.02) but not AD phenotypes; the result did not survive strict correction for multiple testing. All family-based association tests were non-significant (CD p=0.48; CD symptom count age corrected within sex p=0.91; AD p=0.84; alcohol use disorder p=0.52). CONCLUSIONS: Consistent with previous findings, the results do not support the association between GABRA2 SNP rs279871 and AD in adolescents. Our results also do not support an association between rs279871 and CD; the study limitations are reviewed. PMID- 19783385 TI - Daily marijuana users with past alcohol problems increase alcohol consumption during marijuana abstinence. AB - Drug abuse treatment programs typically recommend complete abstinence because of a fear that clients who stop use of one drug will substitute another. A within subjects study investigated whether consumption of alcohol and other substances changes during marijuana abstinence. Twenty-eight daily marijuana users who were not trying to stop or reduce their marijuana consumption completed an 8-day baseline period in which they used marijuana and other drugs as usual, a 13-day marijuana abstinence period, and a 7-day return-to-baseline period. Participants provided self-report of substance use daily and submitted urine samples twice weekly to verify marijuana abstinence. A diagnosis of past alcohol abuse or dependence significantly moderated the alcohol increase from baseline to marijuana abstinence (p<0.01), such that individuals with this diagnosis significantly increased alcohol use (52% increase) but those without this history did not (3% increase). Increases in marijuana withdrawal discomfort scores and alcohol craving scores from baseline to marijuana abstinence significantly and positively correlated with increases in alcohol use. Increases in cigarettes, caffeine, and non-marijuana illicit drugs did not occur. This study provides empirical validation of drug substitution in a subgroup of daily marijuana users, but results need to be replicated in individuals who seek treatment for marijuana problems. PMID- 19783386 TI - Modafinil does not serve as a reinforcer in cocaine abusers. AB - The purpose of this double-blind, randomized, outpatient study was to evaluate the reinforcing and subjective effects of modafinil (200, 400, or 600 mg) in cocaine abusers. Twelve participants (2 female, 10 male) completed this study, consisting of 3 blocks of 7 sessions; each block tested a difference dose of modafinil. During the first 2 sessions of each block, participants "sampled" 1 of the doses of modafinil, and placebo. These doses of modafinil and placebo were available for the subsequent five choice sessions of the block. In each choice session, participants had an opportunity to administer active or placebo capsules. Modafinil administration did not differ from placebo administration, and subjective-effects ratings were not systematically altered as a function of modafinil dose. Results suggest that modafinil does not have abuse liability in cocaine abusers. PMID- 19783387 TI - Nursery care of the newborn with malformation syndrome. AB - Congenital malformations are not so rare, and represent a relevant challenge to health care providers. We delineate a methodology for the clinical approach to the malformed newborn, that takes into account the needs of the patient as single person and as part of a familiar and social context. We consider first the medical problem that the neonatologists face in the nursery and neonatal intensive care unit regarding clinical assistance, diagnosis, parent counselling and hospital discharge. Then we focus on the periodic follow-up, and the role of the primary care physician and the specialist in the assistance of this patients. PMID- 19783388 TI - Neonatal end-of-life decisions and bioethical perspectives. AB - In the nineties the EURONIC project documented the staff views and practices regarding ethical decision-making in neonatal intensive care units of eight Western Europe countries: France, Germany, Great Britain, Italy, Luxembourg, Netherlands, Spain and Sweden. This paper reviews the changes occurred in the ethical and legal background of these countries, and discusses possible influences on neonatal care practices. To a certain extent, many of these changes appear to be in line with the neonatal physicians' views and attitudes previously documented by the EURONIC project, while some are not. Large differences persist within Western Europe on what constitutes appropriate neonatal end-of-life care. PMID- 19783390 TI - Missense mutation of the sodium channel gene SCN2A causes Dravet syndrome. AB - Mutations of the gene encoding the alpha2 subunit of the neuronal sodium channel, SCN2A, have been found in benign familial neonatal-infantile seizures (BFNIS). In Dravet syndrome, only one nonsense mutation of SCN2A was identified, while hundreds of mutations were found in the paralogue gene, SCN1A, which encodes the alpha1 subunit. This study examines whether SCN2A mutations are associated with Dravet syndrome. We screened for mutations of SCN1A, SCN2A and GABRG2 (the gene encoding gamma2 subunit of the GABA(A) receptor) in 59 patients with Dravet syndrome and found 29 SCN1A mutations and three missense SCN2A mutations. Among the three, one de novo SCN2A mutation (c.3935G>C: R1312T) identified in a patient was thought to affect an arginine residue in a voltage sensor of the channel and hence, to be pathogenic. This finding suggests that both nonsense mutations and missense SCN2A mutations cause Dravet syndrome. PMID- 19783389 TI - Women and HIV infection: the makings of a midlife crisis. AB - With the advent of highly active antiretroviral agents, women with HIV infection can expect to live longer than ever before. This increased survival has led to concerns about the long-term implications of HIV disease and its treatment. Women with HIV infection appear to lose ovarian function earlier in life than women without HIV infection. They also have evidence of reduced bone mineral density and increased cardiovascular risk. Moreover, many of these increases in risk factors are present even prior to the menopausal transition. All of these risks, present at midlife, augur poorly for future health and describe a substantially increased burden of disease likely to accrue to HIV-infected women as they enter older age groups. Further compounding the adversity faced by the HIV infected, the demographics of women most vulnerable to this disease include adverse social and economic influences, both of which worsen their long-term prognosis. For example, drug use and poverty are related to more severe menopausal symptoms and chronic stress is related to worse psychological and cardiovascular risk. An understanding of how menopause interacts with HIV infection is therefore most important to alert the clinician to perform surveillance for common health problems in postmenopausal women, and to address directly and appropriately symptomatology during the menopausal transition. PMID- 19783391 TI - [Liposomal amphotericin B as treatment for visceral leishmaniasis in Europe, 2009]. AB - Visceral leishmaniasis (VL) causes an estimated 500,000 new cases of disease and more than 50,000 deaths a year. For more than 60 years, pentavalent antimonies were considered the standard therapy for VL. The emergence of Leishmania strains resistant to antimonials led to the evaluation of other treatments including amphotericin B and its lipidic derivatives. Clinical trials with liposomal amphotericin B demonstrated that total doses of 10 to 20mg/kg, administered according to various regimens, had a 90-98% efficacy in non-immunocompromised patients. Compared to antimonials, liposomal amphotericin B provides favorable efficacy/tolerance and cost efficacy ratios. The WHO recently produced consensus recommendations for the use of liposomal amphotericin B in VL. In Europe, liposomal amphotericin B has progressively become the reference treatment of VL in clinical practice, and it is recommended as the first line therapy. PMID- 19783392 TI - Changes in tumor vascularity precede microbubble contrast accumulation deficit in the process of dedifferentiation of hepatocellular carcinoma. AB - PURPOSE: To elucidate the changes in tumor vascularity and microbubble accumulation on contrast-enhanced sonograms, in relation to the dedifferentiation of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: This prospective study enrolled 10 patients with histologically proven HCC (14.4-39.0mm, 26.1+/-7.4) showing nodule-in-nodule appearance upon contrast-enhanced computed tomography. Contrast-enhanced ultrasound was performed by harmonic imaging under a low mechanical index (0.22-0.25) during the vascular phase (agent injection to 1 min) and late phase (15 min) following the injection of Sonazoid (0.0075 ml/kg). Contrast enhancement in the inner and outer nodules was assessed in comparison with that in adjacent liver parenchyma as hyper-, iso-, or hypo-enhanced. RESULTS: Vascular-phase enhancement of all 10 inner nodules was hyper-enhanced, and that of outer nodules was hyper-enhanced in 3, iso-enhanced in 2, and hypo enhanced in 5. Late-phase enhancement of inner nodules was hypo-enhanced in 8 and iso-enhanced in 2. Furthermore, late-phase enhancement of outer nodules was iso enhanced in the 7 lesions that showed iso- or hypo-enhancement in the vascular phase, and hypo-enhanced in the 3 with hyper-enhancement in the vascular phase. Late-phase hypo-enhancement was significantly more frequent in the nodules showing early-phase hyper-enhancement (11/13) than in the nodules showing early phase iso- or hypo-enhancement (0/7) in both the inner and outer nodules. CONCLUSION: Dedifferentiation of HCC may be accompanied by changes in tumor vascularity prior to a reduction in microbubble accumulation. Observation of the vascular phase may be more useful than late-phase imaging for the early recognition of HCC dedifferentiation when using contrast-enhanced ultrasound with Sonazoid. PMID- 19783393 TI - Role of radiologists in CAD life-cycle. AB - A modern CAD (computer-aided diagnosis) system development involves a multidisciplinary team whose members are experts in medical and technical fields. This study indicates the activities of medical experts at various stages of the CAD design, testing, and implementation. Those stages include a medical analysis of the diagnostic problem, data collection, image analysis, evaluation, and clinical verification. At each stage the physicians knowledge and experience are indispensable. The final implementation involves integration with the existing Picture Archiving and Communication System. The term CAD life-cycle describes an overall process of the design, testing, and implementation of a system that in its final form assists the radiologists in their daily clinical routine. Four CAD systems (applied to the bone age assessment, Multiple Sclerosis detection, lung nodule detection, and pneumothorax measurement) developed in our laboratory are given as examples of how consecutive stages are developed by the multidisciplinary team. Specific advantages of the CAD implementation that include the daily clinical routine as well as research and education activities are discussed. PMID- 19783394 TI - Planimetry of the aortic valve orifice area: comparison of multislice spiral computed tomography and magnetic resonance imaging. AB - OBJECTIVE: We sought to determine the comparability of multislice computed tomography (MSCT) and magnetic resonance imaging (MRI) for measuring the aortic valve orifice area (AVA) and grading aortic valve stenosis. MATERIALS AND METHODS: Twenty-seven individuals, among them 18 patients with valvular stenosis, underwent AVA planimetry by both MSCT and MRI. In the subset of patients with valvular stenosis, AVA was also calculated from transthoracic Doppler echocardiography (TTE) using the continuity equation. RESULTS: There was excellent correlation between MSCT and MRI (r = 0.99) and limits of agreement were in an acceptable range (+/- 0.42 cm(2)) although MSCT yielded a slightly smaller mean AVA than MRI (1.57 +/- 0.83 cm(2) vs. 1.67 +/- 0.98 cm(2), p < 0.05). However, in the subset of patients with valvular stenosis, the mean AVA was not different between MSCT and MRI (1.05 +/- 0.30 cm(2) vs. 1.04 +/- 0.39 cm(2); p > 0.05). The mean AVAs on both MSCT and MRI were systematically larger than on TTE (0.88 +/- 0.28 cm(2), p < 0.001 each). Using an AVA of 1.0 cm(2) on TTE as reference, the best threshold for detecting severe-to-critical stenosis on MSCT and MRI was an AVA of 1.25 cm(2) and 1.30 cm(2), respectively, resulting in an accuracy of 96% each. CONCLUSION: Our study specifies recent reports on the suitability of MSCT for quantifying AVA. The data presented here suggest that certain methodical discrepancies of AVA measurements exist between MSCT, MRI and TTE. However, MSCT and MRI have shown excellent correlation in AVA planimetry and similar accuracy in grading aortic valve stenosis. PMID- 19783395 TI - Prospective versus retrospective ECG gating for dual source CT of the coronary stent: comparison of image quality, accuracy, and radiation dose. AB - OBJECTIVE: To compare image quality, diagnostic accuracy and radiation dose of prospective and retrospective electrocardiogram (ECG) gated dual source computed tomography (DSCT) for the evaluation of the coronary stent, using conventional coronary angiography (CA) as a standard reference. DESIGN, SETTING AND PATIENTS: Sixty patients (heart rates <= 70 bpm) with previous stent implantation who were scheduled for CA were divided in two groups, receiving either prospective or retrospective ECG gated DSCT separately. Two reviewers scored coronary stent image quality and evaluated stent lumen. RESULTS: There was no significant difference in image quality between the two groups. In the prospective group, there were 86.4% (51/59) stents with interpretable images, in the retrospective group, there were 87.5% (49/56) stents with interpretable images. Image quality was not influenced by age, body mass index or heart rate in either group, but heart rate variability had a weak impact on the image quality of the prospective group. Image noise was higher in the prospective group, but this difference reached statistical significance only by using a smooth kernel reconstruction. Per-stent based sensitivity, specificity, and positive and negative predictive value were 100%, 84.1%, 68.2%, and 100%, respectively, in the prospective CT angiography group and 94.4%, 86.8%, 77.3%, and 97.1%, respectively, in the retrospective CT angiography group. There was a significant difference in the effective radiation dose between the two groups, mean effective dose in the prospective and retrospective group was 2.2 +/- 0.5 mSv (1.5-3.2 mSv) and 14.6 +/ 3.3 mSv (10.0-20.4 mSv) (p < .001) respectively. CONCLUSIONS: Compared with retrospective CT angiography, prospective CT angiography has a similar performance in assessing coronary stent patency, but a lower effective dose in selected patients with regular heart rates <= 70 bpm. PMID- 19783398 TI - The use of morphine to treat cancer-related pain: a synthesis of quantitative and qualitative research. AB - Morphine is the most commonly used opioid for severe cancer-related pain. Despite its established effectiveness, it is often used cautiously in clinical practice, particularly outside specialist palliative care. This review identifies the key social, contextual, and physical concerns held by patients, carers, and health care professionals when using morphine, which might explain the caution taken in its use. The review used an approach called critical interpretive synthesis (CIS), which combines conventional systematic review techniques with methods for interpretative synthesis of qualitative research. An existing review examining the effectiveness of morphine and a guideline on its use were synthesized with 19 qualitative articles to establish understanding of how context of use can affect the established effectiveness of morphine. The article argues for the appropriateness of CIS for answering questions of this type. The results demonstrate that using morphine is a balancing act and a trade-off between pain relief and adverse effects. Deep-seated concerns regarding the symbolism of morphine, addiction, and tolerance are held by patients, carers, and clinicians, which influence prescription and use. Cancer pain is a referent for disease status and has existential meaning, with the introduction of morphine becoming a metaphor for impending death. Cancer pain is intersubjective, with its perception and reporting influenced by those with whom the patient interacts. By understanding the context and social meaning surrounding the use of morphine to treat cancer pain, health care professionals can begin to anticipate, acknowledge, and address some of the barriers to its use, thereby enhancing pain control. PMID- 19783397 TI - Morphine inhalation by cancer patients: a comparison of different nebulization techniques using pharmacokinetic, spirometric, and gasometric parameters. AB - Despite numerous case reports suggesting the value of morphine (M) nebulization in the treatment of breathlessness, only a few clinical trials have been able to support this. The reason for this could lie in the lack of understanding of the localization of opioid receptors in the airways and the biopharmaceutics and pharmacokinetics of nebulized morphine. In the present study, we compared two different methods of pneumodosimetric nebulization: the Bronchial Control Treatment System-Sidestream (BCTS-S) and the Bronchial Control Treatment System Micro Cirrus (BCTS-MC). The first method delivers relatively large aerosol particles (2-5microm) preferentially to the bronchial tree and trachea. In the BCTS-MC method, small aerosol particles (0.5-2microm) mostly reach the alveoli. Ten patients with cancer were randomly assigned to either the BCTS-S or BCTS-MC inhalation of 5 mg morphine HCl. Patients using the BCTS-S method inhaled a morphine dose in 6.6+/-2 minutes, whereas with the BCTS-MC method, the inhalation time was 28.8+/-8 minutes. The areas under the curve of morphine and glucuronides were several times higher after BCTS-S than after BCTS-MC. The proportion of morphine-3-glucuronide to morphine-6-glucuronide (M6) was, on average, close to one for both methods. From the same amount of morphine in the BCTS-S method, five times more M6 was produced. In both methods, the time to maximum concentration for morphine metabolites was 20-40 minutes, much shorter than expected from oral, intranasal, or intravenous administration. The study shows that the method of inhalation may have a profound effect on the pharmacokinetics of morphine. It is possible that the lungs metabolize morphine to glucuronides themselves and in different proportions from those seen after systemic administration. The BCTS-S method was found to be potentially superior to the BCTS-MC method in local action in the lungs. PMID- 19783399 TI - Advancing palliative care as a human right. AB - The international palliative care community has articulated a simple but challenging proposition that palliative care is an international human right. International human rights covenants and the discipline of palliative care have, as common themes, the inherent dignity of the individual and the principles of universality and nondiscrimination. However, when we consider the evidence for the effectiveness of palliative care, the lack of palliative care provision for those who may benefit from it is of grave concern. Three disciplines (palliative care, public health, and human rights) are now interacting with a growing resonance. The maturing of palliative care as a clinical specialty and academic discipline has coincided with the development of a public health approach to global and community-wide health problems. The care of the dying is a public health issue. Given that death is both inevitable and universal, the care of people with life-limiting illness stands equal to all other public health issues. The International Covenant on Economic, Social and Cultural Rights (ICESCR) includes the right to health care and General Comment 14 (paragraph 34) CESCR stipulates that "States are under the obligation to respect the right to health by, inter alia, refraining from denying or limiting equal access for all persons, ... to preventive, curative and palliative health services." However, these rights are seen to be aspirational-rights to be achieved progressively over time by each signatory nation to the maximum capacity of their available resources. Although a government may use insufficient resources as a justification for inadequacies of its response to palliative care and pain management, General Comment 14 set out "core obligations" and "obligations of comparable priority" in the provision of health care and placed the burden on governments to justify "that every effort has nevertheless been made to use all available resources at its disposal in order to satisfy, as a matter of priority, [these] obligations." This article describes recent advocacy activities and explores practical strategies for the palliative care community to use within a human rights framework to advance palliative care development worldwide. PMID- 19783400 TI - Improving availability of and access to opioids in Colombia: description and preliminary results of an action plan for the country. AB - Latin America consumes less than 2.7% of the morphine in the world, as reported by the governments to the International Narcotics Control Board. Methods to improve access to opioids for the treatment of pain have been developed by the Pain & Policy Studies Group (PPSG), a World Health Organization Collaborating Center at the University of Wisconsin. This article describes the preparation and implementation of an action plan in Colombia as a part of an international fellowship program on opioid policy developed by the PPSG and funded by the Open Society Institute. The action plan for Colombia included three steps: 1) a survey of regulators and health care providers to identify the current situation and their perceptions of opioid availability in the regions of the country; 2) a workshop with representatives of the Ministry of Health, the national and state competent authorities, pain and palliative care physicians, and international leaders; and 3) implementation workshops at the local level throughout the country. For the survey, response rates of 47% and 96% were registered among physicians and competent authorities, respectively. The survey identified significant regional differences in perceived opioid availability between physicians and regulators. Focus group discussions during the workshop identified several reasons leading to limited availability of opioids in the country, including deficiencies in the procurement process, insufficient human resources, excessive bureaucratic tasks, insufficient number of pharmacies authorized to dispense controlled medications in the country, lack of training in the health care professions, and overly restrictive laws and regulations governing opioid availability. The third step of the action plan has not been implemented. Additional and continuous monitoring needs to be implemented to measure the progress of this project. PMID- 19783401 TI - Mental health outcomes of family members of Oregonians who request physician aid in dying. AB - Oregon legalized physician aid in dying over 10 years ago but little is known about the effects of this choice on family members' mental health. We surveyed 95 family members of decedent Oregonians who had explicitly requested aid in dying, including 59 whose loved one received a lethal prescription and 36 whose loved one died by lethal ingestion. For comparison purposes, family members of Oregonians who died of cancer or amyotrophic lateral sclerosis also were surveyed. A mean of 14 months after death, 11% of family members whose loved one requested aid in dying had major depressive disorder, 2% had prolonged grief, and 38% had received mental health care. Among those whose family member requested aid in dying, whether or not the patient accessed a lethal prescription had no influence on subsequent depression, grief, or mental health services use; however, family members of Oregonians who received a lethal prescription were more likely to believe that their loved one's choices were honored and less likely to have regrets about how the loved one died. Comparing family members of those who requested aid in dying to those who did not revealed no differences in primary mental health outcomes of depression, grief, or mental health services use. Family members of Oregonians who requested aid in dying felt more prepared and accepting of the death than comparison family members. In summary, pursuit of aid in dying does not have negative effects on surviving family members and may be associated with greater preparation and acceptance of death. PMID- 19783402 TI - To spike or not to spike: a probabilistic spiking neuron model. AB - Spiking neural networks (SNN) are promising artificial neural network (ANN) models as they utilise information representation as trains of spikes, that adds new dimensions of time, frequency and phase to the structure and the functionality of ANN. The current SNN models though are deterministic, that restricts their applications for large scale engineering and cognitive modelling of stochastic processes. This paper proposes a novel probabilistic spiking neuron model (pSNM) and suggests ways of building pSNN for a wide range of applications including classification, string pattern recognition and associative memory. It also extends previously published computational neurogenetic models. PMID- 19783403 TI - Neocognitron and the Map Transformation Cascade. AB - Based on our observations of the working principles of the archetypal hierarchical neural network, Neocognitron, we propose a simplified model which we call the Map Transformation Cascade. The least complex Map Transformation Cascade can be understood as a sequence of filters, which maps and transforms the input pattern into a space where patterns in the same class are close. The output of the filters is then passed to a simple classifier, which yields a classification for the input pattern. Instead of a specifically crafted learning algorithm, the Map Transformation Cascade separates two different learning needs: Information reduction, where a clustering algorithm is more suitable (e.g., K-Means) and classification, where a supervised classifier is more suitable (e.g., nearest neighbor method). The performance of the proposed model is analyzed in handwriting recognition. The Map Transformation Cascade achieved performance similar to that of Neocognitron. PMID- 19783404 TI - Epilepsy associated with supratentorial brain tumors under 3 years of life. AB - OBJECTIVE: To investigate the clinical features and outcome of epilepsy in children under 3 years of age with supratentorial brain tumors. METHODS: Patients under 3 years with primary supratentorial hemispheric brain tumors were collected during a 10-year period through a database including demographic and clinical features, neuroimaging, tumor location, developmental outcome, pharmacological and surgical treatment, and tumor histology. Postoperative outcome was assessed according to Engel classification. RESULTS: Among 28 children evaluated, twenty (71.4%) suffered from epilepsy. Mean age at seizure onset was 18.7 months (range: 1-60). In fifteen (75%) children, epilepsy was an early manifestation or the presenting symptom of the tumor; seizures were focal in 8 (53.3%) and generalized in 7 (46.7%) individuals. Three (15%) children presented with an epileptic encephalopathy and continuous spike-waves during sleep. Of the five children with epilepsy onset after surgery, four had focal seizures. Post-surgical follow-up ranged from 4 to 10 years (mean: 7.6+/-3.74). The outcome of epilepsy was generally good, with most children (76.4%) being seizure free (Engel I) or showing >90% improvement in seizure frequency (Engel II) after surgery. However, in about 20% of the cases, epilepsy persisted despite surgery and different AEDs regimen. Best epilepsy outcome was observed in patients with low-grade tumors (p<0.01) and without neurological deficits after surgery (p<0.001). CONCLUSIONS: Epilepsy is a common and early symptom in infants with brain tumors. Its outcome is negatively influenced by high tumor malignancy and by the persistence of neurological deficits after surgery. Treatment of these patients needs a multidisciplinary approach. PMID- 19783405 TI - Prevalence and correlates of school drop-out prior to initial treatment of nonaffective psychosis: further evidence suggesting a need for supported education. AB - BACKGROUND: Because dropping out of high school (i.e., secondary education) contributes prominently to numerous social, economic, and health conditions, formal public health initiatives promoting population health and social justice, especially in at-risk populations, are increasingly encouraged to address high school drop-out. The relative dearth of research attention on school drop-out prior to first treatment contact in young adults with psychotic disorders indicates a need for investigation of the associations between school drop-out and illness-related variables so that interventions may be tailored appropriately to this unique population. METHODS: This study provides a descriptive characterization of the prevalence and correlates of high school drop-out in a sample of 109 patients hospitalized for the evaluation and treatment of a first episode of nonaffective psychosis. RESULTS: Findings from this urban, socially disadvantaged, predominantly African American sample indicate that school drop out is a marker of diverse detrimental social problems in first-episode psychosis, and that further research is required to fully characterize the most appropriate interventions for such individuals. CONCLUSIONS: Future research might seek to intervene through an integrated treatment approach that incorporates supported education, symptom reduction and management, and comorbid substance use treatment in first-episode patients. PMID- 19783406 TI - Auditory gating deficit to human voices in schizophrenia: a MEG study. AB - BACKGROUND: Patients with schizophrenia have auditory gating deficits; however, little is known about P50 auditory gating to human voices and its association with clinical symptoms. We examined the functioning of auditory gating and its relationship with the clinical symptoms in schizophrenia. METHODS: Auditory evoked magnetoencephalography responses to the first and the second voices stimuli were recorded in 22 schizophrenia patients and 28 normal control subjects. The auditory gating ratios of P50m and N100m were investigated and P50m symptom correlations were also investigated. RESULTS: Patients showed significantly higher P50m gating ratios to human voices specifically in the left hemisphere. Moreover, patients with higher left P50m gating ratios showed more severe auditory hallucinations, while patients with higher right P50m gating ratios showed more severe negative symptoms. CONCLUSIONS: The present study suggests that schizophrenia patients have auditory gating deficits to human voices, specifically in the left hemisphere and auditory hallucinations of schizophrenia may be associated with sensory overload to human voices in the auditory cortex. PMID- 19783407 TI - Motivation and its relationship to neurocognition, social cognition, and functional outcome in schizophrenia. AB - OBJECTIVE: A burgeoning area of research has focused on motivational deficits in schizophrenia, producing hypotheses about the role that motivation plays in the well-known relationship between neurocognition and functional outcome. However, little work has examined the role of motivation in more complex models of outcome that include social cognition, despite our increased understanding of the critical role of social cognition in community functioning in schizophrenia, and despite new basic science findings on the association between social cognitive and reward processing in neural systems in humans. Using path analysis, we directly contrasted whether motivation 1) causally influences known social cognitive deficits in schizophrenia, leading to poor outcome or 2) mediates the relationship between social cognitive deficits and outcome in this illness. METHOD: Ninety one patients with schizophrenia or schizoaffective disorder completed interview-based measures of motivation and functional outcome as well as standardized measures of neurocognition and social cognition in a cross sectional design. RESULTS: In line with recent research, motivation appears to mediate the relationship between neurocognition, social cognition and functional outcome. A model with motivation as a causal factor resulted in poor fit indicating that motivation does not appear to precede neurocognition. CONCLUSIONS: Findings in the present study indicate that motivation plays a significant and mediating role between neurocognition, social cognition, and functional outcome. Potential psychosocial treatment implications are discussed, especially those that emphasize social cognitive and motivational enhancement. PMID- 19783408 TI - Isolation, identification and susceptibility of Pyrenochaeta romeroi in a case of eumycetoma of the foot in the UK. PMID- 19783409 TI - Functional brain imaging in 14 patients with dissociative amnesia reveals right inferolateral prefrontal hypometabolism. AB - Dissociative amnesia is a condition usually characterized by severely impaired retrograde memory functioning in the absence of structural brain damage. Recent case studies nevertheless found functional brain changes in patients suffering from autobiographical-episodic memory loss in the cause of dissociative amnesia. Functional changes were demonstrated in both resting state and memory retrieval conditions. In addition, some but not all cases also showed other neuropsychological impairments beyond retrograde memory deficits. However, there is no group study available that examined potential functional brain abnormalities and accompanying neuropsychological deteriorations in larger samples of patients with dissociative retrograde amnesia. We report functional imaging and neuropsychological data acquired in 14 patients with dissociative amnesia following stressful or traumatic events. All patients suffered from autobiographical memory loss. In addition, approximately half of the patients had deficits in anterograde memory and executive functioning. Accompanying functional brain changes were measured by [18F]fluorodeoxyglucose positron emission tomography (FDG-PET). Regional glucose utilization of the patients was compared with that of 19 healthy subjects, matched for age and gender. We found significantly decreased glucose utilization in the right inferolateral prefrontal cortex in the patients. Hypometabolism in this brain region, known to be involved in retrieval of autobiographical memories and self-referential processing, may be a functional brain correlate of dissociative amnesia. PMID- 19783410 TI - Retrosplenial cortex connectivity in schizophrenia. AB - In this paper, we build on our previous analysis [Bluhm, R.L., Miller, J., Lanius, R.A., Osuch, E.A., Boksman, K., Neufeld, R.W.J., et al., 2007 Spontaneous low-frequency fluctuations in the BOLD signal in schizophrenic patients: anomalies in the default network. Schizophrenia Bulletin 33, 1004-1012] of resting state connectivity in schizophrenia by examining alterations in connectivity of the retrosplenial cortex. We have previously demonstrated altered connectivity of the posterior cingulate/precuneus, particularly with other regions of the "default network" (which includes the medial prefrontal cortex and bilateral lateral parietal cortex). It was hypothesized that the retrosplenial cortex would show aberrant patterns of connectivity with regions of the default network and regions associated with memory. Patients with schizophrenia (N=17) and healthy controls (N=17) underwent a 5.5-min resting functional magnetic resonance imaging scan. Lower correlations were observed in patients with schizophrenia than in healthy controls between the retrosplenial cortex and both the temporal lobe and regions of the default network. In patients with schizophrenia, activity in the retrosplenial cortex correlated negatively with activity in bilateral anterior cingulate gyrus/medial prefrontal cortex (BA 32/10), despite the fact that these regions, as part of the default network, were expected to show positive correlations in activity. Connectivity of the retrosplenial cortex was greater in patients with more positive symptoms with areas previously associated with hallucinations, particularly the left superior temporal gyrus. These results suggest that spontaneous activity in the retrosplenial cortex during rest is altered in patients with schizophrenia. These alterations may help to explain alterations in self-oriented processing in this patient population. PMID- 19783412 TI - Test-retest reliability of event-related functional MRI in a probabilistic reversal learning task. AB - Repeated functional magnetic resonance imaging (fMRI) studies aim to detect changes in brain activity over time, e.g. to analyze the cerebral correlates of therapeutic interventions. This approach requires a high test-retest reliability of the measures used to rule out incidental findings. However, reliability studies, especially for cognitive tasks, are still difficult to find in the literature. In this study, 10 healthy adult subjects were scanned in two sessions, 16 weeks apart, while performing a probabilistic reversal learning task known to activate orbitofrontal-striatal circuitry. We quantified the reliability of brain activation by computing intra-class correlation coefficients. Group analysis revealed a high concordance for activation patterns in both measurements. Intra-class correlation coefficients (ICCs) were high for brain activation in the associated regions (dorsolateral prefrontal, anterior prefrontal/insular and cingulate cortices), often exceeding 0.8. We conclude that the probabilistic reversal learning task has a high test-retest reliability, making it suitable as a tool for evaluating the dynamics of deterioration in orbitofrontal-striatal circuitry, e.g. to illustrate the course of a psychiatric disorder. PMID- 19783413 TI - Measuring the force of single protein molecule detachment from surfaces with AFM. AB - Atomic force microscopy (AFM) was used to measure the non-specific detachment force of single fibrinogen molecules from glass surfaces. The identification of single unbinding events was based on the characteristics of the parabolic curves, recorded during the stretching of protein molecules. Fibrinogen molecules were covalently bound to Si(3)N(4) AFM tips, previously modified with 3-aminopropyl dimethyl-ethoxysilane, through a homobifunctional poly(ethylene glycol) linker bearing two hydroxysulfosuccinimide esters. The most probable detachment force was found to be 210 pN, when the tip was retracting with a velocity of 1400 nm/s, while the distribution of the detachment distances indicated that the fibrinogen chain can be elongated beyond the length of the physical conformation before detachment. The dependence of the most probable detachment force on the loading rate was examined and the dynamics of fibrinogen binding to the surface were found amenable to the simple expression of the Bell-Evans theory. The theory's expansion, however, by incorporating the concept of the rupture of parallel residue-surface bonds could only describe the detachment of fibrinogen for a small number of such bonds. Finally, the mathematical expression of the Worm-Like Chain model was used to fit the stretching curves before rupture and two interpretations are suggested for the description of the AFM curves with multiple detachment events. PMID- 19783414 TI - Blue orange light emission from biogenic synthesized silver nanoparticles using Trichoderma viride. AB - Recent advances in nanomaterial have produced a new class of fluorescence labels by conjugating noble metal with biomolecules. The nanometer size metal conjugates are water soluble, biocompatible and provide important advantage over the fluorescence dyes. In this regard we synthesized silver nanoparticles at the size of 2-4 nm using biological route and studied fluorescence property of these nanoparticles. We observe that these silver (Ag(+)) ions when exposed to filtrate of Trichoderma viride are reduced in solution, thereby leading to the formation of an extremely stable silver hydrosol. These silver nanoparticles were characterized by means of UV-vis spectrophotometer, FTIR, HrTEM, EDX, XRD and fluorescence spectroscopy. The nanoparticles exhibit maximum absorbance at 405 nm in UV-vis spectrum. The presence of proteins was identified by FTIR. The HrTEM micrograph revealed the formation of monodispersed spherical nanoparticles and the presence of elemental silver was confirmed by EDX analysis and XRD. These monodispersed silver nanoparticles showed emission in the range of 320-520 nm wavelength. PMID- 19783411 TI - Aberrant high-frequency desynchronization of cerebellar cortices in early-onset psychosis. AB - Sensorimotor integration deficits are routinely observed in both schizophreniform and mood-disordered psychoses. Neurobiological theories of schizophrenia and related psychoses have proposed that aberrations in large-scale cortico-thalamic cerebellar-thalamic-cortical loops may underlie integration abnormalities, and that such dysfunctional connectivity may be central to the pathophysiology. In this study, we utilized a basic mechanoreception task to probe cortical cerebellar circuitry in early-onset psychosis. Ten adolescents with psychosis and 10 controls completed unilateral tactile stimulation of the right and left index finger, as whole-head magnetoencephalography (MEG) data were acquired. MEG data were imaged in the frequency domain, using spatial filtering, and the resulting event-related synchronizations and desynchronizations (ERS/ERD) were subjected to voxel-wise analyses of group and task effects using statistical parametric mapping. Our results indicated bilateral ERD activation of cerebellar regions and postcentral gyri in both groups during stimulation of either hand. Interestingly, during left finger stimulations, adolescents with psychosis exhibited greater alpha and gamma ERD activity in right cerebellar cortices relative to controls. Subjects with psychosis also showed greater ERD in bilateral cerebellum and the right postcentral gyrus during right finger stimulation, and these differences were statistically stronger for higher frequency bins. Lastly, controls exhibited greater alpha ERS of the right postcentral gyrus during right finger stimulation. These findings provide new data on the neurodevelopmental trajectory of basic mechanoreception in adolescents, and also indicate aberrant cerebellar functioning in early-onset psychoses, especially in the right cerebellum, which may be the crucial dysfunctional node in cortico-thalamic-cerebellar-thalamic cortical circuits. PMID- 19783415 TI - Optimising the timing of surgery using serial magnetic resonance imaging after long-course chemoradiotherapy for locally advanced rectal cancer. PMID- 19783416 TI - Pattern of relapse after fractionated external beam radiotherapy for meningioma: experience from Addenbrooke's Hospital. AB - AIMS: Radiotherapy is an important treatment modality for meningioma. We aimed to review the clinical outcomes for meningioma patients treated with radiotherapy in the Addenbrooke's Hospital Oncology Department. MATERIALS AND METHODS: A retrospective chart review was carried out on patients with meningioma referred and treated in the department between 1 November 1996 and 31 October 2006. Patient details and outcomes were recorded and the results were analysed to assess survival outcomes. Survival data were confirmed by the Eastern Cancer Registration and Information Centre. RESULTS: In total, 174 patients were referred to the department for an oncology opinion. Of these, 128 proceeded to radiotherapy. The median follow-up was 5.3 years (range 2.1-11.9 years). Sixty seven per cent of the patients were older than 50 years, and the female: male ratio was 2.2: 1. Overall survival was 78% at the time of follow-up, with death related to meningioma in 7% of the total cohort. Local control was 85% overall, 93% for grade 1 disease, 45% for grade 2 disease and 82% for grade 3 disease. Patients with non-benign disease were more likely to receive >50Gy (27% of grade 1 lesions vs 65% of grade 2/3 lesions), but despite this local control remained poor, even with the higher dose delivered (local control 60 and 40% for grade 2 lesions treated with 50 and >50Gy, respectively, and 100 and 75% for grade 3 lesions treated with 50 and >50Gy, respectively). CONCLUSIONS: Our cohort of patients had an overall local control and survival similar to those documented from other departments. Grade was an important prognostic factor. Patients treated with >50Gy had worse local control outcomes, probably due to selection bias. Dose escalation may still be appropriate for high-risk disease, and may be more effective with more conformal techniques, such as intensity-modulated radiotherapy. PMID- 19783417 TI - Structure and function of dendritic spines within the hippocampus. AB - Most excitatory input in the hippocampus impinges on dendritic spines. Therefore, the dendritic spines are likely to be of major importance for neural processing. The morphology of dendritic spines is very diverse and changes in spine size as well as in their density are thought to reflect changes in the strength of synaptic transmission. Thus, alterations in dendritic spine densities or shape are suspected to be morphological manifestations of psychopathological, pathophysiological, physiological and/or behavioural changes. However, in spite of a long history of research, the specific function of dendritic spines within the hippocampal formation is still not well understood. This review will shed light on the hippocampal dendritic spines, their ultrastructure and morphology, as well as their supposed roles in neuronal plasticity and in certain mental illnesses. PMID- 19783418 TI - Dynamic regulation of Notch signaling in neural progenitor cells. AB - In the developing nervous system, differentiating neurons express Delta and activate Notch signaling in their neighboring cells. As a result of Notch activation, neuronal differentiation is inhibited in neighboring cells and they remain neural progenitor cells. Thus, differentiation of neurons and maintenance of neural progenitor cells are well balanced owing to Notch signaling. Recent studies revealed that Notch signaling is under the control of more complex and dynamic regulation than previously thought, such as cell cycle dependent activation and oscillating gene expression. We discuss here recent advances in understanding how Notch signaling is regulated in the developing nervous system and what outcome each type of regulation of Notch signaling leads to. We highlight the role of Notch signaling in proliferation and differentiation of neural progenitor cells. PMID- 19783419 TI - Fate and effect of linuron and metribuzin on the co-composting of green waste and sewage sludge. AB - The fate and effect of the herbicides linuron and metribuzin on the co-composting of sewage sludge and green waste were addressed in this work. The experiments were conducted in metal cubic containers of 1.0m(3) volume simulating a windrow composting system. A mixture of sludge and green waste was prepared at a ratio of 1:5 v/v. The mixture was split in four equal parts and the two herbicides were added, using a pressure sprayer, as sole or mixed pollutant in each of the three mixtures. The forth mixture was composted without any addition of herbicide, to serve as control. Temperature, physicochemical characteristics, herbicide concentration, carbon dioxide emission, methane emission and microbiological parameters were measured either daily or every time the mixtures were turned, for a period of 80 days. Both herbicides' concentration decreased significantly resulting in removal efficiencies of 99.1-99.7% and 95.8-96.0% for linuron and metribuzin, respectively. Incubation of microbiologically inactive mixtures at a temperature schedule following the spontaneous temperature evolution in the composters resulted in very little (1-11%) decomposition for both herbicides. Comparison of the variation of physicochemical parameters and microbial populations during composting indicated that both herbicides did not affect the composting process. PMID- 19783420 TI - Early detection and evaluation of waste through sensorized containers for a collection monitoring application. AB - The present study describes a novel application for use in the monitoring of municipal solid waste, based on distributed sensor technology and geographical information systems. Original field testing and evaluation of the application were carried out in Pudong, Shanghai (PR China). The local waste management system in Pudong features particular requirements related to the rapidly increasing rate of waste production. In view of the fact that collected waste is currently deployed to landfills or to incineration plants within the context investigated, the key aspects to be taken into account in waste collection procedures include monitoring of the overall amount of waste produced, quantitative measurement of the waste present at each collection point and identification of classes of material present in the collected waste. The case study described herein focuses particularly on the above mentioned aspects, proposing the implementation of a network of sensorized waste containers linked to a data management system. Containers used were equipped with a set of sensors mounted onto standard waste bins. The design, implementation and validation procedures applied are subsequently described. The main aim to be achieved by data collection and evaluation was to provide for feasibility analysis of the final device. Data pertaining to the content of waste containers, sampled and processed by means of devices validated on two purpose-designed prototypes, were therefore uploaded to a central monitoring server using GPRS connection. The data monitoring and management modules are integrated into an existing application used by local municipal authorities. A field test campaign was performed in the Pudong area. The system was evaluated in terms of real data flow from the network nodes (containers) as well as in terms of optimization functions, such as collection vehicle routing and scheduling. The most important outcomes obtained were related to calculations of waste weight and volume. The latter data were subsequently used as parameters for the routing optimization of collection trucks and material density evaluation. PMID- 19783421 TI - Climate balance of biogas upgrading systems. AB - One of the numerous applications of renewable energy is represented by the use of upgraded biogas where needed by feeding into the gas grid. The aim of the present study was to identify an upgrading scenario featuring minimum overall GHG emissions. The study was based on a life-cycle approach taking into account also GHG emissions resulting from plant cultivation to the process of energy conversion. For anaerobic digestion two substrates have been taken into account: (1) agricultural resources and (2) municipal organic waste. The study provides results for four different upgrading technologies including the BABIU (Bottom Ash for Biogas Upgrading) method. As the transport of bottom ash is a critical factor implicated in the BABIU-method, different transport distances and means of conveyance (lorry, train) have been considered. Furthermore, aspects including biogas compression and energy conversion in a combined heat and power plant were assessed. GHG emissions from a conventional energy supply system (natural gas) have been estimated as reference scenario. The main findings obtained underlined how the overall reduction of GHG emissions may be rather limited, for example for an agricultural context in which PSA-scenarios emit only 10% less greenhouse gases than the reference scenario. The BABIU-method constitutes an efficient upgrading method capable of attaining a high reduction of GHG emission by sequestration of CO(2). PMID- 19783422 TI - Selective immobilization of oligonucleotide-modified gold nanoparticles by electrodeposition on screen-printed electrodes. AB - Here, we describe a proof of concept procedure for the selective immobilization of oligonucleotides functionalized gold nanoparticle probes (affinity modules) on arrayed screen-printed gold electrodes. Current microarrays are using many different ways to address their DNA probes onto the transducer area. For that reason, we have mixed the electrodeposition of metals, which is a very well known process, in addition with the DNA-gold nanoparticles formation, which is an area of great interest in biosensing applications in the field of genomics, clinical and warfare applications. Combining these fields, we have developed a novel method for the immobilization of gold nanoparticles conjugated with oligonucleotides (affinity modules) onto screenprinting gold electrodes through electrodeposition at a current positive potential of 800mV vs. Ag/AgCl. The modules were selectively immobilized onto the electrode surface being, afterwards, ready for a successful hybridization. The gold colloids take the advantage of being a carrier that allows the immobilization of any kind of bioreceptor in the same conditions and the capability of quality control analysis before the electrodeposition procedure. With this system, we avoided non-specific interactions between the transduction layer and the bioreceptor and in the case of DNA oligonucleotides allowed us the immobilization of multiple sequences in a multimodular device for a further industrial process of cheaper biochip fabrication. PMID- 19783423 TI - A third-generation hydrogen peroxide biosensor based on horseradish peroxidase immobilized on DNA functionalized carbon nanotubes. AB - In this paper, DNA functionalized SWCNTs were used to immobilize horseradish peroxidase (HRP) on glassy carbon (GC) electrode. Cyclic voltammetry showed that the direct electrochemistry of HRP immobilized on DNA-SWCNTs hybrids was achieved. The DNA interlayer between the SWCNTs and HRP could be used to keep the activity of HRP. Compared with HRP-SWCNTs/GC and HRP-DNA/GC electrodes, the prepared HRP-DNA-SWCNTs/GC electrode exhibited more excellent electrochemical properties. Thus, the prepared HRP-DNA-SWCNTs/GC electrode was proposed as a third-generation H(2)O(2) biosensor. The effect of pH and applied potential on the performance of the biosensor was discussed in detail. Under the optimal conditions, a wide linear range of the propose biosensor for the detection of H(2)O(2) was observed from 6.0x10(-7) to 1.8 x10(-3)M. The detection limit was found to be 3.0 x10(-7)M at a signal-to-noise ratio of 3. Furthermore, the proposed biosensor displayed rapid response, high stability, very good reproducibility and high sensitivity for the detection of H(2)O(2). Determination H(2)O(2) concentration in disinfector sample by the proposed biosensor also showed satisfactory result. PMID- 19783424 TI - Optimizing mesenchymal stem cell-based therapeutics. AB - Mesenchymal stem cell (MSC)-based therapeutics are showing significant benefit in multiple clinical trials conducted by both academic and commercial organizations, but obstacles remain for their large-scale commercial implementation. Recent studies have attempted to optimize MSC-based therapeutics by either enhancing their potency or increasing their delivery to target tissues. Overexpression of trophic factors or in vitro exposure to potency-enhancing factors are two approaches that are demonstrating success in preclinical animal models. Delivery enhancement strategies involving tissue-specific cytokine pathways or binding sites are also showing promise. Each of these strategies has its own set of distinct advantages and disadvantages when viewed with a mindset of ultimate commercialization and clinical utility. PMID- 19783425 TI - Single DNA/protein studies with magnetic traps. AB - Magnetic traps provide a simple technique to pull and twist a variety of biomolecules and monitor the resulting change in extension. They have been used with great success to investigate the interaction of stretched and supercoiled DNA and DNA fibers (e.g. chromatin) with a great variety of enzymes. In this small review we will address their recent use in the study of topoisomerases, gyrase, DNA translocases and various structural proteins. PMID- 19783426 TI - Immediate surgical resection of residual microcalcifications after a diagnosis of pure flat epithelial atypia on core biopsy: a word of caution. AB - The entity of pure flat epithelial atypia remains a challenge due to controversy of the surgical management of residual microcalcifications after core needle biopsies. This study aims to assess the morphological data observed in immediate surgical resection specimen of residual microcalcifications after a diagnosis of pure flat epithelial atypia on mammotome core biopsy. Sixty-two mammotome core biopsy with a diagnosis of pure flat epithelial atypia (flat epithelial atypia without associated atypical ductal hyperplasia, in situ and/or invasive carcinoma) were identified. From these 62 cases, 20 presented residual microcalcifications and underwent an immediate surgical excision after mammotome. Of the 20 patients with excised microcalcifications, 8 (40%)cases had residual pure flat epithelial atypia, 4 (20%) cases had atypical ductal hyperplasia, 4 (20%) cases had lobular in situ neoplasia, no lesions were retrieved in 4 (20%) case. None of the patients had either in situ ductal carcinoma and/or invasive carcinoma. Surgical resection of residual microcalcifications after the diagnosis of pure flat epithelial atypia on core needle biopsy remains still a debate. The present study shows no cases of in situ ductal and/or invasive carcinoma on immediate excision of residual microcalcifications after mammotome core biopsies. PMID- 19783427 TI - Removal of pharmaceuticals in microcosm constructed wetlands using Typha spp. and LECA. AB - Microcosm constructed wetlands systems established with a matrix of light expanded clay aggregates (LECA) and planted with Typha spp. were used to evaluate their ability to remove pharmaceuticals ibuprofen, carbamazepine and clofibric acid from wastewaters. Seasonal variability of these systems' performances was also evaluated. Overall, removal efficiencies of 96%, 97% and 75% for ibuprofen, carbamazepine and clofibric acid, respectively, were achieved under summer conditions after a retention time of 7 days. In winter, a maximum loss of 26% in removal efficiency was observed for clofibric acid. Removal kinetics was characterized by a fast initial step (>50% removal within 6h) mainly due to adsorption on LECA but, on a larger timescale, plants also contributed significantly to the system's performance. Despite the fact that further tests using larger-scale systems are required, this study points to the possible application of these low-cost wastewater treatment systems for dealing with pharmaceuticals contaminated wastewater. PMID- 19783428 TI - Effect of cytostatic drugs on microbial behaviour in membrane bioreactor system. AB - The aim of this work is to evaluate the influence of cyclophosphamide and its principal metabolites (CPs) on microbial behaviour in a membrane bioreactor system. Two laboratory-scale membrane bioreactors (MBR) were run in parallel with a sludge retention time of 70 days (one with the cytostatic drugs, MBR-CPs, the second without, MBR-control). The microbial activity was measured by respirometric analysis. The endogenous and exogenous respirations of heterotrophic micro-organisms were evaluated. Micro-organisms exposed to CPs showed higher endogenous respiration rates and lower exogenous respiration rates than micro-organisms present in MBR-control. The effects were observed several days after adding the cocktail. Reduced sludge production was observed in MBR-CPs compared to MBR-control. This reduction of sludge production and the increase in the endogenous respiration rate in relation to MBR-control suggest that the chemical stress caused by CPs led to a diversion of carbon and/or energy from growth to adaptive responses and protection. In addition, the inhibitory effect on the assimilation of exogenous substrate (reduced exogenous respiration rate) suggests an inhibition of catabolism and anabolism despite the low CPs concentration studied (microg/L). However, this inhibitory effect can be offset by the biomass still active under low ratio (substrate/biomass) conditions in the bioreactor (due to complete retention of biomass and high sludge age), which helped to maintain high overall performance in the removal of conventional pollution. PMID- 19783429 TI - Sawdust pellets from coniferous species as adsorbents for NO2 removal. AB - Carbonaceous adsorbents based on sawdust pellets from coniferous tree species were obtained by carbonisation at different temperatures and different periods of time. The effect of NO(2) adsorption in dry and wet condition on the sorption ability of the chars obtained was tested. The results have shown that NO(2) sorption properties of chars depend on the conditions of pyrolysis and the conditions of adsorption. The best NO(2) sorption capacity of 18.3 and 43.1mg/g in dry and wet conditions, respectively, was noted for the char sample pyrolysed at 800 degrees C for 60 min. The FTIR spectra of the exhausted samples reveal a great increase in the intensity of the band at approximately 1380 cm(-1) assigned to the vibrations of -NO(2), -ONO(2) or NO(3)(-), while in the DTG curves a new peak appears in the range 200-400 degrees C assigned to the release of nitrogen compounds of low stability in high temperatures. PMID- 19783430 TI - Fate of manure-borne pathogen surrogates in static composting piles of chicken litter and peanut hulls. AB - The fate of manure-borne pathogen surrogates (gfp-labeled Escherichia coli O157:H7 and Listeria innocua and avirulent Salmonella Typhimurium) in the field was monitored at both sub-surface (30 cm from surface) and surface sites of static composting piles (3.5-m base diameter) composed of chicken litter and peanut hulls. Despite exposure to elevated temperatures, Salmonella was detected by enrichment culture in sub-surface samples following 14 days of composting. In surface samples, pathogen surrogates were detected in the summer after 4 days of composting by enrichment culture only, whereas E. coli O157:H7 and L. innocua remained detectable by direct plating (>2 log(10)cfu/g) up to 28 days in piles composted during the fall and winter. All three types of bacteria remained detectable by enrichment culture in surface samples composted for 56 days during the winter. PMID- 19783431 TI - Estimating biogas production of biologically treated municipal solid waste. AB - In this work, a respirometric approach, i.e., Dynamic Respiration Index (DRI), was used to predict the anaerobic biogas potential (ABP), studying 46 waste samples coming directly from MBT full-scale plants. A significant linear regression model was obtained by a jackknife approach: ABP=(34.4+/-2.5)+(0.109+/ 0.003).DRI. The comparison of the model of this work with those of the previous works using a different respirometric approach (Sapromat-AT(4)), allowed obtaining similar results and carrying out direct comparison of different limits to accept treated waste in landfill, proposed in the literature. The results indicated that on an average, MBT treatment allowed 56% of ABP reduction after 4weeks of treatment, and 79% reduction after 12weeks of treatment. The obtainment of another regression model allowed transforming Sapromat-AT(4) limit in DRI units, and achieving a description of the kinetics of DRI and the corresponding ABP reductions vs. MBT treatment-time. PMID- 19783433 TI - Analogs of a 4-aminothieno[2,3-d]pyrimidine lead (QB13) as modulators of P glycoprotein substrate specificity. AB - P-glycoprotein (P-gp) is an important factor in the development of multidrug resistance (MDR) in cancer cells. In literature reports, a thieno[2,3 d]pyrimidine (QB13) was described as P-gp modulator and opposed effects on the cell accumulation of distinct P-gp substrates were postulated. On the basis of this lead structure, a series of 2-alkylthio-4-aminothieno[2,3-d]pyrimidines was prepared and tested in a daunorubicin accumulation assay. Modulation of substrate specificity was shown for selected compounds in cytotoxicity (MTT) assays. PMID- 19783432 TI - Puupehanol, a sesquiterpene-dihydroquinone derivative from the marine sponge Hyrtios sp. AB - Puupehanol (1), a new sesquiterpene-dihydroquinone derivative, was isolated from the marine sponge Hyrtios sp., along with the known compounds puupehenone (2) and chloropuupehenone (3) that are responsible for the antifungal activity observed in the extract. The structure of 1 was established as (20R,21R)-21-hydroxy-20,21 dihydropuupehenone by extensive spectroscopic and computational methods. Compound 2 exhibited potent activity against Cryptococcus neoformans and Candida krusei with MFCs of 1.25 and 2.50 microg/mL, respectively. PMID- 19783435 TI - Pyrazole-based arylalkyne cathepsin S inhibitors. Part II: optimization of cellular potency. AB - Basic lipophilic substituents dramatically improved the cellular potency of a previously disclosed series of pyrazole-based arylalkyne cathepsin S inhibitors. The incorporation of substituted benzylamines in the para position of the arylalkyne maintained enzymatic activity (hCatS IC50=80-420 nM) and imparted cellular potency (IC50=0.8-4.0 microM). Further refinement of the morpholine portion of the pharmacophore enabled the identification of bicyclic piperidines with enhanced affinity for CatS (IC50=10-30 nM) and sub-micromolar cellular potency (JY Ii IC50=200-720 nM). PMID- 19783434 TI - Structure-activity relationship study of EphB3 receptor tyrosine kinase inhibitors. AB - A structure-activity relationship study for a 2-chloroanilide derivative of pyrazolo[1,5-a]pyridine revealed that increased EphB3 kinase inhibitory activity could be accomplished by retaining the 2-chloroanilide and introducing a phenyl or small electron donating substituents to the 5-position of the pyrazolo[1,5 a]pyridine. In addition, replacement of the pyrazolo[1,5-a]pyridine with imidazo[1,2-a]pyridine was well tolerated and resulted in enhanced mouse liver microsome stability. The structure-activity relationship for EphB3 inhibition of both heterocyclic series was similar. Kinase inhibitory activity was also demonstrated for representative analogs in cell culture. An analog (32, LDN 211904) was also profiled for inhibitory activity against a panel of 288 kinases and found to be quite selective for tyrosine kinases. Overall, these studies provide useful molecular probes for examining the in vitro, cellular and potentially in vivo kinase-dependent function of EphB3 receptor. PMID- 19783436 TI - Cellular localization and allele-selective inhibition of mutant huntingtin protein by peptide nucleic acid oligomers containing the fluorescent nucleobase [bis-o-(aminoethoxy)phenyl]pyrrolocytosine. AB - Peptide nucleic acid (PNA) is a successful DNA/RNA mimic. A major challenge for research is to invent chemically modified PNAs that retain the favorable properties of the parent compound while improving biological recognition. Here, we test modified PNAs containing [bis-o-(aminoethoxy)phenyl]pyrrolocytosine bases designed to engage guanine with an additional hydrogen bond. We observe elevated melting temperatures, localization to cellular compartments, and allele-selective inhibition of mutant huntingtin protein expression. PMID- 19783437 TI - Discovery of a potent, metabolically stabilized resorcylic lactone as an anti inflammatory lead. AB - With bioactivity-guided phenotype screenings, a potent anti-inflammatory compound f152A1 has been isolated, characterized and identified as the known natural product LL-Z1640-2. Metabolic instability precluded its use for the study on animal disease models. Via total synthesis, a potent, metabolically stabilized analog ER-803064 has been created; addition of the (S)-Me group at C4 onto f152A1 has resulted in a dramatic improvement on its metabolic stability, while preserving the anti-inflammatory activities. PMID- 19783438 TI - Bicyclic alpha,omega-dicarboxylic acid derivatives from a colonial tunicate of the family Polyclinidae. AB - In the course of our search for bioactive metabolites from a colonial tunicate of the family Polyclinidae, six new (1-6) cyclic fatty acid derivatives were isolated. Their planar structures were established on the basis of NMR and MS spectroscopic analyses. The relative configuration was determined by NOESY experiment. Compounds 1-6 represent a fused bicyclic skeleton possibly derived from alpha,omega-dicarboxylic acids such as eicosanedioic acid or docosanedioic acid via a Diels-Alder type of cyclization. Compounds 1-4 and 6 showed mild cytotoxicity against a panel of five human solid tumor cell lines. PMID- 19783439 TI - Unusual presentation of phosphoglycerate mutase deficiency due to two different mutations in PGAM-M gene. AB - Phosphoglycerate mutase (PGAM) deficiency causes a rare metabolic myopathy characterized by exercise-related myalgia and myoglobinuria. This disorder was described in 13 patients and five different mutations in the PGAM-M gene were identified. We report on a new patient with an unusual clinical presentation. As a youth, he participated in different sports without complaining of muscular symptoms, but at 44 years of age, after a brief, intense effort, he experienced lightheadedness without fainting. Serum CK was elevated and the ischemic exercise test showed a pathological lactate response. Muscle biopsy showed only mild abnormalities, but biochemical study revealed a defect of PGAM and genetic analysis showed two different mutations in the PGAM-M gene. Our case expands the clinical spectrum of PGAM deficiency and suggests that the frequency of this metabolic myopathy may be underestimated. PMID- 19783440 TI - Postural sway parameters in seated balancing; their reliability and relationship with balancing performance. AB - This study investigated a representative set of 39 parameters characterizing center of pressure movements (sway) in seated balancing, with the aims to determine test-retest reliability, to clarify the interrelations between these parameters, and to determine which parameters were related to balance loss in seated balancing. 331 subjects volunteered to perform three 30-s seated balancing trials in a single session. Ten subjects lost balance on all three trials, 34 lost balance on one or two trials. The test-retest reliability of postural sway parameters was poor with all intra-class correlations below 0.7 and below 0.4 for 9 parameters. Sway parameters were strongly intercorrelated and many parameters thus provide little added value. Parameters that had no intercorrelations above 0.7 comprised three conventional summary statistics of center of pressure (CoP) movements and 3 parameters reflecting the temporal structure of the CoP trajectories. None of the parameters was related with balance loss in univariate analyses, while multivariate models revealed that higher sway velocity and a lower short-term diffusion coefficient were related with less balance loss. This indicates that a multivariate assessment of CoP trajectories is necessary to characterize balancing performance. PMID- 19783442 TI - Ancient ESCRTs and the evolution of binary fission. AB - Eukaryotic and prokaryotic orthologs of tubulin play key roles in DNA segregation and cell division processes. Remarkably, recent studies have revealed that cell division can occur in the absence of this highly conserved protein. Members of the hyperthermophilic crenarchaea, that lack tubulin-like proteins, undergo division by binary fission. Here we review how this process is dependent on archaeal homologs of the eukaryotic 'endosomal sorting complex required for transport' (ESCRT) system - an apparatus that plays a pivotal role in a wide range of membrane manipulation processes. Thus, two distinct machineries to drive binary fission have evolved in prokaryotes - one dependent on tubulin-like proteins and one dependent on the ESCRT system. PMID- 19783441 TI - Sexual reproduction in Aspergillus species of medical or economical importance: why so fastidious? AB - Heterothallism is dependent upon the obligatory cross-mating between self-sterile homokaryotic individuals and represents a common pattern of sexuality in yeasts and molds. Heterothallic reproductive cycles have recently been discovered in three Aspergillus species of medical and economic importance, namely Aspergillus fumigatus,A. parasiticus and A. flavus. Together with Aspergillus udagawae (Neosartorya udagawae), heterothallism has now been discovered in a total of four aspergilli that affect human health or economy. These fungi appear to express relatively low levels of fertility compared to other heterothallic or homothallic aspergilli and require unusually fastidious environmental parameters to complete the sexual cycle. Because the purpose of sex is to reproduce, we favor the hypothesis that while fertility of these species is on the decline this is compensated by their proficiency to reproduce asexually in a wider range of environmental conditions. Heterothallism in these species could provide an invaluable tool for the recombinational analysis of factors relevant to pathogenicity or toxin production. There is concern, however, whether extensive recombinational analysis can be very practical in light of the fact that formation of ascospores in these species requires a long period of time and the construction of genetically marked strains is likely to decrease fertility even further. PMID- 19783443 TI - Synthesis and biological evaluation of flavan-3-ol derivatives as positive modulators of GABAA receptors. AB - We herein describe the synthesis and positive modulatory activities of a small library of flavan-3-ol derivatives on alpha(1)beta(2)gamma(2L) GABA(A) receptors. Structure-activity relationships of various substituents on the A, B and C rings were evaluated in a functional electrophysiological assay. A trans configuration and a 3-acetoxy moiety are essential for activity. Substitution of the B ring appears to be well tolerated, with substituents on the A ring playing a major role in determining activity. PMID- 19783444 TI - Synthesis and evaluation of novel alpha-heteroaryl-phenylpropanoic acid derivatives as PPARalpha/gamma dual agonists. AB - The synthesis of a new series of phenylpropanoic acid derivatives incorporating an heteroaryl group at the alpha-position and their evaluation for binding and activation of PPARalpha and PPARgamma are presented in this report. Among the new compounds, (S)-3-{4-[3-(5-methyl-2-phenyl-oxazol-4-yl)-propyl]-phenyl}-2-1,2,3 triazol-2-yl-propionic acid (17j), was identified as a potent human PPARalpha/gamma dual agonist (EC(50)=0.013 and 0.061 microM, respectively) with demonstrated oral bioavailability in rat and dog. 17j was shown to decrease insulin levels, plasma glucose, and triglycerides in the ZDF female rat model. In the human apolipoprotein A-1/CETP transgenic mouse model 17j produced increases in hApoA1 and HDL-C and decreases in plasma triglycerides. The increased potency for binding and activation of both PPAR subtypes observed with 17j when compared to previous analogs in this series was explained based on results derived from crystallographic and modeling studies. PMID- 19783445 TI - Pyranonaphthoquinone derivatives of eleutherin, ventiloquinone L, thysanone and nanaomycin A possessing a diverse topoisomerase II inhibition and cytotoxicity spectrum. AB - A series of pyranonaphthoquinone derivatives related to the known topoisomerase II inhibitor eleutherin 1 have been shown to act as specific topoisomerase II catalytic inhibitors, with several analogues displaying greater potency than the natural product itself. Amongst the compounds tested were the natural products ventiloquinone L 4 and thysanone 8 with a diverse range of topoisomerase II inhibition properties being observed. Interestingly, the natural products are generally weaker inhibitors than their synthetic counterparts, emphasising that subtle changes in the basic molecular structure of a natural product led to significant changes in the inhibition profile. It has also been demonstrated for the first time that analogues related to nanaomycin A and cardinalin-type dimeric pyranonaphthoquinones exhibit potent topoisomerase II inhibitory properties. With respect to structural features, it appears that the nature of the substituents at C1 on the pyran ring and oxygenated substituents on the aryl ring are critical for anti-topoII activity. Importantly, the topoisomerase II inhibition strength does not correlate well with the measured cytotoxicity against yeast, indicating that other molecular features in the pyranonaphthoquinone family must be considered for the design and use of this structural class as highly specific topoisomerase II inhibitors. PMID- 19783446 TI - Synthesis and hybridization of 2'-O-methyl-RNAs incorporating 2'-O carbamoyluridine and unique participation of the carbamoyl group in U-G base pair. AB - 2'-O-Carbamoyluridine (U(cm)) was synthesized and incorporated into DNAs and 2'-O Me-RNAs. The oligonucleotides incorporating U(cm) formed less stable duplexes with their complementary and U(cm)-U, U(cm)-C single-base mismatched DNAs and RNAs in comparison with those without the carbamoyl group. On the contrary, the T(m) analyses revealed that the duplexes with a mismatched U(cm)-G base pair showed almost the same thermostability as the corresponding unmodified duplexes. Molecular dynamics (MD) simulations of the U(cm)-modified 2'-O-Me-RNA/RNA duplexes with U(cm)-G mismatched base pair suggested that the carbamoyl group could participate in the U(cm)-G base pair by an additional intermolecular hydrogen bond between the carbamoyl oxygen and the H2 of the guanine base. PMID- 19783447 TI - Synthesis and biological evaluation of 14-(aminoalkyl-aminomethyl)aromathecins as topoisomerase I inhibitors: investigating the hypothesis of shared structure activity relationships. AB - The aromathecin topoisomerase I (top1) inhibitors offer promising scaffolds for the development of novel cancer chemotherapeutics. They are 'composites' of the camptothecin and indenoisoquinoline top1 inhibitors. Interestingly, some structure-activity relationship (SAR) overlap between the aromathecins and the indenoisoquinolines has been observed. For both classes, placement of certain polar groups in similar regions of the heteroaromatic system improves top1 inhibitory and antiproliferative activities. A series of water-soluble aromathecins substituted at position 14 with diaminoalkanes of various lengths has been prepared. These compounds all possess similar antiproliferative potency, but a general trend is observed: aromathecins with longer diaminoalkane substituents (>6 carbons) possess lower anti-top1 activity than their smaller counterparts (2-4 carbons), presumably as a result of unfavorable hydrophobic interactions. This trend is also noted with the indenoisoquinolines, revealing additional SAR overlap that supports the hypothesis that there is a 'universal' top1 inhibitor SAR. PMID- 19783448 TI - Synthesis and evaluation of non-hydrolyzable D-mannose 6-phosphate surrogates reveal 6-deoxy-6-dicarboxymethyl-D-mannose as a new strong inhibitor of phosphomannose isomerases. AB - Non-hydrolyzable d-mannose 6-phosphate analogues in which the phosphate group was replaced by a phosphonomethyl, a dicarboxymethyl, or a carboxymethyl group were synthesized and kinetically evaluated as substrate analogues acting as potential inhibitors of type I phosphomannose isomerases (PMIs) from Saccharomyces cerevisiae and Escherichia coli. While 6-deoxy-6-phosphonomethyl-d-mannose and 6 deoxy-6-carboxymethyl-D-mannose did not inhibit the enzymes significantly, 6 deoxy-6-dicarboxymethyl-D-mannose appeared as a new strong competitive inhibitor of both S. cerevisiae and E. coli PMIs with K(m)/K(i) ratios of 28 and 8, respectively. We thus report the first malonate-based inhibitor of an aldose ketose isomerase to date. Phosphonomethyl mimics of the 1,2-cis-enediolate high energy intermediate postulated for the isomerization reaction catalyzed by PMIs were also synthesized but behave as poor inhibitors of PMIs. A polarizable molecular mechanics (SIBFA) study was performed on the complexes of d-mannose 6 phosphate and two of its analogues with PMI from Candida albicans, an enzyme involved in yeast infection homologous to S. cerevisiae and E. coli PMIs. It shows that effective binding to the catalytic site occurs with retention of the Zn(II)-bound water molecule. Thus the binding of the hydroxyl group on C1 of the ligand to Zn(II) should be water-mediated. The kinetic study reported here also suggests the dianionic character of the phosphate surrogate as a likely essential parameter for strong binding of the inhibitor to the enzyme active site. PMID- 19783449 TI - Natural product leads for drug discovery: isolation, synthesis and biological evaluation of 6-cyano-5-methoxyindolo[2,3-a]carbazole based ligands as antibacterial agents. AB - Indolo[2,3-a]carbazole based inhibitors were synthesized from readily available indigo via a seven-step linear synthetic sequence with a moderate overall yield. The inhibitors were selectively and readily functionalized at the nitrogen on the indole portion of the carbazole unit. The synthesized analogs displayed moderate inhibitory activities toward Bacillus anthracis and Mycobacterium tuberculosis, indicating that indolo[2,3-a]carbazoles could serve as promising leads in the development of new drugs to combat anthrax and tuberculosis infections. PMID- 19783450 TI - Calibration of the direct LSC method for radon in drinking water: Interference from (210)Pb and its progenies accumulated in (226)Ra standard solution. AB - The standard ASTM method is the most commonly applied method for determining (222)Rn in drinking water. The method is calibrated with a (226)Ra standard solution that usually contains variable amounts of (210)Pb, (210)Bi and (210)Po if the standard has not recently been purified. Until now it has not been experimentally confirmed that these progenies do not interfere when the method is calibrated. In this study, interference was examined using three different organic cocktails and alpha/beta liquid scintillation spectrometry to separately assess the effect of three radionuclides. The interference from (210) Po was 4% for one of the cocktails if the (226)Ra standard had been purified 5 years earlier. The interferences from (210)Pb and (210)Bi were negligible compared to that of (210)Po. PMID- 19783451 TI - Passive, integrated measurement of radon using 5A synthetic zeolite and blue silica gel. AB - Synthetic zeolite of 0.5nm pore size (5A) and blue silica gel were tested to determine their capability to be used as radon collectors. Tests conducted in a radon chamber under controlled conditions of temperature and relative humidity indicate that simple, inexpensive and maintenance-free passive devices containing about 250g of synthetic zeolite or about 270g of blue silica gel in open face metal canisters that can measure radon conveniently and adequately, the latter though being suitable only for dry-medium dry atmosphere with quite high radon concentrations. Both materials can be recycled for reuse, in a way similar to the recycle and reuse of active carbon. The amount of radon adsorbed in such collectors is determined by counting the gamma rays from the radon decay products. The lower limit of detection (LLD) is estimated to approximately 45Bqm( 3) for the synthetic zeolite and to approximately 350Bqm(-3) for the blue silica gel, for an exposure of 48h at a relative humidity of about 50%. In comparison, the corresponding LLD for active carbon is estimated to 10Bqm(-3). At relative humidity in the range between 10% and 50%, radon chamber experiments indicate that the measured radon in the canisters is proportional to the mean concentration of radon during the period of exposure. It is estimated that calibration uncertainty lies within +/-20% for both materials, thus suggesting that at least detectors based on the 5A synthetic zeolite presenting a reasonably low LLD, are a feasible and of similar cost alternative to activated carbon for indoors radon concentration measurements in practical situations. PMID- 19783452 TI - Virus-induced gene silencing: a versatile tool for discovery of gene functions in plants. AB - Virus-induced gene silencing (VIGS) is a technology that exploits an antiviral defense mechanism in plants as a tool for plant reverse genetics. VIGS circumvents the need for plant transformation, is methodologically simple and yields rapid results. Various VIGS vectors have been developed and have helped to unravel the functions of genes involved in processes such as disease resistance, abiotic stress, cellular signaling and secondary metabolite biosynthesis. PMID- 19783454 TI - Plasma membrane estrogen receptors. AB - It is now firmly established that estrogen and all sex steroid receptors exist in discrete cellular pools outside the nucleus. Estrogen receptors (ER) have been localized to the plasma membrane where both ERalpha and ERbeta function in a wide variety of cells and organs. ERs have also been found in discrete cytoplasmic organelles including mitochondria and the endoplasmic reticulum. In ligand dependent fashion, each ER pool contributes to the overall, integrated effects of estrogens producing biological outcomes. This review highlights the recent work establishing new roles and targets of membrane ER signaling. Such actions include prevention of vascular injury or cardiac hypertrophy, sexual behavior and pain perception mediated through the central nervous system, osteoblast survival, and fluid resorption in the colon. PMID- 19783453 TI - Systems biology asks new questions about sex differences. AB - Females and males differ in physiology and in the incidence and progression of diseases. The sex-biased proximate factors causing sex differences in phenotype include direct effects of gonadal hormones and of genes represented unequally in the genome because of their X- or Y-linkage. Novel systems approaches have begun to assess the magnitude and character of sex differences in organization of gene networks on a genome-wide scale. These studies identify functionally related modules of genes that are coexpressed differently in males and females, and sites in the genome that regulate gene networks in a sex-specific manner. Measurement of the aggregate behavior of genes uncovers novel sex differences that can be related more effectively to susceptibility to disease. PMID- 19783455 TI - Ex-vivo effect of dexamethasone on cytokine production from whole blood of septic patients: correlation with disease severity. AB - BACKGROUND: Controversial findings of former clinical trials on the effect of low dose hydrocortisone in patients with septic shock led to investigate the effect of corticosteroids on the production of cytokines from endotoxin (LPS)-stimulated whole blood. METHODS: Whole blood from 33 septic patients was sampled within 24h alter diagnosis. Hydrocortisone was not administered during follow-up. Whole blood was stimulated with 30 ng/ml of LPS in the presence of 0.01, 0.1, 1 and 10 microM of dexamethasone. Concentrations of cytokines and of sTREM-1 were estimated in supernatants after six hours of incubation. RESULTS: Dexamethasone inhibited LPS-stimulated release of TauNuFalpha, of IL-6, of IL-8 and of IL-10 in dose-dependent manner. A dual effect on the kinetics of release of IL-1beta and of sTREM-1 was shown. Release of IL-1beta was either decreased, what was connected with unfavorable outcome, or it was unaffected what was connected with a favorable outcome. Release of sTREM-1 was either increased, what was connected with unfavorable outcome, or it was decreased what was connected with a favorable outcome. CONCLUSIONS: Part of the beneficiary effect of corticosteroids in sepsis may be due to an effect on the release of IL-1beta and of sTREM-1. This effect does not seem to be homogeneous for all septic patients. PMID- 19783456 TI - Tunable single-photon ionization TOF mass spectrometry using laser-produced plasma as the table-top VUV light source. AB - Here we report on a laser plasma-based tunable VUV photoionization time-of-flight (TOF) mass spectrometer conceived mainly to study complex gaseous mixtures. Ionizing photons at tunable vacuum UV (VUV) wavelengths are generated by a gas target laser-produced plasma, spectrally dispersed in the range 100-160 nm and efficiently focused onto a sample molecular beam. As a test case, we studied the exhaust gas of a four-stroke moped, a typical example of a complex gaseous mixture. Due to the VUV "soft" ionization, the mass spectra are less congested and more easily interpretable. Substituted benzene derivatives are found to give the most intense signals. Several aliphatic hydrocarbons are also detected. The use of tunable VUV radiation allowed the investigation of the contribution of isomers in the mass spectrum from the onset and shape of the photoionization efficiency spectra. Semiquantitative analysis was performed using known literature data detailing the photoionization cross sections. Our findings suggest that using combined data on the mass/photoionization efficiency spectra may be very helpful for a comprehensive analysis of complex gaseous mixtures. PMID- 19783457 TI - Zinc deposition during ESI-MS analysis of peptide-zinc complexes. AB - Electrospray ionization (ESI) mass spectrometry (MS) has proven to be an extremely powerful technique for studying the stoichiometry and binding strength of peptide-metal complexes. We have found a significant new problem in the ESI-MS of zinc-peptide systems involving the deposition of zinc in the ESI emitter. This deposition of zinc during the experiment removes a significant amount of zinc ions from the solution, impacting the resulting mass spectral intensities used to quantify the amount of the zinc-bound species. Analysis of infused zinc-peptide samples with atomic absorption spectrometry and with a custom-built nanoflow ESI source confirms the alteration of the analyte solutions with positive or negative or no potential applied to the emitter. Ultimately, the location of the zinc deposition was determined to be the stainless steel emitter. The use of a custom built nanoESI interface using glass emitters was found to mitigate the zinc deposition problem. The phenomenon of metal deposition warrants further investigation as it may not be limited to just zinc and may represent a significant obstacle in the ESI-MS analysis of all protein-metal systems. PMID- 19783458 TI - Characterization of variant diphtheria toxin-interleukin-3 fusion protein, DTIL3K116W, for phase I clinical trials. AB - We have produced clinical grade of DTIL3K116W, a variant diphtheria toxin interleukin-3 fusion protein, for treatment of acute myeloid leukemia. The product was filter sterilized, aseptically vialed, and stored at -80 degrees C. It was characterized by Coomassie-stained SDS-PAGE, endotoxin assay, cytotoxicity assay, sterility, mass spectroscopy, receptor binding affinity, ADP-ribosylation, inhibition of normal human CFU-GM, disulfide bond analysis, immunoblots, stability, size exclusion chromatography-HPLC, sequencing, and immunohistochemistry. Vialed product was sterile in 0.25 M NaCl/5 mM Tris, pH 7.9, and had a protein concentration of 1.08 mg/ml. Purity by SDS-PAGE was >99%. Aggregates by HPLC were <1%. Endotoxin levels were 0.296EU/mg. Peptide mapping and mass spectroscopy confirmed its composition and molecular weight. The vialed drug kept reactivity with anti-IL3 and DT antibodies. Potency study revealed a 48 h EC(50) of 0.5 pM on TF1/H-ras cell. Its binding properties were confirmed by competitive experiments showing IC(50) of 1.4 nM. ADP-ribosylation activity was equivalent to DTGM-CSF. Drug did not react with tested frozen human tissue sections by immunohistochemistry. There was no evidence of loss of solubility, proteolysis aggregation, or loss of potency over 6 months at -80 degrees C. Further, the drug was stable at 4 and 25 degrees C in the plastic syringe and administration tubing for 48 h. PMID- 19783459 TI - WHO/KFDA workshop on stability evaluation of vaccines, Seoul, Korea, 23-25 April 2008. AB - In April 2008, the World Health Organization and the Korea Food & Drug Administration jointly organized a workshop on evaluating vaccine stability. The main objective of the workshop was to facilitate implementing newly established WHO guidelines. The value of stability studies in understanding vaccine characteristics, establishing shelf-life and release specifications, and monitoring the stability post-market was well explained. Optimal designs for goal based stability studies were proposed and appropriate statistical analyses presented. A statistical model (the term "estimation model" was adopted) based on regression analysis of potency loss over storage time elapsed, was elaborated for describing the stability profile of vaccines. This model was believed to provide a more precise description of the stability characteristics of a vaccine than the current "compliance model". The use of both models was discussed in relation to specific examples and case studies. A document format for assisting standardized stability report was discussed as a possible annex to the WHO stability guidelines adopted in 2006. The participants agreed that a future revision of vaccine stability guidance should highlight the estimation model and that WHO should provide additional training to support national regulatory authorities with statistical design and analysis, and to assist their transition from the compliance model towards wider use of the estimation model. PMID- 19783460 TI - Patients visiting the emergency room for seizures: insurance status and clinic follow-up. AB - PURPOSE: Epilepsy is a chronic condition that is best treated in the outpatient clinic setting. However, many epilepsy patients use the hospital emergency room (ER) as a primary resource for seizure management. We studied characteristics of these patients in comparison with patients attending an epilepsy clinic. METHODS: We reviewed ER data of patients seen in 2002 and 2003 for seizures, in Vanderbilt University Hospital (VUH) and Metro Nashville General Hospital (MNGH), seeking to identify patients who had visited the emergency room more than once. We collected demographic and insurance information on these patients and identified those who followed up in the epilepsy clinic. RESULTS: There were 1005 patients who visited the VUH ER and 205 the MNGH ER for seizures. Patients visiting the ER for seizures were less likely to be insured than epilepsy patients followed in the clinic, in both institutions. The proportion of patients visiting the ER more than once was 15.2% at VUH and 29.2% at MNGH. Among these patients, 3.2% at VUH and 26.7% at MNGH were uninsured. Clinic follow-up occurred in 68.6% of VUH and 13.3% of MNGH repeat ER visitors. Combining institutions, insured patients were much more likely to follow-up in the clinic. DISCUSSION: Repeated use of the ER for seizures was more common in the county hospital, where the proportion of uninsured patients was also higher. Patients visiting the county hospital ER repeatedly tend not to follow-up in the neurology clinic. This element of disparity of care requires further attention. PMID- 19783461 TI - Potential treatments for insulin resistance in the horse: a comparative multi species review. AB - Insulin resistance and hyperinsulinaemia increase the risk of laminitis and horse owners and veterinarians should attempt to enhance insulin sensitivity in at-risk groups. In obese animals this may be achieved, in part, by promoting weight loss and increasing exercise, but such intervention may not be appropriate in non obese insulin-resistant animals, or where exercise is contra-indicated for clinical reasons. An alternative approach to controlling insulin sensitivity in obese and non-obese horses may be the use of certain herbal compounds that have shown promise in humans and laboratory animals, although little is known of the effects of these compounds in horses. The herbs can be grouped according to their primary mechanism of action, including activators of the peroxisome proliferator activated receptors, anti-obesity compounds, anti-oxidants, compounds that slow carbohydrate absorption, insulin receptor activators and stimulators of glucose uptake, with some herbs active in more than one pathway. Certain herbs have been prioritised for this review according to the quality and quantity of published studies, the reported (or extrapolated) safety profile, as well as potential for efficacy, all of which will hopefully motivate further research in this field. PMID- 19783462 TI - Dynamic nuclear polarization of 13C in aqueous solutions under ambient conditions. AB - The direct enhancement of the (13)C NMR signal of small molecules in solution through Overhauser-mediated dynamic nuclear polarization (DNP) has the potential to enable studies of systems where enhanced signal is needed but the current dissolution DNP approach is not suitable, for instance if the sample does not tolerate a freeze-thaw process or if continuous flow or rapid re-polarization of the molecules is desired. We present systematic studies of the (13)C DNP enhancement of (13)C-labeled small molecules in aqueous solution under ambient conditions, where we observe both dipolar and scalar-mediated enhancement. We show the role of the three-spin effects from enhanced protons on (13)C DNP through DNP experiments with and without broadband (1)H decoupling and by comparing DNP results with H(2)O and D(2)O. We conclude that the efficiency of (13)C Overhauser DNP in small molecules strongly depends on the distance of closest approach between the electron and (13)C nucleus, the presence of a scalar contribution to the coupling factor, and the magnitude of the three-spin effect due to adjacent polarized protons. The enhancement appears to depend less on the translational dynamics of the (13)C-labeled small molecules and radicals. PMID- 19783463 TI - [Debate against: hysterectomy for cervical cancer]. PMID- 19783464 TI - Malnutrition and associated factors in Chinese patients with Parkinson's disease: Results from a pilot investigation. AB - OBJECTIVE: This study was conducted to evaluate the prevalence of malnutrition among patients with Parkinson's disease (PD) and determine the associations between malnutrition and non-motor symptoms (NMS). METHODS: We conducted a cross sectional assessment of 117 consecutive outpatients with PD and their respective caregivers. The participants were interviewed and assessed using various scales, including the Mini Nutritional Assessment (MNA), Non-Motor Symptoms questionnaire for Parkinson's disease (NMS quest), Mini-mental State Examination (MMSE), Pittsburgh Sleep Quality Index (PSQI), Epworth Sleepiness Scale (ESS), Geriatric Depression Scale (GDS), and Hamilton Anxiety Scale (HAMA). We also investigated the socio-demographic characteristics of the subjects. RESULTS: The prevalence of malnutrition (MNA score < 17) was 1.71%, and 19.66% patients were at risk of malnutrition (17 S(1) transition of esculin (lambda(ex)(max) approximately 340nm) appears, which is similar to the lambda(em)(max) of BSA and HSA. The critical distance (R(0)) between BSA and esculin is higher than that of HSA, which showed that the affinity of esculin and HSA should be higher than that of BSA. After centrifugation, the concentrations of esculin bound to albumins were determined by means of the fluorescence of esculin. It was found that much more esculin was bound to HSA than to BSA. However, the bound models for BSA and HSA are almost the same. The concentration of esculin bound to serum albumin at first decreased with the addition of esculin and then increased. From above results, it can be concluded that the affinity of esculin and HSA should be higher than that of esculin and BSA. This example showed that in the presence of FRET, the binding constants between ligands and proteins based on fluorescence quenching might be deviated. PMID- 19783472 TI - Efficient methodologies for sensitive HIV-1 RNA quantitation from plasma and vaginal secretions. AB - BACKGROUND: Quantifying HIV levels in mucosal secretions is essential to study compartmentalized expression of HIV and facilitate development of intervention strategies to prevent disease progression and transmission. OBJECTIVES: To develop a sensitive, reliable, and cost-effective technique to quantify HIV from blood and vaginal secretions that is compatible with efficient implementation in clinical research environments. STUDY DESIGN: A sensitive, reliable, internally controlled real-time reverse transcriptase (RT) PCR assay, which uses the HIV-1 pol gene as a target (Hpol assay) was developed to quantify HIV levels in plasma and genital secretions, and compared to the widely used Roche Amplicor HIV-1 Monitor assay. In addition, a simplified method of sample collection and processing of genital secretions (self-collection and use of RNAlater with batch processing) was compared to provider collection of samples and immediate processing. RESULTS: The sensitivity and reliability of HIV levels detected by the assay described herein correlate well with measurements from Roche Amplicor HIV-1 Monitor assay for both plasma and vaginal secretions (R(2)=0.9179 and R(2)=0.942, respectively). The Hpol assay reproducibly quantifies a lower limit of 5 HIV-1 RNA copies per reaction, with low-levels of inter-assay and intra assay variation. Additionally, vaginal viral levels and detection frequency did not differ significantly between the two the collection and processing methods. CONCLUSIONS: The methodologies developed here provide sensitive, reliable, and cost-effective quantification of HIV levels in plasma and mucosal secretions, and are compatible with efficient use in clinical research studies. PMID- 19783473 TI - Association between report of insomnia and daytime functioning. AB - OBJECTIVES: The relationship between reports of insomnia and daytime functioning was investigated using hierarchical regression. The presence or absence of a report of insomnia was the predictor of primary interest. A number of covariates were included in the model: demographic variables, health variables, and quantitative sleep parameters. METHODS: Data were collected from a community sample in the Memphis, Tennessee area. Data from 734 volunteers, ranging in age from 20 to 96years were analyzed. The sample included 235 individuals who reported having chronic insomnia and 499 individuals who reported no sleep problems. Participants completed a 2-week sleep diary, a battery of daytime functioning questionnaires, and a medical disorders checklist. Demographic information was also collected. The daytime functioning assessment included the Beck Depression Inventory, the State-Trait Anxiety Inventory, the Epworth Sleepiness Scale, the Insomnia Impact Scale, and the Fatigue Severity Scale. The hierarchical regression model included four sets. The first three sets consisted of 18 variables capturing demographic, health, and sleep diary parameters. The fourth set included a single dichotomous variable representing the presence or absence of a report of insomnia. RESULTS: Reports of insomnia were a significant predictor of all five daytime functioning measures, which is consistent with previous research. We also showed that reports of insomnia were able to uniquely explain a significant amount of variability in self-reported daytime functioning after controlling for demographics, health, and sleep diary variables. The pattern of individual variables that reached significance in the first three sets varied depending on which daytime functioning measure was predicted, however, age, the presence of pain, the presence of mental health problems, SOL, and WASO were the most commonly significant predictors of poor daytime functioning from these sets across measures. CONCLUSIONS: Individuals' perceptions of their sleep are related to differences in their reported daytime functioning, which are not accounted for by demographic factors, health surveys, or quantitative sleep assessments. Reports of insomnia may be related to a set of common cognitive factors among individuals who report having insomnia which cause them to be distressed with their sleep and increase their dissatisfaction with daytime functioning. Relevance of the findings to insomnia research and clinical management are discussed. PMID- 19783474 TI - Mechanisms of probiotic actions - A review. AB - Probiotics are gaining more and more interest as alternatives for antibiotics or anti-inflammatory drugs. However, their mode of action is poorly understood. This review will present examples of probiotic actions from three general modes of actions into which probiotic effects can be classified. Probiotics might modulate the host's immune system, affect other microorganisms directly or act on microbial products, host products or food components. What kind of effect(s) a certain probiotic executes depends on its metabolic properties, the molecules presented at its surface or on the components secreted. Even integral parts of the bacterial cell such as its DNA or peptidoglycan might be of importance for its probiotic effectiveness. The individual combination of such properties in a certain probiotic strain determines its specific probiotic action and as a consequence its effective application for the prevention and/or treatment of a certain disease. PMID- 19783475 TI - The synthesis and function of the alarmone (p)ppGpp in firmicutes. AB - In most bacteria, nutrient limitations provoke the stringent control by the rapid synthesis of the alarmones pppGpp and ppGpp. The most prominent and highly conserved reaction is the repression of rRNA synthesis. Additionally, (p)ppGpp synthesis is also linked to many other physiological changes involving gene activation/repression but also protein translation, enzyme activation and replication. Whereas much of the basic research was performed with Escherichia coli there is now growing evidence that in gram-positive bacteria there are fundamental differences in (p)ppGpp synthesis, regulation and molecular function. Here we will focus on basic differences between firmicutes and proteobacteria, particularly E. coli. PMID- 19783476 TI - The role of innate signaling in the homeostasis of tolerance and immunity in the intestine. AB - In the intestine innate recognition of microbes is achieved through pattern recognition receptor (PRR) families expressed in immune cells and different cell lineages of the intestinal epithelium. Toll-like receptor (TLR) and nucleotide binding and oligomerization domain-like receptor (NLR) families are emerging as key mediators of immunity through their role as maturation factors of immune cells and triggers for the production of cytokines and chemokines and antimicrobial factors. At the mucosal surface chronic activation of the immune system is avoided through the epithelial production of a glycocalyx, steady-state production of antimicrobial factors as well as the selective expression and localization of PRRs. Additionally, the polarization of epithelial TLR signaling and suppression of NF-kappaB activation by luminal commensals appears to contribute to the homeostasis of tolerance and immunity. Several studies have demonstrated that TLR signaling in epithelial cells contributes to a range of homeostatic mechanisms including proliferation, wound healing, epithelial integrity, and regulation of mucosal immune functions. The intestinal epithelium appears to have uniquely evolved to maintain mucosal tolerance and immunity, and future efforts to further understand the molecular mechanisms of intestinal homeostasis may have a major impact on human health. PMID- 19783477 TI - Microbe-host interaction in chronic diseases. PMID- 19783478 TI - Recent developments and perspectives in the investigation of probiotic effects. AB - The quest for a better understanding of how probiotics work has boosted an enormous interest in the molecular processes underlying host-microbe interactions. This review covers recent developments and perspectives in the study of probiotic mechanisms. PMID- 19783479 TI - The impact of serine/threonine phosphorylation in Staphylococcus aureus. AB - In prokaryotes and eukaryotes, phosphotransfer represents a common mechanism to regulate cellular functions. Recent work revealed that modulation of cellular processes by eukaryote-like serine/threonine kinases (STKs) and phosphatases (STPs) are widespread in bacteria. During the last two years, first evidence on the role of Ser/Thr phosphorylation/dephosphorylation in Staphylococcus aureus has emerged leading to the identification of a functional STK and corresponding STP. Due to homology to known STKs/STPs in other bacterial species the kinase was designated PknB or alternatively Stk/Stk1, and the phosphatase Stp. The role of these enzymes in S. aureus has been examined by use of knock-out mutants and a kinase-overexpressing strain. These studies uncovered PknB/Stk and Stp as modulators of cell wall structure and susceptibility to cell wall-acting antibiotics such as certain beta-lactams and tunicamycin. By utilizing transcriptional profile analysis a strong regulatory impact of PknB/Stk on the expression of genes encoding proteins which are involved in purine and pyrimidine biosynthesis, cell wall metabolism, autolysis, and glutamine synthesis could be identified. Moreover, PknB/Stk is able to phosphorylate MgrA, thereby regulating activity of the efflux pump NorA. In a mouse pyelonephritis model PknB/Stk has been shown to play a role in virulence. Overall, Ser/Thr phosphorylation/dephosphorylation is a common theme in regulation of cellular functions determining metabolic activity and virulence also in the major human pathogen S. aureus. PMID- 19783481 TI - Illuminating Blood Components. PMID- 19783480 TI - Opening the flood-gates: how neutrophil-endothelial interactions regulate permeability. AB - Many diseases have an inflammatory component, where neutrophil interactions with the vascular endothelium lead to barrier dysfunction and increased permeability. Neutrophils increase permeability through secreted products such as the chemokines CXCL1, 2, 3, and 8, through adhesion-dependent processes involving beta(2) integrins interacting with endothelial ICAM-1, and through combinations where beta(2) integrin engagement leads to degranulation and secretion of heparin binding protein. Some neutrophil products, such as arachidonic acid or the leukotriene LTA4, are further processed by endothelial enzymes via transcellular metabolism before the resulting products thromboxane A2 or LTC4 can activate their cognate receptors. Neutrophils also generate reactive oxygen species that induce vascular leakage. This review focuses on the mechanisms of neutrophil mediated leakage. PMID- 19783482 TI - Electrical and chemical stimulation of the nucleus raphe magnus inhibits induction of retching by afferent vagal fibers. AB - Like pain sensation, vomiting is induced by C afferent fibers of the vagus nerve. Therefore, it can be assumed to be suppressed by the descending inhibitory system (DIS) of pain. In this study we examined this possibility in immobilized decerebrated dogs. Fictive retching was induced by the stimulation of abdominal afferent vagal fibers (stim-abdVAs) and identified by activity patterns of efferent discharges of the phrenic and abdominal muscle nerves. The induction of retching was suppressed by weak stimulation (20microA, 20Hz, 0.5ms duration) of the pontine area corresponding to the nucleus raphe magnus (NRM). Stronger suppressions were produced by stimulation of the rostral part of the NRM at the pontine level where the abducen nucleus exists. Pontamine sky blue, an excitatory neurotoxin, which was microinjected into the NRM area in 5 dogs, completely suppressed the induction of retching during the injection period. The NRM area at the level of the abducen nucleus was commonly stained by the dye in the 5 dogs. These results suggest that the DIS of pain suppresses the induction of retching by afferent vagal fibers. PMID- 19783483 TI - Enteric nervous system development: Recent progress and future challenges. AB - The enteric nervous system is the largest subdivision of the peripheral nervous system that plays a critical role in digestive functions. Despite considerable progress over the last 15 years in understanding the molecular and cellular mechanisms that control the development of the enteric nervous system, several questions remain unanswered. The present review will focus on recent progress on understanding the development of the mammalian enteric nervous system and highlight interesting directions of future research. PMID- 19783484 TI - Fos expression in the NTS in response to peripheral chemoreflex activation in awake rats. AB - Chemoreflex afferent fibers terminate in the nucleus tractus solitarii (NTS), but the specific location of the NTS neurons excited by peripheral chemoreflex activation remains to be characterized. Here, the topographic distribution of chemoreflex sensitive cells at the commissural NTS was evaluated. To reach this goal, Fos-immunoreactive neurons (Fos-ir) were accounted in rostro-caudal levels of the intermediate and caudal commissural NTS, after intermittent chemoreflex activation with intravenous injection of potassium cyanide [KCN (80microg/kg) or saline (0.9%, vehicle), one injection every 3min during 30min]. In response to intermittent intravenous injections of KCN, a significant increase in the number of Fos-ir neurons was observed specifically in the lateral intermediate commissural NTS [(LI)NTS (82+/-9 vs. 174+/-16, cell number mean per section)] and lateral caudal commissural NTS [(LC)NTS (71+/-9 vs. 199+/-18, cell number mean per section)]. To evaluate the influence of baroreceptor-mediated inputs following the increase in blood pressure during intermittent chemoreflex activation, we performed an intermittent activation of the arterial baroreflex by intravenous injection of phenylephrine [1.5microg/kg iv (one injection every 3min during 30min)]. This procedure induced no change in Fos-ir in (LI)NTS (64+/-6 vs. 62+/-12, cell number mean per section) or (LC)NTS (56+/-15 vs. 77+/-12, cell number mean per section). These data support the involvement of the commissural NTS in the processing of peripheral chemoreflex, and provide a detailed characterization of the topographical distribution of activated neurons within this brain region. PMID- 19783485 TI - Very high frequency components of renal sympathetic nerve activity in conscious rats. AB - The aim of this study was to examine whether multifibrenal sympathetic nerve activity (RSNA) of conscious rats contains frequency components of biological interest at frequencies above 25Hz. RSNA was recorded in 10 conscious Sprague Dawley rats under baseline conditions and during infusion of vasoactive drugs that reflexly altered the mean RSNA level. The RSNA signal was band-pass filtered (300-3000Hz) before being sampled at 10,000Hz. The analytic envelope of this raw signal was then extracted using the Hilbert transform, and 132-s periods were submitted to Fourier transform analysis. Spectral power was computed from 0 to 25Hz and from 25 to 3000Hz (P(25-3000)). P(25-3000) was reduced by about 80% after either ganglionic blockade or euthanasia, which indicated that it was of biological origin and derived from the activity of postganglionic sympathetic neurons. After subtraction of post-mortem spectral power, basal P(25-3000) contributed 59.8+/-2.4% of total power. P(25-3000) was strongly barosensitive and thus, accounted for a major part of the reflex changes in total power. In each of the 10 rats, P(25-3000) was linearly correlated with the mean RSNA level (0.984+/ 0.003) and even more so with the spectral power in the 0-25Hz frequency range (0.994+/-0.001). In conclusion, the RSNA of conscious rats contains very high frequency components that account for about 60% of the total spectral power and are modulated by the baroreceptor reflex. A reasonable approximation of this power can be obtained by computing spectra up to 25Hz. PMID- 19783487 TI - Pretreatment of low-abundance peptides on detonation nanodiamond for direct analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Detonation nanodiamond (dND) was firstly employed as adsorbent for pretreatment of peptides in dilute/contaminated sample solution. Detonation nanodiamond showed high efficiency for isolating and enriching peptides in a wide pH range. Remarkably, good tolerance capability toward salts and detergents could be achieved by using dNDs. Due to the inherent specificities of dNDs, dND-bound peptides could be directly analyzed by MALDI-TOF MS, so as to avoid the elution step and reduce sample loss. This pretreatment method also exhibited a better performance for protein identification compared to solvent evaporation and Ziptip pretreatment approach. PMID- 19783486 TI - The migration of autonomic precursor cells in the embryo. AB - The neural crest is an excellent model system to study cell fate and cell guidance signaling. Neural crest cells emerge from a common multipotent subpopulation and follow stereotypical migratory pathways to contribute to many diverse peripheral structures throughout the vertebrate embryo. The neural tube and diverse embryonic microenvironments from which the neural crest originate and migrate through are important sources of signals, yet it is still unclear how a common pool of neural crest stem and progenitor cells diversify and become distributed along specific stereotypical migratory paths. In the post-otic hindbrain and trunk, the neural crest emerge and contribute to the autonomic nervous system, and failure of proper cell navigation and differentiation often leads to congenital disorders that include dysautonomias, Hirschprung's disease, and neuroblastoma cancer. Recent exciting studies of neural crest cell behaviors have revealed the interplay of several molecular signaling pathways that guide and shape autonomic precursor cells to and into proper target structures, suggesting further work may help to better understand autonomic nervous system assembly, derived from a convergence of time-lapse imaging and molecular analyses. In this mini-review, we summarize recent fluorescent cell labeling strategies and cell behavior analyses that elucidate the role of molecular signals on the migration of autonomic precursor cells. We highlight advances in our understanding of the autonomic precursor cell behaviors and fate determination studied within the embryonic microenvironment. PMID- 19783488 TI - Development of a LC/MS/MS method to analyze butyrylcholinesterase inhibition resulting from multiple pesticide exposure. AB - A hybrid LC/MS/MS and proteomics method was developed for the assessment of multiple pesticide exposure. The methodology was based on the analysis of tryptic peptides resulting from inhibited butyrylcholinesterase (BChE) after exposure to pesticides including organophosphates (OPs) and carbamates (CBs). The primary advantage of the assay was its ability to simultaneously examine multiple pesticide exposures in a single analytical experiment. Application of tandem and MS(3) techniques provided identities of the inhibiting pesticide, confirmation and localization of the site of inhibition and relative quantification of phosphorylated peptides present in tryptic digests of equine BChE (eBChE). PMID- 19783489 TI - Acute leukaemia following low dose peptide receptor radionuclide therapy for an intestinal carcinoid. PMID- 19783490 TI - [Chronic suppressive therapy in recurrent herpes labia with valacyclovir in adolescents. Our experience]. PMID- 19783491 TI - [Biliary tract cyst after Kasai portoenterostomy in extrahepatic biliary tract atresia and its relationship with repeated cholangitis]. PMID- 19783492 TI - [Seroprevalence of human parvovirus B19 in ambulatory population of Cantabria, northern Spain]. PMID- 19783493 TI - Assessment of risk factors in diabetic foot ulceration and their impact on the outcome of the disease. AB - AIMS: The current study aims to identify risk factors for diabetic foot ulcer and their impact on the outcome of the disease. METHODS: Three hundred diabetic patients were enrolled in the study. One hundred eighty subjects with diabetic foot ulcer and 120 diabetic controls without foot lesions. All expected risk factors were studied in all patients and after a follow up period, patients with diabetic foot ulcer were classified into group A (patients with healed ulcers) and group B (patients with persistent ulcer or ended by amputation). The risk factors were reanalyzed in both groups to find out their impact on the outcome of the disease. RESULTS: The following variables were significant factors for foot ulceration: Male gender (P=0.009), previous foot ulcer (P=0.003), peripheral vascular disease (P=0.004), and peripheral neuropathy (P=0.006). Also lack of frequent foot self-examination was independently related to foot ulcer risk. The outcome was related to longer diabetes duration (P=0.004), poor glycaemic control (P=0.006) and anaemia (P=0.003) and presence of infection (P<0.001). CONCLUSIONS: Peripheral vascular disease and peripheral neuropathy together with lack of foot self-examination, poor glycaemic control and anaemia are main significant risk factors for diabetic foot ulceration. PMID- 19783494 TI - Identification of a relationship between cervical spine function and rotational movement control. AB - The cervical spine's stabilising function is generated by three interacting systems: an active system (the muscles), a passive system (capsules, intervertebral disks and ligaments) and a neutral system (the nervous system). Functional impairment induced by alteration of one or several systems can disturb movement control. Thus, a decrease in the quality of movement control could be directly linked to the cervical spine's state of impairment. The aim of the present study was to assess the relationship between cervical spine status (measured using a validated questionnaire) and the control of low-amplitude neck movements. Our starting hypothesis was that the more precise the movement, the faster it would be. We devised a test in which a sequence of rotational movements of the neck (to the left and to the right, alternately) was timed while monitoring the targeting of a laser beam (fixed to the right side of a pair of spectacles) on photodetectors placed directly in front of the subject and 30 degrees to the left and to the right of the body line. The test was performed using a system called the "Didren laser". Fifty-six subjects (of varying ages and both genders, classified as "disabled" or "healthy" according to the Neck Disability Index [NDI] questionnaire score) performed the test. Our results showed that: the score differed from one individual to another but was reproducible for a given subject; the score was age- and gender-independent; the highest scores (i.e. the slowest rotations) were generally produced by individuals classified as "disabled" in terms of the NDI questionnaire score. Our results led us to conclude that there is a relationship between functional disorders of the cervical spine and low-amplitude rotational movement control, although we were unable to define the exact nature of this relationship. PMID- 19783496 TI - Noise reduction in computed tomography scans using 3-d anisotropic hybrid diffusion with continuous switch. AB - Noise filtering techniques that maintain image contrast while decreasing image noise have the potential to optimize the quality of computed tomography (CT) images acquired at reduced radiation dose. In this paper, a hybrid diffusion filter with continuous switch (HDCS) is introduced, which exploits the benefits of three-dimensional edge-enhancing diffusion (EED) and coherence-enhancing diffusion (CED). Noise is filtered, while edges, tubular structures, and small spherical structures are preserved. From ten high dose thorax CT scans, acquired at clinical doses, ultra low dose ( 15 mAs ) scans were simulated and used to evaluate and compare HDCS to other diffusion filters, such as regularized Perona Malik diffusion and EED. Quantitative results show that the HDCS filter outperforms the other filters in restoring the high dose CT scan from the corresponding simulated low dose scan. A qualitative evaluation was performed on filtered real low dose CT thorax scans. An expert observer scored artifacts as well as fine structures and was asked to choose one of three scans (two filtered (blinded), one unfiltered) for three different settings (trachea, lung, and mediastinal). Overall, the HDCS filtered scan was chosen most often. PMID- 19783495 TI - Shear modulus decomposition algorithm in magnetic resonance elastography. AB - Magnetic resonance elastography (MRE) is an imaging modality capable of visualizing the elastic properties of an object using magnetic resonance imaging (MRI) measurements of transverse acoustic strain waves induced in the object by a harmonically oscillating mechanical vibration. Various algorithms have been designed to determine the mechanical properties of the object under the assumptions of linear elasticity, isotropic and local homogeneity. One of the challenging problems in MRE is to reduce the noise effects and to maintain contrast in the reconstructed shear modulus images. In this paper, we propose a new algorithm designed to reduce the degree of noise amplification in the reconstructed shear modulus images without the assumption of local homogeneity. Investigating the relation between the measured displacement data and the stress wave vector, the proposed algorithm uses an iterative reconstruction formula based on a decomposition of the stress wave vector. Numerical simulation experiments and real experiments with agarose gel phantoms and human liver data demonstrate that the proposed algorithm is more robust to noise compared to standard inversion algorithms and stably determines the shear modulus. PMID- 19783497 TI - Learning-based vertebra detection and iterative normalized-cut segmentation for spinal MRI. AB - Automatic extraction of vertebra regions from a spinal magnetic resonance (MR) image is normally required as the first step to an intelligent spinal MR image diagnosis system. In this work, we develop a fully automatic vertebra detection and segmentation system, which consists of three stages; namely, AdaBoost-based vertebra detection, detection refinement via robust curve fitting, and vertebra segmentation by an iterative normalized cut algorithm. In order to produce an efficient and effective vertebra detector, a statistical learning approach based on an improved AdaBoost algorithm is proposed. A robust estimation procedure is applied on the detected vertebra locations to fit a spine curve, thus refining the above vertebra detection results. This refinement process involves removing the false detections and recovering the miss-detected vertebrae. Finally, an iterative normalized-cut segmentation algorithm is proposed to segment the precise vertebra regions from the detected vertebra locations. In our implementation, the proposed AdaBoost-based detector is trained from 22 spinal MR volume images. The experimental results show that the proposed vertebra detection and segmentation system can achieve nearly 98% vertebra detection rate and 96% segmentation accuracy on a variety of testing spinal MR images. Our experiments also show the vertebra detection and segmentation accuracies by using the proposed algorithm are superior to those of the previous representative methods. The proposed vertebra detection and segmentation system is proved to be robust and accurate so that it can be used for advanced research and application on spinal MR images. PMID- 19783498 TI - Reproducible classification of infarct heterogeneity using fuzzy clustering on multicontrast delayed enhancement magnetic resonance images. AB - Delayed enhancement MRI (DE-MRI) can be used to identify myocardial infarct (MI). Classification of MI into the infarct core and heterogeneous periphery (called the gray zone) on conventional inversion-recovery gradient echo (IR-GRE) DE-MRI images has been related to inducibility for ventricular tachycardia. However, this classification is sensitive to image noise, depends on the signal intensity characteristics in a remote region of myocardium, and requires manual contours of the endocardial border. Image analysis and fuzzy clustering techniques were developed to analyze images acquired using a multicontrast delayed enhancement (MCDE) sequence in order characterize the infarct zones. The MCDE analysis is automated and uses data fitting of signal intensities acquired at multiple inversion times. In a study of 15 patients with chronic MI, the gray zones derived from IR-GRE and MCDE images were comparable. The variability in the gray zone size associated with random noise and operator input was significantly reduced using the MCDE-based analysis compared to the IR-GRE-based analysis. In summary, the MCDE approach yields a more reproducible measure of the infarct core and gray zones on any given data set. PMID- 19783499 TI - Controlling familywise error rate for matched subspace detection in dynamic FDG PET. AB - Detection of small lesions in fluorodeoxyglucose (FDG) positron emission tomography (PET) is limited by image resolution and low signal to noise ratio. We have previously described a matched subspace detection method that uses the time activity curve to distinguish tumors from background in dynamic FDG PET. Applying this algorithm on a voxel by voxel basis throughout the dynamic image produces a test statistic image or "map" which on thresholding indicates the potential locations of secondary or metastatic tumors. In this paper, we describe a thresholding method that controls familywise error rate (FWER) for the matched subspace detection statistical map. The method involves three steps. First, the PET image is segmented into several homogeneous regions. Then, the statistical map is normalized to a zero mean unit variance Gaussian random field. Finally, the images are thresholded at a fixed FWER by estimating their spatial smoothness and applying a random field theory maximum statistic approach. We evaluate this thresholding method using digital phantoms generated from clinical dynamic images. We also present an application of the proposed approach to clinical PET data from a breast cancer patient with metastatic disease. PMID- 19783500 TI - Liver vessels segmentation using a hybrid geometrical moments/graph cuts method. AB - This paper describes a fast and fully automatic method for liver vessel segmentation on computerized tomography scan preoperative images. The basis of this method is the introduction of a 3-D geometrical moment-based detector of cylindrical shapes within the minimum-cut/maximum-flow energy minimization framework. This method represents an original way to introduce a data term as a constraint into the widely used Boykov's graph cuts algorithm, and hence, to automate the segmentation. The method is evaluated and compared with others on a synthetic dataset. Finally, the relevancy of our method regarding the planning of a necessarily accurate percutaneous high-intensity focused ultrasound surgical operation is demonstrated with some examples. PMID- 19783501 TI - Chemometric approach for improving VCSEL-based glucose predictions. AB - Optical methods are one of the painless and promising techniques that can be used for blood glucose predictions for diabetes patients. The use of thermally tunable vertical cavity surface-emitting lasers (VCSELs) as the light source to obtain blood absorption spectra, along with the multivariate technique partial least squares for analysis and glucose estimation, has been demonstrated. With further improvements by using data preprocessing and two VCSELs, we have achieved a clinically acceptable level in the physiological range in buffered solutions. The results of previous experiments conducted using white light showed that increasing the number of wavelength intervals used in the analysis improves the accuracy of prediction. The average prediction error, using absorption spectra from one VCSEL in aqueous solution, is about 1.2 mM. This error is reduced to 0.8 mM using absorption spectra from two VCSELs. This result confirms that increasing the number of VCSELs improves the accuracy of prediction. PMID- 19783502 TI - PSO-based cloning template design for CNN associative memories. AB - In this brief, a synthesis procedure for cellular neural networks (CNNs) with space-invariant cloning templates is proposed. The design algorithm is based on the use of the evolutionary algorithm of the particle swarm optimization (PSO) with the application to associative memories. The proposed synthesis procedure takes into account requirements in terms of robustness to parametric variations. Numerical results show that the networks also guarantee good performances in terms of correct recall in the presence of noisy patterns. PMID- 19783503 TI - Unequal erasure protection technique for scalable multistreams. AB - This paper presents a novel unequal erasure protection (UEP) strategy for the transmission of scalable data, formed by interleaving independently decodable and scalable streams, over packet erasure networks. The technique, termed multistream UEP (M-UEP), differs from the traditional UEP strategy by: 1) placing separate streams in separate packets to establish independence and 2) using permuted systematic Reed-Solomon codes to enhance the distribution of message symbols amongst the packets. M-UEP improves upon UEP by ensuring that all received source symbols are decoded. The R-D optimal redundancy allocation problem for M-UEP is formulated and its globally optimal solution is shown to have a time complexity of O(2(N)N(L+1)(N+1)) , where N is the number of packets and L is the packet length. To address the high complexity of the globally optimal solution, an efficient suboptimal algorithm is proposed which runs in O(N(2)L(2)) time. The proposed M-UEP algorithm is applied on SPIHT coded images in conjunction with an appropriate grouping of wavelet coefficients into streams. The experimental results reveal that M-UEP consistently outperforms the traditional UEP reaching peak improvements of 0.6 dB. Moreover, our tests show that M-UEP is more robust than UEP in adverse channel conditions. PMID- 19783504 TI - Determining hysteresis thresholds for edge detection by combining the advantages and disadvantages of thresholding methods. AB - Hysteresis is an important technique for edge detection, but the unsupervised determination of its parameters is not an easy problem. In this paper, we propose a method for unsupervised determination of hysteresis thresholds using the advantages and disadvantages of two thresholding methods. The basic idea of our method is to look for the best hysteresis thresholds in a set of candidates. First, the method finds a subset and a overset of the unknown edge points set. Then, it determines the best edge map with the measure chi(2). Compared with a general method to determine the parameters of an edge detector, our method performs well and is less computationally complex. The basic idea of our method can be generalized to other pattern recognition problems. PMID- 19783505 TI - Biologically inspired feature manifold for scene classification. AB - Biologically inspired feature (BIF) and its variations have been demonstrated to be effective and efficient for scene classification. It is unreasonable to measure the dissimilarity between two BIFs based on their Euclidean distance. This is because BIFs are extrinsically very high dimensional and intrinsically low dimensional, i.e., BIFs are sampled from a low-dimensional manifold and embedded in a high-dimensional space. Therefore, it is essential to find the intrinsic structure of a set of BIFs, obtain a suitable mapping to implement the dimensionality reduction, and measure the dissimilarity between two BIFs in the low-dimensional space based on their Euclidean distance. In this paper, we study the manifold constructed by a set of BIFs utilized for scene classification, form a new dimensionality reduction algorithm by preserving both the geometry of intra BIFs and the discriminative information inter BIFs termed Discriminative and Geometry Preserving Projections (DGPP), and construct a new framework for scene classification. In this framework, we represent an image based on a new BIF, which combines the intensity channel, the color channel, and the C1 unit of a color image; then we project the high-dimensional BIF to a low-dimensional space based on DGPP; and, finally, we conduct the classification based on the multiclass support vector machine (SVM). Thorough empirical studies based on the USC scene dataset demonstrate that the proposed framework improves the classification rates around 100% relatively and the training speed 60 times for different sites in comparing with previous gist proposed by Siagian and Itti in 2007. PMID- 19783506 TI - Mining characteristic relations bind to RNA secondary structures. AB - The identification of RNA secondary structures has been among the most exciting recent developments in biology and medical science. It has been recognized that there is an abundance of functional structures with frameshifting, regulation of translation, and splicing functions. However, the inherent signal for secondary structures is weak and generally not straightforward due to complex interleaving substrings. This makes it difficult to explore their potential functions from various structure data. Our approach, based on a collection of predicted RNA secondary structures, allows us to efficiently capture interesting characteristic relations in RNA and bring out the top-ranked rules for specified association groups. Our results not only point to a number of interesting associations and include a brief biological interpretation to them. It assists biologists in sorting out the most significant characteristic structure patterns and predicting structure-function relationships in RNA. PMID- 19783507 TI - Computing consistency between microarray data and known gene regulation relationships. AB - Microarray experiments produce expression patterns for thousands of genes at once. On the other hand, biomedical literature contains large amounts of gene regulation relationship information accumulated over the years. One obvious requirement is an automated way of comparing microarray data with the collection of known gene regulation relationships. Such an automated comparison is imperative because it can help biologists rapidly understand the context of a given microarray experiment. In addition, the consistency measure can be used to either validate or refute the hypothesis being tested using the microarray experiment. In this paper we present a systematic way of examining the consistency between a given set of microarray data and known gene regulation relationships. We first introduce a simple gene regulation network model with two separate algorithms designed to isolate a maximally consistent network. Subsequently, we extend the model to take into account multiple regulating factors for a single gene while highlighting both consistencies and inconsistencies. We illustrate the effectiveness of our approach with two practical examples, one that picks the peroxisome proliferator-activated receptor (PPAR) pathway as highly consistent from multiple pathways of Kyoto encyclopedia of genes and genomes (KEGG), and another that isolates key regulatory relationships involving nfkb1 and others known for macrophage's counter response to inflammation. PMID- 19783508 TI - Characterization of 3-D coronary tree motion from MSCT angiography. AB - This paper describes a method for the characterization of coronary artery motion using multislice computed tomography (MSCT) volume sequences. Coronary trees are first extracted by a spatial vessel tracking method in each volume of MSCT sequence. A point-based matching algorithm, with feature landmarks constraint, is then applied to match the 3-D extracted centerlines between two consecutive instants over a complete cardiac cycle. The transformation functions and correspondence matrices are estimated simultaneously, and allow deformable fitting of the vessels over the volume series. Either point-based or branch-based motion features can be derived. Experiments have been conducted in order to evaluate the performance of the method with a matching error analysis. PMID- 19783509 TI - Segmentation of complementary DNA microarray images by wavelet-based Markov random field model. AB - A wavelet-based modification of the Markov random field (WMRF) model is proposed for segmenting complementary DNA (cDNA) microarray images. For evaluation purposes, five simulated and a set of five real microarray images were used. The one-level stationary wavelet transform (SWT) of each microarray image was used to form two images, a denoised image, using hard thresholding filter, and a magnitude image, from the amplitudes of the horizontal and vertical components of SWT. Elements from these two images were suitably combined to form the WMRF model for segmenting spots from their background. The WMRF was compared against the conventional MRF and the Fuzzy C means (FCM) algorithms on simulated and real microarray images and their performances were evaluated by means of the segmentation matching factor (SMF) and the coefficient of determination (r2). Additionally, the WMRF was compared against the SPOT and SCANALYZE, and performances were evaluated by the mean absolute error (MAE) and the coefficient of variation (CV). The WMRF performed more accurately than the MRF and FCM (SMF: 92.66, 92.15, and 89.22, r2 : 0.92, 0.90, and 0.84, respectively) and achieved higher reproducibility than the MRF, SPOT, and SCANALYZE (MAE: 497, 1215, 1180, and 503, CV: 0.88, 1.15, 0.93, and 0.90, respectively). PMID- 19783510 TI - Effect of central microinjection of carbenoxolone in an experimental model of focal cerebral ischemia. AB - Previous experimental studies have shown the protective effects of CBX on brain ischemic injures in global and in vitro models of ischemia. However, effects of CBX in temporary model of focal cerebral ischemia are not clear. Hence, the aim of this study was to investigate the effects of central microinjection of CBX on post-ischemic reperfusion injuries in a temporary model of focal cerebral ischemia. Transient focal cerebral ischemia was induced in rats by 60 min middle cerebral artery occlusion (MCAO), followed by 23 h reperfusion. CBX was administered into the right ventricle at doses of 1, 12, 25, 50 and/or 100 microg/kg at the beginning of MCAO. Cortical and striatal infarct volumes and motor dysfunctions were assessed 24 h after MCAO. Administration of CBX at doses of 1, 12, 25 and/or 50 microg/kg significantly reduced cortical infarct volumes by 35%, 49%, 41% and 43%, respectively (P<0.001). In addition, CBX only at dose of 25 microg/kg significantly reduced striatal infarct volume and improved neurological dysfunctions (P<0.01). Our findings indicated that central microinjection of CBX has protective effect on against ischemic reperfusion injuries in a transient model of focal cerebral ischemia. PMID- 19783511 TI - Assessment of anticoagulant effect of evening primrose oil. AB - Effect of evening primrose oil (EPO) was assessed on coagulation parameters following 30 and 60 days administration of 90, 180 and 360 microl/kg oil to healthy rabbits of either sex. There was significant increase in all assays except Fibrinogen time. These effects might be due to inactivation or inhibition of factors affecting coagulation. The intake of evening primrose oil also significantly decreased platelet count. Results of this study suggest that evening primrose oil shows considerable anti-anticoagulant and anti-platelet activity in animals and has potential to reduce cardiovascular morbidity and mortality. PMID- 19783512 TI - In vitro study on tamsulosin release kinetics from biodegradable PLGA in situ implants. AB - The objective of this study was to evaluate the effect of drug loading and the effect of excipients on the release pattern of tamsulosin tydrochloride from in situ PLGA implants formed in vitro in gelatin gel. This system is prepared by dissolving a biodegradable polymer (DL-PLGA 70K) in biocompatible solvent, dimethyl sulfoxide (DMSO). Then either the drug or drug with excipients was added to it. The drug solution was poured into the hollow of gelatin gel, the solvent dissipated into the surrounding gelatin base through diffusion leading phase separation and subsequent coagulation of the polymer. The drug formed a rod like implant in situ. Two types of implants were prepared such as implants containing tamsulosin hydrochloride and implants containing tamsulosin hydrochloride with biocompatible excipients such as Tween 20, Tween 60, Span 20, Span 80, Chremophore EL, or Chremophore RH 40. In vitro dissolution studies were performed in static condition using phosphate buffer (pH 7.4) to observe the release of drugs from these implants for 10 days. Formulation containing only tamsulosin hydrochloride showed that drug loading was 83.54%, 90.23%, 86.72%, 89.17% and 94.08% against the actual drug content of 9.09%, 13.04%, 16.67%, 20% and 23.08% respectively. The release rate of drug was 64.51%, 70.64%, 74.08%, 76.12% and 80.05% accordingly. It can be concluded that the release rate of drug increases with increasing drug concentrations. The other formulation containing tamsulosin with excipients showed that the release rate was 74.70%, 75.14%, 60.03%, 63.83%, 70.82% and 76.43% against same conc. of drug (8.7% of drug) but different excipients such as tween 20, tween 60, span 20, span 80, chremophore EL and chremophore RH 40 respectively. The loading efficiency was 79.33%, 87.34%, 91.91%, 94.19%, 88.48% and 95.34% respectively. It can be concluded that excipient lowers the release rate of the drug and may prolong the activity and overall release kinetics. PMID- 19783513 TI - In vitro antioxidant activity of roots of Thespesia lampas Dalz and Gibs. AB - The free radical scavenging potential of roots of Thespesia lampas Dalz and Gibs was studied by different antioxidant models. Free radicals are implicated for more than 80 diseases including Diabetes mellitus, arthritis, cancer, ageing etc. In the treatment of theses diseases, antioxidant therapy has gained an utmost importance. Current research is directed towards finding naturally occurring antioxidant of plant origin. In Indian system of medicine, Thespesia lampas is an important medicinal plant and its root juice has been used in various ailments and as health tonic. To understand the mechanisms of pharmacological actions, the in vitro antioxidant activity of aqueous extract of Thespesia lampas was investigated for the activity of scavenging superoxide anion radicals, nitric oxide radical and lipid peroxidation assay. In all the testing, a significant correlation existed between concentrations of the extract and percentage inhibition of free radicals, metal chelating, reducing power or inhibition of lipid peroxidation. These results clearly indicate that Thespesia lampas is effective against free radical mediated diseases. PMID- 19783514 TI - L-arginine augments the antioxidant effect of garlic against acetic acid-induced ulcerative colitis in rats. AB - Garlic contains many sulfhydryl compounds that act as antioxidants. However, the role of nitric oxide (NO) in inflammation is controversial. The aim of the present study is to investigate the possible protective effect of garlic against acetic acid-induced ulcerative colitis in rats, as well as the probable modulatory effect of L-arginine (NO precursor) on garlic activity. Intra-rectal inoculation of rats with 4% acetic acid for 3 consecutive days caused a significant increase in the colon weight and marked decrease in the colon length. In addition, acetic acid induced a significant increase in serum levels of nitrate as well as colonic tissue content of malondialdehyde (MDA). Moreover, colonic tissue contents of glutathione (GSH), superoxide dismutase (SOD) and catalase (CAT) were markedly reduced. On the other hand, pre-treatment of rats with garlic (0.25 g/kgbwt, orally) for 4 consecutive weeks and 3 days during induction of colitis significantly reduced the increase in the colon weight induced by acetic acid and ameliorated alterations in oxidant and antioxidant parameters. Interestingly, oral co-administration of garlic (0.25 g/kgbwt) and L arginine (625 mg/kgbwt) for the same period of garlic administration mitigated the changes in both colon weight and length induced by acetic acid and increased garlic effect on colon tissue contents of MDA and GSH. In conclusion, L-arginine can augment the protective effect of garlic against ulcerative colitis; an effect that might be mainly attributed to its NO donating property resulting in enhancement of garlic antioxidant effect. Further studies will be needed to determine which one of the active ingredients of garlic has the main antioxidant effect to be used with L-arginine. PMID- 19783515 TI - Diuretic effect of powdered Cerasus avium (cherry) tails on healthy volunteers. AB - In this study, the diuretic activity of powdered cherry stalk was evaluated in 13 healthy volunteers by means of their water balance. In addition to biochemical parameters, such as urinary electrolyte concentration, osmolality and any adverse reaction were determined. The capsules of cherry stalks were administered at an equivalent dose of 2.0 grams of the plant per person. Urinary biochemical determination was made of concentration of electrolytes (sodium, potassium, chloride and calcium), urinary volume and osmolality by standard laboratory procedures. Statistical evaluation was performed by Student's-t and Wilcoxon rank tests. After administration of cherry stalk, the mean of urine calcium, sodium, chloride, and urine volume increased, but the amount of urine potassium and urine osmolality did not change. No adverse reaction was observed. Powdered C. avium stalk increased mild urine volume confirming thus the claimed diuretic effect of the herb. Administration of cherry stalk caused urinary sodium and chloride rising less than loop diuretics but higher than the others. Because of rising calcium excretion, it should be used with cautious in those with urolithiasis. PMID- 19783516 TI - Antiulcer and anticonvulsant activity of Croton zambesicus. AB - The ethanolic root extract of Croton zambesicus was investigated for its potential to protect gastric mucosa against ulcers induced by indomethacin, ethanol and reserpine. The anticonvulsant activity of the root extract against pentylene tetrazol (PTZ)- and picrotoxin-induced convulsion in mice was also studied. The extract (27-81 mg/kg) produced a significant (P<0.005-0.001) dose dependent effects against the ulcerogenic effect of different agents used; indomethacin, ethanol and reserpine. The effect of the extract was lower than that of the standard drug, cimetidine (100 mg/kg) in the indomethacin and reserpine-induced ulcer models and higher than that of propranolol (40 mg/kg) in ethanol-induced ulcer model. The extract (27-81 mg/kg) could not protect mice from convulsion in both PTZ--and picrotoxin-induced convulsion. The root extract significantly (P<0.01-0.001) delayed the onset and latency of convulsion caused by PTZ and picrotoxin. The root extract possesses antiulcer and anticonvulsant properties. PMID- 19783517 TI - Effect of ethanol extract of flowers of Vitex trifolia Linn. on CCL4 induced hepatic injury in rats. AB - Hepatoprotective activity of ethanolic extract of flowers of Vitex trifolia (Verbenaceae) was studied against CCl4 induced hepatic injury in albino rats. The plant extract (EVT) at the dose of 200 mg/kg, p.o. showed a remarkable hepatoprotective activity. CCl4 induced a significant rise in serum glutamate pyruvate transaminase (SGPT), serum glutamate oxaloacetate transaminase (SGOT), alkaline phosphatase (ALP), total bilirubin and gamma glutamate transpeptidase (GGTP). Treatment of rats with EVT significantly (P<0.001) altered serum biomarker enzyme levels to near normal against CCl4 treated rats. The activity of the extract was comparable to the standard drug, silymarin (100 mg/kg, p.o.). Histopathological observations also revealed that treatment with EVT protected the animals from CCl4 induced liver damage. The results indicate that the flowers of V. trifolia possess hepatoprotective activity on CCl4 induced hepatic injury in rats. PMID- 19783518 TI - Study of the anti-inflammatory and analgesic effects of novel rigid benzofuran-3, 4-dihydroxy chalcone by formalin, hot-plate and carrageenan tests in mice. AB - It is reported that dihydroxy chalcones have analgesic and anti-inflammatory effects. Study of the structure activity relationship (SAR) shows that benzofuran 3-one derivatives may be more effective in this respect. In this study, a new (Z) 2-(3,4-dihydroxybenzylidene)-5-methoxybenzofuran-3(2H)-one (compound 5) was synthesized and its analgesic and anti-inflammatory effects were evaluated by formalin, carrageenan and hot-Plate methods in mice. The results showed that, compound 5 induced significant antinociceptive and anti-inflammatory effect (P<0.01). Maximum analgesia (42.6%) was obtained at dose of 25 mg/kg in the first phase of formalin test. The effect of compound 5 was higher (87.7%) in chronic phase of inflammation induced by formalin (P<0.01). Administration of 25 mg/kg of compound 5 inhibited the inflammation induced by carrageenan, 32.8% and 41.7%, 1 and 3 hour after carrageenan injection, respectively. In addition, this dose of compound 5, induces significant analgesia (20.2%) in hot plate test 45 minutes after injection (P<0.01). Therefore it seems that compound 5 has potential for discovery of a compound with potent anti-inflammatory and analgesic effects and its scaffold could be use for further structural modifications. PMID- 19783519 TI - Oral glucose tolerance test (OGTT) in normal control and glucose induced hyperglycemic rats with Coccinia cordifolia l. and Catharanthus roseus L. AB - The aim of this study is to investigate the hypoglycemic effects of petroleum ether, chloroform and ethyl acetate fractions isolated from ethanolic extracts of Coccinia cordifolia and Catharanthus roseus on normal control and orally glucose induced hyperglycemic rats. Single doses (150 mg/kg) of different fractions of C. cordifolia and C. roseus extracts were intraperitonelly administered. The serum blood glucose level was obtained by pricking the tail vein using glucometer at time 0, 30, 60, 90, 150 and 270 minutes. In the orally glucose induced hyperglycemic rats, chloroform-coccinia (CHCl3-CC) fraction showed maximum reduction of blood glucose level by 21.94% on 60 minute of the experiment. On the other hand maximum reduction (p<0.05) of 17.92% was observed for petroleum ether catharanthus (PET-CR) on 30 minute of the experiment. Metformin HCl was used as standard drug. Our results indicate that the CHCl3-CC fraction is relatively more potent than other fractions of C. cordifolia. Similarly the PET-CR is found to be better than other fractions of catharanthus. Phytochemical screening test results showed that chloroform fraction of C. cordifolia contain saponins and flavonoids compounds, which are known to be hypoglycemic. On the other hand petroleum ether fraction of C. roseus contains tannins, flavonoids and alkaloid compounds produced varying degree of blood sugar reduction. On the pharmacological point of view C. cordifolia and C. roseus appears to be a valuable plant, which can be useful, at least as an adjunct, in the therapy of diabetes. PMID- 19783520 TI - Antimicrobial activities of the volatile oils of Ocimum bacilicum L. and Ocimum gratissimum L. (Lamiaceae) against some aerobic dental isolates. AB - Essential or volatile oils of plants have been variously reported to have many medicinal applications. Their probable uses against oral microbes have received little attention. Oral swabs obtained from eighteen dental patients at the University of Benin teaching Hospital, Benin City, Nigeria, led to the isolation of twenty nine bacteria. Using standard methods, the microorganisms were identified as Streptococcus viridians (16; representing 55.17%), Staphylococcus albus (9; 31.04%), Klebisiella pneumonia (2; 6.90%), Pseudomonas aeruginosa (1, 3.45%) and Proteus vulgaris (1, 3.45%). The antimicrobial activities of the volatile oils of Ocimum basilicum L. and O. gratissimum L. were evaluated on the twenty nine organisms using agar diffusion and agar dilution methods. In the susceptibility tests, the volatile oils of O. basilicum and O. gratissimum independently inhibited the growth of Klebisiella pneumonia at a concentration of 0.51% in the agar; Streptococcus viridians and Staphylococcus albus at 1.10% and Pseudomonas aeruginosa at 10.0%. Proteus vulgaris was inhibited at 0.53% by the volatile oil of O. gratissimum and 0.67% by O. basilicum. Separate incorporation of the volatile oils into tooth pastes (2 and 5%), the volatiles oils showed antibacterial activities comparable to a commercial tooth paste (which contains O. basilicum 0.01% among others) against most resistant organisms. As components of mouth washes, the volatile oils completely inhibited the growth of organisms at a concentration of 0.5%. PMID- 19783521 TI - Residual solvent analysis in hydrochloride salts of active pharmaceutical ingredients. AB - GMP conditions commands to control adequately the quality of APIs by checking the levels of residual solvents. Organic solvents such as acetone, ethyl acetate, isopropyl alcohol, methanol, tetrahydrofuran and toluene frequently used in pharmaceutical industry for the manufacturing of Active Pharmaceutical ingredients (APIs). A selective Gas Chromatographic (GC) method has been developed and validated as per ICH guidelines for residual solvent analysis in 10 different hydro chloride salts of APIs. Residual solvents in APIs were monitored using gas chromatography (GC) with Flame Ionisation detector (FID). The separation was carried out on BP 624 column (30 mx0.53 mm i.d.x0.25 m coating thickness), using GC 17 A shimadzu, with nitrogen as carrier gas in the split mode by direct injection method. The method described is simple, sensitive, rugged, reliable and reproducible for the quantitation of acetone, ethyl acetate, isopropyl alcohol, methanol, tetrahydrofuran and toluene at residual level from hydrochloride chloride salts of APIs. PMID- 19783522 TI - Quantitative analysis of virgin coconut oil in cream cosmetics preparations using fourier transform infrared (FTIR) spectroscopy. AB - Today, virgin coconut oil (VCO) is becoming valuable oil and is receiving an attractive topic for researchers because of its several biological activities. In cosmetics industry, VCO is excellent material which functions as a skin moisturizer and softener. Therefore, it is important to develop a quantitative analytical method offering a fast and reliable technique. Fourier transform infrared (FTIR) spectroscopy with sample handling technique of attenuated total reflectance (ATR) can be successfully used to analyze VCO quantitatively in cream cosmetic preparations. A multivariate analysis using calibration of partial least square (PLS) model revealed the good relationship between actual value and FTIR predicted value of VCO with coefficient of determination (R2) of 0.998. PMID- 19783523 TI - Antibacterial activity of oregano (Origanum vulgare Linn.) against gram positive bacteria. AB - The present investigation is focused on antibacterial potential of infusion, decoction and essential oil of oregano (Origanum vulgare) against 111 Gram positive bacterial isolates belonging to 23 different species related to 3 genera. Infusion and essential oil exhibited antibacterial activity against Staphylococcus saprophyticus, S. aureus, Micrococcus roseus, M. kristinae, M. nishinomiyaensis, M. lylae, M. luteus, M. sedentarius, M. varians, Bacillus megaterium, B. thuringiensis, B. alvei, B. circulans, B. brevis, B. coagulans, B. pumilus, B. laterosporus, B. polymyxa, B. macerans, B. subtilis, B. firmus, B. cereus and B. lichiniformis. The infusion exhibited maximum activity against B. laterosporus (17.5 mm mean zone of inhibition+/-1.5 Standard deviation) followed by B. polymyxa (17.0 mm+/-2.0 SD) and essential oil of oregano exhibited maximum activity against S. saprophyticus (16.8 mm+/-1.8 SD) followed by B. circulans (14.5 mm+/-0.5 SD). While all these tested isolates were found resistant to decoction of oregano. PMID- 19783524 TI - Ethnopharmacology of the plants of genus Ajuga. AB - The plants of genus Ajuga are evergreen, clump-forming rhizomatous perennial or annual herbaceous flowering species, with Ajuga being one of the 266 genera of the family Lamiaceae. There are at least 301 species of the genus Ajuga with many variations. These plants, growing in Europe, Asia, Africa, Australia and North America, are used in gardens as ground cover or border for their foliage and beautiful flowers. Many of these plants have been used in traditional medicine as a remedy for fever, toothache, dysentery, malaria, high blood pressure, diabetes, gastrointestinal disorders, as anthelmintic, diuretic and antifungal, anti inflammatory, and antimycobacterial agents. They are also used as insect growth inhibitor s. A large number of compounds have been isolated from the Ajuga plants, including phytoecdysteroids, neo-clerodane-diterpenes and diterpenoids, triterpenes, sterols, anthocyanidin-glucosides and iridoid glycosides, withanolides, flavonoids, triglycerides and essential oils. These compounds possess a broad spectrum of biological, pharmacological and medicinal properties, such as anabolic, analgesic, antibacterial, antiestrogenic, antifungal, anti inflammatory, antihypertensive, antileukemic, antimalarial, antimycobacterial, antioxidant, antipyretic, cardiotonic, cytotoxic, hypoglycemic, and vasorelaxing activity, as well as antifeedant and insect growth-inhibitory properties. Thus, genus Ajuga has significant medicinal and economic importance. PMID- 19783525 TI - An extremely simple method for extraction of lysophospholipids and phospholipids from blood samples. AB - Lipids, lysophospholipids and phospholipids in particular, have been shown to be biomarkers and potential therapeutic targets for human diseases. While many extraction and analytical methods have been developed for quantitative analyses of these molecules, most of them are laborious and time-consuming, with associated issues of poor reproducibility. This becomes one of the critical bottle-necks to move lipid markers to clinics. In the current work, we have developed an extremely simple method for lysophospholipids and phospholipids extraction from human plasma or serum samples, which only utilizes a single methanol (MeOH) solvent and involves a single step of centrifugation. This method has been subjected to strict validation by comparing it with classical lipid extraction methods. This simple method will be extremely useful for the lipidomic, diseases marker, and lipid biochemistry fields not only for its potential wide applications associated with its simplicity and reproducibility, but also for its impact in moving lipid markers into clinics through high throughput processing. PMID- 19783526 TI - Bringing retinoid metabolism into the 21st century. PMID- 19783528 TI - A subset of dysregulated metabolic and survival genes is associated with severity of hepatic steatosis in obese Zucker rats. AB - We aimed to characterize the primary abnormalities associated with fat accumulation and vulnerability to hepatocellular injury of obesity-related fatty liver. We performed functional analyses and comparative transcriptomics of isolated primary hepatocytes from livers of obese insulin-resistant Zucker rats (comprising mild to severe hepatic steatosis) and age-matched lean littermates, searching for novel genes linked to chronic hepatic steatosis. Of the tested genome, 1.6% was identified as steatosis linked. Overexpressed genes were mainly dedicated to primary metabolism (100%), signaling, and defense/acute phase (approximately 70%); detoxification, steroid, and sulfur metabolism (approximately 65%) as well as cell growth/proliferation and protein synthesis/transformation (approximately 70%) genes were downregulated. The overexpression of key genes involved in de novo lipogenesis, fatty acid and glycerolipid import and synthesis, as well as acetyl-CoA and cofactor provision was paralleled by enhanced hepatic lipogenesis and production of large triacylglycerol-rich VLDL. Greatest changes in gene expression were seen in those encoding the lipogenic malic enzyme (up to 7-fold increased) and cell-to-cell interacting cadherin 17 (up to 8-fold decreased). Among validated genes, fatty acid synthase, stearoyl-CoA desaturase 1, fatty acid translocase/Cd36, malic enzyme, cholesterol-7 alpha hydroxylase, cadherin 17, and peroxisome proliferator activated receptor alpha significantly correlated with severity of hepatic steatosis. In conclusion, dysregulated expression of metabolic and survival genes accompany hepatic steatosis in obese insulin-resistant rats and may render steatotic hepatocytes more vulnerable to cell injury in progressive nonalcoholic fatty liver disease. PMID- 19783529 TI - A report on the 2009 SIG on short read sequencing and algorithms (Short-SIG). PMID- 19783527 TI - The genetic architecture of lipoprotein subclasses in Gullah-speaking African American families enriched for type 2 diabetes: the Sea Islands Genetic African American Registry (Project SuGAR). AB - We sought to partition the genetic and environmental influences on lipoprotein subclasses and identify genomic regions that may harbor genetic variants that influence serum lipoprotein levels in a sample of Gullah-speaking African Americans. We genotyped 5,974 SNPs in 979 subjects from 418 pedigrees and used the variance component approach to compute heritability estimates, genetic and environmental correlations, and linkage analyses for selected lipoprotein subclasses. The highest heritability estimate was observed for large VLDL particle concentration (0.56 +/- 0.14). Mean LDL particle size and small LDL particle concentration (-0.94) had the strongest genetic correlation estimate. The highest logarithm of odds (LOD) score detected (3.0) was on chromosome 6p24 for small LDL particle concentration. The strongest signal, obtained with the reduced sample of diabetic individuals only, was observed on chromosome 20p13 for small LDL particle concentration. The highest bivariate linkage signal (LOD 2.4) was observed on chromosome 6p24 for mean LDL particle size and small LDL particle concentration. Our results suggest a significant genetic contribution to multiple lipoprotein subclasses studied in this sample and that novel loci on chromosomes 6, 10, 16, and 20 may harbor genes contributing to small, atherogenic LDL particle concentration and large, triglyceride-rich VLDL particle concentration. PMID- 19783530 TI - Injuries, risk factors and prevention initiatives in youth sport. AB - BACKGROUND: Sports injuries in young athletes are a public health issue which deserves special attention. Effective prevention can be achieved with training programmes originating from the field of physical therapy and medicine. SOURCES OF DATA: A systematic literature search on injury prevention in youth sport was performed in the MEDLINE database. AREAS OF AGREEMENT: For prevention programmes to reduce sports injuries, critical factors must be considered, such as training content, duration and frequency, as well as athlete compliance. AREAS OF CONTROVERSY: Home-based programmes could be inferior to supervised training, but are efficient if compliance is high. So far prevention programmes have focused on team sports and their efficiency in individual sports remains to be proven. GROWING POINTS: Active prevention programmes focusing specifically on the upper extremity are scarce. Initiatives enhancing the awareness of trainers, athletes and therapists about risk factors and systematic prevention measures should be encouraged. PMID- 19783531 TI - Changes in intellectual functioning associated with normal aging. AB - Declines in IQ scores with advancing age have been observed in each successive revision of the Wechsler Intelligence Scales. This study examined age-related changes on the fourth edition of the Wechsler Adult Intelligence Scale and compared these to the effects seen on the 1955, 1981, and 1997 standardizations of the scales. The most pronounced declines were in measures of processing speed and nonverbal reasoning. Declines in nonverbal reasoning were similar on timed and un-timed measures. Verbal abilities remained relatively stable across the life span. General intelligence as assessed by the Full Scale IQ was reduced about 1 SD by age 75 when corrections for age were removed. Age-related declines have become less pronounced since 1955, particularly on measures of processing speed. This effect was essentially linear, unrelated to concurrent IQ increases in the general population, and paralleled a 9-year increase in life expectancy during this time period. PMID- 19783533 TI - U.S. Health reform: a continuing imperative. AB - A new political climate in the United States has raised renewed hope for achieving much needed reform of the U.S. health care system. Opposition to reform raises old arguments, however, including warnings against "big government," currently focused on proposals to include a public plan option in health reform. But greater government involvement in health care is needed to achieve comprehensive reform. Further substantial delay in achieving reform is unthinkable; success will require continued and expanded support efforts. Although a strong public plan option would represent a significant step forward, continued advocacy by proponents of single-payer health care can help strengthen broader efforts to achieve public accountability. Supporters of meaningful health reform will need to continue their efforts long past the passage of reform legislation. PMID- 19783532 TI - BTS guidelines for the management of community acquired pneumonia in adults: update 2009. PMID- 19783534 TI - Massachusetts nurse practitioners step up as one solution to the primary care access problem: a political success story. AB - Massachusetts' political experience with efforts to insure all citizens provided a unique opportunity for nurse practitioners to address the growing need for access to primary care. Passage of a new statute to recognize nurse practitioners as primary care providers that health plan beneficiaries could choose was accomplished through strategic planning and political savvy. The results of a focused effort using the expertise of a professional lobbying team along with organizational support resulted in a groundbreaking new law that is a component of a reform model being examined by the nation as a whole, looking to address accessible, quality, and affordable health care. This article chronicles that journey and its accomplishment. PMID- 19783535 TI - Preconception care: practice and policy implications for nurses. AB - Statistical reports describe a troubling portrait of infant mortality in the United States today. This rate, an indicator of the health of a nation, has not declined in the past 5 years and is marked by enormous disparities among racial and ethnic groups. Although the overall infant mortality rate in the United States is 6.86 per 1,000 live births, the rate for non-Hispanic Black infants is 13.63 deaths per 1,000 live births. Among developed nations, the United States now ranks 29th in infant mortality. It is believed that lack of preconception care and late entry into prenatal care are contributing factors to infant mortality. Preconception care, although not a new concept, has not been universally adopted into the health care setting. This article examines the potential barriers to developing and using preconception care and policy implications related to nursing practice. PMID- 19783536 TI - Patient satisfaction of young adults in rural clinics: policy implications for nurse practitioner practice. AB - In an effort to increase primary care services to Medicare and Medicaid patients, the Rural Health Clinics Services Act of 1977 required collaborative practices to include mid-level providers such as nurse practitioners (NPs). As a result, NPs have increased access to primary care in many rural and underserved areas. Now, in an effort to improve quality of health care, the Centers for Medicare and Medicaid Services (CMS) initiated public reporting of health care quality indicators. Although patient satisfaction is recognized as a quality indicator, few researchers have investigated patient satisfaction with NPs in rural family practice. A patient satisfaction survey (PSS) was distributed to a convenience sample of 213 young adult patients seen by five nurse practitioners in two rural family practice clinics. Survey results are analyzed and discussed within the framework of current CMS policy initiatives such as performance measures, pay for performance (P4P), transparency, and public reporting. PMID- 19783537 TI - Predominant discourses in Swedish nursing. AB - The aim of this study was to elucidate the predominant discourse in the field of Swedish nursing in 2000, 25 years after nursing was introduced as an academic discipline in Sweden. The method used was content analysis and deconstructive analysis of discourses. Laws, statutes, regulations, and examination requirements, including official reports, recruitment campaigns, and media coverage, were analyzed. The findings uncovered competing discourses striving to gain hegemony. In the public sector, official requirements competed against the media fixation on gender stereotypes and the realities of local recruitment campaigns. Media has a major role in disseminating prevailing conceptions and conventions pertaining to the nursing profession. As a result, decision makers, students, patients, and family members could get lower expectations of the professional competence of nursing practitioners than would otherwise have been the case in the absence of media exposure. PMID- 19783538 TI - Magnesium sulphate has beneficial effects as an adjuvant during general anaesthesia for Caesarean section. AB - BACKGROUND: The use of low concentrations of volatile anaesthetics with avoidance of opioids may induce intraoperative awareness and adverse haemodynamic responses during Caesarean section. Magnesium is well known to reduce anaesthetic requirements and to block noxious stimuli. We investigated whether i.v. magnesium sulphate modulates anaesthetic depth and analgesic efficacy during Caesarean section. METHODS: Seventy-two patients undergoing Caesarean section were randomly assigned to receive i.v. saline (control group) or magnesium sulphate 30 mg kg( 1) bolus+10 mg kg(-1) h(-1) continuous infusion (Mg 30 group) or 45 mg kg(-1) bolus+15 mg kg(-1) h(-1) continuous infusion (Mg 45 group) after induction. Bispectral index (BIS) value, mean arterial pressure (MAP), and midazolam, fentanyl, and atracurium consumptions were recorded. RESULTS: BIS values [mean (sd)] at 7.5 and 10 min after surgery and before delivery in the control [64 (9), 66 (8), 67 (8), P<0.001] and the Mg 30 groups [62 (8), P<0.01; 64 (7), 63 (9), P<0.001] were higher than in the Mg 45 group [56 (8), 55 (8), 55 (7)]. MAP was greater in the control group (P<0.05) than in the Mg 30 and Mg 45 groups during the pre-delivery period. The magnesium groups required less midazolam (P<0.05), fentanyl (Mg 30, P<0.05; Mg 45, P<0.01), and atracurium (P<0.001) vs the control group. CONCLUSIONS: Preoperative i.v. magnesium sulphate attenuated BIS and arterial pressure increases during the pre-delivery period. Magnesium sulphate can be recommended as an adjuvant during general anaesthesia for Caesarean section to avoid perioperative awareness and pressor response resulting from inadequate anaesthesia, analgesia, or both. PMID- 19783539 TI - Randomized controlled trial of the Pentax AWS, Glidescope, and Macintosh laryngoscopes in predicted difficult intubation. AB - BACKGROUND: The purpose of this study was to determine the potential for the Pentax AWS and the Glidescope to reduce the difficulty of tracheal intubation in patients at increased risk for difficult tracheal intubation, in a randomized, controlled clinical trial. METHODS: Seventy-five consenting patients presenting for surgery requiring tracheal intubation, and who were deemed to possess characteristics indicating an increased risk for difficult tracheal intubation, were randomly assigned to undergo intubation using a Macintosh, AWS, or Glidescope laryngoscope (n=25 patients per group). All patients were intubated by one of three anaesthetists experienced in the use of each laryngoscope. RESULTS: Both the Glidescope and the AWS significantly reduced the intubation difficulty score compared with the Macintosh. The rate of successful tracheal intubation was lower with the Macintosh (84%) compared with the Glidescope (96%) or the AWS (100%). There were no differences in the duration of tracheal intubation attempts between the devices. Both the Glidescope and the AWS significantly reduced the need for additional manoeuvres and improved the Cormack and Lehane view obtained at laryngoscopy, compared with the Macintosh. Tracheal intubation with the AWS but not the Glidescope reduced the degree of haemodynamic stimulation compared with the Macintosh laryngoscope. CONCLUSIONS: The AWS and the Glidescope laryngoscopes reduced the difficulty of tracheal intubation to a similar extent compared with the Macintosh laryngoscope, in patients at increased risk for difficult tracheal intubation. PMID- 19783540 TI - Arabidopsis NIP1;1 transports antimonite and determines antimonite sensitivity. AB - Antimony (Sb) is toxic to organisms including plants. Although it is not essential to organisms, plants take up Sb from the environment. In this study, we identified an antimonite [Sb(III)] transporter from Arabidopsis thaliana. We examined the Sb(III) tolerance of the disruption mutant plants of arsenite [As(III)] transporters, nodulin 26-like intrinsic proteins (NIPs), since Sb(III) is similar to As(III) in structure. One of the mutants, nip1;1, showed Sb(III) tolerance and accumulated less Sb. Furthermore, yeast expressing NIP1;1 accumulated twice as much Sb as control. These data indicate that NIP1;1 transports Sb(III) and determines the Sb(III) sensitivity of A. thaliana. PMID- 19783541 TI - Dazl promotes germ cell differentiation from embryonic stem cells. AB - It has been demonstrated that through the formation of embryoid bodies (EBs) germ cells can be derived from embryonic stem (ES) cells. Here, we describe a transgene expression approach to derive germ cells directly from ES cells in vitro without EB formation. Through the ectopic expression of Deleted in Azoospermia-Like (Dazl), a germ cell-specific RNA-binding protein, both motile tailed-sperm and oocytes were induced from mouse ES (mES) cells in culture. Furthermore, transient overexpression of Dazl led to suppression of Nanog but induced germ cell nuclear antigen in mES cells. Dazl knockdown resulted in reduction in the expression of germ cell markers including Stella, MVH and Prdm1. Our study indicates that Dazl is a master gene controlling germ cell differentiation and that ectopic expression of Dazl promotes the dynamic differentiation of mouse ES cells into gametes in vitro. PMID- 19783542 TI - A Pom1 gradient is made to measure. AB - In order for cell division to proceed, fission yeast must first attain critical cell size. The mechanism by which size is detected had not been identified until two recent studies showed that cells utilize an intracellular gradient of Pom1p kinase to measure cell length. PMID- 19783544 TI - Surgical treatment of a rare case of tracheal inflammatory pseudotumor in pediatric age. AB - Tracheal inflammatory pseudotumor (IPT) is a rare solid lesion with an unpredictable biological course. Treatment can vary and surgical resection may sometimes be necessary, even in pediatric age. We report the case of a 12-year old male patient who presented to our institution with sudden dyspnoea after some months of wheezing and cough, wrongly considered and treated as asthma. Neck chest CT-scan and fiberbronchoscopy showed an intraluminal tracheal mass, originating from the left antero-lateral wall at the level of the 5th cartilagineous tracheal ring, involving three rings, that was removed by rigid bronchoscopy. Histopathology revealed a tracheal IPT. Due to rapid tendency to recurrence of the lesion, two more endoscopic recanalizations were performed, but a new recurrence appeared, with CT evidence of transmural involvement of the tracheal wall. Resection of the three involved tracheal rings and termino terminal tracheal anastomosis were successfully performed through cervicotomy and sternal split. CT-scan and fiberbronchoscopy at 17 months from surgery show a stable tracheal lumen without signs of recurrence. A tracheal IPT should be suspected in any pediatric patients with tracheal mass and asthmatic symptoms. After radical removal prognosis is generally excellent and recurrences after tracheal resection are rare. PMID- 19783545 TI - Heparin induced thrombocytopenia in a patient with factor V Leiden following cardiac surgery. AB - We report a patient who died as a result of heparin induced thrombocytopenia (HIT) and arterial thromboses following cardiac surgery. The onset was three days after exposure to low molecular weight heparin on the eighth postoperative day. The patient was heterozygous for the factor V Leiden mutation. We have reviewed 15 patients previously diagnosed as HIT on clinical and laboratory criteria and found an incidence of 6.7% (1/15) activated protein C resistance. This second patient had a pulmonary embolus and HIT after only three days exposure to low molecular weight heparin. We postulate that factor V Leiden hastens the onset and magnifies the severity of HIT. PMID- 19783543 TI - The TET family of proteins: functions and roles in disease. AB - Translocated in liposarcoma, Ewing's sarcoma and TATA-binding protein-associated factor 15 constitute an interesting and important family of proteins known as the TET proteins. The proteins function in several aspects of cell growth control, including multiple different steps in gene expression, and they are also found mutated in a number of specific diseases. For example, all contain domains for binding nucleic acids and have been shown to function in both RNA polymerase II mediated transcription and pre-mRNA splicing, possibly connecting these two processes. Chromosomal translocations in human sarcomas result in a fusion of the amino terminus of these proteins, which contains a transcription activation domain, to the DNA-binding domain of a transcription factor. Although the fusion proteins have been characterized in a clinical environment, the function of the cognate full-length protein in normal cells is a more recent topic of study. The first part of this review will describe the TET proteins, followed by detailed descriptions of their multiple roles in cells. The final sections will examine changes that occur in gene regulation in cells expressing the fusion proteins. The clinical implications and treatment of sarcomas will not be addressed but have recently been reviewed. PMID- 19783546 TI - Crutch-induced bilateral brachial artery aneurysms. AB - A 57-year-old man, who was a chronic axillary crutch user as a result of childhood poliomyelitis, was referred to our hospital because of a sudden onset of right forearm ischemia. The right forearm had no pulse, and three-dimensional computed tomography (3DCT) showed an aneurysm of the right brachial artery associated with arterial occlusion. The thrombosed aneurysm of the brachial artery was resected and the brachial artery was successfully revascularized by interposing a saphenous vein graft. Postoperative 3DCT revealed an asymptomatic left brachial artery aneurysm. His postoperative course was uneventful under warfarin anticoagulation therapy. PMID- 19783547 TI - Graft fixation with a side graft holder for sequential and composite graft anastomosis in coronary artery bypass surgery. AB - The purpose of this study was to assess the feasibility and effectiveness of graft fixation with a novel side graft holder for sequential or composite graft anastomosis in coronary artery bypass grafting (CABG). Records of 34 patients who underwent CABG using sequential or composite graft anastomosis technique were reviewed. The device was used on 47 anastomoses (sequential=43; composite graft=4). Excellent fixation and visualization of the graft was obtained in all patients without graft injury. Postoperative angiographic patency rate of distal anastomoses was 95.2% (arterial, 91.2%; venous, 96.7%). All sequential and composite graft anastomoses were patent and without stenosis. One operative death occurred due to low cardiac output after emergent CABG for acute myocardial infarction. No elective patient died during hospitalization. Postoperative complications occurred in two patients (ventricular fibrillation, 1; postoperative catheter intervention, 1). No perioperative myocardial infarctions or re-operations occurred. Our clinical experience shows that graft fixation with the device is safe, reliable, and effective for sequential and composite graft anastomosis during CABG. PMID- 19783548 TI - Preventing Ataxin-3 protein cleavage mitigates degeneration in a Drosophila model of SCA3. AB - Protein cleavage is a common feature in human neurodegenerative disease. Ataxin-3 protein with an expanded polyglutamine (polyQ) repeat causes spinocerebellar ataxia type-3 (SCA3), also called Machado-Joseph disease, and is cleaved in mammalian cells, transgenic mice and SCA3 patient brain tissue. However, the pathological significance of Ataxin-3 cleavage has not been carefully examined. To gain insight into the significance of Ataxin-3 cleavage, we developed a Drosophila SL2 cell-based model as well as transgenic fly models. Our data indicate that Ataxin-3 protein cleavage is conserved in the fly and may be caspase-dependent as reported previously. Importantly, comparison of flies expressing either wild-type or caspase-site mutant proteins indicates that Ataxin 3 cleavage enhances neuronal loss in vivo. This genetic in vivo confirmation of the pathological role of Ataxin-3 cleavage indicates that therapies targeting Ataxin-3 cleavage might slow disease progression in SCA3 patients. PMID- 19783549 TI - Detecting natural selection by empirical comparison to random regions of the genome. AB - Historical episodes of natural selection can skew the frequencies of genetic variants, leaving a signature that can persist for many tens or even hundreds of thousands of years. However, formal tests for selection based on allele frequency skew require strong assumptions about demographic history and mutation, which are rarely well understood. Here, we develop an empirical approach to test for signals of selection that compares patterns of genetic variation at a candidate locus with matched random regions of the genome collected in the same way. We apply this approach to four genes that have been implicated in syndromes of impaired neurological development, comparing the pattern of variation in our re sequencing data with a large-scale, genomic data set that provides an empirical null distribution. We confirm a previously reported signal at FOXP2, and find a novel signal of selection centered at AHI1, a gene that is involved in motor and behavior abnormalities. The locus is marked by many high frequency derived alleles in non-Africans that are of low frequency in Africans, suggesting that selection at this or a closely neighboring gene occurred in the ancestral population of non-Africans. Our study also provides a prototype for how empirical scans for ancient selection can be carried out once many genomes are sequenced. PMID- 19783550 TI - Incidence of retinoblastoma in Dutch children conceived by IVF: an expanded study. AB - BACKGROUND: In 2003, we reported an increased risk of retinoblastoma in children conceived by IVF between 1995 and 2002. However, population-based studies among children conceived by IVF did not find an elevated risk of retinoblastoma. METHODS: From nationwide estimates of numbers of live births conceived by IVF (n = 40 330), we estimated the expected numbers of patients with retinoblastoma conceived by IVF in the period 1995-2007. The observed number of retinoblastoma diagnoses in children conceived by IVF was obtained by questionnaires sent to the parents of children with retinoblastoma diagnosed between 1995 and 2005. For non responders and patients diagnosed after 2005, information was available through the medical files, in which information on fertility treatment has been routinely recorded since 2000. The relative risk (RR) of retinoblastoma among children conceived by IVF was calculated for the total study period (1995-2007) and for the expanded study period (2002-2007). RESULTS: Of all eligible patients with retinoblastoma (n = 162) diagnosed in the period 1995-2007, seven were conceived by IVF. In the total study period (1995-2007) the risk was significantly elevated [RR = 2.54, 95% confidence interval (CI) = 1.02-5.23]. In the expanded study period (2002-2007), no significantly elevated risk (RR = 1.29, 95% CI = 0.16 4.66) was found. CONCLUSIONS: We found a significantly increased risk of retinoblastoma in children conceived by IVF in the total study period 1995-2007. However, this increased risk was mostly based on the much stronger risk increase observed previously, for 1995-2002. Caution and awareness on the one hand and avoiding unnecessary worries on the other hand are important at this stage of our knowledge. PMID- 19783552 TI - Phase II trial of weekly gemcitabine and split-dose cisplatin for advanced non small-cell lung cancer. AB - OBJECTIVE: Cisplatin is widely used for the treatment of non-small-cell lung cancer. However, it can cause unpleasant side effects and also requires prolonged hydration. We conducted a Phase II study of weekly gemcitabine and split-dose cisplatin in patients with advanced non-small-cell lung cancer (NSCLC) in order to reduce toxicity and shorten the time taken by administration. Our aims were to determine the response rate, toxicity and survival time with this regimen in patients with Stage IIIB/IV disease. METHODS: Previously untreated patients with Stage IIIB/IV NSCLC were given gemcitabine (1000 mg/m(2)) and split-dose cisplatin (40 mg/m(2)) on days 1 and 8 at 3-week intervals for four cycles. Gemcitabine was administered over the course of 30 min, and cisplatin was over the course of 60 min on the same days on an outpatient basis. RESULTS: Forty-five patients were enrolled, and all of them were assessable for response and toxicity. None had a complete response and 17 had a partial response (37.8%), for an overall response rate of 37.8% (95% confidence interval, 25.1-52.4%). The survival rate was 56.5% at 1 year and 38.9% at 2 years, with a median survival time of 15.7 months. Leukopenia, neutropenia, anemia and thrombocytopenia were the most common toxic reactions, with Grade > or = 3 reactions occurring at rates of 35%, 51%, 31% and 13%, respectively. CONCLUSIONS: Weekly gemcitabine and split dose cisplatin is active and well tolerated in patients with Stage IIIB/IV NSCLC, administered on an outpatient basis without requiring prolonged hydration or hospitalization. PMID- 19783553 TI - Coronary sequelae of mitral stenosis. PMID- 19783551 TI - Phase I clinical and pharmacokinetic study of RAD001 (everolimus) administered daily to Japanese patients with advanced solid tumors. AB - OBJECTIVE: To determine the pharmacokinetics and safety of RAD001 (everolimus) in Japanese patients with advanced solid tumors. METHODS: An open-label, non randomized, dose-escalation Phase I study of RAD001 administered continuously once daily in a 28-day cycle was performed. The study had a '3 + 3' design, with three patients recruited to each of three successive cohorts treated with RAD001 at 2.5, 5.0 or 10.0 mg/day. RESULTS: The pharmacokinetics of RAD001 in Japanese patients were similar to those previously determined in Caucasians. The drug safety profile was consistent with that of a mammalian target of rapamycin inhibitor. No dose-limiting toxicities were observed. One patient with esophageal cancer and one with gastric cancer treated with RAD001 at 10 mg/day showed marked tumor responses. CONCLUSIONS: Treatment of Japanese cancer patients with RAD001 may be undertaken with the expectation that previously determined pharmacokinetic and safety profiles apply. The drug may hold promise for treatment of esophageal and gastric cancer. PMID- 19783554 TI - C-reactive protein: not only a marker but also a mediator of myocardial damage following acute myocardial infarction. PMID- 19783555 TI - Radiation safety system. AB - The goal of this work is to provide an overview of a Radiation safety system (RSS) designed for protection from prompt radiation hazard at accelerator facilities. RSS design parameters, functional requirements and constraints are derived from hazard analysis and risk assessment undertaken in the design phase of the facility. The two main subsystems of a RSS are access control system (ACS) and radiation control system (RCS). In this text, a common approach to risk assessment, typical components of ACS and RCS, desirable features and general design principles applied to RSS are described. PMID- 19783556 TI - Automated effective dose estimation in CT. AB - European regulations require the dose delivered to patients in CT examinations to be monitored and checked against reference levels. Dose estimation has traditionally been performed manually. This is time consuming and therefore it is typically performed on just a few patients and the results extrapolated to the general case. In this work an automated method to estimate the dose in CT studies is presented. The presented software downloads CT studies from the corporative picture archiving and communication system and uses the information on the DICOM headers to perform the dose calculation. Automation enables dose estimations to be performed on a larger fraction of studies, enabling more significant comparisons with diagnostic reference levels (DRLs). A preliminary analysis involving 5800 studies is presented with details of dose distributions for selected CT protocols in use at a university hospital. Average doses are compared with DRLs. Effective dose estimations are also compared with estimations based on the dose length product. PMID- 19783557 TI - Diversity in public health issues. PMID- 19783558 TI - Alcohol expectancies among high school students in Inner Mongolia, China. AB - OBJECTIVE: This study examines differences in Chinese high school students' alcohol expectancies by drinking status (nondrinker, occasional drinker, regular drinker) and gender (male, female). METHOD: The authors administered the Chinese Adolescent Alcohol Expectancy Questionnaire (CAEQ) to a convenience sample of 1244 high school students (M = 627; F = 617) from schools in Huhhot City and Tongliao City in Inner Mongolia, China. RESULTS: Differences were found in the 8 CAEQ factors (3 negative and 5 positive factors). Regular drinkers had lower negative consequences and higher positive perception expectancies than nondrinkers or occasional drinkers. Nondrinkers had higher harm to person/reputation expectancies than occasional or regular drinkers. Occasional drinkers had higher beneficial/moderation and lower harm to person/ reputation expectancies than nondrinkers. Boys had higher positive perception expectancies than girls. CONCLUSIONS: Expectancies are associated with Chinese adolescents' drinking. Identifying the characteristics of alcohol consuming youth can inform the development of prevention interventions and alcohol policies. PMID- 19783559 TI - Factors contributing to utilization of health care services in Malaysia: a population-based study. AB - OBJECTIVE: This paper examines the factors contributing to the under utilisation of health care services in the Malaysian population. METHODOLOGY: Using data derived from Malaysian Mental Health Survey (MMHS) information on utilisation of four basic health services in the previous three months, namely contact with health care professionals, ward admissions, having diagnostic or laboratory tests done and being on any medications were obtained. RESULTS: A total of 2202 out of 3666 or 60% of the MMHS participants were included in this study. Thirty percent of the subjects (n = 664) had contacts with health care professionals. Those with health complications, disabilities and those aged 50 years and above utilised health services more significantly as compared to those who lacked health facilities near their homes, had little family support during illnesses and were from the Chinese ethnic group. CONCLUSION: Factors leading to the under utilisation of health care services need to be further studied and needs in certain groups in the population should be addressed. Healthcare providers must be prepared to fulfil these needs. PMID- 19783560 TI - Sexual behavior model among young Thai women living in slums in Bangkok, Thailand. AB - There has been a dramatic drop in age at first intercourse and concurrent rise in HIV infections among young Thai women living in slums. The participants included 492 young Thai women (average age = 19.7 years). They provided detailed self perception, emotion, sexual self-efficacy, cognitive strategies, and power in relationships. Logistic regression analysis was used to explore sexual behavior model. Findings highlight the extreme vulnerability of Thai female adolescents who engage in risky sexual behaviors: 55.8% were sexually active with 41.8% having vaginal sex without using condom. Significant enabling factors included perceived ability to precautions (odds ratio [OR] = 1.7), relational gain thinking (OR = 1.5), and curious gain thinking (OR = 1.3). The significant protective factors were decision-making dominance (OR = 0.3), perceived ability to say no (OR = 0.7), and ethical-related punishment avoidance thinking (OR = 0.8). These findings contribute to greater understanding of factors involved in sexual risk taking. Implications for behavioral modification addressing cognition and power in relationships are discussed. PMID- 19783561 TI - A phase II randomized controlled trial to evaluate the safety and efficacy of Praneem polyherbal vaginal tablets compared with betadine vaginal pessary in women with symptoms of abnormal vaginal discharge. AB - Abnormal vaginal discharge (AVD) caused by a variety of reproductive tract infections is a widespread syndrome among women in India and in other developing countries. The purpose of this study was to determine whether a polyherbal formulation, Praneem, can be used for the regression of the syndrome. A phase IotaIota randomized controlled study was carried out with Praneem polyherbal tablets and Betadine vaginal pessary in 99 women with AVD. The authors found that 92% of women using Praneem were relieved of their symptoms of AVD as against 81.6% women using Betadine. Significant reduction was also seen with both treatments in lower abdominal pain, vaginal itching, and dysuria. Thus, the study indicates the efficacy of Praneem for the treatment of AVD and provides a rationale for planning a further Phase III study on a larger sample size for definitive conclusions. PMID- 19783562 TI - Public health and health services development in postconflict communities: a case study of a safe motherhood project in East Timor. AB - Armed conflict causes suffering in many countries; it contributes to poor health and hinders health services development. The effects of conflict are evidenced by weakened community structures and can make reconstruction efforts challenging. East Timor has a history of prolonged conflict and saw a resurgence of internal violence in 2006. This participant observation study discusses considerations for implementing public health and health systems development projects in postconflict settings using a case study of a maternal and child health project. It illustrates the importance of appreciating the historical context and community dynamics when implementing development projects. The sequelae of conflict are often characterized by reduced human resource development capacity, distrust of hierarchy, and limited capacity for resource mobilization. Working in such postconflict communities requires flexibility in program design, stronger efforts for community capacity building, and rebuilding trust between various stakeholders. PMID- 19783563 TI - Migration and hypertension: a cross-sectional study among neo-migrants and settled-migrants in Delhi, India. AB - Understanding the blood pressure (BP) distribution within populations is fundamental to an understanding of the etiology of cardiovascular diseases and to develop effective preventive strategies. This study focuses on whether the BP levels and hypertension prevalence differ between neo-migrants and settled migrants in the city of Delhi. Data on BP, anthropometry, social variables, and demographic variables were collected from a cross-sectional sample of 226 settled migrants and 227 neo-migrants. Men possessed significantly higher BP levels than women. Settled-migrants possessed higher BP levels, except diastolic BP in males. The prevalence of hypertension ranges from 15% (neo-migrant women) to 25% (settled-migrant men), with no significant gender differences. Group differences were significant for men. Hypertension was more prevalent in older settled migrants and younger neo-migrants. Recent migration was found to be a significant contributor to hypertension prevalence. Age contributed significantly to BP variation in both groups except in neo-migrant men. Pulse rate also contributed to systolic BP among neo-migrant women and settled-migrant men. Thus, urban residence and migration to urban areas can be a leading cause of increased prevalence of hypertension. Neo-migrants were subjected to more lifestyle insults and the stress generated during the adjustment process may be contributing to rise of BP even at younger ages. PMID- 19783564 TI - A survey of occupational exposure to blood and body fluids in physiotherapists in Western Australia. AB - The aim of this pilot project was to investigate the occurrence of occupational exposure to blood and body fluids in registered physiotherapists in Western Australia. Surveys were sent to physiotherapists with questions regarding personal background, exposure characteristics, and contributing factors included. Descriptive statistical methods were used to identify the area of practice posing the highest risk of exposure to physiotherapists. The authors found that 56.1% of surveyed physiotherapists recorded one or more exposures within the past 5 years. Work in hospitals was found to carry the highest rate of exposure for the physiotherapy profession. Other areas of practice, including community work, private practice, nursing homes/hostels, and work at sporting events carry comparable but lower risks of exposure. In private practice, 50% of exposures were associated with acupuncture. In nursing homes, 60% of exposures were brought on by exposure to contaminated materials, whereas in the community setting most exposures (64%) were attributed to unpredictable/uncontrollable situations. At sporting events, 90% of all exposures were associated with already existing sources of blood and body fluids (wounds). Within the hospital setting, the 3 dominant immediate causes reported were unpredictable situations (33.3%), existing sources (28.4%), and procedural causes (22.2%). The use of personal protective equipment for prevention of exposure is investigated and discussed. Data collected for this survey were not enough to draw conclusive assumptions regarding hazard management. A repeat of this study on a larger scale may provide physiotherapists with the tools and knowledge to minimize the likelihood of exposure and harm arising from exposure. PMID- 19783565 TI - A time to raise our voice(s). PMID- 19783566 TI - Single-site laparoscopic sleeve gastrectomy: preclinical use of a novel multi access port device. AB - INTRODUCTION: Single-site laparoscopy (SSL) has emerged as an alternative technique for sleeve gastrectomy. The author describes the preclinical technique of SSL sleeve gastrectomy through a novel multichannel port device in the porcine model. METHODS: Anesthetized swine underwent 3-cm longitudinal supra-umbilical incision. A multichannel port device was inserted. A gastric sleeve was created by multiple applications of a 60-mm stapler. The access device's channel housing was removed and the sleeve specimen exteriorized. RESULTS: The mean operative time was 60+/-10 minutes, and the mean estimated blood loss was 30+/-5 cc. The multichannel port device allowed induction and maintenance of pneumoperitoneum throughout the procedure (range 12-15 mm Hg) with efficient rotation and substantial abdominal wall torque and minimal instrument clashing. CONCLUSION: SSL sleeve gastrectomy in the porcine model was facilitated by the use of a novel multichannel port device. Clinical studies are warranted. PMID- 19783567 TI - Barbed suture for gastrointestinal closure: a randomized control trial. AB - In an effort to make laparoscopic suturing more efficient, the V-Loc advanced wound closure device (Covidien, Mansfield, MA) has been produced. This device is a self-anchoring barbed suture that obviates the need for knot tying. The goal of this initial feasibility study was to investigate the use of the barbed suture in gastrointestinal enterotomy closure. A randomized study of 12 pigs comparing enterotomy closure with barbed versus a nonbarbed suture of similar tensile strength was performed. To this end, 25 mm enterotomies were made in the stomach (1 control, 1 treatment), jejunum (2 controls, 2 treatments), and descending colon (1 control, 1 treatment). Animals were killed at 3, 7, and 14 days postoperatively (4 each group) and their gastrointestinal tracts harvested; 6 of the 8 enterotomies from each pig underwent burst strength testing. The remaining 2 were fixed in formalin and sent for histological examination. All 12 pigs survived until they were killed without any major complications. Enterotomy closure with barbed suture revealed adhesion scores, burst strength pressures, and histology scores that were similar to those for the control. Jejunal closures resulted in 6 failures at 7 days (3 control, 3 barbed) and 4 failures at 14 days (2 control, 2 barbed). The barbed suture significantly reduced suturing time in the stomach, jejunum, and colon. The V-Loc wound closure device appears to offer comparable gastrointestinal closure to 3-0 Maxon while being significantly faster. Further studies with V-Loc are required to assess its use in laparoscopic surgery. PMID- 19783569 TI - The effect of claudication pain on temporal and spatial gait measures during self paced ambulation. AB - We determined the effect of claudication pain on temporal and spatial gait characteristics, and on ambulatory symmetry at preferred and rapid self-selected walking paces in patients with unilateral peripheral arterial disease (PAD). Twenty-eight patients with PAD limited by intermittent claudication were studied. Patients ambulated at their preferred and rapid paces over a 7.3-meter portable gait mat system while they were pain-free and after experiencing claudication pain. The order of the pain-free and painful walking trials was randomized, and the following gait parameters were obtained: velocity, cadence, stride length, swing time, stance time, single-support time, and double-support time. During the self-selected rapid pace, patients walked 3% slower (p = 0.020) while in pain due to a 3% shorter stride length (p < 0.001), and they were in double-stance longer (p = 0.024). Claudication pain in the symptomatic leg resulted in an increase in single-stance (p = 0.007). Furthermore, gait became asymmetrical with pain, as the symptomatic leg spent a higher percentage of the gait cycle in the swing phase (p < 0.01) and lower percentages in stance (p < 0.01) and single-stance (p < 0.01) than the asymptomatic leg. Ambulation was symmetrical for all measures during the pain-free trial. In conclusion, claudication pain slows ambulatory velocity at preferred and rapid paces, and increases asymmetry when ambulatory function is challenged with rapid walking. The reduced ambulatory speed with the development of claudication pain may be an adaptation to elicit a safer and less destabilizing gait pattern. PMID- 19783570 TI - Increased intima thickness of the radial artery in patients with coronary heart disease. AB - Ultrabiomicroscopy is a novel high-frequency (55 MHz) ultrasound technique that could be used to non-invasively measure the vessel wall and separate the intima media complex into measurements of intima and media thickness. Since no previous study has measured intima and media thickness separately in vivo in patients with coronary heart disease (CHD), the aim of the current study was to measure intima and intima-media thickness of the radial and the anterior tibial arteries among patients with CHD and healthy subjects (HS). Thirty-two patients with CHD and 46 HS underwent investigations with ultrabiomicroscopy measurements of the radial and anterior tibial arteries. Patients with CHD showed a 19% increase in intima thickness of the radial artery compared with HS (0.088 +/- 0.024 mm versus 0.074 +/- 0.015 mm; p < 0.015), whereas no difference was seen in media thickness. There were no differences in intima or media thickness within the anterior tibial arteries. In conclusion, CHD is associated with thickening of the intima of the radial artery whereas media thickness was unchanged compared with HS. Assessment of intima thickness by high-frequency ultrasound may provide a tool for non invasive early detection of atherosclerosis. PMID- 19783571 TI - Evaluation of genotoxicity of pan masala employing chromosomal aberration and micronucleus assay in bone marrow cells of the mice. AB - Pan masala is commonly consumed in south-east Asian and other oriental countries as an alternate of tobacco chewing and smoking. Genotoxic potential of pan masala (pan masala plain and pan masala with tobacco known as gutkha) was evaluated employing chromosome aberration (CA) and micronucleus (MN) assay in vivo. Animals were exposed to three different doses (0.5%, 1.5% and 3%) of pan masala plain (PMP) and gutkha (PMT) through feed for a period of 6 months and micronucleus and chromosomal aberrations were studied in the bone marrow cells. Induction of mean micronuclei in polychromatic erythrocytes (MNPCE) and normochromatic erythrocyte (MNNCE) was higher in both types of pan masala treated groups with respect to control group. Both pan masala plain and gutkha treatment significantly induced the frequency of MNPCE and MNNCE in the bone marrow cells, indicating the genotoxic potential. Furthermore, slight decline in the ratio of polychromatic erythrocytes to normochromatic erythrocytes was also noticed, suggesting the cytotoxic potential even though the ratio was statistically non significant. A dose-dependent, significant increase in chromosome aberration was observed in both types of pan masala treated mice with respect to control. However, no significant difference in micronucleus and chromosomal aberration induction was noticed between two types of pan masala exposed (PMP and PMT) groups. Results suggest that both types of pan masala, i.e. plain and gutkha, have genotoxic potential. PMID- 19783572 TI - Transforming growth factor-beta3 expression up-regulates on cleft palates induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin in mice. AB - 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has been shown to induce cleft palate, in which the molecular etiology of the defect is poorly characterized. Recently, transforming growth factor-beta3 (TGF-beta3) has been indicated to play an essential role in the development of palatal shelves. In this developmental toxicity study, we investigated the effects of 2,3,7,8-tetrachlorodibenzo-p dioxin (TCDD) on the expression of TGF-beta3 in fetal mice. Pregnant C57BL/6 mice were exposed to corn oil or TCDD (32 microg/kg/day 64 microg/kg/day, per os) at embryonic day 10 (ED10), a drastic inhibition of palatal shelves was induced. By using RT-PCR (reverse transcription-polymerase chain reaction) and Western blot, the expressions of TGF-beta3 was investigated. We found that the expression of TGF-beta3 was gradually up-regulated in TCDD-treated group. These results suggest that cleft palate can be induced by TCDD exposure, the modification of TGF-beta3 is related to its pathogenesis. PMID- 19783573 TI - The effect of the prenatal and post-natal long-term exposure to 50 Hz electric field on growth, pubertal development and IGF-1 levels in female Wistar rats. AB - To investigate prenatal and post-natal effects of extremely low frequency (ELF) electric field (EF) on growth and pubertal development, pregnant Wistar rats were randomly distributed among three groups. The pregnant rats of the prenatal group were exposed to 24-hour EF at 50 Hz EF 10 kV/min during pregnancy and their subsequent randomly selected female pups continued to be exposed until puberty. The post-natal group was unexposed to EF during pregnancy, but randomly selected female pups from this group were exposed to EF between delivery and puberty at the same doses and duration as the prenatal group. The third group was a sham exposed group. The mean birth weight and weight gain of the pups during study period were found significantly reduced in prenatal group than post-natal and sham-exposed groups (p < 0.001). No difference could be found among the three groups for body weight at puberty (p > 0.05). The mean age at vaginal opening and estrous were significantly higher at prenatal group than post-natal and sham exposed groups (p < 0.001). Serum insulin-like growth hormone-1 (IGF-1) levels were found significantly reduced in prenatal exposure group compared with the other two groups (p < 0.001). There was no difference for birth weight, weight gain, the mean age at vaginal opening and estrous and IGF-1 levels between post natal and sham-exposed groups (p > 0.05). There was also no difference for FSH, LH and E2 levels at puberty among the three groups (p > 0.05). Histological examination revealed that both the prenatal and post-natal groups had the evidence of tissue damage on hypothalamus, pituitary gland and ovaries. In conclusion, early beginning of prenatal exposure of rats to 24 hours 50 Hz EF at 10 kV/m until puberty without magnetic field (MF) resulted in growth restriction, delayed puberty and reduced IGF-1 levels in female Wistar rats. These effects probably associated with direct toxic effects of EF on target organs. Post-natal exposure to EF at similar doses and duration seems to be less harmful on target organs. Post-natal exposure to EF at similar doses and duration seems to be less harmful. PMID- 19783574 TI - Effects of piperonyl butoxide on spontaneous behavior in F1-generation mice. AB - Piperonyl butoxide was given in the diet to provide levels of 0 (control), 0.02%, 0.06%, and 0.18% from 5 weeks of age of the F(0) generation to 12 weeks of age of the F(1) generation in mice. Select reproductive and neurobehavioral parameters were then measured. In exploratory behavior in the F(0) generation, vertical time of adult females increased significantly in a dose-related manner. In behavioral developmental parameters, cliff avoidance was delayed significantly in the high dose group in male offspring, and this effect was significantly dose-related. In female offspring, surface righting was significantly delayed in the high-dose group, and this effect was significantly dose-related. In spontaneous behavior in the F(1) generation, females showed more activities in some variables in the high dose group. Dose levels of piperonyl butoxide used in the present study produced several adverse effects in neurobehavioral parameters in mice. PMID- 19783575 TI - Special issue on statistical bioinformatics. PMID- 19783576 TI - HIV vaccine reduces infection rate by a third, study shows. PMID- 19783577 TI - Children are likely to need two doses of swine flu vaccine. PMID- 19783579 TI - Setting the frame: the human brain activates a basic low-frequency network for language processing. AB - Low-frequency fluctuations (LFFs) are a major source of variation in fMRI data. This has been established in numerous experiments-particularly in the resting state. Here we investigate LFFs in a task-dependent setting. We hypothesized that LFFs may contain information about cognitive networks that are specific to the overall task domain without being time locked to stimulus onsets. We analyzed data of 6 fMRI experiments, 4 of which belonged to the language domain. After regressing out specifics of the experimental design and low-pass filtering (<0.1 Hz), we found that the 4 language experiments produced a correlational pattern that was not present in the 2 nonlanguage studies. Specifically, a region in the posterior part of the left superior temporal sulcus/gyrus was consistently correlated with both the left Brodmann's area 44 and the left frontal operculum in all 4 language studies, whereas this correlation was not found in the 2 other experiments. This finding indicates the existence of a basic network that acts as a general framework for language processing. In contrast to networks obtained by a conventional conjunction analysis of activation maps, this network is independent of experimental specifics such as stimulus onsets and exists in the low-frequency range. PMID- 19783578 TI - The number of attentional foci and their precision are dissociated in the posterior parietal cortex. AB - Many everyday tasks require us to track moving objects with attention. The demand for attention increases both when more targets are tracked and when the targets move faster. These 2 aspects of attention-assigning multiple attentional foci (or indices) to targets and monitoring each focus with precision-may tap into different cognitive and brain mechanisms. In this study, we used functional magnetic resonance imaging to quantify the response profile of dorsal attentional areas to variations in the number of attentional foci and their spatiotemporal precision. Subjects were asked to track a specific spoke of either 1 or 2 pinwheels that rotated at various speeds. Their tracking performance declined both when more pinwheels were tracked and when the tracked pinwheels rotated faster. However, posterior parietal activity increased only when subjects tracked more pinwheels but remained flat when they tracked faster moving pinwheels. The frontal eye fields and early visual areas increased activity when there were more targets and when the targets rotated faster. These results suggest that the posterior parietal cortex is specifically involved in indexing independently moving targets with attention but not in monitoring each focus with precision. PMID- 19783580 TI - Introduction of rotavirus vaccine. PMID- 19783584 TI - Association of white matter lesions and lacunar infarcts with executive functioning: the SMART-MR study. AB - The authors investigated the association of white matter lesions and lacunar infarcts with cognitive performance and whether brain atrophy mediates these associations. Within the Second Manifestations of Arterial Disease-Magnetic Resonance study (2001-2005, the Netherlands), cross-sectional analyses of 522 patients were performed (mean age, 57 years (standard deviation, 10); 76% male). Brain segmentation was used to quantify volumes of brain tissue, cerebrospinal fluid, and white matter lesions. Infarcts were rated visually. Brain volume, ventricular volume, and gray matter volume were divided by intracranial volume to obtain indicators of brain atrophy. Neuropsychological tests assessing executive functioning and memory were performed, and scores were transformed into z scores. The authors used linear regression analyses, adjusted for age, sex, education, intelligence, and vascular risk factors, to investigate the association of white matter lesions and number of lacunar infarcts with cognitive performance. A 1 standard-deviation higher volume of white matter lesions (beta = -0.12, 95% confidence interval: -0.20, -0.04) and the presence of >or=2 lacunar infarcts (beta = -0.48, 95% confidence interval: -0.87, -0.09) were associated with worse executive functioning. These associations remained after adjusting for brain atrophy. Both were not associated with worse memory. Results suggest that subcortical ischemic vascular lesions are associated with decreased executive functioning, but not with memory functioning, independent of brain atrophy. PMID- 19783581 TI - Public health impact and cost effectiveness of mass vaccination with live attenuated human rotavirus vaccine (RIX4414) in India: model based analysis. AB - OBJECTIVES: To examine the public health impact of mass vaccination with live attenuated human rotavirus vaccine (RIX4414) in a birth cohort in India, and to estimate the cost effectiveness and affordability of such a programme. DESIGN: Decision analytical Markov model encompassing all direct medical costs. Infection risk and severity depended on age, number of previous infections, and vaccination history; probabilities of use of inpatient and outpatient health services depended on symptom severity. DATA SOURCES: Published clinical, epidemiological, and economic data. When possible, parameter estimates were based on data specific for India. Population Simulated Indian birth cohort followed for five years. MAIN OUTCOME MEASURES: Decrease in rotavirus gastroenteritis episodes (non-severe and severe), deaths, outpatient visits, and admission to hospital; incremental cost effectiveness ratio of vaccination expressed as net cost in 2007 rupees per life year saved. RESULTS: In the base case, vaccination prevented 28,943 (29.7%) symptomatic episodes, 6981 (38.2%) severe episodes, 164 deaths (41.0%), 7178 (33.3%) outpatient visits, and 812 (34.3%) admissions to hospital per 100,000 children. Vaccination cost 8023 rupees (about pound100, euro113, $165) per life year saved, less than India's per capita gross domestic product, a common criterion for cost effectiveness. The net programme cost would be equivalent to 11.6% of the 2006-7 budget of the Indian Department of Health and Family Welfare. Model results were most sensitive to variations in access to outpatient care for those with severe symptoms. If this parameter was increased to its upper limit, the incremental cost effectiveness ratio for vaccination still fell between one and three times the per capita gross domestic product, meeting the World Health Organization's criterion for "cost effective" interventions. Uncertainty analysis indicated a 94.7% probability that vaccination would be cost effective according to a criterion of one times per capita gross domestic product per life year saved, and a 97.8% probability that it would be cost effective according to a criterion of three times per capita gross domestic product. CONCLUSIONS: Across a wide range of assumptions, mass RIX4414 vaccination in India would probably prevent substantial morbidity and mortality at a cost per life year saved below typical thresholds of cost effectiveness. The opportunity costs of such a programme in this or similar settings, however, should be weighed up carefully. PMID- 19783585 TI - Recreational physical activity and steroid hormone levels in postmenopausal women. AB - Recreational physical activity has been both positively and inversely associated with cancer risk for postmenopausal women, acting presumably through hormonal mechanisms. Relatively little is known about the effects of exercise on postmenopausal steroid hormone levels. The authors evaluated the association between recreational activity and plasma steroid hormones among 623 US healthy, postmenopausal women in the Nurses' Health Study not using exogenous hormones at the time of blood draw (1989-1990). Participants self-reported recreational physical activity by questionnaire in 1986, 1988, and 1992. Plasma samples were assayed for estrogens, androgens, and sex hormone-binding globulin. Geometric mean hormone levels adjusted and not adjusted for body mass index were calculated. In general, estrogen and androgen levels were lower in the most- and the least-active women compared with those reporting moderate activity, suggesting a U-shaped relation. For example, estrone sulfate levels in quintiles 1-5 of metabolic equivalent task-hours were 197, 209, 222, 214, and 195 pg/mL, respectively. Tests for nonlinearity using polynomial regression were significant for several estrogens, androgens, and sex hormone-binding globulin (2-sided P or=80 years, reducing the risk of vertebral fracture over 5 years by 31% (P = 0.010) and non-vertebral fracture by 26% (P = 0.019). Adherence to treatment in the trials exceeded 80%, and the adverse event profile of SR was similar to that of placebo. Taken together, these long-term findings clearly demonstrate that SR is safe and effective in reducing both vertebral and non-vertebral (particularly hip) fracture risks for at least 5 years of pre-planned follow-up. PMID- 19783591 TI - Microarchitecture, the key to bone quality. AB - Bone has the ability to adapt its shape and size in response to mechanical loads via a process known as modelling in which bones are shaped or reshaped by the independent action of osteoblasts and osteoclasts. Remodelling is a process that maintains mechanical integrity of the skeleton, allowing it to selectively repair and replace damaged bone. During adulthood, bone remodelling is the dominant process; after the age of 40 years, the age-related decline in bone mass increases the risk of fracture, especially in women. Osteoporosis is defined as a reduction in bone mass and an impairment of bone architecture resulting in thinning and increased cortical porosity, bone fragility and fracture risk. As new products and methods have been developed, focusing on bone fragility, effective and sensitive non-invasive means able to detect early changes in bone fragility process have also been developed. Due to limitations in assessing fracture risk and response to therapy, the evaluation of bone mineral contents by bone densitometry is progressively replaced by new non-invasive and/or non destructive techniques able to estimate bone strength, providing structural information about the pathophysiology of bone fragility by quantitative assessments of macro- and microstructural bone features. DXA and volumetric QCT quantify bone macrostructure, whereas high-resolution CT, microCT, high resolution MR and microMR assess bone microstructure. Knowledge of bone microarchitecture is a clue for understanding osteoporosis pathophysiology and improving its diagnosis and treatment; the response of microarchitecture parameters to treatment should allow assessment of the real efficacy of the osteoporosis therapy. PMID- 19783592 TI - Strontium ranelate improves bone microarchitecture in osteoporosis. AB - In osteoporosis, disruption of bone remodelling leads to bone loss, microarchitectural damage and increased fracture risk, and the goal of any treatment for osteoporosis is to decrease this fracture risk. Available anti resorptive and anabolic agents effectively achieve this goal by either suppressing or stimulating the activation frequency of bone remodelling units, and by improving the biomechanical properties of bone by a number of different mechanisms. Strontium ranelate represents a novel approach in the management of osteoporosis with proven anti-fracture efficacy. Two putative mechanisms have been proposed for the unique dual mode of action of strontium ranelate, rebalancing bone turnover in favour of bone formation: activation of the calcium- or other cation-sensing receptor, and increase in the expression of osteoprotegerin (OPG), coupled with a decrease in RANK ligand expression by the osteoblasts. In addition to these cellular changes, micro-CT analysis of bone biopsies from strontium ranelate-treated patients demonstrate improvement in intrinsic bone tissue quality as evidenced by increased trabecular number, decreased trabecular separation, lower structure model index and increased cortical thickness, associated with a shift in trabecular structure from rod-to plate-like configuration compared with controls. This review examines the evidence for the ability of strontium ranelate to improve bone microarchitecture in osteoporosis and explores the cellular and microstructural changes by which its anti-fracture efficacy may be achieved. No attempt is made at comparing the effects of strontium ranelate on bone microarchitecture with that of other anti resorptive or anabolic osteoporosis agents. PMID- 19783594 TI - Efficacy of peritoneal ultrafiltration in the treatment of refractory congestive heart failure. AB - BACKGROUND: Heart failure (HF) is a major health problem in developed countries. HF is a progressive, lethal disorder, even with adequate treatment. There exists a vicious circle in the pathophysiology of HF that perpetuates and magnifies the problem. Concomitant fluid accumulation may worsen the congestive HF, it is responsible for numerous hospitalizations and it is an important cause of mortality. In this situation, any means of fluid removal may aid in the management of these patients. The objective of this study was to evaluate the efficacy of peritoneal dialysis (PD) in the treatment of refractory HF in terms of functional status, hospitalization and mortality. We also determined the improvement in health-related quality of life with the use of PD, and examined the economic consequences of its use. METHODS: We conducted a single centre, prospective, non-randomized study involving patients showing symptoms and signs of congestive HF refractory to maximum tolerable drug treatment. All of them were treated with PD. We analysed physical and biochemical determinations, functional status (according to the NYHA classification) and echocardiogram parameters. Also, to determine the efficacy of the technique we compared the perceived state of health (measured by the EQ5D) to PD patients respect to those reported with conservative therapies. Finally, we carried out a cost-utility evaluation measured by the incremental cost-utility ratio between these two options. RESULTS: Seventeen patients (65% men, 64 +/- 9 years) were included in the study, and 12 were still undergoing PD treatment at the end of the follow-up period (15 +/- 9 months). All patients improved their NYHA functional status (65% two classes; the rest, one; P < 0.001), with an important improvement in their pulmonary artery systolic pressure (44 +/- 12 versus 27 +/- 9 mmHg; P = 0.007), but no changes in left ventricular ejection fraction. Hospitalization rates underwent a dramatic reduction (from 62 +/- 16 to 11 +/- 5 days/patient/year; P = 0.003) before and after PD treatment. PD treatment raised life expectancy of 82% after 12 months of treatment, and 70% and 56% after 18 and 24 months, respectively, much better outcomes than those reported about conservative therapies, which only use diverse diuretic regimens. PD was associated with a higher perception state of health than the conservative therapy (0.6727 versus 0.4305; P < 0.01). Finally, we found that PD is cost-effective compared with the conservative therapy. CONCLUSIONS: We demonstrate that congestive HF programmes should consider offering PD in hope of seeing better functional status, reduced morbidity and mortality, better quality of life as well as reduced health care costs. PMID- 19783593 TI - Rapid likelihood analysis on large phylogenies using partial sampling of substitution histories. AB - Likelihood-based approaches can reconstruct evolutionary processes in greater detail and with better precision from larger data sets. The extremely large comparative genomic data sets that are now being generated thus create new opportunities for understanding molecular evolution, but analysis of such large quantities of data poses escalating computational challenges. Recently developed Markov chain Monte Carlo methods that augment substitution histories are a promising approach to alleviate these computational costs. We analyzed the computational costs of several such approaches, considering how they scale with model and data set complexity. This provided a theoretical framework to understand the most important computational bottlenecks, leading us to combine novel variations of our conditional pathway integration approach with recent advances made by others. The resulting technique ("partial sampling" of substitution histories) is considerably faster than all other approaches we considered. It is accurate, simple to implement, and scales exceptionally well with dimensions of model complexity and data set size. In particular, the time complexity of sampling unobserved substitution histories using the new method is much faster than previously existing methods, and model parameter and branch length updates are independent of data set size. We compared the performance of methods on a 224-taxon set of mammalian cytochrome-b sequences. For a simple nucleotide substitution model, partial sampling was at least 10 times faster than the PhyloBayes program, which samples substitutions in continuous time, and about 100 times faster than when using fully integrated substitution histories. Under a general reversible model of amino acid substitution, the partial sampling method was 1,600 times faster than when using fully integrated substitution histories, confirming significantly improved scaling with model state-space complexity. Partial sampling of substitutions thus dramatically improves the utility of likelihood approaches for analyzing complex evolutionary processes on large data sets. PMID- 19783595 TI - The effect of the World Kidney Day campaign on the awareness of chronic kidney disease and the status of risk factors for cardiovascular disease and renal progression. AB - BACKGROUND: Chronic kidney disease (CKD) is a worldwide problem. We describe the trends in CKD awareness before and after the World Kidney Day (WKD) campaign and the impact of the WKD campaign in increasing awareness and appropriate management of the risk factors for cardiovascular disease and renal progression. METHODS: We selected 57 718 people who had undergone a routine health check-up. RESULTS: The average CKD awareness was 3.1% (95% CI: 2.6-3.7%) and was increased with progressing CKD stage. The awareness was increased from 1.1% before the WKD campaign to 5.8% after the campaign (P < 0.001). CKD awareness in the post-WKD period was increased in CKD stages 2 (OR 4.535: 95% CI: 2.044-10.062) and 3 (OR 6.614: 95% CI: 4.282-10.217) and profoundly increased in stage 4 (OR 13.800: 95% CI: 2.127-89.524), compared to the pre-WKD period. In the CKD-aware group compared to the CKD-unaware group, the awareness of diabetes mellitus (90.0% versus 54.2%, P < 0.001) and hypertension (87.2% versus 64.7%, P < 0.001) was higher and the levels of systolic blood pressure (116.9 +/- 1.0 versus 120.1 +/- 0.2, P < 0.01) and serum cholesterol (198.3 +/- 2.7 versus 205.0 +/- 0.5, P < 0.05) were lower by covariance analysis. CONCLUSIONS: The WKD campaign had a positive impact on the awareness and control of risk factors in CKD subjects but the absolute frequency of CKD awareness still remains undesirable in Korea. We need new campaign strategies to publicize the importance of early diagnosis and appropriate management of CKD. PMID- 19783596 TI - Cyclooxygenase-2 inhibitor: a potential therapeutic strategy for ultrafiltration failure in peritoneal dialysis. PMID- 19783597 TI - The juxtaglomerular apparatus of Norbert Goormaghtigh--a critical appraisal. PMID- 19783598 TI - Metabolic syndrome predicts mortality in non-diabetic patients on continuous ambulatory peritoneal dialysis. AB - BACKGROUND: Metabolic syndrome is associated with higher morbidity and mortality in the general population, but the corresponding effects in patients on dialysis have not been clearly defined. In this study, we prospectively investigated the effect of metabolic syndrome and its individual components on outcome in non diabetic peritoneal dialysis (PD) patients. Method. The study subjects included 106 stable non-diabetic PD patients who had been on PD for >3 months. We measured baseline characteristics, blood pressure, fasting blood glucose, lipid profiles and high-sensitivity CRP (hsCRP), and defined metabolic syndrome using the modified National Cholesterol Education Program (Adult Treatment Panel III) criteria. Mortality, technical failure and hospitalization were evaluated during the follow-up period. RESULTS: Metabolic syndrome was present in 50 patients (47.2%), and these showed higher baseline hsCRP levels (0.67; 95% CI: 0.50-0.94 versus 1.78 mg/dl; 95% CI: 1.21-2.57; P < 0.001). Patients with metabolic syndrome experienced significantly lower 5-year survival rates than patients without (90% versus 67%, P = 0.02), although these groups did not differ in peritonitis rates, technical failure or hospitalization. A Cox proportional hazards analysis identified the following as predictors of mortality: metabolic syndrome (RR: 3.39; 95% CI: 1.16-9.94; P = 0.02), baseline albumin (RR: 0.06; 95% CI: 0.01-0.30; P = 0.001) and baseline hsCRP levels (RR: 1.14; 95% CI: 1.07-1.22; P < 0.001). CONCLUSION: Metabolic syndrome is prevalent and is a risk factor influencing long-term survival in non-diabetic PD patients. PMID- 19783600 TI - Commentary: contrast-induced nephropathy and long-term adverse events: cause and effect? PMID- 19783599 TI - Use of isoniazid chemoprophylaxis in renal transplant recipients. AB - BACKGROUND: The use of isoniazid (INH) as chemoprophylaxis for tuberculosis (TB) in renal transplant recipients has not been widely studied or reported from a country where TB is endemic. We are reporting here the results of the largest ever-reported randomized, prospective study of the use of INH in renal transplant recipients. METHODS: Four hundred consecutive live related renal transplant recipients between April 2001 and September 2004, from this single center, were randomized to receive or not receive INH for 1 year after transplantation. RESULTS: There were 12 dropouts. Of the remaining 388, 181 recipients received INH for 1 year post-transplant and 207 did not. The primary disease, comorbidities, HLA (human leucocyte antigen) match, immunosuppression, episodes of rejection, the use of anti-rejection agents, a past history of TB in the donor, the recipients and in family members living in same house and a history of TB in the family were factors compared in the two groups. The only significant difference between the two groups was that there was an increased family history of TB in recipients who received INH (P = 0.01). One recipient from the INH group and 16 recipients from the non-INH group developed TB (P = 0.0003). Discontinuation of INH for hepatotoxicity was not required in any patient. CONCLUSION: These results provide evidence that the use of INH following renal transplantation should be considered mandatory in geographical areas where the prevalence of TB is high. Furthermore, these results have important implication in patients from such areas who are immunosuppressed following other kinds of transplantation and for those who are immunocompromised for any other reason. PMID- 19783601 TI - First and subsequent nonmelanoma skin cancers: incidence and predictors in a population of New Zealand renal transplant recipients. AB - BACKGROUND: Renal transplant recipients (RTRs) have an increased risk of developing nonmelanoma skin cancers (NMSCs). The aims of this study were to determine the incidence and subsequent history of NMSCs in RTRs, together with risk factors. METHODS: All patients transplanted between July 1972 and March 2007, and followed up at Christchurch Hospital, New Zealand, were studied. Immunosuppression regimens were mostly prednisone, azathioprine, cyclosporine and prednisone, mycophenolate mofetil, cyclosporine since 1998. RESULTS: Of 384 RTRs, 96 developed at least one NMSC. The median time to first NMSC was 18.3 years (95% CI 14.2, 22.9) from transplant, as estimated by survival analysis. Individual predictors of first NMSC in RTRs were older age at first transplant (P < 0.0001), male sex (P = 0.006) and initial immunosuppression regimen (P = 0.001); only age (P < 0.0001) and male gender (P = 0.003) were significant predictors in a joint model. The mean rate of subsequent NMSCs was 1.67 per year (95% CI = 1.32, 2.11). Older age at first renal transplant (P = 0.009) or at discovery of the first NMSC (P = 0.01) was associated with a higher annual rate of new NMSC following the discovery of the first NMSC. The median survival time to a second NMSC was 2.2 years (CI 1.4, 3.0). Fourteen patients died of metastatic squamous cell carcinoma (15% case fatality). CONCLUSIONS: NMSCs are a major health issue for RTRs, especially in older males. Once RTRs have developed their first NMSC, ongoing surveillance and prompt treatment are essential. PMID- 19783602 TI - Heart rate recovery after exercise is associated with renal function in patients with a homogenous chronic renal disease. AB - BACKGROUND: Attenuated heart rate recovery (HRR) is an independent predictor of cardiac and total mortality. Diminished renal function is a similar predictor. There are no data concerning the interaction between the two risk factors. We studied HRR in patients with a homogeneous renal disease, IgA nephropathy. METHODS: One hundred and seven patients with biopsy-proven chronic IgA nephropathy (71 males, 36 females aged 45 +/- 11 years) performed a graded exercise treadmill stress test. HRR was measured as the heart rate difference between the peak value and the heart rate 1 min after exercise. The patients were divided into three groups based on estimated glomerular filtration rate (eGFR): CKD 1, eGFR >or= 90 ml/min (n = 46); CKD 2, eGFR 60-89 ml/min (n = 38), CKD 3-4, eGFR 15-59 ml/min (n = 23). We compared these data with 29 normal controls (aged 46 +/- 14 years). RESULTS: HRR values corresponded to eGFR as follows: 29.9 +/- 8.8 bpm normal controls, 27.8 +/- 9.2 bpm CKD 1, 24.5 +/- 10.5 bpm CKD 2 and 16.3 +/- 9.3 bpm CKD 3-4. The latter differed from the other groups significantly (P < 0.05). Metabolic syndrome was common in IgA nephropathy patients (27%). Metabolic syndrome patients had a HRR of 19.6 +/- 10.1 bpm, compared to 25.8 +/- 10.4 bpm in patients without metabolic syndrome (P = 0.007). Nevertheless, a multivariate regression analysis accepted only eGFR as an independent predictor of HRR. CONCLUSION: eGFR predicts HRR in patients with a homogenous renal disease. Metabolic syndrome influences HRR, albeit not independently in this cohort. PMID- 19783604 TI - Postmortem brain tissue for drug discovery in psychiatric research. PMID- 19783605 TI - Corynebacterium marinum sp. nov. isolated from coastal sediment. AB - A taxonomic study was performed on strain D7015T, which was isolated from coastal sediment close to a coal-fired power station in Qingdao, China. Cells of strain D7015T were Gram-positive, non-motile, diphtheroid rods that grew in the presence of 0-8% (w/v) NaCl and at 4-37 degrees C, with optimum growth at 1% (w/v) NaCl and 30-32 degrees C. The DNA G+C content was 65.0 mol%. The major fatty acids were C18:1omega9c (56.18%), C16:0 (38.02%), C16:1omega7c (4.45%), C18:0 (1.0%) and C14:0 (0.35%). On the basis of morphological, physiological and phylogenetic characteristics, strain D7015T was classified in the genus Corynebacterium. It exhibited a 16S rRNA gene sequence similarity of 95.9% and a DNA-DNA relatedness value of 20.4% with Corynebacterium halotolerans DSM 44683T. Strain D7015T was sufficiently different from recognized species of the genus Corynebacterium to be considered to represent a novel species. The name Corynebacterium marinum sp. nov. is proposed, with strain D7015T (=CGMCC 1.6998T=NRRL B-24779T) as the type strain. PMID- 19783606 TI - Francisella asiatica sp. nov. isolated from farmed tilapia (Oreochromis sp.) and elevation of Francisella philomiragia subsp. noatunensis to species rank as Francisella noatunensis comb. nov., sp. nov. AB - Bacterial isolates from diseased farmed tilapia (Oreochromis sp.) from Costa Rica (PQ 1104), Atlantic salmon (Salmo salar) from Chile (PQ 1106) and three-line grunt (Parapristipoma trilineatum) from Japan (Ehime-1) were characterized by phenotypic and molecular taxonomic methods. These isolates were Gram-negative, oxidase negative, non-motile, strictly aerobic cocco-bacilli, produced H2S from cysteine supplemented media, which is phenotypically consistent with the genus Francisella. Comparison of 16S rRNA gene sequences and five partial housekeeping gene sequences (groEL, shdA, rpoB, rpoA and pgm) confirmed these isolates to be members of the genus Francisella, with high 16S rRNA similarity (> 99 %) to Francisella philomiragia subsp noatunensis, F. piscicida and Francisella philomiragia subsp philomiragia isolates. Despite the close 16s rRNA relationship with the aforementioned Francisella taxa, isolates PQ 1104 and Ehime-1 form a separate clade on phylogenetic analysis of the 16s rRNA gene and all housekeeping genes investigated, whereas isolate PQ 1106 is highly similar to F. philomiragia subsp noatunensis (NCIMB 14265T) and F. piscicida (DSM 18777T). DNA-DNA hybridization studies revealed mean reassociation values of 60.3 and 72.6 % between isolate PQ 1104 and F. philomiragia subsp noatunensis (NCIMB 14265T) and F. philomiragia subsp philomiragia (ATCC 25015), respectively. Thus, on the basis of molecular genetic evidence, we propose that isolates PQ 1104 and Ehime-1 should be recognised as Francisella asiatica sp. nov. with type strain PQ 1104T (NCIMB and CCUG number not received yet). No separation between F. piscicida and F. philomiragia subsp noatunensis were identified by the same methods and these species constitute heterotypic synonyms for which the epithet noatunensis has priority. However, given the increased evidence of ecological differentiation within the F. philomiragia group and the existence of a specific fish pathogenic clade, we propose that the F. philomiragia subsp noatunensis be elevated to species level as F. noatunensis comb. nov., sp. PMID- 19783603 TI - Epigenetic mediation of environmental influences in major psychotic disorders. AB - The major psychotic disorders schizophrenia and bipolar disorder are etiologically complex involving both heritable and nonheritable factors. The absence of consistently replicated major genetic effects, together with evidence for lasting changes in gene expression after environmental exposures, is consistent with the concept that the biologic underpinnings of these disorders are epigenetic in form rather than DNA sequence based. Psychosis-associated environmental exposures, particularly at key developmental stages, may result in long-lasting epigenetic alterations that impact on the neurobiological processes involved in pathology. Although direct evidence for epigenetic dysfunction in both schizophrenia and bipolar disorder is still limited, methodological technologies in epigenomic profiling have advanced. This means that we are at the exciting stage where it is feasible to start investigating molecular modifications to DNA and histones and examine the mechanisms by which environmental factors can act upon the genome to bring about epigenetic changes in gene expression involved in the etiology of these disorders. Given the dynamic nature of the epigenetic machinery and potential reversibility of epigenetic modifications, the understanding of such mechanisms is of key relevance for clinical psychiatry and for identifying new targets for prevention and/or intervention. PMID- 19783607 TI - Phylogeny of Photorhabdus and Xenorhabdus based on universally conserved protein coding sequences and implications for the taxonomy of these two genera. Proposal of new taxa: X. vietnamensis sp. nov., P. luminescens subsp. caribbeanensis subsp. nov., P. luminescens subsp. hainanensis subsp. nov., P. temperata subsp. khanii subsp. nov., P. temperata subsp. tasmaniensis subsp. nov., and the reclassification of P. luminescens subsp. thracensis as P. temperata subsp. thracensis comb. nov. AB - We used the information from a set of concatenated sequences from four genes (recA, gyrB, dnaN and gltX) to investigate the phylogeny of the genera Photorhabdus and Xenorhabdus (entomopathogenic bacteria associated with nematodes of the genera Heterorhabditis and Steinernema, respectively). The robustness of the phylogenetic tree obtained by this multigene approach was significantly better than that of the tree obtained by a single gene approach. The comparison of the topologies of single gene phylogenetic trees highlighted discrepancies which have implications for the classification of strains and new isolates; in particular, we propose the transfer of Photorhabdus luminescens subsp. thracensis to Photorhabdus temperata subsp. thracensis comb. nov. (type strain CIP 108426T =DSM 15199T). We found that, within the genus Xenorhabdus, strains or isolates that shared less than 97 % nucleotide identity (NI), calculated on the concatenated sequences of the four gene fragments (recA, gyrB, dnaN and gltX) encompassing 3395 nucleotides, did not belong to the same species. Thus, at the 97% NI cutoff, we confirm the current 20 species of the genus Xenorhabdus and propose the description of a novel species, Xenorhabdus vietnamensis sp. nov. (type strain VN01T =CIP 109945T =DSM 22392T). Within each of the three current species of the genus Photorhabdus, P. asymbiotica, P. luminescens and P. temperata, strains or isolates which shared less than 97% NI did not belong to the same subspecies. Comparisons of the four gene fragments plus the rplB gene fragment analysed separately led us to propose four novel subspecies: Photorhabdus luminescens subsp. caribbeanensis subsp. nov. (type strain HG29T =CIP 109949T =DSM 22391T), P. luminescens subsp. hainanensis subsp. nov. (type strain C8404T = CIP 109946T =DSM 22397T), P. temperata subsp. khanii subsp. nov. (type strain C1T =NC19(T) =CIP 109947T =DSM 3369T), and P. temperata subsp. tasmaniensis subsp. nov. (type strain T327T =CIP 109948T =DSM 22387T). PMID- 19783608 TI - Massilia jejuensis sp. nov. and Naxibacter suwonensis sp. nov., isolated from air samples. AB - Two Gram-negative, motile, rod-shaped bacteria (strains 5317J-18T and 5414S-25T) were isolated from air samples collected in the Jeju Island and Suwon region of Korea, respectively. Phylogenetically, strain 5317J-18T was grouped with the genus Massilia with Massilia brevitalea byr23-80T as the closest relative (98.8% sequence similarity). Strain 5414S-25T was affiliated with the genus Naxibacter with Naxibacter haematophilus CCUG 38318T as the closest relative (98.8% sequence similarity). The mean DNA-DNA relatedness values between strain 5317J-18T and M. brevitalea DSM 18925T and Massilia aurea DSM 18055T were 43 and 36%, respectively. The mean DNA-DNA hybridization values between strain 5414S-25T and N. haematophilus KACC 13771T, M. brevitalea DSM 18925T, Massilia timonae DSM 16850T, Naxibacter varians KACC 13770T, M. aurea DSM 18055T, Massilia lutea DSM 17473T and Massilia albidiflava DSM 17472T ranged from 33 to 42%. Both novel strains had ubiquinone Q-8 as the predominant isoprenoid quinone and summed feature 3 (comprising iso-C15:0 2-OH and/or C16:1 omega7c) and C16:0 as the major fatty acids. Both strains also showed similar polar lipid profiles with phosphatidylethanolamine, phosphatidylglycerol and diphosphatidylglycerol as the major polar lipids. The DNA G+C contents of strains 5317J-18T and 5414S-25T were 66.1 and 67.8%, respectively. On the basis of their phenotypic, chemotaxonomic and genotypic characteristics, the new strains represent novel species in the genera Massilia and Naxibacter. Strain 5317J-18T (=KACC 12634T=DSM 21309T) is proposed as the type strain of Massilia jejuensis sp. nov. and strain 5414S-25T (=KACC 12635T=DSM 21311T) is proposed as the type strain of Naxibacter suwonensis sp. nov. PMID- 19783609 TI - Ruegeria pelagia is a later heterotypic synonym of Ruegeria mobilis. AB - The 16S rRNA genes of Ruegeria pelagia NBRC 102038T and Ruegeria mobilis NBRC 101030T were resequenced and the results confirmed that they differ by only one base in their almost full-length sequences (1425 nt). The gyrB gene sequence similarity between the two strains was also high (97.7%). The outcome of API 20NE, API ZYM and antibiotic susceptibility tests showed that the two strains show only one difference, in beta-galactosidase activity, in API tests and five differences in susceptibility among 30 tested antibiotics. In addition, similar BOX-PCR fingerprints were obtained and the DNA-DNA relatedness between the two strains was 91+/-4%. On the basis of these results, it is concluded that Ruegeria pelagia Lee et al. 2007 is a later heterotypic synonym of Ruegeria mobilis Muramatsu et al. 2007. PMID- 19783610 TI - Lactobacillus pobuzihii sp. nov., isolated from pobuzihi (fermented cummingcordia). AB - Twenty-one homofermentative lactic acid bacteria were isolated from fermented cummingcordia (pobuzihi), a traditional food in Taiwan. The isolates had identical 16S rRNA gene sequences that were distinct from those of other lactobacilli, and their closest neighbours in the 16S rRNA gene sequence phylogenetic tree were strains of Lactobacillus acidipiscis. Levels of DNA-DNA relatedness between representative pobuzihi isolates and strains of L. acidipiscis were 17% and below. Furthermore, the new isolates could be differentiated clearly from L. acidipiscis NBRC 102163T and NBRC 102164 in terms of acid production from L-arabinose, rhamnose, mannitol, lactose and 5 ketogluconate. It was concluded that the new isolates represent a single novel species of the genus Lactobacillus, for which the name Lactobacillus pobuzihii sp. nov. is proposed. The type strain is E100301T (=RIFY 6501T =NBRC 103219T =KCTC 13174T). PMID- 19783611 TI - Saccharopolyspora phatthalungensis sp. nov., isolated from rhizosphere soil of Hevea brasiliensis. AB - The taxonomic position of a rhizosphere soil isolate, designated strain SR8.15T, was determined by using a polyphasic approach. Phylogenetic analysis based on an almost-complete 16S rRNA gene sequence of the strain showed that it formed a well separated sub-branch within the radiation encompassing the genus Saccharopolyspora. Highest levels of 16S rRNA gene sequence similarity were found between strain SR8.15T and Saccharopolyspora shandongensis CGMCC 4.3530T (98.9%) and Saccharopolyspora spinosa DSM 44228T (98.5%). However, these strains shared low levels of DNA-DNA relatedness (<26%). Strain SR8.15T had chemical characteristics consistent with its classification in the genus Saccharopolyspora. It contained meso-diaminopimelic acid as the diagnostic diamino acid. Whole-cell hydrolysates contained arabinose and galactose. The diagnostic phospholipids were phosphatidylcholine, phosphatidylglycerol and phosphatidylinositol. The main menaquinone was MK-9(H4). No mycolic acid was detected. The predominant cellular fatty acid was iso-C16:0. The G+C content of the genomic DNA of strain SR8.15T was 70.3 mol%. Strain SR8.15T had a phenotypic profile that readily distinguished it from recognized representatives of the genus Saccharopolyspora. It is evident from its combined genotypic and phenotypic properties that strain SR8.15T represents a novel species of the genus Saccharopolyspora, for which the name Saccharopolyspora phatthalungensis sp. nov. is proposed. The type strain is SR8.15T (=TISTR 1921T=BCC 35844T=NRRL B-24798T). PMID- 19783612 TI - Arthrobacter antarcticus sp. nov., isolated from an Antarctic marine sediment. AB - A bacterial strain, SPC26(T), was isolated from a sediment sample of the Southern Ocean off Antarctica. The strain was Gram-staining- and catalase-positive and contained lysine and alanine in the cell-wall peptidoglycan. The major cellular fatty acids were anteiso-C15:0 (54.92 %), iso-C15:0 (11.47 %), anteiso-C17:0 (6.48 %) and anteiso-C15:1 (6.38 %) and the major menaquinones were MK-8, MK-9 and MK-10. The major polar lipids were phosphatidylethanolamine and diphosphatidylglycerol. The G+C content was 68 +/- 0.5 mol%. Based on 16S rRNA gene sequence similarities, the nearest phylogenetic neighbours of strain SPC26(T) were identified as Arthrobacter gangotriensis Lz1y(T) (98.8 %), A. sulfureus DSM 20167(T) (98.6 %), A. psychrophenolicus DSM 15454(T) (97.9 %) and A. kerguelensis KGN15(T) (97.5). With these strains, strain SPC26(T) exhibited DNA-DNA relatedness values of 36, 21, 12 and 10 %, respectively. Therefore, on the basis of 16S rRNA gene sequence comparisons, phylogenetic analysis, phenotypic characteristics and DNA-DNA relatedness, it is proposed that strain SPC26(T) represents a novel species of Arthrobacter, for which the name Arthrobacter antarcticus sp. nov. is proposed, with strain SPC26(T) (=LMG 24542(T) =NCCB 100228(T)) as the type strain. PMID- 19783613 TI - Paenibacillus glacialis sp. nov., isolated from the Kafni glacier of the Himalayas, India. AB - A novel strain of the genus Paenibacillus, KFC91T, was isolated from the Kafni glacier of the Himalayas. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain KFC91T clustered with Paenibacillus antarcticus LMG 22078T (98.9%) and Paenibacillus macquariensis LMG 6935T (98.7%). The cell wall peptidoglycan contained meso-diaminopimelic acid as the diamino acid, anteiso C15:0 as the predominant fatty acid and MK-7 as the major isoprenoid quinone. Based on the phylogenetic analysis, chemotaxonomic characteristics and other phenotypic traits, strain KFC91T was assigned to the genus Paenibacillus. DNA-DNA hybridization experiments of KFC91T with P. antarcticus and P. macquariensis showed reassociation values of 39 and 52%, respectively. Thus, it is proposed that strain KFC91T should be assigned the status of a novel species of the genus Paenibacillus and the name proposed is Paenibacillus glacialis sp. nov., with KFC91T (=NCCB 100252T =DSM 22343T) as the type strain. PMID- 19783614 TI - Agrococcus terreus sp. nov. and Micrococcus terreus sp. nov., isolated from forest soil. AB - Two bacterial strains, DNG5T and V3M1T, isolated from forest soil of the Changbai mountains in China, were characterized using a polyphasic approach. Analysis of their 16S rRNA gene sequences indicated that strains DNG5T and V3M1T were phylogenetically related to members of the genus Agrococcus (96.0-98.4% similarity) and Micrococcus (96.7-98.0% similarity), respectively, within the order Actinomycetales. Strains DNG5T and V3M1T were Gram-stain-positive and strictly aerobic and formed yellow colonies on LB agar. Cells of strain DNG5T were short, non-motile rods, 0.4-0.5x0.8-1.0 microm. Strain DNG5T contained MK-10 and MK-11 as the major respiratory quinones and anteiso-C15:0 (49.2%) and iso C16:0 (22.4%) as the major fatty acids. The diamino acid in the peptidoglycan of strain DNG5T was 2,4-diaminobutyric acid and the murein was of the acetyl type. Cells of strain V3M1T were cocci, 0.6-0.7 microm in diameter. The cell-wall peptidoglycan of strain V3M1T contained the amino acids lysine, glutamic acid, alanine and glycine. Strain V3M1T contained MK-7, MK-7(H2), MK-8 and MK-8(H2) as respiratory quinones and anteiso-C15:0 (78.2%) and iso-C15:0 (13.1%) as the major cellular fatty acids. The DNA G+C contents of strains DNG5T and V3M1T were 75.9 and 67.2 mol%, respectively. The DNA-DNA relatedness of strain DNG5T to Agrococcus jejuensis DSM 22002T, A. jenensis JCM 9950T, A. baldri JCM 12132T and A. citreus JCM 12398T was 58.3, 43.9, 36.1 and 54.1%, respectively. The DNA-DNA relatedness of strain V3M1T to Micrococcus luteus CGMCC 1.2299T, M. antarcticus CGMCC 1.2373T and M. lylae CGMCC 1.2300T was 57.5, 45.4 and 39.0%, respectively. Combining phenotypic and genotypic traits, strain DNG5T represents a novel species of the genus Agrococcus, for which the name Agrococcus terreus sp. nov. is proposed, with DNG5T (=CGMCC 1.6960T =NBRC 104260T) as the type strain. Strain V3M1T represents a novel species of the genus Micrococcus, for which the name Micrococcus terreus sp. nov. is proposed, with V3M1T (=CGMCC 1.7054T =NBRC 104258T) as the type strain. PMID- 19783615 TI - Description of Francisella hispaniensis sp. nov., isolated from human blood, reclassification of Francisella novicida (Larson et al. 1955) Olsufiev et al. 1959 as Francisella tularensis subsp. novicida comb. nov. and emended description of the genus Francisella. AB - Strain FhSp1T, isolated from human blood in Spain in 2003, was studied for its taxonomic allocation. By 16S rRNA and recA gene sequencing, the strain was shown to belong to the genus Francisella. In the 16S rRNA gene sequence, Francisella sp. FhSp1T shared similarity of more than 99% with strains of Francisella tularensis subspecies and Francisella novicida U112T, 98% with Francisella piscicida GM2212T and 98.4% with Francisella philomiragia ATCC 25015T. In the recA gene sequence, Francisella sp. FhSp1T exhibited 91.6-91.7% similarity to strains of F. tularensis subspecies, 91.2% to F. novicida U112T and 84% to F. philomiragia ATCC 25017. The genus affiliation was supported by a quinone system typical of Francisella (Q-8 as the major component), a complex polar lipid profile similar to that of F. tularensis with the major components diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine and an unknown aminophospholipid (APL4) and a fatty acid profile consisting mainly of C10:0 (17.2%), C14:0 (11.2%), C16:0 (13.1%), C18:0 3-OH (14.2%) and C18:1omega9c (7.1%). DNA-DNA hybridization, which showed unambiguously that FhSp1T represents a novel species, and the results of biochemical tests allowed genotypic and phenotypic differentiation of the isolate from all hitherto-described Francisella species. A multiplex PCR developed in the course of this study discriminated FhSp1T from representatives of all other Francisella species and subspecies, clades A.I and A.II of F. tularensis subsp. tularensis and F. tularensis subsp. holarctica biovar japonica and also between these representatives of the genus. Therefore, we propose the name Francisella hispaniensis sp. nov., with the type strain FhSp1T (=FnSp1T =FSC454T =F62T =DSM 22475T =CCUG 58020T). Furthermore, we formally propose the transfer of the species Francisella novicida to the species Francisella tularensis as Francisella tularensis subsp. novicida comb. nov. (type strain ATCC 15482T =CCUG 33449T =CIP 56.12T). We also present an emended description of the genus Francisella. PMID- 19783616 TI - Kushneria sinocarnis sp. nov., a moderately halophilic bacterium isolated from a Chinese traditional cured meat. AB - A Gram-negative, aerobic, moderately halophilic bacterium, designated strain Z35T, was isolated from a Chinese traditional cured meat produced in Wuhan. The isolate grew with 1-20% NaCl (optimum 10%), at 4-42 degrees C (optimum 37 degrees C) and at pH 4.5-8.5 (optimum pH 7.0). Cells of strain Z35T were not motile and were rod or oval shaped. The genomic DNA G+C content was 59.1 mol%. The isoprenoid quinones were Q-9 (88.96%), Q-8 (9.46%) and Q-10 (1.58%). The major fatty acids were C19:0 cyclo omega8c, C16:0 and C17:0 cyclo. Phylogenetic analysis based on 16S rRNA gene sequence analysis indicated that strain Z35T was closely related to the type strains of Kushneria species with 93.7-95.3% sequence similarities. Phylogenetic analysis based on 23S rRNA gene sequence similarity values also confirmed the phylogenetic position of the isolate. Therefore, based on the phenotypic, chemotaxonomic and phylogenetic evidence, strain Z35T is affiliated to Kushneria, but is clearly differentiated from other species of this genus and represents a new member, for which the name Kushneria sinocarnis sp. nov. is proposed. The type strain is Z35T (=CCTCC AB 209027T =NRRL B-59197T =DSM 23229T). PMID- 19783617 TI - Candida spencermartinsiae sp. nov., Candida taylorii sp. nov. and Pseudozyma abaconensis sp. nov., novel yeasts from mangrove and coral reef ecosystems. AB - Three species of yeasts are taxonomically described for strains isolated from marine environments. Candida spencermartinsiae sp. nov. (type strain CBS 10894T =NRRL Y-48663T) and Candida taylorii sp. nov. (type strain CBS 8508T =NRRL Y 27213T) are anamorphic ascomycetous yeasts in a phylogenetic cluster of marine yeasts in the Debaryomyces/Lodderomyces clade of the Saccharomycetales. The two species were isolated from multiple locations among coral reefs and mangrove habitats. Pseudozyma abaconensis sp. nov. (type strain CBS 8380T =NRRL Y-17380T) is an anamorphic basidiomycete that is related to the smut fungi of the genus Ustilago in the Ustilaginales. P. abaconensis was collected from waters adjacent to a coral reef. PMID- 19783618 TI - Overexpression of antioxidant enzymes in diaphragm muscle does not alter contraction-induced fatigue or recovery. AB - Low levels of reactive oxygen species (ROS) production are necessary to optimize muscle force production in unfatigued muscle. In contrast, sustained high levels of ROS production have been linked to impaired muscle force production and contraction-induced skeletal muscle fatigue. Using genetically engineered mice, we tested the hypothesis that the independent transgenic overexpression of catalase (CAT), copper/zinc superoxide dismutase (CuZnSOD; SOD1) or manganese superoxide dismutase (MnSOD; SOD2) antioxidant enzymes would negatively affect force production in unfatigued diaphragm muscle but would delay the development of muscle fatigue and enhance force recovery after fatiguing contractions. Diaphragm muscle from wild-type littermates (WT) and from CAT, SOD1 and SOD2 overexpressing mice were subjected to an in vitro contractile protocol to investigate the force-frequency characteristics, the fatigue properties and the time course of recovery from fatigue. The CAT, SOD1 and SOD2 overexpressors produced less specific force (in N cm(-2)) at stimulation frequencies of 20-300 Hz and produced lower maximal tetanic force than WT littermates. The relative development of muscle fatigue and recovery from fatigue were not influenced by transgenic overexpression of any antioxidant enzyme. Morphologically, the mean cross-sectional area (in microm(2)) of diaphragm myofibres expressing myosin heavy chain type IIA was decreased in both CAT and SOD2 transgenic animals, and the percentage of non-contractile tissue increased in diaphragms from all transgenic mice. In conclusion, our results do not support the hypothesis that overexpression of independent antioxidant enzymes protects diaphragm muscle from contraction-induced fatigue or improves recovery from fatigue. Moreover, our data are consistent with the concept that a basal level of ROS is important to optimize muscle force production, since transgenic overexpression of major cellular antioxidants is associated with contractile dysfunction. Finally, the transgenic overexpression of independent endogenous antioxidants alters diaphragm skeletal muscle morphology, and these changes may also contribute to the diminished specific force production observed in these animals. PMID- 19783619 TI - Hypopituitarism following traumatic brain injury: prevalence is affected by the use of different dynamic tests and different normal values. AB - OBJECTIVE: Traumatic brain injury (TBI) has emerged as an important cause of hypopituitarism. However, considerable variations in the prevalence of hypopituitarism are reported. These can partly be explained by severity of trauma and timing of hormonal evaluation, but may also be dependent on endocrine tests and criteria used for diagnosis of hypopituitarism. METHODS: Systematic review of studies reporting prevalence of hypopituitarism in adults >or=1 year after TBI focusing on used (dynamic) tests and biochemical criteria. RESULTS: We included data from 14 studies with a total of 931 patients. There was considerable variation in definition of hypopituitarism. Overall, reported prevalences of severe GH deficiency varied between 2 and 39%. Prevalences were 8-20% using the GHRH-arginine test (cutoff <9 microg/l), 11-39% using the glucagon test (cutoff 1 5 microg/l), 2% using the GHRH test (no cutoff), and 15-18% using the insulin tolerance test (ITT; cutoff <3 microg/l). Overall, the reported prevalence of secondary adrenal insufficiency had a broad range from 0 to 60%. This prevalence was 0-60% with basal cortisol (cutoff <220 or <440 nmol/l), 7-19% using the ACTH test, and 5% with the ITT as first test (cutoff <500 or <550 nmol/l). Secondary hypothyroidism was present in 0-19% (free thyroxine) or 5-15% (thyroid-releasing hormone stimulation). Secondary hypogonadism was present in 0-29%. CONCLUSION: The reported variations in the prevalence rates of hypopituitarism after TBI are in part caused by differences in definitions, endocrine assessments of hypopituitarism, and confounding factors. These methodological issues prohibit simple generalizations of results of original studies on TBI-associated hypopituitarism in the perspective of meta-analyses or reviews. PMID- 19783620 TI - Should anterior pituitary function be tested during follow-up of all patients presenting at the emergency department because of traumatic brain injury? AB - CONTEXT: A wide range (15-56%) of prevalences of anterior pituitary insufficiency are reported in patients after traumatic brain injury (TBI). However, different study populations, study designs, and diagnostic procedures were used. No data are available on emergency-department-based cohorts of TBI patients. OBJECTIVE: To assess the prevalence of pituitary dysfunction in an emergency-department based cohort of TBI patients using strict endocrinological diagnostic criteria. METHODS: Of all the patients presenting in the emergency department with TBI over a 2-year period, 516 matched the inclusion criteria. One hundred and seven patients (77 with mild TBI and 30 with moderate/severe TBI) agreed to participate. They were screened for anterior pituitary insufficiency by GHRH arginine testing, evaluation of fasting morning hormone levels (cortisol, TSH, free thyroxine, FSH, LH, and 17beta-estradiol or testosterone), and menstrual history 3-30 months after TBI. Abnormal screening results were defined as low peak GH to GHRH-arginine, or low levels of any of the end-organ hormones with low or normal pituitary hormone levels. Patients with abnormal screening results were extensively evaluated, including additional hormone provocation tests (insulin tolerance test, ACTH stimulation test, and repeated GHRH-arginine test) and assessment of free testosterone levels. RESULTS: Screening results were abnormal in 15 of 107 patients. In a subsequent extensive endocrine evaluation, anterior pituitary dysfunction was diagnosed in only one patient (partial hypocortisolism). CONCLUSION: By applying strict diagnostic criteria to an emergency-department-based cohort of TBI patients, it was shown that anterior pituitary dysfunction is rare (<1%). Routine pituitary screening in unselected patients after TBI is unlikely to be cost-effective. PMID- 19783621 TI - N terminus of type 5 adenylyl cyclase scaffolds Gs heterotrimer. AB - According to accepted doctrine, agonist-bound G protein-coupled receptors catalyze the exchange of GDP for GTP and facilitate the dissociation of Galpha and Gbetagamma, which in turn regulate their respective effectors. More recently, the existence of preformed signaling complexes, which may include receptors, heterotrimeric G proteins, and/or effectors, is gaining acceptance. We show herein the existence of a preformed complex of inactive heterotrimer (Galpha(s) x betagamma) and the effector type 5 adenylyl cyclase (AC5), localized by the N terminus of AC5. GST fusions of AC5 N terminus (5NT) bind to purified G protein subunits (GDP-Galpha(s) and Gbetagamma) with apparent affinities of 270 +/- 21 and 190 +/- 7 nM, respectively. GDP-bound Galpha(s) and Gbetagamma did not compete, but rather facilitated their interaction with 5NT, consistent with the isolation of a ternary complex (5NT, Galpha(s), and Gbetagamma) by gel filtration. The AC5/Gbetagamma interaction was also demonstrated by immunoprecipitation and fluorescence resonance energy transfer (FRET) and the binding site of heterotrimer Galpha(s) x betagamma mapped to amino acids 60 to 129 of 5NT. Deletion of this region in full-length AC5 resulted in significant reduction of FRET between Gbetagamma and AC. 5NT also interacts with the catalytic core of AC, mainly via the C1 domain, to enhance Galpha(s)--and forskolin-stimulated activity of C1/C2 domains. The N terminus also serves to constrain Galpha(i)-mediated inhibition of AC5, which is relieved in the presence of Gbetagamma. These results reveal that 5NT plays a key regulatory role by interacting with the catalytic core and scaffolding inactive heterotrimeric G proteins, forming a preassembled complex that is potentially braced for GPCR activation. PMID- 19783622 TI - Identification of survival genes in human glioblastoma cells by small interfering RNA screening. AB - Target identification and validation remain difficult steps in the drug discovery process, and uncovering the core genes and pathways that are fundamental for cancer cell survival may facilitate this process. Glioblastoma represents a challenging form of cancer for chemotherapy. Therefore, we assayed 16,560 short interfering RNA (siRNA) aimed at identifying which of the 5520 unique therapeutically targetable gene products were important for the survival of human glioblastoma. We analyzed the viability of T98G glioma cells 96 h after siRNA transfection with two orthogonal statistical methods and identified 55 survival genes that encoded proteases, kinases, and transferases. It is noteworthy that 22% (12/55) of the survival genes were constituents of the 20S and 26S proteasome subunits. An expression survey of a panel of glioma cell lines demonstrated expression of the proteasome component PSMB4, and the validity of the proteasome complex as a target for survival inhibition was confirmed in a series of glioma and nonglioma cell lines by pharmacological inhibition and RNA interference. Biological networks were built with the other survival genes using a protein protein interaction network, which identified clusters of cellular processes, including protein ubiquitination, purine and pyrimidine metabolism, nucleotide excision repair, and NF-kappaB signaling. The results of this study should broaden our understanding of the core genes and pathways that regulate cell survival; through either small molecule inhibition or RNA interference, we highlight the potential significance of proteasome inhibition. PMID- 19783623 TI - Promoter strength properties of the complete sigma E regulon of Escherichia coli and Salmonella enterica. AB - The sigma(E)-directed envelope stress response maintains outer membrane homeostasis and is an important virulence determinant upon host infection in Escherichia coli and related bacteria. sigma(E) is activated by at least two distinct mechanisms: accumulation of outer membrane porin precursors and an increase in the alarmone ppGpp upon transition to stationary phase. Expression of the sigma(E) regulon is driven from a suite of approximately 60 sigma(E) dependent promoters. Using green fluorescent protein fusions to each of these promoters, we dissected promoter contributions to the output of the regulon under a variety of in vivo conditions. We found that the sigma(E) promoters exhibit a large dynamic range, with a few strong and many weak promoters. Interestingly, the strongest promoters control either transcriptional regulators or functions related to porin homeostasis, the very functions conserved among E. coli and its close relatives. We found that (i) the strength of most promoters is significantly affected by the presence of the upstream (-35 to -65) region of the promoter, which encompasses the UP element, a binding site for the C-terminal domain of the alpha-subunit of RNA polymerase; (ii) ppGpp generally activates sigma(E) promoters, and (iii) sigma(E) promoters are responsive to changing sigma(E) holoenzyme levels under physiological conditions, reinforcing the idea that the sigma(E) regulon is extremely dynamic, enabling cellular adaptation to a constantly changing environment. PMID- 19783624 TI - LuxS-based quorum sensing does not affect the ability of Salmonella enterica serovar Typhimurium to express the SPI-1 type 3 secretion system, induce membrane ruffles, or invade epithelial cells. AB - Bacterial species can communicate by producing and sensing small autoinducer molecules by a process known as quorum sensing. Salmonella enterica produces autoinducer 2 (AI-2) via the luxS synthase gene, which is used by some bacterial pathogens to coordinate virulence gene expression with population density. We investigated whether the luxS gene might affect the ability of Salmonella enterica serovar Typhimurium to invade epithelial cells. No differences were found between the wild-type strain of S. Typhimurium, SL1344, and its isogenic luxS mutant with respect to the number and morphology of the membrane ruffles induced or their ability to invade epithelial cells. The dynamics of the ruffling process were also similar in the wild-type strain (SL1344) and the luxS mutant. Furthermore, comparing the Salmonella pathogenicity island 1 (SPI-1) type 3 secretion profiles of wild-type SL1344 and the luxS mutant by Western blotting and measuring the expression of a single-copy green fluorescent protein fusion to the prgH (an essential SPI-1 gene) promoter indicated that SPI-1 expression and activity are similar in the wild-type SL1344 and luxS mutant. Genetic deletion of luxS did not alter the virulence of S. Typhimurium in the mouse model, and therefore, it appears that luxS does not play a significant role in regulating invasion of Salmonella in vitro or in vivo. PMID- 19783625 TI - Comparative genomics of ethanolamine utilization. AB - Ethanolamine can be used as a source of carbon and nitrogen by phylogenetically diverse bacteria. Ethanolamine-ammonia lyase, the enzyme that breaks ethanolamine into acetaldehyde and ammonia, is encoded by the gene tandem eutBC. Despite extensive studies of ethanolamine utilization in Salmonella enterica serovar Typhimurium, much remains to be learned about EutBC structure and catalytic mechanism, about the evolutionary origin of ethanolamine utilization, and about regulatory links between the metabolism of ethanolamine itself and the ethanolamine-ammonia lyase cofactor adenosylcobalamin. We used computational analysis of sequences, structures, genome contexts, and phylogenies of ethanolamine-ammonia lyases to address these questions and to evaluate recent data-mining studies that have suggested an association between bacterial food poisoning and the diol utilization pathways. We found that EutBC evolution included recruitment of a TIM barrel and a Rossmann fold domain and their fusion to N-terminal alpha-helical domains to give EutB and EutC, respectively. This fusion was followed by recruitment and occasional loss of auxiliary ethanolamine utilization genes in Firmicutes and by several horizontal transfers, most notably from the firmicute stem to the Enterobacteriaceae and from Alphaproteobacteria to Actinobacteria. We identified a conserved DNA motif that likely represents the EutR-binding site and is shared by the ethanolamine and cobalamin operons in several enterobacterial species, suggesting a mechanism for coupling the biosyntheses of apoenzyme and cofactor in these species. Finally, we found that the food poisoning phenotype is associated with the structural components of metabolosome more strongly than with ethanolamine utilization genes or with paralogous propanediol utilization genes per se. PMID- 19783626 TI - Distribution and phylogeny of light-oxygen-voltage-blue-light-signaling proteins in the three kingdoms of life. AB - Plants and fungi respond to environmental light stimuli via the action of different photoreceptor modules. One such class, responding to the blue region of light, is constituted by photoreceptors containing so-called light-oxygen-voltage (LOV) domains as sensor modules. Four major LOV families are currently identified in eukaryotes: (i) the plant phototropins, regulating various physiological effects such as phototropism, chloroplast relocation, and stomatal opening; (ii) the aureochromes, mediating photomorphogenesis in photosynthetic stramenopile algae; (iii) the plant circadian photoreceptors of the zeitlupe (ZTL)/adagio (ADO)/flavin-binding Kelch repeat F-box protein 1 (FKF1) family; and (iv) the fungal circadian photoreceptors white-collar 1 (WC-1). Blue-light-sensitive LOV signaling modules are also widespread throughout the prokaryotic world, and physiological responses mediated by bacterial LOV photoreceptors were recently reported. Thus, the question arises as to the evolutionary relationship between the pro- and eukaryotic LOV photoreceptor systems. We used Bayesian and maximum likelihood tree reconstruction methods to infer evolutionary scenarios that might have led to the widespread appearance of LOV domains among the pro- and eukaryotes. The phylogenetic study presented here suggests a bacterial origin for the LOV domains of the four major eukaryotic LOV photoreceptor families, whereas the LOV sensor domains were most likely recruited from the bacteria in the course of plastid and mitochondrial endosymbiosis. PMID- 19783627 TI - The low-molecular-weight fraction of exopolysaccharide II from Sinorhizobium meliloti is a crucial determinant of biofilm formation. AB - Sinorhizobium meliloti is a soil bacterium that elicits the formation of root organs called nodules on its host plant, Medicago sativa. Inside these structures, the bacteria are able to convert atmospheric nitrogen into ammonia, which is then used by the plant as a nitrogen source. The synthesis by S. meliloti of at least one exopolysaccharide, succinoglycan or EPS II, is essential for a successful symbiosis. While exopolysaccharide-deficient mutants induce the formation of nodules, they fail to invade them, and as a result, no nitrogen fixation occurs. Interestingly, the low-molecular-weight fractions of these exopolysaccharides are the symbiotically active forms, and it has been suggested that they act as signals to the host plant to initiate infection thread formation. In this work, we explored the role of these rhizobial exopolysaccharides in biofilm formation and their importance in the symbiotic relationship with the host. We showed that the ExpR/Sin quorum-sensing system controls biofilm formation in S. meliloti through the production of EPS II, which provides the matrix for the development of structured and highly organized biofilms. Moreover, the presence of the low-molecular-weight fraction of EPS II is vital for biofilm formation, both in vitro and in vivo. This is the first report where the symbiotically active fraction of EPS II is shown to be a critical factor for biofilm formation and root colonization. Thus, the ability of S. meliloti to properly attach to root surfaces and form biofilms conferred by the synthesis of exopolysaccharides may embody the main function of these symbiotically essential molecules. PMID- 19783628 TI - Comparative genome analysis of Listeria bacteriophages reveals extensive mosaicism, programmed translational frameshifting, and a novel prophage insertion site. AB - The genomes of six Listeria bacteriophages were sequenced and analyzed. Phages A006, A500, B025, P35, and P40 are members of the Siphoviridae and contain double stranded DNA genomes of between 35.6 kb and 42.7 kb. Phage B054 is a unique myovirus and features a 48.2-kb genome. Phage B025 features 3' overlapping single stranded genome ends, whereas the other viruses contain collections of terminally redundant, circularly permuted DNA molecules. Phages P35 and P40 have a broad host range and lack lysogeny functions, correlating with their virulent lifestyle. Phages A500, A006, and B025 integrate into bacterial tRNA genes, whereas B054 targets the 3' end of translation elongation factor gene tsf. This is the first reported case of phage integration into such an evolutionarily conserved genetic element. Peptide fingerprinting of viral proteins revealed that both A118 and A500 utilize +1 and -1 programmed translational frameshifting for generating major capsid and tail shaft proteins with C termini of different lengths. In both cases, the unusual +1 frameshift at the 3' ends of the tsh coding sequences is induced by overlapping proline codons and cis-acting shifty stops. Although Listeria phage genomes feature a conserved organization, they also show extensive mosaicism within the genome building blocks. Of particular interest is B025, which harbors a collection of modules and sequences with relatedness not only to other Listeria phages but also to viruses infecting other members of the Firmicutes. In conclusion, our results yield insights into the composition and diversity of Listeria phages and provide new information on their function, genome adaptation, and evolution. PMID- 19783629 TI - Evolutionary dynamics of ompA, the gene encoding the Chlamydia trachomatis key antigen. AB - Chlamydia trachomatis is the trachoma agent and causes most bacterial sexually transmitted infections worldwide. Its major outer membrane protein (MOMP) is a well-known porin and adhesin and is the dominant antigen. So far, investigation of MOMP variability has been focused mainly on molecular epidemiological surveys. In contrast, we aimed to evaluate the impact of the host pressure on this key antigen by analyzing its evolutionary dynamics in 795 isolates from urogenital infections, taking into account the MOMP secondary structure and the sizes/positions of antigenic regions. One-third of the specimens showed a mutational drift from the corresponding genotype, where approximately 42% of the mutations had never been described. Amino acid alterations were sixfold more frequent within B-cell epitopes than in the remaining protein (P = 0.027), and some mutations were also found within or close to T-cell antigenic clusters. Interestingly, the two most ecologically successful genotypes, E and F, showed a mutation rate 60.3-fold lower than that of the other genotypes (P < 10(-8)), suggesting that their efficacy may be the result of a better fitness in dealing with the host immune system rather than of specific virulence factors. Furthermore, the variability exhibited by some genetic variants involved residues that are known to play a critical role during the membrane mechanical movements, contributing to a more stable and flexible porin conformation, which suggests some plasticity to deal with environmental pressure. Globally, these MOMP mutational trends yielded no mosaic structures or important phylogenetic changes, but instead yielded point mutations on specific protein domains, which may enhance pathogen's infectivity, persistence, and transmission. PMID- 19783630 TI - Dynamics of two Phosphorelays controlling cell cycle progression in Caulobacter crescentus. AB - In Caulobacter crescentus, progression through the cell cycle is governed by the periodic activation and inactivation of the master regulator CtrA. Two phosphorelays, each initiating with the histidine kinase CckA, promote CtrA activation by driving its phosphorylation and by inactivating its proteolysis. Here, we examined whether the CckA phosphorelays also influence the downregulation of CtrA. We demonstrate that CckA is bifunctional, capable of acting as either a kinase or phosphatase to drive the activation or inactivation, respectively, of CtrA. By identifying mutations that uncouple these two activities, we show that CckA's phosphatase activity is important for downregulating CtrA prior to DNA replication initiation in vivo but that other phosphatases may exist. Our results demonstrate that cell cycle transitions in Caulobacter require and are likely driven by the toggling of CckA between its kinase and phosphatase states. More generally, our results emphasize how the bifunctional nature of histidine kinases can help switch cells between mutually exclusive states. PMID- 19783631 TI - The catalase-peroxidase KatG is required for virulence of Xanthomonas campestris pv. campestris in a host plant by providing protection against low levels of H2O2. AB - Xanthomonas campestris pv. campestris katG encodes a catalase-peroxidase that has a role in protecting the bacterium against micromolar concentrations of H(2)O(2). A knockout mutation in katG that causes loss of catalase-peroxidase activity correlates with increased susceptibility to H(2)O(2) and a superoxide generator and is avirulent in a plant model system. katG expression is induced by oxidants in an OxyR-dependent manner. PMID- 19783632 TI - A point mutation in the sensor histidine kinase SaeS of Staphylococcus aureus strain Newman alters the response to biocide exposure. AB - Staphylococcus aureus reacts to changing environmental conditions such as heat, pH, and chemicals through global regulators such as the sae (S. aureus exoprotein expression) two-component signaling system. Subinhibitory concentrations of some antibiotics were shown to increase virulence factor expression. Here, we investigated the S. aureus stress response to sublethal concentrations of a commonly used biocide (Perform), by real-time quantitative PCR (qRT-PCR), promoter activity assay, sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis, and a flow cytometric invasion assay. Perform, acting through the production of reactive oxygen species, generally downregulated expression of extracellular proteins in strains 6850, COL, ISP479C but upregulated these proteins in strain Newman. Upregulated proteins were sae dependent. The Perform component SDS, but not paraquat (another oxygen donor), mimicked the biocide effect. Eap (extracellular adherence protein) was most prominently augmented. Upregulation of eap and sae was confirmed by qRT-PCR. Promoter activity of sae P1 was increased by Perform and SDS. Both substances enhanced cellular invasiveness, by 2.5-fold and 3.2-fold, respectively. Increased invasiveness was dependent on Eap and the sae system, whereas agr, sarA, sigB, and fibronectin-binding proteins had no major effect in strain Newman. This unique response pattern was due to a point mutation in SaeS (the sensor histidine kinase), as demonstrated by allele swapping. Newman saePQRS(ISP479C) behaved like ISP479C, whereas saePQRS(Newman) rendered ISP479C equally responsive as Newman. Taken together, the findings indicate that a point mutation in SaeS of strain Newman was responsible for increased expression of Eap upon exposure to sublethal Perform and SDS concentrations, leading to increased Eap-dependent cellular invasiveness. This may be important for understanding the regulation of virulence in S. aureus. PMID- 19783633 TI - Characterization of the sporulation initiation pathway of Clostridium difficile and its role in toxin production. AB - Clostridium difficile is responsible for significant mortality and morbidity in the hospitalized elderly. C. difficile spores are infectious and are a major factor contributing to nosocomial transmission. The Spo0A response regulator is the master regulator for sporulation initiation and can influence many other cellular processes. Using the ClosTron gene knockout system, we inactivated genes encoding Spo0A and a putative sporulation-associated sensor histidine kinase in C. difficile. Inactivation of spo0A resulted in an asporogeneous phenotype, whereas inactivation of the kinase reduced C. difficile sporulation capacity by 3.5-fold, suggesting that this kinase also has a role in sporulation initiation. Furthermore, inactivation of either spo0A or the kinase resulted in a marked defect in C. difficile toxin production. Therefore, Spo0A and the signaling pathway that modulates its activity appear to be involved in regulation of toxin synthesis in C. difficile. In addition, Spo0A was directly phosphorylated by a putative sporulation-associated kinase, supporting the hypothesis that sporulation initiation in C. difficile is controlled by a two-component signal transduction system rather than a multicomponent phosphorelay. The implications of these findings for C. difficile sporulation, virulence, and transmission are discussed. PMID- 19783634 TI - Multiple two-component systems modulate alkali generation in Streptococcus gordonii in response to environmental stresses. AB - The oral commensal Streptococcus gordonii must adapt to constantly fluctuating and often hostile environmental conditions to persist in the oral cavity. The arginine deiminase system (ADS) of S. gordonii enables cells to produce, ornithine, ammonia, CO(2), and ATP from arginine hydrolysis, augmenting the acid tolerance of the organism. The ADS genes are substrate inducible and sensitive to catabolite repression, mediated through ArcR and CcpA, respectively, but the system also requires low pH and anaerobic conditions for optimal activation. Here, we demonstrate that the CiaRH and ComDE two-component systems (TCS) are required for low-pH-dependent expression of ADS genes in S. gordonii. Further, the VicRK TCS is required for optimal ADS gene expression under anaerobic conditions and enhances the sensitivity of the operon to repression by oxygen. The known anaerobic activator of the ADS, Fnr-like protein (Flp), appeared to act independently of the Vic TCS. Mutants of S. gordonii lacking components of the CiaRH, ComDE, or VicRK grew more slowly in acidified media and were more sensitive to killing at lethal pH values and to agents that induce oxidative stress. This study provides the first evidence that TCS can regulate the ADS of bacteria in response to specific environmental signals and reveals some notable differences in the contribution of CiaRH, ComDE, and VicRK to viability and stress tolerance between the oral commensal S. gordonii and the oral pathogen Streptococcus mutans. PMID- 19783635 TI - Multiple two-component systems of Streptococcus mutans regulate agmatine deiminase gene expression and stress tolerance. AB - Induction of the agmatine deiminase system (AgDS) of Streptococcus mutans requires agmatine and is optimal at low pH. We show here that the VicRK, ComDE, and CiaRH two-component systems influence AgDS gene expression in response to acidic and thermal stresses. PMID- 19783636 TI - Reproductive and sphingolipid metabolic effects of fumonisin B(1) and its alkaline hydrolysis product in LM/Bc mice: hydrolyzed fumonisin B(1) did not cause neural tube defects. AB - Fumonisins are mycotoxins produced by Fusarium verticillioides. They are toxic to animals and exert their effects through mechanisms involving disruption of sphingolipid metabolism. Fumonisins are converted to their hydrolyzed analogs by alkaline cooking (nixtamalization). Both fumonisins and hydrolyzed fumonisins are found in nixtamalized foods such as tortillas, and consumption of tortillas has been implicated as a risk factor for neural tube defects (NTD). Fumonisin B(1) (FB(1)) induced NTD when given (ip) to pregnant LM/Bc mice; however, neither the NTD induction potential of hydrolyzed fumonisin B(1) (HFB(1)) nor its affect on sphingolipid metabolism in pregnant mice have been reported. The teratogenic potential of FB(1) and HFB(1) was therefore compared using the LM/Bc mouse model. Dams were dosed (ip) with 2.5, 5.0, 10, or 20 mg/kg (< or = 49 micromol/kg) body weight (bw) HFB(1) on embryonic day (E)7-E8. Negative and positive control groups were given vehicle or 10 mg/kg (14 micromol/kg) bw FB(1), respectively. The high dose of HFB(1) disrupted sphingolipid metabolism, albeit slightly, but did not cause maternal liver lesions or NTD (n = 8-10 litters per group). In contrast, 10 mg/kg bw FB(1) markedly disrupted maternal sphingolipid metabolism, caused hepatic apoptosis in the dams, increased fetal death rates, and decreased fetal weights. Furthermore, NTD were found in all FB(1)-exposed litters (n = 10), and 66 +/- 24% of the fetuses were affected. The findings indicate that HFB(1) does not cause NTD in the sensitive LM/Bc mouse model and only weakly disrupts sphingolipid metabolism at doses up to sevenfold higher (micromole per kilogram body weight basis) than the previously reported lowest observed adverse effect level for FB(1). PMID- 19783637 TI - High-mobility group box-1 protein and keratin-18, circulating serum proteins informative of acetaminophen-induced necrosis and apoptosis in vivo. AB - Drug-induced hepatotoxicity represents a major clinical problem and an impediment to new medicine development. Serum biomarkers hold the potential to provide information about pathways leading to cellular responses within inaccessible tissues, which can inform the medicinal chemist and the clinician with respect to safe drug design and use. Hepatocyte apoptosis, necrosis, and innate immune activation have been defined as features of the toxicological response associated with the hepatotoxin acetaminophen (APAP). Within this investigation, we have unambiguously identified and characterized by liquid chromatography-tandem mass spectrometry differing circulating molecular forms of high-mobility group box-1 protein (HMGB1) and keratin-18 (K18), which are linked to the mechanisms and pathological changes induced by APAP in the mouse. Hypoacetylated HMGB1 (necrosis indicator), caspase-cleaved K18 (apoptosis indicator), and full-length K18 (necrosis indicator) present in serum showed strong correlations with the histological time course of cell death and was more sensitive than alanine aminotransferase activity. We have further identified a hyperacetylated form of HMGB1 (inflammatory indicator) in serum, which indicated that hepatotoxicity was associated with an inflammatory response. The inhibition of APAP-induced apoptosis and K18 cleavage by the caspase inhibitor N-benzyloxycarbonyl-Val-Ala Asp(OMe) fluoromethyl ketone are associated with increased hepatic damage, by a shift to necrotic cell death only. These findings illustrate the initial verification of K18 and HMGB1 molecular forms as serum-based sensitive tools that provide insights into the cellular dynamics involved in APAP hepatotoxicity within an inaccessible tissue. Based on these findings, potential exists for the qualification and measurement of these proteins to further assist in vitro, in vivo, and clinical bridging in toxicological research. PMID- 19783638 TI - Mechanisms of alveolar epithelial chloride absorption. PMID- 19783639 TI - Unpacking a gel-forming mucin: a view of MUC5B organization after granular release. AB - Gel-forming mucins are the largest complex glycoprotein macromolecules in the body. They form the matrix of gels protecting all the surface epithelia and are secreted as disulfide-bonded polymeric structures. The mechanisms by which they are formed and organized within cells and thereafter released to form mucus gels are not understood. In particular, the initial rate of expansion of the mucins after release from their secretory granules is very rapid (seconds), but no clear mechanism for how it is achieved has emerged. Our major interest is in lung mucins, but most particularly in MUC5B, which is the major gel-forming mucin in mucus, and which provides its major protective matrix. In this study, using OptiPrep density gradient ultracentrifugation, we have isolated a small amount of a stable form of the recently secreted and expanding MUC5B mucin, which accounts for less than 2% of the total mucin present. It has an average mass of approximately 150 x 10(6) Da and size Rg of 150 nm in radius of gyration. In transmission electron microscopy, this compact mucin has maintained a circular structure that is characterized by flexible chains connected around protein-rich nodes as determined by their ability to bind colloidal gold. The appearance indicates that the assembled mucins in a single granular form are organized around a number of nodes, each attached to four to eight subunits. The organization of the mucins in this manner is consistent with efficient packing of a number of large heavily glycosylated monomers while still permitting their rapid unfolding and hydration. For the first time, this provides some insight into how the carbohydrate regions might be organized around the NH(2)- and COOH terminal globular protein domains within the granule and also explains how the mucin can expand so rapidly upon its release. PMID- 19783640 TI - Microbial exposure early in life regulates airway inflammation in mice after infection with Streptococcus pneumoniae with enhancement of local resistance. AB - The immunological explanation for the "hygiene hypothesis" has been proposed to be induction of T helper 1 (Th1) responses by microbial products. However, the protective results of hygiene hypothesis-linked microbial exposures are currently shown to be unlikely to result from a Th1-skewed response. Until now, effect of microbial exposure early in life on airway innate resistance remained unclear. We examined the role of early life exposure to microbes in airway innate resistance to a respiratory pathogen. Specific pathogen-free weanling mice were nasally exposed to the mixture of microbial extracts or PBS (control) every other day for 28 days and intratracheally infected with Streptococcus pneumoniae 10 days after the last exposure. Exposure to microbial extracts facilitated colonization of aerobic gram-positive bacteria, anaerobic microorganisms, and Lactobacillus in the airway, compared with control exposure. In pneumococcal pneumonia, the exposure prolonged mouse survival days by suppressing bacterial growth and by retarding pneumococcal blood invasion, despite significantly low levels of leukocyte recruitment in the lung. Enhancement of airway resistance was associated with a significant decrease in production of leukocyte chemokine (KC) and TNFalpha, and suppression of matrix metalloproteinase (MMP-9) expression/activation with enhancement of tissue inhibitor of MMP (TIMP-3) activation. The exposure increased production of IFN-gamma, IL-4, and monocyte chemoattractant-1 following infection. Furthermore, expression of Toll-like receptor 2, 4, and 9 was promoted by the exposure but no longer upregulated upon pneumococcal infection. Thus, we suggest that hygiene hypothesis is more important in regulating the PMN-dominant inflammatory response than in inducing a Th1-dominant response. PMID- 19783641 TI - Asthma and sarcoplasmic reticulum Ca2+ reuptake in airway smooth muscle. PMID- 19783642 TI - A real-time fluorogenic assay for the visualization of glycoside hydrolase activity in planta. AB - There currently exists a diverse array of molecular probes for the in situ localization of polysaccharides, nucleic acids, and proteins in plant cells, including reporter enzyme strategies (e.g. protein-glucuronidase fusions). In contrast, however, there is a paucity of methods for the direct analysis of endogenous glycoside hydrolases and transglycosidases responsible for cell wall remodeling. To exemplify the potential of fluorogenic resorufin glycosides to address this issue, a resorufin beta-glycoside of a xylogluco-oligosaccharide (XXXG-beta-Res) was synthesized as a specific substrate for in planta analysis of XEH activity. The resorufin aglycone is particularly distinguished for high sensitivity in muro assays due to a low pK(a) (5.8) and large extinction coefficient (epsilon 62,000 M(-1) cm(-1)), long-wavelength fluorescence (excitation 571 nm/emission 585 nm), and high quantum yield (0.74) of the corresponding anion. In vitro analyses demonstrated that XXXG-beta-Res is hydrolyzed by the archetypal plant XEH, nasturtium (Tropaeolum majus) NXG1, with classical Michaelis-Menten substrate saturation kinetics and a linear dependence on both enzyme concentration and incubation time. Further, XEH activity could be visualized in real time by observing the localized increase in fluorescence in germinating nasturtium seeds and Arabidopsis (Arabidopsis thaliana) inflorescent stems by confocal microscopy. Importantly, this new in situ XEH assay provides an essential complement to the in situ xyloglucan endotransglycosylase assay, thus allowing delineation of the disparate activities encoded by xyloglucan endotransglycosylase/hydrolase genes directly in plant tissues. The observation that XXXG-beta-Res is also hydrolyzed by diverse microbial XEHs indicates that this substrate, and resorufin glycosides in general, may find broad applicability for the analysis of wall restructuring by polysaccharide hydrolases during morphogenesis and plant-microbe interactions. PMID- 19783643 TI - DkMyb4 is a Myb transcription factor involved in proanthocyanidin biosynthesis in persimmon fruit. AB - Proanthocyanidins (PAs) are secondary metabolites that contribute to the protection of the plant and also to the taste of the fruit, mainly through astringency. Persimmon (Diospyros kaki) is unique in being able to accumulate abundant PAs in the fruit flesh. Fruits of the nonastringent (NA)-type mutants lose their ability to produce PA at an early stage of fruit development, while those of the normal astringent (A) type remain rich in PA until fully ripened. The expression of many PA pathway genes was coincidentally terminated in the NA type at an early stage of fruit development. The five genes encoding the Myb transcription factor were isolated from an A-type cultivar (Kuramitsu). One of them, DkMyb4, showed an expression pattern synchronous to that of the PA pathway genes in A- and NA-type fruit flesh. The ectopic expression of DkMyb4 in kiwifruit (Actinidia deliciosa) induced PA biosynthesis but not anthocyanin biosynthesis. The suppression of DkMyb4 in persimmon calluses caused a substantial down-regulation of the PA pathway genes and PA biosynthesis. Furthermore, analysis of the DNA-binding ability of DkMyb4 showed that it directly binds to the MYBCORE cis-motif in the promoters of the some PA pathway genes. All our results indicate that DkMyb4 acts as a regulator of PA biosynthesis in persimmon and, therefore, suggest that the reduction in the DkMyb4 expression causes the NA-type-specific down-regulation of PA biosynthesis and resultant NA trait. PMID- 19783644 TI - Soybean oil: genetic approaches for modification of functionality and total content. PMID- 19783645 TI - Peroxisomes are required for in vivo nitric oxide accumulation in the cytosol following salinity stress of Arabidopsis plants. AB - Peroxisomes are unique organelles involved in multiple cellular metabolic pathways. Nitric oxide (NO) is a free radical active in many physiological functions under normal and stress conditions. Using Arabidopsis (Arabidopsis thaliana) wild type and mutants expressing green fluorescent protein through the addition of peroxisomal targeting signal 1 (PTS1), which enables peroxisomes to be visualized in vivo, this study analyzes the temporal and cell distribution of NO during the development of 3-, 5-, 8-, and 11-d-old Arabidopsis seedlings and shows that Arabidopsis peroxisomes accumulate NO in vivo. Pharmacological analyses using nitric oxide synthase (NOS) inhibitors detected the presence of putative calcium-dependent NOS activity. Furthermore, peroxins Pex12 and Pex13 appear to be involved in transporting the putative NOS protein to peroxisomes, since pex12 and pex13 mutants, which are defective in PTS1- and PTS2-dependent protein transport to peroxisomes, registered lower NO content. Additionally, we show that under salinity stress (100 mM NaCl), peroxisomes are required for NO accumulation in the cytosol, thereby participating in the generation of peroxynitrite (ONOO(-)) and in increasing protein tyrosine nitration, which is a marker of nitrosative stress. PMID- 19783646 TI - Deciphering transcriptional and metabolic networks associated with lysine metabolism during Arabidopsis seed development. AB - In order to elucidate transcriptional and metabolic networks associated with lysine (Lys) metabolism, we utilized developing Arabidopsis (Arabidopsis thaliana) seeds as a system in which Lys synthesis could be stimulated developmentally without application of chemicals and coupled this to a T-DNA insertion knockout mutation impaired in Lys catabolism. This seed-specific metabolic perturbation stimulated Lys accumulation starting from the initiation of storage reserve accumulation. Our results revealed that the response of seed metabolism to the inducible alteration of Lys metabolism was relatively minor; however, that which was observable operated in a modular manner. They also demonstrated that Lys metabolism is strongly associated with the operation of the tricarboxylic acid cycle while largely disconnected from other metabolic networks. In contrast, the inducible alteration of Lys metabolism was strongly associated with gene networks, stimulating the expression of hundreds of genes controlling anabolic processes that are associated with plant performance and vigor while suppressing a small number of genes associated with plant stress interactions. The most pronounced effect of the developmentally inducible alteration of Lys metabolism was an induction of expression of a large set of genes encoding ribosomal proteins as well as genes encoding translation initiation and elongation factors, all of which are associated with protein synthesis. With respect to metabolic regulation, the inducible alteration of Lys metabolism was primarily associated with altered expression of genes belonging to networks of amino acids and sugar metabolism. The combined data are discussed within the context of network interactions both between and within metabolic and transcriptional control systems. PMID- 19783647 TI - Untranslated regions of a mobile transcript mediate RNA metabolism. AB - BEL1-like transcription factors are ubiquitous in plants and interact with KNOTTED1 types to regulate numerous developmental processes. In potato (Solanum tuberosum subsp. andigena), the BEL1-like transcription factor StBEL5 and its Knox protein partner regulate tuber formation by targeting genes that control growth. RNA detection methods and heterografting experiments demonstrated that StBEL5 transcripts are present in phloem cells and move across a graft union to localize in stolon tips, the site of tuber induction. This movement of RNA originates in leaf veins and petioles and is induced by a short-day photoperiod, regulated by the untranslated regions, and correlated with enhanced tuber production. Assays for RNA mobility suggest that both 5' and 3' untranslated regions contribute to the preferential accumulation of the StBEL5 RNA but that the 3' untranslated region may contribute more to transport from the leaf to the stem and into the stolons. Addition of the StBEL5 untranslated regions to another BEL1-like mRNA resulted in its preferential transport to stolon tips and enhanced tuber production. Transcript stability assays showed that the untranslated regions and a long-day photoperiod enhanced StBEL5 RNA stability in shoot tips. Upon fusion of the untranslated regions of StBEL5 to a beta-glucuronidase marker, translation in tobacco (Nicotiana tabacum) protoplasts was repressed by those constructs containing the 3' untranslated sequence. These results demonstrate that the untranslated regions of the mRNA of StBEL5 are involved in mediating its long-distance transport, in maintaining transcript stability, and in controlling translation. PMID- 19783649 TI - Pneumatosis intestinalis. PMID- 19783648 TI - Epigenetic regulation of gene programs by EMF1 and EMF2 in Arabidopsis. AB - The EMBRYONIC FLOWER (EMF) genes are required to maintain vegetative development in Arabidopsis (Arabidopsis thaliana). Loss-of-function emf mutants skip the vegetative phase, flower upon germination, and display pleiotropic phenotypes. EMF1 encodes a putative transcriptional regulator, while EMF2 encodes a Polycomb group (PcG) protein. PcG proteins form protein complexes that maintain gene silencing via histone modification. They are known to function as master regulators repressing multiple gene programs. Both EMF1 and EMF2 participate in PcG-mediated silencing of the flower homeotic genes AGAMOUS, PISTILLATA, and APETALA3. Full-genome expression pattern analysis of emf mutants showed that both EMF proteins regulate additional gene programs, including photosynthesis, seed development, hormone, stress, and cold signaling. Chromatin immunoprecipitation was carried out to investigate whether EMF regulates these genes directly. It was determined that EMF1 and EMF2 interact with genes encoding the transcription factors ABSCISIC ACID INSENSITIVE3, LONG VEGETATIVE PHASE1, and FLOWERING LOCUS C, which control seed development, stress and cold signaling, and flowering, respectively. Our results suggest that the two EMFs repress the regulatory genes of individual gene programs to effectively silence the genetic pathways necessary for vegetative development and stress response. A model of the regulatory network mediated by EMF is proposed. PMID- 19783650 TI - Small intestinal involvement revealing sarcoidosis. PMID- 19783651 TI - Intracellular expression of a single domain antibody reduces cytotoxicity of 15 acetyldeoxynivalenol in yeast. AB - 15-Acetyldeoxynivalenol (15-AcDON) is a low molecular weight sesquiterpenoid trichothecene mycotoxin associated with Fusarium ear rot of maize and Fusarium head blight of small grain cereals. The accumulation of mycotoxins such as deoxynivalenol (DON) and 15-AcDON within harvested grain is subject to stringent regulation as both toxins pose dietary health risks to humans and animals. These toxins inhibit peptidyltransferase activity, which in turn limits eukaryotic protein synthesis. To assess the ability of intracellular antibodies (intrabodies) to modulate mycotoxin-specific cytotoxocity, a gene encoding a camelid single domain antibody fragment (V(H)H) with specificity and affinity for 15-AcDON was expressed in the methylotropic yeast Pichia pastoris. Cytotoxicity and V(H)H immunomodulation were assessed by continuous measurement of cellular growth. At equivalent doses, 15-AcDON was significantly more toxic to wild-type P. pastoris than was DON. In turn, DON was orders of magnitude more toxic than 3 acetyldeoxynivalenol. Intracellular expression of a mycotoxin-specific V(H)H within P. pastoris conveyed significant (p = 0.01) resistance to 15-AcDON cytotoxicity at doses ranging from 20 to 100 mug.ml(-1). We also documented a biochemical transformation of DON to 15-AcDON to account for the attenuation of DON cytotoxicity at 100 and 200 mug.ml(-1). The proof of concept established within this eukaryotic system suggests that in planta V(H)H expression may lead to enhanced tolerance to mycotoxins and thereby limit Fusarium infection of commercial agricultural crops. PMID- 19783652 TI - Crystal structure of a mammalian CTP: phosphocholine cytidylyltransferase catalytic domain reveals novel active site residues within a highly conserved nucleotidyltransferase fold. AB - CTP:phosphocholine cytidylyltransferase (CCT) is the key regulatory enzyme in the synthesis of phosphatidylcholine, the most abundant phospholipid in eukaryotic cell membranes. The CCT-catalyzed transfer of a cytidylyl group from CTP to phosphocholine to form CDP-choline is regulated by a membrane lipid-dependent mechanism imparted by its C-terminal membrane binding domain. We present the first analysis of a crystal structure of a eukaryotic CCT. A deletion construct of rat CCTalpha spanning residues 1-236 (CCT236) lacks the regulatory domain and as a result displays constitutive activity. The 2.2-A structure reveals a CCT236 homodimer in complex with the reaction product, CDP-choline. Each chain is composed of a complete catalytic domain with an intimately associated N-terminal extension, which together with the catalytic domain contributes to the dimer interface. Although the CCT236 structure reveals elements involved in binding cytidine that are conserved with other members of the cytidylyltransferase superfamily, it also features nonconserved active site residues, His-168 and Tyr 173, that make key interactions with the beta-phosphate of CDP-choline. Mutagenesis and kinetic analyses confirmed their role in phosphocholine binding and catalysis. These results demonstrate structural and mechanistic differences in a broadly conserved protein fold across the cytidylyltransferase family. Comparison of the CCT236 structure with those of other nucleotidyltransferases provides evidence for substrate-induced active site loop movements and a disorder to-order transition of a loop element in the catalytic mechanism. PMID- 19783653 TI - Depletion of selenoprotein GPx4 in spermatocytes causes male infertility in mice. AB - Phospholipid hydroperoxide glutathione peroxidase (GPx4) is an intracellular antioxidant enzyme that directly reduces peroxidized phospholipids. GPx4 is strongly expressed in the mitochondria of testis and spermatozoa. We previously found a significant decrease in the expression of GPx4 in spermatozoa from 30% of infertile human males diagnosed with oligoasthenozoospermia (Imai, H., Suzuki, K., Ishizaka, K., Ichinose, S., Oshima, H., Okayasu, I., Emoto, K., Umeda, M., and Nakagawa, Y. (2001) Biol. Reprod. 64, 674-683). To clarify whether defective GPx4 in spermatocytes causes male infertility, we established spermatocyte specific GPx4 knock-out mice using a Cre-loxP system. All the spermatocyte specific GPx4 knock-out male mice were found to be infertile despite normal plug formation after mating and displayed a significant decrease in the number of spermatozoa. Isolated epididymal GPx4-null spermatozoa could not fertilize oocytes in vitro. These spermatozoa showed significant reductions of forward motility and the mitochondrial membrane potential. These impairments were accompanied by the structural abnormality, such as a hairpin-like flagella bend at the midpiece and swelling of mitochondria in the spermatozoa. These results demonstrate that the depletion of GPx4 in spermatocytes causes severe abnormalities in spermatozoa. This may be one of the causes of male infertility in mice and humans. PMID- 19783654 TI - The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor. AB - ATP-binding cassette transporter A1 (ABCA1) is a cell membrane protein that exports excess cholesterol from cells to apolipoprotein (apo) A-I, the major protein in high density lipoproteins. Genetic studies have shown that ABCA1 protects against cardiovascular disease. The interaction of apoA-I with ABCA1 promotes cholesterol removal and activates signaling molecules, such as Janus kinase 2 (JAK2), that optimize the lipid export activity of ABCA1. Here we show that the ABCA1-mediated activation of JAK2 also activates STAT3, which is independent of the lipid transport function of ABCA1. ABCA1 contains two candidate STAT3 docking sites that are required for the apoA-I/ABCA1/JAK2 activation of STAT3. The interaction of apoA-I with ABCA1-expressing macrophages suppressed the ability of lysopolysaccaride to induce the inflammatory cytokines interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha, which was reversed by silencing STAT3 or ABCA1. Thus, the apoA-I/ABCA1 pathway in macrophages functions as an anti-inflammatory receptor through activation of JAK2/STAT3. These findings implicate ABCA1 as a direct molecular link between the cardioprotective effects of cholesterol export from arterial macrophages and suppressed inflammation. PMID- 19783655 TI - Palmitoylation of hepatitis C virus core protein is important for virion production. AB - Hepatitis C virus core protein is the viral nucleocapsid of hepatitis C virus. Interaction of core with cellular membranes like endoplasmic reticulum (ER) and lipid droplets (LD) appears to be involved in viral assembly. However, how these interactions with different cellular membranes are regulated is not well understood. In this study, we investigated how palmitoylation, a post translational protein modification, can modulate the targeting of core to cellular membranes. We show that core is palmitoylated at cysteine 172, which is adjacent to the transmembrane domain at the C-terminal end of core. Site-specific mutagenesis of residue Cys(172) showed that palmitoylation is not involved in the maturation process carried out by the signal peptide peptidase or in the targeting of core to LD. However, palmitoylation was shown to be important for core association with smooth ER membranes and ER closely surrounding LDs. Finally, we demonstrate that mutation of residue Cys(172) in the J6/JFH1 virus genome clearly impairs virion production. PMID- 19783656 TI - Differential involvement of Atg16L1 in Crohn disease and canonical autophagy: analysis of the organization of the Atg16L1 complex in fibroblasts. AB - A single nucleotide polymorphism in Atg16L1, an autophagy-related gene (ATG), is a risk factor for Crohn disease, a major form of chronic inflammatory bowel disease. However, it is still unknown how the Atg16L1 variant contributes to disease development. The Atg16L1 protein possesses a C-terminal WD repeat domain whose function is entirely unknown, and the Crohn disease-associated mutation (T300A) is within this domain. To elucidate the function of the WD repeat domain, we established an experimental system in which a WD repeat domain mutant of Atg16L1 is stably expressed in Atg16L1-deficient mouse embryonic fibroblasts. Using the system, we show that the Atg16L1 complex forms a dimeric complex and that the total Atg16L1 protein level is strictly maintained, possibly by the ubiquitin proteasome system. Furthermore, we show that an Atg16L1 WD repeat domain deletion and the T300A mutant have little impact on canonical autophagy and autophagy against Salmonella enterica serovar Typhimurium. Therefore, we propose that Atg16L1 T300A is differentially involved in Crohn disease and canonical autophagy. PMID- 19783657 TI - Involvement of the beta clamp in methyl-directed mismatch repair in vitro. AB - We have examined function of the bacterial beta replication clamp in the different steps of methyl-directed DNA mismatch repair. The mismatch-, MutS-, and MutL-dependent activation of MutH is unaffected by the presence or orientation of loaded beta clamp on either 3' or 5' heteroduplexes. Similarly, beta is not required for 3' or 5' mismatch-provoked excision when scored in the presence of gamma complex or in the presence of gamma complex and DNA polymerase III core components. However, mismatch repair does not occur in the absence of beta, an effect we attribute to a requirement for the clamp in the repair DNA synthesis step of the reaction. We have confirmed previous findings that beta clamp interacts specifically with MutS and MutL (Lopez de Saro, F. J., Marinus, M. G., Modrich, P., and O'Donnell, M. (2006) J. Biol. Chem. 281, 14340-14349) and show that the mutator phenotype conferred by amino acid substitution within the MutS N terminal beta-interaction motif is the probable result of instability coupled with reduced activity in multiple steps of the repair reaction. In addition, we have found that the DNA polymerase III alpha catalytic subunit interacts strongly and specifically with both MutS and MutL. Because interactions of polymerase III holoenzyme components with MutS and MutL appear to be of limited import during the initiation and excision steps of mismatch correction, we suggest that their significance might lie in the control of replication fork events in response to the sensing of DNA lesions by the repair system. PMID- 19783658 TI - Discovery and investigation of misincorporation of serine at asparagine positions in recombinant proteins expressed in Chinese hamster ovary cells. AB - Misincorporation of amino acids in proteins expressed in Escherichia coli has been well documented but not in proteins expressed in mammalian cells under normal recombinant protein production conditions. Here we report for the first time that Ser can be incorporated at Asn positions in proteins expressed in Chinese hamster ovary cells. This misincorporation was discovered as a result of intact mass measurement, peptide mapping analysis, and tandem mass spectroscopy sequencing. Our analyses showed that the substitution was not related to specific protein molecules or DNA codons and was not site-specific. We believe that the incorporation of Ser at sites coded for Asn was due to mischarging of tRNA(Asn) rather than to codon misreading. The rationale for substitution of Asn by Ser and not by other amino acids is also discussed. Further investigation indicated that the substitution was due to the starvation for Asn in the cell culture medium and that the substitution could be limited by using the Asn-rich feed. These observations demonstrate that the quality of expressed proteins should be closely monitored when altering cell culture conditions. PMID- 19783659 TI - GCN2 protein kinase is required to activate amino acid deprivation responses in mice treated with the anti-cancer agent L-asparaginase. AB - Asparaginase depletes circulating asparagine and glutamine, activating amino acid deprivation responses (AADR) such as phosphorylation of eukaryotic initiation factor 2 (p-eIF2) leading to increased mRNA levels of asparagine synthetase and CCAAT/enhancer-binding protein beta homologous protein (CHOP) and decreased mammalian target of rapamycin complex 1 (mTORC1) signaling. The objectives of this study were to assess the role of the eIF2 kinases and protein kinase R-like endoplasmic reticulum resident kinase (PERK) in controlling AADR to asparaginase and to compare the effects of asparaginase on mTORC1 to that of rapamycin. In experiment 1, asparaginase increased hepatic p-eIF2 in wild-type mice and mice with a liver-specific PERK deletion but not in GCN2 null mice nor in GCN2-PERK double null livers. In experiment 2, wild-type and GCN2 null mice were treated with asparaginase (3 IU per g of body weight), rapamycin (2 mg per kg of body weight), or both. In wild-type mice, asparaginase but not rapamycin increased p eIF2, p-ERK1/2, p-Akt, and mRNA levels of asparagine synthetase and CHOP in liver. Asparaginase and rapamycin each inhibited mTORC1 signaling in liver and pancreas but maximally together. In GCN2 null livers, all responses to asparaginase were precluded except CHOP mRNA expression, which remained partially elevated. Interestingly, rapamycin blocked CHOP induction by asparaginase in both wild-type and GCN2 null livers. These results indicate that GCN2 is required for activation of AADR to asparaginase in liver. Rapamycin modifies the hepatic AADR to asparaginase by preventing CHOP induction while maximizing inhibition of mTORC1. PMID- 19783660 TI - Membrane rafts are involved in intracellular miconazole accumulation in yeast cells. AB - Azoles inhibit ergosterol biosynthesis, resulting in ergosterol depletion and accumulation of toxic 14alpha-methylated sterols in membranes of susceptible yeast. We demonstrated previously that miconazole induces actin cytoskeleton stabilization in Saccharomyces cerevisiae prior to induction of reactive oxygen species, pointing to an ancillary mode of action. Using a genome-wide agar-based screening, we demonstrate in this study that S. cerevisiae mutants affected in sphingolipid and ergosterol biosynthesis, namely ipt1, sur1, skn1, and erg3 deletion mutants, are miconazole-resistant, suggesting an involvement of membrane rafts in its mode of action. This is supported by the antagonizing effect of membrane raft-disturbing compounds on miconazole antifungal activity as well as on miconazole-induced actin cytoskeleton stabilization and reactive oxygen species accumulation. These antagonizing effects point to a primary role for membrane rafts in miconazole antifungal activity. We further show that this primary role of membrane rafts in miconazole action consists of mediating intracellular accumulation of miconazole in yeast cells. PMID- 19783661 TI - PGRL1 participates in iron-induced remodeling of the photosynthetic apparatus and in energy metabolism in Chlamydomonas reinhardtii. AB - PGRL1 RNA and protein levels are increased in iron-deficient Chlamydomonas reinhardtii cells. In an RNAi strain, which accumulates lower PGRL1 levels in both iron-replete and -starved conditions, the photosynthetic electron transfer rate is decreased, respiratory capacity in iron-sufficient conditions is increased, and the efficiency of cyclic electron transfer under iron-deprivation is diminished. Pgrl1-kd cells exhibit iron deficiency symptoms at higher iron concentrations than wild-type cells, although the cells are not more depleted in cellular iron relative to wild-type cells as measured by mass spectrometry. Thiol trapping experiments indicate iron-dependent and redox-induced conformational changes in PGRL1 that may provide a link between iron metabolism and the partitioning of photosynthetic electron transfer between linear and cyclic flow. We propose, therefore, that PGRL1 in C. reinhardtii may possess a dual function in the chloroplast; that is, iron sensing and modulation of electron transfer. PMID- 19783662 TI - Two novel functions of hyaluronidase-2 (Hyal2) are formation of the glycocalyx and control of CD44-ERM interactions. AB - It has long been predicted that the members of the hyaluronidase enzyme family have important non-enzymatic functions. However, their nature remains a mystery. The metabolism of hyaluronan (HA), their major enzymatic substrate, is also enigmatic. To examine the function of Hyal2, a glycosylphosphatidylinositol anchored hyaluronidase with intrinsically weak enzymatic activity, we have compared stably transfected rat fibroblastic BB16 cell lines with various levels of expression of Hyal2. These cell lines continue to express exclusively the standard form (CD44s) of the main HA receptor, CD44. Hyal2, CD44, and one of its main intracellular partners, ezrin-radixin-moesin (ERM), were found to co immunoprecipitate. Functionally, Hyal2 overexpression was linked to loss of the glycocalyx, the HA-rich pericellular coat. This effect could be mimicked by exposure of BB16 cells either to Streptomyces hyaluronidase, to HA synthesis inhibitors, or to HA oligosaccharides. This led to shedding of CD44, separation of CD44 from ERM, reduction in baseline level of ERM activation, and markedly decreased cell motility (50% reduction in a wound healing assay). The effects of Hyal2 on the pericellular coat and on CD44-ERM interactions were inhibited by treatment with the Na(+)/H(+) exchanger-1 inhibitor ethyl-N-isopropylamiloride. We surmise that Hyal2, through direct interactions with CD44 and possibly some pericellular hyaluronidase activity requiring acidic foci, suppresses the formation or the stability of the glycocalyx, modulates ERM-related cytoskeletal interactions, and diminishes cell motility. These effects may be relevant to the purported in vivo tumor-suppressive activity of Hyal2. PMID- 19783663 TI - ScFv antibody-induced translocation of cell-surface heparan sulfate proteoglycan to endocytic vesicles: evidence for heparan sulfate epitope specificity and role of both syndecan and glypican. AB - Cellular uptake of several viruses and polybasic macromolecules requires the expression of cell-surface heparan sulfate proteoglycan (HSPG) through as yet ill defined mechanisms. We unexpectedly found that among several cell-surface-binding single chain variable fragment (scFv) anti-HS antibody (alphaHS) clones, only one, AO4B08, efficiently translocated macromolecular cargo to intracellular vesicles through induction of HSPG endocytosis. Interestingly, AO4B08-induced PG internalization was strictly dependent on HS 2-O-sulfation and appeared independent of intact N-sulfation. AO4B08 and human immunodeficiency virus (HIV) Tat, i.e. a well known cell-penetrating peptide, were shown to compete for the internalizing PG population. To obtain a more detailed characterization of this pathway, we have developed a procedure for the isolation of endocytic vesicles by conjugating AO4B08 with superparamagnetic nanoparticles. [(35)S]sulfate-labeled HSPG was found to accumulate in isolated, AO4B08-containing vesicles, providing the first biochemical evidence for intact HSPG co-internalization with its ligand. Further analysis revealed the existence of both syndecan, i.e. a transmembrane HSPG, and glycosyl-phosphatidyl-inositol-anchored glypican in purified vesicles. Importantly, internalized syndecan and glypican were found to co-localize in AO4B08-containing vesicles. Our data establish HSPGs as true internalizing receptors of macromolecular cargo and indicate that the sorting of cell-surface HSPG to endocytic vesicles is determined by a specific HS epitope that can be carried by both syndecan and glypican core protein. PMID- 19783664 TI - ADP signaling in vascular endothelial cells: ADP-dependent activation of the endothelial isoform of nitric-oxide synthase requires the expression but not the kinase activity of AMP-activated protein kinase. AB - ADP responses underlie therapeutic approaches to many cardiovascular diseases, and ADP receptor antagonists are in widespread clinical use. The role of ADP in platelet biology has been extensively studied, yet ADP signaling pathways in endothelial cells remain incompletely understood. We found that ADP promoted phosphorylation of the endothelial isoform of nitric-oxide synthase (eNOS) at Ser(1179) and Ser(635) and dephosphorylation at Ser(116) in cultured endothelial cells. Although eNOS activity was stimulated by both ADP and ATP, only ADP signaling was significantly inhibited by the P2Y(1) receptor antagonist MRS 2179 or by knockdown of P2Y(1) using small interfering RNA (siRNA). ADP activated the small GTPase Rac1 and promoted endothelial cell migration. siRNA-mediated knockdown of Rac1 blocked ADP-dependent eNOS Ser(1179) and Ser(635) phosphorylation, as well as eNOS activation. We analyzed pathways known to regulate eNOS, including phosphoinositide 3-kinase/Akt, ERK1/2, Src, and calcium/calmodulin-dependent kinase kinase-beta (CaMKKbeta) using the inhibitors wortmannin, PD98059, PP2, and STO-609, respectively. None of these inhibitors altered ADP-modulated eNOS phosphorylation. In contrast, siRNA-mediated knockdown of AMP-activated protein kinase (AMPK) inhibited ADP-dependent eNOS Ser(635) phosphorylation and eNOS activity but did not affect eNOS Ser(1179) phosphorylation. Importantly, the AMPK enzyme inhibitor compound C had no effect on ADP-stimulated eNOS activity, despite completely blocking AMPK activity. CaMKKbeta knockdown suppressed ADP-stimulated eNOS activity, yet inhibition of CaMKKbeta kinase activity using STO-609 failed to affect eNOS activation by ADP. These data suggest that the expression, but not the kinase activity, of AMPK and CaMKKbeta is necessary for ADP signaling to eNOS. PMID- 19783665 TI - Off-target effects of epidermal growth factor receptor antagonists mediate retinal ganglion cell disinhibited axon growth. AB - Inhibition of central nervous system axon growth is reportedly mediated in part by calcium-dependent phosphorylation of axonal epidermal growth factor receptor, with local administration of the epidermal growth factor receptor kinase inhibitors AG1478 and PD168393 to an optic nerve lesion site promoting adult retinal ganglion cell axon regeneration. Here, we show that epidermal growth factor receptor was neither constitutively expressed, nor activated in optic nerve axons in our non-regenerating and regenerating optic nerve injury models, a finding that is inconsistent with phosphorylated epidermal growth factor receptor dependent intra-axonal signalling of central nervous system myelin-related axon growth inhibitory ligands. However, epidermal growth factor receptor was localized and activated within most glia in the retina and optic nerve post injury, and thus an indirect glial-dependent mechanism for stimulated retinal ganglion cell axon growth by epidermal growth factor receptor inhibitors seemed plausible. Using primary retinal cultures with added central nervous system myelin extracts, we confirmed previous reports that AG1478/PD168393 blocks epidermal growth factor receptor activation and promotes disinhibited neurite outgrowth. Paradoxically, neurites did not grow in central nervous system myelin extract-containing cultures after short interfering ribonucleic acid-mediated knockdown of epidermal growth factor receptor. However, addition of AG1478 restored neurite outgrowth to short interfering ribonucleic acid-treated cultures, implying that epidermal growth factor receptor does not mediate AG1478 dependent effects. TrkA-/B-/C-Fc fusion proteins and the kinase blocker K252a abrogated the neuritogenic activity in these cultures, correlating with the presence of the neurotrophins brain derived neurotrophic factor, nerve growth factor and neurotrophin-3 in the supernatant and increased intracellular cyclic adenosine monophosphate activity. Neurotrophins released by AG1478 stimulated disinhibited retinal ganglion cell axon growth in central nervous system myelin treated cultures by the induction of regulated intramembraneous proteolysis of p75(NTR) and Rho inactivation. Retinal astrocytes/Muller cells and retinal ganglion cells were the source of neurotrophins, with neurite outgrowth halved in the presence of glial inhibitors. We attribute AG1478-stimulated neuritogenesis to the induced release of neurotrophins together with raised cyclic adenosine monophosphate levels in treated cultures, leading to axon growth and disinhibition by neurotrophin-induced regulated intramembraneous proteolysis of p75(NTR). These off-target effects of epidermal growth factor receptor kinase inhibition suggest a novel therapeutic approach for designing treatments to promote central nervous system axon regeneration. PMID- 19783666 TI - High prevalence of undiagnosed airflow limitation in patients with cardiovascular disease. AB - BACKGROUND: The prevalence of airflow limitation (AL) in patients with cardiovascular disease (CVD) is unknown, and whether AL is adequately diagnosed and treated in these patients has not been investigated before, to our knowledge. METHODS: We compared clinical and spirometric data in three groups of individuals. Two of them were participants in the follow-up of an ongoing population-based study according to the presence or absence of CVD. The third group included patients with coronary artery disease (CAD) confirmed by coronariography regularly visited at a tertiary referral university hospital. AL was defined according to the Global Initiative for Obstructive Lung Disease guidelines. RESULTS: We studied 450 population participants without CVD, 52 population participants with CVD, and 119 hospital patients with CAD. The prevalence of AL in these three groups was 17.5% (95% CI, 14.0-21.0), 19.2% (95% CI, 8.1-30.7), and 33.6% (95% CI, 25.0-42.2), respectively (P < .05). Underdiagnosis of AL ranged from 60% in population participants with CVD up to 87.2% in hospital patients with CAD. Sixty percent of those with spirometrically confirmed AL (in all three groups) did not receive any respiratory treatment. CONCLUSIONS: AL is frequent in individuals with CVD, particularly in those with CAD attended in the hospital, is largely underdiagnosed and therefore is highly undertreated. TRIAL REGISTRATION: Clinicaltrials.gov; Identifier: NCT00787748. PMID- 19783667 TI - Antibiotic use in the management of pulmonary nodules. AB - BACKGROUND: Pulmonary nodules are common incidental findings on thoracic imaging examinations. This study sought to determine whether antibiotic use is associated with any improvement in nodule appearance and to identify clinical findings and nodule characteristics potentially influencing the decision to prescribe antibiotics. METHODS: Electronic medical records were reviewed of outpatients referred to a metropolitan cancer center for pulmonary nodules seen on chest CT scans who did not undergo biopsy. The primary end point was the appearance of each nodule on the first follow-up scan. A subset analysis was performed for patients manifesting symptoms or radiographic findings suggesting infection. An analysis was performed to determine what clinical and radiographic findings were associated with the decision to prescribe antibiotics. RESULTS: Between January 2003 and December 2004, 143 evaluations were performed for 293 nodules. Antibiotics were prescribed to 34 (24%) evaluations. A trend toward improvement was seen with antibiotic use, which was not significant. The percentage of nodules that improved was 33% among those receiving antibiotics and 27% among those who did not (odds ratio 1.33; 95% CI, 0.55-3.27). Among 63 patients with pulmonary symptoms, 41% of nodules improved among those receiving antibiotics and 28% among those who did not (odds ratio 1.78; 95% CI, 0.42-7.78). The decision to prescribe antibiotics was associated only with larger nodule size and bronchiectasis. CONCLUSIONS: These data do not support antibiotic use for pulmonary nodules. However, the trend toward improved nodule appearance suggests that larger prospective trials are warranted to clarify the role of antibiotics in managing lung nodules. PMID- 19783668 TI - Exaggerated pulmonary hypertension during mild exercise in chronic mountain sickness. AB - BACKGROUND: Chronic mountain sickness (CMS) is an important public health problem and is characterized by exaggerated hypoxemia, erythrocytosis, and pulmonary hypertension. While pulmonary hypertension is a leading cause of morbidity and mortality in patients with CMS, it is relatively mild and its underlying mechanisms are not known. We speculated that during mild exercise associated with daily activities, pulmonary hypertension in CMS is much more pronounced. METHODS: We estimated pulmonary artery pressure by using echocardiography at rest and during mild bicycle exercise at 50 W in 30 male patients with CMS and 32 age matched, healthy control subjects who were born and living at an altitude of 3,600 m. RESULTS: The modest, albeit significant difference of the systolic right ventricular-to-right-atrial pressure gradient between patients with CMS and controls at rest (30.3 +/- 8.0 vs 25.4 +/- 4.5 mm Hg, P 5 .002) became more than three times larger during mild bicycle exercise (56.4 +/- 19.0 vs 39.8 +/- 8.0 mm Hg, P < .001). CONCLUSIONS: Measurements of pulmonary artery pressure at rest greatly underestimate pulmonary artery pressure during daily activity in patients with CMS. The marked pulmonary hypertension during mild exercise associated with daily activity may explain why this problem is a leading cause of morbidity and mortality in patients with CMS. PMID- 19783669 TI - Inhaled corticosteroids vs placebo for preventing COPD exacerbations: a systematic review and metaregression of randomized controlled trials. AB - BACKGROUND: Inhaled corticosteroids (ICS) have been shown to decrease the occurrence of COPD exacerbations. However, the relationship of baseline lung function and reduction of exacerbations with the use of ICS remains unknown. Herein, we perform a metaregression to evaluate the efficacy of ICS in preventing COPD exacerbations. METHODS: We searched the PubMed, EmBase, and Cochrane Central Database of Controlled Trials databases (1988-2008) for studies that have reported the efficacy of ICS vs placebo in preventing COPD exacerbations. We pooled the risk ratio (RR) and 95% CIs from individual studies using a random effects model to assess the exacerbations in the two groups. We also performed a weighted random effects metaregression using baseline FEV(1) values. RESULTS: Our search yielded 11 studies (8,164 patients). The use of ICS was associated with reduction in the occurrence of exacerbations (RR, 0.82; 95% CI, 0.73-0.92). There was the presence of significant statistical heterogeneity but no evidence of publication bias. Sensitivity analysis revealed benefit of ICS only in patients with FEV(1) < 50% (RR, 0.79; 95% CI, 0.69-0.89) with persistence of statistical heterogeneity. Metaregression showed that the percentage risk reduction in exacerbations with the use of ICS is invariant across the severity of COPD (assessed by FEV(1)). CONCLUSION: There is only a modest benefit of ICS in preventing COPD exacerbations, which is not related to the level of baseline lung function on metaregression analysis. The benefits of ICS in preventing COPD exacerbations thus seem to be overstated. PMID- 19783670 TI - Abnormal swallowing reflex and COPD exacerbations. AB - BACKGROUND: It is unclear whether an abnormal swallowing reflex affects COPD exacerbations. This study investigated the prevalence of abnormal swallowing reflexes and its relationship with COPD exacerbation prospectively. We also clarified its association with gastroesophageal reflux disease (GERD) and airway bacterial colonization. METHODS: Swallowing reflex and serum C-reactive protein (CRP) levels were examined in subjects with stable COPD and in control subjects. Concurrently, GERD symptoms were assessed using a self-reported questionnaire, and sputum bacterial cultures were investigated in the same subjects. Exacerbations were counted prospectively during the following 12 months. RESULTS: The study group comprised 67 subjects with COPD and 19 controls. The prevalence of abnormal swallowing reflex was significantly higher in subjects with COPD (22/67) than controls (1/19; P = .02). Among subjects with COPD, the serum CRP level, GERD symptoms, isolation of sputum bacteria, and the frequency of exacerbations were significantly increased in those with abnormal swallowing reflexes compared with controls (2.72 vs 1.04 mg/L, P = .04, for serum CRP level; 6.75 vs 4.10 points, P = .04, for GERD symptoms; 5/11 vs 3/22, P = .04, for the isolation of sputum bacteria; and 2.82 vs 1.56/y, P = .007, for the annual frequency of exacerbations). Multivariable analysis confirmed that abnormal swallowing reflex was significantly associated with frequent exacerbations (>or= 3/y; P = 0.01). CONCLUSIONS: Abnormal swallowing reflexes frequently occurred in subjects with COPD and predisposed them to exacerbations. Abnormal swallowing reflexes in COPD might be affected by the comorbidity of GERD, and cause bacterial colonization. PMID- 19783671 TI - Prediction of palmitoylation sites using the composition of k-spaced amino acid pairs. AB - Palmitoylation is an important hydrophobic protein modification activity that participates many cellular processes, including signaling, neuronal transmission, membrane trafficking and so on. So it is an important problem to identify palmitoylated proteins and the corresponding sites. Comparing with the expensive and time-consuming biochemical experiments, the computational methods have attracted much attention due to their good performances in predicting palmitoylation sites. In this paper, we develop a novel automated computational method to perform this work. For a sequence segment in a given protein, the encoding scheme based on the composition of k-spaced amino acid pairs (CKSAAP) is introduced, and then the support vector machine is used as the predictor. The proposed prediction model CKSAAP-Palm outperforms the existing method CSS-Palm2.0 on both cross-validation experiments and some independent testing data sets. These results imply that our CKSAAP-Palm is able to predict more potential palmitoylation sites and increases research productivity in palmitoylation sites discovery. The corresponding software can be freely downloaded from http://www.aporc.org/doc/wiki/CKSAAP-Palm. PMID- 19783672 TI - Antigen-induced increases in pulmonary mast cell progenitor numbers depend on IL 9 and CD1d-restricted NKT cells. AB - Pulmonary mast cell progenitor (MCp) numbers increase dramatically in sensitized and aerosolized Ag-challenged mice. This increase depends on CD4(+) T cells, as no MCp increase occurs in the lungs of sensitized wild-type (WT) mice after mAb depletion of CD4(+) but not CD8(+) cells before aerosol Ag challenge. Neither the genetic absence of IL-4, IL-4Ralpha chain, STAT-6, IFN-gamma, or IL-12p40 nor mAb blockade of IFN-gamma, IL-3, IL-4, IL-5, IL-6, IL-10, IL-13, IL-17A, IL-12p40, or IL-12p40Rbeta1 before Ag challenge in WT mice reduces the pulmonary MCp increase. However, sensitized and Ag-challenged IL-9-deficient mice and sensitized WT mice given mAb to IL-9 just before Ag challenge show significant reductions in elicited lung MCp/10(6) mononuclear cells of 47 and 66%, respectively. CD1d deficient mice and WT mice receiving anti-CD1d before Ag challenge also show significant reductions of 65 and 59%, respectively, in elicited lung MCp/10(6) mononuclear cells, revealing an additional requirement for MCp recruitment. However, in Jalpha18-deficient mice, which lack only type 1 or invariant NKT cells, the increase in the numbers of lung MCp with Ag challenge was intact, indicating that their recruitment must be mediated by type 2 NKT cells. Furthermore, anti-CD1d treatment of IL-9-deficient mice or anti-IL-9 treatment of CD1d-deficient mice does not further reduce the significant partial impairment of MCp recruitment occurring with a single deficiency. These findings implicate type 2 NKT cells and IL-9 as central regulators that function in the same pathway mediating the Ag-induced increase in numbers of pulmonary MCp. PMID- 19783673 TI - Pure Hemozoin is inflammatory in vivo and activates the NALP3 inflammasome via release of uric acid. AB - The role of proinflammatory cytokine production in the pathogenesis of malaria is well established, but the identification of the parasite products that initiate inflammation is not complete. Hemozoin is a crystalline metabolite of hemoglobin digestion that is released during malaria infection. In the present study, we characterized the immunostimulatory activity of pure synthetic hemozoin (sHz) in vitro and in vivo. Stimulation of naive murine macrophages with sHz results in the MyD88-independent activation of NF-kappaB and ERK, as well as the release of the chemokine MCP-1; these responses are augmented by IFN-gamma. In macrophages prestimulated with IFN-gamma, sHz also results in a MyD88-dependent release of TNF-alpha. Endothelial cells, which encounter hemozoin after schizont rupture, respond to sHz by releasing IL-6 and the chemokines MCP-1 and IL-8. In vivo, the introduction of sHz into the peritoneal cavity produces an inflammatory response characterized by neutrophil recruitment and the production of MCP-1, KC, IL-6, IL 1alpha, and IL-1beta. MCP-1 and KC are produced independently of MyD88, TLR2/4 and TLR9, and components of the inflammasome; however, neutrophil recruitment, the localized production of IL-1beta, and the increase in circulating IL-6 require MyD88 signaling, the IL-1R pathway, and the inflammasome components ICE (IL-1beta-converting enzyme), ASC (apoptosis-associated, speck-like protein containing CARD), and NALP3. Of note, inflammasome activation by sHz is reduced by allopurinol, which is an inhibitor of uric acid synthesis. These data suggest that uric acid is released during malaria infection and may serve to augment the initial host response to hemozoin via activation of the NALP3 inflammasome. PMID- 19783674 TI - Novel roles of lysines 122, 125, and 58 in functional differences between human and murine MD-2. AB - The MD-2/TLR4 complex provides a highly robust mechanism for recognition and response of mammalian innate immunity to Gram-negative bacterial endotoxins. Despite overall close structural and functional similarity, human (h) and murine (m) MD-2 show several species-related differences, including the ability of hMD 2, but not mMD-2, to bind endotoxin (E) in the absence of TLR4. Wild-type mMD-2 can support TLR4-dependent cell activation by E only when mMD-2 and mTLR4 are coexpressed in the same cell. However, replacement of Glu122, Leu125, and/or Asn58 of mMD-2 with the corresponding residues (lysines) of hMD-2 was sufficient to yield soluble extracellular MD-2 that reacted with monomeric E . sCD14 complex to form extracellular monomeric E . MD-2 that activated cells expressing TLR4 without MD-2. Moreover, in contrast to wild-type mMD-2, double and triple mMD-2 mutants also supported E-triggered signaling in combination with human TLR4. Conversely, a K125L mutant of hMD-2 reacted with E . CD14 and activated TLR4 only when coexpressed with TLR4, and not when secreted without TLR4. These findings reveal novel roles of lysines 122, 125, and 58 in human MD-2 that contribute to the functional differences between human and murine MD-2 and, potentially, to differences in the sensitivity of humans and mice to endotoxin. PMID- 19783675 TI - Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling. AB - Siglec-F is a sialic acid-binding Ig superfamily receptor that is highly expressed on eosinophils. We have investigated whether administration of an anti Siglec-F Ab to OVA-challenged wild-type mice would reduce levels of eosinophilic inflammation and levels of airway remodeling. Mice sensitized to OVA and challenged repetitively with OVA for 1 mo who were administered an anti-Siglec-F Ab had significantly reduced levels of peribronchial eosinophilic inflammation and significantly reduced levels of subepithelial fibrosis as assessed by either trichrome staining or lung collagen levels. The anti-Siglec-F Ab reduced the number of bone marrow, blood, and tissue eosinophils, suggesting that the anti Siglec-F Ab was reducing the production of eosinophils. Administration of a F(ab')(2) fragment of an anti-Siglec-F Ab also significantly reduced levels of eosinophilic inflammation in the lung and blood. FACS analysis demonstrated increased numbers of apoptotic cells (annexin V(+)/CCR3(+) bronchoalveolar lavage and bone marrow cells) in anti-Siglec-F Ab-treated mice challenged with OVA. The anti-Siglec-F Ab significantly reduced the number of peribronchial major basic protein(+)/TGF-beta(+) cells, suggesting that reduced levels of eosinophil derived TGF-beta in anti-Siglec-F Ab-treated mice contributed to reduced levels of peribronchial fibrosis. Administration of the anti-Siglec-F Ab modestly reduced levels of periodic acid-Schiff-positive mucus cells and the thickness of the smooth muscle layer. Overall, these studies suggest that administration of an anti-Siglec-F Ab can significantly reduce levels of allergen-induced eosinophilic airway inflammation and features of airway remodeling, in particular subepithelial fibrosis, by reducing the production of eosinophils and increasing the number of apoptotic eosinophils in lung and bone marrow. PMID- 19783676 TI - Enhanced Th2 cell differentiation and allergen-induced airway inflammation in Zfp35-deficient mice. AB - Studies of human asthma and of animal models of allergic airway inflammation revealed a crucial role for Th2 cells in the pathogenesis of allergic asthma. Kruppel-type zinc finger proteins are the largest family of a regulatory transcription factor for cellular development and function. Zinc finger protein (Zfp) 35 is an 18-zinc finger motif-containing Kruppel-type zinc finger protein, while its function remains largely unknown. The aim of this study was to clarify the role of Zfp35 in the pathogenesis of Th2-dependent allergic inflammation, such as allergic asthma. We examined airway eosinophilic inflammation and hyperresponsiveness in two mouse models, which use our newly generated Zfp35 deficient (Zfp35(-/-)) mice and adoptive transfer of cells. In Zfp35(-/-) mice, Th2 cell differentiation, Th2 cytokine production, eosinophilic inflammation, and airway hyperresponsiveness were substantially enhanced. Furthermore, adoptive transfer of Ag-sensitized Zfp35(-/-) CD4 T cells into the asthmatic mice resulted in enhanced airway inflammation and airway hyperresponsiveness. These results indicate that Zfp35 controls Th2 cell differentiation, allergic airway inflammation, and airway hyperresponsiveness in a negative manner. Thus, Zfp35 may control Th2-dependent diseases, such as allergic asthma. PMID- 19783677 TI - Lymphoid enhancer binding factor 1 regulates transcription through gene looping. AB - Efficient transcription depends upon efficient physical and functional interactions between transcriptosome complexes and DNA. We have previously shown that IL-1beta-induced lymphoid enhancer binding factor 1 (Lef1) regulates the transcription of its target genes COX2 and MMP13 in mouse chondrocytes by binding to the Lef1 binding sites located in the 3' region. In this study, we investigated how the 3' region-bound Lef1 regulates expression of target genes. IL-1beta stimulation induced gene looping in COX2 and MMP13 genomic loci, which is mediated by the physical interaction of Lef1 with its binding partners, including beta-catenin, AP-1, and NF-kappaB. As shown by chromosome conformation capture (3C) assay, the 5' and 3' genomic regions of these genes were juxtaposed in an IL-1beta-stimulation dependent manner. Lef1 played a pivotal role in this gene looping; Lef1 knockdown decreased the incidence of gene looping, while Lef1 overexpression induced it. Physical interactions between the 3' region-bound Lef1 and promoter-bound transcription factors AP-1 or NF-kappaB in COX2 and MMP13, respectively, were increased upon stimulation, leading to synergistic up regulation of gene expression. Knockdown of RelA or c-Jun decreased the formation of gene loop and down-regulated cyclooxygenase 2 (COX2) or matrix metalloproteinase 13 (MMP13) transcription levels. However, overexpression of RelA or c-Jun along with Lef1 increased the looping and their expression levels. Our results indicate a novel function of Lef1, as a mediator of gene looping between 5' and 3' regions. Gene looping may serve to delineate the transcription unit in the inducible gene transcription of mammalian cells. PMID- 19783678 TI - Ethanol-induced expression of ET-1 and ET-BR in liver sinusoidal endothelial cells and human endothelial cells involves hypoxia-inducible factor-1alpha and microrNA-199. AB - Chronic alcohol consumption leads to inflammation and cirrhosis of the liver. In this study, we observed that liver sinusoidal endothelial cells (LSEC) derived from ethanol-fed rats showed several fold increases in the mRNA expression of endothelin-1 (ET-1), hypoxia-inducible factor-1alpha (HIF-1alpha), and inflammatory cytochemokines compared with control rat LSEC. We also observed the same results in acute ethanol-treated LSEC from control rats and human dermal microvascular endothelial cells. Ethanol-mediated ET-1 expression involved NADPH oxidase and HIF-1alpha activation. Furthermore, ethanol increased the expression of the ET-1 cognate receptor ET-BR in Kupffer cells and THP-1 monocytic cells, which also involved HIF-1alpha activation. Promoter analysis and chromatin immunoprecipitation showed that hypoxia response element sites in the proximal promoter of ET-1 and ET-BR were required for the binding of HIF-1alpha to up regulate their expression. We showed that microRNAs, miR-199 among several microRNAs, attenuated HIF-1alpha and ET-1 expression, while anti-miR-199 reversed the effects, suggesting that ethanol-induced miR-199 down-regulation may contribute to augmented HIF-1alpha and ET-1 expression. Our studies, for the first time to our knowledge, show that ethanol-mediated ET-1 and ET-BR expression involve HIF-1alpha, independent of hypoxia. Additionally, ethanol-induced ET-1 expression in rat LSEC is regulated by miR-199, while in human endothelial cells, ET-1 expression is regulated by miR-199 and miR-155, indicating that these microRNAs may function as novel negative regulators to control ET-1 transcription and, thus, homeostatic levels of ET-1 to maintain microcirculatory tone. PMID- 19783679 TI - Genetic evidence that the differential expression of the ligand-independent isoform of CTLA-4 is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice. AB - Idd5.1 regulates T1D susceptibility in nonobese diabetic (NOD) mice and has two notable candidate genes, Ctla4 and Icos. Reduced expression of one of the four CTLA-4 isoforms, ligand-independent CTLA-4 (liCTLA-4), which inhibits in vitro T cell activation and cytokine production similarly to full-length CTLA-4 (flCTLA 4), has been hypothesized to increase type 1 diabetes (T1D) susceptibility. However, further support of this hypothesis is required since the Idd5.1 haplotypes of the diabetes-susceptible NOD and the resistant B10 strains differ throughout Ctla4 and Icos. Using haplotype analysis and the generation of novel Idd5.1-congenic strains that differ at the disease-associated Ctla4 exon 2 single nucleotide polymorphism, we demonstrate that increased expression of liCTLA-4 correlates with reduced T1D susceptibility. To directly assess the ability of liCTLA-4 to modulate T1D, we generated liCTLA-4-transgenic NOD mice and compared their diabetes susceptibility to nontransgenic littermates. NOD liCTLA-4 transgenic mice were protected from T1D to the same extent as NOD.B10 Idd5.1 congenic mice, demonstrating that increased liCTLA-4 expression alone can account for disease protection. To further investigate the in vivo function of liCTLA-4, specifically whether liCTLA-4 can functionally replace flCTLA-4 in vivo, we expressed the liCTLA-4 transgene in CTLA-4(-/-) B6 mice. CTLA-4(-/-) mice expressing liCTLA-4 accumulated fewer activated effector/memory CD4(+) T cells than CTLA-4(-/-) mice and the transgenic mice were partially rescued from the multiorgan inflammation and early lethality caused by the disruption of Ctla4. These results suggest that liCTLA-4 can partially replace some functions of flCTLA-4 in vivo and that this isoform evolved to reinforce the function of flCTLA-4. PMID- 19783680 TI - MAIL regulates human monocyte IL-6 production. AB - IL-6 is a pleiotropic cytokine implicated in the pathogenesis of disorders such as sepsis and cancer. We noted that human monocytes are excellent producers of IL 6 as compared with monocyte-derived macrophages. Because macrophages from molecule containing ankyrin repeats induced by LPS (MAIL) knockout animals have suppressed IL-6 production, we hypothesized that regulation of MAIL is key to IL 6 production in humans and may explain the differences between human monocytes and macrophages. To test this hypothesis fresh human monocytes and monocyte derived macrophages were compared for MAIL expression in response to LPS. LPS induced monocyte MAIL expression was highly inducible and transient. Importantly for our hypothesis MAIL protein expression was suppressed during differentiation of monocytes to macrophages. Of note, the human MAIL protein detected was the 80 kDa MAIL-L form and human MAIL showed nuclear localization. Human MAIL-L bound to p50 subunit of the NF-kappaB and increased IL-6 luciferase promoter activity in a cEBPbeta, NF-kappaB, and AP-1-dependent fashion. Like the differences in MAIL induction, monocytes produced 6-fold more IL-6 compared with macrophages (81.7 +/ 29.7 vs 12.6 +/- 6.8 ng/ml). Furthermore, suppression of MAIL by small interfering RNA decreased the production of IL-6 significantly in both THP-1 cells and in primary monocytes. Costimulation of monocytes with LPS and muramyl dipeptide induced an enhanced IL-6 response that was suppressed by siMAIL. Our data suggests that MAIL is a key regulator of IL-6 production in human monocytes and plays an important role in both TLR and NOD-like receptor ligand induced inflammation. PMID- 19783681 TI - Prevention of inflammatory activation of human gestational membranes in an ex vivo model using a pharmacological NF-kappaB inhibitor. AB - Intrauterine inflammation plays a major role in the etiology of preterm labor and birth. We established an ex vivo model employing perfused full-thickness term gestational membranes to study membrane transport, function, and inflammatory responses. Exposure of the maternal (decidual) face of the membranes to LPS (5 microg/ml) resulted in increased accumulation of proinflammatory cytokines in the maternal compartment within 4 h, followed by a response in the fetal (amniotic) compartment. Using cytokine arrays, exposure to LPS was found to result in increased secretion of a large number of cytokines and chemokines in both compartments, most notably IL-5, IL-6, IL-7, MDC (macrophage-derived chemokine), MIG (monokine induced by IFN-gamma), TARC (thymus and activation-regulated chemokine), TGF-beta, and TNF-alpha. PGE(2) accumulation also increased in response to LPS, particularly in the fetal compartment. Cotreatment with sulfasalazine, which inhibited nuclear translocation of NF-kappaB p65, had a rapid and marked inhibitory effect on the rate of cytokine accumulation in the maternal compartment, with lesser but significant effects observed in the fetal compartment. While membrane integrity was not discernibly impaired with LPS or sulfasalazine exposure, rates of chorionic apoptosis after 20 h were doubled in sulfasalazine-treated tissues. We conclude that the system described provides a means of accurately modeling human gestational membrane functions and inflammatory activation ex vivo. Decidual LPS exposure was shown to elicit a robust inflammatory response in both the maternal and fetal compartments. Sulfasalazine was an effective antiinflammatory agent in this model, but also exerted proapoptotic effects that raise concerns regarding its placental effects when administered in pregnancy. PMID- 19783682 TI - Malaria-induced murine pregnancy failure: distinct roles for IFN-gamma and TNF. AB - Although an important role for excessive proinflammatory cytokines in compromise of pregnancy has been established, an immunological basis for malaria-induced fetal loss remains to be demonstrated. In this study, the roles of IFN-gamma and TNF in Plasmodium chabaudi AS-induced fetal loss in mice were directly investigated. Pregnant IFN-gamma(-/-) mice experienced a more severe course of infection compared with intact C57BL/6 mice, characterized by high parasitemia, severe anemia, and marked weight loss. However, fetal loss was delayed in these mice relative to intact controls. Because IFN-gamma(-/-) mice exhibited sustained levels of plasma TNF, the role of this cytokine was examined. Whereas splenic tnf expression in C57BL/6 mice was highest 3 days before peak parasitemia, increased placental expression relative to uninfected mice was sustained, indicating that locally produced TNF may be important in malaria-induced pregnancy failure. Indeed, Ab neutralization of TNF resulted in preservation of embryos until day 12 of gestation, at which point all embryos were lost in untreated mice. Histological analysis revealed that TNF ablation preserved placental architecture whereas placentae from untreated infected mice had widespread hemorrhage and placental disruption, with fibrin thrombi in some maternal blood sinusoids. Consistent with a role for cytokine-driven thrombosis in fetal loss, expression of procoagulant tissue factor was significantly increased in the placentae of infected C57BL/6 mice but was reduced in mice treated with anti-TNF Ab. Together, these results suggest that IFN-gamma contributes to malaria-induced fetal loss and TNF is a critical factor that acts by inducing placental coagulopathy. PMID- 19783683 TI - Development of allergen-induced airway inflammation in the absence of T-bet regulation is dependent on IL-17. AB - Dysfunctional expression of T-bet, a transcription factor that is critical for IFN-gamma production, has been implicated in the development of asthma. To investigate in detail the mechanisms responsible for exacerbated disease in the absence of T-bet expression, BALB/c wild-type (WT) and T-bet(-/-) mice were used in a murine model of OVA-induced allergic lung inflammation. Following OVA challenge, T-bet(-/-) mice displayed increased histological inflammation in the lungs as well as greater thickening of the bronchiole linings, increased numbers of eosinophils and neutrophils in the lung, and enhanced airway hyperresponsiveness, compared with WT mice. However, the production of Th2 cytokines in T-bet(-/-) mice did not appear to be significantly greater than in WT mice. Interestingly, a marked increase in the levels of the proinflammatory cytokine IL-17 was observed in T-bet(-/-) mice. Neutralization of pulmonary IL-17 in T-bet(-/-) mice by anti-IL-17 mAb treatment during OVA challenge resulted in decreased levels of neutrophilic infiltration into the airways and decreased airway inflammation, essentially reversing the development of allergic asthma development. These findings indicate that IL-17 is a key mediator of airway inflammation in the absence of T-bet. The results of this study suggest a possible target for therapeutic intervention of human asthma. PMID- 19783684 TI - IL-4R(alpha), a new member that associates with Syk kinase: implication in IL-4 induced human neutrophil functions. AB - Although Syk has been reported to be associated with IL-2R beta [corrected] and IL-15R alpha in some hematopoietic cells, its association has never been investigated in the IL-4/IL-4R system. In this study, we demonstrate for the first time that Syk is constitutively associated with IL-4R(alpha)in human polymorphonuclear neutrophils (PMNs) and that IL-4 stimulation increases the amount of Syk associated with IL-4R(alpha). Moreover, upon IL-4 treatment, a pool of Syk associated with IL-4R(alpha) is phosphorylated. We also report that such association is not unique to PMNs because Syk associates with IL-4R(alpha) in Raji and in PBMC cells. Stimulation of PMNs by IL-4 increased the amount of Syk associated with PLC-gamma2, pAkt, and alpha-tubulin. Pretreatment of cells with the Syk-selective inhibitor piceatannol or Syk inhibitor II, significantly inhibited the ability of IL-4 to enhance phagocytosis and cell adhesion and to delay apoptosis, and these results correlate with the ability of piceatannol to reduce Syk activation and its association with IL-4R(alpha). Down-regulation of Syk by antisense techniques demonstrates the importance of Syk in the antiapoptotic effect of IL-4. We conclude that association of Syk to IL-4R(alpha) is of biological significance and that IL-4R(alpha) is a new candidate to be added to the few cytokine receptor components which associate with Syk. PMID- 19783685 TI - Critical role of IL-17RA in immunopathology of influenza infection. AB - Acute lung injury due to influenza infection is associated with high mortality, an increase in neutrophils in the airspace, and increases in tissue myeloperoxidase (MPO). Because IL-17A and IL-17F, ligands for IL-17 receptor antagonist (IL-17RA), have been shown to mediate neutrophil migration into the lung in response to LPS or Gram-negative bacterial pneumonia, we hypothesized that IL-17RA signaling was critical for acute lung injury in response to pulmonary influenza infection. IL-17RA was critical for weight loss and both neutrophil migration and increases in tissue myeloperoxidase (MPO) after influenza infection. However, IL-17RA was dispensable for the recruitment of CD8(+) T cells specific for influenza hemagglutinin or nucleocapsid protein. Consistent with this, IL-17RA was not required for viral clearance. However, in the setting of influenza infection, IL-17RA(-/-) mice showed significantly reduced levels of oxidized phospholipids, which have previously been shown to be an important mediator in several models of acute lung injury, including influenza infection and gastric acid aspiration. Taken together, these data support targeting IL-17 or IL-17RA in acute lung injury due to acute viral infection. PMID- 19783686 TI - CCR7 deficiency on dendritic cells enhances fungal clearance in a murine model of pulmonary invasive aspergillosis. AB - Aspergillus fumigatus is a sporulating fungus found ubiquitously in the environment and is easily cleared from immunocompetent hosts. Invasive aspergillosis develops in immunocompromised patients, and is a leading cause of mortality in hematopoietic stem cell transplant recipients. CCR7 and its ligands, CCL19 and CCL21, are responsible for the migration of dendritic cells from sites of infection and inflammation to secondary lymphoid organs. To investigate the role of CCR7 during invasive aspergillosis, we used a well-characterized neutropenic murine model. During invasive aspergillosis, mice with a CCR7 deficiency in the hematopoietic compartment exhibited increased survival and less pulmonary injury compared with the appropriate wild-type control. Flow cytometric analysis of the chimeric mice revealed an increase in the number of dendritic cells present in the lungs of CCR7-deficient chimeras following infection with Aspergillus conidia. An adoptive transfer of dendritic cells into neutropenic mice provided a protective effect during invasive aspergillosis, which was further enhanced with the adoptive transfer of CCR7-deficient dendritic cells. Additionally, CCR7-deficient dendritic cells activated in vitro with Aspergillus conidia expressed higher TNF-alpha, CXCL10, and CXCL2 levels, indicating a more activated cellular response to the fungus. Our results suggest that the absence of CCR7 is protective during invasive aspergillosis in neutropenic mice. Collectively, these data demonstrate a potential deleterious role for CCR7 during primary immune responses directed against A. fumigatus. PMID- 19783687 TI - Identification of mycobacterial alpha-glucan as a novel ligand for DC-SIGN: involvement of mycobacterial capsular polysaccharides in host immune modulation. AB - Mycobacterium tuberculosis possesses a variety of immunomodulatory factors that influence the host immune response. When the bacillus encounters its target cell, the outermost components of its cell envelope are the first to interact. Mycobacteria, including M. tuberculosis, are surrounded by a loosely attached capsule that is mainly composed of proteins and polysaccharides. Although the chemical composition of the capsule is relatively well studied, its biological function is only poorly understood. The aim of this study was to further assess the functional role of the mycobacterial capsule by identifying host receptors that recognize its constituents. We focused on alpha-glucan, which is the dominant capsular polysaccharide. Here we demonstrate that M. tuberculosis alpha glucan is a novel ligand for the C-type lectin DC-SIGN (dendritic cell-specific ICAM-3-grabbing nonintegrin). By using related glycogen structures, we show that recognition of alpha-glucans by DC-SIGN is a general feature and that the interaction is mediated by internal glucosyl residues. As for mannose-capped lipoarabinomannan, an abundant mycobacterial cell wall-associated glycolipid, binding of alpha-glucan to DC-SIGN stimulated the production of immunosuppressive IL-10 by LPS-activated monocyte-derived dendritic cells. By using specific inhibitors, we show that this IL-10 induction was DC-SIGN-dependent and also required acetylation of NF-kappaB. Finally, we demonstrate that purified M. tuberculosis alpha-glucan, in contrast to what has been reported for fungal alpha glucan, was unable to activate TLR2. PMID- 19783689 TI - Effect of dietary cation-anion difference on measures of acid-base physiology and performance in beef cattle. AB - Dietary constituents can affect cow acid-base physiology and uterine pH. Dietary cation-anion difference (DCAD) has been shown to affect cow acid-base physiology, but the effect on uterine pH has not been demonstrated. The objective of this work was to determine if DCAD [(Na + K + 0.15Ca + 0.15Mg) - (Cl + 0.60S + 0.50P)] could affect cow DMI, acid-base physiology, and uterine pH, and second, to determine if dietary supplements could alleviate any negative effects of DCAD on these variables. In Exp. 1, 21 cows were utilized to determine the effect of a negative DCAD (-0.9 mEq/100 g of DM; low-DCAD) or positive DCAD (+25.0 mEq/100 g of DM; high-DCAD) diet on cow BW, DMI, and pH of blood, urine, and uterine flush fluid. In Exp. 2, 21 cows were randomly allotted to 1 of 3 treatments: control ( 3.1 mEq/100 g of DM), molasses (+2.9 mEq/100 g of DM), or molasses+buffer (+25.8 mEq/100 g of DM) to determine if supplemental liquid molasses or liquid molasses with a buffer could alleviate the effects of a negative DCAD, forage-based diet. Cows were individually fed their respective diets for 42 d in both experiments. Cow BW, blood, urine, and uterine flush were collected on d 0, 21, and 42 during both experiments. Cow ADG was not different (P = 0.71) in Exp. 1 or Exp. 2 (P = 0.47). Hay DMI did not differ (P < 0.70) between high-DCAD and low-DCAD cows before d 28, but was greater (P < 0.001) for high-DCAD cows after d 28 in Exp. 1. In Exp. 2, mean hay DMI did not differ (P = 0.39) among treatments. In Exp. 1, a treatment x day interaction (P < 0.05) was apparent for blood, pH, base excess, bicarbonate, pCO(2), and urine pH. Blood gas and pH measures peaked on d 21 for high-DCAD and declined from d 0 to 42 in low-DCAD cows. High-DCAD cows had greater (P = 0.08) uterine flush pH compared with low-DCAD cows. In contrast, during Exp. 2 there were no differences (P > 0.14) among treatments for blood, pH, base excess, pCO(2), or uterine flush pH. Urine pH exhibited a treatment x day interaction (P < 0.0001). On d 21 molasses supplemented cow urine pH was greater (P < 0.0001) than control cows, whereas on d 42 molasses+buffer had greater (P = 0.01) urine pH compared with control and molasses cows. Dietary cation-anion difference and the use of molasses-based supplements had minimal effect on forage-fed beef cow DMI. However, DCAD has the capacity to alter forage fed beef cow acid-base physiology and potentially affect uterine physiology. PMID- 19783688 TI - IFN-beta inhibits human Th17 cell differentiation. AB - IFN-beta-1a has been used over the past 15 years as a primary therapy for relapsing-remitting multiple sclerosis (MS). However, the immunomodulatory mechanisms that provide a therapeutic effect against this CNS inflammatory disease are not yet completely elucidated. The effect of IFN-beta-1a on Th17 cells, which play a critical role in the development of the autoimmune response, has not been extensively studied in humans. We have investigated the effect of IFN-beta-1a on dendritic cells (DCs) and naive CD4(+)CD45RA(+) T cells derived from untreated MS patients and healthy controls in the context of Th17 cell differentiation. We report that IFN-beta-1a treatment down-regulated the expression of IL-1beta and IL-23p19 in DCs, whereas it induced the gene expression of IL-12p35 and IL-27p28. We propose that IFN-beta-1a-mediated up regulation of the suppressor of cytokine signaling 3 expression, induced via STAT3 phosphorylation, mediates IL-1beta and IL-23 down-regulation, while IFN beta-1a-induced STAT1 phosphorylation induces IL-27p28 expression. CD4(+)CD45RA(+) naive T cells cocultured with supernatants from IFN-beta-1a treated DCs exhibited decreased gene expression of the Th17 cell markers retinoic acid-related orphan nuclear hormone receptor c (RORc), IL-17A, and IL-23R. A direct IFN-beta-1a treatment of CD45RA(+) T cells cultured in Th17-polarizing conditions also down-regulated RORc, IL-17A, and IL-23R, but up-regulated IL-10 gene expression. Studies of the mechanisms involved in the Th17 cell differentiation suggest that IFN-beta-1a inhibits IL-17 and induces IL-10 secretion via activated STAT1 and STAT3, respectively. IFN-beta's suppression of Th17 cell differentiation may represent its most relevant mechanism of selective suppression of the autoimmune response in MS. PMID- 19783690 TI - Suckling behavior in captive plains zebra (Equus burchellii): sex differences in foal behavior. AB - We predicted that the proportion of suckling attempts rejected and terminated by the mother would be greater for female foals than male foals, based on parent offspring conflict theory and on the assumption that throughout the study, all zebra mothers were in good condition because of captivity. We presumed that an increasing rate of suckling terminated or rejected by a mother would indicate a decreasing effort by the mother to invest in her offspring. We observed foals of captive plains zebras at the Dvur Kralove Zoo, Czech Republic. We found that the probability of successful suckling tended (slope = 0.0016; Z = 1.78; P = 0.074) to increase with increasing age of the female foals, but decreased (slope = 0.0018; Z = -2.51; P = 0.012) with increasing age of the male foals. The proportion of suckling bouts terminated by the mother decreased (slope = -0.0077; Z = -4.27; P < 0.0001) with increasing age of the female foals, but not the male foals (slope = -0.0005; Z = -0.34; P = 0.732). Our results indicate that conflict between mothers and female foals was less than that between mothers and male foals. The observed sex differences in termination and rejection of suckling bouts could be explained by the different behavior of the male and female foals, or by the selective maternal investment. Finally, we revealed no significant effect of herdmates on suckling behavior. PMID- 19783691 TI - Evaluation of elevated dietary corn fiber from corn germ meal in growing female pigs. AB - To evaluate the effects of dietary hemicellulose from corn on growth and metabolic measures, female pigs (n = 48; initial BW 30.8 kg) were fed diets containing 0 to 38.6% solvent-extracted corn germ meal for 28 d. Increasing the hemicellulose level had no impact on ADG or ADFI, but resulted in a quadratic response (P < 0.03) on G:F. To investigate physiological changes that occur with increased dietary hemicellulose, blood, colon contents, and tissue samples from the liver and intestine were obtained from a subset (n = 16; 8 pigs/treatment) of pigs fed the least and greatest hemicellulose levels. The abundance of phospho adenosine monophosphate-activated protein kinase (AMPK) and the mitochondrial respiratory protein, cytochrome C oxidase II (COXII) were determined in liver, jejunum, ileum, and colon by Western blotting. The mRNA expression levels of AMPKalpha1, AMPKalpha2, PPAR coactivator 1alpha (PGC1-alpha), PPARgamma2, and sirtuin 1 (Sirt1) were determined in liver and intestinal tissues. When compared with pigs fed the control diet, pigs fed the high hemicellulose diet had increased (P < 0.02) plasma triglycerides, but there was no difference in plasma cholesterol, glucose, or insulin. Absolute and relative liver weights were decreased (P < 0.03) in pigs consuming the high hemicellulose diet. The high fiber diet led to a tendency (P < 0.12) for decreased liver triglyceride content. In pigs fed the high hemicellulose diet, ileal mucosal alkaline phosphatase activity was increased (P < 0.08) and sucrase activity tended (P < 0.12) to be increased. The high hemicellulose diet had no effect on phospho-AMPK, AMPK mRNA, or colonic VFA, but in pigs consuming the high fiber diet there was a greater (P < 0.05) abundance of COXII in colon tissue. The expression of PGC1-alpha, PPARgamma, or Sirt1 mRNA was not altered by dietary fiber in liver, jejunum, or ileum tissue. In colon tissue from pigs fed the high fiber diet there was an increase (P < 0.09) in Sirt1 mRNA and a trend (P < 0.12) toward increased of PGC1 alpha mRNA. These data suggest that alterations in metabolism involved in adaptation to a diet high in hemicellulose are associated with increased colonic Sirt1 mRNA and COXII expression, indicating an increased propensity for oxidative metabolism by the intestine. PMID- 19783692 TI - Effects of sex and short-term magnesium supplementation on stress responses and longissimus muscle quality characteristics of crossbred cattle. AB - Calf-fed heifers (n = 72) and steers (n = 72) were supplemented with 4 levels (0, 0.25, 0.50, and 0.75%) of dietary Mg as MgO during the final 14 d of finishing and were commingled 1 d before slaughter (inducing stress by mixing unfamiliar cattle) to examine the effects of sex class and Mg supplementation on stress responses and LM quality characteristics. Heifers and steers exhibited markedly different stress responses. Heifers were more excitable than steers during preslaughter handling events and exhibited a short-term physiological stress response that involved acute sympatho-adrenal activation and resulted in increased meat toughness, without a concomitant increase in muscle pH. Steers, on the other hand, exhibited greater physical activity, associated with agonistic behavior, during the mixing period and therefore produced carcasses with lesser (P = 0.008) LM glycogen concentrations and greater (P = 0.042) 48-h LM pH values, compared with heifers. Steers also produced tougher (P = 0.008) LM steaks than did heifers. Within the range of pH values observed in this study (5.3 to 6.1), positive, linear relationships between 48-h LM pH and mean LM shear force (P < 0.05) were observed in both heifers (r = 0.25) and steers (r = 0.37). Effects of pH on LM shear force (P < 0.05), which were most pronounced at 3 and 7 d postmortem, diminished during postmortem aging and were no longer evident (P > 0.05) once LM samples had been aged for 21 d. Results suggested that toughness of LM steaks from beef carcasses with final LM pH values greater than 5.65 could be problematic unless LM cuts are aged for approximately 18 d or longer. Supplementation with dietary Mg increased (P = 0.011) serum Mg concentration, but had no effect (P > 0.05) on any of the physiological stress indicators or LM quality characteristics measured in this study. There was no evidence to support the premise that Mg supplementation of cattle lessens the effects of preslaughter stress on beef quality characteristics. PMID- 19783693 TI - Additive effects of a steroidal implant and zilpaterol hydrochloride on feedlot performance, carcass characteristics, and skeletal muscle messenger ribonucleic acid abundance in finishing steers. AB - This experiment investigated the effects of zilpaterol hydrochloride (ZH) and the steroidal implant Revalor-S (RS; 120 mg of trenbolone acetate and 24 mg of estradiol-17beta) on finishing steer performance and the mRNA concentration of beta-adrenergic receptors (beta-AR) types I and II, and types I, IIA, and IIX myosin heavy chain (MHC) isoforms. A total of 2,279 feedlot steers weighing 426 +/- 6.4 kg were administered no implant or RS on d 0, and fed 0 or 8.3 mg of ZH/kg of diet DM during the last 30 d with a 3-d withdrawal. Treatments were randomly assigned to 24 pens (n = 6 pens/treatment). At slaughter, semimembranosus muscle tissue was excised for RNA isolation from 4 carcasses per pen. No interactions were detected for any of the variables measured in the experiment. Administration of ZH during the last 30 d of the feeding period increased (P < 0.01) ADG, G:F, HCW, and LM area; decreased (P < 0.01) 12th-rib fat depth and marbling; and improved (P < 0.01) yield grade. Treatment had no effect on beta1-AR mRNA levels, but there was an increase (P = 0.01) in beta(2) AR mRNA levels due to ZH inclusion. Myosin heavy chain-I (MHC-I) mRNA levels were unaffected by treatment. For MHC-IIA mRNA concentrations, administration of RS tended (P = 0.08) to increase mRNA levels, whereas ZH feeding the last 30 d tended (P = 0.08) to decrease mRNA levels for this isoform of myosin. Feeding ZH the last 30 d before slaughter increased (P < 0.01) mRNA concentrations of MHC IIX in semimembranosus muscle of steers. These data indicate the combined use of ZH and RS additively contributes to BW and carcass gain in finishing feedlot steers and decreases marbling scores and USDA quality grades. The LM area increased and fat thickness decreased. In addition, ZH feeding changes the mRNA levels of MHC isoforms to a faster, more glycolytic fiber type in bovine skeletal muscle. These changes in mRNA concentrations of MHC isoforms, due to ZH feeding, could be affecting skeletal muscle hypertrophy. PMID- 19783694 TI - Intramuscular fat and fatty acid composition of longissimus muscle from divergent pure breeds of cattle. AB - The objective of this study was to compare the fatty acid (FA) composition of intramuscular fat from the LM of 3 divergent breeds of cattle: Angus (AN, n = 9), Brahman (BR, n = 7), and Romosinuano (RM, n = 11). Cattle were blocked by breed and finished 129 d before slaughter in one year and 157 d in the next year. Longissimus muscle samples were collected from each carcass between the 10th and 13th ribs, trimmed of external fat, frozen in liquid nitrogen, homogenized, and used for fat extraction, using a modified Folch procedure. Extracted fat was analyzed for FA by using a GLC system with an HP-88 capillary column. Fatty acid composition was expressed using both a normalized percentage (%) and gravimetric calculation (mg/g of fresh muscle tissue) in relation to degree of saturation, which was determined using a saturation index (ratio of total SFA to total unsaturated FA). Crude fat determination revealed that LM from AN purebred cattle had the greatest amount of intramuscular fat (7.08%; P = 0.001). Although intramuscular fat of LM from RM contained a reduced percentage of total SFA (P = 0.002) compared with AN, it had the greatest percentage of total PUFA (P < 0.001 and P = 0.020). The percentages of total MUFA were similar among the 3 breeds (P = 0.675). The gravimetric calculation, a measure of actual FA concentration, showed significantly greater concentrations of SFA (26.67 mg/g), MUFA (26.50 mg/g), and PUFA (2.37 mg/g) in LM from AN cattle, as compared with LM from BR and RM cattle (P < 0.001). Interestingly, BR purebreds had the least PUFA concentration (1.49 mg/g; P 0.1). On d 20 of lactation, milk from FS, FSM, and FSO sows had more protein than that from CTL sows (P < 0.01). The FSM piglets weighed more on d 56 (P < 0.05) than FS and FSO piglets. Carcasses of 1-d-old FSM piglets also had greater glycogen (P < 0.001) and DM (P = 0.05) contents than FS and FSO piglets, but organ weights and circulating concentrations of glucose and IGF-I did not differ (P > 0.1). In CTL sows, IFN-gamma production decreased between d 101 of gestation and d 2 of lactation, whereas, in FS sows, IFN-gamma production increased (P < 0.01). Anti OVA for the whole experimental period was greater in FS than in FSO sows (P < 0.05). Concentrations of anti-OVA in milk on d 3 of lactation and lymphocyte proliferative responses were not affected by treatments (P > 0.1). Serum concentrations of anti-OVA in 2-d-old piglets that gained BW during the first 24 h after birth were greater (P < 0.01) in FS, FSM, and FSO litters than in CTL litters and percent mortality on d 2 and 21 postpartum was less (P < 0.05) for FS, FSM, and FSO litters compared with CTL. Therefore, feeding flax to sows may have beneficial effects on immune resistance of piglets and feeding FSM improved postweaning growth of piglets. PMID- 19783708 TI - Effect of phytase on apparent total tract digestibility of phosphorus in corn soybean meal diets fed to finishing pigs. AB - Five experiments were conducted to investigate the ability of different phytase products to improve P digestibility in finishing pigs. A corn-soybean meal basal diet containing 0.50% Ca, 0.32% P, and 0.40% Cr(2)O(3) was used to calculate apparent P and GE digestibility. Pigs were individually penned and fed their respective diet for ad libitum intake for 12 d before fecal sampling on d 13 and 14 and blood collection on d 14 for plasma P determination. Experiments 1 through 4 used gilts with across-trial average initial and final BW of 84 and 97 kg, respectively. Pigs were fed Natuphos (Exp. 1), OptiPhos (Exp. 2), Phyzyme (Exp. 3), or RonozymeP (Exp. 4) at 0, 200, 400, 600, 800, or 1,000 phytase units (FTU)/kg (where 1 FTU is defined as the quantity of enzyme required to liberate 1 micromol of inorganic P per min, at pH 5.5, from an excess of 15 micromol/L of sodium phytate at 37 degrees C). Experiment 5 used barrows with initial and final BW of 98 and 111 kg, respectively, and were fed diets containing 0, 500, or 1,000 FTU/kg of Natuphos, OptiPhos, Phyzyme, or RonozymeP. Pigs fed Natuphos (Exp. 1) and OptiPhos (Exp. 2) exhibited a linear and quadratic (P < 0.01) improvement in P digestibility with increasing levels of dietary phytase, whereas pigs fed Phyzyme (Exp. 3) and RonozymeP (Exp. 4) exhibited a linear (P < 0.01) improvement in apparent P digestibility with increasing levels of dietary phytase. In Exp. 5, the improvement in apparent P digestibility with increasing levels of dietary phytase was linear (P < 0.01) for Natuphos, Phyzyme, and RonozymeP, but was linear and quadratic (P < 0.01) for OptiPhos. Based on regression analysis, inorganic P release at 500 FTU/kg was predicted to be 0.070, 0.099, 0.038, and 0.030% for Natuphos, OptiPhos, Phyzyme, and RonozymeP, respectively. These estimates are comparable with those of pigs in Exp. 5, for which the estimated inorganic P release at 500 FTU/kg was 0.102, 0.039, and 0.028% for OptiPhos, Phyzyme, and RonozymeP, respectively, but not for the 0.034% value determined for Natuphos. The effect of dietary phytase on GE digestibility was inconsistent with a linear (P < 0.01) improvement in GE digestibility noted for OptiPhos (Exp. 2 and 5) and RonozymeP (Exp. 4), but the quadratic (P < 0.01) improvement for Natuphos. There was no effect of dietary phytase on plasma inorganic P. The data presented show clear improvements in P digestibility, with the estimated level of inorganic P release being dependent on phytase source and level. PMID- 19783709 TI - Control of the estrous cycle to improve fertility for fixed-time artificial insemination in beef cattle: a review. AB - Early estrus-synchronization protocols focused on regressing the corpus luteum (CL) with an injection of PGF(2alpha) followed by detection of estrus or involved the use of exogenous progestins that prevent estrus from occurring. Later, protocols combining the use of PGF(2alpha) and exogenous progestins were developed. Gonadotropin-releasing hormone was utilized to control follicular waves, synchronize ovulation, or to luteinize large dominant follicles. Our research aimed to develop reliable protocols that 1) relied solely on fixed-timed AI (TAI); 2) required a maximum of 3 animal handlings, and 3) were successful in estrous-cycling and noncycling females. In cows, insertion of an intravaginal progesterone insert during the 7-d interval between the initial GnRH and PGF(2alpha) injections enhanced pregnancy rates by 9 to 10%. In a multi-location study, a TAI protocol yielded pregnancy rates similar to a protocol involving detection of estrus plus a fixed-time clean-up AI for females not detected in estrus (54 vs. 58%, respectively, for cows and 53 vs. 57%, respectively, for heifers). Initiation of estrous cycles in noncycling cows is likely the primary manner in which beef producers may improve fertility in response to estrus synchronization and TAI protocols. Treatment of noncycling females with progesterone and GnRH increases the percentage of cycling females and improves fertility to a TAI, but inducing cyclicity with hCG failed to enhance fertility in TAI protocols. Supplementing progesterone after TAI failed to increase pregnancy rates in beef cattle. In contrast, administration of hCG 7 d after TAI induced an accessory CL, increased progesterone, and tended to enhance pregnancy rates. Development of TAI protocols that reduce the hassle factors associated with ovulation synchronization and AI provide cattle producers efficient and effective tools for capturing selective genetic traits of economic consequences. Location variables, however, which may include differences in pasture and diet, breed composition, body condition, postpartum interval, climate, and geographic location, affect the success of TAI protocols. PMID- 19783710 TI - Multiple doses of sitagliptin, a selective DPP-4 inhibitor, do not meaningfully alter pharmacokinetics and pharmacodynamics of warfarin. AB - Sitagliptin is an orally active, highly selective dipeptidyl peptidase IV (DPP-4) inhibitor for treatment of type 2 diabetes mellitus. This randomized, open-label, 2-part, 2-period crossover study assessed pharmacokinetics/pharmacodynamics of warfarin in the presence/absence of multiple-dose sitagliptin. Twelve participants received treatments A and B separated by >7-day washout: treatment A involved coadministration of sitagliptin 200 mg/d for 11 days (days 1-11) and warfarin 30 mg on day 5, and treatment B involved warfarin 30 mg alone on day 1. R(+) warfarin, S(-) warfarin, and international normalized ratio (INR) were assayed predose and up to 168 hours postdose. The geometric mean ratios (GMRs; warfarin + sitagliptin/warfarin alone) (90% confidence intervals [CIs]) were 0.99 (0.95, 1.03) and 0.95 (0.90, 1.02) for the AUC(0-infinity) of R(+) and S(-) warfarin, respectively. GMRs (warfarin + sitagliptin/warfarin alone) (90% CIs) were 0.89 (0.86, 0.93) and 0.89 (0.86, 0.92) for the C(max) of R(+) and S(-) warfarin, respectively. INR AUC(0-168 h) and INR(max) GMRs were 1.01 (0.96, 1.06) and 1.08 (1.00, 1.17), respectively. Coadministration of sitagliptin and warfarin was generally well tolerated. Pharmacokinetics (AUC for R(+) and S(-) warfarin) and pharmacodynamics (INR of R(+) or S(-) warfarin) were not meaningfully altered following coadministration of multiple-dose sitagliptin and single-dose warfarin, indicating that no dosage adjustment for warfarin is necessary when coadministered with sitagliptin. PMID- 19783711 TI - Anticholinergic activity of commonly prescribed medications and neuropsychiatric adverse events in older people. AB - This study sought to determine whether the presence of in vitro anticholinergic activity (AA) among different drugs is associated with reporting of neuropsychiatric adverse events (NPAEs) and whether age affects this relationship. Retrospective case/noncase analyses using Australia's spontaneous Adverse Drug Reaction System (ADRS) database containing 150 475 reports determined crude and adjusted reporting odds ratios (RORs) for NPAEs for 23 drugs with various reported in vitro AA. Covariates were age (treated as a dichotomous variable [> or =65 years]), gender, and concomitant use of antipsychotics, benzodiazepines, tricyclic antidepressants, and drugs with recognized inherent anticholinergic properties (anticholinergic drugs). The interaction effect between these covariates and each drug exposure category was examined. Age (> or =65 years) has a significant association with greater odds relative to younger age for reporting NPAEs. Drugs with reported significant AA in vitro were not always associated with RORs greater than 1 for reporting NPAEs, highlighting a dissonance between the in vitro AA index and ADRS observations. Significant interactions were observed between age (> or =65 years) and exposure to cimetidine, anticholinergic drugs, antipsychotics, and tricyclic antidepressants in modifying odds for reporting NPAEs, reinforcing the need for cautious use and monitoring of drugs with AA in older people. PMID- 19783712 TI - Quantitative structure-property relationships modeling to predict in vitro and in vivo binding of drugs to the bile sequestrant, colesevelam (Welchol). AB - Quantitative structure-property relationship (QSPR) models were developed to correlate physicochemical properties of structurally unrelated drugs with extent of in vitro binding to colesevelam, and predicted values were compared with drug exposure changes in vivo following coadministration. The binding of 17 drugs to colesevelam was determined by an in vitro dissolution drug-binding assay. Data from several clinical studies in healthy volunteers to support administration of colesevelam in diabetic patients were also collected along with existing in vivo literature data and compared with in vitro results. Steric, electronic, and hydrophobic descriptors were calculated for test compounds, and univariate and partial least squares regression approaches were used to derive QSPR models to evaluate which of the molecular descriptors correlated best with in vitro binding. A quadrant analysis evaluated the correlation between predicted/actual in vitro binding results and the in vivo data. The in vitro binding assay exhibited high sensitivity, identifying those compounds with a low probability of producing relevant in vivo drug interactions. Drug lipophilicity was identified as the primary determinant of in vitro binding to colesevelam by the final univariate and partial least squares models (R(2) = 0.69 and 0.98; Q(2) = 0.48 and 0.59). The in vitro assay and in silico models represent predictive tools that may allow investigators to conduct only informative clinical drug interaction studies with colesevelam. PMID- 19783713 TI - Bioavailability of mycophenolate mofetil and enteric-coated mycophenolate sodium is differentially affected by pantoprazole in healthy volunteers. AB - The influence of pantoprazole 40 mg twice daily on the bioavailability of a single dose of mycophenolate mofetil 1000 mg or enteric-coated mycophenolate sodium is investigated in healthy volunteers. The plasma concentrations of mycophenolic acid and of the inactive metabolite mycophenolic acid glucuronide are measured by high-performance liquid chromatography. The pharmacokinetic parameters following sole administration are similar for mycophenolate mofetil and enteric-coated mycophenolate sodium except for the time to peak concentration, which is longer in the enteric-coated mycophenolate sodium group. Concomitant treatment with pantoprazole significantly (P < .001) lowers the mycophenolic acid exposure following administration of mycophenolate mofetil. The peak concentrations drop by 57%, and area under the curve decreases from 0 to 12 hours by 27%. In contrast, pantoprazole does not change the pharmacokinetics of enteric-coated mycophenolate sodium. Given that mycophenolic acid exposure correlates with the incidence of biopsy-proven acute rejections in renal transplant recipients, these findings may have clinical implications. Administration of pantoprazole in combination with mycophenolate mofetil could possibly result in an insufficient mycophenolic acid exposure, increasing the risk of treatment failure. PMID- 19783714 TI - Examination of the effect of increasing doses of etoricoxib on oral methotrexate pharmacokinetics in patients with rheumatoid arthritis. AB - The authors designed 2 randomized controlled studies to examine the effects of etoricoxib 60 to 120 mg daily on methotrexate pharmacokinetics in 50 rheumatoid arthritis (RA) patients on stable doses of methotrexate (7.5-20 mg). Patients received oral methotrexate at baseline and on days 7 and 14. In study 1, patients received etoricoxib 60 mg (days 1-7) and then 120 mg (days 8-14); in study 2, patients received etoricoxib 90 mg (days 1-7) and then 120 mg (days 8-14). For study 1, the AUC(0-infinity) geometric mean ratio (GMR) (90% confidence interval [CI]) for day 7 versus baseline was 1.01 (0.91, 1.12) for etoricoxib 60 mg; the area under the plasma concentration-time curve from zero to infinity (AUC(0 infinity)) GMR (90% CI) for day 14 was 1.28 (1.15, 1.42) for etoricoxib 120 mg. For study 2, the AUC(0-infinity) GMR (90% CI) for day 7 versus baseline was 1.07 (1.01, 1.13) for etoricoxib 90 mg; the AUC(0-infinity) GMR (90% CI) for day 14 was 1.05 (0.99, 1.11) for etoricoxib 120 mg. In summary, etoricoxib 60 and 90 mg had no effect on methotrexate plasma concentrations. Although no effect on methotrexate pharmacokinetics was observed with etoricoxib 120 mg in study 2, GMR AUC(0-infinity) fell outside the prespecified bounds in study 1. Standard monitoring of methotrexate-related toxicity should be continued when etoricoxib and methotrexate are administered concurrently, especially with doses >90 mg etoricoxib. PMID- 19783715 TI - Pharmacokinetics, safety, and tolerability of phentermine in healthy participants receiving taranabant, a novel cannabinoid-1 receptor (CB1R) inverse agonist. AB - This study assessed the potential pharmacokinetic interaction and safety/tolerability of taranabant and phentermine coadministration. This was a randomized, double-blind, 3-panel, fixed-sequence study in healthy participants. Panels A, B, and C evaluated the safety/tolerability of phentermine 15 mg coadministered with taranabant 0.5, 1, and 2 mg for 7 days (panel A) and 28 days (panels B and C). In panels A and C, phentermine 15 mg was administered both with (7 days, panel A; 28 days, panel C) and without (7 days) taranabant 0.5 mg or 2 mg to evaluate pharmacokinetics. The primary endpoint was phentermine AUC(0-24 h) in panels A and C. Secondary endpoints were changes from baseline in blood pressure and heart rate for all panels. The geometric mean ratios and 90% confidence intervals for phentermine AUC(0-24 h) in the presence/absence of taranabant 0.5 mg and 2 mg were 1.08 (0.99, 1.17) and 1.04 (0.98, 1.10), respectively. No significant differences in blood pressure and heart rate were observed with any treatment versus placebo. Coadministration of taranabant 0.5 mg, 1 mg, and 2 mg with phentermine was well tolerated with no pharmacokinetic interaction and did not result in meaningful changes in blood pressure or heart rate versus placebo. PMID- 19783716 TI - alpha1-Antitrypsin deficiency: best clinical practice. AB - alpha(1)-Antitrypsin (AAT), a 52 kDa plasma protein, is produced mainly in the liver. It is the most abundant circulating serine proteinase inhibitor (serpin). It has also previously been called protease inhibitor to reflect its function as a general inhibitor of serine proteases. Its main physiological role is to inhibit neutrophil elastase and it contributes to the innate immune system as an anti-inflammatory protein. Severe AAT deficiency is most prevalent in northern Europeans affecting about 1 in 3000 of the population. AAT deficiency predisposes individuals who smoke to developing pulmonary emphysema in the fourth-fifth decade of adult life and to childhood cirrhosis in about 10% of cases, with the initial presentation being prolonged neonatal jaundice. The mean interval from presentation with symptoms to diagnosis in adults is about 8 years. The condition is under-recognised and under-diagnosed. The only effective current treatment for the severe liver disease that occurs in childhood currently is liver transplantation. Replacement therapy with purified AAT from human plasma is being used in clinical practice for the lung disease though it is not known whether this influences the outcome of this chronic condition. The liver pathology arises from intracellular polymerisation of mutant protein, and attenuation of polymerisation is a potential target for therapy. PMID- 19783717 TI - Detection of KRAS mutations in colorectal cancer by high-resolution melting analysis. AB - AIMS: Mutation of the KRAS gene predicts the clinical response to the monoclonal antibody cetuximab in patients with advanced colorectal cancer (CRC). This study aimed to perform KRAS mutation detection on formalin-fixed paraffin-embedded (FFPE) tumour tissue by two different methods for comparison. METHODS: The FFPE sample was microdissected to enrich for tumour cells. KRAS exon 2 mutations were performed on 100 Chinese patients with CRC by direct nucleotide sequencing and high-resolution melting (HRM) analysis. RESULTS: KRAS exon 2 mutations were detected in a total of 62 patients with the two methods combined, comprising 11 different mutant alleles. Three common mutations p.Gly12Asp, p.Gly12Val and p.Gly13Asp accounted for approximately 70% of all cases. The concordant rate between the two methods was 95%. Four mutations not initially detected by direct sequencing were identified by HRM and confirmed by sequencing of the HRM amplicons. One mutation detected by direct sequencing was inadvertently grouped as a wild-type allele by HRM software, but this was readily rectified through manual review. CONCLUSION: HRM analysis is a sensitive method of detecting KRAS mutation on FFPE tumour tissue to guide cetuximab treatment and is applicable to routine molecular diagnostic service. Utilisation of HRM to screen for mutations upfront economises the resource used in the sequencing reaction. PMID- 19783718 TI - BCL2 gene aberration as an IPI-independent marker for poor outcome in non germinal-centre diffuse large B cell lymphoma. AB - AIM: Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy in the western hemisphere, and is characterised by a highly variable outcome that impedes individual risk assessment. Lacking reliable biomarkers, the international prognostic index (IPI) has been the most reliable factor to predict survival and stratify patients for therapy. The aim of this study was to investigate the frequency and potential prognostic role of BCL2 aberrations on the chromosomal level and the protein level in a large DLBCL collective. METHODS: Fluorescence in situ hybridisation (FISH) with commercially available dual-colour break-apart probes and immunohistochemistry were used to assess BCL2 gene abnormalities and bcl2 protein expression on validated tissue microarrays containing 224 well-characterised cases of primary DLBCL. RESULTS: FISH analysis of BCL2 revealed a break in 40/215 cases (19%) and a gain in 66/171 (39%) cases. Only BCL2 gains correlated with bcl2 protein expression (p = 0.001). Presence of any BCL2 gene abnormality, particularly gains, correlated independently of the IPI with a significantly worse prognosis in DLBCL of non-germinal centre (non-GC) phenotype as opposed to DLBCL of non-GC type without this genetic alteration (p = 0.003). DLBCL of germinal centre phenotype did not show this association. CONCLUSIONS: Cases of DLBCL of the non-GC type with BCL2 gene aberration are accompanied by a significantly worse prognosis as opposed to cases without such gene abnormalities. It may be helpful to asses BCL2 gene abnormalities by FISH in addition to assessing established parameters for individual risk estimation in DLBCL. PMID- 19783719 TI - Loss of ALX4 expression in epithelial cells and adjacent stromal cells in breast cancer. AB - BACKGROUND: Loss of the stromally-restricted homeodomain transcription factor, Alx4, causes defective mouse mammary epithelial morphogenesis. AIMS: To begin to define the role of ALX4 in the human breast and in breast cancer, the expression pattern of ALX4 in the normal human breast and changes in expression in breast cancer were determined. METHODS: Cells expressing ALX4 in the human breast were identified by co-immunofluorescence using alpha-ALX4 antibodies and markers of specific mammary cell types. ALX4 expression in breast cancer was then determined by immunohistochemistry on tumour sections that also harboured regions of normal breast tissue. Using criteria that required ALX4 staining in both stromal and epithelial cells, changes in ALX4 expression in tumours on a tissue microarray were determined. RESULTS: ALX4 was expressed in both stromal and luminal epithelial cells in the human breast. Scoring tissue sections of duct carcinoma in situ (DCIS) or invasive ductal carcinoma (IDC) that also harboured regions of normal breast tissue, a loss of ALX4 (p<0.001) in stromal and epithelial cells in breast tumours was observed. Analysis of ALX4 expression in 123 sections on a tissue microarray confirmed a highly significant loss (p<0.001) of ALX4 in breast cancer in the tumours themselves and in adjacent stromal cells. CONCLUSIONS: These data show a distinct pattern of expression of ALX4 in the human breast relative to the murine mammary gland. Furthermore, characterisation of ALX4 in breast cancer showed that loss of ALX4 in tumours and the surrounding untransformed stroma is a basic characteristic of DCIS and IDC. PMID- 19783720 TI - Primary cutaneous Ewing sarcoma/primitive neuroectodermal tumour: a clinicopathological analysis of seven cases highlighting diagnostic pitfalls and the role of FISH testing in diagnosis. AB - AIMS: To perform a clinicopathological analysis of a series of primary cutaneous Ewing sarcomas/primitive neuroectodermal tumours (ES/PNET) to highlight the pathological features, discuss the differential diagnosis, emphasise the role of molecular testing (particularly fluorescence in situ hybridisation, FISH) in diagnosis and outline the patients' clinical course. METHODS: Seven cases of primary cutaneous ES/PNET were identified from the authors' consultation files. RESULTS: The patients were aged 16-61 years (median 25). Five were female and two were male. Five cases involved the limbs and two the trunk. Five were initially misdiagnosed (three as carcinoma and two as melanoma). All cases were characterised histologically by sheet-like growth of small round cells with little cytoplasm and showed strong membranous staining for CD99 and positive but variable staining for FLI-1. Six patients showed an EWS rearrangement (five on FISH analysis and one on RT-PCR). All tumours were completely excised. Three patients received adjuvant chemotherapy, one of whom also received radiotherapy. Follow-up was available in all cases (range 11-57 months; median 41). No recurrences or metastases occurred. CONCLUSIONS: Although rare, primary cutaneous ES/PNET should be considered in the differential diagnosis of cutaneous "small blue cell tumours". Immunostaining for FLI-1 and molecular testing for evidence of an EWS rearrangement are useful ancillary investigations to confirm the diagnosis. The prognosis of primary cutaneous ES/PNET appears to be more favourable than extracutaneous ES/PNET. PMID- 19783721 TI - Investigation of outpatients referred to a chemical pathologist with potential pseudohyperkalaemia. AB - BACKGROUND: Pseudohyperkalaemia is when the in vitro blood potassium concentration is artefactually raised while the in vivo concentration is normal. With unexplained hyperkalaemia, pseudohyperkalaemia needs to be excluded to avoid unnecessary and potentially detrimental therapy. There are numerous causes, but no systematic approach for the investigation of outpatients with potential pseudohyperkalaemia exists in the literature. AIMS: To evaluate the in-house protocol. METHODS: Patients referred for investigation of potential pseudohyperkalaemia underwent an outpatient based protocol which is designed to determine whether the cause was due to delayed blood separation, clotting, centrifugation or a haematological abnormality. RESULTS: 32 patients with serum potassium of 5.5-7.1 mmol/l were referred. All patients had pseudohyperkalaemia; the most frequent causes were full blood count (FBC) abnormalities (28%), time >4 hours from sampling to centrifugation (28%) and sample clotting (25%). Anaemia was more likely to be found in male patients. CONCLUSION: Before a problem can be treated, it must be confirmed and its aetiology identified. A systematic approach to investigate potential pseudohyperkalaemia has been presented. This confirmed the clinician's suspicion of pseudohyperkalaemia and in the majority of patients the aetiology was also identified. The use of serum and plasma potassium with an FBC in the initial investigation will identify whether clotting or a haematological abnormality is the cause in about half of the cases. Assay of whole-blood potassium is less important as centrifugation is a rare cause. Time to centrifugation is likely to play a major part in the majority of the remaining cases. PMID- 19783722 TI - Prevalence of haemoglobinopathies in 34,030 healthy adults in Tehran, Iran. AB - BACKGROUND: Haemoglobinopathies are a group of inherited disorders of haemoglobin synthesis. Their frequency varies considerably with geographic location and ethnic group. AIMS: To establish the prevalence of haemoglobinopathies in a mainly healthy Iranian population. METHODS: All files of the haematology unit of the Boghrat laboratory over a period of 10 years (1998-2007) were analysed in relation to the age, sex, full blood count, haemoglobin electrophoresis results, high performance liquid chromatography (HPLC) findings, and iron profile of healthy subjects referred for consultation before marriage. Other tests were performed if indicated. RESULTS: There were 34,030 files; 13,432 (39.5%) were for men, and 20,567 (60.4%) for women. 0.74% of subjects (255) showed a haemoglobinopathy. The distribution of variant haemoglobins in these 255 subjects was: Hb D 75.67% (193 cases), Hb S 4.7%, Hb E 3.13%, Hb O-Arab 1.96% and Hb Lepore 0.39%. A fast haemoglobin was found in 4.71% of subjects. Of the subjects tested, 13.2% (4478) had beta-thalassaemia minor, 0.2% (52) beta-thalassaemia intermedia and 0.1% (30) beta-thalassaemia major. CONCLUSIONS: In comparison with other parts of world, there is a different pattern of haemoglobinopathy with a high prevalence of Hb D, which appears to be Hb D Iran. PMID- 19783723 TI - The role of laboratory processing in determining diagnostic conclusiveness of breast fine needle aspirations: conventional smearing versus a monolayer preparation. AB - AIM: To compare breast fine needle aspiration (FNA) specimens prepared by conventional smearing (CS) versus monolayer preparation (MP), with respect to the conclusiveness of the cytopathological diagnosis. METHODS: From 1992 to 1996, aspirators prepared aspirates themselves by direct smearing onto 2-4 slides. From 1999 to 2003, aspirate preparation was performed in the laboratory, creating a MP, using a Hettich cytocentrifuge. FNA diagnoses were categorised into inadequate (C1), benign (C2), atypical (C3), suspicious for malignancy (C4) and malignant (C5). The reference standard constituted histological follow-up. A conclusive FNA diagnosis was defined as C2 in lesions benign on follow-up and C5 in lesions malignant on histology. RESULTS: From 1992 to 1996, 692 aspirates were processed by CS, whereas from 1999 to 2003, 1301 aspirates were processed by MP. More FNA were ultrasound-guided in the MP group (85.6% versus 21.5%, p<0.001). When compared with CS, MP-prepared FNA had conclusive diagnoses significantly more often (72.8% versus 58.5%, p<0.001). This effect remained significant when corrected for the difference in ultrasound guidance (adjusted odds ratio 1.7, 95% confidence interval 1.3 to 2.2, p<0.001), and was larger for malignant lesions than for benign lesions (51.7% versus 79.9%, p<0.001). CONCLUSION: Patients presenting with breast lesions can more often be offered a same-day, conclusive cytopathological diagnosis when FNA are prepared by a manual MP processing technique. PMID- 19783724 TI - Utilisation of laboratory services by health workers in a district hospital in Malawi. AB - AIMS: To identify priorities for improving effective use of laboratory services in a district hospital in Malawi. METHODS: A prospective observational study of clinician-patient interactions to analyse laboratory test requesting practices and utilisation of laboratory results. The proportion of tests that was appropriately ordered, processed and ultimately influenced clinical management was used to assess effectiveness of utilisation. RESULTS: 420 clinical consultations between health professionals and patients were observed. 92% of tests were ordered appropriately, 84% were processed by the laboratory and 64% of results influenced patient management. 73-79% of high-volume tests (haemoglobin, microscopy for malaria and tuberculosis) and 32% of low-volume tests influenced management. CONCLUSIONS: 25% of commonly requested laboratory tests were not utilised effectively; because of the high volume, interventions to improve their use are likely to be cost effective. Although 68% of low-volume tests were not used efficiently, the cost of providing support for these tests in a resource poor setting needs to be balanced against their clinical usefulness. In contrast to published information, this study shows significant under-requesting of laboratory tests that were available. Measures to increase appropriate test requests will have implications for clinician education as well as laboratory space, budgets and staffing levels. PMID- 19783725 TI - Uterine adenosarcomas overgrown by sex-cord-like tumour: report of two cases. AB - Mullerian adenosarcomas are tumours of low malignant potential with proliferation of benign glands and low grade endometrial stromal sarcoma (LGESS). Unusually, the latter may include foci of uterine tumours resembling ovarian sex-cord tumours (UTROSCT). Two cases of uterine adenosarcomas massively overgrown by UTROSCT are reported, for the first time. The patients, aged 71 and 64, one receiving tamoxifen, presented with intracavitary polypoid adenosarcomas; each was overgrown by an immunopathologically characteristic UTROSCT that constituted more than 75% of its volume. Periglandular CD10+LGESS represented less than 25%. Both are alive and well after 5 and 3 years, respectively. Compared to the poor prognosis of adenosarcomas overgrown by high grade sarcomata, the cases reported here had a benign behaviour. Quantitative assessment of volume percentage of the potentially aggressive LGESS, CD10+ areas should be considered as a relevant prognostic histological parameter in these tumours. PMID- 19783726 TI - Sarcomatous transformation in a cellular angiofibroma: a case report. AB - Cellular angiofibroma is a rare benign mesenchymal tumour of middle-aged adults. This tumour is usually located in the vulvovaginal or inguinoscrotal region. This report describes the case of a patient with a 3.5 cm subcutaneous mass, 2 cm below the left anterior superior iliac spine. Grossly, the mass had tan-white cut surface with a 1.5 cm tan-yellow, whorled, well-delineated nodule. Histologically, the tumour was composed primarily of cytologically bland spindle cells set in a collagenous stroma, with multiple dilated vessels. Other areas showed an abrupt transition to hypercellular sarcomatous elements, including pleomorphic cells with high mitotic activity. The tumour cells were diffusely positive for vimentin and factor XIIIa, and weakly positive for CD34. The patient did not develop any recurrences or metastases, and expired 3 years later of metastatic poorly differentiated carcinoma of unknown origin. This is believed to be the first reported case of sarcomatous transformation in a cellular angiofibroma. PMID- 19783727 TI - Complex analysis of cyclin D1 expression in mantle cell lymphoma: two cyclin D1 negative cases detected. AB - BACKGROUND AND AIM: The cytogenetic and diagnostic hallmark of mantle cell lymphoma (MCL) is translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1. Cyclin D1 expression was analysed in 32 cases of MCL. METHODS: The t(11;14) translocation was detected by fluorescence in situ hybridisation, level of cyclin D1 mRNA by competitive RT-PCR, and level of cyclin D1 and D2 proteins by immunohistochemistry and/or immunoblotting. RESULTS: In 30 cases, the presence of translocation t(11;14), a high level of cyclin D1 mRNA, and a high level of the cyclin D1 protein were confirmed. Two cyclin D1-negative cases overexpressing cyclin D2 were detected by immunoblotting. CONCLUSIONS: There are rare cyclin D1 negative cases of MCL overexpressing cyclin D2. Anti-cyclin D1 antibodies with low specificity can bind both cyclin D1 and cyclin D2, thus providing false cyclin D1-positive signals in immunohistochemical analysis. PMID- 19783729 TI - Anticipating the Redfern inquiry: a historical note about tissue retention and consent. PMID- 19783730 TI - Minimal added value of further blocks in negative appendicectomy for acute appendicitis. PMID- 19783731 TI - Ode to a pathologist or red and blue. PMID- 19783733 TI - Coming into bloom: the specification of floral meristems. AB - In flowering plants, the founder cells from which reproductive organs form reside in structures called floral meristems. Recent molecular genetic studies have revealed that the specification of floral meristems is tightly controlled by regulatory networks that underpin several coordinated programmes, from the integration of flowering signals to floral organ formation. A notable feature of certain regulatory genes that have been newly implicated in the acquisition and maintenance of floral meristem identity is their conservation across diverse groups of flowering plants. This review provides an overview of the molecular mechanisms that underlie floral meristem specification in Arabidopsis thaliana and, where appropriate, discusses the conservation and divergence of these mechanisms across plant species. PMID- 19783734 TI - Polycomb group-dependent imprinting of the actin regulator AtFH5 regulates morphogenesis in Arabidopsis thaliana. AB - During embryogenesis, Polycomb group (PcG) complexes deposit silencing histone modifications and target homeotic genes, which regulate the patterning of other transcription factors. This transcriptional network further maintains cell fate. However, genome-wide identification of histone modifications has suggested that PcG complexes might regulate genes other than those encoding transcription factors. In Arabidopsis, we show that PcG activity directly targets the actin regulator formin ARABIDOPSIS FORMIN HOMOLOGUE 5 (AtFH5). PcG activity silences the paternal allele of AtFH5, restricting its expression to the maternal allele. AtFH5 thus appears to be a new, maternally expressed imprinted gene. We further demonstrate that AtFH5 is responsible for morphological defects caused by the loss of PcG activity in the seed. PMID- 19783735 TI - Smicl is required for phosphorylation of RNA polymerase II and affects 3'-end processing of RNA at the midblastula transition in Xenopus. AB - Smicl (Smad-interacting CPSF 30-like) is an unusual protein that interacts with transcription factors as well as with the cleavage and polyadenylation specificity factor (CPSF). Previous work has shown that Smicl is expressed maternally in the Xenopus embryo and is later required for transcription of Chordin. In this paper we search for additional targets of Smicl. We identify many genes whose onset of expression at the midblastula transition (MBT) requires Smicl and is correlated with the translocation of Smicl from cytoplasm to nucleus. At least one such gene, Xiro1, is regulated via 3'-end processing. In searching for a general mechanism by which Smicl might regulate gene expression at the MBT, we have discovered that it interacts with the tail of Rpb1, the largest subunit of RNA polymerase II. Our results show that Smicl is required for the phosphorylation of the Rpb1 tail at serine 2 of the repeated heptapeptide YSPTSPS. This site becomes hyperphosphorylated at the MBT, thus allowing the docking of proteins required for elongation of transcription and RNA processing. Our work links the onset of zygotic gene expression in the Xenopus embryo with the translocation of Smicl from cytoplasm to nucleus, the phosphorylation of Rpb1 and the 3'-end processing of newly transcribed mRNAs. PMID- 19783736 TI - Dendrite branching and self-avoidance are controlled by Turtle, a conserved IgSF protein in Drosophila. AB - The dendritic trees of neurons result from specific patterns of growth and branching, and dendrite branches of the same neuron avoid one another to spread over a particular receptive field. Recognition molecules on the surfaces of dendrites influence these patterning and avoidance processes by promoting attractive, repulsive or adhesive responses to specific cues. The Drosophila transmembrane protein Turtle (Tutl) and its orthologs in other species are conserved members of the immunoglobulin superfamily, the in vivo functions of which are unknown. In Drosophila sensory neurons, we show that the tutl gene is required to restrain dendrite branch formation in neurons with simple arbors, and to promote dendrite self-avoidance in neurons with complex arbors. The cytoplasmic tail of Tutl is dispensable for control of dendrite branching, suggesting that Tutl acts as a ligand or co-receptor for an unidentified recognition molecule to influence the architecture of dendrites and their coverage of receptive territories. PMID- 19783737 TI - Early lineage specification of long-lived germline precursors in the colonial ascidian Botryllus schlosseri. AB - In many taxa, germline precursors segregate from somatic lineages during embryonic development and are irreversibly committed to gametogenesis. However, in animals that can propagate asexually, germline precursors can originate in adults. Botryllus schlosseri is a colonial ascidian that grows by asexual reproduction, and on a weekly basis regenerates all somatic and germline tissues. Embryonic development in solitary ascidians is the classic example of determinative specification, and we are interested in both the origins and the persistence of stem cells responsible for asexual development in colonial ascidians. In this study, we characterized vasa as a putative marker of germline precursors. We found that maternally deposited vasa mRNA segregates early in development to a posterior lineage of cells, suggesting that germline formation is determinative in colonial ascidians. In adults, vasa expression was observed in the gonads, as well as in a population of mobile cells scattered throughout the open circulatory system, consistent with previous transplantation/reconstitution results. vasa expression was dynamic during asexual development in both fertile and infertile adults, and was also enriched in a population of stem cells. Germline precursors in juveniles could contribute to gamete formation immediately upon transplantation into fertile adults, thus vasa expression is correlated with the potential for gamete formation, which suggests that it is a marker for embryonically specified, long-lived germline progenitors. Transient vasa knockdown did not have obvious effects on germline or somatic development in adult colonies, although it did result in a profound heterochrony, suggesting that vasa might play a homeostatic role in asexual development. PMID- 19783738 TI - Sonic hedgehog-dependent synthesis of laminin alpha1 controls basement membrane assembly in the myotome. AB - Basement membranes have essential structural and signalling roles in tissue morphogenesis during embryonic development, but the mechanisms that control their formation are still poorly understood. Laminins are key components of basement membranes and are thought to be essential for initiation of basement membrane assembly. Here, we report that muscle progenitor cells populating the myotome migrate aberrantly in the ventral somite in the absence of sonic hedgehog (Shh) signalling, and we show that this defect is due to the failure to form a myotomal basement membrane. We reveal that expression of Lama1, which encodes laminin alpha1, a subunit of laminin-111, is not activated in Shh(-/-) embryos. Recovery of Lama1 expression or addition of exogenous laminin-111 to Shh(-/-);Gli3(-/-) embryos restores the myotomal basement membrane, demonstrating that laminin-111 is necessary and sufficient to initiate assembly of the myotomal basement membrane. This study uncovers an essential role for Shh signalling in the control of laminin-111 synthesis and in the initiation of basement membrane assembly in the myotome. Furthermore, our data indicate that laminin-111 function cannot be compensated by laminin-511. PMID- 19783739 TI - Necl2 regulates epidermal adhesion and wound repair. AB - Differential expression of cell adhesion molecules regulates stem cell location, self-renewal and lineage selection under steady state conditions and during tissue repair. We show that the intercellular adhesion protein nectin-like molecule 2 (Necl2) is highly expressed in bulge stem cells of adult human and mouse hair follicles. Overexpression of Necl2 in cultured human keratinocytes led to upregulation of calcium/calmodulin-associated Ser/Thr kinase (CASK), increased calcium-independent intercellular adhesion, and inhibition of cell motility and in vitro wound healing. Although the rate of cell proliferation was reduced, terminal differentiation was unaffected. To assess the role of Necl2 in vivo, we examined the epidermis of Necl2-null mice and developed transgenic mice that expressed Necl2 in the basal layer of murine epidermis. Necl2 overexpression led to a reduction in S-phase cells and an increase in quiescent cells retaining DNA label in the bulge. Although epidermal homeostasis appeared normal in both transgenic and knockout mice, wound healing was markedly delayed. Necl2 overexpression resulted in reduced proliferation and increased levels of CASK and E-cadherin at the leading edge of healing wounds, consistent with its effects in culture. Our results demonstrate that Necl2 is involved in regulating epidermal stem cell quiescence and location. PMID- 19783740 TI - Patched 1 is a crucial determinant of asymmetry and digit number in the vertebrate limb. AB - The vertebrate hedgehog receptor patched 1 (Ptc1) is crucial for negative regulation of the sonic hedgehog (Shh) pathway during anterior-posterior patterning of the limb. We have conditionally inactivated Ptc1 in the mesenchyme of the mouse limb using Prx1-Cre. This results in constitutive activation of hedgehog (Hh) signalling during the early stages of limb budding. Our data suggest that variations in the timing and efficiency of Cre-mediated excision result in differential forelimb and hindlimb phenotypes. Hindlimbs display polydactyly (gain of digits) and a molecular profile similar to the Gli3 mutant extra-toes. Strikingly, forelimbs are predominantly oligodactylous (displaying a loss of digits), with a symmetrical, mirror-image molecular profile that is consistent with re-specification of the anterior forelimb to a posterior identity. Our data suggest that this is related to very early inactivation of Ptc1 in the forelimb perturbing the gene regulatory networks responsible for both the pre-patterning and the subsequent patterning stages of limb development. These results establish the importance of the downstream consequences of Hh pathway repression, and identify Ptc1 as a key player in limb patterning even prior to the onset of Shh expression. PMID- 19783741 TI - Population structure of the lyme borreliosis spirochete Borrelia burgdorferi in the western black-legged tick (Ixodes pacificus) in Northern California. AB - Factors potentially contributing to the lower incidence of Lyme borreliosis (LB) in the far-western than in the northeastern United States include tick host seeking behavior resulting in fewer human tick encounters, lower densities of Borrelia burgdorferi-infected vector ticks in peridomestic environments, and genetic variation among B. burgdorferi spirochetes to which humans are exposed. We determined the population structure of B. burgdorferi in over 200 infected nymphs of the primary bridging vector to humans, Ixodes pacificus, collected in Mendocino County, CA. This was accomplished by sequence typing the spirochete lipoprotein ospC and the 16S-23S rRNA intergenic spacer (IGS). Thirteen ospC alleles belonging to 12 genotypes were found in California, and the two most abundant, ospC genotypes H3 and E3, have not been detected in ticks in the Northeast. The most prevalent ospC and IGS biallelic profile in the population, found in about 22% of ticks, was a new B. burgdorferi strain defined by ospC genotype H3. Eight of the most common ospC genotypes in the northeastern United States, including genotypes I and K that are associated with disseminated human infections, were absent in Mendocino County nymphs. ospC H3 was associated with hardwood-dominated habitats where western gray squirrels, the reservoir host, are commonly infected with LB spirochetes. The differences in B. burgdorferi population structure in California ticks compared to the Northeast emphasize the need for a greater understanding of the genetic diversity of spirochetes infecting California LB patients. PMID- 19783742 TI - Design of an experimental viscoelastic food model system for studying Zygosaccharomyces bailii spoilage in acidic sauces. AB - Within the field of predictive microbiology, the number of studies that quantify the effect of food structure on microbial behavior is very limited. This is mainly due to impracticalities related to the use of a nonliquid growth medium. In this study, an experimental food model system for studying yeast spoilage in acid sauces was developed by selecting a suitable thickening/gelling agent. In a first step, a variety of thickening/gelling agents was screened, with respect to the main physicochemical (pH, water activity, and acetic acid and sugar concentrations) and rheological (weak gel viscoelastic behavior and presence of a yield stress) characteristics of acid sauces. Second, the rheological behavior of the selected thickening/gelling agent, Carbopol 980, was extensively studied within the following range of conditions: pH 4.0 to 5.0, acetic acid concentration of 0 to 1.0% (vol/vol), glycerol concentration of 0 to 15% (wt/vol), and Carbopol concentration of 1.0 to 1.5% (wt/vol). Finally, the applicability of the model system was illustrated by performing growth experiments in microtiter plates for Zygosaccharomyces bailii at 0, 0.5, 1.0, and 1.5% (wt/vol) Carbopol, 5% (wt/vol) glycerol, 0% (vol/vol) acetic acid, and pH 5.0. A shift from planktonic growth to growth in colonies was observed when the Carbopol concentration increased from 0.5 to 1.0%. The applicability of the model system was illustrated by estimating mu(max) at 0.5% Carbopol from absorbance detection times. PMID- 19783743 TI - Comparison of bacterioneuston and bacterioplankton dynamics during a phytoplankton bloom in a fjord mesocosm. AB - The bacterioneuston is the community of Bacteria present in surface microlayers, the thin surface film that forms the interface between aquatic environments and the atmosphere. In this study we compared bacterial cell abundances and bacterial community structures of the bacterioneuston and the bacterioplankton (from the subsurface water column) during a phytoplankton bloom mesocosm experiment. Bacterial cell abundance, determined by flow cytometry, followed a typical bacterioplankton response to a phytoplankton bloom, with Synechococcus and high nucleic acid content (HNA) bacterial cell numbers initially falling, probably due to selective protist grazing. Subsequently HNA and low-nucleic acid content bacterial cells increased in abundance, but Synechococcus cells did not. There was no significant difference between bacterioneuston and bacterioplankton cell abundances during the experiment. Conversely, distinct and consistent differences between the bacterioneuston and the bacterioplankton community structures were observed. This was monitored simultaneously by Bacteria 16S rRNA gene terminal restriction fragment length polymorphism and denaturing gradient gel electrophoresis. The conserved patterns of community structure observed in all of the mesocosms indicate that the bacterioneuston is distinctive and nonrandom. PMID- 19783744 TI - Calcium oxalate biomineralization by Piloderma fallax in response to various levels of calcium and phosphorus. AB - Piloderma fallax is an ectomycorrhizal fungus commonly associated with several conifer and hardwood species. We examined the formation of calcium oxalate crystals by P. fallax in response to calcium (0.0, 0.1, 0.5, 1, and 5 mM) and phosphorus (0.1 and 6 mM) additions in modified Melin-Norkrans agar medium. Both calcium and phosphorus supplementation significantly affected the amount of calcium oxalate formed. More calcium oxalate was formed at high P levels. Concentrations of soluble oxalate in the fungus and medium were higher at low P levels. There was a strong positive linear relationship between Ca level and calcium oxalate but only under conditions of phosphorus limitation. Calcium oxalate crystals were identified as the monohydrate form (calcium oxalate monohydrate [COM] whewellite) by X-ray diffraction analysis. Prismatic, styloid, and raphide forms of the crystals, characteristic COM, were observed on the surface of fungal hyphae by scanning electron microscopy. P. fallax may be capable of dissolving hyphal calcium oxalate under conditions of limited Ca. The biomineralization of calcium oxalate by fungi may be an important step in the translocation and cycling of Ca and P in soil. PMID- 19783745 TI - Acyl-homoserine lactones can induce virus production in lysogenic bacteria: an alternative paradigm for prophage induction. AB - Prophage typically are induced to a lytic cycle under stressful environmental conditions or when the host's survival is threatened. However, stress independent, spontaneous induction also occurs in nature and may be cell density dependent, but the in vivo signal(s) that can trigger induction is unknown. In the present study, we report that acyl-homoserine lactones (AHL), the essential signaling molecules of quorum sensing in many gram-negative bacteria, can trigger phage production in soil and groundwater bacteria. This phenomenon also was operative in a lambda lysogen of Escherichia coli. In model coculture systems, we monitored the real-time AHL production from Pseudomonas aeruginosa PAO1 using an AHL bioluminescent sensor and demonstrated that lambda-prophage induction in E. coli was correlated with AHL production. As a working model in E. coli, we show that the induction responses of lambda with AHL remained unaffected when recA was deleted, suggesting that this mechanism does not involve an SOS response. In the same lambda lysogen we also demonstrated that sdiA, the AHL receptor, and rcsA, a positive transcriptional regulator of exopolysaccharide synthesis, are involved in the AHL-mediated induction process. These findings relate viral reproduction to chemical signals associated with high host cell abundance, suggesting an alternative paradigm for prophage induction. PMID- 19783746 TI - Gene cloning, protein characterization, and alteration of product selectivity for the trehalulose hydrolase and trehalulose synthase from "Pseudomonas mesoacidophila" MX-45. AB - The naturally occurring structural isomer of sucrose, trehalulose, is produced by sucrose isomerase (SI). Screening of chromosomal DNA from "Pseudomonas mesoacidophila" MX-45 with an SI-specific probe facilitated the cloning of two adjacent gene homologs, mutA and mutB. Both genes were expressed separately in Escherichia coli, and their enzyme products were characterized. MutA hydrolyzed the substrates trehalulose, isomaltulose, and sucrose into glucose and fructose. Due to its highest activity on trehalulose, MutA was referred to as trehalulase. mutB encodes the SI (trehalulose synthase) and catalyzes the isomerization of sucrose to mainly trehalulose. From Northern blot analysis it is apparent that the mutB gene is not transcribed as part of an operon and was transcriptionally upregulated when P. mesoacidophila MX-45 cells were grown in sucrose medium, whereas under investigated conditions no transcript for mutA was detected. Mutants of mutB were created by a random mutagenesis approach in order to alter the product specificity of MutB. Two types of mutants have emerged, one type that prefers the hydrolytic reaction on sucrose and another type that still acts as an SI but with a significant shift in the product from trehalulose to isomaltulose. The hydrolytic character of MutB R311C was demonstrated through its higher catalytic efficiency for glucose production over trehalulose production. MutB D442N favored the transfer reaction, with an isomer preference for isomaltulose. PMID- 19783747 TI - Rumen microbiome composition determined using two nutritional models of subacute ruminal acidosis. AB - Subacute ruminal acidosis (SARA) is a metabolic disease in dairy cattle that occurs during early and mid-lactation and has traditionally been characterized by low rumen pH, but lactic acid does not accumulate as in acute lactic acid acidosis. It is hypothesized that factors such as increased gut permeability, bacterial lipopolysaccharides, and inflammatory responses may have a role in the etiology of SARA. However, little is known about the nature of the rumen microbiome during SARA. In this study, we analyzed the microbiome of 64 rumen samples taken from eight lactating Holstein dairy cattle using terminal restriction fragment length polymorphisms (TRFLP) of 16S rRNA genes and real-time PCR. We used rumen samples from two published experiments in which SARA had been induced with either grain or alfalfa pellets. The results of TRFLP analysis indicated that the most predominant shift during SARA was a decline in gram negative Bacteroidetes organisms. However, the proportion of Bacteroidetes organisms was greater in alfalfa pellet-induced SARA than in mild or severe grain induced SARA (35.4% versus 26.0% and 16.6%, respectively). This shift was also evident from the real-time PCR data for Prevotella albensis, Prevotella brevis, and Prevotella ruminicola, which are members of the Bacteroidetes. The real-time PCR data also indicated that severe grain-induced SARA was dominated by Streptococcus bovis and Escherichia coli, whereas mild grain-induced SARA was dominated by Megasphaera elsdenii and alfalfa pellet-induced SARA was dominated by P. albensis. Using discriminant analysis, the severity of SARA and degree of inflammation were highly correlated with the abundance of E. coli and not with lipopolysaccharide in the rumen. We thus suspect that E. coli may be a contributing factor in disease onset. PMID- 19783748 TI - Molecular characterization of potential nitrogen fixation by anaerobic methane oxidizing archaea in the methane seep sediments at the number 8 Kumano Knoll in the Kumano Basin, offshore of Japan. AB - The potential for microbial nitrogen fixation in the anoxic methane seep sediments in a mud volcano, the number 8 Kumano Knoll, was characterized by molecular phylogenetic analyses. A total of 111 of the nifH (a gene coding a nitrogen fixation enzyme, Fe protein) clones were obtained from different depths of the core sediments, and the phylogenetic analysis of the clones indicated the genetic diversity of nifH genes. The predominant group detected (methane seep group 2), representing 74% of clonal abundance, was phylogenetically related to the nifH sequences obtained from the Methanosarcina species but was most closely related to the nifH sequences potentially derived from the anoxic methanotrophic archaea (ANME-2 archaea). The recovery of the nif gene clusters including the nifH sequences of the methane seep group 2 and the subsequent reverse transcription-PCR detection of the nifD and nifH genes strongly suggested that the genetic components of the gene clusters would be operative for the in situ assimilation of molecular nitrogen (N(2)) by the host microorganisms. DNA-based quantitative PCR of the archaeal 16S rRNA gene, the group-specific mcrA (a gene encoding the methyl-coenzyme M reductase alpha subunit) gene, and the nifD and nifH genes demonstrated the similar distribution patterns of the archaeal 16S rRNA gene, the mcrA groups c-d and e, and the nifD and nifH genes through the core sediments. These results supported the idea that the anoxic methanotrophic archaea ANME-2c could be the microorganisms hosting the nif gene clusters and could play an important role in not only the in situ carbon (methane) cycle but also the nitrogen cycle in subseafloor sediments. PMID- 19783749 TI - Effect of carbohydrate composition in barley and oat cultivars on microbial ecophysiology and proliferation of Salmonella enterica in an in vitro model of the porcine gastrointestinal tract. AB - The influence of the carbohydrate (CHO) composition of cereal cultivars on microbial ecophysiology was studied using an in vitro model of the porcine gastrointestinal tract. Ten hull-less barley cultivars, six barley cultivars with hulls, six oat cultivars, and six oat groats that differed in beta-glucan, nonstarch polysaccharide (NSP), and starch contents and starch type were hydrolyzed enzymatically and incubated for 72 h with pig feces. Fermentation kinetics were modeled, and microbial compositions and short-chain fatty acid (SCFA) profiles were analyzed using terminal restriction fragment length polymorphism and gas chromatography. Cluster analysis and canonical ordination revealed different effects on fermentation and microbial ecology depending on the type of CHO and cultivar. First, in cultivars of barley with hulls and oats, the cellulose and insoluble NSP contents (i) increased Ruminococcus flavefaciens-like and Clostridium xylanolyticum-like phylotypes, (ii) increased acetate production, and (iii) decreased fermentation activity. Second, in hull-less barley cultivars the beta-glucan, amylose, amylopectin, crude protein, and soluble NSP contents determined the microbial community composition and activity as follows: (i) the amylose contents of the hull-less barley varieties increased the butyrate production and the abundance of Clostridium butyricum-like phylotypes, (ii) the beta-glucan content determined the total amounts of SCFA, and (iii) the amylopectin and starch contents affected the abundance of Clostridium ramosum like phylotypes, members of Clostridium cluster XIVa, and Bacteroides-like bacteria. Finally, the effect of CHO on proliferation of Salmonella enterica in the model was determined. Salmonella cell counts were not affected, but the relative proportion of Salmonella decreased with hull-less barley cultivars and increased with oat cultivars as revealed by quantitative PCR. Our results shed light on the complex interactions of cereal CHO with intestinal bacterial ecophysiology and the possible impact on host health. PMID- 19783750 TI - Deformed wing virus implicated in overwintering honeybee colony losses. AB - The worldwide decline in honeybee colonies during the past 50 years has often been linked to the spread of the parasitic mite Varroa destructor and its interaction with certain honeybee viruses. Recently in the United States, dramatic honeybee losses (colony collapse disorder) have been reported; however, there remains no clear explanation for these colony losses, with parasitic mites, viruses, bacteria, and fungal diseases all being proposed as possible candidates. Common characteristics that most failing colonies share is a lack of overt disease symptoms and the disappearance of workers from what appears to be normally functioning colonies. In this study, we used quantitative PCR to monitor the presence of three honeybee viruses, deformed wing virus (DWV), acute bee paralysis virus (ABPV), and black queen cell virus (BQCV), during a 1-year period in 15 asymptomatic, varroa mite-positive honeybee colonies in Southern England, and 3 asymptomatic colonies confirmed to be varroa mite free. All colonies with varroa mites underwent control treatments to ensure that mite populations remained low throughout the study. Despite this, multiple virus infections were detected, yet a significant correlation was observed only between DWV viral load and overwintering colony losses. The long-held view has been that DWV is relatively harmless to the overall health status of honeybee colonies unless it is in association with severe varroa mite infestations. Our findings suggest that DWV can potentially act independently of varroa mites to bring about colony losses. Therefore, DWV may be a major factor in overwintering colony losses. PMID- 19783751 TI - Role of the Streptococcus mutans irvA gene in GbpC-independent, dextran-dependent aggregation and biofilm formation. AB - Dextran-dependent aggregation (DDAG) of Streptococcus mutans is an in vitro phenomenon that is believed to represent a property of the organism that is beneficial for sucrose-dependent biofilm development. GbpC, a cell surface glucan binding protein, is responsible for DDAG in S. mutans when cultured under defined stressful conditions. Recent reports have described a putative transcriptional regulator gene, irvA, located just upstream of gbpC, that is normally repressed by the product of an adjacent gene, irvR. When repression of irvA is relieved, there is a resulting increase in the expression of GbpC and decreases in competence and synthesis of the antibiotic mutacin I. This study examined the role of irvA in DDAG and biofilm formation by engineering strains that overexpressed irvA (IrvA+) on an extrachromosomal plasmid. The IrvA+ strain displayed large aggregation particles that did not require stressful growth conditions. A novel finding was that overexpression of irvA in a gbpC mutant background retained a measure of DDAG, albeit very small aggregation particles. Biofilms formed by the IrvA+ strain in the parental background possessed larger than-normal microcolonies. In a gbpC mutant background, the overexpression of irvA reversed the fragile biofilm phenotype normally associated with loss of GbpC. Real-time PCR and Northern blot analyses found that expression of gbpC did not change significantly in the IrvA+ strain but expression of spaP, encoding the major surface adhesin P1, increased significantly. Inactivation of spaP eliminated the small-particle DDAG. The results suggest that IrvA promotes DDAG not only by GbpC, but also via an increase in P1. PMID- 19783753 TI - In this issue of Occupational Medicine. PMID- 19783752 TI - Impact of host developmental age on the transcriptome of the symbiotic bacterium Buchnera aphidicola in the pea aphid (Acyrthosiphon pisum). AB - Of the 617 genes from Buchnera aphidicola, the obligate bacterial symbiont of the pea aphid, 23% were differentially expressed in embryos compared to adults. Genes involved in flagellar apparatus and riboflavin synthesis exhibited particularly robust upregulation in embryos, suggesting functional differences between the symbiosis in the adult and embryo insect. PMID- 19783754 TI - Fernand Leger Les constructeurs--definitif (1950). PMID- 19783755 TI - Why I became an occupational physician ... PMID- 19783756 TI - Chronic and acute psychological strain in naval personnel. AB - BACKGROUND: Previous surveys have shown that there is a greater prevalence of psychological strain in Naval personnel than in the general population and have described the main psychosocial stressors associated with strain. AIMS: To determine the prevalence of acute strain and of repeated episodes of strain over 6- and 12-month periods. METHODS: Six and twelve months after completing a Phase I Work and Well-Being questionnaire, 2596 personnel were reassessed using a follow-up General Health Questionnaire-12. RESULTS: The response rates at 6 and 12 months ranged from 51 to 60%. There was no evidence of response bias at follow up. The prevalence of acute strain was 31% at Phase I. After 6 months, approximately half of strain cases had recovered. Only 10% had strain over the entire period. Change in strain was linked to change in work role. CONCLUSIONS: Accumulation of strain and recovery occur within 6 months depending on change in work role. Management of strain might best be achieved by management of work demands and deployment length. Further studies will investigate the rate of accumulation of strain over the course of demanding deployments. Exposure to psychosocial stressors such as effort reward imbalance accounted for much of the difference between chronic strain sufferers and those with no strain. PMID- 19783757 TI - Clinical research. PMID- 19783758 TI - Occupational medicine in Brazil. PMID- 19783759 TI - Interpretation questioned. PMID- 19783760 TI - Phage-type RNA polymerase RPOTmp performs gene-specific transcription in mitochondria of Arabidopsis thaliana. AB - Transcription of mitochondrial genes in animals, fungi, and plants relies on the activity of T3/T7 phage-type RNA polymerases. Two such enzymes, RPOTm and RPOTmp, are present in the mitochondria of eudicotyledonous plants; RPOTmp is additionally found in plastids. We have characterized the transcriptional role of the dual-targeted RNA polymerase in mitochondria of Arabidopsis thaliana. Examination of mitochondrial transcripts in rpoTmp mutants revealed major differences in transcript abundances between wild-type and rpoTmp plants. Decreased levels of specific transcripts were correlated with reduced abundances of the respiratory chain complexes I and IV. Altered transcript levels in rpoTmp were found to result from gene-specific transcriptional changes, establishing that RPOTmp functions in distinct transcriptional processes within mitochondria. Decreased transcription of specific genes in rpoTmp was not associated with changes in promoter utilization; therefore, RPOTmp function is not promoter specific but gene specific. This implies that additional gene-specific elements direct the transcription of a subset of mitochondrial genes by RPOTmp. PMID- 19783761 TI - The MYB305 transcription factor regulates expression of nectarin genes in the ornamental tobacco floral nectary. AB - We have isolated and characterized the cDNA encoding the ornamental tobacco (Nicotiana langsdorffii X N. sanderae) homolog of the antirrhinum (Antirrhinum majus) MYB305. This transcription factor was robustly expressed at Stage 12 of nectary development but was only weakly expressed in the earlier Stage 6 nectaries. The ornamental tobacco MYB305 contains a conserved R2R3 MYB DNA binding domain with 76 amino acids in the activation domain. A green fluorescent protein-MYB305 fusion localized to nucleus of tobacco protoplasts and yeast one hybrid assays demonstrated that it functions as a transcription activator. A conserved 23-amino acid C-terminal domain is required to activate gene expression. The coding region of the myb305 cDNA was expressed in Escherichia coli as a glutathione S-transferase fusion protein and was purified to homogeneity. This protein shows binding to two consensus MYB binding sites on the ornamental tobacco Nectarin I (nec1) promoter as well as to the single site located on the Nectarin V (nec5) promoter. Deletions of either of the binding sites from the nec1 promoter significantly reduced expression in nectary tissues. Temporally, MYB305 expression precedes that of nec1 and nec5, as would be expected if the MYB305 factor regulates expression of the nec1 and nec5 genes. Ectopic expression of MYB305 in foliage was able to induce expression of both nec1 and nec5, as well as two flavonoid biosynthetic genes in the foliage. Finally, RNA interference knockdown of MYB305 resulted in reduced expression of both nectarins and flavonoid biosynthetic genes. We conclude that expression of MYB305 regulates expression of the major nectarin genes in the floral nectary. PMID- 19783763 TI - The value of diabetes education: is it cost-effective? PMID- 19783764 TI - Health care reform: AADE outlines the issues. PMID- 19783762 TI - PKC{alpha}{beta}{gamma}- and PKC{delta}-dependent endocytosis of NBCe1-A and NBCe1-B in salivary parotid acinar cells. AB - We examined membrane trafficking of NBCe1-A and NBCe1-B variants of the electrogenic Na(+)-HCO(3)(-) cotransporter (NBCe1) encoded by the SLC4A4 gene, using confocal fluorescent microscopy in rat parotid acinar cells (ParC5 and ParC10). We showed that yellow fluorescent protein (YFP)-tagged NBCe1-A and green fluorescent protein (GFP)-tagged NBCe1-B are colocalized with E-cadherin in the basolateral membrane (BLM) but not with the apical membrane marker zona occludens 1 (ZO-1). We inhibited constitutive recycling with monensin and W13 and detected that NBCe1-A and NBCe1-B accumulated in vesicles marked with the early endosomal marker early endosome antigen-1 (EEA1), with a parallel loss from the BLM. We observed that NBCe1-A and NBCe1-B undergo massive carbachol (CCh)-stimulated redistribution from the BLM into early endosomes. We showed that internalization of NBCe1-A and NBCe1-B was prevented by the general PKC inhibitor GF-109203X, the PKCalphabetagamma-specific inhibitor Go-6976, and the PKCdelta-specific inhibitor rottlerin. We verified the involvement of PKCdelta by blocking CCh-induced internalization of NBCe1-A-cyan fluorescent protein (CFP) in cells transfected with dominant-negative kinase-dead (Lys376Arg) PKCdelta-GFP. Our data suggest that NBCe1-A and NBCe1-B undergo constitutive and CCh-stimulated endocytosis regulated by conventional PKCs (PKCalphabetagamma) and by novel PKCdelta in rat epithelial cells. To help develop a more complete model of the role of NBCe1 in parotid acinar cells we also investigated the initial phase of the secretory response to cholinergic agonist. In an Ussing chamber study we showed that inhibition of basolateral NBCe1 with 5-chloro-2,3-dihydro-3-(hydroxy-2 thienylmethylene)-2-oxo-1H-indole-1-carboxamide (tenidap) significantly decreases an initial phase of luminal anion secretion measured as a transient short-circuit current (I(sc)) across ParC10 cell monolayers. Using trafficking and functional data we propose a model that describes a physiological role of NBC in salivary acinar cell secretion. PMID- 19783765 TI - New therapeutic horizons: mapping the future of glycemic control with incretin based therapy. AB - PURPOSE: More than 24 million adults and children in the United States are living with diabetes, and the vast majority of those individuals have type 2 diabetes. The clinical benefits of good glycemic control have been well established. Most patients eventually require the use of multiple hyperglycemic drugs in combination to approach or achieve the American Diabetes Association's recommended target A1C value of 7%. The role of incretin-based therapies for both glycemic control and beta-cell protection has become an area of intense interest and development. Although current practice guidelines do not include specific recommendations about when and how to incorporate incretin-based agents, a consensus statement published by the American Diabetes Association/European Association for the Study of Diabetes suggests the addition of a glucagon-like peptide-1 (GLP-1) agonist for patients not at goal A1C with metformin and lifestyle changes. The goal of this article is to review this class of agents, discuss their role in the treatment of type 2 diabetes, and address the practical aspects of integrating incretin-based agents into the management of patients with diabetes. CONCLUSION: Currently, 3 incretin-based therapies are available and widely used in clinical practice. Several more agents are either under review by the Food and Drug Administration (FDA) or are in the very late stages of development. For diabetes educators trying to help their patients understand the differences among their antidiabetic medications, a comprehensive understanding of these agents and their role in therapy is imperative. PMID- 19783766 TI - Assessing the value of diabetes education. AB - PURPOSE: The purpose of this study was to evaluate the impact of diabetes self management education/training (DSME/T) on financial outcomes (cost of patient care). METHODS: Commercial and Medicare claims payer-derived datasets were used to assess whether patients who participate in diabetes education are more likely to follow recommendations for care than similar patients who do not participate in diabetes education, and if claims of patients who participate in diabetes education are lower than those of similar patients who do not. RESULTS: Patients using diabetes education have lower average costs than patients who do not use diabetes education. Physicians exhibit high variation in their referral rates to diabetes education. CONCLUSIONS: The collaboration between diabetes educators and physicians yields positive clinical quality and cost savings. The analysis indicates that quality can be improved, and cost reduced, by increasing referral rates to diabetes education among low-referring physicians, specifically among men and people in disadvantaged areas. More needs to be done to inform physicians about ways to increase access to diabetes education for underserved populations. PMID- 19783767 TI - Comparative device assessments: Humalog KwikPen compared with vial and syringe and FlexPen. AB - PURPOSE: The purpose of this study was to compare pen device-naive patients' preferences for Humalog KwikPen (insulin lispro injection) (Eli Lilly and Company, Indianapolis, IN) to use of a vial and syringe and FlexPen(R) (insulin aspart injection) (Novo Nordisk A/S, Bagsvaerd, Denmark). METHODS: This open label, randomized, crossover 1-day study tested the hypotheses that KwikPen was preferred to vial and syringe, and if this was found to be a significant preference, that KwikPen was preferred to FlexPen. Accuracy of doses prepared, ease of use via insulin device assessment battery, and preference via insulin device preference battery were administered following each pen evaluation, and a final preference question administered following the evaluation of both pens. Clinical measures were not included as subjects injected into an appliance to simulate the injection experience. Primary outcome variables were evaluated by Question 13 of the insulin device preference battery and the final preference question. RESULTS: Among 232 enrolled patients randomized to 1 of 4 sequences (n = 58), Humalog KwikPen was significantly preferred over vial and syringe and over FlexPen. After patients were asked to assess Humalog KwikPen or FlexPen versus V&S by choosing "strongly agreed" or "agreed" to the following attributes: easy to use, easy to hold in their hands when injecting, and easy to press the injection button, the results exhibited significant differences in patient responses. Humalog KwikPen was significantly more accurate and was preferred to vial and syringe in appearance, quality, discretion, convenience, public use, easy to learn, easy to use, reliability, dose confidence, following insulin regimen, overall satisfaction, and recommendation to others. CONCLUSIONS: Humalog KwikPen was significantly preferred over vial and syringe and FlexPen. When compared with vial and syringe, Humalog KwikPen and FlexPen were easier to use and operate, demonstrated superior accuracy of doses prepared, and preferred by pen-naive users. PMID- 19783768 TI - Understanding type 2 diabetes: including the family member's perspective. AB - PURPOSE: The purpose of this study was to examine the relationship between psychological and social factors and diabetes outcomes in people with type 2 diabetes and their family members. METHODS: A total of 153 patients with type 2 diabetes were assessed at a diabetes outpatient clinic and postal questionnaires were sent to nominated family members. The measures examined were diabetes knowledge, social support, well-being, and illness perceptions. RESULTS: When compared with those with diabetes, family members reported lower positive well being and lower levels of satisfaction with support. They also perceived diabetes as a more cyclical illness, which was controlled more by treatment than by the individual. Family members also reported that the person with diabetes was more emotionally distressed and knew more about diabetes than the patient had actually reported himself or herself. There were no differences between the family members of those in good or poor glycaemic control. CONCLUSIONS: This study reinforces the importance of understanding social context and illness beliefs in diabetes management. It also highlights the potential for including family members in discussions and education about diabetes management. PMID- 19783769 TI - Organizational factors associated with self-management behaviors in diabetes primary care clinics. AB - PURPOSE: The purpose of this article is to examine the relationship between organizational characteristics as measured by the Chronic Care Model (CCM) and patient self-management behaviors among patients with type 2 diabetes. METHODS: The study design was cross-sectional. The study setting included 20 primary care clinics from South Texas. The sample included approximately 30 consecutive patients that were enrolled from each clinic for a sample of 617 patients. For the data collection procedures, the CCM survey was completed by caregivers in the clinic. Self-management behaviors were obtained from patient exit surveys. For measures, the CCM consisted of 6 structural dimensions: (1) organization support, (2) community linkages, (3) self-management support, (4) decision support system, (5) delivery system design, and (6) clinical information systems. Patient self management behavior included whether the patient reported always doing all 4 of the following behaviors as they were instructed: (1) checking blood sugars, (2) following diabetes diet, (3) exercising, and (4) taking medications. For data analyses, to account for clustering of patients within clinics, hierarchical logistic regression models were used. RESULTS: Self-management support was positively associated with medication adherence, while decision support system was positively associated with exercise and all 4 self-management behaviors. Surprisingly, community linkages were negatively associated with medication adherence, while clinical information system was negatively associated with diet and all 4 behaviors. A total score, including all dimensions, was positively associated with only exercise. CONCLUSIONS: Health care providers and diabetes educators in primary care clinics should consider how organizational characteristics of the clinic might influence self-management behaviors of patients. The focus should be on better access to evidence-based information at the point of care and self-management needs and activities. PMID- 19783770 TI - Mapping of the Saccharomyces cerevisiae Oxa1-mitochondrial ribosome interface and identification of MrpL40, a ribosomal protein in close proximity to Oxa1 and critical for oxidative phosphorylation complex assembly. AB - The Oxa1 protein plays a central role in facilitating the cotranslational insertion of the nascent polypeptide chains into the mitochondrial inner membrane. Mitochondrially encoded proteins are synthesized on matrix-localized ribosomes which are tethered to the inner membrane and in physical association with the Oxa1 protein. In the present study we used a chemical cross-linking approach to map the Saccharomyces cerevisiae Oxa1-ribosome interface, and we demonstrate here a close association of Oxa1 and the large ribosomal subunit protein, MrpL40. Evidence to indicate that a close physical and functional relationship exists between MrpL40 and another large ribosomal protein, the Mrp20/L23 protein, is also provided. MrpL40 shares sequence features with the bacterial ribosomal protein L24, which like Mrp20/L23 is known to be located adjacent to the ribosomal polypeptide exit site. We propose therefore that MrpL40 represents the Saccharomyces cerevisiae L24 homolog. MrpL40, like many mitochondrial ribosomal proteins, contains a C-terminal extension region that bears no similarity to the bacterial counterpart. We show that this C-terminal mitochondria-specific region is important for MrpL40's ability to support the synthesis of the correct complement of mitochondrially encoded proteins and their subsequent assembly into oxidative phosphorylation complexes. PMID- 19783771 TI - Suggestive evidence for Darwinian Selection against asparagine-linked glycans of Plasmodium falciparum and Toxoplasma gondii. AB - We are interested in asparagine-linked glycans (N-glycans) of Plasmodium falciparum and Toxoplasma gondii, because their N-glycan structures have been controversial and because we hypothesize that there might be selection against N glycans in nucleus-encoded proteins that must pass through the endoplasmic reticulum (ER) prior to threading into the apicoplast. In support of our hypothesis, we observed the following. First, in protists with apicoplasts, there is extensive secondary loss of Alg enzymes that make lipid-linked precursors to N glycans. Theileria makes no N-glycans, and Plasmodium makes a severely truncated N-glycan precursor composed of one or two GlcNAc residues. Second, secreted proteins of Toxoplasma, which uses its own 10-sugar precursor (Glc(3)Man(5)GlcNAc(2)) and the host 14-sugar precursor (Glc(3)Man(9)GlcNAc(2)) to make N-glycans, have very few sites for N glycosylation, and there is additional selection against N-glycan sites in its apicoplast-targeted proteins. Third, while the GlcNAc-binding Griffonia simplicifolia lectin II labels ER, rhoptries, and surface of plasmodia, there is no apicoplast labeling. Similarly, the antiretroviral lectin cyanovirin-N, which binds to N-glycans of Toxoplasma, labels ER and rhoptries, but there is no apicoplast labeling. We conclude that possible selection against N-glycans in protists with apicoplasts occurs by eliminating N-glycans (Theileria), reducing their length (Plasmodium), or reducing the number of N-glycan sites (Toxoplasma). In addition, occupation of N glycan sites is markedly reduced in apicoplast proteins versus some secretory proteins in both Plasmodium and Toxoplasma. PMID- 19783772 TI - Developmental regulation of cardiovascular function is dependent on both genotype and environment. AB - Adverse developmental environments can increase the risk of adult cardiovascular disease, but not all individuals are affected, suggesting the importance of genotype. Genetically distinct mouse strains allow the genetic dissection of complex traits; however, they have not been used to evaluate the developmental origins of adult cardiovascular disease. Our objective was to determine the effect of prenatal nutrient restriction (R) on adult cardiovascular function in A/J (AJ) and C57BL/6J (B6) mice and whether a postnatal high-fat (HF) diet exacerbates these effects. Pregnant AJ and B6 mice underwent a 30% R or ad libitum diet, and their offspring underwent a HF or control diet. Hypertension (+17 mmHg; P<0.001) was observed in B6R mice at 9 wk, and their arterial pressure tended to remain high at 25 wk (+13 mmHg; not significant). In AJR mice, the normal decrement in arterial pressure over this age range in this strain was abolished. Heart rate prematurely increased in B6R and decreased in AJR (all; P<0.05) mice from 9 to 25 wk. There was no effect of postnatal HF diet on these relationships. The Tei index (from a 26-wk microultrasound) was increased in both AJR and B6R mice (all; P<0.05), suggesting an improved global myocardial performance. Neither R nor HF alone changed diastolic (ratio of E wave to A wave) or systolic (%fractional shortening) function in either strain; however, R and HE combined improved diastolic function in B6 (P<0.05) but not in AJ mice. Therefore, there are strain-dependent alterations in adult cardiovascular function in response to prenatal nutrient restriction. Unexpectedly, a postnatal HF diet did not exacerbate the effects of prenatal nutrient restriction on postnatal cardiovascular outcomes. PMID- 19783773 TI - Differential regulation of vascular smooth muscle and endothelial cell proliferation in vitro and in vivo by cAMP/PKA-activated p85alphaPI3K. AB - cAMP inhibits proliferation in most cell types, triggering different and sometimes opposing molecular pathways. p85alpha (phosphatidylinositol 3-kinase regulatory subunit) is phosphorylated by cAMP/PKA in certain cell lineages, but its effects on vascular smooth muscle cells (VSMCs) and endothelial cells (ECs) are unknown. In the present study, we evaluated 1) the role of p85alpha in the integration of cAMP/PKA-dependent signaling on the regulation of VSMC and EC growth in vitro; and 2) the effects of PKA-modified p85alpha on neointimal hyperplasia and endothelial healing after balloon injury in vivo. Plasmid constructs carrying wild-type and PKA-modified p85alpha were employed in VSMCs and ECs in vitro and after balloon injury in rat carotid arteries in vivo. cAMP/PKA reduced VSMC proliferation through p85alpha phosphorylation. Transfected PKA-activated p85alpha binds p21ras, reducing ERK1/2 activation and VSMC proliferation in vitro. In contrast, EC proliferation inhibition by cAMP is independent from PKA modification of p85alpha and ERK1/2 inhibition; indeed, PKA activated p85alpha did not inhibit per se ERK1/2 activation and proliferation in ECs in vitro. Interestingly, cAMP reduced both VSMC and EC apoptotic death through p85alpha phosphorylation. Accordingly, PKA-activated p85alpha triggered Akt activation, reducing both VSMC and EC apoptosis in vitro. Finally, compared with controls, vascular gene transfer of PKA-activated p85alpha significantly reduced neointimal formation after balloon injury in rats, without inhibiting endothelial regeneration of the injured arterial segment. In conclusions, PKA activated p85alpha integrates cAMP/PKA signaling differently in VSMCs and ECs. By reducing neointimal hyperplasia without inhibiting endothelial regeneration, it exerts a protective effect against restenosis after balloon injury. PMID- 19783774 TI - Hypersensitivity of excitation-contraction coupling in dystrophic cardiomyocytes. AB - Duchenne muscular dystrophy represents a severe inherited disease of striated muscle. It is caused by a mutation of the dystrophin gene and characterized by a progressive loss of skeletal muscle function. Most patients also develop a dystrophic cardiomyopathy, resulting in dilated hypertrophy and heart failure, but the cellular mechanisms leading to the deterioration of cardiac function remain elusive. In the present study, we tested whether defective excitation contraction (E-C) coupling contributes to impaired cardiac performance. "E-C coupling gain" was determined in cardiomyocytes from control and dystrophin deficient mdx mice. To this end, L-type Ca2+ currents (ICaL) were measured with the whole cell patch-clamp technique, whereas Ca2+ transients were simultaneously recorded with confocal imaging of fluo-3. Initial findings indicated subtle changes of E-C coupling in mdx cells despite matched Ca2+ loading of the sarcoplasmic reticulum (SR). However, lowering the extracellular Ca2+ concentration, a maneuver used to unmask latent E-C coupling problems, was surprisingly much better tolerated by mdx myocytes, suggesting a hypersensitive E C coupling mechanism. Challenging the SR Ca2+ release by slow elevations of the intracellular Ca2+ concentration resulted in Ca2+ oscillations after a much shorter delay in mdx cells. This is consistent with an enhanced Ca2+ sensitivity of the SR Ca2+-release channels [ryanodine receptors (RyRs)]. The hypersensitivity could be normalized by the introduction of reducing agents, indicating that the elevated cellular ROS generation in dystrophy underlies the abnormal RyR sensitivity and hypersensitive E-C coupling. Our data suggest that in dystrophin-deficient cardiomyocytes, E-C coupling is altered due to potentially arrhythmogenic changes in the Ca2+ sensitivity of redox-modified RyRs. PMID- 19783776 TI - Role of nitric oxide as a key mediator on cardiovascular actions of atrial natriuretic peptide in spontaneously hypertensive rats. AB - The objective was to study atrial natriuretic peptide (ANP) effects on mean arterial pressure (MAP) and cardiovascular nitric oxide (NO) system in spontaneously hypertensive rats (SHRs), investigating the receptors and signaling pathways involved. In vivo, SHRs and Wistar-Kyoto (WKY) rats were infused with saline (0.05 ml/min) or ANP (0.2 microg.kg(-1).min(-1)) for 1 h. MAP and nitrites and nitrates excretion (NOx) were determined. NO synthase (NOS) activity and endothelial (eNOS), neuronal (nNOS) and inducible (iNOS) NOS expression were measured in the heart and aorta. In vitro, heart and aortic NOS activity induced by ANP was determined in the presence of iNOS and nNOS inhibitors, natriuretic peptide receptor (NPR)-A/B blocker, G(i) protein, and calmodulin inhibitors. As a result, ANP diminished MAP and increased NOx in both groups. Cardiovascular NOS activity was higher in SHRs than in WKY rats. ANP increased NOS activity, but the activation was lower in SHRs than in WKY rats. ANP had no effect on NOS isoform expression. NOS activity induced by ANP was not modified by iNOS and nNOS inhibitors. NPR-A/B blockade blunted NOS stimulation via ANP in ventricle and aorta but not in atria. Cardiovascular NOS response to ANP was reduced by G(i) protein and calmodulin inhibitors in both groups. In conclusion, in atria, ventricle, and aorta, ANP interacts with NPR-C receptors, activating Ca(2+) calmodulin eNOS through G(i) protein. In ventricle and aorta, NOS activation also involves NPR-A/B. The NOS response to ANP was impaired in heart and aorta of SHRs. The impaired NO-system response to ANP in hypertensive animals, involving alterations in the signaling pathway, could participate in the maintenance of high blood pressure in this model of hypertension. PMID- 19783775 TI - Allogenic stem cell therapy improves right ventricular function by improving lung pathology in rats with pulmonary hypertension. AB - Pulmonary arterial hypertension (PAH) is a chronic lung disease that leads to right ventricular (RV) hypertrophy (RVH), remodeling, and failure. We tested treatment with bone marrow-derived mesenchymal stem cells (MSCs) obtained from donor rats with monocrotaline (MCT)-induced PAH to recipient rats with MCT induced PAH on pulmonary artery pressure, lung pathology, and RV function. This model was chosen to mimic autologous MSC therapy. On day 1, PAH was induced by MCT (60 mg/kg) in 20 female Wistar rats. On day 14, rats were treated with 10(6) MSCs intravenously (MCT + MSC) or with saline (MCT60). MSCs were obtained from donor rats with PAH at 28 days after MCT. A control group received saline on days 1 and 14. On day 28, the RV function of recipient rats was assessed, followed by isolation of the lungs and heart. RVH was quantified by the weight ratio of the RV/(left ventricle + interventricular septum). MCT induced an increase of RV peak pressure (from 27 + or - 5 to 42 +/- 17 mmHg) and RVH (from 0.25 + or - 0.04 to 0.47 + or - 0.12), depressed the RV ejection fraction (from 56 + or - 11 to 43 + or - 6%), and increased lung weight (from 0.96 + or - 0.15 to 1.66 + or - 0.32 g), including thickening of the arteriolar walls and alveolar septa. MSC treatment attenuated PAH (31 + or - 4 mmHg) and RVH (0.32 + or - 0.07), normalized the RV ejection fraction (52 + or - 5%), reduced lung weight (1.16 + or - 0.24 g), and inhibited the thickening of the arterioles and alveolar septa. We conclude that the application of MSCs from donor rats with PAH reduces RV pressure overload, RV dysfunction, and lung pathology in recipient rats with PAH. These results suggest that autologous MSC therapy may alleviate cardiac and pulmonary symptoms in PAH patients. PMID- 19783777 TI - Additive beneficial effects of lactotripeptides and aerobic exercise on arterial compliance in postmenopausal women. AB - Central arterial compliance plays an important role in the functional abilities of the vasculature. Two active tripeptides, valine-proline-proline and isoleucine proline-proline, were isolated from sour milk and were referred to as lactotripeptides (LTP). Because LTP appears to act as an angiotensin-converting enzyme inhibitor, it is plausible to hypothesize that LTP improves arterial compliance. We determined the effects of LTP ingestion alone or in combination with regular aerobic exercise on arterial compliance. A total of 55 postmenopausal women (50-65 yr old) were randomly divided into four groups: placebo, LTP, exercise and placebo (Ex + placebo), or exercise and LTP (Ex + LTP). LTP or placebo was administered orally for 8 wk. The exercise groups completed an 8-wk moderate aerobic exercise intervention. There were no differences in baseline arterial compliance and most other key dependent variables among the groups. Carotid arterial compliance increased significantly in the LTP (0.93 + or - 0.07 vs. 0.99 + or - 0.08 mm(2)/mmHg x 10(-1)), Ex + placebo (0.92 + or - 0.04 vs. 1.00 + or - 0.05 mm(2)/mmHg x 10(-1)), and Ex + LTP groups (0.86 + or - 0.06 vs. 1.00 + or - 0.06 mm(2)/mmHg x 10(-1)), whereas no such changes were observed in the placebo control group (0.86 + or - 0.06 vs. 0.85 + or - 0.07 mm(2)/mmHg x 10(-1)). The magnitude of increases in carotid arterial compliance was significantly greater in the Ex + LTP group (19 + or - 4%) than in other groups. The improvements in arterial compliance with LTP were associated with the corresponding reductions in arterial blood pressure and plasma angiotensin II concentrations. We concluded that LTP ingestion improves carotid arterial compliance and that the combination of LTP ingestion and regular exercise is additive and synergistic in improving arterial compliance in postmenopausal women. PMID- 19783778 TI - Structural adaptation of microvessel diameters in response to metabolic stimuli: where are the oxygen sensors? AB - Maintenance of functional vascular networks requires structural adaptation of vessel diameters in response to hemodynamic and metabolic conditions. The mechanisms by which diameters respond to the metabolic state are not known, but may involve the release of vasoactive substances in response to low oxygen by tissue ("tissue signaling", e.g., CO2, adenosine), by vessel walls ("wall signaling", e.g., prostaglandins, adenosine), and/or by red blood cells (RBCs) ("RBC signaling", e.g., ATP and nitric oxide). Here, the goal was to test the potential of each of these locations of oxygen-dependent signaling to control steady-state vascular diameters and tissue oxygenation. A previously developed theoretical model of structural diameter adaptation based on experimental data on microvascular network morphology and hemodynamics was used. Resulting network characteristics were analyzed with regard to tissue oxygenation (Oxdef; percentage of tissue volume with PO2<1 Torr) and the difference between estimated blood flow velocities and corresponding experimental data [velocity error (Verr); root mean square deviation of estimated vs. measured velocity]. Wall signaling led to Oxdef<1% and to the closest hemodynamic similarity (Verr: 0.60). Tissue signaling also resulted in a low oxygen deficit, but a higher Verr (0.73) and systematic diameter deviations. RBC signaling led to widespread hypoxia (Oxdef: 4.7%), unrealistic velocity distributions (Verr: 0.81), and shrinkage of small vessels. The results suggest that wall signaling plays a central role in structural control of vessel diameters in microvascular networks of given angioarchitecture. Tissue-derived and RBC-derived signaling of oxygen levels may be more relevant for the regulation of angiogenesis and/or smooth muscle tone. PMID- 19783780 TI - An adaptive transfer function for deriving the aortic pressure waveform from a peripheral artery pressure waveform. AB - We developed a new technique to mathematically transform a peripheral artery pressure (PAP) waveform distorted by wave reflections into the physiologically more relevant aortic pressure (AP) waveform. First, a transfer function relating PAP to AP is defined in terms of the unknown parameters of a parallel tube model of pressure and flow in the arterial tree. The parameters are then estimated from the measured PAP waveform along with a one-time measurement of the wave propagation delay time between the aorta and peripheral artery measurement site (which may be accomplished noninvasively) by exploiting preknowledge of aortic flow. Finally, the transfer function with its estimated parameters is applied to the measured waveform so as to derive the AP waveform. Thus, in contrast to the conventional generalized transfer function, the transfer function is able to adapt to the intersubject and temporal variability of the arterial tree. To demonstrate the feasibility of this adaptive transfer function technique, we performed experiments in 6 healthy dogs in which PAP and reference AP waveforms were simultaneously recorded during 12 different hemodynamic interventions. The AP waveforms derived by the technique showed agreement with the measured AP waveforms (overall total waveform, systolic pressure, and pulse pressure root mean square errors of 3.7, 4.3, and 3.4 mmHg, respectively) statistically superior to the unprocessed PAP waveforms (corresponding errors of 8.6, 17.1, and 20.3 mmHg) and the AP waveforms derived by two previously proposed transfer functions developed with a subset of the same canine data (corresponding errors of, on average, 5.0, 6.3, and 6.7 mmHg). PMID- 19783779 TI - Abnormal nitric oxide production in aged rat mesenteric arteries is mediated by NAD(P)H oxidase-derived peroxide. AB - Previous work in our laboratory showed increased basal periarterial nitric oxide (NO) and H2O2 concentrations in the spontaneously hypertensive rat, characterized by oxidant stress, as well as impaired flow-mediated NO production that was corrected by a reduction of periarterial H2O2. Aging is also associated with an increase in vascular reactive oxygen species and results in abnormal vascular function. The current study was designed to assess the role of H2O2 in regulating NO production during vascular aging. In vivo, real-time NO and H2O2 concentrations were measured by microelectrodes in mesenteric arteries of retired breeder (aged; 8-12 mo) and young (2 to 3 mo) Wistar-Kyoto rats under conditions of altered flow. The results in aged rats revealed elevated basal NO (1,611+/-286 vs. 793+/-112 nM, P<0.05) and H2O2 concentrations (16+/-2 vs. 9+/-1 microM, P<0.05) and a flow-mediated increase in H2O2 but not NO production. Pretreatment of aged rats with the antioxidant apocynin lowered both basal H2O2 (8+/-1 microM) and NO (760+/-102 nM) to young levels and restored flow-mediated NO production. Similar results were obtained with the NAD(P)H oxidase inhibitor gp91ds-tat. In addition, acute incubation with topical polyethylene-glycolated catalase lowered the baseline NO concentration and restored flow-mediated NO production. Taken together, the data indicate that elevated baseline and suppressed flow-mediated NO production in aged Wistar-Kyoto rats are mediated by NAD(P)H oxidase-derived H2O2. PMID- 19783781 TI - Altered reactivity to norepinephrine through COX-2 induction by vascular injury in hypercholesterolemic rabbits. AB - Although long-term use of cyclooxygenase (COX)-2 inhibitors may be associated with increased cardiovascular risk, their effects on vascular reactivity in atherosclerosis has remained largely unexplored. The aim of the present study was to evaluate the role of COX-2 induced by an atherosclerotic process, in the local control of vascular tone. New Zealand White rabbits were fed 0.3% cholesterol and subjected to balloon injury of the abdominal aorta. After 2 wk, the aorta was removed and used for organ bath experiments and immunohistochemistry, and the prostaglandins released were measured using enzyme immunoassays. Hypercholesterolemia and vascular injury significantly increased the thickness of the intimal layer, which was associated with an induction of COX-2 immunoreactivity throughout the aortic wall. In these preparations, a significant decrease of the maximal contractions induced by norepinephrine was observed. The norepinephrine-induced contractions of atherosclerotic preparations were restored by the COX inhibitors DuP-697 (0.5 micromol/l) and indomethacin (1.7 micromol/l), to similar contractions as was observed in aortic preparations derived from healthy rabbits. Norepinephrine stimulation of the abdominal aorta was accompanied by increased levels of prostaglandin I(2) but not of prostaglandin E(2), prostaglandin D(2), or thromboxane A(2) in atherosclerotic compared with normal aorta. Selective COX-2 inhibition significantly decreased the prostaglandin I(2) release from atherosclerotic aorta but had no effect on the prostaglandin release from aortic preparations derived from normal rabbits. These observations suggest that the local induction of COX-2 during atherosclerosis decreased the sensitivity to norepinephrine and that COX-2 inhibitors may increase vascular reactivity at sites of atherosclerotic lesions. PMID- 19783783 TI - Life-span extension by dietary restriction is mediated by NLP-7 signaling and coelomocyte endocytosis in C. elegans. AB - Recent studies have shown that the rate of aging can be modulated by diverse interventions. Dietary restriction is the most widely used intervention to promote longevity; however, the mechanisms underlying the effect of dietary restriction remain elusive. In a previous study, we identified two novel genes, nlp-7 and cup-4, required for normal longevity in Caenorhabditis elegans. nlp-7 is one of a set of neuropeptide-like protein genes; cup-4 encodes an ion-channel involved in endocytosis by coelomocytes. Here, we assess whether nlp-7 and cup-4 mediate longevity increases by dietary restriction. RNAi of nlp-7 or cup-4 significantly reduces the life span of the eat-2 mutant, a genetic model of dietary restriction, but has no effect on the life span of long-lived mutants resulting from reduced insulin/IGF-1 signaling or dysfunction of the mitochondrial electron transport chain. The life-span extension observed in wild type N2 worms by dietary restriction using bacterial dilution is prevented significantly in nlp-7 and cup-4 mutants. RNAi knockdown of genes encoding candidate receptors of NLP-7 and genes involved in endocytosis by coelomocytes also specifically shorten the life span of the eat-2 mutant. We conclude that two novel pathways, NLP-7 signaling and endocytosis by coelomocytes, are required for life extension under dietary restriction in C. elegans. PMID- 19783782 TI - Angiotensin II effects on ischemic focal ventricular tachycardia are predominantly mediated through myocardial AT(2) receptor. AB - Ischemic focal ventricular tachycardia (VT) occurs in animals and humans. Angiotensin-converting enzyme inhibitors and receptor blockers reduce sudden death in patients with ischemic heart disease. In our dog model of coronary artery occlusion (CAO), we tested the hypothesis that angiotensin II (AGII) will selectively promote focal VT and that the specific AT(2) blocker PD-123319 (PD), or AT(1) blocker losartan, will affect this VT. Anesthetized dogs (n = 90) underwent CAO, followed by three-dimensional activation mapping of inducible VT. Dogs without VT in 1-3 h after CAO received AGII, and those with VT received either PD or losartan. Focal endocardium excised from ischemic sites was studied in vitro with standard microelectrode. Of 33 dogs with no inducible VT, AGII infusion resulted in sustained VT of only focal Purkinje origin in 13 (39%) compared with 0 of 20 dogs with saline. Of 26 dogs with inducible VT at baseline, given PD, reinduction was blocked in 8 of 10 (P < 0.05) focal VT, but only 1 of 15 with reentry. In contrast, of 11 dogs given losartan, reinduction of either mechanism was not blocked. In vitro triggered activity in Purkinje was blocked by PD in 13 of 19 (P < 0.05), but not by losartan in 8. Also, triggered activity was promoted by AGII, losartan, or the combination in 9 of 12 tissues. AGII promotes only focal, mainly Purkinje ischemic VT. PD, but not losartan, preferentially blocked focal VT, which is likely due to triggered activity due to delayed afterdepolarizations in Purkinje. PMID- 19783784 TI - Structural basis for a reciprocating mechanism of negative cooperativity in dimeric phosphagen kinase activity. AB - Phosphagen kinase (PK) family members catalyze the reversible phosphoryl transfer between phosphagen and ADP to reserve or release energy in cell energy metabolism. The structures of classic quaternary complexes of dimeric creatine kinase (CK) revealed asymmetric ligand binding states of two protomers, but the significance and mechanism remain unclear. To understand this negative cooperativity further, we determined the first structure of dimeric arginine kinase (dAK), another PK family member, at 1.75 A, as well as the structure of its ternary complex with AMPPNP and arginine. Further structural analysis shows that the ligand-free protomer in a ligand-bound dimer opens more widely than the protomers in a ligand-free dimer, which leads to three different states of a dAK protomer. The unexpected allostery of the ligand-free protomer in a ligand-bound dimer should be relayed from the ligand-binding-induced allostery of its adjacent protomer. Mutations that weaken the interprotomer connections dramatically reduced the catalytic activities of dAK, indicating the importance of the allosteric propagation mediated by the homodimer interface. These results suggest a reciprocating mechanism of dimeric PK, which is shared by other ATP related oligomeric enzymes, e.g., ATP synthase. PMID- 19783785 TI - A novel 11-kDa inhibitory subunit in the F1FO ATP synthase of Paracoccus denitrificans and related alpha-proteobacteria. AB - The F(1)F(O) and F(1)-ATPase complexes of Paracoccus denitrificans were isolated for the first time by ion exchange, gel filtration, and density gradient centrifugation into functional native preparations. The liposome-reconstituted holoenzyme preserves its tight coupling between F(1) and F(O) sectors, as evidenced by its high sensitivity to the F(O) inhibitors venturicidin and diciclohexylcarbodiimide. Comparison and N-terminal sequencing of the band profile in SDS-PAGE of the F(1) and F(1)F(O) preparations showed a novel 11-kDa protein in addition to the 5 canonical alpha, beta, gamma, delta, and epsilon subunits present in all known F(1)-ATPase complexes. BN-PAGE followed by 2D-SDS PAGE confirmed the presence of this 11-kDa protein bound to the native F(1)F(O) ATP synthase of P. denitrificans, as it was observed after being isolated. The recombinant 11 kDa and epsilon subunits of P. denitrificans were cloned, overexpressed, isolated, and reconstituted in particulate F(1)F(O) and soluble F(1)-ATPase complexes. The 11-kDa protein, but not the epsilon subunit, inhibited the F(1)F(O) and F(1)-ATPase activities of P. denitrificans. The 11-kDa protein was also found in Rhodobacter sphaeroides associated to its native F(1)F(O) ATPase. Taken together, the data unveil a novel inhibitory mechanism exerted by this 11-kDa protein on the F(1)F(O)-ATPase nanomotor of P. denitrificans and closely related alpha-proteobacteria. PMID- 19783786 TI - Human rhinovirus infection up-regulates MMP-9 production in airway epithelial cells via NF-{kappa}B. AB - Human rhinovirus (HRV) infections up-regulate proinflammatory mediators and growth factors that are associated with exacerbations of inflammatory airway diseases, such as asthma and chronic obstructive pulmonary disease (COPD). Matrix metalloproteinase (MMP)-9 was shown to be increased in the airways of patients with asthma and COPD. We sought to determine whether HRV infection modulated the expression of MMP-9 and its highest-affinity inhibitor, the tissue inhibitor of metalloproteinase (TIMP)-1, and we explored the mechanism by which this modulation occurs. In vitro studies, using RT-PCR, ELISA, zymography, and a fluorescent activity assay, demonstrated that MMP-9 mRNA, protein, and activity were increased upon infection with HRV, whereas TIMP-1 mRNA and protein remained unchanged. These results were verified in vivo, using nasal lavage samples obtained from subjects with confirmed rhinovirus infections. Human rhinovirus infections were shown to up-regulate NF-kappaB, and NF-kappaB has also been reported to play a role in the expression of MMP-9. We therefore investigated the role of NF-kappaB in HRV-induced MMP-9 expression. Using two inhibitors of IkappaBalpha kinase beta, we observed a concentration-dependent decrease in HRV induced MMP-9 expression. The role of NF-kappaB in HRV-induced MMP-9 expression was further confirmed using MMP-9 promoter luciferase constructs, which demonstrated that an NF-kappaB site at -620/-607 base pairs was necessary for HRV induced MMP-9 expression. Electrophoretic mobility shift assays and supershift assays confirmed the nuclear translocation and binding of p50/p65 NF-kappaB subunits to an MMP-9-specific NF-kappaB oligonucleotide. This increase in MMP-9 may be a mechanism by which rhinovirus infections contribute to airway inflammation and, potentially, to airway remodeling. PMID- 19783787 TI - Characterization of PCEng2, a {beta}-1,3-endoglucanase homolog in Pneumocystis carinii with activity in cell wall regulation. AB - Pneumocystis jirovecii pneumonia is an opportunistic fungal infection that causes severe respiratory impairment in immunocompromised patients. The viability of Pneumocystis organisms is dependent on the cyst cell wall, a structural feature that is regulated by essential cell wall-associated enzymes. The formation of the glucan-rich cystic wall has been previously characterized, but glucan degradation in the organism-specifically, degradation during trophic excystment-is not yet fully understood. Most studies of basic Pneumocystis biology have been conducted in Pneumocystis carinii or Pneumocystis murina, the varieties of this genus that infect rats and mice, respectively. Furthermore, all known treatments for P. jirovecii were initially discovered through studies of P. carinii. Accordingly, in this study, we have identified a P. carinii beta-1,3-endoglucanase gene (PCEng2) that is demonstrated to play a significant role in cell wall regulation. The cDNA sequence contained a 2.2-kb open reading frame with conserved amino acid domains homologous to similar fungal glycosyl hydrolases (GH family 81). The gene transcript showed up-regulation in cystic isolates, and the expressed protein was detected within both cyst and trophic forms. Complementation assays in Eng2 deleted Saccharomyces cerevisiae strains showed restoration of the cell wall separation defect during proliferation, demonstrating the importance of PCEng2 protein. during fungal growth. These findings suggest that regulation of cyst cell wall beta-glucans is a fundamental process during completion of the Pneumocystis life cycle. PMID- 19783788 TI - Rhinovirus-induced exacerbations of asthma: How is the {beta}2-adrenoceptor implicated? AB - Rhinovirus (RV) infections are the major cause of asthma exacerbations in children and adults. Under normal circumstances, asthmatic airway obstruction improves spontaneously or characteristically briskly in response to inhaled beta(2)-adrenergic receptor (beta(2)AR) agonists. During virus-associated exacerbations, an impaired response to beta(2)AR agonists is observed; the reason for this is not known. The objective of this study was to determine the effect of RV infection on airway smooth muscle beta(2)AR function. The human cell line Beas 2B and primary human bronchial epithelial cells (HBECs) were infected with RV (multiplicity of infection = 1). After 1 or 5 days for primary and Beas-2B cells, respectively, cell culture supernatants were harvested, UV-irradiated to inactivate RV, and applied to human airway smooth muscle cells for 3 days to assess modifications of beta(2)AR function. RV conditioned medium from Beas-2B and HBECs decreased beta(2)AR agonist-induced cAMP by 50 and 65%, respectively (n = 5; P < 0.05). When cAMP was induced independently of the beta(2)AR using forskolin, no impairment was found. Using flow cytometry, we demonstrated that this decrease was likely the result of beta(2)AR desensitization because membrane but not total cell receptor beta(2)AR was decreased. Pretreatment of HBECs and Beas-2B cells but not human airway smooth muscle cells with the corticosteroids dexamethasone or fluticasone abolished virus-mediated beta(2)AR loss of function. This study shows that epithelial infection with RV induces a decrease of beta(2)AR function on airway smooth muscle cells, potentially explaining the clinical observation of loss of beta(2)AR agonist function during RV-induced asthma exacerbations. PMID- 19783789 TI - Involvement of IL-13 in tobacco smoke-induced changes in the structure and function of rat intrapulmonary airways. AB - Chronic obstructive pulmonary disease (COPD) involves disease of small airways with an increase in airway smooth muscle sensitivity to spasmogens and with structural changes described as airway remodeling. We investigated the effect of tobacco smoke (TS) exposure on the structure and function of small airways in rats and the role of IL-13 in this response. Precision-cut lung slices (230-280 microm) were prepared from male Sprague-Dawley rats after acute (3 d) or chronic (8 or 16 wk) daily exposure to TS or air. Carbachol (CCh) and 5-hydroxytryptamine (5HT) concentration responses were performed on airways (50-400 microm diameter). The effect of IL-13 in vitro on small airway sensitivity to CCh and 5HT was also determined. Acute exposure to TS did not affect the sensitivity of the intrapulmonary airways to either spasmogen. After 8 weeks of TS exposure, airway hyperresponsiveness (AHR) to CCh was evident (log EC(50) CCh: air = 0.22 microM; TS = -0.12 microM; P = 0.019); AHR to 5HT was also observed after the 16-week exposure to TS (air = -0.85 microM; TS = -1.06 microM; P = 0.038). Chronic TS exposure increased airway wall SMA content, which correlated with increased expression of IL-13 and transforming growth factor (TGF)-beta(1) in the lung tissues. In vitro incubation with IL-13, but not TGF-beta(1), induced changes in small airway sensitivity to CCh and 5HT. Chronic TS exposure induces increased responsiveness in intrapulmonary airways of rats that may be mediated in part by an increase in IL-13. PMID- 19783790 TI - DNA double-strand breaks by asbestos, silica, and titanium dioxide: possible biomarker of carcinogenic potential? AB - DNA double-strand breaks (DSBs) can result in cell death or genetic alterations when cells are subjected to radiation, exposure to toxins, or other environmental stresses. A complex DNA-damage-response pathway is activated to repair the damage, and the inability to repair these breaks can lead to carcinogenesis. One of the earliest responses to DNA DSBs is the phosphorylation of a histone, H2AX, at serine 139 (gamma-H2AX), which can be detected by a fluorescent antibody. A study was undertaken to compare the induction of DNA DSBs in normal (small airway epithelial) cells and cancer cells (A549) after exposure to asbestos (crocidolite), a proven carcinogen, silica, a suspected carcinogen, and titanium dioxide (TiO(2)), an inert particle recently reported to be carcinogenic in animals. The results indicate that crocidolite induced greater DNA DSBs than silica and TiO(2), regardless of cell type. DNA DSBs caused by crocidolite were higher in normal cells than in cancer cells. Silica and TiO(2) induced higher DNA DSBs in cancer cells than in normal cells. The production of reactive oxygen species was found to be highest in cells exposed to crocidolite, followed, in potency, by silica and TiO(2). The generation of reactive oxygen species was higher in normal cells than in cancer cells. Cell viability assay indicated that crocidolite caused the greatest cytotoxicity in both cell types. Apoptosis, measured by caspase 3/7 and poly (ADP-Ribose) polymerase activation, was highest in crocidolite-exposed cells, followed by TiO(2) and silica. The results of this study indicate that crocidolite has a greater carcinogenic potential than silica and TiO(2), judged by its ability to cause sustained genomic instability in normal lung cells. PMID- 19783791 TI - Validity and reliability of the chronic heart failure questionnaire mastery subscale in patients with defibrillators. AB - Reliable, valid measures are needed to assess one's sense of mastery, which has the potential for decreasing anxiety and depressive symptoms among patients with implantable cardioverter-defibrillators (ICDs). This study evaluates the reliability and validity of a measure of mastery, the Chronic Heart Failure Questionnaire (CHQ) mastery subscale. One hundred twenty-two (75% men, mean age 65 years) and 100 patients complete baseline and 12-month face-to-face interviews, respectively. The CHQ mastery subscale is found to have internal consistency reliability (Cronbach's alphas = .79, .84), and its validity is supported. Factor analysis yields a single robust factor. Differences in the CHQ mastery subscale scores by the New York Heart Association (NYHA) classes are found: Patients with NYHA Class III or IV have lower mastery than those with Class I or II. Baseline younger age and less frequent ICD shocks and lower mastery are significant predictors of respectively 12-month anxiety (R( 2) = .37) and depressive symptoms (R(2) = .45).The CHQ mastery subscale has demonstrated satisfactory reliability and validity in this sample. PMID- 19783792 TI - Implementing family nursing: how do we translate knowledge into clinical practice? AB - Health care systems worldwide are faced with the challenge of improving the quality of care, closing the knowledge-to-practice gap, and identifying the facilitators in these processes. Knowledge translation that promotes circularity between knowledge and practice is often overlooked. Knowledge transfer and translation are defined and briefly discussed in this article. Examples of knowledge translation in family nursing are provided, including knowledge creation research in pediatrics and adult pulmonary health at a University Hospital in Iceland. A second example focuses on the application of knowledge in mental health urgent care in a community health center in Calgary, Canada. Improving and speeding the circularity between knowledge translation and clinical practice reaps benefits for patients, families, health care providers, and the health care system. Conclusions about facilitating the implementation of family nursing knowledge into clinical practice are offered. The circularity between knowledge translation and practice is emphasized. PMID- 19783793 TI - Bladder cancer-associated protein, a potential prognostic biomarker in human bladder cancer. AB - It is becoming increasingly clear that no single marker will have the sensitivity and specificity necessary to be used on its own for diagnosis/prognosis of tumors. Interpatient and intratumor heterogeneity provides overwhelming odds against the existence of such an ideal marker. With this in mind, our laboratory has been applying a long term systematic approach to identify multiple biomarkers that can be used for clinical purposes. As a result of these studies, we have identified and reported several candidate biomarker proteins that are deregulated in bladder cancer. Following the conceptual biomarker development phases proposed by the Early Detection Research Network, we have taken some of the most promising candidate proteins into postdiscovery validation studies, and here we report on the characterization of one such biomarker, the bladder cancer-associated protein (BLCAP), formerly termed Bc10. To characterize BLCAP protein expression and cellular localization patterns in benign bladder urothelium and urothelial carcinomas (UCs), we used two independent sets of samples from different patient cohorts: a reference set consisting of 120 bladder specimens (formalin-fixed as well as frozen biopsies) and a validation set consisting of 2,108 retrospectively collected UCs with long term clinical follow-up. We could categorize the UCs examined into four groups based on levels of expression and subcellular localization of BLCAP protein and showed that loss of BLCAP expression is associated with tumor progression. The results indicated that increased expression of this protein confers an adverse patient outcome, suggesting that categorization of staining patterns for this protein may have prognostic value. Finally, we applied a combinatorial two-marker discriminator using BLCAP and adipocyte-type fatty acid-binding protein, another UC biomarker previously reported by us, and found that the combination of the two markers correlated more closely with grade and/or stage of disease than the individual markers. The implications of these results in biomarker discovery are discussed. PMID- 19783794 TI - Hutchinson-Gilford Progeria syndrome: its presentation in F. Scott Fitzgerald's short story 'The Curious Case of Benjamin Button' and its oral manifestations. AB - Hutchinson-Gilford Progeria Syndrome (HGPS) was first documented in the medical literature in 1886. A HGPS patient has the physical characteristics and appearances of an elderly individual. In 1921, F. Scott Fitzgerald published a short story entitled 'The Curious Case of Benjamin Button'. The main character of Fitzgerald's fictional work is born with a very rare condition in which he looks like an elderly person. The main difference between the fictional individual and individuals with HGPS is that Fitzgerald's character becomes younger as the years go by. This paper serves three purposes. The first purpose is to scientifically present the possibility that Fitzgerald consciously based his character, Benjamin Button, upon individuals with HGPS. The second purpose is to describe the rare condition of HGPS, along with its many manifestations in the head and neck region. The third purpose is to postulate that HGPS individuals might not only have the appearance of an aged person, but also might actually undergo true physical aging, which would enable researchers to gain valuable information into the treatment of ailments commonly associated with the natural process of aging. PMID- 19783796 TI - Sensitivity of salivary glands to radiation: from animal models to therapies. AB - Radiation therapy for head and neck cancer causes significant secondary side effects in normal salivary glands, resulting in diminished quality of life for these individuals. Salivary glands are exquisitely sensitive to radiation and display acute and chronic responses to radiotherapy. This review will discuss clinical implications of radiosensitivity in normal salivary glands, compare animal models used to investigate radiation-induced salivary gland damage, address therapeutic advances, and project future directions in the field. PMID- 19783797 TI - Runx2, osx, and dspp in tooth development. AB - The transcription factors Runx2 and Osx are necessary for osteoblast and odontoblast differentiation, while Dspp is important for odontoblast differentiation. The relationship among Runx2, Osx, and Dspp during tooth and craniofacial bone development remains unknown. In this study, we hypothesized that the roles of Runx2 and Osx in the regulation of osteoblast and odontoblast lineages may be independent of one another. The results showed that Runx2 expression overlapped with Osx in dental and osteogenic mesenchyme from E12 to E16. At the later stages, from E18 to PN14, Runx2 and Osx expressions remained intense in alveolar bone osteoblasts. However, Runx2 expression was down regulated, whereas Osx expression was clearly seen in odontoblasts. At later stages, Dspp transcription was weakly present in osteoblasts, but strong in odontoblasts where Osx was highly expressed. In mouse odontoblast-like cells, Osx overexpression increased Dspp transcription. Analysis of these data suggests differential biological functions of Runx2, Osx, and Dspp during odontogenesis and osteogenesis. PMID- 19783795 TI - The impact of fluoride on ameloblasts and the mechanisms of enamel fluorosis. AB - Intake of excess amounts of fluoride during tooth development cause enamel fluorosis, a developmental disturbance that makes enamel more porous. In mild fluorosis, there are white opaque striations across the enamel surface, whereas in more severe cases, the porous regions increase in size, with enamel pitting, and secondary discoloration of the enamel surface. The effects of fluoride on enamel formation suggest that fluoride affects the enamel-forming cells, the ameloblasts. Studies investigating the effects of fluoride on ameloblasts and the mechanisms of fluorosis are based on in vitro cultures as well as animal models. The use of these model systems requires a biologically relevant fluoride dose, and must be carefully interpreted in relation to human tooth formation. Based on these studies, we propose that fluoride can directly affect the ameloblasts, particularly at high fluoride levels, while at lower fluoride levels, the ameloblasts may respond to local effects of fluoride on the mineralizing matrix. A new working model is presented, focused on the assumption that fluoride increases the rate of mineral formation, resulting in a greater release of protons into the forming enamel matrix. PMID- 19783798 TI - Primary cilia of odontoblasts: possible role in molar morphogenesis. AB - A primary cilium, a sensory organelle present in almost every vertebrate cell, is regularly described in odontoblasts, projecting from the surfaces of the cells. Based on the hypothesis that the primary cilium is crucial both for dentin formation and possibly in tooth pain transmission, we have investigated the expression and localization of the main cilium components and involvement of the OFD1 gene in tooth morphogenesis. Odontoblasts in vitro express tubulin, inversin, rootletin, OFD1, BBS4, BBS6, ALMS1, KIF3A, PC1, and PC2. In vivo, cilia are aligned parallel to the dentin walls, with the top part oriented toward the pulp core. Close relationships between cilium and nerve fibers are evidenced. Calcium channels are concentrated in the vicinity of the basal body. Analysis of these data suggests a putative role of cilia in sensing the microenvironment, probably related to dentin secretion. This hypothesis is enhanced by the huge defects observed on molars from Ofd1 knockout mice, showing undifferentiated dentin-forming cells. PMID- 19783799 TI - Increased oral fibroblast lifespan is telomerase-independent. AB - Oral mucosal wound-healing is characterized by rapid re-epithelialization and remodeling, with minimal scar formation. This may be attributed to the distinct phenotypic characteristics of the resident fibroblasts. To test this hypothesis, we investigated patient-matched oral mucosal and skin fibroblasts. Compared with skin fibroblasts, oral mucosal fibroblasts had longer proliferative lifespans, underwent more population doublings, and experienced senescence later, which was directly related to longer telomere lengths within oral mucosal fibroblasts. The presence of these longer telomeres was independent of telomerase expression, since both oral oral mucosal fibroblasts and skin fibroblasts were negative for active telomerase, as assessed according to the Telomeric Repeat Amplification Protocol. This study has demonstrated that, compared with skin fibroblasts, oral mucosal fibroblasts are 'younger', with a more embryonic/fetal-like phenotype that may provide a notable advantage for their ability to repair wounds in a scarless fashion. PMID- 19783800 TI - Impact of hydrodynamics on oral biofilm strength. AB - Mechanical removal of oral biofilms is ubiquitously accepted as the best way to prevent caries and periodontal diseases. Removal effectiveness strongly depends on biofilm strength. To investigate the influence of hydrodynamics on oral biofilm strength, we grew single- and multi-species biofilms of Streptococcus oralis J22, Actinomyces naeslundii TV14-J1, and full dental plaque at shear rates ranging from 0.1 to 50 1/sec and measured their compressive strength. Subsequently, biofilm architecture was evaluated by confocal laser scanning microscopy. Multi-species biofilms were stronger than single-species biofilms, with strength values ranging from 6 to 51 Pa and from 5 to 17 Pa, respectively. In response to increased hydrodynamic shear, biofilm strength decreased, and architecture changed from uniform carpet-like to more "fluffy" with higher thickness. S. oralis biofilms grown under variable shear of 7 and 50 1/sec possessed properties intermediate of those measured at the respective single shears. PMID- 19783801 TI - Role of purinergic receptor in alpha fodrin degradation in Par C5 cells. AB - Autoantibodies specific for alpha-fodrin fragments are found in the tissues of persons afflicted with Sjogren's syndrome (SS). However, the mechanism for alpha fodrin degradation remains elusive. The following experiments utilized Par C5 cells to examine the role of P2X7 receptor (P2X7R) in apoptosis, particularly in the cleavage and release of alpha-fodrin, an apparent SS autoantigen. Five mM ATP stimulation induced apoptotic cell death with a sustained Ca2+ influx, which was mimicked in HEK cells transfected with P2X7R. ATP also induced cleavage of alpha fodrin mediated by caspase-3 and calpain, releasing alpha-fodrin fragments through membrane blebs. However, both apoptotic cell death and alpha-fodrin cleavage were inhibited in the presence of 300 microM oxidized-ATP (ox-ATP), an irreversible blocker of P2X7R, or in Ca(2+)-free solution. We concluded that P2X7R plays an important role in apoptosis and alpha-fodrin degradation in salivary epithelial cells, providing an important clue elucidating the presence of alpha-fodrin fragments in SS tissues. PMID- 19783802 TI - How to influence patient oral hygiene behavior effectively. AB - Considerable resources are expended in dealing with dental disease easily prevented with better oral hygiene. The study hypothesis was that an evidence based intervention, framed with psychological theory, would improve patients' oral hygiene behavior. The impact of trial methodology on trial outcomes was also explored by the conducting of two independent trials, one randomized by patient and one by dentist. The study included 87 dental practices and 778 patients (Patient RCT = 37 dentists/300 patients; Cluster RCT = 50 dentists/478 patients). Controlled for baseline differences, pooled results showed that patients who experienced the intervention had better behavioral (timing, duration, method), cognitive (confidence, planning), and clinical (plaque, gingival bleeding) outcomes. However, clinical outcomes were significantly better only in the Cluster RCT, suggesting that the impact of trial design on results needs to be further explored. PMID- 19783803 TI - Lifecourse socio-economic mobility and oral health in middle age. AB - Socio-economic variations in health exist for a wide range of health outcomes, including oral health and oral-health-related quality of life (OHRQoL). Less is known regarding how socio-economic trajectories may influence oral health and OHRQoL. This study examined whether social mobility is related to the number of teeth retained by age 50 years and OHRQoL measured at the same time, using data from the Newcastle Thousand Families Study, a birth cohort established in 1947. Women remaining in the non-manual class had the greatest tooth retention. While promotion of a healthier lifestyle and continued improvements in oral hygiene throughout life appear to be the public health interventions most likely to improve oral health into middle age, there may be sub-groups of the population on which different approaches in terms of public health interventions need to be focused. PMID- 19783804 TI - Missing posterior teeth and risk of temporomandibular disorders. AB - There is disagreement about the association between missing posterior teeth and the presence of temporomandibular disorders (TMD). Here, the purpose was to investigate whether the number of missing posterior teeth, their distribution, age, and gender are associated with TMD. Seven hundred and forty-one individuals, aged 21-60 years, with missing posterior teeth, 386 with and 355 without TMD, were included. Four variables-gender, age, the number of missing posterior teeth, and the number of dental quadrants with missing posterior teeth-were analyzed with a logistic regression model. All four variables-gender (OR = 1.59, men = 1, women = 2), age (OR = 0.98), the number of missing posterior teeth (OR = 0.51), and the number of dental quadrants with missing posterior teeth (OR = 7.71)-were entered into the logistic model (P < 0.01). The results indicate that individuals who lose posterior teeth, with fewer missing posterior teeth but in more quadrants, have a higher prevalence of TMD, especially young women. PMID- 19783805 TI - Periodontal therapy improves gastric Helicobacter pylori eradication. AB - The oral cavity has been proposed as a reservoir for H. pylori that could be responsible for the refractoriness of gastric infection to triple therapy (antibiotics, antimicrobials, and proton pump inhibitors). The aim of this study was to evaluate the efficiency of combined periodontal and triple therapy vs. triple therapy alone, in gastric H. pylori eradication in persons with H. pylori in the subgingival biofilm. Individuals positive for H. pylori in their gastric and oral samples, as determined by nested PCR, were treated either with periodontal and triple therapy or with triple therapy alone. Our results indicate that 77.3% of those treated with the combined therapy exhibited successful eradication of gastric H. pylori, compared with 47.6% who underwent only triple therapy. Analysis of these data suggests that periodontal treatment in combination with systemic therapy could be a promising approach to increasing the therapy's efficacy and decreasing the risk of infection recurrence. PMID- 19783806 TI - Influence of luting material filler content on post cementation. AB - Luting of fiber posts to intra-radicular dentin represents the worst-case scenario in terms of control of polymerization shrinkage. This study tested the hypothesis that filler content of resin cements does not influence luting of fiber posts to intra-radicular dentin, by assaying polymerization stress, push out bond strength, and nanoleakage expression. The polymerization stress of experimental cements containing 10%, 30%, 50%, or 70% in filler content was investigated. Post spaces were prepared in endodontically treated teeth, and fiber posts were cemented with the experimental cements. A push-out test was performed, and interfacial nanoleakage expression was analyzed. Results showed that luting cements with higher filler content were related to increased polymerization stress (p < 0.05), decreased push-out bond strength (p < 0.05), and increased interfacial nanoleakage expression (p < 0.05). Conversely, lower stress luting materials increased bonding of fiber posts to intra-radicular dentin. Further in vivo studies are needed to investigate the long-term clinical performance of these materials. PMID- 19783807 TI - Micro-organism and cell viability on antimicrobially modified titanium. AB - When titanium is anodized by discharge in NaCl solution, both antimicrobial activity and osteoconductivity are conferred. The viability of adherent micro organisms and cells on antimicrobial titanium remains uncertain. We hypothesized that a thin peroxidation barrier would efficiently destroy adherent bacteria, whereas adherent osteoblastic cells would be viable, since these cells adhere to the surface indirectly though serum proteins. The efficacy of antimicrobial titanium appears to be based on peroxidation, since peroxidation products were detected in parallel with the destruction of bacterial cell-surface structures. The peroxidation effect of antimicrobial titanium was confined to the surface within narrow limits. The viability of osteoblastic cells on the surface was strongly dependent on the presence of serum protein, whereas that of adherent Streptococcus mutans was not affected by the presence of serum proteins. Therefore, differences in the adherent systems used by bacteria and osteoblastic cells are important determinants of their viability on antimicrobial titanium. PMID- 19783808 TI - Parental attributions for success in managing the behavior of children with ADHD. AB - OBJECTIVE: The current study evaluated the effects of differing intensities of behavior modification and medication on parents' self-reported success in managing their child's misbehavior and the attributions parents gave for success or failure. METHOD: Children were randomized to receive in counterbalanced orders different levels of behavior modification, each for 3-week cycles. In addition, medication was manipulated using a medication assessment procedure. Parents reported daily how successful they were in managing their child's misbehavior and the attributions for either their success or failure. RESULTS: Parents of children with ADHD generally felt successful in managing their child's behavior, regardless of treatment condition. In the high behavior modification condition, they were more likely to endorse items that attributed their success to their own effort. CONCLUSION: In conditions in which parents were given more intensive tools to manage misbehavior they were more likely to attribute their success to their own effort. PMID- 19783809 TI - Reduced capacity in a dichotic memory test for adult patients with ADHD. AB - OBJECTIVE: To evaluate whether a dichotic memory test would reveal deficits in short-term working-memory recall and long-term memory recall in a group of adult patients with ADHD. METHODS: A dichotic memory test with ipsilateral backward speech distraction in an adult ADHD group (n = 69) and a control group (n = 66) is used to compare performance between the groups and inside the subgroups of ADHD diagnosed with DSM-IV. RESULTS: The ADHD participants showed significant impairment in the dichotic memory test compared with control participants when controlled for age, sex, and education. Study findings reveal that there is no difference in subdivision in the three ADHD subgroups of DSM-IV. A discriminant analysis shows an overall classification rate of 78% and specific in ADHD 80%. CONCLUSIONS: The results indicate that the dichotic test is measuring one of the important ADHD deficits. PMID- 19783810 TI - Predictors of symptom severity and response in patients with metastatic cancer. AB - We examined determinants of symptom severity and response to treatment among 150 patients with cancer participating in a phase II trial of a palliative care team intervention. Patients completed a modified Edmonton Symptom Assessment Scale (ESAS) at baseline and 1 week. Women had a worse baseline ESAS Distress Score (EDS; P = .003) and Total Distress Score (TDS; P = .005); differences were particularly marked for anxiety and appetite. Performance status was inversely associated with EDS, TDS, well-being, appetite, and fatigue (Kruskal-Wallis, all P < .005). Multivariate analysis of covariance (ANCOVA) showed that symptom improvement was independently predicted by worse baseline EDS score and female gender. Performance status, gender, and baseline symptom severity should be accounted for in trials of palliative care interventions; inclusion criteria based on symptom severity should also be considered. PMID- 19783811 TI - FXR activation reverses insulin resistance and lipid abnormalities and protects against liver steatosis in Zucker (fa/fa) obese rats. AB - The farnesoid X receptor (FXR) is a bile acid activated nuclear receptor. Zucker (fa/fa) rats, harboring a loss of function mutation of the leptin receptor, develop diabetes, insulin resistance, obesity, and liver steatosis. In this study, we investigated the effect of FXR activation by 6-ethyl-chenodeoxycholic acid, (6E-CDCA, 10 mg/kg) on insulin resistance and liver and muscle lipid metabolism in fa/fa rats and compared its activity with rosiglitazone (10 mg/kg) alone or in combination with 6E-CDCA (5 mg/kg each). In comparison to lean (fa/+), fa/fa rats on a normal diet developed insulin resistance and liver steatosis. FXR activation protected against body weight gain and liver and muscle fat deposition and reversed insulin resistance as assessed by insulin responsive substrate-1 phosphorylation on serine 312 in liver and muscles. Activation of FXR reduced liver expression of genes involved in fatty acid synthesis, lipogenesis, and gluconeogenesis. In the muscles, FXR treatment reduced free fatty acid synthesis. Rosiglitazone reduced blood insulin, glucose, triglyceride, free fatty acid, and cholesterol plasma levels but promoted body weight gain (20%) and liver fat deposition. FXR activation reduced high density lipoprotein plasma levels. In summary, FXR administration reversed insulin resistance and correct lipid metabolism abnormalities in an obesity animal model. PMID- 19783812 TI - Sports injuries during the Summer Olympic Games 2008. AB - BACKGROUND: Standardized assessment of sports injuries provides important epidemiological information and also directions for injury prevention. PURPOSE: To analyze the frequency, characteristics, and causes of injuries incurred during the Summer Olympic Games 2008. STUDY DESIGN: Descriptive epidemiology study. METHODS: The chief physicians and/or chief medical officers of the national teams were asked to report daily all injuries newly incurred during the Olympic Games on a standardized injury report form. In addition, injuries were reported daily by the physicians at the medical stations at the different Olympic venues and at the polyclinic in the Olympic Village. RESULTS: Physicians and/or therapists of 92 national teams covering 88% of the 10,977 registered athletes took part in the study. In total, 1055 injuries were reported, resulting in an incidence of 96.1 injuries per 1000 registered athletes. Half of the injuries (49.6%) were expected to prevent the athlete from participating in competition or training. The most prevalent diagnoses were ankle sprains and thigh strains. The majority (72.5%) of injuries were incurred in competition. One third of the injuries were caused by contact with another athlete, followed by overuse (22%) and noncontact incidences (20%). Injuries were reported from all sports, but their incidence and characteristics varied substantially. In relation to the number of registered athletes, the risk of incurring an injury was highest in soccer, taekwondo, hockey, handball, weightlifting, and boxing (all >or=15% of the athletes) and lowest for sailing, canoeing/kayaking, rowing, synchronized swimming, diving, fencing, and swimming. CONCLUSION: The data indicate that the injury surveillance system covered almost all of the participating athletes, and the results highlight areas of high risk for sport injury such as the in-competition period, the ankle and thigh, and specific sports. The identification of these factors should stimulate future research and subsequent policy change to prevent injury in elite athletes. PMID- 19783813 TI - FSscan: a mechanism-based program to identify +1 ribosomal frameshift hotspots. AB - In +1 programmed ribosomal frameshifting (PRF), ribosomes skip one nucleotide toward the 3'-end during translation. Most of the genes known to demonstrate +1 PRF have been discovered by chance or by searching homologous genes. Here, a bioinformatic framework called FSscan is developed to perform a systematic search for potential +1 frameshift sites in the Escherichia coli genome. Based on a current state of the art understanding of the mechanism of +1 PRF, FSscan calculates scores for a 16-nt window along a gene sequence according to different effects of the stimulatory signals, and ribosome E-, P- and A-site interactions. FSscan successfully identified the +1 PRF site in prfB and predicted yehP, pepP, nuoE and cheA as +1 frameshift candidates in the E. coli genome. Empirical results demonstrated that potential +1 frameshift sequences identified promoted significant levels of +1 frameshifting in vivo. Mass spectrometry analysis confirmed the presence of the frameshifted proteins expressed from a yehP-egfp fusion construct. FSscan allows a genome-wide and systematic search for +1 frameshift sites in E. coli. The results have implications for bioinformatic identification of novel frameshift proteins, ribosomal frameshifting, coding sequence detection and the application of mass spectrometry on studying frameshift proteins. PMID- 19783814 TI - Ion-induced folding of a kink turn that departs from the conventional sequence. AB - Kink turns (k-turns) are important structural motifs that create a sharp axial bend in RNA. Most conform to a consensus in which a three-nucleotide bulge is followed by consecutive G*A and A*G base pairs, and when these G*A pairs are modified in vitro this generally leads to a failure to adopt the k-turn conformation. Kt-23 in the 30S ribosomal subunit of Thermus thermophilus is a rare exception in which the bulge-distal A*G pair is replaced by a non-Watson Crick A*U pair. In the context of the ribosome, Kt-23 adopts a completely conventional k-turn geometry. We show here that this sequence is induced to fold into a k-turn structure in an isolated RNA duplex by Mg(2+) or Na(+) ions. Therefore, the Kt-23 is intrinsically stable despite lacking the key A*G pair; its formation requires neither tertiary interactions nor protein binding. Moreover, the Kt-23 k-turn is stabilized by the same critical hydrogen-bonding interactions within the core of the structure that are found in more conventional sequences such as the near-consensus Kt-7. T. thermophilus Kt-23 has two further non-Watson-Crick base pairs within the non-canonical helix, three and four nucleotides from the bulge, and we find that the nature of these pairs influences the ability of the RNA to adopt k-turn conformation, although the base pair adjacent to the A*U pair is more important than the other. PMID- 19783815 TI - The single polypeptide restriction-modification enzyme LlaGI is a self-contained molecular motor that translocates DNA loops. AB - To cleave DNA, the single polypeptide restriction-modification enzyme LlaGI must communicate between a pair of indirectly repeated recognition sites. We demonstrate that this communication occurs by a 1-dimensional route, namely unidirectional dsDNA loop translocation rightward of the specific recognition sequence 5'-CTnGAyG-3' as written (where n is either A, G, C or T and y is either C or T). Motion across thousands of base pairs is catalysed by the helicase domain and requires the hydrolysis of 1.5-2 ATP per base pair. DNA loop extrusion is accompanied by changes in DNA twist consistent with the motor following the helical pitch of the polynucleotide track. LlaGI is therefore an example of a polypeptide that is a completely self-contained, multi-functional molecular machine. PMID- 19783816 TI - The HSV-1 ICP27 RGG box specifically binds flexible, GC-rich sequences but not G quartet structures. AB - Herpes simplex virus 1 (HSV-1) protein ICP27, an important regulator for viral gene expression, directly recognizes and exports viral RNA through an N-terminal RGG box RNA binding motif, which is necessary and sufficient for RNA binding. An ICP27 N-terminal peptide, including the RGG box RNA binding motif, was expressed and its binding specificity was analyzed using EMSA and SELEX. DNA oligonucleotides corresponding to HSV-1 glycoprotein C (gC) mRNA, identified in a yeast three-hybrid analysis, were screened for binding to the ICP27 N-terminal peptide in EMSA experiments. The ICP27 N-terminus was able to bind most gC substrates. Notably, the ICP27 RGG box was unable to bind G-quartet structures recognized by the RGG domains of other proteins. SELEX analysis identified GC rich RNA sequences as a common feature of recognition. NMR analysis of SELEX and gC sequences revealed that sequences able to bind to ICP27 did not form secondary structures and conversely, sequences that were not able to bind to ICP27 gave spectra consistent with base-pairing. Therefore, the ICP27 RGG box is unique in its recognition of nucleic acid sequences compared to other RGG box proteins; it prefers flexible, GC-rich substrates that do not form stable secondary structures. PMID- 19783817 TI - EMMA--mouse mutant resources for the international scientific community. AB - The laboratory mouse is the premier animal model for studying human disease and thousands of mutants have been identified or produced, most recently through gene specific mutagenesis approaches. High throughput strategies by the International Knockout Mouse Consortium (IKMC) are producing mutants for all protein coding genes. Generating a knock-out line involves huge monetary and time costs so capture of both the data describing each mutant alongside archiving of the line for distribution to future researchers is critical. The European Mouse Mutant Archive (EMMA) is a leading international network infrastructure for archiving and worldwide provision of mouse mutant strains. It operates in collaboration with the other members of the Federation of International Mouse Resources (FIMRe), EMMA being the European component. Additionally EMMA is one of four repositories involved in the IKMC, and therefore the current figure of 1700 archived lines will rise markedly. The EMMA database gathers and curates extensive data on each line and presents it through a user-friendly website. A BioMart interface allows advanced searching including integrated querying with other resources e.g. Ensembl. Other resources are able to display EMMA data by accessing our Distributed Annotation System server. EMMA database access is publicly available at http://www.emmanet.org. PMID- 19783818 TI - The 3'-5' proofreading exonuclease of archaeal family-B DNA polymerase hinders the copying of template strand deaminated bases. AB - Archaeal family B polymerases bind tightly to the deaminated bases uracil and hypoxanthine in single-stranded DNA, stalling replication on encountering these pro-mutagenic deoxynucleosides four steps ahead of the primer-template junction. When uracil is specifically bound, the polymerase-DNA complex exists in the editing rather than the polymerization conformation, despite the duplex region of the primer-template being perfectly base-paired. In this article, the interplay between the 3'-5' proofreading exonuclease activity and binding of uracil/hypoxanthine is addressed, using the family-B DNA polymerase from Pyrococcus furiosus. When uracil/hypoxanthine is bound four bases ahead of the primer-template junction (+4 position), both the polymerase and the exonuclease are inhibited, profoundly for the polymerase activity. However, if the polymerase approaches closer to the deaminated bases, locating it at +3, +2, +1 or even 0 (paired with the extreme 3' base in the primer), the exonuclease activity is strongly stimulated. In these situations, the exonuclease activity is actually stronger than that seen with mismatched primer-templates, even though the deaminated base-containing primer-templates are correctly base-paired. The resulting exonucleolytic degradation of the primer serves to move the uracil/hypoxanthine away from the primer-template junction, restoring the stalling position to +4. Thus the 3'-5' proofreading exonuclease contributes to the inability of the polymerase to replicate beyond deaminated bases. PMID- 19783819 TI - MiCroKit 3.0: an integrated database of midbody, centrosome and kinetochore. AB - During cell division/mitosis, a specific subset of proteins is spatially and temporally assembled into protein super complexes in three distinct regions, i.e. centrosome/spindle pole, kinetochore/centromere and midbody/cleavage furrow/phragmoplast/bud neck, and modulates cell division process faithfully. Although many experimental efforts have been carried out to investigate the characteristics of these proteins, no integrated database was available. Here, we present the MiCroKit database (http://microkit.biocuckoo.org) of proteins that localize in midbody, centrosome and/or kinetochore. We collected into the MiCroKit database experimentally verified microkit proteins from the scientific literature that have unambiguous supportive evidence for subcellular localization under fluorescent microscope. The current version of MiCroKit 3.0 provides detailed information for 1489 microkit proteins from seven model organisms, including Saccharomyces cerevisiae, Schizasaccharomyces pombe, Caenorhabditis elegans, Drosophila melanogaster, Xenopus laevis, Mus musculus and Homo sapiens. Moreover, the orthologous information was provided for these microkit proteins, and could be a useful resource for further experimental identification. The online service of MiCroKit database was implemented in PHP + MySQL + JavaScript, while the local packages were developed in JAVA 1.5 (J2SE 5.0). PMID- 19783820 TI - A directed evolution design of a GCG-specific DNA hemimethylase. AB - DNA cytosine-5 methyltransferases (C5-MTases) are valuable models to study sequence-specific modification of DNA and are becoming increasingly important tools for biotechnology. Here we describe a structure-guided rational protein design combined with random mutagenesis and selection to change the specificity of the HhaI C5-MTase from GCGC to GCG. The specificity change was brought about by a five-residue deletion and introduction of two arginine residues within and nearby one of the target recognizing loops. DNA protection assays, bisulfite sequencing and enzyme kinetics showed that the best selected variant is comparable to wild-type M.HhaI in terms of sequence fidelity and methylation efficiency, and supersedes the parent enzyme in transalkylation of DNA using synthetic cofactor analogs. The designed C5-MTase can be used to produce hemimethylated CpG sites in DNA, which are valuable substrates for studies of mammalian maintenance MTases. PMID- 19783821 TI - Crystal structure of the EndoG/EndoGI complex: mechanism of EndoG inhibition. AB - EndoG is a ubiquitous nuclease that is translocated into the nucleus during apoptosis to participate in DNA degradation. The enzyme cleaves double- and single-stranded DNA and RNA. Related nucleases are found in eukaryotes and prokaryotes, which have evolved sophisticated mechanisms for genome protection against self-antagonizing nuclease activity. Common mechanisms of inhibition are secretion, sequestration into a separate cellular compartment or by binding to protein inhibitors. Although EndoG is silenced by compartmentalization into the mitochondrial intermembrane space, a nucleus-localized protein inhibitor protects cellular polynucleotides from degradation by stray EndoG under non-apoptotic conditions in Drosophila. Here, we report the first three-dimensional structure of EndoG in complex with its inhibitor EndoGI. Although the mechanism of inhibition is reminiscent of bacterial protein inhibitors, EndoGI has evolved independently from a generic protein-protein interaction module. EndoGI is a two domain protein that binds the active sites of two monomers of EndoG, with EndoG being sandwiched between EndoGI. Since the amino acid sequences of eukaryotic EndoG homologues are highly conserved, this model is valid for eukaryotic dimeric EndoG in general. The structure indicates that the two active sites of EndoG occupy the most remote spatial position possible at the molecular surface and a concerted substrate processing is unlikely. PMID- 19783822 TI - POT1 proteins in green algae and land plants: DNA-binding properties and evidence of co-evolution with telomeric DNA. AB - Telomeric DNA terminates with a single-stranded 3' G-overhang that in vertebrates and fission yeast is bound by POT1 (Protection Of Telomeres). However, no in vitro telomeric DNA binding is associated with Arabidopsis POT1 paralogs. To further investigate POT1-DNA interaction in plants, we cloned POT1 genes from 11 plant species representing major branches of plant kingdom. Telomeric DNA binding was associated with POT1 proteins from the green alga Ostreococcus lucimarinus and two flowering plants, maize and Asparagus. Site-directed mutagenesis revealed that several residues critical for telomeric DNA recognition in vertebrates are functionally conserved in plant POT1 proteins. However, the plant proteins varied in their minimal DNA-binding sites and nucleotide recognition properties. Green alga POT1 exhibited a strong preference for the canonical plant telomere repeat sequence TTTAGGG with no detectable binding to hexanucleotide telomere repeat TTAGGG found in vertebrates and some plants, including Asparagus. In contrast, POT1 proteins from maize and Asparagus bound TTAGGG repeats with only slightly reduced affinity relative to the TTTAGGG sequence. We conclude that the nucleic acid binding site in plant POT1 proteins is evolving rapidly, and that the recent acquisition of TTAGGG telomere repeats in Asparagus appears to have co-evolved with changes in POT1 DNA sequence recognition. PMID- 19783823 TI - SMYD1, the myogenic activator, is a direct target of serum response factor and myogenin. AB - SMYD1 is a heart and muscle specific SET-MYND domain containing protein, which functions as a histone methyltransferase and regulates downstream gene transcription. We demonstrated that the expression of SMYD1 is restricted in the heart and skeletal muscle tissues in human. To reveal the regulatory mechanisms of SMYD1 expression during myogenesis and cardiogenesis, we cloned and characterized the human SMYD1 promoter, which contains highly conserved serum response factor (SRF) and myogenin binding sites. Overexpression of SRF and myogenin significantly increased the endogenous expression level of Smyd1 in C2C12 cells, respectively. Deletion of Srf in the heart of mouse embryos dramatically decreased the expression level of Smyd1 mRNA and the expression of Smyd1 can be rescued by exogenous SRF introduction in SRF null ES cells during differentiation. Furthermore, we demonstrated that SRF binds to the CArG site and myogenin binds to the E-box element on Smyd1 promoter region using EMSA and ChIP assays. Moreover, forced expression of SMYD1 accelerates myoblast differentiation and myotube formation in C2C12 cells. Taken together, these studies demonstrated that SMYD1 is a key regulator of myogenic differentiation and acts as a downstream target of muscle regulatory factors, SRF and myogenin. PMID- 19783824 TI - tRNA over-expression in breast cancer and functional consequences. AB - Increased proliferation and elevated levels of protein synthesis are characteristics of transformed and tumor cells. Though components of the translation machinery are often misregulated in cancers, what role tRNA plays in cancer cells has not been explored. We compare genome-wide tRNA expression in cancer-derived versus non-cancer-derived breast cell lines, as well as tRNA expression in breast tumors versus normal breast tissues. In cancer-derived versus non-cancer-derived cell lines, nuclear-encoded tRNAs increase by up to 3 fold and mitochondrial-encoded tRNAs increase by up to 5-fold. In tumors versus normal breast tissues, both nuclear- and mitochondrial-encoded tRNAs increase up to 10-fold. This tRNA over-expression is selective and coordinates with the properties of cognate amino acids. Nuclear- and mitochondrial-encoded tRNAs exhibit distinct expression patterns, indicating that tRNAs can be used as biomarkers for breast cancer. We also performed association analysis for codon usage-tRNA expression for the cell lines. tRNA isoacceptor expression levels are not geared towards optimal translation of house-keeping or cell line specific genes. Instead, tRNA isoacceptor expression levels may favor the translation of cancer-related genes having regulatory roles. Our results suggest a functional consequence of tRNA over-expression in tumor cells. tRNA isoacceptor over expression may increase the translational efficiency of genes relevant to cancer development and progression. PMID- 19783825 TI - Solid polymeric microparticles enhance the delivery of siRNA to macrophages in vivo. AB - Therapeutics based on small interfering RNA (siRNA) have a great clinical potential; however, delivery problems have limited their clinical efficacy, and new siRNA delivery vehicles are greatly needed. In this report, we demonstrate that submicron particles (800-900 nm) composed of the polyketal PK3 and chloroquine, termed as the PKCNs, can deliver tumor necrosis factor-alpha (TNF alpha) siRNA in vivo to Kupffer cells efficiently and inhibit gene expression in the liver at concentrations as low as 3.5 microg/kg. The high delivery efficiency of the PKCNs arises from the unique properties of PK3, which can protect siRNA from serum nucleases, stimulate cell uptake and trigger a colloid osmotic disruption of the phagosome and release encapsulated siRNA into the cell cytoplasm. We anticipate numerous applications of the PKCNs for siRNA delivery to macrophages, given their high delivery efficiency, and the central role of macrophages in causing diseases such as hepatitis, liver cirrhosis and chronic renal disease. PMID- 19783827 TI - PDBselect 1992-2009 and PDBfilter-select. AB - PDBselect (http://bioinfo.tg.fh-giessen.de/pdbselect/) is a list of representative protein chains with low mutual sequence identity selected from the protein data bank (PDB) to enable unbiased statistics. The list increased from 155 chains in 1992 to more than 4500 chains in 2009. PDBfilter-select is an online service to generate user-defined selections. PMID- 19783826 TI - Recode-2: new design, new search tools, and many more genes. AB - 'Recoding' is a term used to describe non-standard read-out of the genetic code, and encompasses such phenomena as programmed ribosomal frameshifting, stop codon readthrough, selenocysteine insertion and translational bypassing. Although only a small proportion of genes utilize recoding in protein synthesis, accurate annotation of 'recoded' genes lags far behind annotation of 'standard' genes. In order to address this issue, provide a service to researchers in the field, and offer training data for developers of gene-annotation software, we have gathered together known cases of recoding within the Recode database. Recode-2 is an improved and updated version of the database. It provides access to detailed information on genes known to utilize translational recoding and allows complex search queries, browsing of recoding data and enhanced visualization of annotated sequence elements. At present, the Recode-2 database stores information on approximately 1500 genes that are known to utilize recoding in their expression- a factor of approximately three increase over the previous version of the database. Recode-2 is available at http://recode.ucc.ie. PMID- 19783828 TI - TrimerDimer: an oligonucleotide-based saturation mutagenesis approach that removes redundant and stop codons. AB - 9-fluorenylmethoxycarbonyl (Fmoc) and 4,4'-dimethoxytrityl (DMTr) are orthogonal hydroxyl protecting groups that have been used in conjunction to assemble oligonucleotide libraries whose variants contain wild-type and mutant codons randomly interspersed throughout a focused DNA region. Fmoc is labile to organic bases and stable to weak acids, whereas DMTr behaves oppositely. Based on these chemical characteristics, we have now devised TrimerDimer, a novel codon-based saturation mutagenesis approach that removes redundant and stop codons during the assembly of degenerate oligonucleotides. In this approach, five DMTr-protected trinucleotide phosphoramidites (dTGG, dATG, dTTT, dTAT and dTGC) and five Fmoc protected dinucleotide phosphoramidites (dAA, dTT, dAT, dGC and dCG) react simultaneously with a starting oligonucleotide growing on a solid support. The Fmoc group is then removed and the incorporated dimers react with a mixture of three DMTr-protected monomer phosphoramidites (dC, dA and dG) to produce 15 trinucleotides: dCAA, dAAA, dGAA, dCTT, dATT, dGTT, dCAT, dAAT, dGAT, dCGC, dAGC, dGGC, dCCG, dACG and dGCG. After one mutagenic cycle, 20 codons are generated encoding the 20 natural amino acids. TrimerDimer was tested by randomizing the four contiguous codons that encode amino acids L64-G67 of an engineered, nonfluorescent GFP protein. Sequencing of 89 nonfluorescent mutant clones and isolation of two fluorescent mutants confirmed the principle. PMID- 19783829 TI - Combining tissue transcriptomics and urine metabolomics for breast cancer biomarker identification. AB - MOTIVATION: For the early detection of cancer, highly sensitive and specific biomarkers are needed. Particularly, biomarkers in bio-fluids are relatively more useful because those can be used for non-biopsy tests. Although the altered metabolic activities of cancer cells have been observed in many studies, little is known about metabolic biomarkers for cancer screening. In this study, a systematic method is proposed for identifying metabolic biomarkers in urine samples by selecting candidate biomarkers from altered genome-wide gene expression signatures of cancer cells. Biomarkers identified by the present study have increased coherence and robustness because the significances of biomarkers are validated in both gene expression profiles and metabolic profiles. RESULTS: The proposed method was applied to the gene expression profiles and urine samples of 50 breast cancer patients and 50 normal persons. Nine altered metabolic pathways were identified from the breast cancer gene expression signatures. Among these altered metabolic pathways, four metabolic biomarkers (Homovanillate, 4 hydroxyphenylacetate, 5-hydroxyindoleacetate and urea) were identified to be different in cancer and normal subjects (p <0.05). In the case of the predictive performance, the identified biomarkers achieved area under the ROC curve values of 0.75, 0.79 and 0.79, according to a linear discriminate analysis, a random forest classifier and on a support vector machine, respectively. Finally, biomarkers which showed consistent significance in pathways' gene expression as well as urine samples were identified. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 19783830 TI - Automatically classifying sentences in full-text biomedical articles into Introduction, Methods, Results and Discussion. AB - Biomedical texts can be typically represented by four rhetorical categories: Introduction, Methods, Results and Discussion (IMRAD). Classifying sentences into these categories can benefit many other text-mining tasks. Although many studies have applied different approaches for automatically classifying sentences in MEDLINE abstracts into the IMRAD categories, few have explored the classification of sentences that appear in full-text biomedical articles. We first evaluated whether sentences in full-text biomedical articles could be reliably annotated into the IMRAD format and then explored different approaches for automatically classifying these sentences into the IMRAD categories. Our results show an overall annotation agreement of 82.14% with a Kappa score of 0.756. The best classification system is a multinomial naive Bayes classifier trained on manually annotated data that achieved 91.95% accuracy and an average F-score of 91.55%, which is significantly higher than baseline systems. A web version of this system is available online at-http://wood.ims.uwm.edu/full_text_classifier/. PMID- 19783831 TI - Automatic assignment of reaction operators to enzymatic reactions. AB - BACKGROUND: Enzymes are classified in a numerical classification scheme introduced by the Nomenclature Committee of the IUBMB based on the overall reaction chemistry. Due to the manifold of enzymatic reactions the system has become highly complex. Assignment of enzymes to the enzyme classes requires a detailed knowledge of the system and manual analysis. Frequently rearrangements and deletions of enzymes and sub-subclasses are necessary. RESULTS: We use the Dugundji-Ugi model for coding of biochemical reactions which is based on electron shift patterns occurring during reactions. Changes of the bonds or of non-bonded valence electrons are expressed by reaction matrices. Our program calculates reaction matrices automatically on the sole basis of substrate and product chemical structures based on a new strategy for maximal common substructure determination, which allows an accurate atom mapping of the substrate and product atoms. The system has been tested for a large set of enzymatic reactions including all sub-subclasses of the EC classification system. Altogether 147 different representative reaction operators were found in the classified enzymes, 121 of which are unique with respect to an EC sub-subclass. The other 26 comprise groups of enzymes with very similar reactions, being identical with respect to the bonds formed and broken. CONCLUSION: The analysis and comparison of enzymatic reactions according to their electron shift patterns is defining enzyme groups characterised by unique reaction cores. Our results demonstrate the applicability of the Dugundji-Ugi model as a reasonable pre-classification system allowing an objective and rational view on biochemical reactions. AVAILABILITY: The program to generate reaction matrix descriptors is available upon request. PMID- 19783832 TI - Cholesterol worships a new idol. AB - The growing worldwide epidemic of cardiovascular disease suggests that new therapeutic strategies are needed to complement statins in the lowering of cholesterol levels. In a recent paper in Science, Tontonoz and colleagues have identified Idol as a protein that can control cholesterol levels by regulating the stability of the low-density lipoprotein receptor; inhibiting the activity of Idol could provide novel approaches for the treatment of cardiovascular disease. PMID- 19783833 TI - When and why do subfertile couples discontinue their fertility care? A longitudinal cohort study in a secondary care subfertility population. AB - BACKGROUND: A substantial number of subfertile couples discontinues fertility care before achieving pregnancy. Most studies on dropouts are related to IVF. The aim here is to examine dropout rates at all stages of fertility care. METHODS: We analysed a consecutive cohort of 1391 couples, referred to our secondary care hospital between January 2002 and December 2006. Discontinuation rates were studied at six stages. Stage I: immediately after first visit, Stage II: during diagnostic workup, Stage III: after finishing diagnostic workup but before treatment, Stage IV: during or after non-IVF treatment, Stage V: during IVF, Stage VI: after at least 3 cycles of IVF. Reasons to discontinue and spontaneous pregnancy rates after discontinuation were secondary outcomes. RESULTS: In our cohort 319 couples dropped out of fertility care, 76.8%, [95% confidence interval (CI): 72.2-81.4] on their own initiative and 23.2% (95% CI: 18.6-27.8) on doctor's advice. Percentage (95% CI) of couples discontinuing per stage were: Stage I 6.0% (3.4-8.6), Stage II 3.4% (1.5-5.5), Stage III 35.7% (30.5-41.0), Stage IV 23.5% (18.9-28.2), Stage V 17.9% (13.7-22.1) and Stage VI 13.5% (9.7 17.2). Main reasons for dropout (%, 95% CI) were 'emotional distress' (22.3%, 17.7-26.8), 'poor prognosis' (18.8%, 14.5-23.1) and 'reject treatment' (17.2%, 13.1-21.4). The spontaneous ongoing pregnancy rate after discontinuation was 10% (6.7-13.3). CONCLUSION: About half of the couples stopped before any fertility treatment was started and one-third stopped after at least one IVF cycle. The main reasons for withdrawal were emotional distress and poor prognosis. This insight may help to improve quality of patient care by making care more responsive to the needs and expectations of subfertile couples. PMID- 19783834 TI - Association of MICA gene polymorphisms with Chlamydia trachomatis infection and related tubal pathology in infertile women. AB - BACKGROUND: The course and morbidity of Chlamydia trachomatis infections are determined by host genetic factors, virulence of the micro-organism and environmental factors. Major histocompatibility complex class I chain-related A (MICA) gene is highly polymorphic as a potential host genetic candidate. The aim of this study was to investigate the association of polymorphic extracellular domains of MICA with C. trachomatis infection and related tubal factor infertility. METHODS: Effect of MICA on the susceptibility to C. trachomatis infection and its association with tubal pathology were investigated in 214 infertile women recruited during the period from 2004 to 2007. Subjects were tested for C. trachomatis antibodies, and were further divided into two groups: those with (n = 42) and without (n = 59) tubal pathology based on laparoscopy results. The relationship between prevalence of C. trachomatis, tubal pathology and MICA allele polymorphisms was analysed. RESULTS: Women with tubal infertility more often had antibodies to C. trachomatis [66.7 versus 39.1%; odds ratio (OR): 3.12, 95% CI: 1.68-5.78, P = 0.004] than infertile women without tubal pathology. Moreover, allele 008 had a highly negative correlation with C. trachomatis infection (P(c) = 0.0036, OR: 2.14), while other allele polymorphisms showed no significant association with the disease. No statistically significant differences were found in the MICA allele frequencies of C. trachomatis-positive women with or without tubal pathology. CONCLUSIONS: The association of a specific MICA allele with C. trachomatis IgG antibodies among women with infertility suggests that the MICA locus might modify host susceptibility to C. trachomatis infection. PMID- 19783835 TI - Dermal and inhalation exposure to methylene bisphenyl isocyanate (MDI) in iron foundry workers. AB - Diisocyanates are a group of chemically reactive agents, which are used in the production of coatings, adhesives, polyurethane foams, and parts for the automotive industry and as curing agents for cores in the foundry industry. Dermal and inhalation exposure to methylene bisphenyl isocyanate (MDI) is associated with respiratory sensitization and occupational asthma. However, limited research has been performed on the quantitative evaluation of dermal and inhalation exposure to MDI in occupationally exposed workers. The objective of this research was to quantify dermal and inhalation exposure levels in iron foundry workers. Workers involved in mechanized moulding and mechanized production of cores were monitored: 12 core makers, 2 core-sand preparers, and 5 core installers. Personal breathing-zone levels of MDI were measured using impregnated filter sampling. Dermal exposure to MDI was measured using a tape strip technique. Three or five consecutive tape-strip samples were collected from five exposed skin areas (right and left forefingers, left and right wrists, and forehead). The average personal air concentration was 0.55 microg m(-3), 50-fold lower than the Swedish occupational exposure limit of 30 microg m(-3). The core makers had an average exposure of 0.77 microg m(-3), which was not significantly different from core installers' and core-sand preparers' average exposure of 0.16 microg m(-3) (P = 0.059). Three core makers had a 10-fold higher inhalation exposure than the other core makers. The core makers' mean dermal exposure at different skin sites varied from 0.13 to 0.34 microg while the two other groups' exposure ranged from 0.006 to 0.062 microg. No significant difference was observed in the MDI levels between the skin sites in a pairwise comparison, except for left forefinger compared to left and right wrist (P < 0.05). In addition, quantifiable but decreasing levels of MDI were observed in the consecutive tape strip per site indicating MDI penetration into the skin. This study indicates that exposure to MDI can be quantified on workers' skin even if air levels are close to unquantifiable. Thus, the potential for uncured MDI to deposit on and penetrate into the skin is demonstrated. Therefore, dermal exposure along with inhalation exposure to MDI should be measured in the occupational settings where MDI is present in order to shed light on their roles in the development of occupational isocyanate asthma. PMID- 19783836 TI - Nutcracker syndrome. PMID- 19783837 TI - Day hospital vs outpatient care for people with schizophrenia. PMID- 19783838 TI - Microsatellite marker development and Mendelian analysis in the Matschie's tree kangaroo (Dendrolagus matschiei). AB - Matschie's tree kangaroo (Dendrolagus matschiei) is an endangered arboreal macropodid endemic to the Huon Peninsula, Papua New Guinea (PNG). We developed 5 microsatellite markers for D. matschiei, which are the first markers developed for Dendrolagus. We screened 17 additional markers that were developed for other marsupial taxa and identified 3 that were polymorphic in D. matschiei. We estimated allelic and genetic diversity with the set of 8 markers by analyzing 22 D. matschiei from Wasaunon on the Huon Peninsula, PNG. The number of alleles ranged from 2 to 9 and expected heterozygosity ranged from 0.440 to 0.794. We tested for null alleles and Mendelian inheritance by analyzing 19 pairs of D. matschiei parents and offspring from Association of Zoos and Aquariums institutions. Null alleles were not detected and Mendelian inheritance was followed for all 8 markers. We also evaluated the reliability of using the markers to amplify DNA extracted from D. matschiei fecal samples and the ability of the markers to amplify DNA samples from Goodfellow's tree kangaroo (Dendrolagus goodfellowi ssp.), Doria's tree kangaroo (Dendrolagus dorianus ssp.), and Grizzled tree kangaroo (Dendrolagus inustus ssp.). Microsatellite markers can be used to inform management decisions to conserve D. matschiei in captivity and the wild. PMID- 19783839 TI - Instrument response in complex radiation fields. AB - This paper aims at giving an overview of the main issues for estimating the radiation protection quantities in complex radiation fields. The measurability (or non-measurability) of the radiation protection quantities is discussed together with the main approaches for their estimate. The main mechanisms through which the various components of complex radiation fields are generated are also outlined. The main instruments employed for estimating the radiation protection quantities are described and discussed together with their response. Finally, a practical example is given, by discussing the results of an inter-comparison exercise held at the Gesellschaft fur Schwerionenforschung mbH in Darmstadt (Germany) in the framework of the COordinated Network for RAdiation Dosimetry project, funded by the European Commission. PMID- 19783840 TI - Radioactive waste management and decommissioning of accelerator facilities. AB - During the operation of high-energy accelerators, the interaction of radiation with matter can lead to the activation of the machine components and of the surrounding infrastructures. As a result of maintenance operation and during decommissioning of the installation, considerable amounts of radioactive waste are evacuated and shall be managed according to the radiation-protection legislation. This paper gives an overview of the current practices in radioactive waste management and decommissioning of accelerators. PMID- 19783841 TI - Operational radiation protection in high-energy physics accelerators: implementation of ALARA in design and operation of accelerators. AB - This paper considers the historical evolution of the concept of optimisation of radiation exposures, as commonly expressed by the acronym ALARA, and discusses its application to various aspects of radiation protection at high-energy accelerators. PMID- 19783842 TI - Contrast ultrasound molecular imaging of inflammation in cardiovascular disease. AB - The cellular immune response plays an important role in almost every major form of cardiovascular disease. The ability to image the key aspects of the immune response in the clinical setting could be used to improve diagnostic information, to provide important prognostic or risk information, and to customize therapy according to disease phenotype. Accordingly, targeted imaging probes for assessing inflammation have been developed for essentially all forms of medical imaging. Molecular imaging of inflammation with contrast ultrasound relies on the detection of targeted microbubble or other gas-filled particle contrast agents. These agents are confined to the vascular space and, hence, have been targeted to either activated leucocytes or endothelial cell adhesion molecules that are upregulated in inflammation and mediate leucocyte recruitment and adhesion. This review focuses on the inflammation-targeting strategies for ultrasound contrast agents and how they have been matched to cardiovascular disease states such as myocardial ischaemia, infarction, atherosclerosis, transplant rejection, and arteriogenesis. PMID- 19783844 TI - Long-term inhalation toxicity studies with multiwalled carbon nanotubes: closing the gaps or initiating the debate? PMID- 19783843 TI - Mild salinity stimulates a stress-induced morphogenic response in Arabidopsis thaliana roots. AB - Plant roots exhibit remarkable developmental plasticity in response to local soil conditions. It is shown here that mild salt stress stimulates a stress-induced morphogenic response (SIMR) in Arabidopsis thaliana roots characteristic of several other abiotic stresses: the proliferation of lateral roots (LRs) with a concomitant reduction in LR and primary root length. The LR proliferation component of the salt SIMR is dramatically enhanced by the transfer of seedlings from a low to a high NO3- medium, thereby compensating for the decreased LR length and maintaining overall LR surface area. Increased LR proliferation is specific to salt stress (osmotic stress alone has no stimulatory effect) and is due to the progression of more LR primordia from the pre-emergence to the emergence stage, in salt-stressed plants. In salt-stressed seedlings, greater numbers of LR primordia exhibit expression of a reporter gene driven by the auxin sensitive DR5 promoter than in unstressed seedlings. Moreover, in the auxin transporter mutant aux1-7, the LR proliferation component of the salt SIMR is completely abrogated. The results suggest that salt stress promotes auxin accumulation in developing primordia thereby preventing their developmental arrest at the pre-emergence stage. Examination of ABA and ethylene mutants revealed that ABA synthesis and a factor involved in the ethylene signalling network also regulate the LR proliferation component of the salt SIMR. PMID- 19783845 TI - Capture compound mass spectrometry sheds light on the molecular mechanisms of liver toxicity of two Parkinson drugs. AB - Capture compound mass spectrometry (CCMS) is a novel technology that helps understand the molecular mechanism of the mode of action of small molecules. The Capture Compounds are trifunctional probes: A selectivity function (the drug) interacts with the proteins in a biological sample, a reactivity function (phenylazide) irreversibly forms a covalent bond, and a sorting function (biotin) allows the captured protein(s) to be isolated for mass spectrometric analysis. Tolcapone and entacapone are potent inhibitors of catechol-O-methyltransferase (COMT) for the treatment of Parkinson's disease. We aimed to understand the molecular basis of the difference of both drugs with respect to side effects. Using Capture Compounds with these drugs as selectivity functions, we were able to unambiguously and reproducibly isolate and identify their known target COMT. Tolcapone Capture Compounds captured five times more proteins than entacapone Capture Compounds. Moreover, tolcapone Capture Compounds isolated mitochondrial and peroxisomal proteins. The major tolcapone-protein interactions occurred with components of the respiratory chain and of the fatty acid beta-oxidation. Previously reported symptoms in tolcapone-treated rats suggested that tolcapone might act as decoupling reagent of the respiratory chain (Haasio et al., 2002b). Our results demonstrate that CCMS is an effective tool for the identification of a drug's potential off targets. It fills a gap in currently used in vitro screens for drug profiling that do not contain all the toxicologically relevant proteins. Thereby, CCMS has the potential to fill a technological need in drug safety assessment and helps reengineer or to reject drugs at an early preclinical stage. PMID- 19783846 TI - A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome. AB - Mental retardation in Down syndrome (DS), the most frequent trisomy in humans, varies from moderate to severe. Several studies both in human and based on mouse models identified some regions of human chromosome 21 (Hsa21) as linked to cognitive deficits. However, other intervals such as the telomeric region of Hsa21 may contribute to the DS phenotype but their role has not yet been investigated in detail. Here we show that the trisomy of the 12 genes, found in the 0.59 Mb (Abcg1-U2af1) Hsa21 sub-telomeric region, in mice (Ts1Yah) produced defects in novel object recognition, open-field and Y-maze tests, similar to other DS models, but induces an improvement of the hippocampal-dependent spatial memory in the Morris water maze along with enhanced and longer lasting long-term potentiation in vivo in the hippocampus. Overall, we demonstrate the contribution of the Abcg1-U2af1 genetic region to cognitive defect in working and short-term recognition memory in DS models. Increase in copy number of the Abcg1-U2af1 interval leads to an unexpected gain of cognitive function in spatial learning. Expression analysis pinpoints several genes, such as Ndufv3, Wdr4, Pknox1 and Cbs, as candidates whose overexpression in the hippocampus might facilitate learning and memory in Ts1Yah mice. Our work unravels the complexity of combinatorial genetic code modulating different aspect of mental retardation in DS patients. It establishes definitely the contribution of the Abcg1-U2af1 orthologous region to the DS etiology and suggests new modulatory pathways for learning and memory. PMID- 19783847 TI - The Rac1/MKK7/JNK pathway signals upregulation of Atg5 and subsequent autophagic cell death in response to oncogenic Ras. AB - To prevent the development of malignancies, mammalian cells activate disposal programs, such as programmed cell death, in response to deregulated oncogene expression. However, the molecular basis for regulation of cellular disposal machinery in response to activated oncogenes is unclear at present. In this study, we show that upregulation of the autophagy-related protein, Atg5, is critically required for the oncogenic H-ras-induced autophagic cell death and that Rac1/mitogen-activated kinase kinase (MKK) 7/c-Jun N-terminal kinase (JNK) signals upregulation of Atg5. Overexpression of H-ras(V12) induced marked autophagic vacuole formation and cell death in normal fibroblasts, which remained unaffected by a caspase inhibitor. Pretreatment with Bafilomycin A1, an autophagy inhibitor, completely attenuated H-ras(V12)-induced cell death as well as autophagic vacuole formation. Selective production of Atg5 was observed in cells overexpressing H-ras(V12), and small interfering RNA (siRNA) targeting of Atg5 clearly inhibited autophagic cell death. Interestingly, inhibition of JNK or c Jun by specific siRNA suppressed Atg5 upregulation and autophagic cell death. Moreover, inhibition of MKK7, but not MKK4, effectively attenuated H-ras(V12) induced JNK activation. In addition, ectopic expression of RacN17 or Rac1-siRNA effectively inhibited MKK7-JNK activation, Atg5 upregulation and autophagic cell death. These data support the notion that upregulation of Atg5 is required for the oncogenic H-ras-induced autophagic cell death in normal fibroblasts and that activation of Rac1/MKK7/JNK-signaling pathway leads to upregulation of Atg5 in response to oncogenic H-ras. Our findings suggest that in cells acquiring deregulated oncogene expression, oncogenic stress triggers autophagic cell death, which protects cells against malignant progression. PMID- 19783848 TI - P2Y12 receptor protein in cortical gray matter lesions in multiple sclerosis. AB - Although Multiple Sclerosis (MS) is regarded as a white matter disease, the incidence of demyelination and axonal injury is prominent also in gray matter. In MS, extracellular adenosine triphosphate (ATP) is an important mediator of central nervous system pathology via its ability to cause oligodendrocyte excitotoxicity. We have analyzed the distribution pattern of all ionotropic P2X and metabotropic P2Y receptors for ATP in postmortem samples of the cerebral cortex from healthy human subjects as well as MS patients. We focus particularly on the P2Y(12) subtype that is highly enriched in oligodendrocytes. We correlate the expression of this receptor to the extent of gray matter demyelination and pathological alterations occurring during secondary progressive MS. Using triple immunofluorescence and confocal analysis, we show that in sections of cerebral cortex from postmortem MS brains, the P2Y(12) protein is present in myelin and interlaminar astrocytes but absent from protoplasmic astrocytes residing in the deeper cortical layers, from microglia/macrophages, and from intact demyelinated axons. We report that a decreased P2Y(12) receptor immunoreactivity in proximity to the lesions is directly correlated with the extent of demyelination found in all types of gray matter cortical plaques (I-III) and subcortical white matter. Our study provides further insights into the pathogenetic features of MS and suggests that the loss of purinergic P2Y(12) receptors might be detrimental to tissue integrity. PMID- 19783849 TI - Risk assessment of importation of dogs infected with Echinococcus multilocularis into the UK. AB - A risk assessment was undertaken to assess the likelihood of importation of dogs infected with Echinococcus multilocularis should the requirement for treatment with praziquantel be relaxed under the Pet Travel Scheme. The analysis suggested that for every 10,000 dogs going on a short trip to Germany, the probability of at least one returning to the UK infected is approximately 98 per cent. If the dogs had been longer-term residents, this probability rises to over 99 per cent. This indicates that if praziquantel treatment of dogs on importation into the UK is abandoned, then it is almost inevitable that E multilocularis will be introduced. PMID- 19783850 TI - Use of inactivated bluetongue virus serotype 8 vaccine against virulent challenge in sheep and cattle. AB - The immunisation properties of an inactivated bluetongue virus serotype 8 (BTV-8) vaccine were evaluated in sheep and cattle. Five sheep were vaccinated with one dose of vaccine and five cattle were vaccinated with two doses 28 days apart. Six sheep and five cattle served as unvaccinated controls. All animals were subjected to a virulent BTV-8 challenge, and safety and antibody responses were monitored. All control animals developed disease and viraemia, while vaccinated animals were clinically protected and viraemia was completely prevented. PMID- 19783851 TI - Normal function of the hypothalamic-pituitary growth axis in three dwarf Friesian foals. AB - Serial blood samples were collected from three dwarf Friesian foals to examine their endogenous growth hormone (GH) profiles, and the integrity of the GH insulin-like growth factor-1 (IGF-1) axis was tested in one of them by examining its responses to the administration of GH-releasing hormone (GHRH) and to 10 days of treatment with recombinant equine GH. The basal serum concentrations of IGF-1 in the three dwarf foals were compared with those in nine age-matched normal foals. All the dwarf foals secreted endogenous GH. Stimulation with 7.0 microg/kg GHRH led to a 1400 per cent increase in plasma GH concentration in the dwarf foal tested, and 10 daily subcutaneous treatments with 20 microg/kg recombinant equine GH led to a 100 per cent increase in its serum IGF-1 concentration. The basal serum concentrations of IGF-1 in the dwarf foals were not significantly different from those of the normal foals. PMID- 19783852 TI - Two cases of equine pregnancy loss associated with Leptospira infection in England. PMID- 19783853 TI - Endoscopic excision of a gastric polyp causing intermittent pyloric obstruction in a dog. PMID- 19783854 TI - Inguinal herniation of the large colon in a cob gelding four weeks after castration. PMID- 19783855 TI - European bat lyssavirus type 2 in a Daubenton's bat in Scotland. PMID- 19783856 TI - Tracking badger visits to farmyards. PMID- 19783857 TI - Improving communication between vets, SQPs and pharmacists. PMID- 19783858 TI - Lipase maturation factor LMF1, membrane topology and interaction with lipase proteins in the endoplasmic reticulum. AB - Lipase maturation factor 1 (LMF1) is predicted to be a polytopic protein localized to the endoplasmic reticulum (ER) membrane. It functions in the post translational attainment of enzyme activity for both lipoprotein lipase and hepatic lipase. By using transmembrane prediction methods in mouse and human orthologs, models of LMF1 topology were constructed and tested experimentally. Employing a tagging strategy that used insertion of ectopic glycan attachment sites and terminal fusions of green fluorescent protein, we established a five transmembrane model, thus dividing LMF1 into six domains. Three domains were found to face the cytoplasm (the amino-terminal domain and loops B and D), and the other half was oriented to the ER lumen (loops A and C and the carboxyl terminal domain). This representative model shows the arrangement of an evolutionarily conserved domain within LMF1 (DUF1222) that is essential to lipase maturation. DUF1222 comprises four of the six domains, with the two largest ones facing the ER lumen. We showed for the first time, using several naturally occurring variants featuring DUF1222 truncations, that Lmf1 interacts physically with lipoprotein lipase and hepatic lipase and localizes the lipase interaction site to loop C within DUF1222. We discuss the implication of our results with regard to lipase maturation and DUF1222 domain structure. PMID- 19783859 TI - Cellular redistribution of Rad51 in response to DNA damage: novel role for Rad51C. AB - Exposure of cells to DNA-damaging agents results in a rapid increase in the formation of subnuclear complexes containing Rad51. To date, it has not been determined to what extent DNA damage-induced cytoplasmic to nuclear transport of Rad51 may contribute to this process. We have analyzed subcellular fractions of HeLa and HCT116 cells and found a significant increase in nuclear Rad51 levels following exposure to a modest dose of ionizing radiation (2 grays). We also observed a DNA damage-induced increase in nuclear Rad51 in the Brca2-defective cell line Capan-1. To address a possible Brca2-independent mechanism for Rad51 nuclear transport, we analyzed subcellular fractions for two other Rad51 interacting proteins, Rad51C and Xrcc3. Rad51C has a functional nuclear localization signal, and although we found that the subcellular distribution of Xrcc3 was not significantly affected by DNA damage, there was a damage-induced increase in nuclear Rad51C. Furthermore, RNA interference-mediated depletion of Rad51C in HeLa and Capan-1 cells resulted in lower steady-state levels of nuclear Rad51 as well as a diminished DNA damage-induced increase. Our results provide important insight into the cellular regulation of Rad51 nuclear entry and a role for Rad51C in this process. PMID- 19783860 TI - A rare haplotype of the vitamin D receptor gene is protective against diabetic nephropathy. AB - BACKGROUND: Vitamin D and its analogues are reported to have renoprotective effects in chronic kidney disease including diabetic nephropathy (DN). Vitamin D(3) is converted to 1,25(OH)D(3) by CYP2R1 and CYP27B1. The biological action of 1,25(OH)D(3) is mediated via its receptor. VDR, CYP27B1 or CYP2R1 gene variants could modify the biological activity of vitamin D(3). We have conducted the first case-control association study to determine the relationship between polymorphisms in VDR, CYP27B1 and CYP2R1 genes, and the risk of DN in individuals with type 1 diabetes. METHODS: Eight VDR single-nucleotide polymorphisms (SNPs) rs10735810 FokI C>T, rs1544410 BsmI G>A, rs7975232 ApaI G>T, rs731236 TaqI T>C, rs4303288 G>T, rs11168275 C>T, rs12721366 G>A and rs2544043 G>C were investigated with CYP27B1 rs4646536 T>C and CYP2R1 rs10741657 G>A. Genotyping was performed using pyrosequencing, Taqman, Sequenom or direct sequencing technologies in 1329 type 1 diabetics (655 nephropaths, 674 non-nephropaths). RESULTS: No significant differences were observed in genotype or allele frequencies between case and control groups for VDR, CYP27B1 or CYP2R1 SNPs, either before or after stratification by recruitment centre or when restricted to patients with end stage renal disease. A previously identified haplotype block from rs1544410 to rs731236 was confirmed at the 3'-end of VDR. Comparison of haplotype frequencies identified the rare AGT haplotype as significantly protective against DN, 3.1% cases versus 5.8% controls; chi(2) = 11.05, Pc = 0.009 by the permutation test. CONCLUSIONS: Our study has identified a rare VDR haplotype that is protective against DN in patients with type 1 diabetes. Replication in a large, independent cohort is required to confirm this finding. PMID- 19783861 TI - A confusional state associated with use of lanthanum carbonate in a dialysis patient: a case report. PMID- 19783863 TI - Beta-amyloid accumulation in neurovascular units following brain embolism. AB - Nitric oxide (NO) toxicity is in part mediated by generation of peroxynitrite with concomitant production of superoxide under pathological brain conditions such as ischemia and Alzheimer's disease. The pathophysiological relevance of endothelial nitric oxide synthase (eNOS) to brain embolism-induced neurovascular injury has not been documented. We found that microsphere embolism (ME)-induced aberrant eNOS expression in vascular endothelial cells likely mediates blood brain barrier (BBB) disruption via peroxynitrite formation and in turn causes brain edema. We also demonstrated that a mild ME model was useful for investigating the sequential events of neurovascular injury followed by beta amyloid accumulation and tau hyperphosphorylation. Indeed, immunoblotting of purified brain microvessels revealed that beta-amyloid accumulation significantly increased one week after ME induction and remained elevated for twelve weeks in those animals. Moreover, we also confirmed that peroxynitrite formation and eNOS uncoupling-mediated superoxide generation in microvessels are inhibited by a novel calmodulin inhibitor. Thus, peroxynitrite formation via elevated eNOS is associated with endothelial cell injury with concomitant beta-amyloid accumulation in microvessels of aged rats. In this review, we focus on the detrimental effects of eNOS expression following brain embolism and introduce an attractive model representing progressive Alzheimer's disease pathology in brain. PMID- 19783864 TI - Inhibitory effect of lomerizine, a prophylactic drug for migraines, on serotonin induced contraction of the basilar artery. AB - We examined the effects of lomerizine on serotonin (5-hydroxytryptamine, 5-HT) induced contraction of the basilar artery and compared them with those of nifedipine. Although both lomerizine and nifedipine completely blocked K(+) induced vasoconstriction, 5-HT-induced vasoconstriction was more strongly inhibited by lomerizine than nifedipine. A 5-HT(2A) antagonist inhibited the 5-HT induced vasoconstriction, but a 5-HT(1B) antagonist did not. Lomerizine, but not nifedipine, suppressed 5-HT-induced Ca(2+) release in 5-HT(2A)-expressing HEK293 cells. Moreover, neither antagonist affected ATP-induced Ca(2+) release. These results suggest that lomerizine may inhibit not only voltage-dependent Ca(2+) channels but also 5-HT(2A) receptors and so inhibit 5-HT-induced contraction in the basilar artery. PMID- 19783865 TI - Activation of cytosolic phospholipase A2alpha by epidermal growth factor (EGF) and phorbol ester in HeLa cells: different effects of inhibitors for EGF receptor, protein kinase C, Src, and C-Raf. AB - In several types of cancer cells, prostaglandins produced via the over-expression of epidermal growth factor receptor (EGFR) and cyclooxygenases regulate cell growth. We investigated the signaling mechanisms for the release of arachidonic acid (AA, a precursor for prostaglandins) in human cervical carcinoma HeLa cells. Treatment with EGF and 4beta-phorbol 12-myristate 13-acetate (PMA) with A23187 released AA accompanied by the phosphorylation of extracellular signal-regulated kinases (ERK1/2). Pharmacological experiments showed that the responses (ERK phosphorylation and AA release) induced by EGF and PMA were mediated by a mitogen activated protein kinase/ERK kinase (MEK)-ERK-alpha-type cytosolic phospholipase A(2) (cPLA(2)alpha) pathway and that EGFR couples with the pathway in a manner insensitive to sorafenib, an inhibitor of B- and C-Raf, enzymes upstream of MEK. Activation of protein kinase C by PMA couples with the pathway partly in a sorafenib-sensitive and probably C-Raf-mediated manner and partly in a family of Src tyrosine kinases (Src)-dependent and sorafenib-insensitive manner. Co treatment with sorafenib and an inhibitor of Src family members additionally inhibited the PMA-induced release of AA. Cross-talk between EGFR and protein kinase C was not observed. In human lung carcinoma A549 cells, the release of AA by EGF was insensitive to sorafenib. Possible mechanisms for the sorafenib insensitive activation of the MEK-ERK-cPLA(2)alpha pathway are discussed. PMID- 19783867 TI - Methamphetamine- and 3,4-methylenedioxymethamphetamine-induced behavioral changes in histamine H3-receptor knockout mice. AB - Histamine H(3) receptors inhibit the release of not only histamine itself, but also other neurotransmitters including dopamine. Previous papers have reported that histaminergic neurons inhibit psychostimulant-induced behavioral changes. To examine whether deficiency in histamine H(3) receptors influences psychostimulant induced behavioral sensitization and reward, we examined locomotor activity, conditioned place preference (CPP), and c-Fos expression in histamine H(3) receptor-gene knockout mice (H3KO) and their wild-type (WT) counterparts before and after treatment with methamphetamine (METH) and 3,4 methylenedioxymethamphetamine (MDMA). The increase in locomotion induced by treatment with METH or MDMA was lower in histamine H3KO mice than in WT mice, while the locomotor sensitization was developed by METH or MDMA in both strains. However, no significant difference in METH- and MDMA-induced preference scores of CPP between histamine H3KO mice and WT mice was observed. Following treatment with METH, the number of c-Fos-positive neurons in the the caudate-putamen of histamine H3KO mice was lower than that in the caudate-putamen of WT mice. In contrast, there was no significant difference in the number of the psychostimulant-induced c-Fos-positive cells in the nucleus accumbens between the two strains of mice. These findings suggest that deficiency in histamine H(3) receptors may have inhibitory effects on psychostimulant-induced increase in locomotion, but insignificant effects on the reward. PMID- 19783866 TI - A selective thromboxane A2 (TXA2) synthase inhibitor, ozagrel, attenuates lung injury and decreases monocyte chemoattractant protein-1 and interleukin-8 mRNA expression in oleic acid-induced lung injury in guinea pigs. AB - This study examined the effect of ozagrel, a thromboxane A(2) synthase inhibitor, on the accumulation of leucocytes and chemokine mRNA expression in lungs experimentally injured using oleic acid (OA). OA injection into guinea pigs rapidly increased thromboxane A(2) generation and subsequently increased total protein concentration and the numbers of macrophages and neutrophils in bronchoalveolar lavage fluid and increased monocyte chemoattractant protein-1 and interleukin-8 mRNA expression in the whole lung. Administration of ozagrel prevented these changes associated with OA injection. Ozagrel is a promising drug candidate for preventing acute lung injury. PMID- 19783868 TI - Gastrointestinal influence on the electrophysiology of the heart: induction of cardiac arrhythmic episodes by myoelectrical uncoupling within the gut. AB - It is theorized that the triggering of some arrhythmic episodes in cardiac sensitive subjects might be directly linked to the functional uncoupling of gastro myoelectrical activity following the consumption of particular foods or by other influences on the gut. The intent of this research is to reveal the likely adverse mechanism involved through investigative analytical review. The resulting evidence shows there exists a triggering source within the visceral smooth muscle system of the gut and a mode of transmission incorporated in the autonomic nervous system mediated by the central autonomic network that could significantly affect the electrophysiology of the heart. A formal clinical study is indicated to determine the specific types of troublesome foods and other factors associated to better understand the overall process. PMID- 19783869 TI - Hypoxia differentially modulates the activity of pacemaker and smooth muscle cells in the guinea pig stomach antrum. AB - Effects of hypoxic solution (O(2) tension, 161 +/- 11 mmHg) on electrical responses of the membrane (slow waves), intracellular Ca(2+)-responses measured by Fura-2 fluorescence (Ca-transients) and isometric mechanical responses (phasic contraction) were observed in circular smooth muscles isolated from the guinea pig stomach antrum. In normoxic solution (O(2) tension, 362 +/- 28 mmHg), muscle cells generated slow waves spontaneously, and switching to hypoxic solution caused an increase in frequency and decrease in duration of slow waves, with no significant change in the resting membrane potential. Hypoxia also reduced the amplitude and duration and increased the frequency of Ca-transients. The increase in frequency of slow waves by hypoxia was prevented by cyclopiazonic acid (CPA) but not by carbonyl cyanide m-chlorophenyl-hydrazone (CCCP), potassium cyanide (KCN) or low-Ca solution. The reduction by hypoxia of the duration of slow waves was prevented by CCCP or KCN but not by CPA or low-Ca solution. Hypoxia resulted in an increase in frequency and decrease in amplitude of phasic contractions, and the changes were prevented by CPA but not by CCCP. These results suggested that in antrum smooth muscle tissues, the increase in frequency of spontaneous activity by hypoxia is related to the enhanced function of the CPA-sensitive internal Ca-stores in pacemaker cells, while the inhibition in amplitude of phasic contractions by hypoxia may be mainly related to the decrease in Ca(2+) release from the CPA-sensitive internal stores in smooth muscle cells. It is concluded that in hypoxic solution, the function of internal Ca(2+) stores is enhanced in ICC-MY and is inhibited in smooth muscle cells in the guinea-pig stomach antrum. PMID- 19783870 TI - Acupuncture modulates mechanical responses of smooth muscle produced by transmural nerve stimulation in gastric antrum of genetically hyperglycemic rats. AB - Effects of acupuncture treatment on mechanical responses produced by transmural nerve stimulation (TNS) and acetylcholine (ACh) were investigated in circular smooth muscle preparations isolated from the antrum of the stomach of genetically hyperglycemic rats. While control rats had blood glucose levels of about 140 mg/dl, this was approximately tripled in the genetically hyperglycemic rats, but only doubled in the acupuncture treated genetically hyperglycemic rats. Antrum smooth muscle produced phasic contractions spontaneously, with a similar frequency and amplitude in the three groups of rats. Effects of atropine and Nomega-nitro-L-arginine (L-NA) on TNS-induced responses revealed that in the antrum smooth muscle of the control rats, cholinergic excitatory, non-adrenergic non-cholinergic excitatory (NANCE), nitrergic inhibitory and off-responses produced projections: the last projection was considered to be non-adrenergic non cholinergic non-nitrergic (NANCNN) in nature. In genetically hyperglycemic rats, nitrergic and NANCNN projections were enhanced and NANCE projections were absent. Acupuncture treated genetically hyperglycemic rats showed a reduction of NANCNN projection and enhancement of cholinergic projection, with no alteration to nitrergic projection, but a recovery of NANCE projection. ACh elicited inhibitory responses at low concentrations (1-30 nM) and excitatory responses at high concentrations (100-300 nM), in the three groups of rats. L-NA converted the ACh induced inhibitory responses to excitatory responses. Immunohistochemical examination indicated no significant difference in the distribution of c-Kit expressing cells in the antrum smooth muscle from the three groups of rats. The results indicated that in antral smooth muscle, hyperglycemia was associated with enhanced activity in nitrergic and NANCNN projections and attenuation of NANCE projections, and that acupuncture treatment caused both a reduced blood glucose level and attenuated NANCNN projections. In genetically hyperglycemic rats, cholinergic responses were enhanced by acupuncture, possibly due to the enhanced cholinergic projections, with no change in the sensitivity of postjunctional muscarinic receptors to ACh. PMID- 19783871 TI - Effects of four different alpha(1)-adrenoceptor antagonists on alpha-adrenoceptor agonist-induced contractions in isolated mouse and hamster ureters. AB - PURPOSE: To compare the efficacy of the selective alpha(1A)-adrenoceptor antagonist silodosin with those of doxazosin, terazosin, and alfuzosin against alpha-adrenoceptor agonist-induced contractions in mouse and hamster ureters. METHODS: The four alpha(1)-adrenoceptor antagonists were evaluated against norepinephrine-induced phasic contractions in mouse isolated ureteral preparations and against phenylephrine-induced sustained contractions in hamster isolated ureteral preparations using a functional experimental technique. RESULTS: In mouse ureters, silodosin (a selective alpha(1A)-adrenoceptor antagonist), doxazosin (a nonselective alpha(1)-adrenoceptor antagonist), terazosin (a nonselective alpha(1)-adrenoceptor antagonist), and alfuzosin (a nonselective alpha(1)-adrenoceptor antagonist) all shifted the norepinephrine concentration-response curve to the right. The rank order of potencies (pK(B) value) was silodosin (9.47 +/- 0.16) > doxazosin (8.62 +/- 0.15) > terazosin (8.39 +/- 0.16) > alfuzosin (8.03 +/- 0.12). In hamster ureters, all four antagonists shifted the phenylephrine concentration-response curve to the right, the rank order of potencies being silodosin (10.09 +/- 0.13) > doxazosin (8.22 +/ 0.16) > terazosin (7.75 +/- 0.15) > alfuzosin (7.70 +/- 0.10). In each case, silodosin was much more potent than the other three drugs. CONCLUSION: In this study, silodosin suppressed both mouse and hamster ureteral contractions more potently than doxazosin, terazosin, or alfuzosin. Hence, this alpha(1A) adrenoceptor antagonist warrants further study as a potentially very useful medication for stone passage in urolithiasis patients. PMID- 19783872 TI - Phase-contrast MR studies of CSF flow rate in the cerebral aqueduct and cervical subarachnoid space with correlation-based segmentation. AB - PURPOSE: Accurate measurement of cerebrospinal fluid (CSF) flow rate elucidates pathophysiological changes in the intracranial environment and is thus clinically useful. We investigated the feasibility of correlation coefficient (CC) analysis for extracting CSF lumens in the cerebral aqueduct and cervical subarachnoid space (SAS) to quantify CSF flow rate and net flow from data acquired by phase contrast magnetic resonance imaging (PC-MRI). METHODS: First, in phantom studies on pulsatile flow using a 1.5-tesla MR imaging system, we investigated the accuracy of CC analysis and used a statistical approach to determine an optimal threshold value for extracting the CSF lumens (CC(min)). Second, we performed phantom studies on constant flow with various flow rates to estimate the accuracy of low flow measurement by PC-MRI. Finally, in 6 healthy male volunteers aged 24 +/- 2 years, we estimated the CSF lumen areas, net flows, and peak flow rates in the cerebral aqueduct and cervical SAS using CC analysis with the optimal CC(min) value determined in phantom studies. Three observers analyzed results to compare reproducibility of CC analysis with that of manual segmentation. RESULTS: The optimal CC(min) value for CC analysis was 0.41 for a matrix measuring 256 x 256. The CSF lumen area extracted by CC analysis was 6.15 +/- 2.52 mm(2), and the net flow in the cerebral aqueduct was 0.74 +/- 0.38 mL/min; in the cervical SAS, lumen area was 135.60 +/- 17.94 mm(2) and net flow, 12.55 +/- 12.67 mL/min. The reproducibility of CSF lumen extraction was better by CC analysis than manual segmentation. CONCLUSION: CC analysis offers a quick and reproducible method for segmenting CSF lumens and calculating CSF flow rate. PMID- 19783873 TI - Comparison of SPACE and 3D TSE MRCP at 1.5T focusing on difference in echo spacing. AB - PURPOSE: We compared the image quality of SPACE (sampling perfection with application optimized contrasts using different flip angle evolutions) and conventional 3D turbo spin echo (TSE) magnetic resonance cholangiopancreatography (MRCP) at 1.5 tesla with regard to difference in echo spacing. METHODS: Twenty healthy volunteers prospectively underwent navigator-triggered SPACE and 3D TSE MRCP at 1.5T with identical parameters, except for echo spacing. Quantitative analyses of signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), relative contrast, and contour sharpness index of each segment of the pancreaticobiliary tree were compared using paired t-tests. Qualitative analyses on a 5-point scale (1, excellent; 5, poor) scored by 2 independent radiologists were compared using Wilcoxon signed-rank test. RESULTS: The SNR, CNR, and contour sharpness index of each segment were significantly better for the SPACE sequence than 3D TSE (P < 0.05). Relative contrast and subjective image quality were not significantly different (P > 0.05). CONCLUSION: We verified SPACE MRCP quantitatively superior to conventional 3D TSE MRCP at 1.5T as a result of shortening of echo spacing. PMID- 19783874 TI - Reference-based maximum upslope: a CBF quantification method without using arterial input function in dynamic susceptibility contrast MRI. AB - PURPOSE: We assessed errors in cerebral blood flow (CBF) obtained from our proposed reference-based method without using arterial input function (AIF) indices in dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI). MATERIALS AND METHODS: We calculated CBF and the referential tissue related ratio (CBFratio) using numerical simulation and 3 nondeconvolution methods and a deconvolution method of block-circulant singular value decomposition (cSVD). We compared errors with and without simulated noise as parameters of mean transit time (MTT), AIF delay and temporal resolution, and clinical DSC-MRI maps. RESULTS: The errors in CBF obtained using maximum upslope (US) were smallest among the nondeconvolution methods and almost equivalent to errors in the cSVD method under practical imaging conditions. In addition, errors in the CBFratio obtained using reference-based US (Ref-US) referring to white matter were smallest, even compared to all errors in CBF and CBFratio. The Ref-US method introduced less error than the cSVD method, especially at low flow rates, was further robust against AIF noise and coarse temporal resolution, and was comparably robust against transit delay. In pixel-by-pixel correlations between absolute value maps for US and for cSVD-CBF in clinical DSC-MRI, those correlation coefficients (r) between the 2 maps were stable, r > 0.9, despite variation in the slopes of the linear regression line, so the 2 CBFratio maps were visually well correlated in any case. CONCLUSION: The Ref-US technique without AIF measurement can become a practical perfusion methodology for DSC-MRI in patients even with acute stroke because it balances robustness with systematic and random errors and it is simply performed. PMID- 19783875 TI - How does water diffusion in human white matter change following ischemic stroke? AB - PURPOSE: Temporal evolution of the water apparent diffusion coefficients (ADC) parallel (ADC parallel) and perpendicular (ADC perpendicular) to the human white matter tract following ischemia has not been investigated systematically. We attempted to quantify the evolution of ADC parallel and ADC perpendicular and examine whether it can be interpreted by a model of ischemic edema. METHODS: We retrospectively selected 53 patients with ischemic lesions involving the posterior limb of the internal capsule (PLIC) and placed regions of interest in the right and left PLIC on ADC maps. We performed regression analysis of lesion to-contralateral ratios of ADC parallel and ADC perpendicular against the time (t = 1-1600 h) from onset. We then fitted the estimated time courses of ADC parallel and ADC perpendicular obtained from the analysis to a model of nerve tissue composed of cylinders (axons) and spheres corresponding to isotropic structures, particularly focal cytoplasmic swellings of glial cells and axons seen in ischemic white matter. RESULTS: The evolution of ADC perpendicular and ADC parallel differed. The estimated time course of ADC parallel in microm(2)*ms(-1) was 0.64 + 0.88 exp (-0.24t) for 1 < t < 54 h and 0.00059t + 0.61 for t >or= 54 h (contralateral normal value, 1.52). That of ADC perpendicular was 0.19-0.063 exp (-0.24t) for 1 < t < 54 h and 0.00040t + 0.17 for t >or=54 h (normal value 0.22). The model fitted to these values showed that the volume of the cylinders decreased, that of the spheres increased, and extracellular volume changed little from one hour to approximately one day after stroke onset. CONCLUSION: In the human PLIC, ADC parallel continued to decrease from one hour to a few days after stroke onset, and ADC perpendicular tended to increase. The temporal evolution could be interpreted by progression of the focal cytoplasmic swelling of glial cells and axons previously observed in animal studies. PMID- 19783876 TI - Diffusion-weighted imaging of an atypical teratoid/rhabdoid tumor of the cervical spine. AB - Spinal atypical teratoid/rhabdoid tumor (AT/RT) is a rare, aggressive malignant neoplasm of the central nervous system usually seen in young children and infants. We present diffusion-weighted imaging (DWI) findings for an intradural extramedullary AT/RT in the cervical spine of a 6-year-old boy. High signal on DWI and low apparent diffusion coefficients may represent high cellularity of the tumor. These findings indicated a highly malignant tumor. PMID- 19783877 TI - Age-related white matter hyperintensities attenuated by compression from a chronic subdural hematoma: possible contribution of brain interstitial fluid to the formation of leukoaraiosis. AB - The origin of patchy white matter hyperintensities commonly seen in the elderly on magnetic resonance (MR) images with long repetition time (TR) is still controversial. We describe MR findings in older patients in whom white matter hyperintensities were attenuated by compression of the cerebral hemisphere from a chronic subdural hematoma. These sequential MR findings substantiate the hypothesis that leukoaraiosis may arise when drainage of the bulk flow of brain interstitial fluid is disturbed. PMID- 19783878 TI - [Haplotype analysis at R778L mutation of ATP7B gene in Korean patients with Wilson disease]. PMID- 19783879 TI - Molecular targeting for treatment of advanced hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is a major global health problem, which has a grave morbidity and mortality. Over the past few decades, no effective systemic therapeutic modalities have been established for patients with the unresectable HCC in advanced stage. Sorafenib is a small molecule that blocks cancer cell proliferation by targeting the intracellular signaling pathway at the level of Raf-1 and B-Raf serine-threonine kinases, and exerts an anti-angiogenic effect by targeting the vascular endothelial growth factor receptor-1, 2 and 3, and platelet-derived growth factor receptor-beta tyrosine kinases. Recently, two clinical successful applications, SHARP and Asia-Pacific trial, of multikinase inhibitor sorafenib represent a significant advance in the treatment of advanced HCC patients without a curative chance. However, because the results of clinical trials show diverse responses in a subset of HCC patients, a molecular classification of HCC through the excavation of specific biomarkers related to its biological behavior is necessary for sorting HCC patients to each group with a biological homogeneity, ultimately leading to the most suitable individualization of molecular targeted therapy in HCC. PMID- 19783880 TI - [Haplotype analysis and possible founder effect at the R778L mutation of the ATP7B gene in Korean patients with Wilson's disease]. AB - BACKGROUND/AIMS: Wilson's disease (WD) is an inherited disorder of copper metabolism caused by alteration of the P-type adenosine triphosphatase (ATP) 7B gene. In this study, we analyzed the frequency of well-known mutations and constructed the first haplotypes for Koreans. In addition, we evaluated whether a founder effect existed in Korean patients with WD. METHODS: We obtained DNA samples from 21 patients with WD and their parents (total cohort n=63). ATP7B gene mutations were identified by direct sequencing methods, and microsatellite typing was performed at D13S315, D13S1325, and D13S316 with fluorescent dye labeled primers. Any founder effect was identified by using 42 normal alleles from parents with a normal phenotype as a control group. The chi square test and Fisher's exact test were used for statistical analysis. RESULTS: Three common mutations were found in 23 chromosomes obtained from 21 patients: the R778L mutation at exon 8 (15/23, 65.2%), the A874V mutation at exon 11 (6/23, 26.1%), and the N1270S mutation at exon 18 (2/23, 8.7%). D13S315 and D13S316 showed linkage disequilibrium at alleles 5 and 4, respectively, in patients with the R778L mutation (P=0.0157 and 0.0001, respectively). The haplotype made up of these two alleles occurred significantly more frequently in patients with the R778L mutation (5-R778L-4, D13S315-mutation-D13S316) than in the controls (P=0.0018). CONCLUSIONS: The arche haplotype of the ATP7B gene in Korean patients with WD may be 5-R778L-4 (D13S315.mutation.D13S316), and it might illustrate a founder effect. PMID- 19783881 TI - Prognostic value of serum osteopontin in hepatocellular carcinoma patients treated with transarterial chemoembolization. AB - BACKGROUND/AIMS: Osteopontin (OPN) is overexpressed in hepatocellular carcinoma (HCC) with postoperative recurrence or extrahepatic metastasis. However, its prognostic value in patients treated with transarterial chemoembolization (TACE) is unclear. We investigated the utility of serum OPN levels and changes therein as prognostic markers in HCC patients who have received TACE. METHODS: Forty-six patients with HCC were enrolled. Serum OPN levels were measured before and 4 weeks after TACE. Serum biochemistry and computed tomography (CT) scans were analyzed. We evaluated baseline serum OPN levels and subsequent changes therein in relation to tumor responses and cumulative survival rates following TACE. A decreasing pattern was defined as a decrease after TACE of more than 10% relative to baseline levels. A "responder" was defined as a patient who exhibited a tumor necrosis rate of higher than 50% on the follow-up CT scan. RESULTS: Higher initial serum OPN levels were associated with a large tumor, portal vein invasion, and an advanced tumor stage. Patients who had lower initial serum OPN levels and those who exhibited decreasing patterns after TACE tended to have more favorable tumor responses (P=0.043 and 0.055, respectively) and exhibited better cumulative survival rates (P=0.036 and 0.030, respectively). However, the initial serum OPN level and subsequent changes in serum OPN levels were not independent predictors for survival on multivariate analysis. CONCLUSIONS: Serum OPN levels were significantly higher in patients with advanced HCC. In addition, HCC patients with low pretreatment serum OPN levels and those for whom serum OPN declined following TACE exhibited better tumor responses and survived for longer. PMID- 19783882 TI - [Efficacy of 48-week clevudine therapy for chronic hepatitis B]. AB - BACKGROUND/AIMS: Clevudine is a nucleoside analogue that exhibits potent and sustained antiviral effects as a 24-week therapy for chronic hepatitis B (CHB). This study evaluated the efficacy and viral resistance of a 48-week course of clevudine treatment for CHB. METHODS: Data on patients with CHB and detectable serum hepatitis B virus (HBV) DNA who were treated with clevudine for 48 weeks or longer were collected retrospectively for this study. Patients who had taken lamivudine within the 3 years prior to this study were excluded. Serum HBV DNA was measured by polymerase chain reaction hybridization (lower detection limit=316 copies/mL). Serum HBV DNA and biochemical data were analyzed at weeks 24 and 48. Developments of viral breakthrough and resistance to the antiviral drug were also monitored. RESULTS: Data from 74 patients (mean age 44 years; M:F=54:20; HBeAg-positive, 47; HBeAg-negative, 27) were included in this study. Ten patients had experienced previous lamivudine treatment. Median HBV DNA at baseline was 6.49 log(10) copies/mL. Median serum HBV DNA reductions from baseline at week 48 were -4.34 log(10) copies/mL (HBeAg-positive, -4.84 log(10) copies/mL; HBeAg-negative, -3.74 log(10) copies/mL). At week 48, serum HBV DNA was not detected in 83.8% of the patients (HBeAg-positive, 76.6%; HBeAg-negative, 96.3%). Normalization of serum alanine aminotransferase levels was achieved in 84.7% of the patients. Viral breakthrough and antiviral resistance developed in two patients at week 48. The development of antiviral resistance was associated with the presence of previous lamivudine treatment and cirrhosis. CONCLUSION: A 48-week course of clevudine therapy was highly effective in patients with CHB. The risk of development of resistance to clevudine was increased in patients with previous exposure to lamivudine and cirrhosis. PMID- 19783883 TI - Impact of adherence to peginterferon-ribavirin combination therapy in chronic hepatitis C patients on achieving a sustained virologic response. AB - BACKGROUND/AIMS: Various predictive factors for peginterferon alpha and ribavirin therapy in chronic hepatitis C have been reported, but the effect of adherence to therapy has not been established. We investigated how adherence affects the sustained virologic response (SVR). METHODS: We analyzed 92 chronic hepatitis C patients receiving peginterferon alpha and ribavirin combination therapy. Patients were first identified as having either genotype 1 or genotype non-1 infection and then categorized into three groups according to their adherence to the treatment protocol: (1) patients who received >/=80% of the recommended dosage of both peginterferon alpha and ribavirin for > or =80% of the intended duration of therapy, (2) patients who received <60% of the recommended dosage of both peginterferon alpha and ribavirin for <60% of the intended duration of therapy, and (3) patients who were not included in either group 1 or 2. RESULTS: The rates of early virologic response, end of treatment response, and SVR differed significantly with the degree of adherence to the treatment. The SVRs of genotype 1 patients were 86.7%, 26.7%, and 66.7% in groups 1, 2, and 3, respectively (P=0.003), and those of genotype non-1 were 100%, 16.7%, and 88.9%, respectively (P<0.001). CONCLUSIONS: Adherence to therapy is a key factor in achieving an SVR. Supportive strategies to improve adherence will increase overall SVR rates. PMID- 19783885 TI - [A case of metastatic hepatocellular carcinoma of the rib, treated by transcatheter arterial chemoembolization]. AB - Bone is a common site of metastasis in patients with hepatocellular carcinoma (HCC). We report a rare case of rib metastasis from HCC treated by transcatheter arterial chemoembolization (TACE). A 55-year-old man with liver cirrhosis presented with right lower chest pain. The diagnosis was an HCC with a bone metastasis in the right eighth rib. Intra-arterial injections of doxorubicin mixed with Lipiodol and Gelfoam particles were instituted through the right eighth intercostal artery. Computed tomography and a Tc(99)-labeled scan performed 2 months after the third TACE revealed no viable HCC in the right eighth rib. PMID- 19783884 TI - [Comparison of the Model for End-stage Liver Disease and hepatic venous pressure gradient for predicting survival in patients with decompensated liver cirrhosis]. AB - BACKGROUND/AIMS: This study compared the prognostic values of the Model for End stage Liver Disease (MELD) and the hepatic venous pressure gradient (HVPG) in the prediction of death within 3 and 12 months in patients with decompensated liver cirrhosis. METHODS: We used data from 136 consecutive patients with decompensated cirrhosis who underwent HVPG between January 2006 and June 2008. Cox regression analysis was used to investigate the independent relationships with death of MELD and HVPG. The prognostic accuracies of MELD and HVPG were analyzed by calculating the area under the receiver operating characteristic curve (AUROC) for the occurrence of death within 3 and 12 months. RESULTS: Both MELD and HVPG were independent predictors of death [hazard ratio (HR)=1.11 and 1.12, respectively; 95% confidence interval (CI)=1.04~1.20 and 1.08-1.16]. Analysis of the AUROC demonstrated that the prognostic power did not differ between MELD and HVPG for predicting the 3-month survival (HR=0.76 and 0.68, respectively; 95% CI=0.62~0.89 and 0.52~0.84; P=0.22) or the 12-month survival (HR=0.72 and 0.73, 95% CI=0.61~0.83 and CI=0.61~0.84). CONCLUSIONS: Both MELD and HVPG are independent prognostic factors of death within 3 and 12 months in patients with decompensated liver cirrhosis, and their accuracies are similar. However, HVPG has a limited role in the prediction of death in decompensated cirrhosis due to its invasiveness and limited use. PMID- 19783886 TI - [Four patients with hepatitis A presenting with fulminant hepatitis and acute renal failure and who underwent liver transplantation]. AB - Hepatitis A is generally known as a mild, self-limiting disease of the liver, but in rare instances it can progress to fulminant hepatitis, which may require liver transplantation for recovery. Such cases are known to be related to old age and underlying liver disease. We report four cases of hepatitis A in which patients presented with fulminant hepatitis and acute renal failure and underwent liver transplantation. The following common features were observed in our cases: (1) occurrence in relatively old age (>/=39 years old), (2) association with acute renal failure, (3) presence of hepatomegaly, and (4) microscopic features of submassive hepatic necrosis. PMID- 19783887 TI - [A case of sudden-onset hearing loss in a patient treated with peginterferon alpha-2b and ribavirin for chronic hepatitis C]. AB - Combination therapy of pegylated interferon alpha and ribavirin has been associated with various adverse effects, but sudden-onset hearing loss is uncommon. We report a 60-year-old male patient who developed sudden-onset hearing loss during combination therapy with pegylated interferon alpha and ribavirin for chronic hepatitis C. This patient had been diagnosed with chronic hepatitis C (genotype Ib) and early-stage liver cirrhosis 3 years previously, and had been treated with conventional interferon-alpha and ribavirin for 12 months. However, 6 months from the end of the treatment course the patient relapsed and received combination retreatment with pegylated interferon alpha-2b and ribavirin. He developed sudden-onset right-side hearing loss and tinnitus 42 weeks after the start of this retreatment. Pure-tone audiometry revealed a right-side hearing loss of 60 approximately 90 dB. The patient consequently immediately discontinued the pegylated interferon therapy and was given prednisone 60 mg/day for 10 days, after which the hearing loss had almost completely recovered. PMID- 19783888 TI - [Large liver cell change/dysplasia in hepatitis B virus-related liver cirrhosis]. PMID- 19783889 TI - [Peliosis hepatis]. PMID- 19783891 TI - [Practice guidelines for management of hepatocellular carcinoma 2009]. AB - Hepatocellular carcinoma (HCC) is a major cancer in Korea, typically has a poor prognosis, and constitutes the majority of primary hepatic malignancies. It is the number one cause of death among people in their 50s in Korea. The five-year survival rate of liver cancer is poor; at 18.9%. Efforts to increase the survival rate through early diagnosis of HCC and optimal treatments are keenly needed. Western guideline for the management of HCC were developed, but these guidelines are somewhat unsuitable for Korean patients. Thus, the Korean Liver Cancer Study Group (KLCSG) and the National Cancer Center (NCC), Korea jointly produced the Clinical Practice Guidelines for HCC for the first time in Korea in 2003. Owing to medical advances over the following six years, diagnosis and treatment of HCC has changed considerably. As more national and foreign data are accumulated, KLCSG and NCC, Korea recently revised the Clinical Practice Guidelines for HCC. Forty or more specialists in the field of hepatology, general surgery, radiology and radiation oncology participated, and meticulously reviewed national and foreign papers, and collected opinions through advisory committee conferences. These multidisciplinary, evidence-based guidelines summarized diagnosis, surgical resection, liver transplantation, local treatments, transarterial chemoembolization, radiation therapy, chemotherapy, preemptive antiviral treatments, and response evaluation of HCC. These Korean guidelines are expected to be useful for clinical management of and research on HCC. PMID- 19783893 TI - Glucagon-like peptide-1 response to meals and post-prandial hyperglycemia in Type 2 diabetic patients. AB - BACKGROUND: The impaired response of glucagonlike peptide-1 (GLP-1) to meals in diabetic patients can contribute to the pathogenesis of impaired insulin secretion and post-prandial hyperglycemia. This study is aimed at the assessment of the relationship between meal-induced GLP-1 and post-prandial hyperglycemia in Type 2 diabetic patients. METHODS: Twenty-one drug-naive Type 2 diabetic patients were studied. Blood glucose and active GLP-1 levels were measured 0, 30, 60, 90, and 120 min after a standard test meal. A continuous glucose monitoring (CGM) system was applied for the following 3 days. Nutrient intake at each meal was calculated on the basis of patients' food records. For each patient, post prandial 120-min glucose incremental area under the curve (iAUC) was included in linear regression model exploring its relationship with total energy and carbohydrate intake, and the angular coefficient for total energy (EAC) and carbohydrate (CAC) was calculated. RESULTS: GLP-1 levels peaked 30 min after the test meal. Logarithmically transformed 60-min GLP-1 iAUC showed a significant inverse correlation with glycated hemoglobin (HbA1c) (p<0.01). A significant inverse correlation of 60-min GLP-1 iAUC was also observed with EAC and CAC (both p<0.01), meaning that patients with a lower GLP-1 response to the test meal had a higher increment of post-prandial glucose for each additional unit of total energy or carbohydrate intake. CONCLUSIONS: In Type 2 diabetic patients, a lower GLP-1 response to meals is associated with a higher HbA1c, and with a greater degree of meal-induced hyperglycemia, both in a meal test and during CGM in "real life" conditions. PMID- 19783894 TI - Peroxynitrite-induced protein nitration is responsible for renal mitochondrial damage in diabetic rat. AB - Oxidative stress, especially mediated by peroxynitrite (ONOO-), plays a key role in diabetes. Mitochondria, as the generating source of ONOO-, may also be the major damaging target of ONOO-. Whether ONOO--induced protein nitration is responsible for renal mitochondrial damage in diabetes is not fully known. This study was aimed to clarify the relationship between nitration of entire mitochondrial proteins induced by ONOO- and the renal mitochondrial damage in diabetes. Sprague-Dawley male rats were injected ip with streptozotocin to induce diabetes. After 10 weeks, inducible nitric oxide synthase (iNOS) mRNA expression and protein content in renal cortex were detected. Distribution of nitrotyrosine (NT), a specific marker of ONOO-, in renal cortex and NT content in mitochondrial proteins were detected. The ultrastructure of glomerulus was observed. Aminoguanidine was used as a selective inhibitor of iNOS to reduce the derivation of ONOO-. In diabetic rat, increasing levels of iNOS mRNA and protein content, and NT content were observed, in accord with the pathological alterations of glomerulus. In aminoguanidine group, these alterations were attenuated significantly. In conclusion, ONOO- could induce entire mitochondrial proteins nitration, responsible for the damage of renal mitochondria in diabetes. PMID- 19783895 TI - The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography whole body imaging in the evaluation of focal thyroid incidentaloma. AB - BACKGROUND: 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a non-invasive whole-body imaging technique used to evaluate various types of malignancies. Recent advances have rapidly developed it into a diagnostic imaging tool in oncology. OBJECTIVES: In this study, the prevalence of thyroid incidentaloma and its cancer risk rate were investigated by 18F-FDG PET/CT. The threshold of maximal standardized uptake value (SUVmax) for differentiation of benign and malignant tumors was also defined. METHODS: From June 2007 to December 2008, 3600 subjects underwent 18F-FDG PET/CT in our department. Among the population under study, 115 subjects developed focal increased 18F-FDG uptake as thyroid incidentalomas and their SUVmax were analyzed qualitatively and semi-quantitatively. RESULTS: Data from the 18F-FDG PET/CT study suggested that overall prevalence of thyroid incidentaloma was 3.2% (115/3580). Among the 96 incidentalomas (20 confirmed by surgery; 76 confirmed by fine-needle aspiration) with additional cyto- and histopathological diagnoses, 50% were malignant thyroid lesions. Therefore, the cancer risk of thyroid incidentaloma was 50%. SUVmax values of the malignant samples were significantly higher than those of benign (p=0.00, p<0.05). A SUVmax above 8 tended to be malignant. A significant correlation between SUVmax and maximal diameter of the thyroid incidentaloma was also indicated. CONCLUSIONS: Thyroid incidentaloma detected by 18FFDG PET/CT has higher risk rate for thyroid malignancy; SUVmax can be used for differentiating benign from malignant thyroid tumors. PMID- 19783896 TI - A multi-center, open label, crossover designed prospective study evaluating the effects of lipid lowering treatment on steroid synthesis in patients with Type 2 diabetes (MODEST Study). AB - OBJECTIVE: It has been suggested that lipid-lowering treatment with the use of statins adversely affects the steroid hormones. However, the safety of lipid lowering treatment targeting very low levels of LDL with respect to the steroid hormones has not been established. RESEARCH DESIGN AND METHODS: A prospective, randomized, multicenter trial was conducted involving 98 patients. The patients were randomized into 2 groups: group-I received 10 mg of atorvastatin plus 10 mg of ezetimibe and group-II 80 mg of atorvastatin for the first 3 months. After crossover, the first group received 80 mg of atorvastatin and the second group 10 mg of atorvastatin plus 10 mg of ezetimibe for the following 3 months. Cortisol, DHEAS, testosterone, and estradiol levels were measured at the enrollment and at the end of the 1st, 2nd, 3rd, and 6th months. RESULTS: Along with a decrease in LDL level, the levels of DHEAS, testosterone, and estradiol decreased in both groups (p<0.001). While cortisol levels were maintained in the group given 10 mg of atorvastatin plus 10 mg of ezetimibe, it decreased significantly after the crossover to 80 mg of atorvastatin (p<0.001). The group initially given 80 mg of atorvastatin measured a lower level of cortisol for the first 3 months and it returned to normal levels after switching to 10 mg of atorvastatin plus 10 mg of ezetimibe. CONCLUSION: Eighty milligrams of atorvastatin decreased all adrenal and gonadal steroids, whereas 10 mg of ezetimibe combined with 10 mg of atorvastatin had at least no impact on cortisol levels. PMID- 19783897 TI - Ancient drugs, modern targets. PMID- 19783898 TI - High level of AKT activity is associated with resistance to MEK inhibitor AZD6244 (ARRY-142886). AB - MEK/ERK activities are increased in many primary lung cancers, and MEK inhibitors have been tested clinically for treatment of non-small cell lung cancers. The molecular mechanisms of resistance to MEK inhibitors have not been clearly demonstrated, however, and no molecular biomarker that can predict lung cancer response to MEK inhibitors is available. By determining the dose-responses of 35 human lung cancer cell lines to MEK-specific inhibitor AZD6244, we identified subsets of lung cancer cell lines that are either sensitive or resistant to this agent. Subsequent molecular characterization showed that treatment with AZD6244 suppressed ERK phosphorylation in both sensitive and resistant cells, suggesting that resistance is not mediated by the activities of MEK/ERK themselves. Interestingly, we found that levels of phosphorylated AKT were dramatically higher in the resistant cancer cells than in the sensitive cells. Stable transfection of dominant-negative AKT into resistant cells by retroviral infection restored their susceptibility to AZD6244. These results indicate that phosphorylated AKT may be a biomarker of response to AZD6244 and that modulation of AKT activity may be a useful approach to overcome resistance to MEK inhibitors. PMID- 19783899 TI - Design and development of masked therapeutic antibodies to limit off-target effects: application to anti-EGFR antibodies. AB - Therapeutic antibodies frequently cause side effects by binding antigen in non target tissues. Here we demonstrate a novel molecular design of antibodies that addresses this problem by reversibly "masking" antibody complementarity determining regions until they reach diseased tissues containing disease associated proteases. Specifically, two distinct single-chain Fv (scFv) fragments derived from antibodies against the epidermal growth factor receptor (cetuximab and 425) were fused a protease susceptible linker to their epitopes, which were engineered to encourage intermolecular association. Surface plasmon resonance and flow cytometry were used to confirm that the masked complex poorly interacts with native antigen, whereas protease treatment restores antigen recognition. Minimally, the "masked" scFvs possesses an eight-fold lower association with the epitope compared with the individual scFvs unmasked by proteolytic cleavage. This molecular design may have general utility for targeted release of therapeutic antibodies at disease sites. PMID- 19783900 TI - The biology of hormone refractory breast and prostate cancer: An NCI workshop report. AB - The molecular regulation of growth and progression of hormone refractory breast and prostate cancers remains challenging. The Division of Cancer Biology, NCI organized a small "think tank" style workshop and invited scientists in relevant areas to assess the state of science on the biology of hormone refractory tumors and to identify potential research opportunities to enhance a better understanding of the molecular regulation of these tumors. The meeting, held on May 27-29, 2008 in Bethesda, MD, was co-chaired by Drs. Michael Geoffrey Rosenfeld and Michael Press. While expression of estrogen or progesterone receptors (ER/PR) is required for benefit from endocrine manipulations, many women with breast cancer will not respond to primary endocrine manipulations despite ER/PR expression, and others acquire resistance while on treatment. Understanding the mechanisms that lead to Hormone Refractory Breast Cancer (HRBC) and defining interventions that may modulate the resistance to endocrine therapy are currently lacking. In contrast to breast cancers, the vast majority of both early and advanced prostate carcinomas exhibit androgen-pathway activity at diagnosis and the vast majority respond to treatments designed to inhibit AR signaling. However, after initial benefit, advanced prostate cancers regularly progress to a clinical state termed Castration Resistant Prostate Cancer (CRPC) that reflects a diverse array of molecular events maintaining AR signaling. The workshop focused on both common and unique features of hormone refractory breast and prostate cancer with an orientation toward defining major research questions, delineating opportunities and recommending strategies for overcoming barriers to progress in understanding these important clinical disease states. PMID- 19783903 TI - Emerging role of Notch signaling in epidermal differentiation and skin cancer. AB - Signaling mediated by the Notch receptor governs tissue development during embryonal organogenesis, while in adult tissues it contributes to maintenance of cellular differentiation, proliferation and apoptosis. In addition, control by the Notch pathway of stem cell self-renewal and multi-potency points to an expanding role of Notch signaling in the progression of solid tumors. Notch and its ligands are abundantly expressed in the epidermis, where Notch signaling functions as a molecular switch that intervenes in cell transition between different skin layers during the epidermal differentiation process. More recent findings obtained in melanoma and non-melanoma skin cancers show that Notch signaling has a dual action (either as an oncogene or as a tumor suppressor), depending on the tumor cell type and the synchronous activation of other intracellular signaling mechanisms. In this Review, we highlight the pleiotropic roles of the Notch signaling pathway in normal skin homeostasis and differentiation and focus on its altered regulation in the tumorigenesis of melanoma and non-melanoma skin cancer. Further understanding of the roles of Notch signaling in specific skin cancer types may provide a rationale for novel Notch-based therapeutic strategies. PMID- 19783902 TI - Sp1 upregulates expression of TRF2 and TRF2 inhibition reduces tumorigenesis in human colorectal carcinoma cells. AB - EXPERIMENTAL DESIGN: Telomere repeat binding factor 2 (TRF2) plays a key role in the protective activity of telomere and is overexpression in several kinds of solid cancer cells. However, the role of overexpressed TRF2 in colorectal carcinoma remains unclear. The aim of this study was to determine the expression of TRF2, address the mechanism of TRF2 overexpression in human colorectal carcinoma. In present study, we examined the expression of TRF2 in colorectal cancer tissues from 39 patients, peritumoral normal tissues from 21 patients, and colon carcinoma SW480 cell line by quantitative PCR, immunohistochemistry and western blot. After siRNA silencing TRF2 expression in SW480, tumorigenesis of TRF2 was tested by cell proliferation, soft agar assay, cytofluorimetric analysis and cytogenetic analysis. To discover transcription factor that mediated TRF2 expression, Chromatin Immunoprecipitation (Chip) Assay and Electrophoretic mobility shift assays (EMSA) were employed. RESULTS: Overexpression of TRF2 protein was detected in SW480 cells and 19 of 39 colorectal carcinoma tissues (49%), no overexpression was observed in 21 of 21 adjacent peritumoral normal colorectal tissues. After siRNA silencing TRF2 expression, the proliferation and colony formation of SW480 cells were significantly inhibited. Defective TRF2 induced apoptosis and increased chromosomal instability in SW480 cells, in which there were more end-to-end fusions and ring chromosomes. Chip assay and EMSA showed that transcription factor Sp1 is involved in upregulation of TRF2. These results indicate that TRF2 is overexpressed in colorectal carcinoma, Sp1 upregulates TRF2 expression, TRF2 inhibition reduces tumorigenesis of colorectal cancer, which suggests that TRF2 and SP1 may become new targets for the development of anti-cancer therapy in colorectal carcinoma. PMID- 19783901 TI - Inhibition of KSHV-infected primary effusion lymphomas in NOD/SCID mice by gamma secretase inhibitor. AB - Primary effusion lymphoma (PEL) is a common cancer in AIDS patients closely associated with Kaposi's sarcoma-associated herpesvirus (KSHV). Previously, we showed that KSHV latency associated nuclear antigen (LANA) stabilizes intracellular activated Notch1 (ICN) involved in maintenance of the malignant phenotype of KSHV infected PEL cells in vitro. The gamma-secretase inhibitor (GSI) which specifically blocks the production of ICN slows down the proliferation of the KSHV infected PEL cell lines BCBL1, BC3 as well as JSC1 in vitro. In this study, we extended these studies to explore the possibility that manipulation of the Notch signaling by GSI would prevent the growth of the PEL tumors in vivo. We observed that the onset of tumorigenesis of KSHV infected PELs was significantly delayed in GSI treated SCID mice harboring the PEL cell lines. We also found that GSI treatment resulted in necrosis as well as apoptosis in tumors generated by the xenotransplanted KSHV positive PEL cell lines. In contrast, GSI had no effect on mice harboring BJAB cells, a KSHV negative Burkitt's lymphoma cell line where ICN levels were negligible. Our study provides further evidence to suggest that targeted downregulation of abnormal Notch signaling has therapeutic potential for KSHV related primary effusion lymphomas. PMID- 19783905 TI - A combined, rational approach towards inhibition of the MEK-ERK and mTOR pathways in pancreatic ductal adenocarcinoma: promise or deja vu? PMID- 19783906 TI - Triptolide: An inhibitor of a disintegrin and metalloproteinase 10 (ADAM10) in cancer cells. AB - Triptolide, a diterpene triepoxide derived from Trypterygium wilfordii, is documented to have antitumor activity in a broad range of solid tumors and leukemia. The mechanisms that are involved in triptolide-mediated apoptosis or growth inhibition in cancer cells are not fully understood. We identified a disintegrin and metalloproteinase 10 (ADAM10) as a novel molecular target of triptolide using affinity chromatography and mass spectrometry. The identification was confirmed by western blot analysis using an anti-ADAM10 antibody. The expression of ADAM10 is enhanced in several tumors including leukemia and is involved in malignant cell growth and cancer progression. ADAM10 is a type 1 transmembrane glycoprotein that cleaves several plasma membrane proteins. We show that triptolide, at concentrations in the nM range, resulted in a significant decrease in ADAM10 expression followed by the appearance of ADAM10 cleaved product. Furthermore, triptolide reduced the viability of monocytic leukemic U937 cells. Triptolide treatment of MCF-7 breast cancer cells expressing ectopic ADAM10 or dominant negative ADAM10 (DN ADAM10) resulted in a decreased expression of ADAM10 with a concomitant increase in ADAM10 cleaved products. Moreover, siRNA-mediated knockdown of ADAM10 mRNA significantly affected the growth of MCF-7 cells. Interestingly, the combination of siRNA-mediated knockdown of ADAM10 mRNA expression and triptolide treatment lead to a further reduction in cell growth. Taken together, we provide evidence that ADAM10 is a novel target of triptolide, presenting a novel strategy to inhibit ADAM10 activity in tumorigenesis. PMID- 19783904 TI - Roles of mitophagy and the mitochondrial permeability transition in remodeling of cultured rat hepatocytes. AB - In primary culture, hepatocytes dedifferentiate, and their cytoplasm undergoes remodeling. Here, our aim was to characterize changes of mitochondria during remodeling. Hepatocytes were cultured one to five days in complete serumcontaining Waymouth's medium. In rat hepatocytes loaded with MitoTracker Green (MTG), tetramethylrhodamine methylester (TMRM), and/or LysoTracker Red (LTR), confocal microscopy revealed that mitochondria number and mass decreased by approximately 50% between Day 1 and Day 3 of culture. As mitochondria disappeared, lysosomes/autophagosomes proliferated five-fold. Decreased mitochondrial content correlated with (a) decreased cytochrome c oxidase activity and mitochondrial number observed by electron microscopy and (b) a profound decrease of PGC-1alpha mRNA expression. By contrast, mtDNA content per cell remained constant from the first to the third day of culture, although ethidium bromide (de novo mtDNA synthesis inhibitor) caused mtDNA to decrease by half from the first to the third culture day. As mitochondria disappeared, their MTG label moved into LTR-labeled lysosomes, which was indicative of autophagic degradation. A multiwell fluorescence assay revealed a 2.5-fold increase of autophagy on Day 3 of culture, which was decreased by 3-methyladenine, an inhibitor of autophagy, and also by cyclosporin A and NIM811, both selective inhibitors of the mitochondrial permeability transition (MPT). These findings indicate that mitochondrial autophagy (mitophagy) and the MPT underlie mitochondrial remodeling in cultured hepatocytes. PMID- 19783907 TI - Minimized extracorporeal circulation cannot prevent acute kidney injury but attenuates early renal dysfunction after coronary bypass grafting. AB - We studied the impact of minimized extracorporeal circulation (MECC) on acute kidney injury (AKI) after coronary bypass grafting. A retrospective, observational study with 1,685 patients with MECC and 3,046 patients with conventional bypass was done. Primary outcome was AKI defined as a decline > or = 50% in estimated glomerular filtration rate (eGFR) within 48 hours after surgery. Secondary outcome was temporary dialysis. MECC exerts beneficial hemodynamic effects but does not prevent AKI. Fewer patients developed a decline in eGFR <60 mL/min/1.73 m(2) (MECC) compared with conventional extracorporeal circulation (ECC) (30.7% versus 45.5%, p < 0.001). The incidence of eGFR decrease by > or = 50% did not differ (1.8% versus 2.7%, p = 0.20). Temporary dialysis was required in 61 patients with ECC (2%) and in 16 patients with MECC (0.9%, p < 0.001). A preoperative eGFR <60 mL/min/1.73 m(2) increased in both groups the risk for mortality compared with patients with an eGFR >60 mL/min/1.73 m(2) (ECC: odds ratio 3.6, 95% confidence interval 2.6-4.9; MECC: odds ratio 4.9, 95% confidence interval 2.8-8.6). MECC is renoprotective in the early postoperative period but cannot prevent AKI. An impaired preoperative eGFR increases the risk for mortality irrespective of the cardiopulmonary bypass system used. PMID- 19783908 TI - Presidential address, 55th annual American Society for Artificial Internal Organs conference: conflicts of interest: eliminating bias and preserving trust in human subjects research. PMID- 19783911 TI - Solid state polyselenides and polytellurides: a large variety of Se-Se and Te-Te interactions. AB - A large variety of different interactions between the chalcogen atoms, Q, occur in the solid state structures of polyselenides and polytellurides, including both molecular and infinite units. The simplest motifs are classical Q(2)(2-) dumbbells and nonlinear Q(n)(2-) chains (n = 3, 4, 5, ..), e.g. found in alkali metal polychalcogenides. In addition, nonclassical so-called hypervalent motifs exist in the form of linear Q(3)(4-) units or within larger units such as Q(4)(4 ) and Q(5)(4-). Infinitely extended Q units include zigzag, cis/trans and linear chains, as well as planar and slightly puckered layers. Several of those are susceptible to Peierls distortions, leading to the formation of both commensurate and incommensurate superstructures and anomalies in transport properties, including metal-nonmetal transitions. PMID- 19783912 TI - Iodoarylation of arylalkynes with molecular iodine in the presence of hypervalent iodine reagents. AB - Iodoarylation of arylacetylenes was performed using a simple reagent system composed of molecular iodine and [bis(benzoyloxy)iodo]benzene. Most arylacetylenes efficiently underwent the iodoarylation reaction with electron rich arenes to give trans 1,1-diaryl-2-iodoethene adducts regio- and stereoselectively. As an exception, the iodoarylation of p-methoxyphenylacetylene resulted in a mixture of E- and Z-isomers of the corresponding product. PMID- 19783914 TI - Synthesis of novel 3,5-dichloro-2-arylpyridines by palladium acetate-catalyzed ligand-free Suzuki reactions in aqueous media. AB - A highly efficient palladium acetate-catalyzed ligand-free Suzuki reaction of 2,3,5-trichloropyridine with arylboronic acids in aqueous phase was developed. High yields of 3,5-dichloro-2-arylpyridines, a simple Pd source, absence of ligands, and environmentally benign as well as mild reaction conditions are important features of this method. PMID- 19783913 TI - Synthesis and antitumor activity of amino acid ester derivatives containing 5 fluorouracil. AB - A series of amino acid ester derivatives containing 5-fluorouracil were synthesized using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC*HCl) and N-hydroxybenzotriazole (HOBt) as a coupling agent. The structures of the products were assigned by NMR, MS, IR etc. The in vitro antitumor activity tests against leukaemia HL-60 and liver cancer BEL-7402 indicated that (R)-ethyl 2-(2-(5-fluoro-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)acetamido)-3-(4 hydroxyphenyl) propanoate showed more inhibitory effect against BEL-7402 than 5 FU. PMID- 19783915 TI - Intramolecular transformations of 3-cyanoamino- and 3-cyanoimino-1,2 diferrocenylcyclopropenes. AB - 3-Cyanoamino-1,2- and -2,3-diferrocenylcyclopropenes 6a,b and 11a,b prepared by the reaction of diferrocenylcyclopropenylium salts with sodium cyanamide undergo smooth intramolecular transformations with both conservation of the three membered ring [affording 3-cyanoimino-1,2-diferrocenylcyclopropene (8)] and its opening [affording Z-3-morpholino- and Z-3-piperidino-3-(cyanoimino)-1,2 diferrocenylprop-1-enes 7a,b and Z-3-cyanoimino-2,3-diferrocenyl-1-methylthioprop 1-ene (10)]. 3-Cyano-imino-1,2-diferrocenylcyclopropene (8) reacts with hydrazine to form 3-amino-6-ferrocenyl-5-ferrocenylmethyl-1,2,4-triazine (12) and Z-2,3 diferrocenylacrylohydrazide N-cyanoimide (13) as a result of intramolecular transformations. The structures of the compounds obtained were determined by IR, (1)H- and (13)C-NMR spectroscopy and mass spectrometry. The structures of compounds 7a and 10 were additionally confirmed by their X-ray diffraction analysis data. PMID- 19783916 TI - Synthesis and anti-human immunodeficiency virus type 1 activity of (E)-N phenylstyryl-N-alkylacetamide derivatives. AB - A series of (E)-N-phenylstyryl-N-alkylacetamides, 5, were synthesized by direct reduction-acetylation of beta-arylnitroolefins, followed by N-alkylation. The title compounds were characterized by (1)H-NMR, EIMS and IR analysis. All the synthesized compounds were assayed as HIV-1 non-nucleoside reverse transcriptase inhibitors. A SAR study revealed that when group R(1) in 5 was ortho-substituted, the resulting compounds showed better inhibitory activities against HIV-1 RT. Among the tested compounds, 5i (R(1) = 2-Br, R(2) = 3,5-difluorobenzyl) exhibited the highest enzyme activity, with a 88.89% inhibitory ratio against HIV-1 reverse transcriptase at the tested concentration. Further cell-based anti-HIV-1 assays showed that compound 5i exhibited a SI value of 29 with an EC(50) value of 4 microM in C8166 cells. PMID- 19783917 TI - Synthesis, ex vivo and in vitro hydrolysis study of an indoline derivative designed as an anti-inflammatory with reduced gastric ulceration properties. AB - The compound 1-(2,6-dichlorophenyl)indolin-2-one (1), planned as a pro-drug of diclofenac (2), was easily synthesized in 94% yield by an intramolecular reaction in the presence of coupling agent (i.e., EDC). Compound 1 showed anti inflammatory and analgesic activity without gastro-ulcerogenic effects. The chemical and enzymatic hydrolysis profile of the lactam derivative 1 does not indicate conversion to diclofenac (2). This compound is a new non-ulcerogenic prototype for treatment of chronic inflammatory diseases. PMID- 19783918 TI - Molecular docking studies and anti-snake venom metalloproteinase activity of Thai mango seed kernel extract. AB - Snakebite envenomations cause severe local tissue necrosis and the venom metalloproteinases are thought to be the key toxins involved. In this study, the ethanolic extract from seed kernels of Thai mango (Mangifera indica L. cv. 'Fahlun') (Anacardiaceae) and its major phenolic principle (pentagalloylglucopyranose) exhibited potent and dose-dependent inhibitory effects on the caseinolytic and fibrinogenolytic activities of Malayan pit viper and Thai cobra venoms in in vitro tests. molecular docking studies revealed that the binding orientations of the phenolic principles were in the binding pockets of snake venom metalloproteinases (SVMPs). The phenolic principles could form hydrogen bonds with the three histidine residues in the conserved zinc-binding motif and could chelate the Zn(2+) atom of the SVMPs, which could potentially result in inhibition of the venom enzymatic activities and thereby inhibit tissue necrosis. PMID- 19783919 TI - Vibrational spectra study of the interactions between Keggin heteropolyanions and amino acids. AB - A study of the effects of the interactions with amino acids on the vibrational spectra of Keggin heteropolyanions (Na(n)H(3-)n[XM(12)O(40)](n-); n = 0,1,2,3; X = P(V), Si(IV), M = W(VI), Mo(VI)) has been performed. Interactions occurred for all of the studied compounds leading to changes and splits in the stretching frequencies. Depending on the amino acid type, the IR bands for interbridge stretchings (M-O(b)-M) and terminal stretchings (M-O(d)) were affected. PMID- 19783920 TI - Conjugate addition of indoles to alpha,beta-unsaturated ketones using a Bronsted acid ionic liquid as an efficient catalyst. AB - The Bronsted acid ionic liquid [PyN(CH(2))(4)SO(3)H][p-CH(3)PhSO(3)] has been reported as an efficient catalyst for the Michael addition reaction of indoles to alpha,beta-unsaturated ketones. Satisfactory results were obtained, with excellent yields and a simple experimental procedure. The catalyst could be recycled and reused up to three times without any noticeable decrease in the catalytic activity. PMID- 19783921 TI - Theoretical studies of [2,3]-sigmatropic rearrangements of allylic selenoxides and selenimides. AB - Density-functional theory is used to model the endo and exo transition states for [2,3]-sigmatropic rearrangement of allylic aryl-selenoxides and -selenimides. The endo transition state is generally preferred for selenoxides if there is no substitution at the 2 position of the allyl group. Based upon the relative energies of the endo and exo transition states, enantioselectivity of rearrangements is expected to be greatest for molecules with substitutions at the 1- or (E)-3- position of the allyl group. Ortho substitution of a nitro group on the ancillary selenoxide phenyl ring reduces the activation barriers, increases the difference between the endo and exo activation barriers and shifts the equilibrium toward products. PMID- 19783923 TI - Antiproliferative, cytotoxic, antioxidant activity and polyphenols contents in leaves of four Staphylea L. species. AB - Staphylea has been used for long time in Traditional Chinese Medicine (TCM) and by Native Americans in a number of therapeutical indications. The present study describes in vitro antiproliferative, cytotoxic properties (MTT and LDH test) and antioxidant activities (reduction of DPPH radical and peroxynitrite radical) of Staphylea colchica Stev. (SC), S. elegans Zab. (SC), S. holocarpa Hemsl. (SH) and S. pinnata L. (SP) leave water extracts. Time- (24 and 72 h) and dose- (1-150 microg/mL) dependent effects of the above extracts were tested at the mitochondrial (MTT test) and plasma membrane level (LDH leakage) in A431 human skin carcinoma cells. Screening of these properties has shown time and dose dependent increase of harmful effects, the highest activity was observed for the SE, while the less active was the SH extract. The ED(50) values for the mitochondrial and membrane damage were nearly identical for the SE and very similar for SH extract. These findings indicate simultaneous injury of both cell compartments by SE and SH extracts. The highest antioxidant potential of SE species is accompanied by the highest content of flavones/flavonols and polyphenols. Only flavonoid contents are associated with antiproliferative effects and cell membrane injury, while antioxidant properties are the result of polyphenol content. The data clearly demonstrate that individual Staphylea L. species differ, not only in the amount of biologically active compounds, but also by the extent of harmful and beneficial effects. PMID- 19783922 TI - Protein turnover in mycobacterial proteomics. AB - Understanding the biology of Mycobacterium tuberculosis is one of the primary challenges in current tuberculosis research. Investigation of mycobacterial biology using the systems biology approach has deciphered much information with regard to the bacilli and tuberculosis pathogenesis. The modulation of its environment and the ability to enter a dormant phase are the hallmarks of M. tuberculosis. Until now, proteome studies have been able to understand much about the role of various proteins, mostly in growing M. tuberculosis cells. It has been difficult to study dormant M. tuberculosis by conventional proteomic techniques with very few proteins being found to be differentially expressed. Discrepancy between proteome and transcriptome studies lead to the conclusion that a certain aspect of the mycobacterial proteome is not being explored. Analysis of protein turnover may be the answer to this dilemma. This review, while giving a gist of the proteome response of mycobacteria to various stresses, analyzes the data obtained from abundance studies versus data from protein turnover studies in M. tuberculosis. This review brings forth the point that protein turnover analysis is capable of discerning more subtle changes in protein synthesis, degradation, and secretion activities. Thus, turnover studies could be incorporated to provide a more in-depth view into the proteome, especially in dormant or persistent cells. Turnover analysis might prove helpful in drug discovery and a better understanding of the dynamic nature of the proteome of mycobacteria. PMID- 19783924 TI - Carnitine conjugate of nipecotic acid: a new example of dual prodrug. AB - As a novel example of improved entry of poorly delivered drugs into the brain by means of nutrient conjugates, L-carnitine was conjugated to nipecotic acid and the capacity to antagonize PTZ-induced convulsions of this novel entity was evaluated. PMID- 19783925 TI - Conversion of natural aldehydes from Eucalyptus citriodora, Cymbopogon citratus, and Lippia multiflora into oximes: GC-MS and FT-IR analysis. AB - Three carbonyl-containing extracts of essential oils from Eucalyptus citriodora (Myrtaceae), Cymbopogon citratus (Gramineae) and Lippia multiflora (Verbenaceae) were used for the preparation of oximes. The reaction mixtures were analyzed by GC-MS and different compounds were identified on the basis of their retention times and mass spectra. We observed quantitative conversion of aldehydes to their corresponding oximes with a purity of 95 to 99%. E and Z stereoisomers of the oximes were obtained and separated by GC-MS. During GC analysis, the high temperature in the injector was shown to cause partial dehydratation of oximes and the resulting nitriles were readily identified. Based on FT-IR spectroscopy, that revealed the high stability and low volatility of these compounds, the so obtained oximes could be useful for future biological studies. PMID- 19783926 TI - Squalene emulsions for parenteral vaccine and drug delivery. AB - Squalene is a linear triterpene that is extensively utilized as a principal component of parenteral emulsions for drug and vaccine delivery. In this review, the chemical structure and sources of squalene are presented. Moreover, the physicochemical and biological properties of squalene-containing emulsions are evaluated in the context of parenteral formulations. Historical and current parenteral emulsion products containing squalene or squalane are discussed. The safety of squalene-based products is also addressed. Finally, analytical techniques for characterization of squalene emulsions are examined. PMID- 19783927 TI - Synthesis and pharmacological screening of several aroyl and heteroaroyl selenylacetic acid derivatives as cytotoxic and antiproliferative agents. AB - The synthesis and cytotoxic activity of a series of twenty six aroyl and heteroaroyl selenylacetic acid derivatives of general formula Ar-CO-Se-CH(2)-COOH or Heterar-CO-Se-CH(2)-COOH are reported. The synthesis was carried out by reaction of acyl chlorides with sodium hydrogen selenide, prepared in situ, and this led to the formation of sodium aroylselenides that subsequently reacted with alpha-bromoacetic acid to produce the corresponding selenylacetic acid derivatives. All of the compounds were tested against a prostate cancer cell line (PC-3) and some of the more active compounds were assessed against a panel of four human cancer cell lines (CCRF-CEM, HTB-54, HT-29, MCF-7) and one mammary gland-derived non-malignant cell line (184B5). Some of the compounds exhibited remarkable cytotoxic and antiproliferative activities against MCF-7 and PC-3 that were higher than those of the reference compounds doxorubicin and etoposide, respectively. For example, in MCF-7 when Ar = phenyl, 3,5-dimethoxyphenyl or benzyl the TGI values were 3.69, 4.18 and 6.19 microM. On the other hand, in PC-3 these compounds showed values of 6.8, 4.0 and 2.9 microM. Furthermore, benzoylselenylacetic acid did not provoke apoptosis nor did it perturb the cell cycle in MCF-7. PMID- 19783928 TI - A general synthesis of C8-arylpurine phosphoramidites. AB - A general scheme for the synthesis of C8-arylpurine phosphoramidites has been developed. C8-Arylation of C8-bromo-2'-deoxyguanosine is the key step and has been achieved through the use of a Suzuki coupling. Since the coupling reaction is conducted under aqueous conditions, it is unnecessary to protect and then deprotect the hydroxyl groups, thus saving several steps and improving overall yields. Once the C8-arylgroup is introduced, the glycosidic bond becomes very sensitive to acid catalyzed cleavage. Protection of the amino groups as the corresponding N,N-dimethylformamidine derivative improves stability of the derivatives. Synthetic C8-arylpurines were successfully used to prepare synthetic oligonucleotides. PMID- 19783929 TI - Tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP): efficient catalysts for the cyanosilylation and cyanocarbonation of aldehydes and ketones. AB - A variety of aldehydes and ketones were transformed to their corresponding cyanohydrin silyl ethers in good to excellent yields in the presence of 1-5 mol% of tris(2,4,6-trimethoxyphenyl)phosphine (TTMPP). Cyanohydrin carbonates were also readily prepared using 5-10 mol% of TTMPP as an organocatalyst. PMID- 19783930 TI - A new 4alpha-methylated sterol from a Nephthea sp. (Nephtheidae) Bornean soft coral. AB - A new 4alpha-methyl sterol, 4alpha-methyl-ergosta-6,8(14),22E-triene-3beta-ol (1), was isolated along with cholesterol from a Nephthea sp. Bornean soft coral The structure of compound 1 was elucidated on the basis of spectroscopic analysis and comparison of the data with those of the related compounds. PMID- 19783931 TI - Cesium carbonate-catalyzed alpha-phenylchalcogenation of carbonyl compounds with diphenyl dichalcogenide. AB - It was found that cesium carbonate has a unique catalytic ability on the reaction of carbonyl compounds with diphenyl diselenide to give the corresponding alpha phenylseleno carbonyl compounds in moderate to good yields. Similarly, the alpha phenylthiolation of carbonyl compounds with diphenyl disulfide was promoted by the cesium carbonate catalyst. PMID- 19783932 TI - Preparation and characterization of novel gellan gum hydrogels suitable for modified drug release. AB - Innovative hydrogels obtained by physical and chemical crosslinking of deacylated Gellan gum have been characterized in terms of water uptake, rheological properties and compressibility, and the behaviour of the tested materials, according to the type of the obtained network, is thoroughly discussed. The release from the various gels of loaded model molecules of different steric hindrance was also investigated and the trend of the release profiles has been related to the structures proposed for the physical and the chemical hydrogel. PMID- 19783934 TI - Fast and green microwave-assisted conversion of essential oil allylbenzenes into the corresponding aldehydes via alkene isomerization and subsequent potassium permanganate promoted oxidative alkene group cleavage. AB - Essential oil allylbenzenes from have been converted quickly and efficiently into the corresponding benzaldehydes in good yields by a two-step "green" reaction pathway based on a solventless alkene group isomerization by KF/Al(2)O(3) to form the corresponding 1-arylpropene and a subsequent solventless oxidation of the latter to the corresponding benzaldehyde by KMnO(4)/CuSO(4).5H(2)O. The assistance by microwave irradiation results in very short reaction times (<15 minutes). The green conversion of eugenol (4-allyl-2-methoxyphenol) into vanillin (4-hydroxy-3-methoxybenzaldehyde) has been carried out in a similar way, requiring however two additional microwave-assisted synthetic steps for acetylation of the hydroxy group prior to the oxidation reaction, and for the final deacetylation of vanillin acetate (4-acetoxy-3-methoxybenzaldehyde) by KF/Al(2)O(3) under solvent-free conditions, respectively. PMID- 19783933 TI - Identification of a benzamide derivative that inhibits stress-induced adrenal corticosteroid synthesis. AB - Elevated serum glucocorticoid levels contribute to the progression of many diseases, including depression, Alzheimer's disease, hypertension, and acquired immunodeficiency syndrome. Here we show that the benzamide derivative N-[2-(4 cyclopropanecarbonyl-3-methyl-piperazin-1-yl)-1-(tert-butyl-1H-indol-3-yl-methyl) 2-oxo-ethyl]-4-nitrobenzamide (SP-10) inhibits dibutyryl cyclic AMP (dbcAMP) induced corticosteroid synthesis in a dose-dependent manner in Y-1 adrenal cortical mouse tumor cells, without affecting basal steroid synthesis and reduced stress-induced corticosterone increases in rats without affecting the physiological levels of the steroid in blood. SP-10 did not affect cholesterol transport and metabolism by the mitochondria but was unexpectedly found to increase 3-hydroxy-3-methylglutaryl-coenzyme A, low density lipoprotein receptor, and scavenger receptor class B type I (SR-BI) expression. However, it also markedly reduced dbcAMP-induced NBD-cholesterol uptake, suggesting that this is a compensatory mechanism aimed at maintaining cholesterol levels. SP-10 also induced a redistribution of filamentous (F-) and monomeric (G-) actin, leading to decreased actin levels in the submembrane cytoskeleton suggesting that SP-10 induced changes in actin distribution might prevent the formation of microvilli cellular structures required for SRBI-mediated cholesterol uptake in adrenal cells. PMID- 19783935 TI - Microbial growth and quorum sensing antagonist activities of herbal plants extracts. AB - Antimicrobial and antiquorum sensing (AQS) activities of fourteen ethanolic extracts of different parts of eight plants were screened against four Gram positive, five Gram-negative bacteria and four fungi. Depending on the plant part extract used and the test microorganism, variable activities were recorded at 3 mg per disc. Among the Grampositive bacteria tested, for example, activities of Laurus nobilis bark extract ranged between a 9.5 mm inhibition zone against Bacillus subtilis up to a 25 mm one against methicillin resistant Staphylococcus aureus. Staphylococcus aureus and Aspergillus fumigatus were the most susceptible among bacteria and fungi tested towards other plant parts. Of interest is the tangible antifungal activity of a Tecoma capensis flower extract, which is reported for the first time. However, minimum inhibitory concentrations (MIC's) for both bacteria and fungi were relatively high (0.5-3.0 mg). As for antiquorum sensing activity against Chromobacterium violaceum, superior activity (>17 mm QS inhibition) was associated with Sonchus oleraceus and Laurus nobilis extracts and weak to good activity (8-17 mm) was recorded for other plants. In conclusion, results indicate the potential of these plant extracts in treating microbial infections through cell growth inhibition or quorum sensing antagonism, which is reported for the first time, thus validating their medicinal use. PMID- 19783936 TI - The use of MoStBioDat for rapid screening of molecular diversity. AB - MoStBioDat is a uniform data storage and extraction system with an extensive array of tools for structural similarity measures and pattern matching which is essential to facilitate the drug discovery process. Structure-based database screening has recently become a common and efficient technique in early stages of the drug development, shifting the emphasis from rational drug design into the probability domain of more or less random discovery. The virtual ligand screening (VLS), an approach based on high-throughput flexible docking, samples a virtually infinite molecular diversity of chemical libraries increasing the concentration of molecules with high binding affinity. The rapid process of subsequent examination of a large number of molecules in order to optimize the molecular diversity is an attractive alternative to the traditional methods of lead discovery. This paper presents the application of the MoStBioDat package not only as a data management platform but mainly in substructure searching. In particular, examples of the applications of MoStBioDat are discussed and analyzed. PMID- 19783938 TI - Physicochemical properties and antioxidant activities of luteolin-phospholipid complex. AB - A luteolin and phospholipid complex was prepared to improve the lipophilic properties of luteolin. The physicochemical properties of the complex were analyzed by ultraviolet-visible spectrometry (UV), infrared spectrometry (IR), X ray diffractometry (XRD) and differential scanning calorimetry (DSC). The results showed that luteolin and phospholipid in the complex were joined by non-covalent bonds and did not form a new compound. It was found that the complex was an effective scavenger of DPPH radicals, with an IC(50) value of 28.33 microg/mL. In the Rancimat antioxidant test using lard oil as substrate, the complex also showed the strong antioxidant activity. PMID- 19783939 TI - Synthesis and cytotoxicity of novel hexahydrothienocycloheptapyridazinone derivatives. AB - Designed as a new group of tricyclic molecules containing the thienocycloheptapyridazinone ring system, a number of 2N-substituted hexahydrothienocycloheptapyridazinone derivatives were synthesized and their biological activity evaluated. Among the synthesized compounds, derivatives 7d and 7h were found to possess cytotoxic activity against non-small cell lung cancer and central nervous system cancer cell lines, respectively. PMID- 19783940 TI - Mouse models targeting selenocysteine tRNA expression for elucidating the role of selenoproteins in health and development. AB - Selenium (Se) deficiency has been known for many years to be associated with disease, impaired growth and a variety of other metabolic disorders in mammals. Only recently has the major role that Se-containing proteins, designated selenoproteins, play in many aspects of health and development begun to emerge. Se is incorporated into protein by way of the Se-containing amino acid, selenocysteine (Sec). The synthesis of selenoproteins is dependent on Sec tRNA for insertion of Sec, the 21st amino acid in the genetic code, into protein. We have taken advantage of this dependency to modulate the expression of Sec tRNA that in turn modulates the expression of selenoproteins by generating transgenic, conditional knockout, transgenic/standard knockout and transgenic/conditional knockout mouse models, all of which involve the Sec tRNA gene, to elucidate the intracellular roles of this protein class. PMID- 19783941 TI - Ruthenium(III) chloride catalyzed acylation of alcohols, phenols, and thiols in room temperature ionic liquids. AB - Ruthenium(III) chloride-catalyzed acylation of a variety of alcohols, phenols, and thiols was achieved in high yields under mild conditions (room temperature) in the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate ([bmim][PF(6)]). The ionic liquid and ruthenium catalyst can be recycled at least 10 times. Our system not only solves the basic problem of ruthenium catalyst reuse, but also avoids the use of volatile acetonitrile as solvent. PMID- 19783937 TI - The vitamin nicotinamide: translating nutrition into clinical care. AB - Nicotinamide, the amide form of vitamin B(3) (niacin), is changed to its mononucleotide compound with the enzyme nicotinic acide/nicotinamide adenylyltransferase, and participates in the cellular energy metabolism that directly impacts normal physiology. However, nicotinamide also influences oxidative stress and modulates multiple pathways tied to both cellular survival and death. During disorders that include immune system dysfunction, diabetes, and aging-related diseases, nicotinamide is a robust cytoprotectant that blocks cellular inflammatory cell activation, early apoptotic phosphatidylserine exposure, and late nuclear DNA degradation. Nicotinamide relies upon unique cellular pathways that involve forkhead transcription factors, sirtuins, protein kinase B (Akt), Bad, caspases, and poly (ADP-ribose) polymerase that may offer a fine line with determining cellular longevity, cell survival, and unwanted cancer progression. If one is cognizant of the these considerations, it becomes evident that nicotinamide holds great potential for multiple disease entities, but the development of new therapeutic strategies rests heavily upon the elucidation of the novel cellular pathways that nicotinamide closely governs. PMID- 19783942 TI - Electrochemical reduction of coumarins at a film-modified electrode and determination of their levels in essential oils and traditional Chinese herbal medicines. AB - The electrochemical reduction of coumarins on glassy carbon and electrodeposited metal electrodes was investigated in a Britton-Robinson buffer (pH 1.87-11.98). The effects of various factors, such as the deposition material, time, and concentration of mercury, on the precision of the analysis were explored. The possible reaction mechanism of the reduction process with regards to scan rates, peak potentials, and currents is discussed. Electroreduction was used to quantitatively determine the levels of coumarins in some essential oils and traditional Chinese herbal medicines. A comparison with high performance liquid chromatography analysis results shows good agreement. PMID- 19783943 TI - Microwave-assisted solvent-free acetylation of cellulose with acetic anhydride in the presence of iodine as a catalyst. AB - In this work an optimization of the solvent-free acetylation of cellulose with acetic anhydride under microwave heating with iodine as a catalyst was performed. The optimized parameters included the microwave irradiation power from 300 W to 800 W, the reaction time between 5 to 40 min, the reaction temperature from 80 to 130 degrees C, and the amount of iodine from 1 to 15 mol%. The extent of the acetylation was measured by yield and the degree of substitution (DS), which was determined by a back-titration method. Acetylated cellulose was characterized by FT-IR, CP/MAS (13)C-NMR, WRXD, and thermogravimetric analysis. The results showed that within the range of catalyst amounts studied, the DS increased as the amount of iodine used increased, however, it was barely affected by microwave output. It was also found that the reaction time and temperature had an active influence on the extent of acetylation, however, this did not mean that at the higher temperature a better acetylation of cellulose would be obtained. The optimal reaction time and temperature found in this work were 30 min and 130 degrees C. PMID- 19783944 TI - Chemistry of the M (M=Fe, Ca, Ba)-Se-H(2)O systems at 25 degrees C. AB - The chemistry of the M (M=Fe, Ca, Ba)-Se-H(2)O systems at 25 degrees C is reviewed based on our previous papers. In this paper, the phase equilibria in the Fe(III)-Se(IV)-H(2)O, Ca-Se(IV,VI)-H(2)O and Ba-Se(IV,VI)-H(2)O systems at 25 degrees C are discussed. Then, the three-stage process for removal of selenium from industrial waste water [Se(IV,VI) < 1,500 mg/L] containing sulfuric acid was introduced. This seems to be a promising process for selenium removal from acidic sulfate waste water containing high concentration levels of selenium to below 0.1 mg/L. PMID- 19783945 TI - Development of a high-throughput assay for screening of gamma-secretase inhibitor with endogenous human, mouse or Drosophila gamma-secretase. AB - Selective lowering of amyloid-beta levels with small-molecule gamma-secretase inhibitors is a promising therapeutic approach for Alzheimer's disease. In this work, we developed a high throughput assay for screening of gamma-secretase inhibitors with endogenous gamma-secretase and a fluorogenic substrate. The IC(50) values of known gamma-secretase inhibitors generated with this method were comparable with reported values obtained by other methods. The assay was optimized and applied to a small-scale screening of 1,280 compounds. The discovery of several new inhibitors warrants further investigation. This assay was also proven to be easily adopted to test compounds for drosophila and mouse gamma-secretase, which could be very useful to assess compounds activity against gamma-secretase from different species before the in vivo test in animal models. PMID- 19783946 TI - Synthesis of a [2.2.2] cryptand containing reactive functional groups. AB - The functional group-containing potassium ionophore 19(5),24(5)-dibromo 4,7,13,16,20,23-hexaoxa-1,10-diaza-19(1,2),24(1,2) dibenzabicyclo[8.8.6]tetracosaphane has been synthesized. PMID- 19783947 TI - Microwave-assisted synthesis and crystal structure of oxo(diperoxo)(4,4'-di-tert butyl-2,2'-bipyridine)-molybdenum(VI). AB - The oxodiperoxo complex MoO(O2)(2)(tbbpy) (tbbpy = 4,4'-di-tert-butyl-2,2'- bipyridine) was isolated from the reaction of MoO2Cl(2)(tbbpy) in water under microwaveassisted heating at 120 masculineC for 4 h. The structure of the oxodiperoxo complex was determined by single crystal X-ray diffraction. The Mo(VI) centre is seven-coordinated with a geometry which strongly resembles a highly distorted bipyramid. Individual MoO(O2)(2)(tbbpy) complexes are interdigitated along the [010] direction to form a column. The crystal structure is formed by the close packing of the columnar-stacked complexes. Interactions between neighbouring columns are essentially of van der Waals type mediated by the need to effectively fill the available space. PMID- 19783949 TI - Adding chemical cross-links to a physical hydrogel. AB - Synergistic hydrogels are often encountered in polysaccharide mixtures widely used in food and biopharma products. The xanthan and konjac glucomannan pair provides one of the most studied synergistic hydrogels. Recently we showed that the junction zones stabilizing the 3D structure of this gel are present as macromolecular complexes in solution formed by the partially depolymerised polysaccharidic chains. The non-covalent interactions stabilizing the structure of the polysaccharidic complex cause the melting of the ordered structure of the complex in the solution and of the hydrogels. Introduction of chemical cross links in the 3D structure of the synergistic hydrogel removes this behaviour, adding new features to the swelling and to the viscoelastic properties of the cured hydrogel. The use of epichlorohydrin as low molecular weight cross-linker does not impact unfavourably on the viability of NIH 3T3 fibroblasts. PMID- 19783948 TI - Medicinal chemistry of Annonaceous acetogenins: design, synthesis, and biological evaluation of novel analogues. AB - Most Annonaceous acetogenins are characterized by between one and three THF ring(s) with one or two flanking hydroxyl group(s) in the center of a C32/34 fatty acid, and the terminal carboxylic acid is combined with a 2-propanol unit to form an alpha,beta-unsaturated gamma-lactone. While many studies have addressed the properties and synthesis of natural acetogenins due to their attractive biological activities and unique structural features, a number of analogues have also been described. This review covers the design, synthesis, and biological evaluation of acetogenin analogues. PMID- 19783950 TI - Synthesis and antifungal activity of 5-chloro-6-phenylpyridazin-3(2H)-one derivatives. AB - An effective method has been developed for the preparation under mild conditions of novel pyridazine derivatives from the easily accessible starting materials mucochloric acid and benzene. All the synthesized compounds were fully characterized and some of them displayed good antifungal activities against G. zeae, F. oxysporum and C. mandshurica in preliminary antifungal activity tests. PMID- 19783951 TI - Synthesis of novel asymmetric zinc (II) phthalocyanines bearing octadecyloxyl and glucosyl groups. AB - A novel asymmetric zinc (II) phthalocyanine substituted by one lipophilic octadecyloxyl group and three hydrophilic glucosyl groups was synthesized. Using Q-TOF MS, the major byproducts formed during the deprotection processes were identified. An improved procedure was worked out to convert these byproducts to the desired product in quantitative yield. PMID- 19783952 TI - A new cytotoxic 19-nor-cardenolide from the latex of Antiaris toxicaria. AB - A new nor-cardenolide, named toxicarioside H (1), was isolated from the latex of Antiaris toxicaria (Pers.) Lesch (Moraceae). Its structure was elucidated on the basis of HRFAB-MS and spectroscopic techniques (IR, UV, 1D and 2D NMR). Compound 1 showed significant cytotoxicity against K562, SGC-7901, SMMC-7721, and HeLa cell lines in vitro by MTT method. PMID- 19783953 TI - Theoretical study on exciton dynamics in dendritic systems: exciton recurrence and migration. AB - The optical functionalities such as exciton recurrence and migration for dendritic systems, e.g., dendrimers, are investigated using the quantum master equation (QME) approach based on the ab initio molecular orbital configuration interaction (MOCI) method, which can treat both the coherent and incoherent exciton dynamics at the first principle level. Two types of phenylacetylene dendrimers, Cayley-tree dendrimer and nanostar dendrimer with anthracene core, are examined to elucidate the features of excion recurrence and migration motions in relation to their structural dependences. It is found that the nanostar dendrimer exhibits faster exciton migration from the periphery to the core than Cayley-tree dendrimer, which alternatively exhibits exciton recurrence motion among dendron parts in case of small relaxation parameters. Such strong structural dependence of exciton dynamics demonstrates the advantage of dendritic molecular systems for future applications in nano-optical and light-harvesting devices. PMID- 19783954 TI - Carbosilane and carbosiloxane dendrimers. AB - This review focuses on novel carbosilane dendrimers containing branches with Si-C and Si-O-C bonds. Introduction of organic moieties into the dendrimers is performed by hydrosilation of carbon-carbon double/triple bonds. Versatile organic or organometallic moieties are introduced onto the peripheral regions of dendrimers by coupling and complexation reactions, which clearly demonstrates their potential for variation. PMID- 19783955 TI - Dendrimer-capped nanoparticles prepared by picosecond laser ablation in liquid environment. AB - Fifth generation ethylendiamine-core poly(amidoamine) (PAMAM G5) is presented as an efficient capping agent for the preparation of metal and semiconductor nanoparticles by ps laser ablation in water. In particular, we describe results obtained with the fundamental, second and third harmonic of a ps Nd:YAG laser and the influence of laser wavelength and pulse energy on gold particle production and subsequent photofragmentation. In this framework, the role of the dendrimer and, in particular, its interactions with gold clusters and cations are accounted. PMID- 19783956 TI - Nasal delivery of high molecular weight drugs. AB - Nasal drug delivery may be used for either local or systemic effects. Low molecular weight drugs with are rapidly absorbed through nasal mucosa. The main reasons for this are the high permeability, fairly wide absorption area, porous and thin endothelial basement membrane of the nasal epithelium. Despite the many advantages of the nasal route, limitations such as the high molecular weight (HMW) of drugs may impede drug absorption through the nasal mucosa. Recent studies have focused particularly on the nasal application of HMW therapeutic agents such as peptide-protein drugs and vaccines intended for systemic effects. Due to their hydrophilic structure, the nasal bioavailability of peptide and protein drugs is normally less than 1%. Besides their weak mucosal membrane permeability and enzymatic degradation in nasal mucosa, these drugs are rapidly cleared from the nasal cavity after administration because of mucociliary clearance. There are many approaches for increasing the residence time of drug formulations in the nasal cavity resulting in enhanced drug absorption. In this review article, nasal route and transport mechanisms across the nasal mucosa will be briefly presented. In the second part, current studies regarding the nasal application of macromolecular drugs and vaccines with nano- and micro-particulate carrier systems will be summarised. PMID- 19783957 TI - On the chemical stabilities of ionic liquids. AB - Ionic liquids are novel solvents of interest as greener alternatives to conventional organic solvents aimed at facilitating sustainable chemistry. As a consequence of their unusual physical properties, reusability, and eco-friendly nature, ionic liquids have attracted the attention of organic chemists. Numerous reports have revealed that many catalysts and reagents were supported in the ionic liquid phase, resulting in enhanced reactivity and selectivity in various important reaction transformations. However, synthetic chemists cannot ignore the stability data and intermolecular interactions, or even reactions that are directly applicable to organic reactions in ionic liquids. It is becoming evident from the increasing number of reports on use of ionic liquids as solvents, catalysts, and reagents in organic synthesis that they are not totally inert under many reaction conditions. While in some cases, their unexpected reactivity has proven fortuitously advantageous in others is has been a problem, it is imperative that when selecting an ionic liquid for a particular synthetic application, attention be paid to its compatibility with the reaction conditions. Even though, more than 200 room temperature ionic liquids are known, only a few reports have commented their effects on reaction mechanisms or rate/stability. Therefore, rather than attempting to give a comprehensive overview of ionic liquid chemistry, this review focuses on the non-innocent nature of ionic liquids, with a decided emphasis to clearly illuminate the ability of ionic liquids to affect the mechanistic aspects of some organic reactions thereby affecting and promoting the yield and selectivity. PMID- 19783958 TI - Heterocyclic analogs of thioflavones: synthesis and NMR spectroscopic investigations. AB - The synthesis of several hitherto unknown heterocyclic ring systems derived from thioflavone is described. Coupling of various o-haloheteroarenecarbonyl chlorides with phenylacetylene gives 1-(o-haloheteroaryl)-3-phenylprop-2-yn-1-ones, which were treated with NaSH in refluxing ethanol to yield the corresponding bi- and tricyclic annelated 2-phenylthiopyran-4-ones. Detailed NMR spectroscopic investigations of the ring systems and their precursors are presented. PMID- 19783959 TI - Amides from Piper capense with CNS activity - a preliminary SAR analysis. AB - Piper capense L.f. (Piperaceae) is used traditionally in South Africa as a sleep inducing remedy. Bioassay-guided fractionation of the roots of P. capense led to the isolation of piperine (1) and 4,5-dihydropiperine (2), which showed moderate affinity for the benzodiazepine site on the GABA(A) receptor (IC(50) values of 1.2 mM and 1.0 mM, respectively). The present study suggests that strict structural properties of the amides are essential for affinity. Taken together, these observations suggest that the carbon chain must contain not less than four carbons, and that a conjugated double bond, adjacent to the amide group, is necessary for binding to the receptor and that the amine part should be bulky. PMID- 19783960 TI - The effect of gadodiamide on cancer cell lines. AB - AIM: Recent literature suggests that some human cancer cell lines possess a calcium cation receptor. Human myeloma cell lines have demonstrated stimulated cell proliferation by the gadolinium cation through this receptor, and osteosarcoma cell lines possess the same cation receptor. Although enhanced MRI is a very useful diagnostic tool for the treatment of sarcoma in the orthopedic area, incorporating the use of MRI contrast agents based on gadolinium raises the possibility of the stimulation of cancer cell growth. METHODS: Human myeloma (RPMI 8226), osteosarcoma (Saos-2) and rat osteosarcoma (UMR-106) cell lines were exposed to various concentrations of common MRI contrast agent gadodiamide Omniscan (5 microM, 50 microM, 500 microM, 5 mM, 50 mM) in a culture medium. The response of the cells was then assessed by measuring cell proliferation and DNA synthesis. RESULTS: Treatment with 5 microM to 5 mM gadodiamide did not stimulate cell proliferation; only cells exposed to 50 mM gadodiamide showed suppressed proliferation rates. CONCLUSIONS: Since intravenously injected gadodiamide is diluted from 500 microM to 1 mM by patient blood flow at enhanced MRI examinations, the results of the present study suggest that gadodiamide has not effect on these types of cancer cells. PMID- 19783961 TI - Postoperative autovaccinotherapy for patients with gastric cancer and expression of some proteins in tumor tissue. AB - AIM: To study the efficacy of autovaccine in the treatment of gastric cancer and significance of molecular factors having prognostic values for disease outcome to evaluate its efficacy in clinical setting. PATIENTS AND METHODS: 150 patients with histologically proven adenocarcinoma of the stomach of stages II, III or IV were enrolled into study. 86 patients have been treated with autovaccine (AV) after operation. Expression of p53, Bcl-2, receptors of tyrosine kinase, vascular endothelial growth factor (VEGF), capital IE, Cyrillic-cadherin, alpha-catenin and beta-catenin was determined in paraffin embedded tumor samples by means of immunohistochemical method with the use of respective monoclonal antibodies. RESULTS: It was shown that application of AV has resulted in the increase of 3 year overall survival of patients having stage III of disease by more than 30%, but those having stage IV - only around 14%. The increase of 3-year overall survival of patients with metastases in lymph nodes (N1-2) was observed also in more than 30%. It has been suggested the optimal phenotype for vaccine application: small er, Cyrillic53(+), EGFR(+), HER-2 neu (+), beta-catenin (+), VEGF(+) and Bcl-2(+) with no dependence on E-cadherin and alpha-catenin presence. CONCLUSION: It was determined that the best effect of AV application is observed in patients with category capital TE, Cyrillic3-4, poorly-differentiated tumors, metastases in lymph nodes (N1-2), but without distant metastases (capital EM, Cyrillic0). Gastric cancer patients with p53, EGFR, HER-2/neu, beta-catenin, VEGF and Bcl-2-positive tumors are the favorable group for the treatment with AV in the adjuvant regime. PMID- 19783962 TI - Vascular endothelial growth factor exression in uterine cervical cancer: correlation with clinicopathologic characteristics and survival. AB - AIM: This retrospective study was performed to determine the vascular endothelial growth factor (VEGF) expression in cervical cancer cells, and to examine its correlation with clinicopathologic characteristics and survival of patients. METHODS: Seventy-five paraffinembedded primary tumors were stained immunohistochemically for VEGF expression, which was analysed semiquantitatively. RESULTS: The significant correlation between VEGF expression and stages of disease, as well as pelvic lymph node metastasis was observed. There were determined a negative correlations between VEGF expression in tumor cells and both overall and disease-free survival. CONCLUSION: VEGF expression in human cervical cancer may be used as a diagnostic parameter in the clinic. Our results are in accordance with literature data showing association of VEGF overexpression in tumor with a poorer patient survival. PMID- 19783963 TI - DNA double strand breaks repair and apoptosis induction in peripheral blood lymphocytes of head and neck cancer patients. AB - AIM: To evaluate the generation and repair of DNA double strand breaks (DSBs) as a critical factors that define the efficiency of radiation therapy of cancer patients. METHODS: Peripheral blood lymphocytes obtained from 18 patients with head and neck squamous cell carcinoma (HNSCC) and 18 healthy donors were studied. The efficiency of DSBs repair after genotoxic treatment with hydrogen peroxide and gamma-radiation were examined by neutral comet assay. MTT assay was used for cell viability analysis and Annexin V-FITC kit specific for kinase-3 was employed to determine apoptosis. RESULTS: Lymphocytes from HNSCC patients were sensitive to genotoxic treatment and displayed impaired DSBs repair. Finally, as a consequence of this finding we have evidenced higher rate of apoptosis induction after gamma-radiation treatment of lymphocytes from HNSCC patients than those from healthy controls. CONCLUSIONS: DSBs repair and increased apoptosis in cells of patients with head and neck cancer is relevant for efficient therapy of HNSCC. PMID- 19783964 TI - The use of nanoferromagnetics to increase the cytotoxic effect of antitumor drugs. AB - AIM: To investigate the influence of ferromagnetic nanoparticles on antitumor effect of doxorubicin and mitochondria oxidative phosphorylation. METHODS: The study was carried out on the mice-hybrids (C57Bl/6xDBA/2) with intraperitoneally (i/p) transplantated Ehrlich ascitic carcinoma. Single i/p injection of doxorubicin (Dox), stabilized ferromagnetic nanoparticles (Fe3O4; 20-40 nm; FM) or their combination were performed 7 days after tumor transplantation. The cytotoxic effect of agents, morphology and cell cycle of tumor cells were studied 24, 48 and 72 h after Dox administration. RESULTS: The investigations showed that ferromagnetic nanoparticles increased the cytotoxic effect of doxorubicin on Ehrlich ascsmall i, Ukrainiantic carcinoma mainly 48 h after agents' administration. The largest number of apoptotic cells was observed in group of animals in which doxorubicin was administered before ferromagnetic nanoparticles. Moreover, the ferromagnetic nanoparticles at concentration 1.45 microg Fe/ml and, particularly, 7.25 microg Fe/ml decreased mitochondria oxygen consumption in phosphorylation state that may negatively influence their living capability. CONCLUSIONS: Obtained data point out the perspective of use of certain sized FM nanoparticles to increase the cytotoixc effect of antitumor drugs. PMID- 19783965 TI - Platinum nanocolloid-supplemented hydrogendissolved water inhibits growth of human tongue carcinoma cells preferentially over normal cells. AB - AIM: Hydrogen-dissolved water (HD-water) or platinum nanocolloid (Pt-nc) has been individually expected as a new therapeutic agent for oxidative stress-related diseases, whereas little is known about their combined effects on cancer, which were elucidated in the present study. METHODS: HD-water was prepared by microporous gas bubbling, and supplemented with Pt-nc consisting of 0.003-1 ppm Pt and PVP polymers. Antioxidant activities were examined by 1, 1-diphenyl picrylhydrazyl (DPPH)-radicalscavenging assay. Cytotoxic activities were examined by culturing of tumor and normal cell lines, respectively. RESULTS: HD-water accelerated the Pt-nc-based DPPH-radical scavenging. Pt-nc-supplemented HD-water inhibited either colony formation efficiencies or colony sizes of human tongue carcinoma cells HSC-4, in contrast to no effects of HD-water alone, Pt-nc alone or Pt-absent PVP, but not appreciably inhibit normal human tongue epithelial-like cells DOK. Pt-nc-supplemented HD-water also suppressed cell population growth of HSC-4 cells of near-confluence (at higher cell densities) in view of decreases in either cell numbers or mitochondrial function, although less markedly than colony formation starting from a sparse-cell state (at lower cell densities). Dissolved hydrogen, oxygen concentration or oxido-reduced potentials of HD-water was decreased, rather decreased or increased by Pt-nc addition, respectively. CONCLUSIONS: Anti-cancer activity of Pt-nc-supplemented HD-water was shown by its preferential cell-growth inhibition to human tongue carcinoma cells HSC-4 over normal human tongue cells DOK, and might be partly attributed to HD-water-caused enhancement of Pt-nc-relevant antioxidant ability. Pt-nc-supplemented HD-water is expected as a novel agent against human tongue cancers due to its cancer progression-repressive abilities. PMID- 19783966 TI - Antineoplastic effects of nutrient mixture on raji and jurkat t cells: the two highly aggressive non Hodgkin's lymphoma cell lines. AB - Non-Hodgkin lymphomas incidence has increased more than 70% in last 25 years. Aggressiveness, higher relapse rate, and treatment complications pose significant barriers. Decreased food intake and side effects of treatments make cancer patients vulnerable to deficiency of essential nutrients such as vitamin C, lysine, and proline leading to the formation of weak extra cellular matrix susceptible to easy breakdown by matrix metalloproteinase enzymes. Inhibition of these enzymes has shown promise in stopping metastasis. AIM: In this study, we investigated the effects of a specific nutrient mixture, containing ascorbic acid, lysine, proline, green tea extract among others, in most aggressive forms of non-Hodgkin's lymphoma - Burkitt's lymphoma, and T-cell lymphoma - using Raji and Jurkat cells respectively. METHODS: Nutrient mixture (NM) doses of 0, 10, 50, 100, 500, 1000 microg/ml, were used to study effects on cell proliferation, expression of matrix metalloproteinase, Matrigel invasion and apoptosis. RESULTS: The results demonstrated that the dose response toxicity of the nutrient mixture on Raji cells gradually increased with increasing concentration. The nutrient mixture was non-toxic to Jurkat cells, however exhibited anti-proliferative properties at higher concentrations. Zymography demonstrated, NM had a significant inhibitory effect on matrix metalloproteinase-9 expression with total inhibition at 1000 microg/ml for Raji cells and at 500 microg/ml for Jurkat cells. The NM at 100 microg/ml completely inhibited Matrigel invasion for Raji cells, and at 1000 microg/ml for Jurkat cells. After the NM challenge virtually all Raji and Jurkat cells exposed to 1000 microg/ml were in late apoptosis. CONCLUSION: Considering the lack of treatment options and continually increasing incidence, NM could be further explored for its therapeutic potential in Burkitt's lymphoma and T-cell lymphoma. PMID- 19783967 TI - In vivo anti-tumor activities of gelatin. AB - AIM: As reported previously, porcine skin gelatin exerted direct anti-tumor effect in vitro and induced anti-tumor peritoneal macrophages in vitro. The present study investigated whether or not the gelatin exerted anti-tumor effect in vivo. METHODS: In vitro anti-tumor activities of peritoneal macrophages and the gelatin were evaluated with tritium thymidine uptake by target tumor cells. In vivo anti-tumor activity was evaluated with the survival of tumor-bearing animals and the size of the tumor. RESULTS: Intraperitoneal daily administration of 12.5 mg of the gelatin prolonged the survival of mice which had been intraperitoneally inoculated with MH134 (hepatic cell carcinoma cell line) or Colon 26 (colon carcinoma cell line) tumor cells, and there were no tumors in case of MH134 cells inoculation. Intraperitoneal daily administration of 12.5 mg of the gelatin did not affect growth of subcutaneous MH134 tumor. The gelatin administered subcutaneously did not affect the survival of mice with intraperitoneal MH134 tumor. On the other hand, bovine skin gelatin administered subcutaneously achieved statistically significant prolongation of the survival. The contact of MH134 cells with porcine skin gelatin for 5 min was required for the gelatin to exert its anti-tumor activity in vitro. Porcine skin gelatin of 12.5 mg injected intraperitoneally was detected as protein in the peritoneal cavity 5 min after the injection. Peritoneal macrophages elicited by intraperitoneal injection with porcine skin gelatin suppressed tritium thymidine uptake by MH134 cells more strongly than those elicited by thioglycollate injection. CONCLUSION: Porcine skin gelatin administered intraperitoneally prolonged the survival of tumor-bearing mice via activation of peritoneal macrophages and involvement of direct anti-tumor activity of porcine skin gelatin. Key Words: porcine skin, gelatin, dissemination. PMID- 19783968 TI - Molecular profile and cell cycle in MCF-7 and MCF-7/Dox cells exposed to conventional and liposomal forms of doxorubicin. AB - AIM: To compare the molecular profile and cell cycle of sensitive and resistant to doxorubicin MCF-7 breast cancer cells upon exposition to conventional or liposome-encapsulated forms of doxorubicin. METHODS: capital EM, Cyrilliccapital TE, Cyrilliccapital TE, Cyrillic-test, immunocytochemistry, flow cytometry. RESULTS: In sensitive MCF-7 cells the exposure to conventional but not liposomal form of doxorubicin decreased metallothionein (MT) expression demonstrating activation of MT-detoxification system. In doxorubicin-resistant cells (MCF 7/Dsmall o, Cyrillicsmall ha, Cyrillic) MT expression drastically decreased. Conventional but not liposomal form of doxorubicin reduced the levels of expression of steroid hormones receptors on MCF-7 sensitive cells. The exposure of MCF-7 cells to conventional form of doxorubicin resulted in the decrease of p53 expression and the increase of Bcl-2 expression. In MCF-7/Dsmall o, Cyrillicsmall ha, Cyrillic cells neither conventional nor liposomal form of doxorubicin altered Bcl-2 expression. The exposure of MCF-7 but not MCF-7/Dsmall o, Cyrillicsmall ha, Cyrillic to doxorubicin in conventional form caused cell cycle arrest in G0/G1. Upon exposure to doxorubicin in liposomal form, cell cycle blockage in G0/G1 phase was observed in both sensitive and resistant sublines. CONCLUSION: The differential effects of the conventional and liposomal forms of doxorubicin in sensitive and resistant cells have been demonstrated. Exposure of MCF-7 and MCF-7/Dsmall o, Cyrillicsmall ha, Cyrillic cells to doxorubicin in liposomal form alters the molecular profile and cell distribution over cell cycle phases. PMID- 19783969 TI - Helicobacter pylori infection of gastric cancer cells elevates the level of expression and activation of protein kinase D2. AB - AIM: To test the hypothesis, whether H. pylori infection may affect the level of PKD2 expression and/or activation in gastric cancer cells. METHODS: Studies were performed on AGS human gastric adenocarcinoma cell line, gastric tissues samples from 36 cases of different histological variants of gastric cancer. Immunohistochemical, cell and molecular biology, bacteriological and biochemical approaches have been used in this study. RESULTS: H. pylori 16S rRNA gene was detected in 97% cases of gastric tumors, and in 83% of cases csmall a, CyrillicgA gene was detected. In all tested adenocarcinoma samples cagA+ H. pylori was revealed. These cases were characterized by high level of PKD1/2 expression and autophosphorylation. In adenogenic cancer samples the presence of cagA- H. pylori was identified. Carcinoid and nondifferentiated gastric cancers contain H. pylori, with very low numbers of cagA+ copies. All cases of gastric tumors with cagA- H. pylori had very low levels of PKD1/2 autophosphorylation. AGS cell line infection with cagA- and cagA+ H. small er, Cyrillicylori resulted in elevation of PKD2 expression levels in 3.29 and 3.66 times respectively (p < 0.001). In cells infected by cag+ H. small er, Cyrillicylori the level of PKD2 transphosphorylation was 1.39 higher than in cells infected by cagA- H. pylori. For PKD2 autophosphorylation this difference was even higher - 3.27 times (p < 0.001). CONCLUSION: H. pylori infection enhanced the level of protein kinase D2 expression, trans- and autophosphorylation. The level of PKD2 autophosphorylation/activation was higher in AGS cell line inoculated of with cag+ H. pylori than in AGS cells with cagA- H. pylori. These suggest that H. pylori induces activation of PKD1/2 and could exploit PKD2 mediated signaling pathways that may contribute to the pathogenesis of gastric cancer. PMID- 19783970 TI - Ribonucleases in tumor growth. AB - This review summarizes data on ambiguous biological functions of ribonucleases (RNases) at tumor growth. In some cases the raised level of enzyme activity in biological fluids can be regarded as an additional marker of malignant growth (pancreas cancer, chronic myeloid leukemia, etc.). At the same time the activity of RNases is often lowered in tumor tissue. High substrate specificity of particular RNases provides metabolic balance between various kinds of RNAs with various half-time exchange turn. RNases are the important factors of epigenetic regulation of gene activity in cells. The activity of RNases is adjustable by inhibitors and other factors, and defines time of existence of different kinds of RNAs. RNases (the modified variants of RNase A, RNases of semen fluid of the cattle, RNase of amphibia oocytes) can be used as anti-tumor therapeutic agents. On the other hand, some inhibitors of RNases of natural or synthetic origin were demonstrated to be perspective drugs that inhibit tumor growth. PMID- 19783971 TI - Stroma -- regulator of cancer cell progression. PMID- 19783972 TI - Microsurgical clip obliteration of middle cerebral aneurysm using intraoperative flow assessment. AB - Cerebral aneurysms are abnormal widening or ballooning of a localized segment of an intracranial blood vessel. Surgical clipping is an important treatment for aneurysms which attempts to exclude blood from flowing into the aneurysmal segment of the vessel while preserving blood flow in a normal fashion. Improper clip placement may result in residual aneurysm with the potential for subsequent aneurysm rupture or partial or full occlusion of distal arteries resulting in cerebral infarction. Here we describe the use of an ultrasonic flow probe to provide quantitative evaluation of arterial flow before and after microsurgical clip placement at the base of a middle cerebral artery aneurysm. This information helps ensure adequate aneurysm reconstruction with preservation of normal distal blood flow. PMID- 19783973 TI - Ensuring data integrity. PMID- 19783975 TI - A night vision neuron gets a day job. PMID- 19783976 TI - Regional control of cortical lamination. PMID- 19783977 TI - Calcium: an insignificant thing. PMID- 19783978 TI - TR(I)Pping towards treatment for ischemia. PMID- 19783979 TI - Six degrees of separation: the amygdala regulates social behavior and perception. PMID- 19783980 TI - JAK2 phosphorylates histone H3Y41 and excludes HP1alpha from chromatin. AB - Activation of Janus kinase 2 (JAK2) by chromosomal translocations or point mutations is a frequent event in haematological malignancies. JAK2 is a non receptor tyrosine kinase that regulates several cellular processes by inducing cytoplasmic signalling cascades. Here we show that human JAK2 is present in the nucleus of haematopoietic cells and directly phosphorylates Tyr 41 (Y41) on histone H3. Heterochromatin protein 1alpha (HP1alpha), but not HP1beta, specifically binds to this region of H3 through its chromo-shadow domain. Phosphorylation of H3Y41 by JAK2 prevents this binding. Inhibition of JAK2 activity in human leukaemic cells decreases both the expression of the haematopoietic oncogene lmo2 and the phosphorylation of H3Y41 at its promoter, while simultaneously increasing the binding of HP1alpha at the same site. Tauhese results identify a previously unrecognized nuclear role for JAK2 in the phosphorylation of H3Y41 and reveal a direct mechanistic link between two genes, jak2 and lmo2, involved in normal haematopoiesis and leukaemia. PMID- 19783981 TI - A role for a neo-sex chromosome in stickleback speciation. AB - Sexual antagonism, or conflict between the sexes, has been proposed as a driving force in both sex-chromosome turnover and speciation. Although closely related species often have different sex-chromosome systems, it is unknown whether sex chromosome turnover contributes to the evolution of reproductive isolation between species. Here we show that a newly evolved sex chromosome contains genes that contribute to speciation in threespine stickleback fish (Gasterosteus aculeatus). We first identified a neo-sex chromosome system found only in one member of a sympatric species pair in Japan. We then performed genetic linkage mapping of male-specific traits important for reproductive isolation between the Japanese species pair. The neo-X chromosome contains loci for male courtship display traits that contribute to behavioural isolation, whereas the ancestral X chromosome contains loci for both behavioural isolation and hybrid male sterility. Our work not only provides strong evidence for a large X-effect on reproductive isolation in a vertebrate system, but also provides direct evidence that a young neo-X chromosome contributes to reproductive isolation between closely related species. Our data indicate that sex-chromosome turnover might have a greater role in speciation than was previously appreciated. PMID- 19783982 TI - MgZnCa glasses without clinically observable hydrogen evolution for biodegradable implants. AB - Corrosion is normally an undesirable phenomenon in engineering applications. In the field of biomedical applications, however, implants that 'biocorrode' are of considerable interest. Deploying them not only abrogates the need for implant removal surgery, but also circumvents the long-term negative effects of permanent implants. In this context magnesium is an attractive biodegradable material, but its corrosion is accompanied by hydrogen evolution, which is problematic in many biomedical applications. Whereas the degradation and thus the hydrogen evolution of crystalline Mg alloys can be altered only within a very limited range, Mg based glasses offer extended solubility for alloying elements plus a homogeneous single-phase structure, both of which may alter corrosion behaviour significantly. Here we report on a distinct reduction in hydrogen evolution in Zn rich MgZnCa glasses. Above a particular Zn-alloying threshold (approximately 28 at.%), a Zn- and oxygen-rich passivating layer forms on the alloy surface, which we explain by a model based on the calculated Pourbaix diagram of Zn in simulated body fluid. We document animal studies that confirm the great reduction in hydrogen evolution and reveal the same good tissue compatibility as seen for crystalline Mg implants. Thus, the glassy Mg(60+x)Zn(35-x)Ca5 (0 < or = x < or = 7) alloys show great potential for deployment in a new generation of biodegradable implants. PMID- 19783983 TI - Histone H3 methylation links DNA damage detection to activation of the tumour suppressor Tip60. AB - DNA double-strand break (DSB) repair involves complex interactions between chromatin and repair proteins, including Tip60, a tumour suppressor. Tip60 is an acetyltransferase that acetylates both histones and ATM (ataxia telangiectasia mutated) kinase. Inactivation of Tip60 leads to defective DNA repair and increased cancer risk. However, how DNA damage activates the acetyltransferase activity of Tip60 is not known. Here, we show that direct interaction between the chromodomain of Tip60 and histone H3 trimethylated on lysine 9 (H3K9me3) at DSBs activates the acetyltransferase activity of Tip60. Depletion of intracellular H3K9me3 blocks activation of the acetyltransferase activity of Tip60, resulting in defective ATM activation and widespread defects in DSB repair. In addition, the ability of Tip60 to access H3K9me3 is dependent on the DNA damage-induced displacement of HP1beta (heterochromatin protein 1beta) from H3K9me3. Finally, we demonstrate that the Mre11-Rad50-Nbs1 (MRN) complex targets Tip60 to H3K9me3, and is required to activate the acetyltransferase activity of Tip60. These results reveal a new function for H3K9me3 in coordinating activation of Tip60-dependent DNA repair pathways, and imply that aberrant patterns of histone methylation may contribute to cancer by altering the efficiency of DSB repair. PMID- 19783984 TI - Interactions between lipids and voltage sensor paddles detected with tarantula toxins. AB - Voltage-activated ion channels open and close in response to changes in voltage, a property that is essential for generating nerve impulses. Studies on voltage activated potassium (Kv) channels show that voltage-sensor activation is sensitive to the composition of lipids in the surrounding membrane. Here we explore the interaction of lipids with S1-S4 voltage-sensing domains and find that the conversion of the membrane lipid sphingomyelin to ceramide-1-phosphate alters voltage-sensor activation in an S1-S4 voltage-sensing protein lacking an associated pore domain, and that the S3b-S4 paddle motif determines the effects of lipid modification on Kv channels. Using tarantula toxins that bind to paddle motifs within the membrane, we identify mutations in the paddle motif that weaken toxin binding by disrupting lipid-paddle interactions. Our results suggest that lipids bind to voltage-sensing domains and demonstrate that the pharmacological sensitivities of voltage-activated ion channels are influenced by the surrounding lipid membrane. PMID- 19783985 TI - High-resolution structure of the rotor ring of a proton-dependent ATP synthase. AB - The crystal structure of the c-ring from the proton-coupled F1Fo ATP synthase from Spirulina platensis is shown at 2.1-A resolution. The ring includes 15 membrane-embedded c subunits forming an hourglass-shaped assembly. The structure demonstrates that proton translocation across the membrane entails protonation of a conserved glutamate located near the membrane center in the c subunit outer helix. The proton is locked in this site by a precise hydrogen bond network reminiscent of that in Na+-dependent ATP synthases. However, the structure suggests that the different coordination chemistry of the bound proton and the smaller curvature of the outer helix drastically enhance the selectivity of the H+ site against other cations, including H3O+. We propose a model for proton translocation whereby the c subunits remain in this proton-locked state when facing the membrane lipid. Proton exchange would occur in a more hydrophilic and electrostatically distinct environment upon contact with the a subunit interface. PMID- 19783986 TI - The execution of the transcriptional axis mutant p53, E2F1 and ID4 promotes tumor neo-angiogenesis. AB - ID4 (inhibitor of DNA binding 4) is a member of a family of proteins that function as dominant-negative regulators of basic helix-loop-helix transcription factors. Growing evidence links ID proteins to cell proliferation, differentiation and tumorigenesis. Here we identify ID4 as a transcriptional target of gain-of-function p53 mutants R175H, R273H and R280K. Depletion of mutant p53 protein severely impairs ID4 expression in proliferating tumor cells. The protein complex mutant p53-E2F1 assembles on specific regions of the ID4 promoter and positively controls ID4 expression. The ID4 protein binds to and stabilizes mRNAs encoding pro-angiogenic factors IL8 and GRO-alpha. This results in the increase of the angiogenic potential of cancer cells expressing mutant p53. These findings highlight the transcriptional axis mutant p53, E2F1 and ID4 as a still undefined molecular mechanism contributing to tumor neo-angiogenesis. PMID- 19783987 TI - In vivo RNAi screening identifies regulators of actin dynamics as key determinants of lymphoma progression. AB - Mouse models have markedly improved our understanding of cancer development and tumor biology. However, these models have shown limited efficacy as tractable systems for unbiased genetic experimentation. Here, we report the adaptation of loss-of-function screening to mouse models of cancer. Specifically, we have been able to introduce a library of shRNAs into individual mice using transplantable Emu-myc lymphoma cells. This approach has allowed us to screen nearly 1,000 genetic alterations in the context of a single tumor-bearing mouse. These experiments have identified a central role for regulators of actin dynamics and cell motility in lymphoma cell homeostasis in vivo. Validation experiments confirmed that these proteins represent bona fide lymphoma drug targets. Additionally, suppression of two of these targets, Rac2 and twinfilin, potentiated the action of the front-line chemotherapeutic vincristine, suggesting a critical relationship between cell motility and tumor relapse in hematopoietic malignancies. PMID- 19783988 TI - Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitis. AB - Regulatory T cells (T(reg) cells) that express the transcription factor Foxp3 suppress the activity of other cells. Here we show that interleukin 10 (IL-10) produced by CD11b(+) myeloid cells in recombination-activating gene 1-deficient (Rag1(-/-)) recipient mice was needed to prevent the colitis induced by transferred CD4(+)CD45RB(hi) T cells. In Il10(-/-)Rag1(-/-) mice, T(reg) cells failed to maintain Foxp3 expression and regulatory activity. The loss of Foxp3 expression occurred only in recipients with colitis, which indicates that the requirement for IL-10 is manifested in the presence of inflammation. IL-10 receptor-deficient (Il10rb(-/-)) T(reg) cells also failed to maintain Foxp3 expression, which suggested that host IL-10 acted directly on the T(reg) cells. Our data indicate that IL-10 released from myeloid cells acts in a paracrine manner on T(reg) cells to maintain Foxp3 expression. PMID- 19783989 TI - Interactions between PD-1 and PD-L1 promote tolerance by blocking the TCR-induced stop signal. AB - Programmed death 1 (PD-1) is an inhibitory molecule expressed on activated T cells; however, the biological context in which PD-1 controls T cell tolerance remains unclear. Using two-photon laser-scanning microscopy, we show here that unlike naive or activated islet antigen-specific T cells, tolerized islet antigen specific T cells moved freely and did not swarm around antigen-bearing dendritic cells (DCs) in pancreatic lymph nodes. Inhibition of T cell antigen receptor (TCR)-driven stop signals depended on continued interactions between PD-1 and its ligand, PD-L1, as antibody blockade of PD-1 or PD-L1 resulted in lower T cell motility, enhanced T cell-DC contacts and caused autoimmune diabetes. Blockade of the immunomodulatory receptor CTLA-4 did not alter T cell motility or abrogate tolerance. Thus, PD-1-PD-L1 interactions maintain peripheral tolerance by mechanisms fundamentally distinct from those of CTLA-4. PMID- 19783990 TI - Chemokine CXCL13 is essential for lymph node initiation and is induced by retinoic acid and neuronal stimulation. AB - The location of embryonic lymph node development is determined by the initial clustering of lymphoid tissue-inducer (LTi) cells. Here we demonstrate that both the chemokine CXCL13 and the chemokine CCL21 attracted LTi cells at embryonic days 12.5-14.5 and that initial clustering depended exclusively on CXCL13. Retinoic acid (RA) induced early CXCL13 expression in stromal organizer cells independently of lymphotoxin signaling. Notably, neurons adjacent to the lymph node anlagen expressed enzymes essential for RA synthesis. Furthermore, stimulation of parasymphathetic neural output in adults led to RA receptor (RAR) dependent induction of CXCL13 in the gut. Therefore, our data show that the initiation of lymph node development is controlled by RA-mediated expression of CXCL13 and suggest that RA may be provided by adjacent neurons. PMID- 19783991 TI - Chemical genomics in Escherichia coli identifies an inhibitor of bacterial lipoprotein targeting. AB - One of the most significant hurdles to developing new chemical probes of biological systems and new drugs to treat disease is that of understanding the mechanism of action of small molecules discovered with cell-based small-molecule screening. Here we have assembled an ordered, high-expression clone set of all of the essential genes from Escherichia coli and used it to systematically screen for suppressors of growth inhibitory compounds. Using this chemical genomic approach, we demonstrate that the targets of well-known antibiotics can be identified as high copy suppressors of chemical lethality. This approach led to the discovery of MAC13243, a molecule that belongs to a new chemical class and that has a unique mechanism and promising activity against multidrug-resistant Pseudomonas aeruginosa. We show that MAC13243 inhibits the function of the LolA protein and represents a new chemical probe of lipoprotein targeting in bacteria with promise as an antibacterial lead with Gram-negative selectivity. PMID- 19783992 TI - Unmasking the tonic-aversive state in neuropathic pain. AB - Tonic pain has been difficult to demonstrate in animals. Because relief of pain is rewarding, analgesic agents that are not rewarding in the absence of pain should become rewarding only when there is ongoing pain. We used conditioned place preference to concomitantly determine the presence of tonic pain in rats and the efficacy of agents that relieve it. This provides a new approach for investigating tonic pain in animals and for evaluating the analgesic effects of drugs. PMID- 19783993 TI - CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. AB - The mechanisms that determine how information is allocated to specific regions and cells in the brain are important for memory capacity, storage and retrieval, but are poorly understood. We manipulated CREB in a subset of lateral amygdala neurons in mice with a modified herpes simplex virus (HSV) and reversibly inactivated transfected neurons with the Drosophila allatostatin G protein coupled receptor (AlstR)/ligand system. We found that inactivation of the neurons transfected with HSV-CREB during training disrupted memory for tone conditioning, whereas inactivation of a similar proportion of transfected control neurons did not. Whole-cell recordings of fluorescently tagged transfected neurons revealed that neurons with higher CREB levels are more excitable than neighboring neurons and showed larger synaptic efficacy changes following conditioning. Our findings demonstrate that CREB modulates the allocation of fear memory to specific cells in lateral amygdala and suggest that neuronal excitability is important in this process. PMID- 19783994 TI - Transitions in infant learning are modulated by dopamine in the amygdala. AB - Behavioral transitions characterize development. Young infant rats paradoxically prefer odors that are paired with shock, but older pups learn aversions. This transition is amygdala and corticosterone dependent. Using microarrays and microdialysis, we found downregulated dopaminergic presynaptic function in the amygdala with preference learning. Corticosterone-injected 8-d-old pups and untreated 12-d-old pups learned aversions and had dopaminergic upregulation in the amygdala. Dopamine injection into the amygdala changed preferences to aversions, whereas dopamine antagonism reinstated preference learning. PMID- 19783995 TI - Dual roles for hepatic lectin receptors in the clearance of chilled platelets. AB - Rapid chilling causes glycoprotein-Ib (GPIb) receptors to cluster on blood platelets. Hepatic macrophage beta(2) integrin binding to beta-N acetylglucosamine (beta-GlcNAc) residues in the clusters leads to rapid clearance of acutely chilled platelets after transfusion. Although capping the beta-GlcNAc moieties by galactosylation prevents clearance of short-term-cooled platelets, this strategy is ineffective after prolonged refrigeration. We report here that prolonged refrigeration increased the density and concentration of exposed galactose residues on platelets such that hepatocytes, through Ashwell-Morell receptor binding, become increasingly involved in platelet removal. Macrophages rapidly removed a large fraction of transfused platelets independent of their storage conditions. With prolonged platelet chilling, hepatocyte-dependent clearance further diminishes platelet recovery and survival after transfusion. Inhibition of chilled platelet clearance by both beta(2) integrin and Ashwell Morell receptors may afford a potentially simple method for storing platelets in the cold. PMID- 19783996 TI - Inhibition of the c-Abl-TAp63 pathway protects mouse oocytes from chemotherapy induced death. AB - Germ cells are sensitive to genotoxins, and ovarian failure and infertility are major side effects of chemotherapy in young patients with cancer. Here we describe the c-Abl-TAp63 pathway activated by chemotherapeutic DNA-damaging drugs in model human cell lines and in mouse oocytes and its role in cell death. In cell lines, upon cisplatin treatment, c-Abl phosphorylates TAp63 on specific tyrosine residues. Such modifications affect p63 stability and induce a p63 dependent activation of proapoptotic promoters. Similarly, in oocytes, cisplatin rapidly promotes TAp63 accumulation and eventually cell death. Treatment with the c-Abl kinase inhibitor imatinib counteracts these cisplatin-induced effects. Taken together, these data support a model in which signals initiated by DNA double-strand breaks are detected by c-Abl, which, through its kinase activity, modulates the p63 transcriptional output. Moreover, they suggest a new use for imatinib, aimed at preserving oocytes of the follicle reserve during chemotherapeutic treatments. PMID- 19784000 TI - The challenges of caring for twins discordant for anomalies. PMID- 19784001 TI - Congenital tuberculosis as a proxy to maternal tuberculosis: a case report. AB - The diagnosis of congenital tuberculosis (TB) is often difficult as clinical signs are nonspecific. The maternal history of TB therefore remains an important tool in the diagnosis of congenital TB. In this case report, we present a patient with congenital TB, whose diagnosis was delayed because the mother was asymptomatic and there was a delay in eliciting a family history of TB. This highlights the importance of obtaining a detailed history on admission. PMID- 19784002 TI - Congenital Central Hypoventilation syndrome (Ondine's curse): prenatal diagnosis and fetal breathing characteristics. AB - We report a case of Congenital Central Hypoventilation syndrome (CCHS), diagnosed in utero at 18 weeks' gestation analysis of repeats in the PHOX2b gene in fetal amniocytes and confirmed at delivery. Prenatal diagnosis allowed for serial detailed assessment of fetal breathing characteristics. Fetal breathing in this affected fetus was indistinguishable from breathing characteristics in the non affected fetus. PMID- 19784003 TI - Congenital collision tumors, neonatal renal mesoblastic nephroma and pararenal paraganglioma. PMID- 19784004 TI - Angiofibrolipoma of the spermatic cord. PMID- 19784005 TI - Effect of hydrocele on appendix testis in children. AB - The purpose of this study was to investigate the effects of an elevated hydrostatic pressure of hydrocele on the structural integrity and steroid receptor expression pattern of the appendix testis in children. Twenty-six testicular appendages were obtained from boys (aged between 13 and 79 months, mean 40 months) who underwent surgical exploration because of hydrocele or congenital inguinal hernia. The tissue sections of testicular appendages were stained with hematoxylin-eosin. Immunohistochemistry and immunofluorescence laser microscopy were performed using monoclonal mouse anti-human receptors against androgen and estrogen receptors. Patients were divided into three groups: group A (n = 8) represented patients with groin hernia without hydrocele, who served as control group; group B (n = 7) represented patients with communicating hydrocele; and group C (n = 11) represented patients with noncommunicating hydrocele. The tissue sections of appendix testis expressed both androgen and estrogen receptors in all patients in groups A and B, and epithelial destruction was not present. The presence of androgen receptor (two of 11, P < 0.001) and estrogen receptor (four of 11, P = 0.006) was lower and the number of appendix testes with epithelial destruction was higher (eight of 11, P = 0.001) in group C. We demonstrated that groin hernia and communicating hydrocele did not influence the receptor expression pattern and the anatomic structure of testicular appendages, whereas noncommunicating hydrocele caused damage as indicated by the absence of steroid receptors and destruction of the epithelial surface. A better understanding of the physiological role of testicular appendages may change the indications of surgical treatment in patients with noncommunicating hydrocele. PMID- 19784006 TI - Abstracts from the XXIVth International Symposium on Cerebral Blood Flow and Metabolism and the IXth International Conference on Quantification of Brain Function with PET. Chicago, Illinois, USA. June 29-July 3, 2009. PMID- 19784068 TI - Genetic inactivation of ApoJ/clusterin: effects on prostate tumourigenesis and metastatic spread. AB - ApoJ/Clusterin (CLU) is a heterodimeric protein localized in the nucleus, cytoplasm or secretory organelles and involved in cell survival and neoplastic transformation. Its function in human cancer is still highly controversial. In this study, we examined the prostate of mice in which CLU has been genetically inactivated. Surprisingly, we observed transformation of the prostate epithelium in the majority of CLU knockout mice. Either PIN (prostate intraepithelial neoplasia) or differentiated carcinoma was observed in 100 and 87% of mice with homozygous or heterozygous deletion of CLU, respectively. Crossing CLU knockout with TRAMP (prostate cancer prone) mice results in a strong enhancement of metastatic spread. Finally, CLU depletion causes tumourigenesis in female TRAMP mice, which are normally cancer free. Mechanistically, deletion of CLU induces activation of nuclear factor-kB, a potentially oncogenic transcription factor important for the proliferation and survival of prostate cells. PMID- 19784067 TI - Heterogeneous SWI/SNF chromatin remodeling complexes promote expression of microphthalmia-associated transcription factor target genes in melanoma. AB - The microphthalmia-associated transcription factor (MITF) promotes melanocyte differentiation and cell-cycle arrest. Paradoxically, MITF also promotes melanoma survival and proliferation, acting like a lineage survival oncogene. Thus, it is critically important to understand the mechanisms that regulate MITF activity in melanoma cells. SWI/SNF chromatin remodeling enzymes are multiprotein complexes composed of one of two related ATPases, BRG1 or BRM, and 9-12-associated factors (BAFs). We previously determined that BRG1 interacts with MITF to promote melanocyte differentiation. However, it was unclear whether SWI/SNF enzymes regulate the expression of different classes of MITF target genes in melanoma. In this study, we characterized SWI/SNF subunit expression in melanoma cells and observed downregulation of BRG1 or BRM, but not concomitant loss of both ATPases. Re-introduction of BRG1 in BRG1-deficient SK-MEL5 cells enhanced expression of differentiation-specific MITF target genes and resistance to cisplatin. Downregulation of the single ATPase, BRM, in SK-MEL5 cells inhibited expression of both differentiation-specific and pro-proliferative MITF target genes and inhibited tumorigenicity in vitro. Our data suggest that heterogeneous SWI/SNF complexes composed of either the BRG1 or BRM subunit promote expression of distinct and overlapping MITF target genes and that at least one ATPase is required for melanoma tumorigenicity. PMID- 19784069 TI - Chemotherapy induces NEDP1-mediated destabilization of MDM2. AB - MDM2 is an E3 ligase that promotes ubiquitin-mediated destruction of p53. Cellular stresses such as DNA damage can lead to p53 activation due in part to MDM2 destabilization. Here, we show that the stability of MDM2 is regulated by an ubiquitin-like NEDD8 pathway and identify NEDP1 as a chemotherapy-induced isopeptidase that deneddylates MDM2, resulting in MDM2 destabilization concomitant with p53 activation. Concordantly, RNAi-mediated knockdown of endogenous NEDP1 blocked diminution of MDM2 levels and increased chemoresistance of tumor cells. These findings unveil the regulation of MDM2 stability through NEDP1 as a common molecular determinant governing chemotherapy-induced p53 dependent cell death. PMID- 19784070 TI - PAUF functions in the metastasis of human pancreatic cancer cells and upregulates CXCR4 expression. AB - Pancreatic cancer is characterized by early metastatic spread, but the process of tumor cell dissemination is largely unknown. In this study we show that the soluble protein pancreatic adenocarcinoma upregulated factor (PAUF) has an important role in the metastasis and progression of the disease. Variations in the level of PAUF, either by overexpression or knockdown, resulted in altered migration, invasion and proliferation capacity of pancreatic cancer cells. Moreover, depletion of PAUF in metastatic cells dramatically abrogated the spread of the cells to distant organs in an orthotopic xenograft mouse model. PAUF elicited the activation of the extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK) and AKT intracellular signaling cascades and consequently their downstream transcription factors in an autocrine manner. Genome-wide expression analysis revealed that C-X-C chemokine receptor type 4 (CXCR4) expression was induced by PAUF overexpression but was repressed by PAUF knockdown. The PAUF-mediated increase in cancer cell motility was attenuated by the CXCR4 inhibitor, AMD3100, or by anti-CXCR4 antibody. Furthermore, immunohistochemical analysis of pancreatic tumor tissues clearly showed a significant positive correlation between PAUF and CXCR4 expression. Collectively, these findings indicate that PAUF enhances the metastatic potential of pancreatic cancer cells, at least in part, by upregulating CXCR4 expression. PMID- 19784071 TI - The Sonic Hedgehog pathway stimulates prostate tumor growth by paracrine signaling and recapitulates embryonic gene expression in tumor myofibroblasts. AB - The Hedgehog (Hh) pathway contributes to prostate cancer growth and progression. The presence of robust Sonic Hedgehog (Shh) expression in both normal prostate and localized cancer challenged us to explain the unique growth-promoting effect in cancer. We show here that paracrine Hh signaling exerts a non-cell autonomous effect on xenograft tumor growth and that Hh pathway activation in myofibroblasts alone is sufficient to stimulate tumor growth. Nine genes regulated by Hh in the mesenchyme of the developing prostate were found to be regulated in the stroma of Hh overexpressing xenograft tumors. Correlation analysis of gene expression in matched specimens of benign and malignant human prostate tissue revealed a partial five-gene fingerprint of Hh-regulated expression in stroma of all cancers and the complete nine-gene fingerprint in the subset of tumors exhibiting a reactive stroma. No expression fingerprint was observed in benign tissues. We conclude that changes in the prostate stroma due to association with cancer result in an altered transcriptional response to Hh that mimics the growth promoting actions of the fetal mesenchyme. Patients with an abundance of myofibroblasts in biopsy tissue may comprise a subgroup that will exhibit a particularly good response to anti-Hh therapy. PMID- 19784073 TI - Genomic amplification and oncogenic properties of the GASC1 histone demethylase gene in breast cancer. AB - Earlier, mapping of the 9p23-24 amplicon in esophageal cancer cell lines led us to the positional cloning of gene amplified in squamous cell carcinoma 1 (GASC1), which encodes a nuclear protein with a Jumonji C domain that catalyzes lysine (K) demethylation of histones. However, the transforming roles of GASC1 in breast cancer remain to be determined. In this study, we identified GASC1 as one of the amplified genes for the 9p23-24 region in breast cancer, particularly in basal like subtypes. The levels of GASC1 transcript expression were significantly higher in aggressive, basal-like breast cancers compared with nonbasal-like breast cancers. Our in vitro assays demonstrated that GASC1 induces transformed phenotypes, including growth factor-independent proliferation, anchorage independent growth, altered morphogenesis in Matrigel, and mammosphere forming ability, when overexpressed in immortalized, nontransformed mammary epithelial MCF10A cells. Additionally, GASC1 demethylase activity regulates the expression of genes critical for stem cell self-renewal, including NOTCH1, and may be linked to the stem cell phenotypes in breast cancer. Thus, GASC1 is a driving oncogene in the 9p23-24 amplicon in human breast cancer and targeted inhibition of GASC1 histone demethylase in cancer could provide potential new avenues for therapeutic development. PMID- 19784074 TI - Successful first-line treatment with double umbilical cord blood transplantation in severe aplastic anemia. PMID- 19784072 TI - Downregulation of E-cadherin is an essential event in activating beta-catenin/Tcf dependent transcription and expression of its target genes in Pdcd4 knockdown cells. AB - We reported earlier that knockdown of tumor suppressor Pdcd4 (programed cell death 4) downregulates E-cadherin expression and activates beta-catenin/Tcf (T cell factor)-dependent transcription in colon tumor cells. However, the underlying mechanism of these observations remains unknown. In this study, we showed that knockdown of Pdcd4 downregulates E-cadherin expression through elevated protein level of Snail. Over-expression of Pdcd4 upregulates E-cadherin expression and inhibits beta-catenin/Tcf-dependent transcription. We then showed that knockdown of E-cadherin activates beta-catenin/Tcf-dependent transcription. Conversely, over-expression of E-cadherin in Pdcd4 knockdown cells inhibits beta catenin/Tcf-dependent transcription. In addition, Pdcd4 knockdown stimulates urokinase-type plasminogen activator receptor (u-PAR) and c-Myc expression, whereas u-PAR and c-Myc expression can be reversed by over-expressing E-cadherin in Pdcd4 knockdown cells. Using chromatin immunoprecipitation, we showed that beta-catenin/Tcf4 directly binds to the promoters of u-PAR and c-myc in Pdcd4 knockdown cells. Futhermore, knockdown of u-PAR or c-Myc inhibits invasion in Pdcd4 knockdown cells, suggesting that both u-PAR and c-Myc contribute to invasion induced by Pdcd4 knockdown. Taken together, our data showed that elevated Snail expression by Pdcd4 knockdown leads to downregulation of E cadherin resulting in activating beta-catenin/Tcf-dependent transcription and stimulating the expression of c-Myc and u-PAR, thus providing molecular explanation of how Pdcd4 suppresses tumor invasion. PMID- 19784075 TI - Long-term results of rituximab treatment for membranous nephropathy after allogeneic hematopoietic SCT: a case report. PMID- 19784076 TI - Multicenter validation study of a transplantation-specific cytogenetics grouping scheme for patients with myelodysplastic syndromes. AB - Cytogenetics is an important prognostic factor for patients with myelodysplastic syndromes (MDS). However, existing cytogenetics grouping schemes are based on patients treated with supportive care, and may not be optimal for patients undergoing allo-SCT. We proposed earlier an SCT-specific cytogenetics grouping scheme for patients with MDS and AML arising from MDS, based on an analysis of patients transplanted at the Dana-Farber Cancer Institute/Brigham and Women's Hospital. Under this scheme, abnormalities of chromosome 7 and complex karyotype are considered adverse risk, whereas all others are considered standard risk. In this retrospective study, we validated this scheme on an independent multicenter cohort of 546 patients. Adverse cytogenetics was the strongest prognostic factor for outcome in this cohort. The 4-year relapse-free survival and OS were 42 and 46%, respectively, in the standard-risk group, vs 21 and 23% in the adverse group (P<0.0001 for both comparisons). This grouping scheme retained its prognostic significance irrespective of patient age, disease type, earlier leukemogenic therapy and conditioning intensity. Therapy-related disease was not associated with increased mortality in this cohort, after taking cytogenetics into account. We propose that this SCT-specific cytogenetics grouping scheme be used for patients with MDS or AML arising from MDS who are considering or undergoing SCT. PMID- 19784077 TI - The clinical importance of bronchoalveolar lavage in allogeneic SCT patients with pneumonia. AB - Patients who undergo allogeneic hematopoietic SCT (HSCT) are prone to pulmonary infections. Between 1998 and 2004, a total of 450 patients underwent HSCT at Karolinska University Hospital, Huddinge. Pneumonia was diagnosed in 167 patients (37%), including 42 children. Bronchoalveolar lavage (BAL) was performed on 68 occasions in 57 patients (six children). In 110 patients (36 children) with pneumonia, BAL was not performed. BAL contributed to the diagnosis in 43 cases (63%) and to relevant findings in 53 cases: bacteria (n=13, 24%), viruses (n=28, 53%) and fungi (n=12, 23%). In 25 cases BAL was negative. In 15 of these cases, BAL was performed >or=4 days after chest X-ray, and in four cases not in the same segment as the infiltrations. The median time between radiographic findings and positive BAL was 2 (0-15) days, and a negative BAL 6 (1-30) days (P<0.001). Antimicrobial treatment was administered to 79% patients with positive findings, and to 92% with negative findings at the time of BAL. No serious complications due to the procedure were reported. BAL resulted in a changed treatment in 32/68 (47%) episodes of pneumonia. To conclude, BAL is a safe and useful diagnostic procedure that should be performed early after the onset of pneumonia following allogeneic HSCT. PMID- 19784078 TI - Determinants of functional performance in long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD). AB - This study examined factors accounting for functional performance limitations in 100 long-term survivors of allogeneic hematopoietic stem cell transplantation with chronic graft-versus-host disease (cGVHD). Functional performance, measured by the SF-36 physical component summary score, was substantially lower (mean=36.8+/-10.7) than the US population norm of 50 (P<0.001). The most severe decrements were in physical function (mean=38.8+/-10.9) and physical role function (mean=37.88+/-11.88); 68% of respondents exceeded the five-point threshold of minimum clinically important difference below the norm on these subscales. Controlling for age and gender, six variables explained 56% of the variance in functional performance: time since cGVHD diagnosis, cGVHD severity, intensity of immunosuppression, comorbidity, functional capacity (distance walked in 2 min, grip strength, and range of motion), and cGVHD symptom bother (F=11.26; P<0.001). Significant independent predictors of impaired performance were intensive systemic immunosuppression, reduced capacity for ambulation, and greater cGVHD symptom bother (P<0.05). Symptom bother had a direct effect on functional performance, as well as an indirect effect partially mediated by functional capacity (Sobel test, P=0.004). Results suggest two possible mechanisms underlying impaired functional performance in survivors with cGVHD and underscore the importance of testing interventions to enhance functional capacity and reduce symptom bother. PMID- 19784079 TI - Outcome of hematopoietic cell transplantation in children with sickle cell disease, a single center's experience. AB - Multicenter trials have shown that hematopoietic cell transplantation (HCT) has an excellent outcome in children with sickle cell disease (SCD). As a single center, we performed a total of 11 transplants in 10 patients (6 males, 4 females) with SCD between 1997 and 2005. Eight patients had hemoglobin SS disease and two patients had HbSbeta(0) thalassemia. The median age of HCT was 10.1 (range 2.8-16.3) years. All donors were HLA-identical siblings; six patients received bone marrow (BM), two patients received mobilized peripheral blood, one patient received umbilical cord blood (UCB) and one patient received both UCB and BM from the same donor. Myeloablative conditioning regimen consisted of busulfan, horse antithymocyte globulin and cyclophosphamide. One patient had a gradual decrease in donor chimerism to 15% and subsequently received a second bone marrow transplant using a reduced intensity conditioning regimen consisting of alemtuzumab, fludarabine and melphalan leading to stable full engraftment. Currently, 9 out of 10 patients are alive with a median follow-up of 5.5 (range 2.9-11) years. As a single institution's experience with HCT in children with SCD, we report an excellent outcome, and a second HCT may be considered for patients with impending engraftment failure as a cure for SCD. PMID- 19784081 TI - Higher cortical modulation of pain perception in the human brain: Psychological determinant. AB - Pain perception and its genesis in the human brain have been reviewed recently. In the current article, the reports on pain modulation in the human brain were reviewed from higher cortical regulation, i.e. top-down effect, particularly studied in psychological determinants. Pain modulation can be examined by gene therapy, physical modulation, pharmacological modulation, psychological modulation, and pathophysiological modulation. In psychological modulation, this article examined (a) willed determination, (b) distraction, (c) placebo, (d) hypnosis, (e) meditation, (f) qi-gong, (g) belief, and (h) emotions, respectively, in the brain function for pain modulation. In each, the operational definition, cortical processing, neuroimaging, and pain modulation were systematically deliberated. However, not all studies had featured the brain modulation processing but rather demonstrated potential effects on human pain. In our own studies on the emotional modulation on human pain, we observed that emotions could be induced from music melodies or pictures perception for reduction of tonic human pain, mainly in potentiation of the posterior alpha EEG fields, likely resulted from underneath activities of precuneous in regulation of consciousness, including pain perception. To sum, higher brain functions become the leading edge research in all sciences. How to solve the information bit of thinking and feeling in the brain can be the greatest challenge of human intelligence. Application of higher cortical modulation of human pain and suffering can lead to the progress of social humanity and civilization. PMID- 19784082 TI - Neuroimaging study of placebo analgesia in humans. AB - Placebo has been reported to exert beneficial effects in patients regarding the treatment of pain. Human functional neuroimaging technology can study the intact human brain to elucidate its functional neuroanatomy and the neurobiological mechanism of the placebo effect. Blood flow measurement using functional magnetic resonance imaging and positron emission tomography (PET) has revealed that analgesia is related to decreased neural activities in pain-modulatory brain regions, such as the rostral anterior cingulate cortex (rACC), insula, thalamus, and brainstem including periaqueductal gray (PAG) and ventromedial medulla. The endogenous opioid system and its activation of mu-opioid receptors are thought to mediate the observed effects of placebo. The mu-opioid receptor-selective radiotracer-labeled PET studies show that the placebo effects are accompanied by reduction in activation of opioid neural transmission in pain-sensitive brain regions, including rACC, prefrontal cortex, insula, thalamus, amygdala, nucleus accumbens (NAC) and PAG. Further PET studies with dopamine D2/D3 receptor labeling radiotracer demonstrate that basal ganglia including NAC are related to placebo analgesic responses. NAC dopamine release induced by placebo analgesia is related to expectation of analgesia. These data indicate that the aforementioned brain regions and neurotransmitters such as endogenous opioid and dopamine systems contribute to placebo analgesia. PMID- 19784083 TI - Role of muscle spindle in weightlessness-induced amyotrophia and muscle pain. AB - To date, the medium and long-term space flight is urgent in need and has become a major task of our manned space flight program. There is no doubt that medium and long-term space flight has serious damaging impact upon human physiological systems. For instance, atrophy of the lower limb anti-gravity muscle can be induced during the space flight. Muscle atrophy significantly affects the flight of astronauts in space. Most importantly, it influences the precise manipulation of the astronauts and their response capacity to emergencies on returning to the atmosphere from space. Muscle atrophy caused by weightlessness may also seriously disrupt the normal life and work of the astronauts during the re-adaptation period. Here we summarize the corresponding research concentrating on weightlessness-induced changes of muscular structure and function. By combining research on muscle pain, which is a common clinical pain disease, we further provide a hypothesis concerning a dynamic feedback model of "weightlessness condition right triple arrow muscular atrophy <--> muscle pain". This may be useful to explore the neural mechanisms underlying the occurrence and development of muscular atrophy and muscle pain, through the key study of muscle spindle, and furthermore provide more effective therapy for clinical treatment. PMID- 19784084 TI - Neuronal nociceptive responses in thalamocortical pathways. AB - The sensation of pain is critical for the survival of animals and humans. However, the brain mechanisms underlying pain perception remain largely unknown. How does the brain decode the pain-evoked activity into a particular sensory experience? Over the past decade, attempts have been made to answer these questions by employing electrophysiological, functional brain imaging, and behavioral approaches, and some basic properties of pain formation have been revealed. Researchers have gradually recognized that there exists a distributed neural network that participates in the transmission and processing of pain information. These studies will further guide the development of more effective treatment for many disorders such as chronic pain. PMID- 19784080 TI - Roles of the hippocampal formation in pain information processing. AB - Pain is a complex experience consisting of sensory-discriminative, affective motivational, and cognitive-evaluative dimensions. Now it has been gradually known that noxious information is processed by a widely-distributed, hierarchically- interconnected neural network, referred to as neuromatrix, in the brain. Thus, identifying the multiple neural networks subserving these functional aspects and harnessing this knowledge to manipulate the pain response in new and beneficial ways are challenging tasks. Albeit with elaborate research efforts on the cortical responses to painful stimuli or clinical pain, involvement of the hippocampal formation (HF) in pain is still a matter of controversy. Here, we integrate previous animal and human studies from the viewpoint of HF and pain, sequentially representing anatomical, behavioral, electrophysiological, molecular/biochemical and functional imaging evidence supporting the role of HF in pain processing. At last, we further expound on the relationship between pain and memory and present some unresolved issues. PMID- 19784085 TI - Potential pharmacological treatment of fragile X syndrome during adulthood. AB - Fragile X syndrome (FXS) is the most common form of inherited mental retardation, characterized by moderate-to-severe mental retardation, attention deficits, and hyperactivity. This disease results from the expansion of a trinucleotide repeat (CGG) within the X-linked fragile X mental retardation 1 (FMR1) gene, which leads to the lack of the product of the FMR1 gene-fragile X mental retardation protein. Many mental disorders such as FXS and Rett syndrome are thought to originate during early developmental period, but recent findings have suggested the involvement of the processes in the adult nervous system. Here we outline our recent studies and initial clinical trials that may provide an approach to treat FXS in the adulthood. PMID- 19784086 TI - Activation of extracellular signal-regulated kinase in the anterior cingulate cortex contributes to the induction of long-term potentiation in rats. AB - OBJECTIVE: To explore the role of the extracellular signal-regulated kinase (ERK)/cAMP response element binding protein (CREB) pathway in the induction of long-term potentiation (LTP) in the anterior cingulate cortex (ACC) that may be implicated in pain-related negative emotion. METHODS: LTP of field potential was recorded in ACC slice and the expressions of phospho-ERK (pERK) and phospho-CREB (pCREB) were examined using immunohistochemistry method. RESULTS: LTP could be induced stably in ACC slice by high frequency stimulation (2-train, 100 Hz, 1 s), while APv (an antagonist of NMDA receptor) could block the induction of LTP in the ACC, indicating that LTP in this experiment was NMDA receptor-dependent. Bath application of PD98059 (50 micromol/L), a selective MEK inhibitor, at 30 min before tetanic stimulation could completely block the induction of LTP. Moreover, the protein level of pERK in the ACC was transiently increased after LTP induction, starting at 5 min and returning to basal at 1 h after tetanic stimulation. The protein level of pCREB was also increased after LTP induction. The up-regulation in pERK and pCREB expressions could be blocked by pretreatment of PD98059. Double immunostaining showed that after LTP induction, most pERK was co-localized with pCREB. CONCLUSION: NMDA receptor and ERK-CREB pathway are necessary for the induction of LTP in rat ACC and may play important roles in pain emotion. PMID- 19784087 TI - Differential effects of long and short train theta burst stimulation on LTP induction in rat anterior cingulate cortex slices: multi-electrode array recordings. AB - OBJECTIVE: There is substantial evidence supporting the notion that the anterior cingulate cortex (ACC) is an important limbic structure involved in multiple brain functions such as sensory perception, motor conflict monitoring, memory, emotion and cognition. It has been shown that long term potentiation (LTP) is an important synaptic model of neural plasticity in the ACC, however, little is known about the spatiotemporal properties of ACC at network level. The present study was designed to see the LTP induction effects across different layers of the ACC by using different conditioning stimuli (CS) protocols. METHODS: A unique multi-electrode array recording technique was used in the acutely-dissociated ACC slices of rats. Long and short train theta burst stimulation (TBS) paradigms were applied in layer V-VI as the CS and the LTP induction effects were compared across different layers of the ACC. Briefly, both long and short train TBS are composed of bursts (4 pulses at 100 Hz) with a 200 ms interval, however, the former (TBS1) was with 10 trains and the latter (TBS2) was with 5 trains. After test stimulation at layer V-VI in the ACC, network field potentials (FPs) could be simultaneously recorded across all layers of the ACC. RESULTS: The waveforms of FPs were different across different layers. Namely, positive-going waveforms were recorded in layer I and negative-going waveforms were recorded in layers V VI, in contrast, complex waveforms were localized mainly in layers II-III. Following application of two CS protocols, the induction rate of LTP was significantly different between TBS1 and TBS2 regardless of the spatial properties. TBS1 had more than 60% success, while TBS2 was less than 25% in induction of LTP. Moreover, both the 2 CS protocols could induce LTP in layers II III and layers V-VI without layer-related difference. However, no LTP was inducible in layer I. CONCLUSION: The present findings indicate that stimulation protocols may, at least in part, account for a large portion of variations among previous LTP studies, and hence highlight the importance of selecting the best LTP induction protocol when designing such experiments. Moreover, the present results demonstrate the prominent superiority of multi-electrode array recording in revealing the network properties of synaptic activities in the ACC, especially in comparing the spatiotemporal characteristics between different layers of this structure. PMID- 19784090 TI - Diffraction and beam-diameter measurement of Gaussian beams at optical and microwave frequencies. AB - Diffraction of a one-dimensional Gaussian beam by a slit is theoretically investigated. In the visible and microwave regions a new property of the diffracted energy is presented. Analytical expressions for the transmission coefficient and the diffracted energy at normal direction are obtained in simple practical form for experimentalists. These expressions suggest a simple method for measuring Gaussian beams of 1.5-microm diameter or larger. PMID- 19784089 TI - NIH state-of-the-science conference statement: diagnosis and management of ductal carcinoma in situ (DCIS). AB - OBJECTIVE: To provide health care providers, patients, and the general public with a responsible assessment of currently available data on the diagnosis and management of ductal carcinoma in situ (DCIS). PARTICIPANTS: An non-DHHS, nonadvocate 14-member panel representing the fields of fields of oncology, radiology, surgery (general and reconstructive), pathology, radiation oncology, internal medicine, epidemiology, biostatistics, nursing, obstetrics and gynecology, preventative medicine and population health, and social work. In addition, 22 experts from pertinent fields presented data to the panel and conference audience. EVIDENCE: Presentations by experts and a systematic review of the literature prepared by the Minnesota Evidence-based Practice Center, through the Agency for Healthcare Research and Quality. Scientific evidence was given precedence over anecdotal experience. CONFERENCE PROCESS: The panel drafted its statement based on scientific evidence presented in open forum and on published scientific literature. The draft statement was presented on the final day of the conference and circulated to the audience for comment. The panel released a revised statement later that day at http://consensus.nih.gov. This statement is an independent report of the panel and is not a policy statement of the NIH or the Federal Government. CONCLUSIONS: The diagnosis and management of DCIS is highly complex with many unanswered questions, including the fundamental natural history of untreated disease. Because of the noninvasive nature of DCIS, coupled with its favorable prognosis, strong consideration should be given to remove the anxiety-producing term "carcinoma" from the description of DCIS. The outcomes in women treated with available therapies are excellent. Thus, the primary question for future research must focus on the accurate identification of patient subsets diagnosed with DCIS, including those persons who may be managed with less therapeutic intervention without sacrificing the excellent outcomes presently achieved. Essential in this quest will be the development and validation of accurate risk stratification methods based on a comprehensive understanding of the clinical, radiological, pathological, and biological factors associated with DCIS. PMID- 19784088 TI - Intrathecal injection of GluR6 antisense oligodeoxynucleotides alleviates acute inflammatory pain of rectum in rats. AB - OBJECTIVE: To investigate whether the kainate (KA) receptor subunit GluR6 is involved in the acute inflammatory pain. METHODS: Formalin was injected into the mucosa of rectum in Sprague-Dawley rats to induce visceral pain. The antisense oligodeoxynucleotides (ODNs) of GluR6 were injected once per day for 3 d before formalin injection, after which GluR6 protein level was examined by immunoblotting method. The change of visceral pain was also investigated. RESULTS: The expression of GluR6 in the spinal cord of rats increased after the formalin injection. Moreover, pre-treatment of GluR6 antisense ODNs could suppress GluR6 expression in the spinal cord of rats and decrease the scores of visceral pain at 45 min following formalin injection. CONCLUSION: Kainate receptor subunit GluR6 plays an important role in the visceral pain induced by injection of formalin into the wall of rectum. GluR6 may serve as a potential target for the treatment of acute inflammatory visceral pain. PMID- 19784092 TI - Experimental measurements of the statistical properties of a monochromatic speckle pattern. AB - An experimental approach to the measurement of phase of a coherent optical field with a Shack-Hartmann sensor is presented. We demonstrate the usefulness of this sensor by verifying a theoretical model for the distribution of ray directions in a monochromatic speckle pattern. PMID- 19784091 TI - Study of photon migration depths with time-resolved spectroscopy. AB - In this study a light-shielding plate with a hole was placed in an intralipid emulsion. The probability distribution for photons emitted from a surface light source, passing through the hole at different depths, and reaching a surface detector at the other side of the plate was experimentally assessed. We provide qualitative verification for a model derived by Weiss et al. [J. Mod. Opt. 36, 349 (1989)] that the migration depths for the measured photons follow a distribution in depth and that this distribution has a maximum probability at a describable depth beneath the surface. This agreement, corroborated by a parallel study, suggests that we may have assessed the maximum migration depth distribution of photons that reached the detector and that the random walk model may describe the maximum migration depth distribution. The experimental results indicate that photons with the same path lengths within the medium reach a wide range of depths and suggest difficulties in resolving optical structure with time resolved measurement. The results also provide experimental evidence that, for a given source-detector separation, the photons that migrate deeper have longer mean path lengths with larger variation in their path lengths. PMID- 19784093 TI - Self-phase modulation of incoherent light revisited. AB - The effects of self-phase modulation on a Gaussian incoherent field propagating in a dispersionless nonlinear Kerr medium are calculated without assuming the mean-field-theory approximation. Deviations between the exact and approximate solutions for the correlation time compression ratio as a function of the pulse power and fiber length are computed. PMID- 19784094 TI - All-optical ultrafast logic gates that use asymmetric nonlinear directional couplers. AB - All-optical ultrafast AND, OR, and XOR logic functions that use asymmetric nonlinear directional couplers are numerically demonstrated. In such an asymmetric coupler, different Kerr effects are generated when the same power is launched into two waveguides. The output power tends to appear in the waveguide of stronger Kerr effect when only one waveguide is excited. When both waveguides are excited, the output power contrast between the two waveguides depends on the relative phase of the two input signals. The parameters of fiber couplers are used to demonstrate the logic functions. PMID- 19784095 TI - Phase conjugation used as a test of the local and nonlocal characteristics of optical nonlinearities in microemulsions. AB - We report what are to our knowledge the first degenerate four-wave mixing experiments in microemulsions using a cw argon laser. The static and dynamic behavior of the reflectivity of both induced gratings is quantitatively analyzed. The conjugated signal dependence on the angle between the pump and probe waves is used to separate the local electrostrictive and the nonlocal thermodiffusive nonlinear processes, which are both efficient in the studied microemulsion. PMID- 19784096 TI - Numerical study of the Raman effect and its impact on soliton-dragging logic gates. AB - Recent experiments in birefringent optical fibers in which a signal pulse in one polarization is used to switch a control pulse in another polarization are affected by the Raman self-frequency shift. These experiments are modeled numerically, with the experimentally measured Raman profiles used as input to the simulations. Both parallel and perpendicular Raman gain are kept. The effect of keeping the full Raman response rather than just an often-used linear approximation is discussed. The experimental results are in good agreement with theory, although some discrepancies exist. The possibility that these discrepancies could be due to errors in the measurements of the low-frequency portion of the perpendicular Raman gain is examined and ruled out. Other possible sources of this discrepancy are then discussed. PMID- 19784097 TI - Photoinduced second-harmonic generation in rare-earth-doped aluminosilicate optical fibers. AB - The presence of defect states in the band gap is an essential ingredient of recent models of photoinduced second-harmonic generation (SHG) in fibers. We have created such states by doping aluminosilicate glass fibers that do not contain Ge with Ce or Eu and observed SHG from 1.06-microm light after preparation of the fibers with 0.532- and 1.06-microm light. In an aluminosilicate fiber doped with 0.008 wt. % Ce, the SHG conversion efficiency is as high as 1.5% at infrared (1.06-microm) peak powers of 200 W. PMID- 19784098 TI - Soliton switching in an erbium-doped nonlinear fiber coupler. AB - A numerical study of the all-optical switching properties of solitons in an erbium-doped nonlinear fiber coupler is presented. The small gain provided by the erbium both lowers and sharpens the switching threshold, while producing pulse compression factors of 3 to 9. As a result, we show that it is possible to achieve all-optical switching, amplification, and compression of short pulses in a single device. PMID- 19784099 TI - Influence of soliton interaction on amplifier noise-induced jitter: a first-order analytical solution. AB - Amplifier noise induces fluctuations on the soliton's mean frequency and amplitude. These fluctuations disturb the soliton phase difference, which modifies the soliton interaction. Amplifier noise jitter and soliton interaction cannot be studied independently for strongly interacting solitons in high repetition-rate long-distance transmissions. A first-order analytical modeling for the jitter of two interacting solitons with periodic amplification is presented. PMID- 19784100 TI - Analysis of a proposed extension to the Fabry-Perot technique for measurements of loss in semiconductor optical waveguides. AB - A recent paper by Clark and Iqbal [Opt. Lett. 15, 1291 (1990)] proposed a novel modification of the conventional Fabry-Perot technique for measuring losses in semiconductor optical waveguides, which they claim eliminates the need for any knowledge of the reflectivities of the waveguide end facets. We show that the range of validity of this technique is quite limited and in many situations may be difficult to verify. PMID- 19784101 TI - Tunable, cw operation of a multiwatt forsterite laser. AB - We have obtained over 1.8 W of power from a cw chromium-doped forsterite laser operated at 77 K when it is pumped by a 7.3-W Nd:YAG laser at 1.06 microm. The forsterite laser tunes smoothly from 1.2 to 1.32 microm. At room temperature the output power decreases to approximately 35% of the cryogenic power level. PMID- 19784102 TI - Single-longitudinal-mode operation and second-harmonic generation of Nd:YVO(4) microchip lasers. AB - A single-mode output of 221 and 16 mW for the fundamental and second-harmonic light was obtained with the combination of a Nd:YVO(4) microchip laser and an intracavity KTP crystal. It was found that the beam size and laser power in a plano-plano cavity were dependent on the absorption coefficient of the laser medium and that the material that had a higher absorption coefficient produced higher output power and smaller beam size in the laser cavity. This means that Nd:YVO(4) is suitable not only for single-mode oscillation but also for efficient intracavity second-harmonic generation. PMID- 19784103 TI - Continuous-wave mode-locked operation of a chromium-doped forsterite laser. AB - Mode-locked operation of chromium-doped forsterite (Cr:Mg(2)SiO(4)) has been achieved for the first time to our knowledge. The chromium-doped forsterite laser has been mode locked by using two methods: active mode locking, which produced pulses as short as 31 ps tunable between 1204 and 1277 nm, and synchronously pumped mode locking, which produced pulses of 260-ps duration tunable between 1195 and 1295 nm. PMID- 19784104 TI - Noncritical matching of cavity lengths for uninterrupted additive-pulse mode locking of a cw Nd:YLF laser. AB - Stable interferometrically insensitive operation of an additive-pulse mode-locked Nd:YLF laser is observed over 4.8 microm of continuous detuning of the cavity lengths. This phenomenon continuously persists over 250 microm of coarse cavity length detuning. Outside this range interferometric mode locking typically associated with additive-pulse mode locking is observed for detuning lengths of over 1 mm. The external cavity of the system consists of a multimode fiber whose four possible second-order proper modes are all excited. The underlying mechanism is a slow process with response times in the subhertz and hertz regions. PMID- 19784105 TI - Mode locking of Ti:AI(2)O(3) lasers and self-focusing: a Gaussian approximation. AB - We present an ABCD matrix model showing that self-focusing in the laser rod leads to modifications of the Gaussian beam parameters in cw-pumped Ti:Al(2)O(3) lasers. Stabilization of self-mode-locking should result from these beam perturbations. Experimental measurements of beam modifications supporting this model are presented. The role of gain guiding is studied, and the limitations of the model are discussed. PMID- 19784106 TI - Timing-jitter stabilization of a colliding-pulse mode-locked laser by active control of the cavity length. AB - Colliding-pulse mode-locked lasers are an excellent source of ultrashort pulses but exhibit timing jitter that can seriously degrade the temporal resolution in experiments that require synchronization to an external source. We describe a method that synchronizes the colliding-pulse mode-locked laser to a high stability external oscillator by actively controlling the cavity length of the laser and reduces the absolute timing jitter from ~25 ps rms to only 1.7 ps over the 1-kHz bandwidth, which contains most of the laser phase noise. By using this method, the repetition rate of the laser pulses is held constant at 100 MHz. PMID- 19784107 TI - Diode-pumped eye-safe laser source exceeding 1% efficiency. AB - We describe an all-solid-state, diode-pumped, eye-safe laser source at 1.61 microm, based on a Nd:YAG laser and a noncritically phase-matched KTP optical parametric oscillator. Total energy conversion efficiencies of the 1.064-microm pump to 1.61-microm signal and 3.1-microm idler approach 50%, with 35% conversion to 1.61 microm alone. This device produces 1.6 mJ at 1.61 microm with a wallplug efficiency of 1.1% and is readily scalable to higher energies. Tunability over 1.6 to 1.54 microm is obtained by rotation of the KTP crystal about its z axis, with 1.54-microm output obtained for propagation along the y axis under noncritical phase matching. PMID- 19784108 TI - Femtosecond time-resolved interferometry for the determination of complex nonlinear susceptibility. AB - We propose and demonstrate sensitive interferometry that permits the separation of the real and imaginary parts of the nonlinear susceptibility with a femtosecond time resolution by a single measurement. A special reference interferometer compensates for any fluctuations of the fringe and provides high sensitivity to detect a fringe shift as small as 0.025 rad (lambda/250) by averaging only 100 shots with a low-repetition-rate laser. This method can be applied to materials with optical anisotropy and/or absorption with high sensitivity. We apply the method to two materials, CS(2) and CdS(x)Se(1-x) microcrystallite-doped glass. PMID- 19784109 TI - Chirped-pulse amplification in XeCl. AB - By using a 0.25-ps nearly transform-limited pulse and both 16- and 75-ps strongly chirped pulses of the same bandwidth, measurements of the effective saturation fluence (E(sat)) of a XeCl discharge amplifier have been performed. We find that while E(sat) for the 16-ps pulse is comparable with that of the 0.25-ps pulse, pulse stretching to a width of 75 ps increases the effective E(sat) by 35%. However, the measured values of E(sat) for the 16- and 75-ps pulses are significantly less than would be expected for transform-limited pulses of the same pulse widths. A simple rate-equation model, which takes into account variation of the small-signal gain across the gain bandpass and which assumes that E(sat) is enhanced for the longer pulse widths only by population decay of the lower electronic state, predicts the measured values of E(sat) to within the experimental error. PMID- 19784110 TI - Self-starting issues of passive self-focusing mode locking. AB - An analysis of passive mode locking with the intracavity self-focusing effect is presented, and the self-starting issue is addressed. The analysis shows that the initial pulse-shortening force of this mechanism is too weak to start the mode locking from mode beating or noise and how it can be greatly enhanced with a dilute dye saturable absorber in the cavity. This analysis also shows shortening force in cw mode-locking lasers. PMID- 19784111 TI - All-optical bipolar neural network with polarization-modulating neurons. AB - A general all-optical implementation scheme for bipolar neural networks is presented. Bipolar operation is realized by exploiting two orthogonal light polarizations. A three-layer feed-forward bipolar network is demonstrated experimentally by using a liquid-crystal light valve for implementing an array of polarization modulating neurons. PMID- 19784112 TI - Forces on three-level atoms including coherent population trapping. AB - We present a calculation of the force on a stationary three-level atom excited by a nearly resonant Raman light field, which may be composed of an arbitrary combination of standing- and traveling-wave fields. The effects of the ground state coherences are explicitly included and are shown to play a crucial role in the nature of the force on the atom. We show that the force contains terms that vary on length scales both shorter and longer than the optical wavelength and that the magnitude of these terms can be made arbitrarily large. PMID- 19784113 TI - Squeezed amplification in a nondegenerate parametric amplifier. AB - A linearized quantum analysis of an injection-seeded optical parametric amplifier is presented. When the amplifier is operated in a saturated gain regime, the amplified output intensity of the injected coherent-state signal becomes amplitude squeezed, and the signal-to-noise ratio improves. Above threshold, an injection-seeded parametric oscillator is found to generate more single-beam squeezing than an unseeded one. An amplitudesqueezed pump is shown to yield even better results. PMID- 19784114 TI - Triangular phase-modulation approach to an open-loop fiber-optic gyroscope. AB - A new approach to an open-loop, all-fiber gyroscope with a wide dynamic range and a linear scale factor is described. For signal processing, the Sagnac phase shift is converted into a phase shift in the low-frequency electrical signal by using a triangular phase-modulation waveform followed by gate switching. The basic principle of this technique and experimental results are reported. PMID- 19784115 TI - General compressor for ultrashort pulses with nonlinear chirp. AB - A new type of grating compressor capable of compensating, in principle, for any arbitrary group-delay dispersion is described. The system relies on a specially designed grating with a variable groove spacing along its surface as well as a variable angle of incidence. In this manner each wavelength actually sees a different grating, always at Littrow incidence, that gives rise to distinct group delays. The design equations are derived, and the particular case of a cubic compressor is discussed. It is shown that, within practical limits, both quadratic and cubic terms can be simultaneously compensated for in typical optical fibers. PMID- 19784116 TI - Spatially weighted, grating-based, two-mode, elliptical-core optical fiber vibration sensors. AB - Photoinduced refractive-index changes in two-mode, elliptical-core optical fibers affect the beat length and the sensor sensitivity. Chirped gratings are written by attaching such fibers to cantilever beams positioned in a strained state. We show that fibers with in-line chirped gratings, with the chirp being shaped in the form of a vibration-mode shape, can be used as spatially weighted fiber sensors for vibration analysis. We demonstrate enhanced detection of the first and second modes of vibration of a cantilever beam using this process; vibration mode suppression of the order of 10 dB is obtained. PMID- 19784117 TI - Optical square-wave generation in a diode-laser array. AB - We describe a new mechanism for passive generation of rapid-rise-time, high bandwidth optical square waves based on directional switching. By using a diode laser array in an external optical cavity, square-wave optical signals as fast as 250 MHz with detector-limited rise times of less than 200 ps are generated. PMID- 19784118 TI - Acousto-optic generation of two-dimensional spot arrays. AB - We demonstrate, through the use of an acousto-optic system, the generation of two dimensional uniform spot arrays with high diffraction efficiency. The system consists of two acousto-optic cells oriented orthogonally to each other and driven by an arbitrary waveform generator. Determination of the acousto-optic drive signal is discussed, as well as techniques for generating arbitrary spot arrays. PMID- 19784119 TI - Absorption effects on microdroplet resonant emission structure. AB - The effect of absorption on microdroplet resonance emission line intensities was studied in 15-microm-diameter Rhodamine 6G/ethanol solution droplets. Absorption was controlled by varying the concentration of the additive nigrosin. Spectrally integrated intensities of resonant features are found to be proportional to a droplet cavity mode efficiency Q(a)/(Q(a)+Q(o)) expressed in terms of cavity output coupling and absorption factors Q(o) and Q(a), respectively. These Q's are determined from linewidths calculated from Lorenz-Mie theory by using combinations of the real and complex indices of refraction. An experimental upper limit of Q for first-order modes was determined to be 10(8) from the data. PMID- 19784120 TI - LiB(3)O(5): a highly efficient frequency converter for Ti:sapphire lasers. AB - Efficient second-harmonic generation in a LiB(3)O(5) crystal over the spectral range of a Ti:sapphire laser is demonstrated. The angular acceptance and damage threshold of the LiB(3)O(5) crystal are measured and calculated, and a 30% conversion efficiency is achieved (with a 5-mm-long crystal). The potential for increasing the conversion efficiency of second-harmonic generation at the edges of the spectral range of the Ti:sapphire laser is shown. PMID- 19784121 TI - External frequency conversion of cw mode-locked Ti:Al(2)O(3) laser radiation. AB - Efficient frequency conversion of cw mode-locked Ti:A1(2)O(3) laser radiation using lithium triborate, beta-barium borate, and lithium iodate crystals as the nonlinear material is demonstrated. Second-, third-, and fourth harmonic generation results in tunable blue and ultraviolet radiation down to 205 nm with transform-limited pulses and pulse lengths below 1 ps. Maximum average powers (repetition rate 82 MHz) of 700 mW at 400 nm, 120 mW at 272 nm, and 10 mW at 210 nm were obtained. The effects of group-velocity dispersion have to be taken into account to optimize the different frequency-conversion processes. PMID- 19784122 TI - Large second-order nonlinearity in poled fused silica. AB - A large second-order nonlinearity [chi((2)) 1 pm/V 0.2 chi((2)) (22) for LiNbO(3)] is induced in the near-surface ( 4 microm) region of commercial fused silica optical flats by a temperature (250-325 degrees C) and electric-field (E ~ 5 x 10(4) V/cm) poling process. Once formed, the nonlinearity, which is roughly 10(3)-10(4) times larger than that found in fiber second-harmonic experiments, is extremely stable at room temperature and laboratory ambient. The nonlinearity can be cycled by repeated depoling (temperature only) and repoling (temperature and electric field) processes without history effects. Possible mechanisms, including nonlinear moieties and electric-field-induced second-order nonlinearities, are discussed. PMID- 19784123 TI - Effects of randomly varying birefringence on soliton interactions in optical fibers. AB - The effects of randomly varying birefringence on soliton interactions in optical fibers are studied. It is shown that for initial separations of less than 10 pulse widths, the phase-dependent short-range interaction dominates. For separations larger than 10 pulse widths, the soliton interacts through the dispersive radiation that they generate. This interaction is too weak to explain the phase-independent long-range soliton interaction observed experimentally. PMID- 19784124 TI - Remotely switched hollow-core antiresonant reflecting optical waveguide. AB - We describe a hollow-core antiresonant reflecting optical waveguide whose transmission can be remotely modulated by the motion of a glass substrate placed at a distance from the light-guiding core that ranges from tens to hundreds of micrometers. A maximum on-off ratio of 17 dB was observed. An analytical mathematical formalism developed to fit the data predicts the possibility of achieving on-off ratios of 30 dB. PMID- 19784125 TI - Continuous-wave operation of a diode-pumped rotating Nd:glass disk laser. AB - A diode-laser end-pumped cw rotating Nd:glass disk laser that operates in the TEM(00) mode with a slope efficiency of 37% has been demonstrated to have an output power dependent on both the pumping rate and the rotation rate. As the rotation rate increases, the power increases from zero to an optimum and thereafter decreases. The initial increase is due to the lessening of the effect of medium heating on laser operation, while the decrease is due to decreased laser gain caused by sweeping of the excited-state population out of the laser cavity. At the optimum rotation rate of 2.5 Hz we obtained a cw output power of 0.55 W with 2 W of absorbed pump power; the output power was limited by the available pump power as opposed to thermal damage or thermo-optic distortion. PMID- 19784126 TI - Picosecond infrared optical parametric generation in KTP using a diode-laser pumped solid-state laser. AB - We report the generation of tunable picosecond pulses in the near infrared by synchronous pumping of an optical parametric oscillator based on the crystal KTP with a frequency-doubled, actively mode-locked, Q-switched, diode-laser-pumped Nd:YLF laser at 523.5 nm. The oscillator provides tunable radiation over the ranges of 0.946-1.020 microm and 1.075-1.172 microm in pulses of ~8-ps duration, with average output powers approaching 2 mW, at a 500-Hz repetition rate. The threshold Q-switched pulse energy was 4 microJ, and pump depletions as high as 56% were observed when pumping 5.5 times above threshold. At this pumping intensity the amplitude stability of the optical parametric oscillator output pulses was +/-2%. PMID- 19784127 TI - Pr(3+)-doped fluoride fiber amplifier operating at 1.31 microm. AB - We propose what is to our knowledge the first use of a Pr(3+)-doped fluoride fiber amplifier as a practical amplifier operating at the 1.3-microm band, based on a demonstration of signal amplification and a spectroscopic investigation. The feasibility of the fluoride fiber amplifier is confirmed. PMID- 19784128 TI - Frequency-modulation mode locking of a semiconductor laser. AB - We report FM mode locking in an extended-cavity semiconductor laser containing a tunable distributed Bragg reflector gain medium operating near 1.5 microm. We demonstrate the generation of pulses with 24-ps duration at a repetition rate of 1.5 GHz. PMID- 19784129 TI - Pulse statistics in single-mode semiconductor lasers modulated at gigahertz rates. AB - The statistics of switch-on time, maximum light intensity, and pulse width of single-mode lasers modulated at gigahertz rates are analyzed. Numerical results obtained from noise-driven rate equations are reported. Pulse statistics, and in particular timing jitter, are shown to be rather insensitive to the bias current at this high-speed modulation. In addition, pulse statistics become rather independent of the modulation period when biasing slightly below threshold. PMID- 19784130 TI - Femtosecond pulse generation in Ti:Al(2)O(3) using a microdot mirror mode locker. AB - A new nonlinear intracavity device called a microdot mirror mode locker is demonstrated for ultrashort-pulse generation in solid-state lasers. The microdot mirror produces fast saturable absorber action by using self-focusing. Pulse durations of 190 fs are achieved in a Ti:A1(2)O(3) laser. The microdot mirror mode locker is modular, preserves wavelength tunability, and can be extended to a wide range of solid-state lasers. PMID- 19784131 TI - High-speed picosecond pulse generation in semiconductor lasers with incoherent optical feedback. AB - A novel method for producing high-speed picosecond optical pulses from semiconductor laser diodes that uses incoherent optical feedback is proposed. The incoherent optical feedback provides a successive pulselike modulation in carrier density and drives the system to a self-sustained pulsation state whose repetition rate is determined by relaxation oscillations. PMID- 19784132 TI - Regeneratively initiated self-mode-locked Ti:sapphire laser. AB - It is demonstrated that the incorporation of an acousto-optic modulator within the cavity of a self-mode-locked Ti:sapphire laser can lead to self-starting and stable generation of pulses that have durations of 60 fs when the acousto-optic device is driven regeneratively from the laser output. Data are also presented that show that the application of cavity-frequency locking techniques dramatically improves the phase noise characteristics of the mode-locked laser. PMID- 19784133 TI - Harmonic mode locking of a Nd:BEL laser using a 20-GHz dielectric resonator/optical modulator. AB - A 20-GHz dielectric-resonator/optical modulator is developed and used as an FM mode locker at the 84th harmonic of a conventional 238-MHz diode-pumped Nd:BEL laser cavity. Depending on the mode-locker drive frequency, two distinct regimes of mode locking were observed: 2.9-ps pulses at a repetition rate of 238 MHz and 3.9-ps pulses at a repetition rate of 20 GHz. These are to our knowledge the shortest pulses ever reported for active mode locking of a Nd laser. PMID- 19784134 TI - Saturation spectroscopy of infrared molecular transition in an optically thick cell. AB - Low-background sub-Doppler saturated absorption line shapes were obtained for SF(6) with a CO(2) laser. With the use of a high-power pump, linewidths near the collisional relaxation width have been observed. The theory for a two-level model has been calculated and shows that the rate-equation approximation overestimates the line narrowing because of the propagation effect. Consistent with experiments, for linear absorption coefficients alphal of less than 15, no subnatural line is predicted. PMID- 19784135 TI - Use of a persistent photoconductive array in the learning of an optoelectronic neural processor. AB - Persistent photoconductors of npnp doping-modulated amorphous silicon multilayers are investigated for the implementation of variable analog and nonvolatile synaptic weights of an optoelectronic neural processor. The time dependence of the persistent photoconductance of the amorphous silicon multilayers is characterized in experiments. The learning performance of an optical pattern classifier with the persistent photoconductive array is analyzed by computer simulations. PMID- 19784136 TI - Incremental recording for photorefractive hologram multiplexing. AB - We investigate an incremental recording technique for multiplexed hologram storage in photorefractive crystals, in which each hologram is recorded with multiple short exposures. The performance is theoretically compared with that of scheduled (single exposure per hologram) recording. Our analysis shows that this technique systematically controls the signal uniformity and can also decrease the total recording time. We present an experimental demonstration with LiNbO(3) using a binary orthogonal phase-code addressing technique. PMID- 19784137 TI - Postheat treatment of silver halide holograms. AB - A novel method to increase the diffraction efficiency of a common silver halide amplitude hologram, postheat treatment, is proposed and experimentally demonstrated. The method is simple and needs no chemicals. The physical mechanism of this process is also discussed. PMID- 19784138 TI - Three-dimensional optical data storage in refractive media by two-photon point excitation. AB - What is to our knowledge the first high-density (>10(12) bits/cm(3)) optical recording of digital information in a multilayered, three-dimensional format is reported. Information is written as submicrometer volume elements of increased refractive index in a photopolymer by two-photon excitation of a photoinitiator at the waist of a highly focused beam from a colliding-pulse mode-locked laser. Quadratic dependence of two-photon excitation on intensity confines polymerization to the focal volume. Information is read with sufficient axial resolution by differential interference contrast microscopy. This write-once, read-many technique should increase the capacity of the spinning disk format by 100-fold. PMID- 19784139 TI - Collimation method that uses spiral gratings and Talbot interferometry. AB - The tested light is projected onto an arrangement composed of two special spiral gratings, in which the second spiral grating is positioned at the Talbot image of the first one. From the shapes of the resultant moire fringes, the quality of collimation of the tested light can be easily checked. PMID- 19784140 TI - Electrically addressed spatial light modulator that uses a dynamic memory. AB - The operating characteristics of a 64 x 64 array electrically addressed spatial light modulator that uses a dynamic memory on a very-large-scale-integration chip and a ferroelectric liquid-crystal modulator are discussed. PMID- 19784141 TI - 1 x 2 fiber-optic heterodyne array for laser Doppler velocimetry and angular orientation measurements. AB - A 1 x 2 single-mode fiber-optic heterodyne array is presented that simultaneously measures the radial and angular Doppler velocities of a target. This heterodyne array also provides an amplitude-dependent error signal suitable for angular tracking. PMID- 19784142 TI - Pyro-electro-optic phase gratings. AB - A new physical mechanism is proposed for generating transient phase gratings in transparent pyroelectric materials. The mechanism combines the pyroelectric and electro-optic effects to convert spatial intensity variations into transient phase gratings. The grating diffraction efficiency increases with a figure of merit that is proportional to the pyroelectric, electro-optic, and absorption coefficients and is inversely proportional to the specific heat. The grating response time is proportional to the specific heat and inversely proportional to the thermal conductivity. Diffraction efficiencies that approach unity are predicted in several readily available electro-optic materials with modest pulse energies from Q-switched Nd:YAG lasers. Observation with cw laser sources is also proposed. The pyro-electro-optic mechanism is compared with other known mechanisms. PMID- 19784143 TI - Long-range, noncoherent laser Doppler velocimeter. AB - An experimental demonstration of a long-range, noncoherent laser Doppler velocimeter (LDV) is presented. The LDV detects incoming Doppler-shifted signal photons by using the sharp spectral absorption features in atomic or molecular vapors. The edge of the absorption feature is used to convert changes in frequency to large changes in transmission. Preliminary measurements of wind velocity using seeded aerosols showed that the LDV results agreed with mechanical anemometer measurements to within the accuracy of the LDV measurements. With optimization the LDV will provide accurate range-resolved and vibration-tolerant wind-speed measurements at large distances. PMID- 19784144 TI - Experimental demonstration of atmospheric compensation using multiple synthetic beacons. AB - We present experimental results that demonstrate real-time, atmospheric turbulence compensation of a bright star with the use of two synthetic beacons. Each beacon was used to measure the phase aberrations over only part of the telescope aperture, a configuration that is suitable for reducing focal anisoplanatism error. To our knowledge, this is the first demonstration of atmospheric compensation with the use of multiple synthetic beacons. PMID- 19784145 TI - High-speed fiber-optic temperature sensor. AB - The temporal response of a fiber-optic Fabry-Perot-type interferometer, formed by cleaving the ends of a length of highly birefringent (Hi-Bi) fiber, to high frequency heat pulses is investigated both theoretically and experimentally. The heat pulses are produced by amplitude modulating the output of an argon laser with a variable frequency Bragg cell. This beam is focused at one of the cleaved ends of the interferometer; the fastest temporal response occurs when the beam is focused onto the core of the fiber. A time response of ~2.5 micros is measured. PMID- 19784146 TI - Wide-angle self-aligning heterodyning with four-wave mixing. AB - Self-aligning optical heterodyning is demonstrated with an acceptance angle as large as 40 degrees . The receiver consists of a strontium barium niobate (SBN) crystal, a detector, and collecting lenses. The incoming beam interferes with the local oscillator to create a real-time grating in the SBN crystal, which diffracts and aligns the signal with the local oscillator. Heterodyne detection occurs as long as the written grating can diffract the input signal. All alignment requirements between the signal and local oscillator are automatically satisfied by the diffraction process, which permits the large acceptance angle. Insensitivity with respect to crystal orientation and background radiation has also been demonstrated. PMID- 19784147 TI - Triple correlation of the interval probability density at low light levels. AB - A Poisson point process presents a series of characteristics that may be used to define functions with a good signal-to-noise ratio. This research describes a statistical function obtained by handling the measured intervals between photopulses and containing the same information about the signal to be analyzed as the triple correlation. This function can be successfully applied to the analysis of low-light-level signals or images. PMID- 19784148 TI - Physical basis for Descartes ring scattering in laser-irradiated microdroplets. AB - Stimulated Raman scattering from laser-irradiated microdroplets is observed from two distinct spatial regions, the droplet rim and a ringlike region encircling the laser beam axis on the droplet shadow face (the Descartes ring). With the use of two pulsed laser beams, a perturbing beam and a delayed stimulated-Raman scattering pump beam, the physical mechanism for Descartes ring scattering is investigated. Evidence is obtained of a persistent mechanism that continues even after the perturbing laser pulse is turned off. This mechanism is tentatively identified as electrostriction. The possible existence of an additional prompt mechanism that requires overlap between perturbing and pump laser pulses is also discussed. PMID- 19784149 TI - Imaging through scattering media using spatial incoherence techniques. AB - Imaging of objects embedded in scattering media can be accomplished by sources with reduced spatial coherence instead of pulsed light or short temporal coherence light. PMID- 19784150 TI - Nonlinear photon localization for high-intensity laser protection systems for photodetectors and eyes. AB - A multilayer system of alternating high and low nonlinear materials can be designed to respond actively to the radiation intensity, whereby it transmits ambient light but rejects high-intensity light over a broad spectral region. The transmission of the low-intensity light is determined by the linear refractive indices of the multi-layer system, which can be designed to transmit the ambient light totally. The high-intensity laser radiation induces a change in the refractive indices through the nonlinear index, which changes the interface reflectance and randomizes the phase shift of each layer. This induced random one dimensional system will totally reflect the high-intensity laser over a broad spectrum. PMID- 19784151 TI - Clamped-unclamped electro-optic coefficient dilemma in photorefractive phenomena. AB - In a usual photorefractive experiment neither the unclamped nor the clamped linear electro-optic coefficients should be used for calculating the refractive index change. We show that a crystal deformation in a form of a static plane wave is produced by the space-charge electric-field grating. The total refractive index change is then calculated by adding together the strain-free electro-optic contribution and the elasto-optic contribution, properly taking into account also the rotation of the axes of the optical indicatrix that is produced by shear deformations. This roto-optic contribution to the photorefractive effect has been overlooked until now. PMID- 19784152 TI - Numerical modeling of photorefractive response to short-pulsed illumination. AB - Numerical modeling of the nonlinear response of non ferroelectric photorefractive crystals to short-duration laser pulses is demonstrated. The model is based on the band-transport equations for a single-level, single-charge carrier system. The capabilities of the numerical model surpass the capabilities of linearized theories. The accuracy of the model is demonstrated by comparison with published diffraction efficiency data. The growth of the harmonics of a unity-modulation sinusoidal grating and the response of Bi(12)SiO(20) to multiple Q-switched pulses are two examples that demonstrate how the numerical model surpasses the linearized theory. Comparison with experiment dictates that a sinusoidal grating be assumed, but the model is general enough to accommodate arbitrary patterns of incident energy density. PMID- 19784153 TI - Analysis of propagation of Raman-pump-supported solitons in a nonlinear-optical fiber. AB - Propagation of a soliton in a lossy fiber with Raman energy transfer from a continuous pump wave is analyzed under the assumptions that the soliton amplitude is much larger than the pump wave and that the soliton is sufficiently narrow. It is demonstrated that the Raman amplification mechanism gives rise to a continuous downshift of the central frequency of the soliton in agreement with recent numerical simulations. PMID- 19784154 TI - Compression of the coherence time of incoherent signals to a few femtoseconds. AB - We compute in the femtosecond regime the coherence time compression ratio and the corresponding spectral broadening owing to self-phase modulation of an incoherent signal propagating in an optical fiber. We incorporate in our differential equation the terms responsible for group-velocity dispersion, higher-order dispersion terms self-steepening, and induced Raman scattering. Using typical fiber parameters, we show that it is possible to compress the coherence time of an incoherent signal to few femtoseconds. PMID- 19784155 TI - All-optical arbitrary demultiplexing at 2.5 Gbits/s with tolerance to timing jitter. AB - All-optical demultiplexing has been shown with a full-duty-cycle 2.5-Gbit/s signal in a nonlinear fiber Sagnac interferometer. Complete switching of arbitrary pulse patterns in the data stream has been achieved by using two orthogonal polarization states for the switching and switched pulse trains. The polarization dispersion between the two fiber axes defines a window that allows for switching with timing errors as large as 350 ps. PMID- 19784156 TI - Soliton transmission control. AB - The Gordon-Haus limit of long-distance soliton transmission can be partially overcome through the use of linear filters in each amplifier stage. New limits are derived, and they show the possibility of increased bit rates and/or distances of propagation. PMID- 19784157 TI - Annealed proton-exchanged LiNbO(3) waveguides. AB - We report characterization of annealed proton-exchanged waveguides in LiNbO(3). Effective-mode indices and fundamental-mode intensity profiles were measured for a variety of fabrication conditions. Index profile, depth, and surface refractive index change were determined versus exchange depth and anneal time and are presented in a universal form. An empirical concentration-dependent diffusion model describing the annealing process is presented. The refractive-index dispersion in proton-exchanged and annealed proton-exchanged waveguides was determined for wavelengths between 0.4 and 1.1 microm. PMID- 19784158 TI - High-intensity and high-repetition-rate Q-switched diode-pumped Nd:YLF-pumped femtosecond amplifier. AB - We report the amplification of a colliding-pulse mode-locking femtosecond laser to energies of 2 microJ per pulse at a repetition rate of 3 kHz in a two-stage double-confocal resonator dye amplifier pumped by a Q-switched diode-pumped frequency-doubled Nd:YLF laser. The amplified pulses were used to generate a continuum in both an ethylene glycol jet and a single-mode fiber. The spectrally broadened pulses from the fiber were compressed to a duration of 13 fs. PMID- 19784159 TI - Efficient TEM(00)-mode operation of a laser-diode side-pumped Nd:YAG laser. AB - We report operation of a laser-diode side-pumped Nd: YAG laser with a novel pumping geometry that ensures efficient conversion of pump energy into the TEM(00) mode. Of the 1064-nm output, 11.8 mJ of energy was obtained in a 200 micros pulse with 64 mJ of pump energy at 808 nm. The overall conversion and slope efficiencies were 18% and 23%, respectively. PMID- 19784160 TI - Laser frequency translation: a new method. AB - We demonstrate how the frequency of a single-mode cw dye laser can be translated by 1.772 GHz using stimulated Raman scattering in sodium vapor. The output of a sodium Raman laser, the frequency-translated beam, is shown to be highly correlated in frequency with the dye-laser pump beam. The bandwidth of the 1.772 GHz heterodyne beat signal between the two beams is found to be as narrow as 440 Hz, much narrower than the root-mean-square frequency jitter (~1 MHz) of the dye laser pump beam. The Raman laser method can be used with materials other than sodium, such as cesium or magnesium, to obtain frequency translations of a magnitude that may not be easily attainable with acousto-optic or electro-optic techniques. PMID- 19784161 TI - 69% Efficient continuous-wave second-harmonic generation in lithium-rich lithium niobate. AB - Lithium-rich lithium niobate fabricated by vapor transport equilibration is used to frequency double the output of an injection-locked Nd:YAG laser. Internal doubling efficiencies as high as 69% and powers of as much as 1.6 W are achieved by resonant external cavity second-harmonic generation. No evidence of photorefractive damage is observed at the operating temperature of 234 degrees C. PMID- 19784162 TI - Use of time-resolved IR reflection and transmission as a probe of carrier dynamics in semiconductors. AB - We discuss the use of time-resolved IR reflection and transmission for studying semiconductor carrier dynamics. We solve Maxwell's equations for a nonhomogeneous carrier distribution in the limit of small perturbation. We show that the IR probe is sensitive to the spatial profile of the carrier density far below the surface. We present results of measurements for InP:Fe that demonstrate the advantages of this technique. PMID- 19784163 TI - Highly efficient conversion of picosecond Nd laser pulses with the use of group velocity-mismatched frequency doubling in KDP. AB - We report an increase in the conversion efficiency from approximately 40% to approximately 75% for type II frequency doubling of 1.053-microm, 1.6-ps-duration pulses in KDP when a delay of approximately 1.45 +/- 0.1 ps between the extraordinary and ordinary pulses is introduced at the input to the doubling crystal. The delay compensates for the effect of group-velocity dispersion in the crystal with the result that the effective interaction length in the crystal is approximately doubled. PMID- 19784164 TI - Generation of frequency-tunable ultrashort optical pulses with liquid-core fibers. AB - Experimental generation of ultrashort, frequency-tunable optical pulses in liquid core fibers is reported. Passage of high-energy optical pulses through a submillimeter liquid-core fiber reveals a quasi-linear frequency sweep. The subsequent use of a grating dispersion system and a spectral window shortens the Nd:YAG laser pulse duration from 45 ps to less than 2 ps. Based on spectral filtering after the grating pair, the wavelength of the generated short pulses is shown to be tunable. PMID- 19784165 TI - Time-gated imaging through scattering media using stimulated Raman amplification. AB - We propose the use of stimulated Raman scattering for time-gated image amplification and demonstrate its use for the detection of images through a strongly scattering material. Using 30-ps pulses from a frequency-doubled Nd:YAG laser, we have amplified and detected images through a suspension of nondairy creamer with a spatial resolution of less than 300 microm and at concentrations such that the nonscattered extinction ratio was e(-33). Our time-gated image amplifier can produce images under conditions in which the scattering medium is sufficiently dense that an image cannot be seen by using multiple exposures on a streak camera or time-integrated exposures on a sensitive, low-noise CCD camera. PMID- 19784166 TI - Optical attenuator for plastic optical fiber with small dependencies on mode and wavelength. AB - We propose the fabrication of an in-line-type optical attenuator with high performance by thermally replicating carbon-dispersed polymethyl methacrylate film at the end of plastic optical fiber. When carbon with a particle size of 50 nm is employed, the dependency of the attenuation on the mode of excitation is within +/-10% even for variations in FWHM of incident modal width in the range of 10 degrees to 50 degrees . For the dependency of the attenuation on the wavelength, the value was also within +/-variations of wavelength from 400 to 900 nm. PMID- 19784167 TI - Dynamic photorefractive optical memory. AB - We investigate an architectural approach to dynamic three-dimensional volume storage that circulates holograms between two photorefractive crystals. Introduction of an optical amplifier into the system increases the effective write-erase asymmetry of the crystals and permits the amplification of the recalled images. This memory architecture is experimentally shown to provide write-erase storage with robustness to multiple optical readouts. PMID- 19784168 TI - Isotopic shift measurements of the (3)S(3sns)-(3)P(3s3p) transitions of Mg I. AB - We have measured the isotopic shifts of the (3)S(3s6s)-(3)P(3s3p) and (3)S(3s7s) (3)P(3s3p) transitions of Mg I and the values of the hyperfine-structure constant A((3)S(1)) for the 3s6s and 3s7s terms of (25)Mg. The absolute wavelengths have been measured at an accuracy level of +/-3 x 10(-7), mainly limited by the Doppler broadening of the I(2) transitions used as a reference and by the precision of the knowledge of the related wavelengths. The measurements have been performed in an atomic beam rich in metastable atoms by scanning a ring dye laser and observing simultaneously the fluorescence of the beam. PMID- 19784169 TI - Van der Waals-induced spectral distortions in selective-reflection spectroscopy of Cs vapor: the strong atom-surface interaction regime. AB - Frequency-modulated selective-reflection spectroscopy of the 6S-7P Cs resonance line yields Doppler-free anomalous line shapes that we demonstrate to be fully dominated by the long-range atom-surface interaction potential. The spatial inhomogeneous broadening of the observed line shapes, as well as its dependence on the pressure, the nature of the dielectric window, and the light incidence angle, is fully interpreted with a z(-3) van der Waals attraction model. These experiments clearly prove the feasibility of a spectral analysis of atom-surface interactions. PMID- 19784170 TI - Coherence and indistinguishability. AB - It has long been known that the interference produced by two light beams is related both to their mutual coherence and also to the intrinsic indistinguishability of the photon paths. With the help of a decomposition of the density operator it is shown that the degree of indistinguishability equals the degree of coherence. This provides the fundamental link between the wave and the particle descriptions. PMID- 19784171 TI - Ultralong optical dephasing time in Eu(3+):Y(2)SiO(5). AB - We report what is to our knowledge the first measurement of linear and nonlinear spectroscopic properties for the (7)F(0)-(5)D(0) transition of Eu(3+):Y(2)SiO(5). Two clearly resolved lines at 579.879 and 580.049 nm, stemming from different sites, show dissimilar photoluminescence and hole spectra. In addition, these two sites have different inhomogeneous and homogeneous linewidths, which suggests that the local-field effect is smaller for one site. Specifically, the less affected site exhibits the longest dephasing time (822 micros) of any solid, which corresponds to a homogeneous linewidth of 387 Hz, and this linewidth is found to persist for hours without apparent spectral diffusion. PMID- 19784172 TI - Supersonic cooling of rare-gas excimers excited in dc discharges. AB - Emission spectra of the homonuclear rare-gas excimers have been investigated in the wavelength region of 50 to 200 nm by using continuous discharges with supersonic jet expansion. The well-known dimer bands were readily observed in the emission spectra of He, Ar, Kr, and Xe along with an extremely weak band of Ne. A detailed examination of the Ar(2) band at 128 nm was carried out, and its envelope and bandwidth (8.7 nm) indicate significant vibrational cooling owing to supersonic expansion. PMID- 19784173 TI - Time- and frequency-domain hybrid optical memory: 1.6-kbit data storage in Eu(3+):Y(2)SiO(5). AB - We propose and demonstrate a novel type of frequency-selective optical memory that writes and reads the data in both the time domain and the frequency domain. Temporal 16-bit data were stored by accumulated-photon-echo bit-by-bit storage at 103 frequency addresses within the inhomogeneous line of the (7)F(0)-(5)D(0) transition of Eu(3+):Y(2)SiO(5), which yields a total memory capacity of 1.6 kbits in a single spot of 240-microm diameter. The keys to the success of this experiment are this material's long dephasing time and lack of spectral diffusion. PMID- 19784174 TI - Coherent image synthesis from wave-front sensor measurements of a nonimaged laser speckle field: a laboratory demonstrations. AB - We report what are to our knowledge the first coherent images recovered in the laboratory from measurements made with a Shack-Hartmann wave-front sensor of the phase and amplitude of a laser speckle wave front. We discuss the design of our wave-front sensor, which can obtain the phase and amplitude of an optical field with a single intensity measurement, and we point out a particular type of phase jump that cannot be detected by the Shack-Hartmann sensor. We also discuss implementations of this technique that may permit near-diffraction-limited imaging through turbulent media. PMID- 19784175 TI - Bistable fiber-optic Michelson interferometer that uses wavelength control. AB - Feedback of the interference signal of an unbalanced Michelson interferometer to the current supply of the semiconductor-laser source yields bistability under input intensity variation owing to wavelength-induced phase modulation. A linear stability analysis of the system's differential equation gives the ratio of the system time constant tau to the feedback delay time T to determine the critical input intensity for the onset of self-oscillations. Input-output characteristics that exhibit bistability and self-oscillations are obtained experimentally through modulation of the input power by using an integrated-optics intensity modulator. PMID- 19784176 TI - Experimental realization of a fiber-optic-based multichannel digital correlator. AB - An experimental demonstration of a new realization of a multichannel digital correlator is presented. It uses optical fiber networks based on a tree topology to implement the required passive delay lines and intensity addition followed by electronic thresholding to perform the multiplication function. Application of this device to laser light scattering and spectroscopy in radio astronomy and the potential for operating at higher bandwidths are discussed. PMID- 19784177 TI - 1.06-microm all-fiber gyroscope with noise subtraction. AB - An all-fiber gyroscope that uses a 1.06-microm multicore Nd-doped fiber source pumped by a laser-diode array is demonstrated. Intensity noise subtraction is used to reduce the excess noise that arises from a source bandwidth limitation. The random walk coefficient is improved by a factor of 3, to 2.5 x 10(-4) deg radicalh (1-km fiber, 16-cm radius). PMID- 19784178 TI - Depolarized source for fiber-optic applications: erratum. PMID- 19784180 TI - Recovery of particle size distributions by inversion of the optical transform intensity. AB - Using the optical transform intensity and a new inversion formula, we demonstrate the recovery of particulate size distributions. For the optical experiments, chrome masks are fabricated to provide three distributions: the gamma, the log normal, and the bimodal exponential. Excellent agreement with the theory is obtained. PMID- 19784179 TI - Upper bound of the diffraction efficiency of diffractive phase elements. AB - An upper bound of the diffraction efficiency of diffractive elements that only influence the phase of the illumination wave is derived. The derivation only utilizes the specification of the desired diffraction pattern. It is independent of the technique to design and fabricate the diffractive element. The theory is based on the transmittance approach to describe the effect of the element on the illumination wave. PMID- 19784181 TI - Artificial distributed-index media fabricated by zero-order gratings. AB - Zero-order gratings are grating structures with a period that is small compared with the wavelength of light. Only the directly transmitted or reflected light, the zero diffraction order, is nonevanescent and propagates in a distance from the grating. Thus the grating behaves like a slab of ordinary homogeneous material with an effective refractive index. By varying the material composition, i.e., by variation of the duty cycle of the grating, the effective refractive index can be changed. A grating with variable duty cycle therefore behaves like a material with distributed index. Based on such artificial materials, distributed index elements are proposed. The physical principle is demonstrated with water waves. PMID- 19784182 TI - Effect of chirality on the transient signal wave front. AB - We analyze the behavior of the wave front of a transient pulse propagating in an isotropic homogeneous chiral material and discuss the role of chirality and its underlying physics on the pulse's rise time, ringing frequency at the early time of arrival, and state of polarization at the wave front. We use the one-resonance model of dispersion for the material parameters. It is shown that the chirality of the medium decreases the ringing frequency at the early time as compared with the nonchiral case and causes the rotation of the plane of polarization and the evolution of the cross-polarized component at the transient signal wave front. Potential applications and motivations for the present study are also mentioned. PMID- 19784183 TI - Virtual optical nonlinearity in GaAs-AlAs superlattices. AB - We report a full-scale calculation of the third-order susceptibility, X((3)), in GaAs-AlAs superlattices. We present the frequency dependence of X((3)) and find a favorable figure of merit for near-resonant enhancement of X((3)). PMID- 19784184 TI - Experimental results of second-harmonic generation from a polyurethane waveguide on a silver grating coupler. AB - Second-harmonic generation by excitation of guided modes and the surface plasmon in a polyurethane-coated silver grating coupler is presented. In order to study the spectral dependence of the second-harmonic efficiency, two different pump wavelengths are used, 1064 and 1319 nm. For the longer-wavelength pump we observe a large enhancement of the second-harmonic efficiency as the incident angle is scanned through an electromagnetic resonance, whereas for the shorter-wavelength pump the second-harmonic wavelength falls within the absorption band of the polymer, and we observe unexpected minima instead of maxima. PMID- 19784185 TI - Absorption and amplification of dark solitons. AB - Propagation of dark solitons in nonlinear media that include gain and loss is investigated. Two-photon absorption is shown to lead to dark-soliton broadening and attenuation, whereas gain (such as that arising from stimulated Raman scattering) is shown to lead to their narrowing and amplification. The relations describing the adiabatic evolution of dark solitons in the weakly perturbed media are presented. In comparison with fundamental bright solitons, dark solitons are shown to be less sensitive to the perturbations. Stationary propagation of dark solitons is also found to be possible in the presence of both absorption and amplification, but it differs from that in the passive lossless nonlinear media. PMID- 19784187 TI - Phase conjugation involving incoherent counterpropagating beams in photorefractive media. AB - We propose and analyze a new type of phase conjugation between counterpropagating beams in photorefractive materials based on diffraction from transmission gratings only. This effect does not require temporal coherence between the counterpropagating beams and may occur spontaneously, with no external seeding, even with wide (frequency) band light sources. PMID- 19784186 TI - Dissipative damping of dark solitons in optical fibers. AB - The adiabatic evolution of the parameters of a dark soliton in the presence of dissipative fiber losses is considered. It is shown that the rate at which a dark soliton decays and spreads is only half the corresponding rate for a bright soliton. PMID- 19784188 TI - Spatial subharmonic generation of orthogonally polarized light waves in BaTiO(3) by phase-matched nonlinear mixing. AB - The development of a spatial subharmonic, i.e., of a light wave propagating at the bisector of two pump waves, with orthogonal polarizations incident upon a BaTiO(3) crystal in a plane normal to the optical axis is observed and studied. Parametric amplification of a seed wave meeting the phase-matching condition in the presence of two pump waves is shown to be the main reason for subharmonic generation in this crystal. PMID- 19784189 TI - Spatial-harmonic gratings at high modulation depths in photorefractive quantum wells. AB - High-order spatial harmonics of photorefractive gratings are detected directly in multi wave mixing experiments in photorefractive AlGaAs/GaAs quantum wells operating in the Franz-Keldysh geometry. We have observed diffraction signals from the first-, second-, and third-harmonic refractive-index gratings. The quadratic electro-optic effect in the quantum wells second-spatial-harmonic grating. PMID- 19784190 TI - Dispersion in rare-earth-doped fibers. AB - Rare-earth dopants in optical fibers have in general been ignored as a source of dispersion. The host material dispersion has been assumed to be an adequate description of the dispersion properties. Resonant dispersion features owing to absorption by the rare-earth ions were observed that were comparable in magnitude with the host material dispersion. These observations have consequences in the design of fiber lasers, nonlinear fiber transmission systems, and analog information systems. PMID- 19784191 TI - Low-loss erbium-doped ion-exchanged channel waveguides. AB - We report the fabrication of ion-exchanged channel waveguides in an Er-doped Na modified BK-7 glass. The buried waveguides were elliptical in cross section, having approximate cross-sectional dimensions of 10 microm x 30 microm. Characterization of the optical properties of the waveguides revealed that they are single mode in the 10-microm dimension and multimode in the 30-microm dimension and exhibit a total waveguide loss, absorption plus scattering, of 0.8 dB/cm at 0.633 microm. PMID- 19784192 TI - Diode-pumped cw bulk Er:Yb:glass laser. AB - ontinuous-wave laser operation of bulk Er:Yb:phosphate glass pumped at 980 nm by an InGaAs index-guided diode laser has been achieved for the first time to our knowledge, with 2 mW of output power obtained at 1.54 microm. To optimize pumping conditions and to investigate the effects of pump wavelength, the Er(3+):Yb(3+) glass disk has also been pumped by a Ti:Al(2)O(3) laser at 960 and 980 nm, and we obtained high output power (70 mW) and the highest slope efficiency (21% for 980 nm pumping) reported to date for a bulk Er:glass laser. PMID- 19784193 TI - Single-mode oscillation of laser-diode-pumped Nd:YVO(4) microchip lasers. AB - Single-mode-oscillation output power of ~103 mW has been observed in 1.1-at.% doped Nd:YVO(4) pumped with a 500-mW laser diode. Continuous-wave thresholds of ~5.3 mW have been observed with slope efficiencies of greater than 32.4%. The microchip laser can be tuned over 107 GHz, without mode hopping, by heating the laser crystal. PMID- 19784194 TI - AlGaAs/GaAs optically controlled wave-plate modulator. AB - We demonstrate an AlGaAs/GaAs multiple-quantum-well optically controlled electro optic wave-plate modulator that uses integrated optics. For operation as an optically controlled switch, output amplitude contrast ratios of greater than 300:1 are typically obtained with signal beam throughputs of 34% and an extrapolated switching speed of 1.5 ns. For applications as an optically controlled wave plate, we have measured the linear, r(41), and quadratic, R(11) R(12), electro-optic coefficients of the waveguide at the signal wavelengths and the device photo-generated current sensitivity at the control beam wavelength. PMID- 19784195 TI - Mode locking in solitary lasers. AB - We present an analysis of passively mode-locked lasers in which pulse formation is dominated by the interplay between self-phase modulation and negative dispersion in separate cavity elements. Steady-state pulse parameters and stability issues are discussed. Stability in these solitary systems relies on some passive amplitude modulation, and the ultimate system performance is found to depend sensitively on the magnitude of amplitude modulation relative to that of phase modulation. PMID- 19784196 TI - Multikilohertz Ti:A1(2)O(3) amplifier for high-power femtosecond pulses. AB - We amplified femtosecond pulses at repetition rates of as much as 7.2 kHz in a Ti:Al(2)O(3) regenerative amplifier pumped by a frequency-doubled Q-switched Nd:YLF laser. Energies of as much as 1 mJ at 1 kHz and 85 microJ at 7.2 kHz in a 150-fs pulse have been obtained. This source was used to produce 1 W of femtosecond white light through spectral continuum generation. PMID- 19784197 TI - Self-mode locking of a diode-pumped Nd:YLF laser. AB - We report on the self-mode locking of a diode-laser-pumped Nd:YLF laser. Pulses of 6-ps duration have been obtained by using only a glass rod placed at an intracavity focus and an aperturing slit near the output coupler to achieve pulse shaping. The mode-locking mechanism is believed to be that of self-focusing (Kerr lens mode locking) owing to the optical Kerr effect in the glass rod. The pulses are approximately bandwidth limited, and the process can be self-started by a mechanical perturbation to the system. PMID- 19784198 TI - Dual-scale topology optoelectronic processor. AB - The dual-scale topology optoelectronic processor (D-STOP) is a parallel optoelectronic architecture for matrix algebraic processing. The architecture can be used for matrix-vector multiplication and two types of vector outer product. The computations are performed electronically, which allows multiplication and summation concepts in linear algebra to be generalized to various nonlinear or symbolic operations. This generalization permits the application of D-STOP to many computational problems. The architecture uses a minimum number of optical transmitters, which thereby reduces fabrication requirements while maintaining area-efficient electronics. The necessary optical interconnections are space invariant, minimizing space-bandwidth requirements. PMID- 19784199 TI - X-ray third-harmonic generation in plasmas of alkalilike ions. AB - We demonstrate theoretically the feasibility of x-ray near-resonant third harmonic generation in a number of plasmas of Li- and Na-like ions as well as third-harmonic generation enhanced by phase matching using buffer plasmas. PMID- 19784200 TI - Intermediate excited-state absorption in erbium-doped fiber strongly pumped at 980 nm. AB - We report the observation of fluorescence at 530 to 550 nm from erbium-doped germanosilicate fiber under strong pumping in the 980-nm band. The observed nonlinear dependence on pump power is shown to arise from a sequential two-photon absorption from the ground state to the (4)F(7/2) state through the short-lived (4)I(11/2) intermediate state. Rate-equation modeling shows that the pump power dependence of this intermediate excited-state absorption is influenced by population cycling induced by amplified spontaneous emission in the fiber from the metastable (4)I(13/2) state. PMID- 19784201 TI - Twin-image elimination in in-line holography of finite-support complex objects. AB - Reconstruction of in-line holograms suffers from the superposition of two twin images having different foci but identical information content. A simple iterative method of twin-image elimination is presented here. It is based on the fact that, if the object has a finite support and the recording distance is not too small, the out-of-focus field is known on a large part of the reconstruction plane and is only superposed by the in-focus one inside a restricted support. An iterative procedure is developed to recover the out-of-focus wave inside the in focus image support. Inverse diffraction then gives the reconstructed image. This procedure can be easily automated and works for finite-support real or complex objects, recorded in geometries with a Fresnel number of ~1. PMID- 19784202 TI - Durability investigation of a KCI:Li F(A)-center optical memory at room temperature. AB - The reorientation of F(A)(II) centers in electrolytically colored KCl:Li crystals under ruby laser exposure was studied at room temperature. A prolonged series of laser pulses was applied over a period of three days to check the durability and possible fatiguing of the crystals. PMID- 19784203 TI - Femtosecond temporal encoding in barium titanate. AB - We describe two-beam coupling and temporal encoding experiments in barium titanate. Volume gratings are created in the photorefractive material by 50-fs optical pulses. Information in the writing pulses may be encoded as spatially distributed volume gratings in the crystal. Femtosecond temporal waveform reconstruction is demonstrated. PMID- 19784204 TI - Phase and frequency resolution of picosecond optical Kerr nonlinearities. AB - We report on a method aimed at measuring both the real and imaginary parts of the third-order Kerr-type nonlinear-optical susceptibility of isotropic materials. It is based on Kerr ellipsometry in which analysis of the polarization state of transmitted light between a nearly crossed polarizer and an analyzer allows separation of pump-induced dichroism and birefringence. The method provides a natural measurement of nonlinear phase retardations in angle units, without any calibration procedure. By using a white-light continuum as a probe, this property is used to get a simultaneous measurement of the nonlinear dispersion in the whole visible spectrum. It is illustrated in tetramethylsilane, where stimulated Stokes and anti-Stokes Raman contributions to the nonlinearity are observed. PMID- 19784205 TI - Metal-embedded fiber-optic Fabry-Perot sensors. AB - The sensing of temperature and of ultrasonic pressure with fiber-optic Fabry Perot interferometers embedded in aluminum is demonstrated. The metal parts are cast in air by using graphite molds. Breakage of the fibers at the air-metal interface during the casting process is avoided through the use of stainless steel stress-relief tubes. The optical phase in an embedded interferometer is found to be 2.9 times more sensitive to temperature change than for the same interferometer in air, in good agreement with model calculations. An embedded interferometer has also been used to detect ultrasonic waves over the frequency range of 0.1-8 MHz. PMID- 19784206 TI - Self-organizing photorefractive frequency demultiplexer. AB - We demonstrate a self-organizing photorefractive circuit that demultiplexes a beam that has two signals imposed on separate optical carrier frequencies into two beams, each containing one of the signals on its carrier. Unlike conventional demultiplexing techniques, this method requires little a priori knowledge about the carrier frequencies. The signal channels must be spatially uncorrelated, and their frequency separation must be more than the photorefractive response bandwidth (hertz to kilohertz). The optical circuit uses no local oscillator, and the photorefractive response bandwidth places no upper bound on the channel bandwidth. Experimental results for demultiplexing a beam that has two signals, with a BaTiO(3) circuit, show contrast ratios of better than 40:1 at the outputs. PMID- 19784207 TI - Miniature Faraday current sensor based on multiple critical angle reflections in a bulk-optic ring. AB - A novel optical element for a bulk glass current sensor that utilizes the Faraday effect is presented with a demonstrated sensitivity of 1 amp-turn and a flat frequency response in the range of 10-10(4) Hz. The new sensing element overcomes the problems associated with birefringence in optical fiber current sensors and the requirement to make bulk-optic current sensors in complex three-dimensional topologies. PMID- 19784208 TI - All-optical, all-fiber circulating shift register with an inverter. AB - An all-optical fiber Sagnac interferometer switch and erbium amplifier have been combined to form an all-optical 254-bit circulating shift register with an inverter. This simple optical loop memory demonstrates the cascadability of Sagnac interferometer switches. PMID- 19784209 TI - Laser-absorption mass flux sensor for high-speed airflows. AB - We present a laser-based concept for an air mass flux sensor based on the simultaneous measurement of density and velocity of O(2). The sensor uses wavelength modulation absorption spectroscopy at 10 MHz of an AlGaAs laser diode in the b(1)Sigma(g)(+)(v' = 0)-X(3)Sigma(g)(-)(v'' = 0) system of O(2), combined with second-harmonic detection. The apparatus is demonstrated on a high-speed oxygen flow generated behind the incident shock wave in a shock tube. The measurement time is 0.5 ms for typical absorption levels of 0.5%. PMID- 19784210 TI - Kinematic study by speckle photography. AB - From the irregular fringe patterns produced by the Fourier transform of a multiply exposed specklegram we may extract information about the kinematic parameters of a linear motion. The initial velocity, acceleration, and age (i.e., the time interval of the motion) for a uniform accelerated motion are computed from the results of a spatial frequency analysis. PMID- 19784211 TI - High-resolution reflectometry in biological tissues. AB - Optical low-coherence ref lectometry is applied for the first time to our knowledge to investigate diffusive biological tissues with a single-mode fiber probe. Samples of fresh arteries are studied, using the backscattered light from the tissue. The probed volume in the vicinity of the fiber tip is estimated to be below 6.7 x 10(-10) cm(3). This noninvasive method allows one to determine optical parameters, such as the index of refraction and the transmission properties, and the tissue thickness. PMID- 19784212 TI - Phase retardation of the uniform-intensity axilens. AB - A method for determining the phase-retardation function of the uniform-intensity axilens is discussed and compared with that of an earlier publication [Opt. Lett. 16, 523 (1991)]. Within the presented formulation good agreement is achieved between the geometrical-optics prediction and the numerically evaluated diffraction integral. PMID- 19784213 TI - Accurate solution of the Helmholtz equation by Lanczos orthogonalization for media with loss or gain. AB - The numerical scheme for solving the Helmholtz equation, based on the Lanczos orthogonalization scheme, is generalized so that it can be applied to media with space-dependent absorption or gain profiles. PMID- 19784214 TI - Tunable optical frequency division using a phase-locked optical parametric oscillator. AB - We report the experimental demonstration of a novel optical parametric oscillator approach to tunable optical frequency division. The beat frequency of the signal and idler subharmonic outputs of a tunable cw KTP optical parametric oscillator was phase locked to a microwave reference frequency source, which thus permitted precise determination of the output frequencies at approximately half the input pump frequency. PMID- 19784215 TI - Nonlinear theory of nondegenerate beam coupling through phase-locked detection in an ac field. AB - Different frequency beams interact through the static grating recorded by their running interference pattern in an external ac field. The influence of the self diffraction through the regular degenerate and nondegenerate interaction is studied theoretically. The depletion of all the waves is taken into account. PMID- 19784216 TI - Induced focusing and spatial wave breaking from cross-phase modulation in a self defocusing medium. AB - The spatial effects of cross-phase modulation on a weak probe beam as it copropagates with an intense pump beam through a self-defocusing medium are investigated. Experimental results are presented that demonstrate induced focusing, beam deflection, and the spatial analog of optical wave breaking. The experimental results are in good qualitative agreement with theoretical predictions. PMID- 19784217 TI - Dynamics of self-focusing and self-phase modulation in a parabolic index optical fiber. AB - The dynamics that result from the combined effects of spatial diffraction, nonlinearity, and a parabolic graded index for wave propagation in optical fibers are presented. An approximate analytical solution of the nonlinear Schrodinger equation in a graded-index fiber is obtained by using a variational approach. Particular emphasis is put on the variation of both the pulse width and the longitudinal phase delay with the distance of propagation along the fiber. PMID- 19784218 TI - Switching dynamics of helical solitons in a periodically twisted birefringent fiber filter. AB - We discuss the conditions for the formation, switching, and spatial instability of solitary waves with helical evolution of the polarization in optical fibers with periodic birefringence. PMID- 19784219 TI - Self-focusing and self-defocusing by cascaded second-order effects in KTP. AB - We monitor the induced phase change produced by a cascaded chi((2)):chi((2)) process in KTP near the phase-matching angle on a picosecond 1.06-microm wavelength beam using the Z-scan technique. This nonlinear refraction is observed to change sign as the crystal is rotated through the phase-match angle in accordance with theory. This theory predicts the maximum small-signal effective nonlinear refractive index of n(eff)(2) congruent with +/-2 x 10(-14) cm(2)/W (+/ 1 x 10(-11) esu) for an angle detuning of +/-5 degrees from phase match for this 1-mm-thick crystal with a measured d(eff) of 3.1 pm/V. For a fixed phase mismatch, this n(eff)(2) scales linearly with length and as d(eff)(2) however, for the maximum n(eff)(2) the nonlinear phase distortion becomes sublinear with irradiance for phase shifts near pi/4. PMID- 19784220 TI - Generation of asymptotically stable optical solitons and suppression of the Gordon-Haus effect. AB - By a proper design of the frequency-dependent gain characteristic of optical amplifiers, the parameters (amplitude eta and velocity kappa) of optical solitons in fibers can be made to approach a desired fixed point in kappa-eta space. The method is effective in controlling the random walk of solitons caused either by initial jitter and/or by amplifier noise (the Gordon-Haus effect) and in overcoming the bit-rate limitation that they provide. PMID- 19784221 TI - Simulations to demonstrate reduction of the Gordon-Haus effect. AB - The superposition of spontaneous emission noise on a train of soliton pulses produces a random change of the center frequency of the soliton spectrum that causes a change of the group velocity of individual solitons, which in long-light wave systems translates into a random jitter of the position of the pulses at the receiver. This phenomenon is known as the Gordon-Haus effect. If uncontrolled, the Gordon-Haus effect sets a definite limit on the permissible data rate or on the length of soliton-based light-wave systems. Recently Kodama and Hasegawa [Opt. Lett. 17, 31 (1992)] have shown that the Gordon-Haus effect can be suppressed by placing filters along the fiber that reduce the frequency jitter and the concomitant group-velocity changes. We demonstrate the reduction of the Gordon-Haus effect by computer simulations. PMID- 19784222 TI - Pulse compression in a self-filtering Nd:YAG regenerative amplifier. AB - By operating a Nd:YAG regenerative amplifier with an intracavity spatial aperture, it is found that spectral broadening and chirp sufficient for pulse compression are produced at intracavity intensities well below the self-focusing threshold. Stable, synchronous pulse compression of as much as a factor of 4 has been achieved, while a factor of 8 is possible. PMID- 19784223 TI - Pumping configuration without focusing lenses for a small-sized diode-pumped Nd:YAG slab laser. AB - We propose an end-pumping method for a small-sized diode-pumped Nd:YAG laser. The miniature Nd:YAG slab is directly coupled to the pump diode without focusing lenses. With the use of total reflection on the slab surfaces, the pump light is confined to the laser mode volume. With a diode-laser power of 890 mW, a TEM(00) output power of 210 mW is obtained. PMID- 19784224 TI - Electronically tuned diode-laser-pumped Cr:LiSrA1F(6) laser. AB - With a liquid-crystal-based birefringent tuner in a coupled resonator, an AlGaInP diode-laser-pumped Cr:LiSrAlF(6) cube laser has been electronically tuned from 858 nm to beyond 920 nm. At an incident pump power of 42 mW, an output power in excess of 4.3 mW was observed near the peak of the tuning curve at 870 nm. PMID- 19784225 TI - Continuous-wave sum-frequency generation near 194 nm in beta-BaB(2)O(4) crystals with an enhancement cavity. AB - Continuous-wave coherent radiation tunable near 194 nm has been generated by sum frequency generation in beta-BaB(2)O(4) placed inside an external enhancement cavity. An output power of 16 microW has been obtained with a walk-off compensated configuration of beta-BaB(2)O(4) crystals. PMID- 19784226 TI - Frequency stabilization of a semiconductor laser using an external phase modulator. AB - A Ti:LiNbO(3) waveguide phase modulator is used as an external frequency stabilizer to reduce the linewidth of an AlGaAs semiconductor laser. A ring interferometer is used as a frequency discriminator, and a wideband servo controller (dc to 30 MHz) is constructed in which feed-forward control of the external phase modulator is combined with feedback control of the injection current. A linewidth of 45 kHz is obtained. PMID- 19784227 TI - Ion-implanted Nd:GGG channel waveguide laser. AB - We report what is to our knowledge the first fabrication and laser operation of ion-implanted Nd:GGG channel waveguides. Diode-pumped operation has been achieved with absorbed power thresholds as low as ~2 mW and a slope efficiency of ~30% with respect to absorbed power. PMID- 19784228 TI - Properties of an external-cavity traveling-wave semiconductor ring laser. AB - We describe the lasing characteristics of an external-cavity 1.3-microm wavelength traveling-wave semiconductor laser that uses a tilted-stripe optical amplifier. It was found that within a 45-nm-wavelength tuning range the power level does not suffer any discontinuous change. The lasing spectrum remains single mode within a 35-nm range, and the linewidth is less than 50 kHz. The lasing frequency is stable and changes by only 25 MHz/ degrees C and by approximately 1.6 MHz/mA. For cw operation the intracavity power reaches 24 mW, and for long-pulse operation the power level is as high as 175 mW. The lasing power level exhibits long-term stability. Moreover the intracavity power level is found to be insensitive to the coupled output power. PMID- 19784229 TI - Noninterferometric optical subtraction using reflection-electroabsorption modulators. AB - A noninterferometric technique for optical subtraction is demonstrated that employs a multiple-quantum-well reflection-electroabsorption modulator and provides lower insertion loss, larger contrast ratio, and linearity over a larger dynamic range than similar techniques previously reported. PMID- 19784230 TI - Pulse evolution dynamics of a femtosecond passively mode-locked Ti:sapphire laser. AB - The pulse-formation process in a femtosecond passively mode-locked Ti:sapphire laser with a saturable absorber is investigated. The time to reach the steady state is 200 micros. The formation time dependence on the dye concentration and the coincidence of the steady-state pulse width with the self-mode-locked state without a saturable absorber indicate that the function of the saturable absorber is mainly to induce the initial modulation and to shorten the pulse-formation time. PMID- 19784231 TI - Method of generating nearly transform-limited pulses from gain-switched distributed-feedback laser diodes and its application to soliton transmission. AB - A train of nearly transform-limited pulses are generated from a 1.55-microm distributed-feedback laser diode by using gain switching in a novel technique, which is a combination of a spectral window and temporal compression. By amplifying these pulses with erbium-doped fiber amplifiers, we demonstrate soliton transmission in a conventional single-mode fiber. PMID- 19784232 TI - Measurement of the photorefractive phase shift. AB - We present a method to separate the effects of trap gratings and electro-optic gratings in BaTiO(3) crystals, and we determine the true spatial shift between the electro-optic grating and the optical intensity pattern. At small beam crossing angles this spatial shift is strongly affected by a photogalvanic current in the crystal. PMID- 19784233 TI - Parallel subtraction of Fourier power spectrum using holographic interferometry. AB - We propose and demonstrate parallel subtraction of the Fourier power spectrum of two images with the use of real-time holographic interferometry. The subtraction, which exhibits shift invariance, is achieved by employing a Mach-Zehnder interferometer and a photorefractive crystal. The results are presented and discussed. PMID- 19784234 TI - Reduction of quantum fluctuation and suppression of the Gordon-Haus effect with phase-sensitive linear amplifiers. AB - Compared with the use of phase-insensitive linear quantum amplifiers of the same gain G, the use of phase-sensitive linear amplifiers on phase coherent classical light sources in an amplifier-attenuator chain reduces the total quantum noise power by a factor of 4, the homodyne noise variance by 2, and the photon number variance by 2-8 and suppresses the Kerr effect linear phase fluctuation variance as well as the soliton timing-error variance by 2G(2). PMID- 19784235 TI - High-resolution degenerate four-wave mixing spectral profiles of OH. AB - High-resolution degenerate four-wave mixing spectra of the R(1)(9) A(2)Sigma(+) ? X(2)II(0,0) transition of OH have been measured in a hydrogen/oxygen flame at atmospheric pressure where the Doppler and homogeneous linewidths are of comparable magnitude. The observed sub-Lorentzian Doppler-free line profile is fit well by existing perturbative models by using homogeneous broadening consistent with two-photon absorption measurements. Power broadening of the spectral profile with increasing pump-beam intensity was observed and is compared with predictions from a nonperturbative two-level model. PMID- 19784236 TI - Application of a backside-illuminated charge-coupled-device camera for single pulse coherent anti-Stokes Raman spectroscopy N(2) thermometry. AB - The application of an unintensified backside-illuminated CCD for the acquisition of broadband single-pulse coherent anti-Stokes Raman spectroscopy (CARS) spectra is demonstrated. This CCD shows a quantum efficiency 5 times higher than a front illuminated CCD and offers significant advantages compared with intensified linear photodiode array detectors generally used for single-pulse CARS thermometry. It overcomes the main drawbacks of the intensified linear photodiode array detector in single-pulse CARS N(2) spectroscopy: nonlinearity, limited dynamic range, and image persistence. A method for extending the dynamic range is demonstrated in a highly turbulent flame. PMID- 19784238 TI - Single-mode optical fiber goniometer. AB - A two-element single-mode optical fiber goniometer that uses graded-index microlens receivers is presented that measures the angular orientation of a remote laser. The goniometer exhibits a sensitivity of 1.0 V/mrad and a calculated shot-noise-limited angular resolution of 1.0 nrad/ radicalHz. PMID- 19784237 TI - Single-photon detection and imaging with a 10-Hz repetitively pulsed ultrasensitive coherent amplifier. AB - We report an experimental investigation of an ultrasensitive coherent amplifier (USCA) operated at a 10-Hz repetition rate. We measure its quantum-noise-limited sensitivity, amplification, and image resolution. The USCA consisted of two Nd:YAG amplifiers in series with a high-gain four-wave Brillouin mirror with SnCl(4) as the Brillouin medium. We measure a noise-equivalent-energy sensitivity of 1.96 x 10(-19) J/mode or 1 photon/mode at a quantum efficiency of 96%. The system has an overall optical gain of 2.5 x 10(13). With a version of the USCA equipped with an imaging lens system, we demonstrate the amplification and phase conjugation of entire images with a resolution of 164 microrad across a field of view of 4 mrad or 21 x 21 resolution elements. To our knowledge, this is the first demonstration of a repetitively pulsed USCA. PMID- 19784239 TI - Asymptotic scheme for waves in random media. PMID- 19784240 TI - Photorefractive properties of Ce-doped (BaSr)(6)Ti(2)Nb(8)O(30) crystals. PMID- 19784241 TI - Efficient generation of higher-order anti-Stokes VUV radiation by steep-rise pumping. PMID- 19784242 TI - Self-pumped phase conjugation in InP:Fe using band-edge resonance and temperature stabilization: theory and experiments. PMID- 19784243 TI - High photorefractive sensitivity in an n-type 45 degrees-cut BaTiO(3) crystal. PMID- 19784244 TI - Photorefractive diffraction dynamic during writing in paraelectric KTN crystals. PMID- 19784245 TI - High-energy, high-efficiency second-harmonic generation of 1064-nm radiation in KTP. PMID- 19784246 TI - Switch inversion and polarization sensitivity of the nonlinear-optical loop mirror. PMID- 19784247 TI - Influence of stimulated Raman scattering on cross-phase modulation between waves in optical fibers. PMID- 19784249 TI - Stability of the TE(0) guided wave of a nonlinear waveguide with a self defocusing bounding medium. PMID- 19784248 TI - Optically tunable adiabatic beam splitter. PMID- 19784250 TI - Passively Q-switched transverse-diode-pumped Nd(3+):YLF laser oscillator. PMID- 19784251 TI - Efficient sum-frequency upconversion in a resonantly pumped Nd:YAG laser. PMID- 19784252 TI - Ultrafast switching in polarization-bistable laser diodes. PMID- 19784254 TI - Shaping of clean, femtosecond pulses at 1.053 microm for chirped-pulse amplification. PMID- 19784253 TI - Broadband femtosecond infrared parametric amplification in beta-BaB(2)O(4). PMID- 19784255 TI - Generation of transform-limited 32-fs pulses from a self-mode-locked Ti:sapphire laser. PMID- 19784256 TI - Contradirectional two-wave mixing in a strontium barium niobate self-pumped phase conjugate mirror. PMID- 19784257 TI - Optical interferometry between image-bearing beams and their redirected phase conjugates. PMID- 19784258 TI - Heterodyning of AlGaAs lasers: direct frequency measurement of the isotope shift in the oxygen atom. PMID- 19784260 TI - In-line acousto-optic frequency shifter in two-mode fiber. PMID- 19784259 TI - High-speed optical coherence domain reflectometry. PMID- 19784261 TI - First stage in the development of a soft-x-ray reflection imaging microscope in the Schwarzschild configuration using a soft-x-ray laser at 18.2 nm. PMID- 19784262 TI - Electromagnetic wave propogation in stratified anisotropic media in the presence of sources. PMID- 19784264 TI - Measurement of light scattering at 0 degree by micrometer-size quartz fibers. PMID- 19784263 TI - Modification of a quasi-monochromatic beam spatial coherence function through propagation in a two-dimensional Kerr medium. PMID- 19784265 TI - Self-focusing of light pulses in the presence of normal group-velocity dispersion. PMID- 19784266 TI - Two-beam coupling by nitrogen-vacancy centers in diamond. PMID- 19784267 TI - Widely tunable 90 degree phase-matched KTP parametric oscillator. PMID- 19784268 TI - Direct time integration of Maxwell's equations in nonlinear dispersive media for propagation and scattering of femtosecond electromagnetic solitons. PMID- 19784269 TI - Continuous-wave mode-locked optical parametric oscillator synchronously pumped by a diode-laser-pumped solid-state laser. PMID- 19784271 TI - Efficient 1.94-Mum Tm3+ laser in YVO4 host. PMID- 19784270 TI - Highly efficient TEM00 operation of transversely diode-pumped Nd:YAG lasers. PMID- 19784272 TI - Lithium triborate optical parametric oscillator pumped at 266 nm. PMID- 19784273 TI - Generation of 150-fs tunable pulses in Cr:LiSrAlF6. PMID- 19784274 TI - Laser beam quality versus aperture size in a cw argon-ion laser. PMID- 19784275 TI - Disordered garnets Ca3(Nb, Ga)5O12:Nd3+- prospective crystals for powerful ultrashort-pulse generation. PMID- 19784276 TI - Generation of 33-fs optical pulses from a solid-state laser. PMID- 19784277 TI - Incoherent-to-coherent conversion using a photorefractive self-pumped phase conjugator. PMID- 19784278 TI - Optical realization of wavelet transform for a one-dimensional signal. PMID- 19784279 TI - Optically induced lensing effects in Nd3+-doped laser glass measured by photothermal beam-deflection spectroscopy. PMID- 19784280 TI - Compensation of fiber holographic image distortion caused by intrasignal photorefractive coupling by using a phase-conjugate mirror. PMID- 19784281 TI - All-optical gel memory. PMID- 19784282 TI - Generation of optical phase singularities by computer-generated holograms. PMID- 19784283 TI - Spectral holography of shaped femtosecond pulses. PMID- 19784284 TI - Simultaneous one-dimensional visualization of OH, polycyclic aromatic hydrocarbons, and soot in a laminar diffusion flame. AB - Laser-induced fluorescence measurements were performed in several regions of an ethylene-air diffusion flame. With the use of a 290-nm excitation wavelength, the fluorescence emissions from OH molecules and polycyclic aromatic hydrocarbons (PAH's) could be detected. Linear (one-dimensional) visualizations of OH, PAH's, and soot scattering were performed by utilizing an intensified photodiode array detector. Measurements taken at different heights above the burner permitted a two-dimensional reconstruction of the flame structure. Finally the simultaneous visualization of the three species for a rapid determination of the relative distributions was demonstrated. PMID- 19784285 TI - Constant-axial-intensity nondiffracting beam. AB - Numerical solutions of the Fresnel diffraction integral with various apodizing filter functions are used to indicate that a so-called nondiffracting beam can be produced that maintains a constant spot size and constant axial intensity over a considerable range, approximately 30 m in our example. PMID- 19784286 TI - Error-diffusion algorithm in phase synthesis and retrieval techniques. AB - The treatment of phase synthesis and retrieval with the help of projection algorithms often suffers from a stagnation problem. A bandwidth constraint introduces undesired first-order zeros. From the incorporation of error diffusion the stagnation can be avoided. PMID- 19784287 TI - Theoretical model of the shift of the Brewster angle on a rough surface. AB - A physical mechanism is proposed for the explanation of the angular shift of the Brewster angle induced by a rough surface as recently discovered by Saillard and Maystre [J. Opt. Soc. Am. A 7, 982 (1990)]. An explicit formula giving the angular shift as a function of the correlation length sigma and the mean-square departure from the flat surface delta is derived. It is shown that in the case of a rough surface, a minimum rather than a true zero is obtained for the reflection factor. PMID- 19784288 TI - Strong self-defocusing effect and four-wave mixing in bacteriorhodopsin films. AB - We find strong self-defocusing in bacteriorhodopsin films in the near IR with powers in the tens of milliwatts. The defocused beam acquires a ring pattern because of spatial self-phase modulation. We also demonstrate efficient four-wave mixing with phase-conjugate reflectivities of 26%. We discuss the origin of this high nonlinearity. PMID- 19784289 TI - Optical NOR gate using cesium vapor. AB - The transmission of light at the S((1/2))-P((1/2)) resonance in an alkali vapor is strongly dependent on the laser polarization. This polarization dependence can cause a nonlinear interaction between different lasers so that one laser can be used to control the transmission of another laser. An optical NOR gate is demonstrated by using this nonlinearity in a cesium vapor cell. PMID- 19784290 TI - Subharmonics in Bi(12)SiO(20) with an applied ac electric field. AB - The appearance of subharmonics with the aid of an applied square-wave field is reported for the first time to our knowledge. It is shown that the intensity and the order of the subharmonics are dependent on the repetition rate of the square wave. PMID- 19784291 TI - Selective two-wave mixing in photorefractive crystals. AB - A new technique that permits the selective steady-state continuous detection of phase (photorefractive) or amplitude (photochromic) effects in two-wave mixing experiments is described. We show the capabilities of this method for the selective stabilized recording of any one of both types of grating that is chosen. Experimental results from holographic recording in Bi(12)TiO(20) are reported. PMID- 19784292 TI - Phase conjugation in amorphous selenium thin films. AB - We report phase conjugation in amorphous selenium thin films with a 25-mW He-Ne laser. The phase-conjugate signal exhibits a maximum efficiency of 18%. Gratings were recorded with spatial frequencies of 275 lines/mm. We have performed micro Raman spectroscopy measurements between and on the lines that form the grating, and the results reveal the presence of amorphous selenium only. Scanning electron microscopy together with profilometry measurements indicate induced variations of the film thickness. However, this relief does not seem sufficient to explain the observed effects. PMID- 19784293 TI - Optical switching in twin-core erbium-doped fibers. AB - We report the theoretical and experimental investigation of switching in a nonlinear twin-core erbium-doped fiber coupler. It is shown that switching action takes place at a power of a fraction of 1 mW. Thus it provides a practical means of fabricating an all-optical fiber switch. PMID- 19784294 TI - Measurement of nondegenerate nonlinearities using a two-color Z scan. AB - A simple dual-wavelength (two-color) Z-scan geometry is demonstrated for measuring nonlinearities at frequency omega(p) owing to the presence of light at omega(e). This technique gives the nondegenerate two-photon absorption (2PA) coefficient beta(omega(p); omega(e)) and the nondegenerate nonlinear refractive index n(2)(omega(p); omega(e)), i.e., cross-phase modulation. We demonstrate this technique on CS(2) for n(2) and on ZnSe where 2PA and n(2) are present simultaneously. PMID- 19784295 TI - Observation of the formation of dark-soliton trains in optical fibers. AB - We present observations that demonstrate a technique for the generation of trains of dark solitons. The technique consists of the nonlinear copropagation of two delayed visible pulses in a long optical fiber. Single-shot streak-camera temporal images depict the formation of trains of dark solitons with picosecond widths. Single-shot spectra are also observed and depict ringing around spectral holes, which is characteristic of dark solitons on a chirped background pulse. Good agreement is found between theory and both temporal and spectral measurements. PMID- 19784296 TI - Third-order optical nonlinearities of metallotetrabenzoporphyrins and a platinum poly-yne. AB - The third-order optical nonlinearities of two metallotetrabenzoporphyrins and a platinum poly-yne dissolved in tetrahydrofuran were measured by using picosecond and nanosecond laser pulses. The pulse-width-dependent measurements indicated that excited-state absorption was present in both classes of material along with non-resonant two-photon absorption. PMID- 19784297 TI - Self-tapered beams. AB - By introducing material gain within a bulk nonlinear medium, it is possible to taper adiabatically a self-guided beam and to preserve its planar wave front. The amount of tapering can be controlled externally by varying the gain through the intensity of a pump beam. This self-guided beam induces a tapered (linear) waveguide, which in turn can guide a low-power (signal) beam. Two counterpropagating self-guided beams induce tapered, mismatched (linear) couplers that allow for all-optical, tunable, adiabatic power splitting without waveguide fabrication. PMID- 19784298 TI - Coaxial optical-fiber frequency shifter. AB - A fiber-optic frequency shifter utilizing a traveling torsional acoustic wave to couple the polarization eigen-modes of a highly linearly birefringent optical fiber is demonstrated. The frequency-shifter configuration is such that the acoustic-wave generator and optical fiber are coaxial. The device is thus more rugged than previous free-fiber frequency shifters, which have incorporated a T junction between the acoustic generator and optical fiber. The optical frequency shift was 3.204 MHz, and an optical coupling efficiency of 12% was obtained with 4 W of electrical drive power applied to the acoustic transducer. PMID- 19784299 TI - Equivalent-layer method for optical waveguides with a multiple-quantum-well structure. AB - An equivalent-layer method for analyzing multiple-quantum-well (MQW) waveguides is presented. This method not only allows the whole waveguide to be treated as a three-layer waveguide but offers exact solutions for the propagation constant of MQW waveguides and the power confinement factor within the MQW structure as well. A comparison between this method and two other three-layer models is given. PMID- 19784300 TI - Kerr-lens-mediated dynamics of two nonlinearly coupled mode-locked laser oscillators. AB - The dynamics of two nonlinearly coupled femtosecond oscillators are investigated for the case where two distinct nonlinear mechanisms are balanced to determine the temporal relationship and properties of the pulses in the two oscillators. In the time domain the shared bleaching of a common absorber creates an attractive mechanism for the pulses, while interactive Kerr lens deflections create a repulsive mechanism. The interplay of these two mechanisms causes a variety of dynamical behaviors, including pulse synchronization, pulse duration switching, and a latching type of amplitude bistability. PMID- 19784301 TI - Continuously self-mode-locked Ti:sapphire laser that produces sub-50-fs pulses. AB - An external cavity coupled to a dispersion-compensated, self-mode-locked Ti:sapphire laser is shown to maintain cw mode locking to produce pulses as short as 47 fs. The same cavity arrangement is also shown to generate transform-limited pulses of 2-ps duration in the regime of linear external cavity mode locking. PMID- 19784302 TI - Pipelined optoelectronic free-space permutation network. AB - A three-dimensional optoelectronic multistage permutation network is proposed. Shuffle-exchange stages are implemented by using a folded free-space optical system to connect a two-dimensional array of processing elements to itself. The proposed processing elements contain optoelectronic input and output devices coupled to electronic switches. The analysis shows that pipelined operation for large processing element arrays (>1024) can be achieved with a single optical system by interleaving the source-detector pairs of different stages to exploit the large optical space-bandwidth product. PMID- 19784303 TI - Three-dimensional, fine-resolution imaging using laser frequency diversity. AB - Experimental results obtained using a fine-resolution, three-dimensional imaging method are presented. The method consists of flood illuminating an extended object with a laser beam and recording the scattered light as the laser frequency is varied. An image is recovered by three-dimensional Fourier transformation of the recorded data. For the results presented here, a tunable dye-laser source is used, and the obtained range resolution is 287 microm. PMID- 19784304 TI - Ar(2) excimer emission from a pulsed-discharge-excited pulsed supersonic gas jet. AB - We report what is to our knowledge the first observation of argon excimer fluorescence between 115 and 140 nm in a pulsed supersonically cooled gas jet after pulsed-discharge excitation. The emission is observed for measured pressures at the supersonic orifice greater than 3 atm. PMID- 19784305 TI - Isotopic shift of the (5)F degrees (1) ? (3)F(2) transition in (91)Zr. AB - Laser-induced fluorescence spectra of Zr atoms sputtered by ion bombardment have been obtained for the (5)F degrees (1) ? (3)F(2) transition at 595.5 nm. The isotopic shift of (91)Zr is found to be -70 +/- 40 MHz relative to the (90)Zr peak. A discrepancy in literature values for the hyperfine constants of the (5)F degrees (1) state is also resolved. PMID- 19784306 TI - On-axis conoscopic holography without a conjugate image. AB - We present a method for removing the conjugate image in an incoherent-light holographic technique, namely, on-axis conoscopic holography. The point-spread function that we obtain is that of a complex Gabor zone pattern, which thus should allow good-quality reconstructions of objects. Experimental results are also presented, which confirm the validity of this method. PMID- 19784307 TI - Experimental study of achromatic volume holography with dispersive compensation in barium titanate. AB - We carried out an experimental study to verify a proposed theory for achromatic volume holography using dispersive compensation in photorefractive barium titanate crystals. Compensation of the phase mismatch was observed and was consistent with the theory. PMID- 19784308 TI - Computer-generated guided-wave holography: application to beam splitting. AB - The use of guided-wave synthetic holograms in integrated optics is extended beyond the conventional Fresnel lens and Bragg grating technology. As an example, beam splitters based on Fourier-domain holograms are proposed as an alternative to the usual channel waveguide devices. We demonstrate fanout to six with +/-5% (+/-0.2-dB) uniformity error using a binary phase grating and fanout to eight with +/-20% (+/-0.8-dB) uniformity error using a multilevel grating. PMID- 19784309 TI - Two-dimensional digital imaging of the CH distribution in a natural gas/oxygen flame at atmospheric pressure and detection of A-state emission by means of C state excitation. AB - With laser-induced fluorescence, images of the distribution of intermediate species in flames usually have been taken under the condition that the excitation electronic state and emission electronic state are the same. We have successfully photographed two-dimensional CH distribution in a natural gas/oxygen flame through a 431-nm bandpass filter with A-state emission by means of C-state excitation (312 nm). This method provides a smaller signal than the A-state excitation method does but is free from the scattering of the pumping laser beam surrounding the burner nozzle and Rayleigh scattering. Furthermore, this method gives us the opportunity to observe semiquantitative CH distribution. PMID- 19784311 TI - Rowland mounting of a holographic ellipsoidal diffraction grating. PMID- 19784310 TI - Moire signal distortion caused by phase and amplitude nonuniformities of light beams. AB - The distortion suffered by the amplitude and phase of a moire signal when the illuminating beam is not a coherent and monochromatic plane wave has been measured by using different kinds of illuminating sources and a phase-sensitive intensity subtraction technique. A phenomenological model is proposed that explains these effects in terms of an irregular amplitude distribution and a phase evolution of the moire signal with a grating gap. These effects are of great interest in all the measurement techniques related to the moire effect, especially when compact light sources such as light-emitting diodes and incandescent lamps are used. PMID- 19784312 TI - Monte Carlo simulations of the extinction rate of dense media with randomly distributed dielectric spheres based on solution of Maxwell's equations. PMID- 19784313 TI - Shot-noise-corrected measurement of the g((2))(0) of the speckle backscattered from a rotating randomly rough metal surface. PMID- 19784314 TI - Nearly degenerate four-wave mixing using phase-conjugate pump beams. PMID- 19784316 TI - Numerical method for the analysis of optical waveguides. PMID- 19784317 TI - Correspondence of variational finite-difference (relaxation) and imaginary distance propagation methods for modal analysis. PMID- 19784315 TI - Excited-state nonlinearity in polythiophene thin films investigated by the Z-scan technique. PMID- 19784318 TI - Induced spatial incoherence and nonlinear effects in Nd:glass amplifiers. PMID- 19784319 TI - Pulse-forming dynamics of a cw passively mode-locked Ti:sapphire/DDI laser. PMID- 19784321 TI - Numerical solutions of the Maxwell-Bloch equations for a fiber amplifier. PMID- 19784320 TI - Amplification of 193-nm femtosecond seed pulses generated by third-order, nonresonant, difference-frequency mixing in xenon. PMID- 19784322 TI - High-repetition-rate femtosecond pulse generation in the blue. PMID- 19784323 TI - Synchronous detection method for obtaining directional gradients of images. PMID- 19784325 TI - Stimulated Raman scattering in a multimode optical fiber: evolution of modes in Stokes waves. PMID- 19784324 TI - Laser cooling of lithium using relay chirp cooling. PMID- 19784326 TI - Effect of the counterrotating terms in the many-atom Jaynes-Cummings model with cavity losses. PMID- 19784328 TI - Measurement of small optical activities by use of helicoidal waves. PMID- 19784327 TI - Spectrophotopolarimeter: fast simultaneous real-time measurement of light parameters. PMID- 19784329 TI - Measurement of ultralow losses in an optical interferometer. PMID- 19784330 TI - Stripe electrodes for an electrically controlled gray scale in ferroelectric liquid-crystal devices. PMID- 19784331 TI - Smart electro-optical zoom lens. PMID- 19784332 TI - Fiber-optic ac electric-field sensor based on the electrostrictive effect. PMID- 19784333 TI - Optical equalizers. PMID- 19784334 TI - Fused-silica monolithic total-internal-reflection resonator. PMID- 19784335 TI - Monolithic optical fiber stub array. PMID- 19784336 TI - Stimulated anti-Stokes Raman scattering in microdroplets. AB - Stimulated anti-Stokes Raman scattering (SARS) generated by one input beam is observed from CCI(4), ethanol, and water droplets. The first-order SARS intensity is approximately 10(4) times lower than the first-order stimulated-Raman scattering (SRS) intensity for ethanol droplets. Simultaneous detection of SARS and SRS for water droplets shows an occasional lack of correlation between the SARS and SRS spectra. PMID- 19784337 TI - Precise alignment through thick wafers using an optical copying techniquev. AB - Submicrometer alignment of two mask patterns on the top and the bottom surface of a thick glass substrate is possible by using optical copying. The optical copying step transfers an alignment pattern from one surface to the other by shadow casting or Fresnel propagation. In a demonstration experiment, the alignment between the two surfaces of a 3-mm-thick quartz glass substrate was achieved with a precision of 0.5-0.7 microm. PMID- 19784338 TI - Modulation instability of the ground state of the nonlinear wave equation: optical machine gun. AB - The nonstationary (time-dependent) problem of longitudinal modulation instability of a self-focusing beam in a nonlinear medium with and without saturation is solved for the first time, to our knowledge, by using numerical methods. We present the dependence of instability growth rates on the modulation frequency for different saturation parameters. The radial profile of the complex perturbation function is also calculated. The result of modulation instability in the problem considered is the separation of the beam into a periodic sequence of light clumps (light bullets). PMID- 19784339 TI - Experimental study of second-harmonic-generation saturation in fibers by phase modulation between the fundamental and second-harmonic writing beams. AB - We study saturation of photoinduced second-harmonic generation in a Ge-doped silica fiber by modulating the relative phase between the fundamental and second harmonic writing beams. We shift the phase by pi and present measurements that identify saturation that is due to site depletion and saturation that is due to a backfield. PMID- 19784340 TI - Sodium Raman laser: direct measurements of the narrow-band Raman gain. AB - Using a sodium Raman laser that is pumped by a single-frequency cw dye laser, we have measured the narrow-band Raman gain that exists in the vicinity of the sodium D(1) line. Large gains (>10 cm(-1)) are measured at moderate pump intensities and sodium densities. The high gain allows us to detect directly a 1.772-GHz beat on the pump beam after it makes only a single pass through the sodium cell. By scanning the frequency of the sodium Raman laser while keeping the pump intensity and frequency constant, we are able to map out the Raman gain profile. The narrowness of the Raman gain is consistent with the narrow beat signal between the Raman-laser beam and the pump beam that was reported earlier [Opt. Lett. 16, 1853 (1991)]. PMID- 19784341 TI - Continuous-wave mode-locked singly resonant optical parametric oscillator synchronously pumped by a laser-diode-pumped Nd:YLF laser. AB - We describe a continuous-wave synchronously pumped, singly resonant, KTP optical parametric oscillator (OPO). The pump source is a frequency-doubled additive pulse mode-locked Nd:YLF laser pumped by a laser diode. An average pump power threshold of 61 mW is observed for the OPO. At ~3.7 times threshold, the pump depletion is 79%, and the oscillator converts 16% of the pump into external signal output in bandwidth-limited picosecond pulses with 42 mW of average power. The OPO has been tuned over the range of 1.002-1.096 microm. PMID- 19784342 TI - Nonlinear polarization coupling and instabilities in single-mode liquid-cored optical fibers. AB - Polarization coupling is demonstrated in a 0.1-m-long length of nitrobenzene cored weakly birefringent single-mode optical fiber. Self-switching of the launched mode to the orthogonal polarization is observed at peak powers as low as 1 W. A total phase shift of at least 12pi was induced at a launched peak power of approximately 10 W. To our knowledge, this is the largest phase shift observed experimentally in any nonlinear waveguide at such a low power. The low transmission loss of nitrobenzene makes the device highly attractive for a variety of nonlinear switching applications. PMID- 19784343 TI - Pulse amplification and shaping using a nonlinear loop mirror that incorporates a saturable gain. AB - We describe the pulse-amplification characteristics of an erbium-doped fiber amplifier and nonlinear loop mirror combination. The low switching power (less than a milliwatt peak) afforded by high amplifier gain and long loop length has permitted the efficient amplification (17 dB) and intensity filtering of mode locked semi-conductor laser pulses. In addition, saturation of the amplifier gain is shown to result in amplification and shaping characteristics that are remarkably insensitive to the input power. PMID- 19784344 TI - Photoinduced birefringence in optical fibers: a comparative study of low birefringence and high-birefringence fibers. AB - A study of photoinduced birefringence in bow-tie (stress-induced) high birefringence (Hi-Bi) and low-birefringence (Lo-Bi) germanosilicate optical fibers is conducted by using 532-nm light. The study reveals that Hi-Bi fibers are insensitive to light polarized along the fast axis, in contrast to Lo-Bi fibers, which are photosensitive along both axes. The induced birefringence in Lo Bi fibers is reversible, whereas the change in Hi-Bi fibers is permanent. The sign of the induced birefringence is established experimentally for the first time to our knowledge, and the significance of the results to models based on stress and/or glass defects is briefly discussed. PMID- 19784345 TI - Time-resolved M(2) of nanosecond pulses from a Q-switched variable-reflectivity mirror Nd:YAG laser. AB - Time-resolved M(2) numerical computation and experimental measurements of nanosecond pulses from a Q-switched variable-reflectivity-mirror Nd:YAG laser are presented for the first time to our knowledge. The beam quality parameter is seen to vary approximately from 1 at the beginning to 2 at the end of a high-energy pulse, with a value of 1.35 at the peak of the pulse, which also corresponds to the M(2) obtained from the time-averaged detection of the pulse profile. PMID- 19784346 TI - Soliton fiber ring laser. AB - A fiber ring laser that can produce nearly transform-limited soliton pulses is simulated. This laser has an erbium-doped optical-fiber amplifier and allows wavelength tuning through the interplay of fiber chromatic dispersion and the round-trip delay time of the laser. We show that a saturable absorber and a frequency limiter are required for the ring laser to self-start, i.e., to mode lock from initial noise and to operate stably. We also show that nonlinear polarization rotation with polarization selectivity inside the ring can act as a saturable absorber. PMID- 19784347 TI - Continuously tunable single-mode erbium fiber laser. AB - A single-mode linear-cavity fiber laser that utilizes intracore Bragg reflectors for cavity feedback has been continuously tuned, without mode hopping, when both the gratings and enclosed fiber are stretched uniformly. Continuous tuning is achieved in a 1.54-microm erbium fiber laser since the change in the reflected wavelength from a Bragg reflector tracks the change in the cavity resonance wavelength. PMID- 19784348 TI - Fabry-Perot-enhanced self-electro-optic-effect devices. AB - Optically bistable symmetric self-electro-optic-effect devices that use an asymmetric Fabry-Perot resonator are demonstrated and assessed. Contrast ratios exceeding 30 for low bias levels (under 6 V) are measured for low intensities. The Fabry-Perot self-electro-optic-effect device is also shown to saturate readily with intensity, with the contrast ratio decreasing by a factor of 3 for an irradiance of 10 microW/microm(2). Wavelength sensitivity measurements and calculations are also presented. PMID- 19784349 TI - Noise robustness of optical correlation for amplitude or phase modulation of the input image. AB - We analyze the influence of the phase or amplitude coding of the input information in an optical correlator. For binary images, we show that the ratio between the signal-to-noise ratios of both codings is independent of the images when the matched filter is modified in order to have a zero mean value. Moreover these signal-to-noise ratios can be equivalent, but the price is a decrease in the amplitude of the correlation peak in the phase-coding case. With the nonmodified matched filter, characteristics of the phase coding appear to be unattractive. PMID- 19784350 TI - Bose-Einstein photon correlations in the stochastic interferometer. AB - We describe a nonstationary field interferometer, a device for measuring interference among particle Feynman paths that arise from an externally driven stochastic scattering process. Bose-Einstein photon correlations are found to arise from a uniform distribution of the driving noise. A quantum visibility theory valid for any excitation noise distribution is given. The results are considered from the perspective of the probability theory and of statistical mechanics. PMID- 19784351 TI - Hyperfine structure and isotope shifts in the 595.5-nm (a(3)F(2)-z(5)F(1)) ground state transition in Zr I. AB - Two recent determinations of the (91)Zr hyperfine structure in the z(5)F(1) level of Zr I are found to differ by a factor of almost 5. A reexamination of the data confirms the results obtained in our previous investigation: A(z(5)F(1)) = 273.6 +/- 0.3 MHz, B(z(5)F(1)) = 5.9 +/- 0.6 MHz, and hence deltav = -99.6 +/- 1.0 MHz for the (91)Zr-(90)Zr isotope shift in the 595.5-nm (a(3)F(2)-z(5)F(1)) ground state transition. PMID- 19784353 TI - Dynamic holographic memory showing readout, refreshing, and updating capabilities. AB - We propose a new refreshing procedure for reading out a dynamic holographic memory without loss of information. The retrieved images are fed back to the memory after being thresholded and amplified. Experimental demonstration is performed with a LiNbO(3) photorefractive crystal. PMID- 19784352 TI - Spectral quantum fluctuations in a stimulated Raman generator: a description in terms of temporally coherent modes. AB - The probability density of the single-shot mean Stokes frequency from a linear Raman generator is calculated. It is shown that the fluctuations in the Stokes pulse energy spectrum that arise from the quantum initiation of the Stokes light are reduced in the transient regime of amplification. Also, it appears that saturation of the Raman gain does not reduce the phase fluctuations of the Stokes light below those present in the unsaturated gain (linear) regime. PMID- 19784354 TI - Real-time holography in azo-dye-doped liquid crystals. AB - When exposed to an Ar laser at 514 nm, azo-dye molecules in a nematic liquid crystal host undergo photo-isomerization from trans-isomers to cis-isomers. The conformation change of the azo-dye molecules reorients liquid-crystal molecules. Reversible polarization holograms can be recorded dynamically by this effect, with a threshold intensity as low as 3.0 mW/cm(2) and a response time from a few hundred microseconds to 100 ms, depending on the spatial frequency of the recorded grating. PMID- 19784355 TI - Time-resolved attenuation of transmitted laser pulses by a homogeneous scattering medium. AB - The attenuation of a beam of pulses transmitted through a constant thickness of uniform latex microsphere solution is measured as a function of the flight time of the light and of the concentration of microspheres. The implications for the feasibility of time-resolved breast imaging are discussed. PMID- 19784356 TI - Infrared linear diattenuation and birefringence spectra of ferroelectric liquid crystals. AB - Linear diattenuation and linear birefringence spectra of three ferroelectric liquid-crystalline materials, 764E, SCE4, and SCE9, are presented for the wavelength region from 2.5 to 12 microm. Relatively high birefringence (Deltan >/= 0.1) was found in the transmission bands from 2.5 to 3.2 microm and 3.6 to 5.7 microm, with only a small amount of interference from linear diattenuation (D 10(7) unique small RNAs from human embryonic stem cells (hESC) and neural-restricted precursors that were fit to a model of microRNA biogenesis to computationally predict 818 new microRNA genes. These predicted genomic loci are associated with chromatin patterns of modified histones that are predictive of regulated gene expression. 146 of the predicted microRNAs were enriched in Ago2-containing complexes along with 609 known microRNAs, demonstrating association with a functional RISC complex. This Ago2 IP selected subset was consistently expressed in four independent hESC lines and exhibited complex patterns of regulation over development similar to previously known microRNAs, including pluripotency-specific expression in both hESC and iPS cells. More than 30% of the Ago2 IP-enriched predicted microRNAs are new members of existing families since they share seed sequences with known microRNAs. CONCLUSIONS/SIGNIFICANCE: Extending the classic definition of microRNAs, this large number of new microRNA genes, the majority of which are less conserved than their canonical counterparts, likely represent evolutionarily recent regulators of early differentiation. The enrichment in Ago2 containing complexes, the presence of chromatin marks indicative of regulated gene expression, and differential expression over development all support the identification of 146 new microRNAs active during early hESC differentiation. PMID- 19784365 TI - Single tube, high throughput cloning of inverted repeat constructs for double stranded RNA expression. AB - BACKGROUND: RNA interference (RNAi) has emerged as a powerful tool for the targeted knockout of genes for functional genomics, system biology studies and drug discovery applications. To meet the requirements for high throughput screening in plants we have developed a new method for the rapid assembly of inverted repeat-containing constructs for the in vivo production of dsRNAs. METHODOLOGY/PRINCIPAL FINDINGS: The procedure that we describe is based on tagging the sense and antisense fragments with unique single-stranded (ss) tails which are then assembled in a single tube Ligase Independent Cloning (LIC) reaction. Since the assembly reaction is based on the annealing of unique complementary single stranded tails which can only assemble in one orientation, greater than ninety percent of the resultant clones contain the desired insert. CONCLUSION/SIGNIFICANCE: Our single-tube reaction provides a highly efficient method for the assembly of inverted repeat constructs for gene suppression applications. The single tube assembly is directional, highly efficient and readily adapted for high throughput applications. PMID- 19784366 TI - Home educating in an extended family culture and aging society may fare best during a pandemic. AB - Large cities can contain populations that move rapidly from one section to another in an efficient transportation network. An emerging air-borne or contact based pathogen could use these transportation routes to rapidly spread an infection throughout an entire population in a short time. Further, in many developed countries, the aging population is increasing. The family structure in these societies may also affect the course of a disease. To help understand the impact of an epidemic on family structure in a networked population, an individual based computer model that randomly generates networked cities with a specified range of population and disease characteristics and individual schedules, infectivity, transmission and hygiene factors was developed. Several salient issues emerged. First, a city of highly active individuals may in fact diminish the number of fatalities because the average duration of the interactions between agents is reduced. Second, home schooling can significantly improve survival because the institutional clustering of weak individuals is minimized. Third, the worst scenario for an aging population is the nuclear family where the aged population is confined to large housing facilities. Naturally, hygiene is the first barrier to infection. The results suggest that societies where extended families and small groups manage most of their own affairs may also be the most suitable for defense against a pandemic. This may prove applicable in city planning and policy making. PMID- 19784367 TI - Poly[ADP-ribose] polymerase-1 expression is related to cold ischemia, acute tubular necrosis, and delayed renal function in kidney transplantation. AB - Cold ischemia time especially impacts on outcomes of expanded-criteria donor (ECD) transplantation. Ischemia-reperfusion (IR) injury produces excessive poly[ADP-Ribose] Polymerase-1 (PARP-1) activation. The present study explored the hypothesis that increased tubular expression of PARP-1 contributes to delayed renal function in suboptimal ECD kidney allografts and in non-ECD allografts that develop posttransplant acute tubular necrosis (ATN). MATERIALS AND METHODS: Nuclear PARP-1 immunohistochemical expression was studied in 326 paraffin embedded renal allograft biopsies (193 with different degrees of ATN and 133 controls) and in murine Parp-1 knockout model of IR injury. RESULTS: PARP-1 expression showed a significant relationship with cold ischemia time (r coefficient = 0.603), time to effective diuresis (r = 0.770), serum creatinine levels at biopsy (r = 0.649), and degree of ATN (r = 0.810) (p = 0.001, Pearson test). In the murine IR model, western blot showed an increase in PARP-1 that was blocked by Parp-1 inhibitor. Immunohistochemical study of PARP-1 in kidney allograft biopsies would allow early detection of possible delayed renal function, and the administration of PARP-1 inhibitors may offer a therapeutic option to reduce damage from IR in donor kidneys by preventing or minimizing ATN. In summary, these results suggest a pivotal role for PARP-1 in the ATN of renal transplantation. We propose the immunohistochemical assessment of PARP-1 in kidney allograft biopsies for early detection of a possible delayed renal function. PMID- 19784368 TI - Evolutionary descent of prion genes from the ZIP family of metal ion transporters. AB - In the more than twenty years since its discovery, both the phylogenetic origin and cellular function of the prion protein (PrP) have remained enigmatic. Insights into a possible function of PrP may be obtained through the characterization of its molecular neighborhood in cells. Quantitative interactome data demonstrated the spatial proximity of two metal ion transporters of the ZIP family, ZIP6 and ZIP10, to mammalian prion proteins in vivo. A subsequent bioinformatic analysis revealed the unexpected presence of a PrP-like amino acid sequence within the N-terminal, extracellular domain of a distinct sub-branch of the ZIP protein family that includes ZIP5, ZIP6 and ZIP10. Additional structural threading and orthologous sequence alignment analyses argued that the prion gene family is phylogenetically derived from a ZIP-like ancestral molecule. The level of sequence homology and the presence of prion protein genes in most chordate species place the split from the ZIP-like ancestor gene at the base of the chordate lineage. This relationship explains structural and functional features found within mammalian prion proteins as elements of an ancient involvement in the transmembrane transport of divalent cations. The phylogenetic and spatial connection to ZIP proteins is expected to open new avenues of research to elucidate the biology of the prion protein in health and disease. PMID- 19784369 TI - Genetic variation in the familial Mediterranean fever gene (MEFV) and risk for Crohn's disease and ulcerative colitis. AB - BACKGROUND AND AIMS: The familial Mediterranean fever (FMF) gene (MEFV) encodes pyrin, a major regulator of the inflammasome platform controlling caspase-1 activation and IL-1beta processing. Pyrin has been shown to interact with the gene product of NLRP3, NALP3/cryopyrin, also an important active member of the inflammasome. The NLRP3 region was recently reported to be associated with Crohn's disease (CD) susceptibility. We therefore sought to evaluate MEFV as an inflammatory bowel disease (IBD) susceptibility gene. METHODOLOGY AND RESULTS: MEFV colonic mucosal gene expression was significantly increased in experimental colitis mice models (TNBS p<0.0003; DSS p<0.006), in biopsies from CD (p<0.02) and severe ulcerative colitis (UC) patients (p<0.008). Comprehensive genetic screening of the MEFV region in the Belgian exploratory sample set (440 CD trios, 137 UC trios, 239 CD cases, 96 UC cases, and 107 healthy controls) identified SNPs located in the MEFV 5' haplotype block that were significantly associated with UC (rs224217; p = 0.003; A allele frequency: 56% cases, 45% controls), while no CD associations were observed. Sequencing and subsequent genotyping of variants located in this associated haplotype block identified three synonymous variants (D102D/rs224225, G138G/rs224224, A165A/rs224223) and one non-synonymous variant (R202Q/rs224222) located in MEFV exon 2 that were significantly associated with UC (rs224222: p = 0.0005; A allele frequency: 32% in cases, 23% in controls). No consistent associations were observed in additional Canadian (256 CD trios, 91 UC trios) and Scottish (495 UC, 370 controls) sample sets. We note that rs224222 showed marginal association (p = 0.012; G allele frequency: 82% in cases, 70% in controls) in the Canadian sample, but with a different risk allele. None of the NLRP3 common variants were associated with UC in the Belgian Canadian UC samples and no significant interactions were observed between NLRP3 and MEFV that could explain the observed flip-flop of the rs224222 risk allele. CONCLUSION: The differences in association levels observed between the sample sets may be a consequence of distinct founder effects or of the relative small sample size of the cohorts evaluated in this study. However, the results suggest that common variants in the MEFV region do not contribute to CD and UC susceptibility. PMID- 19784370 TI - Early events associated with infection of Epstein-Barr virus infection of primary B-cells. AB - Epstein Barr virus (EBV) is closely associated with the development of a vast number of human cancers. To develop a system for monitoring early cellular and viral events associated with EBV infection a self-recombining BAC containing 172 kb of the Epstein Barr virus genome BAC-EBV designated as MD1 BAC (Chen et al., 2005, J.Virology) was used to introduce an expression cassette of green fluorescent protein (GFP) by homologous recombination, and the resultant BAC clone, BAC-GFP-EBV was transfected into the HEK 293T epithelial cell line. The resulting recombinant GFP EBV was induced to produce progeny virus by chemical inducer from the stable HEK 293T BAC GFP EBV cell line and the virus was used to immortalize human primary B-cell as monitored by green fluorescence and outgrowth of the primary B cells. The infection, B-cell activation and cell proliferation due to GFP EBV was monitored by the expression of the B-cell surface antigens CD5, CD10, CD19, CD23, CD39, CD40 , CD44 and the intercellular proliferation marker Ki-67 using Flow cytometry. The results show a dramatic increase in Ki-67 which continues to increase by 6-7 days post-infection. Likewise, CD40 signals showed a gradual increase, whereas CD23 signals were increased by 6-12 hours, maximally by 3 days and then decreased. Monitoring the viral gene expression pattern showed an early burst of lytic gene expression. This up-regulation of lytic gene expression prior to latent genes during early infection strongly suggests that EBV infects primary B-cell with an initial burst of lytic gene expression and the resulting progeny virus is competent for infecting new primary B-cells. This process may be critical for establishment of latency prior to cellular transformation. The newly infected primary B-cells can be further analyzed for investigating B cell activation due to EBV infection. PMID- 19784371 TI - Optimized quantification of fragmented, free circulating DNA in human blood plasma using a calibrated duplex real-time PCR. AB - BACKGROUND: Duplex real-time PCR assays have been widely used to determine amounts and concentrations of free circulating DNA in human blood plasma samples. Circulatory plasma DNA is highly fragmented and hence a PCR-based determination of DNA concentration may be affected by the limited availability of full-length targets in the DNA sample. This leads to inaccuracies when counting PCR target copy numbers as whole genome equivalents. METHODOLOGY/PRINCIPAL FINDINGS: A model system was designed allowing for assessment of bias in a duplex real-time PCR research assay. We collected blood plasma samples from male donors in pools of 6 to 8 individuals. Circulatory plasma DNA was extracted and separated by agarose gel electrophoresis. Separated DNA was recovered from the gel in discrete size fractions and analyzed with different duplex real-time PCR Taqman assays detecting a Y chromosome-specific target and an autosomal target. The real-time PCR research assays used differed significantly in their ability to determine the correct copy number ratio of 0.5 between Y chromosome and autosome targets in DNA of male origin. Longer PCR targets did not amplify quantitatively in circulatory DNA, due to limited presence of full-length target sequence in the sample. CONCLUSIONS: PCR targets of the same small size are preferred over longer targets when comparing fractional circulatory DNA concentrations by real-time PCR. As an example, a DYS14/18S duplex real-time PCR research assay is presented that correctly measures the fractional concentration of male DNA in a male/female mixture of circulatory, fragmented DNA. PMID- 19784372 TI - Neuroanatomical variability of religiosity. AB - We hypothesized that religiosity, a set of traits variably expressed in the population, is modulated by neuroanatomical variability. We tested this idea by determining whether aspects of religiosity were predicted by variability in regional cortical volume. We performed structural magnetic resonance imaging of the brain in 40 healthy adult participants who reported different degrees and patterns of religiosity on a survey. We identified four Principal Components of religiosity by Factor Analysis of the survey items and associated them with regional cortical volumes measured by voxel-based morphometry. Experiencing an intimate relationship with God and engaging in religious behavior was associated with increased volume of R middle temporal cortex, BA 21. Experiencing fear of God was associated with decreased volume of L precuneus and L orbitofrontal cortex BA 11. A cluster of traits related with pragmatism and doubting God's existence was associated with increased volume of the R precuneus. Variability in religiosity of upbringing was not associated with variability in cortical volume of any region. Therefore, key aspects of religiosity are associated with cortical volume differences. This conclusion complements our prior functional neuroimaging findings in elucidating the proximate causes of religion in the brain. PMID- 19784373 TI - Efferent projections of prokineticin 2 expressing neurons in the mouse suprachiasmatic nucleus. AB - The suprachiasmatic nucleus (SCN) in the hypothalamus is the predominant circadian clock in mammals. To function as a pacemaker, the intrinsic timing signal from the SCN must be transmitted to different brain regions. Prokineticin 2 (PK2) is one of the candidate output molecules from the SCN. In this study, we investigated the efferent projections of PK2-expressing neurons in the SCN through a transgenic reporter approach. Using a bacterial artificial chromosome (BAC) transgenic mouse line, in which the enhanced green fluorescence protein (EGFP) reporter gene expression was driven by the PK2 promoter, we were able to obtain an efferent projections map from the EGFP-expressing neurons in the SCN. Our data revealed that EGFP-expressing neurons in the SCN, hence representing some of the PK2-expressing neurons, projected to many known SCN target areas, including the ventral lateral septum, medial preoptic area, subparaventricular zone, paraventricular nucleus, dorsomedial hypothalamic nucleus, lateral hypothalamic area and paraventricular thalamic nucleus. The efferent projections of PK2-expressing neurons supported the role of PK2 as an output molecule of the SCN. PMID- 19784374 TI - Randomized trial of piperaquine with sulfadoxine-pyrimethamine or dihydroartemisinin for malaria intermittent preventive treatment in children. AB - BACKGROUND: The long terminal half life of piperaquine makes it suitable for intermittent preventive treatment for malaria but no studies of its use for prevention have been done in Africa. We did a cluster randomized trial to determine whether piperaquine in combination with either dihydroartemisin (DHA) or sulfadoxine-pyrimethamine (SP) is as effective, and better tolerated, than SP plus amodiaquine (AQ), when used for intermittent preventive treatment in children delivered by community health workers in a rural area of Senegal. METHODS: Treatments were delivered to children 3-59 months of age in their homes once per month during the transmission season by community health workers. 33 health workers, each covering about 60 children, were randomized to deliver either SP+AQ, DHA+PQ or SP+PQ. Primary endpoints were the incidence of attacks of clinical malaria, and the incidence of adverse events. RESULTS: 1893 children were enrolled. Coverage of monthly rounds and compliance with daily doses was similar in all groups; 90% of children received at least 2 monthly doses. Piperaquine combinations were better tolerated than SP+AQ with a significantly lower risk of common, mild adverse events. 103 episodes of clinical malaria were recorded during the course of the trial. 68 children had malaria with parasitaemia >3000/microL, 29/671 (4.3%) in the SP+AQ group, compared with 22/604 (3.6%) in the DHA+PQ group (risk difference 0.47%, 95%CI -2.3%,+3.3%), and 17/618 (2.8%) in the SP+PQ group (risk difference 1.2%, 95%CI -1.3%,+3.6%). Prevalences of parasitaemia and the proportion of children carrying Pfdhfr and Pfdhps mutations associated with resistance to SP were very low in all groups at the end of the transmission season. CONCLUSIONS: Seasonal IPT with SP+PQ in children is highly effective and well tolerated; the combination of two long-acting drugs is likely to impede the emergence of resistant parasites. TRIAL REGISTRATION: ClinicalTrials.gov NCT00529620. PMID- 19784375 TI - Both conventional and interferon killer dendritic cells have antigen-presenting capacity during influenza virus infection. AB - Natural killer cells are innate effector cells known for their potential to produce interferon-gamma and kill tumour and virus-infected cells. Recently, B220(+)CD11c(int)NK1.1(+) NK cells were found to also have antigen-presenting capacity like dendritic cells (DC), hence their name interferon-producing killer DC (IKDC). Shortly after discovery, it has already been questioned if IKDC really represent a separate subset of NK cells or merely represent a state of activation. Despite similarities with DCs, in vivo evidence that they behave as bona fide APCs is lacking. Here, using a model of influenza infection, we found recruitment of both conventional B220(-) NK cells and IKDCs to the lung. To study antigen-presenting capacity of NK cell subsets and compare it to cDCs, all cell subsets were sorted from lungs of infected mice and co-cultured ex vivo with antigen specific T cells. Both IKDCs and conventional NK cells as well as cDCs presented virus-encoded antigen to CD8 T cells, whereas only cDCs presented to CD4 T cells. The absence of CD4 responses was predominantly due to a deficiency in MHCII processing, as preprocessed peptide antigen was presented equally well by cDCs and IKDCs. In vivo, the depletion of NK1.1-positive NK cells and IKDCs reduced the expansion of viral nucleoprotein-specific CD8 T cells in the lung and spleen, but did finally not affect viral clearance from the lung. In conclusion, we found evidence for APC function of lung NK cells during influenza infection, but this is a feature not exclusive to the IKDC subset. PMID- 19784376 TI - Isoforms of U1-70k control subunit dynamics in the human spliceosomal U1 snRNP. AB - Most human protein-encoding genes contain multiple exons that are spliced together, frequently in alternative arrangements, by the spliceosome. It is established that U1 snRNP is an essential component of the spliceosome, in human consisting of RNA and ten proteins, several of which are post-translationally modified and exist as multiple isoforms. Unresolved and challenging to investigate are the effects of these post translational modifications on the dynamics, interactions and stability of the particle. Using mass spectrometry we investigate the composition and dynamics of the native human U1 snRNP and compare native and recombinant complexes to isolate the effects of various subunits and isoforms on the overall stability. Our data reveal differential incorporation of four protein isoforms and dynamic interactions of subunits U1-A, U1-C and Sm B/B'. Results also show that unstructured post-translationally modified C terminal tails are responsible for the dynamics of Sm-B/B' and U1-C and that their interactions with the Sm core are controlled by binding to different U1-70k isoforms and their phosphorylation status in vivo. These results therefore provide the important functional link between proteomics and structure as well as insight into the dynamic quaternary structure of the native U1 snRNP important for its function. PMID- 19784377 TI - Synergistic antibacterial and anti-inflammatory activity of temporin A and modified temporin B in vivo. AB - Temporins are antimicrobial peptides secreted by the granular glands of the European red frog (Rana temporaria). They are 10-14 amino acid long polypeptides active prevalently against gram positive bacteria. This study shows that a synthetic temporin B analogue (TB-YK), acquires the capacity to act in synergism with temporin A and to exert antimicrobial and anti-inflammatory activity in vivo against gram positive and gram negative bacteria. Administration of 3.4 mg/Kg of temporin A (TA)+1.6 mg/Kg TB-YK, given to individual mice concurrently with a lethal dose of bacteria (gram positive or negative), rescued 100% of the animals. More importantly, the same doses of temporins, administered one week after experimental infection with a sub lethal dose of bacteria, sterilized 100% of the animals within 3-6 days. Also, it is described an animal model based on the use of sub lethal doses of bacteria, which closely mimics bacterial infection in humans. The model offers the possibility to test in a preclinical setting the true potential of TA and TB-YK in combination as antimicrobial and anti inflammatory agents. PMID- 19784378 TI - Isolation of Oct4-expressing extraembryonic endoderm precursor cell lines. AB - BACKGROUND: The extraembryonic endoderm (ExEn) defines the yolk sac, a set of membranes that provide essential support for mammalian embryos. Recent findings suggest that the committed ExEn precursor is present already in the embryonic Inner Cell Mass (ICM) as a group of cells that intermingles with the closely related epiblast precursor. All ICM cells contain Oct4, a key transcription factor that is first expressed at the morula stage. In vitro, the epiblast precursor is most closely represented by the well-characterized embryonic stem (ES) cell lines that maintain the expression of Oct4, but analogous ExEn precursor cell lines are not known and it is unclear if they would express Oct4. METHODOLOGY/PRINCIPAL FINDINGS: Here we report the isolation and characterization of permanently proliferating Oct4-expressing rat cell lines ("XEN-P cell lines"), which closely resemble the ExEn precursor. We isolated the XEN-P cell lines from blastocysts and characterized them by plating and gene expression assays as well as by injection into embryos. Like ES cells, the XEN-P cells express Oct4 and SSEA1 at high levels and their growth is stimulated by leukemia inhibitory factor, but instead of the epiblast determinant Nanog, they express the ExEn determinants Gata6 and Gata4. Further, they lack markers characteristic of the more differentiated primitive/visceral and parietal ExEn stages, but exclusively differentiate into these stages in vitro and contribute to them in vivo. CONCLUSIONS/SIGNIFICANCE: Our findings (i) suggest strongly that the ExEn precursor is a self-renewable entity, (ii) indicate that active Oct4 gene expression (transcription plus translation) is part of its molecular identity, and (iii) provide an in vitro model of early ExEn differentiation. PMID- 19784380 TI - Prevalence of depression in a large urban South Indian population--the Chennai Urban Rural Epidemiology Study (CURES-70). AB - BACKGROUND: In India there are very few population based data on prevalence of depression. The aim of the study was to determine the prevalence of depression in an urban south Indian population. METHODS AND FINDINGS: Subjects were recruited from the Chennai Urban Rural Epidemiology Study (CURES), involving 26,001 subjects randomly recruited from 46 of the 155 corporation wards of Chennai (formerly Madras) city in South India. 25,455 subjects participated in this study (response rate 97.9%). Depression was assessed using a self-reported and previously validated instrument, the Patient Health Questionnaire (PHQ) - 12. Age adjustment was made according to the 2001 census of India. The overall prevalence of depression was 15.1% (age-adjusted, 15.9%) and was higher in females (females 16.3% vs. males 13.9%, p<0.0001). The odds ratio (OR) for depression in female subjects was 1.20 [Confidence Intervals (CI): 1.12-1.28, p<0.001] compared to male subjects. Depressed mood was the most common symptom (30.8%), followed by tiredness (30.0%) while more severe symptoms such as suicidal thoughts (12.4%) and speech and motor retardation (12.4%) were less common. There was an increasing trend in the prevalence of depression with age among both female (p<0.001) and male subjects (p<0.001). The prevalence of depression was higher in the low income group (19.3%) compared to the higher income group (5.9%, p<0.001). Prevalence of depression was also higher among divorced (26.5%) and widowed (20%) compared to currently married subjects (15.4%, p<0.001). CONCLUSIONS: This is the largest population-based study from India to report on prevalence of depression and shows that among urban south Indians, the prevalence of depression was 15.1%. Age, female gender and lower socio-economic status are some of the factors associated with depression in this population. PMID- 19784379 TI - Altered anatomical network in early blindness revealed by diffusion tensor tractography. AB - The topological architecture of the cerebral anatomical network reflects the structural organization of the human brain. Recently, topological measures based on graph theory have provided new approaches for quantifying large-scale anatomical networks. Diffusion MRI studies have revealed the efficient small world properties and modular structure of the anatomical network in normal subjects. However, no previous study has used diffusion MRI to reveal changes in the brain anatomical network in early blindness. Here, we utilized diffusion tensor imaging to construct binary anatomical networks for 17 early blind subjects and 17 age- and gender-matched sighted controls. We established the existence of structural connections between any pair of the 90 cortical and sub cortical regions using deterministic tractography. Compared with controls, early blind subjects showed a decreased degree of connectivity, a reduced global efficiency, and an increased characteristic path length in their brain anatomical network, especially in the visual cortex. Moreover, we revealed some regions with motor or somatosensory function have increased connections with other brain regions in the early blind, which suggested experience-dependent compensatory plasticity. This study is the first to show alterations in the topological properties of the anatomical network in early blindness. From the results, we suggest that analyzing the brain's anatomical network obtained using diffusion MRI data provides new insights into the understanding of the brain's re organization in the specific population with early visual deprivation. PMID- 19784381 TI - Individual and Situational Factors Related to Young Women's Likelihood of Confronting Sexism in Their Everyday Lives. AB - Factors related to young women's reported likelihood of confronting sexism were investigated. Participants were 338 U.S. female undergraduates (M = 19 years) attending a California university. They were asked to complete questionnaire measures and to write a personal narrative about an experience with sexism. Approximately half (46%) the women reported confronting the perpetrator. Individual factors (prior experience with sexism, feminist identification, collective action) and situational factors (familiarity and status of perpetrator, type of sexism) were tested as predictors in a logistic regression. Women were less likely to report confronting sexism if (1) they did not identify as feminists, (2) the perpetrator was unfamiliar or high-status/familiar (vs. familiar/equal-status), or (3) the type of sexism involved unwanted sexual attention (vs. sexist comments). PMID- 19784382 TI - Seeing the world through a third eye: Developmental systems theory looks beyond the nativist-empiricist debate. AB - In response to the commentaries on our paper (Spencer et al., 2009) we summarize what a developmental systems perspective offers for a twenty-first century science of development by highlighting five insights from developmental systems theory. Where applicable, the discussion is grounded in a particular example-the emergence of ocular dominance columns in early development. Ocular dominance columns are a paragon of epigenesis and are inconsistent with the nativist view. We conclude with optimism that developmental science can move beyond the nativist empiricist debate armed with both modern technological tools and strong theory to guide their use. PMID- 19784383 TI - Short arms and talking eggs: Why we should no longer abide the nativist empiricist debate. AB - The nativist-empiricist debate and the nativist commitment to the idea of core knowledge and endowments that exist without relevant postnatal experience continue to distract attention from the reality of developmental systems. The developmental systems approach embraces the concept of epigenesis, that is, the view that development emerges via cascades of interactions across multiple levels of causation, from genes to environments. This view is rooted in a broader interpretation of experience and an appreciation for the nonobvious nature of development. We illustrate this systems approach with examples from studies of imprinting, spatial cognition, and language development, revealing the inadequacies of the nativist-empiricist debate and the inconvenient truths of development. Developmental scientists should no longer abide the nativist empiricist debate and nativists' ungrounded focus on origins. Rather, the future lies in grounding our science in contemporary theory and developmental process. PMID- 19784384 TI - Non-Linear Optical Imaging of Obesity-Related Health Risks: Review. AB - This review highlights the recent applications of non-linear optical (NLO) microscopy to study obesity-related health risks. A strong emphasis is given to the applications of coherent anti-Stokes Raman scattering (CARS) microscopy where multiple non-linear optical imaging modalities including CARS, sum-frequency generation (SFG), and two-photon fluorescence are employed simultaneously on a single microscope platform. Specific examples on applications of NLO microscopy to study lipid-droplet biology, obesity-cancer relationship, atherosclerosis, and lipid-rich biological structures are discussed. PMID- 19784385 TI - Hemodynamics of Cerebral Aneurysms. AB - The initiation and progression of cerebral aneurysms are degenerative processes of the arterial wall driven by a complex interaction of biological and hemodynamic factors. Endothelial cells on the artery wall respond physiologically to blood-flow patterns. In normal conditions, these responses are associated with nonpathological tissue remodeling and adaptation. The combination of abnormal blood patterns and genetics predisposition could lead to the pathological formation of aneurysms. Here, we review recent progress on the basic mechanisms of aneurysm formation and evolution, with a focus on the role of hemodynamic patterns. PMID- 19784386 TI - SYNTHESIS OF 2-[3,3'-DI-(TERT-BUTOXYCARBONYL)-AMINODIPROPYLAMINE]-4,6,-DICHLORO 1,3,5-TRIAZINE AS A MONOMER AND 1,3,5-[TRIS-PIPERAZINE]-TRIAZINE AS A CORE FOR THE LARGE SCALE SYNTHESIS OF MELAMINE (TRIAZINE) DENDRIMERS. PMID- 19784387 TI - In Vivo/Ex Vivo MRI-Based 3D Non-Newtonian FSI Models for Human Atherosclerotic Plaques Compared with Fluid/Wall-Only Models. AB - It has been recognized that fluid-structure interactions (FSI) play an important role in cardiovascular disease initiation and development. However, in vivo MRI multi-component FSI models for human carotid atherosclerotic plaques with bifurcation and quantitative comparisons of FSI models with fluid-only or structure-only models are currently lacking in the literature. A 3D non-Newtonian multi-component FSI model based on in vivo/ex vivo MRI images for human atherosclerotic plaques was introduced to investigate flow and plaque stress/strain behaviors which may be related to plaque progression and rupture. Both artery wall and plaque components were assumed to be hyperelastic, isotropic, incompressible and homogeneous. Blood flow was assumed to be laminar, non-Newtonian, viscous and incompressible. In vivo/ex vivo MRI images were acquired using histologically-validated multi-spectral MRI protocols. The 3D FSI models were solved and results were compared with those from a Newtonian FSI model and wall-only/fluid-only models. A 145% difference in maximum principal stresses (Stress-P(1)) between the FSI and wall-only models and 40% difference in flow maximum shear stress (MSS) between the FSI and fluid-only models were found at the throat of the plaque using a severe plaque sample (70% severity by diameter). Flow maximum shear stress (MSS) from the rigid wall model is much higher (20-40% in maximum MSS values, 100-150% in stagnation region) than those from FSI models. PMID- 19784388 TI - Gene expression analysis of biological systems driving an organotypic model of endometrial carcinogenesis and chemoprevention. AB - An organotypic model of endometrial carcinogenesis and chemoprevention was developed in which normal endometrial organotypic cultures exposed to the carcinogen, DMBA (7,12-dimethylbenz[a]anthracene), developed a cancerous phenotype in the absence, but not presence of subsequent treatment with a flexible heteroarotinoid (Flex-Het), called SHetA2. A discriminant function based on karyometric features of cellular nuclei and an agar clonogenic assay confirmed these histologic changes. Interpretation of microarray data using an internal standard approach identified major pathways associated with carcinogenesis and chemoprevention governed by c-myc, p53, TNFalpha and Jun genes. Cluster analysis of functional associations of hypervariable genes demonstrated that carcinogenesis is accompanied by a stimulating association between a module of genes that includes tumor necrosis factor alpha (TNFalpha), c-myc, and epidermal growth factor-receptor (EGF-R) and a module that includes insulin-like growth factor I-receptor (IGF-IR), p53, and Jun genes. Two secreted proteins involved in these systems, tenascin C and inhibin A, were validated at the protein level. Tenascin C is an EGF-R ligand, and therefore may contribute to the increased EGF R involvement in carcinogenesis. The known roles of the identified molecular systems in DMBA and endometrial carcinogenesis and chemoprevention supports the validity of this model and the potential clinical utility of SHetA2 in chemoprevention. PMID- 19784389 TI - Effect of serum cytokines and VEGF levels on diabetic retinopathy and macular thickness. AB - PURPOSE: To investigate the role of serum inflammatory cytokines and vascular endothelial growth factor (VEGF) in diabetic retinopathy (DR) and evaluate their relationship with macular thickness measurements obtained with optical coherence tomography (OCT). METHODS: The study enrolled 28 healthy subjects (Group 1), 31 patients without DR (Group 2), 49 patients with nonproliferative DR (Group 3), and 46 patients with proliferative DR (Group 4). Macular profile was assessed with Stratus OCT-3 and the serum concentrations of VEGF and interleukin-1 alpha (IL-1 alpha), interleukin-6 (IL-6), interleukin-8 (IL-8), interleukin-10 (IL-10), macrophage inflammatory protein (MIP-1 alpha), monocyte chemoattractant protein (MCP-1), and epidermal growth factor (EGF) were measured using multiplex bead immunoassay. RESULTS: The median value of the visual acuity was 20/20 (Groups 1 and 2), and 20/100 (Group 3), and 20/125 (Group 4). The median value of central subfield macular thickness was estimated as 165.50 microm in Group 1, 202.5 microm in Group 2, 318 microm in Group 3, and 310 microm in Group 4. The median serum VEGF level, which was 98.20 pg/ml in Group 1, demonstrated a progressive rise to 125.37 pg/ml in Group 2, to 153.07 pg/ml in Group 3, and to 149.12 pg/ml in Group 4. Statistical significance was found between all groups (p<0.05) except between Groups 3 and 4 (p=0.87). The median levels of IL-1 alpha and IL-6 were zero in all groups. The median serum levels of IL-8, IL-10, MIP-1 alpha, and EGF revealed a wide range within each group but no statistical significance between the groups (p>0.05). The median serum levels of IL-8, IL-10, MIP-1 alpha, and EGF revealed a wide range within each group, however, no statistically significant relationship was found between the groups (p>0.05). The median values of the serum MCP-1 concentrations presented a statistically significant rise with the progression of DR (p=0.02). No correlation was found between macular thickness and serum cytokine and VEGF levels (p>0.05). CONCLUSIONS: Increased serum levels of VEGF and MCP-1 may act as a key regulator of DR and provide a potential tool for risk assessment in diabetic patients. Further studies that evaluate both vitreous and serum levels in various stages of DR are needed to provide a better understanding of the interaction between systemic and local inflammatory and angiogenic factors. PMID- 19784390 TI - Immunohistochemical study of pig retinal development. AB - PURPOSE: The pig eye is similar to the human eye in terms of anatomy, vasculature, and photoreceptor distribution, and therefore provides an attractive animal model for research into retinal disease. The purpose of this study was to characterize retinal histology in the developing and mature pig retina using antibodies to well established retinal cell markers commonly used in rodents. METHODS: Eyes were enucleated from fetuses in the 9th week of gestation, 1 week old piglets and 6 months old adult animals. Eyeglobes were fixed and cryosectioned. A panel of antibodies to well established retinal markers was employed for immunohistochemistry. Fluorescently labeled secondary antibodies were used for signal detection, and images were acquired by confocal microscopy. Mouse retina at postnatal day (P) 5 was used as a reference for this study to compare progression of histogenesis. Most of the primary antibodies have previously been used on mouse tissue. RESULTS: Most of the studied markers were detected in midgestation pig retina, and the majority had a similar distribution in pig as in P5 mouse retina. However, rhodopsin immunolabeling was detected in pig retina at midgestation but not in P5 mouse retina. Contrary to findings in all rodents, horizontal cells were Islet1-positive and cones were calbindin immunoreactive in pig retina, as has also been shown for the primate retina. Recoverin and rhodopsin immunolabeling revealed an increase in the length of photoreceptor segments in 6 months, compared to 1 week old animals. CONCLUSIONS: Comparison with the published data on human retina revealed similar marker distribution and histogenesis progression in the pig and human retina, supporting the pig as a valuable animal model for studies on retinal disease and repair. Furthermore, this study provides information about the dynamics of retinal histogenesis in the pig and validates a panel of antibodies that reliably detects developing and mature retinal cell phenotypes in the pig retina. PMID- 19784391 TI - The influence of sublethal blue light exposure on human RPE cells. AB - PURPOSE: To evaluate the in vitro response of retinal pigment epithelial (RPE) cells to a nonlethal dose of blue light. METHODS: The human RPE cell line ARPE-19 was irradiated with blue light (405 nm) at an output power of 1 mW/cm(2) or 0.3 mW/cm(2). The following parameters were studied: metabolic activity; apoptosis; reactive oxygen species (ROS) production; mitochondrial membrane potential (MMP); ultrastructural changes of mitochondria; production of advanced glycation endproducts (AGEs); and stress-related cellular proteins. RESULTS: Nonlethal doses of blue light irradiation significantly reduced ARPE-19 metabolic activity and MMP while increasing intracellular ROS levels and expression of stress related proteins heme oxygenase-1 (HO-1), osteopontin, heat shock protein 27 (Hsp 27), manganese superoxide dismutase (SOD-Mn), and cathepsin D. Blue light irradiation also induced ultrastructural conformation changes in mitochondria, resulting in the appearance of giant mitochondria after 72 h. We further found enhanced formation of AGEs, particularly N(epsilon)-(carboxymethyl) lysine (CML) modifications, and a delay in the cell cycle. CONCLUSIONS: ARPE-19 cells avoid cell death and recover from blue light irradiation by activating a host of defense mechanisms while simultaneously triggering cellular stress responses that may be involved in RPE disease development. Continuous light exposure can therefore detrimentally affect metabolically stressed RPE cells. This may have implications for pathogenesis of age-related macular degeneration. PMID- 19784392 TI - Primary open angle glaucoma in a Caucasian population is associated with the p53 codon 72 polymorphism. AB - PURPOSE: Apoptosis has been implicated as the mechanism for retinal ganglion cell death in primary open-angle glaucoma (POAG), a complex neurodegenerative disease. There have been inconsistent reports regarding increased risk of POAG and a polymorphism (Arg72Pro) within the tumor suppressor gene, p53. The goal of this study was to examine the role of this polymorphism in susceptibility to POAG in a Caucasian population from the United States. METHODS: We generated genotypes in 191 unrelated Caucasian POAG patients and 167 unrelated Caucasian controls for the following polymorphisms within p53: rs1042522 (Arg72Pro), rs17878362 (16 bp Ins/Del), and rs1800371 (Pro47Ser) by PCR amplification followed by restriction digestion and sequence analysis. RESULTS: There was a significant difference in genotypic frequencies for rs1042522 (Arg72Pro) between POAG patients and controls (chi(2)= 9.56, p=0.008). Individuals who were homozygous for the arginine allele have a 1.9 fold significantly increased risk of developing glaucoma (95%CI: 1.16 2.82, p=0.01). Interestingly, we found that the frequency of the arginine allele was even higher in the normal-tension glaucoma (NTG) subtype compared to high tension POAG (0.81 versus 0.76). CONCLUSIONS: Our preliminary results indicate that the arginine variant of rs1042522 within p53 is associated with increased risk of POAG. This variant has increased apoptotic potential, thus the retinal ganglion cells in carriers of the arginine allele may have greater susceptibility to apoptosis. PMID- 19784393 TI - The novel Y371D myocilin mutation causes an aggressive form of juvenile open angle glaucoma in a Caucasian family from the Middle-East. AB - PURPOSE: To search for the genetic cause of juvenile open-angle glaucoma (JOAG) in a Caucasian family and to perform genotype/phenotype correlation studies in the kindred. METHODS: Six members of a three-generation family originating from Uzbekistan and now living in the Middle East were recruited from one large clinic in Israel. Ophthalmologic investigations comprised of visual field assessments, intraocular pressure measurements, optic disc evaluation, and gonioscopy. Medical charts were obtained to date the onset of glaucoma and to evaluate aggressivity of the trait. We screened the myocilin gene (MYOC, OMIM 601652) by direct genomic sequencing of its three exons in all family members. RESULTS: JOAG segregated as an autosomal dominant trait in four members of the family. The proband, a 14-year old girl, had been diagnosed with juvenile open-angle glaucoma at 12 years old. Her mother, maternal aunt, and maternal grandfather all had JOAG that started at an early age. The disorder progressed rapidly even under optimal medical treatment, and all four patients had to undergo trabeculectomy. One missense mutation, Y371D (1111t-->g, Tyr [Y] 371 Asp [D]), was identified. This mutation cosegregated with the disorder in all affected members and was absent in 200 Caucasian controls. The Y371D MYOC mutation has not been reported before. One cousin of the proband was a silent heterozygotic carrier of the mutation and was still asymptomatic at nine years of age. CONCLUSIONS: We identified a novel mutation (Y371D) in MYOC from a Caucasian family who presented with an aggressive form of JOAG that required early trabeculectomy. Genetic screening of the MYOC mutation was beneficial in predicting one asymptomatic heterozygotic carrier. PMID- 19784394 TI - Inhibitory effects of polysaccharide extract from Spirulina platensis on corneal neovascularization. AB - PURPOSE: To assess the effects of polysaccharide extract from Spirulina platensis (PSP) on corneal neovascularization (CNV) in vivo and in vitro. METHODS: PSP was extracted from dry powder of Spirulina platensis. Its anti-angiogenic activity was evaluated in the mouse corneal alkali burn model after topical administration of PSP four times daily for up to seven days. Corneal samples were processed for histochemical, immunohistochemical, and gene expression analyses. The effects of PSP on proliferation, migration, tube formation, and serine threonine kinase (AKT) and extracellular regulated kinase1/2 (ERK1/2) signaling levels in vascular endothelial cells were determined using 3-(4,5)-dimethylthiahiazo (-z-y1)-3, 5-di phenytetrazoliumromide (MTT) and carboxyfluorescein succinimidyl ester (CFSE) labeling assays, wound healing assay, Matrigel tube formation assay, and western blot. RESULTS: Topical application of PSP significantly inhibited CNV caused by alkali burn. Corneas treated with PSP showed reduced levels of platelet endothelial cell adhesion molecule (CD31) and stromal cell-derived factor 1 (SDF1) proteins, reduced levels of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP2), matrix metalloproteinase-9 (MMP9), SDF1, and tumor necrosis factor-alpha (TNF-alpha) mRNAs, and an increased level of pigment epithelium-derived factor (PEDF) mRNA. These are parameters that have all been related to CNV and/or inflammation. In human vascular endothelial cells, PSP significantly inhibited proliferation, migration, and tube formation in a dose dependent manner. Furthermore, PSP also decreased the levels of activated AKT and ERK 1/2. CONCLUSIONS: These data suggest that polysaccharide extract from Spirulina platensis is a potent inhibitor of CNV and that it may be of benefit in the therapy of corneal diseases involving neovascularization and inflammation. PMID- 19784396 TI - CGRP receptor antagonists: A new frontier of anti-migraine medications. AB - Migraine is a chronic pain condition that affects 12% of the population. Currently, the most effective treatments are the triptans, but they are limited in their efficacy and have potentially deleterious cardiovascular complications. Based on basic science studies over the past decade, a new generation of anti migraine drugs is now being developed. At the forefront of these studies is a new calcitonin gene-related peptide (CGRP) receptor antagonist that is as effective as triptans in the acute treatment of migraines, without the cardiovascular effects. This review will address the likely mechanisms and therapeutic potential of CGRP receptor antagonists. PMID- 19784395 TI - Effect of dispase denudation on amniotic membrane. AB - PURPOSE: To describe the cellular components, biochemical composition, and membrane surface characteristics of denuded human amniotic membrane (DHAM) treated with Dispase II. METHODS: DHAM was incubated with Dispase II (1.2 U/ml) for 30 min, 60 min, or 120 min. This was followed by gentle scraping to remove any remaining epithelial cells using a cell scraper. Histology, immunohistochemistry for extracellular matrix molecules and growth factors, and transmission (TEM) and scanning electron microscopy (SEM) were performed to assess the effects of increasing durations of incubation on DHAM structure. RESULTS: Dispase II treatment was associated with the digestion of several ECM molecules, particularly those in the basement membrane including collagen VI, fibronectin, and laminin. FGF-2 and PDGF-B expression were unaffected by Dispase II, but TGF-alpha, TGF-beta1, TGF-beta 2R, PDGF-A, VEGF, and EGFR expression were all reduced by Dispase II incubation. TEM confirmed the disruption of DHAM ultrastructure with increasing duration of Dispase II incubation, beginning with disruption of the basal lamina and progressing to loosening of the stromal collagen network as well. CONCLUSIONS: The use of Dispase II in the preparation of DHAM causes significant changes to the ultrastructure of the membrane, particularly the BM. Prolonged incubation with dispase may cause significant disruption in DHAM structure which may affect cell growth in cultured explants. PMID- 19784397 TI - An anisotropic scale-invariant unstructured mesh generator suitable for volumetric imaging data. AB - We present a boundary-fitted, scale-invariant unstructured tetrahedral mesh generation algorithm that enables registration of element size to local feature size. Given an input triangulated surface mesh, a feature size field is determined by casting rays normal to the surface and into the geometry and then performing gradient-limiting operations to enforce continuity of the resulting field. Surface mesh density is adjusted to be proportional to the feature size field and then a layered anisotropic volume mesh is generated. This mesh is "scale-invariant" in that roughly the same number of layers of mesh exist in mesh cross-sections, between a minimum scale size L(min) and a maximum scale size L(max). We illustrate how this field can be used to produce quality grids for computational fluid dynamics based simulations of challenging, topologically complex biological surfaces derived from magnetic resonance images. The algorithm is implemented in the Pacific Northwest National Laboratory (PNNL) version of the Los Alamos grid toolbox LaGriT[14]. Research funded by the National Heart and Blood Institute Award 1RO1HL073598-01A1. PMID- 19784398 TI - HIGH DIMENSIONAL VARIABLE SELECTION. AB - This paper explores the following question: what kind of statistical guarantees can be given when doing variable selection in high dimensional models? In particular, we look at the error rates and power of some multi-stage regression methods. In the first stage we fit a set of candidate models. In the second stage we select one model by cross-validation. In the third stage we use hypothesis testing to eliminate some variables. We refer to the first two stages as "screening" and the last stage as "cleaning." We consider three screening methods: the lasso, marginal regression, and forward stepwise regression. Our method gives consistent variable selection under certain conditions. PMID- 19784399 TI - MULTISCALE MODELS OF TAXIS-DRIVEN PATTERNING IN BACTERIAL POPULATIONS. AB - Spatially-distributed populations of various types of bacteria often display intricate spatial patterns that are thought to result from the cellular response to gradients of nutrients or other attractants. In the past decade a great deal has been learned about signal transduction, metabolism and movement in E. coli and other bacteria, but translating the individual-level behavior into population level dynamics is still a challenging problem. However, this is a necessary step because it is computationally impractical to use a strictly cell-based model to understand patterning in growing populations, since the total number of cells may reach 10(12) - 10(14) in some experiments. In the past phenomenological equations such as the Patlak-Keller-Segel equations have been used in modeling the cell movement that is involved in the formation of such patterns, but the question remains as to how the microscopic behavior can be correctly described by a macroscopic equation. Significant progress has been made for bacterial species that employ a "run-and-tumble" strategy of movement, in that macroscopic equations based on simplified schemes for signal transduction and turning behavior have been derived [14, 15]. Here we extend previous work in a number of directions: (i) we allow for time-dependent signals, which extends the applicability of the equations to natural environments, (ii) we use a more general turning rate function that better describes the biological behavior, and (iii) we incorporate the effect of hydrodynamic forces that arise when cells swim in close proximity to a surface. We also develop a new approach to solving the moment equations derived from the transport equation that does not involve closure assumptions. Numerical examples show that the solution of the lowest order macroscopic equation agrees well with the solution obtained from a Monte Carlo simulation of cell movement under a variety of temporal protocols for the signal. We also apply the method to derive equations of chemotactic movement that are governed by multiple chemotactic signals. PMID- 19784400 TI - Preparation of 2,3-Disubstituted Indoles by Sequential Larock Heteroannulation and Silicon-Based Cross-Coupling Reactions. AB - A simple and convergent synthesis of 2,3-disubstituted indoles has been developed using a sequential Larock indole synthesis and silicon-based, cross-coupling reaction. Substituted 2-iodoanilines reacted with an alkynyldimethylsilyl tert butyl ether to afford indole-2-silanols under the Larock heteroannulation conditions after hydrolysis. The corresponding sodium 2-indolylsilanolate salts successfully engaged in cross-coupling with aryl bromides and chlorides to afford multi-substituted indoles. The development of an alkynyldimethylsilyl tert-butyl ether as a masked silanol equivalent enabled a smooth heteroannulation process and the identification of a suitable catalyst/ligand combination provided for a facile cross-coupling reaction. PMID- 19784401 TI - Contemporary surgery for obstructive sleep apnea syndrome. AB - Surgical treatment of obstructive sleep apnea syndrome (OSAS) has been available in some form for greater than three decades. Early management for airway obstruction during sleep relied on tracheotomy which although life saving was not well accepted by patients. In the early eighties two new forms of treatment for OSAS were developed. Surgically a technique described as a uvulopalatopharyngoplasty (UPPP) was used to treat the retropalatal region for snoring and sleep apnea. Concurrently sleep medicine developed a nasal continuous positive airway pressure (CPAP) device to manage nocturnal airway obstruction. Both of these measures were used to expand and stabilize the pharyngeal airway space during sleep. The goal for each technique was to limit or alleviate OSAS. Almost 30 yr later these two treatment modalities continue to be the mainstay of contemporary treatment. As expected, CPAP device technology improved over time along with durable goods. Surgery followed suit and additional techniques were developed to treat soft and bony structures of the entire upper airway (nose, palate and tongue base). This review will only focus on the contemporary surgical methods that have demonstrated relatively consistent positive clinical outcomes. Not all surgical and medical treatment modalities are successful or even partially successful for every patient. Advances in the treatment of OSAS are hindered by the fact that the primary etiology is still unknown. However, both medicine and surgery continue to improve diagnostic and treatment methods. Methods of diagnosis as well as treatment regimens should always include both medical and surgical collaborations so the health and quality of life of our patients can best be served. PMID- 19784402 TI - Chondroradionecrosis of the larynx: diagnostic and therapeutic measures for saving the organ from radiotherapy sequelae. AB - OBJECTIVES: Chondroradionecrosis (CRN) of the larynx is a rare but fatal complication of radiotherapy. We determined the optimal diagnostic methodology and management of laryngeal CRN in six patients. METHODS: We retrospectively reviewed the records of six patients with Chandler grade IV laryngeal CRN who had received prior radiotherapy (mean total radiation dose, 66.7+/-4.5 Gy) at a tertiary care hospital. Two patients underwent transoral laser microresection of their laryngeal carcinoma plus postoperative radiotherapy. All patients underwent endoscopy, computed tomography (CT), positron emission tomography (PET), removal of necrotic tissue, biopsy under suspension laryngoscopy, administration of antibiotics, and hyperbaric oxygen therapy (HBO). Their diagnostic and therapeutic results were assessed. RESULTS: CT showed CRN of the anterior larynx in three patients and CRN of the posterior larynx in three patients, with one patient having a false-positive result on PET. HBO consisted of a mean of 36+/-6 dives. After early debridement and HBO, five patients showed CRN improvement, but one had aggravation and subsequently underwent total laryngectomy. None of these patients showed local tumor recurrence on pathologic examination or during a mean follow-up of 24 months. CONCLUSION: Although CRN of the larynx may be detected by endoscopic and imaging work-ups, detection may require pathologic examination. Early debridement and HBO may effectively treat CRN, saving the functional larynx. PMID- 19784403 TI - Long term outcomes of early cochlear implantation in Korea. AB - OBJECTIVES: The objective of this study was to compare the long-term auditory performance and language skill depending on the age of cochlear implantation in the Korean population. We especially tried to separate the effect of maturation/development from that of the age at implantation. METHODS: Eighty-six pre-lingual children with profound hearing loss who underwent a cochlear implantation before the age of six and had been followed for more than 3 yr were included in this study prospectively. Categories of Auditory Performance (CAP) and Korean Picture Vocabulary Test (K-PVT) were serially followed up. In order to separate the age at implantation effect, K-PVT results were readjusted to the child's chronological age in the normal hearing population. RESULTS: When the CAP and K-PVT scores were directly compared without chronological readjustment, we failed to show a significant difference for improvements according to the age at implantation. Early cochlear implantation was associated with better language development, only when the K-PVT scores were readjusted to percentile scores of their chronological age. CONCLUSION: Early cochlear implantation was associated with better language development even within the critical period. This advantage may be recognized only when the effect of the age at implantation is separated from the effect of maturation/development. PMID- 19784404 TI - A Relationship between the Obstructive Sleep Apnea Syndrome and the Erythrocyte Sedimentation Rate. AB - OBJECTIVES: The erythrocyte sedimentation rate (ESR) is a marker for inflammation, and it has been identified as a risk factor for atherothrombotic cardiovascular disease. The aim of this study was to determine the relationship between the plasma ESR level and nocturnal oxygen desaturation or other polysomnographic variables and to examine the role of obesity in patients with obstructive sleep apnea syndrome (OSAS). METHODS: This retrospective study included 72 patients with a diagnosis of OSAS who underwent overnight polysomnography and routine blood tests between July and December of 2005. We compared the plasma ESR level with the sum of all the polysomnographic variables and divided the patient group into obese and non-obese patients. RESULTS: The mean ESR level was 8.45 mm/hr. There was a significant difference in the ESR level between genders (P<0.001). A significant correlation was found between the percentage of time spent at a SpO(2) below 90% and the ESR level in the obese group (BMI >/=25, N=43, P=0.012). In addition, the ESR levels had a positive correlation with age in the obese group (P=0.002). However, there was no significant correlation with the percentage of time spent at a SpO(2) below 90% in the whole group of patients and in the non-obese group (BMI <25, N=29). The ESR level showed no correlation with the other polysomnographic variables. CONCLUSION: The duration of deoxygenation in obese patients with OSAS may be associated with the ESR level which is an independent predictor of cardiovascular disease. PMID- 19784405 TI - IgA and Differentiation-associated Transcription Factors in Chronic Otitis Media with Effusion. AB - OBJECTIVES: Inadequate antibody responses to pathogens may lead to the recurrence of otitis media with effusion (OME). Although B-cell production by antibodies is controlled by transcription factors, the status of these factors has not been assessed in patients with OME. METHODS: Expression of immunoglobulin was measured by enzyme-linked immunosorbent assay. Expression of transcription factors Bcl-6, Blimp-1, Pax-5, and XBP-1 was assessed by RT-PCR in the middle-ear fluid of 29 children with >4 OME episodes in 12 months or >3 episodes in 6 months (the OME prone group) and in 32 children with <3 OME episodes in 12 months (OME group). The relationship between recurrence of OME and expression levels of immunoglobulins and transcription factors in middle-ear fluid was determined. RESULTS: The concentration of IgA in middle-ear fluid was significantly lower in the OME-prone than in the OME group, as was the expression of mRNA encoding the transcription factors Blimp-1 and XBP-1 (P<0.05 each). Expression of mRNA encoding the transcription factors Bcl-6 and Pax-5 was more intense in the OME prone than in the OME group, but these differences were not significant (P>0.05). CONCLUSION: Lower concentrations of IgA, Blimp-1 and XBP-1 in middle ear fluid of patients with OME may be related to OME recurrence and chronicity. PMID- 19784406 TI - Early compliance and efficacy of sublingual immunotherapy in patients with allergic rhinitis for house dust mites. AB - OBJECTIVES: Sublingual immunotherapy (SLIT) has recently received much attention around the world as a treatment for allergic rhinitis. This study aimed to investigate the efficacy and adverse effects of SLIT in Korean patients with allergic rhinitis caused by house dust mites. The treatment compliance and the patient satisfaction with SLIT were also assessed. METHODS: The patients who were sensitized to Dermatophagoides pteronyssinus and Dermatophagoides farinae and who started SLIT between November 2007 and July 2008 were included in this study. The symptom questionnaires, which included items on rhinorrhea, sneezing, nasal obstruction, itchy nose, olfactory disturbance, eye discomfort and sleep disturbance, were obtained before and 6 months after SLIT. The patient satisfaction and the adverse effects were also investigated. RESULTS: One hundred forty-two patients started SLIT and 98 of them continued SLIT for 6 months or more. Ninety-two of the 98 patients completed the questionnaires. The duration of receiving SLIT was 9.8 months on average (range, 6 to 13 months). All the symptoms of allergic rhinitis were improved with SLIT. Forty-five percent of the patients were satisfied for SLIT, while 12% were unsatisfied. The incidence of adverse effects was 12% during maintenance therapy, although it was 48% during the up-dosing phase. The drop-out rate of SLIT was 31.0%. CONCLUSION: The subjective symptoms were improved with SLIT in Korean patients with allergic rhinitis for house dust mites. Yet the drop out rate was high despite of the symptomatic improvement. PMID- 19784407 TI - The surgical outcome of endoscopic dacryocystorhinostomy according to the obstruction levels of lacrimal drainage system. AB - OBJECTIVES: Many factors influence the outcome of endoscopic dacryocystorhinostomy (DCR). One of the most important prognostic factors is the level of obstruction in the lacrimal drainage system. The main objective of this report is to evaluate both the frequency of obstruction by anatomical region of the lacrimal drainage system on dacryocystography (DCG) and the surgical outcome of endoscopic DCR according to the obstruction level. METHODS: A retrospective series of 48 patients (60 eyes) who had undergone endoscopic DCR from January 2005 to November 2007 were enrolled. Preoperative evaluation consisted of a standard examination which included lacrimal irrigation, probing, DCG and osteomeatal unit (OMU) computed tomography. Patients were classified into four groups according to the obstruction level on DCG. Surgical outcome was evaluated postoperatively by subjective improvement of epiphora and patent rhinostomy opening on nasal endoscopic exam. RESULTS: Of 60 eyes, the levels of obstruction were the common canaliculus in 14 eyes (23.3%), the lacrimal sac in 13 eyes (21.7%), the duct-sac junction in 13 eyes (21.7%) and the nasolacrimal duct (NLD) in 20 eyes (33.3%). The ductsac junction obstruction was treated most successfully (100%), followed by NLD obstruction (90%), common canaliculus obstruction (78.6%) and saccal obstruction (69.2%). CONCLUSION: In patients with lacrimal drainage system obstruction, preoperative evaluation of obstruction level using DCG may be helpful for predicting the surgical outcome of endoscopic DCR. The saccal obstruction may have a worse prognosis than the other obstruction levels. PMID- 19784408 TI - Results of air caloric and other vestibular tests in patients with chronic otitis media. AB - OBJECTIVES: Air caloric results are supposed to be influenced by anatomic changes of the middle ear. The aims of our study were to evaluate the incidence and characteristics of abnormal air caloric results in patients with unilateral chronic otitis media and without any history of vertigo, and to compare caloric results with there of other vestibular function tests (VFTs). METHODS: Twenty five patients with unilateral chronic otitis media (COM) who were scheduled for surgery underwent VFTs preoperatively. Hearing was assessed using pure-tone audiometry and vestibular function was assessed using a set of VFTs: air caloric, head-shaking nystagmus (HSN), vibration-induced nystagmus (VIN), and subjective visual vertical (SVV) tests. RESULTS: Six patients (24%) showed pathologic canal paresis (CP) on COM-sided ears. Two patients showed pathologic CP on the contralateral side. However, both of the two showed inverted nystagmus to warm air stimulation on the COM-side and hyperactive nystagmus to cold air stimulation on the COM-side, which means that the COM-sided ear was stimulated too much. There was pathologic HSN in 12 patients (48%), pathologic VIN in 7 (28%), and pathologic SVV in 5 (20%). Overall, 20 (80%) patients showed abnormal findings through a set of VFTs. Patients with an interaural difference of bone-conduction hearing thresholds >/=10 dB tended to show more abnormal VFT results than those for whom the interaural difference of bone-conduction hearing thresholds was <10 dB. CONCLUSION: Our data show that one-fourth of patients with unilateral COM show abnormal caloric results on the COM side. However, subclinical latent vestibular imbalances were found to be common, which might be related to the gradual vestibular involvement in inflammatory processes, regardless of the caloric results. Results of a set of VFTs should be referred to when determining vestibular imbalance in patients with COM. PMID- 19784409 TI - Petrous apex cholesterol granuloma presenting as endolymphatic hydrops: a case report. AB - A petrous apex cholesterol granuloma (PACG) is the most common lesion of the petrous apex mass. Affected patients present with various symptoms such as hearing loss, vertigo, headache, tinnitus, facial spasms, and diplopia. We report the case of a 32-yr-old man with a PACG, who was first misdiagnosed with Meniere's disease. He was placed on a low-salt diet, and prescribed medication from another hospital, for several months, but the symptoms persisted and worsened. The patient presented to the emergency room complaining of left facial twitching and numbness. To rule out a central neurological lesion, temporal bone magnetic resonance imaging was carried out and a 2.5 cm mass with high signal intensity on T1- and T2-weighted imaging, without gadolinium enhancement, was found. Because of the hearing and facial problems, we drained cholesterol-bearing material via an infralabyrinthine approach using a computer aided image-guided surgical device, the BrainLAB(R). After the operation, the vertigo and hearing loss were no longer present. It is likely that the patent's Meniere's disease like symptoms were due to the compression of the endolymphatic sac by a PACG. PMID- 19784410 TI - Adenomatous hyperplasia arising from dual ectopic thyroid. AB - Ectopic thyroid tissue is an uncommon embryologic aberration characterized by the presence of thyroid tissue in a site other than its usual pre-tracheal location. Single ectopic thyroid tissue is the most common variant, and the base of the tongue is the most frequent ectopic location. Dual ectopic thyroid is extremely rare, and only eleven cases have been reported in the English literature. Furthermore, adenomatous hyperplasia has never been reported to arise from dual ectopic thyroid. There has been only one reported case of adenomatous hyperplasia arising from a single intratracheal ectopic thyroid. We report a case of adenomatous hyperplasia arising from dual ectopic thyroid tissue that presented as a sublingual mass in a 37-yr-old woman. The diagnosis was made through pathologic examination after surgical resection. We also discuss the diagnosis and treatment of ectopic thyroid, along with a review of the literature. PMID- 19784412 TI - Rhinologists: who are we? PMID- 19784413 TI - Distortion-product otoacoustic emissions and auditory brainstem responses sensitivity assessment in cisplatin-induced ototoxicity in rats. AB - Cisplatin (cis-diamminedicloroplatinum) is an antineoplastic drug used in the treatment of a variety of cancers, especially head-and-neck cancer. Its ototoxicity, however, has been noted as a common side-effect which limits its use and causes significant morbidity. AIM: to assess distortion-product otoacoustic emissions (DPOAE) and brainstem evoked response audiometry (BERA) sensitivity to detect secondary ototoxicity caused by different doses and means of administration of cisplatin in rats. STUDY DESIGN: Experimental. MATERIAL AND METHODS: Male Wistar rats were intraperitoneally (i.p.) injected with 24 mg/kg cisplatin, divided into three equal doses (8 mg/kg) or a single i.p. injection of 16 mg/kg. The animals were evaluated by distortion product otoacoustic emission (DPOAE) or brainstem evoked response audiometry (BERA) on the 3rd and 4th days after the cisplatin injection. RESULTS: Treatment with cisplatin 24 mg/kg resulted in significant DPOAE decrease and it raised the BERA electrophysiological threshold. The 16 mg/kg dose could not significantly reduce the DPOAE amplitude, but it raised the animals' hearing thresholds - detected by the BERA. CONCLUSION: In rats, BERA was more sensitivity than DPOAE at detecting cisplatin-induced ototoxicity in rats considering different doses and means of administration. PMID- 19784414 TI - Youth Attitude to Noise Scale (YANS) questionnaire adaptation into Brazilian Portuguese. AB - The growing exposure of teenagers to environmental noise and music has generated interest in studies about the impact of such exposure, as well as the measures taken in these situations. Therefore, it is fundamental to use a valid and reliable instrument. AIM: to validate a Brazilian Portuguese version of the Youth Attitude to Noise Scale questionnaire. STUDY DESIGN: cross-sectional, repeated measures. MATERIALS AND METHODS: Translation from English into Portuguese, pre test, linguistic adaptation, review of grammar and idiomatic equivalence, and translation from Portuguese back to English. Instrument application. Retesting within 30 to 90 days. Measurement of the questions used following Likert's scale. Through factorial analysis, explanation for the connections among a set of variables. RESULTS: there was a match between translation and counter translation. The questions were satisfactorily understood. The factorial analysis was well defined with the use of four factors. The instrument's reproducibility was proven by the 0.75 Cronback Alpha general index. CONCLUSIONS: Significant correlations, indicating the construction and content validity for its use, serving as a tool to assess the attitudes of the youth facing exposure to environmental noise or music. PMID- 19784415 TI - Indication of elective contralateral neck dissection in squamous cell carcinoma of the hypopharynx. AB - Lymph node metastases (LNM) are common in hypophariyngeal carcinomas; the neck dissection is an important therapeutic approach. AIM: to analyze the incidence and distribution of LNM and failures in treating the contralateral neck. METHODS: a retrospective study of 174 patients with hypopharyngeal cancer treated from 1978 to 2003. The distribution of LNM and regional recurrences were evaluated. RESULTS: 44% of the cases were false negatives and 4.9% were false positives. Among the 48 patients who underwent bilateral ND, 29 had bilateral metastases and one had contralateral metastasis. Contralateral neck recurrences occurred in 12 cases that underwent unilateral ND. Among the nine patients with contralateral neck recurrence alone, eight were surgically salvaged. The risk of contralateral metastases was related to clinical staging (p=0.003) and involvement of the medial wall of the pyriform sinus (p=0.03), but not to radiotherapy (p=0.28). CONCLUSION: Contralateral metastases were more frequent when the medial wall of the pyriform sinus was affected, in the presence of ipsilateral palpable metastases and clinical stage IV. PMID- 19784416 TI - Parotid neoplasms: analysis of 600 patients attended at a single institution. AB - Salivary gland tumors are rare, generally benign and affect mainly the parotid gland. AIM: The purpose of this study was to retrospectively analyze all cases of parotid tumors treated at our institution from 1953 to 2003. METHODS: All patients with primary parotid tumors were selected; clinical and histopathological data were analyzed and described. RESULTS: 600 cases of parotid tumors were selected; 369 were benign and 231 were malignant. Pleomorphic adenoma was the most frequent benign tumor. The most common malignant tumor was the mucoepidermoid carcinoma. Therapy in most cases consisted of parotidectomy. Adjuvant therapy -- mainly radiotherapy -- was used in some cases with malignant tumors. The incidences of local, regional and distant recurrences of malignant tumors were 10%, 8% and 9%. CONCLUSION: Patients with parotid tumors treated at our institution were mainly adults, with marginally more female patients. Benign tumors were mostly the pleomorphic adenoma, which were more frequent than malignancies. Most of the patients were treated by partial or total parotidectomy. Adjuvant therapy, mainly radiotherapy, was used in selected malignant cases. PMID- 19784417 TI - Clinical features of benign paroxysmal positional vertigo. AB - Benign paroxysmal positioning vertigo (BPPV) is considered as the most common vestibular disease. AIM: to evaluate the age, gender, type and site of the lesion, association with other vestibular diseases, progression, and recurrence in these patients. MATERIAL AND METHOD: A retrospective series study. Data from medical reports of BPPV patients examined in series during the past six years were analyzed. RESULTS: prevalences of BPPV were: at age 41-60 years (42.2 %); in females (62.8 %), wit nystagmus and positioning vertigo (81.3%); affecting the posterior canal (87%), unilateral (91.8 %), the right labyrinth (60.2%) - p<0.001). Due to canalithiasis (97.5%), idiopathic (74.8%), association with Meniere's disease compared to other affections (55.4%); healing or recovery by means of the particle repositioning maneuver (77.9%); and possible recurrence (21.8% in a one-year follow-up period). CONCLUSION: BPPV is characterized by its prevalence at age 41 to 60 years, in females, with nystagmus and positioning vertigo, involving mostly the posterior canal of the right labyrinth, associated with canalithiasis or idiopathic, associated with Meniere's disease compared to other affections, healing or recovery by means of particle repositioning maneuver, and possible recurrence. PMID- 19784418 TI - Histological analysis of the distribution pattern of glandular tissue in normal inferior nasal turbinates. AB - Nasal turbinates play an important role in nasal physiology. These functions include the important function of particle filtration by the mucocilliary system. Many nasal mucosal diseases, such as rhinitis and rhinosinusitis, are directly related with structural alterations of the mucosal lining of the turbinates. AIM: To study the distribution pattern of the glandular epithelium of the lamina propria in the normal lower nasal turbinate mucosa of the anterior, medium and posterior portions. MATERIAL AND METHOD: A prospective study in which small linear fragment of the lower nasal turbinate was removed from ten patients undergoing aesthetic nose surgery. The slides were hematoxilin-eosin stained, examined histologically and photographed. Glandular epithelium was delimited individually, the total area of the lamina propria on the anterior, medium and posterior portions of nasal turbinates was calculated (microm2). RESULTS: There was no statistically significant difference in the distribution pattern of the glandular epithelium of the lamina propria. CONCLUSION: This study showed no predominance of glandular epithelium distribution in anterior and posterior portions of lower nasal turbinates in normal subjects. PMID- 19784419 TI - Laryngeal vocal and endoscopic alterations after thyroidectomy under local anesthesia and hypnosedation. AB - Vocal alterations after thyroidectomy are generally related to laryngeal nerve injury or laryngotracheal mobility disorders caused by postoperative fibrosis or strap muscle lesion. AIM: this study aims to evaluate the frequency of vocal and rima glottidis disorders after thyroidectomy. MATERIALS AND METHOD: This is a prospective study based on 35 patients submitted to thyroidectomy under local anesthesia and hypnosedation. All patients underwent voice auditory perception evaluation, voice acoustic tests and videolaryngostroboscopy preoperatively, and at one week and at 30 days postoperatively. Bilateral cricothyroid muscle electromyography was performed on the thirtieth day after surgery to confirm the presence of injury in the external branch of the superior laryngeal nerve. RESULTS: 14.3% of the patients presented posterior glottis deviation before surgery and normal electromyography findings. Transient and permanent vocal alteration occurred in 25.7% and 14.2% of the patients respectively. CONCLUSION: voice disorders evaluated after voice auditory perceptive evaluation and voice acoustic tests were more intense in the group with superior laryngeal nerve external branch injury than in the injury-free dysphonic patient group. Oblique glottis can be present in normal patients; however its onset after thyroidectomy is indicative of superior laryngeal nerve external branch lesion. PMID- 19784420 TI - Is the information available on the Web influencing the way parents see ENT surgical procedures? AB - INTRODUCTION AND AIMS: the Internet is the world's fastest growing source of health related information. Parents and guardians are increasingly turning to the Internet for information about their children's medical conditions and treatments. This paper has the following objectives 1) determine the prevalence of web searches for medical information performed by parents/guardians of children undergoing ENT surgery in a private hospital of Sao Paulo, Brazil. 2) assess whether the gathered information influenced the parents/guardians' decision on the treatment/surgery. METHOD: questionnaire voluntarily responded by 132 parents/guardians of children submitted to ENT surgery in a private hospital in Sao Paulo, Brazil. CONCLUSIONS: 117 parents/guardians (90%) used the Internet to search for information on the disease and surgical treatment of the children. Only 12 parents/guardians (10%) discussed the information with the physician assigned to perform the surgical procedure. 91 parents/guardians (78%) said that the information had impact upon the decision to have surgery performed on their children. PMID- 19784421 TI - Oral cancer: population sample of the state of Alagoas at a reference hospital. AB - The incidence and mortality of oral cancer in Brazil remains high; the disease manifests varying features throughout the country. AIM: To analyze the epidemiology of oral cancer, including the prevalence, type and site of lesions, the distribution in the state of Alagoas, staging, treatment, and social and demographic aspects. MATERIAL AND METHODS: A descriptive retrospective study was carried out. Data were gathered from records of a hospital in Alagoas from January 2000 to December 2006. RESULTS: Of 396 cases (100% of the sample), 62.70% were male and 37.30% female. Most tumors were on the tongue. The mean age was 61.95 years (SD=14.56 years), and 95.2% of the sample were aged over 40 years. Most of lesions were stage II (57.04%). Radiotherapy was the most common treatment. CONCLUSION: This study revealed the epidemiology of oral cancer patients at a reference hospital in the state of Alagoas. The results showed that oral cancer occurs mostly in males in the sixth decade of life; the most common site is the tongue, followed by the floor of the mouth. PMID- 19784422 TI - Risk factors for presbycusis in a socio-economic middle-class sample. AB - Presbycusis, or the aging ear, involves mainly the inner ear and the cochlear nerve, causing sensorineural hearing loss. Risk factors include systemic diseases and poor habits that cause inner ear damage and lead to presbycusis. Correct identification of these risk factors is relevant for prevention. AIM: To evaluate the prevalence and to identify the risk factors of presbycusis in a sample aged over 40 years. STUDY DESIGN: A retrospective case series. SUBJECTS AND METHODS: medical records of 625 patients were evaluated. Presbycusis was identified using pure tone audiometry, speech audiometry and impedance testing of all patients. RESULTS: The prevalence of presbycusis was 36.1%; the mean age was 50.5 years ranging from 40 to 86 years; 85.5% were male and 14.5% werf female. Age, the male gender, diabetes mellitus, and hereditary hearing loss were identified as risk factors. Cardiovascular diseases, smoking and consumption of alcohol were not confirmed as risk factors, although these have often been mentioned as risk factors for presbycusis. CONCLUSION: Notwithstanding the idea that presbycusis has multiple risk factors, this study identified few risk factors for this disease. PMID- 19784423 TI - Social integration and inclusion after pre-maxilla surgical repositioning in patients with bilateral cleft palate and lip. AB - Bilateral alveolar process fissure causes important functional and aesthetical limitations and thus difficulties in terms of social and family integration and interaction for these patients. AIM: (A) to assess motivations and expectations Treatment-wise and (B) to assess social inclusion and integration brought about by the surgery. MATERIALS AND METHODS: retrospective observational study involving 50 participants recruited among the patients submitted to the pre maxilla repositioning procedure from January of 2003 to July of 2005 at the Centro de Atendimento Integral ao Fissurado Labio-Palatal in Curitiba (CAIF), Parana, and an assessment questionnaire was used. RESULTS: as far as the care protocol is concerned, results show a 90% success rate of surgeries. As to surgical and personal satisfaction rates are concerned, 76% sought treatment for personal satisfaction reasons and 86% reported having had more self-confidence after the surgery. CONCLUSIONS: Most of the patients submitted to the maxilla repositioning saw surgery as a continuation of the care previously given, with the expectation of better looks and self-confidence and, 96% of them were pleased with the results attained, which facilitated their social inclusion and re integration. PMID- 19784424 TI - Ki-67 and p53 correlation prognostic value in squamous cell carcinomas of the oral cavity and tongue. AB - Epidermoid carcinomas represent from 90% to 95% of oral cavity malignant neoplasias, making up 13,470 cases/year. AIMS: To correlate p53 and Ki-67 expressions in mouth and tongue carcinomas with lymph node status, gender, histological grade, tumor volume and pathological stage. MATERIALS AND METHODS: We carried out a retrospective study of 28 cases of mouth and tongue epidermoid carcinomas. They were submitted to immunohistochemical study in order to check the expression of p53 and Ki-67 antibodies and statistically compare them in terms of lymph node status, gender, histological grade, tumor volume and pathological staging. RESULTS: The individually analyzed p53 proved to have statistical significance (p<0.05) when compared to tumor volume (p=0.029). Despite a strong tendency, the p53/tumor volume relation was not significant. When p53 + Ki67 were analyzed, tumor volume had p < 0.05 (p = 0.029). DISCUSSION: Literature shows that the expression of p53 and Ki-67 is related to the presence of metastasis to lymph nodes and a worse prognosis. CONCLUSION: In oral cavity and tongue epidermoid carcinomas, p53 and Ki-67 are related to larger tumors, metastasis to lymph nodes and very likely to a worse prognosis. PMID- 19784425 TI - Gustatory alteration evaluation in patients with chronic otitis media. AB - Many studies have shown the consequent gustatory alteration caused by ear surgeries. However, few have reported this alteration in patients with chronic otitis media (COM), prior to surgical treatment. AIM: to identify gustatory alterations due to chorda tympani nerve involvement in patients with COM without prior surgery. METHODS: Clinical essay, with tests based on 'taste strips' with different concentrations of salt, sweet, bitter, and sour, was performed in 45 patients with unilateral cholesteatomatous or suppurated COM not previously submitted to otological surgery, using the disease-free ear on the contralateral side as control. The score ranged between 0 and 16. RESULTS: A total of 25 patients presented cholesteatoma and 20 had non-cholesteatomatous disease. The mean score was 6.65 for the affected side and 9.93 for the half of the tongue on the side of the healthy ear (p<0.001). No patients had complained of gustatory alterations before the examination. Among the 24 patients with unilateral hypogeusia, eight cases of unilateral ageusia were found on the affected side. There was an association between cholesteatoma (p=0.055), disease duration (p=0.07) and worsening in gustatory sensitivity. CONCLUSION: Patients with COM can have gustatory alterations, even in the absence of complaints. PMID- 19784426 TI - Swallowing and quality of life after total laryngectomy and pharyngolaryngectomy. AB - Dysphagia can be a consequence of total laryngectomy even in the absence of symptoms and it could indeed directly or indirectly compromise quality of life. AIM: To evaluate the characteristics of swallowing after total laryngectomy and pharyngolaryngectomy with pharyngeal T closure, correlating them with the Quality of Life in Swallowing Disorders questionnaire. METHODS: A prospective evaluation was performed in 28 patients; fifteen undergoing total laryngectomy and thirteen undergoing total pharyngolaryngectomy. Swallowing was evaluated through videofluoroscopy regarding the preparatory, oral and pharyngeal phases of swallowing, and the quality of life related to swallowing questionnaire was employed to measure quality of life. RESULTS: Anatomical and functional changes were observed under videofluoroscopic evaluation. Dysphagia was diagnosed in 18 patients (64.3%), being mild in 66.6% and moderate/severe in 33.3%. The questionnaire indicated good quality of life in almost all scales. Complaints of dysphagia were associated to the burden (p=0.036) and mental health scale (p=0.031). The questionnaire indicated impact on the mental health scale for patients with severe dysphagia (p=0.012). CONCLUSIONS: High incidence of dysphagia was observed in some quality of life assessments, especially of mild degree. PMID- 19784427 TI - Benign paroxysmal positional vertigo recurrence and persistence. AB - Benign paroxysmal positional vertigo (BPPV) is one of the most common vestibular disorders. AIM: To study the recurrence and persistence of BPPV in patients treated with canalith repositioning maneuvers (CRM) during the period of one year. STUDY DESIGN: longitudinal contemporary cohort series. MATERIALS AND METHODS: One hundred patients with BPPV were followed up during 12 months after a treatment with CRM. Patients were classified according to disease evolution. Aquatic physiotherapy for vestibular rehabilitation (APVR) protocol was applied in cases of persistent BPPV. RESULTS: After CRM, 96% of the patients were free from BPPV's typical nystagmus and dizziness. During the follow up period of 1 year, 26 patients returned with typical BPPV nystagmus and vertigo. Nystagmus and vertigo were persistent in 4% of the patients. Persistent BPPV presented improvement when submitted to APVR. CONCLUSION: During the period of one year, BPPV was not recurrent in 70% of the patients, recurrent in 26% and persistent in 4%. PMID- 19784428 TI - Hearing loss in patients with diabetes mellitus. AB - The relationship between diabetes mellitus and hearing loss is described as 'controversial' in the literature, given that in the clinical realm many patients present dysacusis while others do not. AIM: this study aims to investigate the relationship between hearing loss and diabetes mellitus and add to the knowledge being developed in this area. STUDY DESIGN: cross-sectional clinical trial. MATERIALS AND METHOD: in our study we analyzed the medical charts of 50 adult patients of both genders, aged above 45 years, and diagnosed with diabetes mellitus, seen in our institution in 2006 and 2007, and compared them to the charts of 50 metabolic disease-free individuals. RESULTS: this study found statistically significant worse audiometric thresholds among patients with diabetes mellitus when compared to patients in the control group. CONCLUSION: the results identified in this study point to a correlation between hearing loss and diabetes mellitus. This possibility should therefore be further investigated by health care workers providing care to patients with diabetes mellitus, in the form of closer follow-up on the auditory health of this patient group. PMID- 19784429 TI - Post-auricular muscle reflex in the Middle Latency Evoked Auditory Response. AB - The Middle Latency Auditory Evoked Response may be influenced by the post auricular muscle reflex which occurs at the same latency of this potential. AIM: to evaluate the muscle reflex influence on the middle latency response, identifying the most appropriate place for response recording. MATERIALS AND METHODS: Prospective study in which 40 normal hearing individuals, ranging in age from 18 to 40 years old, were assessed by Middle Latency Response with electrodes placed first on the mastoids, and then on the earlobes. RESULTS: significant statistical differences were seen between the values found with electrodes placed on the mastoids and on the earlobes concerning the Na-Pa amplitude in C3/A1, C3/A2 and C4/A2, concerning the Na wave latency in C3/A2 and C4/A2, and concerning the Pa wave latency in C3/A1 and C3/A2. We found a higher occurrence of the post-auricular reflex when the electrode was placed on the mastoids, in all studied modalities. CONCLUSION: there was post-auricular muscle reflex interference upon the Middle Latency Response obtained when the electrodes were placed on the mastoid, and the most efficient electrode disposition in order to capture and to register more accurately this potential was on the earlobe. PMID- 19784430 TI - Active head rotation in benign positional paroxysmal vertigo. AB - Benign Positional Paroxysmal Vertigo (BPPV) is one of the most common vestibular diseases and the active head rotation test one of the most modern methods of vestibular function assessment. AIM: this study aims to verify if the active head rotation test may reveal signs of horizontal and/or vertical vestibulo-ocular reflex dysfunction in vertigo patients suspected for BPPV. STUDY DESIGN: retrospective series study. MATERIALS AND METHOD: Neurotological evaluation including computerized electronystagmography and active head rotation on the horizontal and vertical axes were conducted in 100 patients suspected for BPPV patients. RESULTS: Isolated or associated abnormalities of the horizontal and/or vertical vestibulo-ocular reflex gain, phase and symmetry were indicative of vestibular involvement and found in 77.0% of the BPPV patients. CONCLUSION: the active head rotation test revealed horizontal and/or vertical vestibulo-ocular reflex dysfunctions in a relevant number of BPPV patients. PMID- 19784431 TI - Risk factors associated with vestibulocochlear nerve schwannoma: systematic review. AB - The vestibulocochlear nerve schwannoma (VS) is a benign tumor that stems from the edge of the Schwann s sheath. It is considered the most frequent intracranial benign tumor, of low lethality rate and unknown etiology. AIM: to identify risk factors associated with VS. STUDY DESIGN: systematic review. METHODS: electronic search of studies using the following key words: 'risk', 'schwannoma', 'vestibular', 'neuroma' and 'acoustic'. All original articles on epidemiological studies published in Portuguese, English or Spanish describing measures of association were included. RESULTS: twenty case-control studies were found, most of them published in the United States. The analysis of those studies shows educational level, household income, occupation, exposure to ionizing radiation and noise, allergic diseases as well as the use of both cellular and cordless phones as risk factors for the VS. CONCLUSION: methodological limitations and lack of precision in the findings impose limits to definitive conclusions concerning those risk factors. The current study contributes with information which can subsidize decisions related to the methodology to be used, having in mind new investigations on risk factors for VS. Therefore, it is of great help for knowledge improvement in this field. PMID- 19784432 TI - Mandible giant-cell reparative granuloma. PMID- 19784433 TI - Adenotonsillectomy -- immediate post operative respiratory distress. PMID- 19784434 TI - Pilomatrixoma in the head and neck. PMID- 19784435 TI - Rhino-orbito-cerebral mucormycosis. PMID- 19784436 TI - Malignant myoepithelioma of the hard palate: 9-year follow-up. PMID- 19784438 TI - Global health risks: progress and challenges. PMID- 19784439 TI - Progress towards national self-sufficiency in organ transplants. PMID- 19784440 TI - Directions in health communication. PMID- 19784441 TI - Countdown to wipe out guinea-worm in Ghana. PMID- 19784442 TI - Europe puts health claims to the test. PMID- 19784443 TI - WHO supports fair access to influenza A (H1N1) vaccine. PMID- 19784445 TI - Integrated malaria vector control with microbial larvicides and insecticide treated nets in western Kenya: a controlled trial. AB - OBJECTIVE: To assess the contributions of both microbial larvicides and insecticide-treated nets (ITNs) in terms of reducing malaria incidence in an integrated vector management programme in an area moderately endemic for malaria in the western Kenyan highlands. METHODS: A pre-post, control group design was used. Larval and adult vector populations were surveyed weekly in six separate valley communities. The incidence of Plasmodium infections in children 6 months to 13 years of age was measured during the long and short rainy seasons each year. Baseline data were collected for 17 months, after which Bacillus-based larvicides were applied weekly to aquatic habitats in three of the valleys for another 19 months. At around the same time the larviciding was initiated, ITNs were introduced gradually into all study communities by the National Malaria Control Programme. The effect of larviciding, ITNs and other determinants of malaria risk was assessed by means of generalized estimating equations. FINDINGS: The risk of acquiring new parasite infections in children was substantially and independently reduced by ITN use (odds ratio, OR: 0.69; 95% confidence interval, CI: 0.48-0.99) and larvicide application (OR: 0.44; 95% CI: 0.23-0.82), after adjusting for confounders. CONCLUSION: Vector control with microbial larvicides enhanced the malaria control achieved with ITNs alone. Anti-larval measures are a promising complement to ITN distribution in the economically important highland areas and similar transmission settings in Africa. PMID- 19784446 TI - Misoprostol to prevent and treat postpartum haemorrhage: a systematic review and meta-analysis of maternal deaths and dose-related effects. AB - OBJECTIVE: To review maternal deaths and the dose-related effects of misoprostol on blood loss and pyrexia in randomized trials of misoprostol use for the prevention or treatment of postpartum haemorrhage. METHODS: We searched the Cochrane Controlled Trials Register and Pubmed, without language restrictions, for '(misoprostol AND postpartum) OR (misoprostol AND haemorrhage) OR (misoprostol AND hemorrhage)', and we evaluated reports identified through the Cochrane Pregnancy and Childbirth Group search strategy. Randomized trials comparing misoprostol with either placebo or another uterotonic to prevent or treat postpartum haemorrhage were checked for eligibility. Data were extracted, tabulated and analysed with Reviewer Manager (RevMan) 4.3 software. FINDINGS: We included 46 trials with more than 40,000 participants in the final analysis. Of 11 deaths reported in 5 trials, 8 occurred in women receiving >or= 600 microg of misoprostol (Peto odds ratio, OR: 2.49; 95% confidence interval, CI: 0.76-8.13). Severe morbidity, defined as the need for major surgery, admission to intensive care, organ failure or body temperature >or= 40 degrees C, was relatively infrequent. In prevention trials, severe morbidity was experienced by 16 of 10,281 women on misoprostol and by 16 of 10,292 women on conventional uterotonics; in treatment trials, it was experienced by 1 of 32 women on misoprostol and by 1 of 32 women on conventional uterotonics. Misoprostol recipients experienced more adverse events than placebo recipients: 8 of 2070 versus 5 of 2032, respectively, in prevention trials, and 5 of 196 versus 2 of 202, respectively, in treatment trials. Meta-analysis of direct and adjusted indirect comparisons of the results of randomized trials showed no evidence that 600 microg are more effective than 400 microg for preventing blood loss > 1000 ml (relative risk, RR: 1.02; 95% CI: 0.71-1.48). Pyrexia was more than twice as common among women who received > 600 microg rather than 400 microg of misoprostol (RR: 2.53; 95% CI: 1.78-3.60). CONCLUSION: Further research is needed to more accurately assess the potential beneficial and harmful effects of misoprostol and to determine the smallest dose that is effective and safe. In this review, 400 microg of misoprostol were found to be safer than > 600 microg and just as effective. PMID- 19784447 TI - Methodological trends in studies based on verbal autopsies before and after published guidelines. AB - OBJECTIVE: To report on the uptake of guidelines published in the early 1990s with specific recommendations about the design of future studies based on verbal autopsy conducted for mortality surveillance. METHODS: We conducted a systematic literature search of all verbal autopsy studies published before January 2006 and extracted from the studies a standard set of data. We then compared studies designed before and after the recommendations were issued in terms of seven key methodological indicators. FINDINGS: We found 102 studies conducted in 39 countries; 60 were designed before and 42 after the guidelines were issued. The methods used in these 102 studies varied considerably. While some encouraging trends were noted, there is no evidence that the design recommendations have been systematically implemented. Specifically, there was no clear increase in the proportion of studies with a combined questionnaire (63% before recommendations versus 74% after; P = 0.3), a trained interviewer (70% versus 70%; P = 1.0), a suitable respondent (98% versus 100%; P = 1.0), an optimal recall period (84% versus 97%; P = 0.2), predefined algorithms (28% versus 38%; P = 0.4), an option for assigning multiple causes of death (30% versus 38%; P = 0.3), or a follow-up validation study (83% versus 72%; P = 0.7). CONCLUSION: Expert recommendations for optimal design of verbal autopsy studies have been incompletely implemented to date. Better uptake of design recommendations through enhanced collaboration between research teams is likely to produce better mortality statistics from an increasing number of verbal autopsy studies. PMID- 19784448 TI - Trends in tuberculosis incidence and their determinants in 134 countries. AB - OBJECTIVE: To determine whether differences in national trends in tuberculosis incidence are attributable to the variable success of control programmes or to biological, social and economic factors. METHODS: We used trends in case notifications as a measure of trends in incidence in 134 countries, from 1997 to 2006, and used regression analysis to explore the associations between these trends and 32 measures covering various aspects of development (1), the economy (6), the population (3), behavioural and biological risk factors (9), health services (6) and tuberculosis (TB) control (7). FINDINGS: The TB incidence rate changed annually within a range of +/-10% over the study period in the 134 countries examined, and its average value declined in 93 countries. The rate was declining more quickly in countries that had a higher human development index, lower child mortality and access to improved sanitation. General development measures were also dominant explanatory variables within regions, though correlation with TB incidence trends varied geographically. The TB incidence rate was falling more quickly in countries with greater health expenditure (situated in central and eastern Europe and the eastern Mediterranean), high-income countries with lower immigration, and countries with lower child mortality and HIV infection rates (located in Latin America and the Caribbean). The intensity of TB control varied widely, and a possible causal link with TB incidence was found only in Latin America and the Caribbean, where the rate of detection of smear-positive cases showed a negative correlation with national incidence trends. CONCLUSION: Although TB control programmes have averted millions of deaths, their effects on transmission and incidence rates are not yet widely detectable. PMID- 19784449 TI - Local governments' dependence on tobacco tax revenue: a deterrent to tobacco control in the Republic of Korea. AB - OBJECTIVE: To investigate, in the Republic of Korea, whether local governments' participation in an anti-smoking programme supported by the National Health Promotion Fund in 2002-2003 was related to the percentage of local tax revenue comprised by the tobacco consumption tax (TCT). METHODS: Using financial and administrative data on 163 municipalities, the authors estimated logit models of local governments' participation in the anti-smoking programme as a function of the proportion of local tax revenue that came from the TCT and a set of control variables, namely local socioeconomic characteristics and the size of the staff in the local public health centre (PHC). FINDINGS: Local governments that derived a greater percentage of their local tax revenue from the TCT, particularly those that ranked in the upper fourth in terms of this percentage, were less likely to participate in the anti-smoking programme. Insufficient staff in the PHC was also found to be associated with lower participation in the anti-smoking programme. CONCLUSION: Local governments' dependence on revenue from the TCT may be a deterrent to tobacco control in the Republic of Korea. PMID- 19784450 TI - Paraffin-related injury in low-income South African communities: knowledge, practice and perceived risk. AB - OBJECTIVE: To explore what individuals at risk of injury from using paraffin (also known as kerosene) know about paraffin safety, what they do to protect themselves and their families from paraffin-related injury, and how they perceive their risk for such injury. Also, to explore interrelations between these factors and age, sex, education and income. METHODS: A sample of 238 individuals was randomly recruited from low-income housing districts near Cape Town, South Africa in 2007. Trained research assistants interviewed participants to explore their knowledge about paraffin-related safety and their perceived risk of injury from using paraffin. Researchers inspected participants' homes to evaluate paraffin safety practices. Descriptive and correlational analyses were conducted. FINDINGS: Participants had relatively low levels of knowledge about paraffin related safety. They had high levels of unsafe practice and their perceived risk of injury was moderate. Knowledge of paraffin safety and safe practices were positively correlated with each other. Greater knowledge showed a negative correlation with the perception of being at risk for injury, but safe practices showed no correlation with perceived risk of injury. Formal education, the number of children in the home and frequency of paraffin use were positively correlated with knowledge but not with safe practices. The only significant correlate to safe practices was greater income, perhaps a reflection of the impact of financial resources on paraffin safety practices. CONCLUSION: To develop successful paraffin safety interventions, it is necessary to understand baseline levels of knowledge, practice and perceived risk of injury among at-risk populations. Our findings could be of value for designing interventions that will increase knowledge, improve safe practices and lead to the accurate perception of the risk of injury from using paraffin. PMID- 19784451 TI - Hepatitis B control by 2012 in the WHO Western Pacific Region: rationale and implications. AB - In 2005, the WHO Western Pacific Region adopted the hepatitis B control goal of reducing the hepatitis B surface antigen seroprevalence in children at least 5 years of age to less than 2% by 2012. Universal infant immunization with three doses of hepatitis B vaccine, including a timely birth dose, is the key recommended strategy. Measuring seroprevalence in children at least 5 years of age takes into account the period when the risk of acquiring a chronic infection is highest and provides an indicator that can be monitored in the short term, within 5 years of vaccine introduction, and which correlates strongly with the long-term consequences of hepatitis B. A time-bound supranational hepatitis B control goal was chosen to create a sense of political urgency for strengthening routine immunization services and improving access to delivery care as well as providing resources for hepatitis B vaccination. Consequently, the programme strategies selected are not stand-alone but also contribute to strengthening health systems. Independent certification of achievement of the control goal, hitherto used mainly for eradication goals, is planned for all countries. Early assessment showed that adopting the regional goal led to greater political commitment, with reduced inequalities in hepatitis B vaccination between and within countries. Previous declining trends in routine immunization coverage also show signs of reversal and there is major progress in providing timely birth doses. A similar approach may be relevant to countries in Africa and South Asia, that have a high hepatitis B disease burden faltering routine immunization and poor access to skilled delivery care. PMID- 19784452 TI - Using indicators to determine the contribution of human rights to public health efforts. AB - There is general agreement on the need to integrate human rights into health policies and programmes, although there is still reluctance to go beyond rhetorical acknowledgement of their assumed significance. To determine the actual value of human rights for the effectiveness of public health efforts requires clarity about what their incorporation looks like in practice and how to assess their contribution. Despite the pervasive use of indicators in the public health field, indicators that specifically capture human rights concerns are not well developed and those that exist are inconsistently used. Even though 'health and human rights indicators' are increasingly being constructed, it is often the case that health indicators are used to draw conclusions about some interaction between human rights and health; or that law and policy or other indicators, traditionally the domain of the human rights community, are used to make conclusions about health outcomes. To capture the added value that human rights bring to health, the differences in the contributions offered by these indicators need to be understood. To determine the value of different measures for advancing programme effectiveness, improving health outcomes and promoting human rights, requires questioning the intended purpose behind the construction of an indicator, who uses it, the kind of indicator it is, the extent to which it provides information about vulnerable populations, as well as how the data are collected and used. PMID- 19784453 TI - Governance of dual-use research: an ethical dilemma. AB - Scenarios where the results of well-intentioned scientific research can be used for both good and harmful purposes give rise to what is now widely known as the 'dual-use dilemma'. There has been growing debate about the dual-use nature of life science research with implications for making biological weapons. This paper reviews several controversial publications that have been the focus of debates about dual-use life science research and critically examines relevant policy developments, particularly in the United States of America. Though the dual-use dilemma is inherently ethical in nature, the majority of debates about dual-use research have primarily involved science and security experts rather than ethicists. It is important that there is more ethical input into debates about the governance of dual-use research. PMID- 19784454 TI - Cultural adaptation of birthing services in rural Ayacucho, Peru. AB - PROBLEM: Maternal mortality is particularly high among poor, indigenous women in rural Peru, and the use of facility care is low, partly due to cultural insensitivities of the health care system. APPROACH: A culturally appropriate delivery care model was developed in poor and isolated rural communities, and implemented between 1999 and 2001 in cooperation with the Quechua indigenous communities and health professionals. Data on birth location and attendance in one health centre have been collected up to 2007. LOCAL SETTING: The international nongovernmental organization, Health Unlimited, and its Peruvian partner organization, Salud Sin Limites Peru, conducted the project in Santillana district in Ayacucho. RELEVANT CHANGES: The model involves features such as a rope and bench for vertical delivery position, inclusion of family and traditional birth attendants in the delivery process and use of the Quechua language. The proportion of births delivered in the health facility increased from 6% in 1999 to 83% in 2007 with high satisfaction levels. LESSONS LEARNED: Implementing a model of skilled delivery attendance that integrates modern medical and traditional Andean elements is feasible and sustainable. Indigenous women with little formal education do use delivery services if their needs are met. This contradicts common victim-blaming attitudes that ascribe high levels of home births to 'cultural preferences' or 'ignorance'. PMID- 19784455 TI - Further reflections on open access. PMID- 19784456 TI - Accuracy of probabilistic record linkage applied to health databases: systematic review. AB - OBJECTIVE: To analyze both national and international literature on validity of record linkage procedure of health databases focusing on quality assessment of results. METHODS: A systematic review of cohort, case-control, and cross sectional studies that evaluated quality of probabilistic record linkage of health databases was conducted. Cochrane methodology of systematic reviews was used. The following databases were widely searched: Medline, LILACS, Scopus, SciELO and Scirus. A time filter was not applied and articles were searched in the following languages: Portuguese, Spanish, French and English. RESULTS: Summary measures of the quality of probabilistic record linkage were sensitivity, specificity, and positive predictive value. There were identified 202 studies, and after applying the inclusion criteria, a total of 33 articles were reviewed. Only six had complete data on the summary measures of interest. The main limitations were: no reviewer to evaluate titles and abstracts; and no blinding of the article's authors in the review process. Most scientific publications in this field were from the United States, United Kingdom, and New Zealand. Overall, the accuracy of probabilistic record linkage of databases ranged from 74% to 98% sensitivity and 99% to 100% specificity. CONCLUSIONS: Probabilistic record linkage of health databases has notably been characterized by high sensitivity and greater flexibility of the procedure's sensitivity, indicating concern with data accuracy. The positive predictive value in studies shows a high proportion of truly positive record pairs. The quality assessment of these procedures has been proved essential for validating the results obtained in these studies, and can also contribute to improve large health databases available in Brazil. PMID- 19784457 TI - Severity of occupational injuries treated in emergency services. AB - OBJECTIVE: To estimate the severity of occupational injuries and associated factors. METHODS: Longitudinal study performed in the city of Salvador, Northeastern Brazil, with all 406 occupational injury cases treated in two emergency rooms of public hospitals, between June and August 2005. Participants were identified during admission to the emergency room and interviewed monthly in their homes, until returning to work or ending the treatment. Severity was defined by the Abbreviated Injury Scale, used to calculate scores from the Injury Severity Score. Hospital lethality and mortality, and length of inpatient and intensive care unit (ICU) stay were estimated. Descriptive variables were sex, age, economic field of activity and occupation. Proportions, proportion ratios and confidence intervals were used for statistical inference and mean, and the Student t test for normal continuous variables. RESULTS: The majority of the 406 cases had a mild (39.4%) and moderate severity (38.7%), followed by serious (17.2%), severe (3.2%) and critical severity (1.5%). Overall lethality was 0.7% and 5.0% among those who stayed for inpatient treatment (14.8%), whereas mean length of inpatient stay was 3.2 days (SD=2.8). A total of three cases (0.7%) required ICU (mean=8.4 days, SD=1.2). The majority of serious cases occurred among men and those older than 37 years of age. Injuries among transport (PR=2.20; 90% CI: 1.06;4.58) and retail workers (PR=1.85; 90% CI: 1.14;3.00) were more serious than those in the reference group. Proportion of serious injuries was 54% higher among commuting accidents than among typical ones. In all, there were 325 days of inpatient stay and 34 days of ICU stay. CONCLUSIONS: Severity of occupational injuries was high, especially those occurring among transport and retail workers, thus affecting emergency services and hospital bed and ICU occupancy. PMID- 19784458 TI - Prevalence of arterial hypertension in young military personnel and associated factors. AB - OBJECTIVE: To estimate the prevalence of arterial hypertension among young military personnel and associated factors. METHODS: Cross-sectional study carried out with a sample of 380 male military personnel aged 19 to 35 years of a Brazilian Air Force unit in the city of Sao Paulo, Southeastern Brazil, in 2000 and 2001. The cut-off points for hypertension were: > or =140 mmHg for systolic pressure and > or = 90 mmHg for diastolic pressure. The studied variables included risk and protective factors for hypertension, such as behavioral and nutritional characteristics. For association analysis, generalized linear model multiple regression was used, with binomial family and logarithmic link, and prevalence ratios were obtained with 90% confidence interval and hierarchical selection of variables. RESULTS: Prevalence of hypertension was 22% (90% CI: 21;29). In the final multiple regression model, it was found that the prevalence of hypertension was 68% higher among ex-smokers when compared to non-smokers (90% CI: 1.13; 2.50). Among subjects with overweight (body mass index - BMI of 25 to 29 kg/m2) and obesity (BMI> 29 kg/m2) the prevalences were, respectively, 75% (90% CI: 1.23;2.50) and 178% (90% CI: 1.82;4.25) higher than among subjects with normal weight. Among those that practiced physical activity regularly, compared to those who did not practice it, the prevalence was 52% lower (90% CI: 0.30;0.90). CONCLUSIONS: Being an ex-smoker and overweight or obese were risk situations for hypertension, while the regular practice of physical activity was a protective factor in young military personnel. PMID- 19784459 TI - Motor vehicle driving after binge drinking, Brazil, 2006 to 2009. AB - The present study aimed to analyze the proportion of adults who drive under the influence of alcohol in the Brazilian capitals and in the Federal District, after Law 11,705 was established. Data from the Vigilancia de Fatores de Risco e Protecao para Doencas Cronicas por Inquerito Telefonico System (VIGITEL - Surveillance System of Risk and Protective Factors for Chronic Diseases by Telephone Interview) were analyzed. In 2008, 1.5% of individuals interviewed reported having driven a motor vehicle after binge drinking in at least one occasion. The frequency of adults who drove after binge drinking remained between 1.8% and 2.2% in the eight months preceding the Law, decreased in the month following its establishment, and increased again two months later, reaching a maximum of 2.6% by the end of 2008 and returning to the initial levels in the first months of 2009. PMID- 19784460 TI - Apoptosis in pulp elimination during physiological root resorption in human primary teeth. AB - Pulp samples of 50 healthy human teeth with indication for extraction were examined to evaluate the role of apoptosis in pulp elimination during physiological root resorption. Two groups were formed: a test group (n=30) composed of pulp samples of primary teeth with physiological root resorption and a control group (n=20) composed of pulp samples of permanent maxillary third molars. Morphological evidence of apoptosis as well as in situ detection of cellular DNA fragmentation by TUNEL assay and detection of internucleosomal pattern of fragmentation of the genomic DNA by electrophoresis were observed. The apoptotic index of the primary tooth group was significantly higher than that of the permanent tooth group (51.01 +/- 0.52 versus 25.32 +/- 0.68) (p<0.001). TUNEL reaction showed intense and diffuse labeling in the pulp samples of primary teeth, which were discrete in the controls. Intense DNA internucleosomal fragmentation, a specific pattern for apoptosis, was observed in primary tooth pulps DNA by electrophoresis, in the permanent tooth pulps this pattern fragmentation of the genomic DNA for apoptosis were not present. These results seem to indicate a role of apoptosis in pulp elimination during the physiological root resorption of human primary teeth. PMID- 19784461 TI - Effect of sodium selenite on bone repair in tibiae of irradiated rats. AB - This study evaluated the radioprotective effect of sodium selenite on the bone repair process in tibiae of female rats. For such purpose, 100 female Wistar rats (Rattus norvegicus, albinus) were randomly assigned to 4 groups (n=25), according to the treatment received: administration of distilled water (control); administration of sodium selenite; gamma radiation; and administration of sodium selenite plus gamma radiation. A bone defect was prepared on both tibiae of all animals. Three days after surgery, the gamma radiation and selenium/gamma radiation groups received 8 Gy gamma rays on the lower limbs. Five animals per group were sacrificed 7, 14, 21, 28 days after surgery for evaluation of the repair process by bone volumetric density analysis. The 5 animals remaining in each group were sacrificed 45 days postoperatively for examination of the mature bone by scanning electron microscopy. Based on all analyzed parameters, the results of the present study suggest that sodium selenite exerted a radioprotective effect in the bone repair of tibia of irradiated rats. PMID- 19784462 TI - Clinical evaluation of a dermic allograft in procedures to increase attached gingiva width. AB - The aim of this study was to clinically evaluate the use of alloderm to increase the width of attached gingiva. Nine patients were selected. The inclusion criteria were: attached gingiva smaller than 1 mm; Miller's class I and II gingival recession; patients able to attend control dental appointments; absence of periodontal pocket and endodontic treatment in the neighboring area where the acellular dermal graft would be placed. The clinical evaluation included: allograft shrinkage 7, 14, 21, 30, 60 and 90 days after surgery; width of attached gingiva at the end of the study; difference in color and mobility of allograft. Allograft shrinkage was calculated by comparing its area immediately after surgery to its areas in the other days. Five standardized photographs were taken, digitized and the allograft area was measured. Paired Student's t-test was used to compare the clinical data (alpha=0.05). The mean allograft shrinkage 90 days after surgery was 90.43% and the mean width was 1.27 mm. Difference in color was observed in only 1 subject and no allograft mobility was detected. The results showed a large shrinkage of allograft 90 days after its insertion, raising doubts as to its validity for increasing the width of attached gingiva. PMID- 19784463 TI - In vitro potential cytotoxicity of an adhesive system to alveolar macrophages. AB - The purpose of this study was to evaluate the potential cytotoxicity of Adper Single Bond 2 (SB) simplified etch-and-rinse adhesive system in alveolar macrophage cultures, as a function of the post-polymerization time and duration of immersion in the culture medium for preparation of extracts, by observing the levels of nitric oxide (NO) release and cell survival rate (MTT assay). Wistar rat alveolar macrophages were exposed to 200 microL of extracts obtained from 24- or 72-h immersion of adhesive samples in culture medium (RPMI), immediately or 24 h after polymerization. Fresh RPMI and E. coli lipopolysaccharides were used as negative and positive controls, respectively. The cells were placed in a humidified incubator for 24 h. The results were analyzed by the Student's-t test (alpha=5%). The amount of NO produced and viable cells were significantly different (p<0.05) between the experimental and the control groups, showing that, irrespective of the post-polymerization time and duration of immersion in the culture medium, the adhesive system caused intense cytotoxicity to the macrophages. The cytotoxic effects were not statistically different (p<0.05) among the experimental groups. In conclusion, chemical components released from SB in aqueous environment were highly toxic to cell culture and thus an inflammatory pulpal response should be considered during the clinical application of dental adhesives. PMID- 19784464 TI - Effect of fluoride-containing solutions on the surface of cast commercially pure titanium. AB - This study evaluated the effects of fluoride-containing solutions on the surface of commercially pure titanium (CP Ti) obtained by casting. CP Ti specimens were fabricated and randomly assigned to 5 groups (n=10): group 1: stored in distilled water at 37 +/- 1 masculineC; group 2: stored in distilled water at 37 +/- 1 masculineC and daily immersed in 0.05% NaF for 3 min; group 3: stored in distilled water at 37 +/- 1 masculineC and daily immersed in 0.2% NaF for 3 min; group 4: stored in distilled water at 37 +/- 1 masculineC; and immersed in 0.05% NaF every 15 days for 3 min; and group 5: stored in distilled water at 37 +/- 1 masculineC and immersed in 0.2% NaF every 15 days for 3 min. Surface roughness was measured with a profilometer immediately after metallographic polishing of the specimens (T0) and at 15-day intervals until completing 60 days of experiment (T15, T30, T45, T60). Data were analyzed statistically by ANOVA and Tukey's test (alpha=0.05). There was no statistically significant difference (p>0.05) in surface roughness among the solutions. In conclusion, fluoride-containing solutions (pH 7.0) used as mouthwashes do not damage the surface of cast CP Ti and can be used by patients with titanium-based restorations. PMID- 19784465 TI - Effect of experimental heat treatment on mechanical properties of resin composites. AB - The aim of this study was to verify the influence of an experimental heat treatment (170 masculineC/10 min) using a casting furnace on the mechanical properties (hardness and flexural strength) of 2 commercial direct resin composites (TPH Spectrum and Filtek P60) compared to a commercial indirect resin system (BelleGlass). Heat treatment temperature was determined after thermal characterization by thermogravimetry (TG) and differential scanning calorimetry (DSC). Data was analyzed by ANOVA and Tukey's test at 5% significance level. There was statistical significance for the main factor heat treatment (p=0.03) and composite (p=0.02), for flexural strength. For Knoop hardness, only the main factor composite was statistically significant (p=0.00). P60 presented higher hardness than TPH. No statistically significant correlation between mechanical properties tested was detected. Based on these results, it was possible to conclude that heat treatment influenced flexural strength of direct composites, while it was not observed for hardness. The association of direct composites with a simple post-cure heat treatment may be an alternative for current indirect composite systems, although more studies are needed to verify other properties of the composites for this application. PMID- 19784466 TI - Effectiveness of different final irrigation protocols in removing debris in flattened root canals. AB - This study evaluated in vitro the capacity of debris removal from the apical third of flattened root canals, using different final irrigation protocols. Thirty human mandibular central incisors with a mesiodistal flattened root were prepared using rotary instrumentation by Endo-Flare 25.12 and Hero 642 30.06, 35.02, 40.02 files, irrigated with 2 mL of 1% NaOCl after each file. The specimens were randomly distributed into 5 groups according to the final irrigation of root canals: Group I: 10 mL of distilled water (control), Group II: 10 mL of 1% NaOCl for 8 min, Group III: 2 mL of 1% NaOCl for 2 min (repeated 4 times), Group IV: 10 mL of 2.5% NaOCl for 8 min, and Group V: 10 mL of 2.5% NaOCl for 2 min (repeated 4 times). The apical thirds of the specimens were subjected to histological processing and 6-microm cross-sections were obtained and stained with hematoxylin-eosin. The specimens were examined under optical microscopy at x40 magnification and the images were subjected to morphometric analysis using the Scion image-analysis software. The total area of root canal and the area with debris were measured in square millimeters. Analysis of variance showed no statistically significant difference (p>0.05) among the groups GI (2.39 +/- 3.59), GII (2.91 +/- 2.21), GIII (0.73 +/- 1.36), GIV (0.95 +/- 0.84) and GV (0.51 +/- 0.22). In conclusion, the final irrigation protocols evaluated in this study using the Luer syringe presented similar performance in the removal of debris from the apical third of flattened root canals. PMID- 19784467 TI - Use of therapeutic laser for prevention and treatment of oral mucositis. AB - Oral mucositis (OM) affects patients who are submitted to hematopoietic stem cell transplantation (HSCT) due to high doses of chemotherapy and/or radiotherapy. The purpose of this investigation was to perform a comparative study of the frequency and evolution of OM among patients subjected to therapeutic laser and to the conventional therapy (use of mouthwash called 'Mucositis Formula'). The patients were subjected to a myeloablative conditioning regimen before the allogeneic HSCT. Twenty-two patients were selected and divided into 2 groups: group I was irradiated with InGaAlP laser (660 nm) and GaAlAs laser (780 nm), 25 mW potency, 6.3J/cm(2) dose, in 10-s irradiation time, followed to conventional treatment; group II was subjected only to the conventional treatment. Both World Health Organization (WHO) scale and the Oral Mucositis Assessment Scale (OMAS) were used to evaluate the results. Data were analyzed by the non-parametric Wilcoxon test, with p<0.05 considered as statistically significant. Group I presented a lower frequency of OM (p=0.02) and lower mean scores, according to WHO and OMAS scales (p<0.01 and p=0.01, respectively). In conclusion, laser reduced the frequency and severity of OM, suggesting that therapeutic laser can be used both as a new form of prevention and treatment of OM. PMID- 19784468 TI - Attitudes and behavior of dental students concerning infection control rules: a study with a10-year interval. AB - The study compared the attitudes and behavior of 4th-year dental students regarding infection control rules in 1995 and 2005. Self-administrated questionnaires were applied to 592 students at 5 different dental schools in 1995 (n=350) and in 2005 (n=242). The chi-square and Fisher's exact tests were used for statistical analysis of data. Significance level was set at p<0.05. The response rate was 90.3% in 1995 and 81.0% in 2005. There was no improvement in the use of rubber gloves (p=0.316), face masks (p=0.572) or gowns (p=0.862) between 1995 and 2005. There was a lesser frequency of the use of protective eyewear in 2005 (p<0.001). No student used the individual protection equipment correctly. There was a decrease in the sterilization of burs in 2005 when compared to 1995 (p<0.001). No student could describe the correct use of the autoclave. Disinfection and use of a dental chair barrier were done correctly by a minority of students in 1995 (2.8%) and 2005 (6.1%) (p=0.069). Most students correctly discarded perforating/cutting instruments in both years (p=0.749). The attitudes and behavior of dental students concerning infection control are worrisome. There was no improvement and, for some parameters, there was a worsening in the procedures over the time period evaluated. PMID- 19784469 TI - Influence of psychopathologies on craniomandibular disorders. AB - Psychopathologies play a role in the etiology and maintenance of craniomandibular disorders (CMD). In this study, the craniomandibular index was applied to valuate signs and symptoms of CMD in 60 dentate patients, who were assigned to 2 groups: symptomatic (n=35) and asymptomatic (n=25). An interview on psychopathologies was carried out with the aim to detect the presence of some mood disorders, such as depression, dysthymic and bipolar I disorders. Among these disturbances, depression was the most significant aspect to be reported (p<0.05) since it was present in most symptomatic patients. This important interaction was also significantly correlated (p<0.05) with the Palpation Index. These results suggest that psychopathological aspects could increase muscle tenderness and pain in addition to sleep dysfuntions and other physical complaints. Therefore, psychopathologies should be regarded as an important aspect in patients with orofacial pains. PMID- 19784470 TI - Double-blind, crossover, placebo-controlled clinical trial with clobetasol propionate in desquamative gingivitis. AB - The aim of this study was to evaluate the efficacy of a 0.05% clobetasol propionate ointment administered in trays to 22 patients with desquamative gingivitis in a double-blind, crossover, placebo-controlled trial. Patients received container number 1 and were instructed to apply the ointment 3 times a day for 2 weeks, and to reduce the application to once a day in the third week. Next, the patients were then instructed to discontinue the treatment for 2 weeks, and were then given container 2, used in the same way and for the same length of time as container 1. Regarding signs, 17 patients presented some improvement, while 5 experienced worsening with clobetasol propionate. With the placebo, 14 patients presented some improvement, and 8 patients presented worsening. For symptoms, there was complete improvement in 2 patients, partial improvement in 12, no response in 7, and worsening in 1 with clobetasol propionate. With the placebo, there was partial improvement in 8 patients, no response in 12 and worsening in 2. No statistically significant difference was found between clobetasol and placebo (p>0.05). Within the period designed to treat the gingival lesions of the patients, clobetasol propionate did not significantly outperform the placebo. PMID- 19784471 TI - Electromyographic activity of masticatory muscles in women with osteoporosis. AB - The purpose of this study was to analyze the electromyographic (EMG) activity and the maximal molar bite force in women diagnosed with osteoporosis in the maxillary and mandibular regions, considering the habits and conditions that lead to development of generalized skeletal bone loss, including on face bones, can disturb the functional harmony of the stomatognathic system. Twenty-seven women with mandibular and maxillary osteoporosis and 27 healthy controls volunteered to participate in the study. A 5-channel electromyographer was used. Muscle activity was evaluated by means of EMG recordings of the masticatory musculature (masseter and temporalis muscles, bilaterally) during the following clinical conditions: rest (5 s); right and left lateral excursions (5 s); protrusion (5 s); maximal dental clenching on Parafilm (4 s) and maximal voluntary contraction (4 s). This latter clinical condition was used as the normalization factor of the sample data. It was observed that individuals with osteoporosis presented greater EMG activity when maintaining mandible posture conditions and less activity during dental clenching and when obtaining maximal molar bite force. It may be concluded that facial osteoporosis can interfere on the patterns of masticatory muscle activation and maximal bite force of the stomatognathic system. PMID- 19784472 TI - Denture-related hyperplasia: a clinical study of a Turkish population group. AB - Inflammatory fibrous hyperplasia (epulis fissuratum) (IFH) and inflammatory papillary hyperplasia (IPH) are oral mucosal diseases caused by ill-fitting denture wearing. A study was carried out on a group of Turkish people consisted of 131 female and 39 male complete denture wearers (n= 170) distributed in two age groups (30-60 and 60-80 years old). The analysis of data collected from patients showed that while the incidence of IFH was higher in women than in men, the incidence of IPH was similar. Most lesions were found in the 30-60 year-old group. The incidence of lesions increased as the denture wearing period increased. Soft tissue growth was the main complaint of the patients with IFH and IPH. In the maxilla, the incidence of IFH was higher than IPH. There was also a significant difference between the distribution of the lesion types in the jaws. There were a larger number of lesions in the maxilla compared to the mandible and most IFH lesions were located in the anterior region of the jaws. PMID- 19784473 TI - Floor of the nose mucosa lysis and labial abscess caused by a bee sting. AB - Hymenoptera order includes bees, which have a stinging apparatus at the tail capable of delivering venom to the affected tissues. Myocardial infarction, acute renal failure, Necrotizing fasciitis, fatal infection and hemifacial asymmetry, are some of the unusual reactions reported following hymenoptera stings. This paper reports a case of bee sting in the right floor of the nose that mimicked an odontogenic infection affecting the upper lip, canine space and nasal cavity such as in cases of infection secondary to pulpal or periodontal pathology of the anterior teeth. After a thorough clinical and radiographic examination, odontogenic infection was discarded and the diagnosis of floor of the nose mucosal lysis and lip abscess secondary to a bee sting was made. This case was successfully managed with adequate incision, drainage and antibiotics without any further complication. There are several reports of unusual reactions following hymenoptera stings. However, just a few of them referred to infections of local reactions and none of them related to the anatomic location affected in the patient of the present case. Early diagnosis and treatment prevented infection dissemination and the likelihood of tissue necrosis as in previously reported cases of Necrotizing fasciitis. PMID- 19784475 TI - Management of a complex dentoalveolar trauma: a case report. AB - This paper describes the case of a 12-year-old male patient who presented a severe lateral luxation of the maxillary central incisors due to a bicycle fall. Treatment involved suture of the soft tissues lacerations, and repositioning and splinting of the injured teeth, followed by endodontic treatment and periodontal surgery. After a 2-year follow-up, clinical and radiographic evaluation revealed that the incisors presented satisfactory esthetic and functional demands. PMID- 19784474 TI - Immediate implants placed into infected sockets: a case report with 3-year follow up. AB - The esthetics and functional integrity of the periodontal tissue may be compromised by dental loss. Immediate implants became a viable option to maintain the periodontal architecture because of their anatomic compatibility with the dental socket and the possibility of eliminating local contamination. This article describes the procedure of immediate implant placement in the anterior maxilla replacing teeth with chronic periapical lesions, which were condemned due to endodontic lesions persisting after failed endodontic treatment and endodontic surgery, and discusses the relationship between the procedure and periapical lesions. Surgical removal of hopeless teeth 11, 12 and 21 was performed conservatively in such a way to preserve the anatomy and gingival esthetics. A second surgical access was gained at the apical level, allowing the debridement of the surgical chamber for elimination of the periapical lesion, visual orientation for setting of the implants and filling of the surgical chamber with xenogenous bovine bone graft. After this procedure, the bone chamber was covered with an absorbent membrane and the healing screws were positioned on the implants. Later, a provisional partial removable denture was installed and the implants were inserted after 6 months. After 3 years of rehabilitation, the implants present satisfactory functional and esthetic conditions, suggesting that immediate implant placement combined with guided bone regeneration may be indicated for replacing teeth lost due to chronic periapical lesions with endodontic failure history in the anterior maxilla. PMID- 19784476 TI - Effect of cyhalothrin on Ehrlich tumor growth and macrophage activity in mice. AB - Cyhalothrin, a pyrethroid insecticide, induces stress-like symptoms, increases c fos immunoreactivity in the paraventricular nucleus of the hypothalamus, and decreases innate immune responses in laboratory animals. Macrophages are key elements in cellular immune responses and operate at the tumor-host interface. This study investigated the relationship among cyhalothrin effects on Ehrlich tumor growth, serum corticosterone levels and peritoneal macrophage activity in mice. Three experiments were done with 10 experimental (single gavage administration of 3.0 mg/kg cyhalothrin daily for 7 days) and 10 control (single gavage administration of 1.0 mL/kg vehicle of cyhalothrin preparation daily for 7 days) isogenic BALB/c mice in each experiment. Cyhalothrin i) increased Ehrlich ascitic tumor growth after ip administration of 5.0 x 106 tumor cells, i.e., ascitic fluid volume (control = 1.97 +/- 0.39 mL and experimental = 2.71 +/- 0.92 mL; P < 0.05), concentration of tumor cells/mL in the ascitic fluid (control = 111.95 +/- 16.73 x 106 and experimental = 144.60 +/- 33.18 x 106; P < 0.05), and total number of tumor cells in the ascitic fluid (control = 226.91 +/- 43.22 x 106 and experimental = 349.40 +/- 106.38 x 106; P < 0.05); ii) increased serum corticosterone levels (control = 200.0 +/- 48.3 ng/mL and experimental = 420.0 +/ 75.5 ng/mL; P < 0.05), and iii) decreased the intensity of macrophage phagocytosis (control = 132.3 +/- 19.7 and experimental = 116.2 +/- 4.6; P < 0.05) and oxidative burst (control = 173.7 +/- 40.8 and experimental= 99.58 +/- 41.7; P < 0.05) in vitro in the presence of Staphylococcus aureus. These data provide evidence that cyhalothrin simultaneously alters host resistance to Ehrlich tumor growth, hypothalamic-pituitary-adrenocortical (HPA) axis function, and peritoneal macrophage activity. The results are discussed in terms of data suggesting a link between stress, HPA axis activation and resistance to tumor growth. PMID- 19784477 TI - Reduced pancreatic beta-cell mass is associated with decreased FoxO1 and Erk1/2 protein phosphorylation in low-protein malnourished rats. AB - A low-protein diet leads to functional and structural pancreatic islet alterations, including islet hypotrophy. Insulin-signaling pathways are involved in several adaptive responses by pancreatic islets. We determined the levels of some insulin-signaling proteins related to pancreatic islet function and growth in malnourished rats. Adult male Wistar rats (N = 20 per group) were fed a 17% protein (normal-protein diet; NP) or 6% protein (low-protein diet; LP), for 8 weeks. At the end of this period, blood glucose and serum insulin and albumin levels were measured. The morphometric parameters of the endocrine pancreas and the content of some proteins in islet lysates were determined. The beta-cell mass was significantly reduced ( congruent with 65%) in normoglycemic but hypoinsulinemic LP rats compared to NP rats. Associated with these alterations, a significant 30% reduction in insulin receptor substrate-1 and a 70% increase in insulin receptor substrate-2 protein content were observed in LP islets compared to NP islets. The phosphorylated serine-threonine protein kinase (pAkt)/Akt protein ratio was similar in LP and NP islets. The phosphorylated forkhead-O1 (pFoxO1)/FoxO1 protein ratio was decreased by 43% in LP islets compared to NP islets (P < 0.05). Finally, the ratio of phosphorylated-extracellular signal related kinase 1/2 (pErk1/2) to total Erk1/2 protein levels was decreased by 71% in LP islets compared to NP islets (P < 0.05). Therefore, the reduced beta-cell mass observed in LP rats is associated with the reduction of phosphorylation in mitogenic-related signals, FoxO1 and Erk proteins. The cause/effect basis of this association remains to be determined. PMID- 19784478 TI - Tonic and reflex cardiovascular autonomic control in trained-female rats. AB - The effects of exercise training on cardiovascular and autonomic functions were investigated in female rats. After an aerobic exercise training period (treadmill: 5 days/week for 8 weeks), conscious female Wistar (2 to 3 months) sedentary (S, N = 7) or trained rats (T, N = 7) were cannulated for direct arterial pressure (AP) recording in the non-ovulatory phases. Vagal (VT) and sympathetic tonus (ST) were evaluated by vagal (atropine) and sympathetic (propranolol) blockade. Baroreflex sensitivity was evaluated by the heart rate responses induced by AP changes. Cardiopulmonary reflex was measured by the bradycardic and hypotensive responses to serotonin. Resting bradycardia was observed in T (332 +/- 7 bpm) compared with S animals (357 +/- 10 bpm), whereas AP did not differ between groups. T animals exhibited depressed VT and ST (32 +/- 7 and 15 +/- 4 bpm) compared to S animals (55 +/- 5 and 39 +/- 10 bpm). The baroreflex and cardiopulmonary bradycardic responses were lower in T (-1.01 +/- 0.27 bpm/mmHg and -17 +/- 6 bpm) than in the S group (-1.47 +/- 0.3 bpm/mmHg and 41 +/- 9 bpm). Significant correlations were observed between VT and baroreflex (r = -0.72) and cardiopulmonary (r = -0.76) bradycardic responses. These data show that exercise training in healthy female rats induced resting bradycardia that was probably due to a reduced cardiac ST. Additionally, trained female rats presented attenuated bradycardic responses to baro- and cardiopulmonary receptor stimulation that were associated, at least in part, with exercise training induced cardiac vagal reduction. PMID- 19784479 TI - Effect of frequency of static stretching on flexibility, hamstring tightness and electromyographic activity. AB - We compared the effect of the number of weekly repetitions of a static stretching program on the flexibility, hamstring tightness and electromyographic activity of the hamstring and of the triceps surae muscles. Thirty-one healthy subjects with hamstring tightness, defined as the inability to perform total knee extension, and shortened triceps surae, defined by a tibiotarsal angle wider than 90 degrees during trunk flexion, were divided into three groups: G1 performed the stretching exercises once a week; G2, three times a week, and G3, five times a week. The parameters were determined before and after the stretching program. Flexibility improved in all groups after intervention, from 7.65 +/- 10.38 to 3.67 +/- 12.08 in G1, from 10.73 +/- 12.07 to 0.77 +/- 10.45 in G2, and from 14.20 +/- 10.75 to 6.85 +/- 12.19 cm in G3 (P < 0.05 for all comparisons). The increase in flexibility was higher in G2 than in G1 (P = 0.018), while G2 and G3 showed no significant difference (G1: 4 +/- 2.17, G2: 10 +/- 5.27; G3: 7.5 +/- 4.77 cm). Hamstring tightness improved in all groups, from 37.90 +/- 6.44 to 29 +/- 11.65 in G1, from 39.82 +/- 9.63 to 21.91 +/- 8.40 in G2, and from 37.20 +/- 6.63 to 26.10 +/- 5.72 degrees in G3 (P < 0.05 for all comparisons). During stretching, a statistically significant difference was observed in electromyographic activity of biceps femoris muscle between G1 and G3 (P = 0.048) and G2 and G3 (P = 0.0009). No significant differences were found in electromyographic activity during maximal isometric contraction. Stretching exercises performed three times a week were sufficient to improve flexibility and range of motion compared to subjects exercising once a week, with results similar to those of subjects who exercised five times a week. PMID- 19784480 TI - Evidence that blood pressure remains under the control of arterial baroreceptors in renal hypertensive rats. AB - The purpose of the present study was to determine the range of the influence of the baroreflex on blood pressure in chronic renal hypertensive rats. Supramaximal electrical stimulation of the aortic depressor nerve and section of the baroreceptor nerves (sinoaortic denervation) were used to obtain a global analysis of the baroreceptor-sympathetic reflex in normotensive control and in chronic (2 months) 1-kidney, 1-clip hypertensive rats. The fall in blood pressure produced by electrical baroreceptor stimulation was greater in renal hypertensive rats than in normotensive controls (right nerve: -47 +/- 8 vs -23 +/- 4 mmHg; left nerve: -51 +/- 7 vs -30 +/- 4 mmHg; and both right and left nerves: -50 +/- 8 vs -30 +/- 4 mmHg; P < 0.05). Furthermore, the increase in blood pressure level produced by baroreceptor denervation in chronic renal hypertensive rats was similar to that observed in control animals 2-5 h (control: 163 +/- 5 vs 121 +/- 1 mmHg; 1K-1C: 203 +/- 7 vs 170 +/- 5 mmHg; P < 0.05) and 24 h (control: 149 +/- 3 vs 121 +/- 1 mmHg; 1K-1C: 198 +/- 8 vs 170 +/- 5 mmHg; P < 0.05) after sinoaortic denervation. Taken together, these data indicate that the central and peripheral components of the baroreflex are acting efficiently at higher arterial pressure in renal hypertensive rats when the aortic nerve is maximally stimulated or the activity is abolished. PMID- 19784481 TI - Use of anti-PGL-1 antibodies to monitor therapy regimes in leprosy patients. AB - The suitability of IgM antibodies to PGL-1 for monitoring the response to multidrug therapy (MDT) was sequentially tested by ELISA in 105 leprosy patients, and bacterial indexes (BI) were also determined. Patients were divided into 3 groups: group 1, 34 multibacillary (MB) patients treated for 12 months with MDT MB; group 2, 33 MB patients treated for 24 months with MDT-MB, and group 3, 38 paucibacillary (PB) patients treated for 6 months with MDT-PB. Untreated MB patients exhibited higher antibody levels (mean +/- SEM): group 1 (6.95 +/- 1.35) and group 2 (12.53 +/- 2.02) than untreated PB patients (1.28 +/- 0.35). There was a significant difference (P < 0.01) in anti-PGL-1 levels in group 1 patients: untreated (6.95 +/- 1.35) and treated for 12 months (2.78 +/- 0.69) and in group 2 patients: untreated (12.53 +/- 2.02) and treated for 24 months (2.62 +/- 0.79). There was no significant difference between untreated (1.28 +/- 0.35) and treated (0.62 +/- 0.12) PB patients. Antibody levels correlated with BI. The correlation coefficient (Pearson's r) was 0.72 before and 0.23 (P < 0.05) after treatment in group 1 and 0.67 before and 0.96 (P < 0.05) after treatment in group 2. BI was significantly reduced (P < 0.01) after 12 and 24 months on MDT (group 1: 1.26 0.26; group 2: 1.66-0.36). Our data indicate that monitoring anti-PGL-1 levels during MDT may be a sensitive tool for evaluating treatment efficacy. These data also indicate that the control of leprosy infection can be obtained with 12 months of MDT in MB patients. PMID- 19784482 TI - Cognitive performance of young and elderly subjects on the free word recall memory test: effect of presentation order on recall order. AB - The influence of aging on memory has been extensively studied, but the importance of short-term memory and recall sequence has not. The objective of the current study was to examine the recall order of words presented on lists and to determine if age affects recall sequence. Physically and psychologically healthy male subjects were divided into two groups according to age, i.e., 23 young subjects (20 to 30 years) and 50 elderly subjects (60 to 70 years) submitted to the Wechsler Adult Intelligence Scale-Revised and the free word recall test. The order of word presentation significantly affected the 3rd and 4th words recalled (P < 0.01; F = 14.6). In addition, there was interaction between the presentation order and the type of list presented (P < 0.05; F = 9.7). Also, both groups recalled the last words presented from each list (words 13-15) significantly more times 3rd and 4th than words presented in all remaining positions (P < 0.01). The order of word presentation also significantly affected the 5th and 6th words recalled (P = 0.05; F = 7.5) and there was a significant interaction between the order of presentation and the type of list presented (P < 0.01; F = 20.8). The more developed the cognitive functions, resulting mainly from formal education, the greater the cognitive reserve, helping to minimize the effects of aging on the long-term memory (episodic declarative). PMID- 19784483 TI - [RBP increases its impact factor]. PMID- 19784484 TI - Brazil launches an innovative program to develop the National Institutes for Science and Technology (INCTs): the INCT for Translational Medicine. PMID- 19784485 TI - Translational research in psychiatry: new developments in Brazil. PMID- 19784486 TI - Importance of retardation and fatigue/interest domains for the diagnosis of major depressive episode after stroke: a four months prospective study. AB - OBJECTIVE: Post-stroke major depressive episode is very frequent, but underdiagnosed. Researchers have investigated major depressive episode symptomatology, which may increase its detection. This study was developed to identify the depressive symptoms that better differentiate post-stroke patients with major depressive episode from those without major depressive episode. METHOD: We screened 260 consecutive ischemic stroke patients admitted to the neurology clinic of a university hospital. Seventy-three patients were eligible and prospectively evaluated. We assessed the diagnosis of major depressive episode using the Structured Clinical Interview for DSM-IV and the profile of depressive symptoms using the 31-item version of the Hamilton Depression Rating Scale. For data analysis we used cluster analyses and logistic regression equations. RESULTS: Twenty-one (28.8%) patients had a major depressive episode. The odds ratio of being diagnosed with major depressive episode was 3.86; (95% CI, 1.23-12.04) for an increase of one unit in the cluster composed by the domains of fatigue/interest and retardation, and 2.39 (95% CI, 1.21-4.71) for an increase of one unit in the cluster composed by the domains of cognitive, accessory and anxiety symptoms. The domains of eating/weight and insomnia did not contribute for the major depressive episode diagnosis. CONCLUSION: The domains of retardation and interest/fatigue are the most relevant for the diagnosis of major depressive episode after stroke. PMID- 19784487 TI - Recreational use of benzydamine as a hallucinogen among street youth in Brazil. AB - OBJECTIVE: To describe the recreational use of benzydamine, an anti-inflammatory drug, among street youth in Brazil. METHOD: DESIGN: a descriptive, cross sectional survey. SETTING: 93 welfare services for the street youth in 27 Brazilian capitals. PARTICIPANTS: 2807 street youth, 10 to 18 years old. MAIN OUTCOME MEASURES: demographic characteristics, drug use pattern (lifetime use, use in the past 30 days, frequency, and characteristics of use in the past month) and effects of benzydamine through the use of a questionnaire. RESULTS: 78 reported lifetime recreational benzydamine use (67 cases identified only in three capitals). Among the 30 respondents reporting drug use in the last month (the month preceding the survey), 66.7% (n = 20) used the drug on 4 or more days (in the month preceding the survey). The most frequently (50%) pleasure effects reported were hallucination and nonspecific sensory changes described as 'trips'. Unwanted effects were reported by 75% of respondents, they were especially nausea and vomiting (21.4%). In the majority of the cases, drug was obtained from drugstores without a medical prescription. CONCLUSION: This study identifies the recreational use of benzydamine among street youth, mainly in the Northeast of Brazil, and also indicates the need for special controls on the dispensation of this substance. PMID- 19784488 TI - Cardiac response and anxiety levels in psychopathic murderers. AB - OBJECTIVE: To compare the emotional response and level of anxiety of psychopathic murderers, non-psychopathic murderers, and nonpsychopathic non-criminals. METHOD: 110 male individuals aged over 18 years were divided into three groups: psychopathic murderers (n = 38); non-psychopathic murderers (n = 37) serving sentences for murder convictions in Maximum Security Prisons in the State of Sao Paulo; and non-criminal, non-psychopathic individuals (n = 35) according to the Psychopathy Checklist-Revised. The emotional response of subjects was assessed by heart rate variation and anxiety level (State-Trait Anxiety Inventory) after viewing standardized pictures depicting pleasant, unpleasant and neutral content from the International Affective Picture System. RESULTS: Psychopathic murderers presented lower anxiety levels and smaller heart rate variations when exposed to pleasant and unpleasant stimuli than nonpsychopathic murderers or non psychopathic non-criminals. The results also demonstrated that the higher the score for factor 1 on the Psychopathy Checklist-Revised, the lower the heart rate variation and anxiety level. CONCLUSION: The results suggest that psychopathic murderers do not present variation in emotional response to different visual stimuli. Although the non-psychopathic murderers had committed the same type of crime as the psychopathic murderers, the former tended to respond with a higher level of anxiety and heart rate variation. PMID- 19784489 TI - Working memory assessment in schizophrenia and its correlation with executive functions ability. AB - OBJECTIVE: Working memory impairment is common in schizophrenia and is possibly a cause of multiple features of the disorder. However few studies have replicated such findings of impairment patterns in Brazilian samples. The main target of this study was to assess auditory and visual working memory in patients with schizophrenia, to assess if they work as separate systems, and to correlate working memory deficits with executive functions. METHOD: Twenty subjects with schizophrenia and twenty healthy subjects matched by gender, age, and schooling have participated. The abilities assessed were auditory and visual working memory, selective attention, inhibitory control, cognitive flexibility, and planning. RESULTS: Patients showed declines in all measures evaluated, except for a measure reaction time of inhibitory control. Auditory working memory was correlated to selective attention, inhibition, flexibility and planning while Visual working memory to planning and flexibility. CONCLUSION: The present study suggests that working memory and executive functions deficits are present in patients with schizophrenia in the Brazilian sample evaluated. Alterations in executive functions may lead to incapacity of operation of processes of working memory. These findings may contribute to delineate and develop new strategies of schizophrenia treatment in the Brazilian population. PMID- 19784490 TI - Drug consumption among medical students in Sao Paulo, Brazil: influences of gender and academic year. AB - OBJECTIVE: To analyze alcohol, tobacco and other drug use among medical students. METHOD: Over a five-year period (1996-2001), we evaluated 457 students at the Universidade de Sao Paulo School of Medicine, located in Sao Paulo, Brazil. The students participated by filling out an anonymous questionnaire on drug use (lifetime, previous 12 months and previous 30 days). The influence that gender and academic year have on drug use was also analyzed. RESULTS: During the study period, there was an increase in the use of illicit drugs, especially inhalants and amphetamines, among the medical students evaluated. Drug use (except that of marijuana and inhalants) was comparable between the genders, and academic year was an important influencing factor. DISCUSSION: Increased inhalant use was observed among the medical students, especially among males and students in the early undergraduate years. This is suggestive of a specific behavioral pattern among medical students. Our findings corroborate those of previous studies. CONCLUSION: Inhalant use is on the rise among medical students at the Universidade de Sao Paulo School of Medicine. Because of the negative health effects of illicit drug use, further studies are needed in order to deepen the understanding of this phenomenon and to facilitate the development of preventive measures. PMID- 19784491 TI - The prevalence of psychopathology in offspring of bipolar women from a Brazilian tertiary center. AB - OBJECTIVE: No previous study has assessed the occurrence of psychopathology in offspring of bipolar women from South America. The objective of this study was to assess the prevalence of psychopathology in offspring of bipolar mothers from Brazil compared with two control groups. METHOD: Children and adolescents aged 6 to 18 years of bipolar disorders mothers (n = 43), mothers with other mild to moderate mental disorders (n = 53) and mothers without any psychiatric disorder (n = 53) were evaluated using the Kiddie Schedule for Affective Disorders and Schizophrenia present and lifetime version, the Child Behavior Checklist and the Youth Self-Report. Raters were blind to the mothers' diagnoses, who were interviewed by means of the Structured Clinical Interview. RESULTS: Bipolar offspring had twice the chance of having one or more lifetime Axis I diagnoses [prevalence ratio = 2.11 (95% CI: 1.30-3.42) and p = 0.003] and 2.8 higher risk of having a lifetime anxiety disorder [prevalence ratio = 2.83 (95% CI: 1.39 5.78) e p = 0.004] than the offspring of mothers with no mental disorder. In addition, significantly higher scores on Child Behavior Checklist thought problems and Youth Self-Report social problems, as well as anxiety/depression and internalizing problems were observed. CONCLUSION: Our results confirm previous findings suggesting higher psychiatric problems in offspring of bipolar mothers and extend them to the Brazilian society. PMID- 19784492 TI - Effect of acute administration of ketamine and imipramine on creatine kinase activity in the brain of rats. AB - OBJECTIVE: Clinical findings suggest that ketamine may be used for the treatment of major depression. The present study aimed to compare behavioral effects and brain Creatine kinase activity in specific brain regions after administration of ketamine and imipramine in rats. METHOD: Rats were acutely given ketamine or imipramine and antidepressant-like activity was assessed by the forced swimming test; Creatine kinase activity was measured in different regions of the brain. RESULTS: The results showed that ketamine (10 and 15mg/kg) and imipramine (20 and 30mg/kg) reduced immobility time when compared to saline group. We also observed that ketamine (10 and 15mg/kg) and imipramine (20 and 30mg/kg) increased Creatine kinase activity in striatum and cerebral cortex. Ketamine at the highest dose (15mg/kg) and imipramine (20 and 30mg/kg) increased Creatine kinase activity in cerebellum and prefrontal cortex. On the other hand, hippocampus was not affected. CONCLUSION: Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, the modulation of energy metabolism (like increase in Creatine kinase activity) by antidepressants could be an important mechanism of action of these drugs. PMID- 19784493 TI - Complaints of insomnia in hospitalized alcoholics. AB - OBJECTIVE: To estimate the prevalence of insomnia complaints in a population of alcoholics hospitalized in addiction clinics in Bogota. METHOD: Alcoholic patients hospitalized for detoxification in addiction clinics were recruited. DESIGN: observational, descriptive and cross-sectional study. Data gathered by means of clinical interviews and measuring scales: Pittsburgh Sleep Quality Index and the Zung Self-rating Anxiety and Depression scales. RESULTS: The prevalence of chronic insomnia complaints was 56.8% (33/58); anxiety symptoms 65.5% (38/58); depressive symptoms 75.9% (44/58) with variations in distribution by gender. CONCLUSION: The prevalence of chronic insomnia complaints measured was found to be high in the population of hospitalized alcoholics. These patients deserve medical care and treatment for sleep disorders in their rehabilitation plan. Further research allowing the extension of the obtained results is needed. PMID- 19784494 TI - [Haloperidol plus promethazine for agitated patients--a systematic review]. AB - OBJECTIVE: Rapid and safe tranquillisation is sometimes unavoidable. We conducted this systematic review to determine the value of the combination haloperidol plus promethazine, frequently used in Brazil. METHOD: We searched the Cochrane Schizophrenia Group's Register and included all randomised clinical trials involving aggressive people with psychosis for which haloperidol plus promethazine was being used. We reliably selected, quality assessed and extracted data from all relevant studies. RESULTS: We identified four relevant high quality studies. The combination haloperidol plus promethazine mix was compared with midazolam, lorazepam, haloperidol alone and olanzapine Intramuscular. In Brazil, haloperidol plus promethazine was effective with over 2/3 of people being tranquil by 30 minutes, but midazolam was more swift and in India, compared with lorazepam, the combination was more effective. Over the next few hours reported differences are negligible. Haloperidol given without promethazine in this situation causes frequent serious adverse effects. Olanzapine is as rapidly tranquillising as haloperidol plus promethazine, but did not have an enduring effect and more people needed additional drugs within 4 hours. CONCLUSION: All treatments evaluated are effective, but this review provides compelling evidence as to clear advantages of the haloperidol plus promethazine combination. PMID- 19784495 TI - Violent sleepwalking in a general hospital ward: a case report. PMID- 19784496 TI - Body dysmorphic and/or obsessive-compulsive disorder: where do the diagnostic boundaries lie? PMID- 19784497 TI - Comment on 'Factor structure of the Rutter Teacher Questionnaire in Portuguese children'. PMID- 19784499 TI - [Mania induced by quetiapine in patients with schizoaffective disorder, depressive type: a case report]. PMID- 19784500 TI - Obsessive-compulsive disorder and 5-HTTLPR. PMID- 19784501 TI - Thyroid traps that every psychiatrist should be aware of. PMID- 19784502 TI - Is the Fagerstrom Test for Nicotine Dependence a good instrument to assess tobacco use in patients with schizophrenia? PMID- 19784503 TI - [Antisocial behavior and impulsivity in antisocial personality disorder]. PMID- 19784506 TI - TMEM16 proteins: the long awaited calcium-activated chloride channels? AB - Currents mediated by calcium-activated chloride channels (CaCCs), observed for the first time in Xenopus oocytes, have been recorded in many cells and tissues ranging from different types of neurons to epithelial and muscle cells. CaCCs play a role in the regulation of excitability in neurons including sensory receptors. In addition, they are crucial mediators of chloride movements in epithelial cells where their activity regulates electrolyte and fluid transport. The roles of CaCCs, particularly in epithelia, are briefly reviewed with emphasis on their function in secretory epithelia. The recent identification by three independent groups, using different strategies, of TMEM16A as the molecular counterpart of the CaCC is discussed. TMEM16A is part of a family that has 10 other members in mice. The discovery of the potential TMEM16 anion channel activity opens the way for the molecular investigation of the role of these anion channels in specific cells and in organ physiology and pathophysiology. The identification of TMEM16A protein as a CaCC chloride channel molecule represents a great triumph of scientific perseverance and ingenuity. The varied approaches used by the three independent research groups also augur well for the solidity of the discovery. PMID- 19784507 TI - Modulation of extracellular matrix by nutritional hepatotrophic factors in thioacetamide-induced liver cirrhosis in the rat. AB - Nutritional substances associated to some hormones enhance liver regeneration when injected intraperitoneally, being denominated hepatotrophic factors (HF). Here we verified if a solution of HF (glucose, vitamins, salts, amino acids, glucagon, insulin, and triiodothyronine) can revert liver cirrhosis and how some extracellular matrices are affected. Cirrhosis was induced for 14 weeks in 45 female Wistar rats (200 mg) by intraperitoneal injections of thioacetamide (200 mg/kg). Twenty-five rats received intraperitoneal HF twice a day for 10 days (40 mL.kg-1.day-1) and 20 rats received physiological saline. Fifteen rats were used as control. The HF applied to cirrhotic rats significantly: a) reduced the relative mRNA expression of the genes: Col-alpha1 (-53%), TIMP-1 (-31.7%), TGF beta1 (-57.7%), and MMP-2 (-41.6%), whereas Plau mRNA remained unchanged; b) reduced GGT (-43.1%), ALT (-17.6%), and AST (-12.2%) serum levels; c) increased liver weight (11.3%), and reduced liver collagen (-37.1%), regenerative nodules size (-22.1%), and fibrous septum thickness. Progranulin protein (immunohistochemistry) and mRNA (in situ hybridization) were found in fibrous septa and areas of bile duct proliferation in cirrhotic livers. Concluding, HF improved the histology and serum biochemistry of liver cirrhosis, with an important reduction of interstitial collagen and increased extracelullar matrix degradation by reducing profibrotic gene expression. PMID- 19784509 TI - [Effects of epidural analgesia and continuous lumbar plexus block on functional rehabilitation after total hip arthroplasty]. AB - BAKGROUND AND OBJECTIVES: Pain after total hip arthroplasty (THA) is severe and it is aggravated by movements, which requires an effective analgesic technique that allows early mobilization, participation in rehabilitation activities, and fast functional recovery. The objective of this study was to compare the effects of epidural and perineural patient-controlled analgesia (PCA) of the lumbar plexus on functional rehabilitation of patients undergoing THA. METHODS: Patients classified as physical status ASA I to III were randomly divided into two groups: Epidural and Lumbar. For THA, patients underwent continuous epidural lumbar block with 0.5% ropivacaine (Epidural) or continuous lumbar plexus block with 0.5% ropivacaine (Lumbar). In the recovery room, PCA with infusion of 0.2% ropivacaine (Lumbar) or 0.2% ropivacaine + fentanyl 3 microg.mL-1 (Epidural) was instituted. Analgesic efficacy in the first 48 hours after THA (pain scores, rescue morphine consumption, and bolus of the PCA pump) was compared between both groups. Different postoperative rehabilitation parameters were analyzed. RESULTS: Forty one patients underwent statistical analysis. Resting pain scores were similar in both groups. Despite more effective control of dynamic pain in the Epidural group and the greater, more frequent, and earlier morphine consumption in the Lumbar group, rehabilitation parameters evaluated did not differ in both groups. Analgesia techniques did not affect rehabilitation failures. CONCLUSIONS: The greater effectivity of epidural analgesia did not translate in improvement of the rehabilitation process nor did it decrease the time necessary to achieve end goals. PMID- 19784508 TI - [Effective anesthetic volumes in sciatic nerve block: comparison between the parasacral and infragluteal-parabiceps approaches with 0.5% bupivacaine with adrenaline and 0.5% ropivacaine]. AB - BACKGROUND AND OBJECTIVES: The volume and mass of local anesthetics (LA) affect the success rate of peripheral nerve blocks. Thus, the main objective of this study was to determine the volumes of local anesthetics in parasacral and infragluteal-parabiceps sciatic nerve block (SNB). METHODS: One hundred and one patients undergoing infragluteal-parabiceps or parasacral SNB with 0.5% ropivacaine or 0.5% bupivacaine with 5 microg.mL-1 of adrenaline were randomly divided into 4 groups. Success was defined as complete sensitive and motor blockades of the sciatic nerve 30 minutes after the administration of the LA. Volumes were calculated by the up-and-down method. RESULTS: In the parasacral approach, the mean effective volume of ropivacaine was 17.6 mL (95% CI: 14.9 20.8) and of bupivacaine it was 16.4 mL (95% CI: 12.3-21.9). In the infragluteal parabiceps approach, the mean effective volume of ropivacaine was 21.8 mL (95% CI: 18.7-25.5), and that of bupivacaine was 20.4 mL (95% CI: 18.6-22.5). Volumes were significantly lower (p < 0.01) in the parasacral than in the infragluteal parabiceps approach. In Probit regression, the estimated effective volume in 95% of the patients in the parasacral approach was 21.8 mL for ropivacaine, and 20.5 mL for bupivacaine; in the infragluteal-parabiceps approach the volumes were 27.2 mL for ropivacaine and 25.5 mL for bupivacaine. The effective volume in 99% of the patients in parasacral SNB was 24 mL for ropivacaine, and 24 mL for bupivacaine; and in the infragluteal-parabiceps approach, 29.9 mL for ropivacaine, and 28.0 mL for bupivacaine. CONCLUSIONS: In sciatic nerve block, significantly smaller volumes were necessary in the parasacral than in the infragluteal-parabiceps approach, but volumes did not differ between both LAs. PMID- 19784510 TI - [Computed tomography in pulmonary evaluation of children with acyanotic congenital heart defect and pulmonary hyperflow]. AB - BACKGROUND AND OBJECTIVES: Respiratory dysfunction is common in children with acyanotic congenital heart defects (ACHD) with pulmonary hyperflow; however, little is known about the pulmonary structure of those patients. The objective of this study was to quantify the volumes of air and tissue, as well as the distribution of pulmonary aeration in this population. METHODS: After approval by the Ethics Committee of the institution and signing of an informed consent, seven children with ACHD with pulmonary hyperflow underwent computed tomographies of the chest. All images included the left and right pulmonary contour, and pulmonary volumes and weight were calculated using volumetric data. Paired Student t test was used to compare left and right, and exponential regression was used for correlations. RESULTS: Patients had a mean age of 20 months and weight of 9.9 kg. Total pulmonary volume (TPV) was 66.7 +/- 23.1 mL.kg-1, tissue volume of 33.5 +/- 15.7 mL.kg-1, and air volume of 33.1 +/- 8.3 mL.kg-1. The right lung represented 57.9% of TPV and the left, 42.1% (p < 0.001). The pulmonary volume of air on the right was 60.5% of the total air volume (p < 0.001), and the volume of pulmonary parenchyma normally aerated was significantly lower on the left (27.6 +/- 6.8 vs . 18.1 +/- 8%, p < 0.001). CONCLUSIONS: The volume of lung tissue was greater than expected in children with ACHD with pulmonary hyperflow, possibly due to interstitial edema. Pulmonary aeration is reduced in the left lung due to the compression of the lung by the heart. PMID- 19784511 TI - [Supplemental oxygen and the incidence of perioperative nausea and vomiting in cesarean sections under subarachnoid block]. AB - BACKGROUND AND OBJECTIVES: Supplemental oxygen can reduce the incidence of postoperative nausea and vomiting in patients under general anesthesia. The objective of the present study was to determine the efficacy of supplemental oxygen to reduce the incidence of perioperative nausea and vomiting in elective cesareans under subarachnoid block. METHODS: After induction of standardized subarachnoid block, 94 parturients undergoing surgical delivery were randomly divided to receive 4 L.min-1 of oxygen (Group O) or medical air (Group S) under nasal cannula throughout the procedure. Patients were questioned on the development of nausea and vomiting during the surgery and in the first six and 24 hours after the procedure. RESULTS: Demographic and perioperative parameters, as well as the data on the newborn, were comparable in both groups. In Group O, the incidence of nausea during the surgery, in the first 6 hours afterwards, and between 6 and 24 hours was 35%, 30%, and 19%, respectively, while in Group S, it was 35%, 30%, and 19%, respectively. In Group O, the incidence of vomiting was 9%, 11% and 6% in the corresponding periods, and in Group S, 21%, 7% and 7%, respectively. Those differences were not statistically significant. CONCLUSIONS: The administration of supplemental oxygen from anesthetic induction until the end of the surgery did not reduce the incidence of intra- and postoperative nausea or vomiting in women undergoing cesarean section under subarachnoid block. PMID- 19784513 TI - [Does abbreviation of preoperative fasting to two hours with carbohydrates increase the anesthetic risk?]. AB - BACKGROUND AND OBJECTIVES: The objective of the present study was to evaluate the incidence of possible anesthetic complications related with the abbreviation of preoperative fasting to two hours with a solution of 12.5% dextrinomaltose within the ACERTO (from the Portuguese for Acceleration of Total Postoperative Recovery) project. METHODS: All patients undergoing different types of digestive tract and abdominal wall surgeries within a new protocol of perioperative conducts, established by the ACERTO project, between August 2005 and December 2007 were evaluated. All patients received oral nutritional supplementation (12.5% dextrinomaltose) six and two hours before the procedure. Data were collected prospectively without the knowledge of the professionals in the department. The length of preoperative fasting and anesthetic complications related with the short fasting time (pulmonary aspiration) were recorded. RESULTS: Three hundred and seventy five patients, 174 male (46.4%) and 201 female (53.6%), ages 18 to 90 years, were evaluated. The mean preoperative fasting time was four hours, ranging from two to 20 hours. Pulmonary aspiration was not observed during the procedures. The length of fasting was longer (p < 0.01) when combined anesthesia (blockade + general) was used. CONCLUSIONS: Adopting the multidisciplinary preoperative measures of the ACERTO project was not associated with any preoperative fasting-associated complications. Dextrinomaltose is a useful and safe nutritional supplement for the patient. PMID- 19784512 TI - [Prophylaxis of postoperative nausea and vomiting in morbidly obese patients undergoing laparoscopic gastroplasties: a comparative study among three methods]. AB - BACKGROUND AND OBJECTIVES: Videolaparoscopic bariatric surgeries are associated with a high incidence of postoperative nausea and vomiting. Those events can lead to significant morbidity, increase hospitalization costs, as well as patient dissatisfaction. The objective of this study was to compare different prophylaxis protocols of postoperative nausea and vomiting in videolaparoscopic gastroplasties. METHODS: This is a randomized prospective study with 77 patients undergoing videolaparoscopic gastroplasty. Patients were divided into four groups as follows: Cont group, control (n = 19) where antiemetics were not administered; Dexa group (n = 16), patients received dexamethasone; Onda group (n = 20), patients received ondansetron; and Dexa+Onda group (n = 22), patients received dexamethasone and ondansetron. All patients underwent standardized anesthesia and postoperative analgesia with intravenous morphine. Patients who were taking gastric protectors or antiemetics and those with hiatal hernia were excluded. Demographic data, duration of the surgery, doses of morphine, and development of nausea and vomiting in the immediate postoperative period (up to six hours) were recorded. RESULTS: Demographic data and doses of morphine administered did not differ among the groups (One-way ANOVA). The incidence of nausea and/or vomiting in the different groups was: Cont group - 78.94%; Dexa group - 62.25%; Onda group - 50%; and Dexa+Onda group - 18.8% (p = 0.0002). CONCLUSIONS: The incidence of postoperative nausea and vomiting in videolaparoscopic gastroplasties was more effectively reduced with the association of ondansetron and dexamethasone than with each drug separately. PMID- 19784514 TI - [A comparative study between ultrasound and neurostimulation guided axillary brachial plexus block]. AB - Conceicao DB, Helayel PE, Oliveira Filho GR - A Comparative Study between Ultrasound- and Neurostimulation-Guided Axillary Brachial Plexus Block. BACKGROUND AND OBJECTIVES: The use of ultrasound in Regional Blocks is increasingly more frequent. However, very few studies comparing ultrasound and neurostimulation have been conducted. The objective of this study was to compare neurostimulation-guided axillary brachial plexus block with double injection and ultrasound-guided axillary plexus block for hand surgeries. The time to perform the technique, success rate, and complications were compared. METHODS: After approval by the Ethics on Research Committee of the Hospital Governador Celso Ramos, 40 patients scheduled for elective hand surgeries under axillary plexus block were selected. Patients were randomly divided into two groups with 20 patients each: Neurostimulation (NE) and Ultrasound (US) groups. The time to perform the technique, success rate, and complication rate were compared. RESULTS: Complete blockade, partial failure, and total failure rates did not show statistically significant differences between the US and NE groups. The mean time to perform the technique in the US group (354 seconds) was not statistically different than that of the NE group (381 seconds). Patients in the NE group had a higher incidence of vascular punctures (40%) when compared with those in the US group (10%, p < 0.05). The rate of paresthesia during the blockade was similar in both groups (15%). CONCLUSIONS: The success rate and time to perform the blockade were similar in ultrasound- and neurostimulation-guided axillary plexus block for hand surgeries. The rate of vascular puncture was higher in neurostimulation guided axillary plexus block. PMID- 19784515 TI - [Comparison of hemodynamic changes in acute intoxication with intravenous bupivacaine and ropivacaine in swine]. AB - BACKGROUND AND OBJECTIVES: Pure levorotatory ropivacaine was introduced to provide a safer alternative to bupivacaine in regional blocks. The objective of this study was to compare the hemodynamic repercussions after the intravenous administration of both agents in swine, simulating the intoxication that can be seen during regional blocks in humans. METHODS: Large-White swine were anesthetized with thiopental, followed by endotracheal intubation and controlled mechanical ventilation. Hemodynamic parameters included non-invasive blood pressure and catheterization of the pulmonary artery. After 30 minutes, animals were randomly divided into two groups, and 4 mg.kg-1 of one of the agents was administered intravenously without the knowledge of the investigator. Hemodynamic parameters were evaluated at rest and 1, 5, 10, 15, 20, and 30 minutes after intoxication. RESULTS: The hemodynamic repercussions of acute bupivacaine intoxication were more important and prolonged than in ropivacaine intoxication. With bupivacaine, the cardiac index showed greater and more prolonged reduction, mean arterial pressure and heart rate had more prolonged reduction, central venous pressure showed a more prolonged increase, and pulmonary wedge pressure increased more for more prolonged time. The impact on the systemic vascular resistance index showed that vasomotricity was partially maintained, increased in both groups, and, paradoxically, was greater and longer-lasting with bupivacaine. CONCLUSIONS: In swine, ropivacaine caused less hemodynamic repercussions than bupivacaine when the same doses were administered intravenously. PMID- 19784516 TI - [Anesthesia in a patient with congenital insensitivity to pain and anhidrosis]. AB - BACKGROUND AND OBJECTIVES: Congenital insensitivity to pain and Anhidrosis (CIPA) or hereditary sensory and autonomic neuropathy type IV (HSAN IV) is a rare autosomal recessive neuropathy of the group of hereditary sensory and autonomic neuropathies (HSAN) characterized by insensitivity to pain, anhidrosis, and mental retardation. Since it is a rare condition, reports on the anesthetic conduct in patients with CIPA are not easily found in the literature. The objective of this report was to present the anesthetic conduct in a patient with CIPA undergoing left ankle arthrodesis with placement of an implant, and to discuss the characteristics of this disorder that concern anesthesiologists the most. CASE REPORT: A female patient with a history of CIPA was admitted for left ankle arthrodesis due to Charcot arthropathy. In the operating room, the patient was monitored with an electrocardiograph, bispectral index, 95% SEF, non-invasive blood pressure, and peripheral hemoglobin saturation; she was pre-medicated with midazolam and underwent intravenous anesthesia with propofol and cisatracurium. The administration of analgesics was not necessary. After tracheal intubation, monitoring of end-expiratory pressure of carbon dioxide and esophageal temperature were added. The patient did not develop postoperative complications. She was discharged from the hospital on the second postoperative day. CONCLUSIONS: Although there is insensitivity to pain, some patients present tactile hyperesthesia that can cause unpleasant feelings during surgical manipulation. Despite reports in the literature of patients undergoing neuroaxis blocks, and even procedures without anesthesia, intravenous anesthesia, which provided adequate conditions for the anesthetic-surgical procedure was used in this case. PMID- 19784517 TI - [Rhinoscope-guided nasotracheal intubation in a one-year old child with Osteogenesis imperfecta: case report]. AB - BACKGROUND AND OBJECTIVES: Osteogenesis imperfecta (OI) is a rare, autosomal dominant disease. Anesthesia for patients with OI has several challenges; among them, management of the airways and the choice of anesthetic technique should be mentioned. The objective of this report was to describe the case of a child with this disorder associated with hydrocephalus who underwent total intravenous anesthesia and rhinoscope-guided nasotracheal intubation for a ventriculoperitoneal shunt. CASE REPORT: This is a 15-month old male with OI (type III) and hydrocephalus who underwent placement of a ventriculoperitoneal shunt. After the oral administration of midazolam (1 mg.kg-1) 30 minutes before the procedure, the child was monitored and, afterwards, a 24G catheter was used for venipuncture. After oxygenation, anesthesia was induced with remifentanil, propofol, and cisatracurium. A 4.5-mm ETT with balloon was used for the rhinoscopeguided (Olimpus) ENF P3) nasotracheal intubation without intercurrences. Anesthesia was maintained with the infusion of remifentanil and propofol. The surgery lasted 120 minutes, without intercurrences. CONCLUSIONS: The present report described an alternative for the access of the upper airways in children undergoing general anesthesia and who, for some reason, cannot be ventilated with a laryngeal mask. Since the rhinolaryngoscope has a reduced diameter, it allows the insertion of ETTs that could not be used with conventional fiberscopes. PMID- 19784518 TI - [Abdominal compartment syndrome during endoscopic clamping of an intestinal perforation secondary to colonoscopy]. AB - BACKGROUND AND OBJECTIVES: Colonoscopy is widely used for diagnosis, treatment, and control of intestinal disorders. Intestinal perforation, although rare, is the most feared complication. Perforations can be treated by endoscopic clamping. The objective of this report was to alert specialists for the development and treatment of abdominal compartment syndrome during endoscopic clamping of an intestinal perforation secondary to colonoscopy. CASE REPORT: This is a 60 years old female, physical status ASA II, who underwent colonoscopy under sedation. During the exam, an accidental intestinal perforation was observed, and it was decided to attempt the endoscopic clamping of the perforation. The patient developed abdominal pain and distension, pneumoperitoneum, abdominal compartment syndrome, dyspnea, and cardiovascular instability. Emergency abdominal puncture was done with clinical improvement until urgent laparotomy was performed. After exploratory laparotomy and stitching of the perforation, the patient presented good clinical evolution. CONCLUSIONS: Endoscopic clamping of an intestinal perforation secondary to colonoscopy can contribute for the development of hypertensive pneumoperitoneum and abdominal compartment syndrome with severe clinical repercussions that demand immediate treatment. Capable professionals and adequate technical resources can be determinant of the prognosis of the patient. PMID- 19784519 TI - [Bougie]. AB - BACKGROUND AND OBJECTIVES: Difficult airways require fast action by the anesthesiologist often requiring complementary devices to ensure patent airways. However, several of those devices are expensive and require training in order to be used. The bougie, a simple and disposable device can also be manufactured by the anesthesiologist, making it a low cost tool. CONTENTS: Bougies are composed of one introducer that when inserted in the trachea helps orienting the introduction of the tracheal tube. It is a simple tool, easy to use, low in cost, and has been shown to be very useful in unexpected difficult airways. CONCLUSIONS: The bougie has shown to be a valuable tool in the armamentarium of the anesthesiologist, and it is indicated in a wide range of situations. PMID- 19784520 TI - [Time and obstetric anesthesia: from chaotic cosmology to chronobiology]. AB - BACKGROUND AND OBJECTIVES: Temporal cycles (dark/light; birth/death; etc.), along with environmental conditions (synchronizers), influence labor physiology because of the presence of endogenous clocks (oscillators) that interact with social diuturnal clues. In this review, the most important cyclic anesthetic-obstetric parameters in parturient care are listed. CONTENTS: Chronobiological analysis of the main events in the obstetric pathophysiology of Mulier sapiens: I) Embryogenesis - risk of teratogenesis; II) From prematurity to post-didacticism: from eutocic labor to cervical cerclage; III) Night and labor: higher incidence of nocturnal labor (physiological facilitation) and daylight cesarean section (choice of the obstetrician); IV) The moon and labor - non-conclusive results; V) The night shift in obstetric anesthesia: riskier professional contingency; VI) Phases of cesarean section: removal of the fetus: UD stage (uterotomy - delivery) as brief as possible; effective correction of hypotension and valorize pre anesthetic fasting; VII) circadian variation of dystocia: pain; uterine contraction; blood loss; hypertension (HTN); risk of allergy and asthma. In the nocturnal phase, the intensity of contraction and risk of hemorrhage, allergy, and asthma are greater. On the other hand, HTN in eclampsia does not show circadian variation; VIII) Obstetric chronopharmacology: local anesthetics, analgesics, hypnotics, general anesthetics, and neuromuscular blockers. Chronoenergy explains the matinal peak of opioid analgesia, vespertine of local anesthetic, and nocturnal of inhalational anesthetics. CONCLUSIONS: The chronobiological approach of labor anesthesia emphasizes the obstetric importance of circadian rhythmicity in labor humanization and safety. PMID- 19784521 TI - Acta Dermatovenerologica Alpina, Pannonica et Adriatica and scientific misconduct. PMID- 19784522 TI - The Abbott RealTime High Risk HPV test: comparative evaluation of analytical specificity and clinical sensitivity for cervical carcinoma and CIN 3 lesions with the Hybrid Capture 2 HPV DNA test. AB - BACKGROUND: The Abbott RealTime High Risk HPV test (RealTime) is a novel assay designed to detect 14 high-risk human papillomavirus genotypes (hr-HPV) and concurrently distinguish HPV-16 and HPV-18 from other hr-HPV within a single test. OBJECTIVE: To evaluate analytical specificity and clinical sensitivity for cervical carcinoma and cervical intraepithelial neoplasia grade 3 (CIN3) of the RealTime test in comparison with the Digene Hybrid Capture II Test (hc2). MATERIALS AND METHODS: Analytical specificity of the RealTime assay was evaluated on 37 samples with previously determined hc2 false-positive results due to cross reactivity of the hc2 high-risk probe cocktail with untargeted low-risk HPV genotypes. All 37 samples were negative for 14 hr-HPV using the RealTime test. Clinical sensitivity of RealTime was evaluated in comparison to hc2 on 95 and 267 archived routine cervical specimens collected from women with histologically confirmed cervical carcinoma and CIN3 lesions, respectively. Archived specimens were selected for the present study after linkage with the Slovenian national registry of CIN3 and cervical cancer to obtain histology data. RESULTS: Concordant results between RealTime and hc2 were obtained in 90/95 cervical cancer samples (94.7% agreement) and in 250/267 CIN3 samples (93.6% agreement). Clinical sensitivity of RealTime and hc2 for cervical cancer in the total study cohort was 88.4% (95% confidence interval (CI): 80.3-93.6%) and 87.3% (95% CI: 79.0-92.8%), respectively, and analytical sensitivity for samples containing at least one targeted hr-HPV was 98.8% (95% CI: 93.0-100.0%) and 95.3% (95% CI: 88.2 98.5%), respectively. Clinical sensitivity of RealTime and hc2 for CIN3 lesions of the total study cohort was 91.8% (95% CI: 87.8-94.5%) and 89.1% (95% CI: 84.8 92.3%), respectively, and analytical sensitivity for samples containing at least one targeted hr-HPV was 96.4% (95% CI: 93.3-98.2%) and 92.5% (95% CI: 88.5 95.2%), respectively. CONCLUSION: The RealTime test showed excellent analytical specificity and no cross-reactivity with low risk HPV genotypes that tested positive with hc2. Clinical sensitivity of the RealTime assay using archived routine cervical specimens was comparable to hc2. The RealTime test is an important new method applicable to cervical carcinoma screening and management of cervical precancerous lesions. PMID- 19784523 TI - Association of cytokine gene polymorphisms with psoriasis in cases from the Nile Delta of Egypt. AB - BACKGROUND: Psoriasis is a chronic inflammatory skin disease with an immunogenetic background. This study was planned to check for the association of polymorphisms related to cytokine genes TNF-alpha-308(G/A), IL-10-1082(G/A), IL-6 174(G/C), and IL-1Ra (VNTR) with psoriasis in cases from Egypt. METHODS: This study included 46 cases with psoriasis recruited from the Department of Dermatology, University Hospitals, Nile Delta region of Egypt. They included 14 males and 32 females with a mean age +/- SD of 46.68 +/- 12.16 years and a range of 15 to 70 years. Their genotypes were compared to 98 healthy controls of matched age and sex from the same locality. Genotyping was done through DNA amplification using PCR with sequence-specific primers for polymorphic alleles. RESULTS: Compared to controls, cases showed a significantly higher frequency of certain genotypes including IL-6-174 CC (p < 0.001, OR = 6.7), IL-10-1082 GG (p < 0.05, OR = 5.1), and TNF-alpha-308 GG (p < 0.05, OR = 3.7). Combined heterozygosity for IL-10 GA, IL-6 GC, and TNF GA showed a significant low frequency among the cases studied. CONCLUSION: Genetic polymorphisms related to the IL6, IL10, and TNF-alpha genes showed a particular pattern of association with psoriasis that may have a potential impact on disease counseling and management. PMID- 19784524 TI - Hereditary palmoplantar keratoderma type papulosa in Slovenia. AB - BACKGROUND: Hereditary palmoplantar keratodermas (HPPK) are relatively frequent in Slovenia; however, the papulosa type of HPPK is rare. Epidemiological data are scarce; a population study in Croatia revealed a prevalence of 1.17/100,000 inhabitants. According to the preliminary data, it seems that HPPK papulosa is more common in Slovenia than in other countries. Efforts were made to identify all patients with HPPK papulosa in Slovenia. PATIENTS AND METHODS: Existing hospital and outpatient records served as a starting point. Patients and their relatives were invited for examination. When necessary for preparing pedigrees, we visited patients. RESULTS: Altogether 66 patients were observed, giving a prevalence of 3.3/100,000 inhabitants. 62 patients belonged to 11 unrelated families with two or more affected members and there were also four isolated cases. Our investigation points to an autosomal dominant mode of inheritance. All of the routine biochemical and hematologic tests were within normal limits. No malignancies were observed, nor were such data revealed in patients' histories. Thickened nail-plates were observed in three patients. CONCLUSIONS: The prevalence of HPPK papulosa in Slovenia is higher than in other countries studied. Further loci mentioned in literature suggest a genetic heterogeneity in this condition. PMID- 19784525 TI - Genetic epidemiology and heritability of vitiligo in the Qassim region of Saudi Arabia. AB - AIM: Assessment of consanguinity and inheritance patterns in relation to clinical subtypes of vitiligo among Saudi cases in the Qassim region based on a vitiligo case series during 2008 taken from the Qassim University-affiliated referral center. METHODS: This study included 111 randomly selected Saudi probands affected by vitiligo and their families. They included 61 males and 50 females. Their mean age of onset was 19.13 +/- 11.97 years. Data were collected using a questionnaire administered by professional dermatologists emphasizing the clinical features as well as consanguinity and segregation pattern. Genetic analyses for inbreeding coefficient, mode of inheritance, and heritability were statistically analyzed. RESULTS: Out of 111 probands, the frequencies of focal, vulgaris, universal, and acrofacial subtypes were 32.4%, 31.5%, 9.9%, and 26.1%, respectively. Parental consanguinity was positive in 32.4% of cases and first cousin consanguinity in 22.5% with an inbreeding coefficient of 0.015. The family history was positive in 56.8% of cases. The mean age of onset was 19.13 +/- 11.97 years with a median of 17 years. The median age of onset was lower for consanguineous cases and cases with a positive family history. Inheritance patterns coincided more with the multifactorial model, especially for the vulgaris subtype followed by the acrofacial subtype, and coincided least with the focal subtype. Heritability or the genetic contribution to the disease showed a high weighted mean of 0.54. CONCLUSION: Genetic factors contribute to the evolution of vitiligo among Saudi families. Discouraging consanguineous marriage is a potential prevention measure. Genetic factors contribute to the evolution of vitiligo among tribal areas of the Saudi community probably through the high consanguinity rate. In that respect, family counseling can be attempted that would discourage consanguinity and combat probable interactive environmental and health factors. PMID- 19784526 TI - Spontaneous endometriosis in an umbilical skin lesion. AB - Cutaneous endometriosis of the umbilicus is an unusual condition with unclear pathogenetic mechanisms that might be mistaken for a malignant condition. A 46 year-old woman presented with a cutaneous black mass in the umbilicus. The lesion was removed surgically and histological analyses revealed that it consisted of endometrial tissue. There was no recurrence at 18-month follow-up. Endometriosis of the umbilicus is a rare condition and the pathogenesis is not completely elucidated. According to one theory, intraperitoneal endometrial tissue is translocated during endoscopic surgery or other surgical procedures that involve the umbilicus. However, in this case there was no history of abdominal wall surgery. We conclude that endometriosis is important to consider in cases of unclear skin lesions of the umbilicus, even in cases with no previous abdominal surgery. Moreover, umbilical endometriosis of the skin can have different appearances that resemble malignant tumors, and radical surgery with histology is therefore indicated. PMID- 19784527 TI - Dermatomyositis-like eruption induced by hydroxyurea: a case report. AB - A 74-year-old patient, suffering for 20 years from polycythemia rubra vera, was treated with hydroxyurea for 2 years. Intensive xerosis (ichthyosis-like) and violaceous papules on the dorsal hand surfaces were observed. There was also reddish purple periorbital erythema resembling "heliotrope erythema". Such a disease pattern has been described as "hydroxyurea-induced dermatomyositis-like eruption" - a drug-adverse reaction associated with hydroxyurea therapy. The reaction has typical dermal features of dermatomyositis without any systemic symptoms (in the case of our patient, antinuclear antibodies absent and creatine phosphokinase within the normal range). The above reaction is associated with chronic hydroxyurea uptake and, after withdrawing the drug, alleviation of skin lesions usually takes place after 10 days to 18 months with no recurrences. In the case of our patient, we observed clinical improvement after 3 months; xerosis decreased, heliotrope erythema vanished, and there was also a decrease in both the number and intensity of violaceous papules on the dorsal hand surfaces. PMID- 19784528 TI - Herpes simplex following intra-articular sacroiliac corticosteroid injection. AB - Localized herpes simplex (HSV) type II following intra-articular corticosteroid injection is remarkable. We describe a 51-year-old woman with sacroiliitis following a fall. She was treated with an intra-articular injection of 80 mg methylprednisolone into her sacroiliac joint, followed 2 days later by a cluster of herpetiform vesicles adjacent to the injection site. Swab of punctured vesicles demonstrated HSV type II by polymerase chain reaction. One plausible explanation is HSV reactivation secondary to localized immunosuppression from corticosteroid injection. PMID- 19784529 TI - Bilateral multiple apocrine hidrocystoma of the eyelids. PMID- 19784530 TI - The elusive differential diagnosis of cutaneous apocrine adenocarcinoma vs. metastasis: the current role of clinical correlation. PMID- 19784531 TI - Retraction: Jawbone metastases: four cases. PMID- 19784532 TI - Retraction: CD30 (Ki-1) molecule expression in human embryonal epithelial cells of the basal layer of the developing epidermis and epidermal buds and its potential significance for embryogenesis. PMID- 19784533 TI - Permeation of a metalworking fluid through a latex glove under field use conditions. AB - Whole glove testing for a metalworking fluid (MWF) in the field was performed for the first time. Green latex gloves used in a machine shop were exposed for 20 min to MWF. The permeated amount (1.0 +/- 0.5 microg/cm(2)) was higher than the threshold (0.25 microg/cm(2)) for the ASTM F739-99a closed-loop normalized breakthrough time. PMID- 19784534 TI - Metal accumulation and growth response in Vigna radiata L. inoculated with chromate tolerant rhizobacteria and grown on tannery sludge amended soil. AB - The effects of inoculation of four chromate tolerant rhizobacterial strains previously isolated from rhizosphere of plants from chromium contaminated area in mung plant Vigna radiata grown on tannery sludge amended soil were evaluated. An increase of 138%, 88%, 256% and 54.14% in root length, shoot length, biomass and total chlorophyll, respectively was observed after 60 days of treatments by consortium. Similarly, a significant enhancement in Fe, Mn, Zn, Ni, Pb, Cr, Cu and Cd accumulation was observed in consortium inoculated plants as compared to non-inoculated plants. Results showed that rhizobacterial strain helps in ameliorating metal induced phytotoxicity, acquiring higher biomass and metal uptake in the plant may be useful in decontamination of metal from polluted soil. PMID- 19784535 TI - Heavy metal contamination in Phrynops geoffroanus (Schweigger, 1812) (Testudines: Chelidae) in a River Basin, Sao Paulo, Brazil. AB - The Piracicaba River basin is considered the most disturbed river basin in the state of Sao Paulo. Considerable amounts of agricultural residues are seasonally drained into the river, and the region is also highly urbanized and industrialized with an incipient sewage treatment system. The presence of heavy metals has been previously reported for the water and riverbed in Piracicaba river basin. In this study we evaluated 13 heavy metals in the blood of 37 Geoffroy's side-necked turtles, Phrynops geoffroanus, from Piracicaba River and Piracicamirim Creek, one of its tributaries. Blood levels of As, Co, Cr, Se and Pb varied among sites, whereas Sn varied between males and females. However, no obvious pathology was detected. Serum level of Cu (2,194 ng g(-1)) and Pb (1,150 ng g(-1)) found in this study are the highest ever described for any reptile; however, no clinical symptoms have been detected in the present study. There is no information about the time scale of such contamination, which could be currently subclinical and yet lead to a breakdown in the population reproductive success in a few years. Based on the present study, legal enforcement is urged in order to locate and extirpate heavy metal sources in the Piracicaba River basin. In addition, monitoring should include humans and commercial fish consumed in local markets. PMID- 19784536 TI - Flame atomic absorption spectrometric determination of Pb, Cd, and Cu in Pinus nigra L. and Eriobotrya japonica leaves used as biomonitors in environmental pollution. AB - The assessment of trace metal pollution in Gaziantep city-Turkey has been studied using plant leaves of Pinus nigra L. and Eriobotrya japonica as biomonitor. The concentrations up to 3,056 mg Pb kg(-1) in the needles of Pinus nigra L., and 367 ng Cd g(-1) in the leaves of Eriobotrya japonica were determined. The observed Cu concentrations were in range of 1.6-7.1 mg kg(-1). The Pb, Cd, and Cu levels in soils were determined to be in the range of 17-602, 0.142-0.656, and 12-38 mg kg( 1), respectively. It was concluded that Pinus nigra L. can be considered as both biomonitor of atmospheric Pb pollution and hyperaccumulator plant. PMID- 19784537 TI - BMD T-score discriminates trochanteric fractures from unfractured controls, whereas geometry discriminates cervical fracture cases from unfractured controls of similar BMD. AB - The ability of bone mineral density (BMD) to discriminate cervical and trochanteric hip fractures was studied. Since the majority of fractures occur among people who are not diagnosed as having osteoporosis, we also examined this population to elucidate whether geometrical risk factors can yield additional information on hip fracture risk beside BMD. The study showed that the T-score criterion was able to discriminate fracture patients from controls in the cases of trochanteric fractures, whereas geometrical measures may discriminate cervical fracture cases in patients with T-score >-2.5. INTRODUCTION: Low bone mineral density (BMD) is a well-established risk factor for hip fracture. However, majority of fractures occur among people not diagnosed as having osteoporosis. We studied the ability of BMD to discriminate cervical and trochanteric hip fractures. Furthermore, we examined whether geometrical measures can yield additional information on the assessment of hip fracture risk in the fracture cases in subjects with T-score >-2.5. METHODS: Study group consisted of postmenopausal females with non-pathologic cervical (n = 39) or trochanteric (n = 18) hip fracture (mean age 74.2 years) and 40 age-matched controls. BMD was measured at femoral neck, and femoral neck axis length, femoral neck and shaft cortex thicknesses (FNC and FSC), and femoral neck-shaft angle (NSA) were measured from radiographs. RESULTS: BMD T-score threshold of -2.5 was able to discriminate trochanteric fractures from controls (p < 0.001). Seventeen out of 18 trochanteric fractures occurred in individuals with T-score -2.5. Within these non-osteoporotic cervical fracture patients (N = 19) and non-osteoporotic controls (N = 35), 83.3% were classified correctly based on a model including NSA and FNC (p < 0.001), area under the receiver operating characteristics curve being 0.85 for the model, while it was only 0.56 for BMD alone. CONCLUSIONS: The study suggests that the risk of trochanteric fractures could be discriminated based on a BMD T-score < 2.5 criterion, whereas cervical fracture cases would remain under-diagnosed if solely using this criterion. Instead, geometrical risk factors are able to discriminate cervical fracture cases even among individuals with T-score >-2.5. For cervical and trochanteric fractures combined, BMD and geometric measures independently contributed to hip fracture discrimination. Our data support changing from T-score <-2.5 to a more comprehensive assessment of hip fracture etiology, in which fracture type is also taken into account. The findings need to be confirmed with a larger sample, preferably in a prospective study. PMID- 19784538 TI - Effect of polyunsaturated fatty acids on the reactive oxygen and nitrogen species production by raw 264.7 macrophages. AB - BACKGROUND: Polyunsaturated fatty acids (PUFAs) can affect various functions of the immune system including inflammatory responses. An oxidative burst of phagocytes accompanied by reactive oxygen species (ROS) and reactive nitrogen species (RNS) formation is one of the phagocyte functions that could be modulated by PUFAs. AIM OF THE STUDY: To investigate the effects of omega-3 (alpha linolenic, docosahexaenoic, eicosapentaenoic) and omega-6 (arachidonic, linoleic) PUFAs on lipopolysaccharide (LPS)-stimulated ROS and RNS production by the murine macrophage cell line RAW 264.7. METHODS: Murine peritoneal macrophages RAW 264.7 were stimulated with LPS (0.1 microg/ml) and treated with 0.1-100 microM omega-3 or omega-6 PUFAs for either 8 (ROS production) or 20 h (RNS production). The cytotoxicity of PUFAs was evaluated by an ATP (adenosine triphosphate) test after both 8 and 20 h of treatment with PUFAs. Changes in ROS production by LPS-treated macrophages subsequently activated with phorbol myristate acetate (PMA) or opsonized zymosan particles (OZP) were determined by luminol-enhanced chemiluminescence, whilst the production of RNS was determined as the concentration of nitrites in cell supernatants (Griess reaction). Changes in inducible nitric oxide synthase (iNOS) expression were evaluated by Western blot analysis. The antioxidant properties of PUFAs were tested by TRAP (total peroxyl radical-trapping antioxidant parameter) assay. RESULTS: All PUFAs in 100 microM concentration except eicosapentaenoic acid decreased ROS production. The effect was most significant when docosahexaenoic acid was used. Arachidonic acid decreased PMA-activated ROS production even in 1 and 10 microM concentrations. On the other hand, 10 and 100 microM eicosapentaenoic acid potentiated ROS production. As concerns RNS production, all the fatty acids that were tested in a concentration of 100 microM decreased iNOS expression and nitrite accumulation. Fatty acids had no significant effect on the viability and proliferation of RAW 264.7 cells. The TRAP assay confirmed that none of the tested PUFAs exerted any significant antioxidant properties. CONCLUSION: High concentrations of PUFAs of both omega-3 and omega-6 groups can inhibit ROS and RNS formation by stimulated macrophages. The expression of iNOS can also be inhibited. This effect, together with the absence of antioxidant activity and cytotoxic properties, indicates that PUFAs can participate in the regulation of enzymes responsible for reactive species production. PMID- 19784540 TI - Assessing the appropriate use of laparoscopic surgery for hepatobiliary diseases. AB - BACKGROUND: The range of indications for laparoscopic surgery has widened since it was first introduced. The aim of the present study was to develop standards for the appropriate use of laparoscopic surgery in patients with choledocholithiasis or cholelithiasis. METHOD: We conducted a study following the RAND appropriateness method (RAM) to develop criteria for hepatobiliary laparoscopy. A panel comprised of 7 experts rated the appropriateness of a set of indications, from 1 (very inappropriate) to 9 (very appropriate). The panelists performed ratings in 2 rounds. The first round was performed independently by every expert. The second round took place during a face-to-face meeting. According to the median of panelists' ratings and agreement criteria, every indication was classified as appropriate, uncertain, or inappropriate. RESULTS: In the first round, 112 (46.7%) indications were judged as appropriate, 102 (42.5%) as uncertain, and 26 (10.8%) as inappropriate. In the second round, 99 indications (48.5%) were considered as appropriate, 81 (39.7%) as uncertain, and 24 (11.8%) as inappropriate. Disagreement between panelists decreased in the second round compared with the first round. Thirteen indications were rated as disagreement (6.4%), 125 as uncertain (61.3%), and 66 as agreement (32.3%), while in the first round, the results and proportions were 44 (18.3%), 132 (55.0%), and 64 (26.7%), respectively. CONCLUSIONS: By using RAM, the panel was able to develop detailed explicit appropriateness criteria for the proper application of hepatobiliary laparoscopy. The criteria may be used prospectively to help in making clinical decisions or retrospectively to assess the overuse of clinical procedures. PMID- 19784539 TI - Astaxanthin suppresses scavenger receptor expression and matrix metalloproteinase activity in macrophages. AB - BACKGROUND: Astaxanthin is a red carotenoid pigment which has significant potential for antioxidant activity. The macrophages in atherosclerotic lesions, known as activated macrophages, express scavenger receptors responsible for the clearance of pathogenic lipoproteins. In addition, the expression and secretion of proteolytic enzymes, matrix metalloproteinases (MMPs), and pro-inflammatory cytokines are remarkably promoted in activated macrophages. AIM OF THE STUDY: In this study, we investigated the effects of astaxanthin on the expression of scavenger receptors, MMPs, and pro-inflammatory cytokines in macrophages. METHODS: THP-1 macrophages were incubated with 5-10 microM astaxanthin for 24 h. The expression levels of scavenger receptors, MMPs, and pro-inflammatory cytokines were determined by Western blot analysis or real-time RT-PCR. The MMP-9 and -2 activities were examined by gelatin zymography and total MMP activity was measured by fluorometry. RESULTS: We found that astaxanthin remarkably decreased the class A scavenger receptor and CD36 expression in the protein and mRNA levels. Astaxanthin also reduced MMP-1, -2, -3, -9, -12, and -14 activity and expression. The mRNA expression of tumor necrosis factor-alpha, interleukin 1beta, interleukin-6, inducible nitric oxide synthase, and cyclooxygenase-2 were significantly suppressed by astaxanthin. Furthermore, astaxanthin inhibited the phosphorylation of nuclear factor-kappaB. CONCLUSIONS: These results indicate that astaxanthin has inhibitory effects on macrophage activation, such as scavenger receptors up-regulation, MMPs activation, and pro-inflammatory cytokines secretion. PMID- 19784541 TI - Immunohistochemical study of mucin expression in periampullary adenomyoma. AB - BACKGROUND/PURPOSE: Benign tumors and tumor-like conditions in the ampullary area are uncommon, and there are extremely rare cases of adenomyoma (AM) and adenomyomatous hyperplasia (AMH). Surgical treatment is necessary if these lesions cause biliary obstruction. In addition, the differential diagnosis of AM and AMH from carcinoma is often difficult by standard endoscopic biopsy and cytopathological analysis that may show differential findings, resulting in unnecessary surgeries sometimes being performed. METHODS: Immunohistochemical (IHC) analysis of periampullary AM and AMH was performed. RESULTS: For both types of lesions, epithelial glandular cells (EGCs) showed diffuse expression of MUC6 and focal expression of HIK1083, mainly in the inner region, and focal expression of MUC5AC, mainly at the surface. The EGCs showed no expression of MUC1 or MUC4, both of which were identified as malignant tumor markers in our previous series of mucin expression studies in pancreatobiliary tumors. The expression of CK7, which was diffusely positive in normal periampullary mucosa, was decreased in the EGCs of AM and AMH. CONCLUSIONS: A combined evaluation of IHC findings may be effective in the detection of AM and AMH, and also in distinguishing benign periampullary lesions, such as AM and AMH, from ampulla of Vater adenocarcinoma, thus avoiding excessive surgery. PMID- 19784542 TI - Rituximab was effective on refractory thrombotic thrombocytopenic purpura but induced a flare of hemophagocytic syndrome in a patient with systemic lupus erythematosus. AB - We report the case of a patient with systemic lupus erythematosus (SLE) who first revealed hemophagocytic syndrome (HPS), which was treated successfully with glucocorticoid and intravenous cyclophosphamide. The patient then demonstrated refractory thrombotic thrombocytopenic purpura (TTP) with normal a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS)-13 activity that responded well to rituximab. After rituximab treatment, the patient showed a flare of HPS that was controlled by additional intravenous cyclophosphamide treatment. This case showed that TTP with normal ADAMTS-13 activity is B-cell dependent and indicated that B-cell depletion might exacerbate some autoimmune conditions in SLE. PMID- 19784543 TI - Acute respiratory distress syndrome associated with rapid aggravation of rheumatoid arthritis. AB - A 76-year-old woman with seropositive rheumatoid arthritis (RA) developed acute respiratory distress syndrome (ARDS) following an appearance of severe inflammatory symptoms in multiple synovial joints. High-dose pulse therapy with methylprednisolone induced a marked improvement in pulmonary conditions. To the best of our knowledge, this is the first case in the literature to show a causal relationship between ARDS and RA. We should be alert to the possibility that ARDS can occur as an acute-type pulmonary complication of RA, particularly when patients show rapid aggravation of rheumatic activity. PMID- 19784545 TI - Low serum osteoprotegerin levels in normoalbuminuric type 1 diabetes mellitus. AB - The aim of this study is to establish whether abnormal mineral metabolism is present in patients with type 1 DM with normal renal function and in the absence of microalbuminuria. Serum levels of 1,25-dihydroxyvitamin D, osteoprotegerin (OPG) and receptor activator for nuclear factor kappa beta ligand (RANKL) and other determinants of bone metabolism were measured in 35 patients with type 1 DM and in 25 age-, sex- and ethnicity-matched healthy controls. Serum OPG (1.98 vs. 2.98 pmol/l: P = 0.001), 1,25-dihydroxyvitamin D (41.1 vs. 48.2 pmol/l: P = 0.035) and magnesium (0.84 vs. 0.89 mmol/l P = 0.029) levels were significantly lower in patients with type 1 DM compared to normal controls. RANKL levels were similar in both groups. The groups did not differ with respect to calcium, phosphate, PTH, 25-hydroxyvitamin D, tubular reabsorption of phosphate and cross linked N-telopeptides of type 1-collagen levels. Abnormalities of mineral metabolism including low serum OPG and 1,25-dihydroxyvitamin D levels occur in patients with type 1 DM with normal renal function and in the absence of microalbuminuria. These abnormalities may promote altered bone metabolism and vascular pathology. PMID- 19784544 TI - Correlation between MMP-13 and HDAC7 expression in human knee osteoarthritis. AB - Recent studies suggest that histone deacetylase (HDAC) inhibitors may therapeutically prevent cartilage degradation in osteoarthritis (OA). Matrix metalloproteinase-13 (MMP-13) plays an important role in the pathogenesis of this disease and in the present study we investigated the correlation between HDACs and MMP-13. Comparing the expression of different HDACs in cartilage from OA patients and healthy donors, HDAC7 showed a significant elevation in cartilage from OA patients. High level of HDAC7 expression in OA cartilage was also confirmed by immunohistochemistry. Knockdown of HDAC7 by small interference RNA (siRNA) in SW1353 human chondrosarcoma cells strongly suppressed interleukin (IL) 1-dependent and independent induction of MMP-13 gene expression. In conclusion, elevated HDAC7 expression in human OA may contribute to cartilage degradation via promoting MMP-13 gene expression, suggesting the critical role of MMP-13 in OA pathogenesis. PMID- 19784546 TI - Long-term outcome and quality of life after nonaneurysmal subarachnoid hemorrhage. AB - PURPOSE: Nonaneurysmal subarachnoid hemorrhage (SAH) is an uncommon form of SAH. As nonaneurysmal SAH is often concentrated around the pons and midbrain, the term perimesencephalic SAH (pmSAH) is widely accepted to describe this entity, though there are patients with a more widespread distribution of subarachnoid blood (non pmSAH). The outcome of pmSAH is commonly regarded as good, although often outcome is not analyzed using standardized tools of outcome measurement. In this study we focused on the patient's quality of life after nonaneurysmal SAH. METHODS: We included 26 patients in this study who experienced a nonaneurysmal SAH between 2003 and 2007. Neurological status upon admission as well as on discharge was recorded. All patients received a detailed postal questionnaire on their current neurological situation, dependence on care (Barthel Index), quality of life regarding their physical and psycho-social well-being (Short-form 36) and current employment situation and ability to work, respectively. RESULTS: After 32.68 +/- 19.81 months, almost all patients achieved a Glasgow Outcome Score of 4 or 5 and a Barthel Index of more than 90, although there was a difference between patients suffering from pmSAH and patients with non-pmSAH. Physical and social functioning recovered to almost normal levels but vitality and individual health were often perceived as reduced in self-evaluation. CONCLUSION: Nonaneurysmal SAH is a begnin entity, though there is a difference between pmSAH and non-pmSAH in outcome. Self-evaluations of vitality and individual health in both groups are often experienced as reduced, thus imposing the question of whether neurological rehabilitation should be recommended despite good neurological outcome. PMID- 19784547 TI - Aneurysmal subarachnoid hemorrhage diagnosis with computed tomographic angiography and OsiriX. AB - PURPOSE: Recent advances in computed tomographic angiography (CTA) have resulted in its replacing digital subtraction angiography (DSA). However, CTA requires a powerful workstation and experienced technicians for image postprocessing. OsiriX, a free open-source medical imaging software with powerful three dimensional (3D) capability, enables neurosurgeons to perform 3D rendering without extensive training. In this study, we examined the sensitivity and specificity of CTA with OsiriX as the primary diagnostic tool for intracranial aneurysms. METHOD: From May 2006 to March 2009, 121 patients with spontaneous subarachnoid hemorrhage (SAH) underwent CTA. The CTA source images were 3D rendered by neurosurgeons using OsiriX. All the possible locations for aneurysms were carefully reviewed. DSA was performed on every patient in any of the following conditions: for negative CTA findings, after surgical clipping of aneurysms or before transarterial embolization of aneurysms. RESULT: Of the 121 patients, 8 were excluded because DSA data were not available. In the remaining 113 patients, 20 patients had negative CTA findings. CTA with OsiriX detected 106 aneurysms in 93 patients, of which 103 were confirmed by DSA or postoperative DSA; 3 infundibular dilated pouches of small arteries were mistaken for aneurysms. Two anterior communicating artery aneurysms (1.5 mm and 1 mm) were missed by CTA from among all 113 patients. The sensitivity and specificity of CTA for detecting aneurysms on a per-patient basis were 98.9% and 100%, respectively. The sensitivity and specificity of CTA for detecting aneurysms on a per-aneurysm basis for detecting aneurysms were 98.1% and 86.3%, respectively. CONCLUSION: CTA with OsiriX enables accurate detection of intracranial aneurysms. Cerebral DSA should be reserved for those patients with negative CTA findings. PMID- 19784548 TI - The PDZ2 domain of zonula occludens-1 and -2 is a phosphoinositide binding domain. AB - Zonula occludens proteins (ZO) are postsynaptic density protein-95 discs large zonula occludens (PDZ) domain-containing proteins that play a fundamental role in the assembly of tight junctions and establishment of cell polarity. Here, we show that the second PDZ domain of ZO-1 and ZO-2 binds phosphoinositides (PtdInsP) and we identified critical residues involved in the interaction. Furthermore, peptide and PtdInsP binding of ZO PDZ2 domains are mutually exclusive. Although lipid binding does not seem to be required for plasma membrane localisation of ZO-1, phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P (2)) binding to the PDZ2 domain of ZO-2 regulates ZO-2 recruitment to nuclear speckles. Knockdown of ZO-2 expression disrupts speckle morphology, indicating that ZO-2 might play an active role in formation and stabilisation of these subnuclear structures. This study shows for the first time that ZO isoforms bind PtdInsPs and offers an alternative regulatory mechanism for the formation and stabilisation of protein complexes in the nucleus. PMID- 19784549 TI - Aggregates of denatured proteins stimulate nitric oxide and superoxide production in macrophages. AB - OBJECTIVE: Denatured proteins are deposited in damaged tissues, around implanted biomaterials, during natural aging as well as in a heterogeneous group of amyloid diseases, such as Alzheimer's disease. There is evidence that tissue damage observed in amyloidosis is mediated mainly by factors released from activated macrophages, such as superoxide and nitric oxide (NO), as opposed to direct interaction between amyloid fibrils and nonimmune cells. METHODS: Mouse resident peritoneal macrophages were stimulated in serum-free medium with different preparations of nonamyloidogenic proteins: alcohol dehydrogenase (AD), bovine serum albumin (BSA) or fibrinogen (FG). Intra- and extracellular superoxide production was measured by, respectively, nitro blue tetrazolium (NBT) reduction and lucigenin-enhanced chemiluminescence. Levels of nitrite (reflecting NO release) were measured in culture supernatants. RESULTS: Aggregates of denatured, nonamyloidogenic proteins, but not their native or denatured but not aggregated counterparts, stimulated superoxide and/or NO production in macrophages. The NO production was mediated by beta(1) and beta(2) integrins, with a possible contribution of receptor for advanced glycation end products (RAGE). It was catalyzed by inducible NO synthase (iNOS), enhanced synergistically by interferon gamma (IFN-gamma), and inhibited by covalently modified proteins-components of advanced glycation end products. Although intracellular superoxide production was stimulated significantly by denatured BSA and AD, but not by FG, both denatured BSA and FG strongly enhanced zymosan-stimulated extracellular release of reactive oxygen species. CONCLUSION: Our results point at similarities in macrophage responses to denatured nonamyloidogenic proteins and to amyloid fibrils. Thus, the tissue injury observed in amyloidosis may result from overstimulation of mechanisms that, under physiological conditions, enable macrophages to recognize and remove denatured proteins. PMID- 19784550 TI - Structure-activity relationships between the Aconitum C20-diterpenoid alkaloid derivatives and the growth suppressive activities of Non-Hodgkin's lymphoma Raji cells and human hematopoietic stem/progenitor cells. AB - The anti-tumor properties of novel derivatives prepared from Aconitum C(20) diterpenoid alkaloid, which show the least toxicity among the Aconitum alkaloids, were investigated in the Non-Hodgkin's lymphoma cell line Raji cells. Two novel Aconitum C(20)-diterpenoid alkaloid derivatives, 11-m-Trifluorometylbenzoyl (Mb) pseudokobuisne and 11-Anisoyl (As)-pseudokobusine, showed significant suppressive effects and their 50% inhibitory concentrations were 2.2 MUg/ml and 2.4 MUg/ml against Raji cells, respectively. Both compounds have the same structure except for a functional group in the C-11 position. One of the active compounds, 11-Mb pseudokobusine, clearly inhibited the phosphorylation of extracellular signal regulated kinase, induced enhanced phosphoinositide 3 kinase phosphorylation and led to the subsequent accumulation of G1 and/or sub G1 phase in Raji cells. In addition, no significant suppressive effects on the growth of human CD34(+) hematopoietic stem/progenitor cells (HSPC) were observed by 11-Mb-pseudokobusine which showed a strong suppressive activity on the growth of Raji cells, whereas 11-As-pseudokobusine also a showed significantly suppressive effect on the growth of HSPC. Therefore, the atisine type structure characteristic of C(20) diterpenoid alkaloids plays a very important role in the pharmacological properties. In particular, the C-11 residues are an important component for the anti-tumor properties and for the lower toxicity to hematopoiesis. PMID- 19784551 TI - TAE226-mediated inhibition of focal adhesion kinase interferes with tumor angiogenesis and vasculogenesis. AB - Neoangiogenesis plays an important role in tumor growth and metastasis. Evaluation of new anti-angiogenic targets may broaden the armament for future therapeutic concepts. Focal adhesion kinase (FAK), expressed in endothelial and tumor cells, is essential for adhesion and mobility of adherent cells. In the current study we analyzed the anti-angiogenic properties of the FAK inhibitor TAE226 on the proliferation of blood outgrowth endothelial cell (OEC) and differentiation of endothelial progenitor cells (EPC), derived from peripheral blood CD133(+) cells, tube formation and on neovascularization in a HT29 xenotransplant model. The effects of TAE226 were compared to those of the rapamycin analogue RAD001. The combination of both drugs was also studied. We showed that HT29 tumor cells and OEC were most sensitive to the action of TAE226 compared to EPC in vitro. In contrast, RAD001 affected the proliferation of both types of endothelial cells stronger than that of HT29 cells. Furthermore we could show that TAE226 inhibited tube formation in a dose dependent manner. In a HT29 subcutaneous tumor model TAE226 and RAD001 diminished MVD at commonly employed doses to a similar degree. Combination of both compounds did not show synergy in vitro or in vivo. Since TAE226 has been shown to inhibit the PI3 kinase, Akt kinase, mTor pathway, addition of RAD001 may not increase this effect. In conclusion, we have shown that treatment with TAE leads to a reduction of neoangiogenesis in vitro and in a mouse model. The effects are mediated by inhibition of angiogenesis and vasculogenic OEC and EPC. PMID- 19784552 TI - Elevated risk of myocardial infarction in very young immigrants from former Yugoslavia. AB - We performed a hospital based case-control study to assess if the risk of myocardial infarction at a very young age (< or =40 years) was elevated in immigrants from the region of former Yugoslavia. Patients were classified as "exposed" if they or both their parents were born in former Yugoslavia. Consecutive myocardial infarction patients were recruited in the immediate post infarction period from two Viennese hospitals over a 3.5-year period. Control patients free of myocardial infarction were frequency matched on age, gender, centre, and time in an approximate 1:2 ratio. Logistic regression was used for the assessment of an association between Yugoslavian descent and myocardial infarction. Overall, we recruited 102 myocardial infarction patients and 200 controls. The median age of infarction patients was 37.3 years. Yugoslavian descent was strongly associated with myocardial infarction (crude OR 7.3, 95% CI 3-18). This association was attenuated after multivariate adjustment (OR 3.9, 95% CI 1.2-13) but remained statistically significant. Using Miettinen's formula for population attributable risk, we calculated that between 15.3% (adjusted) and 17.8% (unadjusted) of myocardial infarction cases in very young patients could be attributable to immigrants from the studied region. In conclusion, we found that the risk of developing myocardial infarction at a young age is elevated in immigrants from the region of former Yugoslavia and their offspring. Even though residual confounding cannot be ruled out definitively, this risk seems to be independent of established cardiovascular risk factors. PMID- 19784553 TI - Investigating spatio-temporal similarities in the epidemiology of childhood leukaemia and diabetes. AB - Childhood acute lymphoblastic leukaemia (ALL) and Type 1 diabetes (T1D) share some common epidemiological features, including rising incidence rates and links with an infectious aetiology. Previous work has shown a significant positive correlation in incidence between the two conditions both at the international and small-area level. The aim was to extend the methodology by including shared spatial and temporal trends using a more extensive dataset among individuals diagnosed with ALL and T1D in Yorkshire (UK) aged 0-14 years from 1978-2003. Cases with ALL and T1D were ascertained from 2 high quality population-based disease registers covering the Yorkshire region of the UK and linked to an electoral ward from the 1991 UK census. A Bayesian model was fitted where similarities and differences in risk profiles of the two diseases were captured by the shared and disease-specific components using a shared-component model, with space-time interactions. The extended model revealed a positive correlation of at least 0.70 between diseases across all time periods, and an increasing risk across time for both diseases, which was more evident for T1D. Furthermore, both diseases exhibited lower rates in the more urban county of West Yorkshire and higher rates in the more rural northern and eastern part of the region. A differential effect of T1D over ALL was found in the south-eastern part of the region, which had a more pronounced association with population mixing than with population density or deprivation. Our approach has demonstrated the utility in modelling temporally and spatially varying disease incidence patterns across small geographical areas. The findings suggest searching for environmental factors that exhibit similar geographical-temporal variation in prevalence may help in the development and testing of plausible aetiological hypotheses. Furthermore, identifying environmental exposures specific to the south-eastern part of the region, especially locally varying risk factors which may differentially affect the development of T1D and ALL, may also be fruitful. PMID- 19784554 TI - Cloning and heterologous expression of glucose oxidase gene from Aspergillus niger Z-25 in Pichia pastoris. AB - A gene of glucose oxidase (GOD) from Aspergillus niger Z-25 was cloned and sequenced. The entire open reading frame (ORF) consisted of 1,818 bp and encoded a putative peptide of 605 amino acids. The gene was fused to the pPICZalphaA plasmid and overexpressed in Pichia pastoris SMD1168. The recombinant GOD (rGOD) was secreted into the culture using MF-alpha factor signal peptide under the control of the AOX1 promoter. Sodium dodecyl sulfate polyacrylamide gel electrophoresis indicated that rGOD exhibited a single band at around 94 kDa. The maximal GOD activity of approximately 40 U/mL was achieved in shake flask by induction under optimal conditions after 7 days. rGOD was purified by ammonium sulfate precipitate leading to a final specific activity of 153.46 U/mg. The optimum temperature and pH of the purified enzyme were 40 degrees C and 6.0, respectively. Over 88% of maximum activity was maintained below 40 degrees C. And the recombinant enzyme displayed a favorable stability in the pH range from 4.0 to 8.0. The Lineweaver-Burk plotting revealed that rGOD exhibited a K (m) value of 16.95 mM and a K (cat) value of 484.26 s(-1). PMID- 19784556 TI - [Ear surgery training using petrosal bone models?]. PMID- 19784559 TI - [Mitral valve insufficiency]. PMID- 19784560 TI - [Echocardiography in interventional mitral valve reconstruction]. AB - Interventional treatment of mitral insufficiency has recently become possible on a limited basis. The developed percutaneous procedures aim at minimizing the trauma in high-risk surgical candidates. Echocardiography has a major role in the preinterventional evaluation, during the interventional procedure, and in the postinterventional follow-up. The preinterventional analysis is focused on the assessment of valvular morphology and mitral insufficiency severity. This allows definition of patients potentially treatable by percutaneous therapy as well as the most suitable interventional approach. During interventional treatment, echocardiography is used as the integral tool to guide the procedure and for immediate assessment of the obtained therapeutic effect. Immediately post intervention, echocardiography should be performed to define the obtained status, allowing detection of subsequent changes in left ventricular function and mitral insufficiency severity. PMID- 19784557 TI - The conflict between horizontal gene transfer and the safeguard of identity: origin of meiotic sexuality. AB - Contrary to a widespread opinion, horizontal gene transfer (HGT) between distantly related microorganisms (such as Bacteria and Archaea) has not been demonstrated to occur on a large scale. Except for transfer of mobile elements between closely related organisms, most alleged HGT events reflect phylogenetic discrepancies that can be explained by a variety of artefacts or by the differential loss of paralogous gene copies either originally present in the Last Universal Common Ancestor (LUCA) to the three Domains (a sophisticated, genetically redundant and promiscuous community of protoeukaryotes), or created by duplications having occurred at later times. Besides, (i) there is no experimental evidence for the facile acquisition of foreign DNA between distant taxa and (ii) important biological constraints operate on the phenotypic success of genetic exchange at several levels, including protein-protein interactions involved in metabolic channelling; stable integration and expression of foreign DNA is, therefore, expected to require strong selection. Explaining phylogenetic discrepancies by artefacts or loss of paralogs does not eliminate difficulties in retracing species genealogy but maintains the picture of a universal tree of life, HGT between distant organisms being reduced to a trickle. We illustrate our thesis by the phylogenetic analysis of carbamoyltransferases, a family of paralogous proteins. Among higher eukaryotes HGT appears of limited scope except in asexual organisms. We suggest that meiotic sexuality (a hallmark of eukaryotes) emerged in the genetically redundant and protoeukaryotic LUCA as a molecular identity check providing a defence mechanism against the deleterious effects of HGT. PMID- 19784561 TI - [Minimally invasive heart and mitral valve surgery]. AB - During the last decades, minimally invasive operative techniques have been established in various subspecialties of modern cardiac surgery, offering now safe and efficient alternative treatment options for most of the patients. Those new and innovative options thereby aimed to reduce the operative trauma and perioperative morbidity, and furthermore, to increase patients' satisfaction and optimize patients' security. After continuous enhancement of these minimally invasive techniques during the last 10 years, numerous current reports demonstrate minimally invasive cardiac surgery techniques to be safe and efficient, resulting in equal or even better mortality and morbidity compared to conventional cardiac surgery. The underlying benefits of minimally invasive cardiac surgery are characterized by shorter hospital stay, less postoperative pain, accelerated rehabilitation, and superior cosmetic results. Minimally invasive treatment options in cardiac surgery should always be considered for suitable patients. PMID- 19784562 TI - [Percutaneous approaches for mitral valve interventions--a real alternative technique for standard cardiac surgery?]. AB - Standard therapy of advanced mitral valve regurgitation currently consists of mitral valve reconstruction through heart surgery including heart-lung machine employment. Typically, a ring is implanted and a leaflet reduced, if necessary, to approximate the posterior and anterior mitral valve leaflets to each other. Because of high comorbidity among this patient population, new and less burdening catheter-based techniques have been developed. Clinical etiology of mitral valve regurgitation is divided into two categories: "structural" versus "functional". The MONARC system of the Edwards Lifesciences company consists of three components--distal stent, bridge with bioabsorbing coating, proximal stent--and is implanted into the coronary sinus. The underlying principle is an indirect annuloplasty of the mitral valve annulus resulting from resorption of the bridge coating and leading to a reduction and indirect tightening of the mitral valve annulus. The EVOLUTION I (EV I) study in patients suffering from functional mitral regurgitation to a degree between 2+ and 4+ revealed--12 months after the MONARC implantation--a mitral valve regurgitation reduction from 2.48 to 1.78. The EV I study found interaction of the foreshortening bridge with the coronary arteries in some patients. This problem is most widely excluded by previous computed tomographic or angiographic examinations in the ongoing follow-up study EV II. Direct annuloplasty is made possible in case of functional mitral regurgitation by using the Mitralign Percutaneous Annuloplasty System (MPAS) of the Mitralign company. In doing so, an improved coadaptation of the mitral valve leaflet is achieved by inserting three sutures into the posterior mitral valve annulus and subsequent plicating.The MitraClip of the Evalve company uses the principle of the edge-to-edge technique. In doing so, the posterior and anterior leaflets are joined by implanting a clip, resulting in a reduction of mitral regurgitation with two diastolic orifices. In contrast to strukthe other two procedures, the MitraClip can be used for both functional and structural mitral valve regurgitation. The EVEREST I study and the EVEREST II study, as far as it has already been published, show that this procedure is secure and its results are very positive. The previous results of all three procedures show that catheter-based techniques for treating high-risk patients suffering from mitral valve regurgitation arrive at positive results in part, so that possibly a real alternative to conventional heart surgery will be available in the future. PMID- 19784563 TI - [Percutaneous mitral valve annuloplasty with the carillon mitral contour system by cardiac dimensions. A minimally invasive therapeutic option for the treatment of severe functional mitral valve regurgitation]. AB - Morbidity in patients with systolic heart failure is significantly increased by functional mitral valve regurgitation. In addition to pharmaceutical treatment or surgical reconstruction of the impaired valve, minimally invasive procedures have continuously advanced into the focus of interest. The Carillon Mitral Contour System (Cardiac Dimensions) is a new catheter-based method to converge dehiscent mitral valve leaflets with implantation of a nitinol clip into the coronary sinus, leading to a closer approach of the valve leaflets with subsequent decrease in mitral regurgitation. The device is implanted via a central venous catheter, using a special delivery system under fluoroscopy. The immediate success of minimizing mitral valve regurgitation is verified by online transesophageal echocardiography (TEE), device-related impairment of perfusion of contiguous coronary vessels is ruled out by coronary angiography performed simultaneously during deployment of the device. As soon as reduction of the mitral valve regurgitation is demonstrated in TEE, the Carillon System is disconnected from the delivery system, before, however, the Carillon device can be withdrawn into the delivery system as necessary. Following the successful implantation of the Carillon Mitral Contour System, a left ventricular lead for cardiac resynchronization therapy can still be successfully placed alongside through the coronary sinus. PMID- 19784564 TI - The role of imaging in percutaneous mitral valve repair. AB - Percutaneous, transcatheter mitral valve repair has recently been introduced and various strategies--loosely based on surgical techniques--are currently under clinical and preclinical evaluation. Since percutaneous mitral valve repair techniques are rather specific regarding both the underlying cause of mitral regurgitation and patient anatomy, careful preinterventional imaging using various techniques is required for appropriate patient selection and essential for procedural success. While echocardiography is the dominant imaging modality for determination of mitral regurgitation severity and etiology, other imaging modalities like contrast-enhanced multidetector computed tomography, magnetic resonance imaging, and fluoroscopy/angiography may play an important role in the preinterventional evaluation process. In addition, imaging is of utmost importance for procedural guidance and the combined use of various imaging modalities, commonly fluoroscopy and echocardiography, is needed in the catheterization laboratory to ensure safety and efficacy of mitral valve repair procedures. Finally, imaging is essential for an adequate patient follow-up aiming to control stable device positioning, persistency of the geometric modifications induced, and continuous reduction of mitral regurgitation. This review highlights the role of various imaging techniques during preinterventional evaluation, procedural guidance and follow-up in the setting of percutaneous mitral valve repair with special focus on edge-to-edge leaflet repair and indirect annuloplasty via the coronary sinus as the best-studied approaches to date. PMID- 19784565 TI - [Percutaneous mitral annuloplasty with the VIACOR coronary sinus system for the treatment of functional mitral regurgitation in heart failure patients. Development and results]. AB - Functional mitral regurgitation (MR) in heart failure patients limits survival in a severity-graded fashion. Even mild MR doubles the mortality risk. The use of a nonstented coronary sinus device to reduce mitral annulus dimension in order to reestablish mitral valve competence is reported. The device (PTMA, Viacor, Inc., Wilmington, MA, USA) consists of a multilumen PTFE (Teflon) PTMA catheter in which nitinol (nickel-titanium alloy) treatment rods are advanced. For individual treatment, up to three rods of different length and stiffness can be used. Therefore, dimension reduction can be performed in an incremental fashion. Fluoroscopy and three-dimensional (3-D) echocardiography are performed through the procedure to visualize the positioning and confirm maximum treatment effect. This report describes an implant case and summarizes the safety and feasibility of the new PTMA treatment device in 27 patients. The cases reflect the learning curve in both device design and implantation technique. In permanent implant, a sustained reduction of mitral annulus septal-lateral dimension from 3-D echo reconstruction dimensions was observed (4.9 +/- 1.2 mm at 3 months). PMID- 19784566 TI - Mechanism of coronary malperfusion due to type-a aortic dissection. PMID- 19784567 TI - [Costs caused by bleeds within the therapy of acute coronary syndromes in Germany]. AB - PURPOSE: To estimate the resources and subsequent costs, to manage bleeds among patients with acute coronary syndrome (ACS) who are treated with antithrombotics or antiplatelets. Bleeds are relatively common but there is little information on the resource use and costs associated with these bleeds. This paper provides estimates by type of bleed to be used in analyses of therapies for managing ACS patients. METHODS: Retrospective chart review of ACS patients experiencing a bleed while hospitalized was conducted in Germany. Qualifying bleeds included symptomatic intracranial hemorrhage (IB), retroperitoneal hemorrhage (RB), gastrointestinal hemorrhage (GB), decrease in hemoglobin by > or = 3 g/dl (HA), puncture site bleed (PS), transfusion of > or = 2 units of blood products, and fatal bleeds. RESULTS: Records of 59 German ACS patients were included in the analysis. The average cost per patient was 1,995 Euros. Costs by bleed type were 2,531 Euros (IB), 3,567 Euros (RB), 3,616 Euros (GB), 891 Euros (HA), 1,379 Euros (PS), and 5,415 Euros (transfusions). CONCLUSION: German hospitals are paid by case severity and diagnosis. Understanding the full costs of managing ACS patients and related bleeds may help decision-making. PMID- 19784568 TI - Arrhythmogenic right ventricular cardiomyopathy as lethal complication factor after cardiac surgery. AB - In patients with arrhythmogenic right ventricular dysplasia (ARVD), the right ventricular myocardium histologically discloses atrophy paralleled by fibrofatty or fatty replacement. Apoptosis is believed to be a putative major pathogenetic mechanism. Altogether, our knowledge of genetics, etiology and pathophysiology of ARVD has increased impressively in the last few years, and effective genetic tests now principally would be possible. Nevertheless, due to often uncharacteristic or even lacking symptoms, clinical diagnosis may be very difficult and could not be made during lifetime of patient presented here, partly due to additional, independent cardiac problems. The question of an effective preoperative diagnostic regimen for cardiosurgical interventions remains and seems to be currently open. PMID- 19784570 TI - Cholesterol gallstone formation in hypercholesterolemia. PMID- 19784571 TI - Structural modification of 5,7-dimethoxyflavone from Kaempferia parviflora and biological activities. AB - 5,7-Dimethoxyflavone, a major compound from Kaempferia parviflora, was used as a starting material for structural modification. Seven flavonoid derivatives have been synthesized from this flavone. Two new oxime derivatives 4 and 6 exhibited cytotoxicity against HepG2 cell line with IC50 values of 36.38 and 25.34 microg/mL, respectively, and against T47D cell line with IC50 values of 41.66 and 22.94 microg/mL, respectively. Compound 7 showed cytotoxicity against HepG2 and T47D cell lines with IC50 values of 21.36 and 25.00 microg/mL, respectively. Compounds 6 and 7 showed cytotoxicity nearly equal to the tamoxifen standard. In addition, oxime 6 exhibited antifungal activity against Candida albicans with an IC50 value of 48.98 microg/mL. PMID- 19784572 TI - Amino and nitro derivatives of 5,7-dimethoxyflavone from Kaempferia parviflora and cytotoxicity against KB cell line. AB - Structural modification of 5,7-dimethoxyflavone isolated from Kaempferia parviflora furnished two nitro and seven amino derivatives. Among these, six new (3, 5-6, 8-10) and three known (2, 4, 7) flavonoid derivatives were synthesized. All compounds were evaluated for cytotoxicity against KB cell line using colorimetric method. Compounds 6 and 8 exhibited strong cytotoxicity with IC50 values of 6.80 and 5.84 microg/mL, respectively. PMID- 19784573 TI - Analgesic, antipyretic, anti-inflammatory and toxic effects of andrographolide derivatives in experimental animals. AB - Andrographolide (1) and 14-deoxy-11,12-didehydroandrographolide (2) are active constituents of Andrographis paniculata (Burm. f.), family Acanthaceae. A. paniculata extracts are reported to have antiviral, antipyretic, immunostimulant and anticancer activities. In this study, 1 and its 14-acetyl- (4) and 3,19 isopropylidenyl- (3) derivatives, as well as 2 and its 3,19-dipalmitoyl derivative (5), were intraperitoneally tested for their analgesic, antipyretic, anti-inflammatory and acute toxicity effects in animal models. Analgesic effects were tested in mice using hot plate and writhing tests to distinguish the central and peripheral effects, respectively. The results showed that, at 4 mg/kg, all tested substances have significant analgesic effects, and the highest potency was seen with 3, 4 and 5. Increasing the dose of 3 and 5 to 8 mg/kg did not increase the analgesic effect. In the writhing test, 3 and 5, but not 1, showed significant results. In a baker's yeast-induced fever model, 3 and 5 significantly reduced rats' rectal temperature (p < 0.05). In a carrageenan induced inflammation model, 1, 3 and 5 significantly reduced rats' paw volume. Doses of 3 and 5 up to 100 mg/kg did not show any serious toxic effects. From this study, 3 and 5 are the most interesting derivatives, showing much greater potency than their parent compounds. These could be further developed as analgesic, antipyretic and anti-inflammatory agents, without any serious toxicity. PMID- 19784574 TI - Design, synthesis, and biological evaluation of phenylpropanamides as novel transient receptor potential vanilloid 1 antagonists. AB - Synthesis and structure-activity relationship of N-benzyl-3-phenylpropanamides as transient receptor potential vanilloid 1 (TRPV1) antagonists are described. A variety of substituents such as halide, ester, nitro, and alkyl groups at 2 or 3 position of 4-(methylsulfonylamino) benzyl unit were examined. These compounds exhibited potent 45Ca2+ uptake inhibition in rat DRG neuron via TRPV1 blockade. Especially compound 28c, has been identified as a potent antagonist with IC50 of 38 nM. PMID- 19784575 TI - 2-Hydroxydiplopterol, a new cytotoxic pentacyclic triterpenoid from the halotolerant fungus Aspergillus variecolor B-17. AB - A new hopane type pentacyclic triterpenoid, 2-hydroxydiplopterol (1) has been isolated from the metabolites produced by the halotolerant fungal strain Aspergillus variecolor B-17. The structure of 1 was determined by spectroscopic methods and single crystal X-Ray diffraction analysis. 2-Hydroxydiplopterol (1) exhibited cytotoxicity against K562 cells with an IC50 value of 22 microM. PMID- 19784576 TI - Chemical constituents from the leaves of Ilex paraguariensis inhibit human neutrophil elastase. AB - Human neutrophil elastase (HNE), a serine protease with broad target specificity, is the only enzyme responsible for the degradation of elastin which is an insoluble elastic fibrous protein in animal connective tissue. Biologically, elastase activity significantly increased with age, which results in a reduced skin elasticity and in the appearance of wrinkles or stretchmarks. In the course of our screening program for HNE inhibitors from natural source, the MeOH extract of Ilex paraguariensis leaves showed strong HNE inhibitory effect. Bioassay guided fractionation led to the isolation of a new pyrrole alkaloid (1), along with seventeen known compounds (2-18) from the MeOH extract of Ilex paraguariensis leaves, and their chemical structures were elucidated on the basis of spectroscopic analysis. All isolated compounds were evaluated for HNE inhibitory activity, and the result demonstrated that dicaffeoylquinic acid derivatives (12, 13, 14, 15 and 16) and flavonoids (8 and 17) exhibited potent HNE inhibitory activity with IC50 values ranging from 1.4 to 7.3 microM. PMID- 19784577 TI - Novel ceramides from aerial parts of Saussurea involucrata Kar. et. Kir. AB - Novel ceramides, together with nine known compounds were isolated from aerial parts of the Saussurea involucrata Kar. et. Kir. The novel structures were determined by spectroscopic methods and microscale chemical degradation. The ceramides showed appreciable cytotoxicity against three human tumor cell lines including human promyelocytic leukemia (HL-60), human melanoma (A375-S2) and human cervical carcinoma (HeLa) cell lines. The results suggested that this class of ceramides may have potential as an antitumor agent. PMID- 19784578 TI - A cyclohexenone derivative from Diaporthaceous fungus PSU-H2. AB - One new cyclohexenone derivative (1) was isolated from Diaporthaceous fungus PSU H2 together with six known compounds, dothiorelone A (2), dothiorelone C (3), 2,3 dihydromycoepoxydiene (4), (+)-mycoepoxydiene (5), deacetylmycoepoxydiene (6) and tyrosol (7). The structures were elucidated by spectroscopic methods. Their cytotoxic activity against human breast cancer cell line, MCF-7, was evaluated. PMID- 19784579 TI - Two new acorane sesquiterpenes from Illicium henryi. AB - Two new acorane sesquiterpenes, 10-hydroxyacoronene (1) and 1beta-isopropyl-4beta methyl-9beta-hydroxy spiro[4.5]dec-6-en-8-one (2), one new natural product, 4 hydroxy-4, 6-dimethyl-1-tetralone (3), and one known acorane sesquiterpene, acoradiepoxide (4) were isolated from the twigs and leaves of Illicium henryi. The structures of the new compounds were elucidated primarily on the basis of analysis of spectroscopic data. In addition, the inhibitory effect on NO production of these compounds were tested. Compounds 1 and 4 exhibited slight inhibitory effects on NO production with IC50 values of 82.4 microg/mL and 76.5 microg/mL, respectively. PMID- 19784580 TI - Anti-inflammatory activity of the constituents of the roots of Aralia continentalis. AB - To assess the anti-inflammatory activity of the constituents of the roots of Aralia continentalis, ent-pimara-8(14),15-diene-19-oic acid (continentalic acid, pimaradienoic acid, compound I), 7beta-hydroxy-ent-pimara-8(14),15-diene-19-oic acid (compound II), 7-oxo-ent-pimara-8(14),15-diene-19-oic acid (compound III), 15alpha,16alpha-epoxy-17-hydroxy-ent-kauran-19-oic acid (compound IV) and ent kaura-16-en-19-oic acid (kaurenoic acid, compound V), their inhibitory effects against cyclooxygenase-2 (COX-2)-catalyzed PGE(2) and inducible nitric oxide synthase (iNOS)-catalyzed NO production by lipopolysaccharide-treated RAW 264.7 cells were examined. Among the compounds tested, compound III and V moderately inhibited NO production. In addition, compound III weakly inhibited PGE2 production, while treatment with compounds II and IV at concentrations of up to 100 microM had no significant effects. Conversely, compound I only weakly inhibited PGE2 and NO production. To elucidate the mechanism by which these changes occurred, the iNOS down-regulating capacity of compound III was investigated. Western blot analysis and an electrophoretic mobility shift assay demonstrated that compound III weakly inhibited COX-2 and iNOS expression at 50 100 microM, and inhibited NF-kappaB activation. When in vivo anti-inflammatory activities of compounds I, III and V were examined, intraperitoneal injection of 4-100 mg/kg of compound I and V significantly inhibited carrageenan-induced paw edema in mice, whereas compound III did not. Taken together, the results of this study suggest that some constituents of A. continentalis, especially compounds I, III and V, exert significant anti-inflammatory activity, which suggests that these constituents contribute, at least in part, to the anti-inflammatory action of the roots of A. continentalis. PMID- 19784581 TI - Acetylcholinesterase inhibitive activity-guided isolation of two new alkaloids from seeds of Peganum nigellastrum Bunge by an in vitro TLC- bioautographic assay. AB - Acetylcholinesterase inhibitors (AChEIs) currently form the basis of the newest drugs available for the treatment of Alzheimer's disease. For the aim of screening effective AChEIs, the methanol extracts of the seeds of genus Peganum were found to show significant inhibitory activity of acetylcholinesterase enzyme (AChE) using an in vitro TLC-bioautographic assay. In further studies to seed of P. nigellastrum Bunge, activity-guided fractionation led to the isolation of two new alkaloids nigellastrine I (9) and nigellastrine II (10), and along with eight known alkaloids, vasicinone (1), vasicine (2), harmine (3), deoxyvasicinone (4), deoxyvasicine (5), harmaline (6), harmol (7), harman (8), in which harmol and harman were first isolated from species P. nigellastrum Bunge. As active constituents, all compounds showed good inhibitory activities against AChE. The results of in vitro semi-quality TLC-bioautographic assay showed that harmine, harmaline and harmol displayed a similar AChE inhibitive activities comparing to galanthamine. These results indicated that these alkaloids in P. nigellastrum Bunge could be a potent class of AChEIs. PMID- 19784582 TI - Alteration of sphingolipid metabolism and pSTAT3 expression by dietary cholesterol in the gallbladder of hamsters. AB - Cholesterol and sphingolipids are major lipid constituents of the plasma membrane and have been implicated in a number of human diseases, such as atherosclerosis, fatty liver, diabetes mellitus, coronary heart disease, and hypertension. However, the relationship between cholesterol and sphingolipid metabolism has not been investigated. The purpose of this study was to determine whether dietary cholesterol would induce the alteration of sphingolipid metabolism in hamsters. Hypercholesterolemia was induced in hamsters by placing them on an experimental diet containing 0.5% cholesterol plus 0.5% choline chloride for 8 and 12 weeks. The serum profile of the hamsters showed that the administration of cholesterol increased the levels of total cholesterol, LDL cholesterol, and triglycerides as well as the activities of GOT and GPT. The levels of ceramide and sphingosine-1 phosphate (So-1-P) were remarkably elevated by 6-fold, respectively, in the bile juice of cholesterol-fed hamsters. Interestingly, the levels of iNOS and GFAP were increased in the gallbladders of cholesterol-fed hamsters. In addition, the immunostaining of pSTAT3 was increased on the gallbladder epithelium after cholesterol feeding. These results suggest that sphingolipid metabolism may be regulated in the bile juice during cholesterol feeding and may be a potential target for the treatment of hypercholesterolemia-induced diseases. PMID- 19784583 TI - Apoptosis induction effects of EGCG in laryngeal squamous cell carcinoma cells through telomerase repression. AB - Epigallocatechin-3-gallate (EGCG), the major component of green tea polyphenol, has potent efficiency to prevent the growth of a variety of cancer cells. As a novel anticancer agent for treatment of cancers, EGCG is promising and the mechanism has not been fully understood. Laryngeal squamous cell carcinoma (LSCC) is one common tumor in head and neck cancers. In the present study, we assess the effects of EGCG on LSCC cell line Hep-2, and their possible involvement in EGCG induced apoptosis. The result showed that treatment of Hep-2 cells with EGCG decreased the cell viability, inhibited the growth and proliferation, induced apoptosis and increased the activity of caspase-3 in a dose-dependent manner. Furthermore, we found that EGCG-treatment repressed telomerase activity effectively in a concentration-dependent manner. The combined results show that EGCG induced apoptosis in Hep-2 cells via inhibiting the telomerase activity. PMID- 19784584 TI - Optimized and validated spectrophotometric methods for the determination of raloxifene in pharmaceuticals using permanganate. AB - Two simple and sensitive spectrophotometric methods are described for the determination of raloxifene hydrochloride (RLX) in pure form and in tablets. The first method (method A) is based on the formation of a yellowish-brown chromogen peaking at 430 nm when RLX was reacted with permanganate in acetic acid medium. In the second method (method B), RLX was reacted with a measured excess of permanganate in H2SO4 medium followed by the spectrophotometric measurement of the unreacted KMnO4 at 550 nm. Under the optimized experimental conditions, Beer's law is obeyed in the concentration range 0.6-6.0 and 1.5-15.0 microg mL( 1) with molar absorptivity of 7.01 x 10(4) and 2.8 x 10(4) L mol(-1) cm(-1) for method A and method B, respectively. The limits of detection (LOD) and quantification (LOQ) have also been reported. The intra-day and inter-day RSD and RE values at three different concentrations were assessed. The proposed methods were applied to the commercially available tablets, and the results were statistically compared with those of the reference method. The accuracy and reliability of the methods were further ascertained by recovery studies. PMID- 19784585 TI - Combined administration of the mixture of honokiol and magnolol and ginger oil evokes antidepressant-like synergism in rats. AB - Magnolia bark combined with ginger rhizome is a common drug pair in traditional Chinese prescriptions for the treatment of depression. In the present study, we examined antidepressant-like effects of the mixture of honokiol and magnolol (HMM) from magnolia bark and essential oil from ginger rhizome (OGR) alone and in combination in chronic unpredictable mild stress (CUMS) of rats. Behavioral (sucrose intake, immobility time of forced swimming test) and biochemical parameters [serotonin (5-HT) in prefrontal cortex, hippocampus, and striatum, gastric mucosa cholecystokinin (CCK) and serum gastrin (GAS) levels] were simultaneously examined in the CUMS rats. 20 mg/kg HMM alone, but not OGR, significantly increased sucrose intake and reduced immobility time in the CUMS rats. Moreover, 20 mg/kg HMM and 14 mg/kg OGR in combination exhibited significant synergistic effects on sucrose intake increase and immobility time reduction in the CUMS rats. HMM elevated 5-HT levels in various brain regions, and OGR reduced gastric mucosa CCK and serum GAS levels in the CUMS rats. These results suggested that the synergistic antidepressant-like effects of compatibility of HMM with OGR might be mediated simultaneously by regulation of the serotonergic and gastroenteric system functions. These findings also provided a pharmacological basis for the clinical application of this drug pair of magnolia bark and ginger rhizome in traditional Chinese medicine. PMID- 19784586 TI - Effects of some 1,3,5-trisubstitued-2-pyrazoline derivatives on depression and anxiety parameters of mice. AB - The aim of the present study was examining the effects of some 1,3,5 trisubstituted-2-pyrazoline derivatives on depression, anxiety and spontaneous locomotor activity parameters of mice. None of the compounds was effective at 50 mg/kg dose whereas at 100 and 200 mg/kg, pyrazoline-benzoxazole derivative test compound 4a and pyrazoline-benzimidazole derivative test compound 4d in the series were exhibited significant antidepressant effects in modified forced swimming tests. These two pyrazolines decreased the immobility and increased the swimming times of mice without any change in climbing durations suggesting the antidepressant-like effects of the test compounds. In spite of significant antidepressant effect, none of the compounds changed the exploratory parameters in hole-board tests or total numbers of spontaneous locomotor activities in activity cage measurements at any of the applied doses. In other words, neither anxiolytic nor sedative effects induced by the test compounds. The results obtained from this study supported the previous findings reporting the antidepressant activities of pyrazoline derivative compounds. Exact mechanism of the antidepressant action exhibited in the present study need to be clarified with further detailed investigations. PMID- 19784587 TI - Timosaponin B-II inhibits pro-inflammatory cytokine induction by lipopolysaccharide in BV2 cells. AB - It was reported that the total polysaccharides extracts from Anemarrhenae asphodeloides Bge (Liliaceae, rhizome) could inhibit inflammatory responses in various models. In the present study, the effects of Timosaponin B-II, a purified extract from A. asphodeloidesb, on the expressions of IL-1beta, TNF-alpha and IL 6, the activity of NF-kappaB and the activation of signal pathway related to NF kappaB were explored in vitro. Timosaponin B-II significantly attenuated increase of these cytokines on both mRNA and protein levels from LPS-stimulated BV2 cells in a dose-dependent manner. The reporter gene assay also showed that the activation of NF-kappaB induced by LPS was inhibited by pre-treatment with Timosaponin B-II. Moreover, western blot results showed that the activation of p38, JNK and P65 had been decreased. These results suggest that both NF-kappaB signal pathway and MAPK pathway were involved in the inhibitory effects of Timosaponin B-II on the expression of pro-inflammatory cytokines. PMID- 19784588 TI - Cell growth inhibition and gene expression regulation by (-)-epigallocatechin-3 gallate in human cervical cancer cells. AB - EGCG [(-)-epigallocatechin-3-gallate] has shown its antitumor ability and perhaps a potential regimen for cancer patients. The goal of this study was to investigate the effect of EGCG on human papilloma virus (HPV) positive cervical cancer cell lines. EGCG inhibited the growth of CaSki (HPV16 positive) and HeLa (HPV18 positive) cells in a time- and concentration-dependent manner. Cell cycle arrest and apoptosis were observed in two cell lines after EGCG exposure. More importantly, we focused on EGCG regulation ability on pivotal genes involved in cervical cancer: viral oncogenes E6/E7, estrogen receptor (ER) and aromatase. Our results suggested that EGCG may be suitable for prevention and treatment of cervical cancer. PMID- 19784589 TI - Two different approaches for the prediction of in vivo plasma concentration-time profile from in vitro release data of once daily formulations of diltiazem hydrochloride. AB - The aim of this study was to employ two different mathematical approaches: first, a convolution approach using computer software; second, a mathematical calculation exploiting Wagner-Nelson calculation to predict in vivo plasma concentration-time profile from the in vitro release study for the once daily formulations of a model drug diltiazem hydrochloride. The once daily extended release tablets (120 mg) were prepared by the wet granulation technique. Ethanol or ethanolic solutions of ethylcellulose (N22), were used as granulating agents along with hydrophilic matrix polymers like hydroxypropyl methylcellulose (HPMC) (K 15M). The granules showed satisfactory flow properties, compressibility, moisture content and drug content. All the tablet formulations showed acceptable properties and complied with pharmacopeial limits. The in vitro drug release study revealed that formula F7-T which contains drug: HPMC ratio 1:1 and 20 mg of ethylcellulose was able to sustain the drug release for 24 h and satisfied the USP dissolution limits. Fitting the in vitro drug release data to Korsmeyer Peppas equation indicated that the mechanism of drug release could be zero-order. The capsule formulation F14-C which consists of drug: HPMC ratio 1:2, 12 mg of ethylcellulose and 20 mg of polyox 100 showed in vitro drug release similar to the tablet F7-T using the similarity factor (f 2). The mechanism of drug release could be coupled diffusion, and polymer matrix relaxation. The percent dissolved data from the two formulations were used as input function to predict the in vivo plasma data by the two approaches (Convolution by Kinetica software and Wagner Nelson calculation). The two methods were validated by prediction of plasma data from in vitro release data of FDA approved 300 mg extended release capsule. Prediction errors were estimated for Cmax and area under the curve (AUC) to determine the validity of the methods. The percent prediction error for each parameter is not exceeding 15%. PMID- 19784591 TI - F(2)-isoprostanes: sensitive biomarkers of oxidative stress in vitro and in vivo: a gas chromatography-mass spectrometric approach. AB - A gas chromatography-mass spectrometric method was developed that allowed the accurate, highly sensitive and specific quantification of F(2)-isoprostanes (F(2) IsoPs) in different tissues and body fluids. Measurement of F(2)-IsoPs in isolated rat brain mitochondria, HaCaT keratinocytes, human plasma, and microdialysates of human skin has established the occurrence of oxidative stress in a variety of model systems and disease states. F(2)-IsoPs correlated with other markers of lipid peroxidation (e.g., TBARS, HETEs) in experimental models of oxidative stress. F(2)-IsoPs were elevated about 100-fold after iron/ascorbate induced oxidative stress and 2- to 4-fold after pentylenetetrazol (PTZ)-induced seizures, in hemodialysis patients with end stage renal disease, in psoriasis patients, in HaCaT keratinocytes, and in microdialysates of human skin following UVB irradiation.Both human and experimental studies have indicated associations of F(2)-IsoPs and inflammatory conditions. Anti-inflammatory drugs such as diclofenac did not only suppress the prostaglandin but also the F(2)-IsoP pathway.Microdialysis allows the "near-in vivo" measurement of prostanoid mediators, released in the interstitial space of the dermis under inflammatory conditions. PMID- 19784592 TI - Volatile oxylipins and related compounds formed under stress in plants. AB - Plants form volatile oxylipins and related compounds under stress. Some of them are important flavor chemicals and give big impact on the flavor quality of food made from plant materials. They are also involved in defense responses of plants against pathogens and herbivores. Furthermore, in some instances, they cause harmful effects on plants themselves. Because of these significances of volatile oxylipins and related compounds, demands to perform comprehensive analyses of these compounds are increasing. In this chapter, we describe the simple but efficient procedures to reveal profiles of volatile oxylipins and related compounds by using HPLC and GC-MS. They are simple and can be performed in biochemical laboratories equipped with common facilities. PMID- 19784593 TI - Quantification of lysophosphatidylcholine species by high-throughput electrospray ionization tandem mass spectrometry (ESI-MS/MS). AB - Lysophosphatidylcholine (LPC) is a bioactive lipid implicated to play a functional role in various diseases including atherosclerosis, diabetes, cancer, and inflammation. Conventional methods are of limited value for a systematic evaluation of LPC species concentrations due to complicated, time-consuming procedures. Here we describe a methodology based on electrospray ionization tandem mass spectrometry (ESI-MS/MS) applicable for high-throughput LPC species quantification. This assay provides accuracy and precision sufficient for the analysis of large clinical studies as well as basic biochemical studies in a broad range of biological material including plasma, tissues, and cell culture material. This method may be combined with methods based on the same analytical setup for glycerophospholipid, sphingolipid, and sterol analysis to evaluate LPC species in relation to other lipid species profiles. PMID- 19784594 TI - Use of lipidomics for analyzing glycerolipid and cholesteryl ester oxidation by gas chromatography, HPLC, and on-line MS. AB - Various analytical techniques have been adopted for the isolation and identification of the oxolipids and for determining their functionality. Gas chromatography in combination with mass spectrometry (MS) has been specifically utilized in analysis of isoprostanes and other low molecular weight oxolipids, although it requires derivatization of the solutes. In contrast, liquid chromatography (LC) in combination with on-line MS has proven to be well suited for analysis of intact oxolipids without (or minimal) derivatization. LC-MS has also been helpful for the identification of lipidomic changes resulting from covalent binding of lipid ester core aldehydes to amino lipids, amino acids, peptides, and proteins. This chapter reviews the use of the above techniques for lipidomic analysis of the autoxidation products of cholesteryl esters and glycerolipids as practiced in the authors' laboratories. PMID- 19784595 TI - Lipid raft-redox signaling platforms in plasma membrane. AB - Membrane lipid rafts (LRs) have been demonstrated to be importantly involved in transmembrane signaling in a variety of mammalian cells. Many receptors can be aggregated within the LR clusters to form signaling platforms. Currently, LRs were reported to be clustered to aggregate, recruit, and assemble NADPH oxidase subunits and related proteins in various cells in response to various stimuli, forming redox signaling platforms. These LR signaling platforms may play important roles in the regulation of cellular activity and cell function, and also in the development of cell dysfunction or injury associated with various pathological stimuli. This LRs clustering-mediated mechanism is considered to take a center stage in redox signaling associated with death receptors. In this chapter, some basic methods and procedures for characterization of LR-redox signaling platforms formation and for determination of the function of these signaling platforms are described in detail, which include identification of LR redox signaling platforms in cell membrane by using fluorescent or confocal microscopy of LR-redox signaling platforms and fluorescent resonance energy transfer analysis, isolation of LR-redox signaling platforms by flotation of detergent-resistant membranes, and function measurement of LR-redox signaling platforms by electron spin resonance spectroscopy. It is expected that information provided here will help readers to design necessary experiments in their studies on LR signaling platforms and redox regulation of cell function. PMID- 19784596 TI - Mass spectrometry analysis of polyisoprenoids alcohols and carotenoids via ESI(Li(+))-MS/MS. AB - Direct analysis of polyisoprenoid alcohols by electrospray ionization mass spectrometry (ESI-MS) often produces poor results requiring off-line time- and sample-consuming derivatization techniques. In this chapter, we describe a simple ESI-MS approach for the direct analysis of polyisoprenoid alcohols from biological samples. Lithium iodide is used to promote cationization by intense formation of [M+Li](+) adducts. Detection of polyisoprenoids with mass determination can thus be performed with high sensitivity (LOD near 100 pM), whereas characteristic collision-induced dissociations observed for both dolichols and polyprenols permit investigation of their structure. We also describe a simple ESI-MS approach for the direct analysis of carotenoids in biological samples using lithium iodide to promote their ionization and the analysis of several carotenoids as proof-of-principle cases. Finally, we applied ESI(Li(+))-MS and ESI(Li(+))-MS/MS to investigate the presence of carotenoids in Plasmodium falciparum. PMID- 19784597 TI - Detection of a lipid-lysine adduct family with an amide bond as the linkage: novel markers for lipid-derived protein modifications. AB - An amide-type adduct, hexanoyl-lysine (HEL) is generated from the reaction between n-6 fatty acid (FA)-derived lipid peroxide and lysine. Immunochemical and chemical methods can be used to detect the formation of HEL. For example, an ELISA kit using the monoclonal antibody to HEL is now commercially available. We recently identified propanoyl-lysine (propionyl-lysine, PRL) from the reaction of an n-3 FA and a lysine residue. The antibody to PRL has been prepared and characterized. Using these monoclonal antibodies, the localization of adducts in tissues has been confirmed. Moreover, both amide-type adducts, HEL and PRL, can be simultaneously measured using liquid chromatography mass spectrometry (LC/MS/MS) with isotope dilution methods. The LC/MS/MS analysis reveals the rigid amounts of the adducts in human urine. Both the chemical and immunochemical methods are useful for the estimation of amide-type adducts in vivo. PMID- 19784598 TI - Assessing the neuroprotective effect of antioxidative food factors by application of lipid-derived dopamine modification adducts. AB - Advances in understanding the neurodegenerative pathologies are creating new opportunities for the development of neuroprotective therapies, such as antioxidant food factors, lifestyle modification, and drugs. However, the biomarker by which to determine the effect of the agent on neurodegeneration is limited. We here address hexanoyl dopamine (HED), one of novel dopamine adducts derived from brain polyunsaturated acid, referring to its in vitro formation, potent toxicity to SH-SY5Y cells, and application to assess the neuroprotective effect of antioxidative food factors. Dopamine is a neurotransmitter and its deficiency is a characterized feature in Parkinson's disease (PD), thereby HED represents a new addition to understanding of dopamine biology and pathophysiology of PD and a novel biomarker for the assessment of neuroprotective therapies. We have established an analytical system using for the detection of HED and its toxicity to the neuroblstoma cell line, SH-SY5Y cells. Here, we discuss the characteristics of the system and its applications to investigate the neuroprotective effect of several antioxidants that originate from food. PMID- 19784599 TI - Mass-spectrometric characterization of phospholipids and their hydroperoxide derivatives in vivo: effects of total body irradiation. AB - Combination of electrospray ionization mass spectrometry (ESI-MS), fluorescence high-performance liquid chromatography (HPLC), and 2D-high-performance thin-layer chromatography (2D-HPTLC) is a powerful approach to identify and quantitatively analyze oxidized phospholipids in vivo. We describe application of this methodology in assessments of phospholipid hydroperoxides using as an example their characterization and quantitative determinations in different tissues of mice exposed to total body irradiation (TBI, 10 and 15 Gy). Using ESI-MS, we identified individual molecular species - with particular emphasis on polyunsaturated molecules as preferred peroxidation substrates - in major classes of phospholipids: cardiolipin (CL), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylserine (PS), and phosphatidylinositol (PI) isolated from mouse brain, lung, muscles, small intestine, and bone marrow. We show that the pattern of phospholipid oxidation 24 h after TBI is nonrandom and does not follow the phospholipid abundance in tissues. The anionic phospholipids - CL, PS, and PI - are the preferred peroxidation substrates. We identified and structurally characterized individual hydroperoxides in these three classes of phospholipids. The protocols described may be utilized in studies of signaling functions of oxidized phospholipids in cell physiology and pathology. PMID- 19784600 TI - Comprehensive mRNA profiling of lipid-related genes in microglia and macrophages using taqman arrays. AB - Quantitative real-time reverse-transcription (RT)-PCR is a precise and sensitive method to measure mRNA levels over a broad dynamic range. This chapter describes the quantitative transcript analysis of 41 selected lipid-related transcripts in macrophages and microglia using a novel "Lipidomic" Taqman Array. The Taqman Array results show that (1) stimulation with the liver-X-receptor and retinoid-X receptor ligands T0901317 and 9-cis retinoic acid induces several genes of lipid metabolism, (2) lipopolysaccharide (LPS) and interferon-g (Ifn-g) strongly repress lipid-related genes, and (3) coincubation with docosahexaenoic acid dampens the repressing effect of LPS. The method described in this chapter can be used to monitor the transcriptional response of 41 dynamic "lipid" genes simultaneously in any cell type. PMID- 19784601 TI - Imaging lipid membrane domains with lipid-specific probes. AB - Imaging membrane lipid domains to characterize their organization and function has been hindered by the lack of reliable lipid-specific probes. In this paper, we provide detailed methods to investigate, mainly by confocal microscopy, the distribution and dynamics of two components of the "lipid rafts," sphingomyelin (SM) and cholesterol, using two specific lipid probes that have been extensively studied in the laboratory: lysenin, a SM-binding toxin and the fluorescent esters of poly(ethylene glycol) cholesteryl ether (PEG-Chol) that label cholesterol-rich domains. The production of nontoxic forms of lysenin as well as its specific binding behavior have allowed monitoring the distribution and the dynamics of SM rich domains in living cell membranes. Because of its water-solubility and low toxicity, the fluorescent PEG-Chol can be used to follow the reorganization of cell surface cholesterol-rich domains as well as intracellular cholesterol dynamics in living cells. These probes can thus provide important informations on lipid distribution and traffic in living cell membranes. PMID- 19784602 TI - Monitoring sterol uptake, acetylation, and export in yeast. AB - Sterols are essential lipid components of eukaryotic membranes. They are synthesized in the endoplasmatic reticulum (ER) from where they are efficiently transported to the plasma membrane, which harbors ~90% of the free sterol pool of the cell. The molecular mechanisms that govern this lipid transport, however, are not well characterized and are challenging to analyze. Saccharomyces cerevisiae offers the opportunity to circumvent some of the technical limitations associated with studying this forward transport of sterols from the ER to the plasma membrane, because the organism can also take up sterols from the environment, incorporate them into the plasma membrane and transport them back to the ER, where the free sterol is converted to steryl esters. This reverse sterol transport, however, occurs only under anaerobic conditions, where the cells become sterol auxotroph, or in mutant cells that cannot synthesize heme. The reverse sterol transport pathway, however, is more amenable to experimental studies, because arrival of the sterol in the ER membrane can be monitored unambiguously by following the formation of steryl esters. Apart from sterol acylation, we have recently described a reversible sterol acetylation cycle that is operating in the lumen of the ER. Acetylation occurs on both cholesterol and pregnenolone, a steroid precursor, and serves as a signal for export of the acetylated sterols into the culture media. The time-dependent appearance of acetylated sterols in the culture supernatant thus provides a new means to monitor the forward transport of chemically modified sterols out of the ER. PMID- 19784603 TI - Methods to monitor Fatty Acid transport proceeding through vectorial acylation. AB - The process of fatty acid transport across the plasma membrane occurs by several mechanisms that involve distinct membrane-bound and membrane-associated proteins and enzymes. Among these are the fatty acid transport proteins (FATP) and long chain acyl CoA synthetases (Acsl). Previous studies in yeast and adipocytes have shown FATP and Acsl form a physical complex at the plasma membrane and are required for fatty acid transport, which proceeds through a coupled process linking transport with metabolic activation termed vectorial acylation. At present, six isoforms of FATP and five isoforms of ACSL have been identified in mice and man. In addition, there are a number of splice variants of different FATP and Acsl isoforms. The different FATP and Acsl isoforms have distinct tissue expression profiles and different cellular locations suggesting they function in the channeling of fatty acids into discrete metabolic pools. The concerted activity of these proteins is proposed to allow cells to discriminate different classes of fatty acids and provides the mechanistic basis underpinning the selectivity and specificity of the fatty acid transport process. PMID- 19784604 TI - Activity-based profiling of lipases in living cells. AB - The ultimate goal of proteomics is to characterize the function of all proteins in parallel and in the most physiologically relevant settings possible. A step toward this goal has been the introduction of activity-based proteomics. The simultaneous detection of individual protein activities can be facilitated directly in the proteome using specific activity-based probes consisting of a recognition site targeting a certain enzyme species, a properly positioned reactive site which forms a covalent bond with the target and a reporter tag for visualization and/or purification of the covalently bound target. As properties like polarity, size, charge, structure, and chemical reactivity of the reporter tag have a large impact on the reactivity of the probes toward the target enzymes probes suitable for reporter tagging after the enzyme-activity probe-binding event were designed. These probes resemble the natural substrates more closely and are small and hydrophobic enough to cross the membrane of living cells. Here the methodology for detection of lipolytic activities in intact living cells, including synthesis of probe and reporter, labeling procedure, and detection of target enzymes is described. PMID- 19784605 TI - Histochemistry and lipid profiling combine for insights into aging and age related maculopathy. AB - Aging is the major risk factor for age-related maculopathy (ARM), the biggest cause of vision loss among the elderly in industrialized societies, and a major change in the affected tissues is the age-related accumulation of neutral lipid in Bruch's membrane (BrM) of the eye throughout adulthood. Here we show that esterified cholesterol (EC) is the major neutral lipid species in this tissue, which has implications for potential sources of this material. The combination of filipin histochemistry and comprehensive lipid profiling made possible this insight on a complex tissue. PMID- 19784606 TI - Instrument-independent software tools for the analysis of MS-MS and LC-MS lipidomics data. AB - Mass spectrometry (MS), particularly electrospray-MS, is the key tool in modern lipidomics. However, as even a modest scale experiment produces a great amount of data, data processing often becomes limiting. Notably, the software provided with MS instruments are not well suited for quantitative analysis of lipidomes because of the great variety of species present and complexities in response calibration. Here we describe the use of two recently introduced software tools: lipid mass spectrum analysis (LIMSA) and spectrum extraction from chromatographic data (SECD), which significantly increase the speed and reliability of mass spectrometric analysis of complex lipidomes. LIMSA is a Microsoft Excel add-on that (1) finds and integrates the peaks in an imported spectrum, (2) identifies the peaks, (3) corrects the peak areas for overlap by isotopic peaks of other species and (4) quantifies the identified species using included internal standards. LIMSA is instrument-independent because it processes text-format MS spectra. Typically, the analysis of one spectrum takes only a few seconds.The SECD software allows one to display MS chromatograms as two-dimensional maps, which is useful for visual inspection of the data. More importantly, however, SECD allows one to extract mass spectra from user-defined regions of the map for further analysis with, e.g., LIMSA. The use of select regions rather than simple time-range averaging significantly improves the signal-to-noise ratio as signals outside the region of interest are more efficiently excluded. LIMSA and SECD have proven to be robust and convenient tools and are available free of charge from the authors. PMID- 19784607 TI - Computer-assisted interpretation of triacylglycerols mass spectra. AB - Triacylglycerols (TGs) are principal components of vegetable oils and animal fats. Natural TGs form extremely complex mixtures composed of tens or hundreds of molecular species. HPLC/MS suits well for their analyses, but manual data processing is laborious and time-consuming. Specialized software algorithms are needed to accelerate the interpretation process. Here we present software named TriglyAPCI for interpreting APCI, APPI, or ESI MS/MS spectra of TGs. The chapter shows how to build and use the software, what are its advantages and limitations. The algorithm uses diacylglycerol fragments and molecular adducts for determining TG structure. Each ion in a spectrum is tested whether it might be a fragment or a molecular adduct. If so, the number of carbons and double bonds is assigned to it. The relations among the ions are searched and possible structures are suggested. TriglyAPCI allows interpreting spectra of single compounds, mixtures, or incomplete spectra lacking one of the diagnostic ions. The fragment intensities are used to distinguish regioisomers. An efficient chromatographic separation of TGs is shown to be crucial for correct spectra interpretation and avoiding false positive results. TriglyAPCI performance is demonstrated for HPLC/APCI-MS data of TGs isolated from bumblebee Bombus rupestris. PMID- 19784608 TI - Visualization of complex processes in lipid systems using computer simulations and molecular graphics. AB - Computer simulation has become an increasingly popular tool in the study of lipid membranes, complementing experimental techniques by providing information on structure and dynamics at high spatial and temporal resolution. Molecular visualization is the most powerful way to represent the results of molecular simulations, and can be used to illustrate complex transformations of lipid aggregates more easily and more effectively than written text. In this chapter, we review some basic aspects of simulation methodologies commonly employed in the study of lipid membranes and we describe a few examples of complex phenomena that have been recently investigated using molecular simulations. We then explain how molecular visualization provides added value to computational work in the field of biological membranes, and we conclude by listing a few molecular graphics packages widely used in scientific publications. PMID- 19784609 TI - Bioinformatics strategies for the analysis of lipids. AB - Owing to their importance in cellular physiology and pathology as well as to recent technological advances, the study of lipids has reemerged as a major research target. However, the structural diversity of lipids presents a number of analytical and informatics challenges. The field of lipidomics is a new postgenome discipline that aims to develop comprehensive methods for lipid analysis, necessitating concomitant developments in bioinformatics. The evolving research paradigm requires that new bioinformatics approaches accommodate genomic as well as high-level perspectives, integrating genome, protein, chemical and network information. The incorporation of lipidomics information into these data structures will provide mechanistic understanding of lipid functions and interactions in the context of cellular and organismal physiology. Accordingly, it is vital that specific bioinformatics methods be developed to analyze the wealth of lipid data being acquired. Herein, we present an overview of the Kyoto Encyclopedia of Genes and Genomes (KEGG) database and application of its tools to the analysis of lipid data. We also describe a series of software tools and databases (KGML-ED, VANTED, MZmine, and LipidDB) that can be used for the processing of lipidomics data and biochemical pathway reconstruction, an important next step in the development of the lipidomics field. PMID- 19784610 TI - The effect of lipid adjustment on the analysis of environmental contaminants and the outcome of human health risks. AB - Past literature on exposure to lipophilic agents such as organochlorines (OCs) is conflicting, posing challenges for the interpretation of their potential human health risks. Since blood is often used as a proxy for adipose tissue, it is necessary to model serum lipids when assessing health risks of OCs. Using a simulation study, we evaluated four statistical models (unadjusted, standardized, adjusted, and two-stage) for the analysis of polychlorinated biphenyls (PCBs) exposure, serum lipids, and health outcome risk. Eight candidate true causal scenarios, depicted by directed acyclic graphs, were used to illustrate the ramifications of misspecification of underlying assumptions when interpreting results. Biased results were produced when statistical models that deviated from the underlying causal assumptions were used with the lipid standardization method found to be particularly prone to bias. We concluded that investigators must consider biology, biological medium, laboratory measurement, and other underlying modeling assumptions when devising a statistical model for assessing health outcomes in relation to environmental exposures. PMID- 19784611 TI - Preventing autoimmunity by regulating regulatory T-cell induction. PMID- 19784613 TI - [Patients of immigrant origin in inpatient psychiatric facilities. Differences between first and second generation: nationwide questionnaire of the Psychiatry and Migration Working Group of the German Federal Conference of Psychiatric Hospital Directors]. AB - In a representative nationwide survey, the Psychiatry and Migration Working Group of the German Federal Conference of Psychiatric Hospital Directors examined the use of inpatient psychiatric and psychotherapeutic services in Germany by patients of immigrant origin. Questionnaires were sent to a total of 350 general hospital psychiatric clinics throughout Germany and 131 responded by the specified deadline (19 July 2006). In our study, persons of immigrant origin comprised 17% of patients in the responding facilities, which confirmed the results of the pilot study in 2004 of 17.4%. This indicates that the percentage of inpatient psychiatric services used by patients of immigrant origin is almost proportionate to these patients' percentage of the general population (18.6%, Microcensus 2005). In this main study patients of immigrant origin were significantly more likely to receive an ICD-10 F2 diagnosis, and it was precisely patients with this diagnosis who were observed to experience difficulties in communication with caregivers. With reference to the F2 diagnoses there were no noticeable differences between first generation of inpatients with migration history and second generation of inpatients with migration history. There were however more first generation of inpatients with migration history diagnosed with affective disorders whereas more second generation of inpatients with migration history were diagnosed with personality and behavioural disorders. Such differences were not found in the group of patients without immigrant origin. Whilst first generation of inpatients with migration history demonstrated higher educational levels, second generation of inpatients with migration history showed fewer linguistic difficulties. PMID- 19784614 TI - [Shaken baby syndrome]. AB - Shaken baby syndrome (SBS) describes the coincidence of subdural hematoma, retinal bleeding and, disadvantageous for the prognosis, diffuse brain damage caused by powerful shaking of the infant. The clinical symptoms include irritability, difficulty with drinking, somnolence, apathy, cerebral cramp attacks, apnoea, temperature regulation disorders and vomiting due to cranial pressure. Milder symptoms of SBS are often not diagnosed and the number of unregistered cases is probably much greater. The diagnosis of SBS is made through the typical symptom constellation, but the lack of retinal bleeding does not exclude the diagnosis. Normally the infants are held by the thorax or upper arms and shaken in a sagittal direction during which the head falls backwards and forwards and is stopped abruptly at each extreme position. The injurious mechanism is considered to be caused by rotational forces which force tissue layers in the brain against each other and also lead to rupture of bridging veins between the skull and the brain. The prognosis is poor and approximately 25% of infants die of SBS within days or weeks. Approximately 75% of survivors suffer from long term damage with physical handicaps, limitations in hearing, visual disturbances up to blindness and mental disorders or combinations of these conditions. Prevention is therefore the most important aspect. PMID- 19784612 TI - The predictability of evolution: glimpses into a post-Darwinian world. AB - The very success of the Darwinian explanation, in not only demonstrating evolution from multiple lines of evidence but also in providing some plausible explanations, paradoxically seems to have served to have stifled explorations into other areas of investigation. The fact of evolution is now almost universally yoked to the assumption that its outcomes are random, trends are little more than drunkard's walks, and most evolutionary products are masterpieces of improvisation and far from perfect. But is this correct? Let us consider some alternatives. Is there evidence that evolution could in anyway be predictable? Can we identify alternative forms of biological organizations and if so how viable are they? Why are some molecules so extraordinarily versatile, while others can be spoken of as "molecules of choice"? How fortuitous are the major transitions in the history of life? What implications might this have for the Tree of Life? To what extent is evolutionary diversification constrained or facilitated by prior states? Are evolutionary outcomes merely sufficient or alternatively are they highly efficient, even superb? Here I argue that in sharp contradistinction to an orthodox Darwinian view, not only is evolution much more predictable than generally assumed but also investigation of its organizational substrates, including those of sensory systems, which indicates that it is possible to identify a predictability to the process and outcomes of evolution. If correct, the implications may be of some significance, not least in separating the unexceptional Darwinian mechanisms from underlying organizational principles, which may indicate evolutionary inevitabilities. PMID- 19784615 TI - Development of public immortal mapping populations, molecular markers and linkage maps for rapid cycling Brassica rapa and B. oleracea. AB - Publicly available genomic tools help researchers integrate information and make new discoveries. In this paper, we describe the development of immortal mapping populations of rapid cycling, self-compatible lines, molecular markers, and linkage maps for Brassica rapa and B. oleracea and make the data and germplasm available to the Brassica research community. The B. rapa population consists of 160 recombinant inbred (RI) lines derived from the cross of highly inbred lines of rapid cycling and yellow sarson B. rapa. The B. oleracea population consists of 155 double haploid (DH) lines derived from an F1 cross between two DH lines, rapid cycling and broccoli. A total of 120 RFLP probes, 146 SSR markers, and one phenotypic trait (flower color) were used to construct genetic linkage maps for both species. The B. rapa map consists of 224 molecular markers distributed along 10 linkage groups (A1-A10) with a total distance of 1125.3 cM and a marker density of 5.7 cM/marker. The B. oleracea genetic map consists of 279 molecular markers and one phenotypic marker distributed along nine linkage groups (C1-C9) with a total distance of 891.4 cM and a marker density of 3.2 cM/marker. A syntenic analysis with Arabidopsis thaliana identified collinear genomic blocks that are in agreement with previous studies, reinforcing the idea of conserved chromosomal regions across the Brassicaceae. PMID- 19784617 TI - [Collagen hydroxyapatite (Healos) saturated with gentamicin or levofloxacin. In vitro antimicrobial effectiveness - a pilot study]. AB - BACKGROUND: The functions of synthetic bone graft substitutes include not only structural support to provide bone healing and osseous ingrowth but also the ability to serve as a local antibiotic delivery system to prevent or treat infections of the spine. MATERIAL AND METHODS: The impregnation and antibiotic efficiency of gentamicin and levofloxacin with Healos was investigated in vitro and compared with Healos without an antibiotic additive. These antibiotic-loaded bone graft substitutes were examined without dilution and with 10-fold and 100 fold dilution for activity against spondylodiscitis-causing bacteria on different agar plates using an agar diffusion method. RESULTS: All hydroxyapatite (HA)/collagen-saturated diluted antibiotics showed elliptical inhibition zones on the corresponding agar plates. For both antibiotics, there was a linear correlation between dilution and area of the inhibition zone. CONCLUSION: The analysis showed that the antimicrobial activity of HA/collagen-saturated antibiotics corresponded to the antimicrobial dilutions. These results should be further analyzed using in vivo studies to determine the remaining antibiotic efficiency after implantation of bone graft substitutes. PMID- 19784619 TI - [Exercise therapy in the treatment of chronic back pain. An integral part of interdisciplinary therapy]. AB - Chronic low back pain requires interdisciplinary and biopsychosocial treatment. Apart from the medical, psychological, and physiotherapeutic aspects of therapy, exercise therapy is an important component. Together with"work hardening," it represents the elements for reconditioning. The isolated effect is scientifically difficult to specify with the available data, but in most analytical studies, exercise therapy is an important component in an interdisciplinary setting. A nonspecific, diversified training program is superior to exercise solely of the trunk muscles. The primary tasks are to recover load capacity and diminish pain avoidance behaviors, with consideration of the principles of"functional restoration." Thorough information and cooperation with the patient, continuous motivation, ratio control, a systematic increase in load, and permanent feedback are necessary. Close communication within the team makes immediate accompanying interventions of other specialized groups possible. PMID- 19784618 TI - [Modular noncemented femoral stem system in revision total hip arthroplasty]. AB - BACKGROUND: In most cases, loosening of a prosthesis stem is accompanied by periprosthetic osteolysis. This article presents the short-term clinical and radiological results after revision of total hip arthroplasty (THA) with bone substance deficiencies using a modular noncemented femoral stem system (LINK MP). PATIENTS AND METHODS: Between March 2003 and November 2005, 91 LINK MP modular revision stems were implanted in 90 patients. Eighty-one patients (51 stem revisions, 24 revisions of stem and shell, and six reimplantations after a Girdlestone situation) were available for prospective clinical and radiological evaluation at an average follow-up time of 16.7+/-6.5 (6-36) months. The average patient age at revision was 67.2+/-10.5 (31-87) years. RESULTS: Bone defects in the proximal femur were evaluated according to the Paprosky classification and showed type 2 in five cases, type 3A in 73 cases, and type 3B in three cases. The Merle d'Aubigne score increased significantly from 10.4+/-2.3 (4-15) preoperatively to 14.7+/-2.2 (9-18) at the latest follow-up (p<0.001). Migration analysis in conventional radiographs revealed an average stem subsidence of 3.4 mm. Thirty-one intraoperative and postoperative complications were noted in 28 (34.5%) patients. CONCLUSION: After a short-term follow-up, the modular noncemented femoral stem system LINK MP was shown to be a reliable tool for revision of THA with bony defects of the proximal femur. Our results are comparable to those for other modular noncemented revision stems. As expected, complication rates were higher than with primary THA. PMID- 19784620 TI - [From GRIP to multimodal pain therapy. A concept asserts itself]. AB - Low back pain is still a big medical and social problem. During the last few decades a change of paradigm in treating non-specific low back pain has happened: physical activity and exercise therapy are now recommended as the first-line treatment in all relevant national and international guidelines. In chronic cases only biopsychosocial treatment concepts are successful, which have been introduced in Germany in 1990 in the form of the GRIP (Gottingen intensive low back program) for the first time. Meanwhile, this treatment has now been recommended by all evidence-based guidelines but we are still in the beginning of a full coverage care in Germany. PMID- 19784621 TI - The evolving role of dedicated weaning facilities in critical care. PMID- 19784622 TI - Patients' characterization, hospital course and clinical outcomes in five Italian respiratory intensive care units. AB - BACKGROUND: Respiratory intensive care units (RICU) dedicated to weaning could be suitable facilities for clinical management of "post-ICU" patients. METHODS: We retrospectively analyzed the time course of patients' characteristics, clinical outcomes and medical staff utilization in five Italian RICUs by comparing three periods of 5 consecutive years (from 1991 to 2005). RESULTS: A total of 3,106 patients (age 76 +/- 4 years; 72% males) were analyzed. The number of co morbidities per patient (from 1.8 to 3.0, p = 0.05) and the previous intensive care unit (ICU) stay (from 25 to 32 days, p = 0.002) increased over time. The doctor-to-patient ratio significantly decreased over time (from 1:3 to 1:5, p < 0.01), whereas the physiotherapist-to-patient ratio mildly increased (from 1:6 to 1:4.5, p < 0.05). The overall weaning success rate decreased (from 87 to 66%, p < 0.001), and the discharge destination changed (p < 0.001) over time; fewer patients were discharged to home (from 22 to 10%), and more patients to nursing home (from 3 to 6%), acute hospitals (from 6 to 10%) and rehabilitative units (from 70 to 75%). The mortality rate increased over time (from 9 to 15%). Significant correlations between the doctor-to-patient ratio and the rates of weaning success (r = 0.679, p = 0.005), home discharge (r = 0.722, p = 0.002) and the RICU length of stay (LOS) (r = -0.683, p = 0.005) were observed. CONCLUSIONS: The clinical outcomes of our units worsened over 15 years, likely as consequence of admitting more severely ill patients. The potential further negative influence of reduced medical staff availability on weaning success, home discharge and LOS warrants future prospective investigations. PMID- 19784623 TI - PCL reconstruction with the tibial inlay technique following intra-medullary nail fixation of an ipsilateral tibial shaft fracture: a treatment algorithm. AB - Our case report highlights the complexity of treating multi-ligament knee injuries in the setting of ipsilateral long bone trauma. We describe the use of the tibial inlay technique for PCL reconstruction in the setting of a tibial shaft fracture treated with an intramedullary nail. We also present a comprehensive treatment algorithm for the treatment of ligamentous knee injuries in the setting of long bone trauma. PMID- 19784624 TI - Avoiding intraoperative complications in open-wedge high tibial valgus osteotomy: technical advancement. AB - Open-wedge high tibial osteotomy for varus osteoarthritis of the knee is a successful treatment option, but is associated with potential intraoperative complications, jeopardizing outcome. We describe four technical hints avoiding complications as tibia plateau fracture, lateral hinge dislocation, over- and undercorrection, and unwanted increase of the posterior tibial slope and axial malrotation. The technique, which is primarily based on placing five Kirschner wires (one for the osteotomy direction, two for the external fixator, and two for rotational and slope control) is simple, reproducible, inexpensive, and readily available. PMID- 19784625 TI - The risk of notching the anterior femoral cortex with the use of navigation systems in total knee arthroplasty. AB - Use of navigation systems has recently been introduced in total knee arthroplasty (TKA) to achieve more reliable prosthetic alignment. In the sagittal plane, there are two important requirements for navigation systems: (1) perpendicular cut to the femoral mechanical axis and (2) prevention of notching of anterior femoral cortex. These two requirements, however, may conflict. The angles between the line of the anterior femoral cortex and four sagittal femoral mechanical axes for navigation systems using radiographs of the entire lower extremity, while standing were measured and compared. These four sagittal axes simulated on the radiographs in navigation systems were in extension relative to the line of the anterior femoral cortex in 40-85% of cases in male and 65-100% in elderly female. The present study showed that navigation systems have the potential risk for notching of anterior femoral cortex. PMID- 19784626 TI - Meniscal repair using the FasT-Fix device in patients with chronic meniscal lesions. AB - The aim of this prospective study was to evaluate meniscal suturing using the FasT-Fix device for chronic meniscal tears. This procedure was carried out on 25 patients between 2006 and 2007. Nineteen patients were male and the median age was 31 (14-47) years. The median waiting time to surgery was 27 (6-80) months and the median follow-up was 20 (14-29) months. Eleven patients (44%) required reconstruction of an associated anterior cruciate ligament (ACL) injury. 20 patients (80%) showed medial meniscus tears. All tears were located in the red zone or red-white zone. According to Barett's criteria, meniscal tear healing was achieved in 21 patients (84%). Lysholm and Tegner scale scores improved from 60 (47-77) preoperatively to 95 (58-100) postoperatively and from 3 (2-6) preoperatively to 6 (3-9) postoperatively, respectively. There were no neurovascular complications. Revision surgery was necessary in one patient, in whom a partial meniscectomy was performed. The results obtained suggest that chronic meniscal tears in the zones described can be healed. PMID- 19784627 TI - Ring meniscus mistaken for incomplete discoid meniscus: a case report and review of literature. AB - Ring meniscus is a known but rare abnormal variant of a meniscus. An incomplete discoid meniscus or an old bucket handle tear of a meniscus can be easily mistaken for a ring meniscus. In this case; during the first arthroscopy, the ring lateral meniscus was mistaken for an incomplete discoid lateral meniscus. On repeat arthroscopy, it was confirmed as ring lateral meniscus. PMID- 19784628 TI - Serial dilation versus extraction drilling in anterior cruciate ligament reconstruction: a biomechanical study. AB - The hamstring tendon graft has become increasingly popular in anterior cruciate ligament reconstruction because of low donor-site morbidity. However, the tibial fixation is considered difficult, mainly because of low tibial mineral bone density. Therefore, we tested whether preparation of the tibial tunnel with compaction by serial dilation provided a stronger anchorage of the graft-fixation device complex than does traditional extraction drilling of the tibial tunnel. In 20 bovine tibiae, the bone tunnels were created with either extraction drilling (group 1) or compaction by serial dilation (group 2). Twenty bovine digital extensor tendons were fixated in the bone tunnel with an Intrafix tibial fastener. The graft-fixation-device complexes were mounted in a hydraulic test machine. The fixation strength was evaluated after cyclic loading. The difference between the serial dilation group and the extraction drilling group ranged from a mean slippage of 0 mm at 70-220 N, to a mean slippage of 0.1 mm at 70-520 N. We found no significant difference in slippage of the graft-fixation-device complex after 1,600 cycles. This study failed to show a significant difference between compaction by serial dilation and extraction drilling of the tibia bone tunnel in anterior cruciate ligament reconstruction. PMID- 19784629 TI - Arthroscopic release of the posterior compartments in the treatment of extension deficit of knee. AB - Fibroarthrosis following knee injury or synovial disease is characterized by the presence of dense adhesions filling the entire joint cavity and the fibrotic involvement of periarticular structures. In this particular subset of knee stiffness, both the open and the arthroscopic treatment may fail not addressing all pathology. The aim of the present study was to evaluate the efficacy of an all-arthroscopic treatment for the flexion contractures addressing both the intra articular posterior adhesions and the fibrotic periarticular structures. From 2003 through 2007, 18 patients of the knee underwent on arthroscopic posterior arthrolysis with release of both gastrocnemius tendons using the trans-septal technique. The median interval between the index procedure and the arthrolysis was 15 (4-22) months. Eight patients had a previous arthroscopic arthrolysis, performed in other hospitals, and two patients had two arthroscopic procedures after the index procedure which failed to regain the extension deficit. The passive extension deficit averaged 34 degrees preoperatively (16 degrees-44 degrees). Six patients underwent a two-staged procedure: the first surgery addressed the presence of adhesions in the suprapatellar pouch and the medial and/or lateral gutters, to regain the flexion of the knee. At final follow-up, the passive extension deficit averaged 3 degrees (0 degree-5 degrees). In all patients, total knee arc of motion increased from 60 degrees (30 degrees-85 degrees) to 95 degrees (5 degrees-110 degrees). The trans-septal portal allows a safe approach of the posterior compartments and allows addressing pathology of both compartments and the release of gastrocnemius tendons. PMID- 19784630 TI - Cross-cultural comparison of patients undergoing ACL reconstruction in the United States and Norway. AB - Data from large prospectively collected anterior cruciate ligament (ACL) cohorts are being utilized to address clinical questions regarding ACL injury demographics and outcomes of ACL reconstruction. These data are affected by patient and injury factors as well as surgical factors associated with the site of data collection. The aim of this article is to compare primary ACL reconstruction data from patient cohorts in the United States and Norway, demonstrating the similarities and differences between two large cohorts. Primary ACL reconstruction data from the Multicenter Orthopaedic Outcomes Network (MOON) in the United States and the Norwegian National Knee Ligament Registry (NKLR) were compared to identify similarities and differences in patient demographics, activity at injury, preoperative Knee injury and Osteoarthritis Outcome Score (KOOS), time to reconstruction, intraarticular pathology, and graft choice. Seven hundred and thirteen patients from the MOON cohort were compared with 4,928 patients from the NKLR. A higher percentage of males (NKLR 57%, MOON 52%; P < 0.01) and increased patient age (NKLR 27 years, MOON 23 years; P?0.001) were noted in the NKLR population. The most common sports associated with injury in the MOON cohort were basketball (20%), soccer (17%), and American football (14%); while soccer (42%), handball (26%), and downhill skiing (10%) were most common in the NKLR. Median time to reconstruction was 2.4 (Interquartile range [IQR] 1.2 7.2) months in the MOON cohort and 7.9 (IQR 4.2-17.8) months in the NKLR cohort (P < 0.001). Both meniscal tears (MOON 65%, NKLR 48%; P < 0.001) and articular cartilage defects (MOON 46%, NKLR 26%; P < 0.001) were more common in the MOON cohort. Hamstring autografts (MOON 44%, NKLR 63%) and patellar tendon autografts (MOON 42%, NKLR 37%) were commonly utilized in both cohorts. Allografts were much more frequently utilized in the MOON cohort (MOON 13%, NKLR 0.04%; P < 0.001). Significant diversity in patient, injury, and surgical factors exist among large prospective cohorts collected in different locations. Surgeons should investigate and consider the characteristics of these cohorts when applying knowledge gleaned from these groups to their own patient populations. PMID- 19784632 TI - Fixed distraction is not necessary for anterior ankle arthroscopy. PMID- 19784631 TI - Effect of tunnel position for anatomic single-bundle ACL reconstruction on knee biomechanics in a porcine model. AB - Attention has been focused on the importance of anatomical tunnel placement in anterior cruciate ligament (ACL) reconstruction. The purpose of this study was to compare the effect of different tunnel positions for single-bundle (SB) ACL reconstruction on knee kinematics. Ten porcine knees were used for the following reconstruction techniques: three different anatomic SB [AM-AM (antero-medial), PL PL (postero-lateral), and MID-MID] (n = 5 for each group), conventional SB (PL high AM) (n = 5), and anatomic double-bundle (DB) (n = 5). Using a robotic/universal force-moment sensor testing system, an 89 N anterior load (simulated KT1000 test) at 30, 60, and 90 degrees of knee flexion and a combined internal rotation (4 N m) and valgus (7 N m) moment (simulated pivot-shift test) at 30 and 60 degrees were applied. Anterior tibial translation (ATT) (mm) and in situ forces (N) of reconstructed grafts were calculated. During simulated KT1000 test at 60 degrees of knee flexion, the PL-PL had significantly lower in situ force than the intact ACL (P < 0.01). In situ force of the MID-MID was higher than other SB reconstructions (at 30 degrees : 94.8 +/- 2.5 N; at 60 degrees : 85.2 +/- 5.3 N; and 90 degrees: 66.0 +/- 8.7 N). At 30 degrees of knee flexion, the PL-high AM had the lowest in situ values (67.1 +/- 19.3 N). At 60 and 90 degrees of knee flexion the PL-PL had the lowest in situ values (at 60 degrees : 60.8 +/- 19.9 N; 90 degrees : 38.4 +/- 19.2 N). The MID-MID and DB had no significant in situ force differences at 30 and 60 degrees of knee flexion. During simulated pivot-shift test at 60 degrees of knee flexion, the PL-PL and PL high AM reconstructions had a significant lower in situ force than the intact ACL (P < 0.01). During simulated KT1000 test at 30, 60, and 90 degrees of knee flexion, the PL-PL and PL-high AM had significantly lower ATT than the intact ACL (P < 0.01). During simulated KT1000 test at 60 and 90 degrees, the MID-MID, AM AM, and DB had significantly lower ATT than the ACL deficient knee (P < 0.01). During simulated KT1000 test at 90 degrees, every reconstructed knee had significantly higher ATT than the intact knee (P < 0.01). In conclusion, the MID MID position provided the best stability among all anatomic SB reconstructions and more closely restored normal knee kinematics. PMID- 19784633 TI - True submalleolar accessory ossicles causing impingement of the ankle. AB - True ossicle in the distal portion of the malleolus is only sporadically observed, and related disease has been rarely reported. We present two cases of atypical ankle impingement resulting from an ankle sprain. Plain radiographs revealed true submalleolar ossicles. Conservative treatment failed, and arthroscopy was performed. Instability of the ossicle and surrounding fibrotic soft tissue was evident; a gap between the ossicle and the tip of the malleolus seen during plantar flexion of the ankle disappeared in dorsal flexion, resulting in compression of the surrounding soft tissue. Arthroscopic excision of the accessory ossicle relieved the symptoms and enabled both patients to return to full preinjury activities. PMID- 19784634 TI - Giant cell tumor of the patella and its management using a patella, patellar tendon, and tibial tubercle allograft. AB - Patellar neoplasms are rare. We present a case of aggressive giant cell tumor of patella with extensive involvement of patella and patellar tendon. Its management with wide resection of tumor and reconstruction of extensor mechanism with patella bone tendon allograft is discussed. The patient has good results at 3 years follow-up. PMID- 19784637 TI - Isotopic analysis for degradation diagnosis of calcite matrix in mortar. AB - Mortar that was used in building as well as in conservation and restoration works of wall paintings have been analysed isotopically (delta(13)C and delta(18)O) in order to evaluate the setting environments and secondary processes, to distinguish the structural components used and to determine the exact causes that incurred the degradation phenomena. The material undergoes weathering and decay on a large proportion of its surface and in depth, due to the infiltration of water through the structural blocks. Mineralogical analysis indicated signs of sulphation and dissolution/recrystallisation processes taking place on the material, whereas stable isotopes provided information relative to the origin of the CO(2) and water during calcite formation and degradation processes. Isotopic change of the initial delta(13)C and delta(18)O in carbonate matrix was caused by alteration of the primary source of CO(2) and H(2)O in mortar over time, particularly by recrystallisation of calcite with porewater, evaporated or re condensed water, and CO(2) from various sources of atmospheric and biogenic origin. Human influence (surface treatment) and biological growth (e.g. fungus) are major exogenic processes which may alter delta(18)O and delta(13)C in lime mortar. PMID- 19784635 TI - Atrial Ca2+ signaling in atrial fibrillation as an antiarrhythmic drug target. AB - Atrial fibrillation (AF) is the most frequent arrhythmia and is associated with increased morbidity and mortality. Current drugs for AF treatment have moderate efficacy and increase the risk of life-threatening antiarrhythmias, making novel drug development crucial. Newer antiarrhythmic drugs like dronedarone and possibly vernakalant are efficient and may have less proarrhythmic potential. Emerging evidence suggests that abnormal intracellular Ca(2+) signaling is the key contributor to focal firing, substrate evolution, and atrial remodeling during AF. Accordingly, identification of the underlying atrial Ca(2+)-handling abnormalities is expected to discover novel mechanistically based therapeutic targets. This article reviews the molecular mechanisms of altered Ca(2+) signaling in AF and discusses the potential value of novel approaches targeting atrial Ca(2+)-handling abnormalities. PMID- 19784636 TI - Extended access to amphetamine self-administration increases impulsive choice in a delay discounting task in rats. AB - BACKGROUND: d-Amphetamine (AMPH) is a widely prescribed attention deficit hyperactivity disorder medication, but little is known about its effects on impulsive choice with escalated use. OBJECTIVE: The current study examined the effects of short and long access to AMPH self-administration on impulsive choice in a delay discounting task in which rats chose between a small immediate reward (one sucrose pellet immediately) and a larger delayed reward (three sucrose pellets after an adjusting delay). METHODS: Following choice stability in delay discounting, all rats received 15 1-h sessions of AMPH self-administration (0.1 or 0.03 mg/kg/infusion); self-administration sessions began 45 min after each delay discounting session. Rats were then either maintained on the short access (ShA) self-administration session or were switched to a long access (LgA) 6-h session for 21 days, followed by a 7-day withdrawal phase in which only the delay discounting task continued. RESULTS: LgA rats in the 0.03 mg/kg/infusion dose group escalated in total number of infusions across sessions, although rats in the 0.1 mg/kg/infusion dose group did not. LgA groups at both unit doses showed decreased mean adjusted delays across sessions compared to the ShA groups, indicating that long access to AMPH increases impulsive choice. During the AMPH withdrawal phase, LgA groups returned back to baseline mean adjusted delays, indicating that the effect on impulsive choice was reversible. CONCLUSION: These results show that extended AMPH self-administration produces a transient loss of inhibitory control, which may play a role in the escalating pattern of drug intake that characterizes the addiction process. PMID- 19784638 TI - Determination of low-level ink photoinitiator residues in packaged milk by solid phase extraction and LC-ESI/MS/MS using triple-quadrupole mass analyzer. AB - A confirmatory and quantitative method based on liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI/MS/MS) has been developed for simultaneous determination of seven photoinitiator residues: benzophenone, (1-hydroxycyclohexyl)phenylketone (Irgacure 184), isopropylthioxanthone (ITX), 2-ethylhexyl-(4-dimethylamino)benzoate (EHA or EHDAB), 2-methyl-1-[4-(methylthio)phenyl]-2-(4-morpholinyl)-1-propanone (Irgacure 907), (2,4,6-trimethylbenzoyl)diphenylphosphine oxide (TPO) and 2-benzyl-2 (dimethylamino)-1-(4-morpholinophenyl)-1-butanone (Irgacure 369) in packaged milk and related packaging materials. Residues of photoinitiators were extracted from milk using acetonitrile, and further enriched and purified on HLB solid-phase extraction cartridges prior to being analyzed by LC-ESI/MS/MS with selected reaction monitoring mode, while photoinitiators in packaging materials were extracted using the same solvent. Satisfactory recovery (from 80 to 111%), intra- and inter-day precision (below 12%), and low limits of quantification (from 0.1 to 5.0 microg kg(-1)) were evaluated from spiked samples at three concentration levels (5.0, 10.0 and 25.0 microg kg(-1) for Irgacure 184 and 2.5, 5.0 and 25.0 microg kg(-1) for others). These excellent validation data suggested the possibility of using the LC-ESI/MS/MS method for simultaneous determination of low-level photoinitiator residues migrating from printed food-packaging materials into milk. The method has been successfully applied to the analysis of real samples of different fat contents ranging from 8 to 30 g L(-1). The photoinitiator residues were revealed to be higher in milk with higher fat content and the most important contaminations were benzophenone and ITX in concentration ranges of 2.84-18.35 and 0.83-8.87 microg kg(-1), respectively. PMID- 19784639 TI - Is simple reaction time affected by visual illusions? AB - A number of studies have shown that while perceptual judgment is deceived by pictorial illusions, grasping and other kinds of motor behaviour are not. This is in keeping with the existence of two different cortical systems: a ventral stream subserving vision-for-perception and a dorsal stream subserving vision-for action. The former is sensitive to illusions, the latter is not. Given this dissociation of functions, one wonders whether simple visuomotor reaction time (RT) follows the ventral or the dorsal rule in perceiving illusory figures. Answering this question might contribute to a better understanding of the different functions of the two systems. We carried out two experiments, one with the Ponzo and the other with the Ebbinghaus-Titchener illusion and found that RT is sensitive to both illusions with faster responses to stimuli appearing illusorily bigger than the others. These results show that motor action is subserved by the ventral system when that action directly reports the presence or onset of a target rather than when that action requires a spatial adjustment that reflects the physical features of the target. PMID- 19784640 TI - CYP3A4*1G genetic polymorphism influences CYP3A activity and response to fentanyl in Chinese gynecologic patients. AB - PURPOSE: To investigate whether the CYP3A4*1G genetic polymorphism contributes to the variability in CYP3A activity and response to fentanyl. METHODS: One hundred and forty-three gynecologic patients who were scheduled to undergo abdominal total hysterectomy or myomectomy with general anesthesia were enrolled in this study. Intravenous fentanyl patient-controlled analgesia was provided postoperatively for satisfactory analgesia. The degrees of pain at rest during PCA treatment were assessed with visual analog scale. The fentanyl consumption and occurrence of any adverse effects were recorded in the first 24 h postoperatively. CYP3A activity was measured by plasma 1'-hydroxymidazolam-to midazolam ratio 1 h after intravenous administration of 0.1 mg/kg midazolam. CYP3A4*1G variant allele was genotyped using the polymerase chain reaction restriction fragment length polymorphism method. RESULTS: The frequency of the CYP3A4*1G variant allele was 0.269 in 143 Chinese gynecologic patients. The activity of CYP3A4 in patients homozygous for the *1G/*1G variant (0.34 +/- 0.15) was significantly lower than that in patients bearing the wild-type allele (*1/*1) (0.46 +/- 0.14) or in patients heterozygous for the *1/*1G variant (0.46 +/- 0.12) (P < 0.05). The patients with the CYP3A4*1G/*1G genotype needed less fentanyl (227.8 +/- 55.2 microg) to achieve pain control than patients carrying the CYP3A4*1/*1 (381.6 +/- 163.6 microg) and CYP3A4*1/*1G (371.9 +/- 180.1 microg) genotypes (P < 0.05) during the first 24 h postoperatively. There was no significant difference in incidence of adverse events among the different genotype groups (P > 0.05). CONCLUSIONS: CYP3A4*1G genetic polymorphism decreases CYP3A activity and fentanyl consumption for postoperative pain control. PMID- 19784641 TI - Sorbitol production from lactose by engineered Lactobacillus casei deficient in sorbitol transport system and mannitol-1-phosphate dehydrogenase. AB - Sorbitol is a sugar alcohol largely used in the food industry as a low-calorie sweetener. We have previously described a sorbitol-producing Lactobacillus casei (strain BL232) in which the gutF gene, encoding a sorbitol-6-phosphate dehydrogenase, was expressed from the lactose operon. Here, a complete deletion of the ldh1 gene, encoding the main L-lactate dehydrogenase, was performed in strain BL232. In a resting cell system with glucose, the new strain, named BL251, accumulated sorbitol in the medium that was rapidly metabolized after glucose exhaustion. Reutilization of produced sorbitol was prevented by deleting the gutB gene of the phosphoenolpyruvate: sorbitol phosphotransferase system (PTS(Gut)) in BL251. These results showed that the PTS(Gut) did not mediate sorbitol excretion from the cells, but it was responsible for uptake and reutilization of the synthesized sorbitol. A further improvement in sorbitol production was achieved by inactivation of the mtlD gene, encoding a mannitol-1-phosphate dehydrogenase. The new strain BL300 (lac::gutF Deltaldh1 DeltagutB mtlD) showed an increase in sorbitol production whereas no mannitol synthesis was detected, avoiding thus a polyol mixture. This strain was able to convert lactose, the main sugar from milk, into sorbitol, either using a resting cell system or in growing cells under pH control. A conversion rate of 9.4% of lactose into sorbitol was obtained using an optimized fed-batch system and whey permeate, a waste product of the dairy industry, as substrate. PMID- 19784643 TI - Effect of dietary monensin on the bacterial population structure of dairy cattle colonic contents. AB - To determine the effect of monensin, a carboxylic polyether ionophore antibiotic, on the bacterial population structure of dairy cattle colonic contents, we fed six lactating Holstein cows a diet containing monensin (600 mg day(-1)) or an identical diet without monensin. Fresh waste samples were taken directly from the animals once a month for 3 months and assayed for their bacterial population structure via 16S rRNA gene sequence analysis. In total 6,912 16S rRNA genes were examined, comprising 345 and 315 operational taxonomic units (OTUs) from the monensin fed and control animals, respectively. Coverage estimates of the OTUs identified were 87.6% for the monensin fed and 88.3% for the control colonic content derived library. Despite this high level of coverage, no significant difference was found between the libraries down to the genus level. Thus we concluded that although monensin is believed to increase milk production in dairy cattle by altering the bacterial population structure within the bovine gastrointestinal tract, we were unable to identify any significant difference in the bacterial population structure of the colonic contents of monensin fed vs. the control dairy cattle, down to the genus level. PMID- 19784642 TI - Characterization of two proline dipeptidases (prolidases) from the hyperthermophilic archaeon Pyrococcus horikoshii. AB - Prolidases hydrolyze the unique bond between X-Pro dipeptides and can also cleave the P-F and P-O bonds found in organophosphorus compounds, including the nerve agents, soman and sarin. The advantages of using hyperthermophilic enzymes in biodetoxification strategies are based on their enzyme stability and efficiency. Therefore, it is advantageous to examine new thermostable prolidases for potential use in biotechnological applications. Two thermostable prolidase homologs, PH1149 and PH0974, were identified in the genome of Pyrococcus horikoshii based on their sequences having conserved metal binding and catalytic amino acid residues that are present in other known prolidases, such as the previously characterized Pyrococcus furiosus prolidase. These P. horikoshii prolidases were expressed recombinantly in the Escherichia coli strain BL21 (lambdaDE3), and both were shown to function as proline dipeptidases. Biochemical characterization of these prolidases shows they have higher catalytic activities over a broader pH range, higher affinity for metal and are more stable compared to P. furiosus prolidase. This study has important implications for the potential use of these enzymes in biotechnological applications and provides further information on the functional traits of hyperthermophilic proteins, specifically metalloenzymes. PMID- 19784644 TI - Efficacy of ultrasonography-guided shoulder MR arthrography using a posterior approach. AB - AIM: Shoulder MR arthrography has an important role in the assessment of rotator cuff lesions, labral tears, glenohumeral ligaments, rotator interval lesions, and postoperative shoulder status. Injection in direct MR arthrography can be performed with palpation, fluoroscopy, ultrasonography (US), or MRI. Recently, the posterior approach is the preferred method due to the presence of fewer stabilizers, absence of important articular structures and less extravasation, has been advocated. Our aim was to assess the efficacy of US-guided MR arthrography via a posterior approach on the glenohumeral joint. MATERIALS AND METHODS: Thirty MR arthrographies were performed on 29 patients. Ultrasonography (Xario, Toshiba) examinations were conducted by a wide-band 5-12 Mhz linear array transducer set to muscle-skeleton. Diluted contrast medium (1 ml gadolinium chelate and 100 ml saline, approximately 15 ml) was delivered into the glenohumeral joint space from between the humeral head and posterior labrum with a 20-gauge spinal needle. MRI examination was conducted by a 1.5 T scanner. Fat saturated T1-weighted spin echo was applied on coronal, axial, and sagittal planes within the first 30 min after contrast material injection. RESULTS: One (3.3%) arthrography was not successful due to technical reasons associated with obesity. Contrast extravasation around the infraspinatus and teres minor muscles was depicted in twelve examinations. One (3.3%) patient developed vasovagal collapse. CONCLUSION: Ultrasonography-guided posterior approach is an easy, reliable, fast, and comfortable method in experienced hands. It may be an alternative for fluoroscopy-guided shoulder MR arthrography. PMID- 19784646 TI - Joint practice guidelines for radionuclide lymphoscintigraphy for sentinel node localization in oral/oropharyngeal squamous cell carcinoma. AB - Involvement of the cervical lymph nodes is the most important prognostic factor for patients with oral/oropharyngeal squamous cell carcinoma (OSCC), and the decision whether to electively treat patients with clinically negative necks remains a controversial topic. Sentinel node biopsy (SNB) provides a minimally invasive method of determining the disease status of the cervical node basin, without the need for a formal neck dissection. This technique potentially improves the accuracy of histological nodal staging and avoids over-treating three-quarters of this patient population, minimizing associated morbidity. The technique has been validated for patients with OSCC, and larger-scale studies are in progress to determine its exact role in the management of this patient population. This article was designed to outline the current best practice guidelines for the provision of SNB in patients with early-stage OSCC, and to provide a framework for the currently evolving recommendations for its use. These guidelines were prepared by a multidisciplinary surgical/nuclear medicine/pathology expert panel under the joint auspices of the European Association of Nuclear Medicine (EANM) Oncology Committee and the Sentinel European Node Trial Committee. PMID- 19784647 TI - Cementless total hip arthroplasty with ceramic-on-ceramic bearing in patients younger than 45 years with femoral-head osteonecrosis. AB - Despite improvements in the quality of alumina ceramics, osteolysis has been reported anecdotally after total hip arthroplasty (THA) with use of a contemporary alumina-on-alumina ceramic bearing. The purpose of this study was to evaluate the clinical and radiographic outcomes of THA using alumina-on-alumina ceramic bearing and to determine osteolysis using radiographs and computed tomographic (CT) scans in young patients. Consecutive primary cementless THA using alumina-on-alumina ceramic bearing were performed in 64 patients (93 hips) who were younger than 45 years of age with femoral-head osteonecrosis. There were 55 men (84 hips) and nine women (nine hips). Average age was 38.2 (range 24-45) years. Average follow-up was 11.1 (range 10-13) years. Preoperative Harris Hip Score was 52.9 (range 22-58) points, which improved to 96 (range 85-100) points at the final follow-up examination. Two of 93 hips (2%) had clicking or squeaking sound. No hip had revision or aseptic loosening. Radiographs and CT scans demonstrated that no acetabular or femoral osteolysis was detected in any hip at the latest follow-up. Contemporary cementless acetabular and femoral components with alumina-on-alumina ceramic bearing couples function well with no osteolysis at a ten year minimum and average of 11.1-year follow-up in this series of young patients with femoral-head osteonecrosis. PMID- 19784649 TI - Risk factors in cutout of sliding hip screw in intertrochanteric fractures: an evaluation of 937 patients. AB - The aim of this study was designed to assess the risk factors of lag-screw cutout in the treatment of intertrochanteric fracture with a dynamic hip screw (DHS). From 2003 to 2007, 1,150 patients who had acute unilateral intertrochanteric fractures of the femur were enrolled to the study. All fractures were managed by closed reduction and internal fixation with 135 degrees DHS devices. Patient demographics, fracture patterns, reduction and fixation and perioperative course parameters were all recorded. The follow-up period was 38 months on average (range 16-60 months). Finally, 937 patients were available for evaluation of final results in which we focused on lag-screw cutout. Excluding complications not related to screw position, 64 patients (6.8%) with screw cutout were encountered, and the remaining 873 patients had uneventful union, with the average union time of 17.5 weeks (range15-24 weeks). Upon analysis with logistic regression, the tip-apex distance (TAD) was shown to be the most important predictive factor for cutout, followed by screw position, fracture pattern, reduction and patient age. In order to decrease the risk of lag-screw cutout, it is important to ensure good fracture reduction and to place the lag screw in either the middle/middle or inferior/middle position with appropriate TAD. PMID- 19784650 TI - Reduction of serum free light chains predict renal recovery. PMID- 19784651 TI - Levels of angiogenic factors in patients with multiple myeloma correlate with treatment response. AB - Angiogenesis plays a significant role in the pathogenesis of multiple myeloma (MM). We have measured concentrations of angiogenesis activators, including vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and hepatocyte growth factor (HGF), and inhibitors, including endostatin, thrombospondin-1 (TSP-1), and angiostatin in the peripheral and bone marrow blood of MM patients at diagnosis and after high-dose chemotherapy. We have analyzed 96 patients with secretory MM. Serial measurements of angiogenesis factors/inhibitors were analyzed in the plasma by subgroups based on the best treatment response. Concentrations of angiogenic factors were determined in the peripheral blood and bone marrow plasma. There were significant decreases of VEGF and HGF levels and a significant increase in TSP-1 concentrations in the bone marrow plasma of patients who achieved complete or very good partial response in contrast to those who had partial or no response. VEGF and HGF levels decrease but those of TSP-1 increase after successful treatment for MM, indicating a reduction in the rate of angiogenesis. PMID- 19784652 TI - [Sialolipoma of the parotid gland]. AB - Sialolipoma is a relatively new and rare variant of lipoma of the salivary glands characterized by the combination of classical lipoma morphology with non neoplastic ductulo-acinary salivary tissue components. Including the presented case, 27 sialolipomas, 14 of them localized in the parotid gland, have been published. We describe the clinical, radiological and pathomorphological characteristics of a parotid sialolipoma in a 43-year-old man. PMID- 19784653 TI - [Warthin tumor with carcinoma: malignant transformation or metastasis?]. AB - We present the unusual case of a cytologically diagnosed Warthin tumor (WT) of long standing with sudden enlargement und subsequent resection. Histologically, the diagnosis of WT was confirmed, but the tumor additionally showed diffuse infiltrates of an adenocarcinoma undergoing unrestrained growth. Warthin tumor with malignant transformation was suspected and radiological staging examinations were conducted. PET scans detected a metastasizing carcinoma of the breast, morphologically identical to the WT infiltrates. Care should always be taken when the diagnosis of malignant WT is made to exclude metastatic disease. PMID- 19784654 TI - [Molecular markers in salivary gland tumors: their use in diagnostic and prognostic workup]. AB - The molecular genetic background of salivary gland neoplasms has not been characterized in detail to date. However, interesting target genes which could be used as prognostic and diagnostic molecular biomarkers have already been identified, e.g. CRTC1-MAML2 in mucoepidermoid carcinoma, or PLAG1 and HMGA2 in pleomorphic adenoma. In particular, CRTC1-MAML2 has shown strong diagnostic and prognostic potential in recent years. One of the major advantages of molecular tumor markers is that valid results are obtained on minute cell and/or tissue samples. Due to high-throughput techniques like comparative genome hybridization (CGH), micro- or gene profiling array detection of new marker genes can be expected in the future. This is also true for the most frequent malignant salivary gland tumors after the mucoepidermoid carcinoma, i.e. adenoid cystic carcinomas and acinic cell carcinomas. PMID- 19784655 TI - Effect of aerobic exercise training on oxygen uptake and kinetics in patients with fibromyalgia. AB - The aim of this study is to investigate relation between cardiopulmonary performance and muscular microcirculation in patients with fibromyalgia syndrome (FMS). Twenty-one female sedentary patients who were diagnosed as FMS, and 15 sedentary females were enrolled in to the study. All participants underwent a modified Bruce multistage maximal treadmill protocol with metabolic measurements and Near-Infrared Spectroscopy measurements. Exercise sessions were performed 3 times a week for 8 weeks. The results of the study suggest that cardiopulmonary system in charge of delivering oxygen to whole body and muscular microcirculation may have dysfunction in patients with FMS. PMID- 19784656 TI - Third ventriculostomy in a single pediatric surgical unit. AB - PURPOSE: Endoscopic third ventriculostomy (ETV) is a successful method of treatment for obstructive hydrocephalus that has become popular over the last 20 years. The purpose of this paper is to study the outcome of infants with obstructive hydrocephalus treated by ETV by a single surgeon and to evaluate the safety, reliability, and efficacy of this treatment. METHODS: All data were collected retrospectively. Between July 1999 and June 2005, 14 children underwent an ETV. In one child, a second ETV was performed. The age of the eight female and six male patients at the time of ETV ranged from less than 1 month up to 13 years and 11 months. The indication for an ETV was an obstructive hydrocephalus. Median follow-up period was 5 years and 9 months. The need of a further operation after ETV was defined as a failure of ETV. RESULTS: In six patients, the first ETV was successful. In the remaining eight patients, there was a need for further treatment (ventriculoperitoneal shunt). Although the follow-up shunt failed in one patient, he was successfully treated by a second ETV. CONCLUSION: Our study suggests that ETV can be successfully done in a small pediatric unit, but with a lower success rate because of small caseload, and therefore, lower experience and routine of the surgeon. Therefore, we propose a centralization of patients to obtain a higher number of cases. We confirm that ETV is a safe, reliable, and efficient method with a better outcome in children than infants. PMID- 19784657 TI - Incidence of spinal abnormalities in patients with spastic diplegia 17 to 26 years after selective dorsal rhizotomy. AB - INTRODUCTION: The aim of this study was to evaluate the mechanical status of the spine in patients with spastic diplegia 17-26 years after selective dorsal rhizotomy (SDR). METHODS: We compared original radiographic reports from our earlier short-term follow-up study with current X-rays. In addition, we obtained magnetic resonance images (MRI) of the spine and additional information regarding back pain and clinical assessments. RESULTS: Thirty patients (17 males and 13 females; median age 26.8 years) participated in the current study, with median follow-up times of 4.0 and 21.4 years. Comparison of the X-ray results showed respectively: scoliosis 0% and 57%; kyphosis 0% and 7%; lordosis 21% and 40%; spondylolysis 18% and 37%; and spondylolisthesis grade I occurred in one patient. The only statistically significant difference was found for scoliosis (p < 0.01). The majority had Cobb angles <30 degrees with only two patients with curves of 35 degrees. MRI scans showed spinal stenosis in 27%, black discs in 10%, and disc protrusion in 3%. Daily back pain was reported in 17%, while 23% reported "moderate disability" as a result of back and leg pain. No patient to date has required any surgical intervention on the spine. CONCLUSIONS: Except for spondylolisthesis, spinal deformities did appear to progress with time. However, this increase was not marked, and the development of relatively mild scoliosis was the only statistically significant increase. This group of patients requires continued follow-up. Further studies are required to ascertain the natural history of spinal deformity in adults with spastic diplegia who have not had SDR. PMID- 19784658 TI - Surgery in sitting position in patient with ventriculoperitoneal shunt in situ may be hazardous! PMID- 19784659 TI - Stereotactic biopsy for brainstem tumors in pediatric patients. AB - OBJECTIVE: Our aim is to describe clinical and paraclinical features in patients who underwent stereotactic-guided biopsy for brainstem tumors. METHODS: A study of case series was made by reviewing the records of patients who underwent stereotactic biopsy for brainstem tumors. RESULTS: Stereotactic biopsy for brainstem tumors was performed (between 2000 and 2008) in 20 children (11 girls, and 9 boys), mean age 7.95 +/- 3.12 years at the time of diagnosis. The mean time from onset of symptoms to diagnosis was 6.59 +/- 13.58 months (0.50-60 months). The most frequent symptoms and signs at onset were related to disturbance of cerebellar function and cranial nerve nuclei. Location was pontomesencephalic (35%), pontine (30%), pontomedullar (25%), and in the whole brainstem (10%). The most common type of image was intrinsic-diffused (55%). The histopathology was anaplastic astrocytoma (30%), followed by fibrillary and pilocytic types (25% each), low-grade astrocytoma (5%), high-grade astrocytoma (5%), and normal tissue (10%). Mild complications were observed in only two cases. CONCLUSIONS: Stereotactic biopsy done for clarifiying a diagnostic imaging in brainstem tumors is important in obtaining a definitive diagnosis with a low rate of complications. PMID- 19784660 TI - Effects of preoperative chemoradiotherapy on anal sphincter functions and quality of life in rectal cancer patients. AB - PURPOSE: Deterioration of anorectal function after long-course preoperative chemoradiotherapy combined with surgery for rectal cancer is poorly defined. We conducted a prospective study to evaluate the acute and long term effects of preoperative chemoradiotherapy on anorectal function and quality of life of the patients. METHODS: There were 26 patients in surgery group and 31 patients in preoperative chemoradiotherapy group. Anorectal function and quality of life of the patients were assessed by anorectal manometry, incontinence score, quality of life questionnaire. RESULTS: Significant lower resting pressures in both groups and lower maximal squeeze pressures in the preoperative chemoradiotherapy group were observed after postsurgical evaluations compared with the paired pretreatment ones. In the surgery group, both the Wexner continence score, FIQL score, and the rectoscopy score were comparable before and after surgery, whereas significant worsening in the Wexner score was observed in the preoperative chemoradiotherapy group postoperatively (P < 0.01). Significant reduction in anal canal resting pressures and squeeze pressures, Wexner score, and FIQL score were observed immediately after the completion of preoperative chemoradiotherapy. Significant lower maximal squeeze pressures and worsening of the Wexner scores were observed in the preoperative chemoradiotherapy group compared to the surgery group during the postoperative assessments (P < 0.05 and P < 0.01, respectively). CONCLUSIONS: Both total mesorectal excision and preoperative chemoradiotherapy may adversely affect the anorectal function. Careful selection of the patients who will benefit from neoadjuvant therapy and identifying the patients with a high risk of developing functional problems may help to improve functional outcomes for the treatment of rectal cancer. PMID- 19784661 TI - Cementless total hip arthroplasty for the management of tuberculosis coxitis. AB - INTRODUCTION: Tuberculosis arthritis of the hip is a crippling disease and there is need for an effective and acceptable treatment for the hips with bone destruction. The aim of this report was to evaluate the efficacy of the diagnostic method for hip tuberculosis and clinical results of the patients to clarify the question of whether a total hip arthroplasty (THA) should be attempted on a patient with a current or previous infection. MATERIALS AND METHODS: Nine patients with active tuberculosis of the hip, treated by cementless THA, were analyzed retrospectively. The mean age of the patients at diagnosis was 43.4 years (range 22-72 years). Laboratory tests of all the patients revealed high erthrocyte sedimentation rates (ESR) and C-reactive proteins. Plain radiographs showed bone destruction with joint space narrowing in all patients. Magnetic resonance imaging (MRI) scans showed fluid within the joint in five patients. Two patients had associated pulmonary tuberculosis. To confirm the clinico-radiological diagnosis, an open biopsy was performed for histopathological examinations of all the hips. Tuberculosis of the hips was treated with primary cementless THA, followed by postoperative antituberculous medication for 1 year. The inflamed soft tissues and the destroyed bones were completely resected and curetted out at the time of operation. RESULTS: At the final evaluation, the mean Harris Hip Score improved to 94.8 (range 90-98; P = 0.003). ESR became normal, less than 15 mm/h, with a mean time of 4 months (range 2-9 months). The C-reactive protein was normal, less than 0.8 mg/dl, after a mean time of 3 months (range 1-7 months). With an average follow-up of 5.6 years (range 2-8 years), no reactivation of tuberculosis infection was found in each patient. All of the femoral stems and acetabular cups were radiologically stable and demonstrated signs of bone ingrowth at the final follow-up. All histopathologic examinations showed granulomatous lesions including epitheloid histiocytes surrounded by lymphocytes. CONCLUSIONS: Cementless THA can be safely performed in advanced tuberculosis of the hip for providing symptomatic relief and functional improvement of the hips. Complete curettage and resection of the infected tissue and postoperative antituberculous chemotherapy with a minimum of 1-year duration are very important in preventing reactivations. PMID- 19784663 TI - Pathologic diagnosis in head and neck practice: how fast is fast enough? PMID- 19784662 TI - Upregulation of chemokine (C-C motif) ligand 20 in adult epidermal keratinocytes in direct current electric fields. AB - Electric fields (EFs) of around 100 mV/mm are present in normal healing wounds and induce the directional migration of epithelial cells. Reepithelialization during wound healing thus may be controlled in part by this electrical signal. In this study, the early transcriptional response of human epidermal keratinocytes to EFs is examined using microarrays. Increased expression of various chemokines, interleukins, and other inflammatory response genes indicates that EFs stimulate keratinocyte activation and immune stimulatory activity. Gene expression activity further suggests that interleukin 1 is either released or activated in EFs. Expression of the chemokine CCL20 steadily increases at 100 mV/mm over time until around 8 h after exposure. This chemokine is also expressed at field strengths of 300 mV/mm-above the level of endogenous wound fields. The early effects of EFs on epithelial gene expression activity identified in these studies suggest the importance of naturally occurring EFs both in repair mechanisms and for the possibility of controlling these responses therapeutically. PMID- 19784664 TI - Histopathologic and functional effects of facial nerve following electrical stimulation. AB - The aim of the study is to investigate the functional and histopathologic changes in facial nerve due to the application of various violent and numerous electrical stimuli to the facial nerve. The study was carried out with Wistar rats weighing between 200 and 300 g. The facial nerves of the subjects were located and stimulated with electrical stimulator. Then five groups were created with 18 subjects in each group: Group 1, 1 milliampere (mA) electrical stimulus applied; Group 2, 2 mA electrical stimulus applied; Group 3, 3 mA electrical stimulus applied; Group 4, 4 mA electrical stimulus applied; Group 5, 5 mA electrical stimulus applied. All groups were divided into three sub-groups, each consisting of six subjects. The facial nerves of the subjects in first sub-group were stimulated 10 times, in second sub-group were stimulated 20 times and those in third sub-group were stimulated 30 times. The functions of the facial nerves were evaluated on first day, first week and first month, respectively. The facial nerves with branches were dissected from the surrounding tissues carefully. These specimens were investigated by light microscope about axonal degeneration, macrovacuolization and vascular congestion. Loss of facial functions was not observed in the subjects during follow-up process. There was no significant difference between groups regarding axonal degeneration, macrovacuolization and vascular congestion (P > 0.05). While less axonal degeneration was observed in group which was stimulated 10 times, more axonal degeneration was observed in groups which were stimulated 20 and 30 times (P < 0.05). The axonal degeneration, macrovacuolization and vascular congestion were observed more in 1-day groups (P < 0.05). Consequently, lesser violence and lesser number of electrical stimulus application to the facial nerve appears to be an important criterion for not damaging the facial nerve in patients in whom stimulators have been used. PMID- 19784665 TI - Altered expression of P2X3 in vagal and spinal afferents following esophagitis in rats. AB - Purinergic P2X(3) receptors are predominantly expressed in small diameter primary afferent neurons and activation of these receptors by adenosine triphosphate is reported to play an important role in nociceptive signaling. The objective of this study was to investigate the expression of P2X(3) receptors in spinal and vagal sensory neurons and esophageal tissues following esophagitis in rats. Two groups of rats were used including 7 days fundus-ligated (7D-ligated) esophagitis and sham-operated controls. Esophagitis was produced by ligating the fundus and partial obstruction of pylorus that initiated reflux of gastric contents. The sham-operated rats underwent midline incision without surgical manipulation of the stomach. Expressions of P2X(3) receptors in thoracic dorsal root ganglia (DRGs), nodose ganglia (NGs), and esophageal tissues were evaluated by RT-PCR, western blot and immunohistochemistry. Esophageal neurons were identified by retrograde transport of Fast Blue from the esophagus. There were no significant differences in P2X(3) mRNA expressions in DRGs (T1-T3) and NGs between 7D-ligated and sham-operated rats. However, there was an upregulation of P2X(3) mRNA in DRGs (T6-T12) and in the esophageal muscle. At protein level, P2X(3) exhibited significant upregulation both in DRGs and in NGs of rats having chronic esophagitis. Immunohistochemical analysis exhibited a significant increase in P2X(3) and TRPV1 co-expression in DRGs and NGs in 7D-ligated rats compared to sham-operated rats. The present findings suggest that chronic esophagitis results in upregulation of P2X(3) and its co-localization with TRPV1 receptor in vagal and spinal afferents. Changes in P2X(3) expression in vagal and spinal sensory neurons may contribute to esophageal hypersensitivity following acid reflux induced esophagitis. PMID- 19784667 TI - The firing statistics of Poisson neuron models driven by slow stimuli. AB - The coding properties of cells with different types of receptive fields have been studied for decades. ON-type neurons fire in response to positive fluctuations of the time-dependent stimulus, whereas OFF cells are driven by negative stimulus segments. Biphasic cells, in turn, are selective to up/down or down/up stimulus upstrokes. In this article, we explore the way in which different receptive fields affect the firing statistics of Poisson neuron models, when driven with slow stimuli. We find analytical expressions for the time-dependent peri-stimulus time histogram and the inter-spike interval distribution in terms of the incoming signal. Our results enable us to understand the interplay between the intrinsic and extrinsic factors that regulate the statistics of spike trains. The former depend on biophysical neural properties, whereas the latter hinge on the temporal characteristics of the input signal. PMID- 19784666 TI - Acute effects of passive stretching on the electromechanical delay and evoked twitch properties. AB - The purpose of this study was to investigate the acute effects of passive stretching on the electromechanical delay (EMD), peak twitch force (PTF), rate of force development (RFD), and compound muscle action potential (M-wave) amplitude during evoked twitches of the plantar flexor muscles. 16 men (mean age +/- SD = 21.1 +/- 1.7 years; body mass = 75.9 +/- 11.4 kg; height = 176.5 +/- 8.6 cm) participated in this study. A single, square-wave, supramaximal transcutaneous electrical stimulus was delivered to the tibial nerve before and after passive stretching. The stretching protocol consisted of nine repetitions of passive assisted stretching designed to stretch the calf muscles. Each repetition was held for 135 s separated by 5-10 s of rest. Dependent-samples t tests (pre- vs. post-stretching) were used to analyze the EMD, PTF, RFD, and M-wave amplitude data. There were significant changes (P < or = 0.05) from pre- to post-stretching for EMD (mean +/- SE = 4.84 +/- 0.31 and 6.22 +/- 0.34 ms), PTF (17.2 +/- 1.3 and 15.6 +/- 1.5), and RFD (320.5 +/- 24.5 and 279.8 +/- 28.2), however, the M-wave amplitude did not change (P > 0.05). These findings suggested that passively stretching the calf muscles affected the mechanical aspects of force production from the onset of the electrically evoked twitch to the peak twitch force. These results may help to explain the mechanisms underlying the stretching-induced force deficit that have been reported as either "mechanical" or "electrical" in origin. PMID- 19784668 TI - Object orientation in two dimensional grasp with friction towards minimization of gripping power. AB - This article reports an analysis of two dimensional grasp where a convex rigid object is grasped by two contact points with friction. The purpose is to find the object orientation that minimizes the norm of the contact force vector, each element of which is composed from the normal force and friction force at each contact point. The formulation of this problem requires some equality or inequality conditions. In the analysis, the solution of the equality conditions is parameterized at first. Based on the fact that the norm of the contact force vector becomes monotonic increasing function of this parameter, the minimal parameter values are calculated by means of the piecewise analysis. Using the relation between the friction coefficient and the apex angle of the friction cone effectively, the following result is obtained: the norm of the contact force, i.e, gripping power becomes locally minimal at the object orientation where the intersection point of the upper sides of two friction cones is located in opposite direction of the gravity from the center of mass of the grasped object. PMID- 19784669 TI - A phase dynamic model of systematic error in simple copying tasks. AB - A crucial insight into handwriting dynamics is embodied in the idea that stable, robust handwriting movements correspond to attractors of an oscillatory dynamical system. We present a phase dynamic model of visuomotor performance involved in copying simple oriented lines. Our studies on human performance in copying oriented lines revealed a systematic error pattern in orientation of drawn lines, i.e., lines at certain orientation are drawn more accurately than at other values. Furthermore, human subjects exhibit "flips" in direction at certain characteristic orientations. It is argued that this flipping behavior has its roots in the fact that copying process is inherently ambiguous-a line of given orientation may be drawn in two different (mutually opposite) directions producing the same end result. The systematic error patterns seen in human copying performance is probably a result of the attempt of our visuomotor system to cope with this ambiguity and still be able to produce accurate copying movements. The proposed nonlinear phase-dynamic model explains the experimentally observed copying error pattern and also the flipping behavior with remarkable accuracy. PMID- 19784670 TI - Floral visitation and reproductive traits of Stamenoid petals, a naturally occurring floral homeotic variant of Capsella bursa-pastoris (Brassicaceae). AB - Homeotic changes played a considerable role during the evolution of flowers, but how floral homeotic mutants initially survive in nature has remained enigmatic. To better understand the evolutionary potential of floral homeotic mutants, we established as a model system Stamenoid petals (Spe), a natural variant of Capsella bursa-pastoris (Brassicaceae). In the flowers of Spe plants, petals are transformed into stamens, whereas all other floral organs are unaffected. In contrast with most other homeotic mutants, the Spe variant occurs in relatively stable populations in the wild. In order to determine how the profound change in floral architecture influences plant performance in the wild, we performed common garden experiments running over 3 years. Here, we show that Spe and wild-type plants attract the same assemblage of floral visitors: mainly hoverflies, wild bees and thrips. However, floral visitation is about twice as frequent in wild type plants as in Spe plants. Nevertheless, the numbers of seeds per fruit were about the same in both variants. Wild-type plants produced more flowers, fruits and seeds per plant than Spe plants, whereas the germination capacity of Spe seeds was higher than that of the wild-type. Determination of volatile composition revealed monoterpenes and 3,4-dimethylbenzaldehyde, which were detected only in wild-type flowers, presumably because they are produced only by petals. Our data indicate that the similar fitness of Spe and wild-type C. bursa pastoris in the field results from complex compensation between plant architecture and germination capacity. In contrast, flower structure and floral visitation are only of minor importance, possibly because C. bursa-pastoris is mainly self-pollinating. PMID- 19784671 TI - Acute Trypanosoma cruzi experimental infection induced renal ischemic/reperfusion lesion in mice. AB - Experimental acute infection with Trypanosoma cruzi in mice promotes an intense myocarditis and other systemic changes. However, the network of pathophysiological disorders and renal injury caused by the infection has not been elucidated. Our previous results with a murine model observed a discrete acute myocarditis and high mortality with significant inflammatory kidney injury with T. cruzi infection. The aim of this study was to investigate the mechanisms of kidney injury caused by the parasite in mice during the experimental acute phase. Results employing BALB/c mice infected with T. cruzi of Y strain showed renal injury on the 6th day postinfection (dpi) caused by a transitory decrease of renal blood flow. Acute kidney injury (AKI) was also observed similar to the model of ischemia/reperfusion lesion in these infected mice. The injury was not related to the presence (or multiplication) of parasites. Only rare nests were microscopically detected, and the presence of scattered parasites in renal parenchyma was seen on the 15th dpi. Thus, it was observed that during the acute phase of the disease, AKI in infected mice is linked to early cardiovascular effects, including heart failure, caused by striking inflammatory lesions in the myocardium, which lead to the high mortality rate of animals. PMID- 19784672 TI - Criteria for the differentiation between young and old Onchocerca volvulus filariae. AB - Drugs exist that show long-lasting inhibition of embryogenesis and microfilaria production or macrofilaricidal activity against Onchocerca volvulus. Therefore, the patients have to be followed-up for several years. Clinical drug trials have to be performed in areas with ongoing transmission to assess the efficacy on younger worms. In addition, future vaccine trials may also require demonstrating efficacy against establishment of new worms. For the evaluation of the efficacy, it is necessary to differentiate between older worms, which were exposed to the drug, and younger worms newly acquired after drug treatment or vaccination. Here, we describe criteria for the differentiation between young and old filariae based on histological studies of worms with a known age from travellers, or from children, or patients living in areas with interrupted transmission in Burkina Faso, Ghana or Uganda. Older worms were larger and presented degenerated tissues. Gomori's iron stain showed that the worms accumulated more iron with increasing age, first in the gut and later in other organs. Using an antibody against O. volvulus lysosomal aspartic protease, the gut of young worms was stained only weakly; whereas, it was stronger labelled in older worms, accompanied by additional staining of hypodermis and epithelia. Using morphological and immunohistological criteria, it was possible to differentiate young (1-3 years old) from older females and to identify young males. PMID- 19784673 TI - Uncovering transcriptional regulation of glycerol metabolism in Aspergilli through genome-wide gene expression data analysis. AB - Glycerol is catabolized by a wide range of microorganisms including Aspergillus species. To identify the transcriptional regulation of glycerol metabolism in Aspergillus, we analyzed data from triplicate batch fermentations of three different Aspergilli (Aspergillus nidulans, Aspergillus oryzae and Aspergillus niger) with glucose and glycerol as carbon sources. Protein comparisons and cross analysis with gene expression data of all three species resulted in the identification of 88 genes having a conserved response across the three Aspergilli. A promoter analysis of the up-regulated genes led to the identification of a conserved binding site for a putative regulator to be 5' TGCGGGGA-3', a binding site that is similar to the binding site for Adr1 in yeast and humans. We show that this Adr1 consensus binding sequence was over represented on promoter regions of several genes in A. nidulans, A. oryzae and A. niger. Our transcriptome analysis indicated that genes involved in ethanol, glycerol, fatty acid, amino acids and formate utilization are putatively regulated by Adr1 in Aspergilli as in Saccharomyces cerevisiae and this transcription factor therefore is likely to be cross-species conserved among Saccharomyces and distant Ascomycetes. Transcriptome data were further used to evaluate the high osmolarity glycerol pathway. All the components of this pathway present in yeast have orthologues in the three Aspergilli studied and its gene expression response suggested that this pathway functions as in S. cerevisiae. Our study clearly demonstrates that cross-species evolutionary comparisons among filamentous fungi, using comparative genomics and transcriptomics, are a powerful tool for uncovering regulatory systems. PMID- 19784674 TI - Polluted environment and cold weather induce laying gaps in great tit and pied flycatcher. AB - We studied the occurrence of laying gaps in free-living populations of the pied flycatcher, Ficedula hypoleuca, and the great tit, Parus major, in a pollution gradient of a copper smelter in south-west Finland. Laying gaps were 2.8 times more common in F. hypoleuca than in P. major. The probability of laying gaps was highest in the heavily polluted zone and lowest in the unpolluted zone for both bird species. Cold weather at the time of laying increased the number of laying gaps in both species, but in P. major this effect was most pronounced in the heavily polluted environment. In the most heavily polluted environment the laying gaps were more likely to occur near the beginning of the laying sequence in both species. The laying gap probability increased with increasing laying date in P. major but not in F. hypoleuca. We suggest that the increased number of laying gaps in the polluted environment results from limited Ca availability and the interference of heavy metals with Ca metabolism in laying females. PMID- 19784675 TI - Differential effects of nutrient-limited primary production on primary, secondary or tertiary consumers. AB - Nutritional imbalances between predator and prey are the rule rather than the exception at the lower end of food webs. We investigated the role of different grazers in the propagation of nutritionally imbalanced primary production by using the same primary producers in a three-trophic-level food chain and a four trophic-level food chain experimental setup. The three-trophic-level food chain consisted of a classic single-cell primary producer (Rhodomonas salina), a metazoan grazer (the copepod Acartia tonsa) and a top predator (the jellyfish Gonionemus vertens), while we added a protozoan grazer (Oxyrrhis marina) as primary consumer to the food chain to establish the four-trophic-level food chain. This setup allowed us to investigate how nutrient-limitation effects change from one trophic level to another, and to investigate the performance of two components of our experimental food chains in different trophic positions. Stoichiometry and fatty acid profiles of the algae showed significant differences between the nutrient-depleted [no N and no P addition (-P), respectively] and the nutrient-replete (f/2) treatments. The differences in stoichiometry could be traced when O. marina was the first consumer. Copepods feeding on these flagellates were not affected by the nutritional imbalance of their prey in their stoichiometry, their respiration rates nor in their developmental rates. In contrast, when copepods were the primary consumer, those reared on the -P algae showed significantly higher respiration rates along with significantly lower developmental rates. In neither of our two experimental food chains did the signals from the base of the food chains travel up to jelly fish, our top predator. PMID- 19784676 TI - Assessing cancer-related fatigue: the psychometric properties of the Revised Piper Fatigue Scale in Italian cancer inpatients. AB - GOALS OF WORK: Fatigue is the most distressing untreated symptom for many cancer patients, and its measurement is of great topical interest. The aim of the present study was to assess psychometric properties of Revised Piper Fatigue Scale (PFS-r) in Italian cancer patients. PATIENTS AND METHODS: From January to June 2007, 115 histologically confirmed cancer inpatients (age >or=18 years; Eastern Cooperative Oncology Group [ECOG] performance status or=0.97) for all subscales. Exploratory factor analysis revealed three dimensions instead of four in the US questionnaire; 68.2% of the common variance was explained. Internal consistency was satisfactory (Cronbach's alpha >0.80) as was the test retest reliability. Good correlations between PFS-r subscale and POMS subscales confirmed criterion validity. CONCLUSIONS: The psychometric properties of the Italian version of PFS-r, as evaluated in cancer patients ongoing chemotherapy, were satisfactory. We suggest the possible implementation of the Italian PFS-r in the assessment of fatigue particularly when it has been more fully validated on a wider range of cancer patients. PMID- 19784677 TI - Percutaneous posterior-lateral lumbar interbody fusion for degenerative disc disease using a B-Twin expandable spinal spacer. AB - Degenerative disc disease (DDD) causes gradual intervertebral space collapse, concurrent discogenic or facet-induced pain, and possible compression radiculopathy. A new minimal invasion procedure of percutaneous posterior-lateral lumbar interbody fusion (PPLIF) using a B-Twin stand-alone expandable spinal spacer (ESS) was designed to treat this disease and evaluated by follow-up more than 1 year. 12 cases with chronic low back pain and compressive radiculopathy due to DDD refractory were selected to conservative treatment. Under fluoroscopy in the posterior-lateral position, a K-wire was advanced into the intervertebral space and a dilator and working cannula were introduced into the disc space step by step. Discectomy and endplate scratching were performed through the cannula using pituitary forceps and endplate curettage. An ESS was inserted into the intervertebral space by a B-Twin expandable spinal delivery system after some bone graft chips implanted into the disc space. The ongoing study includes intraoperative difficulties, complications, radiologic evidence of fusion and clinical outcome as scored by pre- and postoperative questionnaires pertaining to pain intensity and degree of disability. The 12 procedures of lumbar interbody fusion using stand-alone expandable spinal system through percutaneous approach were successful. Radiologic study demonstrated fusion in a total of 11 cases and only 1 exception after more than 1 year visiting. The values of Visual Analog Scale (VAS) on movement and Oswestry Disability Index (ODI) dropped by more than 80 and 67.4%, respectively. Disk space heights averaging 9.0 mm before procedure were increased to 11.5 mm 1 month (a significant difference compared with preprocedure, P < 0.01) after surgery and stabilized at 10.8 mm upon final follow up (a significant difference compared with preprocedure, P < 0.01). The results demonstrated that the percutaneous approach for posterior-lateral lumbar interbody fusion using expandable spinal system is a valuable micro-invasion method for the DDD patients and can achieve the same outcome as with other methods. PMID- 19784678 TI - A possible crystal volume factor in the impact sensitivities of some energetic compounds. AB - We have investigated the possibility of a link between the impact sensitivities of energetic compounds and the space available to their molecules in their crystal lattices. As a measure of this space, we use Delta V=V(eff)-V(0.002), where V(eff) is the effective molecular volume obtained from the crystal density and V(0.002) is that enclosed by the 0.002 au contour of the molecule's gas phase electronic density, determined computationally. When experimental impact sensitivity was plotted against Delta V for a series of 20 compounds, the nitramines formed a separate group showing little dependence upon Delta V. Their impact sensitivities correlate well with an anomalous imbalance in the electrostatic potentials on their molecular surfaces, which is characteristic of energetic compounds in general. The imbalance is symptomatic of the weakness of the N-NO(2) bonds, caused by depletion of electronic charge. The impact sensitivities of non-nitramines, on the other hand, depend much more strongly upon Delta V, and can be quite effectively related to it if an electrostatically based correction term is included. PMID- 19784679 TI - Confinement effects on glass transition temperature, transition breadth, and expansivity: comparison of ellipsometry and fluorescence measurements on polystyrene films. AB - Using ellipsometry, we characterized the nanoconfinement effect on the glass transition temperature (T (g)of supported polystyrene (PS) films employing two methods: the intersection of fits to the temperature (Tdependences of rubbery- and glassy-state thicknesses, and the transition mid-point between rubbery- and glassy-state expansivities. The results demonstrate a strong effect of thickness: T(g) (bulk) - T(g)(23 nm) = 10 degrees C. The T -range needed for accurate measurement increases significantly with decreasing thickness, an effect that arises from the broadening of the transition with confinement and a region below T (g) where expansivity slowly decreases with decreasing T . As determined from expansivities, the T (g) breadth triples in going from bulk films to a 21-nm thick film; this broadening of the transition may be a more dramatic effect of confinement than the T (g) reduction itself. In contrast, there is little effect of confinement on the rubbery- and glassy-state expansivities. Compared with ellipsometry, T (g) 's from fluorescence agree well in bulk films but yield lower values in nanoconfined films: T (g)(bulk) - T (g)(23 nm) = 15( degrees ) C via fluorescence. This small difference in the T (g) confinement effect reflects differences in how fluorescence and ellipsometry report "average T (g) " with confinement. With decreasing nanoscale thickness, fluorescence may slightly overweight the contribution of the free-surface layer while ellipsometry may evenly weight or underweight its contribution. PMID- 19784680 TI - Adhesive contact of rough surfaces: comparison between numerical calculations and analytical theories. AB - The authors have employed a numerical procedure to analyse the adhesive contact between a soft elastic layer and a rough rigid substrate. The solution to the problem, which belongs to the class of the free boundary problems, is obtained by calculating Green's function which links the pressure distribution to the normal displacements at the interface. The problem is then formulated in the form of a Fredholm integral equation of the first kind with a logarithmic kernel. The boundaries of the contact area are calculated by requiring the energy of the system to be stationary. This methodology has been employed to study the adhesive contact between an elastic semi-infinite solid and a randomly rough rigid profile with a self-affine fractal geometry. We show that, even in the presence of adhesion, the true contact area still linearly depends on the applied load. The numerical results are then critically compared with the predictions of an extended version of Persson's contact mechanics theory, which is able to handle anisotropic surfaces, as 1D interfaces. It is shown that, for any given load, Persson's theory underestimates the contact area by about 50% in comparison with our numerical calculations. We find that this discrepancy is larger than for 2D rough surfaces in the case of adhesionless contact. We argue that this increased difference might be explained, at least partially, by considering that Persson's theory is a mean-field theory in spirit, so it should work better for 2D rough surfaces rather than for 1D rough surfaces. We also observe that the predicted value of separation is in agreement with our numerical results as well as the exponents of the power spectral density of the contact pressure distribution and of the elastic displacement of the solid. Therefore, we conclude that Persson's theory captures almost exactly the main qualitative behaviour of the rough contact phenomena. PMID- 19784681 TI - Isolation and characterization of potent antifungal strains of the Streptomyces violaceusniger clade active against Candida albicans. AB - Streptomyces strains were isolated from a sagebrush rhizosphere soil sample on humic acid vitamin (HV) agar and water yeast extract (WYE) agar supplemented with 1.5% (w/w) phenol as a selective medium. Acidic, neutral and alkaline pH conditions were also used in the isolation procedures. The phenol treatment reduced the numbers of both actinomycetes and non-actinomycetes on plates under all three pH conditions. From phenol-amended HV and WYE agar, 16 strains were isolated in pure culture; 14 from the HV agar and two from the WYE agar. All the isolates were tested for their antifungal activities against Pythium ultimum P8 and five yeast strains, including two antifungal drug-resistant Candida albicans strains. HV isolates that showed broad-spectrum antifungal antibiotic activities were all found to be members of the Streptomyces violaceusniger clade, while those that did not were non-clade members. The phenol treatment was not selective for S. violaceusniger clade members. Therefore, we tested the spores of both S. violaceusniger clade and non-clade members using two biocides, phenol and hydrogen peroxide, as selection agents. Spores of non-clade members, such as S. coelicolor M145 and S. lividans TK 21, survived these two biocides just as well as S. violaceusniger clade members. Thus, in our hands, biocide resistance was not S. violaceusniger clade specific as previously reported. However, isolates showing broad-spectrum antifungal and antiyeast activity were all members of the clade. We conclude that screening of isolates for broad-spectrum antifungal/antiyeast activity is the preferred method of isolating S. violaceusniger clade strains rather than biocide-based selection. Phylogenetic analysis of the phenol-resistant isolates revealed that the HV isolates that exhibited broad-spectrum antifungal antibiotic activity were all clustered and closely related to the S. violaceusniger clade, while the isolates that did not exhibit antifungal antibiotic activity were all non-clade members. PMID- 19784682 TI - Upper limb muscle forces during a simple reach-to-grasp movement: a comparative study. AB - Muscle force knowledge during reaching is an important research field and tools development for measuring those forces is a challenging task, especially for clinical routines. The purpose of this study was, during a simple reach-to-grasp movement, to compare forces estimation from a Hill-type model and from the EMG-to Force Processing (EFP) method. Ten healthy male volunteers were tested. Surface EMG signals were recorded from deltoid scapular, deltoid clavicular, triceps brachii, and biceps brachii. Ten repeated measures of right upper limb kinematics had been recorded. Three reaching distances were tested: 20, 30, and 40 cm. Muscle activations were calculated and forces were estimated by the two methods. Correlations and low RMS error found between the two methods indicate that EFP is a good way to estimate muscle forces for this kind of movement. This knowledge is essential in order to integrate these forces in reaching models developed nowadays in robotic, rehabilitation, and ergonomics field of research. PMID- 19784683 TI - Long-chain ceramide produced in response to N-hexanoylsphingosine does not induce apoptosis in CHP-100 cells. AB - It has been previously reported that treatment of CHP-100 human neuroepithelioma cells with N-hexanoylsphingosine (C6-Cer) induces intracellular accumulation of long-chain ceramide (LC-Cer) and apoptosis. Herein, we investigated the existence of any causal relationship between the two phenomena. We report that C6-Cer evoked LC-Cer accumulation is potently attenuated by the ceramide synthase inhibitor fumonisin B1; however, fumonisin B1 neither affects the apoptotic response evoked by C6-Cer administration, nor is toxic by itself to CHP-100 cells. Different to fumonisin B1, the serine-palmitoyltransferase inhibitor L: cycloserine does not attenuate C6-Cer-evoked LC-Cer accumulation, thus suggesting that LC-Cer is produced via the sphingosine salvage pathway. Consistently, CHP 100 cells accumulate LC-Cer in response to sphingosine administration; however, their viability is not affected. The above-reported results indicate that, in the cell system investigated, C6-Cer, but not LC-Cer, is involved in apoptosis induction. As this finding is discussed in the light of the evidence that C6-Cer induced apoptosis associates with cytochrome c release into the cytosol and caspase-9 activation, thus calling for an involvement of the mitochondrial pathway, it also lends support to the notion that caution must be exercised when investigating the biological effects of endogenous ceramide by use of exogenously administered short-chain analogues. PMID- 19784684 TI - Contrasting effects of n-3 and n-6 fatty acids on cyclooxygenase-2 in model systems for arthritis. AB - Cyclooxygenase-2 (COX-2) is intimately involved in symptoms of arthritis while dietary n-3 polyunsaturated fatty acids (PUFA) are thought to be beneficial. In these experiments, using both bovine and human in vitro systems that mimic features of arthritis, we show that the n-3 PUFA eicosapentaenoic acid (EPA) is able to reduce mRNA and protein levels of COX-2. Activity, as assessed through prostaglandin E(2) formation, was also reduced in a dose-dependent manner. These effects of EPA contrasted noticeably with the n-6 PUFA, arachidonic acid. The data provide direct evidence for a molecular mechanism by which dietary n-3 PUFA, such as EPA, can reduce inflammation and, hence, associated symptoms in arthritis. PMID- 19784685 TI - The results of downgrading moderate and severe slipped capital femoral epiphysis by an early Imhauser femur osteotomy. AB - PURPOSE: Patients with moderate and severe slipped capital femoral epiphysis (SCFE) develop osteoarthritis earlier in life in association with mechanical impingement. METHODS: To correct deformity and diminish impingement, we performed epiphysiodesis combined with an Imhauser intertrochanteric osteotomy (ITO) in moderate and severe slipped capital femoral epiphysis. We downgraded the angle of the head relative to the acetabulum into an angle corresponding to a mild slip or even an anatomical position. Our hypothesis is that the avoidance of anterior impingement at an early stage can prevent the development of osteoarthritis. RESULTS: The results of 28 patients (32 hips) were evaluated. Outcome parameters were SF-36, Harris Hip Score, range of motion, Kellgren-Lawrence score, chondrolysis and avascular necrosis. After a median follow-up of 8 (range 2-25) years, the group was clinically, functionally and socially performing well. Radiologically, there was no sign of chondrolysis or avascular necrosis, and more than 80% of the patients did not show any signs of osteoarthritis. CONCLUSIONS: Based on these results, we conclude that a one-stage Imhauser ITO combined with epiphysiodesis performed on patients with moderate and severe SFCE gives satisfactory results. PMID- 19784687 TI - [To give or not to give, that is not the question here! Longterm administration of opioids for non-tumor pain (LONTS)]. PMID- 19784692 TI - Follow-up chest X-ray in patients with Kawasaki disease: the significance and clinical application of coronary artery macro-calcification. AB - Kawasaki disease (KD) related coronary artery (CA) aneurysms may lead to significant and potentially insidious progressive stenosis. It is also well recognized that CA scarring leads to heavy calcification in KD. We intended to correlate the angiographic anomalies associated with coronary calcifications in KD and to evaluate the chronology and the detection rate of KD-related CA calcification on plain chest X-ray. Between 1992 and 2006, 65 CA angiograms were performed in 50 KD patients. Chest fluoroscopies and angiograms were retrospectively reviewed. When angiograms were abnormal, chest X-rays were reviewed by two radiologists blinded to the results of angiograms. CA lesions were identified in 18/50 (36%) patients, including isolated CA aneurysms in 10. All 8 patients who had CA aneurysms associated with stenosis and/or occlusion had CA calcification identifiable on chest X-ray. All significant stenotic lesions were concomitant with calcification. Plain chest X-ray, a simple inexpensive low dose mean, easily identifies KD patients at risk for serious CA stenosis when specific search for CA calcification is pursued. When detected, a closer tracking of coronary artery patency is warranted via other imaging techniques, usually expensive, invasive, requiring sedation in children or exposing to high radiation. PMID- 19784693 TI - Successful staged neonatal repair of tetralogy of Fallot with long-segment hypoplasia of the aorta. AB - We describe an extremely rare combination of tetralogy of Fallot (TOF), right sided cervical aortic arch with long-segment hypoplasia, and other vascular anomalies. A two-stage surgical approach included aortic arch reconstruction followed by right ventricular muscle bundle division and ventricular septal defect closure a few weeks later. The initial clinical presentation, perioperative course, and imaging studies are presented along with a review of the relevant literature. This is the first report of successful neonatal repair of TOF with long-segment hypoplasia of the aorta. PMID- 19784694 TI - Aortic root replacement with re-implantation technique in an infant with Loeys Dietz syndrome and a bicuspid aortic valve. AB - We report on an infant with a Loeys-Dietz Syndrome and a bicuspid aortic valve, who presented with rapid dilatation of the aortic root. We performed a valve sparing aortic root replacement with re-implantation technique using a Dacron graft with pseudo-sinuses (Gelweave Valsalva conduit, Vascutek Terumo, Glasgow, Scotland). PMID- 19784695 TI - Vitamin D receptor (VDR) polymorphisms in the cardiac variant of Gaucher disease. AB - Type 3c Gaucher disease, an ultra-rare cardiac variant with progressive calcification of aortic and/or mitral heart valves, is generally fatal in teenage hood. Vitamin D Receptors (VDR) are involved in calcium transport. The purpose of this pilot was to ascertain if VDR polymorphisms (BsmI, TaqI, ApaI, and FokI) are associated with type 3c Gaucher disease. There was a higher incidence of wild type alleles of all polymorphisms. Although a very small series, results seem to confirm preponderance of the BsmI B allele in type 3c as in other aortic calcifications, but also implicate linkage between ApaI and BsmI genotypes. PMID- 19784696 TI - Progressive left coronary stenosis after rotablator ablation appreciated by Doppler echocardiography. PMID- 19784697 TI - Peritoneal carcinomatosis from ovarian cancer: the role of CT and [18F]FDG PET/CT. AB - PURPOSE: The diagnosis of peritoneal carcinomatosis secondary to ovarian cancer is a real challenge in the cancer imaging field. In this retrospective study, we evaluate the accuracy of Single Detector Computed Tomography (SDCT), Multi Detector Computed Tomography (MDCT), and Positron Emission Tomography-Computed Tomography with F18-fluorodeoxyglucose ([18F]FDG-PET/CT) in the diagnosis of peritoneal seeding and we evaluate the possible applications of MDCT to predict the complete surgical removal of the peritoneal deposits. METHODS AND MATERIALS: A total of 228 scans (91 SDCT, 89 MDCT, and 48 [18F]FDG-PET/CT) of patients with peritoneal carcinomatosis secondary to ovarian cancer proved at laparoscopy and confirmed by histopathology were retrospectively reviewed by two independent groups of Radiologists and Nuclear Medicine Physicians for the evaluation of ascites, peritoneal nodules, and omental cake signs. RESULTS: MDCT showed 81% of true positives, SDCT 72.5%, and [18F]FDG-PET/CT 77%. False negatives were 19% for MDCT, 27.5% for SDCT, and 23% for [18F]FDG-PET/CT. CONCLUSION: From our results, we concluded that MDCT is the technique of choice in the diagnosis of peritoneal seeding, while [18F]FDG-PET/CT, though showing similar accuracy, remains the most accurate technique for monitoring therapeutic response and disease recurrence. MDCT could play an important role due to its ability to predict the possibility of complete surgical removal of disease thus influencing the treatment plan aimed to improve quality of life. PMID- 19784698 TI - Modeling the driving forces of the land use and land cover changes along the upper Yangtze river of China. AB - Induced by high population density, rapid but uneven economic growth, and historic resource exploitation, China's upper Yangtze basin has witnessed remarkable changes in land use and cover, which have resulted in severe environmental consequences, such as flooding, soil erosion, and habitat loss. This article examines the causes of land use and land cover change (LUCC) along the Jinsha River, one primary section of the upper Yangtze, aiming to better understand the human impact on the dynamic LUCC process and to support necessary policy actions for more sustainable land use and environmental protection. Using a repeated cross-sectional dataset covering 31 counties over four time periods from 1975 to 2000, we develop a fractional logit model to empirically determine the effects of socioeconomic and institutional factors on changes for cropland, forestland, and grassland. It is shown that population expansion, food self sufficiency, and better market access drove cropland expansion, while industrial development contributed significantly to the increase of forestland and the decrease of other land uses. Similarly, stable tenure had a positive effect on forest protection. Moreover, past land use decisions were less significantly influenced by distorted market signals. We believe that these and other findings carry important policy implications. PMID- 19784699 TI - Viremia and the magnitude of the immune response upon infection of green monkeys with dengue virus type 2 are strain-dependent. AB - Testing in non-human primates is a generally accepted necessary step preceding the evaluation of dengue vaccine candidates in humans. A reduction of viremia in these animals after virus challenge is generally used as an indicator of vaccine efficacy. In this work, we compared the infectivity of three strains of dengue virus type 2 in a non-human primate model of dengue infection, with the aim of selecting a virus for vaccine protection studies. As a result, strain SB8553 produced the longest duration of viremia, with a mean of 3 days/animal. In addition, it induced the highest antiviral and neutralizing antibody titers. These results support the use of strain SB8553 in challenge assays in this model and demonstrate that infection of green monkeys with dengue virus type 2 is dependent on the strain of virus used. PMID- 19784700 TI - Gender effects on airway closure in normal subjects. AB - The present study was designed to examine age and gender differences with respect to the duration of laryngeal closure, the onset of laryngeal closure in relation to the first cricopharyngeal opening, and the duration of cricopharyngeal opening for six different groups: normal younger men and women (22-29 years), normal middle-aged men and women (45-53 years), and normal older men and women (81-94 years) (10 subjects in each group for a total of 60 subjects). Data were collected by means of videofluoroscopic studies. During swallows of liquid barium, results indicated that normal older subjects had longer cricopharyngeal opening than younger subjects (P = 0.044). Results also revealed that the mean duration of laryngeal closure was significantly longer in women than in men (P = 0.013). The onset of laryngeal closure was significantly earlier in women than in men (P = 0.006). Also, bolus volume effects were observed for both the duration of laryngeal closure (P < 0.0001) and cricopharyngeal opening (P < 0.0001). During liquid barium swallows there was a linear increase in both the duration of laryngeal closure and cricopharyngeal opening. PMID- 19784701 TI - Primary tuberculosis involving epiglottis: a rare case report. AB - The case of a 29-year-old patient with active laryngeal tuberculosis predominantly involving the epiglottis, without pulmonary disease, is presented. The predominant symptoms are dysphagia, odynophagia, and hoarseness. Laryngeal carcinoma, which shares almost the same symptoms and signs, should be ruled out immediately. Laryngeal tuberculosis is discussed with a brief literature review. PMID- 19784702 TI - [11C]Gefitinib ([11c]Iressa): radiosynthesis, in vitro uptake, and in vivo imaging of intact murine fibrosarcoma. AB - OBJECTIVE: Gefitinib (N-(3-chloro-4-fluorophenyl)-7-methoxy-6-[3-(morpholin-4 yl)propoxy]quinazolin-4-amine, Iressa) is an approved anticancer drug. In this study, we labeled gefitinib with carbon-11 and evaluated [(11)C]gefitinib to explore its specific binding in intact fibrosarcoma (NFSa)-bearing mice. METHODS: [(11)C]Gefitinib was synthesized by the reaction of desmethyl precursor (1) with [(11)C]CH(3)I. In vitro uptake of [(11)C]gefitinib into NFSa, human-A431 epidermoid carcinoma, and Jurkat T cells was determined. Positron emission tomography (PET) imaging using [(11)C]gefitinib was performed for NFSa-bearing mice. RESULTS: [(11)C]Gefitinib accumulated into NFSa cells with 2.1 uptake ratio (UR)/mg protein in cells. Addition of nonradioactive gefitinib decreased uptake in a concentration-dependent manner. [(11)C]Gefitinib also had high uptake (2.6 UR/mg protein) into epidermal growth factor receptor/tyrosine kinase (EGFR/TK) rich A431 cells but low uptake (0.2 UR/mg protein) into EGFR/TK-poor Jurkat cells. In vivo distribution study on NFSa-bearing mice by the dissection method revealed that [(11)C]gefitinib specifically accumulated into the tumor. The ratio of radioactivity in tumors to that in blood and muscle as two comparative regions increased from 0.4 to 6.0 and from 0.6 to 5.0 during this experiment (0-60 min), respectively. PET for NFSa-bearing mice produced a clear tumor image, although high radioactivity was distributed throughout the body. Treatment with nonradioactive gefitinib (100 mg/kg) decreased uptake in the tumor. In vivo metabolite analysis demonstrated that [(11)C]gefitinib was stable in the tumor, liver, kidney, and blood. CONCLUSION: These results demonstrated the promising potential of [(11)C]gefitinib to serve as a PET ligand for in vivo imaging of NFSa-bearing mice. PMID- 19784703 TI - Complementary and alternative medicine in rheumatoid arthritis: no longer the last resort! AB - Complementary and alternative medicine (CAM) has become popular with consumers worldwide and accounts for significant private and public health expenditures. According to earlier reports, the prevalence of CAM use by rheumatoid arthritis (RA) patients in the United States is anywhere between 28% and 90%. Extensive use among RA patients and the limited knowledge among physicians had confirmed the need to evaluate the increasing prevalence of various CAM modalities. The primary aim of this study was to identify the incidence of CAM usage among our RA patients. Additionally, we aimed to correlate patient demographics and disease characteristics with the use of specific CAM modalities. An analysis of data extracted from our institution's RA longitudinal registry was performed. The patients were asked to select from a list the modalities they were currently using and/or had used in the past. Of patients, 75.9% reported current or past use of CAM with >10% using 12 different modalities. Nutritional supplements and touch therapies were the most widely used overall, with mind-body therapies more prevalent among younger patients. CAM users were found to have more extra articular manifestations and fewer comorbidities than non-CAM users. The use of CAM among RA patients is widespread with a broad spectrum of CAM modalities being used in early stages of the disease, frequently in conjunction with mainstream conventional treatments. Therefore, CAM may no longer be considered the rheumatoid patients' last resort. PMID- 19784704 TI - A prospective study on the initial results of a low profile ulna shortening osteotomy system. AB - Extra-articular ulna shortening osteotomy, in principle, is an accepted treatment option for symptomatic degenerative and traumatic triangular fibrocartilage complex (TFCC) tears. Despite the benefits of this surgical approach, potential disadvantages include risk of nonunion, soft tissue irritation, and the need for future hardware removal. A recently introduced low profile ulna shortening system was designed to decrease these potential complications. A single-surgeon prospective study was performed to evaluate this system. Ten consecutive patients undergoing ulna shortening for ulnar-sided wrist pain compatible with TFCC pathology participated in the study. Subjective, objective, and radiographic assessments were performed preoperatively and up to 24 weeks postoperatively. Based on visual analog scale (VOS) ratings (0 to 10), pain scores significantly improved (p < 0.05) and average patient satisfaction was 8.7. DASH and PRWE scores improved at three month follow-up (p < 0.05). Osteotomy healing time averaged 10.3 weeks, and there were no nonunions. Average discomfort associated with palpation of the plate at final follow-up was 3.3 (using VOS), and one patient requested removal of the hardware. In this short-term follow-up study, the assessed ulna shortening system appears effective and, in general, well tolerated. PMID- 19784705 TI - When relatives and friends ask physicians for medical advice: ethical, legal, and practical considerations. AB - Physicians often are asked for advice about medical matters by relatives and friends. These range from requests for simple information to requests for medical opinion and judgment and more substantial involvement by the physician. I comment on the motivations and expectations of the requester and the physician, and the legal, ethical, and practical considerations related to such requests. I recommend: (1) Be clear about the expectations of the requester and yourself, including whether you are being asked for simple factual information, your medical judgment and opinion, or more substantial involvement in the situation. (2) Treat your interactions with relatives or friends with the same professional expertise and judgment as you would any patient. (3) Be aware that a physical examination and especially charging a fee strengthen the establishment of a legal relationship with the requester as your patient. (4) Respect the requester's autonomy and confidentiality and conform to HIPAA requirements where applicable. (5) Be aware of the potential conflict between your roles as a relative or friend and as a physician. PMID- 19784706 TI - Gastroesophageal junction leak with serious sepsis after gastric bypass: successful treatment with endoscopy-assisted intraluminal esophageal drainage and self-expandable covered metal stent. AB - We present a case of gastroesophageal junction leak after gastric bypass with serious sepsis and hemodynamic instability. Minimally invasive treatment was performed in two stages: initial sepsis control by lavage and endoscopy-assisted laparoscopic placement of an intraluminal esophageal drainage tube through the leak orifice; this was followed by definitive leak treatment with a self expandable covered metal stent after achieving hemodynamic stability. Patient evolution was satisfactory without the need for open surgery. PMID- 19784707 TI - Tribute to Dr. Marshall Urist: musculoskeletal growth factors: editorial comment. PMID- 19784708 TI - Venous air embolism during deep brain stimulation surgery in an awake child. PMID- 19784709 TI - Intubation using lidocaine, low dose rocuronium, remifentanil and propofol--what should we know? PMID- 19784710 TI - The role of zinc in the modulation of neuronal proliferation and apoptosis. AB - Although a requirement of zinc (Zn) for normal brain development is well documented, the extent to which Zn can modulate neuronal proliferation and apoptosis is not clear. Thus, we investigated the role of Zn in the regulation of these two critical events. A low Zn availability leads to decreased cell viability in human neuroblastoma IMR-32 cells and primary cultures of rat cortical neurons. This occurs in part as a consequence of decreased cell proliferation and increased apoptotic cell death. In IMR-32 cells, Zn deficiency led to the inhibition of cell proliferation through the arrest of the cell cycle at the G0/G1 phase. Zn deficiency induced apoptosis in both proliferating and quiescent neuronal cells via the intrinsic apoptotic pathway. Reductions in cellular Zn triggered a translocation of the pro-apoptotic protein Bad to the mitochondria, cytochrome c release, and caspase-3 activation. Apoptosis is the resultant of the inhibition of the prosurvival extracellular-signal-regulated kinase, the inhibition of nuclear factor-kappa B, and associated decreased expression of antiapoptotic proteins, and to a direct activation of caspase-3. A deficit of Zn during critical developmental periods can have persistent effects on brain function secondary to a deregulation of neuronal proliferation and apoptosis. PMID- 19784711 TI - False-positive interpretations in respiratory cytopathology. PMID- 19784712 TI - In situ and in vitro comparison of laser fluorescence with visual inspection in detecting occlusal caries lesions. AB - The aim of this study was to compare the in situ and in vitro performances of a laser fluorescence (LF) device (DIAGNOdent 2095) with visual inspection for the detection of occlusal caries in permanent teeth. Sixty-four sites were selected, and visual inspection and LF assessments were carried out, in vitro, three times by two independent examiners, with a 1-week interval between evaluations. Afterwards, the occlusal surfaces were mounted on the palatal portion of removable acrylic orthodontic appliances and placed in six volunteers. Assessments were repeated and validated by histological analysis of the tooth sections under a stereomicroscope. For both examiners, the highest intra-examiner values were observed for the visual inspection when in vitro and in situ evaluations were compared. The inter-examiner reproducibility varied from 0.61 to 0.64, except for the in vitro assessment using LF, which presented a lower value (0.43). The methods showed high specificity at the D(1) threshold (considering enamel and dentin caries as disease). In vitro evaluations showed the highest values of sensitivity for both methods when compared to the in situ evaluations at D(1) and D(2) (considering only dentinal caries as the disease) thresholds. For both methods, the results of sensitivity (at D(1) and D(2)) and accuracy (at D(1)) showed significant differences between in vitro and in situ conditions. However, the sensitivity (at D(1) and D(2)), specificity and accuracy (both at D(1)) of the methods were not significantly different when the same condition was considered. It can be concluded that visual inspection and LF showed better performance in vitro than in situ. PMID- 19784713 TI - Prophylactic colectomy for hyperplastic polyposis. AB - BACKGROUND: Hyperplastic polyposis (HP) is important to recognise as it increases the risk of adenomata which may develop dysplastic change or frank adenocarcinoma. We present the case of a 58-year-old woman with HP. CASE: Following a diagnosis of HP in this patient, it was noted that the number of polyps were progressively increasing over time, becoming pancolic and extending into the rectum. Genetic testing for a familial polypotic syndrome was negative. Histological analysis demonstrated that the majority of polyps were hyperplastic, but there were also serrated and tubular adenomata with foci of low-grade dysplasia. Whilst there was no evidence of frank malignancy or high-grade dysplasia, following a risk-benefit discussion the patient underwent a laparoscopic total colectomy with an ileal pouch formation. CONCLUSION: This case highlights the complexity in the management of HP and that even in the absence of confirmed invasive disease, patients may elect to undergo prophylactic colonic resection. PMID- 19784714 TI - Neurological gait abnormalities and risk of falls in older adults. AB - To estimate the validity of neurological gait evaluations in predicting falls in older adults. We studied 632 adults age 70 and over (mean age 80.6 years, 62% women) enrolled in the Einstein Aging Study whose walking patterns were evaluated by study clinicians using a clinical gait rating scale. Association of neurological gaits and six subtypes (hemiparetic, frontal, Parkinsonian, unsteady, neuropathic, and spastic) with incident falls was studied using generalized estimation equation procedures adjusted for potential confounders, and reported as risk ratio with 95% confidence intervals (CI). Over a mean follow up of 21 months, 244 (39%) subjects fell. Mean fall rate was 0.47 falls per person year. At baseline, 120 subjects were diagnosed with neurological gaits. Subjects with neurological gaits were at increased risk of falls (risk ratio 1.49, 95% CI 1.11-2.00). Unsteady (risk ratio 1.52, 95% CI 1.04-2.22), and neuropathic gait (risk ratio 1.94, 95% CI 1.07-3.11) were the two gait subtypes that predicted risk of falls. The results remained significant after accounting for disability and cognitive status, and also with injurious falls as the outcome. Neurological gaits and subtypes are independent predictors of falls in older adults. Neurological gait assessments will help clinicians identify and institute preventive measures in older adults at high risk for falls. PMID- 19784715 TI - How adolescents who cut themselves differ from those who take overdoses. AB - The aims of this study were to identify in what ways adolescents who cut themselves differ from those who take overdoses, and to investigate the role of contagion in these behaviours. Data from an anonymous self-report questionnaire survey of 6,020 adolescents in 41 schools were analysed. Comparison of 220 adolescents who reported self-cutting in the previous year with 86 who had taken overdoses in the previous year as the sole method of deliberate self-harm (DSH) showed that far more of those who cut themselves had friends who had also engaged in DSH in the same period (OR 2.84, 95% CI 1.5-5.3, P < 0.001), and fewer had sought help from friends before cutting (OR 0.5, 95% CI 0.3-0.9, P < 0.02). Self cutting usually involved less premeditation. Analyses at both the individual and school level showed that the association between engaging in DSH and exposure to DSH amongst peers was largely confined to girls who cut themselves. There are important differences between adolescents who cut themselves and those who take overdoses. Contagion may be an important factor in DSH by adolescents, especially in girls who cut themselves. These findings are relevant to the design of prevention and treatment programmes. PMID- 19784717 TI - Stereotactic directional vacuum-assisted breast biopsy using lateral approach. AB - BACKGROUND: In recent years, stereotactic vacuum-assisted breast biopsy [so called Mammotome(r) biopsy (ST-MMT)] has been established as a reliable method for diagnosis of nonpalpable and mammographically detected lesions with microcalcification. However, there are few reports regarding the lateral approach. We performed ST-MMT using the lateral approach. The purpose of this study was to determine the usefulness of the lateral approach. MATERIALS AND METHODS: 124 women with microcalcifications underwent stereotactic vacuum assisted breast biopsy (median age, 52.5 years). All underwent stereotactic biopsy using the lateral approach. We compared our data with those of other institutes using the vertical approach. RESULTS: We removed microcalcifications and used an 11-gauge vacuum-assisted probe in all cases. The range of breast thickness was 10-45 mm. 12 patients had vasovagal reactions, however they quickly recovered without drug intervention. No patients had major complications. Of 124 cases, cancer was diagnosed in 37 patients. In other institutes using the vertical approach, it was impossible to use 11G probes in some cases due to the breast being too thin. In our study, minimum breast thickness was 10 mm (7 cases) and we were able to use 11G probes in all 7 cases with only polyethylene foam. CONCLUSION: With the lateral approach, it is possible to use 11G probes if the breast is thin (in our study minimum thickness was 10 mm) with only polyethylene foam. We believe this to be an advantage of the lateral approach. This advantage is very important in stereotactic biopsy, especially in Japan, as Japanese women's breasts are generally thinner than most Western women's. PMID- 19784716 TI - Gene expression patterns in seed plant shoot meristems and leaves: homoplasy or homology? AB - The fossil record reveals that seed plant leaves evolved from ancestral lateral branch systems. Over time, the lateral branch systems evolved to become determinate, planar and eventually laminar. Considering their evolutionary histories, it is instructive to compare the developmental genetics of shoot apical meristems (SAMs) and leaves in extant seed plants. Genetic experiments in model angiosperm species have assigned functions of meristem maintenance, specification of stem cell identity, boundary formation, polarity establishment and primordium initiation to specific genes. Investigation of roles of the same or homologous genes during leaf development has revealed strikingly similar functions in leaves compared to SAMs. Specifically, the marginal blastozone that characterizes many angiosperm leaves appears to function in a manner mechanistically similar to the SAM. We argue here that the similarities may be homologous due to descent from ancestral roles in an ancestral shoot system. Molecular aspects of SAM and leaf development in gymnosperms is largely neglected and could provide insight into seed plant leaf evolution. PMID- 19784718 TI - Effectiveness assessment of countermeasures against bioterrorist smallpox attacks in Japan using an individual-based model. AB - OBJECTIVES: This study is aimed at the evaluation of countermeasures in terms of the total number of patients and deaths, the number of vaccine doses used, and the time for eradication as examined through simulations of the outbreak of smallpox following a bioterrorist attack in the center of Okayama City. Three countermeasures were considered: traced vaccination (TV), mass vaccination (MV), and school closure. METHODS: An individual-based model was adopted, in which every individual is assigned their own personal information, behavioral pattern, and interactions among social settings to simulate the situation on a realistic basis. The influence of residual immunity obtained by past vaccination reflected age-dependent immunity to smallpox in Japan. RESULTS: MV performed within a 2-day period at the same time in 10 school districts had the highest effectiveness in reducing the total number of patients and deaths among all simulations. Performing both TV and MV simultaneously was much more effective than performing TV or MV individually. The decrease in the number of patients with TV or MV in combination with school closure was faster than that by TV or MV without school closure. CONCLUSIONS: According to the simulations results, it was advisable to carry out MV, or both TV and MV, simultaneously with school closure as countermeasures against a smallpox epidemic initiated by a bioterrorist attack. PMID- 19784719 TI - Gastric emptying, small intestinal transit and fecal output in dystrophic (mdx) mice. AB - Duchenne muscular dystrophy (DMD), which results from deficiency in dystrophin, a sarcolemma protein of skeletal, cardiac and smooth muscle, is characterized by progressive striated muscle degeneration, but various gastrointestinal clinical manifestations have been observed. The aim was to evaluate the possible impact of the dystrophin loss on the gastrointestinal propulsion in mdx mice (animal model for DMD). The gastric emptying of a carboxymethyl cellulose/phenol red dye non nutrient meal was not significantly different at 20 min from gavaging between wild-type and mdx mice. The intestinal transit and the fecal output were significantly decreased in mdx versus normal animals, although the length of the intestine was similar in both animals. The present results provide evidence for motor intestinal alterations in mdx mice in in vivo conditions. PMID- 19784720 TI - Surgical treatment of hepatocellular carcinoma. AB - Local tumor control is still the most important consideration in the treatment of hepatocellular carcinoma (HCC). Surgical treatments, including liver resection and liver transplantation are, and will remain, the first-line therapeutic strategies for local control in patients with primary HCC. Although aggressive liver resection is often performed for advanced HCC in patients with a large tumor, multiple tumors, or tumors with vascular invasion, liver transplantation is the preferred option, after taking into consideration age and tumor-related factors, when there is poor liver functional reserve. Preventing deterioration in liver function is the second priority in the treatment of HCC. When performing liver resection, extensive removal of noncancerous liver parenchyma during lobectomy or hemihepatectomy, should be avoided as much as possible. Anatomic resection, which refers to systematic elimination of the main tumor with its minute metastases, preserves liver function and is highly recommended. A treatment algorithm based on published evidence is now available, which helps us decide on the most suitable therapeutic option for individual patients, depending on the tumor characteristics and liver functional reserve. PMID- 19784721 TI - Importance of preoperative imaging with 64-row three-dimensional multidetector computed tomography for safer video-assisted thoracic surgery in lung cancer. AB - PURPOSE: Video-assisted thoracic surgery (VATS) has recently been adopted for complicated anatomical lung resections. During these thoracoscopic procedures, surgeons view the operative field on a two-dimensional (2-D) video monitor and cannot palpate the organ directly, thus frequently encountering anatomical difficulties. This study aimed to estimate the usefulness of preoperative three dimensional (3-D) imaging of thoracic organs. METHODS: We compared the preoperative 64-row three-dimensional multidetector computed tomography (3DMDCT) findings of lung cancer-affected thoracic organs to the operative findings. RESULTS: In comparison to the operative findings, the branches of pulmonary arteries, veins, and bronchi were well defined in the 3D-MDCT images of 27 patients. CONCLUSION: 3D-MDCT imaging is useful for preoperatively understanding the individual thoracic anatomy in lung cancer surgery. This modality can therefore contribute to safer anatomical pulmonary operations, especially in VATS. PMID- 19784722 TI - A new hydrocolloid dressing prevents surgical site infection of median sternotomy wounds. AB - PURPOSE: This prospective and semi-randomized study was conducted to clarify the effectiveness of a new hydrocolloid dressing placed over median sternotomy wounds using an occlusive dressing technique. METHODS: The subjects were 253 patients undergoing coronary artery bypass grafting (CABG), who were randomized to receive either the new hydrocolloid dressing (Karayahesive, n = 117) or a polyurethane foam dressing (Tegaderm plus Pad, n = 136) immediately after sternal wound closure. Karayahesive was left in place for 7 days, whereas the Tegaderm plus Pad was removed on postoperative day (POD) 2 and replaced with an adhesive wound dressing until POD 7. RESULTS: In the Karayahesive group, complete integrity of the wound was achieved in 91% of the patients, with an infection developing in 3.4%: as a superficial surgical site infection (SSI) in three and as a deep SSI in one. On the other hand, in the Tegaderm plus Pad group, an infection developed in 10.3% (14 patients) of the patients: as a superficial SSI in nine and as a deep SSI in five (P < 0.05). The total treatment costs from the application of the dressing until completion of treatment was 699 yen for the Karayahesive and 910 yen for the Tegaderm plus Pad (P < 0.001). CONCLUSIONS: The new hydrocolloid dressing, applied with an occlusive dressing technique to median sternotomy wounds, prevented SSI and was cost effective. PMID- 19784723 TI - Optimal dose of preoperative enteral immunonutrition for patients with esophageal cancer. AB - PURPOSE: A preoperative immunonutrition pharmaceutics diet (IMPACT) significantly reduced the incidence of postoperative infectious complications, but the optimal regimen still remains unclear. We evaluated the optimal dose of a preoperative IMPACT for patients with esophageal carcinoma and the incidence of postoperative complications based on the dose of IMPACT. METHODS: This study design was a prospective nonrandomized study. Twenty patients with thoracic esophageal carcinoma who underwent a right transthoracic subtotal esophagectomy were divided into two groups. These patients were administered immunonutrition of 500 ml/day (IMP500) or 1000 ml/day (IMP1000) for 7 days before the operation. RESULTS: The incidence of postoperative mortality and morbidity was not different between the IMP500 group and the IMP1000 group. No difference was observed in the perioperative changes in inflammatory, immunological and nutritional variables between the two groups. There were no adverse effects in the IMP500 group, but four patients (40%) had diarrhea and four patients (40%) had appetite loss in the IMP1000 group. In the IMP1000 group, only four patients (40%) could take 1000 ml, but others reduced the quantity of IMPACT because of diarrhea and discomfort. CONCLUSION: This study suggests that 500 ml of IMPACT is recommended as an optimal dose for patients with esophageal cancer. PMID- 19784724 TI - Intussusception in adult and pediatric patients: two different entities. AB - PURPOSE: Intussusception is one of the most common abdominal emergencies in pediatrics, but adult intussusception is an uncommon entity and most surgeons have only limited experience in treating this disease. The purpose of this study was to highlight the differences between pediatric and adult intussusception. METHODS: The records of 40 patients during 14 years were reviewed retrospectively. The symptoms, diagnosis, sites of intussusception, associated pathologies, and treatment methods of each patient were analyzed. RESULTS: A total of 31 pediatric and 9 adult patients were included in the study. In the pediatric group, bloody stool and vomiting were the most common symptoms whereas adult patients commonly presented with abdominal pain. The physical examination was diagnostic in a remarkable proportion of the pediatric patients but the diagnosis was suggested based on imaging techniques in the adults, and preoperative diagnosis was more successful in the pediatric group. Intussusception was more often associated with an underlying pathology in adults and no adult patient underwent nonoperative reduction, whereas pediatric patients were managed either with hydrostatic reduction or surgery. CONCLUSIONS: Although intussusceptions occur at all ages, there are major differences in the clinical presentation, diagnostic approach, and management between pediatric and adult populations. Intussusception is remarkably different in these two age groups and it must be approached from a different clinical perspective. PMID- 19784725 TI - The outcome of postoperative hemorrhaging following a hemorrhoidectomy. AB - PURPOSE: Postoperative hemorrhage (PH) is rare, but it is widely recognized as a postoperative complication of a hemorrhoidectomy. The assessment of this complication may provide information which can be used to improve the clinical outcome of a patient who has undergone a hemorrhoidectomy. METHODS: Between January 2006 and December 2007, a total of 1294 patients with symptomatic hemorrhoids underwent a hemorrhoidectomy at our hospital. The patient records were retrospectively analyzed. RESULTS: In this study, 23 patients had suffered from PH and had undergone a second operation (1.7%). The bleeding points were located as follows: 14 anterior,7 right laterally, 8 left laterally, and 2 posteriorly. Of these patients with early hemorrhage, 1 case was at the anterior, 1 was left lateral, and 2 were posterior. A significant correlation was observed between the period and the location of postoperative hemorrhage (P = 0.0023). From one to four piles were excised (1 in 264 patients, 2 in 240 patients, 3 in 702 patients, 4 in 88 patients). A significant correlation was also observed between the number of piles and the occurrence of PH (P = 0.032). CONCLUSIONS: At the posterior wall, a late period hemorrhage is less likely to be found than an early period hemorrhage. It was found that the more piles that were excised, the greater the occurrence of PH. PMID- 19784726 TI - Laparoscopic subtotal cholecystectomy for severe cholecystitis. AB - PURPOSE: To evaluate the efficacy and outcome of laparoscopic subtotal cholecystectomy (LSC) for patients with severe cholecystitis. METHODS: Between April 1992 and May 2008, 1226 patients underwent laparoscopic cholecystectomy (LC). From 2000 onward 60 patients with severe cholecystitis underwent LSC. The outcomes of LC were compared between patients who underwent the procedure between 1992 and 1999 (group A; n = 643) and those who underwent the procedure between 2000 and 2008 after the introduction of LSC (group B; n = 583), respectively. In Group B, operative outcomes were also compared between the LC and LSC groups. RESULTS: The incidence of bile duct injury (1.6% vs 0.3%, P = 0.040) and conversion to open cholecystectomy (2.2% vs 0.3%, P = 0.046) was significantly lower in group B. The mean operative time was significantly longer (119.6 min vs 71.0 min., P < 0.001), and the mean blood loss was significantly higher (53.4 ml vs 12.9 ml, P < 0.001) in the LSC group. No significant differences were observed between LC and LSC in the incidence of postoperative morbidities or postoperative hospital stay. No patient had remnant gallstones or gallbladder cancers after a median follow-up of 42 months. CONCLUSIONS: Laparoscopic subtotal cholecystectomy is safe and effective for preventing bile duct injuries and lowering the conversion rate in patients with technically difficult severe cholecystitis. PMID- 19784727 TI - Acute pancreatitis, bacterial translocation, and different octreotide regimens: an experimental study. AB - PURPOSE: To determine the effect of octreotide, octreotide with zinc, levamisole, and misoprostol on the bacterial translocation that develops in rats with acute pancreatitis (AP). METHODS: A total of 36 rats were divided into six groups, each consisting of six rats. Only laparotomy was performed on the first group. Acute pancreatitis was performed on the second group. Octreotide was given to the third, fourth, fifth, and sixth groups. Octreotide, octreotide with zinc, levamisole, and misoprostol were given to groups III, IV, V, VI, respectively. Rats were euthanized 48 h after the occurrence of AP. Blood and mesenteric lymph node samples were collected for polymerase chain reaction (PCR). Pancreatic tissue and terminal ileum were obtained for histopathological examinations. RESULTS: The severity of pancreatitis and mucosal damage of the terminal ileum was higher in group II than groups I, III, IV, V, and VI, histopathologically (P < 0.05). There wasn't a significant difference with respect to OA with Zn or L or M and OA group (P > 0.05). A significant difference was found in PCR positivity in blood and mesenteric lymph node between groups I and II (P < 0.05). CONCLUSIONS: In AP, administering octreotide alone significantly prevented the bacterial translocation by preventing mucosal damage. The zinc, levamisole, or misoprostol with octreotide did not influence the results. PMID- 19784728 TI - Neurofibroma adjacent to the thyroid gland and a thyroid papillary carcinoma in a patient with neurofibromatosis type 1: report of a case. AB - Neurofibromatosis (NF) type 1, also known as von Recklinghausen's disease, is an autosomal-dominant inherited disorder. Some tumors may develop in these patients, including optic pathway gliomas, astrocytomas, brainstem gliomas, chronic myeloid leukemia, and rhabdomyosarcoma. Patients with neurofibromatosis type 1 show also an increased risk of endocrine tumors, especially pheochromocytomas, whereas thyroid carcinoma is very rare. It is also rare for a neurofibroma to arise in the tissue neighboring the thyroid gland, and mimicking a nonfunctional thyroid nodule. This report presents a case of a neurofibroma adherent to the thyroid gland with thyroid papillary carcinoma in a 26-year-old woman with NF type 1. PMID- 19784729 TI - A suspected [18F]fluorodeoxyglucose positron emission tomography-negative metastatic lymph node successfully diagnosed by laparoscopic staging in esophageal cancer: report of two cases. AB - An accurate preoperative staging is important for selecting an appropriate therapy for esophageal cancer. In particular, diagnosis of lymph node metastases influences the indication for radical surgery. [18F]Fluorodeoxyglucose positron emission tomography (FDG-PET) has been widely applied primarily as a useful tool for initial staging of esophageal cancer. However, false-negative cases sometimes make it difficult to select the appropriate treatment. We report two patients with esophageal cancer and PET-negative enlarged lymph node successfully diagnosed by laparoscopic sampling. This procedure did not only allow accurate histopathological staging, but also helped to select the optimal minimally invasive management. This technique can be recommended for patients with esophageal cancer in whom the diagnosis of enlarged lymph node cannot be confirmed by preoperative imaging. PMID- 19784730 TI - Carcinosarcoma of the duodenum: Report of a case. AB - This report describes a case of carcinosarcoma of the duodenum. Carcinosarcoma of the duodenum is a very rare tumor. A 72-year-old man was referred to the hospital because of appetite loss. Endoscopy demonstrated an irregularly depressed lesion (type 3) in the descending portion of the duodenum opposite to the ampulla of Vater. Computed tomography showed a thickened duodenal wall and swelling of the abdominal para-aortic lymph nodes. A biopsy specimen revealed a well differentiated adenocarcinoma. A diagnosis of duodenal carcinoma was made (cT3, cN1, cM1, cStage IV according to the TNM classification). A subtotal stomach preserving pancreatoduodenectomy and a lymph node resection were performed. On microscopic examination, adenocarcinoma cells and spindle type sarcoma cells were observed separately in the descending portion of the duodenum opposite to the ampulla of Vater. The adenocarcinoma cells were stained with antibodies against epithelial markers keratin and carcinoembryonic antigen for immunohistochemical analyses. In contrast, the sarcoma cells were stained with antibodies to vimentin and smooth muscle actin. The pathological diagnosis of a true duodenal carcinosarcoma was thus made. PMID- 19784731 TI - Coexistence of mucinous cystic neoplasm occurring in the head of the pancreas with annular pancreas: report of a case. AB - Mucinous cystic neoplasms (MCN) of the pancreas are rare tumors that are almost exclusively located in the body or the tail of the pancreas. A 60-year-old woman with no history of pancreatic disease was referred to our hospital with a chief complaint of dull pain in the upper abdomen. Abdominal computed tomography showed a multilocular cystic mass of 7.0 cm in the head of the pancreas, and endoscopic retrograde cholangiopancreatography showed no communication between the cystic mass and the main pancreatic duct. A pancreatoduodenectomy was performed for the complete resection of the tumor, and an annular pancreas was discovered by accident. The pathological examination of the tumor led to a definitive diagnosis of MCN with ovarian-type stroma. To our knowledge this is the first documented case of MCN occurring in the head of the pancreas and associated with annular pancreas. PMID- 19784732 TI - Lymphoepithelial cyst of the pancreas that was difficult to distinguish from branch duct-type intraductal papillary mucinous neoplasm: report of a case. AB - A 58-year-old woman was admitted to our hospital to optimize the management of her diabetes mellitus. A computed tomography (CT) scan showed a 30-mmdiameter, multilocular cyst in the head of the pancreas. The tumor markers, including DUPAN 2, SPAN-1, and carbohydrate antigen 19-9, were within the normal ranges. A contrast-enhanced CT scan showed a nonenhanced, multilocular cyst. Abdominal magnetic resonance imaging showed a multilocular cyst. Endoscopic retrograde cholangiopancreatography showed that the main pancreatic duct was normal. Based on these findings, we suspected a branch duct type intraductal papillary mucinous neoplasm. A distal pancreatectomy with a splenectomy was performed, since more of the mass was located on the dorsolateral side, inconsistent with the preoperative imaging results. On the resected specimen, a 4-cm-diameter, multilocular cyst containing serous fluid was found. Pathologically, the cyst wall was lined with squamous epithelium surrounded by abundant lymphoid tissue with follicles, consistent with a lymphoepithelial cyst of the pancreas, which is an unusual benign cyst. PMID- 19784733 TI - Chemotherapy-induced sclerosing cholangitis as a rare indication for resection: report of a case. AB - Bile duct stricture due to chemotherapy-induced sclerosing cholangitis (CISC) is a potentially fatal complication of hepatic arterial infusion chemotherapy (HAIC). It is managed primarily with medical treatment and biliary stenting. We report a rare case of a CISC-related biliary stricture requiring resection. The patient had been receiving adjuvant HAIC for 11 months after a curative liver resection for hepatocellular carcinoma, when clinically overt cholangitis developed. Radiologic and biopsy findings suggested a CISC-related biliary stricture limited to the common hepatic duct. We discontinued HAIC and started corticosteroid treatment, which finally became ineffective. Endoscopic biliary stenting was impossible because of her severe biliary sclerosis, necessitating resection of the stricture, which was confirmed histologically to be secondary sclerosing cholangitis. The patient has shown no signs of recurrent cholangitis for 12 postoperative months since her operation. Thus, resection could be a treatment option for a CISC-related biliary stricture in selected patients. PMID- 19784734 TI - Portal vein gas due to gangrenous cholecystitis treated by a laparoscopic procedure: report of a case. AB - Portal pneumatosis is a rare diagnostic factor, which is often associated with ischemic intestinal accidents. It has been associated with a negative prognosis for a very long time, and the presence of portal pneumatosis is usually an indication for the need to perform a laparotomy. A 68-year-old male patient with diabetes, obstructive lung disease, and a previous cerebral stroke associated with left hemiplegia presented with abdominal pain, fever and neutrophil leukocytosis. Computed tomography (CT) scan showed the presence of portal pneumatosis with signs of acute cholecystitis and remarkable gastrectasia. In consideration of the serious clinical picture, the patient first underwent esophagogastroduodenal endoscopy (EGDS), which showed ulcerative hemorrhagic gastritis. He then underwent a laparoscopic cholecystectomy. The histology results confirmed the intraoperative diagnosis of gangrenous cholecystitis. The patient was discharged on the 7th postoperative day. With the use of new diagnostic techniques, especially CT, the incidence of portal pneumatosis has increased and consequently the clinical approach of surgeons to this pathology is also changing. Indeed, when portal pneumatosis is not associated with intestinal ischemia, the therapeutic approach must be guided by the clinical condition of the patient and by the investigation of the causes of this pathology. The laparoscopic approach can be extremely useful either in the diagnosis (if this has not been achieved by noninvasive means) or in treatment, if possible, of the causes implicated by the portal pneumatosis. PMID- 19784735 TI - Liver transplantation from a non-heart-beating donor after pulmonary failure: report of a case. AB - We report a case of successful liver transplantation after controlled donor after cardiac death procurement from a donor who died of pulmonary failure. The donor was a 28-year-old woman with idiopathic pulmonary fibrosis, whose life support could not continue when her condition deteriorated rapidly while waiting for a suitable donor for lung transplantation. She was on noninvasive negative pressure ventilatory support before the donor organs were procured. PMID- 19784736 TI - Primary perivascular epithelioid cell tumor (PEComa) of the liver: report of a case. AB - PEComa is very rare mesenchymal neoplasm which is formed by perivascular epithelioid cells and is characterized by dual melanocytic and myoid differentiation. Up to now only a very few cases of PEComa of the liver have been described worldwide. We herein present a patient who underwent a right hemihepatectomy for a huge tumor which could not be identified by imaging investigations. A final histopathologic examination revealed a benign epithelioid tumor with a solid growth pattern, abundant vascularity, and frequently dilated vascular channels. Immunohistochemically, the tumor cells were strongly positive for HMB-45, moderately positive for actin, and faintly positive for S-100, respectively. Based on the above findings, a diagnosis of a primary clear cell "sugar" tumor was established. Because the natural history of PEComas is mostly unpredictable, the patient has been closely followed up; however, no recurrence has so far been observed. Immunohistochemical findings play a crucial role in avoiding a misdiagnosis, and a surgical resection with an adequate margin of healthy tissue remains the gold standard of treatment. A long-term periodic follow-up is reasonable in all cases presenting with PEComa. PMID- 19784737 TI - An approach to mitral valve surgery by a T-shaped mini-sternotomy with functioning bilateral internal thoracic artery grafts. AB - We herein report successful surgical treatment of mitral valve regurgitation in a 49-year-old man. He was admitted to our hospital due to acute aggravation of dyspnea on effort. He had a surgical history of coronary artery bypass grafting with bilateral internal thoracic artery grafts. A transthoracic echocardiogram showed severely decreased cardiac function and severe mitral regurgitation due to anterolateral mitral valve leaflet prolapse. Computed tomography showed the right internal thoracic artery running over the front of the aorta to the left circumflex artery. To avoid injury to the functioning grafts during median sternotomy, we chose to perform an inferior T-shaped mini-sternotomy. The surgical field was sufficient to perform mitral valve replacement with a mechanical prosthetic valve under fibrillatory arrest. The grafts were neither dissected nor clamped, and access to the aorta and mitral valve was excellent. PMID- 19784738 TI - Medical molecular morphology with imaging mass spectrometry. AB - Imaging mass spectrometry (IMS) is a two-dimensional mass spectrometry to visualize the spatial distribution of biomolecules that does not need either separation or purification of target molecules and enables us to monitor not only the identification of unknown molecules but also the localization of numerous molecules simultaneously. Among the ionization techniques, matrix-assisted laser desorption/ionization (MALDI) is one of those most generally used for IMS, which allows the analysis of numerous biomolecules ranging over wide molecular weights. At present, targets of IMS research have expanded to the imaging of small endogenous metabolites such as lipids, exogenous drug pharmacokinetics, exploring new disease markers, and other new scientific fields. PMID- 19784739 TI - Impact of hepatitis B virus X protein on the DNA damage response during hepatocarcinogenesis. AB - Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide. The main HCC-associated diseases are chronic infections with hepatitis B virus (HBV) and hepatitis C virus (HCV), and HBV-associated HCC is still prevalent in Asia. Many studies have suggested that HBV X protein (HBX), which is the most common ORF integrated into the host genome, plays a crucial role in hepatocarcinogenesis. However, the accumulated evidence regarding HBX-mediated signaling pathways is not concordant, and it is difficult to understand the mechanistic nature of HBX-associated hepatocarcinogenesis. For example, HBX was reported to inactivate the early responses to DNA damage via p53-dependent and independent pathways by interacting with several DNA damage-binding proteins and was also reported to sensitize cells to p53-mediated apoptosis via ataxia telangiectasia and Rad3-related (ATR)-dependent signaling. HBX also interferes with the centrosome replication process, resulting in rearrangement of chromosomes with micronuclei. Moreover, HBX was found to sensitize protein kinases such as Ras/Raf/mitogen-activated protein kinase (MAPK), extracellular signal-regulated kinase (ERK), stress-activated protein kinase/NH2-terminal-Jun kinase (SAPK/JNK), protein kinase B (PKB/Akt), and Janus kinase/STAT (JAK/STAT), indicating that a variety of signaling pathways may be activated by HBX. In this review, we focus on the roles of HBX in DNA damage repair during HCC development, with a view to achieving a better understanding of the significance of HBX in the early steps of hepatocarcinogenesis. PMID- 19784740 TI - Phagocytosis mechanism of apoptotic granulosa cells regulated by milk-fat globule EGF factor 8. AB - In the process of ovary sexual maturation, most immature ovarian follicles degrade into atretic follicles accompanied by apoptosis in granulosa cells. Macrophages can recognize apoptotic cells through specific binding with phosphatidylserine (PS), exposed on the surface of apoptotic cells, which is mediated by milk-fat globule-EGF factor 8 (MFG-E8). In the present research, we examined the involvement of the MFG-E8-dependent phagocytosis system in the atretic follicles of developing mouse ovaries. The number of atretic follicles and DNA-fragmented granulosa cells significantly increased in B6C3F1 mice during 2 to 6 weeks. Chromatin-condensed granulosa cells were engulfed by macrophages, which existed in the stroma or atretic follicles, or by neighboring normal granulosa cells. MFG-E8 mRNA increased in ovaries during 2 to 6 weeks, and immunoreactivity of MFG-E8 was detected at the surface of apoptotic cells existing around the antrum. Immunoelectron microscopic study revealed MFG-E8 positive signals on the membrane of apoptotic cells near macrophages, but apoptotic cells engulfed by neighboring granulosa cells showed few signals. Anti Fas antibody elevated the annexin-V-positive reaction in isolated granulosa cells from 3-week-old mouse ovaries. MFG-E8 seems to act on the phagocytosis of apoptotic granulosa cells via macrophages and contribute to the regression process of atretic follicles. PMID- 19784741 TI - Environmental factors involved in axonal regeneration following spinal cord transection in rats. AB - A recent study of a rat model treated with grafted collagen filament (CF) after spinal cord transection showed dramatic recovery of motor function but did not report on the acute-stage phenomenon. In the present study, we describe molecular and histological aspects of the axonal regeneration process during the acute stage following spinal cord transection. The spinal cord of 8-week-old rats was completely transected, and a scaffold of almost the same size as the resected portion was implanted in the gap. Changes in the mRNA expression of four neurotrophic factors [nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), NT-3, and glial cell-derived neurotrophic factor (GDNF)] were analyzed after 72 h. The expression of BDNF and NT-3 mRNA increased significantly in the CF-grafted group compared to the nongrafted group. Immunostaining for BDNF and NT-3 revealed that cells positive for these neurotrophic factors extended along the collagen filaments in the CF-grafted group. Similarly, astrocytes extended into the collagen filament scaffold together with the neurotrophic factors and partly across a border line. These findings indicate that collagen filament helps to reduce scar tissue, supports the expression of neurotrophic factors, and serves as a scaffold for the outgrowth of regenerating axons. PMID- 19784742 TI - The immunohistochemical expression profile of osteopontin in normal human tissues using two site-specific antibodies reveals a wide distribution of positive cells and extensive expression in the central and peripheral nervous systems. AB - To elucidate the cellular distribution of osteopontin (OPN) in normal human tissues, we undertook immunohistochemistry using two site-specific OPN antibodies. The 10A16 monoclonal antibody was raised against the amino acid sequence just downstream of the thrombin cleavage site, while the O-17 polyclonal antibody was raised against the N-terminal peptide. Each antibody has been confirmed previously to react with both whole OPN and its relevant fragments. The expression pattern for these two antibodies was similar in distribution. In addition, we also identified expression in Ebner's gland, type II pneumocytes, Kupffer cells, cells of the endocrine organs, anterior lens capsule and ciliary body, synovial type A cells, mesothelia, adipocytes, and mast cells. Neurons and glia in the central nervous system and spinal cord, cranial and peripheral nerve sheaths, ganglion cells in the sympathetic ganglion, intestinal plexuses, retina, and choroid plexus also regularly exhibited OPN positivity. Testicular germ cells, pancreatic exocrine cells, and follicular dendritic cells reacted with 10A16 only, whereas lutein cells and taste bud cells exhibited O-17 reactivity alone. These minor differences were hypothesized to reflect the state of OPN in the cells; that is, whether OPN was in its whole molecule or fragmented form. In conclusion, we demonstrate that OPN is widely distributed in normal human cells, particularly those comprising the central and peripheral nervous systems. PMID- 19784743 TI - Morphometric analysis of regional lymph nodes in surgically resected non-small cell lung cancer. AB - Nodal staging is a crucial factor in choosing the treatment option for non-small cell lung cancer (NSCLC). However, so far as we know, a computer-based histomorphometric analysis of lymph nodes in NSCLC has never been developed. We studied 299 surgically resected lymph nodes from 108 patients with NSCLC. Microscopic digital images were analyzed with Scion Image software. Seventy lymph nodes had at least one metastatic focus. The metastasis occupancy area per node ranged from 0.01 to 209.58 mm(2) (mean, 29.58 +/- 5.87 mm(2)). The metastasis occupancy ratio ranged from 0.01% to 100% (mean, 48.70% +/- 42.10%). The short axis diameter of malignant lymph nodes was significantly longer than that of benign lymph nodes (P = 0.0002). The average metastasis occupancy area in the regional lymph nodes of NSCLC is quite small. Various inflammatory conditions can result in a false-positive diagnosis when these techniques are used. Studies that combine analysis of primary tumor size and serum carcinoembryonic antigen (CEA) levels with imaging methods should be considered. Finally, the use of mediastinoscopy or video-assisted thoracoscopic surgery is encouraged in determining the exact nodal status in NSCLC. PMID- 19784744 TI - Pancreatic-type mixed acinar-endocrine carcinoma with alpha-fetoprotein production arising from the stomach: a report of an extremely rare case. AB - An extremely rare case of mixed acinar-endocrine carcinoma (MAEC) arising from the stomach in a 56-year-old Japanese woman is herein presented. An endoscopic examination and computed tomography showed a protruding gastric tumor and a large extragastric mass, respectively. Macroscopic observation on the surgical specimen revealed the extragastric cystic mass was continued to the intragastric tumor. Histologically, the intragastric tumor consisted of large or small solid nests with acinar appearance. The cancer cells had an ovoid nuclei and polygonal cytoplasm, which was frequently amphophilic. Immunohistochemical examination showed that the cancer cells were positive for chromogranin-A, synaptophysin, alpha-amylase, lipase, and alpha-fetoprotein (AFP) but were negative for CD56, insulin, and other hormones. Ultrastructurally, the cancer cells contained 500-nm electron-lucent zymogen granules and 230-nm electron-dense neuroendocrine granules. This tumor was finally diagnosed to be MAEC with AFP production of the stomach. Although no ectopic pancreas was found in the stomach, this tumor may originate from ectopic pancreas. As another theory, it is possible for this tumor to originate from the pluripotent stem cells in the stomach. A gastric MAEC with AFP production has not been reported previously. PMID- 19784745 TI - Primitive neuroectodermal tumor of the kidney. AB - We report a 21-year-old man with a primitive neuroectodermal tumor (PNET) of the kidney that was difficult to distinguish from other small round cell tumors, e.g., small cell carcinoma, malignant lymphoma, and Wilms' tumor. Pathologically, a primitive rosette-like pattern was shown by H&E staining; expression of MIC-2 was indicated by an immunohistochemical test; rather primitive organelles were observed by an ultrastructural method; and translocation of chromosome 22 was confirmed by FISH. We therefore diagnosed the current case as PNET. The patient had undergone a right radical nephrectomy more than 1.5 years earlier. After neither metastases nor recurrences for 0.5 year, imaging examinations revealed masses in his liver. He received chemotherapy and underwent surgery again, but the masses were not composed of viable tumor cells. PNET of the kidney is extremely rare; fewer than 30 cases have been reported in the English literature, and there are few data on the expression of p53, ki67, and bcl2. We investigated the relationships between these markers in the current case using immunohistochemical tests and observed strong expression of p53, Ki-67, and bcl 2. Such results generally indicate poor prognosis, and the patient eventually had some masses in his liver, but no viable tumor cells were found. The prognostic significance of these various markers in PNET of the kidney still remains unclear, but p53, ki-67, and bcl-2 might not be so important as indicators of prognosis in the kidneys as they are in other organs. Further studies are needed to investigate this, and we hope that the patient recovers completely. PMID- 19784746 TI - Extraskeletal myxoid chondrosarcoma: a study using a quick-freezing and deep etching method. AB - A case of extraskeletal myxoid chondrosarcoma (ESMC), which developed in the right thigh of a middle-aged Japanese woman, was studied using immunohistochemistry, conventional electron microscopy, and the quick-freezing and deep-etching (QF-DE) method. In addition to typical light microscopic findings of ESMC, conventional electron microscopy indicated that the tumor cells had features of chondrocytes. Immunohistochemically, the tumor cells showed a positive immunoreaction for S100 protein. A diagnosis of ESMC was made. An interesting observation was the ultrastructural features of collagen fibrils in the myxoid matrix highlighted by the QF-DE method. These collagen fibrils consisted of relatively thin collagen (20-35 nm) with pleated surface structures. The surface striation at 65 nm was obscure. We consider that such a finding of collagen fibrils identified by the QF-DE method is one of the characteristics of the myxoid matrix of ESMC, and this is useful for the differential diagnosis of myxoid soft tissue tumors. PMID- 19784747 TI - Clear cell chondrosarcoma: an ultrastructural study. AB - Clear cell chondrosarcoma (CCC) is a rare neoplasm. We report here a case of CCC. A 67-year-old Japanese man presented with right arthralgia for 1 year, and histological examination of the subsequent surgical resection of the right femoral bone showed the finding of CCC. Ultrastructurally, most organelles were observed in the perinuclear area. Clear neoplastic cells contained many glycogen particles in the area of the cytoplasm lacking organelles, although glycogen particles overall seemed to be evenly distributed in the cytoplasm. Some mitochondria, Golgi complex, actin-like filaments, and rough endoplasmic reticulum were also demonstrated in the cytoplasm of clear cells. Well-developed microvilli were also seen on the surface of neoplastic cells. These structures in neoplastic cells corresponded notably to structures of normal chondrocytes. Finally, our ultrastructural findings support further evidence that clear cells in CCC may show chondrocyte differentiation and a lack of an organelles area as well as abundant glycogen particles, may contribute to the clear cell morphology in CCC. PMID- 19784748 TI - Immunohistochemical and electron microscopy studies of a case of hyalinizing trabecular tumor of the thyroid gland, with special consideration of the hyalinizing mass associated with it. AB - Hyalinizing trabecular tumor (HTT) of the thyroid gland is rare and benign, and it neither recurs nor metastasizes. In this lesion, tumor cells are arranged in trabeculae, in association with hyalinizing mass in the stroma. The origin and nature of the hyalinizing mass are still controversial. We report here a case of HTT with cytological, immunohistochemical, and ultrastructural findings, focused in particular on the hyalinizing mass. Cytologically, tumor cells exhibiting many intranuclear cytoplasmic inclusions and nuclear grooves were found in association with light green-positive, irregular, fluffy membranous structures on touch smear. Staining with antibody to collagen type IV was positive in these membranous structures. Histopathologically, tumor cells exhibited many intranuclear cytoplasmic inclusions, and were positive for staining with antibodies to S100 protein, neuron-specific enolase, thyroglobulin, and vimentin. The hyalinizing eosinophilic mass, which was positive for PAS reaction, and for staining by antibody to collagen type IV, gradually increased in the areas surrounding tumor cells. This mass then appeared to replace the tumor cells, and exhibited a peculiar filiform pattern. We demonstrated ultrastructurally that this pattern was composed of long, irregular, fine cytoplasmic processes of tumor cells and basal lamina-like substance in the hyalinizing mass. In fact, the homogeneous hyalinizing mass, similar to basal lamina-like substance, contained many degenerated cytoplasmic processes at the ultrastructural level. These results suggested that the key cytological finding in differentiating HTT from papillary carcinoma is the fluffy membranous structure, although nuclear pseudoinclusions are important as well. The filiform pattern noted at light microscopic level consisted of long cytoplasmic processes of tumor cells and hyalinized mass at the ultrastructural level. PMID- 19784749 TI - Spigelian hernia mimicking appendicular mass. PMID- 19784750 TI - Upper extremity deep vein thrombosis. AB - Upper extremities deep venous thrombosis (UEDVT) is a rare condition. According to the literature, approximately 4-10% of all cases of venous thrombosis may involve the subclavian, axillary or brachial veins. In the last few decades, the incidence of UEDVT has increased because of more frequent use of central venous catheters (CVCs) and cardiac pacemaker implantation. In addition, another common risk factor for UEDVT is cancer. UEDVT is classified as primary, approximately one-third of cases, which refers either to effort thrombosis or idiopathic UEDVT, or secondary, due to the presence of overt predisposing causes. The onset of UEDVT is usually characterized by arm swelling and pain, but may also be completely asymptomatic especially in patients with a long-term presence of a CVC. Ultrasonography represents a simple and accurate diagnostic tool to demonstrate the problem. UEDVT has major clinical consequences including pulmonary embolism, recurrences, post-thrombotic syndrome, and death. The role of thromboprophylaxis for those patients with a long-term CVC is still controversial. Unfractionated or low molecular weight heparin, followed by an oral anticoagulant are the most common treatments, with strategy of management similar to that of deep vein thrombosis of the leg. Thrombolysis/thrombectomy and surgical decompression are often successful, but less frequently used. Randomized controlled trials are warranted to clarify the optimal management of UEDVT, and to identify patients at the highest risk of recurrence who might benefit from long-term anticoagulation. PMID- 19784751 TI - Presence of low titre of antiphospholipid antibodies in cancer patients: a prospective study. AB - Antiphospholipid antibodies (aPL) represent a well-defined risk factor for thrombotic events. aPL have been observed in the plasma of cancer patients, but the role and clinical relevance of aPL in this clinical setting is still unclear. This is a prospective cohort study whose aims were to: (1) compare the prevalence of aPL antibodies in cancer patients at diagnosis to matched control subjects; (2) compare thrombosis-free survival and overall survival in aPL positive and aPL negative cancer patients. One hundred and thirty-seven patients were enrolled upon a diagnosis of cancer, and were screened for lupus anticoagulant (LA), anticardiolipin antibodies, and anti-beta2 glycoprotein I antibodies (IgG and IgM). Two years of follow-up were scheduled. Low-titre aPL antibody positivity was found in 33 patients (24%), and in 6 controls (4.3%; P < 0.0001). During follow-up, nine patients developed a symptomatic, objectively confirmed, thromboembolic event. One thrombotic event was observed among the 33 aPL positive patients (3%), and 8 among the 104 aPL negative ones (7.6%) (P = NS). During follow-up, 21 patients died, and among them, 3 (9.1%) were aPL positive and 18 (17.3%) were aPL negative (P = 0.39; C.I. 0.28-0.05). In conclusion, a high prevalence of low-titre aPL was found in cancer patients at diagnosis, but no statistical difference in thrombosis-free survival or in overall survival was observed between aPL positive and aPL negative patients. PMID- 19784752 TI - Acquired haemophilia A: a case report. PMID- 19784754 TI - Prediction of Alzheimer dementia with short neuropsychological instruments. AB - The aim of this study was to evaluate the neuropsychological instruments in predicting Alzheimer dementia after 5 years in the context of a longitudinal population-based cohort study. A total of 585 nondemented 75-year-old individuals completed neuropsychological examination at the baseline investigation; 479 subjects were followed after 30 months and 404 after 60 months. Cognition, depression and memory complaints were evaluated with psychometric instruments. Known risk factors for Alzheimer dementia were included in the analyses. Univariate logistic regression analyses and stepwise multiple models were calculated. A combination of reduced verbal memory, reduced visual motor speed, subjective memory complaints and the APOE epsilon4 carriage was best in predicting incident probable Alzheimer dementia (R(2) = 0.42, ROC curve = 0.91). The model achieved a positive predictive value of 23.3%, a negative predictive value of 98.7%, a sensitivity of 82.8% and a specificity of 82.4%. Alzheimer dementia can be predicted by neuropsychological instruments measuring episodic memory and motor speed. A high percentage of 98.7% subjects at age 75 years could be predicted as remaining non-demented at age 80 years. The prediction of those unlikely to develop AD would be more important in the future to spare further expensive diagnostic testing and protective therapies in individuals at low risk. PMID- 19784753 TI - The interplay between mitochondrial complex I, dopamine and Sp1 in schizophrenia. AB - Schizophrenia is currently believed to result from variations in multiple genes, each contributing a subtle effect, which combines with each other and with environmental stimuli to impact both early and late brain development. At present, schizophrenia clinical heterogeneity as well as the difficulties in relating cognitive, emotional and behavioral functions to brain substrates hinders the identification of a disease-specific anatomical, physiological, molecular or genetic abnormality. Mitochondria play a pivotal role in many essential processes, such as energy production, intracellular calcium buffering, transmission of neurotransmitters, apoptosis and ROS production, all either leading to cell death or playing a role in synaptic plasticity. These processes have been well established as underlying altered neuronal activity and thereby abnormal neuronal circuitry and plasticity, ultimately affecting behavioral outcomes. The present article reviews evidence supporting a dysfunction of mitochondria in schizophrenia, including mitochondrial hypoplasia, impairments in the oxidative phosphorylation system (OXPHOS) as well as altered mitochondrial related gene expression. Abnormalities in mitochondrial complex I, which plays a major role in controlling OXPHOS activity, are discussed. Among them are schizophrenia specific as well as disease-state-specific alterations in complex I activity in the peripheral tissue, which can be modulated by DA. In addition, CNS and peripheral abnormalities in the expression of three of complex I subunits, associated with parallel alterations in their transcription factor, specificity protein 1 (Sp1) are reviewed. Finally, this review discusses the question of disease specificity of mitochondrial pathologies and suggests that mitochondria dysfunction could cause or arise from anomalities in processes involved in brain connectivity. PMID- 19784755 TI - The role of actin filaments in ascovirus replication and pathology. AB - Ascoviruses (AVs) are insect viruses transmitted by parasitoid wasps. The unique pathology in host cells upon AV infection includes enlargement, blebbing and cleavage of host cells into virus-containing vesicles that are important in dissemination of the virus. The mechanism of pathogenesis and vesicle formation is largely unknown. Here, we explored involvement of actin filaments in virus entry, replication and pathology. The results suggested that entry of Heliothis virescens ascovirus-3e (HvAV-3e) leads to rearrangement of the actin cytoskeleton. After HvAV-3e infection, actin filaments were found in foci rather than in a homogenous distribution within the cytoplasm. Actin filaments were also found concentrating around blebs and vesiculation areas of the cell cortex following infection. Destabilization of filamentous actin by cytochalasin D did not inhibit entry or replication of the virus but affected vesiculation and pathology associated with HvAV-3e infection. These observations suggested that actin may not be required for virus entry and replication but essential for virus pathology, mainly vesicle formation. PMID- 19784756 TI - Identification and molecular characterization of a marafivirus in Rubus spp. AB - An undescribed virus with isometric particles and a diameter of ca. 30 nm was identified in diseased samples of wild and cultivated Rubus species and molecularly characterized. Its genome was 6,463 nt, excluding the 3'-terminal poly(A) tail, and contained a single open reading frame coding for a 2,035-amino acid-long precursor polypeptide (p223). The amino terminal portion of p223, identified as a replication-associated polyprotein, contained conserved motifs of methyltransferase, endopeptidase/protease, helicase and RNA-dependent RNA polymerase. The carboxy terminus of the large polypeptide is involved in the formation of two viral coat protein subunits with deduced molecular masses of 23 and 21 kDa. Pairwise comparisons and phylogenetic analyses showed closest relationships of this virus with oat blue dwarf virus and citrus sudden death associated virus, sharing levels of genome sequence conservation far below the species demarcation level established for tymovirids. Our data indicate that this virus, for which the name blackberry virus S (BlVS) is proposed, is a hitherto undescribed species of the genus Marafivirus, family Tymoviridae. A survey conducted in Mississippi, USA, has shown that BlVS is also present in cultivated Rubus germplasm. This work represents the first report of a marafivirus infecting small fruits. PMID- 19784757 TI - Urokinase receptor expression involves tyrosine phosphorylation of phosphoglycerate kinase. AB - The interaction of urokinase-type plasminogen activator (uPA) with its receptor, uPAR, plays a central role in several pathophysiological processes, including cancer. uPA induces its own cell surface receptor expression through stabilization of uPAR mRNA. The mechanism involves binding of a 51 nt uPAR mRNA coding sequence with phosphoglycerate kinase (PGK) to down regulate cell surface uPAR expression. Tyrosine phosphorylation of PGK mediated by uPA treatment enhances uPAR mRNA stabilization. In contrast, inhibition of tyrosine phosphorylation augments PGK binding to uPAR mRNA and attenuates uPA-induced uPAR expression. Mapping the specific peptide region of PGK indicated that its first quarter (amino acids 1-100) interacts with uPAR mRNA. To determine if uPAR expression by uPA is regulated through activation of tyrosine residues of PGK, we mutated the specific tyrosine residue and tested mutant PGK for its ability to interfere with uPAR expression. Inhibition of tyrosine phosphorylation by mutating Y76 residue abolished uPAR expression induced by uPA treatment. These findings collectively demonstrate that Y76 residue present in the first quarter of the PGK molecule is involved in lung epithelial cell surface uPAR expression. This region can effectively mimic the function of a whole PGK molecule in inhibiting tumor cell growth. PMID- 19784758 TI - Blood gene expression markers to detect and distinguish target organ toxicity. AB - The purpose of this study was to investigate whether the expression of specific genes in peripheral blood can be used as surrogate marker(s) to detect and distinguish target organ toxicity induced by chemicals in rats. Rats were intraperitoneally administered a single, acute dose of a well-established hepatotoxic (acetaminophen) or a neurotoxic (methyl parathion) chemical. Administration of acetaminophen (AP) in the rats resulted in hepatotoxicity as evidenced from elevated blood transaminase activities. Similarly, administration of methyl parathion (MP) resulted in neurotoxicity in the rats as evidenced from the inhibition of acetyl cholinesterase activity in their blood. Administration of either chemical also resulted in mild hematotoxicity in the rats. Microarray analysis of the global gene expression profile of rat blood identified distinct gene expression markers capable of detecting and distinguishing hepatotoxicity and neurotoxicity induced by AP and MP, respectively. Differential expressions of the marker genes for hepatotoxicity and neurotoxicity were detectable in the blood earlier than the appearance of the commonly used clinical markers (serum transaminases and acetyl cholinesterase). The ability of the marker genes to detect hepatotoxicity and neurotoxicity was further confirmed using the blood samples of rats administered additional hepatotoxic (thioacetamide, dimethylnitrobenzene, and carbon tetrachloride) or neurotoxic (ethyl parathion and malathion) chemicals. In summary, our results demonstrated that blood gene expression markers can detect and distinguish target organ toxicity non invasively. PMID- 19784759 TI - Variable effects of the mitoK(ATP) channel modulators diazoxide and 5-HD in ATP depleted renal epithelial cells. AB - The role of mitochondrial K(ATP) (mitoK(ATP)) channels in renal ischemia reperfusion injury is controversial with studies showing both protective and deleterious effects. In this study, we compared the effects of the putative mitoK(ATP) opener, diazoxide, and the mitoK(ATP) blocker, 5-hydroxydecanoate (5 HD) on cytotoxicity and apoptosis in tubular epithelial cells derived from rat (NRK-52E) and pig (LLC-PK1) following in vitro ischemic injury. Following ATP depletion-recovery, there was a significant increase in cytotoxicity in both NRK cells and LLC-PK1 cells although NRK cells were more sensitive to the injury. Diazoxide treatment attenuated cytotoxicity in both cell types and 5-HD treatment increased cytotoxicity in the sensitive NRK cells in a superoxide-dependant manner. The protective effect of diazoxide was also reversed in the presence of 5 HD in ATP-depleted NRK cells. The ATP depletion-mediated increase in superoxide was enhanced by both diazoxide and 5-HD with the effect being more pronounced in the cells undergoing 5-HD treatment. Further, ATP depletion-induced activation of caspase-3 was decreased by diazoxide in NRK cells. In order to determine the signaling pathways involved in apoptosis, we examined the activation of Erk and JNK in ATP-depleted NRK cells. Diazoxide-activated Erk in ATP-depleted cells, but did not have any effect on JNK activation. In contrast, 5-HD did not impact Erk levels but increased JNK activation even under controlled conditions. Further, the use of a JNK inhibitor with 5-HD reversed the deleterious effects of 5-HD. This study demonstrates that in cells that are sensitive to ATP depletion recovery, mitoK(ATP) channels protect against ATP depletion-mediated cytotoxicity and apoptosis through Erk- and JNK-dependant mechanisms. PMID- 19784760 TI - Low temperature preparation of calcium phosphate structure via phosphorization of 3D-printed calcium sulfate hemihydrate based material. AB - The conversion of newly developed three dimensionally printed calcium sulfate hemihydrate (70-90% wt/wt CaSO(4).0.5.H(2)O) based materials to calcium phosphate bioceramics by phosphorization in di-sodium hydrogen phosphate solution at 80 degrees C for 4, 8, 16 and 24 h was studied. It was found that transformation rate, phase composition and mechanical properties were influenced by porosity in the fabricated samples and by the duration of the phosphorization treatment. Formulation with 85% CaSO(4).0.5 H(2)O showed the fastest transformation rate and resulted in the highest flexural modulus and strength. Depending on the materials formulation, XRD, FT-IR and EDS revealed that calcium deficient hydroxyapatite (CDHA) or a mixture of CDHA and dicalcium phosphate anhydrous (DCPA) were the resulting phases in the transformed samples. After cell culturing for 14 and 21 days, human osteoblast cells were observed to attach to and attain normal morphology on the surface of the transformed sample containing 85% CaSO(4).0.5 H(2)O. Various sizes and shapes of mineralized nodules were also found after 21 days. PMID- 19784761 TI - Self-assembled particles of N-phthaloylchitosan-g-polycaprolactone molecular bottle brushes as carriers for controlled release of indometacin. AB - A series of amphiphilic N-phthaloylchitosan-g-polycaprolactone molecular bottle brushes were prepared by "graft onto" method. The narrow distribution of polycaprolactone macromonomers ensures that the molecular bottle brushes can self assemble into highly monodisperse particles, which have the ability to get a high loading efficiency of the hydrophobic drug, indometacin (INN). Searching for the effective drug loading ratio, three parameters such as polycaprolactone chain length, the grafting content and concentration of the molecular bottle brushes were tested to entrap INN. These encapsulated drug particles show sustained release of the encapsulated INN, of which 91.7% was released in 22 h at 37 degrees C in phosphate buffered saline. The self-assembled particles of the molecular bottle brushes as carriers for INN can effectively prevent the drug from releasing quickly and prolong the release time, which is a promising candidate for potential clinical applications. PMID- 19784762 TI - Engineering of crystalline combination inhalation particles of a long-acting beta2-agonist and a corticosteroid. AB - PURPOSE: Engineering of inhalation particles incorporating, in each individual particle, a combination of a long-acting beta-agonist and a glucocorticosteroid in a pre-determined and constant ratio for delivery via a dry powder inhaler (DPI). METHODS: Individual crystalline particles containing both the glucocorticosteroid fluticasone propionate (FP) and long-acting beta-agonist salmeterol (SX) were prepared, in a ratio of 10:1, using the solution atomization and crystallization by sonication (SAX) process. Combination drug particles were characterized by particle size, morphology, crystallinity and aerosolisation efficiency using inertial impaction. RESULTS: Combination drug particles were spherical and crystalline, with a median diameter of 4.68 +/- 0.01 microm. Aerosolisation of formulations containing combination drug particles resulted in greater uniformity in delivery ratios of both actives across all stages of the impactor before and after storage. CONCLUSIONS: Actives in a pre-determined dose ratio can be crystallised in a single particle using the SAX process. PMID- 19784763 TI - Detection of bifidobacterium species-specific 16S rDNA based on QD FRET bioprobe. AB - Fluorescence resonance energy transfer (FRET) that consists of quantum dot as donors and organic fluorophore dyes as acceptors has been a very important method to detect biomolecules such as nucleic acids. In this work, we established a new FRET detection system of Bifidobacterium species-specific 16S rDNA using QD-ROX FRET bioprobe, in which 525 nm QD-DNA conjugation consisted of the carboxyl modified QD and the amino-modified DNA in the presence of EDC. Both ROX-DNA and the conjugation above could hybridize with the target DNA after forming the QD ROX bioprobe. When the hybridization made the distance between the QD and ROX to meet FRET effect needed, 525 nm QD fluorescence intensity decreased and ROX fluorescence intensity increased. In the control, there was no notable change of fluorescence intensities without target DNA. It is very clear that the change of the QD and ROX fluorescence intensities provide the good base and guaranty for this rapid and simple detection system. PMID- 19784764 TI - Mitochondria, cholesterol and amyloid beta peptide: a dangerous trio in Alzheimer disease. AB - The molecular mechanisms of Alzheimer's disease (AD) are not fully understood. Extensive evidence from experimental models has involved the overgeneration and accumulation of toxic amyloid beta peptides (Abeta) in the onset and progression of the disease. The amyloidogenic processing of amyloid precursor protein into pathogenic Abeta fragments is thought to occur in specific domains of the plasma membrane and favored by cholesterol enrichment. Intracellular Abeta accumulation is known to induce oxidative stress, predominantly via mitochondria targeting of toxic Abeta. Recent evidence using mouse models of cholesterol loading has demonstrated that the specific mitochondrial cholesterol pool sensitizes neurons to Abeta-induced oxidant cell death and caspase-independent apoptosis due to selective mitochondrial GSH (mGSH) depletion induced by cholesterol-mediated perturbation of mitochondrial membrane dynamics. mGSH replenishment by permeable precursors such as glutathione ethyl ester protected against Abeta-mediated neurotoxicity and inflammation. Thus, these novel data expand the pathogenic role of cholesterol in AD indicating that in addition to fostering Abeta generation, mitochondrial cholesterol determines Abeta neurotoxicity via mGSH regulation. PMID- 19784765 TI - The role of cognitive distortion in the relationship between abuse, assault, and non-suicidal self-injury. AB - The purpose of this study was to examine the relationship between childhood abuse, assault, cognitive distortion, and non-suicidal self-injury (NSSI) in a clinical adolescent sample. The sample included one hundred eighty-five psychiatrically hospitalized adolescents and their parents. Adolescent participants were predominantly female (71.4%), Caucasian (84%), and of non Hispanic ethnicity (9.2%). Participants completed a diagnostic interview and self report measures to assess youth history of abuse and assault, cognitive errors, negative self-views, and recent NSSI. No relationship was found between childhood abuse and NSSI. However, a history of assault was associated with NSSI among youth who reported higher cognitive errors and more negative self-views, even after controlling for gender and internalizing disorders. These results suggest that existing affect regulation models of NSSI may be enhanced by incorporating the role of cognitive distortion. Clinically, results also suggest that assessing adolescent victims of assault for cognitive errors and negative self-views, and helping them restructure these cognitive distortions when present, may reduce the likelihood of NSSI. PMID- 19784766 TI - Ischaemic preconditioning and postconditioning do not affect adenosine A(1) and A (2A) receptor sensitivity. PMID- 19784767 TI - (Self-)abusive prophecies, rigorous science, and discursive templates: commentary on Malon (2009). PMID- 19784768 TI - The DSM diagnostic criteria for female orgasmic disorder. AB - This article reviews the DSM diagnostic criteria for Female Orgasmic Disorder (FOD). Following an overview of the concept of female orgasm, research on the prevalence and associated features of FOD is briefly reviewed. Specific aspects of the DSM-IV-TR criteria for FOD are critically reviewed and key issues that should be considered for DSM-V are discussed. The DSM-IV-TR text on FOD focused on the physiological changes that may (or may not) accompany orgasm in women; one of the major recommendations here is that greater emphasis be given to the subjective aspects of the experience of orgasm. Additional specific recommendations are made for revision of diagnostic criteria, including the use of minimum severity and duration criteria, and better acknowledgment of the crucial role of relationship factors in FOD. PMID- 19784769 TI - The DSM diagnostic criteria for sexual aversion disorder. AB - Sexual Aversion Disorder (SAD) is one of two Sexual Desire Disorders in the Diagnostic and Statistical Manual of Mental Disorders (DSM) and is defined as a "persistent or recurrent extreme aversion to, and avoidance of, all or almost all, genital sexual contact with a sexual partner" which causes distress or interpersonal difficulty. This paper reviews the short history of the diagnosis of SAD as well as the existing literature on its prevalence and etiology. Kaplan (1987) emphasized the phobic qualities of individuals with SAD who are highly avoidant of all forms of sexual contact. Much has also been written about the overlap between SAD and panic states, and the more obvious similarities between SAD and anxiety as opposed to sexual desire are described. There has been very little new published data on SAD since the publication of DSM-IV and the precise prevalence remains unknown. This paper critiques the placement of SAD as a Sexual Dysfunction and argues that it might more appropriately be placed within the Specific Phobia grouping as an Anxiety Disorder. PMID- 19784771 TI - Correlation between an in vitro and an in vivo measure of dioxin sensitivity in birds. AB - We describe a statistically significant correlation between two well characterized responses to dioxin-like compounds in birds; induction of 7 ethoxyresorufin-O-deethylase (EROD) activity in cultured hepatocytes, and embryo mortality. Data were obtained from a review of the literature. EROD EC50 values for 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and 6 polychlorinated biphenyls (PCBs) were strongly correlated with LD50 values in chicken embryos (r(2) = 0.93, P < 0.005). Similarly, EROD EC50 values for TCDD and a potent dioxin-like compound, PCB 126, were correlated with embryonic LD50 values in different species of birds (chicken, ring-necked pheasant, turkey, double-crested cormorant, and common tern) (r(2) = 0.92, P < 0.005). Our findings contribute to a developing understanding of the molecular basis for differential dioxin sensitivity in birds, and validate the EROD bioassay as a useful predictive tool for ecological risk assessment. PMID- 19784770 TI - Breast cancer expresses functional NMDA receptors. AB - We demonstrate here that functional NMDAR1 and NMDAR2 receptors are expressed by Mcf-7 and SKBR3 breast cancer cell lines, and possibly by most or all high-grade breast tumors, and that these receptors are important for the growth of human breast cancer xenografts in mice. RT-PCR demonstrated mRNA for both NMDAR1 and NMDAR2 receptors are expressed in both Mcf-7 and SKBR3 cell lines, and these messages likely have sequences identical to those reported for human mRNAs. Proteins of the expected respective sizes 120 and 170 kD are generated from these mRNAs by the tumor cells. Cell growth was found to be significantly (P < 0.0001) impaired down to 10% of normal growth by the irreversible NMDAR1 antagonists MK 801 and memantine with IC 50s ranging from 600 to >800 microM and from 200 to 300 microM for the two lines. Paradoxically, memantine with a lower binding affinity had the greater influence of the two inhibitors on cell viability. Immunohistochemical examination of high-grade invasive ductal and lobular breast cancer with our polyclonal antibodies against a peptide (-Met-Ser-Ile-Tyr-Ser-Asp Lys-Ser-Ile-His-) in the extracellular domain of the NMDAR1 receptor gave specific positive staining for the receptor in all 10 cases examined. Positive staining was chiefly concentrated at the membranes of these tumor tissues. No staining with these antibodies was found for normal breast and kidney tissues. When Mcf-7 cells were grown as tumor xenografts in nu/nu mice, the growth of these tumors was completely arrested by daily treatments with MK-801 over 5 days. All of these data point to active NMDAR receptors being expressed by most breast cancers, and having an important influence on their survival. PMID- 19784773 TI - Accessing primary care: HIV+ Caribbean immigrants in the Bronx. AB - This article describes an ecology of health seeking behavior among Bronx residing HIV+ Caribbean immigrants participating in an arm of a U.S. government-funded multi-site evaluation of peer services in the utilization of HIV primary care. Standardized repeat measures were administered at baseline and three four-month intervals. Clinical markers were obtained through medical chart review. Additionally, local data included ethnographic interviews, focus groups, and progress notes. Clinical outcomes were positive for the 55 subjects, 23 of whom were undocumented. Alienation from family, women's vulnerability to family violence, and difficulties with disclosure, employment, and health care were compounded by undocumented immigration status. Retention was encouraged by the community based site, high levels of peer interaction, and supportive services. Without consideration of broader contexts, peer driven interventions are potentially limited and the realities of immigrant health care are misunderstood through lack of recognition of competing needs. PMID- 19784772 TI - SOD and CAT cDNA cloning, and expression pattern of detoxification genes in the freshwater bivalve Unio tumidus transplanted into the Moselle river. AB - The cDNA sequences encoding manganese superoxide dismutase (Mn-SOD) and catalase (CAT) were isolated in the freshwater bivalve Unio tumidus by reverse transcription polymerase chain reaction (RT-PCR) using degenerate primers. Quantitative real-time PCR approach was used to evaluate the mRNA expression patterns of SOD, CAT, selenium-dependent glutathione peroxidase (Se-GPx), pi class glutathione S-transferase (pi-GST) and metallothionein (MT), in the digestive gland of Unio tumidus transplanted from a control site to four stations in the Moselle River (M1-M4), for periods of 8 and 21 days. These sites were chosen upstream and downstream of populated areas. Chemical analysis performed on sediments from the Moselle river sites did not show high levels of pollutants. Decrease of SOD, CAT, Se-GPx and MT mRNA levels were observed at M3 site after a 21-day exposure compared to control site. These results suggest inefficiency of antioxidant systems affected by cytotoxic mechanisms and confirm an environmental perturbation. Organisms transplanted at M4 site showed a strong increase of biomarkers transcription levels after 21 days of exposure. These inductions could correspond to an adaptive response to an altered environment. Our results showed that biological approaches using multibiomarkers appear as essential tools complementary to measurement of contaminants, to detect environmental degradations. PMID- 19784774 TI - A bioreactor with compliance monitoring for heart valve grafts. AB - The drawbacks of state-of-the-art heart valve prostheses lead researchers to explore the prospect of using tissue-engineered constructs as possible valve substitutes. It is widely accepted that the mechanical properties of the construct are improved with mechanical stimulation during in vitro growth. We designed a new dynamic bioreactor with the perspective of using decellularized valve homografts as scaffolds in order to produce tissue-engineered valve substitutes. The design guidelines were (a) compatibility with the procedures for the treatment of homografts; (b) delivery of finely controlled pulsatile pressure loads, which induce strain stimuli that may drive cells toward repopulation of and integration with the natural scaffold; and (c) monitoring the construct's biomechanical status through a comprehensive index, i.e., its compliance. The handling needs during the set-up of the homograft and the use of the bioreactor were minimized. The bioreactor and its automated control system underwent tests with a compliant phantom valve. The estimated compliances are in good agreement with the measured ones. Tests were also carried out with porcine aortic samples in order to assess the hydrodynamic and biomechanical reliability. In the future, monitoring the construct's compliance might represent a key factor in controlling the recellularization of the valve homografts, which provides awareness of the construct's biomechanical status by real-time, non-destructive, and non-invasive means. PMID- 19784776 TI - Religion and the Catholic church's view on (heart) transplantation: a recent statement of Pope Benedict XVI and its practical impact. AB - Heart transplantation is performed on approximately 4,000 patients per year worldwide and is considered the last resort for treatment of end-stage heart diseases. Due to persistent organ shortage, resources are limited, waiting periods are extensive, and patients still die while being on a waiting list for transplantation. The role of all churches and the support of the representatives of the churches are critical for the spiritual wellbeing of patients awaiting heart transplantation as well as for prospective individual organ donors and their families. The supportive role of the Roman Catholic Church and the recent statement of Pope Benedict XVI on organ donation are discussed. PMID- 19784777 TI - Death of ouabain-treated renal epithelial cells: evidence for p38 MAPK-mediated Na (i) (+) /K (i) (+) -independent signaling. AB - Recent studies demonstrate that cytotoxic actions of ouabain and other cardiotonic steroids (CTS) on renal epithelial cells (REC) are triggered by their interaction with the Na(+),K(+)-ATPase alpha-subunit but not the result of inhibition of Na(+),K(+)-ATPase-mediated ion fluxes and inversion of the [Na(+)](i)/[K(+)](i) ratio. This study examined the role of mitogen-activated protein kinases (MAPK) in the death of ouabain-treated REC. Exposure of C7-MDCK cells that resembled principal cells from canine kidney to 3 microM ouabain led to phosphorylation of p38 without significant impact on phosphorylation of ERK and JNK MAPK. Maximal increment of p38 phosphorylation was observed at 4 h followed by cell death at 12 h of ouabain addition. In contrast to ouabain, neither cell death nor p38 MAPK phosphorylation were affected by elevation of the [Na(+)](i)/[K(+)](i) ratio triggered by Na(+),K(+)-ATPase inhibition in K(+)-free medium. p38 phosphorylation was noted in all other cell types exhibiting death in the presence of ouabain, such as intercalated cells from canine kidney and human colon rectal carcinoma cells. We did not observe any action of ouabain on p38 phosphorylation in ouabain-resistant smooth muscle cells from rat aorta and endothelial cells from human umbilical vein. Both p38 phosphorylation and death of ouabain-treated C7-MDCK cells were suppressed by p38 inhibitor SB 202190 but were resistant to its inactive analogue SB 202474. Our results demonstrate that death of CTS-treated REC is triggered by Na (i) (+) ,K (i) (+) -independent activation of p38 MAPK. PMID- 19784778 TI - Effects of upregulated expression of microRNA-16 on biological properties of culture-activated hepatic stellate cells. AB - In our previous studies, we identified miR-16 as being downregulated during activation of hepatic stellate cells (HSCs) by microarray hybridization. However, the roles and related mechanisms of miR-16 in HSCs are not understood. In this study, The miRNA RNAi technique was used to analyze the effects of miR-16 on biological properties of HSCs in vitro. The lentiviral vector encoding miR-16 was constructed and transfected. Furthermore, the expression level of miR-16 was measured by real-time PCR. Cellular growth and proliferation capacity were assayed using the cell counting kit-8 (CCK-8). The apoptosis rate and cell-cycle distribution were measured by flow cytometry. Cell morphological characteristics were identified by phase-contrast microscopy, fluorescence microscopy and electron microscopy. The underlying mechanisms related to the changes in biological properties were assessed. The identity of the recombinant plasmid was confirmed by restriction endonuclease analysis and DNA sequencing. Virus titer was 10(8) > ifu/m. Restoring the intracellular miRNAs by miR-16 administration greatly reduced the expression levels of cyclin D1 (CD1). Cell-cycle arrest and typical features of apoptosis were detected in activated HSCs treated with pLV miR-16. Our results indicate that transduction of miR-16 offers a feasible approach to significantly inhibit HSC proliferation and increase the apoptosis index. Thus, targeted transfer of miR-16 into HSC may be useful for the treatment of hepatic fibrosis. PMID- 19784779 TI - The problem of application: aesthetics in creativity and health. AB - The Problem of Application investigates the multiple viewpoints in defining a critical aesthetic in applied arts practice. Amongst organisations, participants, and facilitators there are varying wants and needs in any creative project with an educational agenda. The product of arts based health initiatives often seek to inform and educate, whereby an aesthetic standard may seem contrary to this participatory approach. This research maintains that an aesthetic approach is a lively portion of the collaborative dialogue, which requires interrogation and consideration for a successful outcome. Through the analysis of a participatory arts project completed in West Africa addressing youth issues and HIV/AIDS, The Problem of Application seeks to uncover the multiple facets surrounding the defining of aesthetics in applied practice. The project entitled Youth Visions: Transforming our Futures Together worked with students aged 17-21 to develop an outdoor mural and a live performance inspired by the traditions of local festivals. With an anthropological approach to aesthetic criticism, Youth Visions revealed the multiple layers that define our focus of appreciation. PMID- 19784780 TI - Examining creativity in health and care. AB - This paper is drafted as an overview of the process of the Creativity in Health and Care workshop programme the themes arising from the project. It is intended as an introduction to the special edition and the notion of creativity that is being explored. PMID- 19784782 TI - Macrophage migration inhibitory factor expression and protein localization in Amblyomma americanum (Ixodidae). AB - Amblyomma americanum (L.) ticks continue to emerge as disease vectors in many areas of the United States. Tick macrophage migration inhibitory factor (MIF) was first identified in A. americanum females and has been demonstrated to inhibit macrophage movement to the same extent as human MIF. This study was conducted to further characterize and elucidate the physiological role for MIF in tick feeding. A relative quantitative PCR assay was developed to determine the level of MIF gene expression during tick feeding. In addition, RNAi techniques were used to silence MIF prior to blood feeding. Physiological parameters of tick engorgement weight, length of feeding interval, and egg masses were observed to check for phenotypic manifestations of RNA silencing. Specific tick MIF antibody was used to localize MIF protein in frozen tick tissue sections. Tissue specific gene expression indicated that the midgut tissues were the most highly enriched for the MIF. Levels of gene expression did not parallel MIF protein pools seen in tissue sections. Of particular importance was the finding that unfed tick salivary glands appear to contain vesicles that are specific for MIF protein. This is the first demonstration of a pool of MIF that could be secreted during the first hours of tick feeding. While MIF silencing was demonstrated at the molecular level, no physiological phenotype was apparent. The MIF protein pools already available in the tissues may be sufficient to accomplish female tick feeding. Our studies show that the most prominent source of MIF during tick feeding is the midgut tissue. Future studies will address the role of MIF in blood feeding and nutrient digestion in the immature life stages of the tick. PMID- 19784783 TI - Efficacy of Neoseiulus californicus and Phytoseiulus persimilis in suppression of Tetranychus urticae in young clementine plants. AB - Tetranychus urticae is one of the most damaging tetranychid mites affecting clementine orchards in Spain, where natural control is insufficient. Furthermore, in clementine nurseries, tender foliage is highly susceptible to attack and natural enemies are almost always absent. Therefore, acaricides are often used indiscriminately. Alternative control measures are necessary, both in commercial orchards and clementine nurseries. In order to assess the efficacy of inoculative releases of N. californicus and P. persimilis to reduce T. urticae populations in young Spanish clementine plants, a semi-field experiment was conducted and repeated in three seasons (spring, summer and autumn). Phytoseiulus persimilis was highly effective in reducing both T. urticae infestations and the damage level inflicted on plants at both release rates evaluated (40 and 80 phytoseiids/plant) and all three periods considered. By contrast, N. californicus demonstrated low performance under certain conditions. The results of this study could be adapted and transferred to nurseries and young citrus plantations. PMID- 19784781 TI - Effects of circadian disruption on the cardiometabolic system. AB - The presence of day-night variations in cardiovascular and metabolic functioning is well known. However, only recently it has been shown that cardiovascular and metabolic processes are not only affected by the behavioral sleep/wake cycle but are partly under direct control of the master circadian pacemaker located in the suprachiasmatic nucleus (SCN). Heart rate, cardiac autonomic activity, glucose metabolism and leptin-involved in appetite control-all show circadian variation (i.e., under constant behavioral and environmental conditions). This knowledge of behavioral vs. circadian modulation of cardiometabolic function is of clinical relevance given the morning peak in adverse cardiovascular incidents observed in epidemiological studies and given the increased risk for the development of diabetes, obesity, and cardiovascular disease in shift workers. We will review the evidence for circadian control of cardiometabolic functioning, as well its sensitivity to light and melatonin, and discuss potential implication for therapy. PMID- 19784784 TI - The effects of spiromesifen on life history traits and population growth of two spotted spider mite (Acari: Tetranychidae). AB - Laboratory bioassays were conducted to evaluate the effects of spiromesifen on gross fecundity, gross fertility, net fertility and population growth of two spotted spider mite (Tetranychus urticae Koch) after treatments with four acaricide concentrations: 180 mg/l, i.e. maximum recommended concentration for use in glasshouses against spider mites, 18, 1.8, and 0.18 mg/l, i.e. concentration discriminative for eggs and immatures in preliminary studies which produced 100% mortality of these stages. Quiescent female deutonymphs were treated in the first assay, and young pre-ovipositing females in the second and third, in which exposure lasted 6 h and 20 h, respectively. In the first assay, the 180, 18, and 1.8 mg/l concentrations significantly reduced gross fecundity (61-85%), gross fertility (64-87%) and net fertility (85-94%) of the surviving females. In the second one, only the highest concentration achieved a significant statistical reduction in gross fecundity (52%), gross fertility (67%) and net fertility (84%). In the third assay, fecundity and fertility reduction under the two highest concentrations was 98-99% and 93-98%, whereas it was 50-74% under the 1.8 mg/l concentration, and statistically different from control values. In all three trials, treatments with 180, 18, and 1.8 mg/l concentrations significantly reduced the instantaneous rate of increase. In the third assay, treatments with the two highest concentrations caused population decline. Sublethal activity of the 0.18 mg/l concentration was not found in any assay to be statistically significant. Sublethal effects of spiromesifen and its impact on T. urticae management are discussed. PMID- 19784785 TI - Anti-metastatic effects of liposomal gemcitabine in a human orthotopic LNCaP prostate cancer xenograft model. AB - Fatal outcomes of prostate carcinoma (PCa) mostly result from metastatic spread rather than from primary tumor burden. Here, we monitored growth and metastatic spread of an orthotopic luciferase/GFP-expressing LNCaP PCa xenograft model in SCID mice by in vivo imaging and in vitro luciferase assay of tissues homogenates. Although the metastatic spread generally shows a significant correlation to primary tumor volumes, the susceptibility of various tissues to metastatic invasion was different in the number of affected animals as well as in absolute metastatic burden in the individual tissues. Using this xenograft model we showed that treatment with liposomal gemcitabine (GemLip) inhibited growth of the primary tumors (83.9 +/- 6.4%; P = 0.009) as well as metastatic burden in lymph nodes (95.6 +/- 24.0%; P = 0.047), lung (86.5 +/- 10.5%; P = 0.015), kidney (88.4 +/- 9.2%; P = 0.045) and stomach (79.5 +/- 6.6%; P = 0.036) already at very low efficient concentrations (8 mg/kg) as compared to conventional gemcitabine (360 mg/kg). Our data show that this orthotopic LNCaP xenograft PCa model seems to reflect the clinical situation characterized by the fact that at time of diagnosis, prostate neoplasms are biologically heterogeneous and thus, it is a useful model to investigate new anti-metastatic therapies. PMID- 19784786 TI - Prognostic factors and recurrence of hepatitis B-related hepatocellular carcinoma after argon-helium cryoablation: a prospective study. AB - To determine the long-term prognosis of hepatocellular carcinoma (HCC) after argon-helium cryoablation and identify the risk factors that predict metastasis and recurrence. A total of 156 patients with hepatitis B-related HCC less than 5 cm in diameter who underwent curative cryoablation were followed up prospectively for tumor metastasis and recurrence. Immunohistochemistry was used to analyze the expression of vascular endothelial growth factor (VEGF). HBV basal core promoter (BCP) and precore mutations were detected by DNA sequence analysis. Post treatment prognostic factors influencing survival, tumor metastasis and recurrence were assessed by univariate and multivariate analyses. The variables included the expression of VEGF in HCC tissues, clinical and pathologic characteristics of patients, and HBV features (HBV DNA level, HBV genotype, BCP mutation). The median follow-up period of the 156 patients was 37 months (range 8 48 months). The 1-, 2-, and 3-year overall survival rates were 92, 82 and 64%, respectively. The 1-, 2-, and 3-year recurrence-free survival rates were 72, 56 and 43%, respectively. Eighty-five patients (54.5%) had tumor recurrence or metastasis. The multivariate analysis showed that Child-Pugh class and the expression of VEGF in HCC tissues could be used as independent prognostic factors for overall survival. Meanwhile, the expression of VEGF in HCC tissues and HBV BCP mutations were found to be independent prognostic factors for recurrence-free survival. Strong expression of VEGF in HCC tissues and HBV BCP mutations are important risk predictors for recurrence or metastasis of HCC smaller than 5 cm in diameter. PMID- 19784787 TI - Expression of gap junctional protein connexin43 during 4-nitroquinoline-1-oxide induced rat tongue carcinogenesis. AB - Oral carcinogenesis is a multistep process and requires accumulation and interplay of a series of molecular genetic events. Gap junctions are intercellular channels composed of connexin subunits that mediate cell-cell communication. The disfunctions of gap junctions are believed to be associated with cancer development. We therefore investigated the expression of connexin (Cx)43, one of the major connexins in oral epithelia, during 4-nitroquinoline-1 oxide-induced rat tongue carcinogenesis. By immunohistochemistry, Cx43 expression was observed mainly in the cell membrane in normal rat oral epithelia. It was weak in the basal cell layer, increased in the stratum spinosum and stratum granulosum, and negative in the stratum corneum of normal epithelia. Throughout the course of carcinogenesis, both Cx43 immunostained area and mean intensity decreased with significant difference among various histopathological groups (P < 0.05). In cancerous oral epithelia cytoplasmic staining could be observed. However, Cx43 mRNA level showed no significant difference in the progress of oral carcinogenesis (P > 0.05) and without correlation to Cx43 protein immunostained area and mean intensity. Our results indicated that downregulation of Cx43 might be an early event during oral carcinogenesis, which could be a biomarker for early changes in oral malignant transformation. PMID- 19784788 TI - Association of IGF1 and IGFBP3 polymorphisms with colorectal polyps and colorectal cancer risk. AB - PURPOSE: Insulin-like growth factor 1 (IGF1) is a peptide growth factor that promotes cell proliferation and inhibits apoptosis. The bioavailability of IGF1 is regulated by the insulin-like growth factor binding protein 3 (IGFBP3). The purpose of this study was to examine the association of genetic variants in IGF1 (rs6214, rs6220, and rs35767) and IGFBP3 (rs2854744 and rs2854746) with risk of colorectal polyps and colorectal cancer. METHODS: In this ongoing colorectal cancer study of Austria (CORSA), a total of 3,360 Caucasian participants, consisting of 178 colorectal cancer patients, 328 patients with high risk polyps, 1,059 patients with low risk colorectal polyps, and 1,795 colonoscopy-negative controls, were recruited within a large colorectal screening project in the province Burgenland and from three hospitals in Vienna. Multiple logistic regression was applied to compare individuals of the control group against three different risk groups, namely, colorectal cancer group, high risk polyp group, and low risk polyp group. RESULTS: Carriers of the homozygous polymorphic genotype of the SNP rs6214 were associated with an increased colorectal risk (OR = 1.79, 95% CI 1.04-1.90) compared to the colonoscopy-negative controls; this was also found when combining colorectal cancer cases and high risk polyp group (OR = 1.39, 95% CI 1.01-1.90). CONCLUSION: Our results suggest that the SNP rs6214 of IGF1 could have an impact on developing colorectal cancer and colorectal polyps with villous elements. PMID- 19784789 TI - Frequently cited sources in cancer news coverage: a content analysis examining the relationship between cancer news content and source citation. AB - The media are a frequent and sometimes sole source of cancer information for many people. News coverage of cancer can be influential to cancer-related practices such as prevention or detection behaviors, and sources cited by journalists may be influential in shaping this coverage. A content analysis (n = 3,656 stories) revealed that the most frequently cited sources in cancer news articles-research institutions and medical journals-receive disproportionately more attention compared to the National Cancer Institute (NCI), the American Cancer Society (ACS), and pharmaceutical companies. Research institutions were cited twice as frequently as medical journals, and more than three times as frequently as pharmaceutical companies. Most clinical trial stories were optimistic or neutral in tone, and tone was significantly related to citations of pharmaceutical companies and medical journals. Implications for effects of cancer coverage on behaviors, and the influence of sources such as research institutions and pharmaceutical companies, are discussed. PMID- 19784790 TI - Different expression levels of TNF receptors on the rheumatoid synovial macrophages derived from surgery and a synovectomy as detected by a new flow cytometric analysis. AB - TNFalpha plays a crucial role in the pathogenesis of rheumatoid arthritis. It is very important to examine the expression of the TNF receptors, the ligand of TNFalpha. In this study, we developed a triple-color flow cytometric analysis using CD45 and CD14 monoclonal antibodies to simply detect the expression of the TNF receptors on the heterogeneous rheumatoid synovial cells. Using this system, we detected a higher population of macrophages and a greater TNF receptor expression on the synovial macrophages derived from a synovectomy in comparison to the findings obtained from knee joint replacement surgery. PMID- 19784791 TI - Characterization of Newcastle disease viruses isolated from chicken, gamefowl, pigeon and quail in Mexico. AB - Velogenic Newcastle disease has threatened the Mexican poultry industry since 1946. Seven strains of velogenic Newcastle disease virus were isolated from poultry and other avian species in central and northern Mexico from 1998 to 2006 and subjected to phylogenetic analysis and biological characterization using standard pathogenicity tests and challenge studies. Phylogenetic analysis showed that all velogenic strains belonged to genetic group V and are clearly divided in two lineages, since phylogenetic similarities between groups are of only 93-94%. Isolates from 1998 to 2001 are closely related to the strain responsible for the 2000 year outbreak raised in La Laguna region (Torreon strain), and are phylogenetically distinct from viruses isolated between 2004 and 2006 that are genetically related to the Chimalhuacan strain isolated in 1973. All the viruses of both, the Chimalhuacan and the Torreon groups, contained a virulent fusion protein cleavage site represented by the motif "GGRRQKRF", revealing that evolutionary changes occurred at a different site. Chicken embryo mean death time value was shorter for the Chimalhuacan-like viruses (43.9 hours), when compared with the 1998-2001 average (54.3 hours). ICPI average value was higher (1.92) for viruses isolated during 2004-2006 than that for viruses isolated before 2001 (1.74). Microscopic evaluation of bursa of Fabricius and thymus of 5w-o broiler chickens challenged with 106 LD50/0.2 ml showed that Chimalhuacan-like isolate caused more severe lesions at 48 hpi in bursa and 72 and 96 hpi in thymus than Torreon-like isolate. Along with the MDT, ICPI and microscopic results, our findings suggest that some distinct selective pressure on the very virulent Chimalhuacan strain isolated in early 1970's may have led to the appearance of the still velogenic but less virulent new group (Torreon-like) in the middle of 1990's. PMID- 19784792 TI - Postpartum follicular development in Brahman cows under two stocking rates. AB - The aim was to study postpartum follicular population dynamics in Brahman cows in the Mexican humid tropics and under different stocking rates. Lactating adult cows (n = 104) grazed native grammas (Paspalum spp., Axonopus spp.) under two stocking rates: 2.8 (high) or 1.7 (low) cows/ha. Follicle numbers and their size (millimetres) were measured by ovarian ultrasound scanning. Animals detected in oestrus and inseminated were taken out of the study. Both stocking rates produced similar (P < 0.05) body condition scores (BCS) and follicular dynamics. The percent of follicles, averaged over stocking rates, of <4 mm diminished and those of 5-8 mm increased with time, whilst those of >9 mm remained constant; respective values for the previously mentioned sizes were 60 days postpartum (n = 101), 49%, 56% and 5%; 120 days (n = 70), 28%, 66% and 6%; and 180 days (n = 15), 9%, 79% and 12%. There was a positive correlation between BCS and follicle number for size <4 mm (r = 0.73, P < 0.01), whilst for size 5-8 mm, this was negative (r = -0.51, P < 0.05), for follicles >9 mm, no difference was found (r = -0.08, P > 0.05). It was concluded that stocking rate did not affect follicular population dynamics of Brahman cows, but BCS dictated the number and categories of follicles present regardless of the stocking rate utilised. PMID- 19784793 TI - Urine cytokines suggest an inflammatory response in the overactive bladder: a pilot study. AB - PURPOSE: To study the hypothesis of detecting bladder inflammation associated with overactive bladder (OAB) through altered urine levels of cytokines, chemokines, and growth factors. METHODS: Midstream urine specimens were collected from a prospective study done on eight asymptomatic control subjects and 17 idiopathic OAB patients. The urine was analyzed by a multiplex panel screen for 12 chemokines, cytokines, growth factors, and soluble receptors using LuminexTM xMAP((r)) technology. Protein concentration values were normalized to the levels of creatinine. RESULTS: This analysis revealed a significant elevation of seven key proteins in the urine of OAB patients relative to controls (*P < 0.05). A greater than tenfold elevation was measured in OAB, relative to controls, in the levels of monocyte chemotactic protein-1 (MCP-1), soluble fraction of the CD40 ligand (sCD40L) in urine was obtained from OAB patients relative to controls. At least five fold elevations were detected in the levels of macrophage inflammatory protein (MIP-1beta), IL-12p70/p40, IL-5, epidermal growth factor (EGF), and growth-related oncogene GRO-alpha compared to controls. Significant threefold elevation was also noticed in the urine levels of sIL-2Ralpha, and IL-10 in the OAB group. The levels of the remaining proteins tested were not statistically significantly different from control values. CONCLUSIONS: The presence of elevated levels in urine of inflammatory biomarkers involved in inflammation and tissue repair suggests a role for inflammation in OAB, and may help in diagnosis and treatment of this disease. PMID- 19784794 TI - The identity of Penicillium sp. 1, a major contaminant of the stone chambers in the Takamatsuzuka and Kitora Tumuli in Japan, is Penicillium paneum. AB - Penicillium appeared as the major dweller in the Takamatsuzuka Tumulus (TT) and Kitora Tumulus (KT) stone chambers, both located in the village of Asuka, Nara Prefecture, in relation to the biodeterioration of the 1,300-year-old mural paintings, plaster walls and ceilings. Of 662 Penicillium isolates from 373 samples of the TT (sampling period, May 2004-2007) and the KT (sampling period, June 2004-Sep 2007), 181 were phenotypically assigned as Penicillium sp. 1 which shared similar phenotypic characteristics of sect. Roqueforti in Penicillium subg. Penicillium. Fifteen representative isolates of Penicillium sp. 1, 13 from TT and 2 from KT, were selected for molecular phylogenetic analysis. The 28S rDNA D1/D2, ITS, beta-tubulin, and lys2 gene sequence-based phylogenies clearly demonstrated that the three known species P. roqueforti, P. carneum and P. paneum in sect. Roqueforti, and all TT and KT isolates grouped together. In addition to this, TT and KT isolates formed a monophyletic group with the ex-holotype strain CBS 101032 of P. paneum Frisvad with very strong bootstrap supports. So far, P. paneum has been isolated only from mouldy rye breads, other foods, and baled grass silage. Therefore, this is the first report of P. paneum isolation from samples relating to the biodeteriorated cultural properties such as mural paintings on plaster walls. PMID- 19784795 TI - Imaging of multi-color fluorescence emission from leaf tissues. AB - Multi-color fluorescence emission from leaf tissues is presented as a powerful reporter on plant biochemistry and physiology that can be applied both at macro- and micro-scales. The blue-green fluorescence emission is typically excited by ultraviolet (UV) excitation. However, this approach cannot be applied in investigating intact leaf interior because the UV photons are largely absorbed in the epidermis of the leaf surface. This methodological barrier is eliminated by replacing the UV photon excitation by excitation with two infra-red photons of the same total energy. We demonstrate this approach by using two-photon excitation for microscopy of Arabidopsis thaliana leaves infected by pathogenic bacterium Pseudomonas syringae. The leaf structures are visualized by red chlorophyll fluorescence emission reconstructed in 3-D images while the bacteria are detected by the green emission of engineered fluorescence protein. PMID- 19784796 TI - FDG-PET can distinguish inflamed from non-inflamed plaque in an animal model of atherosclerosis. AB - The presence of activated macrophages is an important predictor of atherosclerotic plaque rupture. In this study, our aim was to determine the accuracy of (18)F- fluorodeoxyglucose (FDG) microPET imaging for quantifying aortic wall macrophage content in a rabbit model of atherosclerosis. Rabbits were divided into a control group and two groups post aortic balloon injury: 6 months high-cholesterol diet (HC); and 3 months HC followed by 3 months low-cholesterol diet plus statin (LCS). In vivo and ex vivo microPET, ex vivo well counting and histological quantification of the atherosclerotic aortas were performed for all groups. Macrophage density was greater in the HC group than the LCS group (5.1 +/ 1.4% vs. 0.6 +/- 0.7%, P < 0.001) with a trend towards greater macrophage density in LCS compared to controls (P = 0.08). There was a strong correlation across all groups between macrophage density and standardized uptake value (SUV) derived from ex vivo microPET (r = 0.95, P < 0.001) and well counting (r = 0.96, P < 0.001). Ex vivo FDG SUV was significantly different between the three groups (P < 0.001). However, the correlation between in vivo microPET FDG SUV and macrophage density was insignificant (r = 0.16, P = 0.57) with no statistical differences in FDG SUV seen between the three groups. This study confirms that in an animal model of inflamed and non-inflamed atherosclerosis, significant differences in FDG SUV allow differentiation of highly inflamed atherosclerotic aortas from those stabilized by statin therapy and low cholesterol diet and controls. PMID- 19784797 TI - Using FAM labeled DNA oligos to do RNA electrophoretic mobility shift assay. AB - The electrophoretic mobility shift assay is a useful tool to identify proteins and nucleic acids interactions. Traditionally, the nucleic acids fragments are end-labeled with (32)P. We present here the use of fluorescent methodologies for studies of RNA in place of radioactivity. The method is highly sensitive and quantitative with the use of an infrared fluorescence imaging system. Fluorescently labeled primers can be used to monitor protein-RNA interactions by fluorescent mobility shift assays. The simplicity and validity of this approach may have more advantages than that of previous methods that traditionally used hazardous radioisotopes. This method was successfully tested in the study of the interactions between MS2 Coat Protein and its RNA target. PMID- 19784798 TI - The Unification Space implemented as a localist neural net: predictions and error tolerance in a constraint-based parser. AB - We introduce a novel computer implementation of the Unification-Space parser (Vosse and Kempen in Cognition 75:105-143, 2000) in the form of a localist neural network whose dynamics is based on interactive activation and inhibition. The wiring of the network is determined by Performance Grammar (Kempen and Harbusch in Verb constructions in German and Dutch. Benjamins, Amsterdam, 2003), a lexicalist formalism with feature unification as binding operation. While the network is processing input word strings incrementally, the evolving shape of parse trees is represented in the form of changing patterns of activation in nodes that code for syntactic properties of words and phrases, and for the grammatical functions they fulfill. The system is capable, at least qualitatively and rudimentarily, of simulating several important dynamic aspects of human syntactic parsing, including garden-path phenomena and reanalysis, effects of complexity (various types of clause embeddings), fault-tolerance in case of unification failures and unknown words, and predictive parsing (expectation-based analysis, surprisal effects). English is the target language of the parser described. PMID- 19784801 TI - Evaluation of burnout syndrome in oncology employees. AB - Burnout is an important occupational problem for health care workers. We aimed to assess the burnout levels among oncology employees and to evaluate the sociodemographic and occupational factors contributing to burnout levels. The Maslach Burnout Inventory, which is designed to measure the three stages of burnout-emotional exhaustion (EE), depersonalization (DP), and personal accomplishment (PA), was used. The study sample consisted of 90 participants with a median age of 34 (range 23-56). The mean levels of burnout in EE, DP and PA stages were 23.80 +/- 10.98, 5.21 +/- 4.99, and 36.23 +/- 8.05, respectively, for the entire sample. Among the 90 participants, 42, 20, and 35.6% of the employees had high levels of burnout in the EE, DP, and PA substage, respectively. Sociodemographic and occupational factors associated with higher levels of burnout included age of less than 35, being unmarried, being childless, >40 work hours per week, working on night shifts, and <10 years experience in the medicine/oncology field. Within all oncology clinics, medical oncology employees had the highest levels of burnout. Furthermore, employees who are not pleased with working in oncology field, who would like to change their specialty if they have an opportunity, and whose family and social lives have been negatively affected by their work experienced higher levels of burnout. Burnout syndrome may influence physical and mental health of the employee and affects the quality of health care as well. Therefore, several individual or organizational efforts should be considered for dealing with burnout. PMID- 19784800 TI - A novel indicator of widespread endothelial damage and ischemia in diabetic patients: ischemia-modified albumin. AB - Ischemia-modified albumin (IMA) is a novel marker of tissue ischemia. Nowadays, IMA is accepted as a marker of oxidative stress. In this study, we aimed at establishing an association between IMA and hyperglycemia, blood pressure, lipid parameters, microvascular complications, hsCRP, and microalbuminuria in type 2 diabetes patients without overt macrovascular disease and acute ischemia. Fifty type 2 diabetes mellitus patients without a history of macrovascular disease or end-stage renal disease were enrolled into the study. Age-matched 30 healthy individuals were also included in the study as a control group. Plasma IMA (0.329 +/- 0.046 and 0.265 +/- 0.045 AbsU; P < 0.0001) and hsCRP levels (0.51 +/- 0.36 and 0.32 +/- 0.17 mg/dl; P < 0.0001) were significantly higher in the diabetic group compared to healthy controls. IMA level was significantly correlated with hsCRP (r = 0.76; P < 0.0001), HbA1c (r = 0.72; P < 0.0001), microalbuminuria (r = 0.40; P = 0.004), systolic blood pressure (r = 0.28; P = 0.049), diastolic blood pressure (r = 0.44; P = 0.005), and HOMA-IR (r = 0.42; P = 0.005) levels in the entire diabetic subjects. In the diabetic patients group, presence of microalbuminuria was associated with a higher plasma IMA level (0.355 +/- 0.035 and 0.265 +/- 0.0045 AbsU; P < 0.0001, patients with microalbuminuria and control subjects, respectively). In the type 2 diabetes patients with nephropathy, IMA level (0.355 +/- 0.035 and 0.311 +/- 0.046 AbsU; P = 0.002) was determined higher compared to the diabetes patients without nephropathy. Diabetic patients without an overt cardiovascular disease still have a higher serum IMA level compared to healthy controls. The correlation of high plasma IMA levels with high hsCRP and microalbuminuria levels in diabetic subjects indicates the presence of a chronic ischemic process. Therefore, elevated IMA levels may indicate an underlying subclinical vascular disease in type 2 diabetes mellitus patients. PMID- 19784802 TI - Body dysmorphic disorder, social anxiety and depressive symptoms in Chinese medical students. AB - AIM: This cross-sectional study explored the prevalence of body image dissatisfaction, body dysmorphic disorder, social anxiety and depressive symptoms in first-year medical students in China. METHODS: A self-report survey design was employed, using the Body Shape Questionnaire, Swansea Muscularity Attitudes Questionnaire, Social Interaction Anxiety Scale, Dysmorphic Concern Questionnaire, Self-Rating Depression Scale and the Body Dysmorphic Disorder Questionnaire. A total of 487 first-year medical students participated. RESULTS: About one-third of participants (32.5%) indicated that they were very concerned about some aspect of their appearance unrelated to weight, with six female participants (1.3%) screening positive for body dysmorphic disorder (BDD). Those who displayed concern with their appearance (including those who did not screen positive for BDD) had higher levels of depressive and social anxiety symptoms than those who had no appearance concerns. PMID- 19784803 TI - Determination of oxadiargyl residues in environmental samples and rice samples. AB - Oxadiargyl is a commonly used herbicide in China. We developed a simple, fast, and high-throughput method employing gas chromatography with electron capture detector to determine oxadiargyl residues in food samples (rice, straws) and environmental samples (soil, water). Samples were prepared by a modified QuEChERS procedure. In this method, acetonitrile was used as the extracting solvent. The purifying step was omitted when the chromatographic conditions were optimized. Recoveries ranged from 82.9 to 112.0% for oxadiargyl in all samples, with relative standard deviation values lower than 6.2% at 0.01 mg/kg fortified concentration level. PMID- 19784804 TI - Effect of (C6H5)3PbCl and (C6H5)3SnCl on delayed luminescence intensity, evolving oxygen and electron transport rate in photosystem II of Chlorella vulgaris. AB - The effect of the organometallic compounds containing lead, (C6H5)3PbCl , and tin, (C6H5)3SnCl, on Chlorella green algae photosystem II was studied. Suspension of the algae treated with (C6H5)3SnCl at concentrations of 1.0 and 4.0 micromol dm(-3) for 22 h revealed a decrease in most physiological parameters studied, particularly in decasecond component of delayed chlorophyll luminescence, photosynthetic electron transport rate and diluted oxygen concentration, which implies an inhibition of photosynthetic electron transport as well as oxygen evolving system. On the other hand, (C6H5)3PbCl caused stronger inhibition than (C6H5)3SnCl, particularly in the higher concentration. PMID- 19784805 TI - Modelling the long-term fate of mercury in a lowland tidal river. II. Calibration and comparison of two models with field data. AB - This study presents results of the application of two-one-dimensional/dynamic deterministic models developed to evaluate and predict mercury contamination of a lowland river, the River Yare, Norfolk, UK. As a general indication of model performance, MODEL 1 produced a prediction of the overall mass balance of mercury in the River Yare that was 6% lower than an estimate, based on measurements, and 10% lower than the prediction provided by MODEL 2. The mercury surficial sediment concentrations calculated by MODEL 1 varied from 0.46 mg kg(-1) in 1995 (Reach 3) to 3.55 mg kg(-1) in 1986 (Reaches 6 and 7), whereas the minimum mercury concentration calculated by MODEL 2 was 0.42 mg kg(-1) in 1995 (Reach 3) and the maximum was 8.45 mg kg(-1) in 1986 (Reach 5). Average mercury concentrations experimentally measured in surficial sediments ranged from 0.47 mg kg(-1) in 1995 (Reach 3) to 8.10 mg kg(-1) in 1986 (Reach 6). MODEL 2 gave an excellent prediction of mercury in fish flesh compared with the results obtained from the actual analysis of fish flesh. Both models demonstrated good ability to simulate actual values determined for all compartments, water, surficial sediments, bottom sediments, and fish. PMID- 19784806 TI - Modelling the long-term fate of mercury in a lowland tidal river. I. Description of two finite segment models. AB - Crucial determinants of the potential effects of mercury in aquatic ecosystems are the speciation, partitioning, and cycling of its various species. These processes are affected by site-specific factors, such as water chemistry, sediment transport, and hydrodynamics. This study presents two different approaches to the development of one-dimensional/dynamic-deterministic models for the evaluation and prediction of mercury contamination in a lowland tidal river, the River Yare (Norfolk, UK). The models described here were developed to encompass the entire river system and address the mass balance of mercury in a multicompartment system, including tidal reversal and saline limit. The models were focused on river systems, with the River Yare being used as a case study because previous modelling studies have been centred on lakes and wetlands whilst there is a paucity of information for rivers. Initial comparisons with actual measured water parameters (salinity and suspended solids) indicate that both models exhibit good agreement with the actual values. PMID- 19784807 TI - Effects of zinc ex vivo and intracellular zinc chelator in vivo on taurine uptake in goldfish retina. AB - Taurine and zinc exert neurotrophic effects. Zinc modulates Na(+)/Cl(-)-dependent transporters. This study examined the effect of zinc (ZnSO(4)) ex vivo and zinc chelator N,N,N',N'-tetrakis-(2-pyridylmethyl) ethylenediamine (TPEN) in vivo on [(3)H]taurine transport in goldfish retina. The effect of TPEN in vivo on taurine and zinc levels was determined. Isolated cells were incubated in Ringer with zinc (0.1-100 microM). Taurine transport was done with taurine (0.001-1 mM) and 50 nM [(3)H]taurine. Zinc (100 microM) noncompetitively inhibited taurine transport. TPEN was administered intraocularly and retinas extracted 3, 5 and 10 days later. Taurine was determined by HPLC (nmol/mg protein) and zinc by spectrophotometry ICP (mg/mg protein). Taurine and zinc levels decreased at 3 days and increased at 10 days after TPEN administration. At 10 days after intraocular TPEN, taurine transport affinity increased (K (s) = 0.018 +/- 0.006 vs. 0.028 +/- 0.008 mM). Apparently, zinc deficiency affects the taurine-zinc complex and taurine availability. The increased taurine uptake affinity by TPEN was possibly associated with a response to maximize retinal taurine content at low zinc concentration. PMID- 19784808 TI - Doxorubicin-mediated apoptosis in glioma cells requires NFAT3. AB - Nuclear factor of activated T cells (NFAT), a family of transcription factors, has been implicated in many cellular processes, including some cancers. Here, we characterize, for the first time, the role of NFAT3 in doxorubicin (DOX)-mediated apoptosis, migration, and invasion in SNB19 and U87 glioma cells. This study demonstrates that the specific knockdown of NFAT3 results in a dramatic inhibition of the apoptotic effect induced by DOX and favors cell survival. Inhibition of NFAT3 activation by shNFAT3 (shNF3) significantly downregulated tumor necrosis factor (TNF)-alpha induction, its receptor TNFR1, caspase 10, caspase 3, and poly (ADP-ribose) polymerase, abrogating DOX-mediated apoptosis in glioma cells. DOX treatment resulted in NFAT3 translocation to the nucleus. Similarly, shNF3 treatment in SNB19 and U87 cells reversed DOX-induced inhibition of cell migration and invasion, as determined by wound healing and matrigel invasion assays. Taken together, these results indicate that NFAT3 is a prerequisite for the induction of DOX-mediated apoptosis in glioma cells. PMID- 19784809 TI - Potential adenovirus-mediated gene therapy of glioma cancer. AB - Malignant gliomas are typically characterized by rapid cell proliferation and a marked propensity to invade and damage surrounding tissues. They are the main brain tumors notoriously resistant to currently available therapies, since they fail to undergo apoptosis upon anticancer treatments. With recent advances in neuroscience and improved understanding of the molecular mechanisms of invasive migration, gene therapy provides a new strategy for treating glioma cancer. Brain tumor gene therapy using viral vectors and stem cells has shown promise in animal model and human patient studies. Here, we review recent studies on engineering adenoviral vectors that can be used as therapy for brain tumors. The new findings presented in this study are essential for the further exploration of this cancer and they represent an approach for developing a newer and more effective therapeutic approach in the clinical treatment of human glioma cancer. PMID- 19784810 TI - Methyl groups as probes of supra-molecular structure, dynamics and function. AB - The development of new protein labeling strategies, along with optimized experiments that exploit the label, have significantly impacted on the types of biochemical problems that can now be addressed by solution NMR spectroscopy. Here we describe how methyl labeling of key residues in a highly deuterated protein background has facilitated studies of the structure, dynamics and interactions of supra-molecular particles. The methyl-labeling approach is briefly reviewed, followed by a summary of applications to three different molecular machines so as to illustrate the types of questions that can now be addressed. Areas where future innovations will lead to yet further improvements are highlighted as well. PMID- 19784812 TI - Partial purification and characterization of glutaminase from Lactobacillus reuteri KCTC3594. AB - In this study, we attempted to purify and characterize glutaminase (EC. 3.5.1.2) from Lactobacillus reuteri KCTC3594. The glutaminase was purified approximately 21-fold from the cell-free extract of L. reuteri KCTC3594 by protamine sulfate treatment and chromatography methods including anion exchange and gel filtration. The sizes of two major bands of the enzyme were presumed to be 70 and 50 kDa by sodium dodecyl sulfate polyacrylamide gel electrophoresis. The glutaminase activity of L. reuteri KCTC3594 was assayed in various ranges of pH, temperature, and salt concentrations. The enzyme activity was optimal at 40 degrees C and pH of 7.5. It was shown that the glutaminase was salt-tolerant because the enzyme activity was maintained 50% at 15% (w/v) salt concentrations. On the other hand, the enzyme was strongly inhibited up to 80% by 6-diazo-5-oxo-L-norleucine (10 mM) and iodoacetate (50 mM) indicating that the purified enzyme represents typical characteristics of glutaminase. PMID- 19784811 TI - Retinoid X receptor agonists inhibit phorbol-12-myristate-13-acetate (PMA) induced differentiation of monocytic THP-1 cells into macrophages. AB - Monocyte/macrophage differentiation is an essential process during atherosclerosis development. The retinoid X receptor (RXR) is a member of the nuclear hormone receptor superfamily, which plays an important regulatory role in many metabolic disorders, including atherosclerosis. The purpose of this study was to investigate the effect of RXR agonist on monocyte/macrophage differentiation in vitro. The THP-1 cell line was differentiated into a macrophage-like phenotype by incubation with phorbol-12-myristate-13-acetate (PMA) in the presence or absence of RXR agonist. The viability of adherent differentiated THP-1 cells was determined by MTT assay. Macrophage surface marker CD11b and CD36 was analyzed by flow cytometry. Phagocytosis was measured by fluorescence-labeled latex beads. The production of Cytokine Tunlornecrosisfactor alpha (TNF-alpha), Interlaken-12p70 (IL-12p70), and Matrix metalloproteinase-9 (MMP-9), each of which was analyzed by ELISA. In the presence of the RXR agonists 9-cis retinoic acid or SR11237, PMA-induced THP-1 cells became less adherent, showed decreased macrophage-like morphological changes, decreased cell surface antigen CD11b and CD36 expression, and down regulated the phagocytosis of latex beads and the production of TNF-alpha and MMP-9. These data suggest that RXR agonists inhibit PMA-induced THP-1 cell differentiation into macrophage-like cells, which may be helpful in understanding the anti-atherosclerotic effect of RXR and its agonists. PMID- 19784813 TI - Meta-analysis of randomized, controlled clinical trials in angiogenesis: gene and cell therapy in peripheral arterial disease. AB - We aim to determine the efficacy and safety of gene and cell angiogenic therapies in the treatment of peripheral arterial disease (PAD) and evaluate them for the first time by a meta-analysis. We include in the formal meta-analysis only the randomized placebo-controlled phase 2 studies with any angiogenic gene or cell therapy modality to treat patients with PAD (intermittent claudication, ulcer or critical ischemia) identified by electronic search in MEDLINE and EMBASE databases (1980 to date). Altogether, 543 patients are analyzed from six randomized, controlled trials that are comparable with regard to patient selection, study design, and endpoints. We perform the meta-analysis regarding clinical improvement (improvement of peak walk time, relief in rest pain, ulcer healing or limb salvage) and rate of adverse events. At the end of treatment, therapeutic angiogenesis shows a significantly clinical improvement as compared to placebo in patients with PAD (odds ratio [OR] = 1.437; 95% confidence interval [CI] = 1.03-2.00; P = 0.033). The response rate (improvement of peak walk time) of the pooled groups according to clinical severity does not significantly differ for gene therapy as compared with placebo in the treatment of claudicating patients (OR = 1.304; 95% CI = 0.90-1.89; P = 0.16). Otherwise, we find significant efficacy of the treatment in critical ischemia (OR = 2.20; 95% CI = 1.01-4.79; P = 0.046). The adverse events rates show a slightly significantly higher risk of potential nonserious adverse events (edema, hypotension, proteinuria) in the treated group (OR = 1.81; 95% CI = 1.01-3.38; P = 0.045). We find no differences in mortality from any cause, malignancy, or retinopathy. The patients with PAD, and particularly those with critical ischemia, improve their symptoms when treated with angiogenic gene and cell therapy with acceptable tolerability. PMID- 19784814 TI - Prognostic value of interleukin-6 during a 3-year follow-up in patients with acute ST-segment elevation myocardial infarction. AB - Accumulating evidence suggests that inflammation plays an essential role in the pathogenesis of atherosclerosis. This recognition has stimulated the evaluation of different inflammatory markers as potential predictors of cardiovascular risk. However, the existing data are limited and controversial. This study was designed to simultaneously measure serum levels of interleukin-6 (IL-6), soluble CD40 ligand (sCD40L), metalloproteinase-9 (MMP-9), and tissue inhibitor of metalloproteinase-1 (TIMP-1) in patients with acute ST segment elevation myocardial infarction (STEMI) and to evaluate their ability to predict prognosis. A prospective cohort study was conducted with 263 patients with first STEMI who were admitted to our institute within 6 h of symptoms onset. Clinical data were recorded and serum admission levels of IL-6, sCD40L, MMP-9, and TIMP-1 were measured by sandwich enzyme-linked immunosorbent assay. The patients were then followed prospectively for the occurrence of cardiovascular mortality for 3 years. Follow-up information was available for 228 patients (86.7%) from the 263 STEMI patients; 34 patients died from cardiovascular causes during the 3-year follow-up period. Kaplan-Meier plots demonstrated a significant increase in cardiovascular mortality with increasing IL-6 levels (chi(2) = 14.13, P = 0.0002, by log-rank test). Logistic regression analysis revealed that IL-6 was an independent predictor for cardiovascular mortality. The present study indicates that elevated admission level of IL-6 could provide valuable information for long term risk stratification in patients with STEMI. PMID- 19784815 TI - Effect of balloon inflation time on expansion of sirolimus-eluting stent. AB - There is little information about the relationship between balloon inflation time and sirolimus-eluting stent (SES) expansion. In this randomized intravascular ultrasound (IVUS) study, 92 de novo lesions in native coronary arteries that underwent SES implantation were enrolled. Sirolimus-eluting stent was implanted using an inflation pressure of 14 atm. Stent balloon was gradually inflated until 14 atm in 10 s. In the short inflation group, it was deflated immediately after an image of the balloon inflated at 14 atm was taken. Stent balloon inflation lasted 60 s in the long inflation group. Intravascular ultrasound was then performed. The long balloon inflation resulted in a larger stent cross-sectional area (4.9 +/- 1.6 mm(2) vs 4.3 +/- 1.4 mm(2), P < 0.05) and expansion (71% +/- 13% vs 60% +/- 13%, P < 0.001) compared to the short balloon inflation, although stent expansion was relatively low in both groups. The relatively longer balloon inflation time using an inflation pressure of 14 atm results in better SES expansion. However, in the majority of lesions, adequate stent expansion is not achieved even using long balloon inflation, if it is inflated at 14 atm. PMID- 19784816 TI - Intensive cholesterol-lowering therapy improves large artery elasticity in acute myocardial infarction patients. AB - This study was aimed at probing the effects of intensive cholesterol-lowering therapy with simvastatin on the large artery elasticity of acute myocardial infarction patients. A total of 72 cases of acute myocardial infarction patients were divided into a normocholesterol group (n = 37) and a hypercholesterol group (n = 35) according to their serum low-density lipoprotein. All patients were given oral simvastatin 40 mg/day for 6 months, and their pulse-wave velocity (PWV) of different artery segments and ankle-brachial index (ABI) were measured before and after the therapy. The low-density lipoprotein cholesterol level in both groups decreased significantly (2.13 +/- 0.32 vs 1.56 +/- 0.28, 3.43 +/- 0.80 vs 2.28 +/- 0.47 mmol/l, P < 0.01). The PWV of each artery segment in both the normocholesterol group and the hypercholesterol group decreased significantly (P < 0.05). Pulse-wave velocity in the hypercholesterol group was lowered much more than that of the normocholesterol group (P < 0.05). There were no differences among each artery segment in each group. Ankle-brachial index increased significantly in both groups (1.12 +/- 0.16 to 1.22 +/- 0.12, P < 0.05 in the normocholesterol group, and 1.03 +/- 0.22 to 1.23 +/- 0.16, P < 0.01 in the hypercholesterol group), but ABI increased much more in the hypercholesterol group than in the normocholesterol group (0.21 + 0.15 vs 0.11 + 0.09 P = 0.02). Intensive cholesterol-lowering therapy with simvastatin for acute myocardial infarction patients can significantly improve their large artery elasticity and regress their atherosclerosis. Hypercholesterol patients benefit more from this therapy. PMID- 19784817 TI - Clinical features of early recurrent myocardial infarction. AB - Recurrence of myocardial infarction, especially when occurring early after the prior one, carries a significant morbidity and mortality rate. The aim of this study was to investigate the characteristics of patients who experienced recurrence under secondary prevention therapy. Case record review identified myocardial infarction patients who had a history of previous myocardial infarction within 5 years. Hospital chart records, initial laboratory data, medications, and type of infarction were reviewed. Patients were divided into two groups according to the interval of recurrence: an early group (recurrence within 1 year), and a late group (recurrence after more than 1 year). A total of 89 patients were included in the analysis; 40 patients in the early group, and 49 patients in the late group. Mean age in the early group and late groups was 67.3 +/- 11.9 and 59.4 +/- 8.9, respectively (P = 0.001). Mean body mass index in the early and late groups was 22.1 +/- 3.6 and 25.0 +/- 3.3, respectively (P < 0.001). There were fewer current smokers in the early group (7.5% vs 44.9%, P < 0.001) and more stent thrombosis (17.5% vs 2%, P = 0.02), as compared with the late group. The in-hospital mortality rate tended to be higher in the early group (7.5% vs 0%, P = 0.09). Multiple logistic regression revealed that smoking status (odds ratio [OR] 0.09, 95% confidence interval [CI] 0.02-0.49, P = 0.005), HDL cholesterol level (5 mg/dl increase: OR 1.34, 95% CI 1.04-1.74, P = 0.03), and stent thrombosis (OR 35.59, 95% CI 2.13-595.49, P = 0.01) had significant associations with early recurrence. Early recurrence of myocardial infarction was associated with stent thrombosis, a higher HDL cholesterol level, and a lower frequency of smoking. Early recurrence had a trend toward higher mortality than late recurrence. PMID- 19784818 TI - Long-term prognostic value of coronary flow velocity reserve in patients with hypertrophic cardiomyopathy: 9-year follow-up results from SZEGED study. AB - Reduction in coronary flow velocity reserve (CFR) is a recognized feature in hypertrophic cardiomyopathy (HCM). We sought to assess the long-term prognostic value of CFR by pulsed-wave Doppler transesophageal echocardiography (TEE) in HCM patients. The study comprised 20 patients with typical features of HCM. The patients were enrolled in 1999. All patients underwent a standard transthoracic echo-Doppler study to evaluate left ventricular function and a stress vasodilator TEE study to evaluate CFR. The success rate of follow-up was 18 out of 20 (90%). During a mean follow-up of 90 +/- 24 months, four patients suffered cardiovascular death (2 sudden cardiac deaths and 2 strokes). The other seven patients underwent invasive procedures (coronary angiography, implantable cardioverter defibrillator implantation, percutaneous transluminal septal myocardial ablation) or showed cerebrovascular events. Using receiver operator characteristic analysis, CFR < 2.35 was a significant predictor for cardiovascular event-free survival (sensitivity 91%, specificity 71%, area under the curve 74%, P = 0.05). Multivariable regression analysis showed that only CFR (hazard ratio (HR) 4.21, P < 0.05) was an independent predictor of cardiovascular event-free survival. Despite the relatively small number of patients involved in the study, results could suggest that CFR should be considered as an independent predictor for future cardiovascular events in HCM patients. However, further studies with larger HCM patient populations are warranted. PMID- 19784819 TI - Wave intensity wall analysis: a novel noninvasive method to measure wave intensity. AB - Wave intensity analysis is a concept providing information about the interaction of the heart and the vascular system. Originally, the technique was invasive. Since then new noninvasive methods have been developed. A recently developed ultrasound technique to estimate tissue motion and deformation is speckle tracking echocardiography. Speckle tracking-based techniques allow for accurate measurement of movement and deformation variables in the arterial wall in both the radial and the longitudinal direction. The aim of this study was to test if speckle tracking-derived deformation data could be used as input for wave intensity calculations. The new concept was to approximate changes of flow and pressure by deformation changes of the arterial wall in longitudinal and radial directions. Flow changes (dU/dt) were approximated by strain rate (sr, 1/s) of the arterial wall in the longitudinal direction, whereas pressure changes (dP/dt) were approximated by sign reversed strain rate (1/s) in the arterial wall in the radial direction. To validate the new concept, a comparison between the newly developed Wave Intensity Wall Analysis (WIWA) algorithm and a commonly used and validated wave intensity system (SSD-5500, Aloka, Tokyo, Japan) was performed. The studied population consisted of ten healthy individuals (three women, seven men) and ten patients (all men) with coronary artery disease. The present validation study indicates that the mechanical properties of the arterial wall, as measured by a speckle tracking-based technique are a possible input for wave intensity calculations. The study demonstrates good visual agreement between the two systems and the time interval between the two positive peaks (W1-W2) measured by the Aloka system and the WIWA system correlated for the total group (r = 0.595, P < 0.001). The correlation for the diseased subgroup was r = 0.797, P < 0.001 and for the healthy subgroup no significant correlation was found (P > 0.05). The results of the study indicate that the mechanical properties of the arterial wall could be used as input for wave intensity calculations. The WIWA concept is a promising new method that potentially provides several advantages over earlier wave intensity methods, but it still has limitations and needs further refinement and larger studies to find the optimal clinical use. PMID- 19784820 TI - Low total antioxidative capacity levels are associated with augmentation index but not pulse-wave velocity. AB - It is well known the relationship between oxidative stress and vascular function. However, association between total antioxidative capacity and arterial stiffness was not studied in patients with hypertension (HT). This study investigated whether total antioxidative capacity is associated with arterial stiffness and wave reflections. We studied 46 (age 48.5 +/- 10.6 years) never treated patients with HT and age-matched control group of 40 (age 47 +/- 8.6 years) normotensive individuals. Total antioxidative capacity level was determined in all subjects. We evaluated arterial stiffness and wave reflections of the study population, using applanation tonometry (SphygmoCor). Carotid-femoral pulse-wave velocity (PWV) was measured as index of aortic stiffness. The heart rate-corrected augmentation index (AIx@75) was estimated as a composite marker of wave reflections and arterial stiffness. Carotid-femoral PWV (10.5 +/- 2.2 vs 8.7 +/- 1.6, m/s, P = 0.0001) and AIx@75 (22.7 +/- 9.5 vs 15 +/- 11, %, P = 0.001) were significantly higher in patients with HT compared with age-matched control subjects. Total antioxidative capacity level (274 +/- 70 vs 321 +/- 56 micromol/l, P = 0.001) was significantly lower in hypertensive patients than controls. In the whole population, total antioxidative capacity level negatively correlated with AIx@75 (r = -0.24, P = 0.02) in univariable analysis, but not with carotid-femoral PWV (r = -0.08, P = 0.43). Also, we found that total antioxidative capacity level (beta = -0.21, P = 0.03) was an independent determinant of AIx@75 in multivariable analysis. Our results suggest that the decrease in the ability of antioxidant defenses contributes significantly to increased wave reflections. PMID- 19784821 TI - Uric acid is an independent predictor of arterial stiffness in hypertensive patients. AB - Increased arterial stiffness is an important marker for target organ damage in essential hypertension. Both serum uric acid (UA) and C-reactive protein (CRP) were reported to be associated with target organ damage. However, the influences of UA and CRP on large arterial stiffness were not well elucidated. This study included 200 essential hypertension patients (64 women) whose age was between 20 and 50 years old (mean age 41 +/- 8 years). None of the patients had diabetes mellitus or overt end-organ damage. Arterial stiffness was assessed by pulse-wave velocity (PWV) measured by tonometry from carotid to radial artery. Serum UA, high-sensitivity CRP (hsCRP), glucose, insulin, and lipid profiles were measured at the same time in each patient. PWV levels were significantly correlated with mean blood pressure (r = 0.245, P < 0.001), diastolic blood pressure (r = 0.323, P < 0.001), high-density lipoprotein (r = -0.169, P = 0.016), and UA (r = 0.234, P = 0.001), but not age, body mass index, blood sugar, insulin, low-density lipoprotein, triglyceride, and hsCRP. Pulse-wave velocity levels were significantly higher in males (8.9 +/- 1.2 vs 8.2 +/- 1.2 m/s, P < 0.001) and smokers (9.3 +/- 1.1 vs 8.5 +/- 1.2 m/s, P < 0.001). Uric acid was significantly correlated with hsCRP (r = 0.294, P < 0.001). After multivariate analysis controlling for all possible confounding factors, UA (odds ratio 1.28, 95% confidence interval 1.02-1.61, P = 0.032) was still independently associated with increased PWV. In conclusion, UA but not hsCRP was independently associated with increased PWV in essential hypertension. Although UA was correlated with hsCRP, the association between UA and PWV was not through the effect of enhanced inflammation. PMID- 19784822 TI - Therapeutic hypothermia in combination with percutaneous coronary intervention in out-of-hospital cardiac arrest due to left main coronary artery disease. AB - A 59-year-old man had a witnessed collapse while driving a car. Approximately 10 min after the call to emergency services, paramedics arrived and initiated cardiopulmonary resuscitation. The first electrocardiogram (ECG) obtained by paramedics showed pulseless electrical activity. Review of his prehospital records documented that he experienced approximately 13 min of no flow or low flow before return of spontaneous circulation. On admission, he was still comatose with midrange dilated pupils. Electrocardiogram showed sinus rhythm, ST segment elevation in lead aVR, and ST segment depression in leads I, II, and V4 6. Coronary angiography showed 99% narrowing of the left main coronary artery (LMCA), but did not show any disease in the right coronary artery. A bare-metal stent was placed in the LMCA, and postdilated at 20 atmospheres. Immediately after return to the coronary care unit, therapeutic hypothermia was initiated. Hypothermia with a target temperature of 33.0 degrees C was maintained for 30 h. During this period, no significant hemodynamic instability occurred under intra aortic balloon pumping (IABP) and intravenous catecholamines. Subsequently, he was slowly rewarmed at a rate of 0.3 degrees C/h up to 36.0 degrees C. Next day, the neurological condition improved and IABP was stopped. Creatine kinase increased to 2182 IU/l. Stent thrombosis did not occur despite the ad hoc loading of antiplatelet drugs. Follow-up echocardiography 9 days later showed mild hypokinesia of the anterior wall with an ejection fraction of 77%. He was discharged with no neurologic complications 18 days later. PMID- 19784823 TI - Spontaneous coronary artery dissection: a report of two atypical cases. AB - Spontaneous coronary artery dissection is a rare pathology that has no exact incidence, etiology, pathogenesis and evolution in literature. We report two cases of two women with coronary artery dissection, uncommon clinical presentation of acute coronary syndrome and without identifiable risk factors. A review of the literature and the management of this condition are presented. PMID- 19784824 TI - Cardiotoxicity after low-dose chloroquine antimalarial therapy. AB - Previous reports on antimalarial toxicity have only been related to long-term continuous treatments for nonmalarial indications, which require prolonged use of large doses, up to 1000 g or more every year. We describe a patient with recurrent malaria, prophylactically treated with low-dose chloroquine, who developed heart failure due to biventricular cardiac dysfunction. The right ventricle endomyocardial biopsy was suggestive of chloroquine toxicity. The heart failure improved after drug withdrawal. As a consequence, the potential for reversibility and the severity in undiagnosed cases of these toxic cardiomyopathies emphasize the importance of recognizing early signs of toxicity in order to withdraw antimalarials before the occurrence of life-threatening cardiac toxicity. PMID- 19784825 TI - Resolution of late sirolimus-eluting stent thrombosis after tirofiban treatment. AB - A 40-year-old male patient was admitted to the hospital with acute chest pain. A sirolimus-eluting stent (SES) had been deployed to the circumflex artery (Cx) 3 years before. Now, inferior ST-segment elevations were observed and coronary angiography revealed stent thrombosis with distal TIMI 3 grade flow in the Cx. Tirofiban infusion was administered and the control angiography 2 days later revealed complete resolution of the thrombus. Stent thrombosis is a rare but usually poor prognostic event, frequently associated with large myocardial infarction (MI) or death. Very late drug-eluting stent (DES) thrombosis remains a major problem of interventional cardiology due to its high morbidity and mortality. We conclude that tirofiban may be an interesting candidate drug for treatment of very late stent thrombosis. PMID- 19784827 TI - The mineralization phenotype in Abcc6 ( -/- ) mice is affected by Ggcx gene deficiency and genetic background--a model for pseudoxanthoma elasticum. AB - Pseudoxanthoma elasticum (PXE) is an autosomal recessive disorder characterized by ectopic mineralization of connective tissues and shows considerable intra- and inter-familial phenotypic variability. PXE is caused by mutations in the ABCC6 gene, and targeted ablation of Abcc6 in mouse recapitulates PXE. In this study, we examined the hypothesis that the GGCX gene encoding gamma-glutamyl carboxylase may interfere with the mineralization process in Abcc6 ( -/- ) mice. Thus, Abcc6 ( -/- ) and Ggcx (+/-) mice were generated on 129S1;C57 and 129S1;129X1;C57 genetic backgrounds, respectively, and backcrossed with C57BL/6J for five generations. Thus, these strains differ by the 129X1 contribution to the background of the mice. We then generated Abcc6 ( -/- ) ;Ggcx (+/+) and Abcc6 ( /- ) ;Ggcx (+/-) mice by crossing Abcc6 ( -/- ) and Ggcx (+/-) mice. The degree of mineralization of connective capsule of vibrissae, a biomarker of the mineralization process in PXE, was evaluated by computerized morphometric analysis and quantified colorimetrically by calcium and phosphate levels in tissues. The mineralization of the vibrissae in Abcc6 ( -/- ) mice takes place at approximately 5-6 weeks of age and is significantly enhanced at 3 months of age in comparison to wild-type mice (>10-fold, p < 0.001). However, the onset of mineralization in Abcc6 ( -/- ) ;Ggcx (+/+) mice was delayed until between 3 and 4 months of age, suggesting that the genetic background plays a role in modifying the mineralization process. The mineralization in the Abcc6 ( -/- ) ;Ggcx (+/- ) mice was accelerated in comparison with age-matched Abcc6 ( -/- ) ;Ggcx (+/+) mice, with approximately 3-fold difference at 3, 4, and 9 months of age (p < 0.01). The mineralization process was also accelerated in these mice by a special custom-designed diet with mineral modifications. These findings suggest a role for both the GGCX gene and the genetic background as well as dietary factors in modulating the phenotypic severity of PXE caused by loss-of-function mutations in ABCC6. PMID- 19784828 TI - Multiple antioxidant proteins protect Chlorobaculum tepidum against oxygen and reactive oxygen species. AB - The genome of the green sulfur bacterium Chlorobaculum (Cba.) tepidum, a strictly anaerobic photolithoautotroph, is predicted to encode more than ten genes whose products are potentially involved in protection from reactive oxygen species and an oxidative stress response. The encoded proteins include cytochrome bd quinol oxidase, NADH oxidase, rubredoxin oxygen oxidoreductase, several thiol peroxidases, alkyl hydroperoxide reductase, superoxide dismutase, methionine sulfoxide reductase, and rubrerythrin. To test the physiological functions of some of these proteins, ten genes were insertionally inactivated. Wild-type Cba. tepidum cells were very sensitive to oxygen in the light but were remarkably resistant to oxygen in the dark. When wild-type and mutant cells were subjected to air for various times under dark or light condition, significant decreases in viability were detected in most of the mutants relative to wild type. Treatments with hydrogen peroxide (H(2)O(2)), tert-butyl hydroperoxide (t-BOOH) and methyl viologen resulted in more severe effects in most of the mutants than in the wild type. The results demonstrated that these putative antioxidant proteins combine to form an effective defense against oxygen and reactive oxygen species. Reverse transcriptase polymerase chain reaction studies showed that the genes with functions in oxidative stress protection were constitutively transcribed under anoxic growth conditions. PMID- 19784829 TI - Interaction between hepatocytes and collagen gel in hollow fibers. AB - Gel entrapment culture of primary mammalian cells within collagen gel is one important configuration for construction of bioartificial organ as well as in vitro model for predicting drug situation in vivo. Gel contraction in entrapment culture, resulting from cell-mediated reorganization of the extracellular matrix, was commonly used to estimate cell viability. However, the exact influence of gel contraction on cell activities has rarely been addressed. This paper investigated the gel contraction under varying culture conditions and its effect on the activities of rat hepatocyte entrapped in collagen gel within hollow fibers. The hepatocyte activities were reflected by cell viability together with liver specific functions on urea secretion and cytochrome P450 2E1. Unexpectedly, no gel contraction occurred during gel entrapment culture of hepatocyte under a high collagen concentration, but hepatocytes still maintained cell viability and liver specific functions at a similar level to the other cultures with normal gel contraction. It seems that cell activities are unassociated with gel contraction. Alternatively, the mass transfer resistance induced by the combined effect of collagen concentration, gel contraction and cell density could be a side effect to reduce cell activities. The findings with gel entrapment culture of hepatocytes would be also informative for the other cell culture targeting pathological studies and tissue engineering. PMID- 19784830 TI - Analysis of palladium concentrations in airborne particulate matter with reductive co-precipitation, He collision gas, and ID-ICP-Q-MS. AB - The concentration of platinum group elements (PGE) in the environment has increased significantly in the last 20 years mainly due to their use as catalysts in automotive catalytic converters. The quantitation of these metals in different environmental compartments is, however, challenging due to their very low concentrations and the presence of interfering matrix constituents when inductively coupled plasma-mass spectrometry (ICP-MS) is used for analysis. Previously, the research focus was on the analysis of platinum (Pt) and rhodium (Rh). However, due to the increasing use of palladium (Pd) in automotive catalytic converters, quantitation of this element in airborne particulate matter (PM) is also needed. Compared to Pt and Rh, measurements of Pd using ICP-MS are plagued by greater molecular interferences arising from elements such as copper (Cu), zinc (Zn) strontium (Sr), yttrium (Y), and zirconium (Zr). The aim of this study was to evaluate the applicability of reductive co-precipitation procedures using both mercury (Hg) and tellurium (Te) for the pre-concentration of Pd from airborne PM. Furthermore, helium (He) was tested as a collision gas for isotope dilution-inductively coupled plasma-quadrupole-mass spectrometry (ID-ICP-Q-MS) to measure Pd in the Hg and Te precipitates. Airborne PM samples (PM10) were collected from Neuglobsow (Brandenburg, north-eastern Germany) and Deuselbach (Rhineland-Palatinate, south-western Germany), considered to represent background levels, and from the city Frankfurt am Main (Hesse, Germany), a high-traffic area. Samples were first digested with aqua regia in a high-pressure asher (HPA) at 320 degrees C and 130 bar prior to the application of reductive co precipitation procedures. The method was validated with road dust reference material BCR-723 and the CANMET-CCRMP reference material TDB-1 and WPR-1. In airborne PM collected at the background areas Neuglobsow and Deuselbach, Pd was detected with median concentrations values of 0.5 and 0.6 pg/m3, respectively. Much higher median concentration values of 14.8 pg Pd/m3 (detection limit = 0.01 pg Pd/m3) were detected in samples collected in the city of Frankfurt am Main. Results have shown that Hg co-precipitation depletes the concentrations of interfering matrix constituents by at least one order of magnitude more, compared to Te co-precipitation, making it a more effective method for the isolation and pre-enrichment of Pd from airborne PM prior to analysis. The use of a He gas flow of 120 ml/min in the plasma further minimized interferences, particularly those arising from CuAr+, YO+, and ZrO+ during the determination of Pd. The results demonstrate that Hg co-precipitation and the use of He collision gas, in combination with isotope dilution, are highly effective methods for the quantitation of Pd in airborne PM using ICP-MS. PMID- 19784831 TI - Characterisation of foxing stains in eighteenth to nineteenth century drawings using non-destructive techniques. AB - The reddish-brown, brown or yellowish stains of circular or irregular shape known as foxing spots have been fully described in conservation literature but still, this phenomenon does not find any scientific agreement since many hypotheses have been raised concerning their origin. In this work a contribution to foxing definition not only focussed on its appearance but also reported on its chemical information. For this purpose foxing stains present in drawings from two Portuguese artists dated from the eighteenth to nineteenth centuries were observed under ultra-violet light and optical microscope and analysed by three non-invasive spectroscopy techniques. The observations carried out on the stains provided information on their surface morphology. The use of energy-dispersive X ray fluorescence revealed a variation on the elemental content between foxing and paper region. Although the results from X-ray diffraction analysis showed no signs of cellulose degradation in foxing stains, Fourier-transformed infrared analysis revealed the presence of oxide groups. Both the information on the chemical nature and surface morphology of the stains achieved in this study will contribute to increase foxing formation information and develop future protocols for conservation purposes. PMID- 19784832 TI - Determination of organophosphate flame retardants in sediments by microwave assisted extraction and gas chromatography-mass spectrometry with electron impact and chemical ionization. AB - An efficient microwave-assisted extraction (MAE) procedure coupled to gas chromatography-mass spectrometry (GC-MS) with electron impact (EI) and chemical ionization (CI) has been developed to determine five organophosphate flame retardants (OPFRs) in marine and river sediments. The effects of various operating parameters on the quantitative extraction of the OPFRs through MAE were systematically investigated. Selected OPFRs were extracted from the sediments through MAE using 40 mL of acetone at 120 degrees C for 20 min. The limits of quantitation ranged from 0.1 to 0.4 ng/g (dry weight) in 2 g of the sediment samples. Moreover, as the chlorinated alkyl phosphates present no molecular ions in EI, GC-MS with furan-CI (furan-CI) was applied to confirm their determination in complex environmental samples. The recoveries of the selected OPFRs in spiked sediment samples ranged from 62% to 106% (relative standard derivation, 1-11%). The total concentrations of the selected OPFR residues in marine and river sediments ranged from 1.0 to 12.6 ng/g. PMID- 19784834 TI - Outcome and output-focused research: selling your research in difficult times. PMID- 19784833 TI - Determination of human urinary kanamycin in one step using urea-enhanced surface plasmon resonance light-scattering of gold nanoparticles. AB - The purpose of this study was to establish a simple, sensitive analytical method for kanamycin (KANA) in human urine. Enhancement of the plasmon resonance light scattering (PRLS) of gold nanoparticles (AuNPs) by KANA provided the basis for this analytical method. At pH 6.7, KANA induced AuNPs aggregation with enhanced PRLS. The PRLS of the AuNPs-KANA system was further enhanced by addition of urea. The linear range and detection limit for KANA were from 20-800 nmol L(-1) and 2 nmol L(-1), respectively. Potential interfering substances present in urine had a negligible effect on the determination, thus preliminary sample separations were not necessary. Recovery of KANA from spiked human urine was 94-104%. This simple, sensitive method, using urea to enhance the PRLS of the AuNPs-KANA system, may provide a new approach for determination of compounds rich in OH groups. PMID- 19784835 TI - Synchrotron X-ray imaging via ultra-small-angle scattering: principles of quantitative analysis and application in studying bone integration to synthetic grafting materials. AB - Optimized experimental conditions for extracting accurate information at subpixel length scales from analyzer-based X-ray imaging were obtained and applied to investigate bone regeneration by means of synthetic beta-TCP grafting materials in a rat calvaria model. The results showed a 30% growth in the particulate size due to bone ongrowth/ingrowth within the critical size defect over a 1-month healing period. PMID- 19784836 TI - Effects of extracellular purines on cytotoxicity of methotrexate. AB - PURPOSE: Nucleoside and base modulation of the cytotoxicity of nucleic acid and folate antimetabolite drugs has been widely discussed. Many investigators have observed reduced toxicity due to circumvention of drug-induced inhibition of de novo purine and pyrimidine synthesis. However, exogenous purine nucleosides and bases may also enhance the cytotoxicity of even moderate concentrations of antifolate drugs (MTX and PTX) which inhibit dihydrofolate reductase. In this study, the effects of nucleosides in the medium on the cytotoxicity and deoxyribonucleoside triphosphate pools after brief exposure of cultured cells to methotrexate have been studied in cultured L1210 murine leukaemia cells. METHODS: Cell viability was determined by trypan blue exclusion assay. Colony formation was assessed by microtitration cloning assay. The deoxyribonucleotides were measured by a modification of the DNA polymerase assay. Purines were extracted with trioctylamine and 1,1,2-trichlorotrifluoroethane buffer and concentrations of purine bases were determined by HPLC. RESULTS: Subculture of drug-treated cells in fresh medium containing 10% FCS led to greater toxicity than sub culture in 'conditioned' medium, i.e. fresh medium in which logarithmically growing cells had been cultured for 24 h before separation. Cells resuspended in fresh medium had increased dATP and sustained inhibition of dTTP levels, while cells subcultured in 'conditioned' medium had no elevation of dATP. Hypoxanthine concentration determined by HPLC in 'conditioned' medium was 0.9 microM compared to 6.7 microM in fresh medium. Resuspension of drug-treated cells in conditioned medium supplemented with 10 or 100 microM HX enhanced cytotoxicity and increased the dATP levels. CONCLUSION: These results add further evidence that purines present in normal culture conditions are important determinants of methotrexate cytotoxicity. Elevation of dATP levels after methotrexate treatment is an important modulator of cytotoxicity. PMID- 19784837 TI - Usefulness of chemotherapy beyond the second line for metastatic breast cancer: a therapeutic challenge. AB - PURPOSE: Several lines of chemotherapy can be proposed for patients with metastatic breast cancer, but beyond the second line, agreement is lacking concerning the most appropriate therapeutic strategy. METHODS: We conducted a retrospective analysis of the files of 162 patients, who had received at least 3 lines of chemotherapy (CT3) for metastatic breast cancer during a 5-year period (2000-2004), in order to analyze management practices and search for factors affecting survival from CT3 and predictive factors of non-progressive disease (NPD) after CT3. RESULTS: Multivariate analysis identified seven factors which had a positive influence on survival from CT3 (SBR grade I, absence of adjuvant hormone therapy, free interval >or=2 years, absence of cerebromeningeal metastasis before CT, unique focus at initiation of CT3, use of polychemotherapy for CT2, and complete response to CT1 or CT2) and two predictive factors of NPD (histology and drug group used for CT3). CONCLUSIONS: These factors should help determine the appropriate strategy for proposing a third line of chemotherapy. PMID- 19784838 TI - Clinical potency of methotrexate, aminopterin, talotrexin and pemetrexed in childhood leukemias. AB - PURPOSE: Renewed interest in antifols for the treatment of childhood cancers has resulted from identification of novel antifols with broad spectrums of anti cancer activity and from re-evaluation of the original clinical antifol, aminopterin. In this pre-clinical study we evaluated the in vitro activity of both traditional antifols (methotrexate, aminopterin) and novel antifols (pemetrexed, talotrexin) in childhood acute leukemias and lymphomas. METHODS: We compared the in vitro cytotoxicity of methotrexate, aminopterin, pemetrexed, and talotrexin in a panel of six pediatric leukemia and lymphoma cell lines using the sulforhodamine B assay. In addition to defining a 50% growth inhibitory concentration (IC50) for a 120-h drug exposure, we contrasted the activity of the drugs in the context of clinically achievable (tolerable) drug exposures using the area under the plasma concentration-time curve (AUC). We defined each agent's clinical potency index (CPI) as the AUC achieved with standard pediatric dosing regimens divided by the in vitro IC50. RESULTS: Across all cell lines, talotrexin (median IC50 7 nM) and aminopterin (median IC50 17 nM) had lower IC50's than methotrexate (median IC50 78 nM) and pemetrexed (median IC50 155 nM). However, the CPI for methotrexate (median 0.9) was significantly greater than that for aminopterin (median 0.4). In contrast, pemetrexed had a significantly better CPI (median 13) than the traditional antifols. CONCLUSIONS: Aminopterin does not appear to offer any advantage over methotrexate for the treatment of childhood ALL. Further study of pemetrexed in childhood leukemias is warranted. PMID- 19784839 TI - Comparative pharmacokinetics of RAD001 (everolimus) in normal and tumor-bearing rodents. AB - PURPOSE: Comparative pharmacokinetic (PK) analysis of the mTOR inhibitor RAD001 (everolimus) in rats and mice. METHODS: Blood cell partitioning, plasma protein binding and PK parameters of RAD001 in blood and tissues (including brain) of both mice and rats were determined. PK modeling predicted plasma/blood and tumor levels from a variety of regimens and these were compared with the known human PK profile. DCE-MRI was used to compare tumor vascularity between mice and rats. Estimation of IC50 values in vitro and ED50 values in vivo were used to provide an indication of anti-tumor activity. RESULTS: The PK properties of RAD001 differed between mice and rats, including erythrocyte partitioning, plasma protein binding, plasma/blood t(1/2), oral bioavailability, volume of distribution, tissue/tumor penetration and elimination. Modeling of tumor and blood/plasma PK suggested that in mice, multiple daily administrations result in a 2-fold increase in tumor levels of RAD001 at steady state, whereas in rats, a 7.9-fold increase would occur. Weekly high-dose regimens were predicted not to facilitate tumor accumulation in either species. Total tumor levels of RAD001 were four- to eight-fold greater in rats than in mice. Rat tumors had a >2-fold greater plasma content and permeability compared to mouse tumors, which could contribute to differences in tumor drug uptake. Maximal antitumor effects (T/C of 0.04-0.35) were observed in both species after daily administration with similar C(max) and AUC values of unbound (free) RAD001. These free levels of RAD001 are exceeded in serum from cancer patients receiving clinically beneficial daily regimens. In rodents, brain penetration of RAD001 was poor, but was dose dependent and showed over-proportional uptake in rats with a longer t(1/2) compared to the systemic circulation. CONCLUSIONS: The PK of RAD001 differed between mice and rats, with rats having a PK profile closer to that of humans. High intermittent doses of RAD001 may be more appropriate for treatment of brain tumors. PMID- 19784840 TI - Male gender results in more severe lupus nephritis. AB - Gender may produce different characteristics in the manifestation of systemic lupus erythematosus (SLE). The present study investigated the influence of gender on clinical, laboratory, autoantibodies and histopathological classes of lupus nephritis (LN). As much as 81 patients diagnosed with SLE (ACR criteria) and active nephritis, who underwent renal biopsy between 1999 and 2004, and who had frozen serum samples and clinical data available from the time of biopsy, were selected for this study. The presence of anti-P and antichromatin antibodies was measured using ELISA, and anti-dsDNA was measured using indirect immunofluorescence. All of the renal biopsies were reviewed in a blinded manner by the same expert renal pathologist. The charts were extensively reviewed for demographic and renal features obtained at the time of the biopsy. Of the 81 patients (13.6%), 11 were male SLE patients. Both male and female lupus patients were of similar age and race, and had similar durations of lupus and renal disease. The female patients had more cutaneous (95.7 vs. 45.5%, P = 0.0001) and haematological (52.9 vs. 18.2%, P = 0.04) involvements than the male SLE patients. In addition, the articular data, central nervous system analyses, serositis findings and SLEDAI scores were similar in both experimental groups. Positivity for anti-dsDNA, anti-ribosomal P and antichromatin did not differ between the two groups, and both groups showed similarly low C3 or C4 serum levels. Our analysis indicated that no histopathological class of LN was predominant in both males and females. Interestingly, the serum creatinine levels were higher in the male SLE patients compared to the female SLE group (3.16 +/- 2.49 vs. 1.99 +/- 1.54 mg/dL, P = 0.03), with an increased frequency of high creatinine (81.8 vs. 47.1%, P = 0.04) as well as renal activity index (7.6 +/- 3.5 vs. 4.8 +/- 3.5, P = 0.02). In addition, whilst the mean levels of proteinuria, cylindruria and serum albumin were markedly altered, they were comparable between both lupus men and women. Moreover, the frequencies of dialysis, renal transplantation and death were similar between the two groups. These data suggest that male patients had a more severe LN compared to women diagnosed with this renal abnormality. PMID- 19784841 TI - Nickel-induced allergy and contact dermatitis: does it induce autoimmunity and cutaneous sclerosis? An experimental study in Brown Norway rats. AB - Nickel sensitization is a growing problem and the most common cause of allergic contact dermatitis. The aim of this study was to investigate whether nickel chloride can induce autoimmunity and cutaneous sclerosis in immunosensitive rats. Nickel chloride, in a dose of 4.5 mg in 0.2 ml NS, was administered by the oral and subcutaneous routes to 20 Brown Norway rats. Autoantibodies (ANA, anti-RNP, anti-SCL70 and anti-centromere) were measured and compared in pre- and post challenge serum samples. Histological studies were also performed in skin biopsies obtained from six positively responding rats and compared with an equal number of control rats at the 14th week post-challenge. Serum ANA was high in a significant number of rats in both the oral (P < 0.005) and subcutaneously nickel treated groups (P = 0.02), while the anti-SCL70 was high in a significant number of rats in only the orally nickel-treated group (P = 0.04). Histologically, subcutaneous and oral nickel-treated groups showed sclerodermic features of the skin (P = 0.22, P = 0.5), respectively. It may be concluded that nickel chloride can induce scleroderma-related autoantibodies and cutaneous sclerosis. More prolonged duration of exposure is probably associated with greater risk. This is the first study showing the potential risk of nickel in triggering the development of cutaneous sclerosis in susceptible hosts. PMID- 19784842 TI - Encoding properties of auditory neurons in the brain of a soniferous damselfish: response to simple tones and complex conspecific signals. AB - The fish auditory system encodes important acoustic stimuli used in social communication, but few studies have examined response properties of central auditory neurons to natural signals. We determined the features and responses of single hindbrain and midbrain auditory neurons to tone bursts and playbacks of conspecific sounds in the soniferous damselfish, Abudefduf abdominalis. Most auditory neurons were either silent or had slow irregular resting discharge rates <20 spikes s(-1). Average best frequency for neurons to tone stimuli was approximately 130 Hz but ranged from 80 to 400 Hz with strong phase-locking. This low-frequency sensitivity matches the frequency band of natural sounds. Auditory neurons were also modulated by playbacks of conspecific sounds with thresholds similar to 100 Hz tones, but these thresholds were lower than that of tones at other test frequencies. Thresholds of neurons to natural sounds were lower in the midbrain than the hindbrain. This is the first study to compare response properties of auditory neurons to both simple tones and complex stimuli in the brain of a recently derived soniferous perciform that lacks accessory auditory structures. These data demonstrate that the auditory fish brain is most sensitive to the frequency and temporal components of natural pulsed sounds that provide important signals for conspecific communication. PMID- 19784844 TI - Is frozen section reliable in transoral CO(2) laser-assisted cordectomies? AB - Endoscopic resection of laryngeal tumors is replacing external approaches. One drawback of endoscopic resection is the difficulty of interpretation of histological specimens because of thermal effect of laser on tissues. Our goal is to assess the reliability of frozen section in this setting by comparing its results with those of routine histology. We, retrospectively, reviewed the charts of all consecutive patients, who underwent cordectomies in our institution between January 2000 and 2008, using the CO(2) laser Acublade system (Lumenis, Santa Clara, CA). Age, sex, staging of the tumor, previous treatments, type of cordectomy, frozen section and routine histology results were analyzed. Ninety seven patients fulfilled the inclusion criteria; 22.7% had severe dysplasia, 54.6% had T1 epidermoid carcinoma, 17.5% had T2 carcinoma and finally 5.2% had T3 carcinoma. We performed type I cordectomy in 36.1% of patients, type II cordectomy in 18.6%, type III cordectomy in 10.3%, type IV cordectomy in 5.2%, type V cordectomy in 28.9% and type VI cordectomy in 1% of patients. Most of the patients did not have any previous treatment. The mean number of margins per surgery was 2. Routine histological examination confirmed frozen section in 94.8% of the interventions. Frozen section is reliable in laser-assisted cordectomies, when performed by an experienced team; it has a high negative-predictive value. It can limit the need, cost and emotional stress of second look surgeries. PMID- 19784845 TI - Intravitreal loading injection of ganciclovir with or without adjunctive oral valganciclovir for cytomegalovirus anterior uveitis. AB - BACKGROUND: A pilot study was conducted to evaluate the therapeutic results of intravitreal ganciclovir injection as a loading dose with or without the following oral valganciclovir for the treatment of cytomegalovirus (CMV) anterior uveitis in immunocompetent patients. METHODS: Six consecutive patients in whom active CMV anterior uveitis was detected by polymerase chain reaction assay of the aqueous humor were enrolled between January 2006 and December 2008. These patients received an intravitreal injection of ganciclovir (2 mg/0.05 ml) as a loading dose. Subsequent use of oral valganciclovir (900 mg twice a day) was determined according to the severity of the post-injection aqueous inflammation. Immune status and anterior chamber reaction of individual patients, visual acuity, intraocular pressure (IOP) at study entry, and follow-up intervals were examined. RESULTS: The mean patient-month follow-up period after intravitreal injection was 14.7 months (range, 12-22 months). Two patients received only the intravitreal ganciclovir injection once and four patients had received the following oral valganciclovir for average 2.3 months (range, 1-4 months). With this treatment strategy, the best-corrected visual acuity of the patients improved or stabilized; the IOP and the inflammation of anterior chamber of the patients were well controlled at all time points and there were no treatment associated complications by the end of follow-up. CONCLUSIONS: In patients with CMV anterior uveitis, intravitreal ganciclovir injection as a loading dose with or without the following oral valganciclovir can control the inflammation and IOP well. PMID- 19784846 TI - Loss of GDF-15 abolishes sulindac chemoprevention in the ApcMin/+ mouse model of intestinal cancer. AB - BACKGROUND: Growth-differentiation factor (GDF)-15, a member of the TGF-beta superfamily, is potently induced in the intestine following mechanical injury, genotoxic insult and following non-steroidal anti-inflammatory drugs (NSAIDs) exposure. GDF-15 expression correlates with apoptosis in intestinal cells and has been implicated in the pathogenesis of colorectal cancer formation and the anti tumor effects of NSAIDs. We sought to determine the effect of loss of Gdf15 on animal tumor models of hereditary colon cancer and in the NSAID-mediated prevention of heritable colorectal cancer. METHODS: GDF-15 null (Gdf15 (-/-)) mice and mice with the genetic mutation found in hereditary poliposis coli, Apc ( min/+ ) were bred. Gdf15 ( -/- ), Apc ( min/+ ) and Gdf15 ( +/+ ), Apc ( min/+ ) mice were generated. RESULTS: In Gdf15 ( -/- ), Apc ( min/+ ) mice, intestinal neoplasia formation rate and size were indistinguishable from that in Gdf15 ( +/+ ), Apc ( min/+ ) mice. Sulindac chemoprotection activity although potent in Gdf15 ( +/+ ), Apc ( min/+ ) mice was abolished in Gdf15 ( -/- ), Apc ( min/+ ) mice. CONCLUSIONS: These results demonstrate in a murine model that GDF-15 does not significantly regulate heritable in vivo intestinal carcinogenesis but does mediate sulindac chemoprevention in heritable colon cancer. These data suggest that the use of GDF-15 activated signaling pathways may allow improved chemoprevention and therapies for colorectal cancer. PMID- 19784847 TI - Age as a prognostic factor for patients with osteosarcoma: an analysis of 438 patients. AB - BACKGROUND: It is unclear whether age at diagnosis is an important prognostic factor in patients with osteosarcoma. Understanding this relationship could yield valuable insight into therapeutic rationale, focus patient selection for clinical trials, advance molecular concepts and theories, and expand current principles guiding prognosis. Our aim was to understand if age at diagnosis is a prognostic indicator for eventual outcome, as measured by disease-free survival and overall survival in patients with osteosarcoma. METHODS: Our cohort consisted of 438 patients of all ages who were diagnosed with osteosarcoma between 1 January 1980 and 31 December 2000 and who underwent the majority of their treatment at M.D. Anderson Cancer Center (MDACC). Patient and tumor specific variables were collected including patient demographics, patient history, primary tumor information (i.e., location, size, histology, extension, necrosis, etc.), treatment strategy (i.e., surgery, chemotherapy, and/or radiotherapy), metastatic disease information, long-term follow-up, and eventual outcome. Statistical analyses, including univariate and multivariate analyses were performed, with overall survival and disease-free survival as the primary outcome measures. RESULTS: The median age at diagnosis was 18.1 years (range 2 months to 78.8 years). Median follow-up was 4.2 years (range 5 days to 22.8 years) for all patients and 12.3 years (range 1 month to 22.8 years) for 209 surviving patients. Survival rates at 5, 10, and 15 years were 54.1, 47.2, and 45.2%, respectively. On univariate analyses, age >or= 40 was found to be a poor prognostic factor. Other prognostic factors included tumor size, metastasis at diagnosis, soft tissue tumor extension, surgery type, chemotherapy group, and tumor necrosis. Age was not identified a statistically significant prognostic variable on multivariate analysis. CONCLUSIONS: Age at diagnosis does not appear to be a significant independent prognostic variable for overall survival or disease-free survival in patients with osteosarcoma. Although our data indicate that patients in the fifth decade and older fare worse than younger patients, other variables such as tumor necrosis, tumor extension, and tumor location are likely responsible for the observed decline in overall survival and disease-free survival. PMID- 19784848 TI - Expression status of Zic family member 2 as a prognostic marker for oral squamous cell carcinoma. AB - PURPOSE: To determine the involvement of ZIC2 in oral squamous cell carcinoma (OSCC). METHODS: ZIC2 mRNA and protein expression in primary OSCCs (n = 74), oral premalignant lesions (OPLs, n = 20) and five OSCC-derived cell lines (HSC-2, HSC 3, OK-92, H1, and Sa3) were analyzed by quantitative reverse transcriptase polymerase chain reaction, Western blot and immunohistochemistry (IHC). In addition, we evaluated the correlation between ZIC2 IHC scores in OSCCs and the clinicopathologic status. RESULTS: Significant up-regulation of ZIC2 was detected in OSCC-derived cell lines (P < 0.05), primary OSCCs (P < 0.05) and OPLs (P < 0.05) compared with normal counterparts. Among the clinical variables analyzed, ZIC2 expression was associated with the histopathologic types of OSCC. Furthermore, the survival rates differed significantly between ZIC2-positive cases and ZIC2-negative cases. CONCLUSIONS: These results suggested that ZIC2 expression is correlated with the differentiation type of OSCC and diagnosis and might be a potential prognostic indicator and therapeutic target for OSCCs. PMID- 19784849 TI - Why should a grazer browse? Livestock impact on winter resource use by bharal Pseudois nayaur. AB - Many mammalian herbivores show a temporal diet variation between graminoid dominated and browse-dominated diets. We determined the causes of such a diet shift and its implications for conservation of a medium-sized ungulate-the bharal Pseudois nayaur. Past studies show that the bharal diet is dominated by graminoids (>80%) during summer, but the contribution of graminoids declines to about 50% in winter. We tested the predictions generated by two alternative hypotheses explaining the decline: low graminoid availability during winter causes bharal to include browse in their diet; bharal include browse, with relatively higher nutritional quality, in their diet to compensate for the poor quality of graminoids during winter. We measured winter graminoid availability in areas with no livestock grazing, areas with relatively moderate livestock grazing, and those with intense livestock grazing pressures. The chemical composition of plants contributing to the bharal diet was analysed. The bharal diet was quantified through signs of feeding on vegetation at feeding locations. Population structures of bharal populations were recorded using a total count method. Graminoid availability was highest in areas without livestock grazing, followed by areas with moderate and intense livestock grazing. The bharal diet was dominated by graminoids (73%) in areas with highest graminoid availability. Graminoid contribution to the bharal diet declined monotonically (50, 36%) with a decline in graminoid availability. Bharal young to female ratio was 3 times higher in areas with high graminoid availability than areas with low graminoid availability. The composition of the bharal winter diet was governed predominantly by the availability of graminoids in the rangelands. Our results suggest that bharal include more browse in their diet during winter due to competition from livestock for graminoids. Since livestock grazing reduces graminoid availability, creation of livestock-free areas is necessary for the conservation of grazing species such as the bharal and its predators including the endangered snow leopard in the Trans-Himalaya. PMID- 19784850 TI - Tree species effects on ecosystem water-use efficiency in a high-elevation, subalpine forest. AB - Ecosystem water-use efficiency (eWUE; the ratio of net ecosystem productivity to evapotranspiration rate) is a complex landscape-scale parameter controlled by both physical and biological processes occurring in soil and plants. Leaf WUE (lWUE; the ratio of leaf CO(2) assimilation rate to transpiration rate) is controlled at short time scales principally by leaf stomatal dynamics and this control varies among plant species. Little is known about how leaf-scale variation in lWUE influences landscape-scale variation in eWUE. We analyzed approximately seven thousand 30-min averaged eddy covariance observations distributed across 9 years in order to assess eWUE in two neighboring forest communities. Mean eWUE was 19% lower for the community in which Engelmann spruce and subalpine fir were dominant, compared to the community in which lodgepole pine was dominant. Of that 19% difference, 8% was attributed to residual bias in the analysis that favored periods with slightly drier winds for the spruce-fir community. In an effort to explain the remaining 11% difference, we assessed patterns in lWUE using C isotope ratios. When we focused on bulk tissue from older needles we detected significant differences in lWUE among tree species and between upper and lower canopy needles. However, when these differences were scaled to reflect vertical and horizontal leaf area distributions within the two communities, they provided no power to explain differences in eWUE that we observed in the eddy covariance data. When we focused only on bulk needle tissue of current-year needles for 3 of the 9 years, we also observed differences in lWUE among species and in needles from upper and lower parts of the canopy. When these differences in lWUE were scaled to reflect leaf area distributions within the two communities, we were able to explain 6.3% of the differences in eWUE in 1 year (2006), but there was no power to explain differences in the other 2 years (2003 and 2007). When we examined sugars extracted from needles at 3 different times during the growing season of 2007, we could explain 3.8-6.0% of the differences in eWUE between the two communities, but the difference in eWUE obtained from the eddy covariance record, and averaged over the growing season for this single year, was 32%. Thus, overall, after accounting for species effects on lWUE, we could explain little of the difference in eWUE between the two forest communities observed in the eddy covariance record. It is likely that water and C fluxes from soil, understory plants, and non-needle tissues, account for most of the differences observed in the eddy covariance data. For those cases where we could explain some of the difference in eWUE on the basis of species effects, we partitioned the scaled patterns in lWUE into two components: a component that is independent of canopy leaf area distribution, and therefore only dependent on species-specific differences in needle physiology; and a component that is independent of species differences in needle physiology, and only dependent on species-specific influences on canopy leaf area distribution. Only the component that is dependent on species influences on canopy leaf area distribution, and independent of inherent species differences in needle physiology, had potential to explain differences in eWUE between the two communities. Thus, when tree species effects are important, canopy structure, rather than species-specific needle physiology, has more potential to explain patterns in eWUE. PMID- 19784851 TI - Remarkable spatial memory in a migratory cardinalfish. AB - The ability to orient and navigate within a certain environment is essential for all animals, and spatial memory enables animals to remember the locations of such markers as predators, home, and food. Here we report that the migratory marine cardinalfish Apogon notatus has the potential to retain long-term spatial memory comparable to that of other animals. Female A. notatus establish a small territory on a shallow boulder bottom to pair and spawn with males. We carried out field research in two consecutive breeding seasons on territory settlement by individually marked females. Females maintained a territory at the same site throughout one breeding season. After overwintering in deep water, many of them (82.1%) returned to their breeding ground next spring and most occupied the same site as in the previous season, with only a 0.56 m shift on average. Our results suggest that female A. notatus have long-distance homing ability to pinpoint the exact location of their previous territory, and retain spatial memory for as long as 6 months. PMID- 19784852 TI - Keeping track of time: evidence for episodic-like memory in great apes. AB - Episodic memory, as defined by Tulving, can be described in terms of behavioural elements (what, where and when information) but it is also accompanied by an awareness of one's past (chronesthesia) and a subjective conscious experience (autonoetic awareness). Recent experiments have shown that corvids and rodents recall the where, what and when of an event. This capability has been called episodic-like memory because it only fulfils the behavioural criteria for episodic memory. We tested seven chimpanzees, three orangutans and two bonobos of various ages by adapting two paradigms, originally developed by Clayton and colleagues to test scrub jays. In Experiment 1, subjects were fed preferred but perishable food (frozen juice) and less preferred but non-perishable food (grape). After the food items were hidden, subjects could choose one of them either after 5 min or 1 h. The frozen juice was still available after 5 min but melted after 1 h and became unobtainable. Apes chose the frozen juice significantly more after 5 min and the grape after 1 h. In Experiment 2, subjects faced two baiting events happening at different times, yet they formed an integrated memory for the location and time of the baiting event for particular food items. We also included a memory task that required no temporal encoding. Our results showed that apes remember in an integrated fashion what, where and when (i.e., how long ago) an event happened; that is, apes distinguished between different events in which the same food items were hidden in different places at different times. The temporal control of their choices was not dependent on the familiarity of the platforms where the food was hidden. Chimpanzees' and bonobos' performance in the temporal encoding task was age-dependent, following an inverted U-shaped distribution. The age had no effect on the performance of the subjects in the task that required no temporal encoding. PMID- 19784853 TI - Improved simultaneous production of mycelial biomass and polysaccharides by submerged culture of Hericium erinaceum: optimization using a central composite rotatable design (CCRD). AB - The aim of this study was to optimize the culture medium used for the mycelial growth and production of intracellular polysaccharides (IPS) and exopolysaccharides (EPS) in a submerged culture of Hericium erinaceum. Of the various factors examined, including carbon and nitrogen sources, vitamins, mineral elements, and initial pH, those that proved to have a significant effect were then tested using a 2(4) central composite rotatable design (CCRD). Under the optimal culture conditions, the maximal yield of biomass reached 14.24 +/- 0.45 g l(-1) and was 1.85-fold higher than in the basal medium. The kinetics of EPS biosynthesis in a bioreactor showed that although the highest yield of EPS (2.75 +/- 0.27 g l(-1)) could be obtained on day 8, the process of biosynthesizing high molecular weight polysaccharides proceeded until the depletion of the carbon source in the medium (after 14 days of cultivation). Our results could be very helpful in the large-scale production of bioactive polysaccharides from H. erinaceum. PMID- 19784854 TI - Good judgments do not require complex cognition. AB - What cognitive capabilities allow Homo sapiens to successfully bet on the stock market, to catch balls in baseball games, to accurately predict the outcomes of political elections, or to correctly decide whether a patient needs to be allocated to the coronary care unit? It is a widespread belief in psychology and beyond that complex judgment tasks require complex solutions. Countering this common intuition, in this article, we argue that in an uncertain world actually the opposite is true: Humans do not need complex cognitive strategies to make good inferences, estimations, and other judgments; rather, it is the very simplicity and robustness of our cognitive repertoire that makes Homo sapiens a capable decision maker. PMID- 19784855 TI - Serum protein profiling and proteomics in autistic spectrum disorder using magnetic bead-assisted mass spectrometry. AB - The pathophysiology of autistic spectrum disorder (ASD) is not fully understood and there are no diagnostic or predictive biomarkers. Proteomic profiling has been used in the past for biomarker research in several non-psychiatric and psychiatric disorders and could provide new insights, potentially presenting a useful tool for generating such biomarkers in autism. Serum protein pre fractionation with C8-magnetic beads and protein profiling by matrix-assisted laser desorption/ionisation-time of flight-mass spectrometry (MALDI-ToF-MS) were used to identify possible differences in protein profiles in patients and controls. Serum was obtained from 16 patients (aged 8-18) and age-matched controls. Three peaks in the MALDI-ToF-MS significantly differentiated the ASD sample from the control group. Sub-grouping the ASD patients into children with and without comorbid Attention Deficit and Hyperactivity Disorder, ADHD (ASD/ADHD+ patients, n = 9; ASD/ADHD- patients, n = 7), one peak distinguished the ASD/ADHD+ patients from controls and ASD/ADHD- patients. Our results suggest that altered protein levels in peripheral blood of patients with ASD might represent useful biomarkers for this devastating psychiatric disorder. PMID- 19784856 TI - Levels of reduced and oxidized coenzyme Q-10 and 8-hydroxy-2'-deoxyguanosine in the CSF of patients with Alzheimer's disease demonstrate that mitochondrial oxidative damage and/or oxidative DNA damage contributes to the neurodegenerative process. AB - To investigate the possibility that mitochondrial oxidative damage, oxidative DNA damage or both contribute to the neurodegenerative process of Alzheimer's disease (AD), we employed high-performance liquid chromatography using an electrochemical detector to measure the concentrations of the reduced and oxidized forms of coenzyme Q-10 (CoQ-10) and 8-hydroxy-2'-deoxyguanosine (8-OHdG) in the cerebrospinal fluid (CSF) of 30 patients with AD and in 30 age-matched controls with no neurological disease. The percentage of oxidized/total CoQ-10 (%CoQ-10) in the CSF of the AD group (78.2 +/- 18.8%) was significantly higher than in the control group (41.3 +/- 10.4%) (P < 0.0001). The concentration of 8-OHdG in the CSF of AD patients was greater than in the CSF of controls (P < 0.0001) and was positively correlated with the duration of illness (r(s) = 0.95, P < 0.0001). The %CoQ-10 was correlated with concentrations of 8-OHdG in the CSF of AD patients (r(s) = 0.66, P < 0.001). The present study suggests that both mitochondrial oxidative damage and oxidative DNA damage play important roles in the pathogenesis of early AD development. PMID- 19784857 TI - Prolonged stay at the paediatric intensive care unit associated with paediatric delirium. AB - The objective of this study was to investigate, under circumstances of routine care, the impact of paediatric delirium (PD) on length of stay in the paediatric intensive care unit (PICU) as well as on direct financial costs. A five-year prospective observational study (2002-2007) was carried out in a tertiary eight bed PICU in the Netherlands. Critically ill children aged 1 to 18 years who were acutely, non-electively and consecutively admitted to the PICU and detected as having PD in routine care were compared to critically ill children aged 1 to 18 years without signs of PD. PD, population characteristics and severity of illness at admission were used as predictors for length of PICU stay. Differences in length of stay yielded short-term, direct medical costs associated with PD. Forty nine children with and 98 children without PD were included. PD prolonged length of PICU stay with 2.39 days, independent of severity of illness, age, gender, mechanical ventilation and medical indication for admission (B = 0.38, P < 0.001). PD increased direct medical costs with 1.5%. The results suggest a negative prognostic influence of PD on duration of PICU stay in routine care, resulting in an increase of direct medical costs. PMID- 19784858 TI - Understanding the genetic structure of Symplocos laurina Wall. populations using nuclear gene markers. AB - To characterize the genetic diversity of present populations of Symplocos laurina, which grow in the montane forests in India, we analyzed the DNA sequences of a nuclear gene. Using the 881 bp sequence of cytosolic Glyceraldehyde-3-phosphate dehydrogenase gene, we detected 24 haplotypes among 195 individuals sampled from 14 populations. Two dominant haplotypes were distributed over the entire range of this species in India and several private haplotypes were found. Low genetic diversity within population, high differentiation, number of population specific haplotypes and deviation from neutral evolution characterized the present populations of S. laurina. An analysis of molecular variance indicated the presence of geographic structure within the haplotype distribution. The occurrence of S. laurina preglaciation in India is the most parsimonious explanation for the current geographic structure observed. The populations are presumably ancient and might have spread across its extant distribution range in India through a recent range expansion event. PMID- 19784859 TI - Evaluation of endogenous acidic metabolic products associated with carbohydrate metabolism in tumor cells. AB - Tumor cells have a high tolerance for acidic and hypoxic microenvironments, also producing abundant lactic acid through accelerated glycolysis in the presence or absence of O(2). While the accumulation of lactate is thought to be a major contributor to the reduction of pH-circumscribing aggressive tumors, it is not known if other endogenous metabolic products contribute this acidity. Furthermore, anaerobic metabolism in cancer cells bears similarity to homo fermentative lactic acid bacteria, however very little is known about an alternative pathway that may drive adenosine triphosphate (ATP) production independent of glycolysis. In this study, we quantify over 40 end-products (amines, acids, alcohols, aldehydes, or ketones) produced by malignant neuroblastoma under accelerated glycolysis (+glucose (GLU) supply 1-10 mM) +/- mitochondrial toxin; 1-methyl-4-phenylpyridinium (MPP(+)) to abate aerobic respiration to delineate differences between anaerobic vs. aerobic cell required metabolic pathways. The data show that an acceleration of anaerobic glycolysis prompts an expected reduction in extracellular pH (pH(ex)) from neutral to 6.7 +/ 0.006. Diverse metabolic acids associated with this drop in acidity were quantified by ionic exchange liquid chromatography (LC), showing concomitant rise in lactate (Ctrls 7.5 +/- 0.5 mM; +GLU 12.35 +/- 1.3 mM; +GLU + MPP 18.1 +/- 1.8 mM), acetate (Ctrl 0.84 +/- 0.13 mM: +GLU 1.3 +/- 0.15 mM; +GLU + MPP 2.7 +/- 0.4 mM), fumarate, and a-ketoglutarate (<10 microM) while a range of other metabolic organic acids remained undetected. Amino acids quantified by o-phthalaldehyde precolumn derivatization/electrochemical detection-LC show accumulation of L: alanine (1.6 +/- .052 mM), L: -glutamate (285 +/- 9.7 microM), L: -asparagine (202 +/- 2.1 microM), and L: -aspartate (84.2 +/- 4.9 microM) produced during routine metabolism, while other amino acids remain undetected. In contrast, the data show no evidence for accumulation of acetaldehyde, aldehydes, or ketones (Purpald/2,4-dinitrophenylhydrazine-Brady's reagent), acetoin (Voges-Proskauer test), or alcohols (NAD(+)-linked alcohol dehydrogenase). In conclusion, these results provide preliminary evidence to suggest the existence of an active pyruvate-alanine transaminase or phosphotransacetylase/acetyl-CoA synthetase pathway to be involved with anaerobic energy metabolism of cancer cells. PMID- 19784861 TI - Acquired resistance to the rice blast in transgenic rice accumulating the antimicrobial peptide thanatin. AB - Thanatin is an antimicrobial peptide with a strong and wide-ranging antimicrobial spectrum, including certain species of fungi and Gram-negative and Gram-positive bacteria. To evaluate the application of thanatin to the generation of disease resistant plants, we introduced a synthetic thanatin gene into rice. Several transformants that expressed the introduced gene showed significant level of antimicrobial activity. The substances showing antimicrobial activity were partially purified from these transformants and their properties were determined. The molecule with characteristics similar to those of native thanatin on the elution pattern in HPLC analysis had an identical molecular mass to that of native molecule. It should also be noted that the transformant acquired a sufficient level of resistance to the rice blast fungus, Magnaporthe oryzae, presumably due to the repressive activity of thanatin to its initial stage of infection. This result demonstrates that thanatin has antifungal activity for M. oryzae and that the introduction of the thanatin gene into rice is effective in generating a plant resistant to rice blast disease. PMID- 19784860 TI - Leukocyte telomere length in a population-based case-control study of ovarian cancer: a pilot study. AB - OBJECTIVES: Telomeres are structures at chromosome ends that contribute to maintaining genomic integrity. Telomere shortening with repeated cell divisions may lead to genomic instability and carcinogenesis. Studies suggest that shorter telomeres in constitutional DNA are associated with bladder, breast, lung, and renal cancer. Ovarian cancer tissues also have shortened telomeres and increased telomerase activity, suggesting that telomere abnormalities may be related to ovarian cancer. METHODS: We investigated leukocyte telomere length in 99 women with serous ovarian adenocarcinoma and 100 age-matched cancer-free controls enrolled in a population-based case-control study. RESULTS: Cases tended to have shorter telomeres than controls (P (wilcoxon) = 0.002). Compared to subjects with telomere lengths in the longest tertile, those in the middle and shortest tertiles showed respective age-adjusted odds ratios (95% confidence intervals) of 2.69 (1.23-5.88) and 3.39 (1.54-7.46) (P (trend) = 0.002). Strongest associations were found for subjects with poorly differentiated carcinomas (OR = 4.89, 95% CI 1.93-12.34). CONCLUSIONS: This study shows that short leukocyte telomeres are associated with serous ovarian adenocarcinoma. These findings should be confirmed in large, prospective studies. PMID- 19784862 TI - Selected health and management issues facing working donkeys presented for veterinary treatment in rural Mexico: some possible risk factors and potential intervention strategies. AB - The examination of 216 donkeys presented for treatment at the Donkey Sanctuary World Horse Welfare-Universidad Nacional Autonoma de Mexico mobile clinics revealed a number of health and welfare problems. A general overview of the donkeys' health was made and showed that the median body condition score (BCS) in this population was 2.5. Underweight animals only accounted for 26% of the population. Females, 0-5-year-olds and >21-year-olds, were more likely to be underweight. When analysed, there was no correlation between faecal worm egg count (FEC) and BCS. The prevalence of strongyle infection as assessed by FEC was shown to be 80% with a median FEC of 600 eggs per gramme. Donkeys were assessed for body lesions and showed a high prevalence (71%), particularly in the facial region (54%). Analysis showed that mature animals (6-15 years old) were at increased risk of body lesions compared to older animals (16+ years old) as were donkeys with dental disease and those in particular villages. Risk factor analysis for lesions of the face showed that stallions and geldings are at increased risk as were donkeys wearing halters made from nylon rope. This study has identified areas for further investigation and potential areas where targeted interventions may be made to improve the health and welfare of working donkeys in Mexico. PMID- 19784863 TI - Immune responses to haemorrhagic septicaemia (HS) vaccination in Trypanosoma evansi infected buffalo-calves. AB - To assess the immunosuppressive effect of Trypanosoma evansi infection in buffalo calves on immune responses to heterologous antigen, the study was planned to examine the responses of haemorrhagic septicaemia vaccination in simultaneously and previously (80 days before vaccination) T. evansi-infected buffalo-calves. Eight buffalo-calves were divided into three groups. Buffalo-calves of group A (n = 3) were previously (80 days before primary vaccination with haemorrhagic septicaemia [HS] vaccine) infected with T. evansi (1 x 10(7) tryps.calf(-1); sc) and that of group B (n = 3) were infected with T. evansi (1 x 10(7) tryps.calf( 1); sc) on the day of primary vaccination with HS vaccine. Two healthy uninfected control calves given only HS vaccine were kept in group C. All the buffalo-calves were given a booster dose of vaccine 21 days post-primary vaccination (PPV). Twenty eight days PPV, animals of group A were given trypanocidal quinapyramine prosalt at 6.66 mg kg(-1). Immunosuppressive effect of T. evansi infection was evident from day 7 PPV with HS vaccine. The effect was more pronounced in previously T. evansi-infected buffalo-calves as compared with simultaneously infected buffalo-calves. Group A buffalo-calves appeared to have recovered from the immunosuppressive effect after 28 days post-trypanocidal treatment as observed by humoral and cell-mediated immune responses. Immunosuppressive effect to HS vaccination was observed in T. evansi-infected buffalo-calves, and trypanocidal therapy enabled the calves to mount the responses similar to uninfected controls. PMID- 19784864 TI - Assessment of microsatellite instability in colorectal cancer patients from Brazil. AB - The replication error status analysis of DNA, through microsatellite instability detection, has become an indispensable tool for hereditary non-polyposis colorectal cancer screening. This study investigated the microsatellite instability in Brazilian individuals presenting colorectal cancer. In this study, 66 patients were clinically analyzed according to Amsterdam II and Bethesda guidelines. Normal and tumour tissues were collected and analyzed for MSI degree according to molecular markers BAT25, BAT26, BAT40, APC-D5S346, D2S123, and D17S250. Eight patients (12.1%) fulfilled the Amsterdam II guidelines, and 15 (22.7%) met the Bethesda guidelines. BAT25 was the most sensitive marker (86.7%), while BAT26 was the least sensitive (66.7%). The specificity of both markers was 100%, but all of the markers must be used since the contribution of each marker to the sensitivity and specificity of the test is complementary. Proximal tumours were significantly predominant among RER+ patients. CONCLUSIONS: Patients with a family history of colorectal cancer with the tumour in the proximal colon must be screened to replication error status as early as possible in order to avoid the progression of the disease. PMID- 19784865 TI - Qualitative research and content validity: developing best practices based on science and experience. AB - PURPOSE: Establishing content validity for both new and existing patient-reported outcome (PRO) measures is central to a scientifically sound instrument development process. Methodological and logistical issues present a challenge in regard to determining the best practices for establishing content validity. METHODS: This paper provides an overview of the current state of knowledge regarding qualitative research to establish content validity based on the scientific methodological literature and authors' experience. RESULTS: Conceptual issues and frameworks for qualitative interview research, developing the interview discussion guide, reaching saturation, analysis of data, developing a theoretical model, item generation and cognitive debriefing are presented. Suggestions are offered for dealing with logistical issues regarding facilitator qualifications, ethics approval, sample recruitment, group logistics, taping and transcribing interviews, honoraria and documenting content validity. CONCLUSIONS: It is hoped this paper will stimulate further discussion regarding best practices for establishing content validity so that, as the PRO field moves forward, qualitative research can be evaluated for quality and acceptability according to scientifically established principles. PMID- 19784866 TI - Frictional properties of light-activated antimicrobial polymers in blood vessels. AB - The adhesion of microbes to catheter surfaces is a serious problem and the resulting infections frequently lead to longer hospitalisation and higher risk for the patient. Several approaches have been developed to produce materials that are less susceptible to microbial colonisation. One such approach is the incorporation of photoactivated compounds, such as Toluidine Blue O (TBO), in the polymeric matrix resulting in 'light-activated antimicrobial materials'. The insertion and removal of catheters can cause tissue damage and patient discomfort through frictional forces; hence the lubricity of a catheter material is also very important. In this work the tribological performance of silicone and polyurethane containing TBO and gold nanoparticles were evaluated using two different surfaces, the inner part of the aorta and the superior vena cava of sheep. Static and kinetic friction coefficients of these materials were measured using a tribometric device developed for in vitro applications using dry materials and those lubricated with blood. It was found that neither the preparation process nor the presence of TBO or gold nanoparticles, had an effect on the friction factors in comparison to those of untreated materials. In all cases, static and kinetic friction coefficients on aorta tissue were higher than those on vena cava due to higher surface roughness of the aorta. The presence of blood as a lubricant resulted in lower friction coefficients. PMID- 19784867 TI - Fabrication and biocompatibility of nano non-stoichiometric apatite and poly(epsilon-caprolactone) composite scaffold by using prototyping controlled process. AB - Nano biocomposite scaffolds of non-stoichiometric apatite (ns-AP) and poly(epsilon-caprolactone) (PCL) were prepared by a prototyping controlled process (PCP). The results show that the composite scaffolds with 40 wt% ns-AP contained open and well interconnected pores with a size of 400-500 mum, and exhibited a maximum porosity of 76%. The ns-AP particles were not completely embedded in PCL matrix while exposed on the composite surface, which might be useful for cell attachment and growth. Proliferation of MG(63) cells was significantly better on the composite scaffolds with porosity of 76% than that those with porosity of 53%, indicating that the scaffolds with high porosity facilitated cell growth, and could promote cell proliferation. The composite scaffolds were implanted into rabbit thighbone defects to investigate the in vivo biocompatibility and osteogenesis. Radiological and histological examination confirmed that the new bony tissue had grown easily into the entire composite scaffold. The results suggest that the well-interconnected pores in the scaffolds might encourage cell proliferation, and migration to stimulate cell functions, thus enhancing bone formation in the scaffolds. This study shows that bioactive and biocompatible ns-AP/PCL composite scaffolds have potential applications in bone tissue engineering. PMID- 19784868 TI - Pre-intervention distress moderates the efficacy of psychosocial treatment for cancer patients: a meta-analysis. AB - This meta-analysis examined whether effects of psychosocial interventions on psychological distress in cancer patients are conditional upon pre-intervention distress levels. Published articles and unpublished dissertations between 1980 and 2005 were searched for interventions reporting the Hospital Anxiety and Depression Scale (HADS) or the Spielberger State-Trait Anxiety Inventory (STAI). Multilevel mixed-effects modeling was used to meta-analyze effect-sizes separately for the HADS (27 trials, 2,424 patients) and STAI (34 trials, 2,029 patients). Pre-intervention distress significantly moderated intervention effects, explaining up to 50% of the between-study effect-size variance: effects on anxiety and depression were generally negligible when pre-intervention distress was low and pronounced when it was high. These results could not be explained by differences in intervention type, setting, dose, and whether intervention was targeted at distressed patients. Psychosocial interventions may be most beneficial for cancer patients with elevated distress. Future research should identify which treatment components are most effective for these patients to facilitate optimal treatment tailoring and cost-effective health care. PMID- 19784869 TI - Danthron induced apoptosis through mitochondria- and caspase-3-dependent pathways in human brain glioblastoma multiforms GBM 8401 cells. AB - Danthron (1,8-dihydroxyanthraquinone), is one of component from Rheum palmatum L. (Polygonaceae), has been shown several biological activities but did not show to induce apoptosis in human brain tumor cells. The aim of this study is to investigate the mechanisms by danthron for the induction of apoptotic potential on human brain glioblastoma multiforms GBM 8401 cell line. Danthron showed a marked concentration- and time-dependent inhibition of GBM 8401 cell viability and induced apoptosis in a dose-and time-dependent manner. There was an attenuation of mitochondrial membrane potential (DeltaPsi(m)) with the alterations of Bcl-2/Bax protein ratio in GBM 8401 cells, indicating the participation of a mitochondria-related mechanism. Pretreatment of a caspase-8 inhibitor (Z-IETD-FMK), caspase-9 inhibitor (Z-LEHD-FMK) and caspase-3 inhibitor (Z-DEVE-FMK) significantly increased the viable of GBM 8401 cells implied that the participations of caspases. Western blotting analysis also showed the activation of initiator caspase-8 and caspase-9, and executor caspase-3 in GBM 8401 cells. Meanwhile, danthron also promoted the generation of reactive oxygen species (ROS) and cytosolic Ca(2+) in GBM 8401 cells. Taken together, our data showed that danthron induced apoptosis in GBM 8401 cells through mitochondria related and caspase-related pathways, and it may be further evaluated as a chemotherapeutic agent for human brain cancer. PMID- 19784870 TI - Dystrophin Dp71 is critical for stability of the DAPs in the nucleus of PC12 cells. AB - We have adopted the PC12 cell line as in vitro cell model for studying Dp71 function in neuronal cells. These cells express a cytoplasmic (Dp71f) and a nuclear (Dp71d) isoform of Dp71 as well as various dystrophin-associated proteins (DAPs). In this study, we revealed by confocal microscopy analysis and Western blotting evaluation of cell fractions the presence of different DAPs (beta dystroglycan, beta-dystrobrevin, epsilon-sarcoglycan and gamma1-syntrophin) in the nucleus of PC12 cells. Furthermore, we established by immunoprecipitation assays that Dp71d and the DAPs form a dystrophin-associated protein complex (DAPC) in the nucleus. Interestingly, depletion of Dp71 by antisense treatment (antisense-Dp71 cells) provoked a drastic reduction of nuclear DAPs, which indicates that Dp71d is critical for DAPs stability within the nucleus. Although Up71, the utrophin gene product homologous to Dp71, exhibited increased expression in the antisense-Dp71 cells, its scarce nuclear levels makes unlikely that could compensate for Dp71 nuclear deficiency. PMID- 19784871 TI - The relationship between pulmonary system impedance and right ventricular function in normal sheep. AB - Right ventricular (RV) afterload is a key determinant of RV function and is increased in many cardiopulmonary pathologies. Pulmonary circulation input impedance has been used to quantify afterload previously but due to its complexity has not been widely applied. This study examines the effect of a subset of the impedance spectrum, the zeroth and first harmonic impedance moduli (Z (0), Z (1)), on RV performance in large animals. An artificial circuit with adjustable resistance and compliance (C) was implanted into the pulmonary circulation of five sheep. Resistance was varied to increase Z (0) in increments of 2 mmHg/(L/min) until Z (0) was 8 mmHg/(L/min) above baseline. At each Z (0), C was adjusted between 0, 0.5 and 2 mL/mmHg or 0, 1, and 5 mL/mmHg. Fourier transforms of the pulmonary artery pressure and flow in each situation were used to calculate the pulmonary impedance. Results show that the percent change in cardiac output (%DeltaCO) is linearly related to the change in Z (0) (DeltaZ (0)). Increases in Z (1) (DeltaZ (1)) decreased %DeltaCO but to a much smaller degree, with the effect of DeltaZ (1) increasing with DeltaZ (0). Regression of these results produce the equation: %DeltaCO = (-0.0829DeltaZ (1) - 3.65)DeltaZ (0) - 9.02 (R (2) = 0.69). Blood flow and pressure moduli are small at harmonics higher than the first and are unlikely to affect RV function. Therefore, during acute, high afterload states, Z (0) is the primary determinant of CO, while the effect of Z (1) is minor. PMID- 19784872 TI - A lifetime of low-risk behaviors among HIV-positive Latinas in Los Angeles. AB - The objective is to assess the differences in lifetime and current transmission risk behaviors of HIV-positive and HIV-negative Latinas. In 2005-2006, 214 HIV positive Latinas were recruited from systems of care and 111 HIV-negative Latina matched controls were interviewed in Los Angeles, CA regarding lifetime and recent sexual and drug-taking risk behaviors. Multivariate OLS regression and logistic regression models were used to assess differences in lifetime and current transmission risk. There was no significant difference between the two groups with respect to lifetime exposure through injection drug use. HIV-positive Latinas reported significantly more lifetime sexual partners than HIV-negative Latinas. Rates of current sexual activity were not significantly different across the two groups. HIV-positive Latinas were less likely to report recent unprotected sex relative to HIV-negative Latinas. In Los Angeles, HIV-positive and HIV-negative Latinas were very similar with respect to transmission risk. The challenges these findings pose to prevention efforts that target Latinas and suggestions for new interventions are discussed. PMID- 19784873 TI - LFG: a candidate apoptosis regulatory gene family. AB - The expanding wealth of human, model and other organism's genomic data has allowed the identification of a distinct gene family of apoptotic related genes. Most of these genes are currently unannotated or have been subsumed under two questionably related gene families in the past. For example the transmembrane Bax inhibitor 1 (BI1) motif family has been reported to play a role in apoptosis and to consist of at least seven mammalian protein genes, GRINA, BI1, Lfg/FAIM2, Ghitm, RESC1/Tmbim1, GAAP/Tmbim4, and Tmbm1b. However, a detailed sequence and phylogenetic analysis shows that only five of these form a clear and unique protein family. This now provides information for understanding and investigating the biological roles of these proteins across a wide range of tissues in model organisms. The evolutionary relationships among these genes provide a powerful prospective for extrapolating to human conditions. PMID- 19784876 TI - Sero-epidemiological investigation of bovine toxoplasmosis in traditional and smallholder cattle production systems of Tanga Region, Tanzania. AB - In view of the worldwide importance of Toxoplasma gondii and the fragmented information on the seroprevalence of the disease in animals in Tanzania, a study, using the modified Eiken latex agglutination test (LAT), was conducted from May 2003 to January 2004 to determine the prevalence of antibody to T. gondii in 130 randomly selected farms comprising 655 cattle. The overall seroprevalence of T.gondii antibodies in cattle and farms were 3.6% and 13%, respectively. Risk factors for animal and herd-level toxoplasmosis seropositivity were tested using multivariable logistic regression to control for confounding factors. Cattle managed under traditional husbandry practises were more likely to be seropositive than those managed under smallholder practises (48% versus 4.7%; p < 0.01). Herd size of > or = 9 cattle were at greater risk of acquiring infection than herds holding fewer animals [< or = 9 cattle], (odd ratio [OR] = 3.99; 95% confidence interval [CI], 0.97-16.48; P = 0.001). We concluded that seroprevalence at herd level was high and relatively low at animal level, possibly due to the reduced susceptibility of cattle to T.gondii infection as compared to goats and sheep. The high seroprevalence in animals managed by traditional husbandry practise suggests that the parasite is widely distributed in the environment and could pose a public health threat to the people living in those areas. PMID- 19784875 TI - Brain cancer stem cells. AB - Cancers comprise heterogeneous cells, ranging from highly proliferative immature precursors to more differentiated cell lineages. In the last decade, several groups have demonstrated the existence of cancer stem cells in both nonsolid solid tumors, including some of the brain: glioblastoma multiforme (GBM), medulloblastoma, and ependymoma. These cells, like their normal counterpart in homologous tissues, are multipotent, undifferentiated, self-sustaining, yet transformed cells. In particular, glioblastoma-stem like cells (GBSCs) self-renew under clonal conditions and differentiate into neuron- and glia-like cells, with aberrant, mixed neuronal/astroglial phenotypes. Remarkably, upon subcutaneous and intracerebral transplantation in immunosuppressed mice, GBSCs are able to form secondary tumors that closely resemble the human pathology, a property retained also throughout serial transplantation. The search is up for the identification of the markers and the molecular mechanisms that underpin the tumorigenic potential of these cells. This is critical if we aim at defining new therapeutic approaches for the treatment of malignant brain tumors. Lately, it has been shown that some key regulatory system that plays pivotal roles in neural stem cell physiology can also regulate the tumorigenic ability of cancer stem cells in GBMs. This suggests that the study of cancer stem cells in brain tumors might help to identify new and more specific therapeutic molecular effectors, with the cancer stem cells themselves representing one of the main targets, in fact the Holy Grail, in cancer cell therapy. This review includes a summary review on brain cancer cells and their usefulness as emerging targets in cancer cell therapy. PMID- 19784877 TI - Functional imaging in differentiating bronchial masses: an initial experience with a combination of (18)F-FDG PET-CT scan and (68)Ga DOTA-TOC PET-CT scan. AB - OBJECTIVE: To evaluate the role of combination of (18)F-FDG PET-CT scan and (68)Ga DOTA-TOC PET-CT scan in differentiating bronchial tumors observed in contrast enhanced computed tomography scan of chest. STUDY DESIGN: Prospective observational study. Place of study: All India Institute of Medical Sciences, New Delhi, India. METHODS: 7 patients with bronchial mass detected in computed tomography scan of the chest were included in this study. All patients underwent (18)F-FDG PET-CT scan, (68)Ga DOTA-TOC PET-CT scan and fiberoptic bronchoscope guided biopsy followed by definitive surgical excision. The results of functional imaging studies were analyzed and the results are correlated with the final histopathology of the tumor. RESULTS: Histopathological examination of 7 bronchial masses revealed carcinoid tumors (2 typical, 1 atypical), inflammatory myofibroblastic tumor (1), mucoepidermoid carcinoma (1), hamartoma (1), and synovial cell sarcoma (1). The typical carcinoids had mild (18)F-FDG uptake and high (68)Ga DOTA-TOC uptake. Atypical carcinoid had moderate uptake of (18)F-FDG and high (68)Ga DOTA-TOC uptake. Inflammatory myofibroblastic tumor showed high uptake of (18)F-FDG and no uptake of (68)Ga DOTA-TOC. Mucoepidermoid carcinoma showed mild (18)F-FDG uptake and no (68)Ga DOTA-TOC uptake. Hamartoma showed no uptake on either scans. Synovial cell sarcoma showed moderate (18)F-FDG uptake and mild focal (68)Ga DOTA-TOC uptake. CONCLUSION: This initial experience with the combined use of (18)F-FDG and (68)Ga DOTA-TOC PET-CT scan reveals different uptake patterns in various bronchial tumors. Bronchoscopic biopsy will continue to be the gold standard; however, the interesting observations made in this study merits further evaluation of the utility of the combination of (18)F-FDG PET-CT scan and (68)Ga DOTA-TOC PET-CT scan in larger number of patients with bronchial masses. PMID- 19784878 TI - Utility of SPECT/CT with Meckel's scintigraphy. AB - Meckel's diverticulum is a relatively common source of gastrointestinal tract morbidity in children. Individuals may present with symptoms of lower gastrointestinal tract bleeding, bowel obstruction or diverticulitis. Technetium 99 m pertechnetate scintigraphy is used to demonstrate those Meckel's diverticula that contain heterotopic gastric mucosa. We present a case of an adolescent male patient with rectal bleeding and suspected Meckel's diverticulum where the use of SPECT/CT fusion imaging provided valuable diagnostic information and prevented a false-negative study. PMID- 19784879 TI - Endogenous transforming growth factor (TGF) beta1 promotes differentiation of smooth muscle cells from embryonic stem cells: stable plasmid-based siRNA silencing of TGF beta1 gene expression. AB - Transforming growth factor (TGF) beta1 has been shown to promote differentiation of smooth muscle cells (SMC) from some precursor cells. Whether endogenous TGF beta1 also contributes to SMC differentiation during embryogenesis, however, remains unclear. In this study, a plasmid-based TGF beta1 RNA interference embryonic stem (ES) cell line was constructed. Morphological observation showed that TGF beta1 knockdown significantly prevented differentiated cells from outgrowing from ES cells-derived embryoid bodies (EBs). Immunofluorescence staining indicated that SM alpha-actin-positive cells were confluent and dense in the control group but dispersed in the TGF beta1 knockdown group. RT-PCR and western blot suggested that TGF beta1 knockdown resulted in a decrease in the expression of early SMC markers SM alpha-actin and myocardin in EBs. Both the retarded extension of cell outgrowth and the decrease in SM alpha-actin and myocardin expression could not be rescued by addition of exogenous TGF beta1. These data suggest that endogenous TGF beta1 promotes differentiation of SMC from ES cells. PMID- 19784880 TI - Influence of C3435T multidrug resistance gene-1 (MDR-1) polymorphism on platelet reactivity and prognosis in patients with acute coronary syndromes. AB - BACKGROUND: Genetic C3435T polymorphism of the multidrug resistance gene-1 (MDR 1) limits oral bioavailability of clopidogrel and influences prognosis in patients with myocardial infarction. AIM: To assess the effects of C3435T polymorphism on platelet reactivity and prognosis in patients with acute coronary syndromes treated with percutaneous coronary intervention with stenting. METHODS: Ninety-eight patients were divided into subgroups according to closure time (CT) measured with the Platelet Function Analyzer-100 by means of collagen/adenosine diphosphate (CADP) and collagen/epinephrine (CEPI) cartridges. Patients with CADP CT<130 s and patients with CEPI-CT50% was higher in symptomatic than asymptomatic patients (32 vs. 16, p<0.05). Multivariate analysis revealed a 3.5 times higher probability of Stokes Adams attacks and syncope in patients with confirmed atherosclerotic lesions (OR 3.5, 95% CI 1.2-13.4; p=0.0351). Blood flow disturbances in vertebral arteries were more frequent in symptomatic patients: 26 vs. 11%, p=0.0438. The lowest risk of loss of consciousness was observed in patients with second degree atrioventricular block, with no atherosclerotic lesions: (OR 0.2; 95% CI 0.03 0.06; p=0.0102). CONCLUSIONS: Prevalence of atherosclerotic lesions in carotid and vertebral arteries is higher in symptomatic patients referred for pacemaker implantation. The lowest risk of symptoms was found in patients with a second degree atrioventricular block and no atherosclerotic lesions. Ultrasonographic examination of carotid and vertebral arteries should be considered in all symptomatic patients with indications for pacemaker implantation. PMID- 19784886 TI - [Myocarditis--the first symptom of adult Still's disease]. AB - Myocardial involvement during the course of adult Still's disease is very rare. We present a case of a 34-year-old man admitted with fever, tachycardia, weakness and chest discomfort. The electrocardiogram showed non-specific diffuse ST-T changes, troponin level was slightly elevated and echocardiography did not reveal any abnormalities. After ruling out other relevant diseases, the adult Still's disease was diagnosed. PMID- 19784887 TI - [Acute generalised exanthematosus pustulosis (AGEP) due to diltiazem--a case report]. AB - A case of a patient who developed acute generalised exanthemotosus pustulosis (AGEP) due to diltiazem therapy is presented. On the day of the admission to hospital skin changes were present on the whole body in the form of sterile spots of an erythema origin. The laboratory tests showed anaemia, leucocytosis, hypocalcaemia, increased liver enzymes and increased ESR. The skin changes were accompanied by high temperature and bad condition. On the basis of medical history, clinical picture and medical tests, AGEP was diagnosed. After the application of a general treatment with erythromycin and external preparations, the skin changes subsided completely. PMID- 19784888 TI - [Typical magnetic resonance features of cardiac fibroma--a case report]. AB - Cardiac tumors are rare. Magnetic resonance allows non-invasive, detailed evaluation of myocardial tissue and differential diagnosis. We present a case of a young man with unexplained cardiac mass and typical magnetic resonance features of a left ventricular fibroma. PMID- 19784889 TI - [Myocardial infarction in a 27-year-old woman--five years follow-up. A case report]. AB - A case of a 27-year-old female, who developed acute myocardial infarction is presented. The first ECG revealed T-waves changes. Coronary angiography revealed a critical stenosis of the left descending coronary artery and a successful angioplasty was performed. A five-year follow-up was uneventful. PMID- 19784890 TI - [Contrast-induced nephropathy after percutaneous interventions]. PMID- 19784891 TI - [The role of augmented chemoreceptor sensitivity in the pathophysiology of cardiovascular disease]. PMID- 19784892 TI - [Life-threatening ventricular arrhythmia during simultaneous administration of propafenone and sotatol]. AB - A case of a patient treated with antiarrhythmic drugs for ventricular arrhythmia occurring after viral infection of the respiratory tract is presented. In the course of preliminary cardiologic examination no organic heart disease was diagnosed. Due to numerous ventricular extrasystolic beats (16,500 per day) and short runs of non-sustained ventricular tachycardia (maximum of 4 subsequent beats) propafenone was introduced. Persistent arrhythmia was a reason for adding sotalol to that treatment in an outpatient clinic. After three weeks of such treatment the patient presented cardiac arrest in the mechanism of ventricular tachycardia and fibrillation. Successful resuscitation and drug discontinuation led to complete resolution of the life-threatening arrhythmia. No inducible complex ventricular arrhythmia was observed during electrophysiologic examination. PMID- 19784893 TI - A giant interatrial mass: an unusual presentation of primary amyloidosis. AB - We report a patient with primary systemic amyloidosis who had a very unusual form of clinical and instrumental presentation. PMID- 19784894 TI - Successful percutaneous coronary intervention for severe stenosis of a double right coronary artery. AB - Anomalies of the coronary arteries are uncommon and often asymptomatic. Double right coronary artery (RCA) is a very rare coronary anomaly. So far, the number of reported cases of double RCA is low. We describe a case of a 50-year-old female patient hospitalised with the diagnosis of unstable angina pectoris. RCA injection showed filling of two separately originating RCA, coursing towards the right atrioventricular groove. Coronary angioplasty was successful. PMID- 19784895 TI - [Inappropriate therapy of an implantable cardioverter-defibrillator--is it always an undesired event? A case report]. AB - Inappropriate implantable cardioverter defibrillator (ICD) therapy is the commonest adverse event in patients with ICD. We present a case of sinus rhythm restoration after an inappropriate shock in a man with permanent atrial fibrillation and dilated cardiomyopathy. During follow-up, clinical improvement has been observed. PMID- 19784897 TI - [Safety and efficacy of cardiac rehabilitation following coronary revascularisation in patients with diabetes]. PMID- 19784896 TI - [POL-TAVI First--Polish report on transcatheter aortic valve implantation (TAVI) of Edwards-Sapien prosthesis in the first 19 high risk patients with severe aortic stenosis and comorbidities]. AB - Patients with severe symptomatic aortic stenosis, who from November 2008 to March 2009 were treated with Edwards-Sapien transcatheter aortic valve implantation (TAVI) within the POL-TAVI First Polish Registry, were included in the analysis. Nineteen patients aged 78+/-4.8 years with high operation risk and Logistic EuroSCORE 25+/-7.6% were reported (74% were females). In 15 (79%) patients the valve was implanted transapically (TA), in the other four (21%)--via the femoral arterial access (TF). The valve was successfully implanted in 16 (84%) patients, in one patient aortic valvuloplasty alone was performed. During in-hospital period two patients died (one during periprocedural period and another one--two months after the implantation). During the mean follow-up of 5+/-1.5 months (except for one patient who is still in hospital) all patients are in NYHA class I or II. Results of the initial series of 19 TAVI patients in Poland are satisfactory, and the trial will be continued with careful medical and economical analysis. PMID- 19784898 TI - Factor XIII Val34Leu polymorphism as a modulator of fibrin clot permeability and resistance to lysis in patients with severe coronary artery disease. AB - BACKGROUND: A common G to T transition in codon 34 with the subsequent valine with leucine replacement in the factor (F) XIII A-subunit affects fibrin formation and stabilisation in vitro. Data on the effects of Leu34 allele on cardiovascular thromboembolic events in vivo are conflicting. AIM: We investigated whether FXIII Val34Leu polymorphism is potent enough to affect fibrin clot properties in patients with advanced coronary artery disease (CAD). METHODS: We studied 113 patients, aged 62.8 +/- 6.1 years, who were scheduled for elective isolated coronary artery bypass grafting surgery (CABG). Patients were compared with 98 healthy age-matched controls. Ex vivo fibrin clot permeability and lysis time (t5oo/o) were determined in citrated plasma. RESULTS: Patients scheduled for CABG had lower clot permeability (9.14 + 1.64 vs. 10.02 + 1.12 x 10(-9) cm2; p = 0.0002) and longer t50%, (8.45 +/- 1.94 vs. 7.63 +/- 1.24 min; p < 0.0001) than controls. The Leu34 carriers, i.e. 9 (8%) Leu34Leu homozygous and 23 (20%) Val34Leu heterozygous subjects, had lower permeability by 23% in the CAD group compared with 81 (72%) patients with Val34Val genotype. A similar intergroup difference was observed for t50%, which was longer in Leu34 carriers (p < 0.0001). The FXIII Leu34 allele frequency in the control group was similar as well as the impact of Leu34 allele on fibrin properties. The effect of FXIII Leu34 allele on permeability and t50%, was not affected by homocysteine, C reactive protein and fibrinogen levels in CAD patients and controls. CONCLUSIONS: Like in healthy subjects, in patients scheduled for CABG, the FXIII Leu34 allele is associated with decreased fibrin clot permeability and efficiency of lysis. PMID- 19784899 TI - Sutureless aortic valve bioprothesis '3F/ATS Enable'--4.5 years of a single centre experience. AB - BACKGROUND: Management of patients with acquired heart malformations, including aortic valve disease, is still challenging. Due to ageing of population, patients undergoing valve surgery are older than in the past. The 3F Therapeutics, conducting a programme of construction of heart valves for transarterial or transapical implatation, prepared the 'Enable' bioprosthetic valve for sutureless insertion in the aortic position. The first world implantation was performed in our Department on 13 January 2005. AIM: To present our experience, qualification criteria and methods of implantation of sutureless bioprosthesis of aortic valve 'Enable'. METHODS: The 'Enable' valve is a tubular structure, tailored and sutured of equine pericardium, treated with glutaraldehyde, and mounted on an openwork Nitinol" alloy stent. It consists of two distal rings connected with three vertical sticks. The characteristic property of nitinol is thermoplaticity: due to refrigeration it becomes elastic and easy to bend, after rewarming returns to the initial dimensions and shape, remaining stable at the body temperature. Distension of the nitinol ring make possible strong mounting of the valve in aortic annulus. The examined group consised of 27 patients (16 males, 11 females), aged 60-78 years (average 69.5), with advanced aortic valve disease, left ventricular hypertrophy, and aortic gradient up to 102 mmHg. Exclusion criteria were: severe annular deformations or bicuspid aortic valve, other valves' malformations, coronary disease, severe other comorbidities or no agreement for 'Enable' valve implantation. The patients were operated using extracorporeal circulation, general moderate hypothermia and cold crystalloid cardioplegia. Care was taken to remove calcifications, estimate of aortic annulus geometry, valve size selection, and orientation of the valve toward coronary ostia The mounting time was approximately one min, and the aorta cross-clamp time was reduced to 26-56 min, mean 30 min. RESULTS: There was no mortality in the perioperative period, and during 3 months to 4.5 years of follow-up. No severe complications were present after surgery. One patient needed reoperation on post operative day 4 due to severe perivalvular leak. One other patient presented discrete leak with no need for intervention. The clinical improvement of one to three NYHA classes was observed. Echocardiographic and MSCT examinations confirmed adequate position of the valves, no structural deteriorations, normal movement and coaptation of the leaflets. The average maximal transvalvular gradient was 11.6 mmHg and the mean gradient--6.8 mmHg, which remained stable during the follow-up period. No thromboembolic or infective complications were present. CONCLUSIONS: (1) The 'Enable' aortic bioprosthetic valve has very good hemodynamic properties. (2) Self-expanding thermoplastic nitinol-made ring allows permanent stable mounting. (3) The quick fixation (about 1 min) significantly shortens the operation time. (4) The 'Enable' valve seems to be suitable for patients with increased periopertive risk. PMID- 19784900 TI - Late gadolinium enhancement in cardiovascular magnetic resonance in patients with hypertrophic cardiomyopathy complicated by life-threatening ventricular tachyarrhythmia. AB - BACKGROUND: Late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) has been shown to be associated with ventricular arrhythmias, however, its prognostic role in predicting sudden cardiac death has not yet been established. AIM: To explore a potential relationship between LGE visualised by CMR and life-threatening ventricular tachyarrhythmia in hypertrophic cardiomyopathy (HCM). METHODS: The LGE in CMR was assessed in 55 HCM patients. We compared the frequency and extent of LGE in HCM patients with sustained ventricular tachycardia (VT) or who survived ventricular fibrillation (VF) or sudden death [group VF (+)] versus HCM patients without these tachyarrhythmias [group VF (-)]. There were 14 patients in the VF (+) group and 41 patients in the VF (-) group, and they were followed for a mean period of 37 months. RESULTS: In group VF (+), adequate ICD intervention occurred in 9 patients (8 patients with VF and one patient with sustained VT), and VF arrest occurred in 5 patients (4 patients were resuscitated and one patient had a witnessed sudden death). In group VF (+) all patients had LGE whereas in group VF (-) 85% patients presented this abnormality (p = 0.13). Moreover, there were no statistical differences between groups in the following parameters: age, total left ventricular (LV) mass, maximal LV wall thickness, mass of hyperenhanced myocardium and percent of hyperenhanced myocardium. CONCLUSION: In HCM patients with life-threatening ventricular tachyarrhythmia LGE was both qualitatively and quantitatively comparable with patients without these tachyarrhythmias. PMID- 19784901 TI - Secondary prevention of coronary artery disease in hospital practice over the decade 1996-2006. Results of the Cracovian Program for Secondary Prevention of Ischaemic Heart Disease and Polish parts of the EUROASPIRE II and EUROASPIRE III surveys. AB - BACKGROUND: Both in the European and Polish guidelines the highest priority for preventive cardiology was given to patients with established cardiovascular disease. The Cracovian Program for Secondary Prevention of Ischaemic Heart Disease was initiated in 1996. The main goal of the program was to assess and improve the quality of clinical care in the secondary prevention of ischaemic heart disease. Later, the same centres joined the EUROASPIRE (European Action on Secondary and Primary Prevention Intervention to Reduce Events) II and III surveys. AIM: To compare the quality of secondary prevention in Krakow cardiac departments in 1996/1997, 1998/1999 and 2005/2006. METHODS: Five hospitals serving the area of the city of Krakow and surrounding districts (former Krakow Voivodship), inhabited by 1,200,000 persons, took part in the surveys. Consecutive patients hospitalised from July 1, 1996 to September 31, 1997 (first survey), from March 1, 1998 to March 30, 1999 (second survey), and from April 1, 2005 to July 31, 2006 (third survey) due to acute myocardial infarction, unstable angina or for myocardial revascularisation procedures, below the age of <71 years were recruited and included to the present analysis. All medical records were reviewed by trained reviewers using standardised data collection forms. RESULTS: Medical records of 536 patients treated in 1996/1997, 515 treated 1998/1999, and 540 treated in 2005/2006 were reviewed and analysed. Proportions of medical records with available information on risk factors prior to hospitalisation as well as proportions of medical records with available information on blood pressure (by 10%, p < 0.05) and lipids (by over 30%, p < 0.05) measurements during the first 24 h of hospitalisation as well as on weight and height measurements (by 16%, p < 0.05) increased significantly from 1996/1997 to 2005/2006. Antiplatelets prescription rate at discharge increased from 87% to 97% (p < 0.05), prescription rate for beta-blockers increased from 66% to 91% (p < 0.05), ACE inhibitors/sartans from 50% to 89% (p < 0.05), and lipid lowering drugs from 27% to 96% (p < 0.05) between 1996/1997 and 2005/2006, respectively. CONCLUSIONS: The implementation of secondary prevention guidelines into clinical practice in the Krakow cardiac departments improved in 2005/2006 as compared to 1996/1997 and 1998/1999. Our results suggest that recent decade brought significant improvement in the approach to secondary prevention of ischaemic heart disease in hospital practice. PMID- 19784902 TI - Polyvascular extracoronary atherosclerotic disease in patients with coronary artery disease. AB - BACKGROUND: Cardiovascular diseases are the number one killer in the developed countries, accounting for approximately half of all deaths, with the leading causes being myocardial infarction and ischaemic stroke. In line with the ageing population, the prevalence of coronary artery disease (CAD), lower extremity peripheral arterial disease (PAD), supra-aortic arterial disease (SAD) and renal stenosis (RAS) is increasing. Polyvascular atherosclerosis (PVA) coexisting in several territories has an adverse effect on cardiovascular morbidity and mortality. AIM: To determine prevalence, coexistence and predictors of significant PAD, SAD and RAS in patients with suspected CAD. METHODS: Based on angiography, the frequency of coexisting CAD, SAD, PAD and RAS (stenosis > or =50%) was determined in 687 (487 male) consecutive patients, aged 63.5 +/- 9.1 years, referred for coronary angiography. RESULTS: Significant CAD was found in 545 (79.3%) patients (1-vessel in 164; 2-vessel in 157; 3-vessel in 224). SAD, RAS and PAD were found in 136 (19.8%), 55 (8%), and 103 (15%) patients, respectively. Of the 545 patients with confirmed CAD, 346 (63.5%) had stenoses limited to coronary arteries. 2-, 3- and 4-level PVA was found in 130 (23.8%), 61 (11.2%) and 8 (1.5%) patients, respectively. Of the 142 patients without CAD, 127 (89.4%) had no significant stenoses elsewhere, 12 (8.5%) had 1 extracoronary territory and 3 (2.1%) had 2-territory involvement. Backward stepwise binary logistic regression analysis showed the following independent predictors of at least 2-level PVA: 2- and 3-vessel CAD (p < 0.001), hyperlipidaemia (p = 0.067), smoking (p < 0.001), creatinine level > or = 1.3 ml/dl (p < 0.001), lower extremities claudication (p < 0.001) and female gender (p = 0.003). The relative risk of having at least 2-territory PVA was 15.7-fold higher in patients with claudication, 2.1-fold in patients with multivessel CAD, 2.8-fold for serum creatinine level > 1.3 mg/dl; and 1.9-fold, 2.4-fold and 2-fold in patients with hyperlipidaemia, smokers and women, respectively. CONCLUSIONS: Significant atherosclerosis in extracoronary arterial territories is present in 36% of patients with documented CAD. With advancing PVA, accumulation of atherosclerosis risk factors, previous atherothrombotic events and more severe CAD is observed. PMID- 19784903 TI - Supra-aortic extracranial artery atherosclerotic lesions in patients diagnosed for coronary artery disease: prevalence and predictors. AB - BACKGROUND: In patients with coronary artery disease (CAD), the presence of atherosclerotic lesions in other vascular beds is associated with a markedly worse prognosis. AIM: To determine the prevalence and predictors of extracranial supra-aortic artery atherosclerotic disease (SAD) in patients with suspected CAD. METHODS: Supra-aortic artery angiography was performed in 379 consecutive patients aged 64.2 +/- 8.8 years (231 male) referred for coronary angiography. Clinical and laboratory data (total cholesterol, LDL, HDL cholesterol, hs-CRP, creatinine level) and left ventricular ejection fraction were analysed. RESULTS: Significant stenosis (> or =50% by quantitative angiography) within at least one main branch of the coronary arteries was found in 314 (82.8%) patients, including 87 (27.7%), 96 (30.6%) and 131 (41.7%) with 1-vessel, 2-vessel, and 3-vessel CAD, respectively. Among all 379 patients, stenosis > or =50% of the carotid artery was documented in 9.5%, vertebral in 13.7%, and subclavian in 7.4% of patients. We found 130 stenoses > or =50% within the supra-aortic arteries in 90 patients (23.7% of the whole study group, and 28.7% of CAD patients), including 42 internal carotid artery stenoses in 36 patients, 58 vertebral artery stenoses in 52, and 30 subclavian stenoses in 28 patients. In 24 (6.3%) patients more than one SAD was present. The SAD > or =50% was found in 8 (12.3%) patients without significant CAD, in 22 (25.3%), 17 (17.7%) and 43 (32.8%) with 1-, 2- and 3 vessel CAD, respectively (p = 0.001). Independent predictors of SAD > or =50% identified by multivariate analysis were: previous neurological ischaemic event (p = 0.001), CAD (p = 0.015), creatinine level (p = 0.031), male gender (p = 0.001), claudication (p < 0.001) and low HDL cholesterol (p = 0.033). The following independent predictors of vertebral and/or subclavian artery stenosis > 50% were identified: CAD severity (p = 0.002), creatinine level (p = 0.024), male gender (p = 0.013), claudication (p < 0.001) and low HDL cholesterol level (p = 0.059). CONCLUSIONS: In a large patient sample, we have found that significant supra-aortic atherosclerosis is present in a quater of patients with suspected CAD. Importantly, SAD prevalence increases with CAD severity. Previous neurological ischaemic event, CAD, creatinine level, male gender, claudication and hyperlipidaemia were identified as independent predictors of SAD > or =50%. PMID- 19784904 TI - Intracoronary ultrasound-guided angioplasty for coronary chronic total occlusion. AB - BACKGROUND: Recanalisation for coronary chronic total occlusion (CTO) is associated with high rates of restenosis and reocclusion. The use of intracoronary ultrasound (ICUS) may improve immediate and long-term outcomes following recanalisation. To our knowledge, no study has examined the use of ICUS guided balloon angioplasty in CTO. AIM: To compare the results of ICUS-guided balloon angioplasty and ICUS-guided angioplasty with stent implantation in patients with CTO. METHODS: The study involved 51 CTO patients in whom optimal balloon angioplasty results were achieved according to quantitative coronary angiography (QCA). These patients then underwent ICUS-guided balloon angioplasty with the goal of achieving a minimal luminal cross-sectional area (MLCSA) of > 6.0 mm2 and a residual plaque burden (RPB) of < 65%. Of the 51 patients, the ICUS criteria defining optimal balloon angioplasty were achieved in 23 patients and 7 patients did not undergo stent implantation due to calcification and/or small vessel diameters (group A--30 patients). In 21 patients, the failure to achieve optimal ICUS parameters resulted in stent implantation with the goal of achieving in stent MLCSA > 9 mm2 and > 55% of average total cross-sectional area of the vessel according to distal and proximal reference segments (group B). The two groups were similar in terms of clinical and angiographic characteristics. RESULTS: Balloon angioplasty which was regarded as optimal by QCA, was shown to be non-optimal by ICUS in 41 patients (80.4%). The MLCSA was smaller in group A than group B (6.5 +/- 1.5 vs. 8.9 +/- 2.0 mm2; p < 0.001). Restenosis was found in 8 (26.6%) group A patients and 4 group B patients (19%) (p > 0.05). The restenosis rate in 23 group A patients with optimal ICUS parameters was 8.6% (2 patients). Consecutive ICUS measurements showed a gradual increase in the total vessel area during the PCI procedure and at the 6-month follow-up (p < 0.05). CONCLUSIONS: (1) Achieving an optimal balloon angioplasty result in CTO patients requires confirmation using ICUS. (2) In some patients immediate and long-term outcomes following ICUS-guided optimised balloon angioplasty are comparable to those of ICUS-guided stent implantation. (3) Direct measurement of a chronically occluded coronary artery at pre-intervention, during the intervention and at long term follow-up may argue in favour of using ICUS in recanalisation of CTO. (4) ICUS-guided balloon angioplasty for CTO could be a method of choice in patients in whom long-term dual antiplatelet therapy is associated with a high probability of bleeding complications. PMID- 19784905 TI - Comparison of the efficacy and safety of pharmacological treatment versus percutaneous coronary angioplasty in patients with intermediate coronary artery lesions. AB - BACKGROUND: It is unclear if patients with intermediate coronary artery lesions (40-70% of diameter reduction) benefit from percutaneous coronary intervention (PCI) as compared with pharmacological treatment. AIM: To investigate whether PCI of intermediate coronary artery lesions may improve the outcome in this group of patients. METHODS: We performed a retrospective analysis of data of 232 symptomatic patients with intermediate coronary lesions. Hundred sixty five patients received only pharmacological treatment (group A) while 67 were treated with PCI with or without stent implantation (group B). Primary study endpoints were defined as follows: death (cardiac and non-cardiac), myocardial infarction, unstable angina, recurrent angina and coronary reintervention. Demographic and clinical variables were evaluated to identify predictors of the composite endpoint (exacerbation of angina, hospitalisation because of severe angina, restenosis in the intermediate coronary lesion, acute coronary syndrome and cardiac death). RESULTS: In group A, patients were treated with typical pharmacotherapy including beta-blockers, Ca-blockers, ACE-inhibitors, and antiplatelet drugs. In group B, 68 PCI procedures were performed in 67 patients and optimal pharmacotherapy was administered. The average age of patients in both groups was 58.0 +/- 9.1 years and the majority were males (76%). Preinterventional coronary angiography showed that the intermediate lesions were most frequently localised in the left anterior descending (LAD) coronary artery; the next most frequent localisation was the right coronary artery (RCA). During the 12-month follow-up in 9 (13%) patients from the group B repeated PCI due to restenosis was performed, while in group A intervention was necessary in 7 (4%) of patients due to aggravation of symptoms (p = 0.01). The cumulative probability of restenosis after PCI in intermediate coronary lesions was 14%. Recurrent angina was more frequent in group B as compared to group A (34 vs. 19%; p = 0.005). None of the patients in any group died during 12 months of follow-up. In patients with intermediate coronary lesions, the independent predictors of the composite study endpoint were: history of previous percutaneous coronary angioplasty, type 2 diabetes, persistent ST-segment elevation in 12-lead ECG, heart rhythm disturbances, presence of the intermediate lesion in the LAD, and left ventricular dysfunction. CONCLUSIONS: Patients with intermediate coronary artery stenoses could safely undergo pharmacological treatment and PCI may be postponed until aggravation of symptoms occurs. In the presence of predictors of the composite study endpoint, the use of intracoronary diagnostic methods may be considered to obtain more reliable and precise measurements of coronary stenosis severity. PMID- 19784906 TI - Assessment of resting perfusion defect in patients with acute myocardial infarction: comparison of myocardial contrast echocardiography with contrast enhanced magnetic resonance imaging. AB - BACKGROUND: Contrast-enhanced magnetic resonance imaging (CE-MRI) can identify myocardial scarring following acute myocardial infarction (AMI). AIM: To compare myocardial contrast echocardiography (MCE) and CE-MRI in detection of resting perfusion defect in patients with acute myocardial infarction. METHODS: Twenty four patients (21 men, 3 women, mean age 58.7 +/- 11.4 years) underwent primary percutaneous coronary angioplasty (PCI) for anterior AMI. All patients underwent MCE: segmental perfusion was estimated in real time before and immediately after PCI and on third day after PCI, using low mechanical index (0.3) after 0.3-0.5 ml bolus injections of intravenous OptisonTM. The MCE was scored semiquantitatively as: 1--homogenous contrast enhancement, 2--patchy contrast enhancement, 3--no contrast (non-viable myocardium). All patients underwent CE-MRI on a 1.5 T scanner (SONATA, Siemens) on the third day after PCI. Acquisition of short axis slices was performed before and 20 min after injection of Gd-DPTA (0.15 mmol/kg) with an inversion recovery TurboFLASH sequence (TE 1.1 ms, TR 700 ms, flip angle 300) in multiple breath-holds. The pattern of hyperenhancement representing MI (which intensity was more than 150% intensity of myocardium) was quantified by planimetry. The CE-MRI was scored according to the severity of myocardial scar as: 1--without scar, 2-- <50% of myocardial thickness, 3 - > 50% of myocardial thickness. RESULTS: Myocardial perfusion was analysed using MCE and contrast enhanced MRI in 362 segments. Agreement between MCE and CE-MRI for identification of viable versus necrotic myocardium on third day after PCI was 86% (kappa = 0.73). Thirteen (54%) patients showed transmural necrosis at CE-MRI while 11 (46%) showed non-transmural necrosis. Patients from the transmural necrosis group showed a higher creatine kinase peak (p = 0.0001), higher CK-MB (p = 0.00002) and higher troponine level (p = 0.008), and more impaired baseline regional contractile function (p = 0.045). All angiographic parameters were less favourable in this group before as well as after PCI than in patients with non transmural necrosis. CONCLUSIONS: Myocardial contrast echocardiography correlates very well with CE-MRI in the assessment of myocardial perfusion after PCI in AMI. Contrast-enhanced MRI is accurate technique for assessing the infarct zone. Identification by CE-MRI of transmural necrosis was associated with more impaired left ventricular function, non-reperfused MI, and presence of Q waves in ECG. PMID- 19784907 TI - Usefulness of electrocardiographic and echocardiographic parameters for predicting the efficacy of atrioventricular synchronisation during a single lead VDD/R pacing. AB - BACKGROUND: The VDD/R pacing is accepted as an alternative to DDD/R pacing in patients with atrioventricular conduction block (AVB) and intact sinus node function. AIM: To determine the relationship between parameters obtained during assessment of the patient for the implantation procedure, using electrocardiographic (ECG) and echocardiographic (ECHO) data, and the effectiveness of AV synchronisation. METHODS: The study involved a group of 65 patients (43 males, 22 females), aged 66.6 + 12.7 with clinically significant disturbances of AV conduction, who did not reveal symptoms of concomitant abnormalities in sinus node automaticity. Selected ECG and ECHO parameters were studied prior to the implantation procedure. Repeat examinations were done at 3-4 days and at 1, 3, 6 and 12 months after the procedure. The effectiveness of AV synchronisation (PAS) has been estimated by event counter read-out and ECG Holter monitoring. RESULTS: In 74% patients (subgroup A) synchronisation was highly effective (PAS _ 95%); in the remaining 26% subjects (subgroup B) PAS occasionally fell below 95%. In subgroup B, the P wave was longer than that in subgroup A (105 +/- 16 vs. 92 _ 13 ms; p < 0.05). The dimensions of the right and left heart chambers were greater in subgroup B. Patients in subgroup B had lower ejection fraction (49.4 +/- 13.7% in B vs. 58.2 +/- 11.3% in A) and revealed symptoms of heart failure. The following cut-off values for each echocardiographic and electrocardiographic parameter predisposing to PAS < 95% during VDD/R pacing ('undersensing') were identified: RVEDd > 26 mm, RVESd > 24 mm, LVEDd > 59 mm, LVESd > 37.3 mm, APD LA > 44 mm, SID RA > 52 mm, LMD RA > 48 mm, RAvol> 54 ml, RAarea > 19 cm2, SID LA > 57 mm, LMD LA > 46 mm, EF < 52%, P wave width > 100 ms. Significant predictors of PAS < 95% in the univariate analysis were RVEDd, RVESd, LVEDd, LMD RA, SID RA, RAvol, RAarea, EF, and in the multivariate analysis RVEDd, RVESd, LMD RA, RAarea, EF. CONCLUSIONS: Selected parameters obtained from ECG (P wave width) and echo examinations are correlated with effective AV synchronisation. Enlargement of the right and left heart chambers (atrial, ventricular), reduction of the ejection fraction and congestive heart failure are associated with impaired AV synchronisation in VDD/R pacemakers. In multivariate analysis, only the higher dimensions of the right ventricle and atrium and the lower ejection fraction of the left ventricle were significantly associated with the PAS < 95%. PMID- 19784908 TI - The effects of gender and test protocol on the results of head-up tilt test in patients with vasovagal syncope. AB - BACKGROUND: Head-up tilt testing (HUTT) is a well-established method for the diagnosis of reflex syncope. Some controversies exist whether gender and HUTT protocol influence HUTT results. AIM: To analyse the results of HUTT in patients with syncope in relation to their gender and used protocol of HUTT. METHODS: We retrospectively analysed data of 537 consecutive patients (313 women and 224 men), aged 13-79 years with history of neurally-mediated syncope referred to HUTT. The cardiogenic and neurological aetiology of syncope was excluded in all patients based on previous examination. In 375 patients standard HUTT (STD HUTT), according to the Westminster protocol, was used. In 257 patients in whom STD HUTT was negative, HUTT was continued with pharmacological provocation using isoproterenol intravenous infusion--114 patients (ISO HUTT) or sublingual nitroglycerin--143 patients (NTG HUTT). In the remaining 162 patients HUTT was performed according to the Italian protocol (ITL HUTT). The HUTT results were classified according to the VASIS scale. RESULTS: Female gender dominated, however, syncope was induced in a similar proportion of women and men (77.3 vs. 70.5%, NS). There were also no significant differences in the type of vasovagal response (VVR) to HUTT between women and men. Mixed type of VVR was the most frequent after isoproterenol provocation (ISO HUTT), whereas cardioinhibitory type of VVR was the most frequent after nitroglycerin provocation (NTG HUTT). CONCLUSIONS: There is no significant relationship between gender and the result of HUTT. The type of VVR is related to HUTT protocol--cardioinhibitory response is more frequent following nitroglycerin administration in comparison to standard protocol and HUTT with isoproterenol provocation. PMID- 19784909 TI - [Optimal prevention and pharmacotheraphy in stable angina pectoris]. PMID- 19784910 TI - Therapeutic clues in spinal dural arteriovenous fistulas - a 30 year experience of 156 cases. AB - BACKGROUND: Spinal dural arteriovenous fistulae (SDAVF) are rare but remain the most common type of spinal vascular malformations. Treatment options for SDAVF include endovascular embolization, microsurgical dissection or a combination of both. But the optimal treatment paradigm has yet to be defined and may well be an individualized interdisciplinary combinatorial approach. MATERIAL AND METHODS: From 1980 to 2008, 156 patients with the diagnosis of SDAVF were treated by neuroradiological and neurosurgical means. Based on the procedure-related complications we retrospectively analyzed our data to elucidate the reasons for endovascular failure and the evolution of the surgical technique. RESULTS: 156 patients were included in this study. There were 31 (19.9%) female and 125 (80.1%) male patients. Average age at the time of diagnosis was 60.8 years. 102 out of 156 (65.4%) underwent endovascular obliteration, 54 (34.6%) patients were treated primarily by surgery. 134 (85.9%) underwent follow-up examination. A total of 29 (18.6%) out of 156 patients could not be treated successfully by endovascular (9.4%) or surgical (4.1%) means. CONCLUSION: Microsurgery can be recommended as the first choice treatment when the fistula's point is unmistakably identified intradurally. Endovascular obliteration may be justifiable in cases with an easy access to a monoradicular feeding artery during diagnostic angiography. Surgery is a definitive treatment with stable long-term results in which procedure-related morbidity is low. During evolution of the combined approach, endovascular coil placement for correct localization of the fistula and the use of intraoperative micro-Doppler was found to be very helpful in increasing the safety of the surgical procedure and minimizing surgical exposure. PMID- 19784911 TI - Respiratory syncytial virus infection and palivizumab: are families receiving accurate information? AB - The aim of this study was to assess the accuracy of information provided by medical practitioners to families regarding the efficacy and limitations of prophylaxis with palivizumab for respiratory syncytial virus (RSV) infection in infants. A single-question survey was distributed to medical practitioners who described themselves as having both prescribed palivizumab for infants and discussed the effects of the drug with families. Responses were anonymous and returned immediately after reviewing the survey question. Respondents were requested to choose the answer that most closely resembled their understanding of palivizumab effects on the degree of illness and severity of RSV infection. All surveys distributed were completed and answers assessed by medical specialty. A total of 456 surveys were returned. Neonatologists and pediatricians accounted for the majority of responses. The answer that most closely reflects the medical literature, that palivizumab will decrease hospitalization but have no effect on need for mechanical intubation or mortality, was chosen only 2% of the time. Families are not receiving accurate information regarding the expected potential benefits and limitations of immunoprophylaxis with palivizumab. This is a very expensive drug with unclear cost-effectiveness. If changes are to be made to current recommendations as to use of palivizumab, families must receive informed consent that accurately reflects the literature. PMID- 19784912 TI - The impact of an early Ibuprofen treatment protocol on the incidence of surgical ligation of the ductus arteriosus. AB - This study sought to determine whether early treatment of premature infants with ibuprofen would result in a reduced incidence of surgical ligation of patent ductus arteriosus. Secondary outcomes included duration of hospitalization, assisted ventilation and supplemental oxygen, mortality rate, persistent patent ductus arteriosus (PDA), hypotension, intraventricular hemorrhage, and intestinal perforation. Outcomes among 105 very low-birth-weight (VLBW) infants managed by clinical use of indomethacin were compared with outcomes of 80 infants treated under a standardized protocol for ibuprofen therapy on the first day of life among infants <25 weeks estimated gestational age (EGA) and among infants of 25 to 28 weeks EGA with respiratory distress syndrome or history of antenatal steroids. The incidence of PDA ligation was significantly lower among the early ibuprofen group than among the clinical indomethacin group (0/80 versus 9/105, P = 0.0056). No differences were found in secondary outcomes. The effect persisted (P = 0.0100 to 0.0153) when corrected for birth weight, EGA, gender, Apgar scores, initial pH and base deficit, transport from another hospital, surfactant treatment, and need for assisted ventilation. In our neonatal intensive care unit, the incidence of PDA ligation among VLBW infants decreased after adoption of an early ibuprofen treatment protocol. PMID- 19784913 TI - The association of prepregnancy body mass index with pregnancy outcomes in triplet gestations. AB - The impact of obesity on triplet gestations is poorly understood. In this study, we investigate the association of obesity with birth outcomes in triplets. Triplet births in the state of Missouri from 1989 through 1997 were analyzed. Obesity was defined as maternal prepregnancy body mass index (BMI) >or=30 kg/m(2). We assessed the association between obesity and the following outcomes: stillbirth, preeclampsia, very preterm, small for gestational age (SGA), and a composite adverse birth outcome. We employed logistic regression with further correction for intracluster correlation to obtain adjusted estimates. A total of 667 triplet gestations were analyzed. As compared with normal-weight mothers, the likelihood of stillbirth and preeclampsia was higher among obese mothers (odds ratio[OR] = 3.70; 95% confidence interval [CI] = 1.37 to 9.97 and OR = 3.02; 95% CI = 1.69 to 5.40 respectively). Obese mothers were also about twice as likely to experience at least one of the adverse birth outcomes considered. Obese women with triplet gestations have about four- and threefold elevated risks for stillbirth and preeclampsia as compared with their counterparts with normal weight. This observation may be of utility in the preconceptional counseling of women considering the use of assisted reproductive technology. PMID- 19784914 TI - Pheochromocytoma and Von Hippel-Lindau in pregnancy. AB - Pheochromocytoma is an infrequent but well-acknowledged primary cause of malignant hypertension in pregnancy. Although the majority of pheochromocytomas are sporadic, those that present as bilateral or multifocal tumors may be a manifestation of a rare cancer susceptibility syndrome, such as Von Hippel-Lindau (VHL). Gravidae with unrecognized pheochromocytoma are at risk for recurrent paroxysmal hypertensive crises with ensuant maternal and fetal risks. To further illustrate the challenges of management of pheochromocytoma and VHL in pregnancy, we present two illustrative cases. In the first, a multigravida presented with an intrauterine fetal demise and malignant hypertension and a concurrent diagnosis of bilateral pheochromocytomas. A missense mutation in exon 3 of the VHL gene was identified, confirming the diagnosis of VHL type 2C. In the second case, a multigravida with a prior diagnosis of VHL syndrome but sporadic follow-up underwent renal and adrenal imaging surveillance as part of her prenatal care. Although she was normotensive and clinically asymptomatic, such imaging enabled the detection of bilateral pheochromocytomas. In summary, in this report we discuss our management in gravidae with pheochromocytoma and VHL, emphasizing current recommendations pertaining to obstetric management, genetic testing, and long-term follow-up. PMID- 19784915 TI - Pregestational diabetes: a risk factor for vaginal birth after cesarean section failure? AB - Vaginal birth after cesarean delivery (VBAC) failure is associated with perinatal morbidity. The ability to predict VBAC failure in subgroups of high-risk women is important. Our objectives were: (1) to estimate if women with pregestational diabetes (PDM) who attempt VBAC are at increased risk of failure, and (2) to identify clinical characteristics of PDM women associated with failure. We performed a retrospective cohort study of women eligible for VBAC, delivered between 1995 and 1999 at 17 hospitals to study maternal history/outcomes and neonatal outcomes ascertained through chart abstraction. Women with gestational diabetes were excluded. Student T test was used to compare continuous characteristics. Chi-square/Fisher exact tests were used to compare categorical variables. Multivariable logistic regression analysis was used to control for confounders. Of all eligible women (23,601), 37% of diabetics ( N = 127) and 56% of nondiabetics ( N = 12968) attempted VBAC. The VBAC failure rate for PDM was 38% versus 24% for nondiabetic women ( P < 0.001). The risk of failure for PDM patients was increased after controlling for confounders (adjusted odds ratio 1.61, 95% confidence interval 1.06 to 2.51; P = 0.038). PDM is independently associated with VBAC failure. The success rate for women with PDM who attempted VBAC (62%) is at the lower end of the general published VBAC success rate range. PMID- 19784916 TI - Increased risk of placental abruption in underweight women. AB - We sought to determine if there is a relationship between prepregnancy underweight status and placental abruption. We utilized the Missouri maternally linked cohort data files covering the period 1989 through 1997. We estimated the association between prepregnancy underweight subtypes and placental abruption using adjusted odds ratios. Subanalyses were performed to determine whether the amount of weight gained during pregnancy could modify the association. A total of 439,235 singleton pregnancies with 3696 abruptions were analyzed. Underweight mothers had a 40% greater likelihood for placental abruption (odds ratio 1.4; 95% confidence interval 1.3 to 1.5). The risk increased with ascending severity of underweight status ( P for trend <0.01). There was a trend toward decreased risk for placental abruption among underweight women with adequate weight gain in pregnancy. Prepregnancy maternal underweight status is associated with placental abruption. This risk may be reduced with adequate weight gain during pregnancy. PMID- 19784918 TI - Stent graft closure of a high flow splenorenal shunt after liver transplantation. AB - We describe a patient after liver transplantation with a preexisting surgical splenorenal shunt close to the confluence of the splenic and superior mesenteric veins and a wide, short communication between the splenic and renal veins. To close the shunt, an inferior vena cava filter was inserted in the shunt and a vascular plug was placed in the splenic vein inside the filter. When this failed to stop the flow through the shunt, a covered stent was deployed at the superior mesenteric vein-portal vein junction. PMID- 19784917 TI - Transcatheter treatment of pulmonary artery pseudoaneurysm using a PDA closure device. AB - Aneurysm of the branch pulmonary arteries are rare. The treatment options vary from case to case and include either surgery or percutaneous transcatheter treatment. The authors report a case of a 13-year-old boy who presented with a large pseudoaneurysm arising from the left lower lobe pulmonary artery. It was treated successfully by occluding the neck of the pseudoaneurysm by endovascular deployment of a patent ductus arteriosus closure device across it. There were no complications and the repeat computed tomography angiography of the patient at 3 weeks followup revealed no flow inside the thrombosed smaller aneurysm. PMID- 19784919 TI - Endograft collapse following endovascular repair of traumatic aortic injury. AB - The advent of endovascular treatment of traumatic thoracic aortic injuries offers a valuable, minimally invasive alternative to open surgical repair. However, there are limitations of the current endovascular stent graft technology for this group of patients. After endovascular repair meticulous follow-up is required with a high index of suspicion for potential complications including the lethal complication of endograft collapse. PMID- 19784920 TI - Assessment of human enteric viruses in cultured and wild bivalve molluscs. AB - Standard and real-time reverse transcription-PCR (rRT-PCR) procedures were used to monitor cultured and wild bivalve molluscs from the Ria de Vigo (NW Spain) for the main human enteric RNA viruses, specifically, norovirus (NoV), hepatitis A virus (HAV), astrovirus (AsV), rotavirus (RT), enterovirus (EV), and Aichi virus (AiV). The results showed the presence of at least one enteric virus in 63.4% of the 41 samples analyzed. NoV GII was the most prevalent virus, detected in 53.7% of the samples, while NoV GI, AsV, EV, and RV were found at lower percentages (7.3, 12.2, 12.2, and 4.9%, respectively). In general, samples obtained in the wild were more frequently contaminated than those from cultured (70.6 vs. 58.3%) molluscs and were more readily contaminated with more than one virus. However, NoV GI was detected in similar amounts in cultured and wild samples (6.4 x 10(2) to 3.3 x 10(3) RNA copies per gram of digestive tissue) while the concentrations of NoV GII were higher in cultured (from 5.6 x 10(1) to 1.5 x 10(4) RNA copies per gram of digestive tissue) than in wild (from 1.3 x 10(2) to 3.4 x 10(4) RNA copies per gram of digestive tissue) samples. PMID- 19784921 TI - Diversity and spatial distribution of metal-reducing bacterial assemblages in groundwaters of different redox conditions. AB - The spatial distribution and diversity of metal-reducing bacterial assemblages belonging to Geobacteraceae were studied in groundwaters with different physicochemical characteristics by means of terminal-restriction fragment length polymorphism (T-RFLP) molecular fingerprinting, as applied to the 16S rRNA gene. The physicochemical conditions of these environments were unfavorable to support active-metal-reducing processes. The highest diversity of Geobacteraceae was observed in groundwater samples characterized by the highest dissolved Fe and Mn concentrations. T-RFLP analyses revealed major differences in the Geobacteraceae ribotype diversity and community composition of the groundwater samples as well as a considerable variability and spatial turnover of Geobacteraceae assemblages. Results from this work suggest that changes in the physicochemical characteristics of the aquifer deeply influence the richness and community structure of Geobacteraceae, even in those systems in which metal-reduction processes are not dominant. PMID- 19784922 TI - Genetic and virulence-phenotype characterization of serotypes 2 and 9 of Streptococcus suis swine isolates. AB - The aim of this study was to analyze the genetic characteristics and virulence phenotypes of Streptococcus suis, specifically, in clinical isolates of serotypes 2 and 9 (n = 195), obtained from diverse geographical areas across Spain. Pulsed field gel electrophoresis (PFGE) typing identified 97 genetic profiles, 68% of which were represented by single isolates, indicative of a substantial genetic diversity among the S. suis isolates analyzed. Five PFGE profiles accounted for 33.3% of the isolates and were isolated from 38% of the herds in nine different provinces, indicative of the bacterium's widespread distribution in the Spanish swine population. Representative isolates of the most prevalent PFGE profiles of both serotypes were subjected to multilocus sequence typing (MLST) analysis. The results indicated that serotypes 2 and 9 have distinct genetic backgrounds. Serotype 2 isolates belong to the ST1 complex, a highly successful clone that has spread over most European countries. In accordance with isolates of this complex, most serotype 2 isolates also expressed the phenotype MRP(+)EF(+)SLY(+). Serotype 9 isolates belong to the ST61 complex, which is distantly related to the widespread European ST87 clone. Also, in contrast to most isolates of the European ST87 clone, which express the large variant MRP*, the majority of serotype 9 isolates (97.9%) did not express the protein. PMID- 19784923 TI - Presence of structural homologs of ubiquitin in haloalkaliphilic Archaea. AB - Ubiquitin, a protein widely conserved in eukaryotes, is involved in many cellular processes, including proteolysis. While sequences encoding ubiquitin-like proteins have not been identified in prokaryotic genomes sequenced so far, they have revealed the presence of structural and functional homologs of ubiquitin in Bacteria and Archaea. This work describes the amplification and proteomic analysis of a 400-bp DNA fragment from the haloalkaliphilic archaeon Natrialba magadii. The encoded polypeptide, P400, displayed structural homology to ubiquitin-like proteins such as those of the ThiS family and Urm1. Expression of the P400 DNA sequence in Escherichia coli cells yielded a recombinant polypeptide that reacted with anti-ubiquitin antibodies. In addition, a putative open reading frame encoding P400 was identified in the recently sequenced genome of N. magadii. Together, these results evidence the presence in Archaea of structural homologs of ubiquitin- related proteins. PMID- 19784925 TI - NAD+-dependent post-translational modification of Escherichia coli glyceraldehyde 3-phosphate dehydrogenase. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional housekeeping protein reported to be a target of several covalent modifications in many organisms. In a previous study, enterohemorrhagic (EHEC) and enteropathogenic (EPEC) Escherichia coli strains were shown to secrete GAPDH and the protein to bind human plasminogen and fibrinogen. Here we report that GAPDH of these pathogens is ADP-ribosylated either in the cytoplasm or in the extracellular medium. GAPDH catalyzes its own modification, which involves Cys 149 at the active site. ADP-ribosylation of extracellular GAPDH may play an important role in the host-pathogen interaction, as also proposed in other pathogens. PMID- 19784924 TI - Phylogenetic relationship of phototrophic purple sulfur bacteria according to pufL and pufM genes. AB - The phylogenetic relationship of purple sulfur bacteria (PSB), of the order Chromatiales (class Gammaproteobacteria), was analyzed based on photosynthetic gene sequences of the pufL and pufM genes, and the results compared to phylogenetic trees and groupings of the 16S rRNA gene. Primers for pufL and pufM genes were constructed and successfully used to amplify the pufLM genes of members of 16 genera of Chromatiales. In total, pufLM and 16S rRNA gene sequences of 66 PSB strains were analyzed, including 29 type strains and 28 new isolates. The inferred phylogenetic trees of the pufLM and 16S rRNA genes reflected a largely similar phylogenetic development suggesting coevolution of these essential genes within the PSB. It is concluded that horizontal gene transfer of pufLM genes within the PSB is highly unlikely, in contrast to the situation in other groups of anoxygenic phototrophic bacteria belonging to Alpha- and Betaproteobacteria. The phylogeny of pufLM is therefore in good agreement with the current taxonomic classification of PSB. A phylogenetic classification of PSB to the genus level is possible based on their pufL or pufM sequences, and in many cases even to the species level. In addition, our data support a correlation between Puf protein structure and the type of internal photosynthetic membranes (vesicular, lamellar, or tubular). PMID- 19784926 TI - Salinity dependence of the distribution of multicellular magnetotactic prokaryotes in a hypersaline lagoon. AB - Candidatus Magnetoglobus multicellularis is an unusual magnetotactic multicellular microorganism composed of a highly organized assemblage of gram negative bacterial cells. In this work, the salinity dependence of Ca. M. multicellularis and its abundance in the hypersaline Araruama Lagoon, Brazil were studied. Viability experiments showed that Ca. M. multicellularis died in salinities upper than 55 per thousand and lower than 40 per thousand. Low salinities were also observed to modify the cellular assemblage. In microcosms prepared with different salinities, the microorganism grew better at intermediate salinities whereas in high or low salinities, the size of the population did not increase over time. The concentrations of Ca. M. multicellularis in the lagoon were related to salinity; sites with lower and higher salinities than the lagoon average contained less Ca. M. multicellularis. These results demonstrate the influence of salinity on the survival and distribution of Ca. M. multicellularis in the environment. In sediments, the abundance of Ca. M. multicellularis ranged from 0 to 103 microorganisms/ml, which represented 0.001% of the counts of total bacteria. The ability of Ca. M. multicellularis to accumulate iron and sulfur in high numbers of magnetosomes (up to 905 per microorganism) suggests that its impact on the sequestration of these elements (0.1% for biogenic bacterial iron) is not proportional to its abundance in the lagoon. PMID- 19784927 TI - Pneumococcal biofilms. AB - Over 60% of bacterial infections (and up to 80% of chronic infections) are currently considered to involve microbial growth in biofilms. This peculiar form of life poses an array of problems in human clinical practice, from infections associated with the implant of prosthetic devices and dental plaque formation to diseases such as cystic fibrosis, otitis media, and endocarditis. Biofilms are also at the basis of a variety of problems in industry. This report describes the biofilms produced by Streptococcus pneumoniae. This bacterium often colonizes the upper airways in humans as a normal commensal, yet it may spread to other areas of the body, causing otitis media, pneumonia, or invasive diseases such as bacteremia and meningitis. The capacity of S. pneumoniae to form biofilms had not been explored until recently. Several newly developed in vitro systems have allowed to test the capacity of S. pneumoniae to form biofilms, and to analyze the influence of several factors, including DNA and proteins-which play a role in the virulence of this "supergerm" in the formation and development of biofilms. In this brief review, we update the knowledge available on pneumococcal biofilm formation and the unusual features of this structure. PMID- 19784928 TI - Contribution of mangotoxin to the virulence and epiphytic fitness of Pseudomonas syringae pv. syringae. AB - Mangotoxin is an antimetabolite toxin that inhibits ornithine acetyl transferase, a key enzyme in the biosynthetic pathway of ornithine and arginine and recently reported in strains of Pseudomonas syringae pv. syringae (Pss) isolated from mango. Since symptoms on mango tissues are very difficult to reproduce, in this study the role of mangotoxin in Pss virulence was addressed by analyzing the in planta growth and development of disease symptoms on tomato leaflets. Inoculation experiments were carried out following several procedures using the wild-type strain Pss UMAF0158, two Tn5-mutant derivative strains defective in mangotoxin production, and their complemented derivative strains in which mangotoxin production is restored. The ability of the mangotoxin-defective mutants to grow in planta was similar, and their epiphytic survival on the tomato leaf surface identical to the wild-type and complemented strains. However, both the disease index data of incidence and the severity of necrotic symptoms indicated that mangotoxin-defective mutants were less virulent, indicating that mangotoxin is a virulence factor. Furthermore, competition experiments showed that the survival values of the wild-type strain were slightly but significantly higher than those of the mangotoxin-defective mutants, suggesting that mangotoxin production would improve the epiphytic fitness of Pss. PMID- 19784929 TI - Involvement of several transcriptional regulators in the differential expression of tfd genes in Cupriavidus necator JMP134. AB - Cupriavidus necator JMP134 has been extensively studied because of its ability to degrade chloroaromatic compounds, including the herbicides 2,4 dichlorophenoxyacetic acid (2,4-D) and 3-chlorobenzoic acid (3-CB), which is achieved through the pJP4-encoded chlorocatechol degradation gene clusters: tfdCIDIEIFI and tfdDIICIIEIIFII. The present work describes a different tfd-genes expression profile depending on whether C. necator cells were induced with 2,4-D or 3-CB. By contrast, in vitro binding assays of the purified transcriptional activator TfdR showed similar binding to both tfd intergenic regions; these results were confirmed by in vivo studies of the expression of transcriptional lacZ fusions for these intergenic regions. Experiments aimed at investigating whether other pJP4 plasmid or chromosomal regulatory proteins could contribute to the differences in the response of both tfd promoters to induction by 2,4-D and 3 CB showed that the transcriptional regulators from the benzoate degradation pathway, CatR1 and CatR2, affected 3-CB- and 2,4-D-related growth capabilities. It was also determined that the ISJP4-interrupted protein TfdT decreased growth on 3-CB. In addition, an ORF with 34% amino acid identity to IclR-type transcriptional regulator members and located near the tfdII gene cluster module was shown to modulate the 2,4-D growth capability. Taken together, these results suggest that tfd transcriptional regulation in C. necator JMP134 is far more complex than previously thought and that it involves proteins from different transcriptional regulator families. PMID- 19784930 TI - Inhibitory activity of Phaeobacter strains against aquaculture pathogenic bacteria. AB - A total of 523 bacterial strains were isolated during a 4-year period from mollusc hatcheries (flat oyster and clams) in Galicia (NW Spain). All of the strains were tested for their antibacterial activity against three larval pathogens (Vibrio anguillarum USC-72, V. neptunius PP-145.98, and Vibrio sp. PP 203). Of the isolates, 52 inhibited at least one of the target strains, and 11 inhibited all of them. The main source of active strains was oyster larvae, followed by water, tank surfaces, spat, and broodstock. Four similar strains, belonging to the genus Phaeobacter, showed the strongest activity. Strain PP-154, selected as representative of this group, displayed a wide spectrum of inhibitory activity against aquaculture pathogens, especially against members of the genus Vibrio, which is responsible for the most larval deaths. The inhibitory ability of such strain on solid medium was confirmed in seawater experiments, and the optimal conditions for antibacterial activity were established. These strains are promising probiotics for aquaculture facilities. Their potential benefit is based on the capacity to control the proliferation of a variety of aquaculture bacterial pathogens in mollusc larval cultures. PMID- 19784932 TI - Effect of a heterotrimeric G protein alpha subunit on conidia germination, stress response, and roquefortine C production in Penicillium roqueforti. AB - Heterotrimeric G protein signaling regulates many processes in fungi, such as development, pathogenicity, and secondary metabolite biosynthesis. For example, the Galpha subunit Pga1 from Penicillium chrysogenum regulates conidiation and secondary metabolite production in this fungus. The dominant activating allele, pga1G42R, encoding a constitutively active Pga1 Galpha subunit, was introduced in Penicillium roqueforti by transformation, resulting in a phenotype characterized by low sporulation and slow growth. In this work, the effect of the constitutively active Pga1G42R Galpha subunit on conidial germination, stress tolerance, and roquefortine C production of P. roqueforti was studied. Pga1G42R triggered germination in the absence of a carbon source, in addition to negatively regulating thermal and osmotic stress tolerance. The presence of the Pga1G42R Galpha subunit also had an important effect on roquefortine C biosynthesis, increasing production and maintaining high levels of the mycotoxin throughout a culture period of 30 days. Together, the results suggest that G protein-mediated signaling participates in the regulation of these three processes in P. roqueforti. PMID- 19784931 TI - Differential toxicity of antifungal protein AFP against mutants of Fusarium oxysporum. AB - Antifungal protein (AFP) from Aspergillus giganteus was assayed for toxicity against the Fusarium oxysporum wild-type strain and mutants in genes involved in cell signaling (DeltapacC, pacCc Deltafmk1) or cell-wall biogenesis (DeltachsV, Deltachs7, Deltagas1). The mutants were classified into two groups according to their sensitivity to AFP: DeltapacC, Deltagas1 and Deltachs7, which were significantly more resistant to AFP than the wild-type, and pacCC, Deltafmk1 and DeltachsV, which were more sensitive. Western blot analysis revealed increased binding of AFP to the three resistant mutants, DeltapacC, Deltagas1 and Deltachs7, but also to DeltachsV, indicating that differential binding may not be a key determinant for sensitivity. Addition of Ca2+ or K+ dramatically reduced antifungal activity and binding of AFP, suggesting that these cations compete for the same targets as AFP at the surface of the fungal cell. PMID- 19784933 TI - Bacteriophage induction versus vaginal homeostasis: role of H(2)O(2) in the selection of Lactobacillus defective prophages. AB - Vaginal disorders associated with systemic chemotherapy arise by direct inhibition of the resident microbiota (dominated by lactobacilli) or, possibly, by induction of prophages harbored in their genomes, leading to cell lysis. In the present study, proficient Lactobacillus phages could not be isolated from vaginal exudates. However, lysogeny appeared to be widespread, although about half of the strains harbored prophage sequences that were not responsive to SOS activation. In other cases, prophage induction was achieved, but viable phages were not generated, despite the fact that the induced supernatants of some strains were bactericidal. In one case, this activity was accompanied by the production of a bacteriophage subsequently identified as a member of the family Siphoviridae (isometric capsid and long non-contractile tail). Most of the lactobacilli tested generated hydrogen peroxide, which acted as an inducer of the SOS response, suggesting that H2O2 selects for strains that harbor SOS insensitive, defective prophages, which are thus unable to promote vaginal lactobacilli phage-induced lysis. PMID- 19784934 TI - Contribution of the FeoB transporter to Streptococcus suis virulence. AB - The contribution of iron transporter systems encoded by feo genes to the pathogenic traits of streptococci is largely unknown, despite the fact that those systems are required for the full virulence of several gram-negative bacterial species. In this work, we show that the swine pathogen and zoonotic agent Streptococcus suis has a feoAB operon similar to that encoding an iron transporter system in Escherichia coli. Electrophoretic mobility assays and transcriptional analyses confirmed that the expression of S. suis feo genes is under the negative control of the ferric uptake regulator (Fur) protein. In vivo trials in mice using a feoB defective mutant strain were carried out to investigate the contribution of this gene to the virulence of S. suis. The results showed that the median lethal dose (LD50) of the mutant was approximately 10-fold higher than that of the wild-type parent strain. These data suggest that the Feo metal transporter plays a significant role in streptococcal infectious disease. This is in contrast to previous results reported for this same gene in other gram-positive bacterial species. PMID- 19784935 TI - Determination of fruit origin by using 26S rDNA fingerprinting of yeast communities by PCR-DGGE: preliminary application to Physalis fruits from Egypt. AB - The determination of geographical origin is a demand of the traceability system of import-export food products. One hypothesis for tracing the source of a product is by global analysis of the microbial communities of the food and statistical linkage of this analysis to the geographical origin of the food. For this purpose, a molecular technique employing 26S rDNA profiles generated by PCR DGGE was used to detect the variation in yeast community structures of three species of Physalis fruit (Physalis ixocarpa Brat, Physalis pubescens L, Physalis pruinosa L) from four Egyptian regions (Qalyoubia, Minufiya, Beheira and Alexandria Governments). When the 26S rDNA profiles were analysed by multivariate analysis, distinct microbial communities were detected. The band profiles of Physalis yeasts from different Governments were specific for each location and could be used as a bar code to discriminate the origin of the fruits. This method is a new traceability tool which provides fruit products with a unique biological bar code and makes it possible to trace back the fruits to their original location. PMID- 19784936 TI - Comparative proteomic analysis of Rhodosporidium toruloides during lipid accumulation. AB - Intracellular lipid accumulation is a common biological process for some eukaryotic microorganisms under specific growth conditions, yet study on this phenomenon at an '-omics' level remains rare. In this study we induced lipid accumulation by the oleaginous yeast Rhodosporidium toruloides by transferring cells into a nitrogen-limited medium and performed a comparative and semi quantitative proteomic analysis of cell samples obtained thereafter by a 2D-LC MS/MS approach. A total of 184 proteins were identified, based on the database of yeast Saccharomyces cerevisiae. Semi-quantitative analysis suggested that 46 proteins were notably changed during the lipid production process. Among them, seven, three and four proteins were significantly upregulated only at the late stage, the early stage and both stages, respectively. There were 26 proteins drastically downregulated at both stages. The majority of the downregulated proteins are related to protein metabolism and carbohydrate metabolism, whereas the upregulated proteins are mainly involved in alternative nitrogen sources metabolism and lipid biosynthesis. Our data indicated that a nitrogen deficiency environment had a key impact on cellular metabolism that likely stimulated the lipid accumulation process by R. toruloides. This work provids valuable information for further exploration of the molecular mechanism of cellular lipid metabolism and should be of great interest in oleaginous microorganisms engineering. PMID- 19784937 TI - The physician workforce in Kuwait to the year 2020. AB - The study addresses the supply of and demand for physicians in Kuwait in the light of the emerging variables such as increasing population, economic growth, changes in healthcare strategies, and expansion of healthcare facilities. The objective of the study was to project the future demand for physicians in Kuwait for the years 2007-2020 based on the period 1994-2006. Population projections were derived using the average annual natural increase rate of the 1994-2006 populations. The future demand for physicians was predicted using the average physician to population ratio for the years 1994-2006. The average annual growth rate of indigenous physicians during the period 1994-2006 was 4.08% compared to 2.83% for non-native expatriot physicians. There is a gap between the numbers of native and foreign physicians. In 2006, native physicians constituted 36.6% of the physician workforce in Kuwait. The disparity between the total number of physicians needed and the number of native physicians is expected to decline from 62.14% in 2007 to 48.1% in 2020. The supply of indigenous physicians should be increased. Without shared culture and language, it will be difficult to provide effective and efficient medical care to the people of Kuwait. This can be achieved through an improvement in recruitment and retention of indigenous physicians and medical students. There is also a need for establishment of a standing advisory committee for continuous monitoring of physician workforce planning and policy strategies in Kuwait. PMID- 19784939 TI - Introduction to this issue: correctional mental health care. PMID- 19784940 TI - Mentally ill individuals in limbo: obstacles and opportunities for providing psychiatric services to corrections inmates with mental illness. AB - For more than two millennia, prison reformers and inmate advocates have lamented the ethical and humanitarian injustices experienced by persons with mental illness in correctional settings; yet, we continue to see mentally ill individuals stuck in limbo between health care and custody. Using a case study that exemplifies the challenges that can prevent the provision of efficient mental health care in correctional settings, we identify the gaps and failures in service delivery, and provide specific strategies for streamlining inmates' access to psychiatric assessment and treatment. As a backdrop, we present a brief overview of the reasons why correctional centres experience difficulties in ensuring expedient care (e.g., competence, mental health legislation, waitlists) as well as reviewing the prevalence of mental health needs in correctional settings. Using the partnership and strategic alignment that have been developed for several years between our forensic psychiatric system and our provincial correctional system, we provide a roadmap to successfully reducing wait times and enhancing service delivery to mentally ill inmates. In our view, custody admissions provide a rare opportunity to provide mental health (and other services) to marginalized individuals who often slip through the cracks. imPROVE and related programs and strategies have been found to be effective means of preventing these opportunities from being lost. PMID- 19784941 TI - Psychometric properties of the Coolidge Correctional Inventory in a sample of 3,962 prison inmates. AB - The present study reports on the preliminary psychometric characteristics of a new personality and neuropsychological, 250-item, self-report measure, the Coolidge Correctional Inventory (CCI), in an archival de-identified sample of 3,962 prison inmates. The median internal reliability for the 33 CCI scales and subscales was alpha = .79 (range: alpha = .49 to .93). A prevalence estimate, based on the polythetic criteria in DSM-IV-TR, of at least one personality disorder was 61% of the entire sample, and the prevalence of ADHD was estimated to be 16%. Drug and alcohol problems were also highly prevalent (60%). These results appear to support the preliminary reliability and validity of the CCI and also reveal a high rate of psychopathology and neuropsychological dysfunction among prison inmates. PMID- 19784942 TI - "It's doom alone that counts": can international human rights law be an effective source of rights in correctional conditions litigation? AB - Over the past three decades, the U.S. judiciary has grown increasingly less receptive to claims by convicted felons as to the conditions of their confinement while in prison. Although courts have not articulated a return to the "hands off" policy of the 1950s, it is clear that it has become significantly more difficult for prisoners to prevail in constitutional correctional litigation. The passage and aggressive implementation of the Prison Litigation Reform Act has been a powerful disincentive to such litigation in many areas of prisoners' rights law. From the perspective of the prisoner, the legal landscape is more hopeful in matters that relate to mental health care and treatment. Here, in spite of a general trend toward more stringent applications of standards of proof and a reluctance to order sweeping, intrusive remedies, some courts have aggressively protected prisoners' rights to be free from "deliberate indifference" to serious medical needs, and to be free from excessive force on the part of prison officials. A mostly hidden undercurrent in some prisoners' rights litigation has been the effort on the part of some plaintiffs' lawyers to look to international human rights doctrines as a potential source of rights, an effort that has met with some modest success. It receives support by the inclination of other courts to turn to international human rights conventions-even in nations where such conventions have not been ratified-as a kind of "best practice" in the area. The recent publication and subsequent ratification (though not, as of yet, by the United States) of the UN Convention on the Rights of Persons with Disabilities (CRPD) may add new support to those using international human rights documents as a basis for litigating prisoners' rights claims. To the best of our knowledge, there has, as of yet, been no scholarly literature on the question of the implications of the CRPD on the state of prisoners' rights law in a U.S. domestic context. In this article, we raise this question, and offer some tentative conclusions. PMID- 19784943 TI - Competency courts: a creative solution for restoring competency to the competency process. AB - It is well accepted that jail is a poor setting for treating the acutely mentally ill, yet the number of mentally ill persons in jail has increased such that Los Angeles County Jail and Riker's Island in New York house more mentally ill than any psychiatric hospital. The number of mentally ill persons charged with a crime whose competency to stand trial is in question has also increased dramatically. Inefficiencies within the competency process result in mentally ill persons charged with crimes remaining in jail longer than necessary. One solution is "competency court", a specialty court within a mental health court. The same judges, attorneys, and mental health professionals staff both courts. By combining their Mental Health Court experience, they can work with the mentally ill using their expertise in competency law and processes, and thereby improve the competency process and reduce the unnecessary time that mentally ill persons spend in jail. PMID- 19784944 TI - Treatment of impulsive aggression in correctional settings. AB - PURPOSE: This article reports the implementation of Dialectical Behavioral Therapy-Corrections Modified (DBT-CM) for difficult to manage, impulsive and/or aggressive correctional populations. METHODS: Participants were English-speaking women (n = 18) and men (n = 45) of diverse cultural backgrounds between the ages of 16 and 59 years old retained in state-run prisons in Connecticut. Following consent, and a psychological assessment battery, twice-weekly DBT-CM groups were held over 16 weeks followed by random assignment to DBT coaching or case management condition, with sessions taking place individually for eight weeks. Data analysis. A mixed effects regression model was used to test the hypotheses: participants will show decreased aggression, impulsivity, and psychopathology, as well as improved coping, after completing the DBT-CM groups; and will show greater reduction in targeted behaviors than those receiving case management at the six month and 12 month follow-up assessment periods. RESULTS: Significant reduction in targeted behavior was found from baseline to following the 16 week DBT-CM skills treatment groups. Both case management and DBT coaching were significant at 12 month follow-up. A significant difference was found for adult men and women. CONCLUSIONS: The study supports the value of DBT-CM for management of aggressive behaviors in prison settings. PMID- 19784945 TI - Treating criminal offenders in correctional contexts: identifying interests and distributing responsibilities. AB - In Panetti v. Quarterman, three professional associations advocated commutation of capital sentences for offenders who are incompetent to face execution. Some judicial opinions deny that convicted offenders have any protected interest in avoiding a legally imposed sentence, and other opinions have found that the Eighth Amendment requires treatment for prisoners with serious mental health needs. This article examines some circumstances in which health care providers in the context of criminal punishment encounter apparent conflicts among the treatment interests of the individuals, the comprehensive interests of these individuals, legally protected interests, and the public interest. This analysis pursues clarification of these interests and of potential tensions among legal and professional obligations of health care providers. This article does not provide comprehensive resolution of this tension. Rather, it is intended to promote rigorous ongoing inquiry by clarifying the relevant interests at stake and the responsibilities of various participants in the complex interaction of health care and corrections. PMID- 19784946 TI - Sequential stir bar extraction, thermal desorption and retention time locked GC MS for determination of pesticides in water. AB - A method based on sequential stir bar sorptive extraction followed by automated thermal desorption-GC-MS for the determination of pesticides in underground and superficial water samples has been developed. Retention time locked GC-MS and deconvolution Automated Mass Spectral Deconvolution and Identification System software allows the use of pesticide databases for identification and quantification in routine applications. Quantitation limits and repetitivity using full scan mass spectrometric determination guarantee the applicability of the method, which enables considerable savings to be made in total analysis time, with data processing times of around 2 min/sample. PMID- 19784947 TI - Compliance with dosing recommendations from common references in prescribing antibiotics for preterm neonates. AB - PURPOSE: Incorrect dosage was the most common type of medication errors in neonate patients. Different dosing recommendations from common reference sources may have contributed to the errors. This study assesses the compliance rate with the common reference sources in antibiotic dosage prescribed for preterm infants in a neonatal intensive care unit (NICU). METHODS: A retrospective study using chart review was conducted at a tertiary care medical center with university affiliation in Taiwan. Study subjects were preterm neonates admitted to the NICU of the medical center between 2000 and 2002 and prescribed at least one antibiotic during the stay. Recommendations from three commonly used reference sources (Pediatric Dosage Handbook, Neonatal Drug Formulary, and Neofax) were employed to evaluate the dosage compliance of the antibiotic prescriptions. RESULTS: A total of 433 preterm infants and 3459 prescriptions were included. Depending on the reference source used, the percentages of antibiotic prescriptions where both the dose and the interval were compliant with recommendations ranged from 36.88 to 87.54%. CONCLUSIONS: A significant proportion of antibiotics prescribed for preterm neonates in this medical center did not comply with the recommended dosage from common reference sources. Future studies should investigate the clinical impacts of the dosing deviation. PMID- 19784948 TI - Differentiation of cultivation sources of Ganoderma lucidum by NMR-based metabolomics approach. AB - INTRODUCTION: Ganoderma lucidum is a widely used and high-value medicinal natural product. Correct identification of its cultivation source is important for proper quality assurance, but is so far mostly dependent on subjective morphological examinations. OBJECTIVE: To develop an efficient way of discriminating the cultivation sources of Ganoderma lucidum, particularly those from Korea and China, the two major sources of the mushroom using NMR-based metabolomic differentiation. METHODOLOGY: Ganoderma lucidum samples were collected from Korea (26 samples) and China (20 samples), and their NMR spectra were obtained. The raw data were processed, and analysed using multivariate statistical analysis. RESULTS: Although conventional principal component analysis showed some overlaps, orthogonal projections to latent structure discriminant analysis (OPLS-DA) provided clean distinction between samples from the two countries. Contributing signals were also identified using S-plot, and further verified with independent t-test. Final validation of the model was obtained using prediction test of the unknowns, where the model predicted all of the 14 test samples correctly. Distinction between the cultivation sources within China was also established. CONCLUSION: The easiness and transferability of our NMR-based approach should contribute to addressing an important aspect of quality control process of Ganoderma lucidum. We believe the method can be easily applied to other herbal medical products. PMID- 19784950 TI - Highly sensitive detection of ATPase activity in native gels. AB - Native electrophoresis is a powerful tool for the separation of intact protein complexes. By incubating such gels in a suitable reaction solution, specific enzyme activities can be screened comprehensively. The recent standard procedure for determination of ATP hydrolysis activity in blue or clear native gels is based on formation of a lead phosphate precipitate. The resulting white bands are challenging for detection and documentation of low activities. For the analysis of photosynthetic ATP synthases, the method has to be adapted to deregulate the inhibition of latent ATPase functions. Therefore, we introduced an incubation of gels in detergent solution, whereby taurodeoxycholate turned out to be the most efficient activator. In order to detect low ATPase activities, a short additional incubation step subsequent to the formation of lead phosphate is recommended. By adding ammonium sulfide, the white bands are converted into brownish-black bands of lead sulfide. Our new procedure sustains the linear quantitation range of the original lead phosphate protocol and moreover expands the detection limit. PMID- 19784949 TI - CD46-induced human Treg enhance B-cell responses. AB - Regulatory CD4(+) T cells (Treg) are important modulators of the immune response. Different types of Treg have been identified based on whether they are thymically derived (natural Treg) or induced in the periphery (adaptive Treg). We recently reported on an adaptive Treg phenotype that can be induced by the concomitant stimulation of human CD4(+) T cells through CD3 and the membrane complement regulator CD46. These complement (CD46)-induced regulatory T cells (cTreg) potently inhibit bystander T-cell proliferation through high-level secretion of IL-10. In addition, cTreg express granzyme B and exhibit cytotoxic effects toward activated effector T cells. Here, we analyzed the effect of cTreg on B-cell functions in a co-culture system. We found that cTreg enhance B-cell Ab production. This B-cell support is dependent on cell/cell contact as well as cTreg-derived IL-10. In addition, we show that T cells from a CD46-deficient patient are not capable of promoting B-cell responses, whereas CD46-deficient B cells have no intrinsic defect in Ig production. This finding may relate to a subset of CD46-deficient patients, who present with common variable immunodeficiency. Thus, the lack of cTreg function in optimizing B-cell responses could explain why some CD46-deficient patients develop common variable immunodeficiency. PMID- 19784951 TI - Phosphate-affinity electrophoresis on a microchip for determination of protein kinase activity. AB - We describe microchip-based phosphate-affinity electrophoresis (microPAE) for separation of peptides aimed at determination of kinase activity. The microPAE exploits two recently published technologies: autonomous sample injection for PDMS microchips and a phosphate-specific affinity ligand, Phos-tag. We prepared a fluorescently labeled substrate peptide, specific to human c-Src, and its phosphorylated form. We synthesized a Phos-tag-poly(dimethylacrylamide) conjugate. The conjugate and the sample solutions were autonomously injected into a PDMS-glass hybrid microchip. The two solutions were contacted together in the microchannel. When the peptides were electrophoresed into the Phos-tag poly(dimethylacrylamide) region, the phosphorylated peptide was specifically trapped, and separated from the nonphosphorylated peptide in 10 s. The results were quantified by the areas of the fluorescence peaks. The calibration plot obtained with standard samples showed an excellent linearity and a LOD of 0.9% phosphorylated peptide among the total peptides. For c-Src-reacted samples, the results from the microPAE were in good agreement with those from matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The microPAE was also successful in the presence of inhibitors for c-Src. The measured 50% inhibitory concentration values for staurosporine, PP2, and SU6656 were in good agreement with the literature values. PMID- 19784952 TI - Micropump based on electroosmosis of the second kind. AB - A microfluidic pump based on electroosmosis of the second kind was designed and fabricated. Experimental results using DC and AC voltages showed a close to second-order relationship between flow and voltage, in good agreement with theory. The experimental flow rates were considerably lower than the predicted maximum for the micropumps, which can be attributed to the hydrodynamic resistance of the channel network. This also indicates that higher flow velocities are obtainable for modified pump designs. PMID- 19784954 TI - Formation of CaSO4(aq) and CaSeO4(aq) studied as a function of ionic strength and temperature by CE. AB - Ca(2+) complexation by both sulfate and selenate ligands was studied by CE. The species were observed to give a unique retention peak as a result of a fast equilibrium between the free ions and the complexes. The change in the corresponding retention time was interpreted with respect to the equilibrium constant of the complexation reaction. The results confirmed the formation of CaSO(4)(aq) and CaSeO(4)(aq) under our experimental conditions. The formation data were derived from the series of measurements carried out at about 15, 25, 35, 45 and 55 degrees C in 0.1 mol/L NaNO(3) ionic strength solutions, and in 0.5 and 1.0 mol/L NaNO(3) ionic strength solutions at 25 degrees C. Using a constant enthalpy of reaction enabled to fit all the experimental data in a 0.1 mol/L medium, leading to the thermodynamic parameters: Delta(r)G(0.1M)(25 degrees C)= (7.59+/-0.23) kJ/mol, Delta(r)H(0.1 M)=5.57+/-0.80 kJ/mol, and Delta(r)S(0.1 M)(25 degrees C)=44.0+/-3.0 J mol(-1) K(-1) for CaSO(4)(aq) and Delta(r)G(0.1 M)(25 degrees C)=-(6.66+/-0.23) kJ/mol, Delta(r)H(0.1 M)=6.45+/-0.73 kJ/mol, and Delta(r)S(0.1 M)(25 degrees C)=44.0+/-3.0 J mol(-1) K(-1) for CaSeO(4)(aq). Both formation reactions were found to be endothermic and entropy driven. CaSO(4)(aq) appears to be more stable than CaSeO(4)(aq) by 0.93 kJ/mol under these experimental conditions, which correlates with the difference of acidity of the anions as expected for interactions between hard acids and hard bases according to the hard and soft acids and bases theory. The effect of the ionic medium on the formation constants was successfully treated using the Specific ion Interaction Theory, leading to significantly different binary coefficients epsilon(NA+,SO(2-)(4)) = -(0.15 +/- 0.06) mol/kg-1 and epsilon(NA+,SO(2-)(4)) = (0.26 +/- 0.10) mol/kg-1. PMID- 19784955 TI - Progressive chorion morphology during egg development in Samia ricini (Donovan). AB - The egg of Samia ricini (Donovan), is oval or laterally flattened ellipsoid, freshly laid eggs are candid white while the chorion is colorless and semi transparent. The surface of the chorion is covered with network patterns of polygons and their shapes are common in the whole surface region. The boundaries between polygons made ridges had distinct acropyles at three-cell junctions. The numbers of aeropyles are variable according to their structures both in the lateral flat and marginal regions. During the course of egg development, no significant structural changes were observed in either the polygonal structures or the overall morphology of the egg. However, the size of the aeropyles kept on changing as the egg matures. The aeropyle increases initially upto day-9 of egg development and then decreases as it approach hatching. Lines of weaknesses were not observed at time of hatching or close to it. Hatching process of the newly emerge larvae are through gnawing. The larva eats their way out through the chorion membrane mostly from the anterior region. Egg buster or spine which aid in hatching are not present in the newly emerge larvae.This article was published online on 25 September 2009. An error was subsequently identified. This notice is included in the online and print versions to indicate that both have been corrected 6 January 2010. PMID- 19784953 TI - A novel approach to tag and identify geranylgeranylated proteins. AB - A recently developed proteomic strategy, the "GG-azide"-labeling approach, is described for the detection and proteomic analysis of geranylgeranylated proteins. This approach involves metabolic incorporation of a synthetic azido geranylgeranyl analog and chemoselective derivatization of azido-geranylgeranyl modified proteins by the "click" chemistry, using a tetramethylrhodamine-alkyne. The resulting conjugated proteins can be separated by 1-D or 2-D and pH fractionation, and detected by fluorescence imaging. This method is compatible with downstream LC-MS/MS analysis. Proteomic analysis of conjugated proteins by this approach identified several known geranylgeranylated proteins as well as Rap2c, a novel member of the Ras family. Furthermore, prenylation of progerin in mouse embryonic fibroblast cells was examined using this approach, demonstrating that this strategy can be used to study prenylation of specific proteins. The "GG azide"-labeling approach provides a new tool for the detection and proteomic analysis of geranylgeranylated proteins, and it can readily be extended to other post-translational modifications. PMID- 19784956 TI - Spermatozoon and its relationship with the ovarian lamellae in the internally inseminating catfish Trachelyopterus galeatus. AB - We examined the spermatozoa and their relationship with the ovarian lamellae in the catfish Trachelyopterus galeatus by classical light microscopy, high resolution light microscopy, and transmission electron microscopy. Trachelyopterus galeatus is an internally inseminating species the spermatozoon of which presented an elongated cylindrical head (12.3 +/- 1.5 microm), elongated midpiece (5.0 +/- 0.7 microm), and flagellum (23.9 +/- 2.8 microm). Fertilized eggs or embryos were not found in its ovaries. Spermatozeugmata were demonstrated for the first time in this species. At the ultrastructural level, the anterior region of the head was devoid of chromatin with its shape being rounded with a hyaline tip in frontal sections and flattened in sagittal sections. The proximal centriole and most of the distal centriole were contained within a nuclear fossa. Mitochondria with lamellar cristae, as well as glycogen granules, were located just caudal to the nuclear fossa and distally in the midpiece. A single row of accessory microtubules ran peripherally in the midpiece. The flagellar axoneme had the typical 9 + 2 arrangement, having electron-dense and electron-lucent A tubules at different points along the flagellum; flagellar fins were lacking. The ovarian lamellae were covered by a simple cuboidal epithelium. In maturing/mature females, spermatozoa were free in the ovarian lumen or inserted in pits of the lamellar epithelial cells. Tight junctions and desmosomes were seen between the epithelial cells. In addition to nourishment of the spermatozoon, the lamellar epithelial cells may play a role in protecting the spermatozoa against the female immune system. PMID- 19784957 TI - Autophagosomal glycogen-degrading activity and its relationship to the general autophagic activity in newborn rat hepatocytes: The effects of parenteral glucose administration. AB - The effects of the administration of parenteral glucose on the postnatal glycogen autophagic activity and its relationship to the general autophagic activity, were studied in newborn rat liver using electron microscopy and biochemical methods. Glucose abolished the normal postnatal hypoglycemia and preserved the hepatocytic hyaloplasmic glycogen to the levels of birth. It also inhibited the normal postnatal increase in the number and volume of autophagic vacuoles. Glucose especially decreased the rate of postnatal development of the glycogen-containing autophagic vacuoles. This decrease was greater than that of the autophagic vacuoles in general. In the control animals at the age of 6 h, the total volume of the glycogen-containing autophagic vacuoles accounted for 87% of the autophagic vacuoles in general, whereas in the glucose-treated animals of the same age, for only 62%. The results of this and previous studies support the view that the general autophagic activity that develops in the immediate postnatal period in rat hepatocytes is mainly expressed as glycogen autophagic activity selectively inhibited by glucose. PMID- 19784960 TI - High-fat diet and hydrochlorothiazide increase oxidative stress in brain of rats. AB - This study evaluated the effect of possible synergic interaction between high fat diet (HF) and hydrochlorothiazide (HCTZ) on biochemical parameters of oxidative stress in brain. Rats were fed for 16 weeks with a control diet or with an HF, both supplemented with different doses of HCTZ (0.4, 1.0, and 4.0 g kg(-1) of diet). HF associated with HCTZ caused a significant increase in lipid peroxidation and blood glucose levels. In addition, HF ingestion was associated with an increase in cerebral lipid peroxidation, vitamin C and non-protein thiol groups (NPSH) levels. There was an increase in vitamin C as well as NPSH levels in HCTZ (1.0 and 4.0 g kg(-1) of diet) and HF plus HCTZ groups. Na(+)-K(+)-ATPase activity of HCTZ (4.0 g kg(-1) of diet) and HCTZ plus HF-fed animals was significantly inhibited. Our data indicate that chronic intake of a high dose of HCTZ (4 g kg(-1) of diet) or HF change biochemical indexes of oxidative stress in rat brain. Furthermore, high-fat diets consumption and HCTZ treatment have interactive effects on brain, showing that a long-term intake of high-fat diets can aggravate the toxicity of HCTZ. PMID- 19784961 TI - Tracing of intracellular zinc(II) fluorescence flux to monitor cell apoptosis by using FluoZin-3AM. AB - Changes in the free zinc(II) concentration are closely related to cell proliferation and apoptosis, especially during the early apoptotic process. In the present paper, we demonstrated that zinc(II) probe FluoZin-3AM owns sensitive properties to distinguish different stages of apoptotic cell (induced by an anticancer agent, etoposide) according to trace intracellular zinc(II) fluorescence flux. When apoptosis in HeLa or K562 cells was artificially induced, FluoZin-3AM selectively and strongly stained apoptotic cells only at early and middle stages, which was attributed to significantly increased free zinc(II) flux during these stages. This conclusion was further verified by comparing it with the conventional apoptosis detector probe Annexin-V-FITC and PI. Furthermore, FluoZin-3AM was found cell permeable to detect the intracellular zinc(II) fluorescence enhancement to threefolds within 120 s with low cytotoxicity when zinc(II) was incorporated into the cell by zinc(II) ionophore pyrithione. All the above implied that monitoring intracellular zinc fluorescence flux was an effective method to distinguish cell apoptosis from necrosis, and FluoZin-3AM was found to be a suitable probe acting alone to fulfill the work. PMID- 19784962 TI - Association of cholesteryl ester transfer protein -629C > A polymorphism with high-density lipoprotein cholesterol levels in coronary artery disease patients. AB - In Turkish population, plasma HDL-C levels were found to be lower than in any other country and it is suggested that this is associated with genetic origin. The cholesteryl ester transfer protein (CETP) -629C > A polymorphism is associated with lower plasma CETP concentration, with increased HDL-C level. In the present study, the frequency of -629C > A polymorphism in patients with coronary artery disease (CAD) was investigated and the effect of genotype on HDL C was evaluated in a Turkish population. For this aim CETP -629C > A polymorphism was studied in angiographically documented CAD patients and healthy controls. There was no statistical significance in the distribution of genotypes between patients and controls. Although A allele carriers with CAD had significantly lower HDL-C levels than controls, plasma lipid levels showed no difference according to the genotypes. Adjustment by a logistic regression model predicting CAD status through HDL-C and including some risk factors as covariate indicated that the HDL-C doesn't have a significant association with CAD risk in CA and AA genotype carriers. Smoking, gender and hypertension were the common predictors for the HDL-C levels in CA and AA carriers. Although HDL-C appeared to be the only significant predictor of CAD in our study groups, the contribution of CETP 629C > A polymorphism to the alterations in HDL-C level appears to be weak to mention a protective effect of this polymorphism for CAD. In conclusion, the findings of the present study indicate that the CETP -629C > A polymorphism is not among the determinants of the coronary artery disease in Turks. PMID- 19784963 TI - Prevalence of cross- or multiple resistance to the acetyl-coenzyme A carboxylase inhibitors fenoxaprop, clodinafop and pinoxaden in black-grass (Alopecurus myosuroides Huds.) in France. AB - BACKGROUND: Repeated use of acetyl-CoA carboxylase (ACCase) inhibitors, especially fenoxaprop and clodinafop, since the late 1980s has selected for resistance in Alopecurus myosuroides Huds. (black-grass) in France. We investigated whether resistance to pinoxaden, a phenylpyrazoline ACCase inhibitor to be marketed in France, was present in French black-grass populations. We investigated pinoxaden resistance conferred by five mutant ACCase isoforms. Using 84 French black-grass field samples, we also compared the frequencies of other mechanisms endowing resistance to fenoxaprop, clodinafop or pinoxaden. RESULTS: ACCase mutant isoforms Leu-1781, Gly-2078 and, likely, Cys-2027 conferred cross resistance to pinoxaden, while isoform Asn-2041 possibly conferred moderate resistance. Other mechanisms of resistance to fenoxaprop, clodinafop and pinoxaden were detected in 99, 68 and 64% of the samples investigated, respectively. Cross- or multiple resistance to fenoxaprop or clodinafop and pinoxaden was not systematically observed, suggesting a diversity of mechanisms exist. CONCLUSION: Pinoxaden resistance was observed before pinoxaden release in France. Only a fraction of the mechanisms endowing fenoxaprop or clodinafop resistance also confer pinoxaden resistance. Pinoxaden resistance was likely mostly selected for by ACCase inhibitors, and, in some cases, possibly by herbicides with other modes of action. This illustrates the necessity to use metabolisable herbicides cautiously where black-grass has evolved non-target-site based resistance. PMID- 19784964 TI - PTEN-mediated G1 cell-cycle arrest in LNCaP prostate cancer cells is associated with altered expression of cell-cycle regulators. AB - BACKGROUND: The tumor suppressor PTEN regulates many biological processes. A well known downstream effector of PTEN is phospho-Akt. Although PTEN is the most frequently inactivated gene in prostate cancer, its mode of action is not fully understood. We studied the association of regulated PTEN expression with changes in biological function and gene expression profiles. METHODS: PTEN-negative LNCaP cells were stably transfected with wild-type PTEN cDNA under inducible control, resulting in LNCaP/PTEN cells. Microarray analysis was used to monitor gene expression changes upon induction of PTEN. Expression of selected individual genes was studied in Q-PCR and siRNA experiments. Cell-cycle distribution was analyzed by flow cytometry. RESULTS: Induced expression of PTEN in LNCaP/PTEN cells significantly inhibited cell proliferation, at least partly due to cell cycle arrest at the G1 phase. Expression profiling combined with pathway analysis revealed that PTEN-dependent G1 growth arrest was associated with an altered mRNA expression of the G1 cell-cycle regulators Cdc25a, E2F2, cyclin G2, and RBL2/p130. Specific inhibition of Akt signaling by siRNA resulted in downregulation of both E2F2 and Cdc25a mRNA expression and upregulation of the FOXO target cyclin G2, similar to the effect observed by PTEN induction. However, Akt did not mediate the PTEN-dependent RBL2/p130 mRNA expression in LNCaP/PTEN cells. CONCLUSIONS: The results indicate that PTEN dependent gene expression is important in cell-cycle regulation and is mediated by both Akt-dependent and independent mechanisms. PMID- 19784965 TI - Engineering a beta-helical D,L-peptide for folding in polar media. AB - Beta helices--helices formed by alternating D,L-peptides and stabilized by beta sheet hydrogen bonding--are found naturally in only a handful of highly hydrophobic peptides. This paper explores the scope of beta-helical structure by presenting the first design and biophysical characterization of a hydrophilic D,L peptide, 1, that forms a beta helix in methanol. The design of 1 is based on the beta-hairpin/beta helix--a new supersecondary that had been characterized previously only for hydrophobic peptides in nonpolar solvents. Incorporating polar residues in 1 provided solubility in methanol, in which the peptide adopts the expected beta-hairpin/beta-helical structure, as evidenced by CD, analytical ultracentrifugation (AUC), NMR spectroscopy, and NMR-based structure calculations. Upon titration with water (at constant peptide concentration), the structure in methanol (1 m) transitions cooperatively to an extended conformation (1 w) resembling a cyclic beta-hairpin; observation of an isodichroic point in the solvent-dependent CD spectra indicates that this transition is a two-state process. In contrast, neither 1 m nor 1 w show cooperative thermal melting; instead, their structures appear intact at temperatures as high as 65 degrees C; this observation suggests that steric constraint is dominant in stabilizing these structures. Finally, the (1)H NMR C alphaH spectroscopic resonances of 1 m are downfield-shifted with respect to random-coil values, a hitherto unreported property for beta helices that appears to be a general feature of these structures. These results show for the first time that an appropriately designed beta-helical peptide can fold stably in a polar solvent; furthermore, the structural and spectroscopic data reported should prove useful in the future design and characterization of water-soluble beta helices. PMID- 19784966 TI - Methanol-assisted catalysis by chiral tin methoxides: an alternative asymmetric aldol process. PMID- 19784967 TI - Covalent modification of glassy carbon surfaces by using electrochemical and solid-phase synthetic methodologies: application to bi- and trifunctionalisation with different redox centres. AB - Glassy carbon electrodes functionalised with two redox centres have been prepared by using electrochemical and solid-phase synthetic methodologies. Initially the individual coupling of anthraquinone, nitrobenzene and dihydroxybenzene to a glassy carbon electrode bearing an ethylenediamine linker was optimised by using different coupling agents and conditions. Bifunctionalisation was then carried out, either simultaneously, with a mixture of nitrobenzene and dihydroxybenzene, or sequentially, with anthraquinone then nitrobenzene and with anthraquinone then dihydroxybenzene. Characterisation of these electrodes by cyclic voltammetry and differential pulse voltammetry clearly proved the attachment of the pairs of redox centres to the glassy carbon electrode. Their partial surface coverages can be controlled by varying the coupling agent or by controlling the substrate concentration during the solid-phase coupling process. Trifunctionalisation was also realised according to this methodology. PMID- 19784969 TI - Cationic allyl complexes of the rare-earth metals: synthesis, structural characterization, and 1,3-butadiene polymerization catalysis. AB - Monocationic bis-allyl complexes [Ln(eta(3) C(3)H(5))(2)(thf)(3)](+)[B(C(6)X(5))(4)](-) (Ln = Y, La, Nd; X = H, F) and dicationic mono-allyl complexes of yttrium and the early lanthanides [Ln(eta(3) C(3)H(5))(thf)(6)](2+)[BPh(4)](2)(-) (Ln = La, Nd) were prepared by protonolysis of the tris-allyl complexes [Ln(eta(3)-C(3)H(5))(3)(diox)] (Ln = Y, La, Ce, Pr, Nd, Sm; diox = 1,4-dioxane) isolated as a 1,4-dioxane-bridged dimer (Ln = Ce) or THF adducts [Ln(eta(3)-C(3)H(5))(3)(thf)(2)] (Ln = Ce, Pr). Allyl abstraction from the neutral tris-allyl complex by a Lewis acid, ER(3) (Al(CH(2)SiMe(3))(3), BPh(3)) gave the ion pair [Ln(eta(3)-C(3)H(5))(2)(thf)(3)](+)[ER(3)(eta(1) CH(2)CH=CH(2))](-) (Ln = Y, La; ER(3) = Al(CH(2)SiMe(3))(3), BPh(3)). Benzophenone inserts into the La-C(allyl) bond of [La(eta(3) C(3)H(5))(2)(thf)(3)](+)[BPh(4)](-) to form the alkoxy complex [La{OCPh(2)(CH(2)CH=CH(2))}(2)(thf)(3)](+)[BPh(4)](-). The monocationic half sandwich complexes [Ln(eta(5)-C(5)Me(4)SiMe(3))(eta(3) C(3)H(5))(thf)(2)](+)[B(C(6)X(5))(4)](-) (Ln = Y, La; X = H, F) were synthesized from the neutral precursors [Ln(eta(5)-C(5)Me(4)SiMe(3))(eta(3) C(3)H(5))(2)(thf)] by protonolysis. For 1,3-butadiene polymerization catalysis, the yttrium-based systems were more active than the corresponding lanthanum or neodymium homologues, giving polybutadiene with approximately 90% 1,4-cis stereoselectivity. PMID- 19784968 TI - Polyoxazoline-based crystalline microspheres for carbohydrate-protein recognition. PMID- 19784970 TI - Biology-oriented combined solid- and solution-phase synthesis of a macroline-like compound collection. AB - Macrolines constitute a class of natural products that has more than 100 members and displays diverse biological activities. These compounds feature a cycloocta[b]indole scaffold that represents an interesting target structure for biology-oriented synthesis (BIOS). We have presented a solid-phase synthesis of isomerically pure cycloocta[b]indoles by employing the Pictet-Spengler reaction and the Dieckmann cyclization as key steps. The scope of this reaction sequence was investigated in more detail by using various additional diversification procedures, such as Pd-catalyzed Sonogashira or Suzuki couplings on a solid phase, thus allowing, for example, the generation of 10-substituted cycloocta[b]indole derivatives. Finally, solution-phase decoration of the cycloocta[b]indole skeleton by reduction and saponification was evaluated, thereby further extending the scope of the solid-phase synthesis. PMID- 19784971 TI - A simple chemical tuning of the effective concentration: selection of single-, double-, and triple-stranded binuclear lanthanide helicates. AB - The replacement of terminal 2-benzimidazol-6-carboxypyridine (two internal rotational degrees of freedom) with 2-benzimidazol-8-hydroxyquinoline (one internal rotational degree of freedom) into segmental bis-tridentate ligands in going from L2 and [L3-2 H](2-) to [L12 b-2 H](2-) does not significantly affect the structures of the resulting binuclear lanthanide triple-stranded helical complexes [Ln(2)(L2)(3)](6+), [Ln(2)(L3-2 H)(3)], and [Ln(2)(L12 b-2 H)(3)] (palindromic helices, intermetallic contact distance approximately 9 A, helical pitch approximately 1.4 nm per turn). However, their thermodynamic assemblies are completely different in solution, as evidenced by the spectacular decrease of the effective concentrations by two orders of magnitude for [L12 b-2 H](2-). This key parameter in the [Ln(2)(L12 b-2 H)(n)] (n=2, 3) complexes is further abruptly modulated along the lanthanide series (Ln=La to Lu), which provides an unprecedented tool for 1) tuning the number of ligand strands in the final helicates, 2) selectively coordinating lanthanides in the various complexes, and 3) controlling the ratio of lanthanide-containing polymers over discrete assemblies. PMID- 19784972 TI - Visualization of the local catalytic activity of electrodeposited Pt-Ag catalysts for oxygen reduction by means of SECM. AB - Pt-Ag nanoparticle co-deposits with different Pt-Ag ratios were prepared on a glassy carbon (GC) surface by pulsed electrodeposition and investigated for their catalytic activity in electrocatalytic oxygen reduction by using cyclic voltammetry (CV), rotating disc electrode (RDE) and scanning electrochemical microscopy (SECM) in 0.1 M phosphate buffer (pH 7.0). The atomic composition of the Pt-Ag co-deposits was studied by means of energy-dispersive X-ray analysis (EDAX). In combination with X-ray diffraction (XRD), the presence of partly alloyed Pt and Ag on the GC surface was confirmed. Scanning electron microscopy (SEM) images indicate that the prepared Pt-Ag catalyst particles are homogenously dispersed over the GC surface. Their size and morphology depend on their composition. The electrocatalytic activity of Pt-Ag deposits with high Pt content was the highest, exceeding even that of electrodeposited Pt as evaluated by quantitative RDE analysis. The redox competition mode of scanning electrochemical microscopy (RC-SECM) was successfully used to visualize the local catalytic activity of the deposited Pt-Ag particles. Semi-quantitative assessment of the SECM results confirmed the same order of activity of the different catalysts as the RDE investigations. PMID- 19784973 TI - PI(4,5)P2 degradation promotes the formation of cytoskeleton-free model membrane systems. AB - Giant plasma membrane vesicles (GPMVs) are cell-derived model membrane systems that undergo large-scale lipid phase separation when cooled below room temperature. Because of their presumably more physiological lipid composition, they are increasingly used as alternatives to synthetic model membranes. However, the exact mechanism of GPMV formation, and thus, effects of this process on the physiological integrity of the membrane are still unclear. Herein, we identify the key steps of GPMV formation and characterize their differences with respect to the plasma membrane of intact cells. Addition of GPMV-inducing reagents triggers a steady Ca2+ influx that is accompanied by phosphatidylinositol 4,5 bisphosphate [PI(4,5)P2] degradation and phosphatidyl serine (PS) externalization before detachment of the cytoskeleton and the onset of vesicle formation. When comparing GPMVs to other cell-derived model systems, PI(4,5)P2 is not detectable in phase-separating plasma membrane spheres (PMSs) either, but is present in non phase-separating blebs. GPMVs differ from the physiological state of the plasma membrane in the presence of specific lipids, which limits their use as model systems. Furthermore, we propose that PI(4,5)P2 influences the phase-separation behavior. PMID- 19784974 TI - Synthesis and biological evaluation of chromium bioorganometallics based on the antibiotic platensimycin lead structure. AB - The recent discovery of the natural product platensimycin as a new antibiotic lead structure has triggered the synthesis of numerous organic derivatives for structure-activity relationship studies. Herein, we describe the synthesis, characterization and biological evaluation of the first organometallic antibiotic inspired by platensimycin. Two bioorganometallic compounds containing (eta(6) pentamethylbenzene)Cr(CO)(3) (2) and (eta(6)-benzene)Cr(CO)(3) (3), linked by an amide bond to the aromatic part of platensimycin, were synthesized. Their antibiotic activities were tested against B. subtilis 168 (Gram positive) and E. coli W3110 (Gram negative) bacterial strains. Both compounds were found to be inactive against E. coli but derivative 2 inhibits B. subtilis growth at a moderate MIC value of 0.15 mM. To test the intrinsic toxicity of chromium, several chromium salts along with {eta(6)-(3-pentamethylphenyl propionic acid)}Cr(CO)(3) (5) and {eta(6)-(3-phenyl propionic acid)}Cr(CO)(3) (6) were tested against both bacterial strains. No activity was observed against E. coli for any of the compounds; B. subtilis growth was not inhibited by Cr(NO(3))(3) and only very weakly by 5, K(2)Cr(2)O(7) and Na(2)CrO(4) at MIC values of 0.5, 0.68 and 1.24 mM, respectively. Compounds 2, 3, 5 and 4 (the pure organic analogue of 2) show similar cytotoxicity against HeLa, HepG2 and HT-29 mammalian cell lines. Furthermore, the cellular uptake and the intracellular distribution of compounds 2, 3 and Cr(NO(3))(3) in B. subtilis were studied using atomic absorption spectroscopy to gain insight in to the possible cellular targets. Compound 2 was found to be readily taken up and distributed almost equally among cytosol, cell debris and cell membrane in B. subtilis. PMID- 19784975 TI - Nanocomposites with structure domains of 0.5 to 3 nm by polymerization of silicon spiro compounds. PMID- 19784976 TI - Graphene: the new two-dimensional nanomaterial. AB - Every few years, a new material with unique properties emerges and fascinates the scientific community, typical recent examples being high-temperature superconductors and carbon nanotubes. Graphene is the latest sensation with unusual properties, such as half-integer quantum Hall effect and ballistic electron transport. This two-dimensional material which is the parent of all graphitic carbon forms is strictly expected to comprise a single layer, but there is considerable interest in investigating two-layer and few-layer graphenes as well. Synthesis and characterization of graphenes pose challenges, but there has been considerable progress in the last year or so. Herein, we present the status of graphene research which includes aspects related to synthesis, characterization, structure, and properties. PMID- 19784977 TI - Green fluorescent protein as indicator of nonviral transient transfection efficiency in endometrial and testicular biopsies. AB - In the last years, physical and chemical methods of plasmid delivery have revolutionized the efficiency of nonviral gene transfer, and the success of gene therapy is largely dependent upon the development of gene-delivery methods. The nonviral techniques that lead to a direct transfer of DNA into tissue fragments, like electroporation (EP) and lipofection delivery systems are still insufficiently investigated. Our aim was to test the efficiency of EP and lipofection protocols in endometrial and testicular tissue fragments, using a naked plasmid DNA encoding green fluorescent protein (GFP). Because the transfection efficiency depends upon several factors, we tried to optimize the transfection conditions by testing different lipofectamine 2000 and plasmid ratios, electrical parameters, and culture after transfection. Our results show that these two nonviral methods of gene delivery are feasible and efficient in gene transfection of endometrial and testicular tissue biopsies. We found that the most performing ratio of plasmid:lipofectamine was 10:50 for transient lipofection, whereas two pulses for 10 s at 960 microF of capacitance, 200 V of voltage were the most favorable electrical parameters for EP efficiency in the presence of 5 microL of phMGFP plasmid. After lipofection and EP, the highest GFP intensity was observed respectively after 48 and 72 h of tissue fragment culturing. In conclusion, nonviral methods are attractive for an improvement of the gene therapy and our protocol could provide useful indications for in vivo gene therapy applications. PMID- 19784978 TI - MRT letter: In situ observation method for microstructural changes of steel during hot deformation. AB - We report on the result of an in situ method for observing microstructural changes during hot deformation. The observation of microstructural changes of steel at 1,473 K under tensile strain is demonstrated using the reported method. The development of deformed structures and the formation of a new grain boundary, which subsequently moved with increased strain, were clearly observed. The effectiveness of this method was confirmed by the results of several examples. PMID- 19784979 TI - Rapid characterization of complex viscous liquids at the molecular level. PMID- 19784980 TI - Photoisomerization of all-cis-1,6-diphenyl-1,3,5-hexatriene in the solid state and in solution: a simultaneous three-bond twist process. PMID- 19784981 TI - T-shaped three-coordinate copper(II) heptaphyrin complexes. PMID- 19784982 TI - Synthesis of modular "inorganic-organic-inorganic" polyoxometalates and their assembly into vesicles. PMID- 19784983 TI - Unexpected acid catalysis in reactions of peroxyl radicals with phenols. PMID- 19784984 TI - Aza-Wittig-supported synthesis of the A ring of nosiheptide. PMID- 19784985 TI - Catalytic enantioselective synthesis of chiral tetraphenylenes: consecutive inter and intramolecular cycloadditions of two triynes. PMID- 19784986 TI - Functional profiling, identification, and inhibition of plasmepsins in intraerythrocytic malaria parasites. PMID- 19784987 TI - Tunable, temperature-responsive polynorbornenes with side chains based on an elastin peptide sequence. PMID- 19784988 TI - Synthesis of pyridines and pyrazines using an intramolecular hydroamination-based reaction sequence. PMID- 19784991 TI - Calix[4]arene-based single-molecule magnets. PMID- 19784992 TI - Olefin cyclopropanation by a sequential atom-transfer radical addition and dechlorination in the presence of a ruthenium catalyst. PMID- 19784993 TI - Microwave chemistry in silicon carbide reaction vials: separating thermal from nonthermal effects. PMID- 19784994 TI - Gold- or platinum-catalyzed synthesis of sulfur heterocycles: access to sulfur ylides without using sacrificial functionality. PMID- 19784996 TI - Lawrence T. Scott. PMID- 19784995 TI - Rhodium(I)-catalyzed [4+1] cycloaddition reactions of alpha,beta-unsaturated imines with terminal alkynes for the preparation of pyrrole derivatives. PMID- 19784998 TI - Syringetin, a flavonoid derivative in grape and wine, induces human osteoblast differentiation through bone morphogenetic protein-2/extracellular signal regulated kinase 1/2 pathway. AB - Syringetin (3,5,7,4'-tetrahydroxy-3',5'dimethoxyflavone), a flavonoid derivative, is present in grape and wine. By means of alkaline phosphatase (ALP) activity, osteocalcin, and type I collagen ELISA, we have shown that syringetin exhibits a significant induction of differentiation in MC3T3-E1 mouse calvaria osteoblasts and human fetal osteoblastic 1.19 cell line human osteoblasts. ALP and osteocalcin are phenotypic markers for early-stage differentiated osteoblasts and terminally differentiated osteoblasts, respectively. Our results indicate that syringetin stimulates osteoblast differentiation at various stages, from maturation to terminally differentiated osteoblasts. Induction of differentiation by syringetin is associated with increased bone morphogenetic protein-2 (BMP-2) production. The BMP-2 antagonist noggin blocked syringetin-mediated ALP activity and osteocalcin secretion enhancement, indicating that BMP-2 production is required in syringetin-mediated osteoblast maturation and differentiation. Induction of differentiation by syringetin is associated with increased activation of SMAD1/5/8 and extracellular signal-regulated kinase 1/2 (ERK1/2). Cotreatment of ERK1/2 inhibitor 2'-amino-3'-methoxyflavone inhibited syringetin mediated ALP upregulation and osteocalcin production. In conclusion, syringetin increased BMP-2 synthesis, and subsequently activated SMAD1/5/8 and ERK1/2, and this effect may contribute to its action on the induction of osteoblast maturation and differentiation, followed by an increase of bone mass. PMID- 19784999 TI - A convenient and general iron-catalyzed reduction of amides to amines. PMID- 19785000 TI - The anti-diabetic effect of anthocyanins in streptozotocin-induced diabetic rats through glucose transporter 4 regulation and prevention of insulin resistance and pancreatic apoptosis. AB - Hyperglycemia, abnormal lipid and antioxidant profiles are the most usual complications in diabetes mellitus. Thus, in this study, we investigated the anti diabetic and anti-oxidative effects of anthocyanins (ANT) from black soybean seed coats in streptozotocin (STZ)-induced diabetic rats. The administration of ANT markedly decreased glucose levels and improved heart hemodynamic function (left ventricular end diastolic pressure, +/-dp/dt parameters). ANT not only enhanced STZ-mediated insulin level decreases, but also decreased the triglyceride levels induced by STZ injection in serum. Diabetic rats exhibited a lower expression of glucose transporter 4 proteins in the membrane fractions of heart and skeletal muscle tissues, which was enhanced by ANT. In addition, ANT activated insulin receptor phosphorylation, suggesting an increased utilization of glucose by tissues. Moreover, ANT protected pancreatic tissue from STZ-induced apoptosis through regulation of caspase-3, Bax, and Bcl-2 proteins. Furthermore, ANT significantly suppressed malondialdehyde levels and restored superoxide dismutase and catalase activities in diabetic rats. Interestingly, the observed effects of ANT were superior to those of glibenclamide. Taken together, ANT from black soybean seed coat have anti-diabetic effects that are due, in part, to the regulation of glucose transporter 4 and prevention of insulin resistance and pancreatic apoptosis, suggesting a possible use as a drug to regulate diabetes. PMID- 19785001 TI - Absorption of anthocyanins through intestinal epithelial cells - Putative involvement of GLUT2. AB - Anthocyanins bioavailability is a major issue regarding their biological effects and remains unclear due to few data available on this matter. This work aimed to evaluate the absorption of anthocyanins at the intestine using Caco-2 cells. Anthocyanin extract, rich in malvidin-3-glucoside, was obtained from red grape skins and tested on Caco-2 cells. The absorption of anthocyanins, in absence or presence of 1% ethanol, was detected by HPLC/DAD/LC-MS. Our results showed that this transport was significantly increased in the presence of ethanol especially after 60 min of incubation. In addition, cells that were pretreated for 96 h with anthocyanins (200 microg/mL) showed an increase of their own transport (about 50% increase). Expression of glucose transporters sodium-dependent glucose transporter 1, facilitative glucose transporters 5, and facilitative glucose transporters 2 was assessed by RT-PCR. It was found that facilitative glucose transporters 2 expression was increased (60%) in Caco-2 cells pretreated with anthocyanins, by comparison with controls. When the effect of anthocyanin extract on (3)H-2-deoxy-D-glucose uptake was tested, an inhibitory effect was observed (about 60% decrease). However, the malvidin aglycone was tested and had no effect. In conclusion, anthocyanins could be absorbed through Caco-2 cells, and can interfere with their own transport and also with glucose intestinal uptake. PMID- 19785002 TI - Effect of low-temperature long-time pre-treatment of wheat on acrylamide concentration in short dough biscuits. AB - In April 2002, unexpected high levels of the neurotoxic and suspected carcinogen acrylamide (AA) were found in many heated foods, mainly represented by cereal and potato derivatives. Since then, due to the great consumption of dietary sources of AA among people of different ages and in different countries, worldwide efforts have been carried out to reduce the formation of the toxic molecule in foods. In this paper, the effect of a low-temperature long-time pre-treatment of wheat grains on AA formation in biscuits was investigated. Wheat grains were subjected to heating at 100 degrees C for 8 h and subsequently milled. The obtained flour was used to prepare biscuits that were compared for AA content, texture and color with control samples obtained by using flour from unheated wheat. The low-temperature long-time pre-treatment was responsible for a great decrease (up to 42%) in AA levels in the biscuits, without causing significant changes in the color and texture parameters. As the pre-treatment did not cause any change in sugar and asparagine concentrations, such a reduction in AA concentration can be attributed to a difference in the thermal effect generated in the biscuits obtained by using the unheated and pre-heated flours. In fact, as the heating pre-treatment caused a 2% moisture decrease in the flour, less time at the same temperature was required to obtain biscuits with comparable moisture contents. PMID- 19785003 TI - Rapid differentiation of isobaric and positional isomers of structurally related glycosides from Phytolacca bogotensis. AB - Through the action of glycosyltransferases, a plant can biosynthetically assemble small different aglycons or 'templates' to various polysaccharides to produce numerous glycoconjugates differing in the type of the attached aglycon, the anomeric configuration of C-1 of the glycosylating sugar, the type of sugar and the different position of attachments of the sugar unit present in the polysaccharide chain. The position of attachments and the anomeric configuration of the different sugar present in the polysaccharide create the opportunity to generate molecules with either the same or very close molecular weights, which have relative structural similarity--forming isobaric and positional isomers. Although isomeric differentiation was once considered outside of the domain of mass spectrometry, this task can now be resolved using tandem mass spectrometry. In a standardized purified glycoconjugate fraction (SPT01) from Phytolacca bogotensis, we report conventional electrospray ionization mass spectrometry and collision-induced dissociation (CID) MS/MS parameters which favored the formation of characteristic product ions. This allowed us to suggest the type of sugar linkages present in a specific glycoconjugate. Ten new glycoconjugate are described from this plant and another twelve known saponins were structurally characterized using the automatic MSn acquisition mode. The differentiation of two pairs of positional isomers and four isobaric glycosides and the production of a library of 30 glycosides present in P. bogotensis were accomplished. PMID- 19785004 TI - Stability of thioester intermediates in ubiquitin-like modifications. AB - Ubiquitin-like modifications are important mechanisms in cellular regulation, and are carried out through several steps with reaction intermediates being thioester conjugates of ubiquitin-like proteins with E1, E2, and sometimes E3. Despite their importance, a thorough characterization of the intrinsic stability of these thioester intermediates has been lacking. In this study, we investigated the intrinsic stability by using a model compound and the Ubc9 approximately SUMO-1 thioester conjugate. The Ubc9 approximately SUMO-1 thioester intermediate has a half life of approximately 3.6 h (hydrolysis rate k = 5.33 +/- 2.8 x10(-5) s( 1)), and the stability decreased slightly under denaturing conditions (k = 12.5 +/- 1.8 x 10(-5) s(-1)), indicating a moderate effect of the three-dimensional structural context on the stability of these intermediates. Binding to active and inactive E3, (RanBP2) also has only a moderate effect on the hydrolysis rate (13.8 +/- 0.8 x 10(-5) s(-1) for active E3 versus 7.38 +/- 0.7 x 10(-5) s(-1) for inactive E3). The intrinsically high stability of these intermediates suggests that unwanted thioester intermediates may be eliminated enzymatically, such as by thioesterases, to regulate their intracellular abundance and trafficking in the control of ubiquitin-like modifications. PMID- 19785005 TI - Crystal structure of a 3B3 variant--a broadly neutralizing HIV-1 scFv antibody. AB - We present the crystal structure determination of an anti-HIV-1 gp120 single chain variable fragment antibody variant, 3B3, at 2.5 A resolution. This 3B3 variant was derived from the b12 antibody, using phage display and site-directed mutagenesis of the variable heavy chain (V(H)) complementary-determining regions (CDRs). 3B3 exhibits enhanced binding affinity and neutralization activity against several cross-clade primary isolates of HIV-1 by interaction with the recessed CD4-binding site on the gp120 envelope protein. Comparison with the structures of the unbound and bound forms of b12, the 3B3 structure closely resembles these structures with minimal differences with two notable exceptions. First, there is a reorientation of the CDR-H3 of the V(H) domain where the primary sequences evolved from b12 to 3B3. The structural changes in CDR-H3 of 3B3, in light of the b12-gp120 complex structure, allow for positioning an additional Trp side chain in the binding interface with gp120. Finally, the second region of structural change involves two peptide bond flips in CDR-L3 of the variable light (V(L)) domain triggered by a point mutation in CDR-H3 of Q100eY resulting in changes in the intramolecular hydrogen bonding patterning between the V(L) and V(H) domains. Thus, the enhanced binding affinities and neutralization capabilities of 3B3 relative to b12 probably result from higher hydrophobic driving potential by burying more aromatic residues at the 3B3-gp120 interface and by indirect stabilization of intramolecular contacts of the core framework residues between the V(L) and V(H) domains possibly through more favorable entropic effect through the expulsion of water. PMID- 19785006 TI - MPEx: a tool for exploring membrane proteins. AB - Hydropathy plot methods form a cornerstone of membrane protein research, especially in the early stages of biochemical and structural characterization. Membrane Protein Explorer (MPEx), described in this article, is a refined and versatile hydropathy-plot software tool for analyzing membrane protein sequences. MPEx is highly interactive and facilitates the characterization and identification of favorable protein transmembrane regions using experiment-based physical and biological hydrophobicity scales. Besides allowing the consequences of sequence mutations to be examined, it provides tools for aiding the design of membrane-active peptides. MPEx is freely available as a Java Web Start application from our web site at http://blanco.biomol.uci.edu/mpex. PMID- 19785007 TI - Numb promotes an increase in skeletal muscle progenitor cells in the embryonic somite. AB - Multiple cell types arise from cells in the dermomyotome of the somite that express Pax3 and Pax7, and myogenesis is regulated by Notch signaling. The asymmetric cell fate determinant Numb is thought to promote differentiation of skeletal muscle and other lineages by negatively regulating Notch signaling. We used transgenesis to overexpress Numb spatiotemporally in Pax3(+)/Pax7(+) somitic stem and progenitor cells in mouse embryos using a spatiotemporally regulated enhancer element from the Myf5 locus that can target muscle progenitor cells prior to cell commitment. Molecular analyses as well as examination of dermal and skeletal muscle cell fates in vivo show that although Numb is thought to be associated with muscle differentiation, unexpectedly the common stem/progenitor pool size for these lineages is increased in Numb-transgenic embryos. Prospective isolation of the relevant transgenic cells and analysis by quantitative reverse transcription polymerase chain reaction demonstrated that, in this context, canonical Notch targets are not significantly downregulated. These findings were corroborated using a Notch reporter mouse during the formation of somites and prior to lineage segregation. Thus, we propose that Numb can regulate the self renewal of dermal and muscle progenitors during a lineage progression. PMID- 19785008 TI - Adiponectinemia controls pro-angiogenic cell therapy. AB - Angiogenic cell therapy with the transplantation of endothelial progenitor cells (EPC) or bone marrow mononuclear cells (BM-MNC) receives considerable attention as an approach to revascularize ischemic tissues. Adiponectin is a circulating hormone produced by the apM1 gene in adipocytes. Adiponectin modulates lipid metabolism and obesity, and it was recently found to promote physiological angiogenesis in response to ischemia. Patients with multiple cardiovascular disease risk factors or myocardial infarction may benefit from progenitor cell therapy, but they display depressed adiponectinemia. We hypothesized that adiponectin stimulation of transplanted cells is critical for their pro angiogenic function. We aimed to establish whether adiponectinemia in the cell donor or in the cell recipient determines the success of pro-angiogenic cell therapy. In vitro, we found that conditioned media derived from wild-type adipocytes (adipo-CM) or purified adiponectin strongly enhanced BM-MNC survival and proliferation and stimulated EPC differentiation, whereas adipo-CM from apM1 /- adipocytes was one-half less effective. On the other hand, wild-type and apM1 /- BM-MNC displayed similar resistance to apoptosis and proliferation rates. In vivo, wild-type, and apM1-/- BM-MNC induced similar angiogenic reactions in wild type ischemic hindlimbs. In contrast, wild-type BM-MNC had much diminished effects in apM1-/- ischemic hindlimbs. We concluded that adiponectin enhances BM MNC survival and proliferation, and adiponectinemia in the cell therapy recipient is essential for the pro-angiogenic benefits of cell therapy. These observations imply that progenitor cell transplantation might only induce angiogenesis in patients with high adiponectinemia. PMID- 19785009 TI - Characterization of epithelial cell adhesion molecule as a surface marker on undifferentiated human embryonic stem cells. AB - Human embryonic stem cells (hESCs) have the capacity to remain pluripotent and self-renew indefinitely. To discover novel players in the maintenance of hESCs, we have previously reported the generation of monoclonal antibodies that bind to cell surface markers on hESCs, and not to mouse embryonic stem cells or differentiated embryoid bodies. In this study, we have identified the antigen target of one such monoclonal antibody as the epithelial cell adhesion molecule (EpCAM). In undifferentiated hESCs, EpCAM is localized to Octamer 4 (OCT4) positive pluripotent cells, and its expression is down-regulated upon differentiation. To further understand its biological function in hESCs, endogenous EpCAM expression was silenced using small interfering RNA. EpCAM knockdown had marginal negative effects on OCT4 and TRA-1-60 expression, however cell proliferation was decreased by >40%. Examination of lineage marker expression showed marked upregulation of endoderm and mesoderm genes in EpCAM silenced cells, under both pluripotent and differentiating conditions. These results were validated using a hESC line whose EpCAM expression has been stably knocked down. Data from the stable line confirmed that downregulation of EpCAM decreases cell growth and increases gene expression in the endoderm and mesoderm lineages. In vivo, hESCs lacking EpCAM were able to form teratomas containing tissues representing the three germ layers, and gene expression analysis yielded marked increase in the endoderm marker alpha fetoprotein compared with control. Together these data demonstrate that EpCAM is a surface marker on undifferentiated hESCs and plays functional roles in proliferation and differentiation. PMID- 19785010 TI - Motivational interviewing with perpetrators of intimate partner abuse. AB - Recent controlled trials have shown promising benefits of motivational interviewing (MI) as a pretreatment intervention for perpetrators of intimate partner violence (IPV). A 2-session intake, containing motivational interviewing and structured assessment feedback, was developed for this predominantly court mandated clientele. The goals were to reduce initial hostility toward treatment, facilitate verbalization of motivation to change, resolve ambivalence, and increase receptivity to structured group therapy for IPV. An extended case report illustrates the value of MI spirit and techniques, including empathic reflection, evocative questions, affirmation, and rolling with resistance, in achieving these intervention goals. PMID- 19785011 TI - Introduction to the special series on motivational interviewing and psychotherapy. AB - Clinical and research applications of motivational interviewing (MI) have grown at a remarkable pace over the past 25 years. Most of this work has targeted the addictions and health-related behaviors. The series of articles in this issue highlight a rapidly accelerating recent trend: the application of MI to other problems typically seen in clinical practice. This introductory article describes MI, its core principles, treatment methods, and the variety of ways in which it has been employed. The 6 case reports in this issue are then described. They illustrate how MI can be employed with generalized anxiety, adolescent depression, lifestyle changes, social anxiety disorder, suicidality, and intimate partner violence. The series of articles in this issue concludes with a commentary on the cases and a practice-friendly review of outcome research on MI. PMID- 19785012 TI - Motivational interviewing with a depressed adolescent. AB - Motivational interviewing (MI) is a potentially useful tool for clinicians who are exploring ways to improve treatment outcomes with depressed clients. MI techniques may be particularly appropriate with depressed adolescents, for whom motivation to engage in therapy is often a problem and who often experience ambivalence about life choices. The present article presents a case description of MI with a depressed adolescent who was ambivalent about what life change to pursue. MI was used to help the client identify conflicts between her values, learn how they were contributing to her distress, and move toward resolving them. Advantages and limitations of these techniques are discussed. PMID- 19785013 TI - CXCR2 mediates the recruitment of endothelial progenitor cells during allergic airways remodeling. AB - Airway remodeling is a central feature of asthma and includes the formation of new peribronchial blood vessels, which is termed angiogenesis. In a number of disease models, bone marrow-derived endothelial progenitor cells (EPCs) have been shown to contribute to the angiogenic response. In this study we set out to determine whether EPCs were recruited into the lungs in a model of allergic airways disease and to identify the factors regulating EPC trafficking in this model. We observed a significant increase in the number of peribronchial blood vessels at day 24, during the acute inflammatory phase of the model. This angiogenic response was associated with an increase in the quantity of EPCs recoverable from the lung. These EPCs formed colonies after 21 days in culture and were shown to express CD31, von Willebrand factor, and vascular endothelial growth factor (VEGF) receptor 2, but were negative for CD45 and CD14. The influx in EPCs was associated with a significant increase in the proangiogenic factors VEGF-A and the CXCR2 ligands, CXCL1 and CXCL2. However, we show directly that, while the CXCL1 and CXCL2 chemokines can recruit EPCs into the lungs of allergen sensitized mice, VEGF-A was ineffective in this respect. Further, the blockade of CXCR2 significantly reduced EPC numbers in the lungs after allergen exposure and led to a decrease in the numbers of peribronchial blood vessels after allergen challenge with no effect on inflammation. The data presented here provide in vivo evidence that CXCR2 is critical for both EPC recruitment and the angiogenic response in this model of allergic inflammation of the airways. PMID- 19785014 TI - Assessment of the effects of cellular tissue properties on ADC measurements by numerical simulation of water diffusion. AB - The apparent diffusion coefficient (ADC), as measured by diffusion-weighted MRI, has proven useful in the diagnosis and evaluation of ischemic stroke. The ADC of tissue water is reduced by 30-50% following ischemia and provides excellent contrast between normal and affected tissue. Despite its clinical utility, there is no consensus on the biophysical mechanism underlying the reduction in ADC. In this work, a numerical simulation of water diffusion is used to predict the effects of cellular tissue properties on experimentally measured ADC. The model indicates that the biophysical mechanisms responsible for changes in ADC postischemia depend upon the time over which diffusion is measured. At short diffusion times, the ADC is dependent upon the intrinsic intracellular diffusivity, while at longer, clinically relevant diffusion times, the ADC is highly dependent upon the cell volume fraction. The model also predicts that at clinically relevant diffusion times, the 30-50% drop in ADC after ischemia can be accounted for by cell swelling alone when intracellular T(2) is allowed to be shorter than extracellular T(2). PMID- 19785015 TI - Three-dimensional imaging of ventilation dynamics in asthmatics using multiecho projection acquisition with constrained reconstruction. AB - The purpose of this work is to detect dynamic gas trapping in three dimensions during forced exhalation at isotropic high spatial resolution and high temporal resolution using hyperpolarized helium-3 MRI. Ten subjects underwent hyperpolarized helium-3 MRI and multidetector CT. MRI was performed throughout inspiration, breath-hold, and forced expiration. A multiecho three-dimensional projection acquisition was used to improve data collection efficiency and an iterative constrained reconstruction was implemented to improve signal to noise ratio (SNR) and increase robustness to motion. Two radiologists evaluated the dynamic MRI and breath-held multidetector CT data for gas and air trapping, respectively. Phantom studies showed the proposed technique significantly improved depiction of moving objects compared to view-sharing methods. Gas trapping was detected using MRI in five of the six asthmatic subjects who displayed air trapping with multidetector CT. Locations in disagreement were found to represent small to moderate regions of air trapping. The proposed technique provides whole-lung three-dimensional imaging of respiration dynamics at high spatial and temporal resolution and compares well to the current standard, multidetector CT. While multidetector CT can provide information about static regional air trapping, it is unable to depict dynamics in a setting more comparable to a spirometry maneuver and explore the longitudinal time evolution of the trapped regions. PMID- 19785017 TI - Accelerating SENSE using compressed sensing. AB - Both parallel MRI and compressed sensing (CS) are emerging techniques to accelerate conventional MRI by reducing the number of acquired data. The combination of parallel MRI and CS for further acceleration is of great interest. In this paper, we propose a novel method to combine sensitivity encoding (SENSE), one of the standard methods for parallel MRI, and compressed sensing for rapid MR imaging (SparseMRI), a recently proposed method for applying CS in MR imaging with Cartesian trajectories. The proposed method, named CS-SENSE, sequentially reconstructs a set of aliased reduced-field-of-view images in each channel using SparseMRI and then reconstructs the final image from the aliased images using Cartesian SENSE. The results from simulations and phantom and in vivo experiments demonstrate that CS-SENSE can achieve a reduction factor higher than those achieved by SparseMRI and SENSE individually and outperform the existing method that combines parallel MRI and CS. PMID- 19785016 TI - Detection of lactate with a hadamard slice selected, selective multiple quantum coherence, chemical shift imaging sequence (HDMD-SelMQC-CSI) on a clinical MRI scanner: Application to tumors and muscle ischemia. AB - Lactate is an important metabolite in normal and malignant tissues detectable by NMR spectroscopy; however, it has been difficult to clinically detect the lactate methyl resonance because it is obscured by lipid resonances. The selective homonuclear multiple quantum coherence transfer technique offers a method for distinguishing lipid and lactate resonances. We implemented a three-dimensional selective homonuclear multiple quantum coherence transfer version with Hadamard slice selection and two-dimensional phase encoding (Hadamard encoded-selective homonuclear multiple quantum coherence transfer-chemical shift imaging) on a conventional clinical MR scanner. Hadamard slice selection is explained and demonstrated in vivo. This is followed by 1-cm(3) resolution lactate imaging with detection to 5-mM concentration in 20 min on a 3-T clinical scanner. An analysis of QSel gradient duration and amplitude effects on lactate and lipid signal is presented. To demonstrate clinical feasibility, a 5-min lactate scan of a patient with a non-Hodgkin's lymphoma in the superficial thigh is reported. The elevated lactate signal coincides with the T(2)-weighted image of this tumor. As a test of selective homonuclear multiple quantum coherence transfer sensitivity, a thigh tourniquet was applied to a normal volunteer and an increase in lactate was detected immediately after tourniquet flow constriction. In conclusion, the Hadamard encoded-selective homonuclear multiple quantum coherence transfer chemical shift imaging sequence is demonstrated on a phantom and in two lipid rich, clinically relevant, in vivo conditions. PMID- 19785018 TI - Experimental and numerical assessment of MRI-induced temperature change and SAR distributions in phantoms and in vivo. AB - It is important to accurately characterize the heating of tissues due to the radiofrequency energy applied during MRI. This has led to an increase in the use of numerical methods to predict specific energy absorption rate distributions for safety assurance in MRI. To ensure these methods are accurate for actual MRI coils, however, it is necessary to compare to experimental results. Here, we report results of some recent efforts to experimentally map temperature change and specific energy absorption rate in a phantom and in vivo where the only source of heat is the radiofrequency fields produced by the imaging coil. Results in a phantom match numerical simulation well, and preliminary results in vivo show measurable temperature increase. With further development, similar methods may be useful for verifying numerical methods for predicting specific energy absorption rate distributions and in some cases for directly measuring temperature changes and specific energy absorption rate induced by the radiofrequency fields in MRI experiments. PMID- 19785019 TI - Ex situ endorectal MRI probe for prostate imaging. AB - A unique ex situ MRI probe, which examines samples external to its geometry, is presented. The probe is intended to be used for imaging the prostate gland via an endorectal pathway. It has a semicylindrical shape with a length of 6 cm and typical diameter of approximately 3 cm. The probe's imaging field of view spans almost along its entire length and up to a distance of 2 cm away from its surface, with an angular sector of approximately 90 degrees . The detailed design of the probe is presented, followed by a set of representative results obtained by the current bench prototype of this system. PMID- 19785020 TI - Pattern recognition of MRSI data shows regions of glioma growth that agree with DTI markers of brain tumor infiltration. AB - Gliomas are the most common primary brain tumors and the majority are highly malignant, with one of the worst prognoses for patients. Gliomas are characterized by invasive growth into normal brain tissue that makes complete surgical resection and accurate radiotherapy planning extremely difficult. We have performed independent component analysis of magnetic resonance spectroscopy imaging data from human gliomas to segment brain tissue into tumor core, tumor infiltration, and normal brain, with confirmation by diffusion tensor imaging analysis. Our data are consistent with previous studies that compared anomalies in isotropic and anisotropic diffusion images to determine regions of potential glioma infiltration. We show that coefficients of independent components can be used to create colored images for easy visual identification of regions of infiltrative tumor growth. PMID- 19785021 TI - Hybrid adiabatic-rectangular pulse train for effective saturation of magnetization within the whole heart at 3 T. AB - Uniform T(1)-weighting is a major challenge for first-pass cardiac perfusion MRI at 3 T. Previously proposed adiabatic amplitude of radiofrequency field (B(1)) insensitive rotation (BIR-4) pulse and standard and tailored pulse trains of three nonselective pulses have been important developments but each pulse has limitations at 3 T. As an extension of the tailored pulse train, we developed a hybrid pulse train by synergistically combining two nonselective rectangular radiofrequency pulses and an adiabatic half-passage pulse, in order to achieve effective saturation of magnetization within the heart, while remaining within clinically acceptable specific absorption rate limits. The standard pulse train, tailored pulse train, hybrid pulse train, and BIR-4 pulse train were evaluated through numerical, phantom, and in vivo experiments. Among the four saturation pulses, only the hybrid pulse train yielded residual magnetization <2% of equilibrium magnetization in the heart while remaining within clinically acceptable specific absorption rate limits for multislice first-pass cardiac perfusion MRI at 3 T. PMID- 19785022 TI - Survivors of childhood cancer: an Australian audit of vaccination status after treatment. AB - BACKGROUND: Survivors of childhood and adolescent cancer are at risk of vaccine preventable diseases and are recommended to receive booster vaccinations post chemotherapy. The aim of this study was to describe the compliance of post chemotherapy revaccination of childhood cancer survivors relative to current Australian guidelines. PROCEDURES: A multi-faceted retrospective review of childhood cancer survivors at the Royal Children's Hospital, Melbourne, Australia was undertaken. Immunisation status was reviewed through four sources: (1) hospital records; (2) telephone survey of consenting participants; (3) Australian Childhood Immunization Register (ACIR); and (4) family practitioners immunisation records. Participants were 0-18 years, and at least 6 months post-treatment for their cancer. RESULTS: The study was conducted between March and September 2006. Eighty-nine patients with a median age at diagnosis of 5.3 years were included, 56% of patients had a diagnosis of leukaemia and 44% solid tumours. The median duration since completion of therapy was 3.1 years. Reviewing all sources, 39% (35/89) of participants had no evidence of booster vaccinations post-completion of therapy. Younger age (P = 0.001), and those diagnosed with leukaemia (P = 0.04) were more likely to have received at least one booster vaccine. Forty-seven percent (42/89) had received at least one influenza vaccination. CONCLUSION: This study highlights poor compliance with current guidelines for re-vaccination in survivors of childhood and adolescent cancer. More evidence is required and these re-vaccination guidelines need to take into account treatment intensity. Multi component strategies are essential to ensure protection from vaccine preventable diseases in this population. PMID- 19785023 TI - Peripheral blood stem cell mobilization with pegfilgrastim compared to filgrastim in children and young adults with malignancies. AB - BACKGROUND: Pegfilgrastim, the long acting agent of rh-GCSF, has been shown to be as effective as Filgrastim in children undergoing cytotoxic chemotherapy by reducing the duration of neutropenia. Recent studies in adults have also shown that Pegfilgrastim is effective to mobilize CD34+ stem cells, resulting in earlier peripheral stem cell collections (PSCC). The aim of the study was to compare the efficacy of Pegfilgrastim with Filgrastim for CD34+ stem cell mobilization in children. PROCEDURE: Three groups of patients were compared: Group 1: six patients with Ewing Sarcoma stimulated with Filgrastim; Group 2: five patients with Ewing Sarcoma, Ependymoma, and Neuroblastoma; Group 3: four patients with relapsed neoplasm. Patients of Group 2 and 3 were stimulated with Pegfilgrastim followed by peripheral stem cell collection. Two patients in Group 3 needed further cytokine stimulation with Filgrastim combined with stem cell factor, Ancestim. RESULTS: In Groups 1-3, a median of 4, 3, and 3 PSCC between day 12-24, 6-13, and 8-30 were performed, yielding a median of 14.2, 24.0, and 10.3 x 10(6) CD34+ stem cells/kg BW, respectively. CONCLUSIONS: Group 2 data show that stem cell mobilization with Pegfilgrastim in children when performed during primary or without previous long lasting chemotherapy seems to produce earlier CD34+ peaks and better CD34+ yields than in Group 1. CD34+ cell mobilization with Pegfilgrastim in Group 3-patients with previous long lasting chemotherapy was possible. PMID- 19785024 TI - Health related quality of life in sickle cell disease: just scratching the surface. PMID- 19785025 TI - Chronic idiopathic myelofibrosis with myeloid metaplasia presenting as refractory ascites. AB - Chronic idiopathic myelofibrosis (CIM) with myeloid metaplasia is a myeloproliferative disorder characterized by leukoerythroblastosis, tear drop erythrocytes, extra-medullary hematopoesis (EMH), and varying degree of myelofibrosis. CIM, presenting as refractory ascites secondary to peritoneal hematopoesis, is extremely rare with only six adult cases reported in literature. This is a report of a child with CIM presenting as refractory ascites as a consequence of EMH in the peritoneum. The patient was treated with intermittent hydroxyurea with favorable response over 3 weeks. The patient was thereafter lost to follow up. PMID- 19785026 TI - Low dose, oral epsilon aminocaproic acid for renal papillary necrosis and massive hemorrhage in hemoglobin SC disease. AB - Renal papillary necrosis in sickling hemoglobinopathies can lead to significant complications, including hemorrhage, obstruction, and infection. Despite its frequency, there are limited therapies for protracted hemorrhage. In the past, massive hemorrhage was managed with nephrectomy. Here, we report a patient with hemoglobin SC disease and prolonged, life-threatening hemorrhage from papillary necrosis successfully treated with oral, low-dose epsilon aminocaproic acid (EACA). Although further study is warranted, this case illustrates the need to consider EACA in the conservative management of renal papillary necrosis and significant hemorrhage in sickle cell hemoglobinopathies. PMID- 19785027 TI - Juvenile xanthogranuloma in a child with previously unsuspected neurofibromatosis type 1 and juvenile myelomonocytic leukemia. AB - The association of neurofibromatosis 1 (NF1), juvenile xanthogranulomas (JXG), and juvenile myelomonocytic leukemia (JMML) has been previously reported. We describe herein this triad in a Caucasian male infant with a pathogenic mutation in the NF1 gene (neurofibromin). The clinical course from initial presentation to final diagnosis is detailed; the physical features and hematologic characteristics are discussed. The patient underwent bone marrow transplantation and is currently in remission. Children with concurrent cutaneous cafe-au-lait and JXG lesions should be evaluated and monitored closely for the possible development of JMML. PMID- 19785028 TI - Perforin deficiency attenuates inflammation and tumor growth in colitis associated cancer. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) have a markedly increased risk to develop colon cancer, but there are only limited data about the host antitumor response in such colitis-associated cancer. In the present study we aimed at assessing the role of perforin-dependent effector mechanisms in the immune response in a murine model of colitis-associated colon cancer. METHODS: Wildtype and perforin-deficient mice were analyzed in a mouse model of colitis associated colon cancer using azoxymethane (AOM) and dextran sodium sulfate (DSS). RESULTS: Tumors of wildtype mice showed infiltration of CD4+, CD8+ T cells, natural killer (NK) cells, high numbers of apoptotic cells, and expression of the transcription factor eomesodermin and cytotoxic effector proteins, suggesting a potential role of the antitumor immune response in AOM/DSS tumorigenesis. Furthermore, perforin deficiency resulted in reduced apoptosis of epithelial cells as compared to wildtype mice, whereas tumor infiltration by NK cells, CD8+, and CD4+ T cells was unchanged. However, perforin-deficient mice surprisingly developed significantly fewer tumors than wildtype mice. Subsequent studies identified an important role of perforin in regulating colitis activity, as perforin deficiency caused a significant reduction of DSS colitis activity and proinflammatory cytokine production as compared to wildtype controls. CONCLUSIONS: Perforin is involved in both the antitumor immune response and the regulation of activity of mucosal inflammation in colitis-associated cancer. Our data emphasize the possible consequences for therapeutic strategies targeting colitis-associated colon cancer. PMID- 19785029 TI - Recombinant shrimp (Litopenaeus vannamei) trypsinogen production in Pichia pastoris. AB - Shrimp (Litopenaeus vannamei) trypsinogen has never been isolated from its natural source. To assess the production of L. vannamei trypsinogen, we engineered Pichia pastoris strains and evaluated two culture approaches with three induction culture media, to produce recombinant shrimp trypsinogen for the first time. The trypsinogen II cDNA was fused to the signal sequence of the Saccharomyces cerevisiae alpha mating factor, placed under the control of the P. pastoris AOX1 promoter, and integrated into the genome of P. pastoris host strain GS115. Using standard culture conditions for heterologous gene induction of a GS115 strain in shake flasks, recombinant shrimp trypsinogen was not detected by SDS-PAGE and Western blot analysis. Growth kinetics revealed a toxicity of recombinant shrimp trypsinogen or its activated form over the cell host. Thus, a different culture approach was tested for the induction step, involving the use of high cell density cultures, a higher frequency of methanol feeding (every 12 h), and a buffered minimal methanol medium supplemented with sorbitol or alanine; alanine supplemented medium was found to be more efficient. After 96 h of induction with alanine supplemented medium, a 29-kDa band from the cell-free culture medium was clearly observed by SDS-PAGE, and confirmed by Western blot to be shrimp trypsinogen, at a concentration of 14 microg/mL. Our results demonstrate that high density cell cultures with alanine in the induction medium allow the production of recombinant shrimp trypsinogen using the P. pastoris expression system, because of improved cell viability and greater stability of the recombinant trypsinogen. PMID- 19785030 TI - Rapid media transition: an experimental approach for steady state analysis of metabolic pathways. AB - Commonly steady state analysis of microbial metabolism is performed under well defined physiological conditions in continuous cultures with fixed external rates. However, most industrial bioprocesses are operated in fed-batch mode under non-stationary conditions, which cannot be realized in chemostat cultures. A novel experimental setup-rapid media transition-enables steady state perturbation of metabolism on a time scale of several minutes in parallel to operating bioprocesses. For this purpose, cells are separated from the production process and transferred into a lab-scale stirred-tank reactor with modified environmental conditions. This new approach was evaluated experimentally in four rapid media transition experiments with Escherichia coli from a fed-batch process. We tested the reaction to different carbon sources entering at various points of central metabolism. In all cases, the applied substrates (glucose, succinate, acetate, and pyruvate) were immediately utilized by the cells. Extracellular rates and metabolome data indicate a metabolic steady state during the short-term cultivation. Stoichiometric analysis revealed distribution of intracellular fluxes, which differs drastically subject to the applied carbon source. For some reactions, the variation of flux could be correlated to changes of metabolite concentrations. PMID- 19785031 TI - Smarcc1/Baf155 couples self-renewal gene repression with changes in chromatin structure in mouse embryonic stem cells. AB - Little is known about the molecular mechanism(s) governing differentiation decisions in embryonic stem cells (ESCs). To identify factors critical for ESC lineage formation, we carried out a functional genetic screen for factors affecting Nanog promoter activity during mESC differentiation. We report that members of the PBAF chromatin remodeling complex, including Smarca4/Brg1, Smarcb1/Baf47, Smarcc1/Baf155, and Smarce1/Baf57, are required for the repression of Nanog and other self-renewal gene expression upon mouse ESC (mESC) differentiation. Knockdown of Smarcc1 or Smarce1 suppressed loss of Nanog expression in multiple forms of differentiation. This effect occurred in the absence of self-renewal factors normally required for Nanog expression (e.g., Oct4), possibly indicating that changes in chromatin structure, rather than loss of self-renewal gene transcription per se, trigger differentiation. Consistent with this notion, mechanistic studies demonstrated that expression of Smarcc1 is necessary for heterochromatin formation and chromatin compaction during differentiation. Collectively, our data reveal that Smarcc1 plays important roles in facilitating mESCs differentiation by coupling gene repression with global and local changes in chromatin structure. PMID- 19785032 TI - Efficient transcriptional targeting of human hematopoietic stem cells and blood cell lineages by lentiviral vectors containing the regulatory element of the Wiskott-Aldrich syndrome gene. AB - The ability to effectively transduce human hematopoietic stem cells (HSCs) and to ensure adequate but "physiological" levels of transgene expression in different hematopoietic lineages represents some primary features of a gene-transfer vector. The ability to carry, integrate, and efficiently sustain transgene expression in HSCs strongly depends on the vector. We have constructed lentiviral vectors (LV) containing fragments of different lengths of the hematopoietic specific regulatory element of the Wiskott-Aldrich syndrome (WAS) gene-spanning approximately 1,600 and 170 bp-that direct enhanced green fluorescent protein (EGFP) expression. The performance of vectors carrying the 1,600 and 170 bp fragments of the WAS gene promoter was compared with that of a vector carrying the UbiquitinC promoter in human cord blood CD34(+) cells and their differentiated progeny both in vitro and in vivo in non-obese diabetic mice with severe combined immunodeficiency. All vectors displayed a similar transduction efficiency in CD34(+) cells and promoted long-term EGFP expression in different hematopoietic lineages, with an efficiency comparable to, and in some instances (for example, the 170-bp promoter) superior to, that of the UbiquitinC promoter. Our results clearly demonstrate that LV containing fragments of the WAS gene promoter/enhancer region can promote long-term transgene expression in different hematopoietic lineages in vitro and in vivo and represent suitable and highly efficient vectors for gene transfer in gene-therapy applications for different hematological diseases and for research purposes. In particular, the 170-bp carrying vector, for its reduced size, could significantly improve the transduction/expression of large-size genes. PMID- 19785033 TI - Exploration of human serum albumin binding sites by docking and molecular dynamics flexible ligand-protein interactions. AB - Five-nanosecond molecular dynamics (MD) simulations were performed on human serum albumin (HSA) to study the conformational features of its primary ligand binding sites (I and II). Additionally, 11 HSA snapshots were extracted every 0.5 ns to explore the binding affinity (K(d)) of 94 known HSA binding drugs using a blind docking procedure. MD simulations indicate that there is considerable flexibility for the protein, including the known sites I and II. Movements at HSA sites I and II were evidenced by structural analyses and docking simulations. The latter enabled the study and analysis of the HSA-ligand interactions of warfarin and ketoprofen (ligands binding to sites I and II, respectively) in greater detail. Our results indicate that the free energy values by docking (K(d) observed) depend upon the conformations of both HSA and the ligand. The 94 HSA-ligand binding K(d) values, obtained by the docking procedure, were subjected to a quantitative structure-activity relationship (QSAR) study by multiple regression analysis. The best correlation between the observed and QSAR theoretical (K(d) predicted) data was displayed at 2.5 ns. This study provides evidence that HSA binding sites I and II interact specifically with a variety of compounds through conformational adjustments of the protein structure in conjunction with ligand conformational adaptation to these sites. These results serve to explain the high ligand-promiscuity of HSA. PMID- 19785034 TI - Complement-derived anaphylatoxin C3a regulates in vitro differentiation and migration of neural progenitor cells. AB - Anaphylatoxin C3a is a third complement component (C3)-derived peptide, the multiple functions of which range from stimulation of inflammation to neuroprotection. In a previous study, we have shown that signaling through C3a receptor positively regulates in vivo neurogenesis in adult mouse brain. Here, we studied the direct effects of C3a on adult mouse whole brain-derived neural progenitor cells (NPCs) in vitro. Our results demonstrate that NPCs bind C3a in a specific and reversible manner and that C3a stimulates neuronal differentiation of NPCs. Furthermore, C3a stimulated the migration of NPCs induced by low concentrations of stromal cell-derived factor (SDF)-1alpha, whereas it inhibited NPC migration at high concentration of SDF-1alpha. In the same manner, C3a modulated SDF-1alpha-induced extracellular-signal-regulated kinases 1 and 2 (ERK1/2) phosphorylation in these cells. In addition, C3a had inhibitory effect on SDF-1alpha-induced neuronal differentiation of NPCs. These data show that C3a modulates SDF-1alpha-induced differentiation and migration of these cells, conceivably through the regulation of ERK1/2 phosphorylation. Our results provide the first evidence that C3a regulates neurogenesis by directly affecting the fate and properties of NPCs. PMID- 19785035 TI - A mesenchymal-like ZEB1(+) niche harbors dorsal radial glial fibrillary acidic protein-positive stem cells in the spinal cord. AB - In humans and rodents the adult spinal cord harbors neural stem cells located around the central canal. Their identity, precise location, and specific signaling are still ill-defined and controversial. We report here on a detailed analysis of this niche. Using microdissection and glial fibrillary acidic protein (GFAP)-green fluorescent protein (GFP) transgenic mice, we demonstrate that neural stem cells are mostly dorsally located GFAP(+) cells lying ependymally and subependymally that extend radial processes toward the pial surface. The niche also harbors doublecortin protein (Dcx)(+) Nkx6.1(+) neurons sending processes into the lumen. Cervical and lumbar spinal cord neural stem cells maintain expression of specific rostro-caudal Hox gene combinations and the niche shows high levels of signaling proteins (CD15, Jagged1, Hes1, differential screening selected gene aberrative in neuroblastoma [DAN]). More surprisingly, the niche displays mesenchymal traits such as expression of epithelial-mesenchymal transition zinc finger E-box-binding protein 1 (ZEB1) transcription factor and smooth muscle actin. We found ZEB1 to be essential for neural stem cell survival in vitro. Proliferation within the niche progressively ceases around 13 weeks when the spinal cord reaches its final size, suggesting an active role in postnatal development. In addition to hippocampus and subventricular zone niches, adult spinal cord constitutes a third central nervous system stem cell niche with specific signaling, cellular, and structural characteristics that could possibly be manipulated to alleviate spinal cord traumatic and degenerative diseases. PMID- 19785036 TI - Cross-talk between stem cells and the dysfunctional brain is facilitated by manipulating the niche: evidence from an adhesion molecule. AB - In the injured brain, the behavior of neural stem/progenitor cells (NSCs) is regulated by multiple converging factors encountered in the niche, which is composed of several neural and non-neural cell types. Signals emanating from the host influence the migration, survival, distribution, and fate of transplanted NSCs, which in turn can create host microenvironments that favor a return to homeostasis. We tested the hypothesis that overexpression of key facilitatory molecules that define the injury niche might enhance this bidirectional stem cell host interaction to therapeutic advantage. As proof of concept, we investigated whether conditioning the niche with the neural cell adhesion molecule L1 might enhance recovery in a prototypical neurodegenerative milieu-the MPTP-induced model of Parkinson's disease in aged mice-where cross-talk between NSCs and imperiled host dopaminergic neurons is known to be pivotal in rescuing the function and connectivity of the latter. In lesioned mice (and in unlesioned controls), we overexpressed L1 in the NSCs to be transplanted into the ventral mesencephalon. Several pairwise experimental combinations were tested based on variations of engrafting L1 overexpressing versus nonoverexpressing NSCs into wild-type (WT) versus L1-overexpressing transgenic mice (specifically L1 transcribed from the GFAP promoter and, hence, overexpressed in host astrocytes). Enrichment for L1-particularly when expressed simultaneously in both donor NSCs and host brain-led to rapid and extensive distribution of exogenous NSCs, which in turn rescued (with an efficacy greater than in nonengineered controls) dysfunctional host dopaminergic nigral neurons, even when grafting was delayed by a month. L1 overexpression by NSCs also enhanced their own differentiation into tyrosine hydroxylase-expressing neurons in both WT and transgenic hosts. Graft host interactions were thus favored by progressively increasing levels of L1. More broadly, this study supports the view that manipulating components of the niche (such as an adhesion molecule) that facilitate cross-talk between stem cells and the dysfunctional brain may offer new strategies for more efficacious neurotransplantation, particularly when treatment is delayed as in chronic lesions or advanced stages of a neurodegenerative disease. PMID- 19785037 TI - Enhanced hematovascular contribution of SCL 3' enhancer expressing fetal liver cells uncovers their potential to integrate in extramedullary adult niches. AB - Fetal liver (FL) hematopoietic progenitors have superior blood engraftment competence compared with adult bone marrow (BM), however less is known about FL in vivo vascular capacity. Here we show in transplantation assays that FL cells possess enhanced vascular endothelial potential compared with adult bone marrow. We generated high-level hematopoietic chimeras using donor cells from mice transgenic for the stem cell leukaemia 3' enhancer human placental alkaline phosphatase (SCL3'Enh-PLAP) reporter construct, active in vascular endothelium, and blood progenitor and stem cells. Long-term lineage tracing analysis revealed PLAP(+) vascular-like patches in FL-derived chimeras, whereas adult BM-derived chimeras presented only rare and scattered PLAP(+) cells. PLAP(+) vascular-like patches were formed following transplantation into both newborn and adult recipient mice, although their frequency was reduced in adult recipients. Confocal analysis of multiple labeled tissues revealed that whereas most liver and heart PLAP(+) vascular patch-associated cells were endothelial, PLAP(+) vascular patches in the kidney contained endothelial, hematopoietic, and putative hemangioblastic cells. Moreover, fluorescence-activated cell sorting assays showed that only FL PLAP(bright+) donor cells can generate PLAP(+) vascular patches upon transplantation. Taken together, these data demonstrate superior vascular contribution potential of FL cells, and not only provide new insights into the developmental pathways controlling endothelial development but also may prove informative when addressing the mechanisms involved in vascular regeneration and hemangiogenic recovery in a clinical context. PMID- 19785039 TI - Studies of lysozyme binding to histamine as a ligand for hydrophobic charge induction chromatography. AB - Histamine was immobilized on Sepharose CL-6B (Sepharose) for use as a ligand of hydrophobic charge induction chromatography (HCIC) of proteins. Lysozyme adsorption onto Histamine-Sepharose (HA-S) was studied by adsorption equilibrium and calorimetry to uncover the thermodynamic mechanism of the protein binding. In both the experiments, the influence of salt (ammonium sulfate and sodium sulfate) was examined. Adsorption isotherms showed that HA-S exhibited a high salt tolerance in lysozyme adsorption. This property was well explained by the combined contributions of hydrophobic interaction and aromatic stacking. The isotherms were well fitted to the Langmuir equation, and the equilibrium parameters for lysozyme adsorption were obtained. In addition, thermodynamic parameters (DeltaH(ads), DeltaS(ads), and DeltaG(ads)) for the adsorption were obtained by isothermal titration calorimetry by titrating lysozyme solutions into the adsorbent suspension. Furthermore, free histamine was titrated into lysozyme solution in the same salt-buffers. Compared with the binding of lysozyme to free histamine, lysozyme adsorption onto HA-S was characterized by a less favorable DeltaG(ads) and an unfavorable DeltaS(ads) because histamine was covalently attached to Sepharose via a three-carbon-chain spacer. Consequently, the immobilized histamine could only associate with the residues on the protein surface rather than those in the hydrophobic pocket, causing a less favorable orientation between histamine and lysozyme. Further comparison of thermodynamic parameters indicated that the unfavorable DeltaS(ads) was offset by a favorable DeltaH(ads), thus exhibiting typical enthalpy-entropy compensation. Moreover, thermodynamic analyses indicated the importance of the dehydration of lysozyme molecule and HA-S during the adsorption and a substantial conformational change of the protein during adsorption. The results have provided clear insights into the adsorption mechanisms of lysozyme onto the new HCIC material. PMID- 19785038 TI - Insulin but not glucagon gene is silenced in human pancreas-derived mesenchymal stem cells. AB - We previously characterized human islet-derived precursor cells (hIPCs) as a specific type of mesenchymal stem cell capable of differentiating to insulin (INS)- and glucagon (GCG)-expressing cells. However, during proliferative expansion, INS transcript becomes undetectable and then cannot be induced, a phenomenon consistent with silencing of the INS gene. We explored this possibility by determining whether ectopic expression of transcription factors known to induce transcription of this gene in beta cells, pancreatic and duodenal homeobox factor 1 (Pdx1), V-maf musculoaponeurotic fibrosarcoma oncogene homolog A (Mafa), and neurogenic differentiation 1 (Neurod1), would activate INS gene expression in long-term hIPC cultures. Coexpression of all three transcription factors had little effect on INS mRNA levels but unexpectedly increased GCG mRNA at least 100,000-fold. In contrast to the endogenous promoter, an exogenous rat INS promoter was activated by expression of Pdx1 and Mafa in hIPCs. Chromatin immunoprecipitation (ChIP) assays using antibodies directed at posttranslationally modified histones show that regions of the INS and GCG genes have similar levels of activation-associated modifications but the INS gene has higher levels of repression-associated modifications. Furthermore, the INS gene was found to be less accessible to micrococcal nuclease digestion than the GCG gene. Lastly, ChIP assays show that exogenously expressed Pdx1 and Mafa bind at very low levels to the INS promoter and at 20- to 25-fold higher levels to the GCG promoter in hIPCs. We conclude that the INS gene in hIPCs is modified epigenetically ("silenced") so that it is resistant to activation by transcription factors. PMID- 19785040 TI - Process intensification for the removal of poly-histidine fusion tags from recombinant proteins by an exopeptidase. AB - This study describes the use of a hexa-histidine tagged exopeptidase for the cleavage of hexa-histidine tags from recombinant maltose binding protein (MBP) when both tagged species are bound to an immobilized metal affinity chromatography (IMAC) matrix. On-column exopeptidase cleavage only occurred when the cleavage buffer contained an imidazole concentration of 50 mM or higher. Two strategies were tested for the on-column tag cleavage by dipeptidylaminopeptidase (DAPase): (i) a post-load wash was performed after sample loading using cleavage buffers containing varying imidazole concentrations and (ii) a post-load wash was omitted following sample loading. In the presence of 50 mM imidazole, 46% of the originally adsorbed hexa-histidine tagged MBP was cleaved, released from the column, and recovered in a sample containing 100% native (i.e., completely detagged) MBP. This strategy renders the subsequent purification steps unnecessary as any tagged contaminants remained bound to the column. At higher imidazole concentrations, binding of both hexa-histidine tagged MBP and DAPase to the column was minimized, leading to characteristics of cleavage more closely resembling that of a batch cleavage. An on-column cleavage yield of 93% was achieved in the presence of 300 mM imidazole, albeit with contamination of the detagged protein with tag fragments and partially tagged MBP. The success of the on-column exopeptidase cleavage makes the integration of the poly-histidine tag removal protocol within the IMAC protein capture step possible. The many benefits of using commercially available exopeptidases, such as DAPase, for poly-histidine tag removal can now be combined with the on-column tag cleavage operation. PMID- 19785041 TI - An economic comparison of different fermentation configurations to convert corn stover to ethanol using Z. mobilis and Saccharomyces. AB - Numerous routes are being explored to lower the cost of cellulosic ethanol production and enable large-scale production. One critical area is the development of robust cofermentative organisms to convert the multiple, mixed sugars found in biomass feedstocks to ethanol at high yields and titers without the need for processing to remove inhibitors. Until such microorganisms are commercialized, the challenge is to design processes that exploit the current microorganisms' strengths. This study explored various process configurations tailored to take advantage of the specific capabilities of three microorganisms, Z. mobilis 8b, S. cerevisiae, and S. pastorianus. A technoeconomic study, based on bench-scale experimental data generated by integrated process testing, was completed to understand the resulting costs of the different process configurations. The configurations included whole slurry fermentation with a coculture, and separate cellulose simultaneous saccharification and fermentation (SSF) and xylose fermentations with none, some or all of the water to the SSF replaced with the fermented liquor from the xylose fermentation. The difference between the highest and lowest ethanol cost for the different experimental process configurations studied was $0.27 per gallon ethanol. Separate fermentation of solid and liquor streams with recycle of fermented liquor to dilute the solids gave the lowest ethanol cost, primarily because this option achieved the highest concentrations of ethanol after fermentation. Further studies, using methods similar to ones employed here, can help understand and improve the performance and hence the economics of integrated processes involving enzymes and fermentative microorganisms. PMID- 19785042 TI - Centrifugal seeding of mammalian cells in nonwoven fibrous matrices. AB - Three-dimensional (3D) cell cultures have many advantages over two-dimensional cultures. However, seeding cells in 3D scaffolds such as nonwoven fibrous polyethylene terephthalate (PET) matrices has been a challenge task in tissue engineering and cell culture bioprocessing. In this study, a centrifugal seeding method was investigated to improve the cell seeding efficiency in PET matrices with two different porosities (93% and 88%). Both the centrifugal force and centrifugation time were found to affect the seeding efficiency. With an appropriate centrifugation speed, a high 80-90% cell seeding efficiency was achieved and the time to reach this high seeding efficiency was less than 5 min. The seeding efficiency was similar for matrices with different porosities, although the optimal seeding time was significantly shorter for the low-porosity scaffold. Post seeding cell viability was demonstrated by culturing colon cancer cells seeded in PET matrices for over 5 days. The centrifugal seeding method developed in this work can be used to efficiently and uniformly seed small fibrous scaffolds for applications in 3D cell-based assays for high-throughput screening. PMID- 19785043 TI - Correlation between Etest, disk diffusion, and microdilution methods for antifungal susceptibility testing of Candida species from infection and colonization. AB - The correlation between the microdilution (MD), Etest (ET), and disk diffusion (DD) methods was determined for amphotericin B, itraconazole and fluconazole. The minimal inhibitory concentration (MIC) of those antifungal agents was established for a total of 70 Candida spp. isolates from colonization and infection. The species distribution was: Candida albicans (n=27), C. tropicalis (n=17), C. glabrata (n=16), C. parapsilosis (n=8), and C. lusitaniae (n=2). Non-Candida albicans Candida species showed higher MICs for the three antifungal agents when compared with C. albicans isolates. The overall concordance (based on the MIC value obtained within two dilutions) between the ET and the MD method was 83% for amphotericin B, 63% for itraconazole, and 64% for fluconazole. Considering the breakpoint, the agreement between the DD and MD methods was 71% for itraconazole and 67% for fluconazole. The DD zone diameters are highly reproducible and correlate well with the MD method, making agar-based methods a viable alternative to MD for susceptibility testing. However, data on agar-based tests for itraconazole and amphotericin B are yet scarce. Thus, further research must still be carried out to ensure the standardization to other antifungal agents. PMID- 19785044 TI - Search similar protein structures with classification, sequence and 3d alignments. AB - We have developed an algorithm and web tool to search similar protein structures in the PDB (Protein Data Bank). The algorithm is a combination of a series of methods including protein classification, geometric feature extraction, sequence alignment, and 3D structure alignment. Given a protein structure, the tool can efficiently discover similar structures from hundreds of thousands of structures stored in the PDB. Our experimental results show that it is more accurate than other well-known protein search systems including PSI-BLAST, 3D-BLAST, and SSM in finding proteins that are structurally similar to the query protein, and its speed is also competitive with those systems. The algorithm has been fully implemented and is accessible online at the address http://fpsa.cs.panam.edu/, which is supported by a cluster of computers. PMID- 19785045 TI - Protein fold classification with genetic algorithms and feature selection. AB - Protein fold classification is a key step to predicting protein tertiary structures. This paper proposes a novel approach based on genetic algorithms and feature selection to classifying protein folds. Our dataset is divided into a training dataset and a test dataset. Each individual for the genetic algorithms represents a selection function of the feature vectors of the training dataset. A support vector machine is applied to each individual to evaluate the fitness value (fold classification rate) of each individual. The aim of the genetic algorithms is to search for the best individual that produces the highest fold classification rate. The best individual is then applied to the feature vectors of the test dataset and a support vector machine is built to classify protein folds based on selected features. Our experimental results on Ding and Dubchak's benchmark dataset of 27-class folds show that our approach achieves an accuracy of 71.28%, which outperforms current state-of-the-art protein fold predictors. PMID- 19785046 TI - Predicting local quality of a sequence-structure alignment. AB - Although protein structure prediction has made great progress in recent years, a protein model derived from automated prediction methods is subject to various errors. As methods for structure prediction develop, a continuing problem is how to evaluate the quality of a protein model, especially to identify some well predicted regions of the model, so that the structural biology community can benefit from the automated structure prediction. It is also important to identify badly-predicted regions in a model so that some refinement measurements can be applied to it. We present two complementary techniques, FragQA and PosQA, to accurately predict local quality of a sequence-structure (i.e. sequence-template) alignment generated by comparative modeling (i.e. homology modeling and threading). FragQA and PosQA predict local quality from two different perspectives. Different from existing methods, FragQA directly predicts cRMSD between a continuously aligned fragment determined by an alignment and the corresponding fragment in the native structure, while PosQA predicts the quality of an individual aligned position. Both FragQA and PosQA use an SVM (Support Vector Machine) regression method to perform prediction using similar information extracted from a single given alignment. Experimental results demonstrate that FragQA performs well on predicting local fragment quality, and PosQA outperforms two top-notch methods, ProQres and ProQprof. Our results indicate that (1) local quality can be predicted well; (2) local sequence evolutionary information (i.e. sequence similarity) is the major factor in predicting local quality; and (3) structural information such as solvent accessibility and secondary structure helps to improve the prediction performance. PMID- 19785047 TI - Efficient simulation of ligand-receptor binding processes using the conformation dynamics approach. AB - The understanding of biological ligand-receptor binding processes is relevant for a variety of research topics and assists the rational design of novel drug molecules. Computer simulation can help to advance this understanding, but, due to the high dimensionality of according systems, suffers from the severe computational cost. Based on the framework provided by conformation dynamics and transition state theory, a novel heuristic approach of simulating ligand-receptor binding processes is introduced, which is not dependent on calculating lengthy molecular dynamics trajectories. First, the relevant portion of conformational space is partitioned with meshless methods. Then, each region is sampled separately, using hybrid Monte Carlo. Finally, the dynamical binding process is reconstructed from the static overlaps between the partial densities obtained in the sampling step. The method characterizes the metastable steps of the binding process and can yield the corresponding transition probabilities. PMID- 19785048 TI - Iterative two-pass algorithm for missing data imputation in SNP arrays. AB - Though nowadays high-throughput genotyping techniques' quality improves, missing data still remains fairly common. Studies have shown that even a low percentage of missing SNPs is detrimental to the reliability of down-stream analyses such as SNP-disease association tests. This paper investigates the potentiality for improving the accuracy of an SNP inference method based on the algorithm formerly designed by Roberts and co-workers (NPUTE, 2007). This initial algorithm performs a single scan of an SNP array, inferring missing SNPs in the context of sliding windows. We have first designed a variant, KNNWinOpti, which fully exploits backward and forward dependencies between the overlapping windows and thus restores the genuine dependency of inference upon direction scanning. Our major contribution, algorithm SNPShuttle, therefore iterates bi-directional scanning to predict SNP values with more confidence. We have run simulations on realistic benchmarks built after the high resolution map of mouse strains published by the Perlegen Project. For each of the 20 mouse chromosomes and for missing data percentage varying in range 5%-30%, SNPShuttle has always been shown to increase yet high KNNWinOpti's accuracies. PMID- 19785049 TI - A novel coherence measure for discovering scaling biclusters from gene expression data. AB - Biclustering methods are used to identify a subset of genes that are co-regulated in a subset of experimental conditions in microarray gene expression data. Many biclustering algorithms rely on optimizing mean squared residue to discover biclusters from a gene expression dataset. Recently it has been proved that mean squared residue is only good in capturing constant and shifting biclusters. However, scaling biclusters cannot be detected using this metric. In this article, a new coherence measure called scaling mean squared residue (SMSR) is proposed. Theoretically it has been proved that the proposed new measure is able to detect the scaling patterns effectively and it is invariant to local or global scaling of the input dataset. The effectiveness of the proposed coherence measure in detecting scaling patterns has been demonstrated experimentally on artificial and real-life benchmark gene expression datasets. Moreover, biological significance tests have been conducted to show that the biclusters identified using the proposed measure are composed of functionally enriched sets of genes. PMID- 19785051 TI - A note on the calculation of N-statistics. AB - A class of statistics suitable for testing against equality of multivariate distributions is described by Klebanov and co-workers in 2007. Referred to as N statistics, their discriminating ability is based on various forms of distance kernels in R(d), the intention being to capture distinct forms of deviation from equality. This makes them particularly suitable for large-scale genomic screening applications, in which such variety of alternatives can be anticipated. One of these kernels, denoted as L(4), introduces weighting by directional densities, hence the evaluation of L(4) requires integration on the unit sphere in R(d). In this note we introduce a methodology for the evaluation of integrals related to L(4). It is shown that for a class of directional densities including, but not limited to, the uniform density L(4) reduces to Euclidean distance. For other cases, the methodology permits a direct interpretation of L(4) in terms of the directional weighting. PMID- 19785050 TI - Asymptotics of canonical and saturated RNA secondary structures. AB - It is a classical result of Stein and Waterman that the asymptotic number of RNA secondary structures is 1.104366 . n(-3/2) . 2.618034(n). In this paper, we study combinatorial asymptotics for two special subclasses of RNA secondary structures canonical and saturated structures. Canonical secondary structures are defined to have no lonely (isolated) base pairs. This class of secondary structures was introduced by Bompfunewerer et al., who noted that the run time of Vienna RNA Package is substantially reduced when restricting computations to canonical structures. Here we provide an explanation for the speed-up, by proving that the asymptotic number of canonical RNA secondary structures is 2.1614 . n(-3/2) . 1.96798(n) and that the expected number of base pairs in a canonical secondary structure is 0.31724 . n. The asymptotic number of canonical secondary structures was obtained much earlier by Hofacker, Schuster and Stadler using a different method. Saturated secondary structures have the property that no base pairs can be added without violating the definition of secondary structure (i.e. introducing a pseudoknot or base triple). Here we show that the asymptotic number of saturated structures is 1.07427 . n(-3/2) . 2.35467(n), the asymptotic expected number of base pairs is 0.337361 . n, and the asymptotic number of saturated stem-loop structures is 0.323954 . 1.69562(n), in contrast to the number 2(n - 2) of (arbitrary) stem-loop structures as classically computed by Stein and Waterman. Finally, we apply the work of Drmota to show that the density of states for [all resp. canonical resp. saturated] secondary structures is asymptotically Gaussian. We introduce a stochastic greedy method to sample random saturated structures, called quasi-random saturated structures, and show that the expected number of base pairs is 0.340633 . n. PMID- 19785052 TI - How immunotherapy can enhance the response to other modalities and improve outcome and quality of life. AB - Early studies suggested that the induction of an effective immune response could lead to elimination of residual tumour. Over a hundred years ago Coley invented his eponymous named "toxins" that appeared to induce a strong inflammatory response, leading to tumour reduction. Subsequent attempts to enhance the immune response have essentially been on a vaccine basis, trying to induce a specific response against the tumour. Numerous vaccine approaches have claimed to give significant clinical benefit in clinical response but very few of these have survived a randomised trial. A major reason for this is the heterogeneity of many tumours, as well as the various forms of defence against an immune response that they employ. It was thought that chemotherapy and radiotherapy were mutually exclusive for immunotherapy using the vaccine approach. More recently, however, it has become appreciated that vaccine approaches may enhance subsequent responses to radiotherapy and that certain chemotherapies actually enhance responses to vaccines. It has been suggested that one of the mechanisms of action of chemotherapy is to reduce the cells that suppress T-cells. These cells primarily defend the tumour from an immunological attack, but more recently it has been suggested that the benefit may encompass other aspects, such as enhancing antiangiogenic responses. One reason why immunostimulatory approaches may be so useful in cancer is that many cancers evolve out of a chronic inflammatory environment that actively suppresses cell mediated immune responses and enhances tumour angiogenesis. An ideal cancer drug would therefore be expected to have these properties. One such drug is lenalidomide, which features include marked immune stimulatory properties as well being able to inhibit regulatory T-cells. They have also been shown to enhance anticancer activity with vaccines in both preclinical models and more recently in clinical observations, where the responses to vaccines in patients with myeloma is much higher when they are on lenalidomide than other treatments. A number of regularly used chemotherapy regimens have marked activity in modulating the immune response. These maybe of benefit and the regimens will be reviewed, which include gemcitabine, cyclophosphamide and the IMiDs. PMID- 19785053 TI - Polarization of human monocyte-derived dendritic cells to DC1 by in vitro stimulation with Newcastle Disease Virus. AB - PURPOSE: Dendritic cell (DC)-based tumor vaccines have been tested extensively to treat cancer patients. However, the results of several DC-based clinical trials have been disappointing. Amelioration of such a modality for cancer treatment seems warranted, i.e. by improving DC immunogenicity and polarization. The goal of our study was to evaluate the potential for immune activation of human DCs by incubating them in vitro with the Newcastle Disease Virus (NDV), a paramyxovirus with strong immunostimulatory properties. RESULTS: In vitro infection with NDV of human monocyte-derived DCs--generated from peripheral monocytes cultured with IL 4 and GM-CSF--induces the generation of viral M gene transcripts and RIG-I expression within DCs. Expression of both genes was increased upon co-stimulation with LPS. Surprisingly, LPS and NDV had opposite effects on induction of interferon (IFN)-alpha. Furthermore, NDV induced DC maturation (as measured by TNF-alpha production and CD80 cell surface expression) only in the presence of LPS. Most interestingly, an optimal combination of NDV and LPS caused polarization of the DCs to Th1 type cytokines with a high ratio of interleukin (IL)-12 to IL-10. CONCLUSION: These in vitro results provide a means and protocol for maturation and activation of DCs with enhanced and sustained T helper type 1 polarizing capacity. Such pretreated DCs may significantly improve DC-based cancer immunotherapy. The data encourage the use of RNA-based viral vectors as potential novel and powerful gene transfer modality for cytoplasmic gene expression in professional antigen-presenting cells (APC) to overcome immunosuppression in cancer patients. PMID- 19785054 TI - Targeting innate immune pathways in cancer immunotherapy: state of the art. AB - Complement-based cancer immunotherapy is gaining momentum in recent years due to the growing number of therapeutic anti-tumor antibodies that are receiving approval for clinical trials and are currently used in clinical cancer care. Even though some anti-tumor antibodies have shown moderate therapeutic efficacy, most of them still lag behind, having failed to produce adequately effective responses. The urging need for a therapeutic platform that will enhance both the humoral and cellular effects of antibody treatment prompts the design of more effective combinatorial therapeutics for enhancing complement-mediated tumor cytotoxicity in cancer patients. Cancer cells express or "sequester" host membrane-bound and fluid-phase complement regulators in order to evade complement attack and establish an immunosuppressive microenvironment for tumor growth. Moreover, membrane complement regulators appear to modulate several aspects of T cell immunity that are relevant to the anti-tumor, adaptive T-cell response. Recently, the concept that complement activation is unfavorable for tumor growth has been drastically challenged by evidence that points to a novel immunomodulatory role of complement in the tumor microenvironment. Taken together, these findings form a new conceptual framework that integrates innate immunity to cancer development. Furthermore, they are anticipated to lead to the rational design of strategies that will exploit innate immune systems, such as complement, in a patient-oriented, "individualized" manner for effective cancer immunotherapy. PMID- 19785055 TI - The chemokine system and its contribution to leukemogenesis and treatment responsiveness in patients with acute myeloid leukemia. AB - The chemokine family consists of approximately 50 small (8-14 kDa), basic proteins that are expressed and released by a wide range of normal and malignant cells. Most chemokines act through heptahelical transmembrane G protein- coupled receptors. Based on their molecular structure these cytokines are divided into the two major subgroups CCL and CXCL chemokines that bind to CCR or CXCR receptors respectively. Primary human acute myelogenous leukemia (AML) cells show constitutive release of a wide range of chemokines, but the chemokine release profile differs between patients. Among the commonly expressed chemokines are proangiogenic CXCL8, antiangiogenic CXCL4/9-11 and several leukocyte-chemotactic chemokines. Systemic serum levels of leukocyte-chemotactic chemokines depend both on patient age, disease status, the chemotherapy regimen and development of complicating infections. The local chemokine network in human AML is probably further modulated by the hypoxic bone marrow microenvironment and the local release of chemokines by nonleukemic bone marrow stromal cells. Usually primary AML cells also express several chemokine receptors. Specific chemokine inhibitors are now being developed, including chemokine-neutralizing or receptor-blocking antibodies, antisense strategies, receptor-blocking small molecules or inhibitors of downstream signaling. The use of CXCR4-antagonists for mobilization of peripheral blood stem cells has been documented in several clinical studies. Although animal studies suggest that chemokine inhibition also may become useful in the treatment of graft versus host disease, the possible use of chemokine targeting therapy for other indications than stem cell mobilization requires further studies. PMID- 19785056 TI - Vector vaccination and vector targeted chemotherapy in solid tumors. AB - Gene therapy is one of the promising treatment modalities in cancer therapy. The current gene therapy modalities are mainly focused on the introduction of suppressed tumor suppressor genes into cancer cells, modulation of anti-tumoral immune response, and the suicide gene therapy by introducing pro-drug-activating enzyme genes into the tumor cells. Currently, various gene therapy trials are being conducted in cancer patients. However, the early results of these trials conducted so far are not so encouraging. Combination of gene therapy strategies with conventional treatment modalities such as chemotherapy, immunotherapy or radiotherapy has yielded encouraging results in experimental models and early clinical trials. PMID- 19785057 TI - Clinical relevance of monoclonal antibodies in non small cell lung cancer. AB - Targeted therapies with monoclonal antibodies have been shown to improve the outcome of non-small cell lung cancer (NSCLC). Current strategies focus on the blockade of growth factor receptors and the inhibition of angiogenesis. Epidermal growth factor receptor (EGFR)-directed monoclonal antibodies in combination with platinum-based first-line chemotherapy have shown promising efficacy in phase II trials. In a phase III trial, cetuximab combined with cisplatin/ vinorelbine resulted in superior survival compared to chemotherapy alone in patients with advanced EGFR-positive NSCLC. Inhibition of angiogenesis has also been successfully applied as a new treatment strategy. Bevacizumab added to palliative chemotherapy has improved progression-free survival in two phase III trials and overall survival in one of these trials in selected patients with advanced non squamous cell lung cancer. Bevacizumab is now approved for selected patients with advanced NSCLC in combination with platinum-based chemotherapy. Figitumumab is a monoclonal antibody against the insulin-like growth factor-1 receptor (IGF-1R) which demonstrated activity in preclinical models of NSCLC and in a phase II trial. Because of these promising results, three randomized, open-label, international phase III trials of figitumumab in patients with locally advanced or metastatic NSCLC are in progress. PMID- 19785058 TI - Tumor specific CD8+ T cells in patients with lung cancer and healthy individuals. AB - Lung cancer, one of the leading causes of cancer death in the developed world, presents with a poor 5-year survival, despite improvements in conventional treatments such as surgery, radiotherapy and chemotherapy. Lung cancer-directed immunotherapy promises to harness the body's ability to mount antitumor immune responses and destroy cancer cells. Improving our understanding of tumor biology and the host immune response promises to have a positive impact on the development of novel therapeutic strategies for this disease. This article will present our current understanding on immunotherapy from the perspective of the CD8+ cytolytic T cell response in lung cancer and how elucidation of the mechanisms that affect T-cell memory lineage commitment could improve the outcome of current immunotherapeutic attempts. PMID- 19785059 TI - Controversies around the use of monoclonal antibodies in the treatment of advanced non-small cell lung cancer. AB - First line combination chemotherapy (CT) using platinum-based doublets is established as a standard of care for advanced non-small cell lung cancer (NSCLC). Nevertheless, no significant advances have been recorded during the last years in this field. Therefore, there is a wide consensus among physicians that a plateau has already been reached with this strategy. Targeted therapy using tyrosine-kinase inhibitors (TKIs) and monoclonal antibodies emerged as a new field of development in the NSCLC therapeutics. Recently, the results of the phase III trials testing antibodies against vascular endothelial growth factor VEGF (bevacizumab) and epidermal growth factor receptor-EGFR (cetuximab) challenged the paradigm of the platinum doublets as a gold standard in advanced NSCLC. Their appearance was enthusiastically commended both by patients and the oncological community. However, all medical oncologists have the responsibility to carefully analyze the real benefits of these new agents, to balance the advantages against the implicit risks of therapy and to make the decision having in mind the best interest of their patients. Last but not least, the associated health economic burden should also be considered. This paper addresses some issues related to the use of cetuximab and bevacizumab in advanced NSCLC. The main controversial aspects regarding patient selection, the real benefit of therapy, the molecular and clinical predictors, and the impact of other independent variables are carefully examined and presented. Due to many unsolved questions, no definite conclusions can be supported. The final decision about the optimal use of these agents is left to the clinical judgment of each treating physician. PMID- 19785060 TI - Therapeutic cancer vaccines in cervical cancer: phase I study of Lovaxin-C. AB - Producing effective therapeutic vaccines has proved much more difficult and challenging than developing cancer preventive vaccines. Despite huge research in the area of cancer immunology, FDA/EMEA have not approved any type of cancer treatment vaccine so far. More than 99% of cervical cancers have detectable amounts of human papillomavirus (HPV) DNA. Integration of high-risk HPV into the host cell genome is followed by continual expression of HPV E6 and E7 oncoproteins, making them excellent targets for developing vaccines which could be used in high grade precancerous (CIN) lesions or invasive cancer or in the prevention of cancer recurrence. Therapeutic cervical cancer vaccines have been extensively studied. Strategies used were vaccination with HPV peptides or proteins, alone or in pulsed dendritic cells, DNA vaccines, virus-like particles or viral and bacterial vectors. Lovaxin-C is a recombinant live-attenuated Listeria monocytogenes (Lm) that secretes the antigen HPV-16 E7 fused to a non hemolytic listeriolysin O protein. In a phase I study Lovaxin-C was administered to advanced cervical cancer patients refractory to existing therapies. The dose limiting toxicity was hypotension and flue-like syndrome. There were no serious adverse events. Specific T-cell response was detected as well as clinical response to Lovaxin-C. Several other therapeutic HPV vaccines are in clinical development and in most of the studies specific immunological and clinical responses were seen. Efficacious therapeutic vaccine for the treatment of cervical cancer should be expected in the near future. PMID- 19785061 TI - Genetically modified cellular vaccines against human papillomavirus type 16 (HPV16)-associated tumors: adjuvant treatment of minimal residual disease after surgery/chemotherapy. AB - Local recurrences at the site of tumor resection or after chemotherapy, as well as distant micrometastases represent major problems in oncology. Therapeutic strategies based on insertion of immunostimulatory genes into the genome of tumor cells followed by vaccination with the resulting genetically modified and irradiated cellular vaccines represent a new potential prospect for the treatment of cancer patients. These strategies are based on the presumption that many, if not all tumors, possess cell surface antigens capable of being recognized by defence effectors of the immune system, as well as on the presumption that local treatment of primary tumors can, due to its immunizing potential, result also in the inhibition of distant metastases. Genetically modified cellular vaccines were found to be efficient against cancer both in experimental models and in tumor bearing patients. It was also shown in various systems that the efficacy of conventional therapeutic modalities can be supported by adjuvant administration of genetically modified vaccines, as well as by depletion of immunosuppressive immunocyte subsets. The purpose of this review was to summarize and evaluate the results obtained with the administration of genetically modified cellular vaccines as well as with depletion of immunosuppressive immunocytes performed as treatment of minimal residual disease after surgery / chemotherapy in the experimental model of murine tumors mimicking human HPV16-associated neoplasms. The prospects and limitations of these adjuvant immunotherapeutic modalities are discussed. PMID- 19785062 TI - MicroRNAs and future therapeutic applications in cancer. AB - Every cellular process is likely to be regulated by microRNAs (miRNAs), and an aberrant expression signature of these small non-coding RNAs is a hallmark of several diseases, including cancer. miRNA expression profiling by microarray techniques has provided a powerful tool to reveal the involvement of these tiny molecules in tumor development and progression, showing that they are differentially expressed in tumors as compared to normal tissues. Moreover, specific miRNA signatures have been associated with histopathological and clinical features, suggesting a potential role of these molecules as prognostic and predictive markers. Focusing then on their biological effects and role in cancer, it has been shown that miRNAs can function as potential oncogenes or oncosuppressor genes, depending on the cellular context and on the target genes they regulate. The possibility to modulate miRNA expression either in vitro and in vivo by developing synthetic pre-miRNA molecules or antisense oligonucleotides have at the same time provided a powerful tool to a deeper comprehension of the molecular mechanisms regulated by these molecules, and suggested the intriguing and promising perspective of their possible use in therapy. Herein we review our current knowledge about the involvement of miRNAs in cancer, and their potential as diagnostic, prognostic and therapeutic tools. PMID- 19785063 TI - Future aspects of immunotherapy and gene therapy in neuroblastoma. AB - Immunotherapy against cancer aims at stimulating the immune system or building an immune response against targeted tumor-associated antigens (TAAs). It was proposed theoretically as a potential therapy for cancer over a century ago but it became popular in the past two decades. Gene therapy represents a promising approach for reversing the neoplastic phenotype or driving tumor cells to self destruction. Although survival rates of neuroblastoma (NB) with biologically favorable disease are greater than 90%, outcomes of patients with high risk disease are less than 40%. Stage 4 metastatic NB cases over 18 months of age are often incurable with multimodality chemotherapy regimens. In this article, translation of immuno-gene therapy strategies into clinical trials for NB are reviewed. Future aspects of immuno-gene therapy are discussed. PMID- 19785064 TI - Genomic strategies to improve outcome and individualize therapy in cancer: the paradigm of childhood acute lymphoblastic leukemia. AB - Childhood acute lymphoblastic leukemia (ALL) is the classic example for a drug responsive malignancy, and contemporary risk-directed therapies cure more than 80% of children with ALL in industrialized countries. Antileukemic medications, however, can cause significant adverse drug reactions. Moreover, some children have leukemia cell clones which are resistant to current antileukemic treatment. As ALL is still among the leading causes of death from disease in children aged one to 15 years, further improvement of childhood ALL therapy is urgently needed. The aim of pharmacogenomics is to elucidate functionally relevant genomic determinants for drug disposition and response in order to optimize drug therapy based on a patient's genomic profile. Pharmacogenomics has evolved from the study of single candidate genes to large-scale genome-wide strategies. Results from recent pharmacogenomic investigations in children with ALL hold promise to improve ALL therapy in the near future; and can serve as a model to improve drug therapy in other malignancies as well. PMID- 19785065 TI - Hereditary cancer predisposition syndromes and preimplantation genetic diagnosis: where are we now? AB - Hereditary cancer predisposition syndromes have been model diseases in order to understand carcinogenesis in many different organs such as colon, breast, ovaries, stomach and others. Better understanding and follow up of these diseases have led to the increasing acceptance of cancer genetic testing and the improving survival of young patients with cancer. Once the mutation is identified in the gene, patients and their relatives have the option of preimplantation genetic diagnosis (PGD) in order to select embryos without familial cancer-predisposing mutations. This procedure has already been performed in several syndromes, including the common syndromes of genetic predisposition to colon and breast cancer. Despite the numerous ethical objections and legal arguments, PGD for adult-onset cancers is today a reality and couples with an inherited predisposing mutation deserve the same respect, support and right to choose if their child will be born having an extremely high risk for cancer development as in the case of other life-threatening diseases for which prenatal screening has become a standard. PMID- 19785066 TI - Adoptive T-cell therapy of cancer. AB - Adoptive immunotherapy is determined as "the isolation of antigen-specific cells, their ex vivo expansion and activation, and subsequent autologous administration" and is a promising approach to inducing antitumour immune responses. Identification of tumour antigens and monitoring the persistence and transport of transferred cells has provided our understanding over the mechanisms of tumour immunotherapy. Cell-transfer therapies have seemed beneficial for the treatment of patients with selected metastatic cancers by providing a blueprint for the wider application of adoptive cell transfer (ACT) therapy, and emphasize the requirement for in vivo persistence of the cells for therapeutic efficacy. The magnitude and specificity of immune responses to pathogenic organisms have let a search for ways to arm the immune system and aim it at a specific type of metastatic cancer. Knowledge of immune regulation and effector cell function have accumulated rapidly in the past decade resulting in incremental gains regarding the ability to manipulate host immunity and specifically target tumour cells for immune destruction. Besides, converging information from the fields of molecular biology and cellular immunology has inspired clinical trials using potent immunomodulators and molecularly defined immunogens. The clinical practice of immunotherapy for treating cancer is capitalizing on these advances, and recent efforts in ACT therapy provide an excellent example of this progress. PMID- 19785067 TI - Experimental strategies in gene therapy of cancer. AB - Gene therapy is a new and innovative approach to the treatment of malignant neoplasms, although it is still not capable of eradicating cancer in humans. Selection of the appropriate vector with maximal efficiency and minimal toxicity is crucial for gene therapy and numerous viral and non-viral (synthetic) methods for gene transfer have been developed. There are different gene therapy approaches for cancer treatment such as: 1) gene correction; 2) molecular chemotherapy; 3) proapoptotic gene therapy; 4) antiangiogenic gene therapy; 5) immune gene therapy; and 6) modulation of drug resistance/sensitivity. Cancer gene therapy represents one of the most rapidly developing areas in preclinical and clinical research. However, some problems need to be solved to make sure this strategy is safe, effective and long-lasting before it becomes routinely adopted in clinical practice. PMID- 19785069 TI - siRNA and miRNA for the treatment of cancer. AB - In the process of RNA interference (RNAi), small RNAs pair with complementary messenger RNAs preventing their expression. The discovery of RNAi has revolutionized our understanding of gene regulation. Since cancer is a disease of altered genes, RNAi may have tremendous potential as a therapeutic strategy by downregulating altered genes. Just one decade after its discovery, this process is already being used in clinical trials and new technical achievements in delivering small RNAs to the cells are constantly improving the efficiency of this specific cancer treatment. PMID- 19785070 TI - p53 gene therapy using RNA interference. AB - p53 gene, discovered almost 35 years ago, keeps the main role in cell cycle control, apoptosis pathways and transcription. p53 gene is found mutated in more than 50% of all human cancers in different locations. Many structures from viral to non viral were designed to incorporate and deliver in appropriate conditions forms of p53 gene or its transcripts, systemically to target tumor cells and to eliminate them through apoptosis or to restore the normal tumor suppressor gene role. Each delivery system presents advantages and low performance in relation to immune system recognition and acceptance. One of the major discoveries in the last years, silencing of RNA, represents a powerful tool for inhibiting post transcriptional control of gene expression. According to several studies, the RNA silencing technology for p53 transcripts together with other carriers or transporters at nano level can be used for creating new therapeutic models. RNA interference for p53 uses different double-stranded (ds) molecules like short interfering (si) RNA and, despite the difficulty of introducing them into mammalian cells due to immune system response, it can be exploited in cancer therapy. PMID- 19785068 TI - Novel modular transporters delivering anticancer drugs and foreign DNA to the nuclei of target cancer cells. AB - A major challenge in the development of specific and effective cancer treatments is the paradoxical situation that exploiting a molecular target that is accessible (surface membrane or extracellular matrix) is critical for achieving tumor selectivity whereas delivery of the therapeutic inside the cell, to the cell nucleus is generally required for maximizing the therapeutic effect. Photosensitizers, alpha-particle emitting radionuclides and foreign genetic material could be considered as such therapeutics if they possessed cellular and subcellular specificity. The author describes a novel approach of using modular recombinant transporters to target the therapeutics to the nucleus of cancer cells, where their action is most pronounced or can only be expressed. Photo sensitizer-transporter conjugates displayed up to 3000 times greater efficacy than free photosensitizers and acquired cell specificity in contrast to free photosensitizers. Alpha-emitting radionuclides, conjugated with the modular transporters, acquired similar properties. DNA complexed with analogous transporters efficiently transfected target cells. The different modules of the transporters are interchangeable, meaning that they can be tailored for particular applications. PMID- 19785071 TI - Optimisation of replication-selective oncolytic adenoviral mutants in combination with chemotherapeutics. AB - Replication-selective oncolytic adenoviruses are promising anti-tumour therapeutic agents that have been proven safe in hundreds of patients. While clinical efficacy was limited with the viral mutants alone, outcomes were improved in combination with chemotherapeutics. To further increase efficacy of viral-based therapies it is necessary to explore the cellular mechanisms responsible for enhanced tumour elimination in combination with cytotoxic drugs and to develop mutants with higher potency. To this end we generated a set of novel adenoviral mutants with deletions of the anti-apoptotic E1B19K-gene and the pRb-binding E1ACR2-region. Mutants with the E1B19K deletion significantly increased tumour cell killing in combination with cytotoxic drugs including gemcitabine, 5-fluorouracil (5-FU), docetaxel and mitoxantrone through enhancement of drug-induced apoptosis but did not sensitise normal cells to drugs. The double-deleted AdDeltaDelta (DeltaE1ACR2 and DeltaE1B19K) mutant had high cell killing activity in prostate and pancreatic carcinoma models. Replication was similar to the parental Ad5 and DeltaCR2 viruses in all tumour cells and was attenuated in normal cells. In combination with chemotherapeutics AdDeltaDelta synergistically enhanced cell death in all tested cancer cell lines and in prostate and pancreatic xenografts in vivo. These data suggest that the AdDeltaDelta mutant is a candidate for targeting of solid tumours specifically in combination with cytotoxic factors. Our findings imply that less toxic doses than currently practised in the clinic could efficiently target adenocarcinomas when combined with the AdDeltaDelta mutant. PMID- 19785072 TI - Molecular targeting and gene delivery in bladder cancer therapy. AB - Urothelial carcinoma of the bladder is the second most common genitourinary malignancy and the second most common cause of genitourinary cancer-related deaths with a worldwide estimate of about 300,000 new cases diagnosed every year. A significant problem in this type of cancer is the high recurrence rate of non invasive primary tumors, leading to a high percentage of tumor progression and to a very poor 5-year survival rate. Targeted and gene therapy are currently the two major efforts in cancer treatment. Targeted therapy refers to strategies against specific cellular molecules deregulated in tumors, whereas gene therapy focuses on the genetic modification of tumor cells, mainly for correcting gene defects, inducing selective tumor cell death or modulating host's immune response. Recent advances in our understanding of the pathogenesis of bladder cancer at the molecular level have provided a significant number of cellular targets for therapy and have shown the importance of individualized therapy according to the molecular profile exhibited by the tumor cells. While the major problems of both targeted and gene therapy are far from being solved yet, both lines of cancer therapy hold promising results. This article aims at providing a brief general overview of this broad subject. PMID- 19785073 TI - Cancer gene therapy with oncolytic adenoviruses. AB - Metastatic cancer remains difficult to treat effectively and treatments are in most cases not curative despite significant side effects. Novel, targeted approaches such as gene therapy hold promise for the treatment of various tumor types. Among the most promising cancer gene therapy approaches are oncolytic adenoviruses, which are able to infect, replicate in and lyse tumor cells. Recent data from clinical trials with these vectors have shown that they are safe. However, antitumor efficacy needs to be improved to make oncolytic adenoviruses a viable treatment alternative for cancer patients. This review focuses on targeting strategies to improve tumor cell transduction and cancer cell selective replication. Strategies to improve antitumor efficacy by arming the virus with therapeutic transgenes are also discussed. Furthermore, an overview of the most important clinical approaches with oncolytic adenoviruses is given. PMID- 19785074 TI - Towards targeted epigenetic therapy of cancer. AB - Increasing number of publications in the last 10 years implicated that cancer development depends, except genetic alterations, also on inheritable gene expression patterns that are not bound to DNA sequence alterations. These epigenetic mechanisms manifest mostly through changes in chromatin packing and in localized gene promoter changes that influence the transcription of the genes involved in carcinogenesis. These changes are mitoticaly inheritable and potentially reversible, providing large possibilities of epigenetic therapy of cancer. So far this therapy lacks specificity of targeting certain genes. Instead, epigenetic therapy attempts either to reactivate or to silence genes that are important for the cancer progress. Epigenetic therapy of cancer is based mostly on the usage of inhibitors of DNA methyltransferases (DNMTs), histone deacetylase (HDAC) inhibitors and anti-micro-RNA therapy. Developments that involve integration of the latest technological advances, such as whole genome microarray expression profiling, help identify mechanisms of action of epigenetic drugs, leading to development of second generation of epi-drugs which would have greater specificity and efficacy. The obtained results are promising, leaving great possibilities for improvement of cancer therapy. PMID- 19785075 TI - Immunosurveillance and immunoediting--can the immune response be made more "immunodemocratic"? AB - Increasing evidence has demonstrated that the immune system is able to mount responses against tumors and that these responses can be enhanced using a number of strategies. Several of these strategies are currently being evaluated in clinical trials, where their efficacy and cost effectiveness will be ascertained. Sadly, we have to admit that despite great expectations and enormous achievements in basic immunology and molecular biology, immunotherapeutic interventions relying on the elicitation of cytotoxic cellular immunity so far have had limited success. We have found that gene-based vaccination is effective in breaking tolerance to tumor-associated antigens, but the response is directed towards few of the potential epitopes due to immunodominance. Tumor cells that have lost the immunodominant epitope due to mutations would no longer be recognized and would evade immune surveillance. Designing a protocol for immunotherapy, therefore, necessitates stimulation of an immune response directed against a multitude of epitopes. Increasing the number of epitopes available for presentation to T cells is the initial step. It mandates increased degradation of the antigen following DNA immunization. A logical continuation involves manipulation of the intimate mechanisms controlling the processes of stimulation and/or suppression of T cells recognizing the "sub-dominant" epitopes thus offering to the immunologist ways for overcoming tumor-immune evasion strategies. We now have the necessary instruments to ask all the fundamental questions of tumor immunology. A better understanding of the immune escape mechanisms and those underlying tumor-induced immune suppression will help in designing novel and more efficient protocols for immunotherapy in the clinical setting. PMID- 19785076 TI - Cancer/testis antigens for therapeutic use. AB - Since van der Bruggen and colleagues first identified specific human tumour associated antigens of the MAGE family, numerous potential immunotherapeutic targets have been discovered, often belonging to the so-called cancer/ testis gene family. Several members of this group have been described as immunogenic and have been utilised in clinical trials. In a search for interesting targets within this family, our laboratory has focussed its works for a number of years on two novel cancer/testis antigens called T21 and HAGE. In this article, we will focus our discussion on their levels of expression in a wide variety of both normal and cancer tissues, their possible role in tumour cell development and proliferation, and their immunogenic potential. PMID- 19785077 TI - Red yeast rice may be a statin substitute. People who are statin-intolerant due to side effects of muscle pain may benefit from this ancient Asian dietary and medicinal staple. PMID- 19785078 TI - Plant-based proteins lower LDL and overall cholesterol. Plant-based proteins are higher in fiber, with far less fat and cholesterol than animal protein. PMID- 19785079 TI - Alternative treatments for your arthritis pain. Tai chi, fish oil, and capsaicin gel might be effective, drug-free alternatives to NSAIDs. PMID- 19785080 TI - Early, detectable metabolic changes may predict later onset of diabetes. But monitoring changes in blood sugar, insulin sensitivity, and pancreas function could enable earlier intervention. PMID- 19785081 TI - Easy and accurate self-administered memory test. The "Test Your Memory" screening tool is a new test for Alzheimer's. PMID- 19785082 TI - Can NSAIDs protect people against Parkinson's disease? PMID- 19785083 TI - I have arthritis-related neck pain. Can non-surgical spinal decompression with cold-laser therapy bring some relief? PMID- 19785084 TI - Is it safe for me to do Pilates? I'm 74 and in good health. PMID- 19785085 TI - Cutaneous manifestations of anabolic-androgenic steroid use in athletes. AB - Increased public awareness of the performance-enhancing benefits of anabolic androgenic steroids (AASs) in athletes has resulted from the media coverage of the BALCO scandal and Mitchell report. The impact of this increased notoriety on the consumption of these drugs remains unclear, however. In addition, the negative connotation associated with the use of AASs may make users less forthcoming when interacting with their physicians. Cutaneous manifestations develop early in the use of AASs, placing dermatologists in a unique position to make an early diagnosis of AAS abuse in patients who engage in competitive sports. This review of the literature focuses on dermatologic presentations of AAS use. PMID- 19785086 TI - Skin diseases in patients with beta-thalassemia major. AB - BACKGROUND: Beta-thalassemia major affects multiple organs and is associated with considerable morbidity and mortality. The goal of this analysis was to document the frequency of skin diseases among patients with beta-thalassemia major. METHODS: A sample of 78 patients with beta-thalassemia major was recruited and interviewed at the thalassemia clinic between April and June 2008. A dermatologist completed a skin examination of each patient and recorded any skin disease present. The patients' laboratory results and treatment modalities were recorded from the charts. RESULTS: Sixty-five (83.3%) of the 78 patients examined had a diagnosed skin disease: pruritus (37.2%), xerosis (34.6%), scars (24.4%), ephelides (23.1%), skin irritation/erythema caused by deferoxamine pump (12.8%), idiopathic guttate hypomelanosis (6.4%), pityriasis alba (6.4%), tinea infections (5.1%), verruca vulgaris (5.1%), urticaria (3.8%), hyperhidrosis, contact dermatitis, and acne (2.6%), necrobiosis lipoidica (1.3%), melasma (1.3%), and others (14.1%). Pruritus and xerosis increased in frequency with age. The mean serum ferritin level was higher in patients with xerosis than in those without (5607.7 +/- 2997.5 ng/mL and 4285.2 +/- 4732.4 ng/mL, respectively) (P1/4 0.005). Moreover, xerosis was observed significantly more frequently inpatients using deferoxamine and deferiprone than in those using deferasirox (P1/4 0.047, P1/4 0.027, and P1/4 0.273, respectively). CONCLUSION: Skin diseases, especially pruritus and xerosis, are observed highly frequently inpatients with beta thalassemia major. Treatment is needed for these patients who already have other significant morbidities. PMID- 19785087 TI - Sweet's syndrome with neurologic manifestations in a patient with esophageal adenocarcinoma: case report and review of the literature. AB - BACKGROUND: Sweet's syndrome, also known as febrile neutrophilic dermatosis, can occur in patients with an underlying malignancy and can present with extracutaneous manifestations, including neurologic symptoms. METHODS: This report describes a 62-year-old man with adenocarcinoma of the esophagus who developed Sweet's syndrome and whose postoperative course was complicated by encephalitis. RESULTS: A diagnosis of Sweet's syndrome with neurologic manifestations was made, and the patient was treated with oral corticosteroids. His symptoms improved markedly within 12 h. CONCLUSION: Neurologic symptoms in Sweet's syndrome are infrequently reported and have not been described previously in a patient with adenocarcinoma of the esophagus. PMID- 19785088 TI - Needs assessment survey of psychocutaneous medicine. AB - BACKGROUND: Psychocutaneous medicine studies the boundaries between skin and mind, and takes the unique approach of examining the patients in their biopsychosocial context. It can help patients with chronic skin problems cope with anxiety and the social stigma of their disease. Decreased psychologic stress can contribute to better treatment outcomes and be an important key to patient care. In addition, some primary psychiatric disorders may be expressed in the skin, such as delusions of parasitosis. A psychocutaneous specialist is well placed to treat these disorders. METHODS: To assess the need for psychocutaneous medicine in dermatology, eighty-five attendees of the Wisconsin Dermatological Society (WDS) meeting were asked to complete a needs assessment survey. RESULTS: Forty-two percent of respondents felt that 30% of their patients would benefit from psychiatric interventions. In addition, 43% of respondents did not routinely inquire about mental health issues. When they did recognize psychiatric needs in a patient, 83% of responders did not feel comfortable prescribing psychotropic medications. CONCLUSION: Our data showed that about one-half of the members of WDS attending the meeting believed that a high percentage of their patients would benefit from psychocutaneous intervention. Moreover, it was found that the training during medical school and dermatology residency was insufficient for professionals to confidently prescribe psychotropic medications. Considering the fact that studies have shown psychiatric comorbidity in 30% of dermatologic diseases, and that many of the respondents who felt that their patients would not benefit from psychocutaneous intervention did not inquire about psychologic effects of skin disease in their patients, we conclude that psychocutaneous medicine is an under-recognized field in dermatology. Further evaluation of the demand for psychocutaneous clinics and their integration into daily dermatologic practices and residency training programs is needed. PMID- 19785090 TI - Hypopyon sign in pemphigus vulgaris and pemphigus foliaceus. PMID- 19785089 TI - A rare connexin 26 mutation in a patient with a forme fruste of keratitis ichthyosis-deafness (KID) syndrome. AB - BACKGROUND: Keratitis-ichthyosis-deafness (KID) syndrome is a rare ectodermal dysplasia characterized by generalized erythrokeratotic plaques, sensorineural hearing loss, and vascularizing keratitis. Cutaneous changes and hearing loss typically present in early childhood, whereas ocular symptoms present later. Mutations in the connexin (Cx) 26 gene, GJB2, are now established to underlie many of the affected cases, with the majority of patients harboring the p.D50N mutation. METHODS: A rare patient demonstrating features of incomplete KID syndrome associated with an uncommon Cx26 gene mutation is described. RESULTS: The patient presented late in adolescence with partial features of KID syndrome. There was limited cutaneous involvement and the rare association of cystic acne. Both hearing impairment and ophthalmic involvement were mild in severity. Genetic mutation analysis revealed a previously described, rare mutation in GJB2, resulting in a glycine to arginine change at codon 12 (p.G12R). CONCLUSIONS: This report describes a patient exhibiting characteristics suggestive of a late-onset, incomplete form of KID syndrome with the GJB2 mutation (p.G12R). The p.G12R mutation has only been described in one other patient with KID syndrome, whose clinical presentation was not characterized. PMID- 19785091 TI - Segmental neurofibromatosis of the distal arm in a man who developed Hodgkin lymphoma. PMID- 19785092 TI - The ATPase activity of BfpD is greatly enhanced by zinc and allosteric interactions with other Bfp proteins. PMID- 19785093 TI - NY: Failure to administer TPA to stroke victim: TPA not indicated while in defendants' care. Flanagan v. Catskill Regional Medical Center, 2009-NY-06161 (8/11/2009)-NY. PMID- 19785094 TI - The mechanism of amino acid activation: the work of Mahlon Hoagland. 1956. PMID- 19785095 TI - Uncovering cellular sub-structures by light microscopy. Festschrift to recognise and celebrate the contributions of Christoph Cremer to the field of biophysics on the occasion of his 65th birthday. PMID- 19785096 TI - Infantile and juvenile scoliosis: the crooked path to diagnosis and treatment. AB - Most cases of scoliosis are diagnosed and treated during adolescence; many are detected in school screening programs. For a small percentage of children, however, the onset of scoliosis occurs much earlier than adolescence.Infantile scoliosis (ie, onset from birth to two years of age) and juvenile scoliosis (ie, onset from three to nine years of age) involve very different diagnoses and treatment regimens than adolescent scoliosis. Early onset scoliosis may resolve with growth or may require nonsurgical treatment (eg, orthosis, body cast); surgical intervention (eg, halo traction, growing rods, vertical expandable prosthetic titanium rib); or a combination of both. PMID- 19785097 TI - Correction of organization's name. PMID- 19785098 TI - World Rabies Day promotes prevention of deadly disease. PMID- 19785099 TI - Influenza in the Asia-Pacific. PMID- 19785100 TI - Urgent action needed to defuse HIV treatment timebomb. PMID- 19785101 TI - Design for living. Jack Mackenroth takes his message of hope on the road, battling stigma along the way. Interview by Jeff Berry. PMID- 19785102 TI - HIV and your immune system. How they work and why it's important. PMID- 19785103 TI - OIs and co-infections and STDs. Staying healthy with HIV by keeping on top of bugs and such. PMID- 19785104 TI - What's for breakfast (and lunch and dinner)? HIV and what you eat, drink, and take. PMID- 19785105 TI - Queaze, sneeze, yawn, and runs. A little laundry list of possible side effects of the different HIV drug classes. PMID- 19785106 TI - Exercise: the best therapy for managing side effects. How to stay active and energetic. PMID- 19785107 TI - Clinical courtship or medical matrimony. Finding the doctor who's your ideal partner in care. PMID- 19785108 TI - The financial fallout of HIV: update from the trenches. Managing your money while living longer. PMID- 19785109 TI - HIV stigma and disclosure. Can social support help? PMID- 19785110 TI - Theoretical study of the ArH+ electronic states. AB - Potential energy curves, permanent multipole and transition dipole moments were evaluated for the ground and low-lying excited electronic states of the ArH+ cation over a wide range of internuclear distance by the multireference averaged quadratic coupled cluster method (MR-AQCC). The electric dipole polarisability of the ground X 1sigma state was evaluated by the finite-field method. The permanent multipole moments and dipole polarisabilities corresponding to the ArH+ X 1sigma+ state were used to estimate quantum defect functions of the nonpenetrating d- and f-complex Rydberg states of neutral ArH molecule. The ground state dipole function and potential were tested by a simulation of intensity distributions in the rovibrational deltav = 1 bands, radiative lifetimes and rotational g-factors for the X 1sigma+ state. PMID- 19785111 TI - Study of the upsilon1 band shape of the H2O...HF, H2O...DF, and H2O...HCl complexes in the gas phase. AB - The band shape of the upsilon1 hydrogen fluoride stretch in H20...HF and H2O...DF complexes was studied in the gas phase. The spectra of H2O/HF mixtures at 293 K in cells 20 and 1200 cm long were recorded in the range 4200-3000 cm(-1) at a resolution of 0.2-0.02 cm(-1). The spectra of the 1 : 1 complex in the region of the upsilon1(HF) absorption band were obtained by subtracting the calculated spectra of free H2O and HF molecules from the experimental spectra. The asymmetric upsilon1 band of H2O...HF has a low-frequency head, an extended high frequency wing, and a characteristic vibrational structure. The upsilon1 band shape was reconstructed nonempirically as a superposition of rovibrational bands of the upsilon1 (HF) fundamental transition and hot transitions from excited states of low-frequency modes. The reconstruction was based on an ab initio calculation of the potential energy and dipole moment surfaces and subsequent variational multidimensional anharmonic calculations of the vibrational energy levels, the frequencies and intensities of the transitions considered, and the rotational constants. The calculated spectrum reproduces the structure of the experimental spectrum, in particular, the relative intensities of the peaks. However, the assignment of spectral features differs from that generally accepted. The central, most intense, peak is associated with the transition from the ground state, while the lowest-frequency peak with the P branch head of transition from the upsilon6 (B2) = 1 state. This leads to a value of 3633.8 cm( 1) for the upsilon1 (HF) stretch frequency of H2O...HF, which is higher than the commonly adopted value of 3608 cm(-1). Similar calculations of H2O...DF predict a value of 2689 cm(-1) for the upsilon1(DF) stretch and a less structured band shape. On formation of a 1 : 1 complex with water the frequency is shifted by 331.8 cm(-1) and -229.4 cm(-1) and the intensity is increased by a factor of 3.87 and 3.51 for HF and DF, respectively. Similar calculations of H2O...HCl predicted a value of 2726.5 cm(-1) for the upsilon1 fundamental, a lower frequency for the hot transition from the upsilon6 (B2) = 1 excited state, and a upsilon1(HCl) band shape in agreement with the results of recent low-temperature experiments. PMID- 19785112 TI - Cation diffusion and ionic conductivity in soda-lime silicate glasses. AB - We have studied the mobilities of calcium and sodium ions in silicate glasses of compositions xNa2O (3 - x)CaO x 4SiO2 with x = 0.0, 0.1, 0.3, 1.0 and 3.0 by means of radiotracer diffusion, electrical conductivity measurements, and dynamic mechanical thermal analyses. In glasses containing sodium oxide, the Na+ ions are much more mobile than the Ca2+ ions, and are, therefore, governing the electrical conductivity. In the pure calcium silicate glass, the activation energy of Ca2+ diffusion is higher than the activation energy of the electrical conductivity. This provides strong evidence that the electrical conductivity of this glass is not determined by the migration of Ca2+ ions, but by impurity charge carriers, which are most likely Na+ ions. We sketch the composition-dependent mobilities of Na+ and Ca2+ ions in soda-lime silicate glasses with variable Na2O and CaO content. Our results indicate that the coordination environment of Ca2+ ions remains unchanged when CaO is replaced by Na2O which is consistent with recent results of molecular dynamic simulations. Moreover, our results confirm the formation of dissimilar Na-Ca pairs which lead to a non-random mixing of the cations in the glass. The formation of such pairs was recently deduced from nuclear magnetic resonance spectra of soda-lime silicate glasses. PMID- 19785113 TI - Threshold photoelectron-photoion coincidence spectroscopy study of ChCl2F+, CHClF2+ and CH2ClF+: steric influence of the chlorine, fluorine and hydrogen atoms. AB - The threshold photoelectron spectrum and threshold photoelectron-photoion coincidence spectra of CHCl2F, CHClF2 and CH2ClF are reported in the range 11.3 24.8 eV. Tunable photoionizing radiation with a resolution of 0.3 nm is provided from a synchrotron source with a vacuum-UV monochromator. The coincidence spectra are recorded continuously as a function of photon energy, allowing yields of the fragment ions to be obtained. Energetic comparisons suggest that the major products of the titled molecules dissociate in a similar manner at low photon energy, with the parent and first fragment ion, corresponding to cleavage of the weakest bond, appearing at their thermochemical thresholds. The second major ion, corresponding to cleavage of the second weakest bond, is formed ca. 1 eV higher than its predicted threshold, this disparity implying state-selected dissociation. CHCl2F and CHClF2 fragment in a similar manner at higher photon energies, with minor ions formed by the cleavage of three bonds possessing lower appearance energies than fragment ions formed by the cleavage of two bonds. CH2ClF displays the more expected behaviour, namely sequential bond cleavage as the photon energy increases. These observations can be rationalised in terms of the height of the barrier on the exit channel, as determined by the steric bulk of the leaving group. For the three titled molecules, mean translational kinetic energy releases have also been measured into the channels involving C-F or C-Cl bond fission. These data infer that impulsive dissociations occur at lower energy, with a trend towards statistical behaviour with increasing photon energy. Competition between statistical and impulsive processes is observed, for example C-Cl vs. C-F bond cleavage in CHCl2F+ and CHClF2+. PMID- 19785114 TI - Kinetics and products of the OH radical-initiated reaction of 3-methyl-2-butenal. AB - Kinetics and products of the gas-phase reaction of OH radicals with 3-methyl-2 butenal [(CH3)2C=CHCHO] have been investigated at room temperature and atmospheric pressure of air. Using a relative rate method with methacrolein as the reference compound, a rate constant for the reaction of OH radicals with 3 methyl-2-butenal of (6.21 +/- 0.18) x 10(-11) cm3 molecule(-1) s(-1) at 296 +/- 2 K was measured, where the indicated error does not include the uncertainty in the rate constant for the methacrolein reference compound. Products of this reaction were investigated using in situ Fourier transform infrared (FT-IR) spectroscopy and solid phase microextraction (SPME) fibers coated with O-(2,3,4,5,6 pentafluorobenzyl)hydroxylamine for on-fiber derivatization of carbonyl compounds, with subsequent thermal desorption and analysis by gas chromatography. The products observed and the molar formation yields were: glyoxal, 40 +/- 3%; acetone, 74 +/- 6%; 2-hydroxy-2-methylpropanal, 4.6 +/- 0.7%; CO2, 39% initially, decreasing to 30% at greater extents of reaction; peroxyacyl nitrate(s) [RC(O)OONO2], 5-8%, increasing with the extent of reaction and with the sum of the CO2 and RC(O)OONO2 yields being 38 +/- 6%; and organic nitrates [RONO2], 8.5 +/- 2.3%. The formation of these products is readily explained by a reaction mechanism based on those previously formulated for the corresponding reactions of the alpha,beta-unsaturated aldehydes acrolein, crotonaldehyde and methacrolein. Based on the mechanism proposed, at room temperature H-atom abstraction from the CHO group accounts for 40 +/- 6% of the overall reaction, and OH radical addition to the carbon atoms of the C=C bond accounts for 53 +/- 4% of the overall reaction. Hence 93 +/- 8% of the reaction products and pathways are accounted for. PMID- 19785115 TI - Double many-body expansion potential energy surface for ground state HSO2. AB - A global potential energy surface is reported for the ground electronic state of HSO2 by using the double many-body expansion (DMBE) method. It employs realistic DMBE functions previously reported from accurate ab initio calculations (in some cases, fine tuned to spectroscopic data) for the triatomic fragments, and four body energy terms that were modelled by fitting novel ab initio FVCAS/AVTZ calculations for the tetratomic system. In some cases, FVCAS/AVDZ energies have been employed after being scaled to FVCAS/AVTZ ones. To assess the role of the dynamical correlation, exploratory single-point Rayleigh-Schrodinger perturbation calculations have also been conducted at one stationary point. All reported calculations are compared with previous ab initio results for the title system. The potential energy surface predicts HOSO to be the most stable configuration, in good agreement with other theoretical data available in the literature. In turn, the HSO2 isomer with H bonded to S is described as a local minimum, which is stable with respect to the H + SO2 dissociation asymptote. PMID- 19785116 TI - Relative rates of reaction of 13C16O, 12C18O, 12C17O and 13C18O with OH and OD radicals. AB - A relative rate experiment is carried out for four isotopomers of carbon monoxide (CO) and their reactions with OH and OD radicals. The relative reaction rates of 13C16O, 12Cl8O, 12C17O and 13C18O with OH and OD radicals are measured at 298 +/- 2 K and 1013 +/- 10 mbar. The OH/OD source in the reaction chamber is photolysis of ozone to produce O(1D) in the presence of molecular hydrogen: O(1D) + H2/D2 - > OH/OD + H/D. The relative reaction rates are determined as: k(OH) + 13C16O/k(OH) + 12C18O = 0.98 +/- 0.01, k(OH) + 12C17O/k(OH) + 12C18O = 0.990 +/- 0.008, k(OH) + 13C16O/k(OH) + 13C18O = 0.98 +/- 0.01, k(OD) + 13C16O/k(OD) + 12C18O = 0.99 +/- 0.01, k(OD) + 12C17O/ k(OD) + 12C18O = 1.000 +/- 0.008, k(OD) + 13C16O/k(OD) + 13C18O = 0.98 +/- 0.01. The errors represent 2sigma from the statistical analyses and do not include possible systematic errors. These are novel results for the kinetic isotope effects in the reactions of CO isotopomers with OD radicals. The results for the reactions of CO isotopomers with OH radicals constitute a repeat and a re-analysis of experimental data previously published by this group which have been found to be partly erroneous. This communication serves as a correction to the following paper: K. L. Feilberg, S. R. Sellevag, C. J. Nielsen, D. W. T. Griffith and M. S. Johnson, Phys. Chem. Chem. Phys., 2002, 4, 4687. PMID- 19785118 TI - Electroreduction of tantalum fluoride in a room temperature ionic liquid at variable temperatures. AB - The present paper deals with the electroreduction of TaF5 in the room temperature ionic liquid 1-buty-1-methyl-pyrrolidinium bis(tri-fluoromethylsulfonyl)imide ([BMP]Tf2N) at different temperatures for the sake of electrodeposition of tantalum. The study was carried out using cyclic voltammetry and chronoamperometry measurements complemented by SEM-EDAX and XRD investigations. In situ scanning tunneling microscopy and I-U tunneling spectroscopy were also utilized for characterization of the electrodeposits. The results show that, in addition to the formation of insoluble compounds, Ta can be electrodeposited in the ionic liquid ([BMP]Tf2N) containing 0.5 M TaF5 at 200 degrees C on polycrystalline Pt and Au(111) electrodes. By addition of LiF to the electrolyte, the quality and the adherence of the electrodeposit were found to be improved. An in situ I-U tunneling spectrum with about 300 nm thickness of the electrodeposit shows metallic behaviour indicating the formation of elemental tantalum. Moreover, the XRD patterns of the electrodeposit, obtained potentiostatically at 1.8 V (vs. Pt) in ([BMP]Tf2N) containing 0.25 M TaF5 and 0.25 M LiF on Pt electrode at 200 degrees C, show the characteristic patterns of crystalline tantalum. PMID- 19785117 TI - Nuclear quantum effects on the structure and energetics of (H2O)6H+. AB - The energetics and structure of the protonated water hexamer (H2O)6H+ have been examined employing both model potentials and high-level ab initio methods. To select candidate structures for this cluster, Parallel-Tempering and the OSS2 potential were used as devices to complement the set of stationary points previously optimized by Hodges and Wales, Chem. Phys. Lett., 2000, 324, 279. Structures of these local minima were successively re-optimized using OSS3, B3LYP/aug-cc-pVDZ, and MP2/aug-cc-pVDZ, the latter providing a reference to benchmark the performance of the empirical models and B3LYP method. We found that both OSS2 and OSS3 require a re-parameterization to adequately describe the energetics of some isomers. Zero point energy was found to be important in defining the relative stability of the optimized isomers. The effect of the anharmonicity on the vibrational ground state of (H2O)6H+ was also examined by means of diffusion Monte Carlo (DMC) and the OSS3 potential, and we found that it accounts for a decrease in total energy of roughly 0-4.4 mE(h). This is a significant effect on the energetics considering that many isomers are nearly degenerate. Including the anharmonic corrections computed with DMC, the branched species were found to be the most stable isomers. The height of the barriers separating a cage or cyclic isomer from a branched one was found to vary from 1.5 to 5.8 mE(h). PMID- 19785119 TI - Diffuse neutron scattering in relaxor ferroelectric PbMg1/3Nb2/3O3. AB - High-energy resolution neutron spin-echo spectroscopy has been used to measure the intrinsic width of diffuse scattering discovered earlier in relaxor ferroelectric crystals. The anisotropic and transverse components of the scattering have been observed in different Brillouin zones. Both components are found to be elastic and have been measured within an experimental accuracy of 1 microeV. The possible physical origin of the static-like behavior is discussed for each diffuse scattering contribution. PMID- 19785120 TI - DFT plane wave calculations of the atomic and electronic structure of LaMnO3 (001) surface. AB - We present the results of ab initio DFT plane wave periodic structure calculations of the LaMnO3 (001) surface. The effects related to three different kinds of pseudopotentials, the slab thickness, magnetic ordering, and surface relaxation are studied and discussed. The antiferromagnetic surface lowest in energy (that is, the spins on Mn ions are parallel in basal plane and antiparallel from plane to plane) has a considerable atomic relaxation up to the fourth plane from the surface. The calculated (Bader) effective charges and the electronic density maps demonstrate a considerable reduction of the Mn atom ionicity on the surface accompanied by a covalent contribution to the Mn-O bonding. PMID- 19785121 TI - Packing of adsorbed molecules in microporous polymorphs aluminium methylphosphonates alpha and beta. AB - The adsorption of N2 and CO2 in the microporous aluminium methylphosphonate polymorphs alpha and beta is investigated by adsorption experiments in combination with Monte Carlo (MC) simulations. We find that close steric matching of N2 and polymorph alpha causes a packing transition not observed for the other pairs of adsorbate and adsorbent. This strong effect on adsorption behaviour of small differences in the adsorbent structure and adsorbent-adsorbate interactions suggests that microporous, hybrid inorganic organic materials of this type offer opportunities for highly selective adsorptive separations. The realism of the MC simulations is extraordinarily dependent upon the molecular size parameters used. PMID- 19785122 TI - Comparison of surface structures of poly(ethyl methacrylate) and poly(ethyl acrylate) in different chemical environments. AB - Sum frequency generation (SFG) vibrational spectroscopy has been applied to investigate and compare the chemical structures of poly(ethyl methacrylate) (PEMA) and poly(ethyl acrylate) (PEA) in air, in water, and in a non-polar solvent, FC-75. SFG spectra from both polymer surfaces in air are dominated by vibrational modes from the ester ethyl side groups. The average orientation of these ester ethyl groups on the two polymer surfaces is slightly different. In water, the two polymers show markedly different restructuring behavior. The ester ethyl side chains on the PEMA surface in water reorient to tilt more toward the surface, yet remain ordered. Such a restructuring of the PEMA surface in water is reversible. However, no SFG signal was detected from the PEA/water interface, showing that the surface of PEA becomes disordered upon contacting water, and this process is irreversible. SFG results collected from the C=O range indicate that hydrogen bonding is observed for both polymer/water interfaces, but the order of C=O at the PEA/water interface is much lower than that at the PEMA/water interface. Supplemental experiments support our hypothesis that the PEA surface becomes rough and loses order gradually as it interacts with water. We have demonstrated, for the first time, that the loss of surface structural order is due to the interaction between soft PEA chains with water molecules followed by reorganization of the polymer backbone. This causes the polymer surface to become rough and disordered. However, the surface structures of PEMA and PEA in FC-75 are similar and are also similar to those in air. This indicates that not only T(g), but also the contacting medium plays an important role in determining the surface restructuring behavior of polymer materials. PMID- 19785123 TI - A computational pathway for bracketing native-like structures fo small alpha helical globular proteins. AB - Impressive advances in the applications of bioinformatics for protein structure prediction coupled with growing structural databases on one hand and the insurmountable time-scale problem with ab initio computational methods on the other continue to raise doubts whether a computational solution to the protein folding problem--categorized as an NP-hard problem--is within reach in the near future. Combining some specially designed biophysical filters and vector algebra tools with ab initio methods, we present here a promising computational pathway for bracketing native-like structures of small alpha helical globular proteins departing from secondary structural information. The automated protocol is initiated by generating multiple structures around the loops between secondary structural elements. A set of knowledge-based biophysical filters namely persistence length and radius of gyration, developed and calibrated on approximately 1000 globular proteins, is introduced to screen the trial structures to filter out improbable candidates for the native and reduce the size of the library of probable structures. The ensemble so generated encompasses a few structures with native-like topology. Monte Carlo optimizations of the loop dihedrals are then carried out to remove steric clashes. The resultant structures are energy minimized and ranked according to a scoring function tested previously on a series of decoy sets vis-a-vis their corresponding natives. We find that the 100 lowest energy structures culled from the ensemble of energy optimized trial structures comprise at least a few to within 3-5 angstroms of the native. Thus the formidable "needle in a haystack" problem is narrowed down to finding an optimal solution amongst a computationally tractable number of alternatives. Encouraging results obtained on twelve small alpha helical globular proteins with the above outlined pathway are presented and discussed. PMID- 19785124 TI - A correlation between the proton stretching vibration red shift and the hydrogen bond length in polycrystalline amino acids and peptides. AB - The FTIR spectra of pure and isotopically diluted (H/D and D/H) polycrystalline L glutamine, L-hystidine, L-tyrosine, DL-serine, L-threonine, di-, tri-glycine and di-glycine x HCl x H2O salt were measured in the range 4000-2000 cm(-1) at temperatures from 300 to 10 K. The frequencies of decoupled proton stretching mode bands upsilon1, which can be observed only at low temperature, were used for estimation of the of upsilon1-bands red shift, which occurs upon formation of H bonds involving ionized NH3+ and/or peptide HN-CO groups. The empirical correlation between the red shift and H-bond length, which was found previously for binary gas phase H-bonded complexes, carbohydrates and nucleosides [M. Rozenberg, A. Loewenschuss and Y. Marcus, Phys. Chem. Chem. Phys., 2000, 2, 2699 2702; M. Rozenberg, C. Jung and G. Shoham, Phys. Chem. Chem. Phys., 2003, 5, 1533 1535], was now extended to H-bonded networks in polycrystalline amino acids and peptides. The energies of the different H-bonds present in the crystalline structures could also be successfully estimated from the well-established empirical correlation [A. V. Iogansen, Spectrochim. Acta, 1999, A55, 1585-1612] between this property and the red shifts of the corresponding upsilon1 mode bands. PMID- 19785125 TI - Cation environments and spatial distribution in Na2O-B2O3 glasses: new results from solid state NMR. AB - The spatial distribution of the sodium ions in sodium borate glasses with composition (Na2O)x(B2O3)1+x (0 < or = x < or = 0.30) has been studied by complementary high resolution and dipolar solid state NMR experiments. 23Na-23Na homonuclear dipole-dipole couplings measured via 23Na spin echo decay spectroscopy indicate the absence of cation clustering at all compositions. Consistent with this result, 11B{23Na} rotational echo double resonance (REDOR) measurements indicate that the trigonal BO3/2 groups and the four-coordinate BO4/2(-) units experience 23Na local dipolar fields of similar magnitudes. Both experiments suggest a sodium spatial distribution that is essentially statistical. The dipolar coupling data are modelled consistently on the basis of a cubic NaCl-type lattice, from which an appropriate number of sodium ions have been randomly removed to reproduce the Na+ number density of the glass under consideration. In addition, at very low Na+ concentrations (x < 0.12) a compositionally independent local sodium environment is formed, which is characterized by a significant Na+ BO4/2(-) pair correlation involving an internuclear distance of 316 pm. For higher sodium oxide contents (x > 0.20) the 23Na-23Na dipole-dipole couplings suggest a gradual transition from a random towards a more homogeneous sodium distribution. PMID- 19785126 TI - Pattern formation in heterogeneous catalytic reactions with promoters and poisons. AB - Using one of the simplest models of heterogeneous catalytic reactions occurring on a single-crystal surface and including promoters or poisons, we have performed generic Monte Carlo simulations of the growth of islands composed of reactants and promoters or poisons in the case when the lateral interaction between these species is attractive. The results obtained indicate that in reaction with promoters the islands are traveling and their growth is eventually terminated. These two features are rationalized taking into account that the reaction primarily occurs inside islands and under chemically reactive conditions the balance of adsorbate diffusion there and outside islands can hardly be maintained if the islands are frozen or grow asymptotically. In reaction with poison, in contrast, the model predicts asymptotic power-law island-size growth, because in this case the situation inside islands is kinetically stable and accordingly the conditions in the overlayer are close to those occurring during the Ostwald ripening. The growth exponent obtained for this regime, x approximately or equal to 0.25, is however somewhat smaller than that expected for the Ostwald ripening. PMID- 19785127 TI - Probing the transition state with negative ion photodetachment: experiment and theory. AB - Experimental and theoretical results are presented on the spectroscopy of transition states and pre-reactive van der Waals wells using negative ion photodetachment. Several benchmark reactions are discussed, including the F + H2, OH + H2, and F + OH reactions, as well as the isomerization of cyclo octatetraene. Photoelectron spectra of clustered transtion state precursor anions are presented, which examine the effects of solvation on anion structure and transition state dynamics. Finally, new experiments on the photodetachment of ClH2(-) are discussed in which the Cl . H2 van der Waals well is probed. PMID- 19785128 TI - Exact exchange and Wilson-Levy correlation: a pragmatic device for studying complex weakly-bonded systems. AB - The Wilson-Levy (WL) correlation functional is used together with Hartree-Fock (HF) theory to evaluate interaction energies at intermediate separations (i.e. around equilibrium separation) for several weakly-bonded systems. The HF+WL approach reproduces binding trends for all complexes studied: selected rare-gas dimers, isomers of the methane dimer, benzene dimer and naphthalene dimer, and base-pair stacking structures for pyrimidine, cytosine, uracil and guanine dimers. These HF+WL data are contrasted against results obtained from some popular functionals (including B3LYP and PBE), as well as two newly-developed functionals, X3LYP and xPBE. The utility of HF+WL, with reference to exact exchange (EXX) density-functional theory, is discussed in terms of a suggested EXXWL exchange-correlation functional. PMID- 19785129 TI - Analysis of long-range NMR spin-spin coupling in polyenes and the pi-mechanism. AB - The J-OC-PSP (decomposition of J into Orbital Contributions using Orbital Currents and Partial Spin Polarization) method is applied to analyze NMR spin spin coupling constants in polyenes, which were calculated using coupled perturbed density functional theory in connection with the B3LYP hybrid functional and a [7s,6p,2d/4s,2p] basis set. The analysis revealed that the pi mechanism for Fermi contact (FC) spin coupling is based on passive pi-orbital contributions. The pi-orbitals transfer spin information between sigma orbitals (spin-transport mechanism) or increase the spin information of a sigma orbital by an echo effect. The calculated FC(pi) values are rather constant for small polyenes ranging between 3.5-5.5 Hz for a double bond. They decay more slowly with the distance between perturbing and responding nucleus than the sigma contributions to the FC term. The sign of the passive FC(pi) contribution can be assessed from a Dirac vector model. The limits for long-range coupling in a polyene were determined and their practical implications discussed. PMID- 19785132 TI - Illustrative direct ab initio calculations of surface Raman spectra. AB - Illustrative ab initio calculations of Raman spectra of pyridine (Pyr) and pyridine in metal-molecule complexes with silver (Ag+-Pyr, Ag5+-Pyr) have been undertaken. The Raman spectra were computed numerically in the standard Placzek approximation with the additional feature of a static external electric field, F, perturbation to the system Hamiltonian. F was allowed to change the system equilibrium geometry and symmetry as well as the polarisability, resulting in shifted vibration frequencies and changed Raman intensities. All calculations were done on a Hartree-Fock (HF) level using the 6-31+G* or the Sadlej p-VTZ basis sets for Pyr, and the Stevens Krauss (SBKJC) VDZ ECP basis set for Ag. Raman enhancement factors over 5 orders of magnitude were obtained. The enhancement was analyzed as being due to polarization and charge transfer induced by the metal-molecule contact in the absence of F and in the presence of a strong F as due to increased polarisability derivatives along the surface normal. The use of the present method to qualitatively and quantitatively predict surface Raman spectra is discussed. PMID- 19785136 TI - Ozonolysis of oleic acid particles: evidence for a surface reaction and secondary reactions involving Criegee intermediates. AB - The heterogeneous reactions of ozone with monodisperse oleic acid and methyl oleate particles were studied by monitoring the loss of the condensed-phase species using an aerosol chemical ionization mass spectrometer (Aerosol CIMS). The reaction of ozone with oleic acid was determined to occur at the surface of the particles despite previous assumptions that it reacts in the bulk. The ozonolysis of methyl oleate particles, on the other hand, was found to be limited by the diffusion of ozone and does react in the bulk. The difference in reaction mechanisms is attributed to the larger degree of order in oleic acid known to result from the formation of hydrogen-bonded dimers. The reactive uptake coefficients, gamma, calculated from the rate of loss of the particle species are gamma = (1.38 +/- 0.06) x 10(-3) for oleic acid and gamma = (1.23 +/- 0.10) x 10( 3) for methyl oleate. However, it is found that secondary reactions between Criegee intermediates and the carboxylic acid moiety in oleic acid are responsible for 36% (+/-4%) of its observed loss. Hence, the rate of loss of ozone cannot be equated to the rate of loss of oleic acid. Accounting for this additional reaction the uptake coefficient for ozone on oleic acid particles is calculated to be gamma = (8.8 +/- 0.5) x 10(-4). The magnitude of these secondary reactions quantitatively reconciles discrepancies between previous coated flow tube and particle-based studies, and it illustrates the need to include additional loss mechanisms when calculating uptake coefficients from the rates of loss of particle species. Implications of reactions with Criegee intermediates in atmospheric particles are discussed. PMID- 19785137 TI - Femtosecond transient absorption spectroscopy of single-walled carbon nanotubes in aqueous surfactant suspensions: determination of the lifetime of the lowest excited state. AB - Femtosecond one- and two-colour pump-probe spectroscopy of single-walled carbon nanotubes (SWNTs) individual in aqueous surfactant suspensions has been used to assess the "intrinsic" lifetime of the lowest excited states. We demonstrate that such measurements can be perturbed by several competing photophysical processes thus making lifetime deconvolution difficult. Furthermore we show how these effects, arising primarily from sample heterogeneity, can be reduced. Measurements of induced transients in the near IR yield lifetimes of (35 +/- 10) ps and (56 +/- 10) ps, for nanotubes having mean diameters of 0.95 and 1.2 nm, respectively. Furthermore, a fast decay component in the ps to sub-ps regime is also observed. We tentatively attribute this to relaxation in SWNT bundle components. PMID- 19785138 TI - Localized electrosynthesis of polypyrrole by application of short voltage pulses. AB - By the application of short voltage pulses to a tool electrode in close proximity to a substrate electrode, the electro-polymerization of pyrrole in aqueous solution was locally confined with down to micrometer precision. Depending on the pulse parameters polypyrrole towers with up to 100 microm height and about 50 microm diameter were fabricated on the substrate. The spatial confinement of the electro-polymerization reaction is explained by the local charging behavior of the double layer capacitance during voltage pulses of only 100 ns to 10 micros duration. Additionally, the 3D morphology of the polymer patterns is influenced by the diffusion of the educts and intermediate reaction products in the gap between the tool electrode and the substrate. Proper choice of the tool substrate distance and the pulse to pause ratio of the pulse trains allows the deposition of structures whose morphologies vary from fiber-like to cauliflower-like and compact. PMID- 19785139 TI - EPR studies on the organization of self-assembled spin-labeled organic monolayers adsorbed on GaAs. AB - Characterizing the structure and dynamic properties of a single monolayer is a challenge due to the minute amount of material that is probed. Here, EPR spectroscopy is used for investigating the spatial and temporal organization of self-assembled monolayers of 5- and 16-doxyl stearic acid (5 DSA and 16 DSA, respectively) adsorbed on a GaAs substrate. The results are complemented with FTIR and ellipsometery measurements, which provide the evidence for the formation of monolayers. Moreover, a comparison with the FTIR spectrum of a monolayer of stearic acid shows that the monolayers of the spin labeled molecules are less packed due to the hindrance introduced by the labeling group. The EPR spectra provide a new insight on the ordering in the layer and more interestingly, it reveals the time dependence of the organization. For 5DSA, with the spin-label group situated close to the substrate, the EPR spectrum immediately after adsorption is poorly resolved and dominated by the spin-exchange interaction between neighboring molecules. As time increases (up to 1 week) the resolution of the 14N hyperfine coupling increases, revealing a better organized monolayer where the molecules are more homogenously spaced. Moreover, the spectrum of the layer, after reaching equilibrium, shows that there is no motional freedom near the GaAs surface. Orientation dependence measurements on the equilibrated sample show the presence of a preferred orientation of the molecules, although with a wide distribution. The spectrum of the 16DSA monolayer, where the nitroxide spin label is situated at the end of the chain, far from the surface, also showed a poorly resolved spectrum at short times, but unlike 5DSA, it did not exhibit any time dependence. Through EPR line-shape simulations and by comparison with FTIR results, the differences between 5DSA and 16DSA were attributed to difference in coverage caused by the bulky spin label near the surface in the case of 5DSA. PMID- 19785140 TI - Experimental and theoretical characterisation of sonochemical cells. Part 2: cell disruptors (Ultrasonic horns) and cavity cluster collapse. AB - Cavitation theory is used to predict the acoustic pressure at the boundary of the inertial/non inertial threshold for a range of bubble sizes. The sound field generated from a commonly employed sonoelectrochemical cell is modelled. The model is tested with a calibrated hydrophone far from the transducer to avoid spatial averaging. This allows the model to provide the absolute pressure amplitude as a function of axial distance from the source. An electrochemical technique for detecting both inertial and non-inertial cavitation within the solution is employed. This technique uses a dual microelectrode to map the boundary between the regions where inertial cavitation occurs (associated with surface erosion), and where it does not. This zone occurs close to the transducer for the microelectrode employed (<1.5 mm). Further characterisation of the inertial cavitation zone is achieved by imaging of multibubble sonoluminescence (MBSL). The pressures at the boundary between inertial and non inertial cavitation that are determined from the electrochemical and imaging experiments are compared to a sound field model and cavitation theory. Qualitative arguments for the invasive nature of the electrode into the sound field are proposed. Evidence for cavity cluster collapse and shock wave emission is presented and discussed in relation to luminescence, the electrochemical experiments and cavitation theory. PMID- 19785141 TI - Isothermal activation of Mo2O5(2+)-ZSM-5 precursors during methane reactions: effects of reaction products on structural evolution and catalytic properties. AB - The dynamics of carburization of Mo-oxo precursors exchanged onto H-ZSM-5 strongly influence initial induction periods and steady-state rates during catalytic pyrolysis of CH4 to alkenes and arenes at 900-1000 K. The effects of co reactants and of activating conditions were examined by on-line time-resolved mass spectrometric analysis of effluent streams using rigorous analyses to account for equilibrium effects on measured rates. Ethene co-reactants and the larger hydrocarbons to which it converts on acid sites in H-ZSM-5 led to much faster carburization of exchanged (Mo2O5)(5+) dimers and to shorter induction periods than with pure CH4 reactants, but steady-state pyrolysis rates were unchanged, indicating that CH4 and C2H4 form similar MoCx clusters during carburization of exchanged Mo-oxo precursors. H2 treatment at 973 K before CH4 reactions led to reduction of Mo(6+) species to Mo(4+), which carburize faster than (Mo2O5)(5+) precursors during initial contact with CH4. This H2 pretreatment or the use of CH4-H2 reactant mixtures did not influence steady-state pyrolysis rates, once contributions from reverse reactions were taken into account. With pure CH4 streams, (Mo2O5)(5+)-ZSM-5 converts to active MoCx clusters within zeolite channels via autocatalytic processes, in which higher hydrocarbons, initially formed during initial conversion of MoOx to MoCx structures, lead to faster carburization of downstream catalyst sections. Concurrently, H2O and CO2 formed during this incipient carburization of exchanged (Mo2O5)(5+) and unexchanged MoO3 present in trace amounts inhibit and even prevent carburization and lengthen activation periods. Activation protocols with C2H4 were also successful in the activation of more refractory high-valent metal-oxo species, such as WOx and VOx, exchanged onto H-ZSM-5. The formation of active carbide structures occurred in less than 300 s, instead of 4 ks and 16 ks for VOx and WOx samples, respectively, in pure CH4 reactants. These activation protocols led to VCx-ZSM5 catalysts about three times more active than those activated in pure CH4 reactants. PMID- 19785142 TI - Spectroscopic studies of oligodiacetylenes in solution and polymer film. AB - The photophysical properties of a series of monomeric, dimeric and trimeric oligodiacetylenes (ODAs; oligoenynes) bearing trimethylsilyl, t-butyl and n-octyl end-capping substituents were studied in solution and in a polymer film. Emission studies show a significant emission of oligodiacetylenes in solution, which increased with increased conjugation. This is remarkable given the near absence of fluorescence in oligoenes of similar length (e.g. hexatriene) and polydiacetylenes (PDAs), which constitute the conjugation limit. A large Stokes shift was observed, and shown to originate from an energy difference between the Franck-Condon excited state and the fluorescent state. From near-identical angles obtained for the absorption and emission dipoles it was concluded that the overall geometry of ODAs does not significantly change upon electronic transition. PMID- 19785143 TI - A time-dependent Hartree-Fock approach for studying the electronic optical response of molecules in intense fields. AB - For molecules in high intensity oscillating electric fields, the time-dependent Hartree-Fock (TDHF) method is used to simulate the behavior of the electronic density prior to ionization. Since a perturbative approach is no longer valid at these intensities, the full TDHF equations are used to propagate the electronic density. A unitary transform approach is combined with the modified midpoint method to provide a stable and efficient algorithm to integrate these equations. The behavior of H2+ in an intense oscillating field computed using the TDHF method with a STO-3G basis set reproduces the analytic solution for the two-state coherent excitation model. For H2 with a 6-311++G(d,p) basis set, the TDHF results are nearly indistinguishable from calculations using the full time dependent Schrodinger equation. In an oscillating field of 3.17 x 10(13) W cm(-2) and 456 nm, the molecular orbital energies, electron populations, and atomic charges of H2 follow the field adiabatically. As the field intensity is increased, the response becomes more complicated as a result of contributions from excited states. Simulations of N2 show even greater complexity, yet the average charge still follows the field adiabatically. PMID- 19785144 TI - Level of theory study of magnetic resonance parameters of chalcogen XY- (X, Y = O, S and Se) defects in alkali halides. AB - An extensive level of theory study is performed on diatomic chalcogen defects in alkali halide lattices by density functional theory methods. A variety of exchange correlation functionals and basis sets are used for the calculation of electron paramagnetic resonance (EPR) parameters of XY (X, Y = O, S, Se) molecular ions doped in MZ (M = Na, K, Rb and Z = Cl, Br, I) lattices. Various factors contribute to the EPR values, such as geometrical effects, the choice of basis set and functional form. A sensitivity analysis is made by comparing experimental and theoretical magnetic resonance data. A flow scheme is proposed for obtaining the best agreement between experimental and calculated g-values for chalcogen defects in alkali halides. PMID- 19785145 TI - Redox and spin-trapping properties of phosphoryldithioacetates. AB - The redox properties of ethyl diethoxyphosphoryldithioacetate (1), methyl diethoxyphosphorylfluorodithioacetate (2) and methyl diethoxyphosphoryldifluorodithioacetate (3) were measured by cyclic voltammetry. Addition of free radicals to the three dithioesters led to the detection of the ESR spectra of the spin adducts only with the last two compounds. Based on the reduction potentials of the three dithioacetates, this may be explained by capto dative stabilization of the adducts. On the basis of DFT calculations, the temperature dependent variations of the spectral patterns exhibited by the radicals were attributed to restricted rotation about the Calpha-SMe bond. PMID- 19785146 TI - Environmental effects on vibrational proton dynamics in H5O2+: DFT study on crystalline H5O2+ClO4-. AB - The structure as well as IR and inelastic neutron scattering (INS) spectra of H5O2+ in crystalline H5O2+ClO4- were simulated using Car-Parrinello molecular dynamics with the BLYP functional. The potential of the O...H+...O fragment is very shallow. The Pnma structure, assumed in the X-ray study to be the most suitable choice, is a saddle point on the potential energy surface, while the P2(1)2(1)2(1) minimum structure is only 20 cm(-1) lower in energy. The computed INS and IR spectra enable us to achieve a complete assignment of the observed spectra. The broad band between 1000 and 1400 cm(-1) is due to the asymmetric stretch and one of the bending vibrations of the O...H+...O fragment, while the band between 1600 and 1800 cm(-1) is due to the bending vibration of the water molecules and the second bending of the O...H+...O fragment. Comparison with the vibrational spectra of isolated H5O2+, obtained using Born-Oppenheimer molecular dynamics simulation, reveals environmental effects on vibrational proton dynamics in strong H-bonded species. The most pronounced changes are found for the O...H+...O bending modes because the two bending coordinates become distinctly different for the structure that the H5O2+ ion assumes in the crystal. PMID- 19785147 TI - Lanthanide cation extraction by malonamide ligands: from liquid-liquid interfaces to microemulsions. A molecular dynamics study? AB - According to molecular dynamics simulations, uncomplexed malonamide ligands L and their neutral Eu(NO3)3L2 or charged EuL4(3+) complexes are surface active and adsorb at a water-"oil" interface, where "oil" is modeled by chloroform. Aqueous solvation at the interface is found to induce a trans to gauche rearrangement of the carbonyl groups, i.e., to preorganize the chelating L ligands for complexation. The interface also induces a larger proportion of extended amphiphilic forms, of EE-gauche type. The effect of increased oil/water ratio is also investigated. It shown that the system evolves from a well-defined interface between immiscible phases to water-in-oil cylindrical micelles and micro droplets, onto which L ligands and the lanthanide complexes adsorb, while other ligands are extracted in organic phase. Two electrostatic models of the complexes are compared and, in no case is the neutral or charged complex fully extracted to the organic phase. These features allow us to better understand synergistic and solvation effects in the assisted liquid-liquid extraction of lanthanide or actinide cations. PMID- 19785149 TI - Benzyl alcohol oxidation in supercritical carbon dioxide: spectroscopic insight into phase behaviour and reaction mechanism. AB - Selective oxidation of benzyl alcohol to benzaldehyde with molecular oxygen over an alumina-supported palladium catalyst was performed with high rate at about 95% selectivity in supercritical carbon dioxide. The experiments in a continuous flow fixed-bed reactor showed that the pressure has a strong influence on the reaction rate. A marked increase of the rate (turnover frequency) from 900 h(-1) to 1800 h(-1) was observed when increasing the pressure from 140 to 150 bar. Video monitoring of the bulk fluid phase behavior and the simultaneous investigation by transmission and attenuated total reflection (ATR) infrared spectroscopy at two positions of the view cell showed that the sharp increase in activity is correlated to a transition from a biphasic to a monophasic reaction mixture. In the single phase region, both oxygen and benzyl alcohol are dissolved in the supercritical CO2 phase, which leads to a reduction of the mass transport resistances (both in the external fluid film and in the catalyst pores) and thus to the high reaction rate measured in the catalytic experiments. The phase transition could be effectively and easily monitored by transmission and ATR-IR spectroscopy despite the small concentration of the dense liquid like phase. Deposition of the Pd/Al2O3 catalyst on the ATR-crystal at the bottom of the view cell allowed to gain insight into the chemical changes and mass transfer processes occurring in the solid/liquid interface region during reaction. Analyzing the shift of the upsilon2 bending mode of CO2 gave information on the fluid composition in and outside the catalyst pores. Moreover, the catalytic reaction could be investigated in situ in this spectroscopic batch reactor cell by monitoring simultaneously the reaction progress, the phase behaviour and the catalytic interface. PMID- 19785151 TI - Orienting and aligning molecules for stereochemistry and photodynamics. AB - Production, characterization and control of polarization states of molecules (specifically, alignment and/or orientation) are of importance for investigating in detail the stereodynamics of elementary processes involving elastic, inelastic and reactive events and also to prepare targets for selective photodynamical investigations. The focus here is on those molecular beam techniques which show perspectives in the applications offering appealing features for "duty cycle" and intensity characteristics. After a review of the basic experimental advances, mainly obtained in the last ten years, the attention will be addressed to recent studies carried out on the collisional alignment of hydrocarbon molecules and on orientation of symmetric top molecules by exploiting honeycomb hexapole fields. The first case is a prototype of "natural" polarization techniques, the second one of those where polarization is "forced" by external fields. PMID- 19785152 TI - Photodissociation dynamics of SOCl2. AB - New theoretical and experimental results for the ultraviolet photodissociation dynamics of thionyl chloride (SOCl2) are presented and combined with existing data from a variety of sources in order to provide a unified view of the photodissociation dynamics of SOC12. Time-dependent density functional theory on the basis of the hybrid-type B3LYP functional was employed to calculate vertical excitation energies for the SOCl2 parent molecule up to 6.3 eV. Three-dimensional (3D) imaging of photofragments was performed for a dissociation wavelength of 235 nm. Atomic chlorine fragments were observed in the 2P(3/2) ground state [Cl] and the 2P(1/2) excited spin-orbit state [Cl*] by employing resonance enhanced multi photon ionization (REMPI) and time-of-flight (TOF) techniques. State-specific speed distributions and the speed dependence of the beta anisotropy parameter were obtained from the full 3D momentum vector distribution by appropriate projection methods. Bimodal speed distributions for both spin-orbit states are evidence of a competition between the radical (SOCl2 --> SOCl + Cl/Cl*) and the three-body decay channel (SOCl2 --> SO + 2 Cl/Cl*). No evidence of the molecular fragmentation channel (SOCl2 --> SO + Cl2) was found. With increasing fragment speed the beta anisotropy parameter increases from 0.1 to 0.85 and 0.68 for Cl and Cl*, respectively, suggesting fragmentation via an excited A' state for slow fragments and via an A" state for fast fragments. The calculations allow for the first time to interpret all previous and new experimental data for the ultraviolet photodissociation of SOCl2 by assuming simultaneous excitation of several excited electronic states giving rise to competing dissociation channels. PMID- 19785156 TI - Experimental study of the interaction of HO2 radicals with soot surface. AB - The reaction of HO2 with toluene and kerosene flame soot was studied over the temperature range 240-350 K and at P = 0.5-5 Torr of helium using a discharge flow reactor coupled to a modulated molecular beam mass spectrometer. A flat flame burner was used for the preparation and deposition of soot samples from premixed flames of liquid fuels under well controlled and adjustable combustion conditions. The independent of temperature in the range 240-350 K value of gamma = (7.5 +/- 1.5) x 10(-2) (calculated with geometric surface area) was found for the uptake coefficient of HO2 on kerosene and toluene soot. No significant deactivation of soot surface during its reaction with HO2 was observed. Experiments on soot ageing under ambient conditions showed that the reactivity of aged soot is similar to that of freshly prepared soot samples. The results show that the HO2 + soot reaction could be a significant loss process for HOx in the urban atmosphere with a potential impact on photochemical ozone formation. In contrast this process will be negligible in the upper troposphere even in flight corridors. PMID- 19785157 TI - Quantum yields of OH, HO2 and NO3 in the UV photolysis of HO2NO2. AB - Quantum yields, phi, of OH and HO2 in the ultraviolet photolysis of HO2NO2 (peroxynitric acid, PNA) at 193 and 248 nm and that of NO3 at 193, 248 and 308 nm are reported. Quantum yields were measured using pulsed excimer laser photolysis combined with pulsed laser induced fluorescence (PLIF) detection of OH radicals and cavity ring-down (CRD) detection of NO3 radicals. HO2 radicals were quantified by converting them to OH via the HO2 + NO --> OH + NO2 reaction and detecting OH. The quantum yields obtained at 296 K are: phi193 nm(OH) = 0.21 +/- 0.12, phi248 nm(OH) = 0.085 +/- 0.08, phi193 nm(HO2) = 0.56 +/- 0.09, phi248 nm(HO2) = 0.89 +/- 0.26, phi193 nm(NO3) = 0.35 +/- 0.09, phi248 nm(NO3) = 0.08 +/ 0.04 and phi308 nm(NO3) = 0.05 +/- 0.02. The quoted uncertainties are 2sigma (95% confidence level) and include estimated systematic errors. Our results are compared with the previous quantum yield measurements of OH (MacLeod et al., J. Geophys. Res., 1988, 93, 3813) and NO2 (Roehl et al., 2001, J. Phys. Chem., 105, 1592) at 248 nm and the discrepancies are discussed. The rate coefficients at 298 K for reactions of OH with HO2NO2, H2O2, HNO3 and NO are also reported. PMID- 19785158 TI - Kinetics of the reactions of HO with methanol (210-351 K) and with ethanol (216 368 K). AB - Absolute rate coefficients for the reaction of hydroxyl radicals (HO) with methanol, HO + CH3OH --> products (R1), and with ethanol, HO + C2H5OH --> products (R2) were measured over a range of temperatures using pulsed laser photolytic generation of HO coupled to its time resolved detection by pulsed laser induced fluorescence. The accuracy of the rate constants obtained was enhanced by on-line optical absorption measurements of the alcohol concentration. The temperature dependence of the rate coefficients is given by: k1(210-351 K) = 6.67 x 10(-18) T2 exp(140/T) cm3 molecule(-1) s(-1) with a rate coefficient at room temperature of (9.3 +/- 0.7) x 10(-13) cm3 molecule(-1) s(-1). For k2 we obtained: k2(216-368 K) = 4.0 x 10(-12) exp(-42/T) and a room temperature rate coefficient of (3.35 +/- 0.17) x 10(-12) cm3 molecule(-1) s(-1). The total error (at 95% confidence) associated with the rate coefficients derived from the expressions describing the temperature dependence is estimated as 7% at all temperatures. The present results, which extend the database on these reactions to cover temperatures relevant for the upper troposphere, are compared to previously published measurements, and values of k1 and k2 are recommended for atmospheric modelling. PMID- 19785162 TI - Pressure modulation, a new dynamic technique for the electrochemical determination of adsorption, reaction and activation volumes. AB - A new dynamic method for the measurement of pressure dependent kinetic and thermodynamic quantities is described and its successful operation demonstrated for two example systems. The pressure was modulated with an amplitude of only +/ 1 bar or less by means of a piezo-transducer. The small effect on the reaction rate, potential or charge of the electrode can be detected using the lock in technique. The determination of the reaction volume of the redox couple Fe(CN)6(4 )/Fe(CN)6(3-) served as a control of the validity of the measurement and the reliability of the experimental approach. As a first model system the adsorption of hydrogen on polycrystalline Pt was studied. A volume of adsorption of 4.8 cm3 mol(-1) was found. The partial molar volume for protons in water (upsilon+ = -5.4 cm3 mol(-)) measured by Zana and Yeager, J. Phys. Chem., 1967, 71, 521-536, was used to establish that the partial molar volume of the adsorbed hydrogen was close to zero. PMID- 19785164 TI - Ultrafast deactivation mechanisms of protonated aromatic amino acids following UV excitation. AB - Deactivation pathways of electronically excited states have been investigated in three protonated aromatic amino acids: tryptophan (Trp), tyrosine (Tyr) and phenylalanine (Phe). The protonated amino acids were generated by electrospray and excited with a 266 nm femtosecond laser, the subsequent decay of the excited states being monitored through fragmentation of the ions induced and/or enhanced by another femtosecond pulse at 800 nm. The excited state of TrpH+ decays in 380 fs and gives rise to two channels: hydrogen atom dissociation or internal conversion (IC). In TyrH, the decay is slowed down to 22.3 ps and the fragmentation efficiency of PheH+ is so low that the decay cannot be measured with the available laser. The variation of the excited state lifetime between TrpH+ and TyrH+ can be ascribed to energy differences between the dissociative pi sigma* state and the initially excited pi pi* state. PMID- 19785165 TI - Evidence of overestimation of rate constants for the superoxide trapping by nitrones in aqueous media. AB - Since major disagreements exist regarding the kinetics of superoxide trapping by nitrones, the underlying theory of one of the most popular method used in these studies was reinvestigated. It involves a competition between the nitrone of interest and a superoxide scavenger, and implies that the superoxide spontaneous dismutation, the spin adduct decay, and the consumption of the competitor during the course of the experiments are negligible events. Evidences of the importance of these three unduly neglected reactions are given, and errors connected to their omission are estimated. Hence this Stern-Volmer-like method should be avoided in the determination of rate constants for the trapping of superoxide by nitrones. PMID- 19785168 TI - Vibrational spectroscopy of a non-aromatic amino acid-based model peptide: identification of the gamma-turn motif of the peptide backbone. AB - The first infrared hole burning spectrum of a gas-phase neutral peptide not containing an aromatic amino acid is presented. In the model peptide Z-Pro-NHMe, the amide I and II bands in the 1500-1800 cm(-1) region appear to be a clear diagnostic for the secondary structure of the backbone, while the analysis of a series of coupled CH bending modes in the 1000-1500 cm(-1) region allows to distinguish between different possible orientations of the chromophore. The geometry of the peptide is strongly constrained by the proline and only one conformation of the backbone is observed, which is identified as a hydrogen bonded gamma-turn. PMID- 19785169 TI - Computer aided design of nano-structured materials with tailored ionic conductivities. AB - We show, using simulation techniques, that the high ionic conductivity in BaF2/CaF2 heterolayers is because the interfaces reduce the activation energy barriers to mobility and increase the number of charge carriers. PMID- 19785170 TI - High-field EPR spectroscopy applied to biological systems: characterization of molecular switches for electron and ion transfer. AB - The last decade witnessed a tremendous growth in combined efforts of biologists, chemists and physicists to understand the dominant factors determining the specificity and directionality of transmembrane transfer processes in proteins. A large variety of experimental techniques is being used including X-ray and neutron diffraction, but also time-resolved optical, infrared and magnetic resonance spectroscopy. This is done in conjunction with genetic engineering strategies to construct site-specific mutants for controlled modification of the proteins. As a general perception of these efforts, the substantial influence of weak interactions within the protein and its membrane interfaces is recognized. The weak interactions are subject to subtle changes during the reaction cycle owing to the inherent flexibility of the protein-membrane complex. Specific conformational changes accomplish molecular-switch functions for the transfer process to proceed with optimum efficiency. Characteristic examples of time varying non-bonded interactions are specific H-patterns and/or polarity effects of the microenvironment. The present perception has emerged from the coupling of newly developed spectroscopic techniques - and advanced EPR certainly deserves credit in this respect - with newly developed computational strategies to interpret the experimental data in terms of protein structure and dynamics. By now, the partners of this coupling, particularly high-field EPR spectroscopy and DFT-based quantum theory, have reached a level of sophistication that applications to large biocomplexes are within reach. In this review, a few large paradigm biosystems are surveyed which were explored lately in our laboratory. Taking advantage of the improved spectral and temporal resolution of high frequency/high-field EPR at 95 GHz/3.4 T and 360 GHz/12.9 T, as compared to conventional X-band EPR (9.5 GHz/0.34 T), three biosystems are characterized with respect to structure and dynamics: (1) Light-induced electron-transfer intermediates in wild-type and mutant reaction-centre proteins from the photosynthetic bacterium Rhodobacter sphaeroides, (2) light-driven proton transfer intermediates of site-specifically nitroxide spin-labelled mutants of bacteriorhodopsin proteins from Halobacterium salinarium, (3) refolding intermediates of site-specifically nitroxide spin-labelled mutants of the channel forming protein domain of Colicin A bacterial toxin produced in Escherichia coli. The detailed information obtained is complementary to that of protein crystallography, solid-state NMR, infrared and optical spectroscopy techniques. A unique strength of high-field EPR is particularly noteworthy: it can provide highly desired detailed information on transient intermediates of proteins in biological action. They can be observed and characterized while staying in their working states on biologically relevant time scales. The review introduces the audience to origins and basic experiments of EPR in relation to NMR, describes the underlying strategies for extending conventional EPR to high-field/high frequency EPR, and highlights those details of molecular information that are obtained from high-field EPR in conjunction with genetic engineering and that are not accessible by "classical" spectroscopy. The importance of quantum-chemical interpretation of the experimental data by DFT and advanced semiempirical molecular-orbital theory is emphasized. A short description of the laboratory built 95 GHz and 360 GHz EPR/ENDOR spectrometers at FU Berlin is also presented. The review concludes with an outlook to future opportunities and challenges of advanced bio-EPR in interdisciplinary research. PMID- 19785172 TI - Methane clustering in explicit water: effect of urea on hydrophobic interactions. AB - Methane aggregation in water has been studied by simulation for thirteen systems of different sizes and compositions. It was found that favourable cluster formation only occurs after a certain critical cluster size has been reached. The effect of urea on hydrophobic clustering was studied for two urea concentrations. High urea concentrations result in slightly enhanced methane cluster formation, rather than a reduction of the hydrophobic effect. Structural analysis of the Kirkwood-Buff excess coordination and preferential solvation points at a mechanism in which urea pushes the methane into the water, locally increasing methane concentration and hence promoting cluster formation. PMID- 19785174 TI - Entrance channel X-HF (X = Cl, Br and I) complexes studied by high-resolution infrared laser spectroscopy in helium nanodroplets. AB - Rotationally resolved infrared spectra are reported for halogen atom-HF free radical complexes formed in helium nanodroplets. An effusive pyrolysis source is used to dope helium droplets with Cl, Br and I atoms, formed by thermal dissociation of Cl2, Br2 and I2. A single hydrogen fluoride molecule is then added to the droplets, resulting in the formation of the X-HF complexes of interest. Analysis of the resulting spectra confirms that the observed species have 2Pi3/2 ground electronic states, consistent with the linear hydrogen bound structures predicted from theory. Stark spectra are also reported for these species, from which the permanent electric dipole moments are determined. PMID- 19785175 TI - High-resolution absorption cross sections of formaldehyde at wavelengths from 313 to 320 nm. AB - Absorption cross sections have been measured for the 2(0)(2)4(0)(3) and 2(0)(3)4(0)(1) vibrational bands of the [formula: see text] electronic transition of formaldehyde in the wavelength range 313-320 nm. Accurate values are of considerable importance for atmospheric monitoring and to understand the photochemistry of this compound. The 0.10 cm(-1) FWHM wavenumber resolution of the experiments is determined by the bandwidth of the ultraviolet laser used, and is a factor of 10 or more higher than any previously reported data. The absorption cross section data are thus obtained at a spectrometer resolution close to the Doppler broadening limit at 294 K of 0.07 cm(-1) FWHM, for isolated rotational lines, but lifetime broadening effects contribute a further approximately 0.5 cm(-1) of width. Our spectral resolution is thus higher than required to resolve the sharpest spectral features and, as a consequence, the cross sections peak at greater values than previous studies of these structured rovibronic bands conducted at much lower spectrometer resolutions. Previous data can be quantitatively reproduced by convolution of the newly obtained spectra with lower-resolution instrument functions. Pressure broadening of regions of the spectra in the presence of up to 500 Torr of N2 is examined and the effects on peak absorption cross sections are very small. The influence of reduced temperature on the spectrum is also explored through experimental measurements and spectral simulations. PMID- 19785176 TI - Tetrathiafulvalene-phosphine-based iron and ruthenium carbonyl complexes: electrochemical and EPR studies. AB - The radical cation of the redox active ligand 3,4-dimethyl-3',4'-bis (diphenylphosphino)-tetrathiafulvalene (P2) has been chemically and electrochemically generated and studied by EPR spectroscopy. Consistent with DFT calculations, the observed hyperfine structure (septet due to the two methyl groups) indicates a strong delocalization of the unpaired electron on the central S2C=CS2 part of the tetrathiafulvalene (TTF) moiety and zero spin densities on the phosphine groups. In contrast with the ruthenium(0) carbonyl complexes of P2 whose one-electron oxidation directly leads to decomplexation and produces P2*+, one-electron oxidation of [Fe(P2)(CO)3] gives rise to the metal-centered oxidation species [Fe(I)(P2)(CO)3], characterized by a coupling with two 31P nuclei and a rather large g-anisotropy. The stability of this complex is however modest and, after some minutes, the species resulting from the scission of a P-Fe bond is detected. Moreover, in presence of free ligand, [Fe(I)(P2)(CO)3] reacts to give the complex [Fe(I)(P2)2(CO)] containing two TTF fragments. The two electron oxidation of [Fe(P2)(CO)3] leads to decomplexation and to the P2*+ spectrum. Besides EPR spectroscopy, cyclic voltammetry as well as FTIR spectroelectrochemistry are used in order to explain the behaviour of [Fe(P2)(CO)3] upon oxidation. This behaviour notably differs from that of the Ru(0) counterpart. This difference is tentatively rationalized on the basis of structural arguments. PMID- 19785177 TI - Isotopic induction of the excited-state single-proton transfer in 7-azaindole dimer. AB - The electronic spectrum in 2-methylbutane of the doubly hydrogen-bonded 7 azaindole dimer in monodeuterated form, (7AI)2-hd, is consistent with a single proton transfer that never produces the typical emission for the double proton transfer with its centre at 480 nm and onset at 413 nm. PMID- 19785182 TI - Activity of surface active substances determined from their surface excess. AB - Commonly, the surface excess is determined from surface tension measurements via the Gibbs equation. This equation relates the activity (chemical potential), the surface excess, and the surface tension. When knowing two out of the three quantities, the third one can be calculated. Unfortunately, in the case of surface active components the concentration is in most cases too low to determine the activity from a measurable change in the bulk properties and thus assumptions are made about the activity coefficients. However, if the surface excess is measured directly and the surface tension is known, the activity can be determined making use of the Gibbs equation. The surface excess is the quantity of a surfactant solution which changes most strongly with the concentration. Thus it is obvious that this procedure should be used to determine activity coefficients of surfactants. One of the few techniques for determining the surface excess directly is neutral impact collision ion scattering spectroscopy (NICISS). With NICISS concentration depth profiles can be measured in the surface near region with a depth resolution of a few angstroms. The surface excess and the activities are investigated here for the system tetrabutylphosphonium bromide (Bu4PBr) dissolved in the polar solvent formamide. PMID- 19785184 TI - Headgroup organization and hydration of methylated phosphatidylethanolamines in Langmuir monolayers. AB - Subtle differences in the molecular conformation of fully hydrated phospholipids, and in their interaction with the water reservoir, were assessed as functions of headgroup methylation with surface-sensitive X-ray scattering. To achieve such a structural and functional comparison, diacylphosphatidylethanolamines (PEs) and their mono-, di- and trimethylated (diacylphosphatidylcholine, PC) derivatives in surface monolayers on water have been studied. While the molecular structures of these lipids are quite similar, their subtle distinctions lead to surprisingly large differences in their overall organization. Independent of the surface pressure, pi, the amine function in PE extends 1-2 A further into the subphase than those of the methylated headgroups. Not only is the exposure of the amine moiety to water in PE thus larger than that of the other lipids, but also the phosphate and lipid backbone of PE are more hydrated than that of PC. Overall, the PE headgroup hydration is approximately 25% larger than that of PE-N-Me, PE-N Me2 or PC. The main reason for these differences resides in their distinct capabilities to donate hydrogen bonds, but differences in the hydrophobicities of the amine functions on the lipid headgroups may also play a role. While the impact of amine methylation on the headgroup interaction with the water subphase appears rather straightforward, there are also differences in lipid backbone organization and acyl chain packing. The results presented here provide a deeper understanding of lipid conformation as the hydrophobicity of the terminal headgroup fragment is systematically altered and may also impact on our understanding of the molecular details of membrane fusion. PMID- 19785185 TI - Correlated ionic hopping processes in crystalline and glassy electrolytes resulting in MIGRATION-type and nearly-constant-loss-type conductivities. AB - Solid electrolytes with disordered structures may be crystalline or glassy. Their complex ionic conductivity displays a characteristic frequency dependence. Modelling the dynamics of the mobile ions, we have developed the MIGRATION concept, the acronym standing for MIsmatch Generated Relaxation for the Accommodation and Transport of IONs. With the help of the MIGRATION concept it is possible to reproduce frequency-dependent experimental conductivities and permittivities including their scaling behaviour. Scaling is a property typically observed in and below the radio frequency regime. At sufficiently high frequencies and low temperatures, however, conductivity spectra of crystals and glasses are often found to contain a second component which displays the so called nearly-constant-loss (NCL) behaviour. Suitably modifying the MIGRATION concept, we are able to explain this feature and to show that it is caused by a displacive or hopping ionic motion that stays completely localised. Here, as in the unmodified MIGRATION concept, interactions between the ions play an essential role. Experimentally, interesting differences are detected between the NCL-type dynamics in a crystalline and in a glassy ion conductor. In crystalline gamma RbAg4I5 we find the same elementary rates for the MIGRATION-type and NCL-type hopping movements of the ions, suggesting identical barrier heights for the respective processes. On the other hand, the two rates are found to differ markedly from each other in glassy AgI-AgPO3, not only with regard to their absolute value but also in their temperature dependence. We suggest that the NCL effect in the glass results from dynamic localised displacements involving both the silver ions and negatively charged entities such as iodide ions and/or non bridging oxygen ions. PMID- 19785190 TI - Highly dispersed magnesium oxide species on silica as photoactive sites for photoinduced direct methane coupling and photoluminescence. AB - Photoinduced direct methane coupling proceeded around room temperature over highly dispersed magnesium oxide species on silica, which exhibited fine structure in photoluminescence emission spectra. It was found that increasing the emission intensity tends to give an increase in the photoactivity for this reaction. The emission sites in the silica-supported magnesia have vibrational energy around 950 cm(-1) and lifetime of excited state around 38 ms, which were similar properties to the previously reported other silica-based photoactive systems for this reaction, such as silica-alumina and silica-supported zirconia. These photoluminescence spectra could be similarly quenched by methane molecules. Thus, it is commonly suggested that in the systems of highly dispersed metal oxide species (MOx) on silica, the surface Si-O-M bonds are deeply related to the dominant photoactive sites for both the fine structural photoluminescence spectra and photoinduced direct methane coupling. PMID- 19785192 TI - Real time quantitative Raman spectroscopy of supported metal oxide catalysts without the need of an internal standard. AB - In continuation to the possibility of using a combined operando Raman/UV-Vis-NIR set-up for conducting qualitative Raman spectroscopy, the possibilities for quantitative Raman spectroscopic measurements of supported metal oxide catalysts under working conditions without the need of an internal standard have been explored. The dehydrogenation of propane over an industrial-like 13 wt% Cr/Al203 catalyst was used as a model system. During reaction, the catalytic solid was continuously monitored by both UV-Vis-NIR and Raman spectroscopy. As the dehydrogenation proceeds, the catalyst gradually darkens due to coke formation and consequently the UV-Vis-NIR diffuse reflectance and Raman scattered signal progressively decrease in intensity. The formation of coke was confirmed with TEOM, TGA and Raman. The measured Raman spectra can be used as a quantitative measure of the amount of carbonaceous deposits at the catalyst surface provided that a correction factor G(R(infinity)) is applied. This factor can be directly calculated from the corresponding UV-Vis-NIR diffuse reflectance spectra. The validity of the approach is compared with one, in which an internal boron nitride standard is added to the catalytic solid. It will be shown that the proposed methodology allows measurement of the amount of carbonaceous deposits on a catalyst material inside a reactor as a function of reaction time and catalyst bed height. As a consequence, an elegant technique for on-line process control of e.g. an industrial propane dehydrogenation reactor emerges. PMID- 19785193 TI - [Let us profit from the lessons" of the 15th International Leprosy Congress]. PMID- 19785194 TI - [Early diagnosis of leprosy]. PMID- 19785195 TI - [The study of the genome of Mycobacterium leprae]. PMID- 19785196 TI - [Potential applications of molecular biology to leprosy research]. PMID- 19785198 TI - [Pathogenic agent and host response]. PMID- 19785197 TI - [Vaccine trials against leprosy]. PMID- 19785199 TI - [Hansen's disease and its control]. PMID- 19785200 TI - [Social aspects and rehabilitation]. PMID- 19785201 TI - Criteria for selecting the best articles from the first ten years of the Journal of Agromedicine, 1993-2003. PMID- 19785202 TI - Onchocerciasis control by insecticides and chemotherapy stimulates agricultural development in Central West Africa. AB - The Onchocerciasis Control Programme (OCP) has been successful in controlling transmission of onchocerciasis in large areas of the savanna and rain forest of Central West Africa. Within the center of the OCP, individual infection levels have declined to zero, children born within the last fifteen years are disease free and the progression of ocular disease in older members of the population has been halted. Control has been achieved by the application of insecticides to the aquatic breeding sites of the Simulium intermediate host. Control has been maintained despite development of insecticide resistance in certain areas, migration of infected people into the OCP zone, and temporary recolonization by migratory Simulium. Insecticide mediated control is now beginning to be supplemented by mass chemotherapy using ivermectin. Resettlement into onchocerciasis-free areas, diversification of agricultural practices and enhanced agricultural productivity have been occurring steadily. There now exists a real prospect of significant socioeconomic advancement for the whole of this region of Africa, and by some measures of national agricultural output and gross national product this process is already occurring. PMID- 19785203 TI - Multiple chemical sensitivities: a presenting complaint in two patients. AB - M.C.S. presents with non-specific multi-organ symptoms in individuals who do not manifest evidence of specific organ malfunctioning. Experts disagree about whether the disorder is caused by exposure to environmental chemicals in low concentrations or whether it has a psychological basis. This paper (a) describes two patients who were firmly convinced that they suffered from M.C.S., (b) discusses a differential diagnosis of the disorder, and (c) suggests an approach to management. PMID- 19785204 TI - Policy and institutional challenges for agromedicine. PMID- 19785205 TI - Case report: agrichemicals complicating emergency helicopter transport of a farm worker. AB - This case illustrates the hazards of helicopter transport of trauma patients exposed to agrichemicals. Agrichemical exposure risks to the flight team through dermal and inhalational routes should be considered. Chemical exposure may affect pilot navigational performance as well as patient monitoring by the flight nurse. The importance of decontaminating the patient utilizing the resources of the local fire department should be emphasized. If flight safety is considered dangerous, ground transportation should be substituted. PMID- 19785206 TI - Risk assessment for infectious foodborne diseases: a priority with problems. AB - Quantitative risk assessment is a procedure that can be applied to infectious foodborne diseases to develop effective and efficient risk-based food safety programs. It consists of four steps: hazard identification, dose-response assessment, exposure assessment, and risk characterization. Once hazards have been identified and their risks characterized, this information must be clearly disseminated to the public to facilitate productive policy debate. Increased use of this process in the formulation of food safety policy would help create solid, scientifically justifiable programs offering the greatest public health protection at the lowest cost. PMID- 19785207 TI - Southern Agromedicine Consortium. AB - The Southern Agromedicine Consortium is an affiliation of agricultural and health professionals who have organized to share their resources for the promotion of agricultural medicine in their states and the region. The purpose, history, bylaws and future of the consortium are discussed. PMID- 19785208 TI - Epidemiological perspectives on childhood agricultural injuries within the United States. PMID- 19785210 TI - Food safety in the United States and abroad: an agriculturist's perspective. AB - The topic of food safety in the U.S. frequently is the lead story in the news media and continues to be an important issue for biological scientists of all disciplines. The emotional and sensational aspects of food safety often cloud the facts as reported by journalists. Because we increasingly depend on foreign countries for our food supply, and because of the commonly held belief in our society that foreign suppliers are not required to meet the safety criteria of U.S. regulatory agencies, it is important for agriculturalists with international expertise to offer objective views on the topic of food safety. This report contains the observations and views of one such scientist. PMID- 19785209 TI - Case histories of insect- or arachnid-caused human illness. AB - Insects, arachnids, and other medically important arthropods affect human health directly by bites, stings, and blisters, and indirectly by disease transmission. In this paper, three widely divergent cases of insect- or arachnid-caused human illness are presented--a spider bite, a mosquito-borne disease case, and an imaginary mite problem. Some key references are included for each topic, as well as editorial comment to add perspective. PMID- 19785211 TI - Stress in rural America. PMID- 19785212 TI - Human and ecosystem health: the environment-agriculture connection in developing countries. AB - Agricultural productivity and the health of farming populations are both influenced by environmental change. Farming activities also affect the environment. Six principal dimensions of this agriculture/environment interrelation are explored: water resources; erosion and nonpoint source pollution; pesticides and fertilizers; deforestation; population pressures; and biodiversity. Changes in these environmental dimensions are critical to the health of rural populations in developing countries. National and international policies and incentives for the protection of agricultural environments are described. PMID- 19785213 TI - The poultry scientist and agromedicine. AB - The poultry industry of today is immense and of great economic significance. This has been made possible, in part, by the vast amount of research which has been performed for the purpose of improving the reproduction, growth and health of avian species. Ancillary benefits resulting from this research have been discoveries of importance to human medicine such as: discovery of many essential vitamins and nutrients, knowledge of the immune system, understanding of the mechanisms of viral infection and viral participation in cancer, clarification of mechanisms of heredity, and many other findings. Work in the author's laboratory has the potential of generating knowledge of importance to medical sciences by providing information about diluents useful for cold-storage of cells, about enzymes whose activities may be applicable to studies of human tissues, and about mitochondria. PMID- 19785214 TI - Travel and the emergence of infectious diseases. AB - Travel is a potent force in the emergence of disease. Migration of humans has been the pathway for disseminating infectious diseases throughout recorded history and will continue to shape the emergence, frequency, and spread of infections in geographic areas and populations. The current volume, speed, and reach of travel are unprecedented. The consequences of travel extend beyond the traveler to the population visited and the ecosystem. When they travel, humans carry their genetic makeup, immunologic sequelae of past infections, cultural preferences, customs, and behavioral patterns. Microbes, animals, and other biologic life also accompany them. Today's massive movement of humans and materials sets the stage for mixing diverse genetic pools at rates and in combinations previously unknown. Concomitant changes in the environment, climate, technology, land use, human behavior, and demographics converge to favor the emergence of infectious diseases caused by a broad range of organisms in humans, as well as in plants and animals. PMID- 19785215 TI - Highlights from the first Pennsylvania meeting of the Agromedicine Consortium, the Pennsylvania State University, State College, PA, October 19-20, 1995. PMID- 19785216 TI - Anhydrous ammonia injuries. AB - Anhydrous ammonia, a pungent, colorless gas or liquid, is commonly used around the world as a refrigerant and fertilizer in agriculture. It is an alkali causing liquefaction or freeze-dry lesions with skin contact. Initial emergency response involves evacuation, decontamination, first aid and alerting proper authorities. Decontamination must be complete and rescuers must avoid being overcome by fumes. Emergency department care is directed at respiratory, ocular, skin and gastrointestinal treatment. Respiratory and ocular lesions tend to be the most severe and can be used as a triage guide. The need for a multidisciplinary approach to hospital care is stressed. In severe exposures, adult respiratory distress syndrome is a common finding. In children who have ingested aqua ammonia, early endoscopy, aggressive antibiotic therapy and serial dilatations of strictures are recommended. Long-term complications occur predominately to the eyes and respiratory tract. PMID- 19785217 TI - Cataract blindness in the developing world: is there a solution? AB - Cataracts are the leading cause of blindness worldwide, accounting for half of the world's 40 million blind. The majority of the world's 20 million cataract blind live in the developing world. About 5 million new cases of cataract blindness occur each year. Only a small percentage of persons in the Third World who develop cataracts receive cataract surgery. Cataract blindness causes severe economic and social problems in these countries. Because of increased longevity and population growth in the Third World, the number of untreated cataract cases is escalating rapidly. Governmental, non-governmental and service club organizations have put extraordinary effort and resources into reversing the trend of increasing cataract blindness, but much work still needs to be done. Current surgical methods used in the Third World have not yet succeeded in reducing the backlog of cataracts, due in part to either their prohibitive cost or poor results. Extra capsular cataract extraction (ECCE) with placement of a posterior chamber intraocular lens (PC-IOL) is the hope for preferred method of treatment. This paper discusses a largely overlooked method of cataract surgery which may be an additional, cost-effective and efficacious means of providing good sight rehabilitation. Combining intracapsular cataract extraction, currently the most common method used in the rural developing world, with anterior chamber intraocular lens implantation (ICCE AC-IOL), may prove effective in reducing the cataract backlog in developing countries. PMID- 19785218 TI - Respiratory health and allergy among young farmers and non-farming rural males in Denmark: the SUS study. AB - The respiratory health of 230 female and 1,734 male farming students (FS) and 407 male rural controls was analyzed. A significantly increased prevalence of cough (6.9%) was reported among the male FS compared to the controls (2.5%). Measured FEV1 and FVC did not differ between the male FS and the controls, as opposed to significantly higher values among the female FS compared to a random sample of urban females stratified for height. Skin prick test (SPT) to house dust and storage mites was significantly more prevalent among the controls (18.7%) compared to the male FS (12.8%) and the female FS (11.9%). The size of the house dust mite weal and the number of positive skin prick reactions were significantly associated with bronchial hyperreactivity. The difference in lung function among the female FS and the lower prevalence of skin reaction among the male FS and female FS probably reflects a healthy workers selection. PMID- 19785219 TI - Health and safety issues relating to Maine's fishing industry. AB - The Maine Agricultural Safety and Health Program performed a needs assessment to determine the health and safety concerns of Maine's fishing community. Information for the assessment was obtained from clinicians, focus groups of wives of fishers, and government agencies. Reports from the United States Coast Guard showed that during 1993-1994, sixty-five people were injured on commercial fishing vessels and eight people died. Decompression illness was the most frequently reported non-fatal injury (n = 15). Chronic injuries reported by clinicians included back pain, tendinitis, carpal tunnel syndrome, dysbaric osteonecrosis. Clinicians and family members were also concerned about hand and arm infections from the bait and sun exposure. Family health issues and access to care are addressed in the report. Recommendations include, in part, increasing surveillance, reducing barriers to access, increasing clinicians' knowledge about the fishing industry, and fostering collaboration between agencies providing health and safety information to fishers. PMID- 19785220 TI - Child labor issues in the international setting. AB - Internationally, children are working in situations where there are exposures to many occupational hazards, lack of basic worker rights and, sometimes, forced employment. Many of the child workers are involved in family-based agriculture, cattle tending, crop harvesting, commercial plantation work, and the cleaning and packing of food. Many severe forms of child labor are found in the commercial agriculture of Latin America and the Caribbean. The International Labor Organization states that "few human abuses are so unanimously condemned, while being so widely practiced as child labor...working children, all over the world, deserve better". PMID- 19785221 TI - A cooperative experience in rural health education for medical students. AB - A cooperative venture in medical student education between a rural school of medicine and the county Cooperative Extension service was undertaken. First-year medical students were introduced to health hazards associated with farming via lecture and slide presentations. They then visited farm and agribusiness sites to identify potential work health risks, using a written checklist. Observation sites were identified by Cooperative Extension agents, who accompanied the student groups and a clinical faculty member on each visit. This experience is described, and practical suggestions are offered regarding implementation of a farm visit program for students. PMID- 19785222 TI - Physician training in agricultural safety and health: the Emory Agromedicine Training Project. AB - This paper describes the Emory Agromedicine Training Project, a component of Occupational Medicine residency training at Emory University since 1991. The Project places occupational medicine residents in rural settings, where they perform a range of activities: working on farms, service visits to farms, grand rounds presentations to rural hospitals, public presentations in farm communities, and clinical service in the migrant health program. In addition they complete a directed reading syllabus and a research project. The rotation has been successful in building the residents' knowledge of agricultural safety and health, instilling positive attitudes toward the field, and achieving desired behaviors and skills. In addition, strong statewide networking was accomplished through this initiative. Areas of limited success include the small number of residents trained, some resident dissatisfaction with intense travel requirements and security concerns, and inability to secure long-term funding. We conclude that agricultural safety and health is highly suitable for inclusion in occupational medicine training, and this model should be extended to primary care specialties such as family practice. PMID- 19785223 TI - Assessment of farmers' acceptance of veterinarians as human health advocates. AB - The project goal was to collaborate with veterinarians in delivering skin cancer information to a farming population. Two interventions and a control were utilized: in nine Wisconsin counties veterinarians delivered education materials as part of routine dairy herd health visits, veterinarians in nine additional counties provided client lists so education materials could be mailed, and veterinarians in nine control counties provided client lists but farmers received no education materials. A questionnaire was administered by phone to a random sample of farmers in each group, assessing knowledge, sun protection attitudes and behaviors, acceptance of veterinarians in a human health education role. Farmers responded quite favorably to veterinarians in this role. Veterinarians can be regarded as useful agents to disseminate health information to isolated rural populations. PMID- 19785224 TI - Fire ant anaphylaxis: two critical cases in South Carolina. AB - Two clinical cases illustrate near-fatal reactions to fire ant venom encountered by an infant playing in the backyard, and by a pharmacist working indoors in a hospital setting under a ceiling ventilation duct. PMID- 19785225 TI - Food Allergens Conference highlights (Chicago, IL, July 29-30, 1998). PMID- 19785226 TI - Report on the 31st annual meeting of the Society for Epidemiologic Research. PMID- 19785227 TI - Insecticide resistance and vector control. AB - Insecticide resistance has been a problem in all insect groups that serve as vectors of emerging diseases. Although mechanisms by which insecticides become less effective are similar across all vector taxa, each resistance problem is potentially unique and may involve a complex pattern of resistance foci. The main defense against resistance is close surveillance of the susceptibility of vector populations. We describe the mechanisms of insecticide resistance, as well as specific instances of resistance emergence worldwide, and discuss prospects for resistance management and priorities for detection and surveillance. PMID- 19785228 TI - Health effects of pesticide use among Indonesian women farmers: Part I: Exposure and acute health effects. PMID- 19785229 TI - Epidemiology in agromedicine: the folate model of success. PMID- 19785230 TI - Letting go of the land. PMID- 19785231 TI - A family outbreak of acute organophosphate poisoning: a diagnostic challenge. AB - Acute pesticide poisonings may present with vague symptoms and signs and may require a high index of suspicion for diagnosis. In some instances exposures may be unreported out of ignorance or fear of legal consequences by the patients. Pesticide label information and manufacturer's hotline support can be invaluable in providing optimal care for poisoned patients. PMID- 19785232 TI - Potential health effects of odor from animal operations, wastewater treatment, and recycling of byproducts. AB - Complaints of health symptoms from ambient odors have become more frequent in communities with confined animal facilities, wastewater treatment plants, and biosolids recycling operations. The most frequently reported health complaints include eye, nose, and throat irritation, headache, nausea, diarrhea, hoarseness, sore throat, cough, chest tightness, nasal congestion, palpitations, shortness of breath, stress, drowsiness, and alterations in mood. Typically, these symptoms occur at the time of exposure and remit after a short period of time. However, for sensitive individuals such as asthmatic patients, exposure to odors may induce health symptoms that persist for longer periods of time as well as aggravate existing medical conditions. A workshop was held at Duke University on April 16-17, 1998 cosponsored by Duke University, the Environmental Protection Agency (EPA). and National Institute on Deafness and Other Communication Disorders (NIDCD) to assess the current state of knowledge regarding the health effects of ambient odors. This report summarizes the conclusions from the Workshop regarding the potential mechanisms responsible for health symptoms from ambient odors. Methods for validation of health symptoms, presence of odor, and efficacy of odor management techniques are described as well. PMID- 19785234 TI - Pesticides for human health: three examples. PMID- 19785233 TI - Revival of herbalism and its roots in medicine. AB - The proper use of phytomedicines in human health care may add a dimension currently lacking in the United States in the treatment of certain diseases and syndromes. Sales of botanicals have been rising for the past few years and are expected to increase 12% to 16% annually for the next few years. As agriculturists, we are developing production techniques using good management practices to grow and process these new crops. However, a fundamental understanding of the genesis of this "new" industry is needed to appreciate the historic use of herbs and significance in society. PMID- 19785235 TI - Highlights of International meeting on Alternative Methods of Carcinogenicity Testing, Leesburg, VA, November 1-3, 2000, Sponsored by the Health and Environmental Sciences Institute. PMID- 19785236 TI - Priority risk factors for back injury in agricultural field work: vineyard ergonomics. AB - With support of a NIOSH Community Partners grant, the authors reviewed data from three cooperating vineyard companies in Napa and Sonoma Counties, finding both high rates of evidence of musculoskeletal disorders (MSDs) and identifying priority MSD hazards for intervention. Data from OSHA 200 injury report logs identified 29 reported MSDs and 435 lost workdays in a working population of 194 in a 30-month period. The majority of these (20) involved backstrain. High risk job tasks were identified, including: employer-identified tasks, analysis of injury reports, and ergonomics risk factor checklist survey of task work. Triangulating across these three data groups resulted in identification of high priority tasks, including: hand harvest work, hand pruning, and weeding using shovels. Priority risk factors for back injury in these jobs were: repetitive lifting of heavy loads, repetitive exertion of force by the trunk and upper extremities, and repetitive or sustained awkward postures of the trunk (including full stoop and twisting with loads). PMID- 19785237 TI - Chemophobia, family medicine, and the doctor-patient relationship. PMID- 19785238 TI - Plant chemicals: poisons and cures. PMID- 19785239 TI - Adventures in beekeeping. PMID- 19785240 TI - Parental caregiving and developmental outcomes of infants of mothers with HIV. AB - BACKGROUND: All infants exposed to human immunodeficiency virus (HIV) prenatally, even those who do not become infected, are at risk for developmental problems because of poverty, prenatal substance abuse, and maternal illness. OBJECTIVES: The purpose was to describe the development of infants of mothers with HIV and to determine, using hierarchical linear models, the longitudinal effects of child characteristics, parental caregiver characteristics, family characteristics, and parenting quality on development. METHODS: Eighty-one infants born to women with HIV and their primary parental caregivers were followed-up until 18 to 24 months of age; 53 infants were always cared for by their biologic mothers, 16 were always cared for by kin or foster parents, and 12 had primary caregiver changes. Predictor variables and developmental outcomes were obtained at enrollment and 6, 12, 18, and 24 months. RESULTS: Mental development and adaptive behavior scores decreased over age. Infants with changes in their primary caregiver had lower motor and adaptive behavior scores than infants remaining with consistent caregivers. Higher mental, motor, and adaptive behavior scores were associated with more positive attention and more negative control, whereas better language abilities were associated only with more positive attention. Child, maternal, and family characteristics had lesser effects. HIV-infected infants and infants of mothers with more education had lower mental, motor, and adaptive behavior scores. Male gender and more family conflict were associated with lower motor and adaptive behavior scores. Infants from smaller families had lower mental scores. CONCLUSIONS: Because both parenting quality and consistency of the primary caregiver influenced developmental outcomes, interventions with the mothers of these infants need to focus both on improving the quality of parenting and reducing the frequency of primary caregiver changes. PMID- 19785241 TI - Effect of sexual and physical abuse on symptom experiences in women with irritable bowel syndrome. AB - BACKGROUND: Irritable Bowel Syndrome (IBS) is a common chronic functional bowel disorder characterized by alterations in bowel patterns and abdominal pain. One factor that is conjectured to contribute to the onset of IBS is sexual and/or physical abuse in childhood or as an adult. This conjecture is supported by the increased prevalence of abuse experiences in persons with IBS when compared to healthy controls or those with organically-defined gastrointestinal (GI) disorders. OBJECTIVES: The purposes of the present study were to (a) compare the history of sexual and physical abuse in a sample of women with IBS to a sample of women without IBS and (b) to compare women with IBS who had sexual and physical abusive experiences to those who had not on GI symptoms, psychological distress, healthcare-seeking behavior, and physiological measures. METHODS: Data were collected from two samples of women (ages 18-40 years) with IBS and controls were recruited through community advertisements and letters from a health maintenance organization. Participants completed questionnaires (i.e., Sexual and Physical Abuse, Bowel Disease Questionnaire, Symptom Checklist-90-R) during an in-person interview and completed a symptom diary each night across one menstrual cycle. Cortisol and catecholamine levels were determined in morning urine samples on 6 days across the menstrual cycle. RESULTS: More women in the IBS group reported unwanted sexual contact during childhood relative to control women. Within the IBS group, minimal differences were found between those who had experienced abuse and those who had not. Women with IBS who had experienced abuse reported greater impact of GI symptoms on activity. CONCLUSIONS: The prevalence of a history of childhood sexual abuse experiences is elevated among women with IBS. However, within women with IBS, those with a history of abuse do not appear to be different from those with no history of abuse on GI symptoms, psychological symptoms, or physiological arousal indicators. PMID- 19785242 TI - Tissue oxygenation, perfusion, and position in patients with venous leg ulcers. AB - OBJECTIVES: The purpose of this study was to compare the partial pressure of transcutaneous tissue oxygen (TcPO2) in persons with venous ulcers in four positions with and without inspired oxygen. METHODS: TcPO2 was evaluated two times, 4 weeks apart at a chest reference and three lower extremity sites. RESULTS: Lower extremity resting TcPO2 levels were lower in patients with venous ulcers than in healthy adults. Minimal changes in TcPO2 occurred with position changes when subjects breathed room air. When arterial oxygen saturation was increased using inspired oxygen, TcPO2, used as an indicator of perfusion, was lower during leg elevation, sitting, and standing compared to lying supine (p < 0.05). CONCLUSIONS: Control of peripheral circulation and tissue oxygenation may be impaired in persons with venous ulcers. Leg elevation, sitting, and standing decreased wound perfusion and may not be beneficial to individuals with venous insufficiency and ulceration. Research is needed to explore relationships among tissue oxygenation, blood perfusion, compression, positioning, and venous ulcer healing. PMID- 19785243 TI - Effects of a submaximal exercise protocol to recondition the pelvic floor musculature. AB - BACKGROUND: Although research has documented the efficacy of maximal voluntary contraction (MVC) exercise for improved pelvic floor muscle (PFM) strength, the efficacy of submaximal voluntary contraction (SVC) exercise for treatment of genuine stress urinary incontinence (GSUI) has not been described. OBJECTIVE: To compare the training-induced changes in endurance, strength, and muscle activity recruitment, and continence control in groups of women with GSUI who exercised the PFM using either near-maximal voluntary contraction (NMVC) or SVC effort. METHODS: Training-induced changes in PFM response to exercise were tested by using a quasi-experimental design. Thirty-two women, randomly assigned to either the SVC or NMVC exercise protocol group, were tested before and after training on endurance, muscle contraction strength, muscle activity recruitment, 10-hour weighed pad test for grams of urine loss, and subject-rated severity and frequency of leakage episodes. Repeated measures of specific study variables were retrieved and analyzed from home-training device computer memory and diary records. Changes in muscle activity recruitment, measured as microvolts of electromyogram (EMG) amplitude, were correlated with changes in muscle contraction strength and endurance. RESULTS: Increases in muscle contraction strength (t = 1.75; p = 0.045) and decreases in grams of urine leakage (t = 1.86; p = 0.036) were significant for the SVC group. No significant differences were found between the groups for changes in endurance, muscle activity recruitment, frequency of leakage episodes, or subject-rated severity of urine loss based on a 7-point Likert scale. CONCLUSIONS: Study findings suggest that SVC exercise designed with specificity for gain in neuromuscular control may be beneficial for strengthening the PFM and increasing endurance of contractions to attain and maintain continence in women with GSUI. PMID- 19785244 TI - An explanatory model of fatigue in women receiving adjuvant breast cancer chemotherapy. AB - BACKGROUND: Fatigue is the most common and disturbing complaint reported by women during adjuvant breast cancer chemotherapy, but little is known about the mechanisms influencing it. OBJECTIVES: To test an explanatory model of variables influencing fatigue in women during the first three cycles of adjuvant breast cancer chemotherapy and to determine the extent to which model variables explain fatigue at treatments and predict fatigue at cycle midpoints. METHODS: A prospective, correlational design with repeated measures was used. The sample included 60 women who received chemotherapy after surgery for Stage I or II breast cancer. Fatigue was measured by the Piper Fatigue Scale. Predictor variables and measures were health and functional status (MOS SF-36), chemotherapy protocol, health-promoting lifestyle behaviors (HPLPII), nutritional status (hematocrit [Hct] and body mass index [BMI]), symptom distress (MSDS), and initial reaction to the diagnosis of cancer (RDCQ). Multiple regression was used for path analyses. RESULTS: Trimmed models of influences on fatigue were identified. At treatments, direct influences on fatigue were symptom distress (beta = 0.45-0.76, p = 0.002-0.001), chemotherapy protocol (beta = 0.26, p = 0.02), and interpersonal relations (IPR) behaviors (beta = -0.28, p = 0.02); indirect influences were confronting reaction to the diagnosis through IPR behaviors and through symptom distress. At cycle midpoints, direct influences on fatigue were symptom distress from the previous treatment (beta = 0.36-0.43, p = 0.004-0.001), physical and social function (beta = -0.31-0.50, p = 0.02-0.001), and IPR behaviors (beta = -22, p = 0.05); an indirect influence was confronting reaction to the diagnosis (through IPR behaviors). Variance explained in fatigue ranged from 42% to 62% at treatments and from 40% to 56% at cycle midpoints. CONCLUSIONS: Further testing of the model is warranted. Findings suggest that interventions to reduce symptom distress and promote health and functional status need to be developed and evaluated for effectiveness in modifying fatigue during adjuvant breast cancer chemotherapy. PMID- 19785245 TI - Caregiving experiences after stroke. AB - BACKGROUND: Stroke is a major cause of disability in the United States. Over half a million Americans suffer strokes each year, and many of the 75% who survive are cared for in home settings, by family caregivers. The caregiving experience is often stressful and can result in negative physical and mental health outcomes for the family caregiver. OBJECTIVES: The purpose of this longitudinal study was to examine relationships between patient characteristics, characteristics of the caregiver, and caregiver coping resources with caregiver physical and mental health outcomes at 3 and 6 months after the loved one's stroke. A secondary aim was to compare family members' assessments of patient disability with ratings by clinicians. METHODS: The caregiver study was conducted in collaboration with a study of patient outcome after stroke. Both studies used the same cohort of stroke patients and their primary caregivers. Detailed clinical assessment of patient status was conducted 1, 3, and 6 months after stroke. Caregivers (N = 83) completed mailed questionnaires 1, 3, and 6 months after the patient's stroke. The survey included quantification of fatigue and energy, assessment of mood disturbance, stress, spirituality, and reactions to the caregiving situation, which provided a detailed assessment of caregiver characteristics, coping resources, and physical and mental health status. RESULTS: Caregivers reported stable perceptions of fatigue, vigor, recurrent sorrow, perceived stress, finances, family support, physical health, and depressive state symptoms at 1, 3, and 6 months after the loved one's stroke. The relationship between physical health and depressive symptoms was reciprocal at 3 and 6 months. Perceived stress was related to mental health at 3 and 6 months. Caregiver ratings of disability at 1 month paralleled clinical assessments using the Orpington Prognostic scale. CONCLUSIONS: Part of a comprehensive approach to stroke after-care should include comprehensive assessment of caregiver functioning soon after the loved one's stroke. Early assessment might identify persons at greater risk for physical and mental health problems in a continuing caregiving role. PMID- 19785246 TI - Gender and age differences in nurses' triage decisions using vignette patients. AB - BACKGROUND: Although evidence indicates that women who suffer a myocardial infarction (MI) are less likely than men to be diagnosed based on their presenting symptoms, to receive aggressive treatment, and to survive an acute cardiac event, most studies conducted to date are retrospective chart reviews that examine the triage decision-making practices of physicians. OBJECTIVES: This study examined whether emergency department (ED) nurses' triage decisions were different when the nurse was presented with similar cues for MI, but different patient gender. METHOD: A nonexperimental, descriptive study was conducted. Five hundred ED nurses were randomly selected to receive a mailed clinical vignette questionnaire. Data analysis included descriptive, bivariate, and multivariate analyses. RESULTS: ED nurses perceived the middle-aged male vignette patient to be in need of more urgent triage (t = 2.58; df = 207; p = 0.01) and an admission to an intensive care unit bed (chi2 = 10.43; df = 1; p = 0.001) and were more likely to consider a cardiac diagnosis in the male than the age-matched female (chi2= 37.49; df = 1; p < 0.0001) with identical presentation. However, no such differences were noted in the elderly vignette patients. CONCLUSIONS: The findings of this study suggest that gender bias and ageism may account for the disparities in triage decisions for middle-aged women with complaints suggestive of coronary artery disease. Although middle-aged women may have a lower incidence of MIs than middle-aged men, their increased morbidity and mortality warrants its consideration. PMID- 19785247 TI - [Orthodontics--periodontics: yesterday and today; a review of the literature]. AB - The dental disciplines of orthodontics and periodontics keep a variety of contact points. The development of new treatment options in periodontics and orthodontics, e.g., guided tissue regeneration or orthodontic implants for temporary skeletal anchorage, offer new ways in treatment of periodontally affected patients. The present work is a review of studies and treatment plans in the past thirty years and scrutinises their topicality and evidence. The performance of a systematic review of literature led to a low number of resulting articles. For this reason and their heterogeneity it was not possible to perform a quantifying review. Our results lead to the conclusion that this certain scope of interdisciplinary therapy has further demand for studies with high quality standards and evidence. PMID- 19785248 TI - [The deaf patient--information for a barrier-free conversation with patients in dentistry]. AB - There are about 650,000 people with hearing problems in Switzerland, 10,000 of whom use sign language. About 100,000 people are hard of hearing. Deaf patients require special treatment in the dental office as they have specific communication needs. This community, like many other minority groups, has a sign language and a culture of its own. To prevent misunderstandings it is therefore very important to provide solutions for an enhanced communication. However, guidelines for the communication with deaf dental patients are still missing. Successful communication between deaf patients and dentist is essential for effective care. This paper is concerned with providing background information and introducing recommendations for unrestricted dentist-patient communication. The aim of this article is to improve dentists' knowledge of the appropriate communication with this patient group. PMID- 19785250 TI - Special issue on brain injury: traumatic brain injury and stroke. PMID- 19785249 TI - [Intraosseous anesthesia X-tip system in tooth extraction]. AB - The purpose of this study was to determine the anesthetic efficacy of a intraosseous anesthesia (IOA) as an alternative to the infra alveolar nerve block (IANB) or the maxillary anesthesia. 55 subjects who underwent a tooth extraction received a primary X-tip intraosseous injection (LLC Lakewood, New Jersey, U.S.A.) of Ubistesin forte (articaini hydrochloridum 40 mg, adrenalinum 10 pg ut adrenalini hydrochloridum 1:100000, median 1.5 ml). A pulse oximeter measured the heart rate and the oxygen saturation. The results demonstrated, that the maximum heart rate was higher with the intraosseous injection (average 14.6 beats/min increase) during 1.5-2 minutes, but there was no depression of the oxygen saturation. The wound healing was uneventful. We registered five non-responders which were treated additionally with 1.3 ml of Ubistesin forte terminal anesthesia. For all patients the IOA was unpleasant similar to a "normal" anesthesia. Success of the intraosseous injection was 91%, comparable to the study of Turner et al. (2002) (or the clinical experience after an IANB). For non responders to an IANB the IOA seems to be a good alternative method. PMID- 19785251 TI - Effects of an explicit problem-solving skills training program using a metacomponential approach for outpatients with acquired brain injury. AB - OBJECTIVE: We investigated the effects of an explicit problem-solving skills training program using a metacomponential approach with 33 outpatients with moderate acquired brain injury, in the Hong Kong context. METHOD: We compared an experimental training intervention with this explicit problem-solving approach, which taught metacomponential strategies, with a conventional cognitive training approach that did not have this explicit metacognitive training. RESULTS: We found significant advantages for the experimental group on the Metacomponential Interview measure in association with the explicit metacomponential training, but transfer to the real-life problem-solving measures was not evidenced in statistically significant findings. Small sample size, limited time of intervention, and some limitations with these tools may have been contributing factors to these results. CONCLUSION: The training program was demonstrated to have a significantly greater effect than the conventional training approach on metacomponential functioning and the component of problem representation. However, these benefits were not transferable to real-life situations. PMID- 19785252 TI - Training multitasking in a virtual supermarket: a novel intervention after stroke. AB - OBJECTIVE: To explore the potential of the VMall, a virtual supermarket running on a video-capture virtual reality system, as an intervention tool for people who have multitasking deficits after stroke. METHOD: Poststroke, 4 participants received ten 60-min sessions over 3 weeks using the VMall. The intervention focused on improving multitasking while the participant was engaged in a virtual shopping task. Instruments included the Multiple Errands Test-Hospital Version (MET-HV) in a real mall and in the VMall. RESULTS: Participants achieved improvements ranging from 20.5% to 51.2% for most of the MET-HV measures performed in a real shopping mall and in the VMall. CONCLUSIONS: The data support the VMall's potential as a motivating and effective intervention tool for the rehabilitation of people poststroke who have multitasking deficits during the performance of daily tasks. However, because the sample was small, additional intervention studies with the VMall should be conducted. PMID- 19785253 TI - Application of the spacing effect to improve learning and memory for functional tasks in traumatic brain injury: a pilot study. AB - Research has indicated that many people with traumatic brain injury (TBI) experience learning and memory difficulties because of impairments in the initial acquisition of information. We examined a strategy, the spacing effect, known to enhance new learning in a laboratory setting in healthy control participants (HCs) and in people with TBI. The spacing effect indicates that information is learned better when presentation trials are distributed over time (spaced presentation) rather than consecutively (massed presentation). In this study, we examined the application of the spacing effect in improving functional tasks. We used a within-subject design and included 10 participants with TBI and 15 HCs. In both the TBI and the HC groups, material learned under the spaced learning condition was recalled better than that learned under massed learning conditions. These results provide initial evidence supporting the use of the spacing effect to improve new learning of functional tasks for people with TBI. PMID- 19785254 TI - Use of the Dynamic Interactional Model in self-care and motor intervention after traumatic brain injury: explanatory case studies. AB - PURPOSE: The highest proportion of traumatic brain injuries (TBIs) occurs among adolescents. This study examines the effectiveness of a therapeutic protocol for rehabilitation of adolescents with TBI. This protocol is based on Toglia's (1998, 2005) Dynamic Interactional Model and Expanded Awareness Model (Toglia & Kirk, 2000). METHOD: Explanatory case studies presenting 2 adolescents (ages 16-17) with mild to moderate TBI are combined with qualitative and quantitative data assessing self-care, mobility, and graphomotor abilities as well as deficit awareness in these domains. Outcome measures include the FIM, the Canadian Occupational Performance Measure, the Computerized Penmanship Object Evaluation Tool, and the Awareness of Mobility Deficits Questionnaire. Graphic data analysis compared outcome measures before, during, and after intervention. RESULTS: The Dynamic Interactional Model was effective in improving self-care, mobility, and graphomotor abilities and identified awareness of deficits in these domains. CONCLUSION: These research findings contribute to our theoretical knowledge in rehabilitation and promote adopting this approach for rehabilitation of adolescents with TBI. PMID- 19785255 TI - Qualitative exploration of a client-centered, goal-directed approach to community based occupational therapy for adults with traumatic brain injury. AB - OBJECTIVES: We explored the clinical application of goal-directed therapy in community-based rehabilitation from the perspective of clients with traumatic brain injury (TBI), their significant others, and their treating occupational therapists. METHOD: Twelve people with TBI and their significant others completed an outpatient, goal-directed, 12-week occupational therapy program. Semistructured interviews with 12 participants, 10 significant others, and 3 occupational therapists involved in delivering the therapy programs explored their experiences of goal-directed therapy. RESULTS: Participants, their significant others, and therapists described goal-directed therapy positively, expressing satisfaction with progress made. CONCLUSION: Goals provide structure, which facilitates participation in rehabilitation despite the presence of barriers, including reduced motivation and impaired self-awareness. A therapist facilitated, structured, goal-setting process in which the client, therapist, and significant others work in partnership can enhance the process of goal setting and goal-directed rehabilitation in a community rehabilitation context. PMID- 19785256 TI - Dynamic assessment and prediction of learning potential in clients with unilateral neglect. AB - OBJECTIVE: We investigated the application of dynamic assessment in examining learning potential for adults with right hemisphere stroke and unilateral neglect. METHODS: Forty adults with right cerebrovascular accident were randomly assigned to a control or dynamic group. Both groups were administered standard pretests and posttests of unilateral neglect. The dynamic group received cues, strategy training, and feedback during an object search task. RESULTS: Multivariate analysis of covariance indicated significant differences between groups on the object search task, with reduced unilateral neglect in the dynamic group. Greater initiation of left-sided search, strategy use, and near and intermediate transfer of learning were observed in the dynamic group. CONCLUSIONS: The brief dynamic assessment, developed for this study, provided an opportunity to observe the client's ability to incorporate strategy training and feedback across visual search tasks. This assessment approach has the potential to characterize learning profiles and to guide intervention decisions. PMID- 19785257 TI - Traumatic brain injury and driving assessment: an evidence-based literature review. AB - OBJECTIVE: We conducted a literature review of assessment tools predicting driving performance for people with traumatic brain injury (TBI). METHOD: Data sources were Web of Science, EBSCOhost, PubMed, and recently published literature from experts and team members not yet catalogued in the databases. We used the American Academy of Neurology's classification criteria to extract data from 13 studies, and we assigned a class (I-IV, with I being the highest level of evidence) to each study. We grouped primary studies into categories of driving assessment (neuropsychological; simulator; off-road; self-report, other report, and postinjury disability status; and comprehensive driving evaluation) and synthesized the predictability of these tools as it relates to driving performance for people with TBI. CONCLUSIONS: To assist clinicians and researchers in making decisions regarding testing the driving performance of people with TBI, we provide recommendations for neuropsychological tests; off road tests; self-report, other report, and postinjury disability status; and comprehensive driving evaluation. PMID- 19785258 TI - Kettle test--a brief measure of cognitive functional performance. Reliability and valdity in stroke rehabilitation. AB - OBJECTIVES: We examined the reliability and validity of the Kettle Test, a brief performance measure based on a complex everyday task designed to tap into basic and higher level cognitive processes. METHOD: Participants included 21 people attending stroke rehabilitation and 4 occupational therapists for the reliability analysis, 36 people at discharge from stroke rehabilitation, and 36 age-matched healthy control participants for the validity analyses. Instruments included a battery of conventional cognitive measures and functional outcomes. RESULTS: Interrater reliability was found to be high. Stroke survivors at discharge from rehabilitation were found to require significantly more assistance on the Kettle Test than control participants (p < .000); their scores on the Kettle Test were significantly and moderately correlated with the conventional cognitive and functional outcome measures. CONCLUSIONS: The results support the reliability and validity of the Kettle Test as a top-down measure of cognition-in-function in people at discharge from stroke rehabilitation. PMID- 19785259 TI - Measuring stroke survivors' functional status independence: five perspectives. AB - An understandable measure to describe disabilities after stroke is important for clinical practice; practitioners often use multiple measures that contain different scoring systems and scales to rate activities of daily living (ADL) independence. We compared the construct of independence in five measures used with stroke survivors. The measures evaluated independence of the stroke survivors somewhat differently. The Rasch analysis Partial Credit Model converted items from these measures to a single metric, yielding an item difficulty hierarchy of all items from the measures. Data from the measures should be interpreted carefully because other concepts or constructs in addition to ADL independence are included in some of the measures. Rasch diagnostics regarding construct validity and reliability of the combined measures also indicated that these measures are not interchangeable. Although the items of the combined ADL measures were unidimensional, they measured independence from multiple perspectives, and the scale of the combined measures was not linear. PMID- 19785260 TI - Reengagement in meaningful occupations during the transition from hospital to home for people with acquired brain injury and their family caregivers. AB - OBJECTIVE: To explore people's lived experiences of reengagement in meaningful occupations during the hospital-to-home transition phase after acquired brain injury (ABI). METHOD: Participants included 20 people with ABI and 18 family caregivers. On the basis of a phenomenological approach, data collection entailed in-depth semistructured interviews at predischarge and 1 and 3 months postdischarge. Thematic analysis of interview transcripts involved open, axial, and selective coding techniques. RESULTS: Two primary themes emerged from the analysis: desired versus actual participation and struggle for independence. Theme 1 depicts the key occupations of importance to people and their caregivers during transition and explores desired and actual participation in occupations. Theme 2 highlights the struggle to regain independence and the differing perspectives of the 2 participant groups concerning this process. CONCLUSION: Clinical practice implications relate to client-centered goal setting, contexts and environments in which therapy occurs, and provision of information to patients and families. PMID- 19785261 TI - Changing face of stroke: implications for occupational therapy practice. AB - Stroke is one of the most life-altering syndromes affecting the world population. Rehabilitation for people experiencing stroke is focused almost exclusively on self-care activities and being able to return home and has little to no focus on work rehabilitation or community reintegration. The Cognitive Rehabilitation Research Group (CRRG) at the Washington University School of Medicine in St. Louis was formed with the vision of improving everyday life for people after stroke by translating knowledge from neuroscience into treatment programs for productive living. Descriptive analysis of the intake assessment from the CRRG Clinical Core (N = 7,740) revealed three important findings: The age at stroke is decreasing, most strokes are neurologically mild to moderate in nature, and discharge placement decisions are being made largely on the basis of measures of impairment. The changes in the stroke population require occupational therapy to expand rehabilitation beyond the acute management of stroke to address full participation in work, family, and community life. PMID- 19785262 TI - Pilot study on activities of daily living limitations in adults with hemianopsia. AB - OBJECTIVE: I sought to obtain a general understanding of the limitations in activities of daily living (ADLs) experienced by adults with hemianopsia and quandrantanopsia from acquired brain injury. METHOD: A semistructured interview addressing the perception of difficulty completing ADLs because of vision loss and a reading performance test were administered to 46 participants referred to a low vision rehabilitation program. RESULTS: Participants reported difficulty completing two basic ADLs, personal hygiene-grooming and feeding, and several instrumental ADLs, including driving, shopping, financial management, telephone usage, and meal preparation. ADL limitations appear to be related to the amount of visual search needed to complete the ADL and disruption of the performance skills of reading, writing, and mobility. CONCLUSION: People with hemianopsia experience limitations in specific ADLs as a direct result of the disruption of the visual field. Further investigation is needed to confirm these findings and explore interventions to improve ADL performance. PMID- 19785263 TI - Executive functioning, awareness, and participation in daily life after mild traumatic brain injury: a preliminary study. AB - OBJECTIVE: We investigated the relationship of executive functioning and self awareness to participation in daily life of people after mild traumatic brain injury (mTBI) referred to occupational therapy in the postacute phase. METHOD: Thirteen participants who sustained mTBI (average time since injury = 4.7 months, mean age = 43.4 years) were evaluated with the Behavioral Assessment of the Dysexecutive Syndrome, the Dysexecutive Questionnaire, the Self-Awareness of Deficits Interview, and the Participation Index (PI) of the Mayo-Portland Adaptability Inventory. RESULTS: Analysis revealed high frequencies of deficits in executive functions such as planning and shifting. However, self-awareness of the executive deficits was intact. A significant percentage (62%-85%) of participants experienced restrictions in everyday life activities, and PI scores were significantly correlated with measures of executive functioning. CONCLUSIONS: After mTBI, people may be at significant risk for persistent executive deficits and restrictions in participation that warrant occupational therapy intervention. PMID- 19785264 TI - Showering habits: time, steps, and products used after brain injury. AB - OBJECTIVE: This pilot study describes the showering habits of people with brain injury (BI) compared with those of people without BI (WBI). METHOD: The showering habits of 10 people with BI and 10 people WBI were measured and compared. A videotaped session recorded and documented the shower routine. RESULTS: The BI group spent longer time showering, used more steps, and used fewer products than the WBI group. A moderately significant relationship was found between time and age (r = .46, p = .041). Similarly, we found significant correlations between number of steps and number of products used (r = .64, p = .002) and between the number of products used and education (r = .47, p = .044). CONCLUSION: Results suggest that people with BI have showering habits that differ from those WBI. Correlations, regardless of group, showed that older people showered longer, and people with more education used more showering products. PMID- 19785265 TI - Occupational therapy for service members with mild traumatic brain injury. AB - More occupational therapists are needed to provide client-centered, evidence based rehabilitation to the large numbers of service members who sustained mild traumatic brain injury (mTBI) while deployed in Afghanistan and Iraq. The Proponency for Rehabilitation and Reintegration tasked a team of occupational and physical therapists to assemble evidence-based best practices specific to mTBI. Despite the fact that evidence-based reviews, guidelines, and research regarding occupational therapy for mTBI are sparse, the team developed the Clinical Practice Guidance: Occupational Therapy and Physical Therapy for Mild Traumatic Brain Injury. Occupational therapy practice recommendations specific to client education, vision, cognition, resumption of roles, and emotional well-being are summarized for civilians and characterized as practice standards or practice options. By using evidence-informed and holistic services, occupational therapists have the potential to lead rehabilitation and reintegration efforts for service members with mTBI and advance changes in the profession itself. PMID- 19785266 TI - Generational cohort theory: have we overlooked an important aspect of the entry level occupational therapy doctorate debate? PMID- 19785267 TI - A special issue of JA&WMA on aerosol and atmospheric optics: visual air quality and radiation. PMID- 19785268 TI - Particle optics in the Rayleigh regime. AB - Light scattering and absorption by particles suspended in the atmosphere modifies the transfer of solar energy in the atmosphere, thereby influencing global and regional climate change and atmospheric visibility. Of particular interest are the optical properties of particles in the Rayleigh regime, where particles are small compared with the wavelength of the scattered or absorbed light, because these particles experience little gravitational settlement and may have long atmospheric lifetimes. Optical properties of particles in the Rayleigh regime are commonly derived from electromagnetic theory using Maxwell's equations and appropriate boundary conditions. The size dependence of particle scattering and absorption are derived here from the most basic principles for coherent processes such as Rayleigh scattering (i.e., add amplitudes if in phase) and incoherent processes such as absorption (i.e., add cross sections), at the same time yielding understanding of the upper particle size limit for the Rayleigh regime. The wavelength dependence of Rayleigh scattering and absorption are also obtained by adding a basic scale invariance for particle optics. Simple consequences for particle single-scattering albedo ("whiteness") and the optical measurement of particle mass densities are explained. These alternative derivations complement the conventional understanding obtained from electromagnetic theory. PMID- 19785269 TI - Estimating precision using duplicate measurements. AB - Precision is a concept for which there is no universally accepted metric. Reports of precision vary depending on the formula and inclusion criteria used to calculate them. To properly interpret and utilize reported precisions, the user must understand exactly what the precision represents. This paper uses duplicate Interagency Monitoring of Protected Visual Environments (IMPROVE) measurements to illustrate distinctions among different approaches to reporting precision. Three different metrics are used to estimate the precision from the relative differences between the duplicate measurements: the root mean square (RMS), the mean absolute value, and a percentile spread. Precisions calculated using the RMS relative difference yield wide distributions that tend to overestimate most of the observed differences. Precisions calculated using percentiles of the relative differences yield narrower distributions that tend to fit the bulk of the observed differences very well. Precisions calculated using the mean absolute relative difference lie between the other two precision estimates. All three approaches underestimate the observed differences for a small percentage of outliers. PMID- 19785270 TI - Toward establishing the stability of multi-year monitoring of elements in airborne particles. AB - Crocker Nuclear Laboratory uses a custom built energy-dispersive X-ray fluorescence system with a molybdenum anode to provide routine analysis of elements from nickel to zirconium and lead in Interagency Monitoring of Protected Visual Environments (IMPROVE) samples. Standard methods are used to ensure accuracy and statistical control of the data, including repeated analysis of single-element standards, standard reference materials, and selected actual samples from the IMPROVE network. This paper compares the short-term (week) precision and long-term (2-yr) reproducibility revealed by the actual sample reanalyses. Currently reported analytical uncertainties are shown to predict actual 2-yr reproducibility within a factor of 2. PMID- 19785271 TI - Particulate matter sample deposit geometry and effective filter face velocities. AB - Aerosol filter face velocities can be underestimated when the sample deposit area does not cover the entire face of the filter. In many aerosol samplers, Teflon filters are backed with a metal support screen. In these samplers, air flows through the filter only in the small area upstream of each hole in the screen, resulting in a sample deposit that is an array of tiny dots that mimics the array of holes. Thus, the filter deposit area is smaller than the total filter area and the effective face velocity is greater than that calculated from the sample deposit envelope. The Interagency Monitoring of Protected Visual Environments (IMPROVE) network has used filter holders with two different screen hole arrays. The U.S. Environmental Protection Agency's Chemical Speciation Network (CSN) and the Federal Reference Method samplers also use a metal support screen, but with much smaller screen holes than IMPROVE. These networks also use larger filters and lower flow rates than those used in IMPROVE. Filter face velocities for all of these networks that are calculated using the actual deposit array area range from 1.6 to 3.5 times larger than those calculated incorrectly using the entire sample deposit envelope. PMID- 19785272 TI - Using high time resolution aerosol and number size distribution measurements to estimate atmospheric extinction. AB - Rocky Mountain National Park is experiencing reduced visibility and changes in ecosystem function due to increasing levels of oxidized and reduced nitrogen. The Rocky Mountain Atmospheric Nitrogen and Sulfur (RoMANS) study was initiated to better understand the origins of sulfur and nitrogen species as well as the complex chemistry occurring during transport from source to receptor. As part of the study, a monitoring program was initiated for two 1-month time periods--one during the spring and the other during late summer/fall. The monitoring program included intensive high time resolution concentration measurements of aerosol number size distribution, inorganic anions, and cations, and 24-hr time resolution of PM2.5 and PM10 mass, sulfate, nitrate, carbon, and soil-related elements concentrations. These data are combined to estimate high time resolution concentrations of PM2.5 and PM10 aerosol mass and fine mass species estimates of ammoniated sulfate, nitrate, and organic and elemental carbon. Hour-by-hour extinction budgets are calculated by using these species concentration estimates and measurements of size distribution and assuming internal and external particle mixtures. Summer extinction was on average about 3 times higher than spring extinction. During spring months, sulfates, nitrates, carbon mass, and PM10 - PM2.5 mass contributed approximately equal amounts of extinction, whereas during the summer months, carbonaceous material extinction was 2-3 times higher than other species. PMID- 19785273 TI - Characterization of the winter midwestern particulate nitrate bulge. AB - A previously unobserved multi-state region of elevated particulate nitrate concentration was detected as a result of the expansion of the Interagency Monitoring of Protected Visual Environments (IMPROVE) network of remote-area particulate matter (PM) speciation monitoring sites into the midwestern United States that began in 2002. Mean winter ammonium nitrate concentrations exceed 4 microg/m3 in a region centered in Iowa, which makes it responsible for as much as half of the particle light extinction. Before these observations, particulate nitrate in the United States was only observed to be a dominant component of the fine PM (PM2.5) in parts of California and some urban areas. Comparisons of the spatial patterns of particulate nitrate with spatial patterns of ammonia and nitrogen oxide emissions suggest that the nitrate bulge is the result of the high emissions of ammonia associated with animal agriculture in the Midwest. Nitrate episodes at several locations in the eastern United States are shown to be associated with transport pathways over the Midwest, suggesting long-range transport of either ammonia or ammonium nitrate. Thermodynamic equilibrium modeling conducted by others on data from the Midwest shows the relative importance of atmospheric ammonia and nitric acid in the production of PM2.5. This is a particular concern as the sulfur dioxide emissions in the United States are reduced, which increases the amount of ammonia available for ammonium nitrate production. PMID- 19785274 TI - Source contributions to visibility impairment in the southeastern and western United States. AB - The 1999 Regional Haze Rule requires states to complete comprehensive technical analyses of air pollutants that impair visibility and to define long-term strategies to improve visibility in the nation's 156 visibility-protected federal Class I national parks and wilderness areas. Class I areas in the southeastern United States are among the most impacted in the country; fine particle loadings in the western United States are a fraction of those in the East. In the Southeast, (NH4)2SO4 (ammonium sulfate) predominantly from SO2 (sulfur dioxide) emissions from electric generating utilities and industrial sources contributes 60-70% of the light extinction on the 20% haziest days; particulate organic matter (POM) predominantly from biogenic emissions and biomass burning is the second largest contributor. In the West, the mix of source contributions is more complex. At Class I areas downwind of major urban areas (e.g., California), ammonium nitrate (NH4NO3), predominantly because of mobile sources, is the dominant contributor to haze. For many western Class L areas, POM from wildland fires and fine particles from windblown dust, largely uncontrollable sources, are significant contributors to haze. International emissions are an additional uncontrollable and significant contribution to total sulfate (SO4) and nitrate (NO3) concentrations at the western Class I areas. In the Southeast, SO2 emissions reductions are projected to result in nearly 1:1 regional SO4 reductions; oxides of nitrogen (NO(x)) emissions reductions have minimal impact on NO3 concentrations and haze. In the West, SO2 emissions reductions result in incremental SO4 reductions, whereas mobile NO(x) emissions reductions are projected to reduce NO3 and improve visibility at Class I areas affected by urban areas. Because wildfire, dust, and international emissions have large contributions to the haziest days and are mostly uncontrollable in the West, reductions from anthropogenic sources in the West have less effect in improving visibility compared with the Southeast. PMID- 19785275 TI - Comparison of GOES and MODIS aerosol optical depth (AOD) to aerosol robotic network (AERONET) AOD and IMPROVE PM2.5 mass at Bondville, Illinois. AB - Collocated Interagency Monitoring of Protected Visual Environments (IMPROVE) particulate matter (PM) less than 2.5 microm in aerodynamic diameter (PM2.5) chemically speciated data, mass of PM less than 10 microm in aerodynamic diameter (PM10), and Aerosol Robotic Network (AERONET) aerosol optical depth (AOD) and size distribution at Bondville, IL, were compared with satellite-derived AOD. This was done to evaluate the quality of the Geostationary Operational Environmental Satellite (GOES) and Moderate Resolution Imaging Spectroradiometer (MODIS) AOD data and their potential to predict surface PM2.5 concentrations. MODIS AOD correlated better to AERONET AOD (r = 0.835) than did GOES AOD (r = 0.523). MODIS and GOES AOD compared better to AERONET AOD when the particle size distribution was dominated by fine mode. For all three AOD methods, correlation between AOD and PM2.5 concentration was highest in autumn and lowest in winter. The AERONET AOD-PM2.5 relationship was strongest with moderate relative humidity (RH). At low RH, AOD attributable to coarse mass degrades the relationship; at high RH, added AOD from water growth appears to mask the relationship. For locations such as many in the central and western United States with substantial coarse mass, coarse mass contributions to AOD may make predictions of PM2.5 from AOD data problematic. Seasonal and diurnal variations in particle size distributions, RH, and seasonal changes in boundary layer height need to be accounted for to use satellite AOD to predict surface PM2.5. PMID- 19785276 TI - Apportioning visibility degradation to sources of PM2.5 using positive matrix factorization. AB - Intensive monitoring studies of aerosol have been conducted in two regions of California with poor air quality. Winter monitoring in the Fresno area was conducted in December 2003. Two summer samplings were collected from the eastern Los Angeles Basin, from Rubidoux in 2003 and Riverside in 2005. All three of these studies featured a suite of semicontinuous aerosol monitors. The speciated aerosol data with continuous gaseous measurements from these studies were combined with continuous Automated Surface Observing System (ASOS) measurements of visibility and extinction from nearby airports and modeled aerosol water content to conduct source apportionment analyses. The data were analyzed using three different techniques. A conventional positive matrix factorization (PMF) method was used. Then a novel approach was used that coupled PMF with added extinction and modeled water data. Another technique involved integrating conventional PMF with linear regression to obtain the extinction associated with each source. The novel PMF with added extinction and modeled water data provided the most robust results. The Fresno winter study was meteorologically characterized by stagnant conditions, a shallow mixing height, and intermittent periods of fog and low clouds. Six factors were identified using PMF. The secondary nitrate and gasoline mobile combustion emission associated sources exhibited the highest extinction coefficients. PMF also identified six factors in the summer 2003 study at Rubidoux. The secondary nitrate and the ozone-related secondary semi-volatile organic material (SVOM) sources exhibited the highest extinction levels. Water associated with the aerosols plays an important role because of the marine influence and stratus clouds typically occurring in the basin during the summer months. The summer of 2005 study in Riverside lead to the identification of 11 sources. The highest contributors to extinction are associated with material transported across the basin, the relative humidity secondary source, followed by secondary nitrate. PMID- 19785277 TI - Regional impacts of oil and gas development on ozone formation in the western United States. AB - The Intermountain West is currently experiencing increased growth in oil and gas production, which has the potential to affect the visibility and air quality of various Class I areas in the region. The following work presents an analysis of these impacts using the Comprehensive Air Quality Model with extensions (CAMx). CAMx is a state-of-the-science, "one-atmosphere" Eulerian photochemical dispersion model that has been widely used in the assessment of gaseous and particulate air pollution (ozone, fine [PM2.5], and coarse [PM10] particulate matter). Meteorology and emissions inventories developed by the Western Regional Air Partnership Regional Modeling Center for regional haze analysis and planning are used to establish an ozone baseline simulation for the year 2002. The predicted range of values for ozone in the national parks and other Class I areas in the western United States is then evaluated with available observations from the Clean Air Status and Trends Network (CASTNET). This evaluation demonstrates the model's suitability for subsequent planning, sensitivity, and emissions control strategy modeling. Once the ozone baseline simulation has been established, an analysis of the model results is performed to investigate the regional impacts of oil and gas development on the ozone concentrations that affect the air quality of Class I areas. Results indicate that the maximum 8-hr ozone enhancement from oil and gas (9.6 parts per billion [ppb]) could affect southwestern Colorado and northwestern New Mexico. Class I areas in this region that are likely to be impacted by increased ozone include Mesa Verde National Park and Weminuche Wilderness Area in Colorado and San Pedro Parks Wilderness Area, Bandelier Wilderness Area, Pecos Wilderness Area, and Wheeler Peak Wilderness Area in New Mexico. PMID- 19785278 TI - Willa's 10 tips for nursing students. PMID- 19785280 TI - Florida receives Partners Investing in Nursing's Future grant. PMID- 19785281 TI - Heat activation of Neosartorya and Talaromyces ascospores and enhancement by organic acids. AB - Neosartorya and Talaromyces are typical fungi capable of producing heat resistant ascospores responsible for the spoilage of processed fruit products. In this study, the heat activation rates of Neosartorya and Talaromyces ascospores were investigated in several suspending media at various heating temperatures. Ascospores were dispersed in pH 3.5 McIlvain buffer, organic acid/alcohol supplemented McIlvain buffer and grape juice (pH 3.5, 5.0 degrees Brix) prior to heat treatments. In McIlvain buffer, the number of germinating ascospores increased logarithmically with longer exposure to heating at an test temperatures. Heat activation rates (k values) accelerated with increasing temperature. The calculated activation energy (Ea) values were similar among ascospores from the same genus, but the Ea of the test Neosartorya spp. were greater than that of the test Talaromyces spp. Greater k values were calculated from acetate-supplemented McIlvain buffer and grape juice. Similarly, normal- and branched-chain fatty acids were shown to enhance the heat activation rate of the ascospores in McIlvain buffer systems. These results could assist the food industry in designing adequate thermal processes for food products against the heat resistant fungi. PMID- 19785282 TI - Denitrifying activity and homologous enzyme analysis of Alcanivorax dieselolei strain N1203. AB - An Alcanivorax dieselolei strain, termed strain N1203, was isolated from the consortia of ammonia-oxidizing bacteria (AOB) combined with denitrifying bacteria from our previous study and was shown to have ability to reduce nitrate to nitrite to either nitrous oxide or molecular nitrogen. Analysis of 16S rRNA gene sequences established strain N1203 as a member of the species Alcanivorax dieselolei. In addition, the ability of strain N1203 to utilize various organic substrates as the sole carbon source, supplemented with carbohydrates, amino acids, and n-alkane compounds, was investigated, and this strain was found to have a narrow substrate range of growth such as grycerol, succinate, ethanol and n-alkane hydrocarbon. Furthermore, N1203's stepwise denitrifying activity, utilizing succinate and hexadecane as sole carbon sources, was measured. Gene fragments of nirK and qnorB genes, which are involved in denitrifying activities, were obtained, cloned and sequenced. Phylogenetic analysis for these two genes showed that both the nirK and qnorB sequences, although found in separate branches within clusters, formed subclusters branching from uncultured environmental clones. This demonstrated the typical uniqueness of these genes from any cultivated denitrifiers. Thus, strain N1203 is novel type of denitrifying bacteria that demonstrated denitrifying activities when cultivated using succinate as the sole carbon source. PMID- 19785283 TI - Antiviral activity of proanthocyanidin against feline calicivirus used as a surrogate for noroviruses, and coxsackievirus used as a representative enteric virus. AB - Proanthocyanidin, which consists of (+) catechin, (-) epicatechin and their gallates (15%), (-) epicatechin gallate-dimers, -trimers, and -tetramers (80%), and (-) epicatechin gallate-pentamers, -hexamers, and -heptamers (5%), was evaluated for its antiviral activity against feline calicivirus F9 strain (FCV/F9), which is thought to be a surrogate for noroviruses, and coxsackievirus A7 strain (Cox.A7), which was selected as a representative enteric virus. To achieve a viral inactivation rate of 99% or greater after contact for 10 sec., at least 1 mg/ml and 10 mg/ml of proanthocyanidin were required against FCV/F9 and Cox.A7, respectively. Although the antiviral mechanism of proanthocyanidin is not clear at present, proanthocyanidin may be an effective disinfectant against enteroviruses such as noroviruses. PMID- 19785284 TI - Bactericidal and sporicidal activities of an improved iodide formulation and its derivative. AB - Bactericidal and sporicidal activities of an improved iodide formulation (tentatively designated as the distilled KMT reagent: pH around 3) and its derivative (tentatively designated as the distilled ethanol reagent: pH around 2.5) were examined in several dilutions against vegetative bacteria and Bacillus subtilis spores, and they were compared with two kinds of intermediate-level disinfectants, i.e., 7% povidone-iodine (ISODINE) and ethanol for disinfection (76.9-81.4 vol %). Each solution of distilled KMT reagent up to a dilution of 1:100 showed potent bactericidal activity against most tested bacteria when used for 30 seconds at 20 degrees C. Bactericidal activities at these dilutions were almost comparable with those of the same dilution of ISODINE. Although the 1:10 dilution of ISODINE did not show comparable sporicidal activity, the same dilution of distilled KMT reagent showed potent sporicidal activity. On the other hand, the 1:2 dilution of distilled ethanol reagent showed potent sporicidal activity when used for 5 minutes at 60 degrees C. Ethanol for disinfection did not show any sporicidal activity even with treatment for 60 minutes at 60 degrees C. With treatment for 30 sec at 37 degrees C, the 1:2 dilution of distilled ethanol reagent was found to have effective bactericidal activity almost comparable with that of ethanol for disinfection. Appropriate dilutions of both the distilled KMT reagent and distilled ethanol reagent may be applicable as antiseptics which are able to achieve high-level disinfection. PMID- 19785285 TI - Identification and characterization of a psychrophilic yeast strain newly isolated from the fermentative starter (Loog-pang) of a traditional drink in Thailand. AB - One psychrophilic yeast strain, that grew well in a cold environment such as in a refrigerator, was isolated from the yeast starter (Loog-pang) of a traditional alcohol drink in Thailand. The isolated strain OPU-FC11 was identified as Cryptococcus diffluens by the assay for 26S ribosomal DNA and the test for carbon source assimilation. OPU-FC11 showed a good amount of growth at 4 degrees 0 at which a commonly found yeast like Saccharomyces cerevisiae did not grow, and produced cold-adapted enzymes that showed a relatively high activity at lower temperatures. PMID- 19785286 TI - Evaluation of a new most-probable-number (MPN) dilution plate method for the enumeration of Escherichia coli in water samples. AB - The purpose of this study was to evaluate the most-probable-number dilution plate (MPN plate) method developed for the enumeration of Escherichia coil in water samples. Sterilized water was inoculated with E. coli ATCC 11775 to give between 2-1600 MPN/100 ml. The MPN was determined for both the MPN plate and 5-tube methods from the MPN table. The average of the natural logarithm (In) MPN with standard deviations in 95 samples was 4.26 +/- 1.48 by the 5-tube-method and 4.18 +/- 1.45 by the MPN plate method. The correlation coefficient was 0.96. These results were not significantly different according to the paired t-test (p > 0.05). PMID- 19785287 TI - Development of a predictive program for Vibrio parahaemolyticus growth under various environmental conditions. AB - In this study, we developed a predictive program for Vibrio parahaemolyticus growth under various environmental conditions. Raw growth data was obtained with a V. parahaemolyticus O3:K6 strain cultured at a variety of broth temperatures, pH, and salt concentrations. Data were analyzed with our logistic model and the parameter values of the model were analyzed with polynomial equations. A prediction program consisting of the growth model and the polynomial equations was then developed. After the range of the growth environments was modified, the program successfully predicted the growth for all environments tested. The program could be a useful tool to ensure the bacteriological safety of seafood. PMID- 19785289 TI - Assisted suicide and the law. PMID- 19785288 TI - The preparation of Ag nanoparticle-modified single-walled carbon nanotubes and their antibacterial activity. AB - The sidewall modified single-walled carbon nanotubes (SWNTs) with amino containing substituents were prepared using the radicals generated by the photolysis of acetonitrile. A subsequent treatment of modified SWNTs with the Ag colloid gave an attachment of Ag nanoparticles on the surface of SWNTs through the functionalized linkages. The Ag nanoparticle-modified SWNTs evaluated by antibacterial tests showed strong activities against Escherichia coli and Staphylococcus aureus. However, the use of Ag nanoparticle-modified SWNTs on simulated body fluid exhibited weaker antibacterial activity. PMID- 19785290 TI - Proposed social care reform can end postcode lottery. PMID- 19785291 TI - Satisfaction guaranteed? PMID- 19785292 TI - Practice question. The Aged Care Channel. PMID- 19785293 TI - Nursing students' experiences care. AB - AIM: This study aimed to explore nursing students' experiences of caring for older people in practice and to examine the factors that affected their perceptions of working with these patients. METHOD: A qualitative research design was used and data were collected by focus groups. FINDINGS: Participants entered clinical placements early in their course with clear caring values, which formed a central part of their decision to enter nursing. However, early encounters and observations in the practice setting challenged these ideals. CONCLUSION: Positive learning environments should be developed that enable students to retain clear caring values and to realise the potential of caring practice while reconciling its demands. PMID- 19785294 TI - Fun and games in the open air. PMID- 19785295 TI - How to improve end of life care in acute hospitals. AB - This article highlights the need to improve care for older people dying in acute hospitals. It discusses the role that nurses have to play in promoting better care and making necessary changes easier. PMID- 19785296 TI - Reflections of a researcher interviewing older people. AB - The aim of this article is to remind those involved in research, either as researchers or reading it, of the possible effect of conducting research with participants. At a minimum, thought should be given as to why participants, especially older people, agree to take part in research studies and how they might feel when the research comes to an end. The involvement of older people in the planning and design of research concerning their age group might help to avoid some of the potential issues highlighted in the article. PMID- 19785297 TI - Care and management of patients with pruritus. AB - Pruritus is one of the most common skin conditions in older people. People may develop pruritus for many reasons but often it is not possible to diagnose the cause. Pruritus can cause physical and psychological suffering, affecting quality of life. The persistent itch leads to scratching which is a threat to skin integrity. It can also disrupt sleep and affect relationships. Pruritus should be treated actively. It is essential that people with pruritus receive a holistic assessment and that treatment plans are negotiated to maximise concordance and thus effective outcomes. PMID- 19785298 TI - Face to face. PMID- 19785299 TI - The health reform roller coaster: hang on and stay informed. PMID- 19785300 TI - Pediatric injury prevention: methods of booster seat education. AB - Sixty elementary schools in Minneapolis were asked to participate in a study to evaluate the most effective education method to increase booster seat knowledge and use in kindergarten-age children. School personnel selected one of the following interventions: (1) written information, (2) parent education class and a free booster seat, or (3) student education and a free booster seat. Twenty schools participated, with 132 parents completing the telephone interview 3 to 6 months post-survey. Providing instructions to parent groups and teaching children in the classroom, along with providing an incentive booster seat, was shown to increase booster seat use. Providing information only was found to be ineffective. Pediatric and school nurses should focus their injury prevention efforts beyond written materials. Results indicate that presentations for children and their parents, along with incentives, can result in changes in behavior. PMID- 19785301 TI - Safe patient handling and movement in a pediatric setting. AB - Although evidence-based practice exists to apply the principles of safe patient handling and movement (SPHM) to prevent nursing musculoskeletal injuries in the workplace, nurses and nursing staff continue to use "body mechanics" when moving, lifting, and transferring patients. In this day of a nursing shortage, one that will continue to worsen, valued professionals must remain on the job and free from preventable, work-related injuries. As states enact laws requiring health care facilities to develop and institute SPHM programs, hospitals will be held to task to produce SPHM policies, procedures, plans, and protocols in their institutions. PMID- 19785302 TI - Pediatric falls: state of the science. AB - Falls in the adult inpatient hospital population are an identified safety concern associated with significant morbidity, mortality, prolonged length of stay, and even death. Yet, little is known about falls among pediatric inpatients. A survey of Child Health Corporation of America hospitals was conducted to determine current fall-related practices in pediatric hospitals. The 29 (69%) responding hospitals were found to vary in their definition, classification, and measurement of fall and injury rates. Variability was also described in type of risk assessment tools used, with only six indicating use of a validated tool. A variety of prevention strategies were also described. These findings highlight the need for consensus in a definition of pediatric falls in order to appreciate the prevalence of falls among pediatric inpatients, greater application and testing of published risk assessment tools, and evidence-based prevention strategies among inpatient pediatric patients. PMID- 19785303 TI - Patterns of youths' glycemic control with insulin pump therapy. AB - Youths with type 1 diabetes mellitus may decide to use insulin pump therapy. Limited information describes youths' glycemic control with insulin pump therapy. A repeated-measures design guided data collection at five points from one month before insulin pump therapy through 12 months with insulin pump therapy. The research question was, "How do youths' hemoglobin A(1c) (HbA(1c)) values change with insulin pump therapy?" Glycemic control target was 7.6% HbA(1c) value. Thirty youths (9 to 18 years old) had at least 4 HbA(1c) values. Nineteen youths who achieved glycemic control had three different patterns during 12 months of insulin pump therapy. Eleven youths who did not achieve glycemic control had two different patterns. Multiple factors can influence a youth's glycemic control. Uncontrolled blood glucose levels increase the individual's risk for developing type 1 diabetes complications. Youths and health care providers need to work as a team to identify factors affecting the youth's glycemic control and discuss changes. PMID- 19785304 TI - Supporting families of children with autism spectrum disorders: questions parents ask and what nurses need to know. AB - Autism spectrum disorder is a lifelong condition that currently has an unclear etiology and no known cure. Families of children on the autism spectrum typically have many questions and much to learn as they manage the disorder and create meaningful lives for their children and themselves. Helping families understand both features of autism and the diagnostic process is key to supporting family acceptance of the diagnosis. Nurses can also assist families in navigating the common process of grief and adjustment following diagnosis. As the diagnosis becomes real, many questions about medications and other treatments can be addressed by knowledgeable nurses. Additionally, nurses can support families in the critical areas of managing family life, addressing sibling needs, and planning for the future. Parent-to-parent advice from the mother of a child with autism supplements this article. PMID- 19785305 TI - Physical activity behaviors of rural preschoolers. AB - PURPOSE: The purpose of this qualitative study was to investigate the physical activity and active play of rural preschoolers. METHOD: A micro-ethnography approach using observation, photography, individual interviews, and focus groups led to five major themes describing preschool activity and play in the rural area. FINDINGS: The five major themes describing preschool activity and play in the rural area were Self-Reliance, Learning Through Play, One Big Rural Family, Rural Surroundings, and Money Matters. CONCLUSIONS: Rural areas may not be as conducive to every day physical activity for children as traditionally believed. Nurses can apply these results when intervening to increase physical activity levels of preschool children. PMID- 19785306 TI - Should family members be present when their child is being resuscitated? PMID- 19785307 TI - ECG of the month. Irregular cardiac rhythm immediately after mitral and tricuspid valvular surgery. Diagnosis: Sinus tachycardia with atypical type I (Wenckebach) second-degree atrioventricular (A-V) block and right bundle branch block. PMID- 19785308 TI - Clinical case of the month. A 64-year-old woman with shortness of breath. Diagnosis: Mesothelioma. PMID- 19785309 TI - Radiology Case of the Month. Hearing loss, neck pain, and weakness. Diagnosis: Neurofibromatosis type 2. PMID- 19785310 TI - Race-specific trends in infant mortality: contributions of birth-weight distribution and birth-weight-specific mortality, Louisiana 1991-2002. AB - OBJECTIVES: To assess the race-specific trends in infant mortality rate (IMR) in Louisiana and identify changes in the birth weight distribution (BWD) and birth weight specific mortality (BWSM) and their effect on the overall infant mortality rate. METHODS: We used the state of Louisiana's period-linked birth/infant death file, 1991-2002. The difference in race-specific mortality between our study population and the reference population was partitioned into two components, BWD and BWSM, using the method developed by Kitagawa. RESULTS: The IMR among black infants was at least twice as high as that of white infants for every year except 1991. The difference in BWD is responsible for much of the differences between the IMR among blacks and whites. On average, 80% of the excess deaths among black infants were attributed to BWD; the great majority of the infants who died weighed less than 2500 grams. CONCLUSIONS: There was a significant decline in excess mortality attributable to BWSM among both blacks and whites. But despite this decline, the overall IMR for Louisiana remained high because of the higher proportion of low birth weight infants among blacks. PMID- 19785311 TI - A pitfall in pituitary imaging using standard head magnetic resonance (MR). AB - We present a case of a young girl complaining of headaches in whom a hypointense area was found in the pituitary gland with a standard magnetic resonance (MR) image of the head. This finding did not agree with clinical symptoms, so a dedicated MR of the sellar region was obtained. We determined that the supposed mass was artifact caused by volume averaging. Volume averaging is the effect of expressing the average density of two structures of a 3D slice on a 2D image. Increased slice thickness leads to increased volume averaging and decreased resolution. Dedicated MR uses thinner 3D slices to reconstruct an image and thus has better spatial resolution than standard MR. We emphasize the need of dedicated MR to evaluate pituitary lesions. PMID- 19785312 TI - Langerhans cell histiocytosis, a case of Letterer Siwe disease. AB - An 8-month-old male infant presented with a progressively worsening generalized rash of 5-6 months duration, fever, poor feeding, and abdominal distension. An initial laboratory workup revealed anemia, thrombocytopenia, and hepatosplenomegaly. The patient was started on i.v. antibiotics, and a working diagnosis of Langerhans cell histiocytosis was reached that was later confirmed with a skin biopsy. Subsequently, the patient received first-round chemotherapy with vinblastine and prednisone, on which he appeared to improve clinically; however, he soon relapsed. He then received combination salvage therapy with cladribine (2CdA) and cytarabine (Ara-C) for three cycles. The patient responded well to this regimen with resolution of his condition. The patient was then referred for a bone marrow transplant. PMID- 19785313 TI - Acute, painless vision loss. AB - This article provides a review of various conditions causing sudden, painless vision loss. The conditions of amaurosis fugax, central retinal artery occlusion (CRAO), central retinal vein occlusion (CRVO), vitreous hemorrhage, ischemic optic neuropathies (ION), posterior cerebrovascular accidents, and retinal detachment (RD) are discussed. The history, physical, pathophysiology, and treatment of each disease state are discussed along with possible preventative measures for each. An emphasis is made on early ophthalmologic involvement for potential vision restoration and the importance of a thorough history and physical for all patients with ocular complaints. PMID- 19785314 TI - Upper eyelid swelling in a 5-year-old boy. PMID- 19785315 TI - Paralysis and pernicious anemia in a young woman. AB - Vitamin B12 is important for normal nervous system functioning, and deficiencies are associated with various neurological abnormalities. We present a case of an 18-year-old woman who presented with significant neurological sequelae, but only mild hematologic abnormalities and normal vitamin B12 levels. She was found to have a moderately increased mean corpuscular volume, a markedly elevated homocysteine level, and a greatly increased methylmalonic acid level. In symptomatic patients it is important for physicians to maintain a high index of suspicion for B12 deficiency despite normal serum levels. The measurement of MMA and homocysteine levels provides much more sensitive tests, but even these tests do not completely rule out a deficiency. Although, the traditional treatment for vitamin B12 deficiency has been intramuscular cobalamin injections, recent studies have shown that oral cobalamin may be as efficacious. PMID- 19785316 TI - The complex ethics of nurse migration. PMID- 19785317 TI - Nursing council appreciates feedback. PMID- 19785318 TI - Are you a generation Y registered nurse? PMID- 19785319 TI - No new RN scope--NZNO. PMID- 19785320 TI - Improving outcomes for stroke patients. PMID- 19785321 TI - What' care rationing and what are its effects? PMID- 19785322 TI - Standing up for migrant nurses' rights at work. PMID- 19785323 TI - Generation Y--why nursing must retain this workforce. PMID- 19785324 TI - From South Africa to Reefton- one nurse's jouney. PMID- 19785325 TI - Supporting international nurses in their practice. PMID- 19785326 TI - Reaping the benefits of a treaty of Waitangi workshop. PMID- 19785327 TI - Keeping alert to changes during the pandemic. PMID- 19785328 TI - Global perspectives at ICN congress. PMID- 19785329 TI - Focus on nursing education. PMID- 19785330 TI - Materials management has effect on high-tech acquisitions. PMID- 19785331 TI - Group buys offer relief from tough financial conditions. PMID- 19785332 TI - Prices for elastic bandages bend, but won't break, the bank for your hospital's bottom line. PMID- 19785334 TI - What do YOU know about the value of oral health? PMID- 19785333 TI - You and your dentist: talking about your oral health. PMID- 19785335 TI - Medicaid: a dental safety net in tough times. PMID- 19785336 TI - It's never too late to enjoy that steak. PMID- 19785337 TI - At the dentist, you're home, sweet home. PMID- 19785338 TI - What's the difference between your physician and your dentist! PMID- 19785340 TI - "Why are my gums bleeding"! PMID- 19785339 TI - Are you drinking your teeth away? How soda and sports drinks dissolve enamel. PMID- 19785341 TI - Why flossing is so important. PMID- 19785342 TI - The sleepy side of your dental visit. PMID- 19785343 TI - Getting to the root of things with your endodontist. PMID- 19785344 TI - Are dental implants the right treatment option for you? PMID- 19785345 TI - The scoop on your wisdom teeth. PMID- 19785346 TI - How you can have a whiter, brighter smile. PMID- 19785347 TI - Make the most of your dental insurance benefits. PMID- 19785348 TI - Every baby was born to smile. PMID- 19785349 TI - "How I got through dental school". PMID- 19785351 TI - A salute to our patients. PMID- 19785350 TI - Destination: graduation. PMID- 19785352 TI - Nothing to sneeze at. PMID- 19785353 TI - House committees complete action on healthcare reform. PMID- 19785354 TI - Prevention efforts gain impetus from new 'never events' codes. PMID- 19785355 TI - What's the role of a managing partner? PMID- 19785356 TI - Where doctors work makes a difference in the bottom line. PMID- 19785357 TI - Everything for patients with breast disease--in one place. PMID- 19785358 TI - Nothing to fear but fear itself. PMID- 19785359 TI - Cover up. PMID- 19785360 TI - Mentors are not fads. PMID- 19785361 TI - Self disclosure. How to manage the risk of Medicare fraud and abuse. AB - When you discover an incident of noncompliance with Medicare/Medicaid regulations, step forward and notify the authorities before the government or a whistleblower takes the problem out of your hands. PMID- 19785362 TI - Getting physicians involved in patient safety. A team approach. AB - An evidence-based team training program can get physicians--and everyone else--in your organization to adopt and maintain a culture of patient safety. PMID- 19785364 TI - A hop, skip and kick to the head. PMID- 19785363 TI - A clear & present measure. Take ownership of patient satisfaction. PMID- 19785365 TI - [A reflection on internal medicine]. PMID- 19785366 TI - [Myocarditis]. AB - Myocarditis is a disorder with a wide range of symptoms spanning from light breathlessness or chest pain, ceasing without specific treatment, through cardiogenic shock, requiring left ventricular assistance, to sudden death. Dilated cardiomyopathy with chronic cardiac failure might be the very consequence of the precedent myocarditis. Myocarditis is the most frequently caused by viral infections, less frequently by specific infections, toxic or hypersensitivity reactions to medicines, giant cell myocarditis or sarcoidosis. Prognosis and treatment differ according to the cause, clinical or haemodynamic signs inform decision-making on care provided by cardiology centres, including decisions on execution and interpretation of myocardial biopsy. The present overview aims to provide practical guidance on diagnosis and treatment of myocardial inflammation. PMID- 19785367 TI - [Heart transplantation]. AB - The first heart transplantation (SHT) was performed by Professor Ch. Barnard in 1967 but it was not until 1980s that this method became an established approach to treatment of patients with end-stage heart failure. Considering the limited number of donor organs and the number of potential post-transplantation complications, the decision to perform heart transplantation at the right time in an indicated patient is difficult and complex. Subsequent pharmacological management with immunosuppressive agents and other medication becomes everyday life reality. Knowledge of drug interactions and collaboration with cardiologists are necessary in order to maintain long-term treatment success. Despite the current developments in surgical methods, examination methods and immunosuppressant therapy, a range of complications has to be dealt with. The future of care for patients with transplants will rely on the development of new immunosuppressive drugs with a minimum of adverse effects and discovery of a non invasive technique for graft rejection diagnosis. PMID- 19785368 TI - [Hypertension combination therapy with renin-angiotensin system blockers]. AB - Target blood pressure levels are not being achieved with the current hypertension treatment. Monotherapy that normalizes BP in about 20% of patients does not provide sufficient control to reach this goal and thus combination therapy is required. Results from recent clinical studies showed that a combination of an angiotenzin-converting enzyme inhibitor (ACEi) with a calcium channel blocker (CCB) provide better results and reduced incidence of cardiovascular events than a combination of a diuretic with an ACE inhibitor. Combination therapy based on rennin-angiotenzin system blockade: ACEi with a CCB, ACEi with a diuretic or angiotenzin receptor blocker (AT1) with a diuretic as a first-line treatment of the stage 2 hypertension might lead to significantly better control of blood pressure than monotherapy. PMID- 19785369 TI - [Cholesterol levels according to age]. AB - Cholesterol levels were measured at public places (mostly department stores) from 2005 to 2008. Sampling was conducted at random, from volunteers, without any prior dietary restrictions. In total, 14,539 persons were assessed. We did not find any significant differences between sexes in cholesterol levels (overall median was 5 mmol/l; 4.9 mmol/l in men and 5.1 mmol/l in women). Smaller proportion of women than men had cholesterol levels lower than 5.0 mmol/l (53.0% of men and 45.2% of women). Cholesterol levels raise with age in both sexes, stagnate at a certain point and subsequently decline; we identified a significant difference in this between men and women--the levels start to stagnate at the age of 50 in men and beyond the age of 65-70 years in women. The levels fall with increasing age in both sexes after the age 65 years. Cholesterol levels rise with age in both sexes before the age of 50 years; this trend is the same in both sexes (i.e. there is no significant difference between sexes, p = 0.687). Nevertheless, cholesterol levels are statistically significantly higher in women than in men in the over 55 years age group (the difference in the cholesterol level values median is up to 0.8-0.9 mmol/l). This difference is retained to advanced age of > 75 years. PMID- 19785370 TI - [Echocardiography in patients with ischemic heart disease]. AB - The assessment of the patients with coronary artery disease is one of the most important clinical applications of echocardiography. The importance of this application lies in the fact that coronary artery disease is the most common form of heart disease and the leading cause of death in all industrial countries. Echocardiography plays a diagnostic role at all stages of the disease from the early detection of transient, stress-induced, ischemic dysfunction, through the phase of acute myocardial infarction and its attendant complications, to the development of chronic ischemic heart disease and heart failure. Finally, echocardiography often provides important prognostic data in patients with coronary artery disease. PMID- 19785371 TI - [Transplantation of haematopoietic cells]. AB - Autologous and allogeneic transplantations of haematopoietic cells form an important part of treatment of, particularly haematological, malignancies but have their place in the treatment of other diseases as well. Transplantation brings permanent remission in a number of patients. However, transplantation, and the allogeneic one in particular, is associated with a range of complications. The following review paper provides information on the types of transplants, their collection and processing, on the options for and ways to seek suitable donors of haematopoietic cells. Other sections of the paper focus on preparatory pre-transplantation regimens and complications that might occur after the transplantation. Finally, the paper reviews clinical uses of haematopoietic cell transplantations and provides a summary of diagnoses in which this treatment method can be applied. PMID- 19785372 TI - [B-cell chronic lymphocytic leukaemia and the similar states]. AB - B-cell chronic lymphocytic leukaemia and the similar diseases are seen predominantly in patients above the age 50 years, i.e. at the age when the patients also have other co-morbidities. The knowledge of these diseases on molecular level has improved significantly over the last decade. Molecular and biological prognostic factors are available in routine everyday practice. Assessment of these factors enables prediction of prognosis and, in some cases, also the response to therapy. The aim of the present review is to provide the medical community with the main information on this disease as patients with B cell chronic lymphocytic leukaemia and similar disease states are of older age and very often suffer from a range of co-morbidities. Consequently, care for these patients involves physicians from various specialities. The aim of the following text is to present a clear overview of the basic information about this group of diseases that might be useful to all physicians who provide care to patients with B-cell chronic lymphocytic leukaemia and similar conditions. Since monoclonal immunoglobulin is sometimes identified in patients with these diseases, it is important to consider these conditions in the differential diagnosis of the states with the presence of monoclonal immunoglobulin. PMID- 19785373 TI - [The importance of autologous transplantation in multiple myeloma]. AB - Several randomized clinical trials in multiple myeloma (MM) completed in the last two decades have clearly shown that high-dose chemotherapy with hematopoietic stem cell support significantly increases the number of complete remissions and median overall survival in comparison to conventional chemotherapy. The median survival of MM patients treated with conventional chemotherapy is approximately 4 years in contrast to 5 to 6 years with autologous transplantation. Although high dose chemotherapy with autologous transplantation is not curative and most patients will eventually relapse, more than 20% of patients treated using this strategy experience survival longer than 10 years. Thus, autologous transplantation is the preferred treatment option for all eligible patients with MM. PMID- 19785374 TI - [Liver cirrhosis and its treatment]. AB - Cirrhosis is an end-stage liver disease. It is necessary to always search for the cause, attempt to initiate suitable causal treatment and assess the severity of hepatopathy by evaluating hepatic functional reserve (according to the Child-Pugh classification). It is necessary to continually monitor possible complications of cirrhosis, some can be prevented. Regular clinical and laboratory monitoring as well as ultrasound and endoscopic examinations are required. The paper discusses the treatment of the disease as well as its complications. Cure can only be achieved with a liver transplant; this option should be evaluated by a hepatologist in each patient with functional classification B or with serious complications of portal hypertension mentioned above. Treatment standards compiled by the Czech Society of Hepatology (http://www.ceska-hepatologie.cz) offer the basic algorithms of correct diagnosis and treatment. PMID- 19785375 TI - [Surgical treatment of pulmonary embolism]. AB - BACKGROUND: Surgical embolectomy is established method of treatment of pulmonary embolism. The aim of the study is to evaluate the experience with this procedure. PATIENTS AND METHODS: Twenty two patients, aged 22-77 years, were operated on in Centre of cardiovascular surgery and transplantation in Brno from 1999 to 2009. Nine patients suffered from massive pulmonary embolism with hemodynamic instability, 13 were stable. All the operations were performed in cardiopulmonary bypass with cross clampimg time 50.4 minutes on average. In six patients the retrograde perfusion via pulmonary veins were used. Emboli in the main trunk and/or in both pulmonary branches were found in 16 patients (72.7%). No macroscopic emboli were found in three patients, but they were flushed from the pulmonary vessels during the retrograde perfusion in two of them. Emboli or thrombi in cardiac atria or ventricles were detected in 8 patients simultaneously. RESULTS: Five patients died early after operation (mortality 22.7%). The mortality was different in the group of patients with massive pulmonary embolism and cardiogenic shock (44.4%) and with submassive embolism and hemodynamic stability (7.7%). CONCLUSION: Developments in surgical technique with retrograde perfusion offer removing of emboli not only from the pulmonary trunk and main branches, but also from the peripheral branches. It improves results and facilitates extension of indications for surgical treatment. PMID- 19785376 TI - [The most common heart valve diseases: aortic stenosis and mitral regurgitation. A few comments on guidelines and recommendations by societies of cardiology]. AB - Recommendations of professional societies, frequently called guidelines as per the English translation, provide help to the general practice as well as specialized physicians. These are recommendations, not a legislative norm. Societies of cardiology have issued 3 new guidelines over the recent years; American ACC/AHA in 2006 and European ESC and Czech CSC in 2007. Guidelines for diagnostics and therapy are presented as Class I to III according to the suitability of the procedure and the level of evidence is classified in groups A to C. Emphasised is the effort of societies of cardiology to provide unbiased guidelines. They request the authors to provide a statement confirming they are not in any way related to any organization, institution or company that could be at present or in the future considered as a conflict of interests. Mentioned is the rapid growth of knowledge that does not allow the guidelines to consider the latest advances to trans-catheter therapy of the both most frequently occurring valve disorders. PMID- 19785377 TI - [Diabetes and vascular diabetic disease]. AB - The prevalence of type 2 diabetes mellitus is growing. Vascular disease is here the main cause of morbidity and mortality, and accelerated atherosclerosis is responsible for about 80% of mortality and for about 75% of hospitalizations. In diabetics there is 2-4 times greater risk of ischemic heart disease in comparison to non-diabetics, and this risk is even greater in diabetic-females. Authors put greater attention to pathophysiology of diabetic vascular disease (inflammation and adipose tissue, metabolic and other--AGEs, ADMA--abnormalities, their contribution to endothelial dysfunction). The main concern is devoted to the treatment possibilities of diabetic vascular disease. PMID- 19785378 TI - [Tako-tsubo cardiomyopathy]. AB - Tako-tsubo cardiomyopathy is new clinical syndrome which mimic acute myocardial infarction. The main characteristic is apical ballooning of the left ventricular wall during systole and normal findings on coronary arteries. Pathophysiology is not known, very important is definitively the role of catecholamines. The electrocardiography, echocardiography, left ventricular angiography and coronary angiography are methods used in diagnosis of this syndrome. The therapy is only symptomatic, in cases with severe complications mechanical support of circulation should be used. PMID- 19785379 TI - [Reducing food salt content--a neglected approach to hypertension prevention and treatment in the population]. AB - Long-term dietary salt supply, disproportional to the high metabolic requirements, plays an important role in pathogenesis of arterial hypertension. BP, its rise with age and hypertension prevalence in the population are directly proportional to sodium supply. Consistent effect of salt supply on the BP values is documented from observational as well as randomised controlled studies. It is, therefore, possible to assume that decrease in salt intake in the population could positively affect population BP mean, age-related increase in BP as well as a range of cardiovascular complications of hypertension and could thus contribute to improving the course and prognosis of this "non-infectious epidemy", the incidence of which exceeds 30% in the adult population and increases continually with age. Based on a review of published population-based observations and clinical studies, the paper summarizes briefly the opinions on the impact of the sodium chloride dietary intake modifications on BP, outcomes of these modifications within various historical, ethnic, experimental and clinical contexts, impact on BP morbidity and mortality, population-based importance of the current high salt supply decrease on these indicators and possible utilization in the primary prevention of hypertension. PMID- 19785380 TI - [To treat or not to treat with statins patients with chronic heart failure?]. AB - Two clinical trials--CORONA and GISSI-HF--have been conducted to resolve uncertainties about the effects of statins in patients with chronic heart failure and justified suspicions that treatment with statins in these patients might be detrimental. The CORONA trial researched the effects of 10 mg rosuvastatin compared to placebo on the incidence of serious cardiovascular events in 5,011 patients with systolic heart failure of ischemic aetiology, above 60 years of age and in the NYHA functional class II-IV. Even though rosuvastatin reduced the mean LDL-cholesterol plasma concentrations by 45.0% (p < 0.001) and high-sensitivity C reactive protein (hsCRP) concentrations by 37.1% (p < 0.001), the incidence of cardiovascular events was not importantly affected (HR = 0.92; p = 0.12). Rosuvastatin had no effect on overall mortality. The treatment resulted only in a reduction of the number of hospitalizations for cardiovascular causes (p < 0.001). The GISSI-HF trial involved 4,574 patients with chronic heart failure irrespective of aetiology and the ejection fraction value randomised to take either 10 mg of rosuvastatin or placebo. The results were almost identical. Rosuvastatin had no effect on the incidence of the primary end-point--the sum of cardiovascular mortality and hospitalizations (HR = 1.01; p = 0.903). The overall mortality was not affected either. Administration of rosuvastatin in both studies was safe, the number of adverse events, including myopathies and renal failure, was no different from placebo. However, recent results from the CORONA trial subtrials have suggested that important interactions exist in patients with chronic heart failure between the effects of rosuvastatin and natriuretic peptide and hsCRP plasma concentrations. Rosuvastatin provides clinical benefit in patients with relatively low concentrations of natriuretic peptides, i.e. relatively well-controlled, while it has no clinical effect in patients with high natriuretic peptide concentrations. Similarly, rosuvastatin provides clinical benefit in patients with high hsCRP but has no effect in patients with normal hsCRP (< 2 mg/l). PMID- 19785381 TI - [How to improve response to cardiac resynchronization therapy?]. AB - Cardiac resynchronization therapy decreases mortality and rehospitalization for heart failure. However, around 30% of patients do not respond to this therapy. The paper analyses factors, with a possible impact on the response to this therapy. It is a left ventricular lead proximity to the left ventricle segment with the latest activity, presence and size of postinfarction scar and a percentage of fully captured paced beats. Methods of optimalization of these factors are described as well as circumstances, under which some patients should be indicated for cardiosurgical lead implantation or if a cardiac resynchronization therapy should be ommited. PMID- 19785382 TI - [Monitoring of cardiovascular risk factors in patients with diabetes type 2]. AB - The control of basic cardiovascular risk factors was examined in a sample of 415 diabetes type 2 patients, aged 66 +/- 10 years, with a 9.4 +/- 8 years long history of diabetes, both genders represented proportionally; 95% of the sample were hypertensive. The recommended blood pressure value was achieved by 13% males and 17% females. Antihypertensive monotherapy was indicated in 40% of the sample. Renin-angiotensin-aldosteron system inhibitors were prescibed to 90% of the sample. The fasting glycaemia < or = 6 mmol/L were achieved in 10% males and 11% females; glycosilated hemoglobin < 4.5% in 20% males and 24% females; 60% of the sample had antidiabetic pharmacotherapy--44% males and 48% females used metformin. Total fasting plasma cholesterol < 4.5 mmol/L was achieved in 31% males and 23% females; LDL-cholesterol < 2.5 mmol/L was achieved in 31% males and 41% females. The target values for diabetics in secondary prevention of cardiovascular diseases or with subclinical atherosclerosis was achieved in 13% of the sample. Statins were prescribed in 60% of the sample, fibrates in 4%. Only 2 females achieved all the target values. Hypolipidemic and antihypertensive drug therapy is unsatisfactory; there is certainly a big potential in life style changes among the diabetic patients. PMID- 19785383 TI - [Prediabetes - 2009]. AB - The concept of prediabetes has been discussed since the 1950's. After 1980, WHO expert guidelines on the classification of diabetes according to its stages of development became common. These guidelines also included statistically significant risk groups with diabetes likely to develop in the future. The term Impaired Glucose Tolerance (IGT) was officially introduced by WHO in 1979, with an additional category referring to changes in glucose metabolism to be included later on--the Impaired Fasting Glucose--IFG. The term prediabetes mellitus began to be used again after 2000, and after 2003 diagnostic criteria to delimit diabetes and prediabetes came into use. Progressively, evidence was gathered on the involvement of hyperglycaemia and other metabolic abnormalities in patients with type 2 diabetes in creating conditions for the development of atherosclerosis. The last decade saw re-emerging publications dealing with the abnormalities of glucose metabolism, and subsequent statements from ADA, IDF and other organisations proposing the techniques of screening, diagnosis, monitoring and/or therapy of prediabetes. Recently, the American Diabetes Association clearly specifes the diagnosis of prediabetes, whereby prediabetes is defined within the scope of the diabetic disease. Prediabetes/diabetes reflect the continuum of the risk of microvascular and macrovascular outcomes. For these reasons, methods have been developed to delay the progression of prediabetes to diabetes. An ADA panel suggests that individuals with prediabetes should be enrolled in a program of intensive lifestyle intervention, with a specific group of patients at risk to be considered for therapy with metformin. Additional methods of prevention will be introduced into practice on the basis of new studies. PMID- 19785384 TI - [Some current views on chronic ischemic heart disease]. AB - Chronic myocardial ischemia results from a temporary disbalance between supply of oxygen to myocardium and consumption of oxygen by myocardium. The most frequent cause of ischemic heart disease is atherosclerosis of the coronary arteries. At present, diagnosis of coronary impairment is for practical reasons not possible until myocardial ischemia is detectable. Despite the current pharmacological treatments, data from the recent studies justify stratification of prognosis of patients with chronic ischemic heart disease into subgroups with low, medium and high risk. Mean annual mortality is below 1% in patients with low risk, 1-2% in patients with medium risk and above 2% in patients with high risk. Revascularization procedures might improve prognosis in certain subgroups of patient with chronic ischemic heart disease. Revascularization also decreases the incidence of ischemic episodes and improves the left ventricle function in some subgroups. PMID- 19785385 TI - [Target values in hypertension treatment. Will they apply in older patients with hypertension, diabetics and in patients with IHD?]. AB - The incidence of isolated systolic hypertension increases with age since 50 years. Systolic pressure appears to have higher prognostic importance than diastolic pressure in patients older than 50 years. Treatment of isolated systolic hypertension importantly decreases cerebrovascular events, coronary events as well as overall mortality. Studies providing the relevant evidence have mostly been conducted at the beginning of 1990s. The baseline systolic pressure in all these studies was 160 mmHg and higher. This is because the isolated systolic hypertension then was defined as systolic pressure of 160 mmHg or higher and diastolic hypertension as pressure of 95 mmHg or higher. No study confirming that systolic pressure lowering to the range of 140-159 mmHg in older patients would positively affect morbidity and mortality, with a further aim to achieve systolic pressure levels of less than 140 mmHg, have been conducted so far. The recommendation to aim, even in older patients, for the target values of less than 140 mmHg is based mainly on observational studies. Possible existence of the diastolic pressure J-curve in patients with ischemic heart disease represents another unresolved issue. There is a lack of randomised studies on this subject comparing reduction of the diastolic pressure to below 80, below 70 mmHg and below 60 mm Hg. The joint guidelines of the European Society of Hypertension and European Society of Cardiology recommend the target value of <140/90 mmHg for the treatment of isolated systolic hypertension, and systolic pressure of less than 130 mmHg in patients with diabetes, cardiovascular or renal diseases (following myocardial infarction, cerebrovascular event or renal dysfunction), in patients with metabolic syndrome and in patients with the overall cardiovascular SCORE based risk of > or = 5%. There are no data available confirming that lowering blood pressure to these target values is justified. The 'lower the blood pressure is better' rule applies to cerebrovascular events only. The data from the large ONTARGET study show that lowering of the systolic blood pressure to less than 130 mmHg does not bring any benefit to hypertonics with high cardiovascular risk, except from cerebrovascular events. The J-curve exists for cardiovascular mortality, myocardial infarction and probably also for diabetics, with the turning point at about 130 mmHg. Further reduction of blood pressure increases cardiovascular mortality and myocardial infarctions. We believe that, in the current atmosphere of contradictory data on the diastolic pressure and coronary events relationship J-curve, caution is needed in older patients with isolated systolic hypertension and IHD in cases when the on-treatment diastolic pressure falls below 70 mmHg. In such a situation we would not insist on reaching the systolic pressure target value. We believe that this should apply to older patients with ischemic heart disease in particular. In summary, it is possible to conclude that hypertension treatment target blood pressure values of less than 140/90 mmHg are justified. However, target values of less than 130/80 mmHg in diabetics, in patients with a cardiovascular disease and in other patient groups (metabolic syndrome, overall cardiovascular risk of 5% or higher) are challenged by the results of a range of large studies, and verification in prospective studies is of utmost importance. PMID- 19785386 TI - [AT1-blockers in the treatment of hypertension]. AB - Angiotensin receptor antagonists (AT1-blockers) are considered as one of the major classes of antihypertensive drugs suitable for monotherapy as well as for combination treatment. Mechanisms of antihypertensive effects of AT1-blockers are discussed altogether with the results of large clinical trials and indication in hypertension. PMID- 19785387 TI - [Consensus on providing palliative treatment to patients with incurable organ failure]. PMID- 19785388 TI - High-energy excitations in silicon nanoparticles. AB - We have investigated high energy excitations in approximately 1-2 nm Si nanoparticles (NPs) by ab initio time-dependent density functional calculations, focusing on the influence on excitation spectra, of surface reconstruction, surface passivation by alkyl groups, and the interaction between NPs. We have found that surface reconstruction may change excitation spectra dramatically at both low and high energies above the gap; absorption may be enhanced nonlinearly by the presence of alkyl groups, compared to that of unreconstructed, hydrogenated Si NPs, and by the interaction between NPs. Our findings can help interpret the recent experiments on multielectron generation in colloidal semiconductor NPs as well as help optimize photovoltaic applications of NPs. PMID- 19785389 TI - Further studies on the chemistry of the flustra alkaloids from the bryozoan Flustra foliacea. AB - Since 1980, over a dozen novel brominated alkaloids, named flustramines, have been isolated from Scandinavian and Canadian collections of the marine bryozoan Flustra foliacea. This paper describes the reisolation of the known compound dihydroflustramine C (1) and the isolation of 11 new flustramines (2-4, 6-13), including two dimers (12, 13) that may be isolation artifacts. Together these compounds, some with an unexpected aryl substitution pattern, reveal an intricate network of metabolites present in the extracts of the bryozoan. The structures of these metabolites were solved using a variety of spectroscopic techniques and chemical derivatization and modification. This work also led to the recognition of an unusual rearrangement reaction that occurred slowly over a number of years. PMID- 19785390 TI - Heteroaromatic sulfonates and phosphates as electrophiles in iron-catalyzed cross couplings. AB - Employment of heteroaromatic tosylates and phosphates as suitable electrophiles in iron-catalyzed cross-coupling reactions with alkyl Grignard reagents is reported. These reactions are performed at low temperature allowing good functional group tolerance and full conversion is achieved within minutes. In addition, an aryl-aryl cross-coupling utilizing a heteroaryl sulfamate electrophile is reported. PMID- 19785391 TI - Layered carbon nanotube-polyelectrolyte electrodes outperform traditional neural interface materials. AB - The safety, function, and longevity of implantable neuroprosthetic and cardiostimulating electrodes depend heavily on the electrical properties of the electrode-tissue interface, which in many cases requires substantial improvement. While different variations of carbon nanotube materials have been shown to be suitable for neural excitation, it is critical to evaluate them versus other materials used for bioelectrical interfacing, which have not been done in any study performed so far despite strong interest to this area. In this study, we carried out this evaluation and found that composite multiwalled carbon nanotube polyelectrolyte (MWNT-PE) multilayer electrodes substantially outperform in one way or the other state-of-the-art neural interface materials available today, namely activated electrochemically deposited iridium oxide (IrOx) and poly(3,4 ethylenedioxythiophene) (PEDOT). Our findings provide the concrete experimental proof to the much discussed possibility that carbon nanotube composites can serve as excellent new material for neural interfacing with a strong possibility to lead to a new generation of implantable electrodes. PMID- 19785393 TI - Self-assembly of SbCl3 and 1,4-dioxane: cubic structure connected by very weak bonds. AB - The self-assembly of SbCl(3) and 1,4-dioxane in a 2:3 ratio leads to an interpenetrating extended cubic structure from X-ray crystallography. The structure is held together by very weak Sb-O bonds ( approximately 7 kcal/mol each), which still maintain strong directionality. Parameterization and subsequent simulation of the system using a reactive force field (ReaxFF) gives us insight into the key interactions necessary for self-assembly from a completely random configuration of molecules into the experimentally observed cubic structure. We explain why the porous structure (with no interpenetration of lattices) is not observed, and we trace the important intermediate substructures formed en route to the crystal. PMID- 19785392 TI - Growth and optical properties of gold nanoshells prior to the formation of a continuous metallic layer. AB - The growth and optical properties of incomplete gold layers on silica particles (229 nm) are studied using visible/near-infrared spectroscopy and transmission electron microscopy. The gold particles that eventually coalesce to form a continuous gold layer are found to have droplet-like shapes. The optical properties of these systems are different from those of complete gold nanoshells. Using the discrete dipole approximation, it is found that the plasmon modes of such systems should exhibit two bands: one from 500-600 nm ("high energy") and the other from 600-800 nm ("low energy"). The calculations show that, for increasing coating density of the droplet-like particles, the lower energy band (i) becomes stronger relative to the higher energy band and (ii) is red-shifted. Both of these trends are found in the spectra of the prepared particles. Furthermore, the observed plasmon bands fall within the limits established by the model. PMID- 19785394 TI - Cyclocondensation of alpha-aminonitriles and enones: a short access to 3,4 dihydro-2H-pyrrole 2-carbonitriles and 2,3,5-trisubstituted pyrroles. AB - The reaction of alpha,beta-unsaturated carbonyl compounds with aminoacetonitrile hydrochloride furnishes 3,5-disubstituted 3,4-dihydro-2H-pyrrole-2-carbonitriles in a one-pot reaction sequence. While these products can serve as starting materials for the preparation of polysubstituted pyrrolizidines, they are kinetically stable against the base-induced elimination of HCN. In contrast, their 2-substituted analogues obtained from alpha-substituted alpha-aminonitriles can be readily converted to the corresponding 2,3,5-trisubstituted pyrroles under microwave irradiation. The key step presumably involves the thermal electrocyclization of a stabilized 2-azapentadienyl anion formed by condensation of the reactants and subsequent deprotonation. PMID- 19785395 TI - Synthesis and self-assembly of brush-type poly[poly(ethylene glycol)methyl ether methacrylate]-block-poly(pentafluorostyrene) amphiphilic diblock copolymers in aqueous solution. AB - Well-defined fluorinated brush-like amphiphilic diblock copolymers of poly[poly(ethylene glycol)methyl ether methacrylate] (P(PEGMA)) and poly(pentafluorostyrene) (PPFS) have been successfully synthesized via atom transfer radical polymerization (ATRP). The self-assembly behavior of these polymers in aqueous solutions was studied using (1)H NMR, fluorescence spectrometry, static and dynamic light scattering and transmission electron microscopy techniques. The micellar structure comprised of PPFS as the core and brush-like (hydrophobic main chain and hydrophilic branches) polymers as the coronas. The hydrodynamic radius (R(h)) of the micelles in aqueous solution was in the nanometer range, independent of the polymer concentration, consistent with a closed association model. Diblock copolymers with a longer P(PEGMA) block formed micelles with smaller R(h) and lower aggregation numbers consistent with an improved solubilization of the core. The micelles possessed a thick hydration layer as verified by the ratio of the radius of gyration, R(g) to the hydrodynamic radius, R(h). The aggregation number and ratio of R(g) to R(h) were observed to increase with temperature (20-50 degrees C), while the R(h) of the micelle decreased slightly over the same temperature range. An increase in temperature induced the brush-like PEG segments in the corona to dehydrate and shrink while forming micelles with larger aggregation numbers. PMID- 19785396 TI - Friction of polyaromatic thiol monolayers in adhesive and nonadhesive contacts. AB - We have used friction force microscopy to study the effects of adhesion on the boundary friction of self-assembled monolayers of the aromatic compounds thiophenol, p-phenylthiophenol, p-terphenyl thiol, 2-naphthalenethiol, and benzyl mercaptan on gold. To control the adhesion between the monolayer-covered tip and substrate, the friction measurements were made in dry N(2) gas or in ethanol. At low loads, low adhesion (in ethanol) resulted in a linear dependence of the friction force on load (i.e., F = muL) whereas higher adhesion between the same monolayers (in N(2)) gave an apparent area-dependent friction. The friction in the adhesive systems was well described by F = S(c)A with the contact area, A, calculated for a thin, linearly elastic film confined between rigid substrates using the thin-coating contact mechanics (TCCM) model in a transition regime between its DMT- and JKR-like limits. With increasing packing density of the monolayers, a systematic decrease was found in the friction coefficient (mu) obtained in ethanol and the critical shear stress (S(c)) obtained in N(2). To describe these aromatic monolayers with the extended TCCM model, a higher Young's modulus was neeeded than for fatty acid monolayers of similar packing density. PMID- 19785397 TI - Gold(I)-catalyzed intermolecular oxyarylation of alkynes: unexpected regiochemistry in the alkylation of arenes. AB - The reaction between acetylenes and sulfoxides, studied as a test case for gold catalyzed intermolecular addition, provides the oxyarylation compounds 3 in good yields. Unpredictably, in all cases a single regioisomer arising from the electrophilic aromatic alkylation at the position adjacent to the sulfur atom is obtained instead of the expected Friedel-Crafts regioisomer. A new concerted mechanism based on DFT calculations is proposed to account for the products in this intermolecular gold(I)-catalyzed reaction. PMID- 19785398 TI - Use of surfactants to reduce the driving voltage of switchable optical elements based on electrowetting. AB - The advantage of using electrowetting as a novel principle for a reflective display has been previously demonstrated. The principle is based on the controlled two-dimensional movement of an oil/water interface across a hydrophobic fluoropolymer insulator. The main objective of this paper is to show experimentally the influence of surfactants on the electro-optic behavior of a single electrowetting pixel. The concentration and type of nonionic surfactant (Tween 80 and Span 20) have been varied. The experimental data are compared with calculations from the electro-optic model developed previously. The electro-optic performance is significantly affected by the nature and the concentration of surfactant. In the presence of Tween, at concentrations lower than the critical micelle concentration (CMC), and mixtures of Tween and Span the electro-optic behavior can be related to the interfacial tension. When decreasing the oil/water interfacial tension, the amplitude of the driving voltage required for obtaining a given oil displacement decreases and the switching curve becomes steeper. These effects can be accurately reproduced by means of the previously developed electro optic model. Mixtures of Tween and Span produce a significant synergetic reduction of the driving voltage. For Tween concentrations higher than the CMC and Span, a strong disagreement is observed between the previously developed model and experimental data. Here a new physical model is reported that describes the electro-optic behavior of electrowetting-based optical elements in the presence of surfactants. The model takes into account the actual voltage used to control the liquid movement in electrowetting (lower than the applied voltage), the amount of surfactant adsorbed at the decane/water interface, and the dipole moment of the surfactant molecules. The calculated results are in very good agreement with experimental data without employing fitting parameters. The dipoles interact with the applied field and lower the actual applied field. This reduction of the effective electric field across the solid-liquid interface induces a decrease in the charge density at the solid-liquid interface and reduces the electrowetting force. For surfactant concentrations higher than the CMC, the electro-optic performance does not depend on the surfactant concentration. This demonstrates that the reduction of the electrowetting field due to the large dipole moment of the surfactant molecules occurs at the oil/water interface. A new method for the test cell fabrication is also presented. PMID- 19785399 TI - Tailored growth of In(OH)(3) shell on functionalized polystyrene beads. AB - Fabrication of organic-inorganic composite particles with tailored size, shape, and morphology has been attracting great attention from researchers because of their fascinating properties and applications in a variety of potential fields. In this study, we report on the fabrication of PS-In(OH)(3) (polystyrene-indium hydroxide) composite particles by hydrolyzing the In(OC(3)H(7))(3) (indium isopropoxide) salt in the presence of beta-diketone functionalized PS colloidal particles. A systematic investigation of the employed reaction conditions allowed us to tune the morphology, size, and In(OH)(3) content of the PS-In(OH)(3) composite particles. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) results illustrate that variation in the employed concentration of the In(OC(3)H(7))(3) salt in reaction media can effectively tune the morphology of resulting composite particles between "core-shell" and "raspberry like". X-ray diffraction (XRD) analysis confirms the phase purity of In(OH)(3) nanoparticles precipitated on the surface of PS beads. Colloidal stability of the composite particles has been found to be reduced with increasing the deposited amount of In(OH)(3) nanoparticles. Thermogravimetric analysis (TGA) suggests a continuous increase in the deposited amount of In(OH)(3) nanoparticles with increasing concentration of In(OC(3)H(7))(3) salt in reaction media. The resulting PS-In(OH)(3) composite particles are envisioned to be used in a myriad of potential applications including fabrication of optoelectronic devices, absorption/separation supporting material, catalysts, and hydrophobic surfaces. PMID- 19785400 TI - Multiscale modeling of proteins. AB - The activity within a living cell is based on a complex network of interactions among biomolecules, exchanging information and energy through biochemical processes. These events occur on different scales, from the nano- to the macroscale, spanning about 10 orders of magnitude in the space domain and 15 orders of magnitude in the time domain. Consequently, many different modeling techniques, each proper for a particular time or space scale, are commonly used. In addition, a single process often spans more than a single time or space scale. Thus, the necessity arises for combining the modeling techniques in multiscale approaches. In this Account, I first review the different modeling methods for bio-systems, from quantum mechanics to the coarse-grained and continuum-like descriptions, passing through the atomistic force field simulations. Special attention is devoted to their combination in different possible multiscale approaches and to the questions and problems related to their coherent matching in the space and time domains. These aspects are often considered secondary, but in fact, they have primary relevance when the aim is the coherent and complete description of bioprocesses. Subsequently, applications are illustrated by means of two paradigmatic examples: (i) the green fluorescent protein (GFP) family and (ii) the proteins involved in the human immunodeficiency virus (HIV) replication cycle. The GFPs are currently one of the most frequently used markers for monitoring protein trafficking within living cells; nanobiotechnology and cell biology strongly rely on their use in fluorescence microscopy techniques. A detailed knowledge of the actions of the virus-specific enzymes of HIV (specifically HIV protease and integrase) is necessary to study novel therapeutic strategies against this disease. Thus, the insight accumulated over years of intense study is an excellent framework for this Account. The foremost relevance of these two biomolecular systems was recently confirmed by the assignment of two of the Nobel prizes in 2008: in chemistry for the discovery of GFP and in medicine for the discovery of HIV. Accordingly, these proteins were studied with essentially all of the available modeling techniques, making them ideal examples for studying the details of multiscale approaches in protein modeling. PMID- 19785402 TI - Hyperbranched polyglycerols: from the controlled synthesis of biocompatible polyether polyols to multipurpose applications. AB - Dendritic macromolecules with random branch-on-branch topology, termed hyperbranched polymers in the late 1980s, have a decided advantage over symmetrical dendrimers by virtue of typically being accessible in a one-step synthesis. Saving this synthetic effort once had an unfortunate consequence, though: hyperbranching polymerization used to result in a broad distribution of molecular weights (that is, very high polydispersities, often M(w)/M(n) > 5). By contrast, a typical dendrimer synthesis yields a single molecule (in other words, M(w)/M(n) = 1.0), albeit by a labor-intensive, multistep process. But 10 years ago, Sunder and colleagues reported the controlled synthesis of well-defined hyperbranched polyglycerol (PG) via ring-opening multibranching polymerization (ROMBP) of glycidol. Since then, hyperbranched and polyfunctional polyethers with controlled molar mass and low polydispersities (M(w)/M(n) = 1.2-1.9) have been prepared, through various monomer addition protocols, by ROMBP. In this Account, we review the progress in the preparation and application of these uniquely versatile polyether polyols over the past decade. Hyperbranched PGs combine several remarkable features, including a highly flexible aliphatic polyether backbone, multiple hydrophilic groups, and excellent biocompatibility. Within the past decade, intense efforts have been directed at the optimization of synthetic procedures affording PG homo- and copolymers with different molecular weight characteristics and topology. Fundamental parameters of hyperbranched polymers include molar mass, polydispersity, degree of branching, and end-group functionality. Selected approaches for optimizing and tailoring these characteristics are presented and classified with respect to their application potential. Specific functionalization in the core and at the periphery of hyperbranched PG has been pursued to meet the growing demand for novel specialty materials in academia and industry. A variety of fascinating synthetic approaches now provide access to well-defined, complex macromolecular architectures based on polyether polyols with low polydispersity. For instance, a variety of linear hyperbranched block copolymers has been reported. The inherent attributes of PG based materials are useful for a number of individual implementation concepts, such as drug encapsulation or surface modification. The excellent biocompatibility of PG has also led to rapidly growing significance in biomedical applications, for example, bioconjugation with peptides, as well as surface attachment for the creation of protein-resistant surfaces. PMID- 19785401 TI - PEGylated dendritic unimolecular micelles as versatile carriers for ligands of G protein-coupled receptors. AB - Despite its widespread application in nanomedicine, poly(ethylene glycol) (PEG) is seldom used for covalent modification of ligands for G protein-coupled receptors (GPCRs) due to potential steric complications. In order to study the influence of PEG chains on the biological activity of GPCR ligands bound to a common macromolecular carrier, we prepared a series of G3 polyamidoamine (PAMAM) dendrimers derivatized with Alexa Fluor 488, varying numbers of PEG(550)/PEG(750)/PEG(2000), and nucleoside moieties derived from the A(2A) adenosine receptor (AR) agonist CGS21680 (2-[4-(2-carboxylethyl)phenylethylamino] 5'-N-ethylcarboxamidoadenosine). These dendrimer conjugates were purified by size exclusion chromatography and characterized by (1)H NMR and MALDI MS. In radioligand binding assays, some PAMAM-PEG conjugates showed enhanced subtype selectivity at the human A(2A) AR compared to monomeric ligands of comparable affinity. The functional potency was measured in the A(2A) AR-mediated activation of adenylate cyclase and inhibition of ADP-induced platelet aggregation. Interestingly, the dendrimer conjugate 10c bearing 11 PEG(750) chains (out of theoretical 32 amino end groups) and 14 nucleoside moieties was 5-fold more potent in A(2A) AR-mediated stimulation of cyclic AMP formation than 10d with 4 PEG(2000) chains and 21 nucleosides, although the binding affinities of these 2 compounds were similar. Thus, a relatively small (<=10 nm) multivalent ligand 10c modified for water solubility maintained high potency and displayed increased A(2A) AR binding selectivity over the monomeric nucleosides. The current study demonstrates the feasibility of using short PEG chains in the design of carriers that target ligand-receptor interactions. PMID- 19785403 TI - Antibody internalization after cell surface antigen binding is critical for immunotoxin development. AB - Immunotoxin potency is dependent on cell surface binding specificity as well as internalization efficiency. Current approaches for immunotoxin development are dependent on existing antibodies that were selected for high affinity and/or high production yield. However, these antibodies may demonstrate low internalization efficiency upon cell surface binding and thus are not necessarily the best candidates for immunotoxin design. Here, we have developed an assay with a novel protein, DTG3, to compare and evaluate the internalization efficiency of monoclonal antibodies in order to circumvent the possibility of low internalization. DTG3 is a fusion protein containing the N-terminus of diphtheria toxin (DT) and three copies of streptococci Protein G immunoglobulin binding domains. We show that antibody-DTG3 complexes formed in the test tube are able to bind their antigen on the target cell surface, resulting in cell internalization, DT-mediated protein synthesis inhibition, and host cell apoptosis. We tested this system with two well-studied antibodies, antihuman CD3epsilon, and anti-PSMA antibodies and were able to show efficiency of this assay. We further examined commercially available anti-CD123 antibodies for potential leukemia-targeting immunotoxin development. Finally, we applied this system in the early-stage screening of newly generated anti-CD123 hybridomas. Our data showed that this internalization assay system is sensitive, time efficient, and reproducible, and has provided a tool to compare monoclonal antibodies for the clinical development of effective immunotoxins for the treatment of a variety of neoplasms. PMID- 19785404 TI - Conformation and orientation of proteins in various types of silk fibers produced by Nephila clavipes spiders. AB - Silk fibers harvested from the web, cocoon, and prey wrapping of the spider Nephila clavipes have been studied by polarized Raman spectromicroscopy. The technique is efficient to differentiate the various types of silk by probing monofilaments produced by the major ampullate (MA), minor ampullate (MI), cylindriform, flagelliform, and aciniform glands. The spectra show that the MA, MI, and cylindriform silks belong to the same structural class and are composed of highly oriented beta-sheets (35-37%) with other slightly oriented secondary structures. Spectral markers of particular motifs involved in the beta-sheets have been identified. The flagelliform silk represents a second, very peculiar structural class. It displays a heterogeneous disordered conformation without any preferential orientation. Such characteristics certainly play a role in the large extensibility of this silk. The aciniform silk represents a third class of silk dominated by moderately oriented beta-sheets (approximately 30%) and alpha helices (approximately 24%). Such a structure seems important in explaining the high toughness of this silk. PMID- 19785405 TI - Surface topography induces fibroblast adhesion on intrinsically nonadhesive poly(ethylene glycol) substrates. AB - Important in developing new biomaterials is the prevention of unspecific protein adsorption and cell interactions that in vivo can lead to a foreign body reaction. On the other hand, the material should support the growth of a specific cell type in a defined way. We investigate the possibility of manipulating cellular behavior on an intrinsically nonadhesive material by topographic patterning without additional surface chemistry modifications. The biomaterial applied is a hydrogel cross-linked from star-shaped poly(ethylene glycol) macromonomers (starPEG). Cell biological studies with a mouse fibroblast cell line (L929) showed that, while substrates with a smooth surface are nonadhesive, as expected, imprinted topography enabled cell adhesion and spreading. The fibroblasts aligned to micrometer groove patterns and were, depending on the respective dimensions, able to span or enter the grooves. Especially substrates with topography dimensions in the cell size range or smaller (<10 microm) lead to an establishment of stable cell-surface contacts (vinculin and actin accumulation). On micrometer post patterns the cells spread on top of the pillars and wrapped around the structures. The strong influence of the topography shows that nonadhesive materials do not necessarily have to be specifically biofunctionalized to enable cell adhesion. Possible explanations for the peculiar cell behavior are discussed in terms of (initial) protein adsorption and geometry dependent cytoskeletal arrangements. PMID- 19785406 TI - Copolymerization of vinyl acetate with ethylene by palladium/alkylphosphine sulfonate catalysts. AB - Coordination copolymerization of vinyl acetate (VAc) with ethylene, leading to linear copolymers that possess in-chain -CH(2)CH(OAc)- units, has been accomplished using novel palladium complexes bearing alkylphosphine-sulfonate ligands. PMID- 19785407 TI - Hidden markov analysis of short single molecule intensity trajectories. AB - Photon trajectories from single molecule experiments can report on biomolecule structural changes and motions. Hidden Markov models (HMM) facilitate extraction of the sequence of hidden states from noisy data through construction of probabilistic models. Typically, the true number of states is determined by the Bayesian information criteria (BIC); however, constraints resulting from short data sets and Poisson-distributed photons in radiative processes like fluorescence can limit successful application of goodness-of-fit statistics. For single molecule intensity trajectories, additional information criteria such as peak localization error (LE) and chi-square probabilities can incorporate theoretical constraints on experimental data while modifying normal HMM. Chi square minimization also serves as a stopping point of the iteration in which the system parameters are trained. Peak LE enables exclusion of overfitted and overlapped states. These constraints and criteria are tested against BIC on simulated single molecule trajectories to best identify the true number of emissive levels in any sequence. PMID- 19785408 TI - Managing highly coordinative substrates in asymmetric catalysis: a catalytic asymmetric amination with a lanthanum-based ternary catalyst. AB - Full details of a catalytic asymmetric amination with a lanthanum/amide-based ligand catalyst system are described. A catalyst comprising La(NO(3))(3)*6H(2)O, (R)-3a and H-d-Val-O(t)Bu was identified to promote the catalytic asymmetric amination of nonprotected succinimide derivative 1 with as little as 1 mol % catalyst loading. Mechanistic studies by various spectroscopic analyses and several control and kinetic experiments suggested that the catalyst components were in equilibrium between the associated and dissociated forms, and that the reaction likely proceeded through a La(NO(3))(3)*6H(2)O/(R)-3a/H-d-Val-O(t)Bu ternary complex. This catalyst system was also effective for asymmetric amination of N-nonsubstituted alpha-alkoxycarbonyl amides 7, hitherto unprecedented substrates in asymmetric catalysis, probably due to their attenuated reactivity and difficult stereocontrol, affording the amination products in up to >99% yield and >99% ee. The high catalytic performance and enantiocontrol of the reaction with highly coordinative substrates were achieved by the activation/recognition of the substrates exerted by coordination to lanthanum and hydrogen bonding cooperatively in the transition state. PMID- 19785409 TI - Human insulin-degrading enzyme working mechanism. AB - The possible mechanism by which the insulin-degrading enzyme (IDE) zinc-binding protease carries out its catalytic function toward two peptides of different length, simulating a portion of B chain of insulin, was investigated on an enzymatic model consisting of 130 /159 atoms, using the density functional theory method and the hybrid exchange-correlation functional B3LYP in gas phase and in the protein environment. Based on the geometry and relative stabilities of minima and transition states on the potential energy profiles, we determined that proteolysis reaction is exothermic and proceeds quickly as the barrier in the rate-limiting step falls widely within the range of values expected for an enzymatic catalysis, both in vacuum and in protein medium. PMID- 19785410 TI - Current-driven ion fluxes of polymeric membrane ion-selective electrode for potentiometric biosensing. AB - A polymeric membrane ion-selective electrode (ISE) for rapid potentiometric biosensing has been developed. Butyrylcholinesterase, as a target enzyme, is immobilized on the surface of the polymeric membrane. A macro-command-controlled procedure for switching between the potentiostatic and galvanostatic steps has been designed to provide a current-driven release of the butyrylcholine substrate for in situ biosensing of the enzyme and its inhibitors. This system has the flexibility of trapping substrate ions in the ISE inner filling solution and provides rapid, continuous, and reproducible measurements of enzymes and other bioanalytes involved in enzymatic systems. PMID- 19785411 TI - Conjugated polyelectrolyte-sensitized fluorescent detection of thrombin in blood serum using aptamer-immobilized silica nanoparticles as the platform. AB - The detection of disease-related proteins in complex biological media demands sensitive, reliable, and low-cost sensing methods. We present here an assay with aptamer-functionalized silica nanoparticles (NPs) as the sensory platform for thrombin detection in blood serum. As a result of specific protein/aptamer interaction, the presence of thrombin induces the primary aptamer-functionalized NPs to form a sandwich structure with fluorescein-labeled secondary aptamer and results in fluorescent NPs. A conjugated polyelectrolyte is further added to the NP solution to amplify the fluorescent signal. The assay shows high specificity for thrombin detection in serum. In addition, a detection limit of 1.06 nM is obtained, which is significantly improved as compared to that for many fluorescence-based thrombin detection assays. Using lysozyme as a second example, the NP-based detection strategy is shown to be generic and could be readily applicable to the detection of other proteins in practical samples. PMID- 19785412 TI - Supramolecular solar cells: surface modification of nanocrytalline TiO(2) with coordinating ligands to immobilize sensitizers and dyads via metal-ligand coordination for enhanced photocurrent generation. AB - An elegant method of self-assembly for modification of a TiO(2) surface using coordinating ligands followed by immobilization of variety of sensitizers and a dyad is reported. This highly versatile method, in addition to testing the photoelectrochemical behavior of different zinc tetrapyrroles, allowed the use of fairly complex structures involving more than one donor entity. Utilization of the zinc porphyrin-ferrocene dyad markedly improved the current-voltage performance of the photoelectrochemical cell through an electron transfer-hole migration mechanism. Incident photon-to-current efficiency values up to 37% were obtained for the electrode modified with the dyad, signifying the importance of photocells built on the basis of biomimetic principles for efficient harvesting of solar energy. PMID- 19785413 TI - DOTA-M8: An extremely rigid, high-affinity lanthanide chelating tag for PCS NMR spectroscopy. AB - A new lanthanide chelating tag (M8) for paramagnetic labeling of biomolecules is presented, which is based on an eight-fold, stereoselectively methyl-substituted DOTA that can be covalently linked to the host molecule by a single disulfide bond. The steric overcrowding of the DOTA scaffold leads to an extremely rigid, kinetically and chemically inert lanthanide chelator. Its steric bulk restricts the motion of the tag relative to the host molecule. These properties result in very large pseudocontact shifts (>5 ppm) and residual dipolar couplings (>20 Hz) for Dy-M8 linked to ubiquitin, which are unprecedented for a small, single-point attachment tag. Such large pseudocontact shifts should be well detectable even for larger proteins and distances beyond approximately 50 A. Due to its exceptionally high stability and lanthanide affinity M8 can be used under extreme chemical or physical conditions, such as those applied for protein denaturation, or when it is undesirable that buffer or protein react with excess lanthanide ions. PMID- 19785414 TI - Practical access to amines by platinum-catalyzed reduction of carboxamides with hydrosilanes: synergy of dual Si-H groups leads to high efficiency and selectivity. AB - The synergetic effect of two Si-H groups leads to efficient reduction of carboxamides to amines by platinum catalysts under mild conditions. The rate of the reaction is dependent on the distance of two Si-H groups; 1,1,3,3 tetramethyldisiloxane (TMDS) and 1,2-bis(dimethylsilyl)benzene are found to be an effective reducing reagent. The reduction of amides having other reducible functional groups such as NO(2), CO(2)R, CN, C horizontal lineC, Cl, and Br moieties proceeds with these groups remaining intact, providing a reliable method for the access to functionalized amine derivatives. The platinum-catalyzed reduction of amides with polymethylhydrosiloxane (PMHS) also proceeds under mild conditions. The reaction is accompanied by automatic removal of both platinum and silicon wastes as insoluble silicone resin, and the product is obtained by simple extraction. A mechanism involving double oxidative addition of TMDS to a platinum center is discussed. PMID- 19785415 TI - Omics analyses reveal a potential link between hormone-sensitive lipase and polyamine metabolism. AB - Hormone-sensitive lipase (HSL), a key enzyme in fatty acid mobilization from lipid stores, is expressed in the liver and decreased hepatic insulin sensitivity has been reported in our HSL null mouse model. Here, an integrated approach, comprising transcriptomics and proteomics together with targeted metabolite analysis, was used to investigate the liver phenotype of HSL null mice. Oligonucleotide microarray analysis revealed altered expression of genes involved in lipid and polyamine metabolism in HSL null mice compared with wild-type mice and in genes controlling the immune system in mice on high-fat diet versus mice on normal diet. Two-dimensional gel electrophoresis followed by MS and/or MS/MS allowed identification of 52 and 22 unique proteins differentially regulated according to the genotype and diet, respectively. Changes were observed mainly for proteins related to metabolism, including several proteins involved in polyamine metabolism or exhibiting methyl transferase activity. Despite the coordinated changes in mRNA and protein levels in polyamine pathways, no significant differences in levels of key polyamine metabolites were detected between the two genotypes. This study identifies a link between HSL and polyamine metabolism, which deserves further attention in view of the emerging data suggesting that disturbances in polyamine metabolism may affect insulin sensitivity. The present work also describes a limited correlation between mRNA, protein and metabolite levels, thus, underscoring the importance of integrated approaches. PMID- 19785416 TI - NMR metabolic fingerprinting based identification of grapevine metabolites associated with downy mildew resistance. AB - Grapevine (Vitis vinifera ssp. vinifera L.) and grapes have been extensively studied due to their numerous nutritional benefits and health affecting activities. In this study, metabolite fingerprinting of crude leaf extracts, based on (1)H nuclear magnetic resonance (NMR) spectroscopy and multivariate data analyses, has been used for the metabolic characterization of six different grapevine cultivars including downy and powdery mildew resistant 'Regent' and susceptible 'Lemberger' among others. Several two-dimensional (2D)-NMR techniques were also employed leading to the identification of a number of different types of compounds. Principal component analysis (PCA), hierarchical cluster analysis (HCA), and partial least-squares-discriminant analysis (PLS-DA) of the processed (1)H NMR data revealed clear differences among the cultivars. Metabolites responsible for the discrimination in different grapevine cultivars belong to major classes, that is, organic acids, amino acids, carbohydrates, phenylpropanoids and flavonoids. A differentiation of the cultivars based on their resistance to downy mildew infection was also achieved, and metabolites associated with this trait, namely, quercetin-3-O-glucoside and a trans-feruloyl derivative, were identified. On the basis of these results, the distribution of different plant metabolites among the different grapevine cultivars is presented. PMID- 19785417 TI - Structure of the polyphenolic component of suberin isolated from potato (Solanum tuberosum var. Nikola). AB - Suberin is present in the underground parts of vegetables and in the bark of trees. Characterization of suberin and the structure of its polyphenolic component have been hampered by insolubility of the polymers. Thus, enzymatically isolated and extractive free suberin enriched fraction from potato, Solanum tuberosum var. Nikola, and the chemically further fractionated phenolics were characterized in solid state by FTIR, DSC, and elemental analysis to identify the groups and to verify success of isolation. For MW and quantitative determination of the groups, polymers were solubilized in ionic liquid derivatized and analyzed by GPC and (31)P NMR. Suberin enriched fraction, MW = ca. 44 x 10(3) g/mol, is a mixture of carbohydrates and polyesters of aliphatic long chain hydroxy fatty acids and diacids linked via ester bonds to the phenolics, MW = ca. 27 x 10(3) g/mol, formed by guaiacyl- and p-hydroxyphenyl structures. Phenolics in peels may be important sources of antioxidants for various applications. PMID- 19785418 TI - Identification of alkyl substituted 2H-furo[2,3-c]pyran-2-ones as germination stimulants present in smoke. AB - The butenolide, 3-methyl-2H-furo[2,3-c]pyran-2-one (1), is a major compound in smoke responsible for promoting the seed germination of a wide range of plant species. We now report the structure of five alkyl substituted variants of 1 that are also present in smoke. The concentrations of these analogues, as well as that of 1, in a typical smoke-water solution have been determined using high performance liquid chromatography (HPLC) purification followed by gas chromatography-mass spectrometry (GC-MS) analysis. The analogue, 3,5-dimethyl-2H furo[2,3-c]pyran-2-one (3), was identified at levels that indicate that it is a contributor to the overall germination-promoting activity of crude smoke extracts. PMID- 19785419 TI - Organocatalytic asymmetric vinylogous alpha-ketol rearrangement: enantioselective construction of chiral all-carbon quaternary stereocenters in spirocyclic diketones via semipinacol-type 1,2-carbon migration. AB - The catalytic enantioselective synthesis of all-carbon quaternary stereogenic centers in spirocyclic diketones has been achieved for the first time by an unprecedented asymmetric vinylogous alpha-ketol rearrangement in which an enantiocontrolled semipinacol-type 1,2-carbon migration was realized using multifunctional cinchona-modified primary amine catalysis. PMID- 19785420 TI - Nanoparticle size determination by (1)H NMR spectroscopy. AB - High-resolution solution (1)H NMR spectroscopy has been used to characterize the size of Pd dendrimer-encapsulated nanoparticles (DENs). The Pd nanoparticles measured by this technique contain 55, 147, 200, or 250 atoms, and they are encapsulated within sixth-generation, hydroxyl-terminated poly(amidoamine) PAMAM dendrimers (G6-OH). Detailed analysis of the NMR data shows that signals arising from the innermost protons of G6-OH(Pd(n)) decrease significantly as the size of the encapsulated nanoparticles increase. A mathematical correlation between this decrease in the integral value and the theoretical number of Pd atoms in the nanoparticle is extracted. It enables the elucidation of the size of Pd DENs by (1)H NMR spectroscopy. NMR pulse-field gradient spin-echo experiments demonstrate that G6-OH with and without DENs have identical hydrodynamic radii, which excludes the presence of dendrimer/nanoparticle aggregates. PMID- 19785421 TI - New tool to evaluate a comprehensive antioxidant activity in food extracts: bleaching of 4-nitroso-N,N-dimethylaniline catalyzed by soybean lipoxygenase-1. AB - In this study the 4-nitroso-N,N-dimethylaniline (RNO) bleaching associated with linoleic acid hydroperoxidation catalyzed by the soybean lipoxygenase (LOX)-1 isoenzyme (LOX/RNO reaction) was used to determine the antioxidant activity (AA) of hydrophilic and lipophilic pure antioxidant compounds and of mixtures of antioxidants extracted from durum wheat whole flour (DWWF). By means of a simple and rapid experimental protocol (about 3 min/assay), the LOX/RNO reaction may simultaneously detect many antioxidant functions (scavenging of some physiological radical species, iron ion reducing and chelating activities, inhibition of the pro-oxidant apoenzyme), thus providing a comprehensive AA evaluation. Consistently, the LOX/RNO assay was very sensitive to hydrophilic, lipophilic, and phenolic antioxidant extracts from DWWF, providing AA values at least 35 and 30 times higher than those by TEAC and ORAC methods, respectively. Moreover, the new method was able to highlight synergism (among extracts) 3 times more than the ORAC method, whereas TEAC did not measure synergism under our experimental conditions. PMID- 19785422 TI - Addition of methyl triflate to a hafnocene dinitrogen complex: stepwise n(2) methylation and conversion to a hafnocene hydrazonato compound. AB - Treatment of the hafnocene complex bearing a strongly activated, side-on bound dinitrogen ligand, [(eta(5)-C(5)Me(4)H)(2)Hf](2)(mu(2),eta(2),eta(2)-N(2)), with two equivalents of methyl triflate yielded a mixture of products, one of which was identified as the triflato hafnocene methyl diazenide compound, (eta(5) C(5)Me(4)H)(2)Hf(OTf)(N(2)(CH(3))), arising from methylation of one of the nitrogen atoms. This reactivity contrasts with that of the zirconocene congener, [(eta(5)-C(5)Me(4)H)(2)Zr](2)(mu(2),eta(2),eta(2)-N(2)), where methyl triflate addition yields a variety of products that lack new nitrogen-carbon bonds. The methylated hafnocene product, (eta(5)-C(5)Me(4)H)(2)Hf(OTf)(N(2)(CH(3))) provides a platform for additional transformations for the functionalized dinitrogen core. Treatment with additional methyl triflate results in a second nitrogen-carbon bond formation to yield a rare example of a triflato hafnocene hydrazonato complex. Loss of methane and formation of the hafnocene bis(triflate) accompany the transformation. Isotopic labeling studies and other experiments are consistent with a pathway involving initial methylation of the unsubstituted nitrogen in the methyl diazenido ligand followed by deprotonation by a triflate anion. PMID- 19785423 TI - Competitive retro-cycloaddition reaction in fullerene dimers connected through pyrrolidinopyrazolino rings. AB - Competitive retro-cycloaddition in [60]- and [70]fullerene homodimers (1a,1c) as well as [60]/[70]heterodimer (1b), linked through 2-pyrazolinopyrrolidino bridges, has been studied by means of HPLC, mass spectrometry, and theoretical calculations at the density functional theory (DFT) level by using the two layered ONIOM approach. The results of these investigations indicate that the retro-cycloaddition reaction of pyrrolidinofullerenes is favored compared to the retro-cycloaddition reaction of 2-pyrazolinofullerenes in compounds 1a-c. Evidence of the occurrence of this process have been observed both by HPLC and MS MALDI, these findings being in good agreement with those predicted by theoretical calculations. PMID- 19785424 TI - Grafting oligothiophenes on surfaces by diazonium electroreduction: a step toward ultrathin junction with well-defined metal/oligomer interface. AB - The functionalization of electrode materials through diazonium electroreduction using a heteroaromatic compound, without phenyl groups, has been investigated for the first time. The electrochemical reduction of 2-aminoterthiophenyldiazonium cation, generated in situ, coats the electrode (glassy carbon (GC), gold or platinum) with an ultrathin organic layer, shown by X-ray photoelectron spectroscopy (XPS) of that deposited on gold to consist of terthiophene or oligothiophene. The coating is electroactive at potential close to that of terthiophene in solution. The electrochemical response of the modified GC electrode in the presence of various reversible redox couples shows that the attached layer acts as a conductive switch. It behaves as a barrier to electron transfer when the standard redox potential is below 0.5 V/SCE; in this case diode like behavior is observed. However, for more oxidizing redox probes the layer can be considered as transparent and no barrier effect is observed. The layer deposited on a platinum ultramicroelectrode (UME) behaves similarly to that obtained on the large GC electrode. Scanning electrochemical microscopy (SECM) can be performed using this electroswitchable modified platinum UME which can act as a filter toward competitive redox exchange pathways. PMID- 19785425 TI - Deprotection, tethering, and activation of a one-legged metalloporphyrin on a chemically active metal surface: NEXAFS, synchrotron XPS, and STM study of [SAc]P Mn(III)Cl on Ag(100). AB - The structural and reactive properties of the acetyl-protected "one-legged" manganese porphyrin [SAc]P-Mn(III)Cl on Ag(100) have been studied by NEXAFS, synchrotron XPS and STM. Spontaneous surface-mediated deprotection occurs at 300 K accompanied by spreading of the resulting thio-tethered porphyrin across the metal surface. Loss of the axial chlorine ligand occurs at 498 K, without any demetalation of the macrocycle, leaving the Mn center in a low co-ordination state. At low coverages the macrocycle is markedly tilted toward the silver surface, as is the phenyl group that forms part of the tethering "leg". In the monolayer region a striking transition occurs whereby the molecule rolls over, preserving the tilt angle of the phenyl group, strongly increasing that of the macrocycle, decreasing the apparent height of the molecule and decreasing its footprint, thus enabling closer packing. These findings are in marked contrast with those previously reported for the corresponding more rigidly bound four legged porphyrin [ Turner , M. , Vaughan , O. P. H. , Kyriakou , G. , Watson , D. J. , Scherer , L. J. , Davidson , G. J. E. , Sanders , J. K. M. and Lambert , R. M. J. Am. Chem. Soc. 2009 , 131 , 1910 ] suggesting that the physicochemical properties and potential applications of these versatile systems should be strongly dependent on the mode of tethering to the surface. PMID- 19785426 TI - Protein-sized chiral Fe(168) cages with NbO-type topology. AB - Protein-sized chiral Fe(168) cages with NbO-type topology were successfully prepared by the introduction of l- and d-tartrate ligands into the Fe(3+)/formate/Na(+) systems exhibiting alcohol-guest sorption properties. PMID- 19785427 TI - Formal alkyne aza-prins cyclization: gold(I)-catalyzed cycloisomerization of mixed N,O-acetals generated from homopropargylic amines to highly substituted piperidines. AB - A new gold(I)-catalyzed cycloisomerization to access highly substituted piperidines has been developed. By combining a conceptually new way of generating iminium ions using cationic gold(I) complexes and an efficient cyclization reaction that can minimize a potentially competing aza-Cope rearrangement, the proposed reaction successfully circumvents a long-standing problem in the classical aza-Prins reaction. Synthetic utility of the catalytic reaction was demonstrated by a synthesis of optically active 2-alkyl-piperidin-4-one. PMID- 19785428 TI - Click chemistry grafting of poly(ethylene glycol) brushes to alkyne functionalized pseudobrushes. AB - A versatile method for the grafting of azide-terminated polymer chains to alkyne functionalized pseudobrushes by the Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition has been developed. First, poly[(propargyl methacrylate)-r (glycidyl methacrylate)-r-(methyl methacrylate)] random copolymers with monomer ratios of respectively 27/27/46, 41/31/28, and 45/55/0 were synthesized by RAFT polymerization. Then, dense alkyne-functionalized pseudobrushes were grafted in melt by thermal ring-opening of the glycidyl groups by the silanols from the silicon substrate. Finally, the grafting of tailor-made alpha-methoxy-omega-azido poly(ethylene glycol)s (M(w) approximately 5000, 20,000, and 50,000 g/mol) by Cu(I)-catalyzed Huisgen 1,3-dipolar cycloaddition was performed in sealed reactors at 60 degrees C for 72 h using a polymer weight fraction of 10% in tetrahydrofuran and Cu(PPh(3))(3)Br/DIPEA as the catalytic system. Alkyne functionalized pseudobrushes and poly(ethylene glycol) brushes were characterized by ellipsometry, scanning probe microscopy, and water contact angle measurements. This "grafting-to" approach represents a fast and versatile method to provide thick and homogeneous polymer brushes with a high surface coverage. A major benefit of this strategy is the tunable and versatile tethering of alkyne functionalities to silicon substrates using a straightforward spin-coating procedure. PMID- 19785429 TI - Surface-stress-induced Mott transition and nature of associated spatial phase transition in single crystalline VO2 nanowires. AB - We demonstrate that the Mott metal-insulator transition (MIT) in single crystalline VO(2) nanowires is strongly mediated by surface stress as a consequence of the high surface area to volume ratio of individual nanowires. Further, we show that the stress-induced antiferromagnetic Mott insulating phase is critical in controlling the spatial extent and distribution of the insulating monoclinic and metallic rutile phases as well as the electrical characteristics of the Mott transition. This affords an understanding of the relationship between the structural phase transition and the Mott MIT. PMID- 19785430 TI - Cytotoxic neo-clerodane diterpenoid alkaloids from Scutellaria barbata. AB - Six new neo-clerodane diterpenoid alkaloids, named scutehenanines A-D (1, 4, 5, 6), 6-O-acetylscutehenanine A (2), and 6-O-(2-carbonyl-3 methylbutanoyl)scutehenanine A (3), were isolated from the whole plant of Scutellaria barbata. Their structures were established on the basis of detailed physical data analyses. In vitro, the six new isolated compounds showed cytotoxic activities against three human cancer lines (HONE-1 nasopharyngeal, KB oral epidermoid carcinoma, and HT29 colorectal carcinoma cells) and gave IC50 values in the range 2.8-6.4 microM. PMID- 19785431 TI - Monomeric and oligomeric amine-borane sigma-complexes of rhodium. intermediates in the catalytic dehydrogenation of amine-boranes. AB - A combined experimental/quantum chemical investigation of the transition metal mediated dehydrocoupling reaction of H(3)B.NMe(2)H to ultimately give the cyclic dimer [H(2)BNMe(2)](2) is reported. Intermediates and model complexes have been isolated, including examples of amine-borane sigma-complexes of Rh(I) and Rh(III). These come from addition of a suitable amine-borane to the crystallographically characterized precursor [Rh(eta(6)-1,2 F(2)C(6)H(4))(P(i)Bu(3))(2)][BAr(F)(4)] [Ar(F) = 3,5-(CF(3))(2)C(6)H(3)]. The complexes [Rh(eta(2)-H(3)B.NMe(3))(P(i)Bu(3))(2)][BAr(F)(4)] and [Rh(H)(2)(eta(2) H(3)B.NHMe(2))(P(i)Bu(3))(2)][BAr(F)(4)] have also been crystallographically characterized. Other intermediates that stem from either H(2) loss or gain have been characterized in solution by NMR spectroscopy and ESI-MS. These complexes are competent in the catalytic dehydrocoupling (5 mol %) of H(3)B.NMe(2)H. During catalysis the linear dimer amine-borane H(3)B.NMe(2)BH(2).NHMe(2) is observed which follows a characteristic intermediate time/concentration profile. The corresponding amine-borane sigma-complex, [Rh(P(i)Bu(3))(2)(eta(2) H(3)B.NMe(2)BH(2).NHMe(2))][BAr(F)(4)], has been isolated and crystallographically characterized. A Rh(I) complex of the final product, [Rh(P(i)Bu(3))(2){eta(2)-(H(2)BNMe(2))(2)}][BAr(F)(4)], is also reported, although this complex lies outside the proposed catalytic cycle. DFT calculations show that the first proposed dehydrogenation step, to give H(2)B horizontal lineNMe(2), proceeds via two possible routes of essentially the same energy barrier: BH or NH activation followed by NH or BH activation, respectively. Subsequent to this, two possible low energy routes that invoke either H(2)/H(2)B horizontal lineNMe(2) loss or H(2)B horizontal lineNMe(2)/H(2) loss are suggested. For the second dehydrogenation step, which ultimately affords [H(2)BNMe(2)](2), a number of experimental observations suggest that a simple intramolecular route is not operating: (i) the isolated complex [Rh(P(i)Bu(3))(2)(eta(2)-H(3)B.NMe(2)BH(2).NHMe(2))][BAr(F)(4)] is stable in the absence of amine-boranes; (ii) addition of H(3)B.NMe(2)BH(2).NHMe(2) to [Rh(P(i)Bu(3))(2)(eta(2)-H(3)B.NMe(2)BH(2).NHMe(2))][BAr(F)(4)] initiates dehydrocoupling; and (iii) H(2)B horizontal lineNMe(2) is also observed during this process. PMID- 19785432 TI - Surface polarity shielding and hierarchical ZnO Nano-architectures produced using sequential hydrothermal crystal synthesis and thin film atomic layer deposition. AB - Three-dimensional nanoscale constructs are finding applications in many emerging fields, including energy generation and storage, advanced water and air purification, and filtration strategies, as well as photocatalytic and biochemical separation systems. Progress in these important technologies will benefit from improved understanding of fundamental principles underlying nanostructure integration and bottom-up growth processes. While previous work has identified hydrothermal synthesis conditions to produce nanoscale ZnO rods, sheets, and plates, strategies to systematically integrate these elements into more complex nano-architectures are not previously described. This article illustrates that amorphous nanoscale coatings formed by atomic layer deposition (ALD) are a viable means to modulate and screen the surface polarity of ZnO crystal faces and thereby regulate the growth morphology during successive hydrothermal nanocrystal synthesis. Using this new strategy, this work demonstrates direct integration and sequential assembly of nanocrystalline rods and sheets to produce complex three-dimensional geometric forms, where structure evolution is achieved by modifying the surface growth condition, keeping the hydrothermal growth chemistry unchanged. Therefore, rational planning of seed layer and feature spacing geometries may allow researchers to engineer, at the nanoscale, complex three-dimensional crystalline and semicrystalline constructs for a wide range of future applications. PMID- 19785433 TI - Catalytic direct arylations in polyethylene glycol (PEG): recyclable palladium(0) catalyst for C-H bond cleavages in the presence of air. AB - Two protocols for ruthenium- or palladium-catalyzed direct arylations in user friendly polyethylene glycol (PEG) were devised, which set the stage for the development of user-friendly palladium(0)-catalyzed C-H bond functionalizations in the presence of air with a recyclable phosphine ligand-free palladium complex. PMID- 19785434 TI - Initial excited-state structural dynamics of uracil from resonance Raman spectroscopy are different from those of thymine (5-methyluracil). AB - To explore the origin of the differences in UV photochemistry of uracil (RNA) and thymine (DNA) nucleobases, we have measured the UV resonance Raman spectra of uracil in aqueous solution at wavelengths throughout the lowest-energy absorption band and analyzed the resulting resonance Raman excitation profiles and absorption spectra using a time-dependent wave-packet formalism to obtain the initial excited-state structural changes. In contrast to thymine, which differs from uracil only by the presence of a methyl group at C(5), most of the resonance Raman intensity and resulting initial excited-state structural dynamics for uracil occur along in-plane hydrogen-bond angle deformation, ring stretching, and carbonyl vibrational modes. Weaker intensities and less significant structural dynamics are observed along the C=C stretching mode. These results suggest that the initial excited-state structural dynamics of uracil occur along a carbon pyramidalization coordinate. These dynamics are different from those of thymine, which distorts primarily along a C(5)=C(6) bond lengthening coordinate. These differences in initial excited-state structural dynamics can explain the different primary photoproducts observed for these two pyrimidine nucleobases. PMID- 19785435 TI - Novel L-xylose derivatives as selective sodium-dependent glucose cotransporter 2 (SGLT2) inhibitors for the treatment of type 2 diabetes. AB - The prevalence of diabetes throughout the world continues to increase and has become a major health issue. Recently there have been several reports of inhibitors directed toward the sodium-dependent glucose cotransporter 2 (SGLT2) as a method of maintaining glucose homeostasis in diabetic patients. Herein we report the discovery of the novel O-xyloside 7c that inhibits SGLT2 in vitro and urinary glucose reabsorption in vivo. PMID- 19785437 TI - Twenty-six years of anti-HIV drug discovery: where do we stand and where do we go? PMID- 19785438 TI - Structural basis for catalytic activation of thiocyanate hydrolase involving metal-ligated cysteine modification. AB - Thiocyanate hydrolase (SCNase) is a member of a family of nitrile hydratase proteins, each of which contains a unique noncorrin cobalt center with two post translationally modified cysteine ligands, cysteine-sulfenic acid or -sulfenate (Cys-SO(H)), and cysteine-sulfininate (Cys-SO(2)(-)), respectively. We have found that a partially matured recombinant SCNase was activated during storage. The crystal structures of SCNase before and after storage demonstrated that Cys SO(2)(-) modification of gammaCys131 proceeded to completion prior to storage, while Cys-SO(H) modification of gammaCys133 occurred during storage. SCNase activity was suppressed when gammaCys133 was further oxidized to Cys-SO(2)(-). The correlation between the catalytic activity and the extent of the gammaCys133 modification indicates that the cysteine sulfenic acid modification of gammaCys133 is of primary importance in determining the activity of SCNase. PMID- 19785436 TI - Nanomolar potency pyrimido-pyrrolo-quinoxalinedione CFTR inhibitor reduces cyst size in a polycystic kidney disease model. AB - Inhibitors of the cystic fibrosis transmembrane conductance regulator (CFTR) chloride channel are predicted to slow cyst enlargement in polycystic kidney disease and reduce intestinal fluid loss in secretory diarrheas. Screening of approximately 110000 small synthetic and natural compounds for inhibition of halide influx in CFTR-expressing epithelial cells yielded a new class of pyrimido pyrrolo-quinoxalinedione (PPQ) CFTR inhibitors. Testing of 347 analogues established structure-activity relationships. The most potent compound, 7,9 dimethyl-11-phenyl-6-(5-methylfuran-2-yl)-5,6-dihydro-pyrimido[4',5' 3,4]pyrrolo[1,2-a]quinoxaline-8,10-(7H,9H)-dione, PPQ-102, completely inhibited CFTR chloride current with IC(50) approximately 90 nM. The PPQs, unlike prior CFTR inhibitors, are uncharged at physiological pH, and therefore not subject to membrane potential-dependent cellular partitioning or block efficiency. Patch clamp analysis confirmed voltage-independent CFTR inhibition by PPQ-102 and showed stabilization of the channel closed state. PPQ-102 prevented cyst expansion and reduced the size of preformed cysts in a neonatal kidney organ culture model of polycystic kidney disease. PPQ-102 is the most potent CFTR inhibitor identified to date. PMID- 19785439 TI - (+)-Dihydrorobinetin: a marker of vinegar aging in acacia (Robinia pseudoacacia) wood. AB - The use of acacia wood for the aging of vinegars is increasing because the efficient air transfer through the pores permits a good acetification rate. In this study, vinegars aged in acacia (Robinia pseudoacacia) wood barrels were analyzed and found to contain a characteristic compound, which increased during the aging process. This so far unknown compound was isolated by semipreparative LC and structurally identified by NMR spectroscopy. (1)H and (13)C NMR chemical shifts and optical rotation revealed its structure to be (+)-dihydrorobinetin, a dihydroflavonol identified for the first time in vinegars as a marker of aging in this kind of wood. This study also reports for the first time the complete assignment of (13)C NMR data for this compound. Moreover, it revealed a longer contact time with acacia wood results in higher concentrations of (+) dihydrorobinetin found in vinegars. Another finding was that the vinegars aged with nontoasted acacia chips showed significantly higher concentrations of (+) dihydrorobinetin than found in vinegars aged with toasted acacia chips (384.8 and 23.5 mg/L, respectively). The in vitro antioxidant activity (DPPH(*) and ORAC assays) of (+)-dihydrorobinetin was also determined. (+)-Dihydrorobinetin is reported here for the first time as a chemical marker of vinegars aged in acacia wood and can be used for authenticity purposes. PMID- 19785440 TI - Highly enantioselective organocatalytic Biginelli and Biginelli-like condensations: reversal of the stereochemistry by tuning the 3,3'-disubstituents of phosphoric acids. AB - Organocatalytic enantioselective Biginelli and Biginelli-like reactions by chiral phosphoric acids derived from 3,3'-disubstituted binaphthols have been investigated. The size of 3,3'-substituents of the catalysts is able to control the stereochemistry of the Biginelli reaction. By tuning the 3,3'-disubstituents of the phosphoric acids, the stereochemistry of the Biginelli reaction can be reversed. This organocatalytic Biginelli reaction by Bronsted acids 12b and 13 is applicable to a wide range of aldehydes and various beta-keto esters, providing a highly enantioselective method to access DHPMs. 3,3'-Di(triphenylsilyl) binaphthol-derived phosphoric acid afforded Biginelli-like reactions of a broad scope of aldehydes and enolizable ketones with benzylthiourea, giving structurally diverse dihydropyrimidinethiones with excellent optical purity. Theoretical calculations with the ONIOM method on the transition states of the stereogenic center forming step showed that the imine and enol were simultaneously activated by the bifunctional chiral phosphoric acid through formation of hydrogen bonds. The effect of the 3,3'-substituents in phosphoric acids on the stereochemistry of the Biginelli reaction was also theoretically rationalized. The current protocol has been applied to the synthesis of some pharmaceutically interesting compounds and intermediates, such as chiral thioureas, dihydropyrimidines, guanidines, and the precursor of (S)-l-771688. PMID- 19785441 TI - Deracemization of mexiletine biocatalyzed by omega-transaminases. AB - (S)- as well as (R)-mexiletine [1-(2,6-dimethylphenoxy)-2-propanamine], a chiral orally effective antiarrhythmic agent, was prepared by deracemization starting from the commercially available racemic amine using omega-transaminases in up to >99% ee and conversion with 97% isolated yield by a one-pot two-step procedure. The absolute configuration could be easily switched to the other enantiomer, just by switching the order of the applied transaminases. The cosubstrate pyruvate needed in the first oxidative step was recycled by using an amino acid oxidase. PMID- 19785442 TI - Infrared spectroscopy of phenol-(H2O)(n>10): structural strains in hydrogen bond networks of neutral water clusters. AB - To investigate hydrogen bond network structures of tens of water molecules, we report infrared spectra of moderately size (n)-selected phenol-(H2O)n (approximately 10 < or = n < or = approximately 50), which have essentially the same network structures as (H2O)(n+1). The phenyl group in phenol-(H2O)(n) allows us to apply photoionization-based size selection and infrared-ultraviolet double resonance spectroscopy. The spectra show a clear low-frequency shift of the free OH stretching band with increasing n. Detailed analyses with density functional theory calculations indicate that this shift is accounted for by the hydrogen bond network development from highly strained ones in the small (n < approximately 10) clusters to more relaxed ones in the larger clusters, in addition to the cooperativity of hydrogen bonds. PMID- 19785443 TI - Enantioselective synthesis of 5-epi-citreoviral using ruthenium-catalyzed asymmetric ring-closing metathesis. AB - Chiral ruthenium olefin metathesis catalysts can perform asymmetric ring-closing reactions in > or = 90% ee with low catalyst loadings. To illustrate the practicality of these reactions and the products they form, an enantioselective total synthesis of 5-epi-citreoviral was completed by using an asymmetric ring closing olefin metathesis reaction as a key step early in the synthesis. All of the stereocenters in the final compound were set by using the chiral center generated by asymmetric olefin metathesis. PMID- 19785444 TI - Revision of analytical conditions for determining ligand molecules specific to soft metal ions using dequenching of copper(I)-bathocuproine disulfonate as a detection system. AB - Reoptimization of analytical conditions was performed for a high-performance liquid chromatographic (HPLC) detection system for Cu(I) chelators based on the dequenching of Cu(I)-bathocuproine disulfonate complexes that occurs in the presence of Cu(I) chelators. The revision corrects for emission and excitation wavelengths that were in fact second-order light of the actual optimal wavelengths and for the composition of the postcolumn solution. These revisions resulted in an order of magnitude decrease in detection limits of phytochelatins, a class of cysteine-rich, heavy metal-binding peptides. The revised technique is capable of phytochelatin quantitation at femtomole quantities. PMID- 19785445 TI - Theoretical study on the reaction of Ti+ with acetone and the role of intersystem crossing. AB - Ti(+) is known to react with acetone (CH(3)COCH(3)) to produce TiO(+) and CH(2)CHCH(3) as products, but the detailed reaction mechanism and the most favorable reaction pathway have not yet been elucidated. Here, we investigate the doublet and quartet potential-energy surfaces associated with the gas-phase reaction between Ti(+) and acetone for three plausible pathways, (i) direct metal ion insertion into the C=O bond, (ii) direct H shift, and (iii) metal-mediated H migration, by using the density functional theory (DFT) and ab initio methods. The molecular structures of intermediates and transition states involved in these reaction pathways are optimized at the DFT level by using the PBE0 functional. All transition states are identified by using the intrinsic reaction coordinate (IRC) method, and the resulting reaction coordinates describe how Ti(+) activates the C=O bond of CH(3)COCH(3) (acetone) and yields TiO(+) and CH(2)CHCH(3) (propene) as products. The intersystem crossing (ISC) point is optimized by a multireference ab initio method, and spin-orbit effects are considered around the ISC point. On the basis of the presented results, we propose that the most favorable reaction pathway proceeds via the direct metal-ion insertion into the C=O bond and passes through an ISC point. PMID- 19785446 TI - Simulation of ion motion in FAIMS through combined use of SIMION and modified SDS. AB - A key application of field asymmetric waveform ion mobility spectrometry (FAIMS) has been in selectively transmitting trace analyte ions that are present in a complex ion mixture to a mass spectrometer (MS) for identification and quantification. The overall sensitivity of FAIMS-MS, however, still needs to be significantly improved through the optimization of ion transmission into FAIMS and at the FAIMS-MS interface. Processes that cause ion losses include diffusion, space charge, separation field in the FAIMS and fringe fields around the edges of the FAIMS electrodes. These were studied here by first developing an algorithm using SIMION as its core structure to compute ion trajectory at different ratios of electric field to buffer gas number density (E/N). The E/N was varied from a few Td to approximately 80 Td by using an asymmetric square waveform. The algorithm was then combined with statistical diffusion simulation (SDS) model, columbic repulsion, and a parabolic gas flow profile to realistically simulate current transmission and peak shape. The algorithm was validated using a FAIMS model identical to the Sionex Corporation SVAC model. Ions modeled included low mass ions with K(o) in the range of 2.17 (m = 55) to 1.39 cm(2) x V(-1) x s(-1) (m = 368). Good agreement was achieved between simulated and experimental CV (peak maxima) values, peak width (fwhm), and transmitted ion current I(output). The model was then used to study fringe fields in a simple arrangement where a 0.5 mm (w) gap was created between the FAIMS exit and a capillary inlet (i.d. = 0.5 mm). At an optimum CV (11.8 V), only approximately 17% (1.3 pA) of the total ion current that correlate to CV = 11.8 V, entered the capillary; bulk of the ion loss was caused by the fringe fields. Current transmission into the capillary was improved, however, by applying a 500 V DC bias across w (0.5 mm). PMID- 19785447 TI - Top-down protein fragmentation by infrared multiphoton dissociation in a dual pressure linear ion trap. AB - Infrared multiphoton dissociation (IRMPD) was implemented in a novel dual pressure linear ion trap for rapid top-down proteomics. The high pressure cell provided improved trapping and isolation efficiencies while the isotopic profiles of 10+ charged ions could be resolved by mass analysis in the low pressure cell that enabled effective top down protein identification. Striking differences between IRMPD in the low pressure cell and CID in the high pressure cell were observed for proteins ranging from 8.6 to 29 kDa. Because of secondary dissociation, IRMPD yielded product ions in significantly lower charge states as compared to CID, thus facilitating more accurate mass identification and streamlining product ion assignment. This outcome was especially useful for database searching of larger proteins (approximately 29 kDa) as IRMPD substantially improved protein identification and scoring confidence. Also, IRMPD showed an increased selectivity toward backbone cleavages N-terminal to proline and C-terminal to acidic residues (especially for the lowest charge states), which could be useful for a priori spectral predictions and enhanced database searching for protein identification. PMID- 19785448 TI - Hemimicelles of alkyl carboxylates chemisorbed onto magnetic nanoparticles: study and application to the extraction of carcinogenic polycyclic aromatic hydrocarbons in environmental water samples. AB - In this work, magnetic nanoparticles (MNPs) coated with hemimicelles of alkyl (C(10)-C(18)) carboxylates, which have traditionally been used to prepare ferrofluids for technological applications, were used for the first time to extract organic contaminants from environmental water samples. The nanoparticles were coated by following a simple, rapid procedure (30 min at 85 degrees C) that uses commercially available magnetite of 20-30 nm mean particle diameter. The strong chemical bonding between the surfactant and magnetite relative to the electrostatic forces involved in conventional hemimicelle-based sorbents precludes leaching of the surfactant and facilitates its reuse and the obtainment of surfactant-free extracts. Tetradecanoate hemimicelles were used here to extract carcinogenic polycyclic aromatic hydrocarbons (CPAHs) prior to analysis by liquid chromatography (using a C(18) Supelcosil LC-PAH column and a gradient elution program with water and acetonitrile) and fluorescence detection. The procedure involved stirring filtered aqueous samples (350 mL) with 200 mg of tetradecanoate-coated MNPs for 15 min, isolating the sorbent with a Nd-Fe-B magnet and eluting the CPAHs with a mixture of acetonitrile and tetrahydrofuran. The extraction efficiency was not influenced by salt concentrations up to 1 M and pH values over the range 2.5-9. The preconcentration factor was 116. No cleanup of the extracts was needed, and the method proved matrix-independent. The limits of quantitation thus obtained, 0.2-0.5 ng L(-1), meet the stringent water quality requirements established by the recently amended European Water Framework Directive 2000/60/EC and also the U.S. EPA for the determination of CPAHs in surface and ground waters. The proposed method was successfully applied to the determination of these pollutants in surface and ground environmental water samples collected from various places in southern Spain. Recoveries from samples spiked with CPAHs at concentrations of 1-10 ng L(-1) ranged from 85 to 94% and relative standard deviations from 1 to 7%. CPAHs were only present in the sample from the Navallana reservoir, at concentrations over the range 0.42-0.96 ng L( 1). PMID- 19785449 TI - Identification and characterization of polyphenolic antioxidants using on-line liquid chromatography, electrochemistry, and electrospray ionization tandem mass spectrometry. AB - It is demonstrated that electrochemistry (EC) coupled to liquid chromatography (LC) and electrospray ionization tandem mass spectrometry (LC/EC/ESI-MS/MS) can be used to rapidly obtain information about the antioxidant activity (i.e., oxidation potential) and capacity (i.e., amount) of polyphenolic compounds, including catechin, kaempferol, resveratrol, quercetin, and quercetin glucosides. The described on-line LC/EC/ESI-MS/MS method facilitates the detection and characterization of individual antioxidants based on a combination of the obtained m/z values for the antioxidants and their oxidation products, the potential dependences for the ion intensities, and correlations between the retention times in the LC, EC, and MS chromatograms. As these results provide patterns that can be used in rapid screening for antioxidants in complex samples, the method should be a valuable complement to chemical assays commonly used to determine the total antioxidant capacity of samples. It is shown that the antioxidant capacity for a mixture of polyphenolic compounds depends on the redox potential employed in the evaluation, and this should consequently be taken into account when comparing results from different total antioxidant capacity assays. It is also demonstrated that the inherent antioxidant capacities of phenolic compounds increase with an increasing number of hydroxyl groups and that the potential needed to oxidize the remaining hydroxyl groups increases successively upon oxidation of the compound. Unlike chemical assays, which generally do not provide any information about the identities of the compounds on the molecular level, the present screening method can be used to identify individual antioxidants, rank compounds with respect to their ease of oxidation, and to study the antioxidant capacity at any redox potential of interest. PMID- 19785450 TI - Nanoscale architecture dictates detection profile of surface-confined DNA by MALDI-TOF MS. AB - The design and fabrication of various nanoscale architectures for the effective MALDI-TOF MS analysis of surface-confined DNA are reported. The nanoscale architectures are derived from layer-by-layer assemblies of negatively charged nanoparticles and positively charged polymers. An important finding is that porous structures comprising bottom SiO(2) nanoparticle layers and top Au nanoparticle layers enable the observation of both covalently bound (with Au-S bond) and hybridized oligonucleotides. The achievement of this unprecedented detection capability is attributed to the unique combination of a nanoporous dielectric film and discrete noble metal nanoparticles. The conclusion is supported by control experiments performed on a variety of single and multilayered Au nanoparticle structures, where only the hybridized oligonucleotides in a two- or three-strand system could be detected. PMID- 19785451 TI - TS-1 from first principles. AB - First principles studies on periodic TS-1 models at Ti content corresponding to 1.35% and 2.7% in weight of TiO(2) are presented. The problem of Ti preferential siting is addressed by using realistic models corresponding to the TS-1 unit cell [TiSi(95)O(192)] and adopting for the first time a periodic DFT approach, thus providing an energy scale for Ti in the different crystallographic sites in nondefective TS-1. The structure with Ti in site T3 is the most stable, followed by T4 (+0.3 kcal/mol); the less stable structure, corresponding to Ti in T1, is 5.6 kcal/mol higher in energy. The work has been extended to investigate models with two Ti's per unit cell [Ti(2)Si(94)O(192)] (2.7%). The possible existence of Ti-O-Ti bridges, formed by two corner-sharing TiO(4) tetrahedra, is discussed. By using cluster models cut from the optimized periodic DFT structures, both vibrational (DFT) and electronic excitation spectra (TDDFT) have been calculated and favorably compared with the experimental data available on TS-1. Interesting features emerged from excitation spectra: (i) Isolated tetrahedral Ti sites show a Beer-Lambert behavior, with absorption intensity proportional to concentration. Such a behavior is gradually lost when two Ti's occupy sites close to each other. (ii) The UV-vis absorption in the 200-250 nm region can be associated with transitions from occupied states delocalized on the framework oxygens to empty d states localized on Ti. Such extended-states-to-local-states transitions may help the interpretation of the photovoltaic activity recently detected in Ti zeolites. PMID- 19785452 TI - Structural and electronic properties of reduced transition metal oxide clusters, M3O8 and M3O8- (M = Cr, W), from photoelectron spectroscopy and quantum chemical calculations. AB - We report a comparative study of reduced transition metal oxide clusters, M(3)O(8)(-) (M = Cr, W) anions and their neutrals, via anion photoelectron spectroscopy (PES) and density functional theory (DFT) and molecular orbital theory (CCSD(T)) calculations. Well-resolved PES spectra are obtained for M(3)O(8)(-) (M = Cr, W) at 193 and 157 nm photon energies. Different PES spectra are observed for M = Cr versus M = W. Extensive DFT and CCSD(T) calculations are performed to locate the ground and low-lying excited states for the neutrals and anions. The ground states of Cr(3)O(8) and Cr(3)O(8)(-) are predicted to be the (3)B(2) and (4)B(2) states of a C(2v) structure, respectively, revealing ferromagnetic spin coupling for Cr 3d electrons. In contrast, the ground states of W(3)O(8) and W(3)O(8)(-) are predicted to be the (1)A' state (C(s) symmetry) and the (2)A(1) state (C(2v) symmetry), respectively, showing metal-metal d-d bonding in the anion. The current cluster geometries are in qualitative agreement with prior DFT studies at the PBE level for M = Cr and the B3LYP level for M = W. The BP86 and PW91 functionals significantly outperform the B3LYP functional for the Cr species, in terms of relative energies, electron detachment energies, and electronic excitation energies, whereas the B3LYP functional is better for the W species. Accurate heats of formation for the ground states of M(3)O(8) are calculated from the clustering energies and the heats of formation of MO(2) and MO(3). The energetics have been used to predict redox reaction thermochemistry. PMID- 19785453 TI - Improving quantitative structure-activity relationships through multiobjective optimization. AB - A multiobjective optimization algorithm was proposed for the automated integration of structure- and ligand-based molecular design. Driven by a genetic algorithm, the herein proposed approach enabled the detection of a number of trade-off QSAR models accounting simultaneously for two independent objectives. The first was biased toward best regressions among docking scores and biological affinities; the second minimized the atom displacements from a properly established crystal-based binding topology. Based on the concept of dominance, 3D QSAR equivalent models profiled the Pareto frontier and were, thus, designated as nondominated solutions of the search space. K-means clustering was, then, operated to select a representative subset of the available trade-off models. These were effectively subjected to GRID/GOLPE analyses for quantitatively featuring molecular determinants of ligand binding affinity. More specifically, it was demonstrated that a) diverse binding conformations occurred on the basis of the ligand ability to profitably contact different part of protein binding site; b) enzyme selectivity was better approached and interpreted by combining diverse equivalent models; and c) trade-off models were successful and even better than docking virtual screening, in retrieving at high sensitivity active hits from a large pool of chemically similar decoys. The approach was tested on a large series, very well-known to QSAR practitioners, of 3-amidinophenylalanine inhibitors of thrombin and trypsin, two serine proteases having rather different biological actions despite a high sequence similarity. PMID- 19785454 TI - Hyperbranched and highly branched polymer architectures--synthetic strategies and major characterization aspects. PMID- 19785455 TI - Synthesis of conjugated polymers for organic solar cell applications. PMID- 19785458 TI - Energetics and structure of hydroxynicotinic acids. Crystal structures of 2-, 4-, 6-hydroxynicotinic and 5-chloro-6-hydroxynicotinic acids. AB - The relationship between energetics and structure in 2-, 4-, 5-, and 6 hydroxynicotinic and 5-chloro-6-hydroxynicotinic acids (2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA, respectively) was investigated in the solid and gaseous phases by means of a variety of experimental and computational chemistry techniques. The molecular and crystal structures of the 2HNA, 4HNA, 6HNA, and 5Cl6HNA solid forms used in this study were determined by single crystal X-ray diffraction at 293 +/- 2 K. The 2HNA, 4HNA, and 5Cl6HNA samples were monoclinic (space groups: P2(1)/n for 2HNA and P2(1)/c for 4HNA and 5Cl6HNA), and that of 6HNA was found to be triclinic (space group: P1). The 2HNA sample investigated corresponds to a new polymorphic form of this compound. The 2HNA, 4HNA, 6HNA, and 5Cl6HNA molecules crystallize as oxo tautomers exhibiting N-H and Cring=O bonds. This is also supported by the observation of bands typical of N-H and Cring=O stretching frequencies in the corresponding FT-IR spectra. The absence of these bands in the spectrum of 5HNA indicates that a hydroxy tautomer with an unprotonated N heteroatom and a Cring-OH bond is likely to be present in this case. Results of theoretical calculations carried out at the G3MP2 and CBS-QB3 levels of theory suggest that in the ideal gas phase, at 298.15 K, 2HNA favors the oxo form, 4HNA prefers the hydroxy form, and no strong dominance of one of the two tautomers exists in the case of 6HNA and 5Cl6HNA. The standard molar enthalpies of formation of 2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA in the crystalline state, at 298.15 K, Delta(f)H(m)(o)(cr), were determined by micro combustion calorimetry. The corresponding enthalpies of sublimation, Delta(sub)H(m)(o), were also derived from vapor pressure versus temperature measurements by the Knudsen effusion method. The obtained Delta(f)H(m)(o)(cr) and Delta(sub)H(m)(o) values led to the enthalpies of formation of 2HNA, 4HNA, 5HNA, 6HNA, and 5Cl6HNA in the gaseous phase. These were discussed together with the corresponding predictions by the B3LYP/cc-pVTZ, B3LYP/aug-cc-pVTZ, G3MP2, and CBS-QB3 methods on the basis of isodesmic or atomization reactions. The experimental "stability" order (more stable meaning a more negative Delta(f)H(m)(o)(g) value) found was 5Cl6HNA > 2HNA > 6HNA > 4HNA > 5HNA, and it was accurately captured by the CBS-QB3 and G3MP2 methods, which give 5Cl6HNA > 2HNA approximately 6HNA > 4HNA > 5HNA, irrespective of the use of isodesmic or atomization reactions. In contrast, only when well balanced isodesmic reactions were considered did the DFT results agree with the experimental ones. The picture that emerged from the structural and energetic studies carried out in this work was also discussed in light of that typical of hydroxypyridines, which are generally regarded as the archetype systems for the study of the hydroxy <--> oxo tautomerization in N-heterocyclic compounds. PMID- 19785457 TI - Catalytic carbene insertion into C-H bonds. PMID- 19785459 TI - Reduction of the damping on an AFM cantilever in fluid by the use of micropillars. AB - In single molecule force measurements with soft atomic force microscope (AFM) cantilevers, the force sensitivity is limited by the Brownian motion of the cantilever. When a cantilever is close to the surface, the hydrodynamic interaction between the cantilever beam and the surface, called the "squeezing effect", becomes significant, and the resonance peak of the thermal oscillation of the cantilever is heavily broadened and shifted to lower frequency which makes it difficult to eliminate the thermal noise by low-pass filtering. In this study, we propose an easy and low-cost method to improve the force sensitivity. We demonstrate that by bringing a tip of a cantilever onto the edge of a micropillar structure a significant reduction of the damping and an enhancement of force sensitivity are achieved. PMID- 19785460 TI - Temperature oscillations, complex oscillations, and elimination of extraordinary temperature sensitivity in the iodate-sulfite-thiosulfate flow system. AB - Temperature oscillations and complex pH oscillations in the IO(3)(-)-SO(3)(2-) S(2)O(3)(2-) system were observed in a continuously flow stirred tank reactor. During one period of oscillation, the temperature increases rapidly while the pH shows an extremely sharp change. High-amplitude pH oscillations undergo 1(1) complex oscillations (L(S), oscillations with L large peaks and S small peaks per period) to another kind of higher-amplitude regular oscillations upon increasing the concentration of sulfite step by step. Importantly, the longstanding experimental phenomena, the extraordinary temperature sensitivity of oscillatory behavior reported 20 years ago by Rabai and Beck, can be eliminated by premixing of sulfite and sulfuric acid before entering into the reactor, avoiding local acidification, which brings out fluctuation and temperature sensitivity. The temperature oscillations can be understood by taking into account the interaction between thermal effect of various reactions and heat transfer. Experimental observations, both temperature oscillations and 1(1)-type pH oscillations, are reproduced with a four-step Horvath model by addition of an energy-balance equation. This new detailed dynamical behavior would have potential applications in designing complex chemical waves and pH responsive gels with rhythmical motion. PMID- 19785456 TI - Normal mode analysis of biomolecular structures: functional mechanisms of membrane proteins. PMID- 19785461 TI - Exploring molecular mechanisms of ligand recognition by opioid receptors with metadynamics. AB - Opioid receptors are G protein-coupled receptors (GPCRs) of utmost significance in the development of potent analgesic drugs for the treatment of severe pain. An accurate evaluation at the molecular level of the ligand binding pathways into these receptors may play a key role in the design of new molecules with more desirable properties and reduced side effects. The recent characterization of high-resolution X-ray crystal structures of non-rhodopsin GPCRs for diffusible hormones and neurotransmitters presents an unprecedented opportunity to build improved homology models of opioid receptors, and to study in more detail their molecular mechanisms of ligand recognition. In this study, possible pathways for entry of the nonselective antagonist naloxone (NLX) from the water environment into the well-accepted alkaloid binding pocket of a delta opioid receptor (DOR) molecular model based on the beta2-adrenergic receptor crystal structure are explored using microsecond-scale well-tempered metadynamics simulations. Using as collective variables distances that account for the position of NLX and of the receptor extracellular loop 2 in relation to the DOR binding pocket, we were able to distinguish between the different states visited by the ligand (i.e., docked, undocked, and metastable bound intermediates) and to predict a free energy of binding close to experimental values after correcting for possible drawbacks of the sampling approach. The strategy employed herein holds promise for its application to the docking of diverse ligands to the opioid receptors as well as to other GPCRs. PMID- 19785462 TI - A flavin cofactor-binding PAS domain regulates c-di-GMP synthesis in AxDGC2 from Acetobacter xylinum. AB - The cytoplasmic protein AxDGC2 regulates cellulose synthesis in the obligate aerobe Acetobacter xylinum by controlling the cellular concentration of the cyclic dinucleotide messenger c-di-GMP. AxDGC2 contains a Per-Arnt-Sim (PAS) domain and two putative catalytic domains (GGDEF and EAL) for c-di-GMP metabolism. We found that the PAS domain of AxDGC2 binds a flavin adenine dinucleotide (FAD) cofactor noncovalently. The redox status of the FAD cofactor modulates the catalytic activity of the GGDEF domain for c-di-GMP synthesis, with the oxidized form exhibiting higher catalytic activity and stronger substrate inhibition. The results suggest that AxDGC2 is a signaling protein that regulates the cellular c-di-GMP level in response to the change in cellular redox status or oxygen concentration. Moreover, several residues predicated to be involved in FAD binding and signal transduction were mutated to examine the impact on redox potential and catalytic activity. Despite the minor perturbation of redox potential and unexpected modification of FAD in one of the mutants, none of the single mutations was able to completely disrupt the transmission of the signal to the GGDEF domain, indicating that the change in the FAD redox state can still trigger structural changes in the PAS domain probably by using substituted hydrogen-bonded water networks. Meanwhile, although the EAL domain of AxDGC2 was found to be catalytically inactive toward c-di-GMP, it was capable of hydrolyzing some phosphodiester bond-containing nonphysiological substrates. Together with the previously reported oxygen-dependent activity of the homologous AxPDEA1, the results provided new insight into relationships among oxygen level, c-di-GMP concentration, and cellulose synthesis in A. xylinum. PMID- 19785465 TI - Origin of the unusual stability of B12 and B13(+) clusters. AB - A novel way to analyze the boron clusters is proposed in which the cluster is partitioned as inner and outer rings. Fragment molecular orbital analysis, based on this fragmentation, reveals that the delocalized valence electrons in B(12) and B(13)(+) clusters can be trifurcated as 6pi-6sigma(delo)-6sigma(3-ring), leading to triple aromaticity, which is unique to these clusters. PMID- 19785463 TI - Hydrogen peroxide is a second messenger in phase 2 enzyme induction by cancer chemopreventive dithiolethiones. AB - The ability of three dithiolethione cancer chemopreventives, oltipraz 1, anetholedithione (ADT) 2, 1,2-dithiole-3-thione (D3T) 3, and the major metabolite, 4, of 1, to induce the cytoprotective enzyme NQO1 in Hepa 1c1c7 cells and the inhibition of this induction by catalase are demonstrated. The ability of 1, 3, and 4 to form O(2)(*) has been reported, and it is here demonstrated that 2 decomposes in the presence of GSH to form, upon addition of the nitrone spin trap DMPO, the DMPO-OH adduct that is detectable by EPR. Decomposition of 2 in the presence of GSH elicits, upon the addition of hydroethidine and excitation at 510 nm, fluorescence at 580 nm that is diminished by the addition of superoxide dismutase. The compound 4, is a product of the reduction of 1, and it is demonstrated that 2 and 3 decompose in the presence of reductants such as thiolates and NaBH(4), followed by addition of CH(3)I, to form the dimethylated products of reductive cleavage of the S(1)-S(2) bond. The same products are isolated subsequent to lysis in buffer containing CH(3)I of Hepa 1c1c7 cells treated with 2 or 3. Reductive cleavage of 2 and 3 in aqueous ethanol by NaBH(4) in an argon atmosphere, followed by acidic destruction of remaining borohydride and neutralization and introduction of O(2) results in the reformation of 2 and 3 to the extent of 80 and 33%, respectively. The data in toto are consistent with a model in which dithiolethiones, generally, undergo reductive cleavage in Hepa 1c1c7 cells, thereby resulting in the generation of O(2)(*) that dismutates to H(2)O(2), that subsequently, by direct or indirect means, effects the nuclear translocation of transcription factor Nrf2, that upregulates phase 2 enzyme expression. PMID- 19785464 TI - A library of fluorescent peptides for exploring the substrate specificities of prolyl isomerases. AB - To fully explore the substrate specificities of prolyl isomerases, we synthesized a library of 20 tetrapeptides that are labeled with a 2-aminobenzoyl (Abz) group at the amino terminus and a p-nitroanilide (pNA) group at the carboxy terminus. In this peptide library of the general formula Abz-Ala-Xaa-Pro-Phe-pNA, the position Xaa before the proline is occupied by all 20 proteinogenic amino acids. A conformational analysis of the peptide by molecular dynamics simulations and by NMR spectroscopy showed that the mutual distance between the Abz and pNA moieties in the peptides depends on the isomeric state of the Xaa-Pro bond. In the cis, but not in the trans form, there are significant chemical shift changes of the Abz and pNA moieties, because their aromatic rings are close to each other. This proximity also leads to a strong quenching of Abz fluorescence, which, in combination with a solvent jump, was used to devise a sensitive assay for prolyl isomerases. Unlike the traditional assay, it is not coupled with peptide proteolysis and thus can be employed for protease-sensitive prolyl isomerases as well. The peptide library was used to provide a complete set of P1-site specificities for prototypic human members of the three prolyl isomerase families, FKBP12, cyclophilin 18, and parvulin 14. In a second application, the substrate specificity of SlyD, a protease-sensitive prolyl isomerase from Escherichia coli, was characterized and compared with that of human FKBP12 as well as with homologues from other bacteria. PMID- 19785466 TI - One-pot preparation of dendrimer-gold nanoparticle hybrids in a dipolar aprotic solvent. AB - We present a simple one-pot, one-step method to obtain stable and nearly monodisperse gold nanoparticles in dipolar aprotic solvents. Novel thiomethyl functionalized polyphenylene dendrimers are used to control the growth and stabilize the nanoparticles in suspension. The dendrimer functionalized gold nanoparticles have an average size of roughly 10 nm and are stable in suspension for several weeks. The stability in dipolar aprotic solvents and the great functionalization flexibility offered by the dendrimers make these metal/dendrimer hybrid systems promising for applications such as nanophotonics, molecular electronics, and sensing. PMID- 19785467 TI - Formation of a 3D porous ferric arsenate containing novel cubane-like Fe4F4 building units. AB - The purely inorganic microporous compound [H(3)O][Fe(4)F(4)(AsO(4))(3)] x 3 H(2)O (1), which contains novel cubane-like Fe(4)F(4) cages, exhibiting a 3D configuration with channels of dimensions 8 A x 8 A running along the [001], [010], and [100] directions, presents antiferromagnetic interactions. PMID- 19785468 TI - Facile synthesis of bismuth(III) and antimony(III) complexes supported by silylated calix[5]arenes. AB - A series of bismuth(III) and antimony(III) complexes supported by silicon containing calix[5]arene ligands were synthesized and fully characterized by NMR, X-ray, IR, mp, UV/vis, and elemental analysis. Reaction of the para-tert butylcalix[5]arene [(t)BuC5(H)(5)] disodium salt, Na(2) x (t)BuC5(H)(3), with 1 equiv of R(2)SiCl(2) (R = Me, (i)Pr, Ph, CH=CH(2)) or treatment of the (t)BuC5(H)(5) lower rim monobenzyl ether [(t)BuC5(Bn)(H)(4)] in a 1:1 ratio with Me(2)Si(NMe(2))(2) yields the (t)BuC5(SiRR')(H)(3) (1-5) and (t)BuC5(Bn)(SiMe(2))(H)(2) (6) ligands, respectively. The (1)H NMR spectra of the (t)BuC5(SiRR')(H)(3) (1-5) ligands show three pairs of doublets and three singlets for the (t)Bu peaks, consistent with a C(s) symmetry. In the case of the (t)BuC5(Bn)(SiMe(2))(H)(2) (6) ligand, the presence of the monobenzyl group changes the (1)H NMR patterns to indicate a C(1) symmetry. Treatment of (t)BuC5(SiRR')(H)(3) (1-5) or (t)BuC5(Bn)(SiMe(2))(H)(2) (6) with 1 equiv of M(O(t)Bu)(3) (M = Bi, Sb) or Sb(NMe(2))(2) readily yields metalated products of the type [M{(t)BuC5(SiRR')}] (7-16) and [MX{(t)BuC5(Bn)(SiMe(2))}] (X = O(t)Bu, (NMe(2))(2)) (17-19), respectively. All monometallic complexes [M{(t)BuC5(SiRR')}] (7-19) display excellent solubility in organic solvents including pentane and hexane. The (1)H NMR patterns for complexes 7-16 are consistent with a 1,2- or 1,3-alternate conformation while complexes [MX{(t)BuC5(Bn)(SiMe(2))}] (17-19) display patterns for a C(1) symmetry. All crystals show monomeric structures. Ligand (t)BuC5(SiPh(2))(H)(3) (3) displays a distorted cone conformation while the presence of the monobenzyl ether in (t)BuC5(Bn)(SiMe(2))(H)(2) (6) forces a partial cone conformation. Complexes 7-19 all display a distorted 1,2-alternate conformation with the metal centers displaying coordination numbers of three, four or five. No Si...M interactions were observed. PMID- 19785469 TI - Packing the silica colloidal crystal beads: a facile route to superhydrophobic surfaces. AB - To mimic the structure of the lotus leaf, we present a facile route to prepare superhydrophobic surfaces by depositing nanoparticle clusters onto a solid surface. These clusters were fabricated via solidification of an emulsion droplet containing a nanoparticle in silicone oil. Thus, the microsized clusters and nanoparticles form dual-scale roughness structures. The surface is modified by fluoroalkylsilane and exhibits superhydrophobicity, with a contact angle greater than 165 degrees as well as a sliding angle less than 1 degrees . On the basis of size tuning of the nano/microstructures, various contact angles and sliding angles were investigated. Furthermore, the influence of micro/nanostructures on superhydrophobicity is discussed. PMID- 19785470 TI - Anisotropic dielectric tensor for chiral polyfluorene at optical frequencies. AB - The anisotropic dielectric tensor of chiral poly[9,9-bis((3S)-3,7-dimethyloctyl) 2,7-fluorene] is determined via variable angle spectroscopic ellipsometry and circular dichroism spectroscopy. The uniaxial anisotropy indicates a high in plane alignment of polymer chains in the thin film. Chirality of the polymer results in small but nonzero off-diagonal matrix elements in the dielectric tensor, indicating a helical interchain organization in the vertical direction. This method for determining the dielectric tensor appears to be self-consistent when checked against various theoretical models for the optical activity in the reflection of light. The dielectric constants for the chiral polyfluorene are compared to those for an achiral polyfluorene. PMID- 19785471 TI - Tetrahydroisoquinoline-based spirocyclic lactam as a type II' beta-turn inducing peptide mimetic. AB - We present here spirocyclic lactam derivatives, embodying D-Phe and L-Ala amino acids as the central core and acting as tetrapeptide and hexapeptide mimetics. An efficient route for their synthesis is demonstrated by using the strategic combination of Seebach's self-reproduction of chirality chemistry and the Pictet Spengler condensation as key steps. The conformational behavior of peptide mimetics was investigated by molecular modeling, X-ray crystallography, NMR (solvent and temperature dependence), IR spectroscopy, and circular dichroism. All data suggest very stable and highly predictable type II' beta-turn conformations. PMID- 19785472 TI - Dissociation energy of the HOOO radical. AB - The dissociation of the hydrotrioxy (HOOO) radical to OH and O(2) has been studied theoretically using coupled-cluster methods. The calculated dissociation energy for the trans-HOOO isomer is 2.5 kcal mol(-1) including zero-point corrections. The minimum energy path to dissociation has been explored and an exit barrier has been revealed, which may help to rationalize the apparent disagreement between theory and experiment on the magnitude of the bond energy. PMID- 19785473 TI - Kinetics of liquid phase catalytic hydrogenation of dicyclopentadiene over Pd/C catalyst. AB - To investigate the kinetics behaviors of dicyclopentadiene hydrogenation, a series of experiments were performed at different temperatures (323-353 K) under varying hydrogen pressure (0.5-1.5 MPa) with a range of Pd/C catalyst loading (0.25-1.00 wt %) using ethanol as solvent in a batch reactor. The time dependent concentration variations for each component were traced under the conditions of removing both the internal and external diffusion effects. The Langmuir Hinshelwood mechanism was proposed with the consideration of the noncompetitive adsorption between the organic species with hydrogen, and the surface reaction was the rate-determining step. The kinetic equations for the sequence reaction were derived on the basis of the analysis of mechanisms, and the model parameters were determined by fitting the experimental data in differential temperature using the method of Runge-Kutta. The reaction activation energies for the first and second steps are 3.19 and 31.69 kJ x mol(-1), respectively, and the reliability of the model was verified by these experimental results to change hydrogen pressure, reactant concentration and catalyst loading. The simulation results agreed well with the experimental data. PMID- 19785474 TI - Do quantum mechanical energies calculated for small models of protein-active sites converge? AB - A common approach for the computational modeling of enzyme reactions is to study a rather small model of the active site (20-200 atoms) with quantum mechanical (QM) methods, modeling the rest of the surroundings by a featureless continuum with a dielectric constant of approximately 4. In this paper, we discuss how the residues included in the QM model should be selected and how many residues need to be included before reaction energies converge. As a test case, we use a proton transfer reaction between a first-sphere cysteine ligand and a second-sphere histidine group in the active site of [Ni,Fe] hydrogenase. We show that it is not a good approach to add groups according to their distance to the active site. A better approach is to add groups according to their contributions to the QM/MM energy difference. However, the energies can still vary by up to 50 kJ/mol for QM systems of sizes up to 230 atoms. In fact, the QM-only approach is based on the hope that a large number of sizable contributions will cancel. Interactions with neutral groups are, in general, short-ranged, with net energy contributions of less than 4 kJ/mol at distances above 5 A from the active site. Interactions with charged groups are much more long-ranged, and interactions with buried charges 20 A from the active site can still contribute by 5 kJ/mol to the reaction energy. Thus, to accurately model the influence of the surroundings on enzyme reaction energies, a detailed and unbiased atomistic account of the surroundings needs to be included. PMID- 19785475 TI - Comparative analysis of IR and vibrational circular dichroism spectra for a series of camphor-related molecules. AB - The absorption spectra and vibrational circular dichroism (VCD) spectra in the mid-IR range 1600-950 cm(-1) of 10 camphor-related compounds have been recorded and compared to DFT calculated spectra at the B3PW91/TZ2P level and have been examined together with the corresponding data of the parent molecules. The rigidity of the bridged structure common to all compounds investigated permits (a) identification of three spectroscopic regions in the mid-IR range that can be "used" separately by the interested stereochemist for structural diagnosis and assignment of some major characteristics of the VCD spectra in these regions to what we call "skeletal chiral sense" and (b) recognition of possible conformers for flexible substituent groups, when present. VCD spectra of the 10 molecules have been recorded and analyzed also in the CH-stretching region, 3100-2800 cm( 1). Here, we have been able to identify and characterize features of vibrational excitons by comparison of data within the 10-molecule class. To find a theoretical justification of result (a), we have examined the potential energy distribution of the normal modes in the mid-IR range, the partitioning of the calculated rotational strengths in terms of contributions from all couples of internal coordinates, the angle formed by the two vectors, the electric dipole transition moment and the magnetic dipole transition moment, and finally the overlap of normal modes of different molecules. A discussion is provided as to the usability of the introduced algorithms. PMID- 19785477 TI - Parasites and symbionts from Mytilus galloprovincialis (Lamark, 1819) (Bivalves: Mytilidae) of the Aveiro Estuary Portugal. AB - The primary aim of the present study was to conduct a 1-yr parasitological survey of a Mytilus galloprovincialis mussel population from the Aveiro Estuary, Portugal. In addition, we attempted to assess the host response to parasites by examining host histopathology, including an evaluation of hemocyte infiltration and parasite encapsulation. The parasites present (prevalence) included the following: 1 protozoan, Nematopsis sp. (70%); 1 turbellarian, Urastoma cyprinae, (39%); 2 trematodes, Diphtherostomum sp. (58%) and Prosorhynchus crucibulum (0.3%); 3 crustaceans, Bathylaophonte azorica (0.3%); and 2 species of Mytilicola sp. (3.5%), M. intestinalis and M. orientalis. Highest prevalences for the most abundant species occurred in summer and autumn. Histological sections of the mantle of infected mussels revealed a marked reduction in the reproductive tissue, indicating that P. crucibulum invades the mussel and promotes a severe damage to its reproductive capacity. PMID- 19785476 TI - An orthogonal active site identification system (OASIS) for proteomic profiling of natural product biosynthesis. AB - A significant gap exists between genetics-based investigations of polyketide synthase (PKS) and nonribosomal peptide synthetase (NRPS) biosynthetic pathways and our understanding of their regulation, interaction, and activity in living systems. To help bridge this gap, here we present an orthogonal active site identification system (OASIS) for the proteomic identification and analysis of PKS/NRPS biosynthetic enzymes. OASIS probes target conserved features of PKS/NRPS active sites to provide activity-based enrichment of modular synthases, followed by analysis through multidimensional protein identification technology (MudPIT) LC-MS/MS analysis. When applied to the model bacterium Bacillus subtilis, this functional proteomics method detects and quantifies all four modular synthases in the organism. Furthermore, tandem application of multiple OASIS probes enhances identification of specific PKS/NRPS modules from complex proteomic mixtures. By expanding the dynamic range of proteomic analysis for PKS/NRPS enzymes, OASIS offers a valuable tool for strain comparison, culture condition optimization, and enzyme discovery. PMID- 19785478 TI - Limits on legitimacy: moral and religious convictions as constraints on deference to authority. AB - Various versions of legitimacy theory predict that a duty and obligation to obey legitimate authorities generally trumps people's personal moral and religious values. However, most research has assumed rather than measured the degree to which people have a moral or religious stake in the situations studied. This study tested compliance with and reactions to legitimate authorities in the context of a natural experiment that tracked public opinion before and after the U.S. Supreme Court ruled in a case that challenged states' rights to legalize physician-assisted suicide. Results indicated that citizens' degree of moral conviction about the issue of physician-assisted suicide predicted post-ruling perceptions of outcome fairness, decision acceptance, and changes in perceptions of the Court's legitimacy from pre- to post-ruling. Other results revealed that the effects of religious conviction independently predicted outcome fairness and decision acceptance but not perceptions of post-ruling legitimacy. PMID- 19785480 TI - Culture as common sense: perceived consensus versus personal beliefs as mechanisms of cultural influence. AB - The authors propose that culture affects people through their perceptions of what is consensually believed. Whereas past research has examined whether cultural differences in social judgment are mediated by differences in individuals' personal values and beliefs, this article investigates whether they are mediated by differences in individuals' perceptions of the views of people around them. The authors propose that individuals who perceive that traditional views are culturally consensual (e.g., Chinese participants who believe that most of their fellows hold collectivistic values) will themselves behave and think in culturally typical ways. Four studies of previously well-established cultural differences found that cultural differences were mediated by participants' perceived consensus as much as by participants' personal views. This held true for cultural differences in the bases of compliance (Study 1), attributional foci (Study 2), and counterfactual thinking styles (Study 3). To tease apart the effect of consensus perception from other possibly associated individual differences, in Study 4, the authors experimentally manipulated which of 2 cultures was salient to bicultural participants and found that judgments were guided by participants' perception of the consensual view of the salient culture. PMID- 19785481 TI - Applying the value of equality unequally: effects of value instantiations that vary in typicality. AB - Across 4 experiments, the authors investigated the role of value instantiation in bridging the gap between abstract social values and behavior in specific situations. They predicted and found that participants engaged in more egalitarian behavior (point allocation using the minimal group paradigm) after contemplating a typical instantiation of the value of equality compared to an atypical instantiation or a control condition that simply made the value salient. This effect occurred when participants generated reasons for valuing equality in the instantiation (Experiment 1) and when participants merely read about hypothetical examples of the instantiation context (Experiments 2, 3, and 4). Results across experiments indicated that the effect of prior instantiations was not mediated by changes in the abstract value; instead, the process of applying the abstract value was crucial (Experiment 4). Together, the experiments show that the process of applying an abstract value to a specific situation can be influenced by seemingly unrelated prior episodes. PMID- 19785482 TI - What's inside the minds of securely and insecurely attached people? The secure base script and its associations with attachment-style dimensions. AB - In 8 studies the authors explored the procedural knowledge (secure-base script; H. S. Waters & E. Waters, 2006) associated with secure attachment (i.e., low scores on attachment anxiety and avoidance). The studies assessed the accessibility, richness, and automaticity of the secure-base script and the extent to which it guided the processing of attachment-relevant information. Secure attachment (lower scores on anxiety and avoidance) was associated with greater secure-base "scriptedness" of attachment narratives, greater accessibility of the secure-base script in narratives and dreams about distressing experiences, deeper processing of script-relevant information, and faster and more confident script-relevant judgments. In addition, secure participants' tendency to process secure-base information more deeply was evident even 5 days after being exposed to it and was impervious to the depletion of cognitive resources, indicating automatic processing. The discussion focuses on implications of the findings for understanding the cognitive bases of secure people's affect-regulation strategies and behavior in social relationships. PMID- 19785483 TI - Living with a concealable stigmatized identity: the impact of anticipated stigma, centrality, salience, and cultural stigma on psychological distress and health. AB - The current research provides a framework for understanding how concealable stigmatized identities impact people's psychological well-being and health. The authors hypothesize that increased anticipated stigma, greater centrality of the stigmatized identity to the self, increased salience of the identity, and possession of a stigma that is more strongly culturally devalued all predict heightened psychological distress. In Study 1, the hypotheses were supported with a sample of 300 participants who possessed 13 different concealable stigmatized identities. Analyses comparing people with an associative stigma to those with a personal stigma showed that people with an associative stigma report less distress and that this difference is fully mediated by decreased anticipated stigma, centrality, and salience. Study 2 sought to replicate the findings of Study 1 with a sample of 235 participants possessing concealable stigmatized identities and to extend the model to predicting health outcomes. Structural equation modeling showed that anticipated stigma and cultural stigma were directly related to self-reported health outcomes. Discussion centers on understanding the implications of intraindividual processes (anticipated stigma, identity centrality, and identity salience) and an external process (cultural devaluation of stigmatized identities) for mental and physical health among people living with a concealable stigmatized identity. PMID- 19785484 TI - Social influence and threat in confrontations between competent peers. AB - Five studies investigated social influence processes in confrontations between competent peers and showed a default absence of influence of a competent source on an equally competent target. This default lack of influence is attributed to the representation that competent targets give to the influence encounter, in which different answers from competent peers are incompatible, the error of the source thus being the sine qua non condition of targets' correctness. However, an influence appeared when the representation of the task was modified via a decentering procedure (Study 1), even when controlling for alternative explanations (Study 2). Study 3 demonstrated that this liberating effect of decentering did not appear when the source was incompetent. Study 4 also examined social comparison processes and showed that independence of judgments produced the same liberating effect as decentering. Finally, Study 5 showed that the default lack of influence in confrontations between competent peers is due to the presence of a threat to the self. Indeed, the reduction of threat through a procedure of self-affirmation modified the representation of the task and allowed influence to appear. PMID- 19785485 TI - Big Five predictors of behavior and perceptions in initial dyadic interactions: personality similarity helps extraverts and introverts, but hurts "disagreeables". AB - The authors used the unstructured dyadic interaction paradigm to examine the effects of gender and the Big Five personality traits on dyad members' behaviors and perceptions in 87 initial, unstructured interactions. Most of the significant Big Five effects (84%) were associated with the traits of Extraversion and Agreeableness. There were several significant actor and partner effects for both of these traits. However, the most interesting and novel effects took the form of significant Actor x Partner interactions. Personality similarity resulted in relatively good initial interactions for dyads composed of 2 extraverts or 2 introverts, when compared with dissimilar (extravert-introvert) pairs. However, personality similarity resulted in uniquely poor initial interactions for dyads composed of 2 "disagreeables." In summary, the Big Five traits predict behavior and perceptions in initial dyadic interactions, not just in the form of actor and partner "main effects" but also in the form of Actor x Partner interactions. PMID- 19785486 TI - Prorelationship maintenance behaviors: the joint roles of attachment and commitment. AB - The present research uses a behavioral observation methodology to examine emotional and behavioral reactions to threatening interpersonal situations in married couples. The research shows that although anxious attachment can hinder people's tendencies to react constructively to threatening events, greater relationship commitment may serve as a buffer against the negative effects associated with attachment insecurities, diminishing feelings of rejection, enhancing feelings of acceptance, and promoting more constructive accommodation behaviors. The research also reveals that wives' degree of relationship commitment has stronger effects on emotional outcomes for both partners than does husbands' degree of commitment. Moreover, husbands' and wives' emotional reactions affect their own accommodative behaviors as well as their spouses' behaviors. These dyadic findings are discussed in terms of attachment theory and interdependence theory. PMID- 19785487 TI - Changing, priming, and acting on values: effects via motivational relations in a circular model. AB - Circular models of values and goals suggest that some motivational aims are consistent with each other, some oppose each other, and others are orthogonal to each other. The present experiments tested this idea explicitly by examining how value confrontation and priming methods influence values and value-consistent behaviors throughout the entire value system. Experiment 1 revealed that change in 1 set of social values causes motivationally compatible values to increase in importance, whereas motivationally incompatible values decrease in importance and orthogonal values remain the same. Experiment 2 found that priming security values reduced the better-than-average effect, but priming stimulation values increased it. Similarly, Experiments 3 and 4 found that priming security values increased cleanliness and decreased curiosity behaviors, whereas priming self direction values decreased cleanliness and increased curiosity behaviors. Experiment 5 found that priming achievement values increased success at puzzle completion and decreased helpfulness to an experimenter, whereas priming with benevolence values decreased success and increased helpfulness. These results highlight the importance of circular models describing motivational interconnections between values and personal goals. PMID- 19785488 TI - Examining self-presentation as a motivational explanation for comparative optimism. AB - Five studies examined a self-presentation explanation for comparative optimism. Experiments 1 and 2 laid the foundation for such an account by first showing that people associate a favorable identity-image with the conveyance of an optimistic outlook and that people recognize that an individual may be perceived in a negative light if his or her optimistic estimates are disconfirmed, hence raising the issue of potential accountability demands. Following the issue of accountability, the results across Experiments 3, 4, and 5 provided consistent evidence that people employ comparative optimism in their self-presentation efforts but only if the circumstances involve little risk of being held potentially accountable. Specifically, when self-presentational situations involved greater accountability demands, comparative optimism decreased (less optimistic), whereas, when these situations involved reduced accountability demands, comparative optimism increased (more optimistic). In short, the current experiments present compelling evidence demonstrating that comparative optimism may reflect an individual's goal to self-present a favorable identity-image, with the provision that such efforts are constrained by accountability pressures. PMID- 19785489 TI - The dynamics of death and meaning: the effects of death-relevant cognitions and personal need for structure on perceptions of meaning in life. AB - Do reminders of mortality increase or decrease perceptions of life's meaning? The authors propose that death-relevant thought has divergent effects on meaning perceptions depending on individuals' personal need for structure (PNS) or dispositional desire for structured knowledge. In prior research, high-PNS individuals primed with mortality-related stimuli were found to employ clearly structured conceptions of reality. Consequently, these individuals were expected to show stable or even bolstered perceptions of meaning when death thought was heightened. Low-PNS individuals did not show this tendency and were therefore expected to show decreased meaning under heightened death-thought activation. The results of Studies 1a-1d supported these hypotheses. Studies 2 and 3 sought to identify how low-PNS individuals might reaffirm meaning and found that death thought increased their willingness to explore novelty. Studies 4 and 5 directly tested the meaning-conferring function of novelty seeking among low-PNS individuals, showing that the consideration of novel interpretations of the world and their experiences affirmed a sense of meaning in life following reminders of death. Discussion focuses on the relationship between meaning and death and the unique ways low-PNS individuals respond to mortality concerns. PMID- 19785490 TI - Will non-invasive testing replace liver biopsy in the diagnosis and follow-up of non-alcoholic steatohepatitis (NASH)? PMID- 19785491 TI - Usefulness of an index score as a predictor of hepatic fibrosis in obese patients undergoing bariatric surgery. AB - OBJECTIVE: To evaluate the usefulness of a non-invasive clinical score to predict liver fibrosis in the steatosis associated with morbid obesity. PATIENTS AND METHODS: We included 88 patients, who underwent bariatric surgery in the Sanitary Area of Leon, Spain, and who showed a liver biopsy with steatosis greater than 5%. This is a retrospective study in which the rate of fibrosis is calculated from tests performed during the preoperative period, and is then compared to data from intraoperative hepatic biopsies. The analysis population was grouped according to the presence of advanced fibrosis in the liver biopsy (grade 3-4) or its absence (grade 0-2). The cutoff used for diagnosing advanced fibrosis was 0.676 (high cutoff point), and the cutoff point to exclude advanced fibrosis was 1.455 (low cutoff). RESULTS: The prevalence of advanced fibrosis in the histological samples was 5.5%, and 65.9% of patients had no fibrosis. The cutoff for a low negative predictive value was 100%, and sensitivity was 100%. The cutoff point for a high positive predictive value was 1.7%, and specificity was 31.3%. CONCLUSIONS: This scoring system for morbidly obese patients eligible for bariatric surgery allows to identify those without advanced fibrosis, but cannot predict who may have advanced fibrosis. PMID- 19785492 TI - Surgical management of hereditary colorectal cancer: surgery based on molecular analysis and family history. AB - The importance of colorectal cancer (CRC) is increasing. A proportion show a hereditary component, as in Lynch syndrome and Familial Adenomatous Polyposis, and a recently defined entity as well, namely, Familial Colorectal Cancer type X. The high probability to develop CRC in these groups may, at the time of recognition, change surgical management, including its timing or even the surgical technique. In some cases prophylactic surgery can play an important role. The possibility of using tools that allow recognition of the aforementioned syndromes, including microsatellite instability, immunohistochemistry for DNA mismatch repair system proteins, and especially their mutations, is on the basis of therapeutic strategies that differ from those employed in sporadic CRC cases. PMID- 19785493 TI - Biliary sphincterotomy dilation for the extraction of difficult common bile duct stones. AB - BACKGROUND AND AIM: Endoscopic retrograde cholangiopancreatography (ERCP) with biliary sphincterotomy (BS) is the usual method for extracting common bile duct stones. However, following BS and by means of extraction balloons and Dormia baskets a complete bile duct clearance cannot be achieved in all cases. We present a study on the impact that hydrostatic balloon dilation of a previous BS (BSD) may have in the extraction rate of choledocholithiasis. PATIENTS AND METHODS: A prospective study which included 91 consecutive patients diagnosed with choledocholithiasis who underwent ERCP. For stone removal, extraction balloons and Dormia baskets were used, and when necessary BSD was employed. RESULTS: Complete bile duct clearance was achieved in 86/91 (94.5%) patients. BSD was used in 30 (33%) cases. In these cases, extraction was complete in 29/30 (97%); 23 (76%) patients in the BSD group had anatomic difficulties or bleeding disorders. The most frequently used hydrostatic balloon diameter was 15 mm (60%). There were 7 (7.6%) complications: two self-limited hemorrhage episodes in the BSD group and one episode of cholangitis, one of pancreatitis, and three of bleeding in the group in which BSD was not used. CONCLUSIONS: BSD is a very valuable tool for extracting common bile duct stones. In our experience, there has been an increase in the extraction rate from 73% (Rev Esp Enferm Dig 2002; 94: 340-50) to 94.5% (p = 0.0001, OR 0.1, CI 0.05-0.45), with no increase in complications. PMID- 19785495 TI - Treatment of irritable bowel syndrome with probiotics. An etiopathogenic approach at last? AB - Irritable bowel syndrome (IBS) is the most common functional digestive disorder, and may affect 11-20% of the adult population in industrialized countries. In accordance with Rome III criteria (2006) IBS involves abdominal pain and bowel habit disturbance, which are not explained by structural or biochemical abnormalities. Several hypotheses attempt to account for the pathophysiology of IBS, but the etiology still remains uncertain or obscure, perhaps multifactorial. Abnormalities in colonic microflora have recently been suggested in such patients, as has abnormal small-intestine bacterial overgrowth (SIBO), or in particular a significant reduction in the amount of intraluminal Bifidobacteria or Lactobacilli, with consequences like the production of colonic gas, and motility or sensitivity disturbances of the intestinal tract. The disorder is difficult to treat, and the wide spectrum of non-drug and drug treatments shows our ignorance about the cause of the condition. Newer drugs, both pro- and anti serotonin, have failed to show long-term efficacy or have been withdrawn due to concerns about harmful effects. Recent research has provided increasing support for the idea that disturbances of intestinal microbiota occur in patients with IBS, and that such abnormalities may contribute to IBS symptoms. Studies in Scandinavian countries in the last ten years emphasize the role of probiotics in the modulation of intestinal microbiota, and as a consequence in the regulation of the motility and hypersensitivity of the digestive tract. Although results between studies are difficult to compare because of differences in study design, probiotic dose, strain, and duration of therapy, some studies show symptom improvement. Lactobacilli are found among the normal bacterial flora of the gastrointestinal tract, and Lactobacillus plantarum (Lp) is one of the species frequently isolated from the human mucosa, which is capable of surviving the low pH of the stomach and duodenum, resisting the effect of bile acids in the upper small intestine when ingested, and temporarily colonizing the gastrointestinal tract by binding to the intestinal and colonic mucosa. Concurrent with colonization by Lp there is a decrease in bacterial groups with gas-producing ability, such as Veillonella spp. and Clostridia spp. Evidence has now accumulated to suggest the efficacy of certain probiotics like Lp299v, which may be capable of bringing about a significant reduction in pain, abdominal distension and flatulence, while increasing health-related quality of life in IBS. PMID- 19785494 TI - Training model for teaching endoscopic submucosal dissection of gastric tumors. AB - INTRODUCTION: The elevated risk of complications and technical complexity of endoscopic submucosal dissection (ESD) has limited its implementation in our medical system. OBJECTIVE: To design and evaluate a training program for learning the ESD technique. METHODS: Four endoscopists with no experience with ESD underwent a 4-step training program: 1) review of the existing literature, didactic material, and theoretical aspects of ESD; 2) ESD training in an ex-vivo animal model; 3) ESD training in an in-vivo animal model (supervised by ESD expert); and 4) ESD performance in a patient. A standard gastroscope and an ESD knife (IT, Flex or Hook-knife Olympus) were employed. The classical ESD technique was performed: rising of the lesion, circumferential incision, and submucosal dissection. RESULTS: Ex-vivo animal model: 6 x swine stomach/esophagus -cost < 100 euro; 6 x ESD: antrum (n = 2), body (n = 3) and fundus/cardia (n = 1)-; size of resected specimen: 4-10 cm; ESD duration: 105-240 minutes; therapeutic success: 100%; complications: perforation (1/6: 16%) sealed with clips. In-vivo animal model: 6 ESD (antrum/body of stomach: 4; esophagus: 2); size: 2-5 cm; duration: 40-165 minutes; success: 100%; complications: 0%. PATIENT: ESD of a gastric lesion located in the antrum/body; size: 3 cm; duration 210 minutes; a complete resection was achieved; no complications. CONCLUSIONS: The results of the present study support the usefulness of this model for learning ESD in our system. PMID- 19785496 TI - Perforation of the gallbladder with communicating pericholecystic abscess: ultrasonographic diagnosis. PMID- 19785497 TI - Massive gastric necrosis from hydrochloric acid ingestion. PMID- 19785498 TI - Pancreatitis and systemic lupus erythematosus. AB - Gastrointestinal symptoms in patients with SLE are common, specifically abdominal pain. However, the rate of pancreatic diseases is much lower and does not reach 5% according to published series in Europe and the USA. This association between SLE and pancreatic disease is basically at the expense of episodes of acute pancreatitis. An association with chronic pancreatitis is much more uncommon, and only four articles have been published showing this relationship. Three cases of SLE-associated pancreatitis are described, and disease onset, etiological factors, and clinical progression are analyzed. A review of the literature and a brief discussion about pathophysiological mechanisms and the role of corticosteroids are also included. PMID- 19785499 TI - [Intestinal tuberculosis: an emerging cause of abdominal pain and fever]. PMID- 19785500 TI - [Bronchiolitis obliterans with organizing pneumonia associated with sirolimus in a patient after liver transplantation]. PMID- 19785501 TI - Spontaneous rupture of a hepatic sarcoma in an adult resembling hydatid cyst. PMID- 19785502 TI - Atypical pyoderma gangresosum in inflammatory bowel disease. A severe diagnostic challenge. PMID- 19785503 TI - [Segmentary yeyunal ischemia complicating mesenteric vein thrombosis secondary to a hereditary antithrombin deficit]. PMID- 19785504 TI - [Colonic primary lipoma simulator of an adenocarcinoma]. PMID- 19785505 TI - [Gastrointestinal bleeding secondary to gastrointestinal stromal tumor in two patients with neurofibromatosis]. PMID- 19785506 TI - Surgical diagnosis and management of intestinal obstruction due to Ascaris lumbricoides. AB - BACKGROUND: Ascariasis continues to be one of the most important parasitic diseases in terms of its burden and complications in children in the developing world. METHODS: Case report and literature review (Medline, SCI, and LILACS). RESULTS: We report herein a case in which a Paraguayan infant presented with one of these complications: An intestinal obstruction due to Ascaris lumbricoides being diagnosed during surgery. The patient was managed with a conservative protocol for the extraction of the parasites using liquid petrolatum administered through a nasogastric tube followed with extensive water irrigation through the tube, in conjunction with the administration of piperazine as antiparasitic treatment. CONCLUSIONS: This case, as with others reported previously, shows that this complication can be managed successfully without major intestinal surgery. Early recognition of this condition, based on local prevalence, can prevent serious surgical complications, morbidity, and mortality associated with intestinal obstruction due to A. lumbricoides. PMID- 19785507 TI - Recent patent trends in the field of progesterone receptor agonists and modulators. AB - BACKGROUND: Progesterone receptor agonists are used in female contraception, hormone replacement therapy or some gynecological conditions like endometriosis. The interest for antagonists or selective progesterone receptor modulators (SPRMs) is growing. Recent reports on this class of compounds indicate that they could become the next generation of therapeutics in gynecological treatments. OBJECTIVE: This overview summarizes the work on progesterone receptor agonists, SPRMs and antagonists reported in the patent literature in the past 4 years. METHODS: The focus of the article is the examination of patents, primarily published as WO, EU or US patents since 2005. In some cases, additional data from the public literature is included into the discussion. These data are of substantial interest as the available biological data disclosed in patents are usually limited for new compound classes. RESULTS/CONCLUSION: Some highly active clusters of compounds have been disclosed in the past 4 years. The current research seems to focus on SPRMs and progesterone receptor antagonists. PMID- 19785508 TI - Telomere length in lymphocytes of older South Australian men may be inversely associated with plasma homocysteine. AB - Deficiencies in folate (FOL) and vitamin B12 (B12) result in increased chromosomal aberrations, a validated biomarker of cancer risk. Telomeres, the regions of DNA that cap the ends of each chromosome, are critical for maintaining chromosomal stability but the impact of micronutrients on telomere structure and function remains unclear. We hypothesized that telomere length maintenance might be compromised if the status of FOL and B12 was inadequate and plasma homocysteine (HCY) was increased. We investigated the relationship between telomere length in peripheral blood lymphocytes and plasma FOL, B12, and HCY status, and tested whether any such relationship was dependent on age, gender, body mass index, and common polymorphisms in folate metabolism genes. A single blood sample was collected from 43 younger (18-32 years) and 47 older (65-83 years) adults in South Australia. The younger cohort consisted of 18 males and 25 females, whereas the older group included 24 males and 23 females. Telomere length was determined in lymphocytes by flow cytometry. Telomere length in the younger cohort was 11.52% greater than in the older cohort (p = 0.015). In the older cohort, telomere length in females was 12.5% greater than in males (p = 0.028). In older males, there was a significant inverse correlation between telomere length and HCY (r = -0.57, p = 0.004), but this effect was not observed in the younger cohort or in the older female group. These results provide evidence that telomere length of lymphocytes in older men may be adversely affected by HCY in vivo. PMID- 19785509 TI - Safety of stimulant treatment in attention deficit hyperactivity disorder: Part I. AB - BACKGROUND: The safety profile of newer stimulant products is of interest. Because most studies focus on school-age children, there is also an increased interest in the treatment of other populations. Concern continues for the risk of substance abuse in the use of stimulants. OBJECTIVE: The purpose of this paper is to review published data on the safety and tolerability of the newer forms of stimulants, treatment in special populations, and the risks of substance abuse and dependence in the treatment of attention deficit hyperactivity disorder. METHODS: Literature obtained through Medline and Pubmed from 1995 were reviewed as well as key articles referenced in the literature. CONCLUSIONS: The use of the newer stimulant agents shows a safety profile of frequent, but usually mild side effects. They are generally safe in special populations. The risk of developing long-term substance abuse with attention deficit hyperactivity disorder, without co-morbidities, is small and may decrease with proper treatment. More research is needed. PMID- 19785510 TI - Evaluation of atomoxetine for first-line treatment of newly diagnosed, treatment naive children and adolescents with attention deficit/hyperactivity disorder. AB - OBJECTIVE: To test the hypothesis that first-line treatment with atomoxetine provides superior efficacy than placebo for up to 12 weeks in improving the symptoms of Attention Deficit/Hyperactivity Disorder (ADHD). RESEARCH DESIGN AND METHODS: This double-blind, randomized, placebo-controlled, parallel clinical trial included 151 treatment-naive children (n = 113) and adolescents (n = 38) with newly diagnosed (< or =3 months) ADHD. Atomoxetine dose was uptitrated from 0.5 to 1.2 mg/kg/day after two weeks. Outcome assessments included the ADHD Rating Scale-IV-Parent-reported Investigator-rated (ADHDRS-IV-Parent:Inv), the Clinical Global Impression of Severity of ADHD (CGI-ADHD-S), and the incidence of adverse events. Mixed-model repeated measures analysis was used to compare scale score changes between groups. CLINICAL TRIAL REGISTRATION: Trial registered at www.clinicaltrials.gov (study internal code: B4Z-XM-LYDM, identifier: NCT00191945). RESULTS: Most patients were male (79.2%), of caucasian origin (96.0%) and severely ill (72.5%). Their mean age was 10.3 years. Atomoxetine treated patients showed greater reductions from baseline to week 12 of total ADHDRS-IV-Parent:Inv score than placebo-treated patients (least square mean difference: -7.9 [95% CI: -11.0 to -4.8], corresponding to a large effect size of 0.8). Between-group mean differences increased progressively with treatment exposure from week 6 to 12 (-2.7 [-4.9 to -0.6] for total and -1.6 [-2.9 to -0.3] for inattention scores). At the end of the study, 50% of atomoxetine-treated patients (14% with placebo) showed a reduction > or =40% in total ADHDRS-IV Parent:Inv score, and only 29% (46% with placebo) were severely ill (by CGI-ADHD S). Treatment-related adverse events were significantly more frequent with atomoxetine (65.0%) than with placebo (37.3%), the most frequent being decreased appetite and somnolence. Only one case of decreased appetite was rated as severe. No patient discontinued treatment because of adverse events. CONCLUSIONS: A continued improvement of symptoms is expectable until 12 weeks in treatment-naive ADHD patients treated with atomoxetine as first-line medication. Chief limitations are the small, national sample size and the absence of data beyond the 12-week time-point. PMID- 19785511 TI - Impact of fixed-dose and multi-pill combination dyslipidemia therapies on medication adherence and the economic burden of sub-optimal adherence. AB - OBJECTIVE: To compare medication adherence between patients initiating fixed-dose combination versus multi-pill combination dyslipidemia therapies and assess the association between optimal adherence (MPR > or = 80%) and cardiovascular disease (CVD)-associated total healthcare resource utilization (THR) and costs (THC). RESEARCH DESIGN AND METHODS: The HealthCore Integrated Research Database was used to identify patients > or =18 years newly initiating fixed-dose combination [niacin extended-release (NER) and lovastatin (NERL)] or multi-pill combination therapies [NER and simvastatin (NER/S) or lovastatin (NER/L)] between 1/1/2000 and 6/30/2006 (index date), with minimum 18 months of follow-up. Adherence was measured using medication possession ratio (MPR). Three multivariate models were developed controlling for demographic and clinical characteristics. A logistic model evaluated the association between study cohorts and optimal adherence, while negative binomial and gamma models estimated the association between optimal adherence and CVD-associated THR and THC, respectively. RESULTS: In all, 6638 NERL, 1687 NER/S, and 663 NER/L patients were identified. Fixed-dose combination patients were younger [mean (SD) ages of 51.9 (10.5) vs. 56.0 (9.4) [NER/S] and 56.1 (10.6) [NER/L]; p < 0.01], had lower comorbidity (Deyo-Charlson Index 0.50 +/- 0.9 vs. 0.7 +/- 1.1 and 0.6 +/- 1.1, p < 0.01 and p < 0.05) and comprised fewer males (73.1 vs. 83.0% and 77.7%; p < 0.01 and p = 0.1). Fixed dose combination patients had higher average 1-year MPR versus NER/S and NER/L patients (0.54 +/- 0.35 vs. 0.50 +/- 0.35 and 0.47 +/- 0.34, p < 0.01). NER/S and NER/L patients were 31.3% (95% CI: 22.9-39.5%) and 39.1% (95% CI: 26.7-49.4%) less likely to be optimally adherent than fixed-dose combination patients (p < 0.01). Additionally, optimally adherent patients had 8% and 40% decreases in annual CVD-attributable THR [0.920 (95% CI: 0.857-0.989); p = 0.023] and THC [0.601 (95% CI: 0.427-0.845); p = 0.003] versus sub-optimally adherent patients. Key limitations of the study include the limited ability of MPR to analyze the continuity of medication usage, inability to capture data on other key variables including race, income, and clinical characteristics such as smoking history, absence of laboratory values on all study patients, inability to capture over-the counter fills of niacin, and inability to show causality of results obtained. CONCLUSIONS: Adherence was significantly higher among patients initiating fixed dose combination versus multi-pill combination dyslipidemia therapies in this managed-care population. Additionally, patients with optimal adherence had a significantly lower CVD-associated THR and THC versus patients with sub-optimal adherence. PMID- 19785512 TI - Management of gastro-oesophageal reflux disease in primary care: a European observational study. AB - OBJECTIVE: To describe the management of gastro-oesophageal reflux disease (GERD) in primary care, as part of the RANGE (Retrospective ANalysis of GERD) study. METHODS: Over 4 months, at 134 primary care practices in six European countries, 12 815 patients consulted for GERD-related reasons. A random selection of these patients was invited to enter the study. Data were then collected retrospectively (from the initial consultation) and prospectively (from a follow-up visit). This included information on GERD diagnosis, symptoms and complications, medication use and healthcare resource utilisation. RESULTS: Of 12 815 patients who underwent consultation for GERD-related reasons, 2678 were randomly selected and accepted the invitation to participate in the study. Across countries, 28-47% of patients reported a significant GERD symptom load at initial consultation. Thereafter, 30-100% of patients were prescribed a proton pump inhibitor (PPI), but a significant GERD symptom load was still experienced by 15-30% (all patients combined) at follow-up (median 5.0-7.5 months after initial consultation). In the majority of patients (65-88%), no diagnostic procedures were performed between initial consultation and follow-up. During the follow-up period, the most common form of healthcare utilisation comprised additional GERD-related consultations with a physician. CONCLUSIONS: The findings of this pan-European study indicate that current management of primary care patients with GERD is far from optimal, and accounts for a marked burden on patients and healthcare systems alike. A more structured approach to GERD management, by tailoring treatment according to the impact of the disease, may reduce this burden. PMID- 19785513 TI - Developmental expression of drug metabolizing enzymes and transporter proteins in human placenta and fetal tissues. AB - Transporter proteins and xenobiotic metabolizing enzymes have a crucial role in the fate of xenobiotics in human body. The expression in human placenta and fetal tissues of the proteins most commonly participating in pharmaco/toxicokinetics is reviewed. In case human data are not available, relevant animal data are included. Among transporter proteins ABC transporters, monoamine transporters and organic anion transporters are pharmacologically and toxicologically of main interest. From xenobiotic enzymes, both CYP enzymes and transferases are expressed in fetal liver already during pregnancy. In the placenta, the variety of enzymes is much more restricted. During development dynamic changes occur in both xenobiotic metabolizing enzymes and drug transporters. Although the knowledge has increased substantially over the past years it is apparent from the literature that there are uncharacterized areas, especially regarding developmental expression patterns and regulation of transporters in fetal tissues and placenta. Knowledge about tissue-specific distribution and functional significance will aid our understanding of the differences in drug response and risks for adverse events during fetal development. PMID- 19785514 TI - Role of microRNAs in the regulation of drug metabolism and disposition. AB - BACKGROUND: The important role of nuclear receptors in transcriptional gene regulation of drug-metabolizing enzymes (DMEs) and drug transporters (DTs) has been well documented. In contrast, there is limited understanding of post transcriptional gene regulation of DMEs and DTs. MicroRNAs (miRNAs) represent a large group of non-coding RNAs that control the post-transcriptional expression of target genes. Currently, > 800 miRNAs have been identified in human genome, which are believed to regulate thousands of human protein-coding genes. OBJECTIVE: This review aims to discuss the potential role of miRNAs in drug metabolism and disposition, following an introduction of miRNA biogenesis, regulatory mechanisms, and target identification and validation. RESULTS/CONCLUSIONS: Some miRNAs have been shown to directly or indirectly control the expression of DMEs, DTs or nuclear receptors, and consequently, affect the capacity of drug metabolism and disposition, and influence the sensitivity of cells to xenobiotic agents. Furthermore, the expression of some miRNAs is readily altered in cells after an acute or chronic exposure to medications, toxins or carcinogens. Therefore, dysregulation of specific miRNAs by a xenobiotic agent, which control the expression of DMEs or DTs, might lead to considerable change in the pharmacokinetic and pharmacodynamic property of a concomitant drug or the agent itself. Improved understanding of the regulatory pathways of DMEs and DTs shall provide novel insight into multi-drug resistance and potential drug-drug interaction in clinical pharmacotherapy as well as in drug discovery and development. PMID- 19785515 TI - Regulation of human hepatic drug transporter expression by pro-inflammatory cytokines. AB - BACKGROUND: Sinuosidal and canalicular hepatic drug transporters, involved in drug uptake in the liver and drug secretion in the bile, respectively, play a major role in liver drug clearance. Inflammation is well-known to impair expression of these transporters in rodents; data about this topic have been more recently reported in human hepatocytes. OBJECTIVE: The present review is designed to summarise the effects of pro-inflammatory cytokines such as IL-1beta, TNF alpha and IL-6 toward human hepatic drug and bile salt transporters. METHODS: Recent studies aimed at analyzing transporter expression and activity in cytokines-exposed primary human hepatocytes and well-differentiated human hepatoma cells are resumed and discussed. RESULTS/CONCLUSION: Exposure to IL 1beta, TNF-alpha or IL-6 markedly alters expression profile of human hepatic transporters. Bile salt transporters as well as sinusoidal solute carrier transporters are usually repressed, whereas ATP-binding cassette drug efflux pumps remain unchanged or are either downregulated or upregulated. These changes are observed at mRNA levels, but also, for some of the transporters, at protein and activity levels. They are likely to contribute to alterations of drug pharmacokinetics, impairment of bile salt secretion and cholestasis caused by inflammation in humans. PMID- 19785516 TI - Apoptosis: a clinically useful measure of antiretroviral drug toxicity? AB - Antiretroviral therapy (ART) has improved life expectancy with HIV infection, but long-term toxicities associated with these medications are now a major global disease burden. There is a clear need to develop useful methods for monitoring patients on antiretroviral drugs for early signs of toxicity. Assays with predictive utility -- allowing therapy to be changed before serious end organ damage occurs -- would be ideal. Attempts to develop biochemical methods of monitoring ART toxicity have concentrated on the mitochondrial toxicity of nucleoside analogue reverse transcriptase inhibitors and have not generally lead to assays with widespread clinical applications. For example, plasma lactate and peripheral blood measurements of mitochondrial DNA associate with exposure to potentially toxic nucleoside analogue reverse transcriptase inhibitors but have not reliably predicted clinical toxicity. Better assays are needed, including markers of toxicity from additional drug classes. Apoptosis may be a potential marker of ART toxicity. Increased apoptosis has been demonstrated both in vitro and in vivo in association with various antiretroviral drug classes and a range of clinical toxicities. However, quantifying apoptosis on biopsy specimens of tissue (such as adipose tissue) is impractical for patient monitoring. Novel assays have been described that can quantify apoptosis using minute tissue samples and initial results from clinical samples suggest peripheral blood may have utility in predicting ART toxicities. The limitations and potential of such techniques for monitoring patients for drug side effects will be discussed. PMID- 19785517 TI - Keeping vulnerable children safe from pertussis: preventing nosocomial pertussis transmission in the neonatal intensive care unit. AB - OBJECTIVE: To examine the impact of different acellular pertussis booster vaccination strategies on the probability of a nosocomial pertussis outbreak occurring and the distribution of outbreak sizes observed for each intervention strategy. SETTING: Neonatal intensive care unit. METHODS: We developed a stochastic, agent-based simulation model to examine the impact of booster vaccination strategies for pertussis on health care-related transmission. RESULTS: Our results demonstrate that healthcare worker booster vaccination decreases the probability of secondary transmission from 49% (base case, no boosting) to 2% (if 95% of healthcare workers are boosted) and decreases final outbreak size. Boosting family caregivers did not have a clinically significant impact on nosocomial disease transmission. CONCLUSION: The provision of booster vaccine to healthcare workers in the neonatal intensive care unit substantially reduces the risk of hospital-centered pertussis outbreaks in a manner that enhances the health of hospitalized children. A formal health economic analysis of this finding is currently under way. Policies to protect patient safety in pediatric facilities should include compliance with the United States Advisory Committee on Immunization Practices, which recommends provision of pertussis booster vaccination to healthcare workers. PMID- 19785518 TI - Antimicrobial susceptibility of bacteria isolated from urine samples obtained from nursing home residents. AB - In our study of nursing home residents with clinically suspected urinary tract infection who did not require the use of an indwelling catheter, we identified bacteria isolated from urine samples, the resistance patterns of these isolated bacteria, and the antibiotic therapy prescribed to the residents. Escherichia coli, the predominant organism isolated, frequently was resistant to commonly prescribed oral antibiotics. Trimethoprim-sulfamethoxazole remains the best empiric antimicrobial therapy for a urinary tract infection, but nitrofurantoin should be considered if E. coli is identified. PMID- 19785519 TI - Alterations in serum thyroid-related constituents after thyroid fine-needle biopsy: a systematic review. AB - BACKGROUND: Thyroid fine-needle biopsy (FNB) is a simple, reliable, inexpensive, and generally safe diagnostic procedure in the management of thyroid nodules. Local pain and minor hematomas are the most common clinical complications, and hemorrhage and fibrosis the most common histological alterations after thyroid FNB. FNB can also trigger biochemical alterations in serum, since it may destroy thyroid follicles. In this review we summarized the biochemical alterations in serum that occur after diagnostic thyroid FNB, aiming to review information that would be potentially useful in interpreting thyroid tests in patients who recently had a thyroid FNB. SUMMARY: Computerized advanced search for primary evidence was performed in the PubMed (Public/Publisher MEDLINE) electronic database not limited by publication time and English language. An increase in serum thyroglobulin (Tg) ranging from 35% to 341% occurs in 33-88% of patients subjected to FNB. Serum Tg concentrations typically return to baseline about 2-3 weeks after FNB. The abrupt release of Tg after FNB may induce the production of autoantibodies to Tg and thyroid hormones in a minority of patients. There is little information on the effect of FNB on autoantibodies to thyroid peroxidase. No changes seem to occur in thyroid-stimulating hormone, total thyroxine, free thyroxine, free triiodothyronine (T3), or reverse T3, while controversy exists for T3. CONCLUSIONS: The degree of increase in serum Tg after FNB is highly variable and not a predictor of whether the biopsied nodule is benign or malignant. The increase or development of Tg autoantibodies that occurs in some patients does not appear to be of clinical significance. Development of autoantibodies to thyroid hormones may be more likely in patients whose biopsied nodule is benign than malignant, but further studies are required to confirm this. If changes in serum thyroid-stimulating hormone or thyroid hormones are noted in a patient with a history of a recent fine-needle aspiration, they should be investigated since they are not likely to be related to the biopsy. PMID- 19785520 TI - Decline in thyroid (18)fluorodeoxyglucose uptake associated with selenium supplementation in a patient with autoimmune thyroiditis. PMID- 19785521 TI - Procalcitonin can be used for monitoring sepsis in patients with medullary thyroid carcinoma. PMID- 19785522 TI - Clinical risk factors associated with cervical lymph node recurrence in papillary thyroid carcinoma. AB - BACKGROUND: Recurrence of regional cervical lymph nodes in patients with papillary thyroid carcinoma (PTC) is not uncommon, and is an important factor affecting the quality of life. The aims of this study are to investigate the risk factors that are associated with regional lymph node recurrence by comparing a group of patients with regional lymph node recurrence with a group without lymph node recurrence, and to analyze the clinical characteristics of recurrent regional lymph nodes in PTC. METHODS: A retrospective analysis was performed on 189 patients who underwent surgery for PTC. By comparing a group with recurrent cervical lymph nodes (n = 33) with a group without recurrent cervical lymph nodes (n = 156), the risk factors for cervical lymph node recurrence were investigated and the clinical characteristics of recurrent cervical lymph nodes were analyzed. RESULTS: Tumor size >2 cm, presence of extrathyroid tumor spread, high T stage, and presence of lymph node metastasis were associated with regional lymph node recurrence in univariate analysis (p < 0.05). Among them, only the N stage was significantly associated with regional recurrence in multivariate analysis (p < 0.05). The disease-free survival period was shorter in the lymph node metastasis positive group, and the 10-year disease-free survival rate was 77.8% in the lymph node metastasis-negative group and 57.9% in the lymph node metastasis-positive group (p < 0.05). Among 130 patients without lymph node metastasis, regional recurrence occurred in 13 patients (10%), and the frequent levels of regional recurrence were levels II-IV of ipsilateral neck. In the patients with lymph node metastasis, the frequent levels were levels IV-VI of ipsilateral side and level II of the contralateral side. CONCLUSION: Considering the low incidence of regional lymph node recurrence and the levels with frequent regional recurrence in patients without lymph node metastasis, elective neck dissection in all cases of total thyroidectomy may be immoderate. However, if any risk factors for regional recurrence, including large tumor size, presence of extrathyroid spread, high T stage, and presence of lymph node metastasis, are detected by preoperative and intraoperative evaluation, a systematic compartment-oriented lymphadenectomy should be considered because of the high possibility of regional recurrence. PMID- 19785523 TI - Improved method for analysis of RNA present in long-term preserved thyroid cancer tissue of atomic bomb survivors. AB - BACKGROUND: Since many thyroid cancer tissue samples from atomic bomb (A-bomb) survivors have been preserved for several decades as unbuffered formalin-fixed, paraffin-embedded specimens, molecular oncological analysis of such archival specimens is indispensable for clarifying the mechanisms of thyroid carcinogenesis in A-bomb survivors. Although RET gene rearrangements are the most important targets, it is a difficult task to examine all of the 13 known types of RET gene rearrangements with the use of the limited quantity of RNA that has been extracted from invaluable paraffin-embedded tissue specimens of A-bomb survivors. In this study, we established an improved 5' rapid amplification of cDNA ends (RACE) method using a small amount of RNA extracted from archival thyroid cancer tissue specimens. METHODS: Three archival thyroid cancer tissue specimens from three different patients were used as in-house controls to determine the conditions for an improved switching mechanism at 5' end of RNA transcript (SMART) RACE method; one tissue specimen with RET/PTC1 rearrangement and one with RET/PTC3 rearrangement were used as positive samples. One other specimen, used as a negative sample, revealed no detectable expression of the RET gene tyrosine kinase domain. RESULTS: We established a 5' RACE method using an amount of RNA as small as 10 ng extracted from long-term preserved, unbuffered formalin-fixed, paraffin-embedded thyroid cancer tissue by application of SMART technology. This improved SMART RACE method not only identified common RET gene rearrangements, but also isolated a clone containing a 93-bp insert of rare RTE/PTC8 in RNA extracted from formalin-fixed, paraffin-embedded thyroid cancer specimens from one A-bomb survivor who had been exposed to a high radiation dose. In addition, in the papillary thyroid cancer of another high-dose A-bomb survivor, this method detected one novel type of RET gene rearrangement whose partner gene is acyl coenzyme A binding domain 5, located on chromosome 10p. CONCLUSION: We conclude that our improved SMART RACE method is expected to prove useful in molecular analyses using archival formalin-fixed, paraffin-embedded tissue samples of limited quantity. PMID- 19785524 TI - Revisiting the importance of virulence determinant magA and its surrounding genes in Klebsiella pneumoniae causing pyogenic liver abscesses: exact role in serotype K1 capsule formation. AB - BACKGROUND: Mucoviscosity-associated gene A (magA) is proposed to play a decisive role in the pathogenesis of liver abscesses due to Klebsiella pneumoniae. Although some investigators consider MagA to be a putative O-antigen ligase, it is also reportedly associated with the K1 antigen. METHODS: Using magA-positive serotype K1 K. pneumoniae STL43 isolated from a patient with liver abscess, we constructed 3 bacterial mutants by targeting genes within the same transcription unit, including magA, wcaG, and rfbP. The virulence of these mutants was determined by neutrophil phagocytosis and inoculation of mice. Transmission electron microscopy and Western blot analysis were used to define their surface polysaccharides. RESULTS: STL43 was resistant, and all 3 mutants were highly susceptible, to phagocytosis. None of the mutant strains caused death in mice at the lethal dose of STL43. In contrast to previous reports, transmission electron microscopy revealed that all 3 mutants were nonencapsulated. Analysis of surface polysaccharides revealed that all 3 mutants retained their O antigen but lost their K antigen/capsule. Furthermore, amino acid analysis showed that MagA shared a conserved domain of Wzy, the serotype-specific capsular polysaccharide polymerase. CONCLUSIONS: In accordance with the bacterial polysaccharide gene nomenclature (BPGN) scheme, MagA should be renamed Wzy(KpK1), the capsular polymerase specific to K. pneumoniae serotype K1. PMID- 19785525 TI - Encapsulated Bacillus anthracis interacts closely with liver endothelium. AB - BACKGROUND: The Bacillus anthracis poly-gamma-D-glutamate capsule is essential for virulence. It impedes phagocytosis and protects bacilli from the immune system, thus promoting systemic dissemination. METHODS: To further define the virulence mechanisms brought into play by the capsule, we characterized the interactions between encapsulated nontoxinogenic B. anthracis and its host in vivo through histological analysis, perfusion, and competition experiments with purified capsule. RESULTS: Clearance of encapsulated bacilli from the blood was rapid (>90% clearance within 5 min), with 75% of the bacteria being trapped in the liver. Competition experiments with purified capsule polyglutamate inhibited this interaction. At the septicemic phase of cutaneous infection with spores, the encapsulated bacilli were trapped in the vascular spaces of the liver and interacted closely with the liver endothelium in the sinusoids and terminal and portal veins. They often grow as microcolonies containing capsular material shed by the bacteria. CONCLUSION: We show that, in addition to its inhibitory effect on the interaction with the immune system, the capsule surrounding B. anthracis plays an active role in mediating the trapping of the bacteria within the liver and may thus contribute to anthrax pathogenesis. Because other microorganisms produce polyglutamate, it may also represent a general mechanism of virulence or in vivo survival. PMID- 19785526 TI - Antibody levels and protection after hepatitis B vaccine: results of a 22-year follow-up study and response to a booster dose. AB - BACKGROUND: The duration of protection in children and adults (including health care workers) resulting from the hepatitis B vaccine primary series is unknown. METHODS: To determine the protection afforded by hepatitis B vaccine, Alaska Native persons who had received plasma-derived hepatitis B vaccine when they were >6 months of age were tested for antibody to hepatitis B surface antigen (anti HBs) 22 years later. Those with levels <10 mIU/mL received 1 dose of recombinant hepatitis B vaccine and were evaluated on the basis of anti-HBs measurements at 10-14 days, 30-60 days, and 1 year. RESULTS: Of 493 participants, 60% (298) had an anti-HBs level >or=10 mIU/mL. A booster dose was administered to 164 persons, and 77% responded with an anti-HBs level >or=10 mIU/mL at 10-14 days, reaching 81% by 60 days. Response to a booster dose was positively correlated with younger age, peak anti-HBs response after primary vaccination, and the presence of detectable anti-HBs before boosting. Considering persons with an anti-HBs level >or=10 mIU/mL at 22 years and those who responded to the booster dose, protection was demonstrated in 87% of the participants. No new acute or chronic hepatitis B virus infections were identified. CONCLUSIONS: The protection afforded by primary immunization with plasma-derived hepatitis B vaccine during childhood and adulthood lasts at least 22 years. Booster doses are not needed. PMID- 19785527 TI - Resistance to rotavirus infection in adult volunteers challenged with a virulent G1P1A[8] virus correlated with serum immunoglobulin G antibodies to homotypic viral proteins 7 and 4. AB - BACKGROUND: In a study performed in 1983, 18 adult volunteers received oral challenge with the virulent human rotavirus strain D (G1P1A[8],NSP4[B]). To identify correlates of resistance to rotavirus infection, we analyzed levels of serum immunoglobulin (Ig) A and IgG antibodies to various rotaviral antigens in 16 of the 18 volunteers. METHODS: We used immunocytochemical assays that involved a total of 16 different recombinant baculoviruses, with each baculovirus expressing one of the following major serotype/genotype rotavirus proteins for the serologic assays: (1) viral protein (VP) 4 with P1A[8], P1B[4], P2A[6], P3[9], or P4[10] specificity; (2) VP7 with G1-G4 or G9 specificity; and (3) nonstructural viral protein (NSP) 4 with genotype A, B, C, or D specificity. RESULTS: The prechallenge titers of IgG antibody to VP7 types G1, G3, G4, and G9; VP4 types P1A[8], P1B[4], P2A[6], and P4[10]; and NSP4 type [A] in the group of noninfected volunteers (n = 11) were significantly higher than those in the group of infected volunteers (n = 5; of these 5 volunteers, 4 were symptomatically infected). Moreover, logistic regression analysis showed that resistance to rotavirus infection most closely correlated with higher prechallenge titers of IgG antibody to homotypic VP7 (G1) and VP4 (P1A[8]). CONCLUSIONS: These results suggest that protection against rotavirus infection and disease is primarily VP7/VP4 homotypic and, to a lesser degree, heterotypic. PMID- 19785528 TI - Preoperative percutaneous stone surgery in patients receiving anticoagulant therapy. AB - Percutaneous nephrostolithotomy (PCNL) is an essential component in the management of large volume renal calculi. Either in combination with shockwave lithotripsy but especially as monotherapy, PCNL is recommended as the most effective treatment option for patients with staghorn calculi or large volume stone disease. Multiple tracts allow successful management of nearly every stone burden in a single surgical session. Furthermore, patients with anatomic variations (eg, horseshoe kidney) can be treated by PCNL successfully. Overall stone-free rates of above 78% are described. With the rising age of the overall patient population, another problem occurs. Increasing age frequently leads to an increase in comorbidities; for example, patients receiving anticoagulation may need treatment for stones, which can pose a dilemma. The aim of this review was to provide an overview of thrombotic risk, depending on the underlying disease, and to propose a clinical pathway on how to deal with this selected group of patients. PMID- 19785530 TI - A pilot trial of CFQ for treatment of fibromyalgia. PMID- 19785529 TI - Investigating the reliability of Japanese toyohari meridian therapy diagnosis. AB - BACKGROUND: Toyohari meridian therapy (TMT) is a Japanese system of acupuncture. Acupoint selection follows diagnosis of the primary and secondary patterns of disharmony (sho) and disturbances in the yang channels. Pulse diagnosis and abdominal palpation diagnosis are the two main diagnostic methods used. Little is known about the reliability of pulse, abdominal, and pattern diagnosis in TMT. This is important since diagnosis of the sho determines acupoint treatment. If diagnosis is unreliable, there can be less confidence that the patient will receive optimal treatment. OBJECTIVE: The objective of this study is to assess the level of agreement between two TMT practitioners on pulse diagnosis, abdominal diagnosis, and diagnosis of the primary and secondary sho. METHODS: An inter-rater reliability study was conducted. Two (2) TMT practitioners separately conducted a TMT examination and completed an assessment form, choosing from a range of possible responses relating to pulse characteristics, abdominal diagnosis, and diagnosis of primary sho and secondary sho. The kappa coefficient was used as a measure of inter-rater reliability of the outcome variables. RESULTS: Sixty-two (62) Australians (22 males, 40 females) aged 20-65 years participated (mean age 49.2 +/- 12.2 years). Level of agreement for pulse diagnosis was 57%, 61%, and 77% for pulse depth, speed, and strength, respectively. For abdominal diagnosis, the level of agreement for involvement of the Lung, Kidney, Spleen, and Liver abdominal regions was 58%, 53%, 35%, and 10%, respectively. The overall level of agreement on primary sho diagnosis was 48% and for secondary sho diagnosis, 44%. CONCLUSIONS: Overall, there was a reasonable level of agreement on basic pulse characteristics and on abdominal diagnosis for two of the abdominal regions. Level of agreement on primary and secondary sho diagnosis suggests room for improvement. Further studies are required in order to gain a greater understanding of the reliability of diagnosis in TMT. PMID- 19785531 TI - Algodystrophy treated with needle-free electroacupuncture and raw Chinese herbal decoction: a case report and review of literature. AB - BACKGROUND: Reflex sympathetic dystrophy (RSD) is a serious and potentially disabling condition and is a very complex syndrome, which consists of pain maintained by the sympathetic nervous system. There have been no data present demonstrating that this condition can be treated with electroacupuncture and Chinese herbal medicine effectively. OBJECTIVE: The objective of this study was to present a case treated by electroacupuncture and Chinese herbal decoction successfully. Patient data: A young Australian woman, who presented with the symptoms of severe swollen left foot, foot pain, swollen ankle and ankle pain, and lower-extremity RSDs, was the subject of the treatment. METHOD: A needle-free electroacupuncture method was applied to the affected meridian region. An individually designed Chinese herbal decoction was used for a coordinated approach. RESULTS: Noticeable progress occurred within 2 weeks of the treatment, and 1.5-2 months later, the patient could walk without crutches. A full recovery occurred after a further 2 weeks. OUTCOME MEASUREMENT: The outcome measurement was change in pain score and swollen status (severity of swollenness), as well as function restoration. CONCLUSIONS: There are no published articles showing the efficiency and safety of this needle-free acupuncture and herbal medicine treatment regimen. Therefore, an accumulation of similar clinical cases or further research is needed to evaluate this particular treatment method. PMID- 19785532 TI - Effects of ampicillin, gentamicin, and cefotaxime on the release of Shiga toxins from Shiga toxin-producing Escherichia coli isolated during a diarrhea episode in Faisalabad, Pakistan. AB - The Shiga toxin-producing Escherichia coli (STEC) is an emerging foodborne pathogen. The proportion of cases attributed to STEC in an episode of diarrhea in the Faisalabad region of Pakistan was investigated. In addition, as increase in Shiga toxin (Stx) release after exposure to various antimicrobial agents is widely reported, we also elucidated the in vitro effects of three commonly used antibiotics (ampicillin, gentamicin, and cefotaxime) on Stx release. Isolation and detection of STEC was done using enzyme-linked immunosorbent assay and polymerase chain reaction, followed by phenotypic characterization. In vitro Stx release from isolated STEC was determined using enzyme-linked immunosorbent assay, and Stx-induced verocytotoxicity was quantified using cytotoxicity detection assay. STEC was detected in 5 (21.7%) of 23 patients. Exposure to minimum inhibitory concentration (MIC) of ampicillin, gentamicin, and cefotaxime resulted in a considerable decrease in toxin release and level of cytotoxicity in most of the STEC isolates when compared with control (without antibiotic exposure). Exposure to sub-MIC of ampicillin resulted in a relative increase in Stx release and cytotoxicity (p or=2 mg/L) to ceftriaxone or ceftiofur; 49 (90.7%) contained the CMY-type beta lactamase (bla(CMY)) gene. The 49 bla(CMY)-positive human Heidelberg isolates demonstrated a high degree of relatedness; 4 clusters (25 isolates total) had indistinguishable XbaI and BlnI patterns by pulsed-field gel electrophoresis and were indistinguishable from 42 retail meat Heidelberg isolates. Further characterization of 15 of these isolates demonstrated that all of the bla genes were bla(CMY-2) and plasmid-encoded, and most (11/15) of the plasmids were approximately 100 kb in size and belong to the incompatibility group I1 (IncI1). All five IncI1 plasmids tested by plasmid multilocus sequence typing analysis were ST12. This report suggests that extended-spectrum cephalosporin resistance among human Heidelberg isolates is mediated by the spread of a common IncI1 bla(CMY-2) plasmid, which may have a preference for a particular genetic background. PMID- 19785534 TI - Characterization of the first extended-spectrum beta-lactamase-producing nontyphoidal Salmonella strains isolated in Tehran, Iran. AB - The infections caused by Salmonella remain a significant public health problem throughout the world. beta-Lactams and fluoroquinolones are generally used to treat invasive Salmonella infections, but emergence and spread of antibiotic resistant strains are being increasingly notified in many countries. In particular, detection of extended-spectrum beta-lactamases (ESBLs) in Salmonella spp. is a newly emerging threat worldwide. This study was carried out to characterize beta-lactamase-producing Salmonella strains identified in Tehran, Iran. Over the 2-year period from 2007 to 2008, 6 of 136 Salmonella isolates recovered from pediatrics patients, including three Salmonella enterica serotypes Enteritidis (S. Enteritidis) and three S. Infantis, showed an ESBL-positive phenotype. Polymerase chain reaction and sequencing were used to identify the genetic determinants responsible for ESBL phenotypes. The Salmonella isolates were also compared by pulsed-field gel electrophoresis. All ESBL-producing strains, but one, carried the bla(CTX-M-15) gene. Moreover, three of four strains that proved to be positive for a bla(TEM) gene were producing a TEM-1 beta lactamase. Two strains of S. Infantis tested positive for a previously unidentified CTX-M and TEM ESBL, respectively. All ESBL-producing strains carried the insertion sequence ISEcp1 gene. Except for one strain of serotype Infantis, all strains were able to transfer the ESBL determinants by conjugation. Distinct, but closely related, pulsed-field gel electrophoresis patterns were observed among the strains belonging to both serotypes. This study reports for the first time the emergence and characterization of ESBL-producing S. Enteritidis and Infantis strains in Iran. PMID- 19785535 TI - Multilaboratory validation study of standardized multiple-locus variable-number tandem repeat analysis protocol for shiga toxin-producing Escherichia coli O157: a novel approach to normalize fragment size data between capillary electrophoresis platforms. AB - The PulseNet USA subtyping network recently established a standardized protocol for multiple-locus variable-number tandem repeat analysis (MLVA) to characterize Shiga toxin-producing Escherichia coli O157. To enable data comparisons from different laboratories in the same database, reproducibility and high quality of the data must be ensured. The aim of this study was to test the robustness and reproducibility of the proposed standardized protocol by subjecting it to a multilaboratory validation process and to address any discrepancies that may have arisen from the study. A set of 50 strains was tested in 10 PulseNet participating laboratories that used capillary electrophoresis instruments from two manufacturers. Six out of the 10 laboratories were able to generate correct MLVA types for 46 (92%) or more strains. The discrepancies in MLVA type assignment were caused mainly by difficulties in optimizing polymerase chain reactions that were attributed to technical inexperience of the staff and suboptimal quality of reagents and instrumentation. It was concluded that proper training of staff must be an integral part of technology transfer. The interlaboratory reproducibility of fragment sizing was excellent when the same capillary electrophoresis platform was used. However, sizing discrepancies of up to six base pairs for the same fragment were detected between the two platforms. These discrepancies were attributed to different dye and polymer chemistries employed by the manufacturers. A novel software script was developed to assign alleles based on two platform-specific (Beckman Coulter CEQ8000 and Applied Biosystems Genetic Analyzer 3130xl) look-up tables containing fragment size ranges for all alleles. The new allele assignment method was validated at the PulseNet central laboratory using a diverse set of 502 Shiga toxin-producing Escherichia coli O157 isolates. The validation confirmed that the script reliably assigned the same allele for the same fragment regardless of the platform used to size the fragment. PMID- 19785536 TI - Outbreak caused by cad-negative Shiga toxin-producing Escherichia coli O111, Oklahoma. AB - An outbreak of severe diarrheal illness was recently reported in northeastern Oklahoma, and Shiga toxin-producing Escherichia coli serotype O111 was identified as the etiological agent. Our results indicated that this isolate is unable to decarboxylate lysine, a characteristic that is shared with other outbreak-linked O111 isolates. Therefore, further investigation is recommended to determine whether the lysine decarboxylase test could be used to identify a subset of pathogenic E. coli, particularly Shiga toxin-producing E. coli O111 isolates, that have the potential of causing human infections and outbreaks. PMID- 19785537 TI - Pasteurized milk: efficiency of pasteurization and its microbiological conditions in Brazil. AB - This study aimed to verify the pasteurization efficiency and the microbiological quality of milk sold in the city of Rio de Janeiro, Brazil. The microbial quality of pasteurized milk samples was assessed by sample testing for the presence of Salmonella spp., coliforms at 35 degrees C, coliforms at 45 degrees C, and mesophilic bacterial counts. In addition, the pasteurization efficiency was verified through tests of neutral phosphatase and peroxidase enzymes. Salmonella spp. were not detected in any (100%) of the analyzed samples. However, 85 (70.8%) and 69 (57.5%) of the samples were noncompliant with current legal standards for coliforms at 35 degrees C and 45 degrees C, respectively. As for the aerobic mesophilic bacteria, 48 (40.0%) of the samples were noncompliant. From the 120 samples of pasteurized milk studied, 100% were negative for neutral phosphatase, whereas 12 (10.0%) were negative for peroxidase. Logistic regression indicated the absence of relationship between present lactoperoxidase and all the microbiological parameters studied, which suggested that the quality of pasteurized milk was associated with factors related to steps before or after heat treatment. PMID- 19785538 TI - Survival of clinical and food isolates of Listeria monocytogenes through simulated gastrointestinal tract conditions. AB - Twenty-seven strains of Listeria monocytogenes previously isolated from food (n = 16) and human patients of listeriosis (n = 11) were characterized and compared based on their ability to survive through the simulated gastrointestinal tract conditions. Cells were exposed (60 or 120 min) to low pH in the presence of pepsin, to simulate the digestion in the stomach, and subsequently to bile salts to simulate the digestion in the small intestine (60 or 120 min). Their survival was shown to be origin- (food and clinical) and strain dependent (p < 0.001) and also significantly dependent on the imposed simulated gastric conditions (long vs. quick exposure) (p < 0.001). In comparison to the food isolates, the clinical strains were in general more resistant and survived better to the two challenges imposed. Some of the tested strains, after the exposure to low pH in the presence of pepsin, became injured and subsequently more susceptible to the bile salts challenge. It was demonstrated that one of the most important natural barriers against foodborne pathogens might not be effective since it was shown that L. monocytogenes isolates that survived through the pH challenge were also able to survive the subsequent challenge to bile salts. PMID- 19785539 TI - Potential for growth of Clostridium perfringens from spores in pork scrapple during cooling. AB - We conducted stabilization studies to determine the ability of Clostridium perfringens spores to germinate and grow during exponential cooling of a commercial formulation of pork scrapple. Scrapple was inoculated with a mixture of three strains of C. perfringens spores (NTCC 8238, NCTC 8239, and ATCC 10288), vacuum packaged, and reheated (20 min/93.3 degrees C) in a circulating water bath. The cooked samples were cooled (30 s) in an ice bath before being transferred to a programmable water bath to cool through the temperature range of 54.4 degrees C to 7.2 degrees C in 12, 14, or 21 h to simulate deviations from the required cooling time of 6.5 h. After cooling, the samples, in duplicate, were analyzed to determine if growth from spores had occurred. The samples were plated onto tryptose-sulfite-cycloserine agar and incubated anaerobically at 37 degrees C for 48 h before counting the colonies. Minimal growth (less than 1.0 log) was observed during a 12- or 14 h cooling period. However, when the time to achieve 7.2 degrees C was extended to 21 h, C. perfringens spores germinated and grew from an inoculum of approximately 3.0 log(10) to approximately 7.8 log(10) CFU/g. Thus, scrapple must be cooled after cooking to 7.2 degrees C within 6.5 h, but for no more than 14 h, to prevent a food safety hazard from outgrowth of C. perfringens spores during cooling. PMID- 19785540 TI - Correlation of mannitol fermentation with virulence-associated genotypic characteristics in Vibrio vulnificus isolates from oysters and water samples in the Gulf of Mexico. AB - Vibrio vulnificus strains (n = 469) isolated from the Gulf of Mexico oysters and waters over a period of 2 years were subjected to phenotypic and genotypic characterizations. Of the strains that could be definitively genotyped (n = 465), 58% were classified as genotype A, 29% as genotype B, and 13% as genotype A/B by 16S rRNA genotyping. When the same strain bank was characterized by virulence correlated gene (vcg) typing, 65% were genotype E while 35% were genotype C. Further analysis focusing on strains falling into typical genotype categories (i.e., 16S rRNA types A or B, excluding type A/B strains) showed a high degree of concordance (93%) when comparing the two genotyping methods. d-Mannitol fermentation was also predictive of genotype, with an 86% agreement between 16S rRNA genotype and mannitol fermentation patterns, and an 85% agreement between vcg genotype and mannitol fermentation patterns. d-Mannitol fermentation should be considered as a simple and less expensive alternative to screen V. vulnificus isolates for virulence potential, particularly when analyzing large strain banks. PMID- 19785541 TI - Contribution of the multidrug efflux transporter CmeABC to antibiotic resistance in different Campylobacter species. AB - CmeABC, a multidrug efflux system in Campylobacter jejuni, plays an important role in the resistance to different antimicrobials and toxic compounds. Although this efflux system has been well characterized in C. jejuni and to a less extent in C. coli, it is unknown if CmeABC homologs are functional in other Campylobacter spp. In this study, the cmeABC homologs were identified and functionally characterized in five Campylobacter species including C. jejuni, C. coli, C. lari, C. upsaliensis, and C. fetus. Our results indicated that cmeABC is present in all five Campylobacter spp. and the genomic organization of this efflux operon is similar among the Campylobacter spp. Insertional mutagenesis of cmeB increased the susceptibilities of all the five Campylobacter spp. to structurally diverse antimicrobials. Together, these results indicated that the CmeABC efflux system is conserved at both the genomic and functional levels in all five Campylobacter spp. examined in this study, further highlighting the significant role of CmeABC in Campylobacter pathobiology. PMID- 19785542 TI - Carbon turnover in tissues of a passerine bird: allometry, isotopic clocks, and phenotypic flexibility in organ size. AB - Stable isotopes are an important tool for physiological and behavioral ecologists, although their usefulness depends on a thorough understanding of the dynamics of isotope incorporation into tissue(s) over time. In contrast to hair, claws, and feathers, most animal tissues continuously incorporate carbon (and other elements), and so carbon isotope values may change over time, depending on resource use and tissue-specific metabolic rates. Here we report the carbon turnover rate for 12 tissues from a passerine bird, the zebra finch (Taeniopygia guttata). We measured average carbon retention time (tau) for 8 d for small intestine; 10-13 d for gizzard, kidney, liver, pancreas, and proventriculus; 17 21 d for heart, brain, blood, and flight muscle; and 26-28 d for leg muscle and skin. We used these data, along with the few other published estimates, to confirm that the fractional rate of isotopic turnover for red blood cells, whole blood, liver, and leg muscle scales with body mass to approximately the -1/4 power. Our data also support several key assumptions of the "isotopic-clock" model, which uses differences in isotope value between tissues, along with estimates of turnover rate of these tissues, to predict time elapsed since a diet shift. Finally, we show that between-tissues differences in turnover rate largely, but not entirely, explain the extent of phenotypic flexibility in organs of garden warblers during their long-distance flight across the Sahara Desert during spring. More studies that measure tissue-specific protein synthesis, metabolic rate, and elemental turnover in many tissues from a variety of animals are needed. PMID- 19785543 TI - Heat stress preconditioning improves cognitive outcome after diffuse axonal injury in rats. AB - This study investigates the influence of heat stress preconditioning on cognitive outcome for rats with diffuse axonal injury (DAI), and attempts to examine the underlying mechanisms. Wistar rats were divided into four groups: rats subjected to heat stress preconditioning 24 h before induction of DAI (n = 10; HSDAI group), a DAI alone group (n = 10), a heat stress alone group (n = 10), and a sham-injury group (n = 10). From day 14 post-injury, the rats' learning abilities and memory were tested using the Morris water maze (MWM) task, followed by long term potentiation (LTP) recording of the hippocampus. In addition, hematoxylin and eosin staining (H&E) and immunohistochemical staining (IHC) were conducted to determine the presence of brain lesions and expression of heat shock protein 70 (HSP70) at 24 h, and on days 14 and 20 post-injury. The rats in the DAI group displayed impaired MWM performance and attenuated LTP compared to the sham group (p < 0.05); the rats in the HSDAI and HS groups showed significant improvement in both MWM and LTP compared with the DAI group (p < 0.05), and no significant differences with the sham group (p > 0.05). Following injury, retraction balls, shrunken neurons, and HSP70 expression were visible in the brains of rats from the DAI and HSDAI groups; recovery was expedited in the rats belonging to the HSDAI group, as these pathological changes were alleviated, coincident with higher expression of HSP70. The rats' abilities for learning and memory were impaired following DAI; this may be due to the disconnection of brain regions, damage to neurons in the hippocampus, and a decrease in synaptic plasticity. Heat stress preconditioning is able to significantly attenuate this cognitive impairment, possibly mediated by the neuroprotective effect of HSP70. PMID- 19785544 TI - Promoting axonal myelination for improving neurological recovery in spinal cord injury. AB - Spinal cord injury (SCI) remains a major challenge to neurological research. Progress in both basic and clinical research has shown that neurons and oligodendrocytes are equally susceptible to such injury. In injuries secondary to direct injury to the spinal cord, oligodendrocytes appear to be highly vulnerable to various harmful factors and eventually undergo apoptosis. Due to the loss of myelinating cells, axonal demyelination is likely to affect the neural function of surviving axons. Recently, improved understanding of the pathological changes ongoing in oligodendrocytes following injury has shown that the death of these cells plays a vital role in the demyelination of axons. Because the demise of oligodendrocytes and subsequent axonal demyelination impair the conductive capacity of surviving axons, it seems reasonable to expect that reducing oligodendrocyte death and improving axonal myelination holds potential for the treatment of SCI. In the clinical setting, such therapy may help these patients, including those with complete functional injury and those with white matter preservation. Accordingly, it appears reasonable that improving axonal myelination and the conductive capacity of surviving axons will be of great benefit in patients with mild to moderate injury of the spinal cord. We here present a review of the pathophysiology and mechanisms of oligodendrocyte death and axonal demyelination that follow injury to the spinal cord, and discuss the potential for treating them. Because cell transplantation has recently become a promising strategy for replacing lost oligodendrocytes and improving axonal myelination in SCI, we also discuss the significance of cell transplantation as a novel approach to treating SCI. PMID- 19785547 TI - Preoperative planning and designing of a fluorocompatible endourology operating room. AB - BACKGROUND AND PURPOSE: A dedicated fluoroscopic-compatible operating room (OR) for endourologic procedures, such as percutaneous nephrolithotomy and ureteroscopy, is structurally and functionally different from the general OR. Publications with practical details are scarce, imposing a challenge in construction of such an OR. We outline a practical approach for the design and construction of a modern flourocompatible endourology OR. METHODS: There were no publications related to a dedicated endourology OR in Medline. A search was then performed for English language articles on OR designing, fluoroscopy in the OR, data archiving, and data relay. We also surveyed the existing endourology OR in different hospitals and analyzed the available technology for audiovisual capture and relay in surgery. This article was then prepared, covering the relevant areas on designing a dedicated flourocompatible endourology OR. RESULTS: Close cooperation and interaction between an architect and expert construction manager for designing, development, and construction of an OR are necessary. Strategic equipment placement with booms is essential to increase the efficiency and safety within the surgical space. Distinct features of an endourology OR are thickness of the walls for radiation protection, wide OR gate, central floor water exit drain, flourocompatible rotatable OR table, C-arm unit, minimum three hanging thin-film transistor (TFT) screen monitors, and endoscopic equipment supported on a boom. The anesthetic boom should be retractable and movable from one end of the OR table to other. The OR should have an electronic workstation strategically located at one corner for data capture, archiving, and telementoring. Data relay of the OR procedure is facilitated by a control room located in the vicinity of the OR. CONCLUSION: Designing the layout of the OR is extremely important, necessitating thoughtful planning to provide hassle-free movement, comfort to the surgeon, and efficient data archiving and transmission during a surgical workshop. PMID- 19785548 TI - Preoperative antibiotics before endourologic surgery: current recommendations. AB - The use of antibiotic prophylaxis is an accepted and widely practiced feature of modern surgery. The prevention and control of infection is a priority in healthcare worldwide, and the emergence of antibiotic resistance is a global phenomenon. Hence, rational use of antibiotics is essential. We discuss the guidelines published with regard to endourologic procedures and review the limited evidence currently available. There should be subclassification of endourologic procedures based on infection risk to guide sensible use of antibiotics before surgery. PMID- 19785549 TI - Fluoroscopy-guided percutaneous renal access. AB - Percutaneous renal surgery is dependent upon appropriate access to the targeted portion of the collecting system. Obtaining a well-positioned nephrostomy tract improves the urologist's ability to both obtain the desired surgical outcome and minimize attendant morbidities. The two primary methods of obtaining fluoroscopic guided percutaneous renal access-"bull's eye" targeting and triangulation-are reviewed. The authors' preferred techniques are outlined, technical refinements are noted, and recent modifications and future directions are reviewed. PMID- 19785550 TI - Upper-pole access for percutaneous nephrolithotomy. AB - Although the supracostal approach is thought to increase the difficulties and patient morbidity of PCNL, it facilitates the management of certain urinary infirmities, such as UPJ obstruction, staghorn stone, upper pole stone, proximal ureteral abnormalities, impacted UPJ stone and upper calix diverticulum. Hereby the authors briefly comment on the technical aspects of the supracostal approach, and also discuss the possible complications of this technique and how to avoid them. PMID- 19785551 TI - Endoscopy-guided percutaneous nephrostolithotomy: benefits of ureteroscopic access and therapy. PMID- 19785552 TI - Ultrasonic, pneumatic and combination intracorporeal lithotripsy for percutaneous nephrolithotomy. AB - INTRODUCTION: Refinements in ultrasonic and pneumatic lithotriptors, as well as the development of new dual-modality lithotriptors, have increased the options available for the endourologist. Studies comparing the efficiency of the devices in both bench and clinical models help provide the endourologist with guidance in selecting the most appropriate lithotrite. METHODS: A review of the literature was performed reviewing the current status of pneumatic, ultrasonic, and dual modality lithotriptors. RESULTS: Performance characteristics of currently available lithotriptors differ. Dual-modality lithotriptors offer superior efficiency compared to separate ultrasonic and pneumatic lithotriptors but durability may be a concern with some models. CONCLUSIONS: Ultrasonic and pneumatic devices are the lithotriptors of choice for PCNL. Dual-modality lithotriptors have been shown to be the most efficient in both bench and limited clinical trials. PMID- 19785553 TI - Laparoscopic techniques for removal of renal and ureteral calculi. AB - BACKGROUND AND PURPOSE: Although most ureteral and renal stones are managed using endourologic techniques or shockwave lithotripsy in daily clinical practice, stone surgery has not completely disappeared. The increasing experience with laparoscopy in urology poses the question of whether urolithiasis may be an indication for laparoscopy. MATERIALS AND METHODS: A review of the literature was conducted to point out the indications and techniques of laparoscopic stone surgery. RESULTS: Indications for stone surgery are anatomic abnormalities, such as horseshoe kidneys, malrotated kidneys, or ectopic kidneys; symptomatic stones in diverticula of the renal pelvis; and extremely large stones, especially in children; or concomitant open or laparoscopic surgery. After failure of endourologic stone removal or shockwave lithotripsy, stone surgery may be a second option. In experienced hands, most procedures can be performed laparoscopically, either using a retroperitoneal or a transperitoneal approach. Accurate planning and imaging before surgery is mandatory. Intracorporeal ultrasonography or combined laparoscopic and endourologic techniques may be useful in difficult cases. Functional outcomes and complication rates of the laparoscopic approach are comparable to those of open surgery. The benefits of laparoscopy are lower postoperative morbidity, shorter hospitalization, shorter convalescence time, and better cosmetic results. CONCLUSIONS: Laparoscopic removal of renal and ureteral calculi plays a role in special cases of urolithiasis. In experienced hands, it can be performed safely and efficiently and may therefore replace open stone surgery in most indications. PMID- 19785554 TI - Current role of robot-assisted pyelolithotomy for the management of large renal calculi: a contemporary analysis. AB - BACKGROUND AND PURPOSE: The scope of robot-assisted surgery continues to expand with the application of these systems to management of large upper-tract urinary stones, with or without concomitant pyeloplasty. The known advantages of the robot-assisted approach, including enhanced optics, dexterity, wristed instrumentation, and ergonomics, can facilitate complex reconstruction of the collecting system, including uteropelvic junction repair. With the favorable outcomes of contemporary robot-assisted pyeloplasty series, robot-assisted applications have been translated to pyelolithotomy with or without concomitant upper-tract reconstruction. The early results of robot-assisted lithotomy reveal the procedure is a safe and efficacious approach for patients with large renal stones; nevertheless, the technique has met limited success in cases of large staghorn calculi. Our purpose was to evaluate the current role of robot-assisted pyelolithotomy for the management of large renal calculi. CONCLUSION: Given the known advantages of the robotic system in conjunction with its reconstructive capabilities, the applications of robot-assisted pyelolithotomy, although encouraging, warrant further longitudinal, multi-institutional investigation. This technique is in its early stage of implementation and randomized trials that compare robot-assisted outcomes with other minimally invasive techniques are needed to define clinical efficacy as it pertains to subsets of patients with variable stone size, location, and consistency. PMID- 19785555 TI - Laparoscopic management of caliceal diverticulum. AB - INTRODUCTION: Minimally invasive approaches for the treatment of symptomatic caliceal diverticula have become the standard of care. Laparoscopy has been embraced by many urologists and now accounts for many commonly performed approaches to urologic surgery. The laparoscopic approach to treating symptomatic caliceal diverticula adds yet another tool in the urologist's armamentarium for this pathologic entity. MATERIAL AND METHODS: Laparoscopy for symptomatic caliceal diverticula can be performed on both anteriorly and posteriorly located lesions using either an intraperitoneal or extraperitoneal approach. The goals of the laparoscopic approach are similar to that of percutaneous surgery; the overlying capsule and parenchyma are excised, stones, if present are removed, and the cavity marsupialized. RESULTS: The success rate for laparoscopically treated symptomatic caliceal diverticula is good with greater than 90 percent rates of cavity obliteration and stone removal and an approximately 75 percent rate of symptom resolution. CONCLUSIONS: Minimally invasive approaches to urologic disease continue to advance. The laparoscopic approach to treating symptomatic caliceal diverticula provides yet another reliable method for treating this problem and should be considered by urologists versed in laparoscopic technique. PMID- 19785556 TI - The use of adjunctive hemostatic agents for tubeless percutaneous nephrolithotomy. AB - Tubeless percutaneous nephrolithotomy (PCNL) is a viable option for selected patients, particularly those with solitary calculi, multiple stones located in a single location, or those that can be accessed using one access tract. Benefits over the standard PCNL include reduced hospital stay, decreased pain, and decreased urine leak from the access site that would typically occur from around the nephrostomy tube. Hemostatic agents in the form of fibrin "glue" or gelatin matrix substances have been demonstrated to be safe and effective to augment the tubeless procedure. The most appropriate sealant agent available is yet to be determined. We present a review of the contemporary literature on the use of hemostatic agents for tubeless PCNL. PMID- 19785557 TI - Skin treatment and tract closure for tubeless percutaneous nephrolithotomy: University of California, Irvine, technique. AB - BACKGROUND AND PURPOSE: After percutaneous nephrolithotomy (PCNL), a nephrostomy tube has been routinely placed to ensure hemostasis, provide drainage, and maintain access to the collecting system should a second-look procedure be necessary. Recently, efforts have been expended to either reduce the size of the nephrostomy tube or eliminate it altogether. We describe the tubeless technique of closure and skin treatment after PCNL using FloSeal as a sealant for tubeless PCNL. TECHNIQUE: A 7F 11.5-mm occlusion balloon catheter is passed retrograde over the through-and-through guidewire. Next, under endoscopic guidance, with a rigid or flexible nephroscope, the 30F Amplatz sheath is pulled back to the torn edge of the calix through which the nephrostomy tract enters the kidney. Under endoscopic guidance, the balloon is inflated at the torn edge. Next, the long metal laparoscopic FloSeal applicator is passed through the 30F sheath until it encounters resistance from the occlusion balloon catheter. FloSeal is injected down the sheath as the sheath is slowly withdrawn simultaneously with the FloSeal applicator until both have cleared the nephrostomy incision. The through-and through guidewire is pulled per the urethra under fluoroscopic control until its tip is in the renal pelvis. A 7F double pigtail stent is passed retrograde over the through-and-through guidewire. A bladder catheter is placed. A running subcuticular suture of 4-0 poliglecaprone is placed, and cyanoacrylate adhesive is used to close the skin. No dressing is applied. CONCLUSION: For patients who have been rendered completely stone free during uncomplicated PCNL, administration of hemostatic gelatin matrix to the nephrostomy tract may achieve immediate hemostasis and eliminate the need for placement of a nephrostomy tube. Although there have not been any clinical reports of urinary obstruction caused by the application of hemostatic sealants in the PCNL tract, we recommend using an occlusion balloon and subsequent placement of an indwelling ureteral stent to ensure maximum safety. PMID- 19785559 TI - A platform for global endourological research. PMID- 19785558 TI - Management of pleural injury after percutaneous renal surgery. AB - Abstract Pleural injury is a potential complication of supracostal access for percutaneous renal surgery. Vigilant observation by the surgeon for timely identification and prompt treatment of an injury goes a long way toward saving the patient from serious long-term thoracic morbidity. PMID- 19785560 TI - Enterobius vermicularis infection with tuboovarian abscess and peritonitis occurring during pregnancy. AB - BACKGROUND: Extraintestinal Enterobius vermicularis infections are rare but may occasionally affect the female genital tract. Although mostly asymptomatic or causing minor clinical problems, they may lead to severe infectious complications. METHODS: Case report and review of the pertinent English language literature. RESULTS: A 31-year-old, 30-week-pregnant female was admitted with a clinical suspicion of appendicitis. At surgery, the appendix appeared normal, but generalized peritonitis of unclear origin was present. Eggs of Enterobius vermicularis were found upon microbiological and pathological examination. Because of persisting infectious disease, the patient underwent an elective caesarean section, and at that time the diagnosis of a right tuboovarian abscess was made, and salpingo-oophorectomy was performed. The pathology report confirmed the diagnosis of an E. vermicularis salpingo-oophoritis. CONCLUSION: This case was extraordinary because of a combination of tuboovarian abscess and generalized peritonitis with E. vermicularis infection occurring during late pregnancy. Ectopic enterobiasis should be considered in the differential diagnosis of pelvic infections of gynecological origin. PMID- 19785561 TI - Changes in pulmonary cytokines during antibiotic therapy for ventilator associated pneumonia. AB - BACKGROUND: A major unanswered question in ventilator-associated pneumonia (VAP) management relates to patient response to therapy. We investigated the use of pulmonary cytokines as biomarkers for response to antibiotic therapy for VAP. METHODS: Prospective, observational pilot study of 12 critically ill trauma patients with VAP using a bronchoscopic bronchoalveolar lavage (BAL) (> or =100,000 colony-forming units [cfu]/mL). All patients underwent repeat BAL after three days of adequate antibiotic therapy. Changes in pulmonary effluent interleukin (IL)-8 and tumor necrosis factor (TNF)-alpha concentrations measured on diagnostic and repeat BAL were evaluated on the basis of the presence of a microbiologic response (<10,000 cfu/mL on repeat BAL). RESULTS: Six post-therapy BAL samples showed a microbiologic response. In responders, IL-8 and TNF-alpha concentrations decreased significantly (1,303 +/- 1,150 ng/mL in diagnostic BAL sample vs. 309 +/- 448 ng/mL after response; p = 0.08 and 9.9 +/- 18.4 ng/mL in diagnostic vs. 0.1 +/- 0.1 ng/mL in post-treatment sample; p = 0.06, respectively). In non-responders, IL-8 (449 +/- 426 ng/mL vs. 326 +/- 319 ng/mL; p = 0.59) and TNF-alpha (1.2 +/- 1.9 ng/mL vs. 0.3 +/- 0.3 ng/mL; p = 0.31) did not change significantly. Clinical response measures did not change or increased in responders, whereas these parameters did not change or decreased paradoxically in non-responders. CONCLUSION: This pilot study indicates pulmonary concentrations of IL-8 and TNF-alpha decrease in microbiologic responders with VAP. Conversely, clinical response parameters were discordant with the microbiologic response. The utility of pulmonary cytokine behavior in evaluating the effectiveness of antibiotic therapy for VAP should be studied further. PMID- 19785562 TI - Inadequate antibiotic therapy in solid organ transplant recipients is associated with a higher mortality rate. AB - BACKGROUND: Inadequate antibiotic therapy and failure to administer antibiotics in a timely fashion have been associated with substantial mortality rates in patients in the intensive care unit (ICU). We analyzed the infection pattern in solid organ transplant recipients as well as the impact of antibiotic resistance and inadequate antibiotic treatment on mortality rates and morbidity outcomes. METHODS: Charts of adult solid organ transplant recipients in 2006 from a single institution were reviewed. Data on patients with bacterial and fungal infections acquired within one year after transplantation were compared with the primary outcome of death within 28 days. Statistical analysis included nonparametric tests (Wilcoxon rank sum, Fisher exact, and chi-square) and multivariable logistic regression with p < 0.05 considered significant. RESULTS: Of the 366 patients, 114 (31%) had a total of 208 bacterial or fungal infections, and 44 of them (39%) were admitted to the ICU. Our primary endpoint, the 28-day mortality rate, was 8% overall, whereas the six-month mortality rate was 11%. Patients treated inadequately with antibiotics had a significantly higher mortality rate. The leading causes of infection were multiple organisms, coagulase-negative Staphylococcus, and E. coli, of which 76% were resistant to antibiotics. Antibiotic-resistant infections were associated with longer hospital stays (p = 0.04), intravenous antibiotic use prior to infection (p = 0.04), nucleotide synthesis inhibitor use (p = 0.02), ICU admission (p < 0.01), and respiratory failure (p = 0.03). Most infections were treated inadequately initially (69%) but treated adequately at 24 h (56%). Inadequate antibiotic treatment was significantly associated with younger age (p = 0.04), prior intravenous antibiotic use (p = 0.04), longer stay prior to infection (p = 0.05), and cardiovascular shock (p = 0.014). Inadequate antibiotic therapy at 24 h was associated with a higher mortality rate (14% vs. 2%; p = 0.03) and a trend toward longer ICU and in-hospital stays. CONCLUSIONS: Most bacterial and fungal infections were resistant to antibiotics and were treated inadequately initially. Prior intravenous antibiotic use and longer stay prior to infection were associated with antibiotic resistance and inadequate antibiotic therapy. Failure to provide adequate antibiotic treatment within 24 h had a significant impact on the 28-day mortality rate and was associated with other detrimental clinical outcomes. PMID- 19785564 TI - Human papillomavirus vaccine uptake, predictors of vaccination, and self-reported barriers to vaccination. AB - OBJECTIVE: To describe human papillomavirus (HPV) vaccine uptake, predictors of vaccination, and barriers to vaccination in young women. METHODS: Participants were 13-26-year-old girls and women recruited from an urban, hospital-based clinic. Between June and December 2007, 6 months after they had completed a baseline survey, they were recontacted to assess receipt of at least one HPV vaccine dose and barriers to receiving the vaccine. We assessed whether demographic factors, gynecological history, and attitudes measured at baseline were associated with vaccination at follow-up using logistic regression. RESULTS: Of the 262 women who completed the baseline study, 189 (72%) participated in this follow-up study. At follow-up, 68 of 189 (36%) had received >or=1 HPV vaccine dose. Factors measured at baseline that predicted vaccination 6 months later included insurance coverage for HPV vaccination (odds ratio [OR] 5.31, 95% confidence interval [CI] 1.61-17.49) and the belief that one's parents, partners, and clinicians endorsed HPV vaccination (OR 2.21, 95% CI 1.29-3.79); those with a history of an abnormal Pap test were less likely to have received the vaccine (OR 0.30, CI 0.10-0.92). Of the 121 who were unvaccinated, 54 (45%) had not returned to the clinic since the baseline study, 51 (42%) had returned but were not offered vaccine, and 15 (12%) had declined vaccination. CONCLUSIONS: Interventions to increase HPV vaccination rates in women in the catch-up age group for vaccination should ensure that vaccine costs are covered, promote HPV vaccination as normative, and establish clinic-based systems to prevent missed opportunities for vaccination. PMID- 19785566 TI - The effect of water-based exercise on glucose and insulin response in overweight women: a pilot study. AB - OBJECTIVE: The aim of this study was to investigate the effectiveness of a 12 week moderate intensity, water-based circuit-type training intervention on glucose and insulin responses in overweight women with normal or impaired glucose tolerance. METHODS: Fifteen overweight women (body mass index [BMI] > 25 kg/m(2)) with normal glucose tolerance (NGT; n = 7) or impaired glucose tolerance (IGT; n = 8) were recruited for this study. All women completed a 12-week training intervention utilizing a combination of aerobic and resistance exercises in an aquatic environment, 3 days per week and 60 min per session at 70-75% mode specific maximum heart rate. A standard 75-g oral glucose tolerance test (OGTT) was administered pre- and post-intervention, from which fasting and post-load plasma insulin and glucose levels were assessed. RESULTS: Following the 12-week period, fasting insulin levels had decreased by 44% and 2-h glucose by 30.4% in the group with IGT. Waist circumference (WC) had decreased by 5.3% in this group at the end of the intervention. Only WC and waist-to-hip ratio (WHR) decreased (6.0% and 5.5%, respectively) following the intervention in the NGT group. CONCLUSIONS: Moderate intensity, water-based circuit-type exercises appear to be an effective exercise modality to improve glucose and insulin response to a glucose challenge in overweight women with IGT. PMID- 19785565 TI - Hypertension during pregnancy is associated with coronary artery calcium independent of renal function. AB - BACKGROUND: Hypertension during pregnancy (HDP) increases the risk of future coronary heart disease (CHD), but it is unknown whether this association is mediated by renal injury. Reduced renal function is both a complication of HDP and a risk factor for CHD. METHODS: Logistic regression models were fit to examine the association between a history of HDP and the presence and extent of coronary artery calcification (CAC), a measure of subclinical coronary artery atherosclerosis, in 498 women from the Epidemiology of Coronary Artery Calcification Study (mean age 63.3 +/- 9.3 years). RESULTS: Fifty-two (10.4%) women reported a history of HDP. After adjusting for age at time of study participation, HDP was associated with increased serum creatinine later in life (p = 0.014). HDP was positively associated with the presence of CAC after adjusting for age at time of study participation (OR = 2.7, 95% CI 1.4-5.4). This association was slightly attenuated with adjustment for body size and blood pressure (OR = 2.4, 95% CI 1.2-4.9) but was not further attenuated with adjustment for serum creatinine and urinary albumin/creatinine ratio (OR = 2.6, 95% CI 1.3-5.3). Results were similar for CAC extent. CONCLUSIONS: HDP may increase a woman's risk of future CHD beyond traditional risk factors and renal function. Women with a history of HDP should be monitored for potential increased risk of CHD as they age. PMID- 19785567 TI - Disparities in physicians' interpretations of heart disease symptoms by patient gender: results of a video vignette factorial experiment. AB - BACKGROUND: Previous studies have documented the underdiagnosis of coronary heart disease (CHD) in women, but less is known about which alternate diagnoses take precedence and whether additional patient factors modify possible gender bias. OBJECTIVE: To measure gender variation in clinical decision making, including (1) the number, types, and certainty levels of diagnoses considered and (2) how diagnoses vary according to patient characteristics, when patients have identical symptoms of CHD. METHODS: This was a factorial experiment presenting videotaped CHD symptoms, systematically altering patient gender, age, socioeconomic status (SES) and race, and physician gender and level of experience. The primary end point was physicians' most certain diagnosis. RESULTS: Physicians (n = 128) mentioned five diagnoses on average, most commonly heart, gastrointestinal, and mental health conditions. Physicians were significantly less certain of the underlying cause of symptoms among female patients regardless of age (p = 0.006), but only among middle-aged women were they significantly less certain of the CHD diagnosis (p < 0.001). Among middle-aged women, 31.3% received a mental health condition as the most certain diagnosis, compared with 15.6% of their male counterparts (p = 0.03). An interaction effect showed that females with high SES were most likely to receive a mental health diagnosis as the most certain (p = 0.006). CONCLUSIONS: Middle-aged female patients were diagnosed with the least confidence, whether for CHD or non-CHD conditions, indicating that their gender and age combination misled physicians, particularly toward mental health alternative diagnoses. Physicians should be aware of the potential for psychological symptoms to erroneously take a central role in the diagnosis of younger women. PMID- 19785568 TI - Comparison of pitavastatin with simvastatin in primary hypercholesterolaemia or combined dyslipidaemia. AB - OBJECTIVES: The primary objective of this study was to demonstrate equivalence of pitavastatin compared with simvastatin in the reduction of low-density lipoprotein cholesterol (LDL-C) levels in patients with primary hypercholesterolaemia or combined dyslipidaemia. Secondary objectives included achievement of National Cholesterol Education Program Adult Treatment Panel (NECP) and European Atherosclerosis Society (EAS) LDL-C goals, comparison of other lipid parameters, and assessment of safety and tolerability of the two statins. RESEARCH DESIGN AND METHODS: A prospective, randomised, active controlled double-blind, double-dummy, 12-week therapy trial was conducted in 857 patients with either primary hypercholesterolaemia or combined dyslipidaemia. The trial was designed to demonstrate the equivalence (non-inferiority of presumed equipotent doses) of pitavastatin compared with simvastatin. Patients were randomised to one of four groups: pitavastatin 2 mg/day, pitavastatin 4 mg/day, simvastatin 20 mg/day or simvastatin 40 mg/day. The main study limitation was restriction of the study population to those eligible for administration of simvastatin. TRIAL REGISTRATION: This clinical trial has been registered at www.clinicaltrials.gov NCT# NCT00309777. RESULTS: Pitavastatin 2 mg showed significantly better reductions of LDL-C (p = 0.014), non-high-density lipoprotein cholesterol (non-HDL-C) (p = 0.021) and total cholesterol (TC) (p = 0.041) compared with simvastatin 20 mg and led to more patients achieving the EAS LDL-C treatment target. Reduction of LDL-C in the pitavastatin 2 mg group was 39% compared with 35% in the simvastatin 20 mg group. Pitavastatin 4 mg showed similar effects on all lipid parameters to simvastatin 40 mg. The reductions in LDL-C were 44% and 43%, respectively. The safety profiles of pitavastatin and simvastatin were similar at the two dose levels. Pitavastatin was considered superior to simvastatin in terms of percent reduction of LDL-C in the lower dose group comparison and proved to be equivalent to simvastatin in percent reduction of LDL-C in the higher-dose group. CONCLUSION: As compared with simvastatin, an established first-line lipid-lowering agent, pitavastatin is an efficacious treatment choice in patients with primary hypercholesterolaemia or combined dyslipidaemia. PMID- 19785569 TI - Carlecortemcel-l: an ex vivo expanded umbilical cord blood cell graft for allogeneic transplantation. AB - BACKGROUND: Success of umbilical cord blood transplantation (UCBT) is mostly affected by the cell dose infused and its application is limited by the size of the recipient. For most adults and older children it is not possible to find a single UCB unit large enough for reliable engraftment. One strategy to increase the number of progenitor cells available is ex vivo expansion of the unit. The main challenge of ex vivo expansion systems is how not to deplete the self renewing cell population by driving them into differentiation into committed progenitors. OBJECTIVE: Copper modulates basic cell functions, such as survival, proliferation, and differentiation. Reduction of cellular copper in ex vivo culture conditions enabled preferential proliferation of early progenitors and increased engraftment capabilities. The result of a Phase I study of carlecortemcel-l, a product derived from ex vivo expansion of UCB progenitors in the presence of a copper chelator and early-acting cytokines, and the study design for the current pivotal study are presented. METHODS: A literature review using PubMed and the investigator's brochure from the manufacturer. CONCLUSIONS: Early results suggest that carlecortemcel-l infusion is safe and may be associated with favorable non-relapse mortality rates. A pivotal global study is currently being conducted to evaluate safety and efficacy of this product from centralized manufacturing facilities. PMID- 19785570 TI - Association between provision of initial family planning services and unintended pregnancy among women attending an STD clinic. AB - BACKGROUND: Most sexually transmitted disease (STD) clinics focus solely on STD treatment and prevention. However, women seeking care are also at high risk for unintended pregnancy. We sought to examine the relationship between baseline demographic and clinical characteristics and incident pregnancy among women provided initial contraceptive services in an STD clinic. METHODS: Computerized record review of women attending an STD clinic who initiated contraception, were seen at least twice within a 4-year period (repeat attendees), and indicated no intention of pregnancy were included in these analyses. Associations between baseline demographic, behavioral, and clinical characteristics and incident pregnancy were assessed using multivariate logistic regression. RESULTS: Among 4617 women seen from 2003 to 2006, 710 (15%) were repeat attendees and 3907 (85%) were single attendees (seen only during a single year). Among the repeat attendees, 642 (90%) indicated no interest in pregnancy, of whom 124 (19%) had a subsequent pregnancy. Using multivariate analysis and controlling for age and race/ethnicity, incident pregnancy was associated with previous pregnancy (OR 2.57, 95% CI 1.63-4.04), or=18 years of age in the provinces of Nova Scotia, Quebec, Saskatchewan, Alberta, and British Columbia, who participated in the Canadian Community Health Survey conducted in 2005. The survey included a set of 27 questions about symptoms of depression, which were taken from the Composite International Diagnostic Interview. Based on these questions, depression scores were calculated and used to define depression, which corresponds to a 90% likelihood of a positive diagnosis of major depressive episode. Body weight and height were based on self-report. RESULTS: The prevalence of depression was 5.3% in adults living in the five provinces and was higher in women than in men. People with abnormal body weight tended to have an increased risk of depression. On average, obesity and being underweight were associated with approximately 30% and 40% increases in depression, respectively. Particularly in women, depression was more markedly associated with obesity in the 18-39 year age group (OR 1.67, 95% CI 1.29-2.15) and with being underweight in the 40-59 year age group (OR 2.23, 95% CI 1.45 3.42) than other age groups. CONCLUSIONS: Obesity is associated with an increased risk of depression in younger women. PMID- 19785573 TI - Sex differences in mortality among older frail Mexican Americans. AB - OBJECTIVE: To examine the association between frailty and 10-year mortality among older men and women of Mexican American origin. METHODS: Data were collected from 1995-1996 through 2004-2005 among community-dwelling Mexican Americans aged >or=65 years as part of the Hispanic Established Population for the Epidemiologic Study of the Elderly (HEPESE). A standardized frailty measure based on weight loss, exhaustion, grip strength, walking speed, and physical activity was computed. Data were collected on sociodemographics and health characteristics, comorbidities, and performance-based functional measure. RESULTS: The sample was 59% female, and mean baseline age was 74.5 years of (SD 6.06) at baseline. Hazard ratios (HR) indicated an increased mortality risk in frail men (HR = 3.04, 95% CI 2.16-4.28) compared with frail women (HR = 1.92, 95% CI 1.39-2.65). CONCLUSIONS: Frailty is an independent predictor of mortality among older men and women of Mexican American origin. This association was found to be stronger among men after adjusting for age, marital status, education, body mass index (BMI), health behaviors, and medical conditions. PMID- 19785574 TI - Threonine at position 306 of the KAT1 potassium channel is essential for channel activity and is a target site for ABA-activated SnRK2/OST1/SnRK2.6 protein kinase. AB - The Arabidopsis thaliana K+ channel KAT1 has been suggested to have a key role in mediating the aperture of stomata pores on the surface of plant leaves. Although the activity of KAT1 is thought to be regulated by phosphorylation, the endogenous pathway and the primary target site for this modification remained unknown. In the present study, we have demonstrated that the C-terminal region of KAT1 acts as a phosphorylation target for the Arabidopsis calcium-independent ABA (abscisic acid)-activated protein kinase SnRK2.6 (Snf1-related protein kinase 2.6). This was confirmed by LC-MS/MS (liquid chromatography tandem MS) analysis, which showed that Thr306 and Thr308 of KAT1 were modified by phosphorylation. The role of these specific residues was examined by single point mutations and measurement of KAT1 channel activities in Xenopus oocyte and yeast systems. Modification of Thr308 had minimal effect on KAT1 activity. On the other hand, modification of Thr306 reduced the K+ transport uptake activity of KAT1 in both systems, indicating that Thr306 is responsible for the functional regulation of KAT1. These results suggest that negative regulation of KAT1 activity, required for stomatal closure, probably occurs by phosphorylation of KAT1 Thr306 by the stress-activated endogenous SnRK2.6 protein kinase. PMID- 19785575 TI - Structural and functional analysis of the intrinsic inhibitor subunit epsilon of F1-ATPase from photosynthetic organisms. AB - The epsilon subunit, a small subunit located in the F1 domain of ATP synthase and comprising two distinct domains, an N-terminal beta-sandwich structure and a C terminal alpha-helical region, serves as an intrinsic inhibitor of ATP hydrolysis activity. This inhibitory function is especially important in photosynthetic organisms as the enzyme cannot synthesize ATP in the dark, but may catalyse futile ATP hydrolysis reactions. To understand the structure-function relationship of this subunit in F1 from photosynthetic organisms, we solved the NMR structure of the epsilon subunit of ATP synthase obtained from the thermophilic cyanobacterium Thermosynechococcus elongatus BP-1, and examined the flexibility of the C-terminal domains using molecular dynamics simulations. In addition, we revealed the significance of the C-terminal alpha-helical region of the epsilon subunit in determining the binding affinity to the complex based on the assessment of the inhibition of ATPase activity by the cyanobacterial epsilon subunit and the chimaeric subunits composed of the N-terminal domain from the cyanobacterium and the C-terminal domain from spinach. The differences observed in the structural and biochemical properties of chloroplast and bacterial epsilon subunits explains the distinctive characteristics of the epsilon subunits in the ATPase complex of the photosynthetic organism. PMID- 19785576 TI - Are there enough doctors in my rural community? Perceptions of the local physician supply. AB - PURPOSE: To assess whether people in the rural Southeast perceive that there is an adequate number of physicians in their communities, assess how these perceptions relate to county physician-to-population (PtP) ratios, and identify other factors associated with the perception that there are enough local physicians. METHODS: Adults (n = 4,879) from 150 rural counties in eight southeastern states responded through a telephone survey. Agreement or disagreement with the statement "I feel there are enough doctors in my community" constituted the principal outcome. Weighted chi-square analysis and a generalized estimating equation (GEE) assessed the strength of association between perceptions of an adequate physician workforce and county PtP ratios, individual characteristics, attitudes about and experiences with medical care, and other county characteristics. FINDINGS: Forty-nine percent of respondents agreed there were enough doctors in their communities, 46% did not agree, and 5% were undecided. Respondents of counties with higher PtP ratios were only somewhat more likely to agree that there were enough local doctors (Pearson's correlation coefficient = 0.09, P < .001). Multivariate analyses revealed that perceiving that there were enough local physicians was more common among men, those 65 and older, whites, and those with lower regard for physician care. Perceptions that the local physician supply was inadequate were more common for those who had longer travel distances, problems with affordability, and little confidence in their physicians. Perceptions of physician shortages were more common in counties with higher poverty rates. CONCLUSIONS: County PtP ratios only partially account for rural perceptions that there are or are not enough local physicians. Perceptions of an adequate local physician workforce are also related to how much people value physicians' care and whether they face other barriers to care. PMID- 19785577 TI - Do international medical graduates (IMGs) "fill the gap" in rural primary care in the United States? A national study. AB - CONTEXT: The contribution that international medical graduates (IMGs) make to reducing the rural-urban maldistribution of physicians in the United States is unclear. Quantifying the extent of such "gap filling" has significant implications for planning IMG workforce needs as well as other state and federal initiatives to increase the numbers of rural providers. PURPOSE: To compare the practice location of IMGs and US medical graduates (USMGs) practicing in primary care specialties. METHODS: We used the 2002 AMA physician file to determine the practice location of all 205,063 primary care physicians in the United States. Practice locations were linked to the Rural-Urban Commuting Areas, and aggregated into urban, large rural, small rural, and isolated small rural areas. We determined the difference between the percentage of IMGs and percentage of USMGs in each type of geographic area. This was repeated for each Census Division and state. FINDINGS: One quarter (24.8% or 50,804) of primary care physicians in the United States are IMGs. IMGs are significantly more likely to be female (31.9% vs 29.9%, P < .0001), older (mean ages 49.7 and 47.1 year, P < .0001), and less likely to practice family medicine (19.0% vs 38%, P < .0001) than USMGs. We found only two Census Divisions in which IMGs were relatively more likely than USMGs to practice in rural areas (East South Central and West North Central). However, we found 18 states in which IMGs were more likely, and 16 in which they were less likely to practice in rural areas than USMGs. CONCLUSIONS: IMGs fill gaps in the primary care workforce in many rural areas, but this varies widely between states. Policies aimed to redress the rural-urban physician maldistribution in the United States should take into account the vital role of IMGs. PMID- 19785578 TI - Perspectives on rural health workforce issues: Illinois-Arkansas comparison. AB - CONTEXT: Past research has documented rural physician and health care professional shortages. PURPOSE: Rural hospital chief executive officers' (CEOs') reported shortages of health professionals and perceptions about recruiting and retention are compared in Illinois and Arkansas. METHODS: A survey, previously developed and sent to 28 CEOs in Illinois, was mailed to 110 CEOs in Arkansas. Only responses from rural CEOs are presented (Arkansas n = 39 and Illinois n = 22). FINDINGS: Physician shortages were reported by 51 CEOs (83.6%). Most reported physician shortages in Arkansas were for family medicine, internal medicine, cardiology, obstetrics-gynecology, general surgery, and psychiatry. Most reported physician shortages in Illinois were for family medicine, obstetrics-gynecology, orthopedic surgery, internal medicine, cardiology, and general surgery. Additionally, registered nurses and pharmacists were the top 2 allied health professions shortages. Multivariate analysis (factor and discriminant analyses) examined community attributes associated with ease of recruiting physicians. Six factors were identified and assessed as to their importance in influencing ease of recruitment, with the state included in the model. Three factors were identified as discriminating whether or not physician recruitment was easy: community supportive for family, community cooperates and perceives a good future, and community attractiveness. CONCLUSIONS: Similarities in shortages and attributes influencing recruitment in both states suggest that efforts and policies in health professions workforce development can be generalized between regions. This study further reinforces some important known issues concerning retention and recruitment, such as the importance of identifying providers whose preferences are matched to the characteristics and lifestyle of a given area. PMID- 19785579 TI - Rurality and birth outcomes: findings from southern appalachia and the potential role of pregnancy smoking. AB - CONTEXT: Rates of preterm birth (PTB) and low birth weight (LBW) vary by region, with disparities particularly evident in the Appalachian region of the South. Community conditions related to rurality likely contribute to adverse birth outcomes in this region. PURPOSE: This study examined associations between rurality and related community conditions, and newborn outcomes in southern Appalachia, and explored whether pregnancy smoking explained such associations. METHODS: Data for all births in a southern Appalachian county over a 2-year period were extracted from hospital records. FINDINGS: Data were available for 4,144 births, with 45 different counties of residence. Babies born to women from completely rural counties, on average, weighed 700 g less, were 1.5 inches shorter, and were born over 3 weeks earlier than less rural infants. In addition, these babies were 4.5 times more likely to be LBW, 4 times more likely to be PTB, and 5 times more likely to be admitted to the neonatal intensive care unit (NICU). Effects were also found for per capita income, poverty rate, and unemployment rate, all of which were associated with rurality. Some, but not all of the association was explained by elevated rates of pregnancy smoking. CONCLUSIONS: Babies born to women residing in rural and economically depressed counties in southern Appalachia are at substantially increased risk for poor birth outcomes. Improving these outcomes in the rural South will likely require addressing access to health services and information, health care provider retention, transportation services, employment opportunities, and availability of public health services including smoking cessation assistance. PMID- 19785581 TI - A rural perspective on perinatal depression: prevalence, correlates, and implications for help-seeking among low-income women. AB - CONTEXT/PURPOSE: To examine a low-income sample of women in the rural Midwest (N = 1,086) who were screened for perinatal depression through the outreach and education activities within a Healthy Start Initiative project. Specifically, we describe the frequency and severity of depressive symptoms, explore social and demographic correlates of depression, and examine help-seeking through patterns of self-referral to a Healthy Start perinatal depression project in a rural, medically underserved community. METHODS: Depression screening data using the Primary Care Evaluation of Mental Disorders (PRIME-MD) as well as intake records from the project were analyzed in a retrospective analysis to identify important demographic and psychosocial characteristics associated with elevated levels of depressive symptoms and help-seeking patterns. FINDINGS: Thirty-six percent of screened women met criteria for major, minor, or subthreshold depression, with 13% meeting diagnostic criteria for major depression alone. Less than 8% were currently receiving any type of mental health services or treatment at screening. The most significant correlate of self-referral to the Healthy Start project was meeting symptom criteria for major depression, although minor depression, subthreshold depression, and status as low-income/Temporary Aid to Needy Families (TANF)-eligible were all significantly associated with self-referral. CONCLUSIONS: The findings from this study highlight the potential significance of identifying and addressing the unmet mental health needs of low-income rural women during and around pregnancy. In addition, the study illustrates that low income, in addition to depressive symptoms, impacts mental health service delivery in this rural community with a fragmented mental health service infrastructure. PMID- 19785580 TI - Does rural residence affect access to prenatal care in Oregon? AB - CONTEXT: Identifying how maternal residential location affects late initiation of prenatal care is important for policy planning and allocation of resources for intervention. PURPOSE: To determine how rural residence and other social and demographic characteristics affect late initiation of prenatal care, and how residence status is associated with self-reported barriers to accessing early prenatal care. METHODS: This observational study used data from the 2003 Oregon Pregnancy Risk Assessment Monitoring System (PRAMS) (N = 1,508), with late initiation of prenatal care (after the first trimester) as the primary outcome. We used Rural-Urban Commuting Area (RUCA) codes to categorize maternal residence as urban, large rural, or small/isolated rural. Multivariate logistic regression was used to evaluate whether category of residence was associated with late initiation of prenatal care after adjusting for other maternal factors. Association between categories of barriers to prenatal care and maternal category of residence were determined using the Cochran-Mantel-Haenszel test of association. FINDINGS: We found no significant association between residence category and late initiation of prenatal care, or residence category and barriers to prenatal care initiation. Urban women tended to be over age 34 or nonwhite. Women from large rural areas were more likely to be younger than 18 years, unmarried, and have an unintended pregnancy. Women from small rural areas were more likely to use tobacco during pregnancy. CONCLUSIONS: Maternal residence category is not associated with late initiation of prenatal care or with barriers to initiation of prenatal care. Differences in maternal risk profiles by location suggest possible new foci for programs, such as tobacco education in small rural areas. PMID- 19785582 TI - Screening mammography utilization in Tennessee women: the association with residence. AB - CONTEXT: Approximately 70% of US women over age 40 report mammography screening within 2 years. However, rates are likely to vary by age, income, educational level, and residence. PURPOSE: To describe the prevalence of screening mammography and associated factors in women living in rural and urban areas of Tennessee. METHODS: Using pooled data from the Tennessee Behavioral Risk Factor Surveillance System (BRFSS; 2001 and 2003), utilization of screening mammography within a 2-year period was examined for a sample of 1,922 women, 40 years and older. Demographic, behavior, and health-related variables were used to examine associations with utilization. FINDINGS: The prevalence of screening mammography utilization (71.3% 95% CI 67.4-75.2) in women living in rural areas of Tennessee was significantly lower than utilization among women living in urban areas (78.3% 95% CI 75.9-80.7). Higher utilization was associated with having attained at least a high school education, having health insurance, identifying a personal health care provider, being a nonsmoker, recent use of alcohol, having had a recent clinical breast exam or Papanicolau (Pap) test done, and meeting the Healthy People 2010 (HP 2010) recommendation for physical activity. After controlling for all other factors, rural residence was not associated with utilization. For rural women, identifying a personal health care provider was significantly associated with increased likelihood of utilization. CONCLUSIONS: Lower income and lower education, each associated with lower screening utilization, were more common in rural Tennessee women. The significance of a personal health care provider for utilization in rural women is meaningful for service providers. PMID- 19785583 TI - Bypassing the local rural hospital for outpatient procedures. AB - PURPOSE: To assess the amount of local rural hospital outpatient department (HOPD) bypass for outpatient procedures. METHODS: We analyzed data on colonoscopies and upper gastrointestinal endoscopies performed in the state of Florida over the period 1997-2004. FINDINGS: Approximately, 53% of colonoscopy and 45% of upper gastrointestinal endoscopy patients bypassed their local rural hospital for treatment at either a free-standing ambulatory surgical center (ASC) or a nonlocal hospital outpatient department. Independent predictors of bypass included risk-adjusted severity of the patient's medical condition, insurance status, and race. Patients treated in ASCs were predominately healthier, white and commercially insured. Nonlocal HOPDs tend to treat a sicker cohort of patients who were publicly insured or under managed care. CONCLUSIONS: The results indicate that patients who bypass their local HOPD to an ASC differ from those bypassing to a nonlocal HOPD, and that patient factors influencing bypass for outpatient procedures differ from those influencing inpatient bypass. From a policy perspective, as procedures continue to migrate from the inpatient to the outpatient setting, bypassing the local rural hospital for treatment elsewhere could create conditions that negatively impact rural hospital operations. PMID- 19785584 TI - A population-based survival assessment of categorizing level III and IV rural hospitals as trauma centers. AB - CONTEXT: Patients injured in rural areas are hypothesized to have improved outcomes if statewide trauma systems categorize rural hospitals as Level III and IV trauma centers, though evidence to support this belief is sparse. PURPOSE: To determine if there is improved survival among injured patients hospitalized in states that categorize rural hospitals as trauma centers. METHODS: We analyzed a retrospective cohort of injured patients included in the Healthcare Cost and Utilization Project's Nationwide Inpatient Sample from 1997 to 1999. We used generalized estimating equations to compare survival among injured patients hospitalized in states that categorize rural hospitals as Level III and IV trauma centers versus those that do not. Multivariable models adjusted for important confounders, including patient demographics, co-morbid conditions, injury severity, and hospital-level factors. FINDINGS: There were 257,044 admitted patients from 7 states with a primary injury diagnosis, of whom 64,190 (25%) had a "serious" index injury, 32,763 (13%) were seriously injured (by ICD-9 codes), and 12,435 (5%) were very seriously injured (by ICD-9 codes). There was no survival benefit associated with rural hospital categorization among all patients with a primary injury diagnosis or for those with specific index injuries. However, seriously injured patients (by ICD-9 codes) had improved survival when hospitalized in a categorizing state (OR for mortality 0.72, 95% confidence interval [CI] 0.53-0.97; OR for very seriously injured 0.68, 95% CI 0.52-0.90). CONCLUSIONS: There was no survival benefit to categorizing rural hospitals among a broad, heterogeneous group of hospitalized patients with a primary injury diagnosis; however the most seriously injured patients did have increased survival in such states. PMID- 19785585 TI - Emergency department coverage by primary care physicians in a rural practice based research network: incentives, confidence, and training. AB - CONTEXT: In rural areas of the United States, emergency departments (EDs) are often staffed by primary care physicians, as contrasted to urban and suburban hospitals where ED coverage is usually provided by physicians who are residency trained in emergency medicine. PURPOSE: This study examines the reasons and incentives for rural Oregon primary care physicians to cover the ED and their reported measures of confidence and priorities for additional training. METHODS: We conducted a cross-sectional survey of primary care physicians in rural Oregon who are members of the Oregon Rural Practice-Based Research Network (ORPRN). The survey was sent to 70 primary care physicians in 27 rural Oregon practices. FINDINGS: Fifty-two of 70 (74%) ORPRN physicians representing 24 practices returned the questionnaire. Nineteen of the 52 responding physicians reported covering the ED. The majority (75%) of physicians covering the ED did so as a requirement for practice employment and/or hospital privileges. Physicians covering the ED reported low confidence in pediatric emergencies and expressed the need for additional training in pediatric emergencies as their top priority. CONCLUSIONS: Almost two fifths of surveyed primary care physicians in a rural practice-based research network provide ED coverage. Based on these physicians' low levels of confidence and desire for additional training in pediatric emergencies, effective education models are needed for physicians covering the ED at their rural hospitals. PMID- 19785586 TI - A community perspective on quantifying the economic impact of teleradiology and telepsychiatry. PMID- 19785587 TI - Teledermatology consultations provide specialty care for farmworkers in rural clinics. AB - CONTEXT: Rural patients have limited access to dermatologic care. Farmworkers have high rates of skin disease and limited access to care. PURPOSE: This exploratory study assessed whether teledermatology consultations could help meet the needs of health care providers for farmworkers in rural clinics. METHODS: Dermatologists provided 79 consultations, using store-and-forward teledermatology, to farmworkers who presented with a skin disease to rural North Carolina clinics. Clinic providers rated the value of the consultation. FINDINGS: Most requests for consultations (94%) came from family nurse practitioners or physician assistants. Twelve percent of consultations were rated somewhat helpful, and the remainder helpful or very helpful. After receiving the consultation, providers changed the diagnosis in 13% of cases. The consultation led providers to contact or attempt to contact 21% of patients to change treatment recommendations. CONCLUSIONS: Access to expert dermatologic services is needed by rural health care providers. Teledermatology consultations may be a helpful tool to meet this need. PMID- 19785588 TI - Retail food availability, obesity, and cigarette smoking in rural communities. AB - CONTEXT: Disparities in the availability of nutritionally important foods and their influence on health have been studied in US urban communities. PURPOSE: To assess the availability of selected retail foods and cigarettes, and explore ecologic relationships of the availability with obesity and smoking in rural communities. METHODS: Inventories of all food stores (n = 182) in 2 rural New York counties were surveyed. The study area was divided into 4 regions through cluster analysis of 2000 Census and geographic information system data. Weight adjusted per 10,000-population density of stores carrying selected foods was used as a standardized measure of availability. Prevalence of overweight/obesity (BMI > or =25.0 kg/m(2)) and smoking among adults was obtained from secondary data. Bivariate correlations among availability of foods and cigarettes, overweight/obesity, and smoking were analyzed at the regional level. FINDINGS: Nutritionally important foods, including fresh fruit, vegetables (dark green or orange colored), low-fat (< or =1%) milk, high-fiber (> or =2g per slice) bread, and fish were most available in the semiurbanized region, followed by the rural heartland, the remote mountains region, and the most urbanized inner-town. No significant difference was found in the availability of general food items and cigarettes. Overweight/obesity was inversely associated with the availability of fresh fruit, vegetables, and low-fat milk. Smoking was positively associated with the availability of cigarettes, white bread, whole milk, and eggs. CONCLUSIONS: The observed disparities in food availability and their ecologic association with health risks in rural adults expanded the knowledge base of built environment and its association with health beyond the urban setting. PMID- 19785589 TI - Extra-individual correlates of physical activity attainment in rural older adults. AB - CONTEXT: Challenged with a higher incidence of disease, reduced social support, and less access to physical activity facilities and services, rural older adults may find healthy active living a challenge. Despite these challenges, some rural older adults manage to achieve active lifestyles. PURPOSE: This study investigates the relative importance of 4 extra-individual correlates of physical activity to physical activity achievement in rural seniors. METHODS: Data were drawn from mail questionnaires completed by 454 adults age 65 and over in 7 rural North Carolina counties. FINDINGS: Results from an analysis of covariance indicate that respondents who approached CDC/ACSM recommended levels of physical activity were significantly more likely to report that they lived within walking distance to parks, perceived they had transportation to physical activity areas, had a partner with whom to be active, and felt activity facilities were safe. Next, 7 extra-individual correlates of physical activity were entered into a backward logistic regression. The resultant model predicting physical activity achievement among rural older adults included social support for physical activity, a safe environment for physical activity, and reported ability to walk to a local park. CONCLUSIONS: Interventions designed to provide social support, heighten safety at activity areas and improve park infrastructure may provide opportunities to increase physical activity among seniors. PMID- 19785590 TI - Perspectives on safety and health among migrant and seasonal farmworkers in the United States and Mexico: a qualitative field study. AB - CONTEXT: A large number of hired farmworkers in the United States come from Mexico. Understanding safety and health concerns among the workers is essential to improving prevention programs. PURPOSE: The purpose of this pilot study was to obtain detailed information about safety and health concerns of hired farmworkers in Colorado and in Mexico. METHODS: A total of 10 migrant farmworkers from northern Colorado and 5 seasonal farmworkers from Guanajuato, Mexico, were interviewed using a semi-structured interview process. The social cognitive theory (SCT) served as a framework to gain understanding of safety and health among workers. FINDINGS: Topics of concern identified included causes of farm, home and motor vehicle injuries, and treatment preferences for injuries and illnesses. Four main themes emerged: safety and health concerns, personal control and prevention strategies, factors affecting control and prevention strategies, and the importance of family. CONCLUSIONS: Further study of the themes using a revised semi-structured interview will be done in a larger study among hired farmworkers. The results add to the current work to understand specific health and safety concerns among these workers. PMID- 19785591 TI - High self-reported prevalence of diabetes mellitus, heart disease, and stroke in 11 counties of rural Appalachian Ohio. AB - CONTEXT/PURPOSE: There is an epidemic of obesity and diabetes in the United States, especially in economically at-risk populations such as rural Appalachia. This survey determined the self-reported prevalence of obesity, diabetes mellitus, and associated macrovascular complications in 11 rural counties of Appalachian Ohio. The impacts of lifestyle, cardiovascular risk factors, income, and access to medical care were also determined. METHODS: A telephone survey identical to the 2004 Behavioral Risk Factor Surveillance System (BRFSS) survey was conducted. Surveys were collected from 3,927 randomly selected residents 18 years of age and older in 11 counties of Appalachian Ohio and compared to published aggregate Ohio and national 2004 BRFSS data. FINDINGS: The self reported prevalence of diabetes (11.3%) was markedly higher in Appalachian Ohio counties surveyed compared to aggregate Ohio (7.8%) or national (7.2%) 2004 BRFSS data (P < .044). The prevalence of heart disease (7.6%) and stroke (4.1%) in these counties was slightly higher than aggregate Ohio or national 2004 BRFSS data. In persons with diabetes, the prevalence of heart disease was 2-fold higher (20.0%) and stroke 3-fold higher (11.4%) than among nondiabetics (P < .042) in the region and higher than aggregate Ohio and National 2004 BRFSS data. Lower income levels and decreased access to medications and glucose monitoring supplies correlated with the increased risk for cardiovascular complications in this rural population (P < .042). CONCLUSION: The self-reported prevalence of diabetes mellitus and its associated macrovascular complications are much higher in rural Appalachian Ohio compared to aggregate Ohio and National 2004 BRFSS data. PMID- 19785592 TI - Possible benefit of oral alitretinoin in T-lymphoproliferative diseases: a report of two patients with palmoplantar hyperkeratotic-rhagadiform skin changes and mycosis fungoides or Sezary syndrome. PMID- 19785595 TI - Pemphigus and dyslipidaemia: a case-control study. PMID- 19785593 TI - Comparison of skin barrier function and sensory nerve electric current perception threshold between IgE-high extrinsic and IgE-normal intrinsic types of atopic dermatitis. AB - Background Two types of atopic dermatitis (AD) have been proposed, with different pathophysiological mechanisms underlying this seemingly heterogeneous disorder. The extrinsic type shows high IgE levels presumably as a consequence of skin barrier damage and feasible allergen permeation, whereas the intrinsic type exhibits normal IgE levels and is not mediated by allergen-specific IgE. Objectives To investigate the relationship between pruritus perception threshold and skin barrier function of patients with AD in a comparison between the extrinsic and intrinsic types. Methods Enrolled in this study were 32 patients with extrinsic AD, 17 with intrinsic AD and 24 healthy individuals. The barrier function of the stratum corneum was assessed by skin surface hydration and transepidermal water loss (TEWL), and pruritus perception was evaluated by the electric current perception threshold (CPT) of sensory nerves upon neuroselective transcutaneous electric stimulation. Results Skin surface hydration was significantly lower and TEWL was significantly higher in extrinsic AD than intrinsic AD or normal controls. Although there was no statistically significant difference in CPT among extrinsic AD, intrinsic AD and normal controls, CPT was significantly correlated with skin surface hydration and inversely with TEWL in intrinsic AD and normal controls, but not extrinsic AD. Finally, CPT was correlated with the visual analogue scale of itch in the nonlesional skin of patients with extrinsic but not intrinsic AD. Conclusions Patients with extrinsic AD have an impaired barrier, which increases the pre-existing pruritus but rather decreases sensitivity to external stimuli. In contrast, patients with intrinsic AD retain a normal barrier function and sensory reactivity to external pruritic stimuli. PMID- 19785596 TI - Comparative analysis of subacute cutaneous lupus erythematosus and chronic cutaneous lupus erythematosus: clinical and immunological study of 270 patients. AB - Background Lupus erythematosus (LE) is a chronic, autoimmune disease resulting from an interaction of genetic, environmental and hormonal factors and characterized by a spectrum of clinical forms with variable evolution from a localized cutaneous form to a life-threatening systemic form. Objective To analyse and compare the prevalence and characteristics of the main clinical and immunological manifestations of subacute cutaneous LE (SCLE) and chronic CLE (CCLE). Methods A total of 270 patients with CLE (112 patients with SCLE and 158 patients with CCLE) were studied retrospectively. The clinical and serological characteristics of all the patients were collected in a chart review. Results The patients with SCLE had a higher prevalence of annular and papulosquamous lesions, Raynaud phenomenon, mucous membrane ulcers, malar rashes, photosensitivity, vasculitis and a lower frequency of discoid lesions and alopecia compared with patients with CCLE. Patients with SCLE had a higher prevalence of arthralgias (P < 0.001), xerophthalmia (P = 0.045), arthritis (P < 0.001), nephropathy (P = 0.003) and systemic LE (SLE) (P < 0.001) compared with patients with CCLE. Patients with SCLE also had a higher frequency of laboratory and serological abnormalities than patients with CCLE. Generalized discoid LE (DLE) was associated with a higher prevalence of photosensitivity (P < 0.001), panniculitis (P = 0.009) and SLE (P = 0.003) than localized DLE. In patients with SCLE and those with CCLE, photosensitivity, arthralgias, arthritis, nephropathy and xerophthalmia were associated with SLE. In patients with SCLE, significant correlations existed between clinical and immunological data. Conclusions In our series, differences in the expression of CCLE and SCLE were found with respect to the distribution and type of lesions, systemic features and immunological findings. PMID- 19785597 TI - Increased pachyonychia congenita severity in patients with concurrent keratin and filaggrin mutations. AB - Pachyonychia congenita (PC), a rare autosomal-dominant keratin disorder caused by mutations in keratin genes KRT6A/B, KRT16 or KRT17, is characterized by painful plantar keratoderma and hypertrophic nail dystrophy. Loss-of-function mutations in the filaggrin (FLG) gene underlie the most prevalent skin disorder of cornification, ichthyosis vulgaris (IV), which presents with generalized scaling and is also associated with atopic dermatitis. Recently, FLG mutations have been reported to increase phenotype severity of X-linked ichthyosis and alopecia areata. We report a parent-child trio in which the mother and the son have PC and the father has IV. Both the mother and the son are carriers for the KRT16 mutation p.Leu132Pro. The son, who is much more severely affected than his mother, in addition carries the heterozygous FLG mutation p.R2447X, which was inherited from the father. This observation suggests that coinheritance of mutations in KRT16 and FLG may aggravate the PC phenotype and that FLG could serve as a genetic modifier in PC. PMID- 19785598 TI - Toll-like receptor 2, 4, 7 and 9 expression in primary cutaneous CD30+ T-cell lymphoma. PMID- 19785599 TI - Socioeconomic disability in psoriasis. PMID- 19785600 TI - An overview of skin scores used for quantifying hand eczema: a critical update according to the criteria of evidence-based medicine. AB - The present review gives an overview of the enormous variety of skin scores used for assessing severity in patients suffering from hand eczema. In order to evaluate the validity and practical relevance of different scoring systems according to the criteria of evidence-based medicine, in May 2009 we performed a systematic search of the literature using PubMed and the Cochrane Library. A total of 69 articles reporting on 45 different methods for quantifying hand eczema were identified. The panel of methods varied from pure subjective categories to more or less quantitative scoring systems. Furthermore, by focusing on skin scores used in clinical trials in which the results led to the licensing of a systemic or topical drug for treatment of hand eczema, a panel of different scoring systems was identified. In addition to morphological pattern, some scoring systems included subjective complaints, which might cause an individual bias by overestimation of self-reports. Inter- and intraobserver reliability was rarely reported except for three scores. Among these validated scores interobserver reliability was reported for three scores, but only one of the three included reliability within observers (repeatability). Advantages and disadvantages of the different scoring systems are critically discussed. Depending on different indications and particular settings (e.g. occupational screening vs. clinical examinations, evaluating progress of treatment in everyday clinical practice or for research purposes) scoring systems have to fulfil diverging demands. We draw the conclusion that a standardized diagnostic procedure for assessing the severity of hand eczema would facilitate the comparability of outcome of clinical trials. However, scoring systems used for occupational screening have to fulfil different demands compared with scoring systems used for licensing of drugs. This striking difference might be explained by the skin condition, which is generally supposed to be much better in subjects at medical check-ups at the workplace. PMID- 19785601 TI - Results and relevance of critical temperature threshold testing in patients with acquired cold urticaria. AB - Background Acquired cold urticaria (ACU) is a physical urticaria characterized by local skin reactions after cold exposure. Objective markers of disease severity and activity would be helpful. Unfortunately, such markers are not yet available, even though stimulation time and temperature thresholds are promising candidates. Objectives We assessed and correlated critical temperature thresholds (CTTs) with disease severity and activity in patients with ACU. Methods CTTs were determined in 45 patients with ACU by TempTest-based cold contact stimulation tests (Emo Systems GmbH, Berlin, Germany), and ACU severity and activity were assessed using Likert scales. Results Patients with ACU exhibited mean +/- SEM CTTs of 17 +/- 6 degrees C (range 4-27 degrees C). These thresholds and their changes correlated with the severity (r = 0.53, P < 0.05) and activity of disease (r = 0.64, P < 0.05), respectively. Conclusions These findings indicate that temperature threshold measurements may be used for assessing disease severity and activity as well as the efficacy of therapeutic measures including novel treatment approaches for cold urticaria. PMID- 19785603 TI - Successful ultraviolet A1 phototherapy in the treatment of localized scleroderma: a retrospective and prospective study. AB - BACKGROUND: Ultraviolet (UV) A1 phototherapy is an effective anti-inflammatory treatment modality that influences fibroblast functions. OBJECTIVES: To document the effects of UVA1 treatment in patients with localized scleroderma (LS) in a retrospective study (at least 6 months after UVA1 treatment) and in a prospective study before and immediately after medium-dose UVA1 irradiation. METHODS: In total, 30 patients (retrospective study n = 17, prospective study n = 13) with LS receiving UVA1 phototherapy five times weekly (for 3-6 weeks) were investigated. Improvement was documented using standardized questionnaires and clinical evaluation (using modified Rodnan skin score, Cutometer and 7.5-MHz ultrasound measurements). Levels of collagen I and collagen III metabolites were measured in serum and urine. RESULTS: In the retrospective study, medium-dose UVA1 phototherapy had been performed 6 months-3 years earlier (cumulative dose 750 1400 J cm(-2); mean + or - SD number of irradiations 19.3 + or - 3.8). Fourteen of 17 patients (82%) reported an improvement in symptoms following UVA1 therapy. In the prospective study, skin elasticity increased in 77% of the patients following medium-dose UVA1 phototherapy (cumulative dose 750-1250 J cm(-2); mean + or - SD number of irradiations 20.8 + or - 4.0). 7.5-MHz ultrasound measurements showed a mean reduction of lesional skin thickness of 13% compared with skin thickness before UVA1 phototherapy. The ratio of deoxypyridinoline to creatinine was significantly elevated in about two-thirds of the patients. CONCLUSIONS: This open study showed a positive short- and long-term efficacy of UVA1 phototherapy in patients with LS, with a reduction in sclerotic plaques, an increase in skin elasticity and a reduction of lesional skin thickness. UVA1 phototherapy had a significant effect on collagen metabolism. UVA1 phototherapy can be regarded as a safe treatment modality for patients with LS. PMID- 19785602 TI - Vasoactive intestinal peptide and inflammatory cytokines enhance vascular endothelial growth factor production from epidermal keratinocytes. AB - BACKGROUND: Overexpression of vascular endothelial growth factor (VEGF) in epidermal lesions of psoriasis is well documented; however, its underlying mechanisms are largely unknown. We have recently demonstrated that vasoactive intestinal peptide (VIP) induces the production of cytokines such as interleukin 6 and stem cell factor from keratinocytes, thereby contributing to the development of inflammatory dermatoses such as psoriasis. OBJECTIVES: In this study, we attempted to determine whether VIP could increase the production of VEGF in human keratinocytes. METHODS: We examined the expression of VEGF using reverse transcription-polymerase chain reaction, immunocytochemistry, enzyme linked immunosorbent assay and immunoblotting in normal human epidermal keratinocytes and human epidermal keratinocyte cell line DJM-1 cultured in the absence or presence of VIP and/or inflammatory cytokines. RESULTS: We demonstrate that human keratinocytes produced VEGF in a steady state at both mRNA and protein levels. VIP significantly upregulated the production of VEGF in keratinocytes in a dose- and time-dependent manner. The VIP-mediated production of VEGF was further enhanced by inflammatory cytokines such as interferon-gamma, tumour necrosis factor-alpha and interleukin-4, with maximum enhancement being observed with the combination of VIP and interferon-gamma. CONCLUSIONS: VIP and other cytokines from nerve endings, mast cells and local inflammatory cells are capable of enhancing VEGF production from epidermal keratinocytes, which may underlie excessive angiogenesis and vasodilation in skin lesions of psoriasis. PMID- 19785604 TI - Topical aminolaevulinic acid- and aminolaevulinic acid methyl ester-based photodynamic therapy with red and violet light: influence of wavelength on pain and erythema. AB - BACKGROUND: Photodynamic therapy (PDT) is based on the combination of an exogenously administered precursor of photosensitizer [protoporphyrin IX (PpIX)] synthesis and exposure to light. Choosing the optimal wavelength is important. Red light penetrates deeper into tissue, while violet light is more efficient in activating PpIX but does not penetrate so deeply. OBJECTIVES: We studied PpIX formation and the PDT effect after application to human skin of creams containing aminolaevulinic acid (ALA) and aminolaevulinic acid methyl ester (MAL). The aim of the study was to investigate whether the wavelength of the light used has an influence on pain sensations during topical PDT with the different prodrugs. METHODS: ALA cream (10%) and MAL cream (10%) were topically applied on the skin of 10 healthy volunteers. After 24 h the application site was exposed to 8 mW cm( 2) violet laser or to 100 mW cm(-2) red laser light. The erythema index was monitored up to 24 h after light exposure. For the first time the pain during topical ALA- and MAL-PDT was assessed by measuring the time taken for pain to occur. Also, for the first time, the intensities of the light sources were calibrated so as to have the same relative quantum efficiency. Results The pain sensation during ALA-PDT with red light came 22 s sooner than during ALA-PDT with violet light, which is statistically significant (P < 0.05). Moreover, ALA-PDT with red light gave stronger and more persistent erythema than ALA-PDT with violet light. ALA induced about three times more PpIX than MAL. No statistically significant differences were found for erythema, or for the time for pain to occur, in the case of MAL-PDT with red vs. violet light. CONCLUSIONS: Topical ALA PDT with violet light allows longer exposure times before pain is induced and gives less erythema as compared with topical ALA-PDT with red light. PMID- 19785605 TI - Effects of topical treatment with the raft modulator miltefosine and clobetasol in cutaneous mastocytosis: a randomized, double-blind, placebo-controlled trial. AB - Background Mastocytosis is characterized by the accumulation and activation of mast cells in different organs, most commonly the skin. Miltefosine, a raft modulator, has recently been shown to inhibit the activation of mast cells and to reduce mast cell-driven skin inflammatory responses. Objectives To study the safety and efficacy of topical miltefosine treatment of skin lesions in patients with mastocytosis. Methods Thirty-nine adult patients with mastocytosis with skin involvement were treated in a double-blind, placebo-controlled, parallel trial with topical miltefosine and clobetasol for 2 weeks. Treatment areas were analysed for changes in skin lesions and symptoms following mechanical irritation using novel volumetric imaging techniques and quantitative histomorphometry. Results Miltefosine and clobetasol failed to reduce significantly weals and flare type skin responses following mechanical provocation. Miltefosine showed a trend towards reducing the volume of weals. Clobetasol significantly decreased the volume of weals and the number of mast cells in the upper dermis. Treatment with miltefosine, but not with clobetasol, was often associated with eczematous skin irritation, which may, at least in part, be related to the formulation of miltefosine containing the potentially irritating alkanol propanediol as the vehicle. Conclusions Raft modulators such as miltefosine are promising candidates for novel therapeutic strategies in patients with cutaneous mastocytosis. Future studies should be performed with improved formulations using nonirritant vehicles. PMID- 19785606 TI - Consumer available permanent hair dye products cause major allergic immune activation in an animal model. AB - Background p-Phenylenediamine (PPD) and related substances are ingredients of more than two-thirds of oxidative (permanent) hair dyes currently used. Although PPD is a potent skin sensitizer in predictive assays, the extent to which permanent hair dyes sensitize humans has been questioned due to the in-use conditions, e.g. the presence of couplers in the hair dye gel and rapid oxidation using a developer. Objectives To study the skin sensitizing potential of permanent hair dyes in mice. Methods Two different permanent hair dye products containing PPD were studied in CBA mice using a modified version of the local lymph node assay. The colour gel and developer (oxidant) were tested separately and in combination. Response was measured by ear swelling and cytokine production in ear tissue and serum by enzyme-linked immunosorbent assay. The immune cellular response in the draining lymph nodes was analysed by flow cytometry. Results Application of the colour gel both alone and mixed with the developer induced skin production of interleukin (IL)-1beta, tumour necrosis factor-alpha and IL-6 as well as systemic IL-6 release. Both treatments induced B- and T-cell infiltration as well as T-cell proliferation within the draining lymph nodes. Treatment with the mixture induced at least 20% more skin inflammation, cytokine production and CD4+ T-cell activation compared with the colour gel alone. Conclusions Consumer available PPD-containing permanent hair dyes can be potent and rapid immune activators. Mixing the colour gel and developer (oxidant) increased the induction of skin inflammation compared with application of the colour gel alone. PMID- 19785607 TI - Slow-growing melanoma: a dermoscopy follow-up study. AB - BACKGROUND: Recent evidence suggests that melanoma is a family of different tumours with varying abilities to grow and metastasize. Trends in melanoma epidemiology show a strong increase in the incidence of thin melanoma, with no corresponding increase in mortality or incidence of thick melanoma. We initially evaluated five cases and found that none had baseline features suggestive of melanoma; excision was performed based on slight changes visible only in side-by side comparisons of dermoscopic images. OBJECTIVES: To assess the clinico dermoscopic features and the growth patterns of melanomas that were excised after a follow-up of 1 year or more due to their inconspicuous features at the baseline consultation. METHODS: In a multicentre, retrospective study of histopathologically confirmed melanomas excised after follow-up, we analysed dermoscopic images obtained at the initial consultation and compared them with images obtained at the last follow-up consultation. Images were analysed and graded using standard algorithms and scored for changes in size, symmetrical or asymmetrical structural change, and development of new melanoma-specific criteria. An overall score reflecting the amount of change was calculated for each lesion. RESULTS: Our series consisted of 103 melanomas. After a median follow-up of 20 months, most lesions were still in situ or early invasive (median Breslow thickness of 0.48 mm), with only three lesions showing tumour thickness of 1 mm or more. The most frequent baseline characteristics were asymmetrical pigmentation (78.6% of lesions), reticular overall pattern (62.1%), and regression features (35.9%). Most melanomas (58.3%) showed minor to moderate changes over time, with < 2 mm size increase, with asymmetrical structural change, and without development of new melanoma-specific criteria. Major changes were visible only after a mean follow-up of 33 months. CONCLUSIONS: This study provides evidence for the existence of a subgroup of slow-growing melanomas, which may explain the increase in the incidence of thin melanoma, despite stable rates of thick melanoma and melanoma-associated mortality. PMID- 19785608 TI - The role of human endogenous retroviruses in melanoma. AB - Sequencing of the human genome has established that our DNA harbours many endogenous retrovirus (ERV) sequences, remnants of ancestral exogenous retroviral infections fixed in the germline DNA. In recent years, human ERVs (HERVs) have been implicated in melanomagenesis. Retrovirus-like particles and the expression of HERV mRNA and proteins have been demonstrated in melanoma tissue. In addition, antibodies to HERV proteins have been observed in patients with melanoma. In vitro and mouse models have provided fascinating insights into the potential mechanisms of HERVs in melanomagenesis. This review considers the evidence associating HERVs with melanoma. PMID- 19785609 TI - Iontophoretic delivery of terbinafine in onychomycosis: a preliminary study. AB - Background Onychomycosis is a common disease; topical treatment is usually poorly effective, while systemic treatment is more effective but may be associated with side-effects. Iontophoretic drug delivery may improve drug penetration through the nail and lead to better therapeutic results. Objectives To evaluate the efficacy, safety and tolerability of topical treatments with terbinafine HCl delivered with or without an iontophoretic patch in patients with onychomycosis of the toenails. Methods Patients enrolled into the study were divided randomly into two groups. Group A was treated with terbinafine and an iontophoretic patch (at a constant current density of 100 microA cm(-2)). Group B was treated with terbinafine without iontophoresis. Treatment was overnight wear, every day, 5 days per week, for 4 weeks. Follow-up period was 8 weeks from the end of treatment. Results A significant clinical response was recorded in patients of group A (active group). The percentage of patients having healthy toenail growth of more than 1.5 mm at the end of treatment was 40% compared with 11% in patients treated with terbinafine without current (passive group). The percentage of patients having fungal elements (KOH) in nail specimens decreased significantly at 8 weeks following the completion of treatment: 16% in the active group vs. 53% in the passive group. Patients in the active group reported a tingling sensation that is expected when using an iontophoretic drug delivery treatment. Conclusions The delivery of terbinafine under an electrical current of 100 microA cm(-2) appears to be efficacious and safe and is well tolerated for the treatment of nail onychomycosis. PMID- 19785610 TI - Lipoedema: from clinical presentation to therapy. A review of the literature. AB - Lipoedema is an infrequently recognized disorder in women. Lipoedema is characterized by bilateral enlargement of the legs due to abnormal depositions of subcutaneous fat associated with often mild oedema. There is substantial variability in disease severity. The diagnosis should be made as early as possible to prevent complications of the disorder, which is associated with increasing functional and cosmetic morbidity. This review describes clinical manifestations, pathogenesis, technical investigations, management and therapies of lipoedema, with the aim of optimizing management and care of patients with lipoedema. PMID- 19785611 TI - Predicting risk for early infantile atopic dermatitis by hereditary and environmental factors. AB - BACKGROUND: Hereditary and environmental factors contribute to the occurrence of atopic dermatitis (AD). However, the interaction of these two factors is not totally understood. OBJECTIVES: To evaluate the early risk factors for infantile AD at the age of 6 months and to develop a predictive model for the development of AD. METHODS: In 2005, a representative sample of mother and newborn pairs was obtained by multistage, stratified systematic sampling from the Taiwan national birth register. Information on hereditary and environmental risk factors was collected by home interview when babies were 6 months old. Multivariate regression analysis was applied to determine the risk factors for AD in the infants. RESULTS: A total of 20 687 pairs completed the study satisfactorily. AD was diagnosed in 7.0% of 6-month-old infants by physicians. Parental asthma, atopic dermatitis and allergic rhinitis, and maternal education levels were risk factors for AD in infants. Among environmental factors, fungus on walls at home and renovation/painting in the house during pregnancy were significantly associated with early infantile AD. Using these factors, the probability of having infantile AD was estimated and grouped into low, high and very high. With five runs of tests in mutually exclusive subsets of this population, the likelihood of AD for 6-month-old infants was consistent in all the groups with the predictive model. The highest predicted probability of AD was 70.1%, among boys with maternal education levels > 12 years, both parents with AD, renovation and painting of the house during pregnancy and fungus on walls at home. The lowest probability was 3.1%, among girls with none of the above factors. CONCLUSIONS: This investigation provides a technique for predicting the risk of infantile AD based on hereditary and environmental factors, which could be used for developing a preventive strategy against AD, especially among those children with a family history of atopy. PMID- 19785612 TI - Comparative assessment of enzyme-linked immunosorbent assay and Western blot for the diagnosis of toxocariasis in patients with skin disorders. AB - Background The link between various chronic skin disorders and toxocariasis was previously demonstrated by case reports and several case-control studies. However, these previous studies were based only on the Toxocara canis excretory secretory-enzyme-linked immunosorbent assay (TES-ELISA) serological technique, which is not specific due to cross-reactivity with parasites of the genera Anisakis or Ascaris. Immunoblot analysis is highly specific and can detect very low levels of Toxocara antibodies. Therefore, this technique may be useful in the identification of Toxocara infection in patients with chronic skin disorders. Objectives Because urticaria and pruritus/prurigo are skin conditions previously associated with toxocariasis, we carried out a prospective study using both TES ELISA and Toxocara Western blot on 113 patients with either chronic urticaria (n = 84) or chronic pruritus (n = 29). Methods Patients were matched with controls according to gender, age and residence location (rural or urban area). Data were analysed using a Mantel-Haenszel chi(2) test. Results The proportion of positive TES-ELISA results was not significantly different for patients with chronic skin disorders (urticaria or pruritus/prurigo) from that of control subjects. However, the proportion of positive immunoblot results was significantly higher for patients with chronic urticaria than for control subjects (P = 0.009). Conclusions Our study demonstrates the need to perform Western blotting immunodiagnosis, whatever the TES-ELISA result, to improve diagnosis of human toxocariasis in patients with chronic urticaria caused by Toxocara infection. PMID- 19785613 TI - Th17/Tc17 infiltration and associated cytokine gene expression in elicitation phase of allergic contact dermatitis. AB - BACKGROUND: Allergic contact dermatitis (ACD) is a typical delayed-type hypersensitivity to sensitizing haptens mediated by T cells. Th1/Tc1 cells are currently considered to be the primary effectors in ACD. There is little information concerning the role played in ACD in humans by Th17/Tc17 cells, a recently defined subpopulation of effector T cells. OBJECTIVES: In the present report we attempted to characterize Th17/Tc17 cells in the infiltrates of the skin in the elicitation phase of ACD. METHODS: Th17 as well as Th1/Th2 cytokine gene expression was examined by semiquantitative real-time polymerase chain reaction in paired samples of positive patch test biopsies and normal skin from 11 patients allergic to nine different allergens. The in situ characterization of interleukin (IL)-17-producing cells was carried out using anti-RORC and anti-T cell subset antibodies by double immunofluorescence. RESULTS: Compared with normal paired skin samples, gene expression of transcription factor for human Th17 cells, RORC, and Th17-related cytokines IL-17A, IL-17F and IL-23 was significantly increased in positive patch test biopsies. The mRNA for interferon gamma and IL-4 was also increased. In the dermal infiltrates, about 20% of the infiltrating cells were IL-17-producing cells as they expressed RORC, and such RORC-expressing cells were detected in both CD4+ (approximately 30%) and CD8+ (approximately 20%) subsets. CONCLUSIONS: This is the first demonstration of Th17/Tc17 cells in the elicitation phase of human ACD, showing that they are a regular participant in the immunopathology of this common allergic reaction regardless of the nature of the triggering allergen. PMID- 19785614 TI - Malignant melanoma: how error amplification by screening creates spurious disease. AB - The increased incidence of melanoma with little or no change in mortality has been attributed to the histopathological reclassification of benign disease as malignant, the consequence of diagnostic drift. An entirely new, additional explanation has now been found, and is defined as error amplification by screening. This previously unrecognized artefact is shown to be an inevitable consequence of the uneven operation of routine histopathological error in the diagnosis of borderline malignancy; thus, as the equality of diagnostic plus/minus is lost, it is no longer self-correcting, and the overdiagnosis of malignancy therefore outweighs its underdiagnosis: the error is then amplified by patient screening. The magnitude of this new artefact is a function of the reproducibility of routine histopathological diagnosis and the number of patients screened, and the evidence on this, and from studies done for other purposes, shows the error to be considerable. The artefact of error amplification by screening detracts from a possible role for ultraviolet radiation in the increase in melanoma incidence and provides an explanation of their erroneous association; in addition to melanoma, it could be a major source of misdiagnosis of other cancers associated with patient screening programmes. PMID- 19785615 TI - Coeliac disease associated with psoriasis. AB - BACKGROUND: Psoriasis is a chronic inflammatory disorder of the skin reported to be associated with systemic comorbidities. OBJECTIVES: To investigate the association between psoriasis and coeliac disease (CD). METHODS: Patients with psoriasis were compared with age- and sex-matched controls regarding the prevalence of CD in a case-control study. chi(2) and t-tests were used for univariate analysis and a logistic regression model was used for multivariate analysis. The study was performed utilizing the medical database of Clalit Health Services. RESULTS: The study included 12,502 patients with psoriasis aged > 20 years and 24,285 age- and sex-matched controls. The prevalence of CD in patients with psoriasis was increased compared with the prevalence in controls (0.29% and 0.11%, respectively, P < 0.001). In a multivariate analysis psoriasis was associated with CD (odds ratio 2.73, 95% confidence interval 1.65-4.53). CONCLUSIONS: Patients with psoriasis have a greater prevalence of CD than matched controls. Recent studies showed a possibility of undiagnosed CD among patients with psoriasis. Therefore, physicians treating patients with psoriasis should be aware of this possible association. PMID- 19785616 TI - Clinical predictors of leg ulcer healing. AB - Background Identification of factors associated with healing can help in understanding the causes of delayed healing in chronic leg ulceration, and can allow for programmes to be developed to modify these factors to improve patient outcomes. Objectives To determine factors associated with healing in patients with chronic leg ulceration of all types within a defined patient population. Methods The patients were identified within the combined acute/community leg ulcer service within Wandsworth Primary Care Trust. All identified patients agreed to be interviewed and those who were able underwent clinical and noninvasive testing to determine the cause of the ulceration. Follow ups were to a maximum of 48 weeks, with time to healing given as the principal outcome measure. Analysis was by the Cox proportional hazards model for both univariate and multivariate analysis. Results were expressed as hazard ratio with 95% confidence intervals derived from the models. Results In total, 113 patients took part in this study. Univariate analysis revealed statistically significant differences for delayed healing according to the ulcer duration (P = 0.002), complexity of the ulcer aetiology (P = 0.035), presence of lipodermatosclerosis (P = 0.02), history of deep vein thrombosis (DVT) (P = 0.03) and thrombophlebitis (P = 0.03). Multivariate analysis showed that ulcer duration (P = 0.014), DVT (P = 0.008) and a lack of Pseudomonas on wound swab (P = 0.005) were independently associated with delayed healing. Conclusions The results indicate the complexity of determining risk factors for poor healing in patients with chronic leg ulceration. There appears to be little scope for interventions to improve healing from the factors identified. PMID- 19785617 TI - Is the wearing of elastic stockings for half a day as effective as wearing them for the entire day? AB - Background There is good evidence for the use of compression for some clinical indications but little is known about dosimetry in compression. Objective The aim of this work was to evaluate whether or not the use of compression stockings during part of the day would help in the reduction of evening oedema in patients with clinical, epidemiological, anatomical and physiopathological (CEAP) classifications C0 and C1. Methods The effects of elastic compression stockings on volumetric variations during the working day were evaluated for the legs of two men and 18 women (40 legs). The inclusion criterion was classification as C0 (10 legs) or C1 (30 legs) according to the CEAP criteria. Participants used three quarter-length elastic compression stockings (20-30 mmHg) on three consecutive days for the entire day or only for the morning or they did not use the stockings at all. Volumetry using the water displacement technique was performed in the morning and in the evening. When the patients wore the stockings only during the morning, volumetry was also performed at 13:00 h. Results Significant increases in volume were observed for both legs when stockings were not used compared with the use of stockings in the morning only. After removing the stockings, both legs had significant increases in volume in the afternoon. However, use for half the day was better than not using the stockings at all. Conclusions The use of elastic compression stockings can reduce volumetric variations during working hours, with the use of stockings for the entire day being better than for just half the day. PMID- 19785618 TI - Topical sodium cromoglicate relieves allergen- and histamine-induced dermal pruritus. AB - BACKGROUND: Sodium cromoglicate (SCG) has long been used in the management of allergic diseases, including as an ointment for atopic dermatitis. Although mast cell stabilization was initially considered as its mechanism of action, anti inflammatory actions and modulation of sensory nerve function have also been suggested. OBJECTIVES: To investigate the mechanism(s) by which SCG relieves allergen- and histamine-induced dermal inflammation by assessing its effects on pruritus, flare, skin temperature and weal volume. METHODS: Aqueous cream containing 0.2%, 1% or 4% SCG or no SCG (placebo) was applied in a randomized single-blind manner to four areas on each forearm (two sites per arm) and covered with an occlusive dressing. One hour later, skin-prick tests were performed in 20 allergic subjects with allergens to which they had previously shown sensitization, and in 40 nonallergic subjects with codeine (9 mg mL(-1), 20 subjects) and histamine (10 mg mL(-1), 20 subjects). Weal volume, skin temperature increase, erythema area and pruritus intensity were assessed at 0, 5, 10 and 15 min. RESULTS: SCG significantly (P < 0.05 to P < 0.001) reduced pruritus induced by all stimuli, with 4% SCG being most effective. Significant (P < 0.05 to P < 0.01) reductions of erythema area were also seen but there was no inhibition of weal volume or temperature increase. CONCLUSIONS: SCG is effective in reducing pruritus but has no effect on weals, supporting the proposition that, in the skin, SCG inhibits sensory C-fibre nerve activation rather than preventing mast cell degranulation. We suggest that topical SCG treatment, delivered in an appropriate vehicle, may be beneficial for symptomatic relief of pruritus in patients with cutaneous mastocytosis and other pruritic dermatoses. PMID- 19785619 TI - Melanoma in patients with rheumatoid arthritis treated with antitumour necrosis factor: cause or coincidence? Report of two cases. PMID- 19785620 TI - Comparators, study duration, outcome measures and sponsorship in therapeutic trials of psoriasis: update of the EDEN Psoriasis Survey 2001-2006. AB - BACKGROUND: Several new therapeutic options for psoriasis have been tested in clinical trials in recent years. Choice of comparator, study duration and outcome measures are critical for interpreting application of trial results to clinical practice. OBJECTIVES: We examined whether these trial aspects have changed substantially in recent years in comparison with the past. METHODS: A systematic search and evaluation of all randomized controlled trials (RCTs) for psoriasis published from January 2001 up to December 2006 in 14 leading medical and dermatological journals, compared with those published from 1977 to 2000. RESULTS: There were 140 RCTs of psoriasis in the period 2001-2006 and 249 in the period 1977-2000. The proportion of placebo-controlled studies increased from 44.6% to 69.3%. The median study duration increased from 7 weeks to 12 weeks. The proportion of studies adopting the Psoriasis Area and Severity Index score as an outcome increased from 30.6% to 57.7%, while the number of studies incorporating a quality of life measure increased from only one (0.4%) to 12 studies (7.7%). The proportion of studies sponsored by pharmaceutical companies increased from 61.0% to 73.7%. CONCLUSIONS: Despite the increased number of new options, the number of head-to-head comparative trials has decreased and most trials focus on short-term effects, probably reflecting the increased influence of industrial sponsorship on the research agenda. PMID- 19785621 TI - Birt-Hogg-Dube syndrome: clinical and genetic studies of 10 French families. AB - BACKGROUND: Birt-Hogg-Dube syndrome (BHDS) is an autosomal dominant genodermatosis predisposing to the development of multiple fibrofolliculomas (FFs), pulmonary cysts, spontaneous pneumothorax and renal neoplasms. The association of BHDS with various nonrenal neoplasms has been reported but remains controversial. OBJECTIVES: To report the clinical features and germline mutations in 22 patients from 10 unrelated families with BHDS investigated during a 5-year prospective study by the Department of Dermatology at the University Hospital of Montpellier, France. Also, to define more clearly the characteristics of pulmonary, thyroid, renal and colorectal manifestations associated with BHDS. METHODS: Twenty-two patients with clinical and histological criteria of BHDS confirmed by FLCN (previously BHD) germline mutation were evaluated. Lung cysts and pneumothorax were detected by thoracic computed tomography (CT) scanning. Abdominal magnetic resonance imaging (MRI) or CT scans and/or renal ultrasonography were performed to screen for tumours. Thyroid nodules and goitres were assessed by clinical examination, ultrasound imaging and measurement of serum thyroid-stimulating hormone and thyrocalcitonin. RESULTS: Eighteen of the 22 individuals affected by BHDS (82%) were diagnosed with five or more FFs. Multiple epidermal cysts, severe facial hyperseborrhoea and oral papules were noted, respectively, in three of 22 (14%), nine of 22 (41%) and nine of 21 patients (43%). Spontaneous pneumothorax was reported in seven affected patients (32%). Cystic lesions were detected in 14 of 20 patients (70%) and mainly displayed a subpleural and basal location. Renal ultrasound, CT scan and/or MRI revealed renal cysts in 10 patients (45%), without renal carcinoma diagnosed thus far. Thyroid nodules and/or cysts were disclosed by ultrasound examination in 13 of 20 cases (65%). No medullary carcinoma or other thyroid carcinomas were detected. Colonoscopy failed to detect colorectal carcinoma. CONCLUSIONS: We report here the largest series to date of French patients with BHDS. We noted a high prevalence of thyroid nodules and renal cysts. However, the lack of a control group does not allow assessment of whether or not such association with BHDS is fortuitous. PMID- 19785623 TI - An investigation of medication adherence to 5-aminosalicylic acid therapy in patients with ulcerative colitis, using self-report and urinary drug excretion measurements. AB - BACKGROUND: Non-adherence to 5-aminosalicylic acid (5-ASA) medication can limit the established benefits of this therapy in ulcerative colitis (UC). AIM: To determine rates and predictors of non-adherence to 5-ASA therapy in UC patients. METHODS: Medication adherence was assessed using self-report data and urinary drug excretion measurements. Participants completed a study-specific questionnaire and two validated questionnaires: Beliefs about Medicine Questionnaire (BMQ)-Specific and Satisfaction with Information about Medicines Scale. RESULTS: A total of 169 participants provided self-report adherence data; 151 also provided urine samples. Adherence rates were 111/151 (68%) according to self-report and 90/151 (60%) according to urine analysis, but the two measures were not correlated (chi(2) = 0.12, P = 0.725). Logistic regression identified a significant association between self-reported non-adherence and younger age [odds ratio (OR) for increased age 0.954, 95% confidence interval (CI) 0.932-0.976] and also doubts about personal need for medication (OR for BMQ - Specific Necessity scores 0.578, 95% CI 0.366-0.913). For non-adherence based on urine analysis, only South Asian ethnicity was independently associated with non-adherence (OR 2.940, 95% CI 1.303-6.638). CONCLUSIONS: Our observations confirm the difficulty of accurately assessing medication adherence. Nonmodifiable (younger age, South Asian ethnicity) and potentially modifiable (medication beliefs) predictors of non-adherence were identified. PMID- 19785624 TI - Prevalence of hepatitis B virus DNA polymerase mutations in treatment-naive patients with chronic hepatitis B. AB - BACKGROUND: One of the most important factors in treatment failure using nucleos(t)ide analogues in chronic hepatitis B is anti-viral resistance. Primary drug resistance refers to amino acid changes in the hepatitis B virus polymerase/reverse transcriptase (rt) that result in reduced susceptibility to anti-viral agents. Pre-existing drug resistance mutations may occur in untreated patients and may affect their treatment outcomes. AIM: To determine the prevalence of hepatitis B DNA polymerase mutations in treatment-naive patients. METHODS: We used a direct PCR sequencing test to detect DNA polymerase mutations in 472 consecutive treatment-naive patients at two community gastroenterology clinics in Northern California. RESULTS: A majority of patients were Asians (>95%), had either genotype B or C (95%) and had no evidence of cirrhosis or liver cancer (94%). Mean age was 45 +/- 13 and mean hepatitis B virus DNA was 5.3 +/- 1.8 log(10) IU/mL. Most patients did not have any detectable mutations (82.4%). Some (16.7%) had mutations of unknown clinical significance (rtV207M/L/I) and only 4 patients had rtA181A/S, rtA194S or M250I. CONCLUSIONS: No rtM204V/I or rtN236T mutations were observed in our study. Less than 1% of our patients had mutations that can be associated with primary resistance to existing anti-viral therapies for hepatitis B virus. PMID- 19785622 TI - Review article: new receptor targets for medical therapy in irritable bowel syndrome. AB - BACKGROUND: Despite setbacks to the approval of new medications for the treatment of irritable bowel syndrome, interim guidelines on endpoints for irritable bowel syndrome (IBS) trials have enhanced interest as new targets for medical therapy are proposed based on novel mechanisms or chemical entities. AIMS: To review the approved lubiprostone, two targets that are not meeting expectations (tachykinins and corticotrophin-releasing hormone), the efficacy and safety of new 5-HT(4) agonists, intestinal secretagogues (chloride channel activators, and guanylate cyclase-C agonists), bile acid modulation, anti-inflammatory agents and visceral analgesics. METHODS: Review of selected articles based on PubMed search and clinically relevant information on mechanism of action, safety, pharmacodynamics and efficacy. RESULTS: The spectrum of peripheral targets of medical therapy addresses chiefly the bowel dysfunction of IBS and these effects are associated with pain relief. The pivotal mechanisms responsible for the abdominal pain or visceral sensation in IBS are unknown. The new 5-HT(4) agonists are more specific than older agents and show cardiovascular safety to date. Secretory agents have high specificity, low bioavailability and high efficacy. The potential risks of agents 'borrowed' from other indications (such as hyperlipidaemia, inflammatory bowel disease or somatic pain) deserve further study. CONCLUSIONS: There is reason for optimism in medical treatment of IBS with a spectrum of agents to treat bowel dysfunction. However, visceral analgesic treatments are still suboptimal. PMID- 19785625 TI - A comparison of the acid-inhibitory effects of esomeprazole and pantoprazole in relation to pharmacokinetics and CYP2C19 polymorphism. AB - BACKGROUND: Esomeprazole and pantoprazole are metabolized in the liver and the polymorphic CYP2C19 enzyme is involved in that process. This genetic polymorphism determines fast (70% of Caucasians), intermediate (25-30% of Caucasians) and slow (2-5% of Caucasians) metabolism of PPIs. AIM: To compare the acid-inhibitory effects of esomeprazole 40 mg and pantoprazole 40 mg at 4, 24 and 120 h after oral administration in relation to CYP2C19 genotype and pharmacokinetics. METHODS: CYP2C19*2, *3, *4, *5 and *17 genotypes were determined in healthy Helicobacter pylori-negative Caucasian subjects. 7 wt/wt, 7 wt/*2, 2 wt/*17, 2 *2/*17 and 1 *2/*2 were included in a randomized investigator-blinded cross-over study with esomeprazole 40 mg and pantoprazole 40 mg. Intragastric 24-h pH monitoring was performed on days 0, 1 and 5 of oral dosing. RESULTS: A total of 19 subjects (mean age 24 years, 7 male) completed the study. At day 1 and 5, acid inhibition with esomeprazole was significantly greater and faster than with pantoprazole. Differences in acid-inhibition and pharmacokinetics between wt/wt and wt/*2 genotype were significant for pantoprazole at day 1 and 5. CONCLUSIONS: Esomeprazole provides acid-inhibition faster than and superior to pantoprazole after single and repeated administration. The acid-inhibitory effect and the kinetics of pantoprazole are influenced by CYP2C19 genotype. PMID- 19785626 TI - Mesalazine inhibits the beta-catenin signalling pathway acting through the upregulation of mu-protocadherin gene in colo-rectal cancer cells. AB - BACKGROUND: Several reports indicate that mesalazine (5-aminosalicylic acid, 5 ASA) is a promising candidate for the chemoprevention of colo-rectal cancer because of its ability to reach the purpose avoiding the unwanted side effects usually associated with prolonged administration of nonsteroidal anti inflammatory drugs. This activity of 5-ASA is probably the consequence of a number of effects determined on colo-rectal cancer cells, consisting of reduced proliferation, increased apoptosis and activation of cell cycle checkpoints and DNA repair processes. A recent observation has suggested that inhibition of beta catenin signalling could induce these cellular effects. AIM: To characterize better the capacity of 5-ASA to inhibit the beta-catenin signalling pathway. METHODS: Genes belonging to the beta-catenin signalling pathway were analysed in colo-rectal cancer cell lines treated with 5-ASA using a combination of laboratory assays that are able to detect their phenotypic expression and functional activity. RESULTS: The results obtained indicated that 5-ASA induces the expression of a protein called mu-protocadherin that belongs to the cadherin superfamily and is able to sequester beta-catenin on the plasmatic membrane of treated cells hampering its function. CONCLUSION: These findings suggest that mu protocadherin might be employed as a biological marker to monitor the chemopreventive efficacy of 5-ASA. PMID- 19785628 TI - Pregnancy and lactation have anti-obesity and anti-diabetic effects in A(y)/a mice. AB - AIM: Dominant 'yellow' mutation at the mouse agouti locus (A(y)) results in obesity. Pregnancy and lactation are characterized by large energy demand. The aim of this study was to investigate whether obesity would develop in pregnant and suckling A(y) mice. METHODS: Body weight and food intake in pregnancy, lactation, and after weaning, plasma leptin, insulin, corticosterone and blood glucose concentrations on days 7, 13 and 18 of pregnancy, days 1, 10, 21 and 80 postpartum, glucose and insulin tolerance on pregnancy days 7 and 18 were measured in C57Bl/6J mice of a/a (normal metabolism) and A(y)/a genotypes. The same parameters were also measured in age-matched virgin females. RESULTS: Virgin A(y)/a females exhibited hyperphagia, enhanced body weight, glucose intolerance and normal blood parameters at the mating age. With age, they developed obesity, hyperleptinaemia, hyperinsulinaemia and hyperglycaemia. Obesity did not develop in mated A(y)/a mice; during suckling, they had equal food intake and body weight as a/a mice. During pregnancy, glucose tolerance was enhanced in A(y)/a mice and became equal in both genotypes. In both genotypes, concentrations of hormones increased, and glucose decreased from pregnancy day 7 to day 18 and returned to normal values after parturition. A(y)/a mice did not differ from a/a in corticosterone, insulin and glucose levels during pregnancy and lactation, in leptin levels during suckling; however, A(y)/a mice had two times higher leptin levels than a/a during pregnancy. After weaning, A(y)/a mice began to eat and weigh more than a/a exhibiting normal metabolic parameters for 50 days. CONCLUSION: Pregnancy and lactation retard obesity and diabetes development in A(y) mice. PMID- 19785629 TI - Systemic nitric oxide clamping in normal humans guided by total peripheral resistance. AB - AIM: We wanted to stabilize the availability of nitric oxide (NO) at levels compatible with normal systemic haemodynamics to provide a model for studies of complex regulations in the absence of changes in NO levels. METHODS: Normal volunteers (23-28 years) were infused i.v. with the nitric oxide synthase (NOS) inhibitor N(G)-nitro-l-arginine methyl ester (l-NAME) at 0.5 mg kg(-1) h(-1). One hour later, the NO donor sodium nitroprusside (SNP) was co-infused in doses eliminating the haemodynamic effects of l-NAME. Haemodynamic measurements included blood pressure (MABP) and cardiac output (CO) by impedance cardiography. RESULTS: l-NAME increased MABP and total peripheral resistance (TPR, 1.02 + or - 0.05 to 1.36 + or - 0.07 mmHg s mL(-1), mean + or - SEM, P < 0.001). With SNP, TPR fell to a stable value slightly below control (0.92 + or - 0.05 mmHg s mL( 1), P < 0.05). CO decreased with l-NAME (5.8 + or - 0.3 to 4.7 + or - 0.3 L min( 1), P < 0.01) and returned to control when SNP was added (6.0 + or - 0.3 L min( 1)). A decrease in plasma noradrenaline (42%, P < 0.01) during l-NAME administration was completely reversed by SNP. Plasma renin activity decreased during l-NAME administration and returned towards normal after addition of SNP. In contrast, plasma aldosterone was increased by l-NAME and remained elevated. CONCLUSIONS: Concomitant NOS inhibition and NO donor administration can be adjusted to maintain TPR at control level for hours. This approach may be useful in protocols in which stabilization of the peripheral supply of NO is required. However, the dissociation between renin and aldosterone secretion needs further investigation. PMID- 19785627 TI - Experience-dependent plasticity in hypocretin/orexin neurones: re-setting arousal threshold. AB - The neuropeptide hypocretin is synthesized exclusively in the lateral hypothalamus and participates in many brain functions critical for animal survival, particularly in the promotion and maintenance of arousal in animals - a core process in animal behaviours. Consistent with its arousal-promoting role in animals, the neurones synthesizing hypocretin receive extensive innervations encoding physiological, psychological and environmental cues and send final outputs to key arousal-promoting brain areas. The activity in hypocretin neurones fluctuates and correlates with the behavioural state of animals and intensive activity has been detected in hypocretin neurones during wakefulness, foraging for food and craving for addictive drugs. Therefore, it is likely that hypocretin neurones undergo experience-dependent changes resulting from intensive activations by stimuli encoding changes in the internal and external environments. This review summarizes the most recent evidence supporting experience-dependent plasticity in hypocretin neurones. Current data suggest that nutritional and behavioural factors lead to synaptic plasticity and re organization of synaptic architecture in hypocretin neurones. This may be the substrate of enhanced levels of arousal resulting from behavioural changes in animals and may help to explain the mechanisms underlying the changes in arousal levels induced by physiological, psychological and environmental factors. PMID- 19785630 TI - Independent daily life for young people with myelomeningocele. PMID- 19785631 TI - Is there a relationship between Helicobacter pylori infection and erosive reflux disease in children? AB - AIM: The aim of this study was to investigate the relationship between Helicobacter pylori infection and erosive reflux disease in children. METHODS: A total of 206 children [mean age 8.4 +/- 4.9 (0.16-18) years] who underwent diagnostic upper endoscopy were tested for H. pylori infection between 2002 and 2005 and the relationship between H. pylori infection and gastro-oesophageal reflux disease was investigated retrospectively. Endoscopic and histopathological findings were examined retrospectively. When reflux-related oesophageal damage was identified as a result of the histological examination of endoscopic biopsy samples collected from distal oesophagus, the patients were diagnosed with gastro oesophageal reflux disease and divided into two groups: those with macroscopic erosions or ulceration constituted the erosive oesophagitis group; those without constituted the non-erosive reflux disease group. RESULTS: Prevalence of H. pylori infection was 31.3% in the patients with gastro-oesophageal reflux disease and 36.7% in the control group (p > 0.05). Prevalence of erosive oesophagitis was found to be 23.8% in the patients with H. pylori infection and 41.3% in those without (p > 0.05). CONCLUSION: No negative significant association was found between the prevalence of H. pylori infection and erosive oesophagitis. Presence of H. pylori infection did not influence the severity of oesophagitis either. PMID- 19785632 TI - Interactions among peripheral perfusion, cardiac activity, oxygen saturation, thermal profile and body position in growing low birth weight infants. AB - AIMS: To investigate the correlation between the 'perfusion index' (PI) and other commonly used estimates of cutaneous blood flow [heart rate (HR), surface temperatures (ST) and central-to-peripheral thermal gradients (C-P grad)] and to use this new non-invasive tool to compare differences between prone and supine sleep position in low birth weight (LBW) infants. METHODS: Six-hour continuous recordings of pulse oximetry, cardiac activity and absolute ST from three sites (flank, forearm and leg), along with minute-to-minute assessment of behavioural states were performed in 31 LBW infants. Infants were randomly assigned to the prone or supine position for the first 3 h and then reversed for the second 3 h. PI data were correlated with HR and C-P grad, and compared across sleep positions during quiet sleep (QS) and active sleep (AS). RESULTS: Perfusion index correlated significantly with HR (r(2) = 0.40) and flank-to-forearm thermal gradient (r(2) = 0.28). In the prone position during QS, infants exhibited higher PI (3.7 +/- 0.9 vs. 3.1 +/- 0.7), HR (158.4 +/- 8.9 vs. 154.1 +/- 8.8 bpm), SpO(2) (95.8 +/- 2.6 vs. 95.2 +/- 2.6%), flank (36.7 +/- 0.4 vs. 36.5 +/- 0.4 degrees C), forearm (36.1 +/- 0.6 vs. 35.5 +/- 0.4 degrees C) and leg (35.4 +/- 0.7 vs. 34.7 +/- 0.7 degrees C) temperatures and narrower flank-to-forearm (0.6 +/- 0.4 vs. 0.9 +/- 0.3 degrees C) and flank-to-leg (1.3 +/- 0.6 vs. 1.8 +/- 0.7 degrees C) gradients, compared to those of the supine position. Similar differences were observed during AS. CONCLUSION: Perfusion index is a good non invasive estimate of tissue perfusion. Prone sleeping position is associated with a higher PI, possibly reflecting thermoregulatory adjustments in cardiovascular control. The effects of these position-related changes may have important implications for the increased risk for sudden infant death syndrome in prone position. PMID- 19785633 TI - Emotional reactivity in infants with congenital heart defects: findings from a large case-cohort study in Norway. AB - AIM: Advances in medical treatment in recent years have led to dramatically improved survival rates of children with severe congenital heart defects (CHD). However, very little is known about the psychological consequences for these children, particularly during and after the early period of invasive treatment. In this study, we investigated the extent to which the severity of the CHD affects the child's emotional reactivity at 6 months of age. METHOD: We linked prospective data from the Norwegian Mother and Child Cohort Study, conducted by the Norwegian Institute of Public Health with a nationwide medical CHD registry and identified 212 infants with CHD in a cohort of 61 299 infants. Mothers reported on their child's emotional reactivity at age 6 months by means of a standardized questionnaire. RESULTS: Infants with severe to moderate CHD had 60% higher odds for severe emotional reactivity (cut-off at the 85 percentile) compared with healthy infants, after controlling for important maternal and child confounders. CONCLUSION: Our study is the first to show elevated emotional reactivity in children with moderate to severe CHD, suggesting a need for special parental attention to soothe their distress. Follow-up studies will show whether this emotional reactivity is transient or an early marker of continuing emotional or behavioural problems. PMID- 19785634 TI - Metabolic profiles of fat and glucose differ by gender in healthy 8-year-olds. AB - OBJECTIVE: The aim was to investigate if metabolic markers were associated with anthropometry and weight increase in healthy 8-year-olds. METHODS: Ninety-seven healthy children, 66 of whom had been examined at the age of 4 years, were investigated. Dual energy X-ray absorptiometry was performed to determine fat (FM) and lean body mass (LBM). Plasma glucose and serum levels of insulin, cholesterol, triglycerides, adiponectin and leptin were analysed and HOMA-indices were calculated. RESULTS: Despite similar anthropometry, metabolic markers differed by gender. Sixteen % of the children were overweight or obese. Body mass index (BMI) was strongly correlated to FM. Anthropometric measures except LBM correlated to metabolic markers in the girls. Boys had higher concentrations of plasma glucose than girls. In overweight children, insulin was negatively associated with LBM. Leptin and the ratio between leptin and adiponectin, but not adiponectin, were significantly associated with HOMA-IR and body composition. CONCLUSION: The metabolic profile of plasma glucose, serum leptin, fasting insulin and related HOMA indices differed by gender, despite no difference in BMI or FM. LBM, but not FM correlated to the insulin concentration in the overweight children. Leptin was the best marker of overweight. PMID- 19785635 TI - Recurrent bloody nipple discharge in a 3-year-old boy. PMID- 19785636 TI - IGF-I, leptin and active ghrelin levels in very low birth weight infants during the first 8 weeks of life. AB - AIM: We investigated the relationship between plasma insulin-like growth factor I (IGF-I), leptin, active ghrelin levels, and postnatal growth in very low birth weight (VLBW) infants. METHOD: Plasma IGF-I, leptin, and active ghrelin levels were measured at birth and at 2, 4, 6 and 8 weeks after birth in 61 VLBW infants, including 31 appropriate-for-gestational-age (AGA) and 30 small-for-gestational age (SGA) infants. RESULTS: Insulin-like growth factor I levels were the lowest at birth, but increased gradually over the first 8 weeks of life. IGF-I was positively correlated with body weight, body length and body mass index at all time points. Leptin levels did not change over the study period. Ghrelin levels were significantly lower at birth; however, there were no significant differences between the levels after 2 weeks of age. Leptin and ghrelin levels were not correlated with anthropometrical measures. IGF-I levels at birth were significantly lower in SGA than in AGA infants, but the leptin and ghrelin levels were not significantly different between the two groups. CONCLUSION: Insulin-like growth factor I is related to length and weight gain in the prenatal and the early postnatal periods in VLBW infants, but this does not appear to be the case for leptin and ghrelin. PMID- 19785637 TI - Granular cell tumour of the lacrimal gland. PMID- 19785638 TI - Strong expression of HSP47 in metaplastic nasal mucosa may predict a poor outcome after primary endoscopic dacryocystorhinostomy: a prospective study. AB - PURPOSE: Dacryocystorhinostomy (DCR) is an effective and safe procedure for patients with post-saccal obstruction of the nasolacrimal pathway. The aim of DCR is to relieve symptoms by creating a bypass between the lacrimal sac and the nasal cavity. The most common reason for failure is stenosis caused by a fibrotic process at the rhinostomy site. In this prospective study we assessed the expression of heat shock protein 47 (HSP47), a regulator of fibrosis, in the biopsies of nasal mucosa isolated from patients undergoing primary endoscopic DCR (EN-DCR). METHODS: Thirty consecutive primary EN-DCR procedures in 30 patients were performed using the powered instrumentation technique. The nasal mucosa specimens over the rhinostomy site were collected for histological analysis at the beginning of the operation and the expression of HSP47 was evaluated by immunohistochemistry. The outcome of EN-DCR was estimated in follow-up visits at 1 week, 2 months and 6 months after surgery. RESULTS: At the 6-month follow-up, the overall success rate after primary EN-DCR was 83%. A metaplastic change and strong expression of HSP47 in nasal mucosa were associated with EN-DCR failure (p = 0.009). CONCLUSIONS: HSP47 may be regarded as a novel marker to predict impaired EN-DCR outcome. PMID- 19785639 TI - Amniotic membrane transplantation associated with a corneal patch in a paediatric corneal perforation. PMID- 19785640 TI - Anal sphincter EMG in the diagnosis of parkinsonian syndromes. AB - BACKGROUND: The role of electromyography (EMG) recorded from the external anal sphincter (EAS) in the diagnosis of atypical parkinsonian syndromes is a matter for continuous debate. Most studies addressing this issue are retrospective. METHODS: In this study, we prospectively investigated six patients with Parkinson's Disease (IPD), 14 patients with multiple system atrophy (MSA) and eight with progressive supranuclear palsy (PSP) using EMG of the EAS, motor evoked potential (MEP) to the EAS and EMG of m. gastrocnemius and nerve conduction velocity measured at the sural nerve. Patients were followed up for 2 years to secure correct diagnosis. RESULTS: The mean duration of motor unit potentials (MUPs) recorded from the EAS was significantly longer in patients with MSA and PSP compared with MUPs recorded from patients with PD (P < 0.005 for both). There were no signs of diffuse loss of motor neurons or peripheral neuropathy. MEP revealed signs of supranuclear affection in patients with MSA, whereas in patients with PSP the mechanism is a focal loss of motor neurons in Onuf's nucleus. CONCLUSION: Abnormal EMG of the EAS is strongly suggestive of atypical parkinsonism and the pathophysiology may be different in patients with MSA and PSP. PMID- 19785641 TI - The stability of AQT processing speed, ADAS-Cog and MMSE during acetylcholinesterase inhibitor treatment in Alzheimer's disease. AB - OBJECTIVES: To explore the longitudinal stability of measures of cognition during treatment with acetylcholinesterase inhibitors (AchEI) in patients with Alzheimer's disease (AD). MATERIALS AND METHODS: Cognitive status was measured in a cohort of 60 patients at 6 months after initiation of treatment with AchEI (baseline) and after an additional 6 months of treatment (endpoint). A Quick Test of Cognitive Speed (AQT), Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog), and MMSE were administered concurrently. RESULTS: Correlations (rho) between age and AQT processing speed were non-significant, but were significant for ADAS-Cog and Mini Mental State Examination (MMSE). AQT and ADAS-Cog means did not differ significantly between baseline and endpoint. There was a small, significant reduction in MMSE point scores. Measures of stability (Spearman's rho) were moderate-to-high for all tests. Means for subgroups did not differ as a function of medication type. CONCLUSIONS: AQT processing speed, ADAS-Cog, and MMSE measures proved stable during the second 6 months of treatment with AChEI. PMID- 19785642 TI - Serum heme oxygenase-1 levels are increased in Parkinson's disease but not in Alzheimer's disease. AB - OBJECTIVE: Oxidative stress is implicated in Parkinson's disease (PD) and Alzheimer's disease (AD), and heme oxygenase-1 (HO-1) is a potent antioxidant overexpressed in PD substantia nigra and AD cerebral cortex and hippocampus, indicating a possible up-regulation of antioxidant defenses in both neurodegenerative diseases. The role of HO-1 in peripheral blood of PD and AD patients remains unresolved. METHODS: We measured serum HO-1 levels in 107 patients with PD, 105 patients with AD, 104 controls for PD and 120 controls for AD. RESULTS: The median serum concentration of HO-1 was significantly higher in PD patients (2.04 ng/ml) compared with that of PD controls (1.69 ng/ml, P = 0.016), with PD patients predominating over controls in the upper tertile of serum HO-1 levels, whereas there was more PD controls than PD patients in the lower tertile (P = 0.006). Median serum levels of HO-1 did not differ significantly between AD patients and AD controls. CONCLUSION: The increase of serum HO-1 levels in PD patients could indicate a systemic antioxidant reaction related to a chronic oxidative stress state in PD brain. PMID- 19785643 TI - Hematopoietic stem cell transplantation in multiple sclerosis. AB - Intensive immunosuppresion followed by hematopoietic stem cell transplantation (HSCT) has been suggested as potential treatment in severe forms of multiple sclerosis (MS). Since 1995 ca. 400 patients have been treated with HSCT. Stabilization or improvement occurred in almost 70% of cases at least for 3 years post-transplant. Magnetic resonance revealed the capacity of autologous HSCT to suppress or markedly reduce gadolinium-enhancing lesions. The progression of brain atrophy declined after two years post-HSCT. The profound immunological changes following autologous HSCT may result in restoration of self-tolerance. Relatively young patients with active inflammatory lesions of relatively short duration and rapidly progressive disease, but still low disability scores, unresponsive to conventional therapy seem the best candidates for transplantation. Transplant-related mortality was 6% in the first EBMT report and 5.3% in the second one. No deaths were reported since 2001. Very high-intensity conditioning regimen is associated with higher risk of toxicity without significant increase in efficacy. The effects of transplantation and transplantation-related morbidity are dependent on patient-selection, time of transplantation and conditioning regimens used.This review is a comprehensive study of the results obtained in several single-center and multicenter studies. Patient characteristics, transplantations steps, toxicity and clinical outcome have been monitored and compared. PMID- 19785644 TI - Evidence of orbital B and T cell depletion after rituximab therapy in Graves' ophthalmopathy. PMID- 19785646 TI - Integrated risk assessment and predictive value to humans of non-clinical repolarization assays. AB - The potential for drugs to be associated with the life-threatening arrhythmia, Torsades de Pointes (TdeP), continues to be a topic of regulatory, academic and industrial concern. Despite being an imperfect biomarker, prolongation of the QT interval of the surface ECG is used to assess the risk of a drug being associated with TdeP such that a thorough examination of drug effects on the QT interval is required for all new chemical entities. Numerous studies have investigated the relationship between non-clinical findings and the risk of TdeP and QT prolongation in the general population. There are many literature references supporting the strong correlation between the clinical safety margin over human ether-a-go-go (hERG) inhibitory potency and the risk of drug-induced arrhythmia and sudden death. A quantitative analysis of the relationship between non clinical studies and the outcome of a human Thorough QT study has also been reported. In the current manuscript, based on the outcome of the non-clinical assays the sensitivity and specificity of each assay and an integrated risk assessment for predicting the outcome of the human Thorough QT study has been conducted. The data suggest that for QT prolongation mediated through inhibition of the hERG current the non-clinical assays are highly predictive of drug effects on the QT interval. Based on the literature review and specific quantitative analysis reported above it is concluded that non-clinical assays predict the risk of compounds to prolong the QT interval and cause TdeP in humans if the mechanism is through inhibition of the hERG current. PMID- 19785645 TI - Impact of OATP transporters on pharmacokinetics. AB - Membrane transporters are now recognized as important determinants of the transmembrane passage of drugs. Organic anion transporting polypeptides (OATP) form a family of influx transporters expressed in various tissues important for pharmacokinetics. Of the 11 human OATP transporters, OATP1B1, OATP1B3 and OATP2B1 are expressed on the sinusoidal membrane of hepatocytes and can facilitate the liver uptake of their substrate drugs. OATP1A2 is expressed on the luminal membrane of small intestinal enterocytes and at the blood-brain barrier, potentially mediating drug transport at these sites. Several clinically used drugs have been identified as substrates of OATP transporters (e.g. many statins are substrates of OATP1B1). Some drugs may inhibit OATP transporters (e.g. cyclosporine) causing pharmacokinetic drug-drug interactions. Moreover, genetic variability in genes encoding OATP transporters can result in marked inter individual differences in pharmacokinetics. For example, a single nucleotide polymorphism (c.521T > C, p.Val174Ala) in the SLCO1B1 gene encoding OATP1B1 decreases the ability of OATP1B1 to transport active simvastatin acid from portal circulation into the liver, resulting in markedly increased plasma concentrations of simvastatin acid and an enhanced risk of simvastatin-induced myopathy. SLCO1B1 polymorphism also affects the pharmacokinetics of many other, but not all (fluvastatin), statins and that of the antidiabetic drug repaglinide, the antihistamine fexofenadine and the endothelin A receptor antagonist atrasentan. This review compiles the current knowledge about the expression and function of human OATP transporters, their substrate and inhibitor specificities, as well as pharmacogenetics. PMID- 19785647 TI - Alosetron, cilansetron and tegaserod modify mesenteric but not colonic blood flow in rats. AB - BACKGROUND AND PURPOSE: As the use of the 5-HT(3) receptor antagonist alosetron (GlaxoSmithKline) and the 5-HT(4) receptor agonist tegaserod (Novartis) in patients with irritable bowel syndrome has been associated with cases of ischaemic colitis, the effects of alosetron, cilansetron (Solvay) and tegaserod on the rat splanchnic circulation were evaluated. EXPERIMENTAL APPROACH: Phenobarbital-anaesthetised rats were instrumented to record blood flow in the superior mesenteric artery and transverse colon and to calculate mesenteric and colonic vascular conductance. KEY RESULTS: Intravenous alosetron (0.03-0.3 mg.kg( 1)) did not alter blood pressure or heart rate but reduced mesenteric blood flow and vascular conductance by 15-20%. This activity profile was also seen after intraduodenal alosetron and shared by the 5-HT(3) receptor antagonist cilansetron. In contrast, blood flow, vascular conductance and intraluminal pressure in the colon were not modified by alosetron and cilansetron. Intravenous or intraduodenal tegaserod (0.3-1.0 mg.kg(-1)) had no inhibitory effect on mesenteric and colonic blood flow. Peroral treatment of rats with alosetron or tegaserod for 7 days did not modify mesenteric haemodynamics at baseline and after blockade of nitric oxide synthesis. Mild inflammation induced by dextran sulphate sodium failed to provoke a vasoconstrictor effect of cilansetron in the colon. CONCLUSIONS AND IMPLICATIONS: Alosetron and cilansetron, not tegaserod, caused a small and transient constriction of the rat mesenteric vascular bed, whereas blood flow in the colon remained unaltered. The relevance of these findings to the treatment-associated occurrence of ischaemic colitis in patients with irritable bowel syndrome remains open. PMID- 19785648 TI - Activation of the lung S1P(1) receptor reduces allergen-induced plasma leakage in mice. AB - BACKGROUND AND PURPOSE: It has been suggested that intratracheal administration of the immunomodulator, FTY720, could have anti-inflammatory effects without causing a decrease in blood lymphocyte counts. However, the receptor responsible for this effect has not been defined. EXPERIMENTAL APPROACH: We have described, in a mouse model of allergen-induced inflammation, the use of proton magnetic resonance imaging to non-invasively assess lung fluid accumulation and inflammation. Here, we used this model to investigate the sphingosine-1-phosphate (S1P) receptor responsible for the anti-inflammatory effect of FTY720. KEY RESULTS: When given intranasally, FTY720 (3 and 10 microg.kg(-1)) inhibited by approximately 50% the allergen-induced accumulation of fluid in the lung detected by magnetic resonance imaging, but had no effect on the cellular inflammation in the airway space or on circulating blood lymphocytes. Inhibition of the infiltration of inflammatory cells into the airways was only observed at a dose of FTY720 that induced lymphopenia (100 microg.kg(-1)). Similar results were observed in S1P(3)-deficient mice. The effect of FTY720 was mimicked by intranasal treatment of wild-type mice with a S1P(1)-specific agonist, AUY954. CONCLUSIONS AND IMPLICATIONS: Thus, in contrast to previously published work, our results suggest that systemic exposure of FTY720 is necessary to obtain an airway anti-inflammatory effect. On the contrary, inhibition of the allergen-induced accumulation of fluid in the lung, via activation of the S1P(1) receptor, is obtainable without systemic effects. PMID- 19785650 TI - Actions of hydrogen sulphide on ion transport across rat distal colon. AB - BACKGROUND AND PURPOSE: The aim of this study was to identify the actions of H(2)S on ion transport across rat distal colon. EXPERIMENTAL APPROACH: Changes in short-circuit current (Isc) induced by the H(2)S-donor, NaHS, were measured in Ussing chambers. Cytosolic Ca(2+) concentration was evaluated using fura-2. KEY RESULTS: NaHS concentration-dependently induced a change in Isc, that was only partially inhibited by the neurotoxin, tetrodotoxin. Lower concentrations (< or =10(-3) mol.L(-1)) of NaHS induced a monophasic increase in Isc, whereas higher concentrations induced an additional, secondary fall of Isc, before a third phase when Isc rose again. Blockers of H(2)S-producing enzymes (expression demonstrated immunohistochemically) decreased basal Isc, suggesting that endogenous production of H(2)S contributes to spontaneous anion secretion. The positive Isc phases induced by NaHS were due to Cl(-) secretion as shown by anion substitution and transport inhibitor experiments, whereas the transient negative Isc induced by higher concentrations of the H(2)S-donor was inhibited by mucosal tetrapentylammonium suggesting a transient K(+) secretion. When applied from the serosal side, glibenclamide, an inhibitor of ATP-sensitive K(+) channels, and tetrapentylammonium, a blocker of Ca(2+)-dependent K(+) channels, suppressed NaHS induced Cl(-) secretion suggesting different types of K(+) channels are stimulated by the H(2)S-donor. NaHS-induced increase in cytosolic Ca(2+) concentration was confirmed in isolated, fura-2-loaded colonic crypts. This response was not dependent on extracellular Ca(2+), but was inhibited by blockers of intracellular Ca(2+) channels present on Ca(2+) storage organelles. CONCLUSIONS AND IMPLICATIONS: H(2)S induces colonic ion secretion by stimulation of apical as well as basolateral epithelial K(+) channels. PMID- 19785649 TI - Lactacystin requires reactive oxygen species and Bax redistribution to induce mitochondria-mediated cell death. AB - BACKGROUND AND PURPOSE: The proteasome inhibitor model of Parkinson's disease (PD) appears to reproduce many of the important behavioural, imaging, pathological and biochemical features of the human disease. However, the mechanisms involved in the lactacystin-induced, mitochondria-mediated apoptotic pathway remain poorly defined. EXPERIMENTAL APPROACH: We have used lactacystin as a specific inhibitor of the 20S proteasome in the dopaminergic neuroblastoma cell line SH-SY5Y. We over-expressed a green fluorescent protein (GFP)-Bax fusion protein in these cells to study localization of Bax. Free radical scavengers were used to assess the role of reactive oxygen species (ROS) in these pathways. KEY RESULTS: Lactacystin triggered a concentration-dependent increase in cell death mediated by the mitochondrial apoptotic pathway, and induced a change in mitochondrial membrane permeability accompanied by cytochrome c release. The participation of Bax protein was more critical than the formation of the permeability transition pore in mitochondria. GFP-Bax over-expression demonstrated Bax redistribution from the cytosol to mitochondria after the addition of lactacystin. ROS, but not p38 mitogen-activated protein kinase, participated in lactacystin-induced mitochondrial Bax translocation. Lactacystin disrupted the intracellular redox state by increasing ROS production and depleting endogenous antioxidant systems such as glutathione (GSH). Pharmacological depletion of GSH, using L-buthionine sulphoxide, potentiated lactacystin-induced cell death. Lactacystin sensitized neuroblastoma cells to oxidative damage, induced by subtoxic concentrations of 6-hydroxydopamine. CONCLUSIONS AND IMPLICATIONS: The lactacystin-induced, mitochondrial-mediated apoptotic pathway involved interactions between ROS, GSH and Bax. Lactacystin could constitute a potential factor in the development of sporadic PD. PMID- 19785651 TI - Reversal of temperature-induced conformational changes in the amyloid-beta peptide, Abeta40, by the beta-sheet breaker peptides 16-23 and 17-24. AB - BACKGROUND AND PURPOSE: Aggregates of the protein amyloid-beta (Abeta) play a crucial role in the pathogenesis of Alzheimer's disease (AD). Most therapeutic approaches to AD do not target Abeta, so determination of the factor(s) that facilitate aggregation and discovering agents that prevent aggregation have great potential therapeutic value. EXPERIMENTAL APPROACH: We investigated ex vivo the temperature-sensitive regions of Abeta1-40 (Abeta40) and their interactions with octapeptides derived from sequences within Abeta40 -beta-sheet breaker peptides (betaSBP) - using enzyme-linked immunosorbent assay, and dot blot and far-UV circular dichroism (CD) spectroscopy. We measured changes within the physiological limits of temperature, using antibodies targeting epitopes 1-7, 5 10, 9-14 and 17-21 within Abeta40. KEY RESULTS: Temperature-dependent conformational changes were observed in Abeta40 at epitopes 9-14 and 17-21 at 36 38 and 36-40 degrees C respectively. The betaSBPs 16-23 and 17-24, but not 15-22 and 18-25, could inhibit the changes. Moreover, betaSBPs 16-23 and 17-24 increased digestion of Abeta40 by protease K, indicating a decreased aggregation of Abeta40, whereas betaSBPs 15-22 and 18-25 did not increase this digestion. CD spectra revealed that beta-sheet formation in Abeta40 at 38 degrees C was reduced with betaSBPs 16-23 and 17-24. CONCLUSIONS AND IMPLICATIONS: The epitopes 9-14 and 17-21 are the temperature-sensitive regions within Abeta40. The betaSBPs, Abeta16-23 and 17-24 reversed temperature-induced beta-sheet formation, and decreased Abeta40 aggregation. The results suggest that the 17-23 epitope of Abeta40 is crucially involved in preventing Abeta40 aggregation and consequent deposition of Abeta40 in AD brain. PMID- 19785652 TI - Regulation by FK506 and rapamycin of Ca2+ release from the sarcoplasmic reticulum in vascular smooth muscle: the role of FK506 binding proteins and mTOR. AB - BACKGROUND AND PURPOSE: The sarcoplasmic reticulum (SR), regulates the cytoplasmic Ca(2+) concentration ([Ca(2+)](cyto)) in vascular smooth muscle. Release from the SR is controlled by two intracellular receptor/channel complexes, the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP(3)R). These receptors may be regulated by the accessory FK506 binding protein (FKBP) either directly, by binding to the channel, or indirectly via FKBP modulation of two targets, the phosphatase, calcineurin or the kinase, mammalian target of rapamycin (mTOR). EXPERIMENTAL APPROACH: Single portal vein myocytes were voltage-clamped in whole cell configuration and [Ca(2+)](cyto) measured using fluo-3. IP(3)Rs were activated by photolysis of caged IP(3) and RyRs activated by hydrostatic application of caffeine. KEY RESULTS: FK506 which displaces FKBP from each receptor (to inhibit calcineurin) increased the [Ca(2+)](cyto) rise evoked by activation of either RyR or IP(3)R. Rapamycin which displaces FKBP (to inhibit mTOR) also increased the amplitude of the caffeine evoked, but reduced the IP(3)-evoked [Ca(2+)](cyto) rise. None of the phosphatase inhibitors, cypermethrin, okadaic acid or calcineurin inhibitory peptide, altered either caffeine- or IP(3)-evoked [Ca(2+)](cyto) release; calcineurin did not contribute to FK506-mediated potentiation of RyR- or IP(3)R-mediated Ca(2+) release. The mTOR inhibitor LY294002, like rapamycin, decreased IP(3)-evoked Ca(2+) release. CONCLUSIONS AND IMPLICATIONS: Ca(2+) release in portal vein myocytes, via RyR, was modulated directly by FKBP binding to the channel; neither calcineurin nor mTOR contributed to this regulation. However, IP(3)R-mediated Ca(2+) release, while also modulated directly by FKBP may be additionally regulated by mTOR. Rapamycin inhibition of IP(3)-mediated Ca(2+) release may be explained by mTOR inhibition. PMID- 19785653 TI - Evidence that 5-hydroxytryptamine(7) receptors play a role in the mediation of afferent transmission within the nucleus tractus solitarius in anaesthetized rats. AB - BACKGROUND AND PURPOSE: Central 5-hydroxytryptamine (5-HT)-containing pathways utilizing 5-HT(7) receptors are known to be critical for the mediation of cardiovascular reflexes. The nucleus tractus solitarius (NTS) is a site involved in the integration of cardiovascular afferent information. The present experiments examined the involvement of the 5-HT(7) receptor in the processing of cardiovascular reflexes in the NTS. EXPERIMENTAL APPROACH: In anaesthetized rats extracellular recordings were made from 104 NTS neurones that were excited by electrical stimulation of the vagus nerve and/or activation of cardiopulmonary afferents. Drugs were applied ionophoretically in the vicinity of these neurones. KEY RESULTS: The non-selective 5-HT(7) receptor agonist 5-carboxamidotryptamine maleate (5-CT) applied to 78 neurones increased the firing rate in 18 by 59% and decreased it in 38 neurones by 47%. Similarly, the 5-HT(1A) agonist 8-OH-DPAT applied to 20 neurones had an excitatory (8), inhibitory (7) or no effect (5) on the 20 neurones tested. In the presence of the 5-HT(7) antagonist SB 258719 the 5 CT excitation was attenuated. Furthermore, the excitatory response of NTS neurones evoked by electrical stimulation of the vagus nerve or activation of cardiopulmonary afferents with intra atrial phenylbiguanide was attenuated by SB 258719. The inhibitory action of 5-CT was unaffected by SB 258719 and the 5 HT(1A) antagonist WAY-100635. WAY-100635 failed to have any effect on 5-CT and vagal afferent-evoked excitations. CONCLUSIONS AND IMPLICATIONS: Vagal afferent evoked excitation of NTS neurones can be blocked by SB 258719, a selective 5 HT(7) antagonist. This observation further supports the involvement of 5-HT neurotransmission in NTS afferent processing. PMID- 19785654 TI - Effects of inactivation-resistant agonists on the signalling, desensitization and down-regulation of bradykinin B(2) receptors. AB - BACKGROUND AND PURPOSE: A peptide bradykinin (BK) B(2) receptor agonist partially resistant to degradation, B-9972, down-regulates this receptor subtype. We have used another recently described non-peptide agonist, compound 47a, as a tool to study further the effects of metabolically more stable and thus persistent, agonists of the BK B(2) receptor on signalling, desensitization and down regulation of this receptor. EXPERIMENTAL APPROACH AND KEY RESULTS: Compound 47a was a partial agonist at the B(2) receptor in the human umbilical vein, where it shared with B-9972 a very slow relaxation on washout, and in HEK 293 cell lines expressing tagged forms [myc, green fluorescent protein (GFP)] of the rabbit B(2) receptor. Compound 47a desensitized the umbilical vein to BK. In the cellular systems, the inactivation-resistant agonists induced [Ca(2+)](i) transients as brief as those of BK but affected other functions with a longer duration than BK [12 h; receptor endocytosis, endosomal beta-arrestin(1/2) translocation, protein kinase C-dependent extracellular signal-regulated kinases (ERK)1/2 phosphorylation and c-Fos expression]. The B(2) receptor-GFP was degraded in cells exposed to B-9972 or compound 47a for 12 h. The non-peptide B(2) receptor antagonist LF 16-0687 prevented all effects of compound 47a, which were also absent in cells lacking recombinant B(2) receptors. CONCLUSION AND IMPLICATIONS: Inactivation-resistant agonists revealed a long-lasting assembly of the agonist B(2) receptor-beta-arrestin complexes in endosomal structures and induce 'biased signalling' (in terms of activation of ERK and c-Fos) as a function of time. Further, B-9972 and compound 47a, unlike BK, efficiently down-regulated BK B(2) receptors. PMID- 19785655 TI - Long-term blockade of L/N-type Ca(2+) channels by cilnidipine ameliorates repolarization abnormality of the canine hypertrophied heart. AB - BACKGROUND AND PURPOSE: The heart of the canine model of chronic atrioventricular block is known to have a ventricular electrical remodelling, which mimics the pathophysiology of long QT syndrome. Using this model, we explored a new pharmacological therapeutic strategy for the prevention of cardiac sudden death. EXPERIMENTAL APPROACH: The L-type Ca(2+) channel blocker amlodipine (2.5 mg.day( 1)), L/N-type Ca(2+) channel blocker cilnidipine (5 mg.day(-1)), or the angiotensin II receptor blocker candesartan (12 mg.day(-1)) was administered orally to the dogs with chronic atrioventricular block for 4 weeks. Electropharmacological assessments with the monophasic action potential (MAP) recordings and blood sample analyses were performed before and 4 weeks after the start of drug administration. KEY RESULTS: Amlodipine and cilnidipine decreased the blood pressure, while candesartan hardly affected it. The QT interval, MAP duration and beat-to-beat variability of the ventricular repolarization period were shortened only in the cilnidipine group, but such effects were not observed in the amlodipine or candesartan group. Plasma concentrations of adrenaline, angiotensin II and aldosterone decreased in the cilnidipine group. In contrast, plasma concentrations of angiotensin II and aldosterone were elevated in the amlodipine group, whereas in the candesartan group an increase in plasma levels of angiotensin II and a decrease in noradrenaline and adrenaline concentrations were observed. CONCLUSIONS AND IMPLICATIONS: Long-term blockade of L/N-type Ca(2+) channels ameliorated the ventricular electrical remodelling in the hypertrophied heart which causes the prolongation of the QT interval. This could provide a novel therapeutic strategy for the treatment of cardiovascular diseases. PMID- 19785656 TI - Phosphorylation alters the pharmacology of Ca(2+)-activated Cl channels in rabbit pulmonary arterial smooth muscle cells. AB - BACKGROUND AND PURPOSE: Ca(2+)-activated Cl(-) currents (I(Cl(Ca))) in arterial smooth muscle cells are inhibited by phosphorylation. The Ca(2+)-activated Cl(-) channel (Cl(Ca)) blocker niflumic acid (NFA) produces a paradoxical dual effect on I(Cl(Ca)), causing stimulation or inhibition at potentials below or above 0 mV respectively. We tested whether the effects of NFA on I(Cl(Ca)) were modulated by phosphorylation. EXPERIMENTAL APPROACH: I(Cl(Ca)) was elicited with 500 nM free internal Ca(2+) in rabbit pulmonary artery myocytes. The state of global phosphorylation was altered by cell dialysis with either 5 mM ATP or 0 mM ATP with or without an inhibitor of calmodulin-dependent protein kinase type II, KN 93 (10 microM). KEY RESULTS: Dephosphorylation enhanced the ability of 100 microM NFA to inhibit I(Cl(Ca)). This effect was attributed to a large negative shift in the voltage-dependence of block, which was converted to stimulation at potentials <-50 mV, approximately 70 mV more negative than cells dialysed with 5 mM ATP. NFA dose-dependently blocked I(Cl(Ca)) in the range of 0.1-250 microM in cells dialysed with 0 mM ATP and KN-93, which contrasted with the stimulation induced by 0.1 microM, which converted to block at concentrations >1 microM when cells were dialysed with 5 mM ATP. CONCLUSIONS AND IMPLICATIONS: Our data indicate that the presumed state of phosphorylation of the pore-forming or regulatory subunit of Cl(Ca) channels influenced the interaction of NFA in a manner that obstructs interaction of the drug with an inhibitory binding site. PMID- 19785657 TI - Acute dilation to alpha(2)-adrenoceptor antagonists uncovers dual constriction and dilation mediated by arterial alpha(2)-adrenoceptors. AB - BACKGROUND AND PURPOSE: In mouse tail arteries, selective alpha(2)-adrenoceptor antagonism with rauwolscine caused powerful dilation during constriction to the alpha(1)-adrenoceptor agonist phenylephrine. This study therefore assessed phenylephrine's selectivity at vascular alpha-adrenoceptors and the mechanism(s) underlying dilation to rauwolscine. EXPERIMENTAL APPROACH: Mouse isolated tail arteries were assessed using a pressure myograph. KEY RESULTS: The alpha(2) adrenoceptor agonist UK14,304 caused low-maximum constriction that was inhibited by rauwolscine (3 x 10(-8) M) but not by the selective alpha(1)-adrenoceptor antagonist prazosin (10(-7) M). Concentration-effect curves to phenylephrine, cirazoline or noradrenaline were unaffected by rauwolscine but were inhibited by prazosin, which was more effective at high compared with low levels of constriction. In the presence of prazosin, rauwolscine inhibited the curves and was more effective at low compared with high levels of constriction. Although rauwolscine alone did not affect concentration-effect curves to phenylephrine, noradrenaline or cirazoline, it caused marked transient dilation when administered during constriction to these agonists. Dilation was mimicked by another alpha(2)-adrenoceptor antagonist (RX821002, 3 x 10(-8) M), was dependent on agonist selectivity, and did not occur during adrenoceptor-independent constriction (U46619). During constriction to UK14,304 plus U46619, rauwolscine or rapid removal of UK14,304 caused transient dilation that virtually abolished the combined constriction. Endothelial denudation reduced these dilator responses. CONCLUSIONS AND IMPLICATIONS: Inhibition of alpha(2)-adrenoceptors caused transient dilation that was substantially greater than the contribution of alpha(2)-adrenoceptors to the constriction. This reflects a slowly reversing alpha(2)-adrenoceptor-mediated endothelium-dependent dilation and provides a rapid, sensitive test of alpha(2)-adrenoceptor activity. This approach also clearly emphasizes the poor selectivity of phenylephrine at vascular alpha adrenoceptors. PMID- 19785658 TI - alpha-Fetoprotein as a modulator of the pro-inflammatory response of human keratinocytes. AB - BACKGROUND AND PURPOSE: The immunomodulatory effects of alpha-fetoprotein (AFP) on lymphocytes and macrophages have been described in vitro and in vivo. Recombinant forms of human AFP have been proposed as potential therapeutic entities for the treatment of autoimmune diseases. We examined the effects of embryonic and recombinant human AFP on the spontaneous, UVA- and cytokine-induced pro-inflammatory responses of human keratinocytes. EXPERIMENTAL APPROACH: Cultures of primary and immortalized human keratinocytes (HaCaT) and human blood T lymphocytes were used. The effects of AFP on cytokine expression were studied by bioplexed elisa and quantitative reverse transcriptase polymerase chain reaction assay. Kinase and nuclear factor kappa B (NFkappaB) phosphorylation were quantified by intracellular elisa. Nuclear activator protein 1 and NFkappaB DNA binding activity was measured by specific assays. Nitric oxide and H(2)O(2) production and redox status were assessed by fluorescent probe and biochemical methods. KEY RESULTS: All forms of AFP enhanced baseline expression of cytokines, chemokines and growth factors. AFP dose-dependently increased tumour necrosis factor alpha-stimulated granulocyte macrophage colony stimulating factor and interleukin 8 expression and decreased tumour necrosis factor alpha-induced monocyte chemotactic protein 1 and IP-10 (interferon gamma-produced protein of 10 kDa) expression. AFP induced a marked activator protein 1 activation in human keratinocytes. AFP also increased H(2)O(2) and modulated nitrite/nitrate levels in non-stimulated keratinocytes whereas it did not affect these parameters or cytokine release from UVA-stimulated cells. Phosphorylation of extracellular signal-regulated kinase (ERK1/2) and Akt1 but not NFkappaB was activated by AFP alone or by its combination with UVA. CONCLUSIONS AND IMPLICATIONS: Exogenous AFP induces activation of human keratinocytes, with de novo expression of a number of pro-inflammatory mediators and modulation of their pro-inflammatory response to cytokines or UVA. AFP may modulate inflammatory events in human skin. PMID- 19785659 TI - The NO donor DETA-NONOate reversibly activates an inward current in neurones and is not mediated by the released nitric oxide. AB - BACKGROUND AND PURPOSE: It has been previously shown that high levels of nitric oxide (NO), from NO donors, kill neurones, but the mechanisms are unclear. EXPERIMENTAL APPROACH: The effects of NO donors on the electrical properties of rat cultured cerebellar granule cells (CGC neurones) were investigated using the whole-cell patch-clamp technique. KEY RESULTS: The NO donor (Z)-1-[2-(2 aminoethyl)-N-(2-ammonioethyl)amino]diazen-1-ium-1,2-diolate (DETA-NONOate or NOC 18) caused a rapid, persistent, but fully reversible inward current that was associated with an increase in baseline noise and was concentration dependent (100 microM-10 mM). The response to 3 mM DETA-NONOate was completely inhibited by 1 mM gadolinium, but not by NO scavengers (1 mM haemoglobin or 1 mM PTIO) or glutamate receptor antagonists (10 microM MK-801 or 60 microM CNQX). Application of decomposed 3 mM DETA-NONOate or 3 mM nitrite had no effect. In contrast, the NO donor S-nitrosoglutathione (GSNO) caused a rapid, persistent, but fully reversible outward current that was also concentration dependent (1-10 mM). The 3 mM GSNO response was unaltered by NO scavengers, glutamate antagonists or gadolinium, but was mimicked by decomposed 3 mM GSNO and 3 mM oxidized glutathione. CONCLUSIONS AND IMPLICATIONS: These results suggest that DETA NONOate directly activates cation-selective channels, causing an inward current in CGCs. In contrast, GSNO causes an outward current in these cells. Some of the effects of these NO donors are independent of NO, and thus caution is required in interpreting results when using high concentrations of these compounds. PMID- 19785660 TI - The Scar-in-a-Jar: studying potential antifibrotic compounds from the epigenetic to extracellular level in a single well. AB - BACKGROUND AND PURPOSE: Fibrosis, a pathological accumulation of collagen in tissues, represents a major global disease burden. Effective characterization of potential antifibrotic drugs has been constrained by poor formation of the extracellular matrix in vitro, due to tardy procollagen processing by collagen C proteinase/BMP-1, and difficulties in relating this matrix to cell numbers in experimental samples. EXPERIMENTAL APPROACH: The Scar-in-a-Jar model provided, in vitro, the complete biosynthetic cascade of collagen matrix formation including complete conversion of procollagen by C-proteinase/BMP-1, its subsequent extracellular deposition and lysyl oxidase-mediated cross-linking, achieved by applying the biophysical principle of macromolecular 'crowding'. Collagen matrix deposition, velocity and morphology can be controlled using negatively charged 'crowders' in a rapid (2 days) mode or a mixture of neutral 'crowders' in an accelerated (6 days) mode. Combined with quantitative optical bioimaging, this novel system allows for in situ assessment of the area of deposited collagen(s) per cell. KEY RESULTS: Optical evaluation of known and novel antifibrotic compounds effective at the epigenetic, post transcriptional/translational/secretional level correlated excellently with corresponding biochemical analyses. Focusing on quantitation of deposited collagen, the Scar-in-a-Jar was most effective in assessing novel inhibitors that may have multiple targets, such as microRNA29c, found to be a promising antifibrotic agent. CONCLUSIONS AND IMPLICATIONS: This novel screening system supersedes current in vitro fibroplasia models, as a fast, quantitative and non destructive technique. This method distinguishes a reduction in collagen I deposition, excluding collagen cross-linking, and allows full evaluation of inhibitors of C-proteinase/BMP-1 and other matrix metalloproteinases. PMID- 19785662 TI - Interaction of nilotinib, dasatinib and bosutinib with ABCB1 and ABCG2: implications for altered anti-cancer effects and pharmacological properties. AB - BACKGROUND AND PURPOSE: ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-molecule, tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity. EXPERIMENTAL APPROACH: MDR-ABC transporter function was screened in both membrane and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl positive model cells were coupled with direct determination of intracellular TKI concentrations by high-pressure liquid chromatography-mass spectrometry and analysis of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity. KEY RESULTS: Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters. CONCLUSIONS AND IMPLICATIONS: A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs. PMID- 19785661 TI - Lipoxins: resolutionary road. AB - The resolution of inflammation is an active process controlled by endogenous mediators with selective actions on neutrophils and monocytes. The initial phase of the acute inflammatory response is characterized by the production of pro inflammatory mediators followed by a second phase in which lipid mediators with pro-resolution activities may be generated. The identification of these mediators has provided evidence for the dynamic regulation of the resolution of inflammation. Among these endogenous local mediators of resolution, lipoxins (LXs), lipid mediators typically formed during cell-cell interaction, were the first to be recognized. More recently, families of endogenous chemical mediators, termed resolvins and protectins, were discovered. LXs and aspirin-triggered LXs are considered to act as 'braking signals' in inflammation, limiting the trafficking of leukocytes to the inflammatory site. LXs are actively involved in the resolution of inflammation stimulating non-phlogistic phagocytosis of apoptotic cells by macrophages. Furthermore, LXs have emerged as potential anti fibrotic mediators that may influence pro-fibrotic cytokines and matrix associated gene expression in response to growth factors. Here, we provide a review and an update of the biosynthesis, metabolism and bioactions of LXs and LX analogues, and the recent studies on their therapeutic potential as promoters of resolution and fibro-suppressants. PMID- 19785663 TI - Effects of nucleoside reverse transcriptase inhibitor backbone on the efficacy of first-line boosted highly active antiretroviral therapy based on protease inhibitors: meta-regression analysis of 12 clinical trials in 5168 patients. AB - OBJECTIVES: Tenofovir/emtricitabine (TDF/FTC) and abacavir/lamivudine (ABC/3TC) are widely used with ritonavir (RTV)-boosted protease inhibitors (PIs) as first line highly active antiretroviral therapy (HAART), but there is conflicting evidence on their relative efficacy. The ACTG 5202 and BICOMBO trials suggested higher efficacy for TDF/FTC, whereas the HEAT trial showed no efficacy difference between the nucleoside reverse transcriptase inhibitor (NRTI) backbones. METHODS: A systematic MEDLINE search identified 21 treatment arms in 12 clinical trials of 5168 antiretroviral-naive patients, where TDF/FTC (n=3399) or ABC/3TC (n=1769) was used with RTV-boosted PI. For each NRTI backbone and RTV-boosted PI, the percentage of patients with viral load <50 HIV-1 RNA copies/mL at week 48 by standardized Intent to Treat, Time to Loss of Virological Failure (ITT TLOVR) analysis were combined using inverse-variance weighting. The effect of baseline HIV RNA, CD4 cell count and choice of NRTI backbone were examined using a weighted analysis of covariance. RESULTS: Across all the trials, HIV RNA suppression rates were significantly higher for those with baseline viral load below 100,000 copies/mL (77.2%) vs. above 100,000 copies/mL (70.9%) (P=0.0005). For the trials of lopinavir/ritonavir (LPV/r), atazanavir/ritonavir (ATV/r) and fosamprenavir/ritonavir (FAPV/r) using either TDF/FTC or ABC/3TC, the HIV RNA responses were significantly lower when ABC/3TC was used, relative to TDF/FTC, for all patients (P=0.0015) and for patients with baseline viral load <100,000 copies/mL (70.1%vs. 80.6%, P=0.0161), and was borderline for those with viral load >100,000 copies/mL (67.5%vs. 71.5%, P=0.0523). CONCLUSIONS: This systematic meta-regression analysis suggests higher efficacy for first-line use of a TDF/FTC NRTI backbone with boosted PIs, relative to use of ABC/3TC. However, this effect may be confounded by differences between the trials in terms of baseline characteristics, patient management or adherence. PMID- 19785664 TI - Boosted protease inhibitors as a therapeutic option in the treatment of HIV infected children. AB - OBJECTIVE: Paediatric HIV treatment must address various special considerations. Administration of pharmacokinetically enhanced protease inhibitors (PIs) can improve paediatric therapeutic outcomes. The objective of this study was to review the use of boosted PI regimens in children. METHODS: Systematic literature searches of published manuscripts and conference databases using generic drug names and specific keywords were performed to ensure thorough and balanced reporting of available data. RESULTS: Boosted PI regimens offer multiple options across a range of ages and are efficacious in naive and experienced children; safety and tolerability are similar to those observed in adults. Novel boosted PI simplification approaches may foster adherence and diminish resistance. CONCLUSIONS: Boosted PIs are key components of first- and second-line treatments in children. Identifying factors associated with the response to highly active antiretroviral therapy in children may ultimately permit individualized therapies. PMID- 19785665 TI - Active tuberculosis and Mycobacterium tuberculosis latent infection in patients with HIV/AIDS. AB - OBJECTIVES: Tuberculosis (TB) remains an important disease associated with HIV infection and AIDS in Brazil, even in a setting of free access to antiretroviral therapy (ART) and TB treatment. In previous studies, isoniazid therapy (IT) for latent infection with Mycobacterium tuberculosis (LIMTb) was found to reduce the risk of TB by 62% in patients with a tuberculin test (TT)>5 mm. The objectives of this study were to investigate the occurrence of TB, the prevalence of LIMTb and the coverage of the TT and IT, and to estimate the number of missed opportunities to prevent TB in patients with HIV/AIDS. METHODS: A random sample of patients with HIV/AIDS was selected; data from the medical files were obtained, and a TT was performed in consenting subjects. RESULTS: In the 203 subjects included in the study, TB occurrence was 13.3%, LIMTb prevalence was 20% and the coverage of the TT and IT was 59.2 and 55%, respectively. Patients with TB had a lower nadir CD4 cell count, but their CD4 recovery was comparable to that of non-TB patients. Patients with LIMTb always had a higher CD4 cell count. CONCLUSIONS: By expanding the coverage of the TT and IT to nearly 100%, we could more than double the number of prevented cases of TB. TB prevention programmes must be reinforced to reduce the number of missed opportunities for diagnosis, and IT must be improved to reduce TB among patients with HIV/AIDS. Empowering patients with knowledge about TB, the preventive role of IT and the need for an annual TT may be the best way of lowing rates of TB in patients with HIV/AIDS. PMID- 19785666 TI - The relationship between antiretroviral prescription patterns and treatment guidelines in treatment-naive HIV-1-infected patients. AB - BACKGROUND: Reports have shown that the publication of practice guidelines does not guarantee their use in clinical practice. The objective of this study was to evaluate the agreement between antiretroviral treatments (ARTs) prescribed in clinical practice and the recommendations in published guidelines. METHODS: A retrospective cohort study was carried out in ART-naive adults of the Spanish Asociacion Medica Vach de Estudios Multicentricos (VACH) Cohort for the period from 2003 to 2006. RESULTS: A total of 945 patients initiated ART. Of these patients, 12.3% had a CD4 cell count above 350 cells/microL. A 'nonrecommended' antiretroviral regimen was prescribed to 5.3, 5.1 and 7.8% of patients with CD4 counts <200, 200-350 and >350 cells/microL, respectively. Multivariate analyses demonstrated that only a higher viral load was associated with the selection of a combination treatment that was recommended by the guidelines. CONCLUSIONS: Most patients were prescribed initial treatments in agreement with the recommendations. Appropriate routine data collection in databases can be used to evaluate the level of antiretroviral guideline compliance. We propose that routine evaluations of the guidelines must be part of quality assessment to improve medical care. PMID- 19785667 TI - Impact of hyperglycaemia and cholesterol levels on the outcome of hepatitis C virus (HCV) treatment in HIV/HCV-coinfected patients. AB - OBJECTIVES: High serum total cholesterol and low-density lipoprotein (LDL) levels have been demonstrated to increase the probability of a sustained viral response (SVR) in chronic hepatitis C. Conversely, insulin resistance reduces SVR rates. We investigated the influence of baseline glucose and lipid values on the outcome of hepatitis C virus (HCV) treatment in HIV-1 infected subjects. METHODS: We retrospectively reviewed the charts of HIV/HCV-coinfected patients treated with an interferon-based regimen from 2002 to 2008. Fasting glucose levels and total cholesterol, LDL and triglyceride levels were recorded prior to the initiation of treatment. RESULTS: Of the 96 patients enrolled in the study, 36 (37.5%) had genotype 1, 48 (50%) genotype 2 or 3 and 12 (12.5%) genotype 4. SVR was obtained in 25% (nine of 36) and 70% (42 of 60) of patients with genotype 1 and other genotypes, respectively. In the multivariate analysis, the independent predictors of SVR were: genotype other than genotype 1 [adjusted odds ratio 9.64, confidence interval (CI) 2.7-34.3; P<0.0001], HCV viraemia [adjusted odds ratio 0.36, CI 0.15-0.9; P=0.028], fasting glucose > or =100 mg/dL [adjusted odds ratio 0.13, CI 0.034-0.51; P=0.003], and cholesterol level > or =190 mg/dL [adjusted odds ratio 5.96, CI 1.6-22.3; P=0.008]. CONCLUSIONS: Higher baseline serum glucose and cholesterol levels may be significant prognostic indicators for anti-HCV treatment outcome in HIV/HCV-coinfected patients. PMID- 19785668 TI - Head nodding syndrome and river blindness: a parasitologic perspective. PMID- 19785669 TI - System epilepsy: reply to Luders et al., 2009. PMID- 19785670 TI - Generalized spike-wave discharges and seizures with focal ictal transformation: mechanisms in absence (CAE) and myoclonic (JME) IGEs. PMID- 19785673 TI - Organised stroke care for rural Australians. PMID- 19785674 TI - Equipping patients for a time of helplessness: an educational intervention. AB - OBJECTIVES: Quantify rates of awareness about, and ownership of, End-of-Life Planning (ELP) instruments. Examine whether this rate is increased by brief education during routine team care. Measure the time required by this exercise. DESIGN: Quality Improvement Activity. SETTING: General Practice on Mid-North Coast, New South Wales. PARTICIPANTS: Forty-two consecutive, consenting elderly patients undertaking a Home Health Assessment. MAIN OUTCOME MEASURES: This study assessed rates of ELP instruments at baseline, at 2 weeks, at 2 months and at 2 years following the provision and discussion of a fact sheet while measuring the clinicians' time required. RESULTS: This education exercise increased the number of patients with ELP instruments from one to ten (24%). On average it took 5.6 min of nursing time and 3.9 min for the GP. CONCLUSIONS: Brief education during Home Health Assessments may empower patients to prepare for a scenario where they lost competency to make fully informed decisions. This may alleviate patient's fears about causing problems between those close to them and having treatments against their wishes. PMID- 19785675 TI - Rural pharmacist perceptions of a project assessing their role in the management of depression. AB - OBJECTIVE: This paper explores pharmacist perceptions of a pilot study assessing the impact of specialist training on depression for rural community pharmacists on their understanding of treatment and psychological well-being of patients. DESIGN: Mixed method survey. SETTING: Rural community pharmacies. PARTICIPANTS: Thirty-two rural based community pharmacists. INTERVENTIONS: Recruited pharmacists were allocated to either the 'control' or 'intervention' group. Intervention pharmacists were given training in depression and asked to dispense medication with extra advice and support, while control pharmacists provided usual care. OUTCOME MEASURES: Understanding of depression, current involvement in patients with depression, changes in practice. RESULTS: All pharmacists were more likely to initiate conversation, discuss medication and its side effects, point out the importance of remaining on the medication, provide ongoing follow-up and encourage patients to talk with their GPs and pharmacists by the end of the project. Intervention pharmacists were more likely than the control pharmacists to initiate conversation on dispensing a repeat prescription and to discuss extended support. CONCLUSION: Response to the project by pharmacists was generally very positive. It is recommended that a longitudinal study based on this project be undertaken which involves pharmacists, GPs and other mental health professionals and trials a holistic approach to mental health care. PMID- 19785676 TI - Mediating and moderating effects of work-home interference upon farm stresses and psychological distress. AB - OBJECTIVE: This study investigated whether work-home (WHI) or home-work interference (HWI) explained or affected the strength of the relationship between farmers' stresses and reported psychological distress. DESIGN: Distribution of questionnaire package; included Work-Home Conflict Scale, Farm Stress Survey, Depression Anxiety Stress Scale. Participants recruited via advertising in newsletters and newspapers, and distribution through businesses and meetings. PARTICIPANTS: The majority of farmers (N = 51, male = 45, female = 5) were recruited from the one district. Farmers were individuals who identified their occupation as a farm owner, farm manager, or farm hand. MAIN OUTCOME MEASURES: It was predicted farmers would report higher levels of WHI than HWI; time, a determinant of interference, would mediate the relationship between farmers' stresses and psychological distress; WHI and HWI would moderate farmers' stresses and their psychological distress; overall reported level of psychological distress would be in normal to mild range because of positive general economic conditions. RESULTS: Farmers reported significantly higher levels of WHI than HWI (M = 3.21, M = 2.76, P < 0.001 respectively). WHI and time-based WHI mediated farmers' stresses and psychological distress, particularly anxiety. WHI, time and strain, determinants of WHI mediated personal finances and subcomponents of psychological distress (stress, anxiety, depression). Time-based HWI mediated personal finances and stress. No moderating effects were found for WHI (r = 0.02, P = 0.882) or HWI (r = 0.15, P = 0.306). CONCLUSIONS: Farmers of this specific sample presented a unique work-home interface. Limitations include the small sample size, recruitment methods, and culturally irrelevant measures as well as only assessing work-related stresses. Future research should aim to develop measures appropriate for farmers of Australia. PMID- 19785677 TI - All-terrain vehicle crashes and associated injuries in north Queensland: findings from the Rural and Remote Road Safety Study. AB - OBJECTIVE: To define characteristics of all-terrain vehicle (ATV) crashes occurring in north Queensland from March 2004 till June 2007 with the exploration of associated risk factors. DESIGN: Descriptive analysis of ATV crash data collected by the Rural and Remote Road Safety Study. SETTING: Rural and remote north Queensland. PARTICIPANTS: Forty-two ATV drivers and passengers aged 16 years or over hospitalised at Atherton, Cairns, Mount Isa or Townsville for at least 24 hours as a result of a vehicle crash. MAIN OUTCOME MEASURES: Demographics of participants, reason for travel, nature of crash, injuries sustained and risk factors associated with ATV crash. RESULTS: The majority of casualties were men aged 16-64. Forty-one per cent of accidents occurred while performing agricultural tasks. Furthermore, 39% of casualties had less than one year's experience riding ATVs. Over half the casualties were not wearing a helmet at the time of the crash. Common injuries were head and neck and upper limb injuries. Rollovers tended to occur while performing agricultural tasks and most commonly resulted in multiple injuries. CONCLUSIONS: Considerable trauma results from ATV crashes in rural and remote north Queensland. These crashes are not included in most general vehicle crash data sets, as they are usually limited to events occurring on public roads. Minimal legislation and regulation currently applies to ATV use in agricultural, recreational and commercial settings. Legislation on safer design of ATVs and mandatory courses for riders is an essential part of addressing the burden of ATV crashes on rural and remote communities. PMID- 19785678 TI - Correlates of comorbid mental disorders in a regional community-based sample. AB - OBJECTIVE: The common coexistence of psychiatric disorders has been identified as a significant factor contributing to the disability associated with mental illness. Identifying indicators to the development of coexisting disorders has potential clinical implications. This study aimed to investigate the correlates and impact of coexisting disorders in a rural setting. DESIGN: Cross-sectional analyses of data from a cohort interviewed in two phases. SETTING: A regional community sample in Northern New South Wales, Australia. PARTICIPANTS: A total of 1407 participants were interviewed and 968 were re-interviewed at follow up. MAIN OUTCOME MEASURES: Multinomial logistic regression modelling compared subjects with multiple psychiatric disorders with those with a single disorder for sociodemographic characteristics, measures of personal and social vulnerability, psychological distress, functional disabilities and help-seeking behaviours. RESULTS: Participants with coexisting disorders were more likely to be male, report a history of severe childhood assault and had higher levels of neuroticism, psychological distress and help-seeking behaviour. CONCLUSIONS: The findings suggest the role of early developmental factors on the complexity and severity of adult mental illness in a rural setting and the significant clinical consequences of comorbidity. PMID- 19785679 TI - Linkage, coordination and integration: evidence from rural palliative care. AB - OBJECTIVE: Review the findings from the evaluations of three rural palliative care programs. DESIGN: Review by the authors of the original material from each evaluation. The conceptual framework for the review was provided by the work of Leutz, including his distinction between linkage, coordination and full integration. SETTING: Community-based palliative care in rural Australia. INTERVENTIONS: Fifteen projects across all six states of Australia that focused on integration between general practitioners and other community-based health providers. RESULTS: The projects set out to improve networking and collaboration between providers; improve coordination and integration of care for patients; reduce duplication of services; and achieve a multidisciplinary, collaborative approach to palliative care. The most common interventions were establishment of formal governance structures, provision of education programs, case conferencing, dissemination of information, development of formal arrangements, development of protocols and use of common clinical assessment tools. The terms 'integration' and 'coordination' were used frequently but without clear definitions. Coordination required someone specifically designated to do the coordinating, usually a nurse. Formal arrangements to improve linkage and coordination were difficult to maintain. The main mechanism to achieve full integration was the development of common clinical information systems. CONCLUSIONS: The 'laws' proposed by Leutz and the concepts of linkage, coordination and full integration provide a useful framework to understand the barriers to integrating GPs and other health providers. It is important to be clear on what level of integration is required. Improving links might be sufficient (and realistic), rather than striving for full integration. PMID- 19785680 TI - Kids with confidence: a program for adolescents living in families affected by mental illness. AB - OBJECTIVE: To provide information about a peer support program for adolescents living in families affected by mental illness. DESIGN: This is a descriptive article about the Kids with Confidence Adolescent Program. SETTING: The program operates in rural Victoria using a variety of community venues. PARTICIPANTS: Young people aged between 12-18 years, living in families affected by mental illness. INTERVENTIONS: The program provides respite, education, support and fun through monthly, semistructured activities. The adolescents are encouraged to talk openly about their circumstances and any difficulties they might be having. They learn appropriate social skills, and provide and receive peer support. RESULTS: The group consistently attracts between 7 and 15 adolescents, with an average attendance of 11.25. Verbal feedback from the young people involved and their families has been very positive, with reported improvements in confidence, self-esteem and the formation of strong, trusting friendships. CONCLUSIONS: The Kids with Confidence Adolescent Program provides young people living in families affected by mental illness with peer and worker support, respite, and an opportunity to learn social and mental health skills. This might enhance young people's resilience and ability to cope with difficult situations. PMID- 19785681 TI - Excellence in regional stroke care: an evaluation of the implementation of a stroke care unit in regional Australia. AB - OBJECTIVE: To assess the effectiveness of a formalised stroke service in a regional hospital. DESIGN: A pretest post-test design. SETTING: An acute stroke unit in a regional health service. PARTICIPANTS: Overall sample comprised 80 patients with 36 (45.0%) men. Forty patients (19 men, 21 women) comprised pre intervention group and 40 (17 men, 23 women) post-intervention group. INTERVENTIONS: Establishment of an acute stroke unit. MAIN OUTCOME MEASURE(S): Increased frequency in meeting key performance indicators for acute stroke care as recommended by National Stroke Foundation. RESULTS: On discharge, fewer survivors in the pre-intervention group were independent (n = 5) and returned home (n = 9) than the post-intervention group (n = 13) for both independent and returned home. More survivors in the pre-intervention group were discharged to aged care or inpatient rehab (n = 22) than the post-intervention group (n = 12). Within required time frames, the frequency of CT scans (chi(2) (1, 80) = 4.1, P < 0.05), swallow assessments (chi(2) (1, 80) = 9.0, P < 0.01), occupational therapy assessments (chi(2) (1, 80) = 14.5, P < 0.0001), multidisciplinary meetings involving patient and family (chi(2) (1, 80) = 19.9, P < 0.0001) and self management plans (chi(2) (1, 80) = 10.9, P < 0.05) all increased significantly. CONCLUSIONS: Our evaluation demonstrated that introduction of formalised stroke care to a regional hospital resulted in improved compliance with key performance indicators and better patient outcomes. Thus evidence-based specialised stroke care can be offered with confidence in regional populations. PMID- 19785682 TI - Acute stroke management in a rural setting. PMID- 19785683 TI - Assessment of the efficacy and performance of the New South Wales Rural Mental Health Support line. PMID- 19785684 TI - Clinical leadership in rural psychiatry: farmers' mental health and well-being. PMID- 19785685 TI - Sense of place. PMID- 19785686 TI - Rural nursing and midwifery workforce: sustaining and growing our future workforce. PMID- 19785687 TI - NRHA: responding to the Commission's Report. PMID- 19785688 TI - Impact of micronutrient deficiencies on obesity. AB - Micronutrient deficiencies have been found in obese individuals across age groups worldwide. While the effects of micronutrient deficiencies on human functions have been studied widely in different populations, there is limited information on how these micronutrient deficiencies affect obese populations. An examination of the available literature suggests associations exist between micronutrient deficiencies and obesity in different populations. These associations and possible mechanisms of the deficiencies' metabolic effects, such as their influence on leptin and insulin metabolism, are discussed here. Further studies are needed to clarify the roles of the different micronutrient deficiencies with respect to obesity and its comorbid conditions. PMID- 19785689 TI - Polyunsaturated fatty acid status in attention deficit hyperactivity disorder, depression, and Alzheimer's disease: towards an omega-3 index for mental health? AB - Interest in the role of polyunsaturated fatty acids (PUFAs), particularly long chain (LC) omega-3 (n-3) PUFAs, in mental health is increasing. This review investigates whether n-3 PUFA levels are abnormal in people with three prevalent mental health problems - attention deficit hyperactivity disorder, depression, and dementia. Data sources included PubMed, Web of Science, and bibliographies of papers published in English that describe PUFA levels in the circulation of individuals who have these mental health conditions. Although abnormal blood PUFA levels were reported in a number of studies, weighted comparisons of PUFA status showed no significant differences overall between people with mental health problems and controls. Whether those with low n-3 PUFA status are likely to be more responsive to n-3 PUFA supplementation is not yet resolved. Further studies assessing PUFA levels and mental status with greater uniformity are required in order to clarify the relationship between LC n-3 PUFA status and mental health. PMID- 19785690 TI - Nibbling versus feasting: which meal pattern is better for heart disease prevention? AB - Dietary interventions that limit saturated fat, cholesterol, and energy are generally implemented as the first line of therapy to reduce the risk of coronary heart disease (CHD). Another form of diet therapy that may be effective in protecting against CHD is altering meal frequency without limiting energy. Meal frequency regimens are classified into two major forms: 1) feasting, i.e., consuming all energy needs in one meal/day, and 2) nibbling, i.e., consuming all energy needs in three, six, nine, 12, or 17 regimented meals/day. Whether one meal pattern, feasting or nibbling, is more effective at improving indicators of CHD risk than the other, remains unresolved. Moreover, whether a dose-dependent relationship exists between biomarker improvement and the number of meals consumed per day also remains unknown. The objective of the present review was to determine which meal pattern, nibbling or feasting, is more effective at improving key indicators of CHD risk in normal-weight and obese, non-diabetic individuals. PMID- 19785691 TI - Metabolic osteopathy in celiac disease: importance of a gluten-free diet. AB - Reduced bone mineral density (BMD) is frequently found in individuals with untreated celiac disease (CD), possibly due to calcium and vitamin D malabsorption, release of pro-inflammatory cytokines, and misbalanced bone remodeling. A gluten-free diet (GFD) promotes a rapid increase in BMD that leads to complete recovery of bone mineralization in children. Children may attain normal peak bone mass if the diagnosis is made and treatment is given before puberty, thereby preventing osteoporosis in later life. A GFD improves, but rarely normalizes, BMD in patients diagnosed with CD in adulthood. In some cases, nutritional supplementation may be necessary. More information on therapeutic alternatives is needed. PMID- 19785692 TI - Forward genetics used to identify new gene Mon1a with critical role in controlling macrophage iron metabolism and iron recycling from erythrocytes. AB - A recent study used a forward genetics approach to identify a new gene whose protein product controls erythrocyte iron recycling mediated through macrophages in the spleen. Initially the investigators found a genetic region on chromosome 9 accounting for one third of the variation in spleen iron level in mice. Additional approaches to narrow the genomic region identified the gene Mon1a, which codes for a protein that acts as a novel regulator of spleen iron release. Cell-based studies showed that Mon1a is necessary for vesicular trafficking of proteins, including the iron-export protein ferroportin, to the macrophage cell membrane. The forward genetics approach, which has currently only been used sparingly by the nutrition research community, offers a powerful and unbiased approach to identifying genes important in nutritional metabolism. PMID- 19785694 TI - Introduction for special section on training and supervision. PMID- 19785695 TI - Reflections of two trainees: Person-of-the-Therapist Training for marriage and family therapists. AB - In this article we share our personal and professional experiences, struggles, and growth, as former trainees of the Person-of-the-Therapist Training pilot study, conducted during our master's coursework in the Couple and Family Therapy Department at Drexel University. We include our perceptions of the training process in vivo, the challenges and benefits of doing this work in an academic setting, case examples to convey our journey of personal discovery, and the use of what we learned about ourselves in our development as therapists. This development includes a deepening of awareness of self in our relationship and work with our clients, a greater ability to work with both our personal assets and vulnerabilities, as well as the acquisition of skills to actively and purposefully use our entire person diagnostically and therapeutically in our work with clients. PMID- 19785696 TI - Training the person of the therapist in an academic setting. AB - Drexel University's Couple and Family Therapy Department recently introduced a formal course on training the person of a therapist. The course is based on Aponte's Person-of-the-Therapist Training Model that up until now has only been applied in private, nonacademic institutes with postgraduate therapists. The model attempts to put into practice a philosophy that views the full person of therapists, and their personal vulnerabilities in particular, as the central tool through which therapists do their work in the context of the client-therapist relationship. This article offers a description of how this model has been tested with a group of volunteer students, and subsequently what had to be considered to formally structure the training into the Drexel curriculum. PMID- 19785697 TI - An instrument for person-of-the-therapist supervision. AB - This article introduces a tool that serves as a guide for building an effective bridge between the personal and technical aspects of therapy in supervision. The instrument is based on a model of clinical supervision that emphasizes the purposeful utilization of self-in the moment, with both flaws and strengths-in the therapeutic relationship in combination with the technical interventions with clients. The article also offers some aid to promote a personal integration of the philosophy underlying this supervisory model into a therapist's clinical thinking and practice. PMID- 19785698 TI - Does live supervision make a difference? A multilevel analysis. AB - While the benefit of live supervision on clinical training is largely unquestioned, research that examines how live supervision affects the therapeutic process is lacking. Although marriage and family therapy has embraced this method of supervision, there is little empirical evidence suggesting it "works." This study uses hierarchical linear modeling to examine how therapy cases utilizing live supervision affect perceptions of progress on the problem. Findings indicated that live supervision does appear to make a difference for therapists' ratings of progress on the problem over the course of therapy; however, clients did not rate their progress as improving to the same degree. Implications for the use of live supervision as well as limitations of the study are discussed. PMID- 19785699 TI - Conceptualizing and treating problem gambling as a family issue. AB - Few family therapists have training in the identification, assessment, and treatment of problem gambling and its impact on couple and family relationships. The authors conceptualize problem gambling (PG) as a family issue and encourage clinicians and researchers to pay attention to the systemic antecedents and consequences of PG on family relationships. A review of the literature and clinicians' experiences regarding the impact of PG on couple and family relationships are presented and discussed. In light of the limited systemic-based treatments for PG, marriage and family therapists are urged to begin paying attention to this emerging issue that has significant couple and family ramifications. PMID- 19785700 TI - Family functioning and depression in low-income Latino couples. AB - Although extensive research has found a strong relationship between poor family functioning and depression, previous research has not examined this relationship among low-income Latinos. In this study, we examined how family functioning may be associated with depression in a sample of low-income Latino couples. In addition, we examined how acculturative stress moderates the relationship between family functioning and depression. Our results indicate that the relationship between family functioning and depression is stronger in women and that acculturative stress moderates this relationship in women. Probing this interaction indicates that women who reported high acculturative stress coupled with poor family functioning experienced more depression. Clinical implications are discussed. PMID- 19785701 TI - Relationship quality and stability in couples when one partner suffers from borderline personality disorder. AB - The main goal of the present study was to examine and compare the psychosocial functioning of 35 couples including a woman diagnosed with borderline personality disorder (BPD) to that of a nonclinical control sample of 35 couples. The BPD status of women from the clinical group and the prevalence of personality disorder in their partner were ascertained through the SCID-II. Participants completed self-report measures of couple functioning. A majority of couples in which the woman suffered from BPD (68.7%) evidenced frequent episodes of breakups and reconciliations and, over an 18-month period, nearly 30% of these couples dissolved their relationship. Nearly half of the men involved in a romantic relationship with a woman suffering from BPD met criteria for one personality disorder or more. As compared with nonclinical couples, clinical couples showed lower marital satisfaction, higher attachment insecurity, more demand/withdraw communication problems, and higher levels of violence. PMID- 19785702 TI - Using mock trials to teach students forensic core competencies in marriage and family therapy. AB - This article provides a description of a university-based project that used mock trials to train both practicum-level marriage and family therapy and law students in forensic work, and a qualitative investigation of student experiences with the training. The content of the training focused on American Association for Marriage and Family Therapy (AAMFT) core competencies that relate specifically to the legal aspects of therapy. This article describes the didactic training the students received to prepare for the mock trials, the structure and protocol of the mock trials themselves, and the specific AAMFT core competencies addressed in the project. The results of an analysis of focus group interviews with participating law school (n = 15) and marriage and family therapy (n = 19) students are presented as well as the results of a 36-item Knowledge, Skills, and Comfort Level Questionnaire completed by participating marriage and family therapy students. Participants discussed the value of the training with regard to preparation for mock trial procedures, preparation for testimony, importance of documentation, and cross-discipline collaboration issues. The article concludes with a discussion of how this type of training may be used in developing students' skills with regard to forensic and legal core competencies, and future research directions. PMID- 19785703 TI - Career aspirations and perceived level of preparedness among marriage and family therapy doctoral students. AB - The authors conducted a survey of marriage and family therapy (MFT) doctoral students in programs accredited by the Commission on Accreditation for Marriage and Family Therapy Education (COAMFTE). MFT doctoral students (N = 82) from across the United States responded to a web-based survey that focused on career aspirations, training opportunities, and the level of preparedness they experienced during their doctoral education. Results of this survey indicated that students felt they were well prepared for many aspects of their chosen career path. Some respondents desired more training to prepare them for careers in academia. More men than women indicated a career in academia as their primary career aspiration. While most of the respondents perceived that their internship experiences were beneficial, some expressed the desire for more opportunities to supervise master's-level students, to write grants, and to teach graduate-level MFT courses. The authors conclude with a discussion of how these findings may influence the development of core competencies specific to doctoral education in MFT. PMID- 19785705 TI - Photodynamic therapy using light-emitting diodes for the treatment of viral warts. AB - Photodynamic therapy with topical 5-aminolevulinic acid is an effective and safe treatment for actinic keratosis and superficial non-melanoma skin cancer. Further, some studies have reported good efficacy when using photodynamic therapy to treat viral warts. The light-emitting diode is an incoherent, narrow-spectrum light source. The purpose of this study is to evaluate the efficacy of photodynamic therapy using a light-emitting diode for viral warts. Six patients with a total of 41 foot and hand warts were recruited in this study. They were treated with 20% 5-aminolevulinic acid cream under occlusion for 5 h. Thereafter, the treated area was irradiated with the light from a red light-emitting diode (633 +/- 6 nm) with a dose of 126 J/cm(2). This treatment was repeated at 2- or 3 week intervals. The rate of improvement observed in patients was 68.3%. The adverse effects included mild to moderate pain and erythema, which was well tolerated by all six patients. No patients withdrew from the study due to the adverse effects. Photodynamic therapy with topical 5-aminolevulinic acid using the light from a red light-emitting diode has the advantage of non-invasiveness, minimal associated adverse reactions, and production of good results in a significant proportion of cases: therefore, it is an alternative treatment for recalcitrant viral warts. PMID- 19785706 TI - Skin barrier function recovery after diamond microdermabrasion. AB - Microdermabrasion is a popular method for facial rejuvenation and is performed worldwide. Despite its extensive usage, there are few publications on skin barrier change after microdermabrasion and none concerning diamond microdermabrasion. Our object was to see changes in transepidermal water loss (TEWL), hydration and erythema of the face following diamond microdermabrasion. Twenty-eight patients were included in this spilt face study. TEWL, stratum corneum hydration and the degree of erythema were measured from the right and left sides of the face (forehead and cheek) at baseline. One side of the face was treated with diamond microdermabrasion and the other side was left untreated. Measurements were taken right after the procedure and repeated at set time intervals. Diamond microdermabrasion was associated with a statistically significant increase in TEWL immediately after the procedure and at 24 h. However, on day 2, levels of TEWL were back to baseline. An increase in hydration and erythema was observed right after microdermabrasion, but both returned to baseline on day 1. The results show that skin barrier function of the forehead and cheek recovers within 2 days of diamond microdermabrasion. Diamond microdermabrasion performed on a weekly basis, as presently done, is expected to allow sufficient time for the damaged skin to recover its barrier function in most parts of the face. PMID- 19785707 TI - Differential expression of phosphorylated extracellular signal-regulated kinase 1/2, phosphorylated p38 mitogen-activated protein kinase and nuclear factor kappaB p105/p50 in chronic inflammatory skin diseases. AB - The keratinocytes actively participate in the cutaneous immune responses. Dysregulation and abnormal expression of inflammatory mediators or their receptors in keratinocytes are relevant to the pathogenesis of chronic inflammatory skin diseases. The mechanism of long-lasting inflammatory processes is related with the activation of nuclear factor (NF)-kappaB and mitogen activated protein kinase (MAPK), which play a crucial role in the immune responses. There are potential interaction points between these two pathways. The aim of this study is to investigate the differences in expression levels and distributions of phosphorylated extracellular signal-regulated kinase (ERK)1/2, phosphorylated p38 MAPK and NF-kappaB p105/p50 in chronic inflammatory skin diseases. An immunohistochemical staining technique was employed to measure the expression of these molecules in 25 cases of lichen planus, 22 cases of psoriasis, 26 cases of chronic eczema, seven cases of prurigo and seven cases of normal skin. We observed that the expression of phosphorylated ERK1/2, phosphorylated p38 MAPK and NF-kappaB p105/p50 was significantly more augmented in the lesional epidermis of all the inflammatory skin diseases than those in normal skin (P < 0.05), and the number of positive keratinocytes was significantly more in lichen planus than that in other inflammatory diseases (P < 0.001). Moreover, the positive keratinocytes of these three molecules were more widely distributed in the entire layer of the epidermis in lichen planus than those in other diseases. We concluded that ERK1/2, p38 MAPK and NF-kappaB p105/p50 might play important roles in the pathophysiology of chronic inflammatory skin diseases. PMID- 19785708 TI - Case of pigmented neurofibroma with hypertrichosis with no association to neurofibromatosis. AB - Pigmented neurofibroma (PNF) is a rare cutaneous tumor that has been observed in patients with or without neurofibromatosis (NF). This tumor is histologically characterized by the coexistence of scattered melanin-laden cells and benign spindle cells with neural differentiations. Hypertrichosis is the excessive growth of hair on non-androgen-dependent areas of the body. It has been reported that hypertrichosis may sometimes overlie a neurofibroma. We highlight a case of PNF with hypertrichosis on a 17-year-old woman with no associated NF. We also discuss the possible underlying pathogenic mechanism of a localized hypertrichosis in PNF patients. PMID- 19785709 TI - Giant ectopic hidradenoma papilliferum on the scalp. PMID- 19785710 TI - Rapid detection of Bartonella henselae heat shock protein DNA by nested polymerase chain reaction from swollen lymph nodes of a patient with cat-scratch disease. PMID- 19785711 TI - Cutaneous botryomycosis associated with eosinophilic cellulitis. PMID- 19785712 TI - Hypercalcemia associated with squamous cell carcinoma arising in pyoderma chronica. PMID- 19785713 TI - Extramammary Paget's disease with prominent signet-ring cells. PMID- 19785714 TI - Cutaneous metastasis of thyroid cancer presenting as a nodulocystic mass with ulceration. PMID- 19785715 TI - Dr Shoji Okuda (1886-1962): the great pioneer of punch graft hair transplantation. PMID- 19785716 TI - Guidelines for management of atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic relapsing eczematous skin disease characterized by pruritus and inflammation and accompanied by cutaneous physiological dysfunction (dry and barrier-disrupted skin). Most of the patients have atopic diathesis. A standard guideline for the management (diagnosis, severity classification and therapy) of AD has been established. In our guideline, the necessity of dermatological training is emphasized in order to assure diagnostic skill and to enable evaluation of the severity of AD. The definitive diagnosis of AD requires the presence of all three features: (i) pruritus; (ii) typical morphology and distribution; and (iii) chronic and chronically relapsing course. For the severity classification of AD, three elements of eruption (erythema/acute papules, exudation/crusts and chronic papules/nodules/lichenification) are evaluated in the most severely affected part of each of the five body regions (head/neck, anterior trunk, posterior trunk, upper limbs and lower limbs). The areas of eruption on the five body regions are also evaluated, and both scores are totaled (maximum 60 points). The present standard therapies for AD consist of the use of topical corticosteroids and tacrolimus ointment as the main treatment for the inflammation, topical application of emollients to treat the cutaneous physiological dysfunction, systemic antihistamines and anti-allergic drugs as adjunctive treatments for pruritus, avoidance of apparent exacerbating factors, psychological counseling and advice about daily life. Tacrolimus ointment (0.1%) and its low-density ointment (0.03%) are available for adult patients and 2-15-year-old patients, respectively. The importance of the correct selection of topical corticosteroids according to the severity of the eruption is also emphasized. Furthermore, deliberate use of oral cyclosporine for severe recalcitrant adult AD is referred. PMID- 19785718 TI - Joining forces in the quest for orthologs. AB - Better orthology-prediction resources would be beneficial for the whole biological community. A recent meeting discussed how to coordinate and leverage current efforts. PMID- 19785720 TI - An issue to remember. PMID- 19785719 TI - The netrin protein family. AB - The name netrin is derived from the Sanskrit Netr, meaning 'guide'. Netrins are a family of extracellular proteins that direct cell and axon migration during embryogenesis. Three secreted netrins (netrins 1, 3 and 4), and two glycosylphosphatidylinositol (GPI)-anchored membrane proteins, netrins G1 and G2, have been identified in mammals. The secreted netrins are bifunctional, acting as attractants for some cell types and repellents for others. Receptors for the secreted netrins include the Deleted in Colorectal Cancer (DCC) family, the Down's syndrome cell adhesion molecule (DSCAM), and the UNC-5 homolog family: Unc5A, B, C and D in mammals. Netrin Gs do not appear to interact with these receptors, but regulate synaptic interactions between neurons by binding to the transmembrane netrin G ligands NGL1 and 2. The chemotropic function of secreted netrins has been best characterized with regard to axon guidance during the development of the nervous system. Extending axons are tipped by a flattened, membranous structure called the growth cone. Multiple extracellular guidance cues direct axonal growth cones to their ultimate targets where synapses form. Such cues can be locally derived (short-range), or can be secreted diffusible cues that allow target cells to signal axons from a distance (long-range). The secreted netrins function as short-range and long-range guidance cues in different circumstances. In addition to directing cell migration, functional roles for netrins have been identified in the regulation of cell adhesion, the maturation of cell morphology, cell survival and tumorigenesis. PMID- 19785721 TI - Common variants in polygenic schizophrenia. AB - Common variant single-nucleotide polymorphisms at the MHC locus have recently been associated with schizophrenia. Together with known associations with rare copy-number variants affecting many genes, this reveals the highly polygenic etiology of the disease. PMID- 19785722 TI - Discovery and identification of potential biomarkers of papillary thyroid carcinoma. AB - BACKGROUND: Thyroid carcinoma is the most common endocrine malignancy and a common cancer among the malignancies of head and neck. Noninvasive and convenient biomarkers for diagnosis of papillary thyroid carcinoma (PTC) as early as possible remain an urgent need. The aim of this study was to discover and identify potential protein biomarkers for PTC specifically. METHODS: Two hundred and twenty four (224) serum samples with 108 PTC and 116 controls were randomly divided into a training set and a blind testing set. Serum proteomic profiles were analyzed using SELDI-TOF-MS. Candidate biomarkers were purified by HPLC, identified by LC-MS/MS and validated using ProteinChip immunoassays. RESULTS: A total of 3 peaks (m/z with 9190, 6631 and 8697 Da) were screened out by support vector machine (SVM) to construct the classification model with high discriminatory power in the training set. The sensitivity and specificity of the model were 95.15% and 93.97% respectively in the blind testing set. The candidate biomarker with m/z of 9190 Da was found to be up-regulated in PTC patients, and was identified as haptoglobin alpha-1 chain. Another two candidate biomarkers (6631, 8697 Da) were found down-regulated in PTC and identified as apolipoprotein C-I and apolipoprotein C-III, respectively. In addition, the level of haptoglobin alpha-1 chain (9190 Da) progressively increased with the clinical stage I, II, III and IV, and the expression of apolipoprotein C-I and apolipoprotein C-III (6631, 8697 Da) gradually decreased in higher stages. CONCLUSION: We have identified a set of biomarkers that could discriminate PTC from non-cancer controls. An efficient strategy, including SELDI-TOF-MS analysis, HPLC purification, MALDI-TOF-MS trace and LC-MS/MS identification, has been proved successful. PMID- 19785723 TI - MetaTM - a consensus method for transmembrane protein topology prediction. AB - BACKGROUND: Transmembrane (TM) proteins are proteins that span a biological membrane one or more times. As their 3-D structures are hard to determine, experiments focus on identifying their topology (i. e. which parts of the amino acid sequence are buried in the membrane and which are located on either side of the membrane), but only a few topologies are known. Consequently, various computational TM topology predictors have been developed, but their accuracies are far from perfect. The prediction quality can be improved by applying a consensus approach, which combines results of several predictors to yield a more reliable result. RESULTS: A novel TM consensus method, named MetaTM, is proposed in this work. MetaTM is based on support vector machine models and combines the results of six TM topology predictors and two signal peptide predictors. On a large data set comprising 1460 sequences of TM proteins with known topologies and 2362 globular protein sequences it correctly predicts 86.7% of all topologies. CONCLUSION: Combining several TM predictors in a consensus prediction framework improves overall accuracy compared to any of the individual methods. Our proposed SVM-based system also has higher accuracy than a previous consensus predictor. MetaTM is made available both as downloadable source code and as DAS server at http://MetaTM.sbc.su.se. PMID- 19785724 TI - Two matched filters and the evolution of mating signals in four species of cricket. AB - BACKGROUND: Male field crickets produce pure-tone calling songs to attract females. Receivers are expected to have evolved a "matched filter" in the form of a tuned sensitivity for this frequency. In addition, the peripheral directionality of field crickets is sharply tuned as a result of a pressure difference receiver. We studied both forms of tuning in the same individuals of four species of cricket, where Gryllus bimaculatus and G. campestris are largely allopatric, whereas Teleogryllus oceanicus and T. commodus occur also sympatrically. RESULTS: The sharpness of the sensitivity filter is highest for T. commodus, which also exhibits low interindividual variability. Individual receivers may also vary strongly in the best frequency for directional hearing. In G. campestris, such best frequencies occur even at frequencies outside the range of carrier frequencies of males. Contrary to the predictions from the "matched filter hypothesis", in three of the four species the frequency optima of the two involved filters are not matched to each other, and the mismatch can amount to 1.2 kHz. The mean carrier frequency of the male population is between the frequency optima of both filters in three species. Only in T. commodus we found a match between both filters and the male carrier frequency. CONCLUSION: Our results show that a mismatch between the sensitivity and directionality tuning is not uncommon in crickets, and an observed match (T. commodus) appears to be the exception rather than the rule. The data suggests that independent variation of both filters is possible. During evolution each sensory task may have been driven by independent constraints, and may have evolved towards its own respective optimum. PMID- 19785726 TI - Gastric cancer mortality trends in Spain, 1976-2005, differences by autonomous region and sex. AB - BACKGROUND: Gastric cancer is the second leading cause of oncologic death worldwide. One of the most noteworthy characteristics of this tumor's epidemiology is the marked decline reported in its incidence and mortality in almost every part of the globe in recent decades. This study sought to describe gastric cancer mortality time trends in Spain's regions for both sexes. METHODS: Mortality data for the period 1976 through 2005 were obtained from the Spanish National Statistics Institute. Cases were identified using the International Classification of Diseases 9th and 10th revision (codes 151 and C16, respectively). Crude and standardized mortality rates were calculated by geographic area, sex, and five-year period. Joinpoint regression analyses were performed to ascertain whether changes in gastric cancer mortality trends had occurred, and to estimate the annual percent change by sex and geographic area. RESULTS: Gastric cancer mortality decreased across the study period, with the downward trend being most pronounced in women and in certain regions situated in the interior and north of mainland Spain. Across the study period, there was an overall decrease of 2.90% per annum among men and 3.65% per annum among women. Generally, regions in which the rate of decline was sharpest were those that had initially registered the highest rates. However, the rate of decline was not constant throughout the study period: joinpoint analysis detected a shift in trend for both sexes in the early 1980s. CONCLUSION: Gastric cancer mortality displayed in both sexes a downward trend during the study period, both nationally and regionally. The different trend in rates in the respective geographic areas translated as greater regional homogeneity in gastric cancer mortality by the end of the study period. In contrast, rates in women fell more than did those in men. The increasing differences between the sexes could indicate that some risk factors may be modifying the sex-specific pattern of this tumor. PMID- 19785725 TI - Intracoronary versus intravenous abciximab in ST-segment elevation myocardial infarction: rationale and design of the CICERO trial in patients undergoing primary percutaneous coronary intervention with thrombus aspiration. AB - BACKGROUND: Administration of abciximab during primary percutaneous coronary intervention is an effective adjunctive therapy in the treatment of patients with ST-segment elevation myocardial infarction. Recent small-scaled studies have suggested that intracoronary administration of abciximab during primary percutaneous coronary intervention is superior to conventional intravenous administration. This study has been designed to investigate whether intracoronary bolus administration of abciximab is more effective than intravenous bolus administration in improving myocardial perfusion in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with thrombus aspiration. METHODS/DESIGN: The Comparison of IntraCoronary versus intravenous abciximab administration during Emergency Reperfusion Of ST-segment elevation myocardial infarction (CICERO) trial is a single-center, prospective, randomized open-label trial with blinded evaluation of endpoints. A total of 530 patients with STEMI undergoing primary percutaneous coronary intervention are randomly assigned to either an intracoronary or intravenous bolus of weight-adjusted abciximab. The primary end point is the incidence of >70% ST-segment elevation resolution. Secondary end points consist of post-procedural residual ST-segment deviation, myocardial blush grade, distal embolization, enzymatic infarct size, in-hospital bleeding, and clinical outcome at 30 days and 1 year. DISCUSSION: The CICERO trial is the first clinical trial to date to verify the effect of intracoronary versus intravenous administration of abciximab on myocardial perfusion in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention with thrombus aspiration. PMID- 19785727 TI - Financial incentives to improve adherence to anti-psychotic maintenance medication in non-adherent patients - a cluster randomised controlled trial (FIAT). AB - BACKGROUND: Various interventions have been tested to achieve adherence to anti psychotic maintenance medication in non-adherent patients with psychotic disorders, and there is no consistent evidence for the effectiveness of any established intervention. The effectiveness of financial incentives in improving adherence to a range of treatments has been demonstrated; no randomised controlled trial however has tested the use of financial incentives to achieve medication adherence for patients with psychotic disorders living in the community. METHODS/DESIGN: In a cluster randomised controlled trial, 34 mental health teams caring for difficult to engage patients in the community will be randomly allocated to either the intervention group, where patients will be offered a financial incentive for each anti-psychotic depot medication they receive over a 12 month period, or the control group, where all patients will receive treatment as usual. We will recruit 136 patients with psychotic disorders who use these services and who have problems adhering to antipsychotic depot medication, although all conventional methods to achieve adherence have been tried. The primary outcome will be adherence levels, and secondary outcomes are global clinical improvement, number of voluntary and involuntary hospital admissions, number of attempted and completed suicides, incidents of physical violence, number of police arrests, number of days spent in work/training/education, subjective quality of life and satisfaction with medication. We will also establish the cost effectiveness of offering financial incentives. DISCUSSION: The study aims to provide new evidence on the effectiveness and cost effectiveness of offering financial incentives to patients with psychotic disorders to adhere to antipsychotic maintenance medication. If financial incentives improve adherence and lead to better health and social outcomes, they may be recommended as one option to improve the treatment of non adherent patients with psychotic disorders. TRIAL REGISTRATION: Current controlled trials ISRCTN77769281. PMID- 19785728 TI - Vulvar fibroadenoma: a common neoplasm in an uncommon site. AB - Vulvar fibroadenomas are sporadic lesions informed in the literature and a controversy about origin has been discussed widely. We report a case of a 19 years old woman with a large slow growing mass in the right labia majora with the final diagnosis of fibroadenoma with mammary tissue surrounding it and positive hormone receptors. In this case, we support the origin in ectopic mammary tissue. PMID- 19785729 TI - Justification for the use of Ocimum gratissimum L in herbal medicine and its interaction with disc antibiotics. AB - BACKGROUND: The ethanolic extract of the leaves of Ocimium gratisimum L. (Lamiaceae), used in traditional medicine for the treatment of several ailments such as urinary tract, wound, skin and gastrointestinal infections, was evaluated for its antibacterial properties against four clinical bacteria isolates namely: Escherichia coli, Proteus mirabilis, Staphylococcus aureus and Pseudomonas aeruginosa and the antifungal properties using a clinical isolate of Candida albicans. A typed bacterium of Escherichia coli ATCC 11775 and another typed fungal strain of Candida albicans (ATCC 90028) were also included. The study also intended to verify if the concomitant administration of conventional antibiotics with Ocimium gratisimum which is normally taken as food (spice) will negatively affect its activity. METHODS: The agar diffusion method was used to test the in vitro activity of the plant extract. The interaction of the plant extract with some disc antibiotics namely: ciprofloxacin, septrin, streptomycin, ampicillin, nystatin and ketoconazole was tested using the agar overlay inoculum susceptibility disc method. Phytochemical analysis of the extract was performed following established methods. RESULTS: The extract showed good but varying in vitro activities against all the isolates tested. While ampicillin showed synergistic interaction with the plant extract against clinical isolates of E. coli and P. mirabilis, septrin was synergistic against the clinical isolate of E. coli only. Similarly, the activity of the extract against C. albicans isolate was synergistic with ketoconazole and nystatin. CONCLUSION: The study has validated the folkloric use of O. gratissimum in traditional medicinal practice and goes further to show that the use of this plant material as food spice may not really threaten the efficacy of some conventional antibiotics that may have been taken concomitantly with it as is the popular belief in the practice of herbal medicine in local/rural communities of many countries in the world. PMID- 19785730 TI - Urinary TWEAK as a biomarker of lupus nephritis: a multicenter cohort study. AB - INTRODUCTION: TNF-like weak inducer of apoptosis (TWEAK) has been implicated as a mediator of chronic inflammatory processes via prolonged activation of the NF kappaB pathway in several tissues, including the kidney. Evidence for the importance of TWEAK in the pathogenesis of lupus nephritis (LN) has been recently introduced. Thus, TWEAK levels may serve as an indication of LN presence and activity. METHODS: Multicenter cohorts of systemic lupus erythematosus (SLE) patients and controls were recruited for cross-sectional and longitudinal analysis of urinary TWEAK (uTWEAK) and/or serum TWEAK (sTWEAK) levels as potential biomarkers of LN. The performance of TWEAK as a biomarker for nephritis was compared with routinely used laboratory tests in lupus patients, including anti-double stranded DNA antibodies and levels of C3 and C4. RESULTS: uTWEAK levels were significantly higher in LN patients than in non-LN SLE patients and other disease control groups (P = 0.039). Furthermore, uTWEAK was better at distinguishing between LN and non-LN SLE patients than anti-DNA antibodies and complement levels, while high uTWEAK levels predicted LN in SLE patients with an odds ratio of 7.36 (95% confidence interval = 2.25 to 24.07; P = 0.001). uTWEAK levels peaked during LN flares, and were significantly higher during the flare than at 4 and 6 months prior to or following the flare event. A linear mixed effects model showed a significant association between uTWEAK levels in SLE patients and their disease activity over time (P = 0.008). sTWEAK levels, however, were not found to correlate with the presence of LN or the degree of nephritis activity. CONCLUSIONS: High uTWEAK levels are indicative of LN, as opposed to non-LN SLE and other healthy and disease control populations, and reflect renal disease activity in longitudinal follow-up. Thus, our study further supports a role for TWEAK in the pathogenesis of LN, and provides strong evidence for uTWEAK as a candidate clinical biomarker for LN. PMID- 19785731 TI - The stylomastoid artery as an anatomical landmark to the facial nerve during parotid surgery: a clinico-anatomic study. AB - BACKGROUND: The identification of the facial nerve can be difficult in a bloody operative field or by an incision that limits exposure; hence anatomical landmarks and adequate operative exposure can aid such identification and preservation. In this clinico-anatomic study, we examined the stylomastoid artery (SMA) and its relation to the facial nerve trunk; the origin of the artery was identified on cadavers and its nature was confirmed histologically. METHODS: The clinical component of the study included prospective reviewing of 100 consecutive routine parotidectomies; while, the anatomical component of the study involved dissecting 50 cadaveric hemifaces. RESULTS: We could consistently identify a supplying vessel, stylomastoid artery, which tends to vary less in position than the facial nerve. Following this vessel, a few millimetres inferiorly and medially, we have gone on to identify the facial nerve trunk, which it supplies, with relative ease. The origin of the stylomastoid artery, in our study, was either from the occipital artery or the posterior auricular artery. CONCLUSION: This anatomical aid, the stylomastoid artery, when supplemented by the other more commonly known anatomical landmarks and intra-operative facial nerve monitoring further reduces the risk of iatrogenic facial nerve damage and operative time. PMID- 19785732 TI - Identification of flowering genes in strawberry, a perennial SD plant. AB - BACKGROUND: We are studying the regulation of flowering in perennial plants by using diploid wild strawberry (Fragaria vesca L.) as a model. Wild strawberry is a facultative short-day plant with an obligatory short-day requirement at temperatures above 15 degrees C. At lower temperatures, however, flowering induction occurs irrespective of photoperiod. In addition to short-day genotypes, everbearing forms of wild strawberry are known. In 'Baron Solemacher' recessive alleles of an unknown repressor, SEASONAL FLOWERING LOCUS (SFL), are responsible for continuous flowering habit. Although flower induction has a central effect on the cropping potential, the molecular control of flowering in strawberries has not been studied and the genetic flowering pathways are still poorly understood. The comparison of everbearing and short-day genotypes of wild strawberry could facilitate our understanding of fundamental molecular mechanisms regulating perennial growth cycle in plants. RESULTS: We have searched homologs for 118 Arabidopsis flowering time genes from Fragaria by EST sequencing and bioinformatics analysis and identified 66 gene homologs that by sequence similarity, putatively correspond to genes of all known genetic flowering pathways. The expression analysis of 25 selected genes representing various flowering pathways did not reveal large differences between the everbearing and the short-day genotypes. However, putative floral identity and floral integrator genes AP1 and LFY were co-regulated during early floral development. AP1 mRNA was specifically accumulating in the shoot apices of the everbearing genotype, indicating its usability as a marker for floral initiation. Moreover, we showed that flowering induction in everbearing 'Baron Solemacher' and 'Hawaii-4' was inhibited by short-day and low temperature, in contrast to short-day genotypes. CONCLUSION: We have shown that many central genetic components of the flowering pathways in Arabidopsis can be identified from strawberry. However, novel regulatory mechanisms exist, like SFL that functions as a switch between short day/low temperature and long-day/high temperature flowering responses between the short-day genotype and the everbearing 'Baron Solemacher'. The identification of putative flowering gene homologs and AP1 as potential marker gene for floral initiation will strongly facilitate the exploration of strawberry flowering pathways. PMID- 19785733 TI - Bone and body composition analyzed by Dual-energy X-ray Absorptiometry (DXA) in clinical and nutritional evaluation of young patients with Cystic Fibrosis: a cross-sectional study. AB - BACKGROUND: the improved general therapy has led to reduced morbidity and mortality from Cystic Fibrosis (CF), and bone status may have a potentially greater clinical impact.We investigated the correlation between the severity of the clinical condition, bone status and body composition parameters, in a group of children and young adults with CF. METHODS: we measured lumbar spine bone density and total body composition by dual energy x-ray absorptiometry (DXA) in 82 consecutive CF patients (42 males; median age: 13 years - range: 5-30). Eighty two healthy subjects, matched for age, gender, height and pubertal stage were recruited as a control group. RESULTS: 37 patients (45.1%) had a normal bone mineral density (BMD). A BMD reduction were observed in 45 (54.8%) patients. Lumbar spine Z score was positively related to Body Mass Index (BMI) and a higher Shwachman-Kulczycki score, and negatively related to Crispin-Norman score. A positive and significant correlation was also observed between lumbar spine Z score and total body composition. CONCLUSION: a significant BMD reduction can be present early in CF children and adolescents. A careful follow up of bone status is required starting in childhood. PMID- 19785734 TI - Sparse canonical correlation analysis for identifying, connecting and completing gene-expression networks. AB - BACKGROUND: We generalized penalized canonical correlation analysis for analyzing microarray gene-expression measurements for checking completeness of known metabolic pathways and identifying candidate genes for incorporation in the pathway. We used Wold's method for calculation of the canonical variates, and we applied ridge penalization to the regression of pathway genes on canonical variates of the non-pathway genes, and the elastic net to the regression of non pathway genes on the canonical variates of the pathway genes. RESULTS: We performed a small simulation to illustrate the model's capability to identify new candidate genes to incorporate in the pathway: in our simulations it appeared that a gene was correctly identified if the correlation with the pathway genes was 0.3 or more. We applied the methods to a gene-expression microarray data set of 12, 209 genes measured in 45 patients with glioblastoma, and we considered genes to incorporate in the glioma-pathway: we identified more than 25 genes that correlated > 0.9 with canonical variates of the pathway genes. CONCLUSION: We concluded that penalized canonical correlation analysis is a powerful tool to identify candidate genes in pathway analysis. PMID- 19785735 TI - Fuzzy classification of phantom parent groups in an animal model. AB - BACKGROUND: Genetic evaluation models often include genetic groups to account for unequal genetic level of animals with unknown parentage. The definition of phantom parent groups usually includes a time component (e.g. years). Combining several time periods to ensure sufficiently large groups may create problems since all phantom parents in a group are considered contemporaries. METHODS: To avoid the downside of such distinct classification, a fuzzy logic approach is suggested. A phantom parent can be assigned to several genetic groups, with proportions between zero and one that sum to one. Rules were presented for assigning coefficients to the inverse of the relationship matrix for fuzzy classified genetic groups. This approach was illustrated with simulated data from ten generations of mass selection. Observations and pedigree records were randomly deleted. Phantom parent groups were defined on the basis of gender and generation number. In one scenario, uncertainty about generation of birth was simulated for some animals with unknown parents. In the distinct classification, one of the two possible generations of birth was randomly chosen to assign phantom parents to genetic groups for animals with simulated uncertainty, whereas the phantom parents were assigned to both possible genetic groups in the fuzzy classification. RESULTS: The empirical prediction error variance (PEV) was somewhat lower for fuzzy-classified genetic groups. The ranking of animals with unknown parents was more correct and less variable across replicates in comparison with distinct genetic groups. In another scenario, each phantom parent was assigned to three groups, one pertaining to its gender, and two pertaining to the first and last generation, with proportion depending on the (true) generation of birth. Due to the lower number of groups, the empirical PEV of breeding values was smaller when genetic groups were fuzzy-classified. CONCLUSION: Fuzzy classification provides the potential to describe the genetic level of unknown parents in a more parsimonious and structured manner, and thereby increases the precision of predicted breeding values. PMID- 19785736 TI - The prisoner as patient - a health services satisfaction survey. AB - BACKGROUND: There is evidence for higher morbidity among prison inmates than in the general population. Despite this, patient satisfaction with the prison health services is scarcely investigated. The aim of the present study was to investigate patient satisfaction with prison health services in Norway and to analyze possible patient and service effects. METHODS: The survey took part in 29 prisons in the southern and central part of Norway, representing 62% of the total prison capacity in Norway. A total of 1,150 prison inmates with prison health services experiences completed a satisfaction questionnaire (90% response rate). The patients' satisfaction was measured on a 12-item index. Multilevel analyses were used to analyze both patient and service characteristics as predictors of satisfaction. RESULTS: The study revealed high levels of dissatisfaction with prison health services. There were substantial differences between services, with between-service-variance accounting for 9% of the total variance. Satisfaction was significantly associated with a senior staff member's evaluation of the health services possessing adequate resources and the quality of drug abuse treatment. At the patient level, satisfaction was significantly associated with older age, frequent consultations and better self-perceived health. CONCLUSION: Prison inmates' satisfaction with the health services provided are low compared with patient satisfaction measured in other health areas. The substantial differences observed between services - even when adjusting for several known factors associated with patient satisfaction - indicate a potential for quality improvement. PMID- 19785737 TI - Protein hydrolysates in sports nutrition. AB - It has been suggested that protein hydrolysates providing mainly di- and tripeptides are superior to intact (whole) proteins and free amino acids in terms of skeletal muscle protein anabolism. This review provides a critical examination of protein hydrolysate studies conducted in healthy humans with special reference to sports nutrition. The effects of protein hydrolysate ingestion on blood amino acid levels, muscle protein anabolism, body composition, exercise performance and muscle glycogen resynthesis are discussed. PMID- 19785738 TI - An in vitro based investigation of the cytotoxic effect of water extracts of the Chinese herbal remedy LD on cancer cells. AB - BACKGROUND: Long Dan Xie Gan Wan (LD), a Chinese herbal remedy formulation, is traditionally used to treat a range of conditions, including gall bladder diseases, hepatitis, hyperthyroidism, migraines but it is not used for the management or treatment of cancer. However some of its herbal constituents, specifically Radix bupleuri, Radix scutellariae and Rhizoma alismatis have been shown to inhibit the growth of cancer cells. Thus, the aim of the study was to investigate the impact of LD on cancer cells in vitro. METHODS: HL60 and HT29 cancer cell lines were exposed to water extracts of LD (1:10, 1:50, 1:100 and/or 1:1000 prepared from a 3 mg/30 ml stock) and for both cell lines growth, apoptotic induction, alterations in cell cycle characteristics and genotoxicity were investigated. The specificity of the action of LD on these cancer cell lines was also investigated by determining its effect on human peripheral blood lymphocytes. Preliminary chemical analysis was carried out to identify cytotoxic constituents of LD using HPLC and LCMS. RESULTS: LD was significantly cytotoxic to, and induced apoptosis in, both cell lines. Apoptotic induction appeared to be cell cycle independent at all concentrations of LD used (1:10, 1:50 and 1:100) for the HL60 cell lines and at 1:10 for the HT29 cell line. At 1:50 and 1:100 apoptotic induction by LD appeared to be cell cycle dependent. LD caused significant genotoxic damage to both cell lines compared to their respective controls. The specificity study showed that LD exerted a moderate cytotoxic action against non-proliferating and proliferating blood lymphocytes but not apoptosis. Chemical analysis showed that a number of fractions were found to exert a significant growth inhibitory effect. However, the molecular weights of compounds within these fractions did not correspond to those from the herbal constituents of LD. CONCLUSION: It is possible that LD may have some chemotherapeutic potential. However, further studies are required to determine its cytotoxic constituents. PMID- 19785739 TI - Quadruplex MAPH: improvement of throughput in high-resolution copy number screening. AB - BACKGROUND: Copy number variation (CNV) in the human genome is recognised as a widespread and important source of human genetic variation. Now the challenge is to screen for these CNVs at high resolution in a reliable, accurate and cost effective way. RESULTS: Multiplex Amplifiable Probe Hybridisation (MAPH) is a sensitive, high-resolution technology appropriate for screening for CNVs in a defined region, for a targeted population. We have developed MAPH to a highly multiplexed format ("QuadMAPH") that allows the user a four-fold increase in the number of loci tested simultaneously. We have used this method to analyse a genomic region of 210 kb, including the MSH2 gene and 120 kb of flanking DNA. We show that the QuadMAPH probes report copy number with equivalent accuracy to simplex MAPH, reliably demonstrating diploid copy number in control samples and accurately detecting deletions in Hereditary Non-Polyposis Colorectal Cancer (HNPCC) samples. CONCLUSION: QuadMAPH is an accurate, high-resolution method that allows targeted screening of large numbers of subjects without the expense of genome-wide approaches. Whilst we have applied this technique to a region of the human genome, it is equally applicable to the genomes of other organisms. PMID- 19785740 TI - Ontology and diversity of transcript-associated microsatellites mined from a globe artichoke EST database. AB - BACKGROUND: The globe artichoke (Cynara cardunculus var. scolymus L.) is a significant crop in the Mediterranean basin. Despite its commercial importance and its both dietary and pharmaceutical value, knowledge of its genetics and genomics remains scant. Microsatellite markers have become a key tool in genetic and genomic analysis, and we have exploited recently acquired EST (expressed sequence tag) sequence data (Composite Genome Project - CGP) to develop an extensive set of microsatellite markers. RESULTS: A unigene assembly was created from over 36,000 globe artichoke EST sequences, containing 6,621 contigs and 12,434 singletons. Over 12,000 of these unigenes were functionally assigned on the basis of homology with Arabidopsis thaliana reference proteins. A total of 4,219 perfect repeats, located within 3,308 unigenes was identified and the gene ontology (GO) analysis highlighted some GO term's enrichments among different classes of microsatellites with respect to their position. Sufficient flanking sequence was available to enable the design of primers to amplify 2,311 of these microsatellites, and a set of 300 was tested against a DNA panel derived from 28 C. cardunculus genotypes. Consistent amplification and polymorphism was obtained from 236 of these assays. Their polymorphic information content (PIC) ranged from 0.04 to 0.90 (mean 0.66). Between 176 and 198 of the assays were informative in at least one of the three available mapping populations. CONCLUSION: EST-based microsatellites have provided a large set of de novo genetic markers, which show significant amounts of polymorphism both between and within the three taxa of C. cardunculus. They are thus well suited as assays for phylogenetic analysis, the construction of genetic maps, marker-assisted breeding, transcript mapping and other genomic applications in the species. PMID- 19785741 TI - Evaluation of putative reference genes for gene expression normalization in soybean by quantitative real-time RT-PCR. AB - BACKGROUND: Real-time quantitative reverse transcription PCR (RT-qPCR) data needs to be normalized for its proper interpretation. Housekeeping genes are routinely employed for this purpose, but their expression level cannot be assumed to remain constant under all possible experimental conditions. Thus, a systematic validation of reference genes is required to ensure proper normalization. For soybean, only a small number of validated reference genes are available to date. RESULTS: A systematic comparison of 14 potential reference genes for soybean is presented. These included seven commonly used (ACT2, ACT11, TUB4, TUA5, CYP, UBQ10, EF1b) and seven new candidates (SKIP16, MTP, PEPKR1, HDC, TIP41, UKN1, UKN2). Expression stability was examined by RT-qPCR across 116 biological samples, representing tissues at various developmental stages, varied photoperiodic treatments, and a range of soybean cultivars. Expression of all 14 genes was variable to some extent, but that of SKIP16, UKN1 and UKN2 was overall the most stable. A combination of ACT11, UKN1 and UKN2 would be appropriate as a reference panel for normalizing gene expression data among different tissues, whereas the combination SKIP16, UKN1 and MTP was most suitable for developmental stages. ACT11, TUA5 and TIP41 were the most stably expressed when the photoperiod was altered, and TIP41, UKN1 and UKN2 when the light quality was changed. For six different cultivars in long day (LD) and short day (SD), their expression stability did not vary significantly with ACT11, UKN2 and TUB4 being the most stable genes. The relative gene expression level of GmFTL3, an ortholog of Arabidopsis FT (FLOWERING LOCUS T) was detected to validate the reference genes selected in this study. CONCLUSION: None of the candidate reference genes was uniformly expressed across all experimental conditions, and the most suitable reference genes are conditional-, tissue-specific-, developmental-, and cultivar dependent. Most of the new reference genes performed better than the conventional housekeeping genes. These results should guide the selection of reference genes for gene expression studies in soybean. PMID- 19785742 TI - A system for computerised retinal haemorrhage analysis. AB - BACKGROUND: Our aim was to develop an objective computerised system for measuring different types of retinal haemorrhages in differing digital images, for use as a research tool. Despite developing various fully automated systems of retinal haemorrhage measurement we ultimately found user interaction to be necessary to achieve satisfactory validity of segmentation, and developed an interactive system of haemorrhage assessment based on this. FINDINGS: The Haemorrhage Assessment System (HAS) presented here is an open access interactive program with graphical user interface allowing the ophthalmically trained user to easily delineate different haemorrhage types, optic disc and fovea. The system then automatically calculates a variety of measures, including mean haemorrhage area, total haemorrhage area, centre of mass, distance of centre of mass from disc and fovea, eccentricity and orientation. This paper presents evidence for the validity of HAS by comparison against established software and known results for geometric images. CONCLUSION: The system should be of use to experimenters studying the distribution and topography of vitreoretinal haemorrhages who require a means of accurately quantifying an ophthalmologist's gold standard assessment of a digital image. PMID- 19785744 TI - Management of synchronous adenocarcinoma of the esophago-gastric junction and ampulla of Vater: case report of a surgically challenging condition. AB - We report herein a case of a synchronous presentation of an adenocarcinoma of esophagago-gastric junction type II and an ampullary tumor that was treated by combined Whipple's pancreaticoduodenectomy, total gastrectomy and esophagectomy. The magnitude of this operation was safely achieved with meticulous surgical techniques and perioperative care without any major short or long term complications. Patient returned to a good quality of life at six-month follow up with no further gastrointestinal symptoms or evidence of disease recurrence. PMID- 19785743 TI - c-Myc affects mRNA translation, cell proliferation and progenitor cell function in the mammary gland. AB - BACKGROUND: The oncoprotein c-Myc has been intensely studied in breast cancer and mouse mammary tumor models, but relatively little is known about the normal physiological role of c-Myc in the mammary gland. Here we investigated functions of c-Myc during mouse mammary gland development using a conditional knockout approach. RESULTS: Generation of c-mycfl/fl mice carrying the mammary gland specific WAPiCre transgene resulted in c-Myc loss in alveolar epithelial cells starting in mid-pregnancy. Three major phenotypes were observed in glands of mutant mice. First, c-Myc-deficient alveolar cells had a slower proliferative response at the start of pregnancy, causing a delay but not a block of alveolar development. Second, while milk composition was comparable between wild type and mutant animals, milk production was reduced in mutant glands, leading to slower pup weight-gain. Electron microscopy and polysome fractionation revealed a general decrease in translational efficiency. Furthermore, analysis of mRNA distribution along the polysome gradient demonstrated that this effect was specific for mRNAs whose protein products are involved in milk synthesis. Moreover, quantitative reverse transcription-polymerase chain reaction analysis revealed decreased levels of ribosomal RNAs and ribosomal protein-encoding mRNAs in mutant glands. Third, using the mammary transplantation technique to functionally identify alveolar progenitor cells, we observed that the mutant epithelium has a reduced ability to repopulate the gland when transplanted into NOD/SCID recipients. CONCLUSION: We have demonstrated that c-Myc plays multiple roles in the mouse mammary gland during pregnancy and lactation. c-Myc loss delayed, but did not block proliferation and differentiation in pregnancy. During lactation, lower levels of ribosomal RNAs and proteins were present and translation was generally decreased in mutant glands. Finally, the transplantation studies suggest a role for c-Myc in progenitor cell proliferation and/or survival. PMID- 19785745 TI - The practice of child and adolescent psychiatry: a survey of early-career psychiatrists in Japan. AB - BACKGROUND: Child and adolescent psychiatry (CAP), a subspecialty of psychiatry in Japan, is facing a serious workforce shortage. To resolve this situation, the Japanese government has organized a task force and has been working to increase psychiatrists' clinical skills to improve care for children and adolescents with mental health problems. Using an online questionnaire system, the authors have conducted a survey to investigate the perceptions, experiences, and interests of early-career psychiatrists in CAP. METHODS: The subjects of this study were 182 psychiatrists in Japan whose individual clinical experiences did not exceed 15 years. The authors of this study created an online questionnaire system and e mailed the URL and login password to all subjects. Respondents anonymously answered the questions. Most questions required an answer indicating a level of agreement scored on a nine-point scale. Responding to the questionnaire was considered to constitute consent, and all respondents' privacy was carefully protected. RESULTS: The mean age and clinical psychiatric experience of the subjects were found to be 33.1 +/- 4.5 years and 5.43 +/- 3.5 years, respectively. On a nine-point scale (with nine being the highest), experience and interest in CAP measured 3.05 +/- 1.9 and 5.34 +/- 2.5, respectively; further, these two factors showed significant correlation (r = 0.437, p < 0.0001). The mean score for the early-career psychiatrists' confidence in their ability to diagnose and appropriately treat was notably low, at 3.13 +/- 1.9. CONCLUSION: Our results demonstrated that early-career psychiatrists self-evaluated their CAP clinical experience as insufficient, and these clinicians' CAP experiences and interests correlated significantly. Therefore, in order to improve child and adolescent medical care, we need to expose young psychiatrists to sufficient CAP cases and explore the factors that could attract them to this field. PMID- 19785747 TI - The influenza A(H1N1) epidemic in Mexico. Lessons learned. AB - Several influenza pandemics have taken place throughout history and it was assumed that the pandemic would emerge from a new human virus resulting from the adaptation of an avian virus strain. Mexico, since 2003 had developed a National Preparedness and Response Plan for an Influenza Pandemic focused in risk communication, health promotion, healthcare, epidemiological surveillance, strategic stockpile, research and development. This plan was challenged on April 2009, when a new influenza A(H1N1) strain of swine origen was detected in Mexico. The situation faced, the decisions and actions taken, allowed to control the first epidemic wave in the country. This document describes the critical moments faced and explicitly point out the lessons learned focused on the decided support by the government, the National Pandemic Influenza Plan, the coordination among all the government levels, the presence and solidarity of international organizations with timely and daily information, diagnosis and the positive effect on the population following the preventive hygienic measures recommended by the health authorities. The international community will be able to use the Mexican experience in the interest of global health. PMID- 19785746 TI - Prerequisites for cytokine measurements in clinical trials with multiplex immunoassays. AB - BACKGROUND: Growing knowledge about cellular interactions in the immune system, including the central role of cytokine networks, has lead to new treatments using monoclonal antibodies that block specific components of the immune system. Systemic cytokine concentrations can serve as surrogate outcome parameters of these interventions to study inflammatory pathways operative in patients in vivo. This is now possible due to novel technologies such as multiplex immunoassays (MIA) that allows detection of multiple cytokines in a single sample. However, apparently trivial underappreciated processes, (sample handling and storage, interference of endogenous plasma proteins) can greatly impact the reliability and reproducibility of cytokine detection.Therefore we set out to investigate several processes that might impact cytokine profiles such as blood collecting tubes, duration of storage, and number of freeze thawing cycles. RESULTS: Since under physiological conditions cytokine concentrations normally are low or undetectable we spiked cytokines in the various plasma and serum samples. Overall recoveries ranged between 80-120%. Long time storage showed cytokines are stable for a period up to 2 years of storage at -80 degrees C. After 4 years several cytokines (IL-1alpha, IL-1beta, IL-10, IL-15 and CXCL8) degraded up to 75% or less of baseline values. Furthermore we show that only 2 out of 15 cytokines remained stable after several freeze-thawing cycles. We also demonstrate implementation of an internal control for multiplex cytokine immunoassays. CONCLUSION: All together we show parameters which are essential for measurement of cytokines in the context of clinical trials. PMID- 19785748 TI - 2-DE analysis indicates that Acinetobacter baumannii displays a robust and versatile metabolism. AB - BACKGROUND: Acinetobacter baumannii is a nosocomial pathogen that has been associated with outbreak infections in hospitals. Despite increasing awareness about this bacterium, its proteome remains poorly characterised, however recently the complete genome of A. baumannii reference strain ATCC 17978 has been sequenced. Here, we have used 2-DE and MALDI-TOF/TOF approach to characterise the proteome of this strain. RESULTS: The membrane and cytoplasmatic protein extracts were analysed separately, these analyses revealed the reproducible presence of 239 and 511 membrane and cytoplamatic protein spots, respectively. MALDI-TOF/TOF characterisation identified a total of 192 protein spots (37 membrane and 155 cytoplasmatic) and revealed that the identified membrane proteins were mainly transport-related proteins, whereas the cytoplasmatic proteins were of diverse nature, although mainly related to metabolic processes. CONCLUSION: This work indicates that A. baumannii has a versatile and robust metabolism and also reveal a number of proteins that may play a key role in the mechanism of drug resistance and virulence. The data obtained complements earlier reports of A. baumannii proteome and provides new tools to increase our knowledge on the protein expression profile of this pathogen. PMID- 19785749 TI - Bevacizumab plus FOLFIRI or FOLFOX in chemotherapy-refractory patients with metastatic colorectal cancer: a retrospective study. AB - BACKGROUND: The anti-VEGF antibody bevacizumab associated with an irinotecan or oxaliplatin-based chemotherapy was proved to be superior to the chemotherapy alone in first or second line treatment of metastatic colorectal cancer (mCRC). However, it was reported to have no efficacy in 3rd or later-line, alone or with 5FU. The aim of this study was to evaluate the activity of bevacizumab combined with FOLFIRI or FOLFOX in mCRC who have failed prior chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin. METHODS: Thirty one consecutive patients treated between May 2005 and October 2006 were included in this retrospective study. All of them have progressed under a chemotherapy with fluoropyrimidine plus irinotecan and/or oxaliplatin and received bevacizumab (5 mg/kg) in combination with FOLFIRI or simplified FOLFOX4 every 14 days. RESULTS: Ten patients (32.2%) had an objective response (1 CR, 9 PR) and 12 (38.8%) were stabilized. The response and disease control rates were 45.4% and 100% when bevacizumab was administered in 2nd or 3rd line and 25% and 55% in 4th or later line respectively (p = 0.024 and p = 0.008). Among the patients who had previously received the same chemotherapy than that associated with bevacizumab (n = 28) the overall response rate was 35.7% and 39.3% were stabilized. Median progression free survival (PFS) and overall survival (OS) were of 9.7 and 18.4 months respectively. Except a patient who presented a hypertension associated reversible posterior leukoencephalopathy syndrome, tolerance of bevacizumab was acceptable. A rectal bleeding occurred in one patient, an epistaxis in five. Grade 1/2 hypertension occurred in five patients. CONCLUSION: This study suggests that bevacizumab combined with FOLFOX or FOLFIRI may have the possibility to be active in chemorefractory and selected mCRC patients who did not receive it previously. PMID- 19785750 TI - What have worm models told us about the mechanisms of neuronal dysfunction in human neurodegenerative diseases? AB - The nematode worm Caenorhabditis elegans has become an intensely studied model organism, and worm studies have made significant contributions to developmental biology and other fields. The experimental advantages of C. elegans, particularly its simple anatomy, optical transparency, short lifespan, and facile genetics, have also led researchers to use this model to investigate neuronal cell degeneration and death. Worm studies of neurodegeneration can be divided into two general classes: studies in which mutations of C. elegans genes lead to neuronal dysfunction and death, and studies in which external manipulations (e.g., chemical treatments or introduction of engineered transgenes) are used to induce neurodegeneration. For both types of studies the primary approach has been to use forward genetic, reverse genetic, or candidate gene approaches to identify genes that modify neurodegeneration. The ease and relatively low cost of C. elegans propagation also suggests a role for these C. elegans models for compound screening. An excellent review has been previously published that summarizes much of the work done on mutationally-induced neuronal death in C. elegans 1. This review focuses on studies that have attempted to model specific human neurodegenerative diseases using transgenic approaches. These studies have given us a variety of insights into the specific disruptions of cellular processes that may underlie human neurodegenerative diseases. PMID- 19785751 TI - MicroRNA expression profiling during the life cycle of the silkworm (Bombyx mori). AB - BACKGROUND: MicroRNAs (miRNAs) are expressed by a wide range of eukaryotic organisms, and function in diverse biological processes. Numerous miRNAs have been identified in Bombyx mori, but the temporal expression profiles of miRNAs corresponding to each stage transition over the entire life cycle of the silkworm remain to be established. To obtain a comprehensive overview of the correlation between miRNA expression and stage transitions, we performed a whole-life test and subsequent stage-by-stage examinations on nearly one hundred miRNAs in the silkworm. RESULTS: Our results show that miRNAs display a wide variety of expression profiles over the whole life of the silkworm, including continuous expression from embryo to adult (miR-184), up-regulation over the entire life cycle (let-7 and miR-100), down-regulation over the entire life cycle (miR-124), expression associated with embryogenesis (miR-29 and miR-92), up-regulation from early 3rd instar to pupa (miR-275), and complementary pulses in expression between miR-34b and miR-275. Stage-by-stage examinations revealed further expression patterns, such as emergence at specific time-points during embryogenesis and up-regulation of miRNA groups in late embryos (miR-1 and bantam), expression associated with stage transition between instar and molt larval stages (miR-34b), expression associated with silk gland growth and spinning activity (miR-274), continuous high expression from the spinning larval to pupal and adult stages (miR-252 and miR-31a), a coordinate expression trough in day 3 pupae of both sexes (miR-10b and miR-281), up-regulation in pupal metamorphosis of both sexes (miR-29b), and down-regulation in pupal metamorphosis of both sexes (miR-275). CONCLUSION: We present the full-scale expression profiles of miRNAs throughout the life cycle of Bombyx mori. The whole-life expression profile was further investigated via stage-by-stage analysis. Our data provide an important resource for more detailed functional analysis of miRNAs in this animal. PMID- 19785752 TI - Detection of Viral Hemorrhagic Septicemia virus (VHSV) from the leech Myzobdella lugubris Leidy, 1851. AB - The leech Myzobdella lugubris is widespread in the Lake Erie Watershed, especially Lake St. Clair. However, its role in pathogen transmission is not fully understood. In this same watershed, several widespread fish mortalities associated with the Viral Hemorrhagic Septicemia virus (VHSV) were recorded. Viral Hemorrhagic Septicemia is an emerging disease in the Great Lakes Basin that is deadly to the fish population, yet little is known about its mode of transmission. To assess the potential role of M. lugubris in VHSV transmission, leeches were collected from Lake St. Clair and Lake Erie and pooled into samples of five. Cell culture and reverse transcriptase polymerase chain reaction (RT PCR) were used to determine the presence of the virus and its identity. Results showed that 57 of the 91 pooled leech samples were positive by cell culture for VHSV and 66 of the 91 pooled leech samples were positive by RT-PCR for the VHSV. Two representative virus isolates were sequenced for further genetic confirmation and genotype classification. VHSV detected within M. lugubris was homologous to the Great Lakes strain of VHSV genotype IVb. This is the first record of the VHSV being detected from within a leech, specifically M. lugubris, and suggests the potential of M. lugubris being involved in VHSV transmission. PMID- 19785753 TI - Transforming Boolean models to continuous models: methodology and application to T-cell receptor signaling. AB - BACKGROUND: The understanding of regulatory and signaling networks has long been a core objective in Systems Biology. Knowledge about these networks is mainly of qualitative nature, which allows the construction of Boolean models, where the state of a component is either 'off' or 'on'. While often able to capture the essential behavior of a network, these models can never reproduce detailed time courses of concentration levels. Nowadays however, experiments yield more and more quantitative data. An obvious question therefore is how qualitative models can be used to explain and predict the outcome of these experiments. RESULTS: In this contribution we present a canonical way of transforming Boolean into continuous models, where the use of multivariate polynomial interpolation allows transformation of logic operations into a system of ordinary differential equations (ODE). The method is standardized and can readily be applied to large networks. Other, more limited approaches to this task are briefly reviewed and compared. Moreover, we discuss and generalize existing theoretical results on the relation between Boolean and continuous models. As a test case a logical model is transformed into an extensive continuous ODE model describing the activation of T cells. We discuss how parameters for this model can be determined such that quantitative experimental results are explained and predicted, including time courses for multiple ligand concentrations and binding affinities of different ligands. This shows that from the continuous model we may obtain biological insights not evident from the discrete one. CONCLUSION: The presented approach will facilitate the interaction between modeling and experiments. Moreover, it provides a straightforward way to apply quantitative analysis methods to qualitatively described systems. PMID- 19785754 TI - A social marketing approach to implementing evidence-based practice in VHA QUERI: the TIDES depression collaborative care model. AB - Collaborative care models for depression in primary care are effective and cost effective, but difficult to spread to new sites. Translating Initiatives for Depression into Effective Solutions (TIDES) is an initiative to promote evidence based collaborative care in the U.S. Veterans Health Administration (VHA). Social marketing applies marketing techniques to promote positive behavior change. Described in this paper, TIDES used a social marketing approach to foster national spread of collaborative care models. TIDES SOCIAL MARKETING APPROACH: The approach relied on a sequential model of behavior change and explicit attention to audience segmentation. Segments included VHA national leadership, Veterans Integrated Service Network (VISN) regional leadership, facility managers, frontline providers, and veterans. TIDES communications, materials and messages targeted each segment, guided by an overall marketing plan. RESULTS: Depression collaborative care based on the TIDES model was adopted by VHA as part of the new Primary Care Mental Health Initiative and associated policies. It is currently in use in more than 50 primary care practices across the United States, and continues to spread, suggesting success for its social marketing-based dissemination strategy. DISCUSSION AND CONCLUSION: Development, execution and evaluation of the TIDES marketing effort shows that social marketing is a promising approach for promoting implementation of evidence-based interventions in integrated healthcare systems. PMID- 19785755 TI - Chronic NMDA administration to rats increases brain pro-apoptotic factors while decreasing anti-Apoptotic factors and causes cell death. AB - BACKGROUND: Chronic N-Methyl-d-aspartate (NMDA) administration to rats is reported to increase arachidonic acid signaling and upregulate neuroinflammatory markers in rat brain. These changes may damage brain cells. In this study, we determined if chronic NMDA administration (25 mg/kg i.p., 21 days) to rats would alter expression of pro- and anti-apoptotic factors in frontal cortex, compared with vehicle control. RESULTS: Using real time RT-PCR and Western blotting, chronic NMDA administration was shown to decrease mRNA and protein levels of anti apoptotic markers Bcl-2 and BDNF, and of their transcription factor phospho-CREB in the cortex. Expression of pro-apoptotic Bax, Bad, and 14-3-3zeta was increased, as well as Fluoro-Jade B (FJB) staining, a marker of neuronal loss. CONCLUSION: This alteration in the balance between pro- and anti-apoptotic factors by chronic NMDA receptor activation in this animal model may contribute to neuronal loss, and further suggests that the model can be used to examine multiple processes involved in excitotoxicity. PMID- 19785756 TI - TIR-NBS-LRR genes are rare in monocots: evidence from diverse monocot orders. AB - BACKGROUND: Plant resistance (R) gene products recognize pathogen effector molecules. Many R genes code for proteins containing nucleotide binding site (NBS) and C-terminal leucine-rich repeat (LRR) domains. NBS-LRR proteins can be divided into two groups, TIR-NBS-LRR and non-TIR-NBS-LRR, based on the structure of the N-terminal domain. Although both classes are clearly present in gymnosperms and eudicots, only non-TIR sequences have been found consistently in monocots. Since most studies in monocots have been limited to agriculturally important grasses, it is difficult to draw conclusions. The purpose of our study was to look for evidence of these sequences in additional monocot orders. FINDINGS: Using degenerate PCR, we amplified NBS sequences from four monocot species (C. blanda, D. marginata, S. trifasciata, and Spathiphyllum sp.), a gymnosperm (C. revoluta) and a eudicot (C. canephora). We successfully amplified TIR-NBS-LRR sequences from dicot and gymnosperm DNA, but not from monocot DNA. Using databases, we obtained NBS sequences from additional monocots, magnoliids and basal angiosperms. TIR-type sequences were not present in monocot or magnoliid sequences, but were present in the basal angiosperms. Phylogenetic analysis supported a single TIR clade and multiple non-TIR clades. CONCLUSION: We were unable to find monocot TIR-NBS-LRR sequences by PCR amplification or database searches. In contrast to previous studies, our results represent five monocot orders (Poales, Zingiberales, Arecales, Asparagales, and Alismatales). Our results establish the presence of TIR-NBS-LRR sequences in basal angiosperms and suggest that although these sequences were present in early land plants, they have been reduced significantly in monocots and magnoliids. PMID- 19785757 TI - Large serological survey showing cocirculation of Ebola and Marburg viruses in Gabonese bat populations, and a high seroprevalence of both viruses in Rousettus aegyptiacus. AB - BACKGROUND: Ebola and Marburg viruses cause highly lethal hemorrhagic fevers in humans. Recently, bats of multiple species have been identified as possible natural hosts of Zaire ebolavirus (ZEBOV) in Gabon and Republic of Congo, and also of marburgvirus (MARV) in Gabon and Democratic Republic of Congo. METHODS: We tested 2147 bats belonging to at least nine species sampled between 2003 and 2008 in three regions of Gabon and in the Ebola epidemic region of north Congo for IgG antibodies specific for ZEBOV and MARV. RESULTS: Overall, IgG antibodies to ZEBOV and MARV were found in 4% and 1% of bats, respectively. ZEBOV-specific antibodies were found in six bat species (Epomops franqueti, Hypsignathus monstrosus, Myonycteris torquata, Micropteropus pusillus, Mops condylurus and Rousettus aegyptiacus), while MARV-specific antibodies were only found in Rousettus aegyptiacus and Hypsignathus monstrosus. The prevalence of MARV specific IgG was significantly higher in R. aegyptiacus members captured inside caves than elsewhere. No significant difference in prevalence was found according to age or gender. A higher prevalence of ZEBOV-specific IgG was found in pregnant females than in non pregnant females. CONCLUSION: These findings confirm that ZEBOV and MARV co-circulate in Gabon, the only country where bats infected by each virus have been found. IgG antibodies to both viruses were detected only in Rousettus aegyptiacus, suggesting that this bat species may be involved in the natural cycle of both Marburg and Ebola viruses. The presence of MARV in Gabon indicates a potential risk for a first human outbreak. Disease surveillance should be enhanced in areas near caves. PMID- 19785758 TI - Identification of hemagglutinin structural domain and polymorphisms which may modulate swine H1N1 interactions with human receptor. AB - BACKGROUND: The novel A/H1N1 influenza virus, which recently emerged in North America is most closely related to North American H1N1/N2 swine viruses. Until the beginning of 2009, North American swine H1N1/N2 viruses have only sporadically infected humans as dead-end hosts. In 2009 the A/H1N1 virus acquired the capacity to spread efficiently by human to human transmission. The novel A/H1N1 influenza virus has struck thousands of people in more than 70 countries and killed more than 140, representing a public health emergency of international concern. Here we have studied properties of hemagglutinin of A/H1N1 which may modulate virus/receptor interaction. RESULTS: Analyses by ISM bioinformatics platform of the HA1 protein of North American swine H1N1/N2 viruses and the new A/H1N1 showed that both groups of viruses differed in conserved characteristics that reflect a distinct propensity of these viruses to undergo a specific interaction with swine or human host proteins or receptors. Swine H1N1/N2 viruses that sporadically infected humans featured both the swine and the human interaction pattern. Substitutions F71S, T128S, E302K, M314L in HA1 of swine H1N1 viruses from North America are identified as critical for the human interaction pattern of A/H1N1 and residues D94, D196 and D274 are predicted to be "hot-spots" for polymorphisms which could increase infectivity of A/H1N1 virus. At least one of these residues has already emerged in the A/H1N1 isolates from Spain, Italy and USA. The domain 286-326 was identified to be involved in virus/receptor interaction. CONCLUSION: Our results (i) contribute to better understanding of the origin of the novel A/H1N1 influenza virus, (ii) provide a tool for monitoring its molecular evolution (iii) predicts hotspots associated with enhanced infectivity in humans and (iv) identify therapeutic and diagnostic targets for prevention and treatment of A/H1N1 infection. PMID- 19785759 TI - Patient information in radiation oncology: a cross-sectional pilot study using the EORTC QLQ-INFO26 module. AB - BACKGROUND: The availability of alternative sources of information, e. g. the internet, may influence the quantity and quality of information cancer patients receive regarding their disease and treatment. The purpose of the present study was to assess perception of information in cancer patients during radiotherapy as well as media preferences and specifically the utilization of the internet. METHODS: In a cross-sectional, single-centre study 94 patients currently undergoing radiotherapy were asked to complete two questionnaires. The EORTC QLQ INFO26 module was used to assess the quality and quantity of information received by patients in the areas disease, medical tests, treatment, other services, different places of care and how to help themselves, as well as qualitative aspects as helpfulness of and satisfaction with this information. The importance of different media, in particular the internet, was investigated by a nine-item questionnaire. RESULTS: The response rate was n = 72 patients (77%). Patients felt best informed concerning medical tests (mean +/- SD score 79 +/- 22, scale 0 100) followed by disease (68 +/- 21). Treatment (52 +/- 24) and different places of care and other services (30 +/- 36 and 30 +/- 30, respectively) ranked last. 37% of patients were very satisfied and 37% moderately satisfied with the amount of information received, 61% wished more information. Among eight media, brochures, television and internet were ranked as most important. 41% used the internet themselves or via friends or family, mostly for research of classic and alternative treatment options. Unavailability and the necessity of computer skills were most mentioned obstacles. CONCLUSION: In a single-center pilot study, radiotherapy patients indicated having received most information about medical tests and their disease. Patients very satisfied with their information had received the largest amount of information. Brochures, television and internet were the most important media. Individual patient needs should be considered in the development of novel information strategies. PMID- 19785760 TI - The use of evidence in public governmental reports on health policy: an analysis of 17 Norwegian official reports (NOU). AB - BACKGROUND: Governments increasingly require policy documents to be evidence based. This paper analyses the use of scientific evidence in such documents by reviewing reports from government-appointed committees in Norway to assess the committees' handling of questions of effect. METHODS: This study uses the 'Index of Scientific Quality' (ISQ) to analyse all Norwegian official reports (NOUs) that were: (1) published by the Norwegian Ministry of Health and Care Services during 1994-1998 (N = 20); and (2) concerned with questions of effect either because these were included in the mandate or as a result of the committee's interpretation of the mandate. The ISQ is based on scientific criteria common in all research concerning questions of effect. The primary outcome measure is an ISQ score on a five-point scale. RESULTS: Three reports were excluded because their mandates, or the committees' interpretations of them, did not address questions of effect. For the remaining 17 NOUs in our study, overall ISQ scores were low for systematic literature search and for explicit validation of research. Two reports had an average score of three or higher, while scores for five other reports were not far behind. How committees assessed the relevant factors was often unclear. CONCLUSION: The reports' evaluations of health evidence in relation to questions of effect lacked transparency and, overall, showed little use of systematic processes. A systematic, explicit and transparent approach, following the standards laid down in the ISQ, may help generate the evidence-based decision-making that Norway, the UK, the EU and the WHO desire and seek. However, policy-makers may find the ISQ criteria for assessing the scientific quality of a report too narrow to adequately inform policy-making. PMID- 19785761 TI - Puncture mechanics of cnidarian cnidocysts: a natural actuator. AB - BACKGROUND: Cnidocysts isolated from cnidarian organisms are attractive as a drug delivery platform due to their fast, efficient delivery of toxins. The cnidocyst could be utilized as the means to deliver therapeutics in a wearable drug delivery patch. Cnidocysts have been previously shown to discharge upon stimulation via electrical, mechanical, and chemical pathways. Cnidocysts isolated from the Portuguese Man O' War jellyfish (Physalia physalis) are attractive for this purpose because they possess relatively long threads, are capable of puncturing through hard fish scales, and are stable for years. RESULTS: As a first step in using cnidocysts as a functional component of a drug delivery system, the puncture mechanics of the thread were characterized. Tentacle-contained cnidocysts were used as a best-case scenario due to physical immobilization of the cnidocysts within the tentacle. Ex vivo tentacle-contained cnidocysts from Physalia possessed an elastic modulus puncture threshold of approximately 1-2 MPa, based on puncture tests of materials with a gamut of hardness. Also, a method for inducing discharge of isolated cnidocysts was found, utilizing water as the stimulant. Preliminary lectin-binding experiments were performed using fluorophore-conjugated lectins as a possible means to immobilize the isolated cnidocyst capsule, and prevent reorientation upon triggering. Lectins bound homogeneously to the surface of the capsule, suggesting the lectins could be used for cnidocyst immobilization but not orientation. CONCLUSION: Cnidocysts were found to puncture materials up to 1 MPa in hardness, can be discharged in a dry state using water as a stimulant, and bind homogeneously to lectins, a potential means of immobilization. The information gained from this preliminary work will aid in determining the materials and design of the patch that could be used for drug delivery. PMID- 19785762 TI - Molecular characterization of a cDNA encoding Cu/Zn superoxide dismutase from Deschampsia antarctica and its expression regulated by cold and UV stresses. AB - BACKGROUND: The Copper/Zinc superoxide dismutase (Cu/ZnSOD) gene, SOD gene, was isolated from a Deschampsia antarctica Desv. by cDNA library screening. The expression of SOD gene in the leaves of D. antarctica was determined by RT-PCR and its differential expression of gene transcripts in conditions of cold and UV radiation stresses was revealed by northern blot. FINDINGS: The molecular characterization shows that SOD cDNA is 709 bp in length, which translates an ORF of 152 amino acids that correspond to a protein of predicted molecular mass of 15 kDa. The assay shows that the expression of SOD gene increases when D. antarctica is acclimatised to 4 degrees C and exposed to UV radiation. These results indicate that the SOD gene of D. antarctica is involved in the antioxidative process triggered by oxidative stress induced by the conditions of environmental change in which they live. CONCLUSION: The present results allow us to know the characteristics of Cu/ZnSOD gene from D. antarctica and understand that its expression is regulated by cold and UV radiation. PMID- 19785763 TI - Comparison of balance assessment modalities in emergency department elders: a pilot cross-sectional observational study. AB - BACKGROUND: More than one-third of US adults 65 and over fall every year. These falls may cause serious injury including substantial long-term morbidity (due declines in activities of daily living) and death. The emergency department (ED) visit represents an opportunity for identifying high risk elders and potentially instituting falls-related interventions. The unique characteristic of the ED environment and patient population necessitate that risk-assessment modalities be validated in this specific setting. In order to better identify elders at risk of falls, we examined the relationship between patient-provided history of falling and two testing modalities (a balance plate system and the timed up-and-go [TUG] test) in elder emergency department (ED) patients. METHODS: We conducted a cross sectional observational study of patients > or = 60 years old being discharged from the ED. Patient history of falls in the past week, month, 6 months, and year was obtained. Balance plate center of pressure excursion (COP) measurements and TUG testing times were recorded. COP was recorded under four conditions: normal stability eyes open (NSEO) and closed (NSEC), and perturbed stability eyes open and closed. Correlation between TUG and COP scores was measured. Univariate logistic regression was used to identify the relationship between patient provided falls history and the two testing modalities. Proportions, likelihood ratios, and receiver-operating-characteristic (ROC) curves for prediction of previous falls were reported. RESULTS: Fifty-three subjects were enrolled, 11% had fallen in the previous week and 42% in the previous year. There was no correlation between TUG and any balance plate measurements. In logistic regression, neither testing modality was associated with prior history of falls (p > 0.05 for all time periods). Balance plate NSEO and NSEC testing cutoffs could be identified which were 83% sensitive and had a negative likelihood ratio (LR-) of 0.3 for falls in the past week. TUG testing was not useful for falls in the past week, but performed best for more distant falls in the past month, 6 months, or year. TUG cutoffs with sensitivity over 80% and LR(-) of 0.17-0.32 could be identified for these time periods. CONCLUSION: Over 40% of community dwelling elder ED patients report a fall within the past year. Balance plate and TUG testing were feasibly conducted in an ED setting. There is no relationship between scores on balance plate and TUG testing in these patients. In regression analysis, neither modality was significantly associated with patient provided history of falls. These modalities should not be adopted for screening purposes in elders in the ED setting without validation in future studies or as part of multi-factorial risk assessment. PMID- 19785764 TI - Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension. AB - BACKGROUND: Autosomal dominant inheritance of germline mutations in the bone morphogenetic protein receptor type 2 (BMPR2) gene are a major risk factor for pulmonary arterial hypertension (PAH). While previous studies demonstrated a difference in severity between BMPR2 mutation carriers and noncarriers, it is likely disease severity is not equal among BMPR2 mutations. We hypothesized that patients with missense BMPR2 mutations have more severe disease than those with truncating mutations. METHODS: Testing for BMPR2 mutations was performed in 169 patients with PAH (125 with a family history of PAH and 44 with sporadic disease). Of the 106 patients with a detectable BMPR2 mutation, lymphocytes were available in 96 to functionally assess the nonsense-mediated decay pathway of RNA surveillance. Phenotypic characteristics were compared between BMPR2 mutation carriers and noncarriers, as well as between those carriers with a missense versus truncating mutation. RESULTS: While there was a statistically significant difference in age at diagnosis between carriers and noncarriers, subgroup analysis revealed this to be the case only for females. Among carriers, there was no difference in age at diagnosis, death, or survival according to exonic location of the BMPR2 mutation. However, patients with missense mutations had statistically significant younger ages at diagnosis and death, as well as shorter survival from diagnosis to death or lung transplantation than those with truncating mutations. Consistent with this data, the majority of missense mutations were penetrant prior to age 36 years, while the majority of truncating mutations were penetrant after age 36 years. CONCLUSION: In this cohort, BMPR2 mutation carriers have more severe PAH disease than noncarriers, but this is only the case for females. Among carriers, patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations. These findings suggest that treatment and prevention strategies directed specifically at BMPR2 pathway defects may need to vary according to the type of mutation. PMID- 19785765 TI - Delayed onset of changes in soma action potential genesis in nociceptive A-beta DRG neurons in vivo in a rat model of osteoarthritis. AB - BACKGROUND: Clinical data on osteoarthritis (OA) suggest widespread changes in sensory function that vary during the progression of OA. In previous studies on a surgically-induced animal model of OA we have observed that changes in structure and gene expression follow a variable trajectory over the initial days and weeks. To investigate mechanisms underlying changes in sensory function in this model, the present electrophysiological study compared properties of primary sensory nociceptive neurons at one and two months after model induction with properties in naive control animals. Pilot data indicated no difference in C- or Adelta fiber associated neurons and therefore the focus is on Abeta-fiber nociceptive neurons. RESULTS: At one month after unilateral derangement of the knee by cutting the anterior cruciate ligament and removing the medial meniscus, the only changes observed in Abeta-fiber dorsal root ganglion (DRG) neurons were in nociceptor-like unresponsive neurons bearing a hump on the repolarization phase; these changes consisted of longer half width, reflecting slowed dynamics of AP genesis, a depolarized Vm and an increased AP amplitude. At two months, changes observed were in Abeta-fiber high threshold mechanoreceptors, which exhibited shorter AP duration at base and half width, shorter rise time and fall time, and faster maximum rising rate/maximum falling rate, reflecting accelerated dynamics of AP genesis. CONCLUSION: These data indicate that Abeta nociceptive neurons undergo significant changes that vary in time and occur later than changes in structure and in nociceptive scores in this surgically induced OA model. Thus, if changes in Abeta-fiber nociceptive neurons in this model reflect a role in OA pain, they may relate to mechanisms underlying pain associated with advanced OA. PMID- 19785766 TI - Epidemiology of malaria in the forest-savanna transitional zone of Ghana. AB - BACKGROUND: Information on the epidemiology of malaria is essential for designing and interpreting results of clinical trials of drugs, vaccines and other interventions. As a background to the establishment of a site for anti-malarial drugs and vaccine trials, the epidemiology of malaria in a rural site in central Ghana was investigated. METHODS: Active surveillance of clinical malaria was carried out in a cohort of children below five years of age (n = 335) and the prevalence of malaria was estimated in a cohort of subjects of all ages (n = 1484) over a 12-month period. Participants were sampled from clusters drawn around sixteen index houses randomly selected from a total of about 22,000 houses within the study area. The child cohort was visited thrice weekly to screen for any illness and a blood slide was taken if a child had a history of fever or a temperature greater than or equal to 37.5 degree Celsius. The all-age cohort was screened for malaria once every eight weeks over a 12-month period. Estimation of Entomological Inoculation Rate (EIR) and characterization of Anopheline malaria vectors in the study area were also carried out. RESULTS: The average parasite prevalence in the all age cohort was 58% (95% CI: 56.9, 59.4). In children below five years of age, the average prevalence was 64% (95% CI: 61.9, 66.0). Geometric mean parasite densities decreased significantly with increasing age. More than 50% of all children less than 10 years of age were anaemic. Children less than 5 years of age had as many as seven malaria attacks per child per year. The attack rates decreased significantly with increasing cut-offs of parasite density. The average Multiplicity of Infection (MOI) was of 6.1. All three pyrimethamine resistance mutant alleles of the Plasmodium falciparum dhfr gene were prevalent in this population and 25% of infections had a fourth mutant of pfdhps-A437G. The main vectors were Anopheles funestus and Anopheles gambiae and the EIR was 269 infective bites per person per year. CONCLUSION: The transmission of malaria in the forest-savanna region of central Ghana is high and perennial and this is an appropriate site for conducting clinical trials of anti-malarial drugs and vaccines. PMID- 19785767 TI - Freeze-dried strawberry powder improves lipid profile and lipid peroxidation in women with metabolic syndrome: baseline and post intervention effects. AB - BACKGROUND: Strawberry flavonoids are potent antioxidants and anti-inflammatory agents that have been shown to reduce cardiovascular disease risk factors in prospective cohort studies. Effects of strawberry supplementation on metabolic risk factors have not been studied in obese populations. We tested the hypothesis that freeze-dried strawberry powder (FSP) will lower fasting lipids and biomarkers of oxidative stress and inflammation at four weeks compared to baseline. We also tested the tolerability and safety of FSP in subjects with metabolic syndrome. FSP is a concentrated source of polyphenolic flavonoids, fiber and phytosterols. METHODS: Females (n = 16) with 3 features of metabolic syndrome (waist circumference >35 inches, triglycerides > 150 mg/dL, fasting glucose > 100 mg/dL and < 126 mg/dL, HDL <50 mg/dL, or blood pressure >130/85 mm Hg) were enrolled in the study. Subjects consumed two cups of the strawberry drink daily for four weeks. Each cup had 25 g FSP blended in water. Fasting blood draws, anthropometrics, dietary analyses, and blood pressure measurements were done at baseline and 4 weeks. Biomarkers of oxidative stress and inflammation were measured using ELISA techniques. Plasma ellagic acid was measured using HPLC UV techniques. RESULTS: Total cholesterol and LDL-cholesterol levels were significantly lower at 4 weeks versus baseline (-5% and -6%, respectively, p < 0.05), as was lipid peroxidation in the form of malondialdehyde and hydroxynonenal (-14%, p < 0.01). Oxidized-LDL showed a decreasing trend at 4 weeks (p = 0.123). No effects were noted on markers of inflammation including C reactive protein and adiponectin. A significant number of subjects (13/16) showed an increase in plasma ellagic acid at four weeks versus baseline, while no significant differences were noted in dietary intakes at four weeks versus baseline. Thus, short-term supplementation of freeze-dried strawberries appeared to exert hypocholesterolemic effects and decrease lipid peroxidation in women with metabolic syndrome. PMID- 19785768 TI - A proposed prognostic 7-day survival formula for patients with terminal cancer. AB - BACKGROUND: The ability to identify patients for hospice care results in better end-of-life care. To develop a validated prognostic scale for 7-day survival prediction, a prospective observational cohort study was made of patients with terminal cancer. METHODS: Patient data gathered within 24 hours of hospital admission included demographics, clinical signs and symptoms and their severity, laboratory test results, and subsequent survival data. Of 727 patients enrolled, data from 374 (training group) was used to develop a prognostic tool, with the other 353 serving as the validation group. RESULTS: Five predictors identified by multivariate logistic regression analysis included patient's cognitive status, edema, ECOG performance status, BUN and respiratory rate. A formula of the predictor model based on those five predictors was constructed. When probability was >0.2, death within 7 days was predicted in the training group and validation group, with sensitivity of 80.9% and 71.0%, specificity of 65.9% and 57.7%, positive predictive value of 42.6% and 26.8%, and negative predictive value (NPV) of 91.7% and 90.1%, respectively. CONCLUSION: This predictor model showed a relatively high sensitivity and NPV for predicting 7-day survival among terminal cancer patients, and could increase patient satisfaction by improving end-of-life care. PMID- 19785769 TI - The production of consumption: addressing the impact of mineral mining on tuberculosis in southern Africa. AB - BACKGROUND: Miners in southern Africa experience incident rates of tuberculosis up to ten times greater than the general population. Migration to and from mines may be amplifying tuberculosis epidemics in the general population. DISCUSSION: Migration to and from mineral mines contributes to HIV risks and associated tuberculosis incidence. Health and safety conditions within mines also promote the risk of silicosis (a tuberculosis risk factor) and transmission of tuberculosis bacilli in close quarters. In the context of migration, current tuberculosis prevention and treatment strategies often fail to provide sufficient continuity of care to ensure appropriate tuberculosis detection and treatment. Reports from Lesotho and South Africa suggest that miners pose transmission risks to other household or community members as they travel home undetected or inadequately treated, particularly with drug-resistant forms of tuberculosis. Reducing risky exposures on the mines, enhancing the continuity of primary care services, and improving the enforcement of occupational health codes may mitigate the harmful association between mineral mining activities and tuberculosis incidence among affected communities. SUMMARY: Tuberculosis incidence appears to be amplified by mineral mining operations in southern Africa. A number of immediately-available measures to improve continuity of care for miners, change recruitment and compensation practices, and reduce the primary risk of infection may critically mitigate the negative association between mineral mining and tuberculosis. PMID- 19785770 TI - Collection of Macaca fascicularis cDNAs derived from bone marrow, kidney, liver, pancreas, spleen, and thymus. AB - BACKGROUND: Consolidating transcriptome data of non-human primates is essential to annotate primate genome sequences, and will facilitate research using non human primates in the genomic era. Macaca fascicularis is a macaque monkey that is commonly used for biomedical and ecological research. FINDINGS: We constructed cDNA libraries of Macaca fascicularis, derived from tissues obtained from bone marrow, liver, pancreas, spleen, and thymus of a young male, and kidney of a young female. In total, 5'-end sequences of 56,856 clones were determined. Including the previously established cDNA libraries from brain and testis, we have isolated 112,587 cDNAs of Macaca fascicularis, which correspond to 56% of the curated human reference genes. CONCLUSION: These sequences were deposited in the public sequence database as well as in-house macaque genome database http://genebank.nibio.go.jp/qfbase/. These data will become valuable resources for identifying functional parts of the genome of macaque monkeys in future studies. PMID- 19785771 TI - Identification and classification of high risk groups for Coal Workers' Pneumoconiosis using an artificial neural network based on occupational histories: a retrospective cohort study. AB - BACKGROUND: Coal workers' pneumoconiosis (CWP) is a preventable, but not fully curable occupational lung disease. More and more coal miners are likely to be at risk of developing CWP owing to an increase in coal production and utilization, especially in developing countries. Coal miners with different occupational categories and durations of dust exposure may be at different levels of risk for CWP. It is necessary to identify and classify different levels of risk for CWP in coal miners with different work histories. In this way, we can recommend different intervals for medical examinations according to different levels of risk for CWP. Our findings may provide a basis for further emending the measures of CWP prevention and control. METHODS: The study was performed using longitudinal retrospective data in the Tiefa Colliery in China. A three-layer artificial neural network with 6 input variables, 15 neurons in the hidden layer, and 1 output neuron was developed in conjunction with coal miners' occupational exposure data. Sensitivity and ROC analyses were adapted to explain the importance of input variables and the performance of the neural network. The occupational characteristics and the probability values predicted were used to categorize coal miners for their levels of risk for CWP. RESULTS: The sensitivity analysis showed that influence of the duration of dust exposure and occupational category on CWP was 65% and 67%, respectively. The area under the ROC in 3 sets was 0.981, 0.969, and 0.992. There were 7959 coal miners with a probability value < 0.001. The average duration of dust exposure was 15.35 years. The average duration of ex-dust exposure was 0.69 years. Of the coal miners, 79.27% worked in helping and mining. Most of the coal miners were born after 1950 and were first exposed to dust after 1970. One hundred forty-four coal miners had a probability value > or =0.1. The average durations of dust exposure and ex-dust exposure were 25.70 and 16.30 years, respectively. Most of the coal miners were born before 1950 and began to be exposed to dust before 1980. Of the coal miners, 90.28% worked in tunneling. CONCLUSION: The duration of dust exposure and occupational category were the two most important factors for CWP. Coal miners at different levels of risk for CWP could be classified by the three-layer neural network analysis based on occupational history. PMID- 19785772 TI - Involvement of S-nitrosylation of actin in inhibition of neurotransmitter release by nitric oxide. AB - BACKGROUND: The role of the diffusible messenger nitric oxide (NO) in the regulation of pain transmission is still a debate of matter, pro-nociceptive and/or anti-nociceptive. S-Nitrosylation, the reversible post-translational modification of selective cysteine residues in proteins, has emerged as an important mechanism by which NO acts as a signaling molecule. The occurrence of S nitrosylation in the spinal cord and its targets that may modulate pain transmission remain unclarified. The "biotin-switch" method and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were employed for identifying S-nitrosylated proteins. RESULTS: Here we show that actin was a major protein S-nitrosylated in the spinal cord by the NO donor, S-nitroso-N-acetyl-DL penicillamine (SNAP). Interestingly, actin was S-nitrosylated, more in the S2 fraction than in the P2 fraction of the spinal homogenate. Treatment of PC12 cells with SNAP caused rapid S-nitrosylation of actin and inhibited dopamine release from the cells. Just like cytochalasin B, which depolymerizes actin, SNAP decreased the amount of filamentous actin cytoskeleton just beneath the membrane. The inhibition of dopamine release was not attenuated by inhibitors of soluble guanylyl cyclase and cGMP-dependent protein kinase. CONCLUSION: The present study demonstrates that actin is a major S-nitrosylated protein in the spinal cord and suggests that NO directly regulates neurotransmitter release by S-nitrosylation in addition to the well-known phosphorylation by cGMP-dependent protein kinase. PMID- 19785773 TI - MMP7 expression regulated by endocrine therapy in ERbeta-positive colon cancer cells. AB - BACKGROUND: Many studies have shown that colon cancer is an estrogen-dependent carcinoma. This study explored the efficacy of endocrine therapy in colon cancer cells with high metastatic potential (HT29). We investigated the proliferation of HT29 cells after exposure to endocrine therapy (tamoxifen) and 5-FU. METHODS: Apoptosis was evaluated using flow cytometry. The expression of matrix metalloproteinases 7 (MMP-7) and estrogen receptor beta (ERbeta) was measured by reverse transcription-polymerase chain reaction (RT-PCR) and western blot. The migration capability of treated cells was determined with wound scratch assay. RESULTS: Tamoxifen alone, 5-FU alone, and the combination of the two drugs can significantly inhibit HT29 cell proliferation and migration, block the cells in G2/M phase and induce cell apoptosis. These drugs also can down-regulate MMP7 and ERbeta expression. CONCLUSION: Our findings suggest that endocrine therapy is an efficient therapy for inhibiting ERbeta-positive colon cancer cell proliferation and migration via down-regulation of MMP7. PMID- 19785774 TI - Regulation of the epithelial sodium channel [ENaC] in kidneys of salt-sensitive Dahl rats: insights on alternative splicing. AB - The epithelial sodium channel [ENaC] is critical for the maintenance of sodium balance, extracellular fluid volume and long term blood pressure control. Monogenic disorders causing ENaC hyperactivity have led to a severe form of hereditary hypertension in humans, known as Liddle's syndrome. Similarly, in animal models, ENaC hyperactivity has been well documented in kidneys of salt sensitive [S] Dahl rats [a genetic model of salt-sensitive hypertension] versus their normotensive control [Dahl salt-resistant [R] rats]. The purpose of the present review is to highlight the differential regulation of ENaC in kidneys of Dahl S versus R rats. A systematic overview of the putative role of alternative splicing of the main alpha subunit of ENaC [alpha ENaC] in modulating ENaC expression in kidneys of Dahl rats will be discussed. Finally, a better understanding of the meaningful contribution of ENaC in the pathogenesis of salt sensitive hypertension will be achieved upon completion of this review. PMID- 19785775 TI - Spatial trends of breast and prostate cancers in the United States between 2000 and 2005. AB - BACKGROUND: Breast cancer in females and prostate cancer in males are two of the most common cancers in the United States, and the literature suggests that they share similar features. However, it is unknown whether the occurrence of these two cancers at the county level in the United States is correlated. We analyzed Caucasian age-adjusted county level average annual incidence rates for breast and prostate cancers from the National Cancer Institute and State Cancer Registries to determine whether there was a spatial correlation between the two conditions and whether the two cancers had similar spatial patterns. RESULTS: There was a significant correlation between breast and prostate cancers by county (r = 0.332, p < 0.001). This relationship was more pronounced when we performed a geographically-weighted regression (GWR) analysis (r = 0.552) adjusting for county unemployment rates. There was variation in the parameter estimates derived with the GWR; however, the majority of the estimates indicted a positive association. The strongest relationship between breast and prostate cancer was in the eastern parts of the Midwest and South, and the Southeastern U.S. We also observed a north-south pattern for both cancers with our cluster analyses. Clusters of counties with high cancer incidence rates were more frequently found in the North and clusters of counties with low incidence rates were predominantly in the South. CONCLUSION: Our analyses suggest breast and prostate cancers cluster spatially. This finding corroborates other studies that have found these two cancers share similar risk factors. The north-south distribution observed for both cancers warrants further research to determine what is driving this spatial pattern. PMID- 19785776 TI - Microsatellite based genetic diversity and population structure of the endangered Spanish Guadarrama goat breed. AB - BACKGROUND: Assessing genetic biodiversity and population structure of minor breeds through the information provided by neutral molecular markers, allows determination of their extinction risk and to design strategies for their management and conservation. Analysis of microsatellite loci is known to be highly informative in the reconstruction of the historical processes underlying the evolution and differentiation of animal populations. Guadarrama goat is a threatened Spanish breed which actual census (2008) consists of 3057 females and 203 males distributed in 22 populations more or less isolated. The aim of this work is to study the genetic status of this breed through the analysis of molecular data from 10 microsatellites typed in historic and actual live animals. RESULTS: The mean expected heterozygosity across loci within populations ranged from 0.62 to 0.77. Genetic differentiation measures were moderate, with a mean FST of 0.074, GST of 0.081 and RST of 0.085. Percentages of variation among and within populations were 7.5 and 92.5, respectively. Bayesian clustering analyses pointed out a population subdivision in 16 clusters, however, no correlation between geographical distances and genetic differences was found. Management factors such as the limited exchange of animals between farmers (estimated gene flow Nm = 3.08) mostly due to sanitary and social constraints could be the major causes affecting Guadarrama goat population subdivision. CONCLUSION: Genetic diversity measures revealed a good status of biodiversity in the Guadarrama goat breed. Since diseases are the first cause affecting the census in this breed, population subdivision would be an advantage for its conservation. However, to maintain private alleles present at low frequencies in such small populations minimizing the inbreeding rate, it would necessitate some mating designs of animals carrying such alleles among populations. The systematic use of molecular markers will facilitate the comprehensive management of these populations, which in combination with the actual breeding program to increase milk yield, will constitute a good strategy to preserve the breed. PMID- 19785777 TI - A randomised-controlled trial of two educational modes for undergraduate evidence based medicine learning in Asia. AB - BACKGROUND: As the overall evidence for the effectiveness of teaching of evidence based medicine (EBM) is not strong, and the impact of cultural and societal influences on teaching method is poorly understood, we undertook a randomised controlled trial to test the effectiveness and learning satisfaction with two different EBM teaching methods (usual teaching vs. problem based learning (PBL)) for undergraduate medical students. METHODS: A mixed methods study that included a randomised-controlled crossover trial with two intervention arms (usual teaching and PBL) and a nested qualitative study with focus groups to explore student perceptions of learning and to assess the effectiveness and utility of the two teaching methods.All 129 second-year medical students at the University of Hong Kong in 2007.The main outcomes measures were attitudes towards EBM; personal application and current use of EBM; EBM knowledge; future use of EBM. RESULTS: PBL was less effective at imparting knowledge than usual teaching consisting of a lecture followed by a group tutorial. After usual teaching students showed improvement in scores for 'attitudes towards EBM', 'personal application and current use of EBM' and 'EBM knowledge, which were not evident after PBL. In contrast to the usual teaching, students found PBL difficult as they lacked the statistical knowledge necessary to support discussion, failed to understand core concepts, and lost direction. CONCLUSION: The evidence presented here would suggest that the teaching of EBM within an Asian environment should adopt a format that facilitates both the acquisition of knowledge and encourages enquiry. PMID- 19785778 TI - Induction of cell-cell fusion by ectromelia virus is not inhibited by its fusion inhibitory complex. AB - BACKGROUND: Ectromelia virus, a member of the Orthopox genus, is the causative agent of the highly infectious mousepox disease. Previous studies have shown that different poxviruses induce cell-cell fusion which is manifested by the formation of multinucleated-giant cells (polykaryocytes). This phenomenon has been widely studied with vaccinia virus in conditions which require artificial acidification of the medium. RESULTS: We show that Ectromelia virus induces cell-cell fusion under neutral pH conditions and requires the presence of a sufficient amount of viral particles on the plasma membrane of infected cells. This could be achieved by infection with a replicating virus and its propagation in infected cells (fusion "from within") or by infection with a high amount of virus particles per cell (fusion "from without"). Inhibition of virus maturation or inhibition of virus transport on microtubules towards the plasma membrane resulted in a complete inhibition of syncytia formation. We show that in contrast to vaccinia virus, Ectromelia virus induces cell-cell fusion irrespectively of its hemagglutination properties and cell-surface expression of the orthologs of the fusion inhibitory complex, A56 and K2. Additionally, cell-cell fusion was also detected in mice lungs following lethal respiratory infection. CONCLUSION: Ectromelia virus induces spontaneous cell-cell fusion in-vitro and in-vivo although expressing an A56/K2 fusion inhibitory complex. This syncytia formation property cannot be attributed to the 37 amino acid deletion in ECTV A56. PMID- 19785780 TI - [Traumatic atlas fracture in a child following fall on head]. AB - An 8-year-old girl presented at the Accident & Emergency Department with torticollis and neck pain after falling on her head from a climbing frame. A computed tomography scan revealed a Gehweiler type 1 avulsion fracture combined with widening of an anatomically variant single anterior synchondrosis. The child was successfully treated with halter traction, painkillers and bed rest. Physicians should look out for upper cervical spine injury in children who sustained a cranial axial load injury. Differential diagnosis between pain reactive muscular torticollis and atlantoaxial rotatory subluxation is essential. Children presenting with posttraumatic torticollis require a conventional or dynamic computed tomography scan. PMID- 19785779 TI - Window screening, ceilings and closed eaves as sustainable ways to control malaria in Dar es Salaam, Tanzania. AB - BACKGROUND: Malaria transmission in Africa occurs predominantly inside houses where the primary vectors prefer to feed. Human preference and investment in blocking of specific entry points for mosquitoes into houses was evaluated and compared with known entry point preferences of the mosquitoes themselves. METHODS: Cross-sectional household surveys were conducted in urban Dar es Salaam, Tanzania to estimate usage levels of available options for house proofing against mosquito entry, namely window screens, ceilings and blocking of eaves. These surveys also enabled evaluation of household expenditure on screens and ceilings and the motivation behind their installation. RESULTS: Over three quarters (82.8%) of the 579 houses surveyed in Dar es Salaam had window screens, while almost half (48.9%) had ceilings. Prevention of mosquito entry was cited as a reason for installation of window screens and ceilings by 91.4% (394/431) and 55.7% (127/228) of respondents, respectively, but prevention of malaria was rarely cited (4.3%, 22/508). The median cost of window screens was between US $ 21-30 while that of ceilings was between US $301-400. The market value of insecticide-treated nets, window screening and ceilings currently in use in the city was estimated as 2, 5 and 42 million US$. More than three quarters of the respondents that lacked them said it was too expensive to install ceilings (82.2%) or window screens (75.5%). CONCLUSION: High coverage and spending on screens and ceilings implies that these techniques are highly acceptable and excellent uptake can be achieved in urban settings like Dar es Salaam. Effective models for promotion and subsidization should be developed and evaluated, particularly for installation of ceilings that prevent entry via the eaves, which are the most important entry point for mosquitoes that cause malaria, a variety of neglected tropical diseases and the nuisance which motivates uptake. PMID- 19785781 TI - [Diagnostic image. A breastfeeding woman with a painful, blue nipple]. AB - A 32-year-old breastfeeding woman presented with a painful, blue nipple due to Raynaud's syndrome. PMID- 19785782 TI - [Raynaud's phenomenon; diagnosis and treatment]. AB - Primary Raynaud's phenomenon (RP) is a relatively common disorder. Most patients with primary RP have only mild symptoms and do not develop complications. Distinguishing primary from secondary RP is important with respect to complications, and for prognosis and treatment. Secondary RP mainly manifests as part of systemic connective tissue disease. About 13% of patients diagnosed initially as having primary RP develop a systemic disorder within the following few years. Both auto-immune serology including antinuclear antibodies (ANA), and capillaroscopy are important diagnostic tools if one suspects the existence or development of a systemic disorder. Calcium antagonists are the cornerstone of RP pharmacotherapy. PMID- 19785783 TI - [Variable presentation of antiglomerular basement membrane (anti-GBM) disease: rapid recognition vitally important]. AB - The classic clinical presentation of anti-GBM disease, or Goodpasture's disease, is pulmonary haemorrhage in combination with rapidly progressive glomerulonephritis. However, presenting symptoms vary considerably. To illustrate this, this article describes 3 male patients with anti-GBM disease, aged 25, 27 and 25 years respectively. The first patient presented with massive haemoptysis without glomerulonephritis, the second patient presented with a microcytic anaemia, caused by subclinical alveolar bleeding, and the third patient presented with rapidly progressive glomerulonephritis in combination with respiratory failure. All 3 patients required mechanical ventilation but did survive. Two patients progressed to end-stage renal disease (ESRD). Earlier recognition might prevent respiratory failure and ESRD. Therefore, despite heterogeneous clinical presentation, immediate recognition of anti-GBM disease is vitally important in view of the potentially lethal consequences if left untreated. PMID- 19785785 TI - [Diabetes mellitus in the Netherlands: estimate of the current disease burden and prognosis for 2025]. AB - OBJECTIVE: To estimate the number of people with diagnosed diabetes mellitus in the Netherlands in 2007 using a new method; to describe trends in the past; to predict the situation in 2025. DESIGN: Model calculations. METHODS: Based on five general practice records (Nijmegen Continuous Morbidity Registration [CMR], Netherlands Information Network of General Practice [LINH], Limburg Family Practice Registration Network [RNH-Limburg], Registration Network University Family Practices, Leiden and its environs [RNUH-LEO], and the transition project) the prevalence and incidence of diagnosed diabetes in the Netherlands in 2007 was estimated. Trends in the prevalence of diagnosed diabetes were estimated from the five records over the period 2000-2007. The prevalence of diagnosed diabetes in 2025 was estimated using the Dutch Chronic Diseases Model, which takes into account demographic developments and a further increase in obesity in the Netherlands in the future. RESULTS: In 2007, 740,000 persons (95% CI: 665,000 824,000) with diabetes were undergoing care. The incidence of new diabetes during 2007 was 71,000 (95% CI: 57,000-90,000). The prevalence of diagnosed diabetes increased by almost 80% in 2000-2007. The model projection resulted in an estimate of 1.3 million people with diagnosed diabetes in 2025, i.e. 8% of the Dutch population. There is a high level of uncertainty about these estimates. CONCLUSION: The increase in the number of diabetes patients in 2025 has consequences for care and will require measures to be taken in coming years in the areas of prevalence and care organisation. PMID- 19785786 TI - [The coming diabetes tsunami: the Netherlands should exploit its lead]. AB - Some authors claimed that if current trends prevail, 1.32 million people will have been diagnosed with diabetes mellitus in the Netherlands by 2025. In this commentary, the author sheds doubt on some of the underlying assumptions. First, the author argues that advanced age in itself cannot be an immutable cause of diabetes since there must be underlying mechanisms, which may be modifiable. Second, improved early detection of diabetes, which is a cause for a higher prevalence, also creates possibilities for action. Finally, the author does not believe that the current rates of overweight will be sustained over the next 16 years through to 2025. The author also discusses the debate surrounding the use of the Diabetes Prevention Program in the U.S. and the application of the Archimedes mathematical model to calculate cost-effectiveness of rapid adoption of the Diabetes Prevention Program versus delayed adoption or drug treatment with metformin, as well as the heated debate with the Markov modellers of the Diabetes Prevention Program research group about model details and validations. PMID- 19785787 TI - [Increase in the number of people with diabetes mellitus: need for a master plan]. AB - The predicted increase in the number of people in the Netherlands known to have diabetes mellitus to 1.3 million people in 2025 is rather staggering. Subjects with type 2 diabetes mellitus account for most of the increase. An important part of this rise is due to changing living conditions, including obesity and being overweight, sedentary behaviour, and an unhealthy lifestyle. In order to alleviate this expected rise, much energy will have to be put into preventive measures, with much effort in the initial phases and results only to be expected after a prolonged period. These efforts will be necessary not only within the health care system, but in the population as a whole, with focus on changing attitudes and lifestyles. PMID- 19785788 TI - [Diagnostic image. A man with pain after knee replacement]. AB - A 50-year-old man had a painful knee 4 months after medial unicondylar knee replacement. X-rays revealed rotation of the femoral component of the prosthesis, due to aseptic loosening. PMID- 19785789 TI - [The vicious circle that leads to rheumatoid arthritis; experimental evidence of the steps involved in this circle]. AB - Rheumatoid arthritis (RA) is characterized by chronic inflammation of the joints and the presence of anti-citrullinated protein autoantibodies (ACPA). ACPA are very specific for RA and are involved in its pathophysiology. Five steps, all of which are supported by experimental evidence, can be distinguished during the development of the chronic inflammation in RA. Step 1: During inflammation a large influx of inflammatory cells takes place. These cells will ultimately die via apoptosis. When the dying cells are not cleared efficiently, citrullinated proteins and citrullinating enzymes are released into the extracellular space. Step 2: Extracellular proteins are citrullinated by these enzymes. Step 3: Only individuals with a certain genetic background produce ACPA. Step 4: Arthritis is induced by the formation of immune complexes of ACPA and citrullinated proteins. Step 5: These immune complexes stimulate the inflammation, which leads to the recruitment of new inflammatory cells. This establishes a vicious cycle, the RA cycle. PMID- 19785790 TI - [Prenatally detected orofacial cleft]. AB - An increasing number of pregnancies are presumed being terminated following prenatal detection of orofacial cleft during structural ultrasound.After examining the data and literature on this topic it is concluded that the reported cases are merely incidents. For the interpretation of prenatal detection rates a distinction should be made between isolated orofacial cleft and the frequently occurring associated form of orofacial cleft which is usually characterized by other, often major structural or chromosome anomalies. The ultrasound detection rate of the isolated form is low and varies in the literature between 18 and 56%. Together with all Dutch centres of prenatal medicine a care plan was adopted for the management of prenatally detected orofacial cleft including diagnosis (detailed ultrasound examination and karyotyping), medical support (genetic consultations, plastic surgery and psychosocial counselling) and treatment (obstetric and neonatal management). In the presence of associated major congenital anomalies termination of pregnancy may be considered before the 24th week of pregnancy. PMID- 19785791 TI - [Decubitus ulcers in spinal cord lesion: proactive inspection]. AB - Two patients, a 23-year-old and a 70-year-old man, were admitted to a hospital with a spinal cord lesion. During their stay they developed severe decubitus ulcers which was not noticed until after they were moved to our rehabilitation centre. Despite conventional wound therapy one of the two patients developed an infection deriving from the necrotic decubitus wound which resulted in severe sepsis. A necrotomy had been delayed because of the medical history of this patient and because of the waiting list. These cases show that all parties involved with patients with spinal cord lesions should be aware of the high risk of decubitus ulcers. Frequent skin checks of the sites at risk by both carer and patient are necessary, and early necrotomy is important for the adequate treatment of decubitus. PMID- 19785793 TI - [Decreasing incidence of suicide in the Netherlands, with changing methods]. AB - OBJECTIVE: To determine time trends in the incidence of suicide mortality and in the methods used during the period 1970-2007, and to determine the resulting number of lost life years. DESIGN: Retrospective dynamic cohort study in the Dutch population. METHOD: Analyses were based on national register data (from the Statistics Netherlands) concerning suicide numbers and methods, and demographic characteristics of the population. Data were standardized for age and sex using the direct method, with the Dutch population of 2007 as a reference. Time trends were calculated using the Poisson regression model. RESULTS: Since 1983 the standardized incidence of suicide decreased by 38% (95% confidence interval (95% CI): 36-40) from 14.8 per 100,000 in the peak year of 1983 to 8.3 per 100,000 in 2007. In the age group of 20-59 years the decrease was considerably stronger for women than for men, with rates of 47% (95% CI: 44-51) and 18% (95% CI: 14-22), respectively. The strongest decline was found in the group aged 60 years and over, with a decrease of 58% (95% CI: 55-60). There was a decrease in drowning as the suicide method, while the incidence of hanging increased. Over 43,000 life years were lost to suicide in the Netherlands in 2007. Of the total number of years lost, 82% occurred in the age group of 20 to 59 years. CONCLUSION: The number of suicides in the Netherlands has declined substantially since 1983. Factors that may have contributed to this development remain unknown at present. PMID- 19785794 TI - [Insufficient evidence for oral glucocorticoids as first-line therapy for acute gout]. AB - In a recent equivalence clinical trial, prednisolone was reported to be equally effective as naproxen in the treatment of acute gout arthritis. The authors stated that the study provides a strong argument to consider prednisolone as first-line therapy for acute gout. For this double-blind placebo-controlled trial patients with the clinical diagnosis of acute gout (n = 381) were referred from primary care centers, but only those patients with crystal-proven gout and absence of contraindications for the trial medication were included (n = 120). They were randomly assigned to oral treatment for 5 days with either once-daily prednisolone 35 mg or twice-daily naproxen 500 mg and respective placebos. Points of discussion are whether there was indeed equivalence in effect, whether equivalence in adverse effects of the two treatments can be determined from the trial or from literature, and whether the results may be generalised. Although in selected acute gout patients prednisolone may be a good choice, available data still are too scarce to conclude that oral prednisolone is the first-line therapy for gout arthritis. PMID- 19785795 TI - [Encephalitis lethargica in the Netherlands; renewed interest in a mysterious disease]. AB - In the first half of the 20th century, during the Spanish flu pandemic, more than half a million people died from a mysterious disease sleeping sickness which was named 'encephalitis lethargica'. Despite extensive research, the cause of the disease has not yet been established. In the Netherlands many doctors published cases in the Nederlands Tijdschrift voor Geneeskunde (Dutch Journal of Medicine), also when chronic forms of the disease arose. An attempt to treat patients suffering from the chronic disease with levodopa initially had spectacular results but eventually lead to a new disappointment as a result of severe side effects. The experiment was stopped prematurely. Encephalitis lethargica is still being sporadically diagnosed in the 21st century. Recent research suggests that an autoimmune response targeted at the basal ganglia, possibly caused by a streptococcal infection, plays a role in the aetiology of the disease. PMID- 19785796 TI - [Occult breast cancer discovered following breast reduction]. AB - In plastic surgery, reduction mammaplasty is a common operation. The incidence of occult breast cancer detection is low but if diagnosed, consequences for the patient and the attending physician have a great impact. In this case, a 55-year old woman complained of physical discomfort because of macromastia. Reduction mammaplasty was performed. Histopathological analysis revealed breast cancer of the breast reduction specimen. Once this diagnosis was made, the physicians looked more thoroughly into the patient's history, and a risk analysis focused on breast cancer. On a multidisciplinary level it was decided that ablation of the left breast with limited axillary lymph node dissection was the most feasible treatment. It may be evident that surgical outcomes and treatment options were complicated and limited because of the recently performed operation. This illustrates the value of adequate history taking, supply of information as well as consideration of certain pre- and postoperative screening methods. PMID- 19785797 TI - [Epilepsy from seizure to care]. AB - Epilepsy is very common. The prevalence in the Netherlands is 5:1000 inhabitants. The diagnosis is mostly made on clinical grounds and often incorrectly. If there are doubts about the diagnosis, the patient can be referred to a specialised centre for a seizure registration with an EEG and video recording. The disorder generally responds well to treatment with anti-epileptics. Some 60-70% of patients treated with these remain free of seizures. If medicinal treatment fails then a surgical intervention can be considered. For patients with temporal epilepsy in particular, there is quite a high chance that a surgical intervention will resolve the symptoms. Where it proves difficult to satisfactorily adjust the medication of a patient, stimulation of the left vagus nerve can be considered. Paying more attention to the side effects of the medication and the limitations imposed on the patients can reduce the negative influence of epilepsy on the quality of life. PMID- 19785798 TI - [Acetylsalicylic acid in patients with diabetes mellitus: can be used for secondary but not primary prevention of cardiovascular events]. AB - There is no consensus in international guidelines about the role of acetylsalicylic acid in primary prevention of cardiovascular events in patients with diabetes mellitus.Primary prevention trials suggest that in diabetic patients, acetylsalicylic acid has either no or less favourable effects in preventing cardiovascular events compared to patients with other cardiovascular risk factors.Increased platelet activity, increased activation of clotting factors and interaction between glycation and acetylation are the most plausible explanations for this loss of efficacy in patients with diabetes mellitus.The evidence for the use of alternative antiplatelet therapy in addition or instead of acetylsalicylic acid is too limited to recommend this as an alternative preventive method. Also increasing the dose of acetylsalicylic acid is probably not worthwhile.We do not recommend acetylsalicylic acid as primary prevention of cardiovascular events in patients with diabetes mellitus, but we do recommend it as a means of secondary prevention. PMID- 19785799 TI - [Intoxication with Monkshood (Aconitum napellus)]. AB - Three patients presented with an intoxication caused by Aconitum napellus, commonly known as Aconite, Monkshood or Wolfsbane. The first patient, a woman aged 24, was resuscitated after accidental ingestion of plant material 'from nature'. She experienced severe ventricular tachyarrhythmias. After discharge she returned with identical symptoms, which were now interpreted as intentional intoxication in a suicide attempt. She was referred to the Psychiatry department. The second patient was a 2-year-old boy who had cutaneous exposure to Aconite. Except for some red spots around his mouth there were no other symptoms. The third patient was a 34-year-old woman who ate Monkshood, which she mistook for parsley. Alarmed by the bitter taste she contacted the hospital. She was treated with stomach lavage which removed most of the ingested plant material, and with activated charcoal. She had no symptoms during observation in the hospital. Aconite alkaloids are known to cause ventricular arrhythmia by a prolonged activation of sodium channels. Because there is no antidote, treatment is largely supportive but serious arrhythmias and respiratory arrest need to be anticipated. PMID- 19785801 TI - [Lower costs for anticancer drugs by safety margin around calculated dose and by fine-tuning on ampoule strength]. AB - OBJECTIVE: To determine if the rational application of dose individualization of anticancer drugs leads to a reduction in costs. DESIGN: Data analysis. METHOD: At the Ikazia Hospital in Rotterdam, the Netherlands, over the first 19 weeks of 2006 the costs of the intravenous administration to patients of one or more anticancer drugs were determined. The costs of dosage based on body surface area (BSA) were calculated. Commercially available ampoule strengths were not taken into consideration. Using available pharmacokinetic data, it is reasonable to assume that a deviation of up to 10% based on an individualized dose calculated by body surface area, has a negligible effect on the outcome of treatment. For this reason drug costs by rounding off doses to whole ampoules were also investigated. A condition of this was that the rounded-off dose should not deviate by more than 10% from the dose calculated on body surface area. RESULTS: During the study period, 18 different anticancer drugs were administered a total of 939 times. If dosage had been based strictly on body surface area, drug costs would have been euro 509,664. Rounding off to whole ampoules with a dose margin of a maximum of 10% would have cost euro 465,619: a reduction in cost of 8.6%. CONCLUSION: The rational application of the dose individualization principle based on body surface area may result in a substantial reduction in expenditure on anticancer drugs. PMID- 19785802 TI - [Responsible care requires registration of ethnic origin]. AB - Registration of the ethnic origin of patients in health care is subject to political and public debate. This paper is intended to contribute to that debate. We argue that registration of the ethnic origin of all patients is a necessary condition for responsible patient care. First, similar to sex and age the ethnic origin of a patient is a relevant variable for diagnosis and treatment at the individual patient level. Second, information about the ethnic origin of patients in health care data registries is a necessary condition for good quality research on the quality of care for ethnic minority groups. This research is needed to enable adequate targeting of interventions to improve quality of care for these patients. Consequently, registration of the ethnic origin of patients is a condition for providing good care for all Dutch patients. PMID- 19785803 TI - [Registration of ethnicity allowed with conditions]. AB - Registration of an individual's ethnicity is, in the light of the potential risks of stigmatization and discrimination, rightfully considered a sensitive issue. Traditionally, privacy legislation offers special legal protection in the collection, registration etc. of data relating to race and ethnic background. However, if it can be established that registration of ethnicity is necessary for providing good care, registration is lawful. However, registration for health research purposes requires the explicit consent of the persons involved. PMID- 19785804 TI - [Cardiovascular prevention: not necessary under the age of 40]. AB - Pharmacological treatment of high blood pressure and high cholesterol should not be recommended for young persons, unless their 10 year risk of cardiovascular disease mortality is > 5-10%, their blood pressure > 180/100 mmHg or their cholesterol > 8 mmol/l. PMID- 19785805 TI - [Diagnostic image. A man with an ulcer on his back]. AB - A 58-year-old man presented with a necrotizing ulcus on his back due to a complicated fluoroscopy-guided intervention procedure a few months before with a high total radiation dose. PMID- 19785806 TI - [Cardiovascular prevention: begin young]. AB - Atherosclerotic vascular disease is rare in the young. Nevertheless, the foundations for atherosclerotic disease in later life are laid early by a harmful lifestyle including overweight and smoking. Adolescents who are overweight or have the metabolic syndrome are at increased cardiovascular risk later in life. PMID- 19785808 TI - [Diagnostic image. A man with haematemesis after stent repair of the abdominal aorta]. AB - An 86-year-old man suffered acute necrotizing oesophagitis as a complication of elective repair of an abdominal aortic aneurysm. PMID- 19785809 TI - [Prolonged activated partial thromboplastin time (aPTT): not always indicative of increased risk of bleeding]. AB - A 69-year-old man of Jewish descent with a second local relapse of rectal carcinoma was found to have a markedly prolonged activated partial thromboplastin time (aPTT). Further evaluation revealed a homozygous factor XI deficiency. Despite various operations in the past he had never displayed any bleeding problems. Severe factor XI deficiency did not prevent venous thrombosis in this patient. The management of patients with prolonged aPTT is described and insight into the pathophysiology of factor XI deficiency is provided. The differential diagnosis in patients with a prolonged aPTT depends on their bleeding tendency. There is a large variability in bleeding tendency in patients with factor XI deficiency. Patients with factor XI deficiency and an increased bleeding tendency can be treated with antifibrinolytic agents prior to small interventions, such as tooth extraction, or with plasma prior to surgery. PMID- 19785810 TI - [Combating the new influenza A (H1N1) virus. II. Surveillance and non pharmaceutical interventions]. AB - Intensive surveillance in Mexico, the US, Canada, Spain and the UK has resulted in the first data on the new influenza A (H1N1) virus. As of yet, it is still unknown if, how and where further transmission within the Netherlands will take place. Therefore, intensified surveillance in the Netherlands is essential. Information on individual patients and their contacts is available through the compulsory notification of the new influenza. The number of general practitioners and nursing homes participating in surveillance through national networks is extended. In addition mortality statistics and internet-based surveillance are being used (the Dutch Great Influenza Survey). Based on studies on previous flu epidemics and mathematical models we can estimate the expected effect of non pharmaceutical interventions.The reduction of social contacts, in particular through the closure of schools, hand washing routines and wearing of facemasks if done correctly, are expected to be effective non-pharmaceutical interventions in slowing the transmission of the new influenza virus. PMID- 19785811 TI - [Combating the new influenza A (H1N1) virus. I. Overview of the relevant virological aspects]. AB - In April 2009 a new influenza virus was discovered, which spread from Mexico to the rest of the world. The new influenza A (H1N1) virus is genetically related to swine flu viruses, and differs substantially from circulating human influenza viruses. It is able to spread from person to person. Because it is a completely new virus, there is probably little immunity in the population. The course of the infection is relatively mild, but the virus will mutate and it is not yet certain whether this will affect severity of the influenza. General practitioners have an important role in surveillance and treatment. The Community Health Services must be notified of any patients who are suspected of having the new influenza. Hygiene measures and administration of antiviral drugs to patients and their contacts may slow the spread. A delay in large-scale spread in the Netherlands allows time for the development of vaccines. PMID- 19785812 TI - [Self-neglect in older adults--a complex problem]. AB - A 76-year-old man presented at the emergency department with functional decline and extreme self-neglect. He died after a few days. The probable cause of death was pneumonia. His family consented to autopsy. Surprisingly, the neuropathological findings showed a tauopathy consistent with fronto-temporal dementia. Self-neglect in the elderly is a common and complex problem associated with high mortality and morbidity. This syndrome requires a thorough workup to detect possible causes. The most common etiologies are neurodegenerative disorders, psychiatric illness and alcohol abuse. It is important to elucidate the cause of self-neglect in order to give the proper treatment and support to the patient and family. PMID- 19785813 TI - [Mexican flu: public reaction to news coverage measured using an internet panel]. AB - OBJECTIVE: To determine the reaction of the general public on the information regarding the Mexican flu. DESIGN: Online panel interview. METHOD: From April 30 to May 4 2009, 572 people filled out an online questionnaire. RESULTS AND CONCLUSION: 88% of the respondents had sufficient general knowledge about the Mexican flu. This information was mostly acquired by watching television (69%). More information was desired regarding the symptoms of the flu and those personal measures that could be taken to avoid infection. PMID- 19785815 TI - [Oral blood glucose-lowering medication as a monotherapy in gestational diabetes: a hotly debated topic]. AB - Treatment of gestational diabetes mellitus is a hotly debated topic. In a recent randomized trial, metformin as a monotherapy achieved maternal and neonatal outcomes comparable to insulin treatment. In 2000, a randomized trial reported a similar favourable result with glibenclamide. The logical conclusion would be that either drug could already have a place in the usual treatment strategy in gestational diabetes. However, a number of major methodological, design and interpretation issues and shortcomings have led to the conclusion that such a point of view is not currently tenable. Therefore, neither metformin nor glibenclamide can yet have an established place as monotherapies in gestational diabetes; they can be used only in exceptionally cases. PMID- 19785817 TI - [Diagnostic image. A girl with cramp and tingling of the hands]. AB - An 8-year-old girl presented with cramp and tingling of the hands due to hypocalcaemia caused by pseudohypoparathyroidism. PMID- 19785818 TI - [An unusual cause of acute dyspnoea: neuralgic amyotrophy]. AB - A 40-year-old man presented at the neurology outpatient clinic with sudden severe pain in both shoulders, followed by paresis of the muscles in this region. These complaints, in combination with acute dyspnoea when lying flat, and paradoxal movements of the abdomen during respiration, led to the diagnosis of neuralgic amyotrophy with phrenic nerve involvement. A 43-year-old man was seen on the pulmonary unit with severe pain in the shoulder area, followed by acute severe dyspnoea, worsening when he lay flat. Lung function analysis showed severe restriction and decreased maximal inspiratory mouth pressure. Taking into account the pain in the shoulder in combination with decreased inspiratory mouth pressure suggestive of diaphragmatic paresis, isolated neuralgic amyotrophy with phrenic nerve involvement was diagnosed. As these cases demonstrate, the diagnosis 'neuralgic amyotrophy with phrenic nerve involvement' often can be determined by history taking and physical examination. Unfamiliarity with this condition may lead to severe delay in the diagnostic process and to unnecessary investigations, especially when no accompanying paresis of the shoulder girdle and arm musculature is present. PMID- 19785819 TI - [Diagnostic use of Internet: google the spider]. AB - A 23-year-old woman was working in a factory unpacking jars of Spanish olives when a spider bit her finger. She presented to the emergency outpatient department carrying the spider in a box. She was worried and wanted to know whether the spider, which may have originated from Spain, was poisonous. After a ten minute Internet search the spider was identified as Segestria florentina. It can inject neurotoxins causing temporary local numbness and pain. The patient was reassured and discharged without further treatment. Later, experts confirmed the species. Internet-based search engines can draw attention to unusual diagnoses which otherwise may easily be overlooked. A general search engine can also provide access to subjects that fall outside the scope of the more usual medical sources. PMID- 19785820 TI - [Intrapartum foetal monitoring: from stethoscope to ST analysis of the ECG]. AB - Since the 1970s, intrapartum monitoring of the distressed foetus has been managed by continuous registration of the foetal heart rate, together with uterine activity (cardiotocogram; CTG). Use of CTG without additional foetal information leads to unnecessary interventions because of the high number of false-positive signals. Foetal blood sampling (FBS) is a solution to this problem, but is not always consistently carried out. Automated ST analysis of the foetal electrocardiogram (STAN method), combined with the CTG, may lead to reduction of metabolic acidosis, fewer interventions and fewer foetal blood samples. A disadvantage of application of the STAN method is that it is based on visual interpretation of the CTG, with large inter- and intraobserver variability. In spite of this shortcoming the method may be promising. PMID- 19785821 TI - [Choosing between different treatment options: how should I inform my patients?]. AB - Evidence-based medicine promotes the use of best available evidence to improve the transparency and quality of health care. The physician's clinical expertise and patient preferences are also important. Clear communication with the patient, based on available evidence from scientific research, is pivotal to making a balanced treatment choice, particularly when several equivalent treatment options are available. Although cure is obviously the aim of any medical intervention a certain risk of damage is always involved. Several verbal, numerical and graphical methods are available to inform the patient, with the aim of enabling the patient to make an informed choice when taking part in decisions on available treatment options. The aim should be to explain both beneficial and harmful effects of medical interventions in a straightforward manner. However, the amount and content of this information should be tailored to the patient's wishes. PMID- 19785822 TI - [Early treatment of Parkinson's disease with levodopa]. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterised by tremor, rigidity and bradykinesia. The current treatment, for example with levodopa or dopamine-agonists, is complicated by response fluctuations, dyskinesias and gastro-intestinal side-effects. These, and various other reasons including fear of levodopa toxicity, have led to reluctance in starting medical treatment in PD. Especially during the last decade it has become clear that there is no scientific substrate for this reluctance. The aim should be to minimize the restraints in daily activity caused by PD, where medications including levodopa and dopamine agonists have proven to be effective. PMID- 19785823 TI - [Idiopathic pulmonary fibrosis; description of a Dutch cohort]. AB - OBJECTIVE: To describe the clinical presentation, diagnosis, and prognosis of a cohort of Dutch patients with idiopathic pulmonary fibrosis (IPF), a serious and rapidly progressive lung disease belonging to the idiopathic interstitial pneumonias. DESIGN: Retrospective study of patient records. METHOD: The data from the clinical presentation, diagnosis, treatment and survival of all patients with IPF, diagnosed in the St. Antonius Hospital in Nieuwegein and University Medical Center Utrecht (UMCU), both in the Netherlands, during the period 1998-2007 were investigated. For the diagnosis, the criteria of the American Thoracic Society and the European Respiratory Society from 2002 were adhered to. RESULTS: The records of 113 patients satisfied the inclusion criteria. Mean age at the time of presentation was 61.9 (SD: 12.7) years and a strong male predominance was observed (90 men vs. 23 women). The most common complaints and symptoms at presentation were dyspnoea, cough, basal crepitations and clubbing of the nails. Lung function tests revealed restrictive lung function impairment and a reduced diffusing capacity. In 72% of cases the diagnosis IPF was histologically confirmed by open lung biopsy, which revealed a pattern of usual interstitial pneumonia (UIP). In 17% of patients it concerned a familial form of the disease with diagnosis at a younger age (average 52 years; SD: 14.8). The medical treatment mostly consisted of corticosteroids, which for half of the patients were administered in combination with an immunosuppressant such as azathioprine or cyclophosphamide. After screening, 28 patients were eligible for lung transplantation. Of these, 12 patients underwent a lung transplantation in the study period, 9 died and 7 are still on the waiting list. The median survival period was 3.9 years. CONCLUSION: In the cohort studied, IPF presented as a rapidly progressive disease with only a marginal response to medical treatment and a poor prognosis. It is important to differentiate IPF from other fibrotic interstitial lung diseases and to refer to a specialist centre, especially in the case of patients who could be eligible for a lung transplant or for participation in trials with new drugs. PMID- 19785824 TI - [Fewer blood transfusions after introduction of auto-transfusion system as part of hip- and knee-replacement surgery]. AB - OBJECTIVE: To establish the effect of the introduction of an auto-transfusion system on the number of homologous blood transfusions required as part of total hip- and knee-replacement surgery. DESIGN: Prospective observational study. METHODS: The number of homologous blood transfusions required after total hip or knee replacement was compared between a group of 195 patients before and a group of 176 patients after introduction of an auto-transfusion system. The '4-5-6 Flexinorm' was strictly implemented when deciding to use homologous blood transfusion. Composition of the groups and the number of transfusion units of homologous blood (packed cells) required were compared using Student's t test and the chi2 test. In addition multivariate logistic regression analysis was used with the following variables as risk factors for requirement of homologous blood transfusion: gender, age, type of surgery and the use of an auto-transfusion system. RESULTS: After introduction of the auto-transfusion system there was a reduction in the number of transfusion units given in both the hip- and the knee replacement group (83% and 98% respectively). The use of the auto-transfusion system was the only variable for prediction of the requirement for homologous blood transfusion in the logistic regression model. CONCLUSION: After the introduction of an auto-transfusion system there was a reduction in the number of homologous blood transfusions required as part of total hip and knee surgery. PMID- 19785825 TI - [The depression epidemic does not exist]. AB - There has been much discussion in the media about the question of the existence of a depression epidemic. This leads on to the questions of whether the social and economic approaches are adequate, and what the alternatives are. The concept of the disease 'depression' can be defined using a medical model, or from a patient's or a societal perspective. From a medical perspective, indeed a depression epidemic has ensued from the increased prosperity and the associated decompression of the mortality rate. Society responded with preventative measures and policies aimed at improving functioning in the workplace. However, patients with a major depressive disorder (MDD) who are eligible for treatment are often not motivated to take it up, or are undertreated. Research is necessary in order to explore what patients think about the identification and treatment of depression. The confusion regarding the concept of depression found in the media, needs to be cleared. PMID- 19785826 TI - [Neuroschistosomiasis; an unexpected finding in a Dutch woman]. AB - A 67-year-old Dutch woman presented with neurological symptoms of several months duration. MRI scans of the brain showed intracerebral lesions. Brain biopsy revealed granulomatous inflammation and remnants of worm eggs. Eggs of Schistosoma mansoni were found in the stools and serological tests were positive for Schistosoma. From additional history taking it became clear that the patient contracted schistosomiasis when visiting Brazil several years before. She was treated with praziquantel and corticosteroids. Neuroschistosomiasis is a rare but severe complication of Schistosoma infection. This diagnosis should be considered in patients that travelled to or originate from endemic schistosomiasis areas. PMID- 19785827 TI - [Osteonecrosis as late complication in HIV-infected patients]. AB - Osteonecrosis of the femoral head was diagnosed in a 22-year-old woman and a 46 year-old man, both with HIV infection . Both had groin pain and impaired mobility. Conservative treatment did not relieve the pain. Both patients underwent a surgical procedure, i.e. core decompression and total hip replacement. In HIV-infected patients, osteonecrosis, i.e. avascular necrosis is an increasingly common problem in view of current longer life expectancy. The incidence of osteonecrosis is higher in HIV-infected patients than in the general population. Osteonecrosis should be included in differential diagnosis of groin or hip pain in HIV-positive patients. This may enable more rapid diagnosis and reduce the need for surgery. PMID- 19785828 TI - [Quicker recovery from elective colon surgery: anaesthesiological aspects of the fast-track programme]. AB - A multidisciplinary approach for patients who will undergo colonic resection was introduced in 2006 and 2007 in 26 Dutch hospitals, following several other European centres. This approach aims to place the patient in an optimal metabolic state before operation, with subsequent rapid mobilisation and resumption of oral intake of liquids and solid food. The surgeon, anaesthetist, and nursing staff collaborate in this approach, each taking responsibility for specific tasks. The anaesthesiological tasks consist of withholding preoperative intake of drink and food, appropriate pain reduction, perioperative fluid balance management, use of inotropic and vasopressor drugs, prevention of post-operative nausea and vomiting, and addressing possible immunological consequences of surgery. PMID- 19785829 TI - [Diagnostic image; an infant with suspicious fractures]. AB - A 10-months-old boy with a haematoma of the left upper leg was diagnosed with bucket-handle fractures of the left lower extremity. These fractures may easily be overlooked and carry a high predictive value for abuse in infants. PMID- 19785830 TI - [Bruises in infants should always be accounted for]. AB - Haematomas were observed in three male infants under 1 year of age. In the first case, no suspicion regarding child abuse was raised, but, in retrospect, the appearance of haematomas coincided with the times he had been with a childminder. When he was admitted to hospital for a different reason, namely a serious airway infection, the causal relationship could no longer be established. In the second case, the grandparents told the general practitioner about their suspicion of maltreatment. CT revealed inflicted traumatic brain injury. In the third case, inflicted traumatic brain injury was also observed, in addition to a corner fracture of the tibia. Child abuse is a widespread problem that is not always recognized by physicians. Haematomas in infants should be evaluated carefully with thorough investigations for bleeding disorders on one hand and the possibility of child abuse on the other. A careful history concerning the circumstances of injury is essential, keeping in mind the age and development of the child. Localization and patterns of haematomas should also be evaluated. Haematomas in children who do not crawl or walk should lead to suspicion of child abuse. In the case of child abuse, direct action should be taken to ensure the safety of the child. PMID- 19785831 TI - [Experiences of combined heart-lung transplantations in the University Medical Center Groningen]. AB - OBJECTIVE: Reporting the results of combined heart-lung transplantation in the University Medical Center Groningen (UMCG), the Netherlands. DESIGN: Retrospective study. METHOD: Data were retrieved of patients who underwent a combined heart-lung transplantation in the UMCG between December 1996 and December 2007. Demographic, clinical and other relevant characteristics were recorded, as well as post-transplantation morbidity and mortality. RESULTS: The study group consisted of 14 patients (3 men and 11 women) with a mean age of 41 years. Indications for heart-lung transplantation were: congenital heart disease complicated by pulmonary hypertension (6 patients), idiopathic pulmonary hypertension with severe right ventricle failure (4 patients), lung fibrosis with severe right ventricle failure (1 patient), cystic fibrosis with systolic left ventricle failure (1 patient), pulmonary hypertension after thoracic radiation and chemotherapy (1 patient) and re-transplantation after lung-transplant failure (1 patient). The mean waiting time prior to operation was approximately 1.5 years. 9 of the 14 patients (64%) underwent such a marked clinical deterioration during the waiting period that they were given a 'very high urgency status' for transplantation. Almost half of patients became dependent on supplementary intravenous inotropics during the waiting period. At the end of the study 6 of the 14 patients (43%) were alive, with a mean survival period of 58 months (range: 6-132). Infection was the cause of death in 4 of the 8 patients. Of the 8 deceased patients, 4 were underweight preoperatively (BMI < 18.5 kg/m2) and were cachectic. This was the case in only 1 of the 6 surviving patients. CONCLUSION: A combined heart-lung transplantation is a rare operation in the Netherlands. The waiting time in this study was long and the post-transplantation mortality was high. Underweight (cachexia), a sign of a poor clinical condition, appears to be associated with mortality. PMID- 19785832 TI - [Mild therapeutic hypothermia following resuscitation; experience and results in the first two years after introduction]. AB - OBJECTIVE: To describe the results of mild therapeutic hypothermia (MTH) following resuscitation in the 'Gelderse Vallei' hospital, Ede, the Netherlands. DESIGN: Descriptive, retrospective. METHOD: Patient data was collected from patients who had undergone MTH during the first two years following introduction of this treatment in the intensive care department of the 'Gelderse Vallei' hospital, Ede. Information used in the description included patient characteristics, heart arrest type (ventricular fibrillation or other arrhythmias), place of onset (in hospital or elsewhere), resuscitation data, side effects of the treatment, mortality and neurological outcome. RESULTS: 67 patients were treated with MTH in the period April 2005 to July 2007. The hospital mortality rate within this group was 81%. The mortality rate in the subgroup presenting with ventricular fibrillation as initial arrhythmia was 76%, compared with 89% in the subgroup with other arrhythmias. The mortality rate of patients who were resuscitated outside the hospital was comparable with that for patients resuscitated in hospital (80% versus 83%). Patients who could be discharged from hospital had a good neurological outcome (average Cerebral Performance Category score 1.9; 95%-CI: 1.6-2.2). The most important complications during MTH were electrolyte imbalances and ventilator associated pneumonia. CONCLUSION: The introduction of MTH in the intensive care department of the "Gelderse Vallei" has taken place without major problems. Although the mortality rate following cardiopulmonary resuscitation was relatively high, the neurological outcome in those patients who were discharged from hospital alive was good. PMID- 19785833 TI - [The value of physical training in patients with heart failure]. AB - Several smaller studies have demonstrated neutral or positive effects of moderately intensive exercise on clinical outcome in patients with heart failure. A recent meta-analysis concluded that the current studies were insufficient to conclude that moderate-to-high intensity resistance training in patients with heart failure has beneficial effects on outcome. However, the recently published HF-ACTION trial demonstrated modest effects on death and hospitalisation, and a clear improvement in quality of life. Taken together, these findings support the current advice provided by the heart failure guidelines of the European Society of Cardiology that recommend regular, moderate daily activity in all patients with heart failure. PMID- 19785834 TI - [New strategies for screening cervical cancer; response to the Dutch College of General Practitioner's practice guideline 'Prevention and early diagnosis of cervical cancer']. AB - The publication of a practice guideline for primary and secondary prevention of cervical cancer by the Dutch College of General Practitioners was appropriate since the vaccination against two high-risk human papillomaviruses (hr-HPV 16 and 18) was recently included in the National Immunization Programme of the Netherlands. Despite vaccination, population-based screening for cervical neoplasia needs to be continued. Moreover, it will take over a decade before vaccination will affect the prevalence of cervical neoplasia. Short term improvement of prevention of cervical neoplasia should therefore focus on screening technology and strategy. Molecular tests based on detection of hr-HPV or DNA changes occurring early in cervical carcinogenesis might improve the efficacy of the screening, which in the Netherlands is currently done by Pap smear. In addition, the high number of women not responding on an invitation for screening might be reduced by a self-sampling approach. PMID- 19785835 TI - [Diagnostic image; a neonate with a blueish, swollen scrotum]. AB - A blueish, swollen scrotum in a neonate appeared to be caused by a hydrocele, as shown by the typical transillumination. PMID- 19785836 TI - [A patient with an alpha-foetoprotein producing tumour]. AB - A 45-year-old Turkish man presented with a chronic hepatitis B virus infection, a nodular lesion in the liver and a highly elevated serum alpha-foetoprotein (AFP) concentration. Ultrasound and MRI showed multiple focal liver lesions and a thickened wall of the gastro-oesophageal junction. Biopsies taken from both sites showed stomach type mucosa with a poorly differentiated adenocarcinoma and AFP positive tumour cells. The diagnosis was hepatoid adenocarcinoma of the stomach. The authors' conclusion is that an elevated serum AFP concentration in a patient with chronic hepatitis B and a nodular lesion in the liver is not diagnostic for a hepatocellular carcinoma. AFP measurement should not be used as a screening method for this type of cancer. PMID- 19785837 TI - [Fatal pulmonary tumour embolism as initial manifestation of an occult coecum tumour]. AB - A 57-year-old woman without significant medical history presented. She had suffered from dyspnoea for the past 2 days and persistent spasmodic abdominal complaints for the past 2 weeks. Physical examination revealed tachypnoea, tachycardia and slight abdominal tenderness. Laboratory investigations revealed hypoxaemia and a strongly elevated D-dimer level. Thorax radiography revealed no abnormalities and no indications for pulmonary embolism were revealed by the CT. Abdominal ultrasound revealed multiple enlarged lymph nodes. Shortly after admission and despite resuscitation the patient died. Autopsy revealed massive pulmonary tumour embolism that originated from a primary lymphogenic metastasized coecum carcinoma. Pulmonary tumour embolism is characterised by tumour cells in the pulmonary vascular system, which exhibit no continuity with parenchymal metastases. Due to the less than specific findings revealed by history taking, physical examination and additional tests, the condition is rarely diagnosed ante mortem. PMID- 19785838 TI - [Progress due to genetic research on rheumatoid arthritis: hype or hope?]. AB - Thanks to progress in genetic research, various genetic factors involved in the pathogenesis of rheumatoid arthritis (RA) have been discovered.There is a difference in genetic risk factors for RA in patients with or without antibodies against cyclic citrullinated peptides. This has led to the idea that RA is not a single disease, but a heterogeneous syndrome. Currently known genetic risk factors are not suitable for prediction of the risk of individual patients developing RA, nor for early diagnosis, nor for determining the therapeutic strategy.Research into functional defects of gene products of genetic risk variants will increase the understanding of the pathogenesis of RA. This could lead to insights for the development of new specific medication.In the future, research into genetic factors correlated with the severity of RA disease progression or with the effect of antirheumatic medication is expected to yield interesting and hopefully clinically relevant results. PMID- 19785839 TI - [Why some proton pump inhibitors are more equal than others]. AB - After the omeprazole patent expired in 2002, numerous generic products were introduced on the market. In a relatively short time many patients received substituted treatment. Clinicians noted a substantial number of patients with more reflux symptoms. We describe a male surgeon of 61 and a woman of 59 both with the red flag symptom of dysphagia after generic substitution. The first patient received a generic substitute of omeprazole, the second a therapeutic substitute of pantoprozole, i.e. omeprazole. The literature suggests three possibilities to explain the inadequacy of the substitution: (a) biphasic metabolism where the raised pH in the stomach may prematurely inactivate the PPI, with an unpredictable effect, (b) differences in acid-resistant coating of the generic products, and (c) influence of multiple dosing of PPIs after several days' use. We conclude that all three factors may contribute to a difference in absorption and therefore clinical effectiveness. PMID- 19785840 TI - [The use of imaging in the case of suspected acute appendicitis: opinion of Dutch surgeons]. AB - OBJECTIVE: To gauge the opinion of Dutch surgeons concerning the use of ultrasound and CT in the case of a suspected acute appendicitis. DESIGN: Written survey. METHOD: All 1020 members of the Association of the Surgeons of the Netherlands received a questionnaire with 8 statements concerning the diagnosis of acute appendicitis. The statements could be answered with 'agree', 'disagree', or 'no opinion'. RESULTS: The questionnaire was returned by 439 members (43%). A majority (64%) of these respondents established the diagnosis acute appendicitis on the basis of clinical symptoms, whereas a minority (22%) routinely performed ultrasound. For a classical presentation, 45% of the respondents thought ultrasound was indicated; for less than 3 classical symptoms, 70% of the respondents thought ultrasound was indicated. For women of fertile age, 74% of the respondents thought ultrasound was indicated. Approximately half (46%) of the surgeons always had access to a radiologist who could reliably perform ultrasound imaging, whereas 34% did not. The combination of ultrasound and CT was considered to be a reliable diagnostic procedure by 74% of the surgeons. CONCLUSION: The majority of the surgeons considered acute appendicitis to be mainly a clinical diagnosis. PMID- 19785842 TI - [Colorectal cancer screening: immunological test for faecal occult blood preferred]. AB - In 2003, the European Commission advised the Member States to start colorectal cancer screening. More than 12 million Europeans have been tested to date, not only by means of faecal occult blood testing but often also by opportunistic endoscopy. Nearly all of the screening programmes concerned were opportunistic in nature. The Dutch government is currently considering the implementation of an organised screening programme for the detection of colorectal cancer. The question no longer seems to be whether a screening programme should be started but rather which screening test should be used. We argue that an immunological faecal occult blood test is to be preferred over other screening tests, such as endoscopy. PMID- 19785843 TI - [The Dutch College of General Practitioners guidelines on 'Rectal bleeding': a realistic view of a warning sign]. AB - The new guideline on rectal bleeding presents a clear view on what can and should be done in primary care in cases of visible rectal blood loss. However, it does not elaborate on approaches that can be taken to verify that 'rectal bleeding' really is caused by blood loss from the gastrointestinal tract, notably by use of a faecal occult blood test. Nevertheless, the guideline presents practical risk factors that require further diagnostic testing by colonoscopy. More importantly however, plenty of attention is given to the diagnostics and possible interventions that apply to benign causes of rectal bleeding: haemorrhoids, fissures and proctitis. This guideline should stimulate further broadening of proctological skills among general practitioners. PMID- 19785844 TI - [Diagnostic image. An old man with a cough]. AB - A 72-year-old man presented with chronic coughing due to an infection with Mycobacterium avium complex: Lady Windermere syndrome. PMID- 19785845 TI - [Herpes simplex virus hepatitis; rare in immunocompetent patients]. AB - A 42-year-old woman was referred with fever and abdominal pain with peritoneal irritation. A diagnostic laparoscopy showed hepatic lesions. Histopathological investigation of the liver biopsy showed hepatitis caused by herpes simplex virus (HSV). The patient was treated with acyclovir and recovered well. HSV is a rare cause of viral hepatitis and has a high mortality rate. PMID- 19785846 TI - [Treatment of asthma during pregnancy]. AB - Treatment of asthma during pregnancy leads to discussion concerning medication and complications of pregnancy.Insecurity about possible teratogenity leads in the first trimester in 40% of pregnant women to reduction or cessation of asthma medication.This results, in pregnant women with moderate to severe asthma, in an increased consumption of rescue medication and number of exacerbations, and reduced asthma control. Asthma-exacerbations are significantly correlated with low birthweight. Of the majority of asthma medications, consumption during pregnancy has not been shown to cause harmful effects on the foetus. Adequate therapy for maintenance and exacerbations are essential, noting that the treatment in essence should not differ between pregnant and nonpregnant asthmatic women. A preconceptional consultation by a pulmonary physician and gynaecologist could improve care for pregnant women with asthma. PMID- 19785847 TI - [Imaging techniques in sports medicine]. AB - Sports radiology is a new radiological subspecialty. Traumatic sports-related injuries can be acute, but are more frequently caused by over-use. Close collaboration between the treating physician and radiologist optimizes the choice of the best imaging technique to confirm the tentative diagnosis and to determine the treatment plan. Conventional radiology is indicated when a bone injury is suspected. In the case of discrepancy between the x-ray findings (no abnormality) and the clinical findings (presence of symptoms) additional investigation is, however, indicated. Ultrasound is the indicated technique for lesions of superficial soft tissue, such as tendons and muscles. MRI is very valuable in both acute and over-use injuries involving bone and soft tissue. PMID- 19785848 TI - [Descending necrotizing mediastinitis: the need for early diagnosis and aggressive treatment]. AB - Three patients developed descending necrotizing mediastinitis (DNM): a 44-year old man due to poor dental status; a 54-year-old women due to a throat infection, 6 weeks after a tooth extraction; and a 30-year-old man a few days after a tooth extraction. Presenting symptoms were dyspnoea, fever, trismus, cervical oedema, and pain. The first two patients had multiple drainage of the cervical region and mediastinum in combination with pathogen-specific antibiotics. Both recovered without any complications. The third patient probably had inadequate surgical drainage of the mediastinum directly after diagnosis, and died. If the CT scan is suggestive of DNM, the patient should be referred to a thoracic surgical unit immediately. The optimal treatment consists of vigorous surgical drainage of both the neck and mediastinum with irrigation in combination with pathogen-specific antibiotic therapy. An early diagnosis followed by adequate antibiotic and surgical treatment improves the outcome in patients with DNM. PMID- 19785850 TI - [Psychosocial adjustment in children with a cleft lip and/or palate]. AB - OBJECTIVE: To gain insight into the psychosocial health of children aged 9 to 12 years with a cleft lip and/or palate; to determine the relation between their health and the nature and severity of the cleft as well as other individual characteristics. DESIGN: Descriptive, cross-sectional study. METHOD: Questionnaires completed by parents, teachers and children were used to obtain information about the psychosocial health, nature and severity of the cleft lip and/or palate, and individual characteristics of 80 children. The interrelationship between these parameters was assessed using chi-square tests, single-factor analysis of variance and correlational analysis. RESULTS: In general, the psychosocial health of children with a cleft lip and/or palate did not differ from that of the norm groups. Parents of children with a cleft lip/and or palate reported more withdrawn or depressive behaviour in their child than parents from the norm groups. Children with a cleft lip and/or palate exhibited less rule-breaking behaviour. Teachers reported relatively more social problems. One-third of the children had learning problems. A better psychosocial health was associated with fewer speech problems but not with a more or less abnormal physical appearance. Self-image showed a negative correlation with psychosocial health problems, while learning problems showed a positive correlation. CONCLUSION: In general, the psychosocial health of children with a cleft lip and/or palate does not differ from children without this condition. However, children with a cleft lip and/or palate do exhibit more learning problems. PMID- 19785851 TI - [Bleeding patterns important factor in choosing an IUD]. AB - Recently the Dutch College of General Practitioners issued a revised practice guideline 'The intrauterine device' (IUD). This should help women considering intrauterine contraception to choose between a conventional copper IUD and a levonorgestrel-releasing intrauterine system (LNG-IUS). This guideline states that two aspects of these IUDs are important determinants of the decision, namely reliability and expected bleeding patterns. We argue that women deserve more detailed information than the practice guideline provides, especially about bleeding patterns. We introduce 'tailor-made bleeding' as one of the aspects of contraceptive counselling that is very much determining levels of compliance and patient satisfaction. A table reviewing different aspects of possible bleeding patterns for all intrauterine and hormonal contraceptive methods is presented as an important counselling tool. PMID- 19785852 TI - [Correct use of methotrexate]. AB - Insufficient knowledge about the correct dosage and potential implications of overdose have played an important role in recent accidents involving methotrexate (MTX). Therefore, it is important that the prescribing physician as well as the pharmacist and pharmacist's assistant have sufficient knowledge of the usual dosages, precautionary measures, side-effects, interactions and contraindications of MTX, to ensure a correct dosing regimen is prescribed. For nearly all indications, MTX is prescribed in a weekly dose of 5-30 mg and preferably in combination with 5 mg folic acid twice a week on a day that MTX is not used. The toxic dose of MTX lies very close to the effective MTX dose. It is therefore important to look out for signs of toxicity. PMID- 19785853 TI - [Summary of the practice guideline 'The intrauterine device' from the Dutch College of General Practitioners]. AB - The practice guideline 'The intrauterine device' from the Dutch College of General Practitioners, first published in 2000, has been revised. Copper and hormonal IUDs have more or less the same level of reliability with respect to preventing pregnancy. During the use of a copper IUD, menstruation tends to be longer with a greater loss of blood; in 70% of women who use a hormonal IUD oligomenorrhea or even amenorrhoea develops. Women with a history of venous thromboembolism can use a hormonal IUD safely. In the first weeks after IUD insertion, there is an increased risk of pelvic inflammatory disease (PID). Therefore prior to insertion, the general practitioner should enquire about the risk of a SOA being present and, if necessary, perform SOA tests. In the Netherlands, IUD insertion can usually be performed at a general practice. PMID- 19785854 TI - [Diagnostic image. A woman in childbed with itch and vesicles]. AB - A 37-year-old woman in childbed developed gestational pemphigoid. PMID- 19785855 TI - [Headache following laparotomy; chronic subdural haematoma following epidural anaesthesia]. AB - A 63-year-old man underwent an exploratory laparotomy because of rectal carcinoma. The operation was performed under general anaesthesia in combination with epidural anaesthesia. Since the operation the patient complained of a headache. Eight weeks after the operation he was hospitalized because of worsening of the headache and also drowsiness. A physical examination showed a slight tendency to incline to the left. A CT scan showed a subdural haematoma, which was relieved with surgery. We suspected that accidental puncture of the dura caused the haematoma. The incidence, causes, symptoms, diagnosis and treatment of this rare complication are discussed. PMID- 19785856 TI - [Human spongiform encephalopathies in the Netherlands]. AB - Cases of Creutzfeldt Jakob disease (CJD) have been centrally registered in the Netherlands since 1997. Each year about 35 cases are reported. All patients with a possible, probable or definite diagnosis are registered in a European database. Recently, patients with a transfusion-transmitted form of CJD have been diagnosed in the United Kingdom. Such cases have not yet occurred in the Netherlands. It is important to continue to detect and centrally register patients with CJD. PMID- 19785857 TI - [Methotrexate: safe if prescribed correctly]. AB - Methotrexate (MTX) is an effective medicine that can be safely used for the treatment of rheumatic arthritis and severe cases of psoriasis. For nearly all indications MTX is prescribed as a weekly dose. As a result of prescription errors, miscommunication, failing pharmacovigilance and lack of knowledge, fatal incidents have occurred due to prescriptions for a dosage once daily instead of once weekly. To prevent such incidences in the future, a balanced automatic pharmacovigilance, clear instructions for the use of MTX on the prescription and good patient information are needed. PMID- 19785858 TI - [Round ligament varicosities mimicking inguinal hernia during pregnancy]. AB - 3 pregnant women, aged 34, 28, and 39 years respectively, presented with an inguinal swelling. In one patient the swelling was bilateral and painful. Reposition was possible and ultrasound examination revealed round ligament varicosities, the most common cause of an inguinal swelling during pregnancy. Expectative treatment is advised as the condition usually disappears after parturition. It is concluded that in every pregnant woman with an inguinal swelling, sonography with doppler imaging must be performed to confirm the diagnosis of round ligament varicosities to avoid unnecessary surgery. PMID- 19785859 TI - [Eleven years of autopsy on account of Creutzfeldt-Jakob disease in the Netherlands]. AB - OBJECTIVE: To describe our experience with the diagnostics of Creutzfeldt-Jakob disease (CJD) and other prion diseases in the Netherlands over a period of 11 years (1997-2007). DESIGN: Retrospective. METHODS: In the period 1997-2007 autopsies were carried out on 280 patients with probable or possible CJD at the Dutch Surveillance Center for Prion Diseases in Utrecht. We registered clinical details, results of additional investigations such as EEG, MRI and cerebrospinal fluid tests, and outcomes of neurological investigations. The contribution of the different disorders within this group was estimated retrospectively. RESULTS: A prion disease was diagnosed in 146 patients (52%) with probable or possible CJD. 133 (91%) of these had the sporadic form. 2 patients were diagnosed with the 'variant CJD' (caused by bovine spongiform encephalopathy). 5 patients were diagnosed as having an iatrogenic form of CJD and 6 patients had a genetic form of the disease. A different disease was diagnosed in 134 patients (48%), such as Alzheimer disease (40%), multi-infarct dementia (13%), neoplasm (10%) and Lewy body dementia (8%). In this group, periodic sharp wave complexes were observed on EEG in 17 patients (13%), most frequently in those with Alzheimer disease. The 14 3-3 protein test on cerebrospinal fluid was positive in 28 of these patients (21%), most frequently in patients with vascular dementia and Alzheimer disease. CONCLUSION: In all cases of an unclear clinical picture suggestive of neurodegenerative disease, prion disease must be considered. Periodic sharp wave complexes on EEG and a positive 14-3-3 protein test on cerebrospinal fluid alone are not diagnostic of CJD. PMID- 19785860 TI - [Laparoscopic surgery for inflammatory bowel disease; an update]. AB - OBJECTIVE: To carry out a review of the literature for the short- and long-term effects of various laparoscopic operations in the inflammatory bowel diseases ulcerative colitis and Crohn's disease and to compare these operations with open surgical procedures. DESIGN: Review of the literature. METHOD: PubMed (Medline), Embase and Cochrane databases were searched for randomised clinical trials and meta-analyses on this topic, published between January 1991 and August 2008. If no level A1, A2 or A2B studies were found, we searched for the best available evidence. RESULTS: For Crohn's disease, there was level A2 evidence that, in comparison with open surgery, in experienced hands laparoscopic ileocaecal resection enhanced recovery and led to a shorter hospital stay and lower costs. Following laparoscopic surgery, subjective body image and cosmetic appearance scores were higher, when compared in the long term. In patients with ulcerative colitis, the expected benefits of laparoscopic proctocolectomy have not yet been demonstrated in a randomised study. Although there was a trend towards a reduced hospital stay (1.6 days) when laparoscopy proctocolectomy was performed, the operating time was 1.5 h longer than in conventional surgery. Body image and cosmetic appearance scores were also higher here when compared in the long term. CONCLUSION: Laparoscopic ileocaecal resection is preferable in Crohn's disease, provided that it is performed in a centre with sufficient expertise in laparoscopic surgery. In patients with ulcerative colitis, laparoscopic proctocolectomy with construction of an ileoanal pouch is indicated in young active patients who are concerned for their appearance. Given its complexity, this operation should be performed only in specialist centres. PMID- 19785861 TI - [Organize quality assurance as in aviation; improve patient safety in Dutch hospitals]. AB - Failing teamwork is a major cause of adverse events in hospitals in the Netherlands. Training team-skills can improve the safety standards in clinical heath care. An adapted version of Crew Resource Management (CRM) training is proving to be a usable format in the hospital environment. We emphasize that paying attention to the subject of safety has to start early in medical education in order to incorporate non-technical skills into the hospital culture. PMID- 19785862 TI - [Methotrexate: mainstay of rheumatoid arthritis treatment]. AB - Some accidents due to methotrexate (MTX) have been reported to the Dutch Health Authorities. However, for modern, intensive treatment of patients with rheumatoid arthritis and various other chronic autoimmune diseases, we cannot do without the drug, because of its broad applications and unique properties. Fortunately, it is a safe drug, if used by doctors experienced in using it and who follow MTX guidelines. PMID- 19785863 TI - [Diagnostic image; a man with severe radiation dermatitis]. AB - A 51-year-old man with concurrent radiotherapy and cetuximab for tongue cancer developed a moist desquamation, spontaneous bleeding and necrosis of the skin after 42 Gy. The skin healed after cetuximab was discontinued. PMID- 19785864 TI - ['Rheumatoid arthritis' in a Surinamese man: leprosy]. AB - Rheumatoid arthritis was diagnosed in a 65-year-old man from Suriname, on the basis of clinical and radiological findings. However, he was eventually diagnosed with leprosy. This emerged when the patient developed skin lesions and complained of increasing sensibility disorders during treatment for the alleged rheumatoid arthritis. He was treated with a combination therapy consisting of rifampicin, clofazimine, dapsone, and prednisone. The skin lesions and joint symptoms were resolved as a result of this, but the sensibility disorders persisted. As physicians are not sufficiently familiar with leprosy and the condition has many manifestations that can mimic more frequently occurring diseases, leprosy is often diagnosed at a later stage. This may result in irreversible damage, especially to the peripheral nerves, which may lead to disability. Therefore, for patients who originate from areas where leprosy is endemic and who suffer from joint complaints in combination with skin or sensibility disorders, the diagnosis of leprosy should be considered. PMID- 19785865 TI - [A clinically unrecognised and persistent facial folliculitis: herpes folliculitis]. AB - A 33-year-old woman presented with a 5-year history of a relapsing erythematous, indurated plaque on the left cheek. Herpes simplex virus (HSV) immunostain revealed the presence of HSV in the follicular and perifollicular keratinocytes. After oral treatment with valaciclovir for a period of 3 months the lesion disappeared without leaving a scar. At the last check-up, no recurrence had occurred. Herpes folliculitis has various clinical presentations. In rare cases it mimics a pseudolymphoma, as was the case for this patient. A viral aetiology, such as HSV or varicella-zoster virus, should be considered in patients with folliculitis, especially when the condition does not respond to antibacterial and antifungal therapy. PMID- 19785866 TI - [Antiseptics to prevent or treat wound infections; myths and evidence]. AB - Antiseptics are commonly applied to prevent or treat wound infections. Many common opinions about antiseptics appear not to be supported by convincing evidence. The aim of this review is to compare such traditional beliefs with currently available evidence. While antiseptics obviously reduce the number of pathogens, their value as a supplement to or as replacement of wound cleansing remains unclear.Some antiseptics encourage wound healing, others may even delay it. Many of the adverse effects ascribed to antiseptics are not supported by evidence; nevertheless this has resulted in a reduction of their use.If used as part of a multifaceted approach to wound care, antiseptics are to be preferred over locally applied antibiotics as they are safer, have a broader spectrum of activity (particularly against antibiotic-resistant bacteria), and rarely lead to resistance. PMID- 19785867 TI - [The acute Achilles tendon rupture: new insights in the treatment]. AB - The acute Achilles tendon rupture is a typical sports injury, which most commonly occurs in men. The diagnosis is easy to make but there is no consensus on best treatment: surgical or conservative treatment? In the case of surgical repair, the risk of a re-rupture is considerably smaller compared to conservative treatment by cast immobilisation. The results of conservative treatment using a functional brace are not good enough to serve as a good alternative for surgery. If surgical treatment is chosen, minimally invasive surgery should be performed. The risk of re-rupture is the same as in open reconstruction but the risk of, a possibly severe, wound infection is smaller. Independent of the suture technique chosen, the postoperative rehabilitation should be functional as opposed to full immobilisation. Too little is currently known about the treatment of acute Achilles tendon rupture for a broadly supported treatment guideline to be realised. PMID- 19785868 TI - [Retrograde irrigation of the colon: treatment for faecal incontinence after low anterior resection]. AB - Two patients, a woman aged 75 and a man aged 63 years, developed faecal incontinence after low anterior resection. Their external sphincter function was intact. They were advised to irrigate their bowel with normal tap water and reached complete pseudocontinence. Faecal incontinence is not always due to sphincter dysfunction. One of the other causes of incontinence is the lack of compliance of the rectum, as seen in patients with a low anterior resection. The part of the colon that has replaced the original rectum is not able to distend in the same manner as the rectum. Irrigation of the colon is a simple means of allowing the patient to achieve pseudocontinence. When the colon is cleaned it will take one or two days before new faeces arrive and a risk for incontinence occurs. It is important to irrigate with safe tap water at a temperature of around 37 degrees C. Most patients treated in this way feel safe to go out again. The irrigation can be performed in patients without the need for extensive diagnostics. This method of irrigation can be used in other forms of faecal incontinence as well. PMID- 19785869 TI - [Predicating imminent preterm labour based on a determination of foetal fibronectin in a vaginal smear]. AB - OBJECTIVE: To determine the prognostic value of foetal fibronectin and cervical length for predicting imminent preterm labour among Dutch women, who in the Netherlands normally undergo a digital examination of the cervix prior to referral to a hospital or university medical centre. DESIGN: Prospective observational cohort study. METHODS: Pregnant women with symptoms of preterm labour and a gestational age between 24 and 34 weeks were included. A fibronectin smear was taken from them and the cervical length was measured. Primary outcome was delivery within 7 days after inclusion. Sensitivity, specificity and a receiver-operating characteristics (ROC) curve were calculated. RESULTS: 13 (12%) of the 108 included patients delivered spontaneously within 7 days after inclusion. The fibronectin test had a sensitivity of 92% and specificity of 60%. The positive and negative predictive values were 27% and 98% respectively. For women who had undergone a digital examination prior to testing, the predictive value was slightly less but the difference was not significant. Although measurement of the cervical length scarcely had a predictive value, none of the patients with a cervical length above 35 mm delivered within 7 days. CONCLUSION: In women with an imminent preterm labour, a negative fibronectin test virtually ruled out delivery within 7 days. The fibronectin test can therefore also be used in the Dutch situation. In women with a cervix length greater than 35 mm, the chance of a preterm labour within 7 days is very small and a fibronectin test does not need to be performed in their case. PMID- 19785871 TI - [Pain management during labour--an informed choice]. AB - The main mission of the Dutch practice guideline 'Pharmaceutical pain treatment during labour' is that during labour every woman should have adequate pain treatment at her request. The guideline rightfully addresses a reserve among physicians and midwives to offer pain treatment during labour. Not pain as such contributes to the sense of birth satisfaction, but far more not being in control, fear for the health of the baby, not having a voice in decision making, and a hospital delivery. A pregnant woman should be able to make an informed choice. Informed choice emphasizes the relational aspect of the midwife and the women, both actively participating in the decision-making process. PMID- 19785872 TI - [Interstitial pneumonitis as an adverse effect of thalidomide]. AB - A 67-year-old man was admitted to the hospital with symptoms of progressive dyspnoea. For 2 months he had received second-line treatment with dexamethasone and thalidomide for a multiple myeloma. Physical examination revealed a tachypnoeic patient and arterial blood gas analysis revealed a respiratory alkalosis and severe hypoxaemia. A high-resolution CT scan showed diffuse ground glass opacities in both lungs. Pulmonary function testing indicated severe diffusion capacity impairment. Bronchoalveolar lavage and cultures excluded the possibility of an infectious agent. The thalidomide treatment was discontinued whereupon the hypoxaemia and the ground glass opacities resolved and the diffusion capacity impairment improved. When a patient treated with thalidomide presents with dyspnoea and hypoxaemia with ground glass opacities, thalidomide induced pneumonitis should be considered. Withdrawing thalidomide is the only treatment. PMID- 19785873 TI - [Professional behaviour during medical training]. AB - Assessment of professional behaviour (PB) is increasingly receiving attention in undergraduate and postgraduate medical training. Its aim is to prevent later inappropriate behaviour and to strengthen appropriate behaviour by self reflection and feedback. Assessment should start early in the curriculum and be repeated frequently, preferably by different assessors in differing educational situations, and with longitudinal follow-up. The consequences of the assessment as well as any agreements reached, must be clearly documented. If remediation of inappropriate behaviour is unsuccessful, a consilium abeundi, i.e. a recommendation to leave the programme, should be discussed with the student. The Dutch Higher Education and Scientific Research Act (WHW) does not provide for denying students access to educational activities and exams after completing the first year. However, the new Higher Education and Research Act (WHOO), which has yet not been implemented, will provide for obligatory cessation of studies. PMID- 19785874 TI - [Diagnostic image. A boy with a wrist deformity]. AB - A 16-year-old boy presented with Madelung's wrist deformity. PMID- 19785875 TI - [Interstitial pneumonitis as a side effect of rituximab]. AB - A 42-year-old man with large B-cell non-Hodgkin lymphoma was admitted to hospital after eight chemotherapy cycles of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP). He had high fever, non-productive cough, dyspnoea, and on chest X-ray, interstitial infiltrations. Extensive microbiological investigation excluded any infection, including opportunistic infection. Positron emission tomography (PET) scan was negative at previous lymphoma sites, but showed diffuse fluorodeoxyglucose uptake in both lungs. Pulmonary function testing demonstrated a restrictive pattern and a diffusion deficit. Review of the literature showed that this clinical picture closely corresponded with that of rituximab-induced interstitial pneumonitis. Treatment with prednisolone, 40 mg/day, resulted in a fast and complete recovery. Physicians administering rituximab should be aware of rituximab-induced interstitial pneumonitis, since according to recent literature this condition occurs in 9-14% of patients. It can run a mild course, but can also be fatal. Besides stopping rituximab, most patients need corticosteroid therapy. PMID- 19785876 TI - [Treatment of HIV-infected pregnant women: prevention of virus transmission and adverse effects in mother and child]. AB - Without intervention, the probability of HIV transmission from mother to child varies from less than 10% to over 60%, dependent on the quantity of freely circulating HIV in the plasma. The prevention of HIV transmission from mother to child is based on the perinatal administration of a combination of antiretroviral drugs (highly active antiretroviral therapy; HAART) to both mother and child. The value of elective caesarean section along with an effective treatment with HAART during the pregnancy is very limited. Exclusive breastfeeding does not lead to a higher HIV transmission than bottle-feeding, but this effect does not lead to a successful strategy. As prophylactic treatment with HAART is widely used, it can be assumed that, in general, the use of HAART during pregnancy is relatively safe. Whether the same is true for the use of specific, and often newer drugs, is frequently not known due to the scarcity of data. For pregnant women it is important to carefully monitor adverse effects such as hepatotoxicity during the first few weeks of treatment. The most important adverse effect for the pregnancy appears to be premature birth. Yet this only occurs if HAART has to be used throughout the entire pregnancy. In the neonate mitochondrial toxicity and haematological effects can occur. These appear to be clinically insignificant but longer term effects cannot be excluded. On the basis of the available long-term safety data for children, no single antiretroviral drug has proven safety. PMID- 19785877 TI - [Takotsubo cardiomyopathy; reversible cardiomyopathy induced by stress]. AB - Takotsubo cardiomyopathy was diagnosed in a 79-year-old woman. She visited her husband who had been admitted for primary percutaneous coronary intervention, and during her visit she developed acute chest pain. Further investigation revealed transient left ventricular apical ballooning, diagnosed as takotsubo cardiomyopathy. This clinical syndrome is characterized by transient regional left ventricle wall motion abnormalities without significant epicardial coronary stenosis. It is provoked by stressful events. Especially in elderly women presenting with the clinical features of an ST-elevation myocardial infarction, takotsubo cardiomyopathy should be considered as an alternative diagnosis. Regarding the exact aetiology and pathophysiology many questions remain unanswered. With supportive treatment the prognosis is favourable. PMID- 19785878 TI - [Uniform intervention criteria for jaundice in hyperbilirubinemia in preterm infants]. AB - OBJECTIVE: To compare the guidelines of the 10 Dutch neonatal intensive care units (NICUs) for the treatment of preterm infants with hyperbilirubinemia, in order to develop uniform threshold levels for the total serum concentration of bilirubin (TSB) above which treatment with phototherapy or exchange transfusion is indicated. DESIGN: Survey. METHODS: Guidelines for hyperbilirubinemia in preterm infants (gestational age < 32 weeks) from all 10 Dutch NICUs were obtained and compared with each other and with international guidelines. RESULTS: All 10 NICUs used intervention criteria based on TSB. 9 NICUs used TSB thresholds based on birth weight (1 used gestational age) with 2, 3 or 5 categories. 6 NICUs used age-specific TSB thresholds and 4 NICUs used a constant TSB threshold. The maximum range in TSB thresholds was 170 micromol/l for phototherapy and 125 micromol/l for exchange transfusion. Acidosis, sepsis, asphyxia, active haemolysis and intraventricular haemorrhage were the risk factors most frequently used. During a consensus meeting with representatives of the 10 NICUs, a guideline was agreed upon that will now be used for all neonates with a gestational age < 35 weeks. CONCLUSION: There was considerable variation in the TSB thresholds used to date by the 10 NICUs. Now in the Netherlands, in addition to guideline 'Hyperbilirubinemia' for children with a gestational age >or= 35 weeks, 'uniform yellow thresholds' shall be used for jaundiced preterm infants with a gestational age < 35 weeks. PMID- 19785880 TI - [Insulin therapy on intensive care should not be too intensive]. AB - Intensive insulin therapy for critically ill patients is implemented as standard therapy in many ICUs, even though the evidence supporting this approach comes from just two studies at a single centre. Moreover, the results could not be repeated in other multicenter trials and there is increasing evidence of a risk of hypoglycaemia. However, it appears that many intensive care specialists have been too zealous in their attempts to attain euglycemia during critical care. A recent RCT with over 6000 patients demonstrated that intensive glucose control increases mortality by 2.4%. PMID- 19785881 TI - [Guideline 'Prevention, diagnosis and treatment of hyperbilirubinemia in the neonate with a gestational age of 35 or more weeks']. AB - Bilirubin encephalopathy and kernicterus are preventable conditions. Nevertheless cases continue to occur. It is difficult to identify those infants who may develop severe hyperbilirubinemia, because icterus neonatorum occurs in most newborns. The aim of this guideline is to reduce the incidence of severe neonatal hyperbilirubinemia and bilirubin encephalopathy, and at the same time to minimise the risk of unintended side effects. At the initiative of the Dutch Pediatric Association and with methodological support from the Dutch Institute for Healthcare Improvement (CBO), a multidisciplinary working group adapted the clinical practice guideline on hyperbilirubinemia of the American Academy of Pediatrics (AAP) to the Dutch situation. This guideline provides recommendations for the prevention, diagnosis and treatment of hyperbilirubinemia in neonates (>or= 35 weeks). For all newborns a risk assessment for the development of hyperbilirubinemia is made and they are to be systematically assessed during the first week of life. The guideline provides various intervention thresholds for risk groups, recommendations for the use of intravenous immunoglobulin in the event of severe hyperbilirubinemia on the basis of blood group antagonisms, and recommendations for conjugated hyperbilirubinemia. During the transfer of care, information about the risk factors in particular must be satisfactorily passed on. PMID- 19785882 TI - [Diagnostic image. A man with dyspnoea]. AB - A 55-year-old man with exertional dyspnoea had a chest X-ray with the Westermark sign and a CT scan showing a Hampton hump. Bilateral pulmonary embolisms were diagnosed. PMID- 19785883 TI - [Myocardial infarction aborted by rapid percutaneous coronary intervention]. AB - In a 55-year-old woman and a 51-year-old man with an ST segment elevation myocardial infarction confirmed by ECG, the infarction could still be aborted by percutaneous coronary intervention with stenting. An aborted myocardial infarction can be described as an acute myocardial infarction in which rapid reperfusion therapy allows normalization of ECG abnormalities with no meaningful cardiac enzyme abnormalities found in the blood. Scientific evidence shows fibrinolysis to be effective in aborting myocardial infarction, but for percutaneous coronary intervention this has not been proven. Nevertheless, the results of the 2 cases discussed in our article are promising. PMID- 19785884 TI - [Low literacy and limited health literacy require health care measures]. AB - Health literacy is the combination of cognitive and social skills that is necessary for adequate response to information about health, illness and health care. Subjects with limited health literacy often experience difficulty in understanding the information provided by health care professionals and finding their way in the health care system, with consequent increased morbidity and mortality. Health literacy is a wider concept than literacy. Approximately 1.5 million people in the Netherlands, of which two thirds are of ethnic Dutch origin, have low literacy skills or are illiterate. The group with low health literacy is even larger. Health care professionals, including physicians, must be able to recognise limited health literacy in order to react appropriately, for example by adapting information provision, checking understanding, supporting communication with visual aids, and making longer appointments.Such measures may be expected to improve results, but investigation of their effectiveness is necessary. PMID- 19785885 TI - [Perioperative suspension of anticoagulants: practical recommendations]. AB - If patients being treated with anticoagulants need to undergo an operation then physicians need to consider whether to suspend the use of this medication or to allow its use to be continued. Suspending the use of anticoagulants increases the risk of thrombosis, whereas continued use may cause bleeding complications. No evidence-based scientific research has been carried out regarding best practice for the perioperative use of anticoagulants.Antithrombotic drugs are vitamin K antagonists and platelet aggregation inhibitors. For daily practice, appropriate bridging strategies can be used for perioperative anticoagulant policy for various risk groups, such as patients with venous thromboembolism, atrial fibrillations, mechanical heart valves and coronary heart diseases (including coronary stents) and patients who have experienced a cerebrovascular accident. In the vast majority of cases the treating physician must carefully consider each individual case in order to realise the best policy. PMID- 19785886 TI - [Acute abdominal symptoms: consider heart failure]. AB - A large number of intra-abdominal and extra-abdominal diseases may give rise to abdominal symptoms. Two patients are discussed who presented with abdominal pain due to severe heart failure. Initially, this diagnosis was overlooked, since abdominal complaints are rarely the primary symptoms of this condition. The authors argue that heart failure, the overall prevalence of which is increasing, should be considered in the differential diagnosis of any patient who presents with abdominal pain. In addition, they propose a systematic diagnostic approach for reaching an individualised diagnosis and therapy directed at heart failure. PMID- 19785889 TI - [The doctor: modest and conscious of own limits in knowledge]. AB - A well educated doctor is not characterised by splendid performance and perfect knowledge, but by modesty. The consequences of this proposition with regard to examination in postgraduate education are argued and elucidated. PMID- 19785890 TI - [Medical practitioner status subject to regular examinations]. AB - Patients demand that their doctors receive regular certification, just like the pilots of the aircrafts they travel on. There are many arguments against regular certification: having the correct attitude and other skills are far more important than knowledge; immediate knowledge is not necessary because doctors can easily look up the knowledge they need; continuing education renders regular certification unnecessary; it is impossible to put together the right exams for doctors. This article argues that the right attitude can never be a substitute for knowledge, that immediate knowledge is essential in treating acute illnesses in busy departments, that continuing education is no guarantee that knowledge has been acquired at all and finally that it obviously should be possible, albeit difficult, to formulate suitable questions for regular doctors' exams. PMID- 19785891 TI - [An Indic woman with 'needles' on the X-thorax]. AB - A 91-year-old woman had multiple needle-like structures in the orofacial region, shoulders and in the left upper arm, incidentally discovered on X-thorax. The needles are known as 'susuks' or 'charm needles'. They are worn as talismans and are believed to give the wearer, among other things, health, beauty and protection. The needles cause no harm and can remain in situ. PMID- 19785892 TI - [Acute myocarditis due to Coxsackie virus B3 in two infants]. AB - In the spring and summer of 2008 two seriously ill male infants were admitted to a paediatric intensive care unit. Initially, both had a fever, were drinking less and were pale complexioned. Physical examination revealed tachycardia, slow capillary filling and liver enlargement. Within a few hours, both infants developed circulatory and respiratory failure. A chest radiograph showed that the heart was enlarged and echocardiography revealed that the pump function of both ventricles was severely diminished. Myocarditis caused by Coxsackie virus B3 was diagnosed when the virus was demonstrated in serum and faeces. At the last follow up, one infant still had severe pump function disorders, and the other one died. Coxsackie virus B3 is a non-polio enterovirus that usually causes mild clinical syndromes but is also associated with myocarditis and overwhelming, systemic neonatal infections. In neonates with mild symptoms one should be alert to progression to circulatory insufficiency, especially if the mother experiences a flu-like illness in the perinatal period. Early recognition of heart failure and adequate diagnostic testing for cardiotropic viruses is important as morbidity and mortality is considerable. PMID- 19785893 TI - [Endovascular treatment of ruptured abdominal aortic aneurysms]. AB - Currently, two treatment options for ruptured abdominal aortic aneurysms (AAA) are available: conventional open surgical repair and endovascular minimally invasive repair. Open repair carries a significant morbidity and mortality rate, most probably due to the combined effects of general anaesthesia and surgical exposure. Based on anatomical characteristics as assessed by CT scan, approximately half of the patients with a ruptured AAA are eligible for endovascular minimally invasive repair. The majority of comparative studies show a clear trend towards a lower perioperative mortality rate for endovascular repair compared to open surgery (18-24% and 34-38%, respectively) and more rapid recovery. However, these mainly observational studies show considerable heterogeneity. Furthermore, potential selection bias, where patients with a more favourable anatomic and haemodynamic profile are more likely to be selected for endovascular repair, makes a proper comparison barely possible.The potential benefits of endovascular repair over open surgery are currently being evaluated in a large randomised study. PMID- 19785894 TI - [The radiologist as the treating physician for cancer: interventional oncology]. AB - Interventional oncology is a new specialism which focuses on image-guided minimal invasive treatment of cancer patients. Interventional oncology has joined the traditional treatments of surgery, chemotherapy and radiotherapy as the fourth pillar of cancer care. Oncological interventions can be divided into three categories: intra-arterial techniques, tumour ablation techniques, and palliative procedures. Two examples of such interventions in Dutch hospitals are the intra arterial Yttrium-90 microsphere radioembolisation of colorectal liver metastases and the CT-guided radiofrequency ablation of tumours such as renal cell carcinoma. In interventional oncology all procedures are performed under image guidance. Imaging is used to guide the instruments and for real-time monitoring of the procedure. PMID- 19785895 TI - [Bechterew disease and top level sport: an attainable combination?]. AB - One 23-year-old and two 24- year-old athletes were diagnosed with ankylosing spondylitis. Because of their wish to compete in sport at the highest level, we considered the feasible extent and intensity of physical sports-load regarding the short-, middle- and long-term effects in this particular subgroup of ankylosing spondylitis patients. We could not find any published articles regarding the physical capacities of highly motivated athletes with ankylosing spondylitis. To give 'tailor made' advice to each athlete, we analysed these patients by using a standardized questionnaire, followed by analysis of the case history and a thorough physical examination. As a result we obtained an idea of the maximum individual feasible sports-load in relation to individual capacity for each athlete. Individual and disease characteristics, as well as the sport specific physical load, can influence the physical capacity of the athlete. To register the effects of maximum sports-load in the middle and long term, and to work towards offering the best possible advice to athletes with ankylosing spondylitis, follow-up research in these 3 patients is advisable. PMID- 19785896 TI - [Disciplinary proceedings on screening and preventive diagnostics]. AB - OBJECTIVE: To gain insight into the disciplinary verdicts on screening and preventive diagnostics and their contribution to the professional standard. DESIGN: Descriptive research, analysis of disciplinary proceedings. METHOD: Two Dutch electronic databases containing disciplinary proceedings were searched using 18 search terms for disciplinary court rulings on screening and preventive diagnostics. Two researchers independently examined which of the 213 decisions retrieved actually concerned screening and preventive diagnostics. The selected verdicts were subsequently categorised according to type of prevention and type of screening, followed by a content analysis. RESULTS: 28 out of 213 cases concerned screening or preventive diagnostics. 12 cases related to universal prevention, 12 to indicated prevention, 2 to health-related prevention and 2 cases concerned preventive screening at the request of the patient. Of the 12 universal prevention cases, 6 concerned breast cancer screening and 4 involved cervical cancer screening. Initially, the disciplinary courts applied the same criteria for these proceedings as for curative care. In 3 cases concerning breast cancer screening, the courts ruled that the screening participants should have been better informed. The women should be made aware that breast cancer cannot be ruled out even if no abnormalities are found. CONCLUSION: There are few disciplinary verdicts about screening and preventive diagnostics. In these cases, the courts initially used the same standards as in cases concerning curative care. Through their statements about the duty to provide information to screening subjects, the courts have contributed to the professional standard for universal prevention. PMID- 19785897 TI - [A new, problem oriented medicine curriculum in Utrecht: less basic science knowledge]. AB - OBJECTIVE: To investigate whether the transition from a conventional, discipline based curriculum to a problem-orientated, integrated curriculum at the University Medical Center Utrecht, the Netherlands, has resulted in students having less knowledge of the basic medical sciences. DESIGN: Comparative. METHOD: The difference in the amount of basic science between the curricula was quantitatively assessed. 37 final-year students in each curriculum volunteered to complete a test specifically designed to measure knowledge of the basic sciences, a few weeks before their graduation. RESULTS: The transition from the old to the new curriculum resulted in a decline of almost half in the amount of time dedicated to the basic sciences, from 84 to 48 'fulltime week equivalents'. Students in the old curriculum performed significantly better on the test than students in the new curriculum, with 43.2% (SD: 9.56) correct answers versus 35.8% (SD: 8.19) correct answers respectively, which amounted to an effect size of 0.828 (Cohen-d). Yet, on the pathophysiology/pathology subscale, students in each curriculum showed similar performance: 36.1% (SD: 11.55) correct answers for students in the old curriculum, versus 37.2% (SD: 11.66) correct answers for students in the new curriculum. CONCLUSION: Students in the old curriculum had overall significantly more knowledge of the basic sciences than students in the new curriculum, except for pathophysiology/pathology, though the time devoted to this discipline in the new curriculum had also decreased considerably. PMID- 19785898 TI - [Guideline on abdominal aortic aneurysm: few points of departure for the general practitioner]. AB - A ruptured abdominal aortic aneurysm is often a dramatic event with high mortality. The general practitioner needs more specific tools to select at-risk patients for screening and to identify symptomatic or presymptomatic patients for diagnostic interventions. The evidence-based practice guideline 'Diagnosis and treatment of abdominal aortic aneurysm' offers basic diagnostic and therapeutic concepts. However, general practitioners see patients with non-specific symptoms or even without symptoms at all. Methods to identify patients with the highest risk of rupture are still lacking. PMID- 19785899 TI - [Hyperchloraemic metabolic acidosis in a patient with an ureteroileostomy according to Bricker]. AB - A 79-year-old male with a Bricker loop and chronic renal failure was admitted to hospital because progressive dyspnoea. This was due to severe hyperchloraemic metabolic acidosis. Hyperchloraemic acidosis can occur if urinary diversions are constructed from the colon or ileum. Contact between intestinal mucosa and urine may cause reabsorption of ammonium and chloride, and secretion of bicarbonate. Hyperchloraemic acidosis is rarely seen with an incontinent ileal loop due to its small absorbing surface area and the rapid drainage of urine from the loop. Hyperchloraemic acidosis in a patient with a Bricker loop may point to prolonged contact between the ileum and urine. A loopogram is necessary to investigate the cause. In our patient the loopogram showed that the incorporated bowel segment was too long. After shortening of the Bricker loop, the patient recovered from the hyperchloraemic metabolic acidosis. PMID- 19785900 TI - [Narrative neurology: access to the patient's experiences]. AB - Could the novel fulfil a role in the neurologist's daily clinical practice? A good book or story can indeed make the neurology patient's experiences clearer, both for the patient and for the doctor. The novel is no longer just an end product or form of art, but a method for better understanding disease and experiences. Several neurological examples are given, such as migraine, Parkinson's disease and ALS. The narrative opens a perspective on disease 'from the inside'. Neurology lends itself to a narrative approach, because it is primarily a field to which the patient's story is central. PMID- 19785901 TI - [Diagnostic image. A woman with a growth at a toe nail]. AB - A 34-year-old woman presented with a progressive subungual swelling of the hallux caused by subungual exostosis. PMID- 19785903 TI - [Clinical reasoning and decision making in clinical practice: a boy with fatigue and abdominal pain]. AB - A 14-year-old boy presented with fatigue and abdominal pain. Laboratory tests revealed a primary hypothyroidism with circulating auto-antibodies against thyroid peroxidase (TPO), anaemia and an elevated level of creatine kinase (CK). A diagnosis of auto-immune hypothyroidism with associated anaemia and myopathy was made. Thyroid hormone replacement therapy was started. However, six months later, he still complained of fatigue. He had unexpectedly varying thyroid function tests and the anaemia and the elevated level of CK persisted. Analysis of the other hormonal axes demonstrated a secondary adrenal insufficiency which was treated with hydrocortisone suppletion therapy. If a patient suffering from hypothyroidism does not respond appropriately to therapy or even deteriorates, adrenal insufficiency should always be considered. Patients with one type of auto immune endocrinopathy have a greater risk at developing other types of auto immune endocrinopathies. PMID- 19785904 TI - [Cocaine use and sudden death: excited delirium syndrome]. AB - Three patients, men aged 30, 33 and 32 years respectively, died in police custody in Amsterdam, the Netherlands. According to autopsy reports, all patients died from excited delirium syndrome induced by cocaine use. Excited delirium is a state of mental and physiological hyperarousal commonly associated with the use of cocaine. Patients suffering from excited delirium can be extremely hostile and violent. If a physical struggle arises with police or medical personnel, the episode can end in death due to adrenergic overstimulation. Patients in acute excited states should be regarded as a medical emergency with a serious mortality risk, and should be transferred to the hospital rather than the police station. Medical and police staff should aim to reduce confrontation. When patients are too agitated to cooperate, benzodiazepines should be used for sedation of the patient. Beta blockers and antipsychotic medication should not be administered, as these medications can exacerbate the fatal cardiac effects seen in excited delirium. PMID- 19785907 TI - [Pre-entry medical student selection results in better doctors]. AB - In the Netherlands, most universities use a lottery system, weighted by average examination grades, to admit students to medical school. However, the political climate for pre-entry selection procedures is changing rapidly. A study by the University Medical Center Rotterdam revealed that pre-entry selection reduces the medical school drop-out rate during the first years of medical training. This is an important observation. It is plausible that students selected by pre-entry selection are more motivated than students selected by a lottery system. However, it is unknown whether these students will also display better professional behaviour and skills in their future careers. Further research is required to determine which of the cognitive and non-cognitive characteristics relevant for predicting students' success in their future careers should be included in the assessment to optimize the selection procedure. PMID- 19785908 TI - Association of polymorphisms in exons 2 and 10 of the insulin-like growth factor 2 ( IGF2) gene with milk production traits in Polish Holstein-Friesian cattle. AB - Insulin-like growth factor 2 (IGF2) is considered to be a regulator of post-natal growth and differentiation of the mammary gland. In the present work, associations of two single nucleotide polymorphisms in the bovine IGF2 gene with milk production traits were studied in dairy Holstein-Friesian cows: the already described g.8656C>T transition in exon 2 (RFLP-BsrI) and the newly found g.24507G>T transversion in exon 10 (RFLP-HaeIII), found by sequencing 273-bp exon 10 of the IGF2 gene in six individuals. Associations were analysed individually and in combination with the multi-trait repeatability test-day animal model. The CT/GT haplotype appeared to be associated with most of the milk traits studied (differences were significant at P < or = 0.001). The most frequent CT/GG haplotype seemed inferior to others in fat and protein content and daily yield of fat and protein but superior (together with the TT/GG genotype) when the daily milk yield is considered. PMID- 19785909 TI - Lactobacillus plantarum bacteriophages isolated from Kefir grains: phenotypic and molecular characterization. AB - Two greatly related Lactobacillus plantarum bacteriophages (named FAGK1 and FAGK2) were isolated from Kefir grains of different origins. Both phages belonged to the Siphoviridae family (morphotype B1) and showed similar dimensions for head and tail sizes. The host range of the two phages, using 36 strains as potential host strains, differed only in the phage reactivity against one of them. The phages showed latent periods of 30 min, burst periods of 80+/-10 min and burst size values of 11.0+/-1.0 PFU per infected cell as mean value. Identical DNA restriction patterns were obtained for both phages with PvuI, SalI, HindIII and MluI. The viral DNA apparently did not present extremes cos and the structural protein patterns presented four major bands (32.9, 35.7, 43.0 and 66.2 kDa). This study reports the first isolation of bacteriophages of Lb. plantarum from Kefir grains and adds further knowledge regarding the complex microbial community of this fermented milk. PMID- 19785910 TI - Efficacy of a teat dip containing the bacteriocin lacticin 3147 to eliminate Gram positive pathogens associated with bovine mastitis. AB - On most dairy farms teat dips are applied to the teats of cows either before or after milking in order to prevent pathogens from gaining access to the mammary gland via the teat canal. In the present experiments, a natural teat dip was developed using a fermentate containing the live bacterium Lactococcus lactis DPC 3251. This bacterium produces lacticin 3147, a two-component lantibiotic which was previously shown to effectively kill Gram-positive mastitis pathogens. Lacticin 3147 activity in the fermentate was retained at 53% of its original level following storage for 3 weeks at 4 degrees C. In the initial experiments in vitro, 105 colony-forming units/ml (cfu/ml) of either Staphylococcus aureus, Streptococcus dysgalactiae or Streptococcus uberis were introduced into the lacticin-containing fermentate. Neither Staph. aureus nor Str. dysgalactiae could be detected after 30 min or 15 min, respectively, while Str. uberis was reduced approximately 100-fold after 15 min. Following these trials, preliminary experiments were performed in vivo on teats of lactating dairy cows. In these experiments, teats were coated with each of the challenge organisms and then dipped with the lacticin-containing fermented teat dip. Following a dip contact time of 10 min, staphylococci were reduced by 80% when compared with the undipped control teat. Streptococcal challenges were reduced by 97% for Str. dysgalactiae and by 90% for Str. uberis. These trials showed that the teat dip is able to reduce mastitis pathogens on the teats of lactating cows. PMID- 19785911 TI - Milk emission and udder health status in primiparous dairy cows during lactation. AB - To investigate the relationships between milk flow traits and udder health status in primiparous cows, 74 primiparous Holstein cows were randomly selected in 5 herds and monitored monthly throughout the whole lactation. A total of 2902 quarter milk samples were collected for bacteriological analyses and the determination of lysozyme, N-acetyl-beta-glucosaminidase (NAGase) and somatic cell count (SCC). Milk flow curves of the whole udder of each cow were registered with continuous electronic milk flow meters. Teat conditions and teat thickness changes during milking were assessed monthly. Quarters, udders and cows were classified as healthy, latent, inflamed and subclinical depending on SCC and the results of bacteriological analyses. Lysozyme in milk, teat apex score and teat thickness change did not vary with udder health status while NAGase in milk significantly increased as udder health status worsened (P<0.001). Milk production (P<0.001) and time of plateau phase (P<0.05) were significantly lower in subclinical cows in comparison with the others. Animals with a high frequency of bimodal curves in the first 100 days in milk showed the worst udder health status during the whole lactation (P<0.01). Moreover, cows classified as subclinical in the first 3 months of lactation had higher peak milk flow than healthy cows (3.81 v. 3.48 kg/min; P<0.05) and shorter duration of plateau phase, expressed both as minutes and as percentage of time of milk flow (pTPL; P<0.001). Multivariate logistic analysis showed udder health status to be associated with duration of plateau phase, time of milk flow, bimodality and duration of overmilking phase. With short time of plateau phase (pTPL <25%), short time of milk flow (<5 min), presence of bimodality and long overmilking phase (>0.8 min) there was an increased risk of poor udder health status. These milk flow traits can be predictive indicators of udder health status; time of plateau phase, expressed as percentage of time of milk flow, can also be a useful parameter for animal selection. PMID- 19785912 TI - Retinol binding protein 4 in dairy cows: its presence in colostrum and alteration in plasma during fasting, inflammation, and the peripartum period. AB - Retinol-binding protein 4 (RBP4) is a plasma protein involved in retinol transportation, and recent evidence in rodents suggests that RBP4 is also a metabolic regulator that modifies insulin sensitivity. To assess how RBP4 levels are regulated in ruminants, we determined the RBP4 concentrations in bovine plasma and milk using Western blot analysis. Plasma RBP4 levels in non-pregnant non-lactating (control) cows were around 45 microg/ml, which were sustained during 60-h fasting, but decreased significantly 4 h after lipopolysaccharide (LPS) administration. Basal plasma retinol concentration was around 30 microg/dl, but this decreased to approximately one-third and one-half of these values during fasting and 8 h after LPS challenge, respectively. Plasma RBP4 and retinol levels in cows 3-6 d before parturition were comparable to those of the controls. However, on the day of parturition both were significantly decreased and had returned to basal levels by two weeks after calving. Interestingly, RBP4 was clearly detected in colostrum (16.4+/-5.6 microg/ml) but was only faintly detected in milk from cows at 7 d and 15 d after calving. Retinol concentrations in colostrum were almost 10-fold higher than those in plasma, while those in milk were comparable to those in plasma. These results suggest that RBP4 and retinol levels are independently regulated under physiological and pathophysiological conditions and that RBP4, like retinol, is transferred from maternal stores to calves through colostrum. PMID- 19785913 TI - Concentration of penicillin G in mammary tissue and secretion of end-term dairy heifers following systemic prepartum administration of penethamate hydriodide. AB - The aim of this study was to assess the concentration of penicillin G in mammary tissue and secretion of dry heifers following systemic administration of penethamate hydriodide. Six dairy heifers in late gestation received a single intramuscular injection of 10 g penethamate hydriodide and were sacrificed 24, 48 or 144 h after treatment. Penicillin G concentrations were measured in mammary tissue and secretion samples using HPLC. Penicillin G was detected in the udder of two animals euthanized at 24 h (mammary tissue and secretion) and at 48 h post treatment (mammary secretion only) after administration at concentrations still close to or above MIC90 values reported for the pathogens associated with heifer mastitis. Antibiotic concentration shortly after administration will have been substantially higher indicating a potential for systemic treatment with penethamate hydriodide to control prepartum intramammary infections in heifers without the disadvantages of local therapy such as teat contamination or risk of trauma for the administrator. PMID- 19785915 TI - Duloxetine for pathological laughing and crying. PMID- 19785914 TI - A behavioural comparison of acute and chronic Delta9-tetrahydrocannabinol and cannabidiol in C57BL/6JArc mice. AB - Cannabis contains over 70 unique compounds and its abuse is linked to an increased risk of developing schizophrenia. The behavioural profiles of the psychotropic cannabis constituent Delta9-tetrahydrocannabinol (Delta9-THC) and the non-psychotomimetic constituent cannabidiol (CBD) were investigated with a battery of behavioural tests relevant to anxiety and positive, negative and cognitive symptoms of schizophrenia. Male adult C57BL/6JArc mice were given 21 daily intraperitoneal injections of vehicle, Delta9-THC (0.3, 1, 3 or 10 mg/kg) or CBD (1, 5, 10 or 50 mg/kg). Delta9-THC produced the classic cannabinoid CB1 receptor-mediated tetrad of hypolocomotion, analgesia, catalepsy and hypothermia while CBD had modest hyperthermic effects. While sedative at this dose, Delta9 THC (10 mg/kg) produced locomotor-independent anxiogenic effects in the open field and light-dark tests. Chronic CBD produced moderate anxiolytic-like effects in the open-field test at 50 mg/kg and in the light-dark test at a low dose (1 mg/kg). Acute and chronic Delta9-THC (10 mg/kg) decreased the startle response while CBD had no effect. Prepulse inhibition was increased by acute treatment with Delta9-THC (0.3, 3 and 10 mg/kg) or CBD (1, 5 and 50 mg/kg) and by chronic CBD (1 mg/kg). Chronic CBD (50 mg/kg) attenuated dexamphetamine (5 mg/kg)-induced hyperlocomotion, suggesting an antipsychotic-like action for this cannabinoid. Chronic Delta9-THC decreased locomotor activity before and after dexamphetamine administration suggesting functional antagonism of the locomotor stimulant effect. These data provide the first evidence of anxiolytic- and antipsychotic like effects of chronic but not acute CBD in C57BL/6JArc mice, extending findings from acute studies in other inbred mouse strains and rats. PMID- 19785916 TI - Loneliness in old age: longitudinal changes and their determinants in an Israeli sample. AB - BACKGROUND: There is a paucity of past research concerning longitudinal changes in loneliness in old age and in the factors that correlate with loneliness in older persons. This study examines (a) whether loneliness increases with age, (b) characteristics of the lonely older population, and (c) predictors of becoming lonely in old age. METHODS: Data are from the Cross-Sectional and Longitudinal Aging Study, a national longitudinal study on the health, mental, and social status of people aged 75 and older living in Israel. Loneliness was measured as the frequency at which participants had felt lonely during the last month (range: 0-3). The analysis included two waves of data, with an average gap of 3.5 years between them, with 1147 participants at wave 1 and 588 participants at wave 2. RESULTS: Data showed an increase in the mean level of loneliness over time, rising from 0.62 to 0.80, p<0.001. The strongest correlate of being lonely at wave 1 was unmarried status. Different variables predicted loneliness in the married and the unmarried. Among the married, lonelier persons tended to have experienced more traumatic events, had more doctor's visits, and manifested less cognitive vitality. In contrast, among the unmarried, loneliness was higher in those with financial difficulties, poor health, and less social network support. The longitudinal transition to becoming lonely was more likely in women, those with insufficient financial resources, and people with poorer health. CONCLUSIONS: Results highlight the following implications for the development of preventive programs: (a) helping older persons maintain and develop social networks for preventing increased loneliness, (b) taking demographic factors, health factors, and previous trauma into account when designing interventions, and (c) targeting unmarried women for interventions. PMID- 19785917 TI - Treating delirium in a general hospital: a descriptive study of prescribing patterns and outcomes. AB - BACKGROUND: Delirium exemplifies the interface between medicine and psychiatry. The mainstay of treatment of delirium are the antipsychotic drugs. These are efficacious and safe for the treatment of delirium. In the last decade the use of second generation antipsychotics has been advocated at the expense of the classical drugs, particularly haloperidol. We thus aimed to compare the outcome of delirium treatment in a large, university-affiliated general hospital. METHODS: We used retrospective medical charts analysis over a one-year period. Those included were all patients who had been admitted to an acute internal medicine ward for delirium or who had developed delirium during their hospital stay. RESULTS: 191 patients' records were analysed. Mean age for the group was 78.8 +/- 1.1 years. There were 108 males (56.5%) and 83 (43.5%) female patients. The most frequent co-morbid psychiatric diagnosis was that of dementia (106; 56%). The most common physical conditions were: cardiovascular (75 patients) and sepsis (24 patients). Patients suffering from delirium were mostly treated with an antipsychotic: 147 (77%) were treated either with risperidone (73 patients) or classical antipsychotics (74 patients). The most frequently used classical antipsychotic was haloperidol (59/74). Mean risperidone dose was 1.7 +/- 0.4 mg/daily. Mean haloperidol dose was 7.8 +/- 1.9 mg/daily. Mean duration of antipsychotic treatment was 3.8 days for the classical antipsychotics group and 2.6 for the risperidone group (p = 0.04). In the untreated group, mean delirium episodes lasted 5.6 days - significantly longer than that of either treated groups, p = 0.02.Mean hospital stay (days) for the group was 12.8 +/- 1.4. In the risperidone treated group the mean stay was 10.8 days while in the classical antipsychotics group it was 13.5 and in the untreated group it was 15.5 (p = 0.008). Fourteen patients (7.3%) died during the delirium episode: 10 untreated, 3 treated by classical antipsychotics and 1 risperidone treated (p = 0.04). The majority of patients (65%) were discharged to the community. CONCLUSIONS: The present study adds to the growing body of evidence favoring risperidone as the drug of choice for the treatment of delirium. However, due to the limitations inherent in a retrospective analysis, prospective large-scale trials are needed to support this recommendation. PMID- 19785918 TI - Examining the association between participation in late-life leisure activities and cognitive function in community-dwelling elderly Chinese in Hong Kong. AB - BACKGROUND: Growing evidence suggests that participation in late-life leisure activity may have beneficial effects on cognitive function. The objective of the study was to evaluate the association between leisure activity participation and cognitive function in an elderly population of community-dwelling Hong Kong Chinese. METHODS: 512 participants were assessed in the follow-up study of a population-based community survey of the prevalence of cognitive impairment among Hong Kong Chinese aged 60 years and over. Leisure activities were classified into four categories (physical, intellectual, social and recreational). Information regarding leisure activity participation, cognitive function and other variables was collected. Multivariate linear regression analyses were performed to examine the association between leisure activity participation and cognitive function. RESULTS: A higher level of late-life leisure activity participation, particularly in intellectual activities, was significantly associated with better cognitive function in the elderly, as reflected by the results of the Cantonese Mini-mental State Examination (p = 0.007, 0.029 and 0.005), the Category Verbal Fluency Test (p = 0.027, 0.003 and 0.005) and digit backward span (p = 0.031, 0.002 and 0.009), as measured by the total frequency, total hours per week and total number of subtypes, respectively; the Chinese Alzheimer's Disease Assessment Scale Cognitive Subscale (p = 0.045) and word list learning (p = 0.003), as measured by the total number of subtypes; and digit forward span (p = 0.007 and 0.015), as measured by the total hours per week and total number of subtypes, respectively. CONCLUSION: Late-life intellectual activity participation was associated with better cognitive function among community-dwelling Hong Kong elderly Chinese. PMID- 19785919 TI - Anticipated Benefits of Care (ABC): psychometrics and predictive value in psychiatric disorders. AB - BACKGROUND: Attitudes and expectations about treatment have been associated with symptomatic outcomes, adherence and utilization in patients with psychiatric disorders. No measure of patients' anticipated benefits of treatment on domains of everyday functioning has previously been available. METHOD: The Anticipated Benefits of Care (ABC) is a new, 10-item questionnaire used to measure patient expectations about the impact of treatment on domains of everyday functioning. The ABC was collected at baseline in adult out-patients with major depressive disorder (MDD) (n=528), bipolar disorder (n=395) and schizophrenia (n=447) in the Texas Medication Algorithm Project (TMAP). Psychometric properties of the ABC were assessed, and the association of ABC scores with treatment response at 3 months was evaluated. RESULTS: Evaluation of the ABC's internal consistency yielded Cronbach's alpha of 0.90-0.92 for patients across disorders. Factor analysis showed that the ABC was unidimensional for all patients and for patients with each disorder. For patients with MDD, lower anticipated benefits of treatment was associated with less symptom improvement and lower odds of treatment response [odds ratio (OR) 0.72, 95% confidence interval (CI) 0.57-0.87, p=0.0011]. There was no association between ABC and symptom improvement or treatment response for patients with bipolar disorder or schizophrenia, possibly because these patients had modest benefits with treatment. CONCLUSIONS: The ABC is the first self-report that measures patient expectations about the benefits of treatment on everyday functioning, filling an important gap in available assessments of attitudes and expectations about treatment. The ABC is simple, easy to use, and has acceptable psychometric properties for use in research or clinical settings. PMID- 19785920 TI - Bullying victimization in youths and mental health problems: 'much ado about nothing'? AB - Bullying victimization is a topic of concern for youths, parents, school staff and mental health practitioners. Children and adolescents who are victimized by bullies show signs of distress and adjustment problems. However, it is not clear whether bullying is the source of these difficulties. This paper reviews empirical evidence to determine whether bullying victimization is a significant risk factor for psychopathology and should be the target of intervention and prevention strategies. Research indicates that being the victim of bullying (1) is not a random event and can be predicted by individual characteristics and family factors; (2) can be stable across ages; (3) is associated with severe symptoms of mental health problems, including self-harm, violent behaviour and psychotic symptoms; (4) has long-lasting effects that can persist until late adolescence; and (5) contributes independently to children's mental health problems. This body of evidence suggests that efforts aimed at reducing bullying victimization in childhood and adolescence should be strongly supported. In addition, research on explanatory mechanisms involved in the development of mental health problems in bullied youths is needed. PMID- 19785921 TI - Bidirectional signaling of ErbB and Eph receptors at synapses. AB - Synapse development and remodeling are regulated by a plethora of molecules such as receptor tyrosine kinases (RTKs), a family of cell surface receptors that play critical roles in neural development. Two families of RTKs implicated in synaptic functions, ErbBs and Ephs, share similar characteristics in terms of exhibiting forward and reverse signaling. In this review, we will discuss the latest advances in the functions of ErbBs and Ephs at the synapse, including dendritic spine morphogenesis, synapse formation and maturation, and synaptic transmission and plasticity. In addition to signaling at interneuronal synapses, communication between neuron and glia is increasingly implicated in the control of synaptic functions. Studies on RTKs and their cognate ligands in glial cells enhance our understanding on the nature of 'tripartite synapse'. Implications of these signaling events in human diseases will be discussed. PMID- 19785922 TI - Integration of NG2-glia (synantocytes) into the neuroglial network. AB - NG2-glia are a distinct class of CNS glial cells that are generally classed as oligodendrocyte progenitor cells. However, in the adult CNS a large fraction of NG2 cells does not appear to divide or generate oligodendrocytes. The functions of these adult NG2-glia, which we have termed synantocytes, are unknown. NG2-glia (synantocytes) form interactive domains with astrocytes and neurons. Within their domains, NG2-glia and astrocytes contact the same neurons, form multiple heterologous contacts with each other, and contact pericytes which regulate cerebral blood flow. NG2-glia receive presynaptic input from neurons and respond to neurotransmitters released at synapses. In addition, NG2-glia are intimately associated with astroglia and respond to astroglial signals, a hitherto neglected aspect of NG2-glial cell physiology. The non-overlapping domain organisation of astrocytes is believed to be important in isolating and integrating activity at the synapses and blood vessels within their domains. The domains of NG2-glia overlap with astrocytes, suggesting they could play a role in integrating non overlapping astrocyte domains. PMID- 19785923 TI - Is activity regulation of late myelination a plastic mechanism in the human nervous system? AB - Studies on various animal models have established that neuronal activity can influence the myelination process. Are such mechanisms present in humans, and do they mediate experience-driven white matter plasticity not only during early development but also in adolescents and adults? While there is as yet no direct evidence for this, a number of findings - reviewed here - are consistent with this idea. First, postmortem and neuroimaging studies show that the human white matter development is a protracted process that continues well into adulthood. Second, developmental changes and individual differences in white matter structure are related to differences in neural activity and behavior. Finally, studies on effects of long-term training, in particular in musicians, show strong relations between training and white matter structure. I conclude by briefly discussing possible types of white matter plasticity that could underlie these findings, emphasizing a distinction between indirect myelination plasticity, where the myelin sheath grows in parallel with the axon itself, and direct myelination plasticity, where the myelin sheath thickness is modulated independently of axonal diameter. PMID- 19785924 TI - NG2-positive glia in the human central nervous system. AB - Cells that express the NG2 chondroitin sulfate proteoglycan and platelet-derived growth factor receptor alpha (NG2 glia) are widespread in the adult human cerebral cortex and white matter and represent 10-15% of non-neuronal cells. The morphology and distribution of NG2 glia are similar to, but distinct from, both microglia and astrocytes. They are present as early as 17 weeks gestation and persist throughout life. NG2 glia can be detected in a variety of human central nervous system (CNS) diseases, of which multiple sclerosis is the best studied. NG2 glia show morphological changes in the presence of pathology and can show expression of the Ki-67 proliferation antigen. The antigenic profile and morphology of NG2 glia in human tissues are consistent with an oligodendrocyte progenitor function that has been well established in rodent models. Most antibodies to NG2 do not stain formalin-fixed paraffin-embedded tissues. Advances in our understanding of NG2 glia in human tissues will require the development of more robust markers for their detection in routinely processed human specimens. PMID- 19785925 TI - Hearing loss in patients with Behcet's disease: an audiological and transient evoked otoacoustic emission study. AB - OBJECTIVE: To investigate hearing loss in patients with Behcet's disease. MATERIALS AND METHODS: Twenty-four consecutive cases of Behcet's disease and 24 sex- and age-matched controls were included in this study. Pure tone and high frequency audiometric tests were performed and pure tone average hearing thresholds calculated for both groups. Transient evoked otoacoustic emission testing was also performed. RESULTS: Pure tone audiometry showed a sensorineural hearing loss in 15 of the Behcet's disease ears. Hearing thresholds were significantly higher in the study group than in the control group, on both pure tone frequency (except 0.5 kHz) and high frequency audiometry. Significant reductions in transient evoked otoacoustic emission amplitude were found at 1.4 and 2 kHz in the Behcet's disease patients. There were no significant differences in reproducibility, stimulus intensity or stability, comparing the Behcet's disease patients and controls. CONCLUSION: Significantly lower mid-frequency amplitudes were found in Behcet's patients on transient evoked otoacoustic emission testing. PMID- 19785927 TI - The Kiwi hoop for Boyle-Davies gag suspension during tonsillectomy. AB - We describe an alternative method of suspending the Boyle-Davis gag during tonsillectomy. Use of the traditional Draffin's bipod for positioning patients during tonsillectomy is associated with a number of difficulties. These include limited height adjustment and problems with slipping during operation. We describe an alternative arrangement for suspension of the Boyle-Davis gag. This arrangement has been successfully used for many years, and offers advantages because of its stability and adjustability. PMID- 19785926 TI - Head rotation evoked tinnitus due to superior semicircular canal dehiscence. AB - INTRODUCTION: Superior semicircular canal dehiscence affects the auditory and vestibular systems due to a partial defect in the canal's bony wall. In most cases, sound- and pressure-induced vertigo are present, and are sometimes accompanied by pulse-synchronous tinnitus. CASE PRESENTATION: We describe a 50 year-old man with superior semicircular canal dehiscence whose only complaints were head rotation induced tinnitus and autophony. Head rotation in the plane of the right semicircular canal with an angular velocity exceeding 600 degrees/second repeatedly induced a 'cricket' sound in the patient's right ear. High resolution temporal bone computed tomography changes, and an elevated umbo velocity, supported the diagnosis of superior semicircular canal dehiscence. CONCLUSION: In addition to pulse-synchronous or continuous tinnitus, head rotation induced tinnitus can be the only presenting symptom of superior semicircular canal dehiscence without vestibular complaints. We suggest that, in our patient, the bony defect of the superior semicircular canal ('third window') might have enhanced the flow of inner ear fluid, possibly producing tinnitus. PMID- 19785928 TI - Facial reanimation with end-to-end hypoglossofacial anastomosis: 20 years' experience. AB - OBJECTIVE: This study aimed to evaluate retrospectively the results of experience with end-to-end anastomosis of cranial nerves VII and XII, performed due to transection of the facial nerve during acoustic neuroma removal. METHODS: We assessed the facial reanimation results of 33 patients whose facial nerves had been transected during acoustic neuroma excision via a retrosigmoid approach, between 1985 and 2006, and who underwent end-to-end hypoglossofacial anastomosis. We compared the facial nerve functions of patients receiving short term (two to three years) and long term (more than three years) follow up, and we assessed any complications of the anastomosis. RESULTS: A House-Brackmann grade III facial function was achieved in 46.2 and 86.4 per cent of the patients in the short and long term, respectively. House-Brackmann grade IV facial function was achieved in 53.8 and 13.6 per cent of the patients in the short and long term, respectively. There was a statistically significant difference between the facial recovery results, comparing the short and long term follow-up periods (p = 0.03). Disarticulation was the most common complication, seen in 19 (57.6 per cent) patients; numbness of the tongue was the next commonest (10 (30.3 per cent) patients). None of the patients developed dysphagia. CONCLUSION: Despite such morbidities as disarticulation and tongue numbness, end-to-end hypoglossofacial anastomosis is still an effective procedure for the surgical rehabilitation of static and dynamic facial nerve functions. Significant improvement in facial nerve function can occur more than three years post-operatively. PMID- 19785929 TI - Internal carotid artery dissection following canalith repositioning procedure. AB - OBJECTIVE: To highlight the possibility of internal carotid artery dissection following canalith repositioning procedures. CASE REPORT: A 52-year-old woman with right posterior canal benign paroxysmal positional vertigo sustained a right carotid artery dissection following a canalith repositioning procedure. The patient also had profound mixed hearing loss associated with otosclerosis, so underwent simultaneous cochlear implantation and occlusion of her posterior semicircular canal, following completion of anticoagulation therapy for her dissection. CONCLUSION: While internal carotid artery trauma is a rare adverse outcome following canalith repositioning procedures, clinicians should be aware of this possibility if patients report unusual symptoms following such procedures. PMID- 19785930 TI - Fruit and vegetable consumption in older individuals in Northern Ireland: levels and patterns. AB - Low intakes of fruit and vegetables have previously been reported in the older population of Great Britain, particularly among certain socio-demographic groups. Levels and patterns of consumption in the older population of Northern Ireland, however, remain unknown. A representative sample of 1000 members of the older population of Northern Ireland were contacted by telephone to assess average intake of all fruits and vegetables and various demographic details. Data from 426 individuals (representative of the whole population) reported a mean consumption of 4.0 (sd 1.3) and 4.1 (sd 1.3) portions of fruit and vegetables per weekday and per weekend day respectively. Regression analyses revealed greater consumption on weekdays by females (B 0.53; P < 0.01), younger individuals (B - 0.02; P = 0.01) and those living in less deprived areas (B - 0.01; P = 0.04), and greater consumption at weekends by females (B 0.54; P < 0.01) and younger individuals (B - 0.03; P = 0.01). The amount of fruit and vegetables consumed is slightly higher than that reported in older populations in Great Britain, possibly as a result of differences in farming practices and rural activities, although levels of consumption remain below current recommendations for health. Patterns of consumption are similar across the UK, and suggest that strategies to increase fruit and vegetable consumption should target males, older individuals and those living in more deprived areas. PMID- 19785931 TI - Leptin concentrations and the immune-mediated reduction of feed intake in sheep infected with the nematode Trichostrongylus colubriformis. AB - The hypothesis that increases in the concentration of the anorectic peptide leptin may be responsible for the immune-mediated reduction in feed intake (FI) during gastrointestinal parasitism in sheep was investigated. In a 2 x 2 x 2 factorial design, the first factor was age at the start of infection (5 months old v. 17 months old). The second factor was parasite infection (no infection v. administration of eighty L3 infective Trichostrongylus colubriformis larvae/kg live weight (LW) per d three times per week for 77 d). The third factor was immunosuppressive therapy with a corticosteroid (no therapy or weekly intramuscular injection of 40 mg methylprednisolone acetate/30 kg LW). Relative to their uninfected counterparts, a 20 % reduction in FI per unit LW (FI/LW; g DM/kg LW) was observed in infected non-suppressed 5-month-old lambs from 21 to 63 d post-infection (P < 0.001) but not in comparable17-month-old ewes or in corticosteroid-treated lambs or ewes (P>0.05 for all), allowing the suggestion that the anorexia was a consequence of the developing immune response. The reduction in FI/LW in 5-month-old lambs was not associated with an increase in plasma leptin concentration. Furthermore, plasma leptin concentrations were greater in corticosteroid-treated animals (P < 0.001) and in 17-month-old animals (P < 0.001), none of which displayed an infection-induced reduction in FI/LW. Plasma leptin was positively correlated with carcass fat percentage in both 5 month-old (P = 0.016) and 17-month-old (P < 0.001) animals and did not appear to provide a direct feedback mechanism that restricted energy intake. The results do not support the hypothesis that an increase in circulating leptin is directly responsible for the immune-mediated anorexia in lambs during T. colubriformis infection. PMID- 19785932 TI - Dietary n-3 polyunsaturated fatty acids enhance metastatic dissemination of murine T lymphoma cells. AB - Epidemiological investigation and animal studies have shown that dietary n-3 PUFA prevent the development and progression of certain types of cancer. However, conflicting results have been reported by the few studies that focused on the effect of dietary n-3 PUFA on the development of metastases. In the present study, we investigated the metastatic dissemination of murine T lymphoma lines with different metastatic potential transplanted into mice fed a fish oil diet, compared with mice fed a maize oil diet. Transplantation of highly metastatic S11 cells into animals fed a fish oil diet induced a large lymphomatoid infiltration in the spleen, associated with an eight-fold increase in spleen weight, compared with normal animals on the same diet. In contrast, only a limited increase in spleen weight was found in animals transplanted with S11 cells while fed a maize oil diet. No significant increase in spleen weight was found in animals transplanted with low-metastatic 164T2 cells regardless of whether they were fed a fish oil or a maize oil diet. At the end of experiment, an overt cachexia was shown by animals fed a fish oil diet transplanted with S11 cells, but not by those transplanted with 164T2 cells. The particularly high pro-metastatic effect of dietary n-3 PUFA on S11 cells rules out the generalisation that dietary n-3 PUFA inhibit tumour growth and progression. PMID- 19785933 TI - The experience and meaning of compassion and self-compassion for individuals with depression or anxiety. AB - OBJECTIVES: The objective of this study was to explore the meaning and experiences of compassion and self-compassion for individuals with depression and anxiety. DESIGN: An interpretative phenomenological analysis (IPA) epistemology and methodology were adopted as the study was focused on understanding the meaning and experiences of participants towards self-compassion from existing theory. METHODS: Ten participants were selected based on a Diagnostic and Statistical Manual of Mental Disorders, 4th Ed.-text revision diagnosis of depression or an anxiety disorder. Individuals were excluded from this study if they had additional diagnoses which impacted significantly on their disorder or on ethical grounds if participation was seen as psychologically distressing. Participants completed a semi-structured interview with questions were based on existing self-compassion research. Interviews lasted an hour and were analysed using IPA methodology. RESULTS: Participants' reflections suggested that they saw compassion having two central qualities: kindness and action. Participants reported that they thought having compassion for themselves felt meaningful in relation to their experiences and useful in helping with their depression or anxiety. However, participants reflected that they felt being self-compassionate would be difficult either because the concept itself felt challenging to enact or their experience of psychological disorder had negatively impacted on their ability to be self-compassionate. CONCLUSIONS: Participants' positive perceptions of self-compassion offer encouragement to clinicians as it appears people can connect with the concept meaningfully as well as seeing it as being useful. Clinicians focusing on self-compassion may gain greater efficacy when they incorporate both aspects within interventions. Findings about the difficulties associated with self-compassion provide valuable information as to why people find it difficult to adopt which can be used in the development of future clinical interventions. PMID- 19785935 TI - Laser capture microdissection as a new tool to assess graft-infiltrating lymphocytes gene profile in islet transplantation. AB - Innovative tolerogenic protocols in transplantation would take advantage of the development of new tools capable of evaluating the impact of these treatments on the immune system. These assays have potential for clinical application. Currently, many of these studies are based on the analysis of peripheral lymph nodes and blood-derived cells, where the percentage of alloantigen-specific cells can be low or even unpredictable. We combined a laser capture microdissection (LCM) technique with real-time PCR (RT-PCR) to evaluate gene profile of islet infiltrating lymphocytes. Donor Lewis rats islets were transplanted under the kidney capsule in diabetic Brown Norway rats. Administration of anti-LFA1 mAb or anti-CD28 F(Ab)' was able to prolong islet survival, while the combined treatment resulted in indefinite survival. The analysis of gene expression profile for IL 2, IFN-gamma, and IL-10 production of graft-infiltrating cells revealed high IL 2, IFN-gamma, and IL-10 in untreated rats; on the contrary, the combined treatment selectively abrogated IL-2- and IFN-gamma-producing cells infiltrate. The comparison between cytokine profile in periphery (even during an allogenic extra stimulus) and in the graft revealed the dichotomy between graft and peripheral cytokine assessment. We thus propose that direct analysis of graft infiltrating cells should be used whenever possible to evaluate the effects of a new immunomodulatory protocol. PMID- 19785937 TI - Increased apelin following bone marrow mononuclear cell transplantation contributes to the improvement of cardiac function in patients with severe heart failure. AB - We previously reported that intracoronary implantation of bone marrow mononuclear cells (BMMC) into ischemic hearts improved cardiac function after myocardial infarction. However, the mechanisms have not been elucidated. The present study investigates whether apelin, a newly described inotropic peptide with important cardiovascular regulatory properties, contributes to the functional improvement in patients with severe heart failure after cell transplantation. Forty consecutive patients with severe heart failure secondary to myocardial infarction were assigned to the BMMC therapy group or the standard medication group according to each patient's decision on a signed consent document. In 20 patients intracoronary cell infusion was performed, and another 20 patients were matched to receive standard medication as therapeutic controls. An additional 20 healthy subjects were designated as normal controls. Clinical manifestations, echocardiograms, and biochemical assays were recorded. Plasma apelin and brain natriuretic protein (BNP) levels were determined by enzyme immunoassay. Baseline levels of plasma apelin were significantly lower in all heart failure patients compared to normal subjects. In patients who underwent cell transplantation, apelin increased significantly from 3 to 21 days after operation, followed by significant improvement in cardiac function. In parallel, BNP varied inversely with the increase of apelin. In patients receiving standard medical treatment, apelin remained at a lower level. Our findings indicated that increased apelin levels following cell therapy may act as a paracrine mediator produced from BMMCs and play an important role in the treatment of heart failure through autocrine and paracrine mechanisms. PMID- 19785936 TI - Cross-linking enhances deposition of human endothelial progenitor cells in the rat heart after intracoronary transplantation. AB - Transplantation of human endothelial progenitor cells (hEPCs) may improve vascularization and left ventricular function after myocardial infarction. The scope of this study was to explore, whether cross-linking of EPCs may enhance the deposition of cells in the rat heart after clinical-like, intracoronary transplantation. To this end, (111)In-oxinate-labeled hEPCs were infused by a minimally invasive technique into the coronary arteries of immunosuppressed Wistar rats under control conditions and after ischemia/reperfusion. In a second set of experiments hEPCs were treated with phytohemagglutinin to create small cell clusters prior to transplantation. Continous three-dimensional HiSPECT images for 1 h and after 48 h revealed that cell deposition was significantly higher when hEPCs were cross-linked. Therefore, cross-linking of hEPCs may provide a promising approach to enhance the number of trapped cells also in a clinical setting. PMID- 19785938 TI - Update experience of surgery for acute limb ischaemia in a district general hospital - are we getting any better? AB - INTRODUCTION: The aims of this study were to audit results of a 10-year experience of surgery for acute limb ischaemia (ALI) in terms of limb salvage and mortality rates, and to compare results with a historical published series from our unit. PATIENTS AND METHODS: All emergency operations performed during the period 1993-2003 were identified from theatre registers and patient notes reviewed to determine indications for, and outcome of, surgery. Data were compared to a similar cohort who underwent surgery from 1980 to 1990. RESULTS: There was a 33% increase in workload from 87 to 116 patients between the two time periods. The number of patients with idiopathic ALI reduced (24% versus 4%; P < 0.05), and there were fewer smokers (71% versus 39%; P < 0.05) and a greater number of claudicants (17% versus 35%; P < 0.05) in those treated from 1993-2003. Latterly, more patients underwent pre-operative heparinisation (33% versus 80%; P < 0.05), received prophylactic antibiotics (14% versus 63%; P < 0.05), and had anaesthetic presence in theatre (46% versus 88%; P < 0.05). There was also a reduction in local anaesthetic procedures (80% versus 41%; P < 0.05). Despite increased pre-operative (15% versus 47%; P < 0.05) and on-table imaging (0% versus 16%; P < 0.05) technical success did not improve. Whilst complication rates were identical at 62%, there were fewer cardiovascular complications in the recent cohort. The 30-day mortality rate for embolectomy fell from 45% to 33%. Multivariate analysis revealed age > 70 years, prolonged symptom duration, ASA score > or = III, lack of prophylactic antibiotics, absence of an anaesthetist, and operations performed under local anaesthetic to be associated with increased risk of mortality. Factors adversely affecting limb salvage included prolonged duration from symptom onset to operation, and a history of claudication or smoking. CONCLUSIONS: Despite improvements in pre- and peri-operative management, arterial embolectomy/thrombectomy remains a procedure with a high morbidity and mortality. Further attempts to improve outcome must be directed at early diagnosis and referral as delay from symptom onset to surgery is a major determinant of outcome. PMID- 19785939 TI - Waiting time to lymph node biopsy is dependent on referral method: don't write, phone! AB - INTRODUCTION: Patients with lymphadenopathy are commonly referred to general surgeons for diagnostic lymph node biopsy. We were concerned at potential long waits for this service in our hospital and thus wanted to compare the efficiency of written and telephone referral with a view to identifying the optimum care pathway for these patients. PATIENTS AND METHODS: Sixty patients were included in a 2-year retrospective review (excluding referrals associated with breast lumps which were managed separately). Hospital Episode Statistics data were used to analyse notes for the source and method of referral, waiting time to biopsy, clinic attendance and diagnosis. RESULTS: Of referrals, 33% were from haematology and 28% from general practice. Overall, 47% of patients were referred by letter; of these, 64% were seen in clinic before biopsy. Personal referral between clinicians, by direct discussion, e-mail or fax led to a mean wait of 4 days, compared to 51 days when patients were referred by letter. Clinic attendance had no significant bearing on diagnostic accuracy or complication rate. Neoplasia accounted for 43% of diagnoses and infection (including four cases of tuberculosis) for 10%. Of biopsies, 33% showed benign changes, 8% were unrecorded and 5% were incorrect. CONCLUSIONS: In this study, 43% of biopsies revealed malignancy and we advise that lymph node biopsy requests should be managed on a fast-track pathway, expedited by direct personal request. Following this study, we have implemented a fast-track pathway for such patients. PMID- 19785940 TI - Three-year audit and cost assessment of open abdominal aortic aneurysm repair in a district general hospital. AB - INTRODUCTION: The aims of this study were to audit the outcome of elective open abdominal aortic aneurysm (AAA) repair in a district general hospital, as well as investigate the true costs for this procedure in relation to the national tariff. PATIENTS AND METHODS: A database is maintained on AAA surgery in the trust. Data were supplemented by drawing information from blood bank and clinical notes. Patients with symptomatic or emergency aneurysms were excluded. Data from January 2005 to December 2007 were obtained on demographics, morbidity, 30-day mortality and blood usage. Costs were obtained from the trust finance department. RESULTS: Between January 2005 and December 2007, 79 elective AAA procedures were undertaken. Median age was 75 years (range, 52-85 years), median aneurysm size was 63 mm (range, 42-105 mm) and median ITU stay was 3 days (range, 1-41 days). Major morbidity rate was 20.3% (16 of 79 patients) and 30-day mortality overall was 5.1% (4 of 79 patients). Average cost per case was pound15,012.91 (range, pound4,040.03- pound82,158.00), when National Tariff is pound6,722.00 ( pound5,649.00 x local Market Forces Factor of 1.19). Loss per case for our trust was pound8,290.91 with a total annual loss of pound218,299.56. CONCLUSIONS: Morbidity and mortality in this district general hospital compare well with national studies; however, the total cost is far in excess of the national tariff. PMID- 19785941 TI - Systematic review of internal hernia formation following laparoscopic left nephrectomy. AB - This is the first identifiable description where internal herniation following laparoscopic left nephrectomy necessitated gangrenous small intestinal resection; similar cases and prevention are discussed. PMID- 19785943 TI - The central urology multidisciplinary team - is it time to change the referral criteria? An audit of practice in a district general hospital in London. AB - INTRODUCTION: All cancer patients are discussed in multidisciplinary team meetings (MDTs). Certain patients are referred to the Central MDT based on specific national criteria. We wanted to see whether the Central MDT aided in the decision-making process above that of the Local MDT alone. PATIENTS AND METHODS: All MDT forms (local and central) for 2007 were retrospectively reviewed. RESULTS: A total of 217 patients were reviewed at the Local MDT. Of these 217 cases, 102 (47.0%) cases were referred to the Central MDT and 15 of the 102 (14.7%) cases were awaiting investigations at the time of the Local MDT and were, therefore, excluded. For the prostate cancer cases (n = 67), the Central MDT did not change outright the Local MDT decision in any case, but in 6 of 67 (9.0%), advised/excluded patients from clinical trials. For bladder cancer cases (n = 19), 4 of 19 (21.0%) patients had their management changed by the Central MDT. The one kidney cancer case had its Local MDT decision changed by the Central MDT. CONCLUSIONS: This audit suggests that the Central MDT plays a useful role in the decision-making process for bladder and kidney cancers, and helps determine eligibility for clinical trials in metastatic prostate cancer patients. Its value over the Local MDT alone in the decision-making process for non-metastatic prostate cancer is questionable. PMID- 19785942 TI - Local anaesthetic inguinal hernia repair performed under supervision: early and long-term outcomes. AB - INTRODUCTION: Local anaesthetic inguinal hernia repair may be technically demanding. There are minimal data regarding the outcomes of local anaesthetic hernia repair by trainees in comparison with consultants. PATIENTS AND METHODS: All consecutive local anaesthetic repairs performed by trainees and one consultant over a 9-year period were reviewed. Operation time, volume of local anaesthetic used, early and long-term complications were assessed. A postal survey was conducted to assess chronic groin pain and satisfaction rates. RESULTS: A total of 369 repairs were reviewed of which 265 repairs were performed by the consultant and 104 by trainees. The male-to-female ratio was 25:1 and the median age of the study group was 61 years (range, 18-93 years). The volume of local anaesthetic used was significantly higher for trainees than the consultant (42 ml versus 69 ml; P = 0.03). The operative time for the consultant and the trainees was 35 min and 40 min (P = 0.8). The day-case rate was higher for the consultant than the trainees (84% versus 69%; P = 0.02). Three patients operated by trainees required conversion to a general anaesthetic repair. No difference was noted in chronic groin pain (consultant 28% versus trainees 32%; P = 0.52) on the postal survey. The median follow-up was 5 years (range, 2-7 years). CONCLUSIONS: Local anaesthetic inguinal hernia repair can be performed safely by surgical trainees under consultant supervision with minimal short- and long-term morbidity. A large volume dilute solution of Lignocaine and Marcaine is recommended when hernia repair is undertaken by trainees. PMID- 19785944 TI - Initial experience of laparostomy with immediate vacuum therapy in patients with severe peritonitis. AB - INTRODUCTION: To report our initial experience of laparostomy and immediate intra abdominal vacuum therapy in patients with severe peritonitis due to intra abdominal catastrophes. PATIENTS AND METHODS: Twenty-seven patients underwent emergency laparotomy and laparostomy formation with the application of immediate intra-abdominal TRAC-VAC therapy (male:female ratio, 1:1.2; median age, 73 years; range, 34-84 years). Predicted mortality was assessed using the P-POSSUM score and compared with clinically observed outcomes. RESULTS: Ten patients (37%) with a mean predicted P-POSSUM mortality of 72%, died of sepsis and multi-organ failure. Seventeen patients (mean P-POSSUM 48% expected mortality) survived to discharge. One patient with pancreatitis died from small bowel obstruction 1-year post discharge, two patients developed a small bowel fistula. One patient had an allergic reaction to the VAC dressing. Our patients, treated with laparostomy and TRAC VAC therapy, had a significantly improved observed survival when compared to P-POSSUM expected survival (P = 0.004). CONCLUSIONS: Laparostomy with immediate intraperitoneal VAC therapy is a robust and effective system to manage patients with intra-abdominal catastrophes. There were significantly improved outcomes compared to the mortality predicted by P-POSSUM scores. Damage control surgery with laparostomy formation and intra-abdominal VAC therapy should be considered in patients with severe peritonitis. PMID- 19785945 TI - Ritual circumcision: no longer a problem for health services in the British Isles. AB - INTRODUCTION: Primary care trust (PCT) funding of a ritual circumcision service has recently been withdrawn from our unit, raising concerns that this may result in greater morbidity from community circumcision. The aims of this study were to document our circumcision practice before and after the withdrawal of PCT funding and to determine its effect on the morbidity from circumcision. In addition, we wanted to survey all paediatric surgical centres in the British Isles to ascertain how many still offer a ritual circumcision service. PATIENTS AND METHODS: We retrospectively reviewed our circumcision practice for 1 year prior to the removal of UK Government funding, and then performed a prospective audit of our practice for the 12 months following funding withdrawal. An e-mail survey was also performed of all paediatric surgical units to determine the ritual circumcision service provision throughout the British Isles. RESULTS: A total of 213 boys underwent circumcision during the 12 months prior to the withdrawal of funding, of which 106 cases (50%) were ritual circumcisions. After funding withdrawal, 99 boys underwent circumcision, of which 98 cases (99%) were for medical reasons. A similar number of boys were re-admitted after a hospital circumcision during the two review periods (5 versus 4 patients), whereas the number admitted following a community circumcision rose after funding withdrawal (6 versus 11 patients). Only a third of British paediatric surgical centres offer a ritual circumcision service, and a significant pro- portion of these were either providing the service without PCT funding, or were reconsidering their decision to continue. CONCLUSIONS: PCT funding withdrawal for ritual circumcision had an impact on our unit's procedural case volume. This represented a cost saving to the trust, despite a higher rate of admissions for postoperative complications. There is an inequality in healthcare provision throughout the British Isles for ritual circumcision, and we feel it is vital to offer support and training to medical and non-medical practitioners who are being asked to perform a greater number of circumcisions in the community. PMID- 19785946 TI - Cost-effective laparoscopic cholecystectomy. AB - INTRODUCTION: There is wide variation in costs, both theatre and ward, for the same operation performed in different hospitals. The aim of this study was to compare the true costs for a large number of consecutive laparoscopic cholecystectomy (LC) cases using re-usable equipment with those from an adjacent trust in which the policy was to use disposable LC equipment. PATIENTS AND METHODS: Data were collected prospectively between January 2001 and December 2007 inclusive for all consecutive patients undergoing LC by two upper gastrointestinal (UGI) consultants at the Royal Berkshire Hospital. Data were collected for all the instruments used, in particular any additional disposable instruments used at surgeons' preference. Sterilisation costs were calculated for all re-usable instruments. Costs were also obtained from an adjacent NHS trust which adopted a policy of using disposable ports and clip applicators. Disposable equipment such as drapes, insufflation tubing, and camera sheath were not considered as additional costs, since they are common to both trusts and not available in a re-usable form. RESULTS: Over 7 years, a total of 1803 LCs were performed consecutively by two UGI consultants at the Royal Berkshire Hospital. The grand total for 1803 LC cases for the re-usable group, including initial purchasing, was pound89,844.41 (an average of pound49.83 per LC case). The grand total for the disposable group, including sterilisation costs, was pound574,706.25 (an average of pound318.75 per LC case). Thus the saving for the trust using re-usable trocars, ports and clip applicators was pound268.92 per case, pound69,265.98 per annum and pound484,861.84 over 7 years. CONCLUSIONS: This study has demonstrated that considerable savings occur with a policy of minimal use of disposable equipment for LC. Using a disposable set, the instrument costs per procedure is 6.4 times greater than the cost of using re usable LC sets. It behoves surgeons to be cost-effective and to reduce unnecessary expenditure and wastage. There is no evidence to support use of once only laparoscopic instruments on grounds of patient safety, ease of use or transmission of infection. If the savings identified in this study of two surgeons' work (savings of pound484,861.84 in a 7-year period) was extended not only across the hospital but across the NHS, large savings could be made for laparoscopic cholecystectomy. Even greater savings would accrue if the results were extrapolated to cover all laparoscopic surgery of whatever discipline. PMID- 19785947 TI - [Identification of factors associated with YMDD mutation in patients with chronic hepatitis B receiving lamivudine treatment]. AB - OBJECTIVE: To identify factors associated with YMDD mutation in patients with chronic hepatitis B before and after lamivudine treatment in Zunyi region. METHODS: 53 patients with chronic hepatitis B were enrolled in this study, HBV DNA,HBV markers, ALT, AST, TBil, albumin in the serum were examined at 0, 3, 6, 12, 18 and 24 months after lamivudine treatment. HBV genotype and YMDD mutation were determined by sequencing before lamivudine treatment. YMDD mutation was checked again if serum HBV DNA rebound to more than 1 x 10(4) copies/ml after the initial decrease. RESULTS: HBV genotype in Zunyi region is constitute of B, C and B+C genotype. YMDD mutation occurred in 18 cases after lamivudine treatment, the rate of YMDD mutation was 15.1%, and 34.0% after 1 year and 2 years treatment. There are four types of mutation: rtL180M/M204V, rtL180M/M204I, rtM204I, rtL180M. rtM204V mutation in C gene was always accompanied by rtL180M mutation (100%). The rate of rtL180M/M204V mutation in genotype C group was significantly higher than that in genotype B group (77.8% to 25.0%), the same was true for the rtL180M/ M204I mutation (22.2% to 12.5%). There was no point mutation in genotype C group. The point mutation of rtM204I and rtL180M appeared only in genotype B group. Gender, nation, family history of hepatitis B and HBeAg were not associated with YMDD mutation (P more than 0.05), while the mutation rate was associated with the disease course and severity of disease. YMDD mutation did not occur in patients with low HBV DNA level (less than 10(5) copies/ml). CONCLUSION: YMDD mutation after lamivudine therapy is associated with HBV genotype and P gene mutation type, and prolonged treatment increases the the mutation rate. In order to reduce the incidence of YMDD mutation, patients with shorter disease course, lower HBV DNA level, more serious liver damage should be treated with lamivudine. PMID- 19785948 TI - [The association of genetic polymorphism of dendritic cell-specific ICAM-grabbing nonintegrin and hepatitis C infection]. AB - OBJECTIVE: To investigate the association of genetic polymorphism of dendritic cell-specific ICAM-grabbing nonintegrin (DC-SIGNR) and hepatitis C infection. METHODS: Patients with hepatitis C (n = 268) were genotyped and analysed for the repeat sequences polymorphism of DC-SIGNR using PCR and DNA sequencing. HCV virus load and HCV RNA genotypes were analyzed. Inter-group comparison was analyzed using LSD method. RESULTS: No significant correlation was found between DC-SIGNR genotypes/ alleles and HCV RNA genotypes in patients. HCV-infected patients with 7-repeat (medium) alleles had lower HCV RNA levels compared to patients with 9 repeat (onger) alleles (P = 0.036). HCV-infected patients with 7/7 genotype had lower HCV RNA levels compared to patients with 9/7 genotype (P = 0.025). These findings suggest that optimal attachment of hepatitis C virions to DC-SIGNR may be associated with longer alleles. CONCLUSION: The fact that DC-SIGNR polymorphism might affect HCV loads supports the concept that DC-SIGNR contributes to HCV replication efficacy. There is no significant correlation between the genetic polymorphism of DC-SIGNR and HCV-RNA genotypes. PMID- 19785949 TI - [Effects of galectin-3 on proliferation and apoptosis of hepatic stellate cells]. AB - OBJECTIVE: To observe the effects of galectin-3 on proliferation and apoptosis of hepatic stellate cells. METHODS: RT-PCR and Western blot were used to detect the expression of galectin-3 in hepatic stellate cells. Short hairpin DNA targeting galectin-3 of rat was was ligated into the recombinant vector pGCsilencer U6/Neo/GFP/shRNA plasmid. Then the plasmid was transfected into rat hepatic stellate cells. RT-PCR and Western blot were used to detect the interfering efficiency. Cell proliferation level was observed by CCK8 method at 24, 48 and 72 hours after transfection. Cell apoptosis was measured by Annexin V/PI-labeled flow cytometric analysis. RESULTS: Expression of galectin-3 in HSC was verified by both RT-PCR and Western blot. The recombinant vector was successfully constructed and verified, and was transfected into rat hepatic stellate cells. Western Blot and RT-PCR results demonstrated that the expression level of Galectin-3 was significantly down-regulated in galectin-3 shRNA transfected cells compared to control vector transferred cells. CCK8 assay indicated that proliferation of Galectin-3 knockdown cells was lower than that of control cells 48 and 72 hours post-transfection. Apoptotic cells in shRNA-interfering group were higher than those in control group both in early stage and advanced stage. CONCLUSION: Hepatic stellate cells can express galectin-3. Inhibition of galectin 3 using RNAi technique can suppress proliferation and induce apoptosis in HSC. PMID- 19785950 TI - [Dynamic changes of alpha-AR, beta1-AR and beta2-AR expression during hepatic fibrogenesis]. AB - OBJECTIVE: To investigate the dynamic changes of a-AR, b1-AR and b2-AR expression in hepatic fibrosis. METHODS: Rat hepatic fibrosis model was established by bile duct ligation (BDL). HE and Masson staining were used to determine hepatic fibrosis levels. Immunohistochemistry was applied to detect alpha -smooth muscle actin (alpha -SMA), a marker of hepatic stellate cell (HSC) activation; Western blot and real-time RT-PCR were used to measure the dynamic changes of alpha -AR, beta(1)-AR, beta(2)-AR expression on protein and mRNA levels, respectively, during the development of hepatic fibrosis. RESULTS: (1) HE and Masson trichrome staining showed that the liver fibrosis models were established successfully. (2) At 1, 2, 3, 4 wk after BDL, alpha -SMA positive area density of the model group (10.58% +/- 1.75%, 24.14% +/- 2.02%, 29.74% +/- 2.59%, 34.28% +/- 2.01%) was significantly higher than that of the sham operation group (4.12% +/- 1.51%), P less than 0.01. (3) The expression of alpha -AR, beta(1)-AR, beta(2)-AR protein and mRNA was increased with the development of the hepatic fibrosis (P less than 0.05). (4) alpha -SMA expression was positively associated with alpha -AR, beta(1)-AR, beta(2)-AR, r values were 0.564, 0.753 and 0.606, respectively. CONCLUSION: The expression of alpha -SMA is increased dramatically during the fibrosis, and is positively associated with the expression of alpha -AR, beta(1) AR and beta(2)-AR. PMID- 19785951 TI - [Effects of IFN alpha on the expressions of Collagen I and transforming growth factor beta 1 in hepatic stellate cell activated by PDGF-BB]. AB - OBJECTIVE: To investigate the effect of IFN alpha on the expressions of Collagen I and TGF beta 1 in hepatic stellate cell activated by PDGF-BB. METHODS: Hepatic stellate cells (rHSC-99) treated with IFN alpha of different concentration (0, 0.0125, 0.025, 0.050, 0.100, 0.200, 0.400 ng/ml). The cell viability of HSC was measured by MTT. The levels of Col-I mRNA and TGF beta 1 mRNA were measured by the quantitative reverse-transcription polymerase chain reaction (RT-PCR). RESULTS: (1) When HSC was exposed in PDGF-BB, the cell viability of HSC (1.35 +/- 0.22) was higher than that of the control group (0.890 +/- 0.12) (F = 16.311, P less than 0.05), indicating that PDGF-BB can promote the cell viability of HSC. When HSC was exposed to both PDGF-BB and different concentration of IFN alpha (0.025, 0.05, 0.1, 0.2, 0.4 ng/ml), the cell viability of HSC (0.840 +/- 0.18, 0.450 +/- 0.15, 0.260 +/- 0.01, 0.330 +/- 0.07, 0.30 +/- 0.06) were lower than that of the control group (0.890 +/- 0.12) (F = 7.430, P less than 0.05), indicating that the cell viability of HSC was inhibited when HSC was exposed to both PDGF-BB and different concentrations of IFN alpha. Furthermore, within the range of 0.025 ng/ml to 0.1 ng/ml, the effect of IFN alpha was dose-dependent. (2). The relative expression values of Col-I mRNA in different groups of (0.05, 0.1, 0.2 ng/ml) IFN alpha +PDGF-BB are (0.940 +/- 0.19, 0.610 +/- 0.12, 0.520 +/- 0.02), which were lower than those in the control group (1.410 +/- 0.01) (F = 127.921, P less than 0.05). The relative expression values of TGF beta 1 mRNA in different groups of (0.05, 0.1, 0.2 ng/ml) IFN alpha +PDGF-BB are (1.180 +/- 0.06, 1.150 +/- 0.10, 1.390 +/- 0.04), again were lower than those in the control group (1.620 +/- 0.12) (F = 82.115, P less than 0.05). These results indicated that the expression of Col-I mRNA and TGF beta 1 mRNA was remarkably inhibited when HSC was exposed in both PDGF-BB and IFN alpha. CONCLUSION: The cell viability of HSC and the expression of Col-I mRNA and TGF beta 1 mRNA is remarkably inhibited when HSC is exposed in both PDGF-BB and IFN alpha, and the inhibition is dose-dependent. PMID- 19785952 TI - [Expression of ESM-1 in hepatocellular carcinoma is associated with angiogenesis and tumor invasion]. AB - OBJECTIVE: To study the expression and significance of endothelial cell specific molecule-1 (ESM-1) in hepatocellular carcinoma (HCC) tissue and serum from HCC patients. METHODS: The ESM-1 expression was evaluated by immunohistochemistry staining and quantitative real-time PCR in 30 tumor tissues from HCC patients, 15 surrounding non-cancerous hepatic parenchyma, and 15 normal controls. Serum levels of ESM-1 were also measured in the HCC patients and healthy controls by Enzyme-linked immunosorbent assay (ELISA). RESULTS: ESM-1 was expressed in endothelium of 24 HCC tissues and 6 pericarcinomatous tissues, however, it was not expressed in normal liver tissues. The mRNA level of ESM-1 was 0.064 +/- 0.018, 0.383 +/- 0.103, 0.528 +/- 0.148 in the corresponding tissues, respectively. The mRNA level of ESM-1 in tissues was correlated with the TNM phase of HCC patients, tumor vascular invasion as well as metastasis. The serum ESM-1 was (12.643 +/- 2.280) ng/ml and (4.660 +/- 1.172) ng/ml in hepatic cell carcinoma and normal controls, respectively. CONCLUSION: The expression of ESM-1 is significantly up-regulated in HCC, suggesting that ESM-1 may play an important role in the pathoigenesis of HCC. PMID- 19785953 TI - [Inhibition of angiogenesis of LCI-D20 hepatocellular carcinoma by metronomic chemotherapy of S-1]. AB - OBJECTIVE: To investigate the role of metronomic chemotherapy of S-1 on angiogenesis of hepatocellular carcinoma in animal model. METHOD: S-1 was dissolved in a 0.5% (w/v) HPMC solution. 30 LCI-D20 were randomly devided into five groups: control group(O), 10 mg * kg(-1) * d(-1) S-1 group (A), 1 mg * kg( 1) * d(-1) S-1 group (B), 0.5 mg * kg(-1) * d(-1) S-1 group (C) and 0.25 mg * kg( 1) * d S-1 group (D). 28 days after the treatment with 0.5% (w/v) HPMC solution, tumors in LCI-D20 mice were moved out. Tumor mass was measured and microvessel density (MVD) was used to evaluate angiogenesis in tumor. The cellular apoptosis was determined using flow cytometry. The expression of VEGF, bFGF and TSP-1 was measured by RT-PCR. RESULTS: The mean tumor mass was 2.01, 0.38, 1.12, 1.38, 2.27 g in O, A, B, C, D group, respectively. The mean MVD was 39.57, 19.90, 5.93, 17.10, 29.53 in O, A, B, C, D respectively. The mean tumor cellular apoptosis rate was 4.08%, 44.37%, 31.73%, 19.83%, and 8.25% in O, A, B, C, D respectively. The expression of VEGF and bFGF in O group was highest, and A was slightly low, and C and D taked the third place, and B was the lowst; The expression of TSP-1 in B was highest, and C and D were slightly low, and A taked the third place, and O was the lowst. CONCLUSION: Metronomic chemotherapy of S-1 destabilizes pre existing tumor vasculature and inhibits ongoing angiogenesis. PMID- 19785954 TI - [Differentially expressed proteins in the precancerous stage of rat hepatocarcinogenesis induced by diethylnitrosamine]. AB - OBJECTIVE: To screen the differentially expressed proteins especially at the precancerous stage of diethylnitrosamine (DEN) induced hepatocarcinogenesis by comparative proteome research. METHODS: Rats were divided into normal and DEN groups and sacrificed periodically. The liver samples were stained with gamma glutamyl transpeptidase (GGT) and HE to distinguish the preneoplastic lesion (pre HCC) from the normal and HCC tissues. The two-dimensional electrophoresis (2-DE) and mass spectrometry (MALDI-TOF-MS/MS) were then applied to analyze the differentially expressed protein between pre-HCC and normal tissues, pre-HCC and HCC, as well as HCC and normal tissues. A few of the candidate proteins such as laminin receptor 1 (67LR) and agmatinase were validated by Western blot and RT PCR. RESULTS: Totally, there were 82 proteins that differentially expressed two fold or more in one kind of tissues sample than the other, 47 of which occurred in the pre-HCC tissues. Eight proteins including 67LR were consistently up regulated from normal tissue to pre-HCC and then to HCC tissues, while 22 proteins including agmatinase showed progressively down-regulated in these tissues samples. CONCLUSION: The protein expression profiles are different during the process of hepatocarcinogenesis. Further study on the differentially expressed protein, especially these upregulated in the precancerous stage such as 67LR and agmatinase, might contribute to prevention and early diagnosis of human HCC. PMID- 19785956 TI - [The effect of DHEA on AKT signal pathway on transplanted Morris hepatomas in rats]. AB - OBJECTIVE: To investigate the inhibitory effect of dehydroepaimdrosterone (DHEA) on the growth of transplanted Morris hepatomas (7288CTC) in vivo in rats. METHODS: 21 Buffalo rats were randomly devided into 4 groups, including one blank control group (n = 5), one group for tumor-bearing control (n = 6), and 2 experimental groups with DHEA (n = 6) or DHEA-s (n = 4). DHEA or DHEA-s was fed to the rats for 4 weeks immediately after Morris hepatomas (7288CTC) was implanted in both flanks. Phenotypes of the spleen lymphocytes were examined by flow cytometry, Akt and PTEN expression in tumor cells was detected by Western blot and immunohistochemistry. RESULTS: Tumor weights of DHEA treated group were less than those of the control (P less than 0.05), the inhibitory rate was 43%. The results of Western blot and immunohistochemistry showed that in DHEA tumor group,the expression of phosphorilated Akt protein was decreased, the expression of PTEN was enhanced, the percentage of CD3 positive cells and the ratio of CD4/CD8 were increased (P less than 0.05). CONCLUSION: DHEA can inhibit tumor growth, possibly via the inhibition of the Akt signaling pathway as well as modulating the immune function. PMID- 19785955 TI - [Up-regulation of major histocompatibility complex class I-related molecules A (MICA) induced by 5-aza-2'-deoxycytidine]. AB - OBJECTIVE: Major histocompatibility complex class I C-related molecules A and B (MICA and MICB) are innate immune system ligands for the NKG2D receptor expressed by natural killer cells and activated CD8(+)T cells. Our previous study showed that 5-aza-2'-deoxycytidine (5-aza-dC), a DNA methyltransferase inhibitor, can induce the expression of MICB and sensitized cells to NKL-cell-mediated cytolysis. The aim of this study was to determine the expression level of MICA in HepG2 cells (an HCC cell line) and L02 cells ( a normal liver cell), and to investigate the effect of 5-aza-dC on MICA expression in HepG2 cells. METHODS: Cells were treated with 5-aza-dC, caffeine and ATM-specific siRNA. The cell surface MICA protein on HepG2 cells and L02 cells was determined using flow cytometry. The mRNA level was detected using real time RT-PCR. RESULTS: MICA was undetectable on the surface of L02 cells, but was highly expressed on HepG2 cells. MICA expression was upregulated in response to 5-aza-dC treatment (P less than 0.05), and the upregulation of MICA was partially prevented by pharmacological or genetic inhibition of ataxia telangiectasia mutated (ATM) kinase (P less than 0.05). CONCLUSION: Our data suggest that 5-aza-dC induces the expression of MICA by a DNA damage-dependent mechanism. PMID- 19785957 TI - [Role of resistin in inflammation of hepatocytes in nonalcoholic steatohepatitis]. AB - OBJECTIVE: To investigate the role and molecular mechanism of resistin in inflammation of hepatocytes in nonalcoholic steatohepatitis. METHODS: Rat models of NASH were established successfully. The expression of resistin mRNA and protein were examined by quantitative RT-PCR and immunohistolostaining, respectively. The murine hepatocytes AML-12 were incubated with recombinant resistin or LPS for 48 hours, and the concentration of TNF alpha, IL-6 in supernatant of AML-12 cells were quantified by enzyme linked immunosorbent assay (ELISA), the nuclear translocation NF- kappa B were observed by immunofluorescence. RESULTS: The steatosis of hepatocytes, inflammation in the lobule and perisinusoidal fibrosis in livers were found, and the expression of resistin mRNA and protein were increased in livers of rat model of NASH. The expression of resistin mRNA was 2.5 and 4 time higher in 12 weeks and 16 weeks of rat models respectively than that in normal control. The positive staining of resistin protein can be found mainly around the central veins. The concentration of TNF alpha and IL-6 were (1.856 +/- 0.049) pg/ml and (9.463 +/- 1.216) pg/ml in supernantant of AML-12 cells 48 hours after recombinant resistin treatment, and (1.791 +/- 0.046) pg/ml, (8.738 +/- 1.101) pg/ml 48 hours after LPS treatment. There was no significant difference between them, but both were higher than that in normal control (P < 0.01). The NF- kappa B p65 nuclear translocation had been observed in AML-12 cells 3 hours after resistin or LPS treatment. CONCLUSIONS: Resistin can induce the production of TNF alpha, IL-6 and other inflammatory factors by hepatocytes, and therefore is an important inflammatory factor in NASH. PMID- 19785958 TI - [Study of copper metabolism and liver damage in TX Mice-an animal model for liver disease]. AB - OBJECTIVE: To provide right time points in selection of right aged animals and the normal physiological data of TX mice. METHODS: 7-12 months old TX and DL mice were studied, each group contained 3 female and 3 male mice of TX or DL mice. The concentration of copper in the serum, dry tissues (liver, brain and kidney), together with copper biochemistry indexes were measured. The liver histopathology was observed under light microscopy and electron microscope. RESULTS: Transaminase increased significantly only in 10 and 11-month- old (AST(TX10) = 218.3 U/L, AST(TX11) = 197.5 U/L, AST(DL10) = 171.5 U/L, AST(DL11) = 165.0 U/L, P(10) less than 0.001, P(11) = 0.022), but the copper concentration of liver, brain and kidney was significantly increased during 7-12 month old (the average concentration of copper, Liver(TX) = (750.0 +/- 85.5) mg/kg, Brain(TX) = (39.7 +/ 2.2)mg/kg, Kidney(TX) = (29.8 +/- 5.0) mg/kg, Liver(DL) = (11.6 +/- 1.5) mg/kg, Brain(DL) = (16.8 +/- 0.9) mg/kg, Kidney(DL) = (14.2 +/- 1.0) mg/kg, t = 21.16, 23.60, 7.47, for all these organs P less than 0.05). CONCLUSION: TX mice is a suitable model of liver disease with natural recovery, so selecting animal model of suitable time point is very important. PMID- 19785959 TI - [Establishment of pig acute liver failure model and the role of pig fibrinogen like protein 2]. AB - OBJECTIVE: To establish a pig model of fulminant hepatic failure for evaluating the pre-clinical efficacy of drug treatment on severe hepatitis, and to detect the expression of fibrinogen-like protein-2 (fgl2) prothrombinase in the model, so as to provide basis for gene therapy targeting to fgl2 for fulminant hepatic failure. METHOD: D-galactosamine hydrochloride was used to induce pig model of fulminant hepatic failure, and the experiment animals were divided into model group (rapid injection of D-galactosamine hydrochloride by ear vein, a dose of 1.2 g/kg) and negative control group (5% Glucose). Clinical, biochemical and pathological changes of animals were observed. The expression of pigs fgl2 (pfgl2) mRNA in liver tissue was detected by real time RT-PCR, the expression of pfgl2 protein in liver tissue was detected by immunohistochemistry. RESULTS: A pig model of fulminant hepatic failure was successfully established using the D galactose hydrochloride; Real time RT-PCR of liver fgl2 mRNA showed that fgl2 mRNA expression was increased significantly in liver tissue of fulminant hepatic failure pig model compared with the control group (P = 0.016); Immunohistochemical staining showed that there were fgl2 protein expression in liver tissue of fulminant hepatic failure pig model, mainly in the membrane and cytoplasm of hepatocytes, inflammatory cells, liver sinusoidal endothelial cells and vascular endothelial cells of liver cell necrosis region. However, there are no fgl2 positive staining on negative control. CONCLUSIONS: The pig model of fulminant hepatic failure induced by D-galactosamine hydrochloride is similar to human pathological process and can be used to evaluate the pre-clinical efficacy and safety of drug treatment on fulminant hepatic failure. Abnormal expression of pfgl2 at both mRNA level and protein level in the liver of fulminant hepatic failure pig model shows that pfgl2 induced coagulation pathway is also involved in the development of fulminant hepatic failure. Gene therapy targeting fgl2 genes for fulminant hepatic failure may provide a new means for the treatment of fulminant hepatic failure. PMID- 19785960 TI - [Clinical application of hepatitis B virus PreS1 antigen detection]. PMID- 19785961 TI - [Analysis of the correlation between visceral fat accumulation and the severity of fatty liver in adults]. PMID- 19785962 TI - [Non-invasive assessment of liver fibrosis with the quantitative parameters of contrast-enhanced ultrasonography]. PMID- 19785963 TI - [Effect of protease activated receptor-2 agonists on proliferation of hepatoma cells]. PMID- 19785964 TI - [Relationship between DNA methylation and expressions of p57kip2 in hepatocellular carcinoma]. PMID- 19785965 TI - [A study on gastrointestinal dysmotility in rats with acute liver failure]. PMID- 19785966 TI - [Construction of a recombinant adeno-associated virus hybrid vectors with the HBV capsid for gene therapy of liver diseases]. PMID- 19785967 TI - [Discussions the therapy strategy of chronic hepatitis B by analyzing the therapeutics course of a chronic hepatitis B patient]. PMID- 19785968 TI - [Non-standard discontinuation of adefovir dipivoxil causing acute exacerbation of hepatitis]. PMID- 19785969 TI - [A brief report from the 1st China Viral Hepatitis and Fatty Liver Summit]. PMID- 19785970 TI - [Value of FibroScan in clinical diagnosis]. PMID- 19785971 TI - [Advances on antigen-antibody immunogenic complex therapeutic vaccine for viral hepatitis B]. PMID- 19785972 TI - Guanfacine extended release in the treatment of attention-deficit/hyperactivity disorder. PMID- 19785973 TI - Lisdexamfetamine in the treatment of attention-deficit/hyperactivity disorder in adults. PMID- 19785974 TI - Gaps in addressing problem drinking: overcoming primary care and alcohol treatment deficiencies. AB - Despite the high prevalence of problem drinking among Americans, primary care physicians often fail to address this major health threat. In addition, once alcohol use disorders are identified, patients often fail to receive coordinated medical and substance abuse treatment. This article reviews four types of barriers as well as potential facilitators to improving the prevention and management of problem drinking. First, primary care physicians are poorly trained about the clinical relevance of addressing alcohol problems in their daily patient care. Second, primary care physicians are concerned about the stigma and health insurance problems encountered by patients diagnosed with alcohol use disorders. Third, primary care practices have limited organizational and financial support to identify and address alcohol problems. Fourth, primary care and alcohol treatment settings communicate and collaborate poorly in delivering patient care. Opportunities to overcome these challenges are discussed and must be initiated to reduce the myriad of adverse outcomes resulting from problem drinking. PMID- 19785975 TI - Substance abuse in the United States: findings from recent epidemiologic studies. AB - Recent research on the epidemiology of substance use disorders (SUDs) has provided important insights into these conditions and their impact on public health. In the United States, annual surveys of drug use in household and school populations serve as one of the primary sources of information about the distribution of illicit drug use. This research has demonstrated continued shifts in trends in illicit drug use in the United States and called attention to rising rates of prescription drug misuse and abuse. Findings have also continued to highlight the substantial comorbidity of SUDs with other psychiatric disorders and with the ongoing HIV epidemic. Building on these foundations, future challenges for research in substance abuse epidemiology will include using novel methodologic approaches to further unravel the complex interrelationships that link individual vulnerabilities for SUDs, including genetic factors, with social and environmental risk factors. PMID- 19785976 TI - Treatment of opioid-dependent adolescents and young adults with buprenorphine. AB - Rising rates of opioid use among teenagers and young adults are a public health concern. Despite short durations of opioid use compared with those of adults, youth with opioid dependence have a host of co-occurring conditions, including polysubstance abuse, psychiatric disorders, hepatitis C infection, HIV risk, and high-risk sexual and criminal behaviors. Opioid-dependent youth typically are offered outpatient/residential treatment with brief detoxification, but one study showed that heroin users fare worse following residential treatment. Although abundant research supports the use of medication-assisted treatment for opioid dependent adults, research is only recently emerging for youth. Buprenorphine, a partial opioid agonist, was proven safe and effective in improving abstinence from opioids in two controlled clinical trials. More research is needed to determine several clinically relevant areas: appropriate duration of agonist treatment, ways to enhance medication adherence, the value of integrated treatments for co-occurring conditions, and the role of opioid antagonists in opioid-dependent youth. PMID- 19785977 TI - The genetics of alcoholism. AB - Heritability estimates for alcoholism range from 50% to 60%, pointing out the importance of genetic and environmental factors in its etiology. This review highlights recent advances in translational work investigating genetic influences on alcoholism. We focus on genetic research involving corticotropin-releasing factor, glutamatergic, and opioidergic systems. Variation in the CRF1 receptor gene has been shown to moderate stress-induced alcohol drinking (gene-environment interaction) in animals, and this finding was recently extended to humans. Also, the hyperglutamatergic state, first observed during withdrawal from chronic alcohol exposure in animal models, is associated with aversive and dysphoric states in alcoholics. Pharmacogenetic studies of naltrexone efficacy are in the clinical stages, and recent studies confirmed a differential response dependent on the mu-opioid receptor genotype. Such advances will be essential for the effective treatment of alcoholism in the future. PMID- 19785978 TI - Adaptive interventions may optimize outcomes in drug courts: a pilot study. AB - Adaptive interventions apply a priori decision rules for adjusting treatment services in response to participants' clinical presentation or performance in treatment. This pilot study (n = 30) experimentally examined an adaptive intervention in a misdemeanor drug court. The participants were primarily charged with possession of marijuana (73%) or possession of drug paraphernalia (23%). Results revealed that participants in the adaptive condition had higher graduation rates and required significantly less time to graduate from the program and achieve a final resolution of the case. It took an average of nearly 4 fewer months for participants in the adaptive intervention to resolve their cases compared with those participating in drug court as usual. Participants in the adaptive condition also reported equivalent satisfaction with the program and therapeutic alliances with their counselors. These data suggest that adaptive interventions may enhance the efficiency and effectiveness of drug courts and justify examining adaptive interventions in large-scale drug court studies. PMID- 19785979 TI - Management of opioid medications in patients with chronic pain and risk of substance misuse. AB - When prescribed appropriately and used as prescribed, opioid medications can safely and effectively treat pain. Best practices with respect to their use in chronic non-cancer-related pain (CNCP) are evolving. Opioids may be subject to misuse for a variety of purposes, including self-medication, use for reward, compulsive use because of addiction, and diversion for profit. Individuals with chronic pain and co-occurring substance use, mental health disorders, and other conditions may be at increased risk for misuse of prescribed opioids. Interdisciplinary pain management, the use of universal precautions in all patients, and special attention to the structure of care in those at higher risk for opioid misuse may improve outcomes in opioid treatment of CNCP. This article discusses evolving research and clinical literature related to the care of individuals with CNCP at a higher risk for opioid misuse. PMID- 19785980 TI - Gene-environment interactions in attention-deficit/hyperactivity disorder. AB - Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder characterized by inattention, impulsivity, and/or hyperactivity in children and adults. Putative environmental risk factors for ADHD include toxin and prenatal smoke exposure, low socioeconomic status, and parental marital instability and discord. Genetic associations with ADHD have been found in the dopaminergic, serotonergic, and noradrenergic neurotransmitter systems, but findings are inconsistent across studies. Herein, we review studies of gene-environment interactions for ADHD to better understand how genetic and environmental risk factors may contribute to the disorder in a nonindependent fashion, which may account in part for the inconsistent findings on genetic associations. Although evidence of interactions between prenatal substance exposure and the dopamine genes DAT1 and DRD4 was found, findings across studies have been mixed. We discuss these findings and the future directions and limitations of current gene environment research. PMID- 19785981 TI - New insights into attention-deficit/hyperactivity disorder using structural neuroimaging. AB - This article reviews recent advances in structural neuroimaging in attention deficit/hyperactivity disorder (ADHD). Observational studies have found treatment with psychostimulants to be associated more closely with dimensions of some brain structures in typically developing children than in those found in treatment naive children with ADHD. Novel analytic approaches allow for greater precision in the definition of brain regions that are most compromised in ADHD, with meta analyses highlighting compromise of the basal ganglia. Cortical changes, particularly in the lateral prefrontal and parietal cortex, are also commonly reported, but with less consensus on the exact location of structural change. Anomalies in the shape of subcortical structures, specifically of the basal ganglia, hippocampus, and amygdala, implicate frontostriatal loops and the limbic system in the disorder. Finally, longitudinal data suggest that ADHD in childhood may be characterized by a delay in cortical maturation and that different clinical outcomes may be associated with different developmental trajectories in adolescence and beyond. PMID- 19785982 TI - DSM-V and the future diagnosis of attention-deficit/hyperactivity disorder. AB - In general, recommendations for the DSM-V and future diagnoses of psychiatric disorders include a dimensional approach to complement the standard categorical approach. For the assessment of attention-deficit/hyperactivity disorder (ADHD), dimensional approaches to supplement the rigid categorical approach of the DSM-IV abound. Historically, dimensions based on severity of symptoms of ADHD and severity of general psychopathology have been used. General dimensional approaches described by a workgroup organized by the American Psychiatric Association are reviewed to provide background and context for a discussion of old and new dimensional approaches to complement future categorical diagnosis of ADHD in the DSM-V. PMID- 19785983 TI - School-based interventions for students with attention-deficit/hyperactivity disorder. AB - Children with attention-deficit/hyperactivity disorder typically manifest impairments in multiple settings. Perhaps the most common reason for referral relates to the school impairments experienced by these children. A wide range of intervention strategies have been developed for these children to improve attention and behavior, enhance academic competence, and promote social competence. A strong majority of the research on nonpharmacologic interventions has focused on strategies to improve attention and behavior. More recently, strategies specifically designed to promote the academic and social competence of these children are being developed. Also, most of the research has focused on elementary school-age children, but evidence-based strategies for intervening with preschoolers and adolescents are beginning to emerge. PMID- 19785984 TI - College students with attention-deficit/hyperactivity disorder. AB - As more students with attention-deficit/hyperactivity disorder attend college, studies are emerging that reveal problems in psychosocial and academic functioning. Substance use may magnify deficits in self-regulation. Recommendations are made for comprehensive assessment; however, the usual diagnostic categories may not be developmentally relevant. Students who are identified benefit from medication and nonmedication interventions, strategy support, and accommodations. PMID- 19785985 TI - Macrophages from alpha 7 nicotinic acetylcholine receptor knockout mice demonstrate increased cholesterol accumulation and decreased cellular paraoxonase expression: a possible link between the nervous system and atherosclerosis development. AB - OBJECTIVE: The parasympathetic nervous system regulates inflammation in peripheral tissues through a pathway termed the "cholinergic anti-inflammatory reflex" (CAIR). Mice deficient in the alpha 7 nicotinic acetylcholine receptor (alpha7(-/-)) have an impaired CAIR due to decreased signaling through this pathway. The purpose of this study was to determine if the increased inflammation in alpha7(-/-) mice is associated with enhanced serum and macrophage atherogenicity. METHODS: We measured serum markers of inflammation and oxidative stress, and macrophage atherogenicity in mouse peritoneal macrophages harvested from alpha7(-/-) mice on the background of C57BL/6 mice, as well as on the background of the atherosclerotic Apolipoprotein E-deficient (ApoE(-/-)) mice. RESULTS: alpha7-Deficiency had no significant effects on serum cholesterol, or on markers of serum oxidative stress (TBARS and paraoxonase1 activities). However, alpha7-deficiency significantly increased serum CRP and IL-6 (p<0.05) levels in atherosclerotic mice, confirming an anti-inflammatory role for the alpha7 receptor. Macrophage cholesterol mass was increased by 25% in both normal and atherosclerotic mice in the absence of the alpha7 receptor (p<0.05). This was accompanied by conditional increases in oxidized LDL uptake and in macrophage total peroxide levels. Furthermore, alpha7-deficiency reduced macrophage paraoxonase2 mRNA and activity by 50-100% in normal and atherosclerotic mice (p<0.05 for each), indicating a reduction in macrophage anti-oxidant capacity in the alpha7(-/-) mice. CONCLUSION: The above results suggest an anti-atherogenic role for the macrophage alpha7nAchr, through a mechanism that involves attenuated macrophage oxidative stress and decreased uptake of oxidized LDL. PMID- 19785986 TI - Inhibition of proliferation and differentiation and promotion of apoptosis by cyclin L2 in mouse embryonic carcinoma P19 cells. AB - Cyclin L2 (CCNL2) is a novel member of the cyclin gene family. In a previous study, we demonstrated that CCNL2 expression was upregulated in ventricular septum tissues from patients with ventricular septal defect compared to healthy controls. In the present study, we established a stable CCNL2-overexpressing P19 cell line that can differentiate to myocardial cells when treated with 1% dimethyl sulfoxide (DMSO). Our data showed that stable CCNL2-overexpressing P19 cells were less differentiated after treatment with 1% DMSO and that expression of myocardial cell differentiation-related genes (such as cardiac actin, GATA4, Mef2C, Nkx2.5, and BNP) were reduced compared to vector-only transfected P19. Moreover, P19 cells overexpressing the CCNL2 gene had a reduced growth rate and a remarkably decreased S phase. We also found that these cells underwent apoptosis, as detected by two different apoptosis assays. The anti-apoptotic Bcl-2 protein was also downregulated in these cells. In addition, real-time PCR analysis revealed that expression of Wnt and beta-catenin was suppressed and GSK3beta was induced in the CCNL2-overexpressing P19 cells. These data suggest that overexpression of CCNL2 inhibited proliferation and differentiation of mouse embryonic carcinoma P19 cells and induced them to undergo apoptosis, possibly through the Wnt signal transduction pathway. PMID- 19785987 TI - The LIM domain protein Wtip interacts with the receptor tyrosine kinase Ror2 and inhibits canonical Wnt signalling. AB - Wtip is a LIM domain protein of the Ajuba/Zyxin family involved in kidney and neural crest development; Ror2 is a receptor tyrosine kinase involved in the development of skeleton, heart, lung, genitalia and kidneys. Here we describe Wtip as an intracellular interaction partner of Ror2. Full-length Ror2 recruits Wtip to the cell membrane, a mutant involved in human disease fails to do so. Both genes and proteins show overlapping expression in the mouse embryo. We show that Wtip is able to inhibit canonical Wnt signalling in mammalian cells and in Xenopus embryos linking Wtip to a crucial developmental pathway. PMID- 19785988 TI - RACK1 associates with CLEC-2 and promotes its ubiquitin-proteasome degradation. AB - CLEC-2 is a C-type lectin-like receptor and plays an important role in platelet activation. Snake venom toxin rhodocytin and the endogenous sialoglycoprotein podoplanin are identified as ligands for CLEC-2 and function as stimulators in platelet activation. We also previously indentified two splice variants of murine CLEC-2 as well as a soluble fragment cleaved from the full-length form. However, little is known about the interacting partners with the cytoplasmic region of CLEC-2. In this study, we reported that RACK1, the receptor for activated C kinase 1, associated with the cytoplasmic tail of CLEC-2. Moreover, overexpression of RACK1 decreased the stability of CLEC-2 through promoting its ubiquitin-proteasome degradation, without impairing surface expression and downstream signaling of CLEC-2. Taken together, these results suggest RACK1 as a novel modulator of CLEC-2 expression. PMID- 19785989 TI - Human primordial germ cell-derived progenitors give rise to neurons and glia in vivo. AB - We derived a cell population from cultured human primordial germ cells from early human embryos. The derivates, termed embryoid body-derived (EBD) cells, displayed an extensive capacity for proliferation and expressed a panel of markers in all three germ layers. Interestingly, EBD cells were also positive for markers of neural stem/progenitor cells, such as nestin and glial fibrillary acidic protein. When these cells were transplanted into the brain cavities of fetal sheep and postnatal NOD-SCID mice or nerve-degenerated tibialis anterior muscles, they readily gave rise to neurons or glial cells. To our knowledge, our data are the first to demonstrate that EBD cells can undergo further neurogenesis under suitable environments in vivo. Hence, with the abilities of extensive expansion, self-renewal, and differentiation, EBD cells may provide a useful donor source for neural stem/progenitor cells to be used in cell-replacement therapies for diseases of the nervous system. PMID- 19785990 TI - Modulation of nucleotide binding to the catalytic sites of thermophilic F(1) ATPase by the epsilon subunit: implication for the role of the epsilon subunit in ATP synthesis. AB - Effect of epsilon subunit on the nucleotide binding to the catalytic sites of F(1)-ATPase from the thermophilic Bacillus PS3 (TF(1)) has been tested by using alpha(3)beta(3)gamma and alpha(3)beta(3)gammaepsilon complexes of TF(1) containing betaTyr341 to Trp substitution. The nucleotide binding was assessed with fluorescence quenching of the introduced Trp. The presence of the epsilon subunit weakened ADP binding to each catalytic site, especially to the highest affinity site. This effect was also observed when GDP or IDP was used. The ratio of the affinity of the lowest to the highest nucleotide binding sites had changed two orders of magnitude by the epsilon subunit. The differences may relate to the energy required for the binding change in the ATP synthesis reaction and contribute to the efficient ATP synthesis. PMID- 19785991 TI - Effect of c-myc on the ultrastructural structure of cochleae in guinea pigs with noise induced hearing loss. AB - Noise over-stimulation may induce hair cells loss and hearing deficit. The c-myc oncogene is a major regulator for cell proliferation, growth, and apoptosis. However, the role of this gene in the mammalian cochlea is still unclear. The study was designed to firstly investigate its function under noise condition, from the aspect of cochlear ultrastructural changes. We had established the adenoviral vector of c-myc gene and delivered the adenovirus suspension into the scala tympani of guinea pigs 4 days before noise exposure. The empty adenoviral vectors were injected as control. Then, all subjects were exposed to 4-kHz octave band noise at 110dB SPL for 8h/day, 3 days consecutively. Auditory thresholds were assessed by auditory brainstem response, prior to and 7 days following noise exposure. On the seventh days after noise exposure, the cochlear sensory epithelia surface was observed microscopically and the cochleae were taken to study the ultrastructural changes. The results indicated that auditory threshold shift after noise exposure was higher in the ears treated with Ad.EGFP than that treated with Ad.c-myc-EGFP. Stereocilia loss and the disarrangement of outer hair cells were observed, with greater changes found in the Ad.EGFP group. Also, the ultrastructure changes were severe in the Ad.EGFP group, but not obvious in the Ad.c-myc-EGFP group. Therefore, c-myc gene might play an unexpected role in hearing functional and morphological protection from acoustic trauma. PMID- 19785992 TI - The bHLH transcription factor Hand2 regulates the expression of nanog in ANS differentiation. AB - The basic helix-loop-helix transcription factor Hand2 is induced by bone morphogenetic proteins (BMPs) in neural crest-derived precursor cells during the early stage of development of the autonomic nervous system (ANS). Previous studies showed that Hand2 was essential for the ANS differentiation. However, regulatory mechanism of pluripotent genes has not been elucidated in ANS differentiation. Here, we show that Hand2 regulated nanog expression in ANS differentiation. Our studies demonstrated that the forced expression of Hand2 promoted the ANS differentiation program in P19 embryonal carcinoma (EC) cells without aggregation. Furthermore, our results suggested that Hand2 bound to the promoter of nanog, a gene required for embryonic stem cells self-renewal, and suppressed nanog expression after Hand2 induction. The rapid downregulation of nanog mRNA during ANS differentiation correlated with the Hand2 transcriptional activity and nanog promoter methylation. These findings are evidence for a presence of the novel regulatory mechanism of nanog in ANS differentiation. PMID- 19785993 TI - Significance of differential effects of glucose and fructose on brain food signaling is uncertain. PMID- 19785994 TI - Inhibition of peroxynitrite-mediated DNA strand cleavage and hydroxyl radical formation by aspirin at pharmacologically relevant concentrations: implications for cancer intervention. AB - Epidemiological studies have suggested that the long-term use of aspirin is associated with a decreased incidence of human malignancies, especially colorectal cancer. Since accumulating evidence indicates that peroxynitrite is critically involved in multistage carcinogenesis, this study was undertaken to investigate the ability of aspirin to inhibit peroxynitrite-mediated DNA damage. Peroxynitrite and its generator 3-morpholinosydnonimine (SIN-1) were used to cause DNA strand breaks in phiX-174 plasmid DNA. We demonstrated that the presence of aspirin at concentrations (0.25-2mM) compatible with amounts in plasma during chronic anti-inflammatory therapy resulted in a significant inhibition of DNA cleavage induced by both peroxynitrite and SIN-1. Moreover, the consumption of oxygen caused by 250 microM SIN-1 was found to be decreased in the presence of aspirin, indicating that aspirin might affect the auto-oxidation of SIN-1. Furthermore, EPR spectroscopy using 5,5-dimethylpyrroline-N-oxide (DMPO) as a spin trap demonstrated the formation of DMPO-hydroxyl radical adduct (DMPO OH) from authentic peroxynitrite, and that aspirin at 0.25-2mM potently diminished the radical adduct formation in a concentration-dependent manner. Taken together, these results demonstrate for the first time that aspirin at pharmacologically relevant concentrations can inhibit peroxynitrite-mediated DNA strand breakage and hydroxyl radical formation. These results may have implications for cancer intervention by aspirin. PMID- 19785995 TI - High frequency of mitochondrial DNA D-loop mutations in Ewing's sarcoma. AB - Somatic mutations and polymorphisms in the noncoding displacement (D)-loop of mitochondrial DNA (mtDNA) are present in a variety of human cancers. To investigate whether Ewing's sarcoma (EWS) harbors genetic alterations within the D-loop region and their potential association with EWS carcinogenesis, we analyzed and compared the complete mtDNA D-loop sequences from 17 pairs of tumor tissues and corresponding peripheral blood samples using the direct DNA sequencing method. Our results revealed that 12 of the 17 EWS tumor specimens (70.6%) carried 19 somatic mutations in the D-loop of mtDNA, including 11 single base substitutions, 3 insertions and 5 deletions. Among the tested 17 patients, we screened a total of 40 germline polymorphisms including one novel sequence variant in the D-loop fragment. Most of these identified mutations and germline variations were clustered within two hypervariable segments (HVS1 and HVS2) as well as the homopolymeric C stretch between nucleotide position 303 and 309. In addition, there was no significant correlation between mtDNA D-loop mutations and various clinicopathological factors of EWS. In conclusion, our study reports for the first time that mtDNA D-loop mutations occur at a high frequency in EWS. These data provide evidence of mtDNA alterations' possible involvement in the initiation and/or progression of this rare malignancy. PMID- 19785996 TI - Functional assessment of Nramp-like metal transporters and manganese in Caenorhabditis elegans. AB - Nramp1 (natural resistance-associated macrophage protein-1) is a functionally conserved iron-manganese transporter in macrophages. Manganese (Mn), a superoxide scavenger, is required in trace amounts and functions as a cofactor for most antioxidants. Three Nramp homologs, smf-1, smf-2, and smf-3, have been identified thus far in the nematode Caenorhabditis elegans. A GFP promoter assay revealed largely intestinal expression of the smf genes from early embryonic through adult stages. In addition, smf deletion mutants showed increased sensitivity to excess Mn and mild sensitivity to EDTA. Interestingly, these smf deletion mutants demonstrated hypersensitivity to the pathogen Staphylococcus aureus, an effect that was rescued by Mn feeding or knockdown of the Golgi calcium/manganese ATPase, pmr-1, indicating that Mn uptake is essential for the innate immune system. This reversal of pathogen sensitivity by Mn feeding suggests a protective and therapeutic role of Mn in pathogen evasion systems. We propose that the C. elegans intestinal lumen may mimic the mammalian macrophage phagosome and thus could be a simple model for studying Mn-mediated innate immunity. PMID- 19785998 TI - Catestatin attenuates the effects of intrathecal nicotine and isoproterenol. AB - Catestatin (Cts; human chromogranin A(352-372)) is a neuropeptide derived from chromogranin A (ChgA). In the periphery it is released from the terminals of preganglionic neurons. In the adrenal medulla it inhibits catecholamine release by non-competitively antagonizing nicotinic cholinergic receptors. ChgA is present in the central nervous system, but the extent to which it is present within bulbospinal sympathoexcitatory neurons is unknown. We investigated the distribution of ChgA in the brainstem and its relationship to sympathoexcitatory neurons by combining immunofluorescence and in situ hybridization. A possible role for Cts in modulating the effect of other neurotransmitter systems in the spinal cord was examined by intrathecal injection of Cts, in conjunction with nicotine (1 microg-100 microg) and isoproterenol (0.12 microg-2.5 microg), in the anesthetized rat. Cts attenuated the hypotensive effect of isoproterenol on mean arterial pressure (maximum dose, 2.5 microg isoproterenol; -27 mmHg pre-Cts to 18 mmHg post-Cts), splanchnic sympathetic nerve activity (at 2.5 microg isoproterenol; 10.5% pre-Cts to 2.4% post-Cts), HR (at 2.5 microg isoproterenol; 1.1% pre-Cts to -1.6% post-Cts), and the dp/dt max of carotid pulse pressure (at 2.5 microg isoproterenol 17.3% pre-Cts to 9.3% post-Cts). Cts attenuated the hypertensive effect of nicotine on mean arterial pressure (at 10 microg nicotine, 19.3 mmHg pre-Cts to 6.8 mmHg post-Cts), splanchnic sympathetic nerve activity (at 10 microg nicotine, 10.7% pre-Cts to 4.5% post-Cts), and HR (at 10 microg nicotine, 4.1% pre-Cts to 2.0% post-Cts). The results indicate that Cts antagonizes both central nicotinic acetylcholine receptors and beta-adrenoceptors that are involved in cardiovascular regulation in vivo. PMID- 19785997 TI - Ontogeny and the effects of exogenous and endogenous glucocorticoids on tight junction protein expression in ovine cerebral cortices. AB - Maternal glucocorticoid treatment reduces blood-brain permeability early, but not late in fetal development, and pretreatment with glucocorticoids does not affect barrier permeability in newborn lambs. In addition, endogenous increases in plasma cortisol levels are associated with decreases in blood-brain barrier permeability during normal fetal development. Therefore, we tested the hypotheses that development as well as endogenous and exogenous glucocorticoids alters the expression of tight junction proteins in the cerebral cortex of sheep. Cerebral cortices from fetuses at 60%, 70%, and 90% of gestation, newborn and adult sheep were snap frozen after four 6-mg dexamethasone or placebo injections were given over 48-h to the ewes and adult sheep. Lambs were treated similarly with 0.25 mg/kg-dexamethasone or placebo. Tight junction protein expression was measured by Western immunoblot. Claudin-1 was higher (P<0.05) in fetuses at 60% of gestation than in newborn and adult sheep. Claudin-5 was higher at 60% than 70% of gestation, and than in newborn and adult sheep. ZO-1 was higher in newborn than adult sheep. ZO-2 was higher at 90% gestation, in newborn and adult sheep than 60% gestation. Claudin-5 was higher in dexamethasone than placebo-treated lambs, and ZO-2 was higher in fetuses of dexamethasone than placebo-treated ewes at 90% gestation. ZO-2 expression demonstrated a direct correlation with increases in plasma cortisol during fetal development. We conclude that claudin-1, claudin-5, ZO-1, and ZO-2 expression exhibit differential developmental regulation, exogenous glucocorticoids regulate claudin-5 and ZO-2 in vivo at some, but not all ages, and increases in endogenous fetal glucocorticoids are associated with increases in ZO-2 expression, but not with occludin, claudin-1, claudin-5 or ZO-1 expression in ovine cerebral cortices. PMID- 19785999 TI - Preferential enhancement of working memory in mice lacking adenosine A(2A) receptors. AB - There is evidence that adenosine acting at A(2A) receptors (A(2A)R) can influence striatal plasticity and cognitive functions. We examined spatial working memory in wild-type (WT) and A(2A) receptor knock-out (KO) mice using two assessments: the eight arm radial maze and a repeated trial Morris water maze (MWM) paradigm. Compared to WT littermates, A(2A)R KO mice displayed enhanced working memory as evidenced by a decrease in escape latency in trial 2 compared to trial 1 in the repeated trial MWM, and by a reduction in working memory errors in the radial arm maze. Both MWM and radial maze results indicated that this enhancement of working memory in A(2A)R KO mice was selective for this specific short-term memory. The decrease in escape latency in MWM was detected with an inter-trial interval of 15 s but not with intervals of 10 or 60 min. In the radial maze, spatial reference memory and memory retention after prolonged training (15 days but not 6 days) were not affected by the A(2A)R KO. These results demonstrate preferential improvement in spatial working memory by genetic inactivation of the A(2A)R and support a modulatory role of the A(2A)R in spatial working memory in mice. PMID- 19786000 TI - Time-dependent effects of ipsilateral stimulation on contralaterally elicited responses in the rat's central nucleus of the inferior colliculus. AB - Recordings were made from single neurons in the rat's central nucleus of the inferior colliculus (ICc). Binaural responses were studied when dichotic tone bursts with various interaural-level differences were presented simultaneously or with a contralateral delay. These dichotic tone bursts allowed us to probe temporal changes in the effect produced by an ipsilateral sound on a contralaterally elicited response. Most of the neurons in the rat's ICc were excited by contralateral and inhibited by ipsilateral stimulation. For the majority of neurons with excitatory/inhibitory interactions, the early part of an ipsilateral stimulus caused stronger inhibition than the late part. The ipsilateral stimulus frequently produced an excitatory or inhibitory "offset" effect that was apparent soon after cessation of the stimulus. For many neurons, this aftereffect substantially changed the strength and temporal firing pattern of the response elicited by a lagging contralateral stimulus. Our results suggest that there are time-dependent changes in the effect of ipsilateral stimulation on the pattern and strength of responses to contralateral stimulation. These effects frequently outlast the duration of a leading ipsilateral stimulus. These characteristics of binaural interaction likely reflect the time courses of converging excitatory and inhibitory synaptic inputs to ICc neurons as well as the intrinsic membrane properties of those neurons. PMID- 19786001 TI - Structure-dependent inhibition of human and rat 11beta-hydroxysteroid dehydrogenase 2 activities by phthalates. AB - Phthalates are diesters of phthalic acid and an alcohol moiety. Phthalates have been classified as endocrine disruptors and have a broad range of effects with unknown mechanisms. Some of the effects of phthalate are consistent with disruptions of normal glucocorticoid homeostasis, and in particular, with defective function of 11beta-hydroxysteroid dehydrogenase 2 (11beta-HSD2). In the present study, we tested 12 phthalate diesters and four monoesters for the inhibition of human and rat kidney 11beta-HSD2. We examined the modes of inhibition and looked for a relationship between the potency for inhibition and the chemical structures. Of the phthalate diesters we tested, dipropyl phthalate (DPrP) and di-n-butyl phthalate (DBP) significantly inhibited both human and rat 11beta-HSD2 activities. The IC(50)s were 85.59 microM for DPrP and 13.69 microM for DBP when calculated for rat 11beta-HSD2. As diesters, 8 of the phthalates did not affect 11beta-HSD2 enzyme activity. Compared to the diesters that were inhibitory, the 8 non-inhibitory phthalates, had either fewer carbons, that is 1 or 2 carbons in the alcohol moiety, or more carbons, 5-10, as a branched or unbranched chain in the alcohol moeity. However, phthalates could be inhibitors with six carbons in the alcohol moiety if the carbons were cyclized, as in dicyclohexyl phthalate (DCHP), which inhibited rat 11beta-HSD2 with an IC(50) of 32.64 microM. Thus, whether a phthalate is an inhibitor may reflect the size and shape of the compound. Although the diesters are the compounds used in manufacturing and present as environmental contaminants, it is the monoester metabolites that are detected in human serum and urine. We showed that mono (2 ethylhexyl) phthalate (MEHP) significantly inhibited human (IC50)=110.8+/-10.9) and rat (121.8+/-8.5 microM) 11beta-HSD2 activity even though its parent compound, di(2-ethylhexyl) phthalate (DEHP) did not. MEHP was a competitive inhibitor of 11beta-HSD2 enzymatic activity. We conclude that phthalates of a certain size act as competitive inhibitors. PMID- 19786002 TI - Association of CYP1A1*2A polymorphism with male infertility in Indian population. AB - BACKGROUND: The CYP1A1 gene is a polymorphic gene and encodes for the CYP1A1 enzyme that catalyzes the bioactivation of polycyclic aromatic hydrocarbons (PAHs). PAHs are ubiquitous pollutants in the natural environment, which are capable of forming DNA adducts once being activated to generate DNA reactive metabolites. DNA adducts in sperm cells could be considered as a sign of severe DNA damage, which played an important role in meiotic division during spermatogenesis and could be associated with infertility. Lipophilic compounds undergo metabolic activation by phase I enzymes, which introduce a reactive center into the molecule, followed by phase II conjugation reaction resulting in a water soluble product. METHODS: We genotyped CYP1A1*2A, using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay in a hospital based case-control study including 206 infertile men and 230 healthy fertile (control) subjects. RESULTS: Analysis showed that CYP1A1*2A CC genotype is associated with increased risk of male infertility (OR=6.08, 95% CI=1.91-25.27), while TC genotype showed a non-significantly increased risk of male infertility (OR=1.35 95% CI=0.89-2.05). Further, when the variant genotypes were combined (CYP1A1*2A TC+CC) assuming a co-dominant allele effect, TC plus CC genotypes were also found to be significant with increased risk of male infertility (OR=1.57 95% CI=1.05-2.35 p=0.02). Allele frequencies are calculated for each genotype of CYP1A1*2A and the differences for allele frequencies between the infertile and fertile men are determined using Fisher's exact test. T and C allele frequencies in infertile men are 71% and 29% as against 80% and 20% in fertile men. The differences for allele frequencies are found to be statistically significant (p=0.002). The results showed a drastic decrease in the sperm count and motility and increase in dead sperms in CC genotype when compared to other genotypes in infertile men. CONCLUSION: Based on Indian study we conclude that CC genotype of CYP1A1 is associated in the pathogenesis of male infertility. PMID- 19786004 TI - Urinary uric acid and antioxidant capacity in children and adults with Down syndrome. AB - OBJECTIVES: To evaluate the urinary levels of uric acid (UA) and total antioxidant capacity (TAC) with and without UA relative contribution (TAC(-UA)) in children and adults with Down syndrome (DS) and to prove the clinical use of TAC. DESIGN AND METHODS: Urine samples were obtained from 32 individuals with DS and 29 controls. Two age groups were established (children and adults). Spectrophotometric methods were used for biochemical determinations. RESULTS: Children with DS had significantly higher UA/Cr and TAC/Cr levels than controls, whereas levels of TAC(-UA)/Cr were lower in adults with DS than in controls (P<0.05 for all). In DS, levels of UA/Cr, TAC/Cr and TAC(-UA)/Cr were higher in children than in adults (P<0.05 for all). Positive correlations between UA/Cr and TAC/Cr were found for all groups studied. Negative correlations with age were found for UA/Cr and TAC/Cr in children of both groups. CONCLUSIONS: Our results proved that TAC is decreased in adults with DS. Besides, TAC(-UA) seems to provide more reliable information about the antioxidant status, at least in DS. PMID- 19786003 TI - Mutation analysis of phenylketonuria patients from Morocco: high prevalence of mutation G352fsdelG and detection of a novel mutation p.K85X. AB - OBJECTIVE: The knowledge of the molecular basis of the Phenylketonuria (PKU, MIM# 261600) in different countries provides relevant information for undertaking specific and rational mutation detection strategies in each population and for the implementation of adequate dietary and cofactor treatment. There are no data available in Moroccan population. DESIGN AND METHODS: In this work we describe the genetic analysis by mutation scanning using denaturing gradient gel electrophoresis (DGGE) and subsequent direct sequencing of 20 different PKU families from Morocco. We have also included the study of 7 Moroccan PKU patients living in Spain detected by the Spanish newborn screening program. RESULTS: The mutational spectrum in the first sample included eight different changes, one of them, p.K85X, was novel. The most common mutation was the frame shift change p.G352fsdelG identified in 62.5% of the mutant chromosomes studied. Other changes (p.R176X, IVS10nt-11 g>a, p.W120X, p.A165T, p.R243X and p.R243Q) were identified, respectively, in 2 or 3 mutant alleles. All detected mutations were severe according to the classical phenotype of the patients. In the 7 patients living in Spain we have detected 4 severe mutations (p.G352fs, p.R176X, Y198fs and Exon3del) and also milder changes such as p.A403V, p.S196T, p.D145V and p.R408Q detected in 3 mild hyperphenylalaninemia (MHP) patients and a novel p.L258P found in a mild PKU patient. CONCLUSION: The results provide important information on the distribution of PKU mutations in this Mediterranean area gaining insight into the genetic epidemiology of the disease. PMID- 19786005 TI - CYP11B2 gene haplotypes independently and in concurrence with aldosterone and aldosterone to renin ratio increase the risk of hypertension. AB - OBJECTIVES: Aldosterone synthase produces aldosterone, which regulates electrolytes and thereby blood pressure. Polymorphisms in aldosterone-synthase gene (CYP11B2) may associate with heterogeneous aldosterone production and hypertension. Hence, we investigated -344T/C, Iw/Ic polymorphisms of CYP11B2, plasma renin activity (PRA) and aldosterone concentration (PAC). DESIGN AND METHODS: Consecutive ethnically-matched 450 hypertensive patients and 360 controls were screened by PCR-RFLP for genotypes and haplotypes; PRA and PAC were measured. RESULTS: The Iw/Ic polymorphism distribution differed significantly between the two groups (LRT chi(2)=15.8, df=2, P=0.000). The mutant allele-Ic and genotype-Ic/Ic were overrepresented in patients (35% versus 27% and 13% versus 7%). Overrepresentation of T-Ic haplotype in patients was identified as risk haplotype (P=0.000). Patients had significantly higher PAC and aldosterone-to renin ratio (ARR; P=0.000), which was Ic-allele dependent. CONCLUSIONS: The haplotype T-Ic associated with hypertension susceptibility. Correlation between Ic-allele and raised ARR likely serve in hypertension management. PMID- 19786006 TI - Are anti-Helicobacter pylori urease antibodies involved in atherosclerotic diseases? AB - OBJECTIVES: The ureB subunit of urease is a major target recognized by the antibodies of Helicobacter pylori-infected patients. The minimal epitope was determined to be an 8-mer peptide (H-SIKEDVQF-OH). DESIGN AND METHODS: The aim of this study was to discover whether this synthetic 8-mer peptide (BK-61A) directly recognizes the anti-ureB subunit antibodies of H. pylori-infected and atherosclerotic patients. To achieve a better presentation of the epitopes to antibodies, a new isocyanuric linker was designed and used for to immobilize the peptides on a cellulose support. RESULTS: In this study a new peptide synthesis method is presented. Anti-ureB antibodies were evaluated by the dot blot technique in 26 H. pylori-infected donors and the sera of 20 H. pylori-infected patients with atherosclerosis using the 8-mer peptide. CONCLUSIONS: The results reveal that the BK-61A peptide could be used for diagnosing the presence of anti ureB antibodies that may be involved in the initiation of atherosclerosis. PMID- 19786007 TI - Clinical evaluation of a colorimetric oligonucleotide chip for genotyping hepatitis C virus. AB - INTRODUCTION: Hepatitis C virus (HCV) is a major cause of chronic liver disease worldwide. It is associated with the development of end-stage liver disease and hepatocellular carcinoma. Studies have shown that determination of hepatitis C virus (HCV) genotypes is clinically important for prediction of the clinical course and the outcome of antiviral therapy. The aim of this study was to evaluate a colorimetric oligonucleotide chip, which can be used for the rapid and economical detection of the genotypes/subtypes of hepatitis C virus. DESIGN AND METHODS: A total of 860 serum specimens were tested by an oligonucleotide chip genotyping test. Partial genotype results were compared with those obtained by sequencing method and INNOLiPA HCV II assay. The relative sensitivities of the methods were assessed by using the 5'NCR amplicon from the HCV RNA fluorescent amplicor HCV tests and Light Cycler. RESULTS: Of 860 serum specimens tested for their genotypes/subtypes by the oligonucleotide array, 607 HCV positive serum samples could be typed by the sequencing method and 60 of 607 HCV positive serum specimens were typed by INNOLiPA HCV II method. Identification of genotype/subtypes by nucleotide sequencing and INNOLiPA HCV II assay showed respective coincidence rates of 99.8% and 96.7% with the HCV oligonucleotide chip results. And the colorimetric method exhibited 99.8% of relative sensitivity compared with the fluorescent amplicor HCV tests. CONCLUSION: To our knowledge this oligonucleotide chip genotyping method offers a fast and convenient way to determine the genotype in large-scale settings. The tests can be easily adapted by a clinical diagnostic laboratory. PMID- 19786008 TI - Influence of recovery method and microbial contamination on the response to freezing-thawing in ibex (Capra pyrenaica) epididymal spermatozoa. AB - The method of sperm recovery may influence the initial quality of sperm samples and their response to freezing-thawing. The aim of the present work was to compare two methods for collecting epididymal spermatozoa in order to improve the quality of recovered sperm and reduce possible contamination. Testes were obtained from 23 legally hunted, adult ibex males. The sperm mass of the right epididymis was collected by small longitudinal and transverse cuts made in the cauda epididymidis. The sperm mass of the left epididymis was collected by retrograde flushing from the vas deferens to the cauda epididymidis (using a cannula), employing a Tris, citric acid, glucose, egg yolk-based medium. The flushing method recovered more spermatozoa (P<0.001) than the cutting method. After freezing-thawing, greater acrosomes damage (P<0.001) and more morphological abnormalities (P<0.05) were seen among the sperm cells recovered by the cutting method than among those obtained by retrograde flushing. The method of sperm recovery did not, however, influence the microbial contamination rate. In frozen thawed samples that were microbially contaminated, motility was significantly reduced (P<0.05) and membrane integrity tended to be poorer (P=0.06). In conclusion, retrograde flushing is recommended for ibex sperm collection since it would appear that microbial contamination is no more of a problem than that encountered with the cutting method, while a larger number of sperm cells more resistant to freezing-thawing can be obtained. PMID- 19786009 TI - Cryopreservation of sea urchin embryos (Paracentrotus lividus) applied to marine ecotoxicological studies. AB - Current strategies for marine pollution monitoring are based on the integration of chemical and biological techniques. The sea urchin embryo-larval bioassays are among the biological methods most widely used worldwide. Cryopreservation of early embryos of sea urchins could provide a useful tool to overcome one of the main limitations of such bioassays, the availability of high quality biological material all year round. The present study aimed to determine the suitability of several permeant (dimethyl sulfoxide, Me(2)SO; propylene glycol, PG; and ethylene glycol, EG) and non-permeant (trehalose, TRE; polyvinylpyrrolidone, PVP) cryoprotectant agents (CPAs) and their combination, for the cryopreservation of eggs and embryos of the sea urchin Paracentrotus lividus. On the basis of the CPAs toxicity, PG and EG, in combination with PVP, seem to be most suitable for the cryopreservation of P. lividus eggs and embryos. Several freezing procedures were also assayed. The most successful freezing regime consisted on cooling from 4 to -12 degrees C at 1 degrees C/min, holding for 2 min for seeding, cooling to 20 degrees C at 0.5 degrees C/min, and then cooling to -35 degrees C at 1 degrees C/min. Maximum normal larvae percentages of 41.5% and 68.5%, and maximum larval growth values of 42.9% and 60.5%, were obtained for frozen fertilized eggs and frozen blastulae, respectively. PMID- 19786010 TI - Sperm cryopreservation in guppies and black mollies--a generalized freezing protocol for livebearers in Poeciliidae. AB - In this study, we evaluated various parameters of sperm cryopreservation in two livebearers, guppies (Poecilia reticulata) and black mollies (P. latipinna). Our results suggested a common freezing protocol for the guppies and mollies: suspend sperm in Hanks' balanced salt solution (HBSS) at 300 mOsm/kg, use 14% glycerol as cryoprotectant, cool at 25 degrees C/min, and thaw at 40 degrees C in a water bath for 7s. Live young were produced from females inseminated with frozen-thawed sperm in both species. In guppies, percent fertilization (F) and the number of embryos (N) produced with cryopreserved sperm (F=50%, N=74, from 26 females) were similar to those of fresh controls (F=54%, N=61, from 22 females). Interestingly, this same freezing protocol has been used successfully for sperm cryopreservation in green swordtails Xiphophorus helleri, and platyfish of X. couchianus with post thaw motility as high as 80%. All these species belong to the family of Poeciliidae, and their sperm are similar in morphology exhibiting the absence of acrosome, elongate sperm head, and the long mitochondrial sheaths. Besides their internal fertilization reproduction mode, these fish are also small in size (2-4 cm) and live in a freshwater environment. Sperm cryopreservation in fish has been generally recognized as species specific, and new protocols are required for new species. However, results presented in this study suggested otherwise. Thus, sperm cryopreservation methods optimized for one species may be applicable to others if they are taxonomical closely related species with similar sperm morphology and reproduction mode. Considering the enormous number of fish species on the planet, development of generalized sperm freezing protocols for species in groups could have additional advantages for genetic conservation. PMID- 19786011 TI - Histidine-rich glycoprotein inhibited high mobility group box 1 in complex with heparin-induced angiogenesis in matrigel plug assay. AB - Histidine-rich glycoprotein (HRG) is a heparin-binding glycoprotein present in plasma at 100microg/ml. A recent study revealed that HRG suppressed heparin dependent basic fibroblast growth factor (bFGF)-induced angiogenesis. Additionally, we reported that high mobility group box 1 (HMGB1) in complex with heparin induces angiogenesis; therefore, we examined the effect of HRG on heparin dependent HMGB1-induced angiogenesis in the present study. HRG completely inhibited angiogenesis induced by HMGB1 in complex with heparin. HRG inhibited the diffusion of a complex of HMGB1 with heparin from matrigel into surrounding tissue. HRG also competed with HMGB1 for heparin binding in vitro. Moreover, HRG inhibited heparin-dependent vascular endothelial growth factor-A(165) (VEGF A(165))-induced angiogenesis. These results strongly suggested that HRG might be an inhibitor of angiogenesis induced by growth factors with heparin binding activity and that HRG may be a potential drug for angiogenic diseases, including tumor growth. PMID- 19786012 TI - Lauric acid and myristic acid prevent testosterone induced prostatic hyperplasia in rats. AB - Numerous plants have proven to improve uncontrolled growth of the prostate gland and improve urinary tract symptoms associated with benign prostatic hyperplasia. Major components of those plants were lauric acid and myristic acid. Our study investigated whether lauric acid or myristic acid prevent testosterone induced prostatic hyperplasia in rats. Rats were divided into negative control and testosterone induced prostatic hyperplasia rats (positive control, low dose lauric acid treated, high dose lauric acid treated, low dose of myristic acid treated, high dose of myristic acid treated, finasteride treated). Testosterone and drug treatment were carried out for 14 days. Body weights were recorded before and after treatment. On 15th day, rats were sacrificed, prostates were weighed and histopathological studies were carried out. Lauric acid/myristic acid treatment showed significant inhibition of prostate enlargement and protection of histoarchitecture of prostate when compared with positive control group. In conclusion, the study showed that lauric acid/myristic acid reduced the increase of both prostate weight and prostate weight:body weight ratio, markers of testosterone induced prostatic hyperplasia in rats. PMID- 19786013 TI - Lycopodine from Lycopodium clavatum extract inhibits proliferation of HeLa cells through induction of apoptosis via caspase-3 activation. AB - Crude ethanolic extract of the plant Lycopodium clavatum has long been used in complementary and alternative medicine for treating various liver ailments and Alzheimer's disease. It has also been claimed to have potential anti-cancer properties in vivo in mice chronically fed liver carcinogens, p-dimethylamino azobenzene (initiator) and phenobarbital (promoter). Incidentally, crude ethanolic extract of Lycopodium clavatum is a mixture of some 201 alkaloids. In order to ascertain if any major fraction can be attributed to have pronounced anti-cancer effect, we examined this major fraction by eluting the crude extract in petroleum ether:ethyl aetate (17:3 vol/vol;) solvent and tried to understand its underlying mechanism. Studies on morphological changes, cell viability and cytotoxicity by microscopy and FACS, Western blot and immunofluorescence of Bcl 2, Bax, cytochrome c, caspase-3 were conducted. Lycopodine was found to induce chromatin condensation, inter-nucleosomal DNA fragmentation and enhanced cell population in sub-G1 region along with increase in reactive oxygen species generation and mitochondrial membrane potential depolarization, release of cytochrome c and activation of caspase-3 which are the events closely involved in apoptosis. An overall analysis of results showed that Lycopodine considerably inhibited growth of HeLa cells which indicates its potential use in chemotherapy. PMID- 19786014 TI - Chlorogenic acid against carbon tetrachloride-induced liver fibrosis in rats. AB - This study examined the effects of chlorogenic acid (CGA) on liver fibrosis induced by carbon tetrachloride (CCl(4)) and explored the possible mechanisms of action. Liver fibrosis was induced in male Sprague-Dawley (SD) rats by the injection of 40% CCl(4) subcutaneously twice a week for eight weeks. At the same time, CGA (60 and 30mg/kg) was administered intragastrically once daily to a subset of rats. Upon pathological examination, the CGA-treated rats showed significantly reduced liver damage and symptoms of liver fibrosis. The expression of collagen I and collagen III mRNA was increased markedly by the CCl(4) treatment but this increase was suppressed by CGA. As compared with the CGA treated group, the expression of bcl-2, vascular endothelial growth factor (VEGF), and transforming growth factor (TGF-beta1) mRNA was increased in CCl(4) group, whereas Bax mRNA expression decreased. The expression of Bax and bcl-2 protein was confirmed by western blotting. Intragastric administration of CGA reduced the protein expression of alpha-smooth muscle actin (alpha-SMA) and glucose-regulated proteins 78 and 94 (GRP78 and GRP94) in rats injured by treatment with CCl(4). Our data indicate that CGA can efficiently inhibit CCl(4) induced liver fibrosis in rats. Therefore, CGA could be an effective drug for preventing liver fibrosis. PMID- 19786015 TI - SAM pointed domain ETS factor (SPDEF) regulates terminal differentiation and maturation of intestinal goblet cells. AB - BACKGROUND AND AIMS: SPDEF (also termed PDEF or PSE) is an ETS family transcription factor that regulates gene expression in the prostate and goblet cell hyperplasia in the lung. Spdef has been reported to be expressed in the intestine. In this paper, we identify an important role for Spdef in regulating intestinal epithelial cell homeostasis and differentiation. METHODS: SPDEF expression was inhibited in colon cancer cells to determine its ability to control goblet cell gene activation. The effects of transgenic expression of Spdef on intestinal differentiation and homeostasis were determined. RESULTS: In LS174T colon cancer cells treated with Notch/gamma-secretase inhibitor to activate goblet cell gene expression, shRNAs that inhibited SPDEF also repressed expression of goblet cell genes AGR2, MUC2, RETLNB, and SPINK4. Transgenic expression of Spdef caused the expansion of intestinal goblet cells and corresponding reduction in Paneth, enteroendocrine, and absorptive enterocytes. Spdef inhibited proliferation of intestinal crypt cells without induction of apoptosis. Prolonged expression of the Spdef transgene caused a progressive reduction in the number of crypts that expressed Spdef, consistent with its inhibitory effects on cell proliferation. CONCLUSIONS: Spdef was sufficient to inhibit proliferation of intestinal progenitors and induce differentiation into goblet cells; SPDEF was required for activation of goblet cell associated genes in vitro. These data support a model in which Spdef promotes terminal differentiation into goblet cells of a common goblet/Paneth progenitor. PMID- 19786016 TI - Stanniocalcin-2 is a HIF-1 target gene that promotes cell proliferation in hypoxia. AB - Stanniocalcin-2 (STC2), the paralog of STC1, has been suggested as a novel target of oxidative stress response to protect cells from apoptosis. The expression of STC2 has been reported to be highly correlated with human cancer development. In this study, we reported that STC2 is a HIF-1 target gene and is involved in the regulation of cell proliferation. STC2 was shown to be up-regulated in different breast and ovarian cancer cells, following exposure to hypoxia. Using ovarian cancer cells (SKOV3), the underlying mechanism of HIF-1 mediated STC2 gene transactivation was characterized. Hypoxia-induced STC2 expression was found to be HIF-1alpha dependent and required the recruitment of p300 and HDAC7. Using STC2 promoter deletion constructs and site-directed mutagenesis, two authentic consensus HIF-1 binding sites were identified. Under hypoxic condition, the silencing of STC2 reduced while the overexpression of STC2 increased the levels of phosphorylated retinoblastoma and cyclin D in both SKOV3 and MCF7 cells. The change in cell cycle proteins correlated with the data of the serial cell counts. The results indicated that cell proliferation was reduced in STC2-silenced cells but was increased in STC2-overexpressing hypoxic cells. Solid tumor progression is usually associated with hypoxia. The identification and functional analysis of STC2 up-regulation by hypoxia, a feature of the tumor microenvironment, sheds light on a possible role for STC2 in tumors. PMID- 19786017 TI - Hypothermia prevents the development of ischemic proliferative retinopathy induced by severe perinatal asphyxia. AB - Obstetric complications, such as perinatal asphyxia, may cause retinal injuries as retinopathy of prematurity (ROP), a type of ischemic proliferative retinopathy. Up to date there are no appropriate experimental models for studying the long-term sequels of this disease. In the present work, we present an experimental model of perinatal asphyxia which shows structural and ultrastructural retinal alterations at the most inner layers of the retina, such as neurodegeneration, development of neoformed vessels and glial reaction, which are compatible with the histopathological description of ROP. Besides, the application of hypothermia during perinatal asphyxia showed effective results preventing cellular and morphological alterations. This study may contribute to the development of therapies in order to either ameliorate or prevent retinal damage. In this manner, hypothermia may improve life quality and decrease medical, family and social costs of these avoidable causes of blindness. PMID- 19786018 TI - Propagation of host disease to grafted neurons: accumulating evidence. PMID- 19786019 TI - Flavocoxid counteracts muscle necrosis and improves functional properties in mdx mice: a comparison study with methylprednisolone. AB - Muscle degeneration in dystrophic muscle is exacerbated by the endogenous inflammatory response and increased oxidative stress. A key role is played by nuclear factor(NF)-kappaB. We showed that NF-kappaB inhibition through compounds with also antioxidant properties has beneficial effects in mdx mice, the murine model of Duchenne muscular dystrophy (DMD), but these drugs are not available for clinical studies. We evaluated whether flavocoxid, a mixed flavonoid extract with anti-inflammatory, antioxidant and NF-kappaB inhibiting properties, has beneficial effects in mdx mice in comparison with methylprednisolone, the gold standard treatment for DMD patients. Five-week-old mdx mice were treated for 5 weeks with flavocoxid, methylprednisolone or vehicle. The evaluation of in vivo and ex vivo functional properties and morphological parameters was performed. Serum samples were assayed for oxidative stress markers, creatine-kinase (CK) and leukotriene B-4. Cyclooxygenase-2 (COX-2), 5-lipoxygenase (5-LOX), tumor necrosis factor-alpha, p-38, JNK1 expression was evaluated in muscle by western blot analysis. NF-kappaB binding activity was investigated by electrophoresis mobility shift assay. The administration of flavocoxid: (1) ameliorated functional properties in vivo and ex vivo; (2) reduced CK; (3) reduced the expression of oxidative stress markers and of inflammatory mediators; (4) inhibited NF-kappaB and mitogen-activated protein kinases (MAPKs) signal pathways; (5) reduced muscle necrosis and enhanced regeneration. Our results highlight the detrimental effects of oxidative stress and NF-kappaB, MAPKs and COX/5-LOX pathways in the dystrophic process and show that flavocoxid is more effective in mdx mice than methylprednisolone. PMID- 19786020 TI - Huntington's disease: silencing a brutal killer. PMID- 19786021 TI - The monophyletic origin of a remarkable sexual system in akentrogonid rhizocephalan parasites: a molecular and larval structural study. AB - We use sequences from the nuclear ribosomal genes, 18S and 28S to analyze the phylogeny of the Rhizocephala Akentrogonida including two species, Clistosaccus paguri and Chthamalophilus delagei, that are critical for understanding rhizocephalan evolution but have not previously been part of a molecularly based study. In addition we use light and scanning electron microscopy to compare the cypris larvae of C. paguri, Sylon hippolytes and two species of the family Thompsoniidae, since this larval stage offers a suite of characters for analyzing the evolution of these otherwise highly reduced parasites. The Rhizocephala Akentrogonida form a monophyletic group nested within a paraphyletic "Kentrogonida". C. paguri and S. hippolytes are sistergroups confirming the monophyly of the Clistosaccidae that was originally based on similarities in the cypris larvae. We find numerous LM and SEM level similarities between the two species, many of which appear to be correlated with their specialized sexual system, where male cyprids use an antennule to implant cells into the virgin female parasite. Some of these traits are also found in cyprids of the thompsoniid species. We conclude that the special cypris morphology and the implantation of males by antennular penetration was present in the stem species to the Thompsoniidae and the Clistosaccidae and emphasize the power of larval characters in rhizocephalan systematics. C. delagei is a sister group to Boschmaella balani and the two are nested deep within the Akentrogonida. This confirms the monophyly of the Chthamalophilidae and falsifies the theory that C. delagei should represent the most primitive extant rhizocephalan. Instead, chthamalophilid rhizocephalans represent some of the most highly advanced members of the parasitic barnacles. PMID- 19786022 TI - Cryptosporidium surveillance and risk factors in the United States. AB - Surveillance for Cryptosporidium in the United States indicates that the reported incidence of infection has increased dramatically since 2004. The reasons for this increase are unclear but might be caused by an actual increase in incidence, improved surveillance, improved awareness about cryptosporidiosis, and/or increases in testing practices resulting from the licensing of the first-ever treatment for cryptosporidiosis. While regional differences remain, the incidence of cryptosporidiosis appears to be increasing across the United States. Onset of illness is most common during the summer, particularly among younger children. Cryptosporidiosis case reporting also influences outbreak detection and reporting; the recent rise in cases coincides with an increase in the number of reported cryptosporidiosis outbreaks, particularly in treated recreational water venues. Risk factors include ingesting contaminated recreational or drinking water, exposure to infected animals, having close contacts with cryptosporidiosis, travel to disease-endemic areas, and ingestion of contaminated food. Advances in molecular characterization of clinical specimens have improved our understanding of the changing epidemiology and risk factors. Prevention and control of cryptosporidiosis requires continued efforts to interrupt the transmission of Cryptosporidium through water, food, and contact with infected persons or animals. Of particular importance is continued improvement and monitoring of drinking water treatment and advances in the design, operation, and management of recreational water venues coupled with behavioral changes among the swimming public. PMID- 19786023 TI - Trypanosoma cruzi: do different sylvatic strains trigger distinct immune responses? AB - Strains of Trypanosoma cruzi are multiclonal populations that can be classified in groups or genotypes, differing in pathogenicity, virulence, and histotropism. In this experiment the distinct behavior of two strains of T. cruzi, MORC-1 and MORC-2, was documented. Blood parasitemia, spleen proliferation, nitric oxide, histopathology of the spleen and heart were used as tools to evaluate parasite persistence. Groups of male mice were separated and divided in three groups: Control (C), Infected (IM-1) and Infected (IM-2). The peak of parasitemia occurred on 10days post infection for both strains. LPS stimulated animals, infected MORC-2 group displayed significant higher concentrations of NO when compared to infected MORC-1 group (P<0.05). For ConA stimulated lymphoproliferation, infected MORC-1 group displayed higher proliferation index as compared to infected MORC-2 group. An opposite behavior for IL-4 and TNF-alpha was observed according to the strain. For MORC-1 enhanced concentrations of IL-4 were present with concomitant reduced levels of TNF-alpha, while for MORC-2 enhanced concentrations of TNF-alpha and reduced levels of IL-4 were found. The histopathology of heart and spleen showed important differences in which MORC-1 displayed statistically enhanced number of amastigote in the heart and spleen as compared to MORC-2. Concluding, each strain triggered a distinct immune response with enhanced cytokine TH-1 profile for MORC-2 and TH-2 for MORC-1. PMID- 19786024 TI - Divergent intracellular pathways regulate interleukin-1beta-induced miR-146a and miR-146b expression and chemokine release in human alveolar epithelial cells. AB - We have previously reported that IL-beta-induced miR-146a and miR-146b expression negatively regulates IL-8 and RANTES release in human alveolar A549 epithelial cells. To determine the intracellular pathways that regulate this response, we demonstrate IL-1beta-induced activation of the nuclear factor (NF)-kappaB, extracellular regulated kinase (ERK)-1/2, c-jun N-terminal kinase (JNK)-1/2 and p38 mitogen activated kinase (MAP) kinase pathways. Subsequent pharmacological studies show that IL-1beta-induced miR-146a, IL-8 and RANTES production was regulated via NF-kappaB and JNK-1/2 whilst miR-146b expression was mediated via MEK-1/2 and JNK-1/2. These divergent intracellular pathways likely explain the differential expression and biological action of the miR-146 isoforms. PMID- 19786025 TI - A regulatory domain spanning the repeat sequence RE1 from herpes simplex virus type 1 has cell specific differential functions in trigeminal neurons and fibroblasts. AB - In this report we demonstrate that the herpes simplex virus type 1 reiteration element 1 (RE1) (nt: 117158-117353) in concert with its flanking sequences is both a cell specific and stimulus inducible regulatory domain. This region of the virus genome and specifically the RE1 supports differential reporter gene expression in both baby hamster kidney cells and disassociated rat trigeminal ganglia and is present within a region that is implicated in regulating latency of the virus in neuronal cells. Further we demonstrate that this locus is a transcriptional regulatory domain and a target for the transcription factor CCCTC binding protein. PMID- 19786026 TI - Serum fibrosis markers identify patients with mild and progressive hepatitis C recurrence after liver transplantation. AB - BACKGROUND & AIMS: Significant fibrosis (fibrosis stage [F] >or= 2) and portal hypertension (hepatic venous pressure gradient [HVPG] >or= 6 mm Hg) in patients 1 year after liver transplantation indicate progressive hepatitis C recurrence. This study evaluated whether serum fibrosis markers can predict hepatitis C recurrence during the first year after liver transplantation. METHODS: Hyaluronic acid, amino-terminal propeptide of type-III-procollagen, tissue inhibitor of matrix metalloproteinase type-1 concentrations were measured in serum samples from 133 patients infected with hepatitis C virus (HCV) at 3, 6, and 12 months after liver transplantation; routine laboratory tests were also performed. Liver biopsy samples (n = 133) and HVPGs (n = 94) were analyzed 1 year after transplantation. Sixteen patients who were not infected with HCV served as controls. RESULTS: An algorithm, including the 3 markers (3-M-ALG) and 3 published scores (aspartate aminotransferase [AST]-to-alanine aminotransferase ratio, AST-to-platelet ratio index, and Benlloch) were analyzed. One year after liver transplantation, 50 patients (38%) had significant fibrosis (F >or= 2) and 31 (32%) had an HVPG >or= 6 mm Hg. The area under the receiver operator characteristic curve of the 3-M-ALG used to identify F >or= 2 at 3, 6, and 12 months after transplantation (0.67, 0.77, and 0.78) and of those with HVPG >or= 6 at the same time points (0.75, 0.87, and 0.90) were significantly higher than values obtained with the 3 published scores. At 12 months, a 3-M-ALG >or= 2 identified most patients at risk of decompensation/death. CONCLUSIONS: Serum markers can accurately discriminate between patients with mild and progressive hepatitis C recurrence after liver transplantation. PMID- 19786027 TI - Prolyl hydroxylase-3 is down-regulated in colorectal cancer cells and inhibits IKKbeta independent of hydroxylase activity. AB - BACKGROUND & AIMS: Prolyl hydroxylase (PHD) hydroxylates hypoxia inducible factor (HIF) alpha, leading to HIFalpha degradation. The PHD family comprises PHD1, PHD2, and PHD3. The enzymatic activity of PHDs is O(2)-dependent, so PHDs are believed to be oxygen sensors as well as tumor suppressors. However, the expression pattern of PHDs in colorectal cancer and the correlation between their expression level and tumorigenesis is unclear. METHODS: We determined the expression of PHDs in 60 human primary colorectal carcinoma tissues, paired with normal colorectal tissues. PHD3 expression levels were knocked down using small interfering RNA (siRNA); cells were analyzed by immunoblotting, immunoprecipitation, and histochemical analyses. In vivo tumor growth was analyzed in nu/nu mice. RESULTS: Expression of PHD3 is decreased in colorectal cancer tissues. Decreased expression of PHD3 is associated with higher tumor grade and metastasis. PHD3 inhibits phosphorylation of inhibitor of kappaB (IkappaB) kinase (IKK) beta and activation of (NF) kappaB, independent of its hydroxylase activity. PHD3 associates with IKKbeta but does not target it for destruction; instead, PHD3 blocks the interaction between IKKbeta and Hsp90 that is required for phosphorylation of IKKbeta. Knockdown of PHD3 increased resistance of colorectal cancer cells to the effects of tumor necrosis factor alpha and tumorigenesis. CONCLUSIONS: PHD3 appears to be a tumor suppressor in colorectal cancer cells that inhibits IKKbeta/NF-kappaB signaling, independent of its hydroxylase activity. Activation of NF-kappaB has been observed in colon cancer. Determination of PHD3 status could aid targeted therapy selection for patients with colorectal tumors that have increased NF-kappaB activity. PMID- 19786028 TI - Toll-like receptor-4 inhibits enterocyte proliferation via impaired beta-catenin signaling in necrotizing enterocolitis. AB - BACKGROUND & AIMS: Necrotizing enterocolitis (NEC), the leading cause of gastrointestinal death from gastrointestinal disease in preterm infants, is characterized by exaggerated TLR4 signaling and decreased enterocyte proliferation through unknown mechanisms. Given the importance of beta-catenin in regulating proliferation of many cell types, we hypothesize that TLR4 impairs enterocyte proliferation in NEC via impaired beta-catenin signaling. METHODS: Enterocyte proliferation was detected in IEC-6 cells or in ileum or colon from wild-type, TLR4-mutant, or TLR4(-/-) mice after induction of NEC or endotoxemia. beta-Catenin signaling was assessed by cell fractionation or immunoconfocal microscopy to detect its nuclear translocation. Activation and inhibition of beta catenin were achieved via cDNA or small interfering RNA, respectively. TLR4 in the intestinal mucosa was inhibited with adenoviruses expressing dominant negative TLR4. RESULTS: TLR4 activation significantly impaired enterocyte proliferation in the ileum but not colon in newborn but not adult mice and in IEC 6 enterocytes. beta-Catenin activation reversed these effects in vitro. To determine the mechanisms involved, TLR4 activation phosphorylated the upstream inhibitory kinase GSK3beta, causing beta-catenin degradation. NEC in both mouse and humans was associated with decreased beta-catenin and increased mucosal GSK3beta expression. Strikingly, the inhibition of enterocyte beta-catenin signaling in NEC could be reversed, and enterocyte proliferation restored, through adenoviral-mediated inhibition of TLR4 signaling in the small intestinal mucosa. CONCLUSION: We now report a novel pathway linking TLR4 with inhibition of beta-catenin signaling via GSK3beta activation, leading to reduced enterocyte proliferation in vitro and in vivo. These data provide additional insights into the pathogenesis of diseases of intestinal inflammation such as NEC. PMID- 19786029 TI - Iron-induced expression of bone morphogenic protein 6 in intestinal cells is the main regulator of hepatic hepcidin expression in vivo. AB - BACKGROUND & AIMS: Recent studies identified bone morphogenic protein 6 (BMP6) as a key regulator of hepatic hepcidin expression and iron metabolism, but the cellular source of BMP6 and the reason for its specific effect on hepatocytes are unknown. METHODS: BMP and hepcidin expression upon iron sensing were analyzed in vivo in BMP6(-/-) and BMP6(+/+) mice and ex vivo in tissue and in vitro in cells of the liver and the small intestine. RESULTS: BMP6(-/-) mice developed severe hepatic iron accumulation and reduced hepcidin expression with increasing age. This phenotype could be triggered in younger BMP6(-/-) mice by dietary or parenteral iron application. Furthermore, both treatments induced a marked up regulation of BMP6 expression in the small intestine of BMP6(+/+) mice. Ex vivo treatment of intestinal tissue of BMP6(+/+) mice with iron sulfate or holo transferrin confirmed epithelial cells as an inducible source of BMP6. In contrast, iron overload did not promote a striking induction of BMP6 expression in hepatocytes or macrophages. Furthermore, iron-supplemented diet induced a compensatory up-regulation of BMP2, BMP4, and BMP9 in the small intestine of BMP6(-/-) mice that was apparently not sufficient to assure iron homeostasis. As a potential explanation, analysis of hepatocytes revealed an expression pattern of BMP receptor subunits preferentially used by BMP6, and treatment of hepatocytes with different recombinant BMPs identified BMP6 as the most potent stimulator of hepcidin expression. CONCLUSIONS: Epithelial cells of the small intestine are the predominant cellular source of BMP6 upon iron sensing. Our findings reveal a previously unknown mechanism in which the small intestine controls iron homeostasis. PMID- 19786030 TI - The beta3-adrenoceptor agonist GW427353 (Solabegron) decreases excitability of human enteric neurons via release of somatostatin. AB - BACKGROUND & AIMS: beta3 Adrenoceptor (beta3-AR) is expressed on adipocytes and enteric neurons. GW427353 is a human selective beta3-AR agonist with visceral analgesic effects. Some of its effects may involve release of somatostatin (SST) and actions on enteric neurons. The aim of this study was to investigate the mode of action of GW427353 in human submucous neurons. METHODS: Voltage sensitive dye imaging was used to record from human submucous neurons. SST release from human primary adipocytes was measured with enzyme-linked immunoabsorbent assay. Immunohistochemistry was used to detect adiponectin, beta3-AR, SST, SST2 receptors, tyrosine hydroxylase (TH), and protein gene product 9.5. RESULTS: Confocal imaging showed cytoplasmic beta3-AR labeling in somata of submucous neurons and nerve varicosities. GW427353 had no direct postsynaptic actions but decreased fast synaptic input to submucous neurons. Tissue perfusion with GW427353 reduced nicotine-evoked neuronal spike frequency, an effect prevented by the beta3-AR antagonist SR-59230 and the SST2-receptor antagonist CYN154806 and mimicked by the SST2 receptor agonist octreotide. Adipocytes expressed adiponectin, beta3-AR, and SST. TH-positive fibers were in close proximity to adipocytes. Submucous neurons expressed SST2 receptors. Human primary adipocytes released SST in response to GW427353 in a concentration-dependent manner, an effect abolished by SR-59230. CONCLUSIONS: Inhibitory action of GW427353 involves release of SST which stimulates inhibitory SST2 receptors on human submucous neurons. Adipocytes are a potential source for SST. beta3-AR activation may be a promising approach to reduce enteric neuron hyperexcitability. The action of GW427353 may be the neurophysiologic correlate of its beneficial effect in patients with irritable bowel syndrome. PMID- 19786031 TI - Sex differences in opioid analgesia, hyperalgesia, tolerance and withdrawal: central mechanisms of action and roles of gonadal hormones. AB - This article reviews sex differences in opiate analgesic and related processes as part of a Special Issue in Hormones and Behavior. The research findings on sex differences are organized in the following manner: (a) systemic opioid analgesia across mu, delta and kappa opioid receptor subtypes and drug efficacy at their respective receptors, (b) effects of the activational and organizational roles of gonadal steroid hormones and estrus phase on systemic analgesic responses, (c) sex differences in spinal opioid analgesia, (d) sex differences in supraspinal opioid analgesia and gonadal hormone effects, (e) the contribution of genetic variance to analgesic sex differences, (f) sex differences in opioid-induced hyperalgesia, (g) sex differences in tolerance and withdrawal-dependence effects, and (h) implications for clinical therapies. PMID- 19786032 TI - What is in a name? Integrating homeostasis, allostasis and stress. PMID- 19786033 TI - Emotional sensitivity for motherhood: late pregnancy is associated with enhanced accuracy to encode emotional faces. AB - Previous research suggests that female sex hormones can increase the sensitivity of women's emotion processing systems. The largest rises in sex hormone levels in a woman's life are from early to late pregnancy. The current study, therefore, investigated whether changes in emotion processing are seen across pregnancy. Hypervigilant emotion processing has been implicated in the aetiology of anxiety. Therefore enhanced emotion processing across pregnancy has implications for women's vulnerability to anxiety. Ability to encode facial expressions of emotion was assessed in 101 women during early pregnancy and again in 76 of these women during late pregnancy. Symptoms of anxiety were measured using a clinical interview (The CIS-R). Consistent with previous research, the presence of anxiety symptoms was associated with greater accuracy to encode faces signalling threat (fearful and angry faces). We found that women had higher accuracy scores to encode emotional expressions signalling threat or harm (fearful, angry and disgusted faces) but also a more general negative emotion (sadness) during late, compared with early, pregnancy. Enhanced ability to encode emotional faces during late pregnancy may be an evolutionary adaption to prepare women for the protective and nurturing demands of motherhood by increasing their general emotional sensitivity and their vigilance towards emotional signals of threat, aggression and contagion. However, the results also suggest that, during late pregnancy, women's emotion processing style is similar to that seen in anxiety. The results have implications for our understanding of normal pregnant women's processing of emotional cues and their vulnerability to symptoms of anxiety. PMID- 19786034 TI - Neutralizing antibodies against IFN beta in patients with multiple sclerosis: a comparative study of two cytopathic effect tests (CPE) for their detection. AB - Neutralizing antibodies (NABs) against IFN beta should be measured in specialized laboratories, using a test of inhibition of the cytopathic effect (bioassay or CPE test), based on the capacity of IFNss to block the infection of live monolayer-cultured cells by a virus, depending on the presence or absence of NABs. The European Federation of Neurological Societies (EFNS) considers this assay to be the gold standard. However, the various different ways to perform this assay complicate comparison of the results between laboratories. The World Health Organization (WHO) has published several recommendations to perform this assay using the A549 cell line and the murine encephalomyocarditis virus (EMCV). In order to validate the results previously obtained in our laboratory with HEP2/VSV, we undertook a comparative analysis of the two bioassays, HEP2/VSV and A549/EMCV, to assess whether the use of different cell lines and viruses influences sensitivity. We also calibrated the A549/EMCV assay with a reference IFNss. Our results confirm that the bioassay with HEP2/VSV is as sensitive as the assay with A549/EMCV and that a significant association and correlation exist in the results between both assays. Thus, past results with HEP2/VSV in our laboratory could be comparable with those obtained with A549/EMCV in both our laboratory and others. PMID- 19786035 TI - Genome sequences of Escherichia coli B strains REL606 and BL21(DE3). AB - Escherichia coli K-12 and B have been the subjects of classical experiments from which much of our understanding of molecular genetics has emerged. We present here complete genome sequences of two E. coli B strains, REL606, used in a long term evolution experiment, and BL21(DE3), widely used to express recombinant proteins. The two genomes differ in length by 72,304 bp and have 426 single base pair differences, a seemingly large difference for laboratory strains having a common ancestor within the last 67 years. Transpositions by IS1 and IS150 have occurred in both lineages. Integration of the DE3 prophage in BL21(DE3) apparently displaced a defective prophage in the lambda attachment site of B. As might have been anticipated from the many genetic and biochemical experiments comparing B and K-12 over the years, the B genomes are similar in size and organization to the genome of E. coli K-12 MG1655 and have >99% sequence identity over approximately 92% of their genomes. E. coli B and K-12 differ considerably in distribution of IS elements and in location and composition of larger mobile elements. An unexpected difference is the absence of a large cluster of flagella genes in B, due to a 41 kbp IS1-mediated deletion. Gene clusters that specify the LPS core, O antigen, and restriction enzymes differ substantially, presumably because of horizontal transfer. Comparative analysis of 32 independently isolated E. coli and Shigella genomes, both commensals and pathogenic strains, identifies a minimal set of genes in common plus many strain-specific genes that constitute a large E. coli pan-genome. PMID- 19786036 TI - Substance P selectively modulates GABA(A) receptor-mediated synaptic transmission in striatal cholinergic interneurons. AB - Substance P (SP) is co-localized and co-released with gamma-amino butyric acid (GABA) from approximately 50% of GABAergic medium spiny neurons (MSNs) in the striatum. MSNs innervate several cellular targets including neighboring MSNs and cholinergic interneurons via collaterals. However, the functional role of SP release onto striatal interneurons is unknown. Here we examined SP-mediated actions on inhibitory synaptic transmission in cholinergic interneurons using whole-cell recordings in mouse corticostriatal slices. We found that SP selectively suppressed GABA(A) receptor-mediated inhibitory post-synaptic currents (IPSCs), but not excitatory post-synaptic currents (EPSCs) in cholinergic interneurons. In contrast, SP did not alter IPSCs in fast-spiking interneurons and MSNs. SP suppressed IPSC amplitude in a concentration-dependent and reversible manner, and the NK1 receptor antagonist RP67580 attenuated the SP mediated suppression. In addition, RP67580 alone enhanced the evoked IPSC amplitude in cholinergic interneurons, suggesting an endogenous action of SP on regulation of inhibitory synaptic transmission. SP did not alter the paired-pulse ratio, but reduced the amplitudes of GABA(A) agonist muscimol-induced outward currents and miniature IPSCs in cholinergic interneurons, suggesting SP exerts its effects primarily at the post-synaptic site. Our results indicate that the physiological effects of SP are to enhance the activity of striatal cholinergic interneurons and provide a rationale for designing potential new antiparkinsonian agents. PMID- 19786037 TI - COX-2 inhibition controls P-glycoprotein expression and promotes brain delivery of phenytoin in chronic epileptic rats. AB - Epileptic seizures drive expression of the blood-brain barrier efflux transporter P-glycoprotein via a glutamate/cyclooxygenase-2 mediated signalling pathway. Targeting this pathway may represent an innovative approach to control P glycoprotein expression in the epileptic brain and to enhance brain delivery of antiepileptic drugs. Therefore, we tested the effect of specific cyclooxygenase-2 inhibition on P-glycoprotein expression in two different status epilepticus models. Moreover, the impact of a cyclooxygenase-2 inhibitor on expression of the efflux transporter and on brain delivery of an antiepileptic drug was evaluated in rats with recurrent spontaneous seizures. The highly selective cyclooxygenase 2 inhibitors SC-58236 and NS-398 both counteracted the status epilepticus associated increase in P-glycoprotein expression in the parahippocampal cortex and the ventral hippocampus. In line with our working hypothesis, a sub-chronic 2 week treatment with SC-58236 in the chronic epileptic state kept P-glycoprotein expression at control levels. As described previously, enhanced P-glycoprotein expression in chronic epileptic rats was associated with a significant reduction in the brain penetration of the antiepileptic drug phenytoin. Importantly, the brain delivery of phenytoin was significantly enhanced by sub-chronic cyclooxygenase-2 inhibition in rats with recurrent seizures. In conclusion, the data substantiate targeting of cyclooxygenase-2 in the chronic epileptic brain as a promising strategy to control the expression levels of P-glycoprotein despite recurrent seizure activity. Cyclooxygenase-2 inhibition may therefore help to increase concentrations of antiepileptic drugs at the target sites in the epileptic brain. It needs to be further evaluated whether the approach also enhances efficacy. PMID- 19786038 TI - Body schema and body image--pros and cons. AB - There seems to be no dimension of bodily awareness that cannot be disrupted. To account for such variety, there is a growing consensus that there are at least two distinct types of body representation that can be impaired, the body schema and the body image. However, the definition of these notions is often unclear. The notion of body image has attracted most controversy because of its lack of unifying positive definition. The notion of body schema, onto which there seems to be a more widespread agreement, also covers a variety of sensorimotor representations. Here, I provide a conceptual analysis of the body schema contrasting it with the body image(s) as well as assess whether (i) the body schema can be specifically impaired, while other types of body representation are preserved; and (ii) the body schema obeys principles that are different from those that apply to other types of body representation. PMID- 19786039 TI - On age differences in prefrontal function: the importance of emotional/cognitive integration. AB - Evidence of prefrontal cortex decline among healthy older adults has been widely reported, although many questions remain regarding the functional heterogeneity of the prefrontal lobes and the uniformity (or lack thereof) with which discrete regions decline with age. MacPherson, Phillips, and Della Sala (2002) previously reported age differences in tasks associated with dorsolateral prefrontal cortex (DLPFC) function (executive control), but not for tasks associated with ventromedial prefrontal cortex (VMPFC) function (emotional/cognitive integration). The present study, conducted using 39 younger adults and 39 older adults, replicates the MacPherson et al. findings regarding DLPFC functioning. However, and perhaps due to the use of more sensitive tasks, we also find age differences in tasks associated with VMPFC function. Specifically, both univariate and multivariate analyses indicated older adults showed deficits across the DLPFC and VMPFC tasks. Exploratory factor analysis of the task performance scores indicated four underlying dimensions, two related to DLPFC functioning and two related to VMPFC functioning. A set of structural equation models specifying age effects on the four task performance factors was tested, in order to contrast models of process-specific vs. common age effects. Our results suggest that older adults show deficits in emotional/cognitive integration as well as in executive function, and that those effects do include process-specific age deficits. PMID- 19786040 TI - A new step towards understanding Embedded Figures Test performance in the autism spectrum: the radial frequency search task. AB - The Embedded Figure Test (EFT) requires locating a simple shape embedded within a background of overlapping target-irrelevant scene elements. Observers with autism, or those with high levels of autistic-like traits, typically outperform matched comparison groups on the EFT. This research investigated the critical visual properties which give rise to this improved performance. The EFT is a search task and so here a radial frequency (RF) search task was created to directly explore efficacy of visual search and also the influence of element overlap on performance. In all conditions, the task was to detect whether the target RF3 (a triangular shape chosen for its visual properties) was present among a number of distracter RF4 (a square shape) patterns. The conditions employed were: 'singles', where all the patterns were spatially discrete, 'pairs', where two overlapping elements formed each cluster, and 'quads', comprising four overlapping elements per cluster. Compared to students scoring low on the Autism Spectrum Quotient (AQ; n=27), those scoring high on the AQ (n=23) were faster on the EFT and also significantly less influenced by increasing set size of the stimulus array in all RF search task conditions. However, the group difference in RF search performance was unaffected by the amount of stimulus overlap. Thus a simple search task is sufficient to detect a performance advantage associated with higher levels of autistic traits and has the advantages of a solid footing in visual theory and being readily repeatable for the purpose of assessing performance variability and change with interventions. PMID- 19786042 TI - Preparation and synthetic application of partially protected brassinosteroids. AB - Preparation of partially protected brassinosteroids is achieved through the reaction of the source material (24-epicastasterone and 24-epibrassinolide) with diol-specific reagents (2,2-dimethoxypropane and methylboronic acid). The obtained products were shown to be useful synthetic intermediates for further preparation of minor representatives of this class of natural phytohormones (such as 3,24-diepicastasterone and 3-dehydro-24-epibrassinolide). PMID- 19786041 TI - The effects of chronic glucocorticoid exposure on dendritic length, synapse numbers and glial volume in animal models: implications for hippocampal volume reductions in depression. AB - Glucocorticoids (GCs) are hormones secreted by the adrenal glands as an endocrine response to stress. Although the main purpose of GCs is to restore homeostasis when acutely elevated, animal studies indicate that chronic exposure to these hormones can cause damage to the hippocampus. This is indicated by reductions in hippocampal volume, and changes in neuronal morphology (i.e., decreases in dendritic length and number of dendritic branch points) and ultrastructure (e.g., smaller synapse number). Smaller hippocampal volume has been also reported in humans diagnosed with major depressive disorder or Cushing's disorder, conditions in which GCs are endogenously and chronically elevated. Although a number of studies considered neuron loss as the major factor contributing to the volume reduction, recent findings indicated that this is not the case. Instead, alterations in dendritic, synaptic and glial processes have been reported. The focus of this paper is to review the GC effects on the cell number, dendritic morphology and synapses in an effort to better understand how these changes may contribute to reductions in hippocampal volume. Taken together, the data from animal models suggest that hippocampal volumetric reductions represent volume loss in the neuropil, which, in turn, under-represent much larger losses of dendrites and synapses. PMID- 19786044 TI - Inverse correlation of protein oxidation and proteasome activity in liver and lung. AB - Several studies have demonstrated that proteasome activity decreases whereas protein oxidation increases with aging in various tissues. However, no studies are available correlating both parameters directly comparing different tissues of one organism. Therefore, we determined whether there is an age-related change in proteasome activity and protein oxidation in heart, lung, liver, kidney and skeletal muscle samples of 6-, 10-, 18- and 26-month-old rats. There was a significant age-related increase in protein carbonyls at 18 and 26 months compared to young rats. Thereby, protein carbonyl formation was rather due to a general than a specific protein carbonylation as shown by immunblot studies. The highest increase in protein carbonyl formation was found in liver, lung and kidney samples. Proteasome activity decreased significantly with age in lung and liver samples. Proteasome activity in liver and lung decreased by factor five compared to young rats. Strong correlations between proteasome activity and protein oxidation were found in liver and lung, whereas in other tissues only a trend was found. These results demonstrate that the increase in protein oxidation and the decline in proteasome activity are correlating. Further studies are needed to determine the mechanisms which cause organ-specific aging-rates and their consequences. PMID- 19786045 TI - Weight management advice: what do doctors recommend to their patients? AB - OBJECTIVE: To examine the weight management interventions that a broad population of adults reported receiving from physicians and assess what drug-related and behavioral information physicians provided when they prescribe weight loss medications. METHODS: A random-digit dialed telephone survey was conducted in 2005-2006 with a representative sample of 3,500 American adults. RESULTS: The most frequently reported interventions were having a doctor tell them about the health problems associated with being overweight (48.0%), or suggesting diet and exercise (46.5%). Few respondents reported having been referred to a formal diet program (5.2%), prescribed a weight loss medication (4.0%), recommended a non prescription weight loss product (1.8%), or recommended stomach bypass surgery (1.5%). The proportion of individuals who reported each intervention increased across levels of body mass index (p<0.001). Of those who reported being prescribed a weight loss medication (n=155), only 29.5% (n=44) reported receiving all six counseling interventions that were assessed. CONCLUSIONS: Many overweight patients have not been advised to lose weight, diet, or exercise, and physicians have been particularly reluctant to recommend medications. When physicians do prescribe medications, appropriate counseling too often fails to accompany the prescription. Efforts are needed to increase the involvement of physicians in guiding patients to effective weight management approaches. PMID- 19786046 TI - Interaction of chaperone alpha-crystallin with unfolded state of alpha-amylase: Implications for reconstitution of the active enzyme. AB - Alpha-crystallin is reported to act like molecular chaperone by suppressing the aggregation of damaged crystallins in eye lens. In this work, it is shown that alpha-crystallin increases the reactivation of guanidine hydrochloride (GdnHCl) denatured alpha-amylase from porcine pancreas. 8-Anilinonaphthalene-sulphonate (ANS) binding studies reveal the involvement of hydrophobic interactions in the formation of the complex of alpha-crystallin and alpha-amylase. On the basis of our fluorescence spectroscopic and gel-filtration results, we propose that alpha crystallin blocks the unfavorable pathways that lead to irreversible denaturation of alpha-amylase and keep it in folding-competent intermediate state. PMID- 19786043 TI - Convergence of linkage, gene expression and association data demonstrates the influence of the RAR-related orphan receptor alpha (RORA) gene on neovascular AMD: a systems biology based approach. AB - To identify novel genes and pathways associated with AMD, we performed microarray gene expression and linkage analysis which implicated the candidate gene, retinoic acid receptor-related orphan receptor alpha (RORA, 15q). Subsequent genotyping of 159 RORA single nucleotide polymorphisms (SNPs) in a family-based cohort, followed by replication in an unrelated case-control cohort, demonstrated that SNPs and haplotypes located in intron 1 were significantly associated with neovascular AMD risk in both cohorts. This is the first report demonstrating a possible role for RORA, a receptor for cholesterol, in the pathophysiology of AMD. Moreover, we found a significant interaction between RORA and the ARMS2/HTRA1 locus suggesting a novel pathway underlying AMD pathophysiology. PMID- 19786047 TI - Zinc-, cobalt- and iron-chelated forms of adenylate kinase from the Gram-negative bacterium Desulfovibrio gigas. AB - Adenylate kinase (AK) from the sulphate-reducing bacterium Desulfovibrio gigas (AK) has been characterized earlier as a Co(2+)/Zn(2+)-containing enzyme, which is an unusual characteristic for adenylate kinases from Gram-negative bacteria, in which these enzymes are normally devoid of metal ions. AK was overexpressed in E. coli and homogeneous Co(2+)-, Zn(2+)- and Fe(2+)-forms of the enzyme were obtained under in vivo conditions. Their structural stability and spectroscopic and kinetic properties were compared. The thermal denaturation of Co(2+)- and Zn(2+)-forms of AK was studied as a cooperative two-state process, sufficiently reversible at pH 10, which can be correctly interpreted in terms of a simple two state thermodynamic model. In contrast, the thermally induced denaturation of Fe(2+)-AK is irreversible and strongly dependent upon the scan rate, suggesting that this process is under kinetic control. Practically identical contents of secondary-structure elements were found for all the metal-chelated-forms of AK upon analysis of circular dichroism data, while their tertiary structures were significantly different. The peculiar tertiary structure of Fe(2+)-AK, in contrast to Co(2+)- and Zn(2+)-AK, and the consequent changes in the physico chemical and enzymatic properties of the enzyme are discussed. PMID- 19786048 TI - The role and regulation of hypoxia-inducible factor-1alpha expression in brain development and neonatal hypoxic-ischemic brain injury. AB - During neonatal hypoxic-ischemic brain injury, activation of transcription of a series of genes is induced to stimulate erythropoiesis, anti-apoptosis, apoptosis, necrosis and angiogenesis. A key factor mediating these gene transcriptions is hypoxia-inducible factor-1alpha (HIF-1alpha). During hypoxia, HIF-1alpha protein is stabilized and heterodimerizes with HIF-1beta to form HIF 1, subsequently regulating the expression of target genes. HIF-1alpha participates in early brain development and proliferation of neuronal precursor cells. Under pathological conditions, HIF-1alpha is known to play an important role in neonatal hypoxic-ischemic brain injury: on the one hand, HIF-1alpha has neuroprotective effects whereas it can also have neurotoxic effects. HIF-1alpha regulates the transcription of erythropoietin (EPO), which induces several pathways associated with neuroprotection. HIF-1alpha also promotes the expression of vascular endothelial cell growth factor (VEGF), which is related to neovascularization in hypoxic-ischemic brain areas. In addition, HIF-1alpha has an anti-apoptotic effect by increasing the expression of anti-apoptotic factors such as EPO during mild hypoxia. The neurotoxic effects of HIF-1alpha are represented by its participation in the apoptotic process by increasing the stability of the tumor suppressor protein p53 during severe hypoxia. Moreover, HIF-1alpha plays a role in cell necrosis, by interacting with calcium and calpain. HIF-1alpha can also exacerbate brain edema via increasing the permeability of the blood-brain barrier (BBB). Given these properties, HIF-1alpha has both neuroprotective and neurotoxic effects after hypoxia-ischemia. These events are cell type specific and related to the severity of hypoxia. Unravelling of the complex functions of HIF-1alpha may be important when designing neuroprotective therapies for hypoxic-ischemic brain injury. PMID- 19786049 TI - A new approach to detection of the bregma point on the rat skull. AB - Stereotaxy is commonly used to implant microelectrodes or microprobes in specific structures of the brain in vivo. In this technique, the positions of the brain nuclei are determined as the distance from a defined reference point on the skull. Thus, it is crucial to correctly locate the reference point. On the rodent skull cap, the principal stereotaxic reference point is called the bregma and is defined as the midpoint of the curve of best fit along the coronal suture. Rough determination of the position of the bregma often results in error. In our experiments we developed and tested an alternative method of locating the bregma point on the skull of mature Wistar rats. In this method, a digital picture of the exposed skull cap is analyzed by a computer. The curve is mathematically fitted to the outline of the coronal suture, and the brain midline is delineated based on the temporal ridges of the skull. The crossing of these two lines is defined as the bregma. Systematic, experimental testing of this new method revealed that, in many cases, the position of the bregma point as located by two different methods (old, rough method and the new one) varied by as much as hundreds of microns. The error in stereotaxic positioning of the microprobe in the brain was significantly decreased when the bregma was determined using the new approach. These results confirm that the new method of locating the stereotaxic reference point improves the precision of in vivo electrode implantation. PMID- 19786050 TI - Morphological and biomolecular characterization of the neonatal olfactory bulb ensheathing cell line. AB - Cell transplantation therapy has raised a great interest in the perspective of its employment for nerve tissue repair. Among the various cell populations proposed, olfactory ensheathing glial cells have raised great interest over recent years, especially in the perspective of their employment for neural repair because of their homing capacity in both central and peripheral nervous system. This paper is aimed to provide an in vitro characterization of the NOBEC (neonatal olfactory bulb ensheathing cell) line that was obtained from primary cells dissociated from rat neonatal olfactory bulb (OB) and immortalized by retroviral transduction of SV40 large T antigen. Light and electron microscopy investigation showed that NOBECs are a homogeneous cell population both at structural and ultrastructural level. RT-PCR, Western blotting and immunocytochemistry showed that NOBECs express the glial markers S100, GFAP (Glial Fibrillar Acid Protein) and p75NGFR as well as NRG1 (neuregulin-1) and ErbB1-2-3 receptors; while they are negative for ErbB4. Yet, NOBECs exhibit a high proliferation and migration basal activity and can be transducted with vectors carrying GFP (green fluorescent protein) and NRG1 cDNA. Functional stimulation by means of NRG1-III-beta3 overexpression through viral transduction induced a significant increase in cell proliferation rate while it had no effect on cell migration. Altogether, these results show that NOBEC cell line retain glial features both morphologically and functionally, responding to the NRG1/ErbB mediated gliotrophic stimulus, and represents thus a good tool for in vitro assays of glial cell manipulation and for in vivo experimental studies of glial cell transplantation in the central and peripheral nervous system. PMID- 19786051 TI - Juvenile peer play experience and the development of the orbitofrontal and medial prefrontal cortices. AB - The experience of peer play during the juvenile phase in rats is known to be important for the development of adult social competence. Adult social competence is also compromised by damage to the orbitofrontal cortex (OFC), an area known to be involved in social behavior. We therefore hypothesized that the functioning of the OFC in social behavior is facilitated through the experience of peer play during the juvenile period. Further, because the OFC and medial prefrontal cortex (mPFC) are known to be reciprocally responsive to a variety of manipulations, we suspected that the functioning of the mPFC is also responsive to the experience of peer play during development. Female Long-Evans rats were raised in conditions that varied with respect to the experience of peer play, and Golgi techniques were used to examine the neuronal morphology of the OFC and mPFC. The results indicated that the neurons of the OFC responded to the number of peers present, not whether those peers engaged in play or not, whereas the neurons of the mPFC responded specifically to the experience of play. PMID- 19786052 TI - Dysregulation of hepatocyte cell cycle and cell viability by hepatitis B virus. AB - BACKGROUND/AIMS: Dysregulation of the cell cycle is frequently associated with tumor development. Hepatitis B virus (HBV) is associated with a significant risk of developing hepatocellular carcinoma but the effects of HBV on cell cycle regulation are not completely understood. METHODS: We have used a recombinant adeno-HBV model system to investigate the effect of infection with HBV and the replication defective lamivudine resistant mutant rtM204I mutant on hepatocyte cell cycle and cell viability. RESULTS: Huh7 cells synchronised at the G1/S phase of the cell cycle were arrested at the G2/M following infection with rAdHBV-wt and rAdHBV-M204I. This was accompanied by increased levels of p21(cip1), p-cdc2, cyclins D, A and B. Cell viability was reduced and cleaved caspase 3 levels were increased in HBV- and rtM204I-infected cells. rAdHBV-M204I-infected Huh7 cells also demonstrated significant up-regulation of phospho-ERK, phospho-Akt, p53 and phospho-Mdm2 compared to mock-infected cells. These changes were comparable to those following infection of Huh7 cells with rAdHBV-wt. CONCLUSION: Our results suggest that HBV, regardless of phenotype, produces cell cycle arrest and reduced hepatocyte viability. Perturbations in these cellular processes are likely to underlie HBV-associated liver oncogenic transformation and may help explain the ongoing risk of developing hepatocellular carcinoma in individuals in whom the lamivudine resistant rtM204I mutant emerges. PMID- 19786053 TI - Intense lorazepam-induced sexual arousal. PMID- 19786054 TI - Occurrence of aflatoxin M1 in raw milk of five dairy species in Ahvaz, Iran. AB - During November 2007 to December 2008, 311 samples of raw milk from cow, water buffalo, camel, sheep, and goat were collected in the Ahvaz (southwest Iran). All of the samples were analyzed for presence of aflatoxin M1 (AFM1) by competitive ELISA technique. AFM1 was found in 42.1% of the samples by average concentration of 43.3+/-43.8 ng/kg. The incidence rates of AFM1 in raw cow, water buffalo, camel, sheep, and goat milks were, 78.7%, 38.7%, 12.5%, 37.3%, and 27.1%, respectively. The concentration of AFM1 in all of the samples were lower than Iranian national standard and FDA limit (500 ng/l), but in 36% of raw cow milk, 8% water buffalo milk, 3.9% sheep milk, and 5.7% raw goat milk samples were higher than maximum tolerance limit accepted by European union/Codex Alimentarius Commission (50 ng/l). The results showed that the milk of camel, goat, and sheep is safe respect to AFM1 contamination in this area. PMID- 19786055 TI - Effect of methionine supplement on physical responses and neurological symptoms in broiler chicks fed grass pea (Lathyrus sativus)-based starter ration. AB - Starter feeding experiments of broiler chicks with raw grass pea (Lathyrus sativus L.) supplemented with different levels of DL-methionine were undertaken for 4 weeks to assess the toxicity of grass pea-based feed and to correlate it with neurological symptoms. Four hundred fifty day-old broiler chicks were divided into two groups and were given formulations containing 35% (ration I) or 98.5% (ration II) grass pea, respectively. Each ration included controls and treatments with added methionine of four different concentrations. Feed intake, weight gain and feed conversion efficiency (FCE) were much higher in ration I than in ration II and these parameters significantly improved by addition of methionine in both rations. Significant increase of neurological signs with higher grass pea intake and significant reduction of acute neurological signs with addition of methionine were observed. Tolerance for grass pea was enhanced with increasing methionine in the diet and with age. Despite a similarity in the initial intake, a significant (p0.05) increase in the final feed intake by the chicks with methionine addition was found in both rations. These results suggest that methionine can improve a grass pea-based diet for broiler chicks and especially can protect young chicks from neurological symptoms. PMID- 19786056 TI - Genotoxicity studies of organically grown broccoli (Brassica oleracea var. italica) and its interactions with urethane, methyl methanesulfonate and 4 nitroquinoline-1-oxide genotoxicity in the wing spot test of Drosophila melanogaster. AB - Broccoli (Brassica oleracea var. italica) has been defined as a cancer preventive food. Nevertheless, broccoli contains potentially genotoxic compounds as well. We performed the wing spot test of Drosophila melanogaster in treatments with organically grown broccoli (OGB) and co-treatments with the promutagen urethane (URE), the direct alkylating agent methyl methanesulfonate (MMS) and the carcinogen 4-nitroquinoline-1-oxide (4-NQO) in the standard (ST) and high bioactivation (HB) crosses with inducible and high levels of cytochrome P450s (CYPs), respectively. Larvae of both crosses were chronically fed with OGB or fresh market broccoli (FMB) as a non-organically grown control, added with solvents or mutagens solutions. In both crosses, the OGB added with Tween-ethanol yielded the expected reduction in the genotoxicity spontaneous rate. OGB co treatments did not affect the URE effect, MMS showed synergy and 4-NQO damage was modulated in both crosses. In contrast, FMB controls produced damage increase; co treatments modulated URE genotoxicity, diminished MMS damage, and did not change the 4-NQO damage. The high dietary consumption of both types of broccoli and its protective effects in D. melanogaster are discussed. PMID- 19786057 TI - Antioxidant and antimicrobial properties of Teucrium arduini L. (Lamiaceae) flower and leaf infusions (Teucrium arduini L. antioxidant capacity). AB - Antioxidant and antimicrobial activities, as well as total phenol (TP, Folin Ciocalteu method) and phenolic acid (UPLC-MS/MS) contents of leaf and flower infusions of Teucrium arduini L. from six different mountainous localities in Croatia (Ucka, Vosac, Sveti Jure, Snjeznica, Vaganac, Susanj) were analysed in this study. Antioxidant capacity was evaluated using the ferric reducing/antioxidant power (FRAP) assay, as well as 2,2-diphenyl-1-picrylhydrazyl (DPPH), and 2,2'-azinobis (3-ethylbenzthiazoline-6-sulphonic acid) (ABTS) radical scavenging assays. The antioxidant potency composite index (ACI), giving equal weight to all three methods used to quantify antioxidant capacity, was the highest for the sample from Vosac (96.7) among flower infusions, while maximum ACI (100) was determined for the infusion from Ucka among leaf infusions. Strong positive correlation was found between the total phenols and ACI for leaf (r=0.953) and flower (r=0.977) infusions. Our results point to significantly (p<0.05) different TP content between leaf and flower infusions, as well as across localities. Leaf infusions of T. arduini from Susanj exhibited marked antibacterial activity against Staphylococcus aureus, while none of the tested infusions exhibited antimicrobial activity against gram-negative bacterial species, or the tested fungal species. PMID- 19786058 TI - Risk assessment of PCDD/PCDFs and indicator PCBs contamination in Spanish commercial baby food. AB - Polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) as well as polychlorinated biphenyls (PCBs) are ubiquitous highly toxic environmental pollutants which exhibit a potential risk for human health. PCDD/Fs and PCBs contamination has been measured in samples of commercial baby food products: processed cereal and meat-and-fish-based baby food, which were made of individual samples collected from Spanish markets and pharmacies. They all presented a low dioxin content with a mean concentration ranging between 0.014 pg WHO-TEQ g(-1) product for fish-based baby food and 0.089 pg WHO PCDD/Fs-TEQ g(-1) product for processed cereal containing gluten. The mean concentration of the sum of the seven indicator PCBs was between 0.03 ng g(-1) product for fish-based baby food and 0.29 ng g(-1) product for gluten-free cereals. The estimated PCDD/Fs and indicator PCBs mean daily intake through the consumption of this kind of food has been calculated taking into account body weight and food consumption data for children aged 6-12 months. In order to assess the health risk derived from the exposure to these pollutants in children during the first year of life, data concerning infant formulae contamination has been also considered. PMID- 19786059 TI - Application of the margin of exposure (MOE) approach to substances in food that are genotoxic and carcinogenic. Example: leucomalachite green. AB - Leucomalachite green (LMG) is mutagenic and produces DNA-adducts in vivo, and is carcinogenic in rodent bioassays. Dose-response modelling of the data for hepatocellular adenomas and carcinomas in female mice gave a BMDL10 of 20 mg/kg bw/day. Limited data are available on the concentrations present in fish for human consumption. Human exposure estimates assumed that all consumed fish is contaminated with LMG. The calculated MoEs were 4,000,000 and 400,000 respectively for average and high exposure estimates. PMID- 19786060 TI - Application of the margin of exposure (MoE) approach to substances in food that are genotoxic and carcinogenic - example: 1-methylcyclopropene and its impurities (1-chloro-2-methylpropene and 3-chloro-2-methylpropene). AB - The chlorinated impurities of 1-methylcyclopropene possess weak mutagenicity and are carcinogenic in rodent bioassays. Dose-response modelling of the data for 1 chloro-2-methylpropene gave a BMDL10 for nasal carcinomas in male rats of 11 mg/kg-bw/day (after correction for the 5 days/week dosage schedule). No human exposure data are available and theoretical estimates had to be used to calculate the MoE. The MoEs ranged from 40,000 to 100,000,000 depending on the assumptions used in the exposure estimation. PMID- 19786061 TI - Interaction of nimesulide, a cyclooxygenase-2 inhibitor, with cisplatin in normotensive and spontaneously hypertensive rats. AB - We investigated the effect of administration of nimesulide, a selective cyclooxygenase-2 (COX-2) inhibitor, on cisplatin (CP)-induced nephrotoxicity in rats. WKY rats and SHRs were divided into four groups, each. The first and second groups received saline and oral nimesulide (20mg/kg/day for 6 days), respectively, whereas the third and fourth groups received a single intraperitoneal (i.p.) injection of CP (5mg/kg) and CP (5mg/kg) and nimesulide (20mg/kg/day for 5 days), respectively. At the end of the experiment, rats were anesthetized and blood pressure and renal blood flow (RBF) were monitored, followed by intravenous (i.v.) injection of norepinephrine (NE). Nephrotoxicity was evaluated histopathologically and biochemically. CP caused a reduction in baseline RBF in both WKY and SHRs. It increased the concentrations of urea and creatinine and kidney relative weight, and decreased body weight in both WKY and SHRs. Histopathologically, CP caused remarkable renal damage in both WKY rats and SHRs. Treatment with nimesulide alone did not produce any significant change in any of the above measurements. However, nimesulide aggravated CP-induced renal tissue damage in SHRs, but not in WKY rats. The results show that administration nimesulide augmented the histopathological indices of nephrotoxicity in SHRs, but not in WKY rats. PMID- 19786062 TI - Effect of beta-naphthoflavone on AhR-regulated genes (CYP1A1, 1A2, 1B1, 2S1, Nrf2, and GST) and antioxidant enzymes in various brain regions of pig. AB - The constitutive and inducible expression of aryl hydrocarbon receptor (AhR) and of the AhR-regulated genes coding for CYP1A1, CYP1A2, CYP1B1, CYP2S1, and Nrf2 was investigated by real-time or traditional PCR in cerebral areas (cortex, cerebellum, midbrain, and hippocampus), blood-brain interfaces (meninges and brain microvessels) and liver obtained from control pigs and from pigs treated with beta-naphthoflavone (betaNF), a potent AhR agonist. The enzymatic activities of ethoxyresorufin-O-deethylase (EROD), and methoxyresorufin-O-deethylase (MEROD), marker for CYP1A1 and CYP1A2, the GST and various antioxidant enzymes (catalase, superoxide dismutase, GSSG-reductase, and GSH-peroxidase) were also determined in the same CNS regions. The AhR, CYP1A1, CYP1A2, CYP1B1, Nrf2 mRNAs were detected, although at different extent, in all the CNS regions, while CYP2S1 mRNA was detected only in midbrain. In the blood-brain interfaces, the constitutive basal expression of AhR and CYP1A1 was comparable to the hepatic one and even higher for CYP1B1 and Nrf2. The treatment with betaNF determined the induction of CYP1A1 and 1B1 (but not of AhR, CYP1A2, and Nrf2) mRNA levels in various CNS areas; notably, CYP1A1 mRNA was increased to about 300-fold in the microvessels. The analysis of enzymatic activities revealed that EROD, but not MEROD, was induced in microsomes but not in mitochondria of all the CNS areas. However, the mitochondrial EROD activities were comparable (in midbrain, meninges) or higher (in cortex, cerebellum, hippocampus) than the microsomal ones, suggesting an important metabolic function of CYP1A1 in this subcellular localization. The activities of GST and antioxidant enzymes were detected in all CNS tissues, with levels lower than the hepatic ones, but found quite evenly distributed and marginally affected by betaNF treatment. The high expression of metabolic enzymes found in blood-brain interfaces could represent a very important defence toward toxins of CNS. PMID- 19786063 TI - L-DOPA-induced neurotoxicity is reduced by the activation of the PI3K signaling pathway. AB - L-3,4-Dihydroxyphenylalanine (L-DOPA) is one of the most important drugs for the treatment of Parkinson's disease (PD). Although neurotoxicity of L-DOPA remains controversial, there are many reports suggesting that L-DOPA causes neuronal death. We investigated whether the neurotoxic effect of L-DOPA could be inhibited by the activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Cell counting kit-8, trypan blue staining, and DAPI staining all showed that L-DOPA decreased nPC12 cell viability at high concentrations. However, combined treatment with the PI3K activator and L-DOPA significantly increased the viability of nPC12 cells when compared with treatment with L-DOPA only. Phosphorylated Akt (Ser473), phosphorylated glycogen synthase kinase-3beta (GSK 3beta) (Ser9), and heat shock transcription factor-1, which are survival-related signaling proteins, were decreased in nPC12 cells treated with 200 microM L-DOPA, but were significantly increased with combined treatment with the PI3K activator in a concentration-dependent manner. However, treatment of L-DOPA significantly increased expressions of cytosolic cytochrome c and cleaved caspase-3, which are death-related signaling proteins, in nPC12 cells, but combined treatment with the PI3K activator reduced those expressions. To confirm whether the effect of the PI3K activator is associated with direct activation of PI3K, LY294002, a PI3K inhibitor, was used to pretreat the nPC12 cells prior to combined treatment with the PI3K activator and L-DOPA. The protective effect of the PI3K activator was almost completely blocked. Together, these results suggest that L-DOPA neurotoxicity can be prevented by PI3K activation. PMID- 19786065 TI - Cyclic alternating pattern and sleep quality in healthy subjects--is there a first-night effect on different approaches of sleep quality? AB - OBJECTIVE: Cyclic alternating pattern (CAP) is defined as periodic EEG activity during NREM sleep that reflects unstable sleep and represents a marker of instability of the sleep process. The aim of the present investigation was to analyze sleep quality of 28 healthy subjects (mean age 53.3+/-21.3 years) over two consecutive nights and determine potential differences between them ("first night effect"). METHODS: Evaluations comprised objective and subjective sleep variables as well as macrostructural and microstructural variables of sleep. RESULTS: Macrostructural analysis showed significant differences between the first and the second sleep laboratory night in REM latency (122.39+/-60.46 min vs. 95.43+/-36.60 min; T=3.431; p=0.002) and the amount of sleep stage 1 (42.60+/ 21.80 min vs. 39.70+/-18.95 min; T=2.223; p=0.035). Microstructural analysis revealed a significant decrease in the CAP rate (1st night: 33.29%; 2nd night: 26.34%; T=3.288; p=0.003) and in the amount of subtype A2 (74.79+/-43.47 vs. 58.50+/-23.22; T=2.185; p=0.038). Subjective variables also demonstrated a significant increase of drive (T=2.564; p=0.016). CONCLUSION: Healthy subjects show hardly any macrostructural differences between the first and the second night in the sleep laboratory. On the microstructural level differences in CAP variables were found. SIGNIFICANCE: Microstructural analysis can be seen as a further approach to the classification of sleep and CAP turned out to be sensitive to environmental influences on sleep. PMID- 19786064 TI - Cultural context moderates the relationship between emotion control values and cardiovascular challenge versus threat responses. AB - Cultural context affects people's values regarding emotions, as well as their experiential and behavioral but not autonomic physiological responses to emotional situations. Little research, however, has examined how cultural context influences the relationships among values and emotional responding. Specifically, depending on their cultural context, individuals' values about emotion control (ECV; the extent to which they value emotion control) may have differing meanings, and as such, be associated with differing responses in emotional situations. We examined this possibility by testing the effect of two cultural contexts (28 female Asian-American (AA) versus 28 female European-American (EA) undergraduate students) on the associations between individuals' ECV and emotional responding (experiential, behavioral, and cardiovascular) to a relatively neutral film clip and a laboratory anger provocation. In the AA group, greater ECV were associated with reduced anger experience and behavior, and a challenge pattern of cardiovascular responding. In the EA group, greater ECV were associated with reduced anger behavior but not anger experience, and a threat pattern of cardiovascular responding. These results are consistent with the notion that individuals' values about emotion are associated with different meanings in different cultural contexts, and in turn, with different emotional and cardiovascular responses. PMID- 19786066 TI - Hematopoietic stem cell origin of human fibroblasts: cell culture studies of female recipients of gender-mismatched stem cell transplantation and patients with chronic myelogenous leukemia. AB - OBJECTIVE: Our series of studies using transplantation of single hematopoietic stem cells (HSCs) demonstrated that mouse fibroblasts/myofibroblasts are derived from HSCs. In order to determine the origin of human fibroblasts, we established a method for culturing fibroblasts from human peripheral blood (PB) mononuclear cells and studied fibroblasts from gender-mismatched HSC transplant recipients and patients with untreated Philadelphia chromosome-positive chronic myelogenous leukemia (CML). MATERIALS AND METHODS: We cultured PB cells from three female subjects who showed near-complete hematopoietic reconstitution from transplantation of granulocyte-colony stimulating factor-mobilized male PB cells and examined the resulting fibroblasts using fluorescent in situ hybridization for Y chromosome. Because the mobilized PB cells may contain mesenchymal stem cells, we could not determine the HSC or mesenchymal stem cell origin of the fibroblasts seen in culture. To further document the HSC origin of human fibroblasts, we next examined fibroblasts from two patients with untreated CML, a known clonal disorder of HSCs. RESULTS: All cultured fibroblasts from female recipients of male cells showed the presence of Y chromosome, indicating the donor origin of fibroblasts. Cultured fibroblasts from the CML patients revealed the presence of BCR-ABL translocation. This demonstration provided strong evidence for the HSC origin of human fibroblasts because CML is a clonal disorder of the HSC. CONCLUSIONS: These studies strongly suggest that human fibroblasts are derived from HSCs. In addition, the results suggest that fibrosis seen in patients with CML may be a part of the clonal process. PMID- 19786067 TI - Dasatinib inhibits the secretion of TNF-alpha following TLR stimulation in vitro and in vivo. AB - OBJECTIVE: Dasatinib (SPRYCEL, BMS-354825) is a small molecule Src/Abl tyrosine kinase inhibitor approved for the treatment of chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia. However, kinases inhibited by dasatinib are also involved in the induction and regulation of innate immunity. The purpose of this study was to evaluate the effect of dasatinib on cytokine secretion in response to toll-like receptor (TLR) stimulation. MATERIALS AND METHODS: Dasatinib-treated mice were administered intraperitoneally with lipopolysaccharide (LPS) and serum cytokine (tumor necrosis factor-alpha [TNF-alpha], interleukin [IL]-10, and IL-6) levels and neutrophil accumulation in the lungs were analyzed. Cytokine secretions (TNF alpha and IL-6) from TLR3-, TLR4-, and TLR9-stimulated RAW264.7, as well as TLR4- and TLR9-stimulated bone marrow-derived macrophages (BMDM) were also evaluated. RESULTS: Dasatinib-treated mice had reduced serum levels of TNF-alpha in response to LPS administration; however, other inflammatory hallmarks of systemic LPS administration, such as secretion of IL-6 and accumulation of neutrophils in the lung, were unaffected. In contrast to the reduced TNF-alpha levels, dasatinib treatment increased serum levels of IL-10 following LPS administration. The production of TNF-alpha was also impaired in vitro in response to TLR3, TLR4, and TLR9 stimulation of the mouse macrophage cell line RAW264.7, as well as TLR4 and TLR9 stimulation of BMDM; IL-6 production was also impaired in dasatinib-treated BMDM. CONCLUSIONS: These findings further support the ability of dasatinib to modulate the host immune response and highlights scope for off-target applications of dasatinib for the control of TNF-alpha-mediated inflammatory disorders. PMID- 19786068 TI - 17beta-estradiol inhibits oleic acid-induced rat VSMC proliferation and migration by restoring PGC-1alpha expression. AB - Estrogen shows a vasoprotective role through inhibiting the proliferation and migration of vascular smooth muscle cells (VSMCs). The mechanism underlying the effect of estrogen, however, is not completely understood. Here, we explored the role of peroxisome proliferator-activated receptor-gamma (PPARgamma) coactivator 1alpha (PGC-1alpha) in estrogen-mediated vasoprotection. Firstly, we showed that oleic acid (OA) decreased PGC-1alpha expression while stimulating VSMC proliferation and migration. In contrast, administration of VSMCs with 17beta estradiol (E(2), 1 or 10nM) significantly restored OA-decreased PGC-1alpha expression, treatment with 10nM E(2) almost completely abolished OA-induced VSMC proliferation and migration. Secondly, by using PGC-1alpha siRNA, the inhibitory effect of E(2) on VSMC growth is strongly reduced via suppressing PGC-1alpha expression, indicating that E(2) may exert its role through restoring PGC-1alpha. Finally, E(2) (10nM) treatment inhibits OA-induced extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation, however, suppression of PGC-1alpha expression abolishes this inhibitory effect of E(2). Our findings demonstrate for the first time that in OA-stimulated rat VSMCs, treatment with E(2) (1 or 10nM) diminishes VSMC proliferation and migration via restoring OA-decreased PGC-1alpha expression. This observation offers a novel molecular basis of the vasoprotective effect of estrogen. PMID- 19786069 TI - Steroid-binding proteins and free steroids in birds. AB - Within the comparative literature, corticosteroid-binding globulin (CBG) has recently emerged as a potential modulator of the glucocorticoids-driven stress response. Many avian field studies include the measurement of CBG with the goal of making behavioral and ecological inferences. However, the field of stress physiology is divided on how to interpret the biological importance of the different states of circulating hormones. Here we review evidence for the biological relevance of each fraction of glucocorticoid hormone; the CBG glucocorticoid complex (the bound fraction) and the remainder which is either unbound or loosely attached to albumin (the free fraction). We suggest that the biological importance of free vs. bound hormone depends on the location of interest (plasma or tissues), and the time frame of interest (current or future need). While a large body of evidence suggests that free hormones are the biologically active fraction, evidence also suggests that the bound fraction is a biologically relevant reservoir of glucocorticoids. We review two salient topics from the avian stress literature; stress-induced decreases in CBG capacity and glucocorticoid influences in life history strategies. These topics are discussed with an emphasis on free vs. bound hormone concentration and how that compares to current vs. future glucocorticoid needs. PMID- 19786070 TI - Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. AB - Sex hormone-binding globulin (SHBG) is the main transport binding protein for sex steroid hormones in plasma and regulates their accessibility to target cells. Plasma SHBG is secreted by the liver under the control of hormones and nutritional factors. In the human hepatoma cell line (HepG2), thyroid and estrogenic hormones, and a variety of drugs including the antioestrogen tamoxifen, the phytoestrogen, genistein and mitotane (Op'DDD) increase SHBG production and SHBG gene promoter activity. In contrast, monosaccharides (glucose or fructose) effectively decrease SHBG expression by inducing lipogenesis, which reduces hepatic HNF-4alpha levels, a transcription factor that play a critical role in controlling the SHBG promoter. Interestingly, diminishing hepatic lipogenesis and free fatty acid liver biosynthesis also appear to be associated with the positive effects of thyroid hormones and PPARgamma antagonists on SHBG expression. This mechanism provides a biological explanation for why SHBG is a sensitive biomarker of insulin resistance and the metabolic syndrome, and why low plasma SHBG levels are a risk factor for developing hyperglycemia and type 2 diabetes, especially in women. These important advances in our knowledge of the regulation of SHBG expression in the liver open new approaches for identifying and preventing metabolic disorder-associated diseases early in life. PMID- 19786071 TI - Localization of p27kip1 in the developing avian retina: sustained expression in the mature tissue. AB - p27kip1 is a cyclin/CDK inhibitor that is expressed in cells that exit cell cycle and turn post-mitotic. Here, we characterized the expression and localization of p27kip1 during the development of the chick embryo retina. Expression of p27kip1 in this tissue begins at embryonic day 5 (E5), increasing as development proceeds. In contrast to the expression in the developing rat retina that markedly decreases after postnatal day 6, expression of p27kip1 in the chick retina decreases only slightly ( approximately 30%) after E12. Thereafter, it remains highly expressed in the tissue. p27kip1 expression increases in an orderly succession. By E5, immunoreactivity was observed over beta-tubulin III (TUJ-1) positive cell bodies located in the prospective Ganglion Cell Layer. By E7, p27kip1 was also detected over elongated cell nuclei located in the inner and outer portions of the Neuroblastic Layer and over cell bodies in the middle of the Inner Plexiform Layer. By E12, besides labeled cell bodies, labeled processes from amacrine cells and from cells at the GCL in the IPL were identified. In retinas from post-hatched chicken, immunoreactivity was observed over cell bodies located at all nuclear layers. Several differentiated ChAT positive cholinergic cells were labeled for p27kip1. Our data suggest that, as in the retina of other species, p27kip1 is expressed in cells that are exiting cell cycle and differentiating in the early developing chick embryo retina. However, as opposed to rodents and amphibians, neuronal expression of p27kip1 is sustained in the adult chick retina, indicating that its expression is differently regulated during development in this specie. PMID- 19786072 TI - Matrix metalloproteinases-2 and -3 are reduced in cerebrospinal fluid with low beta-amyloid1-42 levels. AB - Matrix metalloproteinases (MMPs), a family of extracellular soluble or membrane bound endopeptidases, are implicated in many physiological and pathophysiological functions-based on their capability to cleave all protein components of the extracellular matrix. Recent studies have implicated several forms of MMPs in chronic neurodegenerative diseases like Alzheimer's disease (AD), vascular dementia (VD), and Parkinson's disease (PD). The aim of the present study was to analyse eight MMPs (MMP-1, -2, -3, -7, -8, -9, -10, -13) in the human cerebrospinal fluid (CSF) and to correlate with the well established biomarkers beta-amyloid(1-42) (Abeta), total-tau and phospho-tau-181. Our data show a significant decrease of MMP-2 and MMP-3 levels in the CSF in samples with significantly reduced Abeta levels. It is concluded that MMP-2 and MMP-3 are directly linked to Abeta in the brain and a dysfunction may influence the processing of Abeta. PMID- 19786073 TI - State-dependent decrease in levels of brain-derived neurotrophic factor in bipolar disorder: a meta-analytic study. AB - Evidence has suggested a role of brain-derived neurotrophic factor (BDNF) in the pathogenesis of bipolar disorder (BD). Recent studies have examined BDNF levels in BD patients, but showed inconsistent results. In current study, meta-analyses by random-effects model were performed to compare blood BDNF levels between BD patients and healthy controls, and examine patients based on different affective status (manic, depressed, or euthymic state). Fifteen studies from 10 citations were included into the analysis. Pooling of results from all studies indicated that, overall, patients with BD had a lower level of BDNF than healthy controls (p=1x10(-4)). But when separating these studies based on different affective status, it showed that the significance existed only when comparing patients in manic (p=0.0008) or depressed (p=0.02) state with controls, but not in euthymic state (p=0.25). In addition, BDNF level was significantly increased after pharmacological treatment of manic state (p=0.01). These findings indicate that BDNF levels are abnormally reduced in manic and depressed states of BD, and the reduced level in manic state increases after treatment. They suggest a role of blood BDNF level as a state-dependent biomarker of bipolar disorder. PMID- 19786075 TI - Mouse plasmacytoma-expressed transcript 1 knock out induced 5-HT disruption results in a lack of cognitive deficits and an anxiety phenotype complicated by hypoactivity and defensiveness. AB - Serotonin (5-HT) is involved in many developmental processes and influences behaviors including anxiety, aggression, and cognition. Disruption of the serotonergic system has been implicated in human disorders including autism, depression, schizophrenia, and ADHD. Although pharmacological, neurotoxin, and dietary manipulation of 5-HT and tryptophan hydroxylase has added to our understanding of the serotonergic system, the results are complicated by multiple factors. A newly identified ETS domain transcription factor, Pet-1, has direct control of major aspects of 5-HT neuronal development. Pet-1 is the only known factor that is restricted in the brain to 5-HT neurons during development and adulthood and exerts dominant control over 5-HT neuronal phenotype. Disruption of Pet-1 produces an approximately 80% loss of 5-HT neurons and content and results in increased aggression in male Pet-1(-/-) mice [Hendricks TJ, Fyodorov DV, Wegman LJ, Lelutiu NB, Pehek EA, Yamamoto B, Silver J, Weeber EJ, Sweatt JD, Deneris ES (2003) Neuron 37:233-247]. We hypothesized that Pet-1(-/-) mice would also exhibit changes in anxiety and cognition. Pet-1(-/-) mice were hypoactive which may have affected the observed lack of anxious behavior in the elevated zero maze and light-dark test. Pet-1(-/-) mice, however, were more defensive during marble burying and showed acoustic startle hyper-reactivity. No deficits in spatial, egocentric, or novel object recognition learning were found in Pet-1( /-) mice. These findings were unexpected given that 5-HT depleting drugs given to adult or developing animals result in learning deficits [Mazer C, Muneyyirci J, Taheny K, Raio N, Borella A, Whitaker-Azmitia P (1997) Brain Res 760:68-73; Morford LL, Inman-Wood SL, Gudelsky GA, Williams MT, Vorhees CV (2002) Eur J Neurosci 16:491-500; Vorhees CV, Schaefer TL, Williams MT (2007) Synapse 61:488 499]. Lack of differences may be the result of compensatory mechanisms in reaction to a constitutive knock out of Pet-1 or 5-HT may not be as important in learning and memory as previously suspected. PMID- 19786074 TI - Role of matrix vesicles in biomineralization. AB - BACKGROUND: Matrix vesicles have been implicated in the mineralization of calcified cartilage, bone and dentin for more than 40 years. During this period, their exact role, if any in the nucleation of hydroxyapatite mineral, and its subsequent association with the collagen fibrils in the organic matrix has been debated and remains controversial. SCOPE OF REVIEW: This review summarizes studies spanning the whole history of matrix vesicles, but emphasizes recent findings and several hypotheses which have been recently introduced to explain in greater detail how matrix vesicles function in biomineralization. MAJOR CONCLUSIONS: It is now generally accepted that matrix vesicles have some role(s) in mineralization; that they are the initial site of mineral formation; that MV bud from the plasma membrane of mineral forming cells, but that they take with them only a subset of the materials found in the parent membrane; that the three proteins, alkaline phosphatase, nucleotide pyrophosphatase phosphodiesterase and annexin V have important roles in the process and that matrix vesicles participate in regulating the concentration of PPi in the matrix. In contrast, many open questions remain to be answered. GENERAL SIGNIFICANCE: Understanding the role of matrix vesicles in biomineralization will increase our knowledge of this important process. PMID- 19786076 TI - Neuropeptides modulate compound postsynaptic potentials in basolateral amygdala. AB - Previous behavioral studies have shown that neuropeptides intrinsic to the amygdala formation can alter fear and anxiety states. We have previously shown that the anxiogenic neuropeptide cholecystokinin (CCK) increases inhibitory neurotransmission in basolateral amygdala. We have since observed that CCK induces synchronized rhythmic activity composed of compound postsynaptic potentials (cPSPs). We have now further characterized these cPSPs by inducing cPSPs routinely in 5 mM extracellular K(+). CCK facilitated cPSP occurrence in a dose dependent manner in brain slices from both young and mature rats. The cPSPs were attenuated by glutamate receptor antagonists (NBQX or DL-AP5) or low concentrations of GABA(A) receptor antagonists (bicuculline methiodide (BMI), SR95531, or picrotoxin), but not by the GABA(B) receptor antagonist, CGP52432. Low concentrations of tetrodotoxin (TTX, 10 nM) also attenuated the cPSPs. The Na K-2Cl cotransporter blocker, bumetanide (1 or 10 microM) also blocked the cPSPs. The anxiogenic neuropeptide corticotropin-releasing factor (CRF) facilitated cPSPs while anxiolytic neuropeptides (neuropeptide Y (NPY) and somatostatin) attenuated cPSPs. The benzodiazepine agonist diazepam dose-dependently modulated cPSPs. Mefloquine facilitated cPSPs within 10 min of application. We hypothesize that cPSPs are generated by positive feedback between a subset of interneurons and a subset of glutamatergic projection neurons. PMID- 19786078 TI - Enhanced synaptic responses in the piriform cortex associated with sexual stimulation in the male rat. AB - Male rats that copulate to ejaculation with female rats bearing an odor show a learned preference to ejaculate selectively with females that bear the odor. This conditioned ejaculatory preference reflects an association between the odor and the reward state induced by ejaculation. Although little is known about the neuronal mechanisms that mediate this form of learning, convergence of genitosensory and olfactory inputs occurs in both hypothalamic and cortical regions, notably within primary olfactory (piriform) cortex, which may be involved in the encoding or storage of the association. The present study contrasted the ability of genital investigations, mounts, intromissions, ejaculations, and a sexually conditioned olfactory stimulus, to enhance evoked synaptic field potentials in the piriform cortex. Rats in the Paired group underwent conditioning trials in which they copulated with sexually receptive females bearing an almond odor. Rats in the Unpaired control group copulated with receptive females bearing no odor. Responses in the piriform cortex evoked by electrical stimulation of the olfactory bulb were recorded in male rats as they engaged in different aspects of sexual behavior, and were also recorded after conditioning, during exposure to cotton swabs bearing the almond odor. The monosynaptic component of responses was increased during intromission and ejaculation, and the late component of responses was increased during anogenital sniffing and mounting (with or without intromission). However, no differences in the amplitudes of evoked responses were found between the Paired and Unpaired groups, and no differences in synaptic responses were found during presentation of the odor after conditioning. These data indicate that short-term alterations in synaptic responsiveness occur in piriform cortex as a function of sexual stimulation in the male rat, but that responses are not significantly altered by a conditioned odor. PMID- 19786077 TI - Chronic inflammation and estradiol interact through MAPK activation to affect TMJ nociceptive processing by trigeminal caudalis neurons. AB - The mitogen-activated protein kinase/extracellular regulated kinase (MAPK/ERK) pathway plays a key role in mediating estrogen actions in the brain and neuronal sensitization during inflammation. Estrogen status is a risk factor in chronic temporomandibular muscle/joint (TMJ) disorders; however, the basis for this relationship is not known. The present study tested the hypothesis that estrogen status acts through the MAPK/ERK signaling pathway to alter TMJ nociceptive processing. Single TMJ-responsive neurons were recorded in laminae I-II at the spinomedullary (Vc/C(1-2)) junction in naive ovariectomized (OvX) female rats treated for 2 days with high-dose (20 microg/day; HE2) or low-dose estradiol (2 microg/day; LE2) and after chronic inflammation of the TMJ region by complete Freund's adjuvant for 12-14 days. Intra-TMJ injection of ATP (1 mM) was used to activate Vc/C(1-2) neurons. The MAPK/ERK inhibitor (PD98059, 0.01-1 mM) was applied topically to the dorsal Vc/C(1-2) surface at the site of recording 10 min prior to each ATP stimulus. In naive HE2 rats, low-dose PD98059 caused a maximal inhibition of ATP-evoked activity, whereas even high doses had only minor effects on units in LE2 rats. By contrast, after chronic TMJ inflammation, PD98059 produced a marked and similar dose-related inhibition of ATP-evoked activity in HE2 and LE2 rats. These results suggested that E2 status and chronic inflammation acted, at least in part, through a common MAPK/ERK-dependent signaling pathway to enhance TMJ nociceptive processing by laminae I-II neurons at the spinomedullary junction region. PMID- 19786079 TI - Association of PDE4D and IL-1 gene polymorphism with ischemic stroke in a Han Chinese population. AB - BACKGROUND: The single-nucleotide polymorphisms (SNPs) of the phosphodiesterase 4D (PDE4D) and interleukin-1 (IL-1) genes are associated with increased risk for the development of ischemic stroke (IS) in whites. However, little is known about whether this association could also occur in Han Chinese. METHOD: A total of 371 patients with IS and unrelated healthy controls were recruited and the SNPs of the PDE4D (83T/C), (87T/C), IL-1 (-889C/T) and IL-1 (-511C/T) were characterized, respectively, by polymerase chain reactions-restriction fragment length polymorphism (PCR-RFLP). The genotype and allele frequencies of these SNPs in this population were statistically analyzed. RESULTS: The genotype and allele frequencies of the PDE4D (87T/C) and IL-1 (-511C/T) were similar between IS patients and controls. In contrast, the frequencies of CC genotype and C allele of the PDE4D (83T/C) and the T allele frequency of IL-1 (-889C/T) in IS patients were significantly higher than that in healthy controls (p=0.001, p=0.003 and p=0.02, respectively), independent of the conventional risk factors. The values of odds ratio (OR) reached at OR=1.603; 95%CI=1.032-2.489; p=0.036 for the CC genotype of the PDE4D (83T/C) and OR=1.913; 95%CI=1.621-2.375; p=0.034 for the TT genotype of the IL-1 (-889C/T), respectively. CONCLUSIONS: the SNPs of the PDE4D (83T/C) and IL-1 (-889C/T) were associated with increased risk for the development of IS in Northern Han Chinese. PMID- 19786081 TI - An improved kinetics approach to describe the physical stability of amorphous solid dispersions. AB - The recrystallization of amorphous solid dispersions may lead to a loss in the dissolution rate, and consequently reduce bioavailability. The purpose of this work is to understand factors governing the recrystallization of amorphous drug polymer solid dispersions, and develop a kinetics model capable of accurately predicting their physical stability. Recrystallization kinetics was measured using differential scanning calorimetry for initially amorphous efavirenz polyvinylpyrrolidone solid dispersions stored at controlled temperature and relative humidity. The experimental measurements were fitted by a new kinetic model to estimate the recrystallization rate constant and microscopic geometry of crystal growth. The new kinetics model was used to illustrate the governing factors of amorphous solid dispersions stability. Temperature was found to affect efavirenz recrystallization in an Arrhenius manner, while recrystallization rate constant was shown to increase linearly with relative humidity. Polymer content tremendously inhibited the recrystallization process by increasing the crystallization activation energy and decreasing the equilibrium crystallinity. The new kinetic model was validated by the good agreement between model fits and experiment measurements. A small increase in polyvinylpyrrolidone resulted in substantial stability enhancements of efavirenz amorphous solid dispersion. The new established kinetics model provided more accurate predictions than the Avrami equation. PMID- 19786080 TI - The histone demethylase Dmel?Kdm4A controls genes required for life span and male specific sex determination in Drosophila. AB - Histone methylation plays an important role in regulating chromatin-mediated gene control and epigenetic-based memory systems that direct cell fate. Enzymes termed histone demethylases directly remove the methyl marks from histones, thus contributing to a dynamically regulated histone methylated genome; however, the biological functions of these newly identified enzymes remain unclear. The JMJD2A D family belongs to the JmjC domain-containing family of histone demethylases (JHDMs). Here, we report the cloning and functional characterization of the Drosophila HDM gene Dmel?Kdm4A that is a homolog of the human JMJD2 family. We show that homologs for three human JHDM families, JHDM1, JHDM2, and JMJD2, are present in Drosophila and that each is expressed during the Drosophila lifecycle. Disruption of Dmel?Kdm4A results in a reduction of the male life span and a male specific wing extension/twitching phenotype that occurs in response to other males and is reminiscent of an inter-male courtship phenotype involving the courtship song. Remarkably, certain genes associated with each of these phenotypes are significantly downregulated in response to Dmel?Kdm4A loss, most notably the longevity associated Hsp22 gene and the male sex-determination fruitless gene. Our results have implications for the role of the epigenetic regulator Dmel?Kdm4A in the control of genes involved in life span and male specific sex determination in the fly. PMID- 19786082 TI - An evolutionary perspective on middle ears. AB - The traditional view that a tympanic middle ear developed only once, when vertebrates made the transition from fish in water to land-living animals, has been shown to be incorrect. Middle ears with a tympanum connected by one or more ossicles to the cochlea developed very much later in evolutionary history and independently in many amniote vertebrate lineages - most now extinct. The mammalian middle ear is unique but it is not simply an "improved" single-ossicle middle ear. It is a radical and fortuitous new development that owes its origin more to changes in feeding patterns than to hearing. It happened to transmit higher-frequency sounds better than single-ossicle middle ears and enabled the evolution of the high upper-frequency hearing limits of most mammals. Parallel to the development of a tympanic middle ear in therian mammals, the brain increased in size and a secondary palate developed, resulting in the ancestral pressure gradient middle ear being replaced by a purely pressure system. Sound localization then became almost completely dependent on neural computation and this was the most important factor driving up the upper frequency limits of early mammals. This paper presents an historical perspective on these remarkably simple and yet highly effective structures. PMID- 19786083 TI - Measures of hearing threshold and temporal processing across the adult lifespan. AB - Psychophysical data on hearing sensitivity and various measures of supra threshold auditory temporal processing are presented for large groups of young (18-35 y), middle-aged (40-55 y) and older (60-89 y) adults. Hearing thresholds were measured at 500, 1414 and 4000 Hz. Measures of temporal processing included gap-detection thresholds for bands of noise centered at 1000 and 3500 Hz, stimulus onset asynchronies for monaural and dichotic temporal-order identification for brief vowels, and stimulus onset/offset asynchronies for the monaural temporal masking of vowel identification. For all temporal-processing measures, the impact of high-frequency hearing loss in older adults was minimized by a combination of low-pass filtering the stimuli and use of high presentation levels. The performance of the older adults was worse than that of the young adults on all measures except gap-detection threshold at 1000 Hz. Middle-aged adults performed significantly worse than the young adults on measures of threshold sensitivity and three of the four measures of temporal-order identification, but not for any of the measures of temporal masking. Individual differences are also examined among a group of 124 older adults. Cognition and age were found to be significant predictors, although only 10-27% of the variance could be accounted for by these predictors. PMID- 19786084 TI - Anti-inflammatory and anti-asthmatic effects of Viola mandshurica W. Becker (VM) ethanolic (EtOH) extract on airway inflammation in a mouse model of allergic asthma. AB - AIM OF THE STUDY: We investigated the efficacy of Viola mandshurica W. Becker (VM) ethanolic (EtOH) extract in the treatment of bronchial asthma in an ovalbumin (OVA)-induced asthmatic BALB/c mouse model. MATERIALS AND METHODS: Female BALB/c mice were sensitized with intraperitoneal (i.p.) ovalbumin (OVA) on days 0 and 14, and were next given intranasal OVA on days 28-30. Randomized treatment groups of sensitized mice received VM EtOH extract, dexamethasone, or placebo, orally, from days 28 to 30. RESULTS: VM EtOH extract significantly inhibited increases in total immunoglobulin E (IgE) and cytokines IL-4 and IL-13 levels in serum and bronchoalveolar lavage fluid (BALF), and also effectively suppressed airway hyperresponsiveness (AHR), eosinophilia, and mucus hypersecretion, in mice with OVA-induced asthma. CONCLUSIONS: The results suggest that VM EtOH extract and allied extracts could be useful herbal medicines for asthma treatment, and that VM may also be a valuable lead material for anti asthma drug development. PMID- 19786085 TI - Association of biofilm formation and methicillin-resistance with accessory gene regulator (agr) loci in Greek Staphylococcus aureus clones. AB - Pathogenicity of Staphylococcus aureus is coordinated by the accessory gene regulator (agr) system. Previous studies suggested that agr Group II methicillin resistant S. aureus (MRSA), a polymorphism that has been associated with moderate response to vancomycin, may also be related with overproduction of biofilm. In a hospital environment with endemic occurrence of MRSA, the distribution of agr groups and their association with biofilm formation was investigated. Forty-two MRSA and 32 methicillin-susceptible S. aureus (MSSA) isolates were tested and had derived from 10 genotypes and 8 clonal complexes. agr Groups I, II and IV were evenly distributed among MRSAs and MSSAs but agr Group III was not detected. agr Group II MRSAs showed significantly higher levels of biofilm production in comparison with MRSAs of the remaining agr groups as well as with all three agr groups of MSSAs. These findings suggest that agr Group II is simultaneously associated with methicillin-resistance and biofilm overproduction in a region with endemic MRSA. PMID- 19786086 TI - Prediction of phospholipidosis-inducing potential of drugs by in vitro biochemical and physicochemical assays followed by multivariate analysis. AB - An in vitro method to predict phospholipidosis-inducing potential of cationic amphiphilic drugs (CADs) was developed using biochemical and physicochemical assays. The following parameters were applied to principal component analysis, as well as physicochemical parameters: pK(a) and clogP; dissociation constant of CADs from phospholipid, inhibition of enzymatic phospholipid degradation, and metabolic stability of CADs. In the score plot, phospholipidosis-inducing drugs (amiodarone, propranolol, imipramine, chloroquine) were plotted locally forming the subspace for positive CADs; while non-inducing drugs (chlorpromazine, chloramphenicol, disopyramide, lidocaine) were placed scattering out of the subspace, allowing a clear discrimination between both classes of CADs. CADs that often produce false results by conventional physicochemical or cell-based assay methods were accurately determined by our method. Basic and lipophilic disopyramide could be accurately predicted as a nonphospholipidogenic drug. Moreover, chlorpromazine, which is often falsely predicted as a phospholipidosis inducing drug by in vitro methods, could be accurately determined. Because this method uses the pharmacokinetic parameters pK(a), clogP, and metabolic stability, which are usually obtained in the early stages of drug development, the method newly requires only the two parameters, binding to phospholipid, and inhibition of lipid degradation enzyme. Therefore, this method provides a cost-effective approach to predict phospholipidosis-inducing potential of a drug. PMID- 19786087 TI - Induction of apoptosis by esculetin in human leukemia U937 cells: roles of Bcl-2 and extracellular-regulated kinase signaling. AB - In the present study, we reported that apoptosis induced by esculetin, a phenolic compound with apoptotic activity in cancer cells, was markedly blocked by Bcl-2 overexpression, but restored by HA14-1, a small-molecule Bcl-2 inhibitor, in human leukemic U937 cells. The combined use of esculetin and HA14-1 effectively induced Bid cleavage and loss of mitochondrial membrane potential (MMP, Deltapsi(m)) leading to the activation of caspases and cleavage of poly(ADP ribose) polymerase (PARP) in Bcl-2-overexpressing (U937/Bcl-2) cells. Combined treatment with esculetin and HA14-1 upregulated the expression of death receptor 4 (DR4), and activation of extracellular-regulated kinase (ERK) in a time dependent manner. In addition, esculetin and HA14-1-mediated apoptosis was reduced by ERK inhibitors through inhibition of DR4 expression, suggesting that the synergistic effect was at least partially mediated through ERK-dependent induction of DR4 expression. The results indicate that HA14-1-induced reversal of the anti-apoptotic effect of Bcl-2 confers apoptosis sensitivity to esculetin by a mitochondrial amplification step and through the ERK-dependent induction of DR4 expression in U937/Bcl-2 cells. Thus, HA14-1 reversal of Bcl-2-mediated esculetin resistance suggests a novel strategy for increasing esculetin sensitivity in Bcl 2-overexpressing leukemia cells. PMID- 19786088 TI - Hyperoxia augments ER-stress-induced cell death independent of BiP loss. AB - Cytotoxic reactive oxygen species are constantly formed as a by-product of aerobic respiration and are thought to contribute to aging and disease. Cells respond to oxidative stress by activating various pathways, whose balance is important for adaptation or induction of cell death. Our lab recently reported that BiP (GRP78), a proposed negative regulator of the unfolded protein response (UPR), declines during hyperoxia, a model of chronic oxidative stress. Here, we investigate whether exposure to hyperoxia, and consequent loss of BiP, activates the UPR or sensitizes cells to ER stress. Evidence is provided that hyperoxia does not activate the three ER stress receptors IRE1, PERK, and ATF6. Although hyperoxia alone did not activate the UPR, it sensitized cells to tunicamycin induced cell death. Conversely, overexpression of BiP did not block hyperoxia induced ROS production or increased sensitivity to tunicamycin. These findings demonstrate that hyperoxia and loss of BiP alone are insufficient to activate the UPR. However, hyperoxia can sensitize cells to toxicity from unfolded proteins, implying that chronic ROS, such as that seen throughout aging, could augment the UPR and, moreover, suggesting that the therapeutic use of hyperoxia may be detrimental for lung diseases associated with ER stress. PMID- 19786089 TI - Fibroblasts from long-lived mutant mice show diminished ERK1/2 phosphorylation but exaggerated induction of immediate early genes. AB - Skin-derived fibroblasts from long-lived mutant mice, including the Snell dwarf mice and mice defective in growth hormone receptor (GHRKO mice), are resistant to death induced by oxidative stress or by UV light, but the molecular mechanism for their stress resistance is unknown. This study shows that phosphorylation of the stress-activated protein kinases ERK1/2 induced by peroxide, cadmium, or paraquat is attenuated in cells from these mice. Induction of ERK phosphorylation by UV light was not altered in the Snell dwarf cells, and neither JNK nor p38 kinase showed increased phosphorylation in response to any of the stresses tested. Surprisingly, stress-induced elevation of mRNA for certain immediate early genes (Egr-1 and Fos) was higher in Snell-derived cells than in control cells, despite the evidence of lower ERK phosphorylation. Thus cells from Snell dwarf mice differ from controls in two ways: (a) lower induction of ERK1/2 phosphorylation and (b) increased expression of some ERK-dependent immediate early genes. These alterations in kinase pathways may contribute to the resistance of these cells to lethal injury. PMID- 19786090 TI - Downregulation of stathmin expression is mediated directly by Egr1 and associated with p53 activity in lung cancer cell line A549. AB - Stathmin is overexpressed in a variety of assessed human malignancies and is correlated with tumor progression and poor prognosis. Downregulation of its expression will contribute to optimize therapeutic outcomes in the treatment of various malignancies. However, the mechanisms of stathmin gene overexpression are not completely elucidated at present. Early growth response 1 (Egr1) is a transcription factor that triggers transcription of downstream genes mediating cell growth and angiogenesis upon various stimulations. Following the previous computational identification of a site that was thought to be an Egr1 consensus binding sequence at -85 to -94 region in stathmin gene promoter, we analyzed the role of Egr1 in the regulation of stathmin gene expression in lung cancer cell line A549. The results showed that Egr1 transcription factor bound to the sequence 5'-GCGGGGGCG-3' within human stathmin gene promoter; and in reporter gene assays and overexpression experiments, both stathmin gene promoter activity and stathmin gene expression level were downregulated following endogenous or exogenous expression of Egr1. Using wild type Egr1 and knockout Egr1 cell lines, we demonstrated that p53 negatively regulates stathmin expression through Egr1 pathway. In summary, Egr1 is a novel regulator of stathmin expression and p53 mediates the transcriptional repression of stathmin by Egr1 in human lung cancer cells. PMID- 19786092 TI - ARAP3 binding to phosphatidylinositol-(3,4,5)-trisphosphate depends on N-terminal tandem PH domains and adjacent sequences. AB - Pleckstrin homology (PH) domains are modules characterised by a conserved three dimensional protein fold. Several PH domains bind phosphoinositides with high affinity and specificity whilst most others do not. ARAP3 is a dual GTPase activating protein for Arf6 and RhoA which was identified in a screen for phosphatidylinositol-(3,4,5)-trisphophate (PtdIns(3,4,5)P(3)) binding proteins. It is a regulator of cell shape and adhesion, and is itself regulated by PtdIns(3,4,5)P(3,) which acts to recruit ARAP3 to the plasma membrane and to catalytically activate it. We show here that ARAP3 binds to PtdIns(3,4,5)P(3) in an unusual, PH domain-dependent manner. None of the five PH domains are sufficient to bind PtdIns(3,4,5)P(3) in isolation. Instead, the minimal PtdIns(3,4,5)P(3) binding fragment comprises ARAP3's N-terminal tandem PH domains, and an N-terminal linker region. For substantial binding, the N-terminal sterile alpha motif (SAM) domain is also required. Site-directed mutagenesis of either of the two N-terminal PH domains within the fragment greatly reduces binding to PtdIns(3,4,5)P(3), however, in the context of the full-length protein, point mutations in the second PH domain have a lesser effect on binding, whilst deletion of any one of the five PH domains abolishes PtdIns(3,4,5)P(3) binding. We propose a mechanism by which basic residues from the N-terminal tandem PH domains, and from elsewhere in the protein synergise to mediate strong, specific PtdIns(3,4,5)P(3) binding. PMID- 19786093 TI - Role of the extracellular amino terminus and first membrane-spanning helix of dopamine D1 and D5 receptors in shaping ligand selectivity and efficacy. AB - Transmembrane (TM) helices of human D1-like dopaminergic receptors (hD1R and hD5R) harbor the same residues implicated in ligand binding and activation of catecholamine G protein-coupled receptors (GPCRs). Yet, hD1R and hD5R naturally display the distinct functional properties shared by wild type and constitutively active mutant GPCRs, respectively. Interestingly, we show in the present study that a class of synthetic phenylbenzazepine agonists containing a methyl on the azepine ring exhibited lower affinity for the more constitutively activated hD5R. These results cannot be explained by the "allosteric ternary complex model" postulating a higher agonist affinity for constitutively active GPCRs. We have also explored the functional role of distinct extracellular amino terminus (NT) and TM1 regions of hD1R and hD5R using a chimerical approach. Of these two regions, our studies suggest that TM1 predominantly shapes D1-like ligand affinity and selectivity. Additionally, NT and TM1 of hD1R and hD5R play no role in receptor constitutive activity but differentially modulate dopamine-mediated responsiveness. The TM1 exchange mediated drastic changes in intrinsic efficacy and activity of phenylbenzazepine drugs displaying partial agonism at hD1R and hD5R. Phenylbenzazepines were converted into strong partial agonists or full agonists in cells expressing hD1R-TM1(D5) chimera while being switched from full agonists to partial agonists and partial agonists to antagonists in cells harboring hD5R-TM1(D1) chimera. TM1 exchange had no effect on antipsychotic mediated inverse agonism. In summary, our study shows that NT and TM1 of D1-like receptors control ligand binding and agonist-induced activation, poising these regions as important structural determinants for catecholamine GPCR function. PMID- 19786091 TI - Prenylation-deficient G protein gamma subunits disrupt GPCR signaling in the zebrafish. AB - Prenylation of G protein gamma (gamma) subunits is necessary for the membrane localization of heterotrimeric G proteins and for functional heterotrimeric G protein coupled receptor (GPCR) signaling. To evaluate GPCR signaling pathways during development, we injected zebrafish embryos with mRNAs encoding Ggamma subunits mutated so that they can no longer be prenylated. Low-level expression of these prenylation-deficient Ggamma subunits driven either ubiquitously or specifically in the primordial germ cells (PGCs) disrupts GPCR signaling and manifests as a PGC migration defect. This disruption results in a reduction of calcium accumulation in the protrusions of migrating PGCs and a failure of PGCs to directionally migrate. When co-expressed with a prenylation-deficient Ggamma, 8 of the 17 wildtype Ggamma isoforms individually confer the ability to restore calcium accumulation and directional migration. These results suggest that while the Ggamma subunits possess the ability to interact with G Beta (beta) proteins, only a subset of wildtype Ggamma proteins are stable within PGCs and can interact with key signaling components necessary for PGC migration. This in vivo study highlights the functional redundancy of these signaling components and demonstrates that prenylation-deficient Ggamma subunits are an effective tool to investigate the roles of GPCR signaling events during vertebrate development. PMID- 19786094 TI - IKKalpha negatively regulates IRF-5 function in a MyD88-TRAF6 pathway. AB - Transcription factors of IRF family, IRF-3, IRF-5 and IRF-7 play a critical role in the innate antiviral response. In infected cells, IRF-3 and IRF-7 are activated by TBK-1 and IKK epsilon mediated phosphorylation, while the kinase, phosphorylating IRF-5 in the MyD88 signalling pathway has not yet been identified. We now show that IKK alpha phosphorylates IRF-5 and induces formation of IRF-5 dimers, which have been indicative of IRF-5 activation. However, IKK alpha induced IRF-5 phosphorylation exerts inhibitory effect on the transcriptional activation of type 1 interferon and promoters of the inflammatory cytokines. Addressing the molecular mechanism of IKK alpha mediated inhibition of IRF-5 activity, we show that phosphorylation of IRF-5 by IKK alpha inhibits K63 ubiquitination that is essential for IRF-5 activity. Furthermore, we have identified interaction of IRF-5 with alkaline phosphatase, which causes its de phosphorylation. The observation that MyD88 activated IRF-5 induces expression of alkaline phosphatase suggests that IRF-5 is under autoregulating loop. Thus these completely new observations identify IKK alpha kinase and alkaline phosphatase as negative regulators of IRF-5 activity in MyD88 pathway and implicate their role in the control of the inflammatory response by attenuation of IRF-5 activity. PMID- 19786095 TI - Exploring the acidotolerance of beta-galactosidase from Lactobacillus delbrueckii subsp. bulgaricus: an attractive enzyme for lactose bioconversion. AB - The LacZ gene encoding beta-galactosidase from Lactobacillus delbrueckii subsp. bulgaricus ATCC 11842 (L. bulgaricus) was cloned, sequenced and expressed in Escherichia coli, followed by purification and characterization of the protein. The recombinant enzyme was shown to be a homotetramer and could be distinguished from homologues by its relatively low and broad optimal temperature range, from 35 to 50 degrees C, coupled with an optimal pH of 5.0-5.5. Remarkably, the E491A mutant showed the same optimal temperature, but displayed an optimal pH at 6.5 7.0. Whilst these beta-galactosidases are inhibited by Cu(2+) they require only 1mM Mn(2+) and 1mM Co(2+) for optimal activity and thermostability. The wild-type enzyme was remarkably stable at acid pH values when compared to mutant E491A. Kinetic studies demonstrated that the E491A mutation affected catalysis rather than enzyme affinity. Furthermore, the wild-type protein efficiently cleaved lactose extracted from whey; however, in milk the E491A mutant showed the highest lactose bioconversion rate. Thus, these enzymes are interesting at the industrial level for hydrolysis of lactose extracted from whey or milk, and thus could contribute to overcoming the lactose intolerance problem generated by milk products. PMID- 19786096 TI - Proteomic analysis of Marinobacter hydrocarbonoclasticus SP17 biofilm formation at the alkane-water interface reveals novel proteins and cellular processes involved in hexadecane assimilation. AB - Many hydrocarbon-degrading bacteria form biofilms at the hydrocarbon-water interface to overcome the weak accessibility of these poorly water-soluble substrates. In order to gain insight into the cellular functions involved, we undertook a proteomic analysis of Marinobacter hydrocarbonoclasticus SP17 biofilm developing at the hexadecane-water interface. Biofilm formation on hexadecane led to a global change in cell physiology involving modulation of the expression of 576 out of 1144 detected proteins when compared with planktonic cells growing on acetate. Biofilm cells overproduced a protein encoded by MARHY0478 that contains a conserved domain belonging to the family of the outer membrane transporters of hydrophobic compounds. Homologs of MARHY0478 were exclusively found in marine bacteria degrading alkanes or possessing alkane degradation genes, and hence presumably constitute a family of alkane transporters specific to marine bacteria. Interestingly, we also found that sessile cells growing on hexadecane overexpressed type VI secretion system components. This secretion system has been identified as a key factor in virulence and in symbiotic interaction with host organisms. This observation is the first experimental evidence of the contribution of a type VI secretion system to environmental adaptation, and raises the intriguing question about the role of this secretion machine in alkane assimilation. PMID- 19786097 TI - Triosephosphate isomerase deficiency: new insights into an enigmatic disease. AB - The triosephosphate isomerase (TPI) functions at a metabolic cross-road ensuring the rapid equilibration of the triosephosphates produced by aldolase in glycolysis, which is interconnected to lipid metabolism, to glycerol-3-phosphate shuttle and to the pentose phosphate pathway. The enzyme is a stable homodimer, which is catalytically active only in its dimeric form. TPI deficiency is an autosomal recessive multisystem genetic disease coupled with hemolytic anemia and neurological disorder frequently leading to death in early childhood. Various genetic mutations of this enzyme have been identified; the mutations result in decrease in the catalytic activity and/or the dissociation of the dimers into inactive monomers. The impairment of TPI activity apparently does not affect the energy metabolism at system level; however, it results in accumulation of dihydroxyacetone phosphate followed by its chemical conversion into the toxic methylglyoxal, leading to the formation of advanced glycation end products. By now, the research on this disease seems to enter a progressive stage by adapting new model systems such as Drosophila, yeast strains and TPI-deficient mouse, which have complemented the results obtained by prediction and experiments with recombinant proteins or erythrocytes, and added novel data concerning the complexity of the intracellular behavior of mutant TPIs. This paper reviews the recent studies on the structural and catalytic changes caused by mutation and/or nitrotyrosination of the isomerase leading to the formation of an aggregation prone protein, a characteristic of conformational disorders. PMID- 19786098 TI - Reversible and irreversible modifications of skeletal muscle proteins in a rat model of acute oxidative stress. AB - Oxidative stress caused by an imbalance of the production of "reactive oxygen species" (ROS) and cellular scavenging systems is known to a play a key role in the development of various diseases and aging processes. Such elevated ROS levels can damage all components of cells, including proteins, lipids and DNA. Here, we study the influence of highly reactive ROS species on skeletal muscle proteins in a rat model of acute oxidative stress caused by X-ray irradiation at different time points. Protein preparations depleted for functional actin by polymerization were separated by gel electrophoresis in two dimensions by applying first non reductive and then reductive conditions in SDS-PAGE. This diagonal redox SDS-PAGE revealed significant alterations to intra- and inter-molecular disulfide bridges for several proteins, but especially actin, creatine kinase and different isoforms of the myosin light chain. Though the levels of these reversible modifications were increased by oxidative stress, all proteins followed different kinetics. Moreover, a significant degree of protein was irreversibly oxidized (carbonylated), as revealed by western blot analyses performed at different time points. PMID- 19786099 TI - Dynamics of target-mediated drug disposition. AB - We present a mathematical analysis of the basic model underlying target-mediated drug disposition (TMDD) in which a ligand is supplied through an initial bolus or through a constant rate infusion and forms a complex with a receptor (target), which is supplied and removed continuously. Ligand and complex may be eliminated according to first-order processes. We assume that the total receptor pool (free and bound) is constant in time and we give a geometrical description of the evolution of the concentrations of ligand, receptor and receptor-ligand complex which offers a transparent way to compare the full model with simpler models such as the quasi-steady-state (QSS) model, the quasi-equilibrium (QE) model and the empirical Michaelis-Menten (MM) model; we also give precise conditions on the parameters in the TMDD model for the validity of these reduced models. We relate characteristic properties of time courses to parameter regimes and, in particular, we identify and explain non-monotone dependence of the time-to-steady state on the infusion rate. Finally, we discuss how the volume of the central compartment may be overestimated because of singular initial behaviour of the time course of the ligand concentration. PMID- 19786100 TI - A peptidomics study reveals the impressive antimicrobial peptide arsenal of the wax moth Galleria mellonella. AB - The complete antimicrobial peptide repertoire of Galleria mellonella was investigated for the first time by LC/MS. Combining data from separate trypsin, Glu-C and Asp-N digests of immune hemolymph allowed detection of 18 known or putative G. mellonella antimicrobial peptides or proteins, namely lysozyme, moricin-like peptides (5), cecropins (2), gloverin, Gm proline-rich peptide 1, Gm proline-rich peptide 2, Gm anionic peptide 1 (P1-like), Gm anionic peptide 2, galiomicin, gallerimycin, inducible serine protease inhibitor 2, 6tox and heliocin-like peptide. Six of these were previously known only as nucleotide sequences, so this study provides the first evidence for expression of these genes. LC/MS data also provided insight into the expression and processing of the antimicrobial Gm proline-rich peptide 1. The gene for this peptide was isolated and shown to be unique to moths and to have an unusually long precursor region (495 bp). The precursor region contained other proline-rich peptides and LC/MS data suggested that these were being specifically processed and were present in hemolymph at very high levels. This study shows that G. mellonella can concurrently release an impressive array of at least 18 known or putative antimicrobial peptides from 10 families to defend itself against invading microbes. PMID- 19786101 TI - Aphidius ervi teratocytes release an extracellular enolase. AB - We report the cloning of a gene and the characterization of the encoded protein, which is released by the teratocytes of the parasitoid Aphidius ervi in the haemocoel of the host aphid Acyrthosiphon pisum. The studied protein was identified by LC-MS/MS, and the gathered information used for isolating the full length cDNA. The corresponding gene was made of 3 exons and 2 introns, and was highly expressed in the adult wasps and in parasitized hosts. The translation product, which was named Ae-ENO, showed a very high level of sequence identity with insect enolases. In vivo immunodetection experiments evidenced Ae-ENO localization in round spots, present in the teratocytes and released in the host haemocoel. Moreover, strong immunoreactivity was detected on the surface of A. ervi larvae and of host embryos. Ae-ENO expressed in insect cells was not secreted in the medium, indicating the occurrence in the teratocytes of an unknown pathway for Ae-ENO release. The recombinant protein produced in bacteria under native conditions was a dimer, with evident enolase activity (K(m) = 0.086 +/- 0.017 mM). Enolase is a well known enzyme in cell metabolism, which, however, is associated with a multifunctional role in disease, when present in the extracellular environment, on the surface of prokaryotic and eukaryotic cells. In these cases, the enolase mediates the activation of enzymes involved in the invasion of tissues by pathogens and tumour cells, and in the evasion of host immune response. The possible role played by Ae-ENO in the host regulation process is discussed in the light of this information. PMID- 19786102 TI - The brain-specific Neural Zinc Finger transcription factor 2b (NZF-2b/7ZFMyt1) causes suppression of cocaine-induced locomotor activity. AB - Chronic cocaine induces high expression of the brain-specific Neural-Zinc-Finger transcription factor-2b (NZF-2b/7ZFMyt1), particularly in the mesolimbic dopaminergic pathway, resulting in a 11-fold increase in NZF-2b/7ZFMyt1 expression in the Nucleus Accumbens (NAc). Overexpression of this gene in the NAc with a NZF-2b/7ZFMyt1-expressing lentivirus resulted in >55% decrease in locomotor activity upon chronic cocaine administration, compared to control animals. In contrast knocking-down the gene in the NAc with lentiviruses expressing shRNAs against NZF-2b/7ZFMyt1 induced strong hyperlocomotor activity upon cocaine. Strong inhibition of BDNF is observed upon NZF-2b/7ZFMyt1 expression, concomitant with strong induction of transcription factors REST1 (RE silencing transcription factor-1) and NAC1, probably leading to regulation of gene expression by interaction with histone deacetylases. These changes lead to decreased responsiveness of the animal to the locomotor-activating effects of cocaine, indicating that NZF-2b/7ZFMyt1 expression plays an important role in phenotypic changes induced by the drug. PMID- 19786103 TI - A meta-analysis of instructed fear studies: implications for conscious appraisal of threat. AB - In classical Pavlovian fear conditioning, a neutral stimulus (conditioned stimulus, CS) comes to be evaluated as threatening due to its association with an aversive stimulus (unconditioned stimulus, UCS), and elicits fear. In a subtype of fear conditioning paradigms, called instructed fear or anticipatory anxiety, subjects are made aware of the CS-UCS association prior to actually experiencing it. Initial fear elicitation during this type of conditioning results from the negative evaluation of the CS as a consequence of CS-UCS contingency awareness. Prior reports have suggested that this conscious appraisal process is mediated by a variety of brain regions, including rostral dorsomedial prefrontal/dorsal anterior cingulate cortex (dmPFC/dACC), lateral prefrontal cortex (lPFC), posterior cingulate, hippocampus/parahippocampus, and nucleus accumbens, but there is little overlap between results. We reasoned that a formal meta-analysis of existing instructed fear studies should help narrow down the search for conscious appraisal areas in fear conditioning to those consistently activated across studies. We found consistent activation in rostral dmPFC but not in the other candidate areas. These results allow for maintaining the theory that the rostral dmPFC is involved in conscious threat appraisal. We also report a meta analysis of uninstructed (classical) fear conditioning studies in which we found notable activation in more posterior parts of the dmPFC/dACC that overlapped with some of the instructed fear activations. These data suggest that mid regions of the dmPFC/dACC are part of a "core" fear network that is activated irrespective of how fear was learnt. PMID- 19786104 TI - In vivo quantification of hippocampal subfields using 4.7 T fast spin echo imaging. AB - Several neuropsychiatric disorders involving hippocampal structural changes have been studied extensively using volumetric magnetic resonance imaging (MRI). These studies have mostly measured total hippocampal volume while the present study aimed to delineate and measure hippocampal subfields within the whole hippocampus and subdivisions along its longitudinal axis. Images were acquired at 4.7 T in 11 healthy subjects (5 males and 6 females, aged 23-56 years), using a fast spin echo (FSE) sequence with 0.52 x 0.68 x 1.0 mm(3) native resolution, collecting 90 contiguous coronal slices. Subiculum, cornu ammonis (CA1-3), and dentate gyrus were traced manually within the hippocampal head, body, and tail. We reported volumes for the subfields and demonstrated differences in the distribution within the hippocampus and its parts. The biggest part of the dentate gyrus was located in the hippocampal body, following the hippocampal head and tail. In contrast, the hippocampal head had the largest part of CA1-3, following the hippocampal body and tail. The hippocampal tail had the smallest portion of the subiculum compared to hippocampal head and tail. Subfield volumes were consistent between hemispheres and showed distributions within the longitudinal subdivisions that were consistent with histological data. Direct measurements of subfield distribution along the longitudinal axis of the hippocampus may be more sensitive to detecting disease effects than total volume measures and the differential distribution of subfield volumes may aid in the interpretation of measurements obtained at lower field strength and spatial resolution. PMID- 19786106 TI - The identification of interacting networks in the brain using fMRI: Model selection, causality and deconvolution. AB - Functional magnetic resonance imaging (fMRI) is increasingly used to study functional connectivity in large-scale brain networks that support cognitive and perceptual processes. We face serious conceptual, statistical and data analysis challenges when addressing the combinatorial explosion of possible interactions within high-dimensional fMRI data. Moreover, we need to know, and account for, the physiological mechanisms underlying our signals. We argue here that (i) model selection procedures for connectivity should include consideration of more than just a few brain structures, (ii) temporal precedence - and causality concepts based on it - are essential in dynamic models of connectivity and (iii) undoing the effect of hemodynamics on fMRI data (by deconvolution) can be an important tool. However, it is crucially dependent upon assumptions that need to be verified. PMID- 19786105 TI - Genetic and environmental influences on the size of specific brain regions in midlife: the VETSA MRI study. AB - The impact of genetic and environmental factors on human brain structure is of great importance for understanding normative cognitive and brain aging as well as neuropsychiatric disorders. However, most studies of genetic and environmental influences on human brain structure have either focused on global measures or have had samples that were too small for reliable estimates. Using the classical twin design, we assessed genetic, shared environmental, and individual-specific environmental influences on individual differences in the size of 96 brain regions of interest (ROIs). Participants were 474 middle-aged male twins (202 pairs; 70 unpaired) in the Vietnam Era Twin Study of Aging (VETSA). They were 51 59 years old, and were similar to U.S. men in their age range in terms of sociodemographic and health characteristics. We measured thickness of cortical ROIs and volume of other ROIs. On average, genetic influences accounted for approximately 70% of the variance in the volume of global, subcortical, and ventricular ROIs and approximately 45% of the variance in the thickness of cortical ROIs. There was greater variability in the heritability of cortical ROIs (0.00-0.75) as compared with subcortical and ventricular ROIs (0.48-0.85). The results did not indicate lateralized heritability differences or greater genetic influences on the size of regions underlying higher cognitive functions. The findings provide key information for imaging genetic studies and other studies of brain phenotypes and endophenotypes. Longitudinal analysis will be needed to determine whether the degree of genetic and environmental influences changes for different ROIs from midlife to later life. PMID- 19786107 TI - Does the hippocampus mediate objective binding or subjective remembering? AB - Human functional magnetic resonance imaging (fMRI) evidence suggests the hippocampus is associated with context memory to a greater degree than item memory (where only context memory requires item-in-context binding). A separate line of fMRI research suggests the hippocampus is associated with "remember" responses to a greater degree than "know" or familiarity based responses (where only remembering reflects the subjective experience of specific detail). Previous studies, however, have confounded context memory with remembering and item memory with knowing. The present fMRI study independently tested the binding hypothesis and remembering hypothesis of hippocampal function by evaluating activity within hippocampal regions-of-interest (ROIs). At encoding, participants were presented with colored and gray abstract shapes and instructed to remember each shape and whether it was colored or gray. At retrieval, old and new shapes were presented in gray and participants classified each shape as "old and previously colored", "old and previously gray", or "new", followed by a "remember" or "know" response. In 3 of 11 hippocampal ROIs, activity was significantly greater for context memory than item memory, the context memory-item memory by remember-know interaction was significant, and activity was significantly greater for context memory-knowing than item memory-remembering. This pattern of activity only supports the binding hypothesis. The analogous pattern of activity that would have supported the remembering hypothesis was never observed in the hippocampus. However, a targeted analysis revealed remembering specific activity in the left inferior parietal cortex. The present results suggest parietal cortex may be associated with subjective remembering while the hippocampus mediates binding. PMID- 19786108 TI - Nearly complete rRNA genes assembled from across the metazoan animals: effects of more taxa, a structure-based alignment, and paired-sites evolutionary models on phylogeny reconstruction. AB - This study (1) uses nearly complete rRNA-gene sequences from across Metazoa (197 taxa) to reconstruct animal phylogeny; (2) presents a highly annotated, manual alignment of these sequences with special reference to rRNA features including paired sites (http://purl.oclc.org/NET/rRNA/Metazoan_alignment) and (3) tests, after eliminating as few disruptive, rogue sequences as possible, if a likelihood framework can recover the main metazoan clades. We found that systematic elimination of approximately 6% of the sequences, including the divergent or unstably placed sequences of cephalopods, arrowworm, symphylan and pauropod myriapods, and of myzostomid and nemertodermatid worms, led to a tree that supported Ecdysozoa, Lophotrochozoa, Protostomia, and Bilateria. Deuterostomia, however, was never recovered, because the rRNA of urochordates goes (nonsignificantly) near the base of the Bilateria. Counterintuitively, when we modeled the evolution of the paired sites, phylogenetic resolution was not increased over traditional tree-building models that assume all sites in rRNA evolve independently. The rRNA genes of non-bilaterians contain a higher % AT than do those of most bilaterians. The rRNA genes of Acoela and Myzostomida were found to be secondarily shortened, AT-enriched, and highly modified, throwing some doubt on the location of these worms at the base of Bilateria in the rRNA tree--especially myzostomids, which other evidence suggests are annelids instead. Other findings are marsupial-with-placental mammals, arrowworms in Ecdysozoa (well supported here but contradicted by morphology), and Placozoa as sister to Cnidaria. Finally, despite the difficulties, the rRNA-gene trees are in strong concordance with trees derived from multiple protein-coding genes in supporting the new animal phylogeny. PMID- 19786109 TI - Evolutionary placement of Xanthomonadales based on conserved protein signature sequences. AB - Xanthomonadales comprises one of the largest phytopathogenic bacterial groups, and is currently classified within the gamma-proteobacteria. However, the phylogenetic placement of this group is not clearly resolved, and the results of different studies contradict one another. In this work, the evolutionary position of Xanthomonadales was determined by analyzing the presence of shared insertions and deletions (INDELs) in highly conserved proteins. Several distinctive insertions found in most of the members of the gamma-proteobacteria are absent in Xanthomonadales and groups such as Legionelalles, Chromatiales, Methylococcales, Thiotrichales and Cardiobacteriales. These INDELs were most likely introduced after the branching of Xanthomonadales from most of the gamma-proteobacteria and provide evidence for the phylogenetic placement of the early gamma proteobacteria. Moreover, other proteins contain insertions exclusive to the Xanthomonadales order, confirming that this is a monophyletic group and provide important specific genetic markers. Thus, the data presented clearly support the Xanthomonadales group as an independent subdivision, and constitute one of the deepest branching lineage within the gamma-proteobacteria clade. PMID- 19786110 TI - Testing the monophyly of Calocidae (Insecta: Trichoptera) based on multiple molecular data. AB - Calocidae constitute a hypothesised monophyletic group of caddisflies (Trichoptera) being geographically restricted to New Zealand (one genus) and Australia (five genera). This analysis tests the monophyly of the family based on sequences from five different molecular genes. The complete data set includes 29 species and covers a complete genus representation of the Calocidae as well as representatives of other families in which one or more calocid genera have been classified. Sequences from two mitochondrial (cytochrome oxidase I and 16S) and three nuclear (elongation factor 1-alpha, RNA polymerase-II, and Cadherin) genes were used, resulting in a 3958bp data set and 37.1% parsimony informative characters. The Cadherin (CAD) and RNA polymerase-II (POL-II) genes are used for the first time for revealing Trichoptera phylogenies. The character matrix was analyzed by using maximum parsimony (MP) and Bayesian criteria, the latter by applying three different partition strategies for comparison. Two most parsimonious trees were found, differing in the position of one clade within the sister-group to a monophyletic Calocidae. The Bayesian tree based on the maximum number of partitions differs from trees based on a reduced partition analysis with respect to taxa outside the current circumscription of Calocidae. Both the MP and Bayesian analyses left Calocidae monophyletic, with a monophyletic clade of all Australian genera being sister-group to the New Zealand genus. The results from the agreement subtree analysis demonstrates that CAD performs well both separately and in combination with other genes and adds substantial resolution to the calocid phylogeny in a combined MP analysis. PMID- 19786111 TI - Improved outcomes using tacrolimus/sirolimus for graft-versus-host disease prophylaxis with a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplant as treatment of myelofibrosis. AB - Allogeneic hematopoietic cell transplantation (HCT) using reduced-intensity conditioning (RIC) regimens is a potentially curative treatment for patients (patients) with myelofibrosis (MF), as we and others have reported. Nonrelapse mortality (NRM) from graft-versus-host disease (GVHD) and other complications has limited the success of this approach. As part of an ongoing prospective research study at City of Hope, a combination of tacrolimus/sirolimus +/- methotrexate (MTX) for GVHD prophylaxis has become the standard treatment for our allogeneic HCT patients. In this report, we present results for 23 consecutive patients, including extended follow up for 9 patients previously reported who received cyclosporine (CsA)/mycophenolate moffetil (MMF)+/-MTX, and the current series of 14 patients who received tacrolimus/sirolimus+/-MTX, and evaluate the impact of the GVHD prophylaxis regimen on the outcomes. Median follow-up for alive patients was 29.0 months (9.5-97.0). The estimated 2-year overall survival (OS) for the CsA/MMF cohort was 55.6% (confidence interval 36.0, 71.3), and for the tacrolimus/sirolimus cohort it was 92.9% (63.3, 98.8) (P=.047). The probability of grade III or IV acute GVHD (aGVHD) was 60% for the CsA/MMF patients, and 10% for the tacrolimus/sirolimus group (P=.0102). No significant differences were seen for grade II to IV aGVHD in the 2 groups. We conclude that the combination of tacrolimus/sirolimus+/-MTX for GVHD prophylaxis in the setting of RIC HCT for MF appears to reduce the incidence of severe aGVHD and NRM, and leads to improved OS compared to CSA/MMF+/-MTX. PMID- 19786112 TI - Impact of cytomegalovirus (CMV) reactivation after umbilical cord blood transplantation. AB - This study investigated the impact of pretransplant cytomegalovirus (CMV) serostatus and posttransplant CMV reactivation and disease on umbilical cord blood transplant (UCBT) outcomes. Between 1994 and 2007, 332 patients with hematologic malignancies underwent UCBT and 54% were CMV seropositive. Pretransplant recipient CMV serostatus had no impact on acute or chronic graft versus-host disease (aGVHD, cGVHD), relapse, disease-free survival (DFS), or overall survival (OS). There was a trend toward greater day 100 treatment-related mortality (TRM) in CMV-seropositive recipients (P=.07). CMV reactivation occurred in 51% (92/180) of patients with no difference in myeloablative (MA) versus reduced-intensity conditioning (RIC) recipients (P=.33). Similarly, reactivation was not influenced by the number of UCB units transplanted, the degree of HLA disparity, the CD34(+) or CD3(+) cell dose, or donor killer cell immunoglobulin like receptor (KIR) gene haplotype. Rapid lymphocyte recovery was associated with CMV reactivation (P=.02). CMV reactivation was not associated with aGVHD (P=.97) or cGVHD (P=.65), nor did it impact TRM (P=.88), relapse (P=.62), or survival (P=.78). CMV disease occurred in 13.8% of the CMV-seropositive patients, resulting in higher TRM (P=.01) and lower OS (P=.02). Thus, although recipient CMV serostatus and CMV reactivation have little demonstrable impact on UCB transplant outcomes, the development of CMV disease remains a risk, associated with inferior outcomes. PMID- 19786113 TI - Apocynin decreases hydrogen peroxide and nitrate concentrations in exhaled breath in healthy subjects. AB - The imbalance between reactive oxygen species (ROS) synthesis and antioxidants might be involved in the pathogenesis of many inflammatory diseases. NADPH oxidase, an enzyme responsible for ROS production, may represent an attractive therapeutic target to inhibit, for the treatment of these diseases. Apocynin is an inhibitor of activation of NADPH oxidase complex present in the inflammatory cells. In double blind, placebo-controlled, cross-over study, we investigated the effect of nebulized apocynin on ROS synthesis in 10 nonsmoking healthy volunteers. Apocynin (6ml of 0.5mg/ml) was administered by nebulization and its effects on H(2)O(2), NO(2)(-) and NO(3)(-) generation were assessed after 30, 60 and 120min by collecting exhaled breath condensate (EBC) samples using an EcoScreen analyzer. Additionally, respiratory parameters have been evaluated, utilizing spirometry and DLCO. We also analyzed peripheral blood differential counts and NO(2)(-) serum level, cough scale control and blood pressure as safety parameters. Apocynin caused reduction of H(2)O(2) concentration in EBC as compared to placebo, after 60min. of inhalation (0.18microM vs. 0.31microM, p<0.05) as well as after 120min. (0.2microM vs. 0.31microM, p<0.05). Similarly, apocynin significantly decreased concentration of NO(3)(-) as compared to placebo, after 60 and 120min. (6.8microM vs. 14.4microM and 6.5microM vs. 14.9microM respectively, p<0.05). Apocynin was well tolerated and no adverse events have been observed throughout the study. Thus, as apocynin significantly influence ROS concentration, it might have also antiinflammatory properties. As it is safe, it may have a potential to become a drug in airway inflammatory diseases treatment. PMID- 19786114 TI - IGF-I mediated inhibition of leptin receptor expression in porcine hepatocytes. AB - A study was conducted to elucidate hormonal control of leptin receptor gene expression in primary cultures of porcine hepatocytes. Hepatocytes were isolated from swine and seeded into T-25 flasks. Cultures were established in medium containing fetal bovine serum for one day and switched to serum-free medium (William's E medium and 1 ng/mL insulin) for the remainder of the 3d culture period. For the final 24 h, medium was supplemented with porcine growth hormone (GH, 100 or 500 ng/mL), insulin-like growth factor 1 (IGF-1, 50 to 250 ng/mL) or triiodothyronine (T3, 100 ng/mL). RNA was extracted and relative quantitative RT PCR was performed with primers for long form leptin receptor. Receptor expression was calculated relative to 18S rRNA. Insulin had no effect (P>0.05), while T3 increased leptin receptor mRNA abundance (P<0.05). Treatment with GH or IGF-I reduced leptin receptor expression (P<0.05). Phosphorylation of ERK1/2 in response to acute leptin treatment was inhibited by previous exposure to GH or IGF-I. Hepatocytes secreted IGF-I under basal conditions and this was enhanced by GH addition. These data suggest porcine hepatocytes may be less sensitive to leptin stimulation due to the actions of endogenous IGF-I on leptin receptor expression. PMID- 19786116 TI - Highly permissive infection of microglial cells by Japanese encephalitis virus: a possible role as a viral reservoir. AB - Japanese encephalitis virus (JEV), a mosquito-borne Flavivirus, is a major cause of acute encephalitis, and neurons have been proposed to be the principle JEV target cells in the central nervous system. However, clinically, infection with JEV leads to increased levels of cytokines and chemokines in the serum and cerebrospinal fluid (CSF) the levels of which correlate with the mortality rate of patients. This research aimed to study the role of microglial cells in JEV infection. Mouse microglial cells (BV-2) supported the replication of JEV with extracellular production of virus by 10h post-infection, and virus titer reached a maximum (2.55x10(10)pfu/ml) by day 3 post-infection. While apoptosis was induced in response to virus infection, no alteration in nitric oxide production was observed. Microglial cells remained productively infected with JEV for up to 16 weeks without significant morphological alterations, and the released virions were infectious to mouse neuroblastoma (NA) cells. The high virus production and long persistence of JEV in microglial cells suggests that these cells may serve as viral reservoirs for the infection of neurons in the CNS. PMID- 19786115 TI - Sorting of Leishmania-bearing dendritic cells reveals subtle parasite-induced modulation of host-cell gene expression. AB - Once in the mouse skin, Leishmania (L) amazonensis amastigotes are hosted by professional mononuclear phagocytes such as dendritic cells (DCs). When monitored after parasite inoculation, the frequency of amastigote-hosting DCs is very low (<1%) in both the skin and skin-draining lymph nodes. Therefore, we designed and validated an efficient procedure to purify live amastigotes-hosting DCs with the objective to facilitate quantitative and qualitative analysis of such rare cells. To this end, a L. amazonensis transgenic parasite expressing DsRed2 fluorescent protein was generated and added to mouse bone marrow-derived DC cultures. Then, a high speed sorting procedure, performed in BSL-2 containment, was setup to pick out only DCs hosting live amastigotes. This study reveals, for the first time, a unique transcript pattern from sorted live amastigotes-hosting DCs that would have been undetectable in unsorted samples. It was indeed possible to highlight a significant and coordinated up-regulation of L-arginine transporter and arginase2 transcripts in Leishmania-hosting DCs compared to un-parasitized DCs. These results indicate that arginine catabolism for polyamine generation is dominating over L-arginine catabolism for NO generation. In conclusion, this approach provides a powerful method for further characterisation, of amastigote-hosting DCs in the skin and the skin-draining lymph nodes. PMID- 19786117 TI - Gamma-radiation induces micronucleated reticulocytes in 3D bone marrow bioreactors in vitro. AB - Radiation injury to the bone marrow is potentially lethal due to the potent DNA damaging effects on cells of the hematopoietic system, including bone marrow stem cell, progenitor, and the precursor cell populations. Investigation of radiation genotoxic effects on bone marrow progenitor/precursor cells has been challenged by the lack of optimal in vitro surrogate organ culture systems, and the overall difficulty to sustain lineage-specific proliferation and differentiation of hematopoiesis in vitro. We report the investigation of radiation genotoxic effects in bone marrow cultures of C57Bl/6 mice established in 3D bioreactors, which sustain long-term bone marrow cultures. For these studies, genotoxicity is measured by the induction of micronucleated reticulocytes (MN-RETs). The kinetics and dose-response relationship of MN-RET induction in response to gamma-radiation of bioreactor-maintained bone marrow cultures are presented. Our data showed that 3D long-term bone marrow cultures had sustained erythropoiesis capable of generating reticulocytes up to 8 weeks. The peak time-interval of viable cell output and percentage of reticulocytes increased steadily and reached the initial peak between the 14th and 21st days after inoculations. This was followed by a rebound or staying relatively constant until week 8. The percentage of MN-RET reached the maximum between 24 h and 32 h post 1 Gy gamma-ray. There was a near linear MN-RET induction by gamma-radiation from 0 Gy to 1.0 Gy, followed by an attenuated increase to 1.5-2.0 Gy. The MN-RET response showed a downtrend beyond 2 Gy. Our data suggest that bone marrow culture in the 3D bioreactor may be a useful organ culture system for the investigation of radiation genotoxic effect in vitro. PMID- 19786118 TI - The association between glutathione S-transferase gene polymorphisms and pancreatic cancer in a central European Slavonic population. AB - In the first case-control study on pancreatic cancer conducted on 253 cases and 403 controls in the Czech Republic we observed that the GSTP1-codon 105 Val variant allele and the GSTT1-null genotype were associated with an elevated risk for pancreatic cancer (OR = 1.38; 95%CI = 0.96-1.97 and OR = 1.56; 95%CI = 0.93 2.61, respectively). Combination of GSTT1-null and GSTP1-codon 105 Val variants further increased the risk for pancreatic cancer (OR = 2.50; 95%CI = 1.20-5.20). In conclusion, this study suggests population-specific associations of polymorphisms in key biotransformation genes with elevated risk for pancreatic cancer. PMID- 19786119 TI - Omega-3 fatty acids are oxygenated at the n-7 carbon by the lipoxygenase domain of a fusion protein in the cyanobacterium Acaryochloris marina. AB - Lipoxygenases (LOX) are found in most organisms that contain polyunsaturated fatty acids, usually existing as individual genes although occasionally encoded as a fusion protein with a catalase-related hemoprotein. Such a fusion protein occurs in the cyanobacterium Acaryochloris marina and herein we report the novel catalytic activity of its LOX domain. The full-length protein and the C-terminal LOX domain were expressed in Escherichia coli, and the catalytic activities characterized by UV, HPLC, GC-MS, and CD. All omega-3 polyunsaturates were oxygenated by the LOX domain at the n-7 position and with R stereospecificity: alpha-linolenic and the most abundant fatty acid in A. marina, stearidonic acid (C18.4omega3), are converted to the corresponding 12R-hydroperoxides, eicosapentaenoic acid to its 14R-hydroperoxide, and docosahexaenoic acid to its 16R-hydroperoxide. Omega-6 polyunsaturates were oxygenated at the n-10 position, forming 9R-hydroperoxy-octadecadienoic acid from linoleic acid and 11R hydroperoxy-eicosatetraenoic acid from arachidonic acid. The metabolic transformation of stearidonic acid by the full-length fusion protein entails its 12R oxygenation with subsequent conversion by the catalase-related domain to a novel allene epoxide, a likely precursor of cyclopentenone fatty acids or other signaling molecules (Gao et al, J. Biol. Chem. 284:22087-98, 2009). Although omega-3 fatty acids and lipoxygenases are of widespread occurrence, this appears to be the first description of a LOX-catalyzed oxygenation that specifically utilizes the terminal pentadiene of omega-3 fatty acids. PMID- 19786120 TI - Interaction between bone morphogenetic proteins and endothelin-1 in human pulmonary artery smooth muscle. AB - Genetic mutations in bone morphogenetic protein receptor 2 (BMPR2) have been shown to occur in patients with familial and idiopathic pulmonary arterial hypertension (PAH). However the interactions between ligands for this receptor and other mediators implicated in heritable PAH have not been investigated. This study examines the regulation of endothelin-1 (ET-1), a potent vasoconstrictor and comitogen that is implicated in the pathogenesis of heritable PAH, by ligands for the BMPR2. Immunohistochemical studies showed that pulmonary artery segments removed from normotensive human lungs express BMPR2 and bone morphogenetic proteins 2, 4 and 7 (BMP2, BMP4 and BMP7). In the presence of BMP7 and BMP4 there was a significant inhibition of ET-1 release, induced by cytokines, from cultured pulmonary artery smooth muscle cells. Fresh ring segments of pulmonary artery were assessed for their response to ET-1 in the presence and absence of BMP2, BMP4 and BMP7. BMP7 inhibited contraction in response to ET-1 in a concentration dependent manner. BMP2 and BMP4 had no significant effect on the response to ET 1. These results suggest that BMP7 has the ability to regulate the effects of endothelin-1 in the pulmonary circulation. Genetic mutations in BMPR2 may lead to a loss of these regulatory mechanisms and contribute to the pathogenesis of pulmonary hypertension. PMID- 19786121 TI - Identification of a large hybrid zone between sympatric sibling species of Triatoma dimidiata in the Yucatan peninsula, Mexico, and its epidemiological importance. AB - Triatoma dimidiata is one of the major Chagas disease vectors, with an extensive diversity in its morphology, habitat, and level of domiciliation. Molecular studies based on the internal transcribed spacer 2 (ITS-2) have subdivided this species into four potential taxonomic groups. Using both ITS-2 and cytochrome B markers, we confirmed the sibling species status of ITS-2 Group 3 and detected an apparent sympatry of ITS-2 Groups 2 and 3 in the Yucatan peninsula, Mexico. Here we examine the geographic distribution of T. dimidiata ITS-2 genotypes in the region and compare their egg production and Trypanosoma cruzi infection rates, as indicators of biological differences between groups. PCR genotyping of large natural populations showed an extensive sympatry of Groups 2 and 3 in most of the peninsula, often within the same house. We also detected a large proportion of individuals displaying ITS-2 sequences from both Groups 2 and 3, suggesting hybridization. Analysis of ITS-2 genotype frequencies indicated a strong departure from Hardy-Weinberg equilibrium in female hybrids, but not in males, due to a large heterozygote deficit. These results suggest random mating between ITS-2 Groups 2 and 3 combined with reduced viability and/or survival in female hybrids. This and other factors may allow for the maintenance of distinct ITS-2 Groups 2 and 3 populations despite high hybrid frequencies. Importantly, T. cruzi infection was much higher in hybrids compared to ITS-2 Groups 2 and 3 individuals, but all three genotypes appeared to seasonally infest houses in a similar manner in the region. These findings warrant further studies on T. dimidiata taxonomy and its epidemiologic implications. PMID- 19786122 TI - Molecular characterization of INH-resistant Mycobacterium tuberculosis isolates by PCR-RFLP and multiplex-PCR in North India. AB - In the present study, among 327 Mycobacterium tuberculosis (MTB) isolates collected from patients attending three different centres of North India, we attempted to find out the most common mutations occurring both at the Ser315 codon of katG and at the regulatory region of the mabA-inhA operon to evaluate their role for INH drug resistance in India. Out of 121 phenotypically INH resistant MTB isolates, 88 (72.7%) were resistant to INH by genotypic methods viz., PCR-RFLP with MspI and SatI digestion and multiplex-PCR. PCR-RFLP results showed that 67 (55.4%) isolates had mutation in codon 315 of katG by SatI endonuclease. Among these, eight isolates that were found resistant by SatI PCR RFLP were found to be sensitive by MspI PCR-RFLP. By multiplex-PCR we found 49 (40.5%), 21 (17.4%) and 10 (8.3%) isolates having AGC-->ACC substitution in katG only, mutation in inhA(C-15T) only and mutation in both respectively. Simultaneous use of both PCR-RFLP and multiplex-PCR can improve the detection rate of INH-resistant strains and may have an advantage over the liquid culture system of detecting drug resistance. These findings also enhanced our understanding about potential of resistance-related mutations in M. tuberculosis clinical isolates in India and could help in development and designing of molecular methods for revealing the drug susceptibility profiles of M. tuberculosis clinical isolates. PMID- 19786123 TI - Molecular epidemiology of bovine anaplasmosis with a particular focus in Mexico. AB - Bovine anaplasmosis, caused by the rickettsia Anaplasma marginale, has a worldwide distribution and is the cause of great economic losses in developing countries where it is highly endemic. Transmission is carried mainly by ixodid ticks: Dermacentor spp. and Rhipicephalus (Boophilus) spp. Mechanical transmission is important in disseminating the disease within and across herds. The relationship between the rickettsia, the host and the vector is complex. Several surface proteins (Msps) have been described with functions that span from adhesins towards the erythrocyte and tick cells to evasion of the immune system of the host through the generation of antigenic variants. Biologic transmission of A. marginale through Dermacentor ticks has been well studied but many questions are unresolved as to how this organism spreads within and across herds and little is known about the role Rhipicephalus (Boophilus) ticks play in transmission in the Americas. Mechanical transmission in the absence of ticks and lack of transmission through ticks are questions that need to be addressed. Phylogenetic studies of the rickettsia show wide antigenic and genetic mosaics which affects the design of new vaccines. In the present work we will discuss the molecular elements in the relationship between the rickettsia, the tick and the mammalian host associated to the distribution and persistence of the pathogen in nature. PMID- 19786124 TI - Inspiratory aerodynamic valving occurs in the ostrich, Struthio camelus lung: a computational fluid dynamics study under resting unsteady state inhalation. AB - In the avian lung, inhaled air is shunted past the openings of the medioventral secondary bronchi (MVSB) by a mechanism termed 'inspiratory aerodynamic valving' (IAV). Sizes and orientations of the trachea (Tr), syrinx (Sx), extrapulmonary primary bronchus (EPPB), intrapulmonary primary bronchus (IPPB), MVSB, mediodorsal secondary bronchi (MDSB), lateroventral secondary bronchi (LVSB) and the ostium (Ot) were determined in the ostrich, Struthio camelus. Air flow was simulated through computationally generated models and its dynamics analysed. The 'truncated normal model' (TNM) consisted of the Tr, Sx, EPPB, IPPB, MVSB and the Ot. For the 'inclusive normal model' (INM), the MDSB and the LDSB were added. Variations of these models included the 'truncated MVSB1 rotated model' (T(MVSB1)RM), the 'truncated constriction fitted model' (TCFM) and the 'inclusive MVSB1 rotated model' (I(MVSB1)RM). In the TNM, the T(MVSB1)RM and the TCFM, the air flow exited through the MVSB while for the INM and the I(MVSB1)RM, very little of it did: IAV did not occur in the partial models. In the I(MVSB1)RM, rotating the MVSB1 clockwise did not affect IAV. The incomplete models may be faulty because the velocity/pressure profiles in different parts of the interconnected airways form an integrated functional continuum in which different parts of the system considerably impact on each other. PMID- 19786125 TI - Phrenic nerve stimulation in patients with spinal cord injury. AB - Phrenic nerve pacing (PNP) is a clinically useful technique to restore inspiratory muscle function in patients with respiratory failure secondary to cervical spinal cord injury. In this review, patient evaluation, equipment, methods of implementation, clinical outcomes, and the complications and side effects of PNP are discussed. Despite considerable technical development, and clinical success, however, current PNP systems have significant limitations. Even in patients with intact phrenic nerve function, PNP is successful in achieving full-time support in approximately 50% of patients. Inadequate inspired volume generation may arise secondary to incomplete diaphragm activation, reversed recruitment order of motor units, fiber type conversion resulting in reduced force generating capacity and lack of coincident intercostal muscle activation. A novel method of pacing is under development which involves stimulating spinal cord tracts which synapse with the inspiratory motoneuron pools. This technique results in combined activation of the intercostal muscles and diaphragm in concert and holds promise to provide a more physiologic and effective method of PNP. PMID- 19786126 TI - Effect of detergent concentration on the thermal stability of a membrane protein: The case study of bacterial reaction center solubilized by N,N dimethyldodecylamine-N-oxide. AB - We report on the response of reaction center (RC) from Rhodobacter sphaeroides (an archetype of membrane proteins) to the exposure at high temperature. The RCs have been solubilized in aqueous solution of the detergent N,N dimethyldodecylamine-N-oxide (LDAO). Changes in the protein conformation have been probed by monitoring the variation in the absorbance of the bacteriochlorine cofactors and modification in the efficiency of energy transfer from tryptophans to cofactors and among the cofactors (through fluorescence measurements). The RC aggregation taking place at high temperature has been investigated by means of dynamic light scattering. Two experimental protocols have been used: (i) isothermal kinetics, in which the time evolution of RC after a sudden increase of the temperature is probed, and (ii) T-scans, in which the RCs are heated at constant rate. The analysis of the results coming from both the experiments indicates that the minimal kinetic scheme requires an equilibrium step and an irreversible process. The irreversible step is characterized by a activation energy of 205+/-14 kJ/mol and is independent from the detergent concentration. Since the temperature dependence of the aggregation rate was found to obey to the same law, the aggregation process is unfolding-limited. On the other hand, the equilibrium process between the native and a partially unfolded conformations was found to be strongly dependent on the detergent concentration. Increasing the LDAO content from 0.025 to 0.5 wt.% decreases the melting temperature from 49 to 42 degrees C. This corresponds to a sizeable (22 kJ/mol at 25 degrees C) destabilization of the native conformation induced by the detergent. The nature of the aggregates formed by the denatured RCs depends on the temperature. For temperature below 60 degrees C compact aggregates are formed while at 60 degrees C the clusters are less dense with a scaling relation between mass and size close to that expected for diffusion-limited aggregation. The aggregate final sizes formed at different temperatures indicate the presence of an even number of proteins suggesting that these clusters are formed by aggregation of dimers. PMID- 19786127 TI - Cell wall proteome of wheat roots under flooding stress using gel-based and LC MS/MS-based proteomics approaches. AB - Cell wall proteins (CWPs) are important both for maintenance of cell structure and for responses to abiotic and biotic stresses. In this study, a destructive CWP purification procedure was adopted using wheat seedling roots and the purity of the CWP extract was confirmed by minimizing the activity of glucose-6 phosphate dehydrogenase, a cytoplasmic marker enzyme. To determine differentially expressed CWPs under flooding stress, gel-based proteomic and LC-MS/MS-based proteomic techniques were applied. Eighteen proteins were found to be significantly regulated in response to flood by gel-based proteomics and 15 proteins by LC MS/MS-based proteomics. Among the flooding down-regulated proteins, most were related to the glycolysis pathway and cell wall structure and modification. However, the most highly up-regulated proteins in response to flooding belong to the category of defense and disease response proteins. Among these differentially expressed proteins, only methionine synthase, beta-1,3 glucanases, and beta-glucosidase were consistently identified by both techniques. The down-regulation of these three proteins suggested that wheat seedlings respond to flooding stress by restricting cell growth to avoid energy consumption; by coordinating methionine assimilation and cell wall hydrolysis, CWPs played critical roles in flooding responsiveness. PMID- 19786129 TI - Pathway-based genome-wide association analysis identified the importance of EphrinA-EphR pathway for femoral neck bone geometry. AB - Femoral neck (FN) bone geometry is an important predictor of bone strength with high heritability. Previous studies have revealed certain candidate genes for FN bone geometry. However, the majority of the underlying genetic factors remain to be discovered. In this study, pathway-based genome-wide association analysis was performed to explore the joint effects of genes within biological pathways on FN bone geometry variations in a cohort of 1000 unrelated US whites. Nominal significant associations (nominal p value<0.05) were observed between 76 pathways and a key FN bone geometry variable-section modulus (Z), biomechanically indicative of bone strength subject to bending. Among them, EphrinA-EphR pathway was most significantly associated with FN Z even after multiple testing adjustments (p(FWER) value=0.035). The association of EphrinA-EphR pathway with FN Z was also observed in an independent sample from Framingham Osteoporosis Study. Overall, these results suggest the significant genetic contribution of EphrinA-EphR pathway to femoral neck bone geometry. PMID- 19786128 TI - Papillomavirus interaction with cellular chromatin. AB - High-risk human papillomavirus (HPV) infection is the primary risk factor for cervical cancer. HPVs establish persistent infection by maintaining their genomes as extrachromosomal elements (episomes) that replicate along with host DNA in infected cells. The productive life cycle of HPV is intimately tied to the differentiation program of host squamous epithelium. This review examines the involvement of host chromatin in multiple aspects of the papillomavirus life cycle and the malignant progression of infected host cells. Papillomavirus utilizes host mitotic chromosomes as vehicles for transmitting its genetic materials across the cell cycle. By hitchhiking on host mitotic chromosomes, the virus ensures accurate segregation of the replicated viral episomes to the daughter cells during host cell division. This strategy allows persistent maintenance of the viral episome in the infected cells. In the meantime, the virus subverts the host chromatin-remodeling factors to promote viral transcription and efficient propagation of viral genomes. By associating with the host chromatin, papillomavirus redirects the normal cellular control of chromatin to create a cellular environment conducive to both its own survival and malignant progression of host cells. Comprehensive understanding of HPV-host chromatin interaction will offer new insights into the HPV life cycle as well as chromatin regulation. This virus-host interaction will also provide a paradigm for investigating other episomal DNA tumor viruses that share a similar mechanism for interacting with host chromatin. PMID- 19786130 TI - An orally active calcium-sensing receptor antagonist that transiently increases plasma concentrations of PTH and stimulates bone formation. AB - Daily subcutaneous administration of exogenous parathyroid hormone (PTH) promotes bone formation in patients with osteoporosis. Here we describe two novel, short acting calcium-sensing receptor antagonists (SB-423562 and its orally bioavailable precursor, SB-423557) that elicit transient PTH release from the parathyroid gland in several preclinical species and in humans. In an ovariectomized rat model of bone loss, daily oral administration of SB-423557 promoted bone formation and improved parameters of bone strength at lumbar spine, proximal tibia and midshaft femur. Chronic administration of SB-423557 did not increase parathyroid cell proliferation in rats. In healthy human volunteers, single doses of intravenous SB-423562 and oral SB-423557 elicited transient elevations of endogenous PTH concentrations in a profile similar to that observed with subcutaneously administered PTH. Both agents were well tolerated in humans. Transient increases in serum calcium, an expected effect of increased parathyroid hormone concentrations, were observed post-dose at the higher doses of SB-423557 studied. These data constitute an early proof of principle in humans and provide the basis for further development of this class of compound as a novel, orally administered bone-forming treatment for osteoporosis. PMID- 19786131 TI - Mucosal perspectives in pneumococcal vaccine development: a meeting summary: a one-day international workshop focusing on stimulating research and collaborations on this topic. PMID- 19786132 TI - Design and preclinical development of a recombinant protein and DNA plasmid mixed format vaccine to deliver HIV-derived T-lymphocyte epitopes. AB - Coordinated interactions between helper and cytotoxic T-lymphocytes (HTL and CTL) are needed for optimal effector cell functions and the establishment of immunological memory. We, therefore, designed a mixed format vaccine based on the use of highly conserved HIV-derived T-lymphocyte epitopes wherein the HTL epitopes were delivered as a recombinant protein and the CTL epitopes which were encoded in a DNA vaccine plasmid. Immunogenicity testing in HLA transgenic mice and GLP preclinical safety testing in rabbits and guinea pigs were used to document the utility of this approach and to support Phase 1 trial clinical testing. Both vaccine components were immunogenic and safely co-administered. PMID- 19786133 TI - Inactivated influenza vaccine effectiveness against influenza-like illness among young children in Japan--with special reference to minimizing outcome misclassification. AB - The aim of the present study was to investigate the influenza vaccine effectiveness among young children in Japan. Study subjects were recruited from 43 pediatric clinics. Influenza-like illness (ILI) was defined as an acute febrile illness with respiratory symptoms; ILI with a fever of > or =39 degrees C was considered to be severe ILI (SILI). The adjusted OR of vaccination significantly decreased to 0.75 for SILI. Influenza vaccination for young children had a protective effect on the occurrences of SILI. This study also indicated that three key tools (case surveillance with equal scrutiny, confining observation to the peak epidemic period, and adoption of strict criteria for ILI) could minimize outcome misclassification and thus provide adequate methodology for monitoring vaccine effectiveness without laboratory confirmation. PMID- 19786134 TI - Protective effect of the combination BCG vaccination and rifampicin prophylaxis in leprosy prevention. AB - BCG vaccination and rifampicin chemoprophylaxis are both strategies for leprosy prevention. While the combined effect is unknown, the combination may give the desired push to halt leprosy transmission. Secondary analysis was done on results from a single centre, double blind, cluster randomized, and placebo-controlled trial. Individually, BCG (given at infancy) and rifampicin showed to protect against leprosy (57% [95% CI: 24-75%] and 58% [95% CI: 30-74%], respectively). The combined strategies showed a protective effect of 80% (95% CI: 50-92%). This is the first time that the additive effect of BCG and rifampicin are shown; the combined strategies can possibly lower leprosy incidence. PMID- 19786135 TI - The timing of influenza vaccination for older adults (65 years and older). AB - While studies have found influenza vaccination to be cost-effective in older adults (65 years or older), they have not looked at how the vaccine's economic value may vary with the timing of vaccine administration. We developed a set of computer simulation models to evaluate the economic impact of vaccinating older adults at different months. Our models delineated the costs and utility losses in delaying vaccination past October and suggest that policy makers and payors may consider structuring incentives (< or =$2.50 per patient) to vaccinate in October. Our results also suggest that vaccination is still cost-effective through the end of February. PMID- 19786137 TI - Cost-effectiveness of a 3-dose pneumococcal conjugate vaccine program in the province of Quebec, Canada. AB - In the province of Quebec, Canada, the pneumococcal 7-valent conjugate vaccine (PCV-7) was licensed in 2001 and a publicly funded program was implemented in 2004, recommending 3 doses for healthy children. An economic analysis was performed both from a health care and societal perspective. Outcomes possibly prevented by PCV-7 and observed in 2006-2007 were compared to expected frequencies based on rates measured before PCV-7 use. Annual program costs were close to $21M for the health system and $23M for society. Approximately 20,000 infections were prevented annually and estimated economic benefits were $5M for the health system and $23M for society, using a 3% per annum discounting rate. The incremental cost-effectiveness ratio was $18,000 per QALY gained for the health system and the program was close to the break-even threshold in a societal perspective. PMID- 19786138 TI - N255 is a key residue for recognition by a monoclonal antibody which protects against Yersinia pestis infection. AB - Mab7.3 to Yersinia pestis LcrV antigen (LcrV(Ype)) protected J774A.1 macrophages in vitro from killing by a Yersinia pseudotuberculosis strain expressing LcrV(Ype). Of 4 site-directed mutations in the coiled-coil region (148-169) and 7 mutations in the 225-255 sequence of LcrV(Ype), only the mutation of N255 to D255, abrogated the binding of Mab7.3 and reduced its protective capacity against plague. Since the Mab7.3 epitope in LcrV(Ype) (135-275) encompasses a region (136 180) thought to be exposed on the injectisome, we suggest that Mab7.3 protects by binding to LcrV(Ype) and interfering with protein-protein interactions necessary for type three secretion. PMID- 19786136 TI - Optimized subunit vaccine protects against experimental leishmaniasis. AB - Development of a protective subunit vaccine against Leishmania spp. depends on antigens and adjuvants that induce appropriate immune responses. We evaluated a second generation polyprotein antigen (Leish-110f) in different adjuvant formulations for immunogenicity and protective efficacy against Leishmania spp. challenges. Vaccine-induced protection was associated with antibody and T cell responses to Leish-110f. CD4 T cells were the source of IFN-gamma, TNF, and IL-2 double- and triple-positive populations. This study establishes the immunogenicity and protective efficacy of the improved Leish-110f subunit vaccine antigen adjuvanted with natural (MPL-SE) or synthetic (EM005) Toll-like receptor 4 agonists. PMID- 19786140 TI - Detection by ELISA of antibodies to Japanese encephalitis virus nonstructural 1 protein induced in subclinically infected humans. AB - Japanese encephalitis (JE) is a fatal mosquito-borne disease that is vaccine preventable. The natural infection rate is a critical factor for evaluations of the necessity for vaccination. Detection of antibodies to virus nonstructural (NS) proteins is a theoretical strategy to survey natural infections among populations vaccinated with an inactivated JE vaccine consisting of only structural proteins. Here, we present our development of an enzyme-linked immunosorbent assay (ELISA) to detect low levels of NS1 antibodies induced in humans with subclinical infections. We used a casein-based ELISA diluent to minimize nonspecific reactions. A tentative cut-off value (0.185) was statistically calculated from NS1 antibody levels obtained with healthy American individuals negative for antibodies to JE virus. Comparison with our previously developed immunostaining method provided a significant correlation coefficient (0.764; P<0.001) and high qualitative agreement (82.5%). The presence of NS1 antibodies in sera was confirmed by Western blotting analysis. Using serially collected sera, we estimated the duration of NS1 antibodies between seroconversion and seroreversion to be 4.2 years. PMID- 19786139 TI - Characterization of proteins Msp22 and Msp75 as vaccine antigens of Moraxella catarrhalis. AB - Moraxella catarrhalis is a respiratory tract pathogen causing otitis media in children and respiratory tract infections in adults with chronic obstructive pulmonary disease. This study examined two newly identified proteins as potential vaccine antigens. Antisera raised to recombinant purified proteins Msp22 and Msp75 recognized corresponding native proteins in multiple strains of M. catarrhalis. Vaccine formulations individually administered subcutaneously and intranasally showed enhanced clearance of M. catarrhalis in a mouse pulmonary clearance model by both routes of administration. Msp22 and Msp75 are antigenically conserved proteins that induce potentially protective immune responses and should be examined further as vaccine antigens for M. catarrhalis. PMID- 19786141 TI - Seroconversion, neutralising antibodies and protection in bluetongue serotype 8 vaccinated sheep. AB - Bluetongue virus serotype 8 (BTV-8) has caused a major outbreak of disease in cattle and sheep in several countries across northern and western Europe from 2006 to 2008. In 2008 the European Union instigated a mass-vaccination programme in affected countries using whole virus inactivated vaccines. We evaluated vaccinal responses in sheep and the ability of the vaccine to protect against experimental challenge. Sheep vaccinated 10 months previously under field conditions were challenged with BTV-8. One of 7 vaccinated sheep became infected, as evidenced by detection of viral RNA by real-time RT-PCR and by virus isolation. The remaining 6 sheep appeared fully protected from virus replication. None of the vaccinated sheep showed clinical signs of BTV and there was a good correlation between the presence of neutralising antibodies on challenge and protection. Commercially available ELISAs were evaluated for their ability to detect antibodies in sheep vaccinated on a single occasion. The sandwich (double antigen) ELISA assays were found to be more sensitive at detecting antibodies in vaccinated sheep than the competitive ELISAs. PMID- 19786142 TI - Development of recombinant vaccines against IL-12/IL-23 p40 and in vivo evaluation of their effects in the downregulation of intestinal inflammation in murine colitis. AB - Overexpression of IL-12 and IL-23, which share the p40 subunit, has been implicated in the pathogenesis of Crohn's disease. Targeting these cytokines with monoclonal antibodies has emerged as a new and effective therapy, but one with adverse reactions. In this study, we sought to develop p40 peptide-based virus like particle vaccines that elicit autoantibodies to IL-12 and IL-23 for a long term treatment of the disease. Three vaccines (named C, D and F) against the p40 were developed by inserting peptides derived from p40 into the carrier, hepatitis B core antigen, using molecular engineering methods. Immunization with the vaccines, without the use of adjuvants, induced high titered and long-lasting antibodies to IL-12, IL-23 and p40. The three vaccines were evaluated in vivo in 2,4,6-trinitrobenzene sulphonic acid (TNBS)-induced chronic murine colitis. Mice were immunized with a vaccine three times, followed by weekly intrarectal administrations of TNBS. Vaccine groups, especially groups C and F, showed reduced expression of IL-12/IL-23p40, less inflammation, and decreased collagen deposition in colon tissues when compared with controls. We concluded that IL 12/IL-23p40 vaccines may be a potential therapeutic approach in the treatment of Crohn's disease and other autoimmune diseases. PMID- 19786143 TI - Booster vaccinations against tick-borne encephalitis: 6 years follow-up indicates long-term protection. AB - Five and 6 years post-booster, immunity to tick-borne encephalitis (TBE) virus was assessed in 225 and 195 vaccinees, respectively, out of 430 healthy volunteers with at least three TBE-immunizations prior to study inclusion and booster intervals exceeding recommended limits. Neutralizing antibody titers of > or = 1:10 (reliable level of protection) were present in 86-96% depending on age group, with lower percentages in participants >60 years. TBE antibody levels remained stable for many years in most vaccinees. However, in a few persons a shorter period of protection against TBE was indicated. Therefore, recommendations on booster intervals in TBE endemic areas should be adapted by weighting the risk of infection against the risk of short-lived immunity. PMID- 19786144 TI - Protection of chickens against infectious bronchitis by a recombinant fowlpox virus co-expressing IBV-S1 and chicken IFNgamma. AB - A fowlpox virus expressing the chicken infectious bronchitis virus (IBV) S1 gene of the LX4 strain (rFPV-IBVS1) and a fowlpox virus co-expressing the S1 gene and the chicken type II interferon gene (rFPV-IBVS1-ChIFNgamma) were constructed. These viruses were assessed for their immunological efficacy on specific-pathogen free (SPF) chickens challenged with a virulent IBV. Although the antibody levels in the rFPV-IBVS1-ChIFNgamma-vaccinated group were lower than those in the attenuated live IB vaccine H120 group and the rFPV-IBVS1 group, the rFPV-IBVS1 ChIFNgamma provided the strongest protection against an IBV LX4 virus challenge (15 out of 16 chickens immunized with rFPV-IBVS1-ChIFNgamma were protected), followed by the attenuated live IB vaccine (13/16 protected) and the rFPV-IBVS1 (12/16 protected). Compared to those of the rFPV-IBVS1 and the attenuated live IB vaccine groups, chickens in the rFPV-IBVS1-ChIFNgamma group eliminated virus more quickly and decreased the presence of viral antigen more significantly in renal tissue. Examination of affected tissues revealed abnormalities in the liver, spleen, kidney, lung and trachea of chickens vaccinated with the attenuated live IB vaccine and the rFPV-IBVS1 vaccine. In rFPV-IBVS1-ChIFNgamma-vaccinated chickens, pathological changes were also observed in those organs, but were milder and lasted shorter. The lesions in the mock control group were the most severe and lasted for at least 20 days. This study demonstrated that chicken type II interferon increased the immunoprotective efficacy of rFPV-IBVS1-ChIFNgamma and normal weight gain in vaccinated chickens although it inhibited serum antibody production. PMID- 19786145 TI - A novel HIV T helper epitope-based vaccine elicits cytokine-secreting HIV specific CD4+ T cells in a Phase I clinical trial in HIV-uninfected adults. AB - A Phase I human vaccine trial of a novel polypeptide vaccine of HIV T helper epitopes (EP-1043) and a DNA vaccine of HIV CTL epitopes was conducted in 84 healthy adult volunteers. The vaccine immunogenicity was assessed by an intracellular cytokine staining assay for IL-2, IL-4, TNF-alpha and IFN-gamma. Sixty eight percent (32/47) of subjects had a positive CD4+ T response after receiving two vaccinations of the polypeptide vaccine. The responding CD4+ T cells made various combinations of IL-2, IL-4, IFN-gamma, and TNF-alpha. The study demonstrated that the EP-1043 vaccine is safe, well-tolerated, and immunogenic. PMID- 19786147 TI - Stigmasterol: a phytosterol with potential anti-osteoarthritic properties. AB - OBJECTIVE: Although most studies have focused on the cholesterol-lowering activity of stigmasterol, other bioactivities have been ascribed to this plant sterol compound, one of which is a potential anti-inflammatory effect. To investigate the effects of stigmasterol, a plant sterol, on the inflammatory mediators and metalloproteinases produced by chondrocytes. METHOD: We used a model of newborn mouse chondrocytes and human osteoarthritis (OA) chondrocytes in primary culture stimulated with or without IL-1beta (10 ng/ml), for 18 h. Cells were pre-incubated for 48 h with stigmasterol (20 microg/ml) compared to untreated cells. We initially investigated the presence of stigmasterol in chondrocyte, compared to other phytosterols. We then assessed the role of stigmasterol on the expression of various genes involved in inflammation (IL-6) and cartilage turn-over (MMP-3, -13, ADAMTS-4, -5, type II collagen, aggrecan) by quantitative Reverse Transcriptase-Polymerase Chain Reaction (RT-PCR). Additional experiments were carried out to monitor the production of MMP-3 and prostaglandin E2 (PGE(2)) by specific immuno-enzymatic assays. We eventually looked at the role of stigmasterol on NF-kappaB activation by western blot, using an anti IkappaBalpha antibody. RESULTS: After 18 h of IL-1beta treatment, MMP-3, MMP-13, ADAMTS-4, but not ADAMTS-5 RNA expression were elevated, as well as MMP-3 and PGE(2) protein levels in mouse and human chondrocytes. Type II collagen and aggrecan mRNA levels were significatively reduced. Pre-incubation of stigmasterol to IL-1beta-treated cells significantly decreased these effects described above (significant reduction of MMP-3 mRNA in human and mouse, MMP-3 protein in mouse, MMP-13 mRNA in mouse and human, ADAMTS-4 mRNA in human, PGE(2) protein in human and mouse) Finally, stigmasterol was capable of counteracting the IL-1beta induced NF-kappaB pathway. CONCLUSION: This study shows that stigmasterol inhibits several pro-inflammatory and matrix degradation mediators typically involved in OA-induced cartilage degradation, at least in part through the inhibition of the NF-kappaB pathway. These promising results justify further ex vivo and in vivo investigations with stigmasterol. PMID- 19786146 TI - A genetically engineered adenovirus vector targeted to CD40 mediates transduction of canine dendritic cells and promotes antigen-specific immune responses in vivo. AB - Targeting viral vectors encoding tumor-associated antigens to dendritic cells (DCs) in vivo is likely to enhance the effectiveness of immunotherapeutic cancer vaccines. We have previously shown that genetic modification of adenovirus (Ad) 5 to incorporate CD40 ligand (CD40L) rather than native fiber allows selective transduction and activation of DCs in vitro. Here, we examine the capacity of this targeted vector to induce immune responses to the tumor antigen CEA in a stringent in vivo canine model. CD40-targeted Ad5 transduced canine DCs via the CD40-CD40L pathway in vitro, and following vaccination of healthy dogs, CD40 targeted Ad5 induced strong anti-CEA cellular and humoral responses. These data validate the canine model for future translational studies and suggest targeting of Ad5 vectors to CD40 for in vivo delivery of tumor antigens to DCs is a feasible approach for successful cancer therapy. PMID- 19786148 TI - Purple urinary bag syndrome. PMID- 19786149 TI - Diagnosis of Munchausen's syndrome by an electronic health record search. PMID- 19786150 TI - Does he deserve a pacemaker? PMID- 19786151 TI - "Don't look back; something might be gaining on you". PMID- 19786152 TI - The patient-physician-industry-government partnership: a societal good. PMID- 19786153 TI - John Stone, MD. PMID- 19786154 TI - Hypertension in pregnancy and women of childbearing age. AB - Hypertension in women of childbearing age is a challenging medical problem with increasing prevalence. Essential hypertension remains the most common diagnosis in young women. Reproductive goals and possible teratogenic effects must be considered when initiating therapy. Hypertensive disorders of pregnancy are frequent causes of maternal/fetal morbidity and mortality, the most common being preeclampsia/eclampsia. Pregnant patients should be screened routinely. Early recognition and prompt care from a multidisciplinary service, including obstetrics, cardiology, and intensive medicine, are required to prevent deleterious outcomes. Hypertensive disorders of pregnancy reflect endometrial endothelial dysfunction/abnormalities and systemic endothelial dysfunction, which might predict future cardiovascular disease in these young women, prompting early preventive measures. PMID- 19786155 TI - Long-term safety concerns with proton pump inhibitors. AB - Proton pump inhibitors (PPIs) are among the most widely prescribed medications worldwide. Their use has resulted in dramatic improvements in treatment of peptic ulcer disease and gastroesophageal reflux disease. Despite an acceptable safety profile, mounting data demonstrate concerns about the long-term use of PPIs. To provide a comprehensive review regarding the concerns of long-term PPI use, a literature search was performed to identify pertinent original and review articles. Despite study shortcomings, the collective body of information overwhelmingly suggests an increased risk of infectious complications and nutritional deficiencies. Data regarding any increased risk in gastric or colon malignancy are less convincing. PPIs have revolutionized the management and complications of acid-related disorders with a high margin of safety; however, with the data available, efforts to reduce the dosing of or discontinue the use of PPIs must be reassessed frequently. PMID- 19786156 TI - Office management of deep venous thrombosis in the elderly. AB - Deep venous thrombosis is common in the elderly. Diagnosis and management are now a part of office practice. As signs and symptoms are inconsistent and nonspecific, diagnostic testing is necessary. For patients with a low clinical probability, a normal D-dimer result can rule out disease. For patients with a high clinical suspicion or an elevated D-dimer, duplex ultrasonography may confirm the diagnosis. Anticoagulation, usually with low-molecular-weight heparin, should begin on suspicion and continue, along with warfarin, until the international normalized ratio is therapeutic. Arrangements for the initial daily injections can be made with a visiting nurse. Treatment should continue for at least 3 months, when a risk-versus-benefit analysis for continuing anticoagulation should be undertaken. Therapy may be discontinued for thromboses associated with a reversible risk factor or for patients in whom anticoagulant management was unstable or complicated by bleeding. A persistently high D-dimer result or evidence of residual clot on repeat duplex ultrasonography may support continuation. For all patients, the use of compression stockings to prevent the post-thrombotic syndrome is recommended. PMID- 19786157 TI - Cocktail paralysis. PMID- 19786158 TI - A unique complication of a broken heart. PMID- 19786159 TI - Right rhythm, right patient, right ventricle. PMID- 19786160 TI - Bubble-wrapped. PMID- 19786161 TI - Side effects of phytoestrogens: a meta-analysis of randomized trials. AB - BACKGROUND: Phytoestrogens are widely used by postmenopausal women for the treatment of the climacteric syndrome. The risk of adverse effects of this treatment, however, is unknown. METHODS: Using a fixed-effects model, we performed a meta-analysis of side effects comparing phytoestrogen treatment with placebo or no treatment in randomized controlled trials. RESULTS: We identified 174 randomized controlled trials. Side effects were reported in 92/174 randomized controlled trials with 9629 participants. The overall incidence of side effects in the phytoestrogen and control groups was 2019/5502 (36.7%) and 1824/4806 (38.0%), respectively (P=.2; incidence rate ratio [IRR] 1.01; 95% confidence interval [CI], 0.95-1.08). Comparing various side effect categories, we found significantly higher rates of gastrointestinal side effects among phytoestrogen users (P=.003; IRR 1.28; 95% CI, 1.08-1.50). Gynecological (IRR 0.94; 95% CI, 0.74-1.20), musculoskeletal (IRR 1.20; 95% CI, 0.94-1.53), neurological (IRR 0.91; 95% CI, 0.70-1.19), and unspecific side effects (IRR 0.95; 95% CI, 0.88 1.03) were not significantly different between groups. Within side effect categories, we found no significantly higher rates of side effects in women using phytoestrogens. Specifically, the rates of hormone-related side effects such as endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly different between groups. CONCLUSIONS: Based on the available evidence, phytoestrogen supplements have a safe side-effect profile with moderately elevated rates of gastrointestinal side effects. Rates of vaginal bleeding, endometrial hyperplasia, endometrial cancer, and breast cancer were not significantly increased among phytoestrogen users in the investigated studies. PMID- 19786163 TI - Screening for obstructive sleep apnea on the internet: randomized trial. AB - BACKGROUND: Obstructive sleep apnea is underdiagnosed. We conducted a pilot randomized controlled trial of an online intervention to promote obstructive sleep apnea screening among members of an Internet weight-loss community. METHODS: Members of an Internet weight-loss community who have never been diagnosed with obstructive sleep apnea or discussed the condition with their healthcare provider were randomized to intervention (online risk assessment+feedback) or control. The primary outcome was discussing obstructive sleep apnea with a healthcare provider at 12 weeks. RESULTS: Of 4700 members who were sent e-mail study announcements, 168 (97% were female, age 39.5 years [standard deviation 11.7], body mass index 30.3 [standard deviation 7.8]) were randomized to intervention (n=84) or control (n=84). Of 82 intervention subjects who completed the risk assessment, 50 (61%) were low risk and 32 (39%) were high risk for obstructive sleep apnea. Intervention subjects were more likely than control subjects to discuss obstructive sleep apnea with their healthcare provider within 12 weeks (11% [9/84] vs 2% [2/84]; P=.02; relative risk=4.50; 95% confidence interval, 1.002-20.21). The number needed to treat was 12. High-risk intervention subjects were more likely than control subjects to discuss obstructive sleep apnea with their healthcare provider (19% [6/32] vs 2% [2/84]; P=.004; relative risk=7.88; 95% confidence interval, 1.68-37.02). One high-risk intervention subject started treatment for obstructive sleep apnea. CONCLUSION: An online screening intervention is feasible and likely effective in encouraging members of an Internet weight-loss community to discuss obstructive sleep apnea with their healthcare provider. PMID- 19786162 TI - Appropriateness of collaborations between industry and the medical profession: physicians' perceptions. AB - BACKGROUND: Physicians' ratings of the appropriateness of collaboration and of receiving payment for collaboration with the pharmaceutical and medical device industries may differ. METHODS: We administered an anonymous, cross-sectional survey to a convenience sample of faculty and postgraduate physicians from all departments within the 11 hospitals affiliated with the Mount Sinai School of Medicine in New York City and New Jersey. We examined 12 collaborations with the pharmaceutical and medical device industries using 4-point Likert scales, ranging from very appropriate to very inappropriate. RESULTS: Surveys were distributed to physicians within 35 departments at 11 hospitals; 590 surveys were completed by physicians at 9 hospitals, yielding a 67% response rate. Physicians' assessment of appropriateness varied among the different collaborations, ranging from nearly all rating developing a drug or device (92%) and designing a drug/device trial (91%) as appropriate to fewer rating preparing a manuscript of a drug/device trial (60%) and recruiting patients for a drug/device trial (65%) as appropriate for physicians not involved in trial design. Physicians consistently rated receiving payment for collaboration as appropriate less often than they rated the collaboration itself as appropriate and ratings varied among the collaborations. For example, 81% rated receiving payment to develop a drug or device as appropriate, whereas 38% rated receiving payment to recruit patients for a drug/device trial when the physician was not involved in trial design as appropriate. CONCLUSIONS: Physicians' broadly perceived most collaboration with the pharmaceutical and medical device industries, and of receiving payment for collaboration, as appropriate. PMID- 19786164 TI - Interim department chairs in academic medicine. PMID- 19786165 TI - Edward Hopper's corner Drug store. PMID- 19786166 TI - Fundamental and applied analytical science. Preface. PMID- 19786167 TI - Zwitterionic ion-exchangers in ion chromatography: A review of recent developments. AB - Significant advances within the field of ion chromatography (IC) have often had their roots in research focussed on the development of new phase technologies, aimed to both simultaneously increase efficiency and vary selectivity. To increase selectivity it is necessary to develop new selective ion-exchangers, achieved by varying the nature of functional groups and the matrix of the stationary phase. In this comprehensive review, developments over the past decade in the production and application of zwitterionic and amphoteric ion-exchangers are presented and discussed. Zwitterionic and amphoteric ion-exchangers, where positive and negative charges are located in close proximity, exhibit alternative ion selectivity to standard anion and cation ion-exchangers, such as those traditionally used in IC, and have the potential for selectivity optimisation in IC due to control of the ratio of electrostatic attraction/repulsion forces between analyte ions and ion-exchange groups. This can result in the ability to utilise relatively dilute eluents, which increases detector sensitivity, with further advantages of zwitterionic ion-exchangers including their possible application to the simultaneous separation of cationic and anionic species. PMID- 19786168 TI - Separation and sample pre-treatment in bioanalysis using monolithic phases: A review. AB - In order to support drug discovery and development studies within the pharmaceutical industry there has been an increased use of innovative bioanalytical assays and associated analytical technology. Performing quantitative bioanalysis in a variety of biological matrices can also involve the use of sample preparation techniques, complex HLPC column switching and microfluidic systems. Development of assays for diverse therapeutic agents in biomatrices, such as plasma and urine, can be very technically challenging to obtain the sensitivity, speed and specificity required. This challenge focuses on the quantification of drugs and metabolites at very low concentration levels, in an excess of biological matrix and in a high-throughput manner. One area of wide interest is the use and application of monolithic phases where emerging technology has been implemented successfully. This review presents an overview of the application of monolithic phases in a bioanalytical setting, including the bioanalytical challenges that need to be overcome; the synthesis, use and applicability of monolithic phases (with emphasis on polymer-based phases); the currently available bioanalytical techniques and approaches; and future possibilities for these phases. PMID- 19786169 TI - Determination of solute descriptors by chromatographic methods. AB - The solvation parameter model is now well established as a useful tool for obtaining quantitative structure-property relationships for chemical, biomedical and environmental processes. The model correlates a free-energy related property of a system to six free-energy derived descriptors describing molecular properties. These molecular descriptors are defined as L (gas-liquid partition coefficient on hexadecane at 298K), V (McGowan's characteristic volume), E (excess molar refraction), S (dipolarity/polarizability), A (hydrogen-bond acidity), and B (hydrogen-bond basicity). McGowan's characteristic volume is trivially calculated from structure and the excess molar refraction can be calculated for liquids from their refractive index and easily estimated for solids. The remaining four descriptors are derived by experiment using (largely) two-phase partitioning, chromatography, and solubility measurements. In this article, the use of gas chromatography, reversed-phase liquid chromatography, micellar electrokinetic chromatography, and two-phase partitioning for determining solute descriptors is described. A large database of experimental retention factors and partition coefficients is constructed after first applying selection tools to remove unreliable experimental values and an optimized collection of varied compounds with descriptor values suitable for calibrating chromatographic systems is presented. These optimized descriptors are demonstrated to be robust and more suitable than other groups of descriptors characterizing the separation properties of chromatographic systems. PMID- 19786170 TI - Liquid-liquid extraction in flow analysis: A critical review. AB - Liquid-liquid extractions (LLE) are a common sample pre-treatment in many analytical applications. This review aims at providing a critical overview of the distinct automated continuous flow-based approaches that were developed for liquid-liquid extraction with the purpose of pre-concentration and/or separation of multiple analytes, such as ultra-trace metal and metalloid species, phenolic compounds, surfactants, pharmaceuticals, etc., hyphenated with many detection technique such as UV/vis spectrophotometry, atomic spectrometric detection systems and luminescent detectors, including distinct extraction strategies and applications like single and multiple extraction schemes, wetting film extraction, supported liquid membrane extraction, back extraction, closed-loop systems and the utilisation of zone sampling, chromatomembranes and iterative reversal techniques. The analytical performance of the developed flow-based LLE methods and the influence of flow manifold components such as the segmenter, extraction coil and phase separator, is emphasised and object of discussion. An overall presentation of each system components, selectivity, advantages and shortcomings is carried out and exemplified with selected applications. PMID- 19786171 TI - Determination of plutonium isotopes in waters and environmental solids: A review. AB - A number of analytical methods have been developed in the past few years for environmental monitoring of plutonium (Pu) isotopes around nuclear facilities within protocols for emergency preparedness as well as for risk assessment of contaminated areas resulting from nuclear weapon tests, nuclear accidents, and the discharge of nuclear waste. This article summarizes and critically compares recently reported methods for determination of Pu isotopes in waters and environmental solid substrates, in which sample pre-treatment is imperative for separation of the target species from matrix ingredients and/or potentially interfering nuclides prior to detection by radiometric or mass spectrometric techniques. Also discussed, via representative examples, is the automation of the entire analytical protocol by on-line extraction chromatography and ion exchange chromatography using flow injection (FI) or sequential injection (SI) approaches. PMID- 19786172 TI - Periodate oxidation and its contribution to instrumental methods of micro analysis--a review. AB - A comprehensive review that summarizes the periodate oxidation contribution to the development of selective instrumental methods of micro-analysis in the fields of electrochemistry, spectrophotometry, luminometry, chromatography, as well as studies on successful fabrication of sensors or labeling techniques are given in this review. PMID- 19786173 TI - The detection of latent fingermarks on porous surfaces using amino acid sensitive reagents: a review. AB - The introduction of ninhydrin treatment as a chemical technique for the visualisation of latent fingermarks on porous surfaces revolutionised approaches to forensic fingermark examination. Since then, a range of amino acid sensitive reagents has been developed and such compounds are in widespread use by law enforcement agencies worldwide. This paper reviews the development and use of these reagents for the detection of latent fingermarks on porous surfaces. A brief overview is provided, including an historical background, forensic significance, and a general approach to the development of latent fingermarks on porous surfaces. This is followed by a discussion of specific amino acid sensitive treatments. PMID- 19786174 TI - Synergetic enhancement effect of ionic liquid and diethyldithiocarbamate on the chemical vapor generation of nickel for its atomic fluorescence spectrometric determination in biological samples. AB - Room-temperature ionic liquid in combination with sodium diethyldithiocarbamate (DDTC) was used to synergetically improve the chemical vapor generation (CVG) of nickel. Volatile species of nickel were effectively generated through reduction of acidified analyte solution with KBH(4) in the presence of 0.02% DDTC and 25mmolL(-1) 1-butyl-3-methylimidazolium bromide ([C(4)mim]Br) at room temperature. Thus, a new flow injection (FI)-CVG-atomic fluorescence spectrometric (FI-CVG-AFS) method was developed for determination of nickel with a detection limit of 0.65microgL(-1) (3s) and a sampling frequency of 180h(-1). With consumption of 0.5mL sample solution, an enhancement factor of 2400 was obtained. The precision (RSD) for eleven replicate determinations of 20microgL( 1) Ni was 3.4%. The developed FI-CVG-AFS method was successfully applied to determination of trace Ni in several certified biological reference materials. PMID- 19786175 TI - Automated determination of mercury and arsenic in extracts from ancient papers by integration of solid-phase extraction and energy dispersive X-ray fluorescence detection using a lab-on-valve system. AB - A method to detect the presence and determine the concentration of mercury and arsenic in extracts of ancient papers, based on an approach which allows integration of solid-phase concentration of the target analytes and their detection, is proposed. Automation of the overall process (viz. swelling and conditioning of the sorbent, sample introduction for analytes retention, drying of the sorbent by air for proper measurement, elution and conditioning of the sorbent prior to introduction of the next sample) is achieved by on-line connection of a lab-on-valve system to a laboratory-made methacrylate cell for concentration-measurement. After optimization of the variables influencing the method, characterization of the method provided LODs and LOQs of 0.006 and 0.02microgg(-1) of paper, respectively, for Hg; and 0.007 and 0.027microgg(-1), respectively, for As, with repeatability of 6.37% for Hg and 5.62% for As, and reproducibility of 8.13% and 7.46% for Hg and As, respectively. PMID- 19786176 TI - Ultratrace determination of Pb, Se and As in wine samples by electrothermal vaporization inductively coupled plasma mass spectrometry. AB - The determination of Pb, Se and As in wine has a great interest due to health risks and legal requirements. To perform the analysis of wine, two considerations must be taken into account: (i) the low concentration level of the analytes; and (ii) the risk of interferences due to wine matrix components. The goal of this work is to evaluate electrothermal vaporization (ETV) sample introduction for ultratrace determination of Pb, Se and As in wine samples by inductively coupled plasma mass spectrometry (ICP-MS). The results obtained with ETV-ICP-MS were compared to those obtained with conventional liquid sample introduction in ICP-MS and electrothermal atomic absorption spectrometry (ETAAS). Analytical figures of merit of ETV sample introduction strongly depend on the amount of wine sample, on the modifier nature (i.e. Pd, ascorbic acid or citric acid) and concentration and on the temperature program. Wine matrix components exert a great influence on analyte transport efficiency. Due to this fact, the analysis of wine cannot be performed by means of external calibration but the standard addition methodology should be used. The determination of Pb and Se in wine by ETV-ICP-MS provides similar results as conventional liquid sample introduction ICP-MS. For As, the concentration values obtained with ETV sample introduction were between two and four times lower than with the conventional system. These differences are related to the lower intensity of polyatomic interferences (i.e. (40)Ar(35)Cl(+) vs. (75)As(+)) obtained for ETV sample introduction when compared to the conventional system. Finally, no differences for Pb determination were observed between ETV sample introduction and ETAAS. Unfortunately, the limits of detection for As and Se in ETAAS were not low enough to quantify these elements in the wine samples tested. PMID- 19786177 TI - Experimental design in chemistry: A tutorial. AB - In this tutorial the main concepts and applications of experimental design in chemistry will be explained. Unfortunately, nowadays experimental design is not as known and applied as it should be, and many papers can be found in which the "optimization" of a procedure is performed one variable at a time. Goal of this paper is to show the real advantages in terms of reduced experimental effort and of increased quality of information that can be obtained if this approach is followed. To do that, three real examples will be shown. Rather than on the mathematical aspects, this paper will focus on the mental attitude required by experimental design. The readers being interested to deepen their knowledge of the mathematical and algorithmical part can find very good books and tutorials in the references [G.E.P. Box, W.G. Hunter, J.S. Hunter, Statistics for Experimenters: An Introduction to Design, Data Analysis, and Model Building, John Wiley & Sons, New York, 1978; R. Brereton, Chemometrics: Data Analysis for the Laboratory and Chemical Plant, John Wiley & Sons, New York, 1978; R. Carlson, J.E. Carlson, Design and Optimization in Organic Synthesis: Second Revised and Enlarged Edition, in: Data Handling in Science and Technology, vol. 24, Elsevier, Amsterdam, 2005; J.A. Cornell, Experiments with Mixtures: Designs, Models and the Analysis of Mixture Data, in: Series in Probability and Statistics, John Wiley & Sons, New York, 1991; R.E. Bruns, I.S. Scarminio, B. de Barros Neto, Statistical Design-Chemometrics, in: Data Handling in Science and Technology, vol. 25, Elsevier, Amsterdam, 2006; D.C. Montgomery, Design and Analysis of Experiments, 7th edition, John Wiley & Sons, Inc., 2009; T. Lundstedt, E. Seifert, L. Abramo, B. Thelin, A. Nystrom, J. Pettersen, R. Bergman, Chemolab 42 (1998) 3; Y. Vander Heyden, LC-GC Europe 19 (9) (2006) 469]. PMID- 19786178 TI - Spectroscopic correlation analysis of NMR-based metabonomics in exercise science. AB - Spectroscopic studies of complex clinical fluids have led to the application of a more holistic approach to their chemical analysis becoming more popular and widely employed. The efficient and effective interpretation of multidimensional spectroscopic data relies on many chemometric techniques and one such group of tools is represented by so-called correlation analysis methods. Typical of these techniques are two-dimensional correlation analysis and statistical total correlation spectroscopy (STOCSY). Whilst the former has largely been applied to optical spectroscopic analysis, STOCSY was developed and has been applied almost exclusively to NMR metabonomic studies. Using a (1)H NMR study of human blood plasma, from subjects recovering from exhaustive exercise trials, the basic concepts and applications of these techniques are examined. Typical information from their application to NMR-based metabonomics is presented and their value in aiding interpretation of NMR data obtained from biological systems is illustrated. Major energy metabolites are identified in the NMR spectra and the dynamics of their appearance and removal from plasma during exercise recovery are illustrated and discussed. The complementary nature of two-dimensional correlation analysis and statistical total correlation spectroscopy are highlighted. PMID- 19786179 TI - Strategy for reduced calibration sets to develop quantitative structure-retention relationships in high-performance liquid chromatography. AB - In high-performance liquid chromatography, quantitative structure-retention relationships (QSRRs) are applied to model the relation between chromatographic retention and quantities derived from molecular structure of analytes. Classically a substantial number of test analytes is used to build QSRR models. This makes their application laborious and time consuming. In this work a strategy is presented to build QSRR models based on selected reduced calibration sets. The analytes in the reduced calibration sets are selected from larger sets of analytes by applying the algorithm of Kennard and Stone on the molecular descriptors used in the QSRR concerned. The strategy was applied on three QSRR models of different complexity, relating logk(w) or logk with either: (i) logP, the n-octanol-water partition coefficient, (ii) calculated quantum chemical indices (QCI), or (iii) descriptors from the linear solvation energy relationship (LSER). Models were developed and validated for 76 reversed-phase high performance liquid chromatography systems. From the results we can conclude that it is possible to develop logP models suitable for the future prediction of retentions with as few as seven analytes. For the QCI and LSER models we derived the rule that three selected analytes per descriptor are sufficient. Both the dependent variable space, formed by the retention values, and the independent variable space, formed by the descriptors, are covered well by the reduced calibration sets. Finally guidelines to construct small calibration sets are formulated. PMID- 19786180 TI - Potential antioxidant compounds in Mallotus species fingerprints. Part I: Indication, using linear multivariate calibration techniques. AB - Some Mallotus species are used in traditional medicine in Vietnam and China. Some also show interesting activities, such as antioxidant and cytotoxic ones. Combining fingerprint technology with data-handling techniques allows indicating the peaks potentially responsible for given activities. In this study it is aspired to indicate from chromatographic fingerprints the peaks potentially responsible for the antioxidant activity of several Mallotus species. Relevant information was extracted using linear multivariate calibration techniques, both before and after alignment of the fingerprints with correlation optimized warping (COW). From the studied techniques, stepwise multiple linear regression is least recommended as it made an inadequate variable selection. Principal component regression theoretically can take largely varying variables uncorrelated to the antioxidant activity into account. However, in practice in the actual case study this problem was limited. These problems in principle do not occur using partial least squares (PLS) models. Of the tested PLS methods, orthogonal projections to latent structures was preferred because of its simplicity, reproducibility, reduced model complexity and improved interpretability of the regression coefficients, yielding a clearer view on the individual contribution of the compounds. Furthermore, reducing analysis times from 60min to 35 and 22.5min resulted in the same main compounds, indicated responsible for the antioxidant activity. Models built after alignment by COW did not result in additional information. PMID- 19786181 TI - Indirect pulsed electrochemical detection of amino acids and proteins following high performance liquid chromatography. AB - Pulsed electrochemical detection (PED) following liquid chromatographic separation has been applied to the indirect determination of amino acids and proteins. Here, the adsorption of these analytes at noble metal electrodes is exploited to suppress the oxidation of polyols and carbohydrates under alkaline conditions to elicit an indirect response. Of the reagents tested, gluconic acid gave the best overall signal-to-noise values for the indirect detection of amino acids following high performance anion-exchange chromatography (HPAEC). Limits of detection of amino acids were found to be 2-30pmol using optimized potential-time waveforms at an Au electrode. Indirect PED provided much greater detection sensitivity toward amino acids than direct PED. Analytical sensitivity of indirect PED is a function of both the analyte's ability to adsorb to the electrode surface and its molecular size, which was demonstrated by the separation and detection of bovine serum albumin, ovalbumin, and myoglobin following gel-filtration chromatography (GFC). PMID- 19786182 TI - Systematic evaluation of electrode kinetics and impact of surface heterogeneity for surface-confined proteins using analysis of harmonic components available in sinusoidal large-amplitude Fourier transformed ac voltammetry. AB - A systematic approach to quantifying the electrode kinetics of surface-confined proteins and identifying the impact of surface heterogeneity is presented. The evaluation approach is based on analysis of individual harmonics derived from Fourier transformed large-amplitude ac voltammetry, and their peak current magnitude, I(p)(nomegat) versus frequency, f, relationships. Effectively, variability in the time-scale of each harmonic is expected, and advantage is taken of the fact that each individual harmonic displays a different level of sensitivity with respect to the kinetic evaluation. The data strategy protocols have been examined for the azurin Cu(II)/Cu(I) process when this metalloprotein is immobilized on gold electrodes modified alkanethiols having different chain lengths, using both pure and mixed thiol systems. I(p)(nomegat) versusf relationships also offer the advantage of the ability to detect and allow for the ohmic IR(u) drop effect and allow analyses that are independent of protein surface coverage. Estimation of an electron transfer rate is achievable from this form of analysis. However, experimentally observed waveshapes for each individual harmonic are consistently broader than that deduced theoretically on the basis of their rate constants because of kinetic and/or thermodynamic dispersion. In the mixed thiol systems, and with use of the ac method, kinetic discrimination is achieved for fast processes. This systematic study based on a model protein indicates that a more comprehensive level of evaluation of electrode kinetics can be derived from analysis of the ac harmonics available in large-amplitude ac voltammetry, by initially using I(p)(nomegat)-f data to evaluate the electrode kinetics followed by waveshape analysis to detect heterogeneity effects that give rise to kinetic or thermodynamic dispersion. PMID- 19786183 TI - Deployment of DGT units in marine waters to assess the environmental risk from a deep sea tailings outfall. AB - Measurements of total, filterable and DGT-labile concentrations of nine metals (Al, Cd, Cr, Cu, Fe, Pb, Mn, Ni and Zn) have been made at five sites up to 4.2km from a deep sea tailings outfall operated by Lihir Gold Ltd. at Lihir Island, Papua New Guinea. At each site, pairs of DGT units (one containing a 0.4mm and the other a 0.8mm diffusive gel layer) were deployed at three depths (50-70; 105 130; 135-155m) for 4-7 days. Comparison of predicted water column DGT-labile metal concentrations in field deployments showed the 0.8mm DGT units were relatively enriched in metals, with the effect being greatest closer to the outfall for Pb and Mn and least for Fe, Cr, Ni and Zn. The most likely explanation for this is that in addition to simple ion diffusion, kinetic factors associated with ageing or desorption processes govern release of metals from iron and aluminium oxyhydroxide colloids which diffuse through the gels. The thicker gels have a longer residence time over which metals can be released for adsorption. This model explains why enrichment is most pronounced near the outfall; more distant sites have lower colloid concentrations because of the longer time for coagulation to increase particle sizes to the extent they cannot enter the gels. Total and filterable metal (FM) concentrations were frequently below the limits of detection (LOD) achievable by conventional ICP-AES (1 52microgL(-1)) and this limited their usefulness for assessing environmental risk and for metal speciation determination. Because of its pre-concentration step DGT gave metal concentrations above their LODs and these decreased exponentially with distance from the outfall. Concentrations of DGT-labile metal fell below Australian water quality guidelines for protection of 99% of marine organisms within 0.13km of the outfall for Cd, Cr and Ni and below that for protection of 95% of marine organisms within 0.4, 0.7 and 3.6km for lead, zinc and copper, respectively. PMID- 19786184 TI - Study of desorption kinetics of polycyclic aromatic hydrocarbons (PAHs) from solid matrices using internally cooled coated fiber. AB - The kinetics of desorption of hydrophobic organic compounds (HOCs) from soil and sediment particles is important both from environmental and analytical chemistry points of view. Reliable techniques are required for prediction of desorption behaviour of HOCs from contaminated soils and sediments. In this study internally cooled coated fiber device, in which a PDMS hollow fiber extraction phase is cooled with liquid CO(2), was used as an exhaustive extraction sorbent phase for extraction of desorbed organic compounds (e.g. polycyclic aromatic hydrocarbons, PAHs) from both laboratory-spiked and naturally contaminated solid sample into the gaseous headspace in a batch system. The extraction time profiles were obtained at two different elevated temperatures (above 100 degrees C) for spiked sand and silica gel matrices. The slow desorption rate constants at each temperature were determined from desorption plots and the apparent activation energies of desorption were obtained from Arrhenius equations. The apparent activation energies of desorption of naphthalene, acenaphthylene and acenaphthene, from spiked silica gel, were approximately 60kJmol(-1), and were higher, 70 and 100kJmol(-1) for fluoranthene and anthracene, respectively. The fast and slow desorption rates and apparent activation energies of desorption for PAHs were obtained by spiking a naturally contaminated sediment sample with deuterated PAHs (PAHs-d(10)). The activation energies of native PAHs were higher than those of spiked deuterated PAHs, suggesting that the native compounds were more affected by retarded pore diffusion or slow mass transfer through glassy sorbent organic matter (SOM). The proposed technique in the present study is fully automated, and can extract the contaminants from the solid matrix fast and exhaustively, which makes it more time efficient and versatile compared to the commonly used technique for desorption studies, i.e. vial desorption. PMID- 19786185 TI - The use of carrier RNA to enhance DNA extraction from microfluidic-based silica monoliths. AB - DNA extraction was carried out on silica-based monoliths within a microfluidic device. Solid-phase DNA extraction methodology was applied in which the DNA binds to silica in the presence of a chaotropic salt, such as guanidine hydrochloride, and is eluted in a low ionic strength solution, such as water. The addition of poly-A carrier RNA to the chaotropic salt solution resulted in a marked increase in the effective amount of DNA that could be recovered (25ng) compared to the absence of RNA (5ng) using the silica-based monolith. These findings confirm that techniques utilising nucleic acid carrier molecules can enhance DNA extraction methodologies in microfluidic applications. PMID- 19786186 TI - A historical account of conferences devoted to flow methods in analytical chemistry--International Conference on Flow Analysis (FA) and International Conference on Flow Injection Analysis (ICFIA). AB - Flow methods of analysis represent one of the most studied and practiced areas of analytical chemistry. Two major international conferences are regularly held devoted to these methods. The International Conference on Flow Analysis (FA) began in 1979, and the International Conference on Flow Injection Analysis (ICFIA) began in 1989, originally as the Winter Conference on Flow Injection Analysis (WCFIA). ICFIA has been held jointly with the Japanese Association for Flow Injection Analysis (JAFIA) since 1998. A historical account is given of these two conferences, with references to proceedings and reports of the conferences. PMID- 19786187 TI - Development of a gel-to-gel electro-kinetic pinched injection method for an integrated micro-fluidic based DNA analyser. AB - An integrated gel supported micro-fluidic system is reported, in which PCR products can be efficiently injected into a capillary electrophoresis device. The gel supported system is designed to provide greater stability to reagents during long periods of dormancy, enabling the mass production of one use chips encapsulating all required reagents at the time of manufacturing. This simultaneously diminishes the risk of sample contamination, and reduces the amount of external hardware required for auxiliary flow control, thus increasing the potential for portability. After PCR amplification was performed in a polysaccharide gel matrix, the PCR product was injected into the separation gel polymer matrix by executing a capillary-based electro-kinetic pinched injection across a gel-to-gel interface. The gel-to-gel system delivered a precise and accurate plug into the separation polymer, which offered more stable electro kinetic control of the sample compared to solution based methodology even when bubbles were present in the system. Suitable voltage control was proven to provide a repeatable electro-kinetic injection of PCR product sufficient for an on-chip separation of multiple loci by capillary electrophoresis. PMID- 19786188 TI - A permeable membrane capacitance sensor for ionogenic gases Application to the measurement of total organic carbon. AB - We introduce a unique sensor, a tubular membrane capacitance sensor (TMCS). Wire electrodes are wrapped on a porous hydrophobic membrane tube and capacitance is measured with an inexpensive universal serial bus powered capacitance to voltage digital converter. At low solution conductivities, the double layer capacitance of the ionic solution is approximately linearly related to the solution conductance. Porous polypropylene hollow fibers were coated repeatedly with silicone rubber solutions to render the pores highly hydrophobic and hence minimize gradual liquid intrusion into the pores that leads to baseline drift. We applied the sensor to the determination of TOC in water samples where the analyte carbon was oxidized to CO(2) by UV/persulfate. The evolved CO(2) is sensed by the TMCS as the water slowly passing through it absorbs the CO(2) resulting in a change in conductance and capacitance. The system was capable of detecting 800ngC as glucose and 100ngC as inorganic carbonate. The sensor combines the dual functions of gas collection and measurement, thus permitting a simple miniature economic device. PMID- 19786189 TI - Simultaneous detection of selenium by atomic fluorescence and sulfur by molecular emission by flow-injection hydride generation with on-line reduction for the determination of selenate, sulfate and sulfite. AB - An inductively coupled plasma atomic fluorescence spectrometry (ICP-AFS) instrument, was modified so that it was capable of monitoring transient chromatographic or flow-injection profiles and that sulfur molecular emission and selenium atomic fluorescence could be monitored simultaneously in an argon hydrogen diffusion flame on a glass burner. The analytes were introduced as hydrogen selenide and hydrogen sulfide, generated on a flow-injection manifold. Selenate was reduced to hydride-forming selenite by microwave-assisted on-line reaction with hydrochloric acid, and sulfate, or sulfite, was reduced to hydride forming sulfide by a mixture of hydriodic acid, acetic acid and sodium hypophosphite. The effects of the nature of reducing agent, flow rate, microwave power and coil length were studied. The limit of detection (3s) for selenium was 10microgL(-1), and for sulfide was 70microgL(-1) (200-microL injection volume). The calibration was linear for selenium up to 2mgL(-1) and to 10mgL(-1) for sulfide. The throughput was 180h(-1). The three sulfur species could be differentiated on the basis of reactivity at various microwave powers. PMID- 19786190 TI - Investigation of iron(III) reduction and trace metal interferences in the determination of dissolved iron in seawater using flow injection with luminol chemiluminescence detection. AB - A detailed investigation into the performance of two flow injection chemiluminescence (FI-CL) manifolds (with and without a preconcentration column) for the determination of sub-nanomolar dissolved iron (Fe(II)+Fe(III)), following the reduction of Fe(III) by sulphite, in seawater is described. Kinetic experiments were conducted to examine the efficiency of reduction of inorganic Fe(III) with sulphite under different conditions and a rigorous study of the potential interference caused by other transition metals present in seawater was conducted. Using 100microM concentrations of sulphite a reduction time of 4h was sufficient to quantitatively reduce Fe(III) in seawater. Under optimal conditions, cobalt(II) and vanadium(IV)/(III) were the major positive interferences and strategies for their removal are reported. Specifically, cobalt(II) was masked by the addition of dimethylglyoxime to the luminol solution and vanadium(IV) was removed by passing the sample through an 8-hydroxyquinoline column in a low pH carrier stream. Manganese(II) also interfered by suppression of the CL response but this was not significant at typical open ocean concentrations. PMID- 19786191 TI - Determination of arsenic in industrial samples by pervaporation flow injection with amperometric detection. AB - This paper describes a simple and inexpensive pervaporation flow injection (PFI) system for the on-line determination of arsenic in industrial samples based on amperometric detection. The PFI system uses on-line hydride generation for the separation of As(III) from the sample matrix thus substantially reducing matrix interferences associated with "dirty" industrial samples. A method for the speciation of As(III) and As(V) is also described. The PFI system is validated using hydride generation atomic absorption spectrometry. There was no statistically significant difference at the 95% confidence level between the results for the two methods. The proposed PFI method is characterised by a wide analytical concentration range (0.05-60mgL(-1)), a detection limit for As(III) of 1.0microgL(-1) and a sample throughput of 12h(-1). PMID- 19786192 TI - Analysis of small bubbles in glass by glow discharge--time-of-flight mass spectrometry. AB - The chemical reactions occurring during the glass manufacturing processes can give rise to small bubbles, damaging the required glass properties. To avoid eventual bubbles formation, the chemical composition of the bubbles should be known to trace back the gas sources and take appropriate corrective actions. Mass spectrometry is a most adequate detection technique for such purpose due to its ability to provide the required information in a short time. Analysis of these small bubbles in glass requires a system incorporating a very small volume (for a fast evacuation of the entire line and low dilution of the analytes) and a fast mass analyser allowing the quasi-simultaneous detection of the whole spectral interval of interest, such as a time-of-flight mass spectrometer (TOFMS). In this work, the analytical potential of a radiofrequency glow discharge (rf-GD) coupled to a TOFMS was evaluated for the first time for the analysis of bubbles in glasses. The operating conditions of the rf-GD (pressure and applied power) were optimized by introducing into the system known volumes of air. Detection limits in the order of nL were obtained for molecular nitrogen, oxygen and carbon dioxide. Finally, a stainless steel bellows valve was modified to serve as glass breaker for the sampling process. This valve was connected on-line to the mass spectrometer inlet line and proved to be most appropriate for the analysis of the gaseous content of bubbles (with diameters below 0.5mm) entrapped in industrial glasses. PMID- 19786193 TI - Carbon nanotube-quantum dot nanocomposites as new fluorescence nanoparticles for the determination of trace levels of PAHs in water. AB - Amplification of fluorescence is a nanoscale phenomenon which is particularly pronounced in close proximity to metal nanostructures. We have demonstrated for first time that fluorescence amplification can also be produced by single-walled carbon nanotube-quantum dot nanocomposites (SWCNT-QDs). Concretely we exploit the adsorption capabilities of SWCNTs to facilitate the interaction of analytes with the nanoparticle. The fluorescence amplification mechanism is discussed in the paper. The analytical potential of these nanocomposites has been demonstrated for the detection of trace levels of polycyclic aromatic compounds (PAHs) in river water samples. Compared with QDs nanoparticles, the fluorescence enhancement achieved with the SWCNT-QDs nanocomposites was 3.6-5.5 times higher. PMID- 19786194 TI - High-resolution steady-state and time-resolved luminescence studies on the complexes of Eu(III) with aromatic or aliphatic carboxylic acids. AB - Eu(III) luminescence spectroscopy, both in the steady-state and the time-resolved mode, is an appropriate technique to study the properties of complexes between heavy metal ions and humic substances (HS), which play a key role in the distribution of metal species in the environment. Unfortunately, room temperature luminescence spectra of Eu(III) complexes with aromatic and aliphatic carboxylic acids - model compounds of HS binding sites - are too broad to fully exploit their potential analytical information content. It is shown that under cryogenic conditions fluorescence-line-narrowing (FLN) is achieved, and the highly resolved spectra provide detailed information on the complexes. Ten model ligands were investigated. Total luminescence spectra (TLS) were recorded, using the (5)D(0)<- (7)F(0) transition for excitation and the (5)D(0)-->(7)F(1) and (5)D(0)-->(7)F(2) transitions for emission. The energy of the excitation transition depends on the ligand involved and the structure and composition of the complex. For most ligands, discontinuities in the high-resolution TLS indicated that more species, i.e. distinct complex structures, coexisted in the sample. Selective excitation was performed to measure the species-associated luminescence decay times tau. The latter strongly depend on nearby OH oscillators from coordinating water molecules or ligand hydroxyl groups. Furthermore, the asymmetry ratios r, defined as the intensity ratio of the (5)D(0)-->(7)F(2) and (5)D(0)-->(7)F(1) transitions, were calculated and the variation of the excitation energy E(exc) with the splitting of the (7)F(1) triplet (DeltaE) was determined, which yielded the crystal field strength parameter N(nu)(B(2q)), as well as the crystal field parameters B(20) and B(22). An in-depth analysis of the results is presented, providing detailed information on the number of coexisting complexes, their stoichiometry, the number of water molecules in the first coordination sphere and their geometry (symmetry point group). PMID- 19786195 TI - Development and validation of a chemiluminogenic method for the evaluation of antioxidant activity of hydrophilic and hydrophobic antioxidants. AB - A sensitive and simple procedure is described for evaluating the antioxidant activity of 21 known hydrophilic and hydrophobic compounds by using the chemiluminogenic reaction of lucigenin with hydrogen peroxide. The method was validated for linearity, limit of detection, precision, additivity and ruggedness and compared to the DPPH method. Furthermore, the IC(50) values of all compounds were calculated and compared by both methods and results are discussed on the basis of structure-antioxidant activity relationship. Among hydrophilic antioxidants, phenolic compounds with adjacent hydroxyl groups (gallic acid, caffeic acid, pyrocatechol, (+/-)-catechin, oleuropein) were found to be efficient antioxidants in chemiluminescence method with IC(50) values at the sub micromolar range, while phenolic compounds without adjacent hydroxyl groups (p coumaric acid, BHT, BHA, resorcinol) exhibited weak activity with IC(50) values>10microM. Alpha-tocopherol was the most efficient hydrophobic antioxidant (IC(50)=6.7microM) while oleic and linoleic acids were found to be very poor antioxidants (IC(50)>300microM). Finally the method was applied to the estimation of antioxidant activity of complex samples such as olive oils. To the best of our knowledge, this is the first time that total antioxidant activity can be determined directly in olive oil and not in aqueous extracts. PMID- 19786196 TI - Chemiluminescence spectra for the oxidation of sulphite in the presence of fluorescent and non-fluorescent enhancers. AB - The spectral distribution of chemiluminescence provides key evidence in the elucidation of the reaction mechanism and emitting species. We have collected chemiluminescence spectra for the oxidation of sodium sulphite and captopril in the presence of a range of fluorescent and non-fluorescent enhancers. This evidence was used to evaluate several previously proposed light-producing pathways, and revealed some new approaches to enhance the chemiluminescent oxidation of sulphite and thiol compounds. Chemiluminescence reactions between sulphite and permanganate produce two potential emitters: one derived from the oxidation of sulphite (in some cases via energy transfer to a more efficient luminophore) and another derived from the reduction of permanganate. This second light-producing pathway is rarely considered in discussions on the chemiluminescent oxidation of sulphite, but can make a significant contribution to the overall emission. Non-fluorescent enhancers of sulphite chemiluminescence result in several distinct spectral distributions and, contrary to previous postulation, these reactions are unlikely to lead to the same emitting species. Non-fluorescent enhancers of sulphite chemiluminescence can also significantly increase the weak emission from the oxidation of thiol compounds such as captopril. PMID- 19786197 TI - Inkjet printed LED based pH chemical sensor for gas sensing. AB - Predictable behaviour is a critical factor when developing a sensor for potential deployment within a wireless sensor network (WSN). The work presented here details the fabrication and performance of an optical chemical sensor for gaseous acetic acid analysis, which was constructed using inkjet printed deposition of a colorimetric chemical sensor. The chemical sensor comprised a pH indicator dye (bromophenol blue), phase transfer salt tetrahexylammonium bromide and polymer ethyl cellulose dissolved in 1-butanol. A paired emitter-detector diode (PEDD) optical detector was employed to monitor responses of the colorimetric chemical sensor as it exhibits good sensitivity, low power consumption, is low cost, accurate and has excellent signal-to-noise ratios. The chemical sensor formulation was printed directly onto the surface of the emitter LED, and the resulting chemical sensors characterised with respect to their layer thickness, response time and recovery time. The fabrication reproducibility of inkjet printed chemical sensors in comparison to drop casted chemical sensors was investigated. Colorimetric chemical sensors produced by inkjet printing, exhibited an improved reproducibility for the detection of gaseous acetic acid with a relative standard deviation of 5.5% in comparison to 68.0% calculated for drop casted sensors (n=10). The stability of the chemical sensor was also investigated through both intra and inter-day studies. PMID- 19786198 TI - Speciation of selenium dietary supplements; formation of S-(methylseleno)cysteine and other selenium compounds. AB - Speciation of selenium is of interest because it is both essential and toxic to humans, depending on the species and the amount ingested. Following indications that selenium supplementation could reduce the incidence of some cancers, selenium-enriched yeast and other materials have been commercialized as supplements. Most dramatically however, the SELECT trial that utilized l selenomethionine as the active supplement was terminated in 2008 and there is much debate regarding both the planning and the results of efficacy studies. Further, since dietary supplements are not regulated as pharmaceuticals, there are concerns about the quality, storage conditions, stability and selenium content in selenium supplements. Enzymatic hydrolysis enabled selenium speciation profiles to be obtained by high performance liquid chromatography with inductively coupled plasma mass spectrometry (HPLC-ICP-MS) and following derivatization gas chromatography with atomic emission detection (GC-AED). Coated fiber solid phase microextraction (SPME) was used to extract volatile selenium species for determination by GC-AED and GC-MS. Similar speciation patterns were observed between yeast-based supplements subject to extended storage and those heated briefly at elevated temperatures. All the yeast-based supplements and one yeast-free supplement formed S-(methylseleno)cysteine on heating. Evidence was obtained in support of the hypotheses that S-(methylseleno)cysteine is formed from a reaction between dimethyldiselenide and cysteine or cystine. PMID- 19786199 TI - Integration of monolithic frit into the particulate capillary (IMFPC) column in shotgun proteome analysis. AB - Capillary column plays an important role in nano-flow liquid chromatography coupled with tandem mass spectrometry for dealing with the high dynamic range and complexity of protein samples in shotgun proteome analysis. In this study, the integrated monolithic frit into the particulate capillary (IMFPC) column was prepared. By comparing the prepared IMFPC column with conventionally fritless capillary column, smaller size of packing materials could be easily packed into the capillary to achieve higher average peak capacity and proteome coverage. As the monolithic emitter was integrated onto this type of column, the void volume between packing particles and electrospray emitter was eliminated and the electrospray quality was improved. The prepared IMFPC column was applied to proteome analysis of mouse liver extracts, and it was observed that the number of identified proteins and peptides increased 14.9 and 12.9% as well as the peak capacity increased 11.6% by using IMFPC column over conventionally fritless capillary column. PMID- 19786200 TI - The new age of iron: evaluation and management of iron-restricted erythropoiesis. PMID- 19786201 TI - Recycling iron in normal and pathological states. AB - Important advances in our understanding of iron metabolism have been made during the past 10 years, highlighting the mechanisms by which dysregulated iron homeostasis leads to hematologic, metabolic, and neurodegenerative diseases. In particular, the discovery of hepcidin and its fundamental role as the hormonal peptide regulating iron metabolism has delineated the organization of the complex network of proteins that regulates iron metabolism within the body. Maintenance of iron homeostasis is the consequence of tight coordination between iron absorption from the diet by enterocytes, and iron recycling by macrophages following degradation of senescent erythrocytes. Thus, any perturbation of these processes leads to a wide spectrum of diseases, ranging from iron deficiency anemia to iron overload. This review will focus particularly on the mechanisms involved in iron recycling by macrophages and summarize the pathological conditions perturbing this process. PMID- 19786202 TI - Pathogenesis and management of iron deficiency anemia: emerging role of celiac disease, helicobacter pylori, and autoimmune gastritis. AB - The causes of iron deficiency vary significantly during different stages of life, and according to gender and socioeconomic circumstances. Although dietary iron is important, iron deficiency anemia (IDA) is mostly attributed to blood loss and may be the presenting clinical feature of occult bleeding from the gastrointestinal (GI) tract heralding underlying malignancy. Conventional GI diagnostic workup fails to establish the cause of iron deficiency in about one third of patients. However, abnormal iron absorption caused by hereditary iron refractory iron deficiency anemia (IRIDA) or acquired disease is increasingly recognized as an important cause of unexplained iron deficiency. The recent availability of convenient, non-invasive screening methods to identify celiac disease, autoimmune atrophic gastritis and Helicobacter pylori infection has greatly facilitated the recognition of patients with these entities. Cure of previously refractory IDA by H pylori eradication provides strong evidence supporting a cause-and-effect relation. The intriguing recent observations of H pylori antibodies directed against epitopes on gastric mucosal cells in atrophic gastritis imply an autoimmune mechanism triggered by H pylori and directed against gastric parietal cells by means of antigenic mimicry. Improved understanding of the role of abnormal iron absorption in IDA has important implications for current concepts related to the pathogenesis and management of IDA. PMID- 19786203 TI - Animal models of anemia of inflammation. AB - Anemia of inflammation (AI) is a complex multi-organ response to inflammatory disorders. Because AI can result from many infectious and non-infectious inflammatory diseases, multiple mechanisms may contribute to its pathogenesis, including iron restriction, direct erythropoietic suppression, shortened red blood cell survival, and frank hemolysis. Animal models have been helpful in the study of the mechanisms of AI and its potential treatments, but each model reflects distinct aspects of this heterogeneous syndrome. It is therefore important to study a variety of models of AI. This review focuses on the use of infectious and noninfectious mouse models of inflammation that have been shown to manifest anemia. We review many of the models reported in the literature or developed in our laboratory, and discuss their respective merits and drawbacks. PMID- 19786204 TI - Mutations in the gene encoding DMT1: clinical presentation and treatment. AB - Divalent metal transporter 1 (DMT1) is the protein that allows elemental iron entry into the duodenal cell. It is expressed ubiquitously and it also allows the iron exit from the endosomes. This protein plays a central role in iron metabolism and it is strictly regulated. Several animal models elucidate its role in physiology. Recently three patients affected with DMT1 deficiency have been described. This recessively inherited condition appears at birth with severe microcytic anemia. Serum markers could be particularly useful to establish a correct diagnosis: high serum iron, normal total iron-binding capacity (TIBC), increased saturation of transferrin (Tf), slightly elevated ferritin, and increased soluble transferrin receptor (sTfR). Increased free erythrocyte protoporphyrins (FEPs) could address the diagnosis to iron-deficient anemia. All patients appeared to respond to erythropoietin (Epo) administration. Because mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) did not change during Epo treatment, it was concluded that Epo did not improve iron utilization of the erythroblasts but likely reduced the degree or intensity of apoptosis, affecting erythropoiesis. Moreover liver iron overload was present and documented in all of the affected patients. In this review we analyze the role of DMT1 in iron metabolism and the major causes of reduction and their consequences in animal models as well in humans, and we attempt to define the correct treatment for human mutants. PMID- 19786205 TI - Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment. AB - Inherited sideroblastic anemia comprises several rare anemias due to heterogeneous genetic lesions, all characterized by the presence of ringed sideroblasts in the bone marrow. This morphological aspect reflects abnormal mitochondrial iron utilization by the erythroid precursors. The most common X linked sideroblastic anemia (XLSA), due to mutations of the first enzyme of the heme synthetic pathway, delta-aminolevulinic acid synthase 2 (ALAS2), has linked heme deficiency to mitochondrial iron accumulation. The identification of other genes, such as adenosine triphosphate (ATP) binding cassette B7 (ABCB7) and glutaredoxin 5 (GLRX5), has strengthened the role of iron sulfur cluster biogenesis in sideroblast formation and revealed a complex interplay between pathways of mitochondrial iron utilization and cytosolic iron sensing by the iron regulatory proteins (IRPs). As recently occurred with the discovery of the SLC25A38-related sideroblastic anemia, the identification of the genes responsible for as yet uncharacterized forms will provide further insights into mitochondrial iron metabolism of erythroid cells and the pathophysiology of sideroblastic anemia. PMID- 19786206 TI - Iron-refractory iron deficiency anemia. AB - Iron-refractory iron deficiency anemia (IRIDA) is an autosomal recessive disorder characterized by iron deficiency anemia unresponsive to oral iron treatment but partially responsive to parenteral iron therapy. IRIDA has recently been shown to be caused by mutations in the gene TMPRSS6, which encodes a transmembrane serine protease (also known as matriptase-2) expressed by the liver. IRIDA patients show inappropriately elevated levels of hepcidin, a circulating hormone produced by the liver that inhibits both iron absorption from the intestine and iron release from macrophage stores. Recent studies suggest that TMPRSS6 normally acts to downregulate hepcidin expression by cleaving hemojuvelin, a membrane-bound protein that promotes hepcidin signaling in hepatocytes. A discussion of the clinical presentation of IRIDA, the molecular genetics of this disorder, and recent studies elucidating the underlying pathophysiology are presented. PMID- 19786208 TI - Review. PMID- 19786207 TI - Iron sequestration and anemia of inflammation. AB - Anemia of chronic disease, also called anemia of inflammation, is characterized by hypoferremia due to iron sequestration that eventually results in iron restricted erythropoiesis. During the last decade, the molecular mechanisms of iron sequestration have been found to center on cytokine-stimulated overproduction of the iron-regulatory hormone hepcidin. The inflammatory cytokine interleukin-6 (IL-6) is a particularly prominent inducer of hepcidin, but other cytokines are likely to contribute as well. Hepcidin excess causes the endocytosis and proteolysis of the sole known cellular iron exporter, ferroportin, trapping iron in macrophages and iron-absorbing enterocytes. The supply of iron to hemoglobin synthesis becomes limiting, eventually resulting in anemia. Depending on the details of the underlying disease, other inflammation related mechanisms may also contribute to anemia. PMID- 19786209 TI - Extracts from The Cochrane Library: Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer. AB - The "Cochrane Corner" is a quarterly section in the Journal that highlights systematic reviews relevant to otolaryngology-head and neck surgery, with invited commentary to aid clinical decision making. This installment features a Cochrane Review entitled "Erythropoietin as an adjuvant treatment with (chemo) radiation therapy for head and neck cancer," which concludes that erythropoietin should not be administered as an addition to radiation therapy outside the experimental setting. PMID- 19786210 TI - Nonasthmatic nasal polyposis patients with allergy exhibit greater epithelial MMP positivity. AB - OBJECTIVE: To determine the influence of allergic rhinitis (AR) on the expression of matrix metalloproteinase (MMP)-9, MMP-2, and tissue inhibitor-1 of metalloproteinase (TIMP-1) in nasal polyposis. STUDY DESIGN: A case-control study. SETTING: A tertiary referral center. SUBJECTS AND METHODS: The expression of MMP-9, MMP-2, and TIMP-1 was investigated in the nasal polyp tissue (NP) and maxillary sinus mucosa (MM) samples from 20 AR patients and 20 nonallergic patients undergoing endoscopic sinus surgery. Trichrome, periodic acid-Schiff, and hematoxylin-eosin staining were also performed and those expression levels were compared. RESULTS: Infiltration of eosinophils was shown more intensely in NP rather than in MM, especially in the presence of AR. In the NP of AR patients, increased expression of MMP-9, MMP-2, and TIMP-1 was observed more prominently than in that of the control group. In case of MM, however, there was no significant difference between AR patients and the control group. CONCLUSION: The presence of AR may enhance the expression of MMP-9, MMP-2, and TIMP-1 associated with airway remodeling in nasal polyposis. PMID- 19786211 TI - Biofilms correlate with TH1 inflammation in the sinonasal tissue of patients with chronic rhinosinusitis. AB - OBJECTIVE: Determine the prevalence of bacterial biofilms in surgical chronic rhinosinusitis (CRS) patients and characterize the inflammatory response associated with biofilm CRS. STUDY DESIGN: Cross-sectional. SETTING: Tertiary care academic center. SUBJECTS AND METHODS: Sinonasal mucosa and peripheral blood were collected from 60 CRS patients. Mucosal biofilms were demonstrated by scanning electron microscopy. Leukocyte subpopulations were determined by flow cytometry. Cytokines were identified with a luminex-based assay on the lysate of homogenized tissue or plasma. RESULTS: Of the 60 samples, 17 were determined to be positive for the presence of biofilms. Oral steroid-naive CRS patients with biofilm demonstrated a local T(H)1 inflammatory response with significantly elevated levels of interferon-gamma (INF-gamma), granulocyte colony-stimulating factor, macrophage inflammatory protein-1 beta, and neutrophils in the sinonasal mucosa. No differences were present at the systemic level. CONCLUSION: Sinonasal bacterial biofilms correlate to a T(H)1 skewed local but not systemic inflammatory response in CRS. This difference is abrogated by the use of oral steroids. PMID- 19786212 TI - Relationship between clinical measures and histopathologic findings in chronic rhinosinusitis. AB - OBJECTIVE: Describe detailed histopathologic findings from a cohort of patients with chronic rhinosinusitis and evaluate whether histologic measures correlate with baseline clinical factors. STUDY DESIGN: Cross-sectional study with planned data collection. SETTING: Tertiary medical center. SUBJECTS AND METHODS: Adult patients with chronic rhinosinusitis were prospectively enrolled and demographic data and medical comorbidities recorded. Disease severity was measured by computed tomography (CT), endoscopy, Smell Identification Test (SIT), the Chronic Sinusitis Survey, Rhinosinusitis Disability Index, and SF-36 General Health Survey. Mucosal specimens were assessed for the presence of mucosal inflammation, including cellular (eosinophils, neutrophils, lymphocytes, mast cells, plasma cells, macrophages), epithelial (squamous metaplasia, basement membrane thickening, goblet cells), and stromal markers (subepithelial edema, fibrosis). Histopathologic findings were correlated to baseline clinical factors. RESULTS: A total of 147 subjects were enrolled with histologic samples available for review. Presence of inflammatory markers was diverse, with lymphocytes present in 100 percent of subjects, eosinophils in 49.7 percent, and neutrophils found in 0.7 percent. Total eosinophil counts correlated with the presence of nasal polyposis (r = -0.367; P < 0.001), asthma (r = 0.264; P = 0.001), and aspirin intolerance (r = 0.279; P = 0.001). Mucosal eosinophilia correlated with worse disease severity on CT (r = 0.414; P < 0.001), endoscopy (r = 0.376; P < 0.001), and SIT (r = -0.253; P = 0.002), with the highest correlations seen in subgroups without nasal polyps. Histopathologic findings did not significantly correlate with any quality-of-life measure. CONCLUSION: Mucosal eosinophilia correlates with objective disease severity as defined by CT, endoscopy, and SIT scores. Although other histologic markers of inflammation are present, none show similar correlations. The presence of mucosal eosinophils does not correlate with quality of-life scores. PMID- 19786213 TI - Role of acidic mammalian chitinase and chitotriosidase in nasal polyps. AB - OBJECTIVE: Chitin is a recognition element for tissue infiltration by innate cells implicated in allergy and helminth immunity, and this process can be negatively regulated by vertebrate chitinases. Acidic mammalian chitinase (AMCase) and chitotriosidase (ChT) have chitinolytic activity, but little is known about their roles in nasal polyps. STUDY DESIGN: A prospective controlled study. SETTING: A tertiary referral center. SUBJECTS AND METHODS: Nineteen subjects with nasal polyps and 12 subjects with deviated nasal septums were recruited to obtain inferior turbinate mucosa samples. The expression levels of AMCase and ChT were compared in nasal polyp and inferior turbinate tissue samples. The tissue samples were analyzed by reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemical staining. RESULTS: AMCase and ChT were detected in all nasal polyps and inferior turbinate tissues. AMCase and ChT messenger RNA and protein expression were significantly higher in nasal polyps than in inferior turbinate tissues. In nasal polyps, AMCase-positive and ChT-positive cells were detected in the epithelium, inflammatory cells, and submucosal gland. CONCLUSIONS: AMCase and ChT may be important mediators in the pathogenesis of nasal polyps. Nasal polyps appear to have elevated levels of chitinases, and the presence or growth of chitin-containing pathogens might enhance chitinase expression, resulting in nasal polyp formation and growth in susceptible individuals. PMID- 19786214 TI - HER2 expression predicts improved survival in patients with cervical node positive head and neck squamous cell carcinoma. AB - OBJECTIVE: To investigate the prognostic value of HER2 and p63 expression in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: A case review of 186 HNSCCs from the oral tongue, palate, maxillary sinus, floor of mouth, oropharynx, hypopharynx, and larynx. SUBJECTS AND METHODS: All primary tumor specimens were evaluated by immunohistochemistry for HER2 and p63 expressions, which were correlated with clinical parameters including age, sex, grade, lymph node metastases, stage, and survival. RESULTS: One hundred forty-one patients had stage III-IV disease and 109 had lymph node metastases. For all cases, T and N stages were significant prognostic predictors for both overall and disease-free survivals. In the node-positive subgroup, T stage and HER2 expression were significant prognostic predictors for both overall and disease-free survivals. CONCLUSION: HER2 may be associated with longer survival in node-positive patients with HNSCC. PMID- 19786215 TI - Planned neck dissection following primary chemoradiation for advanced-stage head and neck cancer. AB - OBJECTIVES: To determine the prevalence of residual cancer in planned neck dissection specimens for advanced-stage squamous cell carcinoma following chemoradiation. STUDY DESIGN: A case series. SETTING: A single-surgeon community based head and neck practice. SUBJECTS AND METHODS: Twenty-six patients were identified during 2000 to 2007. All patients were treated with external beam radiation; the average dose to the neck was 60 Gy (range 50-72 Gy). Concurrent chemotherapy was given with cisplatin and 5-fluorouracil. Patients presenting with greater than N2 cervical disease and at least one node greater than 3 cm were considered advanced. Post-chemoradiation physical examinations were performed by the primary surgeon and oncologist. Absence of physical evidence of disease was deemed a complete clinical response. RESULTS: Fourteen of 21 (67%; 95% confidence interval [CI], 0.449-0.854) patients were found to have carcinoma in their neck specimens. Seven patients were noted to have a clinically complete response, and two of seven (29%; 95% CI, 0.053-0.659) patients with a clinically complete response were found to have carcinoma in their neck specimens. Fourteen patients were noted to have an incomplete response to therapy. Two of these 14 (14%; 95% CI, 0.026-0.419) patients had negative pathology in their neck dissection specimens. Three patients had local recurrence and succumbed to their disease. CONCLUSION: Planned neck dissection in the setting of advanced neck disease following chemoradiation should remain an important consideration when counseling patients presenting with advanced cervical metastasis from squamous cell head and neck cancer. PMID- 19786216 TI - Prognostic relevance of CD105-assessed microvessel density in laryngeal carcinoma. AB - OBJECTIVE: To examine immunohistochemical expression of CD105 among patients with laryngeal cancer and investigate the prognostic significance of CD105-assessed microvessel density (MVD). STUDY DESIGN: Cross-sectional study. SETTING: University hospital. SUBJECTS AND METHODS: The study comprised 80 patients with laryngeal squamous cell carcinoma who underwent complete excision. Clinicopathological data were collected retrospectively. Immunohistochemical analysis was performed with CD105 (endoglin) antibody. Positive-stained microvessels for CD105 were counted on hot spots of tumors at x200 magnification. RESULTS: Average CD105-assessed MVD in considered laryngeal squamous cell carcinomas (SCCs) was 12.9 (SD 3.84). High expression of CD105 correlated significantly with advanced T (tumor) classification (P = 0.008), advanced TNM (tumor, node, metastasis) stage (P = 0.001), tumor recurrence (P = 0.001), and age > or =65 years (P = 0.026). The multivariate logistic regression showed that a high CD105+ MVD (odds ratio [OR] 4.27; P = 0.019) and advanced TNM stage (OR 3.72; P = 0.047) were independent markers of tumor recurrence. High MVD, advanced clinical stage, the presence of lymph node metastasis at the time of diagnosis, and age <66 years were associated with worse disease-free survival. Cox regression analysis revealed that expression of CD105 (P = 0.016) and advanced clinical stage (P = 0.05) were the independent factors for disease-free survival. CONCLUSION: The present results suggest that MVD evaluation with CD105 is a promising prognostic factor for the outcome of patients with laryngeal SCC. CD105 assessed MVD could help to identify patients with more aggressive disease and increased risk of developing malignancy recurrence after treatment. PMID- 19786217 TI - Increased microsatellite instability and epigenetic inactivation of the hMLH1 gene in head and neck squamous cell carcinoma. AB - OBJECTIVE: The study is designed to elucidate the relationship between epigenetic silencing of the hMLH1 (human MutL homologue 1) gene and microsatellite instability (MSI) and the prognostic values of hMLH1 promoter methylation and MSI in head and neck squamous cell carcinoma (HNSCC). STUDY DESIGN: Cross-sectional study. SETTING: Tertiary referral center. SUBJECTS AND METHODS: A total of 120 cases of HNSCC were analyzed for hMLH1 promoter hypermethylation, protein expression, and MSI by using methylation-specific polymerase chain reaction, immunohistochemical staining, and polymerase chain reaction amplification with the use of 16 fluorescent-labeled microsatellite markers, followed by fragment analysis. RESULTS: Of 120 HNSCCs, hMLH1 promoter hypermethylation and decreased hMLH1 protein expression were shown in 39 (32.5%) and 22 (18.3%), respectively. hMLH1 promoter hypermethylation was detected in 13 of 52 (25%) normal-appearing squamous mucosa adjacent to invasive carcinoma. MSI was detected in 21 (17.5%) tumors at two or more markers and in 99 (82.5%) tumors with no evidence of MSI or at only one marker. Hypermethylation of the hMLH1 gene is significantly associated with decreased hMLH1 protein expression (P < 0.001). High-frequency MSI was significantly associated with promoter hypermethylation (P = 0.01) but not with decreased protein expression (P = 0.069) of hMLH1 gene. hMLH1 promoter hypermethylation is significantly associated with decreased cause-specific survival for HNSCC patients (P = 0.03). CONCLUSIONS: Promoter hypermethylation of the hMLH1 gene could be detected early in head and neck squamous carcinogenesis and may be associated with increased MSI and poor survival in HNSCC. PMID- 19786218 TI - Progesterone receptors identified in vascular malformations of the head and neck. AB - OBJECTIVE: To identify hormone receptors within vascular malformations (arteriovenous malformations [AVMs], venous malformations [VMs], and lymphatic malformations [LMs]) of the head and neck. STUDY DESIGN: Immunohistochemical staining for estrogen receptor (ER) and progesterone receptor (PR) was performed on archival vascular malformation tissue collected from both pediatric and adult patients. SETTING: Tertiary referral center from 2006 to 2008. SUBJECTS AND METHODS: Twelve AVM, 10 VM, and eight LM specimens were stained for both ER and PR. Ten breast carcinoma specimens were used as controls, with the carcinoma cells serving as positive controls, and the endothelium and smooth muscle cells of the blood vessels serving as negative controls. Five normal supraglottic mucosal samples served as head and neck controls. The Fisher exact test was used for statistical analysis. RESULTS: Ten of the 12 (83%) AVM specimens stained diffusely positive for PR within the nuclei of the endothelium and smooth muscle of the malformed vessels (P < 0.0001). Five of the 10 (50%) VM specimens stained positive for PR (2 [20%] focal, 3 [30%] diffuse) within the nuclei of the endothelium and smooth muscle of the malformed vessels (P = 0.0325). Four of the eight (50%) LM specimens stained focally positive for PR within the nuclei of the endothelium of the malformed vessels (P = 0.0229). None of the vascular malformation specimens stained positive for ER. CONCLUSION: Our data suggest that PR, but not ER, is expressed in AVMs, VMs, and LMs of the head and neck. PMID- 19786219 TI - Comparison of LigaSure vessel sealing system, harmonic scalpel, and conventional hemostasis in total thyroidectomy. AB - OBJECTIVE: The aim of the study was to compare the efficiency, safety, and cost of the different methods of hemostasis (conventional hemostasis versus LigaSure vessel sealing system [LVSS] versus harmonic scalpel) currently available for thyroid surgery. STUDY DESIGN: Randomized, controlled trial. SETTING: The study was conducted from September 2007 to December 2008 in a university hospital. PATIENTS AND METHODS: Sixty patients (48 females and 12 males) underwent a total thyroidectomy for multinodular goiter. They were randomly assigned into three groups: group one (n = 20), conventional hemostasis; group two (n = 20), LigaSure; and group three (n = 20), harmonic scalpel. RESULTS: For group three, the mean operative time was 37 minutes shorter than group one (P < 0.001) and eight minutes shorter than group two (P = 0.04). The complications rate was similar among the three groups. The mean postoperative paracetamol consummation in group one was 1.4 g greater than in group two (P = 0.016) and 1.3 g greater than in group three (P = 0.02). The overall average operative cost was 11 and 85 dollars cheaper for groups two and three than for group one, respectively (P < 0.001). CONCLUSION: Total thyroidectomy using the harmonic scalpel was the fastest procedure because it was bloodless, and hemostasis and sectioning were controlled with a single instrument; it was, therefore, the most inexpensive procedure because of the reduction of operative time and staff cost. The operative safety was similar for all three procedures. In our series, the harmonic scalpel and the LVSS caused less pain than the conventional hemostasis. PMID- 19786220 TI - Mutation analysis of SLC26A4 in mainland Chinese patients with enlarged vestibular aqueduct. AB - OBJECTIVE: We have characterized the spectrum of SLC26A4 mutations and clinical features in a population of mainland Chinese patients with nonsyndromic sensorineural hearing loss (SNHL) and enlarged vestibular aqueduct (EVA). STUDY DESIGN: Cross-sectional clinical genetic study. SETTING: Tertiary care outpatient otolaryngology clinic. METHODS: A total of 32 subjects identified with bilateral EVA using high-resolution CT were screened for mutations in SLC26A4 by denaturing high-performance liquid chromatography and direct sequencing methods. RESULTS: A total of 13 different mutations were identified in the SLC26A4 gene, five of which are novel. A total of 88 percent of the patients harbored biallelic mutations, 11 patients were homozygotes, and 17 were compound heterozygotes. Four patients were found to carry a single SLC26A4 mutation. The IVS7-2A>G mutation was the most frequent, accounting for 60 percent of the mutant alleles. We have not found any correlations between the type of SLC26A4 mutations and the type, degree, and progression of hearing loss. There are significant proportions of patients with asymmetric (26%), progressive (32%), or fluctuating hearing loss (21%). CONCLUSION: Our data confirm the high prevalence of SLC26A4 mutations in Chinese patients with SNHL and EVA. We could not establish any relationship between genotype and phenotype. However, the high incidence of asymmetric, progressive, and fluctuating hearing loss found in the current study indicates that patients with those features should be routinely screened for SLC26A4 mutation in addition to diagnosis of EVA using CT or MRI. PMID- 19786221 TI - Topical clindamycin in post-adenotonsillectomy analgesia in children: a double blind, randomized clinical trial. AB - OBJECTIVES: Tonsillectomy, with or without adenoidectomy, is one of the most common surgical procedures in pediatric otolaryngology. Pain is the main cause of morbidity in the postoperative period, where it is serious in some cases, leading to odynophagia and resultant complications such as dehydration. We evaluated the effect of topical clindamycin in the reduction of oropharyngeal pain in children who underwent adenotonsillectomy. Secondary outcomes were otalgia, analgesic use, oral bacterial count, type of diet, secondary bleeding, vomiting, fever, and weight loss. STUDY DESIGN: Double-blind, randomized clinical trial. SETTING: Tertiary hospital. SUBJECTS AND METHODS: Eighty-two children of both sexes between four and 12 years of age who underwent adenotonsillectomy were allocated to receive topical clindamycin or placebo in the immediate preoperative, intraoperative, and eight-to-12-hours postoperative periods. Pain was measured using a faces pain scale for five days. RESULTS: Reduction of oropharyngeal pain was significant with the use of clindamycin only on the first postoperative day (95% confidence interval, 2.22 to 4.41 [clindamycin] vs 4.53 to 6.3 [placebo]; P = .002). No difference was observed in the aerobic and anaerobic counts by tongue swab between premedication and third-postoperative-day samplings. There were no differences with respect to reduction in otalgia, paracetamol use, return to normal diet, variation in weight, secondary hemorrhage, vomiting, and fever. CONCLUSION: The use of topical clindamycin was beneficial in reducing pain on the first postoperative day, without effect on subsequent days. Future investigations could examine the use of topical clindamycin not only in the first 12 hours but also during five days of follow-up. PMID- 19786222 TI - Proposal for staging airway hemangiomas. AB - OBJECTIVE: To describe a method of airway infantile hemangioma staging using standardized assessment of airway narrowing, and hemangioma location and volume, as determined with endoscopy and CT angiography. STUDY DESIGN: Case series with chart review. SETTING: Tertiary pediatric hospital, 2003-2008. SUBJECTS AND METHODS: Subjects included airway hemangioma patients evaluated at a tertiary pediatric hospital. Data collected were age at first symptoms, diagnostic evaluation, percent airway compromise, and estimated hemangioma volume. Data were analyzed with descriptive and Fisher exact statistics. RESULTS: Twelve patients were identified and seven had complete data sets. Mean age at first symptoms was 1.9 months (SD 1.09 months, range 0.5-4 months). Evaluation consisted of nasopharyngoscopy, microlaryngoscopy, CT angiography, and/or MRI. Mean laryngeal airway narrowing was estimated at 63.75 percent (SD 19.0%, range 40%-90%). Total hemangioma volume was less in patients with isolated (focal) endolaryngeal hemangiomas compared with airway hemangiomas associated with extralaryngeal (segmental) hemangiomas. Airway hemangioma stages were stage one (5 of 12; 41.6%), stage two (6 of 12; 50.0%), and stage three (1 of 12; 8.3%). CONCLUSION: This method of airway hemangioma staging may be applicable to treatment planning and used to measure treatment outcomes. PMID- 19786223 TI - Voice outcomes following repeated surgical resection of laryngeal papillomata in children. AB - OBJECTIVES: 1) To apply perceptual and acoustic voice assessments to children treated for juvenile-onset recurrent respiratory papillomatosis (JORRP); 2) to compare voice outcomes following treatment for JORRP using microdebrider versus carbon dioxide (CO(2)) laser. STUDY DESIGN: Prospective cohort study. SETTING: This study was conducted at a tertiary pediatric academic center (March 2008 March 2009). SUBJECTS AND METHODS: Children with active JORRP were assessed using perceptual and acoustic voice analysis following treatment with either CO(2) laser or microdebrider. Outcome measures included overall severity rating, jitter, shimmer, and noise-to-harmonic ratio (NHR). The unpaired Student t test and Pearson correlation tests were used to explore the statistical significance of hypothesis tests. RESULTS: Eleven patients (8 male, 3 female) aged three to 17 years were enrolled. There were six children in the CO(2) laser cohort and five children in the microdebrider cohort. The immediate postoperative scores were significantly lower in the microdebrider cohort (vs the CO(2) cohort) for jitter, shimmer, NHR, and perceptual scores (P < 0.05), indicating a better voice quality in the microdebrider group. Jitter, shimmer, and NHR showed a significant positive correlation with the proportion of CO(2) laser procedures (P < 0.05). CONCLUSION: This is the first study to use perceptual and objective acoustic evaluations to compare voice outcomes following microdebrider or CO(2) laser treatment of JORRP. The results of this study suggest that treatment with the microdebrider results in a better immediate and early postoperative voice outcome. Moreover, the data demonstrate a correlation of worsening voice quality with increased exposure to the CO(2) laser. PMID- 19786224 TI - Visual analog scale (VAS) and nasal obstruction in persistent allergic rhinitis. AB - OBJECTIVE: Nasal airflow resistance, as measured by rhinomanometry, is frequently impaired in allergic rhinitis (AR). However, rhinomanometry is scarcely available. The aim of this study was to verify the suitability of the use of visual analog scales (VAS) as a surrogate for rhinomanometry in quantifying nasal obstruction in patients with persistent allergic rhinitis. STUDY DESIGN: Prospective study on patients with allergic rhinitis. SETTING: ENT clinic. SUBJECTS AND METHODS: Fifty patients (27 males, mean age 23 years, SD 2.24) were studied. VAS for nasal obstruction and other AR symptoms and rhinomanometry were performed in all patients. RESULTS: A significant, very strong correlation has been observed between VAS for nasal obstruction and nasal airflow resistance (Spearman r = 0.879, P < 0.001). Moreover, a significant correlation exists between VAS for rhinorrhea and resistance (Spearman r = 0.313, P = 0.027). CONCLUSION: The use of VAS for assessing the nasal obstruction appears clinically relevant in that it allows, with good reliability, the quantification of this symptom in the absence of rhinomanometry. PMID- 19786225 TI - Local steroid injections in the management of skin growth over the abutment in Baha patients. PMID- 19786226 TI - Clinical photograph. Sinonasal extramedullary plasmacytoma. PMID- 19786227 TI - Clinical photographs. Pleomorphic adenoma of the nasal vestibule. PMID- 19786228 TI - Clinical photograph. Laryngopharyngeal tuberculosis masquerading as chronic laryngopharyngitis. PMID- 19786229 TI - Clinical photographs. Fish bone-induced sialolith. PMID- 19786230 TI - MTHFR polymorphism: associated intralabyrinthine hemorrhage. PMID- 19786231 TI - PEComa of the nasal septum. PMID- 19786232 TI - Diffuse subglottic laryngeal neurofibroma in an adult. PMID- 19786233 TI - Paraneoplastic syndrome in a case of sinonasal adenocarcinoma. PMID- 19786234 TI - Toward a multidisciplinary approach to the treatment of obstructive sleep apnea in the obese child. PMID- 19786235 TI - Open surgical repair after failed endovascular aneurysm repair: is endograft removal necessary? AB - INTRODUCTION: Open surgical repair after failed endovascular aneurysm repair (EVAR) usually involves complete endograft removal and replacement with a prosthetic surgical graft. This is associated with significant morbidity and mortality. We have used an alternative strategy focused on limiting the magnitude of surgical repair by preserving the functioning portion of the endograft and avoiding aortic cross-clamping, when possible. METHODS: Between January 2000 and 2008, patients requiring delayed conversion after EVAR at our institution were managed with (1) complete endograft preservation and external wrap of the aortic neck to secure a proximal seal, or (2) partial endograft removal with interposition grafting from the infrarenal aortic neck to the remaining endograft. Records of all patients were retrospectively reviewed for demographics, operative details, and outcomes. RESULTS: During this time, 12 patients were treated with delayed open surgical conversion. The indication for conversion in all patients was a type I endoleak with aneurysm enlargement not amendable to percutaneous intervention. Mean age was 81 +/- 6.2 years (range, 61 90 years). Average time to conversion was 44.7 months (range, 7-80 months). Complete endograft preservation was attempted in eight patients and was successful in six (75%). The two patients that failed this approach, as well as four additional patients who were not candidates for this approach, underwent partial endograft excision and replacement with an interposition graft sutured to the remaining portion of the stent graft. Complete endograft removal was not required in any patients. There was one post-operative mortality (8.3%) and one significant post-operative morbidity (8.3%). Mean intensive care unit and hospital stays were 2.8 +/- 3.9 days (range, 1-15 days) and 8.4 +/- 5.8 days (range, 3-26 days), respectively. CONCLUSIONS: Open surgical repair of failed EVAR can be accomplished with preservation of all or a significant portion of the endograft in most patients. This may limit the magnitude of the repair procedure and may reduce morbidity and mortality. PMID- 19786236 TI - Intermediate results of a United States multicenter trial of fenestrated endograft repair for juxtarenal abdominal aortic aneurysms. AB - OBJECTIVE: This article reports the intermediate-term (24-month) outcomes of a prospective multicenter trial designed to evaluate the Zenith Fenestrated AAA Endovascular Graft (Cook Medical, Bloomington, Ind) for treating juxtarenal abdominal aortic aneurysms with short proximal necks. The study goals were to evaluate the safety and preliminary effectiveness of the device and refine patient selection criteria. METHODS: Five centers in the United States enrolled 30 patients with juxtarenal aortic aneurysms with >or=50-mm diameter and short proximal necks. Devices were custom-designed for each patient based on measurements from reconstructed computed tomography (CT) data. Follow-up studies included physical examinations, laboratory studies, CT imaging, mesenteric-renal duplex ultrasound imaging, and abdominal flat plate radiographs at hospital discharge, at 1, 6, and 12 months, and yearly thereafter up to 5 years. RESULTS: During a 1-year period, 30 patients (80% men; mean age, 75 years) with a mean aneurysm size of 61.4 mm were enrolled. In these 30 patients, 77 visceral vessels were accommodated by fenestrations located within the sealing segment of the grafts. The most common design accommodated two renal arteries and the superior mesenteric artery (66.7%). All prostheses were implanted successfully. No visceral arteries were lost. Of the 30 patients treated, 27 were available for 12 month follow-up and 23 were available for 24-month follow-up. No aneurysm-related deaths, aneurysm ruptures, or conversions were observed through 24 months of follow-up. No type I or type III endoleaks were observed. Type II endoleaks were noted in six (26.1%) at 12 months and four (20.0%) at 24 months. No patients had aneurysm growth >5 mm. Aneurysm size decreased in 16 of 23 (69.6%) and was stable in the remaining patients at 24 months. Eight patients experienced a renal event (4 renal artery stenoses, 2 renal artery occlusions, and 2 renal infarcts). Five underwent secondary interventions. No renal failure developed requiring dialysis. CONCLUSIONS: The intermediate-term (24-month) results of the 30 patients in this multicenter study are concordant with previous single-center studies and support the concept that placement of fenestrated endovascular grafts is safe and effective at centers with experience in endovascular repair and renal/mesenteric stent placement. PMID- 19786237 TI - Carotid angioplasty and stenting in anatomically high-risk patients: Safe and durable except for radiation-induced stenosis. AB - OBJECTIVE: Carotid angioplasty and stenting (CAS) is used in patients considered high-risk for carotid endarterectomy (CEA). Patients qualify as high-risk because of medical comorbid conditions or for anatomic considerations (previous CEA, radical neck dissection, radiation). We compared the technical feasibility and durability of CAS in medically high-risk patients (MED) vs anatomically high-risk patients (ANAT). METHODS: A retrospective review was performed of all consecutive patients undergoing CAS by a single vascular surgery group. All patients were high risk and evaluated with duplex ultrasound imaging and angiography. Primary end points were technical success, 30-day stroke, myocardial infarction (MI), death, and in-stent restenosis. Standard statistical analysis included Kaplan Meier life tables. RESULTS: From January 2003 to December 2007, 230 CAS (98 ANAT, 132 MED) procedures were attempted. The ANAT cohort comprised 84 patients with a single anatomic risk factor: 71 with a previous ipsilateral CEA, 6 high lesions, 6 history of neck radiation, and 1 with a tracheostomy. Ten patients had two or three anatomic risk factors: nine with radical neck dissection and radiation and one with neck radiation and ipsilateral CEA. The mean age was 71.1 years for ANAT vs 73.9 years for MED (P = .021). Technical success rates were 98% in ANAT and 98.5% in MED (P = .76). Thirty-day stroke rate was 1.0% in ANAT and 5.3% in MED (P = .14); the mortality rate was 2.0% in ANAT and 0.8% in MED (P = .79). The 2 year survival free from stroke was MED, 93.6% and ANAT, 98.9% (P = .118); and from restenosis was MED, 91.9%; and ANAT, 91.0% (P = .98). Two-year overall survival was significantly better in ANAT (84.6%) vs MED (70.1%; P = .026). Four of the seven restenoses in the ANAT group occurred in patients with previous neck radiation. The restenosis rate for radiation-induced (RAD) stenosis treated with CAS was significantly higher at 22.2% (4 of 18) compared with 3.8% (3 of 78) in ANAT group patients without a history of radiation (non-RAD; P = .028). The 2 year restenosis-free survival was 72.7% in the RAD group vs 95.9% in the non-RAD group (P = .017). CONCLUSION: CAS is as technically feasible, safe, and durable in anatomically high-risk patients as in medically high-risk patients, with similar rates of periprocedural stroke and death and late restenosis. However, patients with radiation-induced stenosis appear to be at an increased risk for restenosis. PMID- 19786239 TI - Infrapopliteal balloon angioplasty for the treatment of chronic occlusive disease. AB - OBJECTIVE: There is little documentation of the effectiveness of percutaneous balloon angioplasty (PTA) of infrapopliteal vessels for the treatment of chronic lower extremity ischemia. This study reviewed our recent experience with infrapopliteal PTA in a large series of patients to determine its effectiveness as a treatment modality. METHODS: All patients undergoing primary infrapopliteal PTA from March 2002 to June 2006 were included. Primary study end points were primary patency, assisted patency, limb salvage, and patient survival assessed by Kaplan-Meier life-table analysis. Factors predictive of PTA failure and patient longevity were evaluated by multivariate methods. RESULTS: There were 155 PTAs undertaken in 144 patients (70% men; mean age, 74 years), with critical limb ischemia (86%), diabetes (66%), and renal insufficiency (45%). Infrapopliteal lesions were classified as TransAtlantic Inter-Society Consensus A (7%), B (18%), C (39%), and D (35%). PTA was confined to the infrapopliteal segment in 40 (26%), and 115 (74%) underwent multilevel treatment. Five patients (3%) received stents. Technical success was 95%. The 30-day mortality was 2%, and major morbidity was 3%. The mean follow-up was 22 months (range, 0-54 months). The 40-month actuarial primary patency was 62% (standard error, 5%), with assisted patency (infrapopliteal re-PTA, 25 [16%]) of 90%. Interval conversion to bypass surgery occurred in seven (5%). Nonhealing ulcers occurred in 118 patients (76%), of which 76 (64%) healed during follow-up. Of the 42 unhealed ulcers, 15 (13%) required major amputations for a 40-month limb salvage of 86.2%. Multivariate predictors that were negative for primary patency included 0/1 vessel runoff (P = .01), critical limb ischemia (P = .002), and dialysis (P = .03). Negative predictors of limb salvage included dialysis (P = .007) and failure to improve runoff to the foot (P = .006). At 40-months, patient survival was 54%, with negative predictors including severe pulmonary disease (P = .01), coronary artery disease (P = .04), and renal insufficiency (P < .001). CONCLUSIONS: Infrapopliteal angioplasty can be performed safely with favorable results in patients with limited longevity. Primary patency is related to disease extent. Secondary interventions may be necessary to maintain clinical success. These data indicate that PTA should be considered as initial therapy for infrapopliteal occlusive disease in patients with lower extremity ischemia. PMID- 19786240 TI - Randomized controlled trial of aspirin and clopidogrel versus aspirin and placebo on markers of smooth muscle proliferation before and after peripheral angioplasty. AB - OBJECTIVE: In peripheral arterial disease (PAD) patients, a limiting factor in the success of percutaneous transluminal angioplasty (PTA) is the development of restenosis secondary to vascular smooth muscle cell (SMC) proliferation. Following endothelial damage and platelet activation, there is release of factors and adhesion molecules which affect SMC proliferation. The aim of this study was to determine the effect of combination antiplatelet therapy (clopidogrel and aspirin compared with aspirin and placebo) on the ability of plasma from PAD patients undergoing PTA to stimulate SMCs in vitro. We further aimed to investigate the effect of combination treatment on the levels of circulating adhesion molecules and factors, which are known to mediate SMC proliferation in experimental models. METHODS: Fifty patients were randomized to receive blinded clopidogrel or placebo, for thirty days, in addition to their daily 75 mg aspirin. To measure proliferative capacity, diluted plasma was incubated for 15 minutes with 24 hour-growth-arrested rat vascular smooth muscle cells, and extracellular regulated kinase (ERK)1/2 activation was analyzed by Western blotting at baseline, one hour pre-PTA, one hour, 24 hours and 30 days post-PTA. Plasma platelet-derived growth factor (PDGF), sE-selectin, intracellular adhesion molecule-1 (sICAM-1), and von Willebrand factor (vWF) were measured by ELISA, at the same five timepoints. Platelet activation was measured by flow cytometry of ADP-stimulated platelet fibrinogen binding at baseline and one hour post-PTA. RESULTS: ADP-stimulated platelet fibrinogen binding was significantly inhibited by clopidogrel before and after PTA. ERK 1/2 activation was significantly increased post-PTA in both the aspirin/clopidogrel and aspirin/placebo groups (P < .001). There was a statistically significant decrease in PDGF (P = .004), and increase in vWF (P = .026), following loading with clopidogrel. sICAM-1 levels significantly decreased (P = .016) in the aspirin/placebo group following PTA. There were no other significant changes and also there was no statistically significant difference between the two treatment groups for each of ERK 1/2, sICAM-1, sE-selectin, or vWF. CONCLUSIONS: This is the first study to show in vitro ERK 1/2 activation (a surrogate marker of SMC proliferation) increases post PTA. Combination antiplatelet therapy had no significant effect on this, although it did reduce PDGF. Further work is required to evaluate potential therapeutic treatments, which may reduce peripheral PTA-induced smooth muscle cell activation. CLINICAL RELEVANCE: High rates of restenosis remain the major limitation of peripheral arterial angioplasty and stenting.The restenotic lesion occurs secondary to platelet activation, released circulating factors, and subsequent smooth musclecell proliferation and migration into the intima. Methods to limit the restenotic lesion are poorly understood. This paperinvestigates the effect of PTA on smooth muscle cell activation and the release of factors in plasma which mediate SMCproliferation. It also examines the effect of combination antiplatelet therapy as a potential therapeutic strategy. PMID- 19786241 TI - SVS practice guidelines for the care of patients with an abdominal aortic aneurysm: executive summary. PMID- 19786242 TI - Compression of the left renal artery and celiac trunk by diaphragmatic crura. AB - Symptomatic compression of the celiac trunk by crura of the diaphragm is a rare disorder. Even more infrequent external compression of renal arteries is found. Although the indication for surgical therapy is controversially discussed in the literature for celiac artery compression syndrome, it is unequivocally for renal artery entrapment. We present the case of a young woman who was assigned to our hospital with arterial hypertension and stenosis of the left renal artery. After percutaneous transluminal angioplasty was performed, immediate recoil occurred. Therefore, the suspicion of entrapment by diaphragmatic crura was expressed. Additionally performed diagnostic procedures including computed tomography (CT) angiography verified our suspicion. Surgical decompression of both vessels was successfully performed. PMID- 19786243 TI - Invited commentary. PMID- 19786244 TI - Surgical or endovascular repair of thrombosed dialysis vascular access: is there any evidence? AB - INTRODUCTION: Endovascular and surgical strategies have been used to manage patients with thrombosed vascular access for hemodialysis. We analyzed the evidence to see whether endovascular or surgical treatment has the best outcome in terms of primary success rate and long-term patency. METHODS: We performed a systematic literature search of endovascular and surgical repair of thrombosed hemodialysis vascular access. The analysis included meta-analysis, randomized, and population-based studies of thrombosed arteriovenous fistulae and grafts. RESULTS: One meta-analysis and eight randomized studies on the treatment of arteriovenous graft thrombosis were identified. Studies conducted before 2002 demonstrated a significantly better primary success rate and primary and secondary patencies of surgical thrombectomy vs endovascular intervention. After 2002, similar results of both techniques have been reported. Only population based studies on the treatment of thrombosed autogenous arteriovenous fistulae have been published, showing similar outcome of surgical and endovascular intervention in terms of primary success. The long-term primary and secondary patencies are slightly better for surgical treatment, but this concerns only forearm fistulae. CONCLUSIONS: The outcome of endovascular and surgical intervention for thrombosed vascular access is comparable, in particular for thrombosed prosthetic grafts. Surgical treatment of autogenous arteriovenous fistulae is likely to have benefit compared with endovascular means. Definitive randomized trials are needed to provide the level 1 evidence to resolve this latter issue. PMID- 19786247 TI - Regarding "Gait variability is altered in patients with peripheral arterial disease". PMID- 19786249 TI - Caring for patients with an abdominal aortic aneurysm: data, knowledge, and wisdom. PMID- 19786250 TI - The care of patients with an abdominal aortic aneurysm: the Society for Vascular Surgery practice guidelines. PMID- 19786251 TI - Early worsening heart failure in patients admitted for acute heart failure: time course, hemodynamic predictors, and outcome. AB - BACKGROUND: The most common outcome currently assessed in acute heart failure trials (AHF) is dyspnea improvement. Worsening hear failure (WHF) is a new outcome measure that incorporates failure to improve or recurrent symptoms of AHF requiring rescue intravenous therapy, mechanical circulatory or ventilatory support, or readmission because of AHF, occurring within 30 days of AHF admission. METHODS AND RESULTS: Retrospective data analysis of 120 patients with AHF requiring hemodynamic monitoring who enrolled in the placebo arm of 2 prospective randomized studies. The incidence of WHF was 42% at 30 days from enrollment. Most WHF events occurred in-hospital during the first 7 days after admission (early WHF). Thirty-day readmission from AHF was an infrequent event in the present cohort (5.0%). The strongest hemodynamic predictors of WHF were cardiac power at baseline and its change during the initial 6 hours of monitoring. Other hemodynamic parameters associated with WHF events were blood pressure and its increase, cardiac output, and pulmonary wedge pressure change during the initial 6 hours of monitoring. WHF was found to be a strong predictor of 6-month mortality. CONCLUSIONS: WHF is a common morbid event clustered mostly during the first week of AHF admission and is associated with higher 6-month mortality. The hemodynamic measurements associated with WHF are similar to those predicting adverse outcome in AHF and cardiogenic shock (low cardiac power, higher pulmonary capillary wedge pressure, and vascular resistance), emphasizing the notion that early WHF should become an important AHF-specific outcome measure. PMID- 19786252 TI - Clinical profile and predictors of complications in peripartum cardiomyopathy. AB - BACKGROUND: Clinical profile and predictors of major adverse events (MAE) associated with peripartum cardiomyopathy (PPCM) have not been characterized. METHODS AND RESULTS: A retrospective review and analysis of clinical data of 182 patients with PPCM. Forty-six patients had >or=1 MAE, including death (13), heart transplantation (11), temporary circulatory support (4), cardiopulmonary arrest (6), fulminant pulmonary edema (17), thromboembolic complications (4), and defibrillator or pacemaker implantation (10). Diagnosis of PPCM was delayed >or=1 week in 48% of patients with MAE that preceded the diagnosis in 50% of these patients. Seven (32%) of the surviving patients who had MAE and did not undergo heart transplantation had residual brain damage. Significant predictors of MAE were: left ventricular ejection fraction or=10% from baseline or to <50%. Statistical analysis was done with Fisher exact test, t-test test, and Wilcoxon signed rank test. Cardiomyopathy developed in 52 of 156 (33.3%) of patients being treated with trastuzumab. In the adjuvant group, 23 (19.5%) of women permanently or temporarily discontinued therapy secondary to cardiomyopathy. CONCLUSIONS: Cardiomyopathy is a common side effect of trastuzumab that leads to discontinuation of treatment in a significant proportion of patients. Further studies are indicated to establish the ways to predict, prevent, and treat cardiomyopathy to provide patients with maximal therapeutic benefit of trastuzumab. PMID- 19786255 TI - Central aortic stiffness in patients with nonischemic dilated cardiomyopathy: relationship with neurohumoral activation. AB - BACKGROUND: Increased aortic stiffness has been found in heart failure (HF), but the underlying mechanisms remain to be elucidated. The aim of the present study was to examine the association between aortic stiffness and neurohumoral activation in patients with nonischemic dilated cardiomyopathy (NIDC). METHODS AND RESULTS: We examined 101 patients with NIDC, New York Heart Association Class II-III, LVEF 33.3 +/- 11.6%, and 33 controls. All subjects underwent blood sampling for plasma concentrations of renin, aldosterone, C-reactive protein (CRP), and brain natriuretic peptide (BNP). We evaluated the pulse wave velocity (PWV) of the proximal aorta in the region of the aortic arch with a new echo application. Patients showed increased PWV (P < .001), and increased plasma levels of log-renin (P < .001), log-aldosterone (P = .01), CRP (P = .01), and log BNP (P = .01) compared with controls. PWV was correlated with log-BNP (r = 0.63, P < .001) and log-aldosterone (r = 0.34, P < .001) levels, with LV end-diastolic (r = 0.27, P = .01) and end-systolic (r = 0.33, P = 0.003) volumes, and the PW tissue Doppler imaging systolic wave (r = -0.27, P = .006) and the E/e' ratio (r = 0.45, P < .001). Linear regression analysis showed that log-BNP levels were independently associated with PWV. CONCLUSIONS: In patients with HF from NIDC, there is evidence of increased aortic stiffness that is correlated with LV shape and function. Although aldosterone levels seem to influence the aortic PWV, BNP levels are the best independent predictor of increased PWV. PMID- 19786254 TI - Central aortic stiffness is increased in patients with heart failure and preserved ejection fraction. AB - BACKGROUND: Hypertension is an important risk factor for the development of heart failure with preserved ejection fraction. Although heart failure in hypertensive patients is usually ascribed to intrinsic myocardial abnormalities, noncardiac factors may contribute. METHODS AND RESULTS: Using arterial tonometry and Doppler echocardiography, we assessed arterial stiffness and cardiac diastolic function in 53 individuals with ejection fraction >or=0.50, including 23 with hypertension but no heart failure, 16 with hypertension and heart failure, and 14 healthy, normotensive controls. Relative to healthy controls and hypertensives, subjects with heart failure had higher systolic blood pressure, body mass index, creatinine, and left ventricular mass. Diastolic function, as estimated by myocardial relaxation velocity, was not different among the 3 groups. Peripheral arterial stiffness was similar across all groups, but key measures of central aortic stiffness (carotid-femoral pulse wave velocity, characteristic impedance, forward wave amplitude) steadily increased with progression from healthy to hypertensive to heart failure despite adjustment for body mass index, systolic blood pressure, and renal function and were positively correlated with both left ventricular mass and filling pressure. CONCLUSIONS: We conclude that patients with heart failure and preserved ejection fraction have increased central aortic stiffness relative to age-matched healthy and hypertensive subjects without heart failure. These changes exceed differences in diastolic function and suggest that abnormal ventricular-vascular coupling may contribute to the pathophysiology of heart failure with preserved ejection fraction. PMID- 19786256 TI - Acute hemodynamic effects of intravenous nesiritide on left ventricular diastolic function in heart failure patients. AB - BACKGROUND: Nesiritide is recombinant human B-type natriuretic peptide with vasodilatory effects used in patients with decompensated congestive heart failure. We sought to evaluate the effects of nesiritide on left ventricular diastolic function in heart failure patients. METHODS AND RESULTS: Twenty-five heart failure patients underwent left heart catheterization (using a pressure volume conductance catheter) and echocardiography at baseline and 30 minutes after an intravenous bolus and infusion of nesiritide. Invasive and noninvasive measurements of load-dependent (deceleration time, echocardiographic diastolic function classification, negative dP/dt, left ventricular diastolic pressure, tau) parameters of diastolic function were assessed. The nonlinear slope of the end-diastolic pressure volume relationship (EDPVR) using 2 single-beat methods for measuring left ventricular end-diastolic elastance was calculated to assess load-independent parameters of diastolic function. Nesiritide reduced biventricular diastolic pressure and systemic vascular resistance. Tau and negative dP/dt showed modest improvement. Deceleration time, isovolumetric relaxation time, diastolic stiffness indices (E/E'/stroke volume (SV) and E/E'/left ventricular end-diastolic volume index (LVEDVI)), and the echocardiographic diastolic filling pattern classification did not change. Furthermore, there was no change in the EDPVR. CONCLUSIONS: Although nesiritide is an effective vasodilator resulting in decreased left ventricular preload and afterload in heart failure patients, intrinsic left ventricular diastolic function did not change acutely, suggesting that nesiritide has no significant acute lusitropic effect. PMID- 19786257 TI - Dilated cardiomyopathy after long-term right ventricular apical pacing in children with complete atrioventricular block: role of setting of ventricular pacing. AB - BACKGROUND: Pediatric patients paced for complete atrioventricular block (CAVB) are at risk of developing dilated cardiomyopathy (DCM). We sought to explore the role played by the setting of ventricular pacing. METHODS AND RESULTS: A total of 35 patients <18 years of age at diagnosis were enrolled. Twenty-eight (80%) received pacemakers after a mean follow-up of 10 years, and most were paced from right ventricular (RV) apex (n = 23). None of the 7 patients without pacemakers developed DCM, whereas 8 (35%) paced from RV apex had DCM 2.6 +/- 2.2 years after pacing. The percentage of ventricular pacing was >90% in all patients. Multivariate analysis revealed that the cumulative Z score of lower ventricular rate setting was the single most important risk factor for DCM (HR, 3.14; 95% CI, 1.07-9.19; P = .037). Subgroup analysis in patients with VVI/VVIR modes revealed an even stronger predictive value of the cumulative Z score of lower ventricular rate setting (HR, 9.12; 95% CI, 1.53-54.24; P = .015). CONCLUSIONS: Higher setting of the lower ventricular rate, though still within the age-appropriate range, was associated with increased risk of developing DCM in pediatric patients with CAVB and chronic RV apical pacing. PMID- 19786258 TI - A multicenter study of noninvasive cardiac output by bioreactance during symptom limited exercise. AB - BACKGROUND: Hemodynamic responses to exercise were assessed in patients with varying degrees of chronic heart failure (CHF) to determine the feasibility of using bioreactance during exercise testing in multicenter studies of CHF. METHODS AND RESULTS: A total of 210 symptomatic CHF patients and 22 subjects without heart failure were subjected to symptom-limited exercise testing on a bicycle (105) or treadmill (127) while measuring gas exchange for VO(2), cardiac output (CO) noninvasively by a bioreactance technique, heart rate, and blood pressure. Peak CO (pCO) and VO(2) (pVO(2)) during exercise were lower in patients with higher New York Heart Association (NYHA) class, in females and in older patients. Multiple linear regression analysis showed that pCO (L/min)=19.6+4.M 2.1.NYHA+1.9.G -0.09.Age, where M=1 for treadmill and 0 for bicycle and G=1 for males and 0 for females. Similarly, pVO(2) (mL/kg/min)=24+2.1.M -2.9.NYHA+1.26.G 0.08.Age. VO(2) and CO were also highly correlated to each other: pCO (mL/kg/min)=0.059+0.007.pVO(2)+0.036.M -0.025.G. Similar correlations were determined for other parameters of exercise, including left ventricular power, and the ratio of peak/resting VO(2) (cardiovascular reserve), the ratio of peak/resting CO (cardiac reserve), and total peripheral vascular resistance. CONCLUSION: Bioreactance-based noninvasive measurements of CO at rest and during exertion identified abnormalities of cardiovascular function consistent with those identified by pVO(2) and in prior studies using invasive CO measurements. This technique might therefore be useful for indexing disease severity, prognostication, and for tracking responses to treatment in clinical practice and in clinical trials. PMID- 19786259 TI - Regional distribution of mitochondrial dysfunction and apoptotic remodeling in pacing-induced heart failure. AB - BACKGROUND: Specific myocardial mitochondrial enzymatic dysfunction and apoptotic remodeling occur in pacing-induced heart failure. We sought to define their regional distribution and molecular basis in the failing heart. METHODS AND RESULTS: Enzyme dysfunction was assessed in mitochondrial subpopulations and immunoblot analysis was performed using homogenate proteins from the left atria (LA) and left ventricle (LV) of paced and control mongrel dogs. A greater range of enzymatic defects (complex I, III, and V) was found in mitochondria subpopulations from the LV as compared with the LA (where only complex V was defective). Analysis of paced LV proteins demonstrated a downregulated expression of both mitochondrial genes (eg, cytochrome b) and nuclear genes (eg, ATP synthase beta subunit, mitochondrial creatine kinase). Protease-activated products of both mitochondrial (eg, apoptosis inducing factor) and cytosolic (eg, caspase-3) apoptogenic proteins were increased in both the LA and LV. Nuclear localized apoptotic markers (eg, p53, p21) were also significantly increased in the LV of paced dogs. CONCLUSION: Abnormal activity of several mitochondrial enzymes and increased apoptogenic pathway appear to be mediated, at least in part, by an orchestrated shift in expression (both nuclear and mitochondrial DNA) of respiratory chain subunits (eg, cyt b, ATP-beta), mitochondrial bioenergetic enzymes (eg, mitochondrial creatine kinase), global transcription factor (eg, PGC 1), and apoptotic proteins (eg, p53, p21) with distinct differences in their regional distribution and in the subpopulations of mitochondria affected. PMID- 19786260 TI - 4-Hydroxy-2-nonenal induces calcium overload via the generation of reactive oxygen species in isolated rat cardiac myocytes. AB - BACKGROUND: It has been reported that that the amount of 4-hydroxy-2-nonenal (HNE), which is a major lipid peroxidation product and a cytotoxic aldehyde, is increased in the human failing myocardium. This study was designed to determine whether HNE has a pro-oxidant effect in cardiac myocytes and whether HNE causes Ca(2+) overload. METHODS AND RESULTS: Exposure to HNE for 10 minutes in the presence of ferric nitrilotriacetate induced the production of hydroxyl radical (.OH) in the rat myocardium as assessed by electron spin resonance spectroscopy, and HNE induced the generation of reactive oxygen species (ROS) in a dose dependent manner as assessed by 2', 7'-dichlorofluorescein diacetate fluorescence. HNE increased intracellular Ca(2+) concentration ([Ca(2+)](i)) as assessed by fura-2 ratio in a dose- and time-dependent manner. After 20 minutes of HNE (400 micromol/L) exposure, hypercontracture was induced in 67% of the cells. Catalase, an antioxidative enzyme that can decompose hydrogen peroxide (H(2)O(2)), significantly attenuated the increase in [Ca(2+)](i) and completely inhibited hypercontracture. Carvedilol, a beta-blocker with potent antioxidant activity, also significantly attenuated the increase in [Ca(2+)](i) and completely inhibited hypercontracture, but propranolol had no effect on either [Ca(2+)](i) increase or hypercontracture. CONCLUSIONS: HNE induces the formation of ROS, especially H(2)O(2) and .OH, in cardiomyocytes and subsequently ROS cause intracellular Ca(2+) overload. HNE formation may play an important role as a mediator of oxidative stress in heart failure. PMID- 19786261 TI - Loss of opposite left ventricular basal and apical rotation predicts acute response to cardiac resynchronization therapy and is associated with long-term reversed remodeling. AB - BACKGROUND: Normal left ventricular (LV) torsion is caused by opposite basal and apical rotation. Opposite rotation can be lost in heart failure, but might be restored by pacing; therefore, the predictive value of the loss of opposite base apex rotation in heart failure patients for the response to cardiac resynchronization therapy (CRT) was studied. METHODS AND RESULTS: In 34 CRT candidates and 12 controls, basal and apical LV rotations were calculated using magnetic resonance image tagging. Loss of opposite rotation was quantified by the correlation between both rotation curves: a negative correlation indicates normal, opposite rotation and a positive correlation indicates that base and apex rotate in the same direction. In patients, LV pressure was measured invasively during biventricular stimulation. Acute response to CRT was defined by >10% increase in dP/dt(max) relative to baseline. LV volume was determined at baseline and 8 months follow-up using echocardiography. The base-apex rotation correlation (BARC) was significantly higher in acute responders (n=22) than in nonresponders (n=12) and controls (0.64+/-0.51, -0.23+/-0.67, and -0.68+/-0.22, respectively; P=.001). The sensitivity and specificity for prediction of acute response were 82% and 83%, respectively, at a cutoff value of 0.5. At follow-up, volumes could be analyzed in 18 patients. In the group with BARC >0.5, end-diastolic volume decreased by 7% (NS), end-systolic volume by 16%, and ejection fraction increased by 28% (both P=.02), whereas in the group with BARC <0.5, no significant changes were observed. CONCLUSIONS: The loss of opposite base-apex rotation in patients eligible for CRT is an excellent predictor of acute response and is associated with LV reverse remodeling. PMID- 19786262 TI - T2 cardiac magnetic resonance in infarct patients: sideman or leader? PMID- 19786263 TI - Different patterns of left ventricular enlargement and long-term prognosis after reperfused acute myocardial infarction. AB - BACKGROUND: Dilation of end-systolic and end-diastolic volumes (ESV, EDV) has been used to define left ventricular remodelling after acute myocardial infarction (MI), but the prognostic significance of different enlargement patterns has not been evaluated fully. AIM: To analyse the evolution of left ventricular volumes and parameters of global and regional contractility and their correlations with long-term prognosis in patients treated by angioplasty in the acute phase of MI. METHODS: Seventy-four patients (mean age 56+/-13 years; 77% men), treated successfully by angioplasty in the acute phase of MI, were included prospectively. Significant enlargement of left ventricular volumes was defined as a greater than 20% increase between acute phase and 6-month control, assessed by contrast ventriculography. Clinical follow-up was obtained for all patients at 82+/-19 months. RESULTS: Four groups were identified based on volume evolution: Group I (n=29, 39%; no volume enlargement); Group II (n=8, 11%; isolated EDV enlargement); Group III (n=10, 14%; isolated ESV enlargement); Group IV (n=27, 36%; ESV plus EDV enlargement). Global left ventricular ejection fraction increased in Groups I (p=0.001) and II (p=0.037), but decreased in Groups III (p=0.0002) and IV (p=0.019). The 6-year event-free survival rate was significantly (p=0.0039) better in Groups I and II (100%) than in Groups III and IV (80 and 78%, respectively). CONCLUSION: ESV enlargement in patients with reperfused acute MI impacts negatively on long-term prognosis, while isolated EDV enlargement does not. PMID- 19786264 TI - Noninvasive assessment of the prevalence and characteristics of coronary atherosclerotic plaques by multidetector computed tomography in asymptomatic type 2 diabetic patients at high risk of significant coronary artery disease: a preliminary study. AB - BACKGROUND: There is a need to identify diabetic patients at risk of cardiovascular events before symptom onset. AIMS: To evaluate the prevalence and characteristics of coronary atherosclerotic plaques in asymptomatic type 2 diabetic patients with coronary risk factors but without known coronary artery disease, using multidetector computed tomography. METHODS: High-resolution 40 slice coronary computed tomography was performed prospectively in 42 consecutive type 2 diabetic patients (mean age 62 years; range 50-77 years; 28 men) with over one or more carotid atherosclerotic plaque and no coronary artery disease symptoms. Computed tomography data were evaluated for calcium score and the presence of coronary plaques. Plaque type, distribution, extensive character and obstructive nature were determined per patient for each segment. RESULTS: No plaques were detected in 11 (26.2%) patients. Atherosclerotic plaques were detected in 31 (73.8%) patients. A total of 147 coronary segments with plaque were identified, of which 11 (7.5%) contained hypodense plaques, 28 (19%) mixed plaques and 108 (73.5%) calcified plaques. Hypodense plaques were noted in 4/15 (26.7%) patients without coronary calcifications. Most calcified and hypodense plaques resulted in lumen narrowing of less than 50%; most mixed plaques resulted in lumen narrowing greater than 50%. Obstructive disease was detected in 9/11 patients with a high calcium score (>400). CONCLUSION: This preliminary study demonstrates that a high proportion of asymptomatic type 2 diabetic patients present without coronary plaques detectable by multidetector computed tomography, despite concomitant carotid atherosclerotic lesions. Computed tomography seems to detect a high proportion of plaques compared with conventional angiography in these specific patients. PMID- 19786265 TI - Comparative analysis of neointimal coverage with paclitaxel and zotarolimus drug eluting stents, using optical coherence tomography 6 months after implantation. AB - BACKGROUND: Intrastent thrombosis, while rare, has a poor prognosis. Strut non coverage is one causal factor, especially in cases of resistance to or premature discontinuation of dual antiplatelet therapy. AIM: To compare neointimal coverage with paclitaxel and zotarolimus drug-eluting stents, using optical coherence tomography (OCT). METHODS: Twenty-two drug-eluting stents (11 paclitaxel-eluting stents and 11 zotarolimus-eluting stents) were examined by OCT, 6 months after implantation. Mean neointimal strut-coverage thickness and percentage neointimal hyperplasia were measured every millimetre. On each OCT image, struts were classified into one of four categories: well-apposed to vessel wall with apparent neointimal coverage; well-apposed to vessel wall without neointimal coverage; malapposed to the vessel wall; or located on a major side branch. RESULTS: OCT analysis showed a lower percentage of neointimal hyperplasia with paclitaxel eluting stents than with zotarolimus-eluting stents (17% vs 38% and mean thickness 154 microm vs 333 microm, respectively; p<0.0001). The rate of strut coverage was greater with zotarolimus-eluting stents than with paclitaxel-eluting stents (99.1% vs 87.1%, respectively; p<0.0001). A non-covered/covered strut ratio greater than 0.3 was observed in 0.5% of zotarolimus-eluting stent OCT images compared with 18% of paclitaxel-eluting stent OCT images (p<0.0001). CONCLUSION: Six months after implantation, neointimal hyperplasia was greater with zotarolimus-eluting stents compared with paclitaxel-eluting stents. Conversely, neointimal strut-coverage was better with zotarolimus-eluting stents. PMID- 19786266 TI - Prevalence of unknown peripheral arterial disease in patients with coronary artery disease: data in primary care from the IPSILON study. AB - BACKGROUND: Peripheral arterial disease (PAD) is a marker of increased risk of cardiovascular events and of poor prognosis in patients with coronary artery disease (CAD). The prevalence of unknown PAD among patients with CAD varies between studies according to the mode of diagnosis. AIMS: To evaluate the prevalence of unknown PAD, diagnosed using the ankle-brachial index (ABI), in patients from the IPSILON study with a CAD diagnosis; to assess the profile of these patients; and to determine predictors of PAD. METHODS: IPSILON was an observational, cross-sectional study. General practitioners measured ABI in 5679 consecutive adults aged 55 years or over with signs or symptoms suggestive of PAD (21.3%), a history of an atherothrombotic event (42.1%) or two or more cardiovascular risk factors (36.6%). This analysis focuses on the subgroup of patients with CAD and no other known overt atherothrombotic disease. RESULTS: A total of 1340 patients presented with isolated CAD. PAD (ABI<0.90) was diagnosed in 26.6% of these patients; 16.2% were asymptomatic. Older age, symptoms suggestive of PAD and cardiovascular risk factors were found to be independent predictors of PAD in multivariable analysis. CONCLUSION: Over 26% of patients with CAD present with unknown PAD, as diagnosed using ABI measurement. More than half of these patients are asymptomatic. Screening for PAD in patients with CAD will allow detection of a subpopulation at particularly high cardiovascular risk. An aggressive medical treatment strategy could help to improve their outcome. PMID- 19786267 TI - Cardiac magnetic resonance demonstrates myocardial oedema in remote tissue early after reperfused myocardial infarction. AB - BACKGROUND: Cardiac magnetic resonance can detect myocardial oedema using myocardial transverse relaxation time (T2)-weighted sequences but quantitative data are lacking in patients evaluated early after acute myocardial infarction. AIM: To assess the spatial distribution of T2 in patients with recent acute myocardial infarction. METHODS: Twenty-four consecutive patients (mean age 60+/ 11 years) with acute myocardial infarction (anterior, n=12; inferior, n=12) were evaluated prospectively. T2 was determined using a series of breath-hold T2 weighted segmented half-Fourier turbo-spin echo sequences. No-reflow was defined as the association of early hypoenhancement and delayed enhancement in an akinetic region after a bolus injection of DOTA-Gd (0.2 mmol/kg). RESULTS: No reflow was present in 13 (54%) patients and absent in 11 (46%) patients. Mean T2 was increased in the infarct region (84.9+/-23.7 ms) compared with in the remote myocardium (62.8+/-10.3 ms, p=0.0001) and in control subjects (55.7+/-4.6 ms, p<0.0001), but also in the remote myocardium compared with control subjects (p<0.02). In patients with no-reflow, T2 was further increased within the infarcted subendocardium compared with in patients without no-reflow (97.9+/-24.8 ms vs 76.3+/-24.7 ms, p<0.03). Peak troponin correlated with T2 (r=0.47, p<0.02) and was higher in patients with no-reflow (297.9+/-249.7 microg/L) than in patients without no-reflow (42.4+/-43.1 microg/L, p=0.003). CONCLUSION: T2 was lengthened in both infarcted and remote myocardium and was influenced by the occurrence of no-reflow. PMID- 19786268 TI - Absence of additional improvement in outcome of patients receiving cardiac resynchronization therapy paced at the most delayed left ventricular region. AB - BACKGROUND: The choice of the optimal left ventricular (LV) pacing site remains an issue in patients requiring cardiac resynchronization therapy (CRT). AIM: This prospective study compared the outcome of patients paced at the most delayed LV region with that of patients paced at any other LV site. METHODS: Forty-four patients with severe heart failure underwent three-dimensional (3D) echocardiography before implantation and 3 days after implantation of a CRT device, to determine the most delayed LV region during spontaneous rhythm and during right ventricular pacing. The patients were divided subsequently into four groups: group 1 (n=19), LV lead placed at the most delayed echocardiographic site in spontaneous rhythm; group 2 (n=25), LV lead placed at any other site; group 3 (n=21), LV lead placed at the most delayed echocardiographic site during right ventricular pacing; group 4 (n=23), LV lead placed at any other site. RESULTS: No significant differences were observed between the four groups before implantation. After 6 months of CRT, no significant differences were observed between groups 1 and 2 or between groups 3 and 4 in terms of change in New York Heart Association functional class, Minnesota living with heart failure questionnaire, 6-minute walk test, peak exercise oxygen consumption, 3D ventricular dyssynchrony and 3D LV ejection fraction. CONCLUSION: Implantation of the LV lead in the most delayed region of the left ventricle determined by 3D echocardiography did not result in additional improvement in symptoms or LV function. PMID- 19786269 TI - Sleep apnoea in patients with heart failure. Part I: diagnosis, definitions, prevalence, pathophysiology and haemodynamic consequences. AB - Sleep disorder specialists manage 90% of patients suffering from obstructive sleep apnoea, which affects 10% of the general population. From another perspective, cardiovascular disease specialists are particularly challenged by sleep apnoea, since it affects a large proportion of their patients and its complications are largely cardiovascular. At least 50% of patients with chronic heart failure (HF) suffer from sleep apnoea, predominantly central and/or Cheyne Stokes respiration as opposed to obstructive sleep apnoea. While its effect on survival remains uncertain, sleep apnoea promotes the progression of chronic HF and is a predictor of poor prognosis. After screening by cardiologists, patients presenting with chronic HF and sleep apnoea should be referred to a sleep disorder specialist for diagnostic confirmation and treatment. In Part I of this review, we describe the diagnostic steps recommended when sleep apnoea is suspected in patients with chronic HF. We also review the definitions of abnormal sleep-related respiratory events and the prevalence, pathophysiology and haemodynamic consequences of sleep apnoea in this patient population. PMID- 19786270 TI - Right atrial mass complicating aortic endocarditis. PMID- 19786271 TI - Demonstration of bilateral superior vena cava by contrast echocardiography. PMID- 19786272 TI - Mitral valve repair in acute extensive infectious endocarditis. PMID- 19786273 TI - Critical impact of pressure recovery on assessment of aortic valve stenosis. PMID- 19786274 TI - The prevention of anxiety and depression in children from disadvantaged schools. AB - A randomised controlled trial evaluated the Aussie Optimism Program in preventing anxiety and depression. Grade 7 students (n = 496) from disadvantaged government schools in Perth Western Australia, participated. Six schools were randomly assigned to Aussie Optimism and six schools received their usual health education lessons. Students completed questionnaires on depression, anxiety, attribution style, and social skills. Parents completed the Child Behavior Checklist. No significant group effects were found for student-reported data. Parents of intervention group only students reported reductions in internalizing problems at post-test. No follow-up group effects were significant. Students and teachers found the program acceptable. PMID- 19786275 TI - Are irrational reactions to unfairness truly emotionally-driven? Dissociated behavioural and emotional responses in the Ultimatum Game task. AB - The "irrational" rejections of unfair offers by people playing the Ultimatum Game (UG), a widely used laboratory model of economical decision-making, have traditionally been associated with negative emotions, such as frustration, elicited by unfairness (Sanfey, Rilling, Aronson, Nystrom, & Cohen, 2003; van't Wout, Kahn, Sanfey, & Aleman, 2006). We recorded skin conductance responses as a measure of emotional activation while participants performed a modified version of the UG, in which they were asked to play both for themselves and on behalf of a third-party. Our findings show that even unfair offers are rejected when participants' payoff is not affected (third-party condition); however, they show an increase in the emotional activation specifically when they are rejecting offers directed towards themselves (myself condition). These results suggest that theories emphasizing negative emotions as the critical factor of "irrational" rejections (Pillutla & Murninghan, 1996) should be re-discussed. Psychological mechanisms other than emotions might be better candidates for explaining this behaviour. PMID- 19786276 TI - The neuropsychological profile of cerebellar damage: The sequencing hypothesis. PMID- 19786277 TI - Machete injuries as seen in a Nigerian teaching hospital. AB - BACKGROUND: The morbidity and mortality of machete-related injuries is rather appreciable in Nigeria although it is under-reported. Machetes are multipurpose tools in the farm, home and construction sites. Machetes may also be used as a close-range weapon. In Nigeria, there is no legislation guiding their Acquisition, so they are readily available in many homes. Injuries from machetes could be as detrimental as fatal or non-fatal with long-term morbidity. METHODS: We performed a retrospective study to assess the pattern and outcome of patients presenting with machete injuries in Ebonyi State University Teaching Hospital, Abakaliki, from January 2003 to December 2007. RESULTS: Of 76 patients, 74 met the criteria for the study. The male:female ratio was 10:1. The youth were commonly affected and the average age was 27.86 years. Assaults accounted for 96% of cases whilst accidental injuries accounted for 4% of cases. Early presentation, multiple machete wounds and involvement of head and upper extremities were common. Peripheral nerve palsy was the most common complication and haemorrhagic shock the most common cause of death. Sixty-one patients (87.14%) had complete recovery, and six patients (8.51%) recovered with morbidity. Death occurred in three patients (4.29%). CONCLUSIONS: Management of machete injuries in a developing nation can be quite challenging. Assault with homicidal intention was the major aetiological factor in our own environment and may be a very important and under-recognised aspect of the injuries. Appropriate injury-prevention mechanisms and other aspects of trauma care are recommended. PMID- 19786278 TI - Commercial polymeric fiber as sorbent for solid-phase microextraction combined with high-performance liquid chromatography for the determination of polycyclic aromatic hydrocarbons in water. AB - A novel microextraction method making use of commercial polymer fiber as sorbent, coupled with high-performance liquid chromatography-fluorescence detection for the determination of polycyclic aromatic hydrocarbons (PAHs) in water has been developed. In this technique, the extraction device was simply a length (8 cm) of a strand of commercial polymer fiber, Kevlar (each strand consisted of 1000 filaments, each of diameter ca. 9.23 microm), that was allowed to tumble freely in the aqueous sample solution during extraction. The extracted analytes were desorbed ultrasonically before the extract was injected into HPLC system for analysis. Extraction parameters such as extraction time, desorption time, type of desorption solvent and sample volume were optimized. Each fiber could be used for up to 50 extractions and the method showed good precision, reproducibility and linear response within a concentration range 0.05-5.00 microg L(-1) with correlation coefficients of up to 0.9998. Limits of detection between 0.4 and 4.4 ng L(-1) for seven PAHs could be achieved. The relative standard deviations (n=3) of this technique were between 2.9% and 12.1%. PMID- 19786279 TI - IgG adsorption on a new protein A adsorbent based on macroporous hydrophilic polymers II. Pressure-flow curves and optimization for capture. AB - Pressure-flow curves are obtained for a new protein A adsorbent matrix based on macroporous hydrophilic polymer beads with average diameter of 57 microm and a narrow particle size distribution. Experimental data are obtained in a 1cm diameter laboratory column and in preparative scale columns with diameters of 20, 30, and 45 cm. The results are consistent with a model that assumes a linear relationship between bed compression and relative flow velocity. Surprisingly, the packing compressibility is essentially independent of column diameter for the preparative columns. As a result, after accounting for the variation in extraparticle porosity caused by compression, the column pressure drop is accurately predictable using the Carman-Kozeny equation. A model is also developed to predict productivity for IgG capture as a function of operating conditions based on dynamic binding capacity data presented in Part I of this work. For typical conditions, the model predicts maximum productivity at low residence times, between 1 and 1.5 min, when the dynamic binding capacity is at about 70-80% of the maximum. Combining the two models for column pressure and for dynamic binding capacity allows the design of preparative scale columns that maximize productivity while meeting specified pressure constraints. PMID- 19786280 TI - Characterization of prenylflavonoids and hop bitter acids in various classes of Czech beers and hop extracts using high-performance liquid chromatography-mass spectrometry. AB - Hops contain a wide range of polyphenolic compounds with antioxidant properties divided in various chemical classes. These compounds are detected in hop extracts and also in beer as its main product. Based on the careful optimization of column type, column packing, mobile phase composition and gradient steepness, two high performance liquid chromatography-mass spectrometry (HPLC/MS) methods have been developed. The first method using Purospher Star RP-8e column and the gradient of aqueous acetonitrile containing 0.3% formic acid is optimized for the separation of low polar polyphenolic compounds, while the second one with Zorbax SB-CN column is used for more polar hops and beer components. In this work, more compounds are detected in comparison to previous reports. In total, 49 low polar and 37 polar compounds are detected in studied samples and their molecular weights are determined based on atmospheric pressure chemical ionization (APCI) mass spectra. Some compounds are identified based on the interpretation of their full scan and tandem APCI mass spectra, retention behavior and UV spectra, while the full structure elucidation of other species still requires further research. The quantitation of xanthohumol related prenylflavonoids and bitter acids is done with two detection techniques (APCI-MS and UV detection) providing comparable results. Both compound classes (i.e., prenylflavonoids and bitter acids) are separated and quantitated in a single HPLC run, where numerous other polyphenolics are detected as well. PMID- 19786281 TI - Interleukin 10 family gene polymorphisms are not associated with major depressive disorder and panic disorder phenotypes. AB - Genetic regulation of immune system and inflammatory response may be related to the pathogenesis and manifestations of mood and anxiety disorders. In the present study we examined a range of single-nucleotide polymorphisms (SNP) in chromosomal region 1q32, the locus of interleukin 10 (IL10) gene, in patients with major depressive disorder (n=312) and panic disorder (n=210), and matched healthy controls (n=356). We found no significant associations of the SNPs in IL10 family genes with either diagnostic group. Haplotype analysis revealed seven haplotype blocks, but their frequencies did not differ between patients and controls. Significant associations were detected for SNP rs1539243 in IKBKE (inhibitor of kappa light polypeptide gene enhancer in B-cells, kinase epsilon) gene showing different allelic and genotypic distributions in the total as well as in separate diagnostic groups as compared to controls. IKBKE emerged as a candidate for further studies of genetic factors associated with panic disorder and major depressive disorder. PMID- 19786282 TI - Physical examination is a poor screening test for abdominal-pelvic injury in adult blunt trauma patients. AB - BACKGROUND: To determine if physical examination can reliably detect or exclude abdominal or pelvic injury in adult trauma activation patients. METHODS: Trauma registry and medical record data were retrospectively reviewed for all adult blunt trauma patients with Glasgow coma scale score>8, from 6/30/05 to 12/31/06. Attending surgeons' dictated admission history and physical examination reports were individually reviewed. Patients' subjective reports of abdominal pain were recorded as present or absent. Exam findings of the lower ribs, abdomen, and pelvis were each separately recorded as positive or negative, and were compared with findings on a subsequent objective evaluation of the abdomen (OEA). "Clinically significant" injuries were defined as those that would change patient management. RESULTS: One thousand six hundred sixty-three patients were studied. Of patients with a negative abdominal exam, 10% had a positive OEA. When abdominal pain was absent, and exam of the lower ribs, abdomen, and pelvis was normal, OEA was positive in 7.6%, and 5.7% had a clinically significant injury. While a positive abdominal exam was predictive of a positive OEA (P<0.01), a negative exam, even when broadened (pain, lower ribs, abdomen, pelvis) did not exclude significant injuries. CONCLUSION: Ten percent of trauma activation patients with a negative abdominal exam have occult abdominal/pelvic injuries. Even when exam of the lower ribs, abdomen, and pelvis are all negative and abdominal pain is absent, 5.7% have occult injuries that would change management. OEA should be used liberally for adult blunt trauma activation patients regardless of physical exam findings, to avoid missing clinically significant injuries. PMID- 19786283 TI - Methylenetetrahydrofolate reductase polymorphisms and plasma homocysteine in levodopa-treated and non-treated Parkinson's disease patients. AB - Genetic C677T and A1298C polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) and levodopa therapy in Parkinson's disease (PD) may increase homocysteine (Hcy) level. We examined whether connecting both polymorphisms influences the effect of levodopa on Hcy. MTHFR genotypes and Hcy, vitamin B(12), and folate levels were determined in 48 levodopa-treated PD patients (PD-L), 28 non-treated PD patients (PD-N) and 110 controls. Hcy was remarkably higher in PD L than in PD-N and controls (p<0.001); similarly, the differences were seen in different age subgroups and in both genders. Furthermore, Hcy differences between PD-L and PD-N were evident in 677C/T, T/T, C/T + A/A, T/T + A/A (all p<0.05), and 1298A/A (p<0.001), but not in others such as 677C/C, and C/C + A/A. Hcy in PD-N and controls was comparable for all genotypes. In PD-L, Hcy was the highest in 677T/T, then in C/T, and in C/C with a significant difference from T/T (p=0.014), but was not different among A1298C genotypes. Likewise, Hcy was the highest in 677T/T+1298A/A, intermediate in C/T+A/A, and the lowest in C/C+A/A. In PD-N, Hcy was similar among all genotypes. In conclusion, Hcy elevation may be caused by levodopa administration, and further promoted by 677C/T and T/T, but not by A1298C genotypes. The promoting elevation in 1298A/A is attributed to combining the 677T allele. Neither C677T nor A1298C genotypes contribute to elevating Hcy in PD-N. PMID- 19786284 TI - Acute limbic encephalitis and glutamic acid decarboxylase antibodies: a reality? AB - Limbic encephalitis (LE) associated with glutamic acid decarboxylase antibodies (GAD-Ab) is rare. We describe a 30-year-old male with acute LE and GAD-Ab, with follow-up during 2 years of cognitive status including verbal episodic memory, number of seizures recorded by high-resolution video-EEG, brain MRI, 2-[18F] fluoro-2-deoxyglucose PET and GAD-Ab titres. Treatment with corticosteroids, IV immunoglobulins, immunosuppressors and antiepileptic drugs resulted in improved memory status, disappearance of seizures and decreased GAD-Ab titres. Review of the other cases of literature and this case is in favour of the existence of autoimmune LE associated with GAD-Ab and supports the link between memory, temporal seizures and possibly GAD-Ab titres. PMID- 19786285 TI - Impact and recovery associated with the deposition of capital dredgings at UK disposal sites: lessons for future licensing and monitoring. AB - The majority of studies relating to impacts and recovery at dredgings disposal sites have concentrated on areas subject to regular and frequent disposals of maintenance dredgings over relatively long time periods. In comparison less is known regarding the significance of impacts and the recovery processes associated with the disposal of capital dredgings that commonly involves the infrequent deposition of heterogenous material over relatively restricted time periods. Impacts and recovery processes are likely to be different to those associated with the disposal of maintenance dredgings. For example, findings suggest that capital dredgings deposited at both the Roughs Tower and Barrow-in-Furness result in the occurrence of persistent changes to seafloor substrata within the license area and this subsequently effects the composition of associated faunal communities present. Moreover, whilst the two disposal sites are geographically distinct similar species are identified as being particularly sensitive to capital disposal activities in both areas. PMID- 19786286 TI - Stir bar sorptive extraction-thermal desorption-gas chromatography-mass spectrometry: an effective tool for determining persistent organic pollutants and nonylphenol in coastal waters in compliance with existing Directives. AB - A multi-residual method based on stir bar sorptive extraction coupled with thermal desorption-gas chromatography-mass spectrometry (SBSE-TD-GC-MS) has been developed to measure 49 organic pollutants (organochlorine pesticides, polycyclic aromatic hydrocarbons, polychlorinated biphenyls, polybrominated diphenyl ethers and nonylphenol) in seawater. Using 100ml of water, the method exhibited good linearity, with recoveries between 86% and 118% and relative standard deviation between 2% and 24% for almost all compounds. The method was applied to determine target contaminants in Catalonian seawater, including coastal areas, ports and desalination plant feed water. Overall individual compound levels oscillated between 0.16 and 597 ng l(-1); PAHs and nonylpenol were the compounds found at the highest concentrations. The method provided LODs between 0.011 and 2.5 ng l( 1), lower than the Environmental Quality Standards (EQS) fixed by Directive 2008/105/EC. In compliance with the directive, this method can be used as a tool to survey target compounds and is aimed at protecting coastal ecosystems from chemical pollution. PMID- 19786287 TI - Convergence in the biosynthesis of acetogenic natural products from plants, fungi, and bacteria. AB - This review deals with polyketides to which nature has developed different biosynthetic pathways in the course of evolution. The anthraquinone chrysophanol is the first example of an acetogenic natural product that is, in an organism specific manner, formed via more than one polyketide folding mode: In eukaryotes, like e.g., in fungi, in higher plants, and in insects, it is synthesized via folding mode F, while in prokaryotes it originates through mode S. It has, more recently, even been found to be synthesized by a third pathway, named mode S'. Thus, chrysophanol is the first polyketide synthase product that originates through a divergent-convergent biosynthesis (depending on the respective producing organisms). A second example of a striking biosynthetic convergence is the isoquinoline alkaloids. While all as yet investigated representatives of this large family of plant-derived metabolites (more than 2500 known representatives!) are formed from aromatic amino acids, the biosynthetic origin of naphthylisoquinoline alkaloids like dioncophylline A is unprecedented in following a route to isoquinolines in plants: we have shown that such naphthylisoquinolines represent the as yet only known polyketidic di- and tetrahydroisoquinolines, originating from acetate and malonate units, exclusively. Both molecular halves, the isoquinoline part and the naphthalene portion, are even synthesized from a joint polyketide precursor, the first proven case of the F-type folding mode in higher plants. The biosynthetic origins of the natural products presented in this paper were elucidated by feeding (13)C(2) labeled acetate (or advanced precursors) to the respective producing organisms, with subsequent NMR analysis of their (13)C(2) incorporation patterns using the potent cryoprobe methodology, thus making the full polyketide folding pattern visible. PMID- 19786288 TI - Atypical polycystic echinococcosis without liver involvement in Brazilian patients. AB - Echinococcus vogeli is known to occur in the neotropics, causing polycystic echinococcosis (PE) in humans. The liver and lungs are the most commonly affected organs. In this paper, we report six cases of human PE in the mesenteries without primary liver involvement. All patients, four males and two females (median age 34 years; range 20-48 years), lived in a forested area (Acre, Brazil). Physical examination revealed abdominal masses. The patients were evaluated by abdominal CT scan, exploratory laparotomy and serology by immunoblot assay. CT scans revealed multiple and cystic lesions with calcified edges in the mesenteric segments. During exploratory laparotomy, polycystic lesions were excised from omentum, mesentery, pancreas and inferior vena cava. Positive serology identified 21 and 31 kDa subunits. We recommend that PE should be investigated in patients from tropical forests in northern Brazil exhibiting abdominal masses with no clearly defined diagnosis. PMID- 19786289 TI - Molecular evidence of the camel strain (G6 genotype) of Echinococcus granulosus in humans from Turkana, Kenya. AB - Cystic echinococcosis (CE) is a zoonotic helminthic disease, which is widely distributed throughout the world. Although G1 is the Echinococcus granulosus genotype most commonly involved in CE in humans, the prevalence of infection with other genotypes, such as G6, may be higher than previously thought. We performed molecular analysis to identify which E. granulosus genotypes are the causative agents of CE in humans in Kenya's Turkana district. During a Hydatid Control Programme in 1993-1994, 71 cyst fluid isolates of E. granulosus were collected during PAIR (puncture, aspiration, injection, re-aspiration) sessions. DNA was amplified for two genes from 59 isolates. Of these, 49 isolates (83%) were identified as G1 and 10 (17%) as G6. This is the highest prevalence of G6 detected in humans of the Old World, and our results suggest that, in highly contaminated environments, G6 might be of greater public health significance than previously believed. PMID- 19786290 TI - The optics of aphakic and pseudophakic eyes in childhood. AB - The growth of the eye results in a myopic shift in aphakic and pseudophakic eyes during childhood. Cataract surgery after the age of 6 months, with or without lens implantation, appears to have little effect on the rate of refractive growth. Most children with pseudophakia have a large amount of myopic shift. This myopic shift is greatest in children with surgery at younger ages. It is also greater in eyes with high-power intraocular lenses due to an optical phenomenon analogous to the effect of vertex distance. The amount of myopic shift and the variance in rate of refractive growth can be predicted using an empiric, logarithmic model. We describe a revision of this logarithmic model to extend it patients with surgery before 3 months of age. We also analyze the variance in the rate of refractive growth, based on data from pseudophakic children with the longest follow-up in proportion to age. PMID- 19786291 TI - In situ stabilization of cadmium-, lead-, and zinc-contaminated soil using various amendments. AB - Chemical stabilization is an in situ remediation method that uses inexpensive amendments to reduce contaminant availability in polluted soil. We tested the effects of several amendments (limestone, red-mud, and furnace slag) on the extractability of heavy metals, microbial activities, phytoavailability of soil metals (assessed using lettuce, Lactuca sativa L.), and availability of heavy metals in ingested soil to the human gastrointestinal system (assessed using the physiologically based extraction test). The application of soil amendments significantly decreased the amount of soluble and extractable heavy metals in the soil (p<0.05). The decreased extractable metal content of soil was accompanied by increased microbial activity and decreased plant uptake of heavy metals. Soil microbial activities (soil respiration, urease, and dehydrogenase activity) significantly increased in limestone and red-mud-amended soils. Red-mud was the most effective treatment in decreasing heavy-metal concentrations in lettuce. Compared to non-amended control soil, lettuce uptake of Cd, Pb, and Zn was reduced 86%, 58%, and 73%, respectively, by the addition of red-mud. PMID- 19786292 TI - Use of grape seed and its natural polyphenol extracts as a natural organic coagulant for removal of cationic dyes. AB - Natural organic coagulants (NOCs) such as chitosan and Moringa oleifera seeds have been extensively characterized for potential application in water treatment as an alternative to metal-based coagulants. However, the action of both chitosan and M. oleifera seeds is mainly restricted to anionic organic pollutants because of their cationic functional groups affording poor cationic pollutant coagulation by electrostatic repulsion. In this study, we employed ethanolic grape seed extract (GSE) and grape seed-derived polyphenols such as tannic acid and catechin in an effort to find novel NOCs showing stable anionic forms for removal of cationic organic pollutants. The target substances tested were malachite green (MG) and crystal violet (CV), both mutagenic cationic dyes. Polyphenol treatment induced fast decolorization followed by gradual floc formation concomitant with red or blue shifts in maximum absorbance wavelengths of the cationic dyes. Liquid chromatography analysis of flocs formed by polyphenols directly showed that initial supramolecular complexes attributed mainly to electrostatic attraction between polyphenol hydroxyphenyl groups and cationic dyes further progressed into stronger aggregates, leading to precipitation of dye-polyphenol complexes. Consistent with the results obtained using catechin and tannic acid, use of GSE also resulted in effective decolorization and coagulation of soluble MG and CV in aqueous solutions. Screening of several organic GSE components for NOC activity strongly suggested that natural polyphenols are the main organic ingredients causing MG and CV removal via gradual floc formation. The treatment by natural polyphenols and GSE decreased toxicity of MG- or CV-contaminated water. PMID- 19786293 TI - Diurnal distribution of airborne bacteria and fungi in the atmosphere of Helwan area, Egypt. AB - Airborne bacterial and fungal composition in an industrial town of Helwan, Egypt, was studied using a slit impactor sampler during the period from March 2006 to February 2007. Airborne bacterial concentrations were usually higher than fungi. Bacteria and fungi had similar diurnal variation patterns. Airborne microorganisms reached their concentration peaks in the evening and gradually decreased during the night time. The hourly concentration peaks of the bacteria and fungi appeared at 20:00h. A significant difference (P < or =0.05) was found between the hourly mean concentrations of airborne fungi in winter compared to other seasons. Fungi concentrations were significantly higher (P< or =0.05) on working weekdays than weekends. Aspergillus, Penicillium, Alternaria and Cladosporium were the most predominant airborne fungal genera. Aspergillus showed double peak patterns whereas Penicillium, Alternaria and Cladosporium showed one peak pattern. The diurnal variations of the bacteria and fungi could be divided into four periods: 1) the morning maximum concentration (6:00h-10:00h), 2) midday to afternoon pattern (10:00h-16:00h), 3) the evening concentration peak (18:00h 20:00h) and 4) the gradual decrease of night time concentration (22:00h-24:00h). Geographical location, human activity, growth cycle of organisms and meteorological factors were the main criteria controlling the temporal variations of the air microorganisms in the Wadi Hof area. PMID- 19786294 TI - Analysis and evaluation of soundscapes in public parks through interviews and measurement of noise. AB - The purpose of this work was to investigate the sound environment of public parks using a soundscape study model that analyzes not only noise but also all the types of sound of a given area, as well as other environmental factors. To this end, acoustic measurements were made in the parks under study and interviews were held with their frequent visitors. Noise measurements were conducted in 55 points, and a total of 335 people were interviewed in the 4 parks studied. The parks selected for this study are located in areas very close to streets with intense vehicle flow, raising the hypothesis that this proximity impairs the acoustic comfort of their visitors. The findings confirm the strong influence of traffic noise on the soundscapes of the parks. Noise measurements showed that in all parks, between 50 and 100% of the points evaluated displayed sound levels above 55dB(A), the level established by Curitiba's Municipal Law 10625 as the limit permitted for green areas during daytime. Other conditions in the parks' environments were also identified, which interfere jointly in the soundscape and in its perception, such as spatial factors of each park, the urban setting of its surroundings, and the sounds originating inside the parks. PMID- 19786295 TI - Combined cis-regulator elements as important mechanism affecting FXII plasma levels. AB - INTRODUCTION: Factor XII (FXII) deficiency is a recessive Mendelian trait due to mutations in the F12 gene. There is no bleeding associated with FXII deficiency, but FXII deficiency has been reported to be associated with risk of thrombosis in some studies. MATERIAL AND METHODS: We examined the functional effect of two naturally-occurring mutations in two Spanish FXII deficient families: a C/G substitution at position -8, and a C/T substitution at position -13. Both mutations were located on a putative HNF4 binding site of F12 gene promoter. We also analyzed the F12 C46T polymorphism (rs1801020), associated with a decrease in the FXII levels, which also segregated in both families. A fragment containing each one of both -8 and -13 mutations, was cloned 5' of a reporter gene. We compared the in vitro expression of these constructs to the wild type expression. RESULTS: Our analyses confirm that the -8C/G and the -13C/T mutations decreased expression levels, demonstrating that both mutations are involved in the observed FXII deficiency. In addition, electrophoretic shift analyses suggest that they alter the union of nuclear proteins to the promoter. Coinheritance of these mutations with the C46T polymorphism, result in a significant genotype-phenotype correlation. CONCLUSIONS: We have identified two naturally-occurring mutations in the F12 promoter that drastically reduce FXII levels. Knowing rare genetic alterations in the F12 gene, together with the C46T common variant, may yield further understanding about the genetic architecture of FXII levels, which may have a role in the risk of thrombosis. PMID- 19786296 TI - Platelet glycoprotein GP VI 13254C allele is an independent risk factor of premature myocardial infarction. AB - AIM: The purpose of this study was to asses the impact of haemostatic and platelet receptor gene polymorphisms as an inherited risk factor for premature onset of myocardial infarction (MI). METHODS: Polymorphisms of platelet receptors - GP Ia (807C>T, rs1126643), GP VI (13254T>C, rs1613662), GP IIIa (HPA-1, rs5918), PAR -1 (IVS -14A>T; rs168753), P2Y(12) (34C>T, rs6785930 and H1/H2 haplotype, rs2046934), and genetic variations of the gene coding for cyclooxygenase-1 (COX-1) ( -842A>G, rs10306114 and 50C>T, rs3842787) were investigated. Mutations in the genes coding for coagulation factor V (Q506R (Leiden) mutation, rs6025) and factor II (prothrombin G20210A, rs1799963) were also determined. The prevalence of gene polymorphisms was investigated in 105 consecutive patients with premature MI. This was compared with the same gene polymorphism prevalence in a group of 132 patients in which coronary artery disease had been excluded. Genotyping was done using PCR, followed by melting curve analysis with specific fluorescent hybridization probes. RESULTS: A significant association between GP VI 13254C allele carriers and premature MI was found (p=0.025). No other differences in prevalence of the investigated polymorphisms between the compared patient populations reached statistical significance. In a logistic regression, which took other cardiovascular risk factors into account, the significance of the GP VI 13254C allele and vascular risk was suggested (OR 1.888, 95% C.I. 1.029 to 3.464, p=0.040). In a binary logistic regression the positive relationship between the GP VI genotype and female gender was observed (0R 3.676; 95% C.I. 1.159 to 11.628; p=0.027). The frequencies of GP VI and GP Ia gene polymorphisms were independent of one another (p=0.836). CONCLUSION: The presence of the GP VI 13254C allele is an independent predictor of premature MI. PMID- 19786297 TI - Androgen receptor polymorphism and platelet reactivity in healthy men. PMID- 19786298 TI - Baseline platelet size is increased in patients with acute coronary syndromes developing early stent thrombosis and predicts future residual platelet reactivity. A case-control study. AB - INTRODUCTION: Pre-procedural predictors of early stent thrombosis (ST) and future response to platelet inhibitors are in demand. We sought to evaluate the impact of baseline platelet indices on the occurrence of early ST and future residual platelet reactivity. MATERIALS AND METHODS: Hundred and eight patients with acute coronary syndromes (ACS) in whom stents were implanted were included: 36 consecutive ST cases and 72 matched controls. Platelet indices assessed with flow cytometry before stent implantation were retrieved from the department's data base. Residual platelet reactivity specific to aspirin (aspirin reaction units ARU) and clopidogrel (P2Y12 reaction units-PRU) was assessed prospectively with VerifyNow under dual antiplatelet treatment. RESULTS: Platelet size reported as mean platelet volume (MPV) or proportion of large platelets (LPLT) was significantly higher in ST cases compared with controls (10.4, 95% confidence intervals [CI], 10.1-10.8 vs. 9.7, CI, 9.5-9.9, P=0.0004 and 35.8, CI, 34.2-37.3 vs. 33.3, CI, 32.2-34.3, P=0.007, respectively). Dual aspirin and clopidogrel poor-responsiveness was diagnosed significantly more often in ST cases than in controls (19.6% vs. 1.4%, P=0.004), whereas no difference was observed for single aspirin or clopidogrel poor-responsiveness. A strong correlation was found between MPV and both, ARU (r=0.66, P<0.0001) and PRU (r=0.55, P<0.0001). Similarly, higher LPLT was associated with higher ARU (r=0.47, P<0.0001) and PRU (r=0.38, P=0.0001). CONCLUSIONS: Baseline platelet size is increased in patients with ACS developing early ST and correlates with future residual platelet reactivity under aspirin and clopidogrel therapy. Dual but not isolated aspirin or clopidogrel poor-responsiveness appears to be associated with early ST. PMID- 19786300 TI - Influence of the shape of the layers in photo-cured dental restorations on the shrinkage stress peaks-FEM study. AB - OBJECTIVE: The aim of the paper is to analyse an influence of the shape of the layers in photo-cured dental restorations of Class I on distribution of shrinkage stresses along the tooth-restoration interface. The study is a continuation of the previous considerations (Kowalczyk and Gambin (2008) [1]), where techniques, which reduce stress concentration at the top of the tooth-restoration interface, were considered. The analysis leads to proposition of new layer forming techniques, which diminish the stress peaks at the interface and prevent the crack propagation process. METHODS: To find the stress distributions in the dental restoration layers and the tooth tissues the finite element method implemented in the ABAQUS (Simulia, Providence, USA) software is used. For Class I restoration of the premolar tooth, the axisymmetrical model is assumed. The restoration is made of four layers of a photo-cured composite. Between the tooth tissues and the restoration, a layer of bonding agent 0.01mm thick is placed and modeled by FEM with help of the cohesive elements. The assumed model takes into account an influence of changes of elastic properties and viscous effects. For each case of the restoration layers system, the Huber-Mises stresses are analysed. RESULTS: The investigations show that the stresses near the restoration tooth tissue interface are reduced due to viscous flow of the cured material and due to existence of a thin layer of the bonding agent. However, the stress distribution both, in the restoration and in the tooth tissues, is strongly dependent on a shape of the filling layers. Numerical simulations disclose that stress peaks are located at the top corners of each layer. The top corners of the last layer are the places where microleakage may occur. Stress concentrations at the corners of the preceding layers may lead to a growth of uprising crack. It will be shown that the flat layers in the restoration create relatively high values of the stress peaks. The rounded layers, with shapes close to those used in dental practice, reduce maximal stresses about 40%. According to a common opinion of dentists, the wedge-shaped layers give the best result. In the present paper, another way of the shrinkage stress reduction is proposed. Before the layering, one can cover the surface of the tooth cavity with a thin "pre-layer". Next, the remainder cavity may be filled with flat, rounded or wedged layers. It will be shown, that in the fillings with the pre-layers, stress peaks are reduced up to 75%, with respect to the fillings composed of the rounded layers only. The proposed method considerably reduces the shrinkage stress, both in the tooth restoration, as well as, in the tooth tissues. SIGNIFICANCE: The fillings with the pre-layer are easy in application and its analysis gives promising results. The pre-layer may be applied with other layers of different shapes, and its thickness may vary. The method is recommended for cavities with a great loss of the tooth tissue. PMID- 19786301 TI - Extranodal NK/T-cell lymphoma nasal type: efficacy of pegaspargase. Report of two patients from the United Sates and review of literature. PMID- 19786302 TI - Protein kinase A activators and the pan-PPAR agonist tetradecylthioacetic acid elicit synergistic anti-leukaemic effects in AML through CREB. AB - Targeting of signal transduction pathways and transcriptional regulation represents an attractive approach for less toxic anti-leukaemic therapy. We combined protein kinase A (PKA) activation with a pan-peroxisome proliferator activated receptor (PPAR) activator tetradecylthioacetic acid, resulting in synergistic decrease in viability of AML cell lines. PKA isoform II activation appeared to be involved in inhibition of proliferation but not induction of apoptosis in HL-60 cells. Inhibition of CREB function protected against this anti leukaemic effect with higher efficiency than enforced Bcl-2 expression. Preclinical studies employing the rat AML model Brown Norwegian Myeloid Leukaemia also indicated anti-leukaemic activity of the combination therapy in vivo. In conclusion, combined PKA and pan-PPAR activation should be explored further to determine its therapeutic potential. PMID- 19786303 TI - Induction of IL-8 expression by bacterial flagellin is mediated through lipid raft formation and intracellular TLR5 activation in A549 cells. AB - We investigated the mechanism for the induction of a chemokine, IL-8, by bacterial flagellins in the human alveolar type II epithelial cell line, A549. Bacterial flagellin induced expression of IL-8 mRNA and protein in dose- and time dependent manners. IL-8 expression was inhibited by nystatin (a lipid rafts inhibitor) but not by chlorpromazine (a clathrin-coated pits inhibitor). Interestingly, Toll-like receptor 5 (TLR5) recognizing flagellins was found in the intracellular compartment of A549 but rarely on the cell surface. Flagellin induced IL-8 expression appears to be mediated through TLR5 as determined by in vitro transient transfection experiment in HEK-293 cells expressing TLR5 using a reporter gene construct containing IL-8 promoter. IL-8 expression was attenuated by inhibitors for protein kinase C (PKC) and mitogen-activated protein (MAP) kinases. Furthermore, NF-kappaB and NF-IL6 transcription factors played an important role in the flagellin-induced IL-8 gene expression in A549 cells. Collectively, these results suggest that flagellin-induced IL-8 expression requires formation of lipid rafts, intracellular TLR activation, and subsequent activation of PKC and MAP kinases leading to the activation of the transcription factors NF-kappaB and NF-IL6 in human alveolar type II epithelial cells. PMID- 19786305 TI - Probing the Cu(2+) and Zn(2+) binding affinity of histidine-rich glycoprotein. AB - The zinc(II) and copper(II) binding ability of two oligopeptide fragments, Ac HHPHG-NH(2) and Ac-HHPHGHHPHG-NH(2), derived from the repeat-region of the His Pro-rich domain of histidine-rich glycoprotein (HRG) and the structure of the formed complexes have been investigated by potentiometry, NMR-, UV-visible-, CD-, SRCD- and EPR spectroscopy. Exclusive coordination of the side-chain imidazoles of the peptides has been observed with both metal ions in the acidic and neutral pH range. While the three His units of the pentapeptide resulted in a modest stability of the ML complexes, the decapeptide with its increased number of His residues offered a high-affinity metal binding site for both metal ions with the participation of at least four nitrogen donors. Due to the high number of potential donor groups, the formation of binding isomers of the protonated and parent complexes is very likely. Both peptides show a synchrotron radiation (SR) CD-pattern resembling to that of the polyproline II structure, similarly to that of the His-Pro-rich domain of the HRG protein. The longer sequence was shown to bind a second metal ion in the slightly acidic pH-range. The determined stability data suggest a remarkable extra stabilization emerging in the decapeptide for the coordination of the second metal ions, as compared to the ML complexes of the pentapeptide. Whether the observed cooperativity has similarities to the cooperative metal binding feature of HRG or the two phenomena have different sources is a question yet to be clarified. PMID- 19786304 TI - Role of alveolar epithelial early growth response-1 (Egr-1) in CD8+ T cell mediated lung injury. AB - Influenza infection of the distal airways results in severe lung injury, a considerable portion of which is immunopathologic and attributable to the host responses. We have used a mouse model to specifically investigate the role of antiviral CD8(+) T cells in this injury, and have found that the critical effector molecule is TNF-alpha expressed by the T cells upon antigen recognition. Interestingly, the immunopathology which ensues is characterized by significant accumulation of host inflammatory cells, recruited by chemokines expressed by the target alveolar epithelial cells. In this study we analyzed the mechanisms involved in the induction of epithelial chemokine expression triggered by antigen specific CD8(+) T cell recognition, and demonstrate that the early growth response-1 (Egr-1) transcription factor is rapidly induced in epithelial cells, both in vitro and ex vivo, and that this is a critical regulator of a host of inflammatory chemokines. Genetic deficiency of Egr-1 significantly abrogates both the chemokine expression and the immunopathologic injury associated with T cell recognition, and it directly regulates transcriptional activity of a model CXC chemokine, MIP-2. We further demonstrate that Egr-1 induction is triggered by TNF alpha-dependent ERK activation, and inhibition of this pathway ablates Egr-1 expression. These findings suggest that Egr-1 may represent an important target in mitigating the immunopathology of severe influenza infection. PMID- 19786306 TI - Efficacy of nasal irrigation in the treatment of acute sinusitis in children. AB - BACKGROUND: Nasal irrigation has been used as an adjunctive therapy of sinonasal disease including acute/chronic sinusitis and allergic rhinitis. Several published articles reported it also improves clinical sinus symptoms. OBJECTIVE: To evaluate the effectiveness of normal saline nasal irrigation in the management of acute sinusitis in children. DESIGN: This was a randomized, prospective placebo-controlled study. METHODS: We included 69 participants with acute sinusitis. 30 of 69 participants underwent normal saline nasal irrigation. 39 of 69 participants were not receiving nasal irrigation. All participants performed nasal peak expiratory flow rate (nPEFR) test, nasal smear examination, radiography (Water's projection) and requested to complete the Pediatric Rhinoconjunctivitis Quality of Life Questionnaires (PRQLQ) at the baseline visit. All participants were requested to record the symptom diary card every day and were followed-up every 1 week during this period. A physical examination, nasal smear and nPEFR were performed at each visit, and all daily diary cards collected. At the final visit, the symptoms diaries were reviewed and participants were requested to complete the PRQLQ again. The nPEFR, radiography (Water's projection) and nasal smear were also repeated. RESULTS: Normal saline irrigation group significantly improved mean PRQLQ values and nPEFR values at medium (T=2.816, P<0.05) and final period (T=2.767, P<0.05) compared with the other group. Although there were no statically significant improving rate of radiography (Water's projection) in among two groups (T=0.545, P>0.05), but normal saline irrigation group was better than the other group. The improval rate of mean TSS in the irrigation group significantly improved all symptoms compared with the placebo group, in which rhinorrhea, nasal congestion, throat itching, cough and sleep quality improved. 27 of 66 (40.9%) participants with atopy, 16 of 27 (53.33%) participants underwent normal saline irrigation. Normal saline irrigation atopy group significantly improved rhinorrhea, nasal congestion, throat itching and sleep quality symptoms compared with non-irrigation atopy group. Normal saline irrigation atopy group significantly improved nPEFR values at final period (Z=2.53, P<0.05). CONCLUSION: This study evidence that normal saline nasal irrigation improves Pediatric Rhinoconjunctivitis Quality of Life and decreases acute sinusitis symptoms. Nasal irrigation is an effective adjunctive treatment for pediatric acute sinusitis. Normal saline nasal irrigation in atopy children also improves allergic-related symptoms. We may need larger, longer and extended study to assess the conclusion. PMID- 19786307 TI - The measurement of craniocervical posture: a simple method to evaluate head position. AB - OBJECTIVE: Some studies have correlated craniocervical posture (CCP) with pharyngeal airway space diameter, breathing conditions, neck pain, headache, dentofacial structures and temporomandibular disorders. Several methods have been suggested in an attempt to establish the best way of evaluating head position using teleradiographs and cephalometric analysis. The objectives of this study therefore were to describe a method of measuring the natural head position (NHP) without exposure to radiation or fixture of the cephalostat, and then to test whether there might be a simple method of reproducing this position in the cephalostat to make lateral cephalograms in the study of CCP. METHODS: The sample consisted of 50 healthy children (28 females and 22 males with a mean age of 10.9+/-4.9 years). Each subject was asked to place their feet in a standardized positions (a 30 degrees angle between the medial border of the feet with heels together using a V-podalic stabilizer), to tilt the head backwards and forwards to a decreasing extent until a natural head balance was reached, to adopt a natural posture of the shoulders, and to allow both arms to hang free. A self adhesive circular reflecting cutaneous marker was applied to three points to enable a better view of the landmarks: the most anterior point of the frontonasal suture (N), the auricular tragus (Tr) and the most prominent spinous process of the seventh cervical vertebra (C(7)). An operator marked the specific anatomical points of the children's profiles with a felt-tip pen on a mirror placed to one side of the patient and fixed on the wall: the N point, the Tr point, the most inferior point of the chin in the lateral view (Me) and the deepest point on the posterior contour of the cervical lordosis. A digital body posture measuring system captured a first image of each subject in NHP (T0). Five minutes later, with the same position and orientation of the feet, the operator placed the head of the subject in the cephalostat so that the new head position coincided with the head position previously registered in the mirror and a second picture was taken (T1). After a further 5min, the subject was asked to place himself in NHP again, similarly repositioning their own feet to check the precision of the method of positioning, and a third picture was taken (T2). Three craniocervical angular measurements were taken for head posture measurement: N-Tr-Vert, determined by the extended line from the N point to the Tr point and the vertical line projected onto the image by a line (Vert); C(7)-Tr-Vert, determined by the extended line from C(7) to Tr and Vert; and C(7)-Tr-N, the angle between C(7)-Tr line and Tr-N line. In order to determine the stability of all the measurements of head position at T1, T2 and T3, a paired-sample t-test was used using an alpha of 0.05 and a power of 0.90. RESULTS: It was found that there were no statistically significant differences in head position between the pictures at T0, T1 and T2 (N-Tr-Vert, C(7)-Tr-Vert and C(7)-Tr-N, P>0.05). CONCLUSION: This method was a good procedure for evaluating head posture without exposure to radiation. The results also suggest that a simple and rapid method can be used to apply a craniostat to the patient when a radiograph is required without modifying the NHP. PMID- 19786308 TI - Bilateral lymphangiomatous polyps of the palatine tonsils. AB - Lymphangiomatous polyps of the tonsils are rare with less than 30 cases reported in the literature. All have been unilateral. We report a case of a child with bilateral lymphangiomatous polyps of the palatine tonsils that was suspected on preoperative examination as opposed to an incidental postoperative histologic finding. These findings were also correlated with a further imaging study to establish this entity as a localized rather than a generalized histologic phenomenon. PMID- 19786309 TI - The impact of hip fracture (HF) on the functional status (FS) of older persons in Rio de Janeiro, Brazil: results of a prospective cohort study. AB - There is no prospective study investigating the impact of hip fracture (HF) on functional status (FS) in Brazil. The objective of this study was to investigate the impact of a HF on the FS of older persons 1 year after the fracture and the factors associated with decline in FS 1 year after the fracture. Two hundred and forty-six patients who were admitted to one of four hospitals after HF participated. The sample for this study consisted of 160 patients who were still alive and had information on functional limitations after 1 year. The Brazil Old Age Schedule (BOAS) was used to assess FS before and 1 year after HF. Logistic regression analyses were used to identify predictors of decline 1 year after fracture. Of the patients, 46.3% did not achieve their prior FS. Older age, being underweight, total length of stay and the use of psychotics/sedatives and anxiolitics were associated in multivariate analyses with decline in FS. Working before the fracture was protective of decline in FS. We conclude that HF severely compromised the FS of older persons in Rio de Janeiro, Brazil. PMID- 19786310 TI - Global thinking and global education: philosophy, programs, perspectives. AB - The purpose of this paper is to offer inspiration for all of us toward increased involvement in international veterinary medicine, and also to provide useful information. Because of my early international exposure, my personal and professional horizons expanded and I became a citizen of the world. As a result, my career orientation changed dramatically and I have had a career that is not only interesting, but from my perspective, socially useful. My primary goal has been to communicate these possibilities to my students. Two programs with strong international emphasis at the School of Veterinary Medicine, University of California-Davis are discussed, the Master of Preventive Veterinary Medicine (MPVM) program and the School's Office of International Programs. Many international veterinarians have prepared themselves for careers in population and preventive medicine in the MPVM program. The primary objective of the School's Office of International Programs is to make information on and opportunities in international veterinary medicine available to veterinary students. There is strong justification for increased emphasis in global medicine for veterinarians, and our schools and colleges should take the lead in developing and implementing educational initiatives in this important field. PMID- 19786311 TI - Posture and cognition interfere in later adulthood even without concurrent response production. AB - We investigated adult age differences in dual-task costs in cognitive sensorimotor settings without concurrent response production and with individually adjusted resource demands for the cognitive task. Twenty-four young adults (M=25.42 years, SD=3.55) and 23 older adults (M=68 years, SD=4.46) performed a cognitive task and two postural control tasks (standing on a stable and moving platform) both separately (single-task context) and concurrently (dual task context). The cognitive task did not require response production during posture data collection and its difficulty was individually adjusted to 80% correct performance under single-task conditions. Results showed pronounced age differences in postural control in the moving platform condition, which increased further under dual-task conditions. Our findings support the assumption of increased cognitive resource demands for postural control in older adults. They extend existing work by taking two shortcomings of previous studies into account. We discuss cognitive and posture task constraints in this and previous studies as factors determining multi-tasking and its changes in later adulthood. PMID- 19786312 TI - Characterization of Escherichia coli from raw poultry in Belgium and impact on the detection of Campylobacter jejuni using Bolton broth. AB - A comparative study examining Bolton broth and Preston broth for enrichment and reliable detection of Campylobacter jejuni (both healthy and freeze stressed cells) was performed. Tested as pure cultures, Bolton broth enabled faster resuscitation and growth of C. jejuni compared to Preston broth. When C. jejuni was co-incubated with extended-spectrum-beta-lactamase (ESBL) producing Escherichia coli isolated from Belgian poultry meat preparations, the latter dominated in the Bolton enrichment broth and crowded the mCCDA plates. This resulted in the inability to recover C. jejuni by ISO 10272-1:2006 standard method. Preston broth did not support the growth of the ESBL E. coli isolates, but showed longer detection time of C. jejuni compared to Bolton broth. The use of the same antibiotic (sodium cefoperazone) in Bolton broth and in mCCDA plates may explain the problems encountered for detection of C. jejuni, as high numbers of ESBL E. coli present after enrichment in Bolton broth, also caused overgrowth and masked the few C. jejuni colonies present on the mCCDA plates. The use of Campylobacter spp. specific real-time PCR circumvented these problems and enabled rapid detection of the pathogen after 24h enrichment in both Bolton and Preston broth, for both healthy and freeze stressed cells. PMID- 19786313 TI - Community-associated meticillin-resistant Staphylococcus aureus as a cause of hospital-acquired infections. AB - The worldwide emergence of community-associated meticillin-resistant Staphylococcus aureus (CA-MRSA) during the last decade represents a significant change in the biology of MRSA strains and is changing the epidemiology of MRSA infections. CA-MRSA infections are caused by strains belonging to lineages distinct from HA-MRSA. In the community, CA-MRSA strains typically cause skin and soft tissue infections in children and younger adults. However, CA-MRSA strains increasingly cause healthcare-acquired infections including surgical site infections, ventilator-associated pneumonia and bacteraemia. A mathematical model showing the influence of MRSA transmission in the community on the prevalence of MRSA in hospitals is presented. The increasing prevalence of MRSA in the community also results in an increase in community-onset MRSA (CO-MRSA) among S. aureus bacteraemia and other invasive infections. These patients do not have typical risk factors for MRSA. Such changes may have profound implications for the choice of empirical therapy for serious infections where S. aureus is a possible cause. The new and potentially very large reservoir of MRSA in production animals with subsequent transmission to humans represents an additional serious threat to the control of MRSA both in general and as a cause of healthcare-acquired infections. CA-MRSA is thus a matter of serious concern and should be suppressed. PMID- 19786314 TI - Spatial and temporal small-scale variability of nitrogen mobilization in a forest ecosystem with high N deposition in NW-Germany. AB - For conifer stands in NW-Germany with high DIN load (23-35 kg N ha(-1) a(-1)) and a long history of nitrogen export the risk of N mobilization were investigated. Ammonium is the most mobilized N species, pointing towards either conditions not favoring nitrification or, more likely - under the dominant aerobic conditions - a very high amount of ammonium in the forest floor. Independence of net nitrification and net ammonification from each other indicates the existence of two separate systems. The nitrifying system depends very much on biotic conditions - as a function of energy and moisture - and seems not to be directly related to N deposition. In contrast, for the ammonification system (Oe horizon) a correlation with the sum of ammonium deposition three months prior to sampling was found. However, the role of disturbance, i.e. nitrogen export, during the last centuries and the role of recovery of the N balance during the last 150 years is still not clear. PMID- 19786315 TI - Effect of salt and urban water samples on bacterivory by the ciliate, Tetrahymena thermophila. AB - The effect of road salt on the eating of bacteria or bacterivory by the ciliate, Tetrahymena thermophila, was followed in non-nutrient Osterhout's solution with Escherichia coli expressing green fluorescent protein. Bacterivory was impaired at between 0.025 and 0.050% w/v but the ciliates appeared to have normal morphologies and motilities, whereas at above 0.1%, bacterivory was blocked and many ciliates died. By contrast, E. coli remained viable, suggesting salt could alter predator-prey relationships in microbial communities. In nutrient medium, salt was not toxic and the ciliates grew. After growth in salt, ciliates consumed bacteria in 0.2% salt, indicating the salt acclimation of bacterivory. Bacteria and ciliates were added to urban creek samples to compare their capacity to support exogenous bacterivory. Even though samples were collected weekly for a year and be expected to have fluctuating salt levels as a result of deicing, all creek samples supported a similar level of bacterivory. PMID- 19786316 TI - Auditory space perception in left- and right-handers. AB - Several studies have shown that handedness has an impact on visual spatial abilities. Here we investigated the effect of laterality on auditory space perception. Participants (33 right-handers, 20 left-handers) completed two tasks of sound localization. In a dark, anechoic, and sound-proof room, sound stimuli (broadband noise) were presented via 21 loudspeakers mounted horizontally (from 80 degrees on the left to 80 degrees on the right). Participants had to localize the target either by using a swivel hand-pointer or by head-pointing. Individual lateral preferences of eye, ear, hand, and foot were obtained using a questionnaire. With both pointing methods, participants showed a bias in sound localization that was to the side contralateral to the preferred hand, an effect that was unrelated to their overall precision. This partially parallels findings in the visual modality as left-handers typically have a more rightward bias in visual line bisection compared with right-handers. Despite the differences in neural processing of auditory and visual spatial information these findings show similar effects of lateral preference on auditory and visual spatial perception. This suggests that supramodal neural processes are involved in the mechanisms generating laterality in space perception. PMID- 19786317 TI - Patterns of brain-electrical activity during declarative memory performance in 10 month-old infants. AB - This study of infant declarative memory concurrently examined brain-electrical activity and deferred imitation performance in 10-month-old infants. Continuous electroencephalogram (EEG) measures were collected throughout the activity matched baseline, encoding (modeling) and retrieval (delayed test) phases of a within-subjects deferred imitation task. Infants were divided into two memory performance groups based on the exhibition of ordered-recall after a 24-h delay. Whereas no group differences were found in EEG collected during encoding, performance-group differences in EEG were present during retrieval. Infants who successfully displayed ordered-recall showed a pattern of increasing EEG from baseline to task at anterior temporal scalp locations, whereas infants showing no ordered-recall displayed no changes in EEG from baseline to task. These findings are discussed with respect to the biobehavioral developments underlying declarative memory abilities. PMID- 19786318 TI - Robot assisted laparoscopic transperitoneal para-aortic lymphadenectomy in the management of advanced cervical carcinoma. AB - OBJECTIVES: Adequate staging of advanced cervical cancer is essential in order to optimally treat the patient. FIGO clinical staging, imaging techniques such as CT scan, MRI and PET sometimes underestimate the extension of tumors. The presence of para-aortic lymph node metastases in advanced cervical cancer identifies patients with poor prognosis who need to be treated aggressively. Laparoscopic para-aortic lymph node dissection is now proposed as a diagnostic tool in many guidelines. We evaluated the feasibility and safety of a robot assisted laparoscopic transperitoneal approach to para-aortic lymph node dissection. STUDY DESIGN: Eight patients with advanced cervical carcinoma who were eligible for primary pelvic radiotherapy combined with concurrent cisplatin chemotherapy or pelvic exenteration underwent a pre-treatment robot assisted transperitoneal laparoscopic para-aortic lymphadenectomy. RESULTS: We isolated from 1 to 38 para aortic nodes per patient and had one para-aortic node positive patient who was treated with extended doses of pelvic radiotherapy. We did not encounter any major complications and post-operative morbidity was low. CONCLUSIONS: Robot assisted transperitoneal laparoscopic para-aortic lymphadenectomy is feasible and provides the surgeon with greater precision than classical laparoscopy. Larger prospective multicentric trials are needed to validate the generalised usefulness of this technique. PMID- 19786319 TI - Therapeutic potential of human mesenchymal stem cells producing IL-12 in a mouse xenograft model of renal cell carcinoma. AB - Mesenchymal stem cells (MSCs) represent a new tool for delivery of therapeutic agents to cancer. The cytokine interleukin-12 (IL-12) has demonstrated a potent anti-tumor activity in a variety of mouse tumor models. In this study, human MSCs were isolated from human bone marrow and identified by phenotype analysis and differentiation assays. The anti-tumor activity of human MSCs stably transduced with a recombinant adenoviral vector expressing the murine IL-12 (MSC/IL-12) were evaluated in a mouse xenograft model of renal cell carcinoma (RCC). Expression and bioactivity of the transgenic protein IL-12 from adenoviral vector were confirmed prior to in vivo studies. A nude mouse model of RCC was developed by subcutaneously injection of 786-0 cells into nude mice. MSC/IL-12 was injected into the lateral tail vein with single dose. Results indicated that systemic administration of MSC/IL-12 reduced the growth of 786-0 RCC and significantly prolonged mouse survival. These transfected cells could home to tumors after intravenous injection and largely produce local IL-12 protein. In contrast, systemic level of IL-12 was modestly elevated. Further studies showed that the anti-tumor activity of the MSC/IL-12 was dependent on the presence of natural killer (NK) cells and IFN-gamma in this experimental setting. These data demonstrate the potential of adult MSC constitutively producing IL-12 to reduce the growth of RCC and enhance the tumor-bearing mouse survival. PMID- 19786320 TI - Modelling of the Ni(II) removal from aqueous solutions onto grape stalk wastes in fixed-bed column. AB - Grape stalk wastes generated in the wine production process were used for the removal of nickel (II) from aqueous solution. The experimental breakthrough curves were obtained in fixed-bed columns. Experiments we carry out in order to evaluate the influence of inlet metal concentration (30 and 70 mg L(-1)) and the regeneration process in a double sorption cycle. The CXTFIT code was used to fit the experimental data and to determine the transport and sorption parameters of the convective-dispersive equation (CDE) and the two-site deterministic non equilibrium (TSM/CDE) model by adjusting the models to the experimental breakthrough curves (BTC). The results showed that bed capacity as well as transport and sorption parameters were affected by the initial metal concentration, at the highest Ni(II) concentration the grape stalks column saturated quickly leading to earlier breakthrough. The sorption capacity of the sorbent was slightly reduced in a double sorption cycle, while the recovery of the metal in the desorption step was ranging between 80% and 85% in both cycles. PMID- 19786321 TI - Modeling mercury speciation in combustion flue gases using support vector machine: prediction and evaluation. AB - Mercury emission from coal combustion has become a global environmental problem. In order to accurately reveal the complexly nonlinear relationships between mercury emissions characteristics in flue gas and coal properties as well as operating conditions, an alternative model using support vector machine (SVM) based on dynamically optimized search technique with cross-validation, is proposed to simulate the mercury speciation (elemental, oxidized and particulate) and concentration in flue gases from coal combustion, then the configured SVM model is trained and tested by simulation results. According to predicted accuracy of indicating generalization capability, the model performance is compared and evaluated with the conventional multiple nonlinear regression (MNR) models and the artificial neural network (ANN) models. As a result, it is found that, the SVM provides better prediction performances with the mean squared error of 0.0095 and the correlation coefficient of 0.9164 for testing sample. Moreover, based on the SVM model, the correlativity between coal properties as well as operating condition and mercury chemical form is also analyzed in order to deeply understand mercury emissions characteristics. The result demonstrates that SVM can offer an alternative and powerful approach to model mercury speciation in coal combustion flue gases. PMID- 19786322 TI - Reduction and prevention of vincristine-induced neuropathic pain symptoms by the non-benzodiazepine anxiolytic etifoxine are mediated by 3alpha-reduced neurosteroids. AB - The central processing of peripheral nociceptive messages is highly controlled by the activity of local inhibitory networks in the spinal cord and supraspinal centers. Recently, it has been shown that endogenous 3alpha-reduced neurosteroids (3alphaNS) exert a significant spinal antinociception by potentiating GABA(A) receptor function. Because endogenous 3alphaNS can be produced in many relay structures of the nociceptive system, we tested the potential analgesic efficacy of promoting the production of neurosteroids by using etifoxine (ETX, 50mg/kg i.p.). This prescribed non-benzodiazepine anxiolytic was shown previously to stimulate neurosteroidogenesis in its early step after binding to the mitochondrial translocator protein complex (TSPO). Using an animal model of generalized neuropathic pain resulting from a 2-week treatment with the antitumoral agent vincristine sulfate (VCR, 0.1mg/kg i.p.), we show that injections of ETX (50mg/kg i.p.) given every day reduced the VCR-induced mechanical and thermal pain symptoms but also prevented their appearance, if used in prophylaxia 1 week before VCR. Both the curative and preventive effects of ETX on pain symptoms were mediated by the production of 3alphaNS as demonstrated in animals treated with the enzymatic inhibitor provera (6-medroxyprogesterone acetate; 20mg/kg s.c.). Altogether, this study shows for the first time that promoting 3alphaNS could be a possible therapeutic strategy to treat neuropathic pain symptoms. Since ETX is already available as an anxiolytic, its use in humans, provided that its analgesic properties are confirmed, could be rapidly considered. PMID- 19786323 TI - Even routine painful procedures can be harmful for the newborn. AB - Stressful events can damage neonatal brain through a complexity of events including free radical (FR) generation. We examined whether pain provoked by a routine heel prick can generate an increase in potentially harmful FR in neonatal blood. To this aim, advanced oxidation protein products (AOPP) and total hydroperoxide (TH) concentrations were measured at the beginning (sample A) and at the end (sample B) of each sampling in 64 babies (corrected age: 37.2+/-2.7 weeks) who underwent heel prick for routine blood tests. We scored pain of every procedure in all newborns. No differences were detected between AOPP and TH blood concentrations at the beginning and at the end of heel prick sampling, considering the whole cohort of babies. Conversely, a significant increase was observed between AOPP and TH blood concentrations considering only those babies who showed the highest pain intensity. When babies' pain was high (ABC score >or=4), mean AOPP and TH blood levels increased significantly; in this case, mean AOPP values increased from 53.5microm/l (SD=41.6) to 63.2microm/l (SD=44.3) and TH values from 218.3UCarr (SD=89.2) to 228.7UCarr (SD=93.3), with a significant p value of 0.02 and 0.036, respectively. A significant correlation was also found between AOPP blood levels ratio (sample B/sample A) in each baby, and the correspondent level of pain. These data show that even common routine procedures can be potentially harmful for the newborn if they provoke a high level of pain. PMID- 19786324 TI - Personality traits and mental health states of methamphetamine-dependent and methamphetamine non-using MSM. AB - This analysis considers the relation between personality traits, mental health states and methamphetamine (MA) use in 60 men who have sex with men (MSM). Thirty MA-dependent and 30 MA non-using MSM were assessed on the Neo Five Factor Inventory, the Brief Symptom Inventory, the Perceived Stress Scale, and the Posttraumatic Stress Disorder Checklist-Civilian Version tests. Our results indicate differences between groups on a variety of measures of personality traits and mental states. Specifically, MA-dependent participants were found to be more Neurotic, less Open, less Agreeable, and less Conscientious. Further, MA dependent participants were found to have higher levels of Paranoid Ideation and higher levels of Interpersonal Sensitivity. Given the high prevalence of MA use in the MSM community and the association between MA use and sexual risk taking, our findings provided a clearer understanding of how individual personality traits may be a factor in the continued use of this drug among MSM. Further research should seek to incorporate individual personality traits into the development of efficacious MA-specific treatment interventions. PMID- 19786325 TI - Promiscuous modulation of ion channels by anti-psychotic and anti-dementia medications. AB - There is growing interest in the concept of network pharmacology, as opposed to specific pharmacological targets, as an important drug discovery paradigm. Also known as the "magic shotgun" paradigm, this strategy involves individual drugs interacting with multiple targets to achieve clinical benefit. Pharmacological promiscuity consistent with this paradigm has been suggested in vitro for antidepressants and anticonvulsants, which interact with many classes of ion channels (among other receptor targets). Although the link between certain "off target" interactions and drug side effects is well-accepted, the potential linkage between promiscuity and clinical efficacy remains poorly understood. Here we summarize interactions of clinically useful anti-psychotic and anti-dementia medications with a diverse array of ligand- and voltage-gated ion channels. We hypothesize that promiscuous ion channel modulation may contribute to the efficacy of drugs used to treat psychosis and dementia. PMID- 19786326 TI - Intravenous lipid emulsions combine extracorporeal blood purification: a novel therapeutic strategy for severe organophosphate poisoning. AB - Organophosphorus (OP) pesticide self-poisoning is a major clinical problem in rural Asia and it results in the death of 200,000 people every year. At present, it is lack of effective methods to treat severe organophosphate poisoning. The high mortality rate lies on the amount of toxic absorption. Intravenous lipid emulsions can be used as an antidote in fat-soluble drug poisoning. The detoxification mechanism of intravenous lipid emulsions is "lipid sink", which lipid emulsions can dissolve the fat-soluble drugs and separate poison away from the sites of toxicity. Most of organophosphorus pesticides are highly fat soluble. So, intravenous lipid emulsions have the potentially clinical applications in treatment of OP poisoning. Extracorporeal blood purification especially charcoal hemoperfusion is an efficient way to eliminate the poison contents from the blood. We hypothesize that the combination of intravenous lipid emulsions and charcoal hemoperfusion can be used to cure severe organophosphate poisoning. This novel protocol of therapy comprises two steps: one is obtained intravenous access to infuse lipid emulsions as soon as possible; another is that charcoal hemoperfusion will be used to clear the OP substances before the distribution of OP compounds in tissue is not complete. The advantages of this strategy lie in three points. Firstly, it will alleviate the toxic effect of OP pesticide in the patients by isolation and removal the toxic contents. Secondly, the dosage of antidotes can be reduced and its side-effects will be eased. Thirdly, a large bolus of fatty acids provide energy substrate for the patients who are nil by mouth. We consider that it would become a feasible, safe and efficient detoxification intervention in the alleviation of severe organophosphate poisoning, which would also improve the outcome of the patients. PMID- 19786327 TI - A hypothesis and model of reduced fetal movement as a common pathogenetic mechanism in clubfoot. AB - BACKGROUND: Clubfoot or Talipes equinovarus is characterised by an adducted forefoot, hindfoot varus, and ankle equinus deformity, varying in severity and ease of correction. It is one of the most common congenital defects, with a prevalence of around 1 per 1000. Ambiguity still surrounds the classification and pathogenesis of clubfoot. METHODS: A literature search was performed using Pubmed, Ovid, and the Cochrane Databases, using search terms in isolation or combination: clubfoot, Talipes equinovarus, congenital foot deformities and joint development, identified articles were further hand searched and relevant references identified. CONCLUSION: We propose that the underlying unifying factor in all cases of clubfoot is a lack of fetal movement. Fetal movement is a key developmental signal in the development of joints, and we suggest that this applies to the morphogenesis of the forefoot. Theories exist to explain specific individual features of clubfoot in certain cases and to explain experimental studies, however no common final pathway has been described. We believe that our hypothesis brings together key elements of these and will simplify understanding and classification of clubfoot. PMID- 19786328 TI - Treatment seeking adults with autism or ADHD and co-morbid substance use disorder: prevalence, risk factors and functional disability. AB - BACKGROUND: Little is known about Autism Spectrum Disorder (ASD) in adults, especially not about ASD with co-morbid Substance Use Disorder (SUD). We wanted to examine how adults with ASD compare to adults with ADHD on prevalence and risk factors for co-morbid SUD, and on disability levels associated with SUD. METHODS: We stratified 123 treatment seeking adults with ASD (n=70) or ADHD (n=53), into current, former and no history of SUD (SUD+, SUD(wedge), and SUD-), and conducted interviews to explore associated risk factors and current levels of disability. RESULTS: Prevalence of co-morbid SUD was higher in ADHD than in ASD in our sample (58% versus 30%, p=0.001). There was no statistically significant difference between ASD and ADHD in risk factors or disability scores. Patients with lifetime SUD started regular smoking earlier in life (OR=5.69, C(95%) 2.3-13.8), reported more adverse family events (OR=2.68; CI(95%) 1.2-6.1), and had more parental SUD (OR=5.36; CI(95%) 1.0-14.5). Disability scores were significantly lower in SUD- and SUD(wedge) groups compared to the SUD+ group. DISCUSSION: These findings suggest that ASD and ADHD share similar risk factors for SUD. High disability in ASD and ADHD with SUD may normalize after prolonged abstinence. Early onset of SUD was not associated with more severe disability scores than later onset. Results suggest that a subgroup of patients with former SUD may have a higher level of functioning before the onset of SUD in comparison to those without lifetime SUD. PMID- 19786329 TI - Antibody response to hepatitis B vaccine in substance use disorder patients. AB - The objectives of this study were to assess the prevalence of prognostic factors previously known to be associated with poor antibody response to hepatitis B vaccination in a sample of veterans presenting for substance use disorders treatment at a Veterans Health Administration (VA) Medical Center, assess vaccination response, and identify markers for poor response in this population. Results indicated that most participants had multiple prognostic factors previously known to be associated with poor antibody response including male gender, age over 40, smoking, and obesity. The rate of seroconversion in this sample was 51.9%. This is substantially lower than seen in healthy adults. Alcohol dependence was the only significant independent negative predictor of seroconversion in this sample. Substance use disorders treatment providers who are considering adding hepatitis B vaccination services to their clinics should be aware that the antibody response to the hepatitis B vaccination is inconsistent and that patients with particular demographic characteristics may be at heightened risk of poor antibody response. PMID- 19786330 TI - Sialic acid-dependent binding and transcytosis of serotype D botulinum neurotoxin and toxin complex in rat intestinal epithelial cells. AB - A large toxin complex (L-TC) produced by Clostridium botulinum is composed of neurotoxin (BoNT), non-toxic non-hemagglutinin (NTNHA) and hemagglutinin subcomponents (HA-70, -33 and -17). In animal botulism, BoNT or L-TC is internalized by intestinal epithelial cells. Previous studies showed that L-TC binds to intestinal cells via sugar chains on the cell surface, but the role of toxin binding to sugar chains in the toxin absorption from intestine is unclear. To clarify whether the toxin binding to sugar chains on intestinal cell surface leads to its transcytosis across the cells, we examined binding and permeation of BoNT and L-TC of C. botulinum serotype D strain 4947 to the rat intestinal epithelial cell line IEC-6 in semi-permeable filters in Transwell systems. Both BoNT and L-TC bound to and permeated the cell monolayers, with L-TC showing greater binding and permeation. In addition, both binding and permeation of toxins were potently inhibited by N-acetyl neuraminic acid in the cell culture medium or by treatment of the cells with neuraminidase. However, neither galactose, lactose nor N-acetyl galactosamine inhibited binding or permeation of toxins. These results support the idea that permeation of both BoNT and L-TC through the intestinal cell layer depends on prior binding to sialic acid on the cell surface. This is the first report demonstrating that the binding of botulinum toxins to cell surface sialic acid leads to their transcytosis through intestinal epithelial cells. PMID- 19786331 TI - Distinguishing pathological from constitutional small for gestational age births in population-based studies. AB - BACKGROUND: Small for gestational age (SGA) can occur following a pathological process or may represent constitutionally small fetuses. However, distinguishing these processes is often difficult, especially in large studies, where the term SGA is often used as a proxy for restricted fetal growth. Since biologic variation in fetal size is largely a third trimester phenomenon, we hypothesized that the definition of SGA at term may include a sizeable proportion of constitutionally small fetuses. In contrast, since biologic variation in fetal size is not fully expressed in (early) preterm gestations, it is plausible that SGA in early preterm gestations would comprise a large proportion of growth restricted fetuses. AIM: We compared mortality and morbidity rates between SGA and appropriate for gestational age (AGA) babies. SUBJECTS: A population-based study of over 19million non-malformed, singleton births (1995-04) in the United States was performed. Gestational age (24-44weeks) was based on a clinical estimate. SGA and AGA were defined as sex-specific birthweight <10th and 25-74th centiles, respectively, for gestational age. All analyses were adjusted for a variety of confounding factors. OUTCOME MEASURES: Excess mortality risk in SGA and AGA babies. RESULTS: On an additive scale, stillbirth and neonatal mortality rates were higher at every preterm gestation among SGA than AGA births, and similar at term gestations. An inverse relationship between gestational age and excess deaths between SGA and AGA babies delivered at <37weeks was evident. CONCLUSIONS: In early preterm gestations, the definition of SGA may well be justified as a proxy for IUGR. In contrast, SGA babies that are delivered at term are likely to be constitutionally small. PMID- 19786332 TI - INSURE, Infant Flow, Positive Pressure and Volume Guarantee--tell us what is best: selection of respiratory support modalities in the NICU. AB - Selecting the optimal mode of respiratory support remains a daily challenge for the practicing neonatologist. We are faced with a bewildering array of modalities and a paucity of definitive studies to guide our decisions. In this context the choice of therapies must be guided by evidence-based guidelines, supplemented by a solid understanding of the pathophysiology of lung injury, an appreciation of the individual patient's specific disease process/physiologic derangement. The sequential application of the least invasive treatment to achieve the relevant therapeutic goal with frequent re-evaluation of the patient's need and possible escalation of support as needed, coupled with the application of lung-protective strategies of respiratory support appears to offer the best chance of minimizing adverse pulmonary and neurodevelopmental outcomes. PMID- 19786333 TI - Sperm morphology of beef bulls evaluated by two different methods. AB - The objectives of this study were to compare two different methods of evaluating bull sperm morphology, bright-field (BF) microscopy of eosin-nigrosin (EN) stained dry-mount semen smears and differential interference phase contrast (DIC) microscopy of wet-mount semen 'fixed' in isotonic formal saline, both at 1000x. Ejaculates (n=72) were evaluated, representing both pre- and post-breeding season ejaculates collected from 40 2-yr-old beef bulls via electro-ejaculation. For both methods, 200 sperm were counted in random fields with defects categorized as major (MAD) and minor (MID). Sperm abnormalities were also placed into two other categories: those considered to be most influenced by process (wet or dry, METHDEF) and those with depictions that could be influenced by optics (BF or DIC, OPTIDEF). Differences (P<0.05) occurred between DIC and BF methods respectively: MAD 23.3/16.1, MID 7.6/13.4, acrosome 3.8/1.1, midpiece 9.2/11.7, tail 2.0/4.7, droplets 8.3/4.2, METHDEF 14.2/21.4 and OPTIDEF 13.0/5.5, but not (P>0.05) in percent normal sperm 69.1/70.4 or sperm head defects 7.5/8.3. Acrosome, tail and droplet defects were observed in 98.2/80.5, 86.1/100 and 98.2/94.4 percent of bulls for DIC and BF, respectively (P<0.05). As percent normal sperm did not differ between methods, bright-field microscopy assessment of EN preparations was considered to be a satisfactory method to categorize breeding soundness of bulls. However, DIC was more effective in visualizing major defects, while BF (which included stained smear preparation) was considered to cause more minor defects. Thus DIC was considered to be the preferred method of semen assessment for accurate assessment of sperm morphology in bulls. PMID- 19786334 TI - Health correlates and mode of administration of hormones--are there any differences between parenteral and oral estrogen preparations? AB - OBJECTIVES: To investigate use-associated differences between parental and oral hormone therapy (HT) users in reference to HT non-users regarding self-rated general health status, quality of life, health service utilization, and selected chronic diseases. METHODS: All cases of last-week medicine use were recorded among 2248 women aged 40-79 who participated in the German Health Interview and Examination Survey 1997-1999. 89 current parenteral HT users and 322 oral HT users were identified. Health correlates were compared between the two groups in reference to HT non-users. RESULTS: Oral HT users had a poorer current health status as well as an impaired health status compared to the year before, were less satisfied with their health and life in general, and showed a lower quality of life regarding 'body pain' and 'vitality' in comparison with hormone non-users (all p<.05). Parenteral HT users showed no significant difference compared with HT non-users and oral HT users, respectively, in these health correlates except for a less satisfaction with health found in comparison with HT non-users (p=.002). Prevalences of cerebral-cardiovascular diseases were not different among women using parenteral or oral HT use. Parenteral HT users visited the offices of general practitioner and gynecologists more frequently than oral HT users as well as hormone non-users (all p<.05). CONCLUSIONS: Oral HT use is associated with a negative assessment for health well-being whereas parenteral HT use shows largely a neutral effect. Further designated studies could clarify whether the mode of hormone administration consistently affects health-related quality of life and whether the mode of hormone treatment influences the choice of outpatient facilities for surveillance of therapy. PMID- 19786335 TI - Autopsy report on central pontine myelinolysis triggered by vomiting associated with digoxin intoxication. AB - An 87-year-old male, prescribed digoxin and furosemide for congestive heart failure and Alzheimer disease, had dehydration and anemia due to poor food intake and hemorrhagic cystitis. Repeated vomiting due to an upper respiratory infection caused disturbance of consciousness and hypotension. The patient was admitted to hospital and diagnosed with digoxin intoxication and hypernatremia. The serum sodium (Na(+)) level was corrected, but the patient died 4 days after admission following uncontrollable seizure. A histologic examination after an autopsy revealed characteristic findings of central pontine myelinolysis (CPM). This is the first autopsy report on CPM triggered by vomiting in association with digoxin administration. PMID- 19786336 TI - Coach training can improve the self-efficacy of neonatal nurses. A pilot study. AB - OBJECTIVE: In this pilot study we have investigated the impact of coach training offered to neonatal nurses on their assessment of their ability to meet the needs of the mothers and fathers. METHODS: The effect of a 3-day coaching training offered to neonatal nurses was investigated in an intervention study evaluating the nurses' self-efficacy before and after the course. RESULTS: A total of 39/44 (89%) and 31/40 (78%) neonatal nurses answered the questionnaire before and after the course. The self-efficacy scores increased up to 14.8% and for all but 1 question, the increase was statistically significant. CONCLUSION: Coaching can improve nurses' self-efficacy in relation to meet the needs of the mothers and fathers. PRACTICE IMPLICATIONS: Coaching could be a method that can maximize the personal and professional potential of the staff, and prepare them for the mindful being-in-relation approach that increasingly is being requested. This should be confirmed in a bigger study. PMID- 19786337 TI - Visfatin gene expression in chickens is sex and tissue dependent. AB - The present study investigated the expression of visfatin mRNA in various tissues of male and female broiler chickens. We also studied the effect of leptin, cerulenin, and food deprivation, known effectors of energy balance and insulin action, on visfatin gene expression in chickens. Using reverse transcription polymerase chain reaction (RT-PCR) and Northern blot analysis, we detected chicken visfatin mRNA transcript in the kidney, hypothalamus, gizzard, liver, pancreas, proventriculus, breast and leg muscle, ovary, testis, lung, intestine, adipose tissue, and heart. Expression of the visfatin gene in various tissues of male and female chickens was determined by real-time quantitative PCR and found to be tissue and sex dependent. In both sexes, compared to other tissues, the visfatin gene is highly expressed in the muscle. Females exhibited greater (P<0.001) abundance of visfatin mRNA in adipose tissue compared to males, whereas compared to females, males showed greater (P<0.05) visfatin mRNA abundance in the kidney. Also, the regulation of visfatin gene expression by leptin, cerulenin, and food deprivation is tissue specific. Leptin decreased (P<0.05) visfatin mRNA abundance in the liver and hypothalamus, but not in muscle. In contrast, cerulenin increased (P<0.01) visfatin gene expression in the liver and in muscle, but not in the hypothalamus. Interestingly, visfatin mRNA levels increased (P<0.05) in the liver after 24-h food deprivation, but not in muscle or in the hypothalamus of genetically selected fat and lean line chickens. Our results showed that the visfatin gene is ubiquitously expressed in chickens with greater abundance in muscle, and that it is regulated in a tissue-specific manner by energy balance-related factors. PMID- 19786338 TI - [Postanesthesia cognitive dysfunction]. AB - The cognitive dysfunctions observed in patients after anesthesia are due not only to the effects of but also to the surgery, the disease requiring surgery, and post-operative treatment. Initial cognitive recovery from anesthetic agents is usually fast, from several hours to several days, but can be delayed by postoperative treatment (analgesia, for example) that have deleterious cognitive effects. During the initial period after surgery, acute impairment of cognitive functions is seen in some patients at risk (major surgery, aged patients, brain sensitivity, or sepsis), specifically transitory (1-3 days in most cases) postoperative delirium. This delirium or confusion requires follow-up at 3 months to check cognitive functions, especially in aged patients. Cohort studies show that cognitive impairment can be objectively identified at one week after surgery with general anesthesia in around 40% of patients, regardless of age. This risk is reduced slightly by the use of loco-regional anesthesia. Cognitive dysfunction is still observed at 3 months after surgery in about 10-15% of patients older than 60 years and in about 6% of younger patients. In patients with a pre existing cerebral disease with cognitive symptoms, the incidence of long-lasting additional cognitive impairment remains unknown. The mechanisms of this long-term cognitive dysfunction remain to be elucidated. PMID- 19786339 TI - Symptomatic and functional outcome in youth at ultra-high risk for psychosis: a longitudinal study. AB - The current report assesses the clinical, functioning and demographic data of a cohort enrolled in the P3 prevention program for psychosis; a Spanish National Health System and Ministry of Science funded program. Comparisons are made between those individuals who had converted to psychosis and those who had not at 3years after an average of 24 treatment sessions. Subjects included 61 participants meeting Structured Interview for Prodromal Syndromes criteria, with ages ranging from 17 to 31, and all meeting criteria for ultra-high risk of psychosis. Prospective follow-up data are reported for patients re-evaluated at 1 and 3years. At 1-year follow-up, the conversion rate to psychosis was 18%, but increased to 23% at 3-year follow-up. The converted sample was older than the non converted sample and more likely to have higher ratings on subsyndromal psychotic (positive and disorganized), negative and general symptoms, and lower levels of functioning at baseline assessment. Analyses of change over time indicated a clear clinical improvement in both clinically stable patients and in those who showed a transient psychotic state over time. No gender differences in symptom or functioning levels at the three follow-up time points were found; however, the interactions among conversionxgenderxSOPS total scorextime points significantly reflect that the growth profiles of the four groups (no conversion males, no conversion females, conversion males and conversion females) in the SOPS total score are not parallel and that, consequently, the four groups involved different patterns of change over time, males experiencing faster and longer deterioration when psychotic symptoms arise. PMID- 19786340 TI - Twin study of illness history variables in psychosis. AB - BACKGROUND: Genetic factors are important in the aetiology of psychotic disorders, but it is unclear how far they influence aspects of illness history within psychoses. AIMS: To investigate the extent, and type of familial aggregation for a range of illness history variables in psychosis. METHODS: Two hundred-and-twenty-four proband-wise twin pairs (106 monozygotic, 118 same-sex dizygotic), where probands had psychosis, were ascertained from the Maudsley Twin Register in London. We investigated the following illness history variables, rated using the OPCRIT checklist: age at onset; chronicity of course; mode of onset; psychotic/affective predominance; pre-morbid social adjustment; and the presence of a psychosocial precipitant. We used Mx statistical modelling software to analyse correlations of variables within pairs of monozygotic twins concordant for psychosis; and relationships between variables in probands and risk of psychosis in monozygotic and dizygotic co-twins. RESULTS: There was a high monozygotic within-pair correlation for age at onset (intra-class correlation=0.9); moderate correlations for chronicity of course (polychoric correlation=0.4) and psychotic/affective predominance (polychoric correlation=0.5); and lower non-significant correlations for other variables. No variables consistently predicted risk of psychosis in co-twins. CONCLUSIONS: Illness history variables in psychosis show a broad range of familial aggregation. It is likely that familial influences are predominantly modifying effects, independent of susceptibility factors for psychosis. PMID- 19786341 TI - Infections due to Candida haemulonii: species identification, antifungal susceptibility and outcomes. AB - Here we report the clinical features and treatment outcomes of three patients with Candida haemulonii infection. Candida haemulonii was confirmed by sequence analysis of the internal transcribed spacer (ITS) regions of the rRNA genes and the 18S rRNA genes. Two of the three isolates were associated with fungaemia and reduced susceptibility to fluconazole [minimum inhibitory concentrations (MICs) of 16 mg/L] and amphotericin B (MICs of 2 mg/L). However, one of these two patients responded to fluconazole therapy. Echinocandins, voriconazole and posaconazole demonstrated excellent in vitro potency against the isolates. PMID- 19786342 TI - Nanosized silver-anionic clay matrix as nanostructured ensembles with antimicrobial activity. AB - Nanostructured ensembles of silver nanoparticles/zinc-substituted anionic clay matrix (Ag/ZnLDH) were obtained by a simple synthetic route in which reconstruction of the layered clay, synthesis of the silver nanoparticles and their organisation on the clay surface took place in a single step at room temperature. The morphology, composition and phase structure of the prepared powders were characterised by X-ray diffraction, infrared spectroscopy, transmission electron microscopy, X-ray photoelectron spectroscopy and N(2) adsorption. Results showed that the silver-anionic clay nanoarchitecture consists of nanoparticles of silver (average size 7 nm) deposited on the larger nanoparticles of clay (average size 85 nm). The antimicrobial activity was examined by disk diffusion assay and minimal inhibitory concentration determination as a function of x, where x is a controlled variable parameter that represents the length of time since the sample was synthesised. Ag/ZnLDH showed more stable antimicrobial properties than the unsupported nanosized silver. PMID- 19786344 TI - Analysis of Ki-67 and Bcl-2 protein expression in normal colorectal mucosa of women with breast cancer. AB - The aim of this study was to evaluate Ki-67 and Bcl-2 protein expression in the normal colorectal mucosa adjacent to adenomatous polyps in women with breast cancer. A cross-sectional, controlled study was conducted in 35 women with and without breast cancer who had adenomatous colorectal polyps. The patients were divided into two groups: Group A (a control group of women without breast cancer, n=18) and Group B (a study group of women with breast cancer, n=17). A sample of normal colonic mucosa was collected at a distance of 5 cm from the polypoid lesion to evaluate immunohistochemical expression of the Ki-67 and Bcl-2 proteins. Student's t-test and the chi-square test were used to analyse Ki-67 and Bcl-2 expression, respectively. Statistical significance was established at p<0.05. The mean percentage of Ki-67-stained nuclei in Groups A and B was 25.12+/ 2.08 and 41.50+/-1.85, respectively (p<0.001), whereas the percentage of cases with cells expressing Bcl-2 in Groups A and B was 17.6% and 82.4%, respectively (p<0.003). In the present study, greater proliferative activity and greater expression of the antiapoptotic protein Bcl-2 was found in the normal colorectal mucosa of women with breast cancer. PMID- 19786343 TI - Strategies to avoid opiate withdrawal: implications for HCV and HIV risks. AB - BACKGROUND: Research on heroin withdrawal has primarily been done clinically, thus focussing on symptom severity, physiological manifestations, and how withdrawal impairs normal functioning. However, there is little scientific knowledge on how heroin withdrawal affects injection behaviour. This paper explores how withdrawal episodes heighten unsafe injection practices and how some long-term injectors manage such risks. METHODS: We interviewed 32 injection drug users in New York City who had been injecting drugs for 8-15 years (21 HIV and HCV uninfected; 3 HIV and HCV infected; and 8 singly infected with HCV). We used in-depth life history interviews to inquire about IDUs' life history, injection practices and drug use behaviour over time. Analysis used grounded theory techniques. RESULTS: Withdrawal can enhance risk by undermining IDUs' willingness to inject safely; increasing the likelihood of attending risky settings; raising the number of injection partners; and seeking ad hoc partners for drug or needle sharing. Some IDUs have developed practices to cope with withdrawal and avoid risky practices (examples include carrying clean needles to shooting galleries and sniffing rather than injecting). Strategies to avoid withdrawal include back up methods, resorting to credit, collaborating with others, regimenting drug intake, balancing drug intake with money available, and/or resorting to treatment. CONCLUSION: Withdrawal periods can heighten risky injection practices. Some IDUs have applied strategies to avoid withdrawal or used practices to cope without engaging in risky practices. These behaviours might in turn help IDUs prevent an infection with hepatitis C or HIV. PMID- 19786345 TI - The FAMCARE-Patient scale: measuring satisfaction with care of outpatients with advanced cancer. AB - OBJECTIVE: To provide confirmatory results concerning the psychometric properties of a measure of satisfaction with oncology care for use with advanced stage cancer patients, and test its sensitivity to change. METHODS: We analysed data from 315 outpatients with advanced cancer participating in a randomised controlled trial of early palliative care intervention versus routine oncology care, and their caregivers. Patients completed a 16-item measure of patient satisfaction (FAMCARE-P16), based on the FAMCARE measure of family satisfaction with cancer care, and measures assessing interactions with healthcare providers, performance status and symptom burden. Caregivers completed the original FAMCARE measure. We used confirmatory factor analysis to test the patient satisfaction measure for a single-factor structure. To determine construct validity, we assessed correlations between patient satisfaction and the other patient and caregiver measures. To assess responsiveness to change, we repeated paired t-test analyses on the 13-item and 16-item scales for 150 patients participating in a phase II trial of palliative care effectiveness, in which the FAMCARE-P was measured at baseline, 1-week and 1-month after an outpatient palliative care intervention. RESULTS: A reduced 13-item version of our measure (FAMCARE-P13) possessed a one-factor structure with high reliability. Patient satisfaction was correlated in predicted directions with physical distress, communication and relationship with healthcare providers, and caregiver satisfaction. There were statistically significant increases in patient satisfaction at 1 week (p<0.0001) and 1 month (p<0.001). CONCLUSIONS: We recommend the use of the FAMCARE-P13 to assess satisfaction with outpatient palliative care interventions of patients with advanced stage cancer. PMID- 19786346 TI - Evaluation of the odour reduction potential of alternative cover materials at a commercial landfill. AB - The availability of virgin soils and traditional landfill covers are not only costly and increasingly becoming scarce, but they also reduce the storage capacity of landfill. The problem can be overcome by the utilisation of certain suitable waste streams as alternative landfill covers. The objective of this study was to assess the suitability of Construction & Demolition fines (C&D), Commercial & Industrial fines (C&I) and woodchip (WC) as potential landfill cover materials in terms of odour control. Background odour analysis was conducted to determine if any residual odour was emitted from the cover types. It was deemed negligible for the three materials. The odour reduction performance of each of the materials was also examined on an area of an active landfill site. A range of intermediate cover compositions were also studied to assess their performance. Odour emissions were sampled using a Jiang hood and analysed. Results indicate that the 200 mm deep combination layer of C&D and wood chip used on-site is adequate for odour abatement. The application of daily cover was found to result in effective reduction allowing for the background odour of woodchip. PMID- 19786347 TI - The formation and characterisation of an asymmetric nanofiltration membrane for ammonia-nitrogen removal: effect of shear rate. AB - The focus of this research is to study the potential of nanofiltration membrane technology in removing ammonia-nitrogen from the aquaculture system. One of the major fabrication parameters that directly affect the separation performance is shear rate or casting rate during membrane fabrication. In this study, asymmetric polyethersulfone (PES) nanofiltration membranes were prepared at five different shear rates within the range of 67-400 s(-1). Membrane productivity and separation performance were assessed via pure water, salt and ammonia-nitrogen permeation experiments, and their structural properties were determined by employing the combination of the irreversible thermodynamic (IT) model, solution diffusion model, steric hindrance pore (SHP) model and Teorell-Meyers (TMS) model. The study reveals that the alteration of shear rate enormously affects the membrane morphology and structural parameters, hence subsequently significantly influencing the membrane performance. It was found that, membrane produced at the shear rate 200 s(-1) or equivalent to 10s of casting speed during membrane fabrications managed to remove about 68% of ammonia-nitrogen, in which its separation performance is the most favourable by means of highest flux and rejection ability towards unwanted solutes. Besides, from the research findings, nano-membrane technology is a potential candidate for the treatment of aquaculture wastewater. PMID- 19786348 TI - Benzoxazole piperidines as selective and potent somatostatin receptor subtype 5 antagonists. AB - SAR studies of a recently described SST5R selective benzoxazole piperidine lead series are described with particular focus on the substitution pattern on the benzyl and benzoxazole side-chains. Introduction of a second meta substituent at the benzyl unit significantly lowers residual hH1 activity and insertion of substituents onto the benzoxazole periphery entirely removes remaining h5-HT2B activity. Compounds with single digit nM activity, functional antagonism and favorable physicochemical properties endowed with a good pharmacokinetic profile in rats are described which should become valuable tools for exploring the pharmacological role of the SST5 receptor in vivo. PMID- 19786349 TI - Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives: their cytoprotection effect from rotenone toxicity and preliminary DMPK properties. AB - Pyrimido[5,4-e][1,2,4]triazine-5,7(1H,6H)-dione derivatives exhibited potent cytoprotective effect from rotenone toxicity. Lead optimization focused on the CC50/EC50 ratio and DMPK properties led to the overall improvement of the compound profile of this series with high CC50/EC50 ratio (92 for 1f), good metabolic stability in rat microsomes and medium to high aqueous solubility. PMID- 19786350 TI - Mammalian two-hybrids come of age. AB - A diverse series of mammalian two-hybrid technologies for the detection of protein-protein interactions have emerged in the past few years, complementing the established yeast two-hybrid approach. Given the mammalian background in which they operate, these assays open new avenues to study the dynamics of mammalian protein interaction networks, i.e. the temporal, spatial and functional modulation of protein-protein associations. In addition, novel assay formats are available that enable high-throughput mammalian two-hybrid applications, facilitating their use in large-scale interactome mapping projects. Finally, as they can be applied in drug discovery and development programs, these techniques also offer exciting new opportunities for biomedical research. PMID- 19786351 TI - Simultaneous bilateral versus unilateral computer-assisted total knee arthroplasty: a prospective comparison of early postoperative pain and functional recovery. AB - Whether simultaneous bilateral TKAs (SBTKAs) are more painful and the postoperative functional recovery slower compared to staged bilateral TKAs or unilateral TKAs are issues that frequently concerns patients. The purpose of the current study was to compare the early postoperative pain, function and recovery in simultaneous bilateral versus unilateral computer-assisted TKA. In this prospective study, 50 consecutive patients undergoing unilateral computer assisted total knee arthroplasties (TKAs) were compared with 50 consecutive patients undergoing SBTKAs in terms of pain, length of hospital stay and rehabilitative milestones during the immediate postoperative period. The mean visual analogue pain scores, mean knee range of motion, straight leg raising and extensor lag were equal in both the groups at the time of discharge. Patients in the SBTKA group lagged behind the unilateral group in stick walking by approximately 24 h. The results of this study demonstrate excellent pain relief and functional recovery with simultaneous bilateral computer-assisted TKAs comparable to unilateral TKAs. Patients eligible for bilateral TKAs can undergo them simultaneously without excessive pain or slower functional outcome. PMID- 19786352 TI - Synthesis and structural characterization of carboxyethylpyrrole-modified proteins: mediators of age-related macular degeneration. AB - Protein modifications in which the epsilon-amino group of lysyl residues is incorporated into a 2-(omega-carboxyethyl)pyrrole (CEP) are mediators of age related macular degeneration (AMD). They promote both angiogenesis into the retina ('wet AMD') and geographic retinal atrophy ('dry AMD'). Blood levels of CEPs are biomarkers for clinical prognosis of the disease. To enable mechanistic studies of their role in promoting AMD, for example, through the activation of B- and T-cells, interaction with receptors, or binding with complement proteins, we developed an efficient synthesis of CEP derivatives, that is especially effective for proteins. The structures of tryptic peptides derived from CEP-modified proteins were also determined. A key finding is that 4,7-dioxoheptanoic acid 9 fluorenylmethyl ester reacts with primary amines to provide 9-fluorenylmethyl esters of CEP-modified proteins that can be deprotected in situ with 1,8 diazabicyclo[5.4.0]undec-7-ene without causing protein denaturation. The introduction of multiple CEP-modifications with a wide variety of CEP:protein ratios is readily achieved using this strategy. PMID- 19786353 TI - Design, synthesis and nootropic activity of new analogues of sunifiram and sapunifiram, two potent cognition-enhancers. AB - A series of amides and sulfonamides, structurally related to DM235 (sunifiram) and MN19 (sapunifiram), derived by ring expansion or contraction, or by inversion of the exocyclic amide function, have been synthesized and tested for cognition enhancing activity in the mouse passive-avoidance test. Some of the compounds display good antiamnesic and procognitive activity, with higher potency than piracetam, and with a potency similar to the parent compounds. PMID- 19786354 TI - Retaining a most valuable resource in a healthcare crisis--critical care nurses. PMID- 19786355 TI - Characterization of polyphosphoesters by Fourier transform ion cyclotron resonance mass spectrometry. AB - FT-ICR mass spectrometry, together with collision-induced dissociation and electron capture dissociation, has been used to characterize the polyphosphoester poly[1,4-bis(hydroxyethyl)terephthalate-alt-ethyloxyphosphate] and its degradation products. Three degradation pathways were elucidated: hydrolysis of the phosphate-[1,4-bis(hydroxyethyl)terephthalate] bonds; hydrolysis of the phosphate-ethoxy bonds; and hydrolysis of the ethyl-terephthalate bonds. The dominant degradation reactions were those that involved the phosphate groups. This work constitutes the first application of mass spectrometry to the characterization of polyphosphoesters and demonstrates the suitability of high mass accuracy FT-ICR mass spectrometry, with CID and ECD, for the structural analysis of polyphosphoesters and their degradation products. PMID- 19786356 TI - Analysis of reduced monoclonal antibodies using size exclusion chromatography coupled with mass spectrometry. AB - Size-exclusion chromatography (SEC) has been widely used to detect antibody aggregates, monomer, and fragments. SEC coupled to mass spectrometry has been reported to measure the molecular weights of antibody; antibody conjugates, and antibody light chain and heavy chain. In this study, separation of antibody light chain and heavy chain by SEC and direct coupling to a mass spectrometer was further studied. It was determined that employing mobile phases containing acetonitrile, trifluoroacetic acid, and formic acid allowed the separation of antibody light chain and heavy chain after reduction by SEC. In addition, this mobile phase allowed the coupling of SEC to a mass spectrometer to obtain a direct molecular weight measurement. The application of the SEC-MS method was demonstrated by the separation of the light chain and the heavy chain of multiple recombinant monoclonal antibodies. In addition, separation of a thioether linked light chain and heavy chain from the free light chain and the free heavy chain of a recombinant monoclonal antibody after reduction was also achieved. This optimized method provided a separation of antibody light chain and heavy chain based on size and allowed a direct measurement of molecular weights by mass spectrometry. In addition, this method may help to identify peaks eluting from SEC column directly. PMID- 19786357 TI - Equine transcriptome quantification using human GeneChip arrays can be improved using genomic DNA hybridisation and probe selection. AB - Affymetrix GeneChip arrays are a powerful tool for transcriptome profiling and have been applied to a wide range of species. A genomic DNA (gDNA)-based probe selection method has been developed which broadens the range of species to which GeneChips may be successfully applied. This study demonstrated that gDNA-based probe selection on the Affymetrix U133+2 GeneChip array can be used to study the equine transcriptome which, to date, has received only limited attention. More than 29,000 transcripts can be detected in equine brain and liver and in primary cultures of equine articular chondrocytes. Gene ontology analysis of differentially expressed genes revealed the presence of expected categories within each tissue. The level of gene expression could also be correlated with the phenotypes and specialised functions of each tissue. The results demonstrated that probe selection on a human chip can be successfully used to study the equine transcriptome. PMID- 19786358 TI - Effects of intra-basolateral amygdala administration of rimonabant on nociceptive behaviour and neuronal activity in the presence or absence of contextual fear. AB - The basolateral amygdala (BLA) contains a high density of cannabinoid CB1 receptors and is critically involved in pain and fear-related behaviour. We investigated the effects of bilateral intra-BLA administration of the CB1 receptor antagonist/inverse agonist, rimonabant, on formalin-evoked nociceptive behaviour, fear-conditioned behaviour including analgesia, and associated brain regional alterations in Fos expression in rats. Intra-BLA administration of rimonabant significantly reduced formalin-evoked nociceptive behaviour in the absence, but not presence, of conditioned fear. Rimonabant attenuated a formalin evoked reduction in freezing while emitting 22 kHz ultrasonic vocalisation in the early part of the fear expression trial. Formalin-evoked nociceptive behaviour was associated with increased Fos immunoreactivity (FI) in the CA2/3 region of the hippocampus and rostral ventromedial medulla, effects attenuated by intra-BLA rimonabant. Formalin also decreased FI in the cingulate cortex, an effect which was not observed in fear-conditioned rats. Contextually-induced fear was associated with increased FI in the dorsal caudal periaqueductal grey in the absence, but not presence, of formalin-evoked nociceptive tone. In conclusion, bilateral intra-BLA administration of rimonabant reduces nociceptive behaviour in a model of tonic, persistent inflammatory pain, an effect associated with reduced activation of neurons in the CA2/3 hippocampus and rostral ventromedial medulla. The data also provide evidence for differential pain- and fear-related brain regional activity in the presence or absence of contextually-induced aversion and nociceptive tone. PMID- 19786359 TI - Optimization of stripline-based microfluidic chips for high-resolution NMR. AB - We here report on the optimization, fabrication and experimental characterization of a stripline-based microfluidic NMR probe, realized in a silicon substrate. The stripline geometry was modelled in respect of rf-homogeneity, sensitivity and spectral resolution. Using these models, optimal dimensional ratios were found, which hold for every sample size. Based on the optimized parameters, a simple integrated stripline-based microfluidic chip was realized. The fabrication of this chip is described in detail. We achieved a sensitivity of 0.47 nmol/square root(Hz) and a resolution of 0.7 Hz. The rf-homogeneity (A(810 degrees)/A(90 degrees)) was 76% and was proved to be suitable for 2D-NMR analysis of glucose. PMID- 19786360 TI - Optimal nephroprotection: use, misuse and misconceptions about blockade of the renin-angiotensin system. Lessons from the ONTARGET and other recent trials. AB - Results from the ONTARGET trial remind us that acute haemodynamically mediated renal dysfunction, triggered by low arterial pressure or volume depletion, can occur in high-risk cardiovascular patients (who usually have some degree of diseased intrarenal vessels) treated with renin-angiotensin system (RAS) blockers (especially in combination). However, nephroprotection could not be properly assessed in the trial, as the population was at low renal risk. Although albuminuria remains a useful marker in many patients, it can neither predict acute renal dysfunction nor replace end-stage renal disease (ESRD) as the endpoint in clinical trials. Recent trials using surrogate endpoints suggest that some RAS blockers (ACE inhibitors, angiotensin receptor blockers, the renin inhibitor aliskiren) may be more nephroprotective than others, but proving this requires comparing them (alone or in combination) in populations with identified renal disease (mainly diabetic nephropathy) and the use of hard endpoints. RAS blocker dosages are critical: as some patients need much larger doses to decrease proteinuria than do others, the efficacy of a high-dose RAS blocker needs to be assessed in patients with persistent proteinuria. In patients with massive proteinuria despite maximum RAS-blocker dosages, combination RAS blockade should be considered by nephrologists, but will require close monitoring of renal function; also, the treatment needs to be withdrawn (at least temporarily) as soon as volume depletion or excessively low arterial pressure arises. In recent trials, lowering blood pressure towards values recommended by the current guidelines (130/80mmHg) has reduced microvascular (lower levels of urinary albumin excretion) and macrovascular events in diabetic patients. PMID- 19786361 TI - Reducing non-collision injuries in special transportation services by enhanced safety culture. AB - Previous research has pointed out that non-collision injuries occur among wheelchair users in Special Transportation Services (STS - a demand-responsive transport mode). The organization of such modes is also quite complex, involving both stakeholders and key personnel at different levels. Our objective was therefore to qualitatively explore the state of safety, as perceived and discussed within a workplace context. Focus groups were held with drivers of both taxi companies and bus companies. The results indicated that passengers run the risk of being injured without being involved in a vehicle collision. The pertinent organizational and corporate culture did not prioritize safety. The drivers identified some relatively clear-cut safety threats, primarily before and after a ride, at vehicle standstill. The driver's work place seemed to be surrounded with a reactive instead of proactive structure. We conclude that not only vehicle and wheelchair technical safety must be considered in STS, but also system safety. Instead of viewing drivers' error as a cause, it should be seen as a symptom of systems failure. Human error is connected to aspects of tools, tasks, and operating environment. Enhanced understanding and influence of these connections within STS and accessible public transport systems will promote safety for wheelchair users. PMID- 19786362 TI - Keratoconus associated with the Pierre Robin sequence. AB - A 30-year-old female with known Pierre Robin sequence presented to the emergency department of the Royal Victorian Eye and Ear Hospital, Melbourne, with acute unilateral hydrops as her first presentation of bilateral keratoconus. Initial management consisted of eye patching, hypertonic saline and cycloplegia. However, the long-term prognosis for visual rehabilitation remained poor in this patient because of the presence of a central corneal opacity and inability to comply with contact lenses. She was not an appropriate candidate for keratoplasty due to severe mental retardation. This report highlights an association of keratoconus in patients with the Pierre Robin sequence. PMID- 19786363 TI - An unusual hypertrophic genital mass lesion--a diagnostic and treatment dilemma. PMID- 19786364 TI - Investigation of cue-based vertical and horizontal eye movements with electroencephalographic and eye-tracking data. AB - OBJECTIVE: This study investigates the influence of eye movement direction on patterns of brain activation. METHODS: The processing of visual input was investigated by quantifying event-related desynchronization (ERD) in the electroencephalogram (EEG). Cue-based vertical and horizontal eye movements were measured with an eye tracker. Differences between vertical and horizontal eye movements in EEG and eye-tracking data were analyzed. RESULTS: The results of this study indicate that vertical and horizontal eye movements result in different ERD and ERS patterns. During the execution of a saccade vertical eye movements are accompanied by a stronger ERS whereas the fixation of the cue is related to stronger ERD after horizontal eye movements. CONCLUSION: The fact that eye movements are correlated with a desynchronization of activity in parietal and occipital areas is reasonable, since visual information processing and visual control of movements take place there. Stronger ERD in the alpha band could be related to the fact that information processing tasks like e.g. reading require mostly horizontal and not vertical eye movements. SIGNIFICANCE: The differences in the ERD/ERS patterns in relation to the direction of the eye movement should be considered in future investigations and taken into account in the construction of paradigms. PMID- 19786365 TI - The relationship between preattentive sensory processing deficits and age in schizophrenia patients. AB - OBJECTIVE: Auditory mismatch negativity (MMN) and P3a index preattentive detection of rare stimuli. Their amplitudes normally decrease with age. Previous studies have reported generally smaller than normal MMN and P3a in schizophrenia patients. We aimed to further characterize the course of these deficits over schizophrenia patients' lifespan. METHODS: In 253 schizophrenia patients and 147 normal comparison participants (NCPs) encompassing a wide age range (18-65), event-related potentials were recorded while participants watched a silent video and were presented binaurally with 1-kHz tones 500ms apart, including standards (P=.90, 50-ms duration) and deviants (P=0.10, 100-ms). RESULTS: Over the entire age range, MMN and P3a were smaller in schizophrenia patients than NCPs. MMN amplitude declined with age in both groups, though slightly less steeply in schizophrenia patients than NCPs. P3a amplitude declined with age in NCPs but not in schizophrenia patients. CONCLUSIONS: In our cohort of schizophrenia patients, MMN and P3a deficits were already present at the youngest ages. MMN declined further with age, whereas P3a amplitude remained stable. SIGNIFICANCE: This knowledge about how MMN and P3a amplitudes vary with age in schizophrenia patients compared to NCPs can help improve the utility of these indices as clinical endophenotypes or biomarkers. PMID- 19786367 TI - Autoimmune T cell responses to antigenic peptides presented by bronchoalveolar lavage cell HLA-DR molecules in sarcoidosis. AB - The etiology of sarcoidosis remains unknown. Recently, by mass spectrometric sequencing of peptides eluted from HLA-DR molecules of bronchoalveolar lavage (BAL) cells from DRB10301(pos) patients, we identified potential self-antigens in sarcoidosis. The aim of the present study was to investigate the capacity of selected peptides to stimulate lung and blood T cells of sarcoidosis patients using an interferon-gamma ELISPOT assay. In peripheral blood, there were strong T cell responses to a peptide derived from the cytoskeletal protein vimentin in 6 out of 11 DRB10301(pos) patients with active disease but not in patients with other HLA types. BAL T cell responses against peptides derived from ATP synthase or from lysyl-tRNA synthetase were detected in DRB10301(pos) as well as DRB10301(neg) patients. By using antigenic peptides presented in vivo in the lungs of sarcoidosis patients, we have identified blood and lung T cell autoimmune responses that may help sustain the inflammation in this disease. PMID- 19786366 TI - CD24-Siglec G/10 discriminates danger- from pathogen-associated molecular patterns. AB - It is now well accepted that the innate immune system recognizes both damage (or danger)- and pathogen-associated molecular patterns (DAMP and PAMP, respectively) through pattern recognition receptors, such as Toll-like receptors (TLR) and/or Nod-like receptors (NLR). Less clear are whether and how the response to PAMP and DAMP are regulated differentially. The answers may reveal whether the primary goal of the immune system is to defend against infections or to alert the host of tissue injuries. We demonstrated recently that the host response to DAMP is controlled by a DAMP-CD24-Siglec axis. Here we propose a key role for the CD24 Siglec pathway in discriminating between DAMPs and PAMPs. PMID- 19786368 TI - Evaluation of dissociative experiences and the clinical utility of the Dissociative Experience Scale in patients with coexisting epilepsy and psychogenic nonepileptic seizures. AB - We investigated the relationship between dissociation and psychogenic nonepileptic seizures (PNES) and evaluated the clinical utility of the Dissociative Experience Scale (DES) in patients with epilepsy. The DES was administered to 30 patients with epilepsy and PNES, 50 patients with epilepsy and no PNES, and 85 nonclinical individuals. Patients with epilepsy and PNES scored significantly higher on the DES (29.3) than patients with epilepsy without PNES (13.5) and nonclinical individuals (11.1). High DES scores (>30) were more frequently observed in patients with epilepsy and PNES (53%) than in patients with epilepsy without PNES (12%) and nonclinical individuals (6%). DES score did not differ significantly with respect to epilepsy-related variables. Neither the frequency nor severity of PNES was significantly associated with the DES score. Our findings confirm some associations between PNES and dissociation in patients with coexisting epilepsy and PNES. The DES could be helpful in determining the tendency to have PNES in patients with epilepsy. PMID- 19786369 TI - Is there a circadian variation of epileptiform abnormalities in idiopathic generalized epilepsy? AB - Epileptiform abnormalities often occur at specific times of day or night, possibly attributable to state of consciousness (sleep vs. wake) and/or influences from the endogenous circadian pacemaker. In this pilot study we tested for the existence of circadian variation of interictal epileptiform discharges (IEDs), independent of changes in state, environment, or behavior. Five patients with generalized epilepsy underwent a protocol whereby their sleep/wake schedule was evenly distributed across the circadian cycle while undergoing full-montage electroencephalography and hourly plasma melatonin measurements. Light was <8 lux to prevent circadian entrainment. All patients completed the protocol, testifying to its feasibility. All patients had normal circadian rhythmicity of plasma melatonin relative to their habitual sleep times. In the three patients with sufficient IEDs to assess variability, most IEDs occurred during non-rapid eye movement (NREM) sleep (ratio NREM:wake=14:1, P<0.001). In both patients who had NREM at all circadian phases, there was apparent circadian variation in IEDs but with different phases relative to peak melatonin. PMID- 19786370 TI - Ethanol infusion in the vein of Marshall: Adjunctive effects during ablation of atrial fibrillation. AB - BACKGROUND: The vein of Marshall (VOM) is a left atrial (LA) vein that contains autonomic innervation and triggers of AF. Its location coincides with areas usually ablated during pulmonary vein (PV) antral isolation (PVAI). OBJECTIVE: This study sought to delineate the safety and ablative effects of ethanol infusion in the VOM during catheter ablation of atrial fibrillation (AF). METHODS: Patients undergoing PVAI (n = 14) gave consent for adjunctive VOM ethanol infusion. In 10 of 14 patients, the VOM was cannulated with an angioplasty wire and balloon. Echocardiographic contrast was injected in the VOM under echocardiographic monitoring. Two infusions of 100% ethanol (1 ml each) were delivered via the angioplasty balloon in the VOM. LA bipolar voltage maps were created before and after ethanol infusion. Radiofrequency ablation times required to isolate each PV and other procedural data were compared with those of 10 age-, sex-, AF type- and LA size-matched control subjects undergoing conventional PVAI. RESULTS: The VOM communicated with underlying myocardium, as shown by echocardiographic contrast passage into the LA. There were no acute complications related to VOM ethanol infusion, which led to the creation of a low voltage area in the LA measuring 10.6 +/- 7.6 cm(2) and isolation of the left inferior PV in 4 of 10 patients. Radiofrequency ablation time required to achieve isolation of the left inferior PV was reduced (2.2 +/- 4 min vs. 11.4 +/- 10.3 min in control subjects, P <.05). CONCLUSION: VOM ethanol infusion is safe in humans, decreases radiofrequency ablation time in the left inferior PV, and may have a role as an adjunct to PVAI. PMID- 19786371 TI - Right ventricular substrate mapping using the Ensite Navx system: Accuracy of high-density voltage map obtained by automatic point acquisition during geometry reconstruction. AB - BACKGROUND: Contact point-to-point electroanatomic mapping (Pt-Map) is a validated tool to evaluate right ventricular (RV) substrate. When using the EnSite NavX system (St. Jude Medical, St Paul, Minnesota), geometry reconstruction by dragging the mapping catheter (Geo-Map) allows for quicker acquisition of a large number of points and better definition of anatomy, but it is not validated for substrate mapping. OBJECTIVE: This study evaluates the feasibility and accuracy of Geo-Map. METHODS: Thirteen patients (mean age 38 +/- 12 years) with RV arrhythmias and an apparently normal heart underwent cardiac magnetic resonance imaging (MRI), Pt-Map, and Geo-Map. The 2 maps were compared in terms of mapping procedural time, radiation time, and total number of points acquired. We finally compared the number and characteristics of low-potential areas on each patient's Pt-Map, Geo-Map, and cardiac MRI. RESULTS: Geo-Map required significantly shorter mapping and radiation times in comparison to Pt Map (12.4 +/- 4.6 vs. 31.9 +/- 10.1 and 5.8 +/- 2.1 vs. 12.1 +/- 3.9, P <.001). Furthermore, Geo-Map was based on a significantly higher density of points in comparison to Pt-Map (802 +/- 205 vs. 194 +/- 38, P <.001). Taking into consideration the total number of RV regions analyzed, the Pt-Map and Geo-Map disagreed in 2 of 65 (3%) regions (P = NS), which only Geo-Map identified as low potential areas and indeed corresponded to wall motion abnormalities on MRI. CONCLUSION: Voltage maps obtained through RV geometry acquisition have accuracy comparable to that of conventional point-by-point mapping in detecting low voltage areas, have a good correlation with MRI wall motion abnormalities, and allow a significant reduction in procedural time and x-ray exposure. PMID- 19786372 TI - Phenotypic diversity arising from a single mutation. PMID- 19786373 TI - Sudden cardiac death in children: Do we really know? PMID- 19786374 TI - The height and BMI values of West Point cadets after the Civil War. AB - West Point cadets born in the 1880s were taller (+1.46cm) than those born in the 1860s and had significantly higher BMI values (+0.85). However, the cadets were on average undernourished by modern standards, with today's average reference values being about 5 BMI units higher than those of the cadets. Substantial regional differences existed for both height and weight. While West Point cadets born in the 1880s in the Upper South achieved on average a height of 173.2cm and a BMI of 21.0, their peers from New England were 171.5cm tall with a BMI of 21.6. PMID- 19786375 TI - Prevalence of celiac disease in inflammatory bowel diseases: An IG-IBD multicentre study. AB - BACKGROUND: An association has been described in case reports between celiac disease and inflammatory bowel diseases. The aim of the present study is to assess the prevalence of celiac disease in a large series of Italian patients with inflammatory bowel disease. METHODS: The Italian Group for Inflammatory Bowel Disease conducted a multicentre study between January 2002 and December 2004, in which 22 gastroenterology centres in Italy enrolled 1711 consecutive outpatients with inflammatory bowel disease. 860 (50.2%) had Crohn's disease (415 females, mean age 40, range 18-75), 791 (46.2%) had ulcerative colitis (371 females, mean age 40, range 18-80), and 60 (3.5%) had indeterminate colitis (27 females, mean age 40, range 18-78). All patients underwent serological testing for anti-endomysial antibodies and anti-tissue transglutaminase antibodies; if positive upper GI endoscopy with duodenal biopsy was performed. RESULTS: Nine of the 1711 patients (0.5%) had serological and histological findings compatible with the diagnosis of celiac disease; six of them had ulcerative colitis and three had Crohn's disease. CONCLUSIONS: Overall we found a lower risk of celiac disease in our cohort of inflammatory bowel disease patients than in the general population; prevalence of celiac disease was higher in patients with ulcerative colitis than in those with Crohn's disease. PMID- 19786376 TI - [Impact of radiotherapy on fertility in female patients]. AB - Although insufficiently documented, the impact of radiation therapy on fertility should not be neglected in female patients. Toxicity on reproductive function is dual and is characterized by both mechanistic deleterious effects on the genital tract and partial or complete loss of ovarian function. Moreover, gonadic toxicity may be increased by the concurrent use of chemotherapy or surgical procedure. In some circumstances, ovarian transposition may be justified for young patients. But no compromise may be accepted in terms of carcinologic results. At least, the effect of low-doses of irradiation has not been demonstrated for extra-pelvic radiotherapy. PMID- 19786377 TI - The development of a national salt reduction strategy for Australia. AB - Excess dietary salt is a well established cause of high blood pressure and vascular disease. National and international bodies recommend a significant reduction in population salt intakes on the basis of strong evidence for health gains that population salt reduction strategies could achieve. The Australian Division of World Action on Salt and Health (AWASH) coordinates the Drop the Salt! campaign in Australia. This aims to reduce the average amount of salt consumed by Australians to six grams per day over five years through three main implementation strategies targeting the food industry, the media and government. This strategy has the potential to achieve a rapid and significant reduction in dietary salt consumption in Australia. With industry and government engagement, this promises to be a highly effective, low cost option for preventing chronic disease. PMID- 19786378 TI - Combined nattokinase with red yeast rice but not nattokinase alone has potent effects on blood lipids in human subjects with hyperlipidemia. AB - The purpose of this randomized, double-blind, placebo-controlled, parallel comparison study was to evaluate the lipid-lowering effect of orally administrated nattokinase and nattokinase combined with red yeast rice (RYR) extract on blood lipids in patients with hyperlipidemia. A total of 47 patients with hyperlipidemia were assigned to one of three groups: 1. nattokinase-mono formula (50 mg/capsule), 2. combined formula of nattokinase with RYR (300 mg of extract/capsule) and 3. placebo. Subjects received a twice daily dose of two capsules for six months. The mono formula showed no effects on blood lipids until month six, while the combined formula ameliorated all of measured lipids starting from month one. In the combined group significant decreases were found with regard to: triglycerides (TG) by 15%, total cholesterol (TC) by 25%, low-density lipoprotein cholesterol (LDL-C) by 41%, TC/high-density lipoprotein cholesterol (HDL-C) ratio by 29.5%, and increases in HDL-C by 7.5%. These changes were sustained until the end of study. After controlling for baseline levels, only the combined group, but not mono group, showed a significant difference (p<0.0001) in TC, LDL-C and TC/HDL-C ratio when compared with the placebo group. In summary, this study provides long-term efficacy of nattokinase supplementation and shows that the combined formula has relatively more potent effects than the mono formula on lowering of blood lipids, suggesting that combined nattokinase with RYR will be a better neutraceutical for patients with hyperlipidemia than nattokinase alone. PMID- 19786379 TI - Serum lutein and its dynamic changes during supplementation with lutein in Chinese subjects. AB - Observational epidemiological studies have shown that a high consumption of lutein-containing foods is associated with decreased risk of chronic diseases. However, results are inconsistent, suggesting the possibility that confounders may impact serum lutein concentration after consumption. The present study aimed to determine the factors affecting serum lutein status and to characterize dynamic changes of lutein concentration in serum during lutein supplementation in healthy Chinese subjects. After baseline characteristics were determined, thirty seven healthy participants were randomized to receive 6 mg lutein/d, 12 mg lutein/d, or placebo for 12 weeks, as well as to be observed for 6 additional weeks after the cessation of supplementation. Serum levels of lutein and beta carotene were measured by HPLC at weeks 0, 1, 3, 6, 9, 12 and 18. Dietary intake was estimated by food-frequency questionnaires. No significant sex differences were found in serum concentration of lutein. Serum lutein level positively correlated with dietary lutein, retinol equivalents, vitamin C, vitamin E, beta carotene and fat intake after adjustment for caloric intake, but not with BMI. After 12-weeks of supplementation, lutein levels increased approximately 1.8-fold and 2.3-fold for the 6-, and 12-mg dose groups respectively, approaching a plateau at week 9, and then decreased to baseline values at week 18. No adverse events or reductions in serum beta-carotene were observed throughout the study. Our findings indicate that increasing the consumption of lutein-rich fruit and vegetables can be considered as a long-term, sustainable and safe approach to reach and maintain high serum levels of lutein. PMID- 19786380 TI - Impact of milk consumption on performance and health of primary school children in rural Vietnam. AB - This is a follow-up study to an investigation on the prevalence of malnutrition and micronutrient deficiencies among Vietnamese primary schoolchildren. A total of 454 children aged 7 to 8 years attending three primary schools in the Northern delta province of Vietnam were either provided with regular milk, milk fortified with vitamins, minerals and inulin or served as a reference control group. Children were monitored for anthropometrics, (micro)-nutritional status, faecal microbiota composition, school performance, and health indices. Both weight-for age (WAZ) and height-for-age (HAZ) significantly improved during 6 months of milk intervention; and underweight and stunting dropped by 10% in these groups. During intervention the incidence of anemia decreased and serum ferritin levels increased significantly in all groups. Serum zinc levels increased and consequently the incidence of zinc deficiency improved significantly in all three groups. Serum retinol levels and urine iodine levels remained stable upon intervention with fortified milk whereas in the control group the incidence of iodine deficiency increased. Bifidobacteria composed less than 1% of the total faecal bacteria. After three months of milk intervention total bacteria, bifidobacteria and Bacteroides sp. increased significantly in both milk and inulin fortified milk groups. Children in the milk consuming groups had significantly better short-term memory scores. Parent reported that health related quality of life status significantly improved upon milk intervention. In conclusion, (fortified) milk consumption benefited the children in rural Vietnam including lowering the occurrence of underweight and stunting, improving micronutrients status and better learning indicators as well as improving the quality of life. PMID- 19786381 TI - Average daily intake of phosphorus in 3- to 5-year-old Japanese children as assessed by the duplicate-diet technique. AB - The present study aimed to determine whether there is excessive mean daily intake of phosphorus in 3- to 5-year-old Japanese children and to ascertain relationships between phosphorus intake and various food and beverage groups. Subjects comprised of 90 children, with 15 boys and 15 girls in each age group from 3 to 5 years. The duplicate-diet technique was used to ascertain total dietary intake, including snacks and beverages over a 24-h period on 3 separate days from summer 1999 to winter 2000. After wet ashing food samples, phosphorus was quantified by colourimetry using a spectrophotometer. Median and 25th-75th percentile daily phosphorus intake for 3- to 5-year-old Japanese children was 674 mg (534-890 mg), and phosphorus intake correlated with the intake of many food groups and was closely correlated with total daily intake of food and beverage (rs=0.64). In addition, phosphorus intake correlated with the intake of magnesium and calcium (rs>=0.6, p<0.001). When assessed based on dietary reference intakes for the US, maximum intake did not exceed the tolerable upper intake level in any of the young children, but phosphorus intake was not more than the estimated average requirement (EAR) in 4.4% of subjects, which exceeded the target of 2.5% for the US EAR. We concluded that there is a risk of insufficient phosphorous intake, rather than excessive intake, for 4.4% of 3- to 5-year-old Japanese children. PMID- 19786382 TI - Nutrient intake and blood iron status of male collegiate soccer players. AB - The purpose of this study was: 1) to collect baseline data on nutrient intake in order to advise athletes about nutrition practices that might enhance performance, and 2) to evaluate the dietary iron intake and blood iron status of Japanese collegiate soccer players. The subjects were 31 soccer players and 15 controls. Dietary information was obtained with a food frequency questionnaire. The mean carbohydrate (6.9 g.kg-1 BW) and protein (1.3 g/kg) intakes of the soccer players were marginal in comparisons with recommended targets. The mean intakes of calcium, magnesium, vitamin A, B1, B2, and C were lower than the respective Japanese recommended dietary allowances (RDAs) or adequate dietary intakes in the soccer players. The mean intakes of green and other vegetables, milk and dairy products, fruits, and eggs were lower than the recommended targets. Thus, we recommended athletes to increase the intake of these foodstuffs along with slight increase in carbohydrate and lean meat. The mean intake of iron was higher than the respective RDA in the soccer players. A high prevalence of hemolysis (71%) in the soccer players was found. None of the soccer players and controls had anemia. Two soccer players had iron depletion, while none was found in the controls. In those players who had iron deficiency, the training load need to be lowered and/or iron intake may be increased. PMID- 19786383 TI - A good response to oil with medium- and long-chain fatty acids in body fat and blood lipid profiles of male hypertriglyceridemic subjects. AB - A double blind clinical trial was carried out to clarify the effects of oil with medium- and long-chain triglyceride (MLCT) on body fat and blood lipid profiles in hypertriglyceridemic subjects. One-hundred-and-twelve subjects were enrolled and divided into two groups; those that consumed MLCT oil and those that consumed long-chain triglyceride (LCT) oil for 8 weeks. All subjects were requested to consume 25-30 g of the oils daily and maintain a fixed level of energy intake and exercise. Anthropometric and blood biochemical parameters were measured when the study was initiated and completed. The LCT group consisted of 50 subjects (34 men and 16 women), while the MLCT group consisted of 51 subjects (33 men and 18 women) who completed the study. Larger decreases in body weight, body mass index, waist circumference, body fat, total fat area and subcutaneous fat area in the abdomen and serum triglycerides, low-density lipoprotein cholesterol, apolipoprotein B, C2, C3 and E were observed in male subjects in the MLCT group than those in the LCT group. However, no significant differences in these parameters between the female subjects in the two groups were observed. Data from this study indicate that consumption of medium-and long-chain triglycerides can reduce body weight and body fat and improve blood lipid profiles in male hypertriglyceridemic subjects. PMID- 19786385 TI - Serum 25-hydroxyvitamin D3 is related to fish intake and exercise in Korean adult men. AB - Vitamin D is an important factor for bone health. It is uncertain which lifestyle is associated with vitamin D status, especially in healthy middle aged Asian men. A cross-sectional analysis was performed in 149 men aged 40-69 years who visited a health check-up center in Korea. Serum vitamin D (25-OHD3) was measured and smoking, alcohol, exercise, occupation, frequency of fish and dairy intake were estimated by self-administered questionnaire. The mean (+/-SD) 25-OHD3 concentration was 96.5+/-30.7 nmol/L. Higher and lower 25-OHD3 groups were generated with the median concentration as the cut-off point. By univariate analysis, exercise status and fish intake frequency were significantly different between two 25-OHD3 groups (p=0.012, 0.019 respectively). After multivariable logistic regression, higher fish intake frequency and regular exercise were associated with higher levels of 25-OHD3 (p for trend=0.017 and 0.02 respectively). In conclusion, frequent fish intake and regular exercise are positively associated with serum 25-OHD3 concentrations in healthy Korean men. PMID- 19786384 TI - Association of trans fatty acid intake with metabolic risk factors among free living young Japanese women. AB - OBJECTIVE: We examined cross-sectional associations of total, hydrogenated, and natural trans fatty acid intake with selected metabolic risk factors in young Japanese women. METHODS: Subjects were 1136 Japanese female dietetic students aged 18-22 years. Dietary intake was estimated using a validated, self administered diet history questionnaire. Associations between trans fatty acid intake and metabolic risk factors were examined with multivariate linear regression analysis, with control for potential covariates. Dietary covariates included intake of energy, total fat, and saturated fatty acids (model 1); monounsaturated fatty acids instead of saturated fatty acids (model 2); and polyunsaturated fatty acids instead of saturated fatty acids (model 3). RESULTS: Mean (standard deviation) total trans fatty acid intake was 0.90% (0.30%) of total energy. Hydrogenated trans fatty acids contributed 77% of total trans fatty acid intake. Total trans fatty acid intake was significantly and positively associated with waist circumference, triacylglycerol, and glycated hemoglobin, except in the analysis of triacylglycerol with adjustment for monounsaturated fatty acids. No associations were found between total trans fatty acid intake and body mass index, cholesterol, or glucose. Hydrogenated trans fatty acid intake was significantly and positively associated only with waist circumference and glycated hemoglobin. No association was observed for natural trans fatty acid intake. CONCLUSION: hydrogenated trans fatty acid intake was positively associated with several metabolic risk factors among free-living young Japanese women with relatively low intake. PMID- 19786386 TI - Maternal and neonatal plasma n-3 and n-6 fatty acids of pregnant women and neonates in three regions in China with contrasting dietary patterns. AB - The aim of this study was to investigate concentrations of n-3 and n-6 fatty acids in pregnant women and neonates from River/Lake, Coastal and Inland regions of China. Demographic, nutritional and anthropometric data, as well as blood samples (maternal and cord) were obtained. Plasma choline phosphglyceride (CPG) fatty acids were analysed. Median daily fatty acid intakes of the women from River/Lake, Coastal and Inland women were linoleic acid (LA), 20.2, 22.1, 31.7 g; arachidonic acid (AA), 157.2, 95.6, 141.3 mg; alpha-linolenic acid (ALA), 4.2, 1.0, 1.8 g; eicosapentenoic acid (EPA), 22.4, 28.6, 3.1 mg; docosahexaenoic acid (DHA), 51.7, 54.7, 33.3 mg and the n-3 to n-6 fatty acid ratio, 4.7, 20.9,17.2. The median maternal and cord plasma CPG AA levels of River/Lake, Coastal and Inland groups were 7.3 and 15.7, 6.7 and 16.1%, and 7.2 and 16.9%. The median maternal and neonatal DHA levels in the three regions were 3.2 and 4.7%, 3.0 and 4.3%, and 2.0 and 3.6%. There appears to be a close association between dietary intake of AA, EPA, DHA and the corresponding level in maternal plasma CPG (p<0.05). Based on these results, it can be concluded that the low intake of n-3 long chain polyunsaturated fatty acids such as EPA and DHA and the unbalanced n-6 to n-3 fatty acids ratio are the main problems in terms of dietary fat intake among Chinese pregnant women. Measures could be taken such as increasing the supply of oily fish or ALA rich edible oils to increase n-3 fatty acids intake for pregnant Chinese women. PMID- 19786387 TI - Polyunsaturated fatty acid consumption and concentration among South Indian women during pregnancy. AB - In recent years there is growing interest on the role of long chain omega-3 polyunsaturated fatty acids (omega-3 LC-PUFA) in pregnancy and the growth and development of the offspring. We aim to characterize and provide baseline data on the intake of LCPUFA (omega-3 and omega-6) in a prospective cohort of 829 pregnant Indian women and report associations between LCPUFA intake and erythrocyte membrane phospholipid fatty acid concentration in a sub-group at baseline (1st trimester), the 2nd and 3rd trimesters of pregnancy. The dietary intake of all the macronutrients and of alpha-linolenic acid(ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) significantly increased over the 3 trimesters of pregnancy while that of omega-6 fatty acids (FA) remained unchanged. Median omega-3 FA intakes of ALA, EPA and DHA, however, were on average low at 0.56, 0.003 and 0.011 g/d, respectively while LA was 14.6 g/d during pregnancy. Consequently, the intake ratio of ALA to LA in the women in the present study was very low at 1:26. A significant decline in erythrocyte membrane arachidonic acid (AA) concentration but not of DHA was observed throughout pregnancy. This might be due to increased efficiency in terms of elongation of parent omega-3 FA. Dietary methods for improving the consumption of omega-3 FA need to be considered in the diets of young women as well as during pregnancy. As newborns primarily depend on placental transfer of omega-3 FA there is need to examine the omega-3 LC-PUFA concentration in infants of mother's with low intakes of omega-3 FA. PMID- 19786388 TI - Development and validation of 3-Minute Nutrition Screening (3-MinNS) tool for acute hospital patients in Singapore. AB - It is important to detect and treat malnutrition in hospital patients so as to improve clinical outcome and reduce hospital stay. The aim of this study was to develop and validate a nutrition screening tool with a simple and quick scoring system for acute hospital patients in Singapore. In this study, 818 newly admitted patients aged above 18 years old were screened using five parameters that contribute to the risk of malnutrition. A dietitian blinded to the nutrition screening score assessed the same patients using the reference standard, Subjective Global Assessment (SGA) within 48 hours. Sensitivity and specificity were established using the receiver operator characteristics (ROC) curve and the best cut-off scores determined. The nutrition parameter with the largest area under the ROC curve (AUC) was chosen as the final screening tool, which was named the 3-Minute Nutrition Screening (3-MinNS). The combination of the parameters weight loss, intake and muscle wastage (3-MinNS), gave the largest AUC when compared with SGA. Using 3-MinNS, the best cut-off point to identify malnourished patients is three (sensitivity 86%, specificity 83%). The cut-off score to identify subjects at risk of severe malnutrition is five (sensitivity 93%, specificity 86%). The 3-Minute Nutrition Screening is a valid, simple and rapid tool that identifies acute hospital patients at risk of malnutrition in Singapore. It is able to differentiate patients at risk of moderate malnutrition and severe malnutrition for prioritization and management purposes. PMID- 19786389 TI - Accuracy of body mass index (BMI) thresholds for predicting excess body fat in girls from five ethnicities. AB - The association between body mass index (BMI) and body fat in young people differs among ethnic groups. Consequently, BMI thresholds for defining childhood overweight may not represent an equivalent level of adiposity in multiethnic populations. The objectives of this study were to characterise the relationships between BMI and percentage body fat (%BF) and to determine the appropriateness of universal BMI standards for predicting excess fatness in girls from five ethnic groups. The BMI and %BF of 1,676 European, Maori, Pacific Island, East Asian, and South Asian girls aged 5-16 years were determined using anthropometric and bioimpedance measurements. Receiver operating characteristic (ROC) curves were prepared to assess the sensitivity and specificity of the International Obesity Taskforce (IOTF) and Centers for Disease Control and Prevention (CDC) BMI thresholds for detecting %BF >85th percentile. Compared with European girls, South and East Asians averaged 4.2% and 1.3% more %BF at a fixed BMI and age, whereas Pacific Islanders averaged 1.8% less %BF. Areas under the ROC curves ranged from 89.9% to 92.4%, suggesting that BMI is an acceptable screening tool for identifying excess adiposity. However, the IOTF and CDC thresholds showed low sensitivity for predicting excess %BF in South and East Asian girls, with low specificity in Pacific Island and Maori girls. The development of an ethnic specific definition of overweight improved diagnostic performance. We conclude that BMI can be an acceptable proxy measure of excess fatness in girls from diverse ethnicities, especially when ethnic-specific BMI reference points are implemented. PMID- 19786390 TI - Food variety score is associated with dual burden of malnutrition in Orang Asli (Malaysian indigenous peoples) households: implications for health promotion. AB - This paper reports on the presence of dual burden households in Orang Asli (OA, indigenous people) communities and its associated factors. A total of 182 OA households in two districts in Selangor with the required criteria (182 non pregnant women of child bearing age and 284 children aged 2-9 years old) participated in the study. Height and weight of both women and children were measured. Energy intake and food variety score (FVS) were determined using three 24-hour diet recalls. While 58% were underweight and 64% of the children were stunted, the prevalence of overweight and obesity in women were 31% and 20% respectively. The percentage of dual burden households (overweight mother/underweight child) was 25.8% while 14.8% households had normal weight mother/normal weight child. The mean food variety score (FVS) was similar for women (7.0+/-2.1) and children (6.9+/-1.9). Dual burden households were associated with women's employment status (OR: 3.18, 95% CI: 2.65-5.66), FVS of children (OR: 0.71, 95% CI: 0.51-0.95) and FVS of women (OR: 1.39, 95% CI: 1.02- 1.89). The FVS of children (OR: 0.49, 95% CI: 0.25-0.89) and women (OR: 1.92, 95% CI: 1.64-2.77) remained significant even when dual burden households were compared to only households with normal weight mother/normal weight child. In these OA communities, food variety may predict a healthier diet in children, but may increase the risk of overweight and obesity in adults. Efforts to address households with dual burden malnutrition should consider promotion of healthy diets and lifestyle for all members. PMID- 19786391 TI - What extent of weight loss can benefit the health-related quality of life in motivated obese Chinese? AB - BACKGROUND: A clinical significant improvement in health-related quality of life (HRQOL) is one of the main goals of weight control. OBJECTIVE: To reveal the extent of weight loss on changes of HRQOL in obese Chinese. DESIGN: A total of 119 motivated obese adults (BMI: 33.5 +/- 0.4 kg/m2) completed a 6-month weight loss intervention program by following either low calorie diet suggestions (LCDS; n=18), LCDS plus sibutramine (SG; n=27), LCDS plus orlistat (OG; n=41), or very low calorie diet (VLCD; n=33). Changes in body composition (TBF-410GS, Tanita Co., Tokyo, Japan) and HRQOL (36-item Short-Form (SF-36) questionnaire) were measured accordingly. RESULTS: After 6-months, the greatest weight loss (p<0.001) was found in VLCD group (14.1 +/- 1.2 kg, 15.1%), followed by OG (10.6 +/- 0.9 kg, 11.5%), SG (9.6 +/- 1.3 kg, 10.2%) and LCDS alone (8.7 +/- 1.2 kg, 11.1%). The physical component score of SF-36 were significantly improved at 6-month follow-up (p<0.001), but not the mental component score. Improvements in general health score of SF-36 (Gamma mean: 6.1 +/- 2.8, p<0.05) were greater in females than males. Subjects with weight loss > or = 15 % had the greatest improvements in SF-36 scores whereas no changes in SF-36 scores were found with weight loss < 5%. CONCLUSIONS: The extent, not the type of intervention, of weight loss is highly correlated with the favorable changes in HRQOL at 6-months. Weight loss above 5% of baseline values is necessary to show significant improvements in HRQOL in motivated obese Chinese. PMID- 19786392 TI - Association of major dietary patterns with obesity risk among Mongolian men and women. AB - Mongolia is experiencing changes in its unique nomadic lifestyle and dietary habits in the last two decades with accompanying increase in obesity rate. The dietary pattern approach, which investigates the overall diet in relation to obesity risks, has become appealing in nutrition epidemiology. The aim of this study was to identify major dietary patterns of the Mongolian adults in relation to the risk of having obesity. Dietary intake of a total 418 adults aged ? 25 years was assessed by using a food frequency questionnaire with 68 items. An exploratory factor analysis resulted in three dietary patterns: transitional high in processed meat and potato, traditional rich in whole milk, fats and oils and healthy with greater intake of whole grains, mixed vegetables and fruits. Individuals in the upper quintile of the transitional pattern had significantly greater risk of obesity (BMI > or =25 kg/m2: OR=2.47; 95% CI=1.04-5.86) while subjects in the highest quintile of the healthy dietary pattern were found to have significantly decreased risk of obesity (OR: 0.49; 95% CI=0.25-0.95). Men in the highest quintile of the transitional pattern had greater risk of abdominal obesity WC > or =90 cm: OR= 4.08; 95% CI=1.11-14.97) than those in the lowest quintile. Women in the top quintile of the traditional pattern had a greater odds of having abdominal obesity (WC > or =80 cm: OR=4.59; 95% CI=1.58-13.30) than those in the lowest quintile. The study suggests that public health efforts be targeted at adults in Mongolia to address the undesirable aspects of the transitional and the traditional dietary patterns. PMID- 19786393 TI - Gender differences in "luxury food intake" owing to temporal distribution of eating occasions among adults of Hindu communities in lowland Nepal. AB - Our previous studies in developing countries have indicated that gender differences in intake of luxury foods incur risk of micronutrient deficiencies among women. As the next step, we examined the causes of gender differences in food intake by comparing eating patterns, including meal frequency (skipping) and temporal distribution of food consumption throughout the day among adults of Hindu communities in lowland Nepal. A total of 321 adults (126 men and 195 women) aged 20 years and above were randomly selected from 94 households in three rural communities. A face-to-face questionnaire-based 24-hour dietary recall interview was conducted whereby foods eaten throughout the six eating occasions (morning snack, breakfast, lunch, daytime snack, dinner, and evening snack) were recorded and analyzed. Results shows that men frequently skipped lunch (p <0.001), they also frequently consume daytime snack (p <0.001), and consumed purchased luxury foods such as tea with sugar and milk (p = 0.008) and samosa (p = 0.049) as daytime snack. The six-eating occasion analysis revealed that gender differences in food intake of rural Nepalese adults occurred during lunch and daytime snack, attributing to gender differences in daily activity patterns. PMID- 19786394 TI - Influences on consumption of soft drinks and fast foods in adolescents. AB - Soft drink and fast food are energy dense foodstuffs that are heavily marketed to adolescents, and are likely to be important in terms of risk of obesity. This study sought to examine the influences on soft drink and fast food consumption among adolescents as part of a cross-sectional survey of 2,719 adolescents (aged 11-16) from 93 randomly selected schools in New South Wales, Australia. Students provided information on soft drink and fast food consumption, and responded to statements examining influences over consumption. Over half of the boys and more than one third of the girls reported drinking soft drink daily, and consumption peaked in Grade 8 students. A quarter of students reported choosing soft drinks instead of water or milk, and around 40% agreed that soft drink was usually available in their homes. Availability in the home and drinking soft drinks with meals was most strongly associated with consumption in all age groups. Fast food consumption was higher among boys than girls in all age groups. Convenience and value for money yielded the strongest associations with fast food consumption in boys, while preferring fast food to meals at home and preferring to "upsize" meals were most strongly associated with consumption in girls. Interventions to reduce consumption of soft drinks should target availability in both the home and school environment by removing soft drinks and replacing them with more nutritive beverages. Fast food outlets should be encouraged to provide a greater range of healthy and competitively priced options in reasonable portions. PMID- 19786395 TI - Trends in BMI, diet and lifestyle between 1976 and 2005 in North Sydney. AB - Although the prevalence of overweight and obesity in Australia has increased during the past 30 years, little is known about the dietary and behavioural antecedents of body mass index (BMI). We examined changes in mean BMI, diet, and other lifestyle behaviours between 1976 and 2005 and described the cross sectional associations between these factors and BMI. A series of biennial biomedical surveys by Sydney Adventist Hospital from 1976 to 2005 allowed examination of BMI trends, while the selection of three surveys enabled detailed examination of likely dietary and lifestyle associations. Subjects included in this study were: 384 men and 338 women in 1976; 160 men and 146 women in 1978; 166 men and 141 women in 1980; 164 men and 142 women in 1982; 177 men and 13 women in 1984; 239 men and 227 women in 1986; 210 men and 225 women in 1988; 165 men and 148 women in 1990; 138 men and 167 women in 1992 and 270 men and 62 women in 2005. Height and weight were measured by hospital staff. Mean BMI increased in the early 1990s. Salt, coffee, cola, alcohol and meat consumption, dieting to lose weight and eating between meals were positively associated with BMI while physical activity, food variety, large breakfasts and consumption of spreads were negatively associated. Food consumption and daily activities have important associations with BMI, though their specific associations differ by sex. "Affluent" lifestyle patterns appear to contribute to higher BMI, while a more "prudent" lifestyle seems to protect from such increases. PMID- 19786396 TI - Expert meeting on Child Growth and Micronutrient Deficiencies--New Initiatives for Developing Countries to Achieve Millennium Development Goals: executive summary report. AB - Undernutrition in early childhood has long-term physical and intellectual consequences. Improving child growth should start before the age of two years and be an integrated effort between all sectors, covering all aspects such as diet and nutrient intake, disease reduction, optimum child care, and improved environmental sanitation. To discuss these issues, the Indonesian Danone Institute Foundation organized an expert meeting on Child Growth and Micronutrient Deficiencies: New Initiatives for Developing Countries to Achieve Millennium Development Goals. The objective of the meeting was to have a retrospective view on child growth: lessons learned from programs to overcome under-nutrition in the developed countries and to relate the situation to the Indonesian context, as well as to discuss implications for future programs. Recommendations derived from the meeting include focus intervention on the window of opportunity group, re-activation of the Integrated Health Post at the village level, improvement of infant and young child feeding, expand food fortification intervention programs, strengthen supplementation programs with multi micronutrient, and strengthening public and private partnership on food related programs. PMID- 19786397 TI - Effect of 5-azacytidine induction duration on differentiation of human first trimester fetal mesenchymal stem cells towards cardiomyocyte-like cells. AB - The aim of this study is to investigate effects of 5-azacytidine (5-aza) induction duration on differentiation of bone marrow mesenchymal stem cells (MSCs) from human first-trimester abortus (hfMSCs) towards cardiomyocyte-like cells. hfMSCs were stimulated with 10 micromol/l 5-aza for 24 h (group A), 48 h (group B) and 21 days (group C), respectively. During the induction, 30-40% of the cells gradually enlarged, elongated, connected with adjoining cells and formed myotube-like structures, branches and string-bead-like nuclei. Some of the cells congregated into cell clusters or strips. After the induction, numerous myofilaments in the cytoplasm and conjunction of intercalated disc-like structure between adjoining cells were observed. The induced cells expressed messenger ribonucleic acids (mRNAs) and proteins of myocardium-specific alpha-actin, sarcomeric beta-myocin heavy chain and troponin-T. The positive cell percentages for the three antigens in group C were each significantly higher than those antigens in group A and B (P<0.01) and the cell population doubling time (PDT) of group C was longer than those of group A and B (P<0.01). These indicate that 21-d induction with 10 micromol/l 5-aza slows down proliferation speed of hfMSCs but increases differentiation rate of hfMSCs into cardiomyocyte-like cells if compared with 24-48 h induction. PMID- 19786398 TI - Influence of prenatal nutrition and obesity on tissue specific fat mass and obesity-associated (FTO) gene expression. AB - The recent discovery of an association between body composition, energy intake and the fat mass and obesity-associated (FTO) gene represents a promising new therapeutic target in obesity prevention. In a well, pre-established large animal model, we investigated the regulation of FTO gene expression under conditions either leading to obesity or increased risk of obesity related disorders: i) a sedentary 'Western' lifestyle and ii) prenatal exposure to nutrient restriction. Pregnant sheep were either fed to fully meet their nutritional requirements throughout gestation or 50% of this amount from early-to-mid gestation. Following weaning, offspring were either made obese through exposure to a sedentary obesogenic environment or remained lean. A significant positive relationship between placental FTO gene expression and fetal weight was found at 110 days gestation. In both the newborn and adult offspring, the hypothalamus was the major site of FTO gene expression. Hypothalamic FTO gene expression was upregulated by obesity and was further increased by prenatal nutrient restriction. Importantly, we found a strong negative relationship between the hypothalamic FTO gene expression and food intake in lean animals only that may imply FTO as a novel controller of energy intake. In contrast, FTO gene expression in the heart was downregulated in obese offspring born to nutrient restricted mothers. In addition, FTO gene expression was unaffected by obesity or prenatal diet in insulin-dependent tissues, where it changed with age possibly reflecting adaptations in cellular energetic activity. These findings extend information gained from human epidemiology and provide new insights into the regulation of in vivo energy metabolism to prevent obesity. PMID- 19786399 TI - Angiogenesis and vascular function in the ovary. AB - Ovarian function is dependent on the establishment and continual remodelling of a complex vascular system. This enables the follicle and/or corpus luteum (CL) to receive the required supply of nutrients, oxygen and hormonal support as well as facilitating the release of steroids. Moreover, the inhibition of angiogenesis results in the attenuation of follicular growth, disruption of ovulation and drastic effects on the development and function of the CL. It appears that the production and action of vascular endothelial growth factor A (VEGFA) is necessary at all these stages of development. However, the expression of fibroblast growth factor 2 (FGF2) in the cow is more dynamic than that of VEGFA with a dramatic upregulation during the follicular-luteal transition. This upregulation is then likely to initiate intense angiogenesis in the presence of high VEGFA levels. Recently, we have developed a novel ovarian physiological angiogenesis culture system in which highly organised and intricate endothelial cell networks are formed. This system will enable us to elucidate the complex inter-play between FGF2 and VEGFA as well as other angiogenic factors in the regulation of luteal angiogenesis. Furthermore, recent evidence indicates that pericytes might play an active role in driving angiogenesis and highlights the importance of pericyte-endothelial interactions in this process. Finally, the targeted promotion of angiogenesis may lead to the development of novel strategies to alleviate luteal inadequacy and infertility. PMID- 19786400 TI - Morphological classification of bovine ovarian follicles. AB - Follicle classification is an important aid to the understanding of follicular development and atresia. Some bovine primordial follicles have the classical primordial shape, but ellipsoidal shaped follicles with some cuboidal granulosa cells at the poles are far more common. Preantral follicles have one of two basal lamina phenotypes, either a single aligned layer or one with additional layers. In antral follicles <5 mm diameter, half of the healthy follicles have columnar shaped basal granulosa cells and additional layers of basal lamina, which appear as loops in cross section ('loopy'). The remainder have aligned single-layered follicular basal laminas with rounded basal cells, and contain better quality oocytes than the loopy/columnar follicles. In sizes >5 mm, only aligned/rounded phenotypes are present. Dominant and subordinate follicles can be identified by ultrasound and/or histological examination of pairs of ovaries. Atretic follicles <5 mm are either basal atretic or antral atretic, named on the basis of the location in the membrana granulosa where cells die first. Basal atretic follicles have considerable biological differences to antral atretic follicles. In follicles >5 mm, only antral atresia is observed. The concentrations of follicular fluid steroid hormones can be used to classify atresia and distinguish some of the different types of atresia; however, this method is unlikely to identify follicles early in atresia, and hence misclassify them as healthy. Other biochemical and histological methods can be used, but since cell death is a part of normal homoeostatis, deciding when a follicle has entered atresia remains somewhat subjective. PMID- 19786401 TI - Biomechanics of the wrist after proximal row carpectomy in cadavers. AB - We investigated the biomechanics of the radiocapitate joint after a proximal row carpectomy in six fresh-frozen cadaver wrists using super-low-pressure-sensitive film on a material testing system. The average pressure within the lunate fossa increased significantly from 23.2 to 136.4 N/cm(2) with a sharp decrease in the contact area from 2.08 to 0.30 cm(2) after a proximal row carpectomy. The cartilage of the proximal capitate had four sub-facets and therefore was not as smooth as the normal proximal lunate. We found that the wrist was overloaded after a proximal row carpectomy and the main cause was the anatomical mismatch of the radiocapitate articulation. PMID- 19786402 TI - Is revision bone grafting worthwhile after failed surgery for scaphoid nonunion? Minimum 8 year follow-up of 18 patients. AB - Eighteen patients who underwent revision non-vascularized bone grafting and internal fixation after failed surgery for scaphoid nonunion were reviewed after a minimum of 8.2 years. Eleven of the nonunions were located in the middle and seven in the proximal third of the scaphoid. The mean interval between injury and the revision procedure was 6 years. Sixteen of the 18 nonunions healed, two after a third attempt. Three patients with healed nonunions and one patient with persistent nonunion required salvage procedures for progressive radiocarpal arthrosis. In the remaining 14 cases, the mean loss of wrist flexion/extension arc compared to the contralateral wrist was 36 degrees . Mean reduction of grip strength and key pinch was 9.3 kg and 0.9 kg respectively. The QuickDASH score was 18 and a visual analogue pain score was 21/100 at follow-up. Wrist degeneration increased in all but one case during the observation period. Thirteen of 16 patients with union and one patient with a persisting nonunion experienced moderate symptoms. PMID- 19786403 TI - An association between lunate morphology and scaphoid-trapezium-trapezoid arthritis. AB - The purpose of this study was to determine if an association exists between scaphoid-trapezium-trapezoid arthritis and lunate morphology. Plain neutral posteroanterior radiographs were evaluated for 48 patients with STT arthritis and 96 patients from a control group. Lunate type was determined using capitate triquetrum (C-T) distance. A type I lunate was defined as a C-T distance < or =2 mm. A type II lunate was defined as a C-T distance > or =4 mm. Lunate type was recorded and compared between those with STT arthritis and a control group. The groups were similar with regard to age, gender and handedness. Type II lunates were found in 83% of cases with STT arthritis and in 64% of controls. STT OA was associated with type II lunate wrists (P = 0.02; OR = 0.35; CI: 0.15-0.82). We postulate that variations in scaphoid motion secondary to lunate morphology may contribute to the development of STT OA. PMID- 19786404 TI - The addition of an upper-extremity curriculum in medical school education and its assessment. AB - This study assessed the impact of changes made to address the inadequate upper extremity education through preclinical medical school curriculum reform. After the administration of a new upper-extremity curriculum, which also increased the time devoted to three preclinical medical school courses from 7.25 to 21.25 hours, second-year medical students were evaluated for mastery of these concepts through a national validated objective examination, and attitude and skill through clinical confidence and subjective surveys. After implementation of the new upper-extremity curriculum, students had significantly greater confidence in their ability to perform a physical examination but not in identifying differential diagnoses of the upper-extremity. Students were more satisfied with the amount of time spent on the musculoskeletal system but their performance in the national examination did not change. PMID- 19786405 TI - Correlation between range of motion and implant fracture: a 5 year follow-up of 72 joints in 18 patients in a randomized study comparing Swanson and Avanta/Sutter MCP silicone prosthesis. AB - Eighteen out of 18 rheumatoid patients (at one centre of a two-centre 30 patient study previously reported) with a mean age of 56 years, and 72/72 operated joints were randomized to Avanta/Sutter or Swanson MCP prostheses and followed for 5 years. Both ulnar deviation and extension lag were improved already at 6 weeks and remained improved at 5 years. The Avanta prosthesis had a better range of motion (ROM) than the Swanson. Six of nine patients with Avanta/Sutter implants had at least one implant fracture compared to 1/9 patients with the Swanson implant (P = 0.05) but fracture did not change the outcome subjectively. The ROM at 3 months correlated with the occurrence of an implant fracture at 5 years and a greater early ROM may be related to implant fracture. At 5 years patients remained satisfied and the deformities remained corrected. PMID- 19786406 TI - Surface replacement trapeziometacarpal joint arthroplasty--early results. AB - This study reviews the results of Surface Replacement Trapeziometacarpal (SR TMC, Avanta, San Diego, CA) total joint arthroplasty. Fifty patients (62 joints) were included in the study. Forty-three patients (54 joints) were seen at final follow up. Seven patients (eight joints) were interviewed over the phone. Seven patients were revised to trapeziectomy and ligament reconstruction with tendon interposition, five for aseptic loosening and two for dislocation. At final follow up, the mean Quick DASH score was 30.4 and the Sollerman Score was 77.3. Radiological review of the surviving 55 joints showed subsidence of four trapezial components in asymptomatic patients. Cumulative survival rate was 91% at 3 years. Eighty-five percent of the patients were satisfied with the outcome of their treatment. PMID- 19786407 TI - Narakas classification of obstetric brachial plexus palsy revisited. AB - Narakas classified babies with obstetric palsy into four groups: upper Erb's, extended Erb's, total palsy, and total palsy with a Horner. Over the last 15 years, it was noted at our obstetric palsy clinic that good spontaneous recovery in newborns with extended Erb's palsy (C5, C6, C7 injury) was more likely if they recovered active wrist extension against gravity before 2 months of age. A hypothesis was made that newborns with extended Erb's palsy (Narakas Group II) may be subclassified into two groups according to this 'early recovery of wrist extension.' In a retrospective study of 581 cases with strict inclusion criteria, the hypothesis was found to be true: patients with extended Erb's and 'early recovery of wrist extension' have significantly higher percentages of good spontaneous recovery of limb function than those with extended Erb's and 'no early recovery of wrist extension' (P<0.0001 by chi-squared test). PMID- 19786408 TI - The role of an MMP inhibitor in the regulation of mechanical tension by Dupuytren's disease fibroblasts. AB - Mechanical tension and contracture are two related facets of tissue biology. This study assessed the effect of ilomastat, a broad-spectrum matrix metalloprotease (MMP) inhibitor, on generation of tension by Dupuytren's disease fibroblasts. Nodule and cord-derived fibroblasts were isolated from five patients with Dupuytren's disease; flexor retinaculum acted as the control. A culture force monitor (CFM) provided an in vitro model of tissue organization to assess development of mechanical tension, lattice contraction and spatial remodelling by fibroblasts. Responses to ilomastat were compared to treatment with a control peptide. Nodule and cord-derived fibroblasts exhibited a two-fold increase in tension compared with flexor retinaculum. Ilomastat significantly inhibited development of tension by nodule and cord but not flexor retinaculum derived fibroblasts at 100 microM. These results imply that MMP activity mediates regulation of tensile strength by Dupuytren's disease fibroblasts and may be an important therapeutic target in patients with Dupuytren's disease. PMID- 19786409 TI - Analysis of NHSLA claims in hand and wrist surgery. AB - Claims for negligence are increasing in medical practice. We analysed data provided by the UK NHS Litigation Authority (NHSLA) on all hand and wrist surgery from 1995-2001. The numbers of claims increased from 13 to 40, but the number being successfully defended also increased from 2 to 13 during this period. Claims were most commonly attributed to errors at surgery (56%) or in outpatient clinics (24%). Strikingly the claims are clustered to a few common conditions, particularly the treatment of carpal tunnel syndrome (22%) and wrist fractures (48%). There were no claims related to complex hand surgery. We recommend better training for 'routine surgery', better description of distal radius fracture parameters at each clinic visit and better training in emergency departments (ED). PMID- 19786410 TI - Strength enhancement of the interlocking mechanism in cross-stitch peripheral sutures for flexor tendon repair: biomechanical comparisons by cyclic loading. AB - The fatigue strength of three peripheral suture techniques for flexor tendon repair was compared by cyclic loading of repairs in a cotton dental roll tendon model. Thirty pairs of dental roll were sutured using only peripheral sutures with 6-0 polypropylene. An initial cyclic load of 5 N for 500 cycles was applied and increased by 5 N for an additional 500 cycles at each new load until rupture. The fatigue strength of an interlocking cross-stitch suture was 113% greater than a running suture and 36% greater than a standard cross-stitch suture. Interlocking the cross-stitch prevented shortening of the transverse portions under load and appears to be a useful technique for increasing the strength of the peripheral suture. PMID- 19786411 TI - Epidermoid cysts in the hand. AB - This study details our series of epidermoid cysts in the hand, characterising the incidence, clinical characteristics and recurrence rate after marginal excision. A historical cohort of 101 epidermoid cysts that were excised from a soft tissue or intraosseous location in the hand over a 27 year period were reviewed. The incidence of epidermoid cysts, patient age, sex, occupation, anatomic location, history of trauma, treatment complications and cyst recurrence rate were noted. Key findings of the study were as follows. Epidermoid cysts represented a significant portion of our relatively large series of hand tumours. The majority occurred in male patients, most often involving the soft tissues on the palmar aspect of the hand. Four percent were intraosseous epidermoid cysts. After excision with a marginal tumour margin we found that 11 cysts (11%) recurred. PMID- 19786412 TI - Motion-stable flexor tendon repair with the Mantero technique in the distal part of the fingers. AB - Lacerated flexor digitorum profundus (FDP) tendons in zone 1 and distal zone 2 were reconstructed in 73 consecutive cases using the motion-stable Mantero technique during a 7-year period. Sixty-five (89%) of these patients were re examined an average of 40 (26-82) months postoperatively. According to Moiemen and Elliot (2000) assessment by Strickland's original and modified criteria and in addition the Buck-Gramcko score showed excellent and good results of 54%, 72% and 91% respectively. In contrast, examination of the results measuring the range of movement of the distal interphalangeal (DIP) joint alone provided a more realistic assessment in DIP joint function after Mantero technique with excellent and good results of only 38%. PMID- 19786413 TI - High-resolution ultrasonography of the cutaneous nerve branches in the hand and wrist. AB - Ultrasonography can be used in the diagnosis of various neuropathies, including nerve injury. Nerves often involved in traumatic and iatrogenic injury are small cutaneous branches in the hand and wrist, which cannot be seen in detail using current ultrasound probes. This study explored the potential of high-resolution ultrasonography in seeing these nerve branches in the human. The VisualSonics Vevo 770 system with a 15-82.5 MHz probe was compared to a commonly used 5-12 MHz probe and ultrasound machine. The accuracy was validated by ultrasound guided dye injection into cadaver nerves, with subsequent anatomical dissection and verification. Results were confirmed in two healthy volunteers. The Vevo 770 system was able to accurately identify the small cutaneous nerves. It could also depict the median nerve and its fascicles in greater detail. This may be useful for clinical diagnosis, localisation and follow-up of neuropathies and nerve injuries. PMID- 19786414 TI - Flexor pollicis longus primary repair: further experience with the tang technique and controlled active mobilization. AB - This study reports our treatment of divided flexor pollicis longus tendons by primary repair from January 2004 to September 2007. Fifty flexor pollicis longus repairs carried out using the Tang technique of three Tsuge sutures are reported in this study. A circumferential suture was not used routinely. Excellent or good results were observed in 78/82% of cases (White/Buck-Gramcko assessments, respectively). No patients ruptured repairs as a result of early active mobilization. No patients developed postoperative infections with wound and tendon dehiscence. One patient developed Chronic Regional Pain Syndrome Type 1. We have found this repair of the flexor pollicis longus tendon to be safe for early active mobilization and it is easier to perform than primary repair of this tendon using four strand Kessler-type core sutures and elaborate circumferential sutures, as reported previously. PMID- 19786415 TI - Sequential multiple-assignment randomized trial design of neurobehavioral treatment for patients with metastatic malignant melanoma undergoing high-dose interferon-alpha therapy. AB - BACKGROUND: Interferon-alpha therapy, which is used to treat metastatic malignant melanoma, can cause patients to develop two distinct neurobehavioral symptom complexes: a mood syndrome and a neurovegetative syndrome. Interferon-alpha effects on serotonin metabolism appear to contribute to the mood and anxiety syndrome, while the neurovegetative syndrome appears to be related to interferon alpha effects on dopamine. PURPOSE: Our goal is to propose a design for utilizing a sequential, multiple assignment, randomized trial design for patients with malignant melanoma to test the relative efficacy of drugs that target serotonin versus dopamine metabolism during 4 weeks of intravenous, then 8 weeks of subcutaneous, interferon-alpha therapy. METHODS: Patients will be offered participation in a double-blinded, randomized, controlled, 14-week trial involving two treatment phases. During the first month of intravenous interferon alpha therapy, we will test the hypotheses that escitalopram will be more effective in reducing depressed mood, anxiety, and irritability, whereas methylphenidate will be more effective in diminishing interferon-alpha-induced neurovegetative symptoms, such as fatigue and psychomotor slowing. During the next 8 weeks of subcutaneous interferon therapy, participants whose symptoms do not improve significantly will be randomized to the alternate agent alone versus escitalopram and methylphenidate together. RESULTS: We present a prototype for a single-center, sequential, multiple assignment, randomized trial, which seeks to determine the efficacy of sequenced and targeted treatment for the two distinct symptom complexes suffered by patients treated with interferon-alpha. LIMITATIONS: Because we cannot completely control for external factors, a relevant question is whether or not 'short-term' neuropsychiatric interventions can increase the number of interferon-alpha doses tolerated and improve long-term survival. CONCLUSIONS: This sequential, multiple assignment, randomized trial proposes a framework for developing optimal treatment strategies; however, additional studies are needed to determine the best strategy for treating or preventing neurobehavioral symptoms induced by the immunotherapy interferon alpha. PMID- 19786416 TI - Effect of Warm-Supplementing Kidney Yang (WSKY) added to risperidone on quality of life in patients with schizophrenia: a randomized controlled trial. AB - OBJECTIVE: To evaluate the quality of life, efficacy and safety of Warm Supplementing Kidney Yang (WSKY) added to risperidone in patients with schizophrenia. DESIGN: A randomized controlled trial. SETTING: The outpatient and inpatient departments of three hospitals. SUBJECTS: One hundred and twenty patients with clinically diagnosed schizophrenia with predominantly negative symptoms were included in the study. INTERVENTION: All 120 patients were randomly assigned to double-blind treatment with WSKY group (n = 60) or placebo group (n = 60) added to risperidone for eight weeks. MAIN MEASURE: The efficacy measures included the World Health Organization Quality of Life Scale (WHOQOL-100), the Positive and Negative Syndrome Scale (PANSS), the Social Disability Screening Schedule and the Hamilton Rating Scale for Depression. Safety and tolerability were assessed throughout the trial. RESULTS: The scores of quality of life in the WSKY group showed statistically significant improvement at the end-point of treatment compared with those in the placebo group (WSKY, increasing 40.5 (29.4); placebo, increasing 14.4 (27.1); F =24.900, P<0.001), while the scores of social function and depression symptoms also showed statistically significant improvement. The response rates for the WHOQOL-100 total scores were 50.0% for the WSKY group versus 31.7% for placebo group (chi( 2) = 4.172, P=0.041). There were no significant differences in the safety/tolerability measures between the WSKY group and the placebo group during treatment. CONCLUSIONS: The results suggest that WSKY added to risperidone significantly improved the quality of life, social function, depression symptom compared with placebo added to risperidone. PMID- 19786417 TI - Promoting the use of outcome measures by an educational programme for physiotherapists in stroke rehabilitation: a pilot randomized controlled trial. AB - OBJECTIVE: To determine the influence of tutor expertise on the uptake of a physiotherapists' educational programme intended to promote the use of outcome measures in the management of patients with stroke. DESIGN: Pilot randomized controlled trial. METHODS: Thirty physiotherapists involved in stroke management were randomized into two groups and participated in five tutor-guided educational sessions (the Physiotherapists' Educational Programme on Clinimetrics in Stroke, PEPCiS). Groups differed from each other with respect to tutors: one experienced and one inexperienced in stroke care. Primary outcome was 'actual use' (the frequencies of data of seven recommended outcome measures in the patient records of the participating physiotherapists). RESULTS: The actual use of instruments shifted from a median of 3 to 6 in the expert tutor group and from 3 to 4 in the non-expert tutor group (P = 0.07). Physiotherapists educated by the expert tutor used a broader variety of instruments and appreciated the educational programme, their own knowledge gain and all three scales of tutor style aspects significantly more than their colleagues of the non-expert tutor group (all P<0.05). Univariate analysis on the entire set of data revealed eight factors, including tutors' performance, that were associated with a change score of the use of two or more outcome measures by individual physiotherapists after the educational programme. CONCLUSION: In this pilot trial it was not proven that tutor expertise in stroke care influences the actual use of outcome measures, but it warrants a future study with sufficient power to investigate the influence of the tutor. PMID- 19786418 TI - Effects of Nordic walking training on exercise capacity and fitness in men participating in early, short-term inpatient cardiac rehabilitation after an acute coronary syndrome--a controlled trial. AB - OBJECTIVE: To investigate the effects of Nordic Walking training supplemental to a standard, early rehabilitation programme on exercise capacity and physical fitness in men after an acute coronary syndrome. DESIGN: A controlled trial. SETTING: Cardiac rehabilitation service of a provincial hospital. SUBJECTS: Eighty men 2-3 weeks after an acute coronary syndrome, with good exercise tolerance. INTERVENTIONS: Three-week, inpatient cardiac rehabilitation programme (control group) supplemented with Nordic Walking (Nordic Walking group), or with traditional walking training (walking training group). MAIN MEASURES: Exercise capacity was assessed as peak energy cost (in metabolic equivalents) in symptom limited treadmill exercise test, and physical fitness with the Fullerton Functional Fitness Test. RESULTS: Exercise capacity after the rehabilitation programme was higher in the Nordic Walking group than in the control group (10.8 +/- 1.8 versus 9.2 +/- 2.2 metabolic equivalents, P =0.025). The improvement in exercise capacity in the Nordic Walking group was higher than in the control group (1.8 +/- 1.5 versus 0.7 +/- 1.4 metabolic equivalents, P =0.002). In contrast to the control group, the results of all components of the Fullerton test improved in the Nordic Walking and walking training groups. After the programme, lower body endurance, and dynamic balance were significantly better in the Nordic Walking group in comparison with the walking training and control groups, and upper body endurance was significantly better in the Nordic Walking and walking training groups than in the control group. CONCLUSIONS: Nordic Walking may improve exercise capacity, lower body endurance and coordination of movements in patients with good exercise tolerance participating in early, short term rehabilitation after an acute coronary syndrome. PMID- 19786419 TI - What do acute stroke physiotherapists do to treat postural control and mobility? An exploration of the content of therapy in the UK. AB - OBJECTIVE: To investigate the content of acute stroke physiotherapy to treat postural control and mobility problems. DESIGN: Stroke physiotherapists recorded the interventions used to treat postural control and mobility during treatment sessions. They recorded five sessions for at least five patients each. Descriptive statistics assessed the frequency with which the interventions were used. SETTING: Hospital-based acute stroke care. SUBJECTS: Thirty-six acute stroke physiotherapists recorded 2374 interventions in 364 treatment sessions for 76 patients. MAIN MEASURES: The Stroke Physiotherapy Intervention Recording Tool. RESULTS: Facilitation techniques were the most frequently used interventions (n = 1258, 53%) with exercise (n = 115, 5%), teaching others how to help the patient (n = 99, 4%) and provision of equipment (n = 63, 3%) the least frequently used. CONCLUSIONS: Acute stroke physiotherapists primarily use therapist-led 'hands-on' interventions to treat postural control and mobility problems. Interventions to promote activity or practice outside the treatment session are infrequently used. PMID- 19786420 TI - The psychometric properties and clinical utility of measures of walking and mobility in neurological conditions: a systematic review. AB - OBJECTIVE: To identify psychometrically robust and clinically feasible measures of walking and mobility in people with neurological conditions. DATA SOURCES: MEDLINE, CINAHL, EMBASE, PEDro and AMED. REVIEW METHODS: Independent reviewers selected and extracted data from articles that assessed the reliability, validity, sensitivity to change or clinical utility of measures of walking and mobility in adult neurological conditions. Measures with 'good' psychometrics and 9/10 clinical utility scores were recommended. RESULTS: Seventeen measures were selected. Of these, the 5-m and 10-m walk tests, six-minute walk test, High Level Mobility Assessment Tool (HiMAT) and the Rivermead Mobility Index (RMI) reached the required standards and are usable in clinical practice. None of the recommended measures assessed wheelchair mobility. The least frequently assessed property was sensitivity to change. Further measures could be recommended if the minimal detectable change were demonstrated. CONCLUSION: The 5-m, 10-m and six minute walk test, High Level Mobility Assessment Tool and the Rivermead Mobility Index are psychometrically robust measures of walking and mobility and are feasible for use in clinical practice. PMID- 19786421 TI - An evaluation of self-administration of auditory cueing to improve gait in people with Parkinson's disease. AB - OBJECTIVE: To evaluate a self-administration of auditory cueing on gait difficulties in people with Parkinson's disease over a one-week period. DESIGN: Single group pre and post test. SETTING: Research lab, community. PARTICIPANTS: Twenty-one individuals with Parkinson's disease. INTERVENTIONS: Self-application of an auditory pacer set at a rate 25% faster than preferred cadence. MAIN OUTCOME MEASURES: Self-selected gait speed, cadence, stride length, and double support time with and without the pacer at the initial visit and after one week of pacer use. RESULTS: During the initial visit, the auditory pacer improved gait speed (79.57 (18.13) cm/s vs. 94.02 (22.61) cm/s, P<0.0005), cadence (102.88 (11.34) step/min vs. 109.22 (10.23) steps/min, P=0.036) and stride length (94.33 (21.31) cm vs. 103.5 (22.65) cm, P =0.012). After one week, preferred gait speed was faster than the initial preferred speed (79.57 (18.13) vs. 95.20 (22.23) cm/s, P<0.0005). Stride length was significantly increased (94.33 (21.31) vs. 107.67 (20.01) cm, P =0.001). Double support time was decreased from 21.73 (5.23) to 18.94 (3.59)% gait cycle, P =0.016. CONCLUSION: Gait performance in people with Parkinson's disease improved significantly after walking with the auditory pacer for one week. PMID- 19786422 TI - Filling up the hours: how do stroke patients on a rehabilitation nursing home spend the day? AB - OBJECTIVE: To describe the time use of stroke patients on rehabilitation units of a nursing home focusing on the time spent on therapeutic activities, non therapeutic activities, interactions and the location wherein these took place. DESIGN: A descriptive study. SETTING: Rehabilitation units of a nursing home. SUBJECTS: Seventeen chronic stroke patients, including 9 men, 8 women, with a mean age of 77 years (SD +/- 7.6 years). MAIN MEASURES: Daily activities of patients were measured using Behavioural Mapping, including therapeutic activities, non-therapeutic activities, interactions and their location. Functional status was measured with the Barthel Index. RESULTS: Of the patients 15 (88%) were partly/fully paralysed, with a mean Barthel Index score of 9.4 (SD +/- 4.3). The patients spent 20% of the day on therapeutic activities, whereas 80% of the day was spent on non-therapeutic activities; 9% on therapeutic activities with the nurse. For 60% of the day patients were alone and not interacting with others. CONCLUSIONS: Stroke patients spend only short periods of time during the day on therapeutic activities. For the largest part of the day, the patient is alone and passive. A challenge for nurses is how to activate patients and engage them in purposeful task-oriented training in daily activities. PMID- 19786423 TI - Development of a patient-reported outcome measure for children with streptococcal pharyngitis. AB - OBJECTIVE: The objective of this study was to develop a patient-reported outcome measure (Strep-PRO) for assessing symptoms of group A Streptococcus (GAS) pharyngitis from the child's point of view and to present preliminary data on its internal reliability, construct validity, and responsiveness. METHODS: We selected 8 symptoms for inclusion in the Strep-PRO. We used the Strep-PRO to assess improvement in children who were aged 5 to 15 years and had confirmed GAS pharyngitis. Children completed the scale at study visits and as a diary at home. To evaluate internal reliability, we examined correlations between the items on the scale. To evaluate construct validity, we examined the correlation at entry between Strep-PRO scores and scores on other, previously validated measures of pain and functional status. To evaluate responsiveness, we examined the change in score from enrollment to follow-up. The correlation between the Strep-PRO score and parental assessment of symptoms was also evaluated. RESULTS: A total of 131 children were enrolled; 113 returned completed diaries. The internal reliability of the scale was high. The magnitude of correlations between Strep-PRO scores and other measures of pain and functional status ranged from 0.39 to 0.63. The responsiveness of the Strep-PRO was very good. The overall level of agreement between child Strep-PRO scores and parental assessment of symptoms was 0.57. CONCLUSIONS: The scale seems to measure effectively both pain and overall functional status in children with GAS pharyngitis. These data support the use of Strep-PRO as a measure of outcome in future clinical trials. PMID- 19786425 TI - Implementing electronic health record-based quality measures for developmental screening. AB - OBJECTIVE: The goal was to examine the current abilities and future potential of electronic health record (EHR) systems to measure childhood developmental screening and follow-up rates in primary care settings. METHODS: A group of pediatric clinicians and health informatics experts was convened to develop quality indicators reflecting different aspects of the developmental screening process. These indicators included the administration of a standardized, validated instrument to screen children for developmental delays, the documentation of abnormal screening results, and the provision of follow-up care. Six integrated provider systems across the United States, with fully implemented EHR systems, were evaluated to determine the feasibility of implementing these measures within each system. Barriers related to measure implementation were identified. RESULTS: The EHR systems of all 6 health care organizations could implement measures examining developmental screening rates and could identify and track children with abnormal screening results. However, most of the systems did not have the ability to capture data for more-complex EHR-based measures. In particular, data elements based on workflow actions could not be captured with current EHR system designs. CONCLUSIONS: This study identified 2 main barriers to the implementation of developmental quality measures: concerns about data reliability and the tracking of care coordination within patient records. Potential solutions to these problems, including terminology standardization, patient portal use, and use of a single developmental screening instrument, are discussed. PMID- 19786424 TI - Mental health context of food insecurity: a representative cohort of families with young children. AB - OBJECTIVE: Children from food-insecure families (ie, families that lack access to sufficient, safe, and nutritious food) are at risk for developmental problems. Food insecurity disproportionately occurs among low-socioeconomic status (SES) and low-income families; however, interventions that supplement families' income or diet have not eradicated food insecurity. This may be because food insecurity is also related to nonfinancial factors such as the presence of maternal mental health problems. To clarify whether addressing mothers' mental health problems may be a promising strategy for reducing the burden of food insecurity, we tested the hypothesis that low-SES families are especially vulnerable to food insecurity when the mother experiences depression, alcohol or drug abuse, psychosis spectrum disorder, or domestic violence. METHODS: We used data from a nationally representative cohort of 1116 British families (the Environmental Risk Longitudinal Study). Food insecurity, family SES, maternal mental health and exposure to domestic violence, and children's behavioral outcomes were measured by using validated methods. RESULTS: Overall, 9.7% of study families were food insecure. Among low-SES families, controlling for income variation, food insecurity co-occurred with maternal depression (odds ratio [OR]: 2.82 [95% confidence interval (CI): 1.62-4.93]), psychosis spectrum disorder (OR: 4.01 [95% CI: 2.03-7.94]), and domestic violence (OR: 2.36 [95% CI: 1.18-4.73]). In addition, food insecurity predicted elevated rates of children's behavior problems. CONCLUSIONS: Among families with young children, food insecurity is frequent, particularly when the mother experiences mental health problems. This suggests that interventions that improve women's mental health may also contribute to decreasing the burden of food insecurity and its impact on the next generation. PMID- 19786426 TI - Neonatal S100B protein levels after prenatal exposure to selective serotonin reuptake inhibitors. AB - OBJECTIVE: This study investigated neonatal S100B levels as a biomarker of prenatal selective serotonin reuptake inhibitor (SSRI) exposure. METHODS: Maternal (delivery; N = 53) and neonatal (cord; N = 52) serum S100B levels were compared between prenatally SSRI-exposed (maternal, N = 36; neonatal, N = 37; duration: 230 +/- 71 days) and nonexposed (maternal, N = 17; neonatal, N = 15) groups. Measures of maternal depression and anxiety symptoms were assessed during the third trimester (33-36 weeks), and neonatal outcomes, including Apgar scores, birth weight, gestational age at birth, and symptoms of poor neonatal adaptation, were recorded. RESULTS: S100B levels were significantly lower in prenatally SSRI exposed neonates than in nonexposed neonates, controlling for gestational age and third-trimester maternal mood (P = .036). In contrast, SSRI-exposed mothers had significantly higher maternal serum S100B levels, compared with nonexposed mothers (P = .014), even controlling for maternal mood in the third trimester. S100B levels were not associated with maternal or neonatal drug levels, duration of prenatal exposure, demographic variables, or risk for poor neonatal adaptation. CONCLUSIONS: Prenatal SSRI exposure was associated with decreased neonatal serum S100B levels, controlling for prenatal maternal mood. Neonatal S100B levels did not reflect neonatal behavioral outcomes and were not related to pharmacologic indices. These findings are consistent with prenatal alcohol and cocaine exposures, which also alter central serotonin levels. PMID- 19786427 TI - Prediction of birth weight by cotinine levels during pregnancy in a population of black smokers. AB - OBJECTIVE: The goal was to investigate the association between maternal salivary cotinine levels (SCLs) and pregnancy outcomes among black smokers. METHODS: In a randomized, controlled trial conducted in 2001-2004 in Washington, DC, 714 women (126 active smokers [18%]) were tested for SCLs at the time of recruitment and later in pregnancy. Sociodemographic health risks and pregnancy outcomes were recorded. RESULTS: Birth weights were significantly lower for infants born to mothers with baseline SCLs of > or =20 ng/mL in comparison with <20 ng/mL (P = .024), > or =50 ng/mL in comparison with <50 ng/mL (P = .002), and > or =100 ng/mL in comparison with <100 ng/mL (P = .002), in bivariate analyses. In linear regression analyses adjusting for sociodemographic and medical factors, SCLs of > or =20 ng/mL were associated with a reduction in birth weight of 88 g when SCLs were measured at baseline (P = .042) and 205 g when SCLs were measured immediately before delivery (P < .001). Corresponding results were 129 g (P = .006) and 202 g (P < .001) for > or =50 ng/mL and 139 g (P = .007) and 205 g (P < .001) for > or =100 ng/mL. Gestational age was not affected significantly at any SCL, regardless of when SCLs were measured. CONCLUSIONS: Elevated SCLs early in pregnancy or before delivery were associated with reductions in birth weight. At any cutoff level, birth weight reduction was more significant for the same SCL measured in late pregnancy. Maintaining lower levels of smoking for women who are unable to quit may be beneficial. PMID- 19786428 TI - Higher cumulative doses of erythropoietin and developmental outcomes in preterm infants. AB - OBJECTIVE: We hypothesized that higher cumulative doses of recombinant erythropoietin (rEPO) for extremely preterm infants during the first 6 postnatal weeks would improve developmental outcomes, as evidenced in evaluations with the Bayley Scales of Infant Development-II Revised. METHODS: This was a retrospective cohort study with a data set for a group (N = 366) of infants of <1500 g and < or =30 weeks of gestation that was created initially to examine the association between rEPO treatment and retinopathy of prematurity. Infants who underwent developmental follow-up evaluations at corrected age of >12 months were included. The associations between rEPO doses and higher Bayley Scales of Infant Development Psychomotor Developmental Index and Mental Developmental Index (MDI) scores were estimated in multivariate linear regression analyses. RESULTS: Eighty two infants underwent developmental evaluations after 12 months. The median age of evaluation was 25 months. The median 6-week cumulative rEPO dose was 3750 U/kg. In multivariate analyses, Psychomotor Developmental Index (PDI) scores were associated with transfusions, female gender, birth weight, and 5-minute Apgar scores (R(2) = 0.39). MDI scores were associated with 6-week rEPO dose, female gender, prenatal steroid treatment for > or =48 hours, and breast milk feedings (R(2) = 0.40). CONCLUSIONS: These findings identify a dose-response relationship between rEPO treatment and improved MDI scores. They are consistent with findings of adult studies and animal brain injury models and await confirmation. PMID- 19786429 TI - Disparities in access to pediatric neurooncological surgery in the United States. AB - OBJECTIVE: The objective of this study was to investigate whether disparities in access to high-volume centers for neurooncological care existed in the United States in 1988-2005. METHODS: A retrospective analysis of the Nationwide Inpatient Sample (1988-2005) was performed, with additional factors incorporated from the Area Resource File (2006). International Classification of Diseases, Ninth Revision, diagnosis/procedure coding was used to identify patients. High volume centers were defined as those with > or =50 neurosurgical cases per year. Patients >18 years of age were excluded. Covariates included age, gender, race, Charlson Index score, insurance, and county-level characteristics (including median home value, proportion of foreign born residents, and county neurosurgeon density). Multivariate analysis was performed by using multiple logistic regression models. P values of <.05 were considered statistically significant. RESULTS: A total of 4421 patients were identified; 1651 (37.34%) were admitted to high-volume centers. Overall access to high-volume centers improved slightly over the 18-year period (odds ratio [OR]: 1.04). Factors associated with greater access to high-volume centers included greater county neurosurgeon density (OR: 1.72) and greater county home value (OR: 1.66). Factors associated with worse access included Hispanic ethnicity (OR: 0.68) and each 1% increase in foreign residents per county (OR: 0.59). All reported P values were <.05. CONCLUSION: This study demonstrates that racial and socioeconomic disparities in access to high-volume neurooncological care exist for the pediatric population. We also identify numerous prehospital factors that potentially contribute to persistent disparities and may be amenable to change through national health policy interventions. PMID- 19786430 TI - Relationship of serum S100B levels and intracranial injury in children with closed head trauma. AB - OBJECTIVE: To determine if serum levels of S100B are higher in children with CHT and ICI as detected by cranial CT and if long bone fractures affect the level of S100B in children with CHT and skeletal injury. METHODS: Children <18 years of age who presented to an urban pediatric emergency department or were transferred from a referral hospital within 6 hours after accidental closed head trauma and who underwent cranial computed tomography were enrolled prospectively. Mean serum S100B levels for children with or without intracranial injury (ICI) and long-bone fractures were evaluated through analysis of covariance. RESULTS: One hundred fifty-two children, 24 with ICI and 128 without ICI, were enrolled prospectively. Twenty-five children had long-bone fractures. Children with ICI were significantly younger than those without ICI (6.9 vs 9.8 years; P = .01). The time of venipuncture after injury was significantly later in children with ICI (P = .03). Mean S100B levels were significantly greater for children with ICI (212.9 vs 84.4 ng/L; P = .001), children with long-bone fractures (P = .008), and nonwhite children (P = .03). After controlling for time of venipuncture, long bone fractures, and race, mean S100B levels were still greater for children with ICI (409 vs 118 ng/L; P = .001). The ability of serum S100B measurements to detect ICI, determined as the area under the curve, was 0.67. CONCLUSIONS: After controlling for time of venipuncture, long-bone fractures, and race, S100B levels were still higher in children with ICI than in those without ICI. However, the ability of serum S100B measurements to detect ICI was poor. PMID- 19786431 TI - Mastering diagnostic skills: Enhancing Proficiency in Otitis Media, a model for diagnostic skills training. AB - OBJECTIVE: We developed a program for training in the diagnosis of otitis media that included images illustrating various otoscopic findings, mnemonic guides to recollection, and discrimination sessions that included feedback and assessments of diagnostic skills. METHODS: We prepared a computerized, interactive curriculum, Enhancing Proficiency in Otitis Media (ePROM), that was centered around assemblages of clinically diverse, still and video images of tympanic membranes (TMs). To assess curriculum effectiveness, we constructed a test, the Diagnostic Ear Assessment Resource, that consisted of 50 video TM images. We administered the test to 84 residents in pediatrics or family practice who had not been exposed to ePROM and, varying the order in which the images were presented, to another group of 102 residents in the same programs both before and after exposure to ePROM. RESULTS: o Mean proportions of correct diagnoses in the Diagnostic Ear Assessment Resource were larger among residents who had been exposed to ePROM than among residents at comparable levels of training who had not been exposed (67% vs 62%; P = .007). Among residents exposed to ePROM, mean proportions of correct diagnoses were larger after exposure than before (67% vs 55%; P < .001). CONCLUSION: A structured, computerized curriculum to supplement standard clinical training can enhance residents' abilities to interpret still and video images of TMs and may improve their skills in diagnosing otitis media. PMID- 19786432 TI - Differentiating PFAPA syndrome from monogenic periodic fevers. AB - OBJECTIVES: To analyze whether there were clinical differences between genetically positive and negative patients fulfilling periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome criteria and to test the accuracy of the Gaslini diagnostic score for identifying patients with PFAPA syndrome with higher probabilities of carrying relevant mutations in genes associated with periodic fevers. METHODS: Complete clinical and genetic information was available for 393 children with periodic fever; 82 had positive genetic test results, 75 had incomplete genetic test results, and 236 had negative results for MVK, TNFRSF1A, and MEFV mutations. Current diagnostic criteria for PFAPA syndrome were applied. RESULTS: Of 393 children, 210 satisfied PFAPA syndrome criteria; 43 carried diagnostic mutations (mevalonate kinase deficiency: n = 33; tumor necrosis factor receptor-associated periodic syndrome: n = 3; familial Mediterranean fever: n = 7), 37 displayed low-penetrance mutations or incomplete genotypes, and 130 demonstrated negative genetic testing results. Genetically positive patients had higher frequencies of abdominal pain and diarrhea (P < .001), vomiting (P = .006), and cutaneous rash and arthralgia (P = .01). Genetically negative patients had a higher frequency of exudative pharyngitis (P = .010). Genetically undetermined patients showed the same pattern of symptom frequency as genetically negative patients. The Gaslini diagnostic score was able to identify 91% of genetically positive patients correctly, with a global accuracy of 66%. CONCLUSION: The Gaslini diagnostic score represents a useful tool to identify patients meeting PFAPA syndrome criteria and at low risk of carrying relevant mutations in genes associated with periodic fevers. PMID- 19786433 TI - Estimating blood loss: comparative study of the accuracy of parents and health care professionals. AB - OBJECTIVE: Hematemesis and hematochezia are not uncommon presenting complaints in children. The amount of blood loss reported by the parent is likely to influence the pediatrician's decision regarding investigations and management. Currently, there are only very limited data regarding the ability of laypersons to estimate blood losses visually. This study investigated the accuracy of parents, in comparison to pediatric health care professionals, in estimating blood loss volumes. PATIENTS AND METHODS: We performed a prospective, single-blinded study including 227 participants, comprising 131 parents, 58 nurses, and 38 doctors. Participants visually estimated the volume of 1 randomly allocated sample from each of the 2 categories: (1) 1, 5, or 10 mL of artificial blood applied to a diaper (simulated hematochezia) and (2) 5, 10, or 50 mL placed in a kidney-dish (simulated hematemesis). An "error factor" (=, estimated volume/actual volume shown) was used to facilitate comparisons. RESULTS: Parents provided the most inaccurate estimates overall, although individual accuracy varied considerably. The largest overestimate (518 mL) and the highest error factor (23.4) were recorded in a parent; overall, 71% of the estimates provided by parents were overestimates. The highest proportion of accurate estimates (+/-50% of actual volume) was recorded by nurses (29%). Doctors had a tendency to underestimate volumes (62% of the estimates were less than half the actual volume). However, there was no statistically significant difference between the performance of nurses and doctors. Health care professionals tended to overestimate small volumes and underestimate large volumes. Professional experience had no relevant impact on accuracy, nor did parental gender or age. CONCLUSIONS: Visual estimation of blood losses is highly inaccurate, both by laypersons and by health care professionals. Physicians should, therefore, base management decisions primarily on clinical findings and not overly rely on the history provided, or their own estimates. PMID- 19786434 TI - Familial factors do not confound the association between birth weight and childhood asthma. AB - OBJECTIVE: Studies have found associations between low birth weight and asthma. However, this association could be due to familial confounding. Our objective was to investigate whether fetal growth and birth weight affect the risk of asthma in childhood, controlling for gestational age (GA), and shared (familial) environment and genetic factors. PATIENT AND METHODS: Information on asthma, zygosity, birth characteristics, and potential confounders was collected for all 9- and 12-year-old twins through the Swedish Twin Register and Medical Birth Register. To obtain an overall effect of birth weight on risk of asthma, we performed cohort analyses on all twins (N = 10918). To address genetic and shared environmental confounding, we performed a co-twin control analysis by using the 157 monozygotic and 289 dizygotic same-sex twin pairs who were discordant for asthma. RESULTS: The overall rate of asthma ever was 13.7%. In the cohort analysis, the adjusted odds ratio (OR) for asthma in relation to a 1000-g decrease in birth weight was 1.57 (95% confidence interval [CI]: 1.38-1.79), and for each reduced gestational week the OR was 1.10 (95% CI: 1.07-1.13). In the co twin control analyses, a 1000-g decrease in birth weight corresponded to an OR of 1.25 (95% CI: 0.74-2.10) for dizygotic same-sex twins and 2.42 (95% CI: 1.00 5.88) for monozygotic twins. CONCLUSIONS: There is an association between fetal growth and childhood asthma that is independent of GA and shared (familial) environment and genetic factors, which indicates that fetal growth restriction affects lung development, supporting additional studies on the early metabolic and physiologic mechanisms of childhood asthma. PMID- 19786435 TI - Pediatric adverse drug events in the outpatient setting: an 11-year national analysis. AB - OBJECTIVE: Adverse drug events (ADEs) are a common complication of medical care, but few pediatric data are available describing the frequency or epidemiology of these events. We estimated the national incidence of pediatric ADEs requiring medical treatment, described the pediatric population seeking care for ADEs, and characterized the events in terms of patient symptoms and medications implicated. METHODS: Data were obtained from the National Center for Health Statistics, which collects information on patient visits to outpatient clinics and emergency departments throughout the United States. We analyzed data for children 0 to 18 years of age seeking medical treatment for an ADE between 1995 and 2005. RESULTS: The mean annual number of ADE-related visits was 585922 (95% confidence interval [CI]: 503687-668156) of which 78% occurred in outpatient clinics and 12% occurred in emergency departments. Children 0 to 4 years of age had the highest incidence of ADE-related visits, accounting for 43.2% (95% CI: 35.6%-51.2%) of visits. The most common symptom manifestations were dermatologic conditions (45.4% [95% CI: 36.9%-54.1%]) and gastrointestinal symptoms (16.5% [95% CI: 11.1%-23.8%]). The medication classes most frequently implicated in an ADE were antimicrobial agents (27.5% [95% CI: 21.5%-34.5%]), central nervous system agents (6.5% [95% CI: 4.0% 10.5%]), and hormones (6.1% [95% CI: 3.1%-11.6%]). While ADEs related to antimicrobial agents were most common among children 0 to 4 years old and decreased in frequency among older children, ADEs resulting from central nervous system agents and hormones increased in frequency among children 5 to 11 and 12 to 18 years old. CONCLUSIONS: ADEs result in a substantial number of health care visits, particularly in outpatient clinics. The incidence of ADEs and medications implicated vary by age, indicating that age-specific approaches for monitoring and preventing ADEs may be most effective. PMID- 19786436 TI - Postnatal diagnosis of Down syndrome: synthesis of the evidence on how best to deliver the news. AB - CONTEXT: Many parents of children with Down syndrome (DS) have expressed dissatisfaction with how they learned about their child's diagnosis. DS remains the most common chromosomal condition, occurring in 1 of every 733 births, with the majority of children still diagnosed postnatally. OBJECTIVE: Our goal was to review systematically all available evidence regarding how physicians should approach the conversation in which they explain DS for the first time to new parents. METHODS: We searched online databases from 1960 to 2008, including Medline and PsychInfo, as well as Web sites maintained by academic organizations (eg, American Academy of Pediatrics) and other nonprofit or private organizations (eg, the National Down Syndrome Society), by using the terms "Down syndrome," "trisomy 21," "mongolism," "prenatal diagnosis," "postnatal care," and "delivery of health care." Articles were selected that answered > or =1 research question, established a priori: (1) Who is the best person to communicate the news? (2) When is the best time to share the news? (3) Where is the best place or setting to deliver the news? (4) What information should be delivered? and (5) How should the news be communicated? All studies were evaluated for quality according to the method outlined by the US Preventative Services Task Force. Final recommendations were based on the strength of evidence. RESULTS: Parents prefer to receive the diagnosis together in a joint meeting with their obstetrician and pediatrician. The conversation should take place in a private setting as soon as a physician suspects a diagnosis of DS. Accurate and up-to-date information should be conveyed, including information about local support groups and resources. CONCLUSION: By implementing a few cost-neutral measures, physicians can deliver a postnatal diagnosis of DS in a manner that will be deemed by new parents as sensitive and appropriate. PMID- 19786437 TI - Risk factors for lower respiratory tract infection death among infants in the United States, 1999-2004. AB - OBJECTIVE: To describe maternal and birth-related risk factors associated with lower respiratory tract infection (LRTI) deaths among infants. METHODS: Records for infants with LRTI as a cause of death were examined by using the linked birth/infant death database for 1999-2004. Singleton infants dying with LRTI and a random sample of surviving singleton infants were compared for selected characteristics. RESULTS: A total of 5420 LRTI-associated infant deaths were documented in the United States during 1999-2004, for an LRTI-associated infant mortality rate of 22.3 per 100,000 live births. Rates varied according to race; the rate for American Indian/Alaska Native (AI/AN) infants was highest (53.2), followed by black (44.1), white (18.7), and Asian/Pacific Islander infants (12.3). Singleton infants with low birth weight (<2500 g) were at increased risk of dying with LRTI after controlling for other characteristics, especially black infants. Both AI/AN and black infants born with a birth weight of > or =2500 g were more likely to have died with LRTI than other infants of the same birth weight. Other risk factors associated with LRTI infant death included male gender, the third or more live birth, an Apgar score of <8, unmarried mother, mother with <12 years of education, mother <25 years of age, and mother using tobacco during pregnancy. CONCLUSIONS: Low birth weight was associated with markedly increased risk for LRTI-associated death among all of the racial groups. Among infants with a birth weight of > or =2500 g, AI/AN and black infants were at higher risk of LRTI-associated death, even after controlling for maternal and birth-related factors. Additional studies and strategies should focus on the prevention of maternal and birth-related risk factors for postneonatal LRTI and on identifying additional risk factors that contribute to elevated mortality among AI/AN and black infants. PMID- 19786438 TI - The "fear factor" for surgical masks and face shields, as perceived by children and their parents. AB - OBJECTIVE: The goal was to determine whether young children and their parents prefer physicians wearing clear face shields or surgical masks. METHODS: Eighty children (4-10 years of age) and their guardians were recruited from a pediatric emergency department. A survey and color photographs of the same male and female physicians wearing face shields and surgical masks were distributed. The parents were asked to decide which set of physicians they would prefer to care for their children and with which set of physicians they thought their children would be most comfortable. The children then were asked to decide which set of physicians they would prefer to take care of them and why. The children also were asked whether they found any of the physicians frightening and, if so, why. RESULTS: Fifty-one percent of parents preferred the pictures of physicians wearing face shields, and 62% thought that their children would choose the physicians in the face shields because their faces were visible and therefore less frightening. However, 59% of children stated that either set of physicians would be fine and neither was frightening; if given a choice, 49% would choose physicians in face shields. CONCLUSIONS: Physicians and parents have a perception that surgical masks are frightening to all children. Our study has shown that this perception is not completely true. Face shields may be a better choice, however, because both parents and children would prefer this option. PMID- 19786439 TI - Where all the children are above average. PMID- 19786440 TI - Improvement of short- and long-term outcomes for very low birth weight infants: Edmonton NIDCAP trial. AB - OBJECTIVE: Our objective was to determine the impact of Newborn Individualized Developmental Care and Assessment Program (NIDCAP)-based care on length of stay of very low birth weight (VLBW) infants. Secondary outcome measures were days of ventilation, incidence of chronic lung disease, and 18-month neurodevelopmental outcomes. METHODS: This cluster-randomized, controlled trial took place in a large NICU in Canada, with follow-up evaluation at 18 months of age, from September 1999 to September 2004. One hundred VLBW singleton infants and 10 VLBW twin sets were assigned randomly to NIDCAP-based or control care, and 90% participated in follow-up assessments. The intervention was NIDCAP-based care (N = 56), that is, care by NIDCAP-educated staff members and behavioral observations. The control group (N = 55) received standard NICU care. Statistical analyses were adjusted for cluster randomization. Although the intervention was not blinded, the pediatricians making the decisions to discharge the infants were not involved in the study, and the follow-up staff members were blinded with respect to group. RESULTS: NIDCAP group infants had reduced length of stay (median: NIDCAP: 74 days; control: 84 days; P = .003) and incidence of chronic lung disease (NIDCAP: 29%; control: 49%; odds ratio: 0.42 [95% confidence interval: 0.18-0.95]; P = .035). At 18 months of adjusted age, NIDCAP group infants had less disability, specifically mental delay (NIDCAP: 10%; control: 30%; odds ratio: 0.25 [95% confidence interval: 0.08-0.82]; P = .017). CONCLUSION: NIDCAP-based care for VLBW infants improved short- and long-term outcomes significantly. PMID- 19786441 TI - Effects of individualized developmental care in a randomized trial of preterm infants <32 weeks. AB - OBJECTIVE: The goal was to investigate the effects of the Newborn Individualized Developmental Care and Assessment Program (NIDCAP) on days of respiratory support and intensive care, growth, and neuromotor development at term age for infants born at <32 weeks. METHODS: Infants were assigned randomly, within 48 hours after birth, to a NIDCAP group or basic developmental care (control) group. The NIDCAP intervention consisted of weekly formal behavioral observations of the infants and caregiving recommendations and support for staff members and parents, as well as incubator covers and positioning aids. The control group infants were given basic developmental care, which consisted of only incubator covers and positioning aids. Outcome measures were respiratory support, intensive care, and weight of <1000 g. Growth parameters were measured weekly or biweekly and at term age. Neuromotor development was assessed at term age. RESULTS: A total of 164 infants met the inclusion criteria (NIDCAP: N = 81; control: N = 83). In-hospital mortality rates were 8 (9.9%) of 81 infants in the NIDCAP group and 3 (3.6%) of 83 infants in the control group. No differences in mean days of respiratory support (NIDCAP: 13.9 days; control: 16.3 days) or mean days of intensive care (NIDCAP: 15.2 days; control: 17.0 days) were found. Short-term growth and neuromotor development at term age showed no differences, even with correction for the duration of the intervention. CONCLUSIONS: NIDCAP developmental care had no effect on respiratory support, days of intensive care, growth, or neuromotor development at term age. PMID- 19786442 TI - Impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use. AB - OBJECTIVE: The goal was to assess the impact of universal bilirubin screening on severe hyperbilirubinemia and phototherapy use. METHODS: In this retrospective cohort study of 358086 infants of > or =35 weeks and > or =2000 g born between January 1, 1995, and June 30, 2007, we obtained demographic data, bilirubin levels, and codes for inpatient phototherapy from existing databases. We compared the incidence of high total serum bilirubin (TSB) levels and phototherapy before and after implementation of universal screening and examined risk factors for high TSB levels. RESULTS: A total of 38182 infants (10.6%) were born at facilities that had implemented universal bilirubin screening. Compared with infants born at facilities that were not screening, these infants had a 62% lower incidence of TSB levels exceeding the American Academy of Pediatrics exchange guideline (0.17% vs 0.45%; P < .001), received twice the inpatient phototherapy (9.1% vs 4.2%; P < .001), and had slightly longer birth hospitalization lengths of stay (50.9 vs 48.7 hours; P < .001). Of those receiving phototherapy, 56% after initiation of universal screening had TSB levels at which phototherapy was recommended by the guideline, compared with 70% before screening. The adjusted odds ratio for developing TSB levels exceeding the guideline value was 0.28 (95% confidence interval: 0.20-0.40) for those born at a facility using TSB screening and 0.28 (95% confidence interval: 0.19-0.42) for those born at a facility using transcutaneous bilirubin screening. CONCLUSIONS: Universal bilirubin screening was associated with a significantly lower incidence of severe hyperbilirubinemia but also with increased phototherapy use. PMID- 19786443 TI - Transcutaneous bilirubin nomogram for prediction of significant neonatal hyperbilirubinemia. AB - OBJECTIVE: The goal was to develop a predictive nomogram, based on transcutaneous bilirubin (TcB) measurements, for assessment of the risk of significant hyperbilirubinemia in healthy term and near-term neonates. METHODS: A total of 10382 TcB measurements were performed with 2039 healthy neonates (gestational age of > or =35 weeks and birth weight of > or =2000 g), with a BiliCheck bilirubinometer (SpectRx, Norcross, GA), at designated time points between 12 and 120 hours of life. According to their severity, these TcB measurements were selectively cross-checked with a direct spectrophotometric device, and significant hyperbilirubinemia was defined on the basis of the hour-specific threshold values for phototherapy proposed by the American Academy of Pediatrics. With the use of likelihood ratios (LRs), the high- and low-risk demarcators for each designated time were calculated and presented on an hour-specific nomogram. RESULTS: Significant hyperbilirubinemia was documented for 122 neonates (6%). At 24 hours of life, the high-risk zone of the nomogram had 73.9% sensitivity and a positive LR of 12.1 in predicting significant hyperbilirubinemia, whereas the low risk zone had 97.7% sensitivity and a negative LR of 0.04. At 48 hours, the high risk zone had 90% sensitivity and a positive LR of 12.1, whereas the low-risk zone had 98.8% sensitivity and a negative LR of 0.02. In our study population, the probability of significant hyperbilirubinemia would be >35% for values in the high-risk zone and <0.5% for values in the low-risk zone of the nomogram. CONCLUSIONS: We provide a predictive TcB tool that could allow for a noninvasive, risk-based approach to neonatal hyperbilirubinemia. PMID- 19786444 TI - Family-based treatment of severe pediatric obesity: randomized, controlled trial. AB - OBJECTIVE: We evaluated the efficacy of family-based, behavioral weight control in the management of severe pediatric obesity. METHODS: Participants were 192 children 8.0 to 12.0 years of age (mean +/- SD: 10.2 +/- 1.2 years). The average BMI percentile for age and gender was 99.18 (SD: 0.72). Families were assigned randomly to the intervention or usual care. Assessments were conducted at baseline, 6 months, 12 months, and 18 months. The primary outcome was percent overweight (percent over the median BMI for age and gender). Changes in blood pressure, body composition, waist circumference, and health-related quality of life also were evaluated. Finally, we examined factors associated with changes in child percent overweight, particularly session attendance. RESULTS: Intervention was associated with significant decreases in child percent overweight, relative to usual care, at 6 months. Intent-to-treat analyses documented that intervention was associated with a 7.58% decrease in child percent overweight at 6 months, compared with a 0.66% decrease with usual care, but differences were not significant at 12 or 18 months. Small significant improvements in medical outcomes were observed at 6 and 12 months. Children who attended > or =75% of intervention sessions maintained decreases in percent overweight through 18 months. Lower baseline percent overweight, better attendance, higher income, and greater parent BMI reduction were associated with significantly greater reductions in child percent overweight at 6 months among intervention participants. CONCLUSIONS: Intervention was associated with significant short term reductions in obesity and improvements in medical parameters and conferred longer-term weight change benefits for children who attended > or =75% of sessions. PMID- 19786446 TI - Do parents understand growth charts? A national, Internet-based survey. AB - OBJECTIVE: The objective of this study was to assess parental knowledge and understanding of growth charts. METHODS: An online survey was conducted with 1000 parents selected to be demographically representative of the US population. Questions explored awareness of, knowledge of, and attitudes toward growth monitoring, as well as the ability to interpret growth chart data. RESULTS: Seventy-nine percent of parents surveyed claimed to have seen a growth chart before, with the majority thinking that they understood it well. Sixty-four percent of parents thought it was important to be shown growth charts to see how their child was growing, and 40% expressed the need to see their child's growth chart as confirmation of their health care provider's verbal interpretation. However, when provided with multiple-choice questions and answers, only 64% could identify a child's weight when shown a plotted point on a growth chart. Ninety six percent had heard of the term "percentile," but only 68% identified the percentile of the plotted point, and only 56% could identify the definition of percentile. Up to 77% interpreted incorrectly charts containing height/weight measurements in tandem. CONCLUSIONS: Although growth charts are used frequently as visual aids to educate parents about their children's growth, many parents cannot comprehend the data. This finding is significant because many parents prefer to be shown growth charts by their health care provider, and many parents report recording their children's measurements on growth charts at home. PMID- 19786445 TI - Predictors of early adult outcomes in pediatric-onset obsessive-compulsive disorder. AB - OBJECTIVE: The aim of this study was to determine the childhood clinical predictors of early adult outcomes in pediatric-onset obsessive-compulsive disorder (OCD) and to assess whether dimensional subtypes of OCD and the presence of comorbid tic symptoms influence long-term outcomes. METHODS: We conducted a longitudinal cohort study in which 45 of 62 eligible children with OCD were reassessed an average of 9 years later, in early adulthood. Main outcome measures included expert-rated, obsessive-compulsive (OC) symptom severity and time to remission of OC symptoms. Baseline clinical characteristics were evaluated in terms of their influence on OCD severity in adulthood and time to remission of OC symptoms. RESULTS: Forty-four percent of subjects were determined to have subclinical OC symptoms at the follow-up evaluation. The absence of a comorbid tic disorder and the presence of prominent hoarding symptoms were associated with the persistence of OCD symptoms. Female gender, earlier age at childhood assessment, later age of OCD onset, more-severe childhood OCD symptoms, and comorbid oppositional defiant disorder also were associated with persistence of OCD symptoms into adulthood. CONCLUSIONS: These results confirm that a significant proportion of treated children with OCD experience remission by adulthood. The presence of comorbid tics heralds a positive outcome, whereas primary hoarding symptoms are associated with persistent OCD. PMID- 19786447 TI - Research during pediatric residency training: outcome of a senior resident block rotation. AB - BACKGROUND: The Pediatric Residency Review Committee requires programs to provide a curriculum that advances residents' knowledge of the basic principles of research. In July 2002, the Boston Combined Residency Program instituted a 3 month career-development block (CDB) rotation. During the rotation residents pursue an academic or clinical project under mentorship by a faculty member. OBJECTIVE: Our objective for this study was to evaluate the outcome of the CDB rotation since it was implemented. METHODS: A survey was administered to 165 residents who completed the CDB rotation. RESULTS: Of 165 residents, 136 (82%) responded to the survey. Of 122 residents who reported the type of project they conducted, 59 (48%) completed a clinical/health services project, 24 (20%) completed a project in education or curriculum development, and 7 (6%) worked in basic science. Thirty-five residents (27%) received funding to support their work. Thirty-five residents (26%) presented at national meetings such as the Pediatric Academic Societies Meeting. Fifteen (11%) residents have had manuscripts accepted for publication, and 22 (16%) additional residents have submitted manuscripts for publication. Factors associated with successful publication included having received funding (odds ratio: 3.37 [95% confidence interval: 1.34-8.42]) and the nature of the research project (odds ratio: 3.55 [95% confidence interval: 1.40-9.04]). The majority of residents (84%) stated that the CDB rotation enhanced residency training. CONCLUSIONS: A dedicated academic rotation that includes protected time, senior faculty mentorship, and program funding, can lead to productive research accomplishments by pediatric residents. Support of academic work during residency training may encourage engagement in a variety of academically oriented activities. PMID- 19786448 TI - Beliefs and barriers to follow-up after an emergency department asthma visit: a randomized trial. AB - BACKGROUND: Studies in urban emergency departments (EDs) have found poor quality of chronic asthma care and identified beliefs and barriers associated with low rates of follow-up with a primary care provider (PCP). OBJECTIVES: To develop an ED-based intervention including asthma symptom screening, a video addressing beliefs and a mailed reminder; and measure the effect on PCP follow-up and asthma related outcomes. METHODS: This randomized, controlled trial enrolled children aged 1 to 18 years who were discharged after asthma treatment in an urban pediatric ED. Control subjects received instructions to follow-up with a PCP within 3 to 5 days. In addition, intervention subjects (1) received a letter to take to their PCP if they screened positive for persistent asthma symptoms, (2) viewed a video featuring families and providers discussing the importance of asthma control, and (3) received a mailed reminder to follow-up with a PCP. All subjects were contacted by telephone 1, 3, and 6 months after the ED visit, and follow-up was confirmed by PCP record review. Asthma-related quality of life (AQoL), symptoms, and beliefs about asthma care were assessed by using validated surveys. RESULTS: A total of 433 subjects were randomly assigned, and baseline measures were similar between study groups. After the intervention and before ED discharge, intervention subjects were more likely to endorse beliefs about the benefits of follow-up than controls. However, rates of PCP follow-up during the month after the ED visit (44.5%) were similar to control subjects (43.8%) as were AQoL, medication use, and ED visits. CONCLUSIONS: An ED-based intervention influenced beliefs but did not increase PCP follow-up or asthma-related outcomes. PMID- 19786449 TI - An analysis of the association between parental acculturation and children's medication use. AB - OBJECTIVES: We examined how Hispanic children, with stratification according to language to approximate acculturation, differed with respect to sociodemographic characteristics and medication use. We also examined how different factors were associated with the use of different classes of prescription medications. METHODS: We used data from the 2004 Medical Expenditure Panel Survey linked to the National Health Interview Survey. Independent variables were grouped as predisposing characteristics, enabling factors, perceived need, and evaluated need. Multivariate logistic regression was used to assess the impact of independent variables on the outcomes of overall and specific types of medication use. RESULTS: Hispanic, Spanish-interviewed children were less likely to have a usual source of care than were Hispanic, English-interviewed subjects. Both groups had lower odds of using any prescription medication, compared with white children, which was explained largely by having a usual source of care. The lower use of psychiatric medications in the Spanish-interviewed group was not explained by the independent variables, whereas the difference in the use of antibiotics was. CONCLUSIONS: There are differences between Hispanic children according to acculturation, and acculturation affects prescription medication use. These findings may be used to address more specifically the needs of Hispanic children, particularly mental health needs. PMID- 19786450 TI - Systematic review of screening for bilirubin encephalopathy in neonates. AB - CONTEXT: Severe neonatal hyperbilirubinemia is associated with chronic bilirubin encephalopathy (kernicterus). OBJECTIVE: To systematically review the effectiveness of specific screening modalities to prevent neonatal bilirubin encephalopathy. METHODS: We identified studies through Medline searches, perusing reference lists and by consulting with US Preventive Services Task Force lead experts. We included English-language publications evaluating the effects of screening for bilirubin encephalopathy using early total serum bilirubin (TSB), transcutaneous bilirubin (TcB) measurements, or risk scores. Severe hyperbilirubinemia was used as a surrogate for possible chronic bilirubin encephalopathy, because no studies directly evaluated the latter as an outcome. We calculated the sensitivity and specificity of early TSB, TcB measurements, or risk scores in detecting hyperbilirubinemia. RESULTS: Ten publications (11 studies) were eligible. Seven (2 prospective) studies evaluated the ability of risk factors (n = 3), early TSB (n = 3), TcB (n = 2), or combinations of risk factors and early TSB (n = 1) to predict hyperbilirubinemia (typically TSB > 95th hour-specific percentile 24 hours to 30 days postpartum). Screening had good ability to detect hyperbilirubinemia: reported area-under-the-curve values ranged between 0.69 and 0.84, and reported sensitivities and specificities suggested similar diagnostic ability. Indirect evidence from 3 descriptive uncontrolled studies suggests favorable associations between initiation of screening and decrease in hyperbilirubinemia rates, and rates of treatment or readmissions for hyperbilirubinemia compared with the baseline of no screening. No study assessed harms of screening. CONCLUSIONS: Effects of screening on the rates of bilirubin encephalopathy are unknown. Although screening can predict hyperbilirubinemia, there is no robust evidence to suggest that screening is associated with favorable clinical outcomes. PMID- 19786451 TI - Screening of infants for hyperbilirubinemia to prevent chronic bilirubin encephalopathy: US Preventive Services Task Force recommendation statement. AB - DESCRIPTION: Recommendation on screening newborn infants, based on a recent supplemental review of a 2003 Agency for Healthcare Research and Quality evidence report on the effectiveness of various screening strategies for preventing the development of chronic bilirubin encephalopathy, performed at the request of the US Preventive Services Task Force (USPSTF). This topic has not been previously considered by the USPSTF. METHODS: The USPSTF reviewed experimental and observational studies that included comparison groups. For harms associated with phototherapy, case reports or case series were also included. CONCLUSION: The evidence is insufficient to assess the balance of benefits and harms of screening for hyperbilirubinemia to prevent chronic bilirubin encephalopathy (I statement). PMID- 19786452 TI - Hyperbilirubinemia in the newborn infant > or =35 weeks' gestation: an update with clarifications. PMID- 19786453 TI - Universal bilirubin screening, guidelines, and evidence. PMID- 19786454 TI - Bilirubin screening for normal newborns: a critique of the hour-specific bilirubin nomogram. PMID- 19786456 TI - Who should administer insulin in schools? Sorting out the controversy. PMID- 19786455 TI - NIDCAP: testing the effectiveness of a relationship-based comprehensive intervention. PMID- 19786457 TI - NIDCAP: new controversial evidence for its effectiveness. PMID- 19786458 TI - The prenatal visit. AB - As advocates for children and their families, pediatricians can support and guide expectant parents in the prenatal period. Prenatal visits allow the pediatrician to gather basic information from expectant parents, offer them information and advice, and identify high-risk conditions that may require special care. In addition, a prenatal visit is the first step in establishing a relationship between the family and the pediatrician (the infant's medical home) and in helping the parents develop parenting skills and confidence. There are several possible formats for this first visit. The one used depends on the experience and preference of the parents, the style of the pediatrician's practice, and pragmatic issues of reimbursement. PMID- 19786459 TI - Policy statement--guidance for the administration of medication in school. AB - Many children who take medications require them during the school day. This policy statement is designed to guide prescribing health care professionals, school physicians, and school health councils on the administration of medications to children at school. All districts and schools need to have policies and plans in place for safe, effective, and efficient administration of medications at school. Having full-time licensed registered nurses administering all routine and emergency medications in schools is the best situation. When a licensed registered nurse is not available, a licensed practical nurse may administer medications. When a nurse cannot administer medication in school, the American Academy of Pediatrics supports appropriate delegation of nursing services in the school setting. Delegation is a tool that may be used by the licensed registered school nurse to allow unlicensed assistive personnel to provide standardized, routine health services under the supervision of the nurse and on the basis of physician guidance and school nursing assessment of the unique needs of the individual child and the suitability of delegation of specific nursing tasks. Any delegation of nursing duties must be consistent with the requirements of state nurse practice acts, state regulations, and guidelines provided by professional nursing organizations. Long-term, emergency, and short term medications; over-the-counter medications; alternative medications; and experimental drugs that are administered as part of a clinical trial are discussed in this statement. This statement has been endorsed by the American School Health Association. PMID- 19786460 TI - Hearing assessment in infants and children: recommendations beyond neonatal screening. AB - Congenital or acquired hearing loss in infants and children has been linked with lifelong deficits in speech and language acquisition, poor academic performance, personal-social maladjustments, and emotional difficulties. Identification of hearing loss through neonatal hearing screening, regular surveillance of developmental milestones, auditory skills, parental concerns, and middle-ear status and objective hearing screening of all infants and children at critical developmental stages can prevent or reduce many of these adverse consequences. This report promotes a proactive, consistent, and explicit process for the early identification of children with hearing loss in the medical home. An algorithm of the recommended approach has been developed to assist in the detection and documentation of, and intervention for, hearing loss. PMID- 19786463 TI - Cohort profile: the Canadian HIV-hepatitis C co-infection cohort study. PMID- 19786464 TI - Health care for foster kids: fix the system, save a child. PMID- 19786462 TI - Racial differences in the association between body mass index and serum IGF1, IGF2, and IGFBP3. AB - African-American (AA) race/ethnicity, lower body mass index (BMI), and higher IGF1 levels are associated with premenopausal breast cancer risk. This cross sectional analysis investigated whether BMI or BMI at age 21 years contributes to racial differences in IGF1, IGF2, IGF-binding protein 3 (IGFBP3), or free IGF1. Participants included 816 white and 821 AA women between ages 40 and 79 years across a wide BMI range (18.5-40 kg/m(2)). Compared with white women, AA women had higher mean IGF1 (146.3 vs 134.4 ng/ml) and free IGF1 (0.145 vs 0.127) levels, and lower IGF2 (1633.0 vs 1769.3 ng/ml) and IGFBP3 (3663.3 vs 3842.5 ng/ml) levels (all P<0.01; adjusted for age, height, BMI, BMI at age 21 years, and menopausal status). Regardless of race, IGF1 and free IGF1 levels rose sharply as BMI increased to 22-24 kg/m(2), and then declined thereafter, while IGF2 and IGFBP3 levels tended to rise with BMI. In contrast, BMI at age 21 years was inversely associated with all IGF levels, but only among white women (P interaction=0.01). With the decline in IGF1 with BMI at age 21 years among whites, racial differences in IGF1 significantly increased among women who were obese in early adulthood. In summary, BMI was associated with IGF1 levels regardless of race/ethnicity, while obesity during childhood or young adulthood may have a greater impact on IGF1 levels among white women. The effects of obesity throughout life on the IGF axis and racial differences in breast cancer risk require study. PMID- 19786465 TI - Chemical-by-chemical bans leave people at risk. PMID- 19786466 TI - Listeriosis complicating pregnancy. PMID- 19786467 TI - Episodic palpitations in pheochromocytoma. PMID- 19786468 TI - Incidence and causes of heparin-induced skin lesions. AB - BACKGROUND: Little is known about the incidence and causes of heparin-induced skin lesions. The 2 most commonly reported causes of heparin-induced skin lesions are immune-mediated heparin-induced thrombocytopenia and delayed-type hypersensitivity reactions. METHODS: We prospectively examined consecutive patients who received subcutaneous heparin (most often enoxaparin or nadroparin) for the presence of heparin-induced skin lesions. If such lesions were identified, we performed a skin biopsy, platelet count measurements, and antiplatelet-factor 4 antibody and allergy testing. RESULTS: We enrolled 320 patients. In total, 24 patients (7.5%, 95% confidence interval [CI] 4.7%-10.6%) had heparin-induced skin lesions. Delayed-type hypersensitivity reactions were identified as the cause in all 24 patients. One patient with histopathologic evidence of delayed-type hypersensitivity tested positive for antiplatelet-factor 4 antibodies. We identified the following risk factors for heparin-induced skin lesions: a body mass index greater than 25 (odds ratio [OR] 4.6, 95% CI 1.7 15.3), duration of heparin therapy longer than 9 days (OR 5.9, 95% CI 1.9-26.3) and female sex (OR 3.0, 95% CI 1.1-8.8). INTERPRETATION: Heparin-induced skin lesions are relatively common, have identifiable risk factors and are commonly caused by a delayed-type hypersensitivity reaction (type IV allergic response). PMID- 19786469 TI - Zen and the art of painting. PMID- 19786472 TI - Tales from the C. difficile trenches. PMID- 19786471 TI - Management of asthma in adults. PMID- 19786474 TI - Medical faculties decimated by violence in Iraq. PMID- 19786473 TI - Australia's flying doctors tackle Third World health issues. PMID- 19786475 TI - Defining moments. PMID- 19786476 TI - Pandemic (H1N1) 2009 lives in some people for at least eight days after symptoms develop. PMID- 19786477 TI - Massachusetts considering payment reform. PMID- 19786478 TI - Six of the top achievements in Canadian health research. PMID- 19786479 TI - Celebrating 8 projects that improved our world. PMID- 19786480 TI - Code STEMI: implementation of a city-wide program for rapid assessment and management of myocardial infarction. PMID- 19786481 TI - Male circumcision: a new approach to reducing HIV transmission. PMID- 19786482 TI - Integration of heterogeneous expression data sets extends the role of the retinol pathway in diabetes and insulin resistance. AB - MOTIVATION: Type 2 diabetes is a chronic metabolic disease that involves both environmental and genetic factors. To understand the genetics of type 2 diabetes and insulin resistance, the DIabetes Genome Anatomy Project (DGAP) was launched to profile gene expression in a variety of related animal models and human subjects. We asked whether these heterogeneous models can be integrated to provide consistent and robust biological insights into the biology of insulin resistance. RESULTS: We perform integrative analysis of the 16 DGAP data sets that span multiple tissues, conditions, array types, laboratories, species, genetic backgrounds and study designs. For each data set, we identify differentially expressed genes compared with control. Then, for the combined data, we rank genes according to the frequency with which they were found to be statistically significant across data sets. This analysis reveals RetSat as a widely shared component of mechanisms involved in insulin resistance and sensitivity and adds to the growing importance of the retinol pathway in diabetes, adipogenesis and insulin resistance. Top candidates obtained from our analysis have been confirmed in recent laboratory studies. PMID- 19786483 TI - LIBRUS: combined machine learning and homology information for sequence-based ligand-binding residue prediction. AB - MOTIVATION: Identifying residues that interact with ligands is useful as a first step to understanding protein function and as an aid to designing small molecules that target the protein for interaction. Several studies have shown that sequence features are very informative for this type of prediction, while structure features have also been useful when structure is available. We develop a sequence based method, called LIBRUS, that combines homology-based transfer and direct prediction using machine learning and compare it to previous sequence-based work and current structure-based methods. RESULTS: Our analysis shows that homology based transfer is slightly more discriminating than a support vector machine learner using profiles and predicted secondary structure. We combine these two approaches in a method called LIBRUS. On a benchmark of 885 sequence-independent proteins, it achieves an area under the ROC curve (ROC) of 0.83 with 45% precision at 50% recall, a significant improvement over previous sequence-based efforts. On an independent benchmark set, a current method, FINDSITE, based on structure features achieves an ROC of 0.81 with 54% precision at 50% recall, while LIBRUS achieves an ROC of 0.82 with 39% precision at 50% recall at a smaller computational cost. When LIBRUS and FINDSITE predictions are combined, performance is increased beyond either reaching an ROC of 0.86 and 59% precision at 50% recall. AVAILABILITY: Software developed for this study is available at http://bioinfo.cs.umn.edu/supplements/binf2009 along with Supplementary data on the study. PMID- 19786484 TI - Detection of new protein domains using co-occurrence: application to Plasmodium falciparum. AB - MOTIVATION: Hidden Markov models (HMMs) have proved to be a powerful tool for protein domain identification in newly sequenced organisms. However, numerous domains may be missed in highly divergent proteins. This is the case for Plasmodium falciparum proteins, the main causal agent of human malaria. RESULTS: We propose a method to improve the sensitivity of HMM domain detection by exploiting the tendency of the domains to appear preferentially with a few other favorite domains in a protein. When sequence information alone is not sufficient to warrant the presence of a particular domain, our method enables its detection on the basis of the presence of other Pfam or InterPro domains. Moreover, a shuffling procedure allows us to estimate the false discovery rate associated with the results. Applied to P. falciparum, our method identifies 585 new Pfam domains (versus the 3683 already known domains in the Pfam database) with an estimated error rate <20%. These new domains provide 387 new Gene Ontology (GO) annotations to the P. falciparum proteome. Analogous and congruent results are obtained when applying the method to related Plasmodium species (P. vivax and P. yoelii). AVAILABILITY: Supplementary Material and a database of the new domains and GO predictions achieved on Plasmodium proteins are available at http://www.lirmm.fr/~terrapon/codd/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 19786485 TI - Use of serial qualitative interviews to understand patients' evolving experiences and needs. PMID- 19786486 TI - Healthcare associated infections. PMID- 19786487 TI - Donors raise pound3.2bn for free health care in world's poorest countries. PMID- 19786488 TI - African leaders join forces to boost fight against malaria. PMID- 19786489 TI - Effects of videogame distraction and a virtual reality type head-mounted display helmet on cold pressor pain in young elementary school-aged children. AB - OBJECTIVE: This study examined the effects of videogame distraction and a virtual reality (VR) type head-mounted display helmet for children undergoing cold pressor pain. METHODS: Fifty children between the ages of 6 and 10 years underwent a baseline cold pressor trial followed by two cold pressor trials in which interactive videogame distraction was delivered via a VR helmet or without a VR helmet in counterbalanced order. RESULTS: As expected, children demonstrated significant improvements in pain threshold and pain tolerance during both distraction conditions. However, the two distraction conditions did not differ in effectiveness. CONCLUSIONS: Using the VR helmet did not result in improved pain tolerance over and above the effects of interactive videogame distraction without VR technology. Clinical implications and possible developmental differences in elementary school-aged children's ability to use VR technology are discussed. PMID- 19786491 TI - Doctors explore research potential of blood samples from newborns. PMID- 19786494 TI - Fine-grained annotation and classification of de novo predicted LTR retrotransposons. AB - Long terminal repeat (LTR) retrotransposons and endogenous retroviruses (ERVs) are transposable elements in eukaryotic genomes well suited for computational identification. De novo identification tools determine the position of potential LTR retrotransposon or ERV insertions in genomic sequences. For further analysis, it is desirable to obtain an annotation of the internal structure of such candidates. This article presents LTRdigest, a novel software tool for automated annotation of internal features of putative LTR retrotransposons. It uses local alignment and hidden Markov model-based algorithms to detect retrotransposon associated protein domains as well as primer binding sites and polypurine tracts. As an example, we used LTRdigest results to identify 88 (near) full-length ERVs in the chromosome 4 sequence of Mus musculus, separating them from truncated insertions and other repeats. Furthermore, we propose a work flow for the use of LTRdigest in de novo LTR retrotransposon classification and perform an exemplary de novo analysis on the Drosophila melanogaster genome as a proof of concept. Using a new method solely based on the annotations generated by LTRdigest, 518 potential LTR retrotransposons were automatically assigned to 62 candidate groups. Representative sequences from 41 of these 62 groups were matched to reference sequences with >80% global sequence similarity. PMID- 19786493 TI - A search for small noncoding RNAs in Staphylococcus aureus reveals a conserved sequence motif for regulation. AB - Bioinformatic analysis of the intergenic regions of Staphylococcus aureus predicted multiple regulatory regions. From this analysis, we characterized 11 novel noncoding RNAs (RsaA-K) that are expressed in several S. aureus strains under different experimental conditions. Many of them accumulate in the late exponential phase of growth. All ncRNAs are stable and their expression is Hfq independent. The transcription of several of them is regulated by the alternative sigma B factor (RsaA, D and F) while the expression of RsaE is agrA-dependent. Six of these ncRNAs are specific to S. aureus, four are conserved in other Staphylococci, and RsaE is also present in Bacillaceae. Transcriptomic and proteomic analysis indicated that RsaE regulates the synthesis of proteins involved in various metabolic pathways. Phylogenetic analysis combined with RNA structure probing, searches for RsaE-mRNA base pairing, and toeprinting assays indicate that a conserved and unpaired UCCC sequence motif of RsaE binds to target mRNAs and prevents the formation of the ribosomal initiation complex. This study unexpectedly shows that most of the novel ncRNAs carry the conserved C-rich motif, suggesting that they are members of a class of ncRNAs that target mRNAs by a shared mechanism. PMID- 19786495 TI - Nuclear export factor RBM15 facilitates the access of DBP5 to mRNA. AB - The conserved mRNA export receptor NXF1 (Mex67 in yeast) assembles with messenger ribonucleoproteins (mRNP) in the nucleus and guides them through the nuclear pore complex into the cytoplasm. The DEAD family RNA helicase Dbp5 is essential for nuclear export of mRNA and is thought to dissociate Mex67 from mRNP upon translocation, thereby generating directional passage. However, the molecular mechanism by which Dbp5 recognizes Mex67-containing mRNP is not clear. Here we report that the human NXF1-binding protein RBM15 binds specifically to human DBP5 and facilitates its direct contact with mRNA in vivo. We found that RBM15 is targeted to the nuclear envelope, where it colocalizes extensively with DBP5 and NXF1. Gene silencing of RBM15 leads to cytoplasmic depletion and nuclear accumulation of general mRNA as well as individual endogenous transcripts, indicating that RBM15 is required for efficient mRNA export. We propose a model in which RBM15 acts locally at the nuclear pore complex, by facilitating the recognition of NXF1-mRNP complexes by DBP5 during translocation, thereby contributing to efficient mRNA export. PMID- 19786496 TI - Revisiting the planarity of nucleic acid bases: Pyramidilization at glycosidic nitrogen in purine bases is modulated by orientation of glycosidic torsion. AB - We describe a novel, fundamental property of nucleobase structure, namely, pyramidilization at the N1/9 sites of purine and pyrimidine bases. Through a combined analyses of ultra-high-resolution X-ray structures of both oligonucleotides extracted from the Nucleic Acid Database and isolated nucleotides and nucleosides from the Cambridge Structural Database, together with a series of quantum chemical calculations, molecular dynamics (MD) simulations, and published solution nuclear magnetic resonance (NMR) data, we show that pyramidilization at the glycosidic nitrogen is an intrinsic property. This property is common to isolated nucleosides and nucleotides as well as oligonucleotides-it is also common to both RNA and DNA. Our analysis suggests that pyramidilization at N1/9 sites depends in a systematic way on the local structure of the nucleoside. Of note, the pyramidilization undergoes stereo inversion upon reorientation of the glycosidic bond. The extent of the pyramidilization is further modulated by the conformation of the sugar ring. The observed pyramidilization is more pronounced for purine bases, while for pyrimidines it is negligible. We discuss how the assumption of nucleic acid base planarity can lead to systematic errors in determining the conformation of nucleotides from experimental data and from unconstrained MD simulations. PMID- 19786497 TI - TransmiR: a transcription factor-microRNA regulation database. AB - MicroRNAs (miRNAs) regulate gene expression at the posttranscriptional level and are therefore important cellular components. As is true for protein-coding genes, the transcription of miRNAs is regulated by transcription factors (TFs), an important class of gene regulators that act at the transcriptional level. The correct regulation of miRNAs by TFs is critical, and increasing evidence indicates that aberrant regulation of miRNAs by TFs can cause phenotypic variations and diseases. Therefore, a TF-miRNA regulation database would be helpful for understanding the mechanisms by which TFs regulate miRNAs and understanding their contribution to diseases. In this study, we manually surveyed approximately 5000 reports in the literature and identified 243 TF-miRNA regulatory relationships, which were supported experimentally from 86 publications. We used these data to build a TF-miRNA regulatory database (TransmiR, http://cmbi.bjmu.edu.cn/transmir), which contains 82 TFs and 100 miRNAs with 243 regulatory pairs between TFs and miRNAs. In addition, we included references to the published literature (PubMed ID) information about the organism in which the relationship was found, whether the TFs and miRNAs are involved with tumors, miRNA function annotation and miRNA-associated disease annotation. TransmiR provides a user-friendly interface by which interested parties can easily retrieve TF-miRNA regulatory pairs by searching for either a miRNA or a TF. PMID- 19786498 TI - A protein-protein interaction guided method for competitive transcription factor binding improves target predictions. AB - An important milestone in revealing cells' functions is to build a comprehensive understanding of transcriptional regulation processes. These processes are largely regulated by transcription factors (TFs) binding to DNA sites. Several TF binding site (TFBS) prediction methods have been developed, but they usually model binding of a single TF at a time albeit few methods for predicting binding of multiple TFs also exist. In this article, we propose a probabilistic model that predicts binding of several TFs simultaneously. Our method explicitly models the competitive binding between TFs and uses the prior knowledge of existing protein-protein interactions (PPIs), which mimics the situation in the nucleus. Modeling DNA binding for multiple TFs improves the accuracy of binding site prediction remarkably when compared with other programs and the cases where individual binding prediction results of separate TFs have been combined. The traditional TFBS prediction methods usually predict overwhelming number of false positives. This lack of specificity is overcome remarkably with our competitive binding prediction method. In addition, previously unpredictable binding sites can be detected with the help of PPIs. Source codes are available at http://www.cs.tut.fi/ approximately harrila/. PMID- 19786500 TI - Learning disability nurse education: an opportunity to contribute to shaping the future? PMID- 19786499 TI - Bioinformatics and functional analysis define four distinct groups of AlkB DNA dioxygenases in bacteria. AB - The iron(II)- and 2-oxoglutarate (2OG)-dependent dioxygenase AlkB from Escherichia coli (EcAlkB) repairs alkylation damage in DNA by direct reversal. EcAlkB substrates include methylated bases, such as 1-methyladenine (m(1)A) and 3 methylcytosine (m(3)C), as well as certain bulkier lesions, for example the exocyclic adduct 1,N(6)-ethenoadenine (epsilonA). EcAlkB is the only bacterial AlkB protein characterized to date, and we here present an extensive bioinformatics and functional analysis of bacterial AlkB proteins. Based on sequence phylogeny, we show that these proteins can be subdivided into four groups: denoted 1A, 1B, 2A and 2B; each characterized by the presence of specific conserved amino acid residues in the putative nucleotide-recognizing domain. A scattered distribution of AlkB proteins from the four different groups across the bacterial kingdom indicates a substantial degree of horizontal transfer of AlkB genes. DNA repair activity was associated with all tested recombinant AlkB proteins. Notably, both a group 2B protein from Xanthomonas campestris and a group 2A protein from Rhizobium etli repaired etheno adducts, but had negligible activity on methylated bases. Our data indicate that the majority, if not all, of the bacterial AlkB proteins are DNA repair enzymes, and that some of these proteins do not primarily target methylated bases. PMID- 19786501 TI - Service users leading the way: focus group methodology in developing accessible information DVDs with people with learning disabilities. AB - The English government sees it important to view service users as active partners in the delivery of accessible resources. The current article follows a brief report which described an innovative project on developing an accessible DVD explaining the Birmingham Clinical Psychology Service to people with learning disabilities. The article describes three focus groups involving adults with learning disabilities that met to reflect and evaluate the accessibility of the DVD. This process formed the evaluative phase of the DVD development project where people with learning disabilities evaluated the accessibility, level of understanding, and clarity of the DVD content. The DVD was rated positively by the focus groups, and minor changes were made to the final version of the DVD. The article also reflects upon the use of focus groups as a methodological approach in researching the views of people with learning disabilities. PMID- 19786502 TI - Acceptance and Commitment Therapy (ACT) with a learning disabled young person experiencing anxious and obsessive thoughts. AB - This case study describes how the ACT model was adapted to treat anxious and obsessive thoughts in a young person with moderate/severe learning disabilities. Using mindfulness and ACT-based experiential activities, the client learned to notice her thoughts and distance herself from their literal content. The negative impact that the client's anxious thoughts had on her life was reduced and she was able to return to a part-time college course. The article describes how the client engaged with some ACT-based activities, such as mindfulness and defusion exercises. The outcome suggests that the experiential, activity-based nature of ACT may offer a more accessible intervention model for learning disabled people than traditional CBT models based on verbal reasoning skills. However, the intervention also required considerable individual adaptation and it is likely that this will be the case in work with people with learning disabilities. PMID- 19786503 TI - Patient satisfaction with a hepatitis B vaccination programme among persons with an intellectual disability. AB - This article demonstrates that a patient satisfaction survey can be carried out to evaluate the acceptability of a hepatitis B vaccination programme among persons with an intellectual disability. In this exploratory study, involving six clients, 41 care staff and three managers of intellectual disability services, core themes were identified on the acceptability of the programme. The following recommendations are made: a respectful attitude should be shown to all clients by the healthcare providers; appropriate information about the programme should be provided that is tailored to the needs and receptive capability of all recipients and their carers; the intervention should be delivered in an environment, and by healthcare personnel, familiar to clients; carers should be attentive to the possibility of adverse effects; and explicit, ethically stringent policies should be in place on the use of physical restraint. The article makes suggestions regarding future work in assessing patient satisfaction among this client group. PMID- 19786504 TI - Learning to take the world seriously: an ethnographic study of the management of knowledge in a special school for children with intellectual disabilities. AB - This article reports on an ethnographic and sociological study of the curriculum inside a special school for students with severe intellectual disabilities in the UK. There are few such studies since it is the routing of children into the special education system that has been sociologically captivating. Bernstein's analytical approach to the study of curricula is proposed as useful since it draws attention to the structure of the curriculum and is less concerned with assumptions about its content. It also highlights the social messages that are embedded within the curriculum. The data suggest that two codes were in operation within the curriculum. The first was designed to draw the out-of-school experiences of students into the classroom for greater scrutiny. The second involved the strict regulation of 'dangerous' knowledge, that is sexual knowledge. The implications of findings are discussed in relation to curriculum development, self-identity and the strength and nature of social boundaries. PMID- 19786505 TI - Evaluation of clinical checklists for fragile X syndrome screening in Brazilian intellectually disabled males: proposal for a new screening tool. AB - Patients with fragile X syndrome present a variable phenotype, which contributes to the underdiagnosing of this condition. The use of clinical checklists in individuals with intellectual disability can help in selecting patients to be given priority in the molecular investigation of the fragile X mutation in the FMR1 gene. Some features included in checklists are better predictors than others, but they can vary among different populations and with patient age. In the present study, we evaluated 20 features listed in four clinical checklists from the literature, using a sample of 192 Brazilian male patients presenting with intellectual disability (30 positive and 162 negative for fragile X mutation). After statistical analysis, 12 out of the 20 items analyzed showed significant differences in their distributions between the two groups. These features were grouped in a new checklist that can help clinicians in their referral for fragile X testing in patients with developmental delay. PMID- 19786506 TI - Stereoselective flunoxaprofen-S-acyl-glutathione thioester formation mediated by acyl-CoA formation in rat hepatocytes. AB - Flunoxaprofen (FLX) is a chiral nonsteroidal anti-inflammatory drug that was withdrawn from clinical use because of concerns of potential hepatotoxicity. FLX undergoes highly stereoselective chiral inversion mediated through the FLX-S-acyl CoA thioester (FLX-CoA) in favor of the (R)-(-)-isomer. Acyl-CoA thioester derivatives of acidic drugs are chemically reactive species that are known to transacylate protein nucleophiles and glutathione (GSH). In this study, we investigated the relationship between the stereoselective metabolism of (R)-(-)- and (S)-(+)-FLX to FLX-CoA and the subsequent transacylation of GSH forming FLX-S acyl-glutathione (FLX-SG) in incubations with rat hepatocytes in suspension. Thus, when hepatocytes (2 million cells/ml) were treated with (R)-(-)- or (S)-(+) FLX (100 microM), both FLX-CoA and FLX-SG were detected by sensitive liquid chromatography-tandem mass spectrometry techniques. However, these derivatives were observed primarily from (R)-(-)-FLX incubation extracts, for which the formation rates of FLX-CoA and FLX-SG were rapid, reaching maximum concentrations of 42 and 2.8 nM, respectively, after 6 min of incubation. Incubations with (S) (+)-FLX over 60 min displayed 8.1 and 2.7% as much FLX-CoA and FLX-SG area under the concentration versus time curves, respectively, compared with corresponding incubations with (R)-(-)-FLX. Coincubation of lauric acid (1000 microM) with (R) (-)-FLX (10 microM) led to the complete inhibition of FLX-CoA formation and a 98% inhibition of FLX-SG formation. Reaction of authentic (R,S)-FLX-CoA (2 microM) with GSH (10 mM) in buffer (pH 7.4, 37 degrees C) showed the quantitative formation of FLX-SG after 3 h of incubation. Together, these results demonstrate the stereoselective transacylation of GSH in hepatocyte incubations containing (R)-(-)-FLX, which is consistent with bioactivation by stereoselective (R)-FLX CoA formation. PMID- 19786507 TI - Regulation of gene expression in brain tissues of rats repeatedly treated by the highly abused opioid agonist, oxycodone: microarray profiling and gene mapping analysis. AB - Although oxycodone is the most often used opioid agonist, it remains one of the most understudied drugs. We used microarray analysis to better understand the global changes in gene expression in brain tissues of rats repeatedly treated with oxycodone. Many genes were significantly regulated by oxycodone (e.g., Fkbp5, Per2, Rt1.Dalpha, Slc16a1, and Abcg2). Validation of the microarray data by quantitative real-time-polymerase chain reaction (Q-PCR) indicated that there was a strong significant correlation (r = 0.979, p < 0.0000001) between the Q-PCR and the microarray data. Using MetaCore (a computational platform), many biological processes were identified [e.g., organic anion transport (p = 7.251 x 10(-4)) and regulation of immune response (p = 5.090 x 10(-4))]. Among the regulated genes, Abcg2 mRNA was up-regulated by 2.1-fold, which was further confirmed by immunoblotting (1.8-fold up-regulation). Testing the Abcg2 affinity status of oxycodone using an Abcg2 ATPase assay suggests that oxycodone behaves as an Abcg2 substrate only at higher concentrations (> or = 500 microM). Furthermore, brain uptake studies demonstrated that oxycodone-induced Abcg2 up regulation resulted in a significant (p < 0.05) decrease (approximately 2-fold) in brain/plasma ratios of mitoxantrone. These results highlight markers/mediators of neuronal responses and identify regulatory pathways involved in the pharmacological action of oxycodone. These results also identify genes that potentially modulate tolerance, dependence, immune response, and drug-drug interactions. Finally, our findings suggest that oxycodone-induced up-regulation of Abcg2 enhanced the efflux of the Abcg2 substrate, mitoxantrone, limiting its brain accumulation and resulting in an undesirable drug-drug interaction. Extrapolating these results to other Abcg2 substrates (e.g., daunorubicin and doxorubicin) indicates that the brain uptake of these agents may be affected if they are administered concomitantly with oxycodone. PMID- 19786508 TI - A possible mechanism for the decrease in serum thyroxine level by a 2,3,7,8 tetrachlorodibenzo-p-dioxin-like polychlorinated biphenyl congener, 3,3',4,4',5 pentachlorobiphenyl in mice. AB - Serum total thyroxine (T(4)) and free T(4) levels were markedly decreased 7 days after treatment with 3,3',4,4',5-pentachlorobiphenyl (CB126) (2.5 mg/kg i.p.) in 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-sensitive C57BL/6 mice but not in TCDD resistant DBA/2 mice. At the same time, the level and activity of hepatic T(4) UDP-glucuronosyltransferase (T(4)-UGT) were significantly increased in C57BL/6 mice but not in DBA/2 mice. Furthermore, the amounts of biliary [(125)I]T(4) and [(125)I]T(4) glucuronide after injection of [(125)I]T(4) were increased by CB126 pretreatment in C57BL/6 mice but not in DBA/2 mice. Clearance of [(125)I]T(4) from serum was also promoted by CB126 pretreatment in C57BL/6 mice but not in DBA/2 mice. On the other hand, no significant changes in the steady-state volumes of distribution of [(125)I]T(4) and in the concentration ratio (K(p) value) of the liver to serum by CB126 pretreatment were observed in either strain of mice. Because liver weight was increased by CB126 pretreatment in C57BL/6 mice but not in DBA/2 mice, hepatic total [(125)I]T(4) was increased only in C57BL/6 mice. The present findings indicate that CB126-mediated decrease in serum T(4) occurs through the increase in hepatic T(4)-UGT and the enhanced accumulation of hepatic T(4) along with development of liver hypertrophy. PMID- 19786509 TI - Absorption and disposition of ginsenosides after oral administration of Panax notoginseng extract to rats. AB - Panax notoginseng (Sanqi) is a cardiovascular herb containing ginsenosides that are believed to be responsible for the therapeutic effects of Sanqi. The aim of this study was to evaluate rat exposure to ginsenosides after oral administration of Sanqi extract and to identify the key factors affecting their absorption and disposition. Ginsenosides were administered to rats, either in the form of Sanqi extract or as pure chemicals. The ginsenosides Ra(3), Rb(1), Rd, Re, Rg(1), and notoginsenoside R(1) were the major saponins present in the herbal extract. Systemic exposure to ginsenosides Ra(3), Rb(1), and Rd after oral administration of the extract was significantly greater than that to the other compounds. Considerable colonic deglycosylation of the ginsenosides occurred, but the plasma levels of deglycosylated metabolites were low in rats. Poor membrane permeability and active biliary excretion are the two primary factors limiting systemic exposure to most ginsenosides and their deglycosylated metabolites. In contrast with other ginsenosides, biliary excretion of ginsenosides Ra(3) and Rb(1) was passive. Meanwhile, the active biliary excretion of ginsenoside Rd was significantly slower than that of other saponins. Slow biliary excretion, inefficient metabolism, and slow renal excretion resulted in long-circulating and thus relatively high exposure levels for these three ginsenosides. For these reasons, plasma ginsenosides Ra(3), Rb(1), and Rd were identified as pharmacokinetic markers for indicating rat systemic exposure to Sanqi extract. This is a systematic investigation of the absorption and disposition of ginsenosides from an herb, the information gained from which is important for linking Sanqi administration to its medicinal effects. PMID- 19786510 TI - Comparing views of patients, parents, and clinicians on emotions in anorexia: a qualitative study. AB - Patients with anorexia nervosa (AN) may experience difficulties in emotional processing that can adversely affect treatment and maintenance of the illness. Focus groups or questionnaires were undertaken with patients with AN, parents and clinicians, with the aim to explore the most salient issues pertaining to emotions and social cognition in AN. Qualitative thematic analysis was used to analyse the data. Seven primary themes were identified showing congruence across groups: 'emotional awareness and understanding'; 'emotional intolerance'; 'emotional avoidance'; 'emotional expression and negative beliefs'; 'extreme emotional responses'; 'social interactions and relationships'; and 'lack of empathy'. Clinical and empirical implications are discussed. PMID- 19786511 TI - Social sharing of genetic information in the family: a study on hereditary breast and ovarian cancers. AB - The present study assessed how preventive medical information about hereditary breast and ovarian cancer is spread within the family before actual genetic test results. Forty-two women (19 had a breast or ovarian tumor and 23 did not) were asked to fill out a questionnaire about: (1) the spread within the family of the medical information received during the consultation; and (2) the reasons for sharing this information. Results indicate that all of the women socially shared medical information with an immediate family member for preventive purposes, and generally not for seeking emotional or informative social support. PMID- 19786512 TI - What sense do people make of a theory of planned behaviour questionnaire?: a think-aloud study. AB - This study aimed to understand the processes of interpretation of, and responses to, the task of completing a theory of planned behaviour (TPB) questionnaire. Forty-five adults verbalized their thoughts while completing a full TPB questionnaire on walking behaviour. On average, participants' verbalizations indicated around 16 problems with the 52 questions. Further, problems as identified from verbalizations were associated with increased endorsement of the middle option on the questionnaire. Normative and intention questions were found to be particularly problematic. The current standardized method to develop TPB measures systematically yields problematic questions, as indicated by both talk and questionnaire responses. PMID- 19786513 TI - Correlates of drive for muscularity: the role of anthropometric measures and psychological factors. AB - Drive for muscularity (DM) is associated with anabolic steroid and supplement use, exercise dependence, eating pathology, and low self-esteem. However, only one study has examined how anthropometric measures are related to DM. To extend previous research, and to clarify the relationship between DM and anthropometric indices, 113 college-aged men completed self-report surveys and were assessed for body fat percentage, fat-free mass, and body mass index. We found that supplement use, exercise dependence, and self-esteem, but none of the anthropometric measures, correlated with DM. These results enhance our understanding of DM and can be used to develop interventions to decrease DM. PMID- 19786514 TI - A cost-effectiveness evaluation of a home visit program for adolescent mothers. AB - A home visit intervention program for adolescents throughout their pregnancy and during the early stages of motherhood was evaluated. The participants (N = 90) were part of a larger group of adolescents treated in two health centers in a poor neighborhood in Santiago, Chile. The program was carried out by volunteer community health monitors and evaluated through an experimental, randomized, controlled clinical trial. Cost-effectiveness was examined in comparison with standard health care. Results show higher scores for the intervention group on the mothers' mental health and nutritional state, as well as on the children's levels of linguistic development. PMID- 19786515 TI - Similarity not favorability: the role of donor prototypes in predicting willingness to donate organs while living. AB - Using an extended Prototype/Willingness Model, we examined the predictors of willingness to donate an organ to a partner/family member and a stranger while living. A questionnaire assessed university students' (N = 284) attitudes, subjective norm, prototype favorability, prototype similarity, moral norm, and willingness to donate organs in each recipient scenario. All variables, except prototype favorability, predicted willingness to donate organs in both situations. Future strategies should emphasise perceived approval from important others for living donation, the consistency of living donation with one's own morals, and encourage perceptions of similarity between oneself and living donors to increase acceptance of living donation. PMID- 19786516 TI - The measurement of menstrual symptoms: factor structure of the menstrual symptom questionnaire in adolescent girls. AB - This study examined the factor structure of the Menstrual Symptom Questionnaire (MSQ) in a sample of 210 adolescent girls (11-17 years). Such an examination has not been carried out with an adolescent sample. In addition, the definitions of menstrual disorders have evolved since the creation of the MSQ. Exploratory factor analysis supported a three factor structure indicating abdominal pain, negative affect/somatic complaints, and back pain. Partial correlations indicated all three MSQ factors were correlated with depressive symptoms, but only the negative affect factor was correlated with trait anxiety. Future research should explore potential associations in multiple areas of functioning as menstrual symptoms may alter healthy developmental processes during adolescence. PMID- 19786517 TI - GPs' perceptions of the service needs of South Asian people with chronic pain: a qualitative enquiry. AB - This qualitative study describes GPs' experiences of and needs for management of people from a South Asian community who have chronic pain. Semi-structured interviews were conducted with 18 GPs from practices in two PCTs in Leicester. The data was analysed using grounded theory. The results indicate that managing patients from a South Asian community with chronic pain can be challenging due to differing pain expression and presentation. Emerging themes refer to shortages of services for these patients including the need for CBT, counselling, community support and GP education and training. Potential implications of the results for service provision are discussed. PMID- 19786518 TI - Tobacco use and body mass index: mediated effects through physical inactivity. AB - The current study examined associations between smoking and body mass index (BMI) utilizing a nationally representative sample of adults (N = 1547). Previous research has shown that smokers have lower BMI than non-smokers; however among smokers, tobacco use is positively associated with BMI. Previous authors have hypothesized this is due to poor behavioral habits among smokers. Building on this, we found that smoking was positively associated with physical inactivity, which mediated the association between tobacco use and BMI. Interpretation, limitations, and future directions are discussed. PMID- 19786519 TI - Perceptions of exercise among people who have not attended cardiac rehabilitation following myocardial infarction. AB - Perceptions of exercise among nonattenders of cardiac rehabilitation (CR) were explored using semi-structured interviews. Analysis indicated that participants did not recognize the cardiovascular benefits of exercise, and perceived keeping active through daily activities as sufficient for health. Health professionals were perceived to downplay the importance of exercise and CR, and medication was viewed as being more important than exercise for promoting health. The content of CR programmes and the benefits of exercise need to be further explained to patients post-MI, and in a manner that communicates to patients that these programmes are valued by significant others, particularly health professionals. PMID- 19786520 TI - Stress management training in diabetes mellitus. AB - Good diabetic control minimizes the risk of complications. Stress affects control directly through the release of hormones and indirectly by disrupting self management activities. This review examines the impact of stress management interventions on glycaemic control. Qualifying studies since 1980 were identified using searches of Medline and PsycInfo databases. Ten were identified in adult populations, and four in adolescent populations. The general trend suggested that stress management interventions may be useful in management of diabetes. Further research will provide greater understanding of the particular benefits of various components of stress management training in relation to specific subgroups of the diabetic population. PMID- 19786521 TI - The Latina Breast Cancer Screening Sacle: beliefs about breast cancer and breast cancer screening. AB - The Latina Breast Cancer Screening (LBCS) was developed to measure Latinas' culturally-shared health beliefs about breast cancer and breast cancer screening. A 60-item LBCS scale was tested with 288 participants and reduced to 35 items using principal components analyses. The 35-item LBCS scale and other measures were administered to a second sample of 147 participants to establish the scale's validity and reliability. A six-factor solution suggested six LBCS sub-scales. The LBCS in its entirety displayed strong internal consistency (alpha =.93) with adequate estimates of convergent, discriminant, and predictive validity. The LBCS scale appears to be a valid and reliable measure. PMID- 19786522 TI - The role of rumination in affective distress in people with a chronic physical illness: a review of the literature and theoretical formulation. AB - The role of maladaptive cognitive content among individuals with chronic physical illness has been acknowledged in cognitive models. Rumination has been documented as a key predictor of depression, and to a lesser extent of anxiety, in non clinical samples. This paper provides a preliminary discussion of the potential role of rumination as a causal and maintaining factor for emotional distress in the setting of chronic physical illness. Although a number of methodological limitations exist, the current research on rumination may provide a useful framework for the extension of existing cognitive models in chronic illness. PMID- 19786523 TI - On becoming a first-time mother after an emergency Caesarean section: a journey from alienation to symbolic adoption. AB - This qualitative research focused on the significance of subjective experience of mothers who gave birth in an emergency Caesarean section. Ten first-time mothers experiencing emergency Caesarean section were interviewed, and their narrative accounts were analyzed using Giorgi's phenomenological method. Mothers described alienation from the infant on encountering her/him; primal difficulties in holding; a 'mechanistic' pattern of childcare at home; over-apprehension and fear of a cradle-death. A few of the women seemed to cope with these experiences by performing 'a symbolic adoption' of their infants. In the context of object relations theory, the findings, will potentially inform psychological care in obstetrics and gynaecology. PMID- 19786524 TI - Frequency of use and impact of coping strategies assessed by the COPE Inventory and their relationships to post-event health and well-being. AB - In dealing with a stressful event, 440 participants reported how frequently they used a variety of different coping strategies, rated their separate impacts on problems and the associated emotions, and reported their effects on subsequent health and well-being. Coping strategies did not generally impact problems or emotions differently. Use of planning led to increased self-efficacy, which along with positive reinterpretation, predicted growth. Emotional venting and behavioral disengagement predicted diminishment, which along with mental disengagement and self-injury, predicted illness. Social support buffered against diminishment. Use of acceptance coping and seeking advice from others had both positive and negative effects on well-being. PMID- 19786525 TI - Avoidance and inflexibility as a common clinical pathway in obesity and smoking treatment. AB - This brief study presents reductions in avoidance and inflexibility as a potential common clinical pathway to intervene on for both smoking cessation and weight control. A mediation analysis--using the Avoidance and Inflexibility Scale (AIS)--was conducted on a group of participants (N = 84) who were shown to improve weight control outcomes after receiving an Acceptance and Commitment Therapy (ACT) intervention. Results were then compared to a previous study using the same process measure (AIS) for smoking cessation. Results suggest a common clinical pathway. PMID- 19786526 TI - Oh stuff it! The experience and explanation of diet failure: an exploration using interpretative phenomenological analysis. AB - Successful long-term weight-loss is exceptional, even with the best dietary and psychological interventions. Nomothetic accounts of diet failure focus on cognitive processes and emotional regulation. However, qualitative research suggests that successful dieters draw on wider understandings in explaining their success; this study extends this literature to address diet failure. Individual interviews with 10 self-selected UK dieters are analysed using IPA. Understandings of diet failure are explored and situated within wider cultural discourses. Five themes are identified: 'Dieting mode'; 'Multime'; 'Not me'; 'Modern life'; and 'Challenges of emotional and social eating'. Implications for weight-loss interventions are explored. PMID- 19786527 TI - The moderating role of different sources of perceived social support on the dispositional optimism-- posttraumatic growth relationship in postoperative breast cancer patients. AB - The purpose of this study was to investigate the dispositional optimism posttraumatic growth (PTG) relationship in postoperative breast cancer patients and to examine if perceived social support moderates this relationship. The study was conducted with 104 women undergoing postoperative chemotherapy treatment or coming to the hospital for their routine controls. Hierarchical multiple regression analyses indicated that breast cancer survivors high on dispositional optimism and perceived social support, are more likely to develop PTG. Among the different sources of social support, only social support perceived from a private person moderated the dispositional optimism-PTG relationship. Strengths, limitations and possible implications of the findings are discussed. PMID- 19786528 TI - Unsafe, unwanted: sexual coercion as a barrier to safer sex among men who have sex with men. AB - Individual and focus group interviews with a total of 40 gay and bisexual men, as well as with 23 community and/or professional key informants, highlighted that sexual coercion is an important, yet under-recognized, barrier to the practice of safer sex among men who have sex with men. In this article we discuss how the dynamics of sexual coercion, including subtle forms, can operate to compromise men's ability to practise safer sex, leading men to have sex that is both unsafe and unwanted. PMID- 19786529 TI - Unveiled: pre-wedding weight concerns and health and beauty plans of Australian brides. AB - This study investigated the prevalence of appearance and weight-related concerns in 879 Australian brides-to-be recruited from five bridal websites. Close to 75 per cent of the sample intended to exercise more and follow a 'healthy eating plan', while over 35 per cent planned to cut fat or carbohydrates out of their diets. On average, participants wished to lose over 8 kg (18 lbs) by their wedding day, and one-third had been told to lose weight by someone else for the wedding. These findings demonstrate the salience of appearance concerns among brides-to-be and highlight the need to promote a healthier bridal body ideal. PMID- 19786530 TI - Preventing disability through exercise: investigating older adults' influences and motivations to engage in physical activity. AB - In this qualitative study focus groups were used to gain an in-depth understanding of personal and social influences on physical activity in 48 52-87 year-old participants. A model produced using a Grounded Theory analysis showed that preventing health decline was particularly important in determining physical activity participation. Other influences included enjoyment of exercise, others as motivators to exercise and perceived limited appreciation for older people's needs. The results are discussed in relation to health and exercise interventions designed to motivate exercise behaviour in older adults. PMID- 19786531 TI - 'That's not masculine': masculine capital and health-related behaviour. AB - In recent years increasing attention has been given to how different masculinities are expressed in young men's health behaviour. To examine whether men can use competence in key health-related masculine domains to compensate for other non-masculine behaviour, group discussions were conducted with men aged 18 21 living in London, England. The analysis revealed the ways in which competence in traditionally masculine health-related domains produces masculine 'capital', which can be used to compensate for non-masculine behaviour in other domains. However, the capacity to trade this capital is limited because different masculine and non-masculine behaviours have different values. PMID- 19786532 TI - The survival of memory CD4+ T cells within the gut lamina propria requires OX40 and CD30 signals. AB - Although CD4(+) memory T cells reside within secondary lymphoid tissue, the major reservoir of these cells is in the lamina propria of the intestine. In this study, we demonstrate that, in the absence of signals through both OX40 and CD30, CD4(+) T cells are comprehensively depleted from the lamina propria. Deficiency in either CD30 or OX40 alone reduced CD4(+) T cell numbers, however, in mice deficient in both OX40 and CD30, CD4(+) T cell loss was greatly exacerbated. This loss of CD4(+) T cells was not due to a homing defect because CD30 x OX40 deficient OTII cells were not impaired in their ability to express CCR9 and alpha(4)beta(7) or traffic to the small intestine. There was also no difference in the priming of wild-type (WT) and CD30 x OX40-deficient OTII cells in the mesenteric lymph node after oral immunization. However, following oral immunization, CD30 x OX40-deficient OTII cells trafficked to the lamina propria but failed to persist compared with WT OTII cells. This was not due to reduced levels of Bcl-2 or Bcl-XL, because expression of these was comparable between WT and double knockout OTII cells. Collectively, these data demonstrate that signals through CD30 and OX40 are required for the survival of CD4(+) T cells within the small intestine lamina propria. PMID- 19786533 TI - Gammadelta T cell immune manipulation during chronic phase of simian-human immunodeficiency virus infection [corrected] confers immunological benefits. AB - Vgamma2Vdelta2 T cells, a major human gammadelta T cell subset, recognize the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by mycobacteria and some opportunistic pathogens, and they contribute to innate/adaptive/homeostatic and anticancer immunity. As initial efforts to explore Vgamma2Vdelta2 T cell-based therapeutics against HIV/AIDS-associated bacterial/protozoal infections and neoplasms, we investigated whether a well defined HMBPP/IL-2 therapeutic regimen could overcome HIV-mediated immune suppression to massively expand polyfunctional Vgamma2Vdelta2 T cells, and whether such activation/expansion could impact AIDS pathogenesis in simian HIV (SHIV)-infected Chinese rhesus macaques. While HMBPP/IL-2 coadministration during acute or chronic phase of SHIV infection induced massive activation/expansion of Vgamma2Vdelta2 T cells, the consequences of such activation/expansions were different between these two treatment settings. HMBPP/IL-2 cotreatment during acute SHIV infection did not prevent the increases in peak and set-point viral loads or the accelerated disease progression seen with IL-2 treatment alone. In contrast, HMBPP/IL-2 cotreatment during chronic infection did not exacerbate disease, and more importantly it could confer immunological benefits. Surprisingly, although viral antigenic loads were not increased upon HMBPP/IL-2 cotreatment during chronic SHIV infection, HMBPP activation of Vgamma2Vdelta2 T cells boosted HIV Env-specific Ab titers. Such increases in Abs were sustained for >170 days and were immediately preceded by increased production of IFN-gamma, TNF-alpha, IL-4, and IL-10 during peak expansion of Vgamma2Vdelta2 T cells displaying memory phenotypes, as well as the short-term increased effector function of Vgamma2Vdelta2 T cells and CD4(+) and CD8(+) alphabeta T cells producing antimicrobial cytokines. Thus, HMBPP/Vgamma2Vdelta2 T cell-based intervention may potentially be useful for combating neoplasms and HMBPP producing opportunistic pathogens in chronically HIV-infected individuals. PMID- 19786534 TI - Differential effect of IL-27 on developing versus committed Th17 cells. AB - IL-27 counters the effect of TGF-beta+IL-6 on naive CD4(+) T cells, resulting in near complete inhibition of de novo Th17 development. In contrast, little is known about the effect of IL-27 on already differentiated Th17 cells. A better understanding of how IL-27 regulates these cells is needed to evaluate the therapeutic potential of IL-27 in Th17 cells-associated diseases. In this study, we show that IL-27 had surprisingly little effect on committed Th17 cells, despite its expression of a functional IL-27R. Contrary to de novo differentiation of Th17 cells, IL-27 did not suppress expression of retinoid related orphan receptor (ROR)gammat or RORalpha in committed Th17 cells. Consistent with this finding, the frequency of committed Th17 cells and their cytokine secretion remained unaffected by IL-27. Both memory Th17 cells (CD4(+)CD25(-)CD62L(low)) that developed in vivo and encephalitogenic Th17 cells infiltrating the CNS of mice developing experimental autoimmune encephalomyelitis produced similar amounts of IL-17A when reactivated with IL-23 in the absence and presence of exogenous IL-27. Finally, IL-27 failed to suppress encephalitogenicity of Th17 cells in an adoptive transfer of experimental autoimmune encephalomyelitis. Analysis ex vivo of transferred Th17 cells in the spleen and CNS of recipient mice showed that cells retained similar phenotype irrespective of whether cells were treated or not with IL-27. Our data demonstrate that in contrast to inhibition of de novo differentiation of Th17 cells, IL-27 has little or no effect on committed Th17 cells. These findings indicate that therapeutic applications of IL-27 might have a limited efficacy in inflammatory conditions where aggressive Th17 responses have already developed. PMID- 19786536 TI - Enhanced dendritic cell-induced immune responses mediated by the novel C-type lectin receptor mDCAR1. AB - The dendritic cell (DC) immunoreceptors (DCIR) and DC-immunoactivating receptors (DCAR) represent a subfamily of cell surface C-type lectin receptors (CLR), whose multifunctional capacities range from classical Ag uptake and immunoregulatory mechanisms to the involvement in DC ontogeny. On the basis of the generation of specific mAbs, we functionally characterized mouse DCAR1 (mDCAR1) as a member of the DCIR/DCAR family. Expression of mDCAR1 was strongly tissue dependent. mDCAR1 expression on DCs was restricted to the CD8(+) DC subset in spleen and thymus and on subpopulations of CD11b(+) myeloid cells in bone marrow and spleen, whereas the molecule was not detectable on both cell types in lymph nodes and peripheral blood. With respect to the function of CLRs as pattern recognition receptors, Ag delivered via mDCAR1 was internalized, was trafficked to early and late endosomes/lysosomes and, as a consequence, induced cellular and humoral responses in vivo even in the absence of CD40 stimulation. Intriguingly, upon triggering mDCAR1, CD8(+) DCs increased the secretion of bioactive IL-12, whereas IL-10 release is markedly reduced, thereby indicating that Ag recognized by mDCAR1 induces enhanced proinflammatory responses. These data indicate that mDCAR1 is a functional receptor on cells of the immune system and provides further insights into the regulation of immune responses by CLRs. PMID- 19786535 TI - Involvement of innate and adaptive immunity in a murine model of coronary arteritis mimicking Kawasaki disease. AB - Kawasaki disease (KD) is the most common cause of acquired cardiac disease and acute vasculitis in children in the developed world. Injection of a cell wall extract isolated from Lactobacillus casei (LCCWE) into mice causes a focal coronary arteritis that histopathologically mimics the coronary lesions observed in KD patients. In this study we used this model to investigate the participation of T cells, B cells, and dendritic cells (DC) in the development of coronary arteritis. RAG1(-/-), B cell(null), and wild-type (WT) mice were injected with a single dose of LCCWE (500 microg/mouse i.p.). None of the RAG1(-/-) mice developed coronary arteritis, whereas 70% of WT and 100% of B cell(null) mice developed coronary lesions, indicating that T cells were required for lesion formation. When splenocytes isolated from LCCWE-treated mice were restimulated with LCCWE, we observed significant IFN-gamma secretion in WT but not in RAG1(-/ ) mice. Immunohistochemical staining showed F4/80(+) macrophages, activated MIDC 8(+) myeloid DCs (mDC), plasmacytoid DCs, and colocalization of CD3(+) T cells with mDCs in coronary artery lesions, suggesting an Ag-driven process. T cells but not B cells are required for LCCWE-induced coronary arteritis. Similar to human lesions, the coronary lesions contain macrophages, activated mDCs, and plaslmacytoid DCs all in close proximity to T cells, further strengthening the relevance of this mouse model to the immunopathology of coronary disease in KD. These studies are consistent with the interpretation that macrophages and DCs may collaborate with T cells in the pathological mechanisms of coronary arteritis. PMID- 19786537 TI - Evidence for local expansion of IgA plasma cell precursors in human ileum. AB - IgA plays a crucial role in establishment and maintenance of mucosal homeostasis between host cells and commensal bacteria. To this end, numerous IgA plasma cells are located in the intestinal lamina propria. Whether the (immediate) precursor cells for these plasma cells can expand locally is not completely known and was studied here. The total number of IgA plasma cells in human ileal biopsies was counted. Sequence analysis of IgA V(H) genes from human ileal biopsies revealed the occurrence of many clonally related sequences within a biopsy, but not between different biopsies. This observation strongly argues for local expansion of IgA precursor cells. By comparing the number of unique sequences with the number of clonally related sequences within a biopsy, we estimated that approximately 100-300 precursors were responsible for the 75,000 IgA-producing cells that were present per biopsy. These precursor cells must therefore have divided locally 9-10 times. Since all sequences contained mutations and most of the mutations present in clonally related sequences were shared, the IgA precursor cells must have arrived initially as mutated cells in the lamina propria. Our data show evidence for the existence of two waves of expansion for IgA-producing cells in human ileum. The first wave occurs during initial stimulation in germinal centers as evidenced by somatic hypermutations. A second wave of expansion of IgA-committed cells occurs locally within the lamina propria as evidenced by the high frequency of clonally related cells. PMID- 19786538 TI - Essential impact of NF-kappaB signaling on the H5N1 influenza A virus-induced transcriptome. AB - Systemic infections of humans and birds with highly pathogenic avian influenza A viruses of the H5N1 subtype are characterized by inner bleedings and a massive overproduction of cytokines known as cytokine storm. Growing evidence supports the role of endothelial cells in these processes. The aim of this study was to elucidate determinants of this strong response in endothelial cells with a focus on the transcription factor NF-kappaB. This factor is known as a major regulator of inflammatory response; however, its role in influenza virus replication and virus-induced immune responses is controversially discussed. By global mRNA profiling of infected cells in the presence or absence of a dominant negative mutant of IkappaB kinase 2 that specifically blocks the pathway, we could show that almost all H5N1 virus-induced genes depend on functional NF-kappaB signaling. In particular, activation of NF-kappaB is a bottleneck for the expression of IFN-beta and thus influences the expression of IFN-dependent genes indirectly in the primary innate immune response against H5N1 influenza virus. Control experiments with a low pathogenic influenza strain revealed a much weaker and less NF-kappaB-dependent host cell response. PMID- 19786539 TI - CD8+ cell depletion of SHIV89.6P-infected macaques induces CD4+ T cell proliferation that contributes to increased viral loads. AB - Previous studies have shown that depletion of CD8(+) cells during acute and chronic simian immunodeficiency virus (SIV) infection leads to increased viral replication, morbidity, and mortality, which have been attributed to loss of CD8(+) T cell-mediated control of SIV. However, these studies did not exclude that CD8(+) cell depletion increased homeostatic proliferation of CD4(+) T cells, resulting in increased viral targets and, therefore, viral rebound. Chronically SHIV89.6P-infected cynomolgus macaques were CD8(+) cell-depleted, and the frequency, cell number, and phenotype of CD4(+) T cells and viral infection were examined using flow cytometry and quantitative real-time PCR. The frequency and number of Ki-67-expressing CD4(+) T cells were increased with CD8(+) cell depletion. This proliferation of CD4(+) T cells occurred even in animals with no rebound of viral loads. Most of the proliferating cells were effector memory CD4(+) T cells. Plasma simian HIV (SHIV) RNA copies positively correlated with proliferating CD4(+) T cells and SHIV DNA copies in Ki-67(+) CD4(+) T cells. Although this study does not exclude an important role for virus-specific CD8(+) T cells in SIV and SHIV infection, our data suggest that homeostatic proliferation is an important contributor to increases in plasma viremia that follow CD8(+) cell depletion. PMID- 19786540 TI - Lessons from thymic epithelial heterogeneity: FoxN1 and tissue-restricted gene expression by extrathymic, endodermally derived epithelium. AB - Modeling of thymic epithelial differentiation has been guided by several important underlying assumptions. One is that within epithelial tissues derived from pharyngeal endoderm, FoxN1 expression is signature for the thymic epithelial lineage. Another is that expression of tissue-restricted Ag (TRA) is a unique feature of thymic epithelium. In this murine study, we evaluate the thymic expression of a subset of TRA, parathyroid hormone, calcitonin, and thyroglobulin, as part of an effort to better define the heterogeneity of medullary thymic epithelial cells. In this study, we demonstrate that both conventional and cystic epithelial cells display a history of FoxN1 expression using a cre-lox approach. We also document that extrathymic epithelial tissues that originate from pharyngeal endoderm also have a history of FoxN1 expression, indicating that FoxN1 expression per se is not a signature for the thymic lineage and suggesting that FoxN1 expression, whereas necessary for thymic epithelium, development, is not sufficient for this process to occur. Both cystic and conventional medullary thymic epithelial cells express these TRAs, as do extrathymic epithelial tissues that are not usually considered to be sources of these molecules. This finding supports the proposition that promiscuous gene expression is not unique to the thymus. Furthermore, the pattern of promiscuous gene expression in these extrathymic epithelia is consistent with developmental regulation processes and suggests that it is premature to discard the possibility that some promiscuous gene expression in the thymus reflects normal differentiation programs of epithelia. PMID- 19786541 TI - CD11c(high )dendritic cells are essential for activation of CD4+ T cells and generation of specific antibodies following mucosal immunization. AB - To generate vaccines that protect mucosal surfaces, a better understanding of the cells required in vivo for activation of the adaptive immune response following mucosal immunization is required. CD11c(high) conventional dendritic cells (cDCs) have been shown to be necessary for activation of naive CD8(+) T cells in vivo, but the role of cDCs in CD4(+) T cell activation is still unclear, especially at mucosal surfaces. The activation of naive Ag-specific CD4(+) T cells and the generation of Abs following mucosal administration of Ag with or without the potent mucosal adjuvant cholera toxin were therefore analyzed in mice depleted of CD11c(high) cDCs. Our results show that cDCs are absolutely required for activation of CD4(+) T cells after oral and nasal immunization. Ag-specific IgG titers in serum, as well as Ag-specific intestinal IgA, were completely abrogated after feeding mice OVA and cholera toxin. However, giving a very high dose of Ag, 30-fold more than required to detect T cell proliferation, to cDC-ablated mice resulted in proliferation of Ag-specific CD4(+) T cells. This proliferation was not inhibited by additional depletion of plasmacytoid DCs or in cDC-depleted mice whose B cells were MHC-II deficient. This study therefore demonstrates that cDCs are required for successful mucosal immunization, unless a very high dose of Ag is administered. PMID- 19786542 TI - SH2 domain-containing phosphatase-2 protein-tyrosine phosphatase promotes Fc epsilon RI-induced activation of Fyn and Erk pathways leading to TNF alpha release from bone marrow-derived mast cells. AB - Clustering of the high affinity IgE receptor (Fc(epsilon)RI) in mast cells leads to degranulation and production of numerous cytokines and lipid mediators that promote allergic inflammation. Initiation of FFc(epsilon)RI signaling involves rapid tyrosine phosphorylation of Fc(epsilon)RI and membrane-localized adaptor proteins that recruit additional SH2 domain-containing proteins that dynamically regulate downstream signaling. SH2 domain-containing phosphatase-2 (SHP2) is a protein-tyrosine phosphatase implicated in Fc(epsilon)RI signaling, but whose function is not well defined. In this study, using a mouse model allowing temporal shp2 inactivation in bone marrow-derived mast cells (BMMCs), we provide insights into SHP2 functions in the Fc(epsilon)RI pathway. Although no overt defects in Fc(epsilon)RI-induced tyrosine phosphorylation were observed in SHP2 knock-out (KO) BMMCs, several proteins including Lyn and Syk kinases displayed extended phosphorylation kinetics compared with wild-type BMMCs. SHP2 was dispensable for Fc(epsilon)RI-induced degranulation of BMMCs, but was required for maximal activation of Erk and Jnk mitogen-activated protein kinases. SHP2 KO BMMCs displayed several phenotypes associated with reduced Fyn activity, including elevated phosphorylation of the inhibitory pY531 site in Fyn, impaired signaling to Grb2-associated binder 2, Akt/PKB, and IkappaB kinase, and decreased TNF-alpha release compared with control cells. This is likely due to elevated Lyn activity in SHP2 KO BMMCs, and the ability of Lyn to antagonize Fyn activity. Overall, our study identifies SHP2 as a positive effector of Fc(epsilon)RI induced activation of Fyn/Grb2-associated binder 2/Akt and Ras/Erk pathways leading to TNF-alpha release from mast cells. PMID- 19786543 TI - Role of endothelial TLR4 for neutrophil recruitment into central nervous system microvessels in systemic inflammation. AB - Brain inflammation is a frequent consequence of sepsis and septic shock. We imaged leukocyte recruitment in brain postcapillary venules induced by i.p. administration of LPS as a simple model of systemic inflammation. The i.p. injection of LPS (0.5 mg/kg) induced significant leukocyte rolling and adhesion in brain postcapillary venules of wild-type (WT) mice and more than 90% were neutrophils. However, no emigrated neutrophils were detected in brain parenchyma. High levels of TNF-alpha and IL-1beta were detected in the plasma after LPS injection but a different profile (IL-1beta but not TNF-alpha) was detected in the brain. LPS caused no recruitment in TLR4 knockout mice. In chimeric mice with TLR4-expressing resident cells but TLR4-deficient bone marrow-derived circulating cells, neutrophil rolling and adhesion was similar to WT mice. This observation is consistent with a requirement for resident cells in the LPS-induced neutrophil recruitment into brain microvessels. Transgenic mice engineered to express TLR4 exclusively on endothelial cells had a similar level of leukocyte recruitment in brain as WT mice in response to LPS. High dose LPS (10 mg/kg) led to neutrophil infiltration in the brain parenchyma in WT mice. High KC and MIP-2 production was observed from brain parenchyma microglial cells, and CXCR2 knockout mice failed to recruit neutrophils. However, neither neutrophil infiltration nor KC or MIP-2 was observed in endothelial TLR4 transgenic mice in response to this LPS dose. Our results demonstrate that direct endothelial activation is sufficient to mediate leukocyte rolling and adhesion in cerebral microvessels but not sufficient for emigration to brain parenchyma. PMID- 19786544 TI - Cutting Edge: OX40 agonists can drive regulatory T cell expansion if the cytokine milieu is right. AB - We report that OX40 stimulation drives all lineages of CD4 T cell development, including regulatory T cells (Tregs), and the plasticity of the response is dependant on local cytokines. In TGF-beta1-treated cultures, an OX40 agonist increased IFN-gamma and IL-4 production and diverted T cells from the Treg lineage. However, cytokine blockade in the context of OX40 stimulation promoted enhanced Treg accumulation. This observation was evident in naive mice, as OX40 engagement enhanced Treg proliferation and accumulation in vivo. Lastly, OX40 agonist administration influenced experimental autoimmune encephalomyelitis disease severity in opposing directions, depending on the timing of administration. Given during Ag priming, the OX40 agonist drove Treg expansion and inhibited disease, whereas given later it enhanced T cell effector cytokine production in the CNS and exacerbated disease. Hence, OX40 signaling can augment the accumulation of all CD4 T cell lineages; however, its accentuation of immune responses may have vastly different biologic outcomes depending upon the local cytokine milieu. PMID- 19786545 TI - De novo recruitment of antigen-experienced and naive T cells contributes to the long-term maintenance of antiviral T cell populations in the persistently infected central nervous system. AB - Mice infected with attenuated strains of mouse hepatitis virus, strain JHM, develop a chronic infection in the brain and spinal cord characterized by low levels of viral Ag persistence and retention of virus-specific CD4 and CD8 T cells at the site of infection. It is not known whether these cells are maintained by proliferation of T cells that entered the CNS during acute infection or are newly recruited from Ag-experienced or naive T cell pools. In this study, using adoptive transfer experiments and bone marrow chimeras, we show that at least some of these cells are recruited from the periphery, predominantly from the viral Ag-experienced T cell pool. Both virus-specific CD4 and CD8 T cells are functional, as assessed by cytokine expression and degranulation after peptide exposure. In addition, populations of virus-specific CD4 T cells undergo dynamic changes in the infected CNS, as previously shown for CD8 T cells, because ratios of cells responding to two CD4 T cell epitopes change by a factor of five during the course of persistence. Collectively, these results show that maintenance of T cell responses in the virus-infected CNS is a dynamic process. Further, virus-specific T cell numbers at this site of infection are maintained by recruitment from peripheral Ag-experienced and naive T cell pools. PMID- 19786547 TI - Role of TL1A in the pathogenesis of rheumatoid arthritis. AB - TNF-like ligand 1A (TL1A), a member of the TNF superfamily, is the ligand of DR3 and DcR3. Several types of cells, such as endothelial cells, monocytes/macrophages, dendritic cells, and CD4 and CD8 T cells, are capable of producing this cytokine. In present study, we demonstrated that TL1A aggravated collagen-induced arthritis in mice. It increased collagen-induced arthritis penetrance and clinical scores as well as the severity of the pathological findings. TL1A administration led to the occurrence of multiple enlarged germinal centers in the spleen, and it boosted serum anti-collagen Ab titers in vivo. In vitro, TL1A augmented TNF-alpha production by T cells upon TCR ligation, and it greatly enhanced Th17 differentiation and IL-17 production. We further showed that human rheumatoid arthritis (RA) synovial fluids had elevated TL1A titers, and human chrondrocytes and synovial fibroblasts were capable of secreting TL1A upon TNF-alpha or IL-1beta stimulation. Taken together, these data suggest that TL1A secretion in lymphoid organs might contribute to RA initiation by promoting autoantibody production, and TL1A secretion stimulated by inflammatory cytokines in RA joints might be a part of a vicious circle that aggravates RA pathogenesis. PMID- 19786546 TI - Essential roles for Dok2 and RasGAP in CD200 receptor-mediated regulation of human myeloid cells. AB - The CD200 receptor (CD200R) acts as a negative regulator of myeloid cells by interacting with its widely expressed ligand CD200. Using mutants expressed in U937 cells, we show that inhibition is mediated by the PTB domain binding motif (NPLY) in the receptor's cytoplasmic region. The adaptor protein downstream of tyrosine kinase 2 (Dok2) bound directly to the phosphorylated NPLY motif with a 10-fold higher affinity (K(D) of approximately 1 microM at 37 degrees C) than the closely related Dok1. Both of these proteins have been suggested to play a role in CD200R signaling in murine cells. Dok2 was phosphorylated in response to CD200R engagement and recruited RAS p21 protein activator 1 (RasGAP). Knockdown of Dok2 and RasGAP by RNA interference revealed that these proteins are required for CD200R signaling, while knockdown of Dok1 and the inositol 5-phosphatase SHIP did not affect CD200R-mediated inhibition. We conclude that CD200R inhibits the activation of human myeloid cells through direct recruitment of Dok2 and subsequent activation of RasGAP, which distinguishes this receptor from the majority of inhibitory receptors that utilize ITIMs and recruit phosphatases. PMID- 19786548 TI - Vascular endothelial growth factor is a key mediator in the development of T cell priming and its polarization to type 1 and type 17 T helper cells in the airways. AB - Chronic inflammatory airway diseases including asthma are characterized by immune dysfunction to inhaled allergens. Our previous studies demonstrated that T cell priming to inhaled allergens requires LPS, which is ubiquitously present in household dust allergens. In this study, we evaluated the role of vascular endothelial growth factor (VEGF) in the development of T cell priming and its polarization to Th1 or Th17 cells when exposed to LPS-contaminated allergens. An asthma mouse model was induced by airway sensitization with LPS-contaminated allergens and then challenged with allergens alone. Therapeutic intervention was performed during allergen sensitization. The present study showed that lung inflammation induced by sensitization with LPS-contaminated allergens was decreased in mice with homozygous disruption of the IL-17 gene; in addition, allergen-specific Th17 immune response was abolished in IL-6 knockout mice. Meanwhile, in vivo production of VEGF was up-regulated by airway exposure of LPS. In addition, airway sensitization of allergen plus recombinant VEGF induced both type 1 and type 17 Th cell (Th1 and Th17) responses. Th1 and Th17 responses induced by airway sensitization with LPS-contaminated allergens were blocked by treatment with a pan-VEGF receptor (VEGFR; VEGFR-1 plus VEGFR-2) inhibitor during sensitization. These effects were accompanied by inhibition of the production of Th1 and Th17 polarizing cytokines, IL-12p70 and IL-6, respectively. These findings indicate that VEGF produced by LPS plays a key role in activation of naive T cells and subsequent polarization to Th1 and Th17 cells. PMID- 19786549 TI - Mitochondrial dysfunction increases allergic airway inflammation. AB - The prevalence of allergies and asthma among the world's population has been steadily increasing due to environmental factors. It has been described that exposure to ozone, diesel exhaust particles, or tobacco smoke exacerbates allergic inflammation in the lungs. These environmental oxidants increase the levels of cellular reactive oxygen species (ROS) and induce mitochondrial dysfunction in the airway epithelium. In this study, we investigated the involvement of preexisting mitochondrial dysfunction in the exacerbation of allergic airway inflammation. After cellular oxidative insult induced by ragweed pollen extract (RWE) exposure, we have identified nine oxidatively damaged mitochondrial respiratory chain-complex and associated proteins. Out of these, the ubiquinol-cytochrome c reductase core II protein (UQCRC2) was found to be implicated in mitochondrial ROS generation from respiratory complex III. Mitochondrial dysfunction induced by deficiency of UQCRC2 in airway epithelium of sensitized BALB/c mice prior the RWE challenge increased the Ag-induced accumulation of eosinophils, mucin levels in the airways, and bronchial hyperresponsiveness. Deficiency of UQCRC1, another oxidative damage-sensitive complex III protein, did not significantly alter cellular ROS levels or the intensity of RWE-induced airway inflammation. These observations suggest that preexisting mitochondrial dysfunction induced by oxidant environmental pollutants is responsible for the severe symptoms in allergic airway inflammation. These data also imply that mitochondrial defects could be risk factors and may be responsible for severe allergic disorders in atopic individuals. PMID- 19786550 TI - Long-lived colitogenic CD4+ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis. AB - To understand the perpetuation of inflammatory bowel disease (IBD), it is important to clarify whether the colitogenic CD4(+) T cells are self-limited effector or long-lived memory T cells. We here investigate the latency of colitogenic CD4(+) T cells in the remission stage of colitis under germfree (GF) conditions. We isolated splenic (SP) CD4(+) T cells from colitic CD4(+)CD45RB(high) T cell-injected SCID mice maintained under specific pathogen free (SPF) conditions and transferred them into SPF or GF SCID mice. Donor colitic SP CD4(+) T cells have a characteristic CD44(high)CD62L(-)IL 7Ralpha(high) effector-memory T-type phenotype. Six weeks after transfer of cells to GF SCID mice, one group of mice was continued in GF conditions (GF-->GF), and the other was transferred into SPF conditions (GF-->SPF). GF-->SPF but not GF- >GF SCID mice developed colitis with elevated production of Th1 and Th17 cytokines at 4 wk after transfer. Surprisingly, a large number of CD4(+) effector memory T cells and a small but substantial number of central-memory T cells remained resident in SP and bone marrow, but not in lamina propria, of the GF- >GF SCID recipients. Consistent with this, GF-->SPF but not GF-->GF SCID mice rapidly developed colitis. Taken together, these findings suggest that long-lived colitogenic memory CD4(+) cells can be established even in the presence of commensal Ags, reside outside the intestine in the absence of commensal bacteria, and participate in the perpetuation of colitis. Thus, blocking a stimulus of colitogenic memory CD4(+) cells such as IL-7 may have therapeutic benefit for treatment of inflammatory bowel disease. PMID- 19786551 TI - The effects of host age on follicular dendritic cell status dramatically impair scrapie agent neuroinvasion in aged mice. AB - Following peripheral exposure, many transmissible spongiform encephalopathy (TSE) agents accumulate first in lymphoid tissues before spreading to the CNS (termed neuroinvasion) where they cause neurodegeneration. Early TSE agent accumulation upon follicular dendritic cells (FDCs) in lymphoid follicles appears critical for efficient neuroinvasion. Most clinical cases of variant Creutzfeldt-Jakob disease have occurred in young adults, although the reasons behind this apparent age related susceptibility are uncertain. Host age has a significant influence on immune function. As FDC status and immune complex trapping is reduced in aged mice (600 days old), we hypothesized that this aging-related decline in FDC function might impair TSE pathogenesis. We show that coincident with the effects of host age on FDC status, the early TSE agent accumulation in the spleens of aged mice was significantly impaired. Furthermore, following peripheral exposure, none of the aged mice developed clinical TSE disease during their lifespans, although most mice displayed histopathological signs of TSE disease in their brains. Our data imply that the reduced status of FDCs in aged mice significantly impairs the early TSE agent accumulation in lymphoid tissues and subsequent neuroinvasion. Furthermore, the inefficient neuroinvasion in aged individuals may lead to significant levels of subclinical TSE disease in the population. PMID- 19786552 TI - FAN stimulates TNF(alpha)-induced gene expression, leukocyte recruitment, and humoral response. AB - Factor associated with neutral sphingomyelinase activation (FAN) is an adaptor protein that constitutively binds to TNF-R1. Microarray analysis was performed in fibroblasts derived from wild-type or FAN knockout mouse embryos to evaluate the role of FAN in TNF-induced gene expression. Approximately 70% of TNF-induced genes exhibited lower expression levels in FAN-deficient than in wild-type fibroblasts. Of particular interest, TNF-induced expression of cytokines/chemokines, such as IL-6 and CXCL-2, was impaired in FAN-deficient cells. This was confirmed by real time RT-PCR and ELISA. Upon i.p. TNF or thioglycollate injection, neutrophil recruitment into the peritoneal cavity was reduced by more than 50% in FAN-deficient mice. Nevertheless, FAN-deficient animals did not exhibit an increased susceptibility to different microorganisms including bacteria and parasites, indicating that FAN is not essential for pathogen clearance. Specific Ab response to BSA was substantially impaired in FAN deficient mice and this was associated with a reduced content of leukocytes in the spleen of BSA-challenged FAN-deficient mice as compared with their wild-type counterparts. Altogether, our results indicate the involvement of FAN in TNF induced gene expression and leukocyte recruitment, contributing to the establishment of the specific immune response. PMID- 19786553 TI - Drosophila glycoprotein 93 Is an ortholog of mammalian heat shock protein gp96 (grp94, HSP90b1, HSPC4) and retains disulfide bond-independent chaperone function for TLRs and integrins. AB - Mammalian heat shock protein gp96 is an obligate chaperone for multiple integrins and TLRs, the mechanism of which is largely unknown. We have identified gp93 in Drosophila having high sequence homology to gp96. However, no functions were previously attributed to gp93. To determine whether gp93 and gp96 are functionally conserved, we have expressed gp93 in gp96-deficient mouse cells. Remarkably, the Drosophila gp93 is able to chaperone multiple murine gp96 clients including integrins alpha(4), alpha(L), and beta(2) and TLR2 and TLR9. This observation has led us to examine the structural basis of the chaperone function of gp96 by a close comparison between gp96 and gp93. We report that whereas gp96 undergoes intermolecular disulfide bond formation via Cys(138), gp93 is unable to do so due to the absence of a cysteine near the same region. However, abrogation of disulfide bond formation by substituting C with A (C138A) in gp96 via site directed mutagenesis did not compromise its chaperone function. Likewise, gp93 chaperone ability could not be improved by forcing intermolecular bond formation between gp93 N termini. We conclude that gp93 is the Drosophila ortholog of gp96 and that the chaperone function of the two molecules is conserved. Moreover, gp96 N-terminal disulfide bond formation is not critical for its function, underscoring the importance of N-terminal dimerization via non-disulfide bond mediated interactions in client protein folding by gp96. Further study of gp96 from an evolutionary angle shall be informative to uncover the detailed mechanism of its chaperone function of client proteins in the secretory pathway. PMID- 19786554 TI - Dendritic cells support the in vivo development and maintenance of NK cells via IL-15 trans-presentation. AB - IL-15 is a key component that regulates the development and homeostasis of NK cells and is delivered through a mechanism termed trans-presentation. During development, multiple events must proceed to generate a functional mature population of NK cells that are vital for tumor and viral immunity. Nevertheless, how IL-15 regulates these various events and more importantly what cells provide IL-15 to NK cells to drive these events is unclear. It is known dendritic cells (DC) can activate NK cells via IL-15 trans-presentation; however, the ability of DC to use IL-15 trans-presentation to promote the development and homeostatic maintenance of NK cell has not been established. In this current study, we show that IL-15 trans-presentation solely by CD11c(+) cells assists the in vivo development and maintenance of NK cells. More specifically, DC-mediated IL-15 trans-presentation drove the differentiation of NK cells, which included the up regulation of the activating and inhibitory Ly49 receptors. Although these cells did not harbor a mature CD11b(high) phenotype, they were capable of degranulating and producing IFN-gamma upon stimulation similar to wild-type NK cells. In addition, DC facilitated the survival of mature NK cells via IL-15 trans presentation in the periphery. Thus, an additional role for NK-DC interactions has been identified whereby DC support the developmental and homeostatic niche of NK cells. PMID- 19786555 TI - Fine structural variations of alphabetaTCRs selected by vaccination with natural versus altered self-antigen in melanoma patients. AB - Immunotherapy of cancer is often performed with altered "analog" peptide Ags optimized for HLA class I binding, resulting in enhanced immunogenicity, but the induced T cell responses require further evaluation. Recently, we demonstrated fine specificity differences and enhanced recognition of naturally presented Ag by T cells after vaccination with natural Melan-A/MART-1 peptide, as compared with analog peptide. In this study, we compared the TCR primary structures of 1489 HLA-A*0201/Melan-A(26-35)-specific CD8 T cells derived from both cohorts of patients. Although a strong preference for TRAV12-2 segment usage was present in nearly all patients, usage of particular TRAJ gene segments and CDR3alpha composition differed slightly after vaccination with natural vs analog peptide. Moreover, TCR beta-chain repertoires were broader after natural than analog peptide vaccination. In all patients, we observed a marked conservation of the CDR3beta amino acid composition with recurrent sequences centered on a glycyl leucyl/valyl/alanyl-glycyl motif. In contrast to viral-specific TCR repertoires, such "public" motifs were primarily expressed by nondominant T cell clonotypes, which contrasted with "private" CDR3beta signatures frequently found in T cell clonotypes that dominated repertoires of individual patients. Interestingly, no differences in functional avidity were observed between public and private T cell clonotypes. Collectively, our data indicate that T cell repertoires generated against natural or analog Melan-A peptide exhibited slightly distinct but otherwise overlapping and structurally conserved TCR features, suggesting that the differences in binding affinity/avidity of TCRs toward pMHC observed in the two cohorts of patients are caused by subtle structural TCR variations. PMID- 19786556 TI - Receptor-mediated and lectin-like activities of carp (Cyprinus carpio) TNF-alpha. AB - Functional characterization of TNF-alpha in species other than mammalian vertebrates is limited, and TNF-alpha has been studied in a limited number of fish species, primarily in vitro using recombinant proteins. Studies on TNF-alpha from different fish species so far pointed to several inconsistencies, in particular with respect to some receptor-mediated activities of fish TNF-alpha, such as the ability to directly activate phagocytes. In the present study a comprehensive analysis of in vitro as well as in vivo biological activities of two isoforms of carp TNF-alpha was performed. Our results show that carp TNF alpha directly primes carp phagocytes and indirectly promotes typical receptor mediated activities such as phagocyte activation by acting via endothelial cells. Additionally, for the first time in nonmammalian vertebrate species, the lectin like activity of fish TNF-alpha homologs was investigated. Our results show an evolutionary conservation of function of this receptor-independent activity of TNF-alpha not only in cyprinid fish, but also in perciform and salmonid fish. The role of TNF-alpha in vivo, during infections of carp with the blood parasite Trypanoplasma borreli, was examined using three fundamentally different but complementary approaches: (1) inhibition of TNF-alpha expression, (2) overexpression of TNF-alpha, and (3) inhibition of shedding of membrane-bound TNF alpha. Our results show that, also in fish, a tight regulation of TNF-alpha expression is important, since depletion or excess of TNF-alpha can make an important difference to survival of infection. Finally, we demonstrate a crucial protective role for membrane-bound TNF-alpha, which has a yet unexploited function in fish. PMID- 19786557 TI - NRF2 cysteine residues are critical for oxidant/electrophile-sensing, Kelch-like ECH-associated protein-1-dependent ubiquitination-proteasomal degradation, and transcription activation. AB - Cells respond to oxidants and electrophiles by activating receptor/transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) to coordinate the induction of cytoprotective genes critical for defense against oxidative and other stresses. Activation involves blocking the ubiquitination-proteasomal degradation of Nrf2. Modification of cysteine thiol groups by inducers in the linker region of Kelch-like ECH-associated protein-1 (Keap1), which congregates Nrf2 into the Keap1/Cul3 E3 complex for ubiquitination, is important but not sufficient for activation of Nrf2. Here we show that evolutionarily conserved cysteine residues of Nrf2 are critical for Nrf2 regulation. FlAsH (an arsenic based fluorophore) and phenylarsine oxide (PAO) potently induce Nrf2 target genes and bind to Nrf2 in vitro and in vivo. Binding is inhibited by prototypical inducers arsenic and tert-butylhydroquinone. PAO affinity pull-down and mutation of individual cysteine to alanine reveal that Cys235, Cys311, Cys316, Cys414, and Cys506 are critical for binding, and binding is modulated by intramolecular interactions. To corroborate the functions of cysteine residues, Nrf2 wild-type or mutants are expressed in Nrf2 knockout cells to reconstitute Nrf2 regulation. Nrf2 mutants have reduced t(1/2) that inversely correlates with increased binding to Keap1 and polyubiquitination of mutant proteins. It is remarkable that the mutants fail to respond to arsenic for Nrf2 activation and gene induction. Furthermore, mutations at Cys119, Cys235, and Cys506 impede binding of Nrf2 to endogenous antioxidant response element and to coactivator cAMP response element binding protein-binding protein/p300. The findings demonstrate that Nrf2 cysteine residues critically regulate oxidant/electrophile sensing, repress Keap1 dependent ubiquitination-proteasomal degradation, and promote recruitment of coactivators, such that chemical sensing, receptor activation, and transcription activation are integrated at the receptor molecule. PMID- 19786558 TI - The basic helix-loop-helix proteins differentiated embryo chondrocyte (DEC) 1 and DEC2 function as corepressors of retinoid X receptors. AB - The basic helix-loop-helix proteins differentiated embryo chondrocyte 1 (DEC1) and DEC2 are involved in circadian rhythm control. Because the metabolism of dietary nutrients has been linked to circadian regulation, we examined the effect of DEC1 and DEC2 on the function of the metabolite-sensing nuclear receptors, ligand-dependent transcription factors, including retinoid X receptor (RXR) and liver X receptor (LXR). Transfection assays showed that DEC1 and DEC2 repressed ligand-dependent transactivation by RXR. Knockdown of endogenous DEC1 and DEC2 expression with small interfering RNAs augmented ligand-dependent RXRalpha transactivation. DEC1 and DEC2 interacted directly with RXRalpha, and ligand addition enhanced their association. DEC1 and DEC2 modified interaction of RXRalpha with cofactor proteins. Transfection assays using DEC1 and DEC2 mutants revealed that the C-terminal region of DEC2 is required for repression and that an LXXLL motif in DEC1 and DEC2 is necessary for RXRalpha repression. DEC1 and DEC2 repressed the induction of LXR target genes, associated with the promoter of an LXR target gene, and dissociated from the promoter with ligand treatment. Knockdown of endogenous DEC1 and DEC2 enhanced the LXR target gene expression in hepatocytes. Expression of Dec1, Dec2, and Srebp-1c showed a circadian rhythm in the liver of mice, whereas that of Lxralpha, Lxrbeta, and Rxralpha was not rhythmic. DEC1 and DEC2 also repressed the transactivation of other RXR heterodimers, such as farnesoid X receptor, vitamin D receptor, and retinoic acid receptor. Thus, the repressor function of DEC1 and DEC2 may be extended to other RXR heterodimer nuclear receptors. PMID- 19786559 TI - The enteropathogenic Escherichia coli effector Cif induces delayed apoptosis in epithelial cells. AB - The cycle inhibiting factor (Cif) belongs to a family of bacterial toxins, the cyclomodulins, which modulate the host cell cycle. Upon injection into the host cell by the type III secretion system of enteropathogenic Escherichia coli (EPEC), Cif induces both G(2) and G(1) cell cycle arrests. The cell cycle arrests correlate with the accumulation of p21(waf1) and p27(kip1) proteins that inhibit CDK-cyclin complexes, whose activation is required for G(1)/S and G(2)/M transitions. Increases of p21 and p27 levels are independent of p53 transcriptional induction and result from protein stabilization through inhibition of the ubiquitin/proteasome degradation pathway. In this study, we show that Cif not only induces cell cycle arrest but also eventually provokes a delayed cell death. Indeed, 48 h after infection with EPEC expressing Cif, cultured IEC-6 intestinal cells were positive for extracellular binding of annexin V and exhibited high levels of cleaved caspase-3 and lactate dehydrogenase release, indicating evidence of apoptosis. Cif was necessary and sufficient for inducing this late apoptosis, and the cysteine residue of the catalytic site was required for Cif activity. These results highlight a more complex role of Cif than previously thought, as a cyclomodulin but also as an apoptosis inducer. PMID- 19786560 TI - Coxiella burnetii isolates cause genogroup-specific virulence in mouse and guinea pig models of acute Q fever. AB - Q fever is a zoonotic disease of worldwide significance caused by the obligate intracellular bacterium Coxiella burnetii. Humans with Q fever may experience an acute flu-like illness and pneumonia and/or chronic hepatitis or endocarditis. Various markers demonstrate significant phylogenetic separation between and clustering among isolates from acute and chronic human disease. The clinical and pathological responses to infection with phase I C. burnetii isolates from the following four genomic groups were evaluated in immunocompetent and immunocompromised mice and in guinea pig infection models: group I (Nine Mile, African, and Ohio), group IV (Priscilla and P), group V (G and S), and group VI (Dugway). Isolates from all of the groups produced disease in the SCID mouse model, and genogroup-consistent trends were noted in cytokine production in response to infection in the immunocompetent-mouse model. Guinea pigs developed severe acute disease when aerosol challenged with group I isolates, mild to moderate acute disease in response to group V isolates, and no acute disease when infected with group IV and VI isolates. C. burnetii isolates have a range of disease potentials; isolates within the same genomic group cause similar pathological responses, and there is a clear distinction in strain virulence between these genomic groups. PMID- 19786561 TI - Vaccination with the ML0276 antigen reduces local inflammation but not bacterial burden during experimental Mycobacterium leprae infection. AB - Leprosy elimination has been a goal of the WHO for the past 15 years. Widespread BCG vaccination and multidrug therapy have dramatically reduced worldwide leprosy prevalence, but new case detection rates have remained relatively constant. These data suggest that additional control strategies, such as a subunit vaccine, are required to block transmission and to improve leprosy control. We recently identified several Mycobacterium leprae antigens that stimulate gamma interferon (IFN-gamma) secretion upon incubation with blood from paucibacillary leprosy patients, a group who limit M. leprae growth and dissemination. In this study, we demonstrate that M. leprae-specific mouse T-cell lines recognize several of these antigens, with the ML0276 protein stimulating the most IFN-gamma secretion. We then examined if the ML0276 protein could be used in a subunit vaccine to provide protection against experimental M. leprae infection. Our data demonstrate that combining ML0276 with either a Toll-like receptor 4 (TLR4) (EM005), TLR7 (imiquimod), or TLR9 (CpG DNA) agonist during immunization induces Th1 responses that limit local inflammation upon experimental M. leprae infection. Our data indicate that only the ML0276/EM005 regimen is able to elicit a response that is transferable to recipient mice. Despite the potent Th1 response induced by this regimen, it could not provide protection in terms of limiting bacterial growth. We conclude that EM005 is the most potent adjuvant for stimulating a Th1 response and indicate that while a subunit vaccine containing the ML0276 protein may be useful for the prevention of immune pathology during leprosy, it will not control bacterial burden and is therefore unlikely to interrupt disease transmission. PMID- 19786562 TI - Vaccine potentials of an intrinsically unstructured fragment derived from the blood stage-associated Plasmodium falciparum protein PFF0165c. AB - We have identified new malaria vaccine candidates through the combination of bioinformatics prediction of stable protein domains in the Plasmodium falciparum genome, chemical synthesis of polypeptides, in vitro biological functional assays, and association of an antigen-specific antibody response with protection against clinical malaria. Within the predicted open reading frame of P. falciparum hypothetical protein PFF0165c, several segments with low hydrophobic amino acid content, which are likely to be intrinsically unstructured, were identified. The synthetic peptide corresponding to one such segment (P27A) was well recognized by sera and peripheral blood mononuclear cells of adults living in different regions where malaria is endemic. High antibody titers were induced in different strains of mice and in rabbits immunized with the polypeptide formulated with different adjuvants. These antibodies recognized native epitopes in P. falciparum-infected erythrocytes, formed distinct bands in Western blots, and were inhibitory in an in vitro antibody-dependent cellular inhibition parasite-growth assay. The immunological properties of P27A, together with its low polymorphism and association with clinical protection from malaria in humans, warrant its further development as a malaria vaccine candidate. PMID- 19786563 TI - oxyR, a LysR-type regulator involved in Klebsiella pneumoniae mucosal and abiotic colonization. AB - Colonization of the gastrointestinal tract is the first event in Klebsiella pneumoniae nosocomial infections, followed by colonization of the bladder or respiratory tract or entry into the bloodstream. To survive in the host, bacteria must harbor specific traits and overcome multiple stresses. OxyR is a conserved bacterial transcription factor with a key role both in the upregulation of defense mechanisms against oxidative stress and in pathogenesis by enhancing biofilm formation, fimbrial expression, and mucosal colonization. A homolog of oxyR was detected in silico in the K. pneumoniae sequenced genome and amplified from the LM21 wild-type strain. To determine the role of oxyR in K. pneumoniae host-interaction processes, an oxyR isogenic mutant was constructed, and its behavior was assessed. At concentrations lower than 10(7) ml(-1), oxyR-deficient organisms were easily killed by micromolar concentrations of H(2)O(2) and exhibited typical aerobic phenotypes. The oxyR mutant was impaired in biofilm formation and types 1 and 3 fimbrial gene expression. In addition, the oxyR mutant was unable to colonize the murine gastrointestinal tract, and in vitro assays showed that it was defective in adhesion to Int-407 and HT-29 intestinal epithelial cells. The behavior of the oxyR mutant was also determined under hostile conditions, reproducing stresses encountered in the gastrointestinal environment: deletion of oxyR resulted in higher sensitivity to bile and acid stresses but not to osmotic stress. These results show the pleiotropic role of oxyR in K. pneumoniae gastrointestinal colonization. PMID- 19786564 TI - Bacterial toxins induce sustained mRNA expression of the silencing transcription factor klf2 via inactivation of RhoA and Rhophilin 1. AB - Yersiniae bearing the Yersinia virulence plasmid pYV impact the transcriptome of J774A.1 macrophage-like cells in two distinct ways: (i) by suppressing, in a Yersinia outer protein P (YopP)-dependent manner, the induction of inflammatory response genes and (ii) by mRNA induction of the silencing transcription factor klf2. Here we show that klf2 induction by Yersinia enterocolitica occurs in several cell lines of macrophage and squamous and upper gastrointestinal epithelial origin as well as in bone marrow-derived dendritic cells. Several strains of Pseudomonas aeruginosa and Staphylococcus aureus are equally effective as Y. enterocolitica in inducing klf2 expression. Screening of mutant strains or incubation with recombinant toxins identified the rho-inactivating toxins YopT from Yersinia spp., ExoS from Pseudomonas aeruginosa, EDIN-B from Staphylococcus aureus, and C3bot from Clostridium botulinum as bacterial inducers of klf2 mRNA. klf2 mRNA induction by these toxins does not require de novo protein synthesis. Serum response factor or actin depolymerization does not seem to be involved in regulating klf2 expression in response to bacterial infection. Instead, short hairpin RNA-mediated inactivation of RhoA and its effector rhophilin 1 is sufficient to induce long-term klf2 expression. Thus, bacteria exploit the RhoA rhophilin signaling cascade to mediate sustained expression of the immunosuppressive transcription factor klf2. PMID- 19786565 TI - MyD88-deficient mice exhibit decreased parasite-induced immune responses but reduced disease severity in a murine model of neurocysticercosis. AB - The symptomatic phase of neurocysticercosis (NCC), a parasitic disease of the central nervous system (CNS) in humans, is characterized by inflammatory responses leading to neuropathology and, in some cases, death. In an animal model of NCC in which mice were intracranially inoculated with the parasite Mesocestoides corti, the infection in mice lacking the myeloid differentiation primary response gene 88 (MyD88(-/-)) resulted in decreased disease severity and improved survival compared with that in wild-type (WT) mice. The CNS of MyD88(-/ ) mice was more quiescent, with decreased microgliosis and tissue damage. These mice exhibited substantially reduced primary and secondary microglial nodule formations and lacked severe astrogliotic reactions, which were seen in WT mice. Significantly reduced numbers of CD11b(+) myeloid cells, alphabeta T cells, gammadelta T cells, and B cells were present in the brains of MyD88(-/-) mice in comparison with those of WT mice. This decrease in cellular infiltration correlated with a decrease in blood-brain barrier permeability, as measured by reduced fibrinogen extravasation. Comparisons of cytokine expression indicated a significant decrease in the CNS levels of several inflammatory mediators, such as tumor necrosis factor alpha, gamma interferon, CCL2, and interleukin-6, during the course of infection in MyD88(-/-) mice. Collectively, these findings suggest that MyD88 plays a prominent role in the development of the hyperinflammatory response, which in turn contributes to neuropathology and disease severity in NCC. PMID- 19786566 TI - Phytosterol plasma concentrations and coronary heart disease in the prospective Spanish EPIC cohort. AB - Phytosterol intake with natural foods, a measure of healthy dietary choices, increases plasma levels, but increased plasma phytosterols are believed to be a coronary heart disease (CHD) risk factor. To address this paradox, we evaluated baseline risk factors, phytosterol intake, and plasma noncholesterol sterol levels in participants of a case control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) Spanish cohort who developed CHD (n = 299) and matched controls (n = 584) who remained free of CHD after a 10 year follow-up. Sitosterol-to-cholesterol ratios increased across tertiles of phytosterol intake (P = 0.026). HDL-cholesterol level increased, and adiposity measures, cholesterol/HDL ratios, and levels of glucose, triglycerides, and lathosterol, a cholesterol synthesis marker, decreased across plasma sitosterol tertiles (P < 0.02; all). Compared with controls, cases had nonsignificantly lower median levels of phytosterol intake and plasma sitosterol. The multivariable-adjusted odds ratio for CHD across the lowest to highest plasma sitosterol tertile was 0.59 (95% confidence interval, 0.36-0.97). Associations were weaker for plasma campesterol. The apolipoprotein E genotype was unrelated to CHD risk or plasma phytosterols. The data suggest that plasma sitosterol levels are associated with a lower CHD risk while being markers of a lower cardiometabolic risk in the EPIC-Spain cohort, a population with a high phytosterol intake. PMID- 19786567 TI - Surface plasmon resonance analysis of the mechanism of binding of apoA-I to high density lipoprotein particles. AB - The partitioning of apolipoprotein A-I (apoA-I) molecules in plasma between HDL bound and -unbound states is an integral part of HDL metabolism. We used the surface plasmon resonance (SPR) technique to monitor in real time the reversible binding of apoA-I to HDL. Biotinylated human HDL(2) and HDL(3) were immobilized on a streptavidin-coated SPR sensor chip, and apoA-I solutions at different concentrations were flowed across the surface. The wild-type (WT) human and mouse apoA-I/HDL interaction involves a two-step process; apoA-I initially binds to HDL with fast association and dissociation rates, followed by a step exhibiting slower kinetics. The isolated N-terminal helix bundle domains of human and mouse apoA-I also exhibit a two-step binding process, consistent with the second slower step involving opening of the helix bundle domain. The results of fluorescence experiments with pyrene-labeled apoA-I are consistent with the N-terminal helix bundle domain interacting with proteins resident on the HDL particle surface. Dissociation constants (K(d)) measured for WT human apoA-I interactions with HDL(2) and HDL(3) are about 10 microM, indicating that the binding is low affinity. This K(d) value does not apply to all of the apoA-I molecules on the HDL particle but only to a relatively small, labile pool. PMID- 19786568 TI - Transcript profiling and lipidomic analysis of ceramide subspecies in mouse embryonic stem cells and embryoid bodies. AB - Ceramides (Cers) are important in embryogenesis, but no comprehensive analysis of gene expression for Cer metabolism nor the Cer amounts and subspecies has been conducted with an often used model: mouse embryonic stem cells (mESCs) versus embroid bodies (EBs). Measuring the mRNA levels by quantitative RT-PCR and the amounts of the respective metabolites by LC-ESI/MS/MS, notable differences between R1 mESCs and EBs were: EBs have higher mRNAs for CerS1 and CerS3, which synthesize C18- and C>or=24-carbons dihydroceramides (DH)Cer, respectively; EBs have higher CerS2 (for C24:0- and C24:1-); and EBs have lower CerS5 + CerS6 (for C16-). In agreement with these findings, EBs have (DH)Cer with higher proportions of C18-, C24- and C26- and less C16-fatty acids, and longer (DH)Cer are also seen in monohexosyl Cers and sphingomyelins. EBs had higher mRNAs for fatty acyl-CoA elongases that produce C18-, C24-, and C26-fatty acyl-CoAs (Elovl3 and Elovl6), and higher amounts of these cosubstrates for CerS. Thus, these studies have found generally good agreement between genomic and metabolomic data in defining that conversion of mESCs to EBs is accompanied by a large number of changes in gene expression and subspecies distributions for both sphingolipids and fatty acyl CoAs. PMID- 19786569 TI - Crucial role for Mst1 and Mst2 kinases in early embryonic development of the mouse. AB - Mammalian sterile 20-like kinases 1 and 2 (Mst1 and Mst2, respectively) are potent serine/threonine kinases that are involved in cell proliferation and cell death. To investigate the physiological functions of Mst1 and Mst2, we generated Mst1 and Mst2 mutant mice. Mst1(-/-) and Mst2(-/-) mice were viable and fertile and developed normally, suggesting possible functional overlaps between the two genes. A characterization of heterozygous and homozygous combinations of Mst1 and Mst2 mutant mice showed that mice containing a single copy of either gene underwent normal organ development; however, Mst1(-/-); Mst2(-/-) mice lacking both Mst1 and Mst2 genes started dying in utero at approximately embryonic day 8.5. Mst1(-/-); Mst2(-/-) mice exhibited severe growth retardation, failed placental development, impaired yolk sac/embryo vascular patterning and primitive hematopoiesis, increased apoptosis in placentas and embryos, and disorganized proliferating cells in the embryo proper. These findings indicate that both Mst1 and Mst2 kinases play essential roles in early mouse development, regulating placental development, vascular patterning, primitive hematopoiesis, and cell proliferation and survival. PMID- 19786570 TI - Loss of YY1 impacts the heterochromatic state and meiotic double-strand breaks during mouse spermatogenesis. AB - The progression of spermatogenesis involves global changes in chromatin structure and conformation. However, our understanding of the regulation of chromatin changes in germ cells remains limited. Here we describe both in vivo RNA interference and genetic mouse knockout studies that identify a critical role for Yin Yang 1 (YY1) in mammalian spermatogenesis. In the YY1-deficient spermatocytes, we find a significant decrease in the global level of the heterochromatin markers (H3K9me3 and HP1-gamma) and a concomitant increase in the double-strand break (DSB) signals on chromosomes (gamma-H2AX, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling, and Rad51) at the leptotene/zygotene stages of spermatocytes. These findings support a link between chromatin modifications and meiotic DSB formation, as has been seen in other model organisms. We propose that a depletion of YY1 may alter the structural integrity of heterochromatin, rendering it more accessible to the DSB machinery. In addition, YY1-deficient spermatocytes show univalent formation, increased aneuploidy, and pachytene cell death, which are likely due to defects in DNA repair. Taken together, this study identifies an important role for YY1 in mouse meiosis and provides new insight into mechanisms that regulate mammalian spermatogenesis. PMID- 19786571 TI - Changes in retinoblastoma cell adhesion associated with optic nerve invasion. AB - In the 1970s, several human retinoblastoma cell lines were developed from cultures of primary tumors. As the human retinoblastoma cell lines were established in culture, growth properties and changes in cell adhesion were described. Those changes correlated with the ability of the human retinoblastoma cell lines to invade the optic nerve and metastasize in orthotopic xenograft studies. However, the mechanisms that underlie these changes were not determined. We used the recently developed knockout mouse models of retinoblastoma to begin to characterize the molecular, cellular, and genetic changes associated with retinoblastoma tumor progression and optic nerve invasion. Here we report the isolation and characterization of the first mouse retinoblastoma cell lines with targeted deletions of the Rb family. Our detailed analysis of these cells as they were propagated in culture from the primary tumor shows that changes in cadherin mediated cell adhesion are associated with retinoblastoma invasion of the optic nerve prior to metastasis. In addition, the same changes in cadherin-mediated cell adhesion correlate with the invasive properties of the human retinoblastoma cell lines isolated decades ago, providing a molecular mechanism for these earlier observations. Most importantly, our studies are in agreement with genetic studies on human retinoblastomas, suggesting that changes in this pathway are involved in tumor progression. PMID- 19786572 TI - Autophagy promotes synapse development in Drosophila. AB - Autophagy, a lysosome-dependent degradation mechanism, mediates many biological processes, including cellular stress responses and neuroprotection. In this study, we demonstrate that autophagy positively regulates development of the Drosophila melanogaster larval neuromuscular junction (NMJ). Autophagy induces an NMJ overgrowth phenotype closely resembling that of highwire (hiw), an E3 ubiquitin ligase mutant. Moreover, like hiw, autophagy-induced NMJ overgrowth is suppressed by wallenda (wnd) and by a dominant-negative c-Jun NH(2)-terminal kinase (bsk(DN)). We show that autophagy promotes NMJ growth by reducing Hiw levels. Thus, autophagy and the ubiquitin-proteasome system converge in regulating synaptic development. Because autophagy is triggered in response to many environmental cues, our findings suggest that it is perfectly positioned to link environmental conditions with synaptic growth and plasticity. PMID- 19786574 TI - INTS3 controls the hSSB1-mediated DNA damage response. AB - Human SSB1 (single-stranded binding protein 1 [hSSB1]) was recently identified as a part of the ataxia telangiectasia mutated (ATM) signaling pathway. To investigate hSSB1 function, we performed tandem affinity purifications of hSSB1 mutants mimicking the unphosphorylated and ATM-phosphorylated states. Both hSSB1 mutants copurified a subset of Integrator complex subunits and the uncharacterized protein LOC58493/c9orf80 (henceforth minute INTS3/hSSB-associated element [MISE]). The INTS3-MISE-hSSB1 complex plays a key role in ATM activation and RAD51 recruitment to DNA damage foci during the response to genotoxic stresses. These effects on the DNA damage response are caused by the control of hSSB1 transcription via INTS3, demonstrating a new network controlling hSSB1 function. PMID- 19786575 TI - An eIF4E-binding protein regulates katanin protein levels in C. elegans embryos. AB - In Caenorhabditis elegans, the MEI-1-katanin microtubule-severing complex is required for meiosis, but must be down-regulated during the transition to embryogenesis to prevent defects in mitosis. A cullin-dependent degradation pathway for MEI-1 protein has been well documented. In this paper, we report that translational repression may also play a role in MEI-1 down-regulation. Reduction of spn-2 function results in spindle orientation defects due to ectopic MEI-1 expression during embryonic mitosis. MEL-26, which is both required for MEI-1 degradation and is itself a target of the cullin degradation pathway, is present at normal levels in spn-2 mutant embryos, suggesting that the degradation pathway is functional. Cloning of spn-2 reveals that it encodes an eIF4E-binding protein that localizes to the cytoplasm and to ribonucleoprotein particles called P granules. SPN-2 binds to the RNA-binding protein OMA-1, which in turn binds to the mei-1 3' untranslated region. Thus, our results suggest that SPN-2 functions as an eIF4E-binding protein to negatively regulate translation of mei-1. PMID- 19786576 TI - DNA replication times the cell cycle and contributes to the mid-blastula transition in Drosophila embryos. AB - We examined the contribution of S phase in timing cell cycle progression during Drosophila embryogenesis using an approach that deletes S phase rather than arresting its progress. Injection of Drosophila Geminin, an inhibitor of replication licensing, prevented subsequent replication so that the following mitosis occurred with uninemic chromosomes, which failed to align. The effect of S phase deletion on interphase length changed with development. During the maternally regulated syncytial blastoderm cycles, deleting S phase shortened interphase, and deletion of the last of blastoderm S phase (cycle 14) induced an extra synchronous division and temporarily deferred mid-blastula transition (MBT) events. In contrast, deleting S phase after the MBT in cycle 15 did not dramatically affect mitotic timing, which appears to retain its dependence on developmentally programmed zygotic transcription. We conclude that normal S phase and replication checkpoint activities are important timers of the undisturbed cell cycle before, but not after, the MBT. PMID- 19786580 TI - Absence of a catalytic water confers resistance to the neurotoxin gabaculine. AB - Gabaculine is a potent inhibitor of the vitamin B6-dependent key enzyme in chlorophyll biosynthesis, glutamate-1-semialdehyde aminomutase (GSAM). The inhibition effect is caused by an enzymatic deprotonation of the neurotoxin and requires the aldimine (PLP) form of the cofactor at the active site. In this study, we show that a single-point mutation confers resistance to gabaculine. A combined functional and structural analysis of wild-type GSAM in complex with gabaculine and the GSAM(M248I) form allowed us to decipher in atomic detail the molecular basis of this unique resistance. Interestingly, the gabaculine tolerance is caused by the absence of an essential water molecule that has a dual functional role. It serves as a nucleophilic shuttle for the hydroxyl anion along the reaction pathway and holds active-site Lys273 in a catalytically competent conformation. The single-point mutant is not able to fix this catalytic water between the beta-branched side chain of Ile248 and Lys273. As a consequence, the mutant enzyme is trapped in a gabaculine-insensitive but still enzymatically active amine (PMP) form. PMID- 19786577 TI - Coupled myosin VI motors facilitate unidirectional movement on an F-actin network. AB - Unconventional myosins interact with the dense cortical actin network during processes such as membrane trafficking, cell migration, and mechanotransduction. Our understanding of unconventional myosin function is derived largely from assays that examine the interaction of a single myosin with a single actin filament. In this study, we have developed a model system to study the interaction between multiple tethered unconventional myosins and a model F-actin cortex, namely the lamellipodium of a migrating fish epidermal keratocyte. Using myosin VI, which moves toward the pointed end of actin filaments, we directly determine the polarity of the extracted keratocyte lamellipodium from the cell periphery to the cell nucleus. We use a combination of experimentation and simulation to demonstrate that multiple myosin VI molecules can coordinate to efficiently transport vesicle-size cargo over 10 microm of the dense interlaced actin network. Furthermore, several molecules of monomeric myosin VI, which are nonprocessive in single molecule assays, can coordinate to transport cargo with similar speeds as dimers. PMID- 19786578 TI - Epidermal progenitors give rise to Merkel cells during embryonic development and adult homeostasis. AB - Merkel cells (MCs) are located in the touch-sensitive area of the epidermis and mediate mechanotransduction in the skin. Whether MCs originate from embryonic epidermal or neural crest progenitors has been a matter of intense controversy since their discovery >130 yr ago. In addition, how MCs are maintained during adulthood is currently unknown. In this study, using lineage-tracing experiments, we show that MCs arise through the differentiation of epidermal progenitors during embryonic development. In adults, MCs undergo slow turnover and are replaced by cells originating from epidermal stem cells, not through the proliferation of differentiated MCs. Conditional deletion of the Atoh1/Math1 transcription factor in epidermal progenitors results in the absence of MCs in all body locations, including the whisker region. Our study demonstrates that MCs arise from the epidermis by an Atoh1-dependent mechanism and opens new avenues for study of MC functions in sensory perception, neuroendocrine signaling, and MC carcinoma. PMID- 19786581 TI - Pichia pastoris as a host for secretion of toxic saporin chimeras. AB - Most of the targeting moieties, such as antibody fragments or growth factor domains, used to construct targeted toxins for anticancer therapy derive from secretory proteins. These normally fold in the oxidative environment of the endoplasmic reticulum, and hence their folding in bacterial cells can be quite inefficient. For instance, only low amounts of properly folded antimetastatic chimera constituted by the amino-terminal fragment of human urokinase (ATF) fused to the plant ribosome-inactivating protein saporin could be recovered. ATF saporin was instead secreted efficiently when expressed in eukaryotic cells protected from autointoxication with neutralizing anti-saporin antibodies. Pichia pastoris is a microbial eukaryotic host where these domains can fold into a transport-competent conformation and reach the extracellular medium. We show here that despite some host toxicity codon-usage optimization greatly increased the expression levels of active saporin but not those of an active-site mutant SAP-KQ in GS115 (his4) strain. The lack of any toxicity associated with expression of the latter confirmed that toxicity is due to saporin catalytic activity. Nevertheless, GS115 (his4) cells in flask culture secreted 3.5 mg/L of a histidine-tagged ATF-saporin chimera showing an IC(50) of 6 x 10(-11) M against U937 cells, thus demonstrating the suitability of this expression platform for secretion of toxic saporin-based chimeras. PMID- 19786582 TI - Suppression of Ca2+ syntillas increases spontaneous exocytosis in mouse adrenal chromaffin cells. AB - A central concept in the physiology of neurosecretion is that a rise in cytosolic [Ca(2+)] in the vicinity of plasmalemmal Ca(2+) channels due to Ca(2+) influx elicits exocytosis. Here, we examine the effect on spontaneous exocytosis of a rise in focal cytosolic [Ca(2+)] in the vicinity of ryanodine receptors (RYRs) due to release from internal stores in the form of Ca(2+) syntillas. Ca(2+) syntillas are focal cytosolic transients mediated by RYRs, which we first found in hypothalamic magnocellular neuronal terminals. (scintilla, Latin for spark; found in nerve terminals, normally synaptic structures.) We have also observed Ca(2+) syntillas in mouse adrenal chromaffin cells. Here, we examine the effect of Ca(2+) syntillas on exocytosis in chromaffin cells. In such a study on elicited exocytosis, there are two sources of Ca(2+): one due to influx from the cell exterior through voltage-gated Ca(2+) channels, and that due to release from intracellular stores. To eliminate complications arising from Ca(2+) influx, we have examined spontaneous exocytosis where influx is not activated. We report here that decreasing syntillas leads to an increase in spontaneous exocytosis measured amperometrically. Two independent lines of experimentation each lead to this conclusion. In one case, release from stores was blocked by ryanodine; in another, stores were partially emptied using thapsigargin plus caffeine, after which syntillas were decreased. We conclude that Ca(2+) syntillas act to inhibit spontaneous exocytosis, and we propose a simple model to account quantitatively for this action of syntillas. PMID- 19786583 TI - Inhibition of K(Ca)2.2 and K(Ca)2.3 channel currents by protonation of outer pore histidine residues. AB - Ion channels are often modulated by changes in extracellular pH, with most examples resulting from shifts in the ionization state of histidine residue(s) in the channel pore. The application of acidic extracellular solution inhibited expressed K(Ca)2.2 (SK2) and K(Ca)2.3 (SK3) channel currents, with K(Ca)2.3 (pIC(50) of approximately 6.8) being approximately fourfold more sensitive than K(Ca)2.2 (pIC(50) of approximately 6.2). Inhibition was found to be voltage dependent, resulting from a shift in the affinity for the rectifying intracellular divalent cation(s) at the inner mouth of the selectivity filter. The inhibition by extracellular protons resulted from a reduction in the single channel conductance, without significant changes in open-state kinetics or open probability. K(Ca)2.2 and K(Ca)2.3 subunits both possess a histidine residue in their outer pore region between the transmembrane S5 segment and the pore helix, with K(Ca)2.3 also exhibiting an additional histidine residue between the selectivity filter and S6. Mutagenesis revealed that the outer pore histidine common to both channels was critical for inhibition. The greater sensitivity of K(Ca)2.3 currents to protons arose from the additional histidine residue in the pore, which was more proximal to the conduction pathway and in the electrostatic vicinity of the ion conduction pathway. The decrease of channel conductance by extracellular protons was mimicked by mutation of the outer pore histidine in K(Ca)2.2 to an asparagine residue. These data suggest that local interactions involving the outer turret histidine residues are crucial to enable high conductance openings, with protonation inhibiting current by changing pore shape. PMID- 19786584 TI - Regulation of ClC-1 and KATP channels in action potential-firing fast-twitch muscle fibers. AB - Action potential (AP) excitation requires a transient dominance of depolarizing membrane currents over the repolarizing membrane currents that stabilize the resting membrane potential. Such stabilizing currents, in turn, depend on passive membrane conductance (G(m)), which in skeletal muscle fibers covers membrane conductances for K(+) (G(K)) and Cl(-) (G(Cl)). Myotonic disorders and studies with metabolically poisoned muscle have revealed capacities of G(K) and G(Cl) to inversely interfere with muscle excitability. However, whether regulation of G(K) and G(Cl) occur in AP-firing muscle under normal physiological conditions is unknown. This study establishes a technique that allows the determination of G(Cl) and G(K) with a temporal resolution of seconds in AP-firing muscle fibers. With this approach, we have identified and quantified a biphasic regulation of G(m) in active fast-twitch extensor digitorum longus fibers of the rat. Thus, at the onset of AP firing, a reduction in G(Cl) of approximately 70% caused G(m) to decline by approximately 55% in a manner that is well described by a single exponential function characterized by a time constant of approximately 200 APs (phase 1). When stimulation was continued beyond approximately 1,800 APs, synchronized elevations in G(K) ( approximately 14-fold) and G(Cl) ( approximately 3-fold) caused G(m) to rise sigmoidally to approximately 400% of its level before AP firing (phase 2). Phase 2 was often associated with a failure to excite APs. When AP firing was ceased during phase 2, G(m) recovered to its level before AP firing in approximately 1 min. Experiments with glibenclamide (K(ATP) channel inhibitor) and 9-anthracene carboxylic acid (ClC-1 Cl(-) channel inhibitor) revealed that the decreased G(m) during phase 1 reflected ClC-1 channel inhibition, whereas the massively elevated G(m) during phase 2 reflected synchronized openings of ClC-1 and K(ATP) channels. In conclusion, G(Cl) and G(K) are acutely regulated in AP-firing fast-twitch muscle fibers. Such regulation may contribute to the physiological control of excitability in active muscle. PMID- 19786585 TI - Comparison of regulated passive membrane conductance in action potential-firing fast- and slow-twitch muscle. AB - In several pathological and experimental conditions, the passive membrane conductance of muscle fibers (G(m)) and their excitability are inversely related. Despite this capacity of G(m) to determine muscle excitability, its regulation in active muscle fibers is largely unexplored. In this issue, our previous study (Pedersen et al. 2009. J. Gen. Physiol. doi:10.1085/jgp.200910291) established a technique with which biphasic regulation of G(m) in action potential (AP)-firing fast-twitch fibers of rat extensor digitorum longus muscles was identified and characterized with temporal resolution of seconds. This showed that AP firing initially reduced G(m) via ClC-1 channel inhibition but after approximately 1,800 APs, G(m) rose substantially, causing AP excitation failure. This late increase of G(m) reflected activation of ClC-1 and K(ATP) channels. The present study has explored regulation of G(m) in AP-firing slow-twitch fibers of soleus muscle and compared it to G(m) dynamics in fast-twitch fibers. It further explored aspects of the cellular signaling that conveyed regulation of G(m) in AP-firing fibers. Thus, in both fiber types, AP firing first triggered protein kinase C (PKC) dependent ClC-1 channel inhibition that reduced G(m) by approximately 50%. Experiments with dantrolene showed that AP-triggered SR Ca(2+) release activated this PKC-mediated ClC-1 channel inhibition that was associated with reduced rheobase current and improved function of depolarized muscles, indicating that the reduced G(m) enhanced muscle fiber excitability. In fast-twitch fibers, the late rise in G(m) was accelerated by glucose-free conditions, whereas it was postponed when intermittent resting periods were introduced during AP firing. Remarkably, elevation of G(m) was never encountered in AP-firing slow-twitch fibers, even after 15,000 APs. These observations implicate metabolic depression in the elevation of G(m) in AP-firing fast-twitch fibers. It is concluded that regulation of G(m) is a general phenomenon in AP-firing muscle, and that differences in G(m) regulation may contribute to the different phenotypes of fast and slow-twitch muscle. PMID- 19786586 TI - Unexpected urine drug testing results in a hospice patient on high-dose morphine therapy. PMID- 19786587 TI - Commentary. PMID- 19786588 TI - Commentary. PMID- 19786589 TI - Frontiers in clinical diagnostics. Abstracts of the 41st Oak Ridge Conference, April 16-17, 2009, Baltimore, Maryland, USA. PMID- 19786594 TI - Community-based primary care: improving and assessing diabetes management. AB - Morbidity and mortality associated with diabetes make it a prime target for quality improvement research. Quality gaps and racial/gender disparities persist throughout this population of patients necessitating a sustainable improvement in the clinical management of diabetes. The authors of this study sought (1) to provide a population perspective on diabetes management, and (2) to reinforce evidence-based clinical guidelines through a Web-based educational module.The project also aimed to gain insight into working remotely with a community of rural physicians. This longitudinal pre-post intervention study involved 18 internal medicine physicians and included 3 points of medical record data abstraction over 24 months. A Web-based educational module was introduced after the baseline data abstraction. This module contained chapters on clinical education, practice tools, and self-assessment. The results showed a sustained improvement in most clinical outcomes and demonstrated the effectiveness of using Web-based mediums to reinforce clinical guidelines and change physician behavior. PMID- 19786595 TI - Atomic force microscopy investigation of the morphology and topography of colistin-heteroresistant Acinetobacter baumannii strains as a function of growth phase and in response to colistin treatment. AB - The prevalence of infections caused by multidrug-resistant gram-negative Acinetobacter baumannii strains and the lack of novel antibiotics under development are posing a global dilemma, forcing a resurgence of the last-line antibiotic colistin. Our aim was to use atomic force microscopy (AFM) to investigate the morphology and topography of paired colistin-susceptible and resistant cells from colistin-heteroresistant A. baumannii strains as a function of bacterial growth phase and colistin exposure. An optimal AFM bacterial sample preparation protocol was established and applied to examine three paired strains. Images revealed rod-shaped colistin-susceptible cells (1.65 +/- 0.27 microm by 0.98 +/- 0.07 microm) at mid-logarithmic phase, in contrast to spherical colistin resistant cells (1.03 +/- 0.09 microm); the latter were also more diverse in appearance and exhibited a rougher surface topography (7.05 +/- 1.3 nm versus 11.4 +/- 2.5 nm for susceptible versus resistant, respectively). Cellular elongation up to approximately 18 microm at stationary phase was more commonly observed in susceptible strains, although these "worm-like" cells were also observed occasionally in the resistant population. The effects of colistin exposure on the cell surface of colistin-susceptible and -resistant cells were found to be similar; topographical changes were minor in response to 0.5 microg/ml colistin; however, at 4 microg/ml colistin, a significant degree of surface disruption was detected. At 32 microg/ml colistin, cellular clumping and surface smoothening were evident. Our study has demonstrated for the first time substantial morphological and topographical differences between colistin susceptible and -resistant cells from heteroresistant A. baumannii strains. These results contribute to an understanding of colistin action and resistance in regard to this problematic pathogen. PMID- 19786596 TI - Introduction of ertapenem into a hospital formulary: effect on antimicrobial usage and improved in vitro susceptibility of Pseudomonas aeruginosa. AB - After ertapenem was added to the formulary of a 344-bed community teaching hospital, we retrospectively studied its effect on antimicrobial utilization and on the in vitro susceptibility of various antimicrobial agents against Pseudomonas aeruginosa. Three study periods were defined as preintroduction (months 1 to 9), postintroduction but before the autosubstitution of ertapenem for ampicillin-sulbactam (months 10 to 18), and after the policy of autosubstitution (months 19 to 48) was initiated. Ertapenem usage rose slowly from introduction to a range of 36 to 48 defined daily doses/1,000 patient days (DDD) with a resultant decrease in ampicillin-sulbactam usage due to autosubstitution. Imipenem usage peaked 6 months after the introduction of ertapenem and started to decline coincidently with the increased use of ertapenem. During the second period, imipenem usage decreased (slope = -1.28; P = 0.002). Prior to the introduction of ertapenem, the susceptibility of P. aeruginosa to imipenem increased from 61 to 81% at month 7 but then decreased slightly to 67% at month 9. After the introduction of ertapenem, susceptibility continued to increase; the increasing trend was significant (slope = 1.74; P < 0.001). In the third period, the median susceptibility (interquartile range) was 88% (82 to 95%). This change appeared related to decreased imipenem usage. For every unit decrease in the monthly DDD of imipenem, there was an increase of 0.38% (P = 0.008) in the susceptibility of P. aeruginosa to imipenem in the same month. Ertapenem was effective in our antimicrobial stewardship program and may have helped improve the P. aeruginosa antimicrobial susceptibility to imipenem by decreasing the unnecessary usage and selective pressure of antipseudomonal agents. PMID- 19786597 TI - Fmt bypass in Pseudomonas aeruginosa causes induction of MexXY efflux pump expression. AB - The intrinsic resistance of P. aeruginosa PAO1 to the peptide deformylase inhibitor (PDF-I) LBM415 was mediated by the MexAB-OprM and MexXY-OprM efflux pumps, the latter of which was strongly induced by LBM415. Single-step exposure of PAO1 deleted for mexAB-oprM (therefore lacking both MexAB-OprM and MexXY-OprM functions) to PDF-Is selected for nfxB mutants, which express the MexCD-OprJ efflux pump, indicating that these compounds are also substrates for this pump. Selection of resistant mutants by use of levels of LBM415 greater than that accommodated by efflux yielded two additional groups of mutations, in the methionyl-tRNA(fmet) formyltransferase (fmt) and folD genes. Both mechanisms are known to impose an in vitro growth deficit (also observed here), presumably due to impairment of protein synthesis. We surmised that this inherent impairment of protein synthesis would upregulate expression of mexXY in a fashion similar to upregulation by LBM415 or by ribosome inhibitory compounds. Transcriptional profiling and/or mexX::lux promoter fusion analysis revealed that fmt and folD mutants were strongly upregulated for mexXY and another gene known to be required for upregulation of the pump, PA5471. Complementation of the fmt mutation in trans reversed this constitutive expression. This supports the notion that MexXY has a natural physiological function responding to impairment of ribosome function or protein synthesis and that fmt mutation (Fmt bypass) and folD mutation generate the intracellular mexXY-inducing signal. PMID- 19786598 TI - Spread of bla(CTX-M-14) is driven mainly by IncK plasmids disseminated among Escherichia coli phylogroups A, B1, and D in Spain. AB - Since its first description in 2000, CTX-M-14 has become one of the most widespread extended-spectrum beta-lactamases in Spain. In the present Escherichia coli multilevel population genetic study involving the characterization of phylogroups, clones, plasmids, and genetic platforms, 61 isolates from 16 hospitalized patients and 40 outpatients and healthy volunteers recovered from 2000 to 2005 were analyzed. Clonal relatedness (XbaI pulsed-field gel electrophoresis [PFGE] type, phylogenetic group, multilocus sequence type [MLST]) was established by standard methods. Analysis of transferred plasmids (I-CeuI; S1 nuclease; restriction fragment length polymorphism analysis; and analysis of RNA interference, replicase, and relaxase) was performed by PCR, sequencing, and hybridization. The genetic environment of bla(CTX-M-14) was characterized by PCR on the basis of known associated structures (ISEcp1, IS903, ISCR1). The isolates were mainly recovered from patients in the community (73.8%; 45/61) with urinary tract infections (62.2%; 28/45). They were clonally unrelated by PFGE and corresponded to phylogenetic groups A (36.1%), D (34.4%), and B1 (29.5%). MLST revealed a high degree of sequence type (ST) diversity among phylogroup D isolates and the overrepresentation of the ST10 complex among phylogroup A isolates and ST359/ST155 among phylogroup B1 isolates. Two variants of bla(CTX-M 14) previously designated bla(CTX-M-14a) (n = 59/61) and bla(CTX-M-14b) (n = 2/61) were detected. bla(CTX-M-14a) was associated with either ISEcp1 within IncK plasmids (n = 27), ISCR1 linked to an IncHI2 plasmid (n = 1), or ISCR1 linked to IncI-like plasmids (n = 3). The bla(CTX-M-14b) identified was associated with an ISCR1 element located in an IncHI2 plasmid (n = 1) or with ISEcp1 located in IncK (n = 1). The CTX-M-14-producing E. coli isolates in our geographic area are frequent causes of community-acquired urinary tract infections. The increase in the incidence of such isolates is mostly due to the dissemination of IncK plasmids among E. coli isolates of phylogroups A, B1, and D. PMID- 19786599 TI - Paradoxical growth of Candida dubliniensis does not preclude in vivo response to echinocandin therapy. AB - Candida dubliniensis commonly shows paradoxical or trailing growth effects in vitro in the presence of echinocandins. We tested the in vitro activities of anidulafungin, caspofungin, and micafungin against clinical isolates of C. dubliniensis and evaluated the efficacy of these drugs in two murine models of systemic infection. The three echinocandins were similarly effective in the treatment of experimental disseminated infections with C. dubliniensis strains showing or not showing abnormal growth in vitro. PMID- 19786600 TI - Impact of antifungal prophylaxis on colonization and azole susceptibility of Candida species. AB - Two large studies compared posaconazole and fluconazole or itraconazole for prophylaxis in subjects undergoing allogeneic hematopoietic stem cell transplantation or subjects with acute myelogenous leukemia. To assess the impact of prophylaxis on colonization and the development of resistance in Saccharomyces yeasts, identification and susceptibility testing were performed with yeasts cultured at regular intervals from mouth, throat, and stool samples. Prior to therapy, 34 to 50% of the subjects were colonized with yeasts. For all three drugs, the number of positive Candida albicans cultures decreased during drug therapy. In contrast, the proportion of subjects with positive C. glabrata cultures increased by two- and fourfold in the posaconazole and itraconazole arms, respectively. Likewise, in the fluconazole arm the proportion of subjects with positive C. krusei cultures increased twofold. C. glabrata was the species that most frequently exhibited decreases in susceptibility, and this trend did not differ significantly between the prophylactic regimens. For the subset of subjects from whom colonizing C. glabrata isolates were recovered at the baseline and the end of treatment, approximately 40% of the isolates exhibited more than fourfold increases in MICs during therapy. Molecular typing of the C. albicans and C. glabrata isolates confirmed that the majority of the baseline and end-of treatment isolates were closely related, suggesting that they were persistent colonizers and not newly acquired. Overall breakthrough infections by Candida species were very rare (approximately 1%), and C. glabrata was the colonizing species that was the most frequently associated with breakthrough infections. PMID- 19786601 TI - Correlation of in vitro activity, serum levels, and in vivo efficacy of posaconazole against Rhizopus microsporus in a murine disseminated infection. AB - A broth microdilution method was used to evaluate the in vitro activities of seven antifungal agents against 15 clinical strains of Rhizopus microsporus. Amphotericin B (AMB) and posaconazole (POS) were the most active drugs. In a model of disseminated R. microsporus infection in immunosuppressed mice, we studied the efficacy of POS administered once or twice daily against four of the strains previously tested in vitro and compared it with that of liposomal AMB (LAMB). LAMB was the most effective treatment for the two strains with intermediate susceptibility to POS. For the two POS-susceptible strains, LAMB and POS at 20 mg/kg of body weight twice a day orally showed similar efficacies. The in vivo efficacy of POS administered twice a day orally correlated with the in vitro susceptibility data and the serum drug concentrations. PMID- 19786603 TI - Characteristics of genetic hitchhiking around dihydrofolate reductase gene associated with pyrimethamine resistance in Plasmodium falciparum isolates from India. AB - Sulfadoxine-pyrimethamine (SP) resistance in Plasmodium falciparum has been widespread across continents, causing the major hurdle of controlling malaria. Resistance is encoded mainly by point mutations in P. falciparum dihydrofolate reductase (pfdhfr) and dihydropteroate synthase (pfdhps) target genes. To study the origin and evolution of pyrimethamine resistance on the Indian subcontinent, microsatellite markers flanking the pfdhfr gene were mapped. Here we describe the characteristics of genetic hitchhiking around the pfdhfr gene among 190 P. falciparum isolates. These isolates were collected from five different geographical regions of India (Uttar Pradesh, Madhya Pradesh, Assam, Orissa, and Andaman and Nicobar Islands) where malarial transmission rates and levels of drug resistance vary across regions. Among the isolates, we observed a significant reduction in genetic variation in the +/-20-kb vicinity of the mutant pfdhfr alleles due to hitchhiking. This reduction in genetic diversity was more prominent around quadruple pfdhfr alleles (heterozygosity [H(e)] = 0.23) than around double (H(e) = 0.365) and single (H(e) = 0.465) mutant alleles. Asymmetry in the selective sweep flanking the pfdhfr alleles was observed with regional isolates, emphasizing the drug usage with the parasite population. All the pfdhfr alleles share a single microsatellite haplotype and seem to have originated from a single progenitor similar to that of Southeast Asian (Thailand) pfdhfr mutants. Results of the present study also indicate that the emergence of drug-resistant alleles is a recent phenomenon in India compared to Southeast Asian countries. PMID- 19786602 TI - ADS-J1 inhibits human immunodeficiency virus type 1 entry by interacting with the gp41 pocket region and blocking fusion-active gp41 core formation. AB - We previously identified a small-molecule anti-human immunodeficiency virus type 1 (anti-HIV-1) compound, ADS-J1, using a computer-aided molecular docking technique for primary screening and a sandwich enzyme-linked immunosorbent assay (ELISA) as a secondary screening method. In the present study, we demonstrated that ADS-J1 is an HIV-1 entry inhibitor, as determined by a time-of-addition assay and an HIV-1-mediated cell fusion assay. Further mechanism studies confirmed that ADS-J1 does not block gp120-CD4 binding and exhibits a marginal interaction with the HIV-1 coreceptor CXCR4. However, ADS-J1 inhibited the fusion active gp41 core formation mimicked by peptides derived from the viral gp41 N terminal heptad repeat (NHR) and C-terminal heptad repeat (CHR), as determined by ELISA, native polyacrylamide gel electrophoresis, and circular dichroism analysis. Moreover, using a surface plasmon resonance assay, we found that ADS-J1 could bind directly to IQN17, a trimeric peptide containing the gp41 pocket region, resulting in the conformational change of IQN17 and the blockage of its interaction with a short D peptide, PIE7. The positively charged residue (K574) located in the gp41 pocket region is critical for the binding of ADS-J1 to NHR. These results suggest that ADS-J1 may bind to the viral gp41 NHR region through its hydrophobic and ionic interactions with the hydrophobic and positively charged resides located in the pocket region, subsequently blocking the association between the gp41 NHR and CHR regions to form the fusion-active gp41 core, thereby inhibiting HIV-1-mediated membrane fusion and virus entry. PMID- 19786604 TI - In vivo investigations of selected diamidine compounds against Trypanosoma evansi using a mouse model. AB - Surra is an animal pathogenic protozoan infection, caused by Trypanosoma evansi, that develops into a fatal wasting disease. Control measures rely on diagnosis and treatment. However, with the continuous emergence of drug resistance, this tactic is failing, and the pressing need for new chemotherapeutic agents is becoming critical. With the introduction of novel aromatic diamidines, a new category of antitrypanosomal drugs was discovered. Nevertheless, their efficacy within a T. evansi-infected mouse model was not known. In total, 30 compounds previously selected based on their in vitro activity were tested in a T. evansi mouse model of infection. Six of the compounds were capable of curing T. evansi infected mice at drug doses as low as 0.5 and 0.25 mg/kg of body weight administered for 4 consecutive days, and they were more effective than the standard drugs suramin, diminazene, and quinapyramine. After all selection criteria were applied, three diamidine compounds (DB 75, DB 867, and DB 1192) qualified as lead compounds and were considered to have the potential to act as preclinical candidates against T. evansi infection. PMID- 19786605 TI - Susceptibilities of human cytomegalovirus clinical isolates and other herpesviruses to new acetylated, tetrahalogenated benzimidazole D ribonucleosides. AB - Recently we characterized two inhibitors targeting the human cytomegalovirus (HCMV) terminase, 2-bromo-4,5,6-trichloro-1-(2,3,5-tri-O-acetyl-beta-D ribofuranosyl) benzimidazole (BTCRB) and 2,4,5,6-tetrachloro-1-(2,3,5-tri-O acetyl-beta-D-ribofuranosyl) benzimidazole (Cl(4)RB). The terminase consists of the ATP-hydrolyzing subunit pUL56 and the subunit pUL89 required for duplex nicking. Because mammalian cell DNA replication does not involve cleavage of concatemeric DNA by a terminase, these compounds represent attractive alternative HCMV antivirals. We now have tested these previously identified benzimidazole ribonucleosides in order to determine if they are active against HCMV clinical isolates as well as those of herpes simplex virus type 1, mouse cytomegalovirus, rat cytomegalovirus (RCMV), and varicella-zoster virus (VZV). Antiviral activity was quantified by measurement of viral plaque formation (plaque reduction) and by viral growth kinetics. Interestingly, both BTCRB and Cl(4)RB had an inhibitory effect in ganciclovir (GCV)-sensitive and GCV-resistant clinical isolates, with the best effect produced by Cl(4)RB. Electron microscopy revealed that in cells infected with GCV-sensitive or GCV-resistant isolates, B capsids and dense bodies were formed mainly. Furthermore, pulsed-field gel electrophoresis showed that cleavage of concatenated DNA was inhibited in clinical isolates. In addition, the antiviral effect on other herpesviruses was determined. Interestingly, in plaque reduction assays, BTCRB was active against all tested herpesviruses. The best effects were observed on VZV- and RCMV-infected cells. These results demonstrate that the new compounds are highly active against GCV-resistant and GCV-sensitive clinical isolates and slightly active against other herpesviruses. PMID- 19786606 TI - Susceptibilities of 23 Desulfovibrio isolates from humans. AB - Antimicrobial susceptibilities of 23 strains of Desulfovibrio spp. were tested by Etest. Generally, Desulfovibrio spp. were highly susceptible to sulbactam ampicillin, meropenem, clindamycin, metronidazole, and chloramphenicol: MIC(90)s of 6, 4, 0.19, 0.25, and 8 microg/ml, respectively. In addition, these strains generally showed high MICs to piperacillin and piperacillin-tazobactam. Desulfovibrio fairfieldensis (eight strains) was the species least susceptible to most agents, especially beta-lactams, and was the only species resistant to fluoroquinolones. Desulfovibrio desulfuricans strain Essex 6 isolates were less susceptible to beta-lactams than D. desulfuricans strain MB isolates. PMID- 19786607 TI - Pharmacokinetic-pharmacodynamic modeling of the in vitro activities of oxazolidinone antimicrobial agents against methicillin-resistant Staphylococcus aureus. AB - Linezolid is the first FDA-approved oxazolidinone with activity against clinically important gram-positive pathogens, including methicillin (meticillin) resistant Staphylococcus aureus (MRSA). RWJ-416457 is a new oxazolidinone with an antimicrobial spectrum similar to that of linezolid. The goal of the present study was to develop a general pharmacokinetic (PK)-pharmacodynamic (PD) model that allows the characterization and comparison of the in vitro activities of oxazolidinones, determined in time-kill curve experiments, against MRSA. The in vitro activities of RWJ-416457 and the first-in-class representative, linezolid, against MRSA OC2878 were determined in static and dynamic time-kill curve experiments over a wide range of concentrations: 0.125 to 8 microg/ml (MIC, 0.5 microg/ml) and 0.25 to 16 microg/ml (MIC, 1 microg/ml), respectively. After correction for drug degradation during the time-kill curve experiments, a two subpopulation model was simultaneously fitted to all data in the NONMEM VI program. The robustness of the model and the precision of the parameter estimates were evaluated by internal model validation by nonparametric bootstrap analysis. A two-subpopulation model, consisting of a self-replicating, oxazolidinone susceptible and a persistent, oxazolidinone-insusceptible pool of bacteria was appropriate for the characterization of the time-kill curve data. The PK-PD model identified was capable of accounting for saturation in growth, delays in the onsets of growth and drug-induced killing, as well as naturally occurring bacterial death. The simultaneous fit of the proposed indirect-response, maximum effect model to the data resulted in concentrations that produced a half-maximum killing effect that were significantly (P < 0.05) lower for RWJ-416457 (0.41 microg/ml) than for linezolid (1.39 microg/ml). In combination with the appropriate PK data, the susceptibility-based two-subpopulation model identified may provide valuable guidance for the selection of oxazolidinone doses or dose regimens for use in clinical studies. PMID- 19786608 TI - Modifying culture conditions in chemical library screening identifies alternative inhibitors of mycobacteria. AB - In this study, application of a dual absorbance/fluorescence assay to a chemical library screen identified several previously unknown inhibitors of mycobacteria. In addition, growth conditions had a significant effect on the activity profile of the library. Some inhibitors such as Se-methylselenocysteine were detected only when screening was performed under nutrient-limited culture conditions as opposed to nutrient-rich culture conditions. We propose that multiple culture condition library screening is required for complete inhibitory profiling and for maximal antimycobacterial compound detection. PMID- 19786610 TI - Localization of angiopoietin-1 and Tie2 immunoreactivity in rodent ependyma and adjacent blood vessels suggests functional relationships. AB - Angiopoietin-1 (Angpt1; previously Ang-1) participates in vascular maintenance and remodeling. In the current study, we investigated the distribution of Angpt1 protein in rat brain. We detected Angpt1 immunoreactivity (IR) in cerebral blood vessels, cuboidal ependyma, and tanycytes, which are specialized hypothalamic bipolar ependymal cells. We also evaluated patterns of IR of endothelium-specific receptor tyrosine kinase 2 (Tie2, the receptor for Angpt1). Tie2 IR was present in Angpt1-immunoreactive cuboidal ependyma in a membranous pattern, suggesting an autocrine or paracrine role for Angpt1-Tie2. Tie2 IR was also associated with peri-ependymal blood vessels, some of which were contacted by tips of Angpt1 immunoreactive tanycyte processes, implying a potential functional ligand receptor interaction mediating communication between the cerebrospinal fluid and vascular compartments. Because we previously found that cerebral Angpt1 expression was modulated by 17beta-estradiol (E2), and because some tanycyte functions are modulated by E2, we tested the hypothesis that E2 affects ependymal and tanycyte Angpt1 expression in vivo. No gross E2 effect on the ependymal pattern of Angpt1 IR or cerebral Angpt1 protein content was observed. PMID- 19786609 TI - Gangliosides are important for the preservation of the structure and organization of RBL-2H3 mast cells. AB - Gangliosides are known to be important in many biological processes. However, details concerning the exact function of these glycosphingolipids in cell physiology are poorly understood. In this study, the role of gangliosides present on the surface of rodent mast cells in maintaining cell structure was examined using RBL-2H3 mast cells and two mutant cell lines (E5 and D1) deficient in the gangliosides, GM(1) and the alpha-galactosyl derivatives of the ganglioside GD(1b). The two deficient cell lines were morphologically different from each other as well as from the parental RBL-2H3 cells. Actin filaments in RBL-2H3 and E5 cells were under the plasma membrane following the spindle shape of the cells, whereas in D1 cells, they were concentrated in large membrane ruffles. Microtubules in RBL-2H3 and E5 cells radiated from the centrosome and were organized into long, straight bundles. The bundles in D1 cells were thicker and organized circumferentially under the plasma membrane. The endoplasmic reticulum, the Golgi complex, and the secretory granule matrix were also altered in the mutant cell lines. These results suggest that the mast cell-specific alpha galactosyl derivatives of ganglioside GD(1b) and GM(1) are important in maintaining normal cell morphology. PMID- 19786611 TI - Anti-human vascular endothelial growth factor (VEGF) antibody selection for immunohistochemical staining of proliferating blood vessels. AB - Nine commercially available vascular endothelial growth factor (VEGF) antibodies were investigated for their ability to immunostain vascular malformations (VMs) with or without immature capillary proliferation. First, all antibodies were optimized for their performance in IHC, with placenta and colon adenocarcinoma as positive control tissues. Five antibodies were regarded as unfit for VEGF immunostaining based on poor immunostaining criteria. Subsequently, Western blot analysis using VEGF rabbit polyclonal antibody (Thermo RB-9031) revealed a clear 45-kDa band in tissue extracts from VMs with immature capillary proliferation and a high Ki67-labeling index, whereas tissue extracts from mature VMs without microvascular proliferation and no Ki67-labeling index demonstrated only a very weak 45-kDa band. In contrast, two VEGF antibodies, including the popular Santa Cruz A-20, revealed bands at 45 kDa of similar intensity in tissue extracts from both types of VMs. Staining characteristics of the 45-kDa band were reflected in the results obtained in IHC. PMID- 19786612 TI - Endogenous and transplanted small hepatocytes in retrorsine-treated/partially hepatectomized rat liver show differences in growth, phenotype, and proximity to clusters of gamma-glutamyl transpeptidase-positive host hepatocytes. AB - In the present report, we have compared the phenotype and growth of small hepatocyte progenitors (SHPs) induced by retrorsine/partial hepatectomy (R/PH) and small hepatocytes (SHs) isolated from normal adult liver. SHs were isolated by a combination of differential centrifugation and Percoll isodensity fractionation from a liver cell suspension prepared by collagenase perfusion of a dipeptidyl peptidase IV (DPPIV)-positive Fischer F344 rat liver. Following further purification by flow cytometry, the SH-R3 fraction was transplanted via the portal vein into R/PH-treated, DPPIV-negative Fischer F344 rats. Frozen sections from tissue harvested at 5, 7, and 21 days after transplantation were analyzed by indirect immunofluorescence to compare the phenotypic characteristics of colonies formed by exogenous SH-R3s and endogenous SHPs. Colonies of transplanted SHs and endogenous SHPs displayed similar histologies and phenotypes but were distinguished from surrounding hepatocytes by their elevated expression of transferrin receptor. SH-R3 colonies were frequently located within clusters of gamma-glutamyl transpeptidase-positive host hepatocytes. Although significantly smaller at 5 and 7 days after PH, by day 21, SH-R3 colonies were similar in size to those formed by SHPs. The present results suggest that endogenous SHPs are derived, at least in part, from SHPs. PMID- 19786614 TI - Mutation of the H-bond acceptor S119 in the ADAMTS13 metalloprotease domain reduces secretion and substrate turnover in a patient with congenital thrombotic thrombocytopenic purpura. AB - Hereditary thrombotic thrombocytopenic purpura is caused by mutations in a disintegrin and metalloprotease with thrombospondin motifs (ADAMTS13) resulting in defective processing of von Willebrand factor (VWF) that causes intravascular platelet aggregation culminating in thrombocytopenia with shistocytic anemia. In this study the functional and structural role of a recently identified ADAMTS13 metalloprotease domain mutation S119F was investigated. Secretion from heterologous cells was hampered but not completely eliminated. Secreted S119F was active toward multimeric VWF and FRETS-VWF73 but with abnormal kinetics, having a significantly reduced overall catalytic rate (k(cat); 0.88 +/- 0.04 s(-1) vs 2.78 +/- 0.11 s(-1)) and slightly smaller Michaelis constant (K(M); 1.4 +/- 0.2microM vs 2.3 +/- 0.3microM). A computational model of the metalloprotease domain demonstrates both steric and polar interaction effects caused by S119F. Interestingly, mutant S119A has properties similar to S119F (k(cat) = 0.82 +/- 0.03 s(-1) and K(M) = 1.1 +/- 0.1microM), allowing to assign distorted kinetics to the loss of the H-bond with conserved residue W262. We conclude that the S119 W262 H-bond is crucial for maximal turnover. PMID- 19786613 TI - Low expression of human histocompatibility soluble leukocyte antigen-G (HLA-G5) in invasive cervical cancer with and without metastasis, associated with papilloma virus (HPV). AB - Human leukocyte antigen-G (HLA-G) is a non-classical major histocompatibility complex class Ib molecule that acts as a specific immunosuppressor. Some studies have demonstrated that human papillomavirus (HPV) seems to be involved in lower or absent HLA-G expression, particularly in cervical cancer. In this study, we performed a cross-sectional study, systematically comparing the qualitative expression of the HLA-G5 isoform in invasive cervical carcinoma (ICC), stratifying patients according to the presence [ICC with metastasis (ICC(W))] and absence [ICC without metastasis (ICC(WT))] of metastasis, correlating these findings with interference of HPV and demographic and clinical variables. Seventy nine patients with a diagnosis of ICC were stratified into two groups: ICC(WT) (n=52 patients) and ICC(W) (n=27). Two biopsies were collected from each patient (one from the tumor lesion and one from a lymph node). Immunohistochemistry analyses were performed for the HLA-G5 isoform, for HPV detection, and virus typing. HLA-G5 isoform molecules were detected in 25 cases (31.6%), 17 (32.7%) without metastasis and 8 (29.6%) with metastasis. HPV was detected in the cervical lesions of 74 patients (93.7%), but low expression of the HLA-G5 isoform was observed in all HPV-related cases. These findings are important; however, additional studies are necessary to identify the influence of HPV with HLA-G5 isoform expression on invasive cervical malignancies. PMID- 19786615 TI - Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy. AB - An important hallmark of cancer progression is the ability of tumor cells to evade immune recognition. Understanding the relationship between neoplastic cells and the immune microenvironment should facilitate the design of improved immunotherapies. Here we identify impaired T-cell immunologic synapse formation as an active immunosuppressive mechanism in follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). We found a significant reduction in formation of the F-actin immune synapse in tumor-infiltrating T cells (P < .01) from lymphoma patients compared with age-matched healthy donor cells. Peripheral blood T cells exhibited this defect only in patients with leukemic-phase disease. Moreover, we demonstrate that this T-cell defect is induced after short-term tumor cell contact. After 24-hour coculture with FL cells, previously healthy T cells showed suppressed recruitment of critical signaling proteins to the synapse. We further demonstrate repair of this defect after treatment of both FL cells and T cells with the immunomodulatory drug lenalidomide. Tissue microarray analysis identified reduced expression of the T-cell synapse signature proteins, including the cytolytic effector molecule Rab27A associated with poor prognosis, in addition to reduced T-cell numbers and activity with disease transformation. Our results highlight the importance of identifying biomarkers and immunotherapeutic treatments for repairing T-cell responses in lymphoma. PMID- 19786616 TI - MICA-129 genotype, soluble MICA, and anti-MICA antibodies as biomarkers of chronic graft-versus-host disease. AB - The MHC class I-related chain A (MICA) molecules exist as membrane-bound and soluble isoforms and are encoded by a polymorphic gene. Their genetic and phenotype characteristics have been studied in various pathologic settings but not in the context of hematopoietic stem cell transplantation (HSCT). Here, we evaluated whether MICA-related features namely MICA-129 gene polymorphism, serum levels of soluble MICA (sMICA) and anti-MICA antibodies (MICA Abs) before and after HSCT could influence the incidence of chronic graft-versus-host disease (cGVHD) and relapse of their disease in 211 HLA-identical sibling pairs and in a subset of 116 recipients, respectively. Although the MICA-129 val/val genotype and elevated sMICA serum levels after HSCT are independently associated with the incidence of cGVHD (P = .002 and .001) regardless of history of acute GVHD, the presence of MICA Abs before transplantation confers protection against cGVHD (P = .04). There is an inverse relationship between MICA Abs and sMICA, suggesting an antibody-based neutralization of deleterious effects of sMICA. Similarly, these genetic and phenotype characteristics of MICA influence the incidence of relapse. Altogether, these data suggest that the studied MICA genotype and phenotype specificities could be used as relevant biomarkers for cGVHD monitoring. PMID- 19786617 TI - Allogeneic hematopoietic cell transplantation after conditioning with 131I-anti CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic syndrome. AB - We conducted a study to estimate the maximum tolerated dose (MTD) of (131)I-anti CD45 antibody (Ab; BC8) that can be combined with a standard reduced-intensity conditioning regimen before allogeneic hematopoietic cell transplantation. Fifty eight patients older than 50 years with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS) were treated with (131)I-BC8 Ab and fludarabine plus 2 Gy total body irradiation. Eighty-six percent of patients had AML or MDS with greater than 5% marrow blasts at the time of transplantation. Treatment produced a complete remission in all patients, and all had 100% donor derived CD3(+) and CD33(+) cells in the blood by day 28 after the transplantation. The MTD of (131)I-BC8 Ab delivered to liver was estimated to be 24 Gy. Seven patients (12%) died of nonrelapse causes by day 100. The estimated probability of recurrent malignancy at 1 year is 40%, and the 1-year survival estimate is 41%. These results show that CD45-targeted radiotherapy can be safely combined with a reduced-intensity conditioning regimen to yield encouraging overall survival for older, high-risk patients with AML or MDS. This study was registered at www.clinicaltrials.gov as #NCT00008177. PMID- 19786618 TI - TAPP2 links phosphoinositide 3-kinase signaling to B-cell adhesion through interaction with the cytoskeletal protein utrophin: expression of a novel cell adhesion-promoting complex in B-cell leukemia. AB - Tandem pleckstrin homology domain proteins (TAPPs) are recruited to the plasma membrane via binding to phosphoinositides produced by phosphoinositide 3-kinases (PI3Ks). Whereas PI3Ks are critical for B-cell activation, the functions of TAPP proteins in B cells are unknown. We have identified 40 potential interaction partners of TAPP2 in B cells, including proteins involved in cytoskeletal rearrangement, signal transduction and endocytic trafficking. The association of TAPP2 with the cytoskeletal proteins utrophin and syntrophin was confirmed by Western blotting. We found that TAPP2, syntrophin, and utrophin are coexpressed in normal human B cells and B-chronic lymphocytic leukemia (B-CLL) cells. TAPP2 and syntrophin expression in B-CLL was variable from patient to patient, with significantly higher expression in the more aggressive disease subset identified by zeta-chain-associated protein kinase of 70 kDa (ZAP70) expression and unmutated immunoglobulin heavy chain (IgH) genes. We examined whether TAPP can regulate cell adhesion, a known function of utrophin/syntrophin in other cell types. Expression of membrane-targeted TAPP2 enhanced B-cell adhesion to fibronectin and laminin, whereas PH domain-mutant TAPP2 inhibited adhesion. siRNA knockdown of TAPP2 or utrophin, or treatment with PI3K inhibitors, significantly inhibited adhesion. These findings identify TAPP2 as a novel link between PI3K signaling and the cytoskeleton with potential relevance for leukemia progression. PMID- 19786619 TI - Bayesian computation and model selection without likelihoods. AB - Until recently, the use of Bayesian inference was limited to a few cases because for many realistic probability models the likelihood function cannot be calculated analytically. The situation changed with the advent of likelihood-free inference algorithms, often subsumed under the term approximate Bayesian computation (ABC). A key innovation was the use of a postsampling regression adjustment, allowing larger tolerance values and as such shifting computation time to realistic orders of magnitude. Here we propose a reformulation of the regression adjustment in terms of a general linear model (GLM). This allows the integration into the sound theoretical framework of Bayesian statistics and the use of its methods, including model selection via Bayes factors. We then apply the proposed methodology to the question of population subdivision among western chimpanzees, Pan troglodytes verus. PMID- 19786620 TI - Mapping loci associated with tail color and sex determination in the short-lived fish Nothobranchius furzeri. AB - The African fish Nothobranchius furzeri is the shortest-lived vertebrate species that can reproduce in captivity, with a median life span of 9-11 weeks for the shortest-lived strain. Natural populations of N. furzeri display differences in life span, aging biomarkers, behavior, and color, which make N. furzeri a unique vertebrate system for studying the genetic basis of these traits. We mapped regions of the genome involved in sex determination and tail color by genotyping microsatellite markers in the F(2) progeny of a cross between a short-lived, yellow-tailed strain and a long-lived, red-tailed strain of N. furzeri. We identified one region linked with the yellow/red tail color that maps close to melanocortin 1 receptor (mc1r), a gene involved in pigmentation in several vertebrate species. Analysis of the segregation of sex-linked markers revealed that N. furzeri has a genetic sex determination system with males as the heterogametic sex and markedly reduced recombination in the male sex-determining region. Our results demonstrate that both naturally-evolved pigmentation differences and sex determination in N. furzeri are controlled by simple genetic mechanisms and set the stage for the molecular genetic dissection of factors underlying such traits. The microsatellite-based linkage map we developed for N. furzeri will also facilitate analysis of the genetic architecture of traits that characterize this group of vertebrates, including short life span and adaptation to extreme environmental conditions. PMID- 19786621 TI - Identification of the major sex-determining region of turbot (Scophthalmus maximus). AB - Sex determination in fish is a labile character in evolutionary terms. The sex determining (SD) master gene can differ even between closely related fish species. This group is an interesting model for studying the evolution of the SD region and the gonadal differentiation pathway. The turbot (Scophthalmus maximus) is a flatfish of great commercial value, where a strong sexual dimorphism exists for growth rate. Following a QTL and marker association approach in five families and a natural population, we identified the main SD region of turbot at the proximal end of linkage group (LG) 5, close to the SmaUSC-E30 marker. The refined map of this region suggested that this marker would be 2.6 cM and 1.4 Mb from the putative SD gene. This region appeared mostly undifferentiated between males and females, and no relevant recombination frequency differences were detected between sexes. Comparative genomics of LG5 marker sequences against five model species showed no similarity of this chromosome to the sex chromosomes of medaka, stickleback, and fugu, but suggested a similarity to a sex-associated QTL from Oreochromis spp. The segregation analysis of the closest markers to the SD region demonstrated a ZW/ZZ model of sex determination in turbot. A small proportion of families did not fit perfectly with this model, which suggests that other minor genetic and/or environmental factors are involved in sex determination in this species. PMID- 19786622 TI - Simulating the yield impacts of organ-level quantitative trait loci associated with drought response in maize: a "gene-to-phenotype" modeling approach. AB - Under drought, substantial genotype-environment (G x E) interactions impede breeding progress for yield. Identifying genetic controls associated with yield response is confounded by poor genetic correlations across testing environments. Part of this problem is related to our inability to account for the interplay of genetic controls, physiological traits, and environmental conditions throughout the crop cycle. We propose a modeling approach to bridge this "gene-to-phenotype" gap. For maize under drought, we simulated the impact of quantitative trait loci (QTL) controlling two key processes (leaf and silk elongation) that influence crop growth, water use, and grain yield. Substantial G x E interaction for yield was simulated for hypothetical recombinant inbred lines (RILs) across different seasonal patterns of drought. QTL that accelerated leaf elongation caused an increase in crop leaf area and yield in well-watered or preflowering water deficit conditions, but a reduction in yield under terminal stresses (as such "leafy" genotypes prematurely exhausted the water supply). The QTL impact on yield was substantially enhanced by including pleiotropic effects of these QTL on silk elongation and on consequent grain set. The simulations obtained illustrated the difficulty of interpreting the genetic control of yield for genotypes influenced only by the additive effects of QTL associated with leaf and silk growth. The results highlight the potential of integrative simulation modeling for gene-to-phenotype prediction and for exploiting G x E interactions for complex traits such as drought tolerance. PMID- 19786623 TI - An alpha7 nicotinic acetylcholine receptor-selective agonist reduces weight gain and metabolic changes in a mouse model of diabetes. AB - Type 2 diabetes has become a pervasive public health problem. The etiology of the disease has not been fully defined but appears to involve abnormalities in peripheral and central nervous system pathways, as well as prominent inflammatory components. Because nicotinic acetylcholine receptors (nAChRs) are known to interact with anti-inflammatory pathways and have been implicated in control of appetite and body weight, as well as lipid and energy metabolism, we examined their role in modulating biological parameters associated with the disease. In a model of type 2 diabetes, the homozygous leptin-resistant db/db obese mouse, we measured the effects of a novel alpha7 nAChR-selective agonist [5-methyl-N-[2 (pyridin-3-ylmethyl)-1-azabicyclo[2.2.2]oct-3-yl]thiophene-2-carboxamide (TC 7020)] on body mass, glucose and lipid metabolism, and proinflammatory cytokines. Oral administration of TC-7020 reduced weight gain and food intake, reduced elevated glucose and glycated hemoglobin levels, and lowered elevated plasma levels of triglycerides and the proinflammatory cytokine tumor necrosis factor alpha. These changes were reversed by the alpha7-selective antagonist methyllycaconitine, confirming the involvement of alpha7 nAChRs. Prevention of weight gain, decreased food intake, and normalization of glucose levels were also blocked by the Janus kinase 2 (JAK2) inhibitor alpha-cyano-(3,4-dihydroxy)-N benzylcinnamide (AG-490), suggesting that these effects involve linkage of alpha7 nAChRs to the JAK2-signal transducer and activator of transcription 3 signaling pathway. The results show that alpha7 nAChRs play a central role in regulating biological parameters associated with diabetes and support the potential of targeting these receptors as a new therapeutic strategy for treatment. PMID- 19786625 TI - Editor's letter. PMID- 19786624 TI - Nicotine metabolism in African Americans and European Americans: variation in glucuronidation by ethnicity and UGT2B10 haplotype. AB - Nicotine is the major addictive agent in tobacco smoke, and it is metabolized extensively by oxidation and glucuronide conjugation. The contributions of ethnicity and UGT2B10 haplotype on variation in nicotine metabolism were investigated. Nicotine metabolism was evaluated in two populations of smokers. In one population of African American and European American smokers (n = 93), nicotine and its metabolites were analyzed in plasma and 24-h urine over 3 days while participants were abstinent and at steady state on the nicotine patch. In a second study of smokers (n = 84), the relationship of a UGT2B10 haplotype linked with D67Y to nicotine and cotinine glucuronidation levels was determined. We observed that both African American ethnicity and the UGT2B10 D67Y allele were associated with a low glucuronidation phenotype. African Americans excreted less nicotine and cotinine as their glucuronide conjugates compared with European Americans; percentage of nicotine glucuronidation, 18.1 versus 29.3 (p < 0.002) and percentage of cotinine glucuronidation, 41.4 versus 61.7 (p < 0.0001). In smokers with a UGT2B10 Tyr67 allele, glucuronide conjugation of nicotine and cotinine was decreased by 20% compared with smokers without this allele. Two key outcomes are reported here. First, the observation that African Americans have lower nicotine and cotinine glucuronidation was confirmed in a population of abstinent smokers on the nicotine patch. Second, we provide the first convincing evidence that UGT2B10 is a key catalyst of these glucuronidation pathways in vivo. PMID- 19786628 TI - Induced pluripotent stem cells: it's like deja vu all over again. PMID- 19786629 TI - Functional ischemic mitral regurgitation: myocardial viability as a predictor of postoperative outcome after isolated coronary artery bypass grafting. PMID- 19786630 TI - Coronary artery injury due to catheter ablation in adults: presentations and outcomes. AB - BACKGROUND: Currently, only anecdotal information exists on the presentation and outcome of coronary arterial injury after ablation procedures. METHODS AND RESULTS: Four patients who sustained coronary artery injury of a cohort of patients undergoing 4655 consecutive ablation procedures (0.09%) are described. The patients' mean age was 45+/-11 years, and 1.8+/-0.5 prior ablation attempts had been unsuccessful. Coronary injury occurred from epicardial ventricular tachycardia ablation in 2 patients (irrigated radiofrequency ablation in one and cryoablation in the other) and ablation within the middle cardiac vein with irrigated radiofrequency in 2 patients. All involved branches of the right coronary artery. Acute occlusion presenting with ST-segment elevation immediately after ablation was recognized during the procedure in 2 cases. Occlusion failed to respond to nitroglycerin or balloon dilation, and stenting was required in both cases. Acute myocardial infarction occurred 2 weeks after epicardial ablation as a result of occlusion of a right ventricular branch of the right coronary artery giving rise to the posterior descending coronary artery in 1 patient. A moderate asymptomatic stenosis was seen on angiography after epicardial cryoablation in 1 patient. All patients recovered and remained asymptomatic from the coronary injury and arrhythmias during 37+/-53 months of follow-up. CONCLUSIONS: Coronary arterial injury after ablation procedures is rare. It may present acutely or several weeks after an ablation procedure. Acute occlusion appears to require coronary stenting. Unanticipated anatomic variations can predispose to coronary injury. PMID- 19786631 TI - Cardiomyocyte differentiation of human induced pluripotent stem cells. AB - BACKGROUND: The ability to derive human induced pluripotent stem (hiPS) cell lines by reprogramming of adult fibroblasts with a set of transcription factors offers unique opportunities for basic and translational cardiovascular research. In the present study, we aimed to characterize the cardiomyocyte differentiation potential of hiPS cells and to study the molecular, structural, and functional properties of the generated hiPS-derived cardiomyocytes. METHODS AND RESULTS: Cardiomyocyte differentiation of the hiPS cells was induced with the embryoid body differentiation system. Gene expression studies demonstrated that the cardiomyocyte differentiation process of the hiPS cells was characterized by an initial increase in mesoderm and cardiomesoderm markers, followed by expression of cardiac-specific transcription factors and finally by cardiac-specific structural genes. Cells in the contracting embryoid bodies were stained positively for cardiac troponin-I, sarcomeric alpha-actinin, and connexin-43. Reverse-transcription polymerase chain reaction studies demonstrated the expression of cardiac-specific sarcomeric proteins and ion channels. Multielectrode array recordings established the development of a functional syncytium with stable pacemaker activity and action potential propagation. Positive and negative chronotropic responses were induced by application of isoproterenol and carbamylcholine, respectively. Administration of quinidine, E4031 (I(Kr) blocker), and chromanol 293B (I(Ks) blocker) significantly affected repolarization, as manifested by prolongation of the local field potential duration. CONCLUSIONS: hiPS cells can differentiate into myocytes with cardiac specific molecular, structural, and functional properties. These results, coupled with the potential of this technology to generate patient-specific hiPS lines, hold great promise for the development of in vitro models of cardiac genetic disorders, for drug discovery and testing, and for the emerging field of cardiovascular regenerative medicine. PMID- 19786632 TI - MicroRNA 217 modulates endothelial cell senescence via silent information regulator 1. AB - BACKGROUND: Aging is a major risk factor for the development of atherosclerosis and coronary artery disease. Through a microarray approach, we have identified a microRNA (miR-217) that is progressively expressed in endothelial cells with aging. miR-217 regulates the expression of silent information regulator 1 (SirT1), a major regulator of longevity and metabolic disorders that is progressively reduced in multiple tissues during aging. METHODS AND RESULTS: miR 217 inhibits SirT1 expression through a miR-217-binding site within the 3'-UTR of SirT1. In young human umbilical vein endothelial cells, human aortic endothelial cells, and human coronary artery endothelial cells, miR-217 induces a premature senescence-like phenotype and leads to an impairment in angiogenesis via inhibition of SirT1 and modulation of FoxO1 (forkhead box O1) and endothelial nitric oxide synthase acetylation. Conversely, inhibition of miR-217 in old endothelial cells ultimately reduces senescence and increases angiogenic activity via an increase in SirT1. miR-217 is expressed in human atherosclerotic lesions and is negatively correlated with SirT1 expression and with FoxO1 acetylation status. CONCLUSIONS: Our data pinpoint miR-217 as an endogenous inhibitor of SirT1, which promotes endothelial senescence and is potentially amenable to therapeutic manipulation for prevention of endothelial dysfunction in metabolic disorders. PMID- 19786633 TI - Long-term clinical outcome after fractional flow reserve-guided treatment in patients with angiographically equivocal left main coronary artery stenosis. AB - BACKGROUND: Significant left main coronary artery stenosis is an accepted indication for surgical revascularization. The potential of angiography to evaluate the hemodynamic severity of a stenosis is limited. The aims of the present study were to assess the long-term clinical outcome of patients with an angiographically equivocal left main coronary artery stenosis in whom the revascularization strategy was based on fractional flow reserve (FFR) and to determine the relationship between quantitative coronary angiography and FFR. METHODS AND RESULTS: In 213 patients with an angiographically equivocal left main coronary artery stenosis, FFR measurements and quantitative coronary angiography were performed. When FFR was > or =0.80, patients were treated medically or another stenosis was treated by coronary angioplasty (nonsurgical group; n=138). When FFR was <0.80, coronary artery bypass grafting was performed (surgical group; n=75). The 5-year survival estimates were 89.8% in the nonsurgical group and 85.4% in the surgical group (P=0.48). The 5-year event-free survival estimates were 74.2% and 82.8% in the nonsurgical and surgical groups, respectively (P=0.50). Percent diameter stenosis at quantitative coronary angiography correlated significantly with FFR (r=-0.38, P<0.001), but a very large scatter was observed. In 23% of patients with a diameter stenosis <50%, the left main coronary artery stenosis was hemodynamically significant by FFR. CONCLUSIONS: In patients with equivocal stenosis of the left main coronary artery, angiography alone does not allow appropriate individual decision making about the need for revascularization and often underestimates the functional significance of the stenosis. The favorable outcome of an FFR-guided strategy suggests that FFR should be assessed in such patients before a decision is made "blindly" about the need for revascularization. PMID- 19786634 TI - Final 5-year results of the TAXUS II trial: a randomized study to assess the effectiveness of slow- and moderate-release polymer-based paclitaxel-eluting stents for de novo coronary artery lesions. AB - BACKGROUND: The TAXUS II trial was designed to evaluate the safety and efficacy of the commercialized slow-release (SR) and an investigation-only moderate release (MR) polymer-based TAXUS paclitaxel-eluting stent compared with a bare metal stent for the treatment of de novo coronary lesions. METHODS AND RESULTS: This prospective, randomized, double-blind, controlled trial enrolled 536 patients in 2 consecutive cohorts to compare TAXUS SR (n=131) and TAXUS MR (n=135) with an identical but uncoated bare-metal stent control (n=270). The present analysis reports final 5-year clinical outcomes of TAXUS II. At 5 years, both TAXUS SR and MR showed superior outcomes compared with control. The 5-year rates of major adverse cardiac events were 27.6%, 20.4%, and 15.1% (P=0.01); rates of target-vessel revascularization were 22.5%, 16.6%, and 9.0% (P=0.004); and rates of target-lesion revascularization were 18.4%, 10.3%, and 4.5% (P<0.001) for the control, TAXUS SR, and TAXUS MR groups, respectively. The rates of all-cause death and myocardial infarction were low and similar between groups, with 2 stent thromboses with bare-metal stents compared with no event beyond 2 years with either of the TAXUS stents. CONCLUSIONS: TAXUS II is the first large TAXUS trial to have reached 5-year follow-up. Both the SR and MR stents lowered the rates of target-vessel and target-lesion revascularization, which indicates their sustained efficacy. Furthermore, the low overall rates of all death, myocardial infarction, and stent thrombosis support the long-term safety of the TAXUS stent system. PMID- 19786635 TI - Predictors of technical success and postnatal biventricular outcome after in utero aortic valvuloplasty for aortic stenosis with evolving hypoplastic left heart syndrome. AB - BACKGROUND: Aortic stenosis in the midgestation fetus with a normal-sized or dilated left ventricle predictably progresses to hypoplastic left heart syndrome when associated with certain physiological findings. Prenatal balloon aortic valvuloplasty may improve left heart growth and function, possibly preventing evolution to hypoplastic left heart syndrome. METHODS AND RESULTS: Between March 2000 and October 2008, 70 fetuses underwent attempted aortic valvuloplasty for critical aortic stenosis with evolving hypoplastic left heart syndrome. We analyzed this experience to determine factors associated with procedural and postnatal outcome. The median gestational age at intervention was 23 weeks. The procedure was technically successful in 52 fetuses (74%). Relative to 21 untreated comparison fetuses, subsequent prenatal growth of the aortic and mitral valves, but not the left ventricle, was improved after intervention. Nine pregnancies (13%) did not reach a viable term or preterm birth. Seventeen patients had a biventricular circulation postnatally, 15 from birth. Larger left heart structures and higher left ventricular pressure at the time of intervention were associated with biventricular outcome. A multivariable threshold scoring system was able to discriminate fetuses with a biventricular outcome with 100% sensitivity and modest positive predictive value. CONCLUSIONS: Technically successful aortic valvuloplasty alters left heart valvar growth in fetuses with aortic stenosis and evolving hypoplastic left heart syndrome and, in a subset of cases, appeared to contribute to a biventricular outcome after birth. Fetal aortic valvuloplasty carries a risk of fetal demise. Fetuses undergoing in utero aortic valvuloplasty with an unfavorable multivariable threshold score at the time of intervention are very unlikely to achieve a biventricular circulation postnatally. PMID- 19786636 TI - Cardiovascular benefit of magnitude of low-density lipoprotein cholesterol reduction: a comparison of subgroups by age. AB - BACKGROUND: We examined the effect of the magnitude of low-density lipoprotein cholesterol (LDL-C) reduction across subjects of various ages in a retrospective cohort study. METHODS AND RESULTS: We selected 20,132 male veterans at high risk for an acute cardiovascular event and who had 2 or more LDL-C measurements before their first documented acute myocardial infarction, revascularization, death, or censoring date. LDL-C reduction was categorized as no reduction (<10 mg/dL; reference), small reduction (between 10 and 40 mg/dL), moderate reduction (between 40 and 70 mg/dL), or large reduction (> or =70 mg/dL). The primary outcome was combined acute myocardial infarction or revascularization. The first and last LDL-C levels in the databases were used to calculate the LDL-C reduction in patients who experienced no outcome or who died. Within each age quartile and in a subgroup of patients > or =80 years of age, a Cox proportional hazards model was used to determine hazard ratios for each category of LDL-C reduction compared with the reference category, with adjustment for age, body mass index, current smoking status, medications, and comorbidities. In all age groups, the magnitude of LDL-C reduction was proportional to the magnitude of cardiovascular risk reduction. Risk reduction for the combined outcome in patients who achieved a large LDL-C reduction was similar in all age quartiles, with multivariate adjusted hazard ratios of approximately 0.30. CONCLUSIONS: In a cohort of veterans at high risk for cardiovascular events, patients of all ages, including those 80 years or older, benefitted the most from large reductions in LDL-C. PMID- 19786638 TI - Utility of cardiovascular magnetic resonance in the diagnosis of Anderson-Fabry disease. PMID- 19786637 TI - Predictors of improvement of unrepaired moderate ischemic mitral regurgitation in patients undergoing elective isolated coronary artery bypass graft surgery. AB - BACKGROUND: The persistence of moderate ischemic mitral regurgitation (IMR) after isolated coronary artery bypass graft surgery is an important independent predictor of long-term mortality. The aim of the present study was to identify predictors of postoperative improvement in moderate IMR in patients with ischemic heart disease undergoing elective isolated coronary artery bypass graft surgery. METHODS AND RESULTS: The study population consisted of 135 patients with ischemic heart disease (age, 65+/-9 years; 81% male) and moderate IMR undergoing isolated coronary artery bypass graft surgery. Fourteen patients died before the 12-month follow-up echocardiography and were excluded. At the 12-month follow-up, 57 patients showed no or mild IMR (improvement group), whereas 64 patients failed to improve (failure group). Before coronary artery bypass graft surgery, the improvement group had significantly more viable myocardium and less dyssynchrony between papillary muscles than the failure group (P<0.001). All other preoperative parameters were similar in both groups. Large extent (> or =5 segments) of viable myocardium (odds ratio, 1.45; 95% confidence interval, 1.22 to 1.89; P<0.001) and absence (<60 ms) of dyssynchrony (odds ratio, 1.49; 95% confidence interval, 1.29 to 1.72; P<0.001) were independently associated with improvement in IMR. The majority (93%) of patients with viable myocardium and an absence of dyssynchrony showed an improvement in IMR. In contrast, only 34% and 18% of patients with dyssynchrony and nonviable myocardium, respectively, showed an improvement in IMR, whereas 32% and 49%, respectively, of these patients showed worsening of IMR (P<0.001). CONCLUSIONS: Reliable improvement in moderate IMR by isolated coronary artery bypass graft surgery was observed only in patients with concomitant presence of viable myocardium and absence of dyssynchrony between papillary muscles. PMID- 19786639 TI - Letter by de Miguel Castro et al regarding article, "cardiovascular death and nonfatal myocardial infarction in acute coronary syndrome patients receiving coronary stenting are predicted by residual platelet reactivity to ADP detected by a point-of-care assay: a 12-month follow-up". PMID- 19786642 TI - Surgical management of ischemic mitral regurgitation. PMID- 19786643 TI - Aortic coarctation. PMID- 19786644 TI - Exogenous ghrelin on nitric oxide-endothelin 1 imbalance in metabolic syndrome: can we kill 2 birds with 1 stone? PMID- 19786645 TI - Long-term risk in subjects with white-coat hypertension. PMID- 19786641 TI - Molecular insights and therapeutic targets for diabetic endothelial dysfunction. PMID- 19786646 TI - Inhibition of 20-hydroxyeicosatetraenoic acid synthesis using specific plant lignans: in vitro and human studies. AB - Sesamin, the major lignan found in sesame, has been shown to increase vitamin E levels by inhibiting its metabolism via the cytochrome P450 isozyme CYP4F2. CYP4F2 and CYP4A11 are the predominant human isoforms that synthesize 20 hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid. Considerable evidence suggests that 20-HETE may play a role in the pathogenesis of hypertension. We hypothesized that sesamin could be an inhibitor of 20-HETE synthesis. This study investigated the effects of sesamin on 20-HETE synthesis in vitro and the effect of sesame supplementation on plasma and urinary 20-HETE concentrations in humans. Human microsomes were used to investigate the potency and selectivity of sesamin inhibition of 20-HETE synthesis. Sesamin inhibited human renal and liver microsome 20-HETE synthesis with IC50 <20 micromol/L. It was selective toward CYP4F2 (IC50: 1.9 micromol/L) and had reduced activity toward CYP4A11 (IC50: >150 micromol/L), as well as cytochrome P epoxygenation of arachidonic acid (IC50: >50 micromol/L). In a randomized, controlled crossover trial, overweight men and women (n=33) consumed 25 g/d of sesame (approximately 50 mg/d of sesame lignan) or an isocaloric matched control for 5 weeks each. Relative to control, sesame supplementation resulted in a 28% decrease in plasma and a 32% decrease in urinary 20-HETE (P<0.001). Urinary sodium, potassium, and blood pressure were not affected. This study demonstrates for the first time that sesame supplementation in humans reduces the plasma and urinary levels of 20 HETE, likely via inhibition of CYP4F2 by sesame lignans. These results suggest that sesame lignans could be used for the investigation of potential roles of 20 HETE in humans. PMID- 19786647 TI - Effect of cardiorespiratory fitness on vascular regulation and oxidative stress in postmenopausal women. AB - Increasing evidence exists suggesting an important role for oxidative stress in the pathogenesis and progression of hypertension in women via a decrease of NO production after menopause. Regular physical training has been shown to upregulate antioxidant enzymatic systems, which may slow down the usual increase of oxidative stress in postmenopausal women. The aims of this study were to determine the impact of fitness status on enzymatic antioxidant efficiency, oxidative stress, and NO production and to determine the associations among oxidative stress, enzymatic antioxidant and NO production, mean arterial blood pressure (MABP), and cerebrovascular conductance (CVC) in postmenopausal women (n=40; 50 to 90 years old). Physical fitness, physical activity, resting MABP, and CVC were measured. End product of NO, lipid peroxidation (malondialdehyde and 8-iso-prostaglandin F2alpha), DNA oxidation (8-hydroxy-2'-deoxyguanosine), protein nitration (nitrotyrosine), antioxidant glutathione peroxidase, and catalase activities were measured in plasma. We identified significant negative associations between oxidative stress and indices of physical fitness (malondialdehyde: r=-0.33, P<0.05; 8-iso-prostaglandin F2alpha: r=-0.39, P<0.05; 8-hydroxy-2'-deoxyguanosine: r=-0.35, P<0.05) and physical activity (malondialdehyde: r=-0.30, P<0.05; 8-iso-prostaglandin F2alpha: r=-0.41, P<0.01; 8-hydroxy-2'-deoxyguanosine: r=-0.39, P<0.05). Conversely, glutathione peroxidase was positively correlated with fitness level (r=0.55; P<0.01). Finally, MABP and CVC were significantly associated with 8-hydroxy-2'-deoxyguanosine (MABP: r=0.36, P<0.05; CVC: r=-0.36, P<0.05), nitrotyrosine (MABP: r=0.39, P<0.05; CVC: r=-0.32, P<0.05), and the end product of NO (MABP: r=-0.57, P<0.01; CVC: r=0.44, P<0.01). These findings demonstrate that, after menopause, fitness level and regular physical activity mediate against oxidative stress by maintaining antioxidant enzyme efficiency. Furthermore, these results suggest that oxidative stress and NO production modulate MABP and CVC. PMID- 19786648 TI - Ghrelin restores the endothelin 1/nitric oxide balance in patients with obesity related metabolic syndrome. AB - Obesity is associated with endothelial dysfunction related to decreased NO bioavailability, increased endothelin 1 vasoconstrictor activity, and decreased circulating ghrelin. Therefore, we tested whether exogenous ghrelin may have benefits to improve the balance between endothelin 1 and NO in patients with obesity-related metabolic syndrome. Vasoactive actions of endothelin 1 and NO were assessed in 8 patients with metabolic syndrome and 8 matched controls by evaluating forearm blood flow responses (strain-gauge plethysmography) to intra arterial infusion of BQ-123 (endothelin A receptor antagonist; 10 nmol/min), followed by NG-monomethyl-L-arginine (NO synthase inhibitor; 4 micromol/min), before and after infusion of ghrelin (200 ng/min). In the absence of ghrelin, the vasodilator response to BQ-123 was greater in patients than in controls (P<0.001), whereas infusion of NG-monomethyl-L-arginine induced smaller vasoconstriction in patients than in controls (P=0.006). Importantly, exogenous ghrelin decreased the vasodilator response to BQ-123 (P=0.007 versus saline) and enhanced the magnitude of changes in forearm blood flow induced by NG-monomethyl L-arginine (P=0.003) in patients but not in controls (both P>0.05). The favorable effect of ghrelin on endothelin A-dependent vasoconstriction was likely related to the stimulation of NO production, because no change in the vascular effect of BQ-123 was observed after ghrelin (P=0.44) in 5 patients with metabolic syndrome during continuous infusion of the NO donor sodium nitroprusside (0.2 microg/min). In patients with metabolic syndrome, ghrelin has benefits to normalize the balance between vasoconstrictor (endothelin 1) and vasodilating (NO) mediators, thus suggesting that this peptide has important peripheral actions to preserve vascular homeostasis in humans. PMID- 19786649 TI - Effect of recombinant placental growth factor 2 on hypertension induced by full length mouse soluble fms-like tyrosine kinase 1 adenoviral vector in pregnant mice. AB - The first aim of our study was to develop a pregnant mouse model for preeclampsia using adenoviral vector containing mouse full-length soluble fms-like tyrosine kinase 1 (sFlt-1) but not truncated sFlt-1. The second aim was to evaluate effects of recombinant mouse (rm) vascular endothelial growth factor (VEGF) and rm placental growth factor (PlGF) on a preeclampsia model induced by adenoviral vector containing mouse full-length sFlt-1. We injected adenoviral vector containing mouse full-length sFlt-1 on day 8.5 or 9.5 of gestation into pregnant Institute of Cancer Research mice, resulting in hypertension, proteinuria, and similar glomerular histological changes as those seen in human preeclamptic women with glomerular endotheliosis on day 16.5 or 17.5 of gestation. The preeclampsia models were treated with 100 microg/kg of rmVEGF164 (n=5), 100 microg/kg of rmPlGF-2 (n=5), or vehicle (n=7) twice a day for 2 days IP. The rmVEGF164 treatment significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (85+/-4 versus 97+/-2 mm Hg; P=0.018). The rmPlGF-2 treatment also significantly decreased the mean blood pressure on day 16.5 or 17.5 of gestation compared with the vehicle treatment (86+/-3 versus 97+/-2 mm Hg; P=0.018). However, proteinuria was not affected by either rmVEGF164 or rmPlGF-2. In conclusion, we, for the first time, created a mouse preeclampsia model using mouse full-length sFlt-1. VEGF and PlGF may be promising for ameliorating hypertension in women with preeclampsia. Additional study of PlGF as a potential drug for preeclampsia is warranted. PMID- 19786650 TI - American Society Of Clinical Oncology/Oncology Nursing Society chemotherapy administration safety standards. AB - Standardization of care can reduce the risk of errors, increase efficiency, and provide a framework for best practice. In 2008, the American Society of Clinical Oncology (ASCO) and the Oncology Nursing Society (ONS) invited a broad range of stakeholders to create a set of standards for the administration of chemotherapy to adult patients in the outpatient setting. At the close of a full-day structured workshop, 64 draft standards were proposed. After a formal process of electronic voting and conference calls, 29 draft standards were eliminated, resulting in a final list of 35 draft measures. The proposed set of standards was posted for 6 weeks of open public comment. Three hundred twenty-two comments were reviewed by the Steering Group and used as the basis for final editing to a final set of standards. The final list includes 31 standards encompassing seven domains, which include the following: review of clinical information and selection of a treatment regimen; treatment planning and informed consent; ordering of treatment; drug preparation; assessment of treatment compliance; administration and monitoring; and assessment of response and toxicity monitoring. Adherence to ASCO and ONS standards for safe chemotherapy administration should be a goal of all providers of adult cancer care. PMID- 19786651 TI - Stop and go: yes or no? PMID- 19786652 TI - Relapse/Refractory myeloma patient: potential treatment guidelines. PMID- 19786653 TI - How to treat hormone receptor-positive, human epidermal growth factor receptor 2 amplified breast cancer. PMID- 19786654 TI - Phase I, pharmacokinetic, and pharmacodynamic study of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1. AB - PURPOSE: To determine the maximum-tolerated dose (MTD) and to assess the safety, pharmacokinetics, and evidence of antitumor activity of AMG 479, a fully human monoclonal antibody to insulin-like growth factor receptor 1 (IGF-1R). PATIENTS AND METHODS: Patients with advanced solid malignancies or non-Hodgkin's lymphoma received escalating doses of AMG 479 intravenously (IV) every 2 weeks (Q2W). Blood samples were assayed to determine pharmacokinetic parameters and IGF-1R occupancy on neutrophils; fluorodeoxyglucose-positron emission tomography scans were used to assess tumor metabolic effects. RESULTS: Fifty-three patients received 312 infusions of AMG 479 Q2W. Overall, the most common grades 1 to 2 toxicities were fatigue, thrombocytopenia, fever, rash, chills, and anorexia. One dose-limiting toxicity (ie, grade 3 thrombocytopenia) occurred in a patient at 20 mg/kg during course 1; grade 3 thrombocytopenia (n = 8) and grade 3 transaminitis elevations (n = 1) also were reported but not in the escalation phase. The maximum-planned dose of 20 mg/kg was safely administered; thus, an MTD was not reached. High levels of neutrophil IGF-1R binding and increases from baseline in serum IGF-1 levels were observed in the 12- and 20-mg/kg cohorts. Tumor responses included one durable complete response (CR) and one unconfirmed partial response (PR) in two patients with Ewing/primitive neuroectodermal tumors and included one PR and one minor response in two patients with neuroendocrine tumors. The patients with Ewing/PNET who had a CR have remained disease free on therapy after 28 months. CONCLUSION: AMG 479 can be administered safely at 20 mg/kg IV Q2W. The absence of severe toxicities, attainment of serum concentrations associated with high levels of IGF-1R binding on neutrophils, and provocative antitumor activity warrant additional studies of this agent. PMID- 19786655 TI - Biased hormonal therapy duration analysis makes results uninterpretable. PMID- 19786657 TI - Can chemotherapy be discontinued in unresectable metastatic colorectal cancer? The GERCOR OPTIMOX2 Study. AB - PURPOSE: This study compared chemotherapy discontinuation with maintenance therapy with leucovorin and fluorouracil after six cycles of folinic acid, fluorouracil, and oxaliplatin (FOLFOX) chemotherapy in the first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: Two hundred two patients with untreated metastatic colorectal cancer were randomly assigned to receive six cycles of modified FOLFOX7 (mFOLFOX7) followed by simplified leucovorin plus bolus and infusional fluorouracil until progression (arm 1 or maintenance arm, n = 98) or six cycles of mFOLFOX7 before a complete stop of chemotherapy (arm 2 or chemotherapy-free interval [CFI] arm, n = 104). Reintroduction of mFOLFOX7 was scheduled after tumor progression in both arms. The primary study end point was duration of disease control (DDC). RESULTS: Median DDC was 13.1 months in patients assigned to the maintenance arm and 9.2 months in patients assigned to the CFI arm (P = .046). Median progression-free survival (PFS) and overall survival were 8.6 and 23.8 months, respectively, in the maintenance arm and 6.6 and 19.5 months, respectively, in the CFI arm. Median duration of maintenance therapy (arm 1) and CFIs (arm 2) were 4.8 months and 3.9 months, respectively. Overall response rates were 59.2% and 59.6% for the initial FOLFOX chemotherapy and 20.4% and 30.3% for FOLFOX reintroduction in arms 1 and 2, respectively. CONCLUSION: The planned complete discontinuation of chemotherapy had a negative impact on DDC and PFS compared with the maintenance therapy strategy. These results suggest that chemotherapy discontinuation cannot be decided before therapy is initiated in patients with advanced colorectal cancer. PMID- 19786658 TI - Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. AB - PURPOSE: Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2 positive population. Results In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >or= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. CONCLUSION: This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2. PMID- 19786659 TI - Selection bias is not a good reason for advising more than 5 years of adjuvant hormonal therapy for all patients with locally advanced prostate cancer treated with radiotherapy. PMID- 19786660 TI - Genetic abnormalities of the EGFR pathway in African American Patients with non small-cell lung cancer. AB - PURPOSE: Previous studies in non-small-cell lung cancer (NSCLC) have demonstrated a wide variation in responsiveness to epidermal growth factor receptor (EGFR) targeting agents and in genetic aberrancies of the EGFR pathway according to ethnic background, most notably a higher frequency of activating EGFR mutations among East-Asian patients. We investigated the frequency of EGFR pathway aberrancies among African American patients with NSCLC, for whom limited information presently exists. PATIENTS AND METHODS: EGFR fluorescent in situ hybridization (FISH) was performed on archived tissues from 53 African American patients. Extracted DNA was sequenced for mutational analysis of EGFR exons 18 to 21 and KRAS exon 2. Results were compared by multivariate analysis to an historical control cohort of 102 white patients with NSCLC. RESULTS: African Americans were significantly less likely to harbor activating mutations of EGFR than white patients (2% v 17%; P = .022). Only one EGFR mutation was identified, a novel S768N substitution. EGFR FISH assay was more frequently positive for African Americans than for white patients (51% v 32%; P = .018). KRAS mutational frequency did not differ between the groups (23% v 21%; P = .409). CONCLUSION: African American patients with NSCLC are significantly less likely than white counterparts to harbor activating mutations of EGFR, which suggests that EGFR tyrosine kinase inhibitors (TKIs) are unlikely to yield major remissions in this population. Our findings add to a growing body of evidence that points to genetic heterogeneity of the EGFR pathway in NSCLC among different ethnic groups and that underscores the need for consideration of these differences in the design of future trials of agents that target the EGFR pathway. PMID- 19786662 TI - Geographic distribution of lapatinib-induced skin rash: sparing of abdominal skin persists in the transverse rectus abdominis myocutaneous flap. PMID- 19786661 TI - Dynamic model for predicting death within 12 months in patients with primary or post-polycythemia vera/essential thrombocythemia myelofibrosis. AB - PURPOSE: Current prognostic tools in myelofibrosis (MF) fail to identify patients at the highest risk of death and are limited by their applicability only to the time of diagnosis. We aimed to define an accelerated phase (AP) in MF by characterizing disease features that can identify patients with median overall survival of or= 10%, platelets less than 50 x 10(9)/L, and chromosome 17 aberrations (median overall survival, 10, 12, and 5 months, respectively). In the validation phase, chronic-phase patients who developed AP features during follow up were found to have short subsequent survival times (median overall survival, 12, 15, and 6 months, respectively). AP was a necessary step in the progression to blast phase, with leukemic transformation being exceedingly rare (3% risk at 10 years) in patients who remained persistently in chronic phase. CONCLUSION: Blood or bone marrow blasts >or= 10%, platelets less than 50 x 10(9)/L, and chromosome 17 aberrations defined AP in patients with MF. Patients in AP should be candidates for intensive therapeutic interventions. PMID- 19786663 TI - To tell or not to tell: the community wants to know about expensive anticancer drugs as a potential treatment option. AB - PURPOSE: Many new cancer treatments are available only at significant financial cost to the patient. We previously reported that Australian medical oncologists commonly do not discuss unsubsidized, expensive anticancer drugs (EACD) because of concern about causing distress. We argued that this position was not consistent with modern ethical principals but wanted to seek the community viewpoint. METHODS: A cross-sectional telephone survey of the Australian general public was performed. Respondents' views were sought about three hypothetical scenarios in which they were diagnosed with incurable cancer and an EACD treatment (out-of-pocket cost US$25,000) was available. RESULTS: Responses were obtained from 1,255 respondents (response rate, 43%). One hundred thirty-seven (11%) had a prior cancer diagnosis. Ninety-one percent of respondents wanted to be told by their doctor about an EACD that could improve survival by an additional 4 to 6 months, with 51% prepared to pay for it. People were more willing to pay if the drug could improve quality of life (71%) or if there was no effective standard treatment (76%). Sixty-eight percent believed the government should pay. Cost would be a significant financial burden for 31% of those willing to pay. Those more likely to want to be informed were younger, employed, better educated, or had higher income levels (P < .05). Responses did not vary with the person's personal experience of cancer. Of the 9% who did not wish to be informed, half of these were concerned about the information causing distress. CONCLUSION: The Australian general public wants to be informed about EACD as potential treatment options, even if they are not willing or readily able to pay for them. PMID- 19786664 TI - Immuno-fluorescence in situ hybridization index predicts survival in patients with diffuse large B-cell lymphoma treated with R-CHOP: a GELA study. AB - PURPOSE: To evaluate the prognostic value of cell of origin immunohistochemical markers and BCL2, BCL6, and c-MYC translocations in a homogeneous cohort of patients with diffuse large B-cell lymphoma (DLBCL) treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). PATIENTS AND METHODS: Patients with CD20+ DLBCL were enrolled in the randomized LNH98-5 and 01 5B Groupe d'Etude des Lymphomes de l'Adulte trials. Paraffin-embedded tumor samples of 119 patients treated with R-CHOP were analyzed by immunohistochemistry for CD10, BCL6, MUM1/IRF4, LMO2, and forkhead box protein P1 (FOXP1) expression and for BCL2, BCL6, and c-MYC breakpoints by fluorescence in situ hybridization (FISH) on tissue microarray. RESULTS: LMO2 expression and BCL2 breakpoint were associated with the germinal center (GC) subtype defined by Hans' algorithm, respectively (P < .0001; P = .0002) whereas FOXP1 expression and BCL6 breakpoint were associated with the non-germinal center (non-GC) subtype (P = .008 and P = .0001, respectively). The immunohistochemical markers analyzed independently, GC/non-GC phenotype and BCL2 breakpoint did not predict overall survival (OS). BCL6 breakpoint was significantly associated with an unfavorable impact on OS (P = .04). Interestingly, an immunoFISH index, defined by positivity for at least two of three non-GC markers (FOXP1, MUM1/IRF4, BCL6 breakpoint) was significantly associated with a shorter 5-year OS rate (44%; 95% CI, 28 to 60 v 78%; 95% CI, 59 to 89; P = .01) which was independent (P = .04) of the age-adjusted International Prognostic Index (P = .04) in multivariate analysis. CONCLUSION: Our study demonstrates that combining immunohistochemistry with FISH allows construction of an immunoFISH index that significantly predicts survival in elderly DLBCL patients treated with R-CHOP. PMID- 19786665 TI - Rapid clinical deterioration and leukemoid reaction after treatment of urothelial carcinoma of the bladder: possible effect of granulocyte colony-stimulating factor. PMID- 19786666 TI - Survival after second primary neoplasms of the brain or spinal cord in survivors of childhood cancer: results from the British Childhood Cancer Survivor Study. AB - PURPOSE: Survival after brain or spinal cord neoplasms is poor and varies by diagnostic group, age, grade, treatment and pretreatment factors, and location and size of tumor. We carried out a study to investigate survival and factors affecting survival of all diagnostic types of second primary brain or spinal cord neoplasms. PATIENTS AND METHODS: The British Childhood Cancer Survivor Study (BCCSS) is a long-term population-based follow-up study of 17,980 5-year survivors of childhood cancer. We used relative survival and multivariate Cox regression analysis to determine 5-year relative survival and factors affecting survival in second primary meningiomas and gliomas that developed in survivors included in the BCCSS. RESULTS: There were 247 second primary brain or spinal cord neoplasms, including 137 meningiomas and 73 gliomas in a young adult population. Five-year relative survival after meningiomas was similar for males (84.0%; 95% CI, 72.6% to 91.1%) and females (81.7%; 95% CI, 69.9% to 89.3%). For gliomas, 5-year relative survival was 19.5% (95% CI, 8.6% to 33.7%) for males and females. Multivariate analysis showed significant heterogeneity by decade of treatment (P = .04), grade (P = .03), and genetic risk (P = .03) for rate of mortality after a meningioma. For gliomas, survival was significantly affected by grade (P < .001). CONCLUSION: Our results indicate survival is poor after second primary glioma in this young adult population, although survival after second primary meningioma is good. Our study has clinical implications for the surveillance of childhood cancer survivors at risk of developing second primary brain tumors, in particular survivors of childhood acute lymphoblastic leukemia or childhood brain tumors. PMID- 19786667 TI - Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. AB - PURPOSE: Lenalidomide and bortezomib are active in relapsed and relapsed/refractory multiple myeloma (MM). In preclinical studies, lenalidomide sensitized MM cells to bortezomib and dexamethasone. This phase I, dose escalation study (ie, NCT00153933) evaluated safety and determined the maximum tolerated dose (MTD) of lenalidomide plus bortezomib in patients with relapsed or with relapsed and refractory MM. PATIENTS AND METHODS: Patients received lenalidomide 5, 10, or 15 mg/d on days 1 through 14 and received bortezomib 1.0 or 1.3 mg/m(2) on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20mg or 40 mg on days 1, 2, 4, 5, 8, 9, 11, and 12) was added for progressive disease after two cycles. Primary end points were safety and MTD determination. RESULTS: Thirty-eight patients were enrolled across six dose cohorts. The MTD was lenalidomide 15 mg/d plus bortezomib 1.0 mg/m(2). Dose-limiting toxicities (n = 1 for each) were grade 3 hyponatremia and herpes zoster reactivation and grade 4 neutropenia. The most common treatment-related, grades 3 to 4 toxicities included reversible neutropenia, thrombocytopenia, anemia, and leukopenia. Among 36 response-evaluable patients, 61% (90% CI, 46% to 75%) achieved minimal response or better. Among 18 patients who had dexamethasone added, 83% (90% CI, 62% to 95%) achieved stable disease or better. Median overall survival was 37 months. CONCLUSION: Lenalidomide plus bortezomib was well tolerated and showed promising activity with durable responses in patients with relapsed and relapsed/refractory MM, including patients previously treated with lenalidomide, bortezomib, and/or thalidomide. The combination of lenalidomide, bortezomib, and dexamethasone is being investigated in a phase II study in this setting and in newly diagnosed MM. PMID- 19786669 TI - Targeted high-resolution ultrasound is not an effective substitute for sentinel lymph node biopsy in patients with primary cutaneous melanoma. AB - PURPOSE: To reassess traditional ultrasound descriptors of sentinel lymph node (SLN) metastases, to determine the minimum cross-sectional area (CSA) of an SLN metastasis detectable by ultrasound (US), and to establish whether targeted, high resolution US of SLNs identified by lymphoscintigraphy before initial melanoma surgery can be used as a substitute for excisional SLN biopsy. METHODS: US was performed on SLNs identified in 871 lymph node fields in 716 patients. SLN biopsy was performed within 24 hours of lymphoscintigraphy and US examination. The CSA of each SLN metastatic deposit was determined sonographically and histologically. RESULTS: The sensitivity of targeted US in the detection of positive SLNs was 24.3% (95% CI, 19.5% to 28.7%), and the specificity was 96.8% (95% CI, 95.9% to 97.7%). The sensitivity was highest for neck SLNs (45.8%) and improved with greater Breslow thickness. The median histologic CSA of the SLN metastatic deposits was 0.39 mm(2) (12.75 mm(2) for US true-positive results and 0.22 mm(2) for US false-negative results). True-positive, US-detected SLNs had significantly greater CSAs (t test P < .001) than undetected SLN metastases and were more likely to be spherical in cross-section. More than two sonographic descriptors of SLN metastases or rounding of the node alone were factors highly suggestive of a melanoma deposit. CONCLUSION: US is not an appropriate substitute for SLN biopsy, but it is of value in preoperative SLN assessment and postoperative monitoring. PMID- 19786668 TI - Randomized phase II/III trial assessing gemcitabine/ carboplatin and methotrexate/carboplatin/vinblastine in patients with advanced urothelial cancer "unfit" for cisplatin-based chemotherapy: phase II--results of EORTC study 30986. AB - PURPOSE: There is no standard treatment for patients with advanced urothelial cancer who are ineligible ("unfit") for cisplatin-based chemotherapy (CHT). To compare the activity and safety of two CHT combinations in this patient group, a randomized phase II/III trial was conducted by the EORTC (European Organisation for Research and Treatment of Cancer). We report here the phase II results of the study. PATIENTS AND METHODS: CHT-naive patients with measurable disease and impaired renal function (30 mL/min < glomerular filtration rate [GFR] < 60 mL/min) and/or performance status (PS) 2 were randomly assigned to receive either GC (gemcitabine 1,000 mg/m(2) on days 1 and 8 and carboplatin area under the serum concentration-time curve [AUC] 4.5) for 21 days or M-CAVI (methotrexate 30 mg/m(2) on days 1, 15, and 22; carboplatin AUC 4.5 on day 1; and vinblastine 3 mg/m(2) on days 1, 15, and 22) for 28 days. End points of response and severe acute toxicity (SAT) were evaluated with respect to treatment group, renal function, PS, and Bajorin risk groups. RESULTS: Three of 178 patients who were ineligible or did not start treatment were excluded. SAT was reported in 13.6% of patients on GC and in 23% on M-CAVI. Overall response rates were 42% (37 of 88) for GC and 30% (26 of 87) for M-CAVI. Patients with PS 2 and GFR less than 60 mL/min and patients in Bajorin risk group 2 showed a response rate of only 26% and 20% and an SAT rate of 26% and 25%, respectively. CONCLUSION: Both combinations are active in this group of unfit patients. However, patients with PS 2 and GFR less than 60 mL/min do not benefit from combination CHT. Alternative treatment modalities should be sought in this subgroup of poor-risk patients. PMID- 19786670 TI - Trastuzumab plus anastrozole versus anastrozole alone for the treatment of postmenopausal women with human epidermal growth factor receptor 2-positive, hormone receptor-positive metastatic breast cancer: results from the randomized phase III TAnDEM study. AB - PURPOSE: TAnDEM is the first randomized phase III study to combine a hormonal agent and trastuzumab without chemotherapy as treatment for human epidermal growth factor receptor 2 (HER2)/hormone receptor-copositive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HER2/hormone receptor-copositive MBC were randomly assigned to anastrozole (1 mg/d orally) with or without trastuzumab (4 mg/kg intravenous infusion on day 1, then 2 mg/kg every week) until progression. The primary end point was progression-free survival (PFS) in the intent-to-treat population. Results Overall, 103 patients received trastuzumab plus anastrozole; 104 received anastrozole alone. Patients in the trastuzumab plus anastrozole arm experienced significant improvements in PFS compared with patients receiving anastrozole alone (hazard ratio = 0.63; 95% CI, 0.47 to 0.84; median PFS, 4.8 v 2.4 months; log-rank P = .0016). In patients with centrally confirmed hormone receptor positivity (n = 150), median PFS was 5.6 and 3.8 months in the trastuzumab plus anastrozole and anastrozole alone arms, respectively (log-rank P = .006). Overall survival in the overall and centrally confirmed hormone receptor-positive populations showed no statistically significant treatment difference; however, 70% of patients in the anastrozole alone arm crossed over to receive trastuzumab after progression on anastrozole alone. Incidence of grade 3 and 4 adverse events was 23% and 5%, respectively, in the trastuzumab plus anastrozole arm, and 15% and 1%, respectively, in the anastrozole alone arm; one patient in the combination arm experienced New York Heart Association class II congestive heart failure. CONCLUSION: Trastuzumab plus anastrozole improves outcomes for patients with HER2/hormone receptor-copositive MBC compared with anastrozole alone, although adverse events and serious adverse events were more frequent with the combination. PMID- 19786671 TI - Patient-centered care: what is the best measuring stick? PMID- 19786672 TI - Weighing the benefits and downsides of prostate-specific antigen screening. PMID- 19786673 TI - Shared decision making for prostate cancer screening: do patients or clinicians have a choice? PMID- 19786674 TI - The diabetes mellitus medication choice decision aid: a randomized trial. AB - BACKGROUND: Patient involvement in the choice of antihyperglycemic agents could improve adherence and optimize glycemic control in patients with type 2 diabetes mellitus. METHODS: We conducted a pilot, cluster randomized trial of Diabetes Medication Choice, a decision aid that describes 5 antihyperglycemic drugs, their treatment burden (adverse effects, administration, and self-monitoring demands), and impact on hemoglobin A(1c) (HbA(1c)) levels. Twenty-one clinicians were randomized to use the decision aid during the clinical encounter and 19 to dispense usual care and an educational pamphlet. We used surveys and video analysis to assess postvisit decisional outcomes, and medical and pharmacy records to assess 6-month medication adherence and HbA(1c) levels. RESULTS: Compared with usual care patients (n = 37), patients receiving the decision aid (n = 48) found the tool more helpful (clustered-adjusted mean difference [AMD] in a 7-point scale, 0.38; 95% confidence interval [CI], 0.04-0.72); had improved knowledge (AMD, 1.10 of 10 questions; 95% CI, 0.11-2.09); and had more involvement in making decisions about diabetes medications (AMD, 21.8 of 100; 95% CI, 13.0-30.5). At 6-month follow-up, both groups had nearly perfect medication use (median, 100% of days covered), with better adherence (AMD, 9% more days covered; 95% CI, 4%-14%) and persistence (AMD, 12 more days covered; 95% CI, 3-21 days) in the usual care group, and no significant impact on HbA(1c) levels (AMD, 0.01; 95% CI, -0.49 to 0.50). CONCLUSION: An innovative decision aid effectively involved patients with type 2 diabetes mellitus in decisions about their medications but did not improve adherence or HbA(1c) levels. Trial Registration clinicaltrials.gov Identifier: NCT00388050. PMID- 19786675 TI - Hospital at home for elderly patients with acute decompensation of chronic heart failure: a prospective randomized controlled trial. AB - BACKGROUND: Although the hospital is the standard venue for short-term medical care, it may be hazardous for older persons. This study was performed to evaluate the feasibility and effectiveness of a physician-led hospital-at-home service for selected elderly patients with acute decompensation of chronic heart failure (CHF). METHODS: Prospective, single-blind, randomized controlled trial with 6 month follow-up for patients 75 years or older admitted to the hospital from April 1, 2004, through April 31, 2005, for acute decompensation of CHF. Patients were randomly assigned to the general medical ward (n = 53) or to the Geriatric Home Hospitalization Service (GHHS; n = 48). The GHHS provides diagnostic and therapeutic treatments by hospital health care professionals in the home of the patient. RESULTS: Patient mortality at 6 months was 15% in the total sample, without significant differences between the 2 settings of care. The number of subsequent hospital admissions was not statistically different in the 2 groups, but the mean (SD) time to first additional admission was longer for the GHHS patients (84.3 [22.2] days vs 69.8 [36.2] days, P = .02). Only the GHHS patients experienced improvements in depression, nutritional status, and quality-of-life scores. CONCLUSIONS: Substitutive hospital-at-home care is a viable alternative to traditional hospital inpatient care for elderly patients with acutely decompensated CHF. This type of care demonstrated clinical feasibility and efficacy in comparison with its alternative. Trial Registration clinicaltrials.gov Identifier: NCT00623571. PMID- 19786676 TI - Improvement of hospital care of elderly patients: thinking outside the (hospital) box: comment on "hospital at home for elderly patients with acute decompensation of chronic heart failure". PMID- 19786677 TI - Timely follow-up of abnormal diagnostic imaging test results in an outpatient setting: are electronic medical records achieving their potential? AB - BACKGROUND: Given the fragmentation of outpatient care, timely follow-up of abnormal diagnostic imaging results remains a challenge. We hypothesized that an electronic medical record (EMR) that facilitates the transmission and availability of critical imaging results through either automated notification (alerting) or direct access to the primary report would eliminate this problem. METHODS: We studied critical imaging alert notifications in the outpatient setting of a tertiary care Department of Veterans Affairs facility from November 2007 to June 2008. Tracking software determined whether the alert was acknowledged (ie, health care practitioner/provider [HCP] opened the message for viewing) within 2 weeks of transmission; acknowledged alerts were considered read. We reviewed medical records and contacted HCPs to determine timely follow up actions (eg, ordering a follow-up test or consultation) within 4 weeks of transmission. Multivariable logistic regression models accounting for clustering effect by HCPs analyzed predictors for 2 outcomes: lack of acknowledgment and lack of timely follow-up. RESULTS: Of 123 638 studies (including radiographs, computed tomographic scans, ultrasonograms, magnetic resonance images, and mammograms), 1196 images (0.97%) generated alerts; 217 (18.1%) of these were unacknowledged. Alerts had a higher risk of being unacknowledged when the ordering HCPs were trainees (odds ratio [OR], 5.58; 95% confidence interval [CI], 2.86-10.89) and when dual-alert (>1 HCP alerted) as opposed to single-alert communication was used (OR, 2.02; 95% CI, 1.22-3.36). Timely follow-up was lacking in 92 (7.7% of all alerts) and was similar for acknowledged and unacknowledged alerts (7.3% vs 9.7%; P = .22). Risk for lack of timely follow-up was higher with dual-alert communication (OR, 1.99; 95% CI, 1.06-3.48) but lower when additional verbal communication was used by the radiologist (OR, 0.12; 95% CI, 0.04-0.38). Nearly all abnormal results lacking timely follow-up at 4 weeks were eventually found to have measurable clinical impact in terms of further diagnostic testing or treatment. CONCLUSIONS: Critical imaging results may not receive timely follow-up actions even when HCPs receive and read results in an advanced, integrated electronic medical record system. A multidisciplinary approach is needed to improve patient safety in this area. PMID- 19786679 TI - Mortality and need for mechanical ventilation in acute exacerbations of chronic obstructive pulmonary disease: development and validation of a simple risk score. AB - BACKGROUND: Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) often require hospitalization, may necessitate mechanical ventilation, and can be fatal. We sought to develop a simple risk score to determine its severity. METHODS: We analyzed 88,074 subjects admitted with an AECOPD between 2004 and 2006. We used recursive partition to create risk classifications for in hospital mortality. Need for mechanical ventilation served as a secondary end point. We internally validated the model via 1000 bootstrapping on half of patients and externally validated it on the remaining patients. We assessed predictive ability using the area under the receiver operating curve (AUROC). RESULTS: The in-hospital mortality rate was 2%. Three variables had high discrimination of outcomes: serum urea nitrogen level greater than 25 mg/dL (to convert to millimoles per liter, multiply by 0.357); acute mental status change, and pulse greater than 109/min. For those without any of the 3 factors, age 65 years or younger further differentiated the lowest-risk group. In those with all 3 factors, the mortality rates were 13.1% (131 in 1000) and 14.6% (146 in 1000) in the derivation and validation cohorts, respectively, compared with 0.3% (3 in 1000) in both cohorts among patients without any of the 3 factors and age 65 years or younger (P < .001). The AUROC for mortality in the 2 cohorts were 0.72 (95% confidence interval [CI], 0.70-0.74) and 0.71 (95% CI, 0.70-0.73), respectively. For mechanical ventilation, the AUROCs were 0.77 (95% CI, 0.75 0.79) for both cohorts. CONCLUSIONS: A simple risk class based on clinical variables easily obtained at presentation predicts mortality and need for mechanical ventilation. It may facilitate the triage and care of patients with AECOPD. PMID- 19786680 TI - A model of prostate-specific antigen screening outcomes for low- to high-risk men: information to support informed choices. AB - BACKGROUND: Information is needed to aid individual decision making about prostate-specific antigen (PSA) screening. METHODS: We aimed to provide such information for men aged 40, 50, 60, and 70 years at low, moderate, and high risk for prostate cancer. A Markov model compared patients with vs without annual PSA screening using a 20% relative risk (RR) reduction (RR = 0.8) in prostate cancer mortality as a best-case scenario. The model estimated numbers of biopsies, prostate cancers, and deaths from prostate cancer per 1000 men over 10 years and cumulated to age 85 years. RESULTS: Benefits and harms vary substantially with age and familial risk. Using 60-year-old men with low risk as an example, of 1000 men screened annually, we estimate that 115 men will undergo biopsy triggered by an abnormal PSA screen result and that 53 men will be diagnosed as having prostate cancer over 10 years compared with 23 men diagnosed as having prostate cancer among 1000 unscreened men. Among screened men, 3.5 will die of prostate cancer over 10 years compared with 4.4 deaths in unscreened men. For 1000 men screened from 40 to 69 years of age, there will be 27.9 prostate cancer deaths and 639.5 deaths overall by age 85 years compared with 29.9 prostate cancer deaths and 640.4 deaths overall in unscreened men. Higher-risk men have more prostate cancer deaths averted but also more prostate cancers diagnosed and related harms. CONCLUSIONS: Men should be informed of the likely benefits and harms of PSA screening. These estimates can be used to support individual decision making. PMID- 19786681 TI - Prostate cancer screening decisions: results from the National Survey of Medical Decisions (DECISIONS study). AB - BACKGROUND: Guidelines recommend informing patients about the risks and benefits of prostate cancer screening. We evaluated the medical decision-making process for prostate-specific antigen (PSA) testing. METHODS: We conducted a telephone survey of a randomly selected national sample of 3010 English-speaking US adults 40 years and older. Included in the survey were 375 men who had either undergone or discussed (with health care providers [HCPs]) PSA testing in the previous 2 years. We asked subjects about sociodemographic characteristics, prostate cancer screening discussion features, prostate cancer knowledge, and the importance of various decision factors and sources of information. RESULTS: Overall, 69.9% of subjects discussed screening before making a testing decision, including 14.4% who were not tested. Health care providers most often (64.6%) raised the idea of screening, and 73.4% recommended PSA testing. Health care providers emphasized the pros of testing in 71.4% of discussions but infrequently addressed the cons (32.0%). Although 58.0% of subjects felt well-informed about PSA testing, 47.8% failed to correctly answer any of the 3 knowledge questions. Only 54.8% of subjects reported being asked for their screening preferences. An HCP recommendation (odds ratio, 2.67; 95% confidence interval, 1.08-6.58) was the only discussion characteristic associated with testing. Valuing HCP information was also associated with testing (odds ratio, 1.26; 95% confidence interval, 1.04 1.54). CONCLUSIONS: Recommendations and information from HCPs strongly influenced testing decisions. However, most prostate cancer screening decisions did not meet criteria for shared decision making because subjects did not receive balanced discussions of decision consequences, had limited knowledge, and were not routinely asked for their preferences. PMID- 19786678 TI - Risk of hyperkalemia in nondiabetic patients with chronic kidney disease receiving antihypertensive therapy. AB - BACKGROUND: The incidence and factors associated with hyperkalemia in patients with chronic kidney disease (CKD) treated with angiotensin converting enzyme inhibitors (ACEIs) and other antihypertensive drugs was investigated using the African American Study of Kidney Disease and Hypertension (AASK) database. METHODS: A total of 1094 nondiabetic adults with hypertensive CKD (glomerular filtration rate [GFR], 20-65 mL/min/1.73 m(2)) were followed for 3.0 to 6.4 years in the AASK trial. Participants were randomly assigned to ACEI, beta-blocker (BB), or dihydropyridine calcium channel blocker (CCB). The outcome variables for this analysis were a serum potassium level higher than 5.5 mEq/L (to convert to millimoles per liter, multiply by 1.0), or a clinical center initiated hyperkalemia stop point. RESULTS: A total of 6497 potassium measurements were obtained, and 80 events in 51 subjects were identified (76 events driven by a central laboratory result and 4 driven by a clinical center-initiated hyperkalemia stop point). Compared with a GFR higher than 50 mL/min/1.73 m(2), after multivariable adjustment, the hazard ratio (HR) for hyperkalemia in patients with a GFR between 31 and 40 mL/min/1.73 m(2) and a GFR lower than 30 mL/min/1.73 m(2) was 3.61 (95% confidence interval [CI], 1.42-9.18 [P = .007]) and 6.81 (95% CI, 2.67-17.35 [P < .001]), respectively; there was no increased risk of hyperkalemia if GFR was 41 to 50 mL/min/1.73 m(2). Use of ACEIs was associated with more episodes of hyperkalemia compared with CCB use (HR, 7.00; 95% CI, 2.29-21.39 [P < .001]) and BB group (HR, 2.85; 95% CI, 1.50-5.42 [P = .001]). Diuretic use was associated with a 59% decreased risk of hyperkalemia. CONCLUSIONS: In nondiabetic patients with hypertensive CKD treated with ACEIs, the risk of hyperkalemia is small, particularly if baseline and follow-up GFR is higher than 40 mL/min/1.73 m(2). Including a diuretic in the regimen may markedly reduce risk of hyperkalemia. PMID- 19786684 TI - Reducing missed opportunities to vaccinate adults against influenza: what is realistic? PMID- 19786683 TI - Clinicians' assessments of electronic medication safety alerts in ambulatory care. AB - BACKGROUND: While electronic prescribing (e-prescribing) systems with drug interaction and allergy alerts promise to improve medication safety in ambulatory care, clinicians often override these safety features. We undertook a study of respondents' satisfaction with e-prescribing systems, their perceptions of alerts, and their perceptions of behavior changes resulting from alerts. METHODS: Random sample survey of 300 Massachusetts ambulatory care clinicians who used a commercial e-prescribing system. RESULTS: A total of 184 respondents completed the survey (61%). Respondents indicated that e-prescribing improved the quality of care delivered (78%), prevented medical errors (83%), and enhanced patient satisfaction (71%) and clinician efficiency (75%). In addition, 35% of prescribers said that electronic alerts caused them to modify a potentially dangerous prescription in the last 30 days. They suggested that alerts also led to other changes in clinical care: counseling patients about potential reactions (49% of respondents), looking up information in medical references (44%), and changing the way a patient was monitored (33%). Altogether, 63% of clinicians reported taking action other than discontinuing or modifying an alerted prescription in the previous month in response to alerts. Despite these benefits, fewer than half of respondents were satisfied with drug interaction and allergy alerts (47%). Problems included alerts triggered by discontinued medications (58%), alerts that failed to account for appropriate drug combinations (46%), and excessive volume of alerts (37%). CONCLUSION: Although clinicians were critical of the quality of e-prescribing alerts, alerts may lead to clinically significant modifications in patient management not readily apparent based on "acceptance" rates. PMID- 19786682 TI - A randomized study on the effect of weight loss on obstructive sleep apnea among obese patients with type 2 diabetes: the Sleep AHEAD study. AB - BACKGROUND: The belief that weight loss improves obstructive sleep apnea (OSA) has limited empirical support. The purpose of this 4-center study was to assess the effects of weight loss on OSA over a 1-year period. METHODS: The study included 264 participants with type 2 diabetes and a mean (SD) age of 61.2 (6.5) years, weight of 102.4 (18.3) kg, body mass index (BMI) (calculated as weight in kilograms divided by height in meters squared) of 36.7 (5.7), and an apnea hypopnea index (AHI) of 23.2 (16.5) events per hour. The participants were randomly assigned to either a behavioral weight loss program developed specifically for obese patients with type 2 diabetes (intensive lifestyle intervention [ILI]) or 3 group sessions related to effective diabetes management (diabetes support and education [DSE]). RESULTS: The ILI participants lost more weight at 1 year than did DSE participants (10.8 kg vs 0.6 kg; P < .001). Relative to the DSE group, the ILI intervention was associated with an adjusted (SE) decrease in AHI of 9.7 (2.0) events per hour (P < .001). At 1 year, more than 3 times as many participants in the ILI group than in the DSE group had total remission of their OSA, and the prevalence of severe OSA among ILI participants was half that of the DSE group. Initial AHI and weight loss were the strongest predictors of changes in AHI at 1 year (P < .01). Participants with a weight loss of 10 kg or more had the greatest reductions in AHI. CONCLUSIONS: Physicians and their patients can expect that weight loss will result in significant and clinically relevant improvements in OSA among obese patients with type 2 diabetes. Trial Registration clinicaltrials.gov Identifier: NCT00194259. PMID- 19786685 TI - Dilated inferior vena cava in young adults with vasovagal syncope. PMID- 19786686 TI - The healthy adherer effect. PMID- 19786687 TI - Is insulin the preferred compound in lowering glucose levels in patients after a myocardial infarction? PMID- 19786688 TI - Relationship between bone, fracture, and exercise: the key role of vitamin D. PMID- 19786689 TI - Child Neurology: Dravet syndrome: when to suspect the diagnosis. AB - Dravet syndrome (DS), previously known as severe myoclonic epilepsy in infancy (SMEI), is an epileptic encephalopathy that presents with prolonged seizures in the first year of life. The seizures often occur with fever or illness, and are frequently initially categorized as febrile seizures. The correct diagnosis of DS and appropriate follow-up are typically delayed. The EEG is normal at onset, and neuroimaging reveals no structural lesion. Early development is normal, but signs of regression appear in the second year of life and are often accompanied by convulsive status epilepticus, alternating hemiconvulsions, and myoclonic seizures. Diagnosis can be confirmed by genetic testing that is now available, and shows mutations within the SCN1A gene. Early recognition and diagnosis of DS and management with appropriate anticonvulsants and treatment plan may reduce the seizure burden and improve long-term developmental outcome. PMID- 19786690 TI - Teaching NeuroImages: artery-to-artery embolism from a thrombosed cerebral aneurysm. PMID- 19786691 TI - Patient page. Juvenile myoclonic epilepsy, a common epilepsy syndrome. PMID- 19786693 TI - Apolipoprotein genotype does not influence MS severity, cognition, or brain atrophy. AB - BACKGROUND: The influence of APOE allelic heterogeneity on multiple sclerosis (MS) disease severity has been reported in multiple datasets with conflicting results. Several studies have reported an unfavorable association of APOE epsilon4 with more severe clinical disease course while, in contrast, APOE epsilon2 has been associated with a more benign disease course. In this study, we examine the influence of heterogeneity of the APOE gene on disease severity in a large, Australian, population-based MS cohort. METHODS: Associations between APOE allele status, 2 promoter region single nucleotide polymorphisms (-219 G/T and +113 C/G), and 4 measures of disease severity were tested in 1,006 patients with relapsing-remitting MS and secondary progressive MS: 1) Multiple Sclerosis Severity Score; 2) Progression Index (Expanded Disability Status Scale/disease duration); 3) age at first symptom; and 4) interval between the first and second attack. The Symbol Digit Modalities Test was used as a single cognitive marker in 889 patients. Brain atrophy was measured in 792 patients using the intercaudate ratio. APOE epsilon4 and epsilon3 carriers were stratified by -219 G/T or +113 C/G to investigate haplotypic heterogeneity in the APOE gene region. RESULTS: In this MS study, neither APOE allele status nor promoter region heterogeneity at positions -219 G/T or +113 C/G influenced the clinical disease severity, cognition, or cerebral atrophy. CONCLUSIONS: Allelic and haplotypic heterogeneity of the APOE gene region does not influence multiple sclerosis disease course in this well-defined Australian multiple sclerosis cohort. PMID- 19786694 TI - Increased neuronal proliferation in human bacterial meningitis. AB - OBJECTIVE: Neurogenesis is increased in experimental models of bacterial meningitis. In this study, neurogenesis was examined after bacterial infection of the CNS, and after stroke and brain trauma in humans. METHODS: Brain sections of patients after death from bacterial meningitis, stroke, or brain trauma and from autopsy cases after death from nonneurologic diseases were investigated by immunohistochemistry. RESULTS: In the dentate gyrus, the density of proliferating cellular nuclear antigen-expressing cells was higher after bacterial meningitis compared to the control group (p = 0.0075). Furthermore, the number of cells expressing the immature neuronal marker proteins TUC-4 and doublecortin were increased in brain sections of patients after death from meningitis compared to control cases (p = 0.0067 and p = 0.045). After stroke and brain trauma, higher densities of proliferating cells were observed (p = 0.031 and p = 0.018), while an increase of TUC-4-expressing cells was detected after stroke only (p = 0.0012 and p = 0.47). CONCLUSIONS: The increased proliferation of neural progenitors suggests an endogenous mechanism in response to noxious stimuli. Stimulation of neurogenesis might help to alleviate the consequences of neuronal destruction in bacterial meningitis and other diseases of the brain. PMID- 19786695 TI - Juvenile myoclonic epilepsy 25 years after seizure onset: a population-based study. AB - OBJECTIVE: To document the long-term evolution of juvenile myoclonic epilepsy (JME) in a population-based cohort. METHODS: All patients developing JME by 16 years of age in Nova Scotia between 1977 and 1985 were contacted in 2006-2008. RESULTS: Twenty-four patients (17 women) had JME, 3.5% of all childhood-onset epilepsy. Age at first seizure was 10.4 +/- 4.3 years. We contacted 23 of 24 (96%) at a mean age of 36 +/- 4.8 years. All were initially treated with antiepileptic drugs (AEDs). At the end of a 25.8 +/- 2.4-year follow-up, 11 (48%) had discontinued treatment: 6 were seizure-free (without AEDs for 5-23 years), 3 had myoclonic seizures only (without AEDs for >18 years), and 2 continued with rare seizures. Convulsive status epilepticus occurred in 8 (36%) and 3 had intractable epilepsy. About 70% reported good satisfaction with their health, work, friendships, and social life (Likert scales). Despite 87% high school graduation, 31% were unemployed. Sixteen live with a partner, 7 alone. Nine received antidepressant medications. Ten women had > or =1 pregnancy and 4 men fathered a child. Eleven pregnancies (80%) were unplanned, outside of a stable relationship. At least 1 major unfavorable social outcome was noted in 76%. CONCLUSIONS: Our sample size is modest but the long follow-up and population based sampling is unique. All seizure types in juvenile myoclonic epilepsy (JME) resolved in 17% and for 13%, only myoclonus persisted. Therefore, one-third of people with JME have troublesome seizures vanish and antiepileptic drug treatment is no longer needed. Depression, social isolation, unemployment, and social impulsiveness complicate the lives of many patients. PMID- 19786696 TI - De novo mutations of voltage-gated sodium channel alphaII gene SCN2A in intractable epilepsies. AB - BACKGROUND: Mutations of voltage-gated sodium channel alpha(II) gene, SCN2A, have been described in a wide spectrum of epilepsies. While inherited SCN2A mutations have been identified in multiple mild epilepsy cases, a de novo SCN2A-R102X mutation, which we previously reported in a patient with sporadic intractable childhood localization-related epilepsy, remains unique. To validate the involvement of de novo SCN2A mutations in the etiology of intractable epilepsies, we sought to identify additional instances. METHODS: We performed mutational analyses on SCN2A in 116 patients with severe myoclonic epilepsy in infancy, infantile spasms, and other types of intractable childhood partial and generalized epilepsies and did whole-cell patch-clamp recordings on Na(v)1.2 channels containing identified mutations. RESULTS: We discovered 2 additional de novo SCN2A mutations. One mutation, SCN2A-E1211K, was identified in a patient with sporadic infantile spasms. SCN2A-E1211K produced channels with altered electrophysiologic properties compatible with both augmented (an approximately 18 mV hyperpolarizing shift in the voltage dependence of activation) and reduced (an approximately 22-mV hyperpolarizing shift in the voltage dependence of steady state inactivation and a slowed recovery from inactivation) channel activities. The other de novo mutation, SCN2A-I1473M, was identified in a patient with sporadic neonatal epileptic encephalopathy. SCN2A-I1473M caused an approximately 14-mV hyperpolarizing shift in the voltage dependence of activation. CONCLUSIONS: The identified de novo mutations SCN2A-E1211K, -I1473M, and -R102X indicate that SCN2A is an etiologic candidate underlying a variety of intractable childhood epilepsies. The phenotypic variations among patients might be due to the different electrophysiologic properties of mutant channels. PMID- 19786697 TI - Three-dimensional MR volumetric analysis of the posterior fossa CSF space in hemifacial spasm. AB - BACKGROUND: We hypothesize that a smaller posterior fossa (PF) CSF space may be a risk factor for hemifacial spasm (HFS). OBJECTIVE: We conducted a case-control 3 dimensional magnetic resonance (MR) volumetric study in patients with HFS and determined the clinical predictive factors of PF CSF volume. METHODS: Patients with clinically diagnosed HFS and controls matched for age, sex, race, and hypertension underwent MRI/magnetic resonance angiography examination. The PF CSF space was segmented and quantified on a heavily T2-weighted high-resolution 3 dimensional MR volume slab, centered over the porus acusticus. RESULTS: Eighty two study subjects (41 patients and 41 controls) were included. The mean PF CSF volume in patients with HFS and controls was 17,303.0 +/- 3,900.0 vs 19,216.0 +/- 3,912.0 mm(3). The mean volume in patients with HFS was 11.4% smaller than in controls (p = 0.015). Analysis of differences between individually matched pairs and controls also revealed that PF CSF for controls was larger than that for patients with HFS (p = 0.007). A multivariate linear regression analysis revealed that a small PF CSF volume was associated with HFS (p = 0.01). Decreasing age (p = 0.001) and female gender (p < 0.0005), but not hypertension (p = 0.892), were also found to be predictors of a low PF CSF volume. CONCLUSIONS: Our results showed that the posterior fossa (PF) CSF volume was lower in patients with HFS compared with matched controls. HFS, female gender, and younger age were associated with smaller PF CSF volume. These observations could explain the strong female preponderance in both clinic- and population-based epidemiologic studies. PMID- 19786698 TI - Atrophy patterns in IVS10+16, IVS10+3, N279K, S305N, P301L, and V337M MAPT mutations. AB - OBJECTIVE: To use a case-control study to assess and compare patterns of gray matter loss across groups of subjects with different mutations in the microtubule associated protein tau (MAPT) gene. METHODS: We identified all subjects from Mayo Clinic, Rochester, Minnesota, that screened positive for mutations in MAPT and had a head MRI (n = 22). Voxel-based morphometry was used to assess patterns of gray matter atrophy in groups of subjects with the IVS10+16, IVS10+3, N279K, S305N, P301L, and V337M mutations compared with age- and sex-matched controls. RESULTS: All MAPT groups showed gray matter loss in the anterior temporal lobes, with varying degrees of involvement of the frontal and parietal lobes. Within the temporal lobe, the subjects with IVS10+16, IVS10+3, N279K, and S305N mutations (mutations that influence the alternative splicing of tau pre-messenger RNA) all showed gray matter loss focused on the medial temporal lobes. In contrast to these groups, the subjects with P301L or V337M mutations (mutations that affect the structure of the tau protein) both showed gray matter loss focused on the lateral temporal lobes, with a relative sparing of the medial temporal lobe. CONCLUSION: There seem to be differences in patterns of temporal lobe atrophy across the MAPT mutations, which may aid in the differentiation of the different mutation carriers. Furthermore, there seems to be a possible association between mutation function and pattern of temporal lobe atrophy. PMID- 19786700 TI - Characterizing radiology reports in patients with frontotemporal dementia. PMID- 19786699 TI - Good clinical outcome after ischemic stroke with successful revascularization is time-dependent. AB - BACKGROUND: Trials of IV recombinant tissue plasminogen activator (rt-PA) have demonstrated that longer times from ischemic stroke symptom onset to initiation of treatment are associated with progressively lower likelihoods of clinical benefit, and likely no benefit beyond 4.5 hours. How the timing of IV rt-PA initiation relates to timing of restoration of blood flow has been unclear. An understanding of the relationship between timing of angiographic reperfusion and clinical outcome is needed to establish time parameters for intraarterial (IA) therapies. METHODS: The Interventional Management of Stroke pilot trials tested combined IV/IA therapy for moderate-to-severe ischemic strokes within 3 hours from symptom onset. To isolate the effect of time to angiographic reperfusion on clinical outcome, we analyzed only middle cerebral artery and distal internal carotid artery occlusions with successful reperfusion (Thrombolysis in Cerebral Infarction 2-3) during the interventional procedure (<7 hours). Time to angiographic reperfusion was defined as time from stroke onset to procedure termination. Good clinical outcome was defined as modified Rankin Score 0-2 at 3 months. RESULTS: Among the 54 cases, only time to angiographic reperfusion and age independently predicted good clinical outcome after angiographic reperfusion. The probability of good clinical outcome decreased as time to angiographic reperfusion increased (unadjusted p = 0.02, adjusted p = 0.01) and approached that of cases without angiographic reperfusion within 7 hours. CONCLUSIONS: We provide evidence that good clinical outcome following angiographically successful reperfusion is significantly time-dependent. At later times, angiographic reperfusion may be associated with a poor risk-benefit ratio in unselected patients. PMID- 19786701 TI - Most stroke patients do not get a warning: a population-based cohort study. PMID- 19786702 TI - Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose finding trial. PMID- 19786703 TI - Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. PMID- 19786704 TI - Risk and protective factors associated with speech and language impairment in a nationally representative sample of 4- to 5-year-old children. AB - PURPOSE: To determine risk and protective factors for speech and language impairment in early childhood. METHOD: Data are presented for a nationally representative sample of 4,983 children participating in the Longitudinal Study of Australian Children (described in McLeod & Harrison, 2009). Thirty-one child, parent, family, and community factors previously reported as being predictors of speech and language impairment were tested as predictors of (a) parent-rated expressive speech/language concern and (b) receptive language concern, (c) use of speech-language pathology services, and (d) low receptive vocabulary. RESULTS: Bivariate logistic regression analyses confirmed 29 of the identified factors. However, when tested concurrently with other predictors in multivariate analyses, only 19 remained significant: 9 for 2-4 outcomes and 10 for 1 outcome. Consistent risk factors were being male, having ongoing hearing problems, and having a more reactive temperament. Protective factors were having a more persistent and sociable temperament and higher levels of maternal well-being. Results differed by outcome for having an older sibling, parents speaking a language other than English, and parental support for children's learning at home. CONCLUSION: Identification of children requiring speech and language assessment requires consideration of the context of family life as well as biological and psychosocial factors intrinsic to the child. PMID- 19786706 TI - ACS scores: risky business? PMID- 19786705 TI - Judgments of omitted BE and DO in questions as extended finiteness clinical markers of specific language impairment (SLI) to 15 years: a study of growth and asymptote. AB - PURPOSE: Clinical grammar markers are needed for children with SLI older than 8 years. This study followed children who were previously studied on sentences with omitted finiteness to determine if affected children continue to perform at low levels and to examine possible predictors of low performance. This is the first longitudinal report of grammaticality judgments of questions. METHOD: Three groups of children participated: 20 SLI, 20 age controls, and 18 language-matched controls, followed from ages 6-15 years. An experimental grammaticality judgment task was administered with BE copula/auxiliary and DO auxiliary in wh- and yes/no questions for 9 times of measurement. Predictors were indices of vocabulary, nonverbal intelligence, and maternal education. RESULTS: Growth curve analyses show that the affected group performed below the younger controls at each time of measurement, for each variable. Growth analyses show linear and quadratic effects for both groups across variables, with the exception of BE acquisition, which was flat for both groups. The control children reached ceiling levels; the affected children reached a lower asymptote. CONCLUSION: The results suggest an ongoing maturational lag in finiteness marking for affected children with promise as a clinical marker for language impairment in school-aged and adolescent children and probably adults as well. PMID- 19786707 TI - Emerging transcatheter therapies for aortic and mitral disease. PMID- 19786708 TI - Ischaemic mitral regurgitation: mechanisms and diagnosis. PMID- 19786709 TI - Haemoptysis with a normal chest radiograph: how concerned should we be? PMID- 19786710 TI - Blood glucose: of emerging importance in COPD exacerbations. PMID- 19786711 TI - Identification of those at risk after acute pulmonary embolism. PMID- 19786712 TI - Cough, confusion and flaccid paralysis in a 46-year old man with left apical consolidation and ring-enhancing lesions on cerebral imaging. PMID- 19786715 TI - Rosai-Dorfman disease of the lung. AB - Rosai-Dorfman disease is a rare disorder which seems to involve not only the lymph nodes but most other organs of the body. The case history is presented of a woman who was thought to have atypical carcinoma of the lung but in whom a diagnosis of Rosai-Dorfman disease was eventually made following a range of investigations including CT scans, positron emission tomography (PET) and histological analysis of open lung biopsy specimens. She remains well with no further progression of the disease without treatment. Rosai-Dorfman disease can mimic lung carcinoma and shows increased activity on PET scanning, so histological confirmation should be sought in all cases. PMID- 19786716 TI - Palliation of dyspnoea in advanced COPD: revisiting a role for opioids. AB - Chronic obstructive pulmonary disease (COPD) will be the third leading cause of death worldwide by 2020. The burdens of this increasingly prevalent illness borne by patients, their family caregivers and the healthcare system are substantial. Dyspnoea as the predominant symptom becomes increasingly difficult to palliate as COPD progresses through advanced stages and, for 50% of patients, can become refractory to conventional treatment. This narrative review focuses on the potential role for carefully initiated and titrated opioids in the management of dyspnoea for patients with advanced COPD who are not yet in a terminal stage, yet struggle with symptoms that reflect underlying mechanisms of dyspnoea that lend themselves to this approach. The many barriers that currently exist to the provision of opioids in this setting are addressed, and recommendations are provided for an approach that should engender confidence among patients, their caregivers and the physicians who treat them. PMID- 19786718 TI - Prognosis of patients with COPD admitted to the ICU. PMID- 19786719 TI - Iloprost-induced rash. PMID- 19786720 TI - Hepatotoxicity and antituberculosis therapy: time to revise UK guidance? PMID- 19786721 TI - Thoracic endometriosis: rare presentation as a solitary pulmonary nodule with eccentric cavitations. PMID- 19786722 TI - Botulinum toxin to treat upper-limb spasticity in hemiparetic patients: grasp strategies and kinematics of reach-to-grasp movements. AB - BACKGROUND: Poor control of grasping in spastic, hemiparetic patients could be because of a combination of poor individuation of joints, weakness, spasticity, and sensory loss. OBJECTIVE: To investigate the effect of botulinum toxin injections (BTIs) on grasping objects of different shapes and to assess the effect on upper-limb function, reach-to-grasp kinematics, and hand position and orientation at the time of grasp. METHODS: We included 15 patients with spastic hemiparesis and 9 healthy controls in this open labeled study, in which the patients were assessed before (M0), 1 month after a first (M1), and 1 month after a second BTI (M4, at 4 months). A motion capture system recorded movements. Kinematic variables were computed as well as hand position and orientation at the time of grasping, and finger configurations were coded from video recordings. RESULTS: In contrast with healthy participants, hemiparetic patients rarely used multipulpar grasps but used specific strategies combined with various directions of approach to the object. BTIs did not alter finger configuration but improved the final direction of the approach and the hand posture during the grasp. No significant changes in kinematic parameters were found using post hoc analysis, although a session effect was found for peak hand velocity. Individual analysis showed that the patients with the best potential for functional improvement are those with good proximal and moderate distal motor command. CONCLUSIONS: BTIs can modify hand kinematics as well as the approach and posture of reach-to-grasp movements. Function and grasping strategies are probably more dependent on motor recovery. PMID- 19786723 TI - Binding partner switching on microtubules and aurora-B in the mitosis to cytokinesis transition. AB - The cytoskeleton globally reorganizes between mitosis (M phase) and cytokinesis (C phase), which presumably requires extensive regulatory changes. To reveal these changes, we undertook a comparative proteomics analysis of cells tightly drug-synchronized in each phase. We identified 25 proteins that bind selectively to microtubules in C phase and identified several novel binding partners including nucleolar and spindle-associated protein. C phase-selective microtubule binding of many of these proteins depended on activity of Aurora kinases as assayed by treatment with the drug VX680. Aurora-B binding partners switched dramatically between M phase to C phase, and we identified several novel C phase selective Aurora-B binding partners including PRC1, KIF4, and anaphase-promoting complex/cyclosome. Our approach can be extended to other cellular compartments and cell states, and our data provide the first broad biochemical framework for understanding C phase. Concretely, we report a central role for Aurora-B in regulating the C phase cytoskeleton. PMID- 19786724 TI - CKS proteins protect mitochondrial genome integrity by interacting with mitochondrial single-stranded DNA-binding protein. AB - Cyclin-dependent kinase subunit (CKS) proteins interact with cyclin-dependent kinases (CDKs) with high affinity. Mammalian CKS1 and CKS2 bind CDK1 and CDK2 and partake in the control of cell cycle progression. We identified CKS-interacting proteins by affinity purification followed by mass spectrometry in the human lymphocytic cell line Ramos. Apart from known interactors, such as CDKs, we identified a novel CDK-dependent interaction between CKS proteins and the mitochondrial single-stranded DNA-binding protein (mtSSB). mtSSB bound both CKS1 and CKS2 and underwent CDK-dependent phosphorylation. mtSSB is known to participate in replication of mitochondrial DNA. We demonstrated that mitochondrial morphology and DNA integrity were compromised in cells depleted of both CKS proteins or that had inhibited CDK activity. These features are consistent with the hypothesis of CKS-dependent regulation of mtSSB function and support a direct role of cell cycle proteins in controlling mitochondrial DNA replication. PMID- 19786725 TI - Gender differences in alcohol impairment of simulated driving performance and driving-related skills. AB - AIMS: Considerable laboratory research indicates that moderate doses of alcohol impair a broad range of skilled activities related to driving performance in young adults. Although laboratory studies show that the intensity of impairment is generally dependent on the blood alcohol concentration, some reviews of this literature suggest that women might be more sensitive to the impairing effects of alcohol than men. The present study tested this hypothesis. METHODS: Drawing on data from previous experiments in our laboratory, we compared men and women in terms of the degree to which a challenge dose of alcohol (0.65 g/kg) impaired their simulated driving performance and measures of three separate behavioral and cognitive functions important to driving performance: motor coordination, speed of information processing and information-processing capacity. RESULTS: Alcohol significantly impaired all aspects of performance. Moreover, women displayed greater impairment than men on all behavioral tests and also reported higher levels of subjective intoxication compared with men. CONCLUSIONS: Both biological and social-cultural factors have been implicated in gender differences in the behavioral responses to alcohol. The current evidence of heightened sensitivity to alcohol in women highlights the need for better understanding the biological and environmental factors underlying this gender difference. PMID- 19786726 TI - Changes in exhaled nitric oxide and breath pH during fluticasone wean in asthma. AB - BACKGROUND: Inhaled corticosteroid (ICS) therapy improves asthma outcome. Both the anti-inflammatory efficacy and toxicities of ICS therapy are dose dependent. Therefore, there is interest in monitoring airway inflammation during ICS dose adjustments. OBJECTIVE: Fraction of expired nitric oxide (FENO) and exhaled breath condensate (EBC) pH were studied as noninvasive, corticosteroid-responsive markers of airway inflammation. METHODS: We prospectively studied the effect of stepwise ICS wean on FENO and EBC pH over 6 months in otherwise healthy adults with moderate persistent asthma. RESULTS: Eighteen subjects completed the initial dose titration and 13 completed the protocol. Of these, 7 weaned off ICS completely and 6 had exacerbations. FENO rose significantly with ICS withdrawal, though there was heterogeneity in the starting level and the degree of rise. EBC pH was collected at home in all subjects and fell more in subjects who had an exacerbation than in those who did not. The decrease in pH was associated with hazard of exacerbation. CONCLUSION: FENO can be a patient-specific index of airway inflammation during ICS dose titration; change in EBC pH is one home marker that might possibly be used during ICS dose titration. However, additional studies are required. PMID- 19786727 TI - Pathogenesis of bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) refers to a heterogeneous group of lung disorders in infants that is commonly associated with prematurity and surfactant deficiency. BPD results from the complex interplay between impairments in the premature lung such as surfactant deficiency, perinatal insults such as infection, and damage resulting from supportive care of the infant due to barotrauma or volutrauma from mechanical ventilation and oxygen toxicity from supplemental oxygen administration. These factors result in chronic inflammation in the infant lung with recurring cycles of lung damage and repair that may impair alveolarization and vascularization in the developing lungs. As our insight in how to treat BPD improves along with the ability to do so with developing technology and therapies, the underlying pathogenesis will also change. The term 'new' BPD is now commonly used, to describe the changes seen in the post-surfactant era. This discussion reviews the pathogenesis of BPD according to the current medical literature. PMID- 19786728 TI - Iloprost improves gas exchange and exercise tolerance in patients with pulmonary hypertension and chronic obstructive pulmonary disease. AB - BACKGROUND: Nonselective systemic vasodilators worsen ventilation perfusion (V/Q) matching and gas exchange in patients with chronic obstructive pulmonary disease (COPD). Inhaled iloprost has the potential to act preferentially in ventilated regions of the lung, thereby reducing pulmonary hypertension (PH) while alveolar ventilation is still maintained. OBJECTIVES: To investigate the acute effects of inhaled iloprost on V/Q matching in patients with COPD and PH. METHODS: Ten males with COPD and PH on echocardiography were evaluated before and after inhaling 2 doses of iloprost (2.5 microg). Measurements included lung function, arterial blood gas, 6-min walk test (6MWT) as well as ventilatory equivalents for oxygen (V(E)/VO(2)) and carbon dioxide (V(E)/VCO(2)) taken at baseline, 30 min following each dose of iloprost, and 2 h after the second dose. RESULTS: Mean differences in V(E)/VCO(2) and V(E)/VO(2) were -13.3 (95% CI -36.5 to -2.7; p = 0.002) and 15.0 (95% CI -36.7 to -0.4; p = 0.02), respectively, and the mean change in (A-a) gradient was -3.7 mm Hg (95% CI -6.1 to -1.0; p = 0.01) after a single dose of iloprost, whereas mean improvement in 6MWT was 49.8 m (95% CI 14.8 to 84.7; p = 0.02). Arterial blood gas, venous admixture, dead space fraction and lung functions were maintained after iloprost. The effects of iloprost were reproducible after the second dose. All measurements returned to baseline 2 h after the last dose. No adverse effects on systemic blood pressure or oxygen saturation were seen. CONCLUSIONS: Iloprost inhalation was safe in patients with COPD and PH, and was associated with improved V/Q matching and exercise tolerance. PMID- 19786729 TI - Value of 123I-MIBG Scintigraphy in Paraganglioma. AB - AIM: The aim of the study was to evaluate the current role of (123)I-MIBG scintigraphy in the detection and follow-up of patients with paragangliomas. MATERIALS AND METHODS: 117 patients were referred for diagnostic (123)I-MIBG scintigraphy based on a strong clinical suspicion, positive familial history and genetic testing, or for follow-up of paragangliomas.(123)I-MIBG images were analyzed and correlated with (111)In-octreotide scintigraphy, CT or MRI results. Accuracy of the imaging method was calculated per patient and per tumor per site. RESULTS: A total of 117 patients were referred for (123)I-MIBG diagnostic imaging; 80 patients were diagnosed with paraganglioma; 66 patients had a single neuroendocrine tumor and 14 patients multiple tumors. The total number of all lesions in these patients was 172. (123)I-MIBG scintigraphy demonstrated 65 lesions in 56 patients (overall sensitivity: 56.3%, specificity: 84%). Lesion-per site analysis revealed that sensitivity and specificity significantly varied per tumor site (lowest sensitivity for the head and neck: 17.5% and lowest specificity for the abdomen: 87.5%). Hormones were elevated in 85 patients: 55 (123)I-MIBG tumors were positive and 35 tumors were negative. In 16 patients (13.7%) with a genetic burden and a single neuroendocrine tumor, (123)I-MIBG whole-body imaging was successful at detecting a second tumor. In 2 patients (1.7%) with paragangliomas, (123)I-MIBG unexpectedly detected metastases, so the restaging was properly done. CONCLUSION: (123)I-MIBG scintigraphy remains important in pheochromocytoma and functioning neuroendocrine tumors. The value of (123)I-MIBG scintigraphy is high in familial syndromes with multiple neuroendocrine tumors at different sites, multifocal tumors, and relapsing and metastatic disease. PMID- 19786730 TI - Adherence to continuous positive airway pressure therapy for obstructive sleep apnea: impact of patient education after a longer treatment period. AB - BACKGROUND: Continuous positive airway pressure (CPAP) is the standard treatment for obstructive sleep apnea (OSA) but it is often cumbersome so that adherence to CPAP therapy is limited. OBJECTIVES: We evaluated adherence to CPAP therapy after an additional educative intervention in OSA patients after a longer treatment period. METHODS: A short patient information program covering many aspects of symptoms, consequences and treatment of OSA was created, and standardized information sessions were developed to be given by an experienced sleep physician to >6,000 participants of patient support group meetings throughout Germany. They also received a booklet containing the essential information of the lectures. Of the 526 randomly selected members of these support groups receiving the anonymized questionnaire by mail, 475 CPAP patients sent the questionnaire back. Of these CPAP patients, 243 participated in a lecture und and had received a booklet (information group) and 232 CPAP patients had not attended a lecture (control group). RESULTS: In the information group, a significantly higher daily usage of CPAP devices (6.9 +/- 0.9 h/day) was reported compared with the control group (5.7 +/- 1.3 h/day; p < 0.001). Furthermore, the score in the Epworth Sleepiness Scale (ESS) was found to be significantly lower in the information group (median ESS = 6, interquartile range, IQR, 4-8 vs. median = 11, IQR 8-13; p < 0.001). CONCLUSIONS: Patients who attended our short information program showed a higher daily usage and a lower subjective daytime sleepiness. These results suggest that patients on CPAP therapy may benefit from education even after a longer treatment period. PMID- 19786731 TI - Quality of spirometry in primary care for case finding of airway obstruction in smokers. AB - BACKGROUND: Diagnosis of chronic obstructive pulmonary disease (COPD) and its severity determination is based on spirometry. The quality of spirometry is crucial. OBJECTIVES: Our aim was to assess the quality of spirometry performed using a spirometer with automated feedback and quality control in a general practice setting in Switzerland and to determine the prevalence of airflow limitation in smokers aged > or =40 years. METHOD: Current smokers > or =40 years of age were consecutively recruited for spirometry testing by general practitioners. General practitioners received spirometry training and were provided with an EasyOne spirometer. Spirometry tests were assigned a quality grade from A to D and F, based on the criteria of the National Lung Health Education Program. Only spirometry tests graded A-C (reproducible measurements) were included in the analysis of airflow limitation. RESULTS: A total of 29,817 spirometries were analyzed. Quality grades A-D and F were assigned to 33.9, 7.1, 19.4, 27.8 and 11.8% of spirometries, respectively. 95% required < or =5 trials to achieve spirometries assigned grade A. The prevalence of mild, moderate, severe and very severe airway obstruction in individuals with spirometries graded A-C was 6, 15, 5 and 1%, respectively. CONCLUSION: Spirometries in general practice are of acceptable quality with reproducible spirometry in 60% of measurements. Airway obstruction was found in 27% of current smokers aged > or =40 years. Office spirometry provides a simple and quick means of detecting airflow limitation, allowing earlier diagnosis and intervention in many patients with early COPD. PMID- 19786732 TI - In vivo circadian rhythms in gonadotropin-releasing hormone neurons. AB - Although it is generally accepted that the circadian clock provides a timing signal for the luteinizing hormone (LH) surge, mechanistic explanations of this phenomenon remain underexplored. It is known, for example, that circadian locomotor output cycles kaput (clock) mutant mice have severely dampened LH surges, but whether this phenotype derives from a loss of circadian rhythmicity in the suprachiasmatic nucleus (SCN) or altered circadian function in gonadotropin-releasing hormone (GnRH) neurons has not been resolved. GnRH neurons can be stimulated to cycle with a circadian period in vitro and disruption of that cycle disturbs secretion of the GnRH decapeptide. We show that both period-2 (PER2) and brain muscle Arnt-like-1 (BMAL1) proteins cycle with a circadian period in the GnRH population in vivo. PER2 and BMAL1 expression both oscillate with a 24-hour period, with PER2 peaking during the night and BMAL1 peaking during the day. The population, however, is not as homogeneous as other oscillatory tissues with only about 50% of the population sharing peak expression levels of BMAL1 at zeitgeber time 4 (ZT4) and PER2 at ZT16. Further, a light pulse that induced a phase delay in the activity rhythm of the GnRH-eGFP mice caused a similar delay in peak expression levels of BMAL1 and PER2. These studies provide direct evidence for a functional circadian clock in native GnRH neurons with a phase that closely follows that of the SCN. PMID- 19786733 TI - Cross-sectional study of the characteristics of reported elder self-neglect in a community-dwelling population: findings from a population-based cohort. AB - BACKGROUND: Elder self-neglect is an important public health issue. However, little is known about the characteristics of self-neglect and its association with social factors among community-dwelling populations. OBJECTIVES: (1) To examine the sociodemographic, health-related and psychosocial characteristics of reported elder self-neglect; (2) to examine the association of social network and social engagement with reported self-neglect. METHODS: Population-based study conducted from 1993 to 2005 of community-dwelling subjects (n = 9,056) participating in the Chicago Health and Aging Project (CHAP). Subsets of the CHAP subjects (n = 1,812) were identified for suspected self-neglect by the social services agency, which also assessed the severity. This reported group was compared with the unreported group in the CHAP across the sociodemographic, health-related and psychosocial variables. Logistical regressions were used to assess the association of social factors and self-neglect. RESULTS: Older age, women, African-Americans, and those with lower education or lower income were more likely to be reported for self-neglect. Those reported for self-neglect were more likely to have lower levels of cognitive and physical function, nutritional status, psychosocial function and a higher number of medical comorbidities. After adjusting for confounders, lower levels of social network and social engagement were significantly associated with an increased risk of reported self-neglect. Among the reported cases of self-neglect, the study found increased trends of older age, women, African-American, lower income, lower cognitive and physical function, lower social engagement and a higher number of chronic medical conditions with self-neglect severity. CONCLUSION: Reported self-neglect elders have multiple sociodemographic, health- related and psychosocial characteristics that are different than elders not reported. Lower levels of social network and social engagement were associated with increased risk of self-neglect. PMID- 19786734 TI - Clinical application of exhaled breath condensate analysis in asthma: prediction of FEV1 improvement by steroid therapy. AB - BACKGROUND: Exhaled breath condensate (EBC) measurements have recently been reported to be useful for the detection of inflammatory molecules in the airways. However, the clinical relevance of EBC analysis in asthma therapy has not been determined yet. OBJECTIVES: To investigate whether EBC analysis has any potential for predicting the steroid response in asthmatics. METHODS: Eighteen steroid naive asthmatics were enrolled. EBC collection, spirometry and a methacholine challenge test were performed before and 12 weeks after inhaled steroid therapy. Exhaled IL-4, IL-17, RANTES, macrophage inflammatory protein (MIP)-1alpha, MIP 1beta, IL-8, IFN-gamma-inducible protein (IP)-10, TNF-alpha and TGF-beta were simultaneously analyzed by a protein array, and the relationship between baseline molecule expression and steroid-mediated changes in forced expiratory volume in 1 s (FEV1) and airway responsiveness was investigated. RESULTS: Steroid therapy improved FEV1 values and the methacholine threshold. Among the molecules examined, increased IL-4 and RANTES levels as well as decreased IP-10 levels at baseline were significantly correlated with an improvement in FEV1. By contrast, molecule levels were not related to changes in the responsiveness to methacholine. In addition, changes in FEV1 values were significantly associated with reductions in IL-4 and RANTES levels. CONCLUSIONS: EBC measurements of IL-4, RANTES and IP-10 might be useful for predicting the steroid-mediated FEV1 improvement in asthma. PMID- 19786735 TI - Cardiovascular aspects in obstructive sleep apnea syndrome--molecular issues, hypoxia and cytokine profiles. AB - Obstructive sleep apnea syndrome (OSAS), which is a highly prevalent breathing disorder in sleep, is an independent risk factor for cardiovascular morbidity and mortality. Results from clinical studies as well as animal models and cell culture studies utilizing intermittent hypoxia implicate oxidative stress and inflammation in the pathogenesis of OSAS. However, the underlying mechanisms are not entirely understood. Both oxidative stress and inflammation are major components in the initiation and development of endothelial dysfunction and consequently atherosclerosis. Yet, these fundamental mechanisms are associated with obesity and with components of the metabolic syndrome that also cluster with OSAS. Accumulated evidence indicates that inflammatory cytokines such as TNF alpha that are under the control of nuclear factor KB actively participate in endothelial damage. The current review highlights some of the recent findings on oxidative stress and inflammation in OSAS with specific emphasis on the role of inflammatory pathway activation and expression of cytokines and their possible role in OSAS-related cardiovascular morbidity. In light of the new findings in the field of cytokines, their potential involvement in endothelial dysfunction and cardiovascular morbidity in OSAS is discussed. PMID- 19786736 TI - Medical thoracoscopy: new tricks for an old trade. PMID- 19786737 TI - Modeling of human anti-GBM antibody-alpha3(IV)NC1 interactions predicts antigenic cross-linking through contact of both heavy chains with repeating epitopes on alpha3(IV)NC1. AB - BACKGROUND/AIMS: Patients with anti-glomerular basement membrane diseases produce pathogenic autoantibodies (autoAb) that deposit in the kidney and initiate severe inflammation. Restricted antigenic specificity of the autoAb against 2 regions (with related sequences) within alpha3(IV)NC1, along with shared idiotypes (i.e. structural determinants), among pathogenic human autoAb suggested that common genetic elements encode the autoAb. The aim of this study was to determine whether the idiotypic relatedness of the autoAb was due to the fact that unique and similar genes were used to encode them, divergent genes were used to produce Ab with similar Ag-binding properties and conformation, or if other mechanisms were operative. METHODS: The encoding V gene sequences of pathogenic human anti alpha3(IV)NC1 Ab, derived following immunization of XenoMice which produce human but not murine IgG, with alpha3(IV)NC1 were determined. Predicted conformations of autoAb-alpha3(IV)NC1 interactions were derived using the Ab sequences and molecularmodels of the alpha3(IV)NC1 structure. RESULTS: The pathogenic Ab were encoded by multiple, common V(H) and V(L) gene families indicating that they were not encoded by a unique subset of genes and that normal individuals have the capacity to produce them. However, modeling of the Ag-Ab interactions suggested that although the contact regions varied for individual Ab, the optimized energy constraints facilitate interaction of both Ab-binding regions with pathogenically relevant epitopes on alpha3(IV)NC1. CONCLUSIONS: The results suggest that the repetitive nature and relatedness of the alpha3(IV)NC1 antigenic epitopes facilitate cross-linking of pathogenic Ab, in vivo, by allowing both IgG Fab to bind to the basement membrane. This most likely accounts for the high-affinity Ab binding we and others observed among human anti-alpha3(IV)NC1 Ab. Based on these observations, we postulate that this interaction provides for the stability of the Ab interaction, resulting in a high-affinity interaction that serves as an ideal scaffold for optimal FcR engagement and complement activation, thereby accelerating inflammation and contributing to the rapidly progressive nature of this disease. PMID- 19786738 TI - Positive feedback loop between plasminogen activator inhibitor-1 and transforming growth factor-beta1 during renal fibrosis in diabetes. AB - BACKGROUND/AIMS: Plasminogen activator inhibitor (PAI)-1 is increasingly recognized as a profibrotic factor but the mechanisms are not entirely clear. The present study examined the profibrotic mechanism of PAI-1 focusing on its effect on transforming growth factor (TGF)-beta1 in experimental diabetes. METHODS: PAI 1 knockout (KO) mesangial cells cultured under high glucose (HG) in addition to streptozotocin-induced diabetic PAI-1 KO mice were used. RESULTS: PAI-1 deficiency did not affect plasma glucose significantly but reduced the fractional mesangial area, fibronectin and collagen I expression in the renal cortex after 20 weeks of diabetes as well as in HG-stimulated mesangial cells along with suppression of TGF-beta1 mRNA expression. PAI-1 deficiency also reduced HG induced betaig-h3, a TGF-beta1-induced gene product, mRNA expression. All these losses-of-function in PAI-1 KO mesangial cells were effectively gained by recombinant PAI-1. Recombinant PAI-1-induced fibronectin and collagen I expression was abrogated by TGF-beta1 receptor inhibitor or anti-TGF-beta antibody suggesting that the effect of PAI-1 was mediated by TGF-beta1. In a similar context, recombinant PAI-1 stimulated TGF-beta1 promoter activity to the same extent as TGF-beta1 itself. CONCLUSION: Since TGF-beta1 is well known to stimulate the PAI-1 promoter, we suggest that TGF-beta1 and PAI-1 together constitute a positive feedback loop in the development of renal fibrosis in diabetes. PMID- 19786739 TI - Hemoglobin level variability: anemia management among variability groups. AB - BACKGROUND/AIMS: Hemoglobin level variability in hemodialysis patients is common, and has been associated with comorbidity, intercurrent illness, and mortality risk. We aimed to describe the influence of anemia management interventions (erythropoiesis-stimulating agents [ESAs], intravenous iron, and transfusions) on hemoglobin variability. METHODS: We studied all Medicare primary payer hemodialysis patients who survived and had ESA claims in the first 6 months of 2004 (n = 159,720). Monthly hemoglobin values were categorized as low (<11 g/dl), intermediate (11-12.5 g/dl), and high (>12.5 g/dl). Variability groups were classified based on lowest and highest hemoglobin categories during a 6-month observation period. ESA, intravenous iron, and transfusion use were characterized by variability group. RESULTS: Patients with consistently low or low and intermediate hemoglobin received the highest ESA doses and the most frequent transfusions, while patients with consistently or intermittently intermediate or high hemoglobin received lower ESA doses and fewer transfusions. Intravenous iron doses were highest initially for patients with consistently high hemoglobin; these doses subsequently declined. Iron doses were lowest for patients with consistently intermediate hemoglobin. CONCLUSIONS: Anemia management protocols describing coordinated administration of ESAs and iron may help to increase the number of patients achieving target hemoglobin levels. PMID- 19786740 TI - The effect of early menarche on later body composition and fat distribution in female adolescents: role of birth weight. AB - BACKGROUND: To examine the effect of early menarche (EM) on adolescent body composition and fat distribution, and to explore the possible contribution of birth weight (BW) to this relationship. METHODS: From the cross-sectional AVENA study, 788 girls (aged 13-18.5 years) were selected. Post-menarcheal body composition was estimated by anthropometric methods. RESULTS: BW Z-score was associated with age at menarche (beta = 0.496, p < 0.001). EM (age of menarche <12 years) adolescents were shorter, had a higher body mass index (BMI), fat free mass index (FFMI), fat mass index (FMI) and waist circumference (all p < 0.01). BW was associated with height (p < 0.001), BMI Z-score (p < 0.01), FFMI (p < 0.01) and FMI (p < 0.05). These relationships did not change when the analysis was controlled for age of menarche. Height and FFM were lower in EM (p < 0.01), but these effects seem to be due to the BW (p < 0.01). CONCLUSION: EM was strongly associated with unhealthy body composition in female adolescents, but these relationships seem to be due to the programming effect of BW. PMID- 19786741 TI - Preface. PMID- 19786742 TI - Disease behavior in adult patients: are there predictors for stricture or fistula formation? AB - In the current era, in inflammatory bowel disease step-up vs. top-down therapeutic approaches for the treatment of Crohn's disease (CD) are evaluated. As a consequence, we need to be able to differentiate between patients who will have more aggressive phenotypes to those with potentially more benign CD course. The former would require closer follow-up; however, more important might be the subgroup of patients to whom we want to offer biologic and immunomodulator therapy early on. This strategy is the only one supposed to prevent hospitalization and surgical intervention, specifically in patients with fistulae. Patients with expected fibrostenotic disease phenotype require early identification as well. The data regarding primary prevention of fibrostenosis are scarce; however, the association of biologic therapy with fewer surgeries might suggest that at least a subgroup of these patients would benefit from early, step-up therapeutic strategy. They might also benefit more from early immunomodulator therapy, as this was shown to have a secondary (though modest) preventive effect. The patients with fibrostenotic phenotype are also candidates for the most needed but still practically nonexistent anti-fibrotic therapies. In any case where patients are identified as having a higher chance to develop the more aggressive phenotypes, fibrostenotic and perforating, recommendation to avoid triggers/accelerators of disease progression (smoking, NSAIDS use) should be kept rigorously. Until recently, we based our attempts to predict disease phenotype mainly on clinical characteristics. As would be the case with many clinical features, some of them are not even predictors, but already manifestations of the condition we are trying to predict. Intervention at this stage might be too late for this patient. In addition to known demographic and clinical predictors reported, more recently sophisticated predictors shall be described. These predictors belong to three major groups: serologic markers, genetic markers, mucosal disease/healing. The major serologic markers used: anti Saccharomyces cerevisiae antibodies (ASCA), anti-neutrophil cytoplasmic antibodies (ANCA), outer membrane porin C (OmpC), CBir1-flagellin, antibodies against I2 protein and the anti-glycan antibodies: anti-laminaribioside carbohydrate (ALCA), anti-chitobioside carbohydrate (ACCA) and anti-mannobioside carbohydrate (AMCA) and their associations with penetrating and fibrostenotic disease shall be discussed. The associations of genetic polymorphisms such as CARD15 and TLR4 variants and more aggressive disease phenotype will be described as well. Finally, the data supporting the relationship between inflamed, in contrast to healed intestinal mucosa and more aggressive disease course will be illustrated. These predictors may be used in clinical practice and/or research in order to better stratify CD prognosis. Thus they may be significant in our therapeutic decisions. Models for using these predictors would be presented. PMID- 19786743 TI - Pediatric inflammatory bowel disease: is it different? AB - The clinical manifestations of Crohn's disease (CD) and ulcerative colitis (UC) are highly variable, with significant diversity in phenotypes of the diseases. This diversity may manifest as a difference in age of onset. Pediatric-onset disease may present differently and have a different natural history, with ramifications for disease management. Clear evidence exists at present that pediatric-onset UC may be different than adult-onset UC. The primary difference in disease phenotype is extent of disease. Approximately 60-70% of patients with pediatric-onset UC present with pancolitis, as opposed to approximately 20-30% in adults. Patients are more likely to have severe disease and become steroid dependent. CD may be affected by an age gradient. There is an inverse linear relationship between age and colonic CD, the younger the patient, the more likely is the patient to have colonic CD. This inverse relationship is true through age 10. In addition, pediatric patients are more likely to have upper gastrointestinal involvement than their adult peers. Comparing adult and pediatric phenotypes is fraught with methodological obstacles. Disease behavior, with the exception of growth failure, seems to parallel disease behavior in adults. Patients with growth retardation are a high risk group for complications and should be managed as such. PMID- 19786744 TI - Environmental factors affecting inflammatory bowel disease: have we made progress? AB - The pathogenesis of inflammatory bowel disease (IBD) is only partially understood; various environmental and host (e.g. genetic, epithelial, immune, and nonimmune) factors are involved. The critical role for environmental factors is strongly supported by recent worldwide trends in IBD epidemiology. One important environmental factor is smoking. A meta-analysis partially confirms previous findings that smoking was found to be protective against ulcerative colitis and, after the onset of the disease, might improve its course, decreasing the need for colectomy. In contrast, smoking increases the risk of developing Crohn's disease and aggravates its course. The history of IBD is dotted by cyclic reports on the isolation of specific infectious agents responsible for Crohn's disease or ulcerative colitis. The more recently published cold chain hypothesis is providing an even broader platform by linking dietary factors and microbial agents. An additional, recent theory has suggested a breakdown in the balance between putative species of 'protective' versus 'harmful' intestinal bacteria - this concept has been termed dysbiosis resulting in decreased bacterial diversity. Other factors such as oral contraceptive use, appendectomy, dietary factors (e.g. refined sugar, fat, and fast food), perinatal events, and childhood infections have also been associated with both diseases, but their role is more controversial. Nonetheless, there is no doubt that economic development, leading to improved hygiene and other changes in lifestyle ('westernized lifestyle') may play a role in the increase in IBD. This review article focuses on the role of environmental factors in the pathogenesis and progression of IBDs. PMID- 19786745 TI - Susceptibility genes and overall pathogenesis of inflammatory bowel disease: where do we stand? AB - The rapid accumulation of new knowledge on the genes, gene variations and genetic loci associated with both forms of inflammatory bowel disease (IBD), e.g. Crohn's disease (CD) and ulcerative colitis (UC), is shedding new light on the immunopathogenic mechanisms underlying these conditions. After the initial report of the association of NOD2 mutations with ileal CD, a large number of additional genetic variants and loci has been found to be associated with both CD and UC, CD alone and, quite recently, UC-associated variants have also emerged. Much of this progress is due to the use of methods such as genome-wide associations (GWA) based on large numbers of reasonably well-characterized patient groups. Among several others, some of the most pathophysiologically relevant associations reported so far are with gene variants related to innate immunity, autophagy, apoptosis, Th1 and Th17 responses, T cell activation, and immunosuppression. Some of these associations have lent further support to previously construed disease mechanisms or disclosed brand new mechanisms, like in the case of the autophagy pathway. While this much progress is obviously welcome, it also brings new challenges. These include the fact that all the gene mutations uncovered so far only account for a minority of all IBD cases, the variable distribution of gene mutations among worldwide IBD populations, and the still unknown effects of gene gene and gene-environment interactions. Nevertheless, there is no question that genetic information will be quickly utilized not only for a better understanding of IBD pathogenesis, but it will also soon be incorporated into the armamentarium of better diagnostic and therapeutic tools. PMID- 19786746 TI - Genetic determinants of pediatric inflammatory bowel disease: is age of onset genetically determined? AB - Inflammatory bowel disease (IBD) is thought to develop as a result of dysregulation of the immune response to normal gut flora in a genetically susceptible host. Approximately 25% of incident cases of IBD occur during childhood and the rest occur throughout adulthood, peaking in the second and third decades of life. What determines the age of onset remains unexplained currently. Studying early-onset presentation of complex diseases such as IBD is appealing to geneticists and scientists alike because of the expectation that these efforts will increase the probability of finding novel risk variants. Genome-wide association studies (GWAS) have yielded more susceptible loci in IBD than in any other complex common disease studied. Using 35 confirmed Crohn's disease risk alleles from adult studies, a recent pediatric replication study detected no significant association between risk score and age of onset through age 30, indicating age of onset does not have any impact on increased disease development in IBD. The first GWAS study using an exclusively pediatric IBD cohort found 2 novel risk variants that were not previously reported in predominately adult GWAS studies. However, during the data-mining of adult GWAS, these 2 novel loci (TNFRSF6 and PSMG1) were found with nominal significance suggesting that these risk loci are not restricted to early-onset CD cases. These analyses illustrate that the genetic effects of established CD risk variants is similar in early- and late-onset CD. However, the quest to find early-onset IBD risk variants is continuing. As such, GWAS studies involving large pediatric onset CD cohorts and early-onset ulcerative colitis presentations are presently underway. A future joint analysis of genome-wide association data of early- and late-onset cohorts will likely reveal more IBD risk variants since the power to detect small effects of genes increases. PMID- 19786747 TI - The intestinal epithelial barrier: does it become impaired with age? AB - The proportion of the population aged over 65 is increasing rapidly and malnutrition is a more common problem in elderly patients. The intestinal epithelium covers the surface of the digestive tract and consists of epithelial cells that constitute an efficient physical barrier between the dietary and enteric flora pathogens found in the intestinal lumen and the individuum, while at the same time allowing an exchange between nutrients and the systemic circulation. There is only a very limited amount of information available on whether and how age, with concomitant inflammation, influences the epithelial barrier. Although there is evidence that age does not correlate with the area of the duodenal surface epithelium or the number of intraepithelial lymphocytes, absorption of certain nutrients, e.g. lipids, does seem to be impaired in the elderly. However, impaired blood flow, ischemic changes and the increased use of NSAIDs naturally contribute to an impaired epithelial barrier in elderly patients. PMID- 19786749 TI - The microbiota in inflammatory bowel disease in different age groups. AB - BACKGROUND: Many efforts were made in the past decades to assess the role of gut microbiota in inflammatory bowel diseases (IBD), leading to the hypothesis that an altered microbial composition, other than the presence of a specific pathogen, could be involved in the pathogenesis of the disease. On the other hand, existing differences in gut microbial community between distinct classes of age make sense of an increasing research in microbial shifts in IBD. METHODS: Cultural, molecular, metabolomic and metagenomic approaches are trying to define the human gut microbiota in different age groups. RESULTS AND CONCLUSION: An increase in anaerobic bacteria (Bacteroidesvulgatus, Streptococcus faecalis) was observed in adult IBD, whereas an increase in aerobic and facultative-anaerobic (Escherichia coli) was found in pediatric IBD. Overall higher bacterial cell counts were observed in IBD, jointly with a general loss of biodiversity and a preponderance of Bacteroidetes and a parallel decrease of Firmicutes phylum: a predominance of potential harmful members of Proteobacteria (E. coli) and low abundance of beneficial species (Faecalibacterium prausnitzii) was also reported in pediatric and adult age groups, respectively. Microbial community of elderly subjects contains a wider range of different species than those of children and adults, both in healthy and IBD status. PMID- 19786750 TI - What is the role of serological markers in IBD? Pediatric and adult data. AB - Physicians rely heavily on the presence of disease markers to support or even at times modify their clinical impression for certain diseases that can only be diagnosed clinically. Typically these markers play an important role in helping to establish a diagnosis and to evaluate the activity of a chronic disease over time. The diagnosis of inflammatory bowel disease (IBD), however, is not based solely on clinical grounds. Invasive endoscopic and radiological as well as histopathological criteria need to be met in order to make a correct diagnosis and differentiate disease subtypes. The search for novel diagnostic approaches that accurately distinguishes a group of patients with IBD from those unaffected by the disease has become a focus in IBD research. This search, however, has taken a very exciting turn in the direction of finding biologic and genetic markers that can assess the natural history and predict the course of individual's disease including response to treatments over time. PMID- 19786748 TI - Links between autophagy, innate immunity, inflammation and Crohn's disease. AB - Autophagy is a fundamental biological process that endows eukaryotic cells with the ability to autodigest portions of their own cytoplasm. Autophagy plays roles in aging, development, neurodegeneration, cancer and immunity. The immunological role of autophagy was first recognized for the ability of autophagy to sanitize the cellular interior by killing intracellular microbes and, indirectly, by the adaptations that successful intracellular pathogens have evolved to protect themselves from autophagy. Since then, the repertoire of autophagy functions in immunity has been vastly expanded to include numerous intersections of regulatory and effector nature with innate and adaptive immunity. Autophagy acts both as an effector and a regulator of pattern recognition receptors, it supports MHC II presentation of cytosolic (self and microbial) antigens, it shapes central tolerance via thymic selection of the T cell repertoire, is an effector of Th1/Th2 polarization, affects homeostasis of T, B, and specialized immune cells such as Paneth cells, and - when defective - can be a contributing factor to chronic inflammatory conditions in human populations such as Crohn's disease. PMID- 19786751 TI - Inflammatory bowel diseases: controversies in the use of diagnostic procedures. AB - The term inflammatory bowel disease (IBD) denotes a genetically, immunologically and histopathologically heterogeneous group of inflammatory bowel disorders classified at present time as ulcerative colitis (UC), Crohn's disease (CD) and indeterminate colitis (IC). Diagnosis of IBD is based on a non-strictly defined combination of clinical and diagnostic parameters. In order to guide the treatment, patients must be assessed by determining IBD phenotype, disease extension and distribution, extraintestinal manifestations, disease behavior, disease severity and drug responsiveness. Each element of the diagnostic process cannot be looked at alone, but has to be incorporated into general clinical assessment, bearing in mind that different phenotypes and age groups require specific diagnostic solutions. Advances in technology provided the possibility for the assessment of the entire digestive system with endoscopy leading the way. Sophisticated imaging methods made the analysis of the bowel wall with its vascularity and adjacent mesentery possible. The challenge is still the small bowel, where a combination of endoscopy and imaging methods is used. The use of imaging methods should be, among other things, guided by level of irradiation which is especially important in young patients and in patients requiring repeated investigations. Using abdominal ultrasound as a low-cost, noninvasive procedure, one has to take into account that it is very operator-dependent method. In UC, endoscopy is used for the evaluation of the extent and activity of the disease and to assess complications like stricture, dysplasia and cancer. UC is classified by the disease extent into proctitis, left-sided colitis and extensive colitis beyond the splenic flexure. Pediatric patients with UC have more extensive disease than adults with rectal sparing in up to 30% of patients. The severity of mucosal changes are reported as Baron endoscopic score. Endoscopic findings correlate well with clinical activity and are commonly incorporated into Mayo index, combination of clinical Truelove Witts index and Baron score. Complications like strictures require imaging methods as supplement to endoscopy. The incidence of CD, particularly in children and adolescents, has risen during the past decade, with children often having extensive and severe disease The nature of CD requires the use of wide array of endoscopic and imaging methods, placed properly in the diagnostic algorithms for specific disease phenotypes and complications and adapted for specific age groups. Endoscopic features of CD are very variable and can be quantified as Crohn's Disease Endoscopic Index of Severity (CDEIS) or Simple Endoscopic Score for CD (SES-CD). Disease activity is most commonly assessed by CDAI. Perianal disease activity should be measured by PDAI due to low CDAI scores in these patients. The activity of CD in children should be assessed by the Pediatric Activity Index. IC is part of the IBD spectrum where chronic colitis cannot be defined as either UC or CD after sequential colonoscopies and colonic biopsies or at colectomy. PMID- 19786752 TI - Risk of radiation and choice of imaging. AB - Radiological imaging plays an important role in the diagnosis and management of patients with inflammatory bowel diseases (IBD). The barium or contrast techniques enteroclysis (SBE) and small bowel follow through (SBFT) are still the mainstays in small bowel imaging. However, abdominal CT and MRI, including enteroclysis, have comparable sensitivity and specificity in detecting intestinal pathologies and have gained in popularity over conventional techniques. The cancer risk associated with diagnostic procedures employing radiation has been receiving increasing attention over the last few years. The cumulative exposure to ionizing radiation may be a specific concern in young patients with IBD, who are more susceptible than adults to the risks of ionizing radiation. Substantial exposure to radiation seems to be mainly caused by CT examinations of the abdomen. For that reason, imaging methods such as MRI or ultrasound should be considered first when debating between alternative imaging strategies, particularly in young IBD patients. The major drawbacks of MRI are its limited availability and greater costs compared to CT. Moreover, the diagnostic accuracy of abdominal ultrasound is clearly operator dependent, which limits the range of its applications. In light of these concerns, diagnostic imaging studies using radiation will continue to play an important role in the evaluation of patients with IBD. Therefore, we need to develop low-radiation imaging protocols or improve access to MRI imaging procedures. We also need to identify subsets of IBD patients who are at greater risk of a significant lifetime exposure to radiation and develop methods to monitor their radiation exposure rate. PMID- 19786753 TI - Bowel ultrasound and mucosal healing in ulcerative colitis. AB - BACKGROUND AND AIM: Mucosal healing (MH) after short-term medical treatment is being considered as an important step in the therapeutic work-up of inflammatory bowel disorder (IBD) patients due to the potential prognostic role of MH in predicting disease outcome. However, IBD patients are reluctant to be re endoscoped during follow-up; therefore, there is a need for non-invasive alternative index of MH which can replace endoscopy in clinical practice. We evaluated bowel ultrasound (US) as a surrogate of colonoscopy in a series of consecutive patients with active ulcerative colitis (UC). PATIENTS AND METHODS: 83 patients with moderate to severe UC requiring high-dose steroids were initially recruited; endoscopic severity of UC was graded 0-3 according to Baron score, and US severity was also graded 0-3 according to the colonic wall thickening and the presence of vascular signal at power Doppler. 74 patients responsive to steroids and then maintained on 5-ASA compounds were followed up with repeated colonoscopy and bowel US at 3, 9 and 15 months from entry. Concordance between clinical, endoscopic and US scores at various visits was determined by kappa statistics. Multiple unconditional logistic regression models were used to assess the predictivity of Truelove, Baron and US scores measured at 3 and 9 months on the development of a UC relapse (Baron score 2-3) at 15 months. RESULTS: An inconsistent concordance was found over time between 0 and I Baron scores and Truelove score (weighted kappa between 0.38 and 0.94), with high and consistent concordance between 0 and I Baron scores and US scores (weighted kappa between 0.76 and 0.90). On logistic regression analysis, a moderate/severe Baron score, regardless of their Truelove score, at 3 months was associated with a high risk of endoscopic activity at 15 months (OR 5.2; 95% CI: 1.6-17.6); similarly, patients with severe US scores (2-3) at 3 months had a high risk of severe endoscopic activity at 15 months (OR 9.1; 95% CI: 2.5-33.5). DISCUSSION: In expert hands bowel US may be used as a surrogate of colonoscopy in evaluating the response to high-dose steroids in severe forms of UC. US score after 3 months of steroid therapy accurately predicts clinical outcome of disease at 15 months. PMID- 19786754 TI - Risk/benefit strategies must be employed in the management of pediatric Crohn's disease. AB - Clinicians caring for children with Crohn's disease must consider the long-term implications of therapeutic interventions and cumulative diagnostic studies in their patients whose disease duration will be measured in decades. There is evidence of the increased severity of pediatric Crohn's disease compared to its adult counterpart, its frequent co-morbid growth disturbances, and the frequent need for aggressive medical therapies including immunomodulators and biological agents. The initial management of most children diagnosed with Crohn's disease involves enteral nutritional support, corticosteroids, and immunomodulators. Corticosteroids, while initially helpful in decreasing signs and symptoms of disease, are occasionally ineffective, generally do not heal mucosa, impair growth, and are frequently associated with a state of corticosteroid dependency. Immunomodulators are effective maintenance therapies with corticosteroid sparing effects, but have no value in the acutely ill child. The emergence of biological therapy with its impressive record of rapid efficacy and use as maintenance therapy has prompted discussion of its incorporation into initial management, but has also raised concerns about who are the most suitable candidates, which if any medications can be used concomitantly, and long-term safety. The combined use of thiopurines and anti-TNF agents may predispose to a rare and uniformly fatal lymphoma. Identification of children at high risk for complicated disease may allow us to better evaluate risk/benefit in newly diagnosed children, and biologic agents are likely to assume an increasing role in primary therapy in those deemed at highest risk. Long-term observations will determine whether biologics will change natural history and demonstrate adequate safety. PMID- 19786755 TI - Enteral nutrition should be used to induce remission in childhood Crohn's disease. AB - BACKGROUND: Exclusive enteral nutrition has been used over many years as a therapy to try and achieve a remission in adults and children presenting with acute Crohn's disease. Despite its reported efficacy at achieving clinical responses in excess of 80% in some case series, it has not been taken up widely as a first-line therapy. This is, at least in part, due to the lack of a large prospective randomised study. METHODS: The literature is replete with small case series and anecdotal reports from units who use this therapy. Recent literature is reviewed on efficacy, application, composition and potential mechanisms of action of this therapy. RESULTS: Although the evidence base remains quite limited, further data are available that suggest a clear benefit of exclusive enteral nutrition as an efficacious alternative to steroid therapy at inducing a clinical remission in Crohn's disease. Certain sub-groups are likely to benefit more, with potential benefits on growth making it particularly useful in adolescents and growing young adults. Given the lack of side effects compared to the alternative of steroid therapy, along with the clear nutritional benefits of this therapy, it remains an obvious choice for patients presenting with Crohn's disease and a degree of malnutrition. CONCLUSIONS: This therapy should remain a first-line therapy for children and adults presenting with mild to moderate Crohn's disease. PMID- 19786756 TI - Top-down therapy: is the evidence strong enough? AB - Crohn's disease (CD) has usually been managed in an escalation manner, introducing more powerful (and toxic) drugs only once those with a better safety profile had failed. However, the natural history of CD under conventional therapeutic strategies results in high intestinal resection requirements and high rates of clinical relapse and steroid dependence. Indirect data seem to point at an improved efficacy of drugs when they are introduced early after disease diagnosis. The spreading use of immunomodulators and the appearance of biological agents prompted the idea of their early introduction in order to change the natural history of the disease. By now, only thiopurines have been shown to reduce steroid requirements, relapse rates, and even surgical requirements, at least in pediatric CD. However, many other 'top-down' treatment strategies have not yet been evaluated. In addition, there is a risk of overtreating those 10-30% of patients that will have a benign course of the disease; that's the reason why the implementation of top-down strategies remains as a matter of debate. PMID- 19786757 TI - Immunomodulation with methotrexate: underused and undervalued? AB - Therapeutic options for the treatment of inflammatory bowel disease (IBD) are multiple. There are excellent clinical trials showing in patients with IBD that immunomodulatory therapy is highly efficacious in the disease control in moderate active to severe forms. Most clinical experience was gained over the last years with the purine analogues azathioprine (AZA)/6-mercaptopurine (6-MP). These drugs are now considered as gold standard in the treatment of severe Crohn's disease (CD). However, for patients who fail to respond or who do not tolerate AZA/6-MP therapy, methotrexate is an interesting alternative drug. Two initial clinical trials validated the use of MTX in adult CD cohorts. There are now two retrospective analyses in pediatric cohorts available which nicely demonstrate the efficacy of MTX to maintain long-term remission in CD patients with active and severe disease progression. The remission rates are close to 50% in long-term follow-up, an efficacy comparable to purine analogues. Overall tolerance of MTX was good, with about 10% of adverse events in either study. Taken together, there are first data indicating that MTX might play a role comparable to AZA in the treatment of CD; however, to date it seems to be underused in the routine care of IBD patients. PMID- 19786758 TI - Treatment of severe ulcerative colitis: differences in elderly patients? AB - Almost as many as 10% of patients with ulcerative colitis have late onset with the first flare occurring at 60-70 years of age. The course of the disease and the basic principles of management in geriatric populations do not differ from those in younger patients. However, elderly patients pose distinct problems in therapy choice. In middle-aged patients untreated severe ulcerative colitis has been reduced to <1% in specialized centers at the present time but is still high in the elderly. In general, the management requires close collaboration between gastroenterologists and surgeons. In adult patients, current evidence supports initial treatment with intravenous steroids. However, only 40% of patients show complete response after corticosteroid therapy and almost 30% come to colectomy. Cyclosporine still has a first place as salvage therapy because of its short half life and its established short-term efficacy in about 70% of patients who fail steroids. The drug should be avoided in frail or elderly patients (especially over 80 years old) with significant comorbidity, and also where colectomy is likely to be necessary in the short to medium term. The long-term benefit of this therapy remains unsatisfactory as colectomy is often only delayed. Infliximab is the choice for those patients with a less severe colitis and less likelihood of urgent colectomy. Tacrolimus has only been used in one randomized controlled trial with similar results to cyclosporine. Surgery is still the definitive procedure for the treatment of ulcerative colitis in adult patients, and its timing is of paramount importance. PMID- 19786759 TI - Severe acute ulcerative colitis: the pediatric perspective. AB - Many features of pediatric ulcerative colitis (UC) are similar to adult-onset disease, but the rate of extensive disease is doubled in children. It is, therefore, not surprising that the admission rate for severe UC is higher in childhood-onset UC, reaching 28% by the age of 16 years. Approximately 30-40% of children will fail corticosteroids and require second-line medical therapy or colectomy. A pediatric UC activity index (PUCAI) score of >65 indicates severe disease and the index can assist in determining the need and timing of second line medical therapy or colectomy early during the admission. A PUCAI score of >45 points on day 3 identify patients likely to fail corticosteroids (negative predictive value 90-95%), and a score >70 points on day 5 identify patients who will require short-term treatment escalation (positive predicting value 95-100%). Data in children are limited, but it seems that cyclosporine, tacrolimus and infliximab achieve a similar short-term response rate, in the range of 60-80%. Infliximab has the advantage that it may be given for a prolonged period of time while calcineurin inhibitors should not be used for more than 3-4 months, bridging to a thiopurine regimen. Colectomy is indicated in toxic megacolon or in cases refractory to one salvage therapy. The choice of colectomy in other cases should carefully consider its effect on the patient's quality of life, its impact on the physical and emotional development at a critical age of personality development, and its association with a high infertility rate in females undergoing pouch procedure before childbearing age. PMID- 19786760 TI - Treatment of ulcerative colitis in the elderly. AB - Ulcerative colitis (UC) has a bimodal age distribution, with the majority of patients being diagnosed between the second and fourth decades of life. However, a second peak in diagnosis occurs in older patients and an estimated 15% of patients present after age 65. Caring for older UC patients who have either presented later in life or who have carried an inflammatory bowel disease (IBD) diagnosis for multiple decades may pose additional challenges in management. Recent studies using nationwide administrative databases from the USA have demonstrated that older IBD patients are challenged by worse hospital outcomes. This pattern, seen for both UC and Crohn's disease, demonstrated increased rates of vascular complications (i.e. venous thrombosis), worse post-operative outcomes and increased rates of complicated and prolonged clinical courses compared to younger IBD patients. This article provides an overview of caring for elderly patients with UC, including diagnostic and therapeutic considerations. PMID- 19786761 TI - Surgery in ulcerative colitis: indication and timing. AB - Surgery continues to play an important role in the therapeutic arsenal in ulcerative colitis. In acute colitis, close collaboration between the gastroenterologist and the surgeon is pertinent. Absolute indications for surgery include toxic megacolon, perforation, and severe colorectal bleeding. In addition, surgery should always be considered upon deterioration during medical therapy. The recommended operation in acute colitis is colectomy and ileostomy, with the rectum left in situ; reconstruction is not an option in the acute setting. In chronic continuous colitis, often with long-term steroid therapy, healing conditions are poor. A staged procedure is preferred also in these cases. In cases with dysplasia, surgery should be done after verifying the dysplasia since these patients often have little symptoms from their colitis. The proctocolectomy should in these cases include total mesorectal excision. Ileal pouch-anal anastomosis is the standard bowel reconstruction in ulcerative colitis. The various options should, however, always be thoroughly discussed, considering the pros and cons in each individual patient, before a choice is made. Ileorectal anastomosis is a temporary alternative in select cases (e.g. young women not having had children). Reconstructive surgery is best done approximately 6 months after primary surgery. Surgery for ulcerative colitis should be seen as complementary to medical treatment and may prevent complications, improve the patients' quality of life and occasionally be life saving. Correct assessment and optimised medical treatment are prerequisites for surgery on accurate indications and good surgical results. Therefore, close interactions between gastroenterologists and colorectal surgeons are mandatory for optimal patient outcome. PMID- 19786762 TI - Management of inflammatory bowel diseases during pregnancy. AB - Inflammatory bowel diseases (IBD) have a high prevalence in younger patients with child-bearing potential. Usually, pregnancies in women with IBD will develop normally, if the patient is in remission or has minor disease activity at the time of conception. In contrast, the frequency of normal pregnancies is significantly reduced and the frequency of adverse outcomes like preterm birth or miscarriage is increased, when conception occurs in phases with active IBD. Therefore, it is generally recommended to women with IBD to conceive at a time with minor disease activity or in remission. IBD patients who plan to become pregnant or are pregnant should be treated adequately. Currently, it is widely accepted that the treatment of IBD with corticosteroids and 5-ASA derivatives does not increase the risk of malformations or adverse outcomes in pregnant IBD patients. However, a slight increase in the number of pre-term deliveries or reduced birth weight is observed. More recently, it has also been appreciated that azathioprine and 6-MP and presumably also infliximab and other TNF-alpha blockers can be safely used during pregnancy in IBD, as no significant increase of malformations, miscarriages or adverse pregnancy outcomes is observed. Information on cyclosporine and tacrolimus during pregnancy is scarcer, but it may be continued or started in some situations if clinically needed. Methotrexate is contraindicated, as this drug is known to significantly increase the risk of malformations and spontaneous abortion. Patients, who wish to nurse their babies, may be treated with steroids and 5-ASA derivatives without a significantly increased risk for the newborn. PMID- 19786763 TI - Mild to moderate Crohn's disease: still room for step-up therapies? AB - Step-up therapy in Crohn's disease refers to the classic therapeutic approach resulting in progressive increase of therapies with the increasing severity of the disease. This approach has been recently challenged by the top-down strategy, where biologicals together with thiopurines were used as first-line therapy. Several arguments exist against the top-down therapy. The current ECCO recommendation is in favor of the step-up therapy. ECCO recommended budesonide 9 mg daily as the preferred treatment in mild to moderate Crohn's disease patients. The benefit of mesalazine in small bowel disease is limited and should be considered clinically no more effective than placebo. Antibiotics cannot be recommended unless septic complications are suspected. No treatment is an option for some patients with mild symptoms. Budesonide is preferred to prednisone for mild active Crohn's disease because it is associated with fewer side effects. Active mild colonic disease may be treated with sulfasalazine and when needed with systemic corticosteroids as well. Topical treatment should be considered for distal disease. The national cooperative Crohn's disease study and the European co-operative Crohn's disease study established corticosteroids as an effective therapy for inducing remission in Crohn's disease. Remission is achieved in 60 83% of the patients. A Cochrane review of the efficacy of azathioprine and 6 mercaptopurine for inducing remission in active Crohn's disease showed a benefit for thiopurine therapy compared with placebo. Methotrexate is another effective medication that has been confirmed in a systematic review. Once remission has been achieved with systemic corticosteroids, maintenance with azathioprine should be considered. For patients with extensive colitis, long-term treatment with mesalazine is an option as this may reduce the risk of colon cancer, although this is still unproved in Crohn's disease. In conclusion, the natural course of most patients with Crohn's disease is relatively mild and there is a room for step-up therapy. The efficacy of most medications is similar to the efficacy of infliximab but with less adverse effects. Infliximab should be reserved only for patients where other therapies failed. PMID- 19786764 TI - Anti-tumor necrosis factor nonresponders in Crohn's disease: therapeutic strategies. AB - Anti-TNF antibodies have revolutionized the treatment of Crohn's disease. In pivotal trials, however, the frequencies of primary and secondary nonresponders appeared rather high with, by the end of 1 year of scheduled treatment, only one fifth of the patients initially treated still in sustained remission. Other studies and monocentric experiences have indicated that these seemingly disappointing results were partly due to suboptimal selection of the patients and absence of treatment optimization. Optimal selection of the patient includes proving active intestinal lesions and systemic inflammation as well as excluding stricturing or infectious complications. Treatment optimization includes potential immunosuppressive co-treatment and dose or administration interval adjustment of the anti-TNF. When a failure is confirmed with an anti-TNF despite such optimization, second- or third-line anti-TNFs have proved useful. Beyond that, a transient steroid course and surgical procedures still represent rescue option, waiting for new promising biologics in development. PMID- 19786765 TI - Early inflammatory bowel disease: different treatment response to specific or all medications? AB - BACKGROUND: The literature suggests that medications prescribed for the treatment of inflammatory bowel disease may be more efficacious in children than adults. Care must be exercised in comparing these data, however, as significant differences in disease duration and concomitant therapy are present among studies. METHODS: Review of key clinical trials, meta-analyses and observational registries for which there are treatment response data from both pediatric and adult Crohn's disease (CD) populations. RESULTS: Acute response to corticosteroids is similar in children (84-89%) and adults (80-84%), but prolonged response may be better in children (50-61 vs. 32-44%). Differences in duration of CD among the various studies' subjects and the proportion of subjects receiving concomitant immunomodulators probably explain much of these differences. CD remission rates with thiopurines appear higher in children at both 6 months (85 vs. 31%) and 15-18 months (81 vs. 42%), but the reported outcomes are likely influenced by very short duration of CD in the pediatric populations studied. Similarly, remission of CD 1 year following initiation of infliximab also appears higher in children (56%) than adults (28%), but again differences in study populations' durations of CD and use of concomitant immunomodulators likely are responsible for the observed differences. CONCLUSION: Differences between pediatric and adult responses to a variety of IBD treatments appear to be due more to study design than the age of the subjects evaluated. As published pediatric trials have generally evaluated subjects with potent treatments at or shortly after diagnosis, the consistently higher rates of responses seen in children lend weight to the argument that some form of 'top down' therapy offers the best option to maximize remission rates in all patients with IBD. PMID- 19786766 TI - Beyond tumor necrosis factor: next-generation biologic therapy for inflammatory bowel disease. AB - Even as further refinements of anti-TNF continue to emerge, new biologics targeting alternative mechanisms are progressing through clinical development programs and offer the opportunity for categorically new therapeutics in the years ahead. Several of these target regulatory cytokines occupy important nodal positions in the intricate pathways mediating immune and inflammatory injury. A number of agents which antagonize the IL-12/IL-23 axis appear to offer promise. The apparent efficacy of these anti-cytokine agents has served as a stimulus for development of therapeutics that inhibits the signaling pathway common to their action. In addition to the focus of new biologic development on additional components of the cytokine network, other biologics target mechanisms of recruitment of various key cell populations to mucosa involved in inflammatory bowel disease. Natalizumab is already approved for clinical use and targets alpha4 with proven efficacy in Crohn's disease. A more specific antibody designated finds alpha4beta7 (also known as MAdCAM) trials has had efficacy in ulcerative colitis and probable efficacy in Crohn's disease. Efforts continue to exploit increasing understanding of the mechanisms necessary for T cell activation, and most especially co-stimulatory molecules to intervene in immune related injury. A chimeric protein encompassing CTLA4 and an immunoglobulin tail (abatacept) has yielded promising results. Another mechanistic strategy to intervene with recruitment of key leukocytes to sites of disease activity has focused on members of the chemokine family that appear to be especially critical to the intestinal mucosa. In summary, the expanding knowledge of mechanisms that contribute to the pathogenesis of inflammatory bowel diseases has yielded a wealth of new potential targets and the results of the variety of agents currently being developed offer promise for a rich mix of next-generation biologics. PMID- 19786767 TI - How do we manage vaccinations in patients with inflammatory bowel disease? AB - The mortality in inflammatory bowel disease (IBD) has been reported similar or slightly increased as compared to that of the general population. However, deaths related to infectious and parasitic diseases have been repeatedly reported in clinical trials, open series and registries. The IBD patients are exposed to the same infections affecting the community, added to opportunistic infectious related to the immunosuppression. Some of these infectious diseases may be prevented by the appropriate use of a vaccination program. Thus, vaccination status should be assessed at IBD diagnosis, and from time to time, and vaccination should be updated to every patient as soon as possible, since deaths due to preventable diseases should never occur. Present recommendations include vaccination for influenza (annually), for pneumococcal disease with the 23-valent strain (every 5 years), for hepatitis B virus (in patients with no detectable hepatitis B surface antibodies), combined vaccination against tetanus, diphtheria and inactivated poliomyelitis (every 10 years). The role of human papillomavirus vaccine preventing cervical dysplasia and neoplasia in IBD women taking immunosuppressive are at present unknown. In patients lacking varicella immunization, specific vaccination should be considered. Nevertheless, it should be taken into account that varicella vaccine contains live attenuated virus that cannot be administered in patients taking immunosuppressive. The same consideration should be kept in mind for patients travelling to endemic areas for yellow fever. Finally, IBD patients on immunosuppressive may have an altered response to vaccine immunization. Decreased response has been reported for hepatitis B and pneumoccocal vaccination. In those cases, testing for serological responses to vaccine should be performed and booster doses may be required. PMID- 19786768 TI - Noncolorectal malignancies in inflammatory bowel disease: more than meets the eye. AB - In patients with Crohn's disease, the risk of small bowel adenocarcinoma is 20-40 times higher than the low background risk of the general population. In the subset of patients with longstanding small bowel lesions, the absolute risk of small bowel adenocarcinoma exceeds 1 per 100 patient-years after 25 years of follow-up and becomes equivalent to the risk of colorectal cancer. Growing evidence suggests that the pathogenesis of small bowel adenocarcinoma arising in inflammatory lesions of Crohn's disease is similar to that of colorectal cancer complicating chronic colonic inflammation (inflammation-dysplasia-cancer sequence). However, contrasting with the established endoscopic detection of colonic advanced neoplasias in patients with longstanding extensive colitis, there is no consensus at this time how to face the excess-risk of small bowel adenocarcinoma in patients at high risk. There are no specific clinical or imaging alert signs and endoscopic surveillance of the totality of the inflamed small bowel mucosa would suppose to perform repeated enteroscopies, with the potential limiting factor of stenosis. Very preliminary data suggest that chemoprevention with salicylates could be an alternative way for reducing the risk. Data from referral centers and from the CESAME cohort suggest that intestinal lymphomas may arise in the chronically inflamed segments in patients with inflammatory bowel disease (IBD). Regarding nonintestinal lymphomas, it is now established that IBD patients treated with thiopurines have an excess risk of lymphomas, exhibiting in most cases pathological features of lymphomas associated with immunosuppression, including the frequent presence of EBV in neoplastic tissues. There is growing evidence that treatment with thiopurines is responsible by itself for this excess risk. IBD patients receiving immunomodulators, especially young men, are also at risk (0.4 for 10,000 patient-years in the CESAME study) for developing fatal early post-mononucleosis lymphomas, like in Purtilo's syndrome, maybe in association with a background genetic susceptibility. Finally, patients receiving thiopurines and/or TNF-inhibitors are at risk for developing fatal hepatosplenic T cell lymphomas, but this risk is low (no case in the CESAME study). Whether patients receiving a monotherapy with methotrexate and/or TNF inhibitors are at increased risk of lymphomas is not known. Concordant data suggest that women receiving immunosuppressive therapy are at increased risk for developing uterine cervix dysplasia and require closer surveillance. But it is not established whether the risk of uterine cervix cancer and basal and squamous cell skin cancers (that may be associated with chronic human papillomavirus infection) is increased in patients receiving immunomodulators. PMID- 19786769 TI - Transition from pediatric to adult health care in inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a lifelong disease that has great psychosocial impact on the adolescent patient and his/her family. Starting around age 12-14 years, many changes take place related to school, work, and sexual development. At some point, usually around the age of 16-18 years, these patients need to move from the pediatric clinic to the adult caregivers. A stepwise program for transition of care, aimed at coaching the adolescent patient into self-management will benefit patients, parents, and the 'adult gastroenterologist' who will take over the care from the pediatric gastroenterologist. Differences in pediatric and adult health care, transition goals, tips and tools for successful transition will be discussed. PMID- 19786770 TI - Fistula treatment: the unresolved challenge. AB - Fistulas are common complications in Crohn's disease, as their cumulative prevalence reaches up to two thirds of the patients in the long term. Fistulas worsen the overall patient prognosis, with permanent sphincter and perineal tissue destruction as well as professional and personal disabilities. The importance of healing these fistulas has been less well appreciated than mucosal healing for luminal disease. Management should not be left to any specialty alone, but requires an optimal combination of surgery, infection control, and immunosuppression. Outcome of therapy beyond fistula drainage is unclear and the means of assessing healing over a long time period is poorly characterized. Recent studies suggested that a substantial proportion of patients can achieve fistula healing with surgical and medical therapies. However, studies that measure the benefit of integrated approaches, of early intervention and of precise healing assessment are still missing. Such information is particularly needed in this subset of sick patients that undergo substantial physical and emotional distress because of pain, discharge, incontinence, perineal and genital disfigurement. The advent of adequate pelvic imaging, improved surgical outcomes, and potent biological therapies make it timely to develop best-management strategies and appropriateness of care criteria. PMID- 19786771 TI - Drug monitoring in inflammatory bowel disease: helpful or dispensable? AB - Thiopurines, methotrexate and the calcineurin inhibitors cyclosporin A and tacrolimus are classical immunosuppressive treatment modalities for inflammatory bowel disease (IBD). Since a high inter-patient variability exists in drug efficacy and toxicity, their application requires the knowledge of appropriate indications as well as strategies for individualization of dosage and monitoring for adverse events. Results of pharmacogenetic studies that examine the relationship between single-gene polymorphisms and associated effects on the pharmacokinetics and pharmacodynamics may be helpful for the optimization of individualized therapy. Although 85-95% of patients worldwide present with the homozygote thiopurine S-methyltransferase (TPMT) wild-type genotype and a normal enzyme activity, cost-benefit analyses suggest assessment of TPMT enzyme activity prior to thiopurine therapy for IBD to prevent life-threatening toxicity. Monitoring of 6-mercaptopurine metabolites is a helpful, but not an indispensable tool in thiopurine non-responders to discriminate poor adherence and under-dosing from pharmacogenetic thiopurine resistance and thiopurine refractory disease. Response to and adverse events of methotrexate therapy are hard to predict. Pharmacogenetic indices of methotrexate metabolization have been evaluated in rheumatoid arthritis (RA) but not in IBD yet. In contrast to RA, concentration of methotrexate polyglutamates correlates positively with non-response and adverse effects in IBD. Calcineurin inhibitor metabolism is mainly controlled by cytochrome P-450 isoenzymes 3A4/3A5 and P-glycoprotein that underlie a variety of gene polymorphisms and are susceptible to drug interactions. Independent from pharmacokinetic alterations a MDR1 polymorphism may predict cyclosporin failure in severe ulcerative colitis. Frequent monitoring of whole blood levels is required since efficacy and toxicity are dose-dependent. PMID- 19786772 TI - Growth retardation in early-onset inflammatory bowel disease: should we monitor and treat these patients differently? AB - Growth impairment and associated pubertal delay are common complications of pediatric inflammatory bowel disease (IBD), particularly Crohn's disease (CD). Chronic undernutrition (related primarily to inadequate intake) and pro inflammatory cytokines are the two major and interrelated contributory factors. Pathogenic mechanisms include interference with growth hormone/insulin-like growth factor-1 axis, with gonadotropin-releasing hormone secretion patterns, and direct cytokine effects on growing bone. Chronic corticosteroid therapy compounds disease-related causes of growth impairment. The influence on growth of polymorphisms in IBD susceptibility or modifier genes is under study. Accurate recognition of impaired growth requires appreciation of normal growth. Pre illness standard deviation scores (SDS) for height should be obtained and compared with height SDS at diagnosis, so that the impact of disease on growth can be fully appreciated. The greater the deficit prior to recognition of IBD, the greater is the demand for catch-up growth. Height velocity should be regularly monitored and its adequacy for age and pubertal stage assessed. Restoration and maintenance of pre-illness growth pattern indicate success of therapy. Current treatment regimens limit use of corticosteroids, via optimization of immunomodulatory drugs, use of enteral nutrition in CD, and, if necessary, surgery for ulcerative colitis and for intestinal complications of localized CD. Biologic agents with the potential for mucosal healing hold promise of growth enhancement even among children, whose growth with previously available therapies remained compromised. For all therapies, there is a window of opportunity to achieve normal growth before puberty is too advanced. PMID- 19786773 TI - Prebiotics, probiotics and helminths: the 'natural' solution? AB - BACKGROUND: The pathophysiological mechanisms that generate chronic inflammatory lesions in inflammatory bowel disease (IBD) have, at least in part, been unveiled. Abnormal communication between gut microbial communities and the mucosal immune system is being incriminated as the core defect leading to intestinal injury in genetically susceptible individuals. The therapeutic manipulation of gut microecology has attracted high expectation as a strategic area for the control and prevention of IBD. METHOD: Literature review. RESULTS: The gut is the major site for induction of regulatory T cells, which secrete immunoregulatory cytokines such as IL-10 and TGF-beta and can regulate both Th1 and Th2 responses. Recent findings suggest that some gut commensals, including lactobacilli, bifidobacteria and helminths, play a major role in the induction of regulatory T cells in gut lymphoid follicles. Such T cell-mediated regulatory pathways are essential homeostatic mechanisms by which the host can tolerate the massive burden of innocuous antigens within the gut without responding through inflammation. In clinical practice, the evidence for the use of probiotics or prebiotics is strongest in the case of pouchitis. In addition, one probiotic strain appears to be equivalent to mesalazine in maintaining remission of ulcerative colitis. However, studies of probiotics in Crohn's disease have been disappointing. CONCLUSIONS: Further research is needed to optimize the use of probiotics, prebiotics or helminths for these indications. PMID- 19786775 TI - Absence of TARDBP gene mutations in an italian series of patients with frontotemporal lobar degeneration. AB - BACKGROUND/AIM: Recent studies showed that TAR DNA-binding protein 43 (TDP-43), encoded by the TARDBP gene, is a major pathological protein in both sporadic and familial frontotemporal lobar degeneration (FTLD). The aim of this study was to search for mutations of the TARDBP gene in the disease. METHODS: We sequenced the TARDBP gene in 172 unrelated FTLD patients recruited from 2 Italian memory clinics. RESULTS: We identified 3 different variants of the TARDBP gene in 12 FTLD patients. Three patients showed a silent variant, Ala66Ala (c.332T --> C) in exon 2. A novel heterozygous mutation was found in intron 4 (c.543 + 51A --> G) in 1 patient, which is not located at the splicing site. Finally, a c.208C --> T variant in the 3' untranslated region was detected in 8 probands. None of the aforementioned variants were predicted to affect TDP-43. Hence, pathogenic mutations were not identified in any of the FTLD cases. CONCLUSION: Our study, in accord with previous studies in different populations, found no evidence for a major genetic role of the TARDBP gene in FTLD. PMID- 19786776 TI - Effectiveness of donepezil in reducing clinical worsening in patients with mild to-moderate alzheimer's disease. AB - BACKGROUND: Therapeutic endpoints based on reduced clinical worsening represent clinically relevant and realistic goals for patients suffering from progressive neurodegenerative disorders such as Alzheimer's disease (AD). METHODS: Data from 906 patients (388 receiving placebo; 518 receiving donepezil) with mild-to moderate AD [Mini-Mental State Examination (MMSE) score 10-27] were pooled from 3 randomized, double-blind placebo-controlled studies. Clinical worsening was defined as decline in (1) cognition (MMSE), (2) cognition and global ratings (Clinician's Interview-Based Impression of Change plus Caregiver Input/Gottfries Brane-Steen scale) or (3) cognition, global ratings and function (various functional measures). RESULTS: At week 24, lower percentages of donepezil-treated patients than placebo patients met the criteria for clinical worsening, regardless of the definition. The odds of declining were significantly reduced for donepezil-treated versus placebo patients (p < 0.0001; all definitions). Among patients meeting criteria for clinical worsening, mean declines in MMSE scores were greater for placebo than donepezil-treated patients. CONCLUSION: In this population, donepezil treatment was associated with reduced odds of clinical worsening of AD symptoms. Moreover, patients worsening on donepezil were likely to experience less cognitive decline than expected if left untreated. This suggests that AD patients showing clinical worsening on donepezil may still derive benefits compared with placebo/untreated patients. PMID- 19786777 TI - Mini-mental state examination is sensitive to brain atrophy in Alzheimer's disease. AB - BACKGROUND/AIMS: Screening instruments such as the Mini-Mental State Examination (MMSE) are useful for the early identification of Alzheimer's disease (AD). We tested whether macrostructural differences in brain volume are related to the MMSE. METHODS: The MMSE was related to cortical thickness and the volume of 19 brain structures in 96 patients with mild to moderate AD. In addition, the patients were compared to 93 healthy elderly controls. RESULTS: The MMSE was related to the volume of the total brain, cerebral cortex, accumbens, cerebral white matter, inferior lateral ventricles and hippocampus. Positive correlations with cortical thickness were found for 41% of the brain surface, and 58% of this area was significantly thinner in AD. CONCLUSION: The MMSE is sensitive to macrostructural brain atrophy in AD, but also to morphometric variation not specifically related to AD. PMID- 19786779 TI - Evaluation of cerebrospinal fluid tau/beta-amyloid(42) ratio as diagnostic markers for Alzheimer disease. AB - BACKGROUND: Alzheimer's disease (AD) is the leading cause of dementia. Currently, no definitive diagnostic test for AD exists. Cerebrospinal fluid (CSF) concentrations of amyloid beta (Abeta1-42) peptides and total tau proteins (T tau) may serve as biomarkers for AD. AIM: The objective of this study was to investigate the usefulness of CSF Abeta1-42 and T-tau analyses in the diagnosis of AD with Tunisians. METHODS: We focused on three groups originating from Central Tunisian that matched in age (range 48-85): healthy controls (n = 53), AD patients (n = 93) and non-Alzheimer (nAD) dementia (n = 35) patients. Abeta1-42 and T-tau levels were measured in CSF by sandwich enzyme-linked immunosorbent assay. RESULTS: The ratio of T-tau/Abeta1-42 at baseline yielded a sensitivity of 85.3% for detection of AD and the specificity was 84.8% to differentiate controls and nAD dementia. CONCLUSION: Our findings confirm the use of T-tau/Abeta1-42 ratio in the discrimination of AD patients from all other patients. PMID- 19786778 TI - Performance of FDG PET for detection of Alzheimer's disease in two independent multicentre samples (NEST-DD and ADNI). AB - AIM: We investigated the performance of FDG PET using an automated procedure for discrimination between Alzheimer's disease (AD) and controls, and studied the influence of demographic and technical factors. METHODS: FDG PET data were obtained from the Alzheimer's Disease Neuroimaging Initiative (ADNI) [102 controls (76.0 +/- 4.9 years) and 89 AD patients (75.7 +/- 7.6 years, MMSE 23.5 +/- 2.1) and the Network for Standardisation of Dementia Diagnosis (NEST-DD) [36 controls (62.2 +/- 5.0 years) and 237 AD patients (70.8 +/- 8.3 years, MMSE 20.9 +/- 4.4). The procedure created t-maps of abnormal voxels. The sum of t-values in predefined areas that are typically affected by AD (AD t-sum) provided a measure of scan abnormality associated with a preset threshold for discrimination between patients and controls. RESULTS: AD patients had much higher AD t-sum scores compared to controls (p < 0.01), which were significantly related to dementia severity (ADNI: r = -0.62, p < 0.01; NEST-DD: r = -0.59, p < 0.01). Early-onset AD patients had significantly higher AD t-sum scores than late-onset AD patients (p < 0.01). Differences between databases were mainly due to different age distributions. The predefined AD t-sum threshold yielded a sensitivity and specificity of 83 and 78% in ADNI and 78 and 94% in NEST-DD, respectively. CONCLUSION: The automated FDG PET analysis procedure provided good discrimination power, and was most accurate for early-onset AD. PMID- 19786780 TI - Immunological reactivity against neuronal and non-neuronal antigens in sporadic adult-onset cerebellar ataxia. AB - In recent years, the involvement of the immune system in acquired forms of cerebellar ataxia has been frequently demonstrated. In this study, we describe 6 out of 49 patients with subacute or chronic progressive cerebellar ataxia in whom antibodies against neuronal and non-neuronal antigens were identified. Two women had anti-Yo antibodies; two patients had anti-gliadin antibodies in the presence of celiac disease; one patient had a complex autoimmune disorder associated with anti-Ro-52/SS-A and anti-muscle-specific kinase antibodies, and a patient developed subacute cerebellar syndrome associated with the presence of a prostatic adenocarcinoma and atypical antibodies reacting both with cerebellar tissue and with the prostatic tumor. Our study confirms previous findings in paraneoplastic syndromes, and indicates that at least 10% of sporadic cerebellar ataxia may be related to immune-mediated mechanisms. PMID- 19786781 TI - Three- and four-dimensional fetal echocardiography. AB - The rapid continuing development of 3-dimensional ultrasound imaging technologies has extended capabilities of fetal cardiac scanning beyond 2-dimensional imaging technologies and now provides a wide array of analytic possibilities. The acquisition of the 3D volume information is based on initial application of 2 dimensional imaging techniques including grey scale, Doppler, Power Doppler and B flow modalities. Once the cardiac volume is obtained a combination of postprocessing tools such as surface mode, minimal mode, transverse rendering, inversion and glass body modes allow preferential display of various features of the fetal heart. Motion display modes including cine-loop and spatiotemporal image correlation in combination with automated and semiautomated display of examination planes opens a whole new array of diagnostic possibilities in clinical practice. PMID- 19786782 TI - Management and outcome of pregnancies with parvovirus B19 infection over seven years in a tertiary fetal medicine unit. AB - OBJECTIVES: To determine rates of fetal anaemia and pregnancy outcome in susceptible pregnant women infected with human parvovirus B19 infection in a tertiary fetal medicine department over a 7-year period. Additional features enabling identification of fetuses that progress to severe anaemia were also investigated. METHODS: Forty-seven susceptible, pregnant women with confirmed parvovirus infection referred to a regional fetal medicine unit, over a 7-year period (1999-2006), were identified. Where possible maternal serum AFP measurements were obtained from second-trimester serum screening and the presence or absence of echogenic bowel noted. RESULTS: Of the 47 cases, one was excluded. Of the remaining 46 cases, 34 (74%) showed no signs of fetal anaemia and delivered at term. The remaining 12 (26%) showed signs of fetal anaemia. Eight of the 12 developed hydrops and underwent fetal blood sampling and transfusion (median pretransfusion Hb 3.6 g/dl). Seven of the 8 transfused fetuses were thrombocytopenic with a platelet count <150 x 10(9)/l, with 2 fetuses having platelet counts <50 x 10(9)/l. The median gestation age at transfusion was 22 weeks (range 18-27 weeks). The median number of weeks between seroconversion and transfusion was 6 (range 3-12). The signs of anaemia resolved after one transfusion in 5 of the 8 transfused fetuses and they subsequently delivered at term. There were 2 fetal deaths during or shortly after transfusion and one neonatal death following delivery at 28 weeks gestation due to severe pre eclampsia, 5 days after successful transfusion. CONCLUSIONS: Following parvovirus seroconversion, the incidence of significant fetal anaemia requiring transfusion was 17%. Seroconversion after 21 weeks did not result in severe fetal anaemia. Significant anaemia requiring intervention did not occur 12 weeks after maternal seroconversion. We did not demonstrate a correlation with either maternal serum AFP or the presence of fetal echogenic bowel and the development of severe fetal anaemia. Because of the association between fetal anaemia and severe thrombocytopenia, it may be prudent to have compatible platelets available at the time of fetal blood sampling. PMID- 19786783 TI - Fetal transfusion of red blood cells for alloimmunization: validity of a published equation. AB - OBJECTIVE: To validate the equation published in 1990 by Leduc et al. for red blood cell fetal transfusion where fetoplacental blood volume (VO) = 100 ml/kg, then improve its precision. METHODS: We reviewed 101 fetal transfusions among 32 patients. We analyzed risk factors for an inaccurate estimation with uni- and multivariate analysis. We compared the obtained Leduc formula with three other published equations. RESULTS: Fetal weight and gestational age were risk factors for an inaccurate estimation of the final Hct. Before 32 weeks the estimation of VO was 120 ml/kg instead of 100 ml/kg. All formulae overestimated the mean expected Hct value. However, expected Hct estimated by Leduc's formula is the nearest of the observed final Hct. CONCLUSION: Leduc's equation seems to be accurate, but less so for the youngest fetuses. We propose an adapted formula VO according to gestational age and fetal weight estimation. PMID- 19786784 TI - Reference range of fetal renal volume by three-dimensional ultrasonography using the VOCAL method. AB - OBJECTIVE: To establish reference values for fetal renal volume by three dimensional sonography using the VOCAL (Virtual Organ Computer-Aided Analysis) method. METHODS: This prospective longitudinal study involved 57 healthy pregnant women who were examined between 24 and 34 weeks of pregnancy. Each fetal kidney was evaluated separately using the VOCAL method with a 30 degree rotation angle. For each gestational age, the following measures were obtained for the right and left kidneys: mean, standard deviation, minimum and maximum values, and the 5th, 10th, 25th, 50th, 75th and 90th percentiles. Polynomial regression models were constructed to assess the relationship between renal volume and gestational age, adjusted by the determination coefficient (R(2)). The Wilcoxon test was used to evaluate the concordance between the right and left renal volumes. Bland-Altman graphs were used to assess intra- and inter-observer variability. RESULTS: The right renal volume increased from 4.5 +/- 1.3 cm(3) at 24 weeks to 12.1 +/- 1.5 cm(3) at 34 weeks. The left renal volume increased from 4.6 +/- 0.8 cm(3) at 24 weeks to 11.9 +/- 1.1 cm(3) at 34 weeks. There was a strong correlation between both the right and left renal volumes and gestational age (R(2) = 0.975 and 0.970, respectively). There were no significant differences between the right and left renal volumes. The mean difference between repeated measures by the same examiner was -0.07 cm(3) (-0.88 to 0.75) for the right kidney and -0.21 cm(3) ( 0.95 to 0.75) for the left kidney. The mean difference between repeated measures obtained by two different examiners was -0.07 cm(3) (-1.25 to 1.12) for the right kidney and 0 cm(3) (-1.53 to 1.53) for the left kidney. CONCLUSION: Reference values were generated for fetal renal volume assessed by three-dimensional ultrasonography using the VOCAL method. PMID- 19786785 TI - Gestational age-specific cutoff levels of TDx-FLM II for the prediction of neonatal respiratory distress syndrome. AB - AIM: To construct a predictive model for respiratory distress syndrome (RDS) from gestational age (GA) at delivery and TDx-FLM II value. METHODS: Pregnant women who underwent an amniocentesis in which TDx-FLM II was determined were included in the study. A model for the occurrence of RDS was constructed by means of a logistic regression procedure from TDx-FLM II values and GA at delivery. RESULTS: The mean value of TDx-FLM II was 47.11 mg/g. The mean GA at delivery was 33.4 weeks. The incidence of RDS was 7.8% (18/231). The optimal cutoff of predicted risk for respiratory distress was found to be 8.8%, resulting in a sensitivity and specificity of 89 and 83%, respectively. CONCLUSIONS: The adjustment of the TDx-FLM II value for GA at delivery results in a significant improvement in the predictive capacity of the test for the occurrence of RDS. The use of GA-specific cutoff values may simplify clinical decisions. PMID- 19786786 TI - Monozygotic dichorionic twins heterokaryotypic for duplication chromosome 2q13 q23.3. AB - We present an evaluation of the diagnosis, management and outcome of a pair of heterokaryotypic monozygotic dichorionic twins. The heterokaryotype was an incidental finding from an amniocentesis performed for prenatal diagnosis of beta thalassaemia major in a pair of dichorionic twins. Monozygocity was revealed by QF-PCR showing identical short tandem repeat markers on chromosomes 21, 18, 13, X and Y. The twins were heterokaryotypic for duplication chromosome 2q13-q23.3, as shown by array comparative genomic hybridization. Selective foeticide was performed. This case demonstrates that heterokaryotypic monozygotic dichorionic twins are a genetic possibility that does occur. PMID- 19786787 TI - Conservative management of placenta previa-accreta by prophylactic uterine arteries ligation and uterine tamponade. AB - BACKGROUND: Placenta previa-accreta is associated with severe hemorrhage occurring while separating the placenta during cesarean delivery and hysterectomy is considered the treatment of choice. Conservative management has recently been proposed. CASE: A 26-year-old woman had pregnancy complicated by placenta previa with suspected accreta. During elective cesarean section a prophylactic double bilateral ligation of uterine arteries was performed before removal of the placenta; subsequently, the continuous small bleeding from the placental bed was stopped by tamponade with a balloon catheter filled with saline solution. The patient was discharged 5 days later. An ultrasonographic color Doppler follow-up demonstrated a renewed uterine vascularization. CONCLUSION: Double bilateral ligation of uterine arteries can be used as a prophylactic surgical treatment when a severe bleeding because of placenta previa-accreta is expected, in order to avoid hysterectomy. PMID- 19786788 TI - Gastroschisis associated with an intra-abdominal umbilical vein varix: a report of 2 cases. AB - We describe 2 cases of gastroschisis which were found to be associated with an intra-abdominal umbilical vein varix. PMID- 19786789 TI - Therapy for foetal pericardial tumours: survival following in utero shunting, and literature review. AB - We report the first case of foetal pericardial teratoma, treated successfully in utero by pericardio-amniotic shunting, and review the relevant literature. Foetal treatment improves survival in case of hydrops. Foetal pericardio-amniotic shunting could possibly be an alternative to serial pericardiocentesis. PMID- 19786790 TI - Intervention with the Lidcombe Program for a bilingual school-age child who stutters in Iran. AB - OBJECTIVE: In this study, the immediate and extended effects of the Lidcombe Program were investigated for the first time in Iran. Treatment in the Lidcombe Program is carried out by the child's parent (or carer) in the child's everyday environment. The program has been shown to be effective with preschool children who stutter (i.e. younger than 6 years) and to a lesser extent with older children. PARTICIPANT AND METHOD: The participant was a bilingual (Baluchi Persian) boy aged 8 years 11 months. Treatment was conducted in both languages. Stuttering severity was measured in Baluchi with the parental rating scale, and in Persian with percentage of syllables stuttered (%SS). RESULTS: The child completed stage 1 of the program in 13 weeks. %SS was less than 1 during the last 3 clinic visits and severity ratings made by the parent indicated no stuttering (severity rating = 1) for all days of the final week. Speech recordings made beyond the clinic in both languages also indicated stuttering at below 1%SS. The child met all criteria for stage 2 in both languages, over 10 months. CONCLUSION: This case report suggests that the Lidcombe Program could be suitable for bilingual Iranian children who stutter. PMID- 19786791 TI - Prolactinoma in children and adolescents. AB - The evolution of prolactinomas in children and adolescents continues to be controversial. Girls have more prevalence of microprolactinomas and their signs and symptoms are related to hyperprolactinemia and the resulting hypogonadotrophic hypogonadism. In males, the greater incidence of macroadenomas results in the presence of neuro-ophthalmologic signs. The larger prevalence of macroadenomas in males is consistent with findings in adults and would not be related to a later diagnosis. In patients with asymptomatic hyperprolactinemia, the presence of altered proportions of PRL isoforms should be evaluated. The diagnosis of prolactinoma requires both radiographic evidence of pituitary adenoma and laboratory analysis documenting the presence of sustained hyperprolactinemia. Because of their effectiveness and tolerance, dopaminergic agonists are the initial therapy of choice in pediatric age patients. Finally, molecular biology and genetic studies have brought new insights into the pathogenesis, clinical behavior and different therapeutic responses. PMID- 19786792 TI - Diagnostic approach in children with short stature. AB - For early detection of pathological causes of growth failure proper referral criteria are needed, as well as a thorough clinical, radiological and laboratory assessment. In this minireview we first discuss the two consensus-based and one evidence-based guidelines for referral that have been published. The evidence based guidelines result in a sensitivity of approximately 80% at a false-positive rate of 2%. Then, relevant clues from the medical history and physical examination are reviewed, and specific investigations based on clinical suspicion listed. In the absence of abnormal clinical findings, an X-ray of the hand/wrist and a laboratory screen are usually performed. Scientific evidence for the various components of laboratory screening is scarce, but accumulated experience and theoretical considerations have led to a list of investigations that may be considered until more evidence is available. PMID- 19786793 TI - Growth monitoring to detect children with cystic fibrosis. AB - BACKGROUND/AIMS: Cystic fibrosis (CF) in infancy and childhood is often associated with failure to thrive (FTT). This would suggest that in countries without a newborn screening program for CF, FTT could be used as a clinical screening tool. The aim of this study is to assess the diagnostic performance of FTT for identifying children with CF. METHODS: Longitudinal length and weight measurements up to 2.5 years of age were used from CF patients (n = 123) and a reference group (n = 2,151) in The Netherlands. Growth measurements after diagnosis were excluded. We developed five potential screening rules based upon length, weight and body mass index (BMI) standardized by age and gender (SDS). Outcome measures were sensitivity, specificity and positive predictive value (PPV). RESULTS: BMI SDS had the highest sensitivity at low false-positive rates. An efficient scenario is a BMI SDS below -2.5 SD in combination with a decrease in BMI SDS of at least 0.5 SD. This scenario had a sensitivity of 32%, a specificity of 98.3% and a PPV of 0.75%. CONCLUSION: In the absence of a newborn screening program, young children with FTT for BMI are candidates to consider testing for CF. PMID- 19786795 TI - Early puberty in internationally adopted girls: hormonal and clinical markers of puberty in 276 girls examined biannually over two years. AB - BACKGROUND AND AIMS: Retrospective studies have indicated that internationally adopted girls are at high risk of developing precocious puberty. Hypothetically, this could be due to selection bias. The aim of this study was to determine age at reaching pubertal milestones in healthy internationally adopted girls in a prospective, clinical study. METHODS: A longitudinal cohort study including 276 randomly recruited internationally adopted girls. At baseline, age ranged from 4 to 13 years. Participants were followed with biannual examinations over a period of 2 years. Examinations included height, weight, Tanner staging, blood sampling and bone age assessment. Age distribution at entering pubertal stages B2-B5 (breast development), PH1-PH5 (pubic hair development) and menarche was estimated by probit analysis. Data were compared to a reference population of Danish-born girls, studied cross-sectionally. RESULTS: Mean age at B2+ was 9.5 years (95% prediction interval 7.1-12.0 years) and mean age at menarche was 12.1 (10.2-14.0) years in adopted girls, which was significantly lower compared to the reference group (p < 0.0003). 16% of adopted girls entered stage B2 before 8 years of age. The puberty-related rise in LH, FSH and estradiol was detected at earlier ages in adopted girls compared to the reference group. CONCLUSION: Internationally adopted girls have a significantly higher risk of precocious pubertal maturation compared to Danish-born girls. PMID- 19786794 TI - Plant growth regulator (4-chlorophenoxy acetic acid) increases apoptosis in gonads of rats without changing hormonal levels. AB - BACKGROUND/AIMS: Plant growth regulators are considered to leave minimal amounts of remnants and therefore cause no significant side effects in humans. In this study, we aimed to investigate the hormonal and histopathological effects of 4 chlorophenoxy acetic acid (4-CPA), a commonly used plant growth regulator, on the gonadal functions of rats. METHODS: The study was implemented on 64 Wistar albino rats (20 days old). Forty-eight rats received 4-CPA every day until 50 days of age. The rats were randomized into 4 groups (a control group and three 4-CPA groups with doses of 25, 50 and 100 mg/kg/day); each group was further divided into males and females, making a total of 8 groups. The levels of FSH, LH, testosterone, estradiol, leptin, inhibin-B and neuropeptide-Y were measured. Histopathological examination of the testes and ductus deferens in male rats, and ovaries and uterus of female rats (caspase-3 and -9 immunoreactivity) was performed. RESULTS: Although hormone levels were similar between the groups, rats that received 4-CPA showed significantly higher degrees of apoptosis compared to the control group (p < 0.001) and increased doses of 4-CPA were directly correlated with the amount of apoptosis (p < 0.001). CONCLUSION: 4-CPA induced apoptosis in the gonads of rats without concurrent changes in plasma hormone levels. PMID- 19786796 TI - Classical congenital adrenal hyperplasia due to 21-hydroxylase deficiency in Croatia between 1995 and 2006. AB - AIMS: To evaluate the incidence, gender, symptoms and age at diagnosis of patients with classical congenital adrenal hyperplasia (CAH) due to 21 hydroxylase deficiency in Croatia. METHODS: Data were collected retrospectively for all classical CAH patients born or electively aborted following prenatal diagnosis between January 1, 1995 and December 31, 2006 and were compared with the data of a previously conducted study evaluating CAH patients discovered between 1964 and 1984. RESULTS: During a 12-year period 34 classical CAH patients were born. There were 20 salt-wasting (SW; 12 female/8 male) and 14 simple virilizing (SV; 7 female/7 male) patients. If 3 female, electively aborted fetuses were added, there would be a total of 37 CAH patients. With 532,942 live births and 34 CAH patients born over this period, the incidence of classical CAH was estimated at 1:15,574 or 1:14,403 if the 3 electively aborted fetuses were included. The lower incidence of SW boys compared to SW girls (8:12) and similar number of SW and SV boys (8:7) indicate that a substantial proportion of SW boys die unrecognized. Owing to better healthcare, the diagnosis was established significantly earlier in SW and SV girls compared to the period of 1964-1984 (p < 0.003). During 1995-2006, none of the patients died following the diagnosis of CAH and there was no erroneous sex assignment. CONCLUSION: Despite improvements in healthcare, the diagnosis of CAH in Croatia is still delayed and some of the patients go unrecognized or die. Therefore, the results of our study support the need to introduce newborn screening. PMID- 19786797 TI - Immune-mediated encephalitis and virilization in association with a mature cystic ovarian teratoma in an adolescent girl. AB - BACKGROUND: Mature cystic teratomas are the most common form of ovarian tumor in children and adolescents. These tumors are mostly benign and non-secreting. Virilization from an ovarian teratoma is exceptionally rare in pediatrics. Equally rare is the association of ovarian teratomas with auto-immune encephalitis. METHODS: We describe the case of a 15-year-old girl with menstrual abnormalities and virilization, who had a past medical history of encephalitis of an unknown etiology 16 months prior to presentation. RESULTS: Endocrine evaluation revealed an elevated serum testosterone and 17-hydroxy progesterone. A large left ovarian tumor was seen on a CT scan. Surgical excision revealed a mature cystic teratoma containing 6 liters of clear fluid with high androgen levels. Antibodies to the N-methyl-D-aspartate receptor of the hippocampus were detected in pre-operatively archived serum, but undetectable 6 months postoperatively. Immunohistochemistry studies on the tumor sections revealed that the antibodies in the patient's serum reacted with areas of the tumor expressing the N-methyl-D-aspartate receptor. Postoperatively, the patient's menstrual cycles became regular and her behavioral problems resolved. Her testosterone levels fell precipitously as well. CONCLUSION: Both virilizing mature cystic teratomas and teratoma-associated encephalitis are extremely rare in the pediatric population. We report on the first instance of these 2 rare entities occurring in the same patient. PMID- 19786799 TI - Structural and IgE binding analyses of recombinant Der p 2 expressed from the hosts Escherichia coli and Pichia pastoris. AB - BACKGROUND: The house dust mite allergen Der p 2 is one of the most important indoor allergens associated with allergic disease. Recombinant Der (rDer) p 2 with high IgE binding activity can be readily produced in Escherichia coli and Pichia pastoris, but the structure and IgE binding of the different methods of preparation have not been compared. METHODS: Secondary structure was assessed by circular dichroism (CD). Intrinsic fluorescence and hydrophobic probe (1 anilinonaphthalene 8-sulphonic acid, ANS) were used to study the Der p 2 hydrophobic cavity. IgE binding was assessed by ELISA inhibition. RESULTS: CD analysis showed the expected secondary structure for both nDer p 2 and refolded Der p 2 prepared from E. coli inclusion bodies but primarily random structure for Der p 2 secreted from P. pastoris. The secreted product, however, had disulphide bonding and could be refolded to a similar structure to natural Der (nDer) p 2 after precipitation with trichloro-acetic or ammonium sulphate. ANS binding and intrinsic Trp92 fluorescence showed that all recombinant proteins were different to nDer p 2 and that the allergen secreted from P. pastoris did not form a hydrophobic cavity. Despite the marked structural changes, all preparations of Der p 2 had similar IgE binding to nDer p 2. CONCLUSION: Despite almost identical IgE binding, rDer p 2 prepared from both E. coli and P. pastoris showed structural differences to nDer p 2. Der p 2 secreted from P. pastoris lacked most of the natural structure, but refolding could induce the natural structure. PMID- 19786798 TI - The role of costimulatory molecules in allergic disease and asthma. AB - The prevalence of allergic diseases has increased rapidly in recent years. It is well established that the deleterious allergic response is initiated by T-cell recognition of major histocompatibility class II-peptide complexes at the surface of antigen-presenting cells. While this first signal gives antigen specificity to the adaptive immune response, a second nonspecific costimulatory signal is required by T cells to become fully activated. This signal is provided by interactions between antigen-presenting cells and T cells through molecules borne at the surfaces of the two cell types. Depending on the type of molecules involved, this secondary signal can promote the development of an inflammatory allergic reaction or may favor immune regulation. Several molecules of the B7 family (CD80, CD86, PD-1, ICOS, CTLA-4) and tumor necrosis factor receptor family (OX40, CD30, 4-1BB, Fas, CD27, CD40) play an important role in delivering costimulatory signals in early and late phases of allergic response. Therefore, costimulatory molecules involved in promotion or prevention of allergic immune responses are potential targets for the development of novel therapeutic approaches. This review aims to recapitulate our current understanding of the relationship between allergic diseases and costimulatory molecules. PMID- 19786800 TI - Allergenic differences among pollens of three Salsola species. AB - BACKGROUND: Sensitivity to Chenopodiaceae is a frequent cause of allergic respiratory diseases in geographic areas where sensitization to Salsola kali and Chenopodium album has been reported. The objective of this study was to evaluate the pattern of sensitization to 3 Salsola species in patients residing on the Mediterranean coast of south-eastern Spain. METHODS: S. kali, S. vermiculata and S. oppositifolia pollen extracts were prepared. Patients reporting respiratory and/or cutaneous symptoms were skin prick tested with the 3 Salsola extracts. Individuals with positive skin prick tests to at least 1 of the 3 Salsola species were included. Specific IgE was determined by direct ELISA. SDS-PAGE and 2-D analysis were conducted to elucidate the protein profile. The allergenic profile was investigated by immunoblot. Inhibition experiments were conducted to establish cross-reactivity between different species. RESULTS: 246 patients were included. 237 patients (96.3%) tested positive to S. oppositifolia, 189 (76.8%) to S. kali and 185 (75.2%) to S. vermiculata. Protein profile and immunoblot demonstrated similar patterns in all extracts, except in low-molecular-weight allergens of S. oppositifolia. Immunoblot inhibition experiments demonstrated that most high-molecular-weight allergens of S. oppositifolia were inhibited by S. kali whereas low-molecular-weight allergens were totally inhibited only by C. album. CONCLUSIONS: This study confirms the allergenic importance of other Salsola species, especially S. oppositifolia. We have demonstrated that the 3 species show a high degree of cross-reactivity, but S. oppositifolia shares more allergenic similarities with C. album than S. kali. PMID- 19786801 TI - Allergenicity of recombinant troponin C from Tyrophagus putrescentiae. AB - BACKGROUND: The storage mite, Tyrophagus putrescentiae, produces potent allergens, many of which have not been characterized. This study was undertaken to characterize the allergenicity of troponin C from T. putrescentiae. METHODS: A cDNA encoding 17.7 kDa troponin C, with homology to cockroach allergen Bla g 6, was identified from T. putrescentiae-expressed sequence tags. Recombinant troponin C was expressed and IgE responses to the recombinant protein were assessed in the presence and absence of 10 mM CaCl(2). Cross-reactivity between T. putrescentiae troponin C and Bla g 6 was tested using an inhibition ELISA. RESULTS: Recombinant T. putrescentiae troponin C shares 62.7-85.5% homology with troponin C from various arthropods. Sera from 5 of 47 subjects in our study group (10.6%) showed IgE binding to the recombinant protein. Interestingly, addition of 10 mM CaCl(2) increased the intensity of IgE binding approximately 2-fold. In an immune-inhibition ELISA with these sera, T. putrescetiae troponin C and Bla g 6 did not cross-react significantly. CONCLUSIONS: Troponin C is a new mite allergen with calcium-dependent IgE reactivity. PMID- 19786802 TI - Mast cells induce migration of dendritic cells in a murine model of acute allergic airway disease. AB - BACKGROUND: The migration of dendritic cells (DCs) from the lungs to the regional lymph nodes is necessary for the development of allergic airway disease. Following activation, mast cells release a variety of stored or de novo-produced inflammatory mediators, several of them being capable of activating DCs. In this study, the role of mast cells on DC migration from the lungs to the thoracic lymph nodes was investigated in sensitized mice. METHODS: Mast cell-deficient mice (Kit(W-sh/W-sh)) and their wild-type counterparts were sensitized intraperitoneally with ovalbumine (OVA) in saline and challenged by a single intranasal administration of OVA labeled with a fluorescent dye (OVA-Alexa). RESULTS: Following challenge, the relative and absolute amount of OVA- Alexa positive DCs was clearly increased in sensitized wild-type mice compared to nonsensitized mice. In contrast, sensitized Kit(W-sh/W-sh) showed no increase in OVA-Alexa-positive DCs compared to nonsensitized mast cell-deficient animals. In sensitized Kit(W-sh/W-sh) mice reconstituted with bone marrow-derived mast cells (BMMCs), the number of OVA- Alexa-positive DCs was comparable to that in sensitized wild-type animals. However, transfer of allergen-exposed BMMCs to sensitized mice prior to airway challenge augmented airway inflammation similarly in wild-type and mast cell-deficient mice. In line with this, sensitization with allergen-pulsed DCs induced allergic airway disease independently of mast cells. CONCLUSIONS: This study shows an interaction between mast cells and DCs following allergen challenge in sensitized hosts. However, the function of mast cells can be bypassed in models utilizing activated allergen-exposed DCs to initiate the development of allergic airway disease. PMID- 19786803 TI - Effects of industrial processing on the immunogenicity of commonly ingested fish species. AB - BACKGROUND: Food-processing techniques may induce changes in fish protein immunogenicity. Allergens from >100 fish species have been identified, but little is known on the effects of processing on fish protein immunogenicity. METHODS: IgE binding of sera of patients allergic to fresh and processed (smoked, salted/sugar-cured, canned, lye-treated and fermented) cod, haddock, salmon, trout, tuna, mackerel and herring and of hydrolysates based on salmon and whiting was investigated using immunoblot and inhibition ELISA. RESULTS: Parvalbumin oligomers were identified using monoclonal and polyclonal antibodies. IgE binding was seen in most sera at 12-14 kDa (parvalbumin), and at 17-60 kDa for all fish except tuna. Changes in IgE binding appeared to reflect altered parvalbumin monomers and oligomers. Smoked haddock, salmon and mackerel had increased IgE binding and novel bands at 30 kDa. Chemically processed cod, salmon, trout and pickled herring had reduced or abolished IgE binding. The serum of 1 subject, however, had increased IgE binding to these products and also inhibition of binding by both fish hydrolysates to their constituent fish species. CONCLUSION: Process-induced changes in fish protein immunogenicity were more dependent on process rather than species, although individual responses varied. Changes in the allergenicity of a product may depend on the net effect of processing on parvalbumin oligomerization patterns, which may also vary in different species. Chemical processes generally caused loss in IgE-binding activity, though sensitization may occur to modified or degraded rather than intact peptides as shown by increased binding by chemically processed fish and hydrolysates in 1 subject. The clinical significance of these findings remains to be established. PMID- 19786804 TI - The C-509T promoter polymorphism of the transforming growth factor beta-1 gene is associated with levels of total and specific IgE in a Colombian population. AB - BACKGROUND: The C-509T polymorphism of the transforming growth factor beta-1 (TGFB1) gene has been associated with asthma and asthma-related phenotypes, but its influence on total and specific IgE levels is controversial. OBJECTIVE: To investigate the association between C-509T and asthma, as well as total IgE and specific IgE against Blomia tropicalis and Dermatophagoides pteronyssinus, in a Colombian population. METHODS: The study population consisted of 417 asthmatics, 390 controls and 116 nuclear families. The C-509T polymorphism was genotyped using single-base extension minisequencing or Taq Man probes. IgE and TGFbeta1 levels were measured by ELISA. Regression analysis and family-based association tests were performed in cases/controls and families. Associations were corrected by population structure using a panel of 52 ancestry informative markers in the case-control dataset. RESULTS: There was no association between C-509T and asthma. In asthmatics, the CC genotype was associated with higher total IgE levels compared with the other genotypes [mean IgE: 2.81 +/- 0.42 vs. 2.71 +/- 0.45 log IU/ml; p = 0.016, corrected p value (p(c)) = 0.019]. When only atopic asthmatics were included, the significance remained (p = 0.02, p(c) = 0.03). In the family-based analyses, the C allele was associated with higher total IgE levels (p = 0.02) and the CC genotype with specific IgE to D. pteronyssinus (p = 0.01). CONCLUSIONS: C-509T is associated with total IgE levels and specific IgE to D. pteronyssinus in asthmatic patients. In contrast to other studies, we found the CC genotype to be associated with higher levels of total and specific IgE. Differences in the frequency of this allele among populations could alter its effects as a risk factor for asthma-associated phenotypes. PMID- 19786805 TI - Effects of inhaled corticosteroids on metalloproteinase-8 and tissue inhibitor of metalloproteinase-1 in the airways of asthmatic children. AB - BACKGROUND: The effects of corticosteroids on the level and expression of matrix metalloproteinase-8 (MMP-8; collagenase-2) and tissue inhibitors of metalloproteinases (TIMPs) in airway tissue are poorly characterized in vivo. METHODS: We compared MMP-8 and TIMP-1 levels in induced sputum and their expression in airway inflammatory cells of healthy children (n = 27) and of children with newly diagnosed asthma with mild (n = 20) or moderate symptoms (n = 19), before and after 6 months of treatment with inhaled budesonide. RESULTS: At baseline, MMP-8 was higher in asthmatic children with moderate symptoms, TIMP-1 was lower and the MMP-8/TIMP-1 ratio was higher in both groups of asthmatic children compared with controls. Inhaled budesonide increased TIMP-1 levels in both groups of asthmatic children and normalized the MMP-8/TIMP-1 ratio, and this paralleled the improvement in forced expiratory volume in 1 s in children with mild symptoms. At baseline, asthmatic children had significantly more MMP-8 positive macrophages than control children, whereas the number of TIMP-1-positive macrophages was almost the same. Budesonide decreased the percentage of MMP-8 positive macrophages and increased that of TIMP-1-positive macrophages; these changes were significant in asthmatic children with mild symptoms. CONCLUSIONS: Inhaled budesonide normalized the MMP-8/TIMP-1 ratio in asthmatic children by upregulation of TIMP-1 production and downregulation of MMP-8 production by airway macrophages. This change may be a biochemical marker of an effect on airway inflammation and possibly of an ongoing remodeling process that should be further investigated using biopsy specimens. PMID- 19786806 TI - Prevalence of allergic rhinitis and sensitization to common aeroallergens in a Japanese population. AB - BACKGROUND: Allergic rhinitis (AR) is recognized as a major health problem worldwide, and its prevalence depends on the age range of the subjects. The aims of this study were to determine the current prevalence of AR, effects of age on the prevalence of IgE sensitization to inhalant allergens, and serum total IgE levels in Japanese subjects. METHODS: We conducted a survey of 1,540 subjects between 20 and 49 years of age in 2006 and 2007 and examined the prevalence of AR and sensitization to 7 common aeroallergens. We measured serum total IgE and specific IgE to 7 aeroallergens. AR was determined based on symptoms, predominantly in the nose and eyes, caused by aeroallergens as mentioned in a questionnaire and sensitization to any of the 7 aeroallergens as assessed by measurement of serum specific IgE. RESULTS: The prevalence of AR was 44.2% (681 of the 1,540 subjects) and there was no difference among age decades. Of the 1,540 subjects, 1,073 (69.7%) were sensitized to at least 1 of the 7 aeroallergens. The most common allergen in AR was Japanese cedar pollen (89.6%, 610 of the 681 with AR) in all the age decades examined. The sensitization rate to mites was significantly higher in the younger subjects. CONCLUSION: Our data suggest that the prevalence of AR between 20 and 49 years of age has increased by nearly 10% during the last 10 years. Cedar pollen and mites were predominant allergen sources among the 7 aeroallergens in the Japanese population. PMID- 19786807 TI - Measurement of nasal airway resistance and response in mice. PMID- 19786808 TI - Under construction: classification of hepatitis B virus genotypes and subgenotypes. PMID- 19786809 TI - Cloning, expression, purification and characterization of UL24 partial protein of duck enteritis virus. AB - The UL24 gene of duck enteritis virus (DEV) is conserved across herpesviruses, but its protein characterization has not been reported. We expressed the UL24 gene in Escherichia coli BL21 from a recombinant plasmid pET32a/DEV-UL24 and used the resulting protein to raise antiserum. This antiserum recognized a 38-kDa protein in lysates from infected cells. SDS-PAGE analysis showed that the UL24 partial protein was highly expressed after induction by 0.4 mM IPTG at 30 degrees for 6 h. The results of purification revealed that expression protein was more purified using the method of electrophoresis than that of chromatography, but the yield was lower. In immunogenicity analysis, the protein could significantly elicit a specific antibody response in immunized ducklings when compared with the control groups, and the titers against expression protein reached the peak 1:5,120 (OD(450nm) = 2.5) on day 28 after immunization, while with mean titers of 1:10,240 (OD(450nm) = 3.37) in DEV commercial attenuated vaccine strain immunized duckling groups. It showed that expression protein is immunogenic in laboratory ducklings. On the basis of subcellular location, UL24 appeared to be predominantly nuclear membrane-associated, especially at later times in infection, and provided a good tool to further study the biofunctions of UL24 protein. PMID- 19786810 TI - Decreased neural stem/progenitor cell proliferation in mice with chronic/nonremitting experimental autoimmune encephalomyelitis. AB - It has been reported that autoimmune inflammatory processes in human multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), may induce an alteration in neurogenesis. Studies with transgenic EAE mice have demonstrated an enhancement of neurogenesis in the subventricular zone (SVZ). In contrast, a reduction of stem cell proliferation in the same region has been observed by Pluchino et al. [Brain 2008;131:2564-2578] in myelin oligodendrocyte glycoprotein (MOG)-induced EAE mice. We immunized female C57BL/6 mice with MOG 35-55 peptide and successfully developed chronic/nonremitting EAE, which is believed to be analogous to the progressive form of MS. On day 21 postimmunization, coronal brain sections were collected and stained with anti-5 bromo-2'-deoxyuridine (BrdU) antibody. By counting the number of BrdU-labeled cells, we demonstrated that the neural stem/progenitor cell (NSC/NPC) proliferation decreased in the SVZ, which basically confirms the study of Pluchino et al. on the changes in the SVZ. A reduction of NSC/NPC proliferation also occurred in the hippocampal subgranular zone of the dentate gyrus. The hippocampus is well known to be an important region involved in learning and memory; thus, our finding may offer a possible explanation for the cognitive impairment in human chronic MS. PMID- 19786811 TI - Ligand-dependent activation of the chimeric tumor necrosis factor receptor amyloid precursor protein (APP) reveals increased APP processing and suppressed neuronal differentiation. AB - The beta-amyloid precursor protein (APP) is a type I transmembrane protein whose functions and metabolic processing have been implicated in the pathogenesis of Alzheimer's disease (AD). APP's physical resemblance as a glycosylated receptor and the presence of several conserved motifs which are characteristics of a membrane-associated receptor has prompted interest to study and understand the role of downstream signaling events mediated by the activation of APP during both physiological and pathological conditions. Efforts to elucidate the mechanisms of APP signaling have not been conclusive. In order to further characterize the intracellular signaling activities of APP, we have constructed a chimeric APP receptor which is made up of the extracellular domain of human tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B), the membrane-spanning segment of human APP(770) isoform's beta-cleaved carboxyl-terminal fragment (C99), and the green fluorescent protein (GFP) tagged to the carboxyl-terminus of C99. The mammalian rat pheochromocytoma (PC12) cell line is used as the cellular model for transfection of this TNFRSF1B-APP-GFP (TAF) fusion receptor. Ligand-specific stimulation of this TAF receptor using human recombinant TNF reveals the induction of cytoplasmic TAF phosphorylation on Thr743 (numbering for APP(770) isoform) and an elevated release of APP intracellular domains (AICDs). Time-lapse microscopy shows the trafficking of GFP-tagged AICDs into the nucleus upon TAF receptor activation. The increased presence of AICDs is believed to suppress neuronal differentiation of PC12 cells in response to nerve growth factor treatment, by negatively regulating the levels of p53, cyclin D1 and phosphorylation of the signal transducer and activator of transcription STAT3. PMID- 19786812 TI - [10 years of the Working Group for Geriatric Oncology of the DGHO/DGG/AIO]. PMID- 19786813 TI - [Political impact of demographic change in Germany. A summary view of the causes and consequences of demographic change in Germany and Europe]. AB - In Germany, the increase of life expectancy and the rapid decline of fertility started in the 19th century. The decline of the total fertility rate accelerated since the last decade of the 19th century when the social security system was established in the framework of the social reforms introduced by Bismarck. The process of population change is still going on. Its main demographic dimensions are demographic ageing, population decline, and the internationalisation of the population process by in-migration. The societal consequences are conflicts between the old and young generations as well as conflicts within each generation between the population groups with and without children. The economic impact of demographic change is a reduction of wealth, caused by a lower growth rate of the national product and by a reduction of the growth rate of the per capita income. PMID- 19786814 TI - [Care requirements for elderly cancer patients]. AB - The oncology care system is insufficiently directed to the treatment situation of elderly tumour patients. There is a lack of specific studies focusing on the application and effects of antineoplastic substances in elderly patients to forward the utilisation of all available therapeutical options. The reality of care of elderly patients, especially elderly women, is marked by problems of access to the treatment opportunities. Questions of social support have to be raised. A specialised geriatric assessment in oncology can improve diagnostic preconditions in the treatment of the elderly. Restrictions of activities of daily living, comorbidities, cognitive handicaps, and malnutrition are to be surveyed among all patients > 70 years of age. Studies for the systematic involvement of assessments in the treatment routine are necessary. The cooperation of geriatricians and oncologists has to become a more routine process to work out diagnosis and treatment standards for elderly cancer patients. The oncology care system has to meet the challenge of providing adequate care which links specialised tumour treatment with palliative care, especially for elderly patients with advanced tumour diseases. PMID- 19786815 TI - [Registries and clinical trials in geriatric oncology in Germany]. AB - Regardless of the fact that elderly cancer patients in Germany are more and more recognized as a cohort with special characteristics and potentially specific needs, there is a lack of sound data from clinical trials that could guide the care of this population. This article addresses the issue of underrepresentation of elderly patients in trials and points out why this is not only a missed chance to gain knowledge but also hampers the care of a group that in many cancer entities presents the majority of patients. Finally, an overview of current clinical trials and registries in Germany is presented. PMID- 19786816 TI - [The geriatric assessment]. AB - Due to demographic changes there is an increasing number of elderly and old patients with cancer. This group of patients shows a significant heterogeneity and differs from the average young patient. Identification of relevant functional deficits and comorbidities remains crucial for an efficient treatment strategy of this patient group. For this reason, the geriatric assessment has been developed and integrated in daily oncological practice. Within this diagnostic approach oncologists can for example identify elderly fit patients suitable for aggressive treatments or identify at-risk patients for complications. Recent studies have shown that this approach is feasible in daily practice and capable of improving outcome. There is still the need for more specific instruments for different cancers. PMID- 19786817 TI - [Special considerations in chemo- and radiotherapy and supportive care of elderly patients with cancer]. AB - Differences in tumorbiology and age-associated changes, such as an impaired functional status and the presence of comorbidities, can result in treatment decisions differing from established standards, as standard treatments have often been established through clinical trials mainly including younger patients. Neither therapeutic nihilism due to advanced age nor treatment according to established standards at all costs is the optimal treatment for elderly patients. This article summarizes recently published data regarding the treatment of elderly patients according to main tumor types. PMID- 19786818 TI - [Quality of life and ethics as basic questions in geriatric oncology]. AB - Optimal care for elderly cancer patients requires empathy and alertness about impaired autonomy and an exceptional quality of care. Specific to geriatric oncology is the particular need of attention and care for the patients. Most important from a conceptual point of view is to identify that this will result in additional demands. To care for these patients will require more time as any intervention must be adapted to age specific capabilities. The difficult task of shared decision-making should be preferably based on the quality of life assessment of the individual patient and their needs. The process of assessing quality of life is in itself already an act of enhancing autonomy, because it respects the individual's subjectivity. Many ethical questions arise between the contradictory contexts of paternalism and autonomy. There are conditions to be met and limits of autonomy to be considered, which differ for the elderly patients because of their vulnerability and particular dependencies. As the elderly patient is closer to death and dying, questions of care in these situations are frequently more pressing. It is important to distinguish actively intended euthanasia from the goals and concerns of modern palliative care in order to enable dying with dignity. PMID- 19786819 TI - [[Cancer and aging--biological mechanisms]. AB - Aging is the major risk factor for the development of cancer. An understanding of the molecular mechanisms that induce cancer formation during aging could help to develop cancer prevention strategies and improve cancer screening in the elderly. On the cellular level, it is of utmost importance to decipher molecular alterations leading to dysfunction and transformation of adult stem cells, since there is growing evidence that stem cells acquire the initial lesions that ultimately lead to cancer formation. On the molecular level, the accumulation of DNA damage and chromosomal instability represents a hallmark feature of cancer development in aged tissues. Different mechanisms can contribute to an accumulation of DNA damage and chromosomal instability during aging, including (i) telomere shortening, (ii) a reduction in DNA repair capacity, and (iii) the declining function of checkpoints (e. g. senescence, apoptosis). In addition, alterations in the cell environment can increase the selection of (pre-)malignant clones in aging tissues, involving (i) the loss of proliferative competition of non-transformed organ cells, (ii) the aberrant production of cytokines and growth factors, (iii) an impaired immune surveillance. In this review, we summarize experimental data on the functional role of these different mechanisms increasing the cancer risk during tissue aging. PMID- 19786820 TI - Technique and results of the anterior-to-posterior-to-anterior approach in revision endoscopic sinus surgery. AB - OBJECTIVE: To perform the anterior-to-posterior-to-anterior technique in revision endoscopic sinus surgery, and to assess the effects and safety of this technique in treating recurrent chronic sinusitis and nasal polyps. METHODS: One hundred and thirteen patients with recurrent chronic sinusitis and nasal polyps received anterior-to-posterior-to-anterior revision endoscopic sinus surgery. This surgical technique has 5 important steps, including exposing the choana, enlarging the maxillary sinus ostium, opening the sphenoid sinus and posterior ethmoid sinus anteriorly to posteriorly, resecting the ethmoid sinus posteriorly to anteriorly, and opening the frontal sinus posteriorly to anteriorly. The choana, maxillary sinus ostium, middle turbinate remnant, and the roof and lateral wall of the sphenoid sinus are 4 stable anatomic reference points. RESULTS: Twelve months postoperatively, the mean SNOT-22 score had improved by 18.48 and 100 (88.50%) patients had an improvement in nasal obstruction; thick nasal discharge, loss of smell or taste, and facial pain/pressure improvements were noted in 102 (90.27%), 64 (56.64%) and 76 (67.26%) patients, respectively. Postoperative endoscopic evaluation after 12 months indicated that 29 (25.66%), 12 (10.62%), 5 (4.42%), 6 (5.31%), and 2 (1.77%) patients had mucosal edema, nasal discharge, synechiae, polyps, and crusting, respectively. No severe complications were observed. CONCLUSION: The anterior-to-posterior-to-anterior technique is an effective and safe approach to revision endoscopic sinus surgery. The 4 stable anatomic reference points are helpful for preventing severe complications in total ethmoidectomy. PMID- 19786821 TI - Tetracycline actions relevant to rosacea treatment. AB - Until today, the pathogenesis of rosacea is not known in detail. Yet in recent years evidence has been accumulating that rosacea with its common symptoms such as inflammatory lesions, erythema, telangiectasia, phymatous changes, and ocular symptoms is of inflammatory nature. Tetracycline derivatives like doxycycline successfully used in the treatment of skin diseases like acne and rosacea seem to inhibit different inflammatory pathways involved in the pathogenesis by various modes of action. Although data for skin diseases are relatively scanty, the following modes of action of tetracyclines seem to be most relevant for an effective treatment of acne and rosacea: inhibition of matrix metalloproteinases, downmodulation of cytokines, inhibition of cell movement and proliferation, inhibition of granuloma formation, inhibition of reactive oxygen species, nitric oxide, and angiogenesis, whereas inhibition of phospholipase A2 seems to be of lower importance. The role of the saprophytic mite Demodex folliculorum remains to be clarified. Additional studies are necessary to further elucidate how tetracyclines work in rosacea treatment. PMID- 19786822 TI - Stratum corneum damage and ex vivo porcine skin water absorption - a pilot study. AB - A simple ex vivo screening technique would be of interest for mass screening of substances for potential barrier disruptive qualities. Ex vivo water absorption as a marker of skin barrier integrity was studied on pig ear skin. Skin water absorption was quantified by weighing and weight changes were found to reflect prehydration barrier damage. It is suggested that this simple model may be elaborated to provide a rapid, economical screening tool for potential skin irritants. PMID- 19786823 TI - Skin penetration of epigallocatechin-3-gallate and quercetin from green tea and Ginkgo biloba extracts vehiculated in cosmetic formulations. AB - Green tea (Camellia sinensis) and Ginkgo biloba extracts in cosmetic formulations have been suggested to protect the skin against UV-induced damage and skin ageing. Thus, it is very important to assess the human skin penetration of their major flavonoids to verify if they penetrate and remain in the skin to exert their proposed effects. The aim of this study was to evaluate the human skin penetration of epigallocatechin-3-gallate (EGCG) and quercetin from green tea and G. biloba extracts vehiculated in cosmetic formulations. This study was conducted with fresh dermatomed human Caucasian skin from abdominal surgery mounted on static Franz diffusion cells. Skin samples were mounted between two diffusion half-cells and 10 mg/cm(2) of formulations supplemented with 6% of green tea or G. biloba extract were applied on the skin surface. The receptor fluid was removed after 6 and 24 h and analyzed by high-performance liquid chromatography for the quantification of the flavonoids. The stratum corneum was removed by tape stripping and immersed in methanol and the epidermis was mechanically separated from the dermis and triturated in methanol to extract EGCG and quercetin. The results showed that the flavonoids under study penetrated into the skin, without reaching the receptor fluid. The majority of EGCG was quantified in the stratum corneum (0.87 microg/cm(2)), which was statistically higher than the EGCG concentrations found in viable epidermis (0.54 microg/cm(2)) and in the dermis (0.38 microg/cm(2)). The majority of quercetin was quantified in the viable epidermis (0.23 microg/cm(2)), which was statistically higher than the EGCG concentration found in the stratum corneum layer (0.17 microg/cm(2)). Finally, it can be concluded that EGCG and quercetin from green tea and G. biloba extracts vehiculated in cosmetic formulations presented good skin penetration and retention, which can favor their skin effects. PMID- 19786824 TI - Acrylamide, acrylic acid and N-isopropylacrylamide hydrogels as osmotic tissue expanders. AB - BACKGROUND AND AIM: Osmotically active tissue expanders allow the harvesting of soft tissue for reconstruction after different injuries. However, their expansion properties could be improved. Thus, our goal was to examine the in vivo applicability of acrylamide (AAm), acrylic acid (AAc) and N- isopropylacrylamide (NIPAAm) hydrogels. MATERIALS AND METHODS: Cylinders of AAm, AAc and NIPAAm hydrogels were implanted under the skin of rats in the dorsal region. The diameter and the length of the cylinders were measured daily. After removal of the hydrogels, their mass and rheological properties were determined. Further, biopsies were taken from the adjacent tissue for histological analysis. RESULTS: The hydrogels reached the peak of swelling by the end of the 2nd postoperative week. The wet mass of the removed cylinders was 25 times their dry mass prior to implantation. NIPAAm polymers exhibited the most favourable visco-elastic properties, with the highest tendency to retain their preformed shape. The histological analysis revealed serious tissue damage when the AAc devices were used, whereas the AAm and NIPAAm did not result in such lesions. CONCLUSION: In view of its mechanical and biological properties, NIPAAm hydrogel seems to be the most appropriate of these materials for application in plastic and reconstructive surgery. PMID- 19786825 TI - Reproducibility of cutaneous microvascular function assessment using laser Doppler flowmetry and acetylcholine iontophoresis. AB - AIM: To investigate the reproducibility of direct and axon-reflex vasodilator responses to increasing doses of acetylcholine administered transcutaneously by iontophoresis. METHODS: Increasing doses of acetylcholine ions were introduced into the skin of the volar forearm with weak electric currents. The elicited vasodilatation was measured with laser Doppler flowmetry at the direct site of acetylcholine administration and approximately 5 mm from this site (within the distribution of axon-reflex vasodilatation). To investigate the reproducibility of these measures, iontophoresis was carried out twice at one site after a 50 min interval and once at another site on the forearm of 16 healthy females. Raw scores and data expressed as percentages of baseline, maximum, and response to heating were analysed to determine the most reliable form. RESULTS: The dose response curve was significantly greater at the upper site on the forearm than at the lower site for direct vasodilator responses, but did not differ between the upper and lower forearm for axon-reflex responses. The various forms of data expression yielded weak to moderate correlations for vasodilatation between sites, and moderate to strong correlations when the iontophoresis was repeated at the same site. Direct responses were most reproducible when expressed in proportion to levels recorded after 5-6 min of local 42 degrees C heating (percentage of shared variance was 54.6% within sites and 61.0% between sites). CONCLUSION: Cutaneous vasodilatation to acetylcholine iontophoresis is reproducible over time at a single site but varies across sites. This will allow future research to assess microvascular function before and after a laboratory manipulation in a single session. PMID- 19786826 TI - New and experimental skin-directed therapies for cutaneous lymphomas. AB - Primary cutaneous lymphomas (CLs) originate in the skin and should be differentiated from secondary skin infiltrates, which are manifestations of lymphomas of nodal or extranodal origin. These rare diseases include various lymphoproliferative disorders: cutaneous T-cell lymphomas, cutaneous B-cell lymphomas and some rare subtypes. As definitive cure is often not possible, it is important to control the disease and alleviate symptoms. Patients with early stage disease limited to the skin usually require skin-directed therapies using topical agents including corticosteroids, chemotherapeutic drugs, bexarotene gel, electron beam therapy and phototherapy. Each of these are effective; however, all have some disadvantages and are associated with significant adverse events. In the field of skin-directed therapies there are interesting developments using antineoplastic compounds, the retinoid tazarotene, imiquimod, gene therapy products (adenovirus vector expressing gamma-interferon), the monoclonal anti CD20 antibody rituximab, photodynamic therapy and 308-nm excimer laser to mention a few. This review highlights some of the promising new and experimental local therapies for primary CLs and focuses on their efficacy and side effects. PMID- 19786827 TI - Processing of high-molecular-weight form adrenocorticotropin in human adrenocorticotropin-secreting tumor cell line (DMS-79) after transfection of prohormone convertase 1/3 gene. AB - Ectopic ACTH-producing tumors preferentially secrete biologically inactive ACTH precursors and ACTH-related fragments. DMS-79 is known to secrete unprocessed high-molecular-weight (HMW) form ACTH. To determine whether prohormone convertase (PC) 1/3 is involved in the abnormal processing of proopiomelanocortin (POMC), we studied whether PC1/3 and 2 genes are expressed in DMS-79, and whether overexpression of PC1/3 gene affects POMC processing pattern. Steady-state mRNA levels of PC1/3 and 2 were determined by real-time RT-PCR. Molecular weights of ACTH-related peptides were determined by chromatographical analyses coupled with ACTH and beta-endorphin (beta-END) radioimmunoassays. PC1/3 gene was transfected into DMS-79 by retrovirus transduction using pMX-IP vector encoding PC1/3 cDNA. The steady-state mRNA levels of PC1/3 and 2 in DMS-79 were lower than those in ACTH-secreting and nonfunctioning pituitary tumors. DMS-79 predominantly secreted HMW form with both ACTH and beta-END immunoreactivities by size-exclusion chromatography. After purification by immunoaffinity chromatography with anti ACTH antibody, the apparent molecular weight of HMW form ACTH was estimated to be 16 kDa by sodium dodecyl sulfate-polyacrylamide gel electrophoresis with silver staining. After retroviral transfection of PC1/3 cDNA into DMS-79 and puromycin selection, PC1/3 stably-expressing cell line (DMS-79T) secreted two immunoreactive ACTH components, a major one coeluting with ACTH(1-39) and a minor one as a HMW form as well as two beta- END immunoreactive components coeluting with beta-lipotropic hormone and beta-END, respectively. Thus, we have established PC1/3 stably-expressing cell line (DMS-79T) capable of proteolytically processing ACTH precursor molecule(s) into mature ACTH and beta END. PMID- 19786828 TI - Protective role of cisplatin in ischemic liver injury through induction of autophagy. AB - High mobility group box 1 (HMGB1) is a nuclear protein released from stressed or damaged cells that activates inflammatory cascades involved in the pathogenesis of liver ischemia reperfusion (I/R) injury. In efforts to develop strategies aimed at preventing its release from ischemic cells following I/R, we studied the use of cisplatin, a member of the platinating chemotherapeutic agents capable of inducing DNA lesions that have high binding affinities for high mobility group proteins inside the nucleus of cells. In addition to demonstrating that cisplatin prevents liver damage associated with liver I/R by sequestering HMGB1 inside the nucleus of ischemic cells, cisplatin also alters cell survival signaling through autophagy. Our results provide a potential approach involving the use of platinating agents and their effects on autophagy in mitigating the deleterious effects of ischemia reperfusion-mediated disease processes. PMID- 19786829 TI - Mitochondrial autophagy as a compensatory response to PINK1 deficiency. AB - Macroautophagy (hereafter, autophagy) plays a critical role in maintaining cellular homeostasis by degrading protein aggregates and dysfunctional/damaged organelles. We recently reported that silencing the recessive familial Parkinson disease gene encoding PTEN-induced kinase 1 (PINK1) leads to neuronal cell death accompanied by mitochondrial dysfunction and Drp1-dependent fragmentation. In this model, mitochondrial fission and Beclin 1-dependent autophagy play protective roles, cooperating to sequester and eliminate damaged mitochondria. We discuss the role of superoxide and other reactive oxygen species upstream of mitochondrial depolarization, fission and autophagy in PINK1 knockdown lines. PINK1 deficiency appears to trigger several compensatory responses that together facilitate clearance of depolarized mitochondria, through a mechanism that is further enhanced by increased expression of parkin. These data offer additional insights that broaden the spectrum of potential interactions between PINK1 and parkin with respect to the regulation of mitochondrial homeostasis and mitophagy. PMID- 19786830 TI - Stretching the timescale of intravital imaging in tumors. AB - Since the time it was pioneered in 1992, intravital imaging of tumors at cellular resolution has offered us the extremely important opportunity of "seeing biology." However, until now, most studies were monitoring tumor cell behavior in the same animal over short times, requiring the combining of acquired data into a hypothesis via statistical analysis. In the last year, different groups have independently developed techniques to extend the time scale of intravital imaging to several days. This improvement allows one to address the connection between tumor cell behavior and the microenvironment which surrounds them. We can now assess dynamics of the cell-cell interactions in tumors, analyze tumor cell fate and changes in the tumor extracellular matrix which accompany tumor progression. PMID- 19786831 TI - Autophagy-mediated chemosensitization in cancer cells by fullerene C60 nanocrystal. AB - Autophagy may represent a common cellular response to nanomaterials, and modulation of autophagy holds great promise for improving the efficacy of cancer therapy. Fullerene C60 possesses potent anti-cancer activities, but its considerable toxicity towards normal cells may hinder its practical applications. It has been reported that fullerene C60 induces certain hallmarks of autophagy in cancer cells. Here we show that the water-dispersed nanocrystal of underivatized fullerene C60 (Nano-C60) at noncytotoxic concentrations caused authentic autophagy and sensitized chemotherapeutic killing of both normal and drug resistant cancer cells in a reactive oxygen species (ROS)-dependent and photo enhanced fashion. We further demonstrated that the chemosensitization effect of Nano-C60 was autophagy-mediated and required a functional Atg5, a key gene in the autophagy signaling pathway. Our results revealed a novel biological function for Nano-C60 in enhancing the cytotoxic action of chemotherapeutic agents through autophagy modulation and may point to the potential application of Nano-C60 in adjunct chemotherapy. PMID- 19786832 TI - Hypoxia-induced autophagy contributes to the chemoresistance of hepatocellular carcinoma cells. AB - Hypoxia commonly exists in solid tumors. Under such adverse conditions, adaptive responses including autophagy are usually provoked to promote cell survival. In our study, autophagy, a lysosomal-mediated degradation pathway, is demonstrated as a protective way to make hepatocellular carcinoma cells resistant to chemotherapy under hypoxia. Compared with normoxia, chemotherapeutic agent induced cell death under hypoxia was significantly decreased, as a result of the reduced apoptosis. However, when autophagy was inhibited by 3-MA or siRNA targeted Beclin 1, this reduction was reversed, i.e., chemoresistance was attenuated, which means autophagy mediates the chemoresistance under hypoxia. In conclusion, autophagy decreases hepatoma cells sensitization to chemotherapeutic agents by affecting their apoptotic potential. PMID- 19786833 TI - Dnmt3/transcription factor interactions as crucial players in targeted DNA methylation. AB - Epigenetic gene inactivation in mammalian cells involves many silencing mechanisms. One of these mechanisms is the transcriptional repression by targeted promoter hypermethylation. However, the molecular mechanisms involved in the site specific DNA (hyper)methylation are not fully elucidate. By using the Dnmt3a/c myc interaction as an example, we here showed that this interaction promotes the site-specific methylation of CG dinucleotides localized in c-myc boxes of promoter regions of CDKN2a, CCND1 and TIMP2 genes. Indeed, the invalidation of c myc reveals that c-myc allows the Dnmt3a recruitment on c-myc box of c-myc regulated genes. Acellular experiments corroborated and complemented these results by revealing that the specificity of consensus sequence for DNA methylation of Dnmt3a is increased in presence of c-myc. Indeed, our work indicates that Dnmt3a and Dnmt3b have consensus sequences to methylate DNA (T/A/C)(A/T)(T/G/A)CG(T/G/C)G(G/C/A) and (A/C)(C/G/A)(A/G)CGT(C/G)(A/G). Thus, the low specificity of these sequences (consensual for 162 and 48 possibilities, respectively) does not support the idea of targeted DNA methylation. By monitoring transcription factor arrays spotted with 103 transcription factors, we next identified 42 transcription factors interacting with Dnmt3a and Dnmt3b (such as CREB and FOS), 27 transcription factors interacting with Dnmt3a (such as AP2alpha and p53), 10 transcription factors interacting with Dnmt3b (such as SP1 and SP4) and 24 transcription factors devoid of direct interaction with Dnm3a and Dnmt3b (such as C/EBPalpha and NFkappaB-p65). Thus, The description of direct interaction between Dnmt3a and/or Dnmt3b and transcription factors provides rational molecular explanation to the mechanisms of targeted DNA (hyper)methylation, and to the mechanisms by which transcription factors repress genes expression. PMID- 19786834 TI - Methylation analysis of the imprinted DLK1-GTL2 domain supports the random parental origin of the IGH-involving del(14q) in B-cell malignancies. AB - Leukemias/lymphomas with IGH-involving del(14q)(1) commonly lose the DLK1-GTL2 imprinted domain that comprises several paternally and maternally expressed genes, including a cluster of microRNAs. Given that deletion of this region could lead to inactivation of a monoallelically expressed tumor suppressor gene, our study aimed at determination of the parental origin of del(14q/IGH). The designed allele-specific methylation study of the DLK1/GTL2 intergenic differentially methylated region allowed us to determine the parental origin of del(14q/IGH) in 9/20 analyzed cases. In six cases del(14q/IGH) was of the paternal origin and in three cases of the maternal origin. These findings argue against the concept that a TSG/anti-oncomir located in the imprinted region is systematically inactivated by a targeted deletion of its functional allele. PMID- 19786835 TI - Autophagy is an important event for megakaryocytic differentiation of the chronic myelogenous leukemia K562 cell line. AB - Autophagy is a highly conserved catabolic process for the elimination and recycling of organelles and macromolecules, characterized by the formation of double-membrane vesicles called autophagosomes. To date, the function of autophagy in cell differentiation is poorly documented. Here, we investigated the possibility that megakaryocytic differentiation of the Chronic Myelogenous Leukemia (CML) cell line K562, a process known to be accompanied by accumulation of vacuoles inside the cells, might involve autophagy. Using various complementary approaches, we show that the combination of the phorbol ester PMA and the p38(MAPK) inhibitor SB202190 (SB), which engaged a majority of K562 cells towards the megakaryocytic lineage, also triggered vacuolization and autophagy. The combination of PMA + SB appears to induce both increase in autophagic fluxes and an autophagic degradation blockage. Induction of autophagy was accompanied also by increased expression of Beclin 1 and p62/SQSTM1 and was found to precede the onset of megakaryocytic differentiation. Moreover, knockdown of LC3 and Beclin 1 by specific siRNAs impaired PMA + SB-mediated vacuolization, LC3-II accumulation and megakaryocytic differentiation, as well. To the best of our knowledge, this is the first description that induction of autophagy is involved in megakaryocytic differentiation of K562 CML cells. PMID- 19786836 TI - Investigating repetitively matching short sequencing reads: the enigmatic nature of H3K9me3. AB - Most histone modifications can easily be characterized as either activating or repressive. For example, histone3, lysine 4 trimethylation (H3K4me3) is generally considered a distinct sign of actively transcribed promoters while H3K27me3 is generally found at repressed genes. This is not the case for H3K9me3, the subject of this communication, which is a modification that has traditionally been considered a mark of constitutive heterochromatin, but has also been found in significant levels in expressed genes. We therefore sought to use new high throughput genome-wide maps of H3K9me3 localization to investigate the conflicting hypotheses concerning the nature of this modification. Before we could accurately analyze the locations of H3K9me3 along the genome, and especially in repetitive locations, we developed a method for accurately utilizing short sequencing reads that do not map uniquely to a location in the genome. Investigating the locations of H3K9me3 along the genome allowed us to determine that, while there are high levels of H3K9me3 outside of genes, this modification is not absent from genes. Therefore, we suggest that H3K9me3 may have a role in chromatin organization rather than being directly related to gene expression. In addition, we have found that there is a need to include repetitively matching reads in any high-throughput sequencing experiment. PMID- 19786837 TI - Diverse signaling mechanisms mediate volatile odorant detection in Drosophila. AB - Insects have extraordinary sensitivity to volatile odorants. In the case of pheromone reception, sensitivity approaches the single molecule detection limit. The mystery of how insects detect volatile odorants has intrigued researchers for more than a century, but only recently have the molecular underpinnings been uncovered. In this review we summarize recent work that reveals multiple signaling mechanisms utilizing several distinct receptor families underlie olfaction in Drosophila. Some of these mechanisms have not been observed in other animals, suggesting they evolved relatively late along an evolutionary branch that ultimately gave rise to the insects. PMID- 19786838 TI - Searching for guidance cues: follow the Sidestep trail. AB - Neuronal growth cones migrate along stereotypic pathways to find and select their correct targets. Although it is widely believed that attractive and repulsive guidance molecules provide directional cues for migrating growth cones, it is still only poorly understood how these factors cooperate in a spatial and temporal manner. We have recently proposed that Drosophila motor axons recognize and follow a Sidestep-labeled substrate pathway from the ventral nerve cord to their peripheral target muscles. Sidestep (Side) is a transmembrane protein of the immunoglobulin superfamily and functions as a target-derived attractant. On motor axons, Beaten path Ia (Beat) is required to detect Side. In addition, Beat interacts with Side both genetically and biochemically, leading to the formation of heterophilic adhesion complexes in vitro. Since Side is expressed in sensory neurons, Beat-expressing motor axons fasciculate with sensory axons and use them as migratory substrates. In a similar process, motor axons contact a subset of Side-expressing glial cells, demonstrating that, during the period of axonal pathfinding, motor axons interact with all cell types that later will be the major constituents of peripheral nerves. Here, I discuss the idea that Sidestep mediated attraction might represent the initial step for the controlled assembly of peripheral nerves. PMID- 19786839 TI - Is new always better than old?: The development of human vaccines for anthrax. AB - Anthrax is caused by a Gram-positive aerobic spore-forming bacillus called Bacillus anthracis. Although primarily a disease of animals, it can also infect man, sometimes with fatal consequences. As a result of concerns over the illicit use of this organism, considerable effort is focused on the development of therapies capable of conferring protection against anthrax. while effective concerns over the toxicity of the current vaccines have driven the development of second-generation products. Recombinant Protective Antigen (rPA), the nontoxic cell-binding component of anthrax lethal toxin, is the principal immunogen of the vaccines currently undergoing human clinical trials. While these new vaccines are likely to show reduced side effects they will still require multiple needle based dosing and the inclusion of the adjuvant alum which will make them expensive to administer and stockpile. To address these issues, researchers are seeking to develop vaccine formulations capable of stimulating rapid protection following needle-free injection which are stable at room temperature to facilitate stockpiling and mass vaccination programs. Recent concerns over the potential use of molecular biology to engineer vaccine resistant strains has prompted investigators to identify additional vaccine targets with which to extend the spectrum of protection conferred by rPA. While the injection of research dollars has seen a dramatic expansion of the anthrax vaccine field it is sobering to remember that work to develop the current second generation vaccines began around the time of the first gulf war. Almost two decades and millions of dollars later we still do not have a replacement vaccine and even when we do some argue that the spectrum of protection that it confers will not be as broad as the vaccine it replaces. If we are to respond effectively to emerging biological threats we need to develop processes that generate protective vaccines in a meaningful time frame and yield products in months not decades! PMID- 19786840 TI - Attenuated poxvirus vectors MVA and NYVAC as promising vaccine candidates against HIV/AIDS. AB - As yet, the only human infectious disease eradicated from our planet is smallpox, caused by variola virus a member of the poxvirus family. The vaccination success, with the declaration by WHO in 1980 of a worldwide free of smallpox, was largely due to the availability of a quite effective and stable live vaccine, as well as the restricted human host for virus infection. Variola was considered one of the most devastating diseases of human mankind. With the sudden appearance of the HIV/AIDS in 1981, an infection which spread rapidly to become a pandemic in a short time, causing up to date more than 22 million deaths, about 40 million people infected and a current incidence of about 3 million deaths per year, this dreadful pandemic has become one of the most severe diseases in the World, specially in poor countries. While different antiviral drugs have been developed that block virus replication at various stages of infection, however the rapid virus escape that follows during the drug therapy due to mutations, makes the development of vaccines the most secure option to control and eradicate the disease. Numerous vaccines have been developed, but to date the clinical trials have failed to show any efficacy against HIV infection. Due to the proven success of vaccinia virus in the control of smallpox as well as of poxvirus recombinants against veterinary diseases, a major effort has been directed to document the advantages of poxvirus vectors as vaccines against multiple diseases. Two of the most promising poxvirus vectors are the highly attenuated modified vaccinia virus Ankara (MVA) and the modified Copenhagen strain NYVAC. In this commentary I describe the biological characteristics of the attenuated poxvirus vectors, MVA and NYVAC, with emphasis in their application in HIV preclinical and clinical trials, and considerations as future HIV vaccines. PMID- 19786841 TI - Why is a protective antigen protective? AB - One of the major challenges in vaccine development is the identification of microbial components that give rise to a protective immune response. Over the last decade, genome and proteome-based methods have proven successful in discovering new vaccine candidates for many pathogens through the selection of secreted or surface-exposed protein antigens and their screening in proper biological assays. However, these approaches still require intensive research activities to single out, among the large number of secreted and surface exposed proteins those very few which are protective. The question of which structural properties render an antigen capable of eliciting the production of functional remains most challenging. In such scientific and methodological context, the EU funded project BacAbs was set up in 2007 with the main objective of developing a knowledge-based protocol able to discern protective from non-protective protein antigens, based on their amino acid sequences and molecular properties. The successful BacAbs multidisciplinary approach is highlighted by the recent analysis of three antigens from two diverse pathogens. Here, we describe the work and results carried out so far by the BacAbs Consortium, and discuss its relevance with regards to accelerating antigen selection processes and state-of the-art vaccine development. PMID- 19786842 TI - Plague vaccines and the molecular basis of immunity against Yersinia pestis. AB - Yersinia pestis is the causative agent of bubonic and pneumonic plague, human diseases with high mortality. Due to the microbe's ability to spread rapidly, plague epidemics present a serious public health threat. A search for prophylactic measures was initially based on historical reports of bubonic plague survivors and their apparent immunity. Due to safety and efficacy concerns, killed whole-cell preparations or live-attenuated plague vaccines are no longer considered in the United States. Vaccine developers have focused on specific subunits of plague bacteria. LcrV, a protein at the tip of type III secretion needles, and F1, the capsular pilus antigen, are both recognized as plague protective antigens. Antibodies against LcrV and F1 interfere with Y. pestis type III injection of host cells. While LcrV is absolutely essential for Y. pestis virulence, expression of F1 is dispensable for plague pathogenesis in small animals, non-human primates and presumably also in humans. Several subunit vaccines, for example rF1+rV (rYP002), rF1V or rV10, are being developed to generate plague protection in humans. Efficacy testing and licensure for human use requires the establishment of correlates for plague immunity. PMID- 19786843 TI - The role of the prion protein membrane anchor in prion infection. AB - Normal cellular and abnormal disease-associated forms of prion protein (PrP) contain a C-terminal glycophosphatidyl-inositol (GPI) membrane anchor. The importance of the GPI membrane anchor in prion diseases is unclear but there are data to suggest that it both is and is not required for abnormal prion protein formation and prion infection. Utilizing an in vitro model of prion infection we have recently demonstrated that, while the GPI anchor is not essential for the formation of abnormal prion protein in a cell, it is necessary for the establishment of persistent prion infection. In combination with previously published data, our results suggest that GPI anchored PrP is important in the amplification and spread of prion infectivity from cell to cell. PMID- 19786845 TI - Inpatient admissions and outpatient visits in persons with and without HIV infection in Denmark, 1995-2007. AB - OBJECTIVE: HAART has changed morbidity and mortality in the HIV-infected population dramatically. We aimed to estimate the use of healthcare facilities in HIV-infected patients after the introduction of HAART. DESIGN: This is a prospective nationwide cohort study. METHODS: We identified all Danish HIV patients and a cohort of population controls matched on sex and date of birth. The study period was 1995-2007. We calculated inpatient admission rates and outpatient visit rates stratified by medical speciality and International Classification of Diseases-10 diagnose categories. Relative risks were computed. RESULTS: Four thousand, seven hundred and sixty HIV-infected patients and 23 800 population controls were identified. Overall inpatient admission rates [95% confidence interval (CI)] for HIV-infected patients decreased from 90 (88-93) to 57 (56-58)/100 person-years in the study period. The risk ratio (95% CI) fell from 6.2 (6.0-6.5) to 3.1 (3.1-3.2) predominantly due to reduced inpatient admission rates to departments of infectious diseases. The overall outpatient visit rates (95% CI) for the HIV-infected patients increased from 744 (737-751) to 877 (872-882)/100 person-years, mainly due to visits at departments other than infectious diseases. A marked increase in outpatient visit rates (95% CI) in the background population decreased the risk ratio from 16.5 (16.2-16.8) to 7.1 (7.0 7.2). We observed a decreased relative risk of inpatient admissions and outpatient visits due to cancers and a small increase in relative risk due to cardiovascular disease. CONCLUSION: After the introduction of HAART, the inpatient treatment of HIV-infected patients has decreased, especially at departments of infectious disease. In contrast, this population's use of outpatient facilities has increased in noninfectious disease specialities. PMID- 19786844 TI - PrPs: Proteins with a purpose: Lessons from the zebrafish. AB - The best-known attribute of the prion protein (PrP) is its tendency to misfold into a rogue isoform. Much less understood is how this misfolded isoform causes deadly brain illnesses. Neurodegeneration in prion disease is often seen as a consequence of abnormal PrP function yet, amazingly little is known about the normal, physiological role of PrP. In particular, the absence of obvious phenotypes in PrP knockout mice has prevented scientists from answering this important question. Using knockdown approaches, we previously produced clear PrP loss-of-function phenotypes in zebrafish embryos. Analysis of these phenotypes revealed that PrP can modulate E-cadherin-based cell-cell adhesion, thereby controlling essential morphogenetic cell movements in the early gastrula. Our data also showed that PrP itself can elicit homophilic cell-cell adhesion and trigger intracellular signaling via Src-related kinases. Importantly, these molecular functions of PrP are conserved from fish to mammals. Here we discuss the use of the zebrafish in prion biology and how it may advance our understanding of the roles of PrP in health and disease. PMID- 19786846 TI - Effect of lentivirus encoding HIV-1 Nef-U3 shRNA on the function of HIV-specific memory CD4(+) T cells in patients with chronic HIV-1 infection. AB - OBJECTIVE: To determine whether HIV-1-specific CD4 T cells with proliferative capacity are eliminated or functionally defective because of HIV-1 reactivation. DESIGN: The loss of proliferative capacity by HIV-1-specific CD4 T cells compromises the host's ability to maintain protective immunity against HIV-1 and is a hallmark of disease progression. We used a recombinant lentivirus encoding an HIV-specific short hairpin (sh)RNA (Lenti shNef366) with known HIV-inhibitory activity to analyze the functional state of HIV-1-specific CD4 T cells. METHODS: T lymphocytes from untreated chronically HIV-infected patients with documented high viral loads (above 10 000 HIV-RNA) were transduced with Lenti shNef366, and the proliferation, differentiation, and cytokine production of HIV-specific CD4 T cells were analyzed. RESULTS: Lenti shNef366 restored the proliferation of HIV p24-specific CD4 T cells in eight of 12 patients tested, affecting primarily CD27 or CD28 CD4 T cells that were at an intermediate stage of differentiation. Although cytokine production by CD4 T cells remained poor after transduction with Lenti shNef366, improved proliferative capacity was associated with significantly higher levels of expression of CD107a. CONCLUSION: In chronic stages of HIV-1 infection with high levels of HIV replication, proliferation-competent HIV specific CD4 T cells in an intermediate stage of differentiation are present but are exquisitely and strongly impaired. Blocking HIV reactivation may restore a key functional property of memory T cells. PMID- 19786847 TI - Concomitant cisplatin, paclitaxel, and hyperfractionated radiotherapy in locally advanced head and neck cancer: comparison of two different schedules. AB - PURPOSE: To determine feasibility and efficacy of concurrent paclitaxel and cisplatin with definitive hyperfractionated radiotherapy (HFRT) in locally advanced head-and-neck squamous cell carcinoma (HNSCC). PATIENTS AND METHODS: Forty-two patients stages III to IV head-and-neck squamous cell carcinoma were enrolled in 2 consecutive prospective trials from August 1998 to January 2006. In study 1, 16 patients received HFRT in 2 courses of 39.6 Gy each with a split of 2 weeks with concurrent paclitaxel (175 mg/m) and cisplatin (100 mg/m) on days 1, 21, 36, and 57. In study 2, 26 patients received a continuous course of 74.4 Gy of HFRT with concurrent weekly paclitaxel (50 mg/m) and cisplatin (30 mg/m). RESULTS: Tumor locations included oropharynx 48%, hypopharynx 24%, larynx 12%, paranasal sinuses 7%, salivary gland 2%, oral cavity 2% and unknown primary 5%. In study 1, all patients received 3 to 4 cycles of chemotherapy and completed the programmed radiotherapy course. In study 2, 69% received 5 to 6 cycles of chemotherapy and 92% completed the irradiation. Overall, 93% of objective responses were observed (complete 76%, partial 17%). Median follow-up was 50 months (range: 12-97). Pattern of recurrence was local 8%, distant 13%, and combined 3%. Acute toxicity grades 3 to 4 in studies 1 and 2 was 75% and 88%, respectively (P = ns). Globally, 5-year overall survival were 68%, with a median of 71 months (range: 50-91). On multivariate analysis, male gender (P = 0.04) and complete response (P = 0.01) were predictive of improved survival. CONCLUSION: HFRT combined with cisplatin and paclitaxel is very active but at the expense of severe toxicity. Efficacy and toxicity in studies.1 and 2 were not different despite completely different treatment strategies (chemotherapy dose intensity vs. radiotherapy dose intensity). PMID- 19786848 TI - Cetuximab, paclitaxel, carboplatin, and radiation for head and neck cancer: a toxicity analysis. AB - OBJECTIVE: To determine the feasibility and toxicity of the addition of cetuximab to paclitaxel, carboplatin, and concurrent radiation for patients with head and neck cancer. MATERIALS AND METHODS: Patients with stage III or IV locally advanced squamous cell cancer of the head and neck, without distant organ metastases, were eligible. Patients received 4 weeks of induction cetuximab followed by weekly cetuximab, paclitaxel, carboplatin, and concurrent radiation. RESULTS: Thirty-two patients were assessable for chemoradiation toxicities. Grade 3 and grade 4 mucositis occurred in 53% and 16% of patients, respectively. Grade 3 and grade 4 radiation dermatitis occurred in 44% and 9% of patients, respectively. Grade 3/4 radiation dermatitis was associated with the use of intensity modulated radiation therapy (64% vs.14%, respectively, P < 0.0001). Grade 3 and grade 4 cetuximab associated acneiform rash developed in 6% and 3% of patients. Overall 21 patients (66%) had any grade 3 toxicity and 10 patients (31%) had any grade 4 toxicity. The percentages of the intended total dose delivered of carboplatin, cetuximab, paclitaxel, and radiation were 86%, 89%, 89%, and 96%, respectively. CONCLUSION: Cetuximab, when combined with paclitaxel, carboplatin and intensity modulated radiation therapy, increases dermatologic toxicity but does not increase mucosal toxicity as compared with previous Brown University Oncology Group studies of paclitaxel, carboplatin, and conventional radiation for patients with head and neck cancer. PMID- 19786849 TI - Phase II study of paclitaxel and irinotecan with intercalated gefitinib in patients with advanced non-small-cell lung cancer. AB - OBJECTIVES: We conducted a phase II study of combination chemotherapy with paclitaxel (Pac) and irinotecan (CPT) alternating with gefitinib (Gef) to determine the qualitative and quantitative toxicities and efficacy of this combination against advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with stage IIIB or IV NSCLC were treated with CPT at 60 mg/m2 and Pac at 160 mg/m2 on day 1 followed by Gef at 250 mg per day on days 8 to 14 every 3 weeks. RESULTS: Between April 2005 and March 2006, 16 patients received the chemotherapy with Pac and CPT alternating with Gef. Eleven patients received 4 to 6 cycles, except for 5 patients who discontinued treatment in the second or third cycles because of disease progression in 2, grade 3 pneumonitis with pulmonary infiltration in 2, and decreased performance status in 1. Grade 3 toxicities were neutropenia, an increased glutamic pyruvic transaminase level, allergy, pneumonitis, anorexia, and fatigue. Elevation of the serum glutamic oxaloacetic transaminase level after 1 cycle was the only grade 4 toxicity. Seven of 16 patients achieved a partial response and the overall response rate in the prospective study was 43.8%. The median survival time was 18.1 months. The 1- and 2-year survival rates were 56.3% and 43.8%, respectively. CONCLUSION: Pac and CPT combined with Gef was not effective enough for NSCLC. PMID- 19786850 TI - Safety and efficacy of a combination of docetaxel and cisplatin in patients with unknown primary cancer. AB - OBJECTIVES: Evaluation of the safety and efficacy of docetaxel and cisplatin in the treatment of unknown primary cancer. PATIENTS AND METHODS: Inclusion criteria included histologic evidence of carcinoma originating in an unknown primary organ, no prior chemotherapy, age range 20 to 75 years, WHO PS < or =3, measurable or evaluable lesions, and adequate organ function. Docetaxel (60 mg/m2) followed by cisplatin (80 mg/m2) was administered intravenously every 3 weeks. Patients were assessed for tumor response after 2 cycles of chemotherapy, and 4 additional cycles were administered unless disease progression was demonstrated. RESULTS: Between September 1997 and September 2002, 45 patients were enrolled. The median age was 56.5 years (28-73 years), and their performance status (PS) were 0 (11 patients), 1 (26 patients), and 2 (6 patients), respectively, (2 patients were removed from the trial after initial enrollment). A total of 26 patients (60%) presented with lymphadenopathy, 14 patients (33%) with visceral disease, and 3 (7%) with bone and soft-tissue metastases. The overall response rate was 65.1% (4 complete response, 24 partial response, 8 NC, 7 progressive diseases: 95% confidence interval, 48.0-78.4). The median time to progression was 5.0 months. The median survival time was 11.8 months. No treatment-related deaths were observed. Commonly observed side effects included neutropenia (grade 3-4, 16 patients), nausea (grade 3, 13 patients), and nephrotoxicity (grade 2, 5 patients). CONCLUSIONS: These results indicate that the combination of docetaxel and cisplatin is a safe and effective regimen for patients with unknown primary cancer. PMID- 19786851 TI - "Squamoid eccrine ductal carcinoma": an unusual low-grade case with follicular differentiation. Are these tumors squamoid variants of microcystic adnexal carcinoma? AB - Squamoid eccrine ductal carcinoma is a rare primary cutaneous tumor exhibiting both squamous and adnexal ductal differentiation. The cell of origin of these tumors is unknown, and they have been classified both as variants of cutaneous squamous cell carcinoma and as a type of eccrine carcinoma. Only 6 of these tumors have been reported in the literature to date. We report an additional case of a slow-growing tumor, occurring on the great toe of a 61-year-old woman, which was unusual as it showed follicular differentiation in addition to squamoid and ductal areas. The lesional cells were positive for cytokeratins 7 and 17, carcinoembryonic antigen (which highlighted the ductal structures), and p63 (favoring a primary cutaneous tumor) and showed low levels of staining with Ki-67 and p53, consistent with a low-grade tumor. We postulate that these tumors may be closely related to microcystic adnexal carcinoma and similarly show differentiation along both follicular and ductal lines, likely indicating folliculosebaceous-apocrine, rather than eccrine, origin or differentiation. PMID- 19786852 TI - A nodular syphilid presenting as a pseudolymphoma: mimicking a cutaneous marginal zone B-cell lymphoma. AB - Syphilis has been referred to as the great imitator, the great mimic, and the great masquerader. It often presents with clinical and histological findings similar to many other dermatological conditions. We report a patient presenting with nodular plaques, a rare form of secondary syphilis. The histological features revealed a pseudolymphoma mimicking a cutaneous marginal zone B-cell lymphoma. Syphilis should be considered in the differential diagnosis of a cutaneous lymphoreticular process. PMID- 19786853 TI - Primary mucoepidermoid carcinoma of the skin expressing p63. AB - Primary mucoepidermoid carcinoma (MEC) of the skin is an unusual neoplasm with few cases reported in the English medical literature. It has to be differentiated from adenosquamous carcinoma, usually a high-grade neoplasm with poorer outcome, and metastasis from a primary MEC arising elsewhere in the body. We report a 78 year-old woman with an abdominal skin lesion of recent onset. Histopathological examination revealed a dermal located carcinoma with variable proportions of squamous differentiation and goblet cells. The patient died in a very short time for an unrelated disease. Immunohistochemical study showed staining for cytokeratins (AE1AE3, 7, and 34betaE12), epithelial membrane antigen (EMA), and p63, whereas cytokeratins 18 and 20 and gross cystic disease fluid protein (GCDFP15) were negative. We conclude that primary MEC of the skin is usually a slow-growing neoplasm that should be differentiated from adenosquamous carcinoma. The immunohistochemical staining for p63 is helpful to differentiate primary and metastatic MEC in the skin. PMID- 19786854 TI - Concomitant occurrence of kimura disease and mycosis fungoides in a Lebanese woman: significance and response to rituximab. AB - Kimura disease (KD) is a rare condition that predominantly affects young middle aged Asian men. It is classically characterized by tumors in the head and neck region with associated eosinophilia and elevated serum immunoglobulin E levels. The exact pathogenesis of this condition remains unknown. Although some regard it as a reactive condition, others believe that it is a T-cell-mediated disease. T cell clonality has been recently demonstrated in a few cases. We report a 37-year old Lebanese woman who had both KD and mycosis fungoides (MF). T-cell receptor gene rearrangement studies using 2 different techniques did not detect any clonality for T-cell receptor in both KD and MF lesions. Due to the presence on histology of lymphoid follicles and the persistent high serum immunoglobulin E levels, we elected to attempt treatment with rituximab. Although the KD lesions persisted, they became softer and less nodular. As for the MF lesions, they flared transiently and then exhibited a sustained improvement over a follow-up period of 1 year. PMID- 19786855 TI - Melanotic schwannoma arising in association with nevus of Ota: 2 cases suggesting a shared mechanism. AB - Melanotic schwannoma is a rare markedly pigmented peripheral nerve sheath tumor comprising cells with prominent melanization and schwannian features. The psammomatous variety is associated with Carney complex, a multiple neoplasia syndrome with spotty skin pigmentation. We present the first 2 reported cases of melanotic schwannoma arising in patients with a history of nevus of Ota, a rare dermal melanosis believed to represent a failure of melanocyte migration to the epidermis during embryogenesis. Case 1 involves a 40-year-old woman with a 1.8 cm, deeply pigmented, trigeminal nerve mass and pigmentation of the maxillary sinus mucosa and bone. Case 2 involves a 53-year-old woman with a 1.5-cm mass adjacent to the clavicle. Microscopically, both masses consist of partially encapsulated epithelioid and spindle cells with abundant melanin pigment, arising in association with peripheral nerves. Morphological, immunohistochemical, and ultrastructural features support a diagnosis of melanotic schwannoma. No psammoma bodies are noted, and neither patient exhibits any additional features of Carney complex. Melanotic schwannoma is most often benign but has been associated with malignant behavior in some cases. Distinguishing this nerve sheath tumor from malignant melanoma can be difficult but is of great clinical importance due to differences in prognosis and treatment. PMID- 19786856 TI - A 48-year-old man with a crusted plaque on the left side of the neck: challenge. PMID- 19786857 TI - Long-term cognitive decline: is there a link to surgery and anesthesia? PMID- 19786858 TI - Long-term cognitive decline in older subjects was not attributable to noncardiac surgery or major illness. AB - BACKGROUND: Persistent postoperative cognitive decline is thought to be a public health problem, but its severity may have been overestimated because of limitations in statistical methodology. This study assessed whether long-term cognitive decline occurred after surgery or illness by using an innovative approach and including participants with early Alzheimer disease to overcome some limitations. METHODS: In this retrospective cohort study, three groups were identified from participants tested annually at the Washington University Alzheimer's Disease Research Center in St. Louis, Missouri: those with noncardiac surgery, illness, or neither. This enabled long-term tracking of cognitive function before and after surgery and illness. The effect of surgery and illness on longitudinal cognitive course was analyzed using a general linear mixed effects model. For participants without initial dementia, time to dementia onset was analyzed using sequential Cox proportional hazards regression. RESULTS: Of the 575 participants, 214 were nondemented and 361 had very mild or mild dementia at enrollment. Cognitive trajectories did not differ among the three groups (surgery, illness, control), although demented participants declined more markedly than nondemented participants. Of the initially nondemented participants, 23% progressed to a clinical dementia rating greater than zero, but this was not more common after surgery or illness. CONCLUSIONS: The study did not detect long-term cognitive decline independently attributable to surgery or illness, nor were these events associated with accelerated progression to dementia. The decision to proceed with surgery in elderly people, including those with early Alzheimer disease, may be made without factoring in the specter of persistent cognitive deterioration. PMID- 19786859 TI - "Above all, do no harm": hippocrates. PMID- 19786860 TI - Science marches forward: a new tool to study the progress of labor. PMID- 19786861 TI - Perioperative strokes and beta-blockade. PMID- 19786862 TI - Prevalence of delirium with dexmedetomidine compared with morphine based therapy after cardiac surgery: a randomized controlled trial (DEXmedetomidine COmpared to Morphine-DEXCOM Study). AB - BACKGROUND: Commonly used sedatives/analgesics can increase the risk of postoperative complications, including delirium. This double-blinded study assessed the neurobehavioral, hemodynamic, and sedative characteristics of dexmedetomidine compared with morphine-based regimen after cardiac surgery at equivalent levels of sedation and analgesia. METHODS: A total of 306 patients at least 60 yr old were randomized to receive dexmedetomidine (0.1-0.7 microg x kg( 1) x h(-1)) or morphine (10-70 microg x kg(-1) x h(-1)) with open-label propofol titrated to a target Motor Activity Assessment Scale of 2-4. Primary outcome was the prevalence of delirium measured daily via Confusion Assessment Method for intensive care. Secondary outcomes included ventilation time, additional sedation/analgesia, and hemodynamic and adverse effects. RESULTS: Of all sedation assessments, 75.2% of dexmedetomidine and 79.6% (P = 0.516) of morphine treatment were in the target range. Delirium incidence was comparable between dexmedetomidine 13 (8.6%) and morphine 22 (15.0%) (relative risk 0.571, 95% confidence interval [CI] 0.256-1.099, P = 0.088), however, dexmedetomidine managed patients spent 3 fewer days (2 [1-7] versus 5 [2-12]) in delirium (95% CI 1.09-6.67, P = 0.0317). The incidence of delirium was significantly less in a small subgroup requiring intraaortic balloon pump and treated with dexmedetomidine (3 of 20 [15%] versus 9 of 25 [36%]) (relative risk 0.416, 95% CI 0.152-0.637, P = 0.001). Dexmedetomidine-treated patients were more likely to be extubated earlier (relative risk 1.27, 95% CI 1.01-1.60, P = 0.040, log-rank P = 0.036), experienced less systolic hypotension (23% versus 38.1%, P = 0.006), required less norepinephrine (P < 0.001), but had more bradycardia (16.45% versus 6.12%, P = 0.006) than morphine treatment. CONCLUSION: Dexmedetomidine reduced the duration but not the incidence of delirium after cardiac surgery with effective analgesia/sedation, less hypotension, less vasopressor requirement, and more bradycardia versus morphine regimen. PMID- 19786863 TI - Characterization of the cytotoxic properties of the benzimidazole fungicides, benomyl and carbendazim, in human tumour cell lines and primary cultures of patient tumour cells. AB - The benzimidazoles, benomyl and carbendazim, are fungicides suggested to target microtubules. Benomyl is metabolized to carbendazim, which has already been explored as an anticancer drug in phase 1 clinical trials. We further characterized the cytotoxic properties of benomyl and carbendazim in 12 human cell lines and in primary cultures of patient tumour cells with the overall aims of elucidating mechanisms of action and anticancer activity spectrum. Cytotoxicity was assessed in the short-term fluorometric microculture cytotoxicity assay and was correlated with the activity of other anticancer drugs and gene expression assessed by cDNA microarray analysis. Benomyl was generally more potent than its metabolite, carbendazim. Both showed high drug activity correlations with several established and experimental anticancer drugs, but modest association with established mechanisms of drug resistance. Furthermore, these benzimidazoles showed high correlations with genes considered relevant for the activity of several mechanistically different standard and experimental anticancer drugs, indicating multiple and broad mechanisms of action. In patient tumour samples, benomyl tended to be more active in haematological compared with solid tumour malignancies, whereas the opposite was observed for carbendazim. In conclusion, benomyl and carbendazim show interesting and diverse cytotoxic mechanisms of action and seem suitable as lead compounds for the development of new anticancer drugs. PMID- 19786864 TI - The WHO classification of lymphomas: cost-effective immunohistochemistry using a deductive reasoning "decision tree" approach: part II: the decision tree approach: diffuse patterns of proliferation in lymph nodes. AB - The 2008 World Health Organization Classification of Tumors of the Haematopoietic and Lymphoid Tissues defines current standards of practice for the diagnosis and classification of malignant lymphomas and related entities. More than 50 different types of lymphomas are described. Faced with such a broad range of different lymphomas, some encountered only rarely, and a rapidly growing armamentarium of 80 or more pertinent immunohistochemical (IHC) "stains," the challenge to the pathologist is to use IHC in an efficient manner to arrive at an assured and timely diagnosis. This review uses deductive reasoning following a decision tree or dendrogram model, combining basic morphologic patterns and common IHC markers to classify node-based malignancies by the World Health Organization schema. The review is divided into 2 parts, the first addressing those lymphomas that produce a follicular or nodular pattern of lymph nodal involvement appeared in the previous issue of AIMM. The second part addresses diffuse proliferations in lymph nodes. Emphasis is given to the more common lymphomas and the more commonly available IHC "stains" for a pragmatic and practical approach that is both broadly feasible and cost-effective. By this method, an assured diagnosis may be reached in the majority of nodal lymphomas, at the same time developing a sufficiency of data to recognize those rare or atypical cases that require referral to a specialized center. PMID- 19786865 TI - Quantitative infrared spectroscopy of formalin-fixed, paraffin-embedded tissue specimens: paraffin wax removal with organic solvents. AB - Formalin-fixed, paraffin-embedded tissue specimens form the basis for diagnostic histopathology. Although adequate for morphologic visualization, clinical variability in preparation of formalin-fixed, paraffin-embedded clinical specimens represents an obstacle to quantitative molecular genetic analysis in areas such as genomics and proteomics. A quantitative reexamination of classical histopathology tissue preparation methods was initiated to determine which protocol steps might improve molecular analysis, beginning with deparaffinization. Infrared spectroscopy in the spectral region above 2000/cm of fixed sectioned model cell cultures through glass microscope slides showed all solvents remove over 97% of paraffin. To further compare extractions among solvents xylene, hexane and limonene, the correlation coefficients between the spectrum of paraffin and the spectra of the mounted extracted model tissue sections across the spectral interval containing the prominent CH stretching bands of paraffin were calculated. The correlation coefficients allow different extraction methods to be ranked in terms of how much paraffin remains. The results indicate that among 3 model tissue sample types, xylene extraction removes more paraffin than hexane or limonene. More importantly, these results establish a starting point from which further analysis of preanalytical processing methods can proceed. PMID- 19786866 TI - Aerobic power and the main determinants of blood rheology: is there a relationship? AB - This cross-sectional study aimed to explore the relationship between aerobic power and the main determinants of blood rheology namely plasma viscosity, plasma fibrinogen concentration and haematocrit. Ninety-three normal healthy individuals (VO2max 48.3 ml/kg per min), who were familiarized with the laboratory environment and testing procedures, participated in the study. Aerobic power as assessed by maximal oxygen consumption (VO2max) was determined by using an incremental exercise protocol on either a treadmill or a stationary bike. Oxygen consumption was measured online using a computer-based metabolic system. In a standardized resting condition, venous blood samples were removed from a prominent vein of the nondominant arm. Aliquots of whole blood were measured for haematocrit (in triplicate), whereas plasma was assayed for fibrinogen concentration and viscosity (in duplicate) using semiautomatic coagulometer and capillary viscometer; respectively. The mean values for haematocrit (41.9 +/- 2.5%), plasma viscosity (1.56 +/- 0.27 mPa s) and plasma fibrinogen (272.1 +/- 86.9 mg/dl) were within the normal range for normal participants. Pearson correlation coefficients and regression analysis were used for statistical evaluations. In this population, VO2max negatively correlated with plasma viscosity (P < 0.01) and plasma fibrinogen concentration (P < 0.01). Although VO2max positively correlated with haematocrit, this correlation was not as strong. Thus, high aerobic power as assessed by maximal oxygen consumption appears to be associated with lower plasma viscosity and lower plasma fibrinogen. The significant negative relationships between VO2max and plasma viscosity and plasma fibrinogen might suggest that blood is more dilute in individuals with high aerobic power. This could probably be due to an expansion of plasma volume, which is commonly seen in those who are physically active and exhibit a higher level of cardiorespiratory fitness. PMID- 19786867 TI - Management of acute coronary syndrome in a case of Behcet's disease. AB - Behcet's disease is a multisystemic, rheumatic disorder characterized by oral and genital ulceration and ocular inflammation. Although cardiac involvement is not rare as a manifestation of Behcet's disease, coronary arteritis is reported seldom. We present the first case of left main coronary artery thrombosis in literature leading to acute myocardial infarction that was successfully treated with thrombolytic therapy and glycoprotein IIb/IIIa receptor inhibitors in Behcet's disease. PMID- 19786868 TI - What we have learned about colonic motility: normal and disturbed. AB - PURPOSE OF REVIEW: Disorders of colonic motor and sensory function are common among children and adults and pose significant diagnostic and therapeutic challenges; the purpose of this review, therefore, was to critically assess the recent literature on this topic. RECENT FINDINGS: Considerable progress has been made at the ultrastructural, molecular and electrophysiological level in understanding the normal functions of the muscles, nerves and interstitial cells that generate and control colonic motility. Furthermore, abnormalities in these cell types and in the interstitial cells of Cajal, in particular, have been identified in a number of disease states. Testing of colonic motor and sensory function in clinical practice continues to be a challenge due, in part, not only to the technical issues presented by accessing the organ but also to the intrinsic variability of its physiology. These have not been auspicious times for advances in the therapy of disturbed colonic motility; new agents or new applications for 'old' agents continue to be explored as are more innovative approaches such as those based on neural stimulation and cell therapy. SUMMARY: Considerable progress has been made in understanding the basic pathophysiology of colonic dysmotility; clinical diagnostics and therapeutics continue to lag behind. PMID- 19786869 TI - Recent insights into the pathogenesis of colorectal cancer. AB - PURPOSE OF REVIEW: Colorectal cancer (CRC) is one of the leading causes of cancer related deaths in the Western world, but our understanding of this disease is incomplete. The recent advent of new technologies has provided novel insights into the pathogenesis of CRC. RECENT FINDINGS: Genome-wide association studies have recently linked CRC to 10 common genetic variants or single-nucleotide polymorphisms that map to chromosomes 8q23, 8q24, 10p14, 11q23, 14q22, 15q13, 16q22, 18q21, 19q13 and 20p1. However, the causal significance of these variants is not understood, and some are located in poorly characterized genomic regions or gene deserts. Recent studies indicate that the single-nucleotide polymorphism rs6983267, which maps to 8q24, serves as an enhancer of MYC expression by binding T cell factor 4 (TCF4) and influencing Wnt signaling. In addition, several microRNAs interact with genes such as K-RAS, APC, p53, PTEN, TCF4, COX-2, DNMT3a and DNMT3b. Germline hypermethylation of the DNA mismatch repair genes MLH1 and MSH2 may serve as predisposing events in some CRC patients. SUMMARY: Recent studies have elucidated novel mechanisms involved in CRC, including the involvement of single-nucleotide polymorphisms not located within traditional genes, the role of microRNAs and epimutations in DNA mismatch repair genes. Interestingly, most of this progress has been made by understanding DNA that does not encode genes. PMID- 19786870 TI - Noninvasive radiologic imaging of the large intestine: a valuable complement to optical colonoscopy. AB - PURPOSE OF REVIEW: Radiologic imaging of the large intestine continues to evolve and expand the potential for noninvasive diagnosis. The aim of this review is to provide an update on current and emerging clinical capabilities for a variety of radiologic diagnostic imaging tools for evaluating the colon and rectum. RECENT FINDINGS: The utility of computed tomography for the evaluation of symptomatic inflammatory and neoplastic conditions of the colon is well established, but the clinical role of computed tomography colonography is rapidly evolving. In addition to a number of diagnostic indications, computed tomography colonography is emerging as a potential frontline colorectal screening test for cancer prevention. MRI has become increasingly valuable for rectal cancer staging and inflammatory bowel disease but has yet to gain momentum for polyp evaluation. PET imaging has been primarily utilized for oncologic indications, but also holds considerable potential for inflammatory conditions. Other imaging modalities, such as the barium enema, conventional radiography, and ultrasound, play a much more limited role. SUMMARY: Advances in radiologic imaging of the colorectum will continue to expand the capabilities and clinical indications for noninvasive diagnosis, allowing for a greater emphasis on the complementary roles of tissue sampling and therapy with optical colonoscopy. PMID- 19786871 TI - Stomach and duodenum. PMID- 19786873 TI - Primetime for antiangiogenic therapy. AB - PURPOSE OF REVIEW: To review the current experience with angiogenesis inhibitors in the treatment of gliomas. RECENT FINDINGS: Antiangiogenic therapy has recently reached the clinic with the approval of bevacizumab for recurrent glioblastomas. A number of promising antiangiogenic and vasculature-modifying agents are under investigation for newly diagnosed and recurrent malignant gliomas. A recurrence under ongoing or after antiangiogenic therapy is often characterized by a more aggressive and, in particular, invasive phenotype. SUMMARY: Despite impressively high radiological response rates in patients with recurrent malignant glioma, the duration of response is usually short-lived, and the observed effect to a large extent may be due to normalization of the disrupted blood-brain barrier and less due to a direct antitumor effect. Overall survival remains poor. Induction of invasive phenotypes and escape with proangiogenic alternative pathways are contributing to resistance. Investigation of combination regimes targeting several pathways will determine the possibilities to overcome the resistance to antiangiogenic therapy in malignant gliomas. This article summarizes the results of recent clinical trials in this field, points towards mechanisms of resistance arising under angiogenesis inhibition and discusses the challenges for the future. PMID- 19786872 TI - The neurobiology of deception: evidence from neuroimaging and loss-of-function studies. AB - PURPOSE OF REVIEW: Visualization of how the brain generates a lie is now possible because of recent conceptual and technical advances in functional neuroimaging; this has led to a rapid increase in studies related to the cognitive neuroscience of deception. The present review summarizes recent work on the neural substrates that underlie human deceptive behavior. RECENT FINDINGS: Functional neuroimaging studies in healthy individuals have revealed that the prefrontal cortex plays a predominant role in deception. In addition, recent evidence obtained from loss-of function studies with neuropsychological investigation and transcranial direct current stimulation has demonstrated the functional contribution of the prefrontal cortex to deception. Other research into the relationship between deception and the brain has focused on the potential use of functional MRI for lie detection, neural correlates of pathological lying, and brain mechanisms underlying inference of deceit by others. SUMMARY: Converging evidence from multiple sources suggests that the prefrontal cortex organizes the processes of inhibiting true responses and making deceptive responses. The neural mechanisms underlying various other aspects of deception are also gradually being delineated, although the findings are diverse, and further study is needed. These studies represent an important step toward a neural explanation of complex human deceptive behavior. PMID- 19786874 TI - Effective pandemic preparedness. PMID- 19786875 TI - Observations on past influenza pandemics. PMID- 19786876 TI - Factors influencing clinical course and histological findings in children with chronic hepatitis B. AB - INTRODUCTION: Although the clinical course of chronic hepatitis B (CHB) is relatively mild in a majority of children, a certain proportion of patients develops chronic liver disease that finally results in serious liver injury. Reports regarding clinical outcome of infection are scarce. OBJECTIVE: The aim of this study was to assess inflammatory activity, fibrosis, and their correlation to clinical data in children with CHB before antiviral treatment. MATERIALS AND METHODS: The study included 200 children, aged 1.5-18 years (mean 7.49+/-4.01 years), with CHB hospitalized before liver biopsy between 1992 and 2003. History and clinical data were analyzed. Histopathological assessment was based on the modified Knodell system. Statistical analysis was performed, and results with P<0.05 were considered significant. RESULTS: Necroinflammatory activity was found to be mild in 115 children and moderate in 44. Ninety-three children had minimal fibrosis (S1), 62 children - S2, and the remaining 8 - S3-S4. Alanine aminotransferase (ALT) activity was proportional to staging (Kruskall-Wallis test H=10.84, P=0.028) and was significantly higher in the children with staging >or=S2, P=0.0008. Spontaneous hepatitis B early antigen seroconversion occurred in 30/200 children (15%) and was related to the shorter length of infection, P=0.008. CONCLUSION: Intensity of liver injury in children with CHB varies from minimal to marked necroinflammatory activity and fibrosis varies from none to advanced. Progression of liver fibrosis seems to be proportional to the age at infection. ALT activity appears to be higher in the children with significant (S2 S4) fibrosis. Spontaneous hepatitis B early antigen seroconversion is apparently related to the shorter length of infection and higher ALT activity. PMID- 19786877 TI - Role of the tumor necrosis factor antagonists in the treatment of inflammatory bowel disease: an update. AB - Crohn's disease and ulcerative colitis represent the two major forms of inflammatory bowel disease (IBD). Recent research points out the role of uncontrolled intestinal inflammation in the pathogenesis of IBD. Therefore, there is a growing interest in developing novel biologic therapies targeting specific molecules of the inflammatory cascade. Among them, anti-tumor necrosis factor (anti-TNF) agents (i.e. infliximab, adalimumab, certolizumab pegol) have proved to be effective, particularly for patients with refractory IBD. These biological therapies have changed, at least partially, the clinical course and medical management of IBD. However, the administration of anti-TNF drugs has also been associated with serious side-effects, which have raised concerns on the application of these drugs in clinical practice. The goal of this review is to provide an update and analyze the pros and cons of using anti-TNF therapies in the treatment of IBD. PMID- 19786879 TI - The experience of pleasure before and after hearing rehabilitation. AB - Hearing loss may lead to major changes in the social and emotional aspects of daily life. This follow-up study investigated the effect of hearing-aid use on emotional experience in adults with hearing impairment. Thirteen individuals with impaired hearing were tested before and after 6 months of hearing-aid use, and were compared with 19 individuals who had worn hearing aids for many years. The participants reported their daily emotional experiences, by completing questionnaires relating to sensory and social pleasure. After 6 months of hearing aid use, individuals experienced more physical and social pleasure, whereas individuals using hearing aids for long periods of time reported similar levels of pleasure at the beginning and at the end of a 6-month interval. The participants also performed a visual task, in which they rated the intensity of pleasure they experienced in response to emotionally positive and neutral pictures differing in luminance contrast. In this task, pleasure typically decreases with decreasing contrast of the positive images displayed. Once they had been fitted with hearing aids, the participants reported lower levels of pleasure, especially at low contrast. These findings highlight that the anhedonia scales provide a measure sensitive to emotional improvements that accompany the partial restoration of hearing function, although these scales were not specifically designed for hearing-impaired populations. In contrast, the surprising decrease in pleasure ratings for pictures after the introduction of hearing-aid use may be because of the compensation of hearing loss by changes in visual attention functions. PMID- 19786878 TI - Sex-dependent alterations in erythrocyte trace element levels and antioxidant status after a month of moderate daily red wine consumption. AB - OBJECTIVE: We tested the hypothesis whether trace elements and antioxidant status change in a sex-dependent manner may contribute to sex-dependent hepatic effects of moderate daily wine consumption. PATIENT AND METHODS: Twenty-one healthy young men and women were enrolled to this study who consumed red wine 0.3 and 0.2 l per day, respectively, for a month. Blood was taken at baseline (BV) and at end of the study (EV). Red cell trace element levels, red cell and plasma antioxidant status and serum routine blood chemistry were assessed at baseline and at the end of the study. RESULTS: No sign of hepatotoxicity was detected. BV level of some trace elements (i.e. Zn, Pb) and Zn/Cu ratios were higher in women than in men. Ca, Mg, Pb, Sr and Zn levels and the Zn/Cu ratio had lower EV than BV in women. In men, Al, Ca, Li, Pb and Sr levels had lower EV than BV. The tested antioxidant parameters improved in both the sexes. CONCLUSION: Although no hepatotoxicity was observed, changes in trace element content were detected after 1 month of moderate red wine consumption. The most remarkable sex-specific alteration was the decrease of Zn levels and of the Zn/Cu ratio in women. Given the protective effect of Zn against liver damage, this finding suggests a possible contribution of decreased Zn levels to sex-dependent effects of red wine. PMID- 19786880 TI - Evolution of vocational rehabilitation competencies in Australia. AB - Over the past decade, there has been growth in the delivery of vocational rehabilitation services globally, as countries seek to control disability-related expenditure, yet there has been minimal research outside the United States on competencies required to work in this area. This study reports on research conducted in Australia to determine current job function and knowledge areas in terms of their importance and frequency of use in the provision of vocational rehabilitation. A survey comprising items from the Rehabilitation Skills Inventory-Amended and International Survey of Disability Management was completed by 149 rehabilitation counselors and items submitted to factor analysis. T-tests and analyses of variance were used to determine differences between scores of importance and frequency and differences in scores based on work setting and professional training. Six factors were identified as important and frequently used: (i) vocational counseling, (ii) professional practice, (iii) personal counseling, (iv) rehabilitation case management, (v) workplace disability case management, and (vi) workplace intervention and program management. Vocational counseling, professional practice and personal counseling were significantly more important and performed more frequently by respondents in vocational rehabilitation settings than those in compensation settings. These same three factors were rated significantly higher in importance and frequency by those with rehabilitation counselor training when compared with those with other training. In conclusion, although 'traditional' knowledge and skill areas such as vocational counseling, professional practice, and personal counseling were identified as central to vocational rehabilitation practice in Australian rehabilitation agencies, mean ratings suggest a growing emphasis on knowledge and skills associated with disability management practice. PMID- 19786881 TI - Quality of arithmetic education for children with cerebral palsy. AB - The aim of this exploratory study was to investigate the quality of arithmetic education for children with cerebral palsy. The use of individual educational plans, amount of arithmetic instruction time, arithmetic instructional grouping, and type of arithmetic teaching method were explored in three groups: children with cerebral palsy (CP) in special (CP-special; n = 41) and mainstream schools (CP-mainstream; n = 16) and a control group in mainstream schools (n = 16). The majority of individual educational plans did not include well-formulated arithmetic goals and many were not based on optimal assessment. Special schools scheduled much less arithmetic instruction time. Many CP-mainstream children received individualized instruction, which may help to explain why their arithmetic performance did not differ from controls. Remedial arithmetic teaching methods used in special schools did not seem to be optimal, but more research is required. Suggestions to improve arithmetic education to children with CP were discussed. PMID- 19786882 TI - Measuring self-care in chronic heart failure: a review of the psychometric properties of clinical instruments. AB - BACKGROUND: Improved self-care skills and behaviors are an important outcome of patient education and counseling. Both researchers and health professionals need to utilize instruments that are reliable and valid at measuring this outcome to advance our understanding as to the efficacy of clinical practice directed toward improving self-care. OBJECTIVE: The aim of this study was to identify instruments that measure chronic heart failure (CHF) self-care and demonstrate their psychometric properties. METHODS: A search of Medline, Cumulative Index to Nursing and Allied Health Literature, Medline, PsycArticles, Psychology and Behavioral Sciences Collection, and PsycINFO databases elucidated studies published between January 1980 and February 2009 that measure CHF self-care. The clinical instruments selected were disease-specific measures of CHF self-care behaviors that are promoted in best practice guidelines. Only instruments that reported estimates of reliability and validity were included in this review. Psychometric properties of the instruments were evaluated according to practice guidelines. RESULTS: The literature search identified 14 instruments published in peer-reviewed journals that measured constructs that predict or correlate to self care rather than self-care itself. Only 2 disease-specific measures of self-care were identified (Self-care Heart Failure Index [SCHFI] and European Heart Failure Self-care Behavior Scale [EHFScBS]) that have undergone rigorous psychometric testing in CHF populations. Five aspects of validity had been demonstrated with EHFScBS, and 6 aspects of validity had been demonstrated with SCHFI. Two of 3 aspects of reliability have been demonstrated in both instruments. CONCLUSION: Only 2 reliable and valid tools have been developed to specifically measure CHF self-care. Further use of these instruments in the research arena may reduce gaps in our understanding of CHF self-care and further shape clinical practice directed at improving it. PMID- 19786883 TI - Evidence-based guidelines for cardiovascular risk reduction: the safety and efficacy of high-dose statin therapy. AB - Current clinical guidelines for management of low-density lipoprotein cholesterol (LDL-C) have evolved to reflect the findings of numerous randomized clinical trials and represent an important opportunity to effectively improve the cardiovascular (CV) risk profile of a wide range of patients. Implementation of guideline-recommended LDL-C management strategies facilitates the appropriate use of all available treatments, including lifestyle and dietary changes and pharmacotherapy. Where intensive lowering of LDL-C is required, suboptimal use of statins is a major contributor to the significant number of patients who remain at an unnecessarily increased risk of CV disease as a consequence of failing to reach their guideline-recommended LDL-C goals. This underuse may be explained by concerns over the safety and efficacy of high-dose statin regimens in certain populations. These issues are explored in the context of current, evidence-based clinical guidelines for LDL-C management and, through 3 hypothetical case studies, selection of appropriate starting doses of statins, and titration to a higher dose or switching to a more potent statin, to ensure that patients reach their individual LDL-C goals and reduce their overall CV risk, is also examined. PMID- 19786885 TI - Osborn waves in severe accidental hypothermia secondary to prolonged immobilization and malnutrition. AB - We report the case of a 77-year-old man, in whom accidental hypothermia was secondary to prolonged immobilization and malnutrition. The electrocardiogram showed typical Osborn waves, which disappeared with the rewarming of the patient. The diagnosis of hypothermia is easy in patients with a history of prolonged exposure to a cold environment but accidental hypothermia may also occur as a consequence of prolonged immobilization and malnutrition. ECG analysis is very important for a correct and fast diagnosis. PMID- 19786884 TI - An update on the self-care of heart failure index. AB - BACKGROUND: The Self-care of Heart Failure Index (SCHFI) is a measure of self care defined as a naturalistic decision-making process involving the choice of behaviors that maintain physiological stability (maintenance) and the response to symptoms when they occur (management). In the 5 years since the SCHFI was published, we have added items, refined the response format of the maintenance scale and the SCHFI scoring procedure, and modified our advice about how to use the scores. OBJECTIVE: The objective of this article was to update users on these changes. METHODS: In this article, we address 8 specific questions about reliability, item difficulty, frequency of administration, learning effects, social desirability, validity, judgments of self-care adequacy, clinically relevant change, and comparability of the various versions. RESULTS: The addition of items to the self-care maintenance scale did not significantly change the coefficient alpha, providing evidence that the structure of the instrument is more powerful than the individual items. No learning effect is associated with repeated administration. Social desirability is minimal. More evidence is provided of the validity of the SCHFI. A score of 70 or greater can be used as the cut-point to judge self-care adequacy, although evidence is provided that benefit occurs at even lower levels of self-care. A change in a scale score more than one-half of an SD is considered clinically relevant. Because of the standardized scores, results obtained with prior versions can be compared with those from later versions. CONCLUSION: The SCHFI v.6 is ready to be used by investigators. By publication in this format, we are putting the instrument in the public domain; permission is not required to use the SCHFI. PMID- 19786886 TI - Multimodality imaging of the ace of spades. AB - A 53-year-old man was admitted to our institute with chest pain and palpitation. Using contrast echocardiography, left ventriculography and cardiac MRI, a subsequent diagnosis of mid-ventricular hypertrophic obstructive cardiomyopathy with an apical aneurysm was made. The current case highlights the benefits of multimodality imaging in not only achieving a diagnosis but also in comprehending the pathophysiological origins of this unusual phenomenon. PMID- 19786888 TI - Intracardiac echocardiography and electroanatomic mapping in diagnosis of arrhythmogenic right ventricular dysplasia. AB - A 48-year-old man with an episode of syncope and family history of sudden cardiac death was evaluated. The ECG showed negative T waves from V1 to V3 with evidence of epsilon-wave. Magnetic resonance imaging showed replacement with fibrofatty tissue in midapical regions of free wall of the right ventricle with dyskinesia. Transthoracic echocardiography revealed only mild enlargement of the middle right ventricular cavity. A programmed ventricular stimulation induced only an unsustained monomorphic ventricular tachycardia. Intracardiac echocardiography showed mild right ventricular enlargement and outflow dilatation (26 mm), microaneurysms with systolic bulging along the apical segment of the right ventricle. Bipolar voltage mapping, performed by the Carto system, detected a circumscribed low potential (<1.5 mV) area at the same level of the right ventricular apex. Cardiovascular imaging improves the detection of abnormal myocardial areas. Further studies are warranted to support this hypothesis. PMID- 19786887 TI - Late percutaneous re-canalization of arterial duct-dependent isolated pulmonary artery. AB - A critical infant with unrestrictive ventricular septal defect and absence of the left pulmonary artery underwent transcatheter re-canalization of the occluded arterial duct-left pulmonary artery complex and surgical banding of the right pulmonary artery. After this hybrid approach, the baby was discharged under mild anticongestive therapy in view of a later surgical repair. PMID- 19786889 TI - Predictors of exercise-induced platelet reactivity in patients with chronic stable angina. AB - OBJECTIVE: Previous studies have shown that exercise increases platelet reactivity in patients with coronary artery disease (CAD). However, the response of platelet reactivity to exercise is considerably variable and its predictors are poorly known. METHODS: We studied 214 consecutive patients (age 61.9 +/- 9 years, 167 men) with stable angina and obstructive coronary artery disease. All patients underwent a symptom-limited treadmill exercise stress test. Venous blood samples were collected before and at peak exercise. Platelet reactivity was assessed by the platelet function analyzer system as the time for flowing whole blood to occlude a collagen-adenosine diphosphate ring (closure time: shorter times = higher reactivity). Both closure time at peak exercise and the exercise induced change in closure time from rest were assessed as an expression of exercise-related platelet reactivity. RESULTS: Closure time decreased significantly with exercise in the whole population (from 95.9 +/- 22 to 81.2 +/- 18 s, P < 0.001). The only variable significantly associated with closure time at peak exercise was hematocrit (P = 0.003). Basal systolic blood pressure (P = 0.023) and lack of nitrate use (P = 0.03), on the contrary, were the only variables significantly associated with increased exercise-induced closure time change. Peak hematocrit maintained an independent association with peak closure time in multivariable analysis, although the correlation was mild. No variable, on the contrary, was associated with exercise-induced platelet reactivity after correction for basal closure time values at multivariable analyses. CONCLUSION: Among stable coronary artery disease patients, platelet reactivity after exercise cannot be reliably predicted by several common clinical and laboratory variables. PMID- 19786890 TI - Late complication of total anomalous pulmonary venous drainage in an adult: 'a diagnostic challenge'. AB - Total anomalous venous drainage is a rare congenital cardiac defect seen in 1% of the population; there is usually a concomitant atrial septal defect. We discuss such a diagnostic challenge in a patient who presented on a number of occasions with acute respiratory distress and haemoptysis. True understanding of her underlying congenital heart disease was not appreciated until review in a congenital heart disease clinic - in which she presented for prepregnancy counselling. She was found to have a stricture at the site of anastomosis of the common chamber with the left atrium, resulting in pulmonary venous hypertension leading to acute presentation of pulmonary haemorrhages. She underwent successful full balloon dilatation of the site, leading to full recovery. Most patients are diagnosed at birth and undergo surgical repair. The outcome is good, and historically it has been regarded that it is unusual for them to have long-term complications, although dysrhythmias remain a recognized long-term complication. Surgery for total anomalous pulmonary venous drainage is nevertheless a palliation, and it is vital that the possible role of late complications is considered in all cases. PMID- 19786891 TI - Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension. AB - Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterized by inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) leading to occlusion of pulmonary arterioles. Inhibition of platelet derived growth factor (PDGF) signaling is starting to garner attention as a targeted therapy for IPAH. We assessed the inhibitory effects of simvastatin, a 3 hydroxy-3-methylglutanyl coenzyme A reductase inhibitor, on PDGF-induced proliferation and migration of PASMCs obtained from 6 patients with IPAH who underwent lung transplantation. PDGF stimulation caused a significantly higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs as assessed by (3)H-thymidine incorporation. Simvastatin (0.1 micromol/L) significantly inhibited PDGF-induced cell proliferation of PASMCs from patients with IPAH but did not inhibit proliferation of normal control cells at the same concentration. Western blot analysis revealed that simvastatin significantly increased the expression of cell cycle inhibitor p27. PDGF significantly increased the migration distance of IPAH-PASMCs compared with that of normal PASMCs, and simvastatin (1 micromol/L) significantly inhibited PDGF-induced migration. Immunofluorescence staining revealed that simvastatin (1 micromol/L) inhibited translocation of Rho A from the cytoplasm to membrane and disorganized actin fibers in PASMCs from patients with IPAH. In conclusion, simvastatin had inhibitory effects on inappropriate PDGF signaling in PASMCs from patients with IPAH. PMID- 19786892 TI - Comparison of the effects of simvastatin versus atorvastatin on oxidative stress in patients with type 2 diabetes mellitus. AB - The aim of this study was to determine the effects of simvastatin and atorvastatin on the markers of oxidative stress in patients with type 2 diabetes mellitus (T2DM). The study population consisted of 151 patients with T2DM and 147 control individuals. The patients with T2DM were treated with 40 mg of simvastatin per day or 10 mg of simvastatin per day. Waist circumference, body mass index, blood pressure, and glucose and insulin values were obtained; and fasting serum lipids, malondialdehyde, nitric oxide, glutathione peroxidase and superoxide dismutase activity were determined before and after 12 weeks of treatment. Statin treatment significantly decreased plasma lipids in all patients with diabetes (P < 0.05). No significant differences were detected between the two treatment groups with respect to plasma lipid profile (P < 0.05). In addition, the effects of atorvastatin to increase nitric oxide concentration (33.28 +/- 3.37 micromol/L versus 27.32 +/- 4.15 micromol/L, P < 0.05) and glutathione peroxidase (17.67 +/- 1.41 micromol/L versus 14.28 +/- 1.65 micromol/L, P < 0.05), superoxide dismutase activity (34.28 +/- 4.71 micromol/L versus 27.91 +/- 3.38 micromol/L, P < 0.05 ) and decreased malondialdehyde level (49.52 +/- 5.67 micromol/L versus 42.08 +/- 5.16 micromol/L, P < 0.05) were significantly greater in patients with T2DM compared with simvastatin. The changes in the markers of oxidative stress did not correlate with the changes in plasma lipid profile (P > 0.05). This study suggested that atorvastatin reduced oxidative stress more effectively than simvastatin in patients with T2DM and the clinical benefits of statins may be independent of their cholesterol-lowering effects. PMID- 19786894 TI - Exposure-response relationship and risk assessment for cognitive deficits in early welding-induced manganism. AB - OBJECTIVE: The exposure-response relationship for manganese (Mn)-induced adverse nervous system effects is not well described. Symptoms and neuropsychological deficits associated with early manganism were previously reported for welders constructing bridge piers during 2003 to 2004. A reanalysis using improved exposure, work history information, and diverse exposure metrics is presented here. METHODS: Ten neuropsychological performance measures were examined, including working memory index (WMI), verbal intelligence quotient, design fluency, Stroop color word test, Rey-Osterrieth Complex Figure, and Auditory Consonant Trigram tests. Mn blood levels and air sampling data in the form of both personal and area samples were available. The exposure metrics used were cumulative exposure to Mn, body burden assuming simple first-order kinetics for Mn elimination, and cumulative burden (effective dose). Benchmark doses were calculated. RESULTS: Burden with a half-life of about 150 days was the best predictor of blood Mn. WMI performance declined by 3.6 (normal = 100, SD = 15) for each 1.0 mg/m3 x mo exposure (P = 0.02, one tailed). At the group mean exposure metric (burden; half-life = 275 days), WMI performance was at the lowest 17th percentile of normal, and at the maximum observed metric, performance was at the lowest 2.5 percentiles. Four other outcomes also exhibited statistically significant associations (verbal intelligence quotient, verbal comprehension index, design fluency, Stroop color word test); no dose-rate effect was observed for three of the five outcomes. CONCLUSIONS: A risk assessment performed for the five stronger effects, choosing various percentiles of normal performance to represent impairment, identified benchmark doses for a 2-year exposure leading to 5% excess impairment prevalence in the range of 0.03 to 0.15 mg/m3, or 30 to 150 microg/m3, total Mn in air, levels that are far below those permitted by current occupational standards. More than one-third of workers would be impaired after working 2 years at 0.2 mg/m3 Mn (the current threshold limit value). PMID- 19786893 TI - Postconditioning improves postischemic cardiac dysfunction independently of norepinephrine overflow after reperfusion in rat hearts: comparison with preconditioning. AB - We investigated whether the cardioprotective effect of ischemic postconditioning (postC) against ischemia/reperfusion (I/R)-induced cardiac dysfunction is associated with the negative control of I/R-enhanced norepinephrine (NE) overflow, an aggravating factor of I/R injury, in comparison with the effects induced by ischemic preconditioning (preC). According to the Langendorff technique, isolated rat hearts were subjected to 40-minute global ischemia followed by 30-minute reperfusion. PostC, consisting of three cycles of 30-second reperfusion followed by 30-second ischemia at the end of the 40-minute ischemia, improved I/R-induced cardiac dysfunction. However, the potency of this postC induced improvement was somewhat weaker than that produced by preC, consisting of three cycles of 5-minute ischemia followed by 5-minute reperfusion before 40 minute ischemia. The preC treatment markedly suppressed I/R-enhanced NE overflow, whereas postC had no apparent effect. A nonselective nitric oxide synthase inhibitor, N-nitro-L-arginine, almost completely abolished postC-induced cardiac protection without affecting NE overflow, whereas the effect of preC on I/R induced cardiac dysfunction and NE overflow was only partially inhibited by N nitro-L-arginine. These findings indicate that the beneficial effect of postC on I/R-induced cardiac dysfunction depends on nitric oxide and is irrelevant to NE overflow after reperfusion in contrast to the preC effect. PMID- 19786895 TI - The proactive approach--is it worthwhile? A prospective controlled ergonomic intervention study in office workers. AB - OBJECTIVE: Does proactive ergonomics program enhance office worker health and productivity? METHOD: The investigation was conducted in connection with the move of 1500 office staff to a building with improved ergonomics. It was focused on associations between workstation features, working postures, musculoskeletal pain symptoms, and eye strain before and 18 months after implementation of a proactive ergonomic program. The outcomes were compared between the intervention and a similar reference group. RESULTS: Associations between improvement of postures and less musculoskeletal pain and eye strain were confirmed. A cross association between several features and postures and improved symptoms was noted, along with improved productivity. CONCLUSION: The study suggests that a proactive program adhering to the OSHA recommendations needs to include an individual workstation assessment to be effective in reducing symptoms and increasing productivity. PMID- 19786896 TI - Peripheral and central auditory dysfunction induced by occupational exposure to organic solvents. AB - OBJECTIVE: To examine the effects of solvent exposure on hearing function, through an audiological test battery, in a population not occupationally exposed to high levels of noise. METHODS: One hundred ten workers from a coating factory were studied. Jobs at the factory were divided into three different levels of solvent exposure. Hearing status was assessed with a test battery including pure tone hearing thresholds (0.5-8 kHz), high-frequency hearing thresholds (12 and 16 kHz), and dichotic listening measured through dichotic digits test. Multiple linear regression models were created to explore possible association between solvent exposure and each of the hearing outcomes. RESULTS: Significant associations between solvent exposure and the three hearing outcomes were found. Covariates such as age, gender, race, and ethnicity were also significantly associated with the studied hearing outcomes. CONCLUSIONS: Occupational exposure to solvents may induce both peripheral and central auditory dysfunction. The dichotic digits test seems as a sensible tool to detect central auditory dysfunction associated with solvent exposure. Hearing loss prevention programs may use this tool to monitor hearing in solvent-exposed workers. PMID- 19786897 TI - Mortality rates among workers exposed to dioxins in the manufacture of pentachlorophenol. AB - OBJECTIVE: We sought to determine if workers exposed to dioxins in pentachlorophenol (PCP) manufacturing were at increased risk of death from specific causes. METHODS: We examined death rates among 773 workers exposed to chlorinated dioxins during PCP manufacturing from 1937 to 1980 using serum dioxin evaluations to estimate exposures to five dioxins. RESULTS: Deaths from all causes combined, all cancers combined, lung cancer, diabetes, and ischemic heart disease were near expected levels. There were eight deaths from non-Hodgkin lymphoma (standardized mortality ratios = 2.4, 95% CI = 1.0 to 4.8). We observed no trend of increasing risk for any cause of death with increasing dioxin exposure. However, the highest rates of non-Hodgkin lymphoma were found in the highest exposure group (standardized mortality ratios = 4.5, 95% CI = 1.2 to 11.5). CONCLUSIONS: Other than possibly an increased risk of non-Hodgkin lymphoma, we find no other cause of death related to the mixture of the dioxin contaminants found in PCP. PMID- 19786899 TI - Obstructive sleep apnea screening during commercial driver medical examinations: a survey of ACOEM members. AB - OBJECTIVE: To survey American College of Occupational and Environmental Medicine (ACOEM) members regarding recent consensus guidelines for screening commercial drivers for Obstructive Sleep Apnea (OSA). METHODS: A brief survey instrument was distributed electronically by the American College of Occupational and Environmental Medicine to its members during February 2008 to April 2008. RESULTS: Most (92%) of the 552 examiners opined that screening commercial drivers for OSA was important. Nevertheless, only 42% reported screening using consensus guidelines or another specific protocol. Common reasons for not applying the guidelines included unaware (36%), too complicated (12%), client retention (10%), and driver inconvenience (10%). Most would consider using the guidelines going forward but 39% wanted additional evidence and another 21% only if they became the "community standard." CONCLUSIONS: More education regarding OSA and drivers is needed. A Federal mandate and eliminating "doctor shopping" would likely increase examiners' compliance with screening. PMID- 19786900 TI - Employer model of workplace impacts of anti-TNF therapy for rheumatoid arthritis. AB - OBJECTIVE: Rheumatoid arthritis (RA) greatly affects patients' abilities to perform work, which can translate into substantial employer costs. We developed a customizable model that allows employers to calculate workplace impacts of RA therapies in employees with RA. METHODS: Costs of medical leave (absenteeism)/disability, reduced productivity, job turnover, and work-equipment adaptations for employees with RA were calculated. Costs of the tumor necrosis factor antagonist adalimumab were compared with those of other RA treatments. Default parameters were based on literature, clinical trials, government sources, and employers' data. RESULTS: Annual per-employee workplace cost was $9071 for adalimumab versus $16,335 for other RA therapies. Costs included reduced productivity (57%), absenteeism/disability (21%), and job turnover (21%). CONCLUSION: RA imposes a large financial burden on employers, predominantly owing to lost productivity. When compared with other RA therapies, adalimumab substantially reduced employers' costs. PMID- 19786901 TI - Association of comorbid mental health symptoms and physical health conditions with employee productivity. AB - OBJECTIVE: This study tests the hypothesis that employees with comorbid physical health conditions and mental health symptoms are less productive than other employees. METHODS: Self-reported health status and productivity measures were collected from 1723 employees of a national retail organization. chi2, analysis of variance, and linear contrast analyses were conducted to evaluate whether health status groups differed on productivity measures. Multivariate linear regression and multinomial logistic regression analyses were conducted to analyze how predictive health status was of productivity. RESULTS: Those with comorbidities were significantly less productive on all productivity measures compared with all other health status groups and those with only physical health conditions or mental health symptoms. Health status also significantly predicted levels of employee productivity. CONCLUSION: These findings provide evidence for the relationship between health statuses and productivity, which has potential programmatic implications. PMID- 19786898 TI - Association between fine particulate matter and oxidative DNA damage may be modified in individuals with hypertension. AB - OBJECTIVE: To investigate the association between particulate matter (PM2.5) and urinary 8-hydroxy-2'-deoxyguanosine (8-OHdG) in hypertensive and non-hypertensive individuals. METHODS: Twelve hypertensives and nine non-hypertensives were monitored during a 36-hour period using a repeated-measures panel study design. Personal exposure to PM2.5 was assessed using a real-time continuous monitor. Spot urine samples collected at 12-hour intervals were analyzed for 8-OHdG. RESULTS: Exposure to PM2.5 was associated with a decrease in 8-OHdG in hypertensives compared with an increase in non-hypertensives, after adjusting for age, gender, smoking status, and time of day. CONCLUSIONS: The results suggest modification of the association between PM2.5 exposure and urinary 8-OHdG by hypertension status. Antioxidant activity present in antihypertensive medications may play a role or PM2.5 exposure may reduce the capacity to repair DNA damage in hypertensives. These results should be confirmed with further investigation. PMID- 19786902 TI - The US Department of Defense Millennium Cohort Study: career span and beyond longitudinal follow-up. AB - OBJECTIVE: To describe current and future career-span health research in the US Department of Defense Millennium Cohort Study. METHODS: Collaborating with all military service branches and the Department of Veterans Affairs, the Millennium Cohort Study launched in 2001, before September 11 and the start of deployments in Afghanistan and Iraq, to conduct coordinated strategic research to determine any effects of military occupational and deployment-related exposures, on long term health. RESULTS: More than 150,000 consenting members represent demographic, occupational, military, and health characteristics of the US military. More than 70% of the first two panels have submitted follow-up questionnaires and >50% have deployed since 2001. CONCLUSIONS: Prospective cohort data have identified subgroups of military populations at higher risk or more resilient to decrements in mental and physical health. Continued career span and beyond follow-up will answer long-term health questions related to military service. PMID- 19786903 TI - Correlation between screening for obstructive sleep apnea using a portable device versus polysomnography testing in a commercial driving population. AB - OBJECTIVE: To compare the accuracy of portable monitoring for obstructive sleep apnea (OSA) with polysomnography (PSG) in commercial drivers. METHODS: A consecutive case series of drivers were screened for OSA using recent validated consensus conference criteria at a single occupational medicine clinic; those screening positive were tested with a portable OSA screening device while awaiting PSG. RESULTS: Three hundred forty-six drivers were screened and 34 completed PSG and portable monitoring. Comparing the portable device to PSG at a definition of OSA as an apnea hypopnea index (AHI) >or=15, positive predictive value is 0.64 with a 0.87 negative predictive value. Positive likelihood ratio is 4.20. Linear regression model found statistically significant relationship (P = 0.0004) between the portable device and PSG AHI values. CONCLUSION: Although not perfect, portable monitoring may be useful in further stratifying risk in drivers who have a high probability of having OSA. PMID- 19786904 TI - Cost-effectiveness of pemetrexed plus cisplatin as first-line therapy for advanced nonsquamous non-small cell lung cancer. AB - INTRODUCTION: To estimate the cost-effectiveness of first-line cisplatin/pemetrexed (Cis/Pem) compared with cisplatin/gemcitabine (Cis/Gem), carboplatin/paclitaxel (Carb/Pac), and carboplatin/paclitaxel/bevacizumab (Carb/Pac/Bev) in patients with advanced non-small cell lung cancer (NSCLC), particularly in those with nonsquamous cell histology (i.e., adenocarcinoma, large cell carcinoma, or histology not otherwise specified). METHODS: A semi Markov model was developed to compare the 2-year impact of Cis/Pem to three other first-line regimens from the U.S. payer perspective. Data from the randomized controlled clinical trial of Cis/Pem versus Cis/Gem and a mixed treatment comparison model (no head-to-head data were available for the Cis/Pem to Carb/Pac or Carb/Pac/Bev comparisons) provided clinical inputs. Medicare reimbursement rates were used to determine drug costs. A retrospective claims database analysis was used to obtain estimates of other direct NSCLC-related costs. RESULTS: In all patients with advanced NSCLC regardless of histologic subtype, using Cis/Pem as first-line chemotherapy led to an incremental cost per life-year gained (LYG) of $104,577 for Cis/Pem to Cis/Gem and $231,291 for Cis/Pem to Carb/Pac. In the prespecified subset of patients with nonsquamous cell histology, the incremental cost per LYG was $83,537 for Cis/Pem to Cis/Gem and $178,613 for Cis/Pem to Carb/Pac. The incremental cost per LYG for Carb/Pac/Bev to Cis/Pem was more than $300,000. CONCLUSIONS: Compared with commonly used and reimbursed regimens for first-line chemotherapy in advanced NSCLC, Cis/Pem may be considered cost effective, particularly in patients with nonsquamous cell histology. This analysis emphasizes the importance of histology in identifying the appropriate patient for Cis/Pem first-line chemotherapy. PMID- 19786905 TI - Active influenza vaccine safety surveillance: potential within a healthcare claims environment. AB - BACKGROUND: Rapid safety assessment of novel vaccines, especially those targeted against pandemic influenza, is a public health priority. OBJECTIVES: Assess the feasibility of using healthcare claims data to rapidly detect influenza vaccine adverse events using sequential analytic methods. RESEARCH DESIGN: Retrospective pilot study simulating prospective surveillance using 6 cumulative monthly administrative claims data extracts. The first included encounters occurring in October; each subsequent extract included an additional month of encounters. Ten adverse events were evaluated, comparing postvaccination rates during the 2006 2007 influenza season to those expected based on rates observed in the prior season. SUBJECTS: Members of a large, multistate health insurer who had a claim for influenza vaccination during the 2005-2006 or 2006-2007 influenza seasons. MEASURES: The completeness of monthly claims extracts. RESULTS: Most vaccinations and outcomes were identified early in the 2006-2007 season; about 50% of vaccinations and short latency events were identified in the second monthly data extract, which would typically become available by mid-December, and 80% of vaccinations and events were identified in the third extract. With respect to overall claims lag, approximately 90% of vaccinations and events were identified within 1 to 2 months after vaccination, regardless of vaccination month. CONCLUSIONS: This study suggests that administrative claims data might contribute to same season influenza vaccine safety surveillance in large, defined populations, especially during a threat of pandemic influenza. Based on our previous work, we believe this method could be applied to multiple health plans' data to monitor a large portion of the US population. PMID- 19786906 TI - Trends in disparities in receipt of adjuvant therapy for elderly stage III colon cancer patients: the role of the medical oncologist evaluation. AB - BACKGROUND: Race disparities in adjuvant chemotherapy for stage III colon cancer patients have been documented, and medical oncologist evaluation is a critical step in the treatment process. Recent healthcare system and environmental changes may have reduced treatment gaps. OBJECTIVES: To examine differential rates of oncologist evaluation and conditional treatment, by race, and to determine whether changing evaluation and treatment patterns reduced disparities. RESEARCH DESIGN: Retrospective analysis of Surveillance Epidemiology and End Results Medicare registry, enrollment, and claims data. SUBJECTS: Patients age >65, white or African American race, diagnosed with American Joint Committee on Cancer stage III colon cancer between 1997 and 2002. N = 7176. KEY MEASURES: Oncology specialty evaluation and management visit or chemotherapy claim; receipt of 5 fluorouracil based chemotherapy. Time periods are grouped into early (1997-1998), middle (1999-2000), and late (2001-2002). RESULTS: Initial adjusted oncologist evaluation rates were higher for whites compared with African American patients (58.7% vs. 42.9%), but changes over time reduced the race gap substantially. We did not find significant race-time trends in treatment rates conditional on oncologist evaluation. CONCLUSIONS: Race disparities in medical oncologist evaluations diminished over time, possibly in response to increased provider supply or changing patient and provider attitudes, but there was no parallel reduction in disparities in conditional treatment rates. Projected decreases in oncologist supply suggest the need for further research on this relationship. Research on the role of supplemental medical insurance on disparities in treatment is needed, particularly as the cost of recommended adjuvant therapy increases. PMID- 19786907 TI - How valid is the ICD-9-CM based AHRQ patient safety indicator for postoperative venous thromboembolism? AB - BACKGROUND: Hospital administrative data are being used to identify patients with postoperative venous thromboembolism (VTE), either pulmonary embolism (PE) or deep-vein thrombosis (DVT). However, few studies have evaluated the accuracy of these ICD-9-CM codes across multiple hospitals. METHODS AND MATERIALS: The Agency for Healthcare Research and Quality (AHRQ) Patient Safety Indicator (PSI)-12 was used to identify cases with postoperative VTE in 80 hospitals that volunteered for either an AHRQ or University HealthSystem Consortium (UHC) validation project. Trained abstractors using a standardized tool and guidelines retrospectively verified all coded VTE events. RESULTS: In the combined samples, the positive predictive value of the set of prespecified VTE codes for any acute VTE at any time during the hospitalization was 451 of 573 = 79% (95% CI: 75% 82%). However, the positive predictive value for acute lower extremity DVT or PE diagnosed after an operation was 209 of 452 = 44% (95% CI: 37%-51%) in the UHC sample and 58 of 121 = 48% (95% CI: 42-67%) in the AHRQ sample. Fourteen percent of all cases had an acute upper extremity DVT, 6% had superficial vein thrombosis and 21% had no acute VTE, however, 61% of the latter had a documented prior/chronic VTE. In the UHC cohort, the sensitivity for any acute VTE was 95.5% (95% CI: 86.4%-100%); the specificity was 99.5% (95% CI: 99.4%-99.7%). CONCLUSION: Current PSI 12 criteria do not accurately identify patients with acute postoperative lower extremity DVT or PE. Modification of the ICD-9-CM codes and implementation of "present on admission" flags should improve the predictive value for clinically important VTE events. PMID- 19786908 TI - Developing and validating process measures of health care quality: an application to alcohol use disorder treatment. AB - BACKGROUND: Health care process quality measures usually are designed by expert panels attempting to synthesize nuanced clinical evidence and subsequently operationalized using administrative data. Many quality measures are then adopted without directly validating their presumed links with outcomes. Later efforts to validate process measures often yield negative results, leaving policy makers without a defensible means of measuring quality. This article presents an alternative strategy for developing and validating process quality measures. The development of an alcohol use disorder (AUD) treatment quality measure is used as an example. METHODS: An expert panel generated a range of candidate process quality measures of AUD treatment derivable from administrative data that were then tested to determine which had the strongest associations with facility- and patient-level outcomes. Outcome and process data were from 2701 US Veterans Health Administration patients starting a new episode of care at 54 VA facilities. RESULTS: Several of the candidate process-of-care quality measures predicted facility- and patient-level outcomes. Having at least 3 visits during the first month of specialty AUD treatment was correlated with improvement on the Addiction Severity Index Alcohol composite at the facility level, r = 0.41 (95% Confidence Interval 0.16-0.61), and at the patient level, r = 0.07 (CI: 0.03 0.11). CONCLUSIONS: These "prevalidated" quality measures can now be judged for the extent they map onto the extant clinical literature and other design requirements. The development and validation strategy we describe should aid in efficiently producing quality measures in other areas of health care. PMID- 19786909 TI - Longitudinal racial/ethnic disparities in antimanic medication use in bipolar-I disorder. AB - OBJECTIVE: To examine racial/ethnic longitudinal disparities in antimanic medication use among adults with bipolar-I disorder. METHODS: Observational study using administrative data from Florida's Medicaid program, July 1997 to June 2005, for enrollees diagnosed with bipolar-I disorder (N = 13,497 persons; 126,413 person-quarters). We examined the likelihood of receiving one of the following during a given quarter: (1) any antimanic agent (antipsychotic or mood stabilizer) or none, and (2) mood stabilizers, antipsychotic monotherapy, or neither. Binary and multinomial logistic regression models predicted the association between race/ethnicity and prescription fills, adjusting for clinical and demographic characteristics. Cohort indicators for year that the enrollee met study criteria were included to account for cohort effects. RESULTS: Averaging over all cohorts and quarters, compared with whites, blacks had lower odds of filling any antimanic and mood stabilizer prescriptions specifically (40%-49% and 47%-63%, respectively), but similar odds of filling prescriptions for antipsychotic monotherapy. After Bonferroni adjustment, compared with whites, there were no statistically significant disparities for Hispanics in filling prescriptions for any, or specific antimanic medications. CONCLUSIONS: Rates of antimanic medication use were low regardless of race/ethnicity. However, we found disparities in antimanic medication use for blacks compared with whites and these disparities persisted over time. We found no Hispanic-white disparities. Quality improvement efforts should focus on all individuals with bipolar disorder, but particular attention should be paid to understanding disparities in medication use for blacks. PMID- 19786910 TI - Explaining urban-rural health disparities in China. AB - BACKGROUND: Given strict residency controls and geographic imbalances in health care resources, China may experience serious urban-rural health disparities. OBJECTIVES: To investigate urban-rural disparities in the patterns of health status and health care utilization in China and to examine the evolution of these disparities from 1997 to 2006. SUBJECTS: This study uses data from the China Health and Nutrition Survey 1997-2006 with a sample of 27,897 rural and 13,898 urban respondents aged 18 or older. MEASURES: We use self-reported health status, activity limitations due to illness, and diagnosis of serious diseases to measure health status, and physician visits for illness to measure health care utilization. RESULTS: Self-reported health status of urban residents is consistently worse than their rural counterparts (OR = 0.76; P < 0.01) based on multivariate logistic regression analysis. Urban residents are significantly more likely to have activity limitations due to illness (OR = 1.13; P < 0.01) and to have been diagnosed with a serious disease (OR = 1.69; P < 0.01). Urban residents are less likely to visit physicians for illness than are rural residents, a difference that has increased substantially since 1997. CONCLUSIONS: Urban residents appear to fare worse than rural residents in terms of overall health status and health care utilization in China. Identifying the causes of these urban-rural health disparities and developing appropriate policy responses are critical directions for researchers and policymakers. PMID- 19786911 TI - Impact of interpreters on the receipt of new prescription medication information among Spanish-speaking Latinos. AB - BACKGROUND: For Latinos, limited English proficiency (LEP) is a barrier to receiving important information about a new medication prescription. Access to interpreters may impact the receipt of important medication-related information. OBJECTIVE: To examine the association between interpreter use and reports of new prescription medication advice among Latinos with LEP. METHODS: We examined cross sectional survey data from 1590 Latino adults with LEP from 8 sites across the United States. The main outcomes are 5 measures of new prescription medication advising: (1) explanation of medication purpose, (2) explanation of possible side effects, (3) explanation of medication directions, (4) receipt of written information in Spanish from pharmacy, and (5) receipt of medicine bottle with Spanish language label. RESULTS: Among patients prescribed a new medication, 72% reported being told about the purpose of the medication, 52% about possible side effects, and 70% about how to take the new medicine. Forty-four percent said they received written medication information in Spanish from pharmacy, and 47% said their medicine bottle label was written in Spanish. Interpreter use was independently associated with receiving explanations about: possible side effects (adjusted odds ratio [AOR] = 1.81; 95% confidence intervals [CI]: 1.16-2.45); medication directions (AOR = 2.50; 95% CI: 1.67-3.59); and medication purpose (AOR = 3.55; 95% CI: 2.14-4.65). CONCLUSIONS: Among Latinos with LEP, interpreter use increases patient receipt of important information when a new medication is prescribed. There is a continuing need for effective policies and interventions to improve provider communication with LEP patients. PMID- 19786913 TI - The concentration and persistence of health care expenditures and prescription drug expenditures in Medicare beneficiaries with Alzheimer disease and related dementias. AB - BACKGROUND: Alzheimer disease and related dementias (ADRD) have become a major concern for Medicare because of the increasing prevalence rate and the associated high cost of care. OBJECTIVES: This study investigated the extent of concentration and persistence in total health care expenditures and prescription drug expenditures among the elderly with ADRD, and identified characteristics associated with expenditure persistence that may provide targets for cost containment approaches. RESEARCH DESIGN: This retrospective cohort study analyzed cross-sectional Medicare Current Beneficiary Survey data to examine expenditure concentration by calculating the proportion of total and prescription drug expenditures incurred by the top 10%, top 25%, and top 50% of beneficiaries in each year. A transition probability matrix and logit models were estimated to predict expenditure persistence over a 2-year period. RESULTS: The top 10% of beneficiaries with ADRD accounted for nearly half of total health expenditures and one-third of drug expenditures. Inpatient care comprised the largest share of overall expenditures in the top 10% group, whereas physician visits and prescription medications were the cost drivers in the bottom 50% group. Expenditure persistence was very strong, especially for prescription drugs. Prior expenditures and comorbidity burdens were the strongest predictors of persistence. CONCLUSIONS: The results of our study highlight the challenges to reducing expenditure growth and persistence for high-cost ADRD beneficiaries with prominent comorbidities. It will be important to examine whether better care coordination and disease management tailored to high-cost beneficiaries with ADRD can effectively contain costs. PMID- 19786912 TI - Prolonged hospital stay and the resident duty hour rules of 2003. AB - BACKGROUND: Resident duty hour reforms of 2003 had the potential to create a major impact on the delivery of inpatient care. OBJECTIVE: We examine whether the reforms influenced the probability of a patient experiencing a prolonged hospital length of stay (PLOS), a measure reflecting either inefficiency of care or the development of complications that may slow the rate of discharge. RESEARCH DESIGN: Conditional logistic models to compare PLOS in more versus less teaching intensive hospitals before and after the reform, adjusting for patient comorbidities, common time trends, and hospital site. SUBJECTS: Medicare (N = 6,059,015) and Veterans Affairs (VA) (N = 210,276) patients admitted for medical conditions (acute myocardial infarction, heart failure, stroke, or gastrointestinal bleeding) or surgical procedures (general, orthopedic, and vascular) from July 2000 to June 2005. MEASURES: Prolonged length of stay. RESULTS: Modeling all medical conditions together, the odds of prolonged stay in the first year post reform at more versus less teaching intensive hospitals was 1.01 (95% CI: 0.97-1.05) for Medicare and 1.07 (0.94-1.20) for the VA. Results were similarly negative in the second year post reform. For "combined surgery" the post year 1 odds ratios were 1.04 (0.98-1.09) and 0.94 (0.78-1.14) for Medicare and the VA respectively, and similarly unchanged in post year 2. Isolated increases in the probability of prolonged stay did occur for some vascular surgery procedures. CONCLUSIONS: Hospitals generally found ways to cope with duty hour reform without increasing the prevalence of prolonged hospital stays, a marker of either inefficient care or complications. PMID- 19786914 TI - The role of disability in explaining long-term care utilization. AB - OBJECTIVE: In view of aging populations, it is important to improve our understanding of the determination of long-term care (LTC) service use among the middle-aged and elderly population. We examined the likelihood of using 2 levels of LTC-homecare and institutional care-in the Netherlands and focused on the influence of the measured degree of disability. METHODS: We pooled 2 cross sectional surveys-one that excluded institutionalized and one that was targeted at institutionalized individuals aged 50+. Disability is measured by impairment in (instrumental) activities of daily living (iADL, ADL) and mobility. Consistency with official Dutch LTC eligibility criteria resulted in the selection of an ordered response model to analyze utilization. We compared a model with separate disability indicators to one with a disability index. RESULTS: Age and disability, but not general health, proved to be the main determinants of utilization, with the composite index sufficiently representing the disaggregated components. The presence of at least 1 disability displayed a greater effect on utilization than any additional disabilities. Apart from disability and age, sex, living alone, psychologic problems, and hospitalizations showed a significant influence on LTC use. Some determinants affected the likelihood of homecare or institutional care use differently. CONCLUSIONS: Even after extensive control for disability, age remains an important driver of LTC use. By contrast, general health status hardly affects LTC use. The model and disability index can be used as a policy tool for simulating LTC needs. PMID- 19786915 TI - Trends in prenatal ultrasound use in the United States: 1995 to 2006. AB - BACKGROUND: While controversy continues about the appropriateness of routine ultrasound screening, there are little data on actual clinical practices or trends in the United States. OBJECTIVES: To examine changes in prenatal ultrasound utilization over time and determine whether ultrasound utilization is associated with maternal age, race/ethnicity, payer status, region of the country, or pregnancy risk group. RESEARCH DESIGN: Data on prenatal visits to office-based physicians and hospital outpatient departments from the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey in 1995 to 2000, 2005, and 2006. MEASURE: Prenatal ultrasound use as recorded by a checkbox on the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey survey forms. We calculated the percent of visits with ultrasound, average number of ultrasounds per pregnancy, and adjusted odds ratios (ORs) of receiving an ultrasound. RESULTS: Overall, the estimated average number of ultrasounds per pregnancy increased from 1.5 in 1995 1997 to 2.7 in 2005-2006. For low-risk pregnancies, the estimated number of ultrasounds during that time period increased from 1.3 to 2.1. For high-risk pregnancies, the number increased from 2.2 to 4.2. In an adjusted analysis, the odds of a woman receiving an ultrasound in 2005-2006 were twice those of a visit in 1995-1997 [OR = 2.02; 95% CI (1.36, 3.00); P < 0.01]. High-risk women had odds of receiving an ultrasound that were almost twice that of women in the low-risk group [OR = 1.91; 95% CI (1.41, 2.59); P < 0.01]. CONCLUSIONS: Both low-risk and high-risk pregnant women in the United States are much more likely to receive repeated ultrasound examinations today than they were 10 years ago. PMID- 19786916 TI - Physician evaluation and management of Medicare home health patients. AB - OBJECTIVE: The Medicare home health benefit is predicated on physician referral and involvement. In this study, we investigated (1) the frequency and (2) implications of home health patients' evaluation and management by community physicians. METHODS: The 2005 and 2006 Medicare 5% Standard Analytic Files were linked to the Outcome and Assessment Information Set to examine physician visits among 74,462 fee-for service Medicare beneficiaries with a home health episode of care between July 1, 2005 and December 1, 2006. We examined whether receipt of community physician evaluation and management visits by home health patients was associated with subsequent discharge disposition, comparing discharge from the agency as opposed to inpatient facility transfer. RESULTS: More than one-third (34.6%) of patients did not receive physician evaluation and management visits during their home health episode. Home health patients most commonly incurred physician office visits exclusively (51.5%) or in combination with consultations (6.8%) or house call visits (2.2%), as well as house call visits exclusively (3.3%). Patients who incurred physician evaluation and management visits during their episode of care were more likely to be discharged from home health agencies than their counterparts who did not (77.9% vs. 70.6%, respectively). The association between physician visits and home health discharge was statistically significant in both simple regression models (odds ratio = 1.47; 95% confidence interval [CI], 1.42-1.52) and in multivariate analyses accounting for socio demographic factors, health, and functioning (odds ratio = 1.45; 95% CI, 1.40 1.51). CONCLUSIONS: More systematic integration of physicians in home care processes may reduce subsequent hospital and other inpatient facility use among home health patients. PMID- 19786917 TI - Medicare managed care enrollment by disability-eligible and age-eligible veterans. AB - OBJECTIVE: To assess factors associated with enrollment in a Medicare advantage (MA) plan versus Medicare fee-for-service plan in 2000-2004 by Medicare-eligible veterans. We also assessed whether these factors differed between disability eligible veterans and age-eligible veterans. METHODS: Medicare claims data, VA administrative data, and 2000 census data were constructed in a retrospective cohort study of 20,581 age-eligible veterans and 7541 disability-eligible veterans. MA enrollment in 2000-2004 was estimated in a logistic regression in a pooled sample of age-eligible and disability-eligible veterans that controlled for demographic, socioeconomic, and disease risk factors. Separate logistic regressions also were estimated for age-eligible and disability-eligible veterans. RESULTS: Minority veterans and veterans with lower disease risk scores were more likely to be enrolled in an MA plan in 2000-2004 than white veterans or veterans with higher risk scores. Age-eligible veterans were more likely to be enrolled if aged 75 or older, female, able to receive free VA care, or not enrolled in Medicaid. Disability-eligible veterans were more likely to be enrolled if they were married or elderly. CONCLUSIONS: Medicare Advantage plans appeared to benefit from favorable selection of Medicare-eligible veterans. PMID- 19786918 TI - The health consequences of using physical restraints in nursing homes. AB - BACKGROUND: Using a national longitudinal sample of nursing homes residents (N = 264,068), we examine whether physical restraint use contributes to subsequent physical or psychological health decline. METHODS: The minimum data set, the on line survey certification and recording system, and the area resource file were the data sources used. This data represented the period of 2004 and 2005. To control for the difference in characteristics between residents who were subsequently physically restrained and who were not, we use a propensity score matching method. RESULTS: For all outcomes examined (except depression), that is, behavior issues, cognitive performance, falls, walking dependence, activities of daily living, pressure ulcers, and contractures, were all significantly worse for restrained residents compared with matched residents who were not restrained. DISCUSSION: Physical restraint use represents poor clinical practice, and the benefits to residents of further reducing physical restraint use in nursing homes are substantial. PMID- 19786919 TI - Pediatric clinicians can help reduce rates of early childhood caries: effects of a practice based intervention. AB - OBJECTIVE: Early childhood caries (ECC) is a serious and preventable disease which pediatric clinicians can help address by counseling to reduce risk. RESEARCH DESIGN: We implemented a multifaceted practice-based intervention in a pediatric outpatient clinic treating children vulnerable to ECC (N = 635), comparing results to those from a similar nearby clinic providing usual care (N = 452). INTERVENTION: We provided communication skills training using the approach of patient centered counseling, edited the electronic medical record to prompt counseling, and provided parents/caregivers with an educational brochure. OUTCOME MEASURES: We assessed changes in provider knowledge about ECC after the intervention, and examined providers' counseling practices and incidence of ECC over time by site, controlling for baseline ECC, patient sociodemographics and parents'/caregivers' practice of risk factors (diet, oral hygiene, tooth monitoring), among 1045 children with complete data. RESULTS: Provider knowledge about ECC increased after the intervention training (percentage correct answers improved from 66% to 79%). Providers at the intervention site used more counseling strategies, which persisted after adjustment for sociodemographic characteristics. Children at the intervention site had a 77% reduction in risk for developing ECC at follow up, after controlling for age and race/ethnicity, sociodemographics and ECC risk factors; P A) on the development of recurrent pregnancy loss in embryonic and postembryonic periods. A total of 153 patients were analysed for FVL and FII 20210G>A according to placenta gestation: 94 women with embryonic loss prior 10 weeks of gestation and 59 women with postembryonic (early fetal) loss occurring between 10 and 14 weeks of gestation. The control group consisted of 100 healthy women, with at least one uncomplicated full-term pregnancy. FVL prevalence was not significantly associated with pregnancy loss prior to 10 weeks of gestation (9.6%) compared with controls (7%) [odds ratio (OR) 1.41; 95% confidence interval (CI) 0.454-4.416, P > 0.05], but it was much more pronounced in women with postembryonic loss (10-14 weeks of gestation) - 18.6% (OR 3.05; 95% CI 1.010-9.387, P = 0.047). FII 20210G>A was significantly higher in both groups with embryonic (17%) and early fetal losses (16.9%) as compared to controls (3%) (OR 6.63; 95% CI 1.731-29.752, P = 0.003; OR 6.60; 95% CI 1.572-31.856, P = 0.006). FII 20210G>A is significantly associated with an increased risk of early recurrent pregnancy loss throughout the entire first trimester. FVL was significantly higher only in early fetal period after starting of the placentation process, but not associated with embryonic recurrent pregnancy loss. These results suggested that the first trimester should be viewed rather as a heterogeneous interval, with different relation to FVL in the embryonic and postembryonic fetal period. Genetic testing should be applied according to the diverse contribution of thrombophilic markers to embryonic and postembryonic period. PMID- 19786942 TI - Comparison of six D-dimer assays for the detection of clinically suspected deep venous thrombosis of the lower extremities. AB - Deep venous thrombosis is a common disease that may lead to life-threatening embolism of the lung as a common complication. Therefore, early diagnosis followed by sufficient treatment is necessary to decrease mortality of this disease. D-dimer testing is established as a standard to rule out deep venous thrombosis in selected patient groups. However, there is no standardization among D-dimer assays, and a periodical comparison of assay performance in a select patient group is indispensable. We evaluated six commonly used D-dimer assays for their assay performance in an outpatient cohort with clinically suspected deep venous thrombosis. Although area under the curve for these assays did not differ significantly (0.83-0.88), differences in sensitivity (90-100%) and specificity (10-40%) of the assays were detected. Alternative cut-offs were established, and these cut-offs could enhance assay performance in some cases. This points to the fact that the manufacturers should more regularly review studies on the performance of their respective assays to widen the data basis for their recommended cut-offs and increase assay performance. PMID- 19786943 TI - Ultrastructural changes of platelets and fibrin networks in human asthma: a qualitative case study. AB - Platelets and fibrin networks play an important role in asthma and the BALB/c asthmatic mouse model has previously been successfully used to study platelet ultrastructure. In control BALB/c mice, major, thick fibers and minor thin fibers and tight, platelet aggregates with typical pseudopodia formation, are present. Minor fibers of asthmatic mice have a netlike appearance covering the major fibers, whereas the platelets seem to form loosely connected, granular aggregates. The question that now arises is whether platelets and fibrin networks of humans with asthma will have the same ultrastructure as seen in the BALB/c asthmatic model. In order to answer this question, ultrastructure of platelets and fibrin networks from two participants (controlled asthma and uncontrolled, chronic asthma) were studied and compared with that of human controls and BALB/c asthmatic mice. Peak flow measurements of the controls and patients were also assessed. Results showed that similar platelet and fibrin network ultrastructure is found in uncontrolled, human participants and BALB/c asthmatic animals. The challenge when using animal models is always whether the model adequately mimics the human disease; the current research, therefore, shows morphological support for the use of this model in the study of asthma. These morphological results may also provide additional information to plan treatment regimes for sufferers of this very debilitating disease. PMID- 19786944 TI - A novel in-frame deletion in the factor V C1 domain associated with severe coagulation factor V deficiency in a Korean family. AB - Hereditary coagulation factor V deficiency is a rare bleeding disorder characterized by extremely low levels of functional and immunoreactive factor V in plasma associated with moderate-to-severe bleeding symptoms. The genetic bases of factor V deficiency have been characterized only in a limited number of cases and the majority of causative mutations are truncating mutations providing only limited information about the function of subdomains and of individual residues. Here, we present the first report on a Korean family with inherited factor V deficiency. The proband is a 25-year-old man who showed normal coagulation factor levels except those for factor V antigen and activity (3 and 4%, respectively), and was only suffering from bleeding after tooth extraction. Direct sequencing of the factor V gene disclosed the already known nonsense mutation (R1133X) and a novel in-frame 6-bp deletion (6116-6121delGAACAG, corresponding to the amino-acid deletion N1982-S1983) located in the factor V C1 domain; both mutations were found in the heterozygous state. The structural and functional importance of the in-frame deletion was examined by constructing a molecular model based on the crystal structure of bovine activated factor V that has been inactivated by activated protein C. N1982 and S1983 are located on a loop that is exposed on the surface of the C1 domain, and are in close contact with another loop belonging to the A3 domain. Even though the detailed mechanism of the association of the in frame deletion of our patient and factor V deficiency needs further investigation, this model suggests the possibility that the N1982-S1983 deletion could destabilize the C1-A3 interaction by preventing the potential formation of hydrogen bonds between K1980 and N1986 of the C1 domain with D1604 of the A3 domain. Also, because N1982 is strongly expected to be N-glycosylated judging from its structural homology to factor VIII, loss of this residue can influence proper folding of factor V, resulting in unstable structure, which is vulnerable to intracellular degradation. PMID- 19786945 TI - A novel homozygous missense mutation in the factor VII gene of severe factor VII deficiency in a newborn baby. AB - A term male infant born to nonconsanguineous parents was admitted to the hospital for evaluation of lethargy and a pale appearance on the third day of life. He had anemia from an intracranial hemorrhage, and his coagulation factor assay revealed that his bleeding episode was due to severe congenital factor VII deficiency (5% of normal activity). An A-to-G point mutation in the acceptor splice site of intron 5 was identified at nucleotide position 9418. Sequence analysis of the factor VII gene in the parents revealed that they were both heterozygous for a G to-A transversion at nucleotide position 9418 (IVS5-1) between intron 5 and exon 6. A genetic study involving a patient with a congenitally inherited disease and the parents can confirm the genetic background of the disease and can be used for prenatal guidance to exclude severe bleeding disorders. PMID- 19786947 TI - Visualizing the beating heart in Drosophila. AB - The Drosophila heart has recently emerged as a good model system for examining the genetic, cellular, and molecular mechanisms underlying function in myogenic hearts. A key step in examining heart function in the fly is finding a way to access the heart in a manner that preserves its myogenic function while still allowing the beating heart organ to be observed and recorded. Two different methods for observing and recording the beating heart in both larva and adult Drosophila are described here. Our semi-intact preparation using adult flies allows clear visualization of the abdominal heart without interference from the pigmented cuticle and overlying fat bodies. To record larval heart beats it is necessary to immobilize the larva, which minimizes body wall movements thereby reducing heart movements that are not associated with myocardial contractions. Our methodologies produce stable adult and larval heart preparations that can beat for hours at rates of 1-3 Hz. PMID- 19786949 TI - Data producers deserve citation credit. PMID- 19786948 TI - Paracrine induction of endothelium by tumor exosomes. AB - Cancers use a nanoscale messenger system known as exosomes to communicate with surrounding tissues and immune cells. However, the functional relationship between tumor exosomes, endothelial signaling, angiogenesis, and metastasis is poorly understood. Herein, we describe a standardized approach for defining the angiogenic potential of isolated exosomes. We created a powerful technique to rapidly and efficiently isolate and track exosomes for study using dynamic light scattering in conjunction with fluorescent exosome labeling. With these methods, melanoma exosomes were observed to interact with and influence endothelial tubule morphology as well as move between endothelial tubule cells by means of tunneling nanotube structures. Melanoma exosomes also were observed to rapidly stimulate the production of endothelial spheroids and endothelial sprouts in a dose dependent manner. In concert, tumor exosomes simultaneously elicited paracrine endothelial signaling by regulation of certain inflammatory cytokines. These data suggest that, tumor exosomes can promote endothelial angiogenic responses, which could contribute to tumor metastatic potential. PMID- 19786950 TI - Alzheimer's disease beyond APOE. PMID- 19786951 TI - Tcf proteins are deeply rooted in skin. PMID- 19786957 TI - Intravitreal pegaptanib sodium for choroidal neovascularisation secondary to age related macular degeneration: Pan-European experience. AB - PURPOSE: To evaluate visual outcomes in patients with neovascular age-related macular degeneration (NV-AMD) who were treated with pegaptanib sodium in European clinical ophthalmology practices. METHODS: Thirteen centres in eight European countries participated in this retrospective study. Medical records for patients with any angiographic subtype of subfoveal choroidal neovascularisation secondary to NV-AMD with visual acuities (study eye) of 20/40-20/320 treated with 0.3 mg pegaptanib as first-line treatment and with at least 24 weeks of follow-up were identified. Anonymised data reflecting at least 24 and up to 54 weeks of follow up were recorded. Primary end points were visual acuity outcomes at weeks 24 and 54 compared with those reported at week 54 in the vascular endothelial growth factor (VEGF) Inhibition Study in Ocular Neovascularisation (VISION) trial. RESULTS: In all, 253 patients were followed for at least 24 weeks; 62 patients completed 54 weeks of follow-up. A mean of 4.4 (SD, 1.8) pegaptanib injections were administered through 24 weeks. Compared with the VISION trial, the European experience showed that >90% of patients in the current cohort lost <15 letters from baseline at both time points compared with 70% in the VISION trial at 54 weeks. Pegaptanib was well tolerated with no reported cases of endophthalmitis, traumatic cataract, or iatrogenic retinal detachment. CONCLUSIONS: Pegaptanib was found to stabilise vision in a greater percentage of patients and produced greater overall visual improvement in this group of treatment-naive patients with NV-AMD compared with outcomes reported in the VISION trial; however, interpretation of these results should be tempered given the differences in design between this retrospective study and the prospective controlled trial. PMID- 19786958 TI - Agreement of non-contact pachymetry after LASIK: comparison of combined scanning slit/Placido disc topography and specular microscopy. AB - PURPOSE: To assess the interchangeability of central corneal thickness (CCT) measurements between combined scanning-slit/Placido disc topography (Orbscan-II) and specular microscopy (Topcon SP-2000P) in patients who underwent laser in situ keratomileusis (LASIK) for myopia. PATIENTS AND METHODS: We recruited 118 consecutive patients who underwent LASIK for myopia. The CCT was measured using Orbscan-II and Topcon SP-2000P randomly. Orbscan-II and Topcon SP-2000P CCT data were analysed using the paired-sample t-test and the limits of agreement (LoA) were calculated with the method described by Bland-Altman. RESULTS: The average CCT measurements by Orbscan-II and Topcon SP-2000P were 447.55+/-49.78 microm and 461.38+/-35.35 microm, respectively (P<0.0001; mean difference, 13.83+/-22.31 microm; 95% confidence interval, 9.77-17.09 microm). The Bland-Altman plot showed an inverse association between the average and the difference between the devices: Topcon-Orbscan-II=174.23 -0.353xAverage (P<0.01). The widths of the crude and regression-based 95% limits of agreement were 87.45 and 63.72 microm, respectively. CONCLUSIONS: Orbscan-II measurements of CCT after myopic LASIK were significantly lower than those obtained using Topcon SP-2000P. The limits of agreement between the two devices were too broad and, therefore, both pachymetric values cannot be used interchangeably. Further, the tendency towards comparably Orbscan-II readings in thinner corneas precludes that one technique can directly replace the other. This is important for the adequate medium- and long-term follow-up of the growing LASIK patient population. PMID- 19786959 TI - Structural changes of fovea during remission of Behcet's disease as imaged by spectral domain optical coherence tomography. AB - PURPOSE: To acquire the image of the fovea during remission of ocular Behcet's disease using spectral domain optical coherence tomography (SD-OCT) and to further assess the correlation between best-corrected visual acuity (BCVA) and SD OCT findings. METHODS: A total of 24 eyes of 14 patients with ocular Behcet's disease were examined with SD-OCT. The relationships between BCVA and other clinical characteristics, including foveal thickness and status of external limiting membrane (ELM) or the junction between photoreceptor inner and outer segments (IS/OS), were analysed for statistical significance. RESULTS: BCVA in eyes with intact IS/OS was significantly better than that in eyes with ill defined IS/OS (P=0.0001). Foveal thickness (P=0.0001) and male sex (P=0.03) were also significantly different between eyes with and without complete IS/OS line. CONCLUSIONS: Definition of the IS/OS line by SD-OCT, but not status of the ELM line, appears to be associated with BCVA in patients with ocular Behcet's disease. Accordingly, SD-OCT may prove useful in the evaluation of visual function after ocular attacks of Behcet's disease. PMID- 19786960 TI - Evidence for rare and common genetic risk variants for schizophrenia at protein kinase C, alpha. AB - We earlier reported a genome-wide significant linkage to schizophrenia at chromosome 17 that was identified in a single pedigree (C702) consisting of six affected, male siblings with DSM-IV schizophrenia and prominent mood symptoms. In this study, we adopted several approaches in an attempt to map the putative disease locus. First, mapping the source of linkage to chromosome 17 in pedigree C702. We refined the linkage region in family C702 to a 21-marker segment spanning 11.7 Mb at 17q23-q24 by genotyping a total of 50 microsatellites across chromosome 17 in the pedigree. Analysis of data from 1028 single nucleotide polymorphisms (SNPs) across the refined linkage region identified a single region of homozygosity present in pedigree C702 but not in 2938 UK controls. This spanned ~432 kb of the gene encoding protein kinase C, alpha (PRKCA), the encoded protein of which has been implicated in the pathogenesis of psychiatric disorders. Analysis of pedigree C702 by oligonucleotide-array comparative genome hybridization excluded the possibility that this region of homozygosity was because of a deletion. Mutation screening of PRKCA identified a rare, four-marker haplotype (C-HAP) in the 3' untranslated region of the gene, which was present in the homozygous state in all six affected members of pedigree C702. No other homozygotes were observed in genotype data for a total of 6597 unrelated Europeans (case N=1755, control N=3580 and parents of probands N=1262). Second, association analysis of C702 alleles at PRKCA. The low-frequency haplotype (C HAP) showed a trend for association in a study of unrelated schizophrenia cases and controls from the UK (661 cases, 2824 controls, P=0.078 and odd ratio (OR)=1.9) and significant evidence for association when the sample was expanded to include cases with bipolar (N=710) and schizoaffective disorder (N=50) (psychosis sample: 1421 cases, 2824 controls, P=0.037 and OR=1.9). Given that all the affected members of C702 are male, we also undertook sex-specific analyses. This revealed that the association was strongest in males for both schizophrenia (446 male cases, 1421 male controls, P=0.008 and OR=3.9) and in the broader psychosis group (730 male cases, 1421 male controls, P=0.008 and OR=3.6). Analysis of C-HAP in follow-up samples from Ireland and Bulgaria revealed no evidence for association in either the whole sample or in males alone, and meta analysis of all male psychosis samples yielded no significant evidence of association (969 male cases, 1939 male controls, 311 male probands P=0.304 and OR=1.4). Third, association mapping of the pedigree C702 linkage region. Independent of pedigree C702, genotype data from the Affymetrix 500k GeneChip set were available for 476 patients with schizophrenia and 2938 controls from the United Kingdom. SNPs in PRKCA showed evidence for association with schizophrenia that achieved gene-wide significance (P=0.027). Moreover, the same SNP was the most significantly associated marker out of the 1028 SNPs genotyped across the linkage region (rs873417, allelic P=0.0004). Follow-up genotyping in samples from Ireland, Bulgaria and Germany did not show consistent replication, but meta analysis of all samples (4116 cases and 6491 controls) remained nominally significant (meta-analysis P=0.026, OR=1.1). We conclude that, although we have obtained convergent lines of evidence implicating both rare and common schizophrenia risk variants at PRKCA, none of these is individually compelling. However, the evidence across all approaches suggests that further study of this locus is warranted. PMID- 19786961 TI - Copy number variations of chromosome 16p13.1 region associated with schizophrenia. AB - Deletions and reciprocal duplications of the chromosome 16p13.1 region have recently been reported in several cases of autism and mental retardation (MR). As genomic copy number variants found in these two disorders may also associate with schizophrenia, we examined 4345 schizophrenia patients and 35,079 controls from 8 European populations for duplications and deletions at the 16p13.1 locus, using microarray data. We found a threefold excess of duplications and deletions in schizophrenia cases compared with controls, with duplications present in 0.30% of cases versus 0.09% of controls (P=0.007) and deletions in 0.12 % of cases and 0.04% of controls (P>0.05). The region can be divided into three intervals defined by flanking low copy repeats. Duplications spanning intervals I and II showed the most significant (P = 0.00010) association with schizophrenia. The age of onset in duplication and deletion carriers among cases ranged from 12 to 35 years, and the majority were males with a family history of psychiatric disorders. In a single Icelandic family, a duplication spanning intervals I and II was present in two cases of schizophrenia, and individual cases of alcoholism, attention deficit hyperactivity disorder and dyslexia. Candidate genes in the region include NTAN1 and NDE1. We conclude that duplications and perhaps also deletions of chromosome 16p13.1, previously reported to be associated with autism and MR, also confer risk of schizophrenia. PMID- 19786962 TI - First genome-wide association scan on neurophysiological endophenotypes points to trans-regulation effects on SLC2A3 in dyslexic children. AB - Dyslexia is one of the most common learning disorders affecting about 5% of all school-aged children. It has been shown that event-related potential measurements reveal differences between dyslexic children and age-matched controls. This holds particularly true for mismatch negativity (MMN), which reflects automatic speech deviance processing and is altered in dyslexic children. We performed a whole genome association analysis in 200 dyslexic children, focusing on MMN measurements. We identified rs4234898, a marker located on chromosome 4q32.1, to be significantly associated with the late MMN component. This association could be replicated in an independent second sample of 186 dyslexic children, reaching genome-wide significance in the combined sample (P = 5.14e-08). We also found an association between the late MMN component and a two-marker haplotype of rs4234898 and rs11100040, one of its neighboring single nucleotide polymorphisms (SNPs). In the combined sample, this marker combination withstands correction for multiple testing (P = 6.71e-08). Both SNPs lie in a region devoid of any protein coding genes; however, they both show significant association with mRNA expression levels of SLC2A3 on chromosome 12, the predominant facilitative glucose transporter in neurons. Our results suggest a possible trans-regulation effect on SLC2A3, which might lead to glucose deficits in dyslexic children and could explain their attenuated MMN in passive listening tasks. PMID- 19786964 TI - Mortality and disability: the effect of overweight and obesity. AB - CONTEXT: Prevalence of obesity is increasing globally. The effect of obesity on mortality and morbidity and its implication on the future prevalence of disability in the older population has not been conclusively analyzed. OBJECTIVE: To determine the influence of overweight and obesity on mortality and disability by quantifying the effect in terms of disability-free life expectancy and years lost to disability (YLD) in the older people. DESIGN, SETTING AND PARTICIPANTS: For 5980 participants from the Rotterdam Study cohort, regression techniques were used to estimate the association of body mass index (BMI) and waist circumference (WC) separately with mortality, incident disability and recovery from disability. Disability was assessed using the Stanford Health Assessment Questionnaire Disability Index, an activity of daily living scale. Multistate life table methodology was used to calculate life expectancies. MAIN OUTCOME MEASURES: In total, 15-year mortality risk, 6-year disability incidence, total life expectancy, healthy life expectancy and years of disabled life expectancy. RESULTS: We observed 2388 deaths. Our analysis revealed no association between body mass index, or WC and mortality in the healthy population. Body mass index and WC were related to disability ('overweight' 25 < or =BMI <30, odd ratio (OR)=1.33, 95% confidence interval (CI) (1.10; 1.61), 'obesity I' 30< or = BMI <35, OR=2.03, 95% CI (1.55; 2.65)) and negatively to recovery from disability. We observed an increase of years lost to disability with increasing weight for men ('normal weight'-4.69 years, 'overweight'-5.87 years and 'obesity I'-7.06 years) and for women ('normal weight'-10.95 years, 'overweight'-12.82 years, 'obesity I' 15.17 years and 'obesity II/III'-13.13 years). CONCLUSION: Results do not support the hypothesis that an increased body weight reduces total life expectancy in the older people. Although increased body weight was associated with a higher risk of becoming and remaining disabled. These results remained using WC. PMID- 19786965 TI - Maternal overweight before pregnancy and asthma in offspring followed for 8 years. AB - OBJECTIVE: The aim of this study was to investigate the association between maternal overweight before pregnancy and offspring asthma in an ongoing birth cohort study. Maternal overweight may affect the pulmonary and immunological development of the fetus in utero because of the increased levels of inflammatory factors associated with being overweight and thereby increase the asthma risk in childhood. DESIGN: Birth cohort study with follow-up until 8 years of age. SUBJECTS: The study population included 3963 children and their mothers who participated in the Prevention and Incidence of Asthma and Mite Allergy study. MEASUREMENTS: Maternal overweight before pregnancy was defined as a body mass index (BMI) above 25 kg m(-2). Data on wheeze, dyspnea and prescription of inhaled corticosteroids of the child were reported yearly by the parents in a questionnaire. Sensitization to inhalant allergens and bronchial hyperresponsiveness (BHR) were determined at 8 years. Effect modification by predisposition for asthma in the child was tested. Data were analyzed by logistic regression and generalized estimating equations analyses. RESULTS: At 8 years, 14.4% (n=571) of the children had asthma. In total, 20.9% (n=830) of the mothers were overweight before pregnancy. In children predisposed for asthma (n=1058), maternal overweight before pregnancy was associated with an increased risk of asthma in the child at 8 years (OR=1.52, 95% CI: 1.05-2.18) after adjustment for confounding factors, birth weight and the child's BMI. No association was observed in children without a predisposition (OR=0.86, 95% CI: 0.60-1.23). There was no association with sensitization or BHR. CONCLUSION: Children with a predisposition for asthma may have a higher risk to develop asthma during childhood when their mothers are overweight before pregnancy, irrespective of the child's BMI. PMID- 19786966 TI - LIGHT is associated with hypertriglyceridemia in obese subjects and increased cytokine secretion from cultured human adipocytes. AB - BACKGROUND: LIGHT (lymphotoxin-like inducible protein that competes with glycoprotein D for herpesvirus entry on T cells) is a member of the tumor necrosis factor (TNF) family, primarily expressed in lymphocytes, which was associated with the induction of pro-inflammatory cytokines and alterations of lipid homeostasis in animal models. We aimed to analyze whether LIGHT has a role in the human obesity-associated inflammatory status. METHODS: The association between circulating LIGHT concentrations and clinical variables was studied in 190 subjects with different degrees of obesity and glucose tolerance. The expression and release of 21 different cytokines, and the expression of genes involved in lipid metabolism were also evaluated after stimulation with LIGHT in cultured human differentiated adipocytes. RESULTS: Serum LIGHT concentrations positively associated with body mass index (BMI), fat mass, glycated hemoglobin and fasting triglycerides, and negatively with high-density lipoprotein cholesterol. Circulating LIGHT concentrations were significantly increased in morbidly obese subjects and in patients with type 2 diabetes. LIGHT induced the secretion of several cytokines and upregulated the expression and secretion of interleukin-6 (IL-6), IL-8, Growth Regulated Oncogene (GRO) and monocyte chemotactic protein-1 (MCP-1). These observations were concomitant with the activation of nuclear factor (NF)-kappaB signalling in human differentiated adipocytes. LIGHT also upregulated the expression and synthesis of its own receptor (herpesvirus entry mediator (HVEM)) and decreased the expression of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) and fatty acid synthase. CONCLUSION: These data suggest that LIGHT may have a role in mediating chronic inflammation and alterations of lipid metabolism in obese subjects. PMID- 19786963 TI - The neurobiology of D-amino acid oxidase and its involvement in schizophrenia. AB - D-amino acid oxidase (DAO) is a flavoenzyme that metabolizes certain D-amino acids, notably the endogenous N-methyl D-aspartate receptor (NMDAR) co-agonist, D serine. As such, it has the potential to modulate the function of NMDAR and to contribute to the widely hypothesized involvement of NMDAR signalling in schizophrenia. Three lines of evidence now provide support for this possibility: DAO shows genetic associations with the disorder in several, although not all, studies; the expression and activity of DAO are increased in schizophrenia; and DAO inactivation in rodents produces behavioural and biochemical effects, suggestive of potential therapeutic benefits. However, several key issues remain unclear. These include the regional, cellular and subcellular localization of DAO, the physiological importance of DAO and its substrates other than D-serine, as well as the causes and consequences of elevated DAO in schizophrenia. Herein, we critically review the neurobiology of DAO, its involvement in schizophrenia, and the therapeutic value of DAO inhibition. This review also highlights issues that have a broader relevance beyond DAO itself: how should we weigh up convergent and cumulatively impressive, but individually inconclusive, pieces of evidence regarding the role that a given gene may have in the aetiology, pathophysiology and pharmacotherapy of schizophrenia? PMID- 19786967 TI - Are standard behavioral weight loss programs effective for young adults? AB - OBJECTIVE: To compare the enrollment, attendance, retention and weight losses of young adults in behavioral weight loss (BWL) programs with older participants in the same trials. METHODS: Data were pooled from three NIH-funded adult BWL trials from two clinical centers in different regions of the country (total N=298); young adults were defined as those aged 18-35 years. Both young adults and adults were compared on session attendance, retention at the 6-month assessment, weight loss and physical activity at 6 months. RESULTS: Young adults represented 7% of the sample, attended significantly fewer sessions than did adults (52 vs 74%, respectively; P<0.001) and were less likely to be retained for the 6-month assessment (67 vs 95%, respectively; P<0.05). Controlling for demographic variables, study and baseline weight, the mean weight losses achieved were significantly less for young adults compared with adults (-4.3 kg (6.3) vs -7.7 kg (7.0), respectively; P<0.05); fewer young adults achieved > or =5% weight loss at 6 months compared with older participants (8/21 (38%) vs 171/277 (62%); P<0.05). After controlling for session attendance, differences in the mean weight loss were not significant (P=0.81). Controlling for baseline values, study and demographics, changes in total physical activity over the initial 6 months of treatment were less for young adults compared with adults, but these differences only approached statistical significance (P=0.07). CONCLUSION: These data indicate that standard programs do not meet the weight control needs of young adults. Research is urgently required to improve recruitment and retention efforts with this high-risk group. PMID- 19786968 TI - Knockdown of angiotensinogen by shRNA-mediated RNA interference inhibits human visceral preadipocytes differentiation. AB - OBJECTIVE: The immediate cause of obesity is the massive deposition of subcutaneous and visceral fat attributing to the continuous proliferation and differentiation of preadipocytes. The identification of the underlying molecular mechanisms of preadipocytes differentiation is urgent, and will have an important role in plastic and reconstructive surgical procedures. METHODS: Two small hairpin RNA (shRNA)-mediated RNA interference plasmids have been constructed on the basis of the activity of H1 promoter-driven expression vector psiRNA-hH1neo to suppress the expression of angiotensinogen (AGT) in human preadipocytes visceral (HPA-v). Subsequently, glycerol-3-phosphate dehydrogenase (G3PDH) activity and intracytoplasmic lipids content were detected during the process of HPA-v differentiation. RESULTS: Small hairpin RNA-expressing vectors have been successfully constructed to suppress the expression of AGT significantly. Both intracytoplasmic lipids content and G3PDH activity decreased to a certain extent compared with that in the control group in the whole process of HPA-v differentiation. CONCLUSIONS: Two shRNA-mediated AGT-targeting plasmids inhibited the process of HPA-v differentiation to a certain extent. However, the accumulation of intracytoplasmic lipids was not exclusively determined by the expression of AGT, and it may also be regulated by other factors. In conclusion, this study provided a method to inhibit the process of preadipocytes differentiation, and it may have a role in obesity treatment and adipose tissue engineering application. PMID- 19786969 TI - Human obesity relationship with Ad36 adenovirus and insulin resistance. AB - OBJECTIVES: Infection with specific pathogens may lead to increased adiposity: a specific adiposity-promoting effect of Ad36 human adenovirus, without the involvement of neurological mechanisms, was reported. The aim of this study is to investigate whether non-diabetic patients with earlier Ad36 infection show greater degrees of overweight obesity, of Insulin Resistance (IR), assessed by homoeostasis-model assessment (HOMA), and/or of other related factors. Moreover, the relationship, if any, among these factors and an earlier Ad36 infection, and the hypothesis of a mechanism involving IR are investigated. SUBJECTS: Ad36 seropositivity is assessed in 68 obese and 135 non-obese subjects, along with body composition, HOMA and laboratory investigations. RESULTS: Age, body mass index (BMI), waist-hip ratio, blood pressure, insulin, HOMA and triglycerides are significantly greater in the Ad36 seropositive group. Ad36 seropositivity, along with HOMA and total cholesterol, explains BMI variance. No Ad36 seropositivity effect to HOMA could be envisaged by the same statistical model. CONCLUSION: A significant association of Ad36 seropositivity with obesity and with essential hypertension in human beings is suggested by our study; this association is mostly significant in women. Our results do not support that any Ad36 adipogenic adenovirus effect is operating in human obesity through an insulin-resistance related mechanism. Ad36 seropositive status could also be a hallmark of a clinical-metabolic profile possibly preceding obesity and diabetes in non-obese patients. PMID- 19786970 TI - Growth from birth to adulthood and abdominal obesity in a Brazilian birth cohort. AB - BACKGROUND: Rapid weight gain in childhood may increase the risk of chronic adult diseases. Few studies have examined the effects of lifecourse weight gain on waist circumference (WC), hip circumference (HC), or waist-to-hip ratio (WHR). OBJECTIVE: To evaluate the effects of birthweight and weight gain from birth to age 23 years on WC, HC, and WHR in young adults. DESIGN: Population-based birth cohort study started in 1982. A sample of 856 individuals was examined in 2006. Conditional growth analyses were carried out with adjustment for confounders. WC and HC were also mutually adjusted. RESULTS: Weight gains during all age ranges studied (birthweight, 0-2, 2-4, 4-15, 15-18/19, and 18/19-23 years) were positively associated with WC and HC in both sexes. These effects were strongest from 4 to 15 years range (beta = 5.0 cm for both circumferences). Proxies for visceral adipose tissue (WHR and WC adjusted for HC) were associated with weight gain after 2 years in females and after 4 years in males. Subcutaneous adipose and muscular tissues, assessed by HC adjusted for WC, were associated with birthweight and weight gain from 0 to 2 years in both sexes, and again with weight gains from 4 to 18 years in males and 4 to 15 years in females. CONCLUSIONS: Weight gains in utero and in the first 2 years had long-term effects on HC, but weight gain after age 4 years was strongly associated with WC. Weight gains up to age 2 years may reduce cardiovascular risk associated with adult fat patterns in a middle-income setting. PMID- 19786971 TI - Associations of insulin-like growth factor binding protein-3 gene polymorphisms with IGF-I activity and lipid parameters in adolescents. AB - OBJECTIVE: Childhood obesity is a growing global epidemic. Recent studies indicate that obesity and related metabolic traits are highly heritable. Increasing evidence suggests that growth hormone (GH) and the insulin-like growth factor-I (IGF-I) axis have important functions in regulating adiposity and insulin sensitivity. Five single-nucleotide polymorphisms (SNPs) at IGF-binding protein-3 (IGFBP3) were genotyped to find their associations with IGF-1 activity level and common clinical metabolic traits. PATIENTS AND METHODS: We examined the associations of five SNPs at IGFBP3 with serum IGF-I and IGFBP-3 levels, as well as with obesity-related metabolic traits in 981 Hong Kong Chinese adolescents. Factor analysis was used to reduce the intercorrelated variables to five factor scores indicating body composition, blood pressure, IGF-I activity, triglyceride (TG)+high-density lipoprotein cholesterol (HDL-C) and total cholesterol (TC)+low density lipoprotein cholesterol (LDL-C) factor scores. RESULTS: There was a strong association between the -202A/C polymorphism (rs2854744) and IGF-I activity (P=1.2 x 10(-6)) and TC+LDL-C factor scores (P=0.0085), corrected for age and sex. The C allele was associated with decreased IGFBP-3 levels (P=1.21 x 10(-13)), increased IGF-I/IGFBP-3 molar ratio (P=5.22 x 10(-6)) and decreased LDL C (P=0.020). There was also a significant association between a G/A polymorphism at the 3' flanking sequence (rs13223993) of the IGFBP3 gene and the TG+HDL-C factor score (P=0.0013). The minor A allele carriers of rs13223993 had a lower HDL-C (P=0.0067) level and a tendency toward a high TG level. Haplotype analysis did not increase the significance of associations between single SNPs and phenotypes. CONCLUSION: Our results support the function of IGFBP3 gene polymorphisms in modulating IGF-I activity and lipid levels in adolescents. Given the prognostic significance of IGF-I, IGFBPs and lipids on risk of diabetes, obesity and cancer, long-term studies are required to clarify the clinical meaning of these findings. PMID- 19786972 TI - A case of neuro-Behcet's disease presenting with lumbar spinal cord involvement. AB - STUDY DESIGN: Case report. OBJECTIVES: To report an unusual case of neuro Behcet's disease (NBD) presenting with isolated myelitis that affected the lumbar cord. SETTING: Department of Neurology, West China Hospital, Chengdu, Sichuan, China. METHODS: A 19-year-old man presented with a 3-day history of paresthesia and weakness in both the legs. He had a 6-year history of recurrent oral and genital ulcers with erythema nodosum on his legs. Magnetic resonance imaging (MRI) revealed a T1-hypointense and T2-hyperintense lesion at the L1 level. Nodular enhancement of the lesion was achieved with gadolinium administration. Biopsy specimens from cutaneous lesions were consistent with an active perivasculitic process. RESULTS: Corticosteroid (pulsed methylprednisolone followed by oral prednisolone) therapy was administered immediately. Subsequently, the patient's clinical condition improved dramatically. The spinal cord lesion disappeared on the MRI performed 1 year later. Thus far, there has been no recurrence. CONCLUSION: NBD may involve the lumbar spinal cord. Prompt recognition of this disease and early vigorous steroid therapy are important to prevent further disability and recurrence. PMID- 19786973 TI - ICF Core Sets for individuals with spinal cord injury in the early post-acute context. AB - STUDY DESIGN: A formal decision-making and consensus process integrating evidence gathered from preparatory studies was followed. OBJECTIVES: The aim of this study was to report on the results of the consensus process to develop the first version of a Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set and a Brief ICF Core Set for individuals with spinal cord injury (SCI) in the early post-acute context. SETTING: The consensus conference took place in Switzerland. Preparatory studies were performed worldwide. METHODS: Preparatory studies included an expert survey, a systematic literature review, a qualitative study and empirical data collection involving people with SCI. ICF categories were identified in a formal consensus process by international experts from different backgrounds. RESULTS: The preparatory studies identified a set of 531 ICF categories at the second, third and fourth levels. From 30 countries, 33 SCI experts attended the consensus conference (11 physicians, 6 physical therapists, 5 occupational therapists, 6 nurses, 3 psychologists and 2 social workers). Altogether 162 second-, third- or fourth-level categories were included in the Comprehensive ICF Core Sets with 63 categories from the component Body Functions, 14 from Body Structures, 53 from Activities and Participation and 32 from Environmental Factors. The Brief Core Set included a total of 25 second-level categories with 8 on Body Functions, 3 on Body Structures, 9 on Activities and Participation, and 5 on Environmental Factors. CONCLUSION: A formal consensus process-integrating evidence and expert opinion based on the ICF led to the ICF Core Sets for individuals with SCI in the early post-acute context. Further validation of this first version is needed. PMID- 19786974 TI - Fournier's gangrene in a female with spinal cord injury: a case report. AB - INTRODUCTION: We report the case of a woman with spinal cord injury (SCI) who presented to us with Fournier's gangrene. CASE REPORT: A 60-year-old patient with SCI, ASIA A, neurological level D6, on clean intermittent catheterization presented with rapid necrosis of the perineal region, including the labia and anus, which developed after traumatic catheterizations for clean intermittent catheterization. She required repeated debridement and loop colostomy for management. CONCLUSION: We conclude that patients with SCI are rarely at risk for Fournier's gangrene secondary to neurogenic bladder and bowel, as well as to impaired sensations and genital flora. Treating physicians need to be aware of this complication in order to prevent mortality. PMID- 19786975 TI - Reliability and validity of the International Spinal Cord Injury Basic Pain Data Set items as self-report measures. AB - OBJECTIVE: To evaluate the psychometric properties of a subset of International Spinal Cord Injury Basic Pain Data Set (ISCIBPDS) items that could be used as self-report measures in surveys, longitudinal studies and clinical trials. SETTING: Community. METHODS: A subset of the ISCIBPDS items and measures of two validity criteria were administered in a postal survey to 184 individuals with spinal cord injury (SCI) and pain. The responses of the participants were evaluated to determine: (1) item response rates (as an estimate of ease of item completion); (2) internal consistency (as an estimate of the reliability of the multiple-item measures); and (3) concurrent validity. RESULTS: The results support the utility and validity of the ISCIBPDS items and scales that measure pain interference, intensity, site(s), frequency, duration and timing (time of day of worst pain) in individuals with SCI and chronic pain. The results also provide psychometric information that can be used to select from among the ISCIBPDS items in settings that require even fewer items than are in the basic data set. PMID- 19786976 TI - Sagittal spinal alignment in paraplegics: a new paradigm for the rehabilitation under neuromuscular electrical stimulation. AB - STUDY DESIGN: Radiographic analysis of sagittal spinal alignment of paraplegics in a standing position under surface neuromuscular electrical stimulation (NMES). OBJECTIVES: Describing the radiographic parameters of the sagittal spinal alignment of paraplegics going through a rehabilitation program with NMES. SETTING: The University Hospital's Ambulatory (UNICAMP), Campinas, Sao Paulo, Brazil. METHODS: Panoramic X-ray images in profile were taken for 10 paraplegics. All patients participated in the rehabilitation program and were able to perform gait through NMES of the femoral quadriceps muscles. The radiographic parameters used for the analysis were the same as those described in the literature for healthy people. The results were didactically organized into three groups: anatomical shape of the spine, morphology and kinetics of the pelvis and spinopelvic alignment. RESULTS: The physiological curvature of the spine in paraplegics showed average values similar to those described in the literature for healthy patients. The inversion of the pelvic tilt and the increase in the sacral slope were defined by the anterior backward rotation of the pelvis. The existing theoretical mathematical formulas that define lumbar lordosis, pelvic incidence and pelvic tilt showed normal values, despite the anterior intense sagittal imbalance. CONCLUSIONS: The adaptive posture of the spine in paraplegics standing through the stimulation of the femoral quadriceps does not allow for a neutral sagittal alignment. This novel radiographic detailed description of the various segments of the spine can be of assistance toward the understanding of the global postural control for such subjects. PMID- 19786977 TI - Modified Ashworth scale reliability for measurement of lower extremity spasticity among patients with SCI. AB - STUDY DESIGN: Observational study. OBJECTIVES: To report the intra-rater (one rater), inter-rater (two raters) and inter-session (one subject, sessions 1-5) reliability of lower extremity modified Ashworth scale (MAS) scores among patients with chronic spinal cord injury (SCI). SETTING: Tertiary Academic Rehab Centre in Toronto, Canada. METHODS: MAS scores of 20 subjects with chronic SCI (C5-T10 AIS A-D>12 months) were recorded for the hip abductors and adductors, knee flexors and extensors, and ankle plantar and dorsiflexors. MAS scores were assessed by two blinded raters (A and B) at the same time of day, weekly for 5 weeks using standardized test positions, a one-cycle per second metronome, with ratings recorded on the second cycle. MAS score reproducibility [intra-rater, inter-rater] were calculated using Cohen's Kappa. Intraclass correlation coefficients (ICCs) were calculated to determine inter-session (trials 1-5) reliability; Kappa values >or=0.81 and ICC values >or=0.75 were desired. RESULTS: Intra-rater reliability was fair to almost perfect (0.2T polymorphism correlated with the overall survival: patients with T/T genotype survived longer than C/C carriers (P=0.044). Thrombocytopenia, anemia and neuropathy were less frequent among patients with the GSTM1-null or GSTM3 intron 6 AGG/AGG genotypes. Severe neutropenia was associated with the TP53 72 Pro/Pro, XPD 312 Asp/Asn and XRCC1 399 Arg/Arg genotypes. A higher risk of nephrotoxicity was noted for patients with the heterozygous ERCC1 19007 T/C and 8092 C/A genotypes. No correlations were found between genotypes and complete tumor responses. PMID- 19786981 TI - Expression and prognostic role of syndecan-2 in prostate cancer. AB - Syndecans are a four-member family of transmembrane heparan sulphate proteoglycans that have different functions in cell signalling, adhesion, cytoskeleton organization, migration, proliferation, and angiogenesis. Several studies investigated the role of syndecan-2 (SDC2) in different carcinomas; however, only one being focused on SDC2 in prostate cancer. SDC2 expression and relationship with established prognostic features were assessed in a cohort of 86 patients treated with radical prostatectomy for clinically localized prostate adenocarcinoma. SDC2 expression was present in the majority of prostate cancers and absent in only 11.6% of cases. SDC2 expression was also recorded in cells of prostatic intraepithelial neoplasia, whereas normal prostatic epithelial tissue and stroma did not express SDC2. SDC2 overexpression in prostate cancer was significantly associated with established features indicative of worse prognosis such as higher preoperative PSA (P=0.011), higher Gleason score (P<0.001), positive surgical margins (P<0.003), and extraprostatic extension of disease (P<0.003). Moreover, expression of SDC2 was also associated with biochemical disease progression on univariate analysis (P<0.001). Study results supported the potential role of SDC2 in prostatic carcinogenesis and cancer progression. Moreover, SDC2 could serve as an additional prognostic marker that might help in further stratifying the risk of disease progression in patients with prostate cancer. PMID- 19786982 TI - Performance of transperineal template-guided mapping biopsy in detecting prostate cancer in the initial and repeat biopsy setting. AB - Transrectal ultrasound (TRUS) biopsy can miss 20-30% of clinically significant cancers. We evaluate an alternative approach-transperineal template-guided mapping biopsy (TTMB) in the initial and repeat biopsy setting. From January 2005 through September 2008, 373 consecutive men underwent TTMB (294 men with > or =1 prior negative biopsy and 79 men as the initial biopsy). The location of each positive biopsy core, number of positive cores, and percent involvement of each core was recorded. Cancer detection rate for the initial biopsy was 75.9%. For men with 1, 2, and > or =3 prior negative biopsies detection rates were 55.5%, 41.7%, and 34.4%, respectively. In all, 55.5% of the cancers identified were Gleason > or =7. The majority of the cancers were multifocal. There was no significant change in the number of positive cores or Gleason score as the number of prior biopsies increased. The anterior and apical aspects of the prostate were among the most common cancer locations. TTMB provides a high rate of cancer detection as initial and repeat biopsy. TTMB was particularly effective at diagnosing anterior and apical cancer. TTMB may have particular application for men considering active surveillance, with prior negative TRUS biopsies, and those considering subtotal gland or other minimally invasive treatments. PMID- 19786983 TI - Calcification in atherosclerosis. AB - Coronary calcification has long been known to occur as a part of the atherosclerotic process, although whether it is a marker of plaque stability or instability is still a topic of considerable debate. Coronary calcification is an active process resembling bone formation within the vessel wall and, with the advances in CT technology of the past decade, can be easily quantified and expressed as a coronary artery calcium (CAC) score. The extent of calcium is thought to reflect the total coronary atherosclerotic burden, which has generated interest in using CAC as a marker of risk of cardiovascular events. The current consensus is that large amounts of CAC identify a highly vulnerable patient rather than a vulnerable plaque or vulnerable vessel. Indeed, CAC has incremental prognostic value beyond traditional risk factors in various subsets of the population. Furthermore, whereas the presence of CAC is associated with increased risk, a zero CAC score predicts excellent short-term to mid-term prognosis, even in high-risk patients. The advent of CT angiography has perhaps clouded the importance of CAC as a long-term marker of risk, as opposed to the presence of luminal stenoses that are associated with a more immediate risk of events. PMID- 19786984 TI - Cyclophosphamide and cancer: golden anniversary. AB - Cyclophosphamide remains one of the most successful and widely utilized antineoplastic drugs. Moreover, it is also a potent immunosuppressive agent and the most commonly used drug in blood and marrow transplantation (BMT). It was initially synthesized to selectively target cancer cells, although the hypothesized mechanism of tumor specificity (activation by cancer cell phosphamidases) transpired to be irrelevant to its activity. Nevertheless, cyclophosphamide's unique metabolism and inactivation by aldehyde dehydrogenase is responsible for its distinct cytotoxic properties. Differential cellular expression of aldehyde dehydrogenase has an effect on the anticancer therapeutic index and immunosuppressive properties of cyclophosphamide. This Review highlights the chemistry, pharmacology, clinical toxic effects and current clinical applications of cyclophosphamide in cancer and autoimmune disorders. We also discuss the development of high-dose cyclophosphamide for BMT and the treatment of autoimmune diseases. PMID- 19786985 TI - Internalization of NK cells into tumor cells requires ezrin and leads to programmed cell-in-cell death. AB - Cytotoxic lymphocytes are key players in the orchestration of immune response and elimination of defective cells. We have previously reported that natural killer (NK) cells enter target tumor cells, leading to either target cell death or self destruction within tumor cells. However, it has remained elusive as to the fate of NK cells after internalization and whether the heterotypic cell-in-cell process is different from that of the homotypic cell-in-cell event recently named entosis. Here, we show that NK cells undergo a cell-in-cell process with the ultimate fate of apoptosis within tumor cells and reveal that the internalization process requires the actin cytoskeletal regulator, ezrin. To visualize how NK cells enter into tumor cells, we carried out real-time dual color imaging analyses of NK cell internalization into tumor cells. Surprisingly, most NK cells commit to programmed cell death after their entry into tumor cells, which is distinctively different from entosis observed in the homotypic cell-in-cell process. The apoptotic cell death of the internalized NK cells was evident by activation of caspase 3 and DNA fragmentation. Furthermore, NK cell death after internalization is attenuated by the caspase inhibitor, Z-VAD-FMK, confirming apoptosis as the mode of NK cell death within tumor cells. To determine protein factors essential for the entry of NK cells into tumor cells, we carried out siRNA-based knockdown analysis and discovered a critical role of ezrin in NK cell internalization. Importantly, PKA-mediated phosphorylation of ezrin promotes the NK cell internalization process. Our findings suggest a novel regulatory mechanism by which ezrin governs NK cell internalization into tumor cells. PMID- 19786987 TI - Nutritional programming of the metabolic syndrome. AB - The primary markers of the metabolic syndrome are central obesity, insulin resistance and hypertension. In this review, we consider the effect of changes in maternal nutrition during critical windows in fetal development on an individual's subsequent predisposition to the metabolic syndrome. The fetal origins of obesity, cardiovascular disease and insulin resistance have been investigated in a wide range of epidemiological and animal studies; these investigations highlight adaptations made by the nutritionally manipulated fetus that aim to maintain energy homeostasis to ensure survival. One consequence of such developmental plasticity may be a long term re-setting of cellular energy homeostasis, most probably via epigenetic modification of genes involved in a number of key regulatory pathways. For example, reduced maternal-fetal nutrition during early gestation to midgestation affects adipose tissue development and adiposity of the fetus by setting an increased number of adipocyte precursor cells. Importantly, clinically relevant adaptations to nutritional challenges in utero may only manifest as primary components of the metabolic syndrome if followed by a period of accelerated growth early in the postnatal period and/or if offspring become obese. PMID- 19786988 TI - Management of children with acute malnutrition in resource-poor settings. AB - Approximately 11% of children worldwide suffer from moderate or severe acute malnutrition, which is defined as low weight for height or mid-upper arm circumference with respect to international standards, or the presence of bipedal edema. These children have a considerably increased risk of dying. Experience from the past two decades indicates that children with uncomplicated moderate or severe acute malnutrition can be managed successfully as outpatients, by use of appropriate treatment of infections and either lipid-based, ready-to-use therapeutic foods or appropriately formulated home diets, along with psychosocial care. Children's caregivers prefer community-based treatment, which is also less costly than inpatient care. Children with severe acute malnutrition and life threatening complications require short-term inpatient care for treatment of infections, fluid and electrolyte imbalances, and metabolic abnormalities. Initial dietary management relies on low-lactose, milk-based, liquid formulas but semi-solid or solid foods can be started as soon as appetite permits, after which children can be referred for ambulatory treatment. National programs for the community-based management of acute malnutrition (CMAM) provide periodic anthropometric and clinical screening of young children, and referral of those who meet established criteria. This Review describes the main components of the treatment of young children with acute malnutrition in resource poor settings and some recent advances in CMAM programs. PMID- 19786986 TI - P68 RNA helicase is a nucleocytoplasmic shuttling protein. AB - P68 RNA helicase is a prototypical DEAD box RNA helicase. The protein plays a very important role in early organ development and maturation. Consistent with the function of the protein in transcriptional regulation and pre-mRNA splicing, p68 was found to predominately localize in the cell nucleus. However, recent experiments demonstrate a transient cytoplasmic localization of the protein. We report here that p68 shuttles between the nucleus and the cytoplasm. The nucleocytoplasmic shuttling of p68 is mediated by two nuclear localization signal and two nuclear exporting signal sequence elements. Our experiments reveal that p68 shuttles via a classical RanGTPase-dependent pathway. PMID- 19786989 TI - New methods to diagnose and treat cartilage degeneration. AB - Lesions in articular cartilage can result in significant musculoskeletal morbidity and display unique biomechanical characteristics that make repair difficult, at best. Several surgical procedures have been devised in an attempt to relieve pain, restore function, and delay or stop the progression of cartilaginous lesions. Advanced MRI and ultrasonography protocols are currently used in the evaluation of tissue repair and to improve diagnostic capability. Other nonoperative modalities, such as injection of intra-articular hyaluronic acid or supplementary oral glucosamine and chondroitin sulfate, have shown potential efficacy as anti-inflammatory and symptom-modifying agents. The emerging field of tissue engineering, involving the use of a biocompatible, structurally and mechanically stable scaffold, has shown promising early results in cartilage tissue repair. Scaffolds incorporating specific cell sources and bioactive molecules have been the focus in this new exciting field. Further work is required to better understand the behavior of chondrocytes and the variables that influence their ability to heal articular lesions. The future of cartilage repair will probably involve a combination of treatments in an attempt to achieve a regenerative tissue that is both biomechanically stable and, ideally, identical to the surrounding native tissues. PMID- 19786990 TI - Clinical approaches to early inflammatory arthritis. AB - Several advances have been made in the understanding of the pathogenesis, as well as in the clinical evaluation and treatment, of early inflammatory arthritis. The presence of anti-citrullinated protein antibodies (ACPAs) has emerged as a major new biomarker for use in clinical practice. The presence of ACPAs can be used to divide patients with early arthritis into subsets that are phenotypically similar but have varying pathogenetic and prognostic features. Although the detection of ACPAs is a major development in the diagnosis and prognosis of rheumatoid arthritis (RA), prediction of the outcome of arthritis at the individual level can still be much improved. For patients diagnosed with RA, and who have active polyarthritis, treatment is not dependent on the assessment of prognostic factors, as these patients are best treated with combination therapy; over 40% of these patients achieve remission with such treatment. In patients who present with oligoarthritis, however, management should be based on the assessment of prognostic factors. The success of early treatment of inflammatory arthritis and the recognition of a measurable preclinical phase of RA offer hope that treating the disease before it becomes clinically active might be possible. PMID- 19786991 TI - Mechanisms of the cardiorenal syndromes. AB - The kidney and heart have essential roles in maintaining blood volume homeostasis and in the regulation of systemic blood pressure. Acute or chronic dysfunction in either the heart or kidneys can induce dysfunction in the other organ, resulting in the so-called cardiorenal syndromes, which are classified into five different types. Abrupt worsening of cardiac function predisposes an individual to acute kidney injury from renal hypoperfusion or renal congestion. Progressive, sometimes permanent, chronic kidney impairment can result from chronic renal hypoperfusion or congestion. Heart failure is common in patients with acute kidney injury. Chronic kidney disease predisposes individuals to atherosclerotic, arteriosclerotic and cardiomyopathic disease. Finally, both cardiac and renal disease can also occur secondary to systemic conditions, such as diabetes or autoimmune disease. This Review examines the mechanisms presiding over the first four types of cardiorenal syndromes. These mechanisms provide a template that accounts for the heart-kidney interactions that occur in patients whose concomitant cardiac and renal conditions result from a third cause. PMID- 19786993 TI - Kidney disease: improving global outcomes. AB - Kidney Disease: Improving Global Outcomes (KDIGO) is an independent organization with the mission to improve care and outcomes of patients with kidney disease worldwide through the development and coordination of clinical practice guidelines. KDIGO has established firm links with other organizations that have previously produced clinical practice guidelines in the field of kidney disease. The first three KDIGO guidelines--treatment of hepatitis C, management of bone and mineral disease, and care of kidney transplant recipients--have been finalized and the next three--acute kidney injury, management of glomerulonephritis, and management of blood pressure in chronic kidney disease- are under development. The ultimate goal is to cover most major aspects of care for patients with kidney disease. Corner stones of KDIGO's guideline development process are independent, multidisciplinary, international work groups, close collaboration with professional methodology experts who perform systematic evidence reviews, and open public review of each guideline. Grades of Recommendation Assessment, Development, and Evaluation (GRADE) methodology is applied for grading the quality of evidence and strength of recommendations. International conferences organized by KDIGO support the coordination of guideline development, assess the suitability of guideline topics and help to establish global consensus on definitions and policies. PMID- 19786992 TI - Selective iNOS inhibition for the treatment of sepsis-induced acute kidney injury. AB - The incidence and mortality of sepsis and the associated development of acute kidney injury (AKI) remain high, despite intense research into potential treatments. Targeting the inflammatory response and/or sepsis-induced alterations in the (micro)circulation are two therapeutic strategies. Another approach could involve modulating the downstream mechanisms that are responsible for organ system dysfunction. Activation of inducible nitric oxide (NO) synthase (iNOS) during sepsis leads to elevated NO levels that influence renal hemodynamics and cause peroxynitrite-related tubular injury through the local generation of reactive nitrogen species. In many organs iNOS is not constitutively expressed; however, it is constitutively expressed in the kidney and, in humans, a relationship between the upregulation of renal iNOS and proximal tubular injury during systemic inflammation has been demonstrated. For these reasons, the selective inhibition of renal iNOS might have important implications for the treatment of sepsis-induced AKI. Various animal studies have demonstrated that selective iNOS inhibition-in contrast to nonselective NOS inhibition-attenuates sepsis-induced renal dysfunction and improves survival, a finding that warrants investigation in clinical trials. In this Review, the selective inhibition of iNOS as a potential novel treatment for sepsis-induced AKI is discussed. PMID- 19786994 TI - Serum free light chain assessment in monoclonal gammopathy and kidney disease. AB - Abnormalities of immunoglobulin free light chains (FLCs) are frequently present in patients with monoclonal gammopathies and can cause kidney disease. The recent introduction of highly sensitive immunoassays that measure FLCs to levels below those present in normal individuals has provided a new tool for diagnosis and management in this setting. Here, we review the biology of FLC production in health and disease, and the utility of FLC immunoassays in the assessment of monoclonal gammopathies in kidney disease. PMID- 19786995 TI - The Holy Grail of biomarkers. PMID- 19786996 TI - Chemotherapy: Topotecan or treosulfan--that is the question. PMID- 19786997 TI - Chemotherapy: Optimizing irinotecan regimens for colorectal cancer. PMID- 19786999 TI - Chemotherapy: Adjuvant chemotherapy in older patients with breast cancer. PMID- 19786998 TI - Chemotherapy: Irinotecan or etoposide as front-line therapy for SCLC? PMID- 19787000 TI - Hematology: Thalidomide maintenance in multiple myeloma. PMID- 19787001 TI - Radiotherapy: IMRT reduces xerostomia and potentially improves QoL. PMID- 19787002 TI - Src kinases as therapeutic targets for cancer. AB - Src family kinases (SFKs) have a critical role in cell adhesion, invasion, proliferation, survival, and angiogenesis during tumor development. SFKs comprise nine family members that share similar structure and function. Overexpression or high activation of SFKs occurs frequently in tumor tissues and they are central mediators in multiple signaling pathways that are important in oncogenesis. SFKs can interact with tyrosine kinase receptors, such as EGFR and the VEGF receptor. SFKs can affect cell proliferation via the Ras/ERK/MAPK pathway and can regulate gene expression via transcription factors such as STAT molecules. SFKs can also affect cell adhesion and migration via interaction with integrins, actins, GTPase activating proteins, scaffold proteins, such as p130(CAS) and paxillin, and kinases such as focal adhesion kinases. Furthermore, SFKs can regulate angiogenesis via gene expression of angiogenic growth factors, such as fibroblast growth factor, VEGF, and interleukin 8. On the basis of these important findings, small-molecule SFK inhibitors have been developed and are undergoing early phase clinical testing. In preclinical studies these agents can suppress tumor growth and metastases. The agents seem to be safe in humans and could add to the therapeutic arsenal against subsets of cancers. PMID- 19787003 TI - Breast cancer in a BRCA2 mutation carrier with a history of prostate cancer. AB - BACKGROUND: A 49-year-old patient with high-risk prostate cancer presented to a specialist. He was treated with neoadjuvant hormonal therapy for 6 months, followed by conformal radiotherapy. Three years later, he had a biochemical recurrence and commenced continuous luteinizing hormone-releasing hormone analog and antiandrogen therapy as part of a clinical trial. Aside from notable gynecomastia, he remained asymptomatic. He has a strong family history of breast cancer with multiple sisters affected. INVESTIGATIONS: At 58 years of age, the patient underwent BRCA2 germline testing and was found to be a mutation carrier. Following post-test counseling, he was offered clinical breast examination, which was unremarkable except for gynecomastia. Baseline screening mammography identified a 4 mm cluster of microcalcifications and ductal carcinoma in situ (DCIS) was confirmed by stereotactic biopsy. DIAGNOSIS: DCIS in a male BRCA2 mutation carrier undergoing androgen deprivation therapy for prostate cancer. MANAGEMENT: The patient was treated with bilateral mastectomy and no additional systemic therapy was recommended. This case report illustrates the importance of implementing screening mammography in male BRCA mutation carriers, particularly in those with a BRCA2 mutation. PMID- 19787004 TI - Molecular imaging of solid tumors: exploiting the potential. AB - Targeted treatment has substantially changed the field of oncology. Compared with cytotoxic chemotherapy, many novel targeted therapies are administered over long periods of time, and result in disease stabilization rather than tumor shrinkage. The activity of these novel agents might, therefore, be better reflected by changes in molecular features of the tumor rather than reduction in size or volume. Thus, noninvasive procedures to measure such features are urgently needed. Factors that need to be predicted are early response (silencing of tumor signaling) or resistance to therapy, and whether therapy can be interrupted. Molecular imaging techniques, such as PET, may provide clinically relevant information; however, data are so far available mainly from small, observational, retrospective studies. Findings need to be further assessed in clinical trials to assess whether molecular imaging can be exploited and widely introduced to aid daily practice in oncology. PMID- 19787006 TI - Do psychopathic patients use their DLPFC when making decisions in moral dilemmas? PMID- 19787008 TI - Independent Medical Examinations: facts and fallacies. AB - BACKGROUND: Independent Medical Examinations (IMEs) have protected the rights of workers in the United States since the first laws protecting employees were established in the early 1900s. There have been many social advancements and a great collective struggle over the last 100 years that have ultimately lead to justice for the injured or disabled worker. OBJECTIVE: We describe the origins of the IME as well as the evolution of both medical and social processes that have provided the legal framework for the correct practice of IMEs. This article will summarize the current medical principles, legal process, and social controversy embodying the modern IME. DISCUSSION: Medical professionals must adhere to the same principles of impartial and ethical conduct that they uphold in general patient care when dealing with IMEs. Although previously controversial, it is now clear following successful litigation of many physician examiners that at least a 'limited doctor-patient relationship' is created during an IME. LIMITATIONS: The limitations of this manuscript include a paucity of the literature, lack of IME updates, and certain conflicts with guidelines by various organizations. CONCLUSION: IMEs represent a valuable mechanism for determining alleged impairment and/or disability. In the current economic environment of declining reimbursement to physicians, IMEs exist outside the scope of traditional payment methods and offer competitive compensation. PMID- 19787009 TI - Evidence-based medicine, systematic reviews, and guidelines in interventional pain management: part 6. Systematic reviews and meta-analyses of observational studies. AB - Observational studies provide an important source of information when randomized controlled trials (RCTs) cannot or should not be undertaken, provided that the data are analyzed and interpreted with special attention to bias. Evidence-based medicine (EBM) stresses the examination of evidence from clinical research and describes it as a shift in medical paradigm, in contrast to intuition, unsystematic clinical experience, and pathophysiologic rationale. While the importance of randomized trials has been created by the concept of the hierarchy of evidence in guiding therapy, much of the medical research is observational. The reporting of observational research is often not detailed and clear enough with insufficient quality and poor reporting, which hampers the assessment of strengths and weaknesses of the study and the generalizability of the mixed results. Thus, in recent years, progress and innovations in health care are measured by systematic reviews and meta-analyses. A systematic review is defined as, "the application of scientific strategies that limit bias by the systematic assembly, clinical appraisal, and synthesis of all relevant studies on a specific topic." Meta-analysis usually is the final step in a systematic review. Systematic reviews and meta-analyses are labor intensive, requiring expertise in both the subject matter and review methodology, and also must follow the rules of EBM which suggests that a formal set of rules must complement medical training and common sense for clinicians to integrate the results of clinical research effectively. While expertise in the review methods is important, the expertise in the subject matter and technical components is also crucial. Even though, systematic reviews and meta-analyses, specifically of RCTs, have exploded, the quality of the systematic reviews is highly variable and consequently, the opinions reached of the same studies are quite divergent. Numerous deficiencies have been described in methodologic assessment of the quality of the individual articles. Consequently, observational studies can provide an important complementary source of information, provided that the data are analyzed and interpreted in the context of confounding bias to which they are prone. Appropriate systematic reviews of observational studies, in conjunction with RCTs, may provide the basis for elimination of a dangerous discrepancy between the experts and the evidence. Steps in conducting systematic reviews of observational studies include planning, conducting, reporting, and disseminating the results. MOOSE, or Meta-analysis of Observational Studies in Epidemiology, a proposal for reporting contains specifications including background, search strategy, methods, results, discussion, and conclusion. Use of the MOOSE checklist should improve the usefulness of meta-analysis for authors, reviewers, editors, readers, and decision-makers. This manuscript describes systematic reviews and meta-analyses of observational studies. Authors frequently utilize RCTs and observational studies in one systematic review; thus, they should also follow the reporting standards of the Quality of Reporting of Meta-analysis (QUOROM) statement, which also provides a checklist. A combined approach of QUOROM and MOOSE will improve reporting of systematic reviews and lead to progress and innovations in health care. PMID- 19787010 TI - Herpes zoster radiculopathy treated with fluoroscopically-guided selective nerve root injection. AB - BACKGROUND: Varicella-zoster virus, a member of the herpes virus family, is a neurotrophic virus that primarily affects afferent sensory neurons. Reactivation of latent virus within the dorsal root ganglion and axoplasmic transport to epithelial nerve terminals causes the segmental cutaneous rash and neuralgic pain characteristic of herpes zoster. SETTING: Outpatient orthopedic practice. CASE DESCRIPTION: A 75-year-old male developed a herpetic rash followed by burning pain in the right L5 distribution. The pain was exacerbated by standing or walking. Six weeks later, the rash had improved, but the patient developed a right foot drop requiring use of a molded ankle-foot orthosis. MRI of the lumbar spine revealed mild degenerative changes without evidence of significant spinal stenosis or disc disease. Electrodiagnostic studies confirmed the diagnosis of right L5 radiculopathy. RESULTS: The patient had dramatic improvement of pain and weakness after undergoing a fluoroscopically guided right L5 selective nerve root block with Depo-Medrol and Lidocaine. He then began a course of physical therapy and, 6 weeks later, had only trace weakness of the ankle dorsiflexor group on the right side. The patient has continued without significant weakness or pain since the procedure and has returned to normal functioning. DISCUSSION: This case demonstrates apparent treatment of a relatively uncommon phenomenon, herpes zoster radiculopathy, using selective nerve root block. LIMITATIONS: There is a limited amount of data regarding this disorder presently available regarding Herpes Zoster Radiculopathy. A second limitation would be an inability to exclude spinal pathology as an alternative etiology of this patient's condition. CONCLUSION: Cases of herpes zoster-induced radiculopathy may become more frequent, as evidenced by the increasing number of cases of herpes zoster in the United States noted epidemiologically. PMID- 19787011 TI - Accuracy of diagnostic lumbar facet joint nerve blocks: a 2-year follow-up of 152 patients diagnosed with controlled diagnostic blocks. AB - BACKGROUND: Lumbar facet joint pain is diagnosed by controlled diagnostic blocks. The accuracy of controlled diagnostic blocks has been demonstrated in multiple studies and confirmed in systematic reviews. Controlled diagnostic studies have shown an overall prevalence of lumbar facet joint pain in 31% of the patients with chronic low back pain without disc displacement or radiculitis, with an overall false-positive rate of 30% using a single diagnostic block. STUDY DESIGN: An observational report of outcomes assessment. SETTING: An interventional pain management practice setting in the United States. OBJECTIVE: To determine the accuracy of controlled diagnostic blocks in managing lumbar facet joint pain at the end of 2 years. METHODS: This study included 152 patients diagnosed with lumbar facet joint pain using controlled diagnostic blocks. The inclusion criteria was based on a positive response to diagnostic controlled comparative local anesthetic lumbar facet joint blocks. The treatment included therapeutic lumbar facet joint nerve blocks. OUTCOME MEASURES: The sustained diagnosis of lumbar facet joint pain at the end of one year and 2 years based on pain relief and functional status improvement. RESULTS: At the end of one year 93% of the patients and at the end of 2 years 89.5% of the patients were considered to have lumbar facet joint pain. LIMITATIONS: The study is limited by its observational nature. CONCLUSION: Controlled diagnostic lumbar facet joint nerve blocks are valid utilizing the criteria of 80% pain relief and the ability to perform previously painful movements, with sustained diagnosis of lumbar facet joint pain in at least 89.5% of the patients at the end of a 2-year follow-up period. PMID- 19787012 TI - Occipital neurostimulation-induced muscle spasms: implications for lead placement. AB - BACKGROUND: For many headache types, occipital peripheral nerve stimulation (ONS) provides significant relief of chronic, frequent, and severe headaches. Though rarely reported, ONS may cause painful muscle spasms that make stimulator use impractical. The classic description of the technique advocates placement of the leads transversely at the level of the arch of C1 or at C1-2. At that level, the greater occipital nerve (GON) infrequently pierces the superficial fascia of the neck muscles to become superficial. However, important anatomic variability exists. OBJECTIVE: To report placement of leads higher at the nuchal line rather than the classically recommended C1 level to avoid ONS-induced muscle spasm. METHODS: Four interventional pain physicians independently revised ONS leads due to painful muscle stimulation. Five case reports of surgical ONS lead revision for management of ONS-induced muscle spasms are described and discussed. RESULTS: Placement of peripheral neurostimulator leads at or above the nuchal line in these 5 cases provided good paresthesiae without causing neck muscle spasm. CONCLUSION: Lead placement at the level of C1 or C1-2 may cause some patients to have intolerable neck/occipital spasm during neurostimulation. This is the first known published report of technical variation in the location of lead placement, at the nuchal line in a transverse fashion, for ONS. Placing ONS leads at the level of the occipital protuberance appears to eliminate ONS-induced muscle spasm while allowing good paresthesia coverage. LIMITATIONS: Stimulation parameters vary, thus posting parameters may be misleading as muscle spasms occurred despite multiple reprogramming attempts and were a function of lead position, not program settings. PMID- 19787013 TI - Pain in nursing home residents and correlation with neuropsychiatric disorders. AB - BACKGROUND: Pain is a common problem in older age and strongly interacts with neuropsychiatric disorders. In this paper we studied the prevalence of pain and the connection between pain and neuropsychiatric comorbidities among older nursing home residents. OBJECTIVE: To determine if data provided in 2004 National Nursing Home Survey supports connection between pain and neuropsychiatric comorbidities among older nursing home residents. SETTING: Medical university. DESIGN: Retrospective study of published reports METHODS: We used the results of the 2004 National Nursing Home Survey (NNHS) to determine the rates and correlations of pain parameters with the main neurodegenerative and psychiatric diagnoses in residents over 65 years of age including Alzheimer's and Picks dementia, schizophrenia, depression, bipolar disease, anxiety, and obsessive compulsive disorder. RESULTS: Pain was reported by 22% of residents over 65 years of age. Patients with anxiety or depression had the highest prevalence of pain, 29.4% and 24.4%, respectively. Patients with dementia had the lowest rate of reported pain, 14.5%. All neurodegenerative and psychiatric diagnoses had significant correlations (P = 0.000) with pain rate, however, only anxiety (r = 0.056) and depression (r=0.025) positively correlated with the presence of pain. There were clear differences in the highest levels of reported pain in different neurodegenerative and psychiatric groups. We created the Disease-Specific Pain Intensity Scale (DSPI Scale) which can be calculated for each diagnostic entity. The DSPI was highest in patients with obsessive-compulsive disorder (721) and lowest in patients with bipolar disease (358). The average value of this scale in nursing home residents who reported pain in the last 7 days was 488. LIMITATIONS: The overwhelming majority of patients had chronic somatic diseases that were not included in the analysis and could skew the results. In addition, pain perception could be affected by prescribed medications which were not taken into consideration. Moreover, neurodegenerative and psychiatric disorders could interact among each other and overlapped cases were not regarded in our research. Finally, the new instrument created for evaluating the spectrum of highest pain intensities in a group of patients with a specific diagnosis requires validation. It is a unidimentional scale that does not incorporate the length of time a person has experienced pain, an important parameter in pain chronicity. CONCLUSION: It is important when assessing pain to consider the patient's neuropsychiatric status and especially communication abilities. The information above helps understand the variances in pain parameters in neuropsychiatric patients and may ultimately lead to better pain management in these difficult patients. PMID- 19787014 TI - Successful treatment of meralgia paresthetica with pulsed radiofrequency of the lateral femoral cutaneous nerve. AB - BACKGROUND: Meralgia paresthetica is a rarely encountered sensory mononeuropathy characterized by paresthesia, pain or sensory impairment along the distribution of the lateral femoral cutaneous nerve caused by entrapment or compression of the nerve as it crosses the anterior superior iliac spine and runs beneath the inguinal ligament. OBJECTIVE: We describe the first reported use of pulsed radiofrequency neuromodulation to relieve the intractable pain associated with meralgia paresthetica. CASE REPORT: A 33-year-old morbidly obese female with a history of lower back pain and previous spinal fusion presented with sensory dysesthesias and paresthesias in the right anterolateral thigh, consistent with meralgia paresthetica. Temporary relief occurred with multiple lateral femoral cutaneous nerve and fascia lata blocks at 2 different institutions. The patient expressed dissatisfaction with her previous treatments and requested "any" therapeutic intervention that might lead to long-lasting pain relief. At this time, we located the anterior superior iliac spine and reproduced concordant dysesthesia. Pulsed radiofrequency was then undertaken at 42 degrees C for 120 seconds followed by dexamethasone and bupivicaine. The patient reported exceptional and prolonged pain relief at 6-month follow-up. LIMITATIONS: Since this case report is not a prospective, randomized, controlled or blinded study, no conclusions may be drawn from the results attained on behalf of this single individual. Additional, larger group analyses studying this technique while eliminating bias from patient variables would be essential prior to assuming any validity to using pulsed radiofrequency techniques of neuromodulation for managing peripheral neuropathic pain processes. CONCLUSION: The patient had experienced long-standing pain that was recalcitrant to conservative/pharmacologic therapy and multiple nerve blocks with local steroid instillations. A single treatment with pulsed radiofrequency resulted in complete and sustained cessation of pain. No side effects were evident. Pulsed radiofrequency of the LFCN may offer an effective, low risk treatment in patients with meralgia paresthetica who are refractory to conservative medical management or are unwilling or unfit to undergo surgery. PMID- 19787015 TI - Polymethylmethacrylate and radioisotopes in vertebral augmentation: an explanation of underlying principles. AB - We recently reported a novel concept for combining radioactive isotope technology with polymethylmethacrylate (PMMA) cement used for vertebral augmentation and have advocated that pain physicians become aware of this new concept when treating malignant compression fractures. The use of vertebral augmentation for malignant compression fractures is steadily increasing, and the goal of this novel approach would be to stabilize the fractured vertebral body while also controlling proliferation of the tumor cells in the vertebral body that caused the vertebral fracture. This approach would therefore provide mechanical stabilization of the fractured vertebral body at the same time as direct targeting of the cancer cells causing the fracture. For our analysis, we investigated six specific radioisotopes with regard to physical and biologic properties as they would interact with PMMA and local bone metastatic disease, taking into consideration anatomical, biological and physical characteristics. The radioisotopes investigated include beta emitting (plus and minus) sources, as well as low energy and mid-energy photon sources and are: P-32, Ho-166, Y-90, I 125, F-18, and Tc-99m. We review the advantages and disadvantages of each radioisotope. In addition, this paper serves to provide pain physicians with a basic background of the biologic principles (Biologically Effective Dose) and statistical modeling (Monte Carlo method) used in that analysis. We also review the potential complications when using radioactive sources in a clinical setting. Understanding the methodologies employed in determining isotope selection empowers the practitioner by fostering understanding of this presently theoretical treatment option. We believe that embedding radioisotopes in PMMA is merely a first step in the road of local treatment for symptomatic local lesions in the setting of systemic disease. PMID- 19787016 TI - Low and therapeutic doses of antidepressants are associated with similar response in the context of multimodal treatment of pain. AB - BACKGROUND: Antidepressants are prescribed in a wide range of doses to treat both depression and chronic pain, with optimal psychopharmacology individualized for each patient. In the past decade more antidepressants from different chemical classes have become available and are being used for the treatment of both chronic pain and depression. OBJECTIVE: To review the utilization pattern changes and compare response rates of different classes and doses of antidepressants for various pain conditions in the context of multimodal therapies. DESIGN: Chart review. METHODS: We reviewed 5,916 records at an outpatient multidisciplinary pain center. Of these, 379 records were for patients diagnosed with cancer pain. Because the mechanisms and treatment approaches to cancer pain can differ greatly from non-cancer chronic pain, these records were excluded from the analysis. We assessed 1,506 medical records for patients with chronic non-caner pain who had used at least one antidepressant, with the main outcome measure being the Numeric Rating Pain Scale, 0-10. RESULTS: Of the 5,916 charts reviewed, 1,506 (25.4%) chronic non-cancer pain charts recorded the prescription of at least one antidepressant. Most patients received a combination of medications and procedures. Of the 450 patients receiving secondary amines, favorable responses were recorded for 340 (76%) patients, while 103 (23%) did not respond and 7 had unknown responses. Of the 492 patients receiving tertiary amines, favorable responses were recorded for 375 (76%) patients, while 113 (23%) did not respond, and 4 had unknown responses. Of the 533 patients receiving SSRI/SNRIs, favorable responses were recorded for 382 (72%) patients, while 147 (28%) did not respond, and 4 had unknown responses. Of the 369 patients receiving atypical antidepressants, favorable responses were recorded for 272 (74%) patients, while 94 (25%) did not respond, and 3 had unknown responses. LIMITATIONS: A retrospective study design and the use of antidepressants as a part of multimodal treatment of pain. CONCLUSION: The data suggest that in the context of multimodal treatment for chronic pain, antidepressant therapy at both low and therapeutic doses demonstrates similar response rates. Tricyclic antidepressants (TCAs), which include secondary and tertiary amines, as well as SSRI/SNRIs and atypicals, all appear to show similar favorable response rates. PMID- 19787017 TI - Hydrogen sulfide's involvement in modulating nociception. AB - Hydrogen sulfide (H2S) is a malodorous gas which functions as an endogenous gasotransmitter in humans. It is becoming appreciated that H2S may be involved in a wide variety of processes including nociceptive processes. The molecular mechanisms responsible for many of the activities of H2S remain uncertain, however, H2S increases cAMP levels in neuronal and glial cell lines and primary neuron cultures with hyperpolarization. H2S may be involved in multiple signaling pathways and produce various effects on ion channels (e.g. T-type calcium channel currents, ATP-sensitive K+ (KATP) channels) which may inhibit or promote nociception. It is also conceivable that H2S may affect the n-methyl-d aspartate (NMDA) receptor complex and/or TRPA1 ion channels which may modulate nociceptive processes. It appears that H2S may regulate key neuronal functions, including the induction of hippocampal long-term potentiation, a synaptic model of learning and memory thought to involve the NMDA receptor as well as the release of corticotrophin-releasing hormone from the hypothalamus. It seems that the primary role of H2S in nociceptive processes is the activation of T-type calcium channels leading to facilitation of pronociceptive processes. A secondary contribution to the facilitation of pronociceptive processes may come from H2S-induced activation. It would appear that much like other gasotransmitters (e.g. nitric oxide), endogenous H2S may be involved in multiple physiologic processes and its effects remain complex, difficult to predict, and may vary depending on the specific environment/circumstances/location where it is generated. A greater understanding of the clinically significant human physiology of H2S and hydrogen sulfide's effects on modulating nociceptive processes may potentially lead to novel targets for improving analgesia. PMID- 19787018 TI - Atypical chest pain: evidence of intercostobrachial nerve sensitization in Complex Regional Pain Syndrome. AB - BACKGROUND: Atypical chest pain is a common complaint among Complex Regional Pain Syndrome (CRPS) patients with brachial plexus involvement. Anatomically, the intercostobrachial nerve (ICBN) is connected to the brachial plexus and innervates the axilla, medial arm and anterior chest wall. By connecting to the brachial plexus, the ICBN could become sensitized by CRPS spread and become a source of atypical chest pain. OBJECTIVE: To evaluate the sensitivity of chest areas in CRPS patients and normal controls. DESIGN: Prospective investigation of pressure algometry in chest areas to determine chest wall sensitivity. METHODS: CRPS patients and normal controls volunteered to participate in our study. Each individual was examined to meet inclusion criteria. Patients' report of chest pain history was collected from every participant. Pressure algometry was used to measure pressure sensitivity in the axilla, anterior axillary line second intercostal space, mid-clavicular third rib, mid-clavicular tenth rib, and midsternal. Each of these measurements were compared to an intra-participant abdominal measure to control for an individuals generalized sensitivity. The ratios of chest wall sensitivities were compared between CRPS patients and normal controls. RESULTS: A history of chest pain was reported by a majority (94%) of CRPS patients and a minority (19%) of normal controls. CRPS patients reported lifting their arm as a major initiating factor for chest pain. To pressure algometry, the ratios of CRPS patients were significantly greater than control subjects (p< 0.02 throughout), indicating increased chest wall sensitivity. LIMITATIONS: This study is limited by the relatively small number of patients (n=35) and controls (n=21) used. CONCLUSION: The results of this study support the idea that chest pain is greater in CRPS patients than normal controls. The ICBN could be the source of this sensitization by CRPS spread from the brachial plexus. PMID- 19787019 TI - Chronic regional pain syndrome after subtalar arthrodesis is not prevented by early hyperbaric oxygen. AB - Subtalar arthrodesis was performed on a 48-year-old, non-insulin-dependent diabetic with a history of chronic ankle instability and lateral ankle pain. In the early post-operative period he presented as an emergency with an infection at the operative site. This was treated with 2 returns to the operating theatre for washout and debridement. His wounds were left open and at 3 weeks after emergency admission he was referred for adjunctive hyperbaric oxygen (HBO) therapy to aid healing by secondary intention. He received a total of 19 hyperbaric sessions, at a pressure of 2.2 ATA, one treatment per day for 5 days a week. Shortly after commencing HBO therapy his ankle became increasingly painful, despite the introduction of analgesia. By 7 weeks after emergency admission his wounds had virtually healed but hyperesthesia persisted over the dorsum of the foot. A computerized tomography scan at 5 1/2 months post-operatively showed satisfactory joint fusion and revealed no evidence of infection. Symptoms and signs at this time were compatible with a diagnosis of chronic regional pain syndrome (CRPS). There is published evidence to suggest that HBO therapy may be a useful modality in the treatment of established CRPS. Here, we seek to publicize a case in which early treatment with HBO for another indication did not prevent the simultaneous development of CRPS Type 1. PMID- 19787020 TI - [Abstracts of the XXXIX Congress of the Spanish Nephrology Society, 3-6 October 2009, Pamplona, Spain]. PMID- 19787021 TI - Comparative characterization of a temperature responsive gene (lactate dehydrogenase-B, ldh-b) in two congeneric tropical fish, Lates calcarifer and Lates niloticus. AB - The characterization of candidate loci is a critical step in obtaining insight into adaptation and acclimation of organisms. In this study of two non-model tropical (to sub-tropical) congeneric perciformes (Lates calcarifer and Lates niloticus) we characterized both coding and non-coding regions of lactate dehydrogenase-B (ldh-b), a locus which exhibits temperature-adaptive differences among temperate and sub-tropical populations of the North American killifish Fundulus heteroclitus. Ldh-b was 5,004 and 3,527 bp in length in L. calcarifer and L. niloticus, respectively, with coding regions comprising 1,005 bp in both species. A high level of sequence homology existed between species for both coding and non-coding regions of ldh-b (> 97% homology), corresponding to a 98.5% amino acid sequence homology. All six known functional sites within the encoded protein sequence (LDH-B) were conserved between the two Lates species. Ten simple sequence repeat (SSR) motifs (mono-, di-, tri- and tetranucleotide) and thirty putative microRNA elements (miRNAs) were identified within introns 1, 2, 5 and 6 of both Lates species. Five single nucleotide polymorphisms (SNPs) were also identified within miRNA containing intron regions. Such SNPs are implicated in several complex human conditions and/or diseases (as demonstrated by extensive genome-wide association studies). This novel characterization serves as a platform to further examine how non-model species may respond to changes in their native temperatures, which are expected to increase by up to 6 degrees C over the next century. PMID- 19787022 TI - A disease-mediated trophic cascade in the Serengeti and its implications for ecosystem C. AB - Tree cover is a fundamental structural characteristic and driver of ecosystem processes in terrestrial ecosystems, and trees are a major global carbon (C) sink. Fire and herbivores have been hypothesized to play dominant roles in regulating trees in African savannas, but the evidence for this is conflicting. Moving up a trophic scale, the factors that regulate fire occurrence and herbivores, such as disease and predation, are poorly understood for any given ecosystem. We used a Bayesian state-space model to show that the wildebeest population eruption that followed disease (rinderpest) eradication in the Serengeti ecosystem of East Africa led to a widespread reduction in the extent of fire and an ongoing recovery of the tree population. This supports the hypothesis that disease has played a key role in the regulation of this ecosystem. We then link our state-space model with theoretical and empirical results quantifying the effects of grazing and fire on soil carbon to predict that this cascade may have led to important shifts in the size of pools of C stored in soil and biomass. Our results suggest that the dynamics of herbivores and fire are tightly coupled at landscape scales, that fire exerts clear top-down effects on tree density, and that disease outbreaks in dominant herbivores can lead to complex trophic cascades in savanna ecosystems. We propose that the long-term status of the Serengeti and other intensely grazed savannas as sources or sinks for C may be fundamentally linked to the control of disease outbreaks and poaching. PMID- 19787024 TI - Ensuring integrity in comparative effectiveness research: accentuate the negative. PMID- 19787023 TI - Should burden of disease estimates include cannabis use as a risk factor for psychosis? PMID- 19787025 TI - The risk of fractures associated with thiazolidinediones: a self-controlled case series study. AB - BACKGROUND: The results of clinical trials have suggested that the thiazolidinedione antidiabetic agents rosiglitazone and pioglitazone are associated with an increased risk of fractures, but such studies had limited power. The increased risk in these trials appeared to be limited to women and mainly involved fractures of the arm, wrist, hand, or foot: risk patterns that could not be readily explained. Our objective was to further investigate the risk of fracture associated with thiazolidinedione use. METHODS AND FINDINGS: The self controlled case-series design was used to compare rates of fracture during thiazolidinedione exposed and unexposed periods and thus estimate within-person rate ratios. We used anonymised primary care data from the United Kingdom General Practice Research Database (GPRD). All patients aged 40 y or older with a recorded fracture and at least one prescription for a thiazolidinedione were included (n = 1,819). We found a within-person rate ratio of 1.43 (95% confidence interval [CI] 1.25-1.62) for fracture at any site comparing exposed with unexposed periods among patients prescribed any thiazolidinedione. This association was similar in men and women and in patients treated with either rosiglitazone or pioglitazone. The increased risk was also evident at a range of fracture sites, including hip, spine, arm, foot, wrist, or hand. The risk increased with increasing duration of thiazolidinedione exposure: rate ratio 2.00 (95% CI 1.48-2.70) for 4 y or more of exposure. CONCLUSION: Within individuals who experience a fracture, fracture risk is increased during periods of exposure to thiazolidinediones (both rosiglitazone and pioglitazone) compared with unexposed periods. The increased risk is observed in both men and women and at a range of fracture sites. The risk also increases with longer duration of use. PMID- 19787026 TI - Circadian and social cues regulate ion channel trafficking. AB - Electric fish generate and sense electric fields for navigation and communication. These signals can be energetically costly to produce and can attract electroreceptive predators. To minimize costs, some nocturnally active electric fish rapidly boost the power of their signals only at times of high social activity, either as night approaches or in response to social encounters. Here we show that the gymnotiform electric fish Sternopygus macrurus rapidly boosts signal amplitude by 40% at night and during social encounters. S. macrurus increases signal magnitude through the rapid and selective trafficking of voltage gated sodium channels into the excitable membranes of its electrogenic cells, a process under the control of pituitary peptide hormones and intracellular second messenger pathways. S. macrurus thus maintains a circadian rhythm in signal amplitude and adapts within minutes to environmental events by increasing signal amplitude through the rapid trafficking of ion channels, a process that directly modifies an ongoing behavior in real time. PMID- 19787027 TI - Disease and the dynamics of food webs. PMID- 19787028 TI - Real-time demonstration of split skin graft inosculation and integra dermal matrix neovascularization using confocal laser scanning microscopy. AB - OBJECTIVES: During the first 48 hours after placement, an autograft "drinks" nutrients and dissolved oxygen from fluid exuding from the underlying recipient bed ("plasmatic imbibition"). The theory of inosculation (that skin grafts subsequently obtain nourishment via blood vessel "anastomosis" between new vessels invading from the wound bed and existing graft vessels) was hotly debated from the late 19th to mid-20th century. This study aimed to noninvasively observe blood flow in split skin grafts and Integra dermal regeneration matrix to provide further proof of inosculation and to contrast the structure of vascularization in both materials, reflecting mechanism. METHODS: Observations were made both clinically and using confocal microscopy on normal skin, split skin graft, and Integra. The VivaScope allows noninvasive, real-time, in vivo images of tissue to be obtained. RESULTS: Observations of blood flow and tissue architecture in autologous skin graft and Integra suggest that 2 very different processes are occurring in the establishment of circulation in each case. Inosculation provides rapid circulatory return to skin grafts whereas slower neovascularization creates an unusual initial Integra circulation. CONCLUSIONS: The advent of confocal laser microscopy like the VivaScope 1500, together with "virtual" journals such as ePlasty, enables us to provide exciting images and distribute them widely to a "reading" audience. The development of the early Integra vasculature by neovascularization results in a large-vessel, high-volume, rapid flow circulation contrasting markedly from the inosculatory process in skin grafts and the capillary circulation in normal skin and merits further (planned) investigation. PMID- 19787029 TI - The mechanochemistry of endocytosis. AB - Endocytic vesicle formation is a complex process that couples sequential protein recruitment and lipid modifications with dramatic shape transformations of the plasma membrane. Although individual molecular players have been studied intensively, how they all fit into a coherent picture of endocytosis remains unclear. That is, how the proper temporal and spatial coordination of endocytic events is achieved and what drives vesicle scission are not known. Drawing upon detailed knowledge from experiments in yeast, we develop the first integrated mechanochemical model that quantitatively recapitulates the temporal and spatial progression of endocytic events leading to vesicle scission. The central idea is that membrane curvature is coupled to the accompanying biochemical reactions. This coupling ensures that the process is robust and culminates in an interfacial force that pinches off the vesicle. Calculated phase diagrams reproduce endocytic mutant phenotypes observed in experiments and predict unique testable endocytic phenotypes in yeast and mammalian cells. The combination of experiments and theory in this work suggest a unified mechanism for endocytic vesicle formation across eukaryotes. PMID- 19787030 TI - A novel animal model of Borrelia recurrentis louse-borne relapsing fever borreliosis using immunodeficient mice. AB - Louse-borne relapsing fever (LBRF) borreliosis is caused by Borrelia recurrentis, and it is a deadly although treatable disease that is endemic in the Horn of Africa but has epidemic potential. Research on LBRF has been severely hampered because successful infection with B. recurrentis has been achieved only in primates (i.e., not in other laboratory or domestic animals). Here, we present the first non-primate animal model of LBRF, using SCID (-B, -T cells) and SCID BEIGE (-B, -T, -NK cells) immunocompromised mice. These animals were infected with B. recurrentis A11 or A17, or with B. duttonii 1120K3 as controls. B. recurrentis caused a relatively mild but persistent infection in SCID and SCID BEIGE mice, but did not proliferate in NUDE (-T) and BALB/c (wild-type) mice. B. duttonii was infectious but not lethal in all animals. These findings demonstrate that the immune response can limit relapsing fever even in the absence of humoral defense mechanisms. To study the significance of phagocytic cells in this context, we induced systemic depletion of such cells in the experimental mice by injecting them with clodronate liposomes, which resulted in uncontrolled B. duttonii growth and a one-hundred-fold increase in B. recurrentis titers in blood. This observation highlights the role of macrophages and other phagocytes in controlling relapsing fever infection. B. recurrentis evolved from B. duttonii to become a primate-specific pathogen that has lost the ability to infect immunocompetent rodents, probably through genetic degeneration. Here, we describe a novel animal model of B. recurrentis based on B- and T-cell-deficient mice, which we believe will be very valuable in future research on LBRF. Our study also reveals the importance of B-cells and phagocytes in controlling relapsing fever infection. PMID- 19787031 TI - Two patients with leprosy and the sudden appearance of inflammation in the skin and new sensory loss. PMID- 19787032 TI - Cholinesterase inhibitors and hospitalization for bradycardia: a population-based study. AB - BACKGROUND: Cholinesterase inhibitors are commonly used to treat dementia. These drugs enhance the effects of acetylcholine, and reports suggest they may precipitate bradycardia in some patients. We aimed to examine the association between use of cholinesterase inhibitors and hospitalization for bradycardia. METHODS AND FINDINGS: We examined the health care records of more than 1.4 million older adults using a case-time-control design, allowing each individual to serve as his or her own control. Case patients were residents of Ontario, Canada, aged 67 y or older hospitalized for bradycardia between January 1, 2003 and March 31, 2008. Control patients (3:1) were not hospitalized for bradycardia, and were matched to the corresponding case on age, sex, and a disease risk index. All patients had received cholinesterase inhibitor therapy in the 9 mo preceding the index hospitalization. We identified 1,009 community-dwelling older persons hospitalized for bradycardia within 9 mo of using a cholinesterase inhibitor. Of these, 161 cases informed the matched analysis of discordant pairs. Of these, 17 (11%) required a pacemaker during hospitalization, and six (4%) died prior to discharge. After adjusting for temporal changes in drug utilization, hospitalization for bradycardia was associated with recent initiation of a cholinesterase inhibitor (adjusted odds ratio [OR] 2.13, 95% confidence interval [CI] 1.29-3.51). The risk was similar among individuals with pre-existing cardiac disease (adjusted OR 2.25, 95% CI 1.18-4.28) and those receiving negative chronotropic drugs (adjusted OR 2.34, 95% CI 1.16-4.71). We found no such association when we replicated the analysis using proton pump inhibitors as a neutral exposure. Despite hospitalization for bradycardia, more than half of the patients (78 of 138 cases [57%]) who survived to discharge subsequently resumed cholinesterase inhibitor therapy. CONCLUSIONS: Among older patients, initiation of cholinesterase inhibitor therapy was associated with a more than doubling of the risk of hospitalization for bradycardia. Resumption of therapy following discharge was common, suggesting that the cardiovascular toxicity of cholinesterase inhibitors is underappreciated by clinicians. PMID- 19787033 TI - Novel vaccines to human rabies. AB - Rabies, the most fatal of all infectious diseases, remains a major public health problem in developing countries, claiming the lives of an estimated 55,000 people each year. Most fatal rabies cases, with more than half of them in children, result from dog bites and occur among low-income families in Southeast Asia and Africa. Safe and efficacious vaccines are available to prevent rabies. However, they have to be given repeatedly, three times for pre-exposure vaccination and four to five times for post-exposure prophylaxis (PEP). In cases of severe exposure, a regimen of vaccine combined with a rabies immunoglobulin (RIG) preparation is required. The high incidence of fatal rabies is linked to a lack of knowledge on the appropriate treatment of bite wounds, lack of access to costly PEP, and failure to follow up with repeat immunizations. New, more immunogenic but less costly rabies virus vaccines are needed to reduce the toll of rabies on human lives. A preventative vaccine used for the immunization of children, especially those in high incidence countries, would be expected to lower fatality rates. Such a vaccine would have to be inexpensive, safe, and provide sustained protection, preferably after a single dose. Novel regimens are also needed for PEP to reduce the need for the already scarce and costly RIG and to reduce the number of vaccine doses to one or two. In this review, the pipeline of new rabies vaccines that are in pre-clinical testing is provided and an opinion on those that might be best suited as potential replacements for the currently used vaccines is offered. PMID- 19787034 TI - From molecules to behavior: organismal-level regulation of ion channel trafficking. PMID- 19787035 TI - Exploration of uncharted regions of the protein universe. AB - The genome projects have unearthed an enormous diversity of genes of unknown function that are still awaiting biological and biochemical characterization. These genes, as most others, can be grouped into families based on sequence similarity. The PFAM database currently contains over 2,200 such families, referred to as domains of unknown function (DUF). In a coordinated effort, the four large-scale centers of the NIH Protein Structure Initiative have determined the first three-dimensional structures for more than 250 of these DUF families. Analysis of the first 248 reveals that about two thirds of the DUF families likely represent very divergent branches of already known and well-characterized families, which allows hypotheses to be formulated about their biological function. The remainder can be formally categorized as new folds, although about one third of these show significant substructure similarity to previously characterized folds. These results infer that, despite the enormous increase in the number and the diversity of new genes being uncovered, the fold space of the proteins they encode is gradually becoming saturated. The previously unexplored sectors of the protein universe appear to be primarily shaped by extreme diversification of known protein families, which then enables organisms to evolve new functions and adapt to particular niches and habitats. Notwithstanding, these DUF families still constitute the richest source for discovery of the remaining protein folds and topologies. PMID- 19787036 TI - Dynamic interpretation of hedgehog signaling in the Drosophila wing disc. AB - Morphogens are classically defined as molecules that control patterning by acting at a distance to regulate gene expression in a concentration-dependent manner. In the Drosophila wing imaginal disc, secreted Hedgehog (Hh) forms an extracellular gradient that organizes patterning along the anterior-posterior axis and specifies at least three different domains of gene expression. Although the prevailing view is that Hh functions in the Drosophila wing disc as a classical morphogen, a direct correspondence between the borders of these patterns and Hh concentration thresholds has not been demonstrated. Here, we provide evidence that the interpretation of Hh signaling depends on the history of exposure to Hh and propose that a single concentration threshold is sufficient to support multiple outputs. Using mathematical modeling, we predict that at steady state, only two domains can be defined in response to Hh, suggesting that the boundaries of two or more gene expression patterns cannot be specified by a static Hh gradient. Computer simulations suggest that a spatial "overshoot" of the Hh gradient occurs, i.e., a transient state in which the Hh profile is expanded compared to the Hh steady-state gradient. Through a temporal examination of Hh target gene expression, we observe that the patterns initially expand anteriorly and then refine, providing in vivo evidence for the overshoot. The Hh gene network architecture suggests this overshoot results from the Hh-dependent up regulation of the receptor, Patched (Ptc). In fact, when the network structure was altered such that the ptc gene is no longer up-regulated in response to Hh signaling activation, we found that the patterns of gene expression, which have distinct borders in wild-type discs, now overlap. Our results support a model in which Hh gradient dynamics, resulting from Ptc up-regulation, play an instructional role in the establishment of patterns of gene expression. PMID- 19787038 TI - Genotypic status of the TbAT1/P2 adenosine transporter of Trypanosoma brucei gambiense isolates from Northwestern Uganda following melarsoprol withdrawal. AB - BACKGROUND: The development of arsenical and diamidine resistance in Trypanosoma brucei is associated with loss of drug uptake by the P2 purine transporter as a result of alterations in the corresponding T. brucei adenosine transporter 1 gene (TbAT1). Previously, specific TbAT1 mutant type alleles linked to melarsoprol treatment failure were significantly more prevalent in T. b. gambiense from relapse patients at Omugo health centre in Arua district. Relapse rates of up to 30% prompted a shift from melarsoprol to eflornithine (alpha difluoromethylornithine, DFMO) as first-line treatment at this centre. The aim of this study was to determine the status of TbAT1 in recent isolates collected from T. b. gambiense sleeping sickness patients from Arua and Moyo districts in Northwestern Uganda after this shift in first-line drug choice. METHODOLOGY AND RESULTS: Blood and cerebrospinal fluids of consenting patients were collected for DNA preparation and subsequent amplification. All of the 105 isolates from Omugo that we successfully analysed by PCR-RFLP possessed the TbAT1 wild type allele. In addition, PCR/RFLP analysis was performed for 74 samples from Moyo, where melarsoprol is still the first line drug; 61 samples displayed the wild genotype while six were mutant and seven had a mixed pattern of both mutant and wild-type TbAT1. The melarsoprol treatment failure rate at Moyo over the same period was nine out of 101 stage II cases that were followed up at least once. Five of the relapse cases harboured mutant TbAT1, one had the wild type, while no amplification was achieved from the remaining three samples. CONCLUSIONS/SIGNIFICANCE: The apparent disappearance of mutant alleles at Omugo may correlate with melarsoprol withdrawal as first-line treatment. Our results suggest that melarsoprol could successfully be reintroduced following a time lag subsequent to its replacement. A field-applicable test to predict melarsoprol treatment outcome and identify patients for whom the drug can still be beneficial is clearly required. This will facilitate cost-effective management of HAT in rural resource-poor settings, given that eflornithine has a much higher logistical requirement for its application. PMID- 19787037 TI - Emerging technologies for the detection of rabies virus: challenges and hopes in the 21st century. AB - The diagnosis of rabies is routinely based on clinical and epidemiological information, especially when exposures are reported in rabies-endemic countries. Diagnostic tests using conventional assays that appear to be negative, even when undertaken late in the disease and despite the clinical diagnosis, have a tendency, at times, to be unreliable. These tests are rarely optimal and entirely dependent on the nature and quality of the sample supplied. In the course of the past three decades, the application of molecular biology has aided in the development of tests that result in a more rapid detection of rabies virus. These tests enable viral strain identification from clinical specimens. Currently, there are a number of molecular tests that can be used to complement conventional tests in rabies diagnosis. Indeed the challenges in the 21st century for the development of rabies diagnostics are not of a technical nature; these tests are available now. The challenges in the 21st century for diagnostic test developers are two-fold: firstly, to achieve internationally accepted validation of a test that will then lead to its acceptance by organisations globally. Secondly, the areas of the world where such tests are needed are mainly in developing regions where financial and logistical barriers prevent their implementation. Although developing countries with a poor healthcare infrastructure recognise that molecular-based diagnostic assays will be unaffordable for routine use, the cost/benefit ratio should still be measured. Adoption of rapid and affordable rabies diagnostic tests for use in developing countries highlights the importance of sharing and transferring technology through laboratory twinning between the developed and the developing countries. Importantly for developing countries, the benefit of molecular methods as tools is the capability for a differential diagnosis of human diseases that present with similar clinical symptoms. Antemortem testing for human rabies is now possible using molecular techniques. These barriers are not insurmountable and it is our expectation that if such tests are accepted and implemented where they are most needed, they will provide substantial improvements for rabies diagnosis and surveillance. The advent of molecular biology and new technological initiatives that combine advances in biology with other disciplines will support the development of techniques capable of high throughput testing with a low turnaround time for rabies diagnosis. PMID- 19787039 TI - Treatment response of cystic echinococcosis to benzimidazoles: a systematic review. AB - Over the past 30 years, benzimidazoles have increasingly been used to treat cystic echinococcosis (CE). The efficacy of benzimidazoles, however, remains unclear. We systematically searched MEDLINE, EMBASE, SIGLE, and CCTR to identify studies on benzimidazole treatment outcome. A large heterogeneity of methods in 23 reports precluded a meta-analysis of published results. Specialist centres were contacted to provide individual patient data. We conducted survival analyses for cyst response defined as inactive (CE4 or CE5 by the ultrasound-based World Health Organisation [WHO] classification scheme) or as disappeared. We collected data from 711 treated patients with 1,308 cysts from six centres (five countries). Analysis was restricted to 1,159 liver and peritoneal cysts. Overall, 1-2 y after initiation of benzimidazole treatment 50%-75% of active C1 cysts were classified as inactive/disappeared compared to 30%-55% of CE2 and CE3 cysts. Further in analyzing the rate of inactivation/disappearance with regard to cyst size, 50%-60% of cysts <6 cm responded to treatment after 1-2 y compared to 25% 50% of cysts >6 cm. However, 25% of cysts reverted to active status within 1.5 to 2 y after having initially responded and multiple relapses were observed; after the second and third treatment 60% of cysts relapsed within 2 y. We estimated that 2 y after treatment initiation 40% of cysts are still active or become active again. The overall efficacy of benzimidazoles has been overstated in the past. There is an urgent need for a pragmatic randomised controlled trial that compares standardized benzimidazole therapy on responsive cyst stages with the other treatment modalities. PMID- 19787040 TI - Japanese encephalitis-a pathological and clinical perspective. AB - Japanese encephalitis (JE) is the leading form of viral encephalitis in Asia. It is caused by the JE virus (JEV), which belongs to the family Flaviviridae. JEV is endemic to many parts of Asia, where periodic outbreaks take hundreds of lives. Despite the catastrophes it causes, JE has remained a tropical disease uncommon in the West. With rapid globalization and climatic shift, JEV has started to emerge in areas where the threat was previously unknown. Scientific evidence predicts that JEV will soon become a global pathogen and cause of worldwide pandemics. Although some research documents JEV pathogenesis and drug discovery, worldwide awareness of the need for extensive research to deal with JE is still lacking. This review focuses on the exigency of developing a worldwide effort to acknowledge the prime importance of performing an extensive study of this thus far neglected tropical viral disease. This review also outlines the pathogenesis, the scientific efforts channeled into develop a therapy, and the outlook for a possible future breakthrough addressing this killer disease. PMID- 19787041 TI - 12/15-lipoxygenase is required for the early onset of high fat diet-induced adipose tissue inflammation and insulin resistance in mice. AB - BACKGROUND: Recent understanding that insulin resistance is an inflammatory condition necessitates searching for genes that regulate inflammation in insulin sensitive tissues. 12/15-lipoxygenase (12/15LO) regulates the expression of proinflammatory cytokines and chemokines and is implicated in the early development of diet-induced atherosclerosis. Thus, we tested the hypothesis that 12/15LO is involved in the onset of high fat diet (HFD)-induced insulin resistance. METHODOLOGY/PRINCIPAL FINDINGS: Cells over-expressing 12/15LO secreted two potent chemokines, MCP-1 and osteopontin, implicated in the development of insulin resistance. We assessed adipose tissue inflammation and whole body insulin resistance in wild type (WT) and 12/15LO knockout (KO) mice after 2-4 weeks on HFD. In adipose tissue from WT mice, HFD resulted in recruitment of CD11b(+), F4/80(+) macrophages and elevated protein levels of the inflammatory markers IL-1beta, IL-6, IL-10, IL-12, IFNgamma, Cxcl1 and TNFalpha. Remarkably, adipose tissue from HFD-fed 12/15LO KO mice was not infiltrated by macrophages and did not display any increase in the inflammatory markers compared to adipose tissue from normal chow-fed mice. WT mice developed severe whole body (hepatic and skeletal muscle) insulin resistance after HFD, as measured by hyperinsulinemic euglycemic clamp. In contrast, 12/15LO KO mice exhibited no HFD induced change in insulin-stimulated glucose disposal rate or hepatic glucose output during clamp studies. Insulin-stimulated Akt phosphorylation in muscle tissue from HFD-fed mice was significantly greater in 12/15LO KO mice than in WT mice. CONCLUSIONS: These results demonstrate that 12/15LO mediates early stages of adipose tissue inflammation and whole body insulin resistance induced by high fat feeding. PMID- 19787042 TI - BtubA-BtubB heterodimer is an essential intermediate in protofilament assembly. AB - BACKGROUND: BtubA and BtubB are two tubulin-like genes found in the bacterium Prosthecobacter. Our work and a previous crystal structure suggest that BtubB corresponds to alpha-tubulin and BtubA to beta-tubulin. A 1:1 mixture of the two proteins assembles into tubulin-like protofilaments, which further aggregate into pairs and bundles. The proteins also form a BtubA/B heterodimer, which appears to be a repeating subunit in the protofilament. METHODOLOGY/PRINCIPAL FINDINGS: We have designed point mutations to disrupt the longitudinal interfaces bonding subunits into protofilaments. The mutants are in two classes, within dimers and between dimers. We have characterized one mutant of each class for BtubA and BtubB. When mixed 1:1 with a wild type partner, none of the mutants were capable of assembly. An excess of between-dimer mutants could depolymerize preformed wild type polymers, while within-dimer mutants had no activity. CONCLUSIONS: An essential first step in assembly of BtubA + BtubB is formation of a heterodimer. An excess of between-dimer mutants depolymerize wild type BtubA/B by sequestering the partner wild type subunit into inactive dimers. Within-dimer mutants cannot form dimers and have no activity. PMID- 19787043 TI - Iron labeling and pre-clinical MRI visualization of therapeutic human neural stem cells in a murine glioma model. AB - BACKGROUND: Treatment strategies for the highly invasive brain tumor, glioblastoma multiforme, require that cells which have invaded into the surrounding brain be specifically targeted. The inherent tumor-tropism of neural stem cells (NSCs) to primary and invasive tumor foci can be exploited to deliver therapeutics to invasive brain tumor cells in humans. Use of the strategy of converting prodrug to drug via therapeutic transgenes delivered by immortalized therapeutic NSC lines have shown efficacy in animal models. Thus therapeutic NSCs are being proposed for use in human brain tumor clinical trials. In the context of NSC-based therapies, MRI can be used both to non-invasively follow dynamic spatio-temporal patterns of the NSC tumor targeting allowing for the optimization of treatment strategies and to assess efficacy of the therapy. Iron-labeling of cells allows their presence to be visualized and tracked by MRI. Thus we aimed to iron-label therapeutic NSCs without affecting their cellular physiology using a method likely to gain United States Federal Drug Administration (FDA) approval. METHODOLOGY: For human use, the characteristics of therapeutic Neural Stem Cells must be clearly defined with any pertubation to the cell including iron labeling requiring reanalysis of cellular physiology. Here, we studied the effect of iron loading of the therapeutic NSCs, with ferumoxide-protamine sulfate complex (FE Pro) on viability, proliferation, migratory properties and transgene expression, when compared to non-labeled cells. FE-Pro labeled NSCs were imaged by MRI at tumor sites, after intracranial administration into the hemisphere contralateral to the tumor, in an orthotopic human glioma xenograft mouse model. CONCLUSION: FE Pro labeled NSCs retain their proliferative status, tumor tropism, and maintain stem cell character, while allowing in vivo cellular MRI tracking at 7 Tesla, to monitor their real-time migration and distribution at brain tumor sites. Of significance, this work directly supports the use of FE-Pro-labeled NSCs for real time tracking in the clinical trial under development: "A Pilot Feasibility Study of Oral 5-Fluorocytosine and Genetically modified Neural Stem Cells Expressing Escherichia coli Cytosine Deaminase for Treatment of Recurrent High-Grade Gliomas". PMID- 19787044 TI - Considering usual medical care in clinical trial design. PMID- 19787045 TI - Metagenomic analysis of RNA viruses in a fresh water lake. AB - Freshwater lakes and ponds present an ecological interface between humans and a variety of host organisms. They are a habitat for the larval stage of many insects and may serve as a medium for intraspecies and interspecies transmission of viruses such as avian influenza A virus. Furthermore, freshwater bodies are already known repositories for disease-causing viruses such as Norwalk Virus, Coxsackievirus, Echovirus, and Adenovirus. While RNA virus populations have been studied in marine environments, to this date there has been very limited analysis of the viral community in freshwater. Here we present a survey of RNA viruses in Lake Needwood, a freshwater lake in Maryland, USA. Our results indicate that just as in studies of other aquatic environments, the majority of nucleic acid sequences recovered did not show any significant similarity to known sequences. The remaining sequences are mainly from viral types with significant similarity to approximately 30 viral families. We speculate that these novel viruses may infect a variety of hosts including plants, insects, fish, domestic animals and humans. Among these viruses we have discovered a previously unknown dsRNA virus closely related to Banna Virus which is responsible for a febrile illness and is endemic to Southeast Asia. Moreover we found multiple viral sequences distantly related to Israeli Acute Paralysis virus which has been implicated in honeybee colony collapse disorder. Our data suggests that due to their direct contact with humans, domestic and wild animals, freshwater ecosystems might serve as repositories of a wide range of viruses (both pathogenic and non-pathogenic) and possibly be involved in the spread of emerging and pandemic diseases. PMID- 19787046 TI - Roles of specific membrane lipid domains in EGF receptor activation and cell adhesion molecule stabilization in a developing olfactory system. AB - BACKGROUND: Reciprocal interactions between glial cells and olfactory receptor neurons (ORNs) cause ORN axons entering the brain to sort, to fasciculate into bundles destined for specific glomeruli, and to form stable protoglomeruli in the developing olfactory system of an experimentally advantageous animal species, the moth Manduca sexta. Epidermal growth factor receptors (EGFRs) and the cell adhesion molecules (IgCAMs) neuroglian and fasciclin II are known to be important players in these processes. METHODOLOGY/PRINCIPAL FINDINGS: We report in situ and cell-culture studies that suggest a role for glycosphingolipid-rich membrane subdomains in neuron-glia interactions. Disruption of these subdomains by the use of methyl-beta-cyclodextrin results in loss of EGFR activation, depletion of fasciclin II in ORN axons, and loss of neuroglian stabilization in the membrane. At the cellular level, disruption leads to aberrant ORN axon trajectories, small antennal lobes, abnormal arrays of olfactory glomerul, and loss of normal glial cell migration. CONCLUSIONS/SIGNIFICANCE: We propose that glycosphingolipid-rich membrane subdomains (possible membrane rafts or platforms) are essential for IgCAM-mediated EGFR activation and for anchoring of neuroglian to the cytoskeleton, both required for normal extension and sorting of ORN axons. PMID- 19787047 TI - Susceptibility of pancreatic beta cells to fatty acids is regulated by LXR/PPARalpha-dependent stearoyl-coenzyme A desaturase. AB - Chronically elevated levels of fatty acids-FA can cause beta cell death in vitro. Beta cells vary in their individual susceptibility to FA-toxicity. Rat beta cells were previously shown to better resist FA-toxicity in conditions that increased triglyceride formation or mitochondrial and peroxisomal FA-oxidation, possibly reducing cytoplasmic levels of toxic FA-moieties. We now show that stearoyl-CoA desaturase-SCD is involved in this cytoprotective mechanism through its ability to transfer saturated FA into monounsaturated FA that are incorporated in lipids. In purified beta cells, SCD expression was induced by LXR- and PPARalpha agonists, which were found to protect rat, mouse and human beta cells against palmitate toxicity. When their SCD was inhibited or silenced, the agonist-induced protection was also suppressed. A correlation between beta cell-SCD expression and susceptibility to palmitate was also found in beta cell preparations isolated from different rodent models. In mice with LXR-deletion (LXRbeta(-/-) and LXRalphabeta(-/-)), beta cells presented a reduced SCD-expression as well as an increased susceptibility to palmitate-toxicity, which could not be counteracted by LXR or PPARalpha agonists. In Zucker fatty rats and in rats treated with the LXR-agonist TO1317, beta cells show an increased SCD-expression and lower palmitate-toxicity. In the normal rat beta cell population, the subpopulation with lower metabolic responsiveness to glucose exhibits a lower SCD1 expression and a higher susceptibility to palmitate toxicity. These data demonstrate that the beta cell susceptibility to saturated fatty acids can be reduced by stearoyl coA desaturase, which upon stimulation by LXR and PPARalpha agonists favors their desaturation and subsequent incorporation in neutral lipids. PMID- 19787048 TI - Negative feedback governs gonadotrope frequency-decoding of gonadotropin releasing hormone pulse-frequency. AB - The synthesis of the gonadotropin subunits is directed by pulsatile gonadotropin releasing hormone (GnRH) from the hypothalamus, with the frequency of GnRH pulses governing the differential expression of the common alpha-subunit, luteinizing hormone beta-subunit (LHbeta) and follicle-stimulating hormone beta-subunit (FSHbeta). Three mitogen-activated protein kinases, (MAPKs), ERK1/2, JNK and p38, contribute uniquely and combinatorially to the expression of each of these subunit genes. In this study, using both experimental and computational methods, we found that dual specificity phosphatase regulation of the activity of the three MAPKs through negative feedback is required, and forms the basis for decoding the frequency of pulsatile GnRH. A fourth MAPK, ERK5, was shown also to be activated by GnRH. ERK5 was found to stimulate FSHbeta promoter activity and to increase FSHbeta mRNA levels, as well as enhancing its preference for low GnRH pulse frequencies. The latter is achieved through boosting the ultrasensitive behavior of FSHbeta gene expression by increasing the number of MAPK dependencies, and through modulating the feedforward effects of JNK activation on the GnRH receptor (GnRH-R). Our findings contribute to understanding the role of changing GnRH pulse-frequency in controlling transcription of the pituitary gonadotropins, which comprises a crucial aspect in regulating reproduction. Pulsatile stimuli and oscillating signals are integral to many biological processes, and elucidation of the mechanisms through which the pulsatility is decoded explains how the same stimulant can lead to various outcomes in a single cell. PMID- 19787049 TI - Disinhibition mediates a form of hippocampal long-term potentiation in area CA1. AB - The hippocampus plays a central role in memory formation in the mammalian brain. Its ability to encode information is thought to depend on the plasticity of synaptic connections between neurons. In the pyramidal neurons constituting the primary hippocampal output to the cortex, located in area CA1, firing of presynaptic CA3 pyramidal neurons produces monosynaptic excitatory postsynaptic potentials (EPSPs) followed rapidly by feedforward (disynaptic) inhibitory postsynaptic potentials (IPSPs). Long-term potentiation (LTP) of the monosynaptic glutamatergic inputs has become the leading model of synaptic plasticity, in part due to its dependence on NMDA receptors (NMDARs), required for spatial and temporal learning in intact animals. Using whole-cell recording in hippocampal slices from adult rats, we find that the efficacy of synaptic transmission from CA3 to CA1 can be enhanced without the induction of classic LTP at the glutamatergic inputs. Taking care not to directly stimulate inhibitory fibers, we show that the induction of GABAergic plasticity at feedforward inhibitory inputs results in the reduced shunting of excitatory currents, producing a long-term increase in the amplitude of Schaffer collateral-mediated postsynaptic potentials. Like classic LTP, disinhibition-mediated LTP requires NMDAR activation, suggesting a role in types of learning and memory attributed primarily to the former and raising the possibility of a previously unrecognized target for therapeutic intervention in disorders linked to memory deficits, as well as a potentially overlooked site of LTP expression in other areas of the brain. PMID- 19787050 TI - Demographic and genetic patterns of variation among populations of Arabidopsis thaliana from contrasting native environments. AB - BACKGROUND: Understanding the relationship between environment and genetics requires the integration of knowledge on the demographic behavior of natural populations. However, the demographic performance and genetic composition of Arabidopsis thaliana populations in the species' native environments remain largely uncharacterized. This information, in combination with the advances on the study of gene function, will improve our understanding on the genetic mechanisms underlying adaptive evolution in A. thaliana. METHODOLOGY/PRINCIPAL FINDINGS: We report the extent of environmental, demographic, and genetic variation among 10 A. thaliana populations from Mediterranean (coastal) and Pyrenean (montane) native environments in northeast Spain. Geographic, climatic, landscape, and soil data were compared. Demographic traits, including the dynamics of the soil seed bank and the attributes of aboveground individuals followed over a complete season, were also analyzed. Genetic data based on genome wide SNP markers were used to describe genetic diversity, differentiation, and structure. Coastal and montane populations significantly differed in terms of environmental, demographic, and genetic characteristics. Montane populations, at higher altitude and farther from the sea, are exposed to colder winters and prolonged spring moisture compared to coastal populations. Montane populations showed stronger secondary seed dormancy, higher seedling/juvenile mortality in winter, and initiated flowering later than coastal populations. Montane and coastal regions were genetically differentiated, montane populations bearing lower genetic diversity than coastal ones. No significant isolation-by-distance pattern and no shared multilocus genotypes among populations were detected. CONCLUSIONS/SIGNIFICANCE: Between-region variation in climatic patterns can account for differences in demographic traits, such as secondary seed dormancy, plant mortality, and recruitment, between coastal and montane A. thaliana populations. In addition, differences in plant mortality can partly account for differences in the genetic composition of coastal and montane populations. This study shows how the interplay between variation in environmental, demographic, and genetic parameters may operate in natural A. thaliana populations. PMID- 19787051 TI - Sperm chromatin-induced ectopic polar body extrusion in mouse eggs after ICSI and delayed egg activation. AB - Meiotic chromosomes in an oocyte are not only a maternal genome carrier but also provide a positional signal to induce cortical polarization and define asymmetric meiotic division of the oocyte, resulting in polar body extrusion and haploidization of the maternal genome. The meiotic chromosomes play dual function in determination of meiosis: 1) organizing a bipolar spindle formation and 2) inducing cortical polarization and assembly of a distinct cortical cytoskeleton structure in the overlying cortex for polar body extrusion. At fertilization, a sperm brings exogenous paternal chromatin into the egg, which induces ectopic cortical polarization at the sperm entry site and leads to a cone formation, known as fertilization cone. Here we show that the sperm chromatin-induced fertilization cone formation is an abortive polar body extrusion due to lack of spindle induction by the sperm chromatin during fertilization. If experimentally manipulating the fertilization process to allow sperm chromatin to induce both cortical polarization and spindle formation, the fertilization cone can be converted into polar body extrusion. This suggests that sperm chromatin is also able to induce polar body extrusion, like its maternal counterpart. The usually observed cone formation instead of ectopic polar body extrusion induced by sperm chromatin during fertilization is due to special sperm chromatin compaction which restrains it from rapid spindle induction and therefore provides a protective mechanism to prevent a possible paternal genome loss during ectopic polar body extrusion. PMID- 19787052 TI - Valinomycin biosynthetic gene cluster in Streptomyces: conservation, ecology and evolution. AB - Many Streptomyces strains are known to produce valinomycin (VLM) antibiotic and the VLM biosynthetic gene cluster (vlm) has been characterized in two independent isolates. Here we report the phylogenetic relationships of these strains using both parsimony and likelihood methods, and discuss whether the vlm gene cluster shows evidence of horizontal transmission common in natural product biosynthetic genes. Eight Streptomyces strains from around the world were obtained and sequenced for three regions of the two large nonribosomal peptide synthetase genes (vlm1 and vlm2) involved in VLM biosynthesis. The DNA sequences representing the vlm gene cluster are highly conserved among all eight environmental strains. The geographic distribution pattern of these strains and the strict congruence between the trees of the two vlm genes and the housekeeping genes, 16S rDNA and trpB, suggest vertical transmission of the vlm gene cluster in Streptomyces with no evidence of horizontal gene transfer. We also explored the relationship of the sequence of vlm genes to that of the cereulide biosynthetic genes (ces) found in Bacillus cereus and found them highly divergent from each other at DNA level (genetic distance values >or= 95.6%). It is possible that the vlm gene cluster and the ces gene cluster may share a relatively distant common ancestor but these two gene clusters have since evolved independently. PMID- 19787053 TI - Lysosomal-associated protein multispanning transmembrane 5 gene (LAPTM5) is associated with spontaneous regression of neuroblastomas. AB - BACKGROUND: Neuroblastoma (NB) is the most frequently occurring solid tumor in children, and shows heterogeneous clinical behavior. Favorable tumors, which are usually detected by mass screening based on increased levels of catecholamines in urine, regress spontaneously via programmed cell death (PCD) or mature through differentiation into benign ganglioneuroma (GN). In contrast, advanced-type NB tumors often grow aggressively, despite intensive chemotherapy. Understanding the molecular mechanisms of PCD during spontaneous regression in favorable NB tumors, as well as identifying genes with a pro-death role, is a matter of urgency for developing novel approaches to the treatment of advanced-type NB tumors. PRINCIPAL FINDINGS: We found that the expression of lysosomal associated protein multispanning transmembrane 5 (LAPTM5) was usually down-regulated due to DNA methylation in an NB cell-specific manner, but up-regulated in degenerating NB cells within locally regressing areas of favorable tumors detected by mass screening. Experiments in vitro showed that not only a restoration of its expression but also the accumulation of LAPTM5 protein, was required to induce non-apoptotic cell death with autophagic vacuoles and lysosomal destabilization with lysosomal-membrane permeabilization (LMP) in a caspase-independent manner. While autophagy is a membrane-trafficking pathway to degrade the proteins in lysosomes, the LAPTM5-mediated lysosomal destabilization with LMP leads to an interruption of autophagic flux, resulting in the accumulation of immature autophagic vacuoles, p62/SQSTM1, and ubiqitinated proteins as substrates of autophagic degradation. In addition, ubiquitin-positive inclusion bodies appeared in degenerating NB cells. CONCLUSIONS: We propose a novel molecular mechanism for PCD with the accumulation of autophagic vacuoles due to LAPTM5-mediated lysosomal destabilization. LAPTM5-induced cell death is lysosomal cell death with impaired autophagy, not cell death by autophagy, so-called autophagic cell death. Thus LAPTM5-mediated PCD is closely associated with the spontaneous regression of NBs and opens new avenues for exploring innovative clinical interventions for this tumor. PMID- 19787054 TI - Schistosomiasis in Africa: an emerging tragedy in our new global health decade. PMID- 19787055 TI - Genetic interactions between the Drosophila tumor suppressor gene ept and the stat92E transcription factor. AB - BACKGROUND: Tumor Susceptibility Gene-101 (TSG101) promotes the endocytic degradation of transmembrane proteins and is implicated as a mutational target in cancer, yet the effect of TSG101 loss on cell proliferation in vertebrates is uncertain. By contrast, Drosophila epithelial tissues lacking the TSG101 ortholog erupted (ept) develop as enlarged undifferentiated tumors, indicating that the gene can have anti-growth properties in a simple metazoan. A full understanding of pathways deregulated by loss of Drosophila ept will aid in understanding potential links between mammalian TSG101 and growth control. PRINCIPAL FINDINGS: We have taken a genetic approach to the identification of pathways required for excess growth of Drosophila eye-antennal imaginal discs lacking ept. We find that this phenotype is very sensitive to the genetic dose of stat92E, the transcriptional effector of the Jak-Stat signaling pathway, and that this pathway undergoes strong activation in ept mutant cells. Genetic evidence indicates that stat92E contributes to cell cycle deregulation and excess cell size phenotypes that are observed among ept mutant cells. In addition, autonomous Stat92E hyper activation is associated with altered tissue architecture in ept tumors and an effect on expression of the apical polarity determinant crumbs. CONCLUSIONS: These findings identify ept as a cell-autonomous inhibitor of the Jak-Stat pathway and suggest that excess Jak-Stat signaling makes a significant contribution to proliferative and tissue architectural phenotypes that occur in ept mutant tissues. PMID- 19787056 TI - Rhabdomyolysis in community acquired bacterial sepsis--a retrospective cohort study. AB - BACKGROUND AND OBJECTIVES: Rhabdomyolysis is often associated with sepsis and gram positive bacterial pathogens are reported to be the most frequent cause of sepsis induced rhabdomyolysis. We report the pattern of infecting bacterial pathogens and associated causal factors in a South-Indian cohort. DESIGN, SETTING, PARTICIPANTS #ENTITYSTARTX00026; MEASUREMENTS: Retrospective cohort study of adult patients with community acquired bacterial sepsis complicated by rhabdomyolysis from March 2003--August 2008. Rhabdomyolysis was defined as serum creatine kinase >2000 IU/L. The study population was divided into group-I (sepsis with gram positive pathogens), group-II (sepsis with gram negative pathogens) and group-III (culture negative sepsis). RESULTS: 103 patients (group I -15, group II 34 and group III- 54) formed the study cohort. Mean age was 55 years and two third had diabetes. Mean creatine kinase was 7114 IU/L and mean serum creatinine on admission was 2.4 mg/dl. Causative pathogen of sepsis was identified in 47.5%. Gram negative pathogens were more frequently (33%) associated with rhabdomyolysis than gram positive pathogens (14.5%). Lung was the commonest foci of sepsis (38.8%). 78.6% of the study population had one or more additional causal factor for rhabdomyolysis like statin intake, chronic alcoholism, hypokalemia, hypernatremia and hypophosphatemia. Mortality was 59%. CONCLUSIONS: Gram negative bacterial pathogens were more frequently associated with rhabdomyolysis than gram positive pathogens. Rhabdomyolysis in patients with sepsis is multifactorial and is associated with high mortality. PMID- 19787057 TI - Sustained oscillations of NF-kappaB produce distinct genome scanning and gene expression profiles. AB - NF-kappaB is a prototypic stress-responsive transcription factor that acts within a complex regulatory network. The signaling dynamics of endogenous NF-kappaB in single cells remain poorly understood. To examine real time dynamics in living cells, we monitored NF-kappaB activities at multiple timescales using GFP-p65 knock-in mouse embryonic fibroblasts. Oscillations in NF-kappaB were sustained in most cells, with several cycles of transient nuclear translocation after TNF alpha stimulation. Mathematical modeling suggests that NF-kappaB oscillations are selected over other non-oscillatory dynamics by fine-tuning the relative strengths of feedback loops like IkappaBalpha. The ability of NF-kappaB to scan and interact with the genome in vivo remained remarkably constant from early to late cycles, as observed by fluorescence recovery after photobleaching (FRAP). Perturbation of long-term NF-kappaB oscillations interfered with its short-term interaction with chromatin and balanced transcriptional output, as predicted by the mathematical model. We propose that negative feedback loops do not simply terminate signaling, but rather promote oscillations of NF-kappaB in the nucleus, and these oscillations are functionally advantageous. PMID- 19787058 TI - The risk of virologic failure decreases with duration of HIV suppression, at greater than 50% adherence to antiretroviral therapy. AB - BACKGROUND: We hypothesized that the percent adherence to antiretroviral therapy necessary to maintain HIV suppression would decrease with longer duration of viral suppression. METHODOLOGY: Eligible participants were identified from the REACH cohort of marginally housed HIV infected adults in San Francisco. Adherence to antiretroviral therapy was measured through pill counts obtained at unannounced visits by research staff to each participant's usual place of residence. Marginal structural models and targeted maximum likelihood estimation methodologies were used to determine the effect of adherence to antiretroviral therapy on the probability of virologic failure during early and late viral suppression. PRINCIPAL FINDINGS: A total of 221 subjects were studied (median age 44.1 years; median CD4+ T cell nadir 206 cells/mm(3)). Most subjects were taking the following types of antiretroviral regimens: non-nucleoside reverse transcriptase inhibitor based (37%), ritonavir boosted protease inhibitor based (28%), or unboosted protease inhibitor based (25%). Comparing the probability of failure just after achieving suppression vs. after 12 consecutive months of suppression, there was a statistically significant decrease in the probability of virologic failure for each range of adherence proportions we considered, as long as adherence was greater than 50%. The estimated risk difference, comparing the probability of virologic failure after 1 month vs. after 12 months of continuous viral suppression was 0.47 (95% CI 0.23-0.63) at 50-74% adherence, 0.29 (CI 0.03 0.50) at 75-89% adherence, and 0.36 (CI 0.23-0.48) at 90-100% adherence. CONCLUSIONS: The risk of virologic failure for adherence greater than 50% declines with longer duration of continuous suppression. While high adherence is required to maximize the probability of durable viral suppression, the range of adherence capable of sustaining viral suppression is wider after prolonged periods of viral suppression. PMID- 19787059 TI - New insights into the diversity of marine picoeukaryotes. AB - Over the last decade, culture-independent surveys of marine picoeukaryotic diversity based on 18S ribosomal DNA clone libraries have unveiled numerous sequences of novel high-rank taxa. This newfound diversity has significantly altered our understanding of marine microbial food webs and the evolution of eukaryotes. However, the current picture of marine eukaryotic biodiversity may be significantly skewed by PCR amplification biases, occurrence of rDNA genes in multiple copies within a single cell, and the capacity of DNA to persist as extracellular material. In this study we performed an analysis of the metagenomic dataset from the Global Ocean Survey (GOS) expedition, seeking eukaryotic ribosomal signatures. This PCR-free approach revealed similar phylogenetic patterns to clone library surveys, suggesting that PCR steps do not impose major biases in the exploration of environmental DNA. The different cell size fractions within the GOS dataset, however, displayed a distinct picture. High protistan diversity in the <0.8 microm size fraction, in particular sequences from radiolarians and ciliates (and their absence in the 0.8-3 microm fraction), suggest that most of the DNA in this fraction comes from extracellular material from larger cells. In addition, we compared the phylogenetic patterns from rDNA and reverse transcribed rRNA 18S clone libraries from the same sample harvested in the Mediterranean Sea. The libraries revealed major differences, with taxa such as pelagophytes or picobiliphytes only detected in the 18S rRNA library. MAST (Marine Stramenopiles) appeared as potentially prominent grazers and we observed a significant decrease in the contribution of alveolate and radiolarian sequences, which overwhelmingly dominated rDNA libraries. The rRNA approach appears to be less affected by taxon-specific rDNA copy number and likely better depicts the biogeochemical significance of marine protists. PMID- 19787060 TI - Betaalpha-hairpin clamps brace betaalphabeta modules and can make substantive contributions to the stability of TIM barrel proteins. AB - Non-local hydrogen bonding interactions between main chain amide hydrogen atoms and polar side chain acceptors that bracket consecutive betaalpha or alphabeta elements of secondary structure in alphaTS from E. coli, a TIM barrel protein, have previously been found to contribute 4-6 kcal mol(-1) to the stability of the native conformation. Experimental analysis of similar betaalpha-hairpin clamps in a homologous pair of TIM barrel proteins of low sequence identity, IGPS from S. solfataricus and E. coli, reveals that this dramatic enhancement of stability is not unique to alphaTS. A survey of 71 TIM barrel proteins demonstrates a 4-fold symmetry for the placement of betaalpha-hairpin clamps, bracing the fundamental betaalphabeta building block and defining its register in the (betaalpha)(8) motif. The preferred sequences and locations of betaalpha-hairpin clamps will enhance structure prediction algorithms and provide a strategy for engineering stability in TIM barrel proteins. PMID- 19787061 TI - Convergence of cells from the progenitor fraction of adult olfactory bulb tissue to remyelinating glia in demyelinating spinal cord lesions. AB - BACKGROUND: Progenitor cells isolated from adult brain tissue are important tools for experimental studies of remyelination. Cells harvested from neurogenic regions in the adult brain such as the subependymal zone have demonstrated remyelination potential. Multipotent cells from the progenitor fraction have been isolated from the adult olfactory bulb (OB) but their potential to remyelinate has not been studied. METHODOLOGY/PRINCIPAL FINDINGS: We used the buoyant density gradient centrifugation method to isolate the progenitor fraction and harvest self-renewing multipotent neural cells grown in monolayers from the adult green fluorescent protein (GFP) transgenic rat OB. OB tissue was mechanically and chemically dissociated and the resultant cell suspension fractionated on a Percoll gradient. The progenitor fraction was isolated and these cells were plated in growth media with serum for 24 hrs. Cells were then propagated in N2 supplemented serum-free media containing b-FGF. Cells at passage 4 (P4) were introduced into a demyelinated spinal cord lesion. The GFP(+) cells survived and integrated into the lesion, and extensive remyelination was observed in plastic sections. Immunohistochemistry revealed GFP(+) cells in the spinal cord to be glial fibrillary acidic protein (GFAP), neuronal nuclei (NeuN), and neurofilament negative. The GFP(+) cells were found among primarily P0(+) myelin profiles, although some myelin basic protein (MBP) profiles were present. Immuno-electron microscopy for GFP revealed GFP(+) cell bodies adjacent to and surrounding peripheral-type myelin rings. CONCLUSIONS/SIGNIFICANCE: We report that neural cells from the progenitor fraction of the adult rat OB grown in monolayers can be expanded for several passages in culture and that upon transplantation into a demyelinated spinal cord lesion provide extensive remyelination without ectopic neuronal differentiation. PMID- 19787062 TI - Stress priming in reading and the selective modulation of lexical and sub-lexical pathways. AB - Four experiments employed a priming methodology to investigate different mechanisms of stress assignment and how they are modulated by lexical and sub lexical mechanisms in reading aloud in Italian. Lexical stress is unpredictable in Italian, and requires lexical look-up. The most frequent stress pattern (Dominant) is on the penultimate syllable [laVOro (work)], while stress on the antepenultimate syllable [MAcchina (car)] is relatively less frequent (non Dominant). Word and pseudoword naming responses primed by words with non-dominant stress--which require whole-word knowledge to be read correctly--were compared to those primed by nonwords. Percentage of errors to words and percentage of dominant stress responses to nonwords were measured. In Experiments 1 and 2 stress errors increased for non-dominant stress words primed by nonwords, as compared to when they were primed by words. The results could be attributed to greater activation of sub-lexical codes, and an associated tendency to assign the dominant stress pattern by default in the nonword prime condition. Alternatively, they may have been the consequence of prosodic priming, inducing more errors on trials in which the stress pattern of primes and targets was not congruent. The two interpretations were investigated in Experiments 3 and 4. The results overall suggested a limited role of the default metrical pattern in word pronunciation, and showed clear effect of prosodic priming, but only when the sub-lexical mechanism prevailed. PMID- 19787063 TI - Global transcriptional response to Hfe deficiency and dietary iron overload in mouse liver and duodenum. AB - Iron is an essential trace element whose absorption is usually tightly regulated in the duodenum. HFE-related hereditary hemochromatosis (HH) is characterized by abnormally low expression of the iron-regulatory hormone, hepcidin, which results in increased iron absorption. The liver is crucial for iron homeostasis as it is the main production site of hepcidin. The aim of this study was to explore and compare the genome-wide transcriptome response to Hfe deficiency and dietary iron overload in murine liver and duodenum. Illumina arrays containing over 47,000 probes were used to study global transcriptional changes. Quantitative RT-PCR (Q RT-PCR) was used to validate the microarray results. In the liver, the expression of 151 genes was altered in Hfe(-/-) mice while dietary iron overload changed the expression of 218 genes. There were 173 and 108 differentially expressed genes in the duodenum of Hfe(-/-) mice and mice with dietary iron overload, respectively. There was 93.5% concordance between the results obtained by microarray analysis and Q-RT-PCR. Overexpression of genes for acute phase reactants in the liver and a strong induction of digestive enzyme genes in the duodenum were characteristic of the Hfe-deficient genotype. In contrast, dietary iron overload caused a more pronounced change of gene expression responsive to oxidative stress. In conclusion, Hfe deficiency caused a previously unrecognized increase in gene expression of hepatic acute phase proteins and duodenal digestive enzymes. PMID- 19787064 TI - The genome of the stick insect Medauroidea extradentata is strongly methylated within genes and repetitive DNA. AB - BACKGROUND: Cytosine DNA methylation has been detected in many eukaryotic organisms and has been shown to play an important role in development and disease of vertebrates including humans. Molecularly, DNA methylation appears to be involved in the suppression of initiation or of elongation of transcription. Resulting organismal functions are suggested to be the regulation of gene silencing, the suppression of transposon activity and the suppression of initiation of transcription within genes. However, some data concerning the distribution of methylcytosine in insect species appear to contradict such roles. PRINCIPAL FINDINGS: By comparison of MspI and HpaII restriction patterns in genomic DNA of several insects we show that stick insects (Phasmatodea) have highly methylated genomes. We isolated methylated DNA fragments from the Vietnamese Walking Stick Medauroidea extradentata (formerly known as Baculum extradentatum) and demonstrated that most of the corresponding sequences are repetitive. Bisulfite sequencing of one of these fragments and of parts of conserved protein-coding genes revealed a methylcytosine content of 12.6%, mostly found at CpG, but also at CpT and CpA dinucleotides. Corresponding depletions of CpG and enrichments of TpG and CpA dinucleotides in some highly conserved protein coding genes of Medauroidea reach a similar degree as in vertebrates and show that CpG methylation has occurred in the germline of these insects. CONCLUSIONS: Using four different methods, we demonstrate that the genome of Medauroidea extradentata is strongly methylated. Both repetitive DNA and coding genes appear to contain high levels of methylcytosines. These results argue for similar functions of DNA methylation in stick insects as those already known for vertebrates. PMID- 19787065 TI - The trypanosome Rab-related proteins RabX1 and RabX2 play no role in intracellular trafficking but may be involved in fly infectivity. AB - BACKGROUND: Rab GTPases constitute the largest subgroup of the Ras superfamily and are primarily involved in vesicle targeting. The full extent of Rab family function is unexplored. Several divergent Rab-like proteins are known but few have been characterized. In Trypanosoma brucei there are sixteen Rab genes, but RabX1, RabX2 and RabX3 are divergent within canonical sequence regions. Where known, trypanosome Rab functions are broadly conserved when orthologous relationships may be robustly established, but specific functions for RabX1, X2 and X3 have yet to be determined. RabX1 and RabX2 originated via tandem duplication and subcellular localization places RabX1 at the endoplasmic reticulum, while RabX2 is at the Golgi complex, suggesting distinct functions. We wished to determine whether RabX1 and RabX2 are involved in vesicle transport or other cellular processes. METHODOLOGY/PRINCIPAL FINDINGS: Using comparative genomics we find that RabX1 and RabX2 are restricted to trypanosomatids. Gene knockout indicates that RabX1 and RabX2 are non-essential. Simultaneous RNAi knockdown of both RabX1 and RabX2, while partial, was also non-lethal and may suggest non-redundant function, consistent with the distinct locations of the proteins. Analysis of the knockout cell lines unexpectedly failed to uncover a defect in exocytosis, endocytosis or in the morphology or location of multiple markers for the endomembrane system, suggesting that neither RabX1 nor RabX2 has a major role in intracellular transport. However, it was apparent that RabX1 and RabX2 knockout cells displayed somewhat enhanced survival within flies. CONCLUSIONS/SIGNIFICANCE: RabX1 and RabX2, two members of the trypanosome Rab subfamily, were shown to have no major detectable role in intracellular transport, despite the localization of each gene product to highly specific endomembrane compartments. These data extend the functional scope of Rab proteins in trypanosomes to include non-canonical roles in differentiation-associated processes in protozoa. PMID- 19787066 TI - Performance of humans vs. exploration algorithms on the Tower of London Test. AB - The Tower of London Test (TOL) used to assess executive functions was inspired in Artificial Intelligence tasks used to test problem-solving algorithms. In this study, we compare the performance of humans and of exploration algorithms. Instead of absolute execution times, we focus on how the execution time varies with the tasks and/or the number of moves. This approach used in Algorithmic Complexity provides a fair comparison between humans and computers, although humans are several orders of magnitude slower. On easy tasks (1 to 5 moves), healthy elderly persons performed like exploration algorithms using bounded memory resources, i.e., the execution time grew exponentially with the number of moves. This result was replicated with a group of healthy young participants. However, for difficult tasks (5 to 8 moves) the execution time of young participants did not increase significantly, whereas for exploration algorithms, the execution time keeps on increasing exponentially. A pre-and post-test control task showed a 25% improvement of visuo-motor skills but this was insufficient to explain this result. The findings suggest that naive participants used systematic exploration to solve the problem but under the effect of practice, they developed markedly more efficient strategies using the information acquired during the test. PMID- 19787067 TI - The brain atlas concordance problem: quantitative comparison of anatomical parcellations. AB - Many neuroscientific reports reference discrete macro-anatomical regions of the brain which were delineated according to a brain atlas or parcellation protocol. Currently, however, no widely accepted standards exist for partitioning the cortex and subcortical structures, or for assigning labels to the resulting regions, and many procedures are being actively used. Previous attempts to reconcile neuroanatomical nomenclatures have been largely qualitative, focusing on the development of thesauri or simple semantic mappings between terms. Here we take a fundamentally different approach, discounting the names of regions and instead comparing their definitions as spatial entities in an effort to provide more precise quantitative mappings between anatomical entities as defined by different atlases. We develop an analytical framework for studying this brain atlas concordance problem, and apply these methods in a comparison of eight diverse labeling methods used by the neuroimaging community. These analyses result in conditional probabilities that enable mapping between regions across atlases, which also form the input to graph-based methods for extracting higher order relationships between sets of regions and to procedures for assessing the global similarity between different parcellations of the same brain. At a global scale, the overall results demonstrate a considerable lack of concordance between available parcellation schemes, falling within chance levels for some atlas pairs. At a finer level, this study reveals spatial relationships between sets of defined regions that are not obviously apparent; these are of high potential interest to researchers faced with the challenge of comparing results that were based on these different anatomical models, particularly when coordinate-based data are not available. The complexity of the spatial overlap patterns revealed points to problems for attempts to reconcile anatomical parcellations and nomenclatures using strictly qualitative and/or categorical methods. Detailed results from this study are made available via an interactive web site at http://obart.info. PMID- 19787068 TI - Lipid alterations in experimental murine colitis: role of ceramide and imipramine for matrix metalloproteinase-1 expression. AB - BACKGROUND: Dietary lipids or pharmacologic modulation of lipid metabolism are potential therapeutic strategies in inflammatory bowel disease (IBD). Therefore, we analysed alterations of bioactive lipids in experimental models of colitis and examined the functional consequence of the second messenger ceramide in inflammatory pathways leading to tissue destruction. METHODOLOGY/PRINCIPAL FINDINGS: Chronic colitis was induced by dextran-sulphate-sodium (DSS) or transfer of CD4(+)CD62L(+) cells into RAG1(-/-)-mice. Lipid content of isolated murine intestinal epithelial cells (IEC) was analysed by tandem mass spectrometry. Concentrations of MMP-1 in supernatants of Caco-2-IEC and human intestinal fibroblasts from patients with ulcerative colitis were determined by ELISA. Imipramine was used for pharmacologic inhibition of acid sphingomyelinase (ASM). Ceramide increased by 71% in chronic DSS-induced colitis and by 159% in the transfer model of colitis. Lysophosphatidylcholine (LPC) decreased by 22% in both models. No changes were detected for phosphatidylcholine. Generation of ceramide by exogenous SMase increased MMP-1-protein production of Caco-2-IEC up to 7-fold. Inhibition of ASM completely abolished the induction of MMP-1 by TNF or IL-1beta in Caco-2-IEC and human intestinal fibroblasts. CONCLUSIONS/SIGNIFICANCE: Mucosal inflammation leads to accumulation of ceramide and decrease of LPC in the intestinal epithelium. One aspect of ceramide generation is an increase of MMP-1. Induction of MMP-1 by TNF or IL-1beta is completely blocked by inhibition of ASM with imipramine. Therefore, inhibition of ASM may offer a treatment strategy to reduce MMP-1 expression and tissue destruction in inflammatory conditions. PMID- 19787069 TI - miR-200 enhances mouse breast cancer cell colonization to form distant metastases. AB - BACKGROUND: The development of metastases involves the dissociation of cells from the primary tumor to penetrate the basement membrane, invade and then exit the vasculature to seed, and colonize distant tissues. The last step, establishment of macroscopic tumors at distant sites, is the least well understood. Four isogenic mouse breast cancer cell lines (67NR, 168FARN, 4TO7, and 4T1) that differ in their ability to metastasize when implanted into the mammary fat pad are used to model the steps of metastasis. Only 4T1 forms macroscopic lung and liver metastases. Because some miRNAs are dysregulated in cancer and affect cellular transformation, tumor formation, and metastasis, we examined whether changes in miRNA expression might explain the differences in metastasis of these cells. METHODOLOGY/PRINCIPAL FINDINGS: miRNA expression was analyzed by miRNA microarray and quantitative RT-PCR in isogenic mouse breast cancer cells with distinct metastatic capabilities. 4T1 cells that form macroscopic metastases had elevated expression of miR-200 family miRNAs compared to related cells that invade distant tissues, but are unable to colonize. Moreover, over-expressing miR 200 in 4TO7 cells enabled them to metastasize to lung and liver. These findings are surprising since the miR-200 family was previously shown to promote epithelial characteristics by inhibiting the transcriptional repressor Zeb2 and thereby enhancing E-cadherin expression. We confirmed these findings in these cells. The most metastatic 4T1 cells acquired epithelial properties (high expression of E-cadherin and cytokeratin-18) compared to the less metastatic cells. CONCLUSIONS/SIGNIFICANCE: Expression of miR-200, which promotes a mesenchymal to epithelial cell transition (MET) by inhibiting Zeb2 expression, unexpectedly enhances macroscopic metastases in mouse breast cancer cell lines. These results suggest that for some tumors, tumor colonization at metastatic sites might be enhanced by MET. Therefore the epithelial nature of a tumor does not predict metastatic outcome. PMID- 19787072 TI - Microassembly based on hands free origami with bidirectional curvature. AB - Microassembly based on origami, the Japanese art of paper folding, presents an attractive methodology for constructing complex three-dimensional (3D) devices and advanced materials. A variety of functional structures have been created using patterned metallic, semiconducting, and polymeric thin films, but have been limited to those that curve in a single direction. We report a design framework that can be used to achieve spontaneous bidirectional folds with any desired angle, and we demonstrate theoretical and experimental realizations of complex 3D structures with +90 degrees , -90 degrees , +180 degrees , and -180 degrees folds. The strategy is parallel, versatile, and compatible with conventional microfabrication. PMID- 19787071 TI - Transcriptional profiling of rats subjected to gestational undernourishment: implications for the developmental variations in metabolic traits. AB - A link has been established between prenatal nutrition and the development of metabolic and cardiovascular diseases later in life, a process referred to as developmental programming. It has been suggested that the trajectory of development is shifted by alterations in the maternal nutritional state leading to changes in developmental plasticity, in part underpinned by epigenetic changes in gene regulation. However, to date, only candidate gene approaches have been used to assess expression and molecular changes in the offspring of maternally undernourished animals. Furthermore, most work has focused on animals at an age where the programmed phenotype is already manifest and little is known about changes in gene expression in the offspring prior to development of obesity and related metabolic disorders. Gene expression profiles of liver, retroperitoneal white adipose fat, and biceps femoris skeletal muscle tissue from young adult male rats (55 days old) in which nutritional status had been manipulated in utero by maternal undernutrition (UN) were compared to the profiles of offspring of ad libitum fed mothers serving as the control group (AD) (8 offspring/group). The expression profiles were determined using the Illumina RatRef-12 BeadChip. No significant changes in expression were identified for skeletal muscle or white adipose tissue. However, studies of liver tissue showed 249 differentially expressed genes (143 up regulated, 106 down regulated). Although the animals at day 55 have yet to develop obesity they already show biochemical abnormalities and by day 110 express a phenotype characterized by increased adiposity and altered insulin sensitivity. An analysis of pathways affected suggests that intrauterine programming of UN animals to favor fat as an energy source results in mitochondrial dysfunction which initially affects the postnatal hepatic function and subsequently, via the resultant metabolic changes in other organs leads to the evolution of a phenotype similar to that of the metabolic syndrome. PMID- 19787070 TI - Population-based surveillance for invasive pneumococcal disease in homeless adults in Toronto. AB - BACKGROUND: Identification of high-risk populations for serious infection due to S. pneumoniae will permit appropriately targeted prevention programs. METHODS: We conducted prospective, population-based surveillance for invasive pneumococcal disease and laboratory confirmed pneumococcal pneumonia in homeless adults in Toronto, a Canadian city with a total population of 2.5 M, from January 1, 2002 to December 31, 2006. RESULTS: We identified 69 cases of invasive pneumococcal disease and 27 cases of laboratory confirmed pneumococcal pneumonia in an estimated population of 5050 homeless adults. The incidence of invasive pneumococcal disease in homeless adults was 273 infections per 100,000 persons per year, compared to 9 per 100,000 persons per year in the general adult population. Homeless persons with invasive pneumococcal disease were younger than other adults (median age 46 years vs 67 years, P<.001), and more likely than other adults to be smokers (95% vs. 31%, P<.001), to abuse alcohol (62% vs 15%, P<.001), and to use intravenous drugs (42% vs 4%, P<.001). Relative to age matched controls, they were more likely to have underlying lung disease (12/69, 17% vs 17/272, 6%, P = .006), but not more likely to be HIV infected (17/69, 25% vs 58/282, 21%, P = .73). The proportion of patients with recurrent disease was five fold higher for homeless than other adults (7/58, 12% vs. 24/943, 2.5%, P<.001). In homeless adults, 28 (32%) of pneumococcal isolates were of serotypes included in the 7-valent conjugate vaccine, 42 (48%) of serotypes included in the 13-valent conjugate vaccine, and 72 (83%) of serotypes included in the 23-valent polysaccharide vaccine. Although no outbreaks of disease were identified in shelters, there was evidence of clustering of serotypes suggestive of transmission of pathogenic strains within the homeless population. CONCLUSIONS: Homeless persons are at high risk of serious pneumococcal infection. Vaccination, physical structure changes or other program to reduce transmission in shelters, harm reduction programs to reduce rates of smoking, alcohol abuse and infection with bloodborne pathogens, and improved treatment programs for HIV infection may all be effective in reducing the risk. PMID- 19787073 TI - Pharmacodynamic modeling of acute and chronic effects of methylprednisolone on hepatic urea cycle genes in rats. AB - Corticosteroids (CS) regulate many enzymes at both mRNA and protein levels. This study used microarrays to broadly assess regulation of various genes related to the greater urea cycle and employs pharmacokinetic/pharmacodynamic (PK/PD) modeling to quantitatively analyze and compare the temporal profiles of these genes during acute and chronic exposure to methylprednisolone (MPL). One group of adrenalectomized male Wistar rats received an intravenous bolus dose (50 mg/kg) of MPL, whereas a second group received MPL by a subcutaneous infusion (Alzet osmotic pumps) at a rate of 0.3 mg/kg/hr for seven days. The rats were sacrificed at various time points over 72 hours (acute) or 168 hours (chronic) and livers were harvested. Total RNA was extracted and Affymetrix gene chips (RG_U34A for acute and RAE 230A for chronic) were used to identify genes regulated by CS. Besides five primary urea cycle enzymes, many other genes related to the urea cycle showed substantial changes in mRNA expression. Some genes that were simply up- or down-regulated after acute MPL showed complex biphasic patterns upon chronic infusion indicating involvement of secondary regulation. For the simplest patterns, indirect response models were used to describe the nuclear steroid bound receptor mediated increase or decrease in gene transcription (e.g. tyrosine aminotransferase, glucocorticoid receptor). For the biphasic profiles, involvement of a secondary biosignal was assumed (e.g. ornithine decarboxylase, CCAAT/enhancer binding protein) and more complex models were derived. Microarrays were used successfully to explore CS effects on various urea cycle enzyme genes. PD models presented in this report describe testable hypotheses regarding molecular mechanisms and quantitatively characterize the direct or indirect regulation of various genes by CS. PMID- 19787074 TI - Reconstructing a network of stress-response regulators via dynamic system modeling of gene regulation. AB - Unicellular organisms such as yeasts have evolved mechanisms to respond to environmental stresses by rapidly reorganizing the gene expression program. Although many stress-response genes in yeast have been discovered by DNA microarrays, the stress-response transcription factors (TFs) that regulate these stress-response genes remain to be investigated. In this study, we use a dynamic system model of gene regulation to describe the mechanism of how TFs may control a gene's expression. Then, based on the dynamic system model, we develop the Stress Regulator Identification Algorithm (SRIA) to identify stress-response TFs for six kinds of stresses. We identified some general stress-response TFs that respond to various stresses and some specific stress-response TFs that respond to one specific stress. The biological significance of our findings is validated by the literature. We found that a small number of TFs is probably sufficient to control a wide variety of expression patterns in yeast under different stresses. Two implications can be inferred from this observation. First, the response mechanisms to different stresses may have a bow-tie structure. Second, there may be regulatory cross-talks among different stress responses. In conclusion, this study proposes a network of stress-response regulators and the details of their actions. PMID- 19787075 TI - TAK1 mRNA expression in the tumor tissue of locally advanced head and neck cancer patients. AB - Resistance to radio and chemotherapy is one of the major drawbacks in the progression of head and neck squamous cell cancer (HNSCC) patients, evidencing the importance of finding optimum molecular prognosis markers to develop personalized treatment schedules. TGF-beta effector TAK1 activity has been related to a greater aggressiveness in several types of cancer (Kondo et al. 1998; Edlund et al. 2003; Kaur et al. 2005) and, although there has been described no significant implication of TAK1 in HNSCC development, we have further examined the role of its mRNA expression as a marker of prognosis in HNSCC. Fifty-nine advanced HNSCC patients were recruited for the study. The tumor expression of TAK1 mRNA was analyzed with RT-PCR using Taqman technology and its relationship with the clinical outcome of the patients studied. TAK1 mRNA expression was lower in patients that relapsed than in those that did not, but the difference was only significant between the patients that showed response to treatment (p < 0.001). ROC curve analyses pointed a 0.5 expression ratio TAK1/B2M value as an optimum cut-off point for relapse and response. Our data suggest the TAK1 mRNA analysis by Taqman RT-PCR can predict the risk of relapse in HNSCC patients. PMID- 19787077 TI - Association of vascular endothelial growth factor polymorphisms with asthma in Tunisian children. AB - BACKGROUND: Previous studies demonstrated that the vascular endothelial growth factor (VEGF) was being implicated in the airways inflammation and remodeling process in patients with asthma. AIMS: We explored the relationship of three polymorphisms in the VEGF gene with asthma in both case control and family studies. METHODS: We Genotyped a total of 210 children with asthma, 224 unrelated controls and 160 parents for the +936 C >T (rs3025039), -634 G > C (rs2010963) and -2549 -2567 del 18 of the VEGF promoter region. The Mutations were identified with polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis for the +936 C > T, and -634 G > C polymorphisms. RESULTS: Of the three polymorphisms studied, a borderline association with asthma was found for the G allele in the -634 G > C polymorphism (p = 0.059). No Statistically significant differences were observed for both +936 C > T, and 2549 -2567 del 18 polymorphisms between asthmatic patients and controls, considering either allelic or genotypic frequencies. The distribution of genotypes according to the severity status revealed a significant differences for the +936 C > T, and -2549 -2567 del 18 polymorphisms. In addition, association was found with the haplotypes inferred by the three polymorphisms and asthma susceptibility. CONCLUSION: We suggest that VEGF Gene polymorphisms can be implicated in asthma. PMID- 19787076 TI - Gene regulation system of vasopressin and corticotropin-releasing hormone. AB - The neurohypophyseal hormones, arginine vasopressin and corticotropin-releasing hormone (CRH), play a crucial role in the physiological and behavioral response to various kinds of stresses. Both neuropeptides activate the hypophysial pituitary-adrenal (HPA) axis, which is a central mediator of the stress response in the body. Conversely, they receive the negative regulation by glucocorticoid, which is an end product of the HPA axis. Vasopressin and CRH are closely linked to immune response; they also interact with pro-inflammatory cytokines. Moreover, as for vasopressin, it has another important role, which is the regulation of water balance through its potent antidiuretic effect. Hence, it is conceivable that vasopressin and CRH mediate the homeostatic responses for survival and protect organisms from the external world. A tight and elaborate regulation system of the vasopressin and CRH gene is required for the rapid and flexible response to the alteration of the surrounding environments. Several important regulatory elements have been identified in the proximal promoter region in the vasopressin and CRH gene. Many transcription factors and intracellular signaling cascades are involved in the complicated gene regulation system. This review focuses on the current status of the basic research of vasopressin and CRH. In addition to the numerous known facts about their divergent physiological roles, the recent topics of promoter analyses will be discussed. PMID- 19787078 TI - Calcitriol and TO-901317 interact in human prostate cancer LNCaP cells. AB - Vitamin D receptor (VDR) and liver X receptor (LXR) are nuclear receptors, which regulate gene transcription upon binding of their specific ligands. VDR seems to play a role in the regulation of prostate cancer cell proliferation. ATP-binding cassette transporter A1 (ABCA1) is known to be a target gene of LXR and it has been reported to be inhibited by androgen and to be involved in the regulation of LNCaP proliferation. We find that calcitriol (1 alpha,25(OH)(2)D(3)) inhibits both basal and a LXR agonist, TO-901317, induced ABCA1 mRNA expression but has no effect on the mRNA expression of ATP-binding cassette transporter G1 (ABCG1), LXR alpha nor LXR beta. TO-901317 increases both basal and calcitriol induced 25 hydroxyvitamin D(3)-24-hydroxylase (CYP24) mRNA expression and it slightly but significantly inhibits VDR mRNA expression. The inhibition of ABCA1 by calcitriol appears to be androgen-independent. Cell growth assay shows that when each of calcitriol and 5 alpha-dihydrotestosterone (DHT) was co-treated with ABCA1 blocker, glybenclamide, cell-growth is significantly decreased compared to their own treatments respectively. Our study suggests a possible interaction between calcitriol and TO-901317 in LNCaP cells. Alike DHT, the inhibition of ABCA1 by calcitriol may be involved in its regulation of LNCaP growth. PMID- 19787079 TI - Image analysis and data normalization procedures are crucial for microarray analyses. AB - This study was conducted with the aim of optimizing the experimental design of array experiments. We compared two image analysis and normalization procedures prior to data analysis using two experimental designs. For this, RNA samples from Charolais steers Longissimus thoracis muscle and subcutaneous adipose tissues were labeled and hybridized to a bovine 8,400 oligochip either in triplicate or in a dye-swap design. Image analysis and normalization were processed by either GenePix/MadScan or ImaGene/GeneSight. Statistical data analysis was then run using either the SAM method or a Student's t-test using a multiple test correction run on R 2.1 software. Our results show that image analysis and normalization procedure had an impact whereas the statistical methods much less influenced the outcome of differentially expressed genes. Image analysis and data normalization are thus an important aspect of microarray experiments, having a potentially significant impact on downstream analyses such as the identification of differentially expressed genes. This study provides indications on the choice of raw data preprocessing in microarray technology. PMID- 19787080 TI - Butyrate induced cell cycle arrest in bovine cells through targeting gene expression relevant to DNA replication apparatus. AB - Using real-time RT-PCR and Western blot analysis in bovine kidney epithelial cells, we systematically investigated the effects of butyrate on patterns of gene expression relevant to DNA replication apparatus. The real-time PCR and Western blot data generally confirmed previously reported microarray data. Of the five genes tested by quantitative RT-PCR, CDKN1A (p21(waf1)) was up regulated, CDC2/cdk1, MCM6, ORC1L were down regulated, while ORC3L expression remained unchanged following butyrate treatment. Also consistent with RT-PCR results, Western blot analysis confirmed that butyrate up-regulated cyclin-kinase inhibitor p21(waf1) in a does-dependent manner. In contrast, butyrate treatment had no effect on the expression of ERK 1/2 proteins. Also consistent with mRNA results, ORC1 and MCM3 proteins were down-regulated by butyrate treatment, while ORC2 protein remained unchanged. The present results suggest that ORC1, not ORC2 or ORC3, along with MCM proteins play a critical role in regulating the initiation of DNA replication and cell cycle progression in MDBK cells and are targets of butyrate regulation. PMID- 19787081 TI - Pharmacodynamic/pharmacogenomic modeling of insulin resistance genes in rat muscle after methylprednisolone treatment: exploring regulatory signaling cascades. AB - Corticosteroids (CS) effects on insulin resistance related genes in rat skeletal muscle were studied. In our acute study, adrenalectomized (ADX) rats were given single doses of 50 mg/kg methylprednisolone (MPL) intravenously. In our chronic study, ADX rats were implanted with Alzet mini-pumps giving zero-order release rates of 0.3 mg/kg/h MPL and sacrificed at various times up to 7 days. Total RNA was extracted from gastrocnemius muscles and hybridized to Affymetrix GeneChips. Data mining and literature searches identified 6 insulin resistance related genes which exhibited complex regulatory pathways. Insulin receptor substrate-1 (IRS 1), uncoupling protein 3 (UCP3), pyruvate dehydrogenase kinase isoenzyme 4 (PDK4), fatty acid translocase (FAT) and glycerol-3-phosphate acyltransferase (GPAT) dynamic profiles were modeled with mutual effects by calculated nuclear drug-receptor complex (DR(N)) and transcription factors. The oscillatory feature of endothelin-1 (ET-1) expression was depicted by a negative feedback loop. These integrated models provide testable quantitative hypotheses for these regulatory cascades. PMID- 19787082 TI - MicroRNAs regulate osteogenesis and chondrogenesis of mouse bone marrow stromal cells. AB - MicroRNAs (miRNAs) are non-coding RNAs that bind to target mRNA leading to translational arrest or mRNA degradation. To study miRNA-mediated regulation of osteogenesis and chondrogenesis, we compared the expression of 35 miRNAs in osteoblasts and chondroblasts derived from mouse marrow stromal cells (MSCs). Differentiation of MSCs resulted in up- or downregulation of several miRNAs, with miR-199a expression being over 10-fold higher in chondroblasts than in undifferentiated MSCs. In addition, miR-124a was strongly upregulated during chondrogenesis while the expression of miR-96 was substantially suppressed. A systems biological analysis of the potential miRNA target genes and their interaction networks was combined with promoter analysis. These studies link the differentially expressed miRNAs to collagen synthesis and hypoxia, key pathways related to bone and cartilage physiology. The global regulatory networks described here suggest for the first time how miRNAs and transcription factors are capable of fine-tuning the osteogenic and chondrogenic differentiation of mouse MSCs. PMID- 19787083 TI - Centrality analysis methods for biological networks and their application to gene regulatory networks. AB - The structural analysis of biological networks includes the ranking of the vertices based on the connection structure of a network. To support this analysis we discuss centrality measures which indicate the importance of vertices, and demonstrate their applicability on a gene regulatory network. We show that common centrality measures result in different valuations of the vertices and that novel measures tailored to specific biological investigations are useful for the analysis of biological networks, in particular gene regulatory networks. PMID- 19787084 TI - RNA processing and mRNA surveillance in monogenic diabetes. AB - In the eukaryotic cell a number of molecular mechanisms exist to regulate the nature and quantity of transcripts intended for translation. For monogenic diabetes an understanding of these processes is aiding scientists and clinicians in studying and managing this disease. Knowledge of RNA processing and mRNA surveillance pathways is helping to explain disease mechanisms, form genotype phenotype relationships, and identifying new regions within genes to screen for mutations. Furthermore, recent insights into the regulatory role of micro RNAs (miRNAs) and RNA editing in the pancreas suggests that these mechanisms may also be important in the progression to the diabetic state. PMID- 19787085 TI - Gene expression in Pre-MBT embryos and activation of maternally-inherited program of apoptosis to be executed at around MBT as a fail-safe mechanism in Xenopus early embryogenesis. AB - S-adenosylmethionine decarboxylase (SAMDC) is an enzyme which converts S adenosylmethione (SAM), a methyl donor, to decarboxylated SAM (dcSAM), an aminopropyl donor for polyamine biosynthesis. In our studies on gene expression control in Xenopus early embryogenesis, we cloned the mRNA for Xenopus SAMDC, and overexpressed the enzyme by microinjecting its mRNA into Xenopus fertilized eggs. In the mRNA-injected embryos, the level of SAMDC was enormously increased, the SAM was exhausted, and protein synthesis was greatly inhibited, but cellular polyamine content did not change appreciably. SAMDC-overexpressed embryos cleaved and developed normally up to the early blastula stage, but at the midblastula stage, or the stage of midblastula transition (MBT), all the embryos were dissociated into cells, and destroyed due to execution of apoptosis. During cleavage SAMDC-overexpressed embryos transcribed caspase-8 gene, and this was followed by activation of caspase-9. When we overexpressed p53 mRNA in fertilized eggs, similar apoptosis took place at MBT, but in this case, transcription of caspase-8 did not occur, however activation of caspase-9 took place. Apoptosis induced by SAMDC-overexpression was completely suppressed by Bcl-2, whereas apoptosis induced by p53 overexpression or treatments with other toxic agents was only partially rescued. When we injected SAMDC mRNA into only one blastomere of 8 to 32-celled embryos, descendant cells of the mRNA-injected blastomere were segregated into the blastocoel and underwent apoptosis within the blastocoel, although such embryos continued to develop and became tadpoles with various extents of anomaly, reflecting the developmental fate of the eliminated cells. Thus, embryonic cells appear to check themselves at MBT and if physiologically severely-damaged cells occur, they are eliminated from the embryo by activation and execution of the maternally-inherited program of apoptosis. We assume that the apoptosis executed at MBT is a "fail-safe" mechanism of early development to save the embryo from accidental damages that take place during cleavage. PMID- 19787086 TI - Level of expression of the nonmutant Ferrochelatase allele is a determinant of biochemical phenotype in a mouse model of erythropoietic protoporphyria. AB - Ferrochelatase (FECH) activity is decreased in erythropoietic protoporphyria (EPP), causing increased production and excretion of protoporphyrin. This study examined whether the level of expression of the nonmutant FECH allele is a determinant of phenotype in a mouse model of EPP that carries a heterozygous deletion of exon 10 in FECH. Two mice strains that had a two-fold difference in FECH mRNA levels in bone marrow and liver (low expressing C3H/HeJ and high expressing CBA/J) were used to establish congenic strains containing the mutation. Erythrocyte protoporphyrin levels in C3H/HeJ heterozygous mice were significantly higher than in their wildtype littermates, whereas levels in CBA/J heterozygous mice did not differ significantly from their wildtype littermates. Biliary excretion of protoporphyrin was also significantly higher in C3H/HeJ heterozygous mice. The levels of normal FECH mRNA in bone marrow measured by real time PCR were 138 +/- 30 copies per ug total RNA in C3H/HeJ +/- mice, 320 +/- 59 in C3H/HeJ +/+ mice and 634 +/- 38 in CBA/J +/+ mice. Levels in liver tissue of the mice differed significantly in the same pattern. Thus, the level of expression of the nonmutant FECH allele is a determinant of phenotype in a mouse model of EPP as has been demonstrated in human EPP. PMID- 19787087 TI - Preclinical assessment of wt GNE gene plasmid for management of hereditary inclusion body myopathy 2 (HIBM2). AB - Hereditary Inclusion Body Myopathy (HIBM2) is a chronic progressive skeletal muscle wasting disorder which generally leads to complete disability before the age of 50 years. There is currently no effective therapeutic treatment for HIBM2. Development of this disease is related to expression in family members of an autosomal recessive mutation of the GNE gene, which encodes the bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK). This is the rate limiting bifunctional enzyme that catalyzes the first 2 steps of sialic acid biosynthesis. Decreased sialic acid production, consequently leads to decreased sialyation of a variety of glycoproteins including the critical muscle protein alpha-dystroglycan (alpha-DG). This in turn severely cripples muscle function and leads to the onset of the syndrome. We hypothesize that replacing the mutated GNE gene with the wildtype gene may restore functional capacity of GNE/MNK and therefore production of sialic acid, allowing for improvement in muscle function and/or delay in rate of muscle deterioration. We have constructed three GNE gene/CMV promoter plasmids (encoding the wildtype, HIBM2, and Sialuria forms of GNE) and demonstrated enhanced GNE gene activity following delivery to GNE-deficient CHO-Lec3 cells. GNE/MNK enzyme function was significantly increased and subsequent induction of sialic acid production was demonstrated after transfection into Lec3 cells with the wild type or R266Q mutant GNE vector. These data form the foundation for future preclinical and clinical studies for GNE gene transfer to treat HIBM2 patients. PMID- 19787088 TI - The MAPK signaling cascade is a central hub in the regulation of cell cycle, apoptosis and cytoskeleton remodeling by tripeptidyl-peptidase II. AB - Tripeptidyl-peptidase II (TPPII) is a serine peptidase highly expressed in malignant Burkitt's lymphoma cells (BL). We have previously shown that overexpression of TPPII correlates with chromosomal instability, centrosomal and mitotic spindle abnormalities and resistance to apoptosis induced by spindle poisons. Furthermore, TPPII knockdown by RNAi was associated with endoreplication and the accumulation of polynucleated cells that failed to complete cell division, indicating a role of TPPII in the cell cycle. Here we have applied a global approach of gene expression analysis to gain insights on the mechanism by which TPPII regulates this phenotype. mRNA profiling of control and TPPII knockdown BL cells identified one hundred and eighty five differentially expressed genes. Functional categorization of these genes highlighted major physiological functions such as apoptosis, cell cycle progression, cytoskeleton remodeling, proteolysis, and signal transduction. Pathways and protein interactome analysis revealed a significant enrichment in components of MAP kinases signaling. These findings suggest that TPPII influences a wide network of signaling pathways that are regulated by MAPKs and exerts thereby a pleiotropic effect on biological processes associated with cell survival, proliferation and genomic instability. PMID- 19787089 TI - Role of cytokines during epileptogenesis and in the transition from the interictal to the ictal state in the epileptic mutant EL mouse. AB - PURPOSE: Epileptic mutant EL mice show secondary generalized seizures. Seizure discharges initiate in the parietal cortex and generalize through the hippocampus. We have previously demonstrated an increase in the activity of inducible nitric oxide synthetase (iNOS) as well as a decrease in the activity of superoxide dismutase (SOD) in the hippocampus of EL mice, suggesting that cell toxic free radicals are increased in the brain of EL mice. In parallel with this, neurotrophic factors were significantly increased in the hippocampus of EL mice in earlier developmental stages before exhibiting frequent seizures. These findings were no longer present after frequent seizures, suggesting that these events may trigger ictogenesis. On the other hand, it is reported that limbic seizures rapidly induce cytokines and related inflammatory mediators. It remains to be seen, however, whether cytokines contribute to the transition from interictal to ictal state. The present study was designed to address this issue using EL mice. METHODS: EL mice at the age from 4 to 23 weeks and their control animal, DDY mice at the age of 10 and 20 weeks were used. Seizures were induced in EL mice once every week since 5 weeks. Cytokines, such as interleukin-1 alpha (IL-1a), interleukin 1-beta (IL-1b), IL-6, IL-1 receptor (IL-1r), IL-1 receptor antagonist (IL-ra) and tumor necrosis factor alpha (TNF-a) were examined by Western blotting in the 'focus complex' of brain (namely, in the parietal cortex and hippocampus) of EL mice in the interictal period at different developmental stages. In 15 week old EL mice, which show seizures once a week, these cytokines were similarly determined 5 min, 2 hr, 4 hr, 11 hr, 24 hr, 3 days and 6 days after the last seizure induced. RESULTS: A significant increase in the level of cytokines was observed in the brain of EL mice at any stages during development, compared with the level of cytokines in the brain of control DDY. Cytokines were increased predominantly before experiencing frequent seizures. In EL mice at the age of 15 weeks, the level of cytokines in the hippocampus was highest 6 days after seizures. In the parietal cortex, cytokines were most highly expressed 2 hr after seizures. The results indicate that cytokines were kept up-regulated until next seizures in the hippocampus, whereas they were transiently up-regulated immediately after seizures in the parietal cortex. CONCLUSION: It is concluded that in the brain of EL mice, pro-inflammatory cytokines are increased progressively and periodically in association with the development and the seizure activity, respectively. A periodic increase of cytokines prior to the next seizure episode may play a role in triggering the ictal activity. Namely, alteration of region-specific cytokines may induce ictal activities from the interictal state. It is conceivable that inflammatory cytokines may work together with neuronal factors during epileptogenesis and in the transition from interictal to ictal state. PMID- 19787091 TI - Molecular mechanisms of uterine leiomyosarcomas: involvement of defect in LMP2 expression. AB - Patients with uterine leiomyosarcoma (LMS) typically present with vaginal bleeding, pain, and a pelvic mass. Typical presentations with hypercalcemia or eosinophilia have been reported. Radiographic evaluation with combined positron emission tomography/computed tomography may assist in the diagnosis and surveillance of women with uterine LMS. A recently developed risk-assessment index is highly predictive of disease-specific survival. Ovarian preservation does not appear to negatively impact outcome, and the addition of adjuvant therapy after surgical treatment does not seem to improve survival. It is noteworthy that LMP2-deficient mice exhibit spontaneous development of uterine LMS with a disease prevalence of approximately 37% by 12 months of age. The LMP2 gene is transcribed from a promoter containing an interferon (IFN)-gamma-response factor element; thus, the IFN-gamma-signal strongly induces LMP2 expression. Furthermore, a recent report demonstrated the loss of ability to induce LMP2 expression, which is an interferon (IFN)-gamma-inducible factor, in human uterine LMS tissues and cell lines. Analysis of human uterine LMS shows somatic mutations in the IFN gamma signalling pathway, thus the loss of LMP2 induction is attributable to a defect in the earliest steps of the IFN-gamma signalling pathway. The discovery of an impaired key cell-signalling pathway may provide new targets for diagnostic approaches and therapeutic intervention. PMID- 19787090 TI - Advances in antisense oligonucleotide development for target identification, validation, and as novel therapeutics. AB - Antisense oligonucleotides (As-ODNs) are single stranded, synthetically prepared strands of deoxynucleotide sequences, usually 18-21 nucleotides in length, complementary to the mRNA sequence of the target gene. As-ODNs are able to selectively bind cognate mRNA sequences by sequence-specific hybridization. This results in cleavage or disablement of the mRNA and, thus, inhibits the expression of the target gene. The specificity of the As approach is based on the probability that, in the human genome, any sequence longer than a minimal number of nucleotides (nt), 13 for RNA and 17 for DNA, normally occurs only once. The potential applications of As-ODNs are numerous because mRNA is ubiquitous and is more accessible to manipulation than DNA. With the publication of the human genome sequence, it has become theoretically possible to inhibit mRNA of almost any gene by As-ODNs, in order to get a better understanding of gene function, investigate its role in disease pathology and to study novel therapeutic targets for the diseases caused by dysregulated gene expression. The conceptual simplicity, the availability of gene sequence information from the human genome, the inexpensive availability of synthetic oligonucleotides and the possibility of rational drug design makes As-ODNs powerful tools for target identification, validation and therapeutic intervention. In this review we discuss the latest developments in antisense oligonucleotide design, delivery, pharmacokinetics and potential side effects, as well as its uses in target identification and validation, and finally focus on the current developments of antisense oligonucleotides in therapeutic intervention in various diseases. PMID- 19787092 TI - Systems biology and cancer prevention: all options on the table. AB - In this paper, we outline the status quo and approaches to further development of the systems biology concepts with focus on applications in cancer prevention science. We discuss the biological aspects of cancer research that are of primary importance in cancer prevention, motivations for their mathematical modeling and some recent advances in computational oncology. We also make an attempt to outline in big conceptual terms the contours of future work aimed at creation of large-scale computational and informational infrastructure for using as a routine tool in cancer prevention science and decision making. PMID- 19787093 TI - Exploratory studies on development of the chemokine receptor CXCR4 antagonists toward downsizing. AB - Seven transmembrane (7TM) G-protein-coupled receptor (GPCR) families are important targets for drug discovery, and specific antagonists for GPCR can accelerate research in the field of medicinal chemistry. The chemokine receptor CXCR4 is a GPCR that possesses a unique ligand CXCL12/stromal cell-derived factor 1 (SDF-1). The interaction between CXCL12 and CXCR4 is essential for the migration of progenitor cells during embryonic development of the cardiovascular, hemopoietic and central nervous systems, and also involved in several intractable disease processes, including HIV infection, cancer cell metastasis, progression of acute and chronic leukemias, rheumatoid arthritis and pulmonary fibrosis. Thus, CXCR4 may be an important therapeutic target in all of these diseases, and various CXCR4 antagonists have been proposed as potential drugs. Fourteen-mer peptides, T140 and its analogs, and downsized cyclic pentapeptides have been developed by us as potent CXCR4 antagonists. This article describes the development of a number of specific CXCR4 antagonists in our laboratory, including downsizing. PMID- 19787094 TI - Small family with key contacts: par14 and par17 parvulin proteins, relatives of pin1, now emerge in biomedical research. AB - The parvulin-type peptidyl-prolyl cis/trans isomerase Pin1 is subject of intense biochemical and clinical research as it seems to be involved in the pathogenesis of certain cancers and protein folding illnesses like Alzheimer's and Parkinson's disease. In addition to Pin1, the human genome only contains a single other parvulin locus encoding two protein species-Par14 and Par17. Much less is known about these enzymes although their sequences are highly conserved in all metazoans. Parvulin has been proposed to function as Pin1 complementing enzyme in cell cycle regulation and in chromatin remodelling. Pharmaceutical modulation of Par14 might therefore have benefits for certain types of cancer. Moreover, the Par17 protein that has been shown to be confined to anthropoid primate species only might provide a deeper understanding for human-specific brain development. This review aims at stimulating further research on Par14 and Par17 that are overlooked drug targets in the shadow of an overwhelming plethora of Pin1 literature by summarising all current knowledge on these parvulin proteins. PMID- 19787095 TI - Modifications of antiepileptic drugs for improved tolerability and efficacy. AB - INTRODUCTION: A large number of antiepileptic drugs (AEDs) are available today, but they may not be satisfactory regarding clinical efficacy, tolerance, toxicity or pharmacokinetic properties. The purpose of this review is to focus upon the rationale behind the chemical modifications of several recently marketed AEDs or drugs in development and to categorize them according to the main purposes for the improvements: better efficacy or tolerability accompanied by improved pharmacokinetic properties. MATERIAL AND METHOD: AEDs that have been chemically modified to new derivatives during the last years are reviewed based on recent publications and PubMed-searches. RESULTS AND DISCUSSION: Improvement in pharmacokinetic parameters may affect both tolerability and efficacy. Modifications to improve tolerability include various valproate analogues, divided into aliphatic amides, cyclic derivatives or amino acid conjugates. Furthermore, there are the carbamazepine analogues oxcarbazepine and eslicarbazepine, the felbamate analogues fluorofelbamate and carisbamate (RWJ 33369), and the lamotrigine analogue JZP-4. The levetiracetam analogues brivaracetam and seletracetam and the derivatives of gabapentin, pregabalin and XP13512, have improved selectivity compared to their parent compounds. Other new drugs have new mechanisms of action related to GABA and glutamate receptors; the glutamate antagonists like topiramate (talampanel and NS-1209), and GABA(A) receptor agonists, benzodiazepine or progesterone analogues (ELB-139 and ganaxolone). CONCLUSION: Further challenges for development of new AEDs include investigations of target molecules affected by pathophysiological processes and detailed structure-activity relationships with focus on stereoselectivity. These potential drugs may become of importance in future drug therapy in epilepsy and other CNS disorders. PMID- 19787096 TI - Drug Targeting of alpha-Synuclein Oligomerization in Synucleinopathies. AB - The heterogeneity of symptoms and disease progression observed in synucleinopathies, of which Parkinson's disease (PD) is the most common representative, poses large problems for the discovery of novel therapeutics. The molecular basis for pathology is currently unclear, both in familial and in sporadic cases. While the therapeutic effects of L-DOPA and dopamine receptor agonists constitute good options for symptomatic treatment in PD, the development of neuroprotective and/or neurorestorative treatments for PD and other synucleinopathies faces significant challenges due to the poor knowledge of the putative targets. Recent experimental evidence strongly suggests a central role for neurotoxic alpha-synuclein oligomeric species in neurodegeneration. The events leading to protein oligomerization, as well as the oligomeric species themselves, are likely amenable to modulation by small molecules, which are beginning to emerge in high throughput compound screens in a variety of model organisms. The therapeutic potential of small molecule modulators of oligomer formation demands further exploration and validation in cellular and animal disease models in order to accelerate human drug development. PMID- 19787097 TI - Effects of FK506 on ca release channels (review). AB - Tacrolimus (FK506), which was isolated from the fermentation broth of Streptomyces tsukubaensis No. 9993, has an immunosuppressive effect. In T lymphocytes, FK506 binds to the intracellular receptor, a 12-kDa FK506-binding protein (FKBP12). The FK506-FKBP12 complex binds to the phosphatase calcineurin (CN) and inhibits the activity of CN. By inhibition of the activity of CN, dephosphorylation of a nuclear factor of activated T-cells (NFAT) is inhibited, and translocation of the NFAT to the nucleus is suppressed. Thereby, the production of T-cell-derived mediators such as interleukin 2 (IL-2) is inhibited, and the proliferation of cytotoxic T-cells is suppressed. In muscle cells, FKBP12 and FKBP12.6 are associated with ryanodine-sensitive Ca(2+) release channels (ryanodine receptors: RyRs) on the skeletal and cardiac muscle sarcoplasmic reticulum (SR), respectively. FK506 modulates the RyR by dissociating FKBP12 or FKBP12.6 from the RyR complex. FKBP12 is also associated with inositol 1,4,5 trisphosphate (IP(3))-sensitive Ca(2+) release channels (IP(3) receptors: IP(3)Rs) on the endoplasmic reticulum (ER) of non-muscle cells. The IP(3)R-FKBP12 complex binds to CN, which dephosphorylates the protein kinase C (PKC) phosphorylation site on the receptor. When FKBP12 is dissociated from the IP(3)R complex by FK506, CN is also dissociated from the IP(3)R. Thereby, the IP(3)R is phosphorylated by PKC, and the receptor is modulated. Recently, it was found that FK506 itself induces Ca(2+) release through RyRs in some tissues. PMID- 19787099 TI - Lunasin: a novel cancer preventive seed Peptide. AB - Cancer is one of the leading causes of deaths in the Western world. Approximately one-third of these deaths are preventable by lifestyle factors, including modification of nutritional habits. Studies have demonstrated that adequate nutrition with certain types of foods containing bioactive compounds might offer significant protection against carcinogenesis. Soybeans contain a variety of phytochemicals with demonstrated anticancer activity, including isoflavones, protease inhibitors, and more recently lunasin, a novel cancer preventive seed peptide. Initially isolated from soybean, lunasin has also been reported in barley and wheat. The purpose of this review is to summarize the most recent evidence on the possible benefits of lunasin for cancer prevention. PMID- 19787104 TI - Chiral Pd aqua complex-catalyzed asymmetric C-C bond-forming reactions: a Bronsted acid-base cooperative system. AB - Chiral cationic Pd aqua complexes can function as acid-base catalysts, effectively activating active methylene and methine compounds to give chiral Pd enolates. It is noteworthy that such enolate formation occurs with concomitant formation of a strong protic acid. Although the reactivity of the Pd enolate itself is not sufficient for reactions with carbon-based electrophiles, its cooperative action with the protic acid to activate the electrophiles allows the desired C-C bond-forming reactions to proceed smoothly in a highly enantioselective manner. Based on this mechanistic feature, reactions with acetals have been developed; these are difficult to achieve using conventional basic enolate chemistry. PMID- 19787100 TI - Bioactive and structural metabolites of pseudomonas and burkholderia species causal agents of cultivated mushrooms diseases. AB - Pseudomonas tolaasii, P. reactans and Burkholderia gladioli pv. agaricicola, are responsible of diseases on some species of cultivated mushrooms. The main bioactive metabolites produced by both Pseudomonas strains are the lipodepsipeptides (LDPs) tolaasin I and II and the so called White Line Inducing Principle (WLIP), respectively, LDPs which have been extensively studied for their role in the disease process and for their biological properties. In particular, their antimicrobial activity and the alteration of biological and model membranes (red blood cell and liposomes) was established. In the case of tolaasin I interaction with membranes was also related to the tridimensional structure in solution as determined by NMR combined with molecular dynamic calculation techniques. Recently, five news minor tolaasins, tolaasins A-E, were isolated from the culture filtrates of P. tolaasii and their chemical structure was determined by extensive use of NMR and MS spectroscopy. Furthermore, their antimicrobial activity was evaluated on target micro-organisms (fungi-including the cultivated mushrooms Agaricus bisporus, Lentinus edodes, and Pleurotus spp. chromista, yeast and bacteria). The Gram positive bacteria resulted the most sensible and a significant structure-activity relationships was apparent. The isolation and structure determination of bioactive metabolites produced by B. gladioli pv. agaricicola are still in progress but preliminary results indicate their peptide nature. Furthermore, the exopolysaccharide (EPS) from the culture filtrates of B. gladioli pv. agaricicola, as well as the O-chain and lipid A, from the lipopolysaccharide (LPS) of the three bacteria, were isolated and the structures determined. PMID- 19787098 TI - The role of integrins in cancer and the development of anti-integrin therapeutic agents for cancer therapy. AB - Integrins have been reported to mediate cell survival, proliferation, differentiation, and migration programs. For this reason, the past few years have seen an increased interest in the implications of integrin receptors in cancer biology and tumor cell aggression. This review considers the potential role of integrins in cancer and also addresses why integrins are present attractive targets for drug design. It discusses of the several properties of the integrin based chemotherapeutic agents currently under consideration clinically and provides an insight into cancer drug development using integrin as a target. PMID- 19787105 TI - Solid-state interactions of calixarenes with biorelevant molecules. AB - Among all crystalline complexes of calix-type calix[n]arenes those with organic molecules which are biologically relevant are especially of interest due to their potential medical and pharmaceutical applications. The co-crystallization of drugs with water-soluble calixarenes offers the opportunity to modify chemical and physical properties of APIs (active pharmaceutical ingredients) and to control drug conformation. Such co-crystallization can improve solubility, bioavailability and stability of pharmaceutically active molecules and/or eliminate polymorphism. In this article the solid-state interactions between calixarene hosts and biologically relevant guest molecules are summarized for the currently available structures solved by single-crystal X-ray crystallography. PMID- 19787106 TI - Two guest complexation modes in a cyclotriveratrylene-based molecular container. AB - We report the synthesis of a cyclotriveratrylene-based molecular container and its distinctly different modes of complexation with dimethyldiazapyrenium and 4,4'-biphenylbisdiazonium ions. PMID- 19787107 TI - Spectroelectrochemistry at ultrahigh vacuum: in situ monitoring of electrochemically generated species by X-ray photoelectron spectroscopy. AB - The electrochemical reduction of Fe(III) to Fe(II) in the ionic liquid (IL) mixture of 1-ethyl-3-methylimidazolium ethylsulfate, [C(2)C(1)Im][EtOSO(3)], and 1-butyl-3-methylimidazolium tetrachloroferrate (III), [C(4)C(1)Im][Fe(III)Cl(4)], was monitored in situ by X-ray photoelectron spectroscopy (XPS). PMID- 19787109 TI - Highly enantioselective intramolecular Michael reactions by D-camphor-derived triazolium salts. AB - Camphor-derived chiral triazolium salts have been found to be highly efficient for asymmetric intramolecular Michael reactions. With 1-5 mol% of the catalyst, the desired products were obtained in excellent yields, with up to 99% ee. PMID- 19787108 TI - Functional consequence of plasmid DNA modified site-specifically with 7-deaza deoxyadenosine at a single, programmable site. AB - Replacement of a single dA nucleotide positioned at a programmed site in a DNA plasmid with its 7-deaza-analog is described together with its complete resistance to restriction enzymatic cleavage. PMID- 19787110 TI - A stable near IR switchable electrochromic polymer based on an indole-substituted nickel dithiolene. AB - A novel nickel dithiolene-containing polymer, generated by the electropolymerisation of pendent indole units, has been prepared and shows good stability and fast reversible switching of the near infrared absorption by varying the applied potential of the film. PMID- 19787111 TI - Metal (Cu, Au)-modified silicon nanowires for high-selectivity solvent-free hydrocarbon oxidation in air. AB - Metal (Au, Cu)-modified Si nanowires (SiNWs) are superior catalysts for selective oxidation of hydrocarbons, while SiNWs are a powerful substrate support (enhance efficiency and selectivity) for nanocatalysts. PMID- 19787112 TI - Self-assembly of amphiphilic fluorescent dyes showing aggregate-induced enhanced emission: temperature dependence of molecular alignment and intermolecular interaction in aqueous environment. AB - A 1-cyano-1,2-bis(biphenyl)ethene derivative having hexa(ethylene glycol) groups as amphiphilic side chains showed aggregate-induced enhanced emission in water; upon heating the intensity of the enhanced emission was attenuated in a lower temperature range than the temperature range where exciton interaction is still effective. PMID- 19787113 TI - Reactions of (-)-sparteine with alkali metal HMDS complexes: conventional meets the unconventional. AB - 'Conventional' (-)-sparteine adducts of lithium and sodium 1,1,1,3,3,3 hexamethyldisilazide (HMDS) were prepared and characterised, along with an unexpected and 'unconventional' hydroxyl-incorporated sodium sodiate, [(-) sparteine x Na(mu-HMDS)Na x (-)-sparteine](+)[Na(4)(mu-HMDS)(4)(OH)](-)--the complex anion of which is the first inverse crown ether anion. PMID- 19787114 TI - An ultrasensitive DNAzyme-based colorimetric strategy for nucleic acid detection. AB - An ultrasensitive DNAzyme-based colorimetric DNA detection strategy was developed by utilizing gold nanoparticles modified with both peroxidase-mimicking DNAzymes and capture DNAs and magnetic nanoparticles modified with another capture DNAs, with a detection limit for a model Chlamydia gene of 50 fM. PMID- 19787116 TI - Neutral, panchromatic Ru(II) terpyridine sensitizers bearing pyridine pyrazolate chelates with superior DSSC performance. AB - A new series of neutral, panchromatic Ru(II) terpyridine sensitizers (PRT1-PRT4) exhibit much higher molar extinction coefficients at 400-550 nm and superior DSSC performance in terms of conversion efficiency (eta = 10.05 for PRT4) and stability. PMID- 19787115 TI - Stereoselective glycosylation using oxathiane glycosyl donors. AB - A bicyclic glycosyl donor is activated as an arylsulfonium ion and used to synthesise alpha-glycosides with high stereoselectivity. PMID- 19787117 TI - Reversible RS-NO bond cleavage and formation at copper(I) thiolates. AB - Two coordinate copper(I) thiolates IPrCu-SR undergo rapid, reversible transnitrosation with S-nitrosothiols RSNOs without catalyzing the loss of NO(gas) from these biological carriers of NO. PMID- 19787118 TI - The synthesis of allenes by Cu(I)-catalyzed regio- and stereoselective reduction of propargylic carbonates with hydrosilanes. AB - Cu(I)-catalyzed anti-S(N)2'-type reduction of internal propargylic carbonates with hydrosilanes affords various di- and trisubstituted allenes with high regioselectivities; the reactions are compatible with functional groups and work efficiently for the synthesis of optically-active allenes. PMID- 19787119 TI - Template-free polymorph discrimination and synthesis of calcium carbonate minerals. AB - Template-free polymorph discrimination of CaCO(3) can be easily realized by a so called double-jet method in aqueous solution under mild conditions, which may shed new light on the controlled crystallization of other inorganic material systems in which polymorph selection is of critical importance or is highly relevant to their properties. PMID- 19787120 TI - Enhanced speed of bimetallic nanorod motors by surface roughening. AB - The speed of hydrogen peroxide propelled bimetallic nanorods in water is shown to be proportional to the surface area of the catalytic segment of the nanorods. PMID- 19787121 TI - Diphenylamine end-capped 1,4-diketo-3,6-diphenylpyrrolo[3,4-c]pyrrole (DPP) derivatives with large two-photon absorption cross-sections and strong two-photon excitation red fluorescence. AB - Novel donor-pi-bridge-acceptor-pi-bridge-donor (D-pi-A-pi-D)-type 1,4-diketo-3,6 diphenylpyrrolo[3,4-c]pyrrole (DPP) derivatives with end-capping diphenylamine groups have been synthesized and shown to exhibit large two-photon absorption cross-sections over a wide range of wavelengths with strong two-photon excitation red fluorescence. PMID- 19787122 TI - Saturation transfer difference NMR reveals functionally essential kinetic differences for a sugar-binding repressor protein. AB - The binding kinetics of disaccharides trehalose and trehalose-6-phosphate to repressor protein TreR have been determined using STD NMR and shed light on the contrasting biological roles of these two sugars. PMID- 19787123 TI - On-cue detachment of hydrogels and cells from optically transparent electrodes. AB - The goal of the present communication was to develop a strategy for detachment of cells and biomaterial constructs from indium tin oxide (ITO) electrodes. PMID- 19787124 TI - Highly sensitive oxygen sensors based on Cu(I) complex-polystyrene composite nanofibrous membranes prepared by electrospinning. AB - The first optical oxygen sensor based on Cu(I) complex-polystyrene composite nanofibrous membranes, showing high sensitivity (I(0)/I(100) = 15.56), good linear Stern-Volmer characteristics (R(2) = 0.9966) and short response/recovery time (t(decrease) (s) = 7 and t(increase) (s) = 14), has been prepared; these results represent the best values reported for oxygen sensors based on Cu(I) complexes. PMID- 19787125 TI - Polymorph selection in 2D crystals by phase transition blocking. AB - A phase transition between two-dimensional polymorphs of the buckybowl corannulene on a Cu(111) surface can be suppressed by spatial confinement, allowing stabilisation of the metastable polymorph over the stable one. PMID- 19787126 TI - Double phase transfer of gold nanorods for surface functionalization and entrapment into PEG-based nanocarriers. AB - A novel double phase transfer process was achieved to develop PEG-based targetable nanostructures containing gold nanorods: in the first phase transfer, lipophilic free-CTAB gold nanorods have been obtained, by a straightforward one step ligand exchange reaction in hydro-alcoholic mixture with thiols, then a second phase transfer was performed to entrap them into PEG-based polymeric nanoparticles. PMID- 19787127 TI - Meso-alkylidenyl-thia(p-benzi)porphyrins and their unusual protonation selectivity. AB - Meso-alkylidenyl-thia(p-benzi)porphyrin and its ring expanded analog containing exocyclic C-C double bonds at meso-positions, undergo initial protonation at the exocyclic alkylidene alpha-carbon. PMID- 19787128 TI - Site-specific covalent labeling of His-tag fused proteins with a reactive Ni(II) NTA probe. AB - A new method for covalent labeling of a His-tag fused protein with a small reactive probe was developed; this method is based on the complementary interaction between the His-tag and Ni(II)-NTA, which facilitates a nucleophilic reaction between a histidine residue of the tag and the electrophilic tosyl group of the Ni(II)-NTA probe by the proximity effect. PMID- 19787129 TI - One-pot synthesis of nanomaterials via RAFT polymerization induced self-assembly and morphology transition. AB - A simple and facile strategy has been developed for synthesis of nanomaterials via polymerization in high concentration; multiple morphologies can be created and tuned just by variation of the feed ratio and reaction conditions. PMID- 19787130 TI - Conjugated polyelectrolyte as a colorimetric and fluorescent probe for the detection of glutathione. AB - A sensitive colorimetric and fluorescent probe based on a water-soluble cationic conjugated polyelectrolyte was applied to detect glutathione through an in situ premodification technique. PMID- 19787131 TI - Fabrication of CaFe2O4/MgFe2O4 bulk heterojunction for enhanced visible light photocatalysis. AB - A bulk heterojunction photocatalyst of interfacing CaFe(2)O(4) and MgFe(2)O(4) nanoparticles is highly active for oxidative degradation of isopropyl alcohol and hydrogen production from water under visible light, because the exciton easily reaches the interface and dissociates to minimize recombination. PMID- 19787132 TI - Chemical regeneration of human tooth enamel under near-physiological conditions. AB - Regenerating the microstructure of human tooth enamel under near-physiological conditions (pH 6.0, 37 degrees C, 1 atm) using a simple chemical approach demonstrates a potential application to repair enamel damage in dental clinics. PMID- 19787133 TI - A highly selective fluorescent ESIPT probe for the dual specificity phosphatase MKP-6. AB - A highly selective fluorescent probe for a protein tyrosine phosphatase (PTP) was designed by a simple phosphorylation of the 2-(2'-hydroxyphenyl)benzothiazole (HBT) chromophore: upon selective enzymatic hydrolysis, an excited-state intramolecular proton transfer (ESIPT) occurs, resulting in a large Stokes shift. PMID- 19787134 TI - Pd-silicalite-1 composite membrane for direct hydroxylation of benzene. AB - Pd membranes of excellent stability and flux were prepared with multi-legged anchors by electroless plating of Pd on a porous support modified by a zeolite barrier layer containing Pd seeds; these membranes provide stable phenol production by direct hydroxylation of benzene. PMID- 19787135 TI - Metal oxide-sensitized TiO(2) and TiO(2-x)N(x) with efficient charge transport conduits. AB - NiO-sensitized anatase is designed to share lattice oxygen at the particle interface and is prepared by the topological transformation of atomic-ordered layered metal hydroxides; the interfacial Ti-O-Ni linkages act as efficient electron transfer conduits to achieve photosensitization. PMID- 19787136 TI - A fluorescent chemodosimeter specific for cysteine: effective discrimination of cysteine from homocysteine. AB - A fluorescent chemodosimeter for cysteine detection and bio-imaging has been described which displays an excellent selectivity for cysteine over homocysteine, glutathione and other amino acids. PMID- 19787137 TI - Enantio- and stereoselective route to the phoslactomycin family of antibiotics: formal synthesis of (+)-fostriecin and (+)-phoslactomycin B. AB - A general methodology applicable for the synthesis of the phoslactomycin family of antibiotics, potent and selective protein phosphatase inhibitors, has been developed starting from a beta-isocupreidine-catalyzed asymmetric Baylis-Hillman reaction of 3-(4-methoxybenzyloxy)propanal with hexafluoroisopropyl acrylate, and thereby formal syntheses of (+)-fostriecin and (+)-phoslactomycin B have been accomplished. PMID- 19787138 TI - New enantiopure NHCs derived from camphor. AB - A new class of enantiopure carbene precursors based on cheap camphor has been developed, and a restricted rotation of one N-substituent due to the C-10 methyl group of the camphor skeleton has been found; in situ prepared corresponding carbenes revealed the same behaviour. PMID- 19787139 TI - Spontaneous self-assembly of Cu2O@PPy nanowires and anisotropic crystals. AB - The hydrothermal reduction of commercial CuO by Py yields Cu(2)O@PPy nanowires, branched nanostructures and bigger anisotropic crystals, which form spontaneously through oriented attachment in the absence of any capping agent or template. PMID- 19787140 TI - Self-assembly of ZnO/SiO2 hierarchical nanostructures array on metal substrate. AB - Tin (Sn with 5% of Si by weight) can be used as a liquid substrate to fabricate ZnO/SiO(2) hierarchical nanostructures and self-assemble these three-dimensional nanostructures into a vertical array at the same time. PMID- 19787141 TI - Catalytic stereoselective benzylic C-H functionalizations by oxidative C-H activation and organocatalysis. AB - An organocatalytic stereoselective alpha-alkylation reaction of aldehydes based on C-H activation is presented. PMID- 19787144 TI - Genotyping of methicillin-resistant Staphylococcus aureus isolates obtained in the Northeast region of Brazil. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major agent of hospital infections worldwide. In Brazil, a multiresistant MRSA lineage (ST239 SCCmecIIIA), the so-called Brazilian epidemic clone (BEC), has predominated in all regions. However, an increase in nosocomial infections caused by non multiresistant MRSA clones has recently been observed. In the present study, 45 clinical isolates of MRSA obtained from a university hospital located in Natal city, Brazil, were identified by standard laboratory methods and molecularly characterized using staphylococcal chromosome cassette mec (SCCmec) typing and pulsed-field gel electrophoresis. Antimicrobial susceptibility testing was carried out using CLSI methods. The MRSA isolates studied displayed a total of 8 different pulsed-field gel electrophoresis patterns (types A to H) with predominance (73%) of pattern A (BEC-related). However, MRSA harboring SCCmec type IV were also identified, 3 (7%) of which were genetically related to the pediatric clone--USA800 (ST5-SCCmecIV). In addition, we found a considerable genetic diversity within BEC isolates. MRSA displaying SCCmecIV are frequently susceptible to the majority of non-beta-lactam antibiotics. However, emergence of multiresistant variants of USA800 was detected. PMID- 19787145 TI - High expression of the circadian gene mPer2 diminishes the radiosensitivity of NIH 3T3 cells. AB - Period2 is a core circadian gene, which not only maintains the circadian rhythm of cells but also regulates some organic functions. We investigated the effects of mPeriod2 (mPer2) expression on radiosensitivity in normal mouse cells exposed to 60Co-gamma-rays. NIH 3T3 cells were treated with 12-O-tetradecanoylphorbol-13 acetate (TPA) to induce endogenous mPer2 expression or transfected with pcDNA3.1(+)-mPer2 and irradiated with 60Co-gamma-rays, and then analyzed by several methods such as flow cytometry, colony formation assay, RT-PCR, and immunohistochemistry. Flow cytometry and colony formation assay revealed that irradiated NIH 3T3 cells expressing high levels of mPer2 showed a lower death rate (TPA: 24 h 4.3% vs 12 h 6.8% and control 9.4%; transfection: pcDNA3.1-mPer2 3.7% vs pcDNA3.1 11.3% and control 8.2%), more proliferation and clonogenic survival (TPA: 121.7 +/- 6.51 vs 66.0 +/- 3.51 and 67.7 +/- 7.37; transfection: 121.7 +/- 6.50 vs 65.3 +/- 3.51 and 69.0 +/- 4.58) both when treated with TPA and transfected with mPer2. RT-PCR analysis showed an increased expression of bax, bcl-2, p53, c-myc, mre11, and nbs1, and an increased proportionality of bcl-2/bax in the irradiated cells at peak mPer2 expression compared with cells at trough mPer2 expression and control cells. However, no significant difference in rad50 expression was observed among the three groups of cells. Immunohistochemistry also showed increased protein levels of P53, BAX and proliferating cell nuclear antigen in irradiated cells with peak mPer2 levels. Thus, high expression of the circadian gene mPer2 may reduce the radiosensitivity of NIH 3T3 cells. For this effect, mPer2 may directly or indirectly regulate the expressions of cell proliferation- and apoptosis-related genes and DNA repair-related genes. PMID- 19787147 TI - Ventricular performance and Na+-K+ ATPase activity are reduced early and late after myocardial infarction in rats. AB - Myocardial infarction leads to compensatory ventricular remodeling. Disturbances in myocardial contractility depend on the active transport of Ca2+ and Na+, which are regulated by Na+-K+ ATPase. Inappropriate regulation of Na+-K+ ATPase activity leads to excessive loss of K+ and gain of Na+ by the cell. We determined the participation of Na+-K+ ATPase in ventricular performance early and late after myocardial infarction. Wistar rats (8-10 per group) underwent left coronary artery ligation (infarcted, Inf) or sham-operation (Sham). Ventricular performance was measured at 3 and 30 days after surgery using the Langendorff technique. Left ventricular systolic pressure was obtained under different ventricular diastolic pressures and increased extracellular Ca2+ concentrations (Ca2+e) and after low and high ouabain concentrations. The baseline coronary perfusion pressure increased 3 days after myocardial infarction and normalized by 30 days (Sham 3 = 88 +/- 6; Inf 3 = 130 +/- 9; Inf 30 = 92 +/- 7 mmHg; P < 0.05). The inotropic response to Ca2+e and ouabain was reduced at 3 and 30 days after myocardial infarction (Ca2+ = 1.25 mM; Sham 3 = 70 +/- 3; Inf 3 = 45 +/- 2; Inf 30 = 29 +/- 3 mmHg; P < 0.05), while the Frank-Starling mechanism was preserved. At 3 and 30 days after myocardial infarction, ventricular Na+-K+ ATPase activity and contractility were reduced. This Na+-K+ ATPase hypoactivity may modify the Na+, K+ and Ca2+ transport across the sarcolemma resulting in ventricular dysfunction. PMID- 19787146 TI - Treatment of hemorrhagic shock with hypertonic saline solution modulates the inflammatory response to live bacteria in lungs. AB - Shock and resuscitation render patients more susceptible to acute lung injury due to an exacerbated immune response to subsequent inflammatory stimuli. To study the role of innate immunity in this situation, we investigated acute lung injury in an experimental model of ischemia-reperfusion (I-R) followed by an early challenge with live bacteria. Conscious rats (N = 8 in each group) were submitted to controlled hemorrhage and resuscitated with isotonic saline (SS, 0.9% NaCl) or hypertonic saline (HS, 7.5% NaCl) solution, followed by intratracheal or intraperitoneal inoculation of Escherichia coli. After infection, toll-like receptor (TLR) 2 and 4 mRNA expression was monitored by RT-PCR in infected tissues. Plasma levels of tumor necrosis factor alpha and interleukins 6 and 10 were determined by ELISA. All animals showed similar hemodynamic variables, with mean arterial pressure decreasing to nearly 40 mmHg after bleeding. HS or SS used as resuscitation fluid yielded equal hemodynamic results. Intratracheal E. coli inoculation per se induced a marked neutrophil infiltration in septa and inside the alveoli, while intraperitoneal inoculation-associated neutrophils and edema were restricted to the interseptal space. Previous I-R enhanced lung neutrophil infiltration upon bacterial challenge when SS was used as reperfusion fluid, whereas neutrophil influx was unchanged in HS-treated animals. No difference in TLR expression or cytokine secretion was detected between groups receiving HS or SS. We conclude that HS is effective in reducing the early inflammatory response to infection after I-R, and that this phenomenon is achieved by modulation of factors other than expression of innate immunity components. PMID- 19787148 TI - In vitro larvicidal activity of geraniol and citronellal against Contracaecum sp (Nematoda: Anisakidae). AB - Human infection with fish parasites can result from the ingestion of incompletely cooked or raw fish, giving origin to parasitic diseases such as anisakiasis, caused by parasites of the Anisakidae family. The present study assessed the in vitro larvicidal effect of two monoterpene compounds, geraniol and citronellal, against Contracaecum sp (Nematoda: Anisakidae). Four hundred live larvae of Contracaecum sp obtained from 'traira' fish (Hoplias malabaricus, Bloch, 1974) were analyzed on 40 Petri dishes (10 larvae each) with the compounds to be tested. The final concentrations tested for each compound were 250, 125, 62.5, and 31.2 microg/mL and the evaluation was carried out at five different times (2, 4, 8, 24, and 48 h). The larvicidal action of geraniol and citronellal was statistically superior (P < 0.005) to the control (1% ethanol) at concentrations of 250 and 31.2 microg/mL (geraniol) and 250, 125, and 62.5 microg/mL (citronellal). However, no larvicidal activity was observed at concentrations of 125 and 62.5 microg/mL for geraniol and 31.2 microg/mL for citronellal. When the larvicidal action of geraniol was compared to that of citronellal, the former was found to be statistically superior (P < 0.05) to the latter at concentrations of 250 and 31.2 microg/mL. On the other hand, citronellal was statistically superior (P < 0.005) to geraniol at concentrations of 125 and 62.5 microg/mL. The larval mortality rate in terms of time (hours) was higher for geraniol with the passing of time at the 250 microg/mL concentration. At this concentration (in 48 h) the best larvicidal effect was observed with 90% lethality. The larvae were considered to be dead using no motility and loss of structural integrity as parameters. The data indicate that natural terpene compounds should be more explored for antihelminthic activity and can be useful for other studies about anisakiasis treatment. PMID- 19787149 TI - Can the fractal dimension be applied for the early diagnosis of non-proliferative diabetic retinopathy? AB - The fractal dimension has been employed as a useful parameter in the diagnosis of retinal disease. Avakian et al. (Curr Eye Res 2002; 24: 274-280), comparing the vascular pattern of normal patients with mild to moderate non-proliferative diabetic retinopathy (NPDR), found a significant difference between them only in the macular region. This significant difference in the box-counting fractal dimension of the macular region between normal and mild NPDR patients has been proposed as a method of precocious diagnosis of NPDR. The aim of the present study was to determine if fractal dimensions can really be used as a parameter for the early diagnosis of NPDR. Box-counting and information fractal dimensions were used to parameterize the vascular pattern of the human retina. The two methods were applied to the whole retina and to nine anatomical regions of the retina in 5 individuals with mild NPDR and in 28 diabetic but opthalmically normal individuals (controls), with age between 31 and 86 years. All images of retina were obtained from the Digital Retinal Images for Vessel Extraction (DRIVE) database. The results showed that the fractal dimension parameter was not sensitive enough to be of use for an early diagnosis of NPDR. PMID- 19787151 TI - Celecoxib reduces symptoms in men with difficult chronic pelvic pain syndrome (Category IIIA). AB - We investigated the effectiveness of celecoxib in reducing symptoms in patients with difficult chronic pelvic pain syndrome (CPPS), NIH category IIIA. Sixty-four patients with category IIIA CPPS were randomized into two groups of 32 subjects each. One group was treated with celecoxib (200 mg daily) and the other with placebo. All patients underwent treatment for 6 weeks and were evaluated clinically before (baseline) and after 1, 2, 4, 6, and 8 weeks of treatment. The evaluation included the NIH Chronic Prostatitis Symptom Index (NIH-CPSI) and a subjective global assessment (SGA). Repeated measures analysis of variance was used to evaluate treatment and time effects and their interaction. A decrease (means +/- SD) in total NIH-CPSI score from 23.91 +/- 5.27 to 15.88 +/- 2.51 in the celecoxib group and from 24.25 +/- 5.09 to 19.50 +/- 2.50 in the placebo group was observed during treatment (0 to 6 weeks). A statistically significant decrease was observed in pain subscore (P < 0.006), quality of life subscore (P < 0.032) and total NIH-CPSI score (P < 0.015) after 2, 4 and 6 weeks, but not in urinary subscore. In addition, 38% of the celecoxib and 13% of the placebo subjects had at least a moderate improvement in SGA. The trend was similar for the NIH-CPSI scores. However, the response to treatment in terms of total NIH CPSI score or subscore was not significantly different from placebo after interruption of treatment for 2 weeks. Our results show that celecoxib provides significant symptomatic improvement limited to the duration of the therapy in patients with difficult category IIIA CPPS compared to placebo. PMID- 19787150 TI - Does hepatocellular carcinoma in non-alcoholic steatohepatitis exist in cirrhotic and non-cirrhotic patients? AB - Non-alcoholic steatohepatitis (NASH) has been associated with hepatocellular carcinoma (HCC) often arising in histologically advanced disease when steatohepatitis is not active (cryptogenic cirrhosis). Our objective was to characterize patients with HCC and active, histologically defined steatohepatitis. Among 394 patients with HCC detected by ultrasound imaging over 8 years and staged by the Barcelona Clinic Liver Cancer (BCLC) criteria, we identified 7 cases (1.7%) with HCC occurring in the setting of active biopsy proven NASH. All were negative for other liver diseases such as hepatitis C, hepatitis B, autoimmune hepatitis, Wilson disease, and hemochromatosis. The patients (4 males and 3 females, age 63 +/- 13 years) were either overweight (4) or obese (3); 57% were diabetic and 28.5% had dyslipidemia. Cirrhosis was present in 6 of 7 patients, but 1 patient had well-differentiated HCC in the setting of NASH without cirrhosis (fibrosis stage 1) based on repeated liver biopsies, the absence of portal hypertension by clinical and radiographic evaluations and by direct surgical inspection. Among the cirrhotic patients, 71.4% were clinically staged as Child A and 14.2% as Child B. Tumor size ranged from 1.0 to 5.2 cm and 5 of 7 patients were classified as early stage; 46% of all nodules were hyper echoic and 57% were <3 cm. HCC was well differentiated in 1/6 and moderately differentiated in 5/6. Alpha-fetoprotein was <100 ng/mL in all patients. HCC in patients with active steatohepatitis is often multifocal, may precede clinically advanced disease and occurs without diagnostic levels of alpha-fetoprotein. Importantly, HCC may occur in NASH in the absence of cirrhosis. More aggressive screening of NASH patients may be warranted. PMID- 19787152 TI - Neonatal screening for cystic fibrosis in Sao Paulo State, Brazil: a pilot study. AB - Cystic fibrosis is one of the most common autosomal recessive hereditary diseases in the Caucasian population, with an incidence of 1:2000 to 1:3500 liveborns. More than 1000 mutations have been described with the most common being F508del. It has a prevalence of 23-55% within the Brazilian population. The lack of population-based studies evaluating the incidence of cystic fibrosis in Sao Paulo State, Brazil, and an analysis concerning the costs of implantation of a screening program motivated the present study. A total of 60,000 dried blood samples from Guthrie cards obtained from April 2005 to January 2006 for neonatal screening at 4 reference centers in Sao Paulo State were analyzed. The immunoreactive trypsinogen (IRT)/IRT protocol was used with the cut-off value being 70 ng/mL. A total of 532 children (0.9%) showed IRT >70 ng/mL and a 2nd sample was collected from 418 (80.3%) of these patients. Four affected children were detected at two centers, corresponding to an incidence of 1:8403. The average age at diagnosis was 69 days, and 3 of the children already showed severe symptoms of the disease. The rate of false-positive results was 95.2% and the positive predictive value for the test was 8%. The cost of detecting an affected subject was approximately US$8,000.00 when this cystic fibrosis program was added to an existing neonatal screening program. The present study clearly shows the difficulties involved in cystic fibrosis screening using the IRT/IRT protocol, particularly in a population with no long-term tradition of neonatal screening. PMID- 19787153 TI - Prevalence of vascular-endothelial growth factor, matrix metalloproteinases and tissue inhibitors of metalloproteinases in primary breast cancer. AB - Our objective was to determine the presence of vascular endothelial growth factor (VEGF), matrix metalloproteinase-2 (MMP-2) and MMP-9 and specific tissue inhibitors of matrix metalloproteinase (TIMP-1 and TIMP-2) in tumor samples obtained from patients with primary breast cancer. We attempted to correlate these findings with the status of the sentinel lymph node (SLN) and clinical pathological characteristics such as age, tumor size, histological type, histological grade, and vascular invasion. Tumor samples from 88 patients with primary breast cancer were analyzed. The immunoreactivity of VEGF, MMP-2, MMP-9, TIMP-1, and TIMP-2 in tumors was correlated with clinical and pathological features, as well as SLN status. Nonparametric, Mann-Whittney, Kruskal-Wallis, and Spearmann tests were used. Categorical variables were analyzed by the Pearson test. No statistically significant correlation was found between the amount of VEGF, MMP-2, MMP-9, TIMP-1, and TIMP-2 and the presence of tumor cells in the SLN. However, larger tumor diameter (P < 0.01) and the presence of vascular invasion (P < 0.01) were correlated positively with a positive SLN. A significant correlation of higher VEGF levels (P = 0.04) and lower TIMP-1 levels (P = 0.04) with ductal histology was also observed. Furthermore, lower TIMP-2 levels showed a statistically significant correlation with younger age (<50 years) and larger tumor diameter (2.0-5.0 cm). A positive SLN correlated significantly with a larger tumor diameter and the presence of vascular invasion. Higher VEGF and lower TIMP-1 levels were observed in patients with ductal tumors, while higher TIMP-1 levels were observed in lobular tumors. PMID- 19787154 TI - Reliability of the Brazilian version of HCR-20 Assessing Risk for Violence. AB - OBJECTIVE: Assessing risk for violence is a complex task often based on not objective or structured clinical evaluations. HCR-20 Assessing Risk for Violence has been used in several countries to increase the accuracy of this exam. The purpose of this study was to inform on central aspects of this instrument, as well as the results of the reliability assessment of the HCR-20 Assessing Risk for Violence in a Brazilian inpatient criminal population. METHOD: Two examiners independently assessed a random sample of 30 patients that were under criminal commitment at the Mauricio Cardoso Forensic Psychiatric Institute RESULTS: Mean consensus values means were as follows: Historical = 13.1; Clinical = 4.8 and Risk management = 5.8. The value of the Intraclass Correlation Coefficient for the score of subscale Historical was 0.97, for subscale Clinical it was 0.94, and for subscale Risk management, 0.96. As to the individual items of the HCR-20 Assessing Risk for Violence, the result of the Intraclass Correlation Coefficient was good to excellent (mean = 0.97; interval, from 0.60 to 0.99). CONCLUSION: The interrater reliability of the Brazilian version of the HCR-20 Assessing Risk for Violence scale was similar to the results of studies in other countries. PMID- 19787155 TI - Choking phobia: full remission following behavior therapy. AB - OBJECTIVE: A phobic behavior pattern is learned by classical and operant conditioning mechanisms. The present article reviews the main determinants of choking phobia etiology and describes the behavior therapy of an adult patient. METHOD: Psychoeducation, functional analysis, and graded exposure to aversive stimuli were used to treat the patient, after extensive psychiatric and psychological assessment. Ingesta and anxiety levels were measured along treatment and at follow-up. RESULTS: A multiple assessment baseline design was used to demonstrate the complete remission of symptoms after seven sessions, each of them exposing the patient to a different group of foods. CONCLUSION: Psychoeducation and exposure were critical components of a successful choking phobia treatment. PMID- 19787156 TI - Suicidal ideation and suicide attempts in bipolar disorder type I: an update for the clinician. AB - OBJECTIVE: This article reviews the evidence for the major risk factors associated with suicidal behavior in bipolar disorder. METHOD: Review of the literature studies on bipolar disorder, suicidal behavior and suicidal ideation. RESULTS: Bipolar disorder is strongly associated with suicide ideation and suicide attempts. In clinical samples between 14-59% of the patients have suicide ideation and 25-56% present at least one suicide attempt during lifetime. Approximately 15% to 19% of patients with bipolar disorder die from suicide. The causes of suicidal behavior are multiple and complex. Some strong predictors of suicidal behavior have emerged in the literature such as current mood state, severity of depression, anxiety, aggressiveness, hostility, hopelessness, comorbidity with others Axis I and Axis II disorders, lifetime history of mixed states, and history of physical or sexual abuse. CONCLUSION: Bipolar disorder is the psychiatric condition associated with highest lifetime risk for suicide attempts and suicide completion. Thus it is important to clinicians to understand the major risk factors for suicidal behavior in order to choose better strategies to deal with this complex behavior. PMID- 19787157 TI - Brucellosis in a Singaporean with prolonged fever. AB - Brucellosis, a zoonotic disease of worldwide distribution, is common in many developing countries as well as in countries of the Mediterranean basin. We report brucellosis in a 52-year-old man, who had a recent travel history to Saudi Arabia, and who presented with prolonged fever and deranged liver enzymes. In view of the rarity of brucellosis and its potential life-threatening complications, patients returning from an endemic country need to be questioned for possible Brucella exposure, to ensure that diagnostic tests and treatment are carried out in a timely fashion. In addition to notifying the authorities, the clinician should also warn the laboratory early as cultures of brucellosis are highly transmissible and are one of the most common laboratory-acquired infections. PMID- 19787158 TI - Shoulder girdle lipomatosis. AB - Shoulder girdle lipomatosis is an extremely rare condition, with unique clinical and imaging features. We report shoulder girdle lipomatosis in a 46-year-old man who presented with a gradual soft tissue enlargement in his left shoulder. We discuss the magnetic resonance imaging features of this disease and the approach to accurate diagnosis. A review of the clinical and radiological features of shoulder girdle lipomatosis is also presented. PMID- 19787159 TI - Spontaneous intramural haematoma of the oesophagus: complete resolution on follow up magnetic resonance imaging. AB - Spontaneous oesophageal dissection with intramural haematoma formation is an uncommon form of oesophageal injury with a characteristic imaging appearance. We report the clinical and radiological features of a 66-year-old woman presenting with acute onset chest pain, where computed tomography revealed a large haematoma within the wall of the thoracic oesophagus. The patient responded well to conservative management. Magnetic resonance imaging, performed seven days after the initial presentation, confirmed the resolution of the lesion. PMID- 19787160 TI - Use of a large Rusch hydrostatic catheter balloon to control postpartum haemorrhage resulting from a low placental implantation. AB - We describe the successful use of a balloon catheter in primary postpartum haemorrhage secondary to placenta praevia. A 29-year-old woman was admitted for cervical priming at 37 weeks. Antenatal screening ultrasonography showed a normally-sited placenta. During the surgical induction of labour, bleeding per vaginum was noted, and a mass was felt at the cervical os. Emergency caesarean section was performed, and a placenta praevia was confirmed. Upon reversal of general anaesthesia, vaginal bleeding was noted despite a well-contracted uterus. The estimated blood loss was 1,200 ml. A hydrostatic catheter was inserted vaginally into the uterine cavity. After 17 hours, it was removed with no vaginal bleeding. The insertion for the balloon catheter was easy and simple, requiring minimal analgesia, and it was without significant complication. As obstetricians become more confident in this technique, surgical intervention may be avoided. This may subsequently lead to a reduction in maternal morbidity and mortality. PMID- 19787161 TI - Auditory neuropathy: three cases among a group with sensorineural hearing loss. AB - The prevalence of auditory neuropathy is not known, although the majority of cases are felt to lie within the population of neonatal intensive care unit graduates. We report three cases of auditory neuropathy, out of 211 children with sensorineural hearing loss, seen at our audiology clinic from April 1, 1999 to December 31, 2003. Two patients did not have a risk factor for hearing impairment. Screening policies based solely on transient evoked otoacoustic emissions testing will not detect auditory neuropathy effectively, and may falsely reassure parents and professionals unaware of this condition. PMID- 19787162 TI - Aneurysmal bone cyst of the maxilla. AB - An aneurysmal bone cyst is a rare bone lesion. Its origin and precise nature remain unknown. It is seen as a locally-destructive, rapidly expandable, benign multicystic mass. We report a 17-year-old boy with an aneurysmal bone cyst of the maxilla, with extensive local involvement and bony destruction that was treated surgically. There was no recurrence noted after four years of follow-up. PMID- 19787163 TI - Juxtarenal/pararenal Wilms' tumour in a six-year-old Malay girl. AB - We report a six-year-old Malay girl who presented with a right retroperitoneal tumour that measured 7.5 cm in diameter. A wide excision of the lesion was performed. The tumour was separated from a normal-appearing right kidney by a capsule. Microscopically, this well-encapsulated tumour was composed of classical triphasic components: epithelial, mesenchymal and blastemal areas. The immunohistochemical study showed WT1 expression in the blastemal area. Thus, a diagnosis of Wilms' tumour with favourable histology was made. The patient was well for 12 months. Extrarenal Wilms' tumour is uncommon, with the majority of cases occurring in the retroperitoneal and inguinal areas. Wilms' tumour that is not arising from the intrarenal area but shares a common capsule with the ipsilateral kidney, is even rarer. Indeed, our case would be more appropriately classified as juxtarenal/pararenal Wilms' tumour. Despite its rarity, an extrarenal or even juxtarenal/pararenal Wilms' tumour should be included in the differential diagnosis of retroperitoneal tumour. PMID- 19787164 TI - Localised retroperitoneal amyloidosis mimicking retroperitoneal fibrosis: a rare cause of obstructive uropathy. AB - Primary localised amyloidosis involving the retroperitoneum is a rare disease. We report a 71-year-old diabetic man who presented with generalised fatigue, malaise and elevated serum creatinine. Investigations confirmed obstructive uropathy secondary to a retroperitoneal mass behind the urinary bladder, causing extrinsic compression of both the ureters, resulting in bilateral hydroureteronephrosis. Following initial bilateral percutaneous nephrostomies to stabilise renal function, a computed tomography-guided biopsy of the pelvic lesion which was done, was suggestive of amyloidosis. We present this case due to the rarity of localised retroperitoneal amyloidosis as a cause of obstructive uropathy. PMID- 19787165 TI - Vesicocutaneous fistula presenting as a thigh abscess. AB - Secondary thigh abscesses are rare, and their cause is often obscure. We report a 90-year-old man who complained of a thigh abscess that was found to be secondary to a vesicocutaneous fistula. He had previously sustained a pelvic fracture and vesical injury from a road traffic accident two years prior to this diagnosis. PMID- 19787166 TI - Management of postoperative chyloretroperitoneum in adults. AB - Retroperitoneal chylous effusion after urological surgery is a rare and serious complication. Failure in treatment may result in cachexia, threatening the life of the patient. We present the treatment of two cases of postoperative chyloretroperitoneum with the use of somatostatin, octreotide and total parenteral nutrition. In Case 1, an 87-year-old man, a retroperitoneal lymphatic fistula occurred four days after the resection of the left kidney due to carcinoma, whereas in Case 2, a 56-year-old man, a continuous lymph fistula from the renal fossa occurred one month after resection of the right adrenal pheochromocytoma. Case 1 was treated with intravenous administration of somatostatin, and in Case 2, treatment consisted of subcutaneous administration of octreotide, in combination with total parenteral nutrition and other symptomatic therapies. In both cases, lymph exudation was terminated in about two weeks, and the patients recovered. Somatostatin therapy and total parenteral nutrition can effectively treat chyloretroperitoneum. PMID- 19787167 TI - Publishing and academic promotion. AB - Clearly, academic endeavour has to be the single most important criterion for appointment to an academic position and for subsequent promotion. It is rare for excellence either in teaching or clinical practice to offset a poor publication record. However, the pressure to publish and gain related grant income can lead to problems in the normal academic pursuits of a department or institution. These and other related issues will be explored in this editorial. PMID- 19787168 TI - Wilhelm Conrad Rontgen (1845-1923): a light in the dark. PMID- 19787169 TI - How a submitted manuscript is processed. AB - Processing of a submitted manuscript is a complex and time-consuming process. Authors should be aware of items in the editorial office checklist. The journal editors and peer reviewers are an essential part of the manuscript processing system. Copy editors serve as a link between authors and the printer/publisher, and aim to adapt the accepted manuscript to the journal house style and to improve readability of the article. PMID- 19787170 TI - Liposarcoma of the extremities: a review of the cases seen and managed in a major tertiary hospital in Singapore. AB - INTRODUCTION: Liposarcoma is one of the more common types of soft tissue sarcomas, presenting with a wide spectrum of clinical behaviour. However, there is little information on the outcome, management and survivability of patients with extremity liposarcoma in Singapore. METHODS: A retrospective review of all the patients with extremity liposarcoma, diagnosed between 1997 and 2007, was performed. Univariate and multivariate statistics were used on the data to evaluate the clinical presentations, treatment, outcome and survivability of patients seen. RESULTS: Over a ten-year period, 30 patients were seen for primary liposarcoma of the extremities. Three patients dropped out and 27 were managed and followed-up. Management included surgery and/or radiotherapy. Histological subtypes included 14 (51.9 percent) well-differentiated, five (18.5 percent) myxoid, four (14.8 percent) de-differentiated, and two (7.4 percent) each of round cell and pleomorphic variants. Four patients (14.8 percent) developed local or metastatic recurrent disease. The mean follow-up was 53 months, and the survival rate with primary disease at 53 months was 92.6 percent. The recurrence free survival for primary disease at 53 months was 85.2 percent. CONCLUSION: Liposarcoma of the extremities is relatively rare compared to other major soft tissue tumours. It is a highly pleomorphic disease, whose outcome is dependent on the histological subtype. Limb-sparing management includes wide resection of the tumour with/without radiation postoperatively. PMID- 19787171 TI - Carcinoembryonic antigen screening: how far should we go? AB - INTRODUCTION: The role of carcinoembryonic antigen (CEA) in screening has been previously investigated and found to be inefficient because of its low sensitivity and specificity. Nevertheless, it is still used as a tumour marker in health screening packages, often for asymptomatic patients. We aimed to review all asymptomatic patients who were referred to our department for raised CEA, to determine if this was indeed associated with significant pathology, and to what extent the asymptomatic patients should be investigated. METHODS: All patients with no gastrointestinal symptoms, and whose only indication for endoscopy was a raised CEA level, were entered into the study group. All the investigations were retrospectively reviewed and any pathology was noted. RESULTS: There were 217 asymptomatic patients who presented for endoscopy and further evaluation due to raised CEA, from December 1998 to August 2004. After the initial investigations, a total of 20 primary and eight metastatic cancers were found. The malignancies detected included 11 colorectal cancers, two stomach cancers, five lung cancers, one periampullary carcinoma and one ovarian teratoma. There were two cases of metastasis in the lungs and six with liver metastasis. In the subsequent median follow-up period of 13 (range 6-97) months, an additional 16 (7.4 percent) primary cancers were detected. CONCLUSION: Asymptomatic average-risk patients who present with raised CEA should be investigated endoscopically and radiologically for commonly-associated cancers, and thereafter followed up for at least two years, as up to 7.4 percent present with a subsequent malignancy. PMID- 19787172 TI - Obturator hernia: diagnosis and treatment in the modern era. AB - INTRODUCTION: Obturator hernia is a rare variety of abdominal hernia that nonetheless is a significant cause of morbidity and mortality, especially in the elderly age group. This article aimed to review the diagnosis and management of obturator hernia by describing the anatomy, clinical presentation, predisposing factors, diagnostic modalities and management in the modern era. METHODS: We managed six cases of obturator hernia between 2003 and 2006. Five out of six cases were diagnosed by a preoperative computed tomography (CT) and the sixth case was diagnosed by ultrasonography. All except one were managed by an exploratory laparotomy and repair of the hernia, and one was treated with laparoscopic repair. RESULTS: Correct preoperative diagnosis was made in five out of five (100 percent) patients by clinical signs and CT of the abdomen and pelvis, and the sixth patient was operated on the basis of an ultrasonographical diagnosis and strong clinical suspicion. CONCLUSION: We conclude that the rapid evaluation by CT of the abdomen and pelvis and surgical intervention are possible, thereby reducing the morbidity and mortality of patients with obturator hernia. An algorithm for the management of obturator hernia is proposed. PMID- 19787174 TI - Evaluation of thyroid status of infants in the intensive care setting. AB - INTRODUCTION: Previous studies report the spectrum of thyroid function abnormalities in critically-ill neonates. In this study, we evaluated the thyroid status in critically-ill neonates, and determined whether thyroid function abnormalities are more common in sick neonatal infants. METHODS: In a prospective cohort study, 67 critically-ill infants from the Neonatal Intensive Care Unit (NICU), affiliated to Shiraz University of Medical Sciences, were entered into our study. Of all the included neonates, 33 were premature and seven were under 28 weeks of gestation. In addition to the routine thyroid-stimulating hormone (TSH)-screening (capillary specimen), serum free triiodothyronine (FT3), free thyroxine (FT4) and TSH were checked using radioimmunoassay kit twice (during critical illness and before discharge from the NICU). RESULTS: It was observed that abnormal TSH levels (screening test) were about 40-fold higher in critically ill neonates compared with healthy neonates, while more than four-fifths of them were detected in the second sampling done after recovery. The mean FT3 was significantly lower during the critical illness and it increased after recovery (2.537 and 3.232 pg/ml, respectively). Mean FT4 and mean TSH during the illness and after recovery did not have any significant difference. CONCLUSION: Thyroid function abnormalities are more common in infants under intensive care and most of them manifested as "euthyroid sick syndrome"; abnormal screening tests may be due to the transient elevation of TSH during recovery from illness. Therefore, only in cases in which TSH rises more than 15-20 mIU/L or TSH remains high for a month or longer, that treatment is needed, while other cases must be followed up by serial determination of TSH and FT4. The levels of FT3 and FT4 during the illness were not affected by the duration and severity of the illness. PMID- 19787173 TI - Role of tracheostomy in the management of foreign body airway obstruction in children. AB - INTRODUCTION: Foreign body aspiration in the airway of children is a life threatening clinical situation. Endoscopic retrieval alone is successful in the majority of patients. Occasionally, open surgical intervention in the form of tracheostomy, thoracotomy and bronchotomy and/or pulmonary resection is needed. We analysed the specific indications for tracheostomy during the removal of airway foreign bodies in our study. METHODS: The records of four patients who needed tracheostomy, out of 342 cases of foreign body airway obstruction managed by the senior author, were analysed. These patients underwent an additional tracheostomy for open removal of the foreign body and/or to secure the airway to facilitate the foreign body removal. RESULTS: Rigid bronchoscopy was successful in retrieving the foreign bodies in 338 (98.8 percent) cases, while four (1.2 percent) cases required additional tracheostomy, either to protect the airway during the procedure or to assist in removing the foreign body. The indications for tracheostomy were subglottic foreign bodies of long duration, sharp subglottic foreign bodies and foreign bodies that were larger than the glottic chink. There was no mortality or long-term complication because of the tracheostomies. CONCLUSION: Tracheostomy is occasionally indicated in foreign body extraction, when they are subglottic in location and impacted, or are large foreign bodies that get obstructed at the glottic chink during removal. PMID- 19787175 TI - The efficacy of an enuresis alarm in monosymptomatic nocturnal enuresis. AB - INTRODUCTION: Monosymptomatic nocturnal enuresis (MNE) is a frequent problem in children older than five years of age. Of the various treatment options, the enuresis alarm has been widely advocated for treating nocturnal enuresis. This study was designed to evaluate the success rates of the enuretic alarm device in patients with MNE. METHODS: 40 patients who had significant MNE (three or more wet nights per week) were included. They used an enuretic alarm for 12 weeks initially. If a relapse was observed, reusage of the device was provided. A success criterion was defined as "14 consecutive dry nights" and a relapse criterion was "more than one wet night a week". RESULTS: The patients' mean age was 8.1 (range 6-16) years and the mean follow-up time was 10.2 (range 6-19) months. 27 patients became dry at night at the end of three months. In the follow up period, a relapse was observed in 66.7 percent of the initial responders. For recovery, 14 patients started to reuse the device, and seven of them responded positively. At the end of the treatment, a total of 13 of the patients had benefited from the enuretic alarm. CONCLUSION: During the follow-up, the enuretic alarm device provided acceptable initial and long-term complete dryness in patients with primary nocturnal enuresis. Without the need for expensive pharmacological intervention, the alarm treatment is an effective choice for children with nocturnal enuresis. PMID- 19787177 TI - Clinical predictors of abnormal computed tomography findings in patients with altered mental status. AB - INTRODUCTION: While non-contrast computed tomography (CT) of the brain can be used to rapidly identify patients with altered mental status (AMS) in the emergency department (ED), with an acute intracranial bleed or infarct, a wide variation in its use exists. The aim of this pilot study was to identify the clinical predictors of an abnormal CT result in ED patients with AMS. METHODS: We conducted a retrospective study of patients aged 15 years and older presenting with undifferentiated AMS in a busy urban ED over one year. Data collected included demographical, clinical, laboratory and radiological features. The primary outcome of interest was the presence of an abnormal CT result defined as an acute infarct or intracranial bleed. Secondary outcomes were clinical predictors of an abnormal CT result. The data was analysed using descriptive statistics. Logistic regression was used to identify clinical predictors of an abnormal CT result. Odds ratios (ORs) were reported with 95 percent confidence intervals (CIs). RESULTS: 578 patients were recruited, of which 284 (49.1 percent) were males. 327 (56.6 percent) patients underwent CT of the brain. 128 scans (39.1 percent) were abnormal. Logistic regression revealed seven clinical features that were associated with an abnormal CT result. They were mean age greater than or equal to 73 years (OR 1.03; 95 percent CI 1.015-1.045), drowsiness or unresponsiveness (OR 1.73; 95 percent CI 0.17-17.72), previous cerebrovascular accident (OR 2.03; 95 percent CI 0.82-5.02), previous epilepsy (OR 1.63; 95 percent CI 0.63-4.19), tachycardia [greater than 120/min] (OR 1.16; 95 percent CI 0.38-3.54), bradycardia [less than 60/min] (OR 1.35; 95 percent CI 0.19-9.59) and exposure to drugs (OR 1.90; 95 percent CI 0.58-6.26). CONCLUSION: We identified seven clinical predictors of an abnormal CT result in AMS patients. Future research in prospective studies is needed to validate these findings. PMID- 19787176 TI - Dermatological conditions presenting at an emergency department in Singapore. AB - INTRODUCTION: In Singapore, a significant proportion of patients receive specialist dermatological services via referrals from points of primary care, such as polyclinics and emergency departments (ED). The study hospital, Tan Tock Seng Hospital, is an acute care general hospital with a large catchment area, and has the busiest ED in Singapore. The aim of this paper was to describe the types of dermatological conditions presented at the ED in the year 2007. This information is useful for the future education of junior doctors working in the department, as well as for the allocation of future resources in the treatment of the more common conditions. METHODS: The ED patient database was searched for all dermatological conditions by ICD-9 code and by keywords in the diagnosis description. The two lists were merged and duplications were eliminated. The consultation notes of the patients were reviewed in cases where the diagnosis was ambiguous. Patient demographics were then filtered and analysed. RESULTS: A total of 4,061 patients were seen in the ED with a primary dermatological complaint, out of a total of 157,527 attendances in 2007. The commonest conditions seen were chickenpox and herpes zoster (20.8 percent). Dermatitis/eczema (11.6 percent) and urticaria (11.4 percent), nail conditions including trauma and infections (10.2 percent) and drug rashes (9.7 percent) were also common. Venereal diseases (1 percent) were uncommonly seen in the ED. Interestingly, men (65.3 percent) were seen in the ED for dermatological conditions twice as often as women (34.7 percent). CONCLUSION: The recognition and management of the common conditions should be core modules in the training of doctors and nurses. PMID- 19787178 TI - Gallstones and biliary sludge in Greek patients with complete high spinal cord injury: an ultrasonographical evaluation. AB - INTRODUCTION: We used ultrasonography to detect the presence of biliary sludge or gallstones in Greek patients with complete high spinal cord injury (SCI) above the seventh thoracic segment (T7), within the first six months from injury onset, in order to evaluate the effects of neurological instability and dysfunction of the sympathetic nervous system (SNS) on the gallbladder function in the early post-SCI phase. METHODS: We evaluated 78 asymptomatic patients (57 males, 21 females; mean age 34.8 (range 19-56) years) with complete high SCI located above the T7 segment, and 78 healthy subjects (59 males, 19 females; mean age 35.2 (range 21-59) years) matched for age, gender and race, for a total period of 39 months. All the participants underwent ultrasonographical examination of the gallbladder and common bile duct within the first six months from the injury, in order to investigate the development of biliary sludge and gallstones. RESULTS: The incidence of biliary sludge was significantly higher in patients with SCI compared with the control group. The incidence of biliary sludge and gallstones was also significantly higher in patients with SCI patients in comparison with the healthy subjects. In male SCI patients, the incidence of biliary sludge was significantly increased in comparison with healthy subjects. No significant difference was revealed between the two groups in detection of gallstones. CONCLUSION: Our study indicates that the detection of gallbladder sludge and gallstones are significantly higher in Greek patients with complete high SCI above the T7 segment, as compared with healthy control subjects within the first six months of the injury onset. The complete disruption of the SNS and the neurological instability in the early post-SCI phase is probably responsible for the biliary sludge and gallstone formation. Our results suggest that ultrasonography should be performed in these patients at the first 3-6 months from the injury for the early diagnosis of the lithogenic bile. PMID- 19787179 TI - An appraisal of timely magnetic resonance imaging in diagnosing spinal cord compression. AB - INTRODUCTION: Spinal cord compression is a very debilitating condition and could be secondary to many causes. Urgent magnetic resonance (MR) imaging of the spine is crucial in making the diagnosis and guiding further management. Our objectives were to assess the nature of MR imaging requests, the diagnostic yield, and the subsequent management according to relevant MR imaging findings. METHODS: We focused on all the urgent MR imagings of the spine conducted from July 1, 2007 to December 31, 2007. Clinical data, including the demographical information, presenting symptoms, radiological diagnosis, waiting time for MR imaging and treatment, was reviewed. RESULTS: A total of 33 cases of urgent MR imaging of the spine were performed. Patients were aged 29-85 years, with 18 males and 15 females. Most of them (84.8 percent) presented with neurological symptoms. 84 percent of the MR imaging was performed within 24 hours. 76 percent of the examinations yielded significant cord compression, of which 56 percent were due to vertebral metastasis, while others were due to epidural haematoma (12 percent), infective spondylodiscitis (8 percent), vertebral fracture (8 percent) and disc herniation (16 percent). Of the vertebral metastasis patients, 43 percent had one region imaged. 64 percent of the cord compression patients received surgical treatment or radiotherapy, with a mean waiting time of 1.7 days. CONCLUSION: The urgent MR imaging spine service was able to react promptly with a high diagnostic yield. One-third of the patients with vertebral metastasis had multiple levels involved, and imaging of the whole spine would be useful. PMID- 19787180 TI - The interaction between physical activity and fasting on the serum lipid profile during Ramadan. AB - INTRODUCTION: The serum lipid profiles in Muslims change during the fasting month of Ramadan, but it is not clear whether this change is due to changes in their physical activities. In this study, we compared the patterns of the lipid profile changes in those who engaged in regular physical activity with those who did not. METHODS: In a randomised trial, we assigned 93 students who took a physical education course into two groups--those who had regular physical activity after Ramadan and those who had physical activity during Ramadan. Venous blood (5 ml) was taken just before, at the end, and 40 days after Ramadan, and the fasting glucose sugar and lipid profile were measured. RESULTS: Fasting with physical activity decreased body weight by 1.2 kg (p-value is 0.03). Fasting blood sugar also decreased by 7 mg/dL during Ramadan, but this drop was observed in both groups. Triglyceride decreased in both groups during Ramadan, but cholesterol levels dropped considerably during and after Ramadan for those who concurrently engaged in physical activity and fasted (-12.24 and -8.4 mg/dL, respectively). The patterns of changes in the high-density lipoprotein (HDL), low-density lipoprotein (LDL) and HDL/LDL values were more or less comparable in both groups (p is greater than 0.5). CONCLUSION: Usually, people are less physically active during Ramadan, but our findings show that physical activity alone cannot explain the variations in the lipid profile. Other factors, such as changes in the diet and sleeping hours, may have more important roles. PMID- 19787181 TI - Breast calcifications: which are malignant? AB - Most calcifications depicted on mammograms are benign. However, calcifications are important because they can be the first and earliest sign of malignancy. For detection and analysis of microcalcifications, high-quality images and magnification views are required. The American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) classifies calcifications on mammograms into three categories: typical benign, intermediate concern and higher probability of malignancy, according to types and distribution of calcifications. Benign calcifications are typically larger, coarser, round with smooth margins and have a scattered or diffuse distribution. Malignant calcifications are typically grouped or clustered, pleomorphic, fine and with linear branching. It is important for radiologists to detect, evaluate, classify and provide appropriate recommendations for calcifications perceived on mammograms to provide proper management. PMID- 19787184 TI - Four new cases of non-arteritic anterior ischaemic optic neuropathy in one clinic. A cause for concern? PMID- 19787185 TI - Forceful stretching of the hamstrings at what expense? Sciatic neuropathy in a child. PMID- 19787186 TI - Misleading display of haemodynamic and respiratory parameters: frozen monitor. PMID- 19787187 TI - Comments on: Starting a laparoscopic hepatectomy programme. PMID- 19787189 TI - Allopurinol: a necessary evil. PMID- 19787192 TI - Bone morphogenetic proteins in development and progression of breast cancer and therapeutic potential (review). AB - Bone morphogenetic proteins (BMPs) belong to the TGF-beta superfamily, which plays important roles in foetal and postnatal development and also maintains the homeostasis of various tissues and organs. Due to the critical role played by BMPs in bone formation and bone turnover, the implication of these molecules in bone metastasis has been intensively studied over the past decade. BMPs have been implicated in the development and progression of solid tumours, particularly the disease-specific bone metastasis. In breast cancer, a tumour type which most commonly metastasizes to bones, aberrations of both BMP expression and their signalling have been recently demonstrated. These aberrations have certain correlations with the development and progression of the disease. Recent in vitro studies have also demonstrated that BMPs can regulate a range of biological functions of breast cancer cells. Targeting BMPs or BMP signalling may provide novel therapeutic approaches for breast cancer. In the current review, we discuss the present knowledge on BMP abnormalities and their implication in the development and progression of breast cancer, particularly in the disease specific bone metastasis. PMID- 19787193 TI - STEAP4 regulates focal adhesion kinase activation and CpG motifs within STEAP4 promoter region are frequently methylated in DU145, human androgen-independent prostate cancer cells. AB - The possible roles of STEAP4 in cancer progression have not been reported. In this study, we report that STEAP4 expression is able to inhibit anchorage independent cell growth. We also demonstrate that STEAP4 associates with focal adhesion kinase (FAK) and regulate the activity of FAK through Y397 phosphorylation. Furthermore, we show that CpG sequences in STEAP4 promoter region were frequently methylated in DU145, androgen-independent prostate cancer cells. Demethylation treatment induced STEAP4 expression in DU145, suggesting the possibility that STEAP4 expression in cancer cells is in part epigenetically regulated. Collectively, these data demonstrate a novel function of STEAP4 and that STEAP4 may play an important role in tumor malignancy. PMID- 19787194 TI - Role of Kenae/CCDC125 in cell motility through the deregulation of RhoGTPase. AB - Isaac's syndrome is a movement disorder characterized by hyperexcitability of peripheral motor nerves. Patients with Isaac's syndrome often develop auto antibodies to voltage-gated potassium channels (VGKCs) which block their function. However, anti-VGKC antibodies are not detected in all patients with Isaac's syndrome, suggesting the existence of another etiology. In this study, we performed immunoscreening using the serum from a patient with Isaac's syndrome and identified the novel gene named Kenae/CCDC125. Expression analysis of Kenae/CCDC125 revealed that its transcript was highly expressed in tissues associated with the immune system, such as the thymus, spleen and bone marrow. In cells stably expressing Kenae/CCDC125, delay in cell motility and deregulation of RhoGTPase (RhoA, Rac1 and cdc42) activity to extracellular stimuli were demonstrated. These results suggest that the novel gene, Kenae/CCDC125, acts as a regulator of cell motility through RhoA, Rac1 and cdc42. PMID- 19787195 TI - Differences in gene expression between individuals with multiple primary and single primary malignancies. AB - Cytogenetic and molecular studies have identified imbalanced chromosomal regions leading to the characterization of several candidate genes. Differences in gene expression were examined in the blood by whole genome microarray analysis among individuals with double or single primary malignancies and healthy individuals. Twenty-four individuals with at least two primary malignancies of the breast and/or colon and/or ovary were compared with 32 individuals with single breast, colon or ovarian cancer. The single malignancy group had a median duration of disease of 9 years (range 5-23 years). Validation was obtained by examining each patient separately with quantitative real-time reverse-transcriptase polymerase chain reaction (RT-PCR) analysis for the determined genes. Overall a large number of genes were determined to be deregulated. From the classifiers built, a 9-probe signature was determined between second primary and single tumor patients. Four other genes were determined to be repressed (p<1x10(-4)) in individuals with two primary malignancies when compared with individuals with a single malignancy and also when comparing single malignancies and healthy subjects. The levels of gene deregulation were confirmed by validation with quantitative RT-PCR analysis. Functional analysis, suggested that these genes are associated with protein biosynthesis and folding, inhibition of apoptosis and intracellular signalling via GTP cascade. The outcome of the present study was 13 genes had a statistically significant difference in expression between individuals with double primary malignancies compared to individuals with single primary malignancies. Nine of those were confirmed by the classifier analysis. PMID- 19787196 TI - Activation of peroxisome proliferator-activated receptor-gamma induces apoptosis on acute promyelocytic leukemia cells via downregulation of XIAP. AB - In the present study we investigated the in vitro apoptosis inducing effects of peroxisome proliferator-activated receptor-gamma (PPAR-gamma) ligand ciglitazone (CGZ) on acute promyelocytic leukemia (APL) NB4 cells and its mechanisms of action. The results revealed that CGZ (10-50 micromol/l) inhibited the growth of leukemia NB4 cells and caused apoptosis in a time- and dose-dependent manner. Apoptosis was observed clearly by flow cytometry (FCM) and DNA fragmentation analysis. After treatment by CGZ for 48 h, the percentage of disruption of mitochondrial membrane potential (Deltapsim) was increased in a dose-dependent manner. Western blotting demonstrated the cleavage of caspase-3 zymogen protein and a time-dependent cleavage of poly (ADP-ribose) polymerase (PARP). The results also demonstrated that PPAR-gamma expression was increased concomitantly when apoptosis occurred, and that CGZ-induced apoptosis was inhibited by the PPAR gamma antagonist GW9662, suggesting a PPAR-gamma dependent signaling pathway in CZG-induced cell death. Moreover, CGZ treatment remarkably downregulated the expression of the X-linked inhibitor of apoptosis protein (XIAP), which was inhibited by GW9662. Of note, a small-molecule XIAP antagonist (1396-12) mimicked the effect of CGZ-induced apoptosis via activation of caspase-3, 7 and 9. The apoptosis-inducing effects by CGZ on fresh APL cells were also found to be remarkable by using FCM and Wright's staining observation. Taken together, our results suggest that downregulation of XIAP and activation of capase-3 play an important role in mediating the PPAR-gamma-dependent cell death induced by CGZ in APL cells. These data provide a novel insight into potential therapeutic strategies for treatment of leukemia. PMID- 19787198 TI - Inhibition of angiogenesis in lipodermatosclerosis: implication for venous ulcer formation. AB - Lipodermatosclerosis refers to skin induration of the lower extremities characterized by tortuous, hyperpermeable vessels preceding venous leg ulcerations. Protein ligands and receptor tyrosine kinases that specifically regulate endothelial cell function are mainly involved in physiological as well as in disease-related angiogenesis. These ligand/receptor systems include the vascular endothelial growth factor (VEGF) and the angiopoietin (Ang) families and their receptor the tyrosine kinase with immunoglobulin-like domains (Tie-2) as well as the VEGF receptor family (VEGF-R1 and VEGF-R2). In the present study, the contribution of these endothelium-specific ligand/receptor systems in tissue samples of lipodermatosclerosis was evaluated. Our results provide evidence, that the mRNA-transcripts of VEGF (p<0.01), Ang-1 (p<0.1), Ang-2 (p<0.1) and VEGF-R1 (p<0.01) were significantly upregulated in all samples of lipodermatosclerosis in comparison with healthy skin by using reverse transcriptase-polymerase chain reaction. On protein level VEGF (p<0.01), Ang-1 (p<0.1), Ang-2 (p<0.1) and VEGF R1 (p<0.01) were significantly elevated as well. Solely for Tie-2 and for VEGF-R2 no statistical difference could be detected on mRNA and protein level in patients with lipodermatosclerosis in comparison with healthy skin. By immunohistochemistry we confirmed upregulated protein expression for VEGF, Ang-1, Ang-2 and VEGF-R1 compared with healthy skin. Our findings strongly suggest that an imbalance between these ligand/receptor systems might contribute to the pathophysiology of advanced stages of chronic venous insufficiency. Inhibition of angiogenesis could significantly impact the tissue breakdown in lipodermatosclerosis and could hereby enable the formation of venous leg ulcerations. PMID- 19787197 TI - Novel synthetic inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase activity that inhibit tumor cell proliferation and are structurally unrelated to existing statins. AB - Pilot-scale libraries of eight-membered medium ring lactams (MRLs) and related tricyclic compounds (either seven-membered lactams, thiolactams or amines) were screened for their ability to inhibit the catalytic activity of human recombinant 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase in vitro. A dozen of the synthetic compounds mimic the inhibition of purified HMG-CoA reductase activity caused by pravastatin, fluvastatin and sodium salts of lovastatin, mevastatin and simvastatin in this cell-free assay, suggesting direct interaction with the rate-limiting enzyme of cholesterol biosynthesis. Moreover, several MRLs inhibit the metabolic activity of L1210 tumor cells in vitro to a greater degree than fluvastatin, lovastatin, mevastatin and simvastatin, whereas pravastatin is inactive. Although the correlation between the concentration-dependent inhibitions of HMG-CoA reductase activity over 10 min in the cell-free assay and L1210 tumor cell proliferation over 4 days in culture is unclear, some bioactive MRLs elicit interesting combinations of statin-like (IC50: 7.4-8.0 microM) and anti-tumor (IC50: 1.4-2.3 microM) activities. The HMG-CoA reductase-inhibiting activities of pravastatin and an MRL persist in the presence of increasing concentrations of NADPH. But increasing concentrations of HMG-CoA block the HMG CoA reductase-inhibiting activity of pravastatin without altering that of an MRL, suggesting that MRLs and existing statins may have different mechanisms of enzyme interaction and inhibition. When tested together, suboptimal concentrations of synthetic MRLs and existing statins have additive inhibitory effects on HMG-CoA reductase activity. Preliminary molecular docking studies with MRL-based inhibitors indicate that these ligands fit sterically well into the HMG-CoA reductase statin-binding receptor model and, in contrast to mevastatin, may occupy a narrow channel housing the pyridinium moiety on NADP+. PMID- 19787199 TI - Mitochondria-mediated tumstatin peptide-induced HepG2 cell apoptosis. AB - The effect of a 19-amino-acid C-terminal peptide of tumstatin (aa 185-203, peptide 19) on human hepatoma cell (HepG2) proliferation was studied, as well as the mechanism by which it induces tumor cell apoptosis. Recombinant peptide 19 was purified by chitin affinity chromatography and identified by Tricine-SDS PAGE. The DTT was removed with sephadex G-10. MTT colorimetry was used to evaluate the proliferation of tumor cells. Hematoxylin and eosin staining (H&E staining) and AO/EB double staining were used to view morphological changes during apoptosis. Mitochondrial potential was measured via flow cytometer. Western blot analysis was performed to detect the transfer of cytochrome C from mitochondria to the cytoplasm and to monitor the expression levels of caspase-8, caspase-9, Fas, p53, Bcl-2, Bax and Bid in human hepatoma cells. Recombinant peptide 19 effectively suppressed the proliferation of HepG2 cells and induced apoptosis. Each of the two effects had a dose-dependent relationship with recombinant peptide 19. Peptide 19 upregulated the expression of caspase-9, Fas, p53, Bax and Bid, downregulated the expression of Bcl-2 and had little effect on the expression of caspase 8. Peptide 19 decreased the mitochondrial membrane potential and induced the release of cytochrome C from mitochondria to the cytoplasm. In conclusion, peptide 19 induced HepG2 cell apoptosis through the mitochondrial apoptosis pathway. PMID- 19787200 TI - Copper ions regulate cytotoxicity of disulfiram to myeloid leukemia cells. AB - White blood cell (WBC) count is considered a prognostic risk factor in acute myeloid leukemia. As density of leukemic cells increases, the cytotoxic activity of certain anticancer drugs, such as vincristine and doxorubicin, progressively decreases. In this study, we investigated the cell density-dependent induction of apoptosis of human acute myeloid leukemia U937 and ML-1 cells by disulfiram (DSF), the dithiocarbamate drug recently proposed for treatment of human cancers. This effect is dependent on uptake of extracellular copper and its intracellular accumulation. High-density cells cannot uptake and accumulate this metal to a sufficient level that would allow induction of apoptosis due to progressive decrease of its extracellular concentration. Simple addition of copper can resume sensitivity of high-density leukemic cells to DSF and improve efficiency of anti leukemic therapies using this drug, thus providing benefit to patients with high WBC count. PMID- 19787201 TI - The bone anabolic carotenoid beta-cryptoxanthin enhances transforming growth factor-beta1-induced SMAD activation in MC3T3 preosteoblasts. AB - The xanthophyll beta-cryptoxanthin is a member of the carotenoid family of plant derived pigments endowed with anti-osteoporotic properties in vivo. beta cryptoxanthin was demonstrated to stimulate osteoblastic bone formation and simultaneously repress osteoclastic bone resorption in vitro. However, the mechanisms of action remain to be elucidated. The SMAD signal transduction pathway is established to play a critical role in osteoblast lineage commitment and differentiation. In this study we used transient transfection assays of a SMAD luciferase reporter to investigate whether beta-cryptoxanthin regulates SMAD activation in MC3T3 pre-osteoblastic cells. Beta-cryptoxanthin did not stimulate basal SMAD activity but amplified transforming growth factor (TGF)-beta1-induced SMAD activation. Interestingly, beta-cryptoxanthin did not affect bone morphogenetic protein-2 (BMP-2)-induced SMAD activation in osteoblastic cells, suggesting specificity of action on the TGF-beta1 pathway. This study suggests that the carotenoid beta-cryptoxanthin may promote osteoblast differentiation and activity by amplifying TGF-beta1-induced lineage commitment of osteoblast precursors. PMID- 19787202 TI - Frequent expression of the high molecular, 673-bp CD44v3,v8-10 variant in colorectal adenomas and carcinomas. AB - CD44 is a transmembrane glycoprotein involved in the interaction between cells and the extracellular matrix. A large variety of alternatively spliced CD44 variants are expressed by different tumors with possible implication for tumor progression, formation of metastasis and survival. In colon carcinomas, previous reports described higher molecular bands of CD44 transcripts in neoplastic colonic tissue, although a complete analysis of multiple combinations of CD44v transcripts were not performed. We therefore analyzed the pattern of CD44 standard and variant (v2-v10) transcripts in colorectal adenomas and carcinomas by exon-specific RT-PCR amplification and sought CD44v transcripts specific for colonic neoplasias. Our data indicate that CD44 standard transcripts, including the epithelial form (C-v8,v9,v10-C) corresponding to a 720 bp transcript, were detected in 2/38 (5.2%) samples of normal mucosa, 20/20 (100%) adenomas and in 21/33 (63%) colorectal carcinomas. High molecular CD44v3,v8-10 (673 bp) transcripts were found in 2/33 (6%) samples from normal mucosa, 19/20 (95%) from adenomas and in 29/31 from colorectal carcinomas (93%). Similar CD44v3,v8-10 transcripts were detected in five from seven colorectal liver metastases, while normal liver did not contain high molecular CD44v3 variants. The same CD44v3,v8 10 (673 bp) variant was detected in HT-29 human colon carcinoma cells. Direct sequencing of the CD44v3 (673 bp) transcript in samples from colorectal carcinomas and HT-29 cells confirmed the assumed CD44v (-C-v3-v8-v9-v10-C-) cDNA sequence. Analysis of other CD44 variant transcripts (v4-v10) using exon specific primers were less frequently associated with colorectal neoplasias. These data report for the first time frequent expression of neoplasia-associated CD44v3,v8 10 variants in colorectal adenomas and carcinomas supporting the role of increased CD44 variant expression as an early event in colorectal carcinogenesis. The described CD44v3,v8-10 (673 bp) variant might be relevant for diagnosis and treatment of colorectal cancer. PMID- 19787203 TI - Suppression of tissue inhibitor of metalloproteinase-1 by recombinant adeno associated viruses carrying siRNAs in hepatic stellate cells. AB - Elevated tissue inhibitor of metalloproteinase (TIMP)-1 expression contributes to excess production of extracellular matrix in liver fibrosis. However, there are few studies on sustained suppression of TIMP-1. We aimed to construct a recombinant adeno-associated virus (AAV) carrying small interfering RNAs (siRNAs) of TIMP-1 and investigate the long-term effects of RNA interference upon the TIMP 1 gene in rat hepatic stellate cells (HSCs). Five siRNA oligomers targeting rat TIMP-1 were designed and transfected into HSCs. A U6 promoter followed by the siRNA which had the strongest suppression effect was cloned into the AAV vector and packed into 293 cells to construct the recombinant AAV/siRNA-TIMP-1/neo. After infecting HSCs with this recombinant AAV, the transcription and expression levels of the TIMP-1 and matrix metalloproteinase-13 (MMP-13) genes were detected at 4 and 12 weeks. Three of the five designed siRNA oligomers had a suppressing effect on TIMP-1 expression in rat HSCs within 72 h. The transcription and expression levels of TIMP-1 were suppressed significantly (P<0.05) following recombinant AAV/siRNA1-TIMP-1/neo infection and lasted 12 weeks. TIMP-1 expression in rAAV/siRNA1-TIMP-1/neo-infected HSCs was suppressed by 60% after four weeks and 90% after twelve weeks when compared to the control recombinant AAV/neo and uninfected HSCs. Furthermore, the transcription and protein expression levels of MMP-13, the main substrate of TIMP-1, were elevated by approximately 40% at twelve weeks in rAAV/siRNA-TIMP-1/neo-infected HSCs. RNA interference exerts suppressive effect on the TIMP-1 gene in cultured HSCs for a longer time when a recombinant AAV is utilized as the gene delivery vector. PMID- 19787204 TI - Implications of antioxidant enzymes in human gastric neoplasms. AB - The present study is the first to evaluate the expression and activity of MnSOD, Cu/ZnSOD and catalase in human gastric samples, since ROS play a significant role in the pathogenesis of different forms of malignancy inducing mutations and various diseases such as gastric cancer. Biopsies and surgical samples from 53 patients (male/female 22/31, mean age 56.5+/-15.8 years) consisted of 15 healthy, 12 autoimmune atrophic gastritis, 10 Helicobacter pylori (HP) infection, 8 HP negative chronic gastritis (CG) and 8 adenocarcinoma cases. Enzyme activity and expression were evaluated by spectrophotometry and immunoblotting after specific extraction in phosphate buffer. We found that MnSOD activity was increased in adenocarcinoma, CG and HP tissues (p<0.05-0.001), while Cu/ZnSOD was significantly lower in adenocarcinoma and HP tissues (p<0.001) when compared to the healthy control. MnSOD and Cu/ZnSOD were expressed to a significantly higher degree in adenocarcinoma and HP tissues (p<0.05 and <0.001 respectively) and to a significantly lower degree in CG tissues with respect to the healthy patients (p<0.05 and <0.001). A significant decrease in CAT activity in adenocarcinoma and HP tissues was observed (p<0.01 and <0.05). Gastric human neoplasms showed significant changes in antioxidant enzymes, that represent the first line in antioxidant protection against radical attack. The difficulties in correlating the antioxidant enzyme with the neoplasms was related to the complexity of the biochemical pathways that regulate the cellular redox balance. Our results are important in enhancing the understanding of the role that these enzymes play in the promotion/suppression of the carcinogenesis cascade in human gastric mucosa. PMID- 19787205 TI - Association of genetic variants with myocardial infarction in individuals with or without hypertension or diabetes mellitus. AB - Hypertension and diabetes mellitus are important risk factors for myocardial infarction (MI). The purpose of the present study was to identify genetic variants that confer susceptibility to MI in individuals with or without hypertension or diabetes mellitus, thereby contributing to the personalized prevention of MI in such individuals. The study population comprised 5,835 unrelated Japanese individuals, including 1,339 subjects with MI and 4,496 controls. The 150 polymorphisms were selected by genome-wide association studies of MI and ischemic stroke with the use of the GeneChip Human Mapping 500K Array Set. The genotypes for these polymorphisms were determined by a method that combines the polymerase chain reaction and sequence-specific oligonucleotide probes with suspension array technology. The chi-square test, multivariable logistic regression analysis with adjustment for covariates, as well as a stepwise forward selection procedure revealed that three different polymorphisms were significantly (P<0.005) associated with the prevalence of MI in individuals with or without hypertension or diabetes mellitus: the C --> T polymorphism of CLEC16A (rs9925481) in individuals without hypertension, the A --> G polymorphism of SEMA3F (rs12632110) in individuals without diabetes mellitus and the A --> G polymorphism of ALOX5 (rs7913948) in individuals without hypertension or diabetes mellitus. No polymorphism was significantly associated with MI in individuals with hypertension, in those with diabetes mellitus, or in those with both conditions. Stratification of subjects based on hypertension or diabetes mellitus may thus be important in order to achieve personalized prevention of MI with the use of genetic information. PMID- 19787206 TI - Antitumor activity of asukamycin, a secondary metabolite from the actinomycete bacterium Streptomyces nodosus subspecies asukaensis. AB - Asukamycin, a manumycin-type metabolite, was isolated by a rapid and easily scalable purification scheme. Thus far, studies on the biological activity of asukamycin have been limited to its role as an antibacterial and antifungal agent. By using five different tumor cell lines we demonstrate antineoplastic activity of asukamycin. It inhibited cell growth at concentrations similar to other members of the manumycin family (IC50 1-5 microM). Cytotoxicity of asukamycin was accompanied by activation of caspases 8 and 3 and was diminished by SB 202190, a specific p38 mitogen-activated protein kinase (MAPK) inhibitor. These data, in combination with earlier observations showing its low in vivo toxicity, indicate that further studies on the potential antitumor activity of asukamycin are warranted. PMID- 19787207 TI - JNK and p38 inhibitors increase and decrease apoptosis, respectively, in pyrogallol-treated calf pulmonary arterial endothelial cells. AB - Pyrogallol (PG) as a polyphenol compound induces apoptosis in several types of cells. Here, we investigated the effects of MAPK inhibitors on PG-treated calf pulmonary artery endothelial cells (CPAEC) in relation to cell death, ROS and GSH. PG inhibited the growth of CPAEC and also induced cell death, which was accompanied by the loss of mitochondrial membrane potential (MMP; DeltaPsi(m)). PG decreased the ROS level and increased the GSH depleted cell number in CPAEC. JNK inhibitor intensified the growth inhibition by PG whereas p38 inhibitor attenuated the growth inhibition. While MEK and p38 inhibitors decreased CPAEC death by PG, JNK inhibitor increased. None of the MAPK inhibitors significantly increased ROS level in PG-treated CPAEC. JNK inhibitor increased GSH depleted cell number in PG-treated CPAEC whereas p38 inhibitor decreased the number. MAPK inhibitors differently affected cell growth, death, ROS and GSH levels in control CPACE. In conclusion, PG induced apoptosis via the loss of MMP (DeltaPsi(m)) in CPAEC, which is accompanied by GSH depletion. JNK and p38 inhibitors increased and decreased apoptosis in PG-treated CPAEC, respectively, which were correlated with GSH depletion. PMID- 19787208 TI - Epigenetic DNA hypermethylation: clinical applications in endometrial cancer (Review). AB - Improvements in epigenetics have resulted in identification of a number of genes with aberrant hypermethylation associated with systematic occurrence of cancer. It is now evident that aberrant hypermethylation inactivates cancer-related genes including those associated with cell cycle control, apoptosis, and DNA repair. An epigenetic analysis of DNA hypermethylation in type I endometrial cancer has led to a proposed mechanism for endometrial carcinogenesis. Reduced DNA mismatch repair due to loss of hMLH1 expression is thought to have a major role in carcinogenesis and these findings open up approaches to prevention, diagnosis, risk assessment, and treatment of type I endometrial cancer. Aberrant DNA hypermethylation can be detected with high sensitivity for identification of cancer cells in sputum, blood and other biopsy materials, including in endometrial cancer specimens. There have been many attempts to use methylation inhibitors as anticancer agents, and epigenetic abnormalities may be useful as biomarkers of anticancer drug sensitivity and to identify biological characteristics of tumor cells for determination of treatment options based on hypermethylation. For example, aberrant hypermethylation of the CHFR gene is correlated with cellular sensitivity to microtubule inhibitors, and this may be useful in treatment of type I endometrial cancer. An ultimate objective of epigenetics is to identify the type of hereditary methylation responsible for cancer, with the goal of improved diagnosis and treatment based on control of methylation. PMID- 19787209 TI - Focal adhesion kinase as potential target for cancer therapy (Review). AB - Focal adhesion kinase (FAK) is a 125-kDa non-receptor and non-membrane protein tyrosine. FAK can function with integrins and growth factor receptors to promote cell survival dependent kinase activity and nuclear FAK promotes cell proliferation and survival through FERM (FAK, ezrin, radixin, moesin) domain enhanced p53 degradation independent kinase activity. Many previous studies have indicated that FAK plays a critical role in the biological processes of normal and cancer cells and FAK has been proposed as a potential target in cancer therapy. Small molecule inhibitors (PF-573,228; PF-562,271 and NVP-226) for use as potential cancer therapies have been developed. However, the detailed mechanism of the role for FAK in tumor cell generation and progression remain unclear, so future work is needed to explore these issues. New inhibitors that can be effectively inhibit the function of FAK still need to be explored due to the low specificity, and resistance. PMID- 19787210 TI - Human gonadotropin-releasing hormone receptor-activated cellular functions and signaling pathways in extra-pituitary tissues and cancer cells (Review). AB - Human gonadotropin-releasing hormone receptor (GnRHR) and its natural ligand human gonadotropin-releasing hormone (GnRH) were initially described as signaling complexes that play a key role in reproductive functions. By binding to specific receptors present on pituitary gonadotropes, GnRH regulates the sperm and ovum maturation, as well as steroidogenesis within the context of the hypothalamus hypophysis axis. The expression of GnRH and its receptor has clearly been established in many extra-pituitary organs. Some of them are tumors from non reproductive tissues such as liver, larynx, pancreas, colon, lymphoma, kidney, skin, blood and brain as well as tissues from reproductive track, for example ovary, endometrium, prostate and breast or tumors derived from these organs. Expression of GnRH and its receptor in these organs has gained much attention and several research groups have established their role during cell proliferation and cell motility. Although the signaling pathways and their effector proteins in these samples remain unclear, the molecular mechanism employed for GnRH and its receptor in extra-pituitary tissues could be related with non-classical GnRHR signaling pathways. In the present review, we explore the vast literature reported on GnRH and GnRHR principally in tumors, describing how cross-talk between GnRHR and growth factor receptor, the coupling between GnRHR and many G proteins depending on cell context, and the regulation of several proteins associated with cell proliferation and cell motility are employed by GnRHR/GnRH to regulate their extra-pituitary activities. PMID- 19787211 TI - Myosin VI is a modulator of androgen-dependent gene expression. AB - Myosin VI, one of the so-called unconventional myosins, is an actin-based molecular motor involved in intracellular vesicle and organelle transport. In human prostate, myosin VI is expressed in prostate epithelium. We examined the effect of myosin VI downregulation in the LNCaP human prostate cancer cell line using an RNA interference approach. Further, the expression of myosin VI in human prostate tissue was examined using immunohistochemistry. The expression of androgen receptor (AR) and E-cadherin was examined in myosin VI knocked-down cells and control cells. We determined 3H-testosterone uptake in the myosin knocked-down LNCaP cells. Next, we cotransfected LNCaP cells with the myosin VI specific small interfering RNA (siRNA) duplex and an androgen-responsive luciferase reporter construct and then measured luciferase activity after androgen induction. To clarify whether myosin VI and the AR are interacting proteins, we performed immunoprecipitation studies using myosin VI and AR polyclonal antibodies in androgen-induced LNCaP cells. We confirmed previous results of myosin VI overexpression in human prostate cancer tissue, as in some cases malignant epithelium was more intensively stained than benign epithelium. We found that the expression of AR decreased as a result of myosin VI knock-down. Decreased myosin VI levels did not significantly influence the testosterone uptake of the LNCaP cell line. Instead, we noted a decreased activity of the androgen-regulated mouse mammary tumor virus promoter-reporter vector construct in LNCaP cells cotransfected with myosin VI siRNA duplexes. Finally, we detected the interaction between AR and myosin VI by immunoprecipitation. We propose that myosin VI is a modulator of androgen-dependent gene transcription via interaction with the AR. Thus, myosin VI is a potential therapeutic target for prostate cancer as it could be used as a modulator of AR-dependent gene expression. PMID- 19787212 TI - Three-dimensional alginate spheroid culture system of murine osteosarcoma. AB - Osteosarcoma (OS) is the most common primary malignant tumor of the bone and often forms pulmonary metastases, which are the most important prognostic factor. For further elucidation of the mechanism underlying the progression and metastasis of human OS, a culture system mimicking the microenvironment of the tumor in vivo is needed. We report a novel three-dimensional (3D) alginate spheroid culture system of murine osteosarcoma. Two different metastatic clones, the parental Dunn and its derivative line LM8, which has a higher metastatic potential to the lungs, were encapsulated in alginate beads to develop the 3D culture system. The beads containing murine OS cells were also transplanted into mice to determine their metastatic potential in vivo. In this culture system, murine OS cells encapsulated in alginate beads were able to grow in a 3D structure with cells detaching from the alginate environment. The number of detaching cells was higher in the LM8 cell line than the Dunn cell line. In the in vivo alginate bead transplantation model, the rate of pulmonary metastasis was higher with LM8 cells compared with that of Dunn cells. The cell characteristics and kinetics in this culture system closely reflect the original malignant potential of the cells in vivo. PMID- 19787213 TI - Expression of the FAM5C in tongue squamous cell carcinoma. AB - The purpose of this study was to perform a whole-genome analysis of loss of heterozygosity (LOH) in tongue squamous cell carcinoma (SCC) using the Affymetrix 10K SNP Mapping Array. In the gene which had been identified by whole-genome analysis of LOH, we analyzed allelic imbalance to identify the role of the gene. We applied whole-genome analysis of LOH in the specimens from the 5 cases of tongue SCC using this array. In the chromosomal region which had been identified by whole-genome analysis of LOH, we reconfirmed the existence of LOH in 30 cases using microsatellite markers. The expression levels of the mRNA in the region were examined in 15 cases and in 5 tongue SCC-derived cell lines by real-time quantitative RT-PCR analysis. LOH was observed in all of the 5 cases in the 1q31.1 region. Only 3 microsatellite markers (D1S1189, D1S2151, and D1S2595) existed in the 1q31.1 region. A high frequency of LOH was found at the D1S1189 locus in 18/30 (60%), D1S2151 locus in 16/30 (53%) and D1S2595 locus in 21/30 (70%). Only the Family with sequence similarity 5, member C (FAM5C) gene was located in the 1q31.1 region. There was statistically significant difference in the FAM5C mRNA expression levels between tongue SCC and normal tissues. All tongue SCC-derived cell lines decreased FAM5C mRNA expression compared with normal oral keratinocytes (NOKs). We conclude that FAM5C may be a novel tumor suppressor gene (TSG) in tongue SCC. PMID- 19787214 TI - The status of KRAS mutations in patients with non-small cell lung cancers from mainland China. AB - KRAS mutation is closely associated to carcinogenesis and prognosis of non-small cell lung cancer (NSCLC). Detection of KRAS mutation can also be used to select NSCLC patients for drug targeting with EGFR tyrosine kinase inhibitors. Data regarding the status of KRAS mutation in mainland China, which would assist in these interventions, is lacking. We have detected KRAS mutation from 103 NSCLC patients in mainland China with high resolution melting analysis (HRM) on LightScanner, and compared this method of detection with sequencing, and found HRM to have greater sensitivity. We found 6 patients (5.8%) with KRAS mutation (3 patients, G12C; 1 patient, G12S; 1 patient, G12V; 1 patient, G13D). KRAS mutation was significantly associated to gender (p=0.027) and pathology types (p=0.000), but not to smoking. The mutation frequency of KRAS in NSCLC patients in mainland China is similar to those in East Asian countries, but lower than those in western countries. However, the spectrum of KRAS mutation in mainland China is similar to those found in the USA. The results also exhibit dependence of KRAS mutation in China on ethnicity. The clinical significance of the spectral pattern of KRAS mutations in TKI resistance or tumorigenesis among patients with NSCLC in mainland China requires further investigation. PMID- 19787215 TI - Vitamin D receptor expression is associated with colon cancer in ulcerative colitis. AB - Since the 1970s, it has been well known that long-standing ulcerative colitis (UC) disposes to the development of colorectal adenocarcinoma (CRC). To date, CRC associated with UC is thought to arise along a pathway of dysplasia, however, primary factors for developing of UC-related dysplasia and cancer are unclear. Vitamin D, which works through binding the vitamin D receptor (VDR) has an important role in cancer progression and immune response. In this study, we investigated the impact of VDR expression on UC as well as colon cancer. We examined retrospectively the expression of VDR in extraction specimens of UC (n=124) patients by immunohistochemistry. We counted VDR positive cells in at least 10 fields in each case to evaluate the frequency of VDR positive cells in ductal epithelium. In addition, effect of VDR expression on inflammation was analyzed. On a normal mucosa, the expression of VDR was recognized in 58.8% of ductal cells. In UC patient, the expression of VDR was considerably decreased compared to normal mucosa, VDR positive rate was only 3.4+/-9.0%. Importantly, dysplasia and UC-CRC patients showed lower rate of VDR expression compared to non colon cancer patients, whose expression rates were 0.6+/-1.3% and 3.8+/-10%, respectively. Moreover, long-term UC patients (more than ten years) who were at high-risk of developing CRC showed significantly lower VDR expression than short term patients. We did not detect direct association of VDR expression with inflammation and clinical stage of UC. These findings suggested that correlation seems to exist between the level of VDR expression and carcinogenesis in UC. VDR could be a possible marker to detect dysplasia and cancer in ulcerative colitis. PMID- 19787216 TI - High expression of N-acetylglucosaminyltransferase V in mucinous tumors of the ovary. AB - N-acetylglucosaminyltransferase V (GnT-V) is an enzyme that catalyzes beta1-6 branching of N-acetylglucosamine (GlcNAc) on asparagine-linked oligosaccharides of cell proteins. The present study aimed to investigate GnT-V expression and its prognostic significance in epithelial ovarian cancer. GnT-V expression was studied by immunohistochemistry in 83 surgically resected ovarian cancers, and the staining intensity was evaluated. High GnT-V expression in cancer cells was found in 17 (20.5%) of the 83 cases, and was positively correlated with early FIGO staging. In the histological type, mucinous adenocarcinoma showed significantly strong immunostaining compared to the non-mucinous type (P<0.001). In 36 mucinous tumors, the GnT-V immunostaining score was significantly higher in cancer than in benign and borderline tumors (P<0.001). NOM-1, a human ovarian mucinous adenocarcinoma cell line, expressed strong GnT-V protein and swainsonine treatment suppressed beta1-6GlcNAc branching and reduced migration ability significantly (P<0.001). These results suggested that GnT-V might be involved in the malignant potential of mucinous ovarian cancer. PMID- 19787217 TI - Danthron inhibits the migration and invasion of human brain glioblastoma multiforme cells through the inhibition of mRNA expression of focal adhesion kinase, Rho kinases-1 and metalloproteinase-9. AB - In this study, we investigated the effect of danthron on the cell migration and invasion of human brain glioblastoma multiforme GBM 8401 cells in vitro. The changes of migration and invasion of GBM 8401 cells after treatment with danthron were detected by cell migration assay and cell invasion assay. The levels of mRNA gene expression associated with cell migration and invasion were detected by real time PCR. Results indicated that human brain glioblastoma multiforme GBM 8401 cells treated with danthron in vitro migrated and invaded less than cells treated with phosphate-buffered saline (PBS) (control). Western blotting showed that danthron inhibited the protein levels of FAK, MMP-7, MMP-9 and uPA in GBM 8401 cells. Real-time PCR assay also showed that danthron inhibited the mRNA expression of matrix metalloproteinase-9 (MMP-9), FAK and ROCK-1 of GBM 8401 cells. These results showed that danthron inhibited invasion and migration of GBM 8401 cells by downregulating mRNA expression associated with these processes, resulting in reduced metastasis. Thus, danthron may be considered a therapeutic agent that can inhibit primary tumor growth and prevent metastasis. PMID- 19787218 TI - Use of telomelysin (OBP-301) in mouse xenografts of human head and neck cancer. AB - We previously reported that telomerase-specific replication-component adenovirous, Telomelysin (OBP-301) has cytotoxic activity to the YCUT892, KCCT873, KCCT891, KCCL871, YCUM862, HN12, and KCCOR891 cell lines in vitro, and investigated the association between cytotoxic activity and adenoviral receptor expression. In this study, we evaluated the most appropriate way to administer telomelysin (OBP-301) in the treatment of squamous cell carcinoma of the head and neck (SCCHN), and assessed the effect of OBP-301 in large subcutaneous KCCT873 human SCCHN tumors in immunodeficient mice. We also compared antitumor responses following three intratumoral (i.t.) injections of OBP-301 given daily, every 2 days or weekly. To investigate the mechanism of the antitumor effect, we evaluated cellular infiltration in treated tumors. OBP-301 showed remarkable antitumor activity against large KCCT873 tumors, and three treatment schedules produced similar antitumor effects. The weekly regimen also significantly reduced the growth of large tumors. Immunochemistry revealed that macrophages, but not natural killer cells, were responsible for tumor regression. A regimen of three weekly injections of OBP-301 has remarkable antitumor effects against large KCCT873 tumors. These results may provide a new platform for treating patients with localized SCCHN. PMID- 19787219 TI - Hyperbaric oxygen as a chemotherapy adjuvant in the treatment of osteosarcoma. AB - Although hyperbaric oxygen has been shown to enhance the efficacy of radiotherapy and chemotherapy for the treatment of several malignant tumors, the impact of hyperbaric oxygen on osteosarcoma has not yet been demonstrated. In this study, we investigated the efficacy of hyperbaric oxygen alone and in combination with an anti-cancer drug as an adjuvant to chemotherapy. In vitro, highly metastatic murine osteosarcoma cell lines were exposed to hyperbaric oxygen and cell viability was examined. Hyperbaric oxygen alone significantly suppressed cell proliferation, and hyperbaric oxygen plus carboplatin exhibited significant synergism in suppression of cell proliferation. In vivo, C3H mice were subcutaneously inoculated with osteosarcoma cells and divided into four groups: control, hyperbaric oxygen, carboplatin, and carboplatin plus hyperbaric oxygen. After 5 weeks, increase in both tumor volume and number of lung metastases was significantly suppressed in the hyperbaric oxygen group. Concomitant hyperbaric oxygen clearly enhanced the chemotherapeutic effects of carboplatin on both tumor growth and lung metastasis in osteosarcoma-bearing mice. Moreover, mortality in the carboplatin plus hyperbaric oxygen group was significantly lower than in the other three groups. These findings suggest that hyperbaric oxygen plus carboplatin combination therapy could be an appropriate therapeutic regimen for the treatment of patients with osteosarcoma. PMID- 19787220 TI - Houttuynia cordata Thunb extract induces apoptosis through mitochondrial dependent pathway in HT-29 human colon adenocarcinoma cells. AB - The Houttuynia cordata Thunb (HCT) extract has been used as a traditional Chinese herb medicine and as well as an effective drug for treating allergic inflammation for thousands of years. In this study, we investigated the anti-cancer activity of HCT and its molecular mechanisms in the human colon adenocarcinoma cell line HT-29. HCT inhibited HT-29 cell viability in a dose- and time-dependent manner by MTT assay. Treatment with 450 microg/ml of HCT for 48 and 72 h led to DNA damage and apoptosis by DAPI staining and comet assay. HCT increased reactive oxygen species production and decreased the levels of mitochondria membrane potential (MMP) in HT-29 cells by flow cytometry analysis. HCT caused the release of cytochrome c, Apaf-1, pro-caspase-9 and AIF from mitochondria via a decrease of the MMP. The decrease of MMP was then associated with a decrease in the ratio of Bax/Bcl-2 and activation of caspase-9 and -3 by Western blotting and caspase activity assay. Caspase-9 and -3 inhibitors almost completely suppressed HCT induced caspase-9 and -3 activities. Our results demonstrated that the HCT induced apoptosis in human colon adenocarcinoma cell line HT-29 might be related to a mitochondrial-dependent pathway. PMID- 19787221 TI - Different expression of mimecan as a marker for differential diagnosis between NSCLC and SCLC. AB - Mimecan mRNA was present in a limited number of mouse and human tissues, however, abundant mimecan mRNA was observed in the lung tissue. Therefore, we hypothesize that mimecan could serve as a biomarker for differentiating various histological types of lung cancers. In humans, the mimecan mRNA was found most abundant in ovary and less abundant in lung by using Northern blot analysis. Moreover, the mimecan was expressed strongly in the epithelial cells of the bronchial wall and weaker in the epithelial cells of the alveolar sacs by in situ hybridization and immunohistochemical analysis. Furthermore, the mimecan immunoreactivity was found in 103 (97.2%) of 106 non-small cell lung cancers (NSCLCs). Nevertheless, a large majority of small cell lung cancers (SCLCs) (50/56, 89.3%) showed negative immunoreactivity to mimecan polyclonal antibody. A significant difference of mimecan immunoreactivity was found between NSCLC and SCLC (P<0.00001). This is the first study showing that mimecan could serve as an excellent pathological biomarker to distinguish NSCLCs from SCLCs. PMID- 19787222 TI - Estrogen receptor-beta expression in human laryngeal carcinoma: correlation with the expression of epithelial-mesenchymal transition specific biomarkers. AB - Laryngeal carcinoma is a malignancy of the respiratory tract with a significantly higher male to female ratio, suggesting involvement of gender-depended factors in the pathogenesis. Estrogen influences the pathological processes of hormone dependent cancers, such as breast, prostate and ovarian cancers, through its receptors, estrogen receptor-alpha (ER-alpha) and -beta (ER-beta). While ER-alpha promotes cell proliferation, recent studies indicate that ER-beta is protective against carcinoma progression into an invasive state. However, it is unclear whether ER-beta plays a role in laryngeal cancer. In the present study we examined the expression of ER-beta in 80 invasive human squamous laryngeal carcinomas by immunohistochemistry and correlated ER-beta expression with markers of epithelial-mesenchymal transition (EMT). ER-beta was expressed in 83% of tumour specimens where it was localized in the nuclei of tumour cells. The expression of ER-beta correlated positively with the maintenance of E-cadherin and beta-catenin at cell junctions and negatively with the loss of E-cadherin, nuclear translocation of beta-catenin and increased TNM stage. We concluded that estrogen receptor-beta expression is documented in laryngeal cancer indicating a possible role in the pathogenesis of this malignancy. It is suggested that ER beta could protect tumour cells from acquiring aggressive EMT features such as E cadherin downregulation and nuclear beta-catenin activation. PMID- 19787223 TI - Induction of tumor inhibition and apoptosis by a candidate tumor suppressor gene DRR1 on 3p21.1. AB - Down-regulated in renal cell carcinoma gene (DRR1) is one of the candidate tumor suppressor genes (TSGs) on human 3p21.1. This study was performed to validate the expression status of DRR1 gene in cancer cells and the expression pattern of the protein in clinical specimens of human lung cancer and to examine its potential as a molecular target for treatment of lung cancer in vivo. DRR1 expression was analyzed in 7 human lung cancer cell lines. DRR1 protein expression was also examined in clinical non-small cell lung cancer (NSCLC) specimens. Furthermore, effects of DRR1 re-expression on A549 cells in vitro and A549 xenograft tumors in nude mice were evaluated. Loss of DRR1 mRNA expression was detected in 6 of the 7 human cancer cell lines, the exception was the renal cancer cell line OS-RC-2. DRR1 protein expression was absent in 15 of 20 (75%) human NSCLC specimens by immunostaining. Transfection of DRR1 gene into DRR1-negative-expressing A549 cells resulted in significant cell growth suppression and apoptosis. Plasmids containing DRR1 cDNA complexed with DOTAP:Chol liposomes were administered intravenously via tail vein to nude mice bearing A549 xenograft tumors resulting in tumor growth inhibition and elevation of apoptosis compared with the controls. DRR1 is a potent growth suppressor of NSCLC, acting through apoptosis pathway in vivo and it may be a potential therapeutic gene for human lung cancer. PMID- 19787224 TI - A traditional Chinese medicine formulation consisting of Rhizoma Corydalis and Rhizoma Curcumae exerts synergistic anti-tumor activity. AB - Synergy analysis of anticancer agents is an important approach to determining the ratio and/or dose of drugs for clinical combination therapy. However, this method is rarely used to evaluate the composition of traditional Chinese medicine formulation. 'Yanhusuo San' (YHSS), which consists of yanhusuo (Rhizoma Corydalis) and Ezhu (Rhizoma Curcumae), has been an archaic Chinese medicine prescription since the Song dynasty (960-1279 AD). We previously demonstrated that either yanhusuo or ezhu has strong anticancer effect. Herein, we sought to determine the possible synergic effect between these two Chinese herbs. We measured the IC50 of each herb extract and both extracts at different ratios of doses by MTT assay. Isobologram and combination index (CI) analyses were used to evaluate the synergistic effect of yanhusuo and ezhu in different fixed ratios. Our results indicated that a combination of two herbal extracts exhibits the strongest anticancer cell proliferation effect at the ratio of 3:2 (ezhu to yanhusuo; referred to as E3Y2). Using Boyden Chamber assay, flow cytometry, and fluorescence microscopy analysis, we found that E3Y2 could markedly reduce the cell invasion ability and induce cytochrome c release rather than single use, but E3Y2 could not influence the cell cycle distribution. When the levels of ERK1/2, p-ERK1/2 and p-Rb were determined by Western blot analysis, we found that the E3Y2 significantly suppresses the level of p-ERK. Thus, our studies provide a plausible molecular basis of the synergistic anti-tumor effect of ezhu and yanhusuo. PMID- 19787225 TI - Efficient preparation of highly pure chlorin e6 and its photodynamic anti-cancer activity in a rat tumor model. AB - Photodynamic therapy (PDT) is currently being used as an alternative therapeutic modality for a variety of malignant tumors. This study was performed to show an efficient preparation of second generation of photosensitizer chlorin e6 (Ce6) with high yield and purity, and to test antitumor activity of Ce6-induced PDT (Ce6-PDT) both in vitro and in vivo using a rat tumor model. Three-week-old male Sprague-Dawley (SD) rats were inoculated s.c. on the right flank with 5x10(6) RK3E-ras cells. The animals were administered i.v. with Ce6 (10 mg/kg) and 24 h later, PDT was performed using a laser diode at a light dose of 100 J/cm2. Ce6 PDT generated reactive oxygen species and led to significant growth inhibition in RK3E-ras cell. In addition, Ce6-PDT induced apoptosis through the activation of caspase-3 and its downstream target, PARP cleavage. The protein level of anti apoptotic bcl-2 was also reduced by Ce6-PDT in RK3E-ras cells. In in vivo experiments, application of Ce6-PDT led to a significant reduction of tumor size. PCNA immunostaining and TUNEL assay revealed that Ce6-PDT inhibited tumor cell proliferation and increased apoptosis. These findings suggest that the newly purified Ce6-PDT can effectively arrest tumor growth by inhibiting cell proliferation and inducing apoptosis. PMID- 19787226 TI - Endothelial VEGFR-3 expression in colorectal carcinomas is associated with hematogenous metastasis. AB - Vascular endothelial growth factor receptor 3 (VEGFR-3) is a major inducer of lymphangiogenic signalling and seems to be involved also in angiogenesis. Since both processes are closely linked with tumor metastasis this study investigated the expression of VEGFR-3 in tumor-associated vessels in colorectal carcinomas and evaluated its relevance for lymphogenous and hematogenous metastasis. In a comparative study between microvascular endothelial cells isolated from the tumor (HCTEC) and the corresponding non-neoplastic tissue (HCMEC) from five patients with colorectal cancer VEGFR-3 expression was measured using a specific ELISA. The expression pattern was individually different, with cases showing reduced, elevated and unchanged protein levels. Under hypoxic culture conditions (3% O2 for 24 h), which are more realistic for the tumor situation, the levels remained unchanged. In contrast, hypoxia exposure of macrovascular human umbilical vein endothelial cells (HUVEC) led to a consistent downregulation of VEGFR-3 protein. These data indicate a 'hypoxia-resistant' behaviour of VEGFR-3 in colonic microvasculature. Using immunohistochemistry the endothelial expression pattern of VEGFR-3 in 74 non-metastatic, lymphogenously-metastatic and hematogenously metastatic colorectal carcinoma specimens was assessed. Positive VEGFR-3 expression was highly significantly associated with those cases showing distant metastasis (p=0.0003). In contrast, significant differences in the expression of VEGFR-3 between non-metastatic tumors and carcinomas with lymph node metastasis were not found. The majority of the detectable intratumoral VEGFR-3-positive vessels were of blood vascular origin (CD31 positive, D2-40 negative). Whereas intratumoral lymphatic vessels were collapsed, VEGFR-3 positive peritumoral lymphatic vessels had mostly open lumina. These morphological observations provide evidence for a predominant significance of VEGFR-3-positive, possibly angiogenesis-mediated, tumor-associated blood vessels in hematogenous metastasis of colorectal cancer. In addition, due to their patency VEGFR-3-positive peritumoral, but not intratumoral lymphatics could be the vascular substrate functionally mediating lymphogenous metastasis. PMID- 19787227 TI - Hepatitis B virus X protein (HBx) induces G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase. AB - Hepatitis B virus X protein (HBx) is a multi-functional regulatory protein that is known to be involved in viral proliferation, transcriptional activation and cell growth control. However, the actual role of HBx in cell growth control remains controversial. In this study, the impact of HBx on cell growth in vitro and in vivo was further investigated. HBx was able to inhibit the growth of hepatocellular carcinoma (HCC) cells and induce G2/M arrest in vitro. Moreover, unlike many other G2/M arrest mechanisms, HBx did not inhibit cyclin B1-CDK1 kinase activity, but it persistently activated the cyclin B1-CDK1 kinase. In vivo, HBx inhibited tumor cell growth and induced apoptosis as well as inhibited the growth of vascular endothelial cells. In conclusion, HBx induced G2/M arrest and apoptosis through sustained activation of cyclin B1-CDK1 kinase, and negatively regulated cell growth in vitro and in vivo. PMID- 19787228 TI - Expression and prognostic value of L1-CAM in breast cancer. AB - The L1 adhesion molecule (L1-CAM) is associated with impaired prognosis in many carcinomas. However, limited information about its expression in breast cancer tissue is available. Therefore, we carried out an analysis on L1 expression in primary breast cancers using a combination of Western blot, DNA-microarray analysis and immunohistochemistry. We observed L1 protein and mRNA overexpression in 14-15% of the carcinomas and this was confirmed by immunohistochemical staining. High L1 expression was associated with nodal involvement, high grading, human epidermal growth receptor 2 (Her-2), plasminogen activator inhibitor 1 (PAI 1) and vascular endothelial growth factor (VEGF) expression and a negative estrogen receptor (ER) status, but not with neuroendocrine markers. Moreover, patients with tumors showing high L1-CAM expression had a shorter disease-free and overall survival. Given the emerging functional role of L1 in promoting tumor cell migration, invasion, tumor growth and metastasis, our results suggest that L1 may have this function in breast cancer as well. PMID- 19787229 TI - MMP13 is potentially a new tumor marker for breast cancer diagnosis. AB - Within the past decade, the incidence of breast cancer in Taiwan has been rising year after year. Breast cancer is the first most prevalent cancer and the fourth leading cause of cancer-related deaths among women in Taiwan. The early stage of breast cancer not only have a wider range of therapeutic options, but also obtain a higher success rate of therapy than those with advanced breast cancer. A test for tumor markers is the most convenient method to screen for breast cancer. However, the tumor markers currently available for breast cancer detection include carcinoembryonic antigen (CEA), carbohydrate antigen 15.3 (CA15.3), and carbohydrate antigen 27.29 (CA27.29) exhibited certain limitations. Poor sensitivity and specificity greatly limits the diagnostic accuracy of these markers. This study aims to identify potential tumor markers for breast cancer. At first, we analyzed genes expression in infiltrating lobular carcinoma, metaplastic carcinoma, and infiltrating ductal carcinoma of paired specimens (tumor and normal tissue) from breast cancer patients using microarray technology. We selected 371 overexpressed genes in all of the three cell type. In advanced breast cancer tissue, we detected four genes MMP13, CAMP, COL10A1 and FLJ25416 from 25 overexpressed genes which encoded secretion protein more specifically for breast cancer than other genes. After validation with 15 pairs of breast cancer tissue and paired to normal adjacent tissues by membrane array and quantitative RT-PCR, we found MMP13 was 100% overexpressed and confirmed to be a secreted protein by Western blot analysis of the cell culture medium. The expression level of MMP13 was also measured by immunohistochemical staining. We suggest that MMP13 is a highly overexpressed secretion protein in breast cancer tissue. It has potential to be a new tumor marker for breast cancer diagnosis. PMID- 19787230 TI - Identification and characterization of cancer stem-like cells from primary carcinoma of the cervix uteri. AB - Like many other solid tumors, cervical cancer contains a heterogeneous population of cancer cells. Several investigators have identified putative stem cells from solid tumors and cancer cell lines via the capacity to self renew and drive tumor formation. The aim of this study was to identify and characterize a cancer stem like cell population from primary carcinoma of the cervix uteri. Cervical carcinoma from 19 patients staged I-II following International Federation of Gynecology and Obstetrics (FIGO) criteria were disaggregated and subjected to growth conditions selective for stem cells. Eight of nineteen tumor-derived cultures encompassed stem-like cells capable of self-renewal, extensive proliferation as clonal non-adherent spherical clusters. Cell markers of spheroid were identified as CD44+CK17+. Cell survival assays showed the sphere-forming cells were only 48% inhibited by doxorubicin whereas 78% inhibited by paclitaxel. Chemo-resistance may partly attribute to the exclusive expression of ABC transporter. To investigate the tumorigenicity of these stem-like cells, xenoengraftment of 10(5) dissociated spheroid cells allowed full recapitulation of the original tumor, whereas the same amount of tumor cells without non adherent spheroid selection remained non-tumorigenic. Stemness properties of these spheroid cells were further established by reverse transcription-PCR and Western blotting, demonstrating the expression of embryonic and adult stemness related genes (Oct-4, Piwil2, C-myc, Stat3 and Sox2). Based on these findings, we assert that cervical cancer contain a subpopulation of tumor initiating cells with stem-like properties, thus facilitating the approach to therapeutic strategies aimed at eradicating the tumorigenic subpopulation within cervical cancer. PMID- 19787231 TI - CD44 expression during tumor progression of follicular lymphoma. AB - Follicular lymphoma often progresses to diffuse type lymphoma. To elucidate the mechanisms of the diffuse evolution of follicular lymphoma, we investigated the expression pattern of CD44 in 28 cases of follicular lymphomas (FLs) using an immunohistochemical method and semi-quantitative PCR-Southern blot analysis. The FLs were divided into four groups: i) intrafollicular (IF); ii) infiltrative (INF); iii) partially follicular (PF); and iv) minimally follicular (MF), according to the histological classification by Lukes and Collins. Immunohistochemical analysis of CD44 using antibodies against CD44 common (CD44C) epitopes showed that CD44 was expressed in the diffuse area in the INF (0/8 cases), PF (12/12 cases), and MF (2/2 cases) lymphomas, whereas CD44 was not expressed in the lymphoma cells within the area of follicular growth of IF (0/6 cases) and INF (0/8 cases). Semi-quantitative PCR-Southern blot analysis showed that CD19-selected B cells from the FLs were expressed as a product of 482 base pairs (bp) corresponding to a CD44 standard form (CD44s) (5/5 cases). Additionally, the lymphoma cells from the PF were expressed as products of 600 and 1100 bp and the cells from MF were expressed as products of 600, 900, and 1100 bp with the CD44 exon 10 or 11 probes. The results indicated that the expression of CD44s and CD44 variants containing exon 10 and 11 were up-regulated according to the diffuse evolution of the follicular lymphoma. PMID- 19787232 TI - Analysis of the expression profiles of cytokines and cytokine-related genes during the progression of breast cancer growth in mice. AB - Cytokines are a protein family of regulatory factors derived from tumors and their environmental components that contribute to the growth, invasion and metastasis of breast cancer. However, the way in which tumor progression and cytokines regulate each other is not well understood. In this study, we used an oligoDNA microarray to assess the kinetic expression profile of cytokine genes in tumor tissues and lymph nodes during the progression of tumor growth in mice that had been subcutaneously challenged with breast adenocarcinoma SB5b cells. Our results demonstrated that IL-15, IL-17, IL-18 and IL-18 binding protein (IL 18bp), which are associated with inflammation, were increased in tumor tissues. Conversely, chemokines and their receptors, including CXCR4/CXCL12, CCR7/CCL21, CCL9, CXCL9 and CCL12, were overexpressed in lymph nodes during tumor growth. Furthermore, RT-PCR and Western blot analysis revealed that IL-18, a pro angiogenic factor in tumors, was up-regulated in tumor tissues. Interestingly, CCR3, IL-1R2, SOCS and IL-20 were up-regulated in tumor tissues, but down regulated in lymph nodes during tumor growth. This result suggests that the expression of cytokines and cytokine-related genes was differentially regulated, which resulted in a beneficial effect for tumor progression. PMID- 19787233 TI - CD24 overexpression in cancer development and progression: a meta-analysis. AB - CD24 has emerged as a new oncogene and metastasis promoter. However, there is a controversy as to whether CD24 expression is a prognostic factor for poor outcomes in many human cancers. To shed light on this controversy, we performed a meta-analysis of the relationship between CD24 expression and prognostic parameters in different carcinomas. Studies published in the period 1990-2009 were reviewed for the meta-analysis and selected according to defined criteria. The effect sizes of prognostic parameters and overall survival were calculated by an odds ratio (OR) or an adjusted hazard ratio (HR). Twenty-eight studies reported CD24 expression for 2,925 cases. The frequency of CD24 expression by immunohistochemistry was 68% in all the carcinomas of the breast, female genital tract, gastrointestinal tract, biliary tract and pancreas, urinary system, prostate and skin. Overall, CD24 was more frequently overexpressed in their carcinomas than their benign lesions (OR=4.21; 95% CI, 1.826-9.731; P=0.001) and was significantly associated with lymph node metastasis (OR=2.41; CI, 1.013 5.720; P=0.047), advanced clinical stages (OR=1.59; 95% CI, 1.244-2.032; P<0.001) and shortened overall survival (HR=2.13; 95% CI, 1.656-2.730; P<0.001). CD24 expression was highly associated with lymph node metastases in breast cancer (OR=3.55; 95% CI, 1.664-7.554; P=0.001), advanced clinical stages (OR=2.22; 95% CI, 1.442-3.418; P<0.001) and lymphovascular invasions (OR=2.78; 95% CI, 1.522 5.068; P=0.001) in urothelial carcinomas and with higher grades in endometrial adenocarcinomas (OR=3.88; 95% CI, 1.548-9.715; P=0.004). CD24 was more frequently and strongly expressed in breast (OR=35.80; 95% CI, 8.907-143.921; P<0.001) and ovarian carcinomas (OR=35.92; CI, 7.156-180.311; P<0.001), than in their benign counterparts. In conclusion, the meta-analysis strongly supports the idea that CD24 is an important marker of malignancy and poor prognosis in various cancers. In particular, CD24 may promote cancer development and progression in the breast, ovary and urinary bladder. PMID- 19787234 TI - Induction chemoradiotherapy followed by surgery for locally advanced non-small cell lung cancer. AB - We examined the efficacy and toxicity of a divided schedule of cisplatin and vinorelbine with concurrent radiotherapy followed by surgery in patients with locally advanced non-small cell lung cancer (NSCLC). Patients with clinical stage IIIA or IIIB NSCLC were eligible if they had a performance status of 0 or 1, were 75 years or younger, and had adequate organ function. Patients were treated with cisplatin (40 mg/m2) and vinorelbine (20 mg/m2) on days 1 and 8 every 3 weeks. Thoracic radiotherapy (2 Gy per fraction; total dose, 40 Gy) was given concurrently. Surgical resection was performed after induction therapy had been completed. If disease was considered clinically inoperable after induction therapy, patients received 2 additional cycles of the chemotherapy and 20 Gy of additional radiotherapy. Twenty-three patients (20 men and 3 women; median age, 63 years; age range, 45-72 years) were enrolled. The overall response rate was 78.3%. Although grade 3-4 toxicities included neutropenia in 95.7% of patients and anemia in 39.1%, no grade 3-4 radiation pneumonitis or esophagitis occurred. Thirteen patients (56.5%) underwent thoracotomy and complete resection. There were no treatment-related deaths. The median survival time was 36 months (range, 4-78 months), the 2-year survival rate was 74%, and the median time to disease progression was 15 months (range, 2-59 months). This trimodality therapy is effective and well tolerated and is an acceptable therapeutic option for patients with locally advanced NSCLC. PMID- 19787235 TI - Concurrent chemoradiotherapy for organ function preservation in advanced patients with hypopharyngeal and laryngeal cancer. AB - Preservation of the larynx is the most critical factor influencing quality of life in the treatment of head and neck cancer. This clinical study focuses on laryngeal function-preserving chemoradiotherapy for locally advanced hypopharyngeal and laryngeal cancer. Thirty-two resectable cases with histologically proven squamous cell carcinoma undergoing function-preserving therapy were examined. Induction chemotherapy comprised cisplatin and 5 fluorouracil, and another cycle of chemotherapy was performed for responders. Chemoradiotherapy comprised conventional irradiation and weekly chemotherapy (nedaplatin plus docetaxel). Non-responder patients were excluded from further chemotherapy and were changed to other surgical treatment. Three patients were non-responders for induction chemotherapy, and 29 patients were treated with chemoradiotherapy. Thus, 21 out of 29 patients obtained preserved laryngeal function. Initial larynx preservation rate with these treatment strategies was 93.8%. This study provides a new concept for laryngeal function-preserving treatment that should be considered for locally advanced laryngeal and hypopharyngeal cancer. PMID- 19787236 TI - Tumor necrosis factor-related apoptosis-inducing ligand induces apoptotic cell death through c-Jun NH2-terminal kinase activation in squamous cell carcinoma cells. AB - Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) induces apoptosis in MIT6 cells derived from primary oral squamous cell carcinoma (OSCC), whereas it does not induce apoptosis in MIL6 cells derived from metastases. The present studies were performed to examine whether activation of c-Jun NH2 terminal kinase (JNK) is implicated in the differential sensitivity to TRAIL induced apoptosis. The TRAIL-induced JNK activation in MIT6 cells was stronger than in MIL6 cells, as assessed by Western blotting using antibodies specific for phospho-JNK. To evaluate the role of JNK1 in TRAIL-induced cell death, one clone expressing the dominant-negative form of JNK1 (dnJNK1) was established. The dnJNK1-expressing cells and MIL6 cells expressed TRAIL protein at levels similar to or even greater than MIT6 cells did. When cell death was assessed by annexin V staining and mitochondrial membrane potential, kinetic studies demonstrated that the dnJNK1-expressing cells were substantially more resistant to 100 ng/ml TRAIL, comparable to MIL6 cells, at 36 and 48 h after stimulation. Collectively, the primary OSCC cell line, MIT6, is sensitive to TRAIL but its metastatic line MIL6 is resistant to TRAIL exposure. Thus, the underlying molecular mechanism of TRAIL induced cell death involves JNK activation. These results suggest that the acquisition of TRAIL resistance provides some metastatic capacity to primary tumors. PMID- 19787237 TI - Aberrant promoter hypermethylation of the CHFR gene in oral squamous cell carcinomas. AB - Recent studies have shown that promoter hypermethylation of tumor suppressor genes is an important factor in carcinogenesis of several human organs. The purpose of this study was to examine the methylation status of CHFR, a novel cell cycle regulatory gene, in both primary oral cancer tumors and the adjacent normal mucosa, and to clarify the relation between the methylation status and expression of the CHFR-related chromosomal passenger protein Aurora-A. The methylation status of the CHFR gene was examined by the methylation-specific PCR (MSP) in 49 primary oral squamous cell carcinomas (OSCC) and 6 OSCC cell lines. In 13 cases, the adjacent normal oral mucosal tissues were also examined. Normal oral mucosa from 18 healthy volunteers was used as the control. The mRNA level of Aurora-A and CHFR in OSCC cell lines was investigated by real-time RT PCR and the protein expression of Aurora-A in certain tumor samples was confirmed by immunohistochemistry. Aberrant promoter methylation of the CHFR gene was detected in 34.7% (17 of 49) of OSCC cases. As for the 13 OSCC cases with paired cancerous and adjacent normal tissues, promoter hypermethylation of the CHFR gene was detected in 46.1% (6 of 13) of the cancerous tissues. In contrast, promoter hypermethylation of the CHFR gene was recognized in only 7.7% (1 of 13) of the surrounding normal mucosa. No hypermethylation of the CHFR gene was detected in healthy volunteers. Only one OSCC cell line shows hypermethylation of the CHFR gene with concurrently silenced mRNA expression, however, Aurora-A was expressed abundantly in all cell lines. Furthermore, there is no significant relationship between methylation status of the CHFR gene and Aurora-A protein expression in OSCC. Hypermethylation of the CHFR gene was detected in a certain part of OSCC cases whereas it had very low frequency in adjacent normal oral tissues. Although further study is needed, Aurora-A gene expression seems to be independent from methylation status of the CHFR gene in OSCC. PMID- 19787238 TI - FOXP3 expression of micrometastasis-positive sentinel nodes in breast cancer patients. AB - A number of methods have been established for identifying sentinel nodes (SNs). In the present study, we attempted to clarify the immunological status of SNs with or without micrometastasis in breast cancer patients. SNs were identified by the dye- and gamma probe-guided method. Total RNA was extracted from the SNs, and the expression of T-BET, GATA-3, and FOXP3 were evaluated using quantitative real time reverse transcriptase-polymerase chain reaction (RT-PCR). Micrometastasis was identified as microscopically negative but positive by RT-PCR specific for mammaglobin. Of 88 patients, 17 (19.3%) showed positive metastasis in SNs (pN1, 14; pN2, 3). Of the 71 metastasis-negative SNs, 11 showed positive bands on RT PCR specific for mamma-globin [pN0(mol+)]. There was no significant correlation among clinicopathological features with or without micrometastasis. Immunological parameters were compared among the 60 pN0, 11 pN0(mol+), and 17 pN1-2. Although T BET expression was higher in pN0(mol+) than pN0, FOXP3 expression was also higher in pN0(mol+) than pN0. In pN1-2, T-BET expression decreased compared with pN0(mol+), but FOXP3 expression did not. On the other hand, GATA-3 expression inversely increased in pN1-2 compared with pN0(mol+). In patients with breast cancer, micrometastasis can stimulate Th1 response in SNs. However, the Treg cell response is also induced at the micrometastasis level and persists during the progression of metastasis in SNs. Then, the shift in the Th1/Th2 balance may preferentially lean toward Th2 responses in pN1-2 SNs and suppress antitumor immune responses. Micrometastasis [pN0(mol+)] is a status immunologically distinguishable from pN0 and pN1-2. PMID- 19787239 TI - Let-7a microRNA functions as a potential tumor suppressor in human laryngeal cancer. AB - MicroRNAs (miRNAs) are endogenously expressed non-coding RNAs, which are involved in the gene expression regulation. Lethal-7a (let-7a) is a founding member of miRNA family and recently it was found to be associated with several cancers, such as lung and colon cancers. In the present study, we found that let-7a miRNA expression was significantly downregulated both in human laryngeal squamous cancer tissues and in Hep-2 cells, a laryngeal cancer cell line, as compared with adjacent normal tissues and BEAS-2B cells, respectively. Moreover, we found that let-7a expression levels were significantly further decreased in non differentiated (G3) cancer tissues as compared with moderately and well differentiated cancer tissues (G2 and G1), although no significant difference in let-7a expression levels between the cancer specimens with different T stages or specimens from patients with different lymph node metastasis status was revealed. In Hep-2 cells, let-7a mimics transfection markedly suppressed proliferation and induced apoptosis of Hep-2 cells under the treatment of diamminedichloroplatinum or not and downregulated RAS and c-MYC protein expression without affecting the mRNA levels. In parallel, RAS and c-MYC protein levels were found significantly upregulated only in cancer tissues with downregulated let-7a expression. Thus, we propose that let-7a may be a tumor suppressor in laryngeal cancer by inhibiting cell growth, inducing cell apoptosis and downregulating the oncogenes expression. PMID- 19787240 TI - Enhancement of DNA cancer vaccine efficacy by combination with anti-angiogenesis in regression of established subcutaneous B16 melanoma. AB - Immunotherapy of cancer offers great promise, however translation into human studies has yielded relatively poor results to date. The concept of combining cancer vaccination with angiogenesis inhibition is appealing, due to favorable safety profile of both approaches, as well as possible biological synergies. Here we studied the anti-tumor effects of combining plasmid DNA (pDNA) vaccination and anti-angiogenesis in B16F10 murine model. By using electroporation-mediated gene/pDNA delivery, the anti-tumor efficacy of vaccination with pDNAs encoding gp100, TRP2 and Ii-PADRE was facilitated by administration of soluble form of EphB4 fused with human serum albumin (sEphB4-HSA), or by co-delivery of pDNAs encoding Angiostatin and/or Endostatin. In an optimized administration protocol, melanoma vaccination together with intratumoral delivery of pDNAs encoding Angiostatin and Endostatin resulted in 57% tumor-free survival over 90 days after challenge. These data support the general concept that suppression of angiogenesis may allow for enhanced efficacy of anti-tumor immunity, suggesting the synergetic effects of therapeutic pDNA vaccination and angiogenesis inhibition in cancer therapy. PMID- 19787241 TI - Intronic polymorphisms in TP53 indicate lymph node metastasis in breast cancer. AB - Recent studies have suggested that genetic polymorphisms in the TP53 pathway influence tumour formation, progression and response to therapy. We analysed the three most common TP53 gene polymorphisms as potential genetic markers to predict the development and prognosis of breast cancer. The incidence of R72P, PIN3 Ins 16bp and PIN6 G13494A polymorphisms was determined in a cohort of 117 breast cancer tissues and 108 control specimens by PCR-RFLP. No significant difference was observed in the polymorphism variants in breast cancer specimens compared to controls. Furthermore, no statistically significant association of these polymorphisms with the outcome of the patients was observed. On the other hand we found positive correlation of lymph node metastases with both PIN3 Ins 16bp and PIN6 G13494A polymorphisms. The association of intronic TP53 variants with an aggressive breast cancer phenotype may represent a useful predictive biomarker, particularly in patients of clinical stage I with low or intermediate risk. PMID- 19787242 TI - Co-expression of P1A35-43/beta2m fusion protein and co-stimulatory molecule CD80 elicits effective anti-tumor immunity in the P815 mouse mastocytoma tumor model. AB - A strong CTL response is dependent upon a high level of expression of specific class I major histocompatibility complex (MHC)/peptide complexes at the cell surface. An epitope-linked beta2-microglobulin (beta2m) molecule could provide a simple and more efficient means to enhance the formation of defined MHC/peptide complexes. However, the ability of an epitope-linked beta2m molecule to elicit primary CTL responses in vivo is still unknown. In this study, we modified the P1A tumor cell vaccine by addition of the tumor-associated epitope (TAE)-linked beta2m molecule and co-stimulatory molecule CD80 to improve the efficiency in the application of the vaccine. A eukaryotic co-expression vector consisting of the P1A35-43-linked beta2m molecule and the murine CD80 gene was constructed. P815 cell lines stably expressing P1A35-43-linked beta2m molecule and/or CD80 were established after transfection, by selection under G418. Administration of these inactivated tumor cell vaccines allowed the TAE-specific CD8+ T cell responses to be examined in vivo. Our results indicate that immunization with P815 cells expressing both the P1A35-43-linked beta2m molecule and the murine CD80 gene elicited a significantly stronger antitumor immune response than the single modified tumor cell vaccines (expressing either P1A35-43-linked beta2m or CD80 alone). These findings support the feasibility and effectiveness of developing a dual-modified tumor cell vaccine consisting of the epitope-linked beta2m molecule and a co-stimulatory molecule. PMID- 19787243 TI - Promoter histone H3 lysine 9 di-methylation is associated with DNA methylation and aberrant expression of p16 in gastric cancer cells. AB - In the course of gastric cancer development, gene silencing by DNA hypermethylation is an important mechanism. While DNA methylation often co-exists with histone modifications to regulate gene expression, the function of histone modifications in gene silencing in gastric cancer has not been evaluated in detail. p16, a well-known tumor suppressor gene, is frequently silenced in DNA hypermethylation manner in gastric cancer. Accordingly, we chose p16 to clarify whether there is a correlation among histone H3 lysine 9 (H3-K9) di-methylation, H3-K9 acetylation, DNA methylation and p16 expression in human gastric cancer. Three gastric cancer cells, MKN-45, SGC-7901 and BGC-823, were treated with 5-aza 2'-deoxycytidine (5-Aza-dC) and/or trichostatin A (TSA). We investigated p16 promoter DNA methylation status, p16 mRNA levels, regional and global levels of di-methyl-H3-K9 and acetyl-H3-K9 in four groups: i) 5-Aza-dC, ii) TSA, iii) the combination of 5-Aza-dC and TSA and iv) control group with no treatments. p16 silencing is characterized by DNA hypermethylation, H3-K9 hypoacetylation and H3 K9 hypermethylation at the promoter region. Treatment with TSA, increased H3-K9 acetylation at the hypermethylated promoter, but did not affect H3-K9 di methylation or p16 expression. By contrast, treatment with 5-Aza-dC, reduced H3 K9 di-methylation, increased H3-K9 acetylation at the hypermethylated promoter and reactivated the expression of p16. Combined treatment restored the expression of p16 synergistically. In addition, 5-Aza-dC and the combined treatment did not result in global alteration of H3-K9 di-methylation. These results suggest that H3-K9 di-methylation, H3-K9 acetylation and DNA methylation work in combination to silence p16 in gastric cancer. The decreased H3-K9 di-methylation correlates with DNA demethylation and reactivation of p16. H3-K9 di-methylation as well as DNA methylation related to p16 silencing is limited to the promoter region. In addition to its effect on DNA methylation, 5-Aza-dC can act at histone modification levels to reactivate p16 expression in region-specific and DNA methylation-dependent manner. PMID- 19787244 TI - A role of functional T-type Ca2+ channel in hepatocellular carcinoma cell proliferation. AB - The role of T-type Ca2+ channels in hepatocellular carcinoma cell proliferation was investigated in vitro. Eleven hepatocellular carcinoma cell lines and one immortalized liver cell line (LO2) were examined for the status of T-type Ca2+ channels with RT-PCR and voltage-clamp recordings. Except HBxF344, other cell lines tested had one, two or all three of alpha1-subunits (alpha1G, alpha1H and alpha1I) mRNA expression. Obvious T-type current was recorded in SNU449 cells, while others exhibited a minimal or no T-type current. SNU449, PLC/PRF5, Hep3B and LO2 cell lines were subjected to growth assay in the presence of Mibefradil, a T-type Ca2+ channel blocker, only the proliferation of SNU449 cell which had functional T-type Ca2+ channel was reduced by Mibefradil treatment. Furthermore, the persistent increase of phosphorylated ERK1/2 in SNU449 cells was found when treated with Mibefradil. A microarray assay also demonstrated some down-regulated genes were mainly associated with cell cycle and cell proliferation in Mibefradil treated SNU449 cells. In conclusion, this study showed that the functional T-type Ca2+ channels probably participate in modulating the proliferation of some hepatocellular carcinoma cells. The cell proliferation reduction of SNU449 with Mibefradil treatment is possibly associated with the persistent increase of phosphorylated ERK1/2. PMID- 19787245 TI - Cisplatin cytotoxicity is increased by mifepristone in cervical carcinoma: an in vitro and in vivo study. AB - We investigated the ability of mifepristone, an anti-progestin drug, to modulate the cytotoxic effect of cisplatin in two cervical cancer cell lines and in human xenograft cervical tumors. The effect of cisplatin alone or combined with mifepristone on cellular proliferation was studied with the XTT assay which use a tetrazolium dye {sodium3'-[1-(phenylamino-carbonyl)-3,4-tetrazolium],XTT}. Before and after treatment with mifepristone, the intracellular accumulation of cisplatin in cancer cells and tumors of mice was evaluated by HPLC. The expression of Bcl-2 and Bax genes was also assessed by a reverse transcriptase polymerase chain reaction (RT-PCR) and Western blotting. In addition, single agents and combination treatment in vivo studies were performed with the xenograft cervical model. Tumor measurements were carried out weekly. Analysis of the data by the isobologram method shows a synergistic antiproliferative effect produced by the combination of mifepristone with cisplatin only in the HeLa cervical cancer cell line but not in CaSki cells. The effect of mifepristone on cytotoxicity of cisplatin could be mediated, at least partially, by an increase of intracellular cisplatin accumulation, but not by changes in Bcl-2/Bax gene relation expression in these cells. In vivo studies showed that the combination of these agents has a significant antitumor activity against HeLa xenograft tumors. Our results suggest that mifepristone can improve the efficacy of the antiproliferative effect of cisplatin in vitro and in vivo. This anti-hormonal drug therapy may be a useful candidate for further evaluation in combination with other antineoplastic drugs in the treatment of cancer, particularly with cisplatin. PMID- 19787246 TI - Depletion of the proteasome subunit PSMA7 inhibits colorectal cancer cell tumorigenicity and migration. AB - Colorectal cancer is one of the most common causes of cancer-related deaths throughout the world. Recently, we reported that proteasome subunit PSMA7 located on 20q13 amplicon was overexpressed and associated with liver metastasis of colorectal cancer. The results indicate that PSMA7 may play an important role in the colorectal cancer progression and provide a unique target site for the development of therapeutic drugs. However, it is unknown how aberrant PSMA7 activation critically regulates the metastatic behavior of colorectal cancer cells. To investigate the role of PSMA7 in the progression of colorectal cancer, we employed the RNA interference technology to knock down the PSMA7 gene in human colon cancer cell line RKO and analyzed its effect and explored the involved mechanisms. Depletion of PSMA7 by shRNA in RKO cells inhibited their anchorage independent growth and cell invasion and migration. Moreover, PSMA7 depletion was able to strongly suppress the in vivo tumorigenic ability of RKO cells. These effects may be induced by inhibiting CD44 expression directly or indirectly. Genetic or pharmacological inhibition of PSMA7 may therefore be a beneficial strategy in the treatment of colorectal cancer patients. PMID- 19787247 TI - The characterization of blood flow changes in mouse tumor during Photofrin-based photodynamic therapy by using the color Doppler ultrasonography. AB - Changes in blood flow velocity through the tumors can induce damage of tumor microcirculation and thus may contribute to the final destruction of tumor masses after photodynamic therapy (PDT). The aim of this study was to evaluate the blood flow changes in a SCCVII mouse carcinoma during Photofrin-based photodynamic therapy by analyzing several quantitative spectral Doppler parameters [maximum systolic flow velocity (Vmax), end diastolic velocity (Vmin), resistance index (RI) and pulsatile index (PI)] by using the color Doppler ultrasonography. Blood flow velocities were recorded immediately prior to tumor illumination (0 h) and then 2 and 24 h after the illumination. Statistically significant increase in diastolic blood velocity (Vmin) with a corresponding decline in RI and PI was recorded in tumors of the Photofrin-injected mice prior to tumor illumination. However, 2 h after the illumination a pronounced decrease in both Vmin and Vmax was obtained. There were no changes of these parameters in controls at different times during determination. The observed changes of spectral Doppler parameters in tumors from the PDT group point to the transition of tumor blood vessels from the relaxation state recorded before tumor illumination into a state of increased contraction after the activation of Photofrin by light. Pronounced changes in tumor blood vessel tone might be an additional stress for such vessels leading to their ultimate destruction. PMID- 19787248 TI - Immunophenotyping of diffuse large B-cell lymphoma (DLBCL) defines multiple sub groups of germinal centre-like tumours displaying different survival characteristics. AB - Diffuse large B-cell lymphoma (DLBCL) forms a heterogeneous collection of aggressive non-Hodgkin's Lymphoma in which three principle classes of neoplasia have been defined according to gene expression and immunophenotyping studies. The present investigation sought to examine the immunophenotype of proposed subgroups and relate these to patient survival. A series of 155 DLBCL treated uniformly with anthracycline therapy in clinical trials, were stratified upon the basis of common biomarker expression with combination immunophenotype being related to patient overall survival. Stratification of tumours with respect to combined expression profiles of the three biological markers (CD10, Bcl-6 and MUM-1) revealed six groups showing significant differences in survival (p=0.014). The greatest difference resided between distinct populations of germinal centre (GC) cell tumours; the first being CD10-, Bcl-6+, MUM-1- and the second CD10+ Bcl-6+ MUM-1+ (p=0.002). The former group displayed median survival time of 143 months, the latter only 11 months. A third population of GC tumours (CD10+ Bcl-6+ and MUM 1-) also displayed a relative short median survival (32 months). Of the three groups presenting a non-GC or activated B cell (NGC/ABC) phenotype, only one (CD10-, Bcl-6+ and MUM-1+) presented short-term median survival (27 months) comparable with poor prognosis GC sub-populations. Within the remaining ABC tumour groups (CD10- Bcl-6- MUM-1- and CD10- Bcl-6- MUM-1+) patients presented intermediate median survival times of 54 and 58 months, respectively. Thus, the GC phenotype did not act as a universal indicator of good clinical prognosis, but rather multiple groups of GC tumours were associated with distinct overall survival profiles. Ultimately, the data allowed definition of a predictive algorithm defining three groups predicting poor, intermediate and good clinical prognosis. The first of these comprised two patient sub-populations with GC-like tumours together with one sub-population of NGC/ABC, the second two sub populations of ABC-like tumours, and the final a single group of GC-like tumours associated with optimal long-term survival. PMID- 19787249 TI - Screening for genetic abnormalities involved in ovarian carcinogenesis using retroviral expression libraries. AB - The purpose of this study was to screen for genes involved in ovarian carcinogenesis in an attempt to develop an effective molecular-targeted therapy for ovarian cancer. We constructed retroviral expression libraries for the human ovarian cancer cell lines SHIN-3 and TYK-CPr, and performed a focus formation assay with 3T3 cells. As a result, proteasome subunit beta-type 2 (PSMB2), ubiquitin-specific protease 14 (USP14), and keratin 8 (KRT8) were identified from SHIN-3, and polymerase II RNA subunit (POLR2E), chaperonin containing T-complex polypeptide 1 subunit 4 (CCT4), glia maturation factor beta (GMFB), and neuroblastoma ras viral oncogene homolog (NRAS) from TYK-CPr. NRAS gene analysis revealed a CAA --> AAA substitution at codon 61, resulting in a Glu --> Lys change at position 61. When the mutant NRAS was introduced into fibroblasts for its expression, many transformed foci were generated, confirming the transforming ability of the mutant NRAS. PMID- 19787250 TI - Analysis of candidate target genes for mononucleotide repeat mutation in microsatellite instability-high (MSI-H) endometrial cancer. AB - Microsatellite instability (MSI) is an indicator of DNA instability and is caused by abnormalities in DNA mismatch repair (MMR) genes such as hMLH1, hMSH2 and hMSH6. MSI occurs frequently in endometrial cancer (in approximately 30% of cases), and accumulation of gene mutations due to MSI may therefore have a major role in the mechanism of malignant transformation. However, a responsible target gene has not been identified in endometrial cancer. In this study, we analyzed mutations in 11 cancer-related genes with mononucleotide repeats susceptible to MSI in a coding region [hMSH3 (A8), hMSH6 (C8), TGF-beta RII (A10), MBD4 (A10), BAX (G8), PTEN (A6 in exon 7), HDAC2 (A9), EPHB2 (A9), Caspase-5 (A10), TCF-4 (A9) and Axin2 (G7)] in 22 patients with MSI-H sporadic endometrial cancer. Mutations in hMSH6 (C8) and TGF-beta RII (A10) were found most frequently, at rates of 36.3% (8/22) each. Mutations of BAX (G8) and TCF-4 (A9), which are common in MSI-positive colorectal cancer, occurred at rates of 22.7 and 0%, respectively, which suggests that the MSI target gene may differ between endometrial and colorectal cancers. Mutations in hMSH6 (C8) were correlated with reduced protein expression (p=0.042) and patients with these mutations had significantly more mutations in mononucleotide repeats in other cancer-related genes compared to patients without hMSH6 (C8) mutations (p=0.042). This suggests the possibility of a novel cascade in carcinogenesis of endometrial cancer in which MSI mutates hMSH6 (C8), increases gene instability, and leads to accumulation of mutations in other cancer-related genes. To our knowledge, this is the first report to show that hMSH6 (C8) has an important role as an MSI target gene in sporadic endometrial cancer. PMID- 19787251 TI - Does the expression of HPV16/18 E6/E7 in head and neck squamous cell carcinomas relate to their clinicopathological characteristics? AB - Human papilloma virus (HPV) has been recently proposed to be implicated in the development of head and neck squamous cell carcinoma (HNSCC) in patients without cancer risk. We examined the expression of HPV16/18 E6/E7 in 71 cases of HNSCCs and investigated abnormalities of the p53 gene in 62 of these 71 cases. Expression of HPV16 E6/E7 was observed in 11 of the 71 cases (15.5%), while expression of HPV18 E6/E7 was not observed in any of the cases. Most of the HPV16 E6/E7-positive cases were histopathologically characterized by their verrucous or papillary structure and koilocytosis of the adjacent mucosa. There was no clear relationship between expression of HPV16 E6/E7 and tumor stage, prognosis or the positive rate of p53 abnormality. These results suggest that approximately 15% of HNSCCs are caused by HPV16 infection and the subsequent constitutive expression of E6 and E7, and that some HPV-initiated tumors lose their original characteristics during tumor progression. PMID- 19787252 TI - Regulation of protein tyrosine kinases in tumour cells by the transcription factor Ets-1. AB - Tyrosine phosphorylation is one of the key covalent modifications that occurs in multicellular organisms as a result of intercellular communication. The family of tyrosine kinases (PTKs) are responsible for part of the cellular phosphorylation and are involved in a broad variety of cellular functions including differentiation, proliferation, migration, invasion, angiogenesis and survival under physiological as well as pathological conditions. Aberration in PTK signalling occurs in inflammatory diseases and diabetes, and aberrant expression can lead to benign proliferative conditions as well as to various forms of cancer. Indeed, more than 70% of the known oncogenes and proto-oncogenes involved in cancer code for PTKs. Therefore, these enzymes are now used as targets in the treatment of different tumours. Ets-1 is a transcription factor expressed in a number of human malignancies with demonstrated roles within both neoplastic cells and tumour stroma. These roles include stimulation of tumour cell proliferation and invasion as well as tumour angiogenesis. Database searches have revealed that ETS binding sites are present in several promoters of PTK-encoding genes. We investigated the role of Ets-1 in transcriptional regulation of a panel of 89 PTKs in epithelial HeLa tumour cells. In this study, HeLa cells stably overexpressing and underexpressing Ets-1 were used for real-time PCR analysis of all known human PTKs. The results suggest that Ets-1 is an essential transcription factor that cannot be substituted by other members of the ETS family. Transcription of most PTKs was found to be increased by Ets-1. In contrast Ets-1 seems to act as a transcriptional repressor of other PTKs. The data presented here underscore the importance of Ets-1 in tumour development and progression. PMID- 19787253 TI - Epigenetic regulation of the embryonic oncogene ERas in gastric cancer cells. AB - ERas is a recently identified oncogene that supports the tumorigenic growth of embryonic stem cells, it is constitutively active in the absence of mutation. ERas oncogene is expressed only in viviparity phase cells, but not in somatic cells because of epigenetic transcriptional silencing in the somatic phase. The aim of this study was to clarify the ERas expression and its epigenetic regulation in gastric cancer of somatic phase. Fifteen gastric cancer cell lines were used. ERas mRNA expression and its epigenetic regulation were examined by reverse transcription-polymerase chain reaction and bisulfite sequencing analysis. To identify a subset of cancer stem cells, termed 'side population' (SP) cells, flow cytometry analysis was performed. ERas is expressed in 8 of the 15 gastric cancer cell lines, but is silenced in the remaining 7 cancer cell lines and normal cell lines. Six of 7 cancer cell lines without ERas expression had promoter methylation, which correlated with silencing of ERas expression. ERas expression is re-activated following treatment with the DNA methyltransferase inhibitor 5-aza-CdR. The percentage of SP fraction of ERas positive gastric cancer cells was significantly (p=0.024) higher (3.4+/-1.8%), in comparison to that of ERas-negative cells (1.6+/-0.4%). These findings suggested that the activating ERas oncogene might be associated with tumorigenic growth of somatic cells, and might be a putative molecule responsible for cancer stem cell like characteristics in gastric cancer. Loss of methylation in the promoter of ERas might be one of mechanisms responsible for the re-expression of an embryonic oncogene in gastric cancer. PMID- 19787254 TI - Cytoskeletal changes during epithelial-to-fibroblastoid conversion as a crucial mechanism of des-gamma-carboxy prothrombin production in hepatocellular carcinoma. AB - Des-gamma-carboxy prothrombin (DCP) is a well-established tumor marker for hepatocellular carcinoma (HCC), but the precise mechanism by which HCC cells produce DCP remains unknown. Our preliminary experiments demonstrated that HepG2 cells with chemical induction of epithelial-to-fibroblastoid conversion (EFC) produced DCP through impairment of vitamin K uptake via cytoskeletal rearrangement. Therefore, in this study we further examined this mechanism in vitro and using human HCC samples. Hepatoma cell lines (HepG2 and PLC/PRF/5) were induced EFC or epithelial-mesenchymal transition (EMT) by phorbol 12-myristate 13 acetate (TPA) or transforming growth factor (TGF)-beta1. We analyzed these cells by ELISA, Western blotting and immunofluorescent studies. We also examined DCP production and E-cadherin expression in human surgically resected HCC samples by immunohistochemical studies. Labeled low-density lipoprotein (LDL) uptake (as a surrogate for vitamin K) was significantly impaired in DCP-producing hepatoma cells following induction of EFC or EMT. Further, filamentous actin, which plays a critical role in clathrin-mediated endocytosis, was dissociated in DCP producing cells. Latrunculin A, an actin depolymerizer, induced naive hepatoma cells to produce DCP with impairment of labeled-LDL uptake. In addition, an E cadherin neutralizing antibody did not induce DCP production. Finally, immunohistochemical studies demonstrated that DCP production was inversely correlated with the intensity of E-cadherin expression in human HCC cells. In conclusion, cytoskeletal changes during EFC or EMT plays a critical mechanistic role in DCP production via impairments in vitamin K uptake. PMID- 19787255 TI - PRIMA-1 inhibits growth of breast cancer cells by re-activating mutant p53 protein. AB - Mutation of the p53 tumor suppressor gene is a common event in many types of tumors, including breast cancers. Mutant p53 (mtp53) protein is thought to promote tumor cell survival and resistance to chemotherapeutic drugs. Therefore, restoring p53 function by converting existing mtp53 to the wild-type p53 (wtp53) conformation is being pursued as one strategy to promote apoptosis of tumor cells. PRIMA-1 (p53 re-activation and induction of massive apoptosis) is a non toxic small molecule that converts mtp53 to the active conformation and induces apoptosis in tumor cells. Here we examined whether PRIMA-1 activates mtp53 and induces cell death in vitro and in vivo in estrogen-responsive breast cancer cell lines that express mtp53 (BT-474, HCC-1428, and T47-D). Fluorescent staining with conformation-specific p53 antibodies demonstrated that PRIMA-1 converted mtp53 into the wtp53 conformation. In vitro treatment of tumor cells with PRIMA-1 (0-50 microM) led to a dose-dependent loss of cell viability and induced cell death markers. In contrast, PRIMA-1 had no effect on the viability of MCF-7 cells, normal breast cells, and endothelial cells, all of which express wtp53 protein. PRIMA-1 treatment of mice inhibited the growth of tumors from xenografts of BT 474, HCC-1428, and T47-D cells but did not influence xenografts obtained from MCF 7 cells. Mechanistic studies showed that PRIMA-1 induced the mitochondrial dependent apoptotic pathway in mtp53-expressing breast cancer cells. Our findings suggest that PRIMA-1 renews the susceptibility of mtp53-expressing breast tumors to apoptosis and should be investigated for use in breast cancer therapy. PMID- 19787256 TI - Cepharanthine inhibits angiogenesis and tumorigenicity of human oral squamous cell carcinoma cells by suppressing expression of vascular endothelial growth factor and interleukin-8. AB - Cepharanthine is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata, which is widely used for the treatment of many acute and chronic diseases, and can exert antitumor effects on several human cancer cell lines. However, little is known about the detailed mechanisms of the antitumor activity of Cepharanthine. In the present study, we determined whether Cepharanthine could suppress angiogenesis and growth of human oral squamous cell carcinoma (OSCC) cells in vitro and in vivo. Cepharanthine significantly inhibited expression of two major pro-angiogenic molecules, vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8), in cultured cells and in cells implanted into the subcutaneous tissue of nude mice. Also, Cepharanthine inhibited the nuclear factor-kappaB (NF-kappaB) activity in human OSCC cells in vitro and in vivo. The decreased expression of VEGF and IL-8 correlated with decreased tumor cell growth and decreased vascularization in vitro and in vivo. These findings suggest that Cepharanthine can suppress angiogenesis and growth of OSCC cells by inhibiting expression of VEGF and IL-8 involved in the blockade of NF-kappaB activity. PMID- 19787257 TI - Synergistic effects of lovastatin and celecoxib on caveolin-1 and its down-stream signaling molecules: Implications for colon cancer prevention. AB - Progression of colon cancer is associated with the up-regulation of cyclooxygenase-2 (COX-2) and hydroxymethyl glutaryl CoA reductase (HMG-R). Clinical and preclinical evidence shows that a combination of COX-2 and HMG-R inhibitors provide additive/synergistic chemopreventive effects against colorectal cancer. However, the mechanism by which statins and NSAIDs inhibit cancer growth is not yet fully understood. We aimed to identify critical molecules and signal pathways modulated by a combination of lovastatin and celecoxib in the human HCT-116 colon cancer cell line. HCT-116 cells were exposed to 50 microM celecoxib, 25 microM lovastatin or a combination of both to assess their effect in modulating caveolin-1 expression and its down-stream signaling pathways. Our results suggest that a combination of lovastatin and/or celecoxib suppressed caveolin-1 expression and membrane localization profoundly when compared to either agent alone. Lovastatin and/or celecoxib also inhibited caveolin-1-dependent cell survival signals mediated through Akt activation as well as its down-stream effectors such as phosphorylated ERK and STAT3 in HCT-116 cells. Treatment with lovastatin or celecoxib decreased the levels of cyclin D1, CDK2, pRb and E2F1, while the combination treatment showed more pronounced suppression. In addition, lovastatin and celecoxib also decreased the amount of cholesterol rich cytoplasmic lipid bodies (storehouses of esteridied arachidonates) by 80%, while the combination showed a complete inhibition. Overall, our data suggest that a combination of COX-2 and HMG-R inhibitors synergistically inhibits caveolin-1 and its associated signaling pathways. PMID- 19787258 TI - Impaired medulloblastoma cell survival following activation of the FOXO1 transcription factor. AB - Medulloblastoma is the most frequent type of childhood brain tumour. The insulin like growth factor I receptor (IGF-IR) plays a significant neuroprotective role in medulloblastoma survival through regulation of the downstream effectors of the phosphoinositide-3-kinase-protein kinase-B (PI3K-PKB/c-Akt) pathway. One such target is Forkhead box O1 (FOXO1; FKHR), which is part of the FOXO family of Forkhead transcription factors. Phosphorylation by Akt results in cytoplasmic sequestration of FOXO1 thus inhibiting the expression of genes controlling cell death, cell proliferation, differentiation, cellular metabolism and oxidative stress. Here we show that serum starvation of medulloblastoma cells is accompanied by nuclear translocation of FOXO1. IGF-I stimulation of serum-starved cells resulted in rapid phosphorylation of Akt and FOXO1, and was associated with a significant increase in cell viability. In contrast, expression of a constitutively active form of FOXO1 that cannot be phosphorylated led to a significant reduction in medulloblastoma cell viability, even in the presence of growth factors provided by fetal bovine serum (FBS). These data suggest that the transcription factor FOXO1 may be a critical effector of medulloblastoma growth suppression. PMID- 19787259 TI - Expression of mRNA for human type-I LHRH receptor transcript forms in human benign prostatic hyperplasia. AB - The presence of four different isoforms of luteinizing hormone-releasing hormones (LHRH) and one LHRH receptor (LHRH-R) has been reported in vertebrates. In the human genome only LHRH-I and LHRH-II genes have been identified. The human LHRH-I gene is composed of four exons separated by three introns. Three LHRH receptor or receptor-like genes have been demonstrated. The well-established type-I LHRH receptor (LHRH-R-I) gene is composed of three exons separated by two introns. In this study we investigated the expression of transcript forms of LHRH-R-I in human benign prostatic hyperplasia (BPH) with reverse transcriptase-polymerase chain reaction (RT-PCR) using gene specific primers. Thirty-five human BPH specimens were obtained at surgery. Normal human pituitaries collected at autopsy served as control. RNA extraction and RT-PCR with gene-specific primers for LHRH R-I forward (F1)/reverse (R1), LHRH-R-I F2/R3, LHRH-R-I F1'/R2' were carried out to determine the mRNA expression for LHRH-R-I transcript forms. The expected PCR products amplified with gene specific primers were LHRH-R-I F1/R1 with 319 bp, LHRH-R-I F2/R3 with 309 bp and LHRH-R-I F1'/R2' with 219 bp. PCR products for LHRH-R-I F1/R1 were detected in 21 (60%) and for LHRH-R-I F2/R3 in 5 of 35 (14%) BPH samples. No PCR products for LHRH-R-I F1'/R2' were found. In conclusion, we detected mRNA for LHRH-R-I in human BPH specimens. Our results suggest that LHRH R-I gene may have more than two splice variants or uncharacterised transcript forms of LHRH-R-I. Our findings support the merit of further investigation of the expression of LHRH-R-I and its transcript forms in human BPH. PMID- 19787260 TI - Organophosphorous pesticides and estrogen induce transformation of breast cells affecting p53 and c-Ha-ras genes. AB - Cancer progression has been associated with an increase in genomic instability indicated by inactivation of tumor suppressor genes and activation of oncogenes. Epidemiological and experimental evidence has implicated estrogens in the etiology of breast cancer. To study environmental organophosphorous pesticides is of interest since evidence indicate that pesticides may enhance cell division, increasing the risk of breast cancer. The aim was to evaluate the effects of these pesticides, such as parathion and malathion in the presence of estrogen on malignant transformation as well as on genomic instability, that is in the frequency of loss of heterozygosity (LOH) and microsatellite instability (MSI). The MCF-10F immortalized human breast epithelial cell line, that was treated with parathion or malathion alone and in combination with estrogen was used. These studies indicated that either pesticide alone or in combination with estrogen induced malignant transformation as shown by anchorage-independent growth capability and invasive characteristics in comparison to control. Such malignant phenotypic characteristics were corroborated by significant (P<0.05) increase in p53 and c-Ha-ras protein expression. Results indicated different degrees of allelic imbalance in the form of LOH or MSI with different microsatellite markers. MSI was found in malathion and estrogen-treated cells with a marker used for p53 tumor suppressor gene at loci 17p13.1. The same combination of substances presented MSI with a marker used for c-Ha-ras mapped in chromosome 11p14.1, as well as mutations in c-Ha-ras for codons 12 and 61. LOH was observed in codon 12 in the presence of estrogen or malathion alone. Parathion alone and combined with estrogen induced MSI in codon 61. It can be concluded that the organophosphorous pesticides parathion and malathion induced malignant transformation of breast cells through genomic instability altering p53 and c-Ha-ras, considered pivotal to cancer process. PMID- 19787261 TI - Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE1/Ref-1) in human ovarian cancer and indentification of the therapeutic potential of APE1/Ref-1 inhibitor. AB - Resistance to platinum is a major limitation for the treatment of ovarian cancer. In an effort to overcome the platinum resistance problem in ovarian cancer treatment, we explored the correlation between cisplatin resistance and the human AP endonuclease (APE1 or Ref-1). APE1/Ref-1 is a multifunctional protein that is not only an essential enzyme in base excision repair pathway, but also acts as a major redox-signaling factor that has a wide variety of important cellular functions including transcription factor regulation, oxidative signaling and cell cycle control. In this study, we examined APE1/Ref-1 expression by immunohistochemistry in sections of ovarian cancers from 78 patients who were administered standard adjuvant chemotherapy based on platinum post-operatively. Altered levels and subcellular APE1/Ref-1 expression was found in patients not responding to platinum-based chemotherapy comparing with those who responded to platinum-based chemotherapy. Meanwhile, we detected the APE1/Ref-1 expression in A2780 and CP70 cell lines which have different sensitivity to cisplatin. We found similar altered APE1/Ref-1 expression in them. We hypothesized that the APE1/Ref 1 expression is responsible in part for the cisplatin resistance. To answer this hypothesis, we decreased the APE1/Ref-1 level by silencing RNA targeting technology in A2780 and CP70 cell lines. The A2780 cells treated with APE1-siRNA had IC50 values ranging from 6.70 to 1.74 microM cisplatin compared with 15.81 microM for control A2780 cells. The CP70 cells treated with APE1-siRNA had 1.62 4.63-fold enhancement in cisplatin sensitivity. The apoptosis assays using TUNEL analysis showed that decreased APE1/Ref-1 level resulted in increased apoptosis levels in A2780 and CP70 cell lines compared with the control-treated cells. These data suggest that APE1/Ref-1 levels play an important role in the sensitization of ovarian cancer cells to apoptosis. In vitro studies revealed that it is possible to substantially enhance the cisplatin cytotoxicity by decreasing APE1/Ref-1 level in cisplatin-resistant cell lines. PMID- 19787262 TI - Varying etiologies lead to different molecular changes in Australian and South African hepatocellular carcinomas. AB - There is significant regional variation in the etiologic agents responsible for hepatocellular carcinoma (HCC), which influences the genetic and epigenetic mechanisms of malignant transformation. The aim of the present study was to investigate the prevalence of allelic imbalance (AI) and CpG island methylation in HCCs from Australia and South Africa. Genomic DNA was extracted from malignant and non-malignant liver from 37 Australian and 24 South African HCCs and histologically normal liver from 20 transplant donors. AI was examined at 1p, 4p, 4q, 8p, 9p, 13q, 16q and 17p, using 23 microsatellite markers. Methylation status of p14, p16, p15, RIZ1, E-cadherin and O6-MGMT was examined using methylation specific PCR, while MINTs 1, 2, 12, 25 and 31 were assessed using combined bisulfite restriction analysis. The highest prevalence of AI was observed at 9p (69%) and 17p (52%). AI was significantly higher in South African HCCs (p<0.05). The prevalence of promoter methylation of the six genes was significantly higher in Australian cases in both malignant and non-malignant liver tissue (p<0.05). MINT assays revealed an increasing degree of CpG island methylation in the progression of hepatocarcinogenesis which was significant for MINTs 1, 12 and 31 (p<0.05). MINT methylation was more prominent in Australian HCCs. These data indicate that methylation is an early event preceding malignant transformation. Methylation was more and AI less prevalent in Australian than South African HCCs. These data suggest that there are different mechanisms of malignant transformation in HCCs from Australia and South Africa. PMID- 19787263 TI - Efficacy and mechanism of anti-tumor action of new potential CK2 inhibitors toward glioblastoma cells. AB - Malignant gliomas are highly resistant to current therapeutic approaches due to genetic alterations rendering them resistant to cell death. CK2, a ubiquitous and constitutively active serine/threonine kinase, frequently elevated in tumors, contributes to enhanced cell proliferation and resistance to apoptosis. Inhibition of CK2 expression or treatment with inhibitors of CK2 affected survival or induced apoptosis in various cancer cells. Here we compared cytotoxic effects of well-known and new CK2 inhibitors: 4,5,6,7-tetrabromo-1H-benzotriazole (TBB), 4,5,6,7-tetrabromo-1H-benzimidazole (TBI), 2-dimethylamino-4,5,6,7 tetrabromo-1H-benzimidazole (DMAT), the related 3-(4,5,6,7-tetrabromo-1H benzimidazol-1-yl)propan-1-ol (MB001), 3-(4,5,6,7-tetrabromo-1H-1,2,3 benzotriazol-1-yl) propan-1-ol (MB002), 3-(4,5,6,7-tetrabromo-2H-1,2,3 benzotriazol-2-yl)propan-1-ol (MB003) and also structurally similar to above compounds pentabromobenzylisothiourea (ZKK1) and its derivatives (ZKK2-8) on cultured malignant glioma cells. TBI, ZKK1 and MB001-3 were more effective than TBB in inducing growth arrest and cell death in glioma cells. TBI and ZKK1 strongly induced apoptotic death involving caspase 3 and 7 activation followed by PARP cleavage. DMAT strongly upregulated the expression of cytotoxic ligand and its receptor Fas. Structural modifications of ZKK1 largely affected its efficacy: exchange of Br- to Cl- or F-substituents on the pentabromophenyl ring and inclusion of the bulky N-phenyl substituent in thiourea fragment of ZKK1 diminished cytotoxic activity, while N-substitution with short alkyl groups or an allyl group had opposite effects. Interestingly, TBI at moderate dose did not affect viability of non-transformed astrocytes, suggesting some specificity toward tumor cells in cytotoxic action. TBI, DMAT and ZKK1-induced apoptosis associated with caspase cascade activation in human malignant glioblastoma cells with mutated PT53 and PTEN genes. The reported data demonstrate that suitably modified polybromobenzene molecules exhibit a significant cytotoxic potential towards malignant glioblastoma cells. PMID- 19787264 TI - BRD8 is a potential chemosensitizing target for spindle poisons in colorectal cancer therapy. AB - Survival rate of metastatic colorectal cancers is less than 5%. A major reason is that those cancers respond poorly to chemotherapy drugs. However, factors contributing to chemoresistance in colorectal cancers are barely known, thus isolation of factors involved is the critical first step for mechanistic understanding and therapy improvement. With expression cloning, we isolated human BRD8 (bromodomain 8) as an influential factor for spindle poison sensitivity. BRD8 is an accessory subunit of human NuA4-HAT (histone acetyl transferase) complex (also known as TRRAP/TIP60 complex), but its role in cancer and drug resistance is unknown. Here, we report that BRD8 is involved in cellular survival and in sensitivity to spindle poisons and proteasome inhibitor in aggressive colorectal cancers. BRD8 protein expression level is several-fold higher in human metastatic colorectal cancer cell lines (DLD-1, HCA-7 and HCT-116) than in other cell lines tested. Normal-appearing rat colonic mucosa and azoxymethane (AOM) induced colorectal adenocarcinoma tissue expressed a barely detectable amount of BRD8 protein, but aggressive colon tumors induced with AOM and dextran sodium sulfate expressed BRD8 at a significantly higher level, suggesting that BRD8 expression is associated with tumor progression toward advanced stages and may aid to gain growth advantage. Supporting the notion, siRNA-mediated knockdown of BRD8 induced cell death or growth delay in colorectal cancer cell lines, and surviving BRD8-knockdown cells were particularly sensitive to spindle poisons and a proteasome inhibitor MG132. Conversely, at least one isoform of BRD8 gave growth advantage and resistance to taxol when stably overexpressed in HeLa cells. Targeting BRD8 would improve therapy outcome against aggressive/metastatic colorectal cancers. PMID- 19787265 TI - The microtubule-associated protein MAPRE2 is involved in perineural invasion of pancreatic cancer cells. AB - Perineural invasion of tumor cells is a characteristic feature of human pancreatic cancer. Unrevealing the molecular mechanisms that enable cancer cells to invade and grow along nerves is important for the development of novel therapeutic strategies in this disease. We have previously identified transcriptional changes in highly nerve invasive pancreatic cancer cells. Here we further analyzed one of the identified deregulated genes, MAPRE2, a microtubule associated protein. MAPRE2 expression was significantly increased in high versus less nerve invasive pancreatic cancer cells, and changes of MAPRE2 expression resulted in altered actin distribution in these cells. MAPRE2 was predominately expressed in normal pancreatic acinar cells but absent in ductal cells. In pancreatic cancer, there was strong cytoplasmic and occasionally nuclear expression of MAPRE2 in the cancer cells themselves. Increased MAPRE2 mRNA levels in bulk pancreatic cancer tissues tended to be associated with reduced postoperative survival of pancreatic cancer patients. In conclusion, MAPRE2 is highly expressed in pancreatic cancer cells, and seems to be involved in perineural invasion. Therefore, targeting this microtubule-associated protein might be a promising approach in the therapy of pancreatic cancer. PMID- 19787266 TI - Phosphoglucose isomerase enhances colorectal cancer metastasis. AB - Phosphoglucose isomerase (PGI) is a ubiquitous cytosolic enzyme that plays a key role in glycolysis. PGI is also a multifunctional protein that acts in the extracellular milieu as a potent mitogen/cytokine. Increased expression of PGI and its receptor has been found in a wide spectrum of malignancies and is associated with cancer progression and metastasis. In this study, the role of PGI in the growth and metastasis of colon cancer cells was determined. To elucidate the functional role of PGI in colorectal cancer, we stably transfected PGI cDNA into human colon cancer cells. We used an orthotopic mouse tumor model to assess whether overexpression of PGI enhances liver metastasis. Overexpression of PGI stimulated the in vitro invasion of DLD-1 cells. In vivo, after orthotopic implantation into the cecum of nude mice, parental and empty vector-transfected DLD-1 cells produced small tumors without liver metastasis, whereas PGI overexpressing DLD-1 cells produced large tumors and liver metastases. In conclusion, overexpression of PGI significantly contributes to the aggressive phenotype of human colon cancer and, thus, may provide a novel therapeutic target. PMID- 19787267 TI - The 10q25.3-26.1 G protein-coupled receptor gene GPR26 is epigenetically silenced in human gliomas. AB - Loss of heterozygosity (LOH) of the entire chromosome 10 is the most frequent genetic alteration in human glioblastoma (GBM). In addition to PTEN/MMAC1 on 10q23.3, clustering of partial deletion break-points on 10q25.3-26.1 points to a second suppressor locus. The proposed target gene DMBT1 was not confirmed. By somatic deletion mapping of this region, we identified the complementary DNA encoding the human homologue of rat orphan G protein-coupled receptor GPR26. GPR26 is highly expressed in fetal and adult brain, but frequently reduced or absent in glioma cells and biopsies, due to de novo methylation of its 5' CpG island. Silencing of GPR26 was reversed with 5-aza-deoxycytidine and the histone deacetylase inhibitor trichostatin A. Furthermore, overexpression of GPR26 in HEK and in U87 glioma cells increased intracellular cAMP concentration which is considered to induce astrocytic differentiation. Interestingly, we observed concomitant silencing of GPR26 with O6-methylguanine-DNA methyl transferase (MGMT), a DNA repair gene co-localized on 10q25.3-26.1 (p=0.0001). We conclude that epigenetic silencing is a common mechanism in malignant gliomas that simultaneously inactivates MGMT and GPR26. The 10q25.3-26.1 region may contain an important epigenetic pathway in brain tumorigenesis. PMID- 19787268 TI - Epigenetic modulation of PTEN expression during antiandrogenic therapies in human prostate cancer. AB - Although the tumor-suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) is frequently mutated or deleted in a wide variety of solid tumors, some malignancies, including prostate cancer, exhibit undetectable PTEN protein without loss of PTEN gene. Aim of this study was to evaluate whether the PTEN downmodulation, observed during bicalutamide treatment, was due to epigentic events. We analyzed the expression of PTEN in presence or absence of azacitidine or valproic acid in a panel of 50 primary cultures derived from naive (UNT, 23 ptz) and bicalutamide-based neoadjuvant hormone therapy-treated patients (NHT, 27 pts). Results showed that Western blot and PCR analyses showed that 54 and 68% of primary cultures displayed detectable amounts of PTEN protein and mRNA, respectively. Treatment with azacitidine increased the percentage of PTEN positive cultures up to 72 and 80% for PTEN protein and mRNA determination, respectively. Treatment with valproic acid was able to increase the percentage of PTEN-positive cultures up to 80 and 74% for PTEN protein and mRNA determination, respectively. The percentage of cultures with undetectable levels of PTEN protein was significatively higher in cultures derived NHT patients respect to cultures derived from UNT men (P=0.020). Valproic acid reduced significantly the percentage of cultures PTEN-negative only at protein level and only in NHT (P=0.029) group. In conclusion, our data suggests that antiandrogenic therapy reduced PTEN expression by epigenetic mechanisms suggesting that epigenetic drugs, upmodulating PTEN expression, can reduce Akt activity and probably enhance the efficacy of antiandrogenic therapy. PMID- 19787269 TI - The involvement of HER2 and p53 status in the regulation of telomerase in irradiated breast cancer cells. AB - Cancer cell characteristics may play a pivotal role in the response to therapy by activating or deactivating different molecular pathways. In the present study, we investigated the implication of breast cancer cell features, such as HER2 and p53 in the activation of telomerase upon exposure to ionizing radiation. Telomerase is among the most important cancer biomarkers, conferring to tumor cells unlimited proliferative capacity, increased survival potential and resistance to several types of cellular stress. We investigated possible mechanisms regulating telomerase in six irradiated breast cancer cell lines (MCF-7, MCF-7/HER2, MDA-MB 231, SK-BR-3, BT-474 and HBL-100) differing in their HER2, p53 and ERalpha status. hTERT mRNA expression was evaluated by real-time PCR and telomerase activity by the TRAP assay. HER2, c-myc, p53 and p21 protein levels were evaluated by Western blotting. Silencing of hTERT and HER2 was achieved by small interfering RNA technology. Chromatin immunoprecipitation was used to evaluate H3 histone acetylation status, as well as myc/mad/max and p53 transcription factors interaction with the hTERT promoter. Our results showed for the first time, that only HER2-positive cells, independently of their p53 status, upregulated hTERT/telomerase, while knockdown of hTERT increased radio-sensitivity. Knockdown of HER2 also led to increased radio-sensitivity and downregulation of hTERT/telomerase. We also demonstrated that c-myc and mad1 regulate hTERT expression in all irradiated breast cancer cells. We conclude, for the first time, that HER2 phenotype upregulates hTERT through c-myc activation and confers radio-resistance to breast cancer cells. PMID- 19787270 TI - Selectivity analysis of protein kinase CK2 inhibitors DMAT, TBB and resorufin in cisplatin-induced stress responses. AB - Targeting protein kinases as a therapeutic approach to treat various diseases, especially cancer is currently a fast growing business. Although many inhibitors are available, exhibiting remarkable potency, the major challenge is their selectivity. Here we show that the protein kinase CK2 inhibitors DMAT, TBB and resorufin differ in their selectivity against PI3K family members, since PI3K and DNA-PK are subject to inhibition by DMAT and TBB, however, not by resorufin. TBB and DMAT treatment together with cisplatin lead to an inhibition of cisplatin induced stress signaling (as detected by phosphorylation of JNK and H2AX). In the case of resorufin no interference with the stress-signaling pathway is observed, supporting the notion that TBB and DMAT interfere with upstream molecules involved in genotoxic stress signaling. We have also tested the protein kinase CK2 inhibitors with respect to cell viability and inhibition of endogenous CK2 activity in the absence and presence of the anti-cancer drug cisplatin. The strongest effect on viability was observed with resorufin. In contrast to resorufin, TBB protected cells from cisplatin-induced cell killing. Furthermore, the inhibition of endogenous CK2 activity was cell type-dependent as endogenous CK2 was inhibited to different degrees in the cell lines. PMID- 19787271 TI - Immuno-analysis of phospho-Akt in primary human breast cancers. AB - The aim of this study was to investigate the expression of the activated (phosphorylated) form of Akt (Ser473) in primary breast cancer and to correlate the results with clinicopathological and prognostic variables for clinically relevant associations. Phospho-Akt expression was studied using immunoblot analysis in 49 invasive breast carcinomas (median follow-up time 55 months, range 7-74 months). We assessed the level of phospho-Akt in different types of primary breast cancers and compared the use of autoradiograph X-ray film with a PVDF-DAB staining system. Twelve percent of the tumours had no phospho-Akt protein, 25% had low phospho-Akt expression, 51% had intermediate expression and 12% had high phospho-Akt expression. No relationship was observed between phospho-Akt and tumour grade, tumour size or nodal status. A significant relationship was demonstrated between phospho-Akt score and oestrogen receptor status (P=0.014). Univariate analysis demonstrated that intermediate levels of phospho-Akt in breast tumour tissue are associated with a lower probability of developing recurrences (P=0.035), while in multivariate analyses, none of the phospho-Akt levels appeared to be independent predictors of disease recurrence or death. In addition, it has been clearly established that a suitable composition of reagents and components such as PVDF membranes treated with DAB substrate will enable the performing of sensitive immuno-analyses. PMID- 19787272 TI - Association of H-ras polymorphisms and susceptibility to sporadic colon cancer. AB - High incidence of colon cancer worldwide indicates the importance of studying genetic alterations that lead to its carcinogenesis. Two polymorphisms in H-ras gene, hexanucleotide tandem repeats in the first intron and SNP 81T>C in the first exon, that might be connected with susceptibility to cancer have been described. The aim of our study was to investigate these loci in Croatian population and to determine if any of them is connected with susceptibility to colon cancer in our population. Two hundred healthy volunteers and 200 colon cancer patients were genotyped using PCR and RFLP methods. We noted statistically significant difference in genotype distribution at hexanucleotide locus between healthy population and colon cancer patients (p=0.013) but not in allelic distribution. At SNP 81 T>C statistically significant difference in distribution of both genotypes (p=9.15x10(-6)) and alleles (p=2.77x10(-6)) was found. No differences were found between genders. PMID- 19787273 TI - Transcription factor AP-1 promotes growth and radioresistance in prostate cancer cells. AB - Expression of AP-1 proteins has been associated with a more aggressive clinical outcome in prostate cancer. However, their role and regulation by upstream kinase pathways in response to ionizing radiation has remained elusive. Here, we show that constitutive AP-1 activity in prostate cancer cells is dependent on the activities of EGF-R and PI3K. While inhibition of EGF-R is associated with suppression of c-Jun expression and proliferation, inhibition of PI3K pathway suppresses expression of several AP-1 subunits and proliferation, and also sensitizes prostate cancer cells to gamma-radiation. The importance of AP-1 as a mediator of proliferation and radiation responses is demonstrated by the findings that the expression of JunD, Fra-1 and Fra-2 siRNAs in prostate cancer cells suppress these cellular responses. Together, the findings show that AP-1 activity in prostate cancer cells mediates EGF-R and PI3K signalling, is essential for their proliferation, and confers protection against radiation-induced cell death. Thus, its inhibition would be a lucrative target for therapy in this widely increasing cancer type. PMID- 19787274 TI - Fucoidan-Vitamin C complex suppresses tumor invasion through the basement membrane, with scarce injuries to normal or tumor cells, via decreases in oxidative stress and matrix metalloproteinases. AB - Fucoidan (Fucdn) and vitamin C (VC) were saturatedly dissolved in water and lyophilized and thoroughly ethanol-rinsed until no detection for supernatant vitamin C to form the Fucdn-VC (1:0.23 wt/wt) inclusion body (Fucdn-VC-IB). Fucdn VC-IB increased not only VC-stabilizing at 37 degrees C, but also hydroxyl radical scavenging as shown by ESR/spin-trap method, more markedly than a mere mixture of Fucdn:VC (1:0.23 wt/wt). Invasion of human fibrosarcoma cells HT-1080 through the basement membrane was repressed by Fucdn-VC-IB of non-cytotoxic concentrations without significant inhibition to human skin dermal fibroblasts DUMS-16 cells. Fucdn-VC-IB suppressed the invasiveness-related gelatinases MMP 2/9, and diminished reactive oxygen species inside the cytoplasm around the nucleus, in HT-1080 cells as shown by electrophoretic zymography and the redox indicator NBT assay, respectively. Thus Fucdn-VC-IB markedly exhibits antioxidant and MMP-suppressing activities and preferentially inhibited tumor invasion without cytotoxicity to normal cells, and is suggested as a potent tumor-invasion suppressor. PMID- 19787275 TI - 1,1-Bis(3'-indolyl)-1-(p-bromophenyl)methane and related compounds repress survivin and decrease gamma-radiation-induced survivin in colon and pancreatic cancer cells. AB - 1,1-Bis(3'-indolyl)-1-(p-bromophenyl)methane (DIM-C-pPhBr) and the 2,2'-dimethyl analog (2,2'-diMeDIM-C-pPhBr) inhibit proliferation and induce apoptosis in SW480 colon and Panc28 pancreatic cancer cells. In this study, treatment with 10-20 microM concentrations of these compounds for 24 h induced cleaved PARP and decreased survivin protein and mRNA expression in both cell lines. However, results of time course studies show that DIM-C-pPhBr and 2,2'-diMeDIM-C-pPhBr decrease survivin protein within 2 h after treatment, whereas survivin mRNA levels were decreased only at later time-points indicating activation of transcription-independent and -dependent pathways for downregulation of survivin. In addition, we also observed that gamma-radiation inhibited pancreatic and colon cancer cell growth and this was associated with enhanced expression of survivin after 24 (SW480) or 24 and 48 h (Panc28) and correlated with previous studies on the role of survivin in radiation-resistance. However, in cells co-treated with gamma-radiation plus DIM-C-pPhBr or 2,2'-diMeDIM-C-pPhBr, induction of survivin by gamma-radiation was inhibited after co-treatment with both compounds, suggesting applications for these drugs in combination cancer chemotherapy with gamma-radiation. PMID- 19787276 TI - Promoter hypermethylation of the p16 and Wif-1 genes as an independent prognostic marker in stage IA non-small cell lung cancers. AB - Hypermethylation of promoter CpG islands is a major inactivation mechanism of tumor suppressor genes, some of which are thought to be related to the prognosis of patients with non-small cell lung cancer (NSCLC). Therefore, hypermethylation of the specific genes may be expected to serve as a prognostic biomarker for NSCLC. In this study, the methylation status of 14 genes was analyzed in 44 stage IA NSCLC cases using methylation-specific PCR. Hypermethylation was detected in PTGER2 (70% of cases), DRM/Gremlin (66%), sFRP-2 (57%), IL-12Rbeta2 (48%), Reprimo (41%), APC (39%), CXCL12 (39%), HPP1 (30%), SPARC (30%), sFRP-5 (30%), p16 (25%), RUNX3 (20%), sFRP-1 (20%) and Wif-1 (16%). Patients with p16, sFRP-5, Wif-1 or CXCL12 methylation had a significantly shorter duration of relapse-free survival than their counterparts with an unmethylated gene (p16, P=0.011; sFRP-5, P=0.030, Wif-1, P=0.036; CXCL12, P=0.026). Also, those with methylated HPP1, p16 or Wif-1 had a significantly shorter duration of overall survival (HPP1, P=0.031; p16, P=0.026; Wif-1, P=0.008). Multivariate analysis revealed that p16 methylation in relapse-free survival and Wif-1 methylation in overall survival were the strongest independent prognostic factors (p16, P=0.036; Wif-1, P=0.035). In conclusion, the hypermethylation of the p16 and Wif-1 genes has potential as biomarkers that may be used to predict the prognosis of stage IA NSCLC. PMID- 19787277 TI - Impaired T lymphocyte function increases tumorigenicity and decreases tumor latency in a mouse model of head and neck cancer. AB - Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most frequent cancer worldwide. SCC is the most common malignant tumor of the oral cavity with over 35,000 cases and 8,000 deaths reported in the United States each year. Previous case studies have reported increased incidence of HNSCC in patients on immunosuppressive therapy for organ transplantation. The results of these studies indicate that effective immune surveillance is important for preventing emergence of HNSCC. HNSCC may also inhibit immune response to tumor cells, which may be responsible for progression. We previously reported induction of metastatic HNSCC in p53 null mutant mice. Despite induction with the potent carcinogen dimethylbenzanthracene, each mouse developed only 1-2 primary tumors with a relatively long induction period of 22 weeks. We hypothesized that immune surveillance might eliminate early tumor cells resulting in the relatively small number of primary tumors and long induction time. To test this hypothesis we performed the induction protocol in nude mice which have defective T lymphocyte function. Decreased T lymphocyte function resulted in reduced tumor latency and increased tumor formation. Immunohistochemical studies showed that expression of cell cycle regulatory proteins is similar in mouse and human HNSCC. However, distinct differences exist between primary and metastatic tumors from nude and wild-type mice. We also determined that lymphocytes react to metastatic tumor cells by upregulating immunoglobin gene expression but are prone to apoptosis via decreased expression of survival factors and upregulation of cell death genes. PMID- 19787278 TI - G2-checkpoint abrogation in irradiated lymphocytes: A new cytogenetic approach to assess individual radiosensitivity and predisposition to cancer. AB - Increased yield of chromatid breaks, following in vitro G2-phase lymphocyte irradiation, can be a marker of individual radiosensitivity and cancer predisposing genes whose role is to respond to DNA damage. Mutations or polymorphisms of genes encoding DNA repair pathways may underlie the increased chromosomal radiosensitivity. However, genes that facilitate DNA damage recognition, using signal transduction pathways to activate cell cycle arrest and preserve genomic integrity, are perhaps the most important determinant. Based on the latter hypothesis, an individual radiosensitivity parameter (IRP) is introduced, which expresses, at individual level, the G2-checkpoint potential to facilitate DNA damage recognition and repair of radiation-induced chromosomal damage during G2 to M-phase transition. Based on this parameter a new methodology for assessment of individual radiosensitivity is proposed, which involves G2 checkpoint abrogation by caffeine to obtain the IRP values. To evaluate the proposed methodology, blood samples from 52 healthy donors were taken for inter individual radiosensitivity analysis using both the conventional G2 chromosomal radiosensitivity assay as well as the new approach using caffeine-induced G2 checkpoint abrogation. The two assays were compared in experiments using samples from 5 hypersensitive patients, 3 AT-homozygotes, 3 AT-heterozygotes, and the GM15786, GM03188A, GM09899, HCC1937 and MCF-7 cell lines. Using the G2 chromosomal radiosensitivity assay, donors are predicted as G2 radiosensitive or normal, while according to the new approach, individuals can be classified as highly radiosensitive, radiosensitive, normal, radioresistant and highly radioresistant. Overall, the new approach provides better individual radiosensitivity discrimination and intra-experimental reproducibility. Therefore, the proposed methodology using IRP values may provide a clinically applicable predictive assay for individual radiosensitivity and predisposition to cancer. PMID- 19787279 TI - Volatile organic compounds in a residential and commercial urban area with a diesel, compressed natural gas and oxygenated gasoline vehicular fleet. AB - Air samples were collected in a typical residential and commercial area in Rio de Janeiro, Brazil, where buses and trucks use diesel and light duty vehicles use compressed natural gas, ethanol, and gasohol (gasoline blended with ethanol) as fuel. A total of 66 C3-C12 volatile organic compounds (VOCs) were identified. The most abundant compounds, on a mass concentration basis, included propane, isobutane, i-pentane, m,p-xylene, 1,3,5-trimethylbenzene, toluene, styrene, ethylbenzene, isopropylbenzene, o-xylene and 1,2,4-trimethylbenzene. Two VOCs photochemical reactivity rankings are presented: one involves reaction with OH and the other involves production of ozone. PMID- 19787280 TI - Comment on Kuo: Measurement of detrusor wall thickness in women with overactive bladder by transvaginal and transabdominal sonography. PMID- 19787283 TI - [Options for health care promotion in long-term care: empirical evidence and conceptual approaches]. AB - Using empirical evidence, this paper provides conceptual approaches to prevention and health promotion in long-term care - an area that has gained only limited attention in German discussions on prevention. First, a short analysis of long term care in Germany is provided; existing problems but also resources with regard to prevention and health promotion in order to identify starting points for the development of interventions are presented. The existing pressure and problem accumulation in long-term care that calls for action on maintaining and promoting the health of long-term care professionals as well as long-term care users are illustrated. Considerations on programs for health promotion in long term care focus on the users, in particular the oldest old, of long-term care. Finally, considerations on a conceptual framework for a user-oriented approach to prevention and health promotion in long-term care is presented. PMID- 19787281 TI - Cystocele repair by transobturator four arms mesh: monocentric experience of first 123 patients. AB - INTRODUCTION AND HYPOTHESIS: The aims of the study were to evaluate the per- and post-operative complications and outcomes after cystocele repair with transobturator mesh. METHODS: A retrospective continuous series study was conducted over a period of 3 years. Clinical evaluation was up to 1 year with additional telephonic interview performed after 34 months on average. When stress urinary incontinence (SUI) was associated with the cystocele, it was treated with the same mesh. RESULTS: One hundred twenty-three patients were treated for cystocele. Per-operative complications occurred in six patients. After 1 year, erosion rate was 6.5%, and only three cystoceles recurred. After treatment of SUI with the same mesh, 87.7% restored continence. Overall patient's satisfaction rate was 93.5%. CONCLUSIONS: Treatment of cystocele using transobturator four arms mesh appears to reduce the risk of recurrence at 1 year, along with high rate of patient's satisfaction. The transobturator path of the prosthesis arms seems devoid of serious per- and post-operative risks and allows restoring continence when SUI is present. PMID- 19787284 TI - Role of triggering receptor expressed on myeloid cells-1 in experimental severe acute pancreatitis. AB - BACKGROUND/PURPOSE: Triggering receptor expressed on myeloid cells-1 (TREM-1) is a regulator of immunity and an amplifier of inflammatory signaling. The aim was to clarify the role of TREM-1 in the pathophysiology of experimental severe acute pancreatitis (SAP). METHODS: SAP was induced by retrograde injection of 3 and 20% sodium deoxycholate (DCA) into the biliopancreatic ducts in rats (DCA pancreatitis). Soluble TREM-1 levels in serum, ascitic fluid, pancreas, liver and kidney were determined with an established available enzyme-linked immunosorbent assay (ELISA) kit. To clarify the source of soluble TREM-1 in serum and ascitic fluid, peritoneal macrophage depletion was done. Moreover, the effect of blockade of TREM-1 pathway was examined using LP17 (a synthetic TREM-1 inhibitor). RESULTS: Soluble TREM-1 levels in serum and ascitic fluid were higher in SAP. Membrane-bound TREM-1 protein was increased in pancreas, liver and kidney in SAP. Peritoneal macrophage depletion resulted in the reduction of soluble TREM-1 levels in serum and ascitic fluid. Pretreatment with LP17 improved the hepatic and renal dysfunction (serum aspartate aminotransferase and blood urea nitrogen levels) in SAP. CONCLUSIONS: TREM-1 may act as an important mediator for inflammation and organ injury in SAP. TREM-1 may be a potential therapeutic target for the development of SAP and associated organ dysfunction. PMID- 19787285 TI - Risk factors for postoperative recurrence of non-B non-C hepatocellular carcinoma. AB - BACKGROUND/PURPOSE: The majority of hepatocellular carcinomas are associated with chronic infection with hepatitis B or C virus. Recently, however, the proportion of non-B non-C hepatocellular carcinomas has been increasing. It is necessary to determine the optimal surgical approach for non-B non-C hepatocellular carcinoma. METHODS: Seventy-seven patients with non-B non-C hepatocellular carcinoma who underwent curative hepatic resection were included in this study. Univariate and multivariate analyses were performed to clarify risk factors for postoperative recurrence of non-B non-C hepatocellular carcinoma. RESULTS: On univariate analysis, surgical margin <5 mm (P = 0.001) and the presence of multiple tumors (P = 0.002) were significantly associated with lower disease-free survival rate. On multivariate analysis, surgical margin <5 mm and the presence of multiple tumors were independent risk factors for postoperative recurrence. CONCLUSION: Curative resection with adequate surgical margins for single non-B non-C hepatocellular carcinoma can achieve a good outcome. PMID- 19787286 TI - Significance of mucin expression in pancreatobiliary neoplasms. AB - Mucins are high molecular weight glycoproteins that play important roles in carcinogenesis and tumor invasion. We have described, for the first time, that pancreatic ductal adenocarcinomas (PDACs) with an aggressive behavior and a poor outcome expressed MUC1 (pan-epithelial membrane-associated mucin) but did not express MUC2 (intestinal-type secreted mucin), whereas intraductal papillary mucinous neoplasms (IPMNs) with indolent behavior and a favorable outcome did not express MUC1 but did express MUC2. These expression profiles of MUC1 and MUC2 related to the prognoses of the patients were also observed in biliary neoplasms such as intrahepatic cholangiocarcinoma (ICC)-mass-forming type (MF), mucin producing bile duct tumor (MPBT), and extrahepatic bile duct carcinoma (EHBDC). We also found recently that high expression of MUC4 (tracheobronchial membrane associated mucin) in PDACs, ICCs-MF, and EHBDCs was a new independent poor prognostic factor, although MUC4 was not expressed in normal pancreatobiliary tissue. High de novo expression of MUC5AC (gastric-type secreted mucin) was observed in many types of pancreatobiliary neoplasms, including all grades of pancreatic intraepithelial neoplasia (PanIN) and biliary intraepithelial neoplasia (BilIN), and all types of IPMNs and MPBTs, as well as PDACs and ICCs MF, although MUC5AC was not expressed in normal pancreatobiliary tissue. The combined status of MUC1, MUC2, MUC4, and MUC5AC expression may be useful for the early detection of pancreatobiliary neoplasms and evaluation of their malignancy. In regard to the mechanism of mucin expression, we have recently reported that MUC1, MUC2, MUC4, and MUC5AC gene expression is regulated by epigenetics (DNA methylation and histone H3 lysine 9 modification) in cancer cell lines, including PDAC cells. Translational research of mucin gene expression mechanisms, including epigenetics, in pancreatobiliary neoplasms may give us new tools for the early and accurate detection of these neoplasms. PMID- 19787287 TI - Ultrasound-guided percutaneous drainage may decrease the mortality of severe acute pancreatitis. AB - OBJECTIVES: To evaluate the efficacy and safety of ultrasound-guided percutaneous catheter drainage (PCD) treatment for severe acute pancreatitis compared to conservative and conventional surgical treatments. METHODS: Eighty-one patients with severe acute pancreatitis (SAP) were admitted and divided into three groups: forty-nine cases in the conservative therapy group; nineteen cases in the surgery group; and thirteen cases in the PCD therapy group. Forty-five patients with a CT severity index (CTSI) < or = 8.0 received conservative treatment. One patient with CTSI = 7.0 underwent surgery. Thirty-five patients with a CTSI > 8.0 were randomly selected for surgery or PCD treatment. After randomization, six patients (four patients in the surgery group and two patients in the PCD group) were dropped from the study. The total number of patients included in the surgery and PCD groups was sixteen and thirteen, respectively. RESULTS: Four patients (8.2%) in the conservative therapy group died, five patients (31.3%) in surgery group with a CTSI > 8.0 died, and all patients in the PCD group survived. The mortality rate was lower in the PCD group than in the surgery group (P = 0.048). The serum C-reactive protein (CRP) level recovered more quickly in patients in the PCD group compared to those in the surgery group (P < 0.001). CONCLUSIONS: Patients with SAP and a CTSI < or = 8.0 could be treated with conservative therapy, while patients with a CTSI > 8.0 should be treated with surgery or PCD therapy if the life-threatening complications of extensive fluid collection or necrosis are a factor. However, PCD therapy used in a timely manner for drainage may decrease mortality in patients with SAP, decrease inflammatory mediator release, and avoid incidence of severe sepsis or acute respiratory distress syndrome (ARDS) and emergency surgery. PMID- 19787288 TI - The relationship between coronary artery calcification score, plasma osteoprotegerin level and arterial stiffness in asymptomatic type 2 DM. AB - Because T2DM increases the risk of coronary atherosclerosis and CAD and new noninvasive techniques to assess CVD risk have gained considerable popularity, it is important to know how these tools relate to each other. The aim of this study was to evaluate the relationship between the extent of coronary artery calcification measured by MDCT, plasma OPG levels, baPWV and the established cardiovascular risk factors in Korean patients with T2DM. From November 2006 to December 2007, 110 asymptomatic Korean patients with T2DM without prior evidence of CAD were assessed (mean age 57.2 years). CAC imaging was performed using a 40 slice MDCT. Serum OPG levels were measured by an enzyme-linked immunosorbent assay (Oscotec, Korea) from the serum samples of each subject. We measured the baPWV as an index of arterial stiffness. In addition, we measured fasting glucose, HbA(1)C, hsCRP and lipid profiles. A total of 74 patients (67.3%) had minimal or insignificant CAC (<10). The CACS, OPG and baPWV showed significant positive correlations with each other. The CACS was significantly associated with the baPWV, smoking and use of a statin. The baPWV was significantly associated with age, duration of DM, total cholesterol and CACS by multiple linear regression models of the dependent variables of CACS or baPWV. CAC and baPWV were significant predictors of each other (r = 0.359, P = 0.014 and r = 0.361, P = 0.004). The results of this study showed that CAC, baPWV and serum OPG levels were significantly correlated with each other in asymptomatic Korean patients with T2DM. Furthermore, our results suggest that arterial stiffness, as determined by baPWV, may predict the extent of coronary calcification by MDCT. PMID- 19787289 TI - Excessive maternal transmission of diabetes in Japanese families with young-onset type 2 diabetes and insulin secretion defect according to clinical features. AB - The aim of the study is to identify the clinical characteristics of Japanese patients with young-onset type 2 diabetes (YT2D). Family history of diabetes and clinical data were collected for 30 unrelated males (from 11 to 20 years old at age of onset) and 20 females (from 10 to 20 years old at age of onset) with YT2D diagnosed at <= 20 years of age. Fasting C-peptide levels were measured in all, and glucagon stimulation tests were performed twice in six of them over several years. Moreover, 858 people with type 2 diabetes (T2D) diagnosed at >20 years of age were randomly recruited in order to compare the transmission pattern of them. Among the study subjects, 68% reported at least one parent with diabetes. Diabetes was more frequent among mothers than fathers of probands (P = 0.020), although this tendency was not observed in T2D diagnosed at >20 years of age. Fasting C-peptide levels of patients with diabetes duration of >= 10 years were significantly lower than for patients with diabetes duration of <10 years (0.61 +/- 0.26 vs. 0.84 +/- 0.43 nmol/l, P = 0.036). The fasting C-peptide levels among male patients with a family history of diabetes were also significantly lower than those without a family history (0.56 +/- 0.25 vs. 0.83 +/- 0.37 nmol/l, P = 0.034), while all female subjects had a family history of diabetes. Glucagon stimulation tests showed the following data; 0 min: 0.56 +/- 0.31 vs. 0.39 +/- 0.22 nmol/l, 3 min: 1.41 +/- 0.77 vs. 0.87 +/- 0.47 nmol/l, 6 min: 1.37 +/- 0.80 vs. 0.79 +/- 0.35 nmol/l, 10 min: 1.06 +/- 0.60 vs. 0.81 +/- 0.49 nmol/l, and 30 min: 0.58 +/- 0.30 vs. 0.50 +/- 0.19 nmol/l, respectively. These results demonstrated that YT2D among Japanese people occurring in excess with maternal transmission is associated with beta-cell dysfunction at the onset of diabetes and as the disease advances. PMID- 19787290 TI - Effect of pioglitazone on systemic inflammation is independent of metabolic control and cardiac autonomic function in patients with type 2 diabetes. AB - The aim of this article is to investigate the relation of the anti-inflammatory effect of pioglitazone with cardiac autonomic function and metabolic control in diabetic patients. In this prospective open label trial, 36 type 2 diabetic patients (age 60 +/- 10, 20 M) without overt cardiovascular disease were randomized to add pioglitazone (30 mg) to their therapy or to continue standard therapy. C-reactive protein (CRP) serum levels, metabolic parameters and cardiac autonomic function (assessed by heart rate variability [HRV] on 24-h ECG Holter monitoring) were measured at baseline and after 3 months. Clinical and laboratory variables were similar in the two groups. No significant changes were observed after 3 months for metabolic and anthropometric parameters, except for a mild increase in HDL levels in the pioglitazone group only (P = 0.04 vs. controls). CRP levels decreased significantly at follow-up in the pioglitazone group (3.2 +/ 1.97 vs. 2.37 +/- 1.56 mg/l) but not in the control group (3.0 +/- 1.92 vs. 3.93 +/- 2.14 mg/l; P = 0.003). No differences were found in basal and follow-up HRV variables between the two groups. In type 2 diabetic patients pioglitazone exerts favourable effects on inflammation even after short-term therapy. This effect precedes those on metabolic and anthropometric parameters and is not associated with changes in cardiac autonomic function. PMID- 19787291 TI - DNA damage evaluated by comet assay in Mexican patients with type 2 diabetes mellitus. AB - We conducted a case-control study to assess whether general DNA damage levels evaluated by comet assay (length of tail comet, tail extent moment, and olive tail moment) differ in Mexican patients with type 2 diabetes mellitus (DM2). The sample included 71 Mexican patients with DM2 who had developed the disease >5 years previously and had been treated with oral hypoglycemic drugs (sulfonylurea and/or metformin), with no microvascular or macrovascular complications. These patients were classified into three groups according to age: (I) 40-50 years, (II) 51-60 years, and (III) 61-70 years. A control group of 14 individuals (40-50 years) without DM2 was included. Our results showed there was a slight but not significant increase in DNA damage in the two groups of patients with DM2 aged between 40 and 60 years compared with the 61-70-year-old patient group and controls. In conclusion, given that general DNA damage was similar in the three groups of patients with DM2 and the control group, it is possible that these cells showed similar oxidative damage, as has been proposed previously. PMID- 19787293 TI - Clinical and surgical features of lower brain stem hemangioblastomas in von Hippel-Lindau disease. AB - BACKGROUND: In the context of von Hippel-Lindau disease (VHL), the medulla oblongata is a relatively frequent site of growth of hemangioblastomas, posing related clinical and surgical difficulties. Their management requires a close correlation between clinical evolution and morphological surveillance. In order to describe their clinical and surgical features, we reviewed our experience in the treatment of these lesions. METHODS: Between 2001 and 2009, 14 patients (9 female and 5 male, mean age 34 years) underwent removal of 15 lower brain stem hemangioblastomas. Based on the review of the clinical records and outpatient long-term follow-up visits, their clinical course was analyzed. Functional evaluation was measured with the Karnofsky Performance Scale (KPS) on admission, at discharge and at the last follow-up. The mean follow-up period was 30.8 months (range 4-99). RESULTS: All the operated hemangioblastomas were located in the dorsal medulla oblongata, in the context of multiple lesions, cerebellar and/or spinal. In ten patients hemangioblastomas were located in a median position at the obex area; in four cases a lateral location was observed. Cystic component was absent in two cases. Clinical onset preceded surgery by a mean of 8.5 months. Preoperatively three patients showed a KPS lower than 80, ten patients between 80 and 90, and one patient scored 100 (asymptomatic). There was no surgical mortality. Nine out of 14 patients showed a temporary surgical morbidity. One patient required a tracheostomy. At follow-up ten patients scored a KPS better than before the operation, while the other four patients remained stable. Permanent morbidity was observed in three patients. CONCLUSIONS: Lower brain stem hemangioblastomas in the context of VHL show an often gradual onset of signs and symptoms except for patients who develop an obstructive hydrocephalus. Although transient surgical complications are possible, surgery provides favorable long term results. PMID- 19787294 TI - Trigeminocardiac reflex and ipsilateral mydriasis during stereotactic brain tumor biopsy: an insight into the anatomical and physiological pathways involved. PMID- 19787296 TI - Obesity increase among low SES Australian schoolchildren between 2000 and 2006: time for preventive interventions to target children from low income schools? AB - OBJECTIVES: To examine change from 2000 to 2006 in obesity and overweight by gender, school year and school socioeconomic status (SES) in a national sample of students from Australia. METHODS: Survey of students aged 6-18 years from the same 32 schools in 2000 (N = 3,819) and 2006 (N = 5,524) with measured height and weight. All analyses were adjusted for the cluster survey design. Main outcome measures were height, weight, Z-score distribution of BMI, overweight and obesity [International Obesity Task Force (IOTF) cut-offs], school SES. RESULTS: Obesity and overweight were similar to previous Australian findings with 5.2% and 6.1% obese in 2000 and 2006, respectively, and 16.3 and 19.0% overweight. Significant increase in obesity was observed in students from low SES schools which increased from 5.8 to 8.6% (P < 0.05) compared to 5.5 to 6.3% (P = 0.32) in middle SES and 3.3 to 4.2% (P = 0.92) in high SES schools. CONCLUSIONS: Obesity increased significantly among children in low SES schools and preventive efforts should urgently and carefully target preventive efforts to assist schools, families and communities which are socially and economically, disadvantaged using culturally appropriate physical activity and nutrition promotion interventions. PMID- 19787298 TI - Crystal structure, DNA binding studies, nucleolytic property and topoisomerase I inhibition of zinc complex with 1,10-phenanthroline and 3-methyl-picolinic acid. AB - Crystal structure analysis of the zinc complex establishes it as a distorted octahedral complex, bis(3-methylpicolinato-kappa(2) N,O)(2)(1,10-phenanthroline kappa(2) N,N)-zinc(II) pentahydrate, [Zn(3-Me-pic)(2)(phen)]x5H(2)O. The trans configuration of carbonyl oxygen atoms of the carboxylate moieties and orientation of the two planar picolinate ligands above and before the phen ligand plane seems to confer DNA sequence recognition to the complex. It cannot cleave DNA under hydrolytic condition but can slightly be activated by hydrogen peroxide or sodium ascorbate. Circular Dichroism and Fluorescence spectroscopic analysis of its interaction with various duplex polynucleotides reveals its binding mode as mainly intercalation. It shows distinct DNA sequence binding selectivity and the order of decreasing selectivity is ATAT > AATT > CGCG. Docking studies lead to the same conclusion on this sequence selectivity. It binds strongly with G quadruplex with human tolemeric sequence 5'-AG(3)(T(2)AG(3))(3)-3', can inhibit topoisomerase I efficiently and is cytotoxic against MCF-7 cell line. PMID- 19787297 TI - Production of isotopically labeled heterologous proteins in non-E. coli prokaryotic and eukaryotic cells. AB - The preparation of stable isotope-labeled proteins is necessary for the application of a wide variety of NMR methods, to study the structures and dynamics of proteins and protein complexes. The E. coli expression system is generally used for the production of isotope-labeled proteins, because of the advantages of ease of handling, rapid growth, high-level protein production, and low cost for isotope-labeling. However, many eukaryotic proteins are not functionally expressed in E. coli, due to problems related to disulfide bond formation, post-translational modifications, and folding. In such cases, other expression systems are required for producing proteins for biomolecular NMR analyses. In this paper, we review the recent advances in expression systems for isotopically labeled heterologous proteins, utilizing non-E. coli prokaryotic and eukaryotic cells. PMID- 19787300 TI - Arsenic exposure and cardiovascular disorders: an overview. AB - The incidence of arsenic toxicity has been observed in various countries including Taiwan, Bangladesh, India, Argentina, Australia, Chile, China, Hungary, Peru, Thailand, Mexico and United States of America. Arsenic is a ubiquitous element present in drinking water, and its exposure is associated with various cardiovascular disorders. Arsenic exposure plays a key role in the pathogenesis of vascular endothelial dysfunction as it inactivates endothelial nitric oxide synthase, leading to reduction in the generation and bioavailability of nitric oxide. In addition, the chronic arsenic exposure induces high oxidative stress, which may affect the structure and function of cardiovascular system. Further, the arsenic exposure has been noted to induce atherosclerosis by increasing the platelet aggregation and reducing fibrinolysis. Moreover, arsenic exposure may cause arrhythmia by increasing the QT interval and accelerating the cellular calcium overload. The chronic exposure to arsenic upregulates the expression of tumor necrosis factor-alpha, interleukin-1, vascular cell adhesion molecule and vascular endothelial growth factor to induce cardiovascular pathogenesis. The present review critically discussed the detrimental role of arsenic in the cardiovascular system. PMID- 19787299 TI - Homocysteine modulates the proteolytic potential of human arterial smooth muscle cells through a reactive oxygen species dependant mechanism. AB - Pathological levels of homocysteine induce a dramatic degradation of arterial elastic structures. This severe metalloproteinase-dependant elastolysis affects elastic structures all over the media suggesting that smooth muscle cells (SMC) may participate to this process induced by homocysteine. Therefore, we investigated the effect of physiological (10 microM) and pathological (50, 100, and 500 microM) concentrations of homocysteine on the metalloproteinase-dependant proteolytic potential of human arterial SMC in culture. Pathological levels of homocysteine increased concomitantly the secretion of latent MMP-2 and TIMP-2 while the secretion of other elastolytic matrix metalloproteinases (MMPs) and expression of MT1-MMP were not altered. The increased secretion of latent MMP-2 induced by homocysteine was associated with an increased production of reactive oxygen species (ROS). Moreover, the increased secretion of latent MMP-2 induced by homocysteine was inhibited by antioxidant superoxide dismutase alone or in combination with catalase. These results suggest that SMC could participate, through an oxidative stress dependant secretion of elastolytic MMP-2, to the metalloproteinase-dependant degradation of arterial elastic structures induced by homocysteine. PMID- 19787302 TI - [Overlapping induction]. PMID- 19787301 TI - [Intraoperative echocardiography: impact on surgical decision-making]. AB - Since the introduction of intraoperative echocardiography into clinical practice in the 1970's its use and utility in the perioperative period has become increasingly more evident. Especially in patients undergoing cardiac surgical procedures intraoperative echocardiography has gained great diagnostic importance. Intraoperative transesophageal echocardiography (TEE) and epiaortic ultrasound are two important and complementing diagnostic modalities in this patient population. The clinical information obtained with intraoperative TEE in certain cases might have a direct impact on surgical decision-making and therefore may positively influence patient outcome. In patients undergoing non cardiac surgical procedures, TEE can be a valuable tool in high-risk patients, in patients experiencing hemodynamic instability or in those suffering intraoperative cardiac arrest. Intraoperative TEE might allow a primary diagnosis of the underlying etiology and facilitate the institution of further therapeutic interventions. In addition TEE can be performed during ongoing cardiopulmonary resuscitation and does not interfere with patient management. This review introduces the clinician to the current evidence of the impact of intraoperative echocardiography on intraoperative surgical decisions during surgical procedures. It helps the clinician to identify indications and realize the potential applications of intraoperative echocardiography. PMID- 19787303 TI - [Ketamine racemate and fast track anaesthesia. Influence on recovery times and postoperative opioid needs]. AB - INTRODUCTION: In this study the impact of 25 mg of ketamine racemate given just before surgery on recovery times and postoperative analgesic needs in patients undergoing vaginal hysterectomy and receiving propofol-remifentanil anaesthesia was investigated. METHODS: With ethics committee approval 70 female patients aged 25-65 years were enrolled. All patients received a total intravenous anaesthesia with remifentanil and propofol with the propofol infusion being controlled to a Narcotrend index of 40. Patients in the ketamine group (n=35) received additionally a bolus dose of 25 mg ketamine racemate intravenously 3 min before skin incision. In addition to monitoring haemodynamics and circulation parameters, recovery times, postoperative pain and opioid needs were also recorded. Patients were also questioned on their satisfaction with the pain therapy. RESULTS: All 70 patients completed the study and the groups were similar with respect to demographic data. The haemodynamics of the patients were stable in both groups and the postoperative pain measured over a 24-h period as well as the opioid needs were also comparable. However, recovery times were significantly prolonged in the ketamine group, e.g. the times to extubation were 8.3+/-4.0 min with ketamine compared to 6.1+/-2.1 min in the control group (p<0.01). Undesired side effects were overall rare but occurred to the same extent in both groups. CONCLUSIONS: This study demonstrated that 25 mg ketamine racemate given just before surgery significantly prolongs recovery times without reducing post operative analgesic needs when applied to patients undergoing vaginal hysterectomy and receiving propofol-remifentanil anaesthesia. A bolus dose of 25 mg ketamine racemate cannot therefore be recommended for preemptive analgesia under these conditions. PMID- 19787304 TI - [Speech sounds and their representation for diagnosis]. AB - The assessment of articulation disorders includes, among other things, identifying which speech sounds or sound combinations cannot yet be realized properly. To this end, it is necessary to transcribe children's utterances and thus preserve them for analysis. Transcriptions can be performed using the alphabet, or by means of phonetic or phonological transcription using the International Phonetic Association (IPA) alphabet or the extended IPA alphabet (extIPA). Articulation disorders can only be adequately documented by means of transcription; however, this requires a certain amount of practice. The main features of IPA transcription are outlined here. PMID- 19787305 TI - Defining internet-supported therapeutic interventions. AB - BACKGROUND: The field of Internet-supported therapeutic interventions has suffered from a lack of clarity and consistency. The absence of professional leadership and of accepted governing approaches, terminology, professional standards, and methodologies has caused this field to be diffused and unstructured. Numerous terms have been used to label and describe the activities conducted over the Internet for mental and physical health purposes: web-based therapy, e-therapy, cybertherapy, eHealth, e-Interventions, computer-mediated interventions, and online therapy (or counseling), among others. METHODS: Following a comprehensive review, we conceptualized Internet-supported interventions, using four categories based on prime practice approaches: web based interventions, online counseling and therapy, Internet-operated therapeutic software, and other online activities (e.g., as supplements to face-to-face therapy). We provide a working definition and detailed description of each category, accompanied by numerous examples. CONCLUSIONS: These categories may now serve as guiding definitions and related terminologies for further research and development in this emerging field. PMID- 19787306 TI - Constructing food choice decisions. AB - BACKGROUND: Food choice decisions are frequent, multifaceted, situational, dynamic, and complex and lead to food behaviors where people acquire, prepare, serve, give away, store, eat, and clean up. Many disciplines and fields examine decision making. PURPOSE: Several classes of theories are applicable to food decision making, including social behavior, social facts, and social definition perspectives. Each offers some insights but also makes limiting assumptions that prevent fully explaining food choice decisions. METHODS: We used constructionist social definition perspectives to inductively develop a food choice process model that organizes a broad scope of factors and dynamics involved in food behaviors. RESULTS: This food choice process model includes (1) life course events and experiences that establish a food choice trajectory through transitions, turning points, timing, and contexts; (2) influences on food choices that include cultural ideals, personal factors, resources, social factors, and present contexts; and (3) a personal system that develops food choice values, negotiates and balances values, classifies foods and situations, and forms/revises food choice strategies, scripts, and routines. The parts of the model dynamically interact to make food choice decisions leading to food behaviors. CONCLUSION: No single theory can fully explain decision making in food behavior. Multiple perspectives are needed, including constructionist thinking. PMID- 19787307 TI - A perspective on eating behaviors from the field of judgment and decision making. AB - BACKGROUND: In this commentary, I review a key theme-the construction of preferences-that underlies the psychology of judgment and decision making and may influence eating behaviors. Its central idea is that, in many situations, we do not know what we prefer and, as a result, we construct our preferences "on the spot" based on internal and external cues available at the moment. PURPOSE: To understand the extent of construction processes, one has to know both the decision maker (and how he or she draws meaning from information) and the environment she or he faces. I consider possible roles for affect and deliberation in the construction of eating preferences and also examine some existing evidence for two potentially important individual differences--numeracy (number ability) and aging. CONCLUSION: Research implications concerning ways to improve eating behaviors are considered. PMID- 19787308 TI - Reflective and automatic processes in the initiation and maintenance of dietary change. AB - PURPOSE AND METHODS: This paper examines the social cognitive processes that regulate people's eating behavior. Specifically, we examine how eating behavior can be regulated by reflective, deliberative processes as well as automatic and habitual processes. Moreover, we consider how these processes operate when people are not only initiating a change in behavior but also maintaining the behavior over time. RESULTS AND DISCUSSION: Decomposing action control and behavior change into a 2 (reflective, automatic) x 2 (initiation, maintenance) matrix offers a useful way of conceptualizing the various determinants of eating behavior and suggests that different intervention strategies will be needed to target particular processes during respective phases of behavior change. The matrix also helps to identify key areas of intervention development that deserve attention. PMID- 19787309 TI - Orbitofrontal cortex contributions to food selection and decision making. AB - BACKGROUND: From a neuroeconomics perspective, decisions about what to eat are ultimately determined by basic features of how the brain codes and contrasts the values of different rewards and the potential positive or negative consequences of eating the food. Several brain regions play a role in this valuation and comparison process. Among these regions, the orbitofrontal cortex (OFC), which occupies the ventral surface of the frontal lobe, plays a critical integrative role in these processes. An examination of the influences on valuation both within the OFC and in related brain regions reveals several features that are likely to impact food selection. These include coding of rewards relative to other available rewards, general and specific satiety, and temporal discounting. The OFC also processes information about negative valuations (i.e., cost, negative health consequences), which are influenced by factors such as temporal discounting, probability and ambiguity. CONCLUSION: An understanding of these influences on positive and negative valuation is critical in designing diets and public health programs aimed at promoting healthy eating. PMID- 19787310 TI - Normal uptake of F-18 FDG in the testis as assessed by PET/CT in a pediatric study population. AB - OBJECTIVE: To investigate the correlation between the F-18 FDG uptake in the normal testis as assessed by PET-CT and patient age in a pediatric study population. METHODS: The study population consisted of 22 subjects aged between 9 and 17 years. For these subjects 42 PET-CT scans were available for analysis. The testis was identified on the CT images. Mean standard uptake values and testicular volume were calculated based on manually drawn regions-of-interest over the organ. The correlation between mean SUV and age as well as between testicular volume and age was calculated using Pearson's correlation coefficient. RESULTS: A strong and statistically significant positive correlation between F-18 FDG uptake in the testis and age was documented. The correlation coefficient was 0.406 in the analysis based on 42 PET-CT studies (p = 0.005). The correlation between tracer uptake and age was reassessed based on 22 PET-CT studies including the last recorded PET-CT scan per patient. The correlation coefficient was 0.409 (p = 0.05). In addition, based on 22 PET-CT scans, a strong and statistically significant positive correlation between testicular volume and age was documented (r = 0.67, p < 0.001). CONCLUSION: Whereas it was previously shown that in adult men there was a weak but statistically significant negative correlation between F 18 FDG uptake in the normal testis and age, we found a strong and statistically significant positive correlation in children and teenage boys. PMID- 19787311 TI - PET/CT image fusion error due to urinary bladder filling changes: consequence and correction. AB - OBJECTIVE: A considerable change of urinary bladder (UB) shape in PET compared with CT in integrated PET/CT system is frequently noted. This study initially evaluated this finding with and without oral contrast (OC) use. In addition, a one bed pelvic section (PLV) repeat acquisition was investigated as a solution to this problem. METHODS: (18)FDG PET/CTs of 88 patients were analyzed. OC was administered in 68 patients, of whom 31 had PLV images taken 5-10 min later. Three-dimensional mid-UB CT and PET matching measurements were compared. In addition, UB walls displacement between CT and PET were analyzed. RESULTS: The mean UB height was significantly increased (P < 0.001) in PET when compared with CT, both anteriorly and posteriorly; however, UB width and depth were not significantly different. An upward shift of superior UB wall in PET from equivalent CT images was noted, whereas there was no appreciable displacement of the other UB walls. The percent UB height increase on PET from CT was significantly greater with than without OC use. The UB height difference between PET and CT was markedly reduced on PLV when compared with the original scans. CONCLUSIONS: Caution should be exerted during the interpretation of PET/CT scans of the pelvis as there is significant upward expansion of UB on PET compared with CT that appears to be exaggerated by OC use, likely due to additional fluid load. The PET/CT fusion errors of UB can be substantially resolved through a separate PLV acquisition presumably due to the shorter time interval of UB scan completion between CT and PET. PMID- 19787312 TI - Comparisons of I-123 diagnostic and I-131 post-treatment scans for detecting residual thyroid tissue and metastases of differentiated thyroid cancer. AB - OBJECTIVE: We assessed the performance of 37 MBq I-123 as a diagnostic imaging agent in patients with differentiated thyroid cancer using comparisons with their corresponding high-dose post-treatment I-131 scans. METHODS: We reviewed diagnostic I-123 whole-body scans and post-treatment I-131 scans of 69 patients who underwent I-131 therapy for differentiated thyroid carcinoma (47 papillary and 22 follicular). Diagnostic scans were performed 24 h following the oral administration of 37 MBq of I-123. I-131 doses were administered 3 days after the I-123 diagnostic scans using 2.22-7.4 GBq (median = 5.55 GBq). All images for diagnostic I-123 scans and the corresponding post-treatment I-131 scans were interpreted by consensus of at least 2 experienced radiologists. They evaluated the accumulations of radioiodine in the following 5 sites: thyroid bed, cervical and mediastinal lymph nodes, lung, bone and others. The concordance rates between I-123 scans and I-131 scans were calculated. RESULTS: A total of 108 sites were identified on the post-treatment I-131 scans. Seventy-seven sites (71%) were also identified on the I-123 diagnostic scans. The concordance rates between I-123 diagnostic scans and I-131 post-treatment scans were high for thyroid bed and bone metastases (89 and 86%, respectively), while they were low for lymph node and lung metastases on post-treatment scans (61 and 39%, respectively). CONCLUSIONS: Diagnostic scanning with relatively low dose I-123 is not always predictive of subsequent therapeutic I-131 uptake, especially for lymph node and lung metastases of differentiated thyroid cancer. PMID- 19787313 TI - Usefulness of F-18 FDG PET/CT in the assessment of disseminated Mycobacterium avium complex infection. AB - A patient showing abnormal fluorine-18-fluorodeoxyglucose (FDG) uptake due to disseminated Mycobacterium avium complex (MAC) infection is presented. Increased focal FDG uptake was demonstrated in the cervical and supraclavicular lymph nodes, spleen, and diffuse bone marrow. FDG PET/CT is considered as a useful diagnostic tool to assess the exact extent and activity of disseminated MAC infection. Moreover, it is advantageous over CT and magnetic resonance imaging to assess the treatment response and time course of the disease. PMID- 19787316 TI - [Internet addiction -- the great unknown]. PMID- 19787317 TI - [Banning smoking without compromise is the only way out of misery]. PMID- 19787318 TI - [Sounds in medicine. On the historical basis of modern diagnosis]. PMID- 19787319 TI - Images in clinical medicine. Purpura fulminans in pneumoccocal sepsis. PMID- 19787320 TI - [Computer game playing: clinical characteristics of dependence and abuse among adolescents]. AB - OBJECTIVE AND METHODS: The aim of the study was to investigate the prevalence of excessive computer game playing behaviour among adolescents with psychopathological tendencies that resemble the classic symptoms of addiction. To address this question, criteria for excessive computer game playing behaviour were developed on the basis of diagnostic criteria for substance-related disorders according to ICD-10. RESULTS: Excessive computer playing corresponding to addictive behaviour were found in 12.3% of the adolescents (n = 1068; 9.6% showed abusive and 2.7% dependent behaviour). Adolescents with excessive computer and video game playing behaviour also show substantial correlations with other psychosocial and psychopathological abnormalities, such as alterations in the intensity of social conflict, concentration deficits, maladaptive coping behaviour, stress and psychosomatic challenge, and school phobia. CONCLUSIONS: The study provides the first empirical data about excessive computer game playing among adolescents in Austria. It shows that pathological computer game playing can be well described by criteria developed in accordance to substance dependence, and that abusive or dependent computer game playing shows specific connections with psycho-social, psychopathological and motivational factors. Overall, the results demonstrate a clear need for deeper research on this subject and the need for a design of prevention measures. PMID- 19787321 TI - [Government earnings from cigarette smoking of adolescents in Austria]. AB - Smoking prevalence in minors has increased considerably since 1986. In comparison to other European countries, smoking rates in 15-year-old students are the highest in Austria. Goal of our study was the estimation of government earnings from tobacco consumption of minors in Austria. METHODS: Tobacco tax paid by adolescents aged 11 to 17 years was estimated from smoking prevalences and taxation of cigarettes. RESULTS: In 2006 state revenues from cigarette consumption of minors in Austria amounted to 60.5 million Euro. DISCUSSION: Up to now the fight against business interest of the tobacco industry in Austria has been mainly left to volunteers. Therefore we suggest the funding a professional agency, independent from state budget and interest groups, by a tobacco prevention fund which is financed by the revenues from cigarettes smoked by youth. The mission of this fund should be to lower smoking incidence and smoking prevalence among minors. The WHO framework convention on tobacco control, ratified by Austria in 2005, should be considered in the next amendments of the tobacco law. The efforts of the European Union to reduce tobacco consumption should be supported also by Austria. For this purpose the tobacco prevention fund - similar to the regulation in Switzerland - would give the financial background. PMID- 19787322 TI - The inflammatory response is influenced by FXIII VAL 34 LEU polymorphism in a human LPS model. AB - BACKGROUND: In sepsis, activation of coagulation and inhibition of fibrinolysis lead to microvascular thrombosis. The Val34Leu polymorphism affects the function of FXIII by increasing the rate of FXIII activation by thrombin, which results in an increased and faster rate of fibrin stabilization. Sepsis and multi-organ failure cause disturbance of the normal balance of inflammation and coagulation, one of the most frequent causes of death in ICU patients. Research in polymorphism has shown the possible influence of FXIII in coagulation and inflammation. METHODS: We analyzed the influence of the common FXIII Val34Leu polymorphism on inflammatory and coagulation parameters in human experimental endotoxinemia. Healthy volunteers (n = 62) received 2 ng endotoxin (LPS) per kg body weight as a bolus infusion over 2 min. We developed a new mutagenic separated PCR assay for determination of the FXIII promoter polymorphism. RESULTS: FXIII levels were higher for homozygous carriers of the FXIII polymorphism in comparison with wild-type 34 Val/Val and heterozygous 34 Val/Leu. Interestingly, persons homozygous for the FXIII Val34Leu polymorphism had lower monocyte and neutrophil counts throughout the observation period, yet prothrombin fragment 1+2 and D-dimer levels did not differ after LPS challenge. CONCLUSION: Our findings indicate that the common FXIII Val34Leu polymorphism is associated with differences in monocyte and neutrophil cell counts in response to systemic LPS infusion in humans. PMID- 19787323 TI - [Motivation for physical activity - a survey in a Central European state]. AB - INTRODUCTION: Physical activity has high importance in the prevention of diseases, particularly where lifestyle diseases are concerned. To motivate a person to be physically active often proves to be difficult in clinical practice. Thus it was the aim of this study to find out through interviews how to best motivate most notably the part of the population that is less active. METHODS: 500 persons aged from 15 years onwards were asked in face-to-face interviews about their leisure activities, self-assessment of their personal fitness, and about inhibiting and motivating factors in connection with their physical activity. RESULTS: Only every second interviewed person is intentionally active in order to improve his/her own fitness. The better part of the inactive population can envisage introducing more physical activity into their everyday life. There are various reasons that instigate to be more active: above all, the recommendation of doctors, but also the wish for physical wellbeing or group dynamics act as a stimulant. Would there be an advertising campaign promoting the importance of physical activity, top athletes and physicians would have the most motivating impact. CONCLUSION: A sustainable and favourable effect on health promotion could be achieved most notably by motivating people to add more physical activity to their everyday life. PMID- 19787324 TI - Prevalence of vertebral fracture in elderly men and women with osteopenia. AB - The objective of our cross-sectional, not population-based, observational study was to determine the prevalence of patients with osteopenia in relation to bone mineral density (BMD) and vertebral fractures and to identify risk factors for vertebral fractures above the osteoporotic BMD T-score threshold of -2.5. A total of 698 consecutive hospitalized and ambulatory white patients with T-scores between -1.0 and -2.5 were investigated in an academic medical center in Austria between January 2005 and June 2006. Measurements of BMD (T-score at spine and hip) by DXA, spinal X-ray, laboratory data of bone metabolism and vitamin D, and sex-specific data were assessed. A multivariate general linear model was used to calculate vertebral and non-vertebral fractures, age, BMI and lowest T-score at measured anatomic sites. Overall, 218 patients (31.2%) with a mean age of 72.2 years and mean BMI of 26.0 presented with vertebral fractures; in comparison, patients with non-vertebral fractures had a mean age of 62.6 years and BMI 24.6, and patients without fractures had a mean age of 61.3 years and BMI 24.0 (P < 0.001). Serum markers of bone resorption and formation had no influence on fracture occurrence but 73% of the patients had vitamin D deficiency (25.2 +/- 9.8 ng/ml). The lowest T-score in all fracture patients was found at the femoral neck. At this site 64.3% patients with vertebral fractures had a T-score within the range -1.0 to -2.0 (95% CI 57.3-70.8). The prevalence of vertebral fractures increased stepwise (P < 0.05) and at T-scores between -1.5 and -2.0 the increase was linear. We conclude that a significant proportion of non-osteoporotic elderly men and women with mean age 72 years, BMI 26.0 and a threshold T-score above -2.0 are susceptible to osteoporotic vertebral fractures. These patients are not adequately detected by BMD measurements based on WHO thresholds. Early assessment, prior to their first fracture, is important for identifying individuals with clinical risk factors. PMID- 19787325 TI - Fatal hemorrhage due to thrombosis and rupture of the portal vein and hepatic artery. AB - Portal vein thrombosis is a fairly common clinical condition that is usually not fatal but may give rise to serious complications. We report the case of a woman who was always in good health until the age of 50, when she developed acute gastroenterocolitis with inflammation of the portal vein (pylephlebitis or septic portal thrombophlebitis), resulting in thrombus formation, rupture of the vascular wall and exsanguination. At autopsy, no signs of thrombosis or inflammation were found elsewhere in the body and there was no evidence of any other disease or abnormality. Pylephlebitis may occur following intra-abdominal sepsis from any source. It is a rare condition that carries a high mortality. Rupture of the inflamed portal vein and possibly the adjacent artery is an extremely rare complication. PMID- 19787327 TI - MACC1 - more than metastasis? Facts and predictions about a novel gene. AB - We recently identified the metastasis-associated in colon cancer 1 (MACC1) gene by a genome-wide search for differentially expressed genes in human colon cancer tissues, metastases, and normal tissues. Based on MACC1 expression in primary colon cancers, which did not present with metastases, our negative and positive prediction for metachronous metastasis was correct in 80% and 74% of cases, respectively. The 5-year-survival was 80% for MACC1 low expressors, but 15% for individuals who showed high MACC1 expression in their primary tumors. MACC1 induces migration, invasion and proliferation in cell culture, and liver and lung metastases in xenograft models. Here, we describe features of MACC1 beyond its utility as an indicator of metastasis. We elucidate its genomic localization and organization, its predicted splice variants, and single nucleotide polymorphisms. We discuss the MACC1 protein domain structure, posttranslational modifications, its conservation through evolution, and some family ties to SH3BP4. Furthermore, we summarize the predicted expressions of MACC1 in normal and malignant human tissues. We also evaluate the MACC1 levels in the context of one of its transcriptional targets, the receptor tyrosine kinase Met that activates the hepatocyte growth factor/Met signaling pathway, leading to enhanced cell motility, invasion, and metastasis. PMID- 19787328 TI - [Hearing loss and gait ataxia without dizziness. Hemosiderosis]. AB - Superficial cerebral hemosiderosis is characterized by sensorineural hearing loss, gait ataxia and pyramidal signs with irreversible myelopathy. It is caused by chronic hemorrhage into the subarachnoid space with hemosiderin deposition in the subpial, leptomeningeal and subependymal layers. Imaging of the entire neuroaxis is indicated to localize a source of bleeding, including cerebral and spinal angiography when necessary. Taking into account clinical signs and symptoms the interpretation of T2*-weighted images allows the radiologist to set the course for the optimal therapeutic regimen. PMID- 19787329 TI - [Imaging procedures for gastrointestinal stromal tumors]. AB - Morphological and functional imaging methods are used for staging of gastrointestinal stromal tumors (GIST) and to follow-up GIST patients undergoing therapy. Computed tomography is the most frequently used morphological imaging procedure and has been recommended as the imaging method of choice according to current GIST guidelines. However, positron emission tomography using [(18)F]-2 fluoro-2-deoxy-D-glucose (FDG-PET) as the radiotracer has shown to be advantageous over morphological imaging procedures when assessing therapy response at an early time point. While tumor size reduction in morphological imaging typically requires time to develop, a decrease in FDG uptake can be detected as early as 24 h following therapy initiation. To overcome the limitations of size-based therapy response assessment on morphological imaging procedures, new density-based therapy response criteria have been developed and implemented for GIST. This review addresses both indications and accuracy of morphological and functional imaging modalities for GIST. PMID- 19787331 TI - Construction of a reference molecular linkage map of globe artichoke (Cynara cardunculus var. scolymus). AB - The genome organization of globe artichoke (Cynara cardunculus var. scolymus), unlike other species belonging to Asteraceae (=Compositae) family (i.e. sunflower, lettuce and chicory), remains largely unexplored. The species is highly heterozygous and suffers marked inbreeding depression when forced to self fertilize. Thus a two-way pseudo-testcross represents the optimal strategy for linkage analysis. Here, we report linkage maps based on the progeny of a cross between globe artichoke (C. cardunculus var. scolymus) and cultivated cardoon (C. cardunculus var. altilis). The population was genotyped using a variety of PCR based marker platforms, resulting in the identification of 708 testcross markers suitable for map construction. The male map consisted of 177 loci arranged in 17 major linkage groups, spanning 1,015.5 cM, while female map was built with 326 loci arranged into 20 major linkage groups, spanning 1,486.8 cM. The presence of 84 loci shared between these maps and those previously developed from a cross within globe artichoke allowed for map alignment and the definition of 17 homologous linkage groups, corresponding to the haploid number of the species. This will provide a favourable property for QTL scanning; furthermore, as 25 mapped markers (8%) correspond to coding regions, it has an additional value as functional map and might represent an important genetic tool for candidate gene studies in globe artichoke. PMID- 19787330 TI - [Pathology and molecular biology of gastrointestinal stromal tumors (GIST)]. AB - Gastrointestinal stromal tumors (GIST) show an aggressive behavior with metastases and recurrences in up to 50% of cases. They can be clearly distinguished from other mesenchymal tumors by immunohistochemistry in the vast majority of cases. Of the tumors 85% carry somatic activating mutations in the receptor tyrosine kinases KIT or PDGFRA. The detection of these molecular events has changed the treatment of inoperable and metastatic GISTs dramatically as up to 80% of tumors respond well to tyrosine kinase inhibitors. This treatment has become the gold standard in the last few years with only few side effects. Knowledge of the underlying KIT or PDGFRA mutation is both relevant for the prognosis and treatment response. PMID- 19787332 TI - Heritable variation in the inflorescence replacement program of Arabidopsis thaliana. AB - Owing to their sessile habits and trophic position within global ecosystems, higher plants display a sundry assortment of adaptations to the threat of predation. Unlike animals, nearly all higher plants can replace reproductive structures lost to predators by activating reserved growing points called axillary meristems. As the first step in a program aimed at defining the genetic architecture of the inflorescence replacement program (IRP) of Arabidopsis thaliana, we describe the results of a quantitative germplasm survey of developmental responses to loss of the primary reproductive axis. Eighty-five diverse accessions were grown in a replicated common garden and assessed for six life history traits and four IRP traits, including the number and lengths of axillary inflorescences present on the day that the first among them re-flowered after basal clipping of the primary inflorescence. Significant natural variation and high heritabilities were observed for all measured characters. Pairwise correlations among the 10 focal traits revealed a multi-dimensional phenotypic space sculpted by ontogenic and plastic allometries as well as apparent constraints and outliers of genetic interest. Cluster analysis of the IRP traits sorted the 85 accessions into 5 associations, a topology that establishes the boundaries within which the evolving Arabidopsis genome extends and restricts the species' IRP repertoire to that observable worldwide. PMID- 19787333 TI - [Physical movement - is it good for the back? Nationwide representative study on different effects of physical activity at the workplace and in leisure time]. AB - Physical activity is an important component of primary and secondary prevention of orthopedic complaints such as back pain as well as for many other syndromes. This epidemiologic research project investigated the multifactorial interaction between physical leisure activities and back pain and also the question whether regular physical activity at the workplace can be equated with the effect of regular leisure activity. From a patients point of view this could be construed as an"excuse" to refrain from leisure and fitness sports. Within the framework of a cooperative project between the Orthopedic University Clinic in Heidelberg and the Robert-Koch Institute in Berlin, representative data were gathered for the first time in Germany on physical activity at the workplace and in leisure time as well as the prevalence of back pain. Within the first national health survey a random sample of 3,488 employed German citizens aged 18-69 years old was investigated with multiple logistic regression analyses.The prevalence of 7-day back pain in Germany was 34% and the prevalence for 1-year was 60%. Physical activity at the workplace was associated with a significantly higher risk for back pain whilst leisure sport activity was accompanied by a lower prevalence of back pain. Although 39% of all persons who were inactive in sport and physical activities claimed to have felt back pain at least once in a retrospective 7-day period, the corresponding values for persons active in sport were 33% (1-2 h sport/week), 27% (2-4 h sport/week) and 30% (>4 h sport/week).This study provides population-based epidemiologic data on the prevalence of back pain among employed German citizens for the first time since the reunification. Although causal conclusions cannot principally be derived from cross-sectional data, the results of this analysis allow the multifactorial conditional structure to be unraveled. Our data demonstrate that manual physical employment does not represent a substitute for fitness leisure sports, but physically demanding working conditions themselves represent a significant risk factor for back pain. PMID- 19787334 TI - Severe cutaneous adverse reactions: emergency approach to non-burn epidermolytic syndromes. AB - INTRODUCTION: Although severe cutaneous adverse reactions (SCARs), such as Stevens-Johnson syndrome and toxic epidermal necrolysis, are rare, they are associated with considerable morbidity and mortality. METHODS: The current knowledge regarding background, differential diagnoses, critical care and implications for inter-hospital emergency medical service (EMS) transport of these patients is discussed. CONCLUSION: SCAR patients will substantially benefit from early interdisciplinary care and thorough consideration of complications during EMS transport and intensive care treatment. PMID- 19787335 TI - Beneficial effects of the heme oxygenase-1/carbon monoxide system in patients with severe sepsis/septic shock. AB - PURPOSE: We evaluated the relations among the arterial carbon monoxide (CO) concentration, heme oxygenase (HO)-1 expression by monocytes, oxidative stress, plasma levels of cytokines and bilirubin, and the outcome of patients with severe sepsis or septic shock. METHODS: Thirty-six patients who fulfilled the criteria for severe sepsis or septic shock and 21 other patients without sepsis during their stay in the intensive care unit were studied. HO-1 protein expression by monocytes, arterial CO, oxidative stress, bilirubin, and cytokines were measured. RESULTS: Arterial blood CO, cytokine, and bilirubin levels, and monocyte HO-1 protein expression were higher in patients with severe sepsis/septic shock than in non-septic patients. Increased HO-1 expression was related to the arterial CO concentration and oxidative stress. There was a positive correlation between survival and increased HO-1 protein expression or a higher CO level. CONCLUSIONS: Arterial CO and monocyte HO-1 protein expression were increased in critically ill patients, particularly those with severe sepsis or septic shock, suggesting that oxidative stress is closely related to HO-1 expression. The HO-1/CO system may play an important role in sepsis. PMID- 19787336 TI - Electron microscopy of the remodelling process in hamstring tendon used as ACL graft. AB - The purpose of the present study was to make a histological analysis of the remodelling process of hamstring tendon graft used as Anterior Cruciate Ligament (ACL). The hamstring graft of eight patients was biopsied at different follow-up times from 1 to 10 years. The specimens were analysed with transmission electron microscopy (TEM) at ultrastructural level comparing them with a native ACL and a native hamstring graft. The hamstring graft was found to undergo ultrastructural changes in terms of number and diameter of fibrils with the major changes occurring in the first 2 years. At longer times after surgery (48 and 120 months) no important further changes were evident and the ultrastructure did not vary substantially from 2 to 10 years. In conclusion, the hamstring tendon used as ACL graft undergoes a transformation process but does not match the ultrastructure pattern of a normal ACL up to 10 years. PMID- 19787339 TI - Comparison of single-reflection near-infrared and attenuated total reflection mid infrared spectroscopies to identify and monitor hydrocarbons spilled in the marine environment. AB - The capability of single-reflection near-IR (NIR) spectroscopy to differentiate, characterize and monitor the fate of a set of hydrocarbons spilled in the marine environment was compared with that of multiple-reflection horizontal attenuated total reflection mid-IR (ATR-MIR) spectroscopy. Multivariate pattern recognition techniques [principal component analysis (PCA), multivariate polynomial regression, cluster analysis and potential curves] were applied to unravel the major trends of the weathering processes of four generic types of crude oils and two heavy fuel oils spilled under controlled conditions for almost 4 months. A chemical interpretation of the NIR spectra related the weathering processes and the PCA loadings, which had not already been done in the literature. Weathering for both light and heavy products was characterized by a contrast among the linear aliphatic structures (more volatile and easy to degrade) and the branched and aromatic structures (more recalcitrant). Potential curves were applied to model each product and determine objectively whether unknown samples could be classified correctly. Polynomial regression on the PCA scores was employed to evaluate the time elapsed from the oil spillage to its sampling; this represents a new approach to assess the age of a hydrocarbon lump. In general, NIR spectroscopy yielded good results when light crude oils were studied, whereas ATR MIR spectroscopy led to satisfactory results for both light and heavy products. PMID- 19787337 TI - Motivational effects of opiates in conditioned place preference and aversion paradigm--a study in three inbred strains of mice. AB - RATIONALE: Interstrain differences in the motivational properties of morphine and heroin have been previously reported in mice, suggesting the involvement of a genotype-dependent modulation of the rewarding effects of opiates. Yet, interstrain differences in the motivational effects of naloxone have not been described. OBJECTIVES: The aim of our study was to examine genotype modulation of the motivational effects of opiates in inbred stains of mice with known, distinct, opiate-induced phenotypes, and morphine-induced striatal transcriptional responses. METHODS: We studied the rewarding properties of morphine (5, 10, and 20 mg/kg i.p.) and heroin (1, 5, and 10 mg/kg i.p.) in conditioned place preference (CPP) as well as the aversive properties of naloxone (1, 10, and 20 mg/kg i.p.) in the conditioned place aversion (CPA) paradigm in C57Bl/6J (C57), DBA/2J (DBA), and SWR/J (SWR) inbred strains of mice. RESULTS: Our results show that morphine and heroin as well as naloxone induce CPP and CPA, respectively, in a genotype- and dose-dependent manner in these studied inbred strains of mice. Interestingly, C57 mice are the most sensitive in the case of the rewarding properties of morphine and heroin but are the least sensitive to the aversive effects of naloxone, whereas the DBA strain exhibit the opposite behavioral effects. CONCLUSIONS: We suggest that motivational homeostasis can be modulated by mu opioid receptors in mice, with the C57 mice representing a genotype that is more sensitive to processes related to rewards, whereas the genotype of DBA is more sensitive to aversion. PMID- 19787338 TI - Decreased levels of serum brain-derived neurotrophic factor in drug-naive first episode schizophrenia: relationship to clinical phenotypes. AB - OBJECTIVE: There is accumulating evidence that brain-derived neurotrophic factor (BDNF) may be involved in the pathophysiology of patients with schizophrenia. Clinical studies show reductions in BDNF in schizophrenic patients treated with first generation antipsychotics or second generation antipsychotics. However, there have been few systematic studies to examine the relationship between BDNF levels and psychopathology in first-episode and drug-naive patients with schizophrenia. MATERIALS AND METHODS: Serum BDNF levels were determined using enzyme-linked-immunosorbent assay (ELISA) in the serum of 88 never-medicated first-episode and 90 healthy controls subjects matched for age and gender. The schizophrenia symptomatology and the depressive symptoms were assessed by the positive and negative syndrome scale (PANSS) and the Hamilton rating (HAMD) scale for depression. RESULTS: The results showed that BDNF levels were significantly lower in first-episode patients with schizophrenia than in healthy control subjects (9.0 +/- 4.2 ng/ml vs 12.1 +/- 2.2 ng/ml; F = 37.6; df = 1, 176; p < 0.0001). A significant positive correlation between BDNF levels and PANSS positive subscore was observed (r = 0.29; df = 88; p = 0.008). Furthermore, higher BDNF levels were observed in patients with paranoid subtype of schizophrenia. However, no significant correlation between BDNF and HAMD total score was found. CONCLUSION: Low BDNF levels at the onset of psychosis suggest that it may contribute to the pathogenesis of schizophrenia and perhaps, could be a candidate biological marker for positive symptoms. PMID- 19787340 TI - Detection of microbial volatile organic compounds (MVOCs) by ion-mobility spectrometry. AB - Traces of microbial volatile organic compounds (MVOCs) in air can indicate the presence of growth of moulds in the indoor environment. Ion-mobility spectrometry is a very promising method for detection of these MVOCs, because of its high sensitivity. For development of an in-situ method for detection of MVOCs, a portable ion-mobility spectrometer (IMS) was used and test gases of 14 MVOCs and their respective mixtures were investigated. IMS spectra were recorded as a function of concentration of MVOCs in air. Drift time and mobility of reactant ions formed in positive polarity mode were determined and correlated with the mass-to-charge ratio (m/z) of the MVOCs investigated. The estimated detection limit has a specific value for each MVOC and is in the range 3 to 96 microg m(-3) (1 to 52 ppb(V)). Indoor trials show that IMS can indicate hidden mould growth. PMID- 19787341 TI - FT-NIR spectroscopy for non-invasive identification of natural polymers and resins in easel paintings. AB - In the present study, the analytical strengths and limitations of near-infrared (NIR) spectroscopy to non-invasively characterize organic components in painting materials have been investigated. In spite of the increased amount of information available today from advanced modern analytical instrumentations dedicated to cultural heritage, the non-invasive identification of materials belonging to the wide class of organic compounds historically used in paintings is still a challenging task. Near-infrared spectroscopy offers several attractive features that make this technique particularly suitable to this purpose. In fact, it is non-invasive, allows for non-contact measurements in reflectance mode, gives molecular information on complex macromolecules, and can be performed on-site by means of portable devices. First-derivative transformation of reflectance spectroscopic data has been applied to provide a simple and fast way to deduce more information from NIR spectra. This approach has allowed spectral features to be identified that can be useful to distinguish different compounds belonging to the classes of lipids, proteins, and resins. To this purpose, at first, a spectral database of pure standard has been collected. Our analytical approach was then successfully validated on pictorial models reproducing the typical stratigraphy of an easel painting. As final step, the study of a real painting has been attempted and a drying oil, animal glue, and a terpenic natural resin, as well as an earth pigment were clearly identified, as cross-validated by GC-MS analysis. PMID- 19787342 TI - Optical far- and near-field femtosecond laser ablation of Si for nanoscale chemical analysis. AB - Extending spatial resolution in laser-based chemical analysis to the nanoscale becomes increasingly important as nanoscience and nanotechnology develop. Implementation of femtosecond laser pulses arises as a basic strategy for increasing resolution since it is associated with spatially localized material damage. In this work we study femtosecond laser far- and near-field processing of silicon (Si) at two distinct wavelengths (400 and 800 nm), for nanoscale chemical analysis. By tightly focusing femtosecond laser beams in the far-field, we were able to produce sub-micrometer craters. In order to further reduce the crater size, similar experiments were performed in the near-field through sub-wavelength apertures, resulting in the formation of sub-30-nm craters. Laser-induced breakdown spectroscopy (LIBS) was used for chemical analysis with a goal to identify the minimum crater size from which spectral emission could be measured. Emission from sub-micrometer craters (full width at half maximum) was possible, which are among the smallest ever reported for femtosecond LIBS. PMID- 19787343 TI - Unilateral NMR applied to the conservation of works of art. AB - In conventional NMR, samples from works of art in sizes above those considered acceptable in the field of art conservation would have to be removed to place them into the bore of large superconducting magnets. The portable permanent magnet-based systems, by contrast, can be used in situ to study works of art, in a noninvasive manner. One of these portable NMR systems, NMR-MOUSE(R), measures the information contained in one pixel in an NMR image from a region of about 1 cm(2), which can be as thin as 2-3 microm. With such a high depth resolution, profiles through the structures of art objects can be measured to characterize the materials, the artists' techniques, and the deterioration processes. A novel application of the technique to study a deterioration process and to follow up a conservation treatment is presented in which micrometer-thick oil stains on paper are differentiated and characterized. In this example, the spin-spin relaxation T (2) of the stain is correlated to the iodine number and to the degree of cross linking of the oil, parameters that are crucial in choosing an appropriate conservation treatment to remove them. It is also shown that the variation of T (2) over the course of treatments with organic solvents can be used to monitor the progress of the conservation interventions. It is expected that unilateral NMR in combination with multivariate data analysis will fill a gap within the set of high-spatial-resolution techniques currently available for the noninvasive analysis of materials in works of art, where procedures to study the inorganic components are currently far more developed than those suitable for the study of the organic components. PMID- 19787344 TI - Polystyrene beads as an alternative support material for epitope identification of a prion-antibody interaction using proteolytic excision-mass spectrometry. AB - The binding epitope structure of a protein specifically recognized by an antibody provides key information to prevent and treat diseases with therapeutic antibodies and to develop antibody-based diagnostics. Epitope structures of antigens can be effectively identified by the proteolytic epitope excision-mass spectrometry (MS) method, which involves (1) immobilization of monoclonal or polyclonal antibodies, e.g., on N-hydroxysuccinimide-activated sepharose, (2) affinity binding of the antigen followed by limited proteolytic digestion of the immobilized immune complex, and (3) elution and mass spectrometric analysis of the remaining affinity-bound peptide(s). In the epitope analysis of recombinant cellular bovine prion protein (bPrP(C)) to a monoclonal antibody (mAb3E7), we found that epitope excision experiments resulted in extensive nonspecific binding of bPrP to a standard sepharose matrix employed. Here, we show that the use of amino-modified polystyrene beads with aldehyde functionality is an efficient alternative support for antibody immobilization, suitable for epitope excision MS, with complete suppression of nonspecific bPrP binding. PMID- 19787345 TI - Comparison of error-amplification and haptic-guidance training techniques for learning of a timing-based motor task by healthy individuals. AB - Performance errors drive motor learning for many tasks. Some researchers have suggested that reducing performance errors with haptic guidance can benefit learning by demonstrating correct movements, while others have suggested that artificially increasing errors will force faster and more complete learning. This study compared the effect of these two techniques--haptic guidance and error amplification--as healthy subjects learned to play a computerized pinball-like game. The game required learning to press a button using wrist movement at the correct time to make a flipper hit a falling ball to a randomly positioned target. Errors were decreased or increased using a robotic device that retarded or accelerated wrist movement, based on sensed movement initiation timing errors. After training with either error amplification or haptic guidance, subjects significantly reduced their timing errors and generalized learning to untrained targets. However, for a subset of more skilled subjects, training with amplified errors produced significantly greater learning than training with the reduced errors associated with haptic guidance, while for a subset of less skilled subjects, training with haptic guidance seemed to benefit learning more. These results suggest that both techniques help enhanced performance of a timing task, but learning is optimized if training subjects with the appropriate technique based on their baseline skill level. PMID- 19787346 TI - Properties of rectified averaging of an evoked-type signal: theory and application to the vestibular-evoked myogenic potential. AB - The properties of rectified averages were investigated using the VEMP (vestibular evoked myogenic potential) as an example of an evoked-type response. Recordings were made of surface EMG from the sternocleidomastoid (SCM) muscles of six volunteers, unstimulated, at different levels of tonic activation and then in response to clicks of different intensities. The stochastic properties of the surface EMG recorded were shown to be well modelled using a zero mean normal distribution with a standard deviation equivalent to the mean RMS (root mean squared) value (mean residual error variance 0.87%). Assuming a normal distribution, equations were derived for the expected value of both the rectified and RMS average with the addition of constant waveforms of different sizes. A simulation using recorded EMG and added sine waves of different amplitudes demonstrated that the equations predicted the rectified averages accurately. It also confirmed the importance of the relative amplitude of the added signal in determining whether it was detected using rectified averages. The same equations were then applied to actual data consisting of VEMPs of different relative amplitudes recorded from the volunteers. Whilst the signal-to-noise ratio (measured by corrected amplitude) was a major determinant of the nature of the rectified average, consistent deviations were detected between the predicted and actual rectified averages. Deviations from predicted values indicated that the VEMP did not behave simply like a constant signal added to tonic background EMG. A more complicated model, which included temporal jitter as well as inhibition of background EMG during the VEMP, was required to fit the physiological recordings. Rectified averages are sensitive to physiological properties, which are not apparent when using unrectified averages alone. Awareness of the properties of rectified averages should improve their interpretation. PMID- 19787347 TI - Cloning, purification and characterization of two components of phenol hydroxylase from Rhodococcus erythropolis UPV-1. AB - Phenol hydroxylase that catalyzes the conversion of phenol to catechol in Rhodococcus erythropolis UPV-1 was identified as a two-component flavin-dependent monooxygenase. The two proteins are encoded by the genes pheA1 and pheA2, located very closely in the genome. The sequenced pheA1 gene was composed of 1,629 bp encoding a protein of 542 amino acids, whereas the pheA2 gene consisted of 570 bp encoding a protein of 189 amino acids. The deduced amino acid sequences of both genes showed high homology with several two-component aromatic hydroxylases. The genes were cloned separately in cells of Escherichia coli M15 as hexahistidine tagged proteins, and the recombinant proteins His(6)PheA1 and His(6)PheA2 were purified and its catalytic activity characterized. His(6)PheA1 exists as a homotetramer of four identical subunits of 62 kDa that has no phenol hydroxylase activity on its own. His(6)PheA2 is a homodimeric flavin reductase, consisting of two identical subunits of 22 kDa, that uses NAD(P)H in order to reduce flavin adenine dinucleotide (FAD), according to a random sequential kinetic mechanism. The reductase activity was strongly inhibited by thiol-blocking reagents. The hydroxylation of phenol in vitro requires the presence of both His(6)PheA1 and His(6)PheA2 components, in addition to NADH and FAD, but the physical interaction between the proteins is not necessary for the reaction. PMID- 19787348 TI - Enhanced recombinant protein production in pyruvate kinase mutant of Bacillus subtilis. AB - Previous work demonstrated that acetate production was substantially lower in pyruvate kinase (pyk) mutant of Bacillus subtilis. The significantly lower acetate production in the pyk mutant is hypothesized to have positive effect on recombinant protein production either by lifting the inhibitory effect of acetate accumulation in the medium or redirecting the metabolic fluxes beneficial to biomass/protein synthesis. In this study, the impact of the pyk mutation on recombinant protein production was investigated. Green fluorescent protein (GFP+) was selected as a model protein and constitutively expressed in both the wild type strain and a pyk mutant. In batch cultures, the pyk mutant produced 3-fold higher levels of recombinant protein when grown on glucose as carbon source. Experimental measurements and theoretical analysis show that the higher protein yield of the mutant is not due to removal of an acetate-associated inhibition of expression or gene dosage or protein stability but a much lower acetate production in the mutant allows for a greater fraction of carbon intake to be directed to protein synthesis. PMID- 19787349 TI - Modular organisation and functional analysis of dissected modular beta-mannanase CsMan26 from Caldicellulosiruptor Rt8B.4. AB - CsMan26 from Caldicellulosiruptor strain Rt8.B4 is a modular beta-mannanase consisting of two N-terminal family 27 carbohydrate-binding modules (CBMs), followed by a family 35 CBM and a family 26 glycoside hydrolase catalytic module (mannanase). A functional dissection of the full-length CsMan26 and a comprehensive characterisation of the truncated derivatives were undertaken to evaluate the role of the CBMs. Limited proteolysis was used to define biochemically the boundaries of the different structural modules in CsMan26. The full-length CsMan26 and three truncated derivatives were produced in Escherichia coli, purified and characterised. The systematic removal of the CBMs resulted in a decrease in the optimal temperature for activity and in the overall thermostability of the derivatives. Kinetic experiments indicated that the presence of the mannan-specific family 27 CBMs increased the affinity of the enzyme towards the soluble galactomannan substrate but this was accompanied by lower catalytic efficiency. The full-length CsMan26 and its truncated derivatives were unable to hydrolyse mannooligosaccharides with degree of polymerisation (DP) of three or less. The major difference in the hydrolysis pattern of larger mannooligosaccharides (DP >3) by the derivatives was determined by their abilities to further hydrolyse the intermediate sugar mannotetraose. PMID- 19787350 TI - Effect of nutrient and selective inhibitor amendments on methane oxidation, nitrous oxide production, and key gene presence and expression in landfill cover soils: characterization of the role of methanotrophs, nitrifiers, and denitrifiers. AB - Methane and nitrous oxide are both potent greenhouse gasses, with global warming potentials approximately 25 and 298 times that of carbon dioxide. A matrix of soil microcosms was constructed with landfill cover soils collected from the King Highway Landfill in Kalamazoo, Michigan and exposed to geochemical parameters known to affect methane consumption by methanotrophs while also examining their impact on biogenic nitrous oxide production. It was found that relatively dry soils (5% moisture content) along with 15 mg NH (4) (+) (kg soil)(-1) and 0.1 mg phenylacetylene(kg soil)(-1) provided the greatest stimulation of methane oxidation while minimizing nitrous oxide production. Microarray analyses of pmoA showed that the methanotrophic community structure was dominated by Type II organisms, but Type I genera were more evident with the addition of ammonia. When phenylacetylene was added in conjunction with ammonia, the methanotrophic community structure was more similar to that observed in the presence of no amendments. PCR analyses showed the presence of amoA from both ammonia-oxidizing bacteria and archaea, and that the presence of key genes associated with these cells was reduced with the addition of phenylacetylene. Messenger RNA analyses found transcripts of pmoA, but not of mmoX, nirK, norB, or amoA from either ammonia-oxidizing bacteria or archaea. Pure culture analyses showed that methanotrophs could produce significant amounts of nitrous oxide, particularly when expressing the particulate methane monooxygenase (pMMO). Collectively, these data suggest that methanotrophs expressing pMMO played a role in nitrous oxide production in these microcosms. PMID- 19787351 TI - Hematopoietic progenitor kinase 1 is a critical component of prostaglandin E2 mediated suppression of the anti-tumor immune response. AB - Lung cancer is the leading cause of cancer-related mortality in the world, resulting in over a million deaths each year. Non-small cell lung cancers (NSCLCs) are characterized by a poor immunogenic response, which may be the result of immunosuppressive factors such as prostaglandin E2 (PGE(2)) present in the tumor environment. The effect of PGE(2) in the suppression of anti-tumor immunity and its promotion of tumor survival has been established for over three decades, but with limited mechanistic understanding. We have previously reported that PGE(2) activates hematopoietic progenitor kinase 1 (HPK1), a hematopoietic specific kinase known to negatively regulate T-cell receptor signaling. Here, we report that mice genetically lacking HPK1 resist the growth of PGE(2)-producing Lewis lung carcinoma (LLC). The presence of tumor-infiltrating lymphocytes (TILs) and T-cell transfer into T cell-deficient mice revealed that tumor rejection is T cell mediated. Further analysis demonstrated that this may be significantly due to the ability of HPK1 (-/-) T cells to withstand PGE(2)-mediated suppression of T-cell proliferation, IL-2 production, and apoptosis. We conclude that PGE(2) utilizes HPK1 to suppress T cell-mediated anti-tumor responses. PMID- 19787353 TI - A KNAT3-like homeobox gene from Juglans nigra L., JnKNAT3-like, highly expressed during heartwood formation. AB - The value of black walnut (Juglans nigra L.) is affected by the quality and quantity of darkly colored heartwood in its stem. We are exploring the regulation of heartwood production by identifying genes associated with the transition from sapwood to heartwood. Previous microarray data indicated that heartwood formation may be related to programmed cell death (PCD). To test this hypothesis, we analyzed the region of heartwood formation in walnut stems (i.e., the transition zone, TZ) for the expression of 80 ESTs putatively associated with PCD. Semi quantitative RT-PCR and real-time PCR was performed to detect the expression changes in candidate genes in the TZ and sapwood of trees harvested in summer and fall. The results revealed that the transcript of a clone that encodes a presumed homeobox protein knotted-1-like 3 (KNAT3) was highly expressed in the TZ when compared with other tissues. Analysis of the full-length coding sequence revealed that the black walnut gene contains regions with 67% similarity to Knox1 and Knox2 domains from the Arabidopsis thaliana KNAT3, as well as a putative homeodomain known to be a transcription factor in other plants. JnKNAT3-like transcript was detected in the pith meristem, roots, embryogenic callus, vascular cambium, female flowers, male flowers, green leaves, and partially and fully senescent leaves of black walnut, although transcript abundance varied considerably among tissues. These analyses may provide insight into the mechanism regulating heartwood formation in walnut and other hardwood trees. PMID- 19787352 TI - Impact of infusion speed on the safety and effectiveness of prothrombin complex concentrate: a prospective clinical trial of emergency anticoagulation reversal. AB - Prothrombin complex concentrate (PCC) infusion is preferred for emergency reversal of coumarin therapy. Rapid infusion can potentially save crucial time; however, the possible impact of high infusion speed on PCC safety and effectiveness has not been delineated. In a prospective multinational clinical trial with 43 patients receiving PCC (Beriplex P/N) for emergency reversal of coumarin therapy, infusion speeds were selected by the investigators. In a two phase statistical analysis, the influence of baseline patient variables and dose on selected infusion speed was assessed. Then, the effect of infusion speed on reduction in international normalized ratio (INR) and on thrombogenicity marker pharmacokinetics was evaluated. Infusion speed ranged widely from 2.0 to 40.0 mL min(-1) with a median of 7.5 mL min(-1). Selection of infusion speed was not significantly influenced by gender, age, body mass index, presence of acute bleeding, indication for coumarin therapy, baseline INR, or PCC dose. Infusion speed was higher by a median of 2.2 mL min(-1) (95% confidence interval, 1.0-4.3 mL min(-1)) among patients receiving Beriplex P/N volumes > or =80 mL compared with smaller infusion volumes. Infusion speed did not affect INR attained 30 min following PCC infusion. None of the evaluated thrombogenicity marker pharmacokinetic parameters was affected by infusion speed. Infusions in one patient with questionable hemostatic efficacy and another with a possibly PCC related thromboembolic event were at moderate and slow speeds, respectively. This study provides the first direct evidence that Beriplex P/N can be rapidly infused for emergency coumarin therapy reversal without altering safety or effectiveness. PMID- 19787354 TI - [Morphology of macular holes after pars plana vitrectomy with silicone oil endotamponade : a pilot study with high resolution Fourier domain OCT (Cirrus OCT)]. AB - OBJECTIVE: After unsuccessful surgery for macular holes re-vitrectomy is often conducted with silicone oil endotamponade. In the postoperative management uncertainty exists whether the macular hole is actually closed. Standard time domain OCT (Stratus OCT and its predecessors, Carl Zeiss Meditec AG) is rarely successful in depicting the central retina under silicone oil. High resolution Fourier domain OCT (Cirrus OCT) may be superior in delineating macular structures under these conditions. METHODS: A total of 10 eyes from 10 patients were examined with the Cirrus OCT (Carl Zeiss Meditec AG) after vitrectomy with silicone oil for persistent macular holes. Sufficiently clear optical media were a prerequisite for the examination. Macular morphology was analyzed under silicone oil and compared with the findings after silicone oil removal. RESULTS: Of the 10 eyes 5 showed macular hole closure under silicone oil with retinal tissue in the center of the fovea. In 3 eyes there was a shallow subretinal cyst in the center of the fovea and the other 5 eyes showed a persisting hole. The macular hole remained closed after oil removal in all 5 eyes with a foveal contour. In 4 of the other 5 eyes the macular hole reopened and for 1 eye the hole remained stable. CONCLUSIONS: This pilot study showed that the aspect of macular holes under silicone oil seems to influence the prognosis after oil removal. Thus, silicone oil removal as well as further surgery may be planned. The reliable analysis of macular holes under silicone oil has only become possible with high resolution Fourier domain OCT. PMID- 19787356 TI - [A new toric diffractive multifocal lens for refractive surgery]. AB - BACKGROUND: Up to now only a combination of lens and corneal surgery in the sense of bioptics could be used in refractive surgery for correcting high myopia, hyperopia or presbyopia in combination with astigmatisms. Since the summer of 2007 the first model of a toric diffractive bifocal intraocular lens is available for correcting combined refractive errors. The first results on 10 eyes from 6 patients are presented in this article. METHOD: Refractive lens exchange with implantation of a toric diffractive multifocal lens (Acri.LISA toric, Zeiss/(*)Acritec) was performed on 10 eyes from 6 patients (age 25-57 years old). Preoperatively best corrected visual acuity varied between 0.5 and 1.0 in patients with astigmatisms between 1.5 and 5.75 dpt in combination with hyperopia (one patient) or myopia. RESULTS: Postoperatively uncorrected visual acuity varied between 0.5 and 1.25 and best corrected visual acuity between 0.8 and 1.25. Postoperative refraction as spherical equivalent was 0 to +1.0 dpt with postoperative astigmatisms between 0 and 1.0 dpt. Rotational stability was found in all eyes, early postoperatively and also after 1 year. Patient satisfaction was very high. CONCLUSIONS: The new toric multifocal lens is a new option in refractive surgery. The first results are very promising but further results and a comparison to the bioptics procedure have to be awaited. PMID- 19787355 TI - [Erythropoietin protects retinal ganglion cells and visual function after ocular ischemia and optic nerve compression]. AB - BACKGROUND: The glycoprotein erythropoietin (EPO) has been shown to be protective in models of neuronal disease and reduced apoptosis of retinal ganglion cells (RGC) after transection of the optic nerve and in glaucoma. In this study we assessed in vivo the properties of EPO on survival of RGC after ischemia and optic nerve compression, as well as on postischemic visual function. Furthermore, the safety of intravitreal injection was assessed. METHODS: In all experiments, EPO was administered intravitreally in male Brown Norway rats. Ocular ischemia was induced by elevating the intraocular pressure for 55 min. The calibrated optic nerve compression was performed for 10 s. RGC were marked stereotactically and quantified by fluorescence microscopy. The retinal function was quantified by electroretinography (ERG) and the whole visual pathway by visual evoked potential (VEP). RESULTS: EPO (2 and 20 units per eye, n=9-21) increased the survival of RGC after ischemia by 21+/-21% and 127+/-31% (mean +/- SEM) and after optic nerve compression by 28+/-12% and 58+/-13%. With EPO (20 units), postischemic function was increased, in ERG by 71+/-13% (a-wave) and 75+/-19% (b-wave) and in VEP by 264+/-65% (p=0.053). Neither the ERG parameters, nor the VEP, nor the number of RGC differed significantly after intravitreal injection of EPO (5, 50, and 200 units, n=6-7) in healthy eyes. CONCLUSION: The combination of toxicological safety and protection of retinal neurons makes EPO a promising drug for ischemic retinal diseases and traumatic optic neuropathy. PMID- 19787357 TI - Differential effects of NOD2 polymorphisms on colorectal cancer risk: a meta analysis. AB - INTRODUCTION: Since Kurzawski et al. described an association between the 3020insC NOD2 single nucleotide polymorphism and the risk of colorectal cancer(CRC) in 2004, reports published in the past several years have controversial results regarding the relationship between the development of CRC and NOD2 gene polymorphisms. To clarify the potential role of NOD2 P286S, R702W, G908R, and 3020insC polymorphisms in CRC patients, we have undertaken a systematic review and meta-analysis of published articles. MATERIALS AND METHODS: Studies reporting on NOD2 polymorphisms and CRC were searched in the PubMed, EMBASE, and the Science Citation Index from the inception of each database to May, 2009. The search strategy included the keywords "CRC", "colon cancer", "rectal cancer", "polymorphism", and "NOD2/CARD15". RESULT: Eight eligible case control studies about Caucasians from four countries contributed data on 5,888 subjects (cases: 3,524; controls: 2,364). Compared to the wild genotype, the R702W, G908R, and 3020insC polymorphisms were associated with an increased risk of CRC (odds ratio (OR): 1.59, 1.98, 1.44; 95% confidence interval (CI): 1.09 2.32, 1.14-3.44, 1.13-1.84; P = 0.02, 0.01, 0.003). However, P268S polymorphism did not influence CRC risk (OR: 1.27; CI: 0.32-5.00; P = 0.73). CONCLUSIONS: These findings indicate that NOD2 R702W, G908R, and 3020insC polymorphisms contribute to CRC susceptibility in Caucasians. Meta-analysis of these polymorphisms in NOD2 gene will help determine their role in CRC carcinogenesis. PMID- 19787359 TI - Intraoperative complications using the Bio-Transfix femoral fixation implant in anterior cruciate ligament reconstruction. AB - The use of biodegradable Transfix femoral fixation technique is a safe and well accepted method when performing anterior cruciate ligament reconstruction. We report on three cases of deformation and back out of the Bio-Transfix implant over the lateral, distal femoral cortex, with failure of the passing wire when advancing the graft into the femoral tunnel in one of these patients. Two of the patients presented with symptoms of iliotibial band friction syndrome, while the third patient was asymptomatic. The graft had clinically integrated demonstrating AP and rotational stability. The symptoms relieved after removal of the failed Bio-Transfix implants in the symptomatic patients. The aetiology of the implant failure and the alternative methods to avoid such complications are discussed. PMID- 19787358 TI - CTLA-4 +49A>G polymorphism is associated with the risk but not with the progression of colorectal cancer in Chinese. AB - PURPOSE: Colorectal cancer (CRC) is one of the most common malignancies in the world and a multipathway disease. Cytotoxic T-lymphocyte antigen-4 (CTLA-4) is a potent immunoregulatory molecule that suppresses antitumor response by down regulating T-cell activation. The most studied +49A>G polymorphism of CTLA-4 gene has been associated with several autoimmune or cancer diseases. Our aim was to investigate the association between this genetic variant and the risk as well as progression of colorectal cancer in Chinese. METHODS: We conducted a case-control study of 124 colorectal cancer cases and 407 healthy controls. DNA was extracted from blood specimens, and +49A>G polymorphism in the CTLA-4 gene was genotyped by polymerase chain reaction-ligation detection reaction (PCR-LDR). RESULTS: In our study group, the frequency of AG or GG or carrying at least one G allele at position +49 was significantly different in colorectal cancer patients and the control group, indicating that the risk of CRC was significantly higher among subjects with the AG or GG genotype or carrying at least one G allele at position +49 than among the subjects with the AA genotype. However, we observed no association between CTLA-4 +49A>G polymorphism and the progression of CRC. Interestingly, the CTLA-4 +49A allele was in non-significantly higher numbers in CRC patients with distant metastasis. CONCLUSIONS: Our results suggested that CTLA-4 +49A>G polymorphism was associated with an increased risk of colorectal cancer, but this polymorphism did not play an important role in the progression of CRC in Chinese. PMID- 19787361 TI - Incidental adnexal masses removed at laparoscopic ligation and caesarean section. PMID- 19787360 TI - Bioabsorbable interference screw fixation of distal biceps ruptures through a single anterior incision: a single-surgeon case series and review of the literature. AB - INTRODUCTION: We present a single-surgeon series of 14 acute ruptured distal biceps tendons repaired using a biotenodesis screw through a single anterior incision. PATIENTS: The demographics of this population reveal a typical injury pattern and reflect the preponderance of distal biceps ruptures in the middle aged, active male. Goniometric post-operative assessment of flexion, pronation and supination range demonstrates excellent clinical function in these patients. METHOD: Subjective analysis is afforded by DASH and MEPS scoring at the 6-month follow-up. RESULTS: The results are discussed in relation to previous studies utilising disparate repair methods. This is the first prospective clinical series to be reported using this combination of fixation and approach. Clinical and patient assessed functions are excellent and complications are minimal. CONCLUSION: This is a safe and successful technique for the management of distal biceps tendon ruptures. PMID- 19787362 TI - Diagnostic accuracy of uterine fluid lactate dehydrogenase isoenzyme activity profile and vaginal ultrasound in detecting endometrial cancer in women with postmenopausal bleeding. AB - OBJECTIVE: To evaluate the diagnostic accuracy of lactate dehydrogenase (LD) isoenzyme activity profile in uterine fluid and transvaginal ultrasound (TVS) in detection of endometrial cancer in women with postmenopausal bleeding. STUDY DESIGN: Prospective controlled clinical study. METHODS: One hundred twenty postmenopausal women with one or more episode of vaginal bleeding were studied. Endometrial thickness was classified as >5 mm or <5 mm on TVS. LD isoenzyme activity profile was described as normal or abnormal. LD isoenzyme profile was subsequently related to histopathological diagnosis. RESULTS: Endometrial carcinoma was found in 10 out of 120 patients (8.3%). Sixty-seven patients (56%) were found to have endometrium >5-mm thickness on TVS. LD isoenzyme activity profile was abnormal in 22 (18.3%) cases. Histopathological diagnosis in these cases revealed 10 endometrial cancer and 12 benign endometrium. LD isoenzyme activity profile has 100% sensitivity, 90.1% specificity, 45.4% positive predictive value, 100% negative predictive value, and 88.6% accuracy. CONCLUSION: LD isoenzyme profile of uterine fluid could be added as a marker for endometrial cancer in postmenopausal women with vaginal bleeding and endometrial thickness >5 mm on transvaginal ultrasound. Uterine fluid sampling is easy, highly reliable, minimally invasive, with high patient compliance, and can be performed as an office procedure. Furthermore, this method is insensitive to endometrial thickness, amount of sample, sampling device, and dilution. PMID- 19787363 TI - Intrauterine fetal bone retention after late-term abortion by external force in the 20th week of pregnancy. AB - OBJECTIVES: Intrauterine retention of fetal bones is a rare complication of spontaneous miscarriages or termination of pregnancy. RESULTS: We present a case with fetal bone retention after a miscarriage that occurred after external assault in about the 20th week of gestation. CONCLUSIONS: Since the global mobility has rapidly increased, women from a totally different lifeworld (i.e. escaping from civil war areas in underdeveloped countries) could abruptly present themselves as patients in industrial countries, so every physician should be aware of the described implications. PMID- 19787364 TI - Cytokine-related genes and oxidation-related genes detected in preeclamptic placentas. AB - PURPOSE: To investigate cytokine- and oxidation-related genes for preeclampsia using DNA microarray analysis. METHODS: Placentas were collected from 13 normal pregnancies and 13 patients with preeclampsia. Gene expression was studied using DNA microarray. Among significantly expressed genes, we focused on genes associated with cytokines and oxidation, and the results were confirmed using quantitative real time-polymerase chain reaction (QRT-PCR). RESULTS: 415 genes out of 30,940 genes were altered by > or =2-fold in the microarray analysis. 121 up-regulated genes and 294 down-regulated genes were found to be in preeclamptic placenta. Six cytokine-related genes and 5 oxidation-related genes were found from among the 121 up-regulated genes. The cytokine-related genes studied included oncostatin M (OSM), fms-related tyrosine kinase (FLT1) and vascular endothelial growth factor A (VEGFA), and the oxidation-related genes studied included spermine oxidase (SMOX), l cytochrome P450, family 26, subfamily A, polypeptide 1 (CYP26A1), acetate dehydrogenase A (LDHA). These six genes were also significantly higher in placentas from patients with preeclampsia than in those from women with normal pregnancies. The placental tissue of patients with preeclampsia showed significantly higher mRNA expression of these six genes than the normal group, using QRT-PCR. CONCLUSION: DNA microarray analysis is one of the great methods for simultaneously detecting the functionally associated genes of preeclampsia. The cytokine-related genes such as OSM, FLT1 and VEGFA, and the oxidation-related genes such as LDHA, CYP26A1 and SMOX might prove to be the starting point in the elucidation of the pathogenesis of preeclampsia. PMID- 19787365 TI - Effect of corneal astigmatism on intraocular pressure measurement using ocular response analyzer and Goldmann applanation tonometer. AB - PURPOSE: To assess the effect of corneal astigmatism on intraocular pressure (IOP) measurements using an Ocular Response Analyzer (ORA) and a Goldmann applanation tonometer (GAT). METHODS: We prospectively examined 59 normal eyes of 59 healthy volunteers (18 men, 41 women; age, mean +/- standard deviation, 40.5 +/- 14.2 years; age range, 19-68 years). We quantitatively assessed the values of corneal-compensated intraocular pressure (IOPcc) and Goldmann-correlated intraocular pressure (IOP(G)) using an ORA (Reichert Ophthalmic Instruments). We also measured the IOP using a GAT (GAT-IOP). The amount of corneal astigmatism was assessed with an autokeratometer. We carried out these measurements three times, and the mean value obtained was used for statistical analysis. RESULTS: The mean IOPcc, IOP(G), and GAT-IOP were 14.7 +/- 2.6, 14.0 +/- 2.8, and 14.2 +/- 1.7 mmHg respectively. The mean corneal astigmatism was 0.94 +/- 0.55 D. We found no significant correlation between IOPcc and corneal astigmatism (Pearson's correlation coefficient r = -0.04, p = 0.79), or between IOP(G) and corneal astigmatism (r = 0.09, p = 0.52). However, we found a weak, but significant, correlation between GAT-IOP and corneal astigmatism (Pearson's correlation coefficient r = 0.34, p = 0.009). CONCLUSIONS: Both IOPcc and IOP(G) measured with ORA were less affected by the amount of corneal astigmatism, and the GAT-IOP readings were significantly higher in eyes with greater corneal astigmatism, suggesting that IOPcc as well as IOP(G) may be helpful for accurate IOP measurements in eyes with some corneal astigmatism. PMID- 19787366 TI - Localization of fatty acid binding protein of epidermal type common to dendritic cells and presumptive macrophages in Peyer's patches and epithelial M cells of mouse intestine. AB - Fatty acid binding protein of epidermal type (E-FABP) was expressed/localized in most, if not all, populations of the dendritic cells in the subepithelial domes, follicles and interfollicular regions of Peyer's patches and presumptive macrophages in their germinal centers, and all M cells in the follicle-associated epithelium of mouse intestine. The immunoreactivity in both of the cell populations makes it easy to recognize the accumulation of DCs in the subepithelial domes in close proximity to the base of M cells, which is essential for luminal antigens to be transported to Peyer's patches. E-FABP may play some important roles in the mucosal immune reaction through Peyer's patches and associated structures. PMID- 19787367 TI - The relationship between upper extremity musculoskeletal symptoms attributed to work and risk factors in office workers. AB - PURPOSE: Office workers are exposed to various individual, work-related and psychosocial factors during work that have been associated with the development of musculoskeletal symptoms. There is an increasing in evidence that suggests that musculoskeletal symptoms in the upper extremity are very common among office workers. The aim of this study was to examine the effects of individual, work related physical and psychosocial factors on the prevalence of shoulder, elbow and wrist/hand symptoms attributed to work in office workers. METHODS: A self administered questionnaire was delivered to 2,000 office workers in 54 workplaces in Bangkok, registered at the Social Security Office of Thailand. RESULTS: A total of 1,428 subjects (71%) returned the questionnaire, of whom 1,185 were eligible for the study. Alcohol consumption, frequency of working in an uncomfortable posture and relationships with colleagues were each significantly related to the prevalence of experiencing shoulder symptoms. No significant association between the investigated factors and the prevalence of experiencing elbow symptoms was found. Frequency of working in the position that hands were above the shoulder level and self-rated perception of air circulation in the office were significantly associated with the prevalence of experiencing wrist/hand symptoms. CONCLUSIONS: Various individual, work-related and psychosocial factors were identified to be associated with high prevalence of musculoskeletal symptoms attributed to work in the shoulder and wrist/hand among office workers. Further research investigating the causal relation between these factors and musculoskeletal symptoms should be conducted. PMID- 19787368 TI - Differences in rectal temperatures measured at depths of 4-19 cm from the anal sphincter during exercise and rest. AB - The purpose of the present study was to examine the discrepancies in rectal temperature (T (re)) at various depths. Nineteen young males performed two bouts of bicycle exercise and recovery. T (re) was simultaneously measured at depth of 4, 6, 8, 10, 13, 16, and 19 cm, alongside the measurement of skin temperatures. We found small but statistically significant differences by depth in the absolute T (re), the magnitude of rise in T (re) and the lag of response in T (re). During the stabilization stage before exercise, T (re) at 4 cm-depth was 0.5 degrees C lower than T (re) at 16 cm-depth (p < 0.05). As the depth measured in the rectum was shallower, the rise in T (re) during exercise was greater. However the rise in T (re) at 10, 13, 16 and 19 cm showed no systemic difference. Among seven depths, T (re) at 16 cm-depth had the most stable feature with the longest latent period (3.1 +/- 1.3 min) and the smallest rise (0.8 +/- 0.3 degrees C), while T (re) at 4 cm-depth was the most responsive to the change of exercise and rest with the shortest latent period (1.0 +/- 0.6 min) and the greatest rise (1.2 +/- 0.5 degrees C). The differences observed in the depths from 4 to 19 cm were offset by exercise to some extent. In summary, T (re) appeared in different manners according to the seven depths during the repetition of exercise and rest, but T (re) deeper than 10 cm-depth seemed to have no systematic differences. PMID- 19787369 TI - System properties, feedback control and effector coordination of human temperature regulation. AB - The aim of human temperature regulation is to protect body processes by establishing a relative constancy of deep body temperature (regulated variable), in spite of external and internal influences on it. This is basically achieved by a distributed multi-sensor, multi-processor, multi-effector proportional feedback control system. The paper explains why proportional control implies inherent deviations of the regulated variable from the value in the thermoneutral zone. The concept of feedback of the thermal state of the body, conveniently represented by a high-weighted core temperature (T (c)) and low-weighted peripheral temperatures (T (s)) is equivalent to the control concept of "auxiliary feedback control", using a main (regulated) variable (T (c)), supported by an auxiliary variable (T (s)). This concept implies neither regulation of T (s) nor feedforward control. Steady-states result in the closed control-loop, when the open-loop properties of the (heat transfer) process are compatible with those of the thermoregulatory processors. They are called operating points or balance points and are achieved due to the inherent property of dynamical stability of the thermoregulatory feedback loop. No set-point and no comparison of signals (e.g. actual-set value) are necessary. Metabolic heat production and sweat production, though receiving the same information about the thermal state of the body, are independent effectors with different thresholds and gains. Coordination between one of these effectors and the vasomotor effector is achieved by the fact that changes in the (heat transfer) process evoked by vasomotor control are taken into account by the metabolic/sweat processor. PMID- 19787370 TI - Washout filter aided mean field feedback desynchronization in an ensemble of globally coupled neural oscillators. AB - We propose an approach for desynchronization in an ensemble of globally coupled neural oscillators. The impact of washout filter aided mean field feedback on population synchronization process is investigated. By blocking the Hopf bifurcation of the mean field, the controller desynchronizes the ensemble. The technique is generally demand-controlled. It is robust and can be easily implemented practically. We suggest it for effective deep brain stimulation in neurological diseases characterized by pathological synchronization. PMID- 19787371 TI - Leg recirculation in horizontal plane locomotion. AB - A protocol prescribing leg motion during the swing phase is developed for the planar lateral leg spring model of locomotion. Inspired by experimental observations regarding insect leg function when running over rough terrain, the protocol prescribes the angular velocity of the swing-leg relative to the body in a feedforward manner, yielding natural variations in the leg touch-down angle in response to perturbations away from a periodic orbit. Analysis of the reduced order model reveals that periodic gait stability and robustness to external perturbations depends strongly upon the angular velocity of the leg at touch down. While the leg angular velocity at touch-down provides control over gait stability and can be chosen to stabilize unstable gaits, the resulting basin of stability is much smaller than that observed for the original lateral leg spring model with a fixed leg touch-down angle. Comparisons to experimental leg angular velocity data for running cockroaches reveal that while the proposed protocol is qualitatively correct, smaller leg angular accelerations occur during the second half of the swing phase. Modifications made to the recirculation protocol to better match experimental observations yield large improvements in the basin of stability. PMID- 19787372 TI - Molecular pathology of sarcomas: concepts and clinical implications. AB - The molecular genetic changes that have been described in sarcomas over the past era have aided our understanding of their pathogenesis. The majority of sarcomas carry nonspecific genetic changes within a background of a complex karyotype. These constitute the challenges in sarcoma research for unraveling a putative multistep genetic model, such as for chondrosarcoma, and finding targets for therapeutic strategies. Approximately 15-20% of mesenchymal tumors carry a specific translocation within a relatively simple karyotype. The resulting fusion products act either as transcription factors upregulating genes responsible for tumor growth, as for instance in Ewing sarcoma, or translocate a highly active promoter in front of an oncogene driving tumor formation, as for instance in aneurysmal bone cyst. In addition, a small subset of mesenchymal tumors have specific somatic mutations driving oncogenesis. The specific genetic changes unraveled so far had great impact on the classification of bone and soft tissue tumors. In addition, these changes can assist the pathologist in the differential diagnosis of some of these entities, especially within the groups of small blue round cell tumors and spindle cell tumors, if performed in specialized centers. While a putative association between certain fusion products and outcome is still under debate, the role of predicting response of targeted therapy has been well established for KIT and PDGFRA mutations in gastrointestinal stromal tumors. PMID- 19787373 TI - Has the liver and other visceral organs migrated to its normal position in children with giant omphalocele? A follow-up study with ultrasonography. AB - This study evaluates whether, on the long run, in patients born with a giant omphalocele, the liver and other solid organs reach their normal position, shape, and size. Seventeen former patients with a giant omphalocele, treated between 1970 and 2004, were included. Physical examination was supplemented with ultrasonography for ventral hernia and precise description of the liver, spleen, and kidneys. The findings were compared with 17 controls matched for age, gender, and body mass index. We found an abnormal position of the liver, spleen, left kidney, and right kidney in eight, six, five, and four patients, respectively. An unprotected liver was present in all 17 patients and in 11 controls, the difference being statistically significant (p = 0.04). In ten of the 11 patients with an incisional hernia, the liver was located underneath the abdominal defect. CONCLUSION: In all former patients with a giant omphalocele, an abnormal position of the liver and in the majority of them, an incisional hernia was also found. The liver and sometimes also the spleen and the kidneys do not migrate to their normal position. Exact documentation and good information are important for both the patient and their caretakers in order to avoid liver trauma. PMID- 19787374 TI - Genetic analysis of genes involved in synthesis of modified 4-amino-4,6 dideoxyglucose in flagellin of Pseudomonas syringae pv. tabaci. AB - Glycosylation of flagellin contributes to swimming and swarming motilities, adhesion ability, and consequently virulence in Pseudomonas syringae pv. tabaci 6605. Glycans attached to six serine residues are located in the central region of the flagellin polypeptide. The glycan structure at position Ser 201 was recently revealed to consist of two L-rhamnoses and one modified 4-amino-4,6 dideoxyglucose (viosamine). To clarify the mechanisms for glycosylation of modified viosamine, genes encoding dTDP-viosamine aminotransferase (vioA), dTDP viosamine acetyltransferase (vioB), and viosamine-derivative transferase (vioT) were isolated and defective mutants were generated. MALDI-TOF-MS analysis of a lysyl endopeptidase-digested peptide including all six glycosylation sites from each flagellin indicated that the molecular masses of the three flagellin mutants were reduced with highly heterogeneous patterns at regular intervals of 146 Da in the mass range from m/z 13,819 to 15,732. The data indicated that the glycopeptides obtained from mutants had glycans consisting only of deoxyhexose instead of the flagellin glycans including the viosamine derivatives determined previously. The motility and virulence on host tobacco leaves were strongly impaired in the Delta vioA mutant and were weakly reduced in the Delta vioB and Delta vioT mutant strains. These results suggest that the genes vioA, vioB, and vioT are essential for glycosylation of flagellin, and accordingly are required for bacterial virulence. PMID- 19787375 TI - Biparental inheritance of plastidial and mitochondrial DNA and hybrid variegation in Pelargonium. AB - Plastidial (pt) and mitochondrial (mt) genes usually show maternal inheritance. Non-Mendelian, biparental inheritance of plastids was first described by Baur (Z Indukt Abstamm Vererbungslehre 1:330-351, 1909) for crosses between Pelargonium cultivars. We have analyzed the inheritance of pt and mtDNA by examining the progeny from reciprocal crosses of Pelargonium zonale and P. inquinans using nucleotide sequence polymorphisms of selected pt and mt genes. Sequence analysis of the progeny revealed biparental inheritance of both pt and mtDNA. Hybrid plants exhibited variegation: our data demonstrate that the inquinans chloroplasts, but not the zonale chloroplasts bleach out, presumably due to incompatibility of the former with the hybrid nuclear genome. Different distribution of maternal and paternal sequences could be observed in different sectors of the same leaf, in different leaves of the same plant, and in different plants indicating random segregation and sorting-out of maternal and paternal plastids and mitochondria in the hybrids. The substantial transmission of both maternal and paternal mitochondria to the progeny turns Pelargonium into a particular interesting subject for studies on the inheritance, segregation and recombination of mt genes. PMID- 19787376 TI - Modular architecture and evolution of the map-1 gene family in the root-knot nematode Meloidogyne incognita. AB - In eukaryotes, repeat proteins (i.e. proteins that contain a tandem arrangement of repeated structural elements) are often considered as an extra source of variability, and gains and losses of repeats may be an important force driving the evolution and diversification of such proteins, that could allow fast adaptation to new environments. Here, we report genomic sequences of the MAP-1 protein family from of the asexual, plant-parasitic nematode Meloidogyne incognita. The encoded proteins exhibited highly conserved repeats of 13 and 58 aa, and variation in the number and arrangement of these repeats in the MAP-1 proteins was correlated with nematode (a)virulence, suggesting a possible role in the specificity of the plant-nematode interaction. Search in the complete genome sequence of M. incognita confirmed that a small gene family encoding proteins harboring conserved 58 and 13 aa-repeats is present in this nematode, and that the repetitive region of these proteins is modular. Both gene duplication and intragenic gain and loss of repeats have contributed to the complex evolutionary history of the map-1 gene family, and active selection pressure of the plant host probably induced recent additional gene loss, finally resulting in the present day gene and repeat diversity observed among nematode lines. The genomic differences characterized here between avirulent and virulent individuals are assumed to reflect, at the DNA level, the adaptive capacity of these asexual root knot nematodes. PMID- 19787378 TI - [Abstracts of the German Pain Congress 2009. October 7-10, 2009. Berlin, Germany]. PMID- 19787377 TI - [Epidemiology and therapy of pain and depression during HIV and AIDS]. AB - Pain is one of the most common reasons for admission to hospital for patients suffering from AIDS. Pain and other symptoms very often cover depressive episodes. Pain induced by AIDS therapy represents a progressive problem and induces the necessity to alter the highly active antiretroviral therapy (HAART). Of HIV-infected people 90% complain of headaches. Headache may result from opportunistic infections, from side-effects of HAART or from the HIV in the CNS itself but also the high burden of idiopathic headaches must be considered. Up to 20% of all neuropathies in HIV-infected people are caused by HAART. In most cases changing of HAART is necessary. Problems of interactions between HAART and the substances used for pain therapy via the cytochrome P450 system represents a special therapeutic problem during HAART in order to avoid development of resistance by the HIV. PMID- 19787379 TI - Efficacy of multifaceted interventions in reducing complications of peripherally inserted central catheter in adult oncology patients. AB - PURPOSE: To evaluate the efficacy of multifaceted interventions in reducing complications of peripherally inserted central venous catheter (PICC) in adult oncology patients. METHODS: Multifaceted interventions were implemented in our department in December 2006. These interventions include: (1) A mandatory nurse reeducation was developed by a multidisciplinary task force; (2) Modification of peripherally inserted central catheter insertion: take a chest X-ray before removal of the guidewire and cutting of the catheter. The guidewire in the catheter facilitates the accurate location of the tip of PICC on chest X-ray and make the malposition correction (withdrawing, reinsertion, even reinsertion following withdrawal) easily; (3) Using a 2% chlorhexidine preparation, replace 10% povidone iodine for skin antisepsis; (4) Maintenance of maximum sterile barrier precautions during PICC insertion and aftercare; (5) Designing of a PICC archive form and establishing a PICC archive for each patient. The PICC complication rates of groups before and after interventions were evaluated and compared. RESULTS: Sixty-nine PICC lines were inserted before these interventions, and 165 were inserted after implementation of these interventions. Compared with preintervention group, the postintervention group was associated with a 62.14% decrease in the overall complication rate (11.52% vs 30.43% [P = 0.0004]; incidence density, 1.82 vs 4.62 per 1,000 PICC days) with a 67.48% decrease in the infective complications rate (4.24% vs 13.04% [P = 0.015]) with a 58.19% decrease in the noninfective complications rate (7.27% vs 17.39% [P = 0.0199]). CONCLUSIONS: The results suggest that these interventions implemented in this study may be help in reducing complications of PICC in adult oncology patients. PMID- 19787380 TI - Continuous subcutaneous delivery of medications for home care palliative patients using an infusion set or a pump? AB - PURPOSE: The purpose of this study was to evaluate safety, feasibility, and efficacy of continuous drug delivery by the subcutaneous route through a solution bag connected to an infusion set compared with an infusion pump in a home palliative care setting. METHODS: Patients in need of continuous subcutaneous medication delivery for pain control, nausea, and/or vomiting were recruited. The study was designed as a double-blind, crossover study. The patient was connected to two parallel subcutaneous lines running simultaneously, connected together to a line entering the subcutaneous tissue. One line is connected to an infusion set and the other to a pump. The infusion set included a 500-cc solution bag connected to a 1.5-m plastic tube containing a drip chamber controlled by a roller clamp that is gravity driven without hyaluronidase. Active medications were randomly assigned to start in either administration method and switched after 24 h. An independent research assistant evaluated symptom control and side effects at baseline and every 24 h for 2 days using a structured questionnaire. Another independent research assistant connected the lines after adding medications and evaluated technical and clinical failures. RESULTS: Twenty-seven patients were recruited, and of them, 18 completed the study. Incidents in fluid administration were more common through the infusion set (18 times) compared to the pump (only twice). On the other hand, no clinical significant change was noted in the average symptom levels and side effects when medications were given through the infusion set versus the pump. No local edema or irritation was observed in either way of administration. CONCLUSIONS: In a home palliative care setting with a medical staff on call for 24 h, using medications for symptom control can be considered to be infused to a fluid solution bag through an infusion set instead of using a syringe driver or a pump when there is a responsible caregiver to follow up on the fluid. Subcutaneous constant drug delivery through a pump is more accurate. PMID- 19787381 TI - De novo arteriovenous malformations: case report and review of the literature. AB - Intracerebral arteriovenous malformations (AVMs) are traditionally recognized as congenital lesions. However, with the advent of frequent, noninvasive imaging of the brain, that notion has been challenged. We describe another patient with a de novo cerebral arteriovenous malformation and evaluate the reported literature for trends in the development of these lesions. Cases were selected from the English literature using the PUBMED database using the search term "acquired or de novo cerebrovascular arteriovenous malformations". A total of seven patients (including the one reported in this study) with de novo arteriovenous malformations are reported. Majority of patients were female, and mostly diagnosed as children. Their mean age at diagnosis was 18 years (6-32), and the mean time from the initial intracranial study to the diagnosis of an AVM was 8 years (3-17). De novo formation of AVMs is being increasingly reported, especially in young females. We present only the seventh such case reported in the literature and challenge the traditional view that all arteriovenous malformations are congenital in nature. PMID- 19787382 TI - Introduction to the DISRUPT postprandial database: subjects, studies and methodologies. AB - Dysregulation of lipid and glucose metabolism in the postprandial state are recognised as important risk factors for the development of cardiovascular disease and type 2 diabetes. Our objective was to create a comprehensive, standardised database of postprandial studies to provide insights into the physiological factors that influence postprandial lipid and glucose responses. Data were collated from subjects (n = 467) taking part in single and sequential meal postprandial studies conducted by researchers at the University of Reading, to form the DISRUPT (DIetary Studies: Reading Unilever Postprandial Trials) database. Subject attributes including age, gender, genotype, menopausal status, body mass index, blood pressure and a fasting biochemical profile, together with postprandial measurements of triacylglycerol (TAG), non-esterified fatty acids, glucose, insulin and TAG-rich lipoprotein composition are recorded. A particular strength of the studies is the frequency of blood sampling, with on average 10-13 blood samples taken during each postprandial assessment, and the fact that identical test meal protocols were used in a number of studies, allowing pooling of data to increase statistical power. The DISRUPT database is the most comprehensive postprandial metabolism database that exists worldwide and preliminary analysis of the pooled sequential meal postprandial dataset has revealed both confirmatory and novel observations with respect to the impact of gender and age on the postprandial TAG response. Further analysis of the dataset using conventional statistical techniques along with integrated mathematical models and clustering analysis will provide a unique opportunity to greatly expand current knowledge of the aetiology of inter-individual variability in postprandial lipid and glucose responses. PMID- 19787383 TI - Introductory remarks to a special issue from the "International Niigata Symposium on Diet and Health", November 2008. PMID- 19787384 TI - Using non-homogeneous models of nucleotide substitution to identify host shift events: application to the origin of the 1918 'Spanish' influenza pandemic virus. AB - Nonhomogeneous Markov models of nucleotide substitution have received scant attention. Here we explore the possibility of using nonhomogeneous models to identify host shift nodes along phylogenetic trees of pathogens evolving in different hosts. It has been noticed that influenza viruses show marked differences in nucleotide composition in human and avian hosts. We take advantage of this fact to identify the host shift event that led to the 1918 'Spanish' influenza. This disease killed over 50 million people worldwide, ranking it as the deadliest pandemic in recorded history. Our model suggests that the eight RNA segments which eventually became the 1918 viral genome were introduced into a mammalian host around 1882-1913. The viruses later diverged into the classical swine and human H1N1 influenza lineages around 1913-1915. The last common ancestor of human strains dates from February 1917 to April 1918. Because pigs are more readily infected with avian influenza viruses than humans, it would seem that they were the original recipient of the virus. This would suggest that the virus was introduced into humans sometime between 1913 and 1918. PMID- 19787385 TI - Mutations and lethality in simulated prebiotic networks. AB - The Graded Autocatalysis Replication Domain (GARD) model describes an origin of life scenario which involves non-covalent compositional assemblies, made of monomeric mutually catalytic molecules. GARD constitutes an alternative to informational biopolymers as a mechanism of primordial inheritance. In the present work, we examined the effect of mutations, one of the most fundamental mechanisms for evolution, in the context of the networks of mutual interaction within GARD prebiotic assemblies. We performed a systematic analysis analogous to single and double gene deletions within GARD. While most deletions have only a small effect on both growth rate and molecular composition of the assemblies, ~10% of the deletions caused lethality, or sometimes showed enhanced fitness. Analysis of 14 different network properties on 2,000 different GARD networks indicated that lethality usually takes place when the deleted node has a high molecular count, or when it is a catalyst for such node. A correlation was also found between lethality and node degree centrality, similar to what is seen in real biological networks. Addressing double knockout mutations, our results demonstrate the occurrence of both synthetic lethality and extragenic suppression within GARD networks, and convey an attempt to correlate synthetic lethality to network node-pair properties. The analyses presented help establish GARD as a workable alternative prebiotic scenario, suggesting that life may have begun with large molecular networks of low fidelity, that later underwent evolutionary compaction and fidelity augmentation. PMID- 19787386 TI - Congenitally corrected transposition of the great arteries: a unique case from Iraq. AB - A severely cyanotic 27-month-old Iraqi child was transferred to the United States for surgical treatment of suspected tetralogy of Fallot. Her diagnostic studies showed dextrocardia, congenitally corrected transposition of the great arteries, hypoplastic left-sided ventricle, interrupted inferior vena cava, and severe pulmonic stenosis. Given the anatomic constraints as well as the absence of long term medical care, the decision was made to pursue single-ventricle palliation. The patient recovered from a superior cavopulmonary anastomosis without event and has since returned to her native Iraq. PMID- 19787387 TI - Ventricular angiography images in noncompaction of the left ventricle. PMID- 19787388 TI - Limb ischemic preconditioning reduces heart and lung injury after an open heart operation in infants. AB - Open heart surgery supported by cardiopulmonary bypass is associated with heart and lung ischemia-reperfusion injury (IRI). Limb remote ischemic preconditioning (RIPC) reduces injury caused by ischemia-reperfusion in multiple distant organs. We conducted a prospective clinical trial (randomized and controlled) to test the feasibility and safety of limb RIPC, as well as its protective effects against myocardial and pulmonary IRI for infants undergoing repair of simple congenital heart defects. Infants undergoing repair of ventricular septal defects were enrolled in our study and randomly assigned to one of two treatment groups: limb RIPC or control. RIPC was induced twice (24 h and 1 h preoperatively) via three 5 min cycles of ischemia and reperfusion on the left upper arm using a blood pressure cuff. Lung compliance, respiratory index (RI), and cardiac inotropic score (IS) were calculated for each patient. Serum concentrations of the following factors were measured perioperatively: interleukin (IL)-6, IL-8, IL-10, and tumor necrosis factor (TNF)-alpha; lactate dehydrogenase (LDH), creatine kinase (CK), and its isoenzyme (CK-MB), and troponin I (TnI); malondialdehyde (MDA) and superoxide dismutase (SOD). The expression of heat shock protein 70 (HSP 70) in cardiomyocytes was analyzed by Western blot. Surgical outcomes, including limb movement and sensory function, were recorded in detail. Sixty infants weighting less than 7 kg were studied, with 30 patients in the RIPC group and 30 in the control group. Within 6 months of discharge from the hospital, no limb disability, sensory disturbance, or other surgical complications were found in any patient. Compared with the control group, patients in the RIPC group had higher Cs and Cd, along with lower RI and IS at various postoperative phases. At the beginning of the operation, serum concentrations of IL-6, IL-8, IL-10, TNF alpha, LDH, CK, and TnI were higher in the RIPC group than the control group. Postoperatively, release of cytokines and leakage of heart enzymes were attenuated in the RIPC group; serum concentrations of cytokines and heart enzymes were lower in the RIPC group at some, but not all, postoperative time points. Furthermore, the RIPC group had lower coronary sinus venous concentrations of MDA and higher concentrations of SOD. Similarly, the expression of HSP 70 was upregulated in cardiomyocytes from the RIPC group. Limb RIPC can be applied safely and easily in infants, can attenuate systemic inflammatory response syndrome, and can increase systemic tolerance to IRI, imparting a protective effect against myocardial and pulmonary IRI. The expression of HSP 70 has an important role in the mechanism of action for RIPC. PMID- 19787389 TI - Severe hypertrophic cardiomyopathy in an infant with a novel PRKAG2 gene mutation: potential differences between infantile and adult onset presentation. AB - Hypertrophic cardiomyopathy (HCM) is a heterogeneous disorder characterized by thickening of the heart and an increased incidence of sudden death. This study is aimed to determine the genetic cause of severe cardiac hypertrophy in an infant. An infant was assigned a diagnosis of ventricular preexcitation and severe biventricular HCM requiring septal myectomy. Genetic testing showed a novel heterozygous E506Q mutation of the adenosine monophosphate (AMP)-activated protein kinase (PRKAG2) gene. Endomyocardial biopsy samples did not demonstrate significant glycogen accumulation. Hypertrophic cardiomyopathy due to PRKAG2 mutations may have a degree of cardiac hypertrophy exceeding that expected from observed amounts of glycogen deposition. PMID- 19787391 TI - Endovascular intervention for renal artery stenosis. AB - Renovascular diseases are common conditions with important implications on cardiovascular morbidity and mortality. Renal artery stenosis (RAS) is present in 1-5% of patients with hypertension (HTN) in the US with the vast majority of caused by atherosclerosis. Atherosclerotic RAS is related not only to uncontrolled HTN, but also to renal dysfunction. Atherosclerotic RAS in the USA has been reported to account for approximately 14-16% of new patients requiring dialysis each year. Hence a concerted effort was made in the last decade to treat renovascular stenosis using newly developed endovascular therapies to improve cardiovascular morbidity and renal function. A review on new advances in the endovascular management of renal artery stenosis with low profile stents, embolic protection devices, and drug eluting stents is presented. PMID- 19787390 TI - Frankia and Alnus rubra canopy roots: an assessment of genetic diversity, propagule availability, and effects on soil nitrogen. AB - The ecological importance of microbial symbioses in terrestrial soils is widely recognized, but their role in soils that accumulate in forest canopies is almost entirely unknown. To address this gap, this study investigated the Frankia-Alnus rubra symbiosis in canopy and forest floor roots at Olympic National Park, WA, USA. Sixteen mature A. rubra trees were surveyed and Frankia genetic diversity in canopy and forest floor nodules was assessed with sequence-based nifH analyses. A seedling bioassay experiment was conducted to determine Frankia propagule availability in canopy and forest floor soils. Total soil nitrogen from both environments was also quantified. Nodules were present in the canopies of nine of the 16 trees sampled. Across the study area, Frankia canopy and forest floor assemblages were similar, with both habitats containing the same two genotypes. The composition of forest floor and canopy genotypes on the same tree was not always identical, however, suggesting that dispersal was not a strictly local phenomenon. Frankia seedling colonization was similar in canopy soils regardless of the presence of nodules as well as in forest floor soils, indicating that dispersal was not likely to be a major limiting factor. The total soil nitrogen of canopy soils was higher than that of forest floor soils, but the presence of Frankia nodules in canopy soils did not significantly alter soil nitrogen levels. Overall, this study indicates that the Frankia-A. rubra symbiosis is similar in canopy and forest floor environments. Because canopy roots are exposed to different environmental conditions within very small spatial areas and because those areas can be easily manipulated (e.g., fertilizer or watering treatments), they present microbial ecologists with a unique arena to examine root-microbe interactions. PMID- 19787392 TI - The new face of transplant surgery: a survey on cosmetic surgery in transplant recipients. AB - BACKGROUND: Transplant surgery has undergone tremendous advances within the last decade. Improvements in surgical techniques, availability of potent immunosuppressive medications, and utilization of more sophisticated post transplant immunosuppression protocols have revolutionized the field. These developments have resulted in increased allograft survival, prolonged longevity, and improved quality of life in transplant organ recipients. Elimination of steroids in many postoperative immunosuppressive regimens has tremendously impacted the quality of life and physical appearance of these patients. They are living longer and more normal lives than previously considered possible. As a testament to the success of transplantation surgery, many transplant patients are now seeking aesthetic surgery. METHODS: A survey was sent to ASPS members asking about their experience with transplant patients undergoing aesthetic procedures. RESULTS: Of the 789 (18%) plastic surgeons who responded, 201 (25%) have performed aesthetic surgery on transplant recipients. A total of 278 patients underwent 292 surgical aesthetic procedures and 64 patients underwent 94 nonsurgical aesthetic procedures. The incidence of reported perioperative complications was 3.4%. There were very few additional precautions taken with these patients relative to the general population. With the exception of obtaining medical clearance, these additional precautions were inconsistent among plastic surgeons. CONCLUSION: Cosmetic surgery in transplant recipients is being successfully practiced in the USA. Surgical and nonsurgical aesthetic procedures are being performed safely in organ transplant recipients without a significant increase in the incidence or degree of complications. If certain precautions are undertaken, these patients may expect a degree of success comparable to that of the rest of the population. PMID- 19787393 TI - ArteFill permanent injectable for soft tissue augmentation: II. Indications and applications. AB - Patients ask for procedures with long-lasting effects. ArteFill is the first permanent injectable approved in 2006 by the FDA for nasolabial folds. It consists of cleaned microspheres of polymethylmethacrylate (PMMA) suspended in bovine collagen. Over the development period of 20 years most of its side effects have been eliminated to achieve the same safety standard as today's hyaluronic acid products. A 5-year follow-up study in U.S. clinical trial patients has shown the same wrinkle improvement as seen at 6 months. Long-term follow-up in European Artecoll patients has shown successful wrinkle correction lasting up to 15 years. A wide variety of off-label indications and applications have been developed that help the physician meet the individual needs of his/her patients. Serious complications after ArteFill injections, such as granuloma formation, have not been reported due to the reduction of PMMA microspheres smaller than 20 microm to less than 1% "by the number." Minor technique-related side effects, however, may occur during the initial learning curve. Patient and physician satisfaction with ArteFill has been shown to be greater than 90%. PMID- 19787394 TI - ArteFill permanent injectable for soft tissue augmentation: I. Mechanism of action and injection techniques. AB - After more than 25 years of research and development, in October 2006 ArteFill became the first and only permanent injectable wrinkle filler to receive FDA approval. ArteFill is a third-generation polymeric microsphere-based filler, following its predecessor Artecoll, which was marketed outside the United States between 1994 and 2006. ArteFill is approved for the correction of nasolabial folds and has been used in over 15,000 patients since its U.S. market introduction in February 2007. No serious side effects have been reported to date according to the FDA's MAUDE reporting database. ArteFill consists of polymethylmethacrylate (PMMA) microspheres (20% by volume), 30-50 microm in diameter, suspended in 3.5% bovine collagen solution (80% by volume) and 0.3% lidocaine. The collagen carrier is absorbed within 1 month after injection and completely replaced by the patient's own connective tissue within 3 months. Each cc of ArteFill contains approximately six million microspheres and histological studies have shown that long-term wrinkle correction consists of 80% of the patient's own connective tissue and 20% microspheres. The standard injection technique is subdermal tunneling that delivers a strand of ArteFill at the dermal subdermal junction. This strand beneath a wrinkle or fold acts like a support structure that protects against further wrinkling and allows the diminished thickness of the dermis to recover to its original thickness. PMID- 19787395 TI - Lateral brow fixation in endoscopic forehead lift: long-term results with braided nylon percutaneous sutures. AB - BACKGROUND: Since the introduction of endoscopic forehead surgery, several fixation techniques have been described to remediate the fall of the lateral portion of the brow. Unfortunately, few studies demonstrate good long-term results with these methods. METHODS: This study evaluates long-term results of a lateral brow fixation technique that uses two points in the lateral eyebrow: one in the distal extremity and another corresponding to the midpoint between the pupil and the lateral canthus of the eye. Transcutaneous fixation was performed using the Casagrande needle. Braided white nylon 2-0 suture was passed through the needle and retroceded without exiting the skin, catching the supraorbital adhesions. These sutures were fixed to the deep temporal fascia. RESULTS: A total of 44 patients underwent endoscopic forehead lift between March 2000 and March 2006. Pre- and postoperative forehead position was documented using photos and the Mirror (Canfield, NJ, USA) program. Through a line perpendicular to the interpupillary line, the following measurements were taken between the vertical center of the eyebrow and the (1) lateral canthus (2) midpoint between the lateral canthus and the pupil, and (3) pupillary midpoint. Three groups were studied: Group 1 (n = 32), evaluated at 1-1.5 years after surgery, Group 2 (n = 20), evaluated at 3+ years after surgery, and Group 3 (n = 8), evaluated at both 1-1.5 years and 3+ years after surgery. A student t test for Groups 1 and 2 and a Wilcoxon test for Group 3 indicated statistical significance. CONCLUSION: Through a solid evaluation method, our technique has demonstrated significantly good near and longer-term results. PMID- 19787396 TI - The environmental "risky" region: identifying land degradation processes through integration of socio-economic and ecological indicators in a multivariate regionalization model. AB - Although several studies have assessed Land Degradation (LD) states in the Mediterranean basin through the use of composite indices, relatively few have evaluated the impact of specific LD drivers at the local scale. In this work, a computational strategy is introduced to define homogeneous areas at risk and the main factors acting as determinants of LD. The procedure consists of three steps and is applied to a set of ten environmental indicators available at the municipality scale in Latium, central Italy. A principal component analysis extracting latent patterns and simplifying data complexity was carried out on the original data matrix. Subsequently, a k-means cluster analysis was applied on a restricted number of meaningful, latent factors extracted by PCA in order to produce a classification of the study area into homogeneous regions. Finally, a stepwise discriminant analysis was performed to determine which indicators contributed the most to the definition of homogeneous regions. Three classes of "risky" regions were identified according to the main drivers of LD acting at the local scale. These include: (i) soil sealing (coupled with landscape fragmentation, fire risk, and related processes), (ii) soil salinization due to agricultural intensification, and (iii) soil erosion due to farmland depopulation and land abandonment in sloping areas. Areas at risk for LD covered 56 and 63% of the investigated areas in 1970 and 2000, respectively. PMID- 19787397 TI - Combined endovascular repair of a celiac trunk aneurysm using celiac-splenic stent graft and hepatic artery embolization. AB - Celiac trunk aneurysms are rare and usually asymptomatic lesions. However, treatment is generally warranted to avoid catastrophic rupture. We report a case of a 70-year-old man who sought care for a celiac trunk aneurysm close to the hepatosplenic bifurcation managed endovascularly by using a combined treatment of celiac-splenic stent-graft implantation and hepatic artery embolization. PMID- 19787398 TI - Double-layered PTFE-covered nitinol stents: experience in 32 patients with malignant esophageal strictures. AB - We evaluated the effectiveness of a double-layered polytetrafluoroethylene (PTFE) covered nitinol stent in the palliative treatment of malignant esophageal strictures. A double-layered PTFE-covered nitinol stent was designed to reduce the propensity to migration of conventional covered stent. The stent consists of an inner PTFE-covered stent and an outer uncovered nitinol stent tube. With fluoroscopic guidance, the stent was placed in 32 consecutive patients with malignant esophageal strictures. During the follow-up period, the technical and clinical success rates, complications, and cumulative patient survival and stent patency were evaluated. Stent placement was technically successful in all patients, and no procedural complications occurred. After stent placement, the symptoms of 30 patients (94%) showed improvement. During the mean follow-up of 103 days (range, 9-348 days), 11 (34%) of 32 patients developed recurrent symptoms due to tumor overgrowth in five patients (16%), tumor ingrowth owing to detachment of the covering material (PTFE) apart from the stent wire in 3 (9%), mucosal hyperplasia in 2 (6%), and stent migration in 1 (3%). Ten of these 11 patients were treated by means of placing a second covered stent. Thirty patients died, 29 as a result of disease progression and 1 from aspiration pneumonia. The median survival period was 92 days. The median period of primary stent patency was 190 days. The double-layered PTFE-covered nitinol stent seems to be effective for the palliative treatment of malignant esophageal strictures. We believe that the double-layer configuration of this stent can contribute to decreasing the stent's migration rate. PMID- 19787399 TI - Thoracic discitis as a complication of self-expanding metallic stents in esophageal carcinoma. AB - The role of metallic stents in the palliation of esophageal cancer is well established. Self-expanding metal stents (SEMSs) are frequently used, as they provide an effective and safe method of relieving malignant dysphagia. A number of complications are associated with the use of SEMSs, including esophageal perforation. We report a case of thoracic discitis occurring in a patient with advanced esophageal malignancy, treated with SEMSs. We propose that the likely etiology in this patient was esophageal perforation by a metallic stent. PMID- 19787401 TI - Detection of fiber-digesting bacteria in the ceca of ostrich using specific primer sets. AB - The purpose of this study was to detect three fibrolytic bacteria, Fibrobacter succinogenes, Ruminococcus flavefaciens, and Ruminococcus albus, in the cecal digesta of the ostrich (Struthio camelus) by PCR using a species-specific primer set for each 16S ribosomal RNA gene (16S rDNA). Although amplified DNA fragments obtained from each primer set had the expected size, the clone library derived from the amplimer contained non-specific sequences. The F. succinogenes-specific primer set recovered a partial 16S rDNA sequence of an uncultivated Fibrobacter with low similarity (<95%) and distantly related phylogenetic positioning to Fibrobacter sequences deposited in the databases, indicating a novel species of Fibrobacter. The sequence was considered to be identical to a clone detected in our previous experiment. Thus, we confirm that the gastrointestinal tract of the ostrich is one of the habitats of Fibrobacter species. The clone library derived from the R. flavefaciens-specific primer set contained a 16S rDNA sequence with 97% similarity to R. flavefaciens, indicating it could be one of a major fibrolytic bacterium in the ostrich ceca. No R. albus 16S rDNA sequence was found in the clone library of the R. albus-specific primer set. PMID- 19787402 TI - SAGES guideline for laparoscopic appendectomy. PMID- 19787403 TI - Lavender as a source of novel plant compounds for the development of a natural herbicide. AB - In a previous study, lavender (Lavandula spp.) was found to be highly phytotoxic towards annual ryegrass (Lolium rigidum, ARG), a major weed of winter wheat crops in Australia. This research aimed to further explore this relationship and determine the chemical(s) responsible for the observed effect. In bioassay, it was determined that the stem and leaf extract of L. x intermedia cv. Grosso ranked highest and had the potential to reduce significantly the root growth of several plant species. An extract concentration of 10% almost completely inhibited ARG root growth. When the extract was tested for stability, there was no loss in phytotoxicity after the 256 day trial. Via bioassay-guided fractionation and chromatographic techniques, it was determined that the sub fraction consisting of coumarin and 7-methoxycoumarin was most phytotoxic towards ARG. Chemoassays of 18 structural analogues of coumarin showed that coumarin itself was the most phytotoxic and largely responsible for the observed phytotoxicity of the extract. Soil trials were conducted using pure coumarin and the lavender extract, and in both instances, shoot length and weight were significantly reduced by post-emergence application at all concentrations evaluated. PMID- 19787405 TI - Modeling spatial spread of infectious diseases with a fixed latent period in a spatially continuous domain. PMID- 19787404 TI - Pulsed odors from maize or spinach elicit orientation in European corn borer neonate larvae. AB - Lepidoptera larvae are capable of orienting towards or away from plants by using odors as cues but whether this attraction is innate or secondarily acquired remains unknown. We tested the hypothesis that European corn borer (ECB) neonate larvae express an innate attraction towards odors released from maize, and avoidance towards odors from spinach. Neonate larvae were placed on a locomotion compensator within a constant stream of humidified air that was loaded intermittently with airborne odors drawn from potted plants. The odor stream was delivered continuously or pulsed (1 to 10 sec pulses) at 40 ml/min. ECB larvae oriented toward maize odors pulsed at 2 to 6 sec but walked away from maize odors delivered at lower frequencies (9 and 10 sec pulses or to continuous ones). They consistently walked away from spinach odors, irrespective of the pulsing regime except at 1 sec pulses that did not elicit orientation. We further explored odor intensity on orientation towards maize odors by adjusting the odor stream intensity. At higher intensity (60 ml/min), the direction reversal started at the 6 sec half period, while at lower intensity (20 ml/min), it showed up only for the continuous stimulus. ECB larvae exhibit a striking ability to lock on to a direction, which they maintained despite gaps of up to 10 sec in the odor stream. Our results demonstrate that ECB neonate larvae express innate orientation preferences towards natural odors from plants. These reactions correlate well with the biological value of these plants for ECB: maize generally is accepted by ECB larvae and adults, while spinach represents a poor host because it produces (non-volatile) phytoecdysteroids that are toxic and deterrent. PMID- 19787406 TI - Optimization of virotherapy for cancer. AB - Several viruses preferentially infect and replicate in cancer cells by usurping pathways that are defective in the tumor cell population. Such viruses have a potential as oncolytic agents. The aim of tumor virotherapy is that after injection of the replicating virus, it propagates in the tumor cell population with amplification. As a result, the oncolytic virus spreads to eradicate the tumor. The outcome of tumor virotherapy is determined by population dynamics and different from standard cancer therapy. Several models have been developed that provided considerable insights on the potential therapeutic scenarios. However, virotherapy is potentially risky since large amounts of a replicating virus are injected in the host with a risk of adverse effects. Therefore, the optimal dose, number of doses, and timing are expected to play an important role on the outcome both for the tumor and the host. In the current work, we combine a model of the dynamics of tumor virotherapy that was validated with experimental data with optimization theory to illustrate how we can improve the outcome of tumor therapy. In this first report, we demonstrate that (i) in most circumstances, anything more than two administrations of a vector is not helpful, (ii) correctly timed delivery of the virus provides superior results compared to regularly scheduled therapy or continuous infusion, (iii) a second dose of virus that is not properly timed leads to a worse outcome compared to a single dose of virus, and (iv) it is less costly to treat larger tumors. PMID- 19787407 TI - Modelling disease introduction as biological control of invasive predators to preserve endangered prey. AB - Invasive species are a significant cause of bio-diversity loss particularly in island ecosystems. It has been suggested to release pathogenic parasites as an efficient control measure of these mostly immune-naive populations. In order to explore the potential impacts of such bio-control approach, we construct and investigate mathematical models describing disease dynamics in a host population that acts as a predator embedded in a simple food chain. The consequences of Feline Immunodeficiency Virus (FIV) introduction into a closed ecosystem are addressed using a bi-trophic system, comprising an indigenous prey (birds) and an introduced predator (cats). Our results show that FIV is unlikely to fully eradicate cats on sub-Antarctic islands, but it can be efficient in depressing their population size, allowing for the recovery of the endangered prey. Depending on the ecological setting and disease transmission mode (we consider proportionate mixing as well as mass action), successful pathogen invasion can induce population oscillations that are not possible in the disease-free predator prey system. These fluctuations can be seen as a mixed blessing from a management point of view. On the one hand, they may increase the extinction risk of the birds. On the other hand, they provide an opportunity to eradicate cats more easily in combination with other methods such as trapping or culling. PMID- 19787408 TI - Revisiting an equivalence between maximum parsimony and maximum likelihood methods in phylogenetics. AB - Tuffley and Steel (Bull. Math. Biol. 59:581-607, 1997) proved that maximum likelihood and maximum parsimony methods in phylogenetics are equivalent for sequences of characters under a simple symmetric model of substitution with no common mechanism. This result has been widely cited ever since. We show that small changes to the model assumptions suffice to make the two methods inequivalent. In particular, we analyze the case of bounded substitution probabilities as well as the molecular clock assumption. We show that in these cases, even under no common mechanism, maximum parsimony and maximum likelihood might make conflicting choices. We also show that if there is an upper bound on the substitution probabilities which is 'sufficiently small', every maximum likelihood tree is also a maximum parsimony tree (but not vice versa). PMID- 19787409 TI - Mental health diagnoses and utilization of VA non-mental health medical services among returning Iraq and Afghanistan veterans. AB - BACKGROUND: Over 35% of returned Iraq and Afghanistan veterans in VA care have received mental health diagnoses; the most prevalent is post-traumatic stress disorder (PTSD). Little is known about these patients' use of non-mental health medical services and the impact of mental disorders on utilization. OBJECTIVE: To compare utilization across three groups of Iraq and Afghanistan veterans: those without mental disorders, those with mental disorders other than PTSD, and those with PTSD. DESIGN AND PARTICIPANTS: National, descriptive study of 249,440 veterans newly utilizing VA healthcare between October 7, 2001 and March 31, 2007, followed until March 31, 2008. MEASUREMENTS: We used ICD9-CM diagnostic codes to classify mental health status. We compared utilization of outpatient non mental health services, primary care, medical subspecialty, ancillary services, laboratory tests/diagnostic procedures, emergency services, and hospitalizations during veterans' first year in VA care. Results were adjusted for demographics and military service and VA facility characteristics. MAIN RESULTS: Veterans with mental disorders had 42-146% greater utilization than those without mental disorders, depending on the service category (all P < 0.001). Those with PTSD had the highest utilization in all categories: 71-170% greater utilization than those without mental disorders (all P < 0.001). In adjusted analyses, compared with veterans without mental disorders, those with mental disorders other than PTSD had 55% higher utilization of all non-mental health outpatient services; those with PTSD had 91% higher utilization. Female sex and lower rank were also independently associated with greater utilization. CONCLUSIONS: Veterans with mental health diagnoses, particularly PTSD, utilize significantly more VA non mental health medical services. As more veterans return home, we must ensure resources are allocated to meet their outpatient, inpatient, and emergency needs. PMID- 19787410 TI - TGF-beta3 is expressed in taste buds and inhibits proliferation of primary cultured taste epithelial cells. AB - Transforming growth factor-betas (TGF-betas), expressed in various tissues, play important roles in embryonic development and adult tissue homeostasis through their effects on cell proliferation, cell differentiation, cell death, and cell motility. However, expression of TGF-beta signaling components and their biological effect on taste epithelia has not been elucidated. We performed expression analysis of TGF-beta signaling components in taste epithelia and found that the TGF-beta3 mRNA was specifically expressed in taste buds. Type II TGF betas receptor (TbetaR-II) mRNA was specifically expressed in the tongue epithelia including the taste epithelia. To elucidate the biological function of TGF-beta3 in taste epithelia, we performed proliferation assay with primary cultured taste epithelial cells. In the presence of TGF-beta3, percentage of BrdU labeled cells decreased significantly, suggesting that the TGF-beta3 inhibited the proliferation of cultured taste epithelial cells through inhibiting cell cycle entry into S phase. By quantitative reverse transcription-polymerase chain reaction assay, we found that the TGF-beta3 resulted in an increased level of expression of p15Ink4b and p21Cip1, suggesting that the TGF-beta3 inhibited the taste epithelial cell proliferation through inhibiting G1cyclin-Cdk complexes. Taken together, these results suggested that the TGF-beta3 may regulate taste epithelial cell homeostasis through controlling cell proliferation. PMID- 19787411 TI - The proliferative effects of retinoic acid on primary cultures of adult rat type II pneumocytes depend upon cell density. AB - Retinoic acid (RA) is important for maintaining integrity of alveolar epithelial cells, but the mechanism has not been defined. We cultured type II pneumocytes at confluent, high cell density (10(4) cells/mm(2)) and found that RA (10(-6) M) inhibited thymidine incorporation to 60% of control, despite a dose-dependent increase in epidermal growth factor receptor (EGFR) levels. However, at lower, subconfluent density (10(2) cells/mm(2)), RA stimulated thymidine incorporation to 280% of control. EGF increased thymidine incorporation at concentrations as low as 0.1 ng/mL, but no further increase was observed at higher concentrations up to 100 ng/mL. In subconfluent cells co-treated with EGF (100 ng/mL) and increasing concentrations of RA (10(-8) M-10(-5) M RA), thymidine incorporation was significantly greater at all concentrations than RA alone, with greatest increases observed at 10(-7) (422% of control) and 10(-6) (470% of control) M RA. In summary, the effects of RA on thymidine incorporation are sensitive to changes in cell density. RA inhibits thymidine incorporation at high cell density and stimulates thymidine incorporation at low density. RA increases EGFRs in cultured type II pneumocytes, and EGF stimulates thymidine incorporation independent of the cultured cell density. These data may help to explain how RA mediates lung repair in vivo. PMID- 19787412 TI - Laparoscopic sleeve gastrectomy: an Indian experience-surgical technique and early results. AB - BACKGROUND: Obesity has been observed to be on the rise in the Indian subcontinent. We report our early experience with the laparoscopic sleeve gastrectomy (LSG) for treating morbid obesity in the Indian population along with description of the surgical technique. METHODS: The data of 75 patients who underwent LSG for the treatment of morbid obesity at the Minimal Access, Metabolic and Bariatric Surgery Centre, Sir Ganga Ram Hospital, Delhi, from November 2006 to February 2009, were retrospectively reviewed from prospective database. The gastric sleeve is created laparoscopically using sequential firings of a linear stapling device applied alongside a 36-Fr calibrating bougie. The data collected included age, gender, initial body mass index (BMI) and excess weight, the co-morbidity status, and preoperative investigations. Perioperative parameters and follow-up details [weight, BMI, excess weight loss (%EWL), resolution of co-morbidities, and postoperative investigations] were noted. RESULTS: All procedures were completed laparoscopically. There was no major procedure-related morbidity. Hemorrhage requiring blood transfusion was observed in four patients. One patient died at 2 weeks postoperatively due to pulmonary embolism. There was a steady rise in %EWL from 31.2% at 3 months to 52.3% at 6 months, 59.13% at 1 year, and 65% at 2 years. Type II diabetes was resolved in 81.2%, hypertension in 93.75%, and dyslipidemia in 85% at 1 year. CONCLUSION: Although long-term results are necessary to determine the benefits of the procedure, early results indicate that LSG may be a safe and feasible option for treating the morbidly obese patients. PMID- 19787413 TI - Fractional photothermolysis--an update. AB - The novel concept of non-ablative fractional photothermolysis was introduced to the market in 2003 as an answer to the need for effective, yet low risk, resurfacing techniques. Unlike conventional ablative and non-ablative lasers, fractional ablative and non-ablative photothermolysis treats only a fraction of the skin, leaving up to a maximum of 95% of the skin uninvolved. The undamaged surrounding tissue allows for a reservoir of viable tissue, permitting rapid epidermal repair. Non-ablative fractional photothermolysis is currently approved by the US Food and Drug Administration (FDA) for the treatment of pigmented lesions, periorbital rhytides, skin resurfacing, melasma and soft tissue coagulation, acne and surgical scars, and actinic keratoses. However, its off label use is clearly more extended. In 2007 the concept was further developed, and ablative fractional photothermolysis was introduced, using an erbium yttrium aluminium garnet (Er: YAG) or carbon dioxide laser. These devices are FDA cleared to treat wrinkles, rhytides, furrows, fine lines, textural irregularities, pigmented lesions and vascular dyschromia. In this review we discuss the two concepts, their technical details and clinical indications, and we describe the current literature available. PMID- 19787414 TI - Gene cloning and characterization of an aldehyde dehydrogenase from long-chain alkane-degrading Geobacillus thermoleovorans B23. AB - Geobacillus thermoleovorans B23 is capable of degrading long-chain alkanes at 70 degrees C. Bt-aldh, an aldehyde dehydrogenase gene in B23, was located in the upstream region of p21 whose expression level was dramatically increased when alkane degradation was started (Kato et al. 2009, BMC Microbiol 9:60). Like p21, transcription level of Bt-aldh was also increased upon alkane degradation. Bt Aldh (497 aa, MW = 53,886) was overproduced in Escherichia coli, purified, and characterized biochemically. Bt-Aldh acted as an octamer, required NAD(+) as a coenzyme, and showed high activity against aliphatic long-chain aldehydes such as tetradecanal. The optimum condition for activity was 50-55 degrees C and pH 10.0. The activity was elevated to two- to threefold in the presence of 2 mM Ba(2+), Ca(2+), or Sr(2+), while Mg(2+) and Zn(2+) inhibited the enzyme activity. Bt-Aldh represents thermophilic aldehyde dehydrogenases responsible for degradation of long-chain alkanes. PMID- 19787415 TI - Localized melting of duplex DNA by Cdc6/Orc1 at the DNA replication origin in the hyperthermophilic archaeon Pyrococcus furiosus. AB - The initiation step is a key process to regulate the frequency of DNA replication. Although recent studies in Archaea defined the origin of DNA replication (oriC) and the Cdc6/Orc1 homolog as an origin recognition protein, the location and mechanism of duplex opening have remained unclear. We have found that Cdc6/Orc1 binds to oriC and unwinds duplex DNA in the hyperthermophilic archaeon Pyrococcus furiosus, by means of a P1 endonuclease assay. A primer extension analysis further revealed that this localized unwinding occurs in the oriC region at a specific site, which is 12-bp long and rich in adenine and thymine. This site is different from the predicted duplex unwinding element (DUE) that we reported previously. We also discovered that Cdc6/Orc1 induces topological changes in supercoiled oriC DNA, and that this process is dependent on the AAA+ domain. These results indicate that topological alterations of oriC DNA by Cdc6/Orc1 introduce a single-stranded region at the 12-mer site, that could possibly serve as an entry point for Mcm helicase. PMID- 19787416 TI - Acidithiobacillus ferrivorans, sp. nov.; facultatively anaerobic, psychrotolerant iron-, and sulfur-oxidizing acidophiles isolated from metal mine-impacted environments. AB - Phenotypic and genotypic analysis was carried out on four iron- and sulfur oxidizing acidophilic bacteria (the "NO-37 group") isolated from different parts of the world. 16S rRNA phylogeny showed that they are highly related to each other, but are less related to the type strain of Acidithiobacillus ferrooxidans. The NO-37 group isolates are obligate chemolithoautotrophs, facultative anaerobes, diazotrophic, and psychrotolerant. They are less tolerant of extremely low pH, and in contrast to At. ferrooxidans (T), all of the NO-37 group isolates are motile. The GC contents of genomic DNA of the NO-37 group isolates were around 56 mol% and the DNA-DNA hybridization value between genomic DNA of isolate NO-37 and At. ferrooxidans (T) was 37%. It also appears that the bacteria of the NO-37 group have a different biochemical mechanism for oxidizing ferrous iron than At. ferrooxidans (T); the gene coding for the archetypal rusticyanin (RusA) was not detected in any of the NO-37 group isolates, rather a gene coding for a homologous protein (RusB) was amplified from three of the four novel isolates. Isolates of the NO-37 group clearly belong to a species that is different to those already recognized in the genus Acidithiobacillus, for which the name Acidithiobacillus ferrivorans is proposed. PMID- 19787417 TI - Chryseobacterium septicemia in a renal allograft recipient. PMID- 19787418 TI - Evaluation of inflammation and oxidative stress in ankylosing spondylitis: a role for macrophage migration inhibitory factor. AB - Ankylosing spondylitis (AS) is a chronic inflammatory disease mainly affecting the spine and sacroiliac joints. Mediators such as macrophage migration inhibitory factor (MIF) and interleukin-10 (IL-10) are thought to be involved in several inflammatory conditions, including AS. Proinflammatory cytokines regulate the production of oxidative stress markers, such as nitric oxide (NO) and malondialdehyde (MDA). Although oxidative stress and lipid peroxidation have been reported in AS, the association of AS with commonly known oxidative stress markers and cytokines remains uncertain. We have therefore studied whether serum MIF levels are elevated in patients with AS and whether the levels correlate with oxidative stress markers and disease activity parameters. Twenty-five AS patients and 18 healthy controls participated in this study; subjects with hypertension, diabetes, hyperlipidemia, and obesity were excluded. The levels of acute phase reactants, serum levels of glucose, lipids, MIF, IL-10, NO and MDA were studied. Spinal mobility was assessed by the Bath Ankylosing Spondylitis Metrology Index (BASMI). Patients were also assessed using with the Bath Ankylosing Spondylitis Functional Index and the Bath Ankylosing Spondylitis Disease Activity Index. Age and sex distribution were found to be comparable between AS patients and controls (p > 0.05). Acute phase reactants and MIF levels were significantly higher (p < 0.05) and IL-10 levels were significantly lower (<0.001) in the AS patients than in controls. There was a significant correlation between BASMI and MIF levels in AS patients (r = 0.714, p < 0.001). Based on these results, MIF may be involved in the pathogenesis of the chronic inflammation in AS and, consequently, targeting MIF may be beneficial in preventing complications or in initiating early treatment of the disease. PMID- 19787419 TI - Prediction of DAS28-CRP remission in patients with rheumatoid arthritis treated with tacrolimus at 6 months by baseline variables. AB - We attempted to determine what baseline variables are responsible for the efficacy of tacrolimus at 6 months in Japanese patients with rheumatoid arthritis (RA). One hundred and six RA patients treated with tacrolimus for 6 months were entered in this study. The outcome was set as the achievement of Disease Activity Score 28 C-reactive protein (DAS28-CRP) remission at 6 months. We examined the association of gender, DAS28-CRP at baseline, concomitant use of methotrexate (MTX), and concomitant use of prednisolone with the achievement of DAS28-CRP remission at 6 months by logistic regression analysis. Twenty-three of 106 patients (21.7%) achieved DAS28-CRP remission at 6 months. There was concomitant use of MTX by 20 patients (18.9%), prednisolone by 93 (87.7%), and prednisolone [5 mg/day by 43 (40.6%) at baseline. Logistic regression analysis showed that male gender (first) and moderate disease activity at baseline (second) are independent predictors toward achieving DAS28-CRP remission at 6 months. Maximum tacrolimus dosage administrated for patients over a 6-month period appeared not to be predictive for the DAS28-CRP remission at 6 months. In conclusion, we revealed for the first time that good outcome in RA patients treated with tacrolimus can be predictive by some baseline variables. That is clinically valuable for daily practice in the choice of disease-modifying antirheumatic drugs (DMARDs), especially tacrolimus. PMID- 19787420 TI - Two new monoterpenes from Sibiraea angustata. AB - Two novel monoterpenes, sibiscolacton (1) and sibiraic acid (2), were isolated from the aerial part of Sibiraea angustata RCHD: . along with seven known compounds, namely three phenylpropanoids (3-5), two flavonoids (6,7), one glucityl ferulate (8, sibirate), and a monoterpene glucoside (9, sibiskoside). The structures of 1 and 2 were established on the basis of spectroscopic and chemical data. PMID- 19787421 TI - Antidepressant properties of bioactive fractions from the extract of Crocus sativus L. AB - The aim of this study was to investigate the antidepressant properties of stigmas and corms of Crocus sativus L. The aqueous ethanol extract of C. sativus corms was fractionated on the basis of polarity. Among the different fractions, the petroleum ether fraction and dichloromethane fraction at doses of 150, 300, and 600 mg/kg showed significant antidepressant-like activities in dose-dependent manners, by means of behavioral models of depression. The immobility time in the forced swimming test and tail suspending test was significantly reduced by the two fractions, without accompanying changes in ambulation when assessed in the open-field test. By means of a gas chromatography-mass spectrometry technique, twelve compounds of the petroleum ether fraction were identified. These data show that administration of C. sativus corms extract produces antidepressant-like effects. Aqueous stigmas extract also exerted antidepressive effects in the behavioral models. Crocin 1 and crocin 2 of the aqueous stigmas extract were identified by a reversed-phase HPLC analysis. In addition, the bioactive compound crocin 1 in this herb was quantitatively determined. The data indicate that antidepressant-like properties of aqueous stigma extracts may be due to crocin 1, giving support to the validity of the use of this plant in traditional medicine. All these results suggest that the low polarity parts of C. sativus corms should be considered as a new plant material for curing depression, which merit further studies regarding antidepressive-like activities of chemical compounds isolated from the two fractions and mechanism of action. PMID- 19787422 TI - A new angeloylated triterpenoid saponin from the husks of Xanthoceras sorbifolia Bunge. AB - A new angeloylated oleanane-type triterpenoid saponin, sorbifoliaside (1), and a known saponin, xanifolia O54, were isolated from the husks of Xanthoceras sorbifolia Bunge. Their chemical structures were elucidated on the basis of various spectroscopic analyses coupled with chemical degradation. To our knowledge, compound 1 is the first example of a naturally occurring triterpenoid saponin with an angeloyl group at C-2 of the sugar moiety. PMID- 19787423 TI - Light-induced COP9 signalosome expression in the Indian false vampire bat Megaderma lyra. AB - The COP9 signalosome (CSN) is a multi-subunit protein complex conserved in plants and animals. CSN subunits have been identified as light-mediated master regulators of eukaryotic circadian clocks from fungi to animals. The Indian false vampire bat Megaderma lyra is completely adapted to an anthropic biotope and behavioral studies have reported that M. lyra exhibits light-sampling behavior to assess environmental light. LC-MS-MS results for a 36 kDa protein were analyzed using the Sequest search engine, and COP9 signalosome subunit 5 (CSN5) was pinpointed as having the highest score with 6 matching peptides. To confirm the presence of CSN5, up-regulated cDNA was amplified, sequenced, and identified as CSN5. Furthermore, semi-quantitative RT-PCR analysis demonstrated that the level of induction of CSN5 was regulated by environmental light. We estimated the level of expression across a light-dark cycle and observed a higher level of expression at the end of the light phase. Similarly, when the animal was shifted from continuous dark to light, CSN5 expression was induced. Correspondingly, we detected the similar pattern of translated protein with JAB1 antibody. Knowledge about the circadian rhythm and its molecular mechanism in Chiroptera is very limited and this study suggests that CSN5 might be involved in the M. lyra light signaling process. PMID- 19787424 TI - The elephant's other bits. PMID- 19787425 TI - Defecographic pelvic floor abnormalities in constipated patients: does mode of delivery matter? AB - BACKGROUND: The aim of this study was to demonstrate the distribution of defecographic pelvic floor abnormalities in constipated female patients and to correlate these dysfunctions with the mode of delivery. METHODS: Two hundred and fifty-five female patients who underwent defecography for constipation from 2001 to 2008 were reviewed and pelvic floor abnormalities were assessed. The patients were divided into three groups: group I had 50 nulliparous women, mean age 40.2 (+ or - 15.3), group II had 165 vaginally parous women, mean age 57 (+ or - 13.3), and group III had 40 patients delivered by cesarean section, mean age 50.6 (+ or - 11.9). RESULTS: Significant rectocele was identified in group I (36%), group II (35.8%), and group III (20%) without any statistically significant differences among the groups (p > 0.05). Intussusception was identified in group I (48%), group II (70.3%), and in group III (67.5%; p = 0.014). Intussusception associated with significant rectocele was more common in vaginally parous patients (p = 0.043). Abnormalities on puborectalis relaxation associated or not associated with rectocele were similar among the groups (p = 0.47). Vaginally parous patients had more abnormal exams as compared to other patients (p = 0.005). Significant rectocele was identified in (39%) patients with age > or = 50 years and in (26.3%) patients with age <50 years (p = 0.03). CONCLUSION: There was no specific correlation between distribution of pelvic floor disorders and mode of delivery in this study. Patients of age greater than 50 years had a higher incidence of significant rectocele. PMID- 19787426 TI - Ethical issues on newer technology in colorectal practice. PMID- 19787427 TI - Rare site giant cell tumors: report of two cases on phalanges of the finger and review of literature. AB - Giant cell tumor (GCT) of bone arising from a phalanx of a finger is extremely rare. We report two cases of GCT arising from a phalanx of a finger. One case presented with recurrence following the amputation of the left ring finger (performed elsewhere). He was treated successfully with ray amputation. The other case was treated primarily by intralesional curettage and autogenous bone graft. At their most recent follow-ups (80 and 24 months, respectively), both were recurrence free and had returned to their previous occupational and recreational activities. PMID- 19787429 TI - New evidence in infective and cardiovascular medicine. PMID- 19787428 TI - A 41-year-old woman with paroxysmal abdominal pain, weight loss and an epigastric bruit. PMID- 19787430 TI - Plasma levels and urinary excretion of amino acids by subjects with renal calculi. AB - Plasma levels and urinary amino acid excretions were estimated by high performance liquid chromatography in 15 control subjects and 36 stone formers (SFs) classified according to the stone type: (1) 22 cases with calcium oxalate stones; (2) four cases with pure uric acid stones; (3) 10 cases with magnesium ammonium phosphate stones, either pure or mixed with apatite. Some types of stones (namely oxalate and uric acid calculi) are mainly formed as a result of a metabolic deficiency that may affect the amino acid metabolism, and thus may be reflected in the urinary amino acid pattern. Data demonstrated clearly that there is a general tendency towards decreased amino acid excretions in all SFs with all types of stones. As a whole, one can observe a higher percentage of patients with calcium oxalate and phosphate calculosis, who have low urine excretions of amino acids; about 50% are the SFs with lower urine excretion of serine, glycine, taurine and i-leucine; the high percentage of patients with CaOX calculi shows lower urine excretions of tyrosine and ornithine. PMID- 19787431 TI - Synthesis of the siderophore pyoverdine in Pseudomonas aeruginosa involves a periplasmic maturation. AB - Pyoverdines, the main siderophores produced by fluorescent Pseudomonads, comprise a fluorescent dihydroxyquinoline chromophore attached to a strain-specific peptide. These molecules are thought to be synthesized as non-fluorescent precursor peptides that are then modified to give functional pyoverdines. Using the fluorescent properties of PVDI, the pyoverdine produced by Pseudomonas aeruginosa PAO1, we were able to show that PVDI was not present in the cytoplasm of the bacteria, but large amounts of a fluorescent PVDI precursor PVDIp were stored in the periplasm. Like PVDI, PVDIp is able to transport iron into P. aeruginosa cells. Mutation of genes encoding the periplasmic PvdN, PvdO and PvdP proteins prevented accumulation of PVDIp in the periplasm and secretion of PVDI into the growth medium, indicating that these three enzymes are involved in PVDI synthesis. Mutation of the gene encoding PvdQ resulted in the presence of fluorescent PVDI precursor in the periplasm and secretion of a functional fluorescent siderophore that had different isoelectric properties to PVDI, suggesting a role for PvdQ in the periplasmic maturation of PVDI. Mutation of the gene encoding the export ABC transporter PvdE prevented PVDI production and accumulation of PVDIp in the periplasm. These data are consistent with a model in which a PVDI precursor peptide is synthesized in the cytoplasm and exported to the periplasm by PvdE where siderophore maturation, including formation of the chromophore moiety, occurs in a process involving the PvdN, PvdO, PvdP and PvdQ proteins. PMID- 19787432 TI - Medium optimization for production of gamma-aminobutyric acid by Lactobacillus brevis NCL912. AB - Production of gamma-aminobutyric acid (GABA) was carried out in Erlenmeyer flasks by Lactobacillus brevis NCL912. Traditional methods were first adopted to select the key factors that impact the GABA production to preliminarily determine the suitable concentration ranges of the key factors. It was found that glucose, soya peptone, Tween-80 and MnSO(4).4H(2)O were the key factors affecting GABA production. Then, response surface methodology was applied to analyze the optimum contents of the four key factors in the medium, and the production of GABA was predicted as 349.69 mM under the optimized conditions with this model. Afterward, the experiment was performed under the optimized conditions, and the yield of GABA reached 345.83 mM, which was 130% higher than the initial medium. The results showed that experimental yield and predicted values of GABA yield were in good agreement. PMID- 19787433 TI - A large insert Thellungiella halophila BIBAC library for genomics and identification of stress tolerance genes. AB - Salt cress (Thellungiella halophila), a salt-tolerant relative of Arabidopsis, has turned to be an important model plant for studying abiotic stress tolerance. One binary bacterial artificial chromosome (BIBAC) library was constructed which represents the first plant-transformation-competent large-insert DNA library generated for Thellungiella halophila. The BIBAC library was constructed in BamHI site of binary vector pBIBAC2 by ligation of partial digested nuclear DNA of Thellungiella halophila. This library consists of 23,040 clones with an average insert size of 75 kb, and covers 4x Thellungiella halophila haploid genomes. BIBAC clones which contain inserts over 50 kb were selected and transformed into Arabidopsis for salt tolerant plant screening. One transgenic line was found to be more salt tolerant than wild type plants from the screen of 200 lines. It was demonstrated that the library contains candidates of stress tolerance genes and the approach is suitable for the transformation of stress susceptible plants for genetic improvement. PMID- 19787435 TI - Induction of functional cytochrome P450 and its involvement in degradation of benzoic acid by Phanerochaete chrysosporium. AB - The white rot fungus Phanerochaete chrysosporium has the largest cytochrome P450 contingent known to date in fungi, but the study on the function of these P450s is limited. In this study, induction of functional P450 in P. chrysosporium was first shown and P450-mediate degradation of benzoic acid was demonstrated in this fungus. Carbon monoxide difference spectra indicated significant induction of P450 by benzoic acid, m-chlorobenzoic acid, p-chlorobenzoic acid and n-hexane, and showed the effect of inducer concentration and nutrient condition on the induction of P450. The high contents of P450 in the microsomal fractions facilitated the study on the function of P450. While the n-hexane-induced P450 could not interact with benzoic acid, the microsomal P450 induced by benzoic acid produced type I substrate binding spectra upon the addition of benzoic acid. The benzoic acid degradation by the microsomal P450 was NADPH-dependent at a specific rate of 194 +/- 14 min(-1), and significantly inhibited by piperonyl butoxide (a P450 inhibitor). However, inhibition of benzoic acid degradation by piperonyl butoxide was slight or not detectable in the cultures of this fungus, suggesting presumable involvement of other enzyme in benzoic acid degradation. The extracellular ligninolytic enzymes, lignin peroxidase and manganese-dependent peroxidase, were not involved in initial metabolism of benzoic acid under the test conditions. PMID- 19787436 TI - Modulation of prostate cancer cell gene expression by cell-to-cell contact with bone marrow stromal cells or osteoblasts. AB - After prostate cancer cells (PCa) arrive in bone, interactions with cells that include long bone osteoblasts (LBOB) and bone marrow stromal cells (BMSC) lead to metastasis formation. The effect of heterotypic cell-cell contact between PCa cells and BMSC or LBOB on PCa cell gene expression is poorly understood. To establish the role of heterotypic contact in bone metastasis formation, we mixed and co-cultured PC3 cells with rat BMSC, LBOB, or human prostate stromal cells (PS15). PC3 cells were then re-isolated for gene array analysis, and imaged using in situ hybridization to confirm that heterotypic contact regulates gene expression. The gene expression was examined using focused gene arrays containing 96 each of tumor metastasis genes or osteogenesis genes. A total of 18 out of 192 genes in PC3 cells were found to be under or over expressed subsequent to heterotypic contact with BMSC when analyzed. A total of 15 genes out of 192 were regulated in co-culture with LBOB, and 19 genes with PS15. Only two genes, uPA and Collagen III, were regulated by contact with BMSC or LBOB (both are bone derived cells), but not by contact with PS15. The relationship between cell-cell contact and uPA expression was further explored by varying cell ratios in co culture. uPA over-expression in PC3 was related to the BMSC:PC3 ratio, and was maximum at a 10:1 ratio, where most PC3 cells would be in contact with BMSC, as predicted by a theoretical model of heterotypic contact. In situ staining of micropatterned PC3 and BMSC cells showed that uPA over-expression localizes to regions of heterotypic cell-cell contact. Taken together, our results suggest that heterotypic cell-to-cell contact between PC3 and BMSC proportionally enhances gene expression for uPA, providing a mechanism for localized control of invasiveness. PMID- 19787434 TI - A gene expression analysis of syncytia laser microdissected from the roots of the Glycine max (soybean) genotype PI 548402 (Peking) undergoing a resistant reaction after infection by Heterodera glycines (soybean cyst nematode). AB - The syncytium is a nurse cell formed within the roots of Glycine max by the plant parasitic nematode Heterodera glycines. Its development and maintenance are essential for nematode survival. The syncytium appears to undergo two developmental phases during its maturation into a functional nurse cell. The first phase is a parasitism phase where the nematode establishes the molecular circuitry that during the second phase ensures a compatible interaction with the plant cell. The cytological features of syncytia undergoing susceptible or resistant reactions appear the same during the parasitism phase. Depending on the outcome of any defense response, the second phase is a period of syncytium maintenance (susceptible reaction) or failure (resistant reaction). In the analyses presented here, the localized gene expression occurring at the syncytium during the resistant reaction was studied. This was accomplished by isolating syncytial cells from Glycine max genotype Peking (PI 548402) by laser capture microdissection. Microarray analyses using the Affymetrix soybean GeneChip directly compared Peking syncytia undergoing a resistant reaction to those undergoing a susceptible reaction during the parasitism phase of the resistant reaction. Those analyses revealed lipoxygenase-9 and lipoxygenase-4 as the most highly induced genes in the resistant reaction. The analysis also identified induced levels of components of the phenylpropanoid pathway. These genes included phenylalanine ammonia lyase, chalcone isomerase, isoflavone reductase, cinnamoyl CoA reductase and caffeic acid O-methyltransferase. The presence of induced levels of these genes implies the importance of jasmonic acid and phenylpropanoid signaling pathways locally at the site of the syncytium during the resistance phase of the resistant reaction. The analysis also identified highly induced levels of four S-adenosylmethionine synthetase genes, the EARLY-RESPONSIVE TO DEHYDRATION 2 gene and the 14-3-3 gene known as GENERAL REGULATORY FACTOR 2. Subsequent analyses studied microdissected syncytial cells at 3, 6 and 9 days post infection (dpi) during the course of the resistant reaction, resulting in the identification of signature gene expression profiles at each time point in a single G. max genotype, Peking. PMID- 19787438 TI - An optical-manipulation technique for cells in physiological flows. AB - We have developed a technique to manipulate human red blood cells (RBCs) in hydrodynamic flows. This method applies optical tweezers to trap and move microbead-attached RBCs in a liquid medium at various speeds, while it significantly minimizes laser heating and photon-induced stress for normal operation with laser-trapped cells. Computational fluid dynamics is applied to simulate flow-induced shear stress over the cell membrane and to correlate quantitatively the forces with the cell deformations. RBCs can be manipulated under physiological conditions by this approach, which may open an avenue to design principles for the next generation of cell sorting and delivery. PMID- 19787437 TI - Beliefs about the causes of breast and colorectal cancer among women in the general population. AB - OBJECTIVE: To describe and compare the causal beliefs and attributions about breast and colorectal cancer among unaffected women in the general population. METHODS: A total of 439 unaffected women in the general population were recruited to complete a web-based survey assessing causal beliefs for either breast (n = 211) or colorectal cancer (n = 228). RESULTS: Heredity was ranked as the most important causal factor, followed by diet or eating habits for both cancer sites. Women endorsed the following causes of breast or colorectal cancer, respectively: heredity (84.4, 78.5%), diet or eating habits (46.4, 69.7%), pollution in the environment (57.6, 40.3%), aging (48.8, 57.5%), alcohol (29.9, 40.8%), smoking (58.3, 50.8%), stress (27.5, 29.4%), and lack of exercise (35.7, 44.3%). Other factors such as prior surgery on the breast (23.7%) and colon (32.9%) or changes in one's immune system (60.6%-breast; 59.2%-colon) were also endorsed by some women. Significant differences in the degree of endorsement for various causes of breast and colorectal cancer were identified. CONCLUSIONS: Both genetic and environmental causes for breast and colorectal cancer are endorsed by unaffected women. Misconceptions about the causes of these cancers are important targets for public education and risk communication efforts. PMID- 19787439 TI - TSG101, identified by screening a cancer cDNA library and soft agar assay, promotes cell proliferation in human lung cancer. AB - Understanding the genesis and development of tumors is an essential component in cancer research. It is of interest to discover unknown genes that are responsible for cellular transformation. A cDNA library of a highly metastatic lung adenocarcinoma cell line was constructed. This library was introduced into the NIH3T3 mouse embryonic fibroblast cell line to screen for cDNAs that increase anchorage-independent colony formation in soft agar. The expression of TSG101 in lung cancer cell lines and specimens was confirmed using reverse transcription polymerase chain reaction. The level of TSG101 protein in transfected A549 cells was determined by western blotting. Cell-cycle distribution was analyzed using a FACStar Plus flow cytometer. One of the candidate cDNAs that increases anchorage independent colony formation was shown to correspond to the TSG101 cDNA sequence. Levels of TSG101 mRNA were higher in lung cancer cell lines and specimens compared to matched normal lung tissues. Ectopic expression of TSG101 in the A549 lung adenocarcinoma cell line increased the numbers of cells in S phase, suggesting an increased cell proliferation rate. These results indicate that TSG101 may induce the malignant phenotype of cells. PMID- 19787440 TI - For love or money? The saga of Korean women who provided eggs for embryonic stem cell research. AB - In 2004 and 2005, Woo-Suk Hwang achieved international stardom with publications in Science reporting on successful research involving the creation of stem cells from cloned human embryos. The wonder and success all began to unravel, however, when serious ethical concerns were raised about the source of the eggs for this research. When the egg scandal had completely unfolded, it turned out that many of the women who provided eggs for stem cell research had not provided valid consents and that nearly 75% of the women egg providers had received cash or in kind payments. Among those who did not receive direct benefits, some cited patriotism as their reason for participating in embryonic stem cell research, hence the question "for love or money?"--namely, patriotism versus payment. This paper summarizes the Hwang debacle with particular attention to the egg scandal and ends with some preliminary thoughts on patriotism as a motive for research participation. PMID- 19787441 TI - Assessment of the impact of eating disorders on quality of life using the disease specific, Health-Related Quality of Life for Eating Disorders (HeRQoLED) questionnaire. AB - OBJECTIVE: To evaluate and compare the quality of life (QOL) in patients with eating disorders (ED) and general population, using the disease-specific Health Related Quality of Life for Eating Disorders (HeRQoLED) questionnaire. METHODS: A total of 358 patients with ED completed the HeRQoLED questionnaire as well as the SF-12 and the Eating Attitudes Test (EAT-26) at baseline; 273 patients completed the same instruments after 1 year of multidisciplinary treatment. A total of 305 individuals recruited from the general population completed the HeRQoLED once. Comparison of means was used to assess change. Multivariate models were created to determine variables predictive of change in HeRQoLED scores. RESULTS: Patients with anorexia nervosa had higher baseline scores (indicating worse perception of QOL) on the HeRQoLED questionnaire and experienced smaller improvements than patients with other diagnoses after 1 year of treatment. After adjustment by relevant variables, body-mass index (BMI) and EAT-26 scores were associated with changes in QOL. SF-12 scores showed significant improvement in the physical health component but not in mental health. General population had lower baseline scores on the HeRQoLED. CONCLUSIONS: As measured by the disease-specific HeRQoLED and generic instruments, QOL in patients with ED improved after 1 year of treatment, though it did not reach the values of the general population. PMID- 19787442 TI - A matter of trust? A study of coordination of Swedish stakeholders in return-to work. AB - INTRODUCTION: Stakeholder cooperation in return-to-work has been increasingly emphasized over the last years. However, there is a lack of empirical studies on the subject. This study explores different public stakeholders' experiences of participating in Coordination Associations (CAs), a Swedish form of structured cooperation in return-to-work. The aim of the study is to determine the impact of stakeholder interests on the prerequisites for cooperation. METHODS: Thirty-five representatives from two CAs in eastern Sweden were interviewed regarding the aim, structure and strategies for their common work. RESULTS: Stakeholders' actions are to a high degree determined by their institutional preferences and self-interest. In the CAs, the motives for cooperation differ, and although these differences supposedly could be overcome, they are in fact not. One of the stakeholders, the Public Employment Service, limit its interest to coordinating resources, while the other three wishes to engage in elaborated cooperative work forms, implying the crossing of organizational borders. This discrepancy can largely be attributed to the difficulties for representatives from state authorities in changing their priorities in order to make cooperation work. CONCLUSIONS: Stakeholders' interests have a high impact on the prerequisites for cooperation in return-to-work. By referring to organizational goals, stakeholders engage in non-cooperative behaviour, which threatens to spoil cooperative initiatives and to develop distrust in cooperative work forms. The results of this study expose the complexity of and threats to cooperation, and its conclusions may be used by return-to-work stakeholders in different jurisdictions to improve the possibilities for the development of cooperative structures. PMID- 19787443 TI - Spectroscopic investigation on the toxicological interactions of 4 aminoantipyrine with bovine hemoglobin. AB - The effects of 4-aminoantipyrine (AAP) on bovine hemoglobin (BHb) were investigated by fluorescence spectroscopy, synchronous fluorescence spectroscopy, ultraviolet-visible absorption spectroscopy and circular dichroism spectroscopy (CD) under simulated physiological conditions. The experimental results showed that AAP effectively quenched the intrinsic fluorescence of BHb via static quenching. The number of binding sites, the binding constant K(a), and the thermodynamic parameters (DeltaH(o), DeltaS(o) and DeltaG(o)) were measured at two different temperatures. Van der Waals' interactions and hydrogen bonds were the predominant intermolecular forces in stabilizing the BHb-AAP complex. The experiment results confirmed micro-environmental and conformational changes of BHb in the presence of AAP. The alpha-helix content decreased, indicating that AAP destroys some of the hydrogen bonding networks in the polypeptide chain. PMID- 19787444 TI - "A massive long way": interconnecting histories, a "special child," ADHD, and everyday family life. AB - Focusing on one family from a study of dual-earner middle-class families carried out in Los Angeles, California, this article draws on interview and video recorded data of everyday interactions to explore illness and healing as embedded in the microcultural context of the Morris family. For this family, an important aspect of what is at stake for them in their daily lives is best understood by focusing on 9-year-old Mark, who has been diagnosed with attention deficit/hyperactivity disorder (ADHD). In this article, we grapple with the complexity of conveying some sense of how Mark's condition is experienced and relationally enacted in everyday contexts. Through illuminating connections between lives as lived and lives as told, we explore the narrative structuring of healing in relation to Mark's local moral world with the family at its center. We examine how his parents understand the moral consequences of the child's past for his present and future, and work to encourage others to give due weight to his troubled beginnings before this child joined the Morris family. At the same time, we see how the Morris parents act to structure Mark's moral experience and orient to a desired future in which Mark's "success" includes an appreciation of how he is accountable to others for his actions. Through our analyses, we also seek to contribute to discussions on what is at stake in everyday life contexts for children with ADHD and their families, through illuminating aspects of the cultural, moral and relational terrain that U.S. families navigate in contending with a child's diagnosis of ADHD. Further, given that ADHD is often construed as a "disorder of volition," we seek to advance anthropological theorizing about the will in situations where volitional control over behavior is seen to be disordered. PMID- 19787445 TI - Magical hair as dirt: Ecstatic bodies and postcolonial reform in South India. AB - This paper offers an ethnography of the medicalization of matted locks of hair (jade) worn by female ecstatics in a South Indian devi (goddess) cult. These jade are taken by devotees of the devi Yellamma to be a manifestation of her presence in the bodies of women who enter possession states and give oracles. At her temples across the central Deccan Plateau, Yellamma women can be seen wearing heavy locks of matted hair anointed with turmeric, the color and healing properties of which are identified with this devi. Under a recent government sponsored campaign, reformers cut jade and hand out packets of shampoo as a means of reforming the extended and illicit sexuality of these women. Associations between sexuality and hair practices have long preoccupied anthropologists interested in the relationship between the body and culture. In this paper, I draw on this literature and more than 2 years of field research to consider the encounter between biomedical and Shakta epistemologies of the body dramatized in these jade cutting campaigns. This effort to remake the body as a fit site and sign of modernity elaborates the postcolonial politics of sexuality, gender and religiosity in India. PMID- 19787446 TI - Magnetoencephalographic findings in two cases of juvenile myoclonus epilepsy. AB - The aim of this study is to investigate the electromagnetic sources of epileptic activity in two patients with juvenile myoclonus epilepsy (JME). The first patient was a 22-year old female with JME diagnosis by the age of 17 years old. Her initial EEG recording showed characteristic paroxysmal generalized activity with polyspike-wave complexes. She was on remission for 9 months. The second patient was a 29-year old male with JME diagnosis by the age 18 of years old. He showed an EEG recording with generalized spike-wave complexes of 3.5-4 Hz and presented a great improvement after therapeutic treatment. The MRI examinations for both patients did not disclose any focal lesions or areas of abnormal signal intensity or enhancement by contrast media. Magnetoencephalography (MEG) was recorded with a 122-channel whole-head system, 5 years after the disease onset for the first patient and 11 years for the second patient. For the first patient dipolar sources of MEG paroxysmal activity were localised at the vermis with extension up to the occipital region, whereas, for the second patient dipolar sources of MEG paroxysmal activity were localised at the cerebellar area (vermis and hemisphere). Implication of the cerebellum in JME, as suggested by MEG data in this study, is in accordance with previous reports employing functional MRI or cerebral blood flow evaluation in JME. PMID- 19787447 TI - ADHD and working memory: the impact of central executive deficits and exceeding storage/rehearsal capacity on observed inattentive behavior. AB - Inattentive behavior is considered a core and pervasive feature of ADHD; however, an alternative model challenges this premise and hypothesizes a functional relationship between working memory deficits and inattentive behavior. The current study investigated whether inattentive behavior in children with ADHD is functionally related to the domain-general central executive and/or subsidiary storage/rehearsal components of working memory. Objective observations of children's attentive behavior by independent observers were conducted while children with ADHD (n = 15) and typically developing children (n = 14) completed counterbalanced tasks that differentially manipulated central executive, phonological storage/rehearsal, and visuospatial storage/rehearsal demands. Results of latent variable and effect size confidence interval analyses revealed two conditions that completely accounted for the attentive behavior deficits in children with ADHD: (a) placing demands on central executive processing, the effect of which is evident under even low cognitive loads, and (b) exceeding storage/rehearsal capacity, which has similar effects on children with ADHD and typically developing children but occurs at lower cognitive loads for children with ADHD. PMID- 19787449 TI - Ljubljana nomograms for predicting the likelihood of non-sentinel lymph node metastases in breast cancer patients with a positive sentinel lymph node. AB - Several tools for predicting the likelihood of non-sentinel lymph node (non-SLN) involvement in SLN positive breast cancer patients have been created so far.The aim of our study was to create and validate different nomograms for predicting the likelihood of non-SLN involvement that would be applicable in different institutions and that would also include the results of the preoperative US examination of the axilla. From January 2000 to January 2009, 534 breast cancer patients underwent axillary lymph node dissection (ALND) due to metastatic SLN at our institution. Using logistic regression results three nomograms differing in the inclusion of the results of intraoperative examination of SLN were created. The nomograms were validated using bootstrap methods. In all three nomograms, US examination of the axilla was a powerful independent variable. Other variables included(different in different nomograms) were tumor size, lymphovascular invasion, metastasis size in SLN, number of negative and number of positive SLNs. Mean absolute error and mean area under the ROC curve equals to 0.016 and 0.77 for the first, 0.023 and 0.75 for the second and 0.014 and 0.79 for the third nomogram. Three nomograms for predicting the likelihood of non-SLN metastases including the results of the preoperative US examination of the axilla were created at our institution. They differ in the inclusion of the results of intraoperative examination of SLNs and are thus applicable in different institutions. The validation results seem promising and omission of completion ALND might be considered in patients with the probability of having non-SLN metastases of 10% or less. PMID- 19787448 TI - Dominant-negative myosin Va impairs retrograde but not anterograde axonal transport of large dense core vesicles. AB - Axonal transport of peptide and hormone-containing large dense core vesicles (LDCVs) is known to be a microtubule-dependent process. Here, we suggest a role for the actin-based motor protein myosin Va specifically in retrograde axonal transport of LDCVs. Using live-cell imaging of transfected hippocampal neurons grown in culture, we measured the speed, transport direction, and the number of LDCVs that were labeled with ectopically expressed neuropeptide Y fused to EGFP. Upon expression of a dominant-negative tail construct of myosin Va, a general reduction of movement in both dendrites and axons was observed. In axons, it was particularly interesting that the retrograde speed of LDCVs was significantly impaired, although anterograde transport remained unchanged. Moreover, particles labeled with the dominant-negative construct often moved in the retrograde direction but rarely in the anterograde direction. We suggest a model where myosin Va acts as an actin-dependent vesicle motor that facilitates retrograde axonal transport. PMID- 19787450 TI - Learning to predict relapse in invasive ductal carcinomas based on the subcellular localization of junctional proteins. AB - The complexity of breast cancer biology makes it challenging to analyze large datasets of clinicopathologic and molecular attributes, toward identifying the key prognostic features and producing systems capable of predicting which patients are likely to relapse. We applied machine-learning techniques to analyze a set of well-characterized primary breast cancers, which specified the abundance and localization of various junctional proteins. We hypothesized that disruption of junctional complexes would lead to the cytoplasmic/nuclear redistribution of the protein components and their potential interactions with growth-regulating molecules, which would promote relapse, and that machine-learning techniques could use the subcellular locations of these proteins, together with standard clinicopathological data, to produce an efficient prognostic classifier. We used immunohistochemistry to assess the expression and subcellular distribution of six junctional proteins, in addition to a panel of eight standard clinical features and concentrations of four "growth-regulating" proteins, to produce a database involving 36 features, over 66 primary invasive ductal breast carcinomas. A machine-learning system was applied to this clinicopathologic dataset to produce a decision-tree classifier that could predict whether a novel breast cancer patient would relapse. We show that this decision-tree classifier, which incorporates a combination of only four features (nuclear alpha- and beta-catenin levels, the total level of PTEN and the number of involved axillary lymph nodes), is able to correctly classify patient outcomes essentially 80% of the time. Further, this classifier is significantly better than classifiers based on any subgroup of these 36 features. This study demonstrates that autonomous machine learning techniques are able to generate simple and efficient decision-tree prognostic classifiers from a wide variety of clinical, pathologic and biomarker data, and unlike other analytic methods, suggest testable biologic relationships among explicitly identified key variables. The decision-tree classifier resulting from these analytic methods is sufficiently simple and should be widely applicable to a spectrum of clinical cancer settings. Further, the subcellular distribution of junctional proteins, which influences growth regulatory pathways involved in locoregional and metastatic relapse of breast cancer, helped to identify which patients would relapse while their total concentration did not. This emphasizes the need to evaluate the subcellular distribution of junctional proteins in assessing their contribution to tumor progression. PMID- 19787451 TI - Are the T-wave alternans amplitude "zones" related to T-wave amplitude "zones" in ECG ambulatory recordings? PMID- 19787452 TI - Gender bender: gender errors in L2 pronoun production. AB - To address questions about information processing at the message level, pronoun errors of second language (L2) speakers of English were studied. Some L2 pronoun errors-he/she confusions by Spanish speakers of L2 English-could be due to differences in the informational requirements of the speakers' two languages, providing a window into the composition of the preverbal message that guides grammatical encoding during language production. To study this, Spanish and French speakers of L2 English were made to answer questions designed to elicit pronouns. Spanish speakers produced significantly more gender errors than any other type of pronoun error, and significantly more gender errors than French speakers. The results are as expected given that Spanish is a pro-drop language where many sentences would not have required gender to be encoded had they been uttered in the L1 instead of the L2. The implications for theories about the preverbal message are discussed. PMID- 19787453 TI - My Ishvara is dead: spiritual care on the fringes. AB - Human suffering speaks differently to different lived contexts. In this paper, I have taken a metaphoric representation of suffering, Ishvara, from the lived context of a Hindu immigrant woman to show that suffering is experienced and expressed within one's lived context. Further, a dominant narrative from her world is presented to show that the same lived context can be a resource for spiritual care that could reconstruct her world that has fallen apart with a suffering experience. Having argued that suffering is experienced and expressed within one's lived context, and that lived context could be a resource, in this paper I present that spiritual care is an intervention into the predicaments of human suffering and its mandate is to facilitate certain direction and a meaningful order through which experiences and expectations are rejoined. Finally, I observe that spiritual care is an engagement between the lived context where suffering is experienced and the spiritual experience and orientation of the caregiver. PMID- 19787454 TI - Preferential vitrification of water in small alginate microcapsules significantly augments cell cryopreservation by vitrification. AB - The morphological changes of small (approximately 100 microm) alginate microcapsules and the biophysical alterations of water in the microcapsules during cryopreservation were studied using cryomicroscopy and scanning calorimetry. It was found that water in the small microcapsules can be preferentially vitrified over water in the bulk solution in the presence of 10% (v/v) or more dimethylsulfoxide (DMSO, a cryoprotectant), which resulted in an intact morphology of the microcapsules post cryopreservation with a cooling rate of 100 degrees Celsius/min. A small amount of Ca(2+) (up to 0.15 M) was also found to help maintain the microcapsule integrity during cryopreservation, which is attributed to the enhancement of the alginate matrix strength by Ca(2+) rather than promoting vitrification of water in the microcapsules. The preferential vitrification of water in small microcapsules was further found to significantly augment cell cryopreservation by vitrification at a low concentration of cryoprotectants (i.e., 10% (v/v)) using a small quartz microcapillary (400 microm in diameter). Therefore, the small alginate microcapsule could be a great system for protecting living cells that are highly sensitive to stresses due to freezing (i.e., ice formation) and high concentration of cryoprotectants from injury during cryopreservation. PMID- 19787455 TI - Functional endothelialized microvascular networks with circular cross-sections in a tissue culture substrate. AB - Functional endothelialized networks constitute a critical building block for vascularized replacement tissues, organ assist devices, and laboratory tools for in vitro discovery and evaluation of new therapeutic compounds. Progress towards realization of these functional artificial vasculatures has been gated by limitations associated with the mechanical and surface chemical properties of commonly used microfluidic substrate materials and by the geometry of the microchannels produced using conventional fabrication techniques. Here we report on a method for constructing microvascular networks from polystyrene substrates commonly used for tissue culture, built with circular cross-sections and smooth transitions at bifurcations. Silicon master molds are constructed using an electroplating process that results in semi-circular channel cross-sections with smoothly varying radii. These master molds are used to emboss polystyrene sheets which are then joined to form closed bifurcated channel networks with circular cross-sections. The mechanical and surface chemical properties of these polystyrene microvascular network structures enable culture of endothelial cells along the inner lumen. Endothelial cell viability was assessed, documenting nearly confluent monolayers within 3D microfabricated channel networks with rounded cross-sections. PMID- 19787456 TI - Experimental and numerical characterization of magnetophoretic separation for MEMS-based biosensor applications. AB - Magnetophoretic isolation of biochemical and organic entities in a microfluidic environment is a popular tool for a wide range of bioMEMS applications, including biosensors. An experimental and numerical analysis of magnetophoretic capture of magnetic microspheres in a microfluidic channel under the influence of an external field is investigated. For a given microfluidic geometry, the operating conditions for marginal capture is found to be interrelated in such a manner that a unique critical capture parameter [Pi(crit) = ((Iota(crit)a))(2)/Q(eta)], that is proportional to the ratio of the magnetic force to viscous force, can be identified. Influences of the flow rate, magnetic field and other parameters on the particle trajectories in the microfluidic channel are investigated both numerically and through bright-field imaging under a microscope. Like the event of critical capture, particle trajectories are also found to be guided by a similar parameter, pi. Magnetophoretic capture efficiency of the device is also evaluated as a function of a nondimensional number [Pi(*) = chiP(2)a(2) / (U(null)etah(5)], when both numerical and experimental results are found to agree reasonably well. Results of this investigation can be applied for the selection of the operating parameters and for prediction of device performance of practical microfluidic separators. PMID- 19787457 TI - The ethics of nonmedical sex selection. AB - The aim of this paper is to demonstrate that there are significant ethical problems with nonmedical sex selection, and that prohibitive legislation is justified. The central argument put forward is that nonmedical sex selection is a sexist practice which promotes socially restrictive conceptions of sex, gender and family. Several steps are taken to justify this position: background information on technology and legislation is provided, the neoliberal position that is supportive of nonmedical sex selection is described, and preliminary reasons for rejecting this approach are given. A detailed description of how a harm/benefit based analysis contributes to the argument against nonmedical sex selection, and how it successfully counters most criticism, is provided. The paper concludes by suggesting that virtue ethics further strengthens the moral argument against nonmedical sex selection. PMID- 19787458 TI - Serve the people: understanding ideology and professional ethics of medicine in China. AB - The article explores the communist ideology that has guided the formation of professional ethics of medicine in China. It first explores the constitutions of the People's Republic of China and the Chinese Communist Party and codes of practice for medicine enforced since 1949, showing that the core of the ideology in relation to health provision and doctor-patient relationship has always been 'serving the people wholeheartedly'. The ideological undertaking, however, has never been successfully exercised. In the pre-reform era, the bureaucratisation of health professionals led to the emergence of 'bureaucratic medicine' featuring negligence of patients' interests. In the reform era, the prevailing commercialisation of health care is in fundamental conflict with the ideological commitment to serving the people. As a result, the socialist professional ethics of medicine has not been satisfactorily practiced in reality. PMID- 19787460 TI - Some currently neglected aspects of cholinergic function. AB - At the request of the organizers of the XIII International Symposium on Cholinergic Mechanisms, I have selected for review three topics not well represented at the meeting: the synthesis, storage, and release of acetylcholine at cholinergic nerve endings; cholinergic-specific antigens; and neuropeptides as cholinergic co-transmitters. The first topic is illustrated by work with two model systems, the electromotor nerve terminals of the electric ray and the myenteric plexus of the guinea-pig ileum, the second by work with Chol-1, a group of cholinergic-specific gangliosides sialylated on their N-acetylgalactosamine residues, and the third by vasoactive intestinal polypeptide which is a co transmitter at 70% of cholinergic nerve endings in brain and is also present in both of the model cholinergic systems. PMID- 19787461 TI - Improvement of cephalosporin C production by recombinant DNA integration in Acremonium chrysogenum. AB - Cephalosporins are widely used as anti-infectious beta-lactam antibiotics in clinic. For the purpose of increasing the yield of cephalosporin C (CPC) fermentation, especially in an industrial strain, A. chrysogenum genes cefEF and cefG, which encode the ultimate and penultimate steps in CPC biosynthesis, cefT, which encodes a CPC efflux pump, and vgb, which encodes a bacterial hemoglobin gene were transformed in various combinations into an industrial strain of A. chrysogenum. Both PCR and Southern blotting indicated that the introduced genes were integrated into the chromosome of A. chrysogenum. Carbon monoxide difference spectrum absorbance assay was performed and the result showed that Vitreoscilla hemoglobin was successfully expressed in A. chrysogenum and had biological activity. HPLC analysis of fermentation broth of recombinant A. chrysogenum showed that most transformants had a higher CPC production level than the parental strain. Multiple transformants containing an additional copy of cefG showed a significant increase in CPC production. However, cefT showed little effect on CPC production in this high producer. The highest improvement of CPC titer was observed in the mutant with an extra copy of cefG + cefEF + vgb whose CPC production was increased by 116.3%. This was the first report that three or more genes were introduced simultaneously into A. chrysogenum. Our results also demonstrated that the combination of these genes had a synergy effect in a CPC high producer. PMID- 19787459 TI - Involvement of ERK1/2 pathway in neuroprotection by salidroside against hydrogen peroxide-induced apoptotic cell death. AB - Salidroside is isolated from Rhodiola rosea L., a traditional Chinese medicinal plant, and has a potent antioxidant property. The aim of this study was to investigate the effects of salidroside on hydrogen peroxide (H(2)O(2))-induced cell apoptosis in nerve growth factor (NGF)-differentiated PC12 cells and the possible involvement of the extracellular signal-related protein kinase 1/2 (ERK1/2) signaling pathway. MTT assay, Hoechst 33342 staining, and TdT-mediated dUTP-biotin nick end labeling assay collectively showed that pretreatment with salidroside alleviated, in a dose-dependent manner, cell viability loss and apoptotic cell death induced by H(2)O(2) stimulation in cultured NGF differentiated PC12 cells. According to Western blot analysis, pretreatment with salidroside transiently caused the activation of ERK1/2 pathway; a selective inhibitor of the mitogen-activated protein kinase kinase (MAPKK, MEK) blocked salidroside-activated ERK pathway and thus attenuated the influences of salidroside on H(2)O(2)-induced increase in the level of cleaved caspase-3, a chief executant of apoptosis cascades. Morphological analysis further indicated that in the presence of the MEK inhibitor, the neuroprotective effect of salidroside against H(2)O(2)-evoked cell apoptosis was significantly abrogated. Taken together, the results suggest that the neuroprotective effects of salidroside might be modulated by ERK signaling pathway, especially at the level or upstream of the caspase-3 activation. PMID- 19787463 TI - [Lung cancer and family history of cancer]. AB - There are many studies supporting the family history in lung cancer. The study included 213 subjects with new and former diagnoses of lung cancer. Patients were enrolled from the Department of Chest Diseases Ankara University Faculty of Medicine and Ataturk Chest Diseases and Chest Surgery Training and Research Hospital between January-June 2005. For the control group, 200 healthy subjects were gathered. We aimed to investigate the family predisposition for lung and other cancers, additionally the relationship of this predisposition to age, gender, smoking habits and cell types. The number of first degree relatives of patients and control group were 2058 and 2045, respectively. In conclusion, positive family history for cancer estimated in 38% of 213 individuals with lung cancer. In these individuals, 41.9% had lung cancer, 19% had gastrointestinal system cancer, 7.6% had breast cancer, 5.7% had prostate cancer, 25.7% had other system cancers (larinx, skin, bone, hematologic system, central nervous system). Besides, 4.6% of 213 patients had accompanying other system cancers (urinary bladder, kidney, lung, head-neck). In control group, positive family history for the cancer was 21.5% and this was statistically significant (p< 0.001). In the family members of patients with lung cancer, the risks of lung, gastrointestinal system and breast cancer development were increased. Besides, the lung and other system cancers (except prostate and gastrointestinal system cancers) were significantly increased at the brothers of patients with lung cancer, supporting the genetical transition hypothesis. The presence of head-neck, bladder, prostate, lung and kidney cancers in the history of the patients increase the risk of lung cancer, supporting the genetic transition. PMID- 19787462 TI - Long-term outcome of mesna, ifosfamide, mitoxantrone, etoposide (MINE) regimen as a consolidation in patients with aggressive non-Hodgkin lymphoma responding to CHOP. AB - In aggressive non-Hodgkin lymphoma (NHL), CHOP (cyclophosphamide, vincristine, doxorubicin, prednisolone) regimen has been standard for decades, and rituximab has increased response rates and survival in CD20 positive patients, recently. The aim of this prospective trial was to evaluate the long-term efficacy and toxicity of MINE as a consolidation treatment in aggressive NHL patients who had achieved CR or unproven CR after six cycles of CHOP in the first line setting. The primary end-point was disease-free-survival (DFS). Thirty-eight patients were enrolled between February 1992 and May 2000. All of the patients received two cycles of MINE (mesna 1.3 g/m(2), ifosfamide 1.3 g/m(2), etoposide 65 mg/m(2) on days 1-3, and mitoxantrone 12 mg/m(2) on day 1, every 3 weeks) following response to CHOP. Initial bulky disease sites were also applied radiotherapy. Male/female ratio was 1.53(23/15). Median age was 49(30-73). Most of the patients had advanced stage (84.2% for stage >3) and high IPI score (79% for IPI score >2). Sixty percent had diffuse large cell histology. Median follow-up time was 118 months (9-195). Actual mean dose intensity was 88%. There were seven febrile neutropenia episodes. Two patients had grade two neuropathy, one had grade three mucositis and another one had non-neutropenic pneumonia. There was no early toxic death. No serious late toxicity was observed during long-term follow-up. Five- and 10-year DFS rates were both 65.3%. DFS rate in the patients with more than two poor prognostic factors according to IPI score is remarkably high (88%). Five and 10-year OS was 62.5 and 59%, respectively. MINE regimen seems to be effective as a consolidation regimen, especially, in intermediate/high risk patients and has low early and late toxicities, and it warrants to be evaluated in phase III randomised trials with rituximab in CD20 positive aggressive NHL patients. PMID- 19787464 TI - [The clinical and microbiological comparison of the use of heated humidifiers and heat and moisture exchanger filters with Booster in mechanically ventilated patients]. AB - Ventilator associated pneumonia (VAP) is the most frequent nosocomial infection in intensive care units that is associated with prolonged mechanical ventilation, hospitalization and increased health-care costs. Various humidifiers can be used for humidification during mechanical ventilation. Many studies were conducted to identify the effects of two different humidifiers, i.e. heated humidifiers and heat and moisture exchanger filters (HME), on VAP development; and HME filters were found to decrease the VAP frequency. In this study we aimed to compare the efficacy and safety of heated humidifiers and HME-Booster. Heated humidifier with conventional microbiologic filter (CMF-HH) or HME-Booster were used in randomization to 41 mechanically ventilated patients of our intensive care unit, and patients were divided into two groups as group 1 receiving CMF-HH (20 patients) and group 2 (21 patients) receiving HME-Booster. Daily secretion scores, endotracheal tube occlusion due to secretions, VAP development rate for the assessment of microbiological safety of humidifiers and differences in PETCO(2) and PaCO(2) values for the assessment of their effect on arterial blood gas were recorded prospectively. The measurement of PETCO(2) and PaCO(2) values were performed with the presence of humidifiers and after removing them in both groups. In both groups with the removal of CMF-HH and HME-Booster, a decrease in PETCO(2) value was identified, but the decrease in group 2 was statistically significant (p= 0.016). The decrease in PaCO(2) after removal of humidifiers was greater in group 2 than in group 1, but the difference was not significant (p> 0.05).The rate of VAP and endotracheal tube occlusion was not significantly different between the groups. The mean secretion score was lower in group 1 (p= 0.041). In conclusion, although both humidifiers have similar microbiological effects, heated humidifiers could be preferred particularly for the patients with an underlying chronic lung disease due to its positive effects on PETCO(2) values and secretion scores. PMID- 19787465 TI - [Tuberculin skin test reactivity in patients with chronic renal failure]. AB - The aim of this study was to evaluate the response of tuberculin skin test (TST) and the parameters that affect the response in patients with chronic renal failure (CRF) on different treatment regimens. The study population consisted of 150 patients (78 females, mean age 48.1 + or - 16.7 years, the mean disease duration 6.6 + or - 6.1 years). Of these patients, 50 were on haemodialysis (HD), 50 were renal transplant patients, 26 were on peritoneal dialysis (PD) and 24 were treated medically. TST was performed to all patients, an induration with a diameter of 10 mm or more was accepted as positive response in HD, PD, medical treatment groups, whereas 5 mm or more was considered as positive in transplant group. TST was positive in 52% of the study population (56% in HD group, 54% in PD group, 44% in transplant group, 58% in medical treatment group, p> 0.05). There was a positive correlation between TST and age in patients older than 60 of transplant and medical treatment groups (p= 0.008). In HD patients with negative TST, the number of female patients was higher (p= 0.02). In transplant patients with positive TST, duration of HD was shorter (p= 0.01), the blood urea level was lower (p= 0.04), hemoglobin level was higher (p= 0.04). The ratio of negative TST was higher (p< 0.05), TST reactivity was smaller (p= 0.01) in only transplant patients with no BCG scar. The number of BCG scar was correlated positively with TST (p= 0.04). In the medical treatment group, patients with positive TST response were older (p= 0.02) and in PD group the tuberculin reactivity was not affected by any of the patient-related parameters. It must be considered that the response to TST is low in young patients with uncontrolled CRF and under immunosuppressive therapy. PMID- 19787466 TI - Can hospitalization provide better compliance in smear positive tuberculosis patients? AB - The aim of the study was to explore the relation between hospitalization and the success of therapy in lung tuberculosis. Three hundred and fifty one hospitalized human immunodeficiency virus (HIV) negative, smear positive cases of pulmonary tuberculosis were studied. All cases were World Health Organization (WHO) category 1 patients. The patients with chronic additional disease and those who developed complication during therapy were excluded. Three hundred and six outpatients attending to local dispensaries were also included as control group. The groups were compared with respect to completion rates at 6 months of therapy. The average age was 37.48 + or - 13.87 years; 204 patients were women (31.1%). For inpatients, mean hospital stay was 25.4 + or - 14.2 days. A total of 304 (86.6%) hospitalized patients completed their treatment; the remaining 47 (13.4%) cases were not followed-up. No significant relation was observed between the length of hospital stay and completion of therapy (p> 0.05); 295 (96.4%) outpatients successfully completed their treatment. The probability of not completing the therapy was significantly higher for hospitalized patients (RR: 3.72 95% CI: 1.96-7.05 p< 0.05). Our results show that in category 1 patients without concomitant disorders, initiation of treatment at hospital has an adverse influence on the outcome of treatment, as reflected by the percentage of completers. PMID- 19787467 TI - Pneumoconiosis and work-related health complaints in Turkish dental laboratory workers. AB - Dental technicians make the missing tooth and complementary prosthesis and bridges according to the dentist's measurements. They use various materials including silica. Exposure to these materials increases the multi-systemic health problems in addition to respiratory health problems related with work. We planned to evaluate the work history, working conditions and frequency of health problems including pneumoconiosis. Two hundred and fourteen cases in total from 9 workplaces were evaluated. A face to face questionnaire was used to determine the demographic features of workers and standard chest X-rays were evaluated by an expert reader according to ILO 1980 standards. Mean age of the workers was 28.1 + or - 8.3. Seventy four cases were non-smoker. Mean daily working time was 11.0 + or - 1.6 hours. Mean total working period in this sector was 12.1 + or - 9.0 years. One hundred cases had at least 1 respiratory complaint. Radiological findings were correlated with pneumoconiosis in 33 (23.6%) workers. Pneumoconiosis frequency was 50.0% in cases with sandblasting history. There was not any significant correlation between pneumoconiosis and cough, sputum, dyspnea, wheezing, physical examination findings and tenure. Dental technicians have serious respiratory risks including dermal and muscle-skeleton system arising from occupational setting in Turkey. Working conditions in dental laboratories must be improved by informing the workers and workplaces must be regularly controlled for worker health and hygiene. PMID- 19787468 TI - [How exactly can we predict the prognosis of COPD]. AB - Predictive models play a pivotal role in the provision of accurate and useful probabilistic assessments of clinical outcomes in chronic diseases. This study was aimed to develop a dedicated prognostic index for quantifying progression risk in chronic obstructive pulmonary disease (COPD). Data were collected prospectively from 75 COPD patients during a three years period. A predictive model of progression risk of COPD was developed using Bayesian logistic regression analysis by Markov chain Monte Carlo method. One-year cycles were used for the disease progression in this model. Primary end points for progression were impairment in basal dyspne index (BDI) score, FEV(1) decline, and exacerbation frequency in last three years. Time-varying covariates age, smoking, body mass index (BMI), severity of disease according to GOLD, PaO2, PaCO(2), IC, RV/TLC, DLCO were used under the study. The mean age was 57.1 + or - 8.1. BDI were strongly correlated with exacerbation frequency (p= 0.001) but not with FEV(1) decline. BMI was found to be a predictor factor for impairment in BDI (p= 0.03). The following independent risk factors were significant to predict exacerbation frequency: GOLD staging (OR for GOLD I vs. II and III = 2.3 and 4.0), hypoxemia (OR for mild vs moderate and severe = 2.1 and 5.1) and hyperinflation (OR= 1.6). PaO2 (p= 0.026), IC (p= 0.02) and RV/TLC (p= 0.03) were found to be predictive factors for FEV(1) decline. The model estimated BDI, lung function and exacerbation frequency at the last time point by testing initial data of three years with 95% reliability (p< 0.001). Accordingly, this model was evaluated as confident of 95% for assessing the future status of COPD patients. Using Bayesian predictive models, it was possible to develop a risk stratification index that accurately predicted progression of COPD. This model can provide decision-making about future in COPD patients with high reliability looking clinical data of beginning. PMID- 19787469 TI - The effects of cachexia and related components on pulmonary functions in patients with COPD. AB - Malnutrition is an important problem in patients with chronic obstructive pulmonary disease (COPD). It still remains unclear whether malnutrition contributes to poor pulmonary function through a loss of respiratory muscle mass, or if advanced disease and hypoxemia are the causes of weight loss and malnutrition in COPD patients. This study was made to examine the effects of malnutrition on pulmonary function tests (PFTs) in COPD patients. With this purpose 35 stable COPD patients were enrolled in this study. According to their body mass indexes, the subjects were divided in two groups (group 1: cachectic and group 2: non-cachectic). All subjects were performed PFTs, serum tumor necrosis factor-alpha (TNF-alpha) levels, resting energy expenditure (REE), nutrition parameters, and arterial blood gas tension. PFTs were impaired to a greater degree in cachectic than non-cachectic patients. Serum TNF-alpha levels and REE were higher in cachectic patients than in non-cachectic patients. Significant correlations were observed among PFTs, REE, and serum TNF-alpha level. Furthermore there was a significant correlation between serum albumin level and PFTs. This study demonstrated that cachexia had a negative effect on PFTs in patients with COPD. Additionally, our study showed that serum protein levels can affect airway function and diffusing capacity of lungs in COPD. Another result of this study was that; increased REE and serum TNF-alpha levels could contribute to weight loss in patients with COPD. Further studies are needed to demonstrate the effect of nutritional supplementation containing essential amino acids on PFTs in these patients. PMID- 19787470 TI - [The concordance of manuel (visual) scoring and automatic analysis in sleep staging]. AB - Full night polysomnography (PSG) remains the gold standard diagnostic test for the evaluation of sleep and the detection of sleep disorders. The computer assisted scoring methods have been developed to accelerate the scoring. It is said that there was a concordance up to 80% between these scoring softwares and manual scoring. According to our experiences, it is not matched with this belief. In this study, we intend to examine whether the results of automatic analysis match with manual (visual) evaluation. The PSG records of 30 cases with a diagnosis of obstructive sleep apnea syndrome (OSAS) are chosen randomly. We compare the results of automatic analysis with the results of two scorers who have a concordance of 80-95% and at least 1000 PSG scoring experiences. We evaluated 21.060 epochs of 18 men with 48.83 + or - 13.51 ages, and 12 women with 44.56 + or - 14.28 ages. In automatic analysis; total sleep time (p= 0.003) and sleep efficiency (p= 0.004) were low. AHI (p= 0.802) and ODI (p= 0.193) values were high. The epochs scored differently were 8819 epochs (41.88%). The stage I (88.43%) scored mostly different, was allocated to be awake (572 epochs). Stage II and stage IV were scored as stage III in 2276 and 983 epochs respectively. REM epochs were allocated to stage II (574 epochs). The differences in recording times and sleep architecture of PSG tests which examed by automatic analysis will affect all other parameters. Thus, we believe that it will make mistakes in the diagnosis and treatment of sleep disorders. PMID- 19787471 TI - [The evaluation of 92 interstitial lung disease patients]. AB - Interstitial lung diseases (ILD) include many acute and chronic pulmonary disorders. We aimed to evaluate the patients diagnosed as ILD in our clinic. Between January 2000 and August 2004, 92 patients were included in the study. Fifty eight (63%) of our patients were female, 34 (37%) were male and the median age was 50.2 + or - 14.2 (19-80) years. The most frequent diagnoses were sarcoidosis in females, and IPF in males. The diagnostic methods used were as follows; clinically and radiologically in 36 (39.1%) patients, bronchoscopy in 33 (34.8%) patients, mediastinoscopy in 10 (10.9%) patients, open lung biopsy in 8 (8.7%) patients, skin biopsy in 2 (2.2%), oral mucosal biopsy in 1 (1.1%), lymph node biopsy in 1 (1.1%), renal biopsy in 1 (1.1%) and pleural fluid examination in 1 (1.1%). Bronchoscopic biopsies were diagnostic in 60.9% of sarcoid patients. Twelve (48%) IPF patients had an occupational toxic exposure history. Medical treatment were given to 80 patients. There were good clinical and radiological response in patients with sarcoidosis (96.9%) and cryptogenic organizing pneumonia (COP) (85.7%), however disease was stable in CTD patients and only three of idiopathic pulmonary fibrosis (IPF) patients (15.7%) responded to treatment. In IPF patients, diagnosis was established medially 35.7 months later after the first symptom appeared. Two of the IPF patients had also lung cancer. Treatment related complications occurred in six patients. Fourteen patients died during the follow-up period and eight were IPF. ILD is frequently encountered in general practice of pulmonary physicians and should be considered in differential diagnosis during routine pulmonology clinic. Sarcoidosis and IPF were the most commonly seen diseases. Although ILD is a difficult challenge to diagnose in clinical practice, it may be diagnosed by means of clinical features, radiologic techniques and several biopsy procedures. PMID- 19787472 TI - [Effects of new warning labels on cigarette packets among high school adolescents]. AB - In developing countries, smoking habit develops between the ages of 12-16. In recent years, various ways to struggle against smoking have been implemented and one of them is to print warnings on cigarette packets. The purpose of this study was to determine the effects of these warnings among high school adolescents and their efficiency to make them quit smoking. The total number of the subjects were 917, 103 of whom were female and 814 of whom were male students. The mean age of the subjects was 16.6 + or - 1.1. The rate of the smokers was 24.1%. The rate of the subjects who had tried smoking at least once was 50.6%. When if or not the students were educated about the harmful effects of smoking by any means was evaluated, the rate of educated subjects was 58.3% and 41.7% of the subjects were not educated by any means. All the warnings on cigarette packets were considered to be "important" and "very important" by the subjects. The rate of the subjects who think that the warning phrases will have positive effects on the way to quit was 38.9%, while the rate of the subjects who think that they will have no positive effect was 61.1%. The rate of the subjects who had quitted smoking after reading these warnings was 22.5%, 44.4% of the subjects stated that they were effected but did not quit, and 33.1% of the subjects stated that they were not effected at all by the warnings and continued to smoke. The warnings on cigarette packets were found to serve as an additional information source about the harmful effects of smoking and had beneficial effects on the subjects' decision to quit. It was concluded that the method is an important step in the struggle against smoking. PMID- 19787473 TI - Endobronchial metastasis from oral fibrosarcoma 13 years after treatment of primary tumor. AB - Endobronchial metastasis (EBM) is uncommon and frequently is seen in renal, breast, and colorectal carcinomas. Other reported primary tumors include melanoma, sarcomas, and tumors of the uterine cervix, testis, ovary, prostate, thyroid, pancreas, and adrenal glands. With reviewing the literature, we were able to find only one report of EBM from fibrosarcoma (in Spanish). We described a 56-year-old woman with EBM of oral fibrosarcoma with local recurrence 13 years after treatment of primary tumor. We conclude that the possibility of central airway metastasis should be kept in mind if patients with a past history of malignancy present with symptoms consistent with bronchial tumors, even if there are 13 years interval. Of several mechanisms EBM, we assume direct aspiration and implantation of tumor cells to bronchus from oral cancer. PMID- 19787474 TI - Spindle cell sarcomatoid carcinoma: first case reported in the trachea. AB - A 78-years-old man presented with weight loss, dyspnea, cough and hemoptysis. He was an ex-smoker with a smoking history of 30 pack-years. Imaging studies revealed an endoluminal carinal mass and a tumoral mass arising from the posterior wall of the trachea was observed bronchoscopically. Endoscopic argon plasma coagulation was performed to take biopsies and to regain the airway passage. Recanalisation of the right and left main bronchi and the trachea was achieved together with resection of more than 90% of the tumoural mass. Microscopically, the tumor was composed of fascicular pattern of spindle cells with atypical mitotic figures and nuclear pleomorphism, positively reactive to epithelial membrane antigen supporting a diagnosis of tumour with epithelial differentiation. These findings supported the diagnosis of a spindle cell sarcomatoid carcinoma of trachea. Spindle cell carcinoma cases are reported in many sites, such as head and neck region, larynx, digestive tract, breast, kidney, genital tract, skin and lung, but to our knowledge, not in trachea. Primary malignant tracheal tumours consist mainly of squamous cell carcinoma and adenoid cystic carcinoma and generally have an aggressive course with poor prognosis. We report the first presentation of a spindle cell sarcomatoid carcinoma of trachea together with the clinical course of the patient. PMID- 19787475 TI - [Operative stabilization of traumatic flail chest using a reconstruction plaque]. AB - Flail chest is the most serious form of blunt thoracic trauma that occurs as a result of fracture of three or more ribs from at least two places or sternal fractures and/or separation of costochondral junctions. Existence of life threatening physiopathological changes almost always affects the clinical status of the patients. Typically the fractured segment moves in the interior and exterior directions during inspirations and expirations, respectively and this paradoxical motion is called as flail chest. Non-operative treatment approaches are usually preferred for the flail chest cases. However, surgery constitutes the unavoidable treatment procedure in the existence of severe chest wall deformities, unstable ventilation dynamics, lung and diaphragmatic injuries and prolonged mechanical ventilation. Here we present a case of traumatic flail chest in a patient with traumatic severe chest wall deformity treated by chest wall reconstruction with AO-ASIF [Arbeitsgemeindschaft fur Osteosynthesefragen (Association for the Study of Internal Fixation)] osteosynthesis plaque. PMID- 19787476 TI - Non-invasive positive pressure ventilation for a severe legionella pneumonia case. AB - Legionella pneumonia has a serious clinical course and requires treatment at intensive care unit. The need for mechanical ventilation is one of the determinants of prognosis. Mortality rate is higher in patients treated with mechanical ventilation. Non-invasive positive pressure ventilation (NPPV) provides mechanical ventilation without endotracheal intubation and decreases the incidence of ventilator associated pneumonia. It is a treatment modality for patients with hypoxia due to community acquired pneumonia. The present case was admitted to intensive care unit with a diagnosis of legionella pneumonia, and his hypoxemic respiratory failure was successfully treated with NPPV. PMID- 19787477 TI - An unusual case of Wegener's granulomatosis with tongue involvement. AB - Wegener's granulomatosis is a type of vasculitis characterized by necrotizing granulomatosis respiratory tract lesions and necrotising glomerulonephritis. Nasal, lung and renal biopsies and positive antineutrophil cytoplasmic antibody (c-ANCA) analysis is helpful in diagnosis. Early diagnosis and treatment is critical in prognosis. A 42 years-old male had dyspnea, coughing, hemoptysis, fatigue, loss of appetite, night sweating and arthralgia. Violaceous palpable, purpuric lesions were detected on the sublingual region of the mouth. On chest X ray, there was nonhomogeneous infiltration in the parenchyma of both lungs. There was alveolar density involving upper lobes of both lungs detected in thoracal computerized tomography as well as patchy densities on the right lung upper middle lobes. A nasal mucosa biopsy showed strongly destructive vasculitis. c ANCA test was positive. We report an unusual case with Wegener's granulomatosis, characterized by a rare presentation of tongue involvement and atypical lung radiology with alveolar opacity. PMID- 19787478 TI - [Hyaluronan and the importance of hyaluronan in diagnosis and treatment]. AB - Hyaluronan is a glycosylaminoglycan and is the main component of the extracellular matrix. It was first described in 1934 and has many structural and physiological functions in the human body. An upcoming area of study relates to the hyaluronan receptors, since these affect the metabolism and function of hyaluronan. This knowledge will be useful in evaluating the role of hyaluronan in diseases, as a therapeutic agent for inflammation disorders and as a diagnostic biomarker. In this review, we discussed the structure of hyaluronan and its role in diseases. PMID- 19787487 TI - Psychophysiological effects of emotional dissonance in a face-to-face service interaction. AB - Current research demonstrates that requirements to express emotions which are not genuinely felt in the particular situation (emotional dissonance) are associated with negative long and short-term effects. The aim of the present study was to investigate: (a) the psychophysiological short-term effects of emotional dissonance in a face-to-face service interaction and (b) the moderating role of gender and neuroticism. In total, 32 women and 27 men were instructed to play the role of a service employee, who had to interact with an angry and rude customer. Half of the sample was given information that the organization expected them to be friendly (emotional dissonance), the other half was told they were expected to act naturally and show their genuine feelings (no emotional dissonance). Subjective and behavioral responses revealed that participants in the "friendly" condition modulated their emotional expressions to a greater extent than those in the "naturally" condition. Participants in the "friendly" condition showed stronger systolic and diastolic blood pressure responses. Furthermore, hierarchical regression analyses yielded that gender and neuroticism partly moderated the association between emotional dissonance and participants' psychophysiological response. PMID- 19787490 TI - Are we ignoring the clouds on the horizon while looking for sharks? Commentary on "longitudinal study of maternal report of sleep problems in children with prenatal exposure to cocaine and other drugs". PMID- 19787489 TI - Longitudinal study of maternal report of sleep problems in children with prenatal exposure to cocaine and other drugs. AB - Sleep data were collected by maternal report in a prospective longitudinal follow up of cocaine-exposed and unexposed children. There were 139 participants: 23 with no prenatal drug exposure, 55 exposed to cocaine alone or in combination with other drugs, and 61 exposed to drugs other than cocaine. Characteristics differed between exposure groups including birth size, caretaker changes, maternal socioeconomic status, and postnatal drug use. Compared to those with no drug exposure, children with prenatal drug exposure other than cocaine experienced greater sleep problems (p = .026). Prenatal nicotine exposure was a unique predictor of sleep problems (p = .048). Early sleep problems predicted later sleep problems (all ps < .01). Together, these preliminary findings suggest possible neurotoxic sleep effects that persist over time. Larger studies, however, need to be conducted that better control for potential postnatal confounding factors. PMID- 19787491 TI - Insomnia symptoms and use of health care services and medications: the HUNT-2 study. AB - This study investigated how symptoms of insomnia are related to use of health care services and medications. Data on insomnia symptoms, use of a range of health care services, and potential confounders were gathered from 47,700 individuals aged 20 to 89. The prevalence of insomnia symptoms was higher among health care users across a range of health professionals. The frequency of medication use, alcohol overuse, and hospitalization was also higher among individuals with insomnia symptoms. Overall, much of these associations were explained by medical or mental conditions, but the effects largely remained significant in the fully adjusted analyses. This study concludes that insomnia symptoms represent a significant public health concern, being independently associated with substantially elevated use of health care services, medications, and alcohol overuse. PMID- 19787493 TI - Sleep patterns in patients with Huntington's disease and their unaffected first degree relatives: a brief report. AB - Polysomnographic sleep patterns in Huntington's disease (HD) have been studied sporadically in small groups of patients, providing variable results. In this study, by comparing the polysomnographic sleep patterns of HD patients and their unaffected relatives, identifying sleep traits more specifically related to the HD gene was attempted. The results corroborated previously reported findings of prolonged sleep latency and the virtual absence of nocturnal respiratory disturbances in early HD. Sleep latency in the HD patients positively correlated with the results of a screening test for frontal lobe dysfunction. Larger, more standardized studies will be needed to correlate genetic markers and sleep patterns in HD. PMID- 19787492 TI - Sleep as a mediator in the pathway from violence-induced traumatic stress to poorer health and functioning: a review of the literature and proposed conceptual model. AB - Millions of children are exposed to various forms of violence every year, resulting-for many of them-in psychological problems, decreased social functioning, and poorer overall quality of their relationships and lives. This article reviews the scientific literature investigating the role of sleep as a key mediator in the pathway between violence-induced traumatic stress and resulting negative health and behavioral outcomes. Based on evidence revealed by this review and general research on how exposure to violence influences child health and development, a conceptual model is proposed that posits sleep's role as an important mediator of health effects and that incorporates other factors believed to shape linkages between exposure to violence and health and behavioral outcomes in children. Recommendations are given for future research to test the proposed model. PMID- 19787495 TI - Go/NoGo performance in boys with Tourette syndrome. AB - This study compared performance and performance monitoring in 19 boys with Tourette syndrome (TS) (12.64 years, +/- 2.05) and 19 age-matched controls (13.16 years, +/- 2.29) using a Go/NoGo task. The results indicated similar performance accuracy in the TS group and the control group. TS participants showed slower correct responses than the control group, whereas error response times were not different between the groups. The results are discussed with reference to inhibitory adaptive effects that may be employed by TS participants to maintain high accuracy at the cost of overall slower performance. These effects may be suspended prior to errors. PMID- 19787496 TI - Neuropsychological functioning in children with posttraumatic stress disorder. AB - Posttraumatic stress disorder (PTSD) has been associated with deficits in the areas of verbal memory and learning, executive functioning, working memory, and attention in adults. Findings have been less consistent in the few studies examining neuropsychological functioning in childhood PTSD, which are often limited by comparing children with PTSD to children without trauma histories, making it unclear whether observed neuropsychological deficits are related to trauma exposure or to PTSD symptomatology. In an ethnically diverse sample of 62 children who witnessed intimate partner violence (n = 27 PTSD+ and 35 PTSD-), children with PTSD exhibited slower and less effective learning, heightened sensitivity to interference, and impaired effect of rehearsal on memory acquisition on the California Verbal Learning Test - Children's Version, a word list learning task. Both groups performed in the below average range on measures of executive functioning, attention, and intellectual ability. PMID- 19787497 TI - Design considerations for ceramic resurfaced femoral head: effect of interface characteristics on failure mechanisms. AB - Ceramic hip resurfacing may offer improved wear resistance compared to metallic components. The study is aimed at investigating the effects of stiffer ceramic components on the stress/strain-related failure mechanisms in the resurfaced femur, using three-dimensional finite element models of intact and resurfaced femurs with varying stem-bone interface conditions. Tensile stresses in the cement varied between 1 and 5 MPa. Postoperatively, 20-85% strain shielding was observed inside the resurfaced head. The variability in stem-bone interface condition strongly influenced the stresses and strains generated within the resurfaced femoral head. For full stem-bone contact, high tensile (151-158 MPa) stresses were generated at the cup-stem junction, indicating risk of fracture. Moreover, there was risk of femoral neck fracture due to elevated bone strains (0.60-0.80% strain) in the proximal femoral neck region. Stresses in the ceramic component are reduced if a frictionless gap condition exists at the stem-bone interface. High stresses, coupled with increased strain shielding in the ceramic resurfaced femur, appear to be major concerns regarding its use as an alternative material. PMID- 19787498 TI - Inverse engineering of medical devices made of bioresorbable polymers. AB - The degradation of medical devices made of bioresorbable polymers such as fixation devices in orthopaedic surgeries and scaffolds for tissue engineering can take from months to years. The trial and error approach of device development is therefore problematic and mathematical modelling of the biodegradation can help to accelerate the device development. This paper presents an inverse scheme to obtain the material parameters in a biodegradation model developed by Pan and his co-workers from existing experimental data of bioresorbable devices. The parameters can then be used to predict the degradation rate of new devices made of the same polymer. Firstly, the previously developed model is briefly outlined. Secondly, a finite element scheme and a time integration algorithm are developed for the direct analysis using the biodegradation model. Thirdly, an inverse analysis scheme is presented in combination with the direct analysis. Finally, several case studies of existing degradation data are presented to demonstrate the effectiveness of the inverse engineering approach. PMID- 19787499 TI - A critical review of the systems approach within patient safety research. AB - The application of concepts, theories and methods from systems ergonomics within patient safety has proved to be an expanding area of research and application in the last decade. This paper aims to take a step back and examine what types of research have been conducted so far and use the results to suggest new ways forward. An analysis of a selection of the patient safety literature suggests that research has so far focused on human error, frameworks for safety and risk and incident reporting. The majority of studies have addressed system concerns at an individual level of analysis with only a few analysing systems across multiple system boundaries. Based on the findings, it is argued that future research needs to move away from a concentration on errors and towards an examination of the connections between systems levels. Examples of how this could be achieved are described in the paper. The outcomes from the review of the systems approach within patient safety provide practitioners and researchers within health care (e.g. the UK National Health Service) with a picture of what types of research are currently being investigated, gaps in understanding and possible future ways forward. PMID- 19787500 TI - A systems ergonomics analysis of the Maidstone and Tunbridge Wells infection outbreaks. AB - This paper describes a systems ergonomics analysis of the recent outbreaks of Clostridium difficile, which occurred over the period 2005-07 within the UK Maidstone and Tunbridge Wells NHS Trust. The analysis used documents related to the outbreak, alongside the construction of a system model in order to probe deeper into the nature of contributory factors within the Trust. The findings from the analysis demonstrate the value of looking further at cross-level and whole-system aspects of infection outbreaks. In particular, there is a need for further study of the causal relationships that exist between hospital management and clinical management levels within the system. Finally, the paper discusses ways forward and strategies that could be adopted in order to limit the outbreak of hospital-related infections and shape future research. The approach used for the system analysis described in the paper could be used by healthcare practitioners and ergonomists to probe deeper into the causes of infection outbreaks and to extend the scope of interventions aimed at preventing their occurrence. PMID- 19787501 TI - Increased physical work loads in modern work--a necessity for better health and performance? AB - Shifting workforce proportions to sedentary occupations and technology developments in traditionally physically demanding occupations have resulted in low physical workloads for many workers. Insufficient physical stress is known to have detrimental short- and long-term effects on health and physical capacity. It is argued herein that many modern workers are at risk of insufficient physical workload. Further, it is argued that the traditional physical ergonomics paradigm of reducing risk by reducing physical loads ('less is better') is not appropriate for many modern occupations. It is proposed that a new paradigm is required, where 'more can be better'. The potential for work to be seen as an arena for improving physical health and capability is discussed and the types of changes to work that may be required are outlined. The paper also discusses challenges and responsibilities presented by this new paradigm for ergonomists, employers, health and safety authorities and the community. The majority of workers in affluent communities now face the significant threat to health of insufficient physical workload. Ergonomics can design work to a prescription that can not only reduce injury risk but enhance health and capacity. However, this will require a change in paradigm. PMID- 19787503 TI - Neck pain combined with arm pain among professional drivers of forest machines and the association with whole-body vibration exposure. AB - The purpose of this study was to investigate the existence of neck pain and arm pain among professional forest machine drivers and to find out if pain were related to their whole-body vibration (WBV) exposure. A self-administered questionnaire was sent to 529 forest machine drivers in northern Sweden and the response was 63%. Two pain groups were formed; 1) neck pain; 2) neck pain combined with arm pain. From WBV exposure data (recent measurements made according to ISO 2631-1, available information from reports) and from the self administered questionnaire, 14 various WBV exposure/dose measures were calculated for each driver. The prevalence of neck pain reported both for the previous 12 months and for the previous 7 d was 34% and more than half of them reported neck pain combined with pain in one or both arms. Analysis showed no significant association between neck pain and high WBV exposure; however, cases with neck pain more often experienced shocks and jolts in the vehicle as uncomfortable. There was no significant association between the 14 WBV measures and type of neck pain (neck pain vs. neck pain combined with arm pain). It seems as if characteristics of WBV exposure can explain neither existence nor the type of neck pain amongst professional drivers of forest machines. The logging industry is important for several industrialised countries. Drivers of forest machines frequently report neuromusculoskeletal pain from the neck. The type of neck pain is important for the decision of treatment modality and may be associated with exposure characteristics at work. PMID- 19787502 TI - Risk of musculoskeletal disorders among females and males in repetitive/constrained work. AB - This paper combines epidemiological data on musculoskeletal morbidity in 40 female and 15 male occupational groups (questionnaire data 3720 females, 1241 males, physical examination data 1762 females, 915 males) in order to calculate risk for neck and upper limb disorders in repetitive/constrained vs. varied/mobile work and further to compare prevalence among office, industrial and non-office/non-industrial settings, as well as among jobs within these. Further, the paper aims to compare the risk of musculoskeletal disorders from repetitive/constrained work between females and males. Prevalence ratios (PR) for repetitive/constrained vs. varied/mobile work were in neck/shoulders: 12-month complaints females 1.2, males 1.1, diagnoses at the physical examination 2.3 and 2.3. In elbows/hands PRs for complaints were 1.7 and 1.6, for diagnoses 3.0 and 3.4. Tension neck syndrome, cervicalgia, shoulder tendonitis, acromioclavicular syndrome, medial epicondylitis and carpal tunnel syndrome showed PRs > 2. In neck/shoulders PRs were similar across office, industrial and non-office/non industrial settings, in elbows/hands, especially among males, somewhat higher in industrial work. There was a heterogeneity within the different settings (estimated by bootstrapping), indicating higher PRs for some groups. As in most studies, musculoskeletal disorders were more prevalent among females than among males. Interestingly, though, the PRs for repetitive/constrained work vs. varied/mobile were for most measures approximately the same for both genders. In conclusion, repetitive/constrained work showed elevated risks when compared to varied/mobile work in all settings. Females and males showed similar risk elevations. This article enables comparison of risk of musculoskeletal disorders among many different occupations in industrial, office and other settings, when using standardised case definitions. It confirms that repetitive/constrained work is harmful not only in industrial but also in office and non-office/non industrial settings. The reported data can be used for comparison with future studies. PMID- 19787504 TI - Task exposures in an office environment: a comparison of methods. AB - Task-related factors such as frequency and duration are associated with musculoskeletal disorders in office settings. The primary objective was to compare various task recording methods as measures of exposure in an office workplace. A total of 41 workers from different jobs were recruited from a large urban newspaper (71% female, mean age 41 years SD 9.6). Questionnaire, task diaries, direct observation and video methods were used to record tasks. A common set of task codes was used across methods. Different estimates of task duration, number of tasks and task transitions arose from the different methods. Self report methods did not consistently result in longer task duration estimates. Methodological issues could explain some of the differences in estimates seen between methods observed. It was concluded that different task recording methods result in different estimates of exposure likely due to different exposure constructs. This work addresses issues of exposure measurement in office environments. It is of relevance to ergonomists/researchers interested in how to best assess the risk of injury among office workers. The paper discusses the trade-offs between precision, accuracy and burden in the collection of computer task-based exposure measures and different underlying constructs captures in each method. PMID- 19787505 TI - Inertia artefacts and their effect on the parameterisation of keyboard reaction forces. AB - Reaction force measurements collected during typing on keyboard trays contain inertia artefacts due to dynamic movements of the supporting work surface. To evaluate the effect of these artefacts, vertical forces and accelerations were measured while nine volunteers touch-typed on a rigid desk and a compliant keyboard tray. Two signal processing methods were evaluated: 1) low pass filtering with 20 Hz cut-off; 2) inertial force cancellation by subtracting the accelerometer signal. High frequency artefacts in the force signal, present on both surfaces, were eliminated by low pass filtering. Low frequency artefacts, present only when subjects typed on the keyboard tray, were attenuated by subtracting the accelerometer signal. Attenuation of these artefacts altered the descriptive statistics of the force signal by as much as 7%. For field measurements of typing force, reduction of low frequency artefacts should be considered for making more accurate comparisons across groups using work surfaces with different compliances. Direct measures of physical risk factors in the workplace can improve understanding of the aetiology of musculoskeletal disorders. Findings from this study characterise inertia artefacts in typing force measures and provide a method for eliminating them. These artefacts can add variability to measures, masking possible differences between subject groups. PMID- 19787506 TI - Effects of combined wrist flexion/extension and forearm rotation and two levels of relative force on discomfort. AB - This study investigated perceived discomfort in an isometric wrist flexion task. Independent variables were wrist flexion/extension (55%, 35% flexion, neutral, 35% and 55% extension ranges of motion (ROM)), forearm rotation (60%, 30% prone, neutral, 30% and 60% supine ROM) and two levels of flexion force (10% and 20% maximum voluntary contraction (MVC)). Discomfort was significantly affected by flexion force, forearm rotation and a two-way interaction of force with forearm rotation (each p < 0.05). High force for 60%ROM forearm pronation and supination resulted in increasingly higher discomfort for these combinations. Flexion forces were set relative to the MVC in each wrist posture and this appears to be important in explaining a lack of significant effect (p = 0.34) for flexion/extension on discomfort. Regression equations predicting discomfort were developed and used to generate iso-discomfort contours, which indicate regions where the risk of injury should be low and others where it is likely to be high. Regression equations predicting discomfort and iso-discomfort contours are presented, which indicate combinations of upper limb postures for which discomfort is predicted to be low, and others where it is likely to be high. These are helpful in the study of limits for risk factors associated with upper limb musculoskeletal injury in industry. PMID- 19787507 TI - The effect of military load carriage on 3-D lower limb kinematics and spatiotemporal parameters. AB - The 3-D gait analysis of military load carriage is not well represented, if at all, within the available literature. This study collected 3-D lower limb kinematics and spatiotemporal parameters in order to assess the subsequent impact of carrying loads in a backpack of up to 32 kg. Results showed the addition of load significantly decreased the range of motion of flexion/extension of the knee and pelvic rotation. Also seen were increases in adduction/abduction and rotation of the hip and pelvis tilt. No changes to ankle kinematics were observed. Alterations to the spatiotemporal parameters of gait were also of considerable interest, namely, an increase in double support and a decrease in preferred stride length as carried load increased. Analysing kinematics during military or recreational load carriage broadens the knowledge regarding the development of exercise-related injuries, while helping to inform the human-centred design process for future load carrying systems. The importance of this study is that limited available research has investigated 3-D lower limb joint kinematics when carrying loads. PMID- 19787508 TI - Difference thresholds for the perception of whole-body vertical vibration: dependence on the frequency and magnitude of vibration. AB - When seeking to reduce vibration in transport it is useful to know how much reduction is needed for the improvement to be noticeable. This experimental study investigated whether relative difference thresholds for the perception of whole body vertical vibration by seated persons depend on the frequency or magnitude of vibration. Relative difference thresholds for sinusoidal seat vibration were determined for 12 males at three vibration magnitudes and eight frequencies (2.5, 5, 10, 20, 40, 80, 160, 315 Hz) using the three-down-one-up method in conjunction with a two-interval-forced-choice procedure. The median relative difference thresholds were in the range 9.5% to 20.3%. There appeared to be a frequency dependence at the lowest vibration magnitude, such that higher frequencies had higher difference thresholds. The relative difference thresholds depended on the vibration magnitude only at 2.5 and 315 Hz. The influence of both vibration frequency and vibration magnitude on the measured difference thresholds suggests that vision (at 2.5 Hz) and hearing (at 315 Hz) contributed to the perception of changes in vibration magnitude. PMID- 19787509 TI - A blessing, not a curse: experimental evidence for beneficial effects of visual aesthetics on performance. AB - The present experiment investigated the effect of visual aesthetics on performance. A total of 257 volunteers completed a series of search tasks on a website providing health-related information. Four versions of the website were created by manipulating visual aesthetics (high vs. low) and usability (good vs. poor) in a 2 x 2 between-subjects design. Task completion times and error rates were used as performance measures. A main effect of usability on both error rates and completion time was observed. Additionally, a significant interaction of visual aesthetics and usability revealed that high aesthetics enhanced performance under conditions of poor usability. Thus, in contrast to the notion that visual aesthetics may worsen performance, visual aesthetics even compensated for poor usability by speeding up task completion. The practical and theoretical implications of this finding are discussed. PMID- 19787510 TI - Measuring posture for epidemiology: comparing inclinometry, observations and self reports. AB - The objective of this study was to use and evaluate three postural assessment methods for epidemiological studies of back disorders. The methods were: (1) a data-logging inclinometer; (2) observations by trained observers; (3) self reports by employees. All methods were feasible in 50 heavy industry worksites. Inclinometry provided quantitative measures of flexion-extension (mean 17 degrees, SD 11.2 degrees), lateral flexion (mean 8.5 degrees, SD 2.6 degrees) and trunk movement speed (mean 14.3 degrees per second, SD 4.9 degrees per second). Observations and self-reports provided estimates of time spent in various trunk angles, general postures, materials handling and vehicles. Compared to observations, self-reports under-reported less common tasks, but over-reported task durations. In statistical modelling to determine if observations or self reports could be used to estimate measured postures, observations accounted for 30 to 61% of the inclinometer measurement variance and self-reports for 33 to 40%. A combination of inclinometry and observations would be an ideal option to provide both depth and breadth of data on postures and other physical exposures for epidemiological research. PMID- 19787511 TI - Internal consistency, test-retest reliability and concurrent validity of a questionnaire on work-related exposure related to arm, shoulder and neck symptoms in computer workers. AB - The aim of this study was to determine the internal consistency, test-retest reliability and concurrent validity of the RSI QuickScan, a newly developed questionnaire that aims to identify the presumed risk factors for neck, shoulder and arm symptoms in a population of computer workers. The internal consistency was calculated using item analysis. The test-retest reliability and concurrent validity were analysed by calculating the percentage of agreement, Cohen's Kappa and the Ppositive and Pnegative. The concurrent validity was also tested by comparing the results from the new questionnaire with those from the original questionnaires that the current questionnaire was based on, on-site expert observations and direct measurements. The results indicate that the RSI QuickScan is a measurement tool with acceptable internal consistency, reliability and concurrent validity. The questionnaire can be used as a means to rapidly collect data on a large population of office workers and at low cost. PMID- 19787512 TI - Working height, block mass and one- vs. two-handed block handling: the contribution to low back and shoulder loading during masonry work. AB - The goal of this study was to compare the effects of the task variables block mass, working height and one- vs. two-handed block handling on low back and shoulder loading during masonry work. In a mock-up of a masonry work site, nine masonry workers performed one- and two-handed block-lifting and block-placing tasks at varying heights (ranging from floor to shoulder level) with blocks of varying mass (ranging from 6 to 16 kg). Kinematics and ground reaction forces were measured and used in a 3-D linked segment model to calculate low back and shoulder loading. Increasing lifting height appeared to be the most effective way to reduce low back loading. However, working at shoulder level resulted in relatively high shoulder loading. Therefore, it was recommended to organise masonry work in such a way that blocks are handled with the hands at about iliac crest height as much as possible. PMID- 19787514 TI - Mycotoxin detection in infant formula milks in Italy. AB - After birth, infant formulas constitute an important or often sole food source for infants during the first months of life. In this study, a survey on the presence of aflatoxin M1 (AFM1) and ochratoxin A (OTA) in the 14 leading brands of infant formulas marketed in Italy was conducted. Mycotoxins were determined by immunoaffinity column clean-up and high-performance liquid chromatography (HPLC) with fluorescence detection. AFM1 was found in two of 185 samples, but at levels below the European legislation limit of 25 ng l(-1). OTA was detected in 133 (72%) samples (range = 35.1-689.5 ng l(-1)). It has been observed that OTA contamination was 80% in the ready-to-use preparations and 63% in the powdered samples. The Scientific Committee for Food (SCF) reviewed the toxicology on OTA and concluded that it would be prudent to reduce exposure to OTA ensuring that exposure is towards the lower end of the range of tolerable daily intakes of 1.2 14 ng kg(-1) body weight day(-1). OTA was also evaluated by the Joint FAO/WHO Expert Committee on Food Additives (JECFA) and a provisional tolerable weekly intake (PTWI) of 100 ng kg(-1) body weight was established. The OTA levels in pre term ready-to-use infant formulas were sufficient to cause a higher OTA intake than the suggested TDI. The results point out the need to perform controls for prevention programmes especially when attempting to identify risk markers of the infant feed quality. PMID- 19787515 TI - Mercury and methylmercury intake estimation due to seafood products for the Catalonian population (Spain). AB - This study estimates mercury and methylmercury levels in fish and fishery products commercialized in the city of Barcelona, Spain, from 2001 to 2007. Combining data of mercury levels in food with the consumption data of 2158 people (as the median of two 24-h recall), the total mercury intake of the Catalonian population was calculated. Mercury was detected in 32.8% of analysed samples. The general population average weekly intake of total mercury in the Catalonian population was 0.783 microg kg(-1) of body weight. This value is clearly lower than the Joint FAO/WHO Expert Committee on Food Additives (JECFA) provisional tolerable weekly intakes (PTWI) of 5 microg kg(-1) of body weight. The fish group was the main contributor to this value, mainly due to predatory species. PMID- 19787516 TI - Analytical approaches to identify potential migrants in polyester-polyurethane can coatings. AB - The safety of a polyester-polyurethane can coating has been assessed using a suite of complementary analytical methods to identify and estimate the concentrations of potential chemical migrants. The polyester was based on phthalic acids and aliphatic diols. The polyisocyanate cross-linking agent was 1 isocyanato-3-isocyanatomethyl-3,5,5-trimethyl cyclohexane homopolymer (IPDI) blocked with methylethylketone oxime (MEKO) to make a one-part formulation. The overall migrate, obtained using solvent extraction of cured films, comprised almost completely of 12 cyclic and one linear polyester oligomer up to molecular weight 800 and containing up to six monomer units. These 13 oligomers covered a total of 28 isomeric forms. Other minor components detected were plasticisers and surfactants as well as impurities present in the starting materials. There was no detectable residue of either the blocked isocyanate (<0.01 microg/dm(2)) used as the starting substance or the unblocked isocyanate (<0.02 microg/dm(2)). The level of extractable IPDI was used as an indicator of the completeness of cure in experimental coatings. These studies revealed that there was an influence of time, temperature and catalyst content. Polymerisation was also influenced by the additives used and by the ageing of the wet coating formulation over several months. These studies allow parameters to be specified to ensure that commercial production coatings receive a full cure giving low migration characteristics. PMID- 19787517 TI - Situating experiences of HIV-related stigma in Swaziland. AB - With the world's highest antenatal HIV prevalence rate (39.2%), Swaziland has also been described as among the most stigmatising. Yet, only recently was an anti-HIV stigma and discrimination (S&D) platform included in the government's National Multisectoral HIV and AIDS Policy. This study draws on a medical anthropological project in rural Swaziland to examine experiences of stigma among people living with HIV/AIDS (PLWH). Qualitative methods included a semi structured questionnaire and interviews (n=40) to identify patterns of stigma across three domains: verbal, physical and social. Key informant interviews (n=5) were conducted with health personnel and support group leaders. Descriptive statistics were situated within a thematic analysis of open-ended content. Among the findings, participants reported extensive HIV-related rumouring (36.4%) and pejorative name-calling (37.5%). Nearly one in five (18.2%) could no longer partake of family meals. Homesteads, which are an organising principle of Swazi life, were often markedly stigmatising environments. In contrast to documented discrimination in health care settings, the health centre emerged as a space where PLWH could share information and support. Given the UNAIDS call for national partners to 'know your epidemic' by tracking the prevalence of HIV related S&D, results from this study suggested that unless 'knowing your epidemic' includes the lived experiences of HIV stigma that blister into discernible patterns, effectiveness of national initiatives is likely to be limited. Multidisciplinary and locale-specific studies are especially well suited in examining the cultural dynamics of HIV stigma and in providing grounded data that deepen the impact of comprehensive HIV/AIDS policies and programming. PMID- 19787519 TI - Battles on women's bodies: war, rape and traumatisation in eastern Democratic Republic of Congo. AB - Rape has been used as a weapon in the conflict in eastern Democratic Republic of Congo (DRC) in unprecedented ways. Research into the phenomenon of war-rape is limited, particularly in this context. The aim of this study was to explore perceptions of local leaders in eastern DRC concerning rape and raped women in the war context. Local leaders were chosen for their ability to both reflect and influence their constituencies. Interviews were conducted with 10 local leaders and transcripts subjected to qualitative content analysis. The study suggests that mass raping and the methods of perpetration created a chaos effectively destroying communities and the entire society and that humanitarian aid was often inappropriate. Furthermore, an exclusive focus on raped women missed the extent of traumatisation entire communities suffered. More significantly, the lack of political will, corruption, greed and inappropriate aid creates a tangled web serving to intensify the war. This complexity has implications for humanitarian interventions including public health. PMID- 19787520 TI - Socio-economic inequalities in child health: recent evidence from India. AB - This paper analyses the Indian National Family Health Survey (2005-2006) data to present certain broad descriptive features of child health inequalities in India and their distribution across well-defined socio-economic groups classified by gender and sector-of-origin, and their dispersal across space. This study finds that poorer sections of the population are beleaguered with ill health whether in the quest for child survival or due to anxieties pertaining to child nutrition. The concentration index value for the indicators of under-five mortality, full immunisation and underweight outcomes at the national level is calculated to be 0.159, 0.204 and -0.158, respectively. The other disturbing finding here is that there are reigning regional and gender disadvantages irrespective of the developmental status of the State. This study would not only help policymakers to recognise these persistent inequalities but also would help understand health performance at the state and regional levels thus facilitating targeting intervention. PMID- 19787521 TI - Railway associated injuries in Pakistan. AB - Pakistan is ranked 12th worldwide for passenger kilometres (km) travelled by railway network. The objective of this study was to assess the railway network related morbidity and mortality in Pakistan. Reported deaths and injuries due to this network were extracted from two secondary datasets: (1) an international disaster database and (2) ambulance log registers for the city of Karachi. Over the period from 1997 to 2006, a total of 11 railway disasters resulted in 449 deaths and 840 injuries. An estimated 2.05 passengers died and another 3.84 passengers were injured per billion km travelled in Pakistan, a rate six times higher than Western European countries. The ambulance log showed that one person died every two weeks in Karachi over a period from September 2007 to Jun 2008 (N = 26). The male-to-female ratio of all injury victims (N = 50) was 9:1 with a mean age of 35.6 years. Surveillance of these injuries is essential to implement prevention and control measures in Pakistan. PMID- 19787524 TI - From the editor: is there room for the self in research? PMID- 19787522 TI - Attention and working memory deficits in mild cognitive impairment. AB - Mild cognitive impairment (MCI) has emerged as a classification for a prodromal phase of cognitive decline preceding the emergence of Alzheimer's disease (AD). We examined neuropsychological functioning in a sample of 60 adults with amnestic MCI (a-MCI), 32 with subjective complaints of memory impairment (subjective-MCI, s-MCI), 14 with mild AD, and 25 age-matched controls. Both the a-MCI and s-MCI groups displayed impaired attentional processing, working memory capacity, and semantic language, with a-MCI displaying additional impairments to verbal and/or visual memory. These results indicate that further research is needed to examine cognitive decline in nonamnestic variants of MCI. PMID- 19787523 TI - Declining autobiographical memory and the loss of identity: effects on well being. AB - We investigated the impact of cognitive deterioration and identity loss on well being in older adults with dementia. We predicted that in addition to the negative effects that decline in cognitive ability has on dementia sufferers' well-being, there are also independent negative effects of identity loss. Participants (N = 48) were residents receiving standard care with mild dementia, residents receiving specialized care with severe dementia, and an age-matched community comparison group. Predictably, autobiographical memory and cognitive performance decreased linearly as a function of care level. Life satisfaction was lower for the standard care group with mild dementia than for the community sample, but, unexpectedly, life satisfaction was just as high for the severe dementia group receiving specialized care as for the community group. A similar U shaped pattern was found in ratings of personal identity strength, and this mediated the life satisfaction effect. We conclude that amongst those suffering from dementia, loss of memory serves to compromise well-being primarily because it is associated with loss of identity. PMID- 19787525 TI - Mistrust and self-isolation: barriers to social support for older adult methadone clients. AB - OBJECTIVES: The purpose of this study is to explore barriers to the use, maintenance, and expansion of social supports in older adult methadone clients. METHODS: The data for this analysis were derived from a qualitative study of the needs of aging methadone clients. Data were collected through face-to-face interviews with 24 methadone clients over the age of 50. RESULTS: A lack of trust was identified as a principal barrier to the use, maintenance, and expansion of the social supports of older adult methadone clients. Causes of this mistrust include issues associated with aging, past traumatic experiences, and difficult personal relationships. IMPLICATIONS: These findings imply that addressing the issue of self isolation and recognizing the reason older adult methadone clients engage in this behavior is a key element in getting this specific population to use, maintain, and foster healthy social supports. A common phrase echoed throughout the interviews is that a person cannot trust anybody. Because of this mistrust, some clients keep to themselves by electing to self-isolate and decline to use, maintain, or foster new relationships. As a result, these individuals are less likely foster and/or engage in healthy social relationships, which are a key component of substance abuse treatment and abstinence maintenance. PMID- 19787526 TI - Risk factors and intervention programs for depression in nursing home residents: nursing home staff interview findings. AB - The in-depth qualitative interviews with 25 nursing home staff members were done to examine (a) their perceptions and experiences of risk factors for residents' depression, (b) current depression intervention programs, and (c) specific needs for staff training. The interviewees identified the residents' sense of loss and grief and feelings of isolation and loneliness as the causes of their depression and in-house activities and contract mental health services as current services aimed at reducing depression. They also pointed out the following barriers to providing effective depression interventions: too much dependence on antidepressant medication, low Medicaid reimbursement rate, staff shortage, residents' attitudes, and nursing home culture. The types of training that the staff members desired were: skills to monitor nonverbal signs and changes and to systematically screen different types of depression; education about antidepressants and their effects, side effects, and interaction effects with other medication; and systematic training in different types of psychosocial and behavioral interventions for late-life depression in residents with various levels of physical disabilities and cognitive impairments. PMID- 19787527 TI - Senior gambling: risk or reward? AB - For a growing number of older adults, a day outing to a local casino has become one of the more enjoyable and accessible opportunities for socialization and entertainment. Unfortunately, for some older adults this growing pastime increases their risk for developing a gambling problem or, worse yet, a gambling addiction. The consequences of problematic gambling behaviors for individuals living on a fixed income require greater attention by social work researchers, practitioners, and providers of senior services. The development and implementation of a Gambling Education Workshop for older adults attending senior centers in a large metropolitan area, along with qualitative interviews with a sample of workshop participants, are reported in this article. Among the findings from this project are the needs for greater awareness of the risk factors associated with problematic gambling, as well as greater awareness among older adults about the consequences associated with gambling. PMID- 19787528 TI - Racial differences in attitudes toward professional mental health treatment: the mediating effect of stigma. AB - Stigma associated with mental illness continues to be a pervasive barrier to mental health treatment, leading to negative attitudes about treatment and deterring appropriate care seeking. Empirical research suggests that the stigma of mental illness may exert an adverse influence on attitudes toward mental health treatment and service utilization patterns by individuals with a mental illness, particularly African Americans. However, little research has examined the impact of stigma on racial differences in attitudes toward seeking mental health treatment. This study examined the hypothesis that stigma partially mediates the relationship between race and attitudes towards mental health treatment in a community-based sample of 101 African American and White older adults. Multiple regression analyses and classic path analysis was utilized to test the partial mediation model. Controlling for socio-demographic factors, African American older adults were more likely to have negative attitudes toward mental health treatment, and they also reported more public and internalized stigma than their White counterparts. As hypothesized, the relationship between race and attitudes toward mental health treatment was partially mediated by internalized stigma, suggesting that internalized stigma may cause older adults to develop negative attitudes about mental health treatment. The partial mediation model was not significant for public stigma, however. Implications for social work research and practice are discussed. PMID- 19787529 TI - Meeting the challenges of urban aging: narratives of poor elderly women of Detroit, Michigan. AB - Among the elderly, there is a larger percentage of poor women than men. Many aging minority women in poverty reside in the urban areas of America. This phenomenological study investigates poor urban women living in the inner city of Detroit, Michigan from a strengths perspective. In-depth interviews found that poor urban women exhibited both personal and environmental strengths. These strengths can be successfully utilized by social workers in their practice with this client population. PMID- 19787530 TI - Remission from depressive symptoms among older adults with mood disorders: findings of a representative community sample. AB - OBJECTIVE: To determine factors associated with remission in a community-dwelling sample of older Canadians with mood disorders. METHODS: We used a representative community survey conducted in 6 Canadian provinces. Data were gathered by telephone and in-person interviews. The response rate was 79%. Those in institutions were excluded from the sampling frame. Our sample was limited to community-dwelling individuals, aged 55 and over, who reported that they had been diagnosed by a health professional with a mood disorder at some point in their life. Only those with mood disorders that lasted 6 months or more were included in the sample (n = 1,161). Remission from depression was calculated using the Composite International Diagnostic Interview-Short Form (CIDI-SF). Individuals were classified as in remission if CIDI-SF < 0.9. RESULTS: Three-quarters (76%) of older adults with mood disorders had been symptom-free for the preceding year. The logistic regression analyses indicated that the married, those aged 65 and over, those in good to excellent health, and those who reported minimal stress had the highest odds of remission. Gender, immigration status, education level, household income, number of chronic conditions, activities of daily living limitations, comorbid anxiety disorders, and physical activity level were not associated with the likelihood of remission. CONCLUSION: Remission rates in this community sample of older adults with mood disorders were much higher than in previous clinical samples. Strategies to improve identification and outreach to those least likely to be in remission from depression are discussed. PMID- 19787533 TI - A historical review of additives and modifiers used in paving asphalt refining processes in the United States. AB - The U.S. asphalt paving industry has evolved over time to meet various performance specifications for liquid petroleum asphalt binder (known as bitumen outside the United States). Additives to liquid petroleum asphalt produced in the refinery may affect exposures to workers in the hot mix paving industry. This investigation documented the changes in the composition and distribution of the liquid petroleum asphalt products produced from petroleum refining in the United States since World War II. This assessment was accomplished by reviewing documents and interviewing individual experts in the industry to identify current and historical practices. Individuals from 18 facilities were surveyed; the number of facilities reporting use of any material within a particular class ranged from none to more than half the respondents. Materials such as products of the process stream, polymers, elastomers, and anti-strip compounds have been added to liquid petroleum asphalt in the United States over the past 50 years, but modification has not been generally consistent by geography or time. Modifications made to liquid petroleum asphalt were made generally to improve performance and were dictated by state specifications. PMID- 19787534 TI - A review of changes in composition of hot mix asphalt in the United States. AB - This review researched the materials, methods, and practices in the hot mix asphalt industry that might impact future exposure assessments and epidemiologic research on road paving workers. Since World War II, the U.S. interstate highway system, increased traffic volume, transportation speeds, and vehicle axle loads have necessitated an increase in demand for hot mix asphalt for road construction and maintenance, while requiring a consistent road paving product that meets state-specific physical performance specifications. We reviewed typical practices in hot mix asphalt paving in the United States to understand the extent to which materials are and have been added to hot mix asphalt to meet specifications and how changes in practices and technology could affect evaluation of worker exposures for future research. Historical documents were reviewed, and industry experts from 16 states were interviewed to obtain relevant information on industry practices. Participants from all states reported additive use, with most being less than 2% by weight. Crumb rubber and recycled asphalt pavement were added in concentrations approximately 10% per unit weight of the mix. The most frequently added materials included polymers and anti-stripping agents. Crumb rubber, sulfur, asbestos, roofing shingles, slag, or fly ash have been used in limited amounts for short periods of time or in limited geographic areas. No state reported using coal tar as an additive to hot mix asphalt or as a binder alternative in hot mix pavements for high-volume road construction. Coal tar may be present in recycled asphalt pavement from historical use, which would need to be considered in future exposure assessments of pavers. Changes in hot mix asphalt production and laydown emission control equipment have been universally implemented over time as the technology has become available to reduce potential worker exposures. This work is a companion review to a study undertaken in the petroleum refining sector that investigated current and historical use of additives in producing petroleum-derived asphalt cements. PMID- 19787535 TI - A response to Lawrence's (2009) erotic target location errors. PMID- 19787537 TI - Achievement goals, self-handicapping, and performance: a 2 x 2 achievement goal perspective. AB - Elliot and colleagues (2006) examined the effects of experimentally induced achievement goals, proposed by the trichotomous model, on self-handicapping and performance in physical education. Our study replicated and extended the work of Elliot et al. by experimentally promoting all four goals proposed by the 2 x 2 model (Elliot & McGregor, 2001), measuring the participants' own situational achievement goals, using a relatively novel task, and testing the participants in a group setting. We used a randomized experimental design with four conditions that aimed to induce one of the four goals advanced by the 2 x 2 model. The participants (n = 138) were undergraduates who engaged in a dart-throwing task. The results pertaining to self-handicapping partly replicated Elliot and colleagues' findings by showing that experimentally promoted performance avoidance goals resulted in less practice. In contrast, the promotion of mastery avoidance goals did not result in less practice compared with either of the approach goals. Dart-throwing performance did not differ among the four goal conditions. Personal achievement goals did not moderate the effects of experimentally induced goals on self-handicapping and performance. The extent to which mastery-avoidance goals are maladaptive is discussed, as well as the interplay between personal and experimentally induced goals. PMID- 19787538 TI - Talent identification and promotion programmes of Olympic athletes. AB - The start of a new Olympic cycle offers a fresh chance for individuals and nations to excel at the highest level in sport. Most countries attempt to develop systematic structures to identify gifted athletes and to promote their development in a certain sport. However, forecasting years in advance the next generation of sporting experts and stimulating their development remains problematic. In this article, we discuss issues related to the identification and preparation of Olympic athletes. We provide field-based data suggesting that an earlier onset and a higher volume of discipline-specific training and competition, and an extended involvement in institutional talent promotion programmes, during adolescence need not necessarily be associated with greater success in senior international elite sport. Next, we consider some of the promising methods that have been (recently) presented in the literature and applied in the field. Finally, implications for talent identification and promotion and directions for future research are highlighted. PMID- 19787539 TI - The effect of attentional focus on running economy. AB - In research on motor control, the detrimental effect of an internal focus of attention on movement execution of well-learned motor skills is a frequently replicated finding. This experimental study was designed to determine whether this effect is observed with physiological variables during endurance exercise. We examined whether the focus of attention can influence running economy (oxygen consumption at a set running speed). Trained runners had to focus their attention on three different aspects while running on a treadmill. For three consecutive 10 min periods, runners concentrated on the running movement, on their breathing, and on their surroundings. Results showed an increased running economy in the external focus condition. In line with research on motor control, endurance sport also shows that an external focus of attention is better than an internal focus in terms of the physiological performance measure of oxygen consumption. PMID- 19787540 TI - Understanding the coach's role in the development of mental toughness: perspectives of elite Australian football coaches. AB - The purpose of this study was to explore elite coaches' perceptions of how they can both facilitate and impede the development of key mental toughness characteristics in the context of Australian football. Eleven coaches from a previous study (Gucciardi, Gordon, & Dimmock, 2008) were re-interviewed and the transcribed verbatim data were analysed using grounded theory data analytical procedures (Strauss & Corbin, 1998). Five categories that appear to be central to the coach's role in the development of mental toughness in Australian football emerged. Four of these categories (coach-athlete relationship, coaching philosophy, training environments, and specific strategies) were said to facilitate the developmental process, whereas the final category (negative experiences and influences) was said to impede this process. A grounded theory in which the aforementioned categories enable coaches to nurture a "generalized form" of mental toughness acquired during one's formative years into a "sport specific form" pertinent to Australian football is presented. The theoretical and practical implications of these findings are discussed. PMID- 19787541 TI - Quantifying freestyle kick-count and kick-rate patterns in Paralympic swimming. AB - Swimming speed is a function of the propulsion generated from arm strokes and leg kicks. Kicking is partially obscured underwater, making the kinematics of the kick difficult to analyse. In this study, we quantified 100-m freestyle kick count and kick-rate patterns for 14 Paralympic swimmers using inertial-sensor technology. Swimmers took 145 +/- 39 kicks (mean +/- s) for swimming trials and 254 +/- 74 kicks for kicking-only trials. Kick rate was 124.9 +/- 20.3 kicks . min(-1) for swimming trials and 129.6 +/- 14.0 kicks . min(-1) for kicking-only trials. There were no marked differences in kick count among 25-m segments in the swimming trials. There was a substantial increase of 10.6%[90% confidence interval (90%CI): 7.3 to 14.0%] in the number of kicks in the kicking-only trials by the fourth 25-m segment. There was a substantial decrease in kick rate by the third 25-m segment for swimming (-12.0%; 90%CI: -12.8 to -11.1%) and kicking-only (-7.3%; 90%CI: -8.6 to -5.9%) trials. The relationship between swimming and kicking-only kick rates was r = 0.67 (0.55 to 0.76; P < 0.001). The temporal patterns of the kick in kicking only differed from those in swimming; increases in kick rate can improve freestyle swimming performance. PMID- 19787542 TI - Psychological preparation for the Olympic Games. AB - We review research literature on psychological preparation for Olympic Games performance. We address research identifying psychological characteristics associated with Olympic performance success, studies examining how these attributes are developed, stress and coping in Olympians, evaluation studies of the Olympic experience with particular emphasis on factors influencing performance, and the best practice literature on effective Olympic psychological consultations. Key principles are identified as well as gaps in the knowledge base that need to be addressed by investigators. Finally, implications for preparing individual athletes, coaches, and teams are discussed. PMID- 19787543 TI - Do differences in initial speed persist to the stroke phase in front-crawl swimming? AB - The purpose of the study was to determine the extent to which differences in initial speed persist to the stroke phase in front-crawl swimming. Ten male college swimmers performed trials for three types of start that produced different initial speeds: maximal-effort dive, submaximal-effort dive, and maximal-effort wall push. The submaximal effort was determined by the swimmer himself. Participants swam 25 m for each trial, and their motions were recorded by five fixed cameras positioned lateral to the direction of swimming. The horizontal velocity of the greater trochanter of the femur was used to define swimming speed. Mean swimming speed, evaluated from the initial-speed phase to the stroke phase, differed across trials. The effect sizes of the initial-speed phase were 3.15 between maximal-effort dive and submaximal-effort dive (P < 0.001), 5.00 between maximal-effort dive and maximal-effort wall push (P < 0.001), and 2.71 between submaximal-effort dive and maximal-effort wall push (P < 0.001). However, differences in speed at the stroke phase were small (maximal effort dive: 1.91 +/- 0.07 m . s(-1); submaximal-effort dive: 1.88 +/- 0.06 m . s(-1); maximal-effort wall push: 1.88 +/- 0.07 m . s(-1)), indicating that differences in initial speed do not persist to the stroke phase in front-crawl swimming. PMID- 19787544 TI - The effect of induced alkalosis and submaximal cycling on neuromuscular response during sustained isometric contraction. AB - The aim of this study was to determine if inducing metabolic alkalosis would alter neuromuscular control after 50 min of standardized submaximal cycling. Eight trained male cyclists (mean age 32 years, s = 7; [Vdot]O(2max) 62 ml . kg( 1) x min(-1), s = 8) ingested capsules containing either CaCO(3) (placebo) or NaHCO(3) (0.3 g x kg(-1) body mass) in eight doses over 2 h on two separate occasions, commencing 3 h before exercise. Participants performed three maximal isometric voluntary contractions (MVC) of the knee extensors while determining the central activation ratio by superimposing electrical stimulation both pre ingestion and post-exercise, followed by a 50-s sustained maximal contraction in which force, EMG amplitude, and muscle fibre conduction velocity were assessed. Plasma pH, blood base excess, and plasma HCO(3) were higher (P < 0.01) during the NaHCO(3) trial. After cycling, muscle fibre conduction velocity was higher (P < 0.05) during the 50-s sustained maximal contraction with NaHCO(3) than with placebo (5.1 m x s(-1), s = 0.4 vs. 4.2 m x s(-1), s = 0.4) while the EMG amplitude remained the same. Force decline rate was less (P < 0.05) during alkalosis-sustained maximal contraction and no differences were shown in central activation ratio. These data indicate that induced metabolic alkalosis can increase muscle fibre conduction velocity following prolonged submaximal cycling. PMID- 19787545 TI - An unusual novel anti-oxidant dibenzoyl glycoside from Salvinia natans. AB - An unusual novel and significant anti-oxidant 1,2-dibenzoyl glycoside, natansnin (1), has been isolated from Salvinia natans. The structure of 1 was established by the study of NMR and CD spectral data. PMID- 19787546 TI - Making errorless learning more active: self-generation in an error free learning context is superior to standard errorless learning of face-name associations in people with Alzheimer's disease. AB - Errorless learning (EL) principles have been shown to enable people with memory impairments to acquire various types of information (Grandmaison & Simard, 2003; Wilson, 2005). However, the effects of EL, based on simple repetition only, tend to be limited with regards to their size and longevity. The present study investigated whether EL could be improved by actively engaging people with Alzheimer's disease in the learning process. Patients learned the names of famous faces over 10 training sessions, treated either with a non-learning control, a simple repetition EL procedure, or an EL condition in which responses had to be self-generated. Cued recall rates after the final training session were significantly greater for the names treated with the self-generated EL technique compared to the control and the repetition EL conditions. In addition, there was evidence that patients with less severe general cognitive impairment benefit more from active generation than more severely impaired patients. The implications of this research for individualised memory rehabilitation programmes are discussed. PMID- 19787548 TI - The cognitive neuroscience of deception. PMID- 19787547 TI - Modulation of medial prefrontal and inferior parietal cortices when thinking about past, present, and future selves. AB - Recent functional neuroimaging studies have shown that reflecting on representations of the present self versus temporally distant selves is associated with higher activity in the medial prefrontal cortex (MPFC). In the current fMRI study, we investigated whether this effect of temporal perspective is symmetrical between the past and future. The main results revealed that the MPFC showed higher activity when reflecting on the present self than when reflecting on past and future selves, with no difference between past and future selves. Temporal perspective also modulated activity in the right inferior parietal cortex but in the opposite direction, activity in this brain region being higher when reflecting on past and future selves relative to the present self (with again no difference between past and future selves). These findings show that differences in brain activity when thinking about current versus temporally distant selves are symmetrical between the past and the future. It is suggested that by processing degrees of self-relatedness, the MPFC might sustain the process of identifying oneself with current representations of the self, whereas the right inferior parietal cortex might be involved in distinguishing the present self from temporally distant selves. PMID- 19787549 TI - General intellectual decline and daily living skills. AB - A total of 64 elderly individuals presenting with cognitive decline were administered a test of general intelligence and a measure of adaptive knowledge and daily living skills. Premorbid ability was estimated using a demographic formula and a reading test. After controlling for age and depression, general intellectual ability accounted for a large amount of the variance in a broad range of adaptive knowledge and behavioral skills, reflecting the influence of premorbid ability and especially estimated decline. Different patterns of adaptive knowledge and skills were identified as a function of measured IQ and of estimated decline in IQ. Results suggest a threshold of intellectual decline for deterioration in daily living skills. Studies purporting to demonstrate that impairments in particular neuropsychological domains predict specific functional deficits need to control for general intellectual ability and/or the extent of intellectual decline. PMID- 19787550 TI - Protecting raw data and psychological tests from wrongful disclosure: a primer on the law and other persuasive strategies. AB - Psychologists must advocate for more stringent legal protection of psychological test materials because using standardized tests is the most distinguishing and exclusive feature of psychological evaluation practice. With the rapid growth in forensic consulting, unrestrained discovery of raw data and psychological test materials during litigation erodes the reliability and validity of the test procedures. Dissemination of test materials reduces the interpretive value of the tests and promotes cheating, turning our best methods into junk science in the courtroom. This article proposes to reform the law and to revise the professional ethics of psychologists consistent with the strong public policy of test security as described by the U.S. Supreme Court in Detroit Edison v. NLRB (1979). Currently, federal courts and about 20 states protect psychological tests as a unique methodology, with some states enacting a psychologist nondisclosure privilege/duty to safeguard test materials from wrongful disclosure. The record management practices of psychologists vary considerably and are vulnerable to legal attack unless psychologists are aware of legal arguments to protect test materials from wrongful release. Although this article does not offer legal advice, it describes the most common records management problem confronting neuropsychologists and some practical solutions to the raw data problem. Best practice for protecting psychological tests requires the psychologist to understand the law and to assert the psychologist nondisclosure privilege. Other strategies are presented and evaluated. Organized psychology and the legal community should advocate for a uniform rule to protect the objectivity, fairness, and integrity psychological methods in litigation. PMID- 19787551 TI - Memory reloaded: memory load effects in the attentional blink. AB - When two targets are presented in rapid succession, identification of the first is nearly perfect, while identification of the second is impaired when it follows the first by less than about 700 ms. According to bottleneck models, this attentional blink (AB) occurs because the second target is unable to gain access to capacity-limited working memory processes already occupied by the first target. Evidence for this hypothesis, however, has been mixed, with recent reports suggesting that increasing working memory load does not affect the AB. The present paper explores possible reasons for failures to find a link between memory load and the AB and shows that a reliable effect of load can be obtained when the item directly after T1 (Target 1) is omitted. This finding provides initial evidence that working memory load can influence the AB and additional evidence for a link between T1 processing time and the AB predicted by bottleneck models. PMID- 19787552 TI - The sensory nature of knowledge: Sensory priming effects in semantic categorization. AB - The aim of the present study was to show the perceptual nature of conceptual knowledge by using a priming paradigm that excluded an interpretation exclusively in terms of amodal representation. This paradigm was divided into two phases. The first phase consisted in learning a systematic association between a geometrical shape and a white noise. The second phase consisted of a short-term priming paradigm in which a primed shape (either associated or not with a sound in the first phase) preceded a picture of an object, which the participants had to categorize as representing a large or a small object. The objects were chosen in such a way that their principal function either was associated with the production of noise ("noisy" target) or was not typically associated the production of noise ("silent" target). The stimulus onset asynchrony (SOA) between the prime and the target was 100 ms or 500 ms. The results revealed an interference effect with a 100-ms SOA and a facilitatory effect with a 500-ms SOA for the noisy targets only. We interpreted the interference effect obtained at the 100-ms SOA as the result of an overlap between the components reactivated by the sound prime and those activated by the processing of the noisy target. At an SOA of 500 ms, there was no temporal overlap. The observed facilitatory effect was explained by the preactivation of auditory areas by the sound prime, thus facilitating the categorization of the noisy targets only. PMID- 19787553 TI - [German psychosocial journals from an international perspective]. PMID- 19787554 TI - [Impulse control disorders]. PMID- 19787555 TI - Antithrombotic management of atrial fibrillation. PMID- 19787556 TI - Improving antithrombotic management in patients with atrial fibrillation: current status and perspectives. AB - Despite overwhelming evidence of the benefits of risk-adjusted oral anticoagulation on stroke reduction in patients with atrial fibrillation (AF), there is still considerable undertreatment. A multidisciplinary expert group was formed to discuss issues surrounding anticoagulant treatment of patients with AF to try and achieve consensus on various aspects of the implementation of guidelines on oral anticoagulation therapy in AF. Panel members were cardiologists, hematologists, and laboratory and primary care physicians with specific expertise from Europe and the United States. One of the most important conclusions of the meeting was to enhance guideline adherence by better communication of the data showing that the benefits of stroke reduction outweigh the risk of bleeding associated with treatment with vitamin K antagonists. Management of oral anticoagulation therapy by dedicated centers, such as anticoagulation clinics, or by patient self-management may improve the quality of anticoagulation and facilitate the management of these patients and thereby further facilitate optimal antithrombotic management in patients with AF. PMID- 19787557 TI - Anticoagulant management in patients with atrial fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia and is associated with a high risk of embolic stroke (cause in 15% of all strokes and 30% of strokes in those >75 years of age). Anticoagulation with warfarin will reduce stroke risk by about two thirds. The main risks of anticoagulation, namely bleeding, can be minimized by maintaining anticoagulation control within the international normalized range range of 2.0 to 3.0 (target: 2.5). To have a public health impact, patients with AF need efficient and correct identification, with appropriate treatment directed at those patients at most risk from the condition. PMID- 19787558 TI - Antithrombotic prophylaxis in elderly patients with atrial fibrillation. AB - The burden of atrial fibrillation (AF) worldwide is projected to increase substantially over the next few decades in part due to an aging population. AF increases the risk of stroke approximately fivefold. The population-attributable risk for stroke by age is considerable: 1.5% for those individuals 50 to 59 years of age compared with 23.5% for those > or =80 years of age. Vitamin K antagonists (VKAs) like warfarin have been shown to greatly reduce the risk of stroke. However, despite their proven efficacy, VKAs remain underused, particularly among elderly patients with AF. The preponderance of evidence from randomized trials and observational studies attests to higher bleeding rates among elderly individuals with AF. Antiplatelet therapy is not effective for stroke prevention in AF and is also associated with significant bleeding risk. Strategies to optimize the effectiveness of VKAs and improve their safety profiles among elderly patients in clinical practice are directly needed. An understanding of the pathological changes that predispose to hemorrhage, hazards of polypharmacy, and factors that contribute to variability in dose response will facilitate a more informed use of these medications in clinical care. PMID- 19787559 TI - Use and underuse of oral anticoagulation for stroke prevention in atrial fibrillation: old and new paradigms. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia of the Western world. The increased ischemic stroke risk of the AF patient is one of the most important clinical issues to manage. Despite the well-known benefit of oral anticoagulation in high-risk AF patients, these drugs are widely underused in daily practice all over the world. We describe old and new paradigms of the use of oral anticoagulation. In the future, increased comprehensibility of stroke risk scores, development of a validated clinical bleed risk score, and new patient and physician user-friendly antithrombotic medication may contribute to improved adequate use of oral anticoagulation in AF patients. PMID- 19787560 TI - Management strategies for optimal control of anticoagulation in patients with atrial fibrillation. AB - Most patients with atrial fibrillation need anticoagulant treatment with vitamin K antagonists for prevention of thromboembolism, in particular ischemic stroke. Many studies show the efficacy of this treatment but also that it is difficult to keep patients who use vitamin K antagonists in the proper treatment range. Both a too low and a too high intensity of anticoagulation significantly increase the risk of adverse events. Hence repeated monitoring of the intensity of anticoagulation and dose adjustments are required. Management strategies that improve the time in the therapeutic target range are computer-assisted dosing algorithms and centralized care in anticoagulation clinics. In addition, self testing of the international normalized ratio and self-dosing of vitamin K antagonists has been introduced over the past 20 years and has been shown to be an effective and safe treatment modality. PMID- 19787562 TI - New anticoagulants in atrial fibrillation. AB - Atrial fibrillation (AF) requires anticoagulation for prevention of arterial embolism, especially in the presence of defined risk factors summarized in the CHADS (2) score (congestive heart disease, hypertension, age >75 years, diabetes, history of ischemic stroke or transient cerebral ischemia). Vitamin K antagonists as drugs of choice have several limitations. International normalized ratio (INR) adjustment to 2.0 to 3.0 may be difficult to maintain, and doses vary widely between patients. Inherited variations of the vitamin K epoxide reductase C1 enzyme and of the cytochrome P450 2C9 system influence the dosage as well as exogenous factors such as food and drug intake or intercurrent diseases. Increasing age and risk of falling are the main factors behind the underuse of anticoagulation in AF. Anticoagulants with a lack of all or most of these characteristics and without need of regular monitoring for dose adjustment may improve the adherence to the indication for anticoagulation. Indirect systemic and oral direct factor Xa and oral direct thrombin inhibitors are currently being developed for the prevention of embolism in patients with AF. PMID- 19787561 TI - Different models for oral anticoagulation management may be applied provided that minimal assistance criteria are fulfilled: an Italian experience. AB - The efficacy of adjusted-dose oral anticoagulant therapy (OAT) in the prevention of thrombotic complications in various clinical conditions is well documented. Management of OAT requires a trained physician, an organized system of follow-up, reliable international normalized ratio monitoring, and good patient communication and education. Drug interactions with coumarins are a major cause of excessive anticoagulation and hence could be an important determinant of bleeding in patients on OAT. An analysis conducted in Toscana in 2005 found 31,221 patients persistently on OAT. During the same period, potential drug-drug interactions were detected in 11,778 of these patients (37.7%). Thus, the regional government enacted a specific law for the organization of OAT management to give all patients a minimal standard of quality of OAT. A specific educational campaign was promoted with the slogan "Written is better." Three possible models to follow individual patients were identified in relation to available resources and geographic characteristics of the living area: Anticoagulation Clinic (AC), General Practitioner (GP), or combined AC and GP management. This experience, although obtained in a limited geographic area, could help improve the efficacy and safety of OAT management. PMID- 19787563 TI - [Quo vadis BADO?]. PMID- 19787564 TI - [Psychiatric consultation via internet]. PMID- 19787565 TI - [Ambulatory aftercare of forensic patients after release]. AB - OBJECTIVE: The efficacy of specific forensic outpatient treatment should be investigated. METHODS: In 2000 the Ministry of Social Affairs of the State of Bavaria, Germany, implemented a model for forensic outpatient treatment. Three forensic hospitals established forensic outpatient clinics. The Department of Forensic Psychiatry of the Psychiatric Hospital of the Ludwig Maximilian University of Munich evaluated the treatment and management programs with financial support from the Ministry. RESULTS: 111 mentally ill offenders were included after release from forensic hospitals. 65 % suffered from schizophrenia. In 4.5 years time of observation a recidivism rate of 0.9 % of severe offences could be found (3.6 % including cases of suspicion). 17 % of the patients needed a rehospitalisation and 12 % a legal intervention. At the end of the observation period 42 patients still needed treatment, but 44 patients continued therapy in the forensic outpatient setting out of own interests. CONCLUSIONS: In accordance to literature very low rates of criminal recidivism under specific forensic outpatient aftercare could be found, and in addition a relatively high compliance with the treatment. PMID- 19787566 TI - [Who gets how much psychiatric outpatient care and why?]. AB - AIMS: To elucidate the connections between individual aspects and patients' concerns and the care effort provided in a clinic for the sickest among outpatients. METHODS: Clients of one health insurer were followed for six months (n = 339) in a "Institutsambulanz" or "PIA". All treatment activities, which involved roughly 100,000 working minutes, were recorded. Sociodemographic data, the diagnoses, the individual needs and idiosyncracies, symptoms and case history were noted for multivariate analysis. RESULTS: The linear regression model with the best fit (n = 251, r (2) = 0.512, p < 0.001) included six variables. Lower efforts: living in nursing home (beta = - 0.319; p < 0.001), higher age (beta = - 0.238; p < 0.001), legal incapacity (beta = - 0.165, p = 0.006), own work income (beta = - 0.100; p = 0.044); higher efforts: inpatient stays prior to study treatment (lifetime: beta = 0.181; p = 0.001; number of days in last two years: beta = 0.193; p < 0.001). Treatment aims, functional deficits, and diagnoses did not have a significant influence. CONCLUSIONS: Younger patients who wish for an independent life despite of a grave psychiatric disorder may effectuate higher treatment efforts. Treatments administered to nursing-home inhabitants are far less complex, although these patients are even sicker. The current reimbursement mechanism may serve as a disincentive towards care administration according to individual need. PMID- 19787567 TI - [Demographic change in psychiatry and psychotherapy--relevance of the age relation]. AB - The demographic change will lead to new challenges for the German social and health system in the near future, because it will be accompanied with a large increase of gerontopsychiatric disorders, such as dementia or depression. Age as socio-demographic variable is of high impact in psychiatric and psychotherapeutic research. We aimed to analyze the use of age as sample characteristic or explanatory variable in all publications of the journals "Psychotherapeut" and "Psychiatrische Praxis" in 2007 and 2008. Furthermore, we examined the inclusion of age groups addressed by studies to evaluate the representation of old age studies in German general psychiatric and psychotherapeutic journals. Most studies used age as sample characteristic, but not as explanatory variable in additional analyses. 10 percent of studies addressed old age subjects, especially early detection and diagnosis of dementia. In view of the future population ageing and the associated increasing relevance of mental disorders in old age, more effort in research and publication related to prevention and treatment of mental disorders in old age is required. PMID- 19787568 TI - Cytotoxic serratane triterpenes from Diphasiastrum complanatum with a hydroxy group at C-27. AB - Four serratane-type triterpenes ( 1- 4) were isolated from D. COMPLANATUM. Their chemical structures were elucidated as 14alpha,15alpha,20beta,21beta,24,27alpha,29-heptahydroxyserrat-3-one ( 1), 3beta,14alpha,15alpha,20beta,21beta,24,27alpha,29-octahydroxyserratane ( 2), 3alpha,14alpha,20beta,21beta,24,27alpha,29-heptahydroxyserratane ( 3) and 3beta,14alpha,21beta,24,27alpha-pentahydroxyl-serratane-29-yl ( E)- P-coumarate ( 4) by spectroscopic methods (MS, 1D and 2D NMR) and X-ray crystallography. Interestingly, the most characteristic methylene (C-27) of the serratane ring C was oxidized to a methine. Compound 4 showed significant cytotoxic activity against the human leukemia K562/S and the doxorubicin-resistant K562/R cell lines, but the other compounds were inactive. PMID- 19787569 TI - Inhibitory effect of the alkaloid warifteine purified from Cissampelos sympodialis on B lymphocyte function in vitro and in vivo. AB - The aqueous fraction of the ethanolic extract of the plant CISSAMPELOS SYMPODIALIS (Menispermaceae) was previously described to inhibit B cell function. The alkaloid warifteine is the major component of this extract. In the present study we investigated the effect of warifteine on B lymphocyte function and characterized its mechanism of action. Purified splenic murine B lymphocytes were stimulated with either Toll-like receptor (TLR) ligands (LPS, Pam (3)Cys and CpG oligodeoxynucleotides) or anti-IgM antibody and the effect of warifteine on B cell response was investigated. Warifteine inhibited both the proliferative response and immunoglobulin (Ig) secretion induced by these stimuli. Kinetics studies demonstrated that warifteine blocked B cell function even when added after 24 h of a 72 h culture. The inhibitory effect of warifteine was also detected in cultures activated by phorbol myristate acetate and calcium ionophore. We investigated the signal transduction pathways blocked by warifteine. It did not modify the total protein phosphorylation pattern in LPS and anti-IgM-stimulated B cell cultures. It did, however, decrease the rise in intracellular calcium levels, the phosphorylation of the mitogen activated protein kinase (MAPK) ERK and the intranuclear levels of the transcription factor NFkappaB. Warifteine also induced an increase in cAMP and its effect on LPS induced proliferation was mimicked by the control adenyl cyclase activator forskolin. IN VIVO Ig production induced by the TI-2 antigen TNP-ficoll was also inhibited by warifteine. Taking together, our data suggest that warifteine is a potent inhibitor of B cell response both IN VITRO and IN VIVO and that this effect may be due to the induction of increased intracellular cAMP levels, suggesting that this substance may be useful as a modulator of B cell function. PMID- 19787570 TI - Three major metabolites of mulberroside A in rat intestinal contents and feces. AB - Mulberroside A, a major stilbene constituent of MORUS ALBA L. (Moraceae), displays significant antitussive and antiasthmatic effects in animals. As part of our ongoing research on its biotransformation in rats, mulberroside A was orally administered to rats, and the metabolites in the gastrointestinal contents and feces were investigated. Three major metabolites were isolated from the feces of rats and identified as oxyresveratrol-2- O- beta- D-glucopyranoside ( 1), oxyresveratrol-3'- O- beta- D-glucopyranoside ( 2), and oxyresveratrol ( 3) on the basis of chemical and spectroscopic evidence. The three metabolites were also detected in the small intestinal contents of rats following oral administration of mulberroside A. These findings suggest that mulberroside A is metabolized prior to absorption into the body. PMID- 19787571 TI - Confocal neurolasermicroscopy in human brain - perspectives for neurosurgery on a cellular level (including additional comments to this article). AB - BACKGROUND: During neurosurgery intraoperative imaging of vital neural structures on a cellular level would facilitate the development of new strategies for diagnosis and treatment. In vivo imaging would permit the detection of the tumour centre and infiltration zone. With targeted biopsies the lesion of interest could be determined before performing the biopsy, facilitating the final pathological diagnosis. In this study we present confocal neurolasermicroscopy as a new method in neurosurgery. METHODS: A miniaturised confocal neurolasermicroscope (NLM) was used ex vivo immediately after tumour resection of glioblastoma multiforme (GBM). NLM was performed with subcellular magnification up to a tissue depth of 100 microm. NLM images were compared to conventional histological images of the same tumour. RESULTS: The application of the method in nine patients allowed adequate diagnosis of a malignant glioma fulfilling the WHO criteria when compared to conventional histology. In one patient with glioblastoma multiforme NLM allowed the correct diagnosis of GBM to be made, demonstrating the high mitotic rate and cell pleomorphy of the tumour cells. Additional characteristics such as pleomorphic cells, mitotic figures, fibrillary matrix and the distinction between tumour centre and infiltration zone could be shown. CONCLUSIONS: NLM is a tool which could be adapted for neurosurgical intraoperative applications with the potential to diagnose tumours and recognise the tumour centre and infiltration zone in vivo. Further applications of NLM to characterise subcellular structures and vascular architecture are possible. PMID- 19787572 TI - Paracentesis for successful treatment of tension pneumoperitoneum related to endoscopic submucosal dissection. PMID- 19787573 TI - Rapidly progressive relapsing sclerosing cholangitis following surgery for pancreatic pseudotumor. PMID- 19787574 TI - Late colonic stent perforation following chemotherapy. PMID- 19787575 TI - Endoscopic closure of esophageal fistula using a novel "clips and loop" method. PMID- 19787576 TI - Minute perforation after argon plasma coagulation for management of small colonic polyps. PMID- 19787577 TI - Bleeding angiodysplasia of the jejunum without a visible vessel. PMID- 19787578 TI - A novel stent for management of duodenal obstruction. PMID- 19787579 TI - Fatal case of biliary cast syndrome in nontransplant patient. PMID- 19787580 TI - Esophageal Crohn's disease. PMID- 19787581 TI - Rectal Meckel's diverticulum. PMID- 19787582 TI - [Physician documentation responsibility. Decubitus ulcer--a forensic medicine gray zone]. PMID- 19787584 TI - Surgical treatment in patients with double elevator palsy. AB - PURPOSE: To evaluate the effectiveness of surgical treatment performed in patients with double elevator palsy (DEP). METHODS: Patients diagnosed with congenital DEP between April 2003 and March 2007 were included in the study. The cases with positive traction test had inferior rectus (IR) recession followed by full tendon width muscle transposition Knapp surgery or partial tendon width transposition operation, while those without positive traction test underwent transposition procedure alone. Transposition surgery was combined with recession and resection of horizontal rectus muscles in patients with exotropia according to the amount of horizontal deviation. Eyelid surgery was applied in patients with ptosis following strabismus surgery. RESULTS: The average age of 13 patients was 14+/-32.5 years (range, 3-60 years). Five patients (38%) were female and 8 patients (62%) were male. The mean preoperative hypotropia was decreased from 29.2+/-3.5 prism diopters (PD) (range, 16-45 PD) to 2.6+/-2.8 PD (range, 0-6 PD) postoperatively. The median amount of horizontal deviation in patients with exotropia (n=4) was 30 PD (range, 25-45 PD) preoperatively; it was reduced to 2 PD (range, 0-8 PD) postoperatively. Mean follow-up period was 14.1+/-2.8 months (range, 6-31 months). Five patients (38%) underwent eyelid surgery, and all achieved cosmetically satisfactory results. CONCLUSIONS: Transposition surgery alone or combined with IR recession is an effective procedure in treatment of double elevator palsy. In patients with moderate horizontal deviations, recession and resection of horizontal rectus muscles combined with transposition provide correction of the horizontal deviation at the same time. PMID- 19787585 TI - Expression of alpha-crystallins in human sebaceous carcinoma of the eyelid. AB - PURPOSE: Crystallins are molecular chaperones that protect various cells from apoptosis. This study used immunohistochemistry to examine the expression of alphaA-crystallin and alphaB-crystallin in human sebaceous carcinoma tissues. METHODS: Nine patients with sebaceous carcinoma of the eyelid underwent excision of the eyelid or orbital exenteration. Formalin-fixed, paraffin-embedded tissue sections were submitted for hematoxylin-eosin staining and immunohistochemistry with anti-alphaA- and alphaB-crystallin antibodies. RESULTS: In the noncancerous eyelid, crystallins were weakly and homogeneously expressed in the Meibomian gland lobules. In eyelids with sebaceous carcinoma, alphaA-crystallin and alphaB crystallin were highly expressed in 4 cases, where the cytoplasmic immunoreactivity was heterogeneously detected in the tumor cells. Three and 2 cases were shown to express low levels of alphaA-crystallin and alphaB crystallin, respectively. A statistically significant correlation was observed between expression levels of alphaA-crystallin and alphaB-crystallin in sebaceous carcinomas (p=0.012). All sebaceous carcinoma tissues contained mitotic tumor cells, which showed predominantly perinuclear immunoreactivity of alphaB crystallin. The mitotic rate of tumor cells was 5.85+/-1.76 and 10.72+/-1.64 in high and moderate/low alphaB-crystallin-expressing cases, respectively. The number of mitotic cells was significantly higher in moderate/low alphaB crystallin-positive than in high-positive cases (p<0.01). CONCLUSIONS: Crystallins are expressed in human sebaceous carcinomas including mitotic cells. Expression of alphaB-crystallin correlated with low number of mitotic tumor cells, suggesting that alphaB-crystallin may play a potential role in the regulation of tumor cell proliferation. PMID- 19787586 TI - In vivo characterization of doxycycline effects on tear metalloproteinases in patients with chronic blepharitis. AB - PURPOSE: Matrix metalloproteinases (MMPs) have a role in the pathogenesis of rosacea-associated chronic blepharitis. Doxycycline is largely used as a treatment for recalcitrant chronic blepharitis. It has been shown in vitro that doxycycline inhibits MMPs activation. The aim of this study was to investigate in vivo the effect of doxycycline in modulating MMPs in patients with chronic idiopathic blepharitis. METHODS: Eight patients (6 male, 2 female; mean age 45.7+/-17.5 years) were included in the study. Doxycycline (100 mg) was administered orally, twice a day, for 2 weeks and once a day for an additional 2 weeks. Clinical signs and symptoms were evaluated and scored (0-3) at baseline and after 4 weeks. Total sign (TSS) and total symptom (TSyS) scores were calculated. Tear samples and conjunctival impression cytologies were collected at baseline and after 4 weeks of treatment to evaluate MMP-9 and TIMP-1 expression and activity. RESULTS: An improvement in TSS (4.5+/-1.1 vs 2.7+/-1.5) and TSyS (6.6+/-1.3 vs. 3.1+/-1.9) was observed after 4 weeks, with significant amelioration of hyperemia, marginal blepharitis, and superficial punctuate keratopathy. Zymography revealed a decrease of MMP-9 activity after 4 weeks. MMP 9 mRNA and protein levels did not change, while an upregulation of TIMP-1 expression was observed. CONCLUSIONS: This study suggests that 4-week treatment with doxycycline significantly improved symptoms and signs in patients with chronic blepharitis in association with a decrease in MMP-9 activity. Upregulation of TIMP-1 is proposed as a possible mechanism of MMP-9 inactivation. PMID- 19787587 TI - Prospective study of risk factors for conjunctival bacterial contamination in patients undergoing intraocular surgery. AB - PURPOSE: To determine whether a patient's age, gender, local or systemic risk factors affect the rate of preoperative bacterial contamination. METHODS: Consecutive 1,474 patients undergoing intraocular surgery were enrolled in this prospective masked study. Past medical history was noted and examinations were performed. The patients were divided into four groups: a control group (without local or systemic risk factors), those with local risk factors (chronic use of topical medications, contact lens wear, blepharitis, chronic eyelid or conjunctival inflammation), those with systemic risk factors (immunosuppression, diabetes, autoimmune conditions, and asthma), and those with both. Conjunctival cultures were obtained before surgery. RESULTS: Among the 1,474 patients, 914 bacteria were isolated from 214 (14.9%) patients. Advanced age was associated with a higher rate of positive conjunctival cultures (p<0.005). No statistical difference was found with regard to gender (p=0.7173). Among the 282 patients in the control group, 14 (5%) had a positive conjunctival culture. Compared to the control group, positive conjunctival cultures were found in 118 out of 503 patients (23.5%) with local risk factors (p<0.0001), 65 out of 545 patients (11.9%) with systemic risk factors (p=0.0019), and 22 out of 144 (15.3%) with both (p=0.0006). Two patients developed postoperative endophthalmitis (0.14%), one with both local risk and systemic factors and the other with a systemic risk factor. CONCLUSIONS: Patients with local or systemic risk factors or advanced age were found to have a higher rate of bacterial conjunctival contamination before intraocular surgery. PMID- 19787588 TI - Usefulness of anterior segment optical coherence tomography in Descemet membrane detachment. AB - PURPOSE: To evaluate the usefulness of anterior segment optical coherence tomography (OCT) in diagnosis, choosing the treatment method, and monitoring the treatment outcomes in Descemet membrane detachment DMD). METHODS: We retrospectively reviewed the clinical data for 14 eyes of 13 patients: 8 eyes with DMD after cataract surgery, 2 eyes after deep anterior lamellar keratoplasty (DALK), 2 eyes of 1 patient with Ehlers-Danlos type VI syndrome, 1 eye after contusion, and 1 eye with spontaneous corneal edema of unknown origin. We used OCT to confirm or make the diagnosis, evaluate the configuration of detachment, and monitor treatment results. RESULTS: DMD was diagnosed in 12 eyes, based on the slit lamp examination. In 2 eyes, because of a very hazy view due to corneal edema, DMD was diagnosed based on OCT findings. We chose the treatment method based on DMD configuration evaluated by OCT examination. Eight eyes were treated conservatively and 6 eyes underwent intracameral air injection with additional ab externo stab incisions. In 12 eyes, Descemet membrane reattached successfully. In 2 eyes of 1 patient with Ehlers-Danlos syndrome, the detachment remained, but corneal thickness had decreased. After anterior chamber air tamponade, we observed the decrease of corneal thickness within 7 days. CONCLUSIONS: OCT is useful in precise evaluation of DMD configuration and choosing the treatment method, but has a very limited role in diagnosis and monitoring the treatment results, where the clinical examination is the most important indicating factor. PMID- 19787589 TI - Treatment of primary pterygium: role of limbal stem cells and conjunctival autograft transplantation. AB - PURPOSE: The limbus and its stem cells are important in the pathogenesis of pterygium. In this study, the usefulness of limbal stem cells and conjunctival autograft transplantation for the treatment of primary pterygium is assessed. METHODS: In this prospective noncomparative cohort study, 42 eyes of 42 patients with grade I-III primary pterygium underwent pterygium excision followed by superotemporal limbal stem cells and conjunctival autograft transplantation. Pterygium recurrences and complications within a mean follow-up period of 18.26 months (range, 10-28 months) were assessed. RESULTS: There were no recurrences of pterygium growth except in 2 cases (4.75%). In addition, no significant complications were noted. No further surgical interventions were needed in any case except for reoperation in the 2 recurrent cases. CONCLUSIONS: Although limbal stem cells and conjunctival autograft transplantation is a time-consuming procedure, it is a safe and effective technique for the treatment of different grades of pterygium. It is useful in prevention of pterygium recurrence, which is a major problem in pterygium surgery. PMID- 19787590 TI - Laser in situ keratomileusis for treatment of fully or partially refractive accommodative esotropia. AB - PURPOSE: To evaluate the efficacy and safety of laser in situ keratomileusis (LASIK) in partially refractive accommodative esotropia (pRAE) and fully refractive accommodative esotropia (fRAE). METHODS: Forty-two eyes of 21 patients who had LASIK for correcting hyperopic refractive error were evaluated. Refractive errors, uncorrected visual acuity (UCVA) and best-corrected visual acuity (BCVA), ocular alignment, and stereopsis were recorded before and after LASIK. RESULTS: Sixteen patients with fRAE and 5 with pRAE were evaluated. Mean age at the time of surgery was 19.00+/-3.79 years. Mean follow-up time was 12.19+/-4.51 months. For the fRAE group, the mean preoperative angle of deviation without spectacle correction was +19.13+/-5.87 prism diopters (PD); all were orthophoric with spectacles. Postoperatively, all these patients achieved less than 10 PD of deviation without spectacles. For the pRAE group, the mean preoperative angle of deviation was +32.60+/-9.81 PD and +14.60+/-6.14 PD without and with spectacles, respectively. Postoperatively, the mean angle of deviation was +13.60+/-5.72 PD and +12.80+/-5.40 PD without and with spectacles, respectively. For all 21 patients, the preoperative mean spherical equivalent (SE) with cycloplegia was +4.94+/-1.43 diopters (D); it was +1.49D+/-0.70 D postoperatively. Three eyes lost 1 line of BCVA and 3 eyes gained 1 line. No intraoperative complication was recorded. CONCLUSIONS: LASIK is a safe and effective method for treating refractive error and creating orthophoria in fRAE. In pRAE, it eliminates the refractive component of deviation safely and effectively. PMID- 19787591 TI - Mitomycin C aqueous humor concentration after photorefractive keratectomy: an experimental study. AB - PURPOSE: To evaluate mitomycin C (MMC) aqueous humor concentration after photorefractive keratectomy (PRK). METHODS: In this experimental study, twenty four eyes of 12 male pigmented rabbits were divided into 4 groups and studied at the Institute of Vision and Optics, Department of Medicine, University of Crete, Greece. Eyes in groups 1 and 2 underwent PRK to correct -5 diopters (D) in a 6-mm optical zone, while sponges soaked with 0.02% MMC were applied on the exposed corneal stroma for 60 and 120 seconds, respectively. Similarly, eyes in groups 3 and 4 underwent PRK to correct -10 D in a 6-mm optical zone, while sponges soaked with 0.02% MMC were applied on the exposed corneal stroma for 60 and 120 seconds, respectively. Aqueous humor was extracted from all rabbit eyes 10 minutes after MMC application and high-performance liquid chromatography was performed immediately to detect and quantify MMC levels. RESULTS: The mean aqueous humor concentration of MMC was 0.23+/-0.03 microg/mL, 0.39+/-0.05 microg/mL, 0.28+/ 0.04 microg/mL, and 0.52+/-0.16 microg/mL in groups 1, 2, 3, and 4, respectively. The effect of application time and correction on aqueous humor MMC concentration was significant (p<0.0001 and p=0.019), while the exposure time had a greater impact on aqueous humor MMC concentration when compared with the attempted correction. CONCLUSIONS: Both exposure time of MMC on the corneal stroma and the attempted correction was correlated with MMC aqueous humor concentrations. PMID- 19787592 TI - Customizing the Amadeus II microkeratome: evaluation of cut quality with various settings using electron microscopy. AB - PURPOSE: To evaluate the cut quality of keratectomy specimens created with the new Amadeus II microkeratome (SIS, Ziemer Ophthalmic, Port, Switzerland) using scanning electron microscopy (SEM). Methods. Corneal cuts were performed in 24 freshly enucleated porcine eyes using the Amadeus II microkeratome with combinations of cutting-head depth, oscillation rate, head-advance speed, and reuse of the blade. For the cutting trials, a 140-microm and 160-microm cutting head with three oscillation rates of 8,000, 10,000, and 13,000 rpm and two head advance speed rates of 1.5 and 3.5 mm/s were chosen. In each setting, the blade was reused for a second time. All eyes were included, resulting in 4 groups with 6 eyes for each configuration. The surface and edge of the corneal cut was examined using SEM. RESULTS: At fixed oscillation rates, an increase in head advance speed led to lower quality cuts, higher surface roughness, and irregular cut edges for both cutting heads (140 microm/160 microm), especially when using the blade for a second time. At fixed head-advance speeds an increase in oscillation rates improved the cut quality for both cutting heads (140 microm/160 microm). This results in smoother surface characteristics and more regular cut edges, especially when using the blade for the first time. CONCLUSIONS: Using the Amadeus II microkeratome for laser in situ keratomileusis procedures, the optimum oscillation rate, the optimum head-advance speed, and a single use of the blade will produce a very smooth and regular surface and cut edge for safe, comfortable, and improved customized refractive surgery. PMID- 19787593 TI - Refractive and visual results after implantation of the AcrySof ReSTOR IOL in high and low hyperopic eyes. AB - PURPOSE: To assess the differences in refractive and visual results obtained in eyes with high and low hyperopia after implantation of a multifocal intraocular lens (IOL). METHODS: A prospective study was performed on 172 hyperopic eyes implanted with the AcrySof Re-STOR Natural (SN60D3) IOL. Two groups were created, high and low hyperopes (86 eyes in both cases). We analyzed monocular visual acuity for distance and near, with and without distance correction. Photopic and mesopic contrast sensitivity (CS) were also assessed. All measurements were performed at 6 months after surgery. RESULTS: Monocular best distance-corrected visual acuity was 0.01+/-0.03 logMAR for low hyperopes and 0.04+/-0.10 logMAR for high hyperopes. Monocular best distance-corrected near visual acuity was 0.02+/ 0.04 and 0.05+/-0.06 logMAR for low and high hyperopes, respectively. CS for high hyperopic eyes under photopic conditions was lower, primarily at high spatial frequencies, in relation to low hyperopic eyes. Differences between both groups were statistically significant for all spatial frequencies (p<0.004). At the mesopic level, high hyperopic eyes showed lower values compared to low hyperopic eyes for all spatial frequencies. However, these differences were only statistically significant for 1.5, 12, and 18 cpd (p<0.002). CONCLUSIONS: The visual acuity and CS for both distance and near, with and without distance correction, were statistically better in eyes with low hyperopia compared to those obtained in eyes with high levels of hyperopia. PMID- 19787594 TI - Long-term visual function outcomes of congenital cataract surgery with intraocular lens implantation in children under 5 years of age. AB - PURPOSE: To evaluate the long-term visual function outcomes of intraocular lens (IOL) implantation after congenital cataract surgery in children. METHODS: Forty children who had congenital cataract surgery with IOL implantation and at least 5 years follow-up and were 5 years or younger at the time of surgery were included. There were 18 children in the bilateral cataract group (36 pseudophakic eyes) and 22 children in the unilateral cataract group (22 pseudophakic eyes). The examination for the prospective part of this study included the recording of visual acuity, refraction, stereopsis, and intraocular pressures; preoperative, intraoperative, and postoperative details were obtained from the notes. RESULTS: Mean final best-corrected visual acuity for the bilateral group was 0.57 logMAR (range 0.18 -1.06) and for the unilateral group 0.91 logMAR (range 0.18 -1.40). Nystagmus was recorded in 10 children (56%) of the bilateral group and 5 children (23%) of the unilateral group. Strabismus was recorded in 14 children (78%) of the bilateral group and 19 children (86%) of the unilateral group. Glaucoma was diagnosed in one child. There was a significant myopic shift in the unilateral group. CONCLUSIONS: Reasonably good postoperative visual acuity was achieved in the bilateral cataracts group, but relatively poor acuity in the unilateral cataract group. Poor stereopsis was recorded in both groups. One child developed glaucoma. None of the children developed retinal detachment. The expected myopic shift in the unilateral group compared with the bilateral group was demonstrated. Elective primary capsulotomy and elective anterior vitrectomy are mandatory to keep a clear visual axis. PMID- 19787595 TI - Evolution of visual performance in 250 eyes implanted with the Tecnis ZM900 multifocal IOL. AB - PURPOSE: To evaluate visual performance in relation to time after implantation of the multifocal Tecnis intraocular lens (IOL) in patients with cataract. METHODS: This prospective case series involved 250 eyes of 137 patients with cataract aged 68.5+/-9.9 years. Monocular uncorrected and corrected near visual acuity (NVA and DCNVA) and distance visual acuity (UCVA and BCVA), occurrence of visual symptoms, and patient satisfaction were evaluated at 1-3 days, 30-90 days, and 150-210 days after surgery. Posterior capsule opacification and contrast sensitivity under photopic conditions were also assessed. RESULTS: At the last follow-up visit, mean NVA and DCNVA was 0.215+/-0.082 and 0.189+/-0.045 logMAR, respectively. The majority of eyes (96.8%) could read J2 without correction, including 83.2% reading J1. With best distance correction, 95.6% of eyes were able to read J1. Mean UCVA and BCVA was 0.144+/-0.101 and 0.09+/-0.03 logMAR, including 77.6% and 98.4% of eyes that achieved 20/30 or better, respectively. The majority of patients (>90%) ranked their near, distance, and global vision as good or excellent and 88.4% were free from spectacles. A significant improvement of uncorrected and corrected distance and near VA as well as a decrease in the intensity of subjective photic phenomena was observed over time. At the last follow-up visit, the rate of posterior capsule opacification (grade 1) was 4.4% and mean monocular contrast sensitivity was 1.44+/-0.26. CONCLUSIONS: The multifocal Tecnis IOL provides excellent near vision and good distance vision in patients with cataract. However, most patients required a neuroadaptation period of approximately 6 months to experience full visual benefits of the lens. PMID- 19787596 TI - Meta-analysis of articles evaluating routine intraocular pressure control in monotherapy in the United States and Germany. AB - PURPOSE: To evaluate routine intraocular pressure (IOP) control in monotherapy patients in the United States and Germany. METHODS: Meta-analysis of published articles. We included articles that were prospective studies of ocular hypotensive therapies that measured an unaltered (visit 1) IOP on monotherapy before enrolling into a clinical trial. RESULTS: This meta-analysis included 5 studies with 7913 patients, of whom 3245 were from the United States (n=1) and 4668 were from Germany (n=4). In the United States, 2939 patients (91%), and in Germany, 4059 patients (87%), had glaucoma (p<0.0001). Of these, all the US patients (100%) and 2694 (58%) of those from Germany were treated with monotherapy. The mean IOP with individual monotherapies in the United States was 19.6+/-2.2 and in Germany 20.8+/-0.8 mmHg (p=0.015). Among individual classes of medicine, patients treated with a prostaglandin demonstrated equal pressures (18.8 mmHg, p=0.60) in both countries, whereas the United States showed a lower pressure (20.2 mmHg) than Germany (21.2 mmHg, p=0.0019) with beta blockers. US physicians less often indicated that IOP was adequately controlled (n=1035, 32%) than in Germany (n=2030 of all patients, 44%, p<0.0001). CONCLUSIONS: This study suggests that patients treated by individual monotherapies in the United States demonstrate a lower pressure, but generally are more often considered uncontrolled, than those in Germany. This finding, if true, indicates a possible variance in treatment goals, or access to treatment, between the United States and Germany in treating patients with elevated pressure. PMID- 19787597 TI - Novel 3D computer-automated threshold Amsler grid visual field testing of scotomas in patients with glaucoma. AB - PURPOSE: Three-dimensional (3D) computer-automated threshold Amsler grid testing was used to identify and characterize scotomas typical of glaucoma. METHODS: The 3D test exhibits a grid on a computer screen at a preselected grayscale and angular resolution, and allows patients to trace those areas on the grid that are missing in their visual field using a touch screen. Eleven eyes in patients with an established diagnosis of glaucoma were examined according to the above protocol. A total of 23 eyes from normal subjects were used as controls. The 5 minute test required that patients repeatedly outline scotomas on a touch screen with varied displays of contrast while maintaining their gaze on a central fixation marker. A 3D depiction of the visual field defects was then obtained that was further characterized by the location, shape, extent, depth, and slope of the scotomas. RESULTS: In this pilot study, the 3D depiction of visual field loss demonstrated paracentral, superior and inferior altitudinal, and nasal step defects consistent with glaucomatous damage. The 3D depiction showed a shape, extent, depth, and slope that are consistent with the severity of damage. CONCLUSIONS: The 3D test identified and characterized scotomas typical of glaucoma. The test provides several advantages over conventional perimetry including additional information through 3D depiction of scotomas with the addition of contrast sensitivity and a higher angular/spatial resolution. Improved patient compliance and reliability through shorter testing time and potential interactive accessibility and distribution over the Internet further characterize the test. PMID- 19787598 TI - Comparison of ICare, dynamic contour tonometer, and ocular response analyzer with Goldmann applanation tonometer in patients with glaucoma. AB - PURPOSE: To compare the intraocular pressure (IOP) readings taken by ICare, Pascal dynamic contour tonometer (DCT), and ocular response analyzer (ORA) with those taken by Goldmann applanation tonometer (GAT). We sought to evaluate the influence of central corneal thickness (CCT) on IOP measurements and to compare patients' preferences for the four tonometers. METHODS: In this prospective study, 93 eyes from 93 patients were examined. Patients were randomly divided into 4 groups to vary the order in which the tonometers were applied. CCT was measured with an ultrasound pachymeter. RESULTS: The average CCT was 558+/-47.4 microm. The mean +/- standard deviation IOP for GAT, ICare, DCT, and ORA (Goldmann-correlated IOP) (ORA(GC)) were 15.1+/-4.8, 15.7+/-5.7, 18.2+/-5.1, and 18.3+/-6.6 mmHg, respectively. There was no significant difference between the mean IOP obtained with GAT and ICare (p=0.14). There was also no difference in IOP levels between the mean IOP obtained with DCT and ORA (p=0.26). There was no correlation between IOP measurements and CCT for the 4 instruments. Bland-Altman graphs showed disagreement between the measurements taken by GAT and the other instruments. There was no significant difference in patients' preference among the 4 instruments (p=0.48). CONCLUSIONS: IOP readings from ICare were consistent with those from GAT, whereas DCT readings correspond well to ORA(GC) measurements. DCT and ORA readings both overestimated the GAT readings. There was no correlation between the IOP measurements and the CCT for the 4 instruments. There was no significant difference in patients' preference among the 4 instruments. PMID- 19787599 TI - Visual function, optic nerve structure, and ocular blood flow parameters after 1 year of glaucoma treatment with fixed combinations. AB - PURPOSE: To compare the effects of latanoprost/timolol (LTFC) versus dorzolamide/timolol (DTFC) fixed combinations on intraocular pressure (IOP), visual function, and retrobulbar blood flow in patients with open-angle glaucoma (OAG). METHODS: This was a prospective, randomized, double masked, parallel study on 30 patients with OAG. All patients received 4 weeks of timolol treatment prior to randomization to LTFC or DTFC treatment. Measurements after randomization were taken at 1, 6, and 12 months, including arterial blood pressure; IOP; color Doppler imaging of the ophthalmic artery (OA), central retinal artery, and short posterior ciliary artery (SPCA); scanning laser polarimetry; Humphrey visual field examination; and adverse events. RESULTS: IOP decreased by 5.0 mmHg in the DTFC cohort (p<0.000) and 5.44 mmHg in the LTFC cohort (p=0.0001) after 12 months of treatment. No statistically significant differences in visual field or nerve fiber layer thickness were observed between the treatment groups during 12 months of therapy. Mean increase over 1 year of treatment in ocular perfusion and diastolic perfusion pressures were 10.46% and 10.67% in the DTFC group and 7.47% and 5.61% in the LTFC group, respectively. OA resistive index (RI) and SPCA RI were significantly different at the 12 months visit between the two treatment groups (p=0.05 and p=0.000, respectively): DTFC treatment showed decrease in the RI. CONCLUSIONS: One year of treatment with LTFC or DTFC resulted in similar IOP lowering effects as well as stable visual function and structure. The DTFC group showed lower vascular resistance in retrobulbar vessels compared to the LTFC group. PMID- 19787600 TI - Diurnal variation of corneal biomechanics and intraocular pressure in normal subjects. AB - PURPOSE: To assess and investigate the relationship between diurnal variations in intraocular pressure (IOP) and biomechanical properties of cornea. METHODS: Sixty two healthy volunteers were recruited. Corneal compensated IOP (IOPcc), Goldmann correlated IOP (IOPg), corneal resistance factor (CRF), and corneal hysteresis (CH) parameters were recorded by the Ocular Response Analyzer (ORA). Central corneal thickness (CCT) was measured using an ultrasonic pachymeter. Three consecutive measurements of IOPcc, IOPg, CRF, CH, and CCT were recorded at 8:00 am, 11:00 am, 2:00 pm, and 5:00 pm. One-way analysis of variance and Pearson correlation tests were used for statistical analysis. Intra device repeatability was evaluated using Scheffe multiple comparison. RESULTS: IOPcc, IOPg, CRF, CH, and CCT measurements displayed a stable profile during daytime acquisitions and no statistically significant variation was noted (p>0.05). All measurements of IOPcc, IOPg, CRF, and CH recorded by ORA at 8:00 am, 11:00 am, 2:00 pm, and 5:00 pm were all found to be highly repeatable (p>0.05). There was a statistically significant and inverse correlation between IOPcc and CH (p=0.001), and a positive correlation was detected between IOPcc and CRF (p=0.001). CRF and CH were both found to be positively correlated to CCT (p=0.001). CONCLUSIONS: IOPcc readings and recordings of corneal biomechanics were constant throughout the day in healthy eyes. CRF and CH seem to exert different effects on IOPcc as diverse correlations were detected between CRF, CH, and IOPcc. Assessment of IOP and corneal biomechanics using ORA was found to be a highly repeatable. PMID- 19787601 TI - Incidence, clinical features, causative organisms, and visual outcomes of delayed onset pseudophakic endophthalmitis. AB - PURPOSE: To report the incidence, clinical features, causative organisms, and visual outcomes associated with delayed-onset pseudophakic endophthalmitis. METHODS: We retrospectively reviewed the clinical records and microbiology files of all patients with culture-proven endophthalmitis that was present 6 weeks or more after cataract extraction and posterior chamber intraocular lens (IOL) implantation who were treated at King Khaled Eye Specialist Hospital (KKESH) during a 10-year period. RESULTS: From January 1997 through December 2006, 17 patients with culture-proven, delayed-onset pseudophakic endophthalmitis were treated at KKESH. Of the 17 cases, only 5 cases developed delayed-onset endophthalmitis, among 29,509 cataract surgeries performed at KKESH, indicating an incidence rate of 0.017% (5/29,509). The mean time between cataract surgery and diagnosis of endophthalmitis was 5+/-2.48 months. The culture isolates revealed Propionibacterium acnes in 7 (41.2%) eyes, polymicrobial (mixed) infections in 3 (17.6%) eyes, Staphylococcus species in 3 (17.6 %) eyes, fungal infections in 3 (17.6%) eyes, and Alcaligenes xylosoxidans in 1 (5.9%) eye. The mean follow-up period was 29.8 months. The final visual outcomes were as follows: 7 eyes (41.2%) achieved a final best-corrected visual acuity of >or=20/60; 6 eyes (35.3%) achieved a best-corrected visual acuity of <20/60 to >or= count fingers; 2 eyes (11.8%) had hand motion to light perception vision; and 2 eyes (11.8%) were enucleated. CONCLUSIONS: In this study, infection by P acnes was the most common cause of delayed-onset pseudophakic endophthalmitis and had the most favorable visual outcome, whereas fungal endophthalmitis had the worst visual prognosis. PMID- 19787602 TI - Diagnostic utility of polymerase chain reaction on intraocular specimens to establish the etiology of infectious endophthalmitis. AB - PURPOSE: To evaluate the utility of polymerase chain reaction (PCR) on intraocular clinical specimens (aqueous humor [AH] and vitreous fluid [VF]) as an etiologic diagnostic tool relative to microbiological culture methods in infectious endophthalmitis. METHODS: Conventional bacterial and mycologic cultures and PCR for eubacterial and panfungal genomes were applied for etiologic diagnosis on pairs of AH and VF obtained from 72 patients with clinically established infectious endophthalmitis. RESULTS: Based on cultures, an infectious etiology was established in 27 (37.5%) of 72 patients. PCR detected infectious etiology in all 72 patients. PCR increased the clinical sensitivity over culture by 62.5% (p<0.0001, McNemar test). The frequency of culture positivity, single infections, and polymicrobial infection varied significantly among the types of endophthalmitis (p<0.0001, chi-square test). PCR detected an infectious etiology in 48 patients and polymicrobial infection in 24 patients. An etiology was established by PCR on 56 (77.8%) AH and 65 (90.3%) VF of the 72 patients and this difference had no statistical significance. CONCLUSIONS: PCR on intraocular specimens as an etiologic diagnostic tool has been shown to be specific and severalfold more sensitive than cultures and clinically useful. Therefore, PCR may be considered the gold standard to establish the etiology of infectious endophthalmitis. As there is no statistically significant difference in the results of PCR on AH and VF, PCR on AH could be the method of choice considering safety and simplicity of the procedure of its collection. PMID- 19787603 TI - Intravitreal infliximab in experimental endotoxin-induced uveitis. AB - PURPOSE: Tumor necrosis factor-alpha (TNF-alpha) plays a central role in the pathogenesis of ocular inflammation and the level of TNF-alpha is increased in ocular fluids of patients with uveitis. Intravenous infliximab, a monoclonal antibody against TNF-alpha, has been used for the treatment of uveitis with promising preliminary results. The aim of this study was to evaluate the effect of intravitreal injection of infliximab on experimental uveitis. METHODS: Thirty three white New Zealand rabbits were divided randomly into three groups. Group 1 (n=5) received intravitreal injection of 1 mg/0.1 cc infliximab plus 0.1 cc normal saline, group 2 (n=14) received intravitreal injection of 2 microg Salmonella typhimurium endotoxin plus 1 mg/0.1 cc infliximab, and group 3 (n=14) animals received intravitreal endotoxin 2 microg/0.1 cc plus normal saline 0.1 cc. Inflammation was evaluated by clinical examinations on days 1, 3, 5, and 7 after the injections; measuring the protein concentration and inflammatory cell content of the aqueous humor; and histopathologic examination. RESULTS: No inflammation occurred in group 1 animals. There was a statistically significant difference between group 2 and 3 animals with regard to clinical examination on the third, fifth, and seventh postinjection days. The differences between groups 2 and 3 were significant with regard to aqueous cell counts and protein content at day 7 (p=0.02 and p=0.001, respectively). Histopathologic examination results showed less inflammation in group 2 animals compared to group 3 animals (p=0.009). CONCLUSIONS: The results provide evidence that intravitreal injection of infliximab suppresses ocular inflammation in a rabbit model of severe endotoxin-induced uveitis. PMID- 19787604 TI - Toxoplasmic retinochoroiditis in an Italian referral center. AB - PURPOSE: To evaluate the clinical features of ocular toxoplasmosis (OT). METHODS: Retrospective review of 3080 new patients with uveitis was performed to identify patients with active OT. The main outcome measures were ocular features and ocular complications. RESULTS: Active OT was diagnosed in 88 patients (2.85% of all uveitis), 39 male (44.3%) and 49 female (55.7%), at an average age of 20.4+/ 14.6 years, lower than in other types of uveitis (p<0.0001). Acquired OT diagnosis was possible in 4 cases (4.5%), while in the others a differentiation between acquired or congenital OT was impossible. Unilateral OT occurred in 76 patients (86.36%), with lesions located inside the vascular arcade in 64 of them (84.2%). Among bilateral cases (12 patients, 13.63%), at least one lesion was central in 9 (75%). Isolated peripheral lesions were observed in 12 out of 88 patients (13.6%). During an average follow-up of 70+/-73.5 months, OT recurrences appeared in 70 patients (79.54%). Mean interval between diagnosis and first relapse was 43.57+/-48.46 months, while it shortened between subsequent relapses (24.44+/-26.5 months; p=0.001). CONCLUSIONS: Ocular toxoplasmosis is a highly recurrent disease, mainly unilateral, with an average age at onset lower than those observed in other types of uveitis. Time between relapses shortens significantly over time. PMID- 19787605 TI - Optical coherence tomography in neovascular age related macular degeneration compared to fluorescein angiography and visual acuity. AB - PURPOSE: To assess the sensitivity and specificity of optical coherence tomography (OCT) for monitoring patients with choroidal neovascularization (CNV) after photodynamic therapy (PDT) in comparison to fluorescein angiography (FA). METHODS: Prospective study of 14 patients with CNV secondary to age-related macular degeneration receiving PDT. Best-corrected visual acuity (BCVA), fluorescein angiography, and OCT (Zeiss Stratus OCT3) were performed before and at 2, 6, 12, and 24 weeks after treatment. FA images were assessed for leakage and presence of subretinal or intraretinal fluid was assessed on OCT images. Retinal thickness was measured automatically. OCT sensitivity and specificity levels for detecting leaking CNV were calculated. Retinal thickness was correlated with visual acuity. RESULTS: Mean follow-up time was 14.1 weeks. Sixty one OCT/FA examinations were analyzed. Thirty-one examinations presented leakage (51%). OCT showed intraretinal fluid in 46 (75%) and subretinal fluid in 30 cases (49%). In 49 cases (80%), either intraretinal or subretinal fluid was present. Sensitivity for detecting intraretinal fluid in OCT was 90% (specificity 40%) and 71% (specificity 73%) for subretinal fluid. Combined sensitivity for intraretinal or subretinal fluid was 97% (specificity 37%). Increased central foveal thickness correlated with decreased BCVA. Correlations were significant (p<0.05). CONCLUSIONS: OCT showed good sensitivity in detecting active CNV. Specificity was only moderate. Central foveal thickness correlated negatively with visual acuity. Owing to different aspects of active CNV shown by FA and OCT, OCT should be combined with other examinations, and may not substitute FA for indication/reindication of PDT but can be a valuable addition in difficult cases. PMID- 19787606 TI - Macular pigment optical density relates to foveal thickness. AB - PURPOSE: Macular pigment is composed of 2 dietary carotenoids, lutein and zeaxanthin, and is mainly present at the nerve fiber layers and ganglion cell layers of the retina, with peak concentrations in the fovea. It is thought to function as a blue-light filter and antioxidant, and therefore protect the retina from damaging influences that are thought to play a role in the pathogenesis of age-related macular degeneration. This study was performed to investigate the suggested positive relationship between foveal macular pigment optical density (MPOD) and foveal retinal thickness. METHODS: We determined MPOD and foveal thickness in the right eyes of 40 healthy Caucasian subjects (5 men, 35 women) recruited at the University of Maastricht, The Netherlands. Their mean age was 24.4+/-8.7 years. MPOD was determined by using a novel method of heterochromatic flicker photometry (HFP), where subjects have to detect flicker instead of conventionally minimizing a present flicker motion. Foveal thickness parameters were obtained using optical coherence tomography (OCT 3). RESULTS: We found a positively significant correlation between MPOD and central foveal thickness (r=0.359, p=0.027). In addition, we found a negatively significant correlation between foveal thickness and foveal width (r= -0.558, p<0.001). CONCLUSIONS: Our data confirm the previously suggested positively significant correlation between MPOD and central foveal thickness. The observed negative relationship between foveal thickness and foveal width may be explained by eccentric scans on the OCT. PMID- 19787607 TI - Anti-vascular endothelial growth factor activity in the bevacizumab and triamcinolone acetonide combination for intravitreal use. AB - PURPOSE: To find out if the combination for intravitreal use of the antibody bevacizumab (AvastinTM; Genentech, Inc., San Francisco, CA) and triamcinolone acetonide (TA) (Kenacort; Bristol-Myers Squibb, Anagni, Italy) could affect over time the anti -vascular endothelial growth factor (VEGF) activity of bevacizumab. METHODS: Two different combined preparations were obtained, drawing up together 1.25 mg/0.05 mL of bevacizumab and 2 mg/0.05 mL (B+TA(2mg)) or 4 mg/0.05 mL (B+TA(4mg)) of TA into insulin syringes with 29-G needle. Control preparations were obtained with bevacizumab and an injectable solution (B). The syringes were stored refrigerated at 4 degrees C. The bevacizumab concentration was measured, through its binding to VEGF-165 isoform, at 48 hours and at 1 week. RESULTS: No preparations showed statistically significant changes in bevacizumab concentration with time (p=0.74 for B+T(2mg), p=0.92 for B+T(4mg), p=0.57 for B). The B+TA(2mg) preparations showed a larger percentage of degradation of bevacizumab than the B+TA(4mg) preparations (28.4% versus 17.6% at 48 hours; 26.4% versus 18% at 1 week). The B control preparations showed the lowest drug degradation: 9.6% at 48 hours and 14.8% at 1 week. CONCLUSIONS: After storage at 4 degrees C for 48 hours and 1 week, the combined preparations showed a larger reduction in bevacizumab concentration than the control preparations. No significant change was observed with the length of storage. The preparations obtained mixing 4 mg/0.05 mL of TA and 1.25 mg/0.05 mL of bevacizumab maintained the highest anti-VEGF activity over time. PMID- 19787608 TI - Intravitreal injection of bevacizumab before vitrectomy for proliferative diabetic retinopathy. AB - PURPOSE: To evaluate the use of preoperative intravitreal bevacizumab (IVB) injection in patients undergoing pars plana vitrectomy for complications of proliferative diabetic retinopathy (PDR). METHODS: In this prospective surgeon masked randomized clinical trial, 40 eyes of 40 diabetic patients who were candidates for vitrectomy were randomly assigned to receive 2.5 mg IVB 3-5 days before operation (injected group) or no injection before operation (noninjected group). A preoperative complexity score (CS) was recorded. Best-corrected visual acuity, number of endodiathermy applications, backflush needle applications, duration of surgery, and postoperative vitreous hemorrhage were recorded. RESULTS: Twenty-two patients with a CS of 6+/-0.95 in the injected group and 18 patients with a CS of 5.7+/-1.1 in the noninjected group (p=0.3) were studied. Postoperative visual acuities were significantly better than preoperative visual acuities. Preoperative and 3-month postoperative visual acuities were the same for both groups; however, in the last follow-up examinations (mean 7+/- 3.6 months) the injected group had better visual acuities than the noninjected group (1.1+/-0.4 and 1.4+/-0.3 logMAR, respectively, p=0.006). Mean surgical time was 62+/-57.3 minutes in the injected group vs 95.5+/-36 minutes in the noninjected group (p=0.03): endodiathermy applications 6.0+/-4.3 vs 11.0+/-5.8 (p=0.004), backflush cannula applications 11.0+/-7.2 vs 18.1+/-7.8 (p=0.004). In non silicone-filled eyes, no patient in the injected group developed significant postoperative vitreous hemorrhage obscuring the fundus details, while 7 eyes of noninjected eyes had this complication (p=0.01). CONCLUSIONS: IVB injection before vitrectomy for PDR facilitates the surgery, and may decrease the rate of postoperative vitreous hemorrhage and improve the visual acuity results of the operation. PMID- 19787609 TI - 25-Gauge sutureless vitrectomy with oblique sclerotomies for the management of retinal detachment in pseudophakic and phakic eyes. AB - PURPOSE: To evaluate the anatomic and functional outcomes of 25-gauge sutureless vitrectomy in primary treatment of noncomplex retinal detachments (RD) in pseudophakic and phakic eyes. METHODS: In this interventional clinical case series, 23 pseudophakic and 13 phakic eyes with total RDs with proliferative vitreoretinopathy grade A/B underwent primary 25-gauge sutureless vitrectomy with oblique sclerotomies and gas endotamponade. Eyes with minimum follow-up of 6 months were evaluated. Main outcome measures were single surgery and final reattachment rates, complications, and changes in visual acuity (VA). RESULTS: Mean duration of visual loss was 14.65+/-12.57 and 22.46+/-18.95 days in pseudophakic and phakic eyes, respectively. Eighteen (78.26%) pseudophakic eyes and 12 (92.30%) phakic eyes had macular detachment. In all eyes, 25-gauge sutureless vitrectomy was completed without complication. Mean follow-up period was 11.00+/-6.63 months. Single surgery and final retinal attachment rates were 91.30% and 95.65% in pseudophakic eyes and 61.53% and 84.61% in phakic eyes, respectively (p=0.073, p=0.539). In both groups, mean VA increased significantly at postoperative month 1 (p<0.05) and at the last visit (p<0.001). Transient hypotony was detected in 2 pseudophakic and 3 phakic eyes with spontaneous resolution. Two (15.38%) phakic eyes had cataractous changes. CONCLUSIONS: In this study, 25-gauge sutureless vitrectomy resulted in higher single surgery and final anatomic success rates in primary treatment of noncomplex RDs in pseudophakic versus phakic eyes, with commensurate increase in VA. PMID- 19787610 TI - Determining size and characteristics of metal intraocular foreign bodies using helical CT scan. AB - PURPOSE: To carry out a pilot study comparing the size of various types of metallic intraocular foreign bodies as imaged on computed tomographic (CT) scan to their actual size, and to determine the features of different types of metals on CT scan. METHODS: Metallic foreign bodies of predetermined standardized sizes were prepared from iron, silver, copper, aluminium, and lead. The metallic pieces/shards were each inserted into the vitreous of a cow's eye and helical CT scan (MX twin, Picker) was performed to image the intraocular foreign bodies, using soft tissue and bone window settings. Slice section thickness was 1.3 mm, with intervals of 0.6 mm. Milliampere per second was 265 and pitch 0.7. RESULTS: The size of all types of metals as measured on CT was larger than the actual size. Iron was enlarged by a factor of 2.29, silver 1.77, copper 1.26, and aluminum 1.17. All metals had features including central core, ring density, and artifacts which varied for each type of metal, giving each one a characteristic appearance CONCLUSIONS: Helical CT scan could be useful in estimating the type and size of an intraocular metal foreign body made from iron, silver, copper, aluminium, or lead. PMID- 19787611 TI - A rare case of peripheral ulcerative keratitis in temporal arteritis. AB - PURPOSE: To present a case of peripheral ulcerative keratitis (PUK) that progressed to corneal perforation in the setting of recently diagnosed temporal arteritis. METHODS: A 76-year-old man presented with a 2-week history of red eye and gradual loss of vision in the right eye. His medical history included recently diagnosed temporal arteritis without previous eye involvement. Clinical examination revealed severe peripheral corneal melting leading to corneal perforation. RESULTS: The patient was treated in the acute phase with topical dexamethasone drops and oral prednisolone. Perforation was sealed with cyanoacrylate glue. Azathioprine was also administered. Inflammation was resolved and his eye remains quiet. CONCLUSIONS: To our knowledge, this is the first reported case of PUK in the background of temporal arteritis. PMID- 19787612 TI - Topical bevacizumab for corneal neovascularization after penetrating keratoplasty. AB - PURPOSE: To evaluate the efficacy of topical bevacizumab for corneal neovascularization in graft rejection. METHODS: A 55-year-old man presented with corneal neovascularization and graft rejection 6 months following penetrating keratoplasty (triple procedure) in the left eye. His best-corrected visual acuity (BCVA) was counting fingers at 1 meter. He was administered topical bevacizumab (4 mg/4 mL) in a dose of one drop twice a day for 15 days. No adjunct therapy was given during bevacizumab administration. RESULTS: After 1 month, his BCVA improved to 20/120. Corneal vascularization and stromal haze regressed. After 6 months, his BCVA improved to 20/60 with further regression in corneal vascularization and stromal haze. At 9-month follow-up, he maintained BCVA of 20/60. CONCLUSIONS: Short-term topical bevacizumab therapy may potentially offer a safer and more effective alternative in treating graft rejection after penetrating keratoplasty. PMID- 19787613 TI - Refractive astigmatism in eyes with pseudoexfoliation syndrome. AB - PURPOSE: To determine the effect of pseudoexfoliation syndrome on ocular refractive astigmatism. METHODS: One hundred eyes of 100 patients with pseudoexfoliation syndrome and 100 eyes of 100 age- and sex-matched control subjects were included in the study. Refractive astigmatism was measured prior to ocular examination performing cycloplegic autorefractive measures using an autorefractokeratometer (Charops, MRK3100). RESULTS: All patients in the study and control group had myopic astigmatism. Refractive and ocular residual astigmatism were found to be significantly higher in the pseudoexfoliation syndrome group in comparison to the control group (p<0.05). The mean keratometry reading was significantly steeper in the study group than in the control eyes. CONCLUSIONS: Significant refractive and ocular residual astigmatism were found in pseudoexfoliation syndrome. PMID- 19787614 TI - T-shaped pigmentary changes in tilted disk syndrome. AB - PURPOSE: Many complications associated with tilted disk syndrome may occur in the area bordering on the inferior staphyloma, including macular pigmentary changes, choroidal neovascularization, macular serous retinal detachment, polypoidal choroidal vascular anomalies, and radially orientated chorioretinal folds. The purpose of the present article is to describe an additional complication, T shaped pigmentary changes, orientated radially from the border of the inferior staphyloma, in eyes with tilted disk syndrome. METHODS: Retrospective series of 6 eyes of 6 patients (3 men and 3 women) aged from 35 to 67 years. All eyes were studied by fluorescein angiography. RESULTS: All 6 eyes exhibited pigmentary changes located along the border of the staphyloma, and also radially to it, giving a particular T-shaped pattern of pigmentary changes. These changes were visible as either a linear strip or a triangular or oval-shaped area. Three eyes had a documented history of subretinal leakage that mimicked central serous chorioretinopathy, a well-known complication of tilted disk syndrome. CONCLUSIONS: T-shaped pigmentary changes may develop in the course of tilted disk syndrome, and should be added to the list of this syndrome's possible retinal complications. These changes may indicate the presence of chronic leakage in the area around the superior border of the inferior staphyloma. PMID- 19787615 TI - An unusual case of cocaine-induced maculopathy. AB - PURPOSE: Cocaine is one of the most common substances of abuse. When used intranasally, cocaine is cut with a variety of agents, which may increase local and systemic toxic reactions. METHODS: We examined a 34-year-old man who complained of color disturbance. The patient reported a 10-year history of daily intranasal cocaine use, but denied use during the last year. Color vision testing showed a dysregulation of blue -yellow color vision. Electroretinogram revealed significantly reduced blue cone responses. Dilated fundus examination of both eyes revealed a bilateral maculopathy. Fluorescein angiography disclosed an early hyperfluorescence in both foveal areas which maintained in late phase. Optical coherence tomography was normal in both eyes. The patient was diagnosed with an unusual maculopathy related to a long-term intranasal cocaine use. RESULTS: All 6 eyes exhibited pigmentary changes located along the border of the staphyloma, and also radially to it, giving a particular T-shaped pattern of pigmentary changes. These changes were visible as either a linear strip or a triangular or oval shaped area. Three eyes had a documented history of subretinal leakage that mimicked central serous chorioretinopathy, a well-known complication of tilted disk syndrome. CONCLUSIONS: Ocular complications from topical cocaine abuse are rare. Impaired color vision, as in our patient, has been reported in cocaine withdrawn patients. To our knowledge, this is the first described case of a bilateral and symmetric maculopathy associated with long-term intranasal cocaine use. To avoid a delay of treatment, ophthalmologists should be aware that a maculopathy with small defects in color vision may be related to adulterants added to cocaine when it is used intranasally. PMID- 19787616 TI - Massive spontaneous choroidal hemorrhage in a patient with chronic renal failure and coronary artery disease treated with Plavix. AB - PURPOSE: To report a case of massive spontaneous choroidal hemorrhage in a patient with chronic renal failure and coronary artery disease treated with clopidogrel bisulfate (Plavix). METHODS: Case report. RESULTS: A 75-year-old man presented with pain and loss of vision in the left eye for 1 week. His medical history was remarkable for systemic hypertension, chronic renal failure, and artery coronary disease. For 6 months, he had been taking 75 mg/day of Plavix after coronary angioplasty. Ocular examination revealed the patient to be in angle closure. Ultrasonography and computed tomography scan revealed a massive choroidal hemorrhage pushing the iris-lens diaphragm forward. Pain and intraocular pressure were treated successfully with evacuative sclerotomies, but the final exitus after 6 months was bulbar phthisis. CONCLUSIONS: Massive spontaneous choroidal hemorrhage is an extremely rare event that usually has been described in older patients (65-87 years old) receiving anticoagulants or thrombolytic agents. Systemic hypertension, generalized atherosclerosis, and age related macular degeneration are additional risk factors. In the present case, massive choroidal hemorrhage was associated with use of clopidogrel bisulfate (Plavix) in a patient with chronic renal failure. Our report indicates that Plavix should be administered with caution in patients with chronic renal failure owing to the risk of serious choroidal bleeding. Chronic renal failure should be also included in the list of risk factors for massive spontaneous choroidal hemorrhage. Evacuative sclerotomies may have value in the relief of pain and elevated intraocular pressure but has not been shown to be beneficial in visual and anatomic outcomes. PMID- 19787617 TI - Treatment of serous pigment epithelium detachment with subthreshold micropulse diode laser photocoagulation: a case report. AB - PURPOSE: To propose a possible treatment for symptomatic serous pigment epithelium detachment (SPED) in the setting of dry age-related macular degeneration. METHODS: A 60-year-old woman presented with a SPED, subfoveal in location, enlarging in size and with gradually worsening vision over 1 year of follow-up, without any evidence of choroidal neovascular membrane or neurosensory detachment until it was treated with subthreshold micropulse laser. RESULTS: The last follow-up showed complete resolution of the SPED with restoration of visual function. CONCLUSIONS: Subthreshold micropulse laser could serve as a useful therapeutic modality for the treatment of symptomatic SPED. PMID- 19787618 TI - Foveal geographic atrophy following intravitreal pegaptanib sodium (Macugen) for drusenoid pigment epithelium detachment. AB - PURPOSE: To describe a patient with nonexudative age-related macular degeneration (AMD) who underwent intravitreal pegaptanib sodium injection for drusenoid pigment epithelium detachment (PED). METHODS: A 66-year-old woman, who underwent intravitreal pegaptanib sodium injection in her right eye (RE) for chronic serous drusenoid PED, was submitted to a complete ophthalmologic examination, including fundus biomicroscopy, fluorescein angiography (FA), indocyanine green angiography (ICGA), and optical coherence tomography (OCT-3, Humphrey-Zeiss, San Leandro, CA), 3 days and 1 month after the treatment. RESULTS: Three days after the intravitreal pegaptanib sodium injection, best-corrected visual acuity (BCVA) was 20/32 in the RE. One month later, the patient's BCVA dropped to 20/200 in the RE. Interestingly, fundus biomicroscopy, FA, OCT, and ICGA revealed the development of foveal geographic atrophy. Fundus-related perimetry (MP-1 Micro Perimeter, Nidek Technologies, Padova, Italy) revealed an eccentric and unstable fixation within 2 degrees with central absolute scotoma and pericentral diffuse reduction of sensitivity. CONCLUSIONS: The rapid development of foveal geographic atrophy in our patient may be related to the antivascular endothelial growth factor treatment, in part because of the reduced neuroprotective effect, and in part because of the adjunctive decreased blood flow in an already imbalanced foveal choroidal circulation due to AMD complicated by chronic serous drusenoid PED. PMID- 19787619 TI - Vein of Galen aneurysmal malformation masquerading as carotid cavernous fistula in a child with proptosis. AB - PURPOSE: An infant with proptosis and dilated episcleral vessels was diagnosed with vein of Galen malformation, which is a rare condition presenting initially to an ophthalmologist. METHODS: An 8-month-old child presented with slowly progressive proptosis of the left eye of 5 months' duration. The proptosis was axial, nonpulsatile, with no associated bruit. Dilated corkscrew episcleral vessels were observed. The patient was referred to our center with diagnosis of carotid cavernous fistula. The child had a history of episodes of seizures. RESULTS: Contrast-enhanced computed tomographic scan of the patient showed dilated vessels, hydrocephalus, and dilated vein of Galen. Vein of Galen aneurysmal malformation was confirmed on magnetic resonance venography. CONCLUSIONS: Occasionally patients with Vein of Galen aneurysmal malformation may first present to the ophthalmologist. Ophthalmologists should therefore be aware of this rare but potentially treatable condition. PMID- 19787620 TI - Optic disc pit maculopathy treated with vitrectomy, internal limiting membrane peeling, and gas tamponade: A report of two cases. PMID- 19787622 TI - The Integrated Oncology Program of the Italian Ministry of Health. Analytical and clinical validation of new biomarkers for early diagnosis: network, resources, methodology, quality control, and data analysis. AB - In 2007, an Italian cancer research group proposed a specific concerted action aimed at the "analytical and clinica validation of new biomarkers for early diagnosis: Network, resources, methodology, quality control, and data analysis." The proposal united 37 national operative units involved in different biomarker studies and it created a strong coordinative body with the necessary expertise in methodologies, statistical analysis, quality control, and biological resources to perform ad hoc validation studies for new biomarkers of early cancer diagnosis. The action, financed by the Italian Ministry of Health within the Integrated Oncology Program (PIO) coordinated by NCI-Istituto Tumori Bari, started in 2007 and activated 7 projects, each of which focused on disease-specific biomarker studies. Overall, the 37 participating units proposed studies on 50 biomarkers, including analytical and clinical validation procedures. Clusters of units were specifically involved in research of early-detection biomarkers for cancers of the lung, digestive tract, prostate/bladder, and nervous system, as well as female cancers. Furthermore, a cluster involved in biomarkers for bioimaging and infection-related cancers was created. The first investigators' meeting, "Analytical and clinical validation of new biomarkers for early diagnosis," was held on 9 September 2008 in Bari. During this meeting, methodological aspects, scientific programs and preliminary results were presented and discussed. PMID- 19787623 TI - Detection of breast cancer by surface-enhanced laser desorption/ionization time of-flight mass spectrometry tissue and serum protein profiling. AB - AIM: Novel diagnostic breast cancer markers have been extensively searched for in the proteome, using, among others, surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS). Thus far, the majority of SELDI TOF MS studies have investigated samples originating from biorepositories, which hampers biomarker discovery as they likely suffer from variable adherence to collection protocols. MATERIAL AND METHODS: We investigated breast cancer (n=75) and control (n=26) serum and tissue samples, collected prospectively by rigorous adherence to a strictly defined protocol. Sera were collected preoperatively and postoperatively, and serum and tissue samples were analyzed by SELDI-TOF MS using the IMAC30 Ni and Q10 pH 8 array. RESULTS: Three serum peaks were significantly associated with breast cancer, while in tissue, 27 discriminative peaks were detected. Several peak clusters gradually increased or decreased in intensity from healthy to benign to cancer, or with increasing cancer stage. The constructed classification trees had a tenfold cross-validated performance of 67% to 87%. Two tissue peaks were identified as N-terminal albumin fragments. These are likely to have been generated by (breast) cancer-specific proteolytic activity in the tumor microenvironment. CONCLUSIONS: These albumin fragment scan potentially provide insights into the pathophysiological mechanisms associated with, or underlying, breast cancer, and aid in improving breast cancer diagnosis. PMID- 19787624 TI - Serum tumor necrosis factor-alpha and interleukin-2 concentrations in newly diagnosed ERBB2 (HER2/neu) positive breast cancer patients. AB - AIM: Cytokines have been associated with symptoms and adverse outcomes in breast cancer. Overexpression of ERBB2 (c-erb-b2; formerly HER2/neu), which is a member of the epidermal growth receptor family, is associated with involvement of lymph nodes, large tumor size, high grade, steroid receptor negativity, aneuploidy, high proliferation rate, and low overall survival in breast cancer. The aim of the study was to examine whether ERBB2 amplification has any effect on circulating levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-2 (IL-2) in breast cancer patients. MATERIAL AND METHODS: Fifty patients with primary breast carcinoma, classified as either ERBB2 (+) or (-) by the fluorescence in situ hybridization (FISH) technique, were included in the study. Cytokines were studied by ELISA according to the procedure described in the commercial kit. RESULTS: IL-2 levels were found significantly higher in ERBB2+ patients than in controls (p<0.05). A significant negative correlation existed between ERBB2 positivity and estrogen receptor status (p=0.004). Plasma TNF-alpha and IL-2 levels were positively correlated in ERBB2+ breast cancer patients (p<0.01). CONCLUSION: The increase in IL-2 concentrations observed in our study suggests an activation of T cells by ERBB2 peptides. PMID- 19787625 TI - Evaluation of cell-free DNA in urine as a marker for bladder cancer diagnosis. AB - The diagnosis and follow-up of bladder cancer are mainly based on cystoscopy, an invasive method which could be negative in case of flat malignancies such as carcinoma in situ. Other noninvasive diagnostic methods have not yet given satisfactory results. There is a need for a reliable yet noninvasive method for the detection of bladder cancer. Our aim was to investigate whether cell-free DNA quantified in urine (ucf-DNA) could be a useful marker for the diagnosis of bladder cancer. A standard urine test was performed in 150 naturally voided morning urine samples that were processed to obtain a quantitative evaluation of ucf-DNA. Leukocyturia and/or bacteriuria were found in 18 subjects, who were excluded from the study. Statistical analysis was performed on 45 bladder cancer patients and 87 healthy subjects. Ucf-DNA was extracted from urine samples by a spin column-based method and quantified using four different methods: GeneQuant Pro (Amersham Biosciences, Pittsburg, PA, USA), Quant-iT DNA high-sensitivity assay kit (Invitrogen, Carlsbad, CA, USA), Real-Time PCR (Applied Biosystems, Foster City, CA, USA), and NanoDrop 1000 (NanoDrop Technologies, Houston, TX, USA). Median free DNA quantification did not differ statistically between bladder cancer patients and healthy subjects. A receiver-operating characteristic (ROC) curve was developed to evaluate the diagnostic performance of ucf-DNA quantification for each method. The area under the ROC curve was 0.578 for GeneQuant Pro, 0.573 for the Quant-iT DNA high-sensitivity assay kit, 0.507 for Real-Time PCR, and 0.551 for NanoDrop 1000, which indicated that ucf-DNA quantification by these methods is not able to discriminate between the presence and absence of bladder cancer. No association was found between ucf-DNA quantification and tumor size or tumor focality. In conclusion, ucf-DNA isolated by a spin column-based method and quantified by GeneQuant Pro, Quant-iT DNA high sensitivity assay kit, Real-Time PCR or NanoDrop 1000 does not seem to be a reliable marker for the diagnosis of bladder cancer. PMID- 19787626 TI - Metalloproteinase-1, metalloproteinase-7, and p53 immunoexpression and their correlation with clinicopathological prognostic factors in colorectal adenocarcinoma. AB - AIM: The aim of this study was to analyze the immunoexpression of metalloproteinase-1, metalloproteinase-7, and p53 in colorectal adenocarcinoma, and to correlate this with clinicopathological prognostic factors. MATERIAL AND METHODS: Formalin-fixed paraffin-embedded tumor tissue from 82 patients was analyzed by means of immunohistochemistry, using the streptavidin-biotin method and the tissue microarray technique. Protein tissue expression was correlated with the variables of the degree of cell differentiation, stage, relapse-free survival, recurrence, survival, and specific mortality. RESULTS: All of the tumors were positive for metalloproteinase-1, while 50 (61%) were positive for metalloproteinase-7, and 32 (39%) were negative for the latter. For p53, 70 (85.4%) of the tumors were positive and 12 (14.6%) were negative. Correlation of the marker expressions separately and in conjunction did not produce any statistically significant data. CONCLUSION: The immunoexpression of metalloproteinase-1, metalloproteinase-7, and p53 did not correlate with recurrence, mortality, relapse-free survival, survival, degree of cell differentiation, or staging of colorectal cancer. PMID- 19787627 TI - The expression and significance of Dickkopf-1 in epithelial ovarian carcinoma. AB - The aim of this study was to investigate the presence and prognostic value of Dickkopf-1 (DKK1) in epithelia ovarian carcinoma. The expression of DKK1 was determined in 56 epithelial ovarian carcinoma tissues, 35 benign ovarian cystadenoma tissues, and 12 normal ovarian tissues by quantitative real-time PCR and immunohistochemistry. The DKK1 mRNA level in the carcinoma tissues was upregulated (5.5+/-2.7-fold increase) compared with that in the normal tissues (p<0.0001). The mRNA level of DKK1 in the cystadenoma tissues (1.1+/-0.4-fold increase) was not statistically different from that in the normal tissues (p=0.486). DKK1 protein expression in the carcinoma tissues was also higher (89.29%) than in cystadenoma (65.71%) and normal tissues (58.33%) (p=0.006 and p=0.009, respectively). In epithelial ovarian carcinoma, DKK1 gene and protein overexpression was associated with advanced FIGO stage (p=0.007, p=0.004) and poor differentiation grade (p=0.027, p=0.010). Elevated DKK1 protein levels in ovarian carcinoma samples were associated with a poor outcome in univariate and multivariate analysis (p<0.0001 and p<0.0001, respectively). The study indicated that DKK1 maymbe a useful prognostic and diagnostic indicator for epithelial ovarian carcinoma. PMID- 19787630 TI - Epigenetics in facioscapulohumeral muscular dystrophy (FSHD). PMID- 19787628 TI - Downregulation of ABCD1 in human renal cell carcinoma. AB - Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. Delayed diagnosis may result in progression and metastasis. Markers for early detection of RCC are lacking. The ATP-binding cassette transporter D1 (ABCD1) is located in the human peroxisome membrane. Its mutation causes X-linked adrenoleukodystrophy (X-ALD), a peroxisomal disorder affecting lipid storage. The role of ABCD1 in human renal tumorigenesis was unclear. In this study, three pairs of RCC tissues were examined by cDNA microarray and data suggested that ABCD1 mRNA is downregulated. Downregulation of ABCD1 expression was confirmed by real-time PCR. ABCD1 expression was also downregulated in four renal cancer cell lines compared to immortalized benign renal tubular cells. ABCD1 mRNA and protein expression levels assessed by immunohistochemistry in the RCC tissues were similar between genders, tumor grades, and tumor stages. Immunohistochemical assays also showed that ABCD1 expression was significantly higher in normal than in cancerous tissues (p<0.001). ABCD1 downregulation may be involved in human renal tumorigenesis. PMID- 19787632 TI - The c.-103T>C variant in the 5'-UTR of SLC26A4 gene: a pathogenic mutation or coincidental polymorphism? PMID- 19787634 TI - Post-stroke fatigue: qualitative study of three focus groups. AB - Fatigue affects many persons after cerebrovascular accident, particularly those with mild stroke. A qualitative methodology using focus groups with 19 community living post-stroke survivors was utilized to explore the occupational impact of fatigue as communicated by the participants. Although self-report of a small sample of the United States' post-stroke population will have limitations in generalizability, this study identifies specific health-related quality of life issues that can occur with post-stroke fatigue. The participants felt unprepared for the fatigue phenomenon and struggled to adapt, with fatigue having a debilitating influence upon daily occupational performance and roles, including social participation, return to work, driving, reading and sleeping. The participants indicated that exercise (such as walking and water aerobics) and use of assistive technology were helpful strategies in reducing fatigue. The occupational performance and role impact identified by participants in this study can inform the design of effective occupational therapy interventions and further quantitative study of persons with post-stroke fatigue. PMID- 19787635 TI - Surveillance of prophylactic mastectomy: trends in use from 1995 through 2005. AB - BACKGROUND: Prophylactic mastectomy, prophylactic oophorectomy, and antiestrogen chemoprevention are currently the only available methods for breast cancer risk reduction. To the authors' knowledge there is little published information regarding the prevalence of prophylactic mastectomy for the primary prevention of breast cancer among high-risk women or for the prevention of subsequent tumors among women with breast cancer. METHODS: The objective of the current study was to examine the frequency of prophylactic mastectomy in New York State between 1995 and 2005 using mandated statewide discharge data combined with data from the state cancer registry. RESULTS: Identified were 6275 female residents of New York State receiving prophylactic mastectomy; 19% had no identifiable personal history of breast cancer (including women with lobular carcinoma in situ) and 81% had a personal history of breast cancer (84% with invasive disease and 16% with ductal carcinoma in situ). The increased use of prophylactic mastectomy over time was found to be more pronounced among women with breast cancer compared with those without. Women who underwent prophylactic mastectomies were more likely to be younger and white and to have private insurance compared with women who underwent therapeutic mastectomies and compared with all women with breast cancer. The International Classification of Diseases, Ninth Edition, Clinical Modification diagnostic code for prophylactic mastectomy introduced in 1995 was found to have low sensitivity for identifying prophylactic mastectomies in coded discharge data. CONCLUSIONS: The results of the current analysis demonstrate that, although the discharge data alone are inadequate for surveillance purposes, combining these data with the cancer registry data allowed for the detailed examination of the prevalence of prophylactic mastectomies. Mastectomy among high-risk women for cancer prevention appears to be relatively uncommon, but the use of contralateral mastectomy in women with breast cancer is increasing. PMID- 19787636 TI - Impact of socioeconomic status on prostate cancer diagnosis, treatment, and prognosis. AB - BACKGROUND: The objective of the current study was to evaluate the impact of socioeconomic disparities on prostate cancer presentation, treatment, and prognosis in Geneva, Switzerland, in which healthcare costs, medical coverage, and life expectancy are considered to be among the highest in the world. METHODS: This population-based study included all patients diagnosed with invasive prostate cancer among the resident population between 1995 and 2005. Patients were divided into 3 socioeconomic groups according to their last known occupation. Compared were patient and tumor characteristics and treatment patterns between socioeconomic groups. Cox multivariate regression analysis was used to assess and explain socioeconomic inequalities in prostate cancer-specific mortality. RESULTS: Compared with patients of high socioeconomic class, those of low socioeconomic class were more often foreigners, were found less frequently to have screen-detected cancer, were found to have a more advanced stage of disease at diagnosis, and less often had information regarding disease characteristics and staging. These patients underwent prostatectomy less frequently and were more often managed with watchful waiting. The risk of dying as a result of prostate cancer (hazards ratio [HR]) in patients of a low versus high socioeconomic status was increased 2-fold (95% confidence interval [95% CI], 1.5-2.6). After adjustment for patient and tumor characteristics and treatment, the mortality risk was no longer found to be significantly increased (HR, 1.2; 95% CI, 0.8 1.6). CONCLUSIONS: In the current study, patients of low socioeconomic class were found to be at increased risk of dying as a result of their prostate cancer. This increased mortality is largely attributable to delayed diagnosis, poor diagnostic workup, and less invasive treatments in these individuals. PMID- 19787637 TI - Effects from shear stress on morphology and growth of early stages of Norway spruce somatic embryos. AB - The shear stress effect on directional expansion of pro embryogenic masses (PEMs) and suspensor cell development of somatic embryos of Norway spruce (Picea abies) at the proliferation stage was studied by a direct and quantitative image analysis system. The experimental system allowed for detailed observations of the effect of hydrodynamic shear stress in rotating and deforming liquid cultures of proliferating Norway spruce somatic embryos. Briefly, somatic embryos at an early development stage comprised only of clusters of meristematic cells without suspensor cells were fixed on an alginate film. The alginate film was affixed on the bottom of a flow cell and the somatic embryos were subjected to laminar flow through the chamber of the flow cell. Magnified images of the cell clusters were collected every 24 h. The image data was processed based on a normalized cross correlation method, capable of measuring morphological and size features of individual cell clusters in both temporal and spatial domains. No suspensor cells developed in the cell clusters under shear stress of 140 s(-1) for the duration of the experiments. Cell clusters in the control cultured in stationary liquid conditions developed suspensor cells after 5-9 days in culture. Furthermore, the radial growth of meristematic cell clusters was inhibited by shear rates of 86 and 140 s(-1), corresponding to shear stress of 0.086 and 0.14 N/m(2), compared to growth under stationary conditions. The shear rate showed a significant negative correlation to growth rate. Control group showed no preference for direction during growth under static conditions. PMID- 19787638 TI - Modeling of flow-induced shear stress applied on 3D cellular scaffolds: Implications for vascular tissue engineering. AB - Novel tissue-culture bioreactors employ flow-induced shear stress as a means of mechanical stimulation of cells. We developed a computational fluid dynamics model of the complex three-dimensional (3D) microstructure of a porous scaffold incubated in a direct perfusion bioreactor. Our model was designed to predict high shear-stress values within the physiological range of those naturally sensed by vascular cells (1-10 dyne/cm(2)), and will thereby provide suitable conditions for vascular tissue-engineering experiments. The model also accounts for cellular growth, which was designed as an added cell layer grown on all scaffold walls. Five model variants were designed, with geometric differences corresponding to cell-layer thicknesses of 0, 50, 75, 100, and 125 microm. Four inlet velocities (0.5, 1, 1.5, and 2 cm/s) were applied to each model. Wall shear-stress distribution and overall pressure drop calculations were then used to characterize the relation between flow rate, shear stress, cell-layer thickness, and pressure drop. The simulations showed that cellular growth within 3D scaffolds exposes cells to elevated shear stress, with considerably increasing average values in correlation to cell growth and inflow velocity. Our results provide in-depth analysis of the microdynamic environment of cells cultured within 3D environments, and thus provide advanced control over tissue development in vitro. PMID- 19787639 TI - High-pressure systems for gas-phase free continuous incubation of enriched marine microbial communities performing anaerobic oxidation of methane. AB - Novel high-pressure biotechnical systems that were developed and applied for the study of anaerobic oxidation of methane (AOM) are described. The systems, referred to as high-pressure continuous incubation system (HP-CI system) and high pressure manifold-incubation system (HP-MI system), allow for batch, fed-batch, and continuous gas-phase free incubation at high concentrations of dissolved methane and were designed to meet specific demands for studying environmental regulation and kinetics as well as for enriching microbial biomass in long-term incubation. Anoxic medium is saturated with methane in the first technical stage, and the saturated medium is supplied for biomass incubation in the second stage. Methane can be provided in continuous operation up to 20 MPa and the incubation systems can be operated during constant supply of gas-enriched medium at a hydrostatic pressure up to 45 MPa. To validate the suitability of the high pressure systems, we present data from continuous and fed-batch incubation of highly active samples prepared from microbial mats from the Black Sea collected at a water depth of 213 m. In continuous operation in the HP-CI system initial methane-dependent sulfide production was enhanced 10- to 15-fold after increasing the methane partial pressure from near ambient pressure of 0.2 to 10.0 MPa at a hydrostatic pressure of 16.0 MPa in the incubation stage. With a hydraulic retention time of 14 h a stable effluent sulfide concentration was reached within less than 3 days and a continuing increase of the volumetric AOM rate from 1.2 to 1.7 mmol L(-1) day(-1) was observed over 14 days. In fed-batch incubation the AOM rate increased from 1.5 to 2.7 and 3.6 mmol L(-1) day(-1) when the concentration of aqueous methane was stepwise increased from 5 to 15 mmol L(-1) and 45 mmol L( 1). A methane partial pressure of 6 MPa and a hydrostatic pressure of 12 MPa in manifold fed-batch incubation in the HP-MI system yielded a sixfold increase in the volumetric AOM rate. Over subsequent incubation periods AOM rates increased from 0.6 to 1.2 mmol L(-1) day(-1) within 26 days of incubation. No inhibition of biomass activity was observed in all continuous and fed-batch incubation experiments. The organisms were able to tolerate high sulfide concentrations and extended starvation periods. PMID- 19787640 TI - Power production in MFCs inoculated with Shewanella oneidensis MR-1 or mixed cultures. AB - Power densities and oxidation-reduction potentials (ORPs) of MFCs containing a pure culture of Shewanella oneidensis MR-1 were compared to mixed cultures (wastewater inoculum) in cube shaped, 1-, 2-, and 3-bottle batch-fed MFC reactor configurations. The reactor architecture influenced the relative power produced by the different inocula, with the mixed culture generating 68-480% more power than MR-1 in each MFC configuration. The mixed culture produced the maximum power density of 858 +/- 9 mW m(-2) in the cubic MFC, while MR-1 produced 148 +/- 20 mW m(-2). The higher power by the mixed culture was primarily a result of lower internal resistances than those produced by the pure culture. Power was a direct function of ohmic resistance for the mixed culture, but not for strain MR-1. ORP of the anode compartment varied with reactor configuration and inoculum, and it was always negative during maximum power production but it did not vary in proportion to power output. The ORP varied primarily at the end of the cycle when substrate was depleted, with a change from a reductive environment during maximum power production (approximately -175 mV for mixed and approximately -210 mV for MR-1 in cubic MFCs), to an oxidative environment at the end of the batch cycle ( approximately 250 mV for mixed and approximately 300 mV for MR-1). Mixed cultures produced more power than MR-1 MFCs even though their redox potential was less negative. These results demonstrate that differences between power densities produced by pure and mixed cultures depend on the MFC architecture. PMID- 19787641 TI - Evidentials and source knowledge in Turkish. AB - Recent research has indicated that conceptual development in a specific domain may not be independent of the way it is mapped linguistically. We explore this claim in the semantic domain of evidentiality by considering various sets of data from Turkish-speaking children between one and a half to six years. We present evidence for (1) the appropriate use of grammaticalized markers of direct experience, inference, and linguistic report by age three, (2) the understanding of knowledge source ("theory of knowledge") around age four, (3) the understanding of linguistic form and knowledge source relationship ("theory of evidentiality") by age six, and (4) a predictive relationship between the use of the reported speech marker and memory for knowledge source around age four. PMID- 19787642 TI - Evidentiality and trust: the effect of informational goals. AB - Children's ability to exercise selective trust is crucial for the development of their knowledge and successful socialization. For speakers of some languages, evidentials, which are grammatical source-of-knowledge markers, could provide valuable support of these processes. Focusing on Bulgarian, this chapter situates children's use of evidentials in reliability judgments within the broader context of research on decision making and foregrounds the role of informational goals in children's decisions. PMID- 19787643 TI - Children's understanding of certainty and evidentiality: advantage of grammaticalized forms over lexical alternatives. AB - In verbal communication, the hearer takes advantage of the linguistic expressions of certainty and evidentiality to assess how committed the speaker might be to the truth of the informational content of the utterance. Little is known, however, about the precise developmental mechanism of this ability. In this chapter, we approach the question by elucidating factors that are likely to constrain young children's understanding of linguistically encoded certainty and evidentiality, including the types of linguistic form of these expressions, namely, grammaticalized or lexical forms. PMID- 19787644 TI - Knowing how we know: evidentiality and cognitive development. AB - Evidentials are grammatical elements such as affixes and particles indicating the source of knowledge. We provide an overview of this grammatical category and consider three research domains to which developmental studies on evidentiality contribute: the acquisition of linguistic means to characterize knowledge, the conceptual understanding of knowledge sources, and the evaluation of others' testimony. We also consider the study of evidentiality in relation to the Sapir Whorf hypothesis about the influence of language on thought. PMID- 19787645 TI - Commentary: what we can learn from research on evidentials. AB - Young children's well-documented difficulty reporting the sources of their knowledge, and their susceptibility to misleading suggestions about what they saw for themselves, might be reduced when their linguistic community expresses knowledge sources with grammatical evidential markers. Alternatively, until children have acquired certain cognitive prerequisites, they may interpret evidentials simply as markers of speakers' certainty. There is evidence supportive of both views, but with more precisely formulated research questions, specially tailored tasks, and more cross-linguistic comparisons, we can come to understand better the developmental intertwining of linguistic, metalinguistic, and cognitive aspects of children's handling of sources of knowledge. PMID- 19787646 TI - Cytology of systemic mastocytosis. PMID- 19787647 TI - Evidentiality and suggestibility: a new research venue. AB - Recent research suggests that acquisition of mental-state language may influence conceptual development. We examine this possibility by investigating the conceptual links between evidentiality in language and suggestibility. Young children are disproportionately suggestible and tend to change their reports or memories when questioned. The authors discuss the extent to which components of mental-state understanding, specifically representational understanding and understanding origins of knowledge, are implicated in improvements in resistance to suggestions and comprehending evidentiality. The authors also review social psychological evidence that has implications for evidential understanding. Integration of the literature on both topics is followed by suggestions for new research directions. PMID- 19787648 TI - Historical perspectives on malaria: the Rockefeller antimalaria strategy in the 20th century. AB - Malaria, a serious disease for all of human history, was not effectively handled until methods for control of its insect vector, the Anopheles mosquito, were developed at the beginning of the 20th century. The Rockefeller Foundation's antimalaria program spread vector-control strategies throughout the world, and its adoption of dichlorodiphenyltrichloroethane during World War II created an especially powerful and effective malaria control strategy. However, insect resistance to dichlorodiphenyltrichloroethane and restrictions on dichlorodiphenyltrichloroethane use due to its long-term environmental effects are factors in the persistence of malaria as a serious health problem. Mt Sinai J Med 76:468-473, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787649 TI - The bushmeat trade: increased opportunities for transmission of zoonotic disease. AB - Bushmeat is a term that refers to the use of wild animals, ranging from cane rats to gorillas, for food. The term typically refers to the practice in forests of Africa. The bushmeat trade is an example of an anthropogenic factor that provides opportunities for the transmission of diseases from wildlife to humans. The expansion of the bushmeat trade over the past 2 decades has provided a venue for the emergence of zoonotic diseases by providing an increased opportunity for the transmission of organisms known to cause disease and organisms with an unknown impact on humans. Because the bushmeat trade is embedded in a complex cultural, political, and economic context, efforts to prevent the emergence of zoonoses require a multidisciplinary approach. Mt Sinai J Med 76:429-434, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787650 TI - The significant but understudied impact of pathogen transmission from humans to animals. AB - Zooanthroponotic pathogens, which are transmitted from humans to nonhuman animals, are an understudied aspect of global health, despite their potential to cause significant disease burden in wild and domestic animal populations and affect global economies. Some key human-borne pathogens that have been shown to infect animals and cause morbidity and mortality include measles virus (paramyxoviruses), influenza A virus (orthomyxoviruses), herpes simplex 1 virus (herpesviruses), protozoal and helminthic parasites, and bacteria such as methicillin-resistant Staphylococcus aureus and Mycobacterium tuberculosis. However, zooanthroponotic pathogens are most commonly reported in captive animals or domestic livestock with close human contact; there, the potential for economic loss and human reinfection is most apparent. There is also the potential for infection in wild animal populations, which may threaten endangered species and decrease biodiversity. The emergence and reemergence of human-borne pathogens in wildlife may also have negative consequences for human health if these pathogens cycle back into humans. Many of the anthropogenic drivers of zoonotic disease emergence also facilitate zooanthroponotic transmission. Increasing research to better understand the occurrence of and the potential for bidirectional pathogen transmission between humans and animals is essential for improving global health. Mt Sinai J Med 76:448-455, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787651 TI - Zoonotic infections: an emerging threat to human health. PMID- 19787652 TI - Xenotransplantation, xenogeneic infections, biotechnology, and public health. AB - Xenotransplantation is the attempt to use living biological material from nonhuman animal species in humans for therapeutic purposes. Clinical trials and preclinical studies have suggested that living cells and tissue from other species have the potential to be used in humans to ameliorate disease. However, the potential for successful xenotransplantation to cure human disease is coupled with the risk that therapeutic use of living nonhuman cells in humans may also serve to introduce xenogeneic infections of unpredictable significance. Animal husbandry practices and xenotransplantation product preparation may eliminate most exogenous infectious agents prior to transplantation. However, endogenous retroviruses are present in the genomes of all mammalian cells, have an inadequately defined ability to infect human cells, and have generated public health concern. The history of xenotransplantation, the implications for public health, the global consensus on public safeguards necessary to accompany clinical trials, and the future direction of xenotransplantation are discussed in the context of public health. Mt Sinai J Med 76:435-441, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787653 TI - Outbreak of progressive inflammatory neuropathy following exposure to aerosolized porcine neural tissue. AB - In the fall of 2007, the Minnesota Department of Health was notified of 11 cases of an unexplained neurological illness, all linked to a pork processing plant, Quality Pork Processors, Inc., in Austin, MN. The cluster of workers had been experiencing similar symptoms, including fatigue, pain, numbness, and tingling in their extremities as well as weakness. The symptoms were described as more sensory than motor, and all patients had evidence of polyradiculoneuropathy with signs of nerve root irritation. An epidemiological investigation revealed that the only commonality between cases was their exposure to a pork brain extraction procedure involving compressed air. As relatives of the cases remained asymptomatic and all cultures for known pathogens were negative, the etiology of the syndrome seemed not to be infectious. Clinically, the syndrome was most akin to chronic inflammatory demyelinating polyneuropathy. Laboratory tests corroborated the clinical findings, revealing inflammation of peripheral nerves and nerve roots; however, these cases also had features clinically distinct from chronic inflammatory demyelinating polyneuropathy as well as laboratory testing revealing a novel immunoglobulin G immunostaining pattern. This suggested that the observed inflammation was the result of 1 or more unidentified antigens. This syndrome was ultimately dubbed progressive inflammatory neuropathy and was theorized to be an autoimmune reaction to aerosolized porcine neural tissue. Since the investigation's outset, 18 cases of progressive inflammatory neuropathy have been identified at the Minnesota pork processing plant, with 5 similar cases at an Indiana plant and 1 case at a Nebraskan plant. The plants in which cases have been identified have since stopped the use of compressed air in removing pork brains. All cases have stabilized or improved, with some requiring immunosuppressive and analgesic treatment. The study of progressive inflammatory neuropathy is ongoing, and the details of this investigation highlight the value of epidemiological principles in the identification and containment of outbreaks while researchers attempt to uncover the unique pathophysiology and potential etiology of the illness. Mt Sinai J Med 76:442-447, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787654 TI - Surveillance and control of zoonotic agents prior to disease detection in humans. AB - The majority of newly emerging diseases are zoonoses caused by pathogens transmitted directly or indirectly through arthropod vectors to humans. Transmission chains leading to human infection frequently involve intermediate vertebrate hosts, including wildlife and domestic animals. Animal-based surveillance of domestic and wild animals for zoonotic pathogens is a global challenge. Until recently, there has been no scientific, social, or political consensus that animal-based surveillance for zoonotic pathogens merits significant infrastructural investment, other than the fledgling efforts with avian influenza. National institutions charged with strategic planning for emerging diseases or intentional releases of zoonotic agents emphasize improving diagnostic capabilities for detecting human infections, modifying the immune status of human or domestic animals through vaccines, producing better antiviral or antibacterial drugs, and enhancing human-based surveillance as an early warning system. With the exception of human vaccination, these anthropocentric approaches target post-spillover events, and none of these avenues of research will reduce the risk of additional emergences of pathogens from wildlife. Novel schemes for preventing spillover of human pathogens from animal reservoir hosts can spring only from an understanding of the ecological context and biological interactions that result in zoonotic disease emergence. Although the benefits derived from investments to improve surveillance and knowledge of zoonotic pathogens circulating among wildlife reservoir populations are uncertain, our experience with human immunodeficiency virus and the pandemic influenza inform us of the outcomes that we can expect by relying on detection of post-spillover events among sentinel humans. Mt Sinai J Med 76:421-428, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787655 TI - Controversies in the management of alcoholic liver disease. AB - Alcohol is a risk factor for chronic disease burden in developed countries. Alcoholic liver disease affects 1% of the North American population and is the second most frequent indication for liver transplantation in the United States. It is a spectrum that ranges from simple hepatic steatosis to alcoholic hepatitis to steatohepatitis and eventually cirrhosis. The clinical spectrum of alcoholic hepatitis is wide and ranges from the asymptomatic patient to overt liver failure and death. Liver biopsy as a means of prognostication in alcoholic hepatitis has mostly been replaced with less invasive scoring systems. The management of alcoholic liver disease is challenging. Abstinence is the cornerstone of therapy and should include rehabilitation with a multidisciplinary approach. No specific treatment is required in mild to moderate alcoholic hepatitis. In patients with severe hepatitis, there appears to be a moderate survival benefit from the use of either corticosteroids or pentoxifylline in the absence of contraindications to their use. Nonresponders should have steroid therapy withdrawn by day 7, as persistence with therapy is not beneficial. Orthotopic liver transplantation remains the definitive therapy for decompensated alcoholic cirrhosis despite alcohol abstinence. More studies are needed to define the optimal timing of orthotopic liver transplantation and patients at risk of alcohol relapse post transplant. Mt Sinai J Med 76:484-498, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787656 TI - Treatment of primary vertebral tumors. AB - Advances in the treatment of disease and detection through advanced imaging have led to an increase in the discovery of vertebral tumors. Although the majority of symptomatic spinal lesions are metastatic in origin, a significant number of them arise primarily in the spine. These lesions encompass a wide variety of tumor types classified by their cell of origin: bony tumors, cartilaginous tumors, vascular tumors, plasma cell dyscrasias, and tumors that arise from embryonic rests. Further classification of these tumors into malignant or benign subtypes is based on their clinical progression, histopathological evidence of invasiveness, and response to therapy. We provide a brief overview and description of primary tumors as well as treatment paradigms for the individual tumor types. Mt Sinai J Med 76:499-504, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787657 TI - Paradigm shift in the pathophysiology of postmenopausal and thyrotoxic osteoporosis. AB - Bone loss is an inevitable result of getting older in both sexes. This loss is accelerated in women in the early years following menopause and in both sexes with drugs and diseases, prominently hyperthyroidism. Postmenopausal osteoporosis and hyperthyroid osteoporosis, both of which are widely recognized clinical entities, have been thought to arise from low estrogen levels and high thyroid hormone levels, respectively. However, when estrogen declines, follicle stimulating hormone, an anterior pituitary hormone, rises. Likewise, when thyroid hormone levels rise in hyperthyroidism, thyroid-stimulating hormone levels fall. We have used a complement of mouse genetic, pharmacological, and cell biological approaches to unravel a direct action of follicle-stimulating hormone and thyroid stimulating hormone on bone remodeling and bone mass. Apart from establishing a novel pituitary-bone axis of physiological significance, our studies challenge the existing 1-hormone, 1-disease paradigm in endocrinology and suggest that a plurality of hormonal disturbances involving pituitary hormones cause postmenopausal and hyperthyroid osteoporoses. New therapeutic targets thus emerge from these studies. Mt Sinai J Med 76:474-483, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787658 TI - The plague of Athens: epidemiology and paleopathology. AB - In 430 BC, a plague struck the city of Athens, which was then under siege by Sparta during the Peloponnesian War (431-404 BC). In the next 3 years, most of the population was infected, and perhaps as many as 75,000 to 100,000 people, 25% of the city's population, died. The Athenian general and historian Thucydides left an eye-witness account of this plague and a detailed description to allow future generations to identify the disease should it break out again. Because of the importance of Thucydides and Athens in Western history and culture, the Plague of Athens has taken a prominent position in the history of the West for the past 2500 years. Despite Thucydides' careful description, in the past 100 years, scholars and physicians have disagreed about the identification of the disease. Based on clinical symptoms, 2 diagnoses have dominated the modern literature on the Athenian plague: smallpox and typhus. New methodologies, including forensic anthropology, demography, epidemiology, and paleopathogy, including DNA analysis, have shed new light on the problem. Mathematical modeling has allowed the examination of the infection and attack rates and the determination of how long it takes a disease to spread in a city and how long it remains endemic. The highly contagious epidemic exhibited a pustular rash, high fever, and diarrhea. Originating in Ethiopia, it spread throughout the Mediterranean. It spared no segment of the population, including the statesman Pericles. The epidemic broke in early May 430 BC, with another wave in the summer of 428 BC and in the winter of 427-426 BC, and lasted 4.5 to 5 years. Thucydides portrays a virgin soil epidemic with a high attack rate and an unvarying course in persons of different ages, sexes, and nationalities.The epidemiological analysis excludes common source diseases and most respiratory diseases. The plague can be limited to either a reservoir diseases (zoonotic or vector-borne) or one of the respiratory diseases associated with an unusual means of persistence, either environmental/fomite persistence or adaptation to indolent transmission among dispersed rural populations. The first category includes typhus, arboviral diseases, and plague, and the second category includes smallpox. Both measles and explosive streptococcal disease appear to be much less likely candidates.In 2001, a mass grave was discovered that belonged to the plague years. Ancient microbial typhoid (Salmonella enterica serovar Typhi) DNA was extracted from 3 skeletons. Because typhoid was endemic in the Greek world, it is not the likely cause of this sudden epidemic. Mt Sinai J Med 76:456-467, 2009. (c) 2009 Mount Sinai School of Medicine. PMID- 19787659 TI - Microvascular obstruction after percutaneous coronary intervention. AB - Successful revascularization of the epicardial coronary artery can be achieved in over 90% of percutaneous coronary intervention (PCI) procedures. However, postprocedural microvascular obstruction, despite the presence of normal epicardial flow, remains an important limitation which substantially reduces the beneficial effects of PCI. In this review article, a number of different methods available to diagnose microvascular obstruction after PCI are outlined. We also discussed the various pharmacological and mechanical strategies to reduce the occurrence of microvascular obstruction. In this regard, pretreatment with antiplatelet therapy remains crucial. In urgent PCI for acute myocardial infarction, available data suggest that manual thrombus aspiration device is beneficial in reducing the occurrence of procedure-related microvascular obstruction and possibly improve long-term clinical outcomes. PMID- 19787661 TI - Intravascular ultrasound-guided retrograde wiring for chronic total occlusion. AB - This report describes a retrograde wiring technique, using intravascular ultrasound, for a blunt chronic total occlusion with a side branch at the site of occlusion of which the operator has difficulty of awareness of the proper re entry point with the retrograde wire angiographically. PMID- 19787660 TI - First experience with the BioSTAR-device for various applications in pediatric patients with congenital heart disease. AB - BACKGROUND: Interventional closure of atrial septal defects (ASD) and surgical tunnel fenestrations in Fontan patients has become the procedure of choice for many years. Recently, the BioSTAR Occluder, a modification of the Starflex device with a resorbable matrix has become available. PATIENTS: Ten Biostar devices were implanted in nine children with interatrial septal defects, one within a fontan baffle, eight with secundum atrial septal defects. The age of the patients ranged from 11 months to 17 years, the body weight ranged from 12.9-78 kg. RESULTS: 10 BioSTAR devices were implanted in nine patients. In one patient, two BioSTAR devices were used to occlude multiple defects within the oval fossa. All defects were successfully and uneventfully occluded. Mean procedure time was 56 (range 28 125). Mean fluoroscopy time was 4.8 (range 1.1 to 13.0) min. None of the nine patients showed residual shunts after device implantation. After 30 days no shunt was seen in the control transthoracic echocardiography. No adverse effects like allergic reactions, tachyarrhythmia or thrombembolic events occurred in any of the patients. CONCLUSION: The BioSTAR closure device is a safe and effective device for the closure of a variety of interatrial shunts in children including multifenestrated interatrial defects and fontan fenestrations, however, possible long term consequences (e.g., fractures, recurrent shunts after scaffold degradation) remain to be studied. PMID- 19787662 TI - Leaf nest use and construction in the golden-brown mouse lemur (Microcebus ravelobensis) in the Ankarafantsika National Park. AB - The use of leaf nests has been documented in several mouse lemur species over the last few decades, including the golden-brown mouse lemur. Nest construction, however, has only rarely been observed and detailed descriptions of this process are lacking so far. We aim to determine the relative importance of leaf nests as shelters for the golden-brown mouse lemur, and to test predictions concerning the role of thermoregulation, safety (i.e., protection of infants), and of interspecific competition with the sympatric gray mouse lemurs in regulating nest use. Finally, we intend to clarify whether and how Microcebus ravelobensis constructs the nests, and we provide physical descriptions of seven leaf nests. Nocturnal focal observations were carried out from May 2007 to January 2008 on 18 females, and sleeping sites were regularly monitored during a six-month period. Data were collected from two study sites, one with exclusive presence of M. ravelobensis, and one with co-existence of the two mouse lemur species. Sixty five out of 379 identified daily sleeping sites were leaf nests. These represented a total of 35 different leaf nests, used by 15 out of 18 females. The relative leaf nest use differed between sites during five out of six months, but without a consistent pattern. Interspecific competition can therefore not explain leaf nest use. Leaf nest use differed seasonally and may be partly explained by thermoregulatory advantages in the site with lower minimum temperatures. Nest use was furthermore higher than expected in both sites during the rearing season that indicates the role of nests in infant protection. For the first time, we could confirm that golden-brown mouse lemurs build leaf nests themselves. Nest building lasted between 46 and 68 min, which shows that this task is time consuming and therefore probably costly. PMID- 19787663 TI - Molecular simulation of the water meniscus in dip-pen nanolithography. AB - We report a molecular dynamics simulation of the nanometer water meniscus formed in dip-pen nanolithography (DPN). When an atomic force microscope tip is in contact with a surface, the meniscus is significantly asymmetric around the tip axis. The meniscus as a whole can move away from the tip axis due to surface diffusion. The structure of the meniscus fluctuates and its periphery has a finite thickness as large as 25% of its width. We simulated the transport of nonpolar hydrophobic molecules through a water meniscus. Molecules move on the surface of, not dissolving into the interior of, the meniscus. As a result, an annular pattern forms in DPN. Even if the meniscus is cylindrically symmetric, the molecular flow from the tip and the subsequent pattern growth on the surface are anisotropic at the nanosecond timescale. PMID- 19787664 TI - The current global status of Chinese materia medica. AB - The Chinese government has recently established a national project to improve the standards of Chinese Materia Medica (CMM) products, particularly regarding their quality control and safety evaluation, in order to promote modernization and increase international trade. In 2006, the global sales value of Chinese medicinal products increased to 20 billion US$, and the export value of CMM was up to more than 1 billion US$. However, the standard of these products still needs to be improved to meet the more stringent requirements of the international markets. Over the past decade we have witnessed the increasing growth in popularity of health foods and herbal medicinal products, especially Chinese Materia Medica products (CMM). PMID- 19787665 TI - Water splitting by cooperative catalysis. PMID- 19787667 TI - Cathodic deposition of polypyrrole enabling the one-step assembly of metal polymer hybrid electrodes. PMID- 19787666 TI - Patterning mammalian cells for modeling three types of naturally occurring cell cell interactions. PMID- 19787668 TI - Polyhedral organic microcrystals: from cubes to rhombic dodecahedra. PMID- 19787669 TI - Beyond C-H activation with uranium: a cascade of reactions mediated by a uranium dialkyl complex. PMID- 19787670 TI - Tantalum-amidate complexes for the hydroaminoalkylation of secondary amines: enhanced substrate scope and enantioselective chiral amine synthesis. PMID- 19787671 TI - Enhanced NH3 selective catalytic reduction for NOx abatement. PMID- 19787672 TI - Maximizing the localized relaxation: the origin of the outstanding oxygen storage capacity of kappa-Ce2Zr2O8. PMID- 19787673 TI - One beta hairpin after the other: exploring mechanical unfolding pathways of the transmembrane beta-barrel protein OmpG. PMID- 19787674 TI - Creation of an amino acid network of structurally coupled residues in the directed evolution of a thermostable enzyme. PMID- 19787675 TI - Toward the development of "nano-QSARs": advances and challenges. AB - The most significant achievements and challenges relating to an application of quantitative structure-activity relationship (QSAR) approach in the risk assessment of nanometer-sized materials are highlighted. Recent advances are discussed in the context of "classical" QSAR methodology. The possible ways for the structural characterization of compounds existing at the nanoscale (at least one dimension of 100 nm or less) are briefly reviewed. The applicability of the existing toxicological data for developing QSAR models is evaluated. Finally, the existing models are presented. The need to develop new interpretative descriptors for the nanosystems is also highlighted. It is suggested that, due to high variability in the molecular structures and different mechanisms of toxicity, individual classes of nanoparticles should be modeled separately. PMID- 19787676 TI - Resistive switching in nanogap systems on SiO2 substrates. AB - Voltage-controlled resistive switching in various gap systems on SiO2 substrates is reported. The nanoscale-sized gaps are made by several means using different materials including metals, semiconductors, and amorphous carbon. The switching site is further reduced in size by using multiwalled carbon nanotubes and single walled carbon nanotubes. The switching in all the gap systems shares the same characteristics. This independence of switching on the material compositions of the electrodes, accompanied by observable damage to the SiO2 substrate at the gap region, bespeaks the intrinsic switching from post-breakdown SiO2. It calls for caution when studying resistive switching in nanosystems on oxide substrates, since oxide breakdown extrinsic to the nanosystem can mimic resistive switching. Meanwhile, the high ON/OFF ratio (approximately 10(5)), fast switching time (2 micros, tested limit), and durable cycles show promising memory properties. The observed intermediate states reveal the filamentary nature of the switching. PMID- 19787677 TI - Microfabricated devices for enhanced bioadhesive drug delivery: attachment to and small-molecule release through a cell monolayer under flow. AB - The development of a novel microfabricated device for oral drug delivery that overcomes many of the common barriers present in the gastrointestinal tract is reported. Specifically, the attachment of targeting ligands, subsequent device binding, and small molecule release from the microdevices in flow are investigated. A diffusion chamber that permits the simultaneous study of particle binding and small-molecule release under physiologically relevant shear conditions is developed. It is observed that once the particles bind to the cell surface, they remain attached. A small fraction of the devices detach in flow; however, most of these devices readily reattach to the cell layer in a new location. This steady-state density of microdevices is most likely the result of larger order microdevice clusters releasing their loose interactions with nearby microdevices, shifting slightly downstream, and subsequently reattaching to the cell monolayer. The release of a model small molecule from microdevices over time is roughly linear and approximately ten times greater than that observed with the small molecule alone. Overall, the preparation and characterization of an oral drug-delivery microdevice system capable of both targeting and asymmetric release in flow is reported. PMID- 19787678 TI - Chemically functionalized carbon nanosieves with 1-nm thickness. PMID- 19787679 TI - Nanomolding of PEG-based hydrogels with sub-10-nm resolution. AB - A simple, soft nanolithographic method is used to fabricate sub-10-nm structures on star polyethylene glycol-based hydrogels and perfluoropolyether-based materials. Very small features, for example, gold nanoparticles of size approximately 8 nm with an interparticle distance of approximately 100 nm, are successfully reproduced from a hard silicon master into both elastomers. Scanning force microscopy is used to investigate the replicas, and the original hexagonal pattern of the nanoparticles is clearly recognized. In addition, both replicas are usable as secondary, soft molds yielding positive copies of the primary, hard master. The results presented here show similar replication capabilities for both elastomers despite the markedly different properties of the precursors. Moreover, the hydrogel material can be easily peeled off from both soft and silicon masters without the need for surface treatment. The procedure allows nanopatterning of a biocompatible material over large areas, which is a useful tool to investigate cellular responses to defined nanotopography. PMID- 19787680 TI - Identification of specific angiotensin-converting enzyme variants and haplotypes that confer risk and protection against type 2 diabetic nephropathy. AB - BACKGROUND: Cross-sectional and family studies identified angiotensin-converting enzyme (ACE) gene as a risk factor for diabetic nephropathy (DN). The contribution of ACE gene variants to DN development and progression is controversial and varies among different ethnic/racial groups. METHODS: We investigated the association of three ACE gene variants with DN, rs1799752 insertion/deletion (I/D), rs1800764T/C and rs12449782A/G in 917 Tunisian type 2 diabetic (T2DM) patients: 515 with (DN) and 402 without (DWN) nephropathy. ACE genotyping was done by PCR-based assays; haplotype estimation was performed using H-Plus software (chi(2)-test based). RESULTS: Genotype frequency distributions of the three studied variants were in Hardy-Weinberg equilibrium. Minor allele frequency of rs1800764 was higher in DN patients than DWN patients or healthy controls, and minor allele frequency of rs1799752 was higher in DN than DWN patients. Higher frequency of rs1799752 and rs1800764 homozygous mutant genotypes was seen in DN compared to DWN patients. Of the three variants, only rs1799752 deletion/deletion (D/D) genotype was associated with a significant increase in albumin to creatinine ratios levels, and D/D carriers had elevated low-density lipoprotein, total cholesterol and urea. Three locus haplotype [rs1799752(I/D)/rs1800764(T/C)/rs12449782(A/G)] analysis revealed that the frequency of DCG haplotype was higher, while that of ITG and ICA haplotypes were lower among unselected type 2 diabetic patients. Taking ITA haplotype as reference, multivariate regression analysis confirmed the negative (ITG), and positive (DCG, DTG, DCA and DTA) association of specific ACE haplotypes with DN, after adjusting for potential nephropathy-linked covariates. CONCLUSIONS: Our results support the involvement of specific ACE variants in DN pathogenesis and demonstrate the presence of DN-specific haplotypes at the ACE locus. PMID- 19787681 TI - Droplet-based microfluidic synthesis of anisotropic metal nanocrystals. AB - A droplet-based microfluidic method for the preparation of anisotropic gold nanocrystal dispersions is presented. Gold nanoparticle seeds and growth reagents are dispensed into monodisperse picoliter droplets within a microchannel. Confinement within small droplets prevents contact between the growing nanocrystals and the microchannel walls. The critical factors in translating macroscale flask-based methods to a flow-based microfluidic method are highlighted and approaches are demonstrated to flexibly fine tune nanoparticle shapes into three broad classes: spheres/spheroids, rods, and extended sharp edged structures, thus varying the optical resonances in the visible-near infrared (NIR) spectral range. PMID- 19787682 TI - A fluorescence lifetime imaging scanning confocal endomicroscope. AB - We describe a fluorescence lifetime imaging endomicroscope employing a fibre bundle probe and time correlated single photon counting. Preliminary images of stained pollen grains, eGFP-labelled cells exhibiting Forster resonant energy transfer and tissue autofluorescence are presented. PMID- 19787683 TI - The potential of biophotonic techniques in stem cell tracking and monitoring of tissue regeneration applied to cardiac stem cell therapy. AB - The use of injected stem cells, leading to regeneration of ischemic heart tissue, for example, following coronary artery occlusion, has emerged as a major new option for managing 'heart attack' patients. While some clinical trials have been encouraging, there have also been failures and there is little understanding of the multiplicity of factors that lead to the outcome. In this overview paper, the opportunities and challenges in applying biophotonic techniques to regenerative medicine, exemplified by the challenge of stem cell therapy of ischemic heart disease, are considered. The focus is on optical imaging to track stem cell distribution and fate, and optical spectroscopies and/or imaging to monitor the structural remodeling of the tissue and the resulting functional changes. The scientific, technological, and logistics issues involved in moving some of these techniques from pre-clinical research mode ultimately into the clinic are also highlighted. PMID- 19787685 TI - Why focus on zoo and aquarium education? PMID- 19787684 TI - Use of a novel ionic liquid matrix for MALDI-MS analysis of glycopeptides and glycans out of total tryptic digests. AB - In this study, we investigated a novel ionic liquid matrix (ILM), namely, the 1,1,3,3-tetramethylguanidinium salt of 2,4,6-trihydroxyacetophenone (THAP). This matrix[1,1,3,3-tetramethylguanidinium 2,4,6-trihydroxyacetophenone (GTHAP)] turned out to be well suited for the matrix-assisted laser desorption/ionization mass spectrometric analysis of glycopeptides and glycans, and overcame the well known ionization suppression of carbohydrate structures in the presence of peptides. The matrix was evaluated by two different series of experiments, in each case in comparison with the crystalline THAP matrix. In the first set of experiments, mass spectra were taken from unseparated tryptic digests of three glycoproteins taken as model compounds. Even glycopeptides containing short peptide backbones and large carbohydrate moieties gave high signal intensities when using the ILM though they did not appear in the THAP spectra. In the second set of experiments, the total tryptic digests were treated with endoglycosidase PNGase F to cleave off the N-linked glycans. When using the GTHAP matrix, it was possible to detect the glycans with high intensities in the presence of the tryptic peptides, whereas glycan ionization was completely suppressed when measured with the solid matrix THAP. The extent of metastable decay of glycopeptides was reduced when using the ILM. Altogether, GTHAP proved as a useful ILM particularly being superior to solid matrices in the context of glycosylation analysis. PMID- 19787686 TI - Improved identification of hordeins by cysteine alkylation with 2 bromoethylamine, SDS-PAGE and subsequent in-gel tryptic digestion. AB - Proteomic-based description of varieties of barley (Hordeum vulgare L.) is a very important task especially in the food and brewing industry. This study is focused on major storage proteins in barley--hordeins--as a group of proteins soluble in alcohol/water mixtures that shows up significant changes in proteomic profiles for different varieties of barley. Unusual amino acid composition of hordeins with low numbers of lysine and arginine in combination with high content of proline and glutamine complicates their identification in a common proteomic workflow, because tryptic digestion produces just a few peptides amenable for successful mass spectrometric analysis. To increase the number of cleavage sites, in this work, cysteines in hordeins were chemically modified with 2 bromoethylamine (BEA) for their conversion into aminoethylcysteines. These mimic lysine residues and are recognized by trypsin as potential cleavage sites (if not followed by a proline residue) on the C-terminal side of the modified cysteine. Small extent of side reactions (towards histidine, N-terminus of the peptide, methionine, and also here the newly discovered reaction towards aminoethylcysteine) during modification with BEA could be observed after a longer period of reaction but this did not hinder the analysis when optimal conditions were used. Application of trypsin for in-gel digestion of hordeins, previously modified chemically with BEA, provided a higher number of short peptides and their subsequent mass spectrometric analysis resulted in an improved identification of hordeins. This approach can also be used for the analysis of other similar protein groups (e.g. gliadins in wheat) or other cysteines containing proteins having a low number of lysine and arginine residues in their primary structure. PMID- 19787691 TI - Imidazoline-N-oxyl: a DFT study of its protonation reaction. AB - Imidazoline-based nitroxides are developed as pH probes. Their pKa values vary over a wide range (from 1 to 11), depending on the substituents attached to the five-membered cyclic nitroxide. Density functional calculations using the PBE1PBE method at the 6-31+G(d,p) level, combined with natural bond orbital (NBO), frontier molecular orbital (FMO), geometry, Mulliken charge, and thermodynamic analyses, are carried out to disclose the effects involved in the changes in pKa. The studies show that the decrease of seven pKa units from pyrrolidine (11) to imidazoline-N-oxyl 8 is due to the inductive electron-withdrawing capacity of the nitroxyl group. On the other hand, by combining both the inductive and mesomeric electron-withdrawing capacities of the NO2 group with delocalization of the lone pair on the amino N atom of the pi system of the vinyl linker, the pKa of 4.5 of 8 was increased by around three units to 7.8 for 1/2. PMID- 19787692 TI - Effect of PCBM concentration on photoluminescence properties of composite MEH PPV/PCBM nanoparticles investigated by a Franck-Condon analysis of single particle emission spectra. AB - The emission of composite conjugated polymer (MEH-PPV)/fullerene (PCBM) nanoparticles is investigated by single particle spectroscopy (SPS), and changes in vibronic structure with nanoparticle composition are evaluated by means of a detailed Franck-Condon analysis. Consistent with previous reports we find that the emission spectra can be modeled as the superposition of two types of emitters, one with aggregate character and one with molecular character. Major findings from the fitting of the SPS data to a Franck-Condon model are that 1) the occurrence of each of the two types of emitters changes with nanoparticle composition to the point that no aggregate emitters are detected (at 50 wt% PCBM), 2) at the highest PCBM doping levels (75 wt% PCBM) aggregate emitters reappear due to nanoscale phase separation in the composite nanoparticles, 3) the molecular emitters show small Huang-Rhys factors that increase with PCBM doping, indicative of extensive delocalization and exciton migration that is reduced by the disorder introduced in the polymer material by PCBM doping and 4) the aggregate emitters show large Huang-Rhys factors, indicative of the localized nature of these energy trap sites, with a broad distribution of values of these Huang-Rhys factors. The latter observation suggests a broad heterogeneous distribution of aggregate morphologies in blended conducting polymer materials, which can be attributed to variations in polymer chain folding and stacking at the aggregate sites. The reported results obtained by the SPS approach show how blending conjugated polymers with fullerenes at various doping levels induces changes in interchain interactions and aggregate site density even at length scales below a few tens of nanometers that affect conjugated polymer material properties, an observation that has gone unnoticed in bulk studies of blended conjugated polymer films. PMID- 19787698 TI - Application of near-infrared spectroscopy for monitoring and control of cell culture and fermentation. AB - Near-infrared (NIR) spectroscopy can potentially provide on-line information on substrate, biomass, product, and metabolite concentrations in fermentation processes, which could be useful for improved monitoring or control. However, several factors can negatively influence the quality of chemometric models built for interpretation of the spectra, thus impairing the analyte concentration predictions. The aim of this review was to provide an overview of necessary conditions and challenges that one has to face when developing a NIR application for monitoring of cell culture or fermentation processes. Important practical aspects are introduced, such as sampling, modeling of biomass concentration, influence of microorganism morphology on the spectra, effects of the hydrodynamic conditions in the fermenter, temperature influence, instrument settings, and signal optimization. Several examples from the literature are provided, which will hopefully guide the reader interested in the topic. Furthermore, the general procedure used for the development of calibration models is presented, and the influence of microorganism metabolism-potential source of correlation between analytes-is commented. Other important issues such as wavelength selection and evaluation of robustness are shortly introduced. Finally, some examples of potential applications of NIR monitoring are provided, including the implementation of control strategies, the combination with other monitoring tools (the so-called sensor fusion), and the description of process trajectories. On the basis of the review, we conclude that acceptance of NIR spectroscopy as a standard monitoring tool by the fermentation industry will necessitate considerably more on-line studies using industrially relevant-and highly challenging-fermentation conditions (high aeration intensity, high biomass concentration and viscosity, and filamentous production strain). PMID- 19787699 TI - Prenatal diagnosis of Down syndrome: how best to deliver the news. AB - We sought to provide evidence-based recommendations to physicians on how to best deliver a prenatal diagnosis of DS to expectant parents. Our study design consisted of searching Medline and PsychInfo from 1960 to 2008, as well as Web sites from academic organizations and other nonprofit or private organizations, using the terms "Down syndrome," "Trisomy 21," "mongolism," "prenatal diagnosis," "postnatal care," and "delivery of health care." Our results showed that a health care professional knowledgeable about DS with specific training in the delivery of sensitive diagnoses should be part of the first conversation. A prenatal diagnosis of DS should be presented in person or at a pre-established time by phone. Physicians should provide accurate information about medical conditions associated with DS and connect parents to local DS support groups and other resources. We conclude that physicians can deliver prenatal diagnoses of DS in a sensitive manner that can be appreciated by expectant parents. PMID- 19787701 TI - Aquaporin-1 activity of plasma membrane affects HT20 colon cancer cell migration. AB - Recent studies revealed an important role of aquaporins (AQPs) in cell migration and migration-associated cell function such as angiogenesis, wound healing, and neutrophil motility. Migration of tumor cells is a crucial step in tumor invasion and metastasis. In the present study, we investigated the expression of AQP1 in human HT20 colon cancer cells and characterized its function in cell migration. By reverse transcription-polymerase chain reaction (RT-PCR) and immunoblot analysis, expression of AQP1 was identified in HT20 cell lines. Immunofluorescence analysis indicated expression of AQP1 protein in the plasma membrane of HT20 cells. The recombinant adenovirus expressing human AQP1 increased the mRNA and protein expression of AQP1 in HT20 cells. In contrary, the RNA interference vector of AQP1 effectively inhibited the mRNA and protein expression of AQP1 in HT20 cells. Adenovirus-mediated high expression of AQP1 in HT20 cells increased relative plasma membrane water permeability and migration rate in both wound healing and invasive transwell migration assays. In contrary, RNA interference vector-mediated low expression of AQP1 in HT20 cells reduced relative plasma membrane water permeability and migration rate. AQP1 expression induced relocalization of actin protein and activation of RhoA and Rac. In nude mice, AQP1 increased extravasation of HT20 Cells in lung after tail vein injection. The results provided the direct evidence that aquaporin-mediated plasma membrane water permeability plays an important role in colon cancer cell migration and may be associated with colon cancer invasion and metastasis. PMID- 19787702 TI - Androgen receptor and caveolin-1 in prostate cancer. AB - The androgen receptor (AR) is involved in the development and maintenance of the normal prostate and the development and progression of prostate cancer (PCa). Caveolin-1 (cav-1) is an AR co-regulator. The expression of this integral membrane protein is upregulated in PCa and correlates positively with its development. This review focuses on the likely interactive roles of AR and cav-1, with particular reference to progression to androgen-insensitivity in PCa. The classical role of AR is modulation of gene transcription by binding specific DNA sequences called androgen response elements in the promoter regions of target genes. To carry out this role, AR interacts with many co-regulator proteins which either enhance or repress its activation. Altered expression or misregulated activation of a co-regulator protein may significantly alter AR activity and the basal transcription rate of androgen responsive genes. Cav-1 has roles in cell signalling and trafficking, roles that are important in PCa survival, metastasis, and the development of multidrug resistant phenotypes. Although cav-1 appears to increase AR genomic activity and increase tumor cell survival, there is also mounting evidence that cav-1 can manipulate rapid, non-genomic AR signalling at the plasma membrane. By increasing our understanding of cav-1 as an AR co regulator, we may be able to reinstate appropriate transcriptional responses to androgen signalling and minimise misregulated AR activity, thus permitting more effective targeted therapies for PCa. PMID- 19787700 TI - Molecular biology of K(ATP) channels and implications for health and disease. AB - The ATP-sensitive potassium (K(ATP)) channel is expressed in most excitable tissues and plays a critical role in numerous physiological processes by coupling intracellular energetics to electrical activity. The channel is comprised of four Kir6.x subunits associated with four regulatory sulfonylurea receptors (SUR). Intracellular ATP acts on Kir6.x to inhibit channel activity, while MgADP stimulates channel activity through SUR. Changes in the cytosolic [ATP] to [ADP] ratio thus determine channel activity. Multiple mutations in Kir6.x and SUR genes have implicated K(ATP) channels in various diseases ranging from diabetes and hyperinsulinism to cardiac arrhythmias and cardiovascular disease. Continuing studies of channel physiology and pathology will bring new insights to the molecular basis of K(ATP) channel function, leading to a better understanding of the role that K(ATP) channels play in both health and disease. PMID- 19787703 TI - Emerging roles of glucocorticoid receptor phosphorylation in modulating glucocorticoid hormone action in health and disease. AB - Glucocorticoids (GCs) are hormones naturally released when the body perceives stress and function to return homeostatic balance within various tissues. Synthetic GCs are widely prescribed therapeutics for the treatment of numerous inflammatory disorders and cancers. The effects of GCs are mediated by their binding and activation of the GC receptor (GR), a transcription factor that is subject to hormone-dependent and -independent phosphorylation on several serine and threonine residues. The GR is phosphorylated by kinases such as MAPKs, CDKs, and GSK-3beta, and these modifications modulate the transcriptional activity of the GR within cells. Here, we discuss the phosphorylation status of the GR as a mechanism to dictate how cells will ultimately respond to GCs. In doing so, we will review current knowledge about each phosphorylated residue within the GR and their contributions to modulating GC signaling in normal homeostatic physiology and during the progression of disease. PMID- 19787704 TI - The mitochondrial citrate carrier: metabolic role and regulation of its activity and expression. AB - The citrate carrier (CiC), a nuclear-encoded protein located in the mitochondrial inner membrane, is a member of the mitochondrial carrier family. CiC plays an important role in hepatic lipogenesis, which is responsible for the efflux of acetyl-CoA from the mitochondria to the cytosol in the form of citrate, the primer for fatty acid and cholesterol synthesis. In addition, CiC is a key component of the isocitrate-oxoglutarate and the citrate-malate shuttles. CiC has been purified from various species and its reconstituted function characterized as well as its cDNA isolated and sequenced. CiC mRNA and/or CiC protein levels are high in liver, pancreas, and kidney, but are low or absent in brain, heart, skeletal muscle, placenta, and lungs. A reduction of CiC activity was found in diabetic, hypothyroid, starved rats, and in rats fed on a polyunsaturated fatty acid (PUFA)-enriched diet. Molecular analysis suggested that the regulation of CiC activity occurs mainly through transcriptional and post-transcriptional mechanisms. This review begins with an assessment of the current understanding of CiC structural and biochemical characteristics, underlying the structure-function relationship. Emphasis will be placed on the molecular basis of the regulation of CiC activity in coordination with fatty acid synthesis. PMID- 19787705 TI - Can resveratrol extend your life? AB - Is There An Answer? is intended to serve as a forum in which readers to IUBMB Life may pose questions of the type that intrigue biochemists but for which there may be no obvious answer or one may be available but not widely known or easily accessible. Readers are invited to e-mail ascenzi@uniroma3.it if they have questions to contribute or if they can provide answers to questions that are provided here from time to time. In the latter case, instructions will be sent to interested readers. Answers should be, whenever possible, evidence-based and provide relevant references. PMID- 19787709 TI - Cytochrome P450 enzymes and the heart. AB - The cytochrome P450 monooxygenase system (CYP) is a multigene superfamily of heme thiolate enzymes, which are important in the metabolism of foreign and endogenous compounds. Genetic variations, drug interactions, or pathophysiological factors can lead to reduced, absent, or increased enzymatic activity. This altered CYP activity greatly influences an individual's response to therapeutic treatment. What is not known is the impact of these changes on the many functional roles of CYP in physiological and pathophysiological processes of the heart. Many extrahepatic tissues, like heart, contain active P450 enzymes but lack information regarding their role in cellular injury or homeostasis. Much of our current knowledge about cardiac CYP has been limited to studies investigating the role of fatty acid metabolites in heart. Traditional risk factors including diabetes, smoking, and hypertension have well established links to cardiovascular disease. And new evidence strongly suggests exposure to chemicals and other environmental agents has a profound impact on the cardiovascular system. These risk factors can independently affect the expression and activity of CYP enzymes. Therefore, altered CYP activity is important from a detoxification as well as a bioactivation perspective. Considering CYP, interactions are greatly dependent on inherited differences or acquired changes in enzyme activity further research into their potential impact on pathogenesis, risk assessment, and therapy of heart disease is warranted. This review explores the expression of CYP isoforms, their functional roles, and the effects of genetic variation in the heart. PMID- 19787708 TI - Tuning the properties of the bacterial membrane with aminoacylated phosphatidylglycerol. AB - The bacterial envelope is a semi-permeable barrier that protects the cell from the hostilities of the environment. To survive the ever-changing conditions of their surroundings, bacteria need to rapidly adjust the biochemical properties of their cellular envelope. Amino acid (aa) addition to phosphatidylglycerol (PG) of the membrane is one of the mechanisms used by bacteria to lower the net negative charge of their cellular envelope, thereby decreasing its affinity for several antibacterial agents such as the cationic antimicrobial peptides (CAMPs) produced by the innate immune response during host infection. This process requires the activity of an integral membrane protein, called aa-PG synthase (aaPGS), to transfer the aa of aminoacyl-tRNA (aa-tRNA) onto the PG of the membrane. aaPGSs constitute a new family of virulence factors that are found in a wide range of microorganisms. aa-PGs not only provide resistance to CAMPs but also to other classes of antibacterial agents and to environmental stresses such as those encountered during extreme osmotic or acidic conditions. This review will describe the known biochemical properties of aa-PGSs, their specificity for aa tRNAs and phospholipids, and the growing repertoire of aa used as substrates by these enzymes. Their prevalence in bacteria and the phenotypes and modulations of membrane properties associated with these molecules will be addressed, as well as their regulation as a component of the envelope stress response system in certain bacteria. PMID- 19787710 TI - Chronic pudendal neuromodulation: expanding available treatment options for refractory urologic symptoms. AB - AIMS: Chronic pudendal nerve stimulation (CPNS) is a logical alternative particularly in those who fail sacral stimulation. We evaluated symptoms, complications, and satisfaction after CPNS. METHODS: We retrospectively reviewed patients having a tined lead placed at the pudendal nerve via the ischial-rectal approach. Demographics, history, complications, and pre-implant voiding diary data were collected. In those responding to CPNS, post-implant symptom changes were measured with the Interstitial Cystitis Symptom and Problem indices (ICSI PI) and voiding diaries at 3, 6, and 12 months, and a mailed survey. RESULTS: The majority of 84 patients (78.6% female; age 51.8 +/- 16.9 years) had interstitial cystitis/painful bladder syndrome, or overactive bladder. Pudendal response (>= 50% improvement) occurred in 60/84 (71.4%), however 5 of these chose sacral neuromodulation. Almost all (93.2%) who had previously failed sacral neuromodulation responded to pudendal stimulation. Outcomes were evaluated in 55 continuing on CPNS (median follow up 24.1 months). Seven complications requiring 5 revisions, and 4 other re-operations occurred. Five were explanted. Over time, significant improvements in frequency (P < 0.0001), voided volume (P < 0.0001), incontinence (P < 0.0001), and urgency (P = 0.0019) occurred. ICSI-PI scores significantly improved over 12 months (P < 0.0001). Survey responses indicated that most still had a device (35/40; 87.5%) continuously in use (24/29; 82.8%), and overall bladder, pelvic pain, incontinence, urgency, and frequency symptoms had improved. CONCLUSIONS: CPNS is a reasonable alternative in complex patients refractory to other therapies including sacral neuromodulation. Continued research is needed to fully assess long-term outcomes and identify predictors of success. PMID- 19787707 TI - The tale of transforming growth factor-beta (TGFbeta) signaling: a soigne enigma. AB - Transforming growth factor-beta (TGFbeta) is a secreted cytokine, which intricately controls a plethora of physiological and pathological processes during development and carcinogenesis. TGFbeta exerts antiproliferative effects and functions as a tumor suppressor during early stages of tumorigenesis, whereas at later stages it functions as a tumor promoter aiding in metastatic progression through an autocrine TGFbeta loop. Intricate knowledge of TGFbeta signaling and its regulation are still evolving. In this review, we make an attempt to showcase the associated enigma of TGFbeta signaling in its dual functional role as tumor suppressor and metastatic promoter during early and late stages of carcinogenesis, respectively. PMID- 19787711 TI - The questionnaire for urinary incontinence diagnosis (QUID): validity and responsiveness to change in women undergoing non-surgical therapies for treatment of stress predominant urinary incontinence. AB - AIMS: The Questionnaire for Urinary Incontinence Diagnosis (QUID), a 6-item urinary incontinence (UI) symptom questionnaire, was developed and validated to distinguish stress and urge UI. This study's objective was to evaluate QUID validity and responsiveness when used as a clinical trial outcome measure. METHODS: Participants enrolled in a multi-center trial of non-surgical therapy (continence pessary, pelvic floor muscle training or combined) for stress predominant UI and completed baseline and 3-month diaries, the Urinary Distress Inventory (UDI) and QUID. Data from all treatment groups were pooled. QUID internal consistency (Cronbach's alpha) and convergent/discriminant validity (Pearson correlations) were evaluated. Responsiveness to change was assessed with 3-month score outcomes and distribution-based measurements. RESULTS: Four hundred forty-four women (mean age 50) were enrolled with stress (N = 200) and mixed (N = 244) UI; 344 had 3-month data. Baseline QUID Stress and Urge scores (both scaled 0-15, larger values indicating worse UI) were 8.4 +/- 3.2 and 4.5 +/- 3.3, respectively. Internal consistency of QUID Total, Stress, and Urge scores was 0.75, 0.64 and 0.87, respectively. QUID Stress scores correlated moderately with UDI-Stress scores (r = 0.68, P < 0.0001) and diary stress UI episodes (r = 0.41, P < 0.0001). QUID Urge scores correlated moderately with UDI-Irritative scores (r = 0.68, P < 0.0001) and diary urge UI episodes (r = 0.45, P < 0.0001). Three month QUID Stress and Urge scores improved (4.1 +/- 3.4 and 2.2 +/- 2.7, both P < 0.0001). QUID Stress score effect size (1.3) and standardized response mean (1.2) suggested a large change after therapy. CONCLUSION: The QUID has acceptable psychometric characteristics and may be used as a UI outcome measure in clinical trials. PMID- 19787712 TI - The effect of intravesical oxybutynin on the ice water test and on electrical perception thresholds in patients with neurogenic detrusor overactivity. AB - AIMS: The C-fiber-mediated bladder-cooling reflex and the determination of the current perception thresholds (CPTs) permit to investigate afferent LUT pathways. They have both been proposed to detect and differentiate neurologic bladder dysfunction. This study evaluates, prospectively, the effect of oxybutynin, an antimuscarinic with direct antispasmodic effect on smooth muscle, on repeated ice water test (IWT) and CPTs in patients with a known incomplete neurogenic bladder. METHODS: Patients with a known incomplete lesion of the bladder innervation, detrusor overactivity during cystometric bladder filling and a continuous positive response to repeated IWT were included. After the initial tests, 30 mg intravesical oxybutynin (1 mg/ml) was instilled and left in the bladder for 15 min. Afterwards CPTs and IWT were re-assessed. RESULTS: After the drug application, the bladder-cooling reflex could not be initiated, even after three instillations, in 16/17 patients. The bladder CPT increased from 29.7 +/- 11.3 to 39.1 +/- 15.7 mA after oxybutynin (P = 0.001). No difference was found in CPT of the left forearm (P = 0.208). CONCLUSIONS: Intravesical oxybutynin blocks the bladder-cooling reflex and increases but does not block CPT sensation in the bladder in most patients with incomplete neurogenic lesion and detrusor overactivity. These results help explain the clinical effect of intravesical oxybutynin in neurogenic patients. They also indicate that a pharmacological local influence on C-fiber-related activity can give different clinical effects. PMID- 19787713 TI - Toward a practical protocol for human optic nerve DTI with EPI geometric distortion correction. AB - PURPOSE: To develop a practical protocol for diffusion tensor imaging (DTI) of the human optic nerve with echo planar imaging (EPI) geometric distortion correction. MATERIALS AND METHODS: A conventional DTI protocol was modified to acquire images with fat and cerebrospinal fluid (CSF) suppression and field inhomogeneity maps of contiguous coronal slices covering the whole brain. The technique was applied to healthy volunteers and multiple sclerosis patients with and without a history of unilateral optic neuritis. DTI measures and optic nerve tractography before and after geometric distortion correction were compared. Diffusion measures from left and right or from affected and unaffected eyes in different subject cohorts were reported. RESULTS: The image geometry after correction closely resembled reference anatomical images. Optic nerve tractography became feasible after distortion correction. The diffusion measures from the healthy volunteers were in good agreement with the literature. Statistically significant differences were found in the fractional anisotropy and orthogonal eigenvalues between affected and unaffected eyes in optic neuritis patients with poor recovery. The diffusion measures before and after geometric distortion correction were not significantly different. For cohorts without optic neuritis, the difference between diffusion measures from left and right eyes was not statistically significant. CONCLUSION: The proposed technique could provide a practical DTI protocol to study the human optic nerve. PMID- 19787714 TI - Value of quantitative MRI biomarkers (Evans' index, aqueductal flow rate, and apparent diffusion coefficient) in idiopathic normal pressure hydrocephalus. AB - PURPOSE: To define the value of Evans' index (EI), aqueductal flow rate (FR), and apparent diffusion coefficient (ADC) in the diagnosis of normal pressure hydrocephalus (NPH) and to assess the ability of these markers preoperatively to predict shunt response. To shed some light as to the mechanisms responsible for the symptoms of NPH. MATERIALS AND METHODS: Preoperative EI, FR, and ADC readings in nine cases of clinically diagnosed NPH were compared with those of age- and gender-matched controls. Similar pre- and postoperative readings of responders and nonresponders were subsequently compared. RESULTS: Compared with the controls, all measurements were statistically significant except for peak systolic flow rate (pSfr), which was near statistical significance. Comparison of pre- and postoperative readings of responders and nonresponders revealed a decrease in ADC in all responders (P = 0.032). Subdural hemorrhage was found in all nonresponders (P = 0.012). CONCLUSION: For patients presenting with signs and symptoms of NPH, readings on MRI greater than 0.3, 10 mL/min, -9.0 mL/min, and 10.65 x 10(-4) mm(2)/s for EI, peak diastolic flow rate (pDfr), pSfr, and ADC, respectively, add further weight to the diagnosis. The strong correlation between shunt response and ADC decline support our hypothesis that water accumulation in the cerebrum is the major cause for the symptoms of NPH. The presence of subdural hemorrhage in all nonresponders raises suspicion of decreased compliance as the other major cause. PMID- 19787715 TI - Differentiating multiple sclerosis from other causes of demyelination using diffusion weighted imaging of the corpus callosum. AB - PURPOSE: To compare diffusion weighted imaging metrics in gray and white matter brain regions of patients diagnosed with multiple sclerosis (MS) to those diagnosed with secondary demyelinating diseases such as neurosarcoid and acute disseminated encephalomyelitis (ADEM). MATERIALS AND METHODS: Diffusion weighted scans were performed and apparent diffusion coefficients of 12 regions of interest were determined in 30 MS patients, 21 neurosarcoid patients, and 4 ADEM patients. RESULTS: Mean apparent diffusion coefficients were significantly higher in MS patients than in non-MS patients in 6 of 6 of the corpus callosal regions assessed but not in any of the non-callosal white or gray matter regions assessed. CONCLUSION: Elevated apparent diffusion coefficients within the corpus callosum on diffusion weighted imaging may potentially help differentiate between patients with MS and patients with other diseases affecting the central nervous system white matter. PMID- 19787716 TI - Detecting lesions in multiple sclerosis at 4.7 tesla using phase susceptibility weighting and T2-weighting. AB - PURPOSE: To demonstrate 4.7 Tesla (T) imaging methods for visualizing lesions in multiple sclerosis in the human brain using phase susceptibility-weighting and T2 weighting. MATERIALS AND METHODS: Seven patients with relapsing-remitting multiple sclerosis were imaged at 4.7T using three-dimensional (3D) susceptibility-weighted imaging (SWI) with 0.90 mm(3) voxel volumes, and with 2D T2-weighted fast spin echo (T2WFSE) with 0.34 mm(3) voxels and 1.84 mm(3) voxels. The visibility of MS lesions at 4.7T with phase SWI and T2WFSE was assessed by independent lesion counts made by an experienced neuroradiologist, and by quantitative measures. RESULTS: High resolution T2WFSE at 4.7T provided excellent depiction of hyperintense lesions. When combined with phase SWI, 124 total lesions were identified of which 18% were only visible on phase SWI and not on T2WFSE. The phase lesions had a mean phase shift relative to local background of 11.15 +/- 5.97 parts per billion. CONCLUSION: Imaging at 4.7T can provide both high quality, high resolution T2WFSE and SWI for visualization of lesions in multiple sclerosis. Phase susceptibility-weighting can identify additional lesions that are not visible with high resolution T2WFSE. PMID- 19787717 TI - Quantitative multivoxel proton spectroscopy of the brain in developmental delay. AB - PURPOSE: To assess whether proton MR spectroscopy of the brain in children with developmental delay reveals a consistent pattern of abnormalities. MATERIALS AND METHODS: Eighty-eight patients (median age, 4.6 years; interquartile range, 3.1 8.1 years) with unexplained developmental delay, were compared with 48 normally developing age-matched controls. Patients and controls were assigned to five age groups. Multivoxel MR spectroscopy was performed on a volume of interest superior to the lateral ventricles. The relative levels of choline, creatine, N-acetyl aspartate, and glutamate/glutamine in 24 voxels containing white matter and 12 voxels containing gray matter were quantified in an operator-independent manner and expressed in proportion to the total metabolite peak area in the volume of interest. RESULTS: White matter choline in DD showed less decrease with age. Mean choline levels, compared with mean control levels, increased from 99 to 111% with increasing age. This was statistically significant in the highest age groups (P = 0.015 [7 < yr 0.95, P < 0.001 for all measures), as well as in the assessment of wall motion (kappa statistic 0.75). CONCLUSION: MCLE provided coregistered images for the assessment of viability and wall motion without loss of accuracy in the assessment of quantitative cardiac parameters. MCLE provides accurate quantitative cardiac assessment with reduced scan times compared to the conventional sequences and thus may be used as an alternative to conventional cine SSFP and IR-GRE imaging. PMID- 19787724 TI - Robust tissue-air volume segmentation of MR images based on the statistics of phase and magnitude: Its applications in the display of susceptibility-weighted imaging of the brain. AB - PURPOSE: To develop a robust algorithm for tissue-air segmentation in magnetic resonance imaging (MRI) using the statistics of phase and magnitude of the images. MATERIALS AND METHODS: A multivariate measure based on the statistics of phase and magnitude was constructed for tissue-air volume segmentation. The standard deviation of first-order phase difference and the standard deviation of magnitude were calculated in a 3 x 3 x 3 kernel in the image domain. To improve differentiation accuracy, the uniformity of phase distribution in the kernel was also calculated and linear background phase introduced by field inhomogeneity was corrected. The effectiveness of the proposed volume segmentation technique was compared to a conventional approach that uses the magnitude data alone. RESULTS: The proposed algorithm was shown to be more effective and robust in volume segmentation in both synthetic phantom and susceptibility-weighted images of human brain. Using our proposed volume segmentation method, veins in the peripheral regions of the brain were well depicted in the minimum-intensity projection of the susceptibility-weighted images. CONCLUSION: Using the additional statistics of phase, tissue-air volume segmentation can be substantially improved compared to that using the statistics of magnitude data alone. PMID- 19787726 TI - First-pass and steady-state magnetic resonance angiography of the thoracic vasculature using gadofosveset trisodium. AB - PURPOSE: To compare a high-resolution, ECG-gated, motion-compensated, steady state magnetic resonance angiography (SS-MRA) of the thoracic vasculature to standard first-pass MRA (FP-MRA) using a blood-pool contrast agent (gadofosveset trisodium). MATERIALS AND METHODS: In all, 25 patients >or=18 years with congenital or acquired disease of the thoracic vasculature, who underwent both FP MRA and SS-MRA, were retrospectively identified. Diameters of left superior pulmonary vein (LSPV), left pulmonary artery (LPA), and aortic arch (AA) were measured. Image quality for LSPV, LPA, AA, coronary ostia, and coronary sinus were assessed. Vessel sharpness of LPA and LSPV and contrast ratio (CR) of LSPV, LPA, and AA were calculated. RESULTS: SS-MRA yielded significantly higher image quality for all vessels, and significantly higher vessel sharpness for LSPV and LPA compared to the FP-MRA. SS-MRA revealed lower intra- and interobserver variability for vessel diameters compared with the FP-MRA. The FP-MRA showed higher CR compared to the SS-MRA. CONCLUSION: Motion-compensated high-resolution SS-MRA of the thoracic vasculature using gadofosveset trisodium offers superior image quality compared to standard FP-MRA. Although SS-MRA delivers no dynamic information it may prove specifically helpful as an add-on to FP-MRA for imaging of small vascular structures. PMID- 19787725 TI - Effects of diffusion time on short-range hyperpolarized (3)He diffusivity measurements in emphysema. AB - PURPOSE: To characterize the effect of diffusion time on short-range hyperpolarized (3)He magnetic resonance imaging (MRI) diffusion measurements across a wide range of emphysema severity. MATERIALS AND METHODS: (3)He diffusion MRI was performed on 19 lungs or lobes resected from 18 subjects with varying degrees of emphysema using three diffusion times (1.6 msec, 5 msec, and 10 msec) at constant b value. Emphysema severity was quantified as the mean apparent diffusion coefficient (ADC) and as the percentage of pixels with ADC higher than multiple thresholds from 0.30-0.55 cm(2)/sec (ADC index). Quantitative histology (mean linear intercept) was obtained in 10 of the lung specimens from 10 of the subjects. RESULTS: The mean ADCs with diffusion times of 1.6, 5.0, and 10.0 msec were 0.46, 0.40, and 0.37 cm(2)/sec, respectively (P < 0.0001, analysis of variance [ANOVA]). There was no relationship between the ADC magnitude and the effect of diffusion time on ADC values. The mean linear intercept correlated with ADC (r = 0.91-0.94, P < 0.001) and ADC index (r = 0.78-0.92, P < 0.01) at all diffusion times. CONCLUSION: Decreases in ADC with longer diffusion time were unrelated to emphysema severity. The strong correlations between the ADC at all diffusion times tested and quantitative histology demonstrate that ADC is a robust measure of emphysema. PMID- 19787727 TI - Algorithm-based method for detection of blood vessels in breast MRI for development of computer-aided diagnosis. AB - PURPOSE: To develop a computer-based algorithm for detecting blood vessels that appear in breast dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI), and to evaluate the improvement in reducing the number of vascular pixels that are labeled by computer-aided diagnosis (CAD) systems as being suspicious of malignancy. MATERIALS AND METHODS: The analysis was performed in 34 cases. The algorithm applied a filter bank based on wavelet transform and the Hessian matrix to detect linear structures as blood vessels on a two-dimensional maximum intensity projection (MIP). The vessels running perpendicular to the MIP plane were then detected based on the connectivity of enhanced pixels above a threshold. The nonvessel enhancements were determined and excluded based on their morphological properties, including those showing scattered small segment enhancements or nodular or planar clusters. The detected vessels were first converted to a vasculature skeleton by thinning and subsequently compared to the vascular track manually drawn by a radiologist. RESULTS: When evaluating the performance of the algorithm in identifying vascular tissue, the correct detection rate refers to pixels identified by both the algorithm and radiologist, while the incorrect-detection rate refers to pixels identified by only the algorithm, and the missed-detection rate refers to pixels identified only by the radiologist. From 34 analyzed cases the median correct-detection rate was 85.6% (mean 84.9% +/- 7.8%), the incorrect-detection rate was 13.1% (mean 15.1% +/- 7.8%), and the missed-detection rate was 19.2% (mean 21.3% +/- 12.8%). When detected vessels were excluded in the hot-spot color-coding of the CAD system, they could reduce the labeling of vascular vessels in 2.6%-68.6% of hot-spot pixels (mean 16.6% +/- 15.9%). CONCLUSION: The computer algorithm-based method can detect most large vessels and provide an effective means in reducing the labeling of vascular pixels as suspicious on a DCE-MRI CAD system. This algorithm may improve the workflow of radiologists using CAD for image display, but will be particularly useful for development of automated CAD that gives diagnostic impression. PMID- 19787728 TI - Inhomogeneity of rat vertebrae trabecular architecture by high-field 3D mu magnetic resonance imaging and variable threshold image segmentation. AB - PURPOSE: To analyze the 3D microarchitecture of rat lumbar vertebrae by micro magnetic resonance imaging (micro-MRI). MATERIALS AND METHODS: micro-MR images (20 x 20 x 20 microm(3) apparent voxel size) were acquired with a three dimensional spin-echo pulse sequence on four lumbar vertebrae of two rats. Apparent microarchitectural parameters like trabecular bone fraction (BV/TV), specific bone surface (BS/TV), mean intercept length (MIL), and Euler number per unit volume (Euler density, E(V)) were calculated using a novel semiquantitative variable threshold segmentation technique. The threshold value T was obtained as a point of minimum or maximum of the function E(V) = E(V)(T). RESULTS: Quantitative 3D analysis of micro-MRI images revealed a higher connectivity in the peripheral regions (E(V) = -570 +/- 70 mm(-3)) than in the central regions (E(V) = -130 +/- 50 mm(-3)) of the analyzed rat lumbar vertebrae. Smaller intertrabecular cavities and larger bone volume fractions were observed in peripheral regions as compared to central ones (MIL = 0.18 +/- 0.01 mm and 0.26 +/- 0.01 mm; BV/TV = 34 +/- 3% and 29 +/- 3%, respectively). The quantitative 3D study of MIL showed a structural anisotropy of the trabeculae along the longitudinal axis seen on the images. The inhomogeneity of the bone architecture was validated by micro-computed tomography (micro-CT) images at the same spatial resolution. CONCLUSION: 3D high-field micro-MRI is a suitable technique for the assessment of bone quality in experimental animal models. PMID- 19787729 TI - Local flip angle correction for improved volume T1-quantification in three dimensional dGEMRIC using the Look-Locker technique. AB - PURPOSE: To present an evaluation method for three-dimensional Look-Locker (3D LL) based T1 quantification, calculating correct T1 values independent of local flip angle (FA) variations. The method was evaluated both in phantoms and in vivo in a delayed Gadolinium Enhanced MRI of Cartilage (dGEMRIC) study with 33 subjects. MATERIALS AND METHODS: T1 was measured with 3D-LL, using both local FA correction and a precalculated FA slice profile, and compared with standard constant FA correction, for all slices in phantoms and in both femur condyles in vivo. T1 measured using two-dimensional Inversion Recovery (2D-IR) was used as gold standard. RESULTS: Due to the FA being slice dependent, the standard constant FA correction results in erroneous T1 (systematic error = 109.1 ms in vivo), especially in the outer slices. With local FA correction, the calculated T1 is excellent for all slices in phantoms (<5% deviation from 2D-IR). In vivo the performance is lower (systematic error = -57.5 ms), probably due to imperfect inversion. With precalculated FA correction the performance is very good also in vivo (systematic error = 13.3 ms). CONCLUSION: With the precalculated FA correction method, the 3D-LL sequence is robust enough for in vivo dGEMRIC, even outside the centermost slices. PMID- 19787730 TI - Initial feasibility of a multi-station high resolution three-dimensional dark blood angiography protocol for the assessment of peripheral arterial disease. AB - PURPOSE: To evaluate the feasibility of a multi-station three dimensional (3D) T1 weighted turbo spin echo (TSE) dark-blood Sampling Perfection with Application optimized Contrasts using different flip angle Evolution sequence (T1w-SPACE), to assess aorta, iliac, and superficial femoral (SFA) arteries (inflow vessels) by comparing it with a multi-station contrast enhanced MR angiography (CE-MRA) with identical resolution. MATERIALS AND METHODS: A total of 6 volunteers and 14 peripheral arterial disease (PAD) patients were included in the study. Abdominal and thigh T1w-SPACE and lower leg time-resolved MRA (TR-MRA) with low dose contrast were followed by 3-station CE-MRA. Quantitative measurements of lumen area at 17 locations from T1w-SPACE and CE-MRA were obtained. Additionally, vessel wall areas at the same locations were obtained from the T1w-SPACE images. RESULTS: Quantitative comparison of lumen areas with T1w-SPACE and CE-MRA revealed strong correlation between the two techniques and strong inter-observer agreement for each of the two imaging methods (r > 0.9; P < 0.001). Localized vessel wall area measurements obtained in PAD patients were significantly greater compared with those obtained in normal volunteers (mean difference 43.75 +/- 12.46 mm(2); P < 0.001). Stenosis severity obtained from T1w-SPACE localized measurements showed significant arterial area stenosis in PAD patients. CONCLUSION: T1w-SPACE imaging of inflow vessels is feasible, and in addition to CE-MRA has the ability to assess atherosclerotic plaque and vascular remodeling. PMID- 19787731 TI - Left ventricular infarct size, peri-infarct zone, and papillary scar measurements: A comparison of high-resolution 3D and conventional 2D late gadolinium enhancement cardiac MR. AB - PURPOSE: To compare higher spatial resolution 3D late gadolinium enhancement (LGE) cardiovascular magnetic resonance (Cardiac MR) with 2D LGE in patients with prior myocardial infarction. MATERIALS AND METHODS: Fourteen patients were studied using high spatial resolution 3D LGE (1.3 x 1.3 x 5.0 mm(3)) and conventional 2D LGE (2 x 2 x 8 mm(3)) scans. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were measured. Total infarct volume, peri-infarct volume measured in a limited slab, and papillary muscle scar volume were compared using Bland-Altman analysis. Image quality was graded. RESULTS: 3D LGE had higher scar SNR (P < 0.001), higher myocardial SNR (P = 0.001), higher papillary scar blood CNR (P = 0.01), and greater sharpness (P = 0.01). The scar volumes agreed (14.5 +/- 8.2 for 2D, vs. 13.2 +/- 8.8 for 3D), with bias +/- 2 standard deviations (SDs) of 0.5 +/- 6.8 mL, P = 0.59 R = 0.91. The peri-infarct volumes correlated but less strongly than scar (P = 0.40, R = 0.77). For patients with more heterogeneous scar, larger peri-infarct volumes were measured by 3D (1.9 +/- 1.1 mL for 2D vs. 2.4 +/- 1.6 mL for 3D, P = 0.15, in the matched region). Papillary scar, present in 6/14 (42%) patients, was more confidently identified on 3D LGE. CONCLUSION: Higher spatial resolution 3D LGE provides sharper images and higher SNR, but less myocardial nulling. Scar volumes agree well, with peri infarct volumes correlating less well. 3D LGE may be superior in visualization of papillary muscle scar. PMID- 19787732 TI - Improved correlation to quantitative DCE-MRI pharmacokinetic parameters using a modified initial area under the uptake curve (mIAUC) approach. AB - PURPOSE: To propose a modified initial area under the uptake curve (mIAUC) dynamic contrast-enhanced (DCE)-MRI approach to achieve better distinction of underlying physiology. MATERIALS AND METHODS: The mIAUC is formulated on common characteristics of tissue contrast uptake curves observed over a wide range of physiological conditions. The new metrics, IAUC(Ktrans) and IAUC(ve), are related to the transfer constant (K(trans)) and interstitial volume (v(e)), respectively. Tissue uptake curves were simulated over a range of physiological values and analyzed using the proposed mIAUC, conventional IAUC, and Tofts' pharmacokinetic model. RESULTS: IAUC(Ktrans) and IAUC(ve) are highly correlated to the true K(trans) and v(e) (rho = 0.97 and 0.95, respectively), approaching the performance of Tofts' model based on a 1.5-s sampled arterial input function (AIF) (rho = 0.98 and 0.98) under noise conditions typical in DCE-MRI experiments. Lower correlations were obtained with conventional IAUC(60) and IAUC(120) (rho = 0.82 and 0.61) and Tofts' parameters fitted using a biexponential AIF (rho = 0.81 and 0.90). CONCLUSION: The proposed mIAUC approach retains advantages associated with nonmodel based methods (robust to noise and model fit failure, obviates need for an AIF) while providing better distinction of underlying physiological parameters. It can be a valuable alternative to pharmacokinetic modelling in the analysis of DCE-MRI data. PMID- 19787733 TI - Atypical imaging appearance of toxoplasmosis in an HIV patient as a butterfly lesion. AB - In acquired immunodeficiency syndrome (AIDS) patients, differentiating toxoplasmosis and primary central nervous system (CNS) lymphoma remains a clinical and radiographic dilemma. The presence of butterfly lesions crossing the corpus callosum is customarily used to exclude the possibility of toxoplasmosis. We present an AIDS patient who had Epstein-Barr virus (EBV) polymerase chain reaction (PCR) -positive cerebrospinal fluid studies with a butterfly toxoplasmosis lesion confirmed by multiple methods signifying the importance of including toxoplasmosis in the differential diagnosis of butterfly lesions. PMID- 19787734 TI - Dilution method of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd EOB-DTPA)-enhanced magnetic resonance imaging (MRI). AB - PURPOSE: To elucidate whether a contrast agent dilution method (dilution method), in which gadoxetate disodium (Gd-EOB-DTPA) is diluted with saline, is useful for good-quality arterial-phase images. MATERIALS AND METHODS: In this study we observed 494 hypervascular hepatocellular carcinomas (HCCs) in 327 patients with chronic liver disease. Three Gd-EOB-DTPA injection methods were adopted for comparison: 1) test injection method (undiluted Gd-EOB-DTPA and modified scan delay), in which a test dose of 0.5 mL of Gd-EOB-DTPA was injected to determine scan delay; 2) conventional method (undiluted Gd-EOB-DTPA and fixed scan delay); and (3) dilution method (diluted Gd-EOB-DTPA and fixed scan delay), in which Gd EOB-DTPA was diluted to 20 mL with saline. Lesion-liver contrast was calculated. Image quality and lesion detectability were evaluated by two radiologists blinded to the injection methods. RESULTS: The lesion-liver contrast of the dilution method was significantly higher than that of the other two methods. Lesion detectability of the conventional method (64%) was significantly lower than that of the other two methods (contrast agent dilution method, 95%; test injection method, 93%). The image quality of the contrast agent dilution method was significantly better than that of the other two methods. CONCLUSION: The dilution method contributed to improved image quality, high lesion-liver contrast, and high lesion detectability in the arterial-phase images of GD-EOB-DTPA-enhanced MRI. PMID- 19787736 TI - 3.0-T MR-guided focused ultrasound for preoperative localization of nonpalpable breast lesions: an initial experimental ex vivo study. AB - PURPOSE: To compare the accuracy of magnetic resonance-guided focused ultrasound (MRgFUS) with MR-guided needle-wire placement (MRgNW) for the preoperative localization of nonpalpable breast lesions. MATERIALS AND METHODS: In this experimental ex vivo study, 15 turkey breasts were used. In each breast phantom an artificial nonpalpable "tumor" was created by injecting an aqueous gel containing gadolinium. MRgFUS (n = 7) was performed with the ExAblate 2000 system (InSightec). With MRgFUS the ablated tissue changes in color and increases in stiffness. A rim of palpable and visible ablations was created around the tumor to localize the tumor and facilitate excision. MRgNW (n = 8) was performed by MR guided placement of an MR-compatible needle-wire centrally in the tumor. After surgical excision of the tumor, MR images were used to evaluate tumor-free margins (negative/positive), minimum tumor-free margin (mm), and excised tissue volume (cm(3)). RESULTS: With MRgFUS localization no positive margins were found after excision (0%). With MRgNW two excision specimens (25%) had positive margins (P = 0.48). Mean minimum tumor-free margin (+/-SD) with MRgFUS was significantly larger (5.5 +/- 2.4 mm) than with MRgNW (0.9 +/- 1.4 mm) (P < 0.001). Mean volume +/- SD of excised tissue did not differ between MRgFUS and MRgNW localization, ie, 44.0 +/- 9.4 cm(3) and 39.5 +/- 10.7 cm(3) (P = 0.3). CONCLUSION: The results of this experimental ex vivo study indicate that MRgFUS can potentially be used to localize nonpalpable breast lesions in vivo. PMID- 19787735 TI - Cyclic motion encoding for enhanced MR visualization of slip interfaces. AB - PURPOSE: To develop and test a magnetic resonance imaging-based method for assessing the mechanical shear connectivity across tissue interfaces with phantom experiments and in vivo feasibility studies. MATERIALS AND METHODS: External vibrations were applied to phantoms and tissue and the differential motion on either side of interfaces within the media was mapped onto the phase of the MR images using cyclic motion encoding gradients. The phase variations within the voxels of functional slip interfaces reduced the net magnitude signal in those regions, thus enhancing their visualization. A simple two-compartment model was developed to relate this signal loss to the intravoxel phase variations. In vivo studies of the abdomen and forearm were performed to visualize slip interfaces in healthy volunteers. RESULTS: The phantom experiments demonstrated that the proposed technique can assess the functionality of shear slip interfaces and they provided experimental validation for the theoretical model developed. Studies of the abdomen showed that the slip interface between the small bowel and the peritoneal wall can be visualized. In the forearm, this technique was able to depict the slip interfaces between the functional compartments of the extrinsic forearm muscles. CONCLUSION: Functional shear slip interfaces can be visualized sensitively using cyclic motion encoding of externally applied tissue vibrations. PMID- 19787737 TI - High resolution fast T1 mapping technique for dGEMRIC. AB - PURPOSE: To determine the feasibility of using a high resolution isotropic three dimensional (3D) fast T1 mapping sequence for delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) to assess osteoarthritis in the hip. MATERIALS AND METHODS: T1 maps of the hip were acquired using both low and high resolution techniques following the administration of 0.2 mmol/kg Gd-DTPA(2-) in 35 patients. Both T1 maps were generated from two separate spoiled GRE images. The high resolution T1 map was reconstructed in the anatomically equivalent plane as the low resolution map. T1 values from the equivalent anatomic regions containing femoral and acetabular cartilages were measured on the low and high resolution maps and compared using regression analysis. RESULTS: In vivo T1 measurements showed a statistically significant correlation between the low and high resolution acquisitions at 1.5 Tesla (R(2) = 0.958, P < 0.001). These results demonstrate the feasibility of using a fast two-angle T1 mapping (F2T1) sequence with isotropic spatial resolution (0.8 x 0.8 x 0.8 mm) for quantitative assessment of biochemical status in articular cartilage of the hip. CONCLUSION: The high resolution 3D F2T1 sequence provides accurate T1 measurements in femoral and acetabular cartilages of the hip, which enables the biochemical assessment of articular cartilage in any plane through the joint. It is a powerful tool for researchers and clinicians to acquire high resolution data in a reasonable scan time (< 30 min). PMID- 19787738 TI - Cellular magnetic resonance imaging for the differentiation of infectious and degenerative vertebral disorders: preliminary results. AB - PURPOSE: To evaluate macrophage imaging using the ability of superparamagnetic iron oxide (SPIO) magnetic resonance imaging (MRI) to differentiate infectious vertebral osteomyelitis and degenerative disk-related inflammatory endplates. The in vivo demonstration of the different distribution of macrophages in those two disorders may allow a more accurate characterization of vertebral endplate abnormalities than classical extracellular MR changes. MATERIALS AND METHODS: In 12 patients with endplate abnormalities (six cases of bacteriologically proven spondylodiscitis, six cases of disk degeneration-related endplate changes), two MRI sessions were realized: before and 24 hours after injection of SPIO. The signal-to-noise ratio (SNR) of endplates were qualitatively and quantitatively compared on pre- and post-SPIO injection T1 and T2-weighted (T2w) MR images (Wilcoxon signed rank test). RESULTS: In the infection group, the SNR of abnormal endplates showed a significant signal loss on T2w MR images (P = 0.03) but not on T1w images (P = 0.46). In the degenerative spine group, no significant signal loss was observed on T1 (P = 0.6) nor on T2w MR images (P = 0.6). Signal loss was only visually observable in abnormal endplate in one patient of the spondylodiscitis group on T2w MR images. CONCLUSION: MRI of the spine with iron oxide injection differentiates infection from aseptic inflammation on quantitative analysis, but the use of SPIO makes direct visual evaluation less satisfactory. PMID- 19787739 TI - Cardiovascular magnetic resonance reveals similar damage to the heart of patients with Becker and limb-girdle muscular dystrophy but no cardiac symptoms. AB - Cardiac involvement in patients with a sarcoglycanopathy (limb-girdle muscular dystrophy) has been described previously; however, this is the first cardiovascular magnetic resonance (CMR) study in such a patient demonstrating an interesting pattern of myocardial damage using late gadolinium enhancement (LGE) imaging. Moreover, the wall motion abnormality and the subepicardial pattern of LGE in this patient with a sarcoglycanopathy is in agreement with the findings in another patient with Becker muscular dystrophy. The predominance of LGE in the subepicardial layers of the left ventricular inferolateral wall suggests that such a myocardial damage pattern represents a nonspecific cardiac phenotype in response to exaggerated mechanical stress in this region, at least in patients with a sarcoglycanopathy or dystrophinopathy. PMID- 19787740 TI - Influence of the compliance of the neck arteries and veins on the measurement of intracranial volume change by phase-contrast MRI. AB - PURPOSE: To assess the influence of arterial and venous vascular compliances in the neck region on the measurement of the change in intracranial volume during the cardiac cycle. MATERIALS AND METHODS: Arterial and venous blood flows were imaged by MRI phase contrast at two different locations, one close to the skull base (upper) and one 2-3 cm lower, around C3 level (lower). Maximal intracranial volume change (ICVC) measurements were derived from the momentary difference between the arterial inflow and venous outflow rates at the upper and lower locations separately to assess the influence of the compliances of the vessel segments bounded by the two different imaging locations. Imaging location for the craniospinal cerebrospinal fluid flow was a constant variable in this experiment. RESULTS: The systolic ICVC obtained using the lower location was consistently larger than when using the upper location. Comparison between arterial and venous flow dynamics revealed a much larger changes in flow dynamic and lumen areas in the veins compared with the arteries, which explain the large venous influence on the intracranial volume change measurement. CONCLUSION: Arterial inflow and venous outflow should be sampled at a level close to the skull base (C1-C2) to minimize the influence of the compliance of arteries and the collapsibility of veins for a reliable measurement of ICVC. PMID- 19787741 TI - T2 relaxometry of maturing brains. PMID- 19787744 TI - Investigation using an HER-2/neu transgenic mouse model of a newly developed MR contrast agent with the effect of an antitumor drug. AB - PURPOSE: To assess whether Gd-DTPA-Gel-Cis, a conjugate of gadolinium (Gd), cis diamminedichloroplatinum (Cis), diethylenetriaminepentaacetic acid (DTPA) dianhydride, and bovine gelatin (Gel) can be used as an intravascular contrast agent at MRI and as an antitumor cell proliferation agent in vitro. MATERIALS AND METHODS: We injected Gd-DTPA-Gel-Cis (200 mg/mL) into the caudal vein of female HER-2/neu transgenic mice with spontaneous mammary tumors. The tumor signal intensity was measured with a 0.3 Tesla MRI scanner. HER-2/neu-expressing NT cells were treated with Gd-DTPA-Gel-Cis (5 microM cisplatin, 200 mg/mL Gel), Cis alone (5 microM cisplatin), or Gel alone (200 mg/mL gelatin). Differences of P < 0.05 were considered to be statistically significant. RESULTS: On T1-weighted MRI scans of mice injected with Gd-DTPA-Gel-Cis we observed a 23% increase in signal intensity. The survival rates of cells exposed to Gd-DTPA-Gel-Cis or Cis were 70.9% and 58.3%, respectively, of the survival rates observed after treatment with Gel alone. Gd-DTPA-Gel-Cis showed significant toxicity (P < 0.05). CONCLUSION: Gd-DTPA-Gel-Cis shows promise for use as an MRI contrast medium and as an antitumor agent. PMID- 19787745 TI - In vivo DTI assessment of hepatic ischemia reperfusion injury in an experimental rat model. AB - PURPOSE: To investigate hepatic ischemia reperfusion injury (IRI) using diffusion tensor imaging (DTI). MATERIALS AND METHODS: Ten Sprague-Dawley rats were scanned at 7 Tesla (T) with DTI using b-value of 1000 s/mm(2) and 6 gradient directions before, 2 h, and 1 day after 30-min total hepatic IRI. Apparent diffusion coefficient or mean diffusivity (MD), directional diffusivities and fractional anisotropy (FA) were measured. Seven of the animals were also examined with spin echo echo-planar diffusion-weighted imaging (DWI) with seven b-values up to 2000 s/mm(2) to estimate the true diffusion coefficient (D), blood pseudodiffusion coefficient (D), and perfusion fraction (f) using a bi-compartmental model. RESULTS: MD 2 h after IRI (0.77 +/- 0.07 x 10(-3) mm(2)/s) was significantly lower (P < 0.01) than that before (1.03 +/- 0.07 x 10(-3) mm(2)/s) and 1 day after IRI (1.01 +/- 0.05 x 10(-3) mm(2)/s). Meanwhile, FA 2 h after IRI (0.33 +/- 0.03) was significantly higher (P < 0.01) than that before (0.21 +/- 0.02) and 1 day after IRI (0.20 +/- 0.02). The bi-compartmental model analysis revealed the transient decrease in D, D and f 2 h after IRI. Liver histology showed the multifocal cell swelling 3 h after IRI and widespread cell necrosis/apoptosis 1 day after IRI. Sinusoidal narrowing and congestion of erythrocytes were also observed 3 h and 1 day after IRI. CONCLUSION: DTI can characterize hepatic IRI by detecting the transient change in both MD and FA. PMID- 19787746 TI - Learning styles in two otolaryngology residency programs. AB - OBJECTIVES/HYPOTHESIS: Kolb portrays four learning styles depending on how an individual grasps or transforms experience: accommodating, assimilating, diverging, and converging. Past studies in surgery, medicine, and anesthesia identified the predominant learning style in each of these specialties. The prevalence of different learning styles and existence of a predominant style, if any, has not been reported for otolaryngology residency programs. The purpose of our study was to determine if otolaryngology residents have a preferred learning style that is different from the predominant learning styles reported for other specialties. STUDY DESIGN: We conducted a survey of the otolaryngology-head and neck surgery residents at two residency programs. METHODS: Kolb's Learning Style Index (LSI) version 3.1 was administered to 46 residents from Johns Hopkins University and Kansas University Otolaryngology-Head and Neck Surgery programs. LSI is a widely used 12-item questionnaire, with each item followed by four options. The subjects graded the options depending on how the options applied to them. RESULTS: Forty-three otolaryngology residents completed the survey, with a response rate of 93.47%. The predominant learning style was converging (55.81%) followed by accommodating (18.61%), accounting for the learning styles of 74.42% of the total population. There were only 13.95% assimilating and 6.98% diverging learning styles. Two residents (4.65%) had their preference balanced across four learning styles. CONCLUSIONS: The predominant learning styles in otolaryngology were converging and accommodating, accounting for three fourths of the population. It would be desirable to modify our curriculum in a way that will optimize and facilitate learning. PMID- 19787747 TI - High resolution NMR based analysis of serum lipids in Duchenne muscular dystrophy patients and its possible diagnostic significance. AB - Proton NMR spectroscopic investigations on the lipid extract of the serum of 41 Duchenne muscular dystrophy (DMD) (age, mean +/- SD; 8.0 +/- 3.0 years) patients and 22 healthy subjects (age, mean +/- SD; 9.0 +/- 4.0 years) were performed in the northern Indian population. The concentration of triglycerides, phospholipids, free cholesterol, cholesterol esters and total cholesterol was significantly higher in DMD patients as compared to healthy subjects. Ratio of free-cholesterol to cholesterol-esters was also significantly higher in DMD patients. Among the individual lipids, concentration of phospholipids was found to be consistently higher in DMD patients compared to healthy subjects, with a discriminatory index of 87.5%. The highest discriminatory index of 92% was found along with the ratio of PL (phospholipids) to CHOL (cholesterol), i.e. PL/CHOL. No significant quantitative difference was observed in the serum lipid constituents of positive and negative gene deletion cases of DMD. The inferences drawn from this study may provide the possibility of the diagnostic importance for DMD, especially in cases where genetic analysis fails to provide the diagnosis. PMID- 19787748 TI - Letter 3: Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients (Br J Surg 2009; 96: 473-481). PMID- 19787749 TI - Letter 2: Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients (Br J Surg 2009; 96: 473-481). PMID- 19787750 TI - Letter 1: Randomized clinical trial of antibiotic therapy versus appendicectomy as primary treatment of acute appendicitis in unselected patients (Br J Surg 2009; 96: 473-481). PMID- 19787752 TI - Don't waste money when dressing leg ulcers. PMID- 19787753 TI - Randomized controlled trial and cost-effectiveness analysis of silver-donating antimicrobial dressings for venous leg ulcers (VULCAN trial). AB - BACKGROUND: Antimicrobial silver dressings are used beneath graduated compression in the treatment of venous ulceration. There is little information on whether their use is effective. This was a prospective randomized trial and cost effectiveness analysis of silver-donating versus non-silver low-adherence dressings in the treatment of venous leg ulcers. METHODS: Patients were randomized between the two types of dressing. The primary outcome measure was complete ulcer healing at 12 weeks. Secondary outcomes included time to healing, quality of life and cost-effectiveness. RESULTS: A total of 213 patients were recruited. There was no difference between the dressings in the proportion of ulcers healed at 12 weeks (59.6 per cent for silver and 56.7 per cent for control dressings). Mean utility scores for the EuroQol 5D and Short Form 6D were similar in both groups at 1, 3, 6 and 12 months. Compared with the control group the antimicrobial group had an incremental cost of pounds sterling 97.85 and an incremental quality-adjusted life year gain of 0.0002, giving an incremental cost effectiveness ratio of pounds sterling 489 250 for the antimicrobial dressings. CONCLUSION: No significant differences were found in either primary or secondary endpoints. There was no evidence to support the routine use of silver-donating dressings beneath compression for venous ulceration. REGISTRATION NUMBER: ISRCTN 72485131 (http://www.controlled-trials.com). PMID- 19787754 TI - Systematic review of atraumatic splenic rupture. AB - BACKGROUND: Atraumatic splenic rupture (ASR) is an ill defined clinicopathological entity. METHODS: The aim was to characterize aetiological and risk factors for ASR-related mortality in order to aid disease classification and treatment. A systematic literature review (1980-2008) was undertaken and logistic regression analysis employed. RESULTS: Some 632 publications reporting 845 patients were identified. The spleen was normal in 7.0 per cent (atraumatic idiopathic rupture). One, two or three aetiological factors were found in 84.1, 8.2 and 0.7 per cent respectively (atraumatic-pathological rupture). Six major aetiological groups were defined: neoplastic (30.3 per cent), infectious (27.3 per cent), inflammatory, non-infectious (20.0 per cent), drug- and treatment related (9.2 per cent) and mechanical (6.8 per cent) disorders, and normal spleen (6.4 per cent). Treatment comprised total splenectomy (84.1 per cent), organ preserving surgery (1.2 per cent) or conservative measures (14.7 per cent). The ASR-related mortality rate was 12.2 per cent. Splenomegaly (P = 0.040), age above 40 years (P = 0.007) and neoplastic disorders (P = 0.008) were associated with increased ASR-related mortality on multivariable analysis. CONCLUSION: The condition can be classified simply into atraumatic-idiopathic (7.0 per cent) and atraumatic-pathological (93.0 per cent) splenic rupture. Splenomegaly, advanced age and neoplastic disorders are associated with increased ASR-related mortality. PMID- 19787755 TI - Systematic review of tumour number and outcome after radical treatment of colorectal liver metastases. AB - BACKGROUND: Resection of colorectal liver metastases (CLMs) is potentially curative but the effect of tumour number on prognosis is uncertain. This study compared the prognosis after resection and/or ablation of between one and three, or four or more CLMs. METHODS: A systematic literature review from January 2000 to June 2008 was performed. Study selection and data extraction were standardized, and analysis included assessment of methodological quality, heterogeneity and bias. Main outcomes were 3- and 5-year survival. A meta analysis comparing radical treatment in the two groups was performed using the hazard ratio for overall survival. RESULTS: Of 1307 studies screened, 46 (9934 patients) were included in the analysis. Methodological quality was variable, and there was significant heterogeneity and reporting bias. The overall 5-year survival rate after radical treatment ranged from 7 to 58 per cent. Pooled hazard ratio for overall survival was 1.67 (95 per cent confidence interval 1.43 to 1.95; P < 0.001). Median reported 5-year survival for patients with four or more CLMs was 17.1 per cent. CONCLUSION: Radical treatment of more than three CLMs results in poorer overall survival. Nevertheless, 5-year survival is achievable and the number of lesions should not, of itself, be used to exclude patients from surgery. PMID- 19787756 TI - Randomized clinical trial of efficacy and costs of three dissection devices in liver resection (Br J Surg 2009; 96: 593-601). PMID- 19787758 TI - Randomized clinical trial of techniques for closure of the pancreatic remnant following distal pancreatectomy (Br J Surg 2009; 96: 602-607). PMID- 19787760 TI - Feasibility study of three-nerve-recognizing Lichtenstein procedure for inguinal hernia. AB - BACKGROUND: Inguinal nerve identification during open inguinal hernia repair is associated with less chronic postoperative pain. However, most Dutch surgeons do not identify all three inguinal nerves when carrying out this procedure. The aim of this study was to evaluate the feasibility of a nerve-recognizing Lichtenstein hernia repair and to measure the extra time required for surgery METHODS: Forty patients with primary inguinal hernia were operated on following the nerve recognizing Lichtenstein hernia repair by four experienced hernia surgeons from four different Dutch teaching hospitals. The additional time needed to identify each individual nerve was recorded, and iatrogenic nerve injuries and anatomical characteristics were registered. RESULTS: Identification of the iliohypogastric and ilioinguinal nerves was each performed within 1 min. Identification of the genital branch of the genitofemoral nerve was notably more difficult but could usually be performed within 2 min. Identification of the cremasteric vein, running parallel to the genital branch, was less comprehensive. The incidence of major anatomical variations was low. Twenty-five per cent of ilioinguinal nerves, however, could not be identified. In five patients inguinal nerves were damaged iatrogenically during standard manoeuvres of the Lichtenstein hernia repair. CONCLUSION: Three-nerve-recognizing Lichtenstein hernia repair is feasible and non-time consuming if the surgeon has appropriate anatomical knowledge. In view of the low incidence of major anatomical variations, knowledge of standard inguinal nervous anatomy should be adequate. This procedure could enable the surgeon to prevent or recognize iatrogenic nerve damage and offer an opportunity to perform deliberate neurectomy as an alternative to accidental nerve injury. PMID- 19787762 TI - Lateral mammaplasty reconstruction after surgery for breast cancer. AB - BACKGROUND: Up to 60 per cent of cancers develop laterally in the breast and breast-conserving surgery frequently produces superolateral nipple-areolar complex (NAC) distortion aggravated by postoperative irradiation. Correction is technically demanding and the outcomes are variable. Lateral mammaplasty may allow wider excision margins and prevent such deformities. METHODS: This was a review of 86 consecutive patients who had lateral mammaplasty: combined wide tumour excision with NAC repositioning on a reliable dermoglandular pedicle. Simultaneous axillary surgery was performed via a separate or combined incision. Aesthetic outcomes were assessed. RESULTS: The median age of the women was 54 (range 29-75) years; 55 (64 per cent) had palpable tumours and 73 (85 per cent) underwent simultaneous axillary surgery. Median radiological and histological tumour sizes were 29.8 and 33.6 mm, respectively, and median weight of excised tumour was 150 g. Two patients required haematoma evacuation. Eleven women required revisional surgery for involved or close margins. Aesthetic outcomes were excellent or good in 93 per cent. CONCLUSION: Lateral mammaplasty produced clear margins in 87 per cent of women. It is an option when a deformity is anticipated after breast-conserving surgery, and is particularly valuable when neoadjuvant chemotherapy has downgraded a large tumour. PMID- 19787761 TI - Cellular mechanisms of injury after major trauma. PMID- 19787763 TI - Effect of postoperative radiotherapy on autologous deep inferior epigastric perforator flap volume after immediate breast reconstruction. AB - BACKGROUND: The effect of postoperative radiotherapy following autologous flap breast reconstruction is controversial. The aim of this study was to measure whether adjuvant radiotherapy following immediate deep inferior epigastric perforator (DIEP) free flap breast reconstruction affected flap volume. METHODS: Sixty-eight women underwent immediate autologous DIEP flap reconstruction following mastectomy for breast cancer. Twenty-two of the 68 received postoperative radiotherapy (45Gy in 20 fractions over 4 weeks). Intraoperative flap volume data were collected prospectively. Volumetric assessment was carried out a minimum of 1 year after surgery. Patients who had volume adjustment surgery after initial reconstruction were analysed separately. RESULTS: The mean age of the women was 52 (range 37-69) years and median follow-up was 3.5 (range 1-10) years. There was no statistically significant difference in volume change between patients who had and those who did not have postreconstruction radiotherapy for the whole cohort (median reduction 65 versus 0 ml) or when women who had undergone further volume adjustment surgery were excluded. CONCLUSION: In this study postoperative radiotherapy did not significantly affect breast volume after DIEP flap reconstruction. The potential need for postoperative radiotherapy should not deter women from undergoing immediate DIEP flap breast reconstruction. PMID- 19787764 TI - Transgastric hybrid cholecystectomy. AB - BACKGROUND: Clinical application of natural orifice transluminal endoscopic surgery is under investigation. Preliminary results of transvaginal cholecystectomy in women and associated technical issues have been described. The technique and initial results of hybrid transgastric cholecystectomy are now reported. METHODS: Five patients aged 18-60 years with uncomplicated cholelithiasis underwent transgastric cholecystectomy in a prospective intention to-treat study that included the option of transparietal assistance (hybrid technique) if needed. The gastrotomy was created under laparoscopic guidance through a 5-mm umbilical trocar, which also served to expose the gallbladder, clip the cystic pedicle and close the gastrotomy. Cholecystectomy was carried out using flexible instruments through the endoscope, alone or in combination with laparoscopic instruments. RESULTS: The procedure was successful in all patients with a median operating time of 150 (range 120-180) min. Transparietal assistance was necessary in all patients. There were no intraoperative or postoperative complications. CONCLUSION: Until technical issues have been resolved, a hybrid procedure with liberal use of transparietal assistance is the safest and most efficient approach for transgastric cholecystectomy. Further studies are essential to evaluate the role of this new approach. PMID- 19787765 TI - Therapeutic delay reduces survival of rectal cancer but not of colonic cancer. AB - BACKGROUND: The relationship between therapeutic delay and long-term survival from colorectal cancer is unclear. This association was examined prospectively among patients with colorectal cancer in Denmark. METHODS: A total of 740 patients with colorectal cancer were included in a prospective, population-based study in three Danish counties from 1 January 2001 to 31 July 2002. Delay was determined by self-report during a standardized interview. Cox proportional hazards regression was used to compute the hazard ratio (HR) associated with delay, while adjusting for age, sex and co-morbidity, and also for urgency of surgery in patients with colonic cancer. RESULTS: For rectal cancer only, a time span of at least 60 days from the onset of symptoms until treatment (total therapeutic delay) was associated with a 69 per cent higher risk of mortality compared with a total therapeutic delay of less than 60 days (HR 1.69 (95 per cent confidence interval 1.01 to 2.83)). Provider delay (interval from first physician contact until treatment) and hospital delay (interval from referral to a hospital until treatment) of at least 60 days had no impact on survival from colorectal cancer. CONCLUSION: A total therapeutic delay of at least 60 days was a negative prognostic factor for long-term survival from rectal cancer. PMID- 19787766 TI - Locally recurrent rectal cancer in Norway. AB - BACKGROUND: The purpose of this study was to describe management and outcome in patients with locally recurrent rectal cancer based on data from the Norwegian Colorectal Cancer Registry. METHODS: This was a prospective national cohort study of 577 patients with local recurrence after major resection (R0/R1) for rectal cancer between November 1993 and December 2001 (initial cohort of 4504 patients). RESULTS: Of the 577 patients, 185 (32.1 per cent) had curative resections (R0/R1), 203 (35.2 per cent) had palliative radiotherapy with or without palliative surgery and chemotherapy, and 189 (32.8 per cent) received no treatment at all or only palliative surgery or chemotherapy. The overall 5-year survival rate was 14.9 per cent. Ninety-seven patients had an R0 resection, and 88 had an R1 resection, with 5-year overall survival of 55 and 20 per cent respectively. This outcome reflected surgical treatment in 33 different hospitals. Some 274 patients (47.5 per cent) had metastases. The 5-year survival rate after R0 resection was 62 per cent in patients without metastases. CONCLUSION: Obtaining an R0 resection is the most important prognostic factor in treating recurrent rectal cancer. PMID- 19787767 TI - Comparison of preservation solutions in an experimental model of organ cooling in kidney transplantation. AB - BACKGROUND: Viscous preservation solutions such as University of Wisconsin solution (UW) may be less effective at rapid removal of blood from an organ so that cooling takes longer. This study assessed the temperature changes of kidneys flushed with UW and hyperosmolar citrate (HOC). METHODS: Porcine kidneys were retrieved and flushed with 500 ml UW or HOC at 4 degrees C while monitoring kidney temperature at depths of 5 and 20 mm. Renal function was measured on an isolated organ preservation system. RESULTS: The mean(s.d.) rate of temperature fall was slower with UW (at 20 mm: 0.64(0.11) versus 1.01(0.56) degrees C per min per 100 g; P = 0.016). The perfusion flow rate required to reduce the temperature to less than 10 degrees C at a depth of 20 mm was lower in the UW group (P = 0.002). Kidneys flushed with HOC gained more weight than those flushed with UW (mean(s.d.) 50(8) versus 7(13) per cent; P = 0.002). Flushing with UW was associated with less histological injury but there were no significant differences in renal function parameters between the groups. CONCLUSION: UW cooled kidneys more slowly than HOC, but with no adverse effect on renal function. UW resulted in less oedema and histological injury than HOC. PMID- 19787768 TI - Genetic and epigenetic classifications define clinical phenotypes and determine patient outcomes in colorectal cancer. AB - BACKGROUND: A molecular classification of colorectal cancer has been proposed based on microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in the KRAS and BRAF oncogenes. This study examined the prevalence of these molecular classes, and differences in clinical presentation and outcome. METHODS: Demographics, tumour characteristics and survival were recorded for 391 subjects with colorectal cancer. Tumour DNA was analysed for MSI (high (MSI-H) or microsatellite stable (MSS)), CIMP (high (CIMP-H) or no (CIMP neg)) and BRAF and KRAS mutations. Clinical differences between four phenotypes were examined. RESULTS: Most tumours were MSS/CIMP-neg (69.8 per cent), with a nearly equal distribution of MSI-H/CIMP-H, MSI-H/CIMP-neg and MSS/CIMP-H types. MSS/CIMP-neg tumours were less likely to be poorly differentiated (P = 0.009). CIMP-H tumours were more common in older patients (P < 0.001). MSI-H/CIMP-H tumours had a high frequency of BRAF mutation and a low rate of KRAS mutation; the opposite was true for MSS/CIMP-neg tumours (P < 0.001). The four molecular phenotypes tended towards divergent survival (P = 0.067 for stages 1-III). MSI-H cancers were associated with better disease-free survival (hazard ratio 2.00 (95 per cent confidence interval 1.03 to 3.91); P = 0.040). CONCLUSION: Colorectal cancers are molecularly and clinically heterogeneous. These different molecular phenotypes may reflect variable prognosis. PMID- 19787769 TI - The (non)malignancy of cancerous amino acidic substitutions. AB - The process of natural selection acts both on individual organisms within a population and on individual cells within an organism as they develop into cancer. In this work, we have taken a first step toward understanding the differences in selection pressures exerted on the human genome under these disparate circumstances. Focusing on single amino acid substitutions, we have found that cancer-related mutations (CRMs) are frequent in evolutionarily conserved sites, whereas single amino acid polymorphisms (SAPs) tend to appear in sites having a more relaxed evolutionary pressure. Those CRMs classed as cancer driver mutations show greater enrichment for conserved sites than passenger mutations. Consistent with this, driver mutations are enriched for sites annotated as key functional residues and their neighbors, and are more likely to be located on the surface of proteins than expected by chance. Overall the pattern of CRM and polymorphism is remarkably similar, but we do see a clear signal indicative of diversifying selection for disruptive amino acid substitutions in the cancer driver mutations. The ultimate consequence of the appearance of those mutations must be advantageous for the tumor cell, leading to cell population-growth and migration events similar to those seen in natural ecosystems. PMID- 19787770 TI - Structural studies on cytosolic domain of magnesium transporter MgtE from Enterococcus faecalis. PMID- 19787771 TI - Modeling reaction routes from rhodopsin to bathorhodopsin. AB - The quantum mechanical-molecular mechanical (QM/MM) theory was applied to calculate accurate structural parameters, vibrational and optical spectra of bathorhodopsin (BATHO), one of the primary photoproducts of the functional cycle of the visual pigment rhodopsin (RHO), and to characterize reaction routes from RHO to BATHO. The recently resolved crystal structure of BATHO (PDBID: 2G87) served as an initial source of coordinates of heavy atoms. Protein structures in the ground electronic state and vibrational frequencies were determined by using the density functional theory in the PBE0/cc-pVDZ approximation for the QM part and the AMBER force field parameters in the MM part. Calculated and assigned vibrational spectra of both model protein systems, BATHO and RHO, cover three main regions referring to the hydrogen-out-of-plan (HOOP) motion, the C==C ethylenic stretches, and the C--C single-bond stretches. The S(0)-S(1) electronic excitation energies of the QM part, including the chromophore group in the field of the protein matrix, were estimated by using the advanced quantum chemistry methods. The computed structural parameters as well as the spectral bands match perfectly the experimental findings. A structure of the transition state on the S(0) potential energy surface for the ground electronic state rearrangement from RHO to BATHO was located proving a possible route of the thermal protein activation to the primary photoproduct. PMID- 19787772 TI - Study of the impact of the T877A mutation on ligand-induced helix-12 positioning of the androgen receptor resulted in design and synthesis of novel antiandrogens. AB - Antiandrogen flutamide, an antagonist of the wild-type androgen receptor (AR), is used in the clinics for treating metastatic prostate cancer. However, the T877A mutated AR is paradoxically activated by hydroxyflutamide, an active form of flutamide. Despite of crystallographic studies, how the T877A mutation results in antagonist-agonist conversion of hydroxyflutamide remains a puzzle. Here, started from a structural model of the apo form of AR ligand-binding domain (AR-LBD), we have investigated the impact of the T877A mutation on ligand-induced helix-12 positioning by replica-exchange molecular dynamics (REMD) simulations with an unique protocol, which is capable of simulating the H12 dynamics and keeping the main body of AR-LBD unchanged. Specifically, (i) we have computationally demonstrated that on the binding of hydroxyflutamide, the apo form of H12 rearranges into the agonistic form in the T877A mutant, but into the antagonistic forms in the wild-type receptor, shedding light on hydroxyflutamide agonism/antagonism; (ii) By REMD simulations, we have predicted antiandrogen SC184 is a non-agonist of the T877A mutant. This was confirmed by luciferase assays; and (iii) on the basis of the binding modes of hydroxyflutamide and SC184 from the simulations, we designed a novel flutamide derivative called SC333, which was subsequently predicted to be a pure antagonist of the T877A mutant. We then synthesized and experimentally confirmed SC333 is a pan-antiandrogen effective against the wild-type and the T877A and W741C mutated ARs, showing low micromolar cytotoxicity in LNCaP cells. Importantly, we demonstrated that distribution of the H12 conformations from REMD simulations is correlated with ligand agonist/antagonist activity. PMID- 19787773 TI - Active and inactive state structures of unliganded Lactobacillus casei allosteric L-lactate dehydrogenase. AB - Lactobacillus casei L-lactate dehydrogenase (LCLDH) is activated through the homotropic and heterotropic activation effects of pyruvate and fructose 1,6 bisphosphate (FBP), respectively, and exhibits unusually high pH-dependence in the allosteric effects of these ligands. The active (R) and inactive (T) state structures of unliganded LCLDH were determined at 2.5 and 2.6 A resolution, respectively. In the catalytic site, the structural rearrangements are concerned mostly in switching of the orientation of Arg171 through the flexible intersubunit contact at the Q-axis subunit interface. The distorted orientation of Arg171 in the T state is stabilized by a unique intra-helix salt bridge between Arg171 and Glu178, which is in striking contrast to the multiple intersubunit salt bridges in Lactobacillus pentosus nonallosteric L-lactate dehydrogenase. In the backbone structure, major structural rearrangements of LCLDH are focused in two mobile regions of the catalytic domain. The two regions form an intersubunit linkage through contact at the P-axis subunit interface involving Arg185, replacement of which with Gln severely decreases the homotropic and hetertropic activation effects on the enzyme. These two regions form another intersubunit linkage in the Q-axis related dimer through the rigid NAD-binding domain, and thus constitute a pivotal frame of the intersubunit linkage for the allosteric motion, which is coupled with the concerted structural change of the four subunits in a tetramer, and of the binding sites for pyruvate and FBP. The unique intersubunit salt bridges, which are observed only in the R state structure, are likely involved in the pH-dependent allosteric equilibrium. PMID- 19787774 TI - Crystal structure of the DNA gyrase GyrA N-terminal domain from Mycobacterium tuberculosis. PMID- 19787775 TI - Structure of the ribosome associating GTPase HflX. AB - The HflX-family is a widely distributed but poorly characterized family of translation factor-related guanosine triphosphatases (GTPases) that interact with the large ribosomal subunit. This study describes the crystal structure of HflX from Sulfolobus solfataricus solved to 2.0-A resolution in apo- and GDP-bound forms. The enzyme displays a two-domain architecture with a novel "HflX domain" at the N-terminus, and a classical G-domain at the C-terminus. The HflX domain is composed of a four-stranded parallel beta-sheet flanked by two alpha-helices on either side, and an anti-parallel coiled coil of two long alpha-helices that lead to the G-domain. The cleft between the two domains accommodates the nucleotide binding site as well as the switch II region, which mediates interactions between the two domains. Conformational changes of the switch regions are therefore anticipated to reposition the HflX-domain upon GTP-binding. Slow GTPase activity has been confirmed, with an HflX domain deletion mutant exhibiting a 24-fold enhanced turnover rate, suggesting a regulatory role for the HflX domain. The conserved positively charged surface patches of the HflX-domain may mediate interaction with the large ribosomal subunit. The present study provides a structural basis to uncover the functional role of this GTPases family whose function is largely unknown. PMID- 19787776 TI - Modeling G protein-coupled receptors for structure-based drug discovery using low frequency normal modes for refinement of homology models: application to H3 antagonists. AB - G Protein-Coupled Receptors (GPCRs) are integral membrane proteins that play important role in regulating key physiological functions, and are targets of about 50% of all recently launched drugs. High-resolution experimental structures are available only for very few GPCRs. As a result, structure-based drug design efforts for GPCRs continue to rely on in silico modeling, which is considered to be an extremely difficult task especially for these receptors. Here, we describe Gmodel, a novel approach for building 3D atomic models of GPCRs using a normal mode-based refinement of homology models. Gmodel uses a small set of relevant low frequency vibrational modes derived from Random Elastic Network model to efficiently sample the large-scale receptor conformation changes and generate an ensemble of alternative models. These are used to assemble receptor-ligand complexes by docking a known active into each of the alternative models. Each of these is next filtered using restraints derived from known mutation and binding affinity data and is refined in the presence of the active ligand. In this study, Gmodel was applied to generate models of the antagonist form of histamine 3 (H3) receptor. The validity of this novel modeling approach is demonstrated by performing virtual screening (using the refined models) that consistently produces highly enriched hit lists. The models are further validated by analyzing the available SAR related to classical H3 antagonists, and are found to be in good agreement with the available experimental data, thus providing novel insights into the receptor-ligand interactions. PMID- 19787777 TI - Proteasomal degradation of beta-carotene metabolite--modified proteins. AB - Free radical attack on beta-carotene results in the formation of high amounts of carotene breakdown products (CBPs) having biological activities. As several of the CBPs are reactive aldehydes, it has to be considered that these compounds are able to modify proteins. Therefore, the aim of the study was to investigate whether CBP-modification of proteins is leading to damaged proteins recognized and degraded by the proteasomal system. We used the model proteins tau and ferritin to test whether CBPs will modify them and whether such modifications lead to enhanced proteasomal degradation. To modify proteins, we used crude CBPs as a mixture obtained after hypochloric acid derived BC degradation, as well as several single compounds, as apo8'-carotenal, retinal, or beta-ionone. The majority of the CBPs found in our reaction mixture are well known metabolites as described earlier after BC degradation using different oxidants. CBPs are able to modify proteins, and in in vitro studies, we were able to demonstrate that the 20S proteasome is able to recognize and degrade CBP-modified proteins preferentially. In testing the proteolytic response of HT22 cells toward CBPs, we could demonstrate an enhanced protein turnover, which is sensitive to lactacystin. Interestingly, the proteasomal activity is resistant to treatment with CBP. On the other hand, we were able to demonstrate that supraphysiological levels of CBPs might lead to the formation of protein-CBP-adducts that are able to inhibit the proteasome. Therefore, the removal of CBP-modified proteins seems to be catalyzed by the proteasomal system and is effective, if the formation of CBPs is not overwhelming and leading to protein aggregates. PMID- 19787778 TI - Evidentials in Tibetan: acquisition, semantics, and cognitive development. AB - We describe the nature of the evidential system in Tibetan and consider the challenges that any evidential system presents to language acquisition. We present data from Tibetan-speaking children that shed light on their understanding of the syntactic and semantic properties of evidentials, and their competence in the point-of-view shift required for the use of evidentials in questions. We then examine connections between the mastery of indirect evidentials and children's inferential competence. PMID- 19787781 TI - Methods of monitoring buried flaps. PMID- 19787780 TI - Hyperphosphorylation of replication protein A in cisplatin-resistant and sensitive head and neck squamous cell carcinoma cell lines. AB - BACKGROUND: Resistance to chemotherapy is a major limitation in the treatment of head and neck squamous cell carcinomas (HNSCCs), accounting for high mortality rates in patients. Here, we investigated the role of replication protein A (RPA) in cisplatin and etoposide resistance. METHODS: We used 6 parental HNSCC cell lines. We also generated 1 cisplatin-resistant progeny subline from a parental cisplatin-sensitive cell line, to examine cisplatin resistance and sensitivity with respect to RPA2 hyperphosphorylation and cell-cycle response. RESULTS: Cisplatin-resistant HNSCC cell levels of hyperphosphorylated RPA2 in response to cisplatin were 80% to 90% greater compared with cisplatin-sensitive cell lines. RPA2 hyperphosphorylation could be induced in the cisplatin-resistant HNSCC subline. The absence of RPA2 hyperphosphorylation correlated with a defect in cell-cycle progression and cell survival. CONCLUSION: Loss of RPA2 hyperphosphorylation occurs in HNSCC cells and may be a marker of cellular sensitivities to cisplatin and etoposide in HNSCC. PMID- 19787782 TI - Head and neck squamous cell cancer and the human papillomavirus: summary of a National Cancer Institute State of the Science Meeting, November 9-10, 2008, Washington, D.C. PMID- 19787783 TI - PPFIA1 and CCND1 are frequently coamplified in breast cancer. AB - Recently, amplification of PPFIA1, encoding a member of the liprin family located about 600 kb telomeric to CCND1 on chromosome band 11q13, was described in squamous cell carcinoma of head and neck. Because 11q13 amplification is frequent in breast cancer, and PPFIA1 has been suggested to contribute to mammary gland development, we hypothesized that PPFIA1 might also be involved in the 11q13 amplicon in breast cancer and contribute to breast cancer development. A tissue microarray containing more than 2000 human breast cancers was analyzed for gene copy numbers of PPFIA1 and CCND1 by means of fluorescence in situ hybridization. PPFIA1 amplification was found in 248/1583 (15.4%) of breast cancers. Coamplification with CCND1 was found in all (248/248, 100%) PPFIA1-amplified cancers. CCND1 amplification without PPFIA1 coamplification was found in additional 117 (4.7%) tumors. Amplification of both PPFIA1 and CCND1 were significantly associated with high-grade phenotype (P = 0.0002) but were unrelated to tumor stage (P = 0.7066) or nodal stage (P = 0.5807). No difference in patient prognosis was found between 248 CCND1/PPFIA1 coamplified tumors and 117 tumors with CCND1 amplification alone (P = 0.6419). These data show that PPFIA1 amplification occurs frequently in breast cancer. The higher incidence of CCND1 amplification when compared with PPFIA1, the lack of prognostic relevance of coamplifications, and the fact that PPFIA1 amplification was found exclusively in CCND1-amplified cancers suggest that PPFIA1 gene copy number changes represent concurrent events of CCND1 amplification rather than specific biological incidents. PMID- 19787784 TI - Recurrent copy number gain of transcription factor SOX2 and corresponding high protein expression in oral squamous cell carcinoma. AB - Gene copy number aberrations are involved in oral squamous cell carcinoma (OSCC) development. To delineate candidate genes inside critical chromosomal regions, array-CGH was applied to 40 OSCC specimens using a microarray covering the whole human genome with an average resolution of 1 Mb. Gene copy number gains were predominantly found at 1q23 (9 cases), 3q26 (11), 5p15 (13), 7p11 (7), 8q24 (17), 11q13 (15), 14q32 (8), 19p13 (8), 19q12 (7), 19q13 (8), and 20q13 (9), whereas gene copy number losses were detected at 3p21-3p12 (15), 8p32 (11), 10p12 (8), and 18q21-q23 (10). Subsequent mRNA expression analyses by quantitative real time polymerase chain reaction found high mRNA expression of candidate genes SOX2 in 3q26.33, FSLT3 in 19p13.3, and CCNE1 in 19q12. Tissue microarray (TMA) analyses in a representative OSCC collection found gene copy number gain for SOX2 in 52% (115/223) and for CCNE1 in 31% (72/233) of the tumors. Immunohistochemical analyses on TMA sections of the corresponding proteins detected high expression of SOX2 in 18.1% (49/271) and of CyclinE1 in 23.3% (64/275) of tumors analyzed. These findings indicate that SOX2 and CCNE1 might be activated via gene copy number gain and participate in oral carcinogenesis. The combination of array-CGH with TMA analyses allows rapid pinpointing of novel promising candidate genes, which might be used as therapeutic stratification markers or target molecules for therapeutic interference. PMID- 19787785 TI - Nonparotid parapharyngeal oncocytoma: a case report and literature review. AB - Oncocytoma is a rare, benign salivary neoplasm composed of mitochondria-rich cells called oncocytes. Although oncocytoma usually occurs in the parotid glands, it has much less commonly been reported to occur in minor salivary gland tissues. Although there have been a few reported cases of oncocytomas being found in the parapharyngeal space, most if not all cases seem to be extensions of deep lobe parotid tumors. We present a case of a 73-year-old man with a previous history of prostate cancer that had the incidental finding of an (18)F-fluorodeoxyglucose (FDG) image of a highly avid parapharyngeal space lesion noted on a follow-up positron emission tomography-computed tomography (PET/CT) scan. Excision of the mass, through a transcervical approach, demonstrated it to be an isolated oncocytoma of the parapharyngeal space, noncontiguous with the parotid gland. Based on our literature search, this may be the first such reported case. A brief review of the available literature examining the known body of knowledge regarding these neoplasms is presented. PMID- 19787786 TI - Role of postoperative irradiation for patients with bilateral cervical nodal metastases from cutaneous melanoma: a critical assessment. AB - BACKGROUND: The aim of this study was to evaluate the role of regional nodal radiation therapy (RT) for patients with bilateral cervical nodal metastases from melanoma. METHODS: Between 1998 and 2008, 16 patients with bilateral cervical metastases without distant metastases were treated with postoperative RT (30 Gy in 5 fractions delivered twice weekly). RESULTS: Median follow-up was 5 months (range, 1-34 months). Median survival was 9 months (95% confidence interval [CI], 0-23 months). Overall survival was 68%, 50%, and 27% at 6, 12, and 24 months, respectively. Regional nodal control was 74% and 64% at 6 and 12 months, respectively. Rates of development of distant metastasis were 60%, 70%, and 90% at 6, 12, and 18 months, respectively. The actuarial rate of RT-related complications was 49% at 12 months. CONCLUSION: The limited life expectancy of patients observed with this disease combined with the high rate of RT-related complications argue against the routine use of adjuvant RT for regional nodal disease in this setting. PMID- 19787787 TI - UltraCision harmonic scalpel versus clamp-and-tie total thyroidectomy: a clinical trial. AB - BACKGROUND: Hemostasis is important in thyroid surgery to avoid complications. Our aim was to evaluate the effectiveness of the harmonic scalpel in patients undergoing total thyroidectomy. METHODS: In this study, 90 patients were randomized into group A (classic technique of tying and knots) and group B (harmonic scalpel). We recorded the following: age, sex, pathology, thyroid weight, hemostatic technique, duration of operation, change in calcemia (DeltaCa), change in hematocrit (DeltaHt), change in hemoglobin (DeltaHgb), change in white blood cell count (DeltaWBC), vocal motility, operative difficulty, postoperative vocal alteration, postoperative pain, complications, blood in the drains, operating time, mass of gland excised per minute, and hospitalization. RESULTS: Differences (p < .05) were observed concerning duration of surgery, operative difficulty, postoperative pain, hospitalization, DeltaWBC, and quantity of gland removed per minute. No recurrent laryngeal nerve (RLN) palsies were observed. CONCLUSIONS: Use of the Harmonic Scalpel in total thyroidectomy is more effective than the clamp-and-tie technique: the duration of surgery, intraoperative difficulty, postoperative pain, and hospitalization are reduced. Both techniques are equivalent concerning RLN injuries, postoperative vocal alterations, and blood loss. PMID- 19787788 TI - Biochemical and clinical responses after treatment of a catecholamine-secreting glomus jugulare tumor with gamma knife radiosurgery. AB - BACKGROUND: Functional glomus jugulare tumors (GJTs) are commonly managed with resection. Although primary radiation therapy of functional GJT can provide durable control of tumor growth, little is known of its ability to ablate functional capacity. METHODS AND RESULTS: We describe a case of a 47-year-old man with a symptomatic norepinephrine-hypersecreting GJT treated with definitive single-fraction gamma knife radiosurgery and pharmacologic catecholamine blockade. At a 32-month follow-up, he has experienced significant symptomatic improvement, excellent control of local tumor growth, minimal treatment-related morbidity, and near normalization of catecholamine levels. CONCLUSION: Radiosurgery was safe and effective in significantly reducing the functional capacity of a paraganglioma. Care must be taken to avoid inducing a hypertensive crisis during and following treatment, and longer follow-up will help determine whether and when pharmacologic blockade can be discontinued. PMID- 19787789 TI - Dendritic cells pulsed with GST-EGFR fusion protein: effect in antitumor immunity against head and neck squamous cell carcinoma. AB - BACKGROUND: Overexpression of epidermal growth factor receptor (EGFR) is common in head and neck squamous cell carcinoma (HNSCC). Targeting EGFR is an effective approach to treat EGFR-positive HNSCC. However, the clinical benefits of the present EGFR-targeting agents are still limited in HNSCC patients. METHODS: Recombinant glutathione-S-transferase (GST)-EGFR fusion protein was produced and purified. Dendritic cells (DCs) of C3H mice were pulsed with fusion protein. Mice were challenged with HNSCC cells before or after vaccination with these DCs, and the cytotoxic T-lymphocyte (CTL) response, interferon-gamma (IFN-gamma) secretion, tumor growth, and survival of mice were assessed. RESULTS: Significant in vitro and in vivo antitumor activities were observed for mice immunized with DCs pulsed with GST-EGFR fusion protein, compared with the control groups (p < .05). CONCLUSION: The DCs pulsed with GST-EGFR fusion protein can provide not only preventive but also therapeutic antitumor activities against HNSCC in the animal model. PMID- 19787790 TI - Outcomes of inpatients with and without sickle cell disease after high-volume surgical procedures. AB - In this study, we examined differences in inpatient costs, length of stay, and in hospital mortality between hospitalizations for patients with and without sickle cell disease (SCD) undergoing high-volume surgical procedures. We used Clinical Classification Software (CCS) codes to identify discharges in the 2002-2005 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project for patients who had undergone either cholecystectomy or hip replacement. We limited the non-SCD cohort to hospitals where patients with SCD had undergone the same procedure. We compared inpatient outcomes using summary statistics and generalized linear regression analysis to adjust for patient, hospital, and procedural characteristics. Overall, the median age of surgical patients with SCD was more than three decades less than the median age of patients without SCD undergoing the same procedure. In recognition of the age disparity, we limited the analyses to patients aged 18 to 64 years. Nonetheless, patients with SCD undergoing cholecystectomy or hip replacement were 12.1 and 14.4 years younger, had inpatient stays that were 73% and 82% longer, and incurred costs that were 46% and 40% higher per discharge than patients without SCD, respectively. Inpatient mortality for these procedures was low, approximately 0.6% for cholecystectomy and 0.2% for hip replacement and did not differ significantly between patients with and without SCD. Multivariable regression analyses revealed that higher inpatient costs among patients with SCD were primarily attributable to longer hospital stays. Patients with SCD who underwent cholecystectomy or hip replacement required more health care resources than patients without SCD. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc. PMID- 19787791 TI - Correlation between losses of IGH or its segments and deletions of 13q14 in t(11;14) (q13;q32) multiple myeloma. AB - Multiple myeloma (MM) is a malignancy of the plasma cells (PCs) characterized by a wide variety of genetic and chromosomal abnormalities. In recent years, major attention was drawn to the significance of chromosomal aberrations involving chromosome arm 13q and the IGH region on chromosome band 14q32 as a prognostic indicator in MM. In this study we applied a combined cell morphology and FISH method for the analysis of coexistence of t(11;14)(q13;q32) with deletions of the long arm of chromosome 13 (Delta13) in PCs from 51 MM patients using several probes for the 13q14, 11q13, and IGH regions. We found 15 different variants of the t(11;14) that are the consequence of different 11q13 breakpoints and various deletions of Variable (del IGH Var) or Constant (del IGH Const) IGH segments and also duplications and losses of the IGH gene on the normal nontranslocated chromosome 14 as well as IGH/Cyclin D1 (CCND1) fusion on der(14) and CCND1/IGH fusions on der(11). A strong association between Delta13 and specific variants of t(11;14) was found: variants with deletion of the IGH gene or its segments were found only in MM cases with deleted chromosome 13, while the common translocation t(11;14) was found only in the MM cases with normal chromosome arm 13q. In contrast, we did not find any association between Delta13 and deletions of the IGH gene or its segments in the MM patients with t(4;14)(p16;q32). PMID- 19787793 TI - Existence of MRI-negative clinical (large nerve) perineural squamous cell carcinoma spread. PMID- 19787792 TI - Molecular characterization of commonly used cell lines for bone tumor research: a trans-European EuroBoNet effort. AB - Usage of cancer cell lines has repeatedly generated conflicting results provoked by differences among subclones or contamination with mycoplasm or other immortal mammalian cells. To overcome these limitations, we decided within the EuroBoNeT consortium to characterize a common set of cell lines including osteosarcomas (OS), Ewing sarcomas (ES), and chondrosarcomas (CS). DNA fingerprinting was used to guarantee the identity of all of the cell lines and to distinguish subclones of osteosarcoma cell line HOS. Screening for homozygous loss of 38 tumor suppressor genes by MLPA revealed deletion of CDKN2A as the most common event (15/36), strictly associated with absence of the CDKN2A (p16) protein. Ten cell lines showed missense mutations of the TP53 gene while another set of nine cell lines showed mutations resulting in truncation of the TP53 protein. Cells harboring missense mutations expressed high levels of nuclear TP53, while cell lines with nonsense mutations showed weak/absent staining for TP53. TP53(wt) cell lines usually expressed the protein in 2-10% of the cells. However, seven TP53(wt) osteosarcomas were negative for both mRNA and protein expression. Our analyses shed light on the correlation between immunohistochemical and genetic data for CDKN2A and TP53, and confirm the importance of these signaling pathways. The characterization of a substantial number of cell lines represents an important step to supply research groups with proven models for further advanced studies on tumor biology and may help to make results from different laboratories more comparable. PMID- 19787794 TI - Laryngeal inflammatory myofibroblastic tumors: Different clinical appearance and histomorphologic presentation of one entity. AB - BACKGROUND: Inflammatory myofibroblastic tumors (IMFTs) of the larynx are rare. We report the clinical presentation, histomorphology, and new molecular findings of 2 cases. METHODS: Paraffin-embedded specimens were stained immunohistochemically (eg, vimentin, AE1/3, Alk-1, smooth muscle [sm-]actin, p53, Rb1, immunoglobulin G4 [IgG4]). Epstein-Barr virus-encoded RNA (EBER) in situ hybridization and HHV8-polymerase chain reaction (PCR) were done. Comparative genomic hybridization (CGH) was performed. RESULTS: Case 1 was that of a 56-year old man with an infiltrating plasma-cell-rich tumor (Alk-1-, sm-actin+). Plasma cells were strongly positive for IgG4. CGH was unsuspicious. Case 2 was that of a 34-year-old woman with an exophytic tumor (Alk-1+). CGH revealed losses on 13q14 22. The few plasma cells were negative for IgG4. The proliferation (Ki67) was low in both cases. CONCLUSION: Different types of IMFTs may exist and could indicate different therapeutic strategies. Alk-1-positive cases with only scattered inflammatory cells could represent the neoplastic variant, whereas cases rich in plasma cells could be associated with IgG4 sclerosing diseases. PMID- 19787795 TI - Hemoglobin H-constant spring in North America: an alpha thalassemia with frequent complications. PMID- 19787796 TI - HFE, SLC40A1, HAMP, HJV, TFR2, and FTL mutations detected by denaturing high performance liquid chromatography after iron phenotyping and HFE C282Y and H63D genotyping in 785 HEIRS Study participants. AB - We sought to identify mutations that could explain iron phenotype heterogeneity in adults with previous HFE genotyping to detect C282Y and H63D. HEIRS Study participants genotyped for C282Y and H63D were designated as high transferrin saturation (TS) and/or serum ferritin (SF) (high TS/SF), low TS/SF, or controls. We grouped 191 C282Y homozygotes as high TS/SF, low TS/SF, or controls, and 594 other participants by race/ethnicity as high TS/SF or controls. Using denaturing high-performance liquid chromatography (DHPLC), we screened 20 regions of HFE, SLC40A1, HAMP, HJV, TFR2, and FTL in each participant. DHPLC analyses were successful in 99.3% of 791 participants and detected 117 different mutations. In C282Y homozygotes, 4.0% of high TS/SF participants had SLC40A1 Q248H, HAMP 72C>T, or HAMP R59G heterozygosity (0% Controls; P = 0.1200). In whites, 4.1% with high TS/SF and 1.3% of controls had HFE S65C or E168Q (P = 0.3049). HJV c. 6C>G and FTL L55L frequencies were greater in whites with high TS/SF than controls (0.0811 vs. 0.0200, P = 0.0144; 0.5743 vs. 0.4400, P = 0.0204, respectively). One Hispanic with high TS/SF (1.3%) had HAMP G71D heterozygosity. In blacks, SLC40A1 Q248H frequencies did not differ significantly between high TS/SF and control participants. Among Asians, 2.8% with high TS/SF were HFE V295A heterozygotes. Mutations other than HFE C282Y and H63D reported to be pathogenic were infrequently detected in high TS/SF participants. Genetic regions in linkage disequilibrium with HJV c.-6C>G and FTL L55L could partly explain high TS/SF phenotypes in whites. Am. J. Hematol., 2009. Published 2009 Wiley-Liss, Inc. PMID- 19787797 TI - Treatment with hydroxyurea in a patient compound heterozygote for a high oxygen affinity hemoglobin and beta-thalassemia minor. PMID- 19787798 TI - KIR and HLA-Cw genotypes of donor-recipient pairs influence the rate of CMV reactivation following non-T-cell deleted unrelated donor hematopoietic cell transplantation. PMID- 19787799 TI - A novel missense mutation causing abnormal LMAN1 in a Japanese patient with combined deficiency of factor V and factor VIII. AB - Combined deficiency of coagulation factor V (FV) and factor VIII (FVIII) (F5F8D) is an inherited bleeding disorder characterized by a reduction in plasma concentrations of FV and FVIII. F5F8D is genetically linked to mutations in either LMAN1 or MCFD2. Here, we investigated the molecular basis of F5F8D in a Japanese patient, and identified a novel missense mutation (p.Trp67Ser, c.200G>C) in the LMAN1, but no mutation in the MCFD2. The amount of LMAN1 in Epstein-Barr virus-immortalized lymphoblasts from the patient was found to be almost the same as that in cells from a normal individual. Interestingly, an anti-MCFD2 antibody did not co-immunoprecipitate the mutant LMAN1 with MCFD2 in lymphoblasts from the patient, suggesting the affinity of MCFD2 for the mutant LMAN1 is weak or abolished by the binding of the anti-MCFD2 antibody. In addition, a Myc/6xHis tagged recombinant form of wild-type LMAN1 could bind to D-mannose, but that of the mutant could not. The p.Trp67Ser mutation was located in the carbohydrate recognition domain (CRD), which is thought to participate in the selective binding of LMAN1 to the D-mannose of glycoproteins as well as the EF-motif of MCFD2. Taken together, it was suggested that the p.Trp67Ser mutation might affect the molecular chaperone function of LMAN1, impairing affinity for D-mannose as well as for MCFD2, which may be responsible for F5F8D in the patient. This is the first report of F5F8D caused by a qualitative defect of LMAN1 due to a missense mutation in LMAN1. Am. J. Hematol. 2009. (c) 2009 Wiley-Liss, Inc. PMID- 19787800 TI - Help with HELLP. PMID- 19787801 TI - Cytopathology of alveolar soft part sarcoma: a report of 10 cases. AB - BACKGROUND: Alveolar soft part sarcoma (ASPS) rarely is subjected to cytopathologic evaluation. With the exception of some very small series, the literature is limited to case reports. The objectives of the current study were to evaluate the cytomorphology of 10 ASPS cases on fine-needle aspiration (FNA) or imprint cytology, review the literature, and highlight potential diagnostic pitfalls. METHODS: The authors searched their files for all lesions that were signed out as ASPS or suspicious for ASPS and searched the surgical pathology files for any cases of ASPS that had corresponding cytology. FNA was performed using the standard technique. Scrape preparations were performed on tissues that were sent fresh for frozen section examination. RESULTS: Ten cases of ASPS were retrieved from 7 patients (male-to-female ratio, 4:3; mean age, 22 years). All had subsequent tissue confirmation. Six specimens were from primary lesions, 3 specimens were from metastases, and 1 intraoperative smear was from a previously aspirated primary mass in a newly diagnosed patient. Anatomic sites of involvement included extremities (5 specimens), trunk/pelvis (3 specimens), oral cavity (1 specimen), and lung (1 specimen). Eight specimens were aspirates, and 2 specimens were intraoperative smears. Nine cases were diagnosed correctly as ASPS/consistent with ASPS, and 1 specimen was diagnosed as "tumor, not otherwise specified". Cytomorphology included variably cellular smears composed of large cells with an enormous amount of finely granular or vacuolated cytoplasm, markedly enlarged nuclei/nucleoli, and bare nuclei. The cytomorphology of some cases revealed a strong similarity to renal cell carcinoma, clear cell type. CONCLUSIONS: The results of the current study indicated that ASPS has cytomorphology that overlaps with several other neoplasms, including renal cell carcinoma. Nonetheless, the morphologic features, when combined with the clinical presentation, radiologic findings, and ancillary testing, may allow for a specific diagnosis. PMID- 19787802 TI - Cyclin D1 and D3 overexpression predicts malignant behavior in thyroid fine needle aspirates suspicious for Hurthle cell neoplasms. AB - BACKGROUND: Thyroid fine-needle aspiration (FNA) samples that feature a follicular-patterned, monotonous Hurthle (oncocytic) cell population cannot be diagnosed reliably. The authors of this report recently identified cyclin D3 overexpression on histologic sections of Hurthle cell carcinoma. In this study, they assessed the diagnostic value of cyclin D3 immunohistochemistry added to routine cytology. METHODS: Fifty-one FNA samples that were suspicious for Hurtle cell neoplasia and that had histologic follow-up (19 malignant cases) were examined. Cyclin D3 expression levels were evaluated in cell block preparations and were compared with levels of the closely related cyclin D1 protein. RESULTS: Greater than 25% positive cells were used as the cutoff point, as suggested by previous studies. Cyclin D1 and cyclin D3 were highly specific (100% for both) and fairly accurate (75% and 92%, respectively) in distinguishing between benign and malignant oncocytic lesions; the positive predictive value (PPV) for each was 100%. However, both cyclins D1 and D3 had low sensitivity (32% and 79%, respectively) and low negative predictive value (NPV) (71% and 89%, respectively). In contrast, by adopting balanced receiver operating characteristic-derived positive cutoff values, cyclin D1 (>or=6.5%) and cyclin D3 (>or=7.5%) were found to be highly sensitive (100% for both) and accurate (90% and 94%, respectively); and the NPV was 100% for both. In contrast, cyclins D1 and D3 had low specificity (84% and 91%, respectively) and a low PPV (79% and 86%, respectively); however, these values improved in samples that were positive for both cyclins (sensitivity, 100%; specificity, 94%; PPV, 90%; NPV, 100%; and accuracy, 96%). CONCLUSIONS: Cyclin D3 increased the suspicion of malignancy in indeterminate oncocytic lesions; its diagnostic performance depended on the cutoff point used and was enhanced further when combined with cyclin D1. PMID- 19787803 TI - Long-term outcomes of drug-eluting stents versus bare-metal stents in saphenous vein graft disease: results from the Prairie "Real World" Stent Registry. AB - OBJECTIVES: This study was designed to compare long-term clinical outcomes of drug-eluting stents (DES) versus bare metal stents (BMS) in patients with saphenous vein graft (SVG) disease in the "real world." BACKGROUND: The safety and efficacy of DES versus BMS in SVG remains uncertain due to contradictory reports of either lower revascularization rates with DES; or clinical equivalence to BMS; or even an excess of clinical events associated with DES use. METHODS: We identified consecutive patients who underwent stent placement within a de novo SVG lesion between May 1, 2003 and July 31, 2007. Follow-up was obtained at regular intervals. The Kaplan-Meier method was used to produce actuarial survival estimates. Cox regression analysis was used to predict the risk associated with stent type, and propensity scores were generated to risk-adjust the results. RESULTS: The study group included 379 stent recipients (284 DES; 95 BMS) with 410 stented lesions. BMS were placed more frequently in current smokers, acute myocardial infarctions, larger vessels, and longer lesions. In-hospital mortality was higher in BMS recipients than in their DES counterparts (3.2% vs. 0, respectively; P = 0.015). At 3 years, there was no significant difference in clinical adverse event rates between DES and BMS recipients, even after risk adjustment. CONCLUSIONS: Three-year adverse event rates are similar among patients treated with DES or BMS in SVG lesions. Therefore, while DES are safe, they do not appear to offer an advantage in terms of long-term graft patency. PMID- 19787804 TI - Real case virtual reality training prior to carotid artery stenting. AB - BACKGROUND: The majority of procedural training especially in interventional cardiology, still occurs on patients with direct mentoring by experienced physicians during an actual clinical procedure. In recent years there is an increase use of simulators especially for carotid artery stenting. However, most simulators use "generic" predefined cases. METHODS AND RESULT: We report here a simulation done on data of a real patient prior to intervention. The patient's specific carotid anatomy was modeled using CTA on an endovascular simulator. Pre procedure patient-specific case rehearsal accurately predicted procedure experience. CONCLUSIONS: A case rehearsal prior to an intervention may be useful in the planning and execution of carotid artery stenting. The use of patient specific simulation helps with planning of procedure and device selection, and may lead to use of less contrast and radiation, and shorter procedure duration. These may benefit the patient with increased success and lower complication rates. PMID- 19787805 TI - Variability in the upper limit of normal for serum alanine aminotransferase levels: a statewide study. AB - We conducted a study to characterize the variability in the upper limit of normal (ULN) for alanine aminotransferase (ALT) across different laboratories (labs) in Indiana and to understand factors leading to such variability. A survey was mailed to all eligible labs (n = 108) in Indiana, and the response rate was 62%. The survey queried for ALT ULN, the type of chemical analyzer used, five College of American Pathologists (CAP) sample results, and methods used to establish the reference interval. There was a wide variability in the ALT ULN for both men and women. Eighty-five percent of labs used chemical analyzers belonging to one of the four brands. For all five CAP samples, there was a statistically significant difference in ALT values measured by different analyzers (P < 0.0001), but these differences were not clinically significant. The majority of labs used the manufacturers' recommendations for establishing their ALT ULN rather than in house healthy volunteer testing (only 17%). When healthy volunteers were tested, the process for testing was haphazard in terms of the number of individuals tested, frequency of testing, and criteria for choosing the reference population. After controlling for chemical analyzer type, there was no significant relationship between ALT ULN values and the method used for its establishment. CONCLUSION: Wide variability in ALT ULN across different labs is more likely due to variable reference intervals of different chemical analyzers. It may be possible to minimize variability in ALT ULN by (1) each lab solely following the manufacturers' recommendations and (2) manufacturers of different analyzers following consistent and rigorous methodology in establishing the reference range. Alternatively, studies should be undertaken to identify outcome-based reference intervals for ALT. PMID- 19787806 TI - Priming of CD4+ T cells by liver sinusoidal endothelial cells induces CD25low forkhead box protein 3- regulatory T cells suppressing autoimmune hepatitis. AB - Elucidating cellular mechanisms that maintain the intrahepatic immune balance is crucial to our understanding of viral or autoimmune liver diseases and allograft acceptance. Liver sinusoidal endothelial cells (LSECs) play an important role in modifying local immune responses to tolerance in major histocompatibility complex (MHC) I-restricted models, whereas their contribution in the MHCII context is still controversial. In an MHCII chimeric mouse model that excludes MHCII mediated antigen presentation by professional antigen-presenting cells, we demonstrated that LSECs prime CD4(+) T cells to a CD45RB(low) memory phenotype lacking marker cytokine production for effector cells that was stable in vivo following immunogenic antigen re-encounter. Although these cells, which we term T(LSEC), had the capacity to enter lymph nodes and the liver, they did not function as effector cells either in a delayed-type hypersensitivity reaction or in a hepatitis model. T(LSEC) inhibited the proliferation of naive CD4(+) T cells in vitro although being CD25(low) and lacking expression of forkhead box protein (FoxP)3. Furthermore, these cells suppressed hepatic inflammation as monitored by alanine aminotransferase levels and cellular infiltrates in a T cell-mediated autoimmune hepatitis model in vivo. CONCLUSION: T(LSEC) first described here might belong to the expanding group of FoxP3(-) regulatory T cells. Our findings strengthen the previously discussed assumption that CD4(+) T cell priming by nonprofessional antigen-presenting cells induces anti-inflammatory rather than proinflammatory phenotypes. Because recruitment of CD4(+) T cells is increased upon hepatic inflammation, T(LSEC) might contribute to shifting antigen-dependent immune responses to tolerance toward exogenous antigens or toward endogenous self antigens, especially under inflammatory conditions. PMID- 19787807 TI - Inhibition of extracellular signal-regulated kinase 1 by adenovirus mediated small interfering RNA attenuates hepatic fibrosis in rats. AB - Extracellular signal-regulated kinase 1 (ERK1) is a critical part of the mitogen activated protein kinase signal transduction pathway, which is involved in hepatic fibrosis. However, the effect of down-regulation of ERK1 on hepatic fibrosis has not been reported. Here, we induced hepatic fibrosis in rats with dimethylnitrosamine administration or bile duct ligation. An adenovirus carrying small interfering RNA targeting ERK1 (AdshERK1) was constructed to determine its effect on hepatic fibrosis, as evaluated by histological and immunohistochemical examination. Our results demonstrated that AdshERK1 significantly reduced the expression of ERK1 and suppressed proliferation and levels of fibrosis-related genes in hepatic stellate cells in vitro. More importantly, selective inhibition of ERK1 remarkably attenuated the deposition of the extracellular matrix in fibrotic liver in both fibrosis models. In addition, both hepatocytes and biliary epithelial cells were proven to exert the ability to generate the myofibroblasts depending on the insults of the liver, which were remarkably reduced by AdshERK1. Furthermore, up-regulation of ERK1 paralleled the increased expression of transforming growth factor beta1 (TGF-beta1), vimentin, snail, platelet-derived growth factor-BB (PDGF-BB), bone morphogenetic protein 4 (BMP4), and small mothers against decapentaplegic-1 (p-Smad1), and was in reverse correlation with E-cadherin in the fibrotic liver. Nevertheless, inhibition of ERK1 resulted in the increased level of E-cadherin in parallel with suppression of TGF-beta1, vimentin, snail, PDGF-BB, BMP4, and p-Smad1. Interestingly, AdshERK1 treatment promoted hepatocellular proliferation. CONCLUSION: Our study provides the first evidence for AdshERK1 suppression of hepatic fibrosis through the reversal of epithelial-mesenchymal transition of both hepatocytes and biliary epithelial cells without interference of hepatocellular proliferation. This suggests that ERK1 is implicated in hepatic fibrogenesis and selective inhibition of ERK1 by small interfering RNA may present a novel option for hepatic fibrosis treatment. PMID- 19787808 TI - Spectrum of neurocognitive impairment in cirrhosis: Implications for the assessment of hepatic encephalopathy. PMID- 19787809 TI - Characterization of resistance to the protease inhibitor boceprevir in hepatitis C virus-infected patients. AB - Boceprevir is a hepatitis C virus (HCV) nonstructural protein (NS) 3/4A protease inhibitor that is currently being evaluated in combination with peginterferon alfa-2b and ribavirin in phase 3 studies. The clinical resistance profile of boceprevir is not characterized in detail so far. The NS3 protease domain of viral RNA was cloned from HCV genotype 1-infected patients (n = 22). A mean number of 47 clones were sequenced before, at the end, and after treatment with 400 mg boceprevir twice or three times daily for 14 days for genotypic, phenotypic, and viral fitness analysis. At the end of treatment, a wild-type an NS3 protease sequence was observed with a mean frequency of 85.9%. In the remaining isolates, five previously observed resistance mutations (V36M/A, T54A/S, R155K/T, A156S, V170A) and one mutation (V55A) with unknown resistance to boceprevir were detected either alone or in combination. Phenotypic analysis in the HCV replicon assay showed low (V36G, T54S, R155L; 3.8- to 5.5-fold 50% inhibitory concentration [IC(50)]), medium (V55A, R155K, V170A, T54A, A156S; 6.8- to 17.7-fold IC(50)) and high level (A156T; >120-fold IC(50)) resistance to boceprevir. The overall frequency of resistant mutations and the level of resistance increased with greater declines in mean maximum HCV RNA levels. Two weeks after the end of treatment, the frequency of resistant variants declined and the number of wild-type isolates increased to 95.5%. With the exception of V36 and V170 variants all resistant mutations declined by more than 50%. Mathematical modeling revealed impaired replicative fitness for all single mutations, whereas for combined mutations a relative increase of replication efficiency was suggested. CONCLUSION: During boceprevir monotherapy, resistance mutations at six positions within the NS3 protease were detected by way of clonal sequence analysis. All mutations are associated with reduced replicative fitness estimated by mathematical modeling and show cross-resistance to telaprevir. PMID- 19787810 TI - Minimal hepatic encephalopathy and driving. PMID- 19787812 TI - Hepatic drug transporters, old and new: pharmacogenomics, drug response, and clinical relevance. PMID- 19787811 TI - The liver's dance with death: two Bcl-2 guardian proteins from the abyss. PMID- 19787813 TI - Hepatitis C drug development at a crossroads. PMID- 19787814 TI - Ghrelin--a novel generation of anti-obesity drug: design, pharmacomodulation and biological activity of ghrelin analogues. AB - Ghrelin is a unique bioactive peptide with respect to both the structure and its biological function. This 28-amino acid peptide is modified with an n-octanoyl group at serine-3, and accordingly is the only lipidated biologically active peptide hormone known so far. Ghrelin binds to the so-called ghrelin or GHS receptor, a member of the class A of G-protein coupled receptors, which leads to Ca(2+) release intracellularly due to the activation of the Gq-system. Interestingly, the ghrelin receptor shows a significant constitutive activity which means that in addition to agonists and antagonists, inverse agonists play an important role in receptor modulation. In this review, the major activities of ghrelin are summarized with a strong focus on the regulation of food intake. So far reported agonists, antagonists and inverse agonists are shown and structure activitiy relationships are discussed. Furthermore, the application of ghrelin ligands as novel anti-obesity drugs is outlined and the state of the art in this field is summarized. PMID- 19787815 TI - Synthesis and receptor binding of opioid peptide analogues containing beta3-homo amino acids. AB - beta-Amino acids containing hybrid peptides and beta-peptides show great potential as peptidomimetics. In this paper we describe the synthesis and affinity toward the micro- and delta-opioid receptors of beta-peptides, analogues of Leu-enkephalin, deltorphin I, dermorphin and alpha,beta-hybrides, analogues of deltorphin I. Substitution of alpha-amino acid residues with beta(3)-homo-amino acid residues, in general resulted in decrease of affinity to opioid receptors. However, the incorporation beta(3)h-D-Ala in position 2 or beta(3)hPhe in position 3 of deltorphin I resulted in potent and selective ligand for delta opioid receptor. The NMR studies of beta-deltorphin I analogue suggest that conformational motions in the central part of the peptide backbone are partially restricted and some conformational preferences can be expected. PMID- 19787816 TI - Image of the month. Copper-metallothionein autofluorescence. PMID- 19787817 TI - One step at a time: identification and validation of biomarkers for nonalcoholic steatohepatitis. PMID- 19787818 TI - Hepatitis C virus infection and its clearance alter circulating lipids: implications for long-term follow-up. AB - Hepatitis C associated hypolipidemia has been demonstrated in studies from Europe and Africa. In two linked studies, we evaluated the relationship between hepatitis C infection and treatment with lipid levels in an American cohort and determined the frequency of clinically significant posttreatment hyperlipidemia. First, a case-control analysis of patients with and without hepatitis C was performed. The HCV Group consisted of 179 infected patients. The Uninfected Control Group consisted of 180 age-matched controls. Fasting cholesterol, low density lipoprotein (LDL), high density lipoprotein and triglycerides were compared. Next was a retrospective cohort study (Treated Hepatitis C Group) of 87 treated hepatitis C patients with lipid data before and after therapy was performed. In the case-control analysis, the HCV Group had significantly lower LDL and cholesterol than the Uninfected Control Group. In the retrospective cohort, patients in the Treated Hepatitis C Group who achieved viral clearance had increased LDL and cholesterol from baseline compared to patients without viral clearance. These results persisted when adjusted for age, sex, and genotype. 13% of patients with viral clearance had increased LDL and 33% experienced increases in cholesterol to levels warranting lipid lowering therapy. CONCLUSION: Hepatitis C is associated with decreased cholesterol and LDL levels. This hypolipidemia resolves with successful hepatitis C treatment but persists in nonresponders. A significant portion of successfully treated patients experience LDL and cholesterol rebound to levels associated with increased coronary disease risk. Lipids should be carefully monitored in persons receiving antiviral therapy. PMID- 19787819 TI - Fructose takes a toll. PMID- 19787820 TI - Receptor assay guided structure-activity studies of helicokinin insect neuropeptides and peptidomimetic analogues. AB - Neuropeptides control numerous physiological processes in insects. The regulation of water balance is a crucial aspect of homeostasis in terrestrial insects and has been shown to be under endocrine control, primarily by corticotrophin releasing factor (CRF)-related peptides and kinins. For helicokinin I, a diuretic neuropeptide from the economically important insect pest Heliothis virescens, detailed structure-activity relationships have been established based on truncated structures, diverse amino acid scans and peptidomimetic analogues. The activities of selected compounds on functional expressed helicokinin receptors are compared with the results of a Malphigian tubule assay. Implications for further peptidomimetic variations are provided. PMID- 19787821 TI - The pH sensitivity of histidine-containing lytic peptides. AB - Many bioactive peptides are featured by their unique amino acid compositions such as argine/lysine-rich peptides. However, histidine-rich bioactive peptides are hardly found. In this study, histidine-containing peptides were constructed by selectively replacing the corresponded lysine residues in a lytic peptide LL-1 with histidines. Interestingly, all resulting peptides demonstrated pH-dependent activities. The cell lysis activities of these peptides could be increased up to four times as the solution pHs dropped from pH = 7.4 to pH = 5.5. The pH sensitivity of a histidine-containing peptide was determined by histidine substitution numbers. Peptide derivatives with more histidines were associated with increased pH sensitivity. Results showed that not the secondary structures but pH-affected cell affinity changes were responsible for the pH-dependent activities of histidine-containing peptides. The histidine substitution approach demonstrated here may present a general strategy to construct bioactive peptides with desired pH sensitivity for various applications. PMID- 19787822 TI - Involvement of interleukin-15 and interleukin-21, two gamma-chain-related cytokines, in celiac disease. AB - Celiac disease (CD), an enteropathy caused by dietary gluten in genetically susceptible individuals, is histologically characterized by villous atrophy, crypt cell hyperplasia, and increased number of intra-epithelial lymphocytes. The nature of CD pathogenesis remains unclear, but recent evidence indicates that both innate and adaptive immune responses are necessary for the phenotypic expression and pathologic changes characteristic of CD. Extensive studies of molecules produced by immune cells in the gut of CD patients have led to identification of two cytokines, namely interleukin (IL)-15 and IL-21, which are thought to play a major role in orchestrating the mucosal inflammatory response in CD. Here we review the current knowledge of the expression and function of IL 15 and IL-21 in CD. PMID- 19787823 TI - Anemia and digestive diseases: an update for the clinician. AB - Anemia and iron deficiency are so common in digestive diseases that often are underestimated and undertreated. Our goal is to review from classification to treatment of the diverse types of anemias in different digestive diseases to update our knowledge on diagnosis and treatment. With the goal of improving the prognosis and quality of life of digestive diseases patients, we will review current transfusion, intravenous iron, and erythropoietin roles in the treatment of anemia. PMID- 19787824 TI - An update on iron physiology. AB - Iron is an essential micronutrient, as it is required for adequate erythropoietic function, oxidative metabolism and cellular immune responses. Although the absorption of dietary iron (1-2 mg/d) is regulated tightly, it is just balanced with losses. Therefore, internal turnover of iron is essential to meet the requirements for erythropoiesis (20-30 mg/d). Increased iron requirements, limited external supply, and increased blood loss may lead to iron deficiency (ID) and iron-deficiency anemia. Hepcidin, which is made primarily in hepatocytes in response to liver iron levels, inflammation, hypoxia and anemia, is the main iron regulatory hormone. Once secreted into the circulation, hepcidin binds ferroportin on enterocytes and macrophages, which triggers its internalization and lysosomal degradation. Thus, in chronic inflammation, the excess of hepcidin decreases iron absorption and prevents iron recycling, which results in hypoferremia and iron-restricted erythropoiesis, despite normal iron stores (functional ID), and anemia of chronic disease (ACD), which can evolve to ACD plus true ID (ACD + ID). In contrast, low hepcidin expression may lead to iron overload, and vice versa. Laboratory tests provide evidence of iron depletion in the body, or reflect iron-deficient red cell production. The appropriate combination of these laboratory tests help to establish a correct diagnosis of ID status and anemia. PMID- 19787825 TI - Classification of anemia for gastroenterologists. AB - Most anemia is related to the digestive system by dietary deficiency, malabsorption, or chronic bleeding. We review the World Health Organization definition of anemia, its morphological classification (microcytic, macrocytic and normocytic) and pathogenic classification (regenerative and hypo regenerative), and integration of these classifications. Interpretation of laboratory tests is included, from the simplest (blood count, routine biochemistry) to the more specific (iron metabolism, vitamin B12, folic acid, reticulocytes, erythropoietin, bone marrow examination and Schilling test). In the text and various algorithms, we propose a hierarchical and logical way to reach a diagnosis as quickly as possible, by properly managing the medical interview, physical examination, appropriate laboratory tests, bone marrow examination, and other complementary tests. The prevalence is emphasized in all sections so that the gastroenterologist can direct the diagnosis to the most common diseases, although the tables also include rare diseases. Digestive diseases potentially causing anemia have been studied in preference, but other causes of anemia have been included in the text and tables. Primitive hematological diseases that cause anemia are only listed, but are not discussed in depth. The last section is dedicated to simplifying all items discussed above, using practical rules to guide diagnosis and medical care with the greatest economy of resources and time. PMID- 19787826 TI - A guide to diagnosis of iron deficiency and iron deficiency anemia in digestive diseases. AB - Iron deficiency (ID), with or without anemia, is often caused by digestive diseases and should always be investigated, except in very specific situations, as its causes could be serious diseases, such as cancer. Diagnosis of ID is not always easy. Low serum levels of ferritin or transferrin saturation, imply a situation of absolute or functional ID. It is sometimes difficult to differentiate ID anemia from anemia of chronic diseases, which can coexist. In this case, other parameters, such as soluble transferrin receptor activity can be very useful. After an initial evaluation by clinical history, urine analysis, and serological tests for celiac disease, gastroscopy and colonoscopy are the key diagnostic tools for investigating the origin of ID, and will detect the most important and prevalent diseases. If both tests are normal and anemia is not severe, treatment with oral iron can be indicated, along with stopping any treatment with non-steroidal anti-inflammatory drugs. In the absence of response to oral iron, or if the anemia is severe or clinical suspicion of important disease persists, we must insist on diagnostic evaluation. Repeat endoscopic studies should be considered in many cases and if both still show normal results, investigating the small bowel must be considered. The main techniques in this case are capsule endoscopy, followed by enteroscopy. PMID- 19787827 TI - A short review of malabsorption and anemia. AB - Anemia is a frequent finding in most diseases which cause malabsorption. The most frequent etiology is the combination of iron and vitamin B12 deficiency. Celiac disease is frequently diagnosed in patients referred for evaluation of iron deficiency anemia (IDA), being reported in 1.8%-14.6% of patients. Therefore, duodenal biopsies should be taken during endoscopy if no obvious cause of iron deficiency (ID) can be found. Cobalamin deficiency occurs frequently among elderly patients, but it is often unrecognized because the clinical manifestations are subtle; it is caused primarily by food-cobalamin malabsorption and pernicious anemia. The classic treatment of cobalamin deficiency has been parenteral administration of the vitamin. Recent data suggest that alternative routes of cobalamin administration (oral and nasal) may be useful in some cases. Anemia is a frequent complication of gastrectomy, and has been often described after bariatric surgery. It has been shown that banding procedures which maintain digestive continuity with the antrum and duodenum are associated with low rates of ID. Helicobacter pylori (H. pylori) infection may be considered as a risk factor for IDA, mainly in groups with high demands for iron, such as some children and adolescents. Further controlled trials are needed before making solid recommendations about H. pylori eradication in these cases. PMID- 19787828 TI - Spectrum of anemia associated with chronic liver disease. AB - Anemia of diverse etiology is a common complication of chronic liver diseases. The causes of anemia include acute or chronic gastrointestinal hemorrhage, and hypersplenism secondary to portal hypertension. Severe hepatocellular disease predisposes to hemorrhage because of impaired blood coagulation caused by deficiency of blood coagulation factors synthesized by hepatocytes, and/or thrombocytopenia. Aplastic anemia, which is characterized by pancytopenia and hypocellular bone marrow, may follow the development of hepatitis. Its presentation includes progressive anemia and hemorrhagic manifestations. Hematological complications of combination therapy for chronic viral hepatitis include clinically significant anemia, secondary to treatment with ribavirin and/or interferon. Ribavirin-induced hemolysis can be reversed by reducing the dose of the drug or discontinuing it altogether. Interferons may contribute to anemia by inducing bone marrow suppression. Alcohol ingestion is implicated in the pathogenesis of chronic liver disease and may contribute to associated anemia. In patients with chronic liver disease, anemia may be exacerbated by deficiency of folic acid and/or vitamin B12 that can occur secondary to inadequate dietary intake or malabsorption. PMID- 19787829 TI - Anemia and inflammatory bowel diseases. AB - Too often anemia is considered a rare or unimportant manifestation in inflammatory bowel disease (IBD). However, over the last 10 years a number of studies have been conducted and the most relevant conclusions obtained are: (1) anemia is quite common in IBD; (2) although in many cases anemia parallels the clinical activity of the disease, many patients in remission have anemia, and iron, vitamin B12 and/or folic acid deficiency; (3) anemia, and also iron deficiency without anemia, have important consequences in the clinical status and quality of life of the patient; (4) oral iron can lead to gastrointestinal intolerance and failure of treatment; (5) intravenous iron is an effective and safe way to treat iron deficiency; (6) erythropoietin is needed in a significant number of cases to achieve normal hemoglobin levels. Thus, the clinician caring for IBD patients should have a comprehensive knowledge of anemia, and apply recently published guidelines in clinical practice. PMID- 19787830 TI - Intravenous iron in inflammatory bowel disease. AB - The prevalence of anemia across studies on patients with inflammatory bowel disease (IBD) is high (30%). Both iron deficiency (ID) and anemia of chronic disease contribute most to the development of anemia in IBD. The prevalence of ID is even higher (45%). Anemia and ID negatively impact the patient's quality of life. Therefore, together with an adequate control of disease activity, iron replacement therapy should start as soon as anemia or ID is detected to attain a normal hemoglobin (Hb) and iron status. Many patients will respond to oral iron, but compliance may be poor, whereas intravenous (i.v.) compounds are safe, provide a faster Hb increase and iron store repletion, and presents a lower rate of treatment discontinuation. Absolute indications for i.v. iron treatment should include severe anemia, intolerance or inappropriate response to oral iron, severe intestinal disease activity, or use of an erythropoietic stimulating agent. Four different products are principally used in clinical practice, which differ in their pharmacokinetic properties and safety profiles: iron gluconate and iron sucrose (lower single doses), and iron dextran and ferric carboxymaltose (higher single doses). After the initial resolution of anemia and the repletion of iron stores, the patient's hematological and iron parameters should be carefully and periodically monitored, and maintenance iron treatment should be provided as required. New i.v. preparations that allow for giving 1000-1500 mg in a single session, thus facilitating patient management, provide an excellent tool to prevent or treat anemia and ID in this patient population, which in turn avoids allogeneic blood transfusion and improves their quality of life. PMID- 19787832 TI - Blood transfusion for the treatment of acute anaemia in inflammatory bowel disease and other digestive diseases. AB - Allogeneic blood transfusion (ABT) is frequently used as the first therapeutic option for the treatment of acute anaemia in patients with inflammatory bowel disease (IBD), especially when it developed due to gastrointestinal or perioperative blood loss, but is not risk-free. Adverse effects of ABT include, but are not limited to, acute hemolytic reaction (wrong blood or wrong patient), febrile non-hemolytic transfusional reaction, bacterial contamination, transfusion-related acute lung injury, transfusion associated circulatory overload, transfusion-related immuno-modulation, and transmission of almost all infectious diseases (bacteria, virus, protozoa and prion), which might result in increased risk of morbidity and mortality. Unfortunately, the main physiological goal of ABT, i.e. to increase oxygen consumption by the hypoxic tissues, has not been well documented. In contrast, the ABT is usually misused only to increase the haemoglobin level within a fixed protocol [mostly two by two packed red blood cell (PRC) units] independently of the patient's tolerance to normovolemic anaemia or his clinical response to the transfusion of PRC units according to a "one-by-one" administration schedule. Evidence-based clinical guidelines may promote best transfusion practices by implementing restrictive transfusion protocols, thus reducing variability and minimizing the avoidable risks of transfusion, and the use of autologous blood and pharmacologic alternatives. In this regard, preoperative autologous blood donation (PABD) consistently diminished the frequency of ABT, although its contribution to ABT avoidance is reduced when performed under a transfusion protocol. In addition, interpretation of utility of PABD in surgical IBD patients is hampered by scarcity of published data. However, the role of autologous red blood cells as drug carriers is promising. Finally, it must be stressed that a combination of methods used within well-constructed protocols will offer better prospects for blood conservation in selected IBD patients undergoing elective surgery. PMID- 19787834 TI - Analysis of risk factors for central venous port failure in cancer patients. AB - AIM: To analyze the risk factors for central port failure in cancer patients administered chemotherapy, using univariate and multivariate analyses. METHODS: A total of 1348 totally implantable venous access devices (TIVADs) were implanted into 1280 cancer patients in this cohort study. A Cox proportional hazard model was applied to analyze risk factors for failure of TIVADs. Log-rank test was used to compare actuarial survival rates. Infection, thrombosis, and surgical complication rates (chi(2) test or Fisher's exact test) were compared in relation to the risk factors. RESULTS: Increasing age, male gender and open-ended catheter use were significant risk factors reducing survival of TIVADs as determined by univariate and multivariate analyses. Hematogenous malignancy decreased the survival time of TIVADs; this reduction was not statistically significant by univariate analysis [hazard ratio (HR) = 1.336, 95% CI: 0.966-1.849, P = 0.080)]. However, it became a significant risk factor by multivariate analysis (HR = 1.499, 95% CI: 1.079-2.083, P = 0.016) when correlated with variables of age, sex and catheter type. Close-ended (Groshong) catheters had a lower thrombosis rate than open-ended catheters (2.5% vs 5%, P = 0.015). Hematogenous malignancy had higher infection rates than solid malignancy (10.5% vs 2.5%, P < 0.001). CONCLUSION: Increasing age, male gender, open-ended catheters and hematogenous malignancy were risk factors for TIVAD failure. Close-ended catheters had lower thrombosis rates and hematogenous malignancy had higher infection rates. PMID- 19787833 TI - Clonality and allelotype analyses of focal nodular hyperplasia compared with hepatocellular adenoma and carcinoma. AB - AIM: To identify clonality and genetic alterations in focal nodular hyperplasia (FNH) and the nodules derived from it. METHODS: Twelve FNH lesions were examined. Twelve hepatocellular adenomas (HCAs) and 22 hepatocellular carcinomas (HCCs) were used as references. Nodules of different types were identified and isolated from FNH by microdissection. An X-chromosome inactivation assay was employed to describe their clonality status. Loss of heterozygosity (LOH) was detected, using 57 markers, for genetic alterations. RESULTS: Nodules of altered hepatocytes (NAH), the putative precursors of HCA and HCC, were found in all the FNH lesions. Polyclonality was revealed in 10 FNH lesions from female patients, and LOH was not detected in any of the six FNH lesions examined, the results apparently showing their polyclonal nature. In contrast, monoclonality was demonstrated in all the eight HCAs and in four of the HCCs from females, and allelic imbalances were found in the HCAs (9/9) and HCCs (15/18), with chromosomal arms 11p, 13q and 17p affected in the former, and 6q, 8p, 11p, 16q and 17p affected in the latter lesions in high frequencies (> or = 30%). Monoclonality was revealed in 21 (40%) of the 52 microdissected NAH, but was not found in any of the five ordinary nodules. LOH was found in all of the 13 NAH tested, being highly frequent at six loci on 8p, 11p, 13q and 17p. CONCLUSION: FNH, as a whole, is polyclonal, but some of the NAH lesions derived from it are already neoplastic and harbor similar allelic imbalances as HCAs. PMID- 19787835 TI - A systematic review of treating Helicobacter pylori infection with Traditional Chinese Medicine. AB - AIM: To evaluate the efficacy and safety of Traditional Chinese Medicine (TCM) in the treatment of Helicobacter pylori (H. pylori) infection. METHODS: We electronically and manually searched electronic databases, references lists and conferences compilations, and included all randomized clinical trials comparing the treatment of H. pylori using TCM with proton pump inhibitor or colloidal bismuth subcitrate-based triple therapy as controls. The Jadad score was used to assess trial quality, H. pylori eradication rate and the incidence of side effects were taken as outcome measurements, and heterogeneity analysis, meta analysis and funnel plot analysis were conducted. RESULTS: Sixteen trials were included. The Jadad scores of all the trials were not more than 2. Clinical heterogeneity and substantial statistical heterogeneity existed among the trials (P = 0.001, I(2) = 59%) and meta-analysis was not conducted. The average eradication rates following TCM and triple therapy were 72% and 78% and the incidence of side effects were 2% and 29%, respectively. The funnel plot was obviously asymmetric. CONCLUSION: Available evidence is not convincing enough to show that TCM has the same efficacy as triple therapy in H. pylori treatment. TCM may be safer than triple therapy. TCM should not be recommended as monotherapy in H. pylori infection. PMID- 19787831 TI - Use of agents stimulating erythropoiesis in digestive diseases. AB - Anemia is the most common complication of inflammatory bowel disease (IBD). Control and inadequate treatment leads to a worse quality of life and increased morbidity and hospitalization. Blood loss, and to a lesser extent, malabsorption of iron are the main causes of iron deficiency in IBD. There is also a variable component of anemia related to chronic inflammation. The anemia of chronic renal failure has been treated for many years with recombinant human erythropoietin (rHuEPO), which significantly improves quality of life and survival. Subsequently, rHuEPO has been used progressively in other conditions that occur with anemia of chronic processes such as cancer, rheumatoid arthritis or IBD, and anemia associated with the treatment of hepatitis C virus. Erythropoietic agents complete the range of available therapeutic options for treatment of anemia associated with IBD, which begins by treating the basis of the inflammatory disease, along with intravenous iron therapy as first choice. In cases of resistance to treatment with iron, combined therapy with erythropoietic agents aims to achieve near-normal levels of hemoglobin/hematocrit (11-12 g/dL). New formulations of intravenous iron (iron carboxymaltose) and the new generation of erythropoietic agents (darbepoetin and continuous erythropoietin receptor activator) will allow better dosing with the same efficacy and safety. PMID- 19787836 TI - Correlation between anti-fibrotic effect of baicalin and serum cytokines in rat hepatic fibrosis. AB - AIM: To investigate the correlation between the antifibrotic effect of baicalin and serum cytokine production in rat hepatic fibrosis. METHODS: Forty male Sprague-Dawley rats were divided randomly into four groups: normal control group, model group, baicalin-treated group, and colchicine-treated group. Except for the normal control group, all rats in the other groups were administered with carbon tetrachloride to induce hepatic fibrosis. At the same time, the last two groups were also treated with baicalin or colchicine. At the end of the 8 wk, all animals were sacrificed. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), transforming growth factor (TGF)-beta1, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6 and IL-10 were measured. Liver index, hepatic hydroxyproline content and the degree of liver fibrosis were also evaluated. RESULTS: The levels of ALT, AST and liver index in the baicalin treated group were markedly lower than those in the model group (ALT: 143.88 +/- 14.55 U/L vs 193.58 +/- 24.35 U/L; AST: 263.66 +/- 44.23 U/L vs 404.37 +/- 68.29 U/L; liver index: 0.033 +/- 0.005 vs 0.049 +/- 0.009, P < 0.01). Baicalin therapy also significantly attenuated the degree of hepatic fibrosis, collagen area and collagen area percentage in liver tissue (P < 0.01). Furthermore, the levels of serum TGFbeta1, TNF-alpha and IL-6 were strikingly reduced in the baicalin treated group compared with the model group, while the production of IL-10 was up regulated: (TGF-beta1: 260.21 +/- 31.01 pg/mL vs 375.49 +/- 57.47 pg/mL; TNF alpha: 193.40 +/- 15.18 pg/mL vs 260.04 +/- 37.70 pg/mL; IL-6: 339.87 +/- 72.95 pg/mL vs 606.47 +/- 130.73 pg/mL; IL-10: 506.22 +/- 112.07 pg/mL vs 316.95 +/- 62.74 pg/mL, P < 0.01). CONCLUSION: Baicalin shows certain therapeutic effects on hepatic fibrosis, probably by immunoregulating the imbalance between profibrotic and antifibrotic cytokines. PMID- 19787837 TI - Tumor lysis syndrome after transarterial chemoembolization of hepatocellular carcinoma: case reports and literature review. AB - Tumor lysis syndrome (TLS) is a potentially lethal complication in cancer therapy. It may occur in highly sensitive tumors, especially in childhood cancer and leukemia, whereas, it is rare in the treatment of solid tumors in adults. TLS results from a sudden and rapid release of nuclear and cytoplasmic degradation products of malignant cells. The release of these can lead to severe alterations in the metabolic profile. Here, we present two cases of large hepatocellular carcinoma (HCC) treated by transarterial chemoembolization (TACE) that resulted in TLS. Although TLS rarely happens in the treatment of adult hepatic tumor, only a few cases have been reported. We should keep in mind that all patients with HCC, particularly those with large and rapidly growing tumors, must be closely watched for evidence of TLS after TACE. PMID- 19787838 TI - A rare case of periampullary carcinoma with ectopic ending of Vater's ampulla. AB - A 71-year-old woman was referred to our department complaining of painless progressive jaundice for the last 3 mo. Magnetic resonance imaging and magnetic resonance cholangiopancreatography (MRCP) showed the ectopic hepatopancreatic ampulla draining into the fourth part of the duodenum adjacent to the duodenojejunal flexure; the irregular morphology of the duodenojejunal flexure likely due to a soft tissue mass. Laparotomy confirmed the presence of the abnormal ampulla of Vater located at the fourth part of the duodenum and a soft tissue tumor about 6 cm x 5 cm x 5 cm with a peduncle adjoining the ampulla. Resection of the tumor, including some peripheral tissue, and a Roux-Y loop anastomosis choledochojejunostomy were performed. Pathological examination indicated an intestinal villous adenoma accompanied by severe dysplasia and focal canceration. Periampullary carcinoma with ectopic ending of the Vater's ampulla into the fourth part of the duodenum is rather rare. The embryonic genetic background of this anomaly has not yet been fully explained. It is worth mentioning that MRCP is useful for demonstrating anomalies and anatomic variants of the biliary tract system and pancreatic duct. PMID- 19787840 TI - Proceedings of the 9th International Symposium on Avian Endocrinology. Leuven, Belgium. July 11-15, 2008. PMID- 19787839 TI - Proceedings of the 100th Anniversary Symposium of Umami Discovery: the roles of glutamate in taste, gastrointestinal function, metabolism, and physiology. Tokyo, Japan. September 11-13, 2008. PMID- 19787841 TI - DNA damage: from causes to cures. Proceedings of the 2008 Biochemical Society Annual Symposium. December 15-17, 2008. Cambridge, United Kingdom. PMID- 19787842 TI - Proceedings of the 33rd Annual Meeting of the Japanese Society for Biomedical Mass Spectroscopy. September 25-26, 2008. Tokyo, Japan. PMID- 19787843 TI - How hospitals confront new technology. AB - Hospital technology decision makers now confront a growing pipeline of information technology (IT) and major medical equipment that challenges traditional capital allocation processes. In a highly fragmented industry that is driven by coverage and reimbursement policies set by the Centers for Medicare and Medicaid Services (CMS) and private insurers, the cumulative impact of hospitals' technology investment decisions shapes health care for decades.We propose a framework for the development of a national collaboration for the planning and assessment of emerging technologies, designed to improve the quality and efficiency of hospital decisions. Broader application of technology assessment would restrain inappropriate technology adoption and use. PMID- 19787844 TI - An additional consideration in food safety. PMID- 19787845 TI - Views on primate laboratory research. PMID- 19787846 TI - Cost of home palliative care compared with conventional hospital care for patients with haematological cancers in Greece. AB - This study compared the costs of home palliative with conventional hospital care for cancer haematological patients in Greece. The study was a retrospective cost minimisation analysis using data from the finance department and from patient notes for the period from January to June 2002. A non-parametric bootstrap method was used to estimate the incremental cost between home and conventional care. A sensitivity analysis was also used. The estimated incremental cost was euro 522 (95% confidence interval: euro 516-528). This was not substantially affected by varying the unit costs within reasonable limits and remained statistically significant under all scenarios tested in the sensitivity analysis. Our findings show that home palliative care is more expensive than conventional hospital care. Further studies should be carried out to examine the cost-effectiveness of the particular scheme as well as the preferences of patients and carers. PMID- 19787847 TI - Time preference bias in time trade-off. AB - This study examined whether time trade-off (TTO) values adjusted for time preferences are more consistent with individuals' preferences. This was carried out by testing the constant proportional trade-off (CPTO) assumption, and both individual specific and standard discount rates were used. The results show that the mean adjustment factor is around 0.03. This may influence relative cost effectiveness in economic evaluations. The CPTO assumption holds with respect to both unadjusted TTO values and TTO values adjusted for individuals'time preference, and therefore no conclusions can be drawn as to whether the adjusted values are more consistent with individuals' preferences. However, the CPTO assumption is violated when standard discount rates are used. This clearly shows that the use of standard discount rates should be avoided. Further exploration of the time preference bias and other biases in TTO is identified as an important area of future research. PMID- 19787848 TI - Validating the EQ-5D with time trade off for the German population. AB - The aim of this survey study was to derive the societal values of the general public for the EuroQol EQ-5D. Using the same protocol as previously used in the United Kingdom, we compared the German values with the British. In face-to-face interviews a sample of 339 individuals in northern Germany valued 15 different health states from a sample of 36 states. Values were derived using the York MVH protocol for time trade-off (TTO) and a visual analogue scale (VAS). Values for all 243 health states of the EQ-5D were estimated by a regression model. The VAS values revealed close a resemblance to the British VAS results. German TTO values were higher than the British. This was especially the case for the worse health states. The results suggest that the TTO values are more related to national variables than values derived by VAS. The use of the TTO values of this investigation makes it possible to anticipate these cultural differences in studies carried out in Germany. PMID- 19787849 TI - Improving dementia treatment in care homes. PMID- 19787850 TI - NZNO referendum stance praised. PMID- 19787851 TI - Paperwork before patient care. PMID- 19787852 TI - Critic should laugh more. PMID- 19787853 TI - Nurse to volunteer in Ecuador. PMID- 19787854 TI - When it comes to your orthodontic health, you are in control. PMID- 19787855 TI - Four patients, four healthier smiles! PMID- 19787856 TI - Ultrafast UV-visible and infrared spectroscopic observation of a singlet vinylcarbene and the intramolecular cyclopropenation reaction. AB - Ultrafast UV-vis/IR spectroscopies were used to study the photochemistry of a vinyl diazo ester PhCH=CHCN2CO2CH3 (1) in solution. The results indicate that singlet styrylcarbomethoxy carbene ((1)2) is produced from the excited state of diazo precursor (1*). It is concluded that vinyl singlet carbene ((1)2) undergoes an intramolecular cyclopropenation reaction to produce the cyclopropene product (3), and undergoes intersystem crossing to ground triplet carbene ((3)2). The predictions of DFT calculations are consistent with the observations. PMID- 19787858 TI - Impact of aging on cancer immunity and immunotherapy. PMID- 19787857 TI - Formation of chiral C(sp3)-C(sp) bond by allylic substitution of secondary allylic picolinates and alkynyl copper reagents. AB - To establish allylic substitution of secondary allylic alcohol derivatives with alkynyl copper reagents, allylic esters bearing the (2-pyridine)CO2-, (2 pyrazine)CO2-, (EtO)2PO2-, C6F5CO2-, o-(Ph2P)C6H4CO2-, MeOCO2-, or AcO- group were examined. First, picolinate (R1 = Me, R2 = CH2OPMB) was subjected to reaction with (TMS-C[triple bond]C)2CuLi.LiBr at 0degreesC. Although no substitution took place, MgBr2 (3 equiv) was found to promote the reaction to produce the anti SN2' product in 93% yield with 94% regioselectivity and 99% chirality transfer. In contrast, substitution of the other esters with the copper reagent in the presence of MgBr2 were less reactive ((2-pyrazine)CO2-) or marginally reactive (other cases). Generality of the substitution using picolinates was established with five picolinates (R1 = Me, Ph(CH2)2, PMBO(CH2)3; R2 = Me, CH2OPMB, CH2OTBS, C5H11, c-C6H11) and seven alkynyl copper reagents (R3 = TMS, Ph, p-TBSOC6H4, p- and o-MeOC6H4, p-MeC6H4, p-FC6H4), furnishing anti SN2' products in 61-93% yields with high regioselectivity (usually >90%) and high chirality transfer (usually >95%). In addition, transformation of the products was briefly studied. PMID- 19787859 TI - Proceedings from the 5th World Melioidosis Congress. Khon Kaen, Thailand. November 21-23, 2007. PMID- 19787860 TI - "The most obscure problem of all": autonomy and its vicissitudes in The interpretation of dreams. AB - The unconscious is implicated in Romantic and liberal discourses of autonomous individuality, and these insinuate themselves in complex ways into Freud's descriptions of the psyche. Focusing on "The Interpretation of Dreams," the paper examines the fortunes of notions such as autonomy and selfhood, beginning with a consideration of Freud's languages of determinism, and moving on to the theory of the wish. In particular it examines ambiguities in the accounts of sexual and egotistical wishes, and in the portrayal of egotism itself. It is suggested that behind such ambiguities lies a deeper ambivalence in Freud's understanding of the I and its autonomy, which is in turn related to indeterminacies in the liberal concept of self. These ambiguities are further explored via the unstable political metaphors Freud attaches to the father-son relationship. The paper argues that such instabilities in the idea of selfhood radically unsettle the terms of the psychoanalytic account. PMID- 19787862 TI - Biomedical informatics. Preface. PMID- 19787861 TI - The naked mother or, why Freud did not write about railway accidents. AB - This paper examines Freud's approach to technology from two interrelated perspectives. First it discusses the way his theory presents technology solely in positive terms, as an instrument that expands human power over nature almost infinitely. Here the goal is to underscore a limitation of Freud's way of thinking about human creations, which comes to the fore in his somewhat myopic enthusiasm for technology. Then the essay elaborates on a void in Freud's writings, examining why he did not refer to railway accidents in his discussion of technology. It concludes with a choice of three possible answers: (a) that his theories allowed no conceptual room for accidents, (b) that his silence on accidents was conditioned by the emergence of his oedipal desire on the occasion of a railway journey from Leipzig to Vienna, (c) that his silence was caused by a fear of accidents that threatened to overwhelm him. PMID- 19787864 TI - Psychoanalysis eats its own: or, the heretical Saint Roazen. AB - The author attempts a "Roazenesque" interpretation of Paul Roazen's life and work, and situates his career vis-a-vis that of other revisionist critics of Freud. To these ends, the essay charts the highs and lows of Roazen's long career as a biographer-historian of psychoanalysis. His career is divided into four phases, the first of which is arguably the most important. It was also the most controversial, producing classic books on Victor Tausk and on Freud's followers. Roazen's later work fares less well, even undermining his standing among scholars. If there is a commonality to the work of all four phases, it is Roazen's fairly constant recourse to interviews he conducted in the mid-1960s with many people intimate with Freud. On the good side, these interviews provided him unique access to details about Freud's everyday life and practice. Roazen thus became known as the historian of arcane detail. On the bad side, Roazen came to rely too heavily on these interviews and on his own singular role as interviewer. As a result his work became increasingly self-regarding and nostalgic, and thus less original, interesting, or discerning. His legacy is therefore mixed, although secure enough that future scholars will not easily ignore his contribution in a handful of good books. PMID- 19787863 TI - Saving psychoanalysts: Ernest Jones and the Isakowers. AB - This article examines the role played by Ernest Jones in saving psychoanalysts from Germany and Austria during the 1930s, and , in particular, in the case of Drs Otto and Salomea Isakower from Vienna. Archives from the Library of Congress and the British Psychoanalytical Society are used to document how Jones navigated the considerable difficulties presented in both Europe and London as well as by colleagues and was able to help the Isakowers emigrate to Liverpool where they worked and began the "North of England" training group with others and emigrated to the USA in 1940. As President of the International Society, Jones had responsibilities with psychoanalyst refugees, which he performed with care, commitment and political competence. Although Jones did not succeed in saving psychoanalysis in Europe, he played a crucial role in saving psychoanalysts. He helped to spread the world-wide standing and influence of psychoanalysis. PMID- 19787865 TI - Vaccines for pandemic influenza. Preface. PMID- 19787866 TI - Homocysteine level in Iranian patients with premature acute myocardial infarction. PMID- 19787867 TI - Diagnosis and treatment of epistaxis caused by non-traumatic pseudoaneurysms of carotid artery. PMID- 19787868 TI - Being analysed by Freud in 1921: the diary of a patient. AB - This article presents a unique document, a hitherto unpublished diary of a patient analysis with Freud in 1921. Conclusions on how Freud worked with patients at that period, particularly insofar as transference is concerned, are drawn. PMID- 19787869 TI - Freud's patient calendars: 17 analysts in analysis with Freud (1910-1920). AB - The author examines the course of 17 analyses, as conducted by Freud, on the basis of a new source, Freud's patient notebooks. All analysands (five women, 12 men) were or were to become members of a psychoanalytic society. Their treatments were marked by a relatively short duration (all of them less than a year) and a very high number of hours per week (generally six). The total number of hours ranged between nine and about 250. Compared to the present conditions, both the duration and the number of hours per week show a great historical change has taken place. The author discusses this change as well as some other characteristics, e.g. the customary extra-analytical contact between Freud and his analysands. In an appendix, treatment profiles of all 17 analyses are given, summarizing their duration, the total number of hours, numerous of hours per week and number of hours in each month of treatment. PMID- 19787870 TI - A model high surface area alumina-supported palladium catalyst. AB - A catalyst preparative procedure is described that produces a high surface area alumina-supported palladium catalyst that yields an atypical chemisorbed carbon monoxide infrared spectrum. This inherently residue-free substrate provides a useful reference for evaluation of catalyst crystallite morphology and its effect on reactivity profiles. PMID- 19787871 TI - Combined EXAFS and STEM-EELS study of the electronic state and location of Mn as promoter in Co-based Fischer-Tropsch catalysts. AB - STEM-EELS and EXAFS have been used to investigate the location and electronic state of Mn as promoter in TiO2-supported cobalt Fischer-Tropsch catalysts prepared by two different procedures. It was found that the extent of interaction between Mn and the active Co phase as well as the level of Mn dispersion over the TiO2 surface largely determine the enhancement of the selectivity in the Fischer Tropsch synthesis at pressures of 1 bar. PMID- 19787872 TI - Theoretical evidence for the formation of rotational energy level clusters in the vibrational ground state of PH3. AB - We investigate theoretically the rotational dynamics of pyramidal XY3 molecules in highly excited rotational states. Towards this end we compute, by a variational method, the rotational energy levels in the vibrational ground state of PH3 for J < or = 80. At J > or = 50 the calculated energy levels show a distinct cluster pattern. By monitoring the cluster formation we follow the various stages of the rotational dynamics. We analyze the wavefunctions for the cluster states and compute expectation values which show that the C3v geometrical symmetry of PH3 is broken at high rotational excitation. The conclusions drawn from the quantum-mechanical calculations are confirmed by semi-classical theory, i.e., by an analysis of the stationary points on the rotational energy surface. PMID- 19787873 TI - Reactivity of cobalt dimer and molecular oxygen in rare gas matrices. IR spectrum, photophysics and structure of Co2O2. AB - The reactivity of cobalt dimer towards molecular oxygen has been investigated in rare gas matrices. If the formation of Co2O2 from the condensation of effusive beams of Co and O2 in neon and argon matrices is observed after sample deposition, our results show that the in situ formation does not result from the reaction of ground state Co nor Co2 with molecular oxygen. One reaction channel has been evidenced through reaction of Co2 in excited states, close or above the dissociation limit. Two metastable states of Co2O2 with low-symmetry structures, stabilized by interaction with the matrix cage have also been evidenced between 1.4 and 2 eV above the ground state. Observation of Co2(16)O2, Co2(18)O2 and Co2(16)O(18)O isotopic data for five fundamental and three combination transitions enable determination of all fundamental vibrations for matrix isolated Co2O2 in its cyclic ground state. Semi-empirical harmonic potential calculations lead to estimates of 2.435 N cm(-1) for the Co-O bond force constant, and 93 +/- 5 degrees OCoO bond angle. In comparison with the CoO diatomic molecule, this suggests a near square-planar structure with a 1.765 +/- 0.01 A CoO bond distance. PMID- 19787874 TI - Vibrational dynamics of the hydrogen bonded complexes (CH2)2O-HF and -DF investigated by combined jet- and cell-Fourier transform infrared spectroscopy. AB - Fourier transform infrared spectra of the Vs stretching bands of HF and DF bonded to (CH2)2O have been recorded at 0.5 cm(-1) resolution in a cooled cell and in a supersonic expansion seeded with argon. The analysis of the congested spectra of this type of medium strength hydrogen bonded complexes exploits a combination of controlled temperature effects in the ranges 25-80 K and 200-300 K and a band contour simulation program accounting for homogeneous and inhomogeneous contributions. Significant anharmonic couplings between the donor stretch mode and three of the low frequency intermolecular modes are found to be responsible for the characteristic hot band patterns in the Vs fundamental region of cell spectra. A global analysis of sum and difference combination bands involving Vs provides reliable values of intermolecular frequencies, anharmonic coupling constants and a good estimate of the dissociation energy of the complex which compares favorably with ab initio results. The effective linewidth provides a lower bound for the predissociation lifetime of 1.5 ps for HF and 7 ps for DF containing complexes, respectively. The correlation between effective linewidths and vibrational densities of states for (CH2)2O-HF and -DF underlines the important role of intramolecular vibrational redistribution in the vibrational dynamics of these complexes while the lifetime decrease for HF (or DF) bonded to oxygenated cyclic ethers with respect to sulfured homologues might be explained by the change in the arrangement of the acid relative to the plane of the acceptor subunit. PMID- 19787875 TI - Investigation of two-photon absorption behavior in symmetrical acceptor-pi acceptor derivatives with dimesitylboryl end-groups. Evidence of new engineering routes for TPA/transparency trade-off optimization. AB - Investigations of the non-linear optical properties of a novel series of A-pi-A quadrupoles, based on dimesitylboron end-groups, reveal the promising potential of elongated vinylboranes derivatives for combined enhanced two-photon absorption cross-section and improved transparency in the visible region. In addition, the excited state lifetime can be significantly enhanced in A-pi-A'-pi-A derivatives. This opens a new route towards optimized molecules for optical power limiting. PMID- 19787876 TI - Efficient solid-state NMR methods for measuring heteronuclear dipolar couplings in unoriented lipid membrane systems. AB - Recently (Dvinskikh et al., J. Magn. Reson., 2003, 164, 165 and Dvinskikh et al., J. Magn. Reson., 2004, 168, 194), some of us introduced two efficient solid-state NMR techniques for the determination of heteronuclear dipolar couplings under magic-angle spinning (MAS). These two-dimensional (2D) recoupling methods have been applied previously to simple amino acids, and to columnar systems with high positional and orientational order. In this work, we show that the 2D MAS sequences produce unparalleled 1H-13C dipolar resolution in unoriented lipid membranes. The recoupling experiments were applied to hydrated dimyristoylphosphatidylcholine (DMPC) in the liquid-crystalline Lalpha phase, and the results agreed well with previous NMR investigations using specifically deuterated phospholipids. PMID- 19787877 TI - Mechanistic aspects of hydrogen abstraction for phenolic antioxidants. Electronic structure and topological electron density analysis. AB - Density functional calculations using the B3LYP functional are used to provide insight into the hydrogen abstraction mechanism of phenolic antioxidants. The energy profiles for 13 ortho, meta, para and di-methyl substituted phenols with hydroperoxyl radical have been determined. An excellent correlation between the enthalpy (DeltaH) and activation energy (DeltaEa) was found, obeying the Evans Polanyi rule. The effects of hydrogen bonding on DeltaEa are also discussed. Electron donating groups at the ortho and para positions are able to lower the activation energy for hydrogen abstraction. The highly electron withdrawing fluoro substituent increases the activation energies relative to phenol at the meta position but not at the para position. The electron density is studied using the atoms in molecules (AIM) approach. Atomic and bond properties are extracted to describe the hydrogen atom abstraction mechanism. It is found that on going from reactants to transition state, the hydrogen atom experiences a loss in volume, electronic population and dipole moment. These features suggest that the phenol hydroperoxyl reactions proceed according to a proton coupled electron transfer (PCET) as opposed to a hydrogen atom transfer (HAT) mechanism. PMID- 19787878 TI - Multiplex detection of collisional energy transfer using KCSFI. AB - A new detection method for obtaining collisional transition probabilities P(E',E) of highly vibrationally excited molecules in the gas phase is presented. The technique employs energy-selective probing of the time-dependent vibrational population distribution by "kinetically controlled selective fluorescence (KCSF)". We present experimental results for a test system, the collisional deactivation of toluene by argon, where we use the well-known "kinetically controlled selective ionization (KCSI)" scheme as a reference for comparison. A newly designed setup is employed that allows simultaneous detection of fluorescence and ionization signals under identical experimental conditions ("kinetically controlled selective fluorescence and ionization = KCSFI"). For the system toluene + argon it is demonstrated that KCSF and KCSI yield identical results. A rate-equation model is presented to understand common features and differences of both approaches. The fluorescence detection scheme shows promise for future investigations on collisional energy transfer. The experimental setup is simpler, because it requires no additional ionization wavelength. This will hopefully give access to the P(E',E) of systems where, e.g., ionization schemes are difficult to implement due to short wavelengths required for the ionization step. A few examples will be outlined briefly. PMID- 19787879 TI - Quantum mechanical and quasi-classical trajectory reaction probabilities and cross sections for the S(1D) + H2,D2,HD insertion reactions. AB - Time-independent quantum mechanical (QM) and quasi-classical trajectory (QCT) calculations of reaction probabilities at total angular momentum J = 0 as a function of collision energy for the S(1D) + H2(v = 0, j = 0), S(1D) + D2(v = 0, j = 0) and S(1D) + HD(v = 0, j = 0) reactions have been performed on a recent ab initio potential energy surface. In addition, QCT calculations of integral cross sections as a function of collision energy (the excitation functions) have been carried out for the same reactions. The QCT excitation functions and those obtained by applying a capture model to the QM reaction probabilities are compared with the available experimental determinations. The QCT and QM methods reproduce the shape of the measured excitation functions quite satisfactorily. However, the theoretical intramolecular and intermolecular isotope effects are in disagreement with those obtained experimentally. PMID- 19787880 TI - Influence of pyrolysis parameters on the formation of an aerosol from ethane. AB - The pyrolysis of ethane was performed in tubular reactors at temperatures from 1110 K to 1220 K, at pressures from 40 kPa to 80 kPa and at residence times from 1.4 s to 58 s. The formation of a fog was monitored using laser extinction. The boundaries of the regime of time, temperature and pressure in which a condensed phase was formed were delineated. Five simple analytical models were derived in order to analyze the kinetics of formation of this phase. The parameters in the models were fitted to the experimental data and were compared to the predictions of the kinetic theory. The most successful model involved a steady formation of precursors until a critical pressure was reached. Nucleation then occurred rapidly, followed by a steady growth of the volume of the particles. The temperature dependence of the inverse of the incubation period was determined to be In[(theta/s)(-1))] = -(200 +/- 30) kJ mol(-1)/RT + (20 +/- 4). The rate of particle growth was proportional to the square of the reactant pressure and followed the following Arrhenius expression: In[omega/s(-1)] = -(420 +/- 40) kJ mol(-1)/RT + (39 +/- 4). According to this model the heat of vaporization of the droplets was (210 +/- 50) kJ mol(-1). This was consistent with condensation of polynuclear aromatic hydrocarbons having molecular weights of about (460 +/- 110) g mol(-1). At longer residence times the attenuation of the laser beam reached a plateau. This was interpreted in terms of a decline in the rate of fog formation or in terms of the removal of droplets by deposition on the reactor surface. PMID- 19787881 TI - An experimental study of the gas-phase reaction of the NO3 radical with alpha,beta-unsaturated carbonyl compounds. AB - The relative-rate technique has been used to obtain rate coefficients for the reaction between the NO3 radical and alpha,beta-unsaturated esters and ketones: methyl E-2-butenoate (k1), methyl 3-methyl-2-butenoate (k2), methyl E-2-methyl-2 butenoate (k3), 3-methyl-3-buten-2-one (k4), E-3-penten-2-one (ks), 4-methyl-3 penten-2-one (k6), and E-3-methyl-3-penten-2-one (k7). The rate constants obtained by the relative-rate method at T = 298 +/- 2 K and P = 760 +/- 5 Torr (N2 as bath gas) are: k1 = (1.85 +/- 0.56) x 10(-15) cm3 molecule(-1) s(-1), k2 = (1.41 +/- 0.23) x 10(-14) cm3 molecule(-1) s(-1), k3 = (4.91 +/- 1.15) x 10(-14) cm3 molecule(-1) s(-1), k4 = (8.27 +/- 6.44) x 10(-15) cm3 molecule(-1) s(-1), k5 = (1.03 +/- 0.31) x 10(-14) cm3 molecule(-1) s(-1), k6 = (1.44 +/- 0.26) x 10( 13) cm3 molecule(-1) s(-1) and k7 = (1.55 +/- 0.20) x 10(-13) cm3 molecule(-1) s( 1). The rate constants are used to show the effect of increased substitution at the carbon-carbon double bond. Group-reactivity factors for the ketone and ester groups are also determined. Atmospheric lifetimes of the compounds against night time attack by NO3 are estimated. PMID- 19787882 TI - Desorption of products in 193 nm photo-induced reactions in (O2 + CO) adlayers on Pt(112). AB - The spatial distributions of desorbing products were examined in 193 nm photo induced reactions in O2 + CO adlayers on stepped Pt(112) = [(s)3(111) x (001)]. At high coverage of O2(a) and CO(a), both O2 and CO2 desorption collimated closely along the (111) terrace normal. The results were compared with those in thermal CO oxidation, and the origin of the collimation angle shift in the latter is discussed. On the other hand, at low CO(a) coverage, O2 and CO2 desorption collimated in inclined ways in the plane along the surface trough. At these collimation positions, the kinetic energy of desorbing 02 and CO2 was maximal, confirming the hot-atom collision mechanism. PMID- 19787883 TI - One-electron reduction of 2-aminopurine in the aqueous phase. A DFT and pulse radiolysis study. AB - The electron affinity and the subsequent proton affinity of the electron adducts of 2-aminopurine (abbreviated 2AP) and adenine (A) are calculated with density functional theory (DFT). According to these calculations 2AP*- and A*- have similar thermochemical parameters leading to the conclusion that their reaction pathways should be close to analogous. Using the pulse radiolysis technique 2AP*- is formed by reaction with the hydrated electron (e(-)aq) and the resulting transient absorption spectrum is assigned to 2AP(NH)*. Additionally, it was found, employing the laser flash photolysis technique, that the excited singlet state of 2AP is incapable of oxidizing guanine in the aqueous phase. However, the one-electron oxidized 2AP (2AP*+) has sufficient energy to ionize guanine according to the DFT results in agreement with experimental data from the literature. PMID- 19787884 TI - Control of the surface morphology of solid electrolyte films during field-driven growth in a reactive plasma. AB - Experiments on the generation of non-equilibrium surface patterns on ion conducting thin films (AgCl, silver chloride) during field-driven growth in chlorine rf plasmas are reported. The growth experiments are performed in a vacuum flow reactor in the temperature range between 320 K and 450 K, at chlorine gas pressures in the order of 100 Pa, and by applying current densities in the order of 1 mA cm(-2). The surface morphology of product films is documented by scanning electron microscopy and analysed in terms of typical surface patterns. A large variety of different surface morphologies (often finger-like or dendritic) is prepared with a high lateral uniformity and good reproducibility. A theoretical stability criterion is derived on the basis of a linear stability analysis. The model-type experiments confirm this formal stability criterion: (a) The growth of the product surface is morphologically stable, if the plasma exhibits a higher conductivity than the growing solid. (b) The typical wavelength of the surface patterns that are formed during growth is proportional to the reciprocal root of the electric current. (c) The periodicity of the surface patterns decreases when the temperature is increased, and the growth rate of a surface instability grows with increasing temperature. All theoretical predictions are confirmed by corresponding experimental results. PMID- 19787885 TI - The significance of electrokinetic characterization for interpreting interfacial phenomena at planar, macroscopic interfaces. AB - Streaming potential measurements provide valuable information for the validation and interpretation of interfacial phenomena that occur at flat macroscopic surfaces. Planar substrates have been extensively used for the interpretation of events, which occur at particulate surfaces; however, these flat surfaces are often only questionably representative of their particulate counterparts due to variations in surface chemistry and topography. In this study, the zeta potential from planar macroscopic surfaces of PMMA, mica, graphite, fluorite, and calcite have been calculated from streaming potentials measured in aqueous solutions using an asymmetric clamping cell. These zeta potentials have been found to significantly contribute to understanding and interpretation of interfacial phenomena influenced by Coulombic interactions including adsorption, surface forces, and the structure of surface micelles. PMID- 19787886 TI - Electron stimulated desorption of Cl(-) from adsorbed and condensed Cl2: effects of environment and orientation. AB - Electron stimulated desorption (ESD) of Cl(-) from condensed molecular chlorine in the energy range 0-15 eV is studied. Cl2 is deposited in either multilayer amounts directly on a cryogenically cooled gold crystal or in sub-monolayer quantities on rare gas films (Xe, Kr) or ammonia ice films. Cl(-) desorption from multilayer films shows an intense resonance peaking at 5.5 eV and a comparatively smaller feature at 3 eV in qualitative agreement with an earlier ESD experiment. The desorption signal is enhanced by about one order of magnitude when a 0.2 monolayer (ML) Cl2 is adsorbed on a multilayer rare gas film. In this case, the desorption signal shows two clearly separated resonances peaking at 2.5 and 5.5 eV closely resembling dissociative electron attachment (DEA) from gas phase Cl2. These resonances can be associated to the transitions Cl2(1Sigmag+) --> Cl2( )(2Pig) and Cl2(1Sigmag+) --> Cl2(-)(2Piu), respectively, both final states representing core excited resonances. The shape of the resonance around 5.5 eV splits into different peaks when changing from grazing incidence of the electron beam to an impact angle of 45 degrees with respect to the surface normal. On the basis of the pronounced angular dependence of the Cl(-) intensity reported from gas phase DEA this observation is compatible with a situation in which the molecules are oriented along the surface normal. Compared to the noble gas films, ESD from sub-monolayer Cl2 on top of a multilayer NH3 film is suppressed while the overall shape of the yield function is approximately preserved. None of the present experiments show a Cl(-) desorption signal below 2 eV while the charging behaviour of the film indicates that electron attachment is still operative in this energy domain. This suggests that the transient anion in its electronic ground state (Cl2(-)#(2Sigmau+)) is still formed by low energy electron attachment but is subjected to effective energy dissipation creating either stabilized ions (Cl2(-)(2Sigmau+)) or fragment ions (Cl(-) (2P)) with insufficient kinetic energy to leave the surface. PMID- 19787887 TI - Stabilities of crystal faces of aragonite (CaCO3) compared by atomic force microscopic observation of facet formation processes in aqueous acetic acid. AB - Crystal faces of aragonite in various orientations were dissolved in water or in a dilute aqueous acetic acid. Facet formation processes were observed in situ using atomic force microscopy (AFM). At the polar (001) surface, which gave atom resolved AFM images in air, less polar {112} facets were developed in water. At two other polar faces (110) and (010), which are frequently seen in natural forms, electrically neutral facets such as (130) and (100) were developed in the acidic solution. No facet formation was observed at the neutral (130) and (100) faces. Atom-resolved AFM images observed in air at the latter nearly corresponded to the arrangement of H atoms binding to the carbonate ions. The relative stabilities of polar and neutral surfaces strongly depend on pH, since protonation of the carbonate ions changes distributions of positive and negative electric charges at the surfaces. The equilibrium crystal form of aragonite in acidic conditions most probably consists of {100}, {130} and {112} faces, which is in strong contrast to the cases of alkaline conditions. The (001) face having carbonate ions fully exposed to the solution will not be stabilized without a specific adsorbate. PMID- 19787888 TI - Epitaxial TiO2 nanoparticles on Pt(111): a structural study by photoelectron diffraction and scanning tunneling microscopy. AB - Angle-scanned X-ray photoelectron diffraction (XPD) and scanning tunneling microscopy (STM) are used to characterise the structure of TiO2 nanoparticles grown on a Pt(111) single crystal surface. The nanoparticles grow over a well ordered oxide interfacial layer that displays a (square root 43 x square root 43) - R7.6 degrees superstructure with a unit cell (18.2 x 18.2 A), as demonstrated by STM and low-energy electron diffraction (LEED). Our XPS Ti 2p core level spectra suggest a significant contribution from reduced titanium ions within the interfacial layer. On the contrary, according to XPS binding energy data, the nanoparticles are mostly composed of Ti(IV) ions. During the initial stage of the growth, the nanoparticles are on the average 2 nm high and about some tens of nm wide, and show a flat on-top surface, while the interparticle region show the structure of the ordered interfacial layer. During later stages of the deposition, the particles become larger and they show a more irregular, globular like shape as well as coalescence. But, even at this stage of the growth, large interparticle regions are present. Moreover, the nanoparticles produce a distinct XPD pattern which demonstrates that they grow with a preferential azimuthal orientation with respect to the substrate surface. A simple geometrical analysis of the XPD data in terms of forward scattering events suggests that the particles crystallize in the rutile TiO2 structure and expose the (100) surface. This hypothesis is supported by means of multiple scattering simulations of the XPD patterns. PMID- 19787889 TI - Ion exchange at the electrode/electrolyte interface studied by probe beam deflection techniques. AB - Probe beam deflection (PBD) techniques are a set of in situ electrochemical methods based on the measurement of refractive index gradients in front of the electrode/electrolyte interface. Here, the details of the techniques are described. First, the theory of potential step chronodeflectometry and pulse voltadeflectometry is discussed. Later, different numerical procedures used for data processing and/or simulation of cyclic voltadeflectometry experiments are described. Then, an overview is performed of the techniques use to study electrochemical systems. The systems described are limited to surface species in binary electrolytes, where a clear interpretation of the data is possible. Among the systems studied are: surface reactions on solid electrodes, electrochromic oxides, conducting polymers, redox polymers, double layer charging in nanostructured carbons and ion exchange in layer-by-layer self assembled multilayers. It is shown that PBD techniques have been able to ascertain the effect of different factors on ion exchange: anion size, pH, solvent, film composition, covalent modification, etc. The capability of the techniques to perform fast measurements was also used with success to find out kinetic effects on the ion exchange. PMID- 19787890 TI - Quantum control of unidirectional rotations of a chiral molecular motor. AB - A quantum control method is presented for designing electric fields of laser pulses to drive a chiral molecular motor in desired, rotational directions. Intuitive or counter-intuitive rotational motion of a chiral motor, 2-chloro-5 methyl-cyclopenta-2,4-dienecarbaldehyde, was controlled by electric fields of ps laser pulses with mid-infrared central frequencies. The control mechanism is discussed by analyzing the time- and frequency-resolved spectrum of the electric fields of the laser pulses. Timing of laser pulses is the essential factor for controlling unidirectional motions. PMID- 19787891 TI - A theoretical study of water clusters: the relation between hydrogen-bond topology and interaction energy from quantum-chemical computations for clusters with up to 22 molecules. AB - Quantum-chemical calculations of a variety of water clusters with eight, ten and twelve molecules were performed, as well as for selected clusters with up to 22 water molecules. Geometry optimizations were carried out at the B3LYP/cc-pVDZ level and single-point energies were calculated at the B3LYP/aug-cc-pVDZ level for selected clusters. The electronic energies were studied with respect to the geometry of the oxygen arrangement and six different characteristics of the hydrogen-bond arrangement in the cluster. Especially the effect of the placement of the non-hydrogen bonding hydrogens on the interaction energy was studied. Models for the interaction energy with respect to different characteristics of the hydrogen-bond arrangement were derived through least-square fits. The results from the study of the clusters with eight, ten and twelve molecules are used to predict possible low-energy structures for various shapes of clusters with up to 22 molecules. PMID- 19787892 TI - MRD-CI study of the photodissociative behavior of HOOOCl, a molecule relevant to atmospheric chemistry. AB - Equilibrium geometries have been optimized and harmonic vibrational frequencies calculated for HOOOCl using quadratic configuration interaction and coupled cluster methods with Dunning's correlation-consistent basis sets. There are two conformers of HOOOCl (a cis and a trans structure) that are very close in energy and separated by a barrier of 3.28 kcal mol(-1). In experiments, these two forms may co-exist. Rotational constants that can be used to experimentally characterize and identify HOOOCl are presented. The electronic absorption spectrum for trans-HOOOCl is calculated using multi-reference configuration interaction methods in order to support the spectroscopic search. At 5.84 eV a remarkably strong transition is computed corresponding to a sigma(Cl-O') --> sigma*(Cl-O')-excitation. In addition, possible photodissociation pathways along the Cl-O' and O'-O bonds for trans-HOOOCl have been examined. Potential photochemistry of HOOOCl is suggested for the first time. PMID- 19787893 TI - Indices for predicting the quality of leaving groups. AB - The inherent quality of leaving groups in chemical reactions is related to their ionization potential and electron affinity using a quadratic model for the dependence of the energy on the number of electrons. A good leaving group for nucleophilic substitution/elimination reactions is one where the difference in energy between the system with the "optimum" number of electrons and the anion is small. Similarly, a good leaving group for electrophilic substitution/elimination reactions is one where the difference in energy between the system with the optimum number of electrons and the cation is small. This insight allows us to define indices for the quality of leaving groups in nucleophilic and electrophilic reactivity, which we term the nucleofugality and the electrofugality, respectively. These indices are useful not only for predicting the quality of leaving groups in organic reactions, but also for explaining the stability of carbocations, carbanions, and trends in pKa. PMID- 19787894 TI - Solvation of fluoro and mixed fluoro/chloro complexes of Eu(III) in the [BMI][PF6] room temperature ionic liquid. A theoretical study. AB - We report a molecular dynamics study on the solvation of EuFn(3-n) complexes in the [BMI][PF6] ionic liquid, composed of 1-butyl-3-methyl-imidazolium+ cations and PF6- anions. It is found that the most fluorinated complex in the liquid should be the EuF6(3-) species. In solution the EUF10(7-) and EuF7(4-) complexes indeed loose, respectively, 4 and 1 F anion to form the EuF6(3-) complex, while the first solvation shell of the less fluorinated complexes (n=1 to 5) is completed with 5 to 1 PF6- anions to form an octahedral first shell around Eu3+. There is one case (simulations with a "small" F model) where the EuF7(4-) complex remains stable, and cannot therefore be fully precluded. The anionic complexes are embedded in a cage formed by 6-9 BMI+ cations at ca. 8 A, hydrogen-bonded by imidazolium-CH..F- interactions. Simulations on the mixed EuF(n)Cl(6-n)3- complexes in solution and in gas phase also reveal the highest stability of EuF6(3-) compared to the mixed or the EuCl6(3-) complexes. This is confirmed by free energy perturbation calculations and results from the stronger coordination of F-, compared to Cl- ligands, as well as from better solvation of the fluoro complexes by the ionic liquid. In the gas phase, however, QM and MM calculations indicate that EuF6(3-) is unstable towards the dissociation of 1 to 2 F- ions, which points to the importance of environment and solvation forces on the stability of this octahedrally coordinated lanthanide complex. PMID- 19787895 TI - A site-selective spectroscopy of naphthalene and quinoline in TEOS/MTEOS xerogels. AB - Fluorescence and phosphorescence spectra and decay times are recorded upon a narrow-band laser excitation for naphthalene (N) and quinoline (Q) embedded in xerogels prepared from MTEOS/TEOS mixtures, in the 10-300 K temperature range. A site selectivity of the excitation is observed at T <120 K and T <150 K, for N and Q, respectively. In the case of quinoline, different families of sites are characterized. The results are discussed in terms of comparison with the N and Q emission behaviour in other environments, especially in rare-gas matrices. PMID- 19787896 TI - Sigma-type ethane adsorption complexes with Cu+ ions in Cu(I)-ZSM-5 zeolite. Combined DRIFTS and DFT study. AB - A DRIFTS study of ethane adsorption by the univalent copper cations in Cu(1)-ZSM 5 zeolite prepared by chemical reaction of the corresponding hydrogen form (Si/Al = 150) with CuCl vapour at 573 K reveals an unusual spectrum of adsorbed C2H6. In addition to the weakly perturbed narrow bands in the region of C-H stretching vibrations, the spectrum exhibits two broad IR bands whose frequencies are lowered more than by 300 cm(-1) compared to the C-H stretching vibrations of gaseous or physically adsorbed ethane. This indicates unusually strong perturbation of adsorbed C2H6 molecules by Cu+ ions, which has never been observed before for ethane adsorption on oxides or on any other cationic form of zeolites. Despite such a strong perturbation, the adsorbed ethane molecules are not involved in heterolytic dissociative adsorption at elevated temperatures. DFT cluster modeling of ethane interaction with Cu+ stabilized at alpha-sites (the six-membered ring composed of two five-membered rings from the straight wall of the ZSM-5 zeolite) as possible adsorption sites indicated that C2H6 interaction with Cu+ results in formation of rather strong sigma-type adsorption complexes. The results obtained indicated that the most preferential adsorption geometry is when the alkane bound in an end-on fashion through two hydrogen atoms of one of the methyl groups. The nature of such bonding can be reasonably described by the synergetic combination of the ligand-to-metal donation from the sigma(C-H) orbitals of ethane to the low-occupied Cu+ s-orbital with the metal-to-ligand back donation from the copper d(pi) orbital to the C-H sigma*-orbitals. Both these interactions result in a very strong weakening of the C-H bonds and, therefore, in a very large bathochromic shift of the C-H stretching frequencies of methyl group contacting with Cu+ ion. PMID- 19787897 TI - Low-frequency spectra of the hexamethylbenzene/tetracyanoethylene electron donor acceptor complexes in solution studied by terahertz time-domain spectroscopy. AB - We have measured the frequency dependent extinction coefficients and refractive indices of electron donor-acceptor (EDA) complexes consisting of hexamethylbenzene (HMB; electron donor) and tetracyanoethylene (TCNE; electron acceptor) in the low-frequency region by terahertz time-domain spectroscopy (THz TDS). A mixture of the 1:1 (DA) and 2:1 (D2A) EDA complexes exist in carbon tetrachloride solution, and we successfully obtained the spectral components of the 1:1 and 2:1 EDA complexes separately by analyzing the concentration dependence of the THz spectra. The 1:1 and 2:1 complexes show quite different THz spectra of the extinction coefficient, reflecting unique features of dynamics, fluctuations and intermolecular interactions of these complexes. Polarization selective THz-TDS on the crystalline DA complex shows two peaks at 53 and 70 cm( 1) in the spectral component perpendicular to the crystal axis. On the other hand, the crystalline D2A complex exhibits peaks at 42 and 50 cm(-1) in the perpendicular spectral component. We compare the obtained spectra of the crystalline complex and the results of molecular orbital calculations at the HF/6 31G(d) level of theory to discuss the intermolecular vibrational modes of the complexes. PMID- 19787898 TI - Observation and rovibrational analysis of the intermolecular HCl libration band upsilon6(1) of HCN-HCl, DCN-HCl and H13CN-HCL. AB - The high-resolution far-infrared absorption spectrum of the intermolecular HC1 libration band upsilon6(1) (upsilonB) of the gaseous molecular complex H12CN-HCl and the two isotopically substituted species H13CN-HCl and D12CN-HCl is recorded by means of static gas-phase Fourier transform far-infrared spectroscopy at 205 K using an electron storage ring source. The rotational structure of the upsilon6(1) band has the typical appearance of a perpendicular type band of a linear polyatomic molecule. The structure is analyzed using a standard semi-rigid linear molecule model including l-type doubling to yield the band origin upsilon0, together with values for the upper state rotational constant B', the upper state quartic centrifugal distortion constant D'j and the value for the l type doubling constant q6. The values for the ground-state spectroscopic constants B" and D"j for D12CN-H35Cl and H13CN-H35Cl are determined for the first time by ground state combination difference analyses. A number of upsilon6(1) + upsilon7(1) - upsilon7(1) and upsilon6(1) + 2upsilon7(2) - 2upsilon7(2) hot bands are observed in the spectra and the sum of the anharmonicity constants X(6,7) + g(6,7) is estimated. The observed decrease of the rotational constant B together with the simultaneous increase of the quartic centrifugal distortion constant Dj upon excitation of the HCl libration mode indicate that the hydrogen bond in the molecular complex is significantly destabilized upon intermolecular vibrational excitation. The calculated harmonic force constants for the intermolecular hydrogen bond stretching vibration upsilon(sigma) for the ground state and the excited HCl libration state indicate that the excitation of the HCl libration mode destabilizes the intermolecular interaction between HCN and HCl by almost 20%. The hydrogen bond is elongated by 0.030 A upon excitation of the upsilon6(1) mode. PMID- 19787899 TI - Matrix-isolation and computational study of salicylhydroxamic acid and its photochemical degradation. AB - The IR absorption spectrum of salicylhydroxamic acid (sha) isolated in an argon matrix at 12-21 K has been recorded. Calculations of all the possible entgegen and zusammen keto conformers of sha have been performed at the B3LYP/6 311++G(d,p) level of theory. The computed energies, optimized structures, and relative abundances show that sha exists in the matrix as the z,z,z,z-conformer [relative to the C-O(-H), C-C(-N), C-N and N-O bonds, respectively] and is stabilized by two intramolecular H-bonds. Photofragmentation of the compound in matrix and methanol-water solution has been obtained by irradiation with visible and ultraviolet light. o-Hydroxyphenylisocyanate is the main photolysis product in an argon matrix, while salicylamide is the primary photolysis product in methanol-water solution. PMID- 19787901 TI - Laser induced formation of CsI ion clusters analyzed by delayed extraction time of-flight mass spectrometry. AB - (CsI)nCs+ (n = 1,2) cluster ion formation from polycrystalline CsI irradiated by pulsed-UV laser (337 nm) is analyzed by delayed extraction time-of-flight mass spectrometry technique. Measurements were performed for different laser intensities and for several delayed extraction times. Experimental data show that CsI laser ablation produces the emission of (CsI),Cs+ ions (n = 0, 1, 2), whose yields decrease exponentially with n and increase exponentially with the laser pulse energy. A quasi equilibrium evolution of the clusters is proposed to extract a parameter characteristic of the cluster recombination process. The delayed extraction method of initial velocity determination was improved to take into account collisions in the high density plasma close to the target. The new parameterization helps to describe the dynamics of secondary ions of different masses for laser irradiances above the ion desorption threshold in a collision regime. The initial velocity of the secondary ions [(CsI)nCs+ (n = 0, 1, 2)] as function of the laser irradiance was determined. The distance to the target when the free expansion process starts is reported as function of the secondary ions mass and of the laser irradiance. The collision regime's influence on the secondary ion dynamics is discussed. PMID- 19787900 TI - Gas-solid reactions of single crystals: A study of the reaction of bromine with single crystals of trans-cinnamic acid and a range of its derivatives by infrared and Raman microspectroscopy. AB - Single crystals of trans-cinnamic acid and of a range of derivatives of this compound containing halogen substituents on the aromatic ring have been reacted with 165 Torr pressure of bromine vapour in a sealed desiccator at 20 degrees C for 1 week. Infrared and Raman microspectroscopic examination of the crystals shows that bromination of the aliphatic double bond, but not of the aromatic ring, has occurred. It is demonstrated also that the reaction is truly gas solid in nature. A time-dependent study of these reactions shows that they do not follow a smooth diffusion-controlled pathway. Rather the reactions appear to be inhomogeneous and to occur at defects within the crystal. The reaction products are seen to flake from the surface of the crystal. It is shown, therefore, that these are not single crystal to single crystal transitions, as have been observed previously for the photodimerisation of trans-cinnamic acid and several of its derivatives. It is shown that there are no by-products of the reaction and that finely ground samples react to form the same products as single crystals. PMID- 19787902 TI - Mechanism and rate of the reaction CH3 + O--revisited. AB - The primary products and the rate of the reaction of methyl radicals with oxygen atoms in the gas phase at room temperature have been studied using three different experimental arrangements: (A) laser flash photolysis to produce CH3 and O from the precursors CH3I and SO2 (the educts and the products were detected by quantitative FTIR spectroscopy); (B) the coupling of a conventional discharge flow reactor via a molecular sampling system to a mass spectrometer with electron impact ionization, which allowed the determination of labile and stable species; (C) laser induced multiphoton ionization combined with a TOF mass spectrometer molecular beam sampling-flow reactor, which was used for the specific and sensitive detection of the CH3, CD3, C2H5 and C2D5 radicals and the determination of rate coefficients. The branching ratio of the reaction channels was determined by the experimental arrangements (A) and (B) leading to CH3 + O --> HCHO + H (55 +/- 5)% --> CO + H2 + H (45 +/- 5)%. The rate coefficients of the normal and deuterated methyl and ethyl radicals with atomic oxygen showed no isotope effect: k(CD3 + O)/k(CH3 + O) = 0.99 +/- 0.12, k(C2D5 + O)/k(C2H5 + O) = 1.01 +/- 0.07 (statistical error, 95% confidence level). The absolute rate coefficient of the reaction CH3 + O was derived with reference to the reaction C2H5 + O (k = 1.04 x 10(14) cm3 mol(-1) s(-1)) leading to k(CH3 + O) = (7.6 +/- 1.4) x 10(13) cm3 mol( 1) s(-1). PMID- 19787903 TI - Femtosecond fluorescence up-conversion spectroscopy of a rotation-restricted azobenzene after excitation to the S1 state. AB - Femtosecond time-resolved fluorescence up-conversion spectroscopy has been used in a study of the photoinduced isomerization reactions of a rotation-restricted trans-azobenzene (trans-AB) derivative capped by a crown ether (1), a chemically similar open derivative (2), and unsubstituted trans-AB (3) after excitation to the S1 (npi*) state at lamda=475 nm in dioxane solution. The observed biexponential temporal fluorescence profiles for 1 and 2 were almost indistinguishable within experimental error. The fitted fast fluorescence decay times (+/-2sigma) for the two compounds were tau1 (1) = (0.79 +/- 0.20) and tau1 (2) = (1.05 +/- 0.20) ps, compared to tau1 (3) = (0.37 +/- 0.06) ps. The second decay components could be described with tau2 (1) = (20.3 +/- 9.5) resp. tau2 (2) = (19.0 +/- 6.0) ps, vs. tau2 (3) = (3.26 +/- 0.85) ps. The very similar lifetimes strongly suggest that trans-cis isomerization of 1 and 2 after S1 excitation is governed by the same mechanism. Since 1 cannot isomerize by a simple large-amplitude rotation of one of the phenyl rings about the central NN bond, the isomerization dynamics of both ABs should be better described as "inversion" at the N atom(s) rather than large-amplitude "rotation". PMID- 19787904 TI - Noble gases and hydrogen at high pressures. AB - The equation of state of the noble gases helium, argon, and xenon as well as of hydrogen and deuterium is determined by considering reactions such as dissociation and ionization within a chemical picture. The molecular and atomic constituents, i.e., the neutral particles, are treated within fluid variational theory, while for the charged particles a plasma model is applied. Results are given for densities and temperatures relevant to the interior of giant planets. Comparison is performed with available shock-wave experiments and other theoretical work. PMID- 19787905 TI - Molecular modeling of lipid bilayers and the effect of protein-like inclusions. AB - We examined the effect of the insertion of a trans-membrane peptide or protein on the thermodynamic, structural and mechanical characteristics of a lipid bilayer using self-consistent field (SCF) theory. The peptide or protein is modeled as a rigid cylindrical body with a hydrophobic surface and two hydrophilic end caps. We first characterise the properties of the undisturbed bilayer consisting of lipids with a hydrophilic phosphatidylcholine-like head group of nine segments and two identical tails ranging from 8 to 19 alkyl segments. The structural properties are given in terms of thickness of the hydrophobic core d(l)0 and the area a0 per lipid. The mechanical or elastic properties are characterised by the mean bending modulus k(c), the saddle splay modulus k and the area compression expansion modulus of the bilayer k(a) and its monolayers. Furthermore we calculated the spontaneous curvature J0(m) of the individual monolayer, which can be positive or negative depending on the tail length. Subsequently, we focus on the effect of hydrophobic mismatch between the bilayer and inclusion. The free energy of insertion is parabolic in the mismatch. The minimum is at a small negative mismatch, i.e., when the hydrophobic thickness of the rod is smaller than that of the bilayer. This is attributed to conformational restrictions of the lipid tails close to the rod. This results in a positive curvature of the bilayer adjacent to it, even if the hydrophobic thickness of the rod is larger than that of the bilayer. The bilayer deformation has a wave character which decays exponentially. We show that the decay length of this perturbation is the same as the elastic length (kc(d)2/ka)(1/4), provided that for the thickness d of the bilayer d(l)0 is used. PMID- 19787906 TI - Correlated ab initio study of nucleic acid bases and their tautomers in the gas phase, in a microhydrated environment and in aqueous solution. Part 4. Uracil and thymine. AB - Altogether 13 keto and enol tautomers of uracil and 13 keto and enol tautomers of thymine were studied theoretically in the gas phase, in a microhydrated environment (1 and 2 water molecules) and in a water environment. Bulk water was described using the thermodynamic integration method, Conductor-like polarizable continuum model (C-PCM, COSMO) and hybrid model (C-PCM + 1-2 explicit water molecules). The structures of various tautomers were determined at the RI-MP2 level using the TZVPP basis set while relative energies were determined at the CCSD(T) level. The relative free energies at 298 K were based on the relative energies mentioned above and zero-point vibration energies, and temperature dependent enthalpy terms and entropies evaluated at the MP2/6-31G** level. The effect of bulk solvent on the relative stability of uracil and thymine tautomers was studied using molecular dynamics free energy calculations by means of the thermodynamic integration method and self-consistent reaction field. Despite the completely different nature of these methods they provide comparable solvation free energies. Besides theoretical investigation, experimental detection of uracil and thymine tautomers was performed by means of steady-state fluorescence. We conclude that it is impossible to utilize the method used by Suwaiyan and Morsy (M. A. Morsy, A. M. Al-Somali and A. Suwaiyan, J. Phys. Chem. B, 1999, 103(50), 11205) for tautomer detection, even if a very sensitive fluorimeter is used. Theoretical relative energies and free energies for isolated uracil and thymine tautomers support the existence of the canonical form only. The microhydrated environment and bulk solvent stabilize enol forms more than the canonical keto one, but gas phase destabilization of these enol forms is too high. Population of rare enol forms of uracil and thymine in bulk water will thus be very low and canonical structure will also be dominant in this phase. PMID- 19787908 TI - On the current-voltage characteristics of charge transfer reactions at mixed conducting electrodes on solid electrolytes. AB - Even though the electrochemical oxygen reduction reaction at mixed conducting oxide electrodes is highly important for several applications of solid electrolytes a thorough discussion of the kinetics of electron and ion transfer steps at the corresponding electrode surface is not available yet. A straightforward application of current-voltage (I-V) relations derived for charge transfer reactions at electrode/electrolyte interfaces turns out to be inappropriate. In this contribution, a model is presented that relates concentrations of electrochemically active species and electrostatic potential steps at the electrode/gas interface of mixed conducting electrodes to the applied overpotential, and thus I-V formulas for the corresponding electron and ion transfer reactions are obtained. Depending on the specific parameters surprising effects are found such as an additional factor of two in the exponents of the I-V relation, irrelevance of the symmetry factor or limiting currents even if charge transfer is rate determining. PMID- 19787907 TI - Simulated force-induced unfolding of alpha-helices: dependence of stretching stability on primary sequence. AB - Some of the principles that determine a protein's native fold can be probed with techniques for single-molecule manipulation. Yet, understanding the effects of an external force at atomic level still requires computer simulations. Here, we employ a novel protocol for steered molecular dynamics that allows for internal energy redistribution (and possibly, re-equilibration) while the molecule is subject to a mechanical perturbation. The approach is used to study how the stretching of alpha-helices is qualitatively affected by variations in primary sequence. Despite the simplifications introduces, our results indicate a trend whereby different amino acids can increase the resistance to mechanical unfolding depending on side chain polarity and the dynamics of side-chain internal torsions. Whereas the cooperative transition from alpha-helix to 310-helix and to a rod-like conformer prevails when stretching many sequences, we also find that the onset of the unfolding can be delayed by a range of alternative pathways which include events of helical refolding or long-lived intermediates with partial helical content. PMID- 19787909 TI - Peculiarity of the liquid/vapour interface of an ionic liquid: study of surface tension and viscoelasticity of liquid BMImPF6 at various temperatures. AB - We have measured the surface tension and the capillary wave spectra at the liquid/vapour interface of the ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate at various temperatures up to 400 K. From the weak temperature dependence of the surface tension a low value of the surface excess entropy of approximately 3.5 x 10(5) J K(-1) m(-2) results which is consistent with a strongly aligned surface layer of imidazolium cations previously predicted by MD-calculations. The capillary wave spectra recorded at different wave numbers in the range 170 cm(-1) < or = q < or =500 cm(-1) exhibit strong deviations from the behaviour expected for the free surface of simple liquids. With an extended dispersion relation including the contributions of surface dipole moment density gamma and shear surface excess viscosity mu the spectra have been analyzed. It is found that mu is negligibly small, whereas gamma substantially influences the capillary wave spectra. The electrostatic potential across the interface, which corresponds to the measured dipole moment densities, qualitatively agrees with simulation calculations. The distinct temperature dependence of gamma suggests that with increasing temperature an order-disorder transformation occurs in the surface layer. PMID- 19787910 TI - Phase behaviour of ultrathin crystalline n-heptane films on graphite: an atomistic simulation study. AB - The thermal behaviour of n-heptane films adsorbed on the basal plane of graphite has been investigated using atomistic molecular dynamics simulations performed under constant temperature conditions. An uniaxially commensurate monolayer (UCM), an uniaxially commensurate bilayer (UCB) and a fully commensurate bilayer (FCB) of n-heptane have been studied in order to distinguish the contributions from coverage and in-plane density to the melting process. These ordered adlayers containing molecules whose zig-zag planes were parallel to the substrate, were stabilized at low temperatures. The calculated intermolecular energy per molecule shows that the FCB structure is more stable than the UCB structure, consistent with X-ray and neutron scattering experiments. In all of these systems, disordering processes in the solid state involves a fraction of molecules rotating about their backbone axes, in agreement with scanning tunneling microscopy studies. The molecules present in uniaxially commensurate structures (UCM and UCB) are facile to rotate about their long axes which causes these adlayers to melt at lower temperatures compared to the fully commensurate structure. The spatial correlation functions between such rotated molecules show interesting temperature dependence that indicates a loss of long-range and short range correlations in these overlayers with increasing temperature. The importance of conformational defects for the melting of these quasi-two dimensional systems has also been explored. Axial rotations of molecules present in the first adsorbed layer of FCB are facile between bulk and monolayer melting temperatures. This process leads to the observation of an average angle of rotation of around 40 degrees in excellent agreement with X-ray and neutron scattering experiments. PMID- 19787911 TI - Sr diffusion in undoped and La-doped SrTiO3 single crystals under oxidizing conditions. AB - Strontium titanate SrTiO3(100), (110), and (111) single crystals, undoped or donor doped with up to 1 at% La, were isothermally equilibrated at temperatures between 1523 and 1773 K in synthetic air followed by two different methods of Sr tracer deposition: ion implantation of 87Sr and chemical solution deposition of a thin 86SrTiO3 layer. Subsequently, the samples were diffusion annealed under the same conditions as before. The initial and final depth profiles were measured by SIMS. For strong La-doping both tracer deposition methods yield similar Sr diffusion coefficients, whereas for weak doping the tracer seems to be immobile in the case of ion implantation. The Sr diffusivity does not depend on the crystal orientation, but shows strong dependency on the dopant concentration supporting the defect chemical model that under oxidizing conditions the donor is compensated by Sr vacancies. A comparison with literature data on Sr vacancy, Ti, and La diffusion in this system confirms the concept that all cations move via Sr vacancies. Cation diffusion is several orders of magnitude slower than oxygen diffusion. PMID- 19787912 TI - Anion diffusion in Y- and N-doped ZrO2. AB - Effective single particle potentials governing the motion of O2 and N3- anions have been determined by single crystal neutron diffraction at high temperatures for three samples of ZrO2 doped with different amounts of Y and N. Diffusion jumps take place directly to vacant nearest neighbour anion sites through the edges of the surrounding cation tetrahedra along (100)-directions. Activation enthalpies of migration for O (1.09 eV) and N (1.99 eV) are in good agreement with values obtained from tracer diffusion measurements (M. Kilo, C. Argirusis, G. Borchardt and R. A. Jackson, Phys. Chem. Chem. Phys., 2003, 5, 2219 and M. Kilo, M. A. Taylor, C. Argirusis, G. Borchardt, M. Lerch, O. Kaitasov and B. Lesage, Phys. Chem. Chem. Phys., 2004, 6, 3645). The diffusion process is facilitated by local short range order and anharmonic thermal vibrations. It is therefore advocated that the interactions with the phonons have to be taken into account in the description of the diffusion process. PMID- 19787913 TI - Effect of hole-trapping on mass/charge transport properties in acceptor-doped BaTiO3. AB - The equilibrium conductivity and chemical diffusivity of Al-doped, single crystalline BaTiO3 [C. R. Song and H. I. Yoo, J. Am. Ceram. Soc., 2000, 83, 773] have been re-analyzed by taking account of possible hole-trapping by acceptor dopants (Al) with reference to the data on undoped BaTiO3 [C. R. Song and H. I. Yoo, Phys. Rev. B, 2000, 61, 3975]. The trapping effect is accounted for by the effective mobility of free holes involving the weighted mobility of trapped holes and by the modified thermodynamic factor due to the shift of the stoichiometric composition of the acceptor-doped system. The equilibrium constant of the trapping reaction Al(Ti)x = Al(Ti)' + h* is evaluated as Ka = 1.9 x 10(23) exp( 1.04 eV/kT) cm(-3) and the mobility of trapped holes (Al(Ti)x) as u(x) approximately = 720 exp(-1.04 eV/kT) cm2 V(-1) s(-1) as the upper bound while those of free electrons and holes as un = 0.044 + 0.010 cm2 V(-1) s(-1) and up approximately = 0.024 +/- 0.007 cm2 V(-1) s(-1), respectively, in the temperature range of 800 degrees C to 1100 degres C. The effect of hole-trapping on DC conductivity, chemical diffusivity and oxygen nonstoichiometry is exhaustively analyzed and further experiments are proposed that allow one to determine the trapping energy of acceptor impurities. PMID- 19787914 TI - Comment on "The thermal unimolecular decomposition of HCO: effect of state specific rate constants on the thermal rate constant" by H. Hippler, N. Krasteva and F. Striebel, Phys. Chem. Chem. Phys., 2004, 6, 3383. PMID- 19787915 TI - Experimental determination of the phonon density of states in filled skutterudites: evidence for a localized mode of the filling atom. AB - The generalized density of states of LaFe4Sb12 and CeFe4Sb12 has been determined by inelastic neutron scattering and its main features are found to be in agreement with recently published calculations (J. L. Feldman, D. L. Singh, C. Kendziora, D. Mandrus and B. C. Sales, Phys. Rev. B, 2003, 68, 094301). In both compounds a localized vibrational contribution appears superposed on the low energy Debye response. The distinct inelastic response of La in LaFe4Sb12 is obtained by subtraction of the data for the Ce filled compound and it shows even more clearly the resolution limited peak at 7 meV, attributed to the localized mode of La-atoms. PMID- 19787916 TI - Free volume anomalies in mixed-cation glasses revealed by positron annihilation lifetime spectroscopy (PALS). AB - PALS experiments reveal a minimum in ortho-positronium (o-Ps) lifetimes and a maximum in the corresponding intensities that emerge when mixed-cation (Li/Na) borate glasses are heated from ambient temperatures up to 473 K. These free volume 'anomalies' appear to be a true manifestation of the mixed alkali effect (MAE). They are consistent with a mechanism of ion transport involving cooperation between hops of unlike cations, resulting in increased disturbance of the glass network. The result lends support to the dynamic structure model. PMID- 19787917 TI - The X3LYP extended density functional accurately describes H-bonding but fails completely for stacking. AB - The performance of the recently introduced X3LYP density functional which was claimed to significantly improve the accuracy for H-bonded and van der Waals complexes was tested for extended H-bonded and stacked complexes (nucleic acid base pairs and amino acid pairs). In the case of planar H-bonded complexes (guanine...cytosine, adenine...thymine) the DFT results nicely agree with accurate correlated ab initio results. For the stacked pairs (uracil dimer, cytosine dimer, adenine...thymine and guanine...cytosine) the DFT fails completely and it was even not able to localize any minimum at the stacked subspace of the potential energy surface. The geometry optimization of all these stacked clusters leads systematically to the planar H-bonded pairs. The amino acid pairs were investigated in the crystal geometry. DFT again strongly underestimates the accurate correlated ab initio stabilization energies and usually it was not able to describe the stabilization of a pair. The X3LYP functional thus behaves similarly to other current functionals. Stacking of nucleic acid bases as well as interaction of amino acids was described satisfactorily by using the tight-binding DFT method, which explicitly covers the London dispersion energy. PMID- 19787918 TI - Probing the acid sites in confined spaces of microporous materials by vibrational spectroscopy. AB - The use of IR spectroscopy for the evaluation of the Lewis and Bronsted acidity of microporous systems is illustrated having recourse to examples concerning zeolites, heteropolyacids and sulfonated membranes (NAFION). Methods based on the perturbation of the OH modes by interaction with basic probe molecules are illustrated as well as on the perturbation of the internal modes of the probe itself. The use of H2 as probe is also debated by discussing new data specifically obtained for this review. The illustrated case examples are mainly obtained from the experience gained by the Turin group in 20 years. PMID- 19787919 TI - A computational study of the atmospheric oxidation of nopinone. AB - Electronic structure calculations are used to derive the overall rate coefficient for hydrogen atom abstraction by the hydroxyl radical from a typical volatile organic compound, nopinone. The branching ratios for abstraction from the seven possible different positions are also obtained. Abstraction from the bridgehead position 1 is found to be important, with a branching ratio of 23%. This prediction differs from that derived using a structure-activity relationship, which suggests much less oxidation in this position, but is in agreement with available experimental evidence, showing formation of significant amounts of products such as 1-hydroxynopinone during terpene oxidation. Calculated rate coefficients are derived from standard transition state theory, with energy barriers, vibrational frequencies and rotational constants for reactants and transition states obtained using density functional theory with the KMLYP functional. This approach was calibrated by calculating the well-known rate coefficients for the simpler volatile organic compounds methane, ethane, propane, cyclobutane and acetone. High-level G3 calculations are possible and were carried out for these simpler systems, giving barrier heights in good agreement with KMLYP. Transition state theory gives surprisingly good results for the rate coefficients, probably in part due to error cancellation. This validates the use of the same relatively low level of theory for exploring reactivity and selectivity in oxidation of complex molecules such as nopinone. PMID- 19787920 TI - O(1D2) orbital orientation in the ultraviolet photodissociation of ozone. AB - We present the absolute velocity-dependent orbital orientation for O(1D2) atoms produced from the photodissociation of ozone in the 248-285 nm region obtained using the DC slice imaging method. The results are analyzed in terms of laboratory frame anisotropy parameters describing distinct excitation and dissociation mechanisms possessing characteristic angular distributions. The results show negligible orbital orientation produced in dissociation by circularly polarized light, but strong recoil speed-dependent orientation following photolysis by linearly polarized light at all wavelengths studied. The origin of this polarization is ascribed to nonadiabatic transitions at avoided crossings and at long range. PMID- 19787921 TI - A laser photolysis-resonance fluorescence study of the reactions: I + O3 --> IO + O2, O + I2 --> IO + I, and I + NO2 + M --> INO2 + M at 298 K. AB - Laser flash photolysis coupled to resonance-fluorescence detection of I atoms was used to measure the rate coefficients for the reactions: I + O3 --> IO + O2 (R1), O + I2 --> IO + I (R6) and I + NO2 + M --> INO2 + M (R7). All experiments were conducted under pseudo first-order conditions, and the accuracy of the results was enhanced by online determination of reagent concentrations by optical absorption. Bimolecular rate coefficients for reactions (R1) and (R6) were determined to be k1 = (1.28 +/- 0.06) x 10(-12) and k6 = (1.2 +/- 0.1) x 10(-10) cm3 molecule(-1) s(-1) at 298 +/- 2 K, independent of pressure. Rate coefficients for the termolecular reaction (R7), also at 298 +/- 2 K, were found to be in the falloff region between 3rd and 2nd order behaviour and, when combined with other datasets obtained at higher and lower pressures, were adequately described by a simplified Troe function with the parameters: k7,0 (He, 330 K) = 1.48 x 10(-31) cm6 molecule(-2) s(-1), F(C) (He) = 0.43, and k7, infinity = 1.1 x 10(-10) cm3 molecule(-1) s(-1) for He as bath gas. In N2 (or air) the following parameters were obtained k7,0 (N2, 300 K) = 3.2 x 10(-31) cm6 molecule(-2) s(-1), F(C) ( N2) = 0.48, with k7, infinity set to 1.1 x 10(-10) cm3 molecule(-1) s(-1) as obtained from analysis of the falloff curve obtained in He. PMID- 19787922 TI - Branching ratios and absolute cross sections of dissociative recombination processes of N2O+. AB - We have investigated the dissociative recombination of the N2O+ ion using the CRYRING heavy-ion storage ring at the Manne Siegbahn laboratory in Stockholm, Sweden. The dissociative recombination branching ratios were determined at minimal (approximately 0 eV) collision energy, showing that the dominating pathways involved two-body fragmentation: N2 + O (48%) and NO + N (36%). The branching ratio of the three-body break-up 2N + O was 16%. The overall thermal rate coefficient of the title reaction follows the expression k(T) = 3.34 +/- 0.75 x 10(-7) (T/300) (-0.57+/- 0.03 cm3 s(-1)), which correlates perfectly with earlier flowing afterglow studies on the same process. PMID- 19787923 TI - The influence of heteroligands on the reactivity of Ni2+ in solution. AB - Quantum-mechanics based molecular dynamics simulations were used to investigate mono-, di-, tri- and tetraamino Ni2+ complexes in water. The simulations show an enormous influence of heteroligands on the reactivity of the first solvation shell of the Ni2+ ion. Comparing 17O-NMR measurements of identical systems with our simulation results shows a 10(4) times higher mobility of water molecules in the first solvation shell obtained from QM/MM MD simulations strongly affecting biochemically important properties of Ni2+ in the aqueous environment in living organisms. PMID- 19787924 TI - Chemical interpretation of oscillatory modes at a Hopf point. AB - We present two complementary methods for studying the oscillatory mechanisms in a chemical reaction network in the neighbourhood of a supercritical Hopf bifurcation. The first method is a modification of metabolic control analysis (a form of sensitivity analysis), and focuses on the reactions rather than the chemical species. By rephrasing metabolic control analysis in terms of the amplitude equation of the Hopf bifurcation, we show that control of amplitude and frequency of the oscillations should be considered separately, and that the amplitude control is directly related to the control of the stability of the stationary state. Generally, the frequency of the oscillations is controlled by more reactions than the amplitude is, and those reactions controlling amplitude will generally also exert control of the frequency. The second method focuses on the role of the chemical species. By considering their relative phases and amplitudes, the method reveals to what extent a simple activator-inhibitor interpretation of the amplitude equation associated with the Hopf bifurcation corresponds to an equally simple chemical interpretation. If applicable, the method identifies the activating and inhibiting modes chemically. Prior knowledge of the underlying reaction network is not needed, only phase and amplitude measurements are used in the analysis. Hence, this method is a top-down approach well suited for systems biology. Both methods are exemplified by calculations on the Oregonator model for the Belousov-Zhabotinsky reaction. PMID- 19787925 TI - The effect of oxygen on time-dependent bifurcations in the Belousov-Zhabotinsky oscillating chemical reaction in a batch. AB - We have studied the effect of oxygen on the time-dependent bifurcations of transient oscillations in the Belousov-Zhabotinsky oscillating chemical reaction in a closed system. Experiments show that oscillations disappear through different bifurcations depending on the oxygen concentration in gas phase above the reaction solution. Oscillations disappear through the time-delayed Hopf bifurcation at low oxygen concentrations, whereas at high oxygen concentrations they disappear through the time-dependent SNIPER (saddle-node infinite period) bifurcation. We propose a kinetic scheme that describes the effects observed in experiments. Good agreement between the experimental data and simulations is obtained. PMID- 19787926 TI - Monitoring reagent modification of charged SnxOy nanoclusters using Fourier transform ion cyclotron mass spectrometry. AB - The ion-molecule reactions of laser-generated radical clusters SnxO(x+1)(-) (x = 1-6), SnxO(x-1)(+) (x = 1-6) and SnxOx(+) (x = 2, 3) with the reagents H2S and CH3OH have been investigated using FTICR-MS. For the hypermetallic cations SnxO(x 1)(+), the rates of the sulfur-for-oxygen substitution reactions with H2S appear to be sensitive to LDA/DFT-predicted oxygen binding modes, with mu3-O modes relatively inert with respect to mu-O conformations. The reactions of the hypometallic anions SnxO(x+1)(-) with H2S were dominated by proton transfer, although S-for-O substitution was observed to be kinetically competitive. The rates of the proton transfer were found to vary with both the reagent and cluster anion, and an analysis of the reaction kinetics for SnxO(x+1)(-) afforded the relative cluster proton affinities: PA(Sn2O3-) > PA(SnO2-) >> PA(Sn3O4-) > PA(Sn5O6-) approximately PA(Sn6O7-) approximately PA(CH3O-) = 381 +/- 2 kcal mol( 1) > PA(Sn-) = 352 +/- 10 kcal mol(-1). Ion-molecule reaction results for the hypermetallic cations x = 2-5 with CH3OH are suggestive of gas-phase coordination chemistry, with each cluster undergoing one slow association reaction. A recurrent theme of the chemistry of ionic SnxOy is the initial activation or generation of OySnx(-/+)-OH bonds by a radical mechanism involving hydrogen or hydroxyl abstraction from the reagent. The resulting cluster-hydroxyl bonds are relatively labile with respect to conversion to alkoxy ligands. PMID- 19787927 TI - A theoretical spectroscopic study of HeI and HeBr. AB - Highly accurate potential energy functions for the HeI and HeBr molecules have been calculated using an ab initio treatment that included basis set extrapolation to the complete basis set, as well as spin-orbit coupling in the ground 2sigma+ and first 2pi excited doublet states. The rovibronic bound state energies and resonance lifetimes were also evaluated by a Prony analysis of the autocorrelation function of the evolving wave packet. PMID- 19787928 TI - Theoretical investigation of the absorption and ionization spectrum of the super greenhouse gas SF5CF3. AB - SF5CF3, recently found in the Earth's atmosphere, is an extremely potent greenhouse gas. Its behaviour under irradiation, as in the upper atmosphere, is of great importance for the possible impact on the global climate. The vertical absorption spectrum of the title compound is studied by various single- and multi reference ab initio methods and the results are compared to experiments. The best results for valence states are obtained by the multi-state complete active space second order perturbation theory (MS-CASPT2) approach. In contrast, the popular time-dependent density functional theory (TDDFT) gives very poor results. Multi reference configuration interaction (MRCI) does not yield very accurate energies because only a limited number of valence electrons can be included in the correlation treatment. The Rydberg states are calculated very accurately and efficiently by a frozen-core multi-configuration self-consistent field (FC-MCSCF) method. The accuracy is assessed by quantum defect theory and the experimental and ab initio calculated first ionization potential. The photoelectron spectrum is investigated by the outer-valence Green's functions (OVGF) method. The simulated spectrum is in excellent agreement with a recent experiment. PMID- 19787929 TI - The rotational spectra, electric dipole moments and molecular structures of anisole and benzaldehyde. AB - The rotational spectra of anisole and of benzaldehyde were investigated in supersonic expansion at frequencies up to 41 GHz, and at room temperature in the millimetre-wave region, from 170 to 330 GHz. Accurate spectroscopic constants for the parent isotopomers in the ground vibrational state and for the first excited torsional state were determined for both molecules. The supersonic expansion spectrum allowed measurement, in natural abundance, of all singly substituted 13C isotopomers, as well as of the 18O isotopomer for both anisole and benzaldehyde. The rotational constants were used to determine the r(s) and the r(m)(1) gas phase geometries, which are found to be consistent with prediction of bond length alternation in the phenyl ring induced by the asymmetric substituent. Stark measurements were made on the supersonic expansion spectrum resulting in electric dipole moment determination, /mu a/ = 2.9061(22) D, /mu b/ = 1.1883(10) D, /mu tOt/ = 3.1397(24) D for benzaldehyde and /mu a/ = 0.6937(12) D, /mu b/ = 1.0547(8) D, mu tOt = 1.2623(14) D for anisole. During the investigation it was found that use of a carrier gas mixture consisting of 30% Ar in He carries significant advantages for studies of weak lines, and pertinent experimental details are reported. PMID- 19787930 TI - Femtosecond fluorescence spectroscopy by upconversion with tilted gate pulses. AB - Time-resolved emission bands can be observed by simultaneous sum-frequency mixing with femtosecond near-infrared gate pulses over a wide frequency range. Using tilted gate pulses in a noncollinear geometry we achieve 80 fs time resolution and background-free measurement of upconverted spectra. All components were optimized resulting in a spectrometer for routine applications. As example we report the initial fluorescence from Coumarin 153 in acetonitrile after excitation at 400 nm. The fluorescence is modulated by nuclear coherence in the excited state which affects band width and asymmetry more than the energy gap itself. PMID- 19787931 TI - Photoluminescence properties of vapor deposited films of a bisazomethine dye. AB - Steady-state and time-resolved photoluminescence (PL) measurements on vapor deposited films of a non-ionic bisazomethine dye have been performed. In the films, it is possible to control the ratio between J-aggregate and crystalline phases of the dye by means of exposure to chloroform vapour, and thus the origin of PL can be determined from comparison between several films. In the films, PL was emitted exclusively from the crystalline phase. Although the origin of PL was not from the J-aggregate phase, some features of the observed PL were very similar to those reported for J-aggregates of ionic dyes. We also found that these features in the vapor deposited films were caused by a competition between free excitons and excitons trapped at defect sites. PMID- 19787932 TI - Assessment of theoretical prediction of the NMR shielding tensor of 195PtClxBr(6 x)(2-) complexes by DFT calculations: experimental and computational results. AB - In the present work, the ZORA spin-orbit Hamiltonian, in conjunction with the gauge including orbital (GIAO) method based on DFT theory has been used to calculate 195Pt chemical shift of 195PtClxBr(6-x)(2-) complexes. Excellent agreement with experiments has been obtained for calculations bearing on optimized geometries and all electrons triple zeta + polarization (TZP) STO basis sets: the relative error with respect to experiment amounts to <1.5%. It is found that the Pt chemical shift is dominated by the paramagnetic and the spin orbit contribution, whereas the diamagnetic term remains negligible. The influence of the quality of the basis sets has been studied and found to be small, provided a basis set like TZP is used. Several calculations have been performed in order to establish the sensitivity of the chemical shift to a variation in the bond lengths. A strong dependence has been found, with an increase of the chemical shift amounting to 150 ppm pm(-1) for a distance decrease. Large sensitivity to the solvation, leading to changes in the structure, is then expected. Different tests using conductor-like screening models have been performed in order to establish the sensitivity of the chemical shift to solvation. It has been observed that the changes in the geometry are more important than charge transfers. Finally, the sensitivity of the system to the exchange-correlation functional is found rather weak, at least among the GGA functionals. PMID- 19787933 TI - Location and orientation of adsorbed molecules in zeolites from solid-state REAPDOR NMR. AB - The use of rotational echo adiabatic passage double resonance (REAPDOR) solid state nuclear magnetic resonance (NMR) to determine the site location of an adsorbed polar molecule in a zeolite cage is presented. Nitrogen-15 labeled ammonia is used as a probe molecule to characterize the initial adsorption site in 3A zeolite molecular sieves. The relative position of the ammonia adsorption site in the cage is determined by measuring the internuclear distance between the N on ammonia and both a Na cation site and an Al framework environment using 15N/23Na and 15N/27Al REAPDOR NMR experiments, respectively. The measured internuclear distances are similar to a specific ammonia adsorption site for the zeolite 4A ammonia sorption complex located using X-ray diffraction. Additional details regarding the ammonia hydrogen-bonding environment can be extracted from 1H/23Na and 1H/27Al REAPDOR NMR measurements. PMID- 19787934 TI - Local structure of [Cu(I)(CO)2]+ adducts hosted inside ZSM-5 zeolite probed by EXAFS, XANES and IR spectroscopies. AB - EXAFS spectroscopy, analysed in the frame of the multiple scattering theory, has been able to determine the local structure of [Cu(CO)2]+ complexes hosted inside ZSM-5 channels upon contacting the activated zeolite with CO from the gas phase at room temperature. We found that the number of coordinated CO molecules (1.8 +/ 0.3) is in good agreement with the [Cu(CO)2]+ stoichiometry suggested by IR. The Cu-C distance obtained for the [Cu(CO)2]+ complex is 1.88 +/- 0.02 A, with a C-O distance (1.12 +/- 0.03 A). This work complements a previous one [C. Lamberti, G. Turnes Palomino, S. Bordiga, G. Berlier, F. D'Acapito and A. Zecchina, Angew. Chem. Int. Ed., 2000, 39, 2138], performed at liquid nitrogen temperature, where the structure of [Cu(CO)3]+ complexes was identified by combined EXAFS/XANES/IR spectroscopies. An increase of the Cu-C distance of 0.05 A by moving from [Cu(CO)2]+ to [Cu(CO)3]+ complexes has been observed, which is the local rearrangement needed to accommodate a third CO ligand in the first coordination shell of copper. EXAFS determined that the Cu-C-O bond angle is linear within the error bars (170 +/- 10 degrees), while IR and XANES indicate that intrazeolitic [Cu(CO)2]+ complexes have C2v symmetry. The experimentally obtained moieties are in good agreement with the values obtained with advanced quantum mechanical methods. PMID- 19787935 TI - The vibrational g-factor of dihydrogen from theoretical calculation and analysis of vibration-rotational spectra. AB - We present the first results from quantum-chemical calculation of a vibrational g factor; the calculations were performed at the level of full configuration interaction using a basis set of aug-cc-pVQZ quality. The theoretical results are consistent with experimental results from analysis of pure rotational and vibration-rotational spectra of dihydrogen in six isotopic variants, in which calculated results for either the rotational g-factor or adiabatic corrections are employed to constrain fits of coefficients of radial functions from wave numbers of transitions. When fits are constrained with data for the rotational g factor, we reproduce also the radial dependence of adiabatic corrections relative to their value at equilibrium internuclear separation. PMID- 19787936 TI - Comparison of various Franck-Condon and vibronic coupling approaches for simulating electronic spectra: the case of the lowest photoelectron band of ethylene. AB - Various time independent approaches for simulating electronic absorption spectra are discussed and applied to the lowest band (10.2-11.4 eV) of the photoelectron spectrum of ethylene. The electronic structure calculations for the ionized states of ethylene are performed using the Equation of Motion Coupled Cluster method for Ionization Potentials (IP-EOM-CCSD) in a TZ2P basis set. Various Franck-Condon (FC) and vibronic coupling model Hamiltonian approaches are used to simulate the spectrum and a comparison is made to the experimental data. The potential energy surface is highly anharmonic and it is necessary to use more sophisticated FC approaches than the traditional harmonic approach to obtain a qualitatively correct simulation of the spectrum. Duschinsky rotation is found to play an important role in determining the detailed intensity pattern of the spectrum, while non-adiabatic effects are found not to be important. The spectrum is found to be very sensitive to the precise values of some of the parameters used in the vibronic model, that determine the details of the adiabatic potential energy surface. PMID- 19787937 TI - A new orbital-based model for the analysis of experimental molecular charge densities: an application to (Z)-N-methyl-C-phenylnitrone. AB - An alternative to the usual atom-centred multipole expansion is presented for the analysis of high resolution, low-temperature X-ray scattering data. The molecular electron density is determined in a fixed basis of molecular orbitals with variable orbital occupation numbers, i.e. the same form which is used to represent the density in ab initio electron-correlated calculations. The advantages of such an approach include linear scaling (in the sense that the number of parameters to be determined by fitting varies linearly with system size) and ease of property calculation. The method is applied to experimental high-resolution structure factors for a phenylnitrone, and compared to the results of a multipole model of the same data. Finally, the model is critically compared with several related, published orbital-based models. PMID- 19787938 TI - Intramolecular anharmonicity in the naphthalene molecule: thermodynamics and spectral effects. AB - The anharmonicity of the ground electronic state of the naphthalene molecule has been investigated using a tight-binding potential energy surface model. The vibrational density of states is calculated from a mixed classical quantum theoretical approach. The primary assumption of this model is that the evolution of the mean anharmonic quantum energy as a function of temperature follows the classical evolution. From the thermal expansion of the classical free energy obtained using a reversible-scaling method, the mean vibrational frequency has also been determined as a function of temperature. PMID- 19787939 TI - A molecular theory of liquid interfaces. AB - We propose a site site generalization of the Lovett-Mow-Buff-Wertheim integro differential equation for the one-particle density distributions to polyatomic fluids. The method provides microscopic description of liquid interfaces of molecular fluids and solutions. It uses the inhomogeneous site-site direct correlation function of molecular fluid consistently constructed by nonlinear interpolation between the homogeneous ones. The site site correlations of the coexisting bulk phases are obtained from the reference interaction site model (RISM) integral equation with our closure approximation. For illustration, we calculated the structure of the planar liquid-vapor as well as liquid-liquid interfaces of n-hexane and methanol at ambient conditions. PMID- 19787940 TI - Structure and spatial distribution of the spin-labelled lipopeptide trichogin GA IV in a phospholipid membrane studied by pulsed electron-electron double resonance (PELDOR). AB - The method of pulsed electron-electron double resonance (PELDOR) is exploited to study intra- and intermolecular dipole-dipole interactions between the spin labels of trichogin GA IV analogues. This lipopeptaibol antibiotic was studied in multilamellar membranes of dipalmitoylphosphatidylcholine frozen to 77 K. For mono-labelled trichogin analogues, the molecules are shown not to form aggregates in the lipid membranes studied. For the double-labelled trichogin analogues, a function of the distance distribution between the spin labels has been obtained. We determined that the distribution function has two main maxima located at distances of 1.25 nm and 1.75 nm. The value of 1.25 nm is close to the distance between labels of a alpha-helical structure. On the other hand, a distance of 1.75 nm corresponds to a mixed 3D-structure in which a 3(10)-helix is combined with a more elongated conformation. PMID- 19787941 TI - Supramolecular multilayer structures of wired redox enzyme electrodes. AB - Supramolecular multilayer structures comprised of glucose oxidase (GOx), and Os complex derivatised poly(allylamine) (PAH-Os) have been built by alternate layer by-layer (LBL) electrostatic adsorption in a self-assembly process. The resulting modified electrodes with integrated mediator were tested as reagentless glucose biosensors. The enzyme kinetic parameters and the surface concentration of "wired" enzyme GammaE have been obtained by analysis of the catalytic current dependence on glucose concentrations for the ping-pong mechanism of glucose oxidation. An average osmium volume concentration was estimated by integration of the redox charge in the absence of glucose and the ellipsometric thickness. The total enzyme surface concentration was measured with a quartz crystal microbalance (QCM) during each adsoption step and the fraction of "wired" enzyme and the bimolecular rate constant for FADH2 oxidation by the redox polymer for the different multilayers. The catalytic current increases with the number of LBL layers because the increase in the enzyme loading while the efficiency of enzyme FADH2 oxidation by the Os redox polymer, except for the first dipping cycle remains almost constant at about 2 x 10(4) M(-1) S(-1). PMID- 19787942 TI - Structural and electrochemical characterisation of Pt and Pd nanoparticles electrodeposited at the liquid/liquid interface: part 2. AB - This report discusses some specific mechanistic and structural factors that govern the deposition of palladium and platinum from chloro-complexes at the electrified liquid/liquid interface. Factors studied here include: the age of the platinum solution, reactant depletion effects due to the formation of particles, and the previously noted phenomenon that the platinum particles created at the ITIES are smaller than their palladium counterparts, which is at variance with expectations based on the surface energies of the metals. A preliminary investigation is also made of co-deposition of Pt-Pd at the ITIES. This report builds on the previous publication (Part I) describing the reduction of these metals at the liquid/liquid interface and gives further insight into the factors controlling the interfacial reduction of metals in the absence of an underlying electrode. PMID- 19787943 TI - Light stability of pyrazolotriazole azamethine dyes at oil/aqueous interfaces. AB - Film and dispersion coatings of two pyrazolotriazole azamethine (PT) dyes are used to study the effect of increasing the surface-area-to-volume (SA : V) ratio of the oil/aqueous (solvent/gelatin) interface on nonoxidative and oxidative fade characteristics. High concentration solutions of the dyes in a poly(vinyl acetate)dicyclohexylphthalate mixture as solvent are coated on glass substrates with a gelatin overcoat to produce thin film coatings and are also dispersed in gelatin to create "oil-in-gelatin" dispersion coatings. It is calculated that the dispersion coatings possess a SA : V ratio of approximately 20x greater than the film coatings. In nonoxidative fade conditions both the film and dispersion samples possess similar quantum yields of fade, implying that the presence of a solvent/gelatin interface does not significantly affect any electron transfer fade mechanisms. However, in oxidative fade conditions increasing the SA : V ratio of the interface by 20x leads to an increase in the quantum yield of fade of only a factor of 1.5-2. This disproportionate increase in the fade kinetics in dispersion coatings is explained by a kinetic scheme modelling oxygen diffusion through the coatings. It shows that the rate determining step for dye fade starts to become the diffusion of oxygen through the air/gelatin interface, and explains why changes in the SA : V ratio are not fully transferred to the quantum yield of fade. PMID- 19787944 TI - Decomposition of methanol on Au(310). AB - Experimental results on the interaction of methanol with a Au(310) surface studied using X-ray photoelectron spectroscopy (XPS) and temperature programmed desorption (TPD) are reported. At 80 K methanol forms a physisorbed condensed layer above 5 L of exposure. Interestingly, O-H bond scission takes place above 150 K on the surface resulting in an adsorbed methoxy species which is stable till 500 K. This is in contrast with other gold surfaces like Au(111) and Au(110) which showed no evidence for decomposition. The difference in reactivity of Au(310) surface towards methanol is interpreted in terms of the presence of special sites formed by (110) steps and (100) terraces on this surface. PMID- 19787945 TI - An experimental verification of the possible influence of gas nano-bubbles on the response of an electrochemical quartz crystal microbalance. AB - Electrochemical removal of oxygen and hydrogen from aqueous solution in the vicinity of gold electrodes, with simultaneous measurements of the response of the quartz crystal microbalance, show no evidence of gas nano-bubbles attached to the surface, irrespective of its roughness and hydrophobicity. The contact between gold and frozen electrolyte, which forms a liquid-like layer between them, also does not contain gas bubbles. These statements could be extended to nano-bubbles with characteristic dimensions larger than a few nanometers. PMID- 19787946 TI - Development of a neutron detector based on a position-sensitive photomultiplier. AB - A neutron scintillation detector based on a position-sensitive photomultiplier has been developed for neutron spin echo and small angle neutron scattering measurements. This photomultiplier has good spatial resolution, less than 1 mm2. The detection efficiency of gamma ray background is very low for using a thin ZnS/6LiF scintillator. The effective area of this detector is around 60 cm2. PMID- 19787947 TI - Surface diffusion and surface growth in nanofilms of mixed rocksalt oxides. AB - We have modelled the surface diffusion and growth of BaO and SrO both in the homoepitaxial and heteroepitaxial (BaO on SrO and SrO on BaO) cases. The diffusion proceeds most favourably by an exchange mechanism involving the surface layer. When impurities are adsorbed on the surface this can lead to intermixing between the layers. This strongly suggests that ionic materials may not be grown on a substrate with a similar structure without significant intermixing. Island growth begins with the formation of individual clusters which grow and merge together. PMID- 19787948 TI - In situ NMR and XRD studies of the growth mechanism of SBA-1. AB - In situ 17O, 14N and 29Si nuclear magnetic resonance (NMR) coupled with in situ energy dispersive X-ray diffraction (EDXRD) have been used to investigate the growth of the siliceous mesoporous material, SBA-1, synthesised under acidic conditions from a micellar solution of the surfactant hexadecyltriethylammonium bromide (HTEAB) and tetraethylorthosilicate (TEOS). For the last decade, the mechanism of growth of such materials has been thought to be driven by electrostatic interactions described as a co-assembly process between the silica species (I+) and the micelles (S(+)X(-)). However, this postulated model referred to as the "charge density matching model" has never been fully supported by experimental data for the acidic syntheses. We have carried out a detailed in situ study which challenges the so-called S(+)X(-)I(+) pathway and instead suggests that a salting-out effect coupled with a drastic change in the water activity are responsible for the composite I(1)3 (SBA-1 space group Pm3n) mesophase precipitation. Substantial reorganisation of the precipitated phase then results in the final structure. PMID- 19787949 TI - Towards an understanding of the oxidation state of cobalt and manganese ions in framework substituted microporous aluminophosphate redox catalysts: An electron paramagnetic resonance and X-ray absorption spectroscopy investigation. AB - The local structure of manganese and cobalt ions in both the AlPO-5 and AlPO-18 materials was determined using electron paramagnetic resonance (EPR) and X-ray absorption spectroscopy (XAS). This study strongly suggested that both cobalt and manganese ions are present in the framework tetrahedral sites in the as-prepared materials. Upon calcination, in a dry atmosphere, both manganese and cobalt ions are partially oxidised to the 3+ state; the fraction of oxidised cobalt or manganese ions depends upon both the nature of the framework structure and on the ion type with manganese systems showing a higher proportion of oxidised cations. PMID- 19787950 TI - 2,6-dimethylpyridine as a probe of the strength of Bronsted acid sites: study on zeolites. Application to alumina. AB - The positions of nu8a and nu*(NH) bands in the spectrum of protonated 2,6 dimethylpyridine vary with the strength of Bronsted acidity: the higher the nu*(NH) wavenumber and the lower the nu8a wavenumber, the stronger the acidity. The results obtained with 2,6-dimethylpyridine adsorption correlate with those obtained by CO adsorption experiments on a series of faujasite zeolites (LiHNaY, KHNaY, HY, HY(SA), HNaX). These relations were extended to gamma-Al2O3 having weak Bronsted acidity, not detected by pyridine and hardly detected by CO. The number (0.1 per nm2) and the strength (corresponding to delta nu (OH) by CO = 155 cm(-1)) of the most acidic OH groups of Al2O3, as well as the position of the corresponding nu (OH) band (<3700 cm(-1)) are deduced from 2,6-dimethylpyridine adsorption experiments. PMID- 19787951 TI - Chemical processes of ions--transport and reactivity. 85th International Discussion Meeting of the Deutsche Bunsen-Gesellschaft fur Physikalische Chemie, Marburg, 15-17 September, 2004. PMID- 19787952 TI - Charge-state resolved mid-infrared spectroscopy of a gas-phase protein. AB - Infrared spectra of a 104 amino-acid protein in the gas phase as a function of its charge state are presented. The spectra contain clearly resolvable bands in the amide I and II spectral regions, as well as a band at 1483 cm(-1), which is not observed in solution phase spectroscopy and is especially prominent for the higher charge states. Compared to solution, the amide I band is blue-shifted and the amide II band red-shifted, as expected for species in an environment with reduced hydrogen bonding. The band positions are suggestive of a mostly alpha helical structure of the protein and their widths are comparable to those in solution, suggesting a similar conformational distribution. PMID- 19787953 TI - Template-controlled conformational patterns of insulin fibrillar self-assembly reflect history of solvation of the amyloid nuclei. AB - In the presence of ethanol, insulin forms amyloid morphologically distinct from the ambient specimen. Due to stability of fibrils and the autocatalytic character of the process, the two amyloid templates, when seeded, replicate the initial morphologies (and inter-beta-strand hydrogen bonding patterns) regardless of the environmental biases, such as the cosolvent presence. Such "templated memory" effect is advantageous in synthesizing structurally uniform protein nanofibrils under conditions favoring alternative "wild" forms. This also appears to parallel "prion strains" phenomenon, suggesting that "strains" may reflect a generic trait in all amyloids including those not associated with disease. PMID- 19787954 TI - Self-assembly in green solvents. AB - Recent advances in design of surfactants and polymers for liquid and supercritical carbon dioxide, and partially fluorinated alkanes, are reviewed. The focus is on surfactant structure-performance relationships, development of non-fluorinated surfactants, and applications of CO2 continuous dispersions for nanoparticle and organic synthesis. Future prospects for these emerging technologies are discussed, including the need for economically viable and environmentally friendly stabilizers for CO2 dispersions. PMID- 19787955 TI - A molecular dynamics study of the hydroxyl radical in solution applying self interaction-corrected density functional methods. AB - We have performed density functional theory based molecular dynamics (MD) simulations of the *OH radical in solution using self-interaction corrected (SIC) methods. We use a scheme recently proposed by M. d'Avezac, M. Calandra and F. Mauri [arXiv:cond-mat/0407750] in which a correction is only applied to the spin density within a restricted open shell formulation. In addition to two correction formulas employed within this scheme by M. d'Avezac, M. Calandra and F. Mauri, we propose and test an new empirical form which only introduces a scaled Coulomb term. This new functional leads to good agreement with reference calculations on radical cation dimers and on the hydroxyl water dimer in the gas phase. Applied in ab initio MD simulations, these three SIC methods provide a picture of the *OH solvation that differs qualitatively from the one obtained using the standard generalised gradient approximation (GGA). Hemibonded water, observed in GGA simulations and believed to be an artefact due to self-interaction error, is not present. We find that the *OH acts as a good hydrogen bond donor, but accepts less than two hydrogen bonds on average. These hydrogen bonds are part of a mobile, otherwise quasi-hydrophobic solvation cage. Our results show the potential of this computationally expedient scheme, which might extend the range of problems that can be modelled adequately with density functional theory. PMID- 19787956 TI - The geometric (H/D) isotope effect in porphycene: grid-based Born-Oppenheimer vibrational wavefunctions vs. multi-component molecular orbital theory. AB - Two approaches for the determination of the primary and secondary geometric isotope effect are compared for the exemplary porphyrinoid system porphycene, which has two intramolecular hydrogen bonds. A three-dimensional Born-Oppenheimer potential energy surface is calculated in terms of the symmetric and antisymmetric N-H stretching as well as a low-frequency hydrogen bond vibrational normal mode coordinate. From the respective ground-state nuclear wavefunction the quantum correction to the classical equilibrium geometry is determined. Further, geometry optimization within a full-dimensional multi-component molecular orbital (MC_MO) type calculation, which treats both the electrons and the hydrogen-bonded protons quantum mechanically, is performed. Both approaches yield geometric isotope effects, that is, upon H/D double substitution the hydrogen bonds are weakened and the respective N-N distances increase. In addition the MC_MO calculation gives a H/D isotope effect on the electronic structure, that is, the electronic wavefunction becomes more localized at the deuterium nucleus as compared with the proton case. PMID- 19787957 TI - Environmental effects on proton transfer in a strong hydrogen bond dimer: the 4 methyl-imidazole-aspartate case. AB - Proton transfer in hydrogen bond dimers formed by acetate anion plus 4-methyl imidazole, in both neutral and protonated forms, is studied by means of ab initio correlated calculations at the MP2/6-311++G(d,p) level of theory. These two dimers are selected as systems displaying a short and strong hydrogen bond with possible low barriers to proton transfer, also these systems resemble the dyad formed by histidine aspartate which is present in a variety of enzymes whose catalytic mechanisms involve the formation of short hydrogen bonds in the active site. The purpose of this job is twofold: we focus here on the effect of the polarity of the surrounding medium on the hydrogen bond, and on the other hand we analyse the relevance of the intermonomeric distance for the low barrier to proton transfer between the partners of the dimer. We have carried out an investigation for a number of intermonomeric distances and it was found that polar solvents and short intermonomeric distances lower the barrier, enhancing in that way the proton transfer between neutral imidazole and acetate. However, the binding energy of the dimer does not follow necessarily the same pattern. In the case of protonated imidazole no double well is found at all in the potential energy curve (not even in polar media) and barrierless proton transfer to acetate occurs at the shortest intermonomeric distances. PMID- 19787958 TI - Influence of polarization and many body quantum effects on the solvation shell of Al(III) in dilute aqueous solution--extended ab initio QM/MM MD simulations. AB - Structural properties of the hydrated Al(III) ion have been investigated by ab initio quantum mechanical/ molecular mechanical (QM/MM) molecular dynamics (MD) simulations at double zeta HF quantum mechanical level including only the first and first plus second hydration shell into the QM region. The coordination number in the first shell was found to be 6.0 in both cases, but the inclusion of the second shell into the QM region causes significant changes in the properties of the hydrate. Several structural parameters such as angular distribution functions, radial distribution functions and tilt- and theta-angle distributions were used to fully characterise the hydration structure of Al(III). PMID- 19787959 TI - Temperature and timescale dependence of protein dynamics in methanol : water mixtures. AB - Experimental and computer simulation studies have suggested the presence of a transition in the dynamics of hydrated proteins at around 180-220 K. This transition is manifested by nonlinear behaviour in the temperature dependence of the average atomic mean-square displacement which increases at high temperature. Here, we present results of a dynamic neutron scattering analysis of the transition for a simple enzyme: xylanase in water : methanol solutions of varying methanol concentrations. In order to investigate motions on different timescales, two different instruments were used: one sensitive to approximately 100 ps timescale motions and the other to approximately ns timescale motions. The results reveal distinctly different behaviour on the two timescales examined. On the shorter timescale the dynamics are dictated by the properties of the surrounding solvent: the temperature of the dynamical transition lowers with increasing methanol concentration closely following the melting behaviour of the corresponding water : methanol solution. This contrasts with the longer (ns) timescale results in which the dynamical transition appears at temperatures lower than the corresponding melting point of the cryosolvent. These results are suggested to arise from a collaborative effect between the protein surface and the solvent which lowers the effective melting temperature of the protein hydration layer. Taken together, the results suggest that the protein solvation shell may play a major role in the temperature dependence of protein solution dynamics. PMID- 19787960 TI - A general approach to the calculation of 2H2O NMR lineshapes in microheterogeneous systems: a distorted bicontinuous cubic phase. AB - A new computational method is developed for calculating 2H NMR lineshapes of H2O in microheterogeneous systems, such as lyotropic liquid crystals that exhibit curved lipid/water interfaces. The method presented is based on the stochastic Liouville equation (SLE) in its Langevin form. This means that the Liouville equation of motion is combined with Brownian dynamics simulations to describe the stochastic spin-lattice Liouvillian. The NMR relaxation is caused by translational diffusion of the heavy water molecules, along the curved 2H2O/lipid interface. The model used is a nodal surface approximation of the cubic symmetric gyroid minimal surface. This unit cell is then isotropically expanded or distorted in two dimension. The changes in 2H20 NMR lineshapes have been calculated for the enlarged or the distorted cubic unit cell. The timescale of the residual quadrupole interaction, which determines the NMR lineshape, ranges from the Redfield regime to the slow-motional regime depending on the curvature of the interface. The distortion of the cubic phase illustrates the possibility to explore the intermediate interfaces of a phase transition, by means of 2H2O lineshape analysis. PMID- 19787961 TI - A combined first principles computational and solid-state NMR study of a molecular crystal: flurbiprofen. AB - The 1H, 13C and 19F magic-angle spinning NMR spectra have been recorded for Form 1 of flurbiprofen. In the case of 19F, spinning sideband analysis has produced data for the components of the shielding tensor. The chemical shift of the hydrogen-bonded proton was found to be 14.0 ppm. Shielding parameters for all three nuclei have been calculated using Density Functional Theory (DFT) together with the Gauge Including Projector Augmented Wave (GIPAW) method which takes full allowance for the repetition inherent in crystalline structures. Such computations were made for the reported geometry, for a structure with all the atomic positions relaxed using DFT, and with only the hydrogen positions relaxed. The relationships of the computed shifts to those observed are discussed. In general, the correlations are good. PMID- 19787962 TI - Hyperfine quantum beats from photolytic orientation and alignment. AB - Using Doppler-resolved transient frequency modulation absorption spectroscopy, we have measured both alignment and orientation quantum beats arising from nuclear hyperfine depolarization of low rotational levels of CN X 2sigma+ photofragments produced in the ultraviolet photodissociation of ICN. Under our conditions of fully resolved fine-structure and completely unresolved hyperfine structure, the observed time evolution is insensitive to the rapid depolarization of angular momentum N that would be observed if the fine-structure components were not resolved. Non-statistical spin-rotation populations of CN photofragments, previously observed only for high rotational states, are now observed even for the lowest rotational states, indicating that the electron can not be considered a spectator spin in the depolarization. PMID- 19787963 TI - An investigation of the factors influencing the detection sensitivity of cavity enhanced Raman scattering for probing aqueous binary aerosol droplets. AB - Stimulated Raman scattering (SRS) from single aerosol droplets can be observed at extremely low laser threshold intensities at wavelengths commensurate with whispering gallery modes. Although droplet size can routinely be determined from the ensuing cavity enhanced Raman scattering (CERS) fingerprint, determining droplet composition is a considerably more challenging measurement. We present here an examination of the factors that influence and limit the detection sensitivity of CERS in quantifying the concentrations of sulfate and nitrate in water droplets, 20-50 microm in radius. In particular, we consider the variation in nitrate and sulfate SRS signal with variation in species concentration, probe laser intensity and droplet size. We illustrate that the band contour of the OH stretching band can be used as a relative measure of the internal light intensity circulating within the droplet and experimentally investigate how the threshold condition for SRS is achieved. PMID- 19787964 TI - Absence of molecular mobility on nano-second time scales in amorphous ice phases. AB - High-resolution neutron backscattering techniques are exploited to study the elastic and quasi-elastic response of the high-density amorphous (HDA), the low density amorphous (LDA) and the crystalline ice Ic upon temperature changes. Within the temperature ranges of their structural stability (HDA at T < or = 80 K, LDA at T < or = 135 K, ice Ic at T < or = 200 K) the Debye-Waller factors and mean-square displacements characterise all states as harmonic solids. During the transformations HDA --> LDA (T approximately 100 K), LDA --> Ic (T approximately 150 K) and the supposed glass transition with Tg approximately 135 K no relaxation processes can be detected on a time scale t < 4 ns. It can be concluded from coherent scattering measurements (D2O) that LDA starts to recrystallise into ice Ic at T approximately 135 K, i.e. at the supposed Tg. In the framework of the Debye model of harmonic solids HDA reveals the highest Debye temperature among the studied ice phases, which is in full agreement with the lowest Debye level in the generalised density of states derived from time-of flight neutron scattering experiments. The elastic results at low T indicate the presence of an excess of modes in HDA, which do not obey the Bose statistics. PMID- 19787965 TI - Structure, electronic circular dichroism and Raman optical activity in the gas phase and in solution: a computational and experimental investigation. AB - A computational (ab initio and molecular dynamics) and experimental exploration of the relative importance of molecular conformation and explicit solvent effects on the electronic circular dichroism (ECD) of chiral molecules, is presented. The exploration includes an assessment of the validity of angular correlation (sector) rules linking ECD to molecular conformation. It is based upon studies of 1-(R) phenylethanol (including its Raman optical activity spectrum), the corresponding 'benchmark' base, 1-(R)-phenylethylamine and its protonated cation; their hydrated clusters in the gas phase; and their non-polar and aqueous solutions. Emphasis is placed on the influence of specific, hydrogen bonded interactions with the aqueous solvent. The theoretical validity of the (otherwise empirical) sector rule in the neutral molecules and in their specifically hydrated clusters has been established--but with a reversal of the 'historical' sign convention. Protonation of the amine leads to a breakdown of the conventional sector rule but the change in its ECD intensity can still be related to the side chain dihedral angular dependence of its rotatory strength, computed ab initio for its explicitly hydrated clusters. Comparisons between ECD spectra measured in aqueous and in hydrocarbon solutions and the results of molecular dynamics calculations for aqueous solutions at 300 K, identify solvent induced structural change as the principal determinant of their relative ECD spectral intensities. Further links connecting the structures and conformations of chiral molecules and their explicitly solvated clusters in the gas phase, to their structures and conformational populations in solution can be expected through measurement, ab initio computation and analysis of their vibrational, ROA spectra. PMID- 19787966 TI - Thermal conductivity of crystalline and amorphous ices and its implications on amorphization and glassy water. AB - The thermal conductivities kappa of the crystalline phases and amorphous solid states of water as well as clathrate hydrates are summarized and discussed. In particular, this review concerns the unusual temperature T and pressure p behaviors of kappa for some phases and states, which include glass-like K for crystalline clathrate hydrates and crystal-like kappa for low-density amorphous ice. The latter result implies that glassy water and low-density amorphous ice are different states. The results for the various phases and states are in most cases described well by the equations: kappa = D x T(-x) and 1n kappa = E + F x p, under isobaric and isothermal conditions, respectively. All phases that exhibit negative values for F are known to amorphize upon pressurization at low temperatures. Ice XI, which is obtained by annealing ice Ih below 70 K, exhibits positive F, which indicates that this phase does not amorphize like ice Ih upon pressurization. PMID- 19787967 TI - Radial distribution functions and densities for the SPC/E, TIP4P and TIP5P models for liquid water and ices Ih, Ic, II, III, IV, V, VI, VII, VIII, IX, XI and XII. AB - Monte Carlo computer simulation studies have been undertaken for virtually all of the ice phases as well as for liquid water for three of the most popular model potentials; namely SPC/E, TIP4P and TIP5P. Densities have been calculated for specific thermodynamic state points and compared to experimental results. The SPC/E and TIP4P models overestimate the solid densities by about 2%. The TIP5P model overestimates the solid densities by about 5-10%. The structural pair correlation functions between oxygen-oxygen, hydrogen-hydrogen and oxygen hydrogen atoms were also obtained from the simulations. (These are available as ESIt). It has been found that SPC/E and TIP4P structural predictions are rather similar, with the only exception of ice II for which differences are visible between these two models. Predictions from the TIP5P are clearly different from those of the other models, especially for ices Ih and II. For the higher density ices structural differences between the models are rather small. Experimental data would be highly desirable to test the structural predictions of the different models of water. This is especially true for ice II. We have also found that the oxygen-oxygen correlation function of high density amorphous (HDA) water presents the same broad features as those exhibited by ice XII. PMID- 19787968 TI - Chain-length-dependent conformational transformation and melting behaviour of alkyl/oligo(oxyethylene)/alkyl triblock compounds: alpha-octyl-omega octyloxyoligo(oxyethylene)s. AB - The chain-length-dependent conformational transformation and the melting behaviour of triblock compounds alpha-octyl-omega-octyloxyoligo(oxyethylene)s, H(CH2)8(OCH2CH2)mO(CH2)8H (abbreviated as C8EmC8) (m = 1-8), have been studied by infrared spectroscopy and differential scanning calorimetry. The compounds with m = 1-5 assume the all-trans planar form (gamma-form) in the solid state, while those with m = 7 and 8 assume the planar/ helical/planar form with conformational defects in the alkyl chain (beta'-form). Conformational polymorphism was observed for C8E6C8: the gamma-form for the annealed solid and the planar/helical/planar form without conformational defects (beta-form) for the unannealed solid. The conformational transformation from the planar form into the planar/helical/planar form takes place at a length of the oligo(oxyethylene) chain m = 6. This result for C8EmC8 and a similar conformational transformation for C6EmC6 at m = 5 (previous work) demonstrate that the conformation of the CnEmCn triblock compounds in the solid state is determined by intramolecular conformational restoring force in the central oligo(oxyethylene) block, intermolecular dipole dipole interaction of the C-O bonds and intermolecular packing force in the end alkyl blocks. The melting points of the gamma-form solid of C8EmC8 are much lower than the melting points of n-alkanes with similar molecular masses. The observed thermodynamic quantities show that the planar structure of the oligo(oxyethylene) chain is stabilized by the force of the magnitude that maintains the rotator phase of n-alkanes. For the beta'-form solid of C8EmC8, the alkyl blocks, which are partially noncrystalline, and the oligo(oxyethylene) block melt together at the melting point, unlike the beta-form solid of C6EmC6, for which the melting of the alkyl blocks takes place before the melting of the oligo(oxyethylene) block. The beta-form solid of C8E6C8 (unannealed) melts via the gamma-form solid. PMID- 19787969 TI - Measurement of heteroaggregation rate constants by simultaneous static and dynamic light scattering. AB - The early stages of the heteroaggregation (or heterocoagulation) of latex particles were probed by time resolved simultaneous static and dynamic light scattering (SSDLS). We show that the heteroaggregation rate constant and the apparent hydrodynamic radius of the dimer can be obtained by analyzing the SSDLS data without the need to invoke the optical form factors for the doublets. A similar approach was proposed earlier for homoaggregation. The validity of the present approach was tested by investigating heteroaggregation between sulfate and amidine latex particles of different size, and similar data for smaller particles, which were previously analyzed in terms of the Rayleigh-Debye-Gans (RDG) theory. In this case, the presently obtained rate constants were found to be in excellent agreement with the results based on RDG. The present technique is particularly interesting for larger particles, where RDG cannot be applied, or to particles of more complex shapes, where the optical form factor cannot be easily evaluated. PMID- 19787970 TI - Nanoscopic study of the ion dynamics in a LiAlSiO4 glass ceramic by means of electrostatic force spectroscopy. AB - We use time-domain electrostatic force spectroscopy (TD-EFS) for characterising the dynamics of mobile ions in a partially crystallised LiAlSiO4 glass ceramic, and we compare the results of the TD-EFS measurements to macroscopic electrical conductivity measurements. While the macroscopic conductivity spectra are determined by a single dynamic process with an activation energy of 0.72 eV, the TD-EFS measurements provide information about two distinct relaxation processes with different activation energies. Our results indicate that the faster process is due to ionic movements in the glassy phase and at the glass-crystal interfaces, while the slower process is caused by ionic movements in the crystallites. The spatially varying electrical relaxation strengths of the fast and of the slow process provide information about the nano- and mesostructure of the glass ceramic. PMID- 19787971 TI - Global 1 1A" potential energy surface of CH2 and quantum dynamics of a sideways insertion mechanism for the C(1D) + H2 --> CH(2pi) + H reaction. AB - A global adiabatic potential energy surface (PES) corresponding to the second singlet state 1 1A" (1 1B1) of CH2 has been computed in a similar way as the first singlet state 1 1A' in our previous work [B. Bussery-Honvault et al., J. Chem. Phys., 2001, 115, 10 701]. This PES has a calculated well depth of 79.9 kcal mol(-1) relative to the C(1D) + H2 asymptote and correlates to CH(2pi) + H. It presents large barriers in the C(1D) + H2 arrangement for both collinear and perpendicular geometries but no barrier for geometries about 60 degrees and leads to a sideways insertion mechanism for the reaction C(1D) + H2 --> CH(2pi) + H. The ab initio calculations were carried out for 4644 geometries and the resulting energies were fitted to a many-body expansion. Accurate three-dimensional quantum mechanical scattering calculations have been performed for the C(1D) + H2(v = 0, j = 0) reaction on this ab initio 1 1A" PES in the collision energy range [0-11.5 kcal mol(-1)]. The J = 0 reaction probabilities show dense resonance structures as those obtained with the 1 1A' PES. However some different dynamical features have been found. PMID- 19787972 TI - Growth and characterisation of zirconia surfaces on Cu(111). AB - Ultra-thin films of zirconia have been prepared on a Cu(111) substrate using two different growth methods and characterised by a range of surface analytical techniques. The first method employed zirconium tetra-tert-butoxide [Zr(OC(CH3)3)4] as a precursor which was contacted with the heated substrate surface under high vacuum conditions to produce the oxide in a CVD-type process. TPD, MBS and XPS studies reveal that the precursor is readily adsorbed and decomposes rapidly at substrate temperatures above ca. 550 K to give stoichiometric ZrO2, and predominantly methylpropene and water vapour as gas phase by-products. The second method for oxide film growth involved the vacuum evaporation and oxidation of zirconium metal. Conversion to ZrO2 was achieved using high oxygen exposures and annealing at elevated temperatures to ensure complete oxidation of the base metal. Both methods produce zirconia films on the Cu(111) substrate which are thermally stable in vacuum up to ca. 923 K, and only start to degrade rapidly for temperatures in excess of 1073 K. After annealing at 923 K, LEED showed the zirconia to exhibit long-range ordering with a unit cell indicative of the growth of (111)-oriented cubic zirconia. PMID- 19787973 TI - Ion/surface reactions and ion soft-landing. AB - Ion/surface collision phenomena in the hyperthermal collision energy regime (1 100 eV) are reviewed, with emphasis on chemical processes associated with the impact of small organic and biological ions at functionalized self-assembled monolayer surfaces. Inelastic collisions can lead to excitation of the projectile ion and can result in fragmentation, a process known as surface-induced dissociation which is useful in chemical analysis using tandem mass spectrometry. Changes in charge can accompany ion/surface collisions and those associated with a change in polarity (positive to negative ions or vice versa) are an attractive method for ion structural characterization and isomer differentiation. The surface-induced charge inversion of nitrobenzene and other substituted aromatics is discussed. Reactive collisions occurring between gaseous ions and surfaces depend on the chemical nature of the collision partners. These reactions can be used for selected chemical modifications of surfaces as well as for surface analysis. Particular emphasis is given here to ion soft-landing, another type of ion/surface interaction, in which the projectile ion is landed intact at the surface, either as the corresponding neutral molecule or, interestingly but less commonly, in the form of the ion itself. The ion soft-landing experiment allows for preparative mass spectrometry; for example the preparation of pure biological compounds by using the mass spectrometer as a separation device. After separation, the mass-selected ions are collected by soft-landing, at different spatial points in an array. If the experiment is performed using a suitable liquid medium, in the case of some proteins at least, biological activity is retained. PMID- 19787974 TI - Synthetic ion channels: functional analysis and structural studies. AB - Various synthetic ion channels were derived from the gramicidin A beta-helix-lead structure. The ion transport through these channels was studied by single-channel current measurements in planar lipid bilayers. For asymmetric THF-gramicidin hybrids a selective insertion into the phospholipid bilayer was observed. Ion selectivity could be achieved by the use of synthetic cyclohexyl-ether amino acids as channel building blocks. The balance between the desolvation energy and the binding energy inside the channel is discussed. For minigramicidins, the hydrophobic coupling of the channel with membranes of different thickness was studied by dwelltime analysis. A conformational switch of a double stranded beta helix into a single stranded beta-helix was observed upon addition of Cs(+)-ions. PMID- 19787975 TI - Threshold photoelectron photoion coincidence studies of parallel and sequential dissociation reactions. AB - Recent advances in threshold photoelectron photoion coincidence (TPEPICO) make possible the analysis of several parallel and sequential dissociations of energy selected ions. The use of velocity focusing optics for the simultaneous collection of threshold and energetic electrons not only improves the resolution, but also permits subtraction of coincidences associated with "hot" electrons, thereby yielding TPEPICO data with no contamination from "hot" electrons. The data analysis takes into account the thermal energy distribution of the sample and uses statistical theory rate constants and energy partitioning in dissociation reactions to model the time of flight distributions and the breakdown diagram. Examples include CH2BrCl and P(C2H5)3. Of particular interest is the ability to extract error limits for rate constants and dissociation energies. PMID- 19787976 TI - Effects of dynamic disorder on the charge transport via DNA molecules. AB - Electron hopping transport along the DNA chain is studied theoretically by a straightforward numerical solution of the time-dependent Schrodinger equation. Results are given for the hole transition rates between two guanine bases bridged by sequences of the adenine-thymine bases with various lengths. Two models are considered: (i) with time-independent chain structure and (ii) with positions of bases on the bridge oscillating with time. It is shown that only the latter model is consistent with experimental data. The problem of the incoherence in the hopping transport mechanism is discussed. PMID- 19787977 TI - A combined vacuum ultraviolet laser and synchrotron pulsed field ionization study of BCl3. AB - The pulsed field ionization-photoelectron (PFI-PE) spectrum of boron trichloride (BCl3) in the region of 93 590-95 640 cm(-1) has been measured using vacuum ultraviolet (VUV) laser. At energies 0-1100 cm(-1) above the adiabatic ionization energy (IE) of BCl3, the bending vibration progression of BCl3+ is clearly resolved in the PFI-PE spectrum, whereas the spectrum at energies 1200-1900 cm( 1) above the IE (BCl3) is found to exhibit dense vibrational structure. This observation unambiguously shows that BCl3+ in its ground state has C2v symmetry. Ab initio calculations performed at the CCSD(T)/CBS level with high-level corrections are consistent with this observation, indicating that the BCl3+(X 2B2) ground state has two long and one short B-Cl bonds. Furthermore, the CCSD(T)/CBS calculations predict the existence of two BCl3+ transitional structures with D3h and C2v symmetries lying 800 and 1300 cm(-1), respectively, above the BCl3+ (X 2B2) ground state. This prediction is also consistent with the dense features observed in the PFI-PE spectrum in the region of 1200-1900 cm(-1) above the IE (BCl3). The assignment of the PFI-PE vibrational bands gives the IE (BCl3) = 93 891 +/- 2 cm (11.6410 +/- 0.0003 eV) and the bending frequencies for BCl3+ (X 2B2), v1+ (b2) = 194 cm(-1) and v1+ (a1) = 209 cm We have also examined the dissociative photoionization process BCl3 + hu --> BCl2 (+) + Cl + e- using the synchrotron based PFI-PE-photoion coincidence method, yielding the 0 K threshold or appearance energy (AE) for this process to be 12.495 +/- 0.002 eV. Combining this 0 K AE value and the IE (BCl3), we have determined the 0 K bond dissociation energy (D0) for Cl2B(+) -Cl as 0.854 +/- 0.002 eV. This experimental and theoretical study indicates that the CCSD (T, Full)/CBS calculations with high-level corrections are highly reliable for the predictions of IE (BCl3), AE (BCI2+) and D0 (Cl2B(+) -Cl) with error limits of less than 35 meV. However, the CCSD (T, Full)/CBS predictions for deltaH(f0) degrees (BCl3), deltaH(f0) degrees (BCl2+), and deltaH(f0)degrees (BCl3+) are less reliable with discrepancies up to 0.1 eV as compared to the experimental determinations. PMID- 19787978 TI - The resonance enhanced multiphoton ionisation spectroscopy of ammonia isotopomers NH3, NH2D, NHD2 and ND3. AB - The C' Rydberg states of the ammonia isotopomers NH3, NH2D, NHD2 and ND3 have been investigated by (2 + 1) resonance enhanced multiphoton ionisation spectroscopy. The spectroscopic parameters for the zero point and v'2 = 1 vibrational levels of the C' 1A'1 state have been derived for the first time for the mixed isotopomers. The current work provides the basis for future studies of the chemical reactions of the mixed isotopomers of ammonia ions formed by the REMPI technique. PMID- 19787979 TI - Ion-molecule kinetics at 15-700 Torr. AB - Studies of ion-molecule chemistry are usually made at pressures of a few Torr and below. By contrast, there are numerous plasmas that occur at higher pressures. For that reason we have constructed a turbulent ion flow tube (TIFT) for studying ion-molecule kinetics from 15 to 700 Torr. Currently, the TIFT operates from room temperature to 700 K. Here we present a summary of the measurements we have made to date. The first measurements involved SF6- reactions with SO2, H2O, CH3OH and C2H5OH at room temperature. The SO2 reaction showed the same kinetics as low pressure measurements indicating that the reaction occurs rapidly. The other reactions were all found to be cluster-mediated with branching fractions that depend on pressure. More recently, charge transfer reactions of O2+ to alkylbenzenes have been studied at elevated temperatures, from 400 to 700 K. Both dissociative and non-dissociative charge transfer occurs with the latter being favored at high pressures indicating that excited states live long enough to be stabilized by the buffer gas. Combining the TIFT measurements with detailed statistical adiabatic channel model/classical trajectory (SACM/CT) calculations of the unimolecular decay constant allows energy transfer parameters to be derived. Extending the temperature range upwards to 750 K has allowed thermal decomposition rate constants to be measured. The thermal decomposition has been successfully modeled using the same parameters as for the collision quenching modeling. This allows bond strengths for the dissociation to be derived with high accuracy. Both the measurements and models show that the conditions correspond to the high pressure kinetics regime. PMID- 19787980 TI - Dynamics of ion-molecule complex formation at very low energies and temperatures. AB - The dynamics of complex formation in collisions of rotationally excited diatomic molecules with ions at very low collision energies and translational temperatures is discussed. Under these conditions, the locking of the intrinsic angular momentum of the diatomic molecule to the collision axis occurs in the region of centrifugal barriers, and the motion of collision partners across these barriers bears quantum features (tunneling transmission and overbarrier reflection). The capture in this energy range is described by coupled radial wave equations that are solved numerically. In two limits, the respective rate coefficients are expressed analytically: for low collision energies (adiabatic channel approximation with classical relative motion of partners) and at zero collision energy (Bethe limit, s-wave capture). By comparison with accurate numerical quantum results, it is shown that these two limits are satisfactorily bridged by the so-called axially-nonadiabatic channel model that considers uncoupled relative motion of the colliding partners across effective potentials; the latter are generated by adiabatic channel potentials and Coriolis interaction in the perturbed rotor basis. The limits of applicability of the standard adiabatic channel model are discussed. The general approach is illustrated by the capture of H2 and HCl in collisions with ions. PMID- 19787981 TI - Reduced-dimensionality calculation of reaction cross sections and rate constant for the complex-forming gas-phase S(N)2 reaction Cl(-) + CH3Cl' --> ClCH3 + Cl'-. AB - Employing a 4D CCSD(T) potential energy surface, initial-state selected reaction cross sections for the complex-forming gas-phase identity S(N)2 reaction Cl(-) + CH3Cl' (v1, v2, v3) --> ClCH3 (v'1, v'2, v'3) + Cl'- havebeen calculated by means of time-independent quantum scattering theory in hyperspherical coordinates. The totally symmetric internal modes of the methyl group (C-H stretching vibration, quantum numbers v1 and v'1, and umbrella bending vibration, v2 and v'2) and the two C-Cl stretching modes (v3 and v'3) are included. The results for pure C-Cl stretching excitation in the reactants are similar to those obtained in earlier 2D calculations. The cooperative effect of C-Cl stretching and umbrella bending modes is even more pronounced for cross sections than for reaction probabilities. The same holds for excitations of the pure internal CH3 modes; in particular, the ratio of cross sections for reaction with the C-H stretch excited to reaction out of the vibrational ground state is five orders of magnitude larger than the ratio of the corresponding probabilities. This questions the concept of "spectator" modes in reaction dynamics which is valid only for thermal rate constants where the "spectator" modes play a negligible role due to their low population. Transition state theory rate constants fortuitously show good agreement with experiment while the reduced-dimensionality quantum calculations show larger deviations. Possible sources of this discrepancy are discussed in detail. Neglect of reactant CH3Cl rotation and the related modes in the transition state (doubly degenerate Cl-...CH3...Cl' bend and K rotation) yields very good agreement with experiment. PMID- 19787982 TI - Temperature and pressure dependence of ion-molecule association and dissociation reactions: the N2(+) + N2 (+ M) <--> N4+ (+ M) reaction. AB - Thermal dissociation and the reverse association reactions of molecular ions can be represented within the same framework as unimolecular reactions of neutral molecules. However, because of different intra- and intermolecular interaction potentials, some differences between ionic and neutral systems should also be expected. Starting from these generalities, the present article analyzes the temperature and pressure dependences of dissociation/association rates of ion molecule reaction systems. The reaction N2(+) + N2 (+ M) <--> N4+ (+ M) is considered in particular and falloff curves for this reaction are constructed over the temperature range 5-600 K. Falloff corrections are applied to earlier experiments which allows for a representation of the rate coefficients in terms of a limiting low-pressure rate coefficient k(ass,0)/[N2] cm6 molecule(-2) s(-1) = 6.8 x 10(-29) (300 K/T) 2.23 - 5.6 x 10(-31) (300 K/T)3.12, a limiting high pressure rate coefficient k(ass,infinity)/cm3 molecule(-1) s(-1) = 8.33 x 10(-10) [1 + 0.069(300 K/T) 0.33] and a center broadening factor of the falloff curve F(c) = 0.53 +/- 0.05 nearly independent of the temperature. Other examples such as the reactions NH4(+) + NH3 <--> N2H7+, C7H7(+) + CH3 <--> C8H10+, and C7H7(+) + C2H5 <--> C9H12+ are illustrated for comparison. PMID- 19787983 TI - Ab initio investigations of the C3+ cation and of its role during the reactions of C3+ ions against atomic sulfur. AB - Accurate ab initio calculations are performed in order to characterize the most stable isomers of empirical formula C3S+ and the role of C3S+ during the ion molecule reactions between the C3+ triatomic molecular ions and S atoms. The linear form l-C C-C-S+ (X2sigma+) is found to be the most stable isomer followed by a three-membered carbon ring with an external S {c-C3S+ (X2A1)}. The ion molecule reactions are investigated by doing suitable 1-D cuts of the 6-D potential energy functions (PEFs) of the lowest electronic states of C3S+. After its formation, the C3S+ intermediate may dissociate leading, in addition to the charge transfer products, to C, C+, C2, C2+, CS, CS+, C2S and C2S+ species. Generally, the dynamics of these reactions are found to involve several electronic states of C3S+ and their mutual couplings, including Renner-Teller couplings, spin-orbit interactions and vibronic interactions. These couplings can take place before and/or after intramolecular isomerisation processes. PMID- 19787984 TI - Reactive scattering of rydberg atoms: H* + D2 --> HD + D*. AB - The scattering of highly excited hydrogen Rydberg atoms, H* (n = 36), with deuterium molecules in their rovibrational ground state, D2(v = 0, j = 0), has been investigated at a relative collision energy of 0.53 eV. Time-of-flight distributions of elastically/inelastically scattered H* Rydberg atoms and reactively scattered D* Rydberg atoms have been measured at different laboratory angles. The extracted rovibrationally resolved state distributions of the HD product molecules from reactive collisions resemble closely those reported for the corresponding ion-molecule reaction, H+ + D2 --> HD + D+. This similarity is rationalised using the free electron model which predicts that the Rydberg electron acts as a spectator while the ionic reaction takes place. PMID- 19787985 TI - Probing the structure of CH5+ ions and deuterated variants via collisions. AB - Numerous recent calculations have provided a rather detailed picture how the protonated methane, CHS+, really may look like at very low temperatures; however, there is not yet any experiment, providing information on the correlation of a structure of this fluxional ion with a state to state transition induced by a photon or a collision. Various efforts in spectroscopy and mass spectrometry have contributed important pieces to the puzzle but there are no real final conclusions, e.g. infrared spectra in the region of the C-H stretching vibration are waiting for assignment since several years. This contribution reviews and discusses the potential and the limitations of a variety of detailed collision experiments for learning more about protonated methane and deuterated variants, either via creation, modification or destruction of CH5+. There has been a controversial discussion about an experiment which seemed to indicate that deuteron transfer from CD4+ to CH4 can create stable isotopomers with chemically distinguishable hydrogen atoms, CH3-HD+. Detailed integral and differential cross sections measured with sophisticated ion beam techniques revealed interesting dynamics; but, unfortunately, CH5+ formation is certainly more complicated than just a simple proton transfer into a stable isomer. In collisions of CH4+ with CH4 or CD4, there is significant scrambling and one would need to use differential scattering selection for getting ions produced exclusively via a specific mechanism. There have been several low temperature ion trap studies leading to CH5+, e.g., simply via radiative association of CH3+ with H2 or via hydrogen abstraction in CH4(+) + H2 collisions. Very interesting and in some cases unforeseen observations have been made by using deuterated variants in low temperature collisions. A general conclusion is that H-D exchange is not only influenced by the differences in zero point energies but that symmetry selection rules can significantly restrict the scrambling. For example, conservation of nuclear spin may allow one to synthesize specific CD3H2+ ions with a local ortho hydrogen rotator via radiative association. Cold trapped CH5+ ions have been probed by collisions with HD. Despite the high sensitivity of the trapping technique, no H-D exchange could be observed at all while a few isotopic equivalents of CH7+ grow via radiative association. Finally, our most recent activities are briefly mentioned, probing cold CHR+ ions via collisions with slow H or D atoms. This survey ends with a conclusion and an outlook. It is very sure that all traditional methods of collisional probing are unable to provide evidence for different CH5+ isomers. If, however, spectroscopy, low temperature collision dynamics, multi-electrode traps and supersonic or effusive beams are combined in a suitable way, one may succeed in probing single states of unperturbed cold ions at low temperatures. PMID- 19787986 TI - Comparison of the cis-bending and C-H stretching vibration on the reaction of C2H2+ with H2 using laser induced reactions. AB - Laser induced reaction (LIR) of C2H2(+) + H2 in a 22-pole ion trap at 90 K has been employed to detect the v3 C-H stretching vibration and the v5 cis bending vibration of the acetylene parent ion using the wide tunability of the free electron laser FELIX. The vibrational frequency of the bending vibration, omega5, and the corresponding Renner-Teller parameter, epsilon5, are determined to be 710 cm(-1) and 0.03, respectively. These results differ quite substantially from previous experimental work but are in line with the most recent and advanced theoretical work. The dependence of the LIR-signal of the two vibrational modes is studied systematically with respect to the laser power, storage time, and number density of the hydrogen collision partner. A reaction scheme describing all steps involved in the LIR process is set up. The corresponding rate equation system is solved numerically. From this solution the lifetimes for the vibrational excited states, tau3 = (3 +/- 1) ms and t5 = (200 +/- 50) ms and the vibrational dipole moments micro3 = 0.19(2) D and micro2 = 0.21(2) D are determined under the assumption that the excited parent ion relaxes or reacts with a net rate coefficient equal to the Langevin limit. The lifetime for the C-H stretching vibration is in agreement with a previous LIR experiment and with ab initio calculations. C-H stretching turns out to be about an order of magnitude more efficient than bending in promoting hydrogen abstraction. This strong mode dependence is discussed on the basis of the energetics for hydrogen abstraction and a possible inhibition of complex formation in the entrance channel of the C2H2+..H2 collision system. PMID- 19787987 TI - A petition to Mr Peel: Gideon Mantell and the trial of Hannah Russell. AB - In the summer of 1826, Hannah Russell was tried for petty treason, viz. the murder of her husband, Benjamin Russell, by poisoning. Their lodger, Daniel Leney, was indicted as her accomplice. The exact circumstances surrounding the death were unclear but Hannah was known to have purchased white arsenic (arsenious oxide). A local surgeon, Thomas Evans, supported at the post-mortem examination by two further surgeons, not only reported severe corrosion of the gastrointestinal tract, but also the recovery of nearly an eighth of an ounce of arsenic from the victim's stomach. Both accused were convicted and sentenced to death. Leney was executed, but Hannah Russell was respited because the trial judge, Sir Robert Graham, had doubts as to a direction he had given to the jury. The surgeon and paleontologist Gideon Mantell took up her case, stressing that death from arsenic could not have taken place as quickly as was alleged and maintaining that the chemical evidence of arsenic poisoning was inconclusive. He gained the support of some eminent chemists and physicians. Subsequently, forensic toxicologists [Sir] Robert Christison and Alfred Swaine Taylor pointed out that Mantell's arguments as to the possible time to death in arsenic poisoning were quite wrong. Moreover, Evans gave details of the analyses he and his colleagues had undertaken to Christison, who pronounced the findings sound, as indeed did Mantell after Evans and his colleagues published details of their investigations in the Sussex Advertiser. Papers in The National Archives show that Hannah was pardoned for the offence for which she was indicted, leaving it open to prefer a lesser charge. That this was never done may have been due to Mantell's campaign, at least in part, but the pardon she did receive was due to the concern of the trial judge as to the implications of the evidence presented at trial. PMID- 19787988 TI - Challenges at the interface of working between mental health services and the criminal justice system. AB - Provision of mental health reports for defendants in contact with the criminal justice system is problematic. This paper explores factors that facilitate the flow of information on a defendant between the courts and the mental health services. It identifies key challenges to this information transfer from a court worker's perspective. It also explores potential mismatches in the expectations held by the criminal justice system and the mental health services of the timeframes in which reports should be delivered and examines the perceived usefulness of reports. In Part 1, questionnaires were distributed to a population of 2107 court workers. In Part 2, monitoring forms were completed by court and health professionals on each report request made over a seven month period. Three key challenges to information transfer were identified: delays in report production, perceived inadequacies in the report content and report funding. Perceived timelines within which respondents believed reports should be delivered varied and there is a mismatch between the expectations of the two services. Perceptions on the usefulness of court reports also varied. Poor inter-agency communications are caused by lack of a clear, shared protocol outlining agreed timelines, report content and lines of responsibility relating to resource provision. Clear service level agreements are required between services to achieve clarity. PMID- 19787989 TI - An audit of parents'/guardians' wishes recorded after coronial autopsies in cases of sudden unexpected death in infancy: issues raised and future directions. AB - In the U.K., cases of sudden unexpected death in infancy are under the jurisdiction of the Coroner and consent for a post-mortem is not required. Prior to the Human Tissue Act 2006 (HTA) there was also no requirement to request retention of tissue (blocks and slides). The HTA stipulates that parental/ guardian consent is mandatory to retain or dispose of all tissues after the Coroners' purposes have been fulfilled. In 2007, in order to avoid confusion with the consent needed for hospital post-mortems, a new form was introduced by Sheffield Children's Hospital NHS Foundation Trust (SCH) called Record of parents'/guardians'wishes regarding samples taken at a Coroner's post mortem. This version specifically asks if blocks and slides may be retained as part of the medical record, or are to be disposed of, and for parental agreement (or not) for the frozen tissue, blocks and slides to be used for education, audit, quality control and medical research. One hundred and nineteen Coroners' postmortems covering the years 2006-2007 were reviewed. All parents/guardians (P/G) were contacted and the outcomes of P/G wishes recorded by SCH staff, Coroners' Officers (CO) and Police Family Liaison Officers (PFLO) were analysed and compared (44% from CO were outstanding at the time of audit). Any delay in recording P/G wishes by these three groups was also compared. In 2006, parental agreement to the use of blocks and slides for education, audit, quality control and medical research was 94%, 77% and 75% for SCH, CO and PFLO, respectively. In 2007 it was 84%, 37% and 100% for the same groups. Permission for the retention of frozen tissue given to SCH, CO and PFLO was 90%, 62% and 100% in 2006 and 90%, 44% and 100% in 2007, respectively. Cases where parents did not wish for the retention or use of tissue (including blocks and slides) were 3%, 15% and 0% in 2006 for SCH, CO and PFLO respectively, and 0% for all groups in 2007. Training of staff in all aspects of post-mortem and bereavement care is essential for ascertaining parental wishes. Families should be provided with the knowledge that allows them to make informed choices. The analysis of the results of the audit supports this view. PMID- 19787990 TI - Train-related suicides in Milan, Italy: analysis of cases 1993-2008. AB - Evidence of the frequent use of mainline and metropolitan trains as a means of suicide in and around Milan prompted the authors to analyse the occurrence of this event between 1993 and 2008 in Milan, examining data from the Institute of Legal Medicine. The 155 selected cases were analysed for various aspects, including the chronology and dynamics of the event, the personal, epidemiological and psychiatric profile of the victims and the features of the injuries found during autopsy. PMID- 19787991 TI - Organ donation in France: legislation, epidemiology and ethical comments. AB - The Bioethics Laws revised in 2004 have defined rules concerning organ donation and transplantation. They have also permitted the creation of the French Biomedicine Agency which guarantees the right of enforcement. In France there are three situations in which organs may be harvested: from cadaveric donors, from living donors and, since 2005, from non heart beating donors. Organ harvesting from cadaveric donors is permissible if the deceased did not make known his refusal during his lifetime (this may be recorded in the national registry set up for this purpose). The rule of presumed consent also applies in the case of organs taken after cardiac arrest. With regard to organ harvesting from living persons, a panel of experts is required to give approval. The recipient's spouse, brothers or sisters, sons or daughters, grandparents, uncles or aunts and first cousins may be authorised to donate organs, as well as the spouse of the recipient's father or mother. The donor may be any person who provides proof of having lived with the recipient for at least two years. Some ethical questions will need to be resolved; for example the relevance of maintaining the EEG for brain death diagnosis, enforcement of the law on presumed consent, the real nature of the will of living donors and the definition of death. PMID- 19787992 TI - Offender-victim body mass ratio and the decision to arrest in cases of intimate partner violence. AB - As a result of the growing trend toward criminalisation of cases of domestic violence, there has been a great increase in the number of jurisdictions in the United States that have implemented 'pro-arrest' and 'mandatory arrest' laws. One of the objectives of this legislation is to encourage arrest when there is probable cause to believe that an assault has occurred. Along with the increase in the overall rate of arrest for intimate partner violence there has been a dramatic increase in the arrest of both the parties involved in an incident. In these cases the police do not identify any one party as the primary aggressor. A number of factors may account for this. Analysing these factors can prove beneficial in guiding protocol design and the arresting officer's decision-making process. A yet untested factor that may help explain police arrest practices concerns the relative body mass between the two parties and whether the police use this factor to determine which party is the primary offender. In this study we examine the basic relationship between offender and victim body masses and arrest decisions in 950 cases from police departments in four states: Connecticut, Idaho, Virginia and Tennessee. Our analysis finds that a significant correlation exists between offenders' and victims' body masses, and the resulting arrest decisions. The cause for this relationship remains unspecified, but may involve several factors such as the ability of a larger offender to inflict trauma on a smaller victim, or simply an arresting officer's perception of offender ability to inflict trauma. The cause of this correlation may have significant implications for arrest protocols in those states currently honouring pro-arrest legislation in cases of domestic violence, and those jurisdictions considering them. PMID- 19787993 TI - Autopsy findings of suicidal deaths committed by firearms in Ankara, Turkey. AB - The purpose of this study was to examine autopsy findings from suicidal deaths using firearms in Ankara, Turkey, and to compare the results with those reported from other studies. We retrospectively evaluated suicidal deaths by firearms referred for autopsy to the Morgue Department, Institute of Forensic Medicine, between 2002 and 2004. Results were subjected to discriminant analyses using SPSS 11.5 package program. One hundred and fifteen cases (83.3%) were male, the ratio of male to female was 5 to 1 and the mean age was 31.96 years (range:12-85 years). Forty cases were aged between 12 years and 20 years, 28 were aged between 0 and 18 (20.29%). One hundred and thirty-three cases (96.4%) had one bullet entry and five cases (3.6%) had two bullet entries. Out of 143 bullet entries, 116 (81.12%) were caused by gunshots fired from contact or near contact range. Regarding bullet entry sites, 103 (72.03%) were on the head with 56 (54.37%) located on the right temporal region. Gunshot related crimes are an increasing cause for concern in Turkey. However, a simple preventive measure may prevent the suicidal deaths of many young people. PMID- 19787994 TI - Experimental analysis of the relationship between simulated low-velocity rear-end collisions and fetal outcomes of pregnant rats. AB - Our study aimed to define the risk for a human fetus of rear-end vehicle collisions. We therefore performed drop tests using pregnant SLC Wistar rats. Pressure applied to the rat uterus and rectum at various stages of acceleration was measured. After being dropped, rats were observed throughout pregnancy. At birth, the numbers, weight and the occurrence of physical anomalies among pups were followed-up for 28 days. Uterine pressure increased exponentially from 2.1 +/- 0.3 kPa at 19-fold gravity (G) to 13.9 +/- 0.8 kPa at 92-fold G. These values are much lower than the mechanical failure level of human fetal membrane tissue or of those at risk of adverse fetal outcomes. Neither the average number of offspring per pregnant rat nor the average body weight of newborn pups differed significantly between control pregnant rats and those which had been exposed to acceleration of 46-fold or 92-fold G. Other variables such as maternal mental distress, motion effects of amniotic fluid or seatbelt-induced uterine injuries might contribute to fetal loss. PMID- 19787995 TI - Non-fatal injuries to the cervical spine facet joints after a fatal motor vehicle crash: a case report. AB - Injuries to the lower cervical spine facet joints may be identified in people killed in road traffic crashes. However, many of these injuries are not identified on diagnostic imaging procedures despite histological evidence of injury. This case report illustrates possible non-lethal pathological conditions in the facet joints following fatal road traffic trauma. The cervical spine segments C4 to C7 were removed en bloc and examined with magnetic resonance imaging, computed tomography and conventional radiology. The specimen was fixated in alcohol, embedded in methylmethacrylate, and divided into 3 mm thick parasaggital slices from where 10 microm thick sections were produced and evaluated with light microscopy. Injuries identified on microscopy included haemarthrosis, capsular avulsion, synovial fold contusions and subchondral fractures. None of the injuries were detected on diagnostic imaging or at routine autopsy. Discrete injuries to the cervical spine facet joints were identified using supplemental histological procedures in this case report. Post-mortem diagnostic imaging did not reveal these injuries and future studies should investigate the nature, prevalence and clinical relevance of such lesions. PMID- 19787996 TI - An unusual fatal construction site injury in India: a case report. AB - A 35-year-old male, employed at a construction site, accidentally injured himself when an iron rod, which he was handing up from the ground floor to a fellow worker standing on the first floor, fell backwards. It pierced his suprascapular fossa on the right side, damaging great vessels and the tricuspid valve, and entered the pericardial cavity after puncturing the posterior wall of the right ventricle. The iron rod was taken out by fellow workers at the site and the injured man was immediately taken to a nearby clinic where he was resuscitated and the wound was stitched. He was later transferred to a tertiary care hospital where he died about an hour after admission. Though many bizarre injuries have been reported at construction sites, a fatal injury of this nature deserves a mention in the forensic literature. PMID- 19787998 TI - Criminal evidence. R v Michael Christopher Horncastle (1) David Lee Blackmore (2): R v Abijah Marquis (1) Joseph David Grahan (2): R v David Michael Carter (2009). PMID- 19787997 TI - Civil procedure fraud. Anita Shah v Wasim UI-Haq (1) Samara Khatoon (2) Zahida Parveen (3) (2009). PMID- 19787999 TI - Human rights. DS (India) v Secretary of State for the Home Department (2009). PMID- 19788000 TI - The pharmaceutical package of the European Commission: empowerment for patients? PMID- 19788001 TI - Advance health care directives: towards a coordinated European policy? AB - The aim of this paper is to compare the different existing approaches to advance health care directives within the European context, and to explore the possibility of reaching a deeper consensus among countries on this subject. To this end, it first discusses the shortcomings of Article 9 of the Council of Europe's Biomedicine Convention. Second, it offers a comparative analysis of the legal status of advance directives in a number of European countries. Finally, it presents the conclusions of an international interdisciplinary workshop focused on this topic that was held in Zurich in June 2008. PMID- 19788002 TI - Biobank research: reporting results to individual participants. AB - Over the last years we conducted an extensive study on the question whether and, if so, how, any results to be derived from research with large scale biobanks shoud be communicated to individual research participants. More specifically, our research intended (1) to assess the attitudes and information preferences of major stakeholders (participants/researchers), and (2) to examine whether there are any legal obligations of researchers to provide feedback to individuals. Our aim was to elaborate a general normative framework that could provide (further) guidance in this matter and be taken into account in the establishment and operation of biobanks. In this article, we first summarize the results of the empirical study on attitudes and preferences; subsequently, address the legal aspects. The article ends with a section that discusses our main findings and provides the basis for the guiding principles we propose; the principles themselves are located in an Annex. PMID- 19788003 TI - Taking temperature--a review of European Union regulation in nanomedicine. AB - Nanomedicine, the application of nanotechnology to healthcare offers numerous improvements to medical diagnosis, drug delivery, therapy and implants. The potential impact of nanomedicine is foreseen radically to change health care; however it also challenges existing perceptions, dynamics and standards relating to ethics, safety and governance. This paper introduces the emerging field of nanomedicine and then proceeds to detail the current regulatory framework and regulatory bodies in the European Union relating to medicinal products, medical devices, biologics and therapies. This is followed by a detailed analysis of two nanomedical applications in the context of regulatory challenges. The paper concludes with a discussion of the adequacy of the current regulatory regime in Europe and where problems are likely to arise as nanomedicine evolves. PMID- 19788004 TI - Pre-reading mammograms by specialised breast technologists: legal implications for technologist and radiologist in The Netherlands. AB - This paper focuses on the legal implications in terms of duties and responsibilities for radiologists and radiologic technologists of independent pre reading of mammograms by radiologic technologists, so patients could be discharged without being seen by a radiologist. Pre-reading could be effectuated when preconditions are met to perform reserved procedures by unauthorised professionals as stated in the Individual Health Care Professions (IHCP) Act. Furthermore, compliance with a protocol or code of conduct in combination with adequate training and supervision should be sufficient to disprove potential claims. For a wide implementation, pre-reading should be well-embedded in legal rules and should answer the professional standard of care. PMID- 19788005 TI - ECHR 2009/9 Case of Schlumpf v. Switzerland, 8 January 2009, no. 29002/06 (First section). PMID- 19788006 TI - ECHR 2009/10 Case of Dauti v. Albania, 3 February 2009, no. 19206/05 (Fourth section). PMID- 19788007 TI - ECHR 2009/11 Case of Silih v. Slovenia, 9 April 2007, no. 71463/01 (Grand Chamber). PMID- 19788008 TI - ECHR 2009/12 Case of Women on Waves and others v. Portugal, 3 February 2009, no. 31276/05 (Second Section). PMID- 19788009 TI - ECHR 2009/13 Case of K.H. and others v. Slovakia, 28 April 2009, no. 32881/04 (Fourth Section). PMID- 19788010 TI - ECJ 2009/03 Commission of the European Communities v. Kingdom of Spain, 5 March 2009 (C-88/07). PMID- 19788011 TI - ECJ 2009/04 Hartlauer Handelsgesellschaft mbH v. Wiener Landesregierung, Oberosterreichische Landesregierung, 10 March 2009 (C-169/07). PMID- 19788012 TI - Scotch broom, Cytisus scoparius. PMID- 19788013 TI - The role of viruses in the development and exacerbation of atopic disease. AB - OBJECTIVE: To examine data in support of the viral hypothesis of atopic disease. DATA SOURCES: We retrieved review articles and original research from MEDLINE, OVID, and PubMed (1950-June 2009) that addressed our topic of interest, using the terms respiratory virus, asthma, IgE, atopy, and viral-induced wheeze. STUDY SELECTION: Articles were selected for their relevance to viruses and their role in asthma. RESULTS: Much of the data in support of the viral role in asthma focuses on rhinovirus and respiratory syncytial virus. Epidemiologic studies have used factors such as day-care and family size as surrogates for infection in studies that support and negate the role of viruses in the development of asthma. A large volume of literature supports the theory that virus exacerbates preexisting asthma by setting off the inflammatory cascade. No mechanistic studies fully explain how viral infections can translate or exacerbate atopic disease. We provide information from our mouse model that suggests that dendritic cells, IgE, and FcepsilonRI are critical to the induction of atopy. Studies of patients taking antiviral agents (e.g., ribavirin or palvizumab) support the notion that interfering with respiratory viral infections may decrease the development of atopy. CONCLUSIONS: Many studies suggest strongly that viral infections may predispose patients to the development of asthma and other atopic diseases. Further, mechanistic studies are necessary to allow for the development of targeted therapeutics to prevent the translation of viral into atopic disease. PMID- 19788014 TI - Sleep disturbance in persistent allergic rhinitis measured using actigraphy. AB - BACKGROUND: Tiredness, fatigue, and impaired quality of life are common in patients with persistent allergic rhinitis (PAR). These symptoms may also be associated with reduced sleep quality in individuals with rhinitis. OBJECTIVE: To determine whether sleep disturbance can be detected using actigraphy in patients with PAR. METHODS: Ten house dust mite-allergic rhinitic patients and 10 nonallergic nonrhinitic control subjects were studied for 5 consecutive days and night. Continuous activity monitoring during the study period using actigraphy was used to obtain markers of sleep quality, such as sleep onset, sleep duration, and sleep fragmentation. In addition, participants recorded in a sleep diary the time they went to bed, the time they went to sleep, the time they awoke, and the quality of their sleep. RESULTS: Allergic rhinitic patients were found to have an increased fragmentation index value, indicative of reduced sleep quality and increased sleep disturbance, compared with the control group (P = .007). CONCLUSIONS: Using actigraphy, we identified specific sleep disturbances in patients with PAR that may result in the increased tiredness, fatigue, and impaired quality of life typically experienced in such patients. PMID- 19788015 TI - Effect of smoking on symptoms of allergic rhinitis. AB - BACKGROUND: Tobacco smoking is common in patients with allergic rhinitis. OBJECTIVE: To examine the impact of smoking on allergic rhinitis. METHODS: Two cross-sectional studies (performed between March 1, 2002, and February 28, 2003) assessed the impact of tobacco smoking on the symptoms and quality of life of untreated patients with diagnosed allergic rhinitis who had consulted with primary care physicians (472 patients) and specialists (672 patients). Both studies used the same methods and were combined. Rhinitis was classified according to the Allergic Rhinitis and its Impact on Asthma initiative. The European Community Respiratory Health Survey questionnaire on smoking and the disease-specific Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) were used. RESULTS: A total of 20.8% of the patients were smokers and 10.9% were ex smokers. More than 78% of the patients had moderate to severe symptoms of rhinitis. Fewer patients had moderate to severe nasal pruritus or loss of smell. There appeared to be no significant difference in the severity of nasal symptoms, depending on the smoking status. Moderate to severe nasal obstruction was observed in 78.8% of the nonsmokers, 79.0% of the smokers, and 77.4% of the ex smokers. Overall and individual domain scores in the RQLQ were not altered by the smoking status. The overall median (25th-75th percentiles) RQLQ score was 2.8 (2.1-3.5) in nonsmokers, 2.7 (2.0-3.5) in smokers, and 2.7 (1.9-3.5) in ex smokers. CONCLUSIONS: In the present study, which was performed with a large number of untreated patients with a diagnosis of allergic rhinitis, smoking was found not to alter nasal symptoms or nasal-specific quality of life. PMID- 19788016 TI - Relationship between bronchial hyperreactivity and asthma remission during adolescence. AB - BACKGROUND: Many children with asthma outgrow this disease after the onset of puberty. However, the precise mechanism of outgrowing asthma in children is still unclear. OBJECTIVE: To evaluate the characteristics of respiratory physiology during adolescence. METHODS: The results of the lung function test and methacholine inhalation challenge were prospectively evaluated in adolescent patients with asthma with and without symptoms. One hundred sixty children with asthma participated. Twenty-eight children had symptom-free adolescent asthma (i.e., remission asthma) (boy to girl ratio, 16:12; mean age, 14.6 years), 25 had intermittent adolescent asthma (boy to girl ratio, 16:9; mean age, 14.9 years), and 47 had symptomatic adolescent asthma (boy to girl ratio, 27:20; mean age, 12.7 years). For comparison purposes, 60 younger children with symptomatic asthma participated. The parameters of bronchial hyperresponsiveness, baseline respiratory resistance, threshold of methacholine (Dmin) (bronchial sensitivity), and speed of bronchial constriction (Sm) (bronchial reactivity) were measured by methacholine inhalation challenge using the continuous oscillation method. RESULTS: There was no significant difference in lung function results, such as forced vital capacity and forced expiratory volume in 1 second, between the intermittent asthma and the remission asthma groups. Also, there was no significant difference in baseline respiratory resistance and Dmin between the 2 groups. However, the value of Sm of the remission asthma group was significantly lower than that of the intermittent asthma group (P = .02) and the symptomatic asthma group (P = .02). CONCLUSIONS: These data show that the adolescents with asthma remission showed a significant decrease of Sm, whereas Dmin was not changed. These results suggest one of the mechanisms by which asthma is outgrown in children and explain the common clinical aspects of adolescent asthma, such as symptom-free but bronchial hyperresponsive asthma. PMID- 19788017 TI - Exhaled nitric oxide as a predictor of exacerbation in children with moderate-to severe asthma: a prospective, 5-month study. AB - BACKGROUND: Inhaled corticosteroids (ICSs) are recommended as the first line of treatment in children with moderate-to-severe asthma. Exhaled nitric oxide (ENO) has been proposed as a clinically useful marker of control that might help identify patients in whom ICS dose may be safely reduced. OBJECTIVE: To evaluate the ability of ENO to predict future asthma exacerbations in children with moderate-to-severe asthma undergoing ICS tapering. METHODS: This is an observational study with no control group. ENO was measured biweekly for 14 weeks in 32 children with moderate-to-severe asthma who were undergoing ICS tapering. Clinical evaluations and spirometry were performed concomitantly, and families kept daily diaries to record symptoms between visits. We used generalized estimating equations to model the In (odds) of an asthma exacerbation in the subsequent 2-week interval as a function of ENO level at the start of the interval while adjusting for age, sex, asthma severity, and current medication use. RESULTS: We were able to successfully lower ICS doses in 10 (56%) of the 18 children with moderate asthma and in 3 (21%) of the 14 children with severe asthma. In 83 of the 187 follow-up clinical evaluations, children were determined to have had an exacerbation during the preceding 2 weeks. ENO levels, whether expressed as a continuous variable or dichotomized, were not associated with future risk for exacerbations in either unadjusted or adjusted models. CONCLUSION: ENO was not a useful clinical predictor of future asthma exacerbations for children with moderate-to-severe asthma undergoing ICS tapering. PMID- 19788018 TI - Baseline characteristics of patients enrolled in EXCELS: a cohort study. AB - BACKGROUND: The Epidemiologic Study of Xolair (omalizumab): Evaluating Clinical Effectiveness and Long-term Safety in Patients with Moderate-to-Severe Asthma (EXCELS) is a unique opportunity to evaluate the prospective, long-term clinical safety and effectiveness of the anti-IgE antibody omalizumab (Xolair) in real world clinical practice. OBJECTIVES: To describe the study design and study cohorts of EXCELS at baseline and to compare the characteristics of this population with other large asthma cohorts. METHODS: Patients with moderate-to severe persistent asthma and a positive skin test result or in vitro reactivity to a perennial aeroallergen were eligible for EXCELS. Two cohorts of patients with asthma were enrolled: those treated with omalizumab and those not treated with omalizumab. We analyzed baseline demographic and clinical characteristics, including asthma history and control and allergy history. RESULTS: Large proportions of patients enrolled in EXCELS had historically severe and poorly or not well-controlled asthma at the time of enrollment, objective evidence of airway obstruction, a history of long-term oral corticosteroid use, and/or other allergic disorders. Minor differences were observed between the omalizumab and nonomalizumab cohorts. Our total patient cohort was generally similar to other large cohorts. In a subgroup analysis, patients who had received omalizumab within 7 days before enrollment had more severe asthma and greater degrees of impairment at baseline than nonomalizumab patients. CONCLUSIONS: This study of baseline characteristics in EXCELS offers a unique opportunity to better understand the history of allergic patients with moderate-to-severe asthma in a real-world treatment setting. This analysis of EXCELS baseline data sets the foundation for long-term assessment of the safety and effectiveness of omalizumab. PMID- 19788019 TI - Changes in weather and the effects on pediatric asthma exacerbations. AB - BACKGROUND: Pediatric asthma exacerbations may correlate with changes in weather, yet this relationship is not well defined. OBJECTIVE: To determine the effects of fluctuations in climatic factors (temperature, humidity, and barometric pressure) on pediatric asthma exacerbations. METHODS: A retrospective study was performed at 1 large urban hospital during a 2-year period (January 1, 2004, to December 31, 2005). Children presenting to the emergency department (ED) for an asthma exacerbation were included. Data on climactic factors, pollutants, and aeroallergens were collected daily. The relationship of daily (intraday) or between-day (interday) changes in climactic factors and asthma ED visits was evaluated using time series analysis, controlling for seasonality, air pollution, and aeroallergen exposure. The effects of climactic factors were evaluated on the day of admission (T=0) and up to 5 days before admission (T-5 through T-1). RESULTS: There were 25,401 asthma ED visits. A 10% intraday increase in humidity on day T-1 or day T-2 was associated with approximately 1 additional ED visit for asthma (P < .001 and P = .01, respectively). Interday changes in humidity from day T - 3 to T-2 were also associated with more ED visits (P < .001). Interday changes in temperature from T-1 to T = 0 increased ED visits, with a 10 degrees F increase being associated with 1.8 additional visits (P = .006). No association was found with changes in barometric pressure. CONCLUSION: Fluctuations in humidity and temperature, but not barometric pressure, appear to influence ED visits for pediatric asthma. The additional ED visits occur 1 to 2 days after the fluctuation. PMID- 19788020 TI - Initial test of the seattle asthma severity and control questionnaire: a multidimensional assessment of asthma severity and control. AB - BACKGROUND: The Seattle Asthma Severity and Control Questionnaire (SASCQ) was designed as a short, sensitive, and quantitative measure of asthma severity, impairment, and risk. OBJECTIVES: To evaluate the distribution of responses to the SASCQ in a diverse asthma population and to determine whether the questionnaire is associated with other measures of asthma severity and control. METHODS: A cross-sectional study of 188 asthmatic patients was conducted in a large academic primary care network. Asthma severity was confirmed in a subgroup of 44 patients by means of an in-person interview and lung function measurement. RESULTS: The SASCQ score had a nearly normal distribution across the heterogeneous population and less of a floor effect than the number of asthma free days. The SASCQ score showed a higher symptom burden in the mildest asthmatic patients compared with nonasthmatic controls. Asthma severity evaluated using the questionnaire was correlated with asthma severity evaluated by means of in-person interview and with controller medication class. The SASCQ score was associated with primary care visits for asthma, emergency department treatment for asthma, days missed from work, and confidence to control asthma symptoms; the associations between these measures of impairment and risk were all stronger for the SASCQ score than for asthma-free days. CONCLUSIONS: The SASCQ is a quantitative measure of asthma that accurately discriminates between established levels of asthma severity and that is associated with other measures of asthma control and risk. PMID- 19788021 TI - Lupin allergy and lupin sensitization among patients with suspected food allergy. AB - BACKGROUND: Lupin, a legume with good nutritional value, is used in food production today, most often in bakery products. Lupin sensitization is often seen among patients with reactions to legumes, but the number of reports describing lupin anaphylaxis is also increasing. OBJECTIVE: To investigate the occurrence of lupin sensitization, cross-reactivity, and lupin allergy among patients with suspected food allergy in Finland, where lupin is a labeled ingredient in few products. METHODS: The occurrence of positive skin prick test (SPT) reactions to lupin seed flour was studied among 1522 patients with suspected food allergy from November 1, 2005, through December 31, 2007. Clinical histories and diagnostic SPT results were analyzed among patients with positive SPT results to lupin. For 1 patient, ImmunoSpot and lupin radioallergosorbent test inhibition methods were used. RESULTS: Lupin sensitization was shown in 25 of 1522 patients (1.6%), and probable lupin allergy was diagnosed in 7 of 25 patients, in whom the clinical symptoms varied from anaphylaxis and respiratory symptoms to contact urticaria and itchy mouth. Cross-reactions or concurrent reactions to other legumes were seen in 18 of 25 patients. CONCLUSIONS: Clinically relevant lupin allergy often occurs in patients without atopic background or other food allergies, although lupin sensitization most commonly seems to represent cross-reactivity to other legumes. The occurrence of lupin allergy in a country where lupin has not been traditionally used is surprisingly common, suggesting that short-term use of modest amounts of lupin can cause serious allergic reactions. PMID- 19788022 TI - Increased oxidative stress in the airway and development of allergic inflammation in a mouse model of asthma. AB - BACKGROUND: The exact pathogenic role of oxidative stress in the development of allergic airway inflammation is still largely unknown. OBJECTIVE: To investigate a possible link between increased pulmonary oxidative stress and the pivotal features of asthma during the mounting of an allergic inflammatory response. METHODS: To determine the relationship between oxidative stress and allergic inflammatory responses, we evaluated the sequential kinetics of oxidative stress in the lung, the development of airway inflammation, mucin hypersecretion, and airway hyperresponsiveness (AHR) in an ovalbumin (OVA)-sensitized and challenged mouse with and without antioxidant. Parameters were measured at 9 points for more than 28 days, starting from the first day of OVA challenge with or without antioxidant treatment. The ratio of reduced to oxidized glutathione in the lungs and levels of intracellular reactive oxygen species (ROS) in the bronchial epithelium were serially measured. Bronchoalveolar lavage fluid cells, histopathologic features, and AHR were analyzed at the same time points. RESULTS: The reduced to oxidized glutathione ratio was reduced from immediately after OVA challenge to day 1, remained at this level until day 1, and rapidly recovered to the normal level after more than 2 days. Intracellular ROS levels in the bronchial epithelium followed similar kinetics. The inflammatory cells in bronchoalveolar lavage fluid reached a maximum of 3 days and decreased progressively thereafter. Histopathologic examination revealed that substantial airway inflammation persisted through day 28. The proportion of mucin-producing epithelial cells significantly increased after day 1, reached a maximum at day 3, and remained at this level until day 5. The AHR peaked on day 1 and normalized within 5 days. The pretreatment of antioxidant significantly reduced not only the increased ROS levels but also development of other phenotypes of asthma. CONCLUSION: These results indicate that increased oxidative stress in the lung precedes other pivotal phenotypes of allergic airway disease, suggesting a critical role for increased oxidative stress in the induction of allergic airway inflammation. PMID- 19788023 TI - A randomized, comparative study of formoterol and terbutaline dry powder inhalers in the treatment of mild to moderate asthma exacerbations in the pediatric acute care setting. AB - BACKGROUND: Formoterol is a fast-acting, long-acting beta-agonist. Its on-demand use by outpatients has been beneficial in controlling asthma. OBJECTIVE: To evaluate the efficacy of formoterol as rescue medication for pediatric asthma exacerbation. METHODS: A randomized, double-blind study was conducted on parallel groups involving 79 pediatric patients (mean [SD] age, 9.92 [2.5] years) with mild to moderate asthma exacerbations. They were treated with up to 3 doses of formoterol aerolizer, 12 microg, or terbutaline Turbuhaler, 0.5 mg (dry powder inhalers). Respiratory rate, clinical score, pulse oximetry, and spirometry were analyzed at baseline and 15 minutes after administration of each bronchodilator dose. All the patients received oral prednisolone, 1 mg/kg, at study entry, followed by a single daily dose for 4 days. Forty-one patients were treated with formoterol and 38 with terbutaline. The groups were comparable in age and in severity of asthma exacerbation. RESULTS: Both treatments resulted in similar clinical and functional improvement; 37 patients (47%) required 1 bronchodilator dose. Increases of 19.5% and 15.3% occurred in forced expiratory volume in 1 second in the formoterol and terbutaline groups, respectively. Therapeutic failures occurred in 2 patients. No adverse effects were observed. At 1-week follow-up, patients were stable, with pulmonary function close to normal. CONCLUSION: Formoterol therapy was at least as effective as terbutaline therapy in children and adolescents with mild and moderate asthma exacerbations. PMID- 19788024 TI - Economic evaluation of sublingual immunotherapy vs. symptomatic treatment in allergic asthma. AB - BACKGROUND: The worldwide increased prevalence of allergic diseases, and especially of respiratory allergy, is paralleled by increased health costs. This requires consideration of the cost to efficacy ratio of the available treatment to identify the optimal choice. OBJECTIVE: To compare the different economic relevance, over a long evaluation time, of symptomatic pharmacologic therapy and sublingual immunotherapy (SLIT) in patients with allergic asthma. METHODS: Seventy patients with perennial allergic asthma, sensitized to dust mites, were enrolled; 50 of these patients were treated with SLIT against house dust mites and 20 were treated with symptomatic drugs. The patients were evaluated for 2 years after discontinuing immunotherapy, which was performed for 3 years, to obtain a more complete follow-up. Symptom scores, medication scores, and all other direct medical costs were evaluated with a specific questionnaire. RESULTS: Patients treated with SLIT plus drugs had a higher mean annual cost in the first year of SLIT treatment compared with patients only receiving drug treatment, but the mean annual cost became significantly lower since the end of SLIT both in the whole population and in the subgroups defined by disease severity. CONCLUSION: The economic advantage measured alongside this prospective observational study was long lasting and still present at the fifth year of the follow-up (2 years after discontinuing SLIT) and could positively be related to the persistent good clinical control of patients. PMID- 19788025 TI - Desloratadine for the treatment of cypress pollen-induced allergic rhinitis. AB - BACKGROUND: Few studies have been conducted to assess treatment options for patients with sensitivities to cypress pollens, important triggers of allergic rhinitis (AR) in the Mediterranean region. OBJECTIVE: To evaluate the effect of desloratadine, a second-generation antihistamine, on AR symptoms caused by cypress pollens native to France. METHODS: Adults (N=233) with symptomatic cypress pollen allergies were randomized to receive desloratadine, 5 mg, or placebo daily for 15 days during 2 consecutive cypress pollen seasons. The primary end point was the percentage change from baseline in morning total nasal symptom scores on day 14; secondary assessments included total symptom score, peak nasal inspiratory flow, the Rhinoconjunctivitis Quality of Life Questionnaire, and global response to therapy. RESULTS: On day 14, the desloratadine group had a significantly greater percentage decrease in total nasal symptom score vs the placebo group (-40% vs. -30%; P < .04). Similarly, on day 14, there was a 47% and 37% respective decrease in total symptom score (P = .01). Mean peak nasal inspiratory flow scores showed numeric, albeit not statistically significant, improvements from baseline through day 14 with desloratadine. A significantly greater improvement in Rhinoconjunctivitis Quality of Life Questionnaire scores occurred with desloratadine vs placebo on day 14 ( 1.4 vs. -0.9; P = .004). The mean global response to therapy was better with desloratadine vs placebo (3.4 vs. 3.9; P = .004). The adverse event rate was similar in both groups. CONCLUSION: Desloratadine is efficacious and safe for the treatment of AR induced by cypress pollens; it also improved disease-related quality of life. PMID- 19788026 TI - 11q terminal deletion disorder and common variable immunodeficiency. PMID- 19788027 TI - Microthrombocytopenia in a male infant with cytomegalovirus. PMID- 19788028 TI - The safety of omalizumab therapy in a patient with severe persistent allergic asthma and hepatitis C. PMID- 19788029 TI - Characteristics of cerebrospinal fluid flow in Cavalier King Charles Spaniels analyzed using phase velocity cine magnetic resonance imaging. AB - Syringomyelia is an important morbidity source in Cavalier King Charles Spaniels. Although abnormal cerebrospinal fluid (CSF) flow secondary to Chiari malformations is thought to cause syringomyelia in humans, this relationship is unknown in dogs. We used phase-contrast magnetic resonance (MR) imaging to evaluate CSF flow in dogs. Fifty-nine Cavalier King Charles Spaniels were assigned a neurologic grade reflecting their neurologic status. Five normal control dogs of other breeding were imaged for comparison. The presence of syringomyelia was noted from sagittal MR images. The pattern and velocity of CSF flow were assessed using phase-contrast cine MRI at the foramen magnum, C2-C3 disc space, and within syrinxes. Flow was measured most easily with the neck flexed to mimic standing. CSF flow velocity in the dorsal aspect of the subarachnoid space at the foramen magnum was significantly higher in control dogs than Cavalier King Charles Spaniels (P = 0.035). Flow was obstructed at the foramen magnum in 41 of 59 Cavalier King Charles Spaniels. Turbulent flow and jets were associated with syringomyelia presence and severity, and CSF flow velocity at C2/3 dorsally was inversely related to the presence of syringomyelia (P = 0.0197). Peak dorsal subarachnoid space CSF flow velocity at the foramen magnum and C2-C3 were together highly predictive of syringomyelia. CSF flow can be assessed in dogs using phase-contrast cine MRI. Obstruction to flow at the foramen magnum is common in Cavalier King Charles Spaniels and CSF flow pattern and velocity are related to the presence of syringomyelia. PMID- 19788030 TI - Influence of field strength on intracranial vessel conspicuity in canine magnetic resonance angiography. AB - Eight neurologically normal beagles were imaged using three-dimensional (3D) time of-flight magnetic resonance angiography (MRA) in a 3T magnetic resonance scanner. Four of the eight dogs were also imaged using a 1T unit for comparison. Ten intracranial arteries were consistently identified at 3T: external and internal carotid, basilar, vertebral, rostral cerebral, middle cerebral, caudal cerebral, rostral communicating, caudal communicating, and ventral spinal arteries. Only four were reliably identified at 1T with diagnostic spatial and contrast resolution. At 3 T, vessels as small as 1 mm were reliably detected. Vessel conspicuity was superior using the 3T system. An anatomic atlas of the canine circulus arteriosus cerebri using a 3T scan was constructed. The effect of MRA parameters on vascular spatial resolution a nd conspicuity are reviewed. PMID- 19788031 TI - Prognostic accuracy of the proventriculus: keel ratio for short-term survival in psittacines with proventricular disease. AB - The proventriculus:keel ratio was evaluated as a prognostic indicator for short term survival in parrots with proventricular disease. Measurements were made from right lateral radiographs of 41 parrots with proventricular disease. Results were compared with the previously described abnormal proventriculus:keel ratio range and to short-term clinical outcome at 1-month postdiagnosis. The ratio in all parrots was > 0.52, and 39% of parrots succumbed to their disease within 1 month of diagnosis. There was no significant association between the proventriculus:keel ratio and survival duration (P = 0.9). The proventriculus:keel ratio is a sensitive indicator of proventricular disease in parrots but is insensitive as a prognostic indicator. PMID- 19788032 TI - Computed tomography of the lung of healthy snakes of the species Python regius, Boa constrictor, Python reticulatus, Morelia viridis, Epicrates cenchria, and Morelia spilota. AB - Thirty-nine healthy boid snakes representing six different species (Python regius, Boa constrictor, Python reticulatus, Morelia viridis, Epicrates cenchria, and Morelia spilota) were examined using computed tomography (CT) to characterize the normal appearance of the respiratory tissue. Assessment was done subjectively and densitometry was performed using a defined protocol. The length of the right lung was calculated to be 11.1% of the body length, without a significant difference between species. The length of the left lung in proportion to the right was dependent on the species examined. The most developed left lung was in P. regius (81.2%), whereas in B. constrictor, the left lung was vestigial or absent (24.7%). A median attenuation of -814.6 HU and a variability of 45.9 HU were calculated for all species with no significant difference between species. Within the species, a significantly higher attenuation was found for P. regius in the dorsal and cranial aspect of the lung compared with the ventral and caudal part. In B. constrictor, the reduced left lung was significantly hyperattenuating compared with the right lung. Results of this study emphasize the value of CT and provide basic reference data for assessment of the snake lung in these species. Veterinary Radiology & PMID- 19788033 TI - Radiographic quantification of tracheal dimensions of the normal Thoroughbred horse. AB - Radiographic measurement of tracheal dimensions in the horse may be useful in evaluating upper and lower respiratory tract conditions due to the gradient of pressure changes between these areas. Lateral radiographs of the trachea of 15 normal sedated Thoroughbred horses were made at inspiration and expiration and magnification-corrected mean airway heights measured were, respectively: larynx: 5.89 and 5.86 cm; trachea at the third cervical vertebra (C3): 4.17 and 4.04cm; at the fifth cervical vertebra (C5): 3.62 and 3.59 cm; at the first thoracic vertebra (T1): 3.4 and 3.23cm; and carina: 3.85 and 4.12 cm. The ratio of airway height to nearby vertebral body lengths, at inspiration and expiration were, respectively: laryngeal height at C3: 0.56 and 0.56; tracheal height at C3: 0.4 and 0.39; at C5: 0.37 and 0.37; at T1: 0.59 and 0.59; and carina height: 0.91 and 0.94. The ratio of tracheal height to the thoracic inlet at inspiration and expiration was, respectively, 0.15 and 0.15. There was not a statistically significant association between airway diameter and phase of respiration. No association was found between tracheal height and body mass or height at the withers. Radiographic tracheal height can be measured independent of respiratory phase in sedated horses. It is suggested that the ratio of tracheal height to an adjacent bony landmark is more reliable for comparison between horses and tracheal height measurement should be made at C5, due to a lower standard deviation. If only thoracic radiographs are made, measurements of tracheal height at the thoracic inlet may be valuable. PMID- 19788034 TI - Imaging diagnosis: traumatic dural tear diagnosed using intrathecal gadopentate dimeglumine. AB - A dog with traumatic monoplegia had a spinal cord lesion, identified using conventional magnetic resonance imaging. In addition, the intrathecal use of gadopentate dimeglumine allowed identification of two sites of cerebrospinal fluid leakage from the vertebral canal, supporting a diagnosis of brachial plexus avulsion. Veterinary PMID- 19788035 TI - Imaging diagnosis--congenital venous aneurysm of the left external jugular vein. AB - Primary congenital jugular vein aneurysms are rare with only one prior report in a canine patient. Herein, we describe an 18-week-old Flat Coated Retriever dog in which ultrasound was used to diagnose a primary congenital external jugular vein aneurysm with concurrent dilatation of the internal jugular vein. The aneurysm was successfully removed and the dog remains disease free 24 months postoperatively. Histopathologic analysis was used to validate the ultrasound based diagnosis. PMID- 19788036 TI - Imaging diagnosis--enostosis-like lesion in the femur of a horse. AB - An enostosis-like lesion was diagnosed in the left femur of a Swedish Warmblood horse that had a left hindlimb lameness of 3 weeks duration. With scintigraphy using technetium 99m-hydroxymethylene diphosphonate (99mTc-HDP) a marked regional focal increase in radioactivity was identified in the medullary cavity of the left femur. Radiographically there was a corresponding focal increase in bone opacity in the middiaphysis of the left femur. Histopathologically, a 5cm area of bone matrix was present in the diaphysis of the left femur and confirmed as an enostosis-like lesion. Enostosis-like lesions should be considered as a source of pain in horses with difficult to localize, moderate to severe chronic lameness. PMID- 19788037 TI - Can sonographic findings predict the results of liver aspirates in dogs with suspected liver disease? AB - While abdominal ultrasound and ultrasound-guided fine-needle aspiration cytology are often combined to help determine the type of liver disease in dogs, little is known about the relationship that may exist between the results of these tests. We hypothesized that specific sonographic findings, or combinations of findings, may predict results of liver ultrasound-guided fine-needle aspiration cytology. Hepatic and extrahepatic sonographic findings were recorded prospectively using a standardized form in 70 dogs with clinically suspected liver disease and in which liver ultrasound-guided fine-needle aspiration cytology was performed. The predictive value of sonographic findings in regard to the category of cytology results was assessed with stepwise logistic regression analysis. Sonographic detection of a hepatic mass (> or = 3cm; risk ratio [RR] 3.83, 95% Wald confidence intervals [95% CI] 2.42-3.93, P = 0.0036), ascites (RR 3.82, 95% CI 1.94-4.28, P = 0.0044), abnormal hepatic lymph node(s) (RR 3.01, 95% CI 1.22 4.88, P= 0.0262), and abnormal spleen (RR 3.26, 95% CI 1.20-3.85, P = 0.0274) were the most predictive of liver neoplasia on cytology. Conversely, sonographic detection of hepatic nodules (< 3cm; RR 1.97, 95% CI 0.95-2.96, P = 0.0666) was most predictive of vacuolar hepatopathy on cytology. In dogs with suspected liver disease, several sonographic findings, alone or combined, are thus predictive of liver ultrasound-guided fine-needle aspiration cytology results. In the light of the fact that ultrasound-guided fine-needle aspiration cytology of the liver has limitations, these predictabilities could influence the selection of diagnostic tests to reach a reliable diagnosis. PMID- 19788038 TI - Determination of fish gender using fractal analysis of ultrasound images. AB - The gender of cod Gadus morhua can be determined by considering the complexity in their gonadal ultrasonographic appearance. The fractal dimension (D(B)) can be used to describe this feature in images. B-mode gonadal ultrasound images in 32 cod, where gender was known, were collected. Fractal analysis was performed on these images and D(B) was determined using the box counting method. A receiver operating curve (ROC) was drawn for D(B) as a test for male fish. Using a range of D(B) values, the maximum accuracy for this test was calculated and compared with the accuracy for identifying male fish by subjective analysis alone. The mean (and standard deviation) of the fractal dimension D(B) for male fish was 1.554 (0.073) while for female fish it was 1.468 (0.061); the difference was statistically significant (P = 0.001). The area under the ROC curve was 0.84 indicating the value of fractal analysis in gender determination in cod. Maximum accuracy (0.84) for D(B) as a test for male fish was obtained using the threshold value D(B) = 1.5058 compared with an accuracy of 0.78 for subjective image evaluation. The use of two thresholds, D(B) < 1.4475 (females) and D(B) > 1.5054 (males) gives an 80% certainty in the classification result. Fractal analysis is useful for gender determination in cod. This or a similar form of analysis may have wide application in veterinary imaging as a tool for quantification of complexity in images. PMID- 19788039 TI - Pathologic correlation of resistive and pulsatility indices in canine abdominal lymph nodes. AB - We assessed the ability of the resistive index (RI) and pulsatility index (PI) to allow differentiation between normal, reactive, and neoplastic lymph nodes. Forty seven medial iliac and 54 mesenteric lymph nodes from 83 dogs were evaluated sonographically. A cytologic sample was obtained in each dog that allowed categorization into one of the categories defined above. We found a significant difference in the RI and PI in nonneoplastic vs. neoplastic medial iliac and mesenteric lymph nodes. Values higher than 0.67 for the RI and 1.02 for the PI in medial iliac lymph nodes and higher than 0.76 for the RI and 1.23 for the PI in mesenteric lymph nodes had a high sensitivity and specificity for differentiating benign from neoplastic lymph nodes. PMID- 19788040 TI - Assessing Circle of Willis blood circulation in dogs with transcranial color coded duplex sonography. AB - Insonation of Circle of Willis by transcranial Doppler duplex color sonography is described in 30 healthy dogs with 15 weighing < 33 lb and 15 weighing >33 lb. Imaging was via a temporal window to explore the rostral, middle, and caudal cerebral arteries on both the left and right-hand sides; and through an suboccipital window to study the basilar artery. Normal mean values of the peak systolic velocity (PSV), end diastolic velocity, mean velocity, resistance index (RI), and pulsatility index (PI) were characterized and compared with those obtained in previous studies. There was significant differences in the PSV, RI, and PI in the rostral cerebral artery between dogs weighing < 33 vs. > 33 lb. Mean PSV was higher in weighing over 33 lb, whereas the mean resistive index and mean PI were lower in these dogs. PMID- 19788041 TI - Scintigraphic assessment of the metacarpophalangeal and metatarsophalangeal joints of horses with joint pain. AB - Our aims were to evaluate the pattern of radiopharmaceutical uptake in horses with lameness related to the metacarpophalangeal and/or metatarsophalangeal joint and compare the results with similar information from sound horses. It was hypothesized bthat there would be a difference in radiopharmaceutical uptake between the lame and contralateral limb in unilaterally lame horses and that there would be a difference between lame and sound horses. Nuclear scintigraphic images of 43 horses with forelimb lameness and 30 horses with hindlimb lameness were evaluated. In all horses lameness was improved by intraarticular analgesia of the joint, or by perineural analgesia of the palmar/plantar (at the junction of the proximal 3/4 and the distal 1/4 of the metacarpal/metatarsal regions) and palmar/plantar metacarpal/metatarsal nerves. All images were assessed subjectively and a quantitative image analysis was performed by drawing a vertical line profile through the center of each joint in the lateral images and using region of interest analysis in both lateral and dorsal/plantar images. Ratios of radiopharmaceutical uptake were compared for each region between lame and contralateral limbs in unilaterally lame horses and between lame and control horses. There was a significant difference in the ratio of radiopharmaceutical uptake in the proximal aspect of the proximal phalanx between lame and nonlame forelimbs in unilaterally lame horses and in both lame and contralateral limbs of lame horses compared with control horses for the regions of the distal aspect of the third metacarpal/metatarsal bone and the proximal sesamoid bones. However, the profile analysis was of limited clinical value. PMID- 19788042 TI - In vitro evaluation of feline leukocytes radiolabeled in whole blood with 99mTc stannous colloid. AB - Technetium-99m stannous colloid (9mTcSnC) has been used to radiolabel human leukocytes to investigate various inflammatory disorders. We investigated the in vitro behavior of feline leukocytes labeled in whole blood with 99mTcSnC. Heparinized blood samples were collected from healthy cats and divided into control and test aliquots. The latter were labeled with 99mTcSnC using a standard procedure. Leukocyte viability was determined for each sample using a trypan blue exclusion test. Labeling efficiency was determined for test aliquots. Test aliquots were layered onto Histopaque-1077 and centrifuged before measurement of radioactivity of the blood components. Leukocytes from radiolabeled and control samples were washed and incubated with opsonized zymosan particles to allow assessment of phagocytic function. Aliquots were taken from radiolabeled feline leukocyte samples at 1, 3, 4, and 7 h postlabelling. After centrifugation of each aliquot, radioactivity of the supernatant and pellet was measured and the labeling retention determined. Leukocyte viability in both radiolabeled and control samples was > 98%. The labeling efficiency was 95.2 +/- 0.14%. The distribution of radioactivity in feline blood was found to be 3.4 +/- 0.18% in plasma, 39.0 +/- 0.37% in erythrocytes, and 57.6 +/- 0.38% in leukocytes. Labeled feline leukocytes had phagocytic activity of 90.9 +/- 0.18% (control 91.3 +/- 0.15%). The radiolabeled leukocytes retained 93.4 +/- 0.19% of the radioactivity up to 7h postlabeling. 99TcSnC efficiently labeled feline leukocytes with no effect on viability and minimal effect on phagocytic function. The percentage retention of radioactivity by the leukocytes was still high at 7h postlabeling. PMID- 19788043 TI - Assessment of the accuracy and precision of a patient immobilization device for radiation therapy in canine head and neck tumors. AB - The positioning accuracy and precision of a head and neck immobilization device for radiation therapy of tumors in the canine skull was evaluated. Nineteen dogs with a spontaneous tumor of the head were enrolled including 12 with an intracranial mass and seven with an intranasal or maxillary tumor. Three hundred thirty-three pairs of orthogonal digital portal radiographs were analyzed to assess patient displacement in the cranial-caudal, lateral, and dorso-ventral directions. The mean systematic displacement was 0.8, 1, and 0.9 mm. The mean random displacement was 1.9, 1.6, and 1.5 mm. These values resulted in an overall displacement of 2.1 mm in the cranial-caudal direction, 1.8mm in the lateral direction, and 1.7 mm in the dorsal-ventral direction. The mean displacement value of the three dimensional (3D) vector was 2.4 mm with a standard deviation of 2.1. Ninety-five percent of all vectors were < 6.4 mm. This study quantifies the precision and accuracy of this particular positioning device. Knowing the limitations and setup variability of the system being used to set patients up for daily radiotherapy is paramount to planning and delivering appropriate radiation doses, especially as more complex treatment methods are used. PMID- 19788044 TI - Effect of wetness level on the suitability of wet gauze as a substitute for Superflab as a bolus material for use with 6 mv photons. AB - Despite the availability of commercial tissue equivalent bolus material, wet gauze has an application in radiation therapy to provide superior conformance to irregular contours. Wet gauze bolus has the potential to reduce air gaps between the bolus and surface, which could decrease surface dose if sufficiently large to disrupt electronic equilibrium. Wet gauze bolus is often fabricated and wetness judged qualitatively. We assessed the effect of specific gauze wetness levels, quantified in terms of physical density, at various field sizes with respect to their effectiveness as bolus material compared with Superflab. For large fields, > 7 x 7 cm2 in this study, wet gauze sponges with a physical density of 1.02 g/cm3 performed essentially identical to Superflab; at a smaller field size the wet gauze was slightly less effective, likely due to the heterogeneity of the gauze-water matrix. Gauze that was wetter, with a physical density of 1.2 g/cm3, or less wet, with a physical density of 0.75 g/cm3 was not as effective either due to enhanced photon absorption in the wetter sponges, or less effective establishment of electronic equilibrium in the less wet sponges. The presence of an air gap under Superflab led to reduced surface dose, especially for small fields and large air gaps. Thus, if Superflab use leads to poor contact with the skin, wet gauze having a physical density of 1.02 g/cm3 can be used as a substitute. Judging the water content of wet gauze subjectively is not acceptable as over- or under wetness can lead to decreased effectiveness of the bolus material. PMID- 19788045 TI - Radiation therapy communication: equine hemangioma. AB - A 13-month-old Standardbred Colt had a recurrent hemangioma at the level of the coronary band. Multiple excisions had led to a nonhealing skin and hoof defect. Using 14 MV electrons, a total dose of 36 Gy was administered, given as six fractions of 6 Gy twice a week. Wound healing by second intention was achieved over the next 4 months and the colt began race training 6 months after the end of therapy. Twenty months later the colt is sound and there is no evidence of tumor recurrence. PMID- 19788046 TI - Statistical briefing: summarizing non-normal and ordinal data. PMID- 19788047 TI - Localization of disease-related PrP in Danish patients with different subtypes of prion disease. AB - OBJECTIVE: The transmissible spongiform encephalopathies are characterized by vacuolization, neuronal loss, gliosis and deposition of a misfolded and Proteinase K resistant isoform of the prion protein (PrP(Sc)) in the central nervous system. METHODS MATERIALS AND PATIENTS: Paraffin-embedded tissue blot (PET-blot), immunohistochemistry (IHC) and Western blotting (WB) were combined to study the morphology and localization of disease related PrP in Danish patients with different subtypes of sporadic Creutzfeldt-Jakob disease, familiar Creutzfeldt-Jakob disease and Gerstmann-Straussler-Scheinker disease. RESULTS AND CONCLUSION: There was a good morphological and anatomical concordance between what was found with PET-blot and IHC in all patients. In some specific cases, the PET-blot was superior to IHC in sensitivity. To our knowledge, this is the first report where PET-blot analysis is applied to hereditary forms of human transmissible spongiform encephalopathies and compared with sporadic cases of Creutzfeldt-Jakob disease. PMID- 19788048 TI - Homocysteine-induced endoplasmic reticulum protein (herp) is up-regulated in parkinsonian substantia nigra and present in the core of Lewy bodies. AB - BACKGROUND: Recent studies highlight the role of endoplasmic reticulum (ER) stress and aberrant protein degradation in the pathogenesis of neurodegenerative disorders. Herp which is encoded by the HERPUD 1 (homocysteine-inducible, endoplasmic reticulum stress-inducible, ubiquitin-like domain member 1) gene is a stress-response protein localized in the ER membrane of neurons and other cell types. Herp has been suggested to improve ER-folding, decrease ER protein load, and participate in ER-associated degradation (ERAD) of proteins. METHODS: Based on microarray expression profiling results we have predicted an increased expression of HERPUD1 in the substantia nigra of Parkinson's disease (PD) patients. We have now used brain tissue of some of the same and additional cases of sporadic PD to localize Herp mRNA and protein in individual cell types. RESULTS: We found expression of Herp in neurons and in glial cells including astrocytes. These findings were corroborated by in situ hybridization. Accumulation of Herp protein was also detected in the core of Lewy bodies suggesting a role in their formation. Hierarchical clustering analysis identified TWINKLE (PEO1) as the gene whose expression profile was most similar to that of Herp across the PD cohort. CONCLUSIONS: The nigral glial cells that expressed Herp at a high level resembled TUNEL-positive glia. While some of these cells likely undergo degeneration, the strong up-regulation of Herp in glia could help to explain the inflammation-like changes observed in PD ("neuroinflammation") as it has been shown that the unfolded protein response serves as an important regulator of inflammatory genes in other organs. PMID- 19788049 TI - The p62 antibody reveals various cytoplasmic protein aggregates in spinocerebellar ataxia type 6. AB - Neuronal protein aggregates are considered as pathological hallmarks of various human neurodegenerative diseases, including the so-called CAG-repeat disorders, such as spinocerebellar ataxia Type 6 (SCA6). Since the immunocytochemical findings of an initial post-mortem study using a specific antibody against the disease protein of SCA6 (i.e., pathologically altered alpha-1A subunit of the P/Q type voltage-dependent calcium channel, CACNA1A) have not been confirmed so far, the occurrence and central nervous system distribution of neuronal protein aggregates in SCA6 is still a matter of debate. Owing to the fact that the antibody against the pathologically altered CACNA1A is not commercially available, we decided to apply a recently generated p62 antibody on brain tissue from two clinically diagnosed and genetically confirmed SCA6 patients. Application of this p62 antibody revealed numerous cytoplasmic neuronal inclusions in the degenerated cerebellar dentate nucleus and inferior olive of both SCA6 patients studied, whereby a subset of these aggregates were also ubiquitin-immunopositive. In view of the known role of p62 in protein degradation as well as aggresome/sequestosome formation, the p62 aggregate formation observed in the present study suggests that SCA6 not only is associated with an impairment of the calcium channel function and an elongated polyglutamine stretch in CACNA1A, but also with a defective protein handling by the protein quality control system. PMID- 19788050 TI - Laminar distribution of the pathological changes in frontal and temporal cortex in 8 patients with progressive supranuclear palsy. AB - OBJECTIVE: To determine the laminar distribution of the pathological changes in the cerebral cortex in progressive supranuclear palsy (PSP). METHOD: The distribution of the abnormally enlarged neurons (EN), surviving neurons, neurofibrillary tangles (NFT), glial inclusions (GI), tufted astrocytes (TA), and neuritic plaques (NP) were studied across the cortex in tau immunolabeled sections of frontal and temporal cortex in 8 cases of PSP. RESULTS: The distribution of the NFT was highly variable with no consistent pattern of laminar distribution. The GI were distributed either in the lower laminae or uniformly across the cortex. Surviving neurons exhibited either a density peak in the upper laminae or a bimodal distribution was present with density peaks in the upper and lower laminae. The EN and glial cell nuclei were distributed primarily in the lower cortical laminae. There were positive correlations between the densities of the EN and glial cell nuclei and negative correlations between the surviving neurons and glial cells. No correlations were present between the densities of the NFT and GI. CONCLUSION: Cortical pathology in PSP predominantly affects the lower laminae but may spread to affect the upper laminae in some cases. The NFT and GI may have different laminar distributions and gliosis occurs concurrently with neuronal enlargement. PMID- 19788051 TI - Evaluation of brain apoptosis in a CADASIL postmortem case. AB - OBJECTIVE: To evaluate the role of apoptosis in the pathogenesis of brain lesions in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), a hereditary microangiopathy leading to cognitive decline and dementia, caused by mutations in the NOTCH3 gene. MATERIALS AND METHODS: Detection of apoptotic nuclei in temporal lobe, brain stem, medulla oblongata, hippocampus and basal ganglia from one young CADASIL patient was performed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL). RESULTS: Our results showed a great involvement of glial cells in apoptotic cell death in the majority of the brain regions examined; neuronal apoptosis was significantly present only in the brain stem region. CONCLUSIONS: We hypothesized that in the early stages of the disease neuronal involvement of apoptosis is limited to the cells of the brain stem, sparing the cortical area which is involved in neuronal apoptosis and cognitive decline later. PMID- 19788052 TI - Clinical and immunohistochemical prognostic factors in adult glioblastoma patients. AB - OBJECTIVE: Glioblastomas are the commonest and the most malignant of all adult brain tumors, characterized by genetic instability, intratumoral histopathological variability, and unpredictable clinical behavior. The utility of tumor markers that reflect their underlying biology is becoming increasingly important with respect to patient prognostication and their potential role as molecular targets of therapy is being recognized. In this study, we aimed to identify the clinical factors and some immunohistochemical markers that could have an effect on patient survival in supratentorial glioblastomas. MATERIALS AND METHODS: We evaluated 54 cases of adult supratentorial glioblastomas operated over a span of 1 year, with respect to clinical features such as age, Karnofsky performance score (KPS), extent of resection, adjuvant therapy, and immunohistochemical expression of p53, EGFR (Epidermal Growth Factor Receptor) and PTEN (Phosphatase and Tensin homolog). RESULTS: Radiotherapy and KPS at presentation were significant predictors of outcome in both univariate and multivariate analyses. Among immunohistochemical variables; loss of PTEN expression in association with over-expression of EGFR showed a trend towards poorer survival, in univariate analysis. Over-expression of EGFR and/or p53 emerged as significant predictors of poor outcome on multivariate analysis, despite failing to prognosticate on univariate analysis. CONCLUSIONS: Our study shows that EGFR and p53 overexpression along with loss of PTEN expression are important adjuncts to clinical variables in prognosticating glioblastoma patients. PMID- 19788053 TI - Podoplanin is a potential marker for the diagnosis of ependymoma: a comparative study with epithelial membrane antigen (EMA). AB - Podoplanin is a mucin-type transmembrane sialoglycoprotein that is characteristically expressed in lymphatic endothelia. It is also expressed in the ependyma of the central nervous system as well as in ependymomas. Particularly, membrane-bound structures along the luminal surface, ring-like structures, and dot-like structures in the cytoplasm, all of which were originally reported for epithelial membrane antigen (EMA) immunohistochemistry in ependymoma, were also reported for podoplanin immunohistochemistry in ependymoma. This study was undertaken to evaluate podoplanin as compared with EMA as a marker of ependymoma. A total of 16 ependymomas (WHO Grade (G) II, 9 cases; GIII, 4; myxopapillary, 2; GIII clear cell, (1) were immunohistochemically studied using antibodies against podoplanin (clones D2-40 and NZ-1) as well as an antibody against EMA (clone E29). In all cases, D2-40 and NZ-1 excellently labeled linear signals along the luminal surface of ependymal canals/rosettes, dot-like structures, and/or ringlike structures, as did E29. These structures were generally more abundant in GII ependymomas than in GIII ependymomas. A semiquantitative analysis between the immunopositive structures of D2-40 or NZ-1 and E29 was conducted with a focus on the dot-like structures and the ring-like structures in the cases of GII and GIII ependymoma. The result showed that there was no statistical difference between D2 40 or NZ-1 and E29. Our study suggests that podoplanin is a potential marker for the diagnosis of ependymoma that corresponds to EMA. Anti-podoplanin antibodies and anti-EMA antibodies could cooperate with each other for the diagnostic immunohistochemistry of ependymoma. PMID- 19788054 TI - An unusual case of intraventricular gliosarcoma. AB - Gliosarcoma is an uncommon variant of glioblastoma characterized by a biphasic pattern of glial and mesenchymal differentiation in the tumor. These tumors occur mostly in the cerebral hemispheres. Intraventricular location is extremely rare. Extensive review of literature revealed only two cases of intraventricular gliosarcoma. The first case arose by malignant transformation of a preexisting ependymoma. The second case was a gliosarcoma involving the frontal lobe with extension into the lateral ventricle. We report a case of an exclusively lateral ventricular tumor probably arising from the interventricular septum and blocking the CSF pathway. To the best of our knowledge, this is the first reported case of an exclusively intraventricular gliosarcoma. PMID- 19788055 TI - Schwannosis induced medullary compression in VACTERL syndrome. AB - A 7-year-old boy with a history of VACTERL syndrome was found collapsed in bed. MRI had shown basilar invagination of the skull base and narrowing of the foramen magnum. Angulation, swelling and abnormal high signal at the cervicomedullary junction were felt to be secondary to compression of the medulla. Neuropathologic examination showed bilateral replacement of the medullary tegmentum by an irregularly circumscribed cellular lesion which was composed of elongated GFAP/S 100-positive cells with spindled nuclei and minimal atypia. The pathologic findings were interpreted as intramedullary schwannosis with mass effect. Schwannosis, is observed in traumatized spinal cords where its presence may represent attempted, albeit aberrant, repair by inwardly migrating Schwann cells ofperipheral origin. In our view the compressive effect of the basilar invagination on this boy's medulla was of sufficient magnitude to have caused tumoral medullary schwannosis with resultant intermittent respiratory compromise leading to reflex anoxic seizures. PMID- 19788056 TI - Primary pineal melanoma with leptomeningeal spreading: case report and review of the literature. AB - OBJECTIVE: Primary melanomas of the pineal region are exceedingly rare and may be difficult to diagnose. Clinical, radiological and pathological features as well as diagnostic procedures are discussed. CASE HISTORY We report herein on a 44 year-old man who presented with uncontrolled epileptic seizures. Magnetic resonance imaging revealed a pineal mass hyperintense on T1-weighted and isointense on T2-weighted sequences with diffuse leptomeningeal involvement and intense homogeneous contrast enhancement after gadolinium administration. A frontal leptomeningeal and cortical biopsy was performed. Histological examination showed a malignant melanocytic tumor cell proliferation expressing Melan-A, but not HMB-45 or S100 protein. Even if we have no proof that the tumor actually arose in the pineal gland, based on the radiological and histological findings, and on the unremarkable dermatologic and ophthalmologic examinations, a primary pineal melanoma with leptomeningeal dissemination was diagnosed. The patient received temozolomide-based chemotherapy followed by whole brain irradiation. The patient died 52 weeks after disease onset and 13 weeks after treatment initiation. CONCLUSION: A diagnosis of pineal melanoma should be considered in the presence of a pineal mass that appears hyperintense on T1 weighted images and hypo- to isointense on T2-weighted images. The diagnosis is provided by pathological examination of tumor specimens obtained at surgical resection or at leptomeningeal biopsy. However, immunochemistry using anti-Melan A, -S100 protein and/or -HMB45 antibodies on cerebrospinal fluid and leptomeningeal samples may be helpful in diagnosing such a disease. The prognosis of primary pineal melanoma is variable but meningeal spreading carries a dismal prognosis. The best therapeutic management is yet to be defined. PMID- 19788057 TI - Diffuse follicle center lymphoma of the spine: a primary epidural lymphoma? AB - A 72-year-old right-handed woman presented with a 6-month history of right thoracic wall discomfort. An MRI of the thoracic spine showed a small dumbbell shaped mass centered within the right T7-8 foramen. The patient was asked to return to clinic for reevaluation to include a new MRI of the thoracic spine in 6 months. She did not comply with this recommendation and 1 year later, she presented with increasing difficulty ambulating and spastic paraparesis. A follow up MRI of the thoracic spine now demonstrated significant interval growth of the mass with an extra-foraminal component extending into the thoracic cavity. She was taken to the operating room for resection of the epidural tumor. The pathology was consistent with diffuse follicle center lymphoma as cells were immunohistologically positive for CD20, CD 10, BCL-2 and BCL-6. Primary spinal follicle center lymphomas of the spine are rare with the current case being the first diffuse follicle center type reported in the literature. PMID- 19788058 TI - Deaths: final data for 2006. AB - OBJECTIVES: This report presents final 2006 data on U.S. deaths, death rates, life expectancy, infant and maternal mortality, and trends by selected characteristics such as age, sex, Hispanic origin, race, marital status, educational attainment, injury at work, state of residence, and cause of death. It also presents more detailed information than previously presented about the mortality experience of the American Indian or Alaska Native and the Asian or Pacific Islander populations. METHODS: Information reported on death certificates, which are completed by funeral directors, attending physicians, medical examiners, and coroners, is presented in descriptive tabulations. The original records are filed in state registration offices. Statistical information is compiled in a national database through the Vital Statistics Cooperative Program of the Centers for Disease Control and Prevention's National Center for Health Statistics. Causes of death are processed in accordance with the International Classification of Diseases, Tenth Revision (ICD-10). RESULTS: In 2006, a total of 2,426,264 deaths were reported in the United States. The age adjusted death rate was 776.5 deaths per 100,000 standard population, a decrease of 2.8 percent from the 2005 rate and a record low historical figure. Life expectancy at birth rose 0.3 years, from a revised 2005 value of 77.4 years to a record 77.7 years in 2006. Age-specific death rates increased for those aged 25 34 years but decreased for most other age groups: 5-14 years, 35-44 years, 45-54 years, 55-64 years, 65-74 years, 75-84 years, and 85 years and over. The 15 leading causes of death in 2006 remained the same as in 2005. Heart disease and cancer continued to be the leading and second-leading causes of death, together accounting for almost half of all deaths. The infant mortality rate in 2006 was 6.69 deaths per 1,000 live births. CONCLUSIONS: Mortality patterns in 2006, such as the decline in the age-adjusted death rate to a record historical low, were generally consistent with long-term trends. Life expectancy increased in 2006 from 2005. PMID- 19788059 TI - Contribution of Ser463 residue to the enzymatic and autoprocessing activities of Escherichia coli gamma-glutamyltranspeptidase. AB - A serine residue Ser463, required for proper function of E. coli y glutamyltranspeptidase (EcGGT) was identified by site-directed mutagenesis on the basis of sequence alignment of human, pig, rat, and three bacterial enzymes. Thr , Asp-, and Lys-substituted variants were overexpressed in E. coli M15 cells and the recombinant proteins were purified to near homogeneity by nickel-chelate chromatography. With the exception of S463T, the other two variants completely lost GGT activity, implying the importance of this residue in EcGGT. Moreover, substitution of Ser463 with either Lys or Asp impaired the capability of autocatalytic processing of the precursor into alpha- and beta-subunit. Computer modeling showed that the critical bonding distance of Gln390 C-Thr391 OG1 was significantly increased in S463D and S463K, indicating that these distance changes might be responsible for the lack of enzyme maturation. Measurements of intrinsic tryptophan fluorescence revealed alteration of the microenvironment of aromatic amino acid residues in S463D and S463K, while circular dichroism (CD) spectra were nearly identical for wild-type and all mutant enzymes. The temperature-dependent signal in the far-UV region for S463T was consistent with that of wild-type enzyme, but S463D and S463K showed a different sensitivity towards temperature-induced denaturation. These results implied that a significant conformational change occurred as a result of Asp- and Lys substitution. PMID- 19788060 TI - Molecular cloning and expression analysis of evolutionarily conserved stathmin from Gekko japonicus spinal cord. AB - The cDNA encoding stathmin is identified from the brain and spinal cord cDNA library of Gekko japonicus. It contains a 450 bp open-reading-frame, corresponding to a deduced protein of 149 amino acids. At amino acid level. gecko stathmin shares more than 76.4% identities with vertebrate stathmins, and especially, it shares 100% identity with human stathmin, suggesting that the selective pressure must have been extremely high for the conservation of stathmin during the vertebrates including reptile evolution. Reverse transcriptase polymerase chain reaction (RT-PCR) shows that gecko stathmin is ubiquitously expressed in all tissues examined. In situ hybridization reveals that stathmin transcript mainly appear in the gray matter of spinal cord. The change of stathmin expression in spinal cord after tail amputation is examined by semiquantitative RT-PCR. Stathmin expression increases at 1 day and 3 day after amputation and decreases to the control level at I week. However, the expression level increases again at 2 weeks. These suggest that stathmin may be associated with the immune protection of the injury, as well as in the regeneration of spinal cord. PMID- 19788061 TI - Properties of alkaline protease genetically engineered on cell surface of the yeast Yarrowia lipolytica. AB - ALP2 gene encoding alkaline protcase cloned from Aureobasidium pullulans HN2-3 was ligated into the surface display plasmid and expressed in the cells of the yeast Yarrowia lipolytica. The expressed alkaline protease was immobilized on the yeast cells. The activity of the immobilized enzyme with 6 x His tag was found to be significantly higher than that of without 6 x His tag. The immobilized enzyme showed lower optimal temperature and a lower affinity for azocasein than the free enzyme purified from A. pullulans HN2-3. The thermal stability of the immobilized enzyme enhanced and the pH stability decreased, compared to that of the free enzyme. PMID- 19788062 TI - Iron-zinc interaction during uptake in human intestinal Caco-2 cell line: kinetic analyses and possible mechanism. AB - Iron and zinc interact at the enterocyte during absorption, but the mechanism(s) remain elusive. The aim was, therefore, to understand the mechanism of interaction using kinetic analyses of iron and zinc uptake, individually and in combination under normal and altered cellular mineral concentrations in human intestinal Caco-2 cell line. Striking differences in kinetic parameters were observed between iron and zinc uptake. Iron uptake followed a two-component model, while zinc uptake followed a three-component model. Iron uptake had a Km of 3.6 microM and Vmax of 452 pmol/mg protein/min, while zinc uptake had a Km of 42 microM and Vmax of 3.09 pmol/mg protein/min. Zinc dose-dependently inhibited iron uptake through mixed-inhibition but iron marginally increased zinc uptake. Cellular zinc repletion doubled iron uptake and eliminated inhibition, but zinc depletion decreased iron uptake. Iron pre-treatment had no effect on zinc uptake. Based on these results, a two-transporter model of iron uptake, comprising the apical iron uptake transporter divalent metal ion transporter-1 (DMT-1) and an unknown putative transporter was derived. This model for DMT-1 was verified by immunoblotting. These results implied that cellular zinc status profoundly influenced iron uptake and its interactions with zinc during uptake. DMT-1 might not simultaneously transport iron and zinc, providing a mechanistic basis for observed interactions. PMID- 19788063 TI - Homeopathic drugs Natrum sulphuricum and Carcinosin prevent azo dye-induced hepatocarcinogenesis in mice. AB - The study was undertaken to examine whether Carcinosin-200 (Car-200) could provide additional ameliorative effect, if used intermittently with Natrum sulphuricum-30 (Nat Sulph-30) against hepatocarcinogenesis induced by chronic feeding of p-dimethylaminoazobenzene (p-DAB) and phenobarbital (PB) in mice (Mus mnusculus). Mice were randomly divided into seven sub-groups: (i) normal untreated; (ii) normal + succussed alcohol; (iii) p-DAB (0.06%) + PB (0.05%); (iv) p-DAB + PB + succussed alcohol, (v) p-DAB + PB + Nat Sulph-30, (vi) p-DAB + PB + Car-200, and (vii) p-DAB + PB + Nat Sulph-30 + Car-200. They were sacrificed at 30, 60, 90 and 120 days for assessment of genotoxicity through cytogenetical end-points like chromosome aberrations, micronuclei, mitotic index and sperm head anomaly and cytotoxicity through assay of widely accepted biomarkers and pathophysiological parameters. Additionally, electron microscopic studies and gelatin zymography for matrix metalloproteinases (MMPs) were conducted in liver at 90 and 120 days. Results showed that administration of Nat Sulph-30 alone and in combination with Car-200 reduced the liver tumors with positive ultrastructural changes and in MMPs expression, genotoxic parameters, lipid peroxidation, gamma-glutamyl transferase, lactate dehydrogenase, blood glucose, bilirubin, creatinine, urea and increased GSH, glucose-6-phosphate dehydrogenasc, superoxide dismutase, catalase, glutathione reductase activities and hemoglobin, cholesterol, and albumin levels. Thus, intermittent use of Car-200 along with Nat Sulph-30 yielded additional benefit against genotoxicity, cytotoxicity, hepatotoxicity and oxidative stress induced by the carcinogens during hepatocarcinogenesis. PMID- 19788064 TI - Identification of alpha2u-globulin and bound volatiles in the Indian common house rat (Rattus rattus). AB - The alpha2u-globulin (alpha2u) is a pheromone carrier urinary protein believed to be relevant for sexual communication among rats and is characterized in laboratory rats. In the present study 17 kDa protein and the bound pheromones were characterized in a population of wild-type Indian common house rat (Rattus rattus). The protein was purified by two runs of Sephadex G-50 chromatography and analyzed with SDS-PAGE with MALDI-TOF/MS. The results of MASCOT search identified the protein as an alpha2u and suggested a role for binding pheromones. To confirm the protein bound volatiles, purified alpha2u was extracted with dichloromethane and volatile molecules were detected using of gas chromatography linked to mass spectrometry (GC-MS). 1-Chlorodecane was detected as the predominant compound and 2-methyl-N-phenyl-2-propenamide, hexadecane and 2,6,11-trimethyl decane as the minor compounds. The simple method of protein purification and the identification of bound volatiles may help in designing efficient pheromone-based rat traps. PMID- 19788065 TI - Characterization of erythrosine B binding to bovine serum albumin and bilirubin displacement. AB - The interaction of crythrosine B (ErB), a commonly used dye for coloring foods and drinks, with bovine scrum albumin (BSA) was investigated both in the absence and presence of bilirubin (BR) using absorption and absorption difference spectroscopy. ErB binding to BSA was reflected from a significant red shift of 11 nm in the absorption maximum of ErB (527 nm) with the change in absorbance at lamdamax. Analysis of absorption difference spectroscopic titration results of BSA with increasing concentrations of ErB3 using Benesi-Hildebrand equation gave the association constant, K as 6.9 x 10(4) M(-1). BR displacing action of ErB was revealed by a significant blue shift in the absorption maximum, accompanied by a decrease in absorbance difference at lamdamax in the difference spectrum of BR BSA complex upon addition of increasing concentrations of ErB. This was further substantiated by fluorescence spectroscopy, as addition of increasing concentrations of ErB to BR-BSA complex caused a significant decrease in fluoresccnce at 510 nm. The results suggest that ErB binds to a site in the vicinity of BR binding site on BSA. Therefore, intake of ErB may increase the risk of hyperbilirubinemia in the healthy subjects. PMID- 19788066 TI - Effect of nickel on root growth and the kinetics of metal ions transport in onion (Allium cepa) root. AB - The effect of different concentrations of nickel nitrate (0.25, 0.50, 1.00 and 2.00 mM) uptake by the roots, on root growth of onion (Allium cepa) and the transport of Ni2+, Fe2+, Mn2+, Zn2+, K+, Na+ and H+ ions were investigated spectrophotometrically. The uptake of Ni2+, Fe+, Mn2+ and Zn2+ was monitored by flame atomic absorption spectrometry with a 24-h period for 7 days and the amounts of K+ and Na+ were determined in solutions by flame photometer. The mineral content of the solution, instead of the root material was measured. Ni2+ ions showed inhibitory effect on the root growth at all concentrations during the entire treatment. The ECso (effective concentration that reduced root growth by 50%) was found at 0.25 mM Ni2+. No significant change in inhibitory effect was observed after at 0.50 mM Ni2+ concentrations. A large amount of Ni2+ was translocated into the roots. The kinetics of metal ion transport followed a pseudo-first order reaction in all metal ion concentrations. Ni2+, Zn2+ Fe2+ Mn2+ and H+ ions transferred together into plant, but Na+ and K+ ions transferred to the solution from the plant. The amount of H+ in the solution decreased at all Ni2+ concentrations. PMID- 19788067 TI - Purification and characterization of bacteriocin produced by strain of Lactobacillus brevis MTCC 7539. AB - Bacteriocin, an antimicrobial agent having potential for food biopreservation was purified from Lactobacillus brevis (a safe food-grade bacteria isolated from Vari Kandal, a traditional fermented food of Himachal Pradesh by adopting a novel repeated washing method. Its purity was confirmed by SDS-PAGE and Native-PAGE. The relative molecular mass of bacteriocin was 93.74 kD, while specific activity and recovery were 35.52 folds and 17.13%, respectively. It showed high thermal stability and was active over wide range of pH and exhibited sensitivity to trypsin. PMID- 19788068 TI - Serum biochemical markers in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) characterized by local and systemic effects of inflammation has a wide range of biochemical markers implicated directly or indirectly to its pathogenesis. In the present study, homocysteine, cortisol, adenosine deaminase (ADA), ferritin, malondialdehyde (MDA) and alpha-tocopherol in serum of RA patients and healthy individuals were estimated to assess if they contribute to the disease process. The markers of disease activity such as erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF) were also measured. The study group included a total of 45 subjects, including 30 RA patients and the rest being healthy individuals. RA group showed a significant increase in the levels of homocysteine, ADA and MDA, and a significant decrease in alpha-tocopherol compared to the healthy individuals. However, cortisol and ferritin levels did not show any significant change. Also, there was no significant correlation between the studied serum markers and markers of disease activity. Our results indicate that these biochemical markers contribute independently to the pathogenesis of RA. PMID- 19788069 TI - [Time-order expression of caspase-3 and iNOS in contused human brain tissue]. AB - OBJECTIVE: To investigate the expression of caspase-3 and iNOS in different intervals and to provide evidence for estimation of injury intervals after brain contusion in human. METHODS: Thirty cases died of serious brain injury were included into the injury groups and 5 cases died of non-brain injury were served as control group. To analyze the changes of caspase-3 and iNOS expression in brain samples at different intervals (2h, 4-8h, 10-14h, 1-2d, 3-5d, 8-11d) by immunohistochemistry and auto-image analysis system. RESULTS: The level of caspase-3 expression started to increase in 2 hours after brain contusion compared to the control group (P<0.05). The level of caspase-3 expression continued to increase in 1-2 days and maintained high level in 3-5 days compared to the control group (P<0.05), then decreased gradually. There was no statistically significant difference between the expression level of iNOS in 2 hours with the control group (P>0.05). But the expression level of iNOS began to increase in 4-8 hours after brain contusion and reached its maximum in 1-2 days, then decreased. Weak expression of iNOS still could be detected in 8-11 days. CONCLUSION: The expression of caspase-3 and iNOS can be used as effective evidence for human brain contusion interval. PMID- 19788070 TI - [Expression of Bcl-2 and Bax proteins in myocardial cells after Macleaya cordata alkaloids poisoning in rats]. AB - OBJECTIVE: To observe the expression of Bcl-2 and Bax proteins in rat's myocardial cells after Macleaya cordata alkaloids poisoning, and to provide certain molecular biology references for the detection of Macleaya cordata alkaloids poisoning. METHODS: Experimental model of Macleaya cordata alkaloids poisoning was established, the expression levels of Bcl-2 and Bax proteins in these cells were detected by immunohistochemistry, and the results were analyzed by computer image system. RESULTS: The expression levels of Bcl-2 and Bax proteins in myocardial cells in poisoning groups were much greater than those in the control groups (P<0.05). CONCLUSION: If the clinical symptoms may not be obvious, the detection of Bcl-2 and Bax proteins level by immunohistochemistry still could be ancillary method. PMID- 19788071 TI - [Changes of HSP70, bFGF and TGF-beta1 expression in rat brain after concussion]. AB - OBJECTIVE: To study the changes of expression of relevant factors in rat brain after concussion injury and to provide scientific basis for forensic estimation of brain injury interval. METHODS: Brain tissues were sampled from the established SD rat animal model of brain concussion, routinely processed and stained with HE and immunohistochemically stained with antibodies directed against heat shock protein 70 (HSP70), transforming growth factor beta 1 (TGF beta1) and basic fibroblast growth factor (bFGF). The sections were examined under light microscope with IMAGE analytical system and homologous statistical analysis. RESULTS: The expression of HSP 70 was observed in 30 minutes after brain injury. The amount of neurons expressing HSP 70 increased gradually, reached its peak at 12 hours and then declined at 24 hours after brain injury. The expression of bFGF was observed 3 hours after injury in brain stem, reached its peak at 12 hours, and then declined. The expression of TGF-beta1 was detected 6-24 hours after brain injury, remained at its peak up to 3 days. CONCLUSION: Brain injury can induce a chronological expression of HSP70, bFGF and TGF-beta1. The results can be a potential for estimating the age of brain injury using several markers. PMID- 19788072 TI - [Comparison between application of imaging techniques and autopsy in the identification of injury manner]. AB - OBJECTIVE: To explore the application of imaging techniques in determining the death cause and injury manner. METHODS: One case due to high fall was fully examined using multi-slice spiral computed tomography (MSCT), 3-D imaging creation and magnetic resonance imaging (MRI). The systemic and detailed autopsy was subsequently performed to compare with the results from imaging studies. The advantages and disadvantages of autopsy and imaging studies were then analyzed. RESULTS: Most of the important information such as trauma, fracture and hemorrhage could be obtained by imaging techniques. Furthermore, imaging methods can predict injuries in internal body before autopsy and be minimal or non invasive to the cadaver. However, the imaging techniques probably also can not find some details in comparison to autopsy in forensic practice and need to improve in their future application. CONCLUSION: Application of imaging techniques can be used as the guidance and complimentary for the forensic autopsy in the identification of injury manner. In addition, the application can even be used to replace autopsy in some special circumstances. PMID- 19788073 TI - [Study on pelvic injury mechanisms in road traffic fatalities according to Young Burgess classification]. AB - OBJECTIVE: To explore the pelvic injury mechanisms in road traffic fatalities (RTFs) according to Young-Burgess classification and its practical value in forensic medicine. METHODS: Retrospective study was performed on pelvic X-ray radiographs of adult RTFs outside the automobiles in 128 cases. Pelvic injury mechanisms were investigated according to Young-Burgess classification and then were analyzed statistically combined with the real circumstance. RESULTS: The accuracy of pelvic injury mechanism identification using APC subtype (94.1%) and LC subtype (92.9%) were significantly higher than that without using subtypes (63.6% and 70.7%) (P<0.05). LC subtype was helpful to discriminate the direction of force, for example the rear lateral force, anterior lateral force or continuous anterior lateral force. CONCLUSION: Young-Burgess classification discriminated by various methods of medical imaging may be helpful to study the pelvic injury mechanisms and provide reliable reference for road traffic accidents reconstruction. PMID- 19788074 TI - [Comparison between auditory steady-state response and 40 Hz auditory event related potential in the evaluation of hearing thresholds]. AB - OBJECTIVE: To compare the results between auditory steady-state response (ASSR) and 40 Hz auditory event related potential (AERP), and explore the accuracy of hearing thresholds by using ASSR and AERP and the clinic forensic value. METHODS: Thirty seven ears were tested with pure-tone audiometer, 40Hz AERP and ASSR, respectively. All the volunteers in our study were awake during 40 Hz AERP test and ASSR test. RESULTS: Thresholds acquired with ASSR and 40Hz AERP test had a close correlativity and showed higher than those acquired with PTA test. There was no significant difference between the accuracy of ASSR and 40Hz AERP in estimating pure-tone thresholds. CONCLUSION: After determining the correct value, ASSR can be used directly to evaluate hearing loss objectively. PMID- 19788075 TI - [Application of the number of allele shared among autosomal STR loci in full sibling identification]. AB - OBJECTIVE: To establish and evaluate the method of full sibling identification based on the number of allele shared among autosomal STR Loci. METHODS: Two hundred and eighty full sibling pairs and 2,003 unrelated individual pairs were genotyped in 15 STR loci with Identifiler Kit, and the number of allele shared among the 15 STR loci (S15) and full sibling index (FSI) were calculated. Fisher discriminant functions were established with SAS 8.2 software based on S15, the power of which were compared with ITO method. RESULTS: The distribution of S15, in full sibling pair group and unrelated individual pair group were in accord with normal distribution. The established Fisher discriminant functions for each group were Z(FS)= 3.26970S15-31.51174 and Z(UI)=1.70058S15-8.524 11, respectively. The average error of probability in sibling and unrelated pair group was 0.0298. There was no statistically significant difference on the power of full sibling discriminant between the method based on the number of allele shared among the 15 STR loci or the CODIS 13 STR loci and the ITO method. CONCLUSION: The method based on the number of allele shared among the 15 STR loci in full sibling identification is convenient, credible, easy to handling and unaffected by the allele frequency of STR loci. PMID- 19788076 TI - [A new method for calculating paternity index]. AB - OBJECTIVE: To introduce a new method for calculating the paternity index (PI). METHODS: Assuming that each allele from parents has undergone a transition before it segregates and transmits to child. The transition probability is 1 when parent allele is the same as child's, the transition probability is 0 when parent allele is different from the child's. Every allele has a transmission probability with 0.5. Base on these theories, it is easy to gain the probability that child inherits an allele from the alleged father or mother. Thus, the X value (numerator) and Y value (denominator) of PI formula can be calculated, as unknown man provide an allele for child with the allele frequency. RESULTS: A general formula that calculated the PI for trios, duos and missing child cases was deduced. CONCLUSION: The new method is practical in all kinds of forensic paternity case. PMID- 19788077 TI - [Analysis of 90 autopsy cases in medical legal dispute]. AB - OBJECTIVE: To analyze the significance of forensic autopsy in medical tangle. METHODS: Ninety autopsy cases of medical legal dispute were retrospectively analyzed from the database of our department from 2001 to 2008. All cases were analyzed and classified based on age, sex, cause of death, clinic diagnosis and forensic diagnosis. RESULTS: The age ranged from 1 day to 72 years, and the ratios of male to female is 1:1. The most common healthcare facilities involved were county hospitals (30 cases, 33.33%). The coincidence rate between clinical diagnoses and pathological diagnoses was 33.33%. CONCLUSION: The forensic autopsy is valuable to solve or even avoid the occurrence of medical legal dispute. PMID- 19788078 TI - [Analysis of 574 cases of high-fall death]. AB - OBJECTIVE: To establish a database of high-fall death cases for future forensic study and practice, based on the scene investigation, injury characteristics and other informations. METHODS: Five hundred and four cases of high-fall death from 5 provinces and cities were included in the study. Data including personal information of the deceased, scene investigation, autopsy findings, history of mental illness and the results of toxicology were collected and analyzed. RESULTS: The male accidental death rate was significantly higher than that of female. No case of suicide was found in the 0-10 age group, while the suicide rate was apparently higher in the 60 years or over age group than that of accident. Most of the accident cases occurred at workplace, with head landing first and foot or lower-extremity landing first observed from height below 10 m and between 10-25 m, respectively. CONCLUSION: The majority of cases have obvious conclusions. A substantial set of the cases, however, is still difficult to determine the mechanism of injury and the manner of death. So further study should be performed. PMID- 19788079 TI - [Retrospective study on forty cases of medical legal dispute]. AB - OBJECTIVE: To analyze the main causes of medical dispute and the main types of medical malpractice. The related problems were discussed in forensic expertise. METHODS: Forty cases of medical dispute from 2006 to 2008 in our institute were analyzed retrospectively. RESULTS: In 40 cases of medical dispute, city-level hospitals, county-level hospitals, town-level hospitals and private clinics were 11 (27.5%), 24 (60.0%), 2 (5.0%) and 3 (7.5%) cases respectively. The internal medicine departments, surgical departments, gynaecological and obstetric departments, pediatric departments and outpatient center were 16 (40.0%),10 (25.0%), 9 (22.5%), 2 (5.0%) and 3 (7.5%) cases, respectively. The amount of cases from city-level hospitals, county-level hospitals diagnosed by the medical experts as the medical malpractice showed less than that from town-level hospitals and private clinics. CONCLUSION: The amount of cases of medical dispute from city-level and county-level hospitals were more than that of town-level hospitals. But the amount of cases diagnosed by the medical experts as medical malpractice from city-level and county-level hospitals were less than that of town-level hospital and private clinics. PMID- 19788080 TI - [Establishment and evaluation of animal model with methamphetamine poisoning]. AB - Amphetamine-type stimulants (ATS) is the most widespread narcotics in the 21st century. The methamphetamine's intoxication mechanism, psychological dependence, drug resistance and therapeutic drug development are the hot spots in current research. Establishment of animal model with methamphetamine poisoning is the basic for the relative studies, the normalization and standardization of the animal model settles the foundation for methamphetamine's further research. This article reviews the animal model of methamphetamine poisoning in China and abroad, the brief history of the acute, subacute and chronic animal model of methamphetamine poisoning, as well as the principles and methods of the animal model establishment and its evaluation criteria. The necessity, significance and its scientific expansion of performing experimental research on the methamphetamine poisoning animal model are also discussed. PMID- 19788081 TI - [The application of computed tomography (CT) in postmortem examination]. AB - Since first application of computed tomography (CT) in postmortem examination in 1990, investigators have been discussing the value and advantage of CT in full body examination in cadaver. CT examination before autopsy is able to provide not only the informations to guide the autopsy, but also the significant findings to analysis the causes of death, which may be not fount in autopsy. This review focuses on the value of CT in analysis of the death causes, injury manners, and personal identifications in postmortem examination as well as its development in the field of forensic medicine. It is our belief that CT in combination with other newly developed technologies will make more contribution to forensic medicine in the future. PMID- 19788082 TI - [Perspective of DNA methylation in forensic genetics and new progress of its detection methods]. AB - As an important epigenetic marker, DNA methylation has exhibited a valuable perspective in the fields of forensic genetics, especially in cases of paternity identification in duos and discrimination of monozygotic twins, which may be a useful complement to the classic genetics markers, such as short tandem repeats, single nucleotide polymorphism. Various methods for DNA methylation detection have been developed and validated based on methylation sensitive restriction endonuclease, bisulfite modification or methylation-CpG binding domain protein. Methylation-sensitive single nucleotide primer extension, real-time PCR, methylation-specific PCR, methylation-specific multiplex ligation-dependent probe amplification and the Illumina's Human Methylation 27 have been all applicable for analyzing identified CpG loci or short sequences, and can be effectively used in forensic laboratory. However, Amplification of Inter-Methylated Sites (AIMS), Hpa II tiny fragment Enrichment by Ligation-mediated PCR (HELP) or Combination of Methylated-DNA Precipitation and Methylation-Sensitive Restriction Enzymes (COMPARE-MS) are useful in genome wide methylation scanning to find new CpG loci which may be valuable in forensic fields. PMID- 19788088 TI - [Self help groups, a first assessment]. PMID- 19788090 TI - [The psychiatric day clinic, a nostalgic affair?]. PMID- 19788091 TI - [The day clinic, from experience to tentative theorization]. PMID- 19788092 TI - [Interior lives, an encounter between patient and nurse]. PMID- 19788093 TI - [The social worker, an ant tested by psychosis]. PMID- 19788094 TI - [Occupational therapy, a place of encounters and discovery]. PMID- 19788095 TI - [The therapeutic bar, a social space for rehabilitation]. PMID- 19788096 TI - [Empathy, a just milieu between clinical and daily ethics]. PMID- 19788097 TI - [Which indicators for mental health?]. PMID- 19788098 TI - Case management in the ED isn't a 'luxury' anymore, consultant says. PMID- 19788099 TI - Compile data to make the case for ED CMs. PMID- 19788100 TI - CMS postpones payment reduction in 2010 IPPS. PMID- 19788101 TI - Coordinating care throughout continuum keeps patients out of hospital, emergency department. PMID- 19788102 TI - The secret to improved throughput? Communicate. PMID- 19788103 TI - Anticipated discharge date improves throughput. PMID- 19788104 TI - Mentoring program enhances CM training. PMID- 19788105 TI - NHS nurse workforce set to shrink by at least 6500. PMID- 19788106 TI - Trauma tsar puts nurses at the centre of his plans. PMID- 19788107 TI - Nurses must consider the benefits of having the swine flu vaccine. PMID- 19788108 TI - Preparing for swine flu: 10 questions that all nurses need to ask themselves. AB - Human swine flu is spreading rapidly and it is timely to reflect on how well we as individuals are prepared for a pandemic. Being prepared includes nurses not only being confident they have a mask that fits but also being practised at putting on and removing personal protective equipment safely. It also involves being familiar with the latest guidance from the Department of Health, having an understanding of the processes in their workplace and an appreciation of some of the ethical challenges if numbers of affected patients overwhelm the health system's resources. This article suggests staff ask themselves 10 questions to assess their level of preparedness. PMID- 19788109 TI - When should staff wear face masks? PMID- 19788110 TI - The global swine flu pandemic 1: exploring the background to influenza viruses. AB - This first in a two-part unit on pandemic flu examines background information on influenza viruses and previous pandemics. As the 2009 flu pandemic gathers force, nurses and other healthcare professionals need to understand the scientific background to one of the most common and potentially the most lethal of pandemic infections. This part explores the characteristics of influenzaviruses and reviews the history and context in which human pandemics occur. PMID- 19788111 TI - Using oseltamivir (Tamiflu) as a first line treatment for seasonal or pandemic flu. PMID- 19788112 TI - Developing a school team to improve links between education and mental health services. AB - The school mental health teamis a relatively new service in Hackney, east London, set up in line with recent government recommendations. Its work is an outreach service of the tier 3 child and family consultation service. The team offers a child and adolescent mental health service to three pupil referral units, which schoolchildren attend when they have been excluded from or cannot attend mainstream school, and one special schooL It uses a different model from the traditional one of mental health professionals going into schools on a sessional basis for specific work. The team joins the teaching staff and becomes an integrated part of the school Results show positive outcomes for most children and young people who have used the service. PMID- 19788113 TI - On why effective leadership means listening to staff. PMID- 19788114 TI - The NHS is envied for its principle of caring for all. PMID- 19788115 TI - An opportunity to take a strategic focus. PMID- 19788116 TI - More needed, and now. PMID- 19788117 TI - Last chance for change. PMID- 19788118 TI - Families in transit. PMID- 19788119 TI - Focusing on young men: developing integrated services for young fathers. AB - While some girls cope well as teenage mothers and often have a range of support services, young fathers do not often access services in their own right. This paper reviews literature about services for young men from the time they become sexually active. Through the use of a case study, it then asks questions about the type and nature of services required by young fathers. Health and social care practitioners may identify critical points in the life of a young father and offer appropriate services and 'joined-up' intervention, thereby facilitating long- and short-term involvement in the life of the child. PMID- 19788120 TI - Long-acting reversible contraception: reducing unintended pregnancies. AB - This paper gives a brief history of the development of contraception and looks at the methods available in the U.K., with particular emphasis on National Institute for Health and Clinical Excellence guidance about long-acting reversible contraception--injections, implants and intrauterine methods. These methods have the potential to reduce unintended pregnancies, but at present remain underused. Providing positive messages about their ease of use and reversibility, and describing them as 'lasting' rather than 'long-acting' may increase their acceptability. PMID- 19788121 TI - Supportive care for children and young people during cancer treatment. AB - Children, young people and their families come into contact with a large number of health and social care professionals within hospital, education and community settings following a cancer diagnosis. The multiprofessional team best supports these families through an open and communicative approach to care. The side effects of cancer treatment include fever, infection, gastrointestinal upset, altered body image and psychological impact on children, young people and their families. Debate continues as to how children, young people, their siblings and parents cope with childhood cancer and its treatment due to its impact on family quality of life. It is considered that the short- and long-term wellbeing of children, young people and their families during treatment is best supported by continuing routine daily activities, such as attending nursery, school or college. PMID- 19788122 TI - Ready for swine flu. PMID- 19788123 TI - Suspecting child maltreatment. PMID- 19788124 TI - DDH: causes and examination. PMID- 19788125 TI - Speaking up about bad practice. PMID- 19788126 TI - [System of biocide products control in Poland]. AB - In this article we presented actual legislation concerning biocide products in Poland. Rules of reporting and archiving of biocide products exposure were discussed. We presented the first results of monitoring of biocide poisoning cases in Poland from July 2007 to June 2008. PMID- 19788127 TI - [Some aspects of suicide in the years 1980-1996]. AB - The reduction of suicide death index in 1981 year and 1989 year, that is in the period of temporary and definitive "Solidarity" victory confirms Emile Durkheim theory that revolution processes increase social integration and prevent suicide decisions. In the years 1991-1994 the number of suicide deaths in Poland was distinctly lower than in other countries of the Soviet Block and republics of the Soviet Union. PMID- 19788128 TI - [Correlation between carbamazepine serum level and clinical condition of acute poisoned patient]. AB - The aim of our study was to find out the relationship between the serum CBZ level and the clinical symptoms of acute intoxication. The research was conducted on 130 patients including 64 females and 66 males, aged from 14 to 59 years. We noted 65 cases of acute CBZ intoxication and 65 cases of mixed intoxications. In 115 patients the CBZ plasma level was higher than therapeutic range. Acute pulmonary failure was observed in 3 persons. CONCLUSIONS: 1. Positive correlation has been found at the serum CBZ concentrations and systolic blood pressure and pulse. 2. We failed to find any significant correlation between CBZ plasma level and the remaining parameters. 3. The heavier course of poisoning was not affirmed in the case of mixed intoxication in comparison to poisonings with only CBZ. 4. In persons treated with CBZ earlier, the course of poisoning was less severe. PMID- 19788129 TI - [Stinging catfish spine envenamation]. AB - The stinging catfish Heteropneustes fossilis (Bloch, 1794) has become a popular aquarium fish in Poland and is available in almost every pet shop. The toxicological centers in Cracow, Gdansk and Warsaw have recorded twelve cases of envenomations caused by stinging catfish in the years 1994-2008. In most cases the injury was accompanied by oedema, erythema, intense pain, numbness of the site and dizziness. Schema of medical management was prepared using analysis of cases. PMID- 19788130 TI - Lionfish envenomations in Poland. AB - 14 injuries caused by lionfish Pterois volitans (L) kept in home aquariums were noted over a time period of 3 years. All the punctures occurred in the victims' hands. Intense pain and systemic findings observed in 11 patients. Enveno-mations had a mild course, the patients were treated for their symptoms. Toxicology information centers have also recorded 3 cases of exposure to tank-bred lionfish in which typical envenomation symptoms did not appear. Those cases were probably what is referred to as "empty stings", in which no toxin is injected into the victim's body. Empty stings are known to be made by snakes, which can consciously inject no venom, while for lionfish, the lack of exposure to venom was probably caused by the structure of the venom organ in which there was no channel to deliver the venom. PMID- 19788131 TI - [Medical treatment during fish envenomation]. AB - Expositions to fish venoms should be treated as a separate group of intoxications because of their different diagnostic procedure. Until now, there are over 220 venomous fish species described, but skin excretions are potentially toxic for humans. Cases of fish envenomations (37), consulted by Poison Information Centres in Poland, as well as described in literature and contained in Micromedex database were analyzed. The course of envenomation, medical management during exposition to venomous of Chondrichthyes and Osteichthyes, freshwater and marine fishes were resolved. Injuries caused by venoms fishes were similarly treated, usually symptomatic. Specific antivenoms are available only for two fish species. Each patient exposed to sting or bite should be examined and observed. If characteristic sings and symptoms of envenomation are present, proper medical management should be proceed. PMID- 19788132 TI - [Misuse of substances theoretically without abuse potential--case series]. AB - The aim of our study was to present cases of misuse of different substances theoretically without abuse potential. In the last few years such behavior became an increasing problem in toxicological and emergency units. Lack of typical signs of intoxication with psychoactive substances, and negative results of standard toxicological tests may be a challenge for toxicologists and emergency medicine practitioners. PMID- 19788133 TI - [The usage of psychoactive substances among secondary school students in Nowy Sacz]. AB - The results of anonymous questionnaire research on psychoactive substances in two last classes of high school pupils in Nowy Sacz are presented in the study. Only 1.7% of the examined students do not perceive the psychoactive substances as a real problem existing at school, 9.6% have no opinion. The rest (88.7%) perceive it as an already existing problem, where 36% as a very serious one. Alcohol, cigarette smoking, marijuana, hashish or crack and medical drugs are the most common substances, being used mostly for fun and relaxation. Pupils opinions were evaluated on addictive properties of the substances. The essential difference between those who initiated drugs vs. those who did not has was also evaluated. Tobacco, cocaine, heroine and crack have been considered the most addictive. Health consequences followed by moral and ethical principles are the main rules against taking drugs. Only 4.1% of examined individuals question the fact that schools should take involvement in whether students take drugs the rest expect some punishment for a school drug dealers and prophylaxis (proposal of interesting work-shops, lectures). PMID- 19788134 TI - [The knowledge about "date rape drugs" among Polish students]. AB - The Main Department of Police in Poland notes about 2000 rapes a year. Some of the crimes are performed with "Date Rape Drugs". The term means substances helping comitting a rape such as GHB (gamma hydroxybutyric acid), ketamine, flunitrazepam and other benzodiazepines derivatives, MDMA ("ecstasy"), marihuana, amphetamine. The substances are often joined with alcohol. The victims are usually young women, and not all the cases are recorded by the police or physicians, because the victims often do not remember details of the event. The toxicological analysis of blood or urine would be helpful to explain the circumstances of the case and to prove using "Date Rape Drug". The samples for toxicological determinations should be collected as soon as possible (24 to 72 hours after admission). Preventing violence with "Date Rape Drugs" include wide education by media, police, teachers and parents. The purpose of the research was to check the level of knowledge about "Date Rape Drugs". The consciousness of risk behavior when the kind of substances is used and the ways of preventing the risk of being a sexual victim were checked. Material for the research were the results of questionnaire prepared by The Department of Medicine Sociology Collegium Medicum Jagiellonian University in Krakow, carried out on 740 students. Most of respondents (77%) were women. The age of respondents was between 19-36 years (mean 21.41; SD - 1.29). The results of the research showed, that respondents didn't have completed knowledge about "Date Rape Drugs". They did not know the ways of recognizing and preventing the risk of being given this kind of substances. The main source of information about "Date Rape Drugs" were internet and colleagues. There is a need to start education about "Date Rape Drugs" by serious institutions such as the police and schools in Poland. This is the best way to prevent young people against a risk of being given "Date Rape Drugs" and being a victim of sexual crimes. PMID- 19788135 TI - [The knowledge about gamma-hydroxybutyric acid as by students of Physical Education Academy]. AB - Gamma-hydroxybutyric acid is a substance stealthily used by criminals to facilitate sexual assaults. It is also known as doping agent in sports. Physical Education Academies should prepare their graduates to be educators for young people, their trainers, organizers of sports and recreational events. Second year students of two majors: physical education and tourism and recreation were surveyed by means of questionnaire on "date-rape drug". As much as 320 among 327 students surveyed had heard about "date-rape drug". However their knowledge on it was shallow and unsystematic. None of the surveyed knew that the substance of "date-rape drug" could also be used as a doping agent. Only 31% of respondents were aware of existence of the test to detect "date-rape drug" in drinks. Physical Education Academy students should be thoroughly and relevantly educated on the matter of pharmacologic doping agents and drugs endangerment. PMID- 19788136 TI - [Emotional regulations among benzodiazepines dependent patients--preliminary results]. AB - BACKGROUND: The aim was to examine emotional states among benzodiazepine dependent patients who have been recently successfully detoxified and their coping strategies. METHOD: 32 patients dependent from benzodiazepines had been chosen to participate in the study and they were examined with State-Trait Anxiety Inventory (STAI), The Coping Inventory for Stressful Situations (CISS), The UWIST Mood Adjective Checklist (UMACL). RESULTS: Detoxified benzodiazepine dependent patients experience symptoms such as: high levels of anxiety (both state and trait), tense arousal, unpleasant mood and low body energy level. CONCLUSIONS: In the examined group, the most common coping strategy has been the emotions oriented style which does not affect sources of emotional problems. Presented results point towards necessity of psychological therapy, based around strengthening of coping resources and anxiety removal (relaxation) techniques. PMID- 19788137 TI - [Emotional identification and management disorders among benzodiazepine dependent patients as a factor leading towards interpersonal relations problems]. AB - BACKGROUND: The aim was to examine an ability to identify and manage the emotions defined as Emotional Intelligence Quotient (EQ) among benzodiazepine-dependent patients. METHOD: 32 benzodiazepine-dependent patients had been chosen to participate in the study. They were examined by the following EQ measurement surveys: INTE, SIE-T. Personality traits and anxiety levels have been studied using NEO-FFI and State-Trait Anxiety Inventory (STAI). RESULTS: Research points toward EQ decrease among benzodiazepine dependent patients, particularly in face expression recognition ability. Most characteristic results are the neurotic trait (high results), extrovert and scrupulous. CONCLUSIONS: Improving abilities enabling proper use of emotional intelligence in problem-solving and effective social functioning is apparently an important component of therapeutic programmes for benzodiazepine dependent patients. PMID- 19788138 TI - [Amphetamine and its analogues determination in urine from patients hospitalized in the Department of Toxicology Jagiellonian University Collegium Medicum in Krakow]. AB - The most popular stimulant drugs in Poland are amphetamine and its analogues: ecstasy (MDMA) and methamphetamine (MA). The substances are usually determined by immunoassays (EMIT, FPIA, Rapid Tests) in medical, toxicological laboratories. The methods are not useful for identification of the substances. Chromatography methods are reference, confirmation methods that identify stimulant drugs in biological samples. The aim of the study was investigation of kinds of amphetamine derivatives abused by poisoned patients treated in the Clinic of Toxicology of the Jagiellonian University Collegium Medicum in Krakow. Materials for the study were urine samples collected from 46 patients. All the samples were positive for amphetamine presence by EMIT (cut off = 300nn/ mL). Amphetamine analogues were identified by high performance liquid chromatography with diode array detector (HPLC-DAD). Amphetamine alone was present in 54.3% samples; amphetamine and it's analogues (MDMA, MDA, MA) were present in 26.0%; MDA and MDMA (no amphetamine) were present in 19.5% samples. In one case no amphetamine neither its analogues were detected in the sample. The positive amphetamine EMIT result was caused by fenfluramine--the substance present in slimming product. CONCLUSIONS: the most often determined stimulant drug in the group of poisoned patients was amphetamine. The frequency of MDMA and MA intoxications were occasional and with probably increase. Immunoassay tests are useful for routine analysis in clinic laboratories but in some cases when the history is unreliable, confirmation analysis by reference method should be performed to identify the abused substance. PMID- 19788139 TI - [Evaluation of cardiovascular autonomic nervous system in ethanol withdrawal]. AB - The aim of the study was to assess the risk factors and state of cardiovascular autonomic nervous system injury in ethanol dependent patients. The group examined consisted of 85 alcoholics (17 females and 68 males) aged from 27 to 68 y (45.7 +/- 8.82) hospitalized at the Ward of Toxicology and Environmental Diseases because of alcohol withdrawal. Ethanol dependence was diagnosed according to ICD 10 criteria, withdrawal syndrome was scored according to CIWA - A scale. A blood ethanol concentration, creatinine, urine, coagulation parameters and liver enzymes activity were measured on admission. Cardiovascular autonomic nervous system was evaluated by standard Ewing battery tests using VariaCardio TF5 system. The parasympathetic system was assessed by the heart rate response to forced breathing, the heart rate response to standing up, and to heart response to the Valsalva maneuver. The sympathetic system was evaluated by the blood pressure response to standing up. The original Ewing normal values were used. RESULTS: The mean duration of ethanol dependence was 13.7 +/- 8.2 y. In 92% of examined patients heavy and in 8% moderate ethanol withdrawal syndrome was diagnosed. The mean blood ethanol concentration was 1.07 +/- 1.21g/l. Liver injury was diagnosed in 43.5% of the examined group. No changes in autonomic battery tests were found only in 28.2% of the examined subjects. Early parasympathetic damage was stated in 23.5%, definite parasympa-thetic damage in 44.7%, combined para-sympathetic and sympathetic damage was diagnosed in 3.5% of patients examined. The relative risk for parasympathetic and sympathetic system injury rose together with CIWA - scoring, blood ethanol concentration on admission (OR = 1,4 95% CI: 0,81 +/- 2,4), and when GTP activity was three times greater than normal (OR = 1.2 95% CI: 0.92 +/- 1.7). PMID- 19788140 TI - [History of the usage of chosen psychoactive substances]. AB - The some facts from the history of the usage of chosen psychoactive substances including natural narcotics, tobbacco and alcohol were described. PMID- 19788141 TI - [Clinical practice guidelines in acetaminophen poisoning--pre-hospital management]. AB - We described guidelines for personel working in poison information service in case of acute paracetamol overdose. The guidelines were created with respect to EBM (Evidence Based Medicine) by the American Association of Control Centers. PMID- 19788142 TI - Acute exposure to urea. AB - According to the best of our knowledge there are no reports in medical literature about massive and acute exposure to carbamide. We have described a man who has fallen into the wagon car full of granulated urea. A 34-year old male, without previous medical history, has fallen into train car full of carbamide. For about 10 minutes the patient was fully covered with granulate. After one year of follow up the patient was still having symptoms of obturative respiratory insufficiency. Despite the fact that urea is thought as non toxic agent massive exposures to it, in some circumstances, may cause chronic respiratory problems. PMID- 19788143 TI - [Significant periodical fluctuation of insulin requirement in patients with type 2 diabetes]. AB - We have described three physicians aged 65-70 years, who had noticed during their insulintherapy significant, periodically recurrent variations of insulin requirement (max. 50 i.u./24h vs 25 i.u./24h) in the periods of 4-16 weeks. They had been characterized by similar diet and physical activity, stable normal body mass (av. BMI 24.6) and normal glycosylated hemoglobin (av. HbA1c 5.9%). The hypothesis was put forward that the cause of this phenomenon may be periodical changes in the incretin system activity or increased proliferation of pancreatic beta cells leading to decrease of insulin requirement. PMID- 19788144 TI - Acute poisoning with Tricholoma equestre. AB - Four cases, including three adults and one child, suffering from acute poisoning with Tricholoma equestre were described. The patients had eaten from 100 to 400 grams of the mushroom within a few consecutive meals. After consuming about 1000 grams of Tricholoma equestre for 3-4 days, the subjects developed fatigue, muscle weakness, myalgia, and in two cases acute respiratory failure with the need of respiratorotherapy. Maximal serum CK was 48136 U/L in the adults and 306 U/L in children. Maximal serum levels of AST and ALT were 802 U/L and 446 U/L in adults and 39 U/L, and 56 U/L in a child. All routine biochemical tests were within normal range. No other causes of rhabdomyolysis such as parasitic or viral infections, immune diseases, trauma or exposure to medications were found. Patient, aged 72 yrs., who developed acute respiratory failure, died in the second day of hospitalization. In other patients all the above mentioned symptoms and biochemical abnormalities disappeared from 2 to 3 weeks of hospitalization. Physicians should be aware of the possibility of appearance of rhabdo-myolysis after repeated consumption of large quantities of Tricholoma equestre. PMID- 19788145 TI - [Severe nonfatal poisoning after intravenous abuse of transdermal fentanyl--a case report]. AB - Fentanyl is a potent synthetic opioid with short-acting analgesic activity after intravenous or subcutaneous administration. The potency and lipid solubility of fentanyl make it suitable for delivery via the transdermal therapeutic system in the treatment of chronic pain. In this paper a case of nonfatal, severe poisoning after intravenous injection of the content from four transdermal patches (Durogesic 75 microg/h) in the 18-year-old male opiate abuser is presented. The present case demonstrates the possibility of intravenous abuse of transdermal patches and the risk of severe intoxication. In the cases of suspected fentanyl overdose specific assays should be utilized for the detection of fentanyl because it may not be detected by the routine opiate screening procedure. PMID- 19788146 TI - [Drug-induced agranulocytosis--case reports and literature review]. AB - Drug-induced agranulocytosis is believed to be an extremely rare adverse drug reaction. It can be caused by various drugs, but it is mostly described in patients taking antithyroid drugs, antipsychotics and antibiotics. Four cases of patients treated for drug-induced agranulocytosis from January 2006 to March 2007 were described. In two cases agranulocytosis appeared in the course of therapy with methimazole. In one patient agranulocytosis was caused by perazine and by promazine or olanzapine in the last one. In all of the cases the leading symptom was fever, three of our patients had changes of mouth mucosa. All patients were treated with betalactam antibiotics. Granulocyte colony-stimulating factor (G CSF) was not used in anyone. The recovery of white blood cell count and granulocyte count in all of the patients was detected in the first ten days of hospitalization. PMID- 19788147 TI - [Mild clinical course of left ventricular pseudoaneurysm]. AB - Left ventricular pseudoaneurysm from myocardial infarction is rare but is associated with a high risk of rapid enlargement and rupture. This report describes a 57 year old woman with left ventricular pseudoaneurysm and delayed surgical repair. Seven weeks after myocardial infarction control transthoracic echocardiography revealed a inferolateral left ventricular pseudoaneurysm. Early surgical intervention was recommended but the patient refused hospitalization and surgical repair and continued every day home activity. The symptoms and signs were so mild that she was qualified to 1st class of NYHA classification and 1st class of CCS classification. Six weeks later-ventriculography confirmed the primary diagnosis. During heart surgery the pseudoaneurysm was incised, its fibrous wall with thrombus was resected and the ruptured left ventricular myocardium was satured. She had an uneventful postoperative course. Definitive diagnosis of the pseudoaneurysm was confirmed by histopathological evaluation of the excised left ventricular wall. PMID- 19788148 TI - [Diabetes and road traffic collisions]. AB - Insulin-treated diabetes influences motor vehicle driving mainly through the possibility to induce hypoglycemia in patients. However, there has never been any consistent evidence to suggest that patients with insulin-treated diabetes cause significantly more accidents than the general population. Diabetes and its complications have very various individual courses in patients, because of that candidates for driver's license should always be qualified individually. Drivers with diabetes complications, especially the elderly, quite often themselves limit driving. The programme facilitating the diagnosis of early hypoglycemic symptoms- Blood Glucose Awareness Training--decreases road traffic collision number. PMID- 19788149 TI - [Weak anti-inflammatory effects of acetaminophen are related with its free radicals scavenger activity]. AB - The main target of acetaminophen application is bifunctional enzyme- prostaglandin endoperoxide H2 synthase (PGHS)--which has cyclo-oxygenase and peroxidase activities and synthesizes initial intermediates in prostanoid synthesis. The reaction catalyzed by PGHS is radical-based and it is initiated and then maintained by the constant presence of peroxides especially peroxynitrate, which generate so-called "peroxide tone" in the enzyme surrounding. Currently it is known that inhibitory effect of acetaminophen on PGHS activity is directly connected with the elimination of "peroxide tone". High concentrations of reactive compounds (e.g. peroxynitrate and lipid peroxides)- produced by cellular defending mechanism at inflammatory sites--significantly decrease inhibitory impact of acetaminophen on PGHS activity. Such observation allows explanation of weak antiinflammatory effect of acetaminophen together with its strong analgesic and antipyretic properties. PMID- 19788150 TI - [Hypercholesterolaemia among patients of the cardiology ward of a Regional Hospital in Wejherowo]. AB - The strong positive relationship between cholesterolaemia and ischaemic heart disease is unquestioned and comes from several lines of evidence. In this paper results of questionnaire studies concerning cholesterolemia performed among patients of the Cardiology Ward of a Regional Hospital in Wejherowo are presented. PMID- 19788151 TI - [Energy metabolism in the failing heart]. AB - Daily heart consumption of energy (about 6 kg of ATP) exceeds significantly energy consumption of other organs. Deprivation of energy is considered as one of the main factors in development of heart failure. Currently available research methods permit not only to evaluate more precisely the role of impaired energy metabolism in the heart failure, but also give a hope for the future metabolic therapy. PMID- 19788152 TI - Health inequalities--fair inequality? PMID- 19788153 TI - Confessions of a scholastic distortionist and selectivist. PMID- 19788154 TI - Public health law. PMID- 19788155 TI - Media maladies. PMID- 19788156 TI - All things being equal... PMID- 19788157 TI - Humanity and equality--will they ever be fully compatible? PMID- 19788158 TI - Tackling health inequalities in India. PMID- 19788159 TI - Social differences in populations and their implications for public health. PMID- 19788160 TI - Strengthening health systems and cross-government capacity to address health inequalities. PMID- 19788161 TI - Misfortunes never come singly. PMID- 19788162 TI - Overhead or opportunity? PMID- 19788163 TI - The Infant Mortality National Support Team. PMID- 19788164 TI - An evaluation of performance-arts based HIV-prevention events in London with 13- 16-year-olds. AB - AIM: The London borough of Newham is ethnically diverse and is one of the poorest regions in the UK. Rates of teenage pregnancy, sexually transmitted infections (STIs) and HIV are high compared to the rest of the country. One strand of the local school-based HIV-prevention programme for young people utilizes performance arts as a tool for HIV education and prevention. This study evaluated HIV knowledge, confidence and intention to use a condom in two groups of 13- 16-year olds who had participated in performance-based events. METHOD: Group 1 (n = 14) participated in a six-week programme of performance arts-based HIV education and prevention workshops, which culminated in a theatre-based performance. Group 2 (n = 65) were audience members who attended the performance. Participants completed a short questionnaire containing both qualitative and quantitative items. RESULTS: Qualitative data suggested that the participants had learned about condoms and their efficacy in preventing acquisition of HIV and sexually transmitted diseases. Quantitative results indicated that after participation in the events, respondents had more information about HIV and condom use; were more confident that they could insist on condom use with partners; and planned to use condoms in the future. There was a statistically significant difference between Groups 1 and 2 but because of the small numbers in Group 1 this result should be interpreted cautiously. CONCLUSIONS: Performance-based HIV-prevention activities may be a useful way to deliver HIV-prevention messages to young people. This evaluation will form the basis of a more systematic and robust evaluation of future events. PMID- 19788165 TI - Postnatal depression: a global public health perspective. AB - The aim of this paper is to discuss whether or not postnatal depression is a global public health concern. Public health is the study of the morbidity, mortality and the cause and course of disease, at a population rather than an individual level. Public health is also concerned with examining factors that cause health inequalities. Postnatal depression is a mental and emotional condition that can affect women during the first postnatal year. Since the effects of postnatal depression are known to go beyond the mother in that it also affects the partner and the child, it can be deemed a public health problem. Additionally, severe postnatal depression can lead to infanticide as well as maternal death, often by suicide. Furthermore, evidence demonstrates that all countries are faced with the challenge of postnatal depression, but low- to middle-income countries face the greatest burden. The literature revealed various treatment options for this complex condition. However, it also uncovered that not all women are assessed for postnatal depression, nor do all women receive treatment. The emerging picture is that postnatal depression is indeed a public health problem, particularly as the incidence is much higher than the quoted rate of 10%-15%. This paper recommends direction for public health-orientated perinatal mental health research and suggests that service providers should consider the routine assessment of all postnatal women. PMID- 19788166 TI - Sociocultural dimensions of HIV/AIDS among Middle Eastern immigrants in the US: bridging culture with HIV/AIDS programmes. AB - The population of Middle Eastern immigrants in the US has been increasing dramatically over the past 30 years, growing from 200,000 in 1970 to 1.5 million in 2000. These immigrants and their descendants constitute an important new population of interest for public health and other social programmes. With this addition to the cultural diversity of American society, it is important for healthcare programmes to be responsive to the unique cultural needs of those of Middle Eastern origin and to include them in healthcare curricula. This need is particularly imperative for human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) intervention programmes, where the reduction of risky behaviours is essential to controlling the epidemic. When Middle Easterners emigrate to the US they must adjust to the American culture, which leads to preservation of some aspects of their culture and adjustment of behaviors to match American customs. This article aims to present sociocultural factors of HIV risk behaviours that are specific to Middle Eastern culture. The article also provides recommendations for HIV/AIDS-culturally appropriate intervention programmes. PMID- 19788167 TI - Using practice development methodology to develop children's centre teams: ideas for the future. AB - The Children's Centre Programme is a recent development in the UK and brings together multi-agency teams to work with disadvantaged families. Practice development methods enable teams to work together in new ways. Although the term practice development remains relatively poorly defined, its key properties suggest that it embraces engagement, empowerment, evaluation and evolution. This paper introduces the Children's Centre Programme and practice development methods and aims to discuss the relevance of using this method to develop teams in children's centres through considering the findings from an evaluation of a two year project to develop inter-agency public health teams. The evaluation showed that practice development methods can enable successful team development and showed that through effective facilitation, teams can change their practice to focus on areas of local need. The team came up with their own process to develop a strategy for their locality. PMID- 19788168 TI - Halogenoids as ligands in superhalogen anions. AB - The superhalogen compounds are of great importance in chemistry due to their enormously high electron affinities (approaching 13 eV). The utilizing halogenoids as ligands in the superhalogen anionic species is proposed and discussed on the basis of the ab initio outer valence Green function (OVGF) theoretical results. The representative species, such as LiX(2)(-), NaX(2)(-), BeX(3)(-), MgX(3)(-), CaX(3)(-), BX(4)(-), and AlX(4)(-) (where X stands for a halogenoid group), were designed and studied at the OVGF/6-311+G(3df)//MP2/6 311+G(d) level. It was found that the halogenoids (CN, NC, OCN, NCO, SCN, and NCS) might be used as ligands while designing novel superhalogen anions. The lowest and highest electron binding energies for the species considered were found for the Na(NCS)(2)(-) (5.010 eV) and Al(NC)(4)(-) (9.209 eV), respectively. The desired range of the electronic stability of the resulting species might be achieved by the proper choice of the central metal atom and the halogenoid ligand. PMID- 19788169 TI - An expeditious I2-catalyzed entry into 6H-indolo[2,3-b]quinoline system of cryptotackieine. AB - A synthesis of a series of novel 6H-indolo[2,3-b]quinolines with different substituents on the quinoline ring is described. The method involves reaction of indole-3-carboxyaldehyde with aryl amines in the presence of a catalytic amount of iodine in refluxing diphenyl ether to yield indolo[2,3-b]quinolines in one pot. The present approach provides a new route for the synthesis of polycyclic structures related to an alkaloid cryptotackieine (neocryptolepine). PMID- 19788170 TI - Structure-based stability analysis of an extremely stable dimeric DNA binding protein from Sulfolobus islandicus. AB - ORF56 is a small and thermodynamically extremely stable dimeric protein from the archaeon Sulfolobus islandicus. This DNA binding protein is encoded on plasmid pRN1 and possibly controls the copy number of the plasmid. We report the solution NMR structure as well as the crystal structure of ORF56 comprising a ribbon-helix helix fold. The homodimer consists of an antiparallel intersubunit beta-sheet and two alpha-helices per monomer, which is a common DNA binding fold of plasmid- and phage-encoded gene regulation proteins. NMR titration experiments with ORF56 and double-stranded DNA derived from its promoter binding site revealed that it is largely the beta-sheets that interact with the DNA. The beta-sheet experiences high local fluctuations, which are conserved among DNA binding ribbon-helix-helix dimers from mesophilic and hyperthermophilic organisms. In contrast, residues strongly protected against H-D exchange are localized in helix 2, forming the hydrophobic intermolecular core of the dimer. A structure-based comparison of the intermolecular binding surface and the change in accessible surface area upon unfolding of various ribbon-helix-helix dimers with the Gibbs free energy changes and m values show a correlation between hydrophobicity of these surface areas and stability. These findings provide possible explanations for the very high thermodynamic stability of ORF56 with retained DNA binding capacity. PMID- 19788171 TI - High-throughput synthesis of graphene by intercalation-exfoliation of graphite oxide and study of ionic screening in graphene transistor. AB - We report a high-throughput method of generating graphene monolayer (>90% yield) from weakly oxidized, poorly dispersed graphite oxide (GO) aggregates. These large-sized GO aggregates consist of multilayer graphite flakes which are oxidized on the outer layers, while the inner layers consist of pristine or mildly oxidized graphene sheets. Intercalation-exfoliation of these GO aggregates by tetrabutylammonium cations yields large-sized conductive graphene sheets (mean sheet area of 330 +/- 10 microm(2)) with high monolayer yield. Thin-film field effect transistors made from these graphene sheets exhibit high mobility upon nullifying Coulomb scattering by ionic screening. Ionic screening versus chemical doping effects of different ions such as chloride and fluoride on these graphene films were investigated with a combination of in situ Raman spectroscopy and transport measurement. PMID- 19788173 TI - Catalytic asymmetric Passerini-type reaction: chiral aluminum-organophosphate catalyzed enantioselective alpha-addition of isocyanides to aldehydes. AB - A chiral Lewis acid catalyst was prepared by mixing 2 equiv of chiral binol derived organophosphoric acid and 1 equiv of Et(2)AlCl. In the presence of a catalytic amount of [4j](2)Al(III)Cl complex (0.05 equiv), reaction between alpha isocyanoacetamides (2) and aldehydes (3) afforded the corresponding 5 aminooxazoles (1) in good yields and enantioselectivities. Complex [4j](2)Al(III)Cl isolated as a white solid displayed similar reactivity as that prepared in situ. PMID- 19788172 TI - Host-guest chemistry of dendrimer-drug complexes. 3. Competitive binding of multiple drugs by a single dendrimer for combination therapy. AB - The host-guest chemistry of dendrimer-drug complexes is of great significance to the design and optimization of dendrimer-based drug delivery systems. The competitive binding of multiple drugs by a single dendrimer in aqueous solutions was investigated by (1)H NMR and 2D-NOESY studies. These rapid, noninvasive, and accurate NMR techniques allow us to monitor the signals of various drugs as well as carriers in a complicated host-guest system. Ethanol was used as an internal standard to simultaneously quantify dendrimers and drugs and to estimate the binding ability of dendrimers toward different drug molecules. The results suggested that supramolecular structure of dendrimer-multiple drug complexes is formed based on electrostatic interactions and hydrophobic/hydrogen-bond interactions. Factors including hydrophobic properties, sizes, pK(a) values, charged groups, and spatial hindrance effects of the drugs influenced the localization of drug molecules on the surface and in the interior pockets. In a ternary host-guest system of dendrimer/mycophenolic acid/phenylbutazone, many more phenylbutazone molecules localized in the inner pockets than mycophenolic acid, while more mycophenolic acid bound on the surface by ion-pairs than phenylbutazone. These results provide new insight into host-guest chemistry of dendrimer-drug complexes and the design/optimization of dendrimer-based drug delivery systems. PMID- 19788174 TI - Direct visualization of cationic surfactant aggregates at a cellulose-water interface. AB - The structure of adsorbed aggregates of the cationic surfactant cetyltrimethylammonium bromide (C(16)TAB) at the cellulose-water interface was determined using soft-contact atomic force microscopy imaging. C(16)TAB was adsorbed to the surface from a solution with a concentration above the critical micelle concentration. Imaging of the surfactant aggregate layer showed predominantly spherical micellar structures at the cellulose-water interface with some areas of short rodlike aggregates. These structures are similar to those previously observed for C(16)TAB adsorbed to other hydrophilic surfaces such as silica; hence, a similar mechanism for the arrangement of C(16)TAB on cellulose is suggested, in agreement with previous neutron reflectivity data. The buildup of the surfactant layer proceeds via direct micelle adsorption to the uncharged cellulose surface. This occurs through polar interactions between the C(16)TAB headgroup and the hydrophilic substrate to form the observed admicelle structures. PMID- 19788175 TI - Single-step conjugation of bioactive peptides to proteins via a self-contained succinimidyl bis-arylhydrazone. AB - This paper describes a method for a single-step, site-specific conjugation of bioactive peptides to proteins that exploits the monitoring advantages provided by the unique UV signature absorbance of a bis-arylhydrazone. The utility of this method is demonstrated by the conjugation of a decapeptide molecular adjuvant, YSFKDMP(MeL)aR (EP67), to two test proteins, ovalbumin (OVA) and bovine serum albumin (BSA), and to proteins expressed on intact influenza virons and fungal arthroconidia (spores) of Coccidioides. Conjugation is accomplished with a version of EP67 in which its N-terminus is modified with succinimidyl-4 benzoylhydrazino-nicotinamide (S4BHyNic) (peptide 7), thus enabling conjugation to these large entities via formation of amide bonds with surface-exposed amino groups. The presence of the strongly absorbing bis-arylhydrazone S4BHyNic (epsilon(354 nm) = 29 000 L mol(-1) cm(-1)) allows for determination of EP67-to protein molar substitution ratios (MSR), which are in good agreement with the MSRs determined by amino acid analysis. Conjugation to OVA does not compromise the ability of EP67 to engage C5a receptor bearing antigen presenting cells (APC) as measured by the EP67-mediated release of interleukin-6 (IL-6) from APCs. Mice immunized with the resulting OVA-EP67 vaccine conjugate produce high serum titers of OVA-specific IgG antibodies relative to OVA alone. Also, the conjugation of EP67 does not affect the surface integrity of influenza virons or the biological viability of Coccidioides spores. This method of conjugating bioactive peptides to proteins and other large biological entities may represent a convenient and effective way of generating various bioconjugates for use in mechanistic studies or novel therapeutic entities such as EP67-containing vaccines. PMID- 19788176 TI - Synthesis of (S)- and (R)-5-oxo-piperazine-2-carboxylic acid and its application to peptidomimetics. AB - A straightforward synthesis of (S)- and (R)-N-Boc-5-oxo-piperazine-2-carboxylic acid is reported starting from L- or D-serine and ethyl glyoxylate. Those were evaluated as constituents in two tetrapeptides by studying their secondary structure by (1)H NMR spectroscopy. In the case of Boc-Val-(S)-PCA-Gly-Leu-OMe, two readily interconverting conformations (in a 40%:60% ratio) were observed, differing for the cis-trans isomerizaton of the tertiary amide bond, while Boc Val-(R)-PCA-Gly-Leu-OMe displayed an equilibrium between a gamma-turn and a type II beta-turn conformation. PMID- 19788178 TI - Ring-closing metathesis of allylsilanes/electrophilic desilylation to prepare exo methylidenecycloalkanes. Short syntheses of teucladiol and poitediol. AB - A general strategy for the synthesis of exo-methylidenecycloalkanes, which are salient features of many terpenoid natural products, is presented. Ring-closing alkene metathesis of allylsilanes provides intermediates that can be protodesilylated with alkene transposition to afford the exocyclic alkene; alternatively, the reactivity of the cyclic allylsilane intermediate can be harnessed to introduce allylic functionality. These two modes of reactivity are showcased in short syntheses of the sesquiterpene natural products teucladiol and poitediol, respectively. PMID- 19788179 TI - Surface-enhanced Raman scattering captures conformational changes of single photoactive yellow protein molecules under photoexcitation. AB - Distinct conformational changes of single photoactive yellow protein (PYP) molecules were captured under photoexcitation, using a SERS substrate approach. These steps conform to those in PYP's photocycle. At the single molecule level, SERS of PYP yields well-resolved peaks, some of which were not reported earlier. Further, exclusive peak pairs have been identified that can elucidate PYP's conformational steps and chemisorption configuration on Ag using the SERS selection rules. Despite the "weak chemisorption" of PYP on silver that only allows the single molecule signal to sustain for approximately 1 s, this duration may be long enough to resolve PYP's photocycle (approximately 0.3 s). PMID- 19788180 TI - Novel platelet substitutes: disk-shaped biodegradable nanosheets and their enhanced effects on platelet aggregation. AB - We have studied biocompatible spherical carriers carrying a dodecapeptide, HHLGGAKQAGDV (H12), on their surface as platelet substitutes. This peptide is a fibrinogen gamma-chain carboxy-terminal sequence (gamma400-411) and specifically recognizes the active form of glycoprotein IIb/IIIa on activated platelets. Our purpose is to assess the possibility of making a novel platelet substitute consisting of disk-shaped nanosheets having a large contact area for the targeting site, rather than conventional small contact area spherical carriers. The H12 peptide was conjugated to the surface of the free-standing nanosheets made of biodegradable poly(d,l-lactide-co-glycolide) (PLGA). These H12-PLGA nanosheets were fabricated onto 3 MUm disk-shaped patterned hydrophobic octadecyl regions on a SiO(2) substrate. By way of comparison, spherical H12-PLGA microparticles with the same surface area and conjugation number of H12 were also prepared. The resulting H12-PLGA nanosheets specifically interacted with the activated platelets adhered on the collagen surface at twice the rate of the H12 PLGA microparticles under flow conditions, and showed platelet thrombus formation in a two-dimensional spreading manner. Thus, H12-PLGA nanosheets might be a suitable candidate novel platelet alternative substitute for infused human platelet concentrates for the treatment of bleeding in patients with severe thrombocytopenia. PMID- 19788181 TI - A combined QM/MM study on the reductive half-reaction of xanthine oxidase: substrate orientation and mechanism. AB - Quantum mechanical/molecular mechanical (QM/MM) methods were used to investigate the conversion of xanthine to uric acid in xanthine oxidase. Seven mechanistic variants were considered with different tautomeric forms of xanthine, different protonation states of the active-site residues, and different substrate orientations. The most favorable pathway (setup G) has a B3LYP/MM barrier of about 14 kcal mol(-1), consistent with the available experimental data. This multistep mechanism starts with Glu1261 deprotonating the xanthine at the N3 position followed by a proton transfer from the cofactor to the N9 atom of xanthine; the thus activated cofactor and substrate then react to form a tetrahedral intermediate, and a subsequent rate-limiting hydride transfer generates the product. The substrate orientation that has commonly been assumed in the literature leads to the most stable reactant complex, but the opposite orientation ("upside down") is computed to be the most favorable one during the reaction (setup G). In the "upside down" conformation, the Arg880 residue can best stabilize the reactive xanthine species with the negatively charged N3 atom, especially the tetrahedral intermediate and the following transition state for hydride transfer which is generally the highest point on the computed energy profiles. QM-only calculations for a minimal gas-phase model and for larger cluster models are performed for comparison, in particular for establishing intrinsic reactivities and a common energy scale. An analysis of the computational results provides detailed insight into the essential mechanistic role of the active-site residues. PMID- 19788182 TI - Facile high-yield solvothermal deposition of inorganic nanostructures on zeolite crystals for mixed matrix membrane fabrication. AB - Separation membranes with high performance can potentially be made by incorporating zeolites (or other nanoporous molecular sieves) in polymeric materials. However, the fabrication of technologically viable membranes has been hampered by poor adhesion between the inorganic crystals and the polymer and by inadequate dispersion of the inorganic particles. We report a facile, high-yield, and inexpensive solvothermal deposition process to prepare roughened inorganic Mg(OH)(2) nanostructures on zeolite (MFI) crystal surfaces in a controlled manner. The functionalized zeolite crystals result in high-quality "mixed matrix" membranes, wherein the zeolite crystals are well-adhered to the polymeric matrix. Substantially enhanced CO(2) and CH(4) gas permeation characteristics were observed in mixed matrix membranes containing up to 35 wt % of solvothermally modified MFI crystals. Gas permeation measurements on membranes containing nonporous uncalcined MFI revealed that the performance enhancements are indeed due to significantly enhanced MFI-polymer adhesion and distribution of MFI crystals. PMID- 19788183 TI - A new pnictide superconductor without iron. AB - LiCu(2)P(2) and LiFeP have been synthesized by conventional solid-state reaction. LiCu(2)P(2) has a crystal structure similar to that of BaFe(2)As(2); LiFeP has the same crystal structure as that of LiFeAs. Resistivity and magnetization measurements reveal that they become superconductive at 3.5 K for LiCu(2)P(2) and 4.1 K for LiFeP. PMID- 19788184 TI - Purification and characterization of nattokinase from Bacillus subtilis natto B 12. AB - Bacillus subtilis natto B-12 was isolated from natto, a traditional fermented soybean food in Japan. A fibrinolytic enzyme (B-12 nattokinase) was purified from the supernatant of B. subtilis natto B-12 culture broth and showed strong fibrinolytic activity. The enzyme was homogenously purified to 56.1-fold, with a recovery of 43.2% of the initial activity. B-12 nattokinase was demonstrated to be homogeneous by SDS-PAGE and was identified as a monomer of 29000 +/- 300 Da in its native state by SDS-PAGE and size exclusion methods. The optimal pH value and temperature were 8.0 and 40 degrees C, respectively. Purified nattokinase showed high thermostability at temperatures from 30 to 50 degrees C and alkaline stability within the range of pH 6.0-9.0. The enzyme activity was activated by Zn(2+) and obviously inhibited by Fe(3+) and Al(3+). This study provides some important information for the effect factors of fibrinolytic activity, the purification methods, and characterization of nattokinase from B. subtilis natto B-12, which enriches the theoretical information of nattokinase for the research and development of nattokinase as a functional additive of food. PMID- 19788185 TI - An altered pattern of liver apolipoprotein A-I isoforms is implicated in male chronic hepatitis B progression. AB - Chronic hepatitis B (CHB) appears to progress more rapidly in males than in females, and CHB-related hepatic cirrhosis and hepatocellular carcinoma are predominately diseases that tend to occur in men and postmenopausal women. To obtain more insight into the underlying mechanisms of gender disparity of CHB progress, two-dimensional difference gel electrophoresis was employed to compare liver proteome of C57BL/6 and HBV transgenic (HBV-Tg) mice both in male and female groups. We identified 8 differently expressed proteins in male HBV-Tg mice and 12 in female HBV-Tg mice. Apolipoprotein A-I (Apo A-I) was found to be down regulated in male and female HBV-Tg mouse liver. It is more interesting that the pattern of liver Apo A-I isoforms was altered in male HBV-Tg mice but not in female HBV-Tg mice. Our further results indicated that the basic Apo A-I isoform, based on pI positions from serum 2-dimensional Western blotting, increased in male CHB patient sera but not in female CHB patient sera. Finally, we identified that the oxidative modification Apo A-I mainly reside in basic isoform. This pattern of selectively modified Apo A-I isoforms may be considered as a pathological hallmark that may extend our knowledge of the molecular pathogenesis of CHB progression. PMID- 19788186 TI - Differentiation of dried sea cucumber products from different geographical areas by surface desorption atmospheric pressure chemical ionization mass spectrometry. AB - Without any sample pretreatment, mass spectral fingerprints of 486 dried sea cucumber slices were rapidly recorded in the mass range of m/z 50-800 by using surface desorption atmospheric pressure chemical ionization mass spectrometry (DAPCI-MS). A set of 162 individual sea cucumbers (Apostichopus japonicus Selenka) grown up in 3 different geographical regions (Weihai: 59 individuals, 177 slices; Yantai: 53 individuals, 159 slices; Dalian: 50 individuals, 150 slices;) in north China sea were successfully differentiated according to their habitats both by Principal Components Analysis (PCA) and Soft Independent Modeling of Class Analogy (SIMCA) of the mass spectral raw data, demonstrating that DAPCI-MS is a practically convenient tool for high-throughput differentiation of sea cucumber products. It has been found that the difference between the body wall tissue and the epidermal tissue is heavily dependent on the habitats. The experimental data also show that the roughness of the sample surface contributes to the variance of the signal levels in a certain extent, but such variance does not fail the differentiation of the dried sea cucumber samples. PMID- 19788187 TI - Cross-coupling of alkenyl/aryl carboxylates with Grignard reagent via Fe catalyzed C-O bond activation. AB - Iron-catalyzed cross-coupling of alkenyl/aryl carboxylates with primary alkyl Grignard reagent was described. This reaction brought a new family of electrophiles to iron catalysis. The combination of an inexpensive carboxylate electrophile and an iron catalyst would generate ample advantages. PMID- 19788188 TI - Biorecognition of chemically modified bovine serum albumin with lactose prepared under different conditions. AB - Glycoconjugates consist of glycans attached to proteins or lipids. Glycans are involved in important biological functions such as trafficking of glycoconjugates, mediation, and modulation of cell adhesion and signaling. This study was conducted to obtain neoglycoconjugates containing a large number of carbohydrates, added through the condensation of reducing sugars with protein amino groups, whose structures were recognized by lectins. Neoglycoconjugates (BSA-Lac) of bovine serum albumin (BSA) with d-lactose were obtained using two sets of glycation conditions, each previously selected by its ability to glycate proteins extensively. The conditions included dry heat at 60 degrees C (for 7, 14, 21, and 28 days) and wet heat in 43% relative humidity (RH) at 50 degrees C (for 5, 10, 15, and 20 h). Products were characterized by gel electrophoresis, tryptophan fluorescence emission spectra, mass spectrometry, free amino group analysis, and their biological recognition established by a galactose-specific lectin and Escherichia coli K88 adhesins. BSA-Lac when compared to BSA revealed an increase in monomer mass due to addition of either 13 (dry heat) or 14 (wet heat) lactoses and formation of polymers (in wet conditions). All BSA-Lac products showed reduced intensity of intrinsic fluorescence, decreased amino groups' availability, and were recognized by Ricinus communis I lectin (RCAI) and by E. coli K88 adhesins. Overall, glycation using both conditions was time dependent, but greater biorecognition was observed with wet-heat products, due to a higher global glycation and/or to the carbohydrate accessibility. The strategy used in this work represents a simple procedure to obtain glycoconjugates that could be used for recognition studies in biological systems. PMID- 19788177 TI - Coordination chemistry of bacterial metal transport and sensing. PMID- 19788189 TI - Application of conventional solid-phase extraction for multimycotoxin analysis in beers by ultrahigh-performance liquid chromatography-tandem mass spectrometry. AB - A new analytical method has been developed and validated for the simultaneous analysis of mycotoxins (aflatoxins B1, B2, G1, G2, and M1, fumonisins B1 and B2, deoxynivalenol, ochratoxin A, HT-2 and T-2 toxins, and zearalenone) in beers. Mycotoxins were extracted by solid-phase extraction (SPE) using C18 as the cartridge. Several parameters such as type of sorbent, elution solvent, and dilution of the sample were evaluated. The separation and determination were carried out by ultrahigh performance liquid chromatography coupled to tandem mass spectrometry (UHPLC-MS/MS). The method was validated, and mean recoveries ranging from 70 to 106% were obtained. Repeatability and intermediate precision, expressed as relative standard deviations, were lower than 21% for all mycotoxins and levels assayed. The limits of quantification were lower than 0.5 microg/L. The developed method has been applied for the analysis of several types of beers with different alcoholic content (nonalcoholic, normal, and special), and T2, HT 2 toxins, aflatoxin B1, and fumonisin B2 were detected. This methodology combines the simplicity of SPE using conventional cartridges and UHPLC-MS/MS, producing a rapid, sensitive, and reliable procedure. PMID- 19788190 TI - Transition metal-catalyzed living radical polymerization: toward perfection in catalysis and precision polymer synthesis. PMID- 19788191 TI - The mechanism of dephosphorylation of bis(2,4-dinitrophenyl) phosphate in mixed micelles of cationic surfactants and lauryl hydroxamic acid. AB - Mixed micelles of cetyltrimethylammonium bromide (CTABr) or dodecyltrimethylammonium bromide (DTABr) and the alpha-nucleophile, lauryl hydroxamic acid (LHA) accelerate dephosphorylation of bis(2,4 dinitrophenyl)phosphate (BDNPP) over the pH range 4-10. With a 0.1 mole fraction of LHA in DTABr or CTABr, dephosphorylation of BDNPP is approximately 10(4)-fold faster than its spontaneous hydrolysis, and monoanionic LHA(-) is the reactive species. The results are consistent with a mechanism involving concurrent nucleophilic attack by hydroxamate ion (i) on the aromatic carbon, giving an intermediate that decomposes to undecylamine and 2,4-dinitrophenol, and (ii) at phosphorus, giving an unstable intermediate that undergoes a Lossen rearrangement yielding a series of derivatives including N,N-dialkylurea, undecylamine, undecyl isocyanate, and carbamyl hydroxamate. PMID- 19788192 TI - Pd(II)-catalyzed hydroxylation of arenes with 1 atm of O(2) or air. AB - Pd(II)-catalyzed ortho-hydroxylation of variously substituted benzoic acids under 1 atm of O(2) or air is achieved under nonacidic conditions. Extensive labeling studies support a direct oxygenation of aryl C-H bonds with molecular oxygen. PMID- 19788193 TI - Microstructure and deformation behavior of polyethylene/montmorillonite nanocomposites with strong interfacial interaction. AB - Deformation behavior of polyethylene/modified montmorillonites with polymerizable surfactant (PE/P-MMT) nanocomposite with strong interfacial interaction was studied by means of morphology observation and X-ray scattering measurements. The orientation of PE chains was accompanied by the orientation of well-dispersed MMT platelets due to the presence of strong interfacial interaction, and both of the orientations were parallel to the deformation direction. The high degree of orientation of MMT platelets and PE chains resulted from the synergistic movement of PE matrix and MMTs, which originated from the presence of a network-like structure. Meanwhile, the existence of MMT platelets with good mobility during deformation and strong interfacial interaction with PE matrix could further improve the break energy of material by restraining the initiation and growth of cavities during deformation. In contrast, PE/MMT nanocomposite with no strong interfacial interaction and poor dispersed state of MMT sheets showed the weaker orientation of both PE chains and MMT platelets, and a strong cavitation during deformation. PMID- 19788195 TI - How chain length and charge affect surfactant denaturation of acyl coenzyme A binding protein (ACBP). AB - Using intrinsic tryptophan fluorescence, equilibria and kinetics of unfolding of acyl coenzyme A binding protein (ACBP) have been investigated in sodium alkyl sulfate surfactants of different chain length (8-16 carbon atoms) and with different proportions of the nonionic surfactant dodecyl maltoside (DDM). The aim has been to determine how surfactant chain length and micellar charge affect the denaturation mechanism. ACBP denatures in two steps irrespective of surfactant chain length, but with increasing chain length, the potency of the denaturant rises more rapidly than the critical micelle concentration (cmc) declines. Increasing proportions of DDM, which significantly reduce the amount of monomeric sodium dodecyl sulfate (SDS), make the first denaturation step occur at lower concentrations but weaken and eventually remove the second denaturation step. The logarithm of the unfolding rate constants increases linearly with denaturant concentration below the cmc but declines at higher concentrations. Both shortening chain length and decreasing micellar charge reduce the overall kinetics of unfolding and makes the dependence of unfolding rate constants on surfactant concentration more complex. This behavior contrasts with the simplicity of unfolding in chemical denaturants and highlights the changing properties of surfactant micelles. We suggest that the transition from spherical to more elongated micelles leads to inhibition of unfolding kinetics, while weaker binding sites may cause a subsequent rise in unfolding rate constants at higher surfactant concentrations. We propose that shifting micellar binding sites on globular proteins such as ACBP, as opposed to the predefined binding sites on membrane protein surfaces, may lead to nonlinear correlations between activation unfolding energies and SDS mole fraction. PMID- 19788194 TI - Protein binding and the electronic properties of iron(II) complexes: an electrochemical and optical investigation of outer sphere effects. AB - Metalloenzymes and electron transfer proteins influence the electrochemical properties of metal cofactors by controlling the second-sphere environment of the protein active site. Properties that tune this environment include the dielectric constant, templated charge structure, van der Waals interactions, and hydrogen bonds. By systematically varying the binding of a redox-active ligand with a protein, we can evaluate how these noncovalent interactions alter the electronic structure of the bound metal complex. For this study, we employ the well characterized avidin-biotin conjugate as the protein-ligand system, and have synthesized solvatochromic biotinylated and desthiobiotinylated iron(II) bipyridine tetracyano complexes ([Fe(BMB)(CN)(4)](2-) (1) and [Fe(DMB)(CN)(4)](2 ) (2)). The binding affinities of 1 and 2 with avidin are 3.5 * 10(7) M(-1) and 1.5 * 10(6) M(-1), respectively. The redox potentials of 1 and 2 (333 mV and 330 mV) shift to 193 mV and 203 mV vs Ag/AgCl when the complex is bound to avidin and adsorbed to a monolayer-coated gold electrode. Upon binding to avidin, the MLCT1 band red-shifts 20 nm for 1 and 10 nm for 2. Similarly, the MLCT2 band for 1 red shifts 7 nm and the band for 2 red-shifts 6 nm. For comparison, the electronic properties of 1 and 2 were investigated in organic solvents, and similar shifts in the MLCT bands and redox potentials were observed. An X-ray crystal structure of 1 bound to avidin was obtained, and molecular dynamics simulations were performed to analyze the protein environment of the protein-bound transition metal complexes. Our studies demonstrate that changes in the binding affinity of a ligand-receptor pair influence the outer-sphere coordination of the ligand, which in turn affects the electronic properties of the bound complex. PMID- 19788196 TI - Brownian molecular dynamics simulation on self-assembly behavior of diblock copolymers: influence of chain conformation. AB - Brownian molecular dynamic simulations are applied on the self-assembly behavior of AB-type diblock copolymers. The influence of chain conformation of core forming A-block changing from rigid to flexible on the aggregation structure formed by AB copolymers is investigated. It is found that at a high rigid fraction f(R) of A-block, a disk structure can be formed at a high aggregation interaction epsilon(AA) of A-bead pairs because of the tendency of orientational packing of rigid portion within the aggregate core. Transitions of aggregation structure from disk to string, further to small aggregates, and to unimers are observed with decreasing epsilon(AA). The packing of A-blocks becomes more random at relatively lower values of f(R), resulting in the formation of spherical structure. The region of string becomes narrower while the regions of the small aggregates and sphere become wider as decreasing f(R). Meanwhile, the onsets of string, disk, and sphere formation move to higher epsilon(AA). The phase diagrams for the influences of rigid potion location within the A-block and the chain rigidity of the A-block are mapped. The comparison of simulation results with existing experimental observations is also presented. Our simulation results tend to bridge a gap of different micellization behaviors between rod-coil block copolymers and coil-coil block copolymers and extend to investigate chain conformation influence on phase diagram. PMID- 19788197 TI - Rotational structure of a super-excited state of the NO molecule revealed by OODR multiphoton laser spectroscopy. AB - The optical-optical double resonance time of flight (OODR-TOF) spectroscopy technique was employed to examine the 65,000-66,500 cm(-1) region of the nitric oxide spectrum. In this region, we detected the following three electronic states: E (2)Sigma(+) (nu = 2) (Rydberg state), B (2)Pi (nu = 23) (valence state), and L (2)Pi (nu = 4) (valence state). The rotational structure analysis of an unexpected band in the red part of the spectra revealed the presence of a new super-excited (2)Sigma(+) Rydberg state at approximately 13.3 eV, which was populated through a three-photon transition from the intermediate A (2)Sigma(+) (nu = 0) state. This super-excited state converges to the NO (a(3)Sigma(+)) ionic state with electronic configuration (1sigma)(2)(2sigma)(2)(3sigma)(2)(4sigma)(2)(5sigma)(2)(1pi)(3)(2pi)(1)(3ssigma)( ). PMID- 19788199 TI - CO-free hydrogen production for fuel cell applications over Au/CeO2 catalysts: FTIR insight into the role of dopant. AB - The impact of ceria doping by Zn (atomic ratio Zn/(Zn + Ce) = 0.05) on the structural and catalytic properties of Au/CeO(2) catalyst was studied. The ceria modification influenced the catalytic activity toward purification of hydrogen via water-gas shift (WGS) and preferential CO oxidation (PROX) reactions in a different way: it diminished the WGS activity and improved the PROX performance. A characterization by FTIR spectroscopy was conducted to explain differences in the catalytic performance. The nature of gold active species after different pretreatments, under different atmospheres (H(2), D(2)), and after admission of CO and its subsequent interaction with (18)O(2) was investigated. Evidence has been found of the dissociation of hydrogen at room temperature on gold, producing on the oxidized sample a broad absorption assigned to Au-OH vibrations, whereas on the reduced one, bands at 3200 and 1800 cm(-1) ascribed, respectively, to Au OH and Au-H species have been detected. For the first time, the formation of Au hydride on supported heterogeneous catalysts was proposed. These features were stronger on the Au/CeO(2) sample than on the Au/Zn-CeO(2) sample. The availability of highly dispersed gold clusters in contact with oxygen vacancies on the ceria surface could contribute to higher WGS activity, whereas the steps of small gold particles are the active sites for both CO and oxygen activation during the PROX reaction. PMID- 19788198 TI - Interaction of serotonin and fluoxetine: toward understanding the importance of the chirality of fluoxetine (S form and R form). AB - The present investigation reports the importance of the S and R forms of fluoxetine, as an antidepressant with regards to the chirality taking different types of interactions associated with the neurotransmitter, serotonin. The goal of the present study is to provide predictions and to help experimental and theoretical studies toward understanding the chirality of fluoxetine in drug ligand interaction, associated with serotonin-reuptake inhibitor drug design studies. Several different conformations for serotonin and fluoxetine complexes have been considered for quantum mechanical calculations. Both the S and R forms of fluoxetine associated with serotonin and fluoxetine complexes are found to be similar in total energy and binding energy values. The present study also supports the conformational effect of the 3-phenyl group of fluoxetine as stereo independent and is consistent with in vitro and in vivo data which indicates that the the eudismic ratio of fluoxetine enantiomers is near unity. The calculated highest stabilization energy values, binding energy values, both in the gas and aqueous phases at MP2/6-31+G*//B3LYP/6-31+G* identify the most possible stable conformer for the serotonin-fluoxetine complex. PMID- 19788200 TI - Further studies on arylpiperazinyl alkyl pyridazinones: discovery of an exceptionally potent, orally active, antinociceptive agent in thermally induced pain. AB - A number of pyridazinone derivatives bearing an arylpiperazinylalkyl chain were synthesized and tested icv in a model of acute nociception induced by thermal stimuli in mice (tail flick). The most interesting and potent compound in this series was 6a, which showed an ED(50) = 3.5 microg, a value about 3-fold higher with respect to morphine by the same route of administration. When administered per os, 6a was 4-fold more potent than morphine in the same test, suggesting a significant bioavailability. The same compound also showed high potency in the hot plate test. The antinociceptive effect of 6a was completely reversed by pretreatment with yohimbine both in the hot plate test and in the tail flick test. This demonstrated the involvement of the adrenergic system, which was confirmed by in vitro radioligand binding studies. PMID- 19788201 TI - Pentapeptides displaying mu opioid receptor agonist and delta opioid receptor partial agonist/antagonist properties. AB - Chronic use of mu-opioid agonists has been shown to cause neurochemical adaptations resulting in tolerance and dependence. While the analgesic effects of these drugs are mediated by mu-opioid receptors (MOR), several studies have shown that antagonism or knockdown of delta-opioid receptors (DOR) can lessen or prevent development of tolerance and dependence. On the basis of computational modeling of putative active and inactive conformations of MOR and DOR, we have synthesized a series of pentapeptides with the goal of developing a MOR agonist/DOR antagonist peptide with similar affinity at both receptors as a tool to probe functional opioid receptor interaction(s). The eight resulting naphthylalanine-substituted cyclic pentapeptides displayed variable mixed efficacy profiles. The most promising peptide (9; Tyr-c(S-CH(2)-S)[D-Cys-Phe-2 Nal-Cys]NH(2)) displayed a MOR agonist and DOR partial agonist/antagonist profile and bound with equipotent affinity (K(i) approximately 0.5 nM) to both receptors, but also showed kappa opioid receptor (KOR) agonist activity. PMID- 19788202 TI - Intersystem crossings of the triplet and singlet States in cobalt and copper mononitrosyls. AB - Local minima on the singlet, triplet, and quintet potential energy surfaces (PES) of cobalt and copper mononitrosyls are studied by DFT with the B3LYP functional. While quintet states are separated from the triplet and singlet states by a high energy gap, the linear singlet local minimum and the triplet transition state of CoNO lie close together. The ordering of local minima by relative stability of low-lying excited states with respect to the ground state was assessed by B3LYP, the coupled-cluster method CCSD(T), and complete active space calculations (CAS MP2). The ground state of CoNO is (3)A'; two local minima were found in singlet states: linear, (1)Sigma(+), and side-on configuration, (1)A(1). The occurrence of bound states on the triplet and singlet PES of CoNO and CuNO was examined by CASSCF. The crossing of the singlet and triplet PES of CoNO is a conical intersection; the geometry of the bound state is linear, with elongated N-O bond. The activation energy for the spin-forbidden transition (3)A' --> (1)Sigma(+) is estimated to be 154.7 kJ mol(-1). For CuNO, the triplet and singlet PES do not cross but are separated by a small energy gap. Copper nitrosyl is of lower thermodynamic stability than cobalt nitrosyl. A triplet ground state (3)A'' with bent configuration is predicted by B3LYP, confirmed by CAS MP2, and a very close lying singlet state (1)A' is found with nearly identical geometry. Unlike CoNO, the linear triplet CuNO in (3)Sigma(-) state is not a transition state, but a local minimum, lying close to the dissociation limit Cu + NO. Vibrational frequencies are calculated for the gas-phase molecules and for the metal nitrosyl entrapped in solid Ar matrix. Under the influence of the noble gas matrix, the energy gap between the singlet and the triplet CuNO is reduced, and the singlet and triplet states of bent CuNO become nearly isoenergetic in agreement with experimental data. The linear CoNO in (1)Sigma(+) state is the most stable configuration in the Ar matrix, with one Ar atom coordinated to the metal center. PMID- 19788203 TI - Fabrication of functional silver nanobowl arrays via sphere lithography. AB - We report a low-cost and high-throughput method to fabricate large-area silver nanobowl arrays via thermal evaporation of silver on a self-assembled monolayer of nanospheres. The nanobowl array is a hierarchical structure, composed of silver nanoparticles with average diameter size of ca.10 nm, which can serve as a reaction container and catalyst. The optical absorption spectra indicates that surface plasmon resonance of silver nanoparticles exists on the nanobowl array, and it can serve as an excellent surface enhanced Raman scattering (SERS)-active substrate. PMID- 19788204 TI - One-dimensional alignment of SBA-15 films in microtrenches. AB - SBA-15 thin films were synthesized by dip-coating in two different types of microtrenches: (a) silicon microtrenches and (b) silicon microtrenches with a deposited low-temperature oxide (LTO) layer. In the upper part of the synthesized films, the pores were aligned along the concave surface in both microtrenches. This alignment was attributed to the capillary force acting during solvent evaporation. In the lower part of the films, the pores were aligned tangentially with the wall in a silicon microtrench whereas they were aligned normal to the wall in a silicon microtrench with a deposited LTO layer. The LTO layer could suppress the growth of mesostructures from the substrate and promote growth from the vapor-liquid interface. The effects of the composition of the precursor solution and relative humidity on pore alignment were also clarified. PMID- 19788205 TI - Real-time in situ atomic force microscopy imaging of bismuth crystal growth. AB - We have performed real-time atomic force microscopy (AFM) imaging of bismuth crystals that were grown under electrochemical control at low overpotentials to ensure a slow growth rate and allow in situ observation of the growth. A two step chronoamperometric potential was applied to a boron-doped diamond (BDD) working electrode with a short high overpotential, -0.4 V (2 s), to nucleate the bismuth, and then a long low overpotential for slow growth, -0.32 V (4.4 h). Growth rates of individual crystals and detailed growth mechanisms could be followed in real time because of the slow crystal growth. The close proximity of the AFM tip and tip holder to the working electrode appears to hinder the diffusion of bismuth to the BDD surface, as evidenced by the significantly lower density of crystals under the cantilever as compared to the rest of the electrode, therefore slowing down the growth process. PMID- 19788206 TI - Dispersing nanoparticles in a polymer matrix: are long, dense polymer tethers really necessary? AB - Dispersing nanoparticles in a polymer matrix is intrinsically challenging because of unfavorable entropic interactions between the matrix and the nanoparticle. Similar to suspensions of larger colloidal particles, it has been found that thermodynamically stable dispersions of nanoparticles can be achieved in polymer matrices when the nanoparticles are decorated with dense layers of polymer tethers whose molecular weight is comparable to or greater than that of the matrix. Utilizing molecular dynamics simulations, we demonstrate that, in contrast to larger colloidal particles, repulsive interactions between nanoparticles can be achieved with tethered polymers much shorter than the polymer matrix when relatively sparse grafting is employed. PMID- 19788207 TI - Acute degradation of surface-bound unsaturated polyolefins in common solvents under ambient conditions. AB - We describe the detachment of covalently grafted polybutadiene and polynorbornene chains, which were prepared by surface-initiated ring-opening metathesis polymerization (SiROMP), from Si/SiO2 substrates upon brief exposure to common solvents in air. Degradation and disappearance of grafted polybutadiene films after successive rinses with dichloromethane were monitored by ellipsometry. Changes in surface topography were analyzed by atomic force microscopy. The rapid auto-oxidation of allylic carbon-hydrogen bonds renders these thin films extremely susceptible to degradation under ambient conditions. Polymers in the tethered state suffer more acute degradation (on the time scale of seconds) compared to those dissolved in solution (not detectable after days). To prevent degradation, unsaturated polymers prepared by SiROMP and the subsequent conversion (of unsaturated groups) need to be carried out under inert atmosphere. For example, smooth polybutadiene thin films of approximately 100 A thickness were covalently attached to silicon substrates via SiROMP of cyclooctadiene in the vapor phase. Solvent rinsing to remove unreacted monomers and free oligomers/polymers was carried out prior to the conversion of double bonds to epoxide groups. When these steps were carried out under nitrogen, negligible film loss was observed, and surface topography of the thin films was preserved. Once the unsaturation was removed from polybutadiene, the epoxidized and hydroxylated polybutadiene films were stable toward solvent exposure in air. PMID- 19788208 TI - Fabrication of silica-coated gold nanorods functionalized with DNA for enhanced surface plasmon resonance imaging biosensing applications. AB - A novel method for preparing gold nanorods that are first coated with a thin silica film and then functionalized with single-stranded DNA (ssDNA) is presented. Coating the nanorods with 3-5 nm of silica improves their solubility and stability. Amine-modified ssDNA is attached to the silica-coated gold nanorods via a reductive amination reaction with an aldehyde trimethoxysilane monolayer. The nanorods exhibit an intense absorption band at 780 nm, and are used to enhance the sensitivity of surface plasmon resonance imaging (SPRI) measurements on DNA microarrays. PMID- 19788209 TI - Durable large-area thin films of graphene/carbon nanotube double layers as a transparent electrode. AB - We prepared durable, uniform, large-area ultrathin transparent films composed of double layers of reduced graphene oxide (RG-O) and multiwalled carbon nanotubes (MWNTs) via a self-assembly process. The adsorption of MWNTs onto RG-O films considerably decreased the sheet resistance of the films without compromising much on transparency. This self-assembly approach could be used to fabricate transparent electronic devices without post-transfer processes on a large scale. PMID- 19788210 TI - Formation of patterned arrays of polystyrene colloidal crystal structures on flexible functional substrates. AB - This contribution presents the first preparation of patterned arrays of highly ordered polystyrene colloidal crystal structures on flexible functional substrates. The formation of patterned arrays of colloidal crystals over large areas (5x1 cm) with periodic line patterns ranging in pitch from 25 to 450 microm is demonstrated. The protocol developed to achieve this is applicable to a wide range of substrates and is inherently scalable. Interestingly, directed colloidal deposition was found to be more susceptible to fluctuations in the deposition conditions than bulk deposition. The conditions required for directed deposition were systematically investigated, and the success of the optimized protocol was illustrated by the deposition of ordered structures on a range of functionalized rigid and flexible substrates. These advances-low-cost production on flexible functional substrates and the fabrication of structures of controlled geometry address two of the major challenges in developing devices using colloidal crystal structures. PMID- 19788211 TI - Aqueous-core lipid nanocapsules for encapsulating fragile hydrophilic and/or lipophilic molecules. AB - This paper presents the original method of producing aqueous-core lipid nanocapsule, able to encapsulate both hydrophilic and lipophilic species with relevant yields. The scope offered by the integration of both hydrophilic and lipophilic molecules within the same colloidal objects make this method a prime candidate for the numerous anticancer therapies for which chemotherapy frequently requires the association of several molecules. The proof of concept study is proposed here (i) describing in detail the formulation of such objects and their characterization (TEM, cryo-TEM, soft particle analysis), (ii) showing the encapsulation of hydrophilic species alone, using examples of very different molecular weights, such as a dye (methylene blue) and a protein (BSA isothycianate fluorecein labeled), and (iii) showing the simultaneous encapsulation of hydrophilic (methylene blue) and lipophilic (also a dye, red Sudan III) species. PMID- 19788212 TI - Postformation Modification of SAMs: using click chemistry to functionalize organic surfaces. AB - We have investigated a recently established strategy of modifying organic surfaces exposed by thiolate SAMs (self-assembled monolayers) deposited on Au substrates by employing so-called click chemistry. This term is used to denote a modified Huisgen 1,3-dipolar cycloaddition. We demonstrate the potential of this method by coupling ferrocene and azido acetic acid to alkyne/azide-terminated SAMs. After the surface reaction, the modified organic monolayers were analyzed using infrared spectroscopy (IR), X-ray photoelectron spectroscopy (XPS), and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. Under the conditions used in this study, only for the azide-terminated SAMs could successful grafting of the ferrocene be achieved whereas for the alkyne terminated SAMs the spectroscopic studies reveal a rather low yield of the coupling reaction. PMID- 19788214 TI - Modeling of charged amphiphilic copolymer stars near hydrophobic surfaces. AB - Numerical self-consistent field theory has been applied to amphiphilic copolyelectrolyte stars in the solution and at interfaces both in one- and two gradient coordinate systems. Our focus is on polymer stars for which the solvent is poor for the short blocks in the center and good for the longer charged chain parts at the periphery of the star. Both in solution as well as near an interface, the structure of the core is influenced by the hydrophobic interactions that tend to form a compact globule with size Rc and the forces exerted by the charged peripheral chain parts that like to expand the core. When the distance H of the center of the star to the surface becomes smaller than the total size R, the interaction force becomes significant; it is positive for RcRHcr, water menisci freely form and spread along the interface between the rough surfaces. PMID- 19788225 TI - Enhancing the photoluminescence of polymer-stabilized CdSe/CdS/ZnS core/shell/shell and CdSe/ZnS core/shell quantum dots in water through a chemical activation approach. AB - We report a method for preparing highly photoluminescent, water-soluble CdSe/CdS/ZnS core/shell/shell and CdSe/ZnS core/shell quantum dots (QDs) colloidally stabilized by double hydrophilic copolymers. The polymers, either a diblock copolymer poly(ethylene glycol-b-2-N,N-dimethylaminoethyl methacrylate) (PEG-b-PDMA) or a statistical copolymer poly(oligoethylene glycol methacrylate-co 2-N,N-dimethylaminoethyl methacrylate) (POEG-co-PDMA), were able to replace the hexadecylamine (HDA) or trioctylphosphine oxide (TOPO) ligands on the surface of the as-synthesized QDs and impart water-solubility and colloidal stability to the QD nanocrystals. In water, the [CdSe/ZnS]/POEG-co-PDMA colloids were present in the form of aggregates with a mean apparent hydrodynamic radius Rh of 54 nm and a narrow size distribution. Although the photoluminescence (PL) quantum yield (QY) of the polymer-treated QDs decreased upon transfer from an organic medium to water, much of this loss in brightness could be restored by the addition to the solution of an excess of a water-soluble primary amine such as 3-amino-propanol (APP). This chemical-activation strategy of adding primary amines as PL activators to polymer-stabilized QDs did not lead to a spectral shift of either the absorption or emission of the QDs in water. PMID- 19788226 TI - Mechanisms of oxygen plasma nanotexturing of organic polymer surfaces: from stable super hydrophilic to super hydrophobic surfaces. AB - Plasma processing is used to fabricate super hydrophilic or super hydrophobic polymeric surfaces by means of O2 plasma etching of two organic polymers, namely, poly(methyl methacrylate) (PMMA) and poly(ether ether ketone) (PEEK); a C4F8 plasma deposition follows O2 plasma etching, if surface hydrophobization is desired. We demonstrate high aspect ratio pillars with height ranging from 16 nm to several micrometers depending on the processing time, and contact angle (CA) close to 0 degrees after O2-plasma treatment or CA of 153 degrees (with CA hysteresis lower than 5 degrees) after fluorocarbon deposition. Super hydrophobic surfaces are robust and stable in time; in addition, aging of super hydrophilic surfaces is significantly retarded because of the beneficial effect of the nanotextured topography. The mechanisms responsible for the plasma-induced PMMA and PEEK surface nanotexturing are unveiled through intelligent experiments involving intentional modification of the reactor wall material and X-ray photoelectron spectroscopy, which is also used to study the surface chemical modification in the plasma. We prove that control of plasma nanotexture can be achieved by carefully choosing the reactor wall material. PMID- 19788227 TI - Exfoliated graphite oxide decorated by PDMAEMA chains and polymer particles. AB - Exfoliated graphite oxide (GO) sheets with hydroxyl groups and amine groups on the surface were prepared by modification of graphite. Atom transfer radical polymerization (ATRP) initiator molecules were grafted onto the GO sheets by reactions of 2-bromo-2-methylpropionyl bromide with hydroxyl groups and amine groups. Poly(2-(dimethylamino)ethyl methacrylate) (PDMAEMA) chains on the surface of GO sheets were synthesized by in-situ ATRP. X-ray photoelectron spectroscopy, thermogravimetric analysis, and transmission electron microscopy (TEM) results all demonstrated that polymer chains were successfully produced. After grafting of PDMAEMA, the dispersity of GO sheets in solvents was improved significantly. Poly(ethylene glycol dimethacrylate-co-methacrylic acid) particles were deposited on GO sheets via hydrogen bonding between MAA units on polymer particles and amine groups of PDMAEMA. TEM and scanning electron microscopy were used to characterize the structure of the nanocomposites. PMID- 19788228 TI - One-step hydrothermal creation of hierarchical microstructures toward superhydrophilic and superhydrophobic surfaces. AB - This article describes a simple and convenient method to fabricate hierarchically structured coatings on glass substrates from soda lime glass by one-step hydrothermal method. The surfaces of the coatings are rough and are composed of flower-like particles assembled by nanoflakes or urchin-like particles constructed by nanowires. These rough surfaces exhibit superhydrophilicity, their water contact angles reaching 0 degrees in less than 40 ms. After surface modification by 1H,1H,2H,2H-perfluorooctyltriethoxysilane, the wetting properties of these coatings switch from superhydrophilicity to superhydrophobicity, with water contact angles as high as 160 degrees and slide angle as low as 1 degrees . The formation mechanism of the hierarchically structured coatings is discussed in detail on the basis of experimental results. PMID- 19788229 TI - Multiple particle tracking investigations of acid milk gels using tracer particles with designed surface chemistries and comparison with diffusing wave spectroscopy studies. AB - Multiple particle tracking (MPT) has been used in an attempt to probe the heterogeneity of acid milk gels, made with and without added pectin, by following the distribution of the displacements of added tracer beads during and after gelation using the Van Hove distribution. Furthermore, the surface chemistry of the latex probe particles was modified in an attempt to control their location in the system and probe the microrheological properties of the protein network and aqueous-phase voids independently. In addition, the mean square displacement (MSD) of the casein micelles/casein aggregates themselves, obtained by diffusing wave spectroscopy (DWS), has been compared to the ensemble-averaged MSD calculated from the data obtained by tracking the movement of the added tracers, with and without a kappa-casein coating. For the kappa-casein-coated tracer particles, upon acidification and subsequent gel formation, the MSDs obtained by MPT superimpose remarkably well with the MSDs obtained by DWS, despite the fact that one is obtained by tracking the movement of the particle network elements themselves and the other is obtained from directly tracking added tracers. This result has important implications: (i) it demonstrates that, although the DWS measurement is intrinsically ensemble-averaged, it really gives insight into the dynamics of the colloidal gel network; (ii) it confirms that the kappa-casein coated probes used in this MPT experiment are well incorporated into the gel network; and hence (iii) that at least in gelled systems kappa-casein-coated latex probes are interesting probes that reveal the dynamics of the casein network. PMID- 19788230 TI - Selective growth of Ag nanodewdrops on Au nanostructures: a new type of bimetallic heterostructure. AB - A new type of bimetallic Au-Ag heterostructured material was prepared by a selective growing strategy of a Ag nanodewdrop on the petal tip of a Au flower using an electrochemical method. The whole process was strictly controlled by forming the reactive tip of the flower petal and passivating the facet along the body of the metal petal using poly(vinyl pyrrolidone) (PVP) coating film. The formed Au-Ag heterostructured flowers (HSFs) were observed to be about 2 microm in diameter and have the Ag particles of about 50 nm settled on the tips of Au petals. The Au-Ag HSFs were found to display the superior properties on the surface-enhanced Raman scattering (SERS). The presence of Ag nanodewdrops could also facilitate the oxidation of Ru(bpy)3(2+) complex in electrogenerated chemiluminescence (ECL) measurements and dramatically enhance the emission intensity. The features of Au-Ag HSFs can promise a new type of heterogeneous bimetallic alloy material for the potential applications in chemical and biological sensors. PMID- 19788231 TI - Ag dendrite-based Au/Ag bimetallic nanostructures with strongly enhanced catalytic activity. AB - Dendritic Ag/Au bimetallic nanostructures have been synthesized via a galvanic replacement reaction (GRR) of Ag dendrites in a chlorauric acid (HAuCl4) solution. After short periods of time, one obtains structures with protruding flakes; these will mature into very porous structures with little Ag left over. The morphological, compositional, and crystal structural changes involved with reaction time t were analyzed by using scanning and transmission electron microscopy (SEM and TEM, respectively), energy-dispersive X-ray spectrometry (EDX), and X-ray diffraction. High-resolution TEM combined with EDX and selected area electron diffraction confirmed the replacement of Ag with Au. A proposed formation mechanism of the original Ag dendrites developing pores while growing Au flakes cover this underlying structure at longer reaction times is confirmed by exploiting surface-enhanced Raman scattering (SERS). Catalytic reduction of 4 nitrophenol (4-NP) by sodium borohydride (NaBH4) is strongly enhanced, implying promising applications in catalysis. PMID- 19788232 TI - High-resolution nanoprobe X-ray fluorescence characterization of heterogeneous calcium and heavy metal distributions in alkali-activated fly ash. AB - The nanoscale distribution of elements within fly ash and the aluminosilicate gel products of its alkaline activation ("fly ash geopolymers") are analyzed by means of synchrotron X-ray fluorescence using a hard X-ray Nanoprobe instrument. The distribution of calcium within a hydroxide-activated (fly ash/KOH solution) geopolymer gel is seen to be highly heterogeneous, with these data providing for the first time direct evidence of the formation of discrete high-calcium particles within the binder structure of a geopolymer synthesized from a low calcium (<2 wt % as oxides) fly ash. The silicate-activated (fly ash/potassium silicate solution) sample, by contrast, shows a much more homogeneous geopolymer gel binder structure surrounding the unreacted fly ash particles. This has important implications for the understanding of calcium chemistry within aluminosilicate geopolymer gel phases. Additionally, chromium and iron are seen to be very closely correlated within the structures of both fly ash and the geopolymer product and remain within the regions of the geopolymer which can be identified as unreacted fly ash particles. Given that the potential for chromium release has been one of the queries surrounding the widespread utilization of construction materials derived from fly ash, the observation that this element appears to be localized within the fly ash rather than dispersed throughout the gel binder indicates that it is unlikely to be released problematically into the environment. PMID- 19788233 TI - Nonisothermal model for the direct isotropic/smectic-A liquid-crystalline transition. AB - An extension to a high-order model for the direct isotropic/smectic-A liquid crystalline phase transition was derived to take into account thermal effects including anisotropic thermal diffusion and latent heat of phase ordering. Multiscale multitransport simulations of the nonisothermal model were compared to isothermal simulation, showing that the presented model extension corrects the standard Landau-de Gennes prediction from constant growth to diffusion-limited growth under shallow quench/undercooling conditions. Nonisothermal simulations, where metastable nematic preordering precedes smectic-A growth, were also conducted, and novel nonmonotonic phase-transformation kinetics were observed. PMID- 19788234 TI - Impedance analysis for hydrogen adsorption pseudocapacitance and electrochemically active surface area of Pt electrode. AB - Electrochemically active surface area (ECA) of a polycrystalline Pt electrode is measured from the pseudocapacitance (Cp) values that are associated with hydrogen underpotential deposition. The potential-dependent Cp values are extracted from the raw impedance data by removing the interferences coming from the double-layer charging and hydrogen evolution. Three different approaches have been made: (i) by using the proportionality between the capacitance and area of the capacitive peak on imaginary capacitance plots, (ii) by complex nonlinear least-squares (CNLS) fitting on both the imaginary and real part of complex capacitance with appropriate equivalent circuits, and (iii) by using the modified Kramers-Kronig (K-K) relation. The first approach is the simplest one for the Cp measurement but cannot be used in the hydrogen evolution region (<0.05 V vs RHE), whereas the measurement can be extended down to -0.01 V with the second method. The isotherm fitting on the Cp(E) profile shows that the saturation of adsorbed hydrogen is reached at -0.1 V vs RHE. Faster data acquisition is possible with the third approach since the data analysis can be made without the time-consuming low frequency data (<100 Hz). The roughness factor and ECA of the Pt electrode are calculated from the electric charge that is obtained by integrating the potential dependent Cp values; the roughness factor (1.4-1.5) lies within the normal range for planar electrodes. PMID- 19788236 TI - Suicide inactivation of MauG during reaction with O(2) or H(2)O(2) in the absence of its natural protein substrate. AB - MauG is a diheme protein that catalyzes the six-electron oxidation of a biosynthetic precursor protein of methylamine dehydrogenase (PreMADH) with partially synthesized tryptophan tryptophylquinone (TTQ) to yield the mature protein with the functional protein-derived TTQ cofactor. The biosynthetic reaction proceeds via a relatively stable high valent bis-Fe(IV) intermediate. Oxidizing equivalents ([O]) for this reaction may be provided by either O(2) plus electrons from an external donor or H(2)O(2). The presence or absence of PreMADH has no influence on the reactivity of MauG with [O]; however, it is demonstrated that MauG is inactivated when supplied with [O] in the absence of PreMADH. The mechanism of inactivation appears to differ depending on the source of [O]. Repeated reaction of diferrous MauG with O(2) leads to loss of activity but not inactivation of heme, as judged by absorption spectroscopy and pyridine hemochrome assay. Repeated reaction of diferric MauG with H(2)O(2) leads to loss of activity and inactivation of heme, as well as some covalent cross-linking of MauG molecules. None of these deleterious effects with either source of [O] are observed when PreMADH is present to react with MauG. The radical scavenger hydroxyurea and small molecule mimics of the monohydroxylated Trp residue of PreMADH also reacted with bis-Fe(IV) MauG and afforded protection against inactivation. These results demonstrate that while O(2) and H(2)O(2) readily react with MauG in the absence of PreMADH, the presence of this substrate is necessary to prevent suicide inactivation of MauG after formation of the bis Fe(IV) intermediate. PMID- 19788237 TI - Optimization of the antitumor efficacy of a synthetic mitochondrial toxin by increasing the residence time in the cytosol. AB - Plasma membrane drug efflux pumps of the multidrug resistance associated protein (MRP) family blunt the effectiveness of anticancer drugs and are often associated with drug resistance. GSAO, a tripeptide trivalent arsenical that targets a key mitochondrial transporter in angiogenic endothelial cells, is an example of a compound whose efficacy is limited by tumor cell expression of MRP isoforms 1 and 2. A cysteine mimetic analogue of GSAO was made, PENAO, which accumulates in cells 85 times faster than GSAO due to increased rate of entry and decreased rate of export via MRP1/2. The faster rate of accumulation of PENAO corresponds to a 44-fold increase in antiproliferative activity in vitro and approximately 20-fold better antitumor efficacy in vivo. This information could be used to improve the efficacy of other small molecule cancer therapeutics. PMID- 19788238 TI - Structure-based optimization of potent and selective inhibitors of the tyrosine kinase erythropoietin producing human hepatocellular carcinoma receptor B4 (EphB4). AB - The tyrosine kinase EphB4 is an attractive target for drug design because of its recognized role in cancer-related angiogenesis. Recently, a series of commercially available xanthine derivatives were identified as micromolar inhibitors of EphB4 by high-throughput fragment-based docking into the ATP binding site of the kinase domain. Here, we have exploited the binding mode obtained by automatic docking for the optimization of these EphB4 inhibitors by chemical synthesis. Addition of only two heavy atoms, methyl and hydroxyl groups, to compound 4 has yielded the single-digit nanomolar inhibitor 66, with a remarkable improvement of the ligand efficiency from 0.26 to 0.37 kcal/(mol per non-hydrogen atom). Compound 66 shows very high affinity for a few other tyrosine kinases with threonine as gatekeeper residue (Abl, Lck, and Src). On the other hand, it is selective against kinases with a larger gatekeeper. A 45 ns molecular dynamics (MD) simulation of the complex of EphB4 and compound 66 provides further validation of the binding mode obtained by fragment-based docking. PMID- 19788239 TI - Rational design and synthesis of potent dibenzazepine motifs as beta-secretase inhibitors. AB - We have identified small-molecule dibenzazepine inhibitors of beta-secretase (BACE1). These BACE1 inhibitors possess two key salient features. The first is a seven-membered heterocyclic ring fused to two aromatic rings representing the P3 P2 residues. The second is an amide and/or amide bioisostere representing the P1' residue. Rational optimization led to the identification of potent analogues, such as 10 (K(I) = 211 nM). PMID- 19788240 TI - Antibacterial activity of essential oil components and their potential use in seed disinfection. AB - Among the main (> or = 0.7%) components of some essential oils, considerable antibacterial activity was shown by terpenoid and phenylpropanoid derivatives containing phenol and alcohol functionalities. A reduced or no activity was shown by those derivatives containing ketones, aldehydes, ethers, and ester functionalities as well as the remaining terpenoids. Eugenol emulsion treatments (1-8 mg/mL) of bean seeds bearing about 2.6 x 10(6) cfu/seed of strain ICMP239 of Xanthomonas campestris pv. phaseoli var. fuscans determined a highly significant reduction of the bacteria on seeds. In particular, eugenol at 4 mg/mL disinfect seeds bearing about 7.0 x 10(2) cfu/seed and lower densities. However, after 72 h, incubation treatments with 2, 4, and 8 mg/mL of eugenol caused germination reduction of 3%, 7%, and 16%, respectively, which was significantly different from the controls. No effect on germination was observed with 1 mg/mL eugenol emulsion treatment. These data indicate eugenol as potentially useful for bean seed disinfection from X. campestris pv. phaseoli var. fuscans. Further studies on the effects on seed vitality and on formulation of essential oils are needed. PMID- 19788241 TI - Detoxification of cytotoxic alachlor by glutathione: characterization of conjugated adducts by electrospray ionization tandem mass spectrometry. AB - The most commonly used chloroacetamide herbicide, alachlor, and its conjugated adducts have been characterized by electrospray ionization mass spectrometry (ESI MS). The reactivity of glutathione toward alachlor has been evaluated by changing experimental parameters, such as pH, temperature, and tube lens offset voltage (TLOV) in aqueous methanol, and the products were subjected to collision-induced dissociation (CID) for further characterization. In the positive mode, CID proves the formation of cyclic species by elimination of glycine and NH(3) moiety, which is similar to protonated cysteine. The results confirm that, only under basic conditions, glutathione is able to detoxify alachlor. PMID- 19788242 TI - Electrochemical sensor for rapid detection of triclosan using a multiwall carbon nanotube film. AB - It is of great importance to develop a rapid analytical method for triclosan because it has been widely added in household products and can form highly toxic dioxin-type derivatives. Herein, an electrochemical sensor based on a multiwall carbon nanotube (MWCNT) film was developed for the rapid detection of triclosan. The electrochemical responses of triclosan were examined, given that its oxidation is irreversible and involves one electron. At the MWCNT film, the oxidation signals of triclosan remarkably increase, suggesting that the MWCNT film exhibits a considerable enhancement effect with triclosan. The analytical parameters, such as pH value, amount of MWCNT suspension, and accumulation time, were optimized. The linear range is from 50 microg L(-1) to 1.75 mg L(-1), and the limit of detection is 16.5 microg L(-1) (about 57 nM). Finally, the new method was successfully employed to detect triclosan in different toothpaste samples, which was testified using high-performance liquid chromatography (HPLC). PMID- 19788243 TI - Identification of phenolic compounds from lingonberry (Vaccinium vitis-idaea L.), bilberry (Vaccinium myrtillus L.) and hybrid bilberry (Vaccinium x intermedium Ruthe L.) leaves. AB - Phenolic compounds from leaves of lingonberry (Vaccinium vitis-idaea L.), bilberry (Vaccinium myrtillus L.), and the natural hybrid of bilberry and lingonberry (Vaccinium x intermedium Ruthe L., hybrid bilberry) were identified using LC/TOF-MS and LC/MS/MS after extraction from the plant material in methanol in an ultrasonicator. The phenolic profiles in the plants were compared using the LC/TOF-MS responses. This is the first thorough report of phenolic compounds in hybrid bilberry. In total, 51 different phenolic compounds were identified, including flavan-3-ols, proanthocyanidins, flavonols and their glycosides, and various phenolic acid conjugates. Of the identified compounds, 35 were detected in bilberry, 36 in lingonberry, and 46 in the hybrid. To our knowledge, seven compounds were previously unreported in Vaccinium genus and many of the compounds are reported for the first time from bilberry and lingonberry. PMID- 19788244 TI - Integrated platform for proteome analysis with combination of protein and peptide separation via online digestion. AB - An integrated platform with the combination of protein and peptide separation was established via online protein digestion, by which proteins were first separated by a microcolumn packed with mixed weak anion and weak cation exchange (WAX/WCX) particles under a series of salt steps, online digested by a trypsin immobilized microenzymatic reactor (IMER), trapped and desalted by two parallel C8 precolumns, separated by microreversed-phase liquid chromatography (muRPLC) under a linear gradient of organic modifier concentration, and finally identified by electrospray ionization-MS/MS (ESI-MS/MS). To evaluate the performance of such a platform, a mixture of myoglobin, cytochrome c, bovine serum albumin (BSA), and alpha-casein, with mass ranging from 25 ng to 2 microg, was analyzed. Compared to the methods by off-line protein fractionation and shotgun based strategy, the analysis time, including sample preparation, digestion, desalting, separation, and detection, was shortened from ca. 30 to 5 h, and cytochrome c with abundance of 25 ng could be identified with improved sequence coverage. Furthermore, such an integrated platform was successfully applied into the analysis of proteins extracted from human lung cancer cells. Compared with the results obtained by the shotgun approach, the identified protein number was increased by 30%. All these results demonstrated that such an integrated approach would be an attractive alternative to commonly applied approaches for proteome research. PMID- 19788246 TI - Synthesis, kinase inhibitory potencies, and in vitro antiproliferative evaluation of new Pim kinase inhibitors. AB - Members of the Pim kinase family have been identified as promising targets for the development of antitumor agents. After a screening of pyrrolo[2,3-a]- and [3,2-a]carbazole derivatives toward 66 protein kinases, we identified pyrrolo[2,3 a]carbazole as a new scaffold to design potent Pim kinase inhibitors. In particular, compound 9 was identified as a low nM selective Pim inhibitor. Additionally, several pyrrolo[2,3-a]carbazole derivatives showed selectivity for Pim-1 and Pim-3 over Pim-2. In vitro antiproliferative activities of 9 and 28, the most potent Pim inhibitors identified, were evaluated toward three human solid cancer cell lines (PA1, PC3, and DU145) and one human fibroblast primary culture, revealing IC50 values in the micromolar range. Finally, the crystal structure of Pim-1 complexed with lead compound 9 was determined. The structure revealed a non-ATP mimetic binding mode with no hydrogen bonds formed with the kinase hinge region and explained the selectivity of pyrrolo[2,3-a]carbazole derivatives for Pim kinases. PMID- 19788245 TI - Lycorine, the main phenanthridine Amaryllidaceae alkaloid, exhibits significant antitumor activity in cancer cells that display resistance to proapoptotic stimuli: an investigation of structure-activity relationship and mechanistic insight. AB - Twenty-two lycorine-related compounds were investigated for in vitro antitumor activity using four cancer cell lines displaying different levels of resistance to proapoptotic stimuli and two cancer cell lines sensitive to proapoptotic stimuli. Lycorine and six of its congeners exhibited potency in the single-digit micromolar range, while no compound appeared more active than lycorine. Lycorine also displayed the highest potential (in vitro) therapeutic ratio, being at least 15 times more active against cancer than normal cells. Our studies also showed that lycorine exerts its in vitro antitumor activity through cytostatic rather than cytotoxic effects. Furthermore, lycorine provided significant therapeutic benefit in mice bearing brain grafts of the B16F10 melanoma model at nontoxic doses. Thus, the results of the current study make lycorine an excellent lead for the generation of compounds able to combat cancers, which are naturally resistant to proapoptotic stimuli, such as glioblastoma, melanoma, non-small-cell-lung cancers, and metastatic cancers, among others. PMID- 19788247 TI - Single molecule nanocontainers made porous using a bacterial toxin. AB - Encapsulation of a biological molecule or a molecular complex in a vesicle provides a means of biofriendly immobilization for single molecule studies and further enables new types of analysis if the vesicles are permeable. We previously reported on using DMPC (dimyristoylphosphatidylcholine) vesicles for realizing porous bioreactors. Here, we describe a different strategy for making porous vesicles using a bacterial pore-forming toxin, alpha-hemolysin. Using RNA folding as a test case, we demonstrate that protein-based pores can allow exchange of magnesium ions through the vesicle wall while keeping the RNA molecule inside. Flow measurements indicate that the encapsulated RNA molecules rapidly respond to the change in the outside buffer condition. The approach was further tested by coencapsulating a helicase protein and its single-stranded DNA track. The DNA translocation activity of E. coli Rep helicase inside vesicles was fueled by ATP provided outside the vesicle, and a dramatically higher number of translocation cycles could be observed due to the minuscule vesicle volume that facilitates rapid rebinding after dissociation. These pores are known to be stable over a wide range of experimental conditions, especially at various temperatures, which is not possible with the previous method using DMPC vesicles. Moreover, engineered mutants of the utilized toxin can potentially be exploited in the future applications. PMID- 19788248 TI - Small and stable peptidic PEGylated quantum dots to target polyhistidine-tagged proteins with controlled stoichiometry. AB - The use of the semiconductor quantum dots (QD) as biolabels for both ensemble and single-molecule tracking requires the development of simple and versatile methods to target individual proteins in a controlled manner, ideally in living cells. To address this challenge, we have prepared small and stable QDs (QD-ND) using a surface coating based on a peptide sequence containing a tricysteine, poly(ethylene glycol) (PEG), and an aspartic acid ligand. These QDs, with a hydrodynamic diameter of 9 +/- 1.5 nm, can selectively bind to polyhistidine tagged (histag) proteins in vitro or in living cells. We show that the small and monodisperse size of QD-ND allows for the formation of QD-ND/histag protein complexes of well-defined stoichiometry and that the 1:1 QD/protein complex can be isolated and purified by gel electrophoresis without any destabilization in the nanomolar concentration range. We also demonstrate that QD-ND can be used to specifically label a membrane receptor with an extracellular histag expressed in living HeLa cells. Here, cytotoxicity tests reveal that cell viability remains high under the conditions required for cellular labeling with QD-ND. Finally, we apply QD-ND complexed with histag end binding protein-1 (EB1), a microtubule associated protein, to single-molecule tracking in Xenopus extracts. Specific colocalization of QD-ND/EB1 with microtubules during the mitotic spindle formation demonstrates that QD-ND and our labeling strategy provide an efficient approach to monitor the dynamic behavior of proteins involved in complex biological functions. PMID- 19788249 TI - Preparation of (14)C-labeled multiwalled carbon nanotubes for biodistribution investigations. AB - A new method allowing the (14)C-labeling of carboxylic acid functions of carbon nanotubes is described. The key step of the labeling process is a decarbonylation reaction that has been developed and optimized with the help of a screening method. The optimized process has been successfully applied to multiwalled carbon nanotubes (MWNTs), and the corresponding (14)C-labeled nanotubes were used to investigate their in vivo behavior. Preliminary results obtained after i.v. contamination of rats revealed liver as the main target organ. Radiolabeling of NTs with a long-life radioactive nucleus like (14)C, coupled to a highly sensitive autoradiographic method, that provides a unique detection threshold, will make it possible to determine for a long time period whether or not NTs remain in any organs after animal exposure. PMID- 19788251 TI - Development of an information-rich LC-MS/MS database for the analysis of drugs in postmortem specimens. AB - With several instrument configurations available from various manufacturers, liquid chromatography-tandem mass spectrometry (LC-MS/MS) technology is currently intensively studied for comprehensive drug screen and confirmation. An LC-MS/MS database, including 780 drug and toxic compounds, has been constructed, featuring information-rich MS/MS spectra derived from a novel fragmentation approach incorporating voltage ramping and broadened mass window for activation. The resulting spectra are rich in high- and low-mass fragment ions, highly effective for matching and proven reproducible over a 6 month test period. Coupled to effective sample preparation protocols, the database-searching process greatly improved the identification of drugs in postmortem specimens by the LC electrospray ionization (ESI)-MS/MS technology. This method has significantly improved the efficiency of our routine laboratory operation that was based on a two-step [fluorescence polarization immunoassay (FPIA) and gas chromatography/mass spectrometry (GC/MS)] approach in the past. PMID- 19788250 TI - Development of different analysis platforms with LC-MS for pharmacokinetic studies of protein drugs. AB - Three different analysis platforms using LC-MS were successfully developed for pharmacokinetic (PK) studies of an antibody drug in serum. These analysis platforms can be selectively used for different types of protein drugs, which ranged from a very specific for a particular drug (antibody enrichment) to a less specific for any antibody drugs with an Fc domain (protein A enrichment), and to a very generic method that can be used for any protein drugs (albumin depletion method). In this manner, the three platforms will be applicable to a wide range of antibody therapeutic studies for different species. The analysis using an albumin depletion method (with sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)) achieved the detection of the drug (to 1 ng) in an aliquot of serum (30 microL) with a 5-order magnitude of linearity. The analysis using protein A enrichment (with SDS-PAGE) achieved the detection of the drug at a 50-fold lower level (to 0.02 ng). Without the use of SDS-PAGE for separation, the use of protein A enrichment achieved the detection to 10 ng and using the antidrug antibody enrichment achieved the detection to 0.1 ng, with a similar linear dynamic range. These three analysis platforms produced good agreement with a mimic PK study of the drug in monkey serum, as compared to the enzyme-linked immunosorbent assay (ELISA) approach. In addition, these analysis platforms can be selectively applied for PK studies of drugs with different requirements of development time and resources. Such as, the antibody enrichment method can be used in a high-throughput manner but limited to a specific protein drug only. On the other hand, the albumin depletion method can be applied to many types of protein drugs but with the laborious sample preparation steps (SDS-PAGE and the subsequent in-gel digestion). When antidrug antibodies are not available for antibody drugs or the sensitivity requirement is not stringent (e.g., >10 ng), using protein A enrichment (without using SDS-PAGE) seems to be a good choice for PK studies which require fast throughput. PMID- 19788252 TI - Conformational sampling for large-scale virtual screening: accuracy versus ensemble size. AB - We introduce the TrixX Conformer Generator (TCG), a novel tool for generating conformational ensembles. The tool addresses especially the requirements of large scale computer-aided drug design applications using conformer databases. For these, the trade-off between accuracy, i.e. rmsd to biologically active conformers, and database size, i.e. the number of conformers in an ensemble, is of central interest. Based on a tree data structure representing the molecule, conformations are generated incrementally in a best-first-search build-up process employing an internal rmsd clustering. This way TCG builds conformational ensembles of low energy conformers utilizing conformational energy as a scoring function. A crucial parameter is the amount of search space to be covered in the build-up process. This parameter is determined according to an exponential function employing a user-specified quality level as base and an exponent which depends on the molecule's flexibility. The quality level allows the user to set the aforementioned trade-off while taking into account the exponentially growing number of combinations of torsion angles. Tested on a set of 778 molecules, we show that on average 20 conformers per ensemble suffice to achieve an average accuracy of 1.13 A. We observed that an improvement in accuracy goes along with an exponential rise of the number of conformations per ensemble (e.g., 100 conformations per ensemble yield an accuracy of 0.99 A). Furthermore, we show that for molecules with less than nine rotatable bonds, ensembles with an average accuracy better than 1 A can be generated with an average ensemble size of 20 conformers. However, this value deteriorates for more flexible molecules. A comparison to CATALYST and OMEGA shows that TCG achieves a comparable performance in terms of accuracy. Furthermore, it performs well with respect to the trade-off between accuracy and ensemble size. PMID- 19788253 TI - Molybdenum(VI) dioxo complexes with tridentate phenolate ligands. AB - A series of new molybdenum(VI) dioxo complexes of the type [MoO(2)ClL(X)] with potentially monoanionic phenolate ligands L(X) (L = 4,6-di-tert-butyl-2 {[(X)methylamino]methyl}-phenolate; L(OMe), where X = 2'-methoxyethyl; L(SEt), where X = 2'-ethylthioethyl; L(NEt2), where X = 2'-diethylaminoethyl; and L(NMe2), where X = 2'-dimethylaminoethyl) have been synthesized as models for molybdoenzymes. All molybdenum complexes were readily accessible by employing the eta(2)-coordinate pyrazolate complex [MoO(2)Cl(eta(2)-t-Bu(2)pz)]. The nitrogen ligand can easily be exchanged by the monoanionic phenolate ligands L(X) in toluene at room temperature, leading to monosubstituted complexes 1-4 as yellow to red powders in good yields. Suitable single crystals for X-ray diffraction analysis of complexes 2 and 3 were obtained from a concentrated benzene solution. Both complexes reveal a six-coordinate molybdenum atom in a distorted octahedral surrounding, with a tridentate fac coordination of the ligand. Additionally, the complexes were characterized by elemental analysis; IR, UV/vis, and NMR spectroscopy; and mass spectrometry. For complexes 1 and 2, only one isomer can be detected in solution, whereas complexes 3 and 4 reveal the formation of two isomers in a 1:1 ratio for 3 and in a 1:3 ratio for 4. Optimized geometries and relative free energies of all possible isomers have been established by DFT calculations, indicating two isomers in solutions of 3 and 4 to be two types of facially coordinated complexes. Furthermore, this is supported by gauge independent atomic orbital calculations of the (1)H NMR shifts with a high correlation of experimental and calculated shifts for the fac compounds. Oxygen atom transfer reactions of 1 to PMe(3) quickly form monooxo molybdenum compound cis,mer-[MoOCl(2)(PMe(3))(3)]. PMID- 19788256 TI - Crystallization behavior and controlling mechanism of iron-containing Si-C-N ceramics. AB - The crystallization behavior and controlling mechanism of the Si-Fe-C-N system based on polymer-derived SiCN ceramic filled with iron metal powder has been studied. The composite preparation conditions allow the formation of a random distribution of metallic particles in the polymer matrix volume for the Si-C-N system. Pyrolysis of the composite material at 1100 degrees C indicates the presence of one crystalline phase Fe(3)Si. While the sample pyrolyzed at 1200 degrees C reveals the formation of both Fe(3)Si and Fe(5)Si(3) phases, a crystallization of beta-SiC is additionally observed by increasing the temperature up to 1300 degrees C. The propensity for the formation of SiC is due to the presence of Fe(5)Si(3), where a solid-liquid-solid (SLS) growth mechanism was suggested to occur. X-ray diffraction (XRD), scanning electron microscopy (SEM), differential thermal analysis (DTA), and thermal gravimetric analysis with mass spectroscopic detection (TGA-MS) were employed to investigate the crystallization behavior of the Si-Fe-C-N system. PMID- 19788254 TI - Wavelength-dependent differential interference contrast microscopy: selectively imaging nanoparticle probes in live cells. AB - Gold and silver nanoparticles display extraordinarily large apparent refractive indices near their plasmon resonance (PR) wavelengths. These nanoparticles show good contrast in a narrow spectral band but are poorly resolved at other wavelengths in differential interference contrast (DIC) microscopy. The wavelength dependence of DIC contrast of gold/silver nanoparticles is interpreted in terms of Mie's theory and DIC working principles. We further exploit this wavelength dependence by modifying a DIC microscope to enable simultaneous imaging at two wavelengths. We demonstrate that gold/silver nanoparticles immobilized on the same glass slides through hybridization can be differentiated and imaged separately. High-contrast, video-rate images of living cells can be recorded both with and without illuminating the gold nanoparticle probes, providing definitive probe identification. Dual-wavelength DIC microscopy thus presents a new approach to the simultaneous detection of multiple probes of interest for high-speed live-cell imaging. PMID- 19788257 TI - Theory of hyperspherical Sturmians for three-body reactions. AB - In this paper we present a theory to describe three-body reactions. Fragmentation processes are studied by means of the Schrodinger equation in hyperspherical coordinates. The three-body wave function is written as a sum of two terms. The first one defines the initial channel of the collision while the second one describes the scattered wave, which contains all the information about the collision process. The dynamics is ruled by an nonhomogeneous equation with a driven term related to the initial channel and to the three-body interactions. A basis set of functions with outgoing behavior at large values of hyperradius is introduced as products of angular and radial hyperspherical Sturmian functions. The scattered wave is expanded on this basis and the nonhomogeneous equation is transformed into an algebraic problem that can be solved by standard matrix methods. To be able to deal with general systems, discretization schemes are proposed to solve the angular and radial Sturmian equations. This procedure allows these discrete functions to be connected with the hyperquatization algorithm. Finally, the fragmentation transition amplitude is derived from the asymptotic limit of the scattered wave function. PMID- 19788258 TI - Structural investigation of lanthanoid coordination: a combined XANES and molecular dynamics study. AB - This is the first systematic study exploring the potentiality of the X-ray absorption near edge structure (XANES) technique as a structural tool for systems containing lanthanoid(III) ions. A quantitative analysis of the XANES spectra at the K- and L(3)-edges has been carried out for three hydrated lanthanoid(III) ions, namely, Yb, Nd, and Gd, in aqueous solution and in the isostructural trifluoromethanesulfonate salts. The structural and dynamic properties of the hydrated lanthanoid(III) ions in aqueous solution have been investigated by a combined experimental-theoretical approach employing X-ray absorption spectroscopy and molecular dynamics (MD) simulations. This method allows one to perform a quantitative analysis of the XANES spectra of ionic solutions using a proper description of the thermal and structural fluctuations. XANES spectra have been computed starting from the MD trajectory, without carrying out any minimization in the structural parameter space. A comparative K- and L(3)-edge XANES data analysis is presented, demonstrating the clear advantages of the L(3) edge XANES analysis over the K-edge studies for structural investigations of lanthanoid compounds. The second hydration shells provide a detectable contribution to the L(3)-edge spectra while the K-edge data are insensitive to the more distant coordination spheres because of the strong damping and broadening of the signal caused by the extremely large core hole widths. The XANES technique has been found to be a new valuable tool for the structural characterization of metal complexes both in the solid and in the liquid state, especially in the presence of low symmetry. PMID- 19788259 TI - Full- or half-encapsulation of sulfate anion by a tris(3-pyridylurea) receptor: effect of the secondary coordination sphere. AB - Self-assembly of the [Fe(DABP)(3)]SO(4) (DABP = 5,5'-diamino-2,2'-bipyridine) or [Fe(bipy)(3)]SO(4) (bipy = 2,2'-bipyridine) complex with a tripodal tris(3 pyridylurea) ligand (L) results in a layered structure that includes a sulfate anion in the cleft of one L molecule. The two compounds, [Fe(DABP)(3)][SO(4) L] x 10 H(2)O (2) and [Fe(bipy)(3)][SO(4) L] x 9 H(2)O (3), show very similar sheets formed by the anionic units [SO(4) L](2-) and cationic building blocks ([Fe(DABP)(3)](2+) or [Fe(bipy)(3)](2+)). However, there are different water clusters that link the adjacent layers in the two products, that is, water parallelograms and quasi "water cubes" in 2 versus single water molecules, water dimers, and hexamers in 3. The half-encapsulation of sulfate by a single L molecule contrasts with the previously reported full-encapsulation of the sulfate ion by two L molecules in [M(H(2)O)(6)][SO(4) L(2)] (1). This different anion encapsulation is traced to the hydrogen-acceptor properties of the pyridyl groups of L together with the hydrogen-bonding properties of the cation secondary coordination sphere for a solid-state packing optimization. In 1 the direct hydrogen bonding from the secondary coordination sphere of octahedral [M(H(2)O)(6)](2+) to L-pyridyl helps in the formation of an octahedral cation anion coordination in the NaCl-type structure. In 2 and 3, crystal water instead of the cations has to satisfy the hydrogen-accepting demands of L. Consequently, a non-spherical and only partly water-surrounded half-encapsulated [SO(4) L](2-) anion allows for a closer approach of the [Fe(DABP)(3)](2+) or [Fe(bipy)(3)](2+) cations than the [SO(4) L(2)](2-) anion. Then, the similar cation and anion size in 2 and 3 with the Coulomb attraction confined to a two-dimensional plane leads to the formation of a hexagonal BN (or graphite) lattice. Competition experiments with different anions for compound 2 reveal that SO(4)(2-) can be selectively crystallized against NO(3)(-), OAc(-), or ClO(4)(-). PMID- 19788260 TI - Halide-capped tellurium-containing macrocycles. AB - The reaction of 1,1,2,3,3-pentamethyltrimethylenephosphinic acid (cycPO(2)H) with bis(p-methoxyphenyl)tellurium dichloride (1) affords a 12-membered macrocycle [((p-MeOC(6)H(4))(2)Te)(2)(mu-O)(mu-cycPO(2))(mu(4)-Cl)](2) x C(6)H(6) (2) in good yield. The latter reacts with sodium iodide to give [((p MeOC(6)H(4))(2)Te)(2)(mu-O)(mu-cycPO(2))(mu(4)-I)](2) x 4 C(6)H(6) (3). 2 and 3 are isostructural dicationic macrocycles and contain a Te(4)P(2)O(6) framework. An interesting aspect of both of these structures is that two counter halide atoms are present as capping ligands above and below the macrocyclic plane enabled by Te-X interactions. In contrast to the macrocyclic product obtained with diorganotellurium dihalide the reaction of diphenyltin dichloride with cycPO(2)H resulted in the formation of an oxygen-capped cluster [(PhSn)(3)(mu(3) O)(mu-cycPO(2))(3)(mu-OH)(3)][cycPO(2)] x CH(3)CN. The latter is formed by a Sn Ph cleavage reaction. PMID- 19788261 TI - Localized states in 1D Frenkel exciton systems: a comparison between infinite range and nearest-neighbor transfer for normal and inverted bands. AB - We investigate localized states in one-dimensional Frenkel exciton systems that are created by a shift in the optical transition frequency of a single chromophore. In this paper, we focus on localized states lying below the exciton band that can act as exciton traps. A comparison is made between systems with infinite-range (r(-n), n = 2, 3, ...) transfer and those with nearest-neighbor (n = infinity) transfer. A distinction is also made between normal bands (minimum exciton energy at k = 0) and inverted bands (minimum energy at k = pi). The position of the localized state relative to the bottom of the band is calculated as a function of the shift in the single-chromophore transition frequency. The nature of the localized state is displayed in calculations of the participation ratio and the effective oscillator strength. Similarities and differences in localized states between normal and inverted band systems and between infinite range and nearest-neighbor transfer are analyzed. PMID- 19788262 TI - Does [I3]+ act as an "[I]+" donor to CH3CN and N2O? Structure of [H3CCN-I-NCCH3]+ [AsF6]-. AB - The solid state structure of the [(CH(3)CN)(2)I](+) cation in [(CH(3)CN)(2)I][AsF(6)] was determined using single crystal X-ray diffraction. The highly reactive cation was prepared by reaction of [I(3)][AsF(6)] with CH(3)CN in liquid SO(2). In the solid state, the CNI backbone consisting of seven atoms is linear and shows a dicoordinate iodine center. The ability of [I(3)][AsF(6)] to act as a source of "[I](+)" to CH(3)CN and N(2)O is compared, and the computed structures of the [CH(3)CNI](+), [(CH(3)CN)(2)I](+), [IN(2)O](+) and [ION(2)](+) cations are discussed. PMID- 19788263 TI - Searching chemical space with the Bayesian Idea Generator. AB - The Pfizer Global Virtual Library (PGVL) is defined as a set compounds that could be synthesized using validated protocols and monomers. However, it is too large (10(12) compounds) to search by brute-force methods for close analogues of a given input structure. In this paper the Bayesian Idea Generator is described which is based on a novel application of Bayesian statistics to narrow down the search space to a prioritized set of existing library arrays (the default is 16). For each of these libraries the 6 closest neighbors are retrieved from the existing compound file, resulting in a screenable hypothesis of 96 compounds. Using the Bayesian models for library space, the Pfizer file of singleton compounds has been mapped to library space and is optionally searched as well. The method is >99% accurate in retrieving known library provenance from an independent test set. The compounds retrieved strike a balance between similarity and diversity resulting in frequent scaffold hops. Four examples of how the Bayesian Idea Generator has been successfully used in drug discovery are provided. The methodology of the Bayesian Idea Generator can be used for any collection of compounds containing distinct clusters, and an example using compound vendor catalogues has been included. PMID- 19788264 TI - Facile chemical conversion synthesis and luminescence properties of uniform Ln3+ (Ln = Eu, Tb)-doped NaLuF4 nanowires and LuBO3 microdisks. AB - Uniform NaLuF(4) nanowires and LuBO(3) microdisks have been successfully prepared by a designed chemical conversion method. The lutetium precursor nanowires were first prepared through a simple hydrothermal process. Subsequently, uniform NaLuF(4) nanowires and LuBO(3) microdisks were synthesized at the expense of the precursor by a hydrothermal conversion process. The whole process was carried out in aqueous condition without any organic solvents, surfactant, or catalyst. The conversion processes from precursor to the final products have been investigated in detail. The as-obtained Eu(3+) and Tb(3+)-doped LuBO(3) microdisks and NaLuF(4) nanowires show strong characteristic red and green emissions under ultraviolet excitation or low-voltage electron beam excitation. Moreover, the luminescence colors of the Eu(3+) and Tb(3+) codoped LuBO(3) samples can be tuned from red, orange, yellow, and green-yellow to green by simply adjusting the relative doping concentrations of the activator ions under a single wavelength excitation, which might find potential applications in the fields such as light display systems and optoelectronic devices. PMID- 19788265 TI - Highly enantioselective synthesis of chiral cyclic amino alcohols and conhydrine by ruthenium-catalyzed asymmetric hydrogenation. AB - A highly efficient enantio- and diastereoselective synthesis of chiral cis-beta-N alkyl/arylamino cyclic alcohols has been realized by asymmetric hydrogenation of racemic alpha-amino cyclic ketones via DKR catalyzed by [RuCl(2)((S)-Xyl SDP)((R,R)-DPEN)]. The enantioselectivities of the reaction were up to 99.9% ee with 99:1 cis-selectivities. A practical catalytic asymmetric synthesis of all four isomers of conhydrine was also developed. PMID- 19788266 TI - Internally referenced diffusion coefficient-formula weight (D-FW) analysis of 31P diffusion-ordered NMR spectroscopy (DOSY). AB - The development of (31)P DOSY NMR with diffusion coefficient-formula weight (D FW) analysis is reported. Commercially available trialkyl phosphine internal references were used in a model system to establish the molecular weight of a phosphorous containing organolithium compound. The feasibility of (31)P DOSY D-FW studies is established. This extension of DOSY D-FW analysis expands its applicability to solution structure studies of a wide variety of compounds. PMID- 19788267 TI - Biocatalytic promiscuity of lipase in chemoselective oxidation of aryl alcohols/acetates: a unique synergism of CAL-B and [hmim]Br for the metal-free H2O2 activation. AB - A unique synergistic combination of lipase and ionic liquid [hmim]Br is reported for metal-free H(2)O(2) activation, which is the first example of biocatalytic promiscuity of CAL-B for chemoselective oxidation of aryl alcohols/acetates. The catalytic system exhibits excellent functional group compatibility under neutral conditions besides reusability up to ten cycles thereby making the process economically and environmentally viable. PMID- 19788268 TI - Peptide nucleic acid containing a meta-substituted phenylpyrrolocytosine exhibits a fluorescence response and increased binding affinity toward RNA. AB - Peptide nucleic acids (PNA) containing meta-substituted 6-phenylpyrrolocytosine (PhpC), [mono-m-(aminoethoxy)phenyl]pyrrolocytosine (mmePhpC), [mono-m (aminopropoxy)phenyl]pyrrolocytosine (mmpPhpC), and [mono-m (guanidinoethoxy)phenyl]pyrrolocytosine (mmguaPhpC), have been synthesized. Meta substituted PhpCs have been hybridized with overall higher binding affinity toward DNA and RNA than previously synthesized moePhpC or newly synthesized mopPhpC. The guanidinium-containing nucleobase, mmguaPhpC, exhibited the highest increase in binding affinity toward RNA while fluorometrically responding on the state of hybridization. PMID- 19788269 TI - Rhodium nanoparticles supported on carbon nanofibers as an arene hydrogenation catalyst highly tolerant to a coexisting epoxido group. AB - Rhodium nanoparticles supported on a carbon nanofiber (Rh/CNF-T) show high catalytic activity toward arene hydrogenation under mild conditions in high turnover numbers without leaching the Rh species; the reaction is highly tolerant to epoxido groups, which often undergo ring-opening hydrogenation with conventional catalysts. PMID- 19788270 TI - Bioactive scalaranes from the Thai sponge Hyrtios gumminae. AB - Chemical investigation of the Thai sponge Hyrtios gumminae collected from Similan Island in the Andaman Sea, Thailand, yielded four new sesterterpenoids, similan A (1), 12beta,20-dihydroxy-16beta-acetoxy-17-scalaren-19,20-olide (2), 12beta acetoxy-20-hydroxy-17-scalaren-19,20-olide (3), and 12beta,16alpha,20-trihydroxy 17-scalaren-19,20-olide (4), together with seven known compounds. The structures of these new compounds were elucidated on the basis of their spectroscopic data and chemical transformations. Some of the isolated compounds were tested for their cytotoxic activity. PMID- 19788271 TI - Mechanistic investigation of the endo-alpha-N-acetylgalactosaminidase from Streptococcus pneumoniae R6. AB - The large (1767-amino acid) endo-alpha-N-acetylgalactosaminidase from Streptococcus pneumoniae (SpGH101) specifically removes an O-linked disaccharide Gal-beta-1,3-GalNAc-alpha from glycoproteins. While the enzyme from natural sources has been used as a reagent for many years, very few mechanistic studies have been performed. Using the recently determined three-dimensional structure of the recombinant protein as a background, we report here a mechanistic investigation of the SpGH101 retaining alpha-glycoside hydrolase using a combination of synthetic and natural substrates. On the basis of a model of the substrate complex of SpGH101, we propose D764 and E796 as the nucleophile and general acid-base residues, respectively. These roles were confirmed by kinetic and mechanistic analysis of mutants at those positions using synthetic substrates and anion rescue experiments. pK(a) values of 5.3 and 7.2 were assigned to D764 and E796 on the basis of the pK(a) values derived from the bell-shaped dependence of k(cat)/K(m) upon pH. The enzyme contains several putative carbohydrate binding modules whose glycan binding specificities were probed using the printed glycan array of the Consortium for Functional Glycomics using the inactive D764A and D764F mutants that had been labeled with Alexafluor 488. These studies revealed binding to galacto-N-biose, consistent with a role for these domains in localizing the enzyme near its substrates. PMID- 19788272 TI - Making Mn substitutional impurities in InAs using a scanning tunneling microscope. AB - We describe in detail an atom-by-atom exchange manipulation technique using a scanning tunneling microscope probe. As-deposited Mn adatoms (Mn(ad)) are exchanged one-by-one with surface In atoms (In(su)) to create a Mn surface substitutional (Mn(In)) and an exchanged In adatom (In(ad)) by an electron tunneling induced reaction Mn(ad) + In(su) --> Mn(In) + In(ad) on the InAs(110) surface. In combination with density-functional theory and high resolution scanning tunneling microscopy imaging, we have identified the reaction pathway for the Mn and In atom exchange. PMID- 19788273 TI - Analysis of the structural and functional diversity of plant cell wall specific family 6 carbohydrate binding modules. AB - Carbohydrate binding modules (CBMs) play important biological roles in targeting appended catalytic modules to their dedicated substrate(s) within complex macromolecular structures such as the plant cell wall. Because of the large potential in ligand diversity within nature and our continually expanding knowledge of sequence-based information of carbohydrate-modifying enzymes, empirical determination of CBM binding specificity and identification of novel mechanisms in carbohydrate recognition by these proteins have become time consuming and complicated processes. To help overcome these experimental hurdles, we present here a predictive model for family 6 CBMs (CBM6) that is based upon several factors, including phylogenetic relatedness, and structural and functional evidence. This analysis has determined that five regions within the binding site, termed A-E, play key roles in ligand selection and affinity. Regions A-C are located in a primary subsite and contribute mainly to binding energy and selection for O2, O3, and O4 equatorial hydroxyls. Region D appears to determine whether the CBM will interact with internal or terminal structures of the carbohydrate ligand. Region E displays the largest degree of variation and is thus predicted to make the most significant contribution to specificity. This model is supported by the biochemical properties and structure of a CBM6 from Clostridium cellulolyticum (CcCBM6), which we also report here. The protein bound specifically to xylose and the nonreducing of end of polymers containing this pentose sugar. The crystal structure of CcCBM6 in complex with xylose showed that a tyrosine residue made hydrophobic contacts with the unsubstituted C5 atom of xylose and sterically hindered decorations at this sugar ring position. The mechanism, by which the CBM recognizes xylose but not glucose, a specificity not previously observed in this family, supports our predictive model that holds that variation in region E plays a key role in the diverse ligand selection evident in CBM6. PMID- 19788274 TI - Detection and quantification of chemical warfare agent precursors and surrogates by selected ion flow tube mass spectrometry. AB - The rate coefficients and branching ratios of 15 chemical warfare agent precursor and surrogate compounds reacting with H(3)O(+), NO(+), and O(2)(+) have been measured in the laboratory using the selected ion flow tube (SIFT) technique. Measurement of the relevant kinetic parameters for these agents has enabled quantitative monitoring using the SIFT-MS analytical technique. Thirteen of the 15 compounds studied were found to have real-time detection limits in the parts per-trillion-by-volume concentration range when measured on a standard commercial Voice100 instrument, with specific compounds having detection limits below 100 parts-per-trillion-by-volume. PMID- 19788275 TI - Path-dependent morphologies in oil/water/diblock copolymer mixtures. AB - Amphiphilic block copolymer surfactants have been studied primarily in binary or pseudobinary systems, where they form a variety of dispersions, including micelles and vesicles, characterized by extremely low critical micelle concentrations (CMCs). In this study, a poly(1,2-butadiene-b-ethylene oxide) (OB) diblock copolymer (M(n) = 33 kg/mol, and 72 wt % PEO) was combined with water (W) and 1,5-cyclooctadiene (C) in binary (OB/W and OB/C) and ternary (OB/W/C and OB/C/W) mixtures, where the order of components indicates the mixing sequence. The resulting morphologies were characterized by small-angle X-ray scattering (SAXS) and cryogenic scanning electron microscopy (cryo-SEM). Addition of 1,5 cyclooctadiene to premicellized OB in water (OB/W) leads to swelling of the initially spherical hydrophobic micelle cores followed by micelle fusion leading to three-dimensional network structures. Combining water with premixed OB in 1,5 cyclooctadiene (OB/C) transforms a periodic sheet-like lamellar microstructure into a complex state of phase separation built on water-swollen poly(ethylene oxide) bilayers, which are manifested as uniformly sized small vesicles. Thus, two entirely different microstructures, which are stable for at least a month, have been prepared from a single three-component formulation. This pronounced nonequilibrium phase behavior, attributed to the non-ergodic character of amphiphilic block copolymers, may offer new processing strategies for the preparation of desirable self-assembled structures. PMID- 19788276 TI - Three-dimensional nanoscale imaging of polymer bulk-heterojunction by scanning electrical potential microscopy and C60(+) cluster ion slicing. AB - Solution-processable fullerene and copolymer bulk-heterojunctions are widely used as the active layer of solar cells. It is known that the controlled phase separation in the film provides a pathway for carrier transportation and is crucial to efficiency. In this work, scanning electrical potential microscopy (SEPM) is used to examine the surface distribution of [6,6]phenyl-C61-butyric acid methyl ester and poly(3-hexylthiophene), which form the bulk-heterojunction. Because the two components have different energies in the highest occupied molecular orbital (HOMO), the differences in contact potential yield strong contrast in SEPM. A cluster ion beam (C(60)(+)) is used to remove the surface in order to determine the structure below, and SEPM is used to analyze the newly exposed surface. With the SEPM images acquired from different depth through the material stacked, a 3D volume image is obtained. It is demonstrated that using SEPM with cluster ion slicing is an effective tool for studying the 3D nanostructures of soft materials. PMID- 19788277 TI - Characterization and testing of periodic mesoporous organosilicas as potential selective benzene adsorbents. AB - The effects of surface imprinting on the adsorption and desorption properties of benzene- and diethylbenzene-bridged periodic mesoporous organosilicas (PMOs) acting as GC stationary-phase preconcentration sorbents for benzene and xylene were examined. Surface-imprinted and nonimprinted PMOs with diethylbenzene (DEB), benzene (BENZ), and ethane (BTSE) bridges and nonimprinted mesoporous silica (MCM 41) were prepared via well-established surfactant templating synthetic methods. The imprinted materials were synthesized using a surfactant demonstrated to produce trinitrotoluene (TNT) selective sorbents with increased adsorption capacity for cresol and 4-nitrophenol as well as TNT. Powder XRD and nitrogen sorption measurements revealed that all of the materials were mesoporous with the DEB materials having a random pore structure and lower surface area than the other materials which had ordered pore structures. Results for maximum uptake of benzene and p-xylene indicate a small but consistent positive effect on the adsorption of benzene and p-xylene due to surface imprinting. Comparing the surface area normalized uptakes (mg/m(2)) for materials having the same organic bridge with and without imprinting (DEB vs TDMI-DEB and BENZ vs TDMI-BENZ) shows that in seven of eight comparisons the imprinted analogue had a higher aromatic uptake. The imprinted samples showed higher weight normalized uptakes (mg/g) in five of eight cases. When used as a GC stationary phase, the organosilica materials yield more symmetrical chromatographic peaks and better separation than MCM-41, indicating superior trapping of BTX analytes, particularly at low concentrations. Additionally, these materials rapidly desorb the preconcentrated compounds. PMID- 19788278 TI - Reagentless bidirectional lateral flow bioactive paper sensors for detection of pesticides in beverage and food samples. AB - A reagentless bioactive paper-based solid-phase biosensor was developed for detection of acetylcholinesterase (AChE) inhibitors, including organophosphate pesticides. The assay strip is composed of a paper support (1 x 10 cm), onto which AChE and a chromogenic substrate, indophenyl acetate (IPA), were entrapped using biocompatible sol-gel derived silica inks in two different zones (e.g., sensing and substrate zones). The assay protocol involves first introducing the sample to the sensing zone via lateral flow of a pesticide-containing solution. Following an incubation period, the opposite end of the paper support is placed into distilled deionized water (ddH(2)O) to allow lateral flow in the opposite direction to move paper-bound IPA to the sensing area to initiate enzyme catalyzed hydrolysis of the substrate, causing a yellow-to-blue color change. The modified sensor is able to detect pesticides without the use of any external reagents with excellent detection limits (bendiocarb approximately 1 nM; carbaryl approximately 10 nM; paraoxon approximately 1 nM; malathion approximately 10 nM) and rapid response times (approximately 5 min). The sensor strip showed negligible matrix effects in detection of pesticides in spiked milk and apple juice samples. Bioactive paper-based assays on pesticide residues collected from food samples showed good agreement with a conventional mass spectrometric assay method. The bioactive paper assay should, therefore, be suitable for rapid screening of trace levels of organophosphate and carbamate pesticides in environmental and food samples. PMID- 19788280 TI - Design of molecular beacons as signaling probes for adenosine triphosphate detection in cancer cells based on chemiluminescence resonance energy transfer. AB - In the present study, binary and triplex DNA molecular beacons, as signaling probes based on a luminol-H(2)O(2)-horseradish peroxidase (HRP)-fluorescein chemiluminescence resonance energy transfer (CRET) system and structure-switching aptamers for highly sensitive detection of small molecules, are developed using adenosine triphosphate (ATP) as a model analyte to demonstrate the generality of the strategy. This CRET process occurs from donor luminol to acceptor fluorescein, which is oxidized by H(2)O(2) and catalyzed by HRP. DNA aptamer for ATP is first attached on the surface of magnetic nanoparticles (MNPs). The cDNA linker has an extension that hybridizes with two other DNAs (LumAuNP-DNA and F DNA) or three other DNAs (HRP-DNA, LumAuNP-DNA, and F-DNA) to fabricate CRET-BMBP MNP or CRET-TMBP-MNP conjugates that provide the CRET signals. Thus, in the absence of ATP, when the MNPs are removed from the solution, they also take with them the linker DNA and the CRET signal probes, and no CRET signal can be detected. However, when ATP is introduced, a competition for the ATP aptamer between ATP and the cDNA linker occurs. As a result, CRET-BMBP and CRET-TMBP are forced to dissociate from the MNP surface based on the structure switching of the aptamer. The CRET signals are proportional to the concentration of ATP. In order to accelerate the rate of the aptamer structure-switching process, an invader DNA is introduced into the proposed strategy. The present CRET system provides a low detection limit of 1.1 x 10(-7) and 3.2 x 10(-7) M for ATP detection by BMBP and TMBP, respectively, which also exhibits a good selectivity for ATP detection. Sample assays of ATP in K562 leukemia cells and 4T1 breast cancer cells confirm the reliability and practicality of the protocol, which reveal a good prospect of this platform for biological sample analysis. PMID- 19788282 TI - Colorimetric detection of thiols using a chromene molecule. AB - A new thiol-containing colorimetric probe has been developed by using a chromene derivative, 7-nitro-2,3-dihydro-1H-cyclopenta[b]chromen-1-one (1). The molecule exhibited high selectivity and sensitivity for detecting thiol species as cysteine, homocysteine, and glutathione in aqueous solution through a rapid visual color change from colorless to yellow. PMID- 19788281 TI - Visualization of volatile substances in different organelles with an atmospheric pressure mass microscope. AB - We have developed a mass microscope (mass spectrometry imager with spatial resolution higher than the naked eye) equipped with an atmospheric pressure ion source chamber for laser desorption/ionization (AP-LDI) and a quadrupole ion trap time-of-flight (QIT-TOF) analyzer. The optical microscope combined with the mass spectrometer permitted us to precisely determine the relevant tissue region prior to performing imaging mass spectrometry (IMS). An ultraviolet laser tightly focused with a triplet lens was used to achieve high spatial resolution. An atmospheric pressure ion-source chamber enables us to analyze fresh samples with minimal loss of intrinsic water or volatile compounds. Mass-microscopic AP-LDI imaging of freshly cut ginger rhizome sections revealed that 6-gingerol ([M + K](+)at m/z 333.15, positive mode; [M - H](-) at m/z 293.17, negative mode) and the monoterpene ([M + K](+) at m/z 191.09), which are the compounds related to pungency and flavor, respectively, were localized in oil drop-containing organelles. AP-LDI-tandem MS/MS analyses were applied to compare authentic signals from freshly cut ginger directly with the standard reagent. Thus, our atmosphere-imaging mass spectrometer enabled us to monitor a quality of plants at the organelle level. PMID- 19788283 TI - Indirect and direct detection of the 4-(benzothiazol-2-yl)phenylnitrenium ion from a putative metabolite of a model anti-tumor drug. AB - 2-(4-Aminophenyl)benzothiazoles related to 1 are potentially important pharmaceuticals. Metabolism apparently involves oxidation and esterification to 3. In water, hydrolysis and photolysis of 3 generates the nitrenium ion 4 that can be detected indirectly by N(3)(-) trapping and directly by UV-vis spectroscopy following laser flash photolysis. The transient, with lambda(max) 570 nm, and a lifetime of 530 ns, reacts with N(3)(-) at a diffusion-controlled rate and generates the quinol 6 by reaction with water. PMID- 19788284 TI - Water and alanine: from puddles(32) to ponds(49). AB - The solvation of alanine is investigated, with a focus on adding a sufficient number of discrete water molecules to determine the first solvation shell for both the nonionized (N) and zwitterionic (Z) forms to converge the enthalpy of solvation and the enthalpy difference for the two forms of alanine. Monte Carlo sampling was employed using the generalized effective fragment potential (EFP) method to determine the global minimum of both conformers, with the number of EFP water molecules ranging from 32-49. A subset of sampled geometries were optimized with second-order perturbation theory (MP2) using the 6-31++G(d,p) basis set. Single point energies were calculated at these geometries using the polarizable continuum model (PCM). The predicted 298.15 K enthalpy of solvation ranges for MP2/6-31++G(d,p) and MP2+PCM//MP2/6-31++G(d,p) are 10.0-13.2 kcal/mol and 10.1 12.6 kcal/mol, respectively. PMID- 19788285 TI - Computational studies of aqueous interfaces of SrCl(2) salt solutions. AB - The electron density profiles and corresponding surface structures of an aqueous interface of SrCl(2) salt solution were computed by use of molecular dynamics simulations. We used both polarizable and nonpolarizable potential models to describe molecular interactions. The results demonstrate that the polarizable models captured the essential features of the corresponding X-ray reflectivity experimental data while the corresponding nonpolarizable models could not. In addition, we demonstrated that the shape of the X-ray reflectivity curve could be quantitatively reproduced if the simulations were carried out at lower SrCl(2) concentrations, making it likely that the polarizable models used in this study somewhat overestimate the surface concentration of ions. However, significant interfacial enhancement of both Sr(2+) and Cl(-) appears necessary to reproduce the experimental spectra. This is in contrast to systems with monovalent cations, which have generally been found to have a double layer, in which anions are enhanced at the surface but cations are repelled. PMID- 19788286 TI - Selective reactions and adsorption geometries of a multifunctional molecule: cis 2-butene-1,4-diol on Si(100)-2 x 1. AB - The adsorption geometry of cis-2-butene-1,4-diol (BEDO, HOCH(2)CH=CHCH(2)OH) on Si(100)-2 x 1 was studied using scanning tunneling microscopy (STM), high resolution X-ray photoemission spectroscopy (XPS), and near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. Bias-voltage-dependent STM images exhibited features characteristic of two distinct BEDO adsorption geometries. One feature was a bright protrusion located on the center of a single dimer, indicating an on top configuration. The low bias-voltage STM image clearly showed dark features indicative of the formation of Si-H bonds on adjacent dimers in the same dimer row. The other feature was a bright protrusion bridged on end between two adjacent dimers in the same dimer row, indicating an end-bridge configuration. Accompanying this feature, two dark features attributed to Si-H bonds were observed on opposite positions to the bridged protrusion. From the XPS results, the Si 2p core level spectra revealed that the dimer atoms are involved in the formation of Si-O and Si-H bonds. On the other hand, carbon K-edge NEXAFS spectra showed that the C=C bond does not participate in the adsorption reaction and remains as an unreacted group. Collectively, the experimental results indicate that the adsorption of BEDO on Si(100)-2 x 1 occurs through the formation of two Si-O bonds via nucleophilic reaction between the two OH groups of BEDO and two Si Si dimers. Importantly, the maintenance of the C=C bond means that the C=C functional group can be utilized as a new reaction site for further surface chemical reactions. PMID- 19788287 TI - Conformational study of a bent-core liquid crystal: 13C NMR and DFT computation approach. AB - A detailed conformational study is carried out by means of density functional theory (DFT) on a bent-core mesogen (A131) in order to shed light on its uniaxial biaxial nematic phase transition. The most probable conformational states for this V-shaped core are found, from the potential energy surface (PES) of a five ring model of A131, to fall into two distinct structural groups, namely, the banana-shaped and the hockey-stick-shaped forms. The chemical shielding tensors (CSTs) of the aromatic carbons, for the four prevalent conformers, have been calculated using the GIAO-DFT approach. The derived CSTs are found to compare well with the chemical shift anisotropy (CSA) tensors measured by the 2D-NMR SUPER technique. The CSA tensors are then used to aid the assignment of the aromatic carbon peaks, and the observed (13)C chemical shifts from its nematic phases are revisited to provide new structural and local orientational order parameters. In light of the conformational states found from the in vacuo DFT calculations, the "average" configuration shapes of the A131 molecule are found to be different in the nematic phases based on their new local order parameters S and D of the aromatic rings. PMID- 19788288 TI - Application of the diffusion Monte Carlo method to the binding of excess electrons to water clusters. AB - The diffusion Monte Carlo (DMC) method is used to calculate the electron binding energies of two forms of (H(2)O)(6)(-). It is found that the DMC method, when using either Hartree-Fock or density functional theory trial wave functions, gives electron binding energies in excellent agreement with the results of large basis set CCSD(T) calculations. This demonstrates that the DMC method will be a viable method for characterizing larger (H(2)O)(n)(-) ions for which CCSD(T) calculations are not feasible. PMID- 19788289 TI - Activity of mangosteen xanthones and teleocidin a-2 in death receptor expression enhancement and tumor necrosis factor related apoptosis-inducing ligand assays. AB - A screening study using a luciferase assay to identify natural products that enhance death receptor 5 (DR5) expression was carried out, and bioassay-guided fractionation of two organisms, the pericarp of Garcinia mangostana (mangosteen) and actinomycete CKK609 strain, led to the isolation of eight xanthone derivatives (1-8) and teleocidin A-2 (9). Among them, compounds 1, 2, and 5, isolated from G. mangostana, and 9, from the actinomycete, showed potent DR5 promoter activity. Furthermore, we revealed that combined treatment with gartanin (5) and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) showed a potentiation effect in sensitizing TRAIL-resistant human gastric adenocarcinoma (AGS) cells. Thus, the present results suggested that 5 has the ability to overcome TRAIL resistance via the up-regulation of DR5 and may be an effective sensitizer of TRAIL-resistant cells. PMID- 19788291 TI - Robust forests of vertically aligned carbon nanotubes chemically assembled on carbon substrates. AB - Forests of vertically aligned carbon nanotubes (VACNTs) have been chemically assembled on carbon surfaces. The structures show excellent stability over a wide potential range and are resistant to degradation from sonication in acid, base, and organic solvent. Acid-treated single-walled carbon nanotubes (SWCNTs) were assembled on amine-terminated tether layers covalently attached to pyrolyzed photoresist films. Tether layers were electrografted to the carbon substrate by reduction of the p-aminobenzenediazonium cation and oxidation of ethylenediamine. The amine-modified surfaces were incubated with cut SWCNTs in the presence of N,N'-dicyclohexylcarbodiimide (DCC), giving forests of vertically aligned carbon nanotubes (VACNTs). The SWCNT assemblies were characterized by scanning electron microscopy, atomic force microscopy, and electrochemistry. Under conditions where the tether layers slow electron transfer between solution-based redox probes and the underlying electrode, the assembly of VACNTs on the tether layer dramatically increases the electron-transfer rate at the surface. The grafting procedure, and hence the preparation of VACNTs, is applicable to a wide range of materials including metals and semiconductors. PMID- 19788290 TI - Cytotoxic clerodane diterpenoids from Casearia obliqua. AB - A crude bioactive EtOH extract of the twigs of Casearia obliqua afforded two new clerodane diterpenes, caseobliquins A (1) and B (2). Additionally, bioactivity directed fractionation on a bioactive hexane extract of the leaves from this species led to the isolation of the known clerodane diterpenes rel-6beta hydroxyzuelanin-2beta-benzoate and rel-2alpha-hydroxyzuelanin-6beta-benzoate (3 and 4) as a mixture and 2beta-hydroxyzuelanin-6beta-cinnamate (5). The structures of the new clerodanes 1 and 2 were established on the basis of their 1D and 2D NMR spectroscopic data, and the new compound 1 and the known substance 5 had their absolute configurations determined by circular dichroism spectroscopy. The cytotoxicity of several of the compounds isolated was evaluated against a small panel of human tumor cell lines. PMID- 19788292 TI - Quantum-mechanical ab initio simulation of the Raman and IR spectra of Fe3Al2Si3O12 almandine. AB - The IR and Raman spectra of the Fe(3)Al(2)Si(3)O(12) almandine garnet were simulated using the periodic CRYSTAL code with an all-electron Gaussian-type basis set and the hybrid B3LYP functional. The wavenumbers of the 25 Raman-active modes (3 of A(1g), 8 of E(g), and 14 of F(2g) symmetry) and 34 F(1u) IR-active modes (17 TO and 17 LO) were computed, as were the IR intensities. Calculated wavenumbers are in excellent agreement with the various sets of experimental results, with the mean absolute difference |Delta| being between 4 and 8 cm(-1). Graphical animation, available on the CRYSTAL Web site, provides a very comprehendible description of the movement of atoms and groups in each vibrational mode. The simulated reflectivity spectrum, obtained using a classical dispersion relation, is in excellent agreement with the measured one. PMID- 19788293 TI - In silico characterization of a fourfold magnesium organometallic compound in PTCDA thin films. AB - In this contribution, using first principles calculations within a density functional theory framework, we report, for the first time, evidence for the formation of a fourfold magnesium organometallic compound upon metal deposition on perylene-3,4,9,10-tetracarboxyl dianhydride (PTCDA) organic semiconductor. Current investigation clearly indicates that in the bulk of the organic crystallographic structure the magnesium atom mainly interacts with three PTCDA molecules. The reactive metal is bound both to carboxylic oxygen atoms of the anhydride-end moieties and to a perylene carbon atom which changes its hybridization state, from sp(2) to sp(3), in the presence of metal impurities. In turn, the analysis of the electronic structure of the reacted system prevalently reveals the formation of four covalent bonds, as a consequence of a weak charge transfer toward the organic material. Such a result confirms the capability of the PTCDA thin films to host metal atoms providing, inside their structural empty channels, a rather accessible and soft chemical environment. Interestingly, in the light of these findings and of previous works, a relationship between first ionization potential of the doping metal and the character of the newly formed chemical bonds is confirmed. PMID- 19788294 TI - Fluorine bonding--how does it work in protein-ligand interactions? AB - Although fluorination of pharmacologically active compounds has long been a common strategy to increase their metabolic stability and membrane permeation, the functionality of protein-ligand interactions involving fluorine atoms (fluorine bonding) was only recently recognized in the chemistry and biology communities. In this study, the geometric characteristics and the energetic behaviors of fluorine bonding were systematically investigated by combining two quite disparate but complementary approaches: X-ray structural analysis and theoretical calculations. We found that the short contacts involving fluorine atoms (generalized fluorine bonding) between proteins and fluorinated ligands are very frequent, and these contacts, compared to those routine hydrogen/halogen bonding, are more similar to sulfur-involved hydrogen bonding observed in proteins. ONIOM-based quantum mechanics/molecular mechanics analysis further revealed that fluorine bonding does play an essential role in protein-ligand binding, albeit the strength of isolated fluorine bonding is quite modest. Furthermore, 14 quantum mechanics (QM) and molecular mechanics (MM) methods were performed to reproduce fluorine bonding energies obtained at the rigorous MP2/aug cc-pVDZ level of theory, and the results showed that most QM and very few MM methods perform well in the reproducibility; the MPWLYP functional and MMFF94 force field are recommended to study moderate and large fluorine bonding systems, respectively. PMID- 19788295 TI - A planar copolymer for high efficiency polymer solar cells. AB - An alternating copolymer, poly(2-(5-(5,6-bis(octyloxy)-4-(thiophen-2 yl)benzo[c][1,2,5]thiadiazol-7-yl)thiophen-2-yl)-9-octyl-9H-carbazole) (HXS-1), was designed, synthesized, and used as the donor material for high efficiency polymer solar cells. The close packing of the polymer chains in the solid state was confirmed by XRD. A J(sc) of 9.6 mA/cm(2), a V(oc) of 0.81 V, an FF of 0.69, and a PCE of 5.4% were achieved with HXS-1 and [6,6]-phenyl C(71)-butyric acid methyl ester (PC(71)BM) as a bulk heterojunction active layer spin-coated from a solvent mixture of 1,2-dichlorobenzene and 1,8-diodooctane (97.5:2.5) under air mass 1.5 global (AM 1.5 G) irradiation of 100 mW/cm(2). PMID- 19788296 TI - PCR with an expanded genetic alphabet. AB - Expansion of the genetic alphabet with a third base pair would lay the foundation for a semisynthetic organism with an expanded genetic code and also have immediate in vitro applications. Previously, the unnatural base pairs formed between d5SICS and either dNaM or dMMO2 were shown to be well-replicated by DNA polymerases under steady-state conditions and also transcribed by T7 RNA polymerase efficiently in either direction. We now demonstrate that DNA containing either the d5SICS-dNaM or d5SICS-dMMO2 unnatural base pair may be amplified by PCR with fidelities and efficiencies that approach those of fully natural DNA. These results further demonstrate that the determinants of a functional unnatural base pair may be designed into predominantly hydrophobic nucleobases with no structural similarity to the natural purines or pyrimidines. Importantly, the results reveal that the unnatural base pairs may function within an expanded genetic alphabet and make possible many in vitro applications. PMID- 19788297 TI - Intramolecular oxamidation of unsaturated O-alkyl hydroxamates: a remarkably versatile entry to hydroxy lactams. AB - The development of a versatile method for the preparation of five- to eight membered hydroxy lactams that involves the iodine(III)-mediated oxamidation of unsaturated O-alkyl hydroxamates is described. This transformation, which is believed to proceed through the intermediacy of singlet nitrenium and bicyclic N acyl-N-alkoxyaziridinium ions, is both stereospecific and highly regioselective in most of the 22 cases examined. PMID- 19788299 TI - Subtype polymorphisms among HIV-1 protease variants confer altered flap conformations and flexibility. AB - Human immunodeficiency virus type 1 (HIV-1) protease plays a fundamental role in the maturation and life cycle of the retrovirus HIV-1, as it functions in regulating post-translational processing of the viral polyproteins gag and gag pol; thus, it is a key target of AIDS antiviral therapy. Accessibility of substrate to the active site is mediated by two flaps, which must undergo a large conformational change from an open to a closed conformation during substrate binding and catalysis. The electron paramagnetic resonance (EPR) method of site directed spin labeling (SDSL) with double electron-electron resonance (DEER) spectroscopy was utilized to monitor the conformations of the flaps in apo HIV-1 protease (HIV-1PR), subtypes B, C, and F, CRF01_A/E, and patient isolates V6 and MDR 769. The distance distribution profiles obtained from analysis of the dipolar modulated echo curves were reconstructed to yield a set of Gaussian-shaped populations, which provide an analysis of the flap conformations sampled. The relative percentages of each conformer population described as "tucked/curled", "closed", "semi-open", and "wide-open" were determined and compared for various constructs. The results and analyses show that sequence variations among subtypes, CRFs, and patient isolates of apo HIV-1PR alter the average flap conformation in a way that can be understood as inducing shifts in the relative populations, or conformational sampling, of the previously described four conformations for HIV-1PR. PMID- 19788300 TI - Electric-field-induced charge-transfer phase transition: a promising approach toward electrically switchable devices. AB - Much research has been directed toward the development of electrically switchable optical materials for applications in memory and display devices. Here we present experimental evidence for an electric-field-induced charge-transfer phase transition in two cyanometalate complexes: Rb(0.8)Mn[Fe(CN)(6)](0.93).1.62H(2)O and Co(3)[W(CN)(8)](2)(pyrimidine)(4).6H(2)O, involving changes in their magnetic, optical, and electronic properties as well. Application of an electric field above a threshold value and within the thermal hysteresis region leads to a transition from the high- to the low-temperature phase in these compounds. A model is proposed to explain the main observations on the basis of a para ferroelectric transition. Our observations suggest that this new concept of electrical switching, based on materials exhibiting charge-transfer phase transitions with large thermal hysteresis loops, may open up doors for novel electro-optical devices. PMID- 19788301 TI - Programmed synthesis of tetraarylthiophenes through sequential C-H arylation. AB - A general protocol for the programmed synthesis of tetraarylthiophenes has been established. The utilization of three catalysts, RhCl(CO){P[OCH(CF(3))(2)](3)}(2), PdCl(2)/P[OCH(CF(3))(2)](3), and PdCl(2)/bipy, enables regioselective sequential arylations at the three C-H bonds of 3 methoxythiophene with iodoarenes. Interesting metal- and ligand-controlled regiodivergent C-H arylations have been uncovered during this study. The installation of fourth aryl groups to the thus-generated 2,4,5-triaryl-3 methoxythiophenes has been accomplished through a sequence of demethylation, triflation, and Suzuki-Miyaura coupling. PMID- 19788303 TI - Interaction of ClO radical with liquid water. AB - In the present work, the interaction between ClO radical and liquid water is studied using molecular dynamics simulations. We perform simulations of collisions of a ClO radical with the surface of liquid water to understand the accommodation of ClO by liquid water. Simulation results show that the ClO radical has a higher propensity to be adsorbed on the air-water interface than to be dissolved in the bulk. The free energy profile is also calculated, and the solvation free energy and Henry's law constant are determined for ClO as DeltaG(s) of -2.9 kcal/mol and 5.5 M/atm, respectively. The mechanism of the ClO recombination reaction is also discussed, and the results are consistent with laboratory findings. PMID- 19788302 TI - Cell-penetrating peptides and peptide nucleic acid-coupled MRI contrast agents: evaluation of cellular delivery and target binding. AB - Molecular imaging of cells and cellular processes can be achieved by tagging intracellular targets such as receptors, enzymes, or mRNA. Seeking to visualize the presence of specific mRNAs by magnetic resonance (MR) imaging, we coupled peptide nucleic acids (PNA) with gadolinium-based MR contrast agents using cell penetrating peptides for intracellular delivery. Antisense to mRNA of DsRed2 protein was used as proof of principle. The conjugates were produced by continuous solid-phase synthesis followed by chelation with gadolinium. Their cellular uptake was confirmed by fluorescence microscopy and spectroscopy as well as by MR imaging of labeled cells. The cell-penetrating peptide D-Tat(57-49) was selected over two other derivatives of HIV-1 Tat peptide, based on its superior intracellular delivery of the gadolinium-based contrast agents. Further improved delivery of conjugates was achieved upon coupling peptide nucleic acids (antisense to mRNA of DsRed2 protein and nonsense with no natural counterpart). Significant enhancement in MR contrast was obtained in cells labeled with concentrations as low as 2.5 MUM of these agents. Specific binding of the targeting PNA containing conjugate to its complementary oligonucleotide sequence was proven by in vitro cell-free assay. In contrast, a lack of specific enrichment was observed in transgenic cells containing the target due to nonspecific vesicular entrapment of contrast agents. Preliminary biodistribution studies showed conjugate-related fluorescence in several organs, especially the liver and bladder, indicating high mobility of the agent in spite of its high molecular weight. No conjugate related toxicity was observed. These results are encouraging, as they warrant further molecular optimization and consecutive specificity studies in vivo of this new generation of contrast agents. PMID- 19788304 TI - The organometallic fluorine chemistry of palladium and rhodium: studies toward aromatic fluorination. AB - Although springing from two established fields, organometallic chemistry and fluorine chemistry, organometallic fluorine chemistry is still in its early stages. However, developments in this area are expected to provide new tools for the synthesis of selectively fluorinated organic compounds that have been in high demand. Selectively fluorinated organic molecules currently account for up to 40% of all agrochemicals and 20% of all pharmaceuticals on the market. Our research efforts have been focused on the development of new organometallic and catalytic methods for the selective introduction of fluorine and the CF(3) group into the aromatic ring. Monofluorinated and trifluoromethylated aromatic compounds are still made by the old technologies that employ stoichiometric quantities of hazardous and costly materials. In this Account, we describe our studies toward the development of safe, catalytic alternatives to these methods. We have synthesized, characterized, and studied the reactivity of the first aryl palladium(II) fluoride complexes. We have demonstrated for the first time that a Pd-F bond can be formed in a soluble and isolable molecular complex: this bond is more stable than previously thought. Toward the goal of fluoroarene formation via Ar-F reductive elimination, we have studied a number of sigma-aryl Pd(II) fluorides stabilized by various P, N, and S ligands. It has been established that numerous conventional tertiary phosphine ligands, most popular in Pd catalysis, are unlikely to be useful for the desired C-F bond formation at the metal center because of the competing, kinetically preferred P-F bond-forming reaction. A metallophosphorane mechanism has been demonstrated for the P-F bond-forming processes at Rh(I) and Pd(II), which rules out the possibility of controlling these reactions by varying the amount of phosphine in the system, a most common and often highly efficient technique in homogeneous catalysis. The novel F/Ph rearrangement of the fluoro analogue of Wilkinson's catalyst [(Ph(3)P)(3)RhF] and P-F bond-forming reactions at Pd(II) are insensitive to phosphine concentration and, because of the small size of fluorine, occur even with bulky phosphine ligands. These observations may guide further efforts toward metal-catalyzed nucleophilic fluorination of haloarenes. We have also developed aryne-mediated and CuF(2)/TMEDA-promoted aromatic fluorination reactions. The formation of fluoroarenes from the corresponding iodo- and bromoarenes in the presence of the CuF(2)/TMEDA system is the first example of a transition metal-mediated fluorination of nonactivated aryl halides in the liquid phase. Progress has also been made toward the development of aromatic trifluoromethylation. We have found unexpectedly facile and clean benzotrifluoride formation as a result of Ph-CF(3) reductive elimination from [(Xantphos)Pd(Ph)CF(3)]. This observation demonstrates for the first time that the notoriously strong and inert metal-CF(3) bond can be easily cleaved (at 50-80 degrees C) as a result of reductive elimination to produce the desired aryl-trifluoromethyl bond, the only previously missing link of the catalytic loop. Our study of the novel complex [(Ph(3)P)(3)RhCF(3)] has led to a rationale for the long-puzzling strong trans influence (electron donation) of the CF(3) group which, in complete contrast, is known to be an electron acceptor in organic chemistry. PMID- 19788306 TI - Computational studies on the interactions of inhalational anesthetics with proteins. AB - Despite the widespread clinical use of anesthetics since the 19th century, a clear understanding of the mechanism of anesthetic action has yet to emerge. On the basis of early experiments by Meyer, Overton, and subsequent researchers, the cell's lipid membrane was generally concluded to be the primary site of action of anesthetics. However, later experiments with lipid-free globular proteins, such as luciferase and apoferritin, shifted the focus of anesthetic action to proteins. Recent experimental studies, such as photoaffinity labeling and mutagenesis on membrane proteins, have suggested specific binding sites for anesthetic molecules, further strengthening the proteocentric view of anesthetic mechanism. With the increased availability of high-resolution crystal structures of ion channels and other integral membrane proteins, as well as the availability of powerful computers, the structure-function relationship of anesthetic-protein interactions can now be investigated in atomic detail. In this Account, we review recent experiments and related computer simulation studies involving interactions of inhalational anesthetics and proteins, with a particular focus on membrane proteins. Globular proteins have long been used as models for understanding the role of protein-anesthetic interactions and are accordingly examined in this Account. Using selected examples of membrane proteins, such as nicotinic acetyl choline receptor (nAChR) and potassium channels, we address the issues of anesthetic binding pockets in proteins, the role of conformation in anesthetic effects, and the modulation of local as well as global dynamics of proteins by inhaled anesthetics. In the case of nicotinic receptors, inhalational anesthetic halothane binds to the hydrophobic cavity close to the M2-M3 loop. This binding modulates the dynamics of the M2-M3 loop, which is implicated in allosterically transmitting the effects to the channel gate, thus altering the function of the protein. In potassium channels, anesthetic molecules preferentially potentiate the open conformation by quenching the motion of the aromatic residues implicated in the gating of the channel. These simulations suggest that low-affinity drugs (such as inhalational anesthetics) modulate the protein function by influencing local as well as global dynamics of proteins. Because of intrinsic experimental limitations, computational approaches represent an important avenue for exploring the mode of action of anesthetics. Molecular dynamics simulations-a computational technique frequently used in the general study of proteins-offer particular insight in the study of the interaction of inhalational anesthetics with membrane proteins. PMID- 19788305 TI - Importance of charge independent effects in readout of the trimethyllysine mark by HP1 chromodomain. AB - Histone modifications are implicated in epigenetic inheritance and are of central importance in regulating chromatin structure and gene expression. A prototype example is the trimethylation (Me3) of lysine 9 on histone 3 (H3), which is a readout by an aromatic cage of the chromodomain of heterochromatin-associated protein 1 (HP1) thereby leading to transcriptional repression and heterochromatin formation. Considering that the lysine methylation does not change the charge state of the histone tail and such aromatic-cage mediated recognition of the quaternary ammonium moiety is emerging as the most striking mechanistic commonality for the state-specific recognition of histone lysine methylation, it is of particular interest and importance to understand the physical origin regarding how the aromatic cage distinguishes between the H3K9Me3 mark and its unmethylated counterpart. Here we have simulated relative binding free energies among HP1 chromodomain-H3 tail complexes differing at position 9 of the H3 tail. Our simulated results further confirm the essential role of cation-pi interactions for the binding of a methylated H3 tail by an HP1 chromodomain but indicate that the effect from an electrostatic origin is not dominant in distinguishing between the H3K9Me3 mark and its unmethylated counterpart. Meanwhile, our calculated free energy difference between H3-tert-butyl norleucine 9 and H3-methylnorleucine 9 in their binding to the HP1 clearly reveals the importance of the charge independent interactions for the state-specific readout of histone lysine trimethylation marks. PMID- 19788307 TI - Recombinant silk-elastinlike protein polymer displays elasticity comparable to elastin. AB - We evaluated the mechanical properties of the genetically engineered, recombinant silk-elastinlike protein copolymer, SELP-47K. In tensile stress-strain analysis, methanol-treated non-cross-linked SELP-47K films exceeded the properties of native aortic elastin, attaining an ultimate tensile strength of 2.5 +/- 0.4 MPa, an elastic modulus of 1.7 +/- 0.4 MPa, an extensibility of 190 +/- 60%, and a resilience of 86 +/- 4% after 10 cycles of mechanical preconditioning. Stress relaxation and creep analysis showed that films substantially maintained their elastic properties under sustained deformation. Chemical cross-linking of SELP 47K films doubled the elastic modulus and ultimate tensile strength and enhanced the extensibility and resilience. The underlying conformational and microstructural features of the films were examined. Raman spectroscopy revealed that the silklike blocks of SELP-47K existed in antiparallel beta-sheet crystals in the films, likely responsible for the robust physical cross-links. Scanning electron microscopy (SEM) revealed that the various processing treatments and the mechanical deformation of the films induced changes in their surface microstructure consistent with the coagulation and alignment of polymer chains. These results demonstrate that films with excellent elasticity, comparable to native aortic elastin, are obtainable from SELP-47K, a protein copolymer combining both silk- and elastin-derived sequences in a single polymer chain. PMID- 19788309 TI - Lipids, proteins, and their interplay in the dynamics of temperature-stressed membranes of a cyanobacterium, Synechocystis PCC 6803. AB - Proper responses to low- and high-temperature stresses are essential for the survival of many organisms. It has been established that at low-temperature stress the sufficient microviscosity of the lipids is decisive in this respect. In many organisms, adapting the level of lipid unsaturation to the low growth temperature regulates this feature. At high-temperature stresses, however, there are no unequivocal results concerning the role of the lipids. In these temperature ranges, the lipids are all disordered and fluid and their physical parameters change slowly with increasing temperatures, while biological organisms give characteristic stress responses in rather narrow temperature ranges. Therefore, one may speculate that other membrane parameters/components, which change sharply in the range of the high-temperature stress, may give a signal to initiate the general response of the cells. For such a role, proteins are the trivial candidates. To reveal the role of the lipids and the proteins in these processes, we used a genetically engineered system, based on a cyanobacterium, Synechocystis PCC 6803. In the wild-type cells of this bacterium, by altering the growth temperature, the polyunsaturated lipid content of the cell membranes can be varied considerably (as required by the homeoviscous adaptation principle). In the case of desA(-)/desD(-) mutant cells, which can contain only monounsaturated fatty acyl chains in their lipids, homeoviscous adaptation of the lipids is not possible. Since desA(-)/desD(-) mutation affects only the lipids, additional perturbations (e.g., altered protein content) should minimally disturb the comparison of the lipid behaviors in wild-type and mutant cells. Infrared spectra of thylakoid and cytoplasmic membranes isolated from wild-type and mutant cells were recorded in 3 degrees C steps between 8 and 92 degrees C. By analyzing the rates of protein structural changes, hydrogen-deuterium exchange, in-membrane lipid disorder, and water-membrane interfacial order/hydration as functions of the temperature, we conclude that (i) the gel-to-liquid crystalline phase transition of the lipids correlates with the growth temperature in the wild-type cells but not in the desA(-)/desD(-) mutants, (ii) over the physiological temperature range, both protein and lipid dynamics are regulating/regulated, providing remarkably constant dynamics for both the thylakoid and cytoplasmic membrane, (iii) in the high-temperature stress region, protein structure and dynamics are changing sharply without any correlation with growth temperature and/or mutation, i.e., membrane protein stability does not seem to depend on the lipid composition of the membrane (this finding points to the possible primacy of proteins as initiators/targets of heat-shock alarms), and (iv) there are substantial differences between the dynamics of the proteins of the thylakoid and cytoplasmic membranes, reflecting their different protein complexes and lipid-to protein ratios. PMID- 19788308 TI - Functional disulfide-stabilized polymer-protein particles. AB - Polymer-protein hybrid particles (PPHPs) have a significant potential in drug delivery, diagnosis, and biomedical imaging applications. Herein, we describe a simple route to disulfide cross-linked, poly(ethylene glycol)-streptavidin hybrid particles with tunable diameters. These particles have great versatility and potential for a number of reasons. First, they possess free biotin binding sites on their streptavidin (SAv) coated surface, enabling the conjugation of any biotinylated-molecule such as biotinylated antibodies. Second, core-stabilization can easily be controlled using reversible disulfide cross-links, and third, thiol and ene-reactive functionalities in the core are available for the conjugation of drugs and labels. In detail, micelles having a biotinylated poly(ethylene glycol) corona and a disulfide cross-linked, reactive core were formed using alpha-biotin PEG-b-poly(pyridyldisulfide ethylmethacrylate) block copolymers synthesized via RAFT polymerization. Functionalization of the micelle core was performed in a one-pot reaction concurrent with the micellization and cross linking processes by using a thiol-reactive model compound (a maleimide derivative of a green fluorophore). The resultant micelles displayed spherical morphology with a diameter of 54 +/- 4 nm. Biotin functionality was largely exposed on the micelle corona (75 mol % availability), as determined by a streptavidin/HABA assay. The micelles were subsequently decorated with (red fluorophore-labeled) streptavidin (SAv) through the accessible biotins on the surface, yielding SAv-linked micelle aggregates with tunable dimensions (in the range between 350 nm and 2 microm), as determined by transmission electron microscopy. Fluorescent-labels on the particles were monitored using confocal microscopy, revealing that the SAv coats the periphery of the PPHPs. PMID- 19788310 TI - Structure elucidation and preliminary assessment of hydrolase activity of PqsE, the Pseudomonas quinolone signal (PQS) response protein. AB - In bacteria, the transcription of virulence genes is usually controlled by a cell density-dependent process known as "quorum sensing" (QS). QS relies on small diffusible signaling molecules that cross the bacterial cell wall and activate target transcription factors after a threshold concentration has been reached. Besides two hierarchical QS circuits based on N-acylhomoserine lactones, the human opportunistic pathogen Pseudomonas aeruginosa integrates a signaling system that depends on 2-heptyl-3-hydroxy-4-quinolone, termed "Pseudomonas quinolone signal" (PQS). PQS is produced from genes encoded in the pqs operon, which in addition to the biosynthetic enzymes PqsA-D contains a fifth gene, pqsE, that is not required for production of PQS but whose disruption leads to loss of signal transduction in several but not all pqs operon-dependent processes. PqsE was hence termed "PQS response protein", but its exact mechanism of action is unknown. We have determined the crystal structure of recombinant PqsE and show that it possesses a metallo-beta-lactamase fold with an Fe(II)Fe(III) center in the active site. A copurified ligand was assigned as benzoate and may indicate that PqsE exerts its regulatory effect by converting a chorismate-derived molecule. Further, PqsE was found to slowly hydrolyze phosphodiesters including single- and double-stranded DNA as well as mRNA and also the thioester S-(4 nitrobenzoyl)mercaptoethane. Higher activity was observed after incubation with Co(2+) and, to lesser entent, Mn(2+), suggesting that the Fe(II)Fe(III) center of recombinant PqsE may be an artifact of heterologous expression. A crystal complex of the E182A mutant with bis-pNPP was obtained and suggests a catalytic mechanism for hydrolysis. PMID- 19788311 TI - Role of tryptophan-tryptophan interactions in Trpzip beta-hairpin formation, structure, and stability. AB - A series of beta-hairpin peptides based on variations of the TrpZip2 sequence, SWTWENGKWTWK, of Cochran and co-workers were studied using electronic circular dichroism (CD) and infrared (IR) spectra by varying temperature and pH. Selected tryptophan residues were substituted with Val to test the impact of specific Trp interactions on hairpin stability. Native-state structures of two of the variants were determined using 2-D NMR and shown to have the same cross-strand edge-to face Trp-Trp interaction as in Trpzip2. Thermally induced conformational changes of the hairpins formed with these various sequences were studied with CD and IR. Thermodynamic analyses of the temperature variation of both IR (as analyzed using the amide I' frequency shift) and CD (intensity) spectra were fit to a two-state model that yielded different T(m) values, consistent with a multistate process of folding/unfolding. At low pH these differences were minimized, suggesting a change in the energetics. Cross-strand interacting Trp residues with an edge-to face orientation had the strongest impact on hairpin stability, as judged by CD and IR data. The diagonal interaction between Trp2 and Trp9, which have a more parallel orientation in Trpzip2, contribute to the spectral response but do not independently stabilize the structure. Comparative study of these various physical interactions emphasizes the complex folding pathways that are important even for these small peptides. PMID- 19788312 TI - Analysis of protein conformation and dynamics by hydrogen/deuterium exchange MS. AB - Understanding as much as possible about proteins in the shortest amount of time has long been a goal of hydrogen exchange (HX) MS. Recent technological advances have led to improvements in the technique, but has this goal yet been achieved? (To listen to a podcast about this Feature, please go to the Analytical Chemistry Web site at pubs.acs.org/journal/ancham.). PMID- 19788313 TI - Fluorescence polarization combined capillary electrophoresis immunoassay for the sensitive detection of genomic DNA methylation. AB - Genomic DNA hypomethylation is epigenetically associated with aberrant gene expression and chromosome instability. Here we describe a method for rapid and sensitive detection of genomic DNA methylation without the need for bisulfite conversion, enzymatic digestion, or PCR amplification. The methylated DNA is first specifically recognized by an anti-5-methylcytosine IgG1 antibody and noncovalently labeled by a monovalent, fluorescently labeled, Fc-specific anti IgG1 Fab fragment (secondary antibody). The formed immuno-complex of methylated DNA can be efficiently focused and separated from the DNA unbound secondary antibody by capillary electrophoresis (CE). The free fluorescent dye comigrates with the immuno-complex. However, by taking advantage of online laser-induced fluorescence polarization detection (LIFP), the target immuno-complex can be distinguished and accurately measured from the overlapped dye without further separation. The developed method is highly sensitive with a LOD of 0.3 nM and is highly specific for the detection of methylated DNA. Moreover, the CE-LIFP immunoassay is rapid (1.2 min for one analysis) and only consumes less than 0.1 ng of genomic DNA. The method was validated by examining human cell lines treated by methyltransferase inhibitor 5-aza-2'-deoxycytidine at low doses (10 nM-10 microM). Because of its sensitivity and speed, our method will be applicable for rapid epigenetic evaluation and for the study of tumorigenesis and chemical-cell interactions. PMID- 19788314 TI - Adsorption of glucose oxidase onto single-walled carbon nanotubes and its application in layer-by-layer biosensors. AB - In this study, we describe the use of a sodium cholate suspension-dialysis method to adsorb the redox enzyme glucose oxidase (GOX) onto single-walled carbon nanotubes (SWNT). By this method, solutions of dispersed and debundled SWNTs were prepared that remained stable for 30 days and which retained 75% of the native enzymatic activity. We also demonstrate that GOX-SWNT conjugates can be assembled into amperometric biosensors with a poly[(vinylpyridine)Os(bipyridyl)2Cl(2+/3+)] redox polymer (PVP-Os) through a layer-by-layer (LBL) self-assembly process. Incorporation of SWNT-enzyme conjugates into the LBL films resulted in current densities as high as 440 microA/cm2, which were a 2-fold increase over the response of films without SWNTs. We also demonstrate that the adsorption pH of the redox polymer solution and the dispersion quality of SWNTs were important parameters in controlling the electrochemical and enzymatic properties of the LBL films. PMID- 19788315 TI - Monitoring dynamic changes in lymph metabolome of fasting and fed rats by electrospray ionization-ion mobility mass spectrometry (ESI-IMMS). AB - Ambient pressure ion mobility time-of-flight mass spectrometry (IMMS) has recently emerged as a rapid and efficient analytical technique for applications to metabolomics. An important application of metabolomics is to monitor metabolome shifts caused by stress due to toxin exposure, nutritional changes, or disease. The research presented in this paper uses IMMS to monitor metabolic changes in rat lymph fluid caused by dietary stresses over time. Extracts of metabolites found in the lymph fluid collected from dietary stressed rats were subjected to analysis by electrospray (ESI) IMMS operated both in positive and negative ion detection mode. Metabolites detected were tentatively identified based on their mass to charge ratio (m/z). In one sample, 1180 reproducible tentative metabolite ions were detected in negative mode and 1900 reproducible tentative metabolite ions detected in positive mode. Only biologically reproducible ions, defined as metabolite ions that were measured in different rats under the same treatment, were analyzed to reduce the complexity of the data. A metabolite peak list including m/z, mobility, and intensity generated for each metabolome was used to perform principle component analysis (PCA). Dynamic changes in metabolomes were investigated using principle components PC1 and PC2 that described 62% of the variation of the system in positive mode and 81% of the variation of the system in negative mode. Analysis of variance (ANOVA) was performed for PC1 and PC2 and means were statistically evaluated. Profiles of intensities were compared for tentative metabolite ions detected at different times before and after the rats were fed to identify the metabolites that were changing the most. Mobility-mass correlation curves (MMCC) were investigated for the different classes of compounds. PMID- 19788316 TI - Prefluorescent nitroxide probe for the highly sensitive determination of peroxyl and other radical oxidants. AB - Fluorescamine derivatized 3-amino-2,2,5,5,-tetramethyl-1-pyrrolidinyloxy (I) is shown to undergo an irreversible reaction with peroxyl radicals and other radical oxidants to generate a more highly fluorescent diamagnetic product (II) and thus can be used as a highly sensitive and versatile probe to determine oxidant production optically, either by monitoring the changes in fluorescence intensity, by HPLC analysis with fluorescence detection, or by a combination of both approaches. By changing the [O2]/[I] ratio, we show that peroxyl radicals can be detected and quantified preferentially in the presence of other radical oxidants. Detection of photochemically produced peroxyl radicals is achieved by employing 3 amino-2,2,5,5,-tetramethyl-1-pyrrolidinyloxy (3-ap) alone, followed by derivatization with fluorescamine. With employment of HPLC analysis, the detection limit of II at a S/N of 2 is approximately 3 nM for a 125 microL injection. Preliminary applications include the detection of peroxyl radicals generated thermally in soybean phosphatidylcholine liposomes and produced photochemically in tap water. PMID- 19788318 TI - Generalized temperature measurement equations for Rhodamine B dye solution and its application to microfluidics. AB - Temperature mapping based on fluorescent signal intensity ratios is a widely used noncontact approach for investigating temperature distributions in various systems. This noninvasive method is especially useful for applications, such as microfluidics, where accurate temperature measurements are difficult with conventional physical probes. However, the application of a calibration equation to relate fluorescence intensity ratio to temperature is not straightforward when the reference temperature in a given application is different than the one used to derive the calibration equation. In this report, we develop and validate generalized calibration equations that can be applied for any value of reference temperature. Our analysis shows that a simple linear correction for a 40 degrees C reference temperature produces errors in measured temperatures between -3 to 8 degrees C for three previously published sets of cubic calibration equations. On the other hand, corrections based on an exact solution of these equations restrict the errors to those inherent in the calibration equations. The methods described here are demonstrated for cubic calibration equations derived by three different groups, but the general method can be applied to other dyes and calibration equations. PMID- 19788317 TI - Integrated algorithms for high-throughput examination of covalently labeled biomolecules by structural mass spectrometry. AB - Mass spectrometry based structural proteomics approaches for probing protein structures are increasingly gaining in popularity. The potential for such studies is limited because of the lack of analytical techniques for the automated interpretation of resulting data. In this article, a suite of algorithms called ProtMapMS is developed, integrated, and implemented specifically for the comprehensive automatic analysis of mass spectrometry data obtained for protein structure studies using covalent labeling. The functions include data format conversion, mass spectrum interpretation, detection, and verification of all peptide species, confirmation of the modified peptide products, and quantification of the extent of peptide modification. The results thus obtained provide valuable data for use in combination with computational approaches for protein structure modeling. The structures of both monomeric and hexameric forms of insulin were investigated by oxidative protein footprinting followed by high resolution mass spectrometry. The resultant data was analyzed both manually and using ProtMapMS without any manual intervention. The results obtained using the two methods were found to be in close agreement and overall were consistent with predictions from the crystallographic structure. PMID- 19788319 TI - Development of new conjugated polymers with donor-pi-bridge-acceptor side chains for high performance solar cells. AB - Two new conjugated polymers have been designed and synthesized for polymer solar cells. Both of them exhibit excellent photovoltaic properties with a power conversion efficiency as high as 4.74%. Different from the traditional linear donor-acceptor (D-A) type conjugated polymers, these newly designed polymers have a two-dimensional conjugated structure with their tunable acceptors located at the end of D-A side chains and connected with the donors on the main chain through an efficient pi-bridge. This approach provides great flexibility in fine tuning the absorption spectra and energy levels of the resultant polymers for achieving high device performance. PMID- 19788320 TI - Exploring ion permeation energetics in gramicidin A using polarizable charge equilibration force fields. AB - All-atom molecular dynamics simulations have been applied in the recent past to explore the free energetics underlying ion transport processes in biological ion channels. Roux and co-workers, Kuyucak and co-workers, Busath and co-workers, and others have performed rather elegant and extended time scale molecular dynamics simulations using current state-of-the-art fixed-charge (nonpolarizable) force fields to calculate the potential of mean force defining the equilibrium flux of ions through prototypical channels such as gramicidin A. An inescapable conclusion of such studies has been the gross overestimation of the equilibrium free energy barrier, generally predicted to be from 10 to 20 kcal/mol depending on the force field and simulation protocol used in the calculation; this translates to an underestimation of experimentally measurable single channel conductances by several orders of magnitude. Next-generation polarizable force fields have been suggested as possible alternatives for more quantitative predictions of the underlying free energy surface in such systems. (1) Presently, we consider ion permeation energetics in the gramicidin A channel using a novel polarizable force field. Our results predict a peak barrier height of 6 kcal/mol relative to the channel entrance; this is significantly lower than the uncorrected value of 12 kcal/mol for nonpolarizable force fields such as GROMOS and CHARMM27 which do not account for electronic polarization. These results provide promising initial indications substantiating the long-conjectured importance of polarization effects in describing ion-protein interactions in narrow biological channels. PMID- 19788321 TI - Electronic relaxation dynamics in isolated and aggregated hollow gold nanospheres. AB - Electronic relaxation and interparticle electromagnetic coupling processes in hollow gold nanospheres (HGNs) and HGN aggregates are described. These plasmon tunable HGNs exhibit an unexpected, but systematic, blue shift of the surface plasmon resonance spectral position when the particles are aggregated. Femtosecond transient absorption measurements and finite-difference time-domain (FDTD) calculations are used to demonstrate that this blue shift is the result of delocalization of the Fermi-gas over multiple particles, an effect not observed with solid spherical particles. The ultrafast electron-phonon coupling lifetimes for the thin-shelled HGNs increase upon aggregation, indicating significant enhancement in interparticle electromagnetic coupling. For instance, a 48-nm HGN with a shell thickness of 7 nm shows ultrafast electron-phonon coupling with a lifetime of 300 +/- 100 fs, and upon aggregation, this lifetime increases to 730 +/- 140 fs. The experimental data strongly suggest that confinement effects in HGNs allow for enhanced energy transport over nanometer distances and this effect can be applied to developing more efficient devices, including photovoltaics. PMID- 19788323 TI - Polymeric monosaccharide receptors responsive at neutral pH. AB - We present the first detailed report of the synthesis of Wulff-type styrenic monomers and their polymerization by radical addition-fragmentation chain transfer (RAFT) methods. The resulting polymers and block copolymers exhibit sugar-responsive solubilization in aqueous buffer solutions (pH = 7.4-7.8) in the presence of monosaccharides such as D-fructose and D-glucose. PMID- 19788322 TI - Conditional RNA interference mediated by allosteric ribozyme. AB - Conditional RNA interference (RNAi) enables spatial and/or temporal control over gene silencing. The currently available methods require coexpression of engineered proteins and/or modified promoters which may limit their applications. We designed a novel RNA architecture that combines a drug-inducible allosteric ribozyme with a microRNA precursor analogue that allows chemical induction of RNAi in mammalian cells. The compact and highly modular RNA design should facilitate the construction of conditional RNAi systems that can sense and respond to a variety of molecules recognized by RNA aptamers to regulate virtually any desired genes sensitive to RNAi. PMID- 19788324 TI - Chelating N-heterocyclic carbene alkoxide as a supporting ligand for Pd(II/IV) C H bond functionalization catalysis. AB - A Pd(IV) complex that represents a viable catalytic intermediate in Pd-catalyzed C-H bond halogenation reactions has been isolated and structurally characterized. It contains the first examples of both a Pd(IV) NHC bond and a Pd(IV) alkoxide bond and serves as a precatalyst for C-H bond halogenation. As such, this represents a new class of tunable supporting ligand systems in Pd(IV) catalysis. PMID- 19788325 TI - Unexpected long-term instability of ZnO nanowires "protected" by a TiO2 shell. AB - We revealed the aggravated instability of (0001)-oriented ZnO nanowires when they were deposited by a TiO(2) shell even under ambient conditions. Trace UV photons from daylight and moisture from air, which generally have negligible effects on "bare" ZnO nanowires, can obviously enhance their photocorrosion due to the high bandgap of TiO(2) as well as this conformal core-shell heterostructure. PMID- 19788326 TI - Highly enantioselective alkenylation of glyoxylate with vinylsilane catalyzed by chiral dicationic palladium(II) complexes. AB - Chiral dicationic palladium complex-catalyzed vinylation and dienylation of glyoxylate with vinylsilanes and dienylsilanes to produce highly optical active allylic alcohols has been achieved. The advantages of this reaction are that the chiral palladium catalyst is readily employed and that vinylsilanes as nucleophiles are easily synthesized, storable, and air- and moisture-stable. PMID- 19788327 TI - General approach for monolayer formation of covalently attached aryl groups through electrografting of arylhydrazines. AB - An electrochemical approach is presented for carrying out controlled modification of carbon and metal surfaces with aryl groups through mild anodic oxidation of arylhydrazines. Electrochemical, PM-IRRAS, and ellipsometrical measurements reveal that monolayers are formed, the thickness of which is essentially independent of the substituent, pH, and grafting time and potential. This feature makes the approach very tolerant toward variations in the experimental conditions. Hence, this method should be considered as a strong option if the aim is to form thin, well-defined, and covalently assembled aryl layers on surfaces. PMID- 19788328 TI - A short enantioselective total synthesis of the fundamental pentacyclic triterpene lupeol. AB - The first enantioselective synthesis of lupeol has been developed by applying two carefully crafted cation-pi cyclization stages to generate the pentacyclic structure with complete stereocontrol. The synthesis (Scheme 1) is noteworthy because of its brevity and also because it solves a longstanding problem in the field of natural product synthesis. PMID- 19788329 TI - Hetero-epitaxial anion exchange yields single-crystalline hollow nanoparticles. AB - Anion exchange with S was performed on ZnO colloidal nanoparticles. The resulting hollow ZnS nanoparticles are crystal whose shape is dictated by the initial ZnO. Crystallographic and elemental analyses provide insight into the mechanism of the anion exchange. PMID- 19788330 TI - Structure-reactivity effects on primary deuterium isotope effects on protonation of ring-substituted alpha-methoxystyrenes. AB - Primary product isotope effects (PIEs) on L(+) and carboxylic acid catalyzed protonation of ring-substituted alpha-methoxystyrenes (X-1) to form oxocarbenium ions X-2(+) in 50/50 (v/v) HOH/DOD were calculated from the yields of the alpha CH(3) and alpha-CH(2)D labeled ketone products, determined by (1)H NMR. A plot of PIE against reaction driving force shows a maximum PIE of 8.7 for protonation of 4-MeO-1 by Cl(2)CHCOOH (DeltaG(o) = 1.0 kcal/mol). The PIE decreases to 8.1 for protonation of 4-MeO-1 by L(3)O(+) (DeltaG(o) = -2.8 kcal/mol) and to 5.1 for protonation of 3,5-di-NO(2)-1 by MeOCH(2)COOH (DeltaG(o) = 13.1 kcal/mol). The PIE maximum is around DeltaG(o) = 0. Arrhenius-type plots of PIEs on protonation of 4-MeO-1 and 3,5-di-NO(2)-1 by L(3)O(+) and on protonation of X-1 by MeOCH(2)COOH in 50/50 (v/v) HOH/DOD give similar slopes and intercepts. These were used to calculate values of [(E(a))(H) - (E(a))(D)] = -1.2 kcal/mol and (A(H)/A(D)) = 1.0 for the difference in activation energy for reactions of A-H and A-D and for the limiting PIE at infinite temperature, respectively. These parameters are consistent with reaction of the hydron over an energy barrier. There is no evidence for quantum mechanical tunneling of the hydron through the barrier. These PIEs suggest that the transferred hydron at the transition state lies roughly equidistant between the acid donor and base acceptor and contrast with the recently published Bronsted parameters [Richard, J. P.; Williams, K. B. J. Am. Chem. Soc. 2007, 129, 6952-6961], which are consistent with a product-like transition state. An explanation for these seemingly contradictory results is discussed. PMID- 19788331 TI - Facile photochemical synthesis and characterization of highly fluorescent silver nanoparticles. AB - Highly fluorescent silver nanoparticles (AgFNP) have been prepared by a facile photochemical method, yielding these materials in just a few minutes and with excellent long-term stability. The method makes use of photogenerated ketyl radicals that reduce Ag(+) from silver trifluoroacetate in the presence of amines. While as functional materials these AgFNP can be described as of nanometer dimensions, we believe that the luminescence arises from particle supported small metal clusters (predominantly Ag(2)). The materials have been characterized by electron microscopy, fluorescence and absorption spectroscopy, fluorescence lifetime studies, and (19)F NMR spectroscopy. Exploratory work shows that the fluorescence from AgFNP can be efficiently quenched by paramagnetic quenchers, and these studies have been combined with electron paramagnetic resonance work. PMID- 19788332 TI - The influence of protein dynamics on the success of computational enzyme design. AB - We characterize the molecular dynamics of a previously described computational de novo designed enzyme optimized to perform a multistep retrol-aldol reaction when engineered into a TIM barrel protein scaffold. The molecular dynamics simulations show that the protein dynamics under physiological conditions of temperature and aqueous environment distorts the designed geometric factors of the substrate enzyme reaction intermediates, such that catalysis is limited by the primary retrol-aldol step of proton abstraction from the covalently bound substrate and its interactions with a histidine-aspartate dyad. These results emphasize that computational enzyme designs will benefit from considerations of dynamical fluctuations when optimizing active site geometries. PMID- 19788334 TI - Herpes simplex virus-1 helicase-primase: roles of each subunit in DNA binding and phosphodiester bond formation. AB - The helicase-primase complex from herpes simplex virus-1 contains three subunits, UL5, UL52, and UL8. We generated each of the potential two-subunit complexes, UL5 UL52, UL5-UL8, and UL52-UL8, and used a series of kinetic and photo-cross-linking studies to provide further insights into the roles of each subunit in DNA binding and primer synthesis. UL8 increases the rate of primer synthesis by UL5-UL52 by increasing the rate of primer initiation (two NTPs --> pppNpN), the rate-limiting step in primer synthesis. The UL5-UL8 complex lacked any detectable catalytic activity (DNA-dependent ATPase, primase, or RNA polymerase using a RNA primer template and NTPs as substrates) but could still bind DNA, indicating that UL52 must provide some key amino acids needed for helicase function. The UL52-UL8 complex lacked detectable DNA-dependent ATPase activity and could not synthesize primers on single-stranded DNA. However, it exhibited robust RNA polymerase activity using a RNA primer-template and NTPs as substrates. Thus, UL52 must contain the entire primase active site needed for phosphodiester bond formation, while UL5 minimally contributes amino acids needed for the initiation of primer synthesis. Photo-cross-linking experiments using single-stranded templates containing 5-iodouracil either before, in, or after the canonical 3'-GPyPy (Py is T or C) initiation site for primer synthesis showed that only UL5 cross-linked to the DNA. This occurred for the UL5-UL52, UL5-UL52-UL8, and UL5-UL8 complexes and whether the reaction mixtures contained NTPs. Photo-cross-linking of a RNA primer template, the product of primer synthesis, containing 5-iodouracil in the template generated the same apparent cross-linked species. PMID- 19788336 TI - Kinetic analysis of the genome packaging reaction in bacteriophage lambda. AB - Bacteriophage lambda is a double-stranded DNA virus that infects the Escherichia coli bacterium. lambda genomic DNA is replicated via rolling circle replication, resulting in multiple genomes linked head to tail at the cos site. To insert a single lambda genome into the viral capsid, the lambda terminase enzyme introduces symmetric nicks, 12 bp apart, at the cos site, and then promotes a strand separation reaction, releasing the tail end of the previous genome and leaving a binary complex consisting of lambda terminase bound to the head end of the adjacent genome. Next, the genome is translocated into the interior of the capsid particle, in a process that requires ATP hydrolysis by lambda terminase. Even though DNA packaging has been studied extensively, currently no bulk assays are available that have been optimized to report directly on DNA translocation. Rather, these assays are sensitive to assembly steps reflecting formation of the active, DNA packaging machine. In this work, we have modified the DNase protection assay commonly used to study DNA packaging in several bacteriophage systems, such that it reports directly on the kinetics of the DNA packaging reaction. We have analyzed our DNA packaging data according to an N-step sequential minimal kinetic model and have estimated an overall packaging rate of 119 +/- 8 bp/s, at 4 degrees C and 1 mM ATP. Furthermore, we have measured an apparent step size for the this reaction (m(obs)) of 410 +/- 150 bp. The magnitude of this value indicates that our assay is most likely sensitive to both mechanical steps associated with DNA insertion as well as occasional slow steps that are repeated every >410 bp. These slow steps may be reflective of the pausing events observed in recent single-molecule studies of DNA packaging in bacteriophage lambda [Fuller, D. N., et al. (2007) J. Mol. Biol. 373, 1113-1122]. Finally, we show that either ATP or ADP is required for terminase cutting at cos, to generate the active, DNA packaging complex. PMID- 19788335 TI - Single-molecule dynamics of the DNA-EcoRII protein complexes revealed with high speed atomic force microscopy. AB - The study of interactions of protein with DNA is important for gaining a fundamental understanding of how numerous biological processes occur, including recombination, transcription, repair, etc. In this study, we use the EcoRII restriction enzyme, which employs a three-site binding mechanism to catalyze cleavage of a single recognition site. Using high-speed atomic force microscopy (HS-AFM) to image single-molecule interactions in real time, we were able to observe binding, translocation, and dissociation mechanisms of the EcoRII protein. The results show that the protein can translocate along DNA to search for the specific binding site. Also, once specifically bound at a single site, the protein is capable of translocating along the DNA to locate the second specific binding site. Furthermore, two alternative modes of dissociation of the EcoRII protein from the loop structure were observed, which result in the protein stably bound as monomers to two sites or bound to a single site as a dimer. From these observations, we propose a model in which this pathway is involved in the formation and dynamics of a catalytically active three-site complex. PMID- 19788337 TI - Introduction of Miodrag (Mike)Belosevic, recipient of the 2009 Clark P. Read Mentor Award. PMID- 19788339 TI - The American Society of Parasitologists: Ninety-Ninth Annual Council Meeting 14 August 2009 Crowne Plaza Knoxville, Knoxville, Tennessee. PMID- 19788340 TI - Emission of biocides from hospitals: comparing current survey results with European Union default values. AB - Under the European Union (EU) Biocidal Products Directive 98/8/EC, comprehensive evaluations on substances of the Third Priority List were conducted until 31 July 2007. This list includes, among other categories, disinfectants for human hygiene (e.g., skin and surface disinfection). For environmental exposure assessment of biocides, the EU emission scenarios apply. Currently available default values for disinfectants are based on consumption data from not more than 8 hospitals and were originally assembled for other purposes. To revalidate these default values, a survey on annual consumption data was performed in 27 German hospitals. These data were analyzed to provide consumption data per bed and day and per nurse and day for particular categories of active ingredients and were compared with default values from the EU emission scenario documents. Although several deviations were detected, an overall acceptable correspondence between Emission Scenario Documents default values and the current survey data was found. PMID- 19788341 TI - Individual- and population-level effects of the synthetic musk, HHCB, on the deposit-feeding polychaete, Capitella sp. I. AB - A life table response experiment lasting 120 d was used to investigate the effects of the synthetic polycyclic musk HHCB (1,3,4,6,7,8-hexahydro-4,6,6,7,8 hexamethylcyclopenta-gamma-2-benzopyrane; 0, 1.5, 26, 123, and 168 mg/kg dry wt sediment) on the life history of the infaunal polychaete Capitella species I. The HHCB exposure showed no detectable effects on adult survival, age at first reproduction, length of the reproductive period, number of broods, individual worm body volumes, or body size-specific egestion rates. In contrast, HHCB significantly affected juvenile survival (>or=123 mg/kg), maturation time (168 mg/kg), total number of eggs produced (>or=26 mg/kg), and brood size (>or=123 mg/kg) and marginally increased time between breeding attempts (>or=26 mg/kg). A declining trend was observed for population growth rate with increasing HHCB concentrations, but differences between the control and exposed groups were not significant. Thus, despite detectable effects of HHCB on individual life-history traits, the results suggest that environmentally realistic concentrations of HHCB are not likely to reduce the growth rate of Capitella sp. I populations. PMID- 19788343 TI - Perinatal status and help-seeking for intimate partner violence. AB - BACKGROUND: Although there has been much research examining the relationship between pregnancy and abuse, this study is one of the few to investigate whether perinatal status (defined as pregnancy or early postpartum) impacts the help seeking of abused women. METHODS: We retrospectively reviewed 3 years of prosecutor administrative records, police incident reports, and hospital medical records for a countywide population of adult females (n = 964) assaulted by an intimate partner in 2000. Perinatal and nonperinatal victims were compared using chi-square and a series of logistic regression models, controlling for all demographic and incident-related factors. RESULTS: Compared with women across the county, abused women were twice as likely to become pregnant (p < 0.001). Perinatal status did not change the rate of help seeking from police (OR 1.1, p = 0.67) or emergency departments (ED) (OR 1.1, p = 0.94), but it did change the pattern of help seeking with higher ED use in the 6 months prior to the assault (p < 0.01) and a trend toward seeking help with fewer injuries (p = 0.10). CONCLUSIONS: Abused women are more likely to become pregnant. Perinatal status impacts how victims seek help from criminal justice agencies and EDs. PMID- 19788345 TI - Development of a new assay system for evaluating the permeability of various substances through three-dimensional tissue. AB - A novel assay system with cell-dense three-dimensional (3D) tissue was developed for measuring the permeability of substances. In this paper, the permeabilities of various molecules containing nutrients, a cytokine, and a chemokine were examined and analyzed. A single-layered cell sheet was approximately 20 mum thick, and as the number of layers of these cell sheets increased, so did the total thickness of the tissue. The diffusion rates of glucose and pyruvic acid were reduced to approximately 30-40% by a single-layered cell sheet compared with the control without the cell sheet, and the diffusion of both substances were completely inhibited by a quadruple-layered cell sheet. The diffusion rate of creatinin was reduced to approximately 50% and 15-20% by a single-layered and by a quintuplet-layered cell sheet, respectively. On the other hand, the diffusion rate of stromal cell-derived factor 1alpha, vascular endothelial growth factor, beta2-microglobulin, and transferrin was reduced to approximately 10%, 5%, 20%, and 10%, by only a single-layered cell sheet, respectively. The diffusion of these substances were completely inhibited by a double-layered cell sheet. These results show that the permeability of substances through 3D tissue significantly decreased with the increase of the molecular weight. Therefore, the system could give a simulated living-tissue condition for measuring the permeability of substances. To our knowledge, this is the first report about measuring the permeability of substances through cell-dense 3D tissues without scaffolds. The assay system is believed to contribute to the progress of physiology, metabology, biochemistry, and pharmacokinetics. Further, the system may give some hints for developing a new dialysis membrane technology for an artificial kidney. PMID- 19788344 TI - Retention and attendance of women enrolled in a large prospective study of HIV-1 in the United States. AB - OBJECTIVE: The objective was to assess study retention and attendance for two recruitment waves of participants in the Women's Interagency HIV Study (WIHS). METHODS: The WIHS, a prospective study at six clinical centers in the United States, has experienced two phases of participant recruitment. In phase one, women were screened and enrolled at the same time, and in phase two, women were screened and enrolled at separate visits. Compliance with study follow-up was evaluated by examining semiannual study retention and visit attendance. RESULTS: After 10 study visits, the retention rate in the original recruits (enrolled in 1994-1995) was 83% for the HIV-infected women and 69% for the HIV-uninfected women compared with 86% and 86%, respectively, in the new recruits (enrolled in 2001-2002). In logistic regression analysis of the HIV-infected women, factors associated with early (visits 2 and 3) nonattendance were temporary housing, moderate alcohol consumption, use of crack/cocaine/heroin, having a primary care provider, WIHS site of enrollment, lower CD4 cell count, and higher viral load. Among HIV-uninfected women, the factors associated with early nonattendance were recruitment into the original cohort, household income >or=$12,000 per year, temporary housing, unemployment, use of crack/cocaine/heroin, and WIHS site of enrollment. Factors associated with nonattendance at later visits (7-10) among HIV-infected participants were younger age, white race, not having a primary care provider, not having health insurance, WIHS site of enrollment, higher viral load, and nonattendance at a previous visit. In HIV-uninfected participants, younger age, white race, WIHS site of enrollment, and nonattendance at a previous visit were significantly associated with nonattendance at later visits. CONCLUSIONS: Preventing early loss to follow-up resulted in better study retention early, but late loss to follow-up may require different retention strategies. PMID- 19788346 TI - An optical method for evaluation of geometric fidelity for anatomically shaped tissue-engineered constructs. AB - Quantification of shape fidelity of complex geometries for tissue-engineered constructs has not been thoroughly investigated. The objective of this study was to quantitatively describe geometric fidelities of various approaches to the fabrication of anatomically shaped meniscal constructs. Ovine menisci (n = 4) were imaged using magnetic resonance imaging (MRI) and microcomputed tomography (microCT). Acrylonitrile butadiene styrene plastic molds were designed from each imaging modality and three-dimensional printed on a Stratasys FDM 3000. Silastic impression molds were fabricated directly from ovine menisci. These molds were used to generate shaped constructs using 2% alginate with 2% CaSO(4). Solid freeform fabrication was conducted on a custom open-architecture three dimensional printing platform. Printed samples were made using 2% alginate with 0.75% CaSO(4). Hydrogel constructs were scanned via laser triangulation distance sensor. The point cloud images were analyzed to acquire computational measurements for key points of interest (e.g., height, width, and volume). Silastic molds were within + or - 10% error with respect to the native tissue for seven key measurements, microCT molds for six of seven, microCT prints for four of seven, MRI molds for five of seven, and MRI prints for four of seven. This work shows the ability to generate and quantify anatomically shaped meniscal constructs of high geometric fidelity and lends insight into the relative geometric fidelities of several tissue engineering techniques. PMID- 19788347 TI - The synergistic effect of treadmill running on stem-cell transplantation to heal injured skeletal muscle. AB - Muscle-derived stem-cell (MDSC) transplantation presents a promising method for the treatment of muscle injuries. This study investigated the ability of exercise to enhance MDSC transplantation into the injured muscle. Mice were divided into four groups: contusion + phosphate-buffered saline (C + PBS; n = 14 muscles), C + MDSC transplantation (n = 12 muscles), C + PBS + treadmill running (C + PBS + TM; n = 17 muscles), and C + MDSC + TM (n = 13 muscles). One day after injury, the TM groups began running for 1 or 5 weeks. Two days after injury, muscles of C + MDSC and C + MDSC + TM groups were injected with MDSCs. One or 5 weeks later, the number and differentiation of transplanted MDSCs, myofiber regeneration, collagen I formation, and vascularity were assessed histologically. In vitro, MDSCs were subjected to mechanical stimulation, and growth kinetics were quantified. In vitro, mechanical stimulation decreased the MDSC population doubling time (18.6 +/- 1.6 h) and cell division time (10.9 +/- 0.7 h), compared with the controls (population doubling time: 23.0 +/- 3.4 h; cell division time: 13.3 +/- 1.1 h) (p = 0.01 and 0.03, respectively). In vivo, 5 weeks of TM increased the myogenic contribution of transplanted MDSCs, compared with the controls (p = 0.02). C + MDSC, C + PBS + TM, and C + MDSC + TM demonstrated decreased fibrosis at 5 weeks, compared with the C + PBS controls (p = 0.00, p = 0.03, and p = 0.02, respectively). Results suggest that the mechanical stimulation favors MDSC proliferation, both in vitro and in vivo, and that exercise enhances MDSC transplantation after injury. PMID- 19788348 TI - Warfarin and UDP-glucuronosyltransferases: writing a new chapter of metabolism. AB - The widely prescribed anticoagulant, Coumadin (racemic R/S-warfarin), Bristol Myers Squibb Company, Clinton, NY has a narrow therapeutic range and wide interindividual response due, in part, to drug metabolism. Early identification of hydroxywarfarins (OHWARs), especially S-7-OHWAR, as major metabolites fostered studies characterizing cytochrome P450s responsible for those reactions. Nevertheless, phase II metabolism by sulfotransferases and, especially uridine diphosphate (UDP)-glucuronosyltransferases (UGTs), marks the next chapter in warfarin inactivation and clearance. Rodents converted OHWARs to glucuronides (O GLUC), including high levels of 4'-, 7-, and 8-O-GLUC. Similarly, humans generated significant levels of glucuronides following treatment with warfarin. 7 O-GLUC was a major metabolite, while 6- and 8-O-GLUC were minor ones. Surprisingly, warfarin glucuronidation accounted for up to 13% of metabolites. This capacity in humans derives from several UGTs, as shown by studies with recombinant enzymes and racemic warfarin and OHWARs. 7-OHWAR was a high-affinity substrate for UGT1A1, compared to other UGTs. UGT1A1 and UGT1A10 also glucuronidated 6-OHWAR. Of five UGT1A enzymes, UGT1A10 was approximately 7-fold more efficient than the rest. Broad substrate specificity for UGT1A10 derives, in part, from an active site-binding motif, specifically F90-M91-V92-F93. Unlike glucuronidation, less is known about sulfonation of warfarin and its metabolites, except that low capacities are shown by rats and, possibly, humans. Collectively, phase I and II metabolic steps create pathways for inactivating and eliminating warfarin that require elucidation. These findings will ultimately enrich our understanding of warfarin metabolism and facilitate the interpreting of metabolic profiles of patients. This knowledge will possibly avoid complications during warfarin therapy related to metabolism by personalizing therapy for the patient. PMID- 19788349 TI - Static electromagnetic fields induce vasculogenesis and chondro-osteogenesis of mouse embryonic stem cells by reactive oxygen species-mediated up-regulation of vascular endothelial growth factor. AB - Electromagnetic fields (EMFs) are used to treat bone diseases. Herein, the effects of static EMFs on chondroosteogenesis and vasculogenesis of embryonic stem (ES) cells and bone mineralization of mouse fetuses were investigated. Treatment of differentiating ES cells with static EMFs (0.4-2 mT) stimulated vasculogenesis and chondro-osteogenesis and increased reactive oxygen species (ROS), which was abolished by the free radical scavengers trolox, 1,10 phenanthroline (phen), and the NAD(P)H oxidase inhibitor diphenylen iodonium (DPI). In contrast, EMFs of 10 mT field strength exerted inhibitory effects on vasculogenesis and chondro-osteogenesis despite robust ROS generation. EMFs of 1 mT and 10 mT increased and decreased vascular endothelial growth factor (VEGF) expression, respectively, which was abolished by DPI and radical scavengers. EMFs activated extracellular-regulated kinase 1/2 (ERK1/2), p38, and c-jun N-terminal kinase (JNK), which was sensitive to DPI treatment. The increase in VEGF by EMFs was inhibited by the ERK1/2 inhibitor U0126 but not by SB203580 and SP600125, which are p38 and JNK inhibitors, respectively, suggesting VEGF regulation by ERK1/2. Chondroosteogenesis and vasculogenesis of ES cells was blunted by trolox, DPI, and the VEGF receptor-2 (flk-1) antagonist SU5614. In mouse fetuses 1 mT EMFs increased and 10 mT EMFs decreased bone mineralization, which was abolished in the presence of trolox. Hence, EMFs induced chondro-osteogenesis and vasculogenesis in ES cells and bone mineralization of mouse fetuses by a ROS dependent up-regulation of VEGF expression. PMID- 19788350 TI - Gastroduodenal toxicity of low-dose acetylsalicylic acid: a comparison with non steroidal anti-inflammatory drugs. AB - BACKGROUND: Low-dose acetylsalicylic acid (ASA; aspirin; 75-325 mg/day) is effective for the prevention of cardiovascular events, and its use in this indication is rapidly increasing. However, the use of ASA and, indeed, other non steroidal anti-inflammatory drugs (NSAIDs) is limited by the incidence of adverse gastroduodenal events. OBJECTIVES AND SCOPE: To review the clinical evidence for, and the pharmacodynamic basis of, ASA-induced gastroduodenal toxicity in comparison with NSAIDs, and address the question of whether low-dose ASA is 'safe' from a gastroduodenal perspective. This was a narrative, descriptive review, rather than a formal systematic review. FINDINGS: Adverse gastroduodenal effects, which are well known to occur with NSAIDs, are also prevalent in patients receiving low-dose ASA for cardiovascular protection even at doses as low as 75 mg/day. The risk of gastroduodenal toxicity is particularly high among 'at-risk' low-dose ASA patients (aged >70 years, previous ulcer or upper gastrointestinal bleeding and users of antiplatelets or NSAIDs). There are important differences in the mechanism of ASA-induced gastroduodenal toxicity, relative to NSAIDs. These differences include the effects on the cyclooxygenase (COX)-1 isoenzyme, local effects on the gastroduodenal mucosa specific to ASA and a reduction in platelet aggregation. CONCLUSION: Data suggest that ASA causes significant gastroduodenal damage even at the low doses used for cardiovascular protection. These effects (both systemic and possibly local) may be pharmacodynamically distinct from the gastroduodenal toxicity seen with NSAIDs. Studies are required to establish strategies for improving the tolerability of low-dose ASA, allowing patients to continue to benefit from the cardiovascular protection associated with such therapy. PMID- 19788351 TI - Management of neuropathic pain after surgical and non-surgical trauma with lidocaine 5% patches: study of 40 consecutive cases. AB - OBJECTIVE: To determine the efficacy of lidocaine 5% patches [Versatis, commercialised by Grunenthal GmbH, Aachen, Germany] in patients with PNCCP. BACKGROUND: This study focuses on chronic pain states of a neuropathic nature, located at the scar or over a larger area of the skin around the scar. This post operative/post-traumatic neuropathic chronic cutaneous pain (PNCCP) may be a side effect of any incision of the skin in the context of a surgical procedure or a traumatic event. RESEARCH DESIGN AND METHODS: A single-centre, open, non randomised, prospective study was performed in a university hospital referral centre for patients with chronic neuropathic pain after surgical or non-surgical trauma. Forty consecutive patients with chronic PNCCP, a VAS score > or =5, a LANSS score > or =12, and a stable consumption of pain medication were prospectively evaluated. All patients were given lidocaine 5% patches, following a 12 h on/off schedule. MAIN OUTCOME MEASURES: Visual analogue scale (VAS) and the Leeds Assessment of Neuropathic Symptoms and Signs (LANSS) scorings were performed pretreatment (day 0), on the 28th day (4 weeks), and after 84 days (12 weeks). RESULTS: The mean pretreatment VAS score (VAS(0)) was 7.225 +/- 1.209, and the mean pretreatment LANSS score (LANSS(0)) was 18.60 +/- 2.610. The number of patients with a VAS score <5 at the latest follow-up (VAS(84)) was 21 (52.5%). Mean VAS(84) was 4.625 +/- 1.675. Seventeen patients (42.5%) had a LANSS score <12 at the latest follow-up. Overall mean LANSS(84) was 12.85 +/- 3.093. CONCLUSION: Lidocaine 5% patches seem to be an effective treatment of post surgical and post-traumatic pain. These results should be supported with randomised and placebo-controlled studies with larger sample sizes and longer follow-ups. PMID- 19788352 TI - Lindane-induced cytotoxicity and the role of vitamin E in Chinese Hamster Ovary (CHO-K1) cells. AB - Lindane, a toxic insecticide from the persistent organic pollutants (POP's) group, may act as an endocrine disrupter affecting crucial tissues of reproductive system. In this study a Chinese Hamster Ovary cell line (CHO-K1) was applied to assess the potential of lindane cytotoxicity at the cellular level. The methods of Trypan blue exclusion, MTT and Kenacid blue assays were used to assess cytotoxicity and confirmed a decrease in the number of viable CHO-K1 cells at 34.4-344 microM lindane during 24, 48 and 72 hours of exposure. The cell proliferation tests showed significant inhibition (p < 0.025-0.001 vs control) and a progressive increase in toxicity with increasing lindane concentrations. Corresponding IC(50) values were determined with each applied method. After 72 h of lindane exposure, IC(50) values were 184 microM according to the Trypan blue method and 272 and 256 microM with the Kenacid blue and MTT assays, respectively. Morphological changes induced by the cytotoxicity of lindane were followed by the fluorescence microscopy and only necrotic cells were detected. Vitamin E (25 and 50 microg/mL) was used for protection of ovarian cells against lidane-induced oxidative stress damage, and lipid peroxidation was postulated as a possible mechanism of lindane toxicity. The viability of cells pre-incubated with vitamin E was significantly enhanced (up to p < 0.025) compared to the results observed in cells exposed to lindane only, but vitamin E treatment could not prevent complete lindane-induced cytotoxicity. Results suggest that vitamin E may exert a slightly protective role in cell defense against lipophilic pro-oxidant xenobiotics such as lindane. PMID- 19788353 TI - Species' range: adaptation in space and time. AB - Populations living in a spatially and temporally changing environment can adapt to the changing optimum and/or migrate toward favorable habitats. Here we extend previous analyses with a static optimum to allow the environment to vary in time as well as in space. The model follows both population dynamics and the trait mean under stabilizing selection, and the outcomes can be understood by comparing the loads due to genetic variance, dispersal, and temporal change. With fixed genetic variance, we obtain two regimes: (1) adaptation that is uniform along the environmental gradient and that responds to the moving optimum as expected for panmictic populations and when the spatial gradient is sufficiently steep, and (2) a population with limited range that adapts more slowly than the environmental optimum changes in both time and space; the population therefore becomes locally extinct and migrates toward suitable habitat. We also use a population-genetic model with many loci to allow genetic variance to evolve, and we show that the only solution now has uniform adaptation. PMID- 19788354 TI - Macrophysiology: a conceptual reunification. AB - Widespread recognition of the importance of biological studies at large spatial and temporal scales, particularly in the face of many of the most pressing issues facing humanity, has fueled the argument that there is a need to reinvigorate such studies in physiological ecology through the establishment of a macrophysiology. Following a period when the fields of ecology and physiological ecology had been regarded as largely synonymous, studies of this kind were relatively commonplace in the first half of the twentieth century. However, such large-scale work subsequently became rather scarce as physiological studies concentrated on the biochemical and molecular mechanisms underlying the capacities and tolerances of species. In some sense, macrophysiology is thus an attempt at a conceptual reunification. In this article, we provide a conceptual framework for the continued development of macrophysiology. We subdivide this framework into three major components: the establishment of macrophysiological patterns, determining the form of those patterns (the very general ways in which they are shaped), and understanding the mechanisms that give rise to them. We suggest ways in which each of these components could be developed usefully. PMID- 19788356 TI - Signatures of high-altitude adaptation in the major hemoglobin of five species of andean dabbling ducks. AB - Hypoxia is one of the most important factors affecting survival at high altitude, and the major hemoglobin protein is a likely target of selection. We compared population genetic structure in the alphaA and betaA hemoglobin subunits (HBA2 and HBB) of five paired lowland and highland populations of Andean dabbling ducks to unlinked reference loci. In the hemoglobin genes, parallel amino acid replacements were overrepresented in highland lineages, and one to five derived substitutions occurred at external solvent-accessible positions on the alpha and beta subunits, at alpha(1)beta(1) intersubunit contacts, or in close proximity to inositolpentaphosphate (IPP) binding sites. Coalescent analyses incorporating the stochasticity of drift and mutation indicated that hemoglobin alleles were less likely to be transferred between highland and lowland populations than unlinked alleles at five other loci. Amino acid replacements that were overrepresented in the highlands were rarely found within lowland populations, suggesting that alleles segregating at high frequency in the highlands may be maladaptive in the lowlands and vice versa. Most highland populations are probably nonmigratory and locally adapted to the Altiplano, but gene flow for several species may be sufficiently high to retard divergence at unlinked loci. Heterozygosity was elevated in the alphaA or betaA subunits of highland populations exhibiting high gene flow between the southern lowlands and the highlands and in highland species that disperse seasonally downslope to midelevation environments from the central Andean plateau. However, elevated heterozygosity occurred more frequently in the alphaA subunit but not simultaneously in both subunits, suggesting that selection may be more constrained by epistasis in the betaA subunit. Concordant patterns among multiple species with different evolutionary histories and depths of historical divergence and gene flow suggest that the major hemoglobin genes of these five dabbling duck species have evolved adaptively in response to high altitude hypoxia in the Andes. PMID- 19788357 TI - Salicylates and pandemic influenza mortality, 1918-1919 pharmacology, pathology, and historic evidence. AB - The high case-fatality rate--especially among young adults--during the 1918-1919 influenza pandemic is incompletely understood. Although late deaths showed bacterial pneumonia, early deaths exhibited extremely "wet," sometimes hemorrhagic lungs. The hypothesis presented herein is that aspirin contributed to the incidence and severity of viral pathology, bacterial infection, and death, because physicians of the day were unaware that the regimens (8.0-31.2 g per day) produce levels associated with hyperventilation and pulmonary edema in 33% and 3% of recipients, respectively. Recently, pulmonary edema was found at autopsy in 46% of 26 salicylate-intoxicated adults. Experimentally, salicylates increase lung fluid and protein levels and impair mucociliary clearance. In 1918, the US Surgeon General, the US Navy, and the Journal of the American Medical Association recommended use of aspirin just before the October death spike. If these recommendations were followed, and if pulmonary edema occurred in 3% of persons, a significant proportion of the deaths may be attributable to aspirin. PMID- 19788358 TI - Incidence and severity of respiratory syncytial virus pneumonia in rural Kenyan children identified through hospital surveillance. AB - BACKGROUND: Although necessary for developing a rationale for vaccination, the burden of severe respiratory syncytial virus (RSV) disease in children in resource-poor settings remains poorly defined. METHODS: We conducted prospective surveillance of severe and very severe pneumonia in children aged <5 years admitted from 2002 through 2007 to Kilifi district hospital in coastal Kenya. Nasal specimens were screened for RSV antigen by immunofluorescence. Incidence rates were estimated for the well-defined population. RESULTS: Of 25,149 hospital admissions, 7359 patients (29%) had severe or very severe pneumonia, of whom 6026 (82%) were enrolled. RSV prevalence was 15% (20% among infants) and 27% during epidemics (32% among infants). The proportion of case patients aged 3 months was 65%, and the proportion aged 6 months was 43%. Average annual hospitalization rates were 293 hospitalizations per 100,000 children aged <5 years (95% confidence interval, 271-371 hospitalizations per 100,000 children aged <5 years) and 1107 hospitalizations per 100,000 infants (95% confidence interval, 1012-1211 hospitalizations per 100,000 infants). Hospital admission rates were double in the region close to the hospital. Few patients with RSV infection had life threatening clinical features or concurrent serious illnesses, and the associated mortality was 2.2%. CONCLUSIONS: In this low-income setting, rates of hospital admission with RSV-associated pneumonia are substantial; they are comparable to estimates from the United States but considerably underestimate the burden in the full community. An effective vaccine for children aged >2 months (outside the age group of poor responders) could prevent a large portion of RSV disease. Severity data suggest that the justification for RSV vaccination will be based on the prevention of morbidity, not mortality. PMID- 19788359 TI - Intravenous immunoglobulin in children with streptococcal toxic shock syndrome. AB - BACKGROUND: Streptococcal toxic shock syndrome (TSS) is a rare and severe manifestation of group A streptococcal infection. The role of intravenous immunoglobulin (IVIG) for streptococcal TSS in children is controversial. This study aims to describe the epidemiology of streptococcal TSS in children and to determine whether adjunctive therapy with IVIG is associated with improved outcomes. METHODS: A multicenter, retrospective cohort study of children with streptococcal TSS from 1 January 2003 through 31 December 2007 was conducted. Propensity scores were used to determine each child's likelihood of receiving IVIG. Differences in the primary outcomes of death, hospital length of stay, and total hospital costs were compared after matching IVIG recipients and nonrecipients on propensity score. RESULTS: The median patient age was 8.2 years. IVIG was administered to 84 (44%) of 192 patients. The overall mortality rate was 4.2% (95% confidence interval, 1.8%-8.0%). Differences in mortality between IVIG recipients (n = 3; 4.5%) and nonrecipients (n = 3; 4.5%) were not statistically significant (p > .99). Although patients receiving IVIG had higher total hospital and drug costs than nonrecipients, differences in hospital costs were not significant once drug costs were removed (median difference between matched patients, $6139; interquartile range, -$8316 to $25,993; P = .06). No differences were found in length of hospital stay between matched IVIG recipients and nonrecipients. CONCLUSION: This multicenter study is, to our knowledge, the largest to describe the epidemiology and outcomes of children with streptococcal TSS and the first to explore the association between IVIG use and clinical outcomes. IVIG use was associated with increased costs of caring for children with streptococcal TSS but was not associated with improved outcomes. PMID- 19788361 TI - Assessing the impact of intravenous immunoglobulin in the management of streptococcal toxic shock syndrome: a noble but difficult quest. PMID- 19788360 TI - Defining immune reconstitution inflammatory syndrome: evaluation of expert opinion versus 2 case definitions in a South African cohort. AB - BACKGROUND: There is no validated case definition for human immunodeficiency virus-associated immune reconstitution inflammatory syndrome (IRIS). We measured the level of agreement of 2 published case definitions (hereafter referred to as CD1 and CD2) with expert opinion in a prospective cohort of patients who were starting antiretroviral therapy in South Africa. METHODS: A total of 498 adult patients were monitored for the first 6 months of antiretroviral therapy. All new or worsening clinical events were reviewed by 2 investigators and classified on the basis of expert opinion, CD1, and CD2. Events were categorized according to whether they were paradoxical or unmasking in presentation. We measured positive, negative, and chance-corrected agreement (kappa) with expert opinion for CD1 and CD2, and reviewed areas of disagreement. RESULTS: A total of 620 clinical events were recorded, of which, on the basis of expert opinion, 144 (23.2%) were defined as probable IRIS and 112 (18.1%) were defined as possible IRIS. Of the 144 probable IRIS events, 93 (64.6%) were unmasking in presentation, 99 (68.8%) were associated with dermatological or orogenital disease, and 45 (31.3%) were associated with tuberculosis or major opportunistic infections. Of the 620 clinical events recorded, 41 (6.6%) were classified as IRIS on the basis of CD1, and 156 (25.2%) were classified as IRIS on the basis of CD2. Positive agreement between CD1 and expert opinion was low for both unmasking (17.2%; kappa = 0.24) and paradoxical events (37.3%; kappa = 0.43), mainly because 1 major criterion requires IRIS to be atypical and either an opportunistic infection or a tumor, although negative agreement was >98%. In contrast, CD2 had good positive agreement (>75% for most event types), with a kappa value of 0.75 for paradoxical and 0.62 for unmasking. CONCLUSIONS: CD2 agreed well with expert opinion, with additional clinical events, such as arthropathy and inflammatory dermatoses, being classified as IRIS and added to CD2. We propose revised case definitions for both paradoxical and unmasking IRIS. PMID- 19788362 TI - Magnetic resonance imaging of chondrocytes labeled with superparamagnetic iron oxide nanoparticles in tissue-engineered cartilage. AB - The distribution of cells within tissue-engineered constructs is difficult to study through nondestructive means, such as would be required after implantation. However, cell labeling with iron-containing particles may prove to be a useful approach to this problem, because regions containing such labeled cells have been shown to be readily detectable using magnetic resonance imaging (MRI). In this study, we used the Food and Drug Administration-approved superparamagnetic iron oxide (SPIO) contrast agent Feridex in combination with transfection agents to label chondrocytes and visualize them with MRI in two different tissue-engineered cartilage constructs. Correspondence between labeled cell spatial location as determined using MRI and histology was established. The SPIO-labeling process was found not to affect the phenotype or viability of the chondrocytes or the production of major cartilage matrix constituents. We believe that this method of visualizing and tracking chondrocytes may be useful in the further development of tissue engineered cartilage therapeutics. PMID- 19788363 TI - Ethnic disparities in cervical cancer survival among Texas women. AB - OBJECTIVE: The aim of this work was to determine whether minority women are more likely to die of cervical cancer. A population-based cohort study was performed using Texas Cancer Registry (TCR) data from 1998 to 2002. METHODS: A total of 5,166 women with cervical cancer were identified during 1998-2002 through the TCR. Measures of socioeconomic status (SES) and urbanization were created using census block group-level data. Multilevel logistic regression was used to calculate the odds of dying from cervical cancer by race, and Cox proportional hazards modeling was used for cervical cancer-specific survival analysis. RESULTS: After adjusting for age, SES, urbanization, stage, cell type, and treatment, Hispanic women were significantly less likely than non-Hispanic White women to die from cervical cancer (adjusted hazard ratio [aHR] = 0.69; 95% CI [confidence interval] = 0.59-0.80), whereas Black women were more likely to die (aHR = 1.26; 95% CI = 1.06-1.50). Black and Hispanic women were more likely to be diagnosed at a later stage than White women. Black women were significantly less likely to receive surgery among those diagnosed with localized disease (p = 0.001) relative to both White and Hispanic women. CONCLUSIONS: Relative to non Hispanic White women, Black women were more likely to die of cervical cancer while Hispanic women were less likely to die; these survival differences were not explained by SES, urbanization, age, cell type, stage at diagnosis, or treatment. PMID- 19788364 TI - Vaginal estrogen therapy for the treatment of atrophic vaginitis. AB - The prevalence of atrophic vaginitis (AV) is particularly high among postmenopausal women who experience decreased ovarian estrogen production. This common menopausal condition, which is often underreported and underdiagnosed, is caused by estrogen-related changes to the vaginal epithelium and can adversely affect quality of life. An accurate diagnosis of AV and its severity is important in choosing the appropriate treatment. Numerous formulations for estrogen therapy are available, and the safety and efficacy of these preparations for the treatment of AV have been evaluated in randomized controlled clinical trials. Although systemic administration of estrogen is effective in treating acute vasomotor symptoms typically associated with perimenopause and early menopause, standard doses may not be sufficient for the treatment of AV-related symptoms that generally arise after long-term estrogen deficiency. Thus, vaginal estrogen preparations (e.g., creams, tablets, rings) are more often recommended for women with moderate to severe AV. With any estrogen therapy, consideration of the potential adverse effects vs. associated benefits is necessary. Appropriate clinical intervention with vaginal estrogen formulations may safely offer postmenopausal women relief from undesirable symptoms and emotional distress associated with AV. PMID- 19788365 TI - Correlates of absolute and excessive weight gain during pregnancy. AB - OBJECTIVE: Factors associated with weight gain during pregnancy that may be linked to maternal overweight and obesity were examined. METHODS: In this observational study, 144 women reported on demographics, (prepregnancy) body weight, and lifestyles in self-reported questionnaires at 30 weeks gestation. Body weight at the end of pregnancy (self-reported at 6 weeks postpartum) was used to determine total gestational weight gain. Multivariate prediction models were developed to identify factors associated with total gestational weight gain and excessive gestational weight gain (i.e., higher weight gain than recommended by the Institute of Medicine). RESULTS: Women gained 14.4 (+/-5.0) kg during pregnancy. Obese women gained almost 4 kg less than normal weight women. Pregnant women judging themselves to be less physically active or women who reported increased food intakes during pregnancy gained significantly more weight. Over one third of women (38%) gained more weight than recommended. Being overweight, judging yourself to be less physically active than others, and a perceived elevated food intake during pregnancy were significantly associated with excessive weight gain (odds ratio [OR] = 6.33, 95% confidence interval [CI]: 2.01 19.32; OR = 3.96, 95% CI: 1.55l, 10.15; and OR = 3.14, 95% CI: 1.18, 8.36, respectively). A higher age at menarche and hours of sleep reduced the odds for excessive weight gain (OR = 0.75, 95% CI: 0.57, 0.99; and OR = 0.35, 95% CI: 0.57, 0.93, respectively). CONCLUSIONS: Mean hours of sleep, perceived physical activity, and measures of food intake at 30 weeks gestation were identified as modifiable behavioral correlates for excessive gestational weight gain. Strategies to optimize gestational weight gain need to be explored, with a focus on the identified factors. PMID- 19788367 TI - Addressing cancer survivorship through public health: an update from the Centers for Disease Control and Prevention. AB - Currently, there are nearly 12 million cancer survivors living in the United States. They face a myriad of personal and health issues related to their cancer treatment. Increased recognition of cancer survivorship as a distinct and important phase that follows the diagnosis and treatment of cancer has contributed to the development of public health-related strategies and plans to address those strategies. CDC's Division of Cancer Prevention and Control (DCPC) uses an interdisciplinary public health approach to address the needs of cancer survivors through applied research, public health surveillance and data collection, education, and health promotion, especially among underserved populations that may be at risk for health disparities. Our surveillance activities contribute to population-based descriptions of the health and treatment experiences of cancer survivors in the United States. These data inform applied research activities as well as provide baseline data on cancer survivors for local comprehensive cancer control programs. The knowledge gained by our research efforts informs the development of interventions, awareness and education campaigns, and other outreach activities targeting cancer survivors and those who care for and support them. Our partnerships with national organizations, state health agencies, and other key groups are essential in the development, implementation, and promotion of effective cancer control practices related to cancer survivorship. This article provides an overview of the cancer survivorship activities currently being implemented by DCPC. We highlight several public health surveillance, research, and programmatic outreach and partnership activities currently underway. PMID- 19788366 TI - Sexual function outcomes in women treated for posttraumatic stress disorder. AB - BACKGROUND: This study examined dysfunctional sexual behavior and sexual concerns in women treated for posttraumatic stress disorder (PTSD). There were three objectives: to characterize the relationship between symptoms of PTSD and sexual outcomes, to examine the effect of treatment on sexual outcomes, and to examine the relationship between change in PTSD and change in sexual outcomes. METHODS: Female veterans and active duty personnel with PTSD (n = 242), 93% of whom had experienced sexual trauma, were randomly assigned to receive 10 weekly sessions of either Prolonged Exposure or Present-Centered Therapy. PTSD and sexual outcomes were assessed before and after treatment and then 3 and 6 months later. RESULTS: At baseline, the reexperiencing, numbing, and hyperarousal symptom clusters were related to one or both sexual outcomes. Although prior analyses had shown that Prolonged Exposure resulted in better PTSD outcomes, there were no differences between treatments for either dysfunctional sexual behavior or sexual concerns. However, loss of PTSD diagnosis was associated with improvements in sexual concerns. CONCLUSIONS: The findings suggest that clinically meaningful improvements in PTSD are necessary in order to reduce sexual problems in traumatized women. PMID- 19788368 TI - AMWA position statement on emergency contraception. PMID- 19788369 TI - Toward optimal health: advances in chronic back pain management for women. PMID- 19788370 TI - Stage-specific role for shh in dopaminergic differentiation of human embryonic stem cells induced by stromal cells. AB - Stromal cells have been used to induce dopaminergic differentiation of mouse, primate, and human embryonic stem cells (hESCs), but the mechanism that governs this induction is unknown. In this manuscript, we show that medium conditioned by the stromal cell line PA6 (PA6-CM) can induce dopaminergic differentiation in neural stem cells (NSCs) derived from hESCs but not directly from hESCs, indicating that soluble factors produced by PA6 cells act at the NSC stage to specify a dopaminergic fate. To identify such soluble factors, we analyzed the transcriptomes of PA6 cells, NSCs, and dopaminergic populations induced by PA6-CM from hESC-derived NSCs. We focused our analysis on growth factors expressed by PA6 and receptors expressed by NSCs, and generated a list of growth factors and receptors that are differentially expressed. Some of the growth factor/receptor pairs are categorized into the Shh, Wnt5A, TGFbeta, and IGF pathways. The expression of genes activated by these pathways in dopaminergic populations was analyzed to confirm that these signals were likely candidates for specifying dopaminergic fate. Results were verified for Shh by using perturbation agents such as cyclopamine to show that Shh is indeed one of the active agents in PA6 CM, and by showing that Shh and FGF8 can substitute for PA6-CM at the NSC induction stage. We conclude that PA6-CM can induce dopaminergic differentiation in hESCs in a stage-specific manner. Shh is likely an important soluble dopaminergic inducing factor secreted by stromal cells and acts after the neural fate determination. PMID- 19788371 TI - Human umbilical cord blood cells decrease microglial survival in vitro. AB - When human umbilical cord blood (HUCB) cells are systemically administered following middle cerebral artery occlusion (MCAO) in rats, they produce a reduction in infarct size resulting in recovery of motor function. Rats receiving HUCB cells have a less severe inflammatory response compared to MCAO stroke rats. The purpose of this study was to determine the interaction between HUCB cells and the main resident immune cells of the brain (microglia) under normoxic and hypoxic conditions in vitro. Primary microglial cultures were incubated for 2 h in no oxygen (95% N, 5% CO(2)) and low glucose (1%) media. Mononuclear HUCB cells were added to half the cultures at the beginning of the hypoxia conditions. Microglial viability was determined using fluorescein diacetate/propidium iodide (FDA/PI) labeling and cytokine expression using ELISA. In some studies, CD11b+ or CD19+ cells isolated from the HUCB mononuclear fraction with magnetic antibody cell sorting (MACS) were used instead of the mononuclear fraction. Co-culturing mononuclear HUCB cells with microglia decreased viability of the microglia during hypoxia. In the microglial monocultures, hypoxia significantly increased release of IL-1beta compared to normoxia, while adding HUCB cells in the hypoxia condition decreased IL-1beta concentrations to the same level as in the normoxia monocultures. Both CD11b+ and CD19+ HUCB cells decreased microglial viability during normoxia and hypoxia. Our data suggest that HUCB cells may produce a soluble factor that decreases viability of microglia. PMID- 19788372 TI - Evaluation of methylcellulose and dimethyl sulfoxide as the cryoprotectants in a serum-free freezing media for cryopreservation of adipose-derived adult stem cells. AB - Developing effective techniques for the cryopreservation of human adipose-derived adult stem cells (ASCs) could increase the usefulness of these cells in tissue engineering and regenerative medicine. To this end, we investigated the post freeze/thaw viability and apoptotic behavior of Passage 1 (P1) adult stem cells (ASCs) in 11 different media: (i) the traditional media containing Dulbecco's modified Eagle's medium (DMEM) with 80% fetal calf serum (FCS) and 10% dimethyl sulfoxide (DMSO), (ii) DMEM with 80% human serum (HS) and 10% DMSO, (iii) DMEM with 1% methyl cellulose (MC) and 10% of either HS or FCS or DMSO, and (iv) DMEM with 0%, 2%, 4%, 6%, 8%, or 10% DMSO. Approximately 1 mL (10(6) cells/mL) of P1 ASCs were frozen overnight in a -80 degrees C freezer and stored in liquid nitrogen for 2 weeks before being rapidly thawed in a 37 degrees C water bath (1 2 min of agitation), resuspended in culture media, and seeded in separate wells of a 6-well plate for a 24-h incubation period at 37 degrees C. After 24 h, the thawed samples were analyzed by bright-field microscopy and flow cytometry. The results suggest that the absence of DMSO (and the presence of MC) significantly increases the fraction of apoptotic and/or necrotic ASCs. However, the percentage of viable cells obtained with 2% DMSO and DMEM was comparable with that obtained in freezing media with 10% DMSO and 80% serum (HS or FCS), that is, approximately 84% +/- 5% and approximately 84% +/- 8%, respectively. Adipogenic and osteogenic differentiation behavior of the frozen thawed cells was also assessed using histochemical staining. Our results suggest that post-thaw ASC viability, adipogenic and osteogenic differentiability can be maintained even when they are frozen in the absence of serum but with a minimal concentration of 2% DMSO in DMEM. PMID- 19788373 TI - Expression of cell cycle-related genes with cytokine-induced cell cycle progression of primitive hematopoietic stem cells. AB - Primitive marrow lineage-negative rhodamine low and Hoechst low (LRH) stem cells isolated on the basis of quiescence respond to the cytokines thrombopoietin, FLT3L, and steel factor by synchronously progressing through cell cycle. We have now profiled the mRNA expression, as determined by real-time RT-PCR, of 47 hematopoietic or cell cycle-related genes, focusing on the variations in the cell cycle regulators with cycle transit. LRH stem cells, at isolation, showed expression of all interrogated genes, but at relatively low levels. In our studies, there was a good deal of consistency with regard to cell cycle regulatory genes involved in the G1/S progression point of LRH murine stem cells. The observed pattern of expression of cyclin A2 is consistent with actions at these phases of cell cycle. Minimal elevations were seen at 16 h with higher elevations at 24, 32, 40, and 48 h times encompassing S, G2, and M phases. CDK2 expression pattern was also consistent with a role in G1/S transition with a modest elevation at 24 h and more substantial elevation at 32 h. The observed pattern of expression of cyclin F mRNA with marked elevations at 16-40 h was also consistent with actions in S and G2 phases. Cyclin D1 expression pattern was less consistent with its known role in G1 progression. The alterations in multiple other cell cycle regulators were consistent with previous information obtained in other cell systems. The cycle regulatory mechanics appears to be preserved across broad ranges of cell types. PMID- 19788374 TI - Reserves, functional, immunoregulatory, and cytogenetic properties of bone marrow mesenchymal stem cells in patients with myelodysplastic syndromes. AB - Defective hematopoiesis supporting capacity of bone marrow (BM) stroma has been implicated in the pathophysiology of myelodysplastic syndromes (MDS). The aim of this study is to explore whether the BM stroma progenitors, namely the mesenchymal stem cells (MSCs), are primarily affected in MDS by evaluating the reserves, the functional properties, as well as the cytogenetic characteristics, in comparison to BM hematopoietic cells, in patients with de novo MDS (n = 13). The number, differentiation potential toward adipocytes/chondrocytes/osteoblasts and immunosuppressive function in terms of inhibition of mitogen-induced T-cell proliferation did not differ significantly between patient and normal (n = 20) MSCs. Patient MSCs did not show any aberrations in the production of proinflammatory or growth-promoting cytokines and did not harbor the cytogenetic abnormalities present in hematopoietic cells. Occasional patient and normal MSC cultures, however, developed irrelevant chromosomal alterations (trisomies 5 and 7) with uncertain pathophysiologic significance. Compared to controls, patient MSCs displayed impaired proliferative and clonogenic potential through passages that might represent a nonspecific abnormality associated with the chronic inflammatory process present in patients' BM. These data suggest that BM MSCs from MDS patients do not belong to the abnormal clone and do not represent the main cellular source contributing to the inflammatory marrow microenvironment. PMID- 19788375 TI - Blog function revisited: a content analysis of MySpace blogs. AB - The present study concerns the content of MySpace blogs and whether it differs from the blog style found on sites specifically designed for blogging. A content analysis of MySpace blogs was conducted to investigate trends in purpose, format, and style and to compare these across sex and age categories. Most blogs were written in a positive tone, and the main motivations for blogging appeared to be writing a diary and as an emotional outlet. Findings also indicate that while there were no significant sex differences, blog purpose and style differed across age groups; for example, bloggers over 50 were more likely to use the blog as an emotional outlet with a negative tone. Bloggers between 18 and 29 predominantly used a semiformal language style, whereas bloggers over 30 were equally as likely to use a semiformal or formal style. Results suggest that MySpace blogs are not dissimilar from other forms of blogging because they provide an important outlet for emotion and self-expression. PMID- 19788376 TI - The attitudes, feelings, and experiences of online gamers: a qualitative analysis. AB - The playing of massively multiplayer online role-playing games (MMORPGs) is now a highly popular leisure activity. The present study set out to explore the attitudes, experiences, and feelings of online gamers. The study entailed 71 interviews with online gamers (52 males, 19 females) from 11 different countries. Six main themes emerged from the analyses of the interview transcripts: (a) online gaming and integration into day-to-day lives; (b) online gaming, excessive play, and problems; (c) addiction; (d) psychosocial impact of online gaming; (e) online gaming, dissociation, and time loss; and (f) online gaming and the alleviation of negative feelings and mood states. These findings specifically showed how gamers used MMORPGs to alleviate negative feelings and provided detailed descriptions of personal problems that had arisen due to playing MMORPGs. The implications of these findings are discussed in relation to previous qualitative and quantitative research in the area. PMID- 19788377 TI - The theory of planned behavior applied to young people's use of social networking Web sites. AB - Despite the increasing popularity of social networking Web sites (SNWs), very little is known about the psychosocial variables that predict people's use of these Web sites. The present study used an extended model of the theory of planned behavior (TPB), including the additional variables of self-identity and belongingness, to predict high-level SNW use intentions and behavior in a sample of young people ages 17 to 24 years. Additional analyses examined the impact of self-identity and belongingness on young people's addictive tendencies toward SNWs. University students (N = 233) completed measures of the standard TPB constructs (attitude, subjective norm, and perceived behavioral control), the additional predictor variables (self-identity and belongingness), demographic variables (age, gender, and past behavior), and addictive tendencies. One week later, they reported their engagement in high-level SNW use during the previous week. Regression analyses partially supported the TPB: attitude and subjective norm significantly predicted intentions to engage in high-level SNW use with intention significantly predicting behavior. Self-identity, but not belongingness, significantly contributed to the prediction of intention and, unexpectedly, behavior. Past behavior also significantly predicted intention and behavior. Self-identity and belongingness significantly predicted addictive tendencies toward SNWs. Overall, the present study revealed that high-level SNW use is influenced by attitudinal, normative, and self-identity factors, findings that can be used to inform strategies that aim to modify young people's high levels of use or addictive tendencies for SNWs. PMID- 19788378 TI - Fourteen is fourteen and a girl is a girl: validating the identity of adolescent bloggers. AB - This study focuses on the phenomenon of lying on adolescents' weblogs. The sample consisted of 113 completed surveys out of 120 in total. The age of participants ranged between 13 and 17 years old. Interviews were conducted with 10 randomly selected participants whose answers were then verified. The results suggest not only that adolescents present personal information such as their age, gender, and place of residence but that these pieces of information are presented truthfully. Generally, the level of dishonesty was low, with young adolescents tending to lie more often about their interests. Public topics (school and life) had the most truthful answers, whereas the least truthful answers concerned intimate topics (family life, partnership). These results suggest that adolescents' blogs serve as a place where the writers can both present themselves and communicate with their peers in a way that goes beyond a traditional diary. PMID- 19788379 TI - A pilot study of problem gambling among student online gamblers: mood states as predictors of problematic behavior. AB - Within the last decade, interest in online gambling has increased. This pilot study examined online gambling among students to identify the extent to which student Internet gamblers manifest a propensity for problem gambling and to understand if mood states at various times are predictors of problem gambling. A questionnaire was administered to 127 student Internet gamblers. In addition to questions asking for basic demographic data, the questionnaire included the Positive and Negative Affect Schedule (PANAS) and the South Oaks Gambling Screen (SOGS). Results showed that approximately one in five online gamblers (19%) was defined as a probable pathological gambler using the SOGS. Among this sample, results also showed that problem gambling was best predicted by negative mood states after gambling online and negative mood states more generally. PMID- 19788380 TI - Instant messaging addiction among teenagers in China: shyness, alienation, and academic performance decrement. AB - This exploratory research proposes the concept of instant messaging (IM) addiction and examines (a) whether IM addiction exists among Chinese teenagers and, if so, who the addicts are, what their symptoms are, and to what extent they are addicted; (b) whether psychological variables such as shyness and alienation can predict IM use or addiction among teenagers; and (c) whether IM use or IM addiction can impair the academic performance of teenagers. Using Young's classic definition of Internet addiction, results of a stratified random sample of 330 teenagers in China in 2007 found 95.8% of participants use IM, and 9.8% of them can be classified as IM addicts. Factor analysis identified four major IM addiction symptoms among teenagers: preoccupation with IM, loss of relationships due to overuse, loss of control, and escape. Results also showed that shyness and alienation from family, peers, and school are significantly and positively associated with levels of IM addiction. As expected, both the level of IM use and level of IM addiction are significantly linked to teenagers' academic performance decrement. PMID- 19788381 TI - Avatars mirroring the actual self versus projecting the ideal self: the effects of self-priming on interactivity and immersion in an exergame, Wii Fit. AB - As exergames are increasingly being used as an interventional tool to fight the obesity epidemic in clinical studies, society is absorbing their impact to a more intense degree. Interactivity and immersion are key factors that attract exergame consumers. This research asks, What are the effects of priming the actual self versus the ideal self on users' perceived interactivity and immersion in avatar based exergame playing? and What are important moderators that play a role in exergame users' self-concept perception? To answer these research questions, this study leveraged the Wii's avatar-creating function (Mii Channel) and exergame feature (Wii Fit) in a controlled, randomized experimental design (N = 126). The results of a 2 x 2 factorial design experiment demonstrated the significant main effect of self-priming on interactivity and the moderating role of the actual ideal self-concept discrepancy in influencing immersion during exergame playing. Game players who created an avatar reflecting the ideal self reported greater perceived interactivity than those who created a replica avatar mirroring the actual self. A two-way ANOVA demonstrated the moderating role of the actual-ideal self-concept discrepancy in determining the effects of the primed regulatory focus on immersion in the exergame play. The underlying theoretical mechanism is derived from and explained by Higgins's self-concept discrepancy perspective. Practical implications for game developers and managerial implications for the exergame industry are discussed. PMID- 19788382 TI - Quality of interpersonal relationships and problematic Internet use in adolescence. AB - International literature has identified a stable correlation between problems in the sphere of adolescents' personal relationships and potential Internet dependence. The objective of this research is to verify in an Italian context the relationship among problematic Internet use (PIU), the quality of interpersonal relationships, and the cognitive strategies habitually used by adolescents to face daily problems. The participants in the research were 98 adolescents ages 14 to 19 (M = 16.28 years). The following instruments were administered to the participants: the Internet Addiction Test (IAT), the Test of Interpersonal Relationships (TRI); and the Children's Coping Strategies Checklist (CCSC). Parents of the participants were administered the Child Behavior Checklist (CBCL). Of the participants, 36.7% showed signs of PIU. These adolescents use the Internet for many hours per week; most utilize dysfunctional coping strategies and show worse interpersonal relations than peers who do not show signs of PIU. PMID- 19788384 TI - Protective response against type 1 diabetes in nonobese diabetic mice after coimmunization with insulin and DNA encoding proinsulin. AB - Type 1 diabetes (T1D) in both humans and nonobese diabetic (NOD) mice is a T cell mediated autoimmune disease characterized by lymphocytic infiltration of pancreatic islets with subsequent destruction of the insulin-producing cells. The T regulatory (Treg) cell has been suggested to play an important role in controlling T cell-mediated inflammatory T1D. We previously demonstrated that induction of antigen-specific Treg cells in vivo by co-immunization with a DNA vaccine and its encoded protein can effectively inhibit T cell-mediated inflammatory diseases. To further demonstrate the potential of this strategy, we show here that co-immunization of NOD mice twice with DNA encoding proinsulin plus insulin protein prevents the onset of T1D and induces the impairment of antigen-specific T cell responses in a dose-dependent manner. We further show that the inhibitory function is due to the induction of TGF-beta-producing CD4(+)CD25(-) islet-specific iTreg cells against the onset of T1D in NOD mice. Induced iTreg cells were observed only in the co-immunization group, but derived neither from the DNA vaccine nor the protein alone, suggesting that a biased helper T cell type 1 response plays no inhibitory role. A strategy based on co immunization to induce a protective response against the onset of diabetes in NOD mice may lead to the development of an immunotherapeutic/preventive protocol against T1D in humans. PMID- 19788383 TI - Acinetobacter baumannii-associated skin and soft tissue infections: recognizing a broadening spectrum of disease. AB - BACKGROUND: Acinetobacter baumannii is gaining importance as a cause of nosocomial infections, but its role in skin and soft tissue infection (SSTI) is not well defined. As a result of the outbreak of A. baumannii occurring in military personnel in Iraq and Afghanistan, reports of severe wound infections and SSTI caused by this pathogen are increasing in frequency. METHODS: We describe four cases of monomicrobial and polymicrobial A. baumannii-associated necrotizing SSTI accompanied by A. baumannii bacteremia and offer a review of similar experiences published in the literature. RESULTS: Our comparative analysis reveals four unique features associated with necrotizing SSTI associated with A. baumannii: i) Occurs in hosts with underlying comorbidities (e.g., trauma, cirrhosis); ii) is often accompanied by bacteremia; iii) multiple drug resistance and the presence of co-pathogens frequently complicated treatment (64% of cases); iv) the cases reported here and in our review required surgical debridement (84% of cases) and led to substantial mortality (approximately 30%). CONCLUSIONS: As the prevalence of A. baumannii continues to increase in our health care system, SSTIs caused by this organism may become more common. Clinicians must be aware that the spectrum of disease caused by A. baumannii could include severe necrotizing SSTI and that vigilance for potential complications is necessary. PMID- 19788385 TI - Infection and killing of multiple myeloma by adenoviruses. AB - Oncolytic virotherapy makes use of the natural ability of viruses to infect and kill cancer cells. Adenovirus serotype 5 (Ad5) has been approved for use in humans as a therapy for solid cancers. In this study, we have tested whether Ad5 and low-seroprevalence adenoviruses can be used as oncolytics for multiple myeloma (MM). We show that Ad5 productively infects most myeloma cell lines, replicates to various degrees, and mediates oncolytic cell killing in vitro and in vivo. Comparison of Ad5 with low-seroprevalence Ads on primary marrow samples from MM patients revealed striking differences in the abilities of different adenoviral serotypes to kill normal CD138(-) cells and CD138(+) MM cells. Ad5 and Ad6 from species C and Ad26 and Ad48 from species D all mediated killing of CD138(+) cells with low-level killing of CD138(-) cells. In contrast, Ad11, Ad35, Ad40, and Ad41 mediated weak oncolytic effects in all of the cells. Comparison of cell binding, cell entry, and replication revealed that Ad11 and Ad35 bound MM cells 10 to 100 times better than other serotypes. However, after this efficient interaction, Ad11 and Ad35 viral DNA was not replicated and cell killing did not occur. In contrast, Ad5, Ad6, Ad26, and Ad48 all replicated 10- to 100-fold in MM cells and this correlated with cell killing. These data suggest that Ad5 and other low-seroprevalence adenoviruses may have utility as oncolytic agents against MM and other hematologic malignancies. PMID- 19788386 TI - Functional efficacy of dystrophin expression from plasmids delivered to mdx mice by hydrodynamic limb vein injection. AB - In these studies we delivered by hydrodynamic limb vein (HLV) injection plasmid DNA (pDNA) expressing the full-length mouse dystrophin gene to skeletal muscles throughout the hind limbs of the mdx mouse model for Duchenne muscular dystrophy (DMD). We evaluated the levels and stability of dystrophin expression and measured the resulting muscle protection, using Evans blue dye (EBD) to mark the damaged myofibers. Plasmid delivery was as efficient in the dystrophic mice as in wild-type mice and equally efficient in young adult and old mice, as long as the dose of pDNA was adjusted for the target muscle weight. The HLV gene delivery procedure was tolerated well by the dystrophic mice and repeat injections could be performed over an extended period of time. Multiple gene deliveries additively increased the amount of dystrophin protein and also increased the percentages of dystrophin-expressing myofibers. Plasmids expressing dystrophin from a cytomegalovirus (CMV) promoter construct containing the HMG1 intron provided stable dystrophin expression for the life of the mouse and provided significant benefit to the limbs. EBD staining showed that dystrophin gene delivery preserved myofibers in the CMV-HMGi-mDys-injected leg by 2.5- to 5-fold in large groups of muscles and by 2.5-fold throughout the injected legs, compared with the contralateral control legs injected with a nonexpressing plasmid. A similar degree of protection was measured in young adult mice evaluated soon after the last gene delivery and in aged mice injected over an extended period of time. This degree of protection resulted from 18 to 20% of the normal level of dystrophin protein, with 11-16% dystrophin-expressing myofibers. These studies show promise for the use of HLV injections to deliver therapeutic doses of full length dystrophin-expressing plasmids for long-lasting protection of skeletal muscles in patients with DMD. PMID- 19788387 TI - Poly(ethylene glycol)-grafted polyethylenimine modified with G250 monoclonal antibody for tumor gene therapy. AB - To improve the biocompatibility of a gene vector and to avoid its being eliminated by the immune system, polyethylenimine (PEI) was modified with poly(ethylene glycol) (PEG) before G250 monoclonal antibody (mAb) conjugation. G250-PEI-PEG was capable of forming complexes with DNA in the right size distribution, and the G250 mAb modification significantly improved PEI transfection of G250-positive cells. The highest transfection efficiency was seen in HeLa cells as determined by flow cytometry after transfection with the gene encoding green fluorescent protein: 2-fold higher compared with the transfection of HepG2 cells. Blocking the surface antigen on the cell membrane of HeLa cells by incubation with free G250 mAb, or by downregulating G250 expression by small interfering RNA transfection, resulted in a remarkable decrease in transfection efficiency. These data indicate the targeting effect of G250 antibody modification. The presence of serum decreased transfection efficiency in a concentration-dependent manner. However, the transfection of HeLa cells with G250 PEI-PEG remained significant in the presence of 30% serum. In an in vivo study, G250-PEI-PEG exhibited high transfection efficiency in tumors. In addition, pathological analysis did not show obvious toxicity caused by the materials used. These suggest that PEG- and G250 mAb-modified PEI could be a useful nonviral gene vector for in vivo study. PMID- 19788388 TI - Impact of chronic pulmonary infection with Pseudomonas aeruginosa on transfection mediated by viral and nonviral vectors. AB - Pseudomonas aeruginosa plays a crucial role in the lung pathology of cystic fibrosis (CF). We showed that acute infection with P. aeruginosa has a substantial impact on gene transfer into lung epithelial cells mediated by polyplexes. As an extension of those studies we report here on the effect of chronic pulmonary infection with P. aeruginosa on transfection of lung epithelial cells by viral and nonviral vectors. As an in vivo model of the persistent chronic infection in patients with CF we used C57BL/6 mice intratracheally infected with P. aeruginosa encapsulated in agar beads. Two weeks after infection the presence of viable bacteria in the lungs was confirmed, mostly in the bronchial lumen. In lung tissue sections stained with hematoxylin and eosin, extensive inflammatory infiltrations were found. At that time point the mice received an intratracheal dose of luciferase gene complexed with either Lipofectamine (Lf), a GL67 lipid mixture (GL67), or polyethylenimine (PEI) or with lentivirus (LV) as a carrier system. Luciferase activity was determined by a luminescence assay in supernatants of lung homogenates. The transfection level induced by PEI/DNA polyplexes complexed with serum albumin was decreased in infected mice. Lf-mediated transfection was almost completely blocked in infected mice. Transfection levels in mice treated with LV or plain PEI/DNA polyplexes were unchanged in infected animals as compared with control mice. The only carrier that displayed a clearly increased transfection level in infected mice was the GL67 lipid mixture, which is tentatively ascribed to the presence of polyethylene glycol in this carrier. PMID- 19788389 TI - Adenovirus 5-fiber 35 chimeric vector mediates efficient apical correction of the cystic fibrosis transmembrane conductance regulator defect in cystic fibrosis primary airway epithelia. AB - In vivo gene transfer to the human respiratory tract by adenovirus serotype 5 (Ad5) vectors has revealed their limitations related to inefficient gene transfer, host antiviral response, and innate adenoviral toxicity. In the present work, we compared the cytotoxicity and efficiency of Ad5 and a chimeric Ad5F35 vector with respect to CFTR gene transfer to cystic fibrosis (CF) and non-CF human airway epithelial cells. We found that high doses of Ad5 vector had an adverse effect on the function of exogenous and endogenous CFTR. Results obtained with Ad5 capsid mutants suggested that the RGD motifs on the penton base capsomers were responsible for the negative effect on CFTR function. This negative interference did not result from a lower level of biosynthesis and/or altered cellular trafficking of the CFTR protein, but rather from an indirect mechanism of functional blockage of CFTR, related to the RGD integrin-mediated endocytic pathway of Ad5. No negative interference with CFTR was observed for Ad5F35, an Ad5-based vector pseudotyped with fibers from Ad35, a serotype that uses another cell entry pathway. In vitro, Ad5F35 vector expressing the GFP tagged CFTR (Ad5F35-GFP-CFTR) showed a 30-fold higher efficiency of transduction and chloride channel correction in CFTR-deficient cells, compared with Ad5GFP CFTR. Ex vivo, Ad5F35-GFP-CFTR had the capacity to transduce efficiently reconstituted airway epithelia from patients with CF (CF-HAE) via the apical surface, restored chloride channel function at relatively low vector doses, and showed relatively stable expression of GFP-CFTR for several weeks. PMID- 19788390 TI - Optimized adeno-associated virus (AAV)-protein phosphatase-5 helper viruses for efficient liver transduction by single-stranded AAV vectors: therapeutic expression of factor IX at reduced vector doses. AB - Abstract Our studies have shown that coinjection of conventional single-stranded adeno-associated virus 2 (ssAAV2) vectors carrying the enhanced green fluorescent protein (EGFP) gene with self-complementary (sc) AAV2-T cell protein tyrosine phosphatase (TC-PTP) and scAAV2-protein phosphatase-5 (PP5) vectors resulted in an approximately 16-fold increase in EGFP expression in primary murine hepatocytes in vivo [Jayandharan, G.R., Zhong, L., Li, B., Kachniarz, B., and Srivastava, A. (2008). Gene Ther. 15, 1287-1293]. In the present studies, this strategy was further optimized to achieve transgene expression at reduced vector/helper virus doses. These included the use of scAAV helper viruses containing (1) hepatocyte-specific promoters, (2) tyrosine-mutant AAV2 capsids, and (3) additional AAV serotype vectors known to efficiently transduce hepatocytes. The hepatocyte-specific transthyretin (TTR) promoter was approximately 6- to 7-fold more efficient than the Rous sarcoma virus (RSV) promoter; tyrosine-mutant AAV2 capsids were approximately 6- to 11-fold more efficient than the wild-type AAV2 capsids; and the AAV8 serotype helper virus was approximately 16-fold more efficient than AAV2 serotype helper virus. With these modifications, the vector dose of the helper virus could be further reduced by approximately 50-fold. Last, coadministration of scAAV8-PP5 helper virus increased coagulation factor IX expression from an ssAAV2 vector by approximately 7- to 10-fold, thereby achieving therapeutic levels at lower vector doses. No adverse effect on hepatocytes was observed under any of these experimental conditions. The strategy presented here should be adaptable to any ssAAV transgene cassette and, specifically, liver-directed applications of ssAAV2 vectors containing larger genes that cannot be encapsidated in scAAV vectors. PMID- 19788391 TI - Phase 1 trial of allogeneic gene-modified tumor cell vaccine RCC-26/CD80/IL-2 in patients with metastatic renal cell carcinoma. AB - Preclinical studies showed that the allogeneic tumor cell line RCC-26 displayed natural immunogenic potential that was enhanced through expression of CD80 costimulatory molecules and secretion of interleukin-2. Here we report the study of RCC-26/CD80/IL-2 cells in a phase 1 vaccine trial of renal cell carcinoma patients with metastatic disease (mRCC). Fifteen patients of the HLA-A*0201 allotype, with at least one metastatic lesion, were included. Irradiated vaccine cells were applied in increasing doses of 2.5, 10, and 40 x 10(6) cells over 22 weeks. Primary study parameters included safety and toxicity. Sequential blood samples were analyzed by interferon-gamma enzyme-linked immunospot assays to detect tumor antigen-associated (TAA) effector cells. The vaccine was well tolerated and the designated vaccination course was completed in 9 of 15 patients. Neither vaccine-induced autoimmunity nor systemic side effects were observed. Delayed-type hypersensitivity skin reactions were detected in 11 of 12 evaluated patients and were particularly strong in patients with prolonged survival. In parallel, vaccine-induced immune responses against vaccine or overexpressed TAA were detected in 9 of 12 evaluated patients. No tumor regressions occurred according to RECIST (Response Evaluation Criteria in Solid Tumors) criteria; however, median time to progression was 5.3 months and median survival was 15.6 months, indicating substantial disease stabilization. We conclude that vaccine use was safe and feasible in mRCC. Clinical benefits were limited in these patients with advanced disease; however, immune monitoring revealed vaccine-induced responses against multiple TAAs in the majority of study participants. These results suggest that this vaccine could be useful in combination therapies and/or minimal residual disease. PMID- 19788392 TI - Redox control of vascular smooth muscle function. PMID- 19788393 TI - Clearance and control mechanisms of hemoglobin from cradle to grave. AB - Hemoglobin is a highly reactive molecule, and besides its oxygen-carrying capacity, it has multiple enzymatic and ligand-binding activities that have only recently been explored as fundamental pathophysiologic mechanisms. Nitric oxide neutralization, generation of potentially toxic radical species, and heme mediated inflammation are among the most extensively studied mechanisms of Hb mediated pathology. Extracellular Hb has an established role in sickle cell disease and other hemolytic disorders. However, extracellular Hb seems also to have relevant disease-modifying activities in many other important pathologic conditions, such as malaria and atherosclerosis. In this Forum, we summarize the current knowledge of mechanisms of Hb toxicity. Special emphasis is given to the highly efficient endogenous scavenger and detoxification pathways, such as alpha hemoglobin stabilizing protein (AHSP), haptoglobin, hemopexin, CD163, and heme oxygenase. Systemic and local activity of these pathways finally determines the impact of extracellular Hb on physiology and tissue homeostasis. PMID- 19788394 TI - Dehydroepiandrosterone stimulates neurogenesis in mouse embryonal carcinoma cell- and human embryonic stem cell-derived neural progenitors and induces dopaminergic neurons. AB - To evaluate the effect of dehydroepiandrosterone (DHEA) as a neurosteroid on the rate of neurogenesis, neural survival, and proliferation of pluripotent stem cell derived neurons, we have added DHEA to mouse P19 embryonal carcinoma cell- and human embryonic stem cell-derived neural progenitors (ECC- and ESC-NPs). In ECC derived NPs, flow cytometric analysis of nestin and Tuj1-positive cells revealed that the percentages of these cells increased significantly for the markers following DHEA treatment of the cells. Moreover, the percentages of tyrosine hydroxylase (TH)-positive cells, the marker of dopaminergic neurons, significantly increased in the presence of DHEA. The expression of neural specific genes such as Mash1, Pax6, Tuj1, and TH was also detected by RT-PCR analysis. BrdU incorporation and estrogen receptor (EsR) were found to be increased after DHEA induction. Moreover, apoptosis was significantly decreased after DHEA treatment. DHEA effect was also confirmed on human ESC-NPs by the enhancement of Tuj1- and TH-immunofluorescent-positive cells and TH and Nurr1 transcripts, as detected by quantitative RT-PCR. In conclusion, these results have presented evidence that DHEA was able to induce neurogenesis in mouse ECC and human ESC-NPs. This observation was related to the division of NPs and the reduction of apoptosis. Moreover, DHEA has dopaminergic potential in the cells of both orders. This provides a better insight into the differentiation and maintenance of neural cells and treatment of a wide variety of neurological diseases such as Alzheimer's and Parkinson's by stem cells. PMID- 19788395 TI - Functional differences between mesenchymal stem cell populations are reflected by their transcriptome. AB - Stem cells are widely studied to enable their use in tissue repair. However, differences in function and differentiation potential exist between distinct stem cell populations. Whether those differences are due to donor variation, cell culture, or intrinsic properties remains elusive. Therefore, we compared 3 cell lines isolated from 3 different niches using the Affymetrix Exon Array platform: the cord blood-derived neonatal unrestricted somatic stem cell (USSC), adult bone marrow-derived mesenchymal stem cells (BM-MSC), and adult adipose tissue-derived stem cells (AdAS). While donor variation was minimal, large differences between stem cells of different origin were detected. BM-MSC and AdAS, outwardly similar, are more closely related to each other than to USSC. Interestingly, USSC expressed genes involved in the cell cycle and in neurogenesis, consistent with their reported neuronal differentiation capacity. The BM-MSC signature indicates that they are primed toward developmental processes of tissues and organs derived from the mesoderm and endoderm. Remarkably, AdAS appear to be highly enriched in immune-related genes. Together, the data suggest that the different mesenchymal stem cell types have distinct gene expression profiles, reflecting their origin and differentiation potential. Furthermore, these differences indicate a demand for effective differentiation protocols tailored to each stem cell type. PMID- 19788396 TI - Liver sinusoidal endothelial cells promote B lymphopoiesis from primitive hematopoietic cells. AB - Although the bone marrow (BM) microenvironment is the main inducer niche of early B lymphopoiesis during the adult life, other extramedullar microenvironments, such as the liver, may also have potential for supporting B-cell development. Previously, we reported that murine liver sinusoidal endothelial cells (LSECs) support in vitro and in vivo hematopoietic stem cell (HSC) proliferation and myeloid differentiation. In the present study, we investigated the capacity of LSEC to promote B lymphopoiesis from BM progenitor lineage-negative (Lin(-)) cells. Murine BM Lin(-) cells were co-cultured with LSEC, in the absence of exogenous cytokines. B cells were characterized by flow cytometry and cytokine expression by RT-PCR. We show that BM Lin(-) cells differentiated to early B lymphoid progenitors (B220(+)) and subsequently to mature (CD19(+)) B cells. Functional studies showed the presence of a high number of non-adherent cells (NACs), collected from lipopolysaccharide (LPS)-treated Lin(-)/LSEC co-cultures, expressing IgM on their surface (sIgM). Colony formation from NAC was observed in the presence of IL-7 (CFU-IL-7). LSEC constitutively express IL-7, Flt-3L, and SCF at the mRNA level, and VCAM-1 on their surface, which may explain the capacity of these cells to promote B lymphopoiesis. These data demonstrate that LSEC promote all stages of B lymphopoiesis. To our knowledge, this is the first report that LSEC constitute an in vitro microenvironment for B lymphopoiesis. Further studies will establish whether LSEC can serve in vivo as a B lymphopoietic niche under physiological or pathological condition, or when HSC are mobilized. PMID- 19788397 TI - The inherent differentiation program of short-term hematopoietic repopulating cells changes during human ontogeny. AB - Human umbilical cord blood (CB) could be an attractive source of hematopoietic repopulating cells for clinical stem cell therapy because of its accessibility and low propensity for unwanted immune reaction against the host. However, CB recipients suffer from severely delayed and often chronically deficient platelet recovery of unknown cause. Here we show that human short-term repopulating cells (STRCs), which predominantly carry early hematopoietic reconstitution after transplantation, display an intrinsically fixed differentiation program in vivo that changes during ontogeny. Compared to adult sources of hematopoietic cells, CB myeloidrestricted STRC-M showed a markedly reduced megakaryocytic and erythroid cell output in the quantitative xenotransplantation of human short-term hematopoiesis in NOD/SCID-beta2m(-/-) mice. This output in vivo was not altered by pre-treating CB cells before transplantation with growth factors that effectively stimulate megakaryocytopoiesis in vitro. Moreover, injecting mice with granulocyte colony-stimulating factor did not affect the differentiation of human STRC. These findings demonstrate that the differentiation capacity of human STRCs is developmentally regulated by mechanisms inaccessible to currently available hematopoietic growth factors, and explain why thrombopoiesis is deficient in clinical CB transplantation. PMID- 19788398 TI - Characterization of the DsbA oxidative folding catalyst from Pseudomonas aeruginosa reveals a highly oxidizing protein that binds small molecules. AB - Bacterial antibiotic resistance is an emerging global crisis, and treatment of multidrug-resistant gram-negative infections, particularly those caused by the opportunistic human pathogen Pseudomonas aeruginosa, remains a major challenge. This problem is compounded by a lack of new antibiotics in the development pipeline: only two new classes have been developed since the 1960s, and both are indicated for multidrug-resistant gram-positive infections. A promising new approach to combat antibiotic resistance is by targeting bacterial virulence, rather than bacterial viability. The bacterial periplasmic protein DsbA represents a central point for antivirulence intervention because its oxidoreductase activity is essential for the folding and function of almost all exported virulence factors. Here we describe the three-dimensional structure of this DsbA target from P. aeruginosa, and we establish for the first time that a member of this enzyme family is capable of binding small molecules. We also describe biochemical assays that validate the redox activity of PaDsbA. Together, the structural and functional characterization of PaDsbA provides the basis for future studies aimed at designing a new class of antivirulence compounds to combat antibiotic-resistant P. aeruginosa infection. PMID- 19788399 TI - The negative co-signaling molecule b7-h4 is expressed by human bone marrow derived mesenchymal stem cells and mediates its T-cell modulatory activity. AB - Though experimental evidence shows that human bone marrow-derived mesenchymal stem cells (hBMSCs) are able to suppress T-cell activation and proliferation, the precise mechanisms are still not completely understood. Here, we investigated the role of the negative costimulatory molecule B7-H4 in the immunosuppressive effect of hBMSCs on T-cell activation. We showed that B7-H4 expresses abundantly on hBMSCs assessed by reverse transcription, immunofluorescence staining, and flow cytometric analysis. Further studies demonstrated that B7-H4 expressed on hBMSCs inhibits T-cell activation and proliferation via induction of cell cycle arrest and inhibition of NF-kappaB nuclear translocation. Blocking B7-H4 would decrease the secretion of transforming growth factor-beta1 (TGF-beta1) in the supernatant of activated T cells co-cultured with hBMSCs. Addition of neutralizing antibodies against B7-H4 significantly attenuated the inhibitory effects of hBMSCs on T cells. Thus, our study established the novel role of B7-H4 molecule in the suppressive effect of hBMSCs on T-cell activation and proliferation. Taken together, these results highlight the complex role of hBMSCs in regulating the immune response, asserting the possibility of their therapeutic application in transplantation, the treatment of graft-versus-host disease (GVHD), and autoimmune diseases. PMID- 19788401 TI - Phenotype of hepatic xenobiotic metabolizing enzymes and CYP450 isoforms of sanguinarine treated rats: effect of P450 inducers on its toxicity. AB - Catalytic and immunochemical activities of cytochrome P450 (CYP) isoforms were investigated in argemone alkaloid, sanguinarine (SAN) intoxicated rats, pre treated with different CYP inducers. SAN treated control (CON) and ethanol (ET), 3- methylcholantherene (MC) or dexamethasone (DEX) pre-exposed rats, resulted in 48, 64, 47 and 33% decrease in CYP content. SAN exposure to CON, and DEX, MC or ET pre-treated animals caused a decrease (22-37%) in glutathione-S-transferase (GST) activity, however, quinone reductase (QR) activity decreased (26-45%) in the MC pre-exposed group. Similarly, western-blot analysis of hepatic CYP1A1 and CYP1A2 showed a decrease (27-37%) in MC pre-treated SAN exposed animals. Further, a decrease in mortality in the SAN+MC (25%) group compared to SAN treated animals was also observed. The results suggest that inhibition of CYP 1A1, 1A2, 2D1, 2E1, 3A1, and Phase II enzymes by SAN augments its toxicity, whereas attenuation of SAN toxicity by MC may be due to removal of parent compound/metabolites from the body. PMID- 19788402 TI - Evaluation of activity and phenotype of alpha1-antitrypsin in a civil population with respiratory complications following exposure to sulfur mustard 20 years ago. AB - BACKGROUND AND AIMS: The reduced alpha1-antitrypsin (AAT) activities of some phenotypes have been suggested as contributing to the development of respiratory diseases. MATERIALS AND METHODS: One hundred patients with respiratory disease following exposure to sulfur mustard were divided into two groups of 50 based on their respiratory symptoms and compared with a healthy control group. AAT phenotypes were determined in the plasma of all patient and control subjects by isoelectric focusing (IEF). RESULTS: Mean AAT activities in patient and control groups were 3.4 +/- 0.3 and 4.2 +/- 0.1 micromol min(-1) ml(-1), respectively (p < 0.001). No phenotypic alterations were detected. CONCLUSIONS: The difference in the clinical pulmonary symptoms of the two groups was attributed to reduced AAT activity, but this was not manifested as phenotypic changes identifiable by IEF. PMID- 19788403 TI - Role of cytokines in anti-implantation activity of H2 receptor blockers in albino Wistar rats. AB - In this study, the negative effects of 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD) on the immune system and body weight gain of rats and the preventive effects of curcumin were examined. For this purpose, 3-4 months old 128 Wistar albino rats with 280-310g body weights were used. The 2microg/kg dose of 2,3,7,8-TCDD and 100mg/kg dose of curcumin were dissolved in corn oil and orally given to the rats found in the experimental and control groups. Then, the serum samples were taken from all rats at 15, 30, 45 and 60th days to analyzed for the determination of TNF-alpha, IFN-gamma, IL-12 and IL-13 levels by ELISA method. The data of body weight gain was measured at 15, 30, 45 and 60th days. The results indicated that 2,3,7,8,3,7,8-TCDD caused to increase significantly (p<0.05) in serum TNF-alpha levels. However, it caused significantly (p<0.05) decreases in the levels of IFN gamma, IL-12 and IL-13 in rats. On contrary, curcumin increased IFN-gamma, IL-12 and IL-13 levels, but decreased TNF-alpha level in rats. Additionally, TCDD caused significantly (P<0.01) reductions in the body weight gain. However curcumin reversed this effect of TCDD.In conclusion, 2,3,7,8-TCDD significantly suppressed the humoral immunity and body weight gain in rats at doses of 2microg/kg. However curcumin, which was found in some plants, eliminated the effect of TCDD on immune system and body weight when it was given together with 2,3,7,8-TCDD. It is thought that this effect may have occurred via curcumin and TCDD were binding aryl hydrocarbon receptor (AhR) competitively. PMID- 19788404 TI - In situ gelling xyloglucan/alginate liquid formulation for oral sustained drug delivery to dysphagic patients. AB - BACKGROUND: The oral administration of liquid dosage forms of suitable consistency and with sustained release characteristics may provide a means of improving the compliance of geriatric patients who experience difficulties in swallowing conventional solid dosage forms. AIM: We have designed and evaluated liquid preparations for administration to dysphagic patients, composed of aqueous mixtures of xyloglucan, which has thermally reversible gelation characteristics, and sodium alginate, which has ion-responsive gelation characteristics. METHOD: The gelation and in vitro and in vivo release characteristics of liquid formulations containing appropriate concentrations of xyloglucan and sodium alginate with mannuronate/guluronate ratios of either 0.5 or 0.8 were assessed. RESULTS: Aqueous mixtures of 1.5% xyloglucan and 0.5% alginate had suitable viscosities for ease of swallowing and appropriate gelation temperatures (approximately 33 degrees C) to ensure in situ gelation following oral administration. The in vitro release of paracetamol at pH 5.0 from gels formed by these formulations and also by a 1.5% xyloglucan solution was diffusion controlled. Plasma levels of paracetamol after oral administration to gastric acidity controlled rats (pH 5) of a solution containing 1.5% xyloglucan/0.5% alginate showed that a more sustained release was achieved from the gels formed by the in situ gelation of this formulation compared with that of a 1.5% xyloglucan solution. Visual observation of the contents of the rat stomach after oral administration showed that the inclusion of alginate in the xyloglucan solutions was effective in reducing gel erosion, so sustaining drug release. CONCLUSIONS: Liquid formulations of xyloglucan and sodium alginate in appropriate proportions are of suitable consistency for ease of administration to dysphagic patients and form gels in situ in the rat stomach capable of sustaining the release of paracetamol over a 6-hour period. PMID- 19788405 TI - Electrospray technique for solid lipid-based particle production. AB - BACKGROUND: Different preparation methods for the production of lipid micro- and nanoparticles as controlled release formulations have been widely developed. Novel techniques are attracting increasing attention for their preparation. METHOD: The objective of the present investigation was to produce solid lipid based micro-nanospheres using the electrohydrodynamic atomization (electrospraying) and to evaluate whether it is a suitable method to prepare drug loaded particles. RESULTS: Narrowly dispersed spherical particles lower than 1 mum, easily internalized in cells, were obtained using stearic acid and ethylcellulose in a 4.5:0.5 (w/w) ratio. Tamoxifen, as model drug, was encapsulated with good entrapment efficiency. The in vitro release, after an initial burst effect, showed a prolonged drug release. CONCLUSION: The electrospraying method might be proposed to prepare in a single-step monodisperse lipid-based micro- and nanoparticles in powder form for drug delivery. PMID- 19788406 TI - Total healthcare costs in the US for preterm infants with respiratory syncytial virus lower respiratory infection in the first year of life requiring medical attention. AB - BACKGROUND: Respiratory syncytial virus (RSV) lower respiratory infection (LRI) is the most common cause of hospitalization among infants <1 year of age. The healthcare costs of preterm infants with RSV LRI were compared with those without RSV LRI in the first year of life. METHODS: This retrospective cohort study propensity-matched premature infants < or =36 weeks' gestational age (wGA) and/or < or =2499 g birth weight, born May 1, 2001 through April 30, 2006 (five RSV seasons) with RSV LRI to those without RSV LRI in a national United States health plan. The primary outcome was first-year healthcare costs and utilization excluding the birth hospitalization compared between the study cohorts. Subgroup analysis evaluated costs and healthcare resource utilization by GA (< or =32 wGA and 33-36 wGA) and hospitalization status (hospitalized and outpatient). RESULTS: A total of 2995 infants with RSV LRI were matched to 2995 controls. Infants with RSV LRI had $9115 higher healthcare costs (RSV LRI group: $19 559; control group: $10 444; p < 0.001) in the first year of life. Late preterm infants (33-36 wGA) with an RSV hospitalization incurred $21 977 higher costs (p < 0.001) and those with an outpatient RSV LRI incurred $3898 higher costs (p < 0.001) compared to corresponding controls. Similar results were found among infants < or =32 wGA with higher costs in the RSV LRI group. Rates of all-cause hospitalizations, emergency department visits, and ambulatory visits were significantly higher among infants with RSV LRI compared to controls. CONCLUSION: Development of RSV LRI among preterm and late preterm infants is associated with significantly higher healthcare costs in the first year of life. These findings must be considered in the context of potential study limitations that may have over- or underestimated costs, such as unconfirmed RSV infection, unintentional omission of fatal cases, and unobserved imbalances between groups. PMID- 19788408 TI - Sensitivity analysis on a physiologically-based pharmacokinetic and pharmacodynamic model for diisopropylfluorophosphate-induced toxicity in mice and rats. AB - A physiologically-based pharmacokinetic and pharmacodynamic (PBPK/PD) model was recently developed to study the effect of diisopropylfluorophosphate (DFP) on acetylcholinesterase (AChE) activity in mouse and rat. That model takes into account relatively complex interactions involving many parameters, some of which may be uncertain and/or highly variable, especially those characterizing AChE activity after DFP intoxication. The primary objective of this study was to identify parameters that contribute most to the variability of AChE dynamics for model optimization against data. For this purpose, the influence of the variability of the rate constants for synthesis (K(syn)) and degradation (K(deg)) of AChE, and regeneration (K(reg)) and aging (K(age)) of inhibited AChE on the variability of AChE activity in mice and rat venous blood and brain was first calculated by a global sensitivity analysis. Next, the mouse PBPK/PD model was calibrated by optimizing the values of K(syn), K(deg), K(reg) and K(age). Thereafter, scale-up of the DFP-induced AChE activity was performed from mouse to rat. Validation of the rat model was performed by comparing the time course of venous blood and brain AChE activities from a Monte Carlo analysis to those obtained in vivo. Sensitivity analysis on the verified models showed that K(reg) and K(syn) were the most influential factors of AChE activity at shorter and longer durations, respectively, after DFP challenge. Scale-up of the AChE dynamics from mouse to rat was also successful, as evidenced by significant overlapping between the predicted 95(th) percentile confidence intervals and the experimental data. PMID- 19788409 TI - Prevalence of urinary incontinence and its association with body mass index among women in Puerto Rico. AB - OBJECTIVE: Urinary incontinence (UI) affects the quality of life of millions of women world-wide. Prevalence estimates for UI range from 10% to 40%, but information on young and mid-life women, especially among Hispanics, is limited. This study estimated UI prevalence and its association with body mass index (BMI) in a population-based sample of 276 female residents of Bayamon, Puerto Rico (PR) aged 21-64 years. METHODS: A cluster sampling design was employed. Women were interviewed to gather data on sociodemographic, clinical, gynecologic, and UI characteristics. Descriptive statistics were used to characterize the study sample. Bivariate analyses of factors potentially associated with UI and BMI were conducted using generalized linear models (GLM). Multivariate GLM was used to determine the covariate adjusted association between BMI and UI. RESULTS: The prevalence of UI was 34.8% (95% confidence interval [CI]: 29.4-40.6%). Among women with UI, stress incontinence was most frequent (46.8%), followed by mixed (41.5%) and urge incontinence (11.7%). More than 45% of participants were either overweight (25 kg/m(2) or= 30 kg/m(2)). The adjusted analysis revealed that women with a BMI >or= 30 kg/m(2) had 1.96 (p = 0.06) times the probability of having UI compared to women with a BMI < 25 kg/m(2). CONCLUSIONS: UI is a public health problem among this population, and obesity marginally increases the possibility of having this condition. Public health efforts should focus on reducing obesity in PR, in order to have an impact on UI morbidity. PMID- 19788410 TI - Synthesis of model morpholine derivatives with biological activities by laccase catalysed reactions. AB - The efficient enzyme-catalysed reaction of morpholines as model structures for bioactive compounds with para-dihydroxylated aromatic systems was carried out using the oxidoreductase laccase and atmospheric oxygen to produce eight novel morpholine-substituted aromatics. The laccase of Myceliophthora thermophila was used for cross-linking morpholines containing primary or secondary amino groups with para-dihydroxylated laccase substrates. We demonstrate that not only primary amino groups, but also secondary amino groups, are able to couple with para dihydroxylated aromatic systems in laccase-catalysed reactions. The resulting model products (yields up to 80%) were isolated, structurally characterized and tested for their antibacterial, antifungal and cytotoxic activities. Four of the eight products showed low to moderate growth inhibition against several Gram positive and -negative bacterial strains and against the yeasts Candida maltosa and Candida albicans. The antibacterial and antifungal activities were determined by an agar disc diffusion test and a modified method according to the EUCAST discussion document E.Dis 7.1 [Rodriguez-Tudela et al. (2003) Clin. Microbiol. Infect. 9, i-viii] for the evaluation of MIC (minimal inhibitory concentration). Differences in cytotoxicity against the human urinary bladder carcinoma cell line 5637 are discussed. PMID- 19788411 TI - A constitutively active and uninhibitable caspase-3 zymogen efficiently induces apoptosis. AB - The caspase-3 zymogen has essentially zero activity until it is cleaved by initiator caspases during apoptosis. However, a mutation of V266E in the dimer interface activates the protease in the absence of chain cleavage. We show that low concentrations of the pseudo-activated procaspase-3 kill mammalian cells rapidly and, importantly, this protein is not cleaved nor is it inhibited efficiently by the endogenous regulator XIAP (X-linked inhibitor of apoptosis). The 1.63 A (1 A = 0.1 nm) structure of the variant demonstrates that the mutation is accommodated at the dimer interface to generate an enzyme with substantially the same activity and specificity as wild-type caspase-3. Structural modelling predicts that the interface mutation prevents the intersubunit linker from binding in the dimer interface, allowing the active sites to form in the procaspase in the absence of cleavage. The direct activation of procaspase-3 through a conformational switch rather than by chain cleavage may lead to novel therapeutic strategies for inducing cell death. PMID- 19788412 TI - Positive contribution of ERdj5/JPDI to endoplasmic reticulum protein quality control in the salivary gland. AB - In eukaryotic cells, most membrane and secretory proteins are modified post translationally in the ER (endoplasmic reticulum) for correct folding and assembly. Disulfide-bond formation is one of the important modifications affecting folding and is catalysed by the PDI (protein disulfide isomerase) family proteins. ERdj5 [also known as JPDI (J-domain-containing PDI-like protein)] is a member of the PDI family proteins and has been reported to act as a reductase in ERAD (ER-associated degradation). However, the role of ERdj5 at the whole-body level remains unclear. Therefore in the present study we generated ERdj5-knockout mice {the mouse gene of ERdj5 is known as Dnajc10 [DnaJ (Hsp40) homologue, subfamily C, member 10]} and analysed them. Although ERdj5-knockout mice were viable and healthy, the ER stress response was activated in the salivary gland of the knockout mice more than that of control mice. Furthermore, in ERdj5-knockout cells, the expression of exogenous ERdj5 mitigated the ER stress caused by overproduction of alpha-amylase, which is one of the most abundant proteins in saliva and has five intramolecular disulfide bonds. This effect was dependent on the thioredoxin-like motifs of ERdj5. Thus we suggest that ERdj5 contributes to ER protein quality control in the salivary gland. PMID- 19788413 TI - A single genetic locus in the phytopathogen Pantoea stewartii enables gut colonization and pathogenicity in an insect host. AB - Aphids are typically exposed to a variety of epiphytic and phytopathogenic bacteria, many of which have entomopathogenic potential. Here we describe the interaction between Pantoea stewartii ssp. stewartii DC283 (DC283), an enteric phytopathogen and causal agent of Stewart's wilt, and the pea aphid, Acyrthosiphon pisum. When ingested by aphids, DC283 establishes and aggregates in the crop and gut, preventing honeydew flow and excretion, resulting in aphid death in 72 h. A mutagenesis screen identified a single locus, termed ucp1 (youcannot pass), whose disruption abolishes aphid pathogenicity. Moreover, the expression of ucp1 in Escherichia coli is sufficient to mediate the hindgut aggregation phenotype by this normally avirulent species. Ucp1 is related to six other proteins in the DC283 genome, each having a common N-terminal region and a divergent C-terminus, but only ucp1 has a role in pathogenicity. Based on predicted motifs and secondary structure, Ucp1 is a membrane-bound protein that functions in bacterial adhesion and promotes the formation of aggregates that are lethal to the insect host. These results illustrate that the enteric plant pathogenic bacteria have the capacity to exploit alternative non-plant hosts, and retain genetic determinants for colonizing the gut. PMID- 19788414 TI - Microbial community dynamics in a seasonally anoxic fjord: Saanich Inlet, British Columbia. AB - Dissolved oxygen concentration plays a major role in shaping biotic interactions and nutrient flows within marine ecosystems. Throughout the global ocean, regions of low dissolved oxygen concentration (hypoxia) are a common and expanding feature of the water column, with major feedback on productivity and greenhouse gas cycling. To better understand microbial diversity underlying biogeochemical transformations within oxygen-deficient oceanic waters, we monitored and quantified bacterial and archaeal community dynamics in relation to dissolved gases and nutrients during a seasonal stratification and deep water renewal cycle in Saanich Inlet, British Columbia, a seasonally anoxic fjord. A number of microbial groups partitioned within oxygen-deficient waters including Nitrospina and SAR324 affiliated with the delta-proteobacteria, SAR406 and gamma proteobacteria related to thiotrophic gill symbionts of deep-sea clams and mussels. Microbial diversity was highest within the hypoxic transition zone decreasing dramatically within anoxic basin waters and temporal patterns of niche partitioning were observed along defined gradients of oxygen and phosphate. These results provide a robust comparative phylogenetic framework for inferring systems metabolism of nitrogen, carbon and sulfur cycling within oxygen-deficient oceanic waters and establish Saanich Inlet as a tractable model for studying the response of microbial communities to changing levels of water column hypoxia. PMID- 19788415 TI - Apoptosis and autophagy: Targeting autophagy signalling in cancer cells -'trick or treats'? AB - Macroautophagy (hereafter referred to as autophagy) is a tightly regulated lysosome-dependent catabolic pathway. During this process, cytosolic constituents are sequestered into autophagosomes, which subsequently fuse with lysosomes to become autolysosomes, where their contents are degraded. Autophagy contributes to the maintenance of the cellular energy homeostasis, to the clearance of damaged organelles and to adaptation to environmental stresses. Accordingly, autophagy defects have been linked to a wide range of human pathologies, including cancer. The recent discovery of several evolutionarily conserved genes involved in autophagosome formation has greatly stimulated the autophagy research, and the complex signalling networks regulating mammalian autophagy have begun to emerge. Here, we draw the current picture of signalling pathways connecting mitogenic and stress-induced signals to the initiation and maturation of autophagosomes and discuss the possibilities of their targeting as therapeutic adjuvants in anticancer therapy. PMID- 19788416 TI - Apoptosis and autophagy: Regulation of apoptosis by DNA damage signalling - roles of p53, p73 and HIPK2. AB - Genomic stability is constantly threatened by DNA damage, caused by numerous environmental and intrinsic sources, including radiation, chemicals and oncogene expression. Consequently, cells have evolved a sophisticated signal transduction network to sense DNA damage and to mount an appropriate DNA damage response. Dysregulation of the DNA damage response leads to genomic instability and cancer. Dependent on the cellular background and extent of DNA damage, the DNA damage response triggers cell cycle arrest and DNA repair, or in the case of irreparable damage, inactivation of the cells by senescence or apoptosis. In this minireview, we concentrate on the apoptotic response to DNA damage and signalling pathways linked to the cell nucleus and nuclear bodies, with a particular focus on the molecular players p53 and p73 and on the DNA damage-activated kinase homeodomain interacting protein kinase 2 (HIPK2). PMID- 19788417 TI - Apoptosis and autophagy: Regulation of caspase-9 by phosphorylation. AB - Cell death by the process of apoptosis plays important roles in development, tissue homeostasis, diseases and drug responses. The cysteine aspartyl protease caspase-9 plays a central role in the mitochondrial or intrinsic apoptotic pathway that is engaged in response to many apoptotic stimuli. Caspase-9 is activated in a large multimeric complex, the apoptosome, which is formed with apoptotic peptidase activating factor 1 (Apaf-1) in response to the release of cytochrome c from mitochondria. Once activated, caspase-9 cleaves and activates the effector caspases 3 and 7 to bring about apoptosis. This pathway is tightly regulated at multiple steps, including apoptosome formation and caspase-9 activation. Recent work has shown that caspase-9 is the direct target for regulatory phosphorylation by multiple protein kinases activated in response to extracellular growth/survival factors, osmotic stress or during mitosis. Here, we review these advances and discuss the possible roles of caspase-9 phosphorylation in the regulation of apoptosis during development and in pathological states, including cancer. PMID- 19788418 TI - Apoptosis and autophagy: BIM as a mediator of tumour cell death in response to oncogene-targeted therapeutics. AB - The BCL-2 homology domain 3 (BH3)-only protein, B-cell lymphoma 2 interacting mediator of cell death (BIM) is a potent pro-apoptotic protein belonging to the B cell lymphoma 2 protein family. In recent years, advances in basic biology have provided a clearer picture of how BIM kills cells and how BIM expression and activity are repressed by growth factor signalling pathways, especially the extracellular signal-regulated kinase 1/2 and protein kinase B pathways. In tumour cells these oncogene-regulated pathways are used to counter the effects of BIM, thereby promoting tumour cell survival. In parallel, a new generation of targeted therapeutics has been developed, which show remarkable specificity and efficacy in tumour cells that are addicted to particular oncogenes. It is now apparent that the expression and activation of BIM is a common response to these new therapeutics. Indeed, BIM has emerged from this marriage of basic and applied biology as an important mediator of tumour cell death in response to such drugs. The induction of BIM alone may not be sufficient for significant tumour cell death, as BIM is more likely to act in concert with other BH3-only proteins, or other death pathways, when new targeted therapeutics are used in combination with traditional chemotherapy agents. Here we discuss recent advances in understanding BIM regulation and review the role of BIM as a mediator of tumour cell death in response to novel oncogene-targeted therapeutics. PMID- 19788419 TI - Control of apoptosis and autophagy by cellular signalling pathways. PMID- 19788420 TI - A novel splicing variant form suppresses the activity of full-length signal transducer and activator of transcription 5A. AB - Signal transducers and activators of transcription (STATs) regulate a variety of cellular functions, including differentiation and proliferation. STAT3 and STAT5 are known to play important roles in brain processes, such as energy homeostasis and neuronal development. We isolated a novel splicing variant of STAT5A from a cDNA library of the mouse brainstem. This variant, STAT5A_DeltaE18, lacked exon 18 and caused a frameshift in the C-terminus, resulting in deletion of a tyrosine phosphorylation site and a transactivation domain. Although the frameshift region had no characteristic motifs, it was highly serine/threonine-rich and contained a short proline-rich sequence. Expression of STAT5A_DeltaE18 was detected in the mouse brainstem, lung and thymus, but not in the mouse cerebrum or cerebellum. We developed a specific antibody against STAT5A_DeltaE18 and investigated the intracellular localization of this variant. STAT5A_DeltaE18 showed dot-like structures in the cytoplasm and could not translocate into the nucleus after prolactin treatment. STAT5A_DeltaE18 showed a strong tendency to aggregate, which led to coaggregation with STAT5A_full-length. This coaggregation inhibited the nuclear transport of STAT5A and suppressed prolactin-induced activation of STAT5A. PMID- 19788421 TI - Rice cytosine DNA methyltransferases - gene expression profiling during reproductive development and abiotic stress. AB - DNA methylation affects important developmental processes in both plants and animals. The process of methylation of cytosines at C-5 is catalysed by DNA methyltransferases (MTases), which are highly conserved, both structurally and functionally, in eukaryotes. In this study, we identified and characterized cytosine DNA MTase genes that are activated with the onset of reproductive development in rice. The rice genome (Oryza sativa L. subsp. japonica) encodes a total of 10 genes that contain the highly conserved MTase catalytic domain. These genes have been categorized into subfamilies on the basis of phylogenetic relationships. A microarray-based gene expression profile of all 10 MTases during 22 stages/tissues that included 14 stages of reproductive development and five vegetative tissues together with three stresses, cold, salt and dehydration stress, revealed specific windows of MTase activity during panicle and seed development. The expression of six methylases was specifically/preferentially upregulated with the initiation of floral organs. Significantly, one of the MTases was also activated in young seedlings in response to cold and salt stress. The molecular studies presented here suggest a greater role for these proteins and the epigenetic process in affecting genome activity during reproductive development and stress than was previously anticipated. PMID- 19788422 TI - A superoxide dismutase-human hemoglobin fusion protein showing enhanced antioxidative properties. AB - Much of the toxicity of Hb has been linked to its redox activity; Hb may generate reactive oxygen species, such as the superoxide anion. Superoxide is intrinsically toxic, and superoxide dismutase (SOD) provides important cellular protection. However, if the Hb molecule is located outside the red blood cell, the normal protection systems involving SOD and catalase are no longer closely associated with it, exposing Hb and its cellular surroundings to oxidative damage. In order to produce less toxic Hb molecules, we have explored gene fusion to obtain homogeneous SOD-Hb conjugates. The chimeric protein was generated by coexpressing the human Hb alpha-chain/manganese SOD gene together with the beta chain gene in Escherichia coli. We show that the engineered SOD-Hb fusion protein retains the oxygen-binding capacity and, moreover, decreases cytotoxic ferrylHb (HbFe(4+)) formation when challenged with superoxide radicals. The SOD-Hb fusion protein also exhibits a 44% lower autoxidation rate and higher thermal stability than Hb alone. PMID- 19788423 TI - Trends in the prevalence of traumatic dental injuries in Brazilian preschool children. AB - OBJECTIVE: The aim of this paper was to report trends in traumatic dental injuries (TDI) in preschool children in Brazil between 2002 and 2006, and assess whether gender, family structure, and socio-economic differences in TDI are significant, and confirm the relationship between TDI and anatomic predisposing factors such as overjet and lip coverage. METHODS: Three cross-sectional surveys were conducted in 2002, 2004 and 2006 in Diadema using the same protocol. It was estimated that a minimum sample size of 778 5-59 months old children was required to achieve a level of precision with a standard error of <2% Participants were systematically selected from all children attending the National Day of Children's Vaccination carried out in the city of Diadema. The criteria used to assess TDIs were a modified version of Ellis' classification. RESULTS: There was a significant increase in TDIs between 2002 and 2006 (47.9%, P = 0.002). The prevalence of TDIs was 9.4% (95% CI 7.63, 11.42) in 2002, 12.9% (95% CI 11.06, 14.96) in 2004, and 13.9% (95% CI 12.03, 15.84) in 2006 in 5-59 months old children and the treatment of TDI was seriously neglected. There was no significant gender, family structure, and socio-economic differences in the prevalence of TDIs. The relationship between TDI and anatomic predisposing factors such as overjet, lip coverage, and anterior overbite was highly statistically significant (P < 0.01). CONCLUSION: The prevalence of TDIs in preschool children in Diadema increased between 2002 and 2006, the treatment of TDIs was neglected, thus it is crucial to generate considerable efforts to implement health promotion strategies to reverse the observed trends and to provide treatment to TDIs to prevent their biologic and psychologic consequences. PMID- 19788424 TI - Esthetic considerations for reshaping of autotransplanted premolars replacing maxillary central incisors: a case report. AB - Autotransplantation is a safe and currently common procedure in cases of agenesis and tooth loss. Autotransplantation of premolars to replace missing maxillary central incisors has been shown to be an excellent treatment choice, especially in young patients in the 9-12-year-old age range. The choice for adequate restorative materials and techniques is also essential, direct composite resin being indicated in most cases. This paper reports the case of two premolars autotransplanted to replace both maxillary central incisors and addresses the esthetic issues involved in the reshaping of these teeth to incisor morphology. PMID- 19788425 TI - Effectiveness and fabrication of mouthguards. AB - Although mouthguards have been suggested as a means for preventing dental traumatic injuries, there are still some controversies over some aspects such as effectiveness in preventing concussions, material selections, method for fabrication, design, side effects and so on. The purpose of this literature review was to clarify differences in opinions with supporting evidence on these issues and find the best guidelines for promoting usage and providing mouthguards with better protective capability and fewer side effects such as difficulty in breathing and speaking. PMID- 19788426 TI - The management of mandibular body fractures in young children. AB - This article reviews the management of mandibular body fractures in young children. Treatment principles of this fracture type differ from that of adults due to concerns regarding mandibular growth processes and dentition development. The goal of this fracture treatment is to restore the underlying bony architecture to its preinjury position in a stable fashion as non-invasively as possible and with minimal residual esthetic and functional impairment. The management of mandibular body fractures in children depends on the fracture type and the stage of skeletal and dental development; treatment modalities range from conservative non-invasive, through closed reduction and immobilization methods to open reduction with internal fixation. Disruption of the periosteal envelope of the mandibular body may have an unpredictable effect on growth. Thus, if intervention is required closed reduction is favored. PMID- 19788427 TI - Fracture of the tympanic plate with soft tissue extension into the auditory canal resulting from an unfavorable chewing experience. AB - We present a case where a patient sustained a tympanic plate fracture of the right side while chewing a sandwich. Intense pain with temporomandibular joint (TMJ) symptoms such as restrained painful mouth opening and functional pain in full occlusion followed the incident and the fracture was diagnosed after ocular and CT-examination of the right external auditory canal. Non-ruptured soft tissue could be seen protruding into the external auditory canal and the size of the mass changed during movement of the TMJ. Treatment was not needed to resolve the situation and at 3-year follow-up the patient has no clinical symptoms. PMID- 19788428 TI - Knowledge of general dentists in the current guidelines for emergency treatment of avulsed teeth and dental trauma prevention. AB - A high prevalence of dental trauma exists and its effects on function and esthetics deserve the attention of general dentists. The aim of this study was to assess the level of general dental practitioners' (GDPs) knowledge about guidelines for dental avulsion and its prevention using a questionnaire. The 21 item questionnaire was distributed among 264 GDPs and the survey was realized between August-November 2006. The data obtained were statistically analyzed using descriptive analysis and Pearson's Chi-square test to determine associations between knowledge regarding emergency treatment and dentists from public or private dental schools and years of experience. The results showed that the participants exhibited appropriate knowledge concerning procedures in cases of tooth avulsion and its prevention. The number of correct answers was low in relation to recommended treatment at the site of injury. Storage medium, preparation of the alveolus and splint time for receiving the avulsed tooth received a high number of correct answers. One statistically significant association between years of experience and recommended treatment at the site of the injury in the case an avulsed tooth (chi(2) = 9.384, P = 0.009). In conclusion, this survey showed appropriate knowledge of dental avulsion management and its prevention among the surveyed dentists. The findings also showed that communication between dentists and the population is deficient, especially concerning practitioners of high risk and contact sports. PMID- 19788429 TI - Insulin use and increased risk of mortality in type 2 diabetes: a cohort study. AB - AIM: To compare population-based rates of all-cause and cardiovascular (CV) mortality in newly treated patients with type 2 diabetes according to levels of insulin exposure. METHODS: Using the administrative databases of Saskatchewan Health, 12272 new users of oral antidiabetic therapy were identified between 1991 and 1996 and grouped according to cumulative insulin exposure based on total insulin dispensations per year: no exposure (reference group); low exposure (0 to <3); moderate exposure (3 to <12) and high exposure (> or =12). Time-varying multivariable Cox proportional hazards models were used to examine the relationship between insulin exposure and all-cause, CV-related and non-vascular mortality after adjustment for demographics, medications and comorbidities. RESULTS: Average age was 65 (s.d. 13.9) years, 45% were female, and mean follow up was 5.1 (s.d. 2.2) years. In total, 1443 (12%) subjects started insulin, and 2681 (22%) deaths occurred. The highest mortality rates were in the high exposure group; 95 deaths/1000 person-years compared with 40 deaths/1000 person-years in the no exposure group [unadjusted hazard ratio (HR): 2.32; 95% confidence interval (CI): 1.96-2.73]. After adjustment, we observed a graded risk of mortality associated with increasing exposure to insulin: low exposure [adjusted HR (aHR): 1.75; 95% CI: 1.24-2.47], moderate exposure (aHR: 2.18; 1.82-2.60) and high exposure (aHR: 2.79; 2.36-3.30); p = 0.005 for trend. Analyses restricted to CV-related (p = 0.042 for trend) and non-vascular (p = 0.004 for trend) mortality showed virtually identical results. CONCLUSIONS: We observed a significant and graded association between mortality risk and insulin exposure level in an inception cohort of patients with type 2 diabetes that persisted despite multivariable adjustment. PMID- 19788430 TI - How can structured self-management patient education improve outcomes in people with type 2 diabetes? AB - Type 2 diabetes (T2DM) is a long-term chronic condition that is complex to manage, with the majority of management being done by the person with diabetes outside of the clinical setting. Because of its complexities, effective self management requires skills, confidence and the ability to make decisions and choices about treatments and lifestyle on a day-to-day basis. Equipping a person with these self-management skills is in itself challenging and it is now widely accepted that structured education is an integral part of the management of T2DM. This paper explores whether structured self-management education can improve outcomes in people with diabetes. The authors explore what self-management education is, why it is needed and then go on to examine the recent evidence from clinical trials from 2006 onwards. PMID- 19788431 TI - Future perspectives for insulinotropic agents in the treatment of type 2 diabetes DPP-4 inhibitors and sulphonylureas. AB - The introduction of dipeptidyl-peptidase IV inhibitors (DPP-4 inhibitors) brought a novel class of insulinotropic agents into the treatment options for type 2 diabetes. This paper compares the actions, clinical efficacy and safety of sulphonylureas with those of the DPP-4 inhibitors. First, the mode of action of both classes of antidiabetic agents is described. Then clinical studies for both substances in monotherapy and combination therapies are compared concerning their effects on glycaemic parameters and long-term duration of action. Hypoglycaemia incidence and other adverse effects are compared and data on cardiovascular parameters and endpoints are summarized. The effects of sulphonylureas and DPP-4 inhibitors on beta-cell function and beta-cell mass are highlighted. The present and future indications for both sulphonylureas and DPP-4 inhibitors are discussed. PMID- 19788432 TI - Managing women with gestational diabetes mellitus in the postnatal period. AB - Guidelines for management of women with a history of gestational diabetes mellitus (GDM) in the postpregnancy period have lagged behind the recognition that this is an important time for medical intervention. However, in the past decade, the evidence-base for screening algorithms, contraceptive management, diabetes prevention strategies and implications for offspring has expanded. In this review, we discuss current recommendations for managing women with GDM in the postnatal period, with particular attention to postpartum diabetes screening, prevention of future glucose intolerance and family planning. PMID- 19788433 TI - The glucose lowering effect of an oral insulin (Capsulin) during an isoglycaemic clamp study in persons with type 2 diabetes. AB - AIM: Randomized, open, single-centre, two-way crossover study comparing the pharmacokinetic (PK) and pharmacodynamic (PD) properties of subcutaneous (sc) regular human insulin (Actrapid) and oral insulin in a capsule form (Capsulin). METHODS: Sixteen persons (12 males) with type 2 diabetes on oral hypoglycaemic agents (OHAs) participated. Mean (s.d.) age 60.2 (5.5) years, BMI 28.3 (3.4) kg/m(2), haemoglobin A(1c) (HbA(1c)) 7.4% (1.1). Two 6-h isoglycaemic glucose clamp studies were conducted 11 days apart. All subjects received in random order 12U sc Actrapid on one clamp study day and either 150U or 300U Capsulin (Cap) on the other day. Glucose infusion rates (GIRs), plasma insulin and C-peptide concentrations were determined throughout each 6-h isoglycaemic clamp. Between the clamp study days, all patients received 150U Capsulin twice daily, dropping all their standard OHAs apart from metformin. Self-monitored blood glucose (SMBG) levels were taken four times a day between the clamp study days. RESULTS: Administration of either Actrapid or Capsulin (150 and 300U) increased GIRs reaching a maximum values at approximately 280-330 min. Overall values for maximum GIR values were higher for Actrapid than either dose of Capsulin (p < 0.05). The significantly greater systemic insulin concentrations following Actrapid were reflected in the AUC(0-6 h) (910 +/- 270 vs. 472 +/- 245 pmol h/L; 950 +/- 446 vs. 433 +/- 218 pmol h/L; both p < 0.05 for Actrapid vs. 150U Capsulin and 300U Capsulin respectively). No difference was observed between 150U and 300U Capsulin. During the repeat-dosing period, good safety and tolerability were observed with Capsulin, and SMBG levels remained stable. At the poststudy visit, significant falls in HbA(1c), weight and triglycerides were observed. CONCLUSIONS: Administration of the oral insulin Capsulin preparation demonstrated a significant hypoglycaemic action over a period of 6 h associated with only a small increase in circulating plasma insulin concentrations. PMID- 19788434 TI - Rediscovering bile acid sequestrants. AB - AIM: In the recently published The Justification for the Use of statins in Primary prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) mega trial, rosuvastatin significantly reduced cardiovascular events at the expense of a small but significant increase in the risk of developing type 2 diabetes. The increased risk of new-onset diabetes was in keeping with a recent meta-analysis which suggested that statins, with the possible exception of pravastatin, marginally increase the risk of developing type 2 diabetes. METHODS: Although the net effect of rosuvastatin was obviously very positive, we hypothesized that the addition of a bile aid sequestrant to a statin would not only further decrease lipid levels and potentially further decrease cardiovascular events but also protect against the development of diabetes. This is particularly relevant because the bile acid sequestrant, colesevelam, has recently been approved for therapy of diabetes. RESULTS: Colesevelam like other bile acid sequestrants lowers low-density lipoprotein levels by 16% and C-reactive protein by 22% beyond the reductions that occur with statin therapy alone. Bile acid sequestrants confer lipid-lowering, glucose-lowering, and anti-inflammatory benefits, and have been shown to reduce risk of cardiovascular events. CONCLUSIONS: Therefore, colesevelam should be the most effective and logical agent to add to a statin in the diabetic and insulin-resistant patient, because in addition to lowering cardiac risk it may prevent the development of diabetes, as well as improving glycaemic control in the established diabetic patient. PMID- 19788435 TI - Multiple molecular targets underlie the antidiabetic effect of Nigella sativa seed extract in skeletal muscle, adipocyte and liver cells. AB - AIM: Nigella sativa (N. sativa) is a plant widely used in traditional medicine of North African countries. During the last decade, several studies have shown that extracts from the seeds of N. sativa have antidiabetic effects. METHODS: Our group has recently demonstrated that N. sativa seed ethanol extract (NSE) induces an important insulin-like stimulation of glucose uptake in C2C12 skeletal muscle cells and 3T3-L1 adipocytes following an 18 h treatment. The purpose of the present study was to elucidate the pathways mediating this insulin-like effect and the mechanisms through which these pathways are activated. RESULTS: Results from western immunoblot experiments indicate that in C2C12 cells as well as in H4IIE hepatocytes, but not in 3T3-L1 cells, NSE increases activity of Akt, a key mediator of the effects of insulin, and activity of AMP-activated protein kinase (AMPK), a master metabolic regulating enzyme. To test whether the activation of AMPK resulted from a disruption of mitochondrial function, the effects of NSE on oxygen consumption were assessed in isolated liver mitochondria. NSE was found to exhibit potent uncoupling activity. CONCLUSION: Finally, to provide an explanation for the effects of NSE in adipocytes, PPARgamma stimulating activity was tested using a reporter gene assay. Results indicate that NSE behaves as an agonist of PPARgamma. The data supports the ethnobotanical use of N. sativa seed oil as a treatment for diabetes, and suggests potential uses of this product, or compounds derived thereof, against obesity and the metabolic syndrome. PMID- 19788436 TI - Toxicity and outcomes after chemoradiation for esophageal cancer in patients age 75 or older. AB - Randomized trials of chemoradiation for esophageal cancer have included very few patients age > or = 75. In this retrospective study, we describe the outcomes and toxicity of full-dose chemoradiation in elderly patients with esophageal cancer. Patients, age > or = 75, treated with full-dose chemoradiation for esophageal carcinoma from 2002 to 2008 were retrospectively reviewed. Thirty-four patients were identified with a median age of 79.5 (range 75-89). The median Eastern Cooperative Oncology Group performance status was 1 (range 0-3) and the median Adult Comorbidity Evaluation-27 score was 1 (range 0-3). Twenty-eight patients received definitive and six received neoadjuvant chemoradiation. The median radiation dose delivered was 50.4 Gray (range 3.6-68.4 Gray). Platinum-based chemotherapy was used in 79.4% of patients. Fifty percent of the patients completed all planned radiation therapy (RT) and chemotherapy; 85.3% completed RT. Acute toxicity > or = grade 4 occurred in 38.2% of patients, and 70.6% of the patients required hospitalization, emergency department visit, and/or RT break. Median follow-up was 14.5 months among 7 survivors, and median survival was 12.0 months (95% confidence interval [CI]: 9.7 to 24.1 months). The actuarial overall survival at 2 years was 29.7% (95% CI: 16.6 to 52.6%). There were four treatment related deaths. The median time to any recurrence was 10.4 months. Nineteen patients had a local and/or distant recurrence. In conclusion, elderly patients experienced substantial morbidity from chemoradiation, and long-term survival was low. Future efforts to improve treatment tolerability in the elderly are needed. PMID- 19788437 TI - Expression of FOXP3 in esophageal squamous cell carcinoma relating to the clinical data. AB - Forkhead box protein 3 (FOXP3) has been studied as a biomarker in many human malignancies recently. But in esophageal squamous cell carcinoma (ESCC) the studies are limited. In this study, expression of FOXP3 in ESCC tissue was evaluated in relation to the clinical data. Detection of FOXP3 mRNA was made by using quantitative real-time PCR while protein expression was assessed by immunocytochemistry (n = 112). The results were correlated to the clinical data including age, gender, carcinoma size, carcinoma differentiation, lymphatic invasion and pathological stage. A significantly higher FOXP3 expression in tumors was confirmed than in normal-appearing mucosa. The FOXP3 mRNA and protein expressions were higher in advanced stages (stage II B and III) than in early stages (stage I and stage II A). A significantly higher FOXP3 expression in tumors with lymph node metastasis was also confirmed than in those without lymph node metastasis. No significant correlation was found in age, gender, carcinoma size, or carcinoma differentiation. These results suggest that expression of FOXP3 was higher in ESCC tissue and was closely correlated to lymphatic invasion and pathological stage. It may imply that FOXP3 might play an important role in esophageal carcinoma progression. PMID- 19788438 TI - Time trends of endoscopic and pathological diagnoses related to gastroesophageal reflux disease in a Chinese population: eight years single institution experience. AB - The discrepancy between Eastern and Western countries exists regarding the time trends of Barrett's esophagus (BE)/adenocarcinoma. We aimed to elucidate this issue through a retrospective review of the endoscopic and pathological diagnoses of gastroesophageal reflux disease (GERD) over time in a Chinese population. All records were analyzed from 2000 to 2007. Records included demographic data, clinical indication for endoscopy, and endoscopic findings. The total number of endoscopic procedures increased over time. The indications for referral endoscopy secondary to GERD increased from 366 cases (4.9%) in the beginning of the study to 1439 cases (14.1%) at the end. Concomitant GERD symptoms did not significantly change (range, 13-15.1%) in screening endoscopic studies. Endoscopic detection of erosive esophagitis increased in referral populations from 1546 (20.7%) to 5207 cases (51%) and by screening endoscopy from 791 (14.5%) to 1983 cases (23.5%). The prevalence of nonerosive reflux disease and BE did not change over time. BE associated dysplasia and adenocarcinoma were rare. The detection of Los Angeles class A disease increased with time in referral endoscopy cases with a focus on erosive esophagitis composition. The endoscopic demand for GERD investigation and the GERD endoscopic diagnosis increased in our population. The results were related to a higher prevalence of low-grade erosive disease diagnosed. The incidence of BE-associated dysplasia and adenocarcinoma has been the same and the increased screening did not detect more cancers. PMID- 19788439 TI - A pilot study of fully covered self-expandable metal stents prior to neoadjuvant therapy for locally advanced esophageal cancer. AB - Self-expandable metal stents (SEMS) have been mostly reserved for palliation of dysphagia because of advanced esophageal cancer. Fully covered SEMS (FCSEMS) (ALIMAXX-E, Alveolus Inc, Charlotte, NC, USA) offer the choice of removability if complications occur or maximum therapeutic benefit is achieved. To our knowledge, their use has not been studied in patients undergoing neoadjuvant therapy. The objectives of this study were the following: (i) to evaluate whether FCSEMS are useful in patients receiving neoadjuvant therapy; and (ii) to assess ease of removability and tissue reaction to FCSEMS. FCSEMS (ALIMAXX-E, Alveolus Inc) were deployed in consecutive patients with locally advanced esophageal cancer over a period of 14 months. All patients were referred for neoadjuvant chemoradiation therapy after stenting. Dysphagia scores were assessed at 0 month, 1 month, 3 months, and 6 months. Barium swallow and endoscopy were performed for new symptoms and follow-up. Eleven patients were treated with FCSEMS prior to neoadjuvant therapy (mean age 60.5 years, 55% white, 91% male). All but one stent were successfully placed. Strictures were located in the upper esophagus (n= 1), middle esophagus (n= 4), lower esophagus (n= 2), and gastroesophageal junction (n= 4). Dysphagia was significantly improved at 1 month (mean difference 3.12; 2.53-3.79 95% confidence interval [CI]), 3 months (mean difference 2.86, 2.19 3.53 95% CI), and 6 months (mean difference 2.56, 1.79-3.34 95% CI) compared with baseline. Three patients (27%) experienced chest pain or heartburn immediately following deployment. Only two patients ultimately underwent surgical resection. The others were diagnosed with metastatic disease prior to surgery, had disease progression in spite of neoadjuvant treatment, or died with the stent in place. Three patients developed delayed complications: recurrent dysphagia (n= 2) and tracheal-esophageal fistula (n= 1). Eight (73%) stents were subsequently removed, one because of complication (tracheal-esophageal fistula), one because of migration (recurrent dysphagia), one was incorrectly deployed, and five were felt to have satisfied their purpose. Stents remained in place for a mean duration of 100.36 days (range 0-105, median 84). Removal was characterized as very easy in all cases. Upon removal, ulcerations at the proximal or distal edge of stents were noted in six patients (75%), polyps in four (50%), and granulation in six (75%). One stent (13%) became embedded but was easily lifted from tissue. There were no perforations. Neoadjuvant treatment may have contributed to improvement in dysphagia scores. FCSEMS can be used to re-establish esophageal luminal patency in patients undergoing neoadjuvant therapy for locally advanced esophageal cancer, resulting in significant improvement in dysphagia over baseline. Tissue reaction to stents occurs but does not appear to impair removability. PMID- 19788440 TI - Prospective randomized controlled study on the effects of perioperative administration of a neutrophil elastase inhibitor to patients undergoing video assisted thoracoscopic surgery for thoracic esophageal cancer. AB - Sivelestat sodium hydrate (Ono Pharmaceutical Co., Osaka, Japan) is a selective inhibitor of neutrophil elastase (NE) and is effective in reducing acute lung injury associated with systemic inflammatory response syndrome (SIRS). We conducted a prospective randomized controlled study to investigate the efficacy of perioperative administration of sivelestat sodium hydrate to prevent postoperative acute lung injury in patients undergoing thoracoscopic esophagectomy and radical lymphadenectomy. Twenty-two patients with thoracic esophageal cancer underwent video-assisted thoracoscopic esophagectomy with extended lymph node dissection in our institution between April 2007 and November 2008. Using a double-blinded method, these patients were randomly assigned to one of two groups preoperatively. The active treatment group received sivelestat sodium hydrate intravenously for 72 hours starting at the beginning of surgery (sivelestat-treated group; n= 11), while the other group received saline (control group; n= 11). All patients were given methylprednisolone immediately before surgery. Postoperative clinical course was compared between the two groups. Two patients (one in each group) were discontinued from the study during the postoperative period because of surgery-related complications. Of the remaining 20 patients, 2 patients who developed pneumonia within a week after surgery were excluded from some laboratory analyses, so data from 18 patients (9 patients in each group) were analyzed based on the arterial oxygen pressure/fraction of inspired oxygen ratio, white blood cell count, serum C-reactive protein level, plasma cytokine levels, plasma NE level, and markers of alveolar type II epithelial cells. In the current study, the incidence of postoperative morbidity did not differ between the two groups. The median duration of SIRS in the sivelestat-treated group was significantly shorter than that in the control group: 17 (range 9-36) hours versus 49 (15-60) hours, respectively (P= 0.009). Concerning the parameters used for the diagnosis of SIRS, the median heart rates on postoperative day (POD) 2 were significantly lower in the sivelestat-treated group than in the control group (P= 0.007). The median arterial oxygen pressure/fraction of inspired oxygen ratio of the sivelestat-treated group were significantly higher than those of the control group on POD 1 and POD 7 (POD 1: 372.0 [range 284.0-475.0] vs 322.5 [243.5-380.0], respectively, P= 0.040; POD 7: 377.2 [339.5-430.0] vs 357.6 [240.0-392.8], P= 0.031). Postoperative white blood cell counts, serum C-reactive protein levels, plasma interleukin-1beta, tumor necrosis factor-alpha levels, and plasma NE levels did not differ significantly between the two groups at any point during the postoperative course, nor did serum Krebs von den Lungen 6, surfactant protein-A, or surfactant protein-D levels, which were used as markers of alveolar type II epithelial cells to evaluate the severity of lung injury. Plasma interleukin-8 levels were significantly lower in the sivelestat-treated group than in the control group on POD 3 (P= 0.040). In conclusion, perioperative administration of sivelestat sodium hydrate (starting at the beginning of surgery) mitigated postoperative hypoxia, partially suppressed postoperative hypercytokinemia, shortened the duration of SIRS, and stabilized postoperative circulatory status after thoracoscopic esophagectomy. PMID- 19788441 TI - Expression of survivin and human telomerase reverse transcriptase in extramammary Paget's disease. AB - BACKGROUND: Extramammary Paget's disease (EMPD) is a rare neoplasm of apocrine gland-bearing skin. It is known that over-expression of survivin and human telomerase reverse transcriptase (hTERT) correlates with malignancies. We investigated the expression of hTERT and survivin by Paget's cells and their role in the tissue invasion and recurrence of EMPD. METHOD: Forty-two patients were enrolled into the study. Expression of survivin and hTERT were analyzed by immunohistochemistry and in situ hybridization techniques. The variables including the expression level of survivin and hTERT, gender, age, lesion location, invasion level and number of surgeries were statistically analyzed using Fisher's exact test. RESULTS: Survivin was positively stained in 18 of 22 cases (81.8%), and hTERT in 18 of 29 cases (62.1%). Significantly higher level of survivin expression was detected in patients with multiple surgeries than those with single one (p = 0.0458). Expression of hTERT was significantly higher in the patients with micro-invasive and invasive lesions than those with non-invasive lesions (p = 0.0478). CONCLUSIONS: Over-expression of survivin and hTERT correlated strongly with recurrence and local invasion of EMPD lesions. EMPD has male gender predominance in Oriental population. PMID- 19788442 TI - Immunohistochemical techniques to compare primary vs. metastatic mucinous carcinoma of the skin. AB - BACKGROUND: Primary and metastatic mucinous carcinomas in skin are histologically indistinguishable. Immunohistochemical panels help differentiate primary and metastatic adenocarcinoma of skin, but data regarding mucinous carcinoma is scant. METHODS: We stained five primary mucinous carcinomas, two mucinous carcinomas metastatic to skin and five primary breast and colon mucinous carcinomas with p63, CD15, CK5/6, CK7, CK20, calponin and D2-40 to identify patterns that might differentiate primary from metastatic disease. We also searched for myoepithelial cells in all cases. RESULTS: All cases of primary mucinous carcinoma of the skin were positive for CK7, 40% showed rare cells labeled for p63 and 20% of cases labeled focally for CK5/6. The breast mucinous carcinomas metastatic to the skin were negative for all markers except CK7, although 60% of primary breast carcinomas labeled for p63. Colon mucinous carcinoma labeled only for CK20. CONCLUSIONS: In a small subset of mucinous carcinomas (20% in this series), positive labeling for CK5/6 indicated primary cutaneous tumor. Staining with p63 also favored primary over metastatic disease. Myoepithelial cell layers were not consistently identified to enable the identification of primary disease. PMID- 19788443 TI - Blimp-1: a marker of terminal differentiation but not of sebocytic progenitor cells. AB - BACKGROUND: The role of stem cells in maintaining the sebaceous gland throughout the various stages of life is not satisfactorily resolved. In a recent article, the transcription factor B lymphocyte-induced maturation protein 1 (Blimp-1) was proposed as a marker of a population of unipotent progenitor cells that reside in the sebaceous gland, regulating its size and activity. METHODS: We used standard immunohistochemical methods to examine Blimp-1 expression in samples from embryonic, fetal and adult human skin and in 119 sebaceous lesions comprising all major categories of sebocytic lineage, including hamartomas, cysts and benign and malignant neoplasms. RESULTS: Blimp-1 is expressed late in embryonic development and is restricted to the evolving sebaceous gland, the terminally differentiating components of the hair follicle and nail organ and the granular layer. This pattern is preserved into adult life. In all sebaceous lesions, Blimp-1 labels only the most mature cellular constituents. CONCLUSIONS: The reported expression pattern is difficult to reconcile with a function of Blimp-1 as a marker for sebocytic progenitor cells but indicates a major role in terminal differentiation. Within the interfollicular epidermis, its exclusive localization to the granular layer suggests a central function in skin barrier homeostasis in the human. PMID- 19788444 TI - Oncogenic BRAF and the tumor suppressor IGFBP7 in the genesis of atypical spitzoid nevomelanocytic proliferations. AB - Rare reports indicate that the frequency of BRAFV600E mutations is high in atypical Spitz nevi. The purpose of this study was to ascertain the utility of the RAF/RAS mutational status as a diagnostic adjunct in lesions with histologic features that deviate from a typical Spitz nevus and, to examine expression of Insulin growth factor binding protein 7 (IGFBP7), a tumor suppressor acting through autocrine/paracrine pathways to inhibit BRAF-MEK-ERK signaling, in the same. Genomic DNA for genotyping was isolated from 6 regular Spitz nevi and 14 atypical spitzoid nevomelanocytic proliferations (including 1 melanoma with spitzoid histomorphology). NRAS1, NRAS2 and KRAS were analyzed, in addition to BRAFV600E. A mutation in BRAFV600E was noted in only one case-that of a regular Spitz nevus. IGFBP7 expression appeared to be maintained in this case, but was absent in 7/17 cases, which included 5 atypical spitzoid nevomelanocytic proliferations. Lack of expression of IGFBP7 in atypical spitzoid nevomelanocytic proliferations with histologically concerning features but BRAF-WT indicates that the evolutionary path in atypical spitzoid nevomelanocytic proliferations is genetically distinct from that of IGFBP7-negative BRAF-positive melanoma. From an oncogenic BRAF perspective, our findings suggest that the majority of 'atypical' spitzoid nevomelanocytic proliferations are probably no different from conventional Spitz nevi. PMID- 19788445 TI - Myxofibrosarcoma mimicking cutaneous myxoma. PMID- 19788446 TI - IMP-3 expression in melanocytic lesions. AB - BACKGROUND: Insulin-like growth factor-II mRNA-binding protein 3 (IMP-3 ), a member of the insulin-like growth factor mRNA-binding protein family, is expressed in several human malignancies, including melanomas. However, the expression of IMP-3 has not been explored in melanoma in situ, various histologic subtypes of invasive melanomas and atypical Spitz tumors. METHODS: IMP-3 immunostain was performed in 157 melanocytic lesions. RESULTS: Nearly all benign (8/8), dysplastic (8/8) and Spitz nevi (8/9) were negative for IMP-3. Focal IMP-3 positivity was observed in 5/12 melanoma in situ and 4/15 superficial melanomas (Breslow depth 1 mm) and 25/52 metastatic melanomas demonstrated strong IMP-3 staining. IMP-3 expression differs significantly between non-desmoplastic melanomas (superficial and deep) and benign or dysplastic or Spitz nevi (p = 0.0427, respectively). Four of 23 desmoplastic melanomas expressed IMP-3 , which was significantly different from deep melanomas (p = 0.0109). IMP-3 stained 7 of 10 atypical Spitz tumors. The difference between atypical Spitz tumors and Spitz nevi was statistically significant (p = 0.0256). CONCLUSION: A malignant circumstance, such as non desmoplastic melanoma or atypical Spitz tumor, can be inferred when IMP-3 is expressed, suggesting potential diagnostic value of IMP-3 in melanocytic lesions. PMID- 19788447 TI - A case of porocarcinoma arising in pigmented hidroacanthoma simplex with multiple lymph node, liver and bone metastases. AB - Porocarcinoma is a rare skin appendage carcinoma that may arise de novo or be associated with pre-existing poroma and hidroacanthoma simplex (HAS). Here, we report a case of porocarcinoma arising in pigmented HAS, which led to death from multiple lymph node, liver and bone metastases. A 72-year-old Japanese man presented with a brown to focal black flat plaque, measuring 17 * 12 mm, on the posterior region of his right thigh. Histopathological study of the tumor revealed that there was intraepidermal proliferation of small-sized basaloid cells, and it exhibited the 'Jadassohn phenomenon', with dendritic melanocytes, and a few ductal structures were observed. Continuing to the intraepidermal nests, the invasive proliferation of large polygonal cells with occasional intracytoplasmic ductal structures was observed. Carcinoembryonic antigen and epithelial membrane antigen were expressed in some carcinoma cells and they highlighted the intracytoplasmic ductal structures. Multiple lymph node, liver and bone metastases were observed, and the patient died 8 months after the initial surgery. Clinical diagnosis of HAS is extremely rare. Porocarcinoma may be associated with pre-existing HAS and sometimes shows aggressive behavior. Therefore, pigmented HAS must be included in the differential diagnosis of brown or black lesions. Ishida M, Hotta M, Kushima R, Okabe H. A case of porocarcinoma arising in pigmented hidroacanthoma simplex with multiple lymph node, liver and bone metastases. PMID- 19788448 TI - Intraoperative blood salvage and leukocyte depletion during liver transplantation with bacterial contamination. AB - BACKGROUND: Bacterial contamination is considered to be a contraindication for intraoperative blood salvage (IBS) during OLT. The aims of this study were to evaluate the efficiency of the autotransfusion device with an additional leukocyte depletion filter (LDF) for eliminating bacterial contaminations, and its clinical outcomes in terms of post-operative infections during OLT. METHODS: Forty-five patients with end-stage liver disease and cirrhotic ascites were enrolled in this study. The blood from the surgical field was collected and processed by an autotransfusion device (Cell Saver 5) and a LDF for bacteriological analysis. Among them, 12 patients with chronic severe hepatitis B received autologous transfusion for analysis of the effect on post-operative infections. RESULTS: Spontaneous bacterial peritonitis (SBP) (p < 0.05, OR = 20.1) and a long duration of operation (p < 0.01, OR = 8.3) were found to be critical risk factors for contamination. Autotransfusion devices with an additional LDF significantly eliminated bacterial contaminants from shed blood (p < 0.05). About 33% (4/12) of the patients who received autologous transfusion with salvaged and filtered erythrocytes got post-operative bacterial infection. CONCLUSIONS: Autotransfusion devices with an additional LDF could significantly eliminate bacterial contaminants of shed blood during OLT. The new mode of IBS might be a good option in reducing post-operative infections, and deserves a large-scale clinical trial. PMID- 19788449 TI - Physical training effects in renal transplant recipients. AB - INTRODUCTION: Several studies demonstrated the benefits of rehabilitation in uraemic patients. This study evaluates physical and psychosocial effects of exercise on renal transplant recipients (RTRs). PATIENTS AND METHODS: Eight RTRs were evaluated before and after an exercise training consisting of thirty 40 minute sessions, three times a week, performed with the interval training technique. RESULTS: Hospital Anxiety and Depression Scale (HADS) significantly decreased (p<0.04 and <0.008, respectively). Quality of life mean scores (SF-36 test) significantly increased (p<0.000). No differences were recorded for muscle and fat mass, maximal explosive power of the lower limbs, alkaline and acid phosphatase, parathormone (PTH), myoglobin, lipoprotein-A, glomerular filtration rate (GFR), at rest heart rate, and cardiac troponin. IL-6 decreased from 2.8+/ 0.6 to 1.7+/-0.5 pg/mL (p<0.01). Resting MAP fell from 112+/-4 to 99+/-3 mmHg (p<0.02). The metabolic threshold rose from 33+/-4 to 43+/-5% (p<0.033). The blood lactate level at peak exercise increased from 5.2+/-0.9 to 6.2+/-0.7 mmol/L (p<0.012). The maximum oxygen uptake increased from 1200+/-210 to 1359+/-202 mL/min (p<0.05), iso-load oxygen uptake decreased from 1110+/-190 to 1007+/-187 mL/min (p<0.034). The maximum working capacity increased from 90+/-14 to 115+/-15 watts (p<0.000). CONCLUSION: This study suggests that an appropriate dose of physical training is a useful, safe and non-pharmacologic contribution to RTR treatment. PMID- 19788450 TI - Comparison of nutritional status in hemodialysis patients with and without failed renal allografts. AB - BACKGROUND: The survival of patients returning to hemodialysis (HD) following kidney transplant failure is unfavorable. However, the factors responsible for this poor outcome are largely unknown; chronic inflammation due to failed allograft and malnutrition may contribute to morbidity and mortality. We aimed to compare the nutritional status and its relation with inflammation in patients on HD with and without previous kidney transplantation. METHODS: Forty-three patients with failed renal allografts (27 males; mean age 36+/-9 yr) and 40 never transplanted HD patients (24 males; mean age 39+/-9 yr) were included in the study. Body weight, triceps (TSF), biceps (BSF), subscapular (SSSF), and suprailiac skinfold thicknesses (SISF); mid-arm, mid-arm muscle, hip and waist circumferences; as well as body mass indices (BMIs) were determined as anthropometric parameters. Moreover, biochemical markers of nutritional status, including serum cholesterol and albumin as well as high-sensitive C-reactive protein (hs-CRP), as a marker of inflammation, were measured. Associations among these variables were analyzed. RESULTS: There were no significant differences considering age, gender or duration of renal replacement therapy between the two groups. The TSF (p<0.0001), BSF (p=0.005), SSSF (p=0.001), SISF (p<0.0001) skinfold thicknesses; mid-arm (p=0.003) and mid-arm muscle circumferences (p=0.037) and BMIs (p=0.001) of the patients with failed renal allografts were significantly lower than those of the never transplanted HD patients. Waist circumference was significantly lower as well (p=0.028). Patients with failed transplants were characterized by lower serum albumin (p<0.0001) and higher hs CRP levels (p=0.001) as compared with never transplanted HD patients. CONCLUSIONS: This study confirms the concept that retained failed allografts may induce chronic inflammation in chronic HD patients which may result in a worse nutritional status. PMID- 19788451 TI - Family initiated discussions about organ donation at the time of death. AB - Some family members initiate organ donation discussions before being approached by donor coordinators or healthcare providers. We examined differences between families that did vs. did not initiate organ donation discussions and factors predicting donation consent among those families that self-initiated the discussion. Next-of-kin of donor-eligible individuals (147 donors, 138 non donors) from one organ procurement organization completed a telephone interview. Seventy-three families (25.6%) first mentioned organ donation, and 54 (74%) of them consented to donation. Several characteristics of the deceased and next-of kin were associated with whether family members initiated the donation discussion with donation coordinators or healthcare providers. Moreover, family mention of donation was more likely to yield consent when the deceased was younger (OR=0.95, CI=0.92-0.99), next-of-kin was a registered donor (OR=3.86, CI=2.84-6.76), and when family was more satisfied with the healthcare team (OR=1.20, CI=1.04-1.39). Knowing the deceased's donation intentions and being exposed to positive organ donation messages are more likely to trigger families to raise donation with providers. Organ procurement organizations (OPOs) and healthcare providers should work collaboratively to develop strategies for how best to respond to families who initiate this conversation. PMID- 19788453 TI - Liver support 2009: time for another revolution? PMID- 19788454 TI - Hemodynamic effects of albumin dialysis in patients with liver failure: for better or for worse? AB - Liver failure, irrespective of is cause, is frequently associated with multi organ dysfunction, including hemodynamic instability, and renal and cerebral insufficiency. As a result of the combined impact of these complications, liver failure carries an exceptionally high risk of mortality. A central role in the etiopathogenesis of different end-organ manifestations, as well as in the aggravation of the underlying liver failure, has been attributed to the hyperdynamic (hypotensive) state, which is characterized by a reduced systemic vascular resistance and mean arterial pressure, as well as an increased cardiac index, heart rate, and total plasma volume. Since the accumulation of toxins due to the decreased detoxification capacity by the failing liver is considered vital herein, the emergence of extracorporeal liver support has provided a rational basis for the potential reversal of these phenomena. The present article critically reviews data with regard to the hemodynamic effects of artificial liver support in the context of liver failure. Although these are scarce for acute liver failure, several uncontrolled series and small randomized trials have clearly documented that artificial liver support is able to improve both portal hypertension and the associated systemic circulatory dysfunction in patients with acute-on-chronic liver failure. The molecular basis for these effects have been related to temporary changes and/or elimination in endogenous vasoactive substances, improved albumin binding capacity, or restoration of oxidative stress mediated damage to albumin. PMID- 19788455 TI - Albumin dialysis molecular adsorbents recirculating system: impact of dialysate albumin concentration on detoxification efficacy. AB - Albumin dialysis with the molecular adsorbent recirculating system (MARS) or single pass albumin dialysis (SPAD) uses human serum albumin (HSA) as an addendum of the dialysate fluid. The purpose of this in vitro study was to evaluate the impact of the dialysate albumin concentration on removal efficacy. Heparinized human plasma (3 L/test) was spiked with creatinine (1000 mg/L), unconjugated bilirubin (100 mg/L), chenodeoxycholic acid (CDCA) (100 mg/L), and diazepam (3 mg/L). The MARS albumin circuit was primed with different amounts of HSA (150, 100, 60, and 40 g). The plasma, albumin, and dialysate flow rates were 200, 200, and 40 mL/min, respectively. Clearances were calculated based on repeated sampling during the experiments, which lasted 480 min. The effective HSA concentrations in the dialysate were 175, 115, 77, and 46 g/L, respectively. They decreased over treatment time to 147, 99, 63, and 41 g/L, respectively, due to surface adsorption. The plasma-HSA concentration remained unchanged over time in all experiments (average 39 g/L). The creatinine clearance was not impacted by dialysate HSA concentration. For the albumin-bound markers a clear correlation between HSA-concentration and clearance was demonstrated with the highest clearances for the 100 and 150 g HSA experiments. The 100 g HSA setup appeared to be the one with best cost-benefit ratio, resulting in clearances (after 1 h of treatment) of 31 mL/min creatinine, 0.3 mL/min unconjugated bilirubin, 11 mL/min CDCA, and 35 mL/min diazepam. Low albumin concentrations, such as in SPAD, result in low clearance rates for albumin-bound substances. The optimal clearances in these experiments were reached with a priming dose of 100 g HSA. PMID- 19788456 TI - Early molecular adsorbents recirculating system treatment of Amanita mushroom poisoning. AB - Acute poisoning due to ingestion of hepatotoxic Amanita sp. mushrooms can result in a spectrum of symptoms, from mild gastrointestinal discomfort to life threatening acute liver failure. With conventional treatment, Amanita phalloides mushroom poisoning carries a substantial risk of mortality and many patients require liver transplantation. The molecular adsorbent recirculating system (MARS) is an artificial liver support system that can partly compensate for the detoxifying function of the liver by removing albumin-bound and water-soluble toxins from blood. This treatment has been used in acute liver failure to enable native liver recovery and as a bridging treatment to liver transplantation. The aim of the study is to evaluate the outcome of 10 patients with Amanita mushroom poisoning who were treated with MARS. The study was a retrospectively analyzed case series. Ten adult patients with accidental Amanita poisoning of varying severity were treated in a liver disease specialized intensive care unit from 2001 to 2007. All patients received MARS treatment and standard medical therapy for mushroom poisoning. The demographic, laboratory, and clinical data from each patient were recorded upon admission. The one-year survival and need for liver transplantation were documented. The median times from mushroom ingestion to first-aid at a local hospital and to MARS treatment were 18 h (range 14-36 h) and 48 h (range 26-78 h), respectively. All 10 patients survived longer than one year. One patient underwent a successful liver transplantation. No serious adverse side-effects were observed with the MARS treatment. In conclusion, MARS treatment seems to offer a safe and effective treatment option in Amanita mushroom poisoning. PMID- 19788457 TI - Predictive criteria for the outcome of patients with acute liver failure treated with the albumin dialysis molecular adsorbent recirculating system. AB - The aim of this study was to evaluate the improvement of prognostic parameters after treatment with the molecular adsorbent recirculating system (MARS) in patients with fulminant hepatitis (FH). The parameters conducive to a positive prognosis include: Glasgow Coma Scale (GCS) score >/=11, intracranial pressure (ICP) <15 mm Hg or an improvement of the systolic peak flow of 25-32 cm/s via Doppler ultrasound in the middle cerebral artery, lactate level <3 mmol/L, tumor necrosis factor-alpha <20 pg/mL, interleukin (IL)-6 <30 pg/mL, and a change in hemodynamic instability from hyperkinetic to normal kinetic conditions, and so define the timing (and indeed the necessity) of a liver transplant (LTx). From 1999 to 2008 we treated 45 patients with FH with MARS in the intensive care unit of our institution. We analyzed all the parameters that were statistically significant using univariate analysis and considered the patients to be candidates for inclusion in a multivariate logistic regression analysis. Thirty six patients survived: 21 were bridged to liver transplant (the BLT group) and 15 continued the extracorporeal method until native liver recovery (the NLR group) with a positive resolution of the clinical condition. Nine patients died before transplantation due to multi-organ failure. We stratified the entire population into three different groups according to six risk factors (the percentage reduction of lactate, IL-6 and ICP, systemic vascular resistance index values, GCS <9, and the number of MARS treatments): group A (0-2 risk factors), group B (3-4 risk factors), and group C (5-6 risk factors). Analyzing the prevalence of these parameters, we noted that group A perfectly corresponded to the NLR group, group B corresponded to the BLT group, and group C was composed of patients from the non-survival group; thus, we were able to select the patients who could undergo a LTx using the predictive criteria. For patients with an improvement of neurological status, cytokines, lactate, and hemodynamic parameters, LTx was no longer necessary and their treatment continued with MARS and standard medical therapy. PMID- 19788458 TI - Is it possible to gain extra waiting time to liver transplantation in acute liver failure patients using albumin dialysis? AB - Hepatic encephalopathy (HE)-associated brain edema is a common cause of death in acute liver failure (ALF). Molecular Adsorbent Recirculating System (MARS) albumin dialysis detoxifies endogenous and exogenous toxins from blood and improves HE. In this study we assessed the effect of MARS on increasing the length of time available while waiting for liver graft. Thirty-seven patients with ALF who received a high-urgent liver transplant (LTx) were divided into three groups according to the amount of histological necrosis in the explanted liver: group I = 100% necrosis; group II = 80-99% necrosis; group III = less than 80% necrosis. MARS was used continuously until LTx. Median time (range) on MARS treatment prior to LTx in groups I-III was 7 days (2-26), 6 days (1-17), and 5 days (1-15), and the median time on the waiting list was 5 days (1-11), 3 days (0 13), and 1 day (0-12), respectively. The HE grade prior to and after MARS was similar in all groups. In two patients the HE grade decreased during MARS treatment, even though the explanted liver showed a complete lack of viable cells. Overall 30-day and one-year survival were 97% and 92%, respectively, without differences between the three groups. In ALF patients the liver cell damage progressed to total or near total necrosis of the liver when the waiting time was prolonged. Yet, with MARS treatment some patients with total hepatic necrosis showed an absence of encephalopathy. With MARS treatment some patients might be able to wait longer for a LTx with good results. PMID- 19788459 TI - Albumin dialysis in liver failure: comparison of molecular adsorbent recirculating system and single pass albumin dialysis--a retrospective analysis. AB - Despite improvement in critical care, liver failure is still associated with high mortality. Therapeutic concepts are aimed at restoring endogenous liver function or to bridge the time to liver transplantation. In addition to standard medical treatment, extracorporeal liver support with albumin dialysis is used for this purpose. The aim of this study was to analyze the efficacy of single pass albumin dialysis (SPAD) in comparison to the molecular adsorbent recirculating system (MARS) in patients treated at our university hospital intensive care unit between July 2004 and August 2008. In this retrospective analysis we studied patients presenting with liver failure who were treated with albumin dialysis. Laboratory parameters, daily health scoring, the number of transfusions, and mortality were recorded. The (paired) t-test, Mann-Whitney U-test, and Wilcoxon test were used for statistical analysis. In all, 163 albumin dialysis treatments, 126 with MARS and 37 with SPAD, in 57 patients were performed. MARS resulted in a significant decrease in bilirubin (-38 +/- 66.5 micromol/L from a baseline of 301 +/- 154.6 micromol/L), gamma-glutamyltransferase (gamma-GT), alanine aminotransferase, creatinine, and urea. SPAD resulted in a significant decrease in bilirubin (-41 +/- 111.2 micromol/L from a baseline of 354 +/- 189.4 micromol/L) and gamma-GT, while lactate levels increased. No differences in the need for blood transfusion, health scoring, or mortality between the two treatment modalities were detected. This retrospective analysis suggests equal efficacy of MARS and SPAD; however, prospective assessment to further define the role of SPAD in the treatment of acute or acute-on-chronic liver failure is needed. PMID- 19788460 TI - Extracorporeal liver support therapy with Prometheus in patients with liver failure in the intensive care unit. AB - Acute liver failure (ALF) and acute-on-chronic liver failure (AoCLF) are associated with a high mortality. In these patients an accumulation of both water soluble and water-insoluble, protein-bound, metabolic waste products occurs. Conventional extracorporeal blood purification techniques based on diffusion and/or convection such as hemodialysis or hemofiltration may only eliminate small molecular weight, water-soluble compounds. In recent years, fractionated plasma separation and adsorption (FPSA) with the Prometheus system has been introduced for extracorporeal liver support therapy. To date, however, only limited data is available regarding the effect of this treatment on mortality and outcome of patients with advanced liver disease. Here we report on our experience with 23 patients with severe liver failure who were treated with Prometheus in our medical intensive care unit. Fourteen patients had AoCLF, and nine patients experienced ALF. The median bilirubin level at the start of Prometheus therapy was 30.5 mg/dL and the median Acute Physiology and Chronic Health Evaluation II (APACHE II) score was 26. During 40 individual treatment sessions lasting 5-6 h, Prometheus therapy reduced serum bilirubin levels from 23.7 mg/dL to 15.0 mg/dL (median values) (P < 0.001), and the overall survival was 26%. ALF patients had a better survival compared to AoCLF patients (44% vs. 22%; P = 0.022). Apart from one patient who developed hemodynamic instability during a treatment session, Prometheus therapy was well tolerated without relevant side-effects. In conclusion, extracorporeal liver support therapy with Prometheus is a novel and safe treatment option in patients with severe liver failure. In this series, patients with ALF showed a significantly better outcome with Prometheus therapy compared to AoCLF patients. PMID- 19788461 TI - Effect of extracorporeal liver support by molecular adsorbents recirculating system and Prometheus on redox state of albumin in acute-on-chronic liver failure. AB - Oxidative stress is believed to play an important role in acute-on-chronic liver failure (AoCLF). Albumin, an important transport vehicle, was found to be severely oxidized in AoCLF patients. Extracorporeal liver support systems may exert beneficial effects in AoCLF via removal of albumin-bound toxins. At present, two systems are commercially available, the molecular adsorbents recirculating system (MARS) and fractionated plasma separation, adsorption and dialysis (FPAD, also known as Prometheus). The aim of this study was to compare the effect of MARS and Prometheus treatments on the redox state of human serum albumin. Eight patients with AoCLF underwent alternating treatments with either MARS or Prometheus in a randomized cross-over design. Sixteen treatments (eight MARS and eight Prometheus) were available for analysis. The fraction of human mercaptalbumin (HMA), human nonmercaptalbumin-1 (HNA1), and human nonmercaptalbumin-2 (HNA2) were measured before and after single MARS and Prometheus treatments and during follow-up. In AoCLF patients the oxidized fractions of albumin, HNA1, and HNA2 were markedly increased. Both MARS and Prometheus treatments resulted in a shift of HNA1 to HMA, while HNA2 was not significantly affected. This shift in albumin fractions was transient and disappeared within 24 h after treatment. There were no significant differences between MARS and Prometheus treatments with respect to the redox state of albumin. Both MARS and Prometheus treatments lead to transient improvements of the redox state of albumin, which could be beneficial in the treatment of AoCLF. PMID- 19788462 TI - Increase of octanoate concentrations during extracorporeal albumin dialysis treatments. AB - Extracorporeal liver support procedures based on albumin dialysis require the use of pharmaceutical-grade human serum albumin (HSA). Those preparations contain octanoate, which is added as stabilizer during the production process. For octanoate, a direct involvement in the pathogenesis of liver failure complications as well as an indirect influence by competitive displacement effects at the albumin molecule have been described. During five Single Pass Albumin Dialysis (SPAD) and three Molecular Adsorbent Recirculating System (MARS) treatments the changes of octanoate concentrations in blood and dialysate were investigated. An octanoate increase in patient blood was observed during passage of the filter for both SPAD (585 micromol/L [338-1022 micromol/L]) (median [range]) and MARS (182 micromol/L [71-437 micromol/L]) during the first three hours of treatment. The molar ratio of octanoate/albumin at the blood outflow was significantly higher during SPAD treatments (1.73 [0.86-2.64] vs. 0.54 [0.31 1.1]; P = 0.001) during MARS. Changes of octanoate blood levels during SPAD were significantly higher than during MARS (P < 0.001). The shift of octanoate from the dialysate to the patient was persistent during SPAD (median 67.6 micromol/min), whereas during MARS a decrease over time was observed (from 25.5 to 7.5 micromol/min). During albumin dialysis procedures a transfer of octanoate into patient blood occurs. The time-course and extent are different between both albumin dialysis procedures. Given the positive clinical effects reported mainly for MARS, the clinical impact of albumin dialysis-associated transfer of octanoate during extracorporeal liver support needs to be evaluated further. PMID- 19788464 TI - Peritoneal clearance and transport of procalcitonin. PMID- 19788463 TI - Safety evaluation for a cell-based immune support system in an ex vivo rat model of gram-negative sepsis. AB - Granulocyte dysfunction is a central component of immunodeficiency in septic patients. Granulocyte transfusions appear to be pathophysiologically useful; however, they cause unwanted side-effects in the lungs and other organs. This study evaluates the safety of an extracorporeal immune support system with granulocytic cells in a rat model of Gram-negative sepsis. Three groups of male CD rats received either saline (control group, I), a dose of Escherichia coli O7:K1 lethal to 90% of the animals (LD90) (septic group, II), or an LD90 dose of E. coli that was incubated with the human promyelocytic leukemia cell line (HL 60) (differentiated into the granulocytic direction) for 20 min prior to infusion (second septic group, III). The animals were observed for seven days. Pre treatment with HL-60 cells resulted in no adverse effects in the group III animals. Significantly lower bacterial counts and endotoxin levels in the plasma were detected after 24 h as compared to group II (P < 0.05). Group III animals had better weight gain and more stable hemodynamics than group II animals (P < 0.01). Seven day survival was 0/8 in group II, 6/8 in group III, and 8/9 in group I (log-rank test: II-III: P < 0.001). The data suggest that extracorporeal use of granulocytes allows the therapeutic use of these cells while avoiding unwanted effects resulting from direct contact to internal organs. PMID- 19788465 TI - Cascade filtration in the therapy of the dry form of age-related macular degeneration. PMID- 19788468 TI - Elevated saliva calcitonin gene-related peptide levels during acute migraine predict therapeutic response to rizatriptan. AB - OBJECTIVES: (1) To measure calcitonin gene-related peptide (CGRP) levels in the saliva of individuals with migraine during the premonitory period, mild headache, moderate to severe headache, and post-resolution phases as compared with baseline (interictal) CGRP levels. (2) To correlate response to rizatriptan administered during moderate headache with levels of CGRP levels measured in saliva. BACKGROUND: CGRP is implicated in the underlying pathophysiology of migraine. To date no study has measured changes of saliva CGRP through the clinical evolution of a migraine attack and correlated saliva CGRP levels to clinical response to therapy. METHODS: Data were summarized using tables and descriptive statistics. Statistical analysis was performed with the non-parametric signed-rank test using Minitab15 statistical software. Results of statistical analyses were considered significant at P < .05. Responding subjects were defined as those who were symptom free at the time of the last collected saliva sample and did not have to rescue. Non-responding subjects were defined as those who rescued with an additional dose of rizatriptan or another medication or who were not symptom free at the end of the collection period. RESULTS: Statistically significant elevations of CGRP were noted in the premonitory, mild headache, and moderate to severe headache phase of the migraine compared with baseline (interictal) levels. A better therapeutic response to rizatriptan was observed in subjects with elevated saliva CGRP levels. Successful treatment with rizatriptan correlated with saliva CGRP levels returning to near baseline levels. In the rizatriptan non responder group, no significant change in saliva CGRP levels was found at any phase of the migraine attack. CONCLUSIONS: Elevation of saliva CGRP is predictive of responsiveness to rizatriptan. In the rizatriptan responsive population, CGRP levels are elevated beginning with the premonitory period and throughout mild and moderate/severe headache. Successful response to rizatriptan correlated with return of saliva CGRP levels to near baseline (interictal) values. PMID- 19788469 TI - PTSD, combat injury, and headache in Veterans Returning from Iraq/Afghanistan. AB - OBJECTIVE: To examine the relationship between posttraumatic stress disorder, combat injury, and headache in Operation Iraqi Freedom and Operation Enduring Freedom veterans at the VA San Diego Healthcare System. BACKGROUND: Previous investigations suggest that a relationship between posttraumatic stress disorder and primary headache disorders exists and could be complicated by the contribution of physical injury, especially one that results in loss of consciousness. These associations have not been systematically examined in Operation Iraqi Freedom and Operation Enduring Freedom veterans. METHODS: In this observational cross-sectional study, a battery of self-report, standardized questionnaires was completed by 308 newly registered veterans between March and October 2006. The Davidson Trauma Scale was used to determine the degree of posttraumatic stress disorder symptoms and combat-related physical injury was assessed by self-report. The presence of headache was based on a symptom checklist measure and self-reported doctor diagnoses. Logistic regression analysis was performed to predict presence of headache and determine odds ratios and 95% confidence intervals associated with demographic, military, in-theatre, and mental health characteristics. RESULTS: About 40% of the veterans met the criteria for posttraumatic stress disorder; 40% self-reported current headache, 10% reported a physician diagnosis of migraine, 12% a physician diagnosis of tension-type headache, and 6% reported both types of headache. Results from the logistic regression model indicated that combat-related physical injury (odds ratio: 2.25; 95% confidence interval: 1.17-4.33) and posttraumatic stress disorder (odds ratio: 4.13; 95% confidence interval: 2.44-6.99) were independent predictors of self-reported headache. Additional analyses found that veterans with both tension and migraine headache had higher rates of posttraumatic stress disorder (chi-square [d.f. = 3] = 15.89; P = .001) whereas veterans with migraine headache alone had higher rates of combat-related physical injury (chi-square [d.f. = 9] = 22.00; P = .009). CONCLUSION: Posttraumatic stress disorder and combat-related physical injury were related to higher rates of self-reported headache in newly returning veterans. Our finding that posttraumatic stress disorder and injury during combat are differentially related to migraine and tension-type headache, point to a complex relationship between physical and psychological trauma and headache. These findings have implications for a comprehensive approach to interventions for headache and the physical and psychological sequelae of trauma. PMID- 19788470 TI - Variation in almotriptan effectiveness according to different prophylactic treatments. AB - OBJECTIVE: To evaluate the effect of different migraine prophylaxis medications on subject responsiveness to almotriptan. BACKGROUND: There is evidence supporting an increase of responsiveness of symptomatic medications for migraine attacks by some prophylactic treatments although this has not been probed. METHODS: A total of 345 patients (230 women, mean age 37.3) with episodic or chronic migraine were classified according to the prophylaxis they were taking in the following groups: (1) no prophylactic medication; (2) propranolol; (3) topiramate; (4) flunarizine. Decrease in Analogical Visual Scale and pain-free at 2 hours after almotriptan intake was assessed at 2 months. Side effects and discontinuation or treatment were also assessed. RESULTS: Headache severity was reduced 4.2 in control group, 5.3 in propranolol group, 4.1 in topiramate group, and 4.0 in flunarizine group, whereas pain-free status was achieved in 37.3%, 48.7%, 36.1%, and 38.1% respectively. These two parameters were statistically significative between propranolol and control groups. Side effects were similar in all groups. CONCLUSIONS: Our results displayed a higher efficacy of almotriptan in propranolol group and we hypothesized it may be due to a common mechanism of action at serotoninergic receptors. PMID- 19788471 TI - Safety and tolerability of short-term preventive frovatriptan: a combined analysis. AB - OBJECTIVE: To assess the safety and tolerability profile of the 5-HT(1B/1D) agonist frovatriptan (Frova(R), Endo Pharmaceuticals Inc., Chadds Ford, PA, USA) when used as a 6-day regimen for the short-term prevention of menstrual migraine scheduled over multiple perimenstrual periods. BACKGROUND: Two randomized controlled trials have established the efficacy of a 6-day regimen of frovatriptan for reducing the incidence and severity of menstrual migraine over 1 to 3 perimenstrual periods; long-term data are needed to further assess the safety and tolerability profile of this regimen. METHODS: Two multinational trials were included in the analysis: Study 1 was a randomized, placebo controlled double-blind parallel trial (3 perimenstrual periods treated) with an open-label extension (3 additional perimenstrual periods treated), and Study 2 was a long-term (12 perimenstrual periods treated over 12-15 months) open-label study. Enrolled women experienced menstrual migraine defined as predictable migraine attacks that started -2 days to +3 (Study 1) or +4 (Study 2) days relative to the first day of menses and that occurred in at least 2 out of 3 menstrual cycles. Frovatriptan or placebo was given 2 days before anticipated menstrual migraine and continued for 6 days. Adverse events, serious adverse events, vital signs, cardiovascular events, electrocardiograms, and laboratory parameters were assessed and recorded periodically and summarized using descriptive statistics. Adverse event data from Study 1 and Study 2 were compared using event rates. RESULTS: The demographic characteristics of the 2 study populations were similar: the mean age was approximately 38 years, > or =94% of participants were white, and 85% reported menstrual migraine began on days -2 to +1 of the menstrual cycle. The mean reported history of menstrual migraine was approximately 11 years. A large percentage of the respective safety populations completed each study or study period: 87% (362/416) and 88% (273/309) completed the double-blind period and open-label periods of Study 1, respectively, and 59% (308/525) completed treatment of 12 perimenstrual periods in Study 2. Major reasons for discontinuation in Study 1 included adverse events (5%, double-blind period) and "other" (10% double-blind period and 5% open-label period). In Study 2, major reasons for discontinuation included patient request (17.3%) and adverse event (10.2%). The most common treatment emergent adverse events in the double blind period of Study 1 (placebo vs frovatriptan twice daily) were upper respiratory infection (9% vs 9%), nausea (6% vs 8%), dizziness (7% vs 7%), fatigue (4% vs 7%), dysmenorrhea (3% vs 7%), influenza (3% vs 6%), neck pain (4% vs 6%), and migraine (4% vs 4%). With the exception of migraine (which was reported using a different method in each study), prevalence rates for Studies 1 and 2 were numerically similar. The most frequently reported cardiovascular adverse events during double-blind treatment (placebo vs frovatriptan twice daily) were chest discomfort (2% and 3%), chest pain (2% and 2%), and hypertension (0 and 2%). The corresponding adverse event rates in Study 2 were 2% (chest pain), 3% (chest discomfort), and 3% (hypertension). In both studies, most adverse events were of mild or moderate intensity and their incidence numerically declined with each perimenstrual period/cycle, as did the incidence of menstrual migraine. The observed rate of intercurrent migraine in Study 2 over 12 perimenstrual periods was 1.5 per month, compared with 1.7 at baseline. There was no observable increase in the first occurrence of migraine in the 5 days following the perimenstrual period, indicating a lack of rebound headache. CONCLUSIONS: During treatment of up to 12 perimenstrual periods over a 12- to 15 month period, the safety and tolerability of frovatriptan for short-term prevention of menstrual migraine was similar to that observed with acute use of triptans. Adverse events were generally mild or moderate in severity, there was no evidence of an increased risk of cardiovascular adverse events relative to acute treatment, and rebound headache was not evident. A short-term regimen with frovatriptan presents a safe and viable treatment option for preventing predictable migraine such as menstrual migraine. PMID- 19788472 TI - Zolmitriptan nasal spray in the acute treatment of cluster headache: a meta analysis of two studies. AB - OBJECTIVE: To conduct an individual subject meta-analysis of available controlled studies of zolmitriptan nasal spray in the acute treatment of cluster headache. BACKGROUND: Two double-blind, placebo-controlled, randomized, crossover studies of zolmitriptan nasal spray in the acute treatment of cluster headache, with similar patient populations, protocol designs, doses, and clinical endpoints have been published. METHODS: In both double-blind studies, each patient was to treat 3 attacks, 1 with placebo, 1 with zolmitriptan 5 mg, and 1 with zolmitriptan 10 mg in a randomized, crossover manner. Headache intensity was rated on a 5-point scale (none to very severe). The primary endpoint was headache relief at 30 minutes post dose: reduction from moderate, severe, or very severe pain to mild or none. A multilevel, random-effects, logistic regression model was used to analyze the data. RESULTS: A total of 121 patients (100 male; 64.5% with episodic cluster headache) provided efficacy data for at least 1 attack. Zolmitriptan 5 mg and 10 mg were significantly more effective at providing headache relief at 30 minutes post treatment than placebo (odds ratio 3.48; 95% confidence interval 1.49-8.10 and odds ratio 8.68; 95% confidence interval: 3.35-22.5, respectively). For episodic cluster headache, response rates were 35.6%, 51.7%, and 73.7% for placebo, zolmitriptan 5 mg (odds ratio 2.5; P = .06 vs placebo), and 10 mg (odds ratio 9.9; P < .001 vs placebo), respectively. For chronic cluster headache, response rates were 17.2%, 41.9%, and 40.7% for placebo, zolmitriptan 5 mg (odds ratio 8.1; P = .035), and 10 mg (odds ratio 7.6; P = .046), respectively. Zolmitriptan was well tolerated in both studies with no serious adverse events reported. CONCLUSION: Zolmitriptan nasal spray at a dose of 5 mg and 10 mg is efficacious in the acute treatment of episodic and chronic cluster headache. PMID- 19788473 TI - Allodynia in migraine: association with comorbid pain conditions. AB - BACKGROUND: Cutaneous allodynia (CA) in migraine is a clinical manifestation of central nervous system sensitization. Several chronic pain syndromes and mood disorders are comorbid with migraine. In this study we examine the relationship of migraine-associated CA with these comorbid conditions. We also evaluate the association of CA with factors such as demographic profiles, migraine characteristics, and smoking status that may have an influence on the relationships of CA to pain and mood. METHODS: Data are from a cross-sectional multicenter study of comorbid conditions in persons seeking treatment in headache clinics. Diagnosis of migraine was determined by a physician based on the International Classification of Headache Disorders-II criteria. Participants completed a self-administered questionnaire ascertaining sociodemographics, migraine-associated allodynia, physician-diagnosed comorbid medical and psychiatric disorders, headache-related disability, current depression, and anxiety. RESULTS: A total of 1413 migraineurs (mean age = 42 years, 89% women) from 11 different headache treatment centers completed a survey on the prevalence of comorbid conditions. Aura was reported by 38% and chronic headache by 35% of the participants. Sixty percent of the study population reported at least one migraine-related allodynic symptom, 10% reported > or =4 symptoms. Symptoms of CA were associated with female gender, body mass index, current smoking, presence of aura, chronic headaches, transformed headaches, severe headache-related disability, and duration of migraine illness from onset. The prevalence of self reported physician diagnosis of comorbid pain conditions (irritable bowel syndrome, chronic fatigue syndrome, fibromyalgia) and psychiatric conditions (current depression and anxiety) was also associated with symptoms of CA. Adjusted ordinal regression indicated a significant association between number of pain conditions and severity of CA (based on symptom count). Adjusting for sociodemographics, migraine characteristics, and current depression and anxiety, the likelihood of reporting symptoms of severe allodynia was much higher in those with 3 or more pain conditions (odds ratio = 3.03, 95% confidence interval: 1.78 5.17), and 2 pain conditions (odds ratio = 2.67, 95% confidence interval: 1.78 4.01) when compared with those with no comorbid pain condition. CONCLUSION: Symptoms of CA in migraine were associated with current anxiety, depression, and several chronic pain conditions. A graded relationship was observed between number of allodynic symptoms and the number of pain conditions, even after adjusting for confounding factors. This study also presents the novel association of CA symptoms with younger age of migraine onset, and with cigarette smoking, in addition to confirming several previously reported findings. PMID- 19788475 TI - Stress and migraine. PMID- 19788476 TI - Menstrual migraine. PMID- 19788477 TI - Feeding tubes and dysphagia: cause or effect in head and neck cancer patients. PMID- 19788478 TI - History, heresy and radiology in scientific discovery. AB - Nowadays, most drugs reach the market after research has established their pharmacology, safety and efficacy. That was not always the case 50 years ago. Thalidomide was used before its target cell or mode of action were known. Commencing with the thalidomide catastrophe--an epidemic of gross birth defects (1958-1962)--thalidomide's origins are revisited to show how this drug came to be made and sold in the 1950s. Thalidomide intersected with Australian radiology in the 1970s. The site and mode of action of the drug was deduced from X-rays of thalidomide-induced bone defects, which have classical radiological signs of sensory neuropathic osteoarthropathy. The longitudinal reduction deformities follow the distribution of segmental sensory innervation of the limb skeleton, indicating neural crest as the target organ. Injury to one level of neural crest halts normal neurotrophism and deletes the dependent segment--a previously unrecognised embryonic mechanism that explains most non-genetic birth defects. The final common pathway is neural crest injury and failure of normal neurotrophism to result in longitudinal reduction deformities, for example, phocomelia. PMID- 19788479 TI - Invasive breast cancers detected by screening mammography: a detailed comparison of computer-aided detection-assisted single reading and double reading. AB - To compare double reading plus arbitration for discordance, (currently best practice, (BP)) with computer-aided-detection (CAD)-assisted single reading (CAD R) for detection of invasive cancers detected within BreastScreen Australia. Secondarily, to examine characteristics of cancers detected/rejected using each method. Mammograms of 157 randomly selected double-read invasive cancers were mixed 1:9 with normal cancers (total 1569), all detected in a BreastScreen service. Cancers were detected by two readers or one reader (C2 and C1 cancers, ratio 70:30%) in the program. The 1569 film-screen mammograms were read by two radiologists (reader A (RA) and reader B(RB)), with findings recorded before and after CAD. Discordant findings with BP were resolved by arbitration. We compared CAD-assisted reading (CAD-RA, CAD-RB) with BP, and CAD and arbitration contribution to findings. We correlated cancer size, sensitivity and mammographic density with detection methods. BP sensitivity 90.4% compared with CAD-RA sensitivity 86.6% (P = 0.12) and CAD-RB 94.3% (P = 0.14). CAD-RB specificity was less than BP (P = 0.01). CAD sensitivity was 93%, but readers rejected most positive CAD prompts. After CAD, reader's sensitivity increased 1.9% and specificity dropped 0.2% and 0.8%. Arbitration decreased specificity 4.7%. Receiving operator curves analysis demonstrated BP accuracy better than CAD-RA, borderline significance (P = 0.07), but not CAD-RB. Secondarily, cancer size was similar for BP and CAD-R. Cancers recalled after arbitration (P = 0.01) and CAD-R (P = 0.10) were smaller. No difference in cancer size or sensitivity between reading methods was found with increasing breast density. CAD-R and BP sensitivity and cancer detection size were not significantly different. CAD-R specificity was significantly lower for one reader. PMID- 19788480 TI - The Royal Australian and New Zealand College of Radiologists (RANZCR) relative value unit workload model, its limitations and the evolution to a safety, quality and performance framework. AB - The study reports on the evolution of the Australian radiologist relative value unit (RVU) model of measuring radiologist reporting workloads in teaching hospital departments, and aims to outline a way forward for the development of a broad national safety, quality and performance framework that enables value mapping, measurement and benchmarking. The Radiology International Benchmarking Project of Queensland Health provided a suitable high-level national forum where the existing Pitman-Jones RVU model was applied to contemporaneous data, and its shortcomings and potential avenues for future development were analysed. Application of the Pitman-Jones model to Queensland data and also a Victorian benchmark showed that the original recommendation of 40,000 crude RVU per full time equivalent consultant radiologist (97-98 baseline level) has risen only moderately, to now lie around 45,000 crude RVU/full-time equivalent. Notwithstanding this, the model has a number of weaknesses and is becoming outdated, as it cannot capture newer time-consuming examinations particularly in CT. A significant re-evaluation of the value of medical imaging is required, and is now occurring. We must rethink how we measure, benchmark, display and continually improve medical imaging safety, quality and performance, throughout the imaging care cycle and beyond. It will be necessary to ensure alignment with patient needs, as well as clinical and organisational objectives. Clear recommendations for the development of an updated national reporting workload RVU system are available, and an opportunity now exists for developing a much broader national model. A more sophisticated and balanced multidimensional safety, quality and performance framework that enables measurement and benchmarking of all important elements of health-care service is needed. PMID- 19788481 TI - Comparison of paper print and soft copy reading in plain paediatric radiographs. AB - With the introduction of a Picture Archiving and Communication System, Computed (CR) and Digital Radiography (DR), reading digital images takes place from a computer screen. Laser paper print rather than laser film would be a significantly more cost-effective option for hard copy production, but would need to demonstrate acceptable diagnostic quality compared to the reference standard of screen reading. A comparative study of 51 digital paediatric CR radiographs presented in laser paper print and soft copy format to determine the diagnostic value of the paper print when compared to the reference standard of screen reading. Chest radiography had a poor sensitivity of 66.1% while musculoskeletal and abdominal radiography had acceptable sensitivities of 90% and 99%, respectively. Specificity was excellent for the different regions (98.6-99.5%). The paper print format should not be used for diagnostic purposes in paediatric chest radiography, but may still be used for demonstration when accompanied by the radiology rapport obtained from soft copy reading. Further studies would be needed to investigate the use of paper prints in abdominal and musculoskeletal radiography owing to the low number of abdominal radiographs and lack of musculoskeletal case variety in our study. PMID- 19788482 TI - Metastatic cutaneous malignant melanoma: spectrum of imaging findings and the role of multimodality imaging. AB - Cutaneous malignant melanoma is one of the most lethal and widely metastasising cancers with unpredictable pathways of spread. One of the most significant factors associated with survival in patients who have distant metastases is the number of organ sites involved. Innovative treatment options are now available for metastatic melanoma, and diagnostic imaging has become crucial for accurate staging and restaging of disease. The objective of this pictorial review is to illustrate the imaging spectrum of metastatic cutaneous malignant melanoma including both the common and the relatively ubiquitous sites of involvement using both conventional cross-sectional and metabolic molecular imaging. This review also highlights the importance of combining multiple imaging methods for accurate staging of metastatic melanoma. PMID- 19788483 TI - Imaging of ovarian teratomas: appearances and complications. AB - Ovarian teratomas are the most common germ cell neoplasm. Subtypes of teratoma include mature cystic, immature and the monodermal teratomas. The benign cystic teratoma shows typical imaging manifestations and can be complicated by torsion, rupture and uncommonly malignant degeneration. Uncommon subtypes of teratomas include the immature, which is usually malignant at diagnosis. The growing teratoma syndrome is an uncommon complication reported in patients treated for immature teratomas. The monodermal teratomas which include the struma ovarii may also have specific imaging characteristics that should be recognised on imaging. This paper aims to provide a comprehensive review describing the spectrum of imaging findings of these ovarian tumours and associated complications. PMID- 19788484 TI - Vertebroplasty in the management of traumatic burst fractures: a case series. AB - This study aimed to assess the role of percutaneous vertebroplasty (VP) in the management of acute traumatic burst fractures. We describe three cases where percutaneous VP was carried out for traumatic non-osteoporotic burst vertebral fractures. For clinical symptoms and the effect of the VP procedure to be assessed, all patients completed a visual analogue scale and a mobility score before the procedure and at day 1 and 3 months post procedure. Improvements in both pain and mobility scores immediately post procedure were seen in all patients, and these results persisted at 3-month follow up. Percutaneous VP provided a successful, minimally invasive treatment of these patients' traumatic fractures while avoiding major surgical procedures and associated surgical morbidity and complications. PMID- 19788486 TI - Prophylactic gastrostomy tubes for patients receiving radical radiotherapy for head and neck cancers: a retrospective review. AB - Patients undergoing radical radiotherapy for head and neck cancers often experience significant complications. We sought to evaluate the impact of prophylactic gastrostomy tubes (PGTs) among these patients on four easily evaluable adverse outcomes, namely, absolute weight loss, percentage weight loss, admissions for nutritional reasons and treatment interruptions. A retrospective review was carried out on patients undergoing radical radiotherapy for primary head and neck cancers from September 1999 to October 2005 at the Wellington Blood and Cancer Centre (n = 71). PGTs were placed in 7 (10%) patients. Patients with PGTs were compared with the patients without PGTs (the control group) by univariate and multivariate analyses. By univariate analysis, there was no significant difference in absolute or percentage weight loss between those with PGTs and the control group. By multivariate analysis, those with PGTs lost 5.2% (P = 0.016) less weight than the control group. There were no significant differences between the two groups with regard to admissions for nutritional reasons or treatment interruptions. The use of PGTs can reduce weight loss in patients undergoing radical radiotherapy for head and neck cancers, and its use should be further evaluated in future studies. PMID- 19788487 TI - The effect of an intensive nutritional program on daily set-up variations and radiotherapy planning margins of head and neck cancer patients. AB - This is a prospective case-control study to assess nutritional supplementation in limiting weight loss and its impact on daily set-up variations and planning target volume (PTV) margins in head and neck (H&N) radiotherapy (RT). Twenty sequential H&N patients were recruited for this study. Ten patients had a percutaneous endoscopic gastrostomy (PEG) tube inserted prior to RT and 10 did not. PEG use was determined by departmental guidelines for patients considered at high risk for weight loss. Daily 2D electronic portal images were taken for orthogonal verification. Set-up variations were determined for both PEG and non PEG patients by calculating systematic (Sigma) and random (sigma) errors, and PTV margins were derived. PEG patients lost less weight (P = 0.04) over the course of RT and had a reduction in set-up variation in the superior-inferior (SI) and anterior-posterior (AP) planes compared to those without. Mean correctional shifts in mm (range) for PEG patients were: Right-Left (RL) 0.1 (-1.9-2.1), SI 1.7 (-2.9-0.0), AP -0.4 (-2.0-0.8), and for non-PEG patients were: RL -0.2 (-2.7 1.3), SI -1.3 (-3.1-1.0), AP 0.4 (-1.5-2.8). The adapted PTV margins (mm) in the RL, SI and AP planes, respectively, for PEG patients were 4.1, 3.3 and 3.6, and for non-PEG were 3.9, 4.9 and 4.8. Intensive enteral support maintained weight stability in H&N patients considered at risk of weight loss during RT and this was associated with reduced set-up variation. PMID- 19788488 TI - Geographic miss in radiation oncology: have we missed the boat? PMID- 19788490 TI - Laparoscopic peritoneal lavage for perforated colonic diverticulitis: a systematic review. AB - AIM: This systematic review aimed to evaluate the efficacy, morbidity and mortality of laparoscopic peritoneal lavage for patients with perforated diverticulitis. METHOD: We searched PubMed, EMBASE, Web of Science, the Cochrane Library and CINAHL databases, Google Scholar and five major publisher websites without language restriction. All articles which reported the use of laparoscopic peritoneal lavage for patients with perforated diverticulitis were included. RESULTS: Two prospective cohort studies, nine retrospective case series and two case reports reporting 231 patients were selected for data extraction. Most (77%) patients had purulent peritonitis (Hinchey III). Laparoscopic peritoneal lavage successfully controlled abdominal and systemic sepsis in 95.7% of patients. Mortality was 1.7%, morbidity 10.4% and only four (1.7%) of the 231 patients received a colostomy. CONCLUSION: There have been no publications of high methodological quality on laparoscopic peritoneal lavage for patients with perforated colonic diverticulitis. The published papers do, however, show promising results, with high efficacy, low mortality, low morbidity and a minimal need for a colostomy. PMID- 19788491 TI - Intestinal pseudo-obstruction in patient affected by multiple sclerosis: case report. PMID- 19788492 TI - Role of enterocele in the obstructed defecation syndrome (ODS): a new radiological point of view. AB - AIM: The aim of this study was to understand the role of enterocele in the pathogenesis of the obstructed defecation syndrome (ODS) a new defecographic classification based on function. METHOD: A total of 597 patients (551 women, 46 men) who underwent cinedefecography between November 2001 and November 2005 were studied. A total of 567 (95%) underwent cinedefecography as they had symptoms of ODS. Enterocele was classified into three types. RESULTS: Enterocele was found in 127 (23%) female and one (2.2%) male patients. Thirty-eight (6.9%) patients had type A, 38(6.9%) type B, and 27(4.9%) type C enterocele. A total of 24 patients (4.35%) had sigmoidocele. In patients with type C enterocele, the finding of a radiological pattern of ODS was higher (26/27) than that in the other groups (A + B + Sigmoidocele) (23/100) (P < 0.001). An obstructed evacuation pattern was found in 49 (38.5%) patients with enterocele and in 148 (34.9%) patients in the control group. CONCLUSION: Type C enterocele is often associated with a radiological pattern of ODS and usually presents as an isolated condition. Type B is less frequently associated with ODS and is more frequently accompanied by other pathological conditions. PMID- 19788493 TI - Laparoscopic ventral rectopexy for internal rectal prolapse: short-term functional results. AB - OBJECTIVE: Over the last 15 years, posterior rectopexy, which causes rectal autonomic denervation, was discredited for internal rectal prolapse because of poor results. The condition became medical, managed largely by biofeedback. We aimed to audit the short-term functional results of autonomic nerve-sparing laparoscopic ventral rectopexy (LVR) for internal rectal prolapse. METHOD: Prospectively collected data on LVR for internal rectal prolapse were analysed. End-points were changes in bowel function (Wexner Constipation Score and Fecal Incontinence Severity Index) at 3 and 12 months. Analysis was performed using Mann-Whitney U-test for unpaired data and Wilcoxon signed rank test for paired data (two-sided p-test). Functional outcomes were compared with those achieved previously for external rectal prolapse (ERP). RESULTS: Seventy-five patients underwent LVR (median age 58, range 25-88 years, median follow up was 12 months). Mortality (0%), major (0%) and minor morbidity (4%) were acceptably low. Median length of stay was 2 days. Preoperative constipation (median Wexner score 12) and faecal incontinence (median FISI score 28) improved significantly at 3 months (Wexner 4, FISI 8, both P < 0.0001) and 12 months (Wexner 5, FISI 8, both P < 0.0001). No patient had worse function. Functional outcomes were similar to those for ERP. CONCLUSION: Laparoscopic ventral rectopexy for internal rectal prolapse improves symptoms of obstructed defaecation and faecal incontinence in the short term. This establishes proof of concept for a nerve-sparing surgical treatment for internal rectal prolapse. PMID- 19788494 TI - Differential activation of the HCO(3)(-) conductance through the cystic fibrosis transmembrane conductance regulator anion channel by genistein and forskolin in murine duodenum. AB - BACKGROUND AND PURPOSE: Many cystic fibrosis (CF)-associated mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) anion channels affect CFTR-activated HCO(3)(-) transport more than Cl(-) transport. Targeting the CFTR HCO(3)(-) conductance, if possible, may therefore be of major therapeutic benefit. In the present study, we examined the effects of genistein and forskolin on duodenal mucosal HCO(3)(-) and Cl(-) secretion. EXPERIMENTAL APPROACH: Murine duodenal mucosal HCO(3)(-) and Cl(-) secretions were examined in vitro in Ussing chambers by the pH stat and short circuit current (I(sc)) techniques. KEY RESULTS: Genistein markedly stimulated duodenal HCO(3)(-) secretion and I(sc) in a dose-dependent manner in CFTR wild-type mice, but not in CFTR null mice. CFTR(inh)-172, a highly specific CFTR inhibitor, inhibited genistein-stimulated duodenal HCO(3)(-) secretion and I(sc) in wild-type mice. Genistein induced 59% net HCO(3)(-) increase and 123% net I(sc) increase over basal value, whereas forskolin, an activator of adenylate cyclase, induced 94% net HCO(3)(-) increase and 507% net I(sc) increase, indicating that, compared with forskolin, genistein induced a relatively high HCO(3)(-)/I(sc) ratio. Further data showed that CFTR HCO(3)(-)/Cl(-) conductance ratio was 1.05 after genistein stimulation, whereas after forskolin stimulation, the CFTR HCO(3)(-)/Cl(-) conductance ratio was 0.27. CONCLUSIONS AND IMPLICATIONS: Genistein stimulates duodenal HCO(3)(-) and Cl(-) secretion through CFTR, and has a relatively high selectivity for the CFTR HCO(3)(-) conductance, compared with forskolin. This may indicate the feasibility of selective targeting of the HCO(3)(-) conductance of the CFTR channels. PMID- 19788495 TI - Differential actions of ethanol and trichloroethanol at sites in the M3 and M4 domains of the NMDA receptor GluN2A (NR2A) subunit. AB - BACKGROUND AND PURPOSE: Alcohol produces its behavioural effects in part due to inhibition of N-methyl-d-aspartate (NMDA) receptors in the CNS. Previous studies have identified amino acid residues in membrane-associated domains 3 (M3) and 4 (M4) of the NMDA receptor that influence ethanol sensitivity. In addition, in other alcohol-sensitive ion channels, sedative-hypnotic agents have in some cases been shown to act at sites distinct from the sites of ethanol action. In this study, we compared the influence of mutations at these sites on sensitivity to ethanol and trichloroethanol, a sedative-hypnotic agent that is a structural analogue of ethanol. EXPERIMENTAL APPROACH: We constructed panels of mutants at ethanol-sensitive positions in the GluN2A (NR2A) NMDA receptor subunit and transiently expressed these mutants in human embryonic kidney 293 cells. We used whole-cell patch-clamp recording to assess the actions of ethanol and trichloroethanol in these mutant NMDA receptors. KEY RESULTS: Ethanol sensitivity of mutants at GluN2A(Ala825) was not correlated with any physicochemical measures tested. Trichloroethanol sensitivity was altered in two of three ethanol insensitive mutant GluN2A subunits: GluN2A(Phe637Trp) in M3 and GluN2A(Ala825Trp) in M4, but not GluN2A(Met823Trp). Trichloroethanol sensitivity decreased with increasing molecular volume at Phe637 or increasing hydrophobicity at Ala825 and was correlated with ethanol sensitivity at both sites. CONCLUSIONS AND IMPLICATIONS: Evidence obtained to date is consistent with a role of GluN2A(Ala825) as a modulatory site for ethanol and trichloroethanol sensitivity, but not as a binding site. Trichloroethanol appears to inhibit the NMDA receptor in a manner similar, but not identical to, that of ethanol. PMID- 19788496 TI - Vasodilator efficacy of nitric oxide depends on mechanisms of intracellular calcium mobilization in mouse aortic smooth muscle cells. AB - BACKGROUND AND PURPOSE: Reduction of intracellular calcium ([Ca(2+)](i)) in smooth muscle cells (SMCs) is an important mechanism by which nitric oxide (NO) dilates blood vessels. We investigated whether modes of Ca(2+) mobilization during SMC contraction influenced NO efficacy. EXPERIMENTAL APPROACH: Isometric contractions by depolarization (high potassium, K(+)) or alpha-adrenoceptor stimulation (phenylephrine), and relaxations by acetylcholine chloride (ACh), diethylamine NONOate (DEANO) and glyceryl trinitrate (GTN) and SMC [Ca(2+)](i) (Fura-2) were measured in aortic segments from C57Bl6 mice. KEY RESULTS: Phenylephrine-constricted segments were more sensitive to endothelium-derived (ACh) or exogenous (DEANO, GTN) NO than segments contracted by high K(+) solutions. The greater sensitivity of phenylephrine-stimulated segments was independent of the amount of pre-contraction, the source of NO or the resting potential of SMCs. It coincided with a significant decrease of [Ca(2+)](i), which was suppressed by sarcoplasmic reticulum (SR) Ca(2+) ATPase (SERCA) inhibition, but not by soluble guanylyl cylase (sGC) inhibition. Relaxation of K(+) stimulated segments did not parallel a decline of [Ca(2+)](i). However, stimulation (BAY K8644) of L-type Ca(2+) influx diminished, while inhibition (nifedipine, 1-100 nM) augmented the relaxing capacity of NO. CONCLUSIONS AND IMPLICATIONS: In mouse aorta, NO induced relaxation via two pathways. One mechanism involved a non-cGMP-dependent stimulation of SERCA, causing Ca(2+) re uptake into the SR and was prominent when intracellular Ca(2+) was mobilized. The other involved sGC-stimulated cGMP formation, causing relaxation without changing [Ca(2+)](i), presumably by desensitizing the contractile apparatus. This pathway seems related to L-type Ca(2+) influx, and L-type Ca(2+) channel blockers increase the vasodilator efficacy of NO. PMID- 19788497 TI - The NADPH oxidase inhibitor diphenyleneiodonium is also a potent inhibitor of cholinesterases and the internal Ca(2+) pump. AB - BACKGROUND AND PURPOSE: Diphenyleneiodonium (DPI) is often used as an NADPH oxidase inhibitor, but is increasingly being found to have unrelated side effects. We investigated its effects on smooth muscle contractions and the related mechanisms. EXPERIMENTAL APPROACH: We studied isometric contractions in smooth muscle strips from bovine trachea. Cholinesterase activity was measured using a spectrophotometric assay; internal Ca(2+) pump activity was assessed by Ca(2+) uptake into smooth muscle microsomes. KEY RESULTS: Contractions to acetylcholine were markedly enhanced by DPI (10(-4) M), whereas those to carbachol (CCh) were not, suggesting a possible inhibition of cholinesterase. DPI markedly suppressed contractions evoked by CCh, KCl and 5-HT, and also unmasked phasic activity in otherwise sustained responses. Direct biochemical assays confirmed that DPI was a potent inhibitor of acetylcholinesterase and butyrylcholinesterase (IC(50) approximately 8 x 10(-6) M and 6 x 10(-7) M, respectively), following a readily reversible, mixed non-competitive type of inhibition. The inhibitory effects of DPI on CCh contractions were not mimicked by another NADPH oxidase inhibitor (apocynin), nor the Src inhibitors PP1 or PP2, ruling out an action through the NADPH oxidase signalling pathway. Several features of the DPI-mediated suppression of agonist-evoked responses (i.e. suppression of peak magnitudes and unmasking of phasic activity) are similar to those of cyclopiazonic acid, an inhibitor of the internal Ca(2+) pump. Direct measurement of microsomal Ca(2+) uptake revealed that DPI modestly inhibits the internal Ca(2+) pump. CONCLUSIONS AND IMPLICATIONS: DPI inhibits cholinesterase activity and the internal Ca(2+) pump in tracheal smooth muscle. PMID- 19788498 TI - Oral bioavailability and brain penetration of (-)-stepholidine, a tetrahydroprotoberberine agonist at dopamine D(1) and antagonist at D(2) receptors, in rats. AB - BACKGROUND AND PURPOSE: (-)-Stepholidine has high affinity for dopamine D(1) and D(2) receptors. The aims of the present study were to examine the oral bioavailability and brain penetration of (-)-stepholidine and to gain understanding of mechanisms governing its transport across the enterohepatic barrier and the blood-brain barrier. EXPERIMENTAL APPROACH: The pharmacokinetics of (-)-stepholidine was studied in rats and microdialysis was used to measure delivery to the brain. These studies were supported by biological measurement of unbound (-)-stepholidine. Membrane permeability was assessed using Caco-2 cell monolayers. Metabolite profiling of (-)-stepholidine in rat bile and plasma was performed. Finally, in vitro metabolic stability and metabolite profile of (-) stepholidine were examined to compare species similarities and differences between rats and humans. KEY RESULTS: Orally administered (-)-stepholidine was rapidly absorbed from the gastrointestinal tract; two plasma concentration peaks were seen, and the second peak might result from enterohepatic circulation. Due to extensive pre-systemic metabolism, the oral bioavailability of (-) stepholidine was poor (<2%). However, the compound was extensively transported across the blood-brain barrier, demonstrating an AUC (area under concentration time curve) ratio of brain : plasma of approximately 0.7. (-)-Stepholidine showed good membrane permeability that was unaffected by P-glycoprotein and multidrug resistance-associated protein 2. In vitro (-)-stepholidine was metabolized predominantly by glucuronidation and sulphation in rats and humans, but oxidation of this substrate was very low. CONCLUSIONS AND IMPLICATIONS: Although (-) stepholidine exhibits good brain penetration, future development efforts should aim at improving its oral bioavailability by protecting against pre-systemic glucuronidation or sulphation. In this regard, prodrug approaches may be useful. PMID- 19788500 TI - The multifunctional role of mTOR in innate immunity: implications for transplant immunity. AB - The mammalian target of rapamycin (mTOR) is an evolutionary conserved serine threonine kinase that senses various environmental stimuli in most cells primarily to control cell growth. Restriction of cellular proliferation by mTOR inhibition led to the use of mTOR inhibitors as immunosuppressants in allogeneic transplantation as well as novel anticancer agents. However, distinct inflammatory side effects such as fever, pneumonitis, glomerulonephritis or anemia of chronic disease have been observed under this treatment regime. Apart from the mere cell-cycle regulatory effect of mTOR in dividing cells, recent data revealed a master regulatory role of mTOR in the innate immune system. Hence, inhibition of mTOR promotes proinflammatory cytokines such as IL-12 and IL-1beta, inhibits the anti-inflammatory cytokine IL-10 and boosts MHC antigen presentation via autophagy in monocytes/macrophages and dendritic cells. Moreover, mTOR regulates type I interferon production and the expression of chemokine receptors and costimulatory molecules. These results place mTOR in a complex immunoregulatory context by controlling innate and adaptive immune responses. In this review, we discuss the clinical consequences of mTOR-inhibitor therapy and aim to integrate this recent data into our current view of the molecular mechanisms of clinically employed mTOR inhibitors and discuss their relevance with special emphasis to transplantation. PMID- 19788502 TI - Influence of cyclooxygenase-2 (COX-2) gene promoter polymorphism -765 on graft loss after renal transplantation. AB - A G-->C polymorphism has been identified in the human cyclooxygenase-2 (COX-2) gene promoter at position -765 with C allele leading to a decreased promoter activity with low prostaglandin E2 (PGE2) production. PGE2 has strong immunomodulatory properties that could influence graft survival. We studied the association between this polymorphism and allograft failure in two independent cohorts of renal transplant recipients (RTRs) including a total of 603 patients. The functional effect of COX-2 gene promoter polymorphism was analyzed by measuring serum levels of PGE2. Median follow-up was 8.7 and 7.9 years for the first and second cohort, respectively. Analysis of 603 patients identified 20 CC (3.3%), 179 GC (29.7%) and 404 GG (67%) carriers. Patients with the GG genotype had significantly higher serum PGE2 concentrations than patients with the C allele. Carriers with a C allele have an independent increased risk of graft loss (hazard ratio (HR) 2.43 [95% CI 1.19-4.97], p = 0.015 for cohort 1; HR 1.72 [95% CI 0.99-3.77], p = 0.051 for cohort 2) compared to GG patients. COX-2 gene promoter polymorphism at position -765 (G-->C) is associated with a higher rate of graft loss in RTRs. Such findings may be used to influence immunosuppressive strategies and optimize patient management. PMID- 19788501 TI - TNF receptors differentially signal and are differentially expressed and regulated in the human heart. AB - Tumor necrosis factor (TNF) utilizes two receptors, TNFR1 and 2, to initiate target cell responses. We assessed expression of TNF, TNFRs and downstream kinases in cardiac allografts, and compared TNF responses in heart organ cultures from wild-type ((WT)C57BL/6), TNFR1-knockout ((KO)), TNFR2(KO), TNFR1/2(KO) mice. In nonrejecting human heart TNFR1 was strongly expressed coincidentally with inactive apoptosis signal-regulating kinase-1 (ASK1) in cardiomyocytes (CM) and vascular endothelial cells (VEC). TNFR2 was expressed only in VEC. Low levels of TNF localized to microvessels. Rejecting cardiac allografts showed increased TNF in microvessels, diminished TNFR1, activation of ASK1, upregulated TNFR2 co expressed with activated endothelial/epithelial tyrosine kinase (Etk), increased apoptosis and cell cycle entry in CM. Neither TNFR was expressed significantly by cardiac fibroblasts. In (WT)C57BL/6 myocardium, TNF activated both ASK1 and Etk, and increased both apoptosis and cell cycle entry. TNF-treated TNFR1(KO) myocardium showed little ASK1 activation and apoptosis but increased Etk activation and cell cycle entry, while TNFR2(KO) myocardium showed little Etk activation and cell cycle entry but increased ASK1 activation and apoptosis. These observations demonstrate independent regulation and differential functions of TNFRs in myocardium, consistent with TNFR1-mediated cell death and TNFR2 mediated repair. PMID- 19788499 TI - Drug transporters in the human blood-placental barrier. AB - Studies on the increasing number of transporters found in the placental barrier are gaining momentum, because of their tissue-specific expression, significance in physiology and disease, and the possible utilization of the emerging knowledge in pharmacology. In the placenta, both syncytiotrophoblast and fetal capillary endothelium express transporters. Fetal exposure is determined by the net effect of combination of transporters, their nature and localization in relation to placental cells and their substrate specificity. Although the significance of placental transporters on human fetal drug exposure is almost an unstudied field so far, their potential use to design drugs that do not cross the placenta is already being pursued. It is thus of interest to review the existing knowledge of human placental transporters. Transporters in all groups which take part in drug transport are found in human placenta. Especially, ATP-binding cassette transporters ABCG2/breast cancer resistance protein, ABCB1/P-glycoprotein and ABCC2/MRP2 are all expressed at the apical surface of syncytiotrophoblast facing maternal blood and are putatively important protective proteins both for placental tissue and the fetus, because they are efflux transporters and their substrates include many drugs and also environmental chemicals. Such protective effect has been shown in animals, but these results cannot be directly extrapolated to humans due to interspecies differences in placental structure and function. Experimental models utilizing human placental tissue, especially human placental perfusion, offer valuable possibilities, which have been insufficiently studied so far. PMID- 19788503 TI - Reimbursing live organ donors for incurred non-medical expenses: a global perspective on policies and programs. AB - Methods to reimburse living organ donors for the non-medical expenses they incur have been implemented in some jurisdictions and are being considered in others. A global understanding of existing legislation and programs would help decision makers implement and optimize policies and programs. We searched for and collected data from countries that practice living organ donation. We examined legislation and programs that facilitate reimbursement, focusing on policy mechanisms, eligibility criteria, program duration and types of expenses reimbursed. Of 40 countries, reimbursement is expressly legal in 16, unclear in 18, unspecified in 6 and expressly prohibited in 1. Donor reimbursement programs exist in 21 countries; 6 have been enacted in the last 5 years. Lost income is reimbursed in 17 countries, while travel, accommodation, meal and childcare costs are reimbursed in 12 to 19 countries. Ten countries have comprehensive programs, where all major cost categories are reimbursed to some extent. Out-of-country donors are reimbursed in 10 jurisdictions. Reimbursement is conditional on donor income in 7 countries, and recipient income in 2 countries. Many nations have programs that help living donors with their financial costs. These programs differ in operation and scope. Donors in other regions of the world are without support. PMID- 19788505 TI - Disengaging the IL-2 receptor with daclizumab enhances IL-7-mediated proliferation of CD4(+) and CD8(+) T cells. AB - Allograft rejection is mainly driven by the production of IL-2, which expands T cells by linking the IL-2 receptor (IL-2R) composed of three subunits: CD25, CD122 and CD132. Daclizumab, widely used in immunosuppression, is a humanized anti-CD25 antibody that disrupts IL-2 signaling by binding to CD25 and preventing the assembly of the high-affinity IL-2R. Here we show that Daclizumab, while blocking the T-cell response to IL-2, increases CD4(+) and CD8(+) T-cell proliferative response to the homeostatic cytokine IL-7. The IL-7R shares CD132 with the IL-2R and blocking of CD25 by Daclizumab results in the enhanced formation of the IL-7R that in turn allows IL-7 to bind more efficiently on the cell surface. The consequently increased IL-7R signaling boosts intracellular phosphorylated STAT5 and T-cell proliferation. In addition, treatment with Daclizumab delays the internalization of CD127 upon IL-7 treatment, retaining T cell sensitivity to IL-7 for a prolonged time. This effect of Daclizumab highlights the redundancy of the cytokine system, which may influence T-cell proliferation in transplanted patients, and provides information to improve future immunosuppressive strategies. PMID- 19788504 TI - Connective tissue growth factor promotes fibrosis downstream of TGFbeta and IL-6 in chronic cardiac allograft rejection. AB - Cardiac transplantation is an effective treatment for multiple types of heart failure refractive to therapy. Although immunosuppressive therapeutics have increased survival rates within the first year posttransplant, chronic rejection (CR) remains a significant barrier to long-term graft survival. Indicators of CR include patchy interstitial fibrosis, vascular occlusion and progressive loss of graft function. Multiple factors have been implicated in the onset and progression of CR, including TGFbeta, IL-6 and connective tissue growth factor (CTGF). While associated with CR, the role of CTGF in CR and the factors necessary for CTGF induction in vivo are not understood. To this end, we utilized forced expression and neutralizing antibody approaches. Transduction of allografts with CTGF significantly increased fibrotic tissue development, though not to levels observed with TGFbeta transduction. Further, intragraft CTGF expression was inhibited by IL-6 neutralization whereas TGFbeta expression remained unchanged, indicating that IL-6 effects may potentiate TGFbeta-mediated induction of CTGF. Finally, neutralizing CTGF significantly reduced graft fibrosis without reducing TGFbeta and IL-6 expression levels. These findings indicate that CTGF functions as a downstream mediator of fibrosis in CR, and that CTGF neutralization may ameliorate fibrosis and hypertrophy associated with CR. PMID- 19788506 TI - Platelet transfusions in adult patients with particular reference to patients undergoing surgery. AB - Descriptive information on platelet (PLT) recipients, particularly during surgery, is limited. A description of the current epidemiology of PLT-transfused patients is required to optimize platelet transfusion care and to follow trends in PLT use. In 2004 and 2005, information was combined from several computerized medical systems. Participating hospitals (9 hospital districts of 21) handled approximately 64% of annual Finnish hospital admissions. A total of 6321 adult patients were transfused with 37,761 PLT products. Most PLT products (43.1%) were transfused to patients suffering from haematological malignancies. Only 1.0% of all surgical patients received PLTs (53.8% of PLT recipients and 35.8% of transfused PLTs). The most common single operation connected with PLT transfusion was coronary artery bypass while 27.1% of surgery-related PLTs were given to patients having an operation involving the digestive system or spleen. Only 36.4% of all PLT-transfused (operated and conservatively treated) patients were discharged directly home; in-hospital mortality was 9.5%. PLTs were given 40 products per 1000 hospital admissions requiring an operation in 2004, and 38 products in 2005. Perioperative PLT use is slightly decreasing in adult patients. As a single-operation type, coronary artery bypass patients receive most of the PLT products and have experienced no decline in PLT use over the years. Overall, PLT recipients have high in-hospital mortality. PMID- 19788507 TI - Rubella vaccination and transitory false-positive test results for human immunodeficiency virus Type 1 in blood donors. PMID- 19788508 TI - Delayed hemolytic transfusion reaction with hyperhemolysis after first red blood cell transfusion in child with beta-thalassemia: challenges in treatment. AB - BACKGROUND: Delayed hemolytic transfusion reaction (DHTR) can manifest with hyperhemolysis, a serious complication of red blood cell (RBC) transfusions. This has mostly been described in sickle cell anemia but occasionally in beta thalassemia. Treatment is challenging; immunosuppressive medication has been reported to be useful by some but not others. CASE REPORT: A 1.5-year-old girl with homozygous beta-thalassemia was put on a regular RBC transfusion program because of anemia with stunted growth and abnormal bone development. After the first transfusion she developed DHTR with hyperhemolysis. Further RBC transfusions could not be avoided. Despite treatment with prednisone, immunoglobulins, rituximab, and azathioprine hemolysis continued. She received an allogeneic bone marrow transplantation after conditioning using cyclophosphamide, treosulfan, melfalan, and ATG. The transplantation was followed by treatment with cyclosporin A, methotrexate, and prednisone. Because of poor engraftment and later rejection, she received a retransplantation after conditioning using fludarabine instead of cyclophosphamide and was subsequently treated with prednisone, but hemolysis continued. Only after splenectomy did she no longer need RBC transfusions and the direct antiglobulin test turned negative. DISCUSSION AND CONCLUSION: Treatment of DHTR remains challenging. The role of immunosuppressive medication such as azathioprine, cyclosporin A, and rituximab remains to be seen. Splenectomy may be helpful. Mainstay is to minimize RBC transfusions as much as possible. PMID- 19788509 TI - Pressure-aided transfusion of platelets: does it affect the platelets? AB - BACKGROUND: In massively bleeding patients, pressure infusers are used for transfusion of red blood cells and plasma but not for platelets (PLTs) due to an assumed negative effect on the PLTs. This study examined whether pressure-aided in vitro transfusion affected the number, activation state, and/or function of the PLTs as measured by flow cytometry and thrombelastography (TEG). STUDY DESIGN AND METHODS: PLT concentrates stored for 1 (n = 8) or 8 (n = 7) days were transfused in vitro by means of a pressure inducer (300 mmHg). Samples before and after transfusion were measured for PLT concentration and expression of CD62P, CD63, and PAC-1. These activation markers were measured by flow cytometry on resting PLTs as well as PLTs stimulated with thrombin receptor-activating peptide. Clot generation and strength was examined by TEG by measuring the angle (degree) and maximum amplitude (mm), values that are highly dependent on the PLT function. RESULTS: PLT concentrations were unchanged after pressure-aided transfusion reflecting no destruction. With respect to activation state and in vitro functional capacity either no or only minor differences (<7%) were detected. CONCLUSION: In this study, use of a pressure inducer decreased the transfusion time of in vitro PLT transfusion by approximately 50%. No or only minor and inconsistent changes of the PLT number and function were observed. Consequently, this study indicates that pressure infusers could be used for transfusion of PLTs if clinically indicated, that is, in massively bleeding patients. However, in vivo studies to assess the safety and utility of pressure aided PLT transfusion are warranted. PMID- 19788510 TI - Adoptive therapy by transfusing expanded donor murine natural killer T cells can suppress acute graft-versus-host disease in allogeneic bone marrow transplantation. AB - BACKGROUND: Invariant natural killer T cells (iNKT cells) may suppress graft versus-host disease (GVHD) after allogeneic transplantation. The purpose of this study was to investigate the therapeutic potential of iNKT cells from major histocompatibility complex (MHC)-mismatched donors for preventing GVHD after allogeneic bone marrow transplantation (BMT). STUDY DESIGN AND METHODS: In vitro, mouse iNKT cells were expanded with alpha-galactosylceramide and interleukin (IL) 2 treatment. In the NKT-treated group, lethally irradiated DBA/2(H-2K(d)) mice were adoptively transferred with expanded iNKT, bone marrow (BM), and spleen cells (SCs) from C57BL/6 (H-2K(b)) mice. Recipients in the control group were transferred only BM and SCs. The two groups were compared in survival, weight, histopathologic specimens, and serum cytokine analysis. RESULTS: In the iNKT treated group, 80% of mice survived past Day 60 after BMT, but all died within 38 days in the control group. The mice treated with iNKT did not exhibit signs of GVHD after Day 42 except for a change in fur color. There were higher IL-4 levels by Day 7 in serum of mice that received iNKT compared to those without iNKT treatment, while the interferon-gamma levels showed no significant difference between two groups. Levels of IL-2 and IL-5 increased by Day 21 only in iNKT treated mice. CONCLUSION: The results suggest that donor iNKT cells could alleviate GVHD symptoms and prolong survival after MHC-mismatched allogeneic BMT, which may be associated with the maintenance in IL-4 levels. These findings indicate that the therapy based on iNKT cells from MHC-mismatched donors has great potential in protection against GVHD after allogeneic hematopoietic stem cell transplantation. PMID- 19788511 TI - Pharmacokinetic analysis of human plasma-derived pasteurized C1-inhibitor concentrate in adults and children with hereditary angioedema: a prospective study. AB - BACKGROUND: Hereditary angioedema (HAE) is a rare and potentially life threatening disease presenting with acute edema of subcutaneous tissues and/or mucous membranes. Patients with HAE have abnormally low or dysfunctional C1 inhibitor (C1-INH). Preventing the progression of acute attacks is the main goal of C1-INH replacement therapy; knowledge of the C1-INH concentrate half-life is of crucial importance. This pharmacokinetic study was conducted to investigate the pharmacokinetics of pasteurized human plasma-derived C1-INH concentrate (pC1 INH). STUDY DESIGN AND METHODS: This was a prospective, single-center study of six children and 34 adults with an established diagnosis of HAE. On-demand treatment with pC1-INH was administered to all children, whereas adults received either pC1-INH on-demand treatment or individual replacement therapy (IRT). Functional C1-INH plasma levels were fitted to a single-compartment model with nonlinear regression, and the area under the curve was standardized to a dose equivalent of 15 U/kg body weight of pC1-INH concentrate. RESULTS: The median half-life of functional C1-INH plasma levels in pediatric patients receiving on demand therapy was 32.9 hours (mean, 31.5 hr). In adults, the median half-lives of functional C1-INH plasma levels after on-demand therapy were 39.1 hours (mean, 47.8 hr) and 30.9 hours (mean 33.3 hr) for patients on IRT. The median times to achieve maximum plasma activity after administration were 0.6 hour for children, 1.0 hour for adults receiving on-demand treatment, and 0.5 hour for adults on IRT. CONCLUSIONS: pC1-INH concentrate has a long median terminal elimination half life and rapidly reaches maximum plasma concentrations. This rapid onset of clinical efficacy is essential in patients suffering from HAE. PMID- 19788512 TI - International variation in volunteer whole blood donor eligibility criteria. AB - BACKGROUND: This study assesses international variation in volunteer whole blood donor eligibility criteria. STUDY DESIGN AND METHODS: In February 2008, Web sites of major blood collection organizations in 17 countries were queried for the volume of whole blood donations and six donor eligibility criteria: allowed donation frequency, donor age, hemoglobin (Hb), weight, and deferrals for tattoo and pregnancy/breast-feeding. RESULTS: The allowed frequency of whole blood donation ranged from 56 to 120 days, some with sex- and age-specific limitations. While blood collection agencies in three countries did not have an upper age limit for donation, the remainder mandated donor retirement at ages from 60 to 81 years. The minimum Hb level was 11.5 to 12.5 g/dL for women and 12.5 to 13.5 g/dL for men. Blood collection organizations in only three countries required a minimum donor weight of less than 50 kg. Tattoo and pregnancy deferrals ranged from 4 to 12 months and 6 weeks to 12 months, respectively. The volume of whole blood donations ranged from 300 to 500 mL. The percentage of total blood volume donated, the absolute grams of Hb expected to be restored per deferral period and per day of donor deferral, and the concentration of Hb expected to be restored per deferral period were calculated. CONCLUSIONS: International volunteer whole blood donor eligibility criteria demonstrate marked variation. These differences likely cause international variation in the prevalence of adverse donor reactions and iron deficiency anemia. The reasons underlying these dissimilarities are unclear, but may include varying cultural influences and average donor body habitus. PMID- 19788513 TI - A novel association of acquired ADAMTS13 inhibitor and acute dengue virus infection. AB - BACKGROUND: Dengue is a mosquito-borne viral disease with an increasing incidence worldwide. Thrombocytopenia is a common finding in dengue virus (DV) infection; however, the underlying mechanisms remain unknown. CASE REPORT: Here we provide the first evidence of a case of antibody formation against ADAMTS13 (ADAMTS13 inhibitor) in the course of a severe acute DV infection resulting in thrombotic microangiopathy (TMA). The patient presented with classical dengue symptoms (positive epidemiology, high fever, myalgia, predominantly in the lower limbs and lumbar region for 1 week) and, after 11 days of initial symptoms, developed TMA. Clinical and laboratorial investigation of dengue and TMA was performed. RESULTS: The patient presented with ADAMTS13 inhibitor (IgG) during the acute phase of the disease, without anti-platelet antibodies detectable. Dengue infection had laboratorial confirmation. There were excellent clinical and laboratory responses to 11 serial plasma exchanges. Anti-ADAMTS13 inhibitor disappeared after remission of TMA and dengue resolution. No recurrence of TMA symptoms was observed after 2-year follow-up. CONCLUSIONS: Although the real incidence of dengue-related TMA is unknown, this case provides the basis for future epidemiologic studies on acquired ADAMTS13 deficiency in DV infection. The prompt clinical recognition of this complication and early installment of specific therapy with plasma exchange are likely to improve the outcome of severe cases of dengue. PMID- 19788514 TI - Storage of buffy-coat-derived platelets in additive solutions: in vitro effects on platelets stored in reformulated PAS supplied by a 20% plasma carry-over. AB - BACKGROUND AND OBJECTIVES: Platelet additive solutions (PAS) have been shown to be suitable for extended platelet (PLT) storage. Depending on the PAS formulation, the percentage of plasma carry-over contributes to success. Improving PLT quality by optimizing the composition of PAS may allow a reduction to be made in the amount of plasma carried over to the final unit. Reducing the proportion of plasma carried over would probably decrease transfusion of unwanted antibodies and make greater amounts of plasma available for other needs. STUDY DESIGN AND METHODS: Platelets from eight pools of 25 buffy coats were aliquoted and prepared for storage in plasma and different PAS units: InterSol and three alternate PAS named PSM1, PSM2 and PSM3. All PAS units were supplied with a 20% plasma carry-over and stored at room temperature with agitation for 9 days with in vitro testing for metabolic, cellular and activation parameters. Results During storage, PLTs stored in InterSol displayed significantly lower glucose concentration (P < 0.01), lower adenosine triphosphate levels (P < 0.01), a higher mean PLT volume (P < 0.01), a lower response to hypotonic shock response activity (P < 0.01) and a higher CD62P expression (P < 0.01) when compared with PLTs stored in plasma and PSM1-3 solutions. pH was maintained at > 6.8 (day 9) and swirling remained at the highest level (score = 2) for all units throughout storage. CONCLUSION: Our results suggest that PLTs stored in PAS with addition of magnesium, potassium and glucose (PSM2 and PSM3) and 20% plasma carry-over maintained metabolic and cellular characteristics, equivalent to PLTs stored in 100% plasma during 9 days of storage. Our results also suggest that presence of potassium in addition to magnesium or alternatively the concentration of phosphate as well as the supply of additional glucose to normal plasma levels improve in vitro data of PLTs stored in PAS. PMID- 19788515 TI - Effect of dimethyl sulfoxide on cell cycle synchronization of goldfish caudal fin derived fibroblasts cells. AB - Several studies have previously been conducted regarding cell cycle synchronization in mammalian somatic cells. However, limited work has been performed on the control of cell cycle stages in the somatic cells of fish. The aim of this study was to determine the cell cycle arresting effects of several dimethyl sulfoxide (DMSO) concentrations for different times on different cell cycle stages of goldfish caudal fin-derived fibroblasts. Results demonstrated that the cycling cells or control group (68.29%) yields significantly higher (p < 0.05) arrest in G0/G1 phase compared with the group treated for 24 h with different concentrations (0.5%, 1.0% or 1.5%) of DMSO (64.88%, 65.70%, 64.22% respectively). The cell cycle synchronization in the treatment of cells with 1.0% DMSO at 48 h (81.14%) was significantly higher than that in the groups treated for 24 h (76.82%) and the control group (77.90%). Observations showed that treatment of DMSO resulted in an increase in the proportion of cells at G0/G1 phase for 48 h of culture. However, high levels of apoptotic cells can be detected after 48 h of culture treated with 1% concentration of DMSO. PMID- 19788516 TI - Effects of retinoids on the in vitro development of Capra hircus embryos to blastocysts in two different culture systems. AB - The objective of this study was to evaluate the effect of retinol (RT) and retinoic acid (RA) on the in vitro development of pre-implantation goat embryos cultured in potassium simplex optimized medium or synthetic oviduct fluid or cocultured in oviductal cells monolayer either in potassium simplex optimized medium or synthetic oviduct fluid. A total of 2407 cumulus-oocyte complexes were aspirated from 2 to 6 mm ovarian follicles from slaughtered animals. Selected cumulus-oocyte complexes were subjected to in vitro maturation in TCM 199 for 24 h at 39 degrees C in an atmosphere of 5% (v/v) CO(2) in humidified air. In vitro fertilization was performed in modified defined medium. Eighteen hours after in vitro fertilization, cumulus cells were removed and presumptive zygotes were randomly distributed into experimental groups. In Experiment 1, presumptive zygotes were cultured in potassium simplex optimized medium, potassium simplex optimized medium + RT, potassium simplex optimized medium + retinoic acid, synthetic oviduct fluid, synthetic oviduct fluid + RT and synthetic oviduct fluid + RA at 39 degrees C in a humidified atmosphere of 5% (v/v) CO(2), 5% (v/v) O(2) and 90% (v/v) N(2). In Experiment 2, presumptive zygotes were cocultured in potassium simplex optimized medium + oviductal cells monolayer, potassium simplex optimized medium + RT + oviductal cells monolayer, potassium simplex optimized medium + RA + oviductal cells monolayer, synthetic oviduct fluid + oviductal cells monolayer, synthetic oviduct fluid + RT + oviductal cells monolayer and synthetic oviduct fluid + RA + oviductal cells monolayer in an atmosphere of 5% (v/v) CO(2) in humidified air. In both experiments, media were partially changed on day 2 after in vitro fertilization and unfertilized oocytes were excluded from the experiment. Embryos were cultured or cocultured for 8 days. In Experiment 1, there was no effect of RT or RA supplementation on the proportion of oocytes that reached the morula or blastocyst stages. By contrast, Experiment 2 demonstrated that the addition of 0.28 MUg/ml RT and 0.5 MUm RA to the embryo culture media stimulated (p < 0.05) development to the morula and blastocyst stages under the coculture conditions tested. In conclusion, retinoids play an important role in pre-implantation development of goat embryos and can be used to enhance in vitro embryo production. PMID- 19788517 TI - Exogenous DNA uptake of boar spermatozoa by a magnetic nanoparticle vector system. AB - The sperm-mediated gene transfer method is applicable to transgenesis in many species that use spermatozoa for reproduction recently, which has been shown various results. In the current study, we show that transgenic porcine embryos can be efficiently produced by employing a simple transfection method that uses magnetic nanoparticles (MNPs). The complexes formed between plasmid DNA and MNPs were bounded on ejaculated boar spermatozoa at a higher efficiency compared to methods using DNA alone or lipofection. Using confocal microscopy, rhodamine fluorophore-labelled MNPs were detected on external surfaces of the spermatozoa membrane, which were bounded on zona pellucida of in vitro maturated oocyte during in vitro fertilization. Electron microscopy revealed that clusters of MNPs were detected in inside of plasma membrane and nucleus of the spermatozoa head. Additionally, we found that magnetofected boar spermatozoa could be fertilized with oocytes in vitro and that the resulting gene of green fluorescent protein was detected in fertilized eggs by genomic PCR analysis. Taken together, these results suggest that MNPs can be used to efficiently introduce a transgene into embryo via spermatozoa. PMID- 19788518 TI - Effect of lycopene on cytoplasmic maturation of porcine oocytes in vitro. AB - The aim of the present study was to improve cytoplasmic maturation of porcine oocytes by the addition of lycopene into in vitro maturation (IVM) media. We designed six experimental groups; IVM medium was supplemented with 10 IU/ml FSH, FSH and 10 IU/ml human chorionic gonadotrophin (hCG), or FSH and 7 MUm lycopene in the first half of the IVM culture (0-22 h) followed by further culture (22-44 h) with or without hCG. The addition of lycopene into IVM media delayed the interruption of communication between an oocyte and the cumulus cells. Although meiotic competence was similar among the six groups, the glutathione level of matured oocytes was significantly higher in the lycopene-supplemented group (9.89 pmol per oocyte) than that in other groups (7.25 and 7.81 pmol per oocyte). Fertilization rate was significantly improved in lycopene-supplemented groups (58.3%) more than that in the group supplemented with FSH only (43.1%), whereas there were no differences in developmental competence among the groups (blastocyst rate: 20.1-29.5%). These results indicate that insufficient cytoplasmic maturation during conventional IVM resulted by disconnection of the gap junction between an oocyte and the cumulus cells in the early phase during IVM culture. We concluded that lycopene induced a prolonged sustainment of gap junctional communication between an oocyte and the cumulus cells during porcine IVM culture, which was an effective cytoplasmic maturation of porcine IVM oocytes. PMID- 19788519 TI - Factors affecting the readiness and preparation of replacement heifers in tropical breeding environments. AB - The future of beef cattle production in tropical regions is uncertain because of land tenure concerns, threatening the survival of extensive management programmes in these areas of the world. The need to intensify production systems will inevitably lead to changes in the management of replacement animals in existing herds. The present review underlines the main constraints, which in the past could be resolved by the sheer numbers of animals present in beef cattle operations, with replacements reliant only on finding enough heifers to substitute the adult females destined for culling. This scenario is rapidly changing as beef cattle units in tropical regions subdivide to share out the land between as many farmers as possible. Consequently, issues such as the efforts needed to manage the pregnant cow, particularly her nutritional status and its effect on the new-born calf, the future replacement heifer growing in the presence of the dam, weaning management and procedures required before a heifer can be introduced into a breeding programme, need to be adequately and efficiently addressed by farmers in tropical regions. PMID- 19788520 TI - Expression of progesterone receptor in the utero-tubal junction after intra uterine and deep intra-uterine insemination in sows. AB - The aim of this study was to investigate the expression of progesterone receptor (PR) in the utero-tubal junction (UTJ) of sows at 24 h after intra-uterine insemination (IUI) and deep intra-uterine insemination (DIUI) compared with conventional artificial insemination (AI) in pigs. Fifteen multiparous sows were used: AI (n = 5), IUI (n = 5) and DIUI (n = 5). The sows were inseminated with a single dose of diluted semen during the second oestrus after weaning at 6-8 h prior to ovulation (AI: 3000 * 10(6) spermatozoa, IUI: 1000 * 10(6) spermatozoa and DIUI: 150 * 10(6) spermatozoa). The UTJ was collected and subject to immunohistochemical staining using avidin-biotin immunoperoxidase technique with mouse monoclonal antibody to PR. In the oviductal part of the UTJ, the intensity of PR in the tunica muscularis and the proportion of PR-positive cells in the surface epithelium after DIUI were lower than AI (p < 0.05). The intensity and the proportion of PR-positive cells between AI and IUI in all compartments of the UTJ did not differ significantly (p > 0.05). When comparing between tissue compartments, prominent staining was observed in the muscular layer of the UTJ. It could be concluded that the expression of PR in the UTJ prior to fertilization after DIUI with a reduced number of spermatozoa was lower than that after AI. This might influence sperm transportation and the fertilization process. PMID- 19788521 TI - An inter-subspecies cloned buffalo (Bubalus bubalis) obtained by transferring of cryopreserved embryos via somatic cell nuclear transfer. AB - The aim of this study was to explore the feasibility of cryopreservation of inter subspecies cloned embryos in buffalo. In our experiment, river buffalo ear fibroblast nucleus was fused into swamp buffalo oocyte cytoplasm. The blastocyst formation rate for nuclear transfer of freshly thawed cells was not different from those of growing cells, confluent or serum-starved cells. A total of 122 cloned blastocysts derived from cryopreserved fibroblasts were cryopreserved and thawed, 37 were survived, the cryosurvival rate was 30.3%. The survived blastocysts were transferred into 15 recipient buffalos. Five of the recipients established pregnancy, but four of them aborted on day 53, 59, 145 and 179 of gestation respectively. One cross-bred buffalo (Murrah * Swamp buffalo (2n = 49) received three embryos delivered a 40.5 kg female calf by natural delivery on day 320 of gestation. Up to now (13-month old), the cloned calf has been growing well with no abnormity observed. These results demonstrated that cryopreservation of inter-subspecies cloned embryos is feasible to produce buffalo offspring. PMID- 19788522 TI - Ultraviolet radiation dose to be applied in recipient zebrafish embryos for germ line chimaerism is strain dependent. AB - Germ-line chimaerism is a powerful technique that has proved to be useful to produce viable gametes when transplanted blastomeres colonize the germinal ridges in recipient embryos and obtaining offspring from such transplanted cells. In fish, ionizing radiations were commonly used for embryo penalization to cancelling the cell participation of recipient embryos in development and in gamete production. The ultraviolet (UV) radiation when compared with other radiation types is cheaper, easier and no special installations are required for its use. So, the aim of this work was to establish the optimal UV radiation dose to be applied in zebrafish embryos at mid-blastula transition stage of development, in order to use them as penalized recipient embryos in futures chimaerism assays. A UV germicide lamp was used as radiation source (0.529 mW/cm(2)). Four exposure levels and three exposure times of UV radiation were tested. The survival rates obtained with the non-dechorionated embryos without lid group suggested that it could be the optimal exposure level to achieve the objective proposed. With the obtained results, we concluded that this UV radiation dose for 60 and 30 s are optimal parameters to penalize recipient wild and gold strain zebrafish embryos, respectively in chimaerism assays, but without involving their survival and apparently normal development. PMID- 19788523 TI - Synchronizing cell cycle of goat fibroblasts by serum starvation causes apoptosis. AB - Cell cycle stage and synchronization of donor cells are important factors influencing the success of somatic cell nuclear transfer. This study examined whether serum starvation has any effect on specific cell death. We also studied the effects of serum starvation, culture to confluence, and full confluency (confluent + 72 h) on cell cycle characteristics and apoptosis of goat dermal fibroblast cells. The cells were obtained from the ear of a 1.5-year-old female goat. The following experimental groups were analysed for fibroblast cells: (i) normally growing, (ii) confluent, (iii) full confluency, (iv) cells starved for 48 h and (v) cells starved for 72 h. Analysis of cell cycle distribution by flow cytometry showed that 4.56 and 51.88% of normal cycling cells were at the G0 and G1 phases respectively. In the confluent group, 80% of the cells were arrested in the G0/G1 phase. Serum starvation for 48 and 72 h arrested 84.78% and 90.1% cells at the G0/G1 phase respectively which showed a significant difference when compared with the control group (p < 0.05). Double staining by PI and FITC distinguishes G0 phase from G1 phase. In the full confluency group, 91.53% of cells were at G0/G1 stage, but in contrast to the serum starved group, this high percentage of G0/G1 cells was mainly associated with G1 cells. Under normal culture conditions, 6.39% of cells underwent early apoptosis. In the confluent group 8.93% of cells showed early apoptosis. Serum starvation for 48 and 72 h caused early apoptosis in 8.91 and 39.83% of the cells respectively. Full confluency treatment did not increase the number of apoptotic cells significantly (8.67%). After 72 h, serum starvation significantly increased early apoptosis (p < 0.05). In conclusion, the use of full confluency is suitable for cell cycle synchronization because it arrests cells at the G0/G1 phase and also induces less apoptosis in comparison with the serum starvation group. PMID- 19788524 TI - Two unusual cases of canine prostatitis: prostatitis in a castrated dog and preputial oedema in an intact male. AB - In this study, two unusual presentations of canine prostatitis are described; in the first case a 10-years-old neutered Boxer dog was presented to the Veterinary Teaching Hospital of the University of Extremadura with a complaint of anorexia, apathy and preputial discharge. In the second case, a local veterinarian referred an 8-years-old male Labrador to the Veterinary Teaching Hospital of the University of Extremadura. The dog had a history of pain in the caudal abdomen and preputial oedema. The final diagnosis in both cases was acute prostatitis. It is concluded that although canine prostatitis is a common disease, sometimes can have presentations that may differ from those classically described in the literature. PMID- 19788525 TI - The pattern of embryonic fixation and its relationship to pregnancy loss in thoroughbred mares. AB - Ultrasonographic pregnancy records of 195 mares from six Thoroughbred stud farms, over a period of 7 years were retrospectively analysed to assess the effect of various factors on embryonic vesicle (EV) fixation pattern and pregnancy outcome. Of the total of 746 pregnancies analysed, significantly (p < 0.01) more EV fixations were evident in the right uterine horn than in the left (53.35% vs 46.65% respectively). There was no significant effect of either, the side of ovulation, or age of the mare, on the side of EV fixation. However, EV fixation, was significantly (p < 0.001) more likely to occur in the right uterine horn in maiden and barren mares (65.75% vs 57.45% respectively). The age and reproductive status of the mare as well as foal heat breeding failed to demonstrate a consistent effect on pregnancy loss relative to the side of EV fixation. In lactating and foal heat bred mares, EVs were significantly (p < 0.0001) more frequently established in the contralateral horn to the one from which the mare delivered her most recent foal. In lactating mares, significantly (p < 0.05) higher embryonic and pregnancy losses were observed in the ipsilateral horn. In conclusion, (a) side of EV fixation was (i) independent of the side of ovulation and mare age (ii) significantly (p < 0.001) affected by reproductive status, (b) neither age of mare nor reproductive status had any effect on pregnancy loss rates relative to the side of EV fixation and (c) in lactating mares the EV had a greater chance of fixation and survival in the horn contralateral to the one from which the mare delivered her most recent foal. PMID- 19788526 TI - Interaction of potential porcine sperm ligands with the oocyte plasma membrane. AB - We previously identified 62, 39, 27 and 7 kDa porcine sperm plasma membrane proteins that demonstrated a predominant affinity for the porcine oocyte plasma membrane by Western ligand blotting. The current experiments were designed to further investigate the potential roles of these molecules in sperm-oocyte plasma membrane interaction. Abilities of these proteins to bind to the oocyte plasma membrane and to inhibit sperm-oocyte interaction were evaluated. Plasma membrane was isolated primarily from the head of ejaculated porcine sperm by nitrogen cavitation and density gradient centrifugation. Fractions containing the 62, 39, 27 and 7 kDa proteins were electroeluted from one dimensional SDS polyacrylamide gels, dialysed and proteins biotinylated. Following incubation with zona-free porcine oocytes, bound protein was visualized with 20 MUg TRITC-avidin/ml using confocal microscopy. Fractions of the dialysed, electroeluted proteins were added to porcine in vitro fertilization assays. The 62, 39, 27 and 7 kDa proteins all demonstrated binding to the oocyte plasma membrane in contrast to a biotinylated control protein. Addition of unlabelled sperm plasma membrane proteins to the biotinylated protein visibly reduced binding. Addition of each of these protein fractions to in vitro fertilization assays reduced sperm interaction with the porcine oocyte plasma membrane in a concentration-dependent manner. Binding of these sperm plasma membrane proteins to the oocyte plasma membrane and inhibition of fertilization are consistent with these proteins being involved in sperm oocyte plasma membrane interaction. PMID- 19788527 TI - In vitro effect of the reproductive hormones on the oxidative burst activity of polymorphonuclear leucocytes from cows: a flow cytometric study. AB - In this study, the effect of reproductive hormones and substances with hormonal activity on the oxidative burst activity of blood polymorphonuclear leucocytes (PMN) high yielding dairy cows was evaluated. Different concentrations of: progesterone, oestradiol 17beta, FSH, LH, GnRH, cortisol and PGF2alpha were incubated in vitro for 4 h with PMN of seven high milk yielding cows, during the period of anoestrous postpartum. Controls were run in parallel in which each hormone was replaced by its solvent. After incubation with hormones the competence of PMN to generate H(2) O(2) was monitored by flow cytometry. A down regulation on the oxidative burst activity of PMA-stimulated PMN was observed when cells were incubated with progesterone. Significant (p <= 0.001) differences between control and progesterone incubated cells were observed from 6.56 MUg/ml. The same predisposition was observed when PMNs were incubated with cortisol. Besides for all concentrations employed, a decrease in the burst activity was observed, only beyond 0.19 mg/ml, statistical differences between the results obtained by the control and the cortisol incubated cells were obtained. Concerning oestradiol 17beta, an increase on H(2) O(2) -production was observed when PMN were incubated with 15 pg/ml and 45 pg/ml of this steroid (p <= 0.05), followed by a depression of the cell's activity when unphysiological concentrations were employed. Significant (p <= 0.05) differences between the obtained with the control and oestradiol 17beta incubated cells were observed only in the highest concentration of oestradiol. No statistical differences were observed in the metabolic burst activity of PMN incubated with FSH, GnRH and LH when compared with the results obtained by the control. PMID- 19788528 TI - Asymmetrical body perception: a possible role for neural body representations. AB - Perception of one's body is related not only to the physical appearance of the body, but also to the neural representation of the body. The brain contains many body maps that systematically differ between right- and left-handed people. In general, the cortical representations of the right arm and right hand tend to be of greater area in the left hemisphere than in the right hemisphere for right handed people, whereas these cortical representations tend to be symmetrical across hemispheres for left-handers. We took advantage of these naturally occurring differences and examined perceived arm length in right- and left-handed people. When looking at each arm and hand individually, right-handed participants perceived their right arms and right hands to be longer than their left arms and left hands, whereas left-handed participants perceived both arms accurately. These experiments reveal a possible relationship between implicit body maps in the brain and conscious perception of the body. PMID- 19788529 TI - Suppression during binocular rivalry broadens orientation tuning. AB - During binocular-rivalry suppression, an ordinarily visible stimulus is erased from awareness, but how is the sensory representation of that stimulus affected? Although it is established that rivalry suppression attenuates signal strength, the influence of suppression on signal fidelity remains unknown. Here, we show that noise plays a hitherto undiscovered role in the degradation of the percept under suppression. In Experiment 1, we measured psychometric functions for a stimulus presented under dominance and suppression, and found that the slope of these functions was shallower under suppression-a result suggesting that the signal representation was rendered noisier. Experiment 2 then revealed the source of this noise: An examination of the influence of suppression on the orientation bandwidth of noise masking showed that tuning bandwidth is significantly broadened under suppression. Thus, the discriminability of a suppressed stimulus is weakened not only by a general decrease in signal strength, but also by broader orientation tuning that introduces more noise in the neural representation of the suppressed stimulus. PMID- 19788530 TI - When are attention and saccade preparation dissociated? AB - To understand the mechanisms of visual attention, it is crucial to know the relationship between attention and saccades. Some theories propose a close relationship, whereas others view the attention and saccade systems as completely independent. One possible way to resolve this controversy is to distinguish between the maintenance and shifting of attention. The present study used a novel paradigm that allowed simultaneous measurement of attentional allocation and saccade preparation. Saccades toward the location where attention was maintained were either facilitated or suppressed depending on the probability of making a saccade to that location and the match between the attended location and the saccade location on the previous trial. Shifting attention to another location was always associated with saccade facilitation. The findings provide a new view, demonstrating that the maintenance of attention and shifting of attention differ in their relationship to the oculomotor system. PMID- 19788531 TI - A picture's worth: partner photographs reduce experimentally induced pain. PMID- 19788532 TI - The unconscious eye opener: pupil dilation reveals strategic recruitment of resources upon presentation of subliminal reward cues. PMID- 19788533 TI - Enhancement of DNA repair using topical T4 endonuclease V does not inhibit melanoma formation in Cdk4(R24C/R24C)/Tyr-Nras(Q61K) mice following neonatal UVR. AB - To further investigate the use of DNA repair-enhancing agents for skin cancer prevention, we treated Cdk4(R24C/R24C)/Nras(Q61K) mice topically with the T4 endonuclease V DNA repair enzyme (known as Dimericine) immediately prior to neonatal ultraviolet radiation (UVR) exposure, which has a powerful effect in exacerbating melanoma development in the mouse model. Dimericine has been shown to reduce the incidence of basal-cell and squamous cell carcinoma. Unexpectedly, we saw no difference in penetrance or age of onset of melanoma after neonatal UVR between Dimericine-treated and control animals, although the drug reduced DNA damage and cellular proliferation in the skin. Interestingly, epidermal melanocytes removed cyclobutane pyrimidine dimers (CPDs) more efficiently than surrounding keratinocytes. Our study indicates that neonatal UVR-initiated melanomas may be driven by mechanisms other than solely that of a large CPD load and/or their inefficient repair. This is further suggestive of different mechanisms by which UVR may enhance the transformation of keratinocytes and melanocytes. PMID- 19788534 TI - Sunbeds as vitamin D sources. AB - The objectives of this work were: (1) To determine whether repeated exposures to small doses from a commercial sun bed (Wolff Solarium Super Plus 100 W) over 5 weeks gave less vitamin D than repeated exposures to twice as large, but still nonerythemogenic, doses. (2) To investigate whether the contribution to the vitamin D status from such sessions of exposures was dependent on the baseline status before the start of the sessions. (3) To determine the decay rate of the induced increment of vitamin D. The sun bed sessions raised the 25-hydroxyvitamin D levels from typical winter values to typical summer values. The mean value after exposure being 80 nm (+/-14) and the increase being 15 nm on average. Persons with the lowest initial levels got the largest increase. The level in this group was back to the pre-exposure level after 2-4 weeks. To maintain a summer level through the winter, when no vitamin D is produced by the sun in northern countries, one should consider increasing the recommended intake of vitamin D intake significantly, or encouraging the population to get moderate, nonerythemal sun bed exposures. PMID- 19788535 TI - Molecular pathogenesis of malignant melanoma: a different perspective from the studies of melanocytic nevus and acral melanoma. AB - The Clark model for melanoma progression emphasizes a series of histopathological changes beginning from benign melanocytic nevus to melanoma via dysplastic nevus. Several models of the genetic basis of melanoma development and progression are based on this Clark's multi-step model, and predict that the acquisition of a BRAF mutation can be a founder event in melanocytic neoplasia. However, our recent investigations have challenged this view, showing the polyclonality of BRAF mutations in melanocytic nevi. Furthermore, it is suggested that many melanomas, including acral and mucosal melanomas, arise de novo, not from melanocytic nevus. While mutations of the BRAF gene are frequent in melanomas on non-chronic sun damaged skin which are prevalent in Caucasians, acral and mucosal melanomas harbor mutations of the KIT gene as well as the amplifications of cyclin D1 or cyclin-dependent kinase 4 gene. Amplifications of the cyclin D1 gene are detected in normal-looking 'field melanocytes', which represent a latent progression phase of acral melanoma that precedes the stage of atypical melanocyte proliferation in the epidermis. Based on these observations, we propose an alternative genetic progression model for melanoma. PMID- 19788536 TI - Residential proximity to main roads during pregnancy and the risk of allergic disorders in Japanese infants: the Osaka Maternal and Child Health Study. AB - The role of traffic-related air pollution in the initiation of allergic disorders in children is still not clearly understood. The present prospective study examined the relation between proximity of the home during pregnancy to the nearest main road, which was used as a surrogate for traffic-related air pollutants, and the risk of allergic disorders in Japanese infants in an urban area. Subjects were 756 mother-child pairs. Distance of each subject's home during pregnancy from the center line of all of the 235 main roads in Osaka Prefecture was computed using geographical information system software. The first survey during pregnancy and the second survey between 2 and 9 months post-partum collected information on potential confounding factors. In the third survey, which was from 16 to 24 months post-partum, a self-administered questionnaire included questions on allergic disorders. In the third survey, 22.1% and 18.7% of infants became positive for wheeze and atopic eczema based on criteria of the International Study of Asthma and Allergies in Childhood (ISAAC), respectively. The risk of doctor-diagnosed asthma and doctor-diagnosed atopic eczema was 4.4% and 8.9%, respectively. A shorter distance of the residence during pregnancy from the nearest main road was associated with an increased risk of doctor-diagnosed asthma and atopic eczema (adjusted odds ratios for comparison of <50 m with 200 m or more = 4.01 and 2.26, 95% confidence intervals: 1.44-11.24 and 1.08-4.59, p for trend = 0.02 and 0.03, respectively). No evident relationships were observed between the distance of the residence during pregnancy from the nearest main road and the risk of wheeze or atopic eczema based on the ISAAC criteria. It was difficult to distinguish the effect of the pre-natal from the post-natal exposure because most subjects lived at the same home address both before and after childbirth. Our results are likely to support the hypothesis that intrauterine exposure to traffic-related air pollutants and/or such exposure after birth may increase the risk of more extreme manifestations of allergic disorders in infants. PMID- 19788537 TI - Non-invasive markers of airway inflammation and remodeling in childhood asthma. AB - To evaluate the relationship between pro-inflammatory and pro-remodeling mediators and severity and control of asthma in children, the levels of IL-8, MMP 9, TIMP-1 in induced sputum supernatants, the number of sputum eosinophils, as well as FeNO, were investigated in 35 asthmatic children, 12 with intermittent (IA) and 23 with moderate asthma (MA), and 9 controls (C). The patients with asthma were followed for 1 yr and sputum was obtained twice during the follow-up. Biomarker levels were correlated with the number of exacerbations. We found that IL-8, MMP-9, TIMP-1 and the numbers of eosinophils in induced sputum, as well as FeNO, were increased in children with IA and MA in comparison to C. The ongoing inflammation was confirmed by increased nuclear p65 NF-kappaB subunit localization in sputum cells. In MA, FeNO measurements, sputum eosinophils and IL 8 levels, positively correlated with the occurrence of disease exacerbations during a 1-yr follow-up. According to FeNO, sputum eosinophils and IL-8 sputum concentrations, and the number of exacerbations, two distinct phenotypes of MA were identified. This study shows that the presence of bronchial inflammation is detectable in the airways of some IA, as well as in the airways of MA, despite the regular ICS treatment. This study also proposes the need to perform large prospective studies to confirm the importance of measuring specific biomarkers in induced sputum, concomitantly to FeNO analyses, to assess sub-clinical airway inflammation and disease control in children with asthma. PMID- 19788538 TI - Prevalence of rhinitis-related symptoms in Latin American children - results of the International Study of Asthma and Allergies in Childhood (ISAAC) phase three. AB - The aim of this study was to evaluate the prevalence of rhinitis-related symptoms among children living in different parts of Latin America (LA) considering all centers involved in ISAAC Phase Three (Ph3). 93,851 children (6-7 yr-old) from 35 centers in 14 LA countries and 165,917 adolescents (13-14 yr-old) from 56 centers in 17 LA countries were enrolled. The mean prevalence rate of current rhinoconjunctivitis was 12.7% and ranged from 5.5% in Rosario City (Argentina) to 21.2% in Caracas (Venezuela) for the schoolchildren. The mean prevalence rate of current rhinoconjunctivitis was 18.5% and ranged from 7.1% in Cuernavaca (Mexico) to 45.1% in Asuncion (Paraguay) for the adolescents. These indexes were among the higher observed during ISAAC Ph3. In general the prevalence of rhinitis-related symptoms was higher among the Spanish speaking centers. Environmental risk factors must be evaluated in order to explain the differences observed even in centers from the same country. PMID- 19788539 TI - Development of atopic dermatitis in the DARC birth cohort. AB - The aim was to describe the relapsing pattern, sensitization and prognosis of atopic dermatitis (AD) in the first 6 yr in a population-based, prospective birth cohort. The DARC cohort includes 562 children with clinical examinations, specific-IgE and skin prick test at all follow-ups. All children were examined for the development of AD using Hanifin-Rajka criteria and for food hypersensitivity by oral challenges. Severity of AD was measured by objective SCORing Atopic Dermatitis (SCORAD). Point-prevalence of AD peaked at 18 months of age (10%) and decreased at 36 and 72 months to slightly below 7%. The 6-yr cumulative incidence was 22.8% and sensitization was found in 43% of children with AD. It was predominately sensitization to foods, however shifting toward inhalant allergens with age. Sensitization at >or=2 follow-ups affected severity, whereas short-term sensitization at one follow-up does not. Children with early, non-IgE mediated (intrinsic) AD outgrew more often their eczema; however if they develop persistent AD, they remain intrinsic. Early long-term sensitization worsens the prognosis, but 38% of all children have a debut later than 18 months of age. Boys had earlier onset of AD than girls. The large number of follow-ups gives a detailed picture of the relapsing pattern and shows that the relapses occur independently of time of onset. We could not establish any clear correlation between elimination diets and AD duration nor severity. PMID- 19788540 TI - Lipid body formation plays a central role in cell fate determination during developmental differentiation of Myxococcus xanthus. AB - Cell differentiation is widespread during the development of multicellular organisms, but rarely observed in prokaryotes. One example of prokaryotic differentiation is the gram-negative bacterium Myxococcus xanthus. In response to starvation, this gliding bacterium initiates a complex developmental programme that results in the formation of spore-filled fruiting bodies. How the cells metabolically support the necessary complex cellular differentiation from rod shaped vegetative cells into spherical spores is unknown. Here, we present evidence that intracellular lipid bodies provide the necessary metabolic fuel for the development of spores. Formed at the onset of starvation, these lipid bodies gradually disappear until they are completely used up by the time the cells have become mature spores. Moreover, it appears that lipid body formation in M. xanthus is an important initial step indicating cell fate during differentiation. Upon starvation, two subpopulations of cells occur: cells that form lipid bodies invariably develop into spores, while cells that do not form lipid bodies end up becoming peripheral rods, which are cells that lack signs of morphological differentiation and stay in a vegetative-like state. These data indicate that lipid bodies not only fuel cellular differentiation but that their formation represents the first known morphological sign indicating cell fate during differentiation. PMID- 19788541 TI - Paralogous antirepressors acting on the master regulator for biofilm formation in Bacillus subtilis. AB - Matrix production during biofilm formation by Bacillus subtilis is governed by a gene control circuit at the heart of which are three dedicated regulatory proteins, the antirepressor SinI, the repressor SinR and the downstream regulator SlrR. Matrix production is triggered by the synthesis of SinI, which binds to and inactivates SinR, thereby derepressing genes for matrix production as well as the gene for SlrR. Recently, two additional regulators of matrix genes were identified: SlrA, which was reported to be an activator of SlrR, and YwcC, a repressor of SlrA synthesis (Kobayashi, 2008). We present evidence indicating that SlrA, which is a paralogue of SinI, is like SinI, an antirepressor that binds to, and inactivates, SinR. We also show that SlrA does not activate SlrR for expression of matrix genes. Instead, SlrR binds to, and inhibits the activity of, SlrA. Thus, the YwcC-SlrA-SinR-SlrR pathway is a negative feedback loop in which SlrA indirectly stimulates the synthesis of SlrR, and SlrR, in turn, inhibits the activity of SlrA. Finally, we report that under standard laboratory conditions SlrA makes only a small contribution to the expression of genes for matrix production. We propose that in response to an unknown signal recognized by the YwcC repressor, SlrA transiently boosts matrix production. PMID- 19788542 TI - Ras1 and Ras2 play antagonistic roles in regulating cellular cAMP level, stationary-phase entry and stress response in Candida albicans. AB - The GTPase Ras1 activates the yeast-to-hypha transition in Candida albicans by activating cAMP synthesis. Here, we have characterized Ras2. Ras2 belongs to a group of atypical Ras proteins in some fungal species that share poor identity with other Ras GTPases with many variations in conserved motifs thought to be crucial for Ras-associated activities. We find that recombinant Ras2 is enzymatically as active as Ras1. However, only RAS1 can rescue the lethality of the Saccharomyces cerevisiae ras1 ras2 mutant, suggesting functional divergence of the two genes. ras2Delta is normal in hyphal growth, but deleting RAS2 in the ras1Delta background greatly aggravates the hyphal defect, indicating that Ras2 also has a role in hyphal development. Strikingly, while RAS1 deletion causes a approximately 20-fold decrease in cellular cAMP, further deletion of RAS2 restores it to approximately 30% of the wild-type level. Consistently, while the ras1Delta mutant enters the stationary phase prematurely, the double mutant does so normally. Moreover, ras1Delta cells exhibit increased resistance to H(2)O(2) and higher sensitivity to the heavy metal Co(2+), whereas ras2Delta cells show the opposite phenotypes. Together, our data reveal a novel regulatory mechanism by which two antagonizing Ras GTPases balance each other in regulating multiple cellular processes in C. albicans. PMID- 19788543 TI - Genetic and biochemical analysis of the serine/threonine protein kinases PknA, PknB, PknG and PknL of Corynebacterium glutamicum: evidence for non-essentiality and for phosphorylation of OdhI and FtsZ by multiple kinases. AB - We previously showed that the 2-oxoglutarate dehydrogenase inhibitor protein OdhI of Corynebacterium glutamicum is phosphorylated by PknG at Thr14, but that also additional serine/threonine protein kinases (STPKs) can phosphorylate OdhI. To identify these, a set of three single (DeltapknA, DeltapknB, DeltapknL), five double (DeltapknAG, DeltapknAL, DeltapknBG, DeltapknBL, DeltapknLG) and two triple deletion mutants (DeltapknALG, DeltapknBLG) were constructed. The existence of these mutants shows that PknA, PknB, PknG and PknL are not essential in C. glutamicum. Analysis of the OdhI phosphorylation status in the mutant strains revealed that all four STPKs can contribute to OdhI phosphorylation, with PknG being the most important one. Only mutants in which pknG was deleted showed a strong growth inhibition on agar plates containing glutamine as carbon and nitrogen source. Thr14 and Thr15 of OdhI were shown to be phosphorylated in vivo, either individually or simultaneously, and evidence for up to two additional phosphorylation sites was obtained. Dephosphorylation of OdhI was shown to be catalysed by the phospho-Ser/Thr protein phosphatase Ppp. Besides OdhI, the cell division protein FtsZ was identified as substrate of PknA, PknB and PknL and of the phosphatase Ppp, suggesting a role of these proteins in cell division. PMID- 19788544 TI - Two NDR kinase-MOB complexes function as distinct modules during septum formation and tip extension in Neurospora crassa. AB - NDR kinases are important for growth and differentiation and require interaction with MOB proteins for activity and function. We characterized the NDR kinases and MOB activators in Neurospora crassa and identified two NDR kinases (COT1 and DBF2) and four MOB proteins (MOB1, MOB2A, MOB2B and MOB3/phocein) that form two functional NDR-MOB protein complexes. The MOB1-DBF2 complex is not only essential for septum formation in vegetative cells and during conidiation, but also functions during sexual fruiting body development and ascosporogenesis. The two MOB2-type proteins interact with both COT1 isoforms and control polar tip extension and branching by regulating COT1 activity. The conserved region directly preceding the kinase domain of COT1 is sufficient for the formation of COT1-MOB2 heterodimers, but also for kinase homodimerization. An additional N terminal extension that is poorly conserved, but present in most fungal NDR kinases, is required for further stabilization of both types of interactions and for stimulating COT1 activity. COT1 lacking this region is degraded in a mob-2 background. We propose a specific role of MOB3/phocein during vegetative cell fusion, fruiting body development and ascosporogenesis that is unrelated to the three other MOB proteins and NDR kinase signalling. PMID- 19788545 TI - The Bacillus subtilis SftA (YtpS) and SpoIIIE DNA translocases play distinct roles in growing cells to ensure faithful chromosome partitioning. AB - In several bacterial species, the faithful completion of chromosome partitioning is known to be promoted by a conserved family of DNA translocases that includes Escherichia coli FtsK and Bacillus subtilis SpoIIIE. FtsK localizes at nascent division sites during every cell cycle and stimulates chromosome decatenation and the resolution of chromosome dimers formed by recA-dependent homologous recombination. In contrast, SpoIIIE localizes at sites where cells have divided and trapped chromosomal DNA in the membrane, which happens during spore development and under some conditions when DNA replication is perturbed. SpoIIIE completes chromosome segregation post-septationally by translocating trapped DNA across the membrane. Unlike E. coli, B. subtilis contains a second uncharacterized FtsK/SpoIIIE-like protein, SftA (formerly YtpS). We report that SftA plays a role similar to FtsK during each cell cycle but cannot substitute for SpoIIIE in rescuing trapped chromosomes. SftA colocalizes with FtsZ at nascent division sites but not with SpoIIIE at sites of chromosome trapping. SftA mutants divide over unsegregated chromosomes more frequently than wild-type unless recA is inactivated, suggesting that SftA, like FtsK, stimulates chromosome dimer resolution. Having two FtsK/SpoIIIE paralogues is not conserved among endospore-forming bacteria, but is highly conserved within several groups of soil- and plant-associated bacteria. PMID- 19788546 TI - It takes two DNA translocases to untangle chromosomes from the division septum. AB - The DNA translocase function of Bacillus subtilis SpoIIIE is essential for spore development and is important during vegetative growth for moving trapped chromosomal DNA away from division septa. Two papers in this issue of Molecular Microbiology, from the teams of Peter Graumann and William Burkholder, have characterized a second SpoIIIE/FtsK-like protein in B. subtilis, SftA. This protein lacks any recognizable transmembrane domain possessed by the other characterized members of the family, yet the protein is shown to be associated with the division septum and, like SpoIIIE, is required for clearing DNA from the septum. However, SftA and SpoIIIE act at different stages of septation and together they ensure maximum fidelity in chromosome segregation. PMID- 19788547 TI - The first evidence that a single cellulase can be essential for cellulose degradation in a cellulolytic microorganism. AB - Summary Cellulose is the most abundant carbon source in nature but it is very difficult to degrade because of its insolubility, quasi-crystalline structure and its presence in plant cell walls in a matrix with other polymers that limit access to the cellulose surface. Most cellulose in soils is degraded by cellulolytic microorganisms that use a number of different approaches to overcome the recalcitrance of cellulose in plant cell walls. All of these approaches involve multiple cellulases and, since cellulose is insoluble and microorganisms cannot ingest particles, the cellulases are present outside of the cell although they can be attached to its outer surface. An impressive article by Tolonen et al. in this issue of Molecular Microbiology shows that deletion of the single family 9 cellulase gene in Clostridium phytofermentans prevents growth on cellulose although the mutant strain grows perfectly well on glucose and its other cellulase genes are transcribed normally. These results show for the first time that a single cellulase can be essential for cellulose degradation by an organism despite the presence of several other cellulases. It will be interesting to learn the detailed mechanism that C. phytofermentans uses to degrade cellulose. PMID- 19788548 TI - Site-specific population dynamics and variable olfactory marker protein expression in the postnatal canine olfactory epithelium. AB - The main olfactory epithelium is a pseudostratified columnar epithelium that displays neurogenesis over the course of a lifetime. New olfactory neurons arise basally and are transferred to the middle third of the epithelium during maturation. It is generally believed that this pattern is present throughout the olfactory area. In the present study, we show that the postnatal canine olfactory epithelium is composed of two distinct types of epithelium, designated A and B, which not only differ in olfactory neuron morphology, marker expression and basal cell proliferation but also display a patchy distribution and preferential localization within the nasal cavity. Type A epithelium, abundant in the caudal part of the olfactory area, contains well-differentiated olfactory neurons positive for olfactory marker protein but low numbers of immature neurons and proliferating basal cells, as visualized by TrkB/Human Natural Killer-1 (HNK-1) glyco-epitope and Ki-67 immunostaining, respectively. In contrast, type B epithelium is mainly found in the rostral part and contains smaller and elongated neurons that display increased levels of TrkB/Human Natural Killer-1 (HNK-1) glyco-epitope immunoreactivity and a higher number of Ki-67-positive basal cells but lower and variable levels of olfactory marker protein. The vomeronasal organ displays a uniform distribution of molecular markers and proliferating basal cells. The observation that olfactory marker protein in type A and B epithelium is preferentially localized to the nucleus and cytoplasm, respectively, implies correlation between subcellular localization and olfactory neuron maturation and may indicate distinct functional roles of olfactory marker protein. Whether the site-specific population dynamics in the postnatal canine olfactory epithelium revealed in the present study are modulated by physiological parameters, such as airflow, has to be clarified in future studies. PMID- 19788549 TI - Dynamics of emotion regulation in infants of clinically depressed and nondepressed mothers. AB - BACKGROUND: Emotion regulation (ER) has been conceptualized as an ongoing process of the individual's emotion patterns in relation to moment-to-moment contextual demands. In contrast to traditional approaches of descriptively quantizing ER, we employed a dynamic approach to ER by examining key transitions in infants of clinically depressed and nondepressed mothers in the context of maternal still face (SF). METHODS: Mothers with (n = 48) and without a clinical diagnosis of depression (n = 68) were seen in a modified SF paradigm with their 5-month-olds. Infant states and self-soothing behaviors were coded in 1-sec time intervals. RESULTS: Infants of nondepressed mothers used attentional regulatory strategies, whereas infants of depressed mothers used internally directed strategies of self soothing to reduce negativity and maintain engagement with mother. CONCLUSIONS: This study advances our understanding of processes underlying infant ER and points to possible mechanisms for the development of long-term maladaptive ER strategies in infants of depressed mothers. PMID- 19788550 TI - Comorbidity of learning disorders: prevalence and familial transmission. AB - BACKGROUND: In order to fully specify the profiles of risk and protective factors of developmental disorders, a better understanding of the conditions under which they co-occur is required. So far, empirical evidence on comorbidities of specific learning disorders in arithmetic, reading and spelling is scarce. METHODS: Prevalence and gender ratios of specific learning disorders in arithmetic (AD), reading (RD), and spelling (SD) and their co-occurrence were assessed in a large (N = 2586) population-based sample of elementary school children and in a subsample of 293 children with at least one learning disorder (LD-sample). A questionnaire on familial transmission was given to a subsample of 256 parents of children with a learning disorder and 146 typically developing children. RESULTS: The rates of deficits in arithmetic, reading, or spelling were four to five times higher in samples already experiencing marked problems in one academic domain compared to the full population. Thus, comorbidity of learning disorders was confirmed in a fairly standard school population. Rates of co occurrence decreased for AD and RD, but not isolated SD when more stringent cutoff criteria were applied, suggesting that the comorbidity of arithmetic and spelling disorder may be more strongly biologically mediated than the comorbidity of arithmetic and reading disorder. We found a preponderance of girls with AD and boys with SD. These imbalanced gender ratios were especially marked for isolated problems, while for comorbid problems gender ratios were mostly balanced with the exception of deficits in arithmetic and reading (but not spelling) which were more typical for girls. The parental questionnaire provided evidence for disorder specific familial transmission and co-segregation of arithmetic and literacy deficits. CONCLUSIONS: Comorbidities of learning disorders are not artificial. They are the result of a complex interplay between both general and disorder specific aetiological factors. PMID- 19788551 TI - Reduced electrodermal fear conditioning from ages 3 to 8 years is associated with aggressive behavior at age 8 years. AB - BACKGROUND: Poor fear conditioning characterizes adult psychopathy and criminality, but it is not known whether it is related to aggressive/antisocial behavior in early childhood. METHODS: Using a differential, partial reinforcement conditioning paradigm, electrodermal activity was recorded from 200 male and female children at ages 3, 4, 5, 6, and 8 years. Antisocial/aggressive and hyperactive-inattentive measures were collected at age 8. RESULTS: Poor electrodermal fear conditioning from ages 3 to 8 years was associated with aggressive behavior at age 8 in both males and females. CONCLUSIONS: Results indicate that the relationship between poor fear conditioning and aggression occurs early in childhood. Enhanced electrodermal fear conditioning may protect children against future aggressive/violent behavior. Abnormal amygdala functioning, as indirectly assessed by fear conditioning, may be one of the factors influencing the development of childhood aggression. PMID- 19788552 TI - Anxiety and depression are risk factors rather than consequences of functional somatic symptoms in a general population of adolescents: the TRAILS study. AB - BACKGROUND: It is well known that functional somatic symptoms (FSS) are associated with anxiety and depression. However, evidence is lacking about how they are related to FSS. The aim of this study was to clarify these relationships and examine whether anxiety and depression are distinctly related to FSS. We hypothesized that anxiety contributes to the development of FSS and that depression is a consequence of FSS. METHODS: FSS, anxiety, and depression were measured in adolescents (N = 2230, 51% women) by subscales of the Youth Self Report during three assessment waves (adolescents successively aged: 10-12, 12 14, and 14-17) and by corresponding subscales of the Child Behavior Checklist. Using structural equation models, we combined trait and state models of FSS with those of anxiety and depression, respectively. We identified which relationships (contemporaneous and two-year lagged) significantly connected the states of FSS with the states of anxiety and depression. RESULTS: Trait variables were all highly interrelated (r = .54-.63). Contrary to our hypothesis, both state anxiety (beta = .35) and state depression (beta = .45) had a strong contemporaneous effect on state FSS. In turn, state FSS had a weak two-year lagged effect on state anxiety (beta = .11) and an even weaker effect on state depression (beta = .06). CONCLUSIONS: While the effect of anxiety and depression on FSS is strong and immediate, FSS exert a weaker and delayed influence on anxiety and depression. Further research should be done to detect the exact ways in which anxiety and depression lead to FSS, and FSS lead to anxiety and depression. PMID- 19788554 TI - The representation of fathers by children of depressed mothers: refining the meaning of parentification in high-risk samples. AB - BACKGROUND: Children's representations of mothers in doll-play are associated with child adjustment. Despite the importance of fathers for children's adjustment, especially in the context of maternal psychopathology, few studies have considered children's representations of their fathers. METHOD: We examined the portrayal of fathers by 5-year-old children of depressed (N = 55) and non depressed (N = 39) mothers in a doll-play procedure concerning family experience. RESULTS: Children gave equal prominence in their play to mothers and fathers. Representations of fathers were unrelated to maternal mood, but were associated with parental conflict. Representations of child care for the father that was unreciprocated predicted poor child adjustment in school, but only in children exposed to maternal postnatal depression. CONCLUSIONS: It may be clinically useful to consider children's distinctive representations of their mother and father; but the concept of parentification in relation to risk and resilience effects requires refinement. PMID- 19788553 TI - Emotion identification in girls at high risk for depression. AB - BACKGROUND: Children of depressed mothers are themselves at elevated risk for developing a depressive disorder. We have little understanding, however, of the specific factors that contribute to this increased risk. This study investigated whether never-disordered daughters whose mothers have experienced recurrent episodes of depression during their daughters' lifetime differ from never disordered daughters of never-disordered mothers in their processing of facial expressions of emotion. METHOD: Following a negative mood induction, daughters completed an emotion identification task in which they watched faces slowly change from a neutral to a full-intensity happy, sad, or angry expression. We assessed both the intensity that was required to accurately identify the emotion being expressed and errors in emotion identification. RESULTS: Daughters of depressed mothers required greater intensity than did daughters of control mothers to accurately identify sad facial expressions; they also made significantly more errors identifying angry expressions. CONCLUSION: Cognitive biases may increase vulnerability for the onset of disorders and should be considered in early intervention and prevention efforts. PMID- 19788555 TI - Patients' perceptions of discrimination during hospitalization. AB - OBJECTIVE: To identify sources of perceived discrimination during hospitalization and examine the relationship of perceived discrimination to patient and hospital stay characteristics, and to patient ratings of care. BACKGROUND: Patient experiences of discrimination within the health-care system are associated with delays in care seeking, non-adherence to medical advice and poorer health status. Most research to date has focused on race and ethnicity-based discrimination, and few studies have included hospitalized patients. METHODS: Questions about patients' experiences of discrimination were added to a regular patient opinion survey conducted at the Geneva University Hospitals. Participants were 1537 adult residents of Switzerland discharged from the hospital between 15 February and 15 March 2007. RESULTS: A total of 171 (11.1%) respondents reported at least one source of discrimination. Most (93, 54.4%) reported a single cause of discrimination. The most frequent causes of discrimination were language, age, nationality and having a disease that is viewed negatively by others. Fifteen percentage of non-European respondents reported at least one of the following types of discrimination: language, nationality, religion and skin colour. Reporting discrimination from any cause was associated with higher Picker Patient Experience problem scores, and patients who reported discrimination were less likely to describe their care as very good or excellent and less likely to recommend the hospital to others. CONCLUSIONS: Patient experiences of discrimination during hospitalization are relatively frequent and are associated with lower patient ratings of care. Collection of data on patient experiences of discrimination may contribute to the development of interventions aimed at ensuring respectful, quality care for all patients. PMID- 19788556 TI - Geotrichum siamensis sp. nov. and Geotrichum phurueaensis sp. nov., two asexual arthroconidial yeast species isolated in Thailand. AB - Two asexual arthroconidial yeast strains, TM3-44(T) and LYSM5(T), were isolated, respectively, from estuarine water in a mangrove forest and soil in a terrestrial forest in Thailand. Analysis of the D1/D2 domains of the large-subunit rRNA gene sequences revealed that strain TM3-44(T) differed from the closest species in terms of pairwise sequence similarity, Dipodascus albidus, by 11.7% nucleotide substitutions, while strain LYSM5(T) was closest to Galactomyces geotrichum with only 2.9% nucleotide substitutions. The phylogenetic tree further demonstrated that strain TM3-44(T) was at a distant position from the closest species, D. albidus, and other related species in the Dipodascus clade, while strain LYSM5(T) clustered with G. geotrichum, it closest relative in the Galactomyces clade. The phenotypic characteristics of the two strains were typical of the genus Geotrichum. On the basis of the above findings, strain TM3-44(T) was assigned as a novel species of Geotrichum, for which the name Geotrichum siamensis sp. nov. is proposed. The type strain is TM3-44(T) (BCC 29903(T)=NBRC 104880(T)=CBS 10929(T)). Strain LYSM5(T) represented another novel species of Geotrichum, which was named Geotrichum phurueaensis sp. nov. The type strain is LYSM5(T) (BCC 34756(T)=NBRC 105674(T)=CBS 11418(T)). PMID- 19788557 TI - An upstream activation sequence controls the expression of AOX1 gene in Pichia pastoris. AB - Alcohol oxidase I gene (AOX1) promoter (P(AOX1)) is a key promoter in the methylotrophic yeast Pichia pastoris. To identify the cis-acting element in the AOX1 promoter, we constructed expression plasmids in which the green fluorescent protein (GFP) gene coding region was fused to a series of internal deletion mutants of the AOX1 promoter. By analyzing the expression and transcription level of GFP by each plasmid, we identified a positive cis-element, Region D, which is located between positions -638 and -510 of the AOX1 promoter. This region contains an invert repeat-like sequence GTGGGGTCAAATAGTTTCATGTTCCCCAA that is similar to the upstream activation sequence 1 (UAS1) of alcohol dehydrogenase II gene (ADH2) in Saccharomyces cerevisiae. The inverted repeat sequence in the UAS1 is known to contain the binding site for alcohol dehydrogenase II synthesis regulator (Adr1p). When three tandem copies of Region D were inserted into the Region D-deleted AOX1 promoter, the expression of GFP at the protein level and the mRNA level increased to 157% and 135% of the wild type, respectively. An electrophoretic mobility shift assay indicated that Region D could form a DNA protein complex with cell extracts under methanol-induced and glucose/methanol repressed conditions. These data suggest that Region D may function as a cis acting regulatory element in the AOX1 promoter to positively regulate the expression of AOX1. PMID- 19788558 TI - Candida albicans iron acquisition within the host. AB - As a commensal and opportunistic pathogen, Candida albicans possesses a range of determinants that contribute to survival, persistence and virulence. Among this repertoire of fitness and virulence attributes are iron acquisition factors and pathways, which allow fungal cells to gain this essential mineral in the iron poor environment of the host. The aim of this review is to present the strategies used by C. albicans to exploit host iron reservoirs and their impact on C. albicans pathogenicity. Because iron in the human host is mostly linked to host proteins, pathogens such as C. albicans must possess mechanisms to gain iron from these proteins. Here, we introduce the most important groups of human proteins, including haemoglobin, transferrin, lactoferrin and ferritin, which contain iron and that are potential iron sources for invading microorganisms. We then summarize and discuss the known and proposed strategies by which C. albicans exploits or may exploit iron from host proteins and compare these with strategies from other pathogenic microorganisms. PMID- 19788559 TI - Effects of groundwater development on uranium: Central Valley, California, USA. AB - Uranium (U) concentrations in groundwater in several parts of the eastern San Joaquin Valley, California, have exceeded federal and state drinking water standards during the last 20 years. The San Joaquin Valley is located within the Central Valley of California and is one of the most productive agricultural areas in the world. Increased irrigation and pumping associated with agricultural and urban development during the last 100 years have changed the chemistry and magnitude of groundwater recharge, and increased the rate of downward groundwater movement. Strong correlations between U and bicarbonate suggest that U is leached from shallow sediments by high bicarbonate water, consistent with findings of previous work in Modesto, California. Summer irrigation of crops in agricultural areas and, to lesser extent, of landscape plants and grasses in urban areas, has increased Pco(2) concentrations in the soil zone and caused higher temperature and salinity of groundwater recharge. Coupled with groundwater pumping, this process, as evidenced by increasing bicarbonate concentrations in groundwater over the last 100 years, has caused shallow, young groundwater with high U concentrations to migrate to deeper parts of the groundwater system that are tapped by public-supply wells. Continued downward migration of U-affected groundwater and expansion of urban centers into agricultural areas will likely be associated with increased U concentrations in public-supply wells. The results from this study illustrate the potential long-term effects of groundwater development and irrigation-supported agriculture on water quality in arid and semiarid regions around the world. PMID- 19788560 TI - Groundwater modeling in integrated water resources management--visions for 2020. AB - Groundwater modeling is undergoing a change from traditional stand-alone studies toward being an integrated part of holistic water resources management procedures. This is illustrated by the development in Denmark, where comprehensive national databases for geologic borehole data, groundwater-related geophysical data, geologic models, as well as a national groundwater-surface water model have been established and integrated to support water management. This has enhanced the benefits of using groundwater models. Based on insight gained from this Danish experience, a scientifically realistic scenario for the use of groundwater modeling in 2020 has been developed, in which groundwater models will be a part of sophisticated databases and modeling systems. The databases and numerical models will be seamlessly integrated, and the tasks of monitoring and modeling will be merged. Numerical models for atmospheric, surface water, and groundwater processes will be coupled in one integrated modeling system that can operate at a wide range of spatial scales. Furthermore, the management systems will be constructed with a focus on building credibility of model and data use among all stakeholders and on facilitating a learning process whereby data and models, as well as stakeholders' understanding of the system, are updated to currently available information. The key scientific challenges for achieving this are (1) developing new methodologies for integration of statistical and qualitative uncertainty; (2) mapping geological heterogeneity and developing scaling methodologies; (3) developing coupled model codes; and (4) developing integrated information systems, including quality assurance and uncertainty information that facilitate active stakeholder involvement and learning. PMID- 19788561 TI - Geostatistical modeling of a heterogeneous site bordering the Venice lagoon, Italy. AB - Geostatistical methods are well suited for analyzing the local and spatial uncertainties that accompany the modeling of highly heterogeneous three dimensional (3D) geological architectures. The spatial modeling of 3D hydrogeological architectures is crucial for polluted site characterization, in regards to both groundwater modeling and planning remediation procedures. From this perspective, the polluted site of Porto Marghera, located on the periphery of the Venice lagoon, represents an interesting example. For this site, the available dense spatial sampling network, with 769 boreholes over an area of 6 km(2), allows us to evaluate the high geological heterogeneity by means of indicator kriging and sequential indicator simulation. We show that geostatistical methodologies and ad hoc post processing of geostatistical analysis results allow us to effectively analyze the high hydrogeological heterogeneity of the studied site. PMID- 19788562 TI - Candida stigmatis sp. nov., a new anamorphic yeast species isolated from flowers. AB - Four strains of a previously unknown yeast species are described for which the name Candida stigmatis is proposed. The strains were isolated from stigmas of ant visited Magnolia flowers in the Indian city of Hyderabad. The sequences of the D1/D2 domains of the large subunit rRNA genes, the internal transcribed spacer (ITS) regions and the 18S rRNA genes were identical in the isolates and differed from the corresponding sequences of all known yeast species. In a phylogenetic analysis of these sequences, the new species formed a cluster with a group of six closely related anamorph Candida species (the closest species was Candida magnoliae, with 5% nucleotide substitution in the D1/D2 domain). Sexual reproduction was not observed in the isolates. The type strain is 11-465(T). It has been deposited in Centralbureau voor Schimmelcultures (Utrecht, the Netherlands) as CBS 11464(T) and Culture Collection of Yeasts (Bratislava, Slovakia) as CCY 29-179-1(T). The GenBank accession numbers for the nucleotide sequences of its D1/D2 domain, ITS and 18S regions are GQ184144, GQ184143 and GQ184142, respectively. PMID- 19788563 TI - Three new species of bipolar budding yeasts of the genus Hanseniaspora and its anamorph Kloeckera isolated in Thailand. AB - In the course of a survey of yeast biodiversity in the natural substrates in Thailand, eight strains were found to represent three hitherto undescribed species of Hanseniaspora/Kloeckera. They were isolated from insect frass, flower, lichen, rotted fruit and rotted wood. Based on the morphological and physiological characteristics, and sequences of D1/D2 domain, six strains represent a single species of the genus Hanseniaspora, described as Hanseniaspora thailandica sp. nov. (type BCC 14938(T)=NBRC 104216(T)=CBS 10841(T)), and another strain as Hanseniaspora singularis sp. nov. (type BCC 15001(T)=NBRC 104214(T)=CBS 10840(T)). A further strain, which belongs to Kloeckera and does not produce ascospores, is described as Kloeckera hatyaiensis sp. nov. (type BCC 14939(T)=NBRC 104215(T)=CBS 10842(T)). Strains belonging to H. thailandica sp. nov. differed by 17-19 nucleotide substitutions from Hanseniaspora meyeri, the closest species. DNA reassociation between the two taxa showed 30-48% relatedness. Kloeckera hatyaiensis sp. nov. and H. singularis sp. nov. differed by eight and 16 nucleotide substitutions with one gap from the nearest species, Hanseniaspora clermontiae and Hanseniaspora valbyensis, respectively. PMID- 19788564 TI - Ribavirin therapeutic drug monitoring: why, when and how? AB - Recent studies suggest the potential interest of ribavirin therapeutic drug monitoring to improve sustain virological response rate in hepatitis C virus infected patients. The present review details the pharmacokinetic properties of ribavirin, suggesting that it may be a good candidate for therapeutic drug monitoring, the different possible strategies and the analytical methods that could be employed. PMID- 19788565 TI - The gastrointestinal effects that may follow the administration of theophylline reflect the pharmacodynamic profiles of both the parent drug and its metabolites. AB - This study investigates the effect of theophylline along the rabbit gastrointestinal tract in comparison with the pharmacodynamic effect produced by the combined application of its three major metabolites. At concentrations up to 10(-3) m, theophylline relaxed, in a declining order from the lower oesophageal sphincter (LOS) to pylorus, all regions of the upper gastrointestinal tract, but only the ascending colon from the intestinal regions studied. At concentrations higher than 10(-3) m, instead of relaxing, theophylline strongly contracted the antrum and pylorus. In all three small intestinal regions, at concentrations up to 10(-3) m, theophylline produced a weak contraction, which at higher concentrations became very strong, and at 10(-2) m was comparable to that produced by a supramaximal dose of acetylcholine. The additive relaxing effect resulting from the combined application of the theophylline's metabolites was, from oesophagus to pylorus, weaker than that produced by theophylline, while on the ascending colon it was comparable to that of the parent drug. In contrast, the additive contractile effect of the metabolites on the three small intestinal regions was four to five times higher the one produced by theophylline. In conclusion, this study shows that the additive effect of the combined application of theophylline's major metabolites on the rabbit gastrointestinal tract plays a major role in the final response of the intestine, and a minor one in the final responses of the gastric regions, while both the parent drug and the metabolites contribute to the final responses of the oesophagus and LOS. PMID- 19788566 TI - Dissociable functional roles of the human action-observation network (Commentary on E. S. Cross et al.). PMID- 19788567 TI - Dissociable substrates for body motion and physical experience in the human action observation network. AB - Observation of human actions recruits a well-defined network of brain regions, yet the purpose of this action observation network (AON) remains under debate. Some authors contend that this network has developed to respond specifically to observation of human actions. Conversely, others suggest that this network responds in a similar manner to actions prompted by human and non-human cues, and that one's familiarity with the action is the critical factor that drives this network. Previous studies investigating human and non-human action cues often confound novelty and stimulus form. Here, we used a dance-learning paradigm to assess AON activity during observation of trained and untrained dance cues where a human model was present or absent. Results show that individual components of the AON respond differently to the human form and to dance training. The bilateral superior temporal cortex responds preferentially to videos with a human present, regardless of training experience. Conversely, the right ventral premotor cortex responds more strongly when observing sequences that had been trained, regardless of the presence of a human. Our findings suggest that the AON comprises separate and dissociable components for motor planning and observing other people's actions. PMID- 19788568 TI - Modulation of movement-associated cortical activation by transcranial direct current stimulation. AB - Transcranial direct current stimulation (tDCS) is currently attracting increasing interest as a tool for neurorehabilitation. However, local and distant effects of tDCS on motor-related cortical activation patterns remain poorly defined, limiting the rationale for its use. Here we describe the results of a functional magnetic resonance imaging (MRI) experiment designed to characterize local and distant effects on cortical motor activity following excitatory anodal stimulation and inhibitory cathodal stimulation. Fifteen right-handed subjects performed a visually cued serial reaction time task with their right hand in a 3 T MRI scanner both before and after 10 min of 1-mA tDCS applied to the left primary motor cortex (M1). Relative to sham stimulation, anodal tDCS led to short lived activation increases in the M1 and the supplementary motor area (SMA) within the stimulated hemisphere. The increase in activation in the SMA with anodal stimulation was found also when directly comparing anodal with cathodal stimulation. Relative to sham stimulation, cathodal tDCS led to an increase in activation in the contralateral M1 and dorsal premotor cortex (PMd), as well as an increase in functional connectivity between these areas and the stimulated left M1. These increases were also found when directly comparing cathodal with anodal stimulation. Significant within-session linear decreases in activation occurred in all scan sessions. The after-effects of anodal tDCS arose primarily from a change in the slope of these decreases. In addition, following sham stimulation compared with baseline, a between-session decrease in task-related activity was found. The effects of cathodal tDCS arose primarily from a reduction of this normal decrease. PMID- 19788569 TI - The semaphorin 4D-plexin-B signalling complex regulates dendritic and axonal complexity in developing neurons via diverse pathways. AB - Semaphorins and their receptors, plexins, have emerged as key regulators of various aspects of neuronal development. In contrast to the Plexin-A family, the cellular functions of Plexin-B family proteins in developing neurons are only poorly understood. An activation of Plexin-B1 via its ligand, semaphorin 4D (Sema4D), produces an acute collapse of axonal growth cones in hippocampal and retinal neurons over the early stages of neurite outgrowth. However, the functional role of Sema4D-Plexin-B interactions over subsequent stages of neurite development, differentiation and maturation has not been characterized. Here we addressed this question using morphogenetic assays and time-lapse imaging on developing rat hippocampal neurons as a model system. Interestingly, Sema4D treatment over several hours was observed to promote branching and complexity in hippocampal neurons via the activation of Plexin-B1. The activation of receptor tyrosine kinases and the Rho kinase following Sema4D treatment was found to control dendritic and axonal morphogenesis by differentially regulating branching and extension. Phosphoinositide-3-kinase, but not extracellular signal-regulated kinase 1/2, was observed to be important for the stimulatory effects of Sema4D on dendritic branching. Furthermore, we observed that the mammalian target of rapamycin is activated downstream of Plexin-B1 and contributes to Sema4D-induced effects on dendritic branching. In contrast, glycogen synthase kinase-3 beta, another effector of phosphoinositide-3-kinase signalling, was not involved. Thus, our results show that Sema4D-Plexin-B interactions modulate dendritic and axonal arborizations of developing neurons by co-ordinated and concerted activation of diverse signalling pathways. PMID- 19788570 TI - NCAM expression induces neurogenesis in vivo. AB - Neural cell adhesion molecule (NCAM) plays an important role during neural development and in the adult brain, whereby most functions of NCAM have been ascribed to its unique polysialic acid (PSA) modification. Recently we presented evidence suggesting that expression of NCAM in vivo interferes with the maintenance of forebrain neuronal stem cells. We here aimed at investigating the fate of cells generated from NCAM-overexpressing stem cells in postnatal mouse brain and at elucidating the functional domains of NCAM mediating this effect. We show that ectopic expression of the NCAM140 isoform in radial glia and type C cells induces an increase in cell proliferation and consequently the presence of additional neuronal type A cells in the rostral migratory stream. A mutant NCAM protein comprising only fibronectin type III repeats and immunoglobulin-like domain 5 was sufficient to induce this effect. Furthermore, we show that the neurogenic effect is independent of PSA, as transgenic NCAM is not polysialylated in radial glia and type C cells. These results suggest that heterophilic interactions of NCAM with other components of the cell membrane must be involved. PMID- 19788572 TI - Preconditioning selective ventral root injury promotes plasticity of ascending sensory neurons in the injured spinal cord of adult rats--possible roles of brain derived neurotrophic factor, TrkB and p75 neurotrophin receptor. AB - Preconditioning sciatic nerve injury enhances axonal regeneration of ascending sensory neurons after spinal cord injury. A key question is whether direct injury of sensory nerves is necessary for the enhanced regeneration. The lumbar 5 ventral root transection (L5 VRT) model, a model of selective motor nerve injury, provides a useful tool to address this question. Here we examined the effects of a preconditioning L5 VRT on the regeneration after a subsequent dorsal column transection (DCT) in adult Sprague-Dawley rats. We found that L5 VRT 1 week before DCT increased the number of Fast Blue (FB)-labeled neurons in the L5 dorsal root ganglia (DRG) and promoted sprouting/regenerating axons to grow into the glial scar. L5 VRT also induced a dramatic upregulation of expression of brain-derived neurotrophic factor (BDNF) in the preconditioned DRG and in the injured spinal cord. Moreover, almost all of the FB-labeled sprouting/regenerating neurons expressed BDNF, and approximately 55% of these neurons were surrounded by p75 neurotrophin receptor-positive glial cells. This combined injury led to an increase in the number of BDNF- and TrkB-immunoreactive nerve fibers in the dorsal column caudal to the lesion site. Taken together, these findings demonstrate that L5 VRT promotes sprouting/regeneration of ascending sensory neurons, indicating that sensory axotomy may not be essential for the plasticity of injured dorsal column axons. Thus, the sensory neurons could be preprimed in the regenerative milieu of Wallerian degeneration and neuroinflammation, which might alter the expression of neurotrophic factors and their receptors, facilitating sprouting/regeneration of ascending sensory neurons. PMID- 19788571 TI - Lateral habenula projections to dopamine and GABA neurons in the rat ventral tegmental area. AB - Ventral tegmental area (VTA) dopamine (DA) neurons and their forebrain projections are critically involved in reward processing and cognitive functions. Descending projections from the lateral habenula (LHb) play a central role in inhibiting DA cell activity in response to the absence of expected rewards. As LHb efferents are reportedly glutamatergic, their ability to inhibit DA cells would theoretically require a disynaptic connection involving VTA GABA neurons and their local collateral inputs to DA cells. We therefore used anterograde tract-tracing from the LHb to investigate the relative selectivity of LHb synapses onto GABA versus DA VTA neurons. LHb axons were visualized using immunoperoxidase, and DA and GABA cells were marked by immunogold-silver labeling for tyrosine hydroxylase (TH) or GABA, respectively. By ultrastructural analysis, 16% of LHb axons were observed to form synaptic contacts in the VTA, and most of these were of an intermediate morphological type that did not exhibit definitive asymmetric or symmetric character. LHb axons synaptically targeted TH- and GABA labeled dendrites to a comparable extent (45 and 52% observed incidence, respectively). Pre-embedding immunogold labeling for the vesicular glutamate transporter type 2 and post-embedding immunogold staining for GABA confirmed that approximately 85% of LHb terminals were glutamatergic and not GABAergic. These results suggest that the robust inhibition of DA cells evoked by the LHb is unlikely to arise from a selective innervation of VTA GABA neurons. Moreover, the LHb may mediate a direct excitation of DA cells that is over-ridden by indirect inhibition originating from an extrinsic source. PMID- 19788573 TI - Spatiotemporal frequency and speed tuning in the owl visual wulst. AB - The avian visual wulst is hodologically equivalent to the mammalian primary visual cortex (V1). In contrast to most birds, owls have a massive visual wulst, which shares striking functional similarities with V1. To provide a better understanding of how motion is processed within this area, we used sinusoidal gratings to characterize the spatiotemporal frequency and speed tuning profiles of 131 neurones recorded from awake burrowing owls. Cells were found to be clearly tuned to both spatial and temporal frequencies, and in a way that is similar to what has been reported in the striate cortex of primates and carnivores. Our results also suggest the presence of spatial frequency tuning domains in the wulst. Speed tuning was assessed by several methods devised to measure the degree of dependence between spatial and temporal frequency tuning. Although many neurones were found to be independently tuned, a significant proportion of cells showed at least some degree of dependence, compatible with the idea that some kind of initial transformation towards an explicit representation of speed is being carried out by the owl wulst. Interestingly, under certain constraints, a higher incidence of spatial frequency-invariant speed tuned profiles was obtained by combining our experimentally measured responses using a recent cortical model of speed tuning. Overall, our findings reinforce the notion that, like V1, the owl wulst is an important initial stage for motion processing, a function that is usually attributed to areas of the tectofugal pathway in lateral-eyed birds. PMID- 19788574 TI - Contrasting early visual cortical activation states causally involved in visual imagery and short-term memory. AB - Whether visual imagery and visual short-term memory (STM) share the same neural resources, and the extent to which the early visual cortex (V1/V2) is involved in these processes, has been the subject of much debate. Here, we used transcranial magnetic stimulation (TMS) in two separate experiments to contrast the neural states associated with visual imagery and visual STM in the early visual cortex. In Experiment 1, we investigated V1/V2 activation states at the end of the retention phase in a visual imagery and a visual STM task. V1/V2 TMS facilitated performance in both tasks; the finding that imagery and STM interacted with TMS in the same way suggests that the two processes have similar effects on early visual cortical excitability. In Experiment 2, we investigated V1/V2 activation states at the beginning of the retention phase. V1/V2 TMS impaired performance in the visual STM task, whereas it had no effect on the imagery task. Taken together, our findings show that the late phases of the early visual cortical activation state associated with visual imagery and visual STM are similar; differences between the two processes are apparent in the early phases of the tasks. Our results also suggest that the causal role of the early visual cortex in visual STM includes both the initial translation of the visual input into working memory and the subsequent maintenance of the mental representation. Finally, our findings indicate that visual STM sensory recruitment in working memory might act via excitability modulation of V1/V2 neurons. PMID- 19788575 TI - Tuning to non-symbolic proportions in the human frontoparietal cortex. AB - Humans share with many species a non-verbal system to estimate absolute quantity. This sense of number has been linked to the activity of quantity-selective neurons that respond maximally to preferred numerosities. With functional magnetic resonance imaging adaptation, we now show that populations of neurons in the human parietal and frontal cortex are also capable of encoding quantity ratios, or proportions, using the same non-verbal analog code as for absolute number. Following adaptation to visually presented constant proportions (specified by the ratio of line lengths or numerosities), we introduced novel relative magnitudes to examine the tuning characteristics of the population of stimulated neurons. In bilateral parietal and frontal cortex we found that blood oxygenation level-dependent signal recovery from adaptation was a function of numerical distance between the deviant proportion and the adaptation stimulus. The strongest effects were observed in the cortex surrounding the anterior intraparietal sulcus, a region considered pivotal for the processing of absolute magnitudes. Overall, there was substantial overlap of frontoparietal structures representing whole numbers and proportions. The identification of tuning to non symbolic ratio stimuli, irrespective of notation, adds to the magnitude system a remarkable level of sophistication by demonstrating automatic access to a composite, derived quantitative measure. Our results argue that abstract concepts of both absolute and relative number are deeply rooted in the primate brain as fundamental determinants of higher-level numerical cognition. PMID- 19788576 TI - Sensory deprivation regulates the development of the hyperpolarization-activated current in auditory brainstem neurons. AB - Hyperpolarization-activated and cyclic nucleotide-gated (HCN) channels are highly expressed in the superior olivary complex, the primary locus for binaural information processing. This hyperpolarization-activated current (I(h)) regulates the excitability of neurons and enhances the temporally precise analysis of the binaural acoustic cues. By using the whole-cell patch-clamp technique, we examined the properties of I(h) current in neurons of the lateral superior olive (LSO) and the medial nucleus of the trapezoid body (MNTB) before and after hearing onset. Moreover, we tested the hypothesis that I(h) currents are actively regulated by sensory input activity by performing bilateral and unilateral cochlear ablations before hearing onset, resulting in a chronic auditory deprivation. The results show that after hearing onset, I(h) currents are rapidly upregulated in LSO neurons, but change only marginally in neurons of the MNTB. We also found a striking difference in maximal current density, voltage dependence and activation time constant between the LSO and the MNTB in mature-like animals. Following bilateral cochlear ablations before hearing onset, the I(h) currents were scaled up in the LSO and scaled down in the MNTB. Consequently, in the LSO this resulted in a depolarized resting membrane potential and a lower input resistance of these neurons. This type of activity-dependent homeostatic change could thus result in an augmented response to the remaining inputs. PMID- 19788577 TI - Frequency-selectivity of a thalamocortical relay neuron during Parkinson's disease and deep brain stimulation: a computational study. AB - In this computational study, we investigated (i) the functional importance of correlated basal ganglia (BG) activity associated with Parkinson's disease (PD) motor symptoms by analysing the effects of globus pallidus internum (GPi) bursting frequency and synchrony on a thalamocortical (TC) relay neuron, which received GABAergic projections from this nucleus; (ii) the effects of subthalamic nucleus (STN) deep brain stimulation (DBS) on the response of the TC relay neuron to synchronized GPi oscillations; and (iii) the functional basis of the inverse relationship that has been reported between DBS frequency and stimulus amplitude, required to alleviate PD motor symptoms [A. L. Benabid et al. (1991)Lancet, 337, 403-406]. The TC relay neuron selectively responded to and relayed synchronized GPi inputs bursting at a frequency located in the range 2-25 Hz. Input selectivity of the TC relay neuron is dictated by low-threshold calcium current dynamics and passive membrane properties of the neuron. STN-DBS prevented the TC relay neuron from relaying synchronized GPi oscillations to cortex. Our model indicates that DBS alters BG output and input selectivity of the TC relay neuron, providing an explanation for the clinically observed inverse relationship between DBS frequency and stimulus amplitude. PMID- 19788579 TI - Post-pubertal emergence of a dopamine phenotype in netrin-1 receptor-deficient mice. AB - During the pubertal period the mesocortical dopamine (DA) system undergoes substantial reorganization of neuronal connectivity and functional refinement. Netrins are guidance cues involved in the organization of neuronal circuitry. We have previously shown that adult mice that develop with reduced levels of the netrin-1 receptor [deleted in colorectal cancer (DCC)] display selective reorganization of mesocortical DA circuitry, show enhanced mesocortical DA function and exhibit a behavioural phenotype opposite to that observed in animal models of schizophrenia. Here we assess whether the dcc behavioural and DA phenotypes are present prior to the maturation of the mesocortical DA system by comparing dcc-heterozygous and wild-type mice at the post-weaning and peri pubertal periods on various indices of DA function. At both the post-weaning and peri-pubertal ages, but unlike in adulthood, dcc-heterozygous and wild-type mice show no differences in the number of midbrain DA neurones or in tyrosine hydroxylase protein levels in the medial prefrontal cortex. Furthermore, the elevated baseline concentration of mesocortical DA and DA metabolites observed in adult dcc-heterozygous mice is not present in either post-weanling or peri pubertal mice. Interestingly, post-weanling, but not peri-pubertal, dcc heterozygous mice show greater baseline concentrations of DA metabolites in the nucleus accumbens, opposite to what was observed in adulthood. Finally, neither post-weanling nor peri-pubertal dcc-heterozygous mice demonstrate the blunted amphetamine-induced locomotor response observed in adulthood. Thus, these findings show that the 'protective' dcc phenotype has a post-pubertal emergence and indicate that DCC may play a role in the normal maturation of the mesocorticolimbic DA system. PMID- 19788578 TI - Influence of age on behavioral, immune and endocrine responses to the T-cell superantigen staphylococcal enterotoxin A. AB - Aged subjects are more vulnerable to administration of the endotoxin lipopolysaccharide, but research on age-associated sensitivity to other immune stimulants has been limited. The current study examined the effects of administering the superantigen, staphylococcal enterotoxin A (SEA), to young (4 month-old) and aged (20-month-old) male C57BL/6J mice on consumption of a novel liquid, cytokine production, corticosterone levels, and expression of central mRNA levels of cytokines and corticotropin-releasing hormone. SEA produced exaggerated hypophagia in aged mice, as they showed decreased consumption that persisted for 24 h. SEA increased hypothalamic mRNA levels of interleukin-1beta in the aged, but not the young, mice 2 h after administration. No differences in cytokine expression were observed 24 h after SEA. Both age groups showed increased plasma corticosterone levels 2 h after SEA administration. However, 24 h after SEA exposure the aged, but not the young, mice showed an augmented corticosterone response to the consumption test. Collectively, these data show that aging may exacerbate the behavioral and neuroinflammatory response to superantigen exposure. Further, the present study suggests that immune activation may result in delayed alterations in stress-induced corticosterone production in aged subjects. PMID- 19788580 TI - Does subliminal visual perception have an error-monitoring system? AB - There is substantial evidence that subliminal stimuli, i.e. stimuli that cannot be perceived consciously, may influence visually guided human behaviour. Two important points require further investigation, namely, the neural bases and the functional capability of unconscious stimulus processing. In this study we aimed at studying one specific aspect of the latter question, i.e. whether unconscious vision can feed into an error-monitoring system in much the same way as conscious vision. We therefore tested whether the event-related potential component known as error-related negativity, which represents the electrophysiological correlate of an error-monitoring system, is produced by unconscious errors. We found an error-related negativity not only for errors committed in a discrimination task with visible stimuli but also for those committed with subthreshold stimuli. Moreover, behavioural analysis showed post-error slowing of reaction time for correct responses following unconscious as well as conscious errors. Thus, the present results provide both electrophysiological and behavioural evidence of an error-monitoring system operating even when stimuli cannot access consciousness. PMID- 19788582 TI - Microcystic adnexal carcinoma - aggressive infiltrative tumor often with innocent clinical appearance. AB - Microcystic adnexal carcinoma is a rare sweat gland malignancy, characterized by slow, but aggressive infiltrative growth. Histologic characteristics are follicular and glandular differentiation, as well as bland cytologic features. The benign histologic appearance, particularly in the upper level of the tumor, can be confused with syringoma or benign follicular neoplasm. Thus the risk of misdiagnosis is considerable, especially if only superficial biopsies are provided. We report two patients with microcystic adnexal carcinoma, using them as a basis to discuss, pathogenesis, diagnosis, histology and therapy of the tumor. PMID- 19788581 TI - The limbic circuitry underlying cocaine seeking encompasses the PPTg/LDT. AB - The direct glutamatergic projection from the medial prefrontal cortex (mPFC) to the nucleus accumbens plays a critical role in mediating the reinstatement of cocaine seeking behavior. The mPFC also sends glutamatergic projections to the pedunculopontine tegmental nucleus (PPTg) and laterodorsal tegmental nucleus (LDT), which in turn send glutamatergic and cholinergic efferents to the ventral tegmental area (VTA) where they synapse on dopaminergic cells that innervate limbic structures including the nucleus accumbens. The goal of these experiments was to examine a potential role for the PPTg/LDT in the reinstatement of cocaine seeking. All rats were trained to self-administer cocaine (0.25 mg, i.v.) on a fixed-ratio 5 schedule of reinforcement. Cocaine self-administration behavior was extinguished and a series of subsequent pharmacological experiments were performed to assess the potential role of the mPFC, PPTg/LDT and VTA in the reinstatement of cocaine seeking. Administration of the D1-like dopamine receptor agonist SKF-81297 (1.0 microg) directly into the mPFC produced a small, but statistically significant, increase in cocaine seeking behavior. Furthermore, microinjection of the ionotropic glutamate receptor antagonist CNQX (0.3 microg) into the PPTg/LDT attenuated the reinstatement of drug seeking induced by a priming injection of cocaine (10 mg/kg, i.p.). Intra-VTA administration of CNQX, the nicotinic receptor antagonist mecamylamine (10.0 microg) or the muscarinic receptor antagonist scopolamine (24.0 microg) also blocked cocaine seeking. Taken together, these results suggest that cocaine priming-induced reinstatement of drug seeking is mediated in part by a serial polysynaptic limbic subcircuit encompassing the mPFC, PPTg/LDT and VTA. PMID- 19788583 TI - Successful treatment of a large hemangioma with propranolol. AB - Hemangiomas are the most common vascular tumors in children. They occur in 8-12% of all infants and in 22% of premature infants (female: male = 3: 1). Hemangiomas are usually sporadic; their etiology is unknown. A premature female infant, born at 28 weeks of gestation, presented with a large hemangioma of the right thoracic wall. Within the first few weeks, the hemangioma showed rapid horizontal and vertical growth as well as ulceration, which led us to initiate systemic therapy. The effectiveness of propranolol (non-selective ss-blocker) in the management of severe cases of hemangioma has been shown in a recent series of cases. We began oral propranolol treatment, in close interdisciplinary cooperation. After a few days of therapy, the tumor had stopped expanding. After 18 weeks, there has been marked regression but the therapy is still being continued. We propose that propranolol may be an effective and relatively well tolerable alternative in the management of selected cases of severe hemangiomas in infancy, providing interdisciplinary cooperation between dermatologists and pediatricians is available. PMID- 19788584 TI - Disorders of pigmentation. AB - Skin color is highly individual and the variations are controlled by numerous genes. The different skin colors result from the size and number of melanosomes and do not mirror the amount of melanocytes. Disorders of pigmentation can result from migration abnormalities of melanocytes from the neural crest to the skin during embryogenesis. In addition, impairment of melanosome transfer to the surrounding keratinocytes, an alteration in melanin synthesis and a defective degradation or removal of melanin may lead to abnormal skin pigmentation. Immunologic or toxic mediated destructions of melanocytes can end in pigmentation disorders. Disorders of pigmentation are classified in hypo- or hyperpigmentation which can occur as a genetic or acquired disease. They can manifest locally or diffuse. Congenital hypopigmentation can be restricted to the skin as in piebaldism or they represent a systemic disease as in Menkes disease or phenylketonuria. Localized hypo- or hyperpigmentation in children may serve as markers for systemic diseases. Ash-leaf hypopigmentation are characteristic for tuberous sclerosis and more than 5 cafe-au-lait spots suggest neurofibromatosis 1 (von Recklinghausen disease). The most common autoimmune-induced depigmentation is vitiligo. Generalized hyperpigmentation only rarely reflects a primary genetic disorder but is most often from acquired diseases as in Addison disease, secondary hemochromatosis or primary biliary cirrhosis. Treatment of pigmentation disorders are based on a diagnosis which sometimes allow a specific intervention. Cosmetically acceptable results are difficult to obtain. PMID- 19788585 TI - The stem cells of small intestinal crypts: where are they? AB - Recently, there has been resurgence of interest in the question of small intestinal stem cells, their precise location and numbers in the crypts. In this article, we attempt to re-assess the data, including historical information often omitted in recent studies on the subject. The conclusion we draw is that the evidence supports the concept that active murine small intestinal stem cells in steady state are few in number and are proliferative. There are two evolving, but divergent views on their location (which may be more related to scope of capability and reversibility than to location) several lineage labelling and stem cell self-renewing studies (based on Lgr5 expression) suggest a location intercalated between the Paneth cells (crypt base columnar cells (CBCCs)), or classical cell kinetic, label-retention and radiobiological evidence plus other recent studies, pointing to a location four cell positions luminally from the base of the crypt The latter is supported by recent lineage labelling of Bmi-1 expressing cells and by studies on expression of Wip-1 phosphatase. The situation in the human small intestine remains unclear, but recent mtDNA mutation studies suggest that the stem cells in humans are also located above the Paneth cell zone. There could be a distinct and as yet undiscovered relationship between these observed traits, with stem cell properties both in cells of the crypt base and those at cell position 4. PMID- 19788586 TI - Lomerizine, a Ca2+ channel blocker, protects against neuronal degeneration within the visual center of the brain after retinal damage in mice. AB - The purpose of this study was to determine whether lomerizine, a Ca(2+) channel blocker, protects against neuronal degeneration within the dorsal lateral geniculate nucleus (dLGN) and superior colliculus (SC) after the induction of retinal damage by intravitreal injection of N-methyl-D-aspartate (NMDA) in mice. NMDA (20 mM/2 microL) was injected into the vitreous body of the left eye in mice (DAY 0). Lomerizine at 30 mg/kg, p.o. was administered daily from immediately after the injection of NMDA (DAY 0) to 90 days after (DAY 90). To investigate the neuroprotective effects of lomerizine, the retina, dLGN, and SC were examined using histochemistry and immunohistochemistry. Lomerizine reduced the retinal damage induced by NMDA and partially prevented the transsynaptic neuronal degeneration within dLGN and SC on the contralateral side. Moreover, lomerizine reduced the intravitreal NMDA induced decrease in the light-induced expression of c-Fos in the contralateral dLGN (used in this study to evaluate residual vision). These results indicate that lomerizine affords some protection against transsynaptic neuronal degeneration within the visual center of the mouse brain. PMID- 19788587 TI - Genetic variation in CXCL12 and risk of cervical carcinoma: a population-based case-control study. AB - CXCL12 provides a chemotactic signal-directing leucocyte migration and regulates metastatic behaviour of tumour cells. We conducted a population-based case control study to test the hypothesis that common genetic variation in CXCL12 individual single nucleotide polymorphism (SNP) alleles and haplotypes] is associated with the risk of cervical carcinoma. Cases (n = 917) were residents of western Washington State diagnosed with invasive squamous cell cervical carcinoma (SCC), invasive adenocarcinoma or adenosquamous carcinoma, or adenocarcinoma in situ of the cervix. Control participants (n = 849) were identified from the source population by random digit telephone dialling and frequency matched to cases on county and age. Nine CXCL12 tagSNPs chosen from the SeattleSNPs database were genotyped. The minor allele of intronic SNP rs266085 was inversely associated with cervical cancer under a recessive genetic effects model (OR = 0.74, 95% CI: 0.56-0.98). Among the ten common haplotypes inferred from the nine tagSNPs, one haplotype defined by minor alleles at 5'-flanking SNP rs17885289 and rs266085, and common alleles at the other seven SNPs occurred among 7.8% of cases and 10.6% of controls (dominant model OR = 0.72, 95% CI: 0.56-0.93; recessive model OR = 0.35, 95% CI: 0.12-0.97; and log-additive model OR = 0.72, 95% CI: 0.57-0.90). A stepwise procedure identified rs17885289, rs266085 and 3' untranslated region (UTR) SNP rs266093 as the most parsimonious subset of SNPs necessary to define the haplotype inversely associated with cervical cancer risk in our study. A 3'-UTR SNP, rs1801157, previously found to be related to HIV pathogenesis, was not associated with cervical cancer risk. Further population based studies are warranted to confirm these associations between genetic variation in CXCL12 and cervical cancer risk. PMID- 19788588 TI - Attention to novelty in behaviorally inhibited adolescents moderates risk for anxiety. AB - BACKGROUND: Individual differences in specific components of attention contribute to behavioral reactivity and regulation. Children with the temperament of behavioral inhibition (BI) provide a good context for considering the manner in which certain components of attention shape behavior. Infants and children characterized as behaviorally inhibited manifest signs of heightened orienting to novelty. The current study considers whether this attention profile moderates risk for clinical anxiety disorders among adolescents with a history of BI. METHODS: Participants were assessed at multiple time points for BI, beginning in early childhood. At adolescence, event-related potentials (ERPs) were recorded during a three-stimulus auditory novelty oddball task, which employed frequent standard and infrequent deviant tones as well as a set of complex, novel sounds. Clinical diagnosis was carried out using the Schedule for Affective Disorders and Schizophrenia for School-Age Children-Present and Lifetime Version (K-SADS-PL). P3 and mismatch negativity (MMN) components were examined at midline frontal, central, and parietal electrode sites. RESULTS: Individuals who displayed high levels of BI during childhood and increased P3 amplitude to novelty in adolescence were more likely to have a history of anxiety disorders compared to behaviorally inhibited adolescents with lower P3 amplitudes. Groups did not differ on measures of MMN. CONCLUSIONS: Increased neural responses to novelty moderate risk for anxiety disorders amongst individuals with a history of BI. PMID- 19788589 TI - Is cerebrospinal fluid leptin altered in idiopathic intracranial hypertension? PMID- 19788590 TI - Pseudohypoaldosteronism type 1: the index case revisited. PMID- 19788591 TI - How should we manage patients with mildly increased serum thyrotrophin concentrations? AB - A mildly increased serum thyrotrophin (TSH) is usually because of mild thyroid failure, and the most common aetiology in iodine-replete communities is chronic autoimmune thyroiditis. It is more common in women, and the prevalence increases with age in both men and women and is associated with the presence of antithyroid antibodies. The majority will have serum TSH levels between 5-10 mIU/l, normal free thyroxine (T4) levels and relatively few symptoms. In 2004, US evidence based consensus guidelines concluded that there were no adverse outcomes of a mildly increased serum TSH other than a risk of progression to overt hypothyroidism and few data to justify levothyroxine therapy. There is still debate as to what constitutes an increased serum TSH, particularly in older subjects. Although some subjects will progress to overt hypothyroidism, recent data suggest a significant proportion revert to a serum TSH within the reference range without treatment. Two recent meta-analyses have suggested that the possible cardiovascular risks may be more significant in younger adults. Other data suggest that mild thyroid failure may be the only reversible cause of left ventricular diastolic dysfunction. No appropriately powered prospective, randomized, controlled, double-blinded interventional trial of levothyroxine therapy for a mildly increased serum TSH exists. However, treatment in subjects who are symptomatic, pregnant or preconception, aged less than 65 years and older subjects with evidence of heart failure appear justified. PMID- 19788592 TI - Neuroendocrine response to supine posture in healthy children and patients with nocturnal enuresis. AB - OBJECTIVE: To elucidate the background behind the attenuated circadian rhythm of vasoactive hormones in patients with nocturnal enuresis, we tested the hypothesis that enuretic children exhibit an abnormal neuroendocrine response to a baroreflex stimulus during daytime. DESIGN AND PATIENTS: In fifteen children and adolescents (aged 13.4 +/- 0.9 years) with severe nocturnal enuresis and 10 age- and sex-matched healthy controls, we performed a 'daytime supine posture' (DSP) study at 10:00 h. MEASUREMENTS: Blood was sampled for measurements of plasma vasopressin (P(AVP)), angiotensin II (P(ANGII)), atrial natriuretic peptide (P(ANP)) and serum aldosterone (S(ALDO)), and mean arterial blood pressure (MAP) and heart rate (HR) were measured during the study. RESULTS: In both controls and patients with enuresis, DSP at 10:00 h resulted in a marked fall in MAP and HR, a rise in pulse pressure (PP) and estimated plasma volume (PV) and a significant suppression of P(AVP), P(ANGII) and S(ALDO), whereas P(ANP) increased. There were no significant differences between groups in haemodynamic or neuroendocrine responses to DSP. CONCLUSIONS: The study showed that children with nocturnal enuresis exhibit a normal neuroendocrine response to supine posture during daytime indicating that baroregulatory mechanisms per se are not playing a significant pathogenic role. Interestingly, the normal neuroendocrine response to supine posture seems to undergo marked circadian changes, as supine posture at night-time is associated with increased levels of vasoactive hormones. PMID- 19788596 TI - Fifty years of Australian gastroenterology and hepatology: a golden era of contributions to the region. PMID- 19788597 TI - Building a better mousetrap? Impedance measurement in gastroesophageal reflux disease. PMID- 19788598 TI - Esophageal cancer in North Queensland: another symptom of indigenous disadvantage in Australia. PMID- 19788599 TI - Adiponectin in non-alcoholic steatohepatitis: an ideal culprit, but what are the proofs of its guilt? PMID- 19788600 TI - Second Asia-Pacific Consensus Guidelines for Helicobacter pylori infection. AB - The Asia-Pacific Consensus Conference was convened to review and synthesize the most current information on Helicobacter pylori management so as to update the previously published regional guidelines. The group recognized that in addition to long-established indications, such as peptic ulcer disease, early mucosa associated lymphoid tissue (MALT) type lymphoma and family history of gastric cancer, H. pylori eradication was also indicated for H. pylori infected patients with functional dyspepsia, in those receiving long-term maintenance proton pump inhibitor (PPI) for gastroesophageal reflux disease, and in cases of unexplained iron deficiency anemia or idiopathic thrombocytopenic purpura. In addition, a population 'test and treat' strategy for H. pylori infection in communities with high incidence of gastric cancer was considered to be an effective strategy for gastric cancer prevention. It was recommended that H. pylori infection should be tested for and eradicated prior to long-term aspirin or non-steroidal anti inflammatory drug therapy in patients at high risk for ulcers and ulcer-related complications. In Asia, the currently recommended first-line therapy for H. pylori infection is PPI-based triple therapy with amoxicillin/metronidazole and clarithromycin for 7 days, while bismuth-based quadruple therapy is an effective alternative. There appears to be an increasing rate of resistance to clarithromycin and metronidazole in parts of Asia, leading to reduced efficacy of PPI-based triple therapy. There are insufficient data to recommend sequential therapy as an alternative first-line therapy in Asia. Salvage therapies that can be used include: (i) standard triple therapy that has not been previously used; (ii) bismuth-based quadruple therapy; (iii) levofloxacin-based triple therapy; and (iv) rifabutin-based triple therapy. Both CYP2C19 genetic polymorphisms and cigarette smoking can influence future H. pylori eradication rates. PMID- 19788601 TI - Epidemiology of irritable bowel syndrome in Asia: something old, something new, something borrowed. AB - In this review we have unearthed epidemiological data that; support the 'old' concept of irritable bowel syndrome (IBS) as a disorder of civilization, build a 'new' symptom profile of IBS for Asia, and persuade us against the use of 'borrowed' Western diagnostic criteria and illness models by Asian societies. In the 1960s, IBS was described as a disorder of civilization. Early studies from Asia suggested a prevalence of IBS below 5%. Recent studies from Asia suggest a trend for the more affluent city states like Singapore and Tokyo, to have higher prevalence of 8.6% and 9.8%, respectively, while India had the lowest prevalence of 4.2%. Furthermore, there was a trend among the better educated and more affluent strata of society in several urban Chinese populations for a higher prevalence of IBS, as well as a trend for a higher consultation rate. Across Chinese and Indian predominant populations, a majority of patients with IBS criteria report upper abdominal symptoms such as epigastric pain relieved by defecation, bloating and dyspepsia. Bloating and incomplete evacuation appear to be more important determinants of consultation behavior, than psychological factors. The failure of the Rome criteria to recognize the relationship to meals, may have led to a substantial misclassification of IBS as dyspepsia. The relevance of the Western model of psychological disturbance as a determinant of consultation behavior is questionable because of the accessibility and acceptability of medical consultation for gastrointestinal complaints in many Asian communities. PMID- 19788602 TI - Bone marrow stem cells and the liver: are they relevant? AB - The contribution of bone marrow stem cell responses to liver homeostasis, injury and malignancy is discussed in this review. Pluripotent stem cells or their more committed progenitor progeny are essential to tissue development, regeneration and repair and are widely implicated in the pathogenesis of malignancy. Stem cell responses to injury are the focus of intense research efforts in the hope of future therapeutic manipulation. Stem cells occur within tissues, such as the liver, or arise from extrahepatic sites, in particular, the bone marrow. As the largest reservoir of stem cells in the adult, the bone marrow has been implicated in the stem cell response associated with liver injury. However, in liver injury, the relative contribution of bone marrow stem cells compared to intrahepatic progenitor responses is poorly characterized. Intrahepatic progenitor responses have been recently reviewed elsewhere. In this review, we have summarized liver specific extrahepatic stem cell responses originating from the bone marrow. The physiological relevance of bone marrow stem cell responses to adult liver homeostasis, injury and malignancy is discussed with emphasis on mechanisms of bone marrow stem cell recruitment to sites of liver injury and its contribution to intrahepatic malignancy. PMID- 19788603 TI - Ease of early gastric cancer demarcation recognition: a comparison of four magnifying endoscopy methods. AB - BACKGROUND AND AIM: Various techniques using magnifying endoscopy (ME) have been developed to enhance images of early gastric cancer (EGC) demarcations, which are often obscure. We investigated four ME methods to determine which is most effective in enhancing the recognition of EGC demarcations: conventional ME (CME), ME with narrow band imaging (NBI-ME), enhanced-magnification endoscopy with acetic acid (EME), and ME with NBI and acetic acid (NBI-EME). METHODS: Thirty-seven successive patients having a total of 40 EGCs participated in the investigation. The endoscope was fixed and magnification images of EGC demarcations in each patient were recorded using four different ME methods (CME, NBI-ME, EME and NBI-EME). Eight experts and eight non-experts scored each of the four images of each lesion for ease of recognition of demarcation (1 to 4, with 4 being easiest). RESULTS: The mean scores of expert and non-expert judges, respectively, for images acquired using each technique were: CME 1.23, 1.24; NBI ME 2.61, 2.95; EME 2.62, 2.32 and NBI-EME 3.54, 3.50. There were significant differences between the mean scores for the four techniques (P < 0.0001) using one-way repeated-measures anova. In a Bonferroni's multiple comparison, the average scores (expert and non-expert) of images acquired using NBI-EME were significantly higher than those acquired using other methods; images acquired by NBI-ME or EME also scored significantly higher than those by CME. Non-experts also scored NBI-ME images significantly higher than CME and EME images. CONCLUSIONS: Early gastric cancer demarcations were recognized most easily using NBI-EME, and more easily using EME or NBI-ME than CME. PMID- 19788604 TI - RIFLE classification as predictive factor of mortality in patients with cirrhosis admitted to intensive care unit. AB - BACKGROUND AND AIM: To evaluate the association of the Risk, Injury, Failure, Loss and End-stage renal failure (RIFLE) score on mortality in patients with decompensated cirrhosis admitted to intensive care unit (ICU). METHODS: A cohort of 412 patients with cirrhosis consecutively admitted to ICU was classified according to the RIFLE score. Multivariable logistic regression analysis was used to evaluate the factors associated with mortality. Liver-specific, Acute Physiology and Chronic Health Evaluation (APACHE) II, Sequential Organ Failure Assessment (SOFA) and RIFLE scores on admission, were compared by receiver operator characteristic curves. RESULTS: The overall mortality during ICU stay or within 6 weeks after discharge from ICU was 61.2%, but decreased over time (76% during first interval, 1989-1992 vs 50% during the last, 2005-2006, P < 0.001). Multivariate analysis showed that RIFLE score (odds ratio: 2.1, P < 0.001) was an independent factor significantly associated with mortality. Although SOFA had the best discrimination (area under receiver-operator characteristic curve = 0.84), and the APACHE II had the best calibration, the RIFLE score had the best sensitivity (90%) to predict death in patients during follow up. CONCLUSIONS: RIFLE score was significantly associated with mortality, confirming the importance of renal failure in this large cohort of patients with cirrhosis admitted to ICU, but it is less useful than other scores. PMID- 19788605 TI - Presence of hepatitis C virus in syringes confiscated in prisons in Australia. AB - BACKGROUND AND AIMS: Needlestick injuries are an occupational hazard for prison officers. This study aimed to assess the presence of hepatitis C virus (HCV) in syringes found in prisons. METHODS: Sixty-nine syringes found in prisons were tested for HCV RNA using previously published methods. RESULTS: Three syringes tested positive for HCV RNA. CONCLUSION: Compared to the prevalence of HCV among injecting drug users in prisons, few syringes were found to contain HCV RNA. It is likely that conditions under which syringes are kept in prisons are not favorable for survival of detectable HCV RNA. Further work is needed to establish the risk of HCV transmission posed by needlestick injuries in prison settings. PMID- 19788606 TI - Roles of adipose restriction and metabolic factors in progression of steatosis to steatohepatitis in obese, diabetic mice. AB - BACKGROUND AND AIMS: We previously reported that steatohepatitis develops in obese, hypercholesterolemic, diabetic foz/foz mice fed a high-fat (HF) diet for 12 months. We now report earlier onset of steatohepatitis in relation to metabolic abnormalities, and clarify the roles of dietary fat and bodily lipid partitioning on steatosis severity, liver injury and inflammatory recruitment in this novel non-alcoholic steatohepatitis (NASH) model. METHODS: Foz/foz (Alms1 mutant) and wild-type (WT) mice were fed a HF diet or chow, and metabolic characteristics and liver histology were studied at 2, 6, 12 and 24 weeks. RESULTS: After 12 weeks HF-feeding, foz/foz mice were obese and diabetic with approximately 70% reduction in serum adiponectin. Hepatomegaly developed at this time, corresponding to a plateau in adipose expansion and increased adipose inflammation. Liver histology showed mild inflammation and hepatocyte ballooning as well as steatosis. By 24 weeks, HF-fed foz/foz mice developed severe steatohepatitis (marked steatosis, alanine aminotransferase elevation, ballooning, inflammation, fibrosis), whereas dietary and genetic controls showed only simple steatosis. While steatosis was associated with hepatic lipogenesis, indicated by increased fatty acid synthase activity, steatohepatitis was associated with significantly higher levels of CD36, indicating active fatty acid uptake, possibly under the influence of peroxisome proliferator-activated receptor-gamma. CONCLUSION: In mice genetically predisposed to obesity and diabetes, HF feeding leads to restriction of adipose tissue for accommodation of excess energy, causing lipid partitioning into liver, and transformation of simple steatosis to fibrosing steatohepatitis. The way in which HF feeding 'saturates' adipose stores, decreases serum adiponectin and causes hepatic inflammation in steatohepatitis may provide clues to pathogenesis of NASH in metabolic syndrome. PMID- 19788607 TI - Adiponectin knockout mice on high fat diet develop fibrosing steatohepatitis. AB - BACKGROUND AND AIM: Low levels of serum adiponectin have been reported to be associated with obesity, diabetes, and non-alcoholic steatohepatitis (NASH), as well as several malignancies. Adiponectin knockout (KO) mice have been reported to cause insulin resistance and neointimal formation of the artery. We used adiponectin KO mice fed a high fat (HF) diet, and investigated the effect of adiponectin on the progression of steatohepatitis and carcinogenesis in vivo. METHODS: Adiponectin KO mice and wild type (WT) mice were fed a HF diet or normal chow for the periods of 24 and 48 weeks. The HF diet contained 60% of calories from fat. RESULTS: The adiponectin KO mice on the HF diet showed obesity, marked elevation of serum transaminase levels, and hyperlipidemia. At 24 weeks, hepatic expression of tumor necrosis factor-alpha and procollagen alpha (I) was higher in KO mice as compared with WT mice. At 48 weeks, liver triglyceride contents in KO mice on normal chow were significantly higher than those in WT mice. Hepatocyte ballooning, spotty necrosis, and pericellular fibrosis around central veins were observed in KO mice on the HF diet. The pericellular fibrosis was more severe in KO mice on the HF diet than that in WT mice (1.62% vs 1.16%, P = 0.033). Liver adenoma and hyperplastic nodules developed in a KO mouse on the HF diet at 48 weeks (12.5%, n = 1/8), whereas no tumor was detected in WT mice (n = 10). CONCLUSIONS: Adiponectin may play a protective role in the progression of NASH in the early stages by suppressing tumor necrosis factor-alpha expression and liver fibrosis. PMID- 19788609 TI - Lymph node staging in esophageal squamous cell carcinoma: a comparative study of endoscopic ultrasonography versus computed tomography. AB - BACKGROUND AND AIM: Endoscopic ultrasonography (EUS) is established as a standard approach for locoregional staging of esophageal cancer. However, only a few published studies have attempted to correlate the station of the abnormal lymph nodes detected by EUS with the definitive histology. We compared EUS and computed tomography (CT) in the initial staging of esophageal squamous cell carcinoma. METHODS: Consecutive patients with esophageal cancer undergoing EUS were evaluated. EUS findings and patient data including histopatology were collected prospectively and analyzed retrospectively. Lymph node locations were divided into three groups; abdominal (A), paraesophageal (B), and thoracic paratracheal (C). RESULTS: A total of 365 consecutive patients underwent EUS and 159 patients underwent esophagectomy without neoadjuvant chemotherapy. Thirty-eight patients were excluded (insufficient EUS, etc.), and 121 patients were enrolled. The overall accuracy of EUS was 64% (sensitivity 68%, specificity 58%, positive predictive value [PPV] 68%), CT was 51% (sensitivity 33%, specificity 75%, PPV 64%), and CT + EUS was 64% (sensitivity 74%, specificity 50%, PPV 66%). The accuracy of EUS was higher than CT in Groups A and C. Sensitivity of CT was lower than that of EUS alone and CT + EUS. CONCLUSIONS: This study has demonstrated that EUS is a more accurate technique than contrast-enhanced CT for detecting abnormal lymph nodes. Sensitivity of CT was lower than that of EUS alone and CT + EUS. But some metastatic lymph nodes in neck and abdominal fields are only detectable by CT. Therefore, both EUS and CT should be undertaken for routine examination prior to treatment of esophageal cancer. PMID- 19788608 TI - Evaluation of esophageal function in patients with gastroesophageal reflux disease using transnasal endoscopy. AB - BACKGROUND AND AIMS: To investigate the utility of a new method of carrying out esophageal manometry using a narrow gauge manometry catheter via a transnasal endoscope. METHODS: The Frequency Scale for the Symptoms of gastroesophageal reflux disease (GERD) (FSSG), a GERD-specific questionnaire, was given to 45 subjects. Subjects underwent transnasal endoscopy with three dry and three wet (3 mL water) swallows. Direct observations of the primary peristaltic wave and peristaltic pressure measurement were conducted simultaneously. RESULTS: Endoscopic observation of lower esophageal motility associated with swallowing revealed dilatation of the esophageal lumen after swallowing, followed by contraction in association with the primary peristaltic wave. The peristaltic pressure was significantly lower with increased FSSG scores for dry swallows (r = -0.347, P = 0.0212), but no significant correlation was seen for wet swallows. CONCLUSIONS: The significant negative correlation between reflux symptoms and peristaltic pressure in dry swallows was thought to be that reduced pressure immediately rostral to the lower esophageal sphincter leads to decreased clearance following gastric acid reflux, playing a large part in the onset of symptoms. PMID- 19788610 TI - Education and Imaging. Gastrointestinal: gastric mucosa-associated lymphoma presented with unique vascular features on magnified endoscopy combined with narrow-band imaging. PMID- 19788611 TI - Education and Imaging. Gastrointestinal: contrast-enhanced harmonic EUS for pancreatic cancer. PMID- 19788612 TI - Education and Imaging. Hepatobiliary and pancreatic: idiopathic portal hypertension. PMID- 19788614 TI - Characterization of endoglin and Ki-67 expression in endothelial cells from benign and malignant lesions of the uterine cervix. AB - Activation of endothelial cells is often associated with the cellular proliferation in vitro. CD105 is a more specific marker of activated endothelial cells from tumor vessels and Ki-67 is used to assess the proliferation status of both tumor and endothelial cells. The aim of the present study was to evaluate the status of endothelial cells using CD105 and Ki-67 immunohistochemistry in benign and malignant lesions of the uterine cervix. Double stain for CD105/Ki-67 in benign and malignant lesions of the uterine cervix showed that these two markers had divergent expression on endothelial cells from associated tumor blood vessels dependent on lesion type and proliferation status of tumor cells. Absence of CD105/Ki-67 coexpression in endothelial cells was correlated with histopathology of the uterine cervix lesions and tumor proliferative status. The present findings suggest that CD105 expression is an early event, specific for premalignant lesions of the uterine cervix, while endothelial proliferation assessed on Ki-67 combined with the lack of CD105 expression is often associated with invasive cervical carcinoma. PMID- 19788615 TI - Mucosal remodeling in long-standing ulcerative colitis with colorectal neoplasia: significant alterations of NCAM+ or alpha-SMA+ subepithelial myofibroblasts and interstitial cells. AB - Evidence has been provided in ulcerative colitis (UC) that early genomic instability of both epithelial and stromal cells is important for colorectal tumorigenesis, as well as remodeling and morphological alterations of mucosal crypts. To clarify roles of stromal cells in tumor development in UC, the present study focused on heterogeneous phenotypes of subepithelial myofibroblasts and interstitial cells, in association with mucosal remodeling. To clarify the relationship of alterations to tumorigenesis, mucosa of resected rectae from patients with UC (n= 49) and sporadic cancer (n= 10) were analyzed on immunohistochemistry and also on immunoelectron microscopy. Heterogeneous phenotypes of neural cell adhesion molecule (NCAM)+ and/or alpha-smooth muscle actin (alpha-SMA)+ subepithelial myofibroblasts and interstitial cells were demonstrated, corresponding to colonic stellate cells. Decrease of NCAM+ subepithelial myofibroblasts and interstitial cells, and increase of alpha-SMA+ interstitial cells were significant in UC with neoplasia as compared to without neoplasia. alpha-SMA+ muscularis mucosae was significantly more thickened in tumor cases. Deposits of Masson's trichrome+ and type III and I collagen in the muscularis mucosae and lamina propria appeared to increase in relation to the numbers of alpha-SMA+ interstitial cells. Mucosal remodeling with alterations of NCAM+ or alpha-SMA+ subepithelial and interstitial cells may play a critical role in UC-associated tumorigenesis. PMID- 19788616 TI - Diagnostic findings of ultrasound-guided fine-needle aspiration cytology for gastrointestinal stromal tumors: proposal of a combined cytology with newly defined features and histology diagnosis. AB - Recently, endoscopic ultrasonography-guided fine needle aspiration (EUS-FNA) has been applied for diagnosis of gastrointestinal submucosal tumors. There have been no definite criteria, however, for the adequate cytological diagnosis of gastrointestinal stromal tumor (GIST) in practice. To facilitate this a novel method is proposed that combines cytology and histology. For 49 cases of submucosal tumor of gastrointestinal tract, EUS-FNA was performed. The aspirated materials were processed for cytology and histology. Both cytological and histological findings were examined on immunocytochemical and immunohistochemical staining of c-kit. Of 49 cases, 40 (81.6%) proved adequate for cytological and/or histological examination. On cytology, cluster types were classified into type A (piled clusters with high cellularity showing a fascicular pattern), type B (thin layered clusters with high cellularity showing a fascicular pattern), and type C (mono-layered clusters or scattered cells). Types A and B were strongly associated with histological diagnosis of GIST. Type C clusters needed confirmation on c-kit positivity and histology. Thus, the combined cytology with newly defined features, and classification and histological diagnostic method for EUS-FNA materials can contribute to improved routine diagnosis for GIST. PMID- 19788617 TI - Lung cysts in Birt-Hogg-Dube syndrome: histopathological characteristics and aberrant sequence repeats. AB - Birt-Hogg-Dube (BHD) syndrome is a rare disorder inherited in an autosomal dominant manner. The affected patients are predisposed to cutaneous fibrofolliculomas, renal cell tumors and lung cysts with recurrent pneumothorax. Contrary to neoplastic events in the skin and the kidney, the lung cysts have frequently been confused with non-neoplastic changes such as blebs or bullae. Herein is reported a case of multiple lung cysts associated with BHD syndrome. Detailed histopathological characteristics of the lesion are also given. The lung cysts were closely associated with the peripheral interlobular septum, visceral pleura or septal-pleural junctional region. These cysts were partly abutting alveolar structures, and lined by a layer of alveolar epithelium. These unique microscopic features supported the notion that the BHD lung lesions are distinct from other types of bullous changes. Genomic DNA analysis indicated an aberrant sequence repeat that caused frameshift mutation. Immunohistochemistry showed the localization of folliculin, the BHD gene-encoding protein, in macrophages and epithelial cells in the patient's and normal control's lungs. Haploinsufficiency of folliculin may cause deranged alveolar development, leading to the aberrant cystic alveolar formation. The unique mutation patterns of abnormal sequence repeats in patients with BHD syndrome are also reviewed. PMID- 19788618 TI - Decreased protein and gene expression of hepatic cholesterol 7a-hydroxylase associated with dilated endoplasmic reticulum in chronic hypothyroid rats. AB - Chronic hypothyroidism is associated with an increased risk for cardiovascular disease attributed, in part, to increased serum cholesterol and atherosclerosis. Decreased hepatic activity of cholesterol 7a-hydroxylase (CYP7A1) is thought to contribute to hypercholesterolemia in hypothyroidism. The endoplasmic reticulum (ER) has been shown to be a central organelle, and it is the location of CYP7A1 in hepatocyte. The aim of the present study was to determine whether the expression of CYP7A1 mRNA and protein could be decreased and whether ER could undergo morphological changes in a rodent model of chronic hypothyroidism induced by methimazole (MMI). Male Wistar rats were treated with MMI (0.04% wt/vol) or regular water for 14 weeks. Hepatic CYP7A1 mRNA was analyzed on quantitative real time polymerase chain reaction (PCR). Hepatic CYP7A1 protein expression was assessed on western blot. In conjunction with these molecular biological assessments the morphology of ER was evaluated on transmission electron microscopy (TEM). Serum total cholesterol increased significantly compared to controls and was associated with decreased CYP7A1 mRNA and protein, and TEM indicated remarkable dilation of ER in hepatocytes in the chronic hypothyroid rats. These findings suggest that a relationship between the decreased expression of hepatic CYP7A1 mRNA and protein and dilated ER could exist, which may contribute to hypercholesterolemia in chronic hypothyroidism. PMID- 19788619 TI - Atypical cell clusters expressing both neuronal and oligodendrocytic markers: novel histological pattern of glioneuronal tumors? AB - Glioneuronal tumors are a group of brain tumors that consist of both neuronal and glial cells. The spectrum of glioneuronal tumors is currently expanding, and many atypical glioneuronal tumors require further characterization. Two patients are described who had an atypical glioneuronal tumor with peculiar pathological features. One patient was a 7-year-old girl with a tumor in the right cerebellar hemisphere. This patient had no recurrence after total resection. The other was a 37-year-old man with a tumor in the spinal cord. He suffered incessant recurrence and received operative treatment four times. Although the clinical features (age at diagnosis, tumor location, and recurrence) were very different in these patients, the tumors had a characteristic common feature of atypical cell clusters. Intriguingly, the tumor cells in the clusters expressed both neuronal and oligodendroglial markers, indicating aberrant differentiation. Furthermore, the cluster-forming cells had modest proliferative indices and CD133 expression, indicating their role in the growth of the tumor. It is believed that these atypical cell clusters are a novel pattern of differentiation of glioneuronal tumors and that they need further investigation. PMID- 19788620 TI - Small invasive ductal adenocarcinoma of the pancreas associated with lymphoplasmacytic sclerosing pancreatitis. AB - An asymptomatic 59-year-old man underwent pancreatoduodenectomy for a pancreatic mass that was discovered during a health check-up. Histopathology indicated typical features of lymphoplasmacytic sclerosing pancreatitis (LPSP) or autoimmune pancreatitis along with the presence of abundant IgG4-positive plasma cells throughout the mass. A small invasive ductal adenocarcinoma was observed in the center of the area affected by LPSP. The present case suggests that LPSP may be closely related to carcinogenesis of the pancreas. PMID- 19788621 TI - Small cell carcinoma with skeletal muscle differentiation of urinary bladder. AB - Reported herein is a case of small cell carcinoma (SCC) with skeletal muscle differentiation of urinary bladder in a 76-year-old woman presenting macrohematuria. Ultrasonography and CT detected a mass at the anterior wall of the urinary bladder, and total cystectomy followed. The tumor consisted of solid growth of small round cells with high nucleocytoplasmic ratio admixed with rhabdoid cells with eosinophilic cytoplasmic inclusions, invading the perivesical tissue. On immunohistochemistry the tumor cells were diffusely positive for neural markers and CD99, and sporadically for skeletal muscle markers. Fluorescence in situ hybridization showed no translocation of EWS. The patient died from massive recurrence in the pelvis 4 months after operation. This rare tumor indicates a potential of myoid differentiation in SCC of the urinary bladder and differential diagnosis from primitive neuroectodermal tumor is important because the treatment is different. PMID- 19788622 TI - Osteopontin expression in pulmonary tumor thrombotic microangiopathy caused by gastric carcinoma. AB - Pulmonary tumor thrombotic microangiopathy (PTTM) is characterized by fibrocellular intimal proliferation and thrombus formation in small pulmonary arteries and arterioles in patients with metastatic carcinoma. Osteopontin (OPN) is a multifunctional cytokine and adhesive protein, and has been demonstrated to be implicated in fibrosis, neointima formation, arterial occlusion by thrombus, and tumor metastases in cooperation with platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). Herein is described an autopsy case of gastric adenocarcinoma with severe pulmonary hypertension due to PTTM. Histologically, tumor cell emboli markedly induced both fibromuscular intimal thickening and thrombosis, resulting in luminal stenosis and occlusion of small pulmonary arteries and arterioles. Tumor cells, both in the PTTM lesions and primary gastric carcinoma, had positive immunoreactivity for OPN, PDGF, and VEGF. In addition, proliferating fibromuscular intimal cells also showed expression of OPN, PDGF, and VEGF. These findings suggest that OPN may be involved in fibrocellular intimal proliferation and thrombus formation in PTTM together with PDGF and VEGF. To the best of the authors' knowledge this is the first report to demonstrate the possible involvement of OPN in PTTM. It is postulated that OPN is one of the candidate molecules for the development of PTTM. PMID- 19788623 TI - Heparin-induced thrombocytopenia with multiple organized thrombi accompanied by unusual cholesterin deposition: autopsy case after long-term follow up. AB - Heparin-induced thrombocytopenia (HIT) is characterized by a reduction in the platelet count and systemic thromboembolism during heparin therapy. Herein is reported a case of HIT with characteristic thrombus formation. A 68-year-old man who had been treated for hypertension for 27 years suffered a brain infarction and was treated with heparin. After this treatment, other new infarctions occurred in multiple organs. Because serum antibodies against heparin/PF4 complex were detected, he was diagnosed as having HIT, and warfarin and argatroban were administered instead of heparin. He died, however, 119 days after the first onset. At autopsy infarction due to organized thrombi with cholesterin deposition in multiple organs were found, similar to usual atherosclerotic emboli, but different to them with regard to clinical course and distribution of thrombi. This case in which organization and frequent cholesterin deposition were found in thromboembolized lesions of multiple organs after relatively long-term follow up, is unusual. The findings suggest that HIT accompanied by marked hypercholesterolemia of long duration contributes to a characteristic form of thromboembolism that needs careful management. PMID- 19788624 TI - Mucinous cystadenoma of the pancreas with huge mural hematoma. AB - A 60-year-old woman was referred for evaluation of a cystic mass in the pancreatic body that extended to the tail. Transabdominal ultrasonography demonstrated an oval cystic mass 24 cm in diameter, filled with debris. On the cyst wall there was a wide-based, smooth-surfaced, heterogeneous high-echoic protrusion that was 5 cm in diameter. On CT the protrusion showed internal enhancement. Endoscopic pancreatography showed no intraductal mucin or communication with the cyst. A distal pancreatectomy was performed under the diagnosis of mucinous cystadenocarcinoma. Grossly there was a brownish, hemispherical protrusion into the thin monolocular cyst. The cut surface of the protrusion showed a peripheral yellow-brownish area and an internal wine-colored area. Histopathologically the cyst wall consisted of tall columnar cells without atypical nuclei, ovarian-type stroma beneath the epithelium, and fibrotic tissue with abundant capillary vessels, suggestive of a mucinous cystadenoma. The protrusion was composed of peripheral organized hematoma without a covering epithelium, and internal hemorrhage and many capillary vessels, with no evidence of tumor cell necrosis. These histopathological findings appear to be similar to those of chronic expanding hematoma. The formation of a huge mural hematoma in a mucinous cystic neoplasm can occur as a repair process after the breaking of intrawall vessels. PMID- 19788625 TI - Hypercalcemic-type ovarian small cell carcinoma with unique CD34 expression. PMID- 19788626 TI - Perivascular epithelioid cell tumor of the nasal cavity with TFE3 expression. PMID- 19788627 TI - Announcement. Japan Pathology Award in 2009. PMID- 19788628 TI - Development of DSM-V and ICD-11: tendencies and potential of new classifications in psychiatry at the current state of knowledge. AB - A reason for the necessity to revise ICD-10 and DSM-IV is the increase of knowledge in the past 20 years, especially neurobiological knowledge. But is this increase of knowledge, for example in the field of neurogenetics, of such magnitude that a revision of the psychiatric classification is necessary and promises to be fruitful? The current plans for DSM-V or ICD-11, respectively, focus on different improvements. In this context also the introduction of a purely syndromatic/dimensional approach without including etiopathogenetic hypotheses, is discussed. A switch to such a dimensional approach, which was discussed among others in the DSM-V task force Deconstructing Psychosis, would be the most radical development. It could avoid many theoretical pre-assumptions about causal hypotheses, which are still associated with ICD-10 and DSM-IV. This would indeed increase the validity of psychiatric classification, but it would also reduce the information as compared to traditional diagnostic categories with all the current implications concerning etiopathogenesis, therapy and prognosis. Such a dimensional approach would also mean that the syndromes would have to be assessed in a standardized way for each person seeking help from the psychiatric service system or for each person undergoing psychiatric research. This would have to be a multi-dimensional assessment covering all syndromes existing within different psychiatric disorders. Based on the different aspects that must be considered in this context, a careful revision seems more advisable than a radical change of classification. PMID- 19788629 TI - Central nervous system effects of natural and synthetic glucocorticoids. AB - Natural glucocorticoids (NGC) physiologically modulate body homeostasis and coordinate adaptive responses to stress, involving almost all organs and tissues, including brain. Since their therapeutic availability, synthetic GC (SGC) have been successfully prescribed for a variety of diseases. Mounting evidence, however, demonstrated pleiotropic adverse effects (AE), including central nervous system (CNS) disturbances, which are often misdiagnosed or underestimated. The aim of the present study was therefore to review and discuss the CNS effects of both NGC and SGC. A detailed search was carried out of the available literature using the PubMed (US National Library of Medicine) database. Cortisolemia plays a crucial role in control of behavior, cognition, mood, and early life programming of stress reactivity. Hypercortisolemia or SGC treatments may induce behavioral, psychic and cognitive disturbances, due to functional and, over time, structural alterations in specific brain target areas. These AE are generally dose and time dependent (infrequent at prednisone-equivalent doses <20 mg/day) and usually reversible. Pediatric patients are particularly susceptible. Behavioral changes, including feeding and sleeping modifications, are common. Psychic AE are unpredictable and heterogeneous, usually mild/moderate, severe in 5-10% of cases. Manic symptoms have been mostly associated with short SGC courses, and depressive disorder with long-term treatments. Suicidality has been reported. Cognitive AE peculiarly affect declarative memory performance. Physiologic levels of NGC are essential for efficient brain functions. Otherwise, hypercortisolemia and SGC treatments may cause dose-/time-dependent neuropsychic AE and, over time, structural alterations in brain target areas. Clinicians should carefully monitor patients, especially children and/or when administering high doses SGC. PMID- 19788630 TI - Neural correlates of memory in depression measured by brain perfusion SPECT at rest. AB - AIM: Brain metabolism activated studies have indicated associations between memory and the anterior cingulate cortex and hippocampus in patients with depression. The aim of the present study was therefore to investigate memory function, measured as performance on the Wechsler Memory Scale-Revised (WMS-R), and its relationship to brain perfusion using single-photon emission computed tomography (SPECT) at rest in patients with depression. METHODS: The Hamilton Rating Scale for Depression (HAMD) and WMS-R were measured for 17 patients with depression by an independent clinical evaluation team. Voxel-based correlation analyses were performed with statistical parametric mapping at an extent threshold of 200 voxels. Associations were controlled for state and trait factors. RESULTS: WMS-R measurements of verbal, visual, and general memory were inversely correlated with brain perfusion in the right anterior cingulate cortex, left premotor cortices, and both regions, respectively. The HAMD directly correlated with brain perfusion in the right anterior cingulate cortex. CONCLUSION: Brain perfusion SPECT measurements of the anterior cingulate cortex at rest were associated with the severity of depression and immediate memory scores measured with the WMS-R. PMID- 19788631 TI - Oxidative mechanisms in schizophrenia and their relationship with illness subtype and symptom profile. AB - AIM: The aim of the present study was to investigate the differences in the antioxidant-oxidant balance (AO-OB) between schizophrenic patients and healthy individuals and to explore the relationship of AO-OB with illness subtypes and symptom profiles. METHODS: After a 15-day drug-free period, schizophrenia patients (n = 50) in a clinical sample, and age- and sex-matched healthy subjects (n = 49) were enrolled. Total antioxidant potentials (TAOP) and total peroxide levels (TPEROX) of all participants were measured and the oxidative stress index (OSI) was calculated. The assessment included structured measurements, including the Positive and Negative Syndrome Scale (PANSS), and the Brief Psychiatric Rating Scale (BPRS). RESULTS: TAOP had a significant positive correlation with age at onset of schizophrenia (P = 0.013), a negative correlation with the PANSS negative subscale scores (P = 0.008), a negative correlation with the PANSS total scores (P < 0.001), and a significant negative correlation with BPRS scores (P = 0.001). OSI had a significant negative correlation with age at onset (P = 0.046) and a significant positive correlation with PANSS negative subscale (P = 0.015). A multiple regression model indicated a significant linear combination of age, gender, duration of illness, subtype of schizophrenia, and PANSS scores, in which only the subtype of schizophrenia made a statistically significant contribution to predicting mean OSI (F[5,35] = 2.44, P = 0.04). CONCLUSION: Several parameters in the pathogenesis of schizophrenia, such as age of onset, level of negative symptoms, and subtype of illness, but not the presence of the illness itself, are associated with the level of oxidative stress. PMID- 19788632 TI - Suicide rate in Bali. PMID- 19788633 TI - Trichotilliomania responding to low-dose fluvoxamine. PMID- 19788634 TI - No correlation between Continuous Performance Test and optimal methylphenidate dosage in ADHD children. PMID- 19788635 TI - Effects of cellular phone email use on the mental health of junior high school students in Japan. PMID- 19788637 TI - Continuous intraventricular infusion of pentosan polysulfate: clinical trial against prion diseases. AB - Prion diseases are progressive neurological disorders due to abnormal prion protein (PrP(Sc)) deposition in the central nervous system. At present, there is no effective treatment available for any form of prion disease. Pentosan polysulfate (PPS) has been shown to prolong significantly the incubation period in mice with PrP(Sc) infection when administered to the cerebral ventricles in preclinical trials. In human studies conducted in European countries and Japan, intraventricular PPS was administered to patients with different forms of prion disease and was well tolerated. We report 11 patients with prion disease treated with intraventricular PPS at Fukuoka University from 2004. Cases included three familial CJD (two with V180I mutation, one GSS with P102L mutation), two iatrogenic CJD, and six sporadic CJD cases. At present, average survival period after treatment was 24.2 months (range, 4-49). Seven cases died of sepsis and pneumonia. Subdural effusion with various degrees was seen on CT scan in most cases. Except for these, adverse effects did not occur in the treatment period. Although our preliminary study of the new treatment with PPS by continuous intraventricular infusion showed no apparent improvement of clinical features in patients with prion disease, the possibility of extended survival in some patients receiving long-term PPS was suggested. PMID- 19788638 TI - A model-averaging method for assessing groundwater conceptual model uncertainty. AB - This study evaluates alternative groundwater models with different recharge and geologic components at the northern Yucca Flat area of the Death Valley Regional Flow System (DVRFS), USA. Recharge over the DVRFS has been estimated using five methods, and five geological interpretations are available at the northern Yucca Flat area. Combining the recharge and geological components together with additional modeling components that represent other hydrogeological conditions yields a total of 25 groundwater flow models. As all the models are plausible given available data and information, evaluating model uncertainty becomes inevitable. On the other hand, hydraulic parameters (e.g., hydraulic conductivity) are uncertain in each model, giving rise to parametric uncertainty. Propagation of the uncertainty in the models and model parameters through groundwater modeling causes predictive uncertainty in model predictions (e.g., hydraulic head and flow). Parametric uncertainty within each model is assessed using Monte Carlo simulation, and model uncertainty is evaluated using the model averaging method. Two model-averaging techniques (on the basis of information criteria and GLUE) are discussed. This study shows that contribution of model uncertainty to predictive uncertainty is significantly larger than that of parametric uncertainty. For the recharge and geological components, uncertainty in the geological interpretations has more significant effect on model predictions than uncertainty in the recharge estimates. In addition, weighted residuals vary more for the different geological models than for different recharge models. Most of the calibrated observations are not important for discriminating between the alternative models, because their weighted residuals vary only slightly from one model to another. PMID- 19788639 TI - Prevalence of and risk factors for hepatitis B and C infection among Mongolian blood donors. AB - BACKGROUND: Mongolia has one of the highest rates of viral hepatitis infections worldwide yet risk factors have been largely unstudied. This sentinel study of hepatitis infection in Mongolia determined the prevalence of hepatitis B virus surface antigen (HBsAg) and hepatitis C virus antibody (anti-HCV) among a sample of blood donors and identified demographic and behavioral factors associated with hepatitis infection. STUDY DESIGN AND METHODS: Data were collected by interview from 923 Ministry of Health Blood Center donors between August 2004 and February 2005. The exposure variables collected included donor demographics and health and behavioral risk factors. Bivariate and multivariate analyses assessed the prevalence ratio of hepatitis infection for each exposure. RESULTS: Of 923 donors, 72 tested positive for HBsAg (7.8%; 95% confidence interval [CI], 6.1% 9.7%), 89 donors tested positive for anti-HCV (9.6%; 95% CI, 7.8%-11.5%), and six (0.6%) tested positive for both HBsAg and anti-HCV. Prevalence of HBsAg was highest among donors 18 to 19 years and anti-HCV tended to be most prevalent among those more than 40 years of age. Both pregnancy and alcohol use were associated with seroprevalent anti-HCV. CONCLUSION: This sentinel study of hepatitis prevalence among Mongolian blood donors sheds considerable light on the epidemiology of hepatitis virus infection as well as the sociodemographic and behavioral risk factors associated with infection. Young age (HBsAg) and pregnancy (anti-HCV) were significant risk factors for hepatitis virus infection, indicating that improvements in education, vaccination rates, and general infection control procedures in health care institutions may reduce behavioral and nosocomial transmission. PMID- 19788640 TI - Evaluation of blood donor deferral causes in the Trinidad and Tobago National Blood Transfusion Service. AB - The majority of blood donations in Trinidad and Tobago are made as replacement by family members or friends. National Blood Transfusion Policy was drafted in 2007 to promote voluntary, repeated donation. The objective of this study is to assess the current rate and reasons for donor deferral, and the aim is to guide the proposed donor education and recruitment programme. A retrospective study of pre donation deferral of prospective blood donors at the National Blood Transfusion Centre, Port of Spain, Trinidad and Tobago, was conducted. Records of all pre donation deferrals over a 12-month period were studied. As many as 11,346 pre donation screening interviews were conducted. There were 4043 (35.6%) deferrals. The most common reasons for donor deferral were exposure to high-risk sexual activity (27.6%), low haemoglobin 22.2% and hypertension 17.5%. Other reasons such as medication, chronic medical illness, tattoos, travel history, recent pregnancy, surgery or presentation outside the accepted age limit caused 33.8% of all deferrals and the majority (34.7%) of male deferrals. Low haemoglobin (44.5%) was the most common reason among females. The rate of deferral of voluntary donors was not significantly different from that for replacement donors (31.7 vs. 35.4%, P = 0.25). This study exposed a lack of public awareness as the principal reason for an unacceptably high rate of donor deferral. Donor education about selection criteria needs to be urgently addressed as an objective of the National Policy. Monitoring and evaluation of deferral rates and reasons could be used as one indicator of the effectiveness of the Policy. PMID- 19788641 TI - Near-peer videos for physical examination instruction. PMID- 19788642 TI - A procedures curriculum for medical students. PMID- 19788643 TI - Structured, three-way, role-play activity for improving history-taking skills. PMID- 19788644 TI - Surgical Intern Olympics: skills assessment. PMID- 19788645 TI - Presidential address: The ethics of recognition, responsibility, and respect. AB - Ethics can be understood as a code of behaviour or as the study of codes of behaviour. While the mission of the International Association of Bioethics is a scholarly examination of moral issues in health care and the biological sciences, many people in the field believe that it is also their task to create new and better codes of practice. Both ways of doing bioethics are sound, but it is important to be aware of the distinction. In this paper, I will study the sources and aims of ethics and suggest a code of conduct for bioethicists based on recognition, responsibility, and respect. PMID- 19788646 TI - The cross-cultural importance of satisfying vital needs. AB - Ethical beliefs may vary across cultures but there are things that must be valued as preconditions to any cultural practice. Physical and mental abilities vital to believing, valuing and practising a culture are such preconditions and it is always important to protect them. If one is to practise a distinct culture, she must at least have these basic abilities. Access to basic healthcare is one way to ensure that vital abilities are protected. John Rawls argued that access to all-purpose primary goods must be ensured. Amartya Sen and Martha Nussbaum claim that universal capabilities are what resources are meant to enable. Len Doyal and Ian Gough identify physical health and autonomy as basic needs of every person in every culture. When we disagree on what to prioritize, when resources to satisfy competing demands are scarce, our common needs can provide a point of normative convergence. Need-based rationing, however, has been criticized for being too indeterminate to give guidance for deciding which healthcare services to prioritize and for tending to create a bottomless-pit problem. But there is a difference between needing something (first-order need) and needing to have the ability to need (second-order need). Even if we disagree about which first-order need to prioritize, we must accept the importance of satisfying our second-order need to have the ability to value things. We all have a second-order need for basic healthcare as a means to protect our vital abilities even if we differ in what our cultures consider to be particular first-order needs. PMID- 19788647 TI - How to connect bioethics and environmental ethics: health, sustainability, and justice. AB - In this paper, I explore one way to bring bioethics and environmental ethics closer together. I focus on a question at the interface of health, sustainability, and justice: How well does a society promote health with the use of no more than a just share of environmental capacity? To address this question, I propose and discuss a mode of assessment that combines a measurement of population health, an estimate of environmental sustainability, and an assumption about what constitutes a fair or just share. This mode of assessment provides an estimate of the just and sustainable life expectancy of a population. It could be used to monitor how well a particular society promotes health within just environmental limits. It could also serve as a source of information that stakeholders use when they deliberate about programs, policies, and technologies. The purpose of this work is to focus attention on an ethical task: the need to fashion institutions and forms of life that promote health in ways that recognize the claims of sustainability and justice. PMID- 19788648 TI - The window of opportunity: decision theory and the timing of prognostic tests for newborn infants. AB - In many forms of severe acute brain injury there is an early phase when prognosis is uncertain, followed later by physiological recovery and the possibility of more certain predictions of future impairment. There may be a window of opportunity for withdrawal of life support early, but if decisions are delayed there is the risk that the patient will survive with severe impairment. In this paper I focus on the example of neonatal encephalopathy and the question of the timing of prognostic tests and decisions to continue or to withdraw life sustaining treatment. Should testing be performed early or later; and how should parents decide what to do given the conflicting values at stake? I apply decision theory to the problem, using sensitivity analysis to assess how different features of the tests or different values would affect a decision to perform early or late prognostic testing. I draw some general conclusions from this model for decisions about the timing of testing in neonatal encephalopathy. Finally I consider possible solutions to the problem posed by the window of opportunity. Decision theory highlights the costs of uncertainty. This may prompt further research into improving prognostic tests. But it may also prompt us to reconsider our current attitudes towards the palliative care of newborn infants predicted to be severely impaired. PMID- 19788649 TI - Cryoethics: seeking life after death. AB - Cryonic suspension is a relatively new technology that offers those who can afford it the chance to be 'frozen' for future revival when they reach the ends of their lives. This paper will examine the ethical status of this technology and whether its use can be justified. Among the arguments against using this technology are: it is 'against nature', and would change the very concept of death; no friends or family of the 'freezee' will be left alive when he is revived; the considerable expense involved for the freezee and the future society that will revive him; the environmental cost of maintaining suspension; those who wish to use cryonics might not live life to the full because they would economize in order to afford suspension; and cryonics could lead to premature euthanasia in order to maximize chances of success. Furthermore, science might not advance enough to ever permit revival, and reanimation might not take place due to socio political or catastrophic reasons. Arguments advanced by proponents of cryonics include: the potential benefit to society; the ability to cheat death for at least a few more years; the prospect of immortality if revival is successful; and all the associated benefits that delaying or avoiding dying would bring. It emerges that it might be imprudent not to use the technology, given the relatively minor expense involved and the potential payoff. An adapted and more persuasive version of Pascal's Wager is presented and offered as a conclusive argument in favour of utilizing cryonic suspension. PMID- 19788653 TI - Identification of genes regulated by the MvaT-like paralogues TurA and TurB of Pseudomonas putida KT2440. AB - The genome of the Pseudomonas putida strain KT2440 contains five paralogous proteins (TurA, TurB, TurC, TurD and TurE) of the H-NS-like MvaT class of transcription regulators. TurA and TurB belong to groups I and II, respectively, both containing orthologous MvaT proteins that are present in all Pseudomonadaceae species. On the contrary, TurC, TurD and TurE belong to group III, which contains species-specific paralogous MvaT proteins. We analysed the global effects on the P. putida KT2440 transcriptome of eliminating the conserved TurA and TurB proteins, which had been identified in our previous studies aimed to search for novel specific co-regulators of the upper TOL operon for toluene biodegradation. While the loss of TurA de-repressed the expression of many genes covering a broad range of functional classes in both mid-exponential and early stationary phases, the absence of TurB brought about a very different outcome. Although the loss of TurB affected also very different functions, the number of genes that changed in the turB mutant was fivefold smaller than that of TurA. Furthermore, TurB does not act generally as repressor. Interestingly, the degree of overlap between their mutual regulons is very limited. A closer examination of one case where such overlap clearly occurs (a gene cluster for biosynthesis of lipodepsinonapeptide phytotoxins) revealed that TurA and TurB can act in concert, perhaps by forming a heterodimer. In addition, our results indicate that TurA is the master regulator of TurB as well as of the other paralogues, TurD and TurE. PMID- 19788654 TI - Widespread known and novel phosphonate utilization pathways in marine bacteria revealed by functional screening and metagenomic analyses. AB - Phosphonates (Pn), compounds with a direct C-P bond instead of the more common C O-P ester bond, constitute a significant fraction of marine dissolved organic phosphorus and recent evidence suggests that they may be an alternative source of P for marine microorganisms. To further characterize the microorganisms and pathways involved in Pn utilization, we screened bacterioplankton genomic libraries for their ability to complement an Escherichia coli strain unable to use Pns as a P source. Using this approach we identified a phosphonatase pathway as well as a novel pair of genes that allowed utilization of 2 aminoethylphosphonate (2-AEPn) as the sole P source. These pathways are present in diverse bacteria common in marine plankton including representatives of Proteobacteria, Planctomycetes and Cyanobacteria. Analysis of metagenomic databases for Pn utilization genes revealed that they are widespread and abundant among marine bacteria, suggesting that Pn metabolism is likely to play an important role in P-depleted surface waters, as well as in the more P-rich deep water column. PMID- 19788655 TI - The turnover of medium-chain-length polyhydroxyalkanoates in Pseudomonas putida KT2442 and the fundamental role of PhaZ depolymerase for the metabolic balance. AB - Polyhydroxyalkanoates (PHAs) are biodegradable polymers produced by a wide range of bacteria, including Pseudomonads. These polymers are accumulated in the cytoplasm as carbon and energy storage materials when culture conditions are unbalanced and hence, they have been classically considered to act as sinks for carbon and reducing equivalents when nutrients are limited. Bacteria facing carbon excess and nutrient limitation store the extra carbon as PHAs through the PHA polymerase (PhaC). Thereafter, under starvation conditions, PHA depolymerase (PhaZ) degrades PHA and releases R-hydroxyalkanoic acids, which can be used as carbon and energy sources. To study the influence of a deficient PHA metabolism in the growth of Pseudomonas putida KT2442 we have constructed two mutant strains defective in PHA polymerase (phaC1)- and PHA depolymerase (phaZ)-coding genes respectively. By using these mutants we have demonstrated that PHAs play a fundamental role in balancing the stored carbon/biomass/number of cells as function of carbon availability, suggesting that PHA metabolism allows P. putida to adapt the carbon flux of hydroxyacyl-CoAs to cellular demand. Furthermore, we have established that the coordination of PHA synthesis and mobilization pathways configures a functional PHA turnover cycle in P. putida KT2442. Finally, a new strain able to secrete enantiomerically pure R-hydroxyalkanoic acids to the culture medium during cell growth has been engineering by redirecting the PHA cycle to biopolymer hydrolysis. PMID- 19788656 TI - Glaucoma guidelines: help or hindrance? PMID- 19788657 TI - A new niche for the corneal epithelial stem cell. PMID- 19788658 TI - Patients' preferences for positioning during phaco-emulsification under topical intracameral anaesthesia. AB - In many eye departments it is routine to ask patients to lie completely flat for cataract surgery. However, many patients prefer not to lie completely flat, if given the choice. It is our practice to ensure patients are in a comfortable position before commencing surgery. We conducted a prospective observational study of our routine practice comprising 125 consecutive cataract operations conducted by a single surgeon with local anaesthesia (occasional phaco under general anaesthetic was not included). All patients were initially positioned lying flat on the reclining chair and were given the option of staying in that position throughout the operation or having the chair-back raised until they were comfortable. Only 27% (34 patients of 125 total) were happy to lie flat (angle between 0 degrees and 5 degrees ). The majority of our patients (62%--78 patients) preferred to sit up slightly, with the chair-back 10 degrees to 25 degrees above the horizontal; 8% (10 patients) of the patients were sited at an angle of 30 degrees to 35 degrees and 2% (three patients) needed to be sited at 35 degrees or more. Patients who sat up above 30 degrees generally had a medical reason such as orthopnoea (3%--four patients), back pain (5%--six patients), anxiety (2%--two patients), Meniere's disease (1%--one patient). Patients who sat up below 25 degrees chose this position for comfort or preference. Our results show that patient preferences for positioning during cataract phaco emulsification under topical-intracameral anaesthesia should increase overall patient satisfaction without the need to compromise safety. PMID- 19788659 TI - Revisiting transconjunctival sutureless 25-gauge vitrectomy: still worthwhile? AB - To present the outcomes of various retinal conditions treated with the sutureless 25-gauge (25G) vitrectomy technique. Retrospective case review of 232 eyes of 228 patients who underwent 25G vitrectomy from January 2003 to August 2006. Follow-up was a minimum of 3 months. Indications for surgery included idiopathic macular hole, rhegmatogenous retinal detachment, epiretinal membrane and proliferative diabetic retinopathy. Main outcome measures included final visual acuity, re operation rate and surgical complications such as endophthalmitis, hypotony and retinal (re)detachment. For all cases, the mean overall visual acuity (logMAR) improved from 0.9 preoperatively to 0.5 (P < 0.0001). The improvement in acuity was highest in the rhegmatogenous detachment and diabetic groups. Transient postoperative hypotony was observed in 15 cases (9.2%) on day 1 after surgery but all these cases resolved. In 7.3% of the cases (17 out of 232) additional surgery was performed due to retina (re)detachment but final anatomic success was achieved in all cases; the detachments occurred within the first 3 months. One patients developed endophthalmitis (0.4%) which coincided with subconjunctival antibiotics being discontinued in favour of topical treatment. The 25G system remains a safe and effective technique for a variety of retinal conditions; significant fast visual rehabilitation is an advantage. PMID- 19788660 TI - Management of exudative retinal detachment in choroidal melanoma. AB - Exudative retinal detachment is the most common source of visual loss associated with malignant melanoma of the uveal tract. Management has historically been conservative, leading to irreversible visual loss from photoreceptor damage during the several months needed for post-radiation resolution. The purpose of this paper is to describe timely vitreoretinal surgical intervention for exudative retinal detachments associated with choroidal melanomas. This was an interventional case series including six consecutive patients with malignant melanoma who experienced VA reduction secondary to associated exudative retinal detachment. Patients underwent complete ophthalmic evaluation and B-scan ultrasound. Treatment included proton-beam radiation or brachytherapy, prognostic transretinal tumour biopsy with 25-gauge vitrector and surgical treatment of exudative retinal detachment, including vitrectomy and drainage of subretinal fluid at the time of irradiation. Successful management of exudative retinal detachments associated with choroidal melanomas was observed in all cases, with significant restoration of vision. Steady regression of tumour thickness was noted clinically and ultrasonographically, without extrascleral extension or metastasis, and with no recurrence of exudative retinal detachment found over follow up. In the present study, the investigators have showed effective surgical treatment of exudative retinal detachment associated with malignant melanoma. These patients had significant restoration of vision, confirming that timely intervention of exudative retinal detachment associated with malignant melanoma can reverse visual loss in these patients. These findings are in contrast to previous reports of irreversible visual loss after exudative retinal detachments, and suggest that photoreceptor atrophy might play a role in visual loss associated with chronic exudative retinal detachments. PMID- 19788661 TI - Posterior scleral reinforcement in the treatment of macular retinoschisis in highly myopic patients. AB - The objective of this study was to evaluate the clinical curative effect of posterior scleral reinforcement for macular retinoschisis in highly myopic patients. Twenty-four highly myopic eyes with macular retinoschisis were treated with posterior scleral reinforcement surgery from September 2005 to March 2007 in our hospital. Visual field, best corrected vision acuity (BCVA), refractive error, optical coherence tomography and A/B Scan ultrasound graphy results were retrospectively analysed. The central visual field in 18 eyes was improved after surgery; optical coherence tomography showed complete resolution of the myopic foveoschisis in 20 (83.33%) of the 24 eyes after surgery. The postoperative BCVA was improved by 0.1 or more in 18 eyes (75%), and remained within 0.1 of the preoperative BCVA in five eyes (20.83%) at the end of follow-up. Compared with the preoperative data of 23 eyes, the final magnitude of myopia after surgery was significantly decreased (t = 3.527, P = 0.002). In conclusion, this procedure can effectively treat highly myopic patients with macular retinoschisis without macular hole or retinal detachment, and might be better for maintaining central vision and preventing the occurrence of complications. PMID- 19788662 TI - The effect of micro-incision and small-incision coaxial phaco-emulsification on corneal astigmatism. AB - PURPOSE: To evaluate the effect of micro-incision (2.2 mm) and small-incision (2.6 mm or 3.0 mm) coaxial phaco-emulsification on surgically induced astigmatism (SIA). METHODS: Cataract patients (n = 83, 129 eyes) were randomized into three groups: 43 eyes in the 2.2-mm incision group, 42 eyes in the 2.6-mm group and 44 eyes in the 3.0-mm group. Torsional phaco-emulsification was followed by intraocular lens implantation via the Monarch II injector with the C cartridge (Alcon Laboratories Inc., Fort Worth, TX, USA). Corneal astigmatism, SIA and uncorrected distance visual acuity were assessed 30 and 90 days after cataract surgery. RESULTS: At 30 and 90 days postoperative, SIA of the 3.0-mm group was greater than SIA of the 2.2-mm and 2.6-mm groups (P < or = 0.015), but SIA was similar between the 2.2-mm group and the 2.6-mm group. Timewise, mean SIA at 30 days was greater than SIA at 90 days in the 3.0-mm group (P = 0.04), while SIA did not change with time for the 2.2-mm and 2.6-mm groups. Postoperative uncorrected distance visual acuity tended to be better with the smaller incisions, but this trend did not reach statistical significance (P > or = 0.07). CONCLUSION: Incision size contributed to postoperative corneal astigmatism. When incision size was reduced from 3.0 mm to 2.6 mm, SIA was reduced and refractive stabilization was faster. Reduction of incision size from 2.6 mm to 2.2 mm offered no greater reduction of SIA when using the C cartridge; however, the D cartridge (designed for 2.2-mm incisions) should be evaluated. PMID- 19788663 TI - Relationship between myopia and allergen-specific serum IgE levels in patients with allergic conjunctivitis. AB - PURPOSE: Various exogenous allergens can cause allergic conjunctivitis, whereas refractive errors are also related (as an endogenous factor) to the pathogenesis of allergic conjunctivitis. However, little is known about the interaction between exogenous and endogenous factors in patients with allergic conjunctivitis. We investigated the relationship between refractive errors and exogenous allergens in patients with allergic conjunctivitis. METHODS: Sixty patients with allergic conjunctivitis and 60 healthy subjects (non-allergy patients) were enrolled. Refraction was carried out in all subjects. In addition, total immunoglobulin E (IgE) and specific IgE levels for 12 inhaled allergens were measured by the capsulated hydrolic carrier polymer system. RESULTS: The patients who were positive for-specific IgE to indoor allergens had higher myopia than those who were negative, including those positive for house dust IgE (-3.66 +/- 2.95 vs. -1.05 +/- 3.39, P = 0.0015), Dermatophagoides pteronyssinus (D. pteronyssinus) IgE (-3.50 +/- 2.91 vs. -1.01 +/- 3.46, P = 0.0021), and acarus IgE (-3.45 +/- 2.21 vs. -1.51 +/- 3.73, P = 0.0087), whereas antibody-positive and antibody-negative patients for outdoor allergens showed no significant differences of refraction. Refractions in indoor group (-3.58 +/- 3.42) and indoor/outdoor (-3.70 +/- 2.64) group were higher than those in outdoor group ( 0.84 +/- 2.30, P = 0.0047 and P = 0.0032) and the non-allergy group (-1.30 +/- 1.48, P = 0.0082 and P = 0.0054) [-refraction] was significantly correlated with total IgE (r = 0.333, P = 0.0093), house dust (r = 0.355, P = 0.0054) and D. pteronyssinus (r = 0.379, P = 0.0028), while no correlation between refractive error and outdoor allergens was proven. CONCLUSION: These results suggest that specific IgE levels for indoor allergens, such as house dust, might be associated with refractive errors. PMID- 19788664 TI - Multifocal pupillographic visual field testing in glaucoma. AB - PURPOSE: This preliminary study investigated a means of concurrently assessing the visual field defects of both eyes by recording pupillary responses to multifocal stimuli. METHODS: Twenty normal subjects and 26 primary open angle glaucoma patients, age and sex matched, were examined by slit-lamp, Humphrey Field Analyser II achromatic 24-2 perimetry and fundus photography. The patients had moderate to severe fields in at least one eye. Two stereoscopically arranged displays presented an array of 24 stimulus regions per eye extending from fixation to 30 degrees eccentricity. Pupil responses were recorded by video cameras under infrared illumination. Four stimulus conditions were tested: each stimulus region containing either a single or a 2 x 2 array of patches, presented either steadily for 133 ms or flickered at 15 Hz for 266 ms. Mean presentation rate was 1/s/region. The 4-min duration stimuli were presented in 8 segments of 30 s. Segments did not need to be repeated unless more than 15% of a segment record was lost as a result of blinks or fixation losses. RESULTS: The 48 stimuli produced 96 direct and consensual responses per subject. The single patch, non flickered stimulus condition produced the best diagnostic performance, an area under the curve of 84%. The contraction amplitudes for that stimulus gave a median z-score of 3.2. CONCLUSIONS: The method produced diagnostic accuracy approaching that of automated perimetry, but unlike perimetry provides standard errors for every point in each field as well as information on response delay and efferent defects. Only one pupil needs to function to measure both visual fields. PMID- 19788665 TI - The iCare rebound tonometer: comparisons with Goldmann tonometry, and influence of central corneal thickness. AB - PURPOSE: To assess agreement between the iCare rebound tonometer and Goldmann tonometry and to assess the influence of central corneal thickness and the value of scleral rebound tonometer readings. METHODS: Prospective single-centre cross sectional study comparing iCare rebound tonometer (RT) intraocular pressure (IOP) readings taken from corneal and scleral locations to Goldmann applanation tonometer (GAT) readings in 100 subjects attending ophthalmology clinics. RESULTS: There was a significant difference between RT and GAT, with RT tending to overestimate IOP. The mean difference between RT and GAT measurements was 3.36 mmHg. The mean difference between the log of RT and the log of GAT measurements was 0.2356, a ratio of 1.27 (P < 0.0001). A formula derived from a linear regression analysis suggested that a 10% increase in CCT increased the RT IOP reading by 9.9%. Scleral RT readings showed no relationship to GAT readings. CONCLUSIONS: The rebound tonometer cannot replace the Goldmann tonometer in the office setting given the wide limits of agreement between the two devices. Corneal rebound tonometer readings are influenced by CCT whereas scleral rebound tonometer readings are of no value. PMID- 19788666 TI - Endoscopic cyclophotocoagulation for the treatment of glaucoma: an Asian experience. AB - BACKGROUND: To describe the efficacy and safety of endoscopic cyclophotocoagulation in Asian patients with glaucoma. METHODS: Retrospective case series. Consecutive cases of endoscopic cyclophotocoagulation performed by one surgeon during the study period were included. Patients' records were reviewed for clinical and demographic factors, treatments, intraocular pressure (IOP), visual acuity and any complications. RESULTS: Twenty-nine eyes of 29 patients were treated. Their mean age was 73.6 +/- 9.4 years. The mean follow-up duration was 15.9 +/- 8.9 months. Eleven patients had primary open-angle glaucoma, two normal tension glaucoma, six chronic angle-closure glaucoma, five neovascular glaucoma, four secondary open-angle glaucoma and one secondary angle closure glaucoma. Twenty patients had endoscopic cyclophotocoagulation combined with cataract surgery. Mean pretreatment IOP was 21.8 +/- 6.6 mmHg. Mean post treatment IOP at 18 months (n = 17) was 16.2 +/- 4.1 mmHg (P = 0.02) and 17.9 +/- 4.9 mmHg (P = 0.18) at 24 months (n = 10). The mean number of anti-glaucoma medications pretreatment was reduced from 2.0 +/- 1.0 to 0.9 +/- 0.9 at 18 months post-treatment (P = 0.04) and 1.2 +/- 0.8 at 24 months (P = 0.13). The overall success rate based on IOP reduction of 20% or greater at last follow-up was 48.3%. Visual acuity was reduced in five eyes. Complications included one case each of hyphaema, bullous keratopathy, transient pigment dispersion and iris burn. CONCLUSION: Endoscopic cyclophotocoagulation may have a treatment role in Asian patients with glaucoma. The success rate appears poorer than previously reported in Caucasian populations. The treatment effect appeared to wane between 18 and 24 months post-treatment. PMID- 19788667 TI - Eye injuries in rural Victoria, Australia. AB - BACKGROUND: Eye injury causes significant morbidity and is a leading cause of blindness worldwide. This study investigates the incidence, spectrum and patterns of eye injury presenting to a rural hospital in Victoria, Australia. METHODS: A retrospective review of the medical records of all patients presenting with eye injury to the emergency department of Mildura Base Hospital, Victoria, Australia in year 2004 was conducted. As the emergency department of Mildura Base Hospital also acts as the outpatient department for this hospital, the series included all patients treated for eye injury at Mildura Base Hospital in year 2004, including admissions. RESULTS: There were 435 patients present to Mildura Base Hospital emergency department for eye injury in 2004, which represented approximately 1% of the population of Mildura. The majority of eye injuries were superficial. Fifty-six (13%) patients required specialist attention. Most patients were male (83%) and were middle-aged. The most common locations where eye injuries took place were residential homes (47%) and workplaces (32%). The most common causes of eye injuries were trade tools and machinery (47%), followed by chemicals (12%) and branches/sticks/twigs (11%). Of particular concern for Mildura is that approximately one-quarter of the patients treated at Mildura Base Hospital for eye injury in 2004 had been treated at Mildura Base Hospital for a separate episode of eye injury in the past. CONCLUSION: Eye injuries represent a significant socioeconomic burden. This research contributes to the knowledge required for the design and implementation of effective preventative strategy. PMID- 19788668 TI - An audit of genetic testing in diagnosis of inherited retinal disorders: a prerequisite for gene-specific intervention. AB - BACKGROUND: There has been an exponential increase in the number of genes implicated in inherited retinal disease over the last decade, but the genetic and phenotypic heterogeneity limited mutation detection. The high cost of sequencing and long turn around times meant that gene testing was not a viable option, particularly in New Zealand. Recently, advancements including development of micro-array-based mutation analysis and non-for-profit laboratories have resulted in affordable and time-efficient testing. This has enabled genetic diagnostics to become an integral component of the work-up for inherited retinal disease. METHODS: Genetic testing for inherited retinal disorders was initiated via the Ocular Genetic Clinic in Auckland 2 years ago. A retrospective audit of genetic testing over this period was carried out. The results of these tests and outcomes are discussed. RESULTS: Thirty-five probands have undergone genetic testing for retinal disorders. This has included X-Linked Retinoschisis, Leber Congenital Amaurosis, Retinitis Pigmentosa, Albinism, Achromatopsia, Usher syndrome, Stargardt disease and Mitochondrial disease. Of these, 54% of tests (19/35) showed a rare variant or pathogenic mutation. Three couples have proceeded to investigate the options of prenatal diagnosis and/or pre-implantation genetic diagnosis. CONCLUSION: The introduction of genetic testing, largely via disease arrays, has been highly successful at clarifying disease genotype in our cohort. It is now a timely and cost-effective investigation that should be elemental to the assessment of inherited retinal disease. Genetic testing in an opportune fashion permits genetic counselling, enables families to make reproductive choices and might allow the possibility of gene therapy interventions. PMID- 19788669 TI - Optic perineuritis secondary to Wegener's granulomatosis. AB - BACKGROUND: Optic perineuritis (OPN) is an inflammatory condition involving the optic nerve sheath because of a variety of causes. We describe three patients in whom OPN was secondary to Wegener's granulomatosis (WG) and compare the clinical findings in these cases with those of idiopathic OPN. METHODS: This is a retrospective small case series derived from patients with OPN seen in an outpatient neuro-ophthalmology clinic. Medical records and imaging studies of these patients were reviewed. RESULTS: These patients shared clinical similarities with idiopathic OPN including age, sex, symptoms, radiographic findings and steroid responsiveness. However, recurrence of symptoms on lowering the prednisone dose below 40 mg distinguished these patients from those with idiopathic OPN. CONCLUSIONS: Steroid dependency in idiopathic OPN should raise suspicion of WG. Patients with OPN should be specifically questioned regarding pre-existing upper respiratory tract disorders and rheumatic symptoms and laboratory testing should include acute phase reactants, anti-neutrophil cytoplasmic antibodies and tests of renal function. PMID- 19788670 TI - Possible neuroprotective effect of brimonidine in a mouse model of ischaemic optic neuropathy. AB - PURPOSE: To investigate the neuroprotective effect of brimonidine following induction of ischaemic optic neuropathy in rodents (rAION). METHODS: Mice were treated with an intraperitoneal injection of brimonidine 48, 24 or 0 h before rAION induction or eye drops for 5 days after rAION induction. Retinal ganglion cell (RGC) loss and expression of genes involved in the angiogenesis (vascular endothelial growth factor [VEGF], pigment epithelium-derived factor [PEDF], The epidermal growth factor homology domains-2 [Tie-2]), ischaemia (haem oxygense-1 [HO-1], hypoxia-inducible factor 1alpha[HIF-1alpha], endothelial nitric oxide synthase [eNOS]) and oxidative stress (superoxide dismutase-1 [SOD-1], glutathione peroxidase-1 [GPX-1]) response to ischaemic damage were compared with sham or rAION-untreated mice. RESULTS: No RGC loss was detected in the brimonidine-treated mice. Effect of post-rAION eye drops: day 1--no decrease in retinal mRNA levels of angiogenesis-related genes, increase in ischaemia- and oxidative stress-related genes except HIF-1alpha; day 3--baseline or higher levels of oxidative and ischaemia-related genes except HIF-1alpha, increase in VEGF, decrease in PEDF; day 21--no change in angiogenesis-related genes. Effect of pre-rAION injection: baseline levels of angiogenesis-related genes with all injection schedules; increase in ischaemia-related genes with 48-h and 0-h pretreatment; decrease in HO-1 and eNOS with 24-h pretreatment; increase in oxidative-related genes except GPX-1. In optic nerve tissue, HO-1, HIF-1alpha and SOD-1 decreased on day 1 after topical administration and were still below baseline on day 3. CONCLUSIONS: The increase in HO-1 associated with rAION is mitigated with brimonidine treatment, especially when administered intraperitoneally. Topical brimonidine apparently reduces VEGF, Tie-2, HIF-1alpha and GPX-1 expression on day 21. These results agree with published data and may have therapeutic implications for patients diagnosed with AION in the acute phase. PMID- 19788671 TI - Effect of bevacizumab on corneal neovascularization in experimental rabbit model. AB - PURPOSE: To investigate the effect of bevacizumab in an experimental rabbit model of corneal neovascularization. METHODS: The right eyes of 24 white New Zealand rabbits were included in a corneal neovascularization model using alkaline burn. They were divided into four groups. Topical bevacizumab was installed three times daily in group 1, 5 mg bevacizumab subconjunctivally every 2 days in group 2, 10 mg bevacizumab subconjunctivally every 2 days in group 3 and 0.2 cc of normal saline in the same way in group 4 (control group). All eyes were treated for 7 days. Then the animals were killed and corneal specimens sent for histopathological analysis. Tear film and aqueous humour samples were obtained to assess vascular endothelial growth factor (VEGF) levels. RESULTS: Seven days after topical bevacizumab treatment the neovascular index in group 1 was lower than that in the control group (P = 0.028). In groups 2 and 3 the neovascular index was lower 2 days after subconjunctival bevacizumab treatment than that in control group (P = 0.009 and P = 0.009, respectively). In the control group the VEGF level in aqueous humour increased by 66% from day 7 to 14. In groups 1-3 it decreased by 49.80%, 70.20% and 76.44%, respectively (P = 0.043). The VEGF level in tear film of the control group increased by 35.23% from day 7 to 14, which was not significant (P = 0.893), while in groups 1-3 it decreased by 57.26%, 34.59% and 67.97%, respectively, which was only significant in groups 1 and 3 (P = 0.043). CONCLUSIONS: Subconjunctival 5 mg/mL bevacizumab is effective in reducing corneal neovascularization in animal models and in reducing VEGF levels. Further research is needed to assess the potential side effects and minimal effective dose. PMID- 19788672 TI - In vivo confocal microscopy in the diagnosis and management of acanthamoeba keratitis showing new cystic forms. PMID- 19788673 TI - Anterior complications in case of recurrent acute lymphoblastic leukaemia diagnosed by biopsy of aqueous humour. PMID- 19788674 TI - Irido-cilio-choroidal melanoma in a 5-year-old boy treated by Ru-106 brachytherapy. PMID- 19788675 TI - Pegylated interferon and ribavirin therapy for hepatitis C causing cataract. PMID- 19788676 TI - Pseudo-Parinaud syndrome: eyelid retraction and upgaze palsy associated with oculomotor nucleus syndrome. PMID- 19788677 TI - Concordance of congenital ptosis in monozygotic twins. PMID- 19788678 TI - Sequential bilateral central retinal artery occlusions in a female carrier of Fabry disease. PMID- 19788679 TI - Choroidal detachment in association with topical dorzolamide: is hypotony always the cause? PMID- 19788680 TI - A case of neurofibromatosis type I presenting with rapid enophthalmos caused by thoracoentesis. PMID- 19788683 TI - Molecular targets for liver cancer therapy: From screening of target genes to clinical trials. AB - Cancer arises from the accumulation of genetic alterations, and the inactivation of oncogenes, or recovery of suppressor genes, are promising strategies for cancer treatment. Genome-based drug research starts with identification of target genes and is accomplished by exploitation of target-based drugs such as monoclonal antibodies, small molecules and antisense drugs. Recently, clinical trials for treatment of advanced hepatocellular carcinoma (HCC) have been performed, and the effectiveness of sorafenib, an oral multikinase inhibitor of the vascular endothelial growth factor receptor and Ras kinase, has been demonstrated. In addition to known target genes, microarray technology has enabled us to constitute novel therapeutic targets, and many researchers have applied this technology in studies of HCC and have identified candidate target genes, validated to affect cell growth. In addition, promoter arrays for whole genome epigenetic aberration analysis, ChIP-chip analysis using tiling arrays, and high-throughput sequencing systems have been applied to drug discovery. To elucidate the status of therapeutic target genes in vivo, development of diagnostic markers for stratification of patients is a pressing need. Here, we review recent advances in microarray technology for liver cancer, discuss the innovations and approaches to therapeutic target discovery, and present data regarding the outcome of gene target therapy using monoclonal antibodies and molecular diagnostic markers in our laboratory. PMID- 19788684 TI - Development of HCC in patients receiving adefovir dipivoxil for lamivudine resistant hepatitis B virus mutants. AB - AIM: To identify factors for the development of hepatocellular carcinoma (HCC) in the patients who receive adefovir add-on lamivudine for treatment of lamivudine resistant hepatitis B virus (HBV) mutants. METHODS: A total of 247 patients who developed lamivudine-resistant HBV mutants, with an increase of HBV DNA >/= 1 log copies/mL, received adefovir dipivoxil 10 mg add-on lamivudine 100 mg daily during a median of 115 weeks (range: 25-282 weeks). They were followed for the development of HCC by imaging modalities every 3-6 months. RESULTS: HCC developed in 18 of the 247 (7.3%) patients. Eight factors were in significant association with the development of HCC by the univariate analysis. They included age, cirrhosis, platelet counts, levels of bilirubin, aspartate aminotransferase (AST), alanine aminotransferase and alpha-fetoprotein, as well as YMDD mutants at the start of adefovir dipivoxil. By the multivariate analysis, AST levels, YIDD mutants, cirrhosis and age were independent factors for the development of HCC. By the Kaplan-Meier analysis, AST levels >/= 70 IU/L, YIDD mutants, cirrhosis and age >/= 50 years increased the risk of HCC (P = 0.018, P = 0.035, P = 0.002 and P = 0.014, respectively). HCC developed more frequently in the patients with than without cirrhosis at the start of adefovir (10/59 [16.9%] vs. 8/188 [4.3%], P = 0.002). CONCLUSION: HCC can develop in cirrhotic patients receiving adefovir add on lamivudine. Hence, the patients with baseline AST >/= 70 IU/L and YIDD mutants would need to be monitored closely for HCC. PMID- 19788685 TI - Antiangiogenesis gene armed tumor-targeting adenovirus yields multiple antitumor activities in human HCC xenografts in nude mice. AB - AIM: Gene therapy represents a promising therapeutic strategy for hepatocellular carcinoma (HCC). To improve the ratio of killing efficacy on tumor cells to side effect on normal cells, we constructed an oncolytic adenovirus vector, AdSu-hE, expressing the human endostatin (hE) gene, in which the chimeric promoter of human epidermal growth factor receptor 2 enhancer and human telomerase reverse transcriptase promoter was used to control the adenoviral E1a gene. METHODS: Tumor-selective replication of adenovirus AdSu-hE and its concomitant expression of endostatin were measured by 50% tissue culture infective dose method, fluorescent protein expression, Western blot and enzyme linked immunosorbent assay in cancer and normal cell lines. The antitumor efficacy was observed in nude mice bearing human HCCs. RESULTS: The oncolytic adenovirus AdSu-hE replicated restrictedly in telomerase-positive cancer cells and resulted in oncolysis, but did not replicate in normal cell lines. Along with virus replication, AdSu-hE mediated 5-fold increased expression of endostatin in tumor cells compared with that in normal cells. Moreover, AdSu-hE expressed more endostatin in cancer cells than the non-replicative adenovirus vector Ad-hE. In vivo administration of the oncolytic adenovirus AdSu-hE into HCC-bearing nude mice produced a significant tumor reduction by synergistic effects of virus oncolysis and endostatin antiangiogenesis. CONCLUSION: The oncolytic virus with antiangiogenesis gene driven by the chimeric promoter has an improved killing efficacy on tumor cells, and may be useful for cancer gene therapy. PMID- 19788686 TI - Role of Kupffer cells in the outgrowth of colorectal cancer liver metastases. AB - Colorectal cancer is one of the commonest malignancies in the "developed" world. The liver constitutes the main host organ for its distant metastases which, when present, augur a bad prognosis for the disease. Kupffer cells (KCs) are macrophages that constantly reside within the liver and form an effective first line defence against multiple harmful agents which reach the hepatic sinusoids via the portal circulation. KCs remove chemical compounds and dead or damaged cells, eliminate bacteria and protect against invading tumour cells. They may play a crucial tumouricidal role, exerting cytotoxic and cytostatic functions through the release of multiple cytokines and chemokines. Subsequently, colorectal metastasising cells are destroyed either by KC-performed phagocytosis or via the stimulation of other immune cells which migrate into the sinusoids and act accordingly. On the contrary, KC products, including cytokines, growth factors and matrix-degrading enzymes may promote liver metastasis, supporting tumour cell extravasation, motility and invasion. Current research aims to exploit the antineoplastic properties of KCs in new therapeutic approaches of colorectal cancer liver metastasis. Numerous agents, such as the granulocyte macrophage-colony stimulating factor, interferon gamma, muramyl peptide analogues and various antibody based treatments, have been tested in experimental models with promising results. Future trials may investigate their use in everyday clinical practice and compare their therapeutic value with current treatment of the disease. PMID- 19788687 TI - Susceptibility to experimental biliary atresia linked to different hepatic gene expression profiles in two mouse strains. AB - AIM: To compare hepatic gene expression during the development of experimental biliary atresia (BA) in two different mouse strains. METHODS: Balb/c mice and C57Black/6 (Black/6) mice were infected with rhesus rotavirus (RRV) postpartum, clinical signs of BA and survival were noted. Liver sections were assessed for cluster of differentiation antigen (CD) 3, CD4 and CD8 expression, and the hepatic virus load was determined. Second, mice of both strains were sacrificed three days after infection. Isolated hepatic RNA was subjected to gene expression analysis using Affymetrix Gene Chip MOE 430 2.0. RESULTS: The incidence of BA was significantly lower in Black/6 mice compared to Balb/c mice (13.5% vs. 67%, P < 0.05). The mean virus titers were higher in mice with BA compared to mice without BA. Different gene profiles three days after virus infection were noted, with differential expression of 201 genes, including those regulating apoptosis, nucleic acid binding, transport function and particularly the immune response (chemokine C-C motif ligand 2, toll-like receptor 3, CD antigen 14, chemokine (C X-C motif) ligands 10 and 11). This correlated with a significant increase of CD4 positive cells only in Balb/c mice with BA compared to healthy mice (13.5 vs. 5.0; P < 0.05). Black/6 mice did not exhibit any significant increase of CD3 or CD4 leukocytes despite cholestasis. CONCLUSION: The different susceptibility to experimental BA was associated with an increase of CD4 T-cells in the liver of Balb/c mice, which is linked to different gene profiles at the onset of bile duct obstruction. PMID- 19788688 TI - Interstitial chemotherapy using thermosensitive gel-coated ricin in nude mice bearing a human hepatoma. AB - AIM: To investigate the anti-tumor effects and mechanisms of interstitial chemotherapy using intra-tumor injection of thermosensitive gel-coated ricin in nude mice bearing a human hepatoma. METHODS: In a subcutaneous mouse model of hepatoma, saline, blank gel, ricin, or thermosensitive gel-coated ricin (TGR) was injected directly into tumors. Fourteen days later, eight mice in each group were sacrificed. The tumors were removed and weighed for calculating tumor growth inhibition rate. Serum alpha-fetoprotein levels, as well as hepatic and renal functions, were measured. Tumor tissue was analyzed under an optical microscope. Terminal deoxynucleotidyl transferase mediated dUTP nick end labeling was used to detect the apoptotic index. Moreover, caspase-3 activity and protein expression in tumor tissue were examined. The survival time of the tumor bearing mice was determined. RESULTS: Following interstitial chemotherapy by intra-tumor injection of TGR in nude mice, serum alpha-fetoprotein levels were significantly reduced with no significant impact on hepatic or renal functions. The rate of tumor growth inhibition was 58.5% following a single, local injection. Histological analysis revealed abundant necrosis. The apoptotic index was 45.96 +/- 7.41%. Caspase-3 activity was increased, and caspase-3 protein was significantly activated in tumor cells. Compared to the saline group, the survival time of mice in the TGR group was significantly extended. At the observation terminal time, day 120, two mice were still alive and fully recovered. CONCLUSION: Interstitial chemotherapy by intra-tumor injection of TGR was highly efficient and safe for the treatment of nude mice bearing a human hepatoma. Interstitial chemotherapy exhibits inhibitory effects by inducing apoptosis and directly killing tumor cells. PMID- 19788689 TI - Impact of amino acid substitutions in the core region of HCV on multistep hepatocarcinogenesis. AB - AIM: The core protein of hepatitis C virus (HCV) has multiple functions for not only viral replication but also hepatocellular carcinogenesis. A significant association of the substitutions in the core region with hepatocarcinogenesis has recently been reported. In this report, we evaluated the association of the substitutions in the core region with multistep hepatocarcinogenesis. METHODS: Sixty-nine non-cancerous and cancerous liver tissues were obtained from the patients with primary developed hepatocellular carcinoma (HCC) due to HCV and 17 cirrhotic liver tissues were obtained from the patients without HCC. A sequence analysis of the core protein of HCV was performed and the association between the substitution rates in the core gene and the degree of fibrosis or steatosis during the primary development of HCC and tumor differentiation was analyzed. RESULTS: The substitution rates of amino acid 70, 75, 91 and 147 exceeded 25% (amino acid 70, 51%; 75, 45%; 91, 36%; 147, 30%). All substitution rates were comparable among cancerous and non-cancerous region of patients with HCC and non cancerous region without HCC. The substitution rates of these four amino acids were not associated with the degree of fibrosis, steatosis or tumor differentiation during the primary development of HCC. In addition, the substitution rates were comparable between the patients with or without HCC. The cumulative substitution numbers in the core region were also not associated with the degree of fibrosis and steatosis. CONCLUSIONS: It is possible that the substitutions in the core region are not associated with HCV-related multistep hepatocarcinogenesis. PMID- 19788690 TI - Effects of HCV proteins in current HCV transgenic models. AB - Hepatits C virus (HCV) is an enveloped virus with positive-sense single-stranded RNA genome that causes both acute and persistent infections associated with chronic hepatitis, cirrhosis and hepatocellular carcinoma, which needs fully functional human hepatocytes for its development. Due to the strict human tropism of HCV, only human and higher primates such as chimpanzees have been receptive to HCV infection and development, cognition about pathophysiololgy and host immune responses of HCV infection is limited by lacking of simple laboratory models of infection for a long time. During the past decade, gene transfer approaches have been helpful to the understanding of the molecular basis of human disease. Transgenic cell lines, chimeric and transgenic animal models were developed and had been demonstrated their invaluable benefits. This review focuses on the existing HCV transgenic models and summarize the relative results about probable pathophysical changes induced by HCV proteins. PMID- 19788691 TI - Compartmentalization and its implication for peripheral immunologically-competent cells to the liver in patients with HBV-related acute-on-chronic liver failure. AB - AIMS: This study attempts to characterize the feature of immunologically competent cells (ICCs) and evaluate its clinical implication in patients with acute-on-chronic liver failure (ACLF) in relation to chronic hepatitis B virus (HBV) infection. METHODS: Circulating ICCs were examined in ACLF patients (n = 75), as well as in patients with hepatitis B (CHB, n = 31), CHB-related liver cirrhosis (LC, n = 36), and normal controls (NC, n = 30). Intrahepatic ICCs in some patients were further analyzed via immunohistochemical and flow cytometric assays. RESULTS: Total lymphocytes, CD4(+) T cells, CD8(+) T cells, and NK cells in circulation were numerically lower in the ACLF and LC groups compared to the CHB and NC groups. Importantly, the number of these cells was significantly lower in non-surviving ACLF patients compared with surviving ACLF patients. In comparison to NC, ACLF patients displayed a significantly higher ratio of liver infiltrating CD4(+) T-cell frequency than its circulating counterpart, suggesting that the possiblility of the ICCs compartmentalization from the peripheral blood into the liver in ACLF. Immunohistochemical analysis showed that intrahepatic CD4(+) cells, CD8(+) cells, and CD56(+) cells were significantly higher in the ACLF group compared with the other three groups, suggesting a stronger cellular immune response-mediated inflammation in ACLF group than other patient groups. CONCLUSIONS: The abnormal prevalence of circulating and intrahepatic ICCs possibly acts as an important factor that may drive the progression of HBV related ACLF. PMID- 19788692 TI - Hematoporphyrin derivative-mediated photodynamic therapy inhibits tumor growth in human cholangiocarcinoma in vitro and in vivo. AB - AIM: To investigate the effects of hematoporphyrin derivative-mediated photodynamic therapy (HPD-PDT) on cell growth in human cholangiocarcinoma in vitro and in vivo, as well as the underlying mechanisms of these effects. METHODS: 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to evaluate growth status of human cholangiocarcinoma cell line (QBC939). Hoechst 33258 staining and flow cytometry assays were applied to determine cell apoptosis. Western blotting analysis was performed to detect the release of cytochrome c in QBC939 cells, and caspases enzymatic assay was used to investigate the activation of caspase-3, -8, and -9. Further, tumor growth after subcutaneous implantation of QBC939 cells in nude mice was monitored. RESULTS: HPD-PDT inhibits QBC939 cell growth via cell apoptosis in vitro, and initiates cell mitochondria apoptosis pathway by the release of cytochrome c and the activation of caspase-9 and -3. Moreover, HPD-PDT also inhibits subcutaneous tumor growth of QBC939 cells and reduces tumor cell mitosis in nude mice. CONCLUSION: HPD-PDT inhibits tumor growth of human cholangiocarcinoma, suggesting that HPD-PDT is useful in cholangiocarcinoma therapy. PMID- 19788693 TI - Altered regulation of extrinsic apoptosis pathway in HCV-infected HCC cells enhances susceptibility to mapatumumab-induced apoptosis. AB - BACKGROUND: Hepatitis C virus (HCV)-infected patients, including those co infected with human immunodeficiency virus (HIV), are at increased risk of developing hepatocellular carcinoma (HCC). We evaluated the ability of agonistic human monoclonal antibodies to tumor necrosis factor-related apoptosis inducing ligand (TRAIL) receptors, mapatumumab and lexatumumab, respectively, to induce TRAIL-receptor mediated apoptosis (TRMA) in HCC (HCV-infected and -uninfected) cells and in peripheral blood cells (HIV-infected and -uninfected). METHODS: Susceptibility to antibody-mediated TRMA was measured by caspase 3/7 activity and by confocal microscopy. Surface expression of receptors on HCV-uninfected and infected Huh7.5 cells was measured by flow cytometry and confocal microscopy. Inhibitor of Apoptosis Protein (IAP) RNA levels were quantified by RT-PCR. DNA Microarray was performed using RNA isolated from Huh7.5 cells (HCV-infected and uninfected) using Affymetrix U133A chips. RESULTS: Mapatumumab preferentially induces TRMA of HCV-infected Huh7.5 cells by binding to TRAIL-R1. Higher basal expression of TRAIL-R2 compared to that of TRAIL-R1 on HCV-uninfected Huh7.5 cells were observed. Lexatumumab induces TRMA of both HCV-infected and uninfected cells by binding to TRAIL-R2. IFN-alpha has minimal effect on mapatumumab- and lexatumumab-induced TRMA. HCV infection of Huh7.5 cells up regulates TRAIL-R1 expression and X-linked Inhibitor of apoptosis protein and survivin gene expression. Neither antibody had a pro-apoptotic effect on PBMCs from patients with HIV infection ex vivo. CONCLUSION: Both mapatumumab and lexatumumab are excellent candidates for therapy of HCC. HCV infection of Huh7.5 cells selectively up-regulates TRAIL-R1 receptor, associated with increased susceptibility to mapatumumab-mediated TRMA. HCV infection up-regulated IAP genes, offering promise for future combination therapy using TRAIL agonists and IAP inhibitors. PMID- 19788694 TI - Prolonged treatment with pegylated interferon alpha 2b plus ribavirin improves sustained virological response in chronic hepatitis C genotype 1 patients with late response in a clinical real-life setting in Japan. AB - AIM: This study was conducted to clarify the factors related to sustained virological response (SVR) to pegylated interferon alpha 2b (PEG-IFN) plus ribavirin (RBV) combination therapy administered for 48 weeks in patients with chronic hepatitis C virus (CHCV) and to evaluate the usefulness of prolonged treatment in patients with late virological response (LVR). METHODS: Of 2257 patients registered at 68 institutions, those with genotype 1 and high viral load were selected to participate in two studies. Study 1 (standard 48-week group, n = 1480) investigated SVR-determining factors in patients who received the treatment for 1 year and correlated it with HBV DNA and alanine aminotransferase (ALT) levels to evaluate if these measurements can provide a practical option for monitoring patients in clinical practice and define early switch from lamivudine therapy. METHODS: Of the 929 patients receiving lamivudine for > 1 year, 359 patients who maintained an ALT level of /= 3 years. RESULTS: The incidence of YMDD motif in patients receiving lamivudine for < 3 years was 27% in patients with ALT /=5 microM was required to induce apoptosis in hepatocytes (BRL 3A). CONCLUSION: Further studies using malondialdehyde measurement, Western blot, antioxidant, inhibitors for p53, caspase 8 and 9 - as well as anti-Fas neutralizing antibody - have shown that in HSC-T6, fenretinide-induced apoptosis involves a reactive oxygen species (ROS)-generated, P53-independent, mitochondria associated intrinsic pathway, whereas in hepatocytes (BRL-3A), a ROS-generated, P53-dependent, Fas-related extrinsic pathway is triggered only at high concentration. PMID- 19788700 TI - Molecular analysis of a mutant Anticarsia gemmatalis multiple nucleopolyhedrovirus (AgMNPV) shows an interruption of an inhibitor of apoptosis gene (iap-3) by a new class-II piggyBac-related insect transposon. AB - A new piggyBac-related transposable element (TE) was found in the genome of a mutant Anticarsia gemmatalis multiple nucleopolyhedrovirus interrupting an inhibitor of apoptosis gene. This mutant virus induces apoptosis upon infection of an Anticarsia gemmatalis cell line, but not in a Trichoplusia ni cell line. The sequence of the new TE (which was named IDT for iap disruptor transposon) has 2531 bp with two DNA sequences flanking a putative Transposase (Tpase) ORF of 1719 bp coding for a protein with 572 amino acids. These structural features are similar to the piggyBac TE, also reported for the first time in the genome of a baculovirus. We have also isolated variants of this new TE from different lepidopteran insect cells and compared their Tpase sequences. PMID- 19788701 TI - Sugar sweet springtails: on the transcriptional response of Folsomia candida (Collembola) to desiccation stress. AB - Several species of Collembola survive stressful desiccating conditions by absorbing water vapour from the environment. To obtain insight into the transcriptomic responses underlying this 'water vapour absorption' mechanism we subjected Folsomia candida (Collembola) to transcriptome profiling. We show that ecologically relevant desiccation stress leads to strong time-dependent transcriptomic changes. Exposure of F. candida to 98.2% relative humidity over an interval of 174 h resulted in a high number of gene transcripts being differentially expressed (up to 41%; P-value < 0.05). Additional Gene Ontology analyses suggest that carbohydrate transport, sugar catabolism and cuticle maintenance are biological processes involved in combating desiccation. However, many additional pathways seem to be affected; additional experiments are needed to elucidate which responses are primarily linked to desiccation resistance. PMID- 19788702 TI - Biting through an arteriovenous hemodialysis graft: an unusual method of suicide. AB - Patients on long-term hemodialysis often have multiple medical and social problems with associated psychological stress and depression. The suicide rate in this population is higher than the general population, and suicides have been reported following severing or disconnection of hemodialysis vascular access sites. We report a patient on chronic hemodialysis with a history of depression and suicidal ideation who bit into his forearm arteriovenous graft and exsanguinated. PMID- 19788703 TI - Potentially lethal behaviors associated with rapid eye movement sleep behavior disorder: review of the literature and forensic implications. AB - Rapid eye movement (REM) sleep behavior disorder (RBD) is characterized by loss of the muscle atonia of REM sleep, with release of complex and violent behaviors that are often attempted dream-enactments. This study reviewed the literature on RBD with regard to potentially lethal behavior. A total of 39-41 clinical cases of RBD associated with potentially lethal behaviors to self and/or others were found, involving a child and adults of all age groups, that manifested as choking/headlock (n = 22-24), defenestration/near-defenestration (n = 7), and diving from bed (n = 10). A total of 80.8% (n = 21) were males; 19.2% (n = 5) were females; mean age was 65.6 +/- (SD) 13.8 years (range: 27-81 years, and a child). (Gender/age data were not listed in the remaining cases.) An etiologic association of RBD with a neurologic disorder (or with pharmacotherapy of psychiatric disorders, n = 4) was present in 21-23 patients. Thus, RBD carries well-documented, potential forensic consequences during RBD episodes that could possibly have been misinterpreted as suicidal or homicidal behavior. PMID- 19788704 TI - Alcohol-related mortality risk in natural and non-natural death cases. AB - Determination of the associations between alcohol influence and sudden natural death represents challenges for medicolegal investigations. The aim of this study was to investigate the prevalence of alcohol influence in medicolegal autopsies. In our study of natural and non-natural deaths cases (5496 total: 4045 males, 1451 females) were examined. Blood alcohol concentrations (BACs) were detected by headspace gas chromatographic method. We investigated the alcohol-related mortality using hierarchical log-linear statistical models. Severe BACs were detected among suicidal victims in the oldest age group (>65 years) (InF = 0.442) and among the homicide victims between the age of 40-65 years (InF = 0.234). Correlations we found between manner-of-death and sex suggested that the rate of males in accidents (lnF = 0.140) and the rate of females in homicides (lnF = 0.193) were higher. It was concluded that the accurate statistical mortality database may provide a huge support for the determination of alcohol effects on human health and mortality. PMID- 19788705 TI - Computerized image analysis in differentiation of skin lesions caused by electrocution, flame burns, and abrasion. AB - In the practice of forensic science, sometimes, it is not easy to understand whether skin lesion is due to electrocution and to differentiate the thermal burns and abrasion-type lesions, especially when electricity source cannot be revealed by death science investigation. Based on the causes of the lesions, cases were classified into three groups. Group 1 included 30 deaths from electrocution. Group 2 included 30 deaths with flame burns. Group 3 included 30 deaths from traffic accident cases, which had abrasions. In this study, epidermal nuclear area, perimeter, nuclear form factor, nuclear minimum axes, nuclear maximum axes, and minimum axes/maximum axes ratio were measured. As a result, we think that computerized image analysis beside light microscopic examination can be useful in the differentiation of the electrocution, flame burn, and abrasion type lesions. PMID- 19788706 TI - Reliability of the School Food Checklist for in-school audits and photograph analysis of children's packed lunches. AB - BACKGROUND: Assessment of children's diets is problematic, typically relying on error-prone parent or child recall or reporting, or resource intensive direct observation. The School Food Checklist (SFC) is an objective instrument comprising of 20 food and beverage categories designed to measure the foods contained in children's packed lunches. The present study aimed to assess intra rater and inter-rater reliability of each of the food and beverage categories of the SFC for both in-school audits and photograph analysis of children's school lunches. METHODS: Participants comprised 176 children aged 5-8 years from five primary schools in Northern Metropolitan Melbourne. The SFC was used to measure the foods contained in children's packed lunches in the school setting and using photographs. Photograph analysis was conducted by the auditors 2-3 months after completion of in-school audits. RESULTS: Both intra-rater [intra-class correlation coefficient (ICC) = 0.78-1] and inter-rater (ICC = 0.50-0.95) reliability analysis indicated strong agreement for in-school auditing. With the exception of the food category titled 'leftovers', there was strong intra-rater reliability for auditors' live audits and their analysis of photographs [ICC = 0.57-0.98 (Auditor 1); ICC = 0.72-0.90 (Auditor 2)], and strong inter-rater reliability for photograph analysis (ICC = 0.68-0.92). CONCLUSIONS: The SFC is a reliable method of measuring the foods and beverages contained in children's packed lunches when used in the school setting or for photograph analysis. This finding has broad implications, particularly for the use of photograph analysis, because this approach offers a convenient and cost effective method of measuring what food and beverages children bring to school in home packed lunches. PMID- 19788707 TI - Nutritional status of Irish older people in receipt of meals-on-wheels and the nutritional content of meals provided. AB - BACKGROUND: Research has suggested that meals-on-wheels recipients can be at risk for poor nutritional status. Despite this, few countries have statutory minimum requirements for the nutrient content of meals-on-wheels. This study examined both the nutritional status of a sample of Irish recipients and the nutrient content of a sample of meals provided to determine whether Irish recipients would benefit from statutory minimum nutritional standards. METHODS: The study had two phases. First, a nutritional assessment was carried out to analyse the nutritional status of a sample of Irish meals-on-wheels recipients (Mini Nutritional Assessment and 24-h dietary recall with 63 self-selected respondents). Second, an assessment of the nutrient content of a sample of 46 meals from eight meals-on-wheels services was undertaken to characterise the nutritional content of the meals. RESULTS: Over one-third of recipients (38.5%) were malnourished or at-risk of malnutrition and over half (52.3%) were overweight or obese. The mean (SD) energy [kJ (kcal)] content of the meals assessed was 3008 (498) kJ [719 (119.1) kcal], contributing 35-40% of the recommended dietary allowance (RDA) for males aged 65 years and over and 42-45% of the RDA for females aged 65 years and over. In the meals assessed, the levels of vitamin C (25.3%), vitamin D (11.6%), folate (24.8%) and calcium (20.9%) were below one-third of the Irish RDA for these nutrients. CONCLUSIONS: Irish recipients may not be receiving adequate micronutrients from meals-on-wheels. Legislation that sets out minimum standards for the nutrient content of meals-on wheels and greater variation in the portion sizes offered may benefit recipients. PMID- 19788708 TI - Adoption and maintenance of a Mediterranean diet in patients with coronary heart disease from a Northern European population: a pilot randomised trial of different methods of delivering Mediterranean diet advice. AB - BACKGROUND: A Mediterranean diet has been shown to protect against coronary heart disease (CHD). Adherence to a Mediterranean diet can be assessed using a Mediterranean diet score. The primary aim of this pilot study was to examine whether CHD patients in a Northern European population would adopt and maintain a Mediterranean diet, with a secondary aim of comparing the effectiveness of different methodologies aimed at improving compliance. METHODS: Sixty-one patients with a diagnosis of CHD were randomised to one of three groups: either to receive conventional dietetic advice for CHD or advice to implement a Mediterranean-style diet using either behavioural counselling or nutritional counselling. Patients received a follow-up assessment at 6 months (adoption) and a subset of patients was followed up at 12 months (maintenance). The primary outcome measure was the between-group difference in the mean change in Mediterranean diet score (MDS). RESULTS: The change in MDS was not significantly different between groups. However, all three groups reported a significant within group increase in MDS (P < 0.01) at 6 and 12 months follow-up. CONCLUSIONS: All three groups made dietary changes towards a Mediterranean diet, but behavioural counselling did not have significant additional benefit over nutritional counselling in initiating and maintaining dietary change, and neither method offering specific Mediterranean diet advice had any significant benefit in terms of improvement in MDS over conventional dietetic practice. PMID- 19788709 TI - The prevalence of dietary-related complementary and alternative therapies and their perceived usefulness among cancer patients. AB - BACKGROUND: The present study aimed to directly assess and compare the usage, benefits and side-effects of dietary-related complementary and alternative medicine (CAM) use among adult cancer patients and non-cancer adults in Norwich, UK. METHODS: Self-administered questionnaires were completed by 98 cancer patients and 92 non-cancer adults to compare demographics, types of CAM usage with reasons, benefits, side-effects and CAM information sources. The groups were matched for gender, age, marital status, education and household income. The mean ages were 62.7 and 59.7 years, respectively, with slightly more female than male participants. RESULTS: CAM use was high in both groups (47% in cancer and 53% in non-cancer respondents, P > 0.05). The most widely-used diet-related CAM among both groups was the large intake of fruit, vegetables and juice, multivitamins, fish oils and glucosamine. Fish oil intake was significantly higher in the non cancer group (P < 0.05), whereas selenium and beta-carotene supplements were significantly higher in the cancer group (P < 0.01 and P = 0.02, respectively). The main reasons for using CAM were to boost the immune system and to improve quality of life (P > 0.05). Reported benefits included increased optimism and hope for the cancer group and increased optimism and pain relief for the non cancer group. CONCLUSIONS: Diet-related CAM is used frequently by both cancer patients and non-cancer adults, with many reported benefits and few reported side effects. Significant differences between the groups included a higher prevalence of fish oil used by the non-cancer group, and a higher use of selenium and beta carotene supplements in the cancer group. PMID- 19788710 TI - Communication skills for behaviour change in dietetic consultations. AB - BACKGROUND: Both the UK's National Health Service (NHS) and the National Institute of health and Clinical Excellence (NICE) have recommended increased training for health professionals in communication skills. There is evidence to suggest that communication skills are important in helping people to change health-related behaviour, which is a key role for dietitians. This study investigated the views of UK dietitians about their training needs and experience in relation to communication skills in dietetic practice. METHODS: In October 2007, a cross-sectional survey was mailed to all British Dietetic Association members (n = 6013). The survey gathered quantitative data and free-text comments to ascertain the level, type and effect of communication skills training received by dietitians at both the pre- and post-registration level. RESULTS: There were 1158 respondents; a response rate of 19.3%. Ninety-eight percent (n = 1117) rated communication skills as either very or extremely important in client consultations. Post-registration training had been undertaken by 73% (n = 904). Of these, over 90% of respondents perceived that post-registration training had led to improvements in their relationships with patients, their confidence in client interviews and their ability to cope with challenging clients. However, 248 (21.4%) felt time keeping in interviews had worsened. Lack of time for client interviews was also the most commonly identified barrier (19%, n = 216) to implementing the skills. CONCLUSIONS: This study has explored an important and under-researched area. Respondents strongly endorsed the importance of good communication skills and the benefits of post-registration training in this area. Some felt that good communication was time consuming but others felt that time management had improved. Further research and training is required to support the implementation of these skills into dietetic practice. PMID- 19788711 TI - Lactobacillus reuteri ingestion and IK(Ca) channel blockade have similar effects on rat colon motility and myenteric neurones. AB - BACKGROUND: We have previously shown that ingestion of Lactobacillus reuteri may modulate colonic enteric neuron activity but with unknown effects on colon motility. The aim of the present report was to elucidate the neuronal mechanisms of action of the probiotic by comparing the effects on motility of L. reuteri ingestion with blockade of a specific ionic current in enteric neurons. METHODS: We have used intraluminal pressure recordings from ex vivo rat colon segments and whole cell patch clamp recordings from neurons of rat longitudinal muscle myenteric plexus preparations to investigate the effects of L. reuteri and TRAM 34 on colon motility and neurophysiology. The effects of daily feeding of 10(9) L. reuteri bacteria or acute application of TRAM-34 on threshold fluid filling pressure or pulse pressure was measured. KEY RESULTS: Lactobacillus reuteri increased intraluminal fluid filling pressure thresholds for evoking pressure pulses by 51% from 0.47 +/- 0.17 hPa; the probiotic also decreased the pulse pressure amplitudes, but not frequency, by 18% from 3.91 +/- 0.52 hPa. The intermediate conductance calcium-dependent potassium (IK(Ca)) channel blocker TRAM-34 (3 micromol L(-1)) increased filling threshold pressure by 43% from 0.52 +/- 0.22 hPa and reduced pulse pressure amplitude by 40% from 2.63 +/- 1.11 hPa; contraction frequency was unaltered. TRAM-34 (3 micromol L(-1)) reduced membrane polarization, leak conductance and the slow afterhyperpolarization current in 16/16 myenteric rat colon AH cells but 19/19 S cells were unaffected. CONCLUSIONS & INFERENCES: The present results are consistent with L. reuteri enhancing tonic inhibition of colon contractile activity by acting via the IK(Ca) channel current in AH cells. PMID- 19788712 TI - What is the evidence for chronic pain being etiologically associated with the DSM IV category of sleep disorder due to a general medical condition? A structured evidence-based review. AB - DESIGN: This is a structured evidence-based review of all available studies on the relationship between chronic pain and sleep problems as defined by the Diagnostic and Statistical Manual of Mental Disorders Fourth Edition (DSM-IV) category of sleep disorder due to a general medical condition. OBJECTIVES: To determine whether chronic pain is etiologically associated with this sleep category. METHODS: Computer and manual literature searches yielded 146 references that addressed this area of study. One hundred and five studies were excluded from detailed review based on exclusion criteria detailed by this category of sleep disorders. Forty-one studies were reviewed in detail and sorted according to six natural groupings: multivariate analysis, prospective studies, path analysis, correlation between pain and sleep problems, univariate analysis using comparison groups, and do nonsedating drugs with analgesic properties improve sleep? Study characteristics were abstracted into tabular form and each report was characterized by the type of study it represented according to the Agency for Health Care Policy and Research (AHCPR) guidelines. Each study was independently evaluated by two raters according to 12 quality criteria and an independent quality score was calculated. Studies were not utilized in the calculations unless their quality score (utilizing both raters) was greater than 60%. For each of the above groupings, an average quality score was calculated and a calculation performed as to the percentage of studies that supported the hypothesis that pain is etiologically related to the above DSM-IV category of sleep disorders. Finally, the strength and consistency of the evidence for this hypothesis was rated according to the AHCPR guidelines. RESULTS: Of the 41 reports, all had quality scores greater than 60%. In all the above groupings except for multivariate analysis, 100% of the studies supported this hypothesis. In the multivariate analysis grouping, 77.2% of the studies supported this hypothesis. The strength and consistency of this evidence was rated at A (highest possible) for all study groupings except multivariate (B rating) and path analysis where there were too few studies to generate a conclusion. For all the studies combined, 89.7% of the studies supported this hypothesis. This evidence was rated as A: consistent, multiple studies. CONCLUSIONS: The results of this evidence based structured review indicate that for the pain-sleep studies defined by the DSM-IV category of sleep disorder due to a general medical condition,chronic pain may be etiologically related to that sleep problem. However, these results do not preclude this relationship from being bidirectional. PMID- 19788713 TI - Contralateral stimulation, using TENS, of phantom limb pain: two confirmatory cases. AB - OBJECTIVES: This study aims to evaluate the effectiveness of trans-electric nerve stimulation (TENS) for phantom limb pain applied to contralateral limb (nonamputated limb). DESIGN: Two detailed single case studies using TENS on the contralateral limb are reported in a longitudinal study with one-year follow-up. Five variables were measured across this period. The study comprised of five sequential stages (Pre-assessment, Preliminary baseline, Start of intervention, Extended assessment, One-year follow-up). SETTING AND PATIENTS: Patients were identified at the Rookwood Hospital in Cardiff. They subsequently received regular home visits. The first patient was a 24-year-old male who had suffered a left below-elbow amputation following a car crash. The second patient was a 38 year-old male who had a transfemoral right amputation further to a viral infection. MEASURES: The following semistructured interview and questionnaires were used: McGill Comprehensive pain questionnaire part A and B; The Cambridge Phantom Limb Profile; The Groningen Questionnaire: Problems after Arm Amputation; and 13 Visual Analog Scales. CONCLUSIONS: Both patients showed a significant improvement in their perception of phantom limb pain and sensations that was maintained at one-year follow-up. A randomized blinded controlled trial to confirm these positive outcomes is required. PMID- 19788714 TI - Intravenous immunoglobulin for the treatment of diabetic lumbosacral radiculoplexus neuropathy. AB - OBJECTIVE: The objective of this study was to evaluate the effect of intravenous immunoglobulin (IVIg) therapy in diabetic lumbosacral radiculoplexus neuropathy (DLRPN) patients who did not respond to analgesic drug therapy and corticosteroids. Background. DLRPN is a rare painful condition that may occur in diabetes mellitus (DM). At the moment, there are limited therapeutic options for DLRPN. METHODS: We recruited five patients affected by type 2 DM and DLRPN. They were selected from a cohort of 13 consecutive DLRPN patients. Inclusion criteria were severe pain (visual analog scale [VAS] > 4/10) and no response to pain symptomatic therapy and corticosteroids. Patients were treated with IVIg (0.4 g/kg/day for 5 days). Outcome measures were VAS, time of onset and duration of pain relief, the Medical Research Council (MRC) scale for lower limb muscle strength, and walking distance. Electrophysiology and needle electromyography (EMG) were retested after IVIg. RESULTS: Four of the patients had positive pain response after IVIg. VAS reduction started 5-10 days after IVIg infusion. Two patients underwent additional IVIg infusions due to pain reappearance after 7-18 months, again with positive response. VAS, MRC scale, and walking distance significantly improved at 1 month (Wilcoxon nonparametric test, two-tailed, P < 0.05). Electrodiagnostic testing was unchanged, but needle EMG showed reduction of denervation signs after IVIg. CONCLUSIONS: IVIg may rapidly reduce pain and improve motor function in DLRPN despite previous negative response to corticosteroids. IVIg may be repeated in those patients who experience disease relapse. Future double-blind trials are needed to evaluate the role of IVIg in DLRPN. PMID- 19788715 TI - Robot-assisted vessel harvesting for penile revascularization. AB - INTRODUCTION: Ideal candidates for penile revascularization include young patients with documented vasculogenic erectile dysfunction usually resulting from pelvic trauma. Historically, large midline incisions were necessary to harvest the epigastric vessels for penile revascularization. We report our experience with robot-assisted epigastric vessel harvesting for use in penile revascularization procedures. AIM: To describe our technique and experience with robot-assisted vessel harvesting for use in penile revascularization. METHODS: Five patients were selected for penile revascularization. Each patient suffered pelvic crush injuries resulting in post-traumatic erectile dysfunction. Each patient had no significant prior medical history and had normal erectile function prior to injury. Penile duplex Doppler ultrasound studies using vasoactive agents demonstrated decreased arterial inflow. Complementary pelvic angiography documented the corresponding arterial lesions. Each patient underwent attempted penile revascularization using a modified Virag-V technique. The epigastric artery was harvested robotically and transposed through a 3 cm incision at the base of the penis. Microscopic revascularization was performed by anastamosing the epigastric artery to the deep dorsal vein. Distal dorsal vein ligation of the subcoronal plexus was performed to limit glans hyperemia. MAIN OUTCOME MEASURES: Description of a new method of vessel harvesting for penile revascularization. RESULTS: Penile revascularization was successful in four out of five patients. One patient had complete thrombosis of the deep dorsal penile vein and underwent subsequent penile prosthesis implantation. Each patient undergoing successful revascularization was discharged home two days postoperatively and has reported resumption of sexual activity. CONCLUSIONS: The robot-assisted approach to epigastric vessel harvesting is an ideal minimally-invasive complement to penile revascularization. This procedure negates the need for a large midline incision and may shorten recovery time. Our described technique offers a novel option for the application of minimally-invasive technology, but longer-term follow-up is needed to further evaluate the success of penile revascularization. PMID- 19788717 TI - Multi-modal Aedes aegypti mosquito reduction interventions and dengue fever prevention. AB - OBJECTIVE: To systematically review the effectiveness of biological, chemical and educational dengue fever prevention programs on the reduction of entomologic indicators. METHODS: Searches of PubMed, GoogleScholar, CabDirect databases and reference lists yielded over 1000 articles containing mosquito abatement interventions. Inclusion criteria were: Vector control programs targeting Aedes aegypti and Aedes albopictus mosquitoes; Studies providing pre- and post-test data. Intervention effectiveness was assessed using Mulla's formula to determine percent reductions for all studies with control groups. Twenty-one studies were reviewed. RESULTS: Twelve dependent variables were presented, however, the Breteau, House and Container indices were the primary measurement tools for monitoring larval populations. Behavioural methods consisting of educational campaigns and maintaining water containers to reduce the mosquito population were applied in eight studies. Eight studies involved the use of biological methods such as predatory organisms or bacteria. Finally, eight studies used chemical control techniques including insecticide sprays, larvicides, insecticide-treated materials, and cleaning water of containers with household chemicals with three studies using a combination of intervention techniques. Post-intervention reduction in entomologic indices ranged from 100% to an increase of 13.9% from baseline. CONCLUSION: Little evidence exists to support the efficacy of mosquito abatement programs owing to poor study designs and lack of congruent entomologic indices. Creation of a standard entomological index, use of clustered and randomized-controlled trials, and testing the generalizability of proven methods are recommended for future research. PMID- 19788716 TI - Urotensin II: a novel target in human corpus cavernosum. AB - INTRODUCTION: Urotensin II (U-II) is a cyclic peptide originally isolated from the teleost neurosecretory system and subsequently identified in other species, including man. U-II was identified as the natural ligand of an orphan G-protein coupled receptor (UT receptor). U-II and UT receptor are expressed in a variety of peripheral organs and especially in cardiovascular tissue. U-II caused both constrictor and vasodilator effect, depending by vascular bed. The in vivo functional consequences of U-II on the cardiovascular hemodynamics are not clearly understood. AIM: To investigate the presence of UT receptor and the effect of U-II in human corpus cavernosum (HCC) strips. To evaluate the effect of U-II in vivo in anesthetized rats. METHODS: UT receptor expression as protein and as mRNA were assessed by Western blot and reverse transcriptase polymerase chain reaction. Next, the UT receptor localization was evaluated by immunohistochemical analysis. By using HCC strips, with or without endothelium, the effect of U-II (0.1 nM-10 microM) was evaluated. In order to asses the nitric oxide (NO) involvement, the strips were incubated with N (G)-nitro-L-arginine methyl ester (NO synthase inhibitor, 100 microM). U-II (0.1, 0.3, 1.0 nmol/rat) effect in vivo was studied in anesthetized rats by monitoring the intracavernous and systemic blood pressure. MAIN OUTCOME MEASURES: HCC expresses the UT receptor and its activation, by UII, causes an endothelium- and NO-dependent relaxation. RESULTS: UT receptor is expressed in human and rat corpus cavernosum. In HCC UT receptor is localized on endothelial cells. U-II significantly relaxed HCC strips in endothelium- and -NO-dependent fashion. The peptide caused a significant increase in intracavernous pressure in anesthetized rats. CONCLUSION: This study demonstrates that UT receptor is expressed on the endothelium of HCC. U-II/UT receptor system is involved in HCC function and it involves endothelium and NO pathway. Thus, U-II/UT receptor pathway could be involved in erectile function. PMID- 19788718 TI - Malaria preventive measures, health care seeking behaviour and malaria burden in different epidemiological settings in Sudan. AB - OBJECTIVES: To provide information about preventive measures and treatment seeking behaviour as well as an estimate of the malaria burden in different epidemiological settings for effective monitoring and evaluation of the ongoing efforts. METHODS: Cross-sectional survey carried out in four areas representing different levels of transmission to explore the use of preventive measures, care seeking behaviour and accessibility in addition to point prevalence was followed by a follow-up phase in which the health workers registered and reported all fever cases including malaria. The relation between the reported malaria incidence, the product of symptomatic/asymptomatic ratio and the prevalence of confirmed malaria cases was used to develop the equation that could predict the true malaria incidence. RESULTS: Thousand households and 3628 individuals were surveyed. The presence of any net varied between 6.6% and 40%; the percentage of people who reportedly slept under mosquito nets in the previous night varied between 35 and 80. Prompt use of medications ranged between 14 and 48% with a delay of more than 24 h noticed in different areas. The mean number of individuals per household who reported use of anti-malarial drugs in the last 2 weeks ranged between 0.6 (SD = 0.92) and 1.2 (SD = 1.1), with variable cost per treatment and affordability. The prevalence of asymptomatic parasitaemia, fever and confirmed malaria at time of the survey differed by area. The incidence of malaria during the follow-up period was estimated to be 8.5, 178.6, 23.7 and 10.3 episodes per 1000 population in Malakal, Elrank, Elhosh and El Matama, respectively. Based on this, a prediction equation was developed. CONCLUSION: We found suboptimal health care seeking behaviour, coverage and use of preventive measures with a high malaria burden. We developed a model for future estimation of malaria episodes. PMID- 19788719 TI - Certification of disease eradication: lessons from dracunculiasis. PMID- 19788721 TI - General practitioners' role in cancer care: a French-Norwegian study. AB - BACKGROUND: In cancer care, a GP's work is rarely defined clearly. Our aim was to assess GPs' work with cancer patients in France and in Norway, where the roles of the GP and the organization of the system are rather different. FINDINGS: A questionnaire with 40 closed-ended questions about GP involvement in diagnosis, treatment, follow-up and terminal care was constructed and mailed to samples of GPs. The patients had seen the doctor at least once over the past year. In France 1679 and in Norway 386 individual patient questionnaires were completed. GPs have a major role in the diagnosis of cancer, and this role varies according to cancer type. The GPs participated actively in different phases of follow-up after cancer treatment. Low response rates do not allow direct comparison between countries, but higher PSA screening rates in France seem to increase the percentage of patients diagnosed after screening rather than after a clinical suspicion. Interaction between GPs and specialists during cancer treatment and follow-up was important in both countries. CONCLUSION: Both in France and in Norway GPs participate actively in cancer care. Early clinical diagnosis is a challenge. More research is needed about how GPs can improve their early diagnostic work. Organisational issues may influence cancer responsibilities for the GP, and national health systems should be challenged to look at possible new roles for GPs in cancer care. Medical training, both pre- and post-graduate, should prepare doctors for collaboration between primary and secondary care, particularly important in cancer care. PMID- 19788720 TI - Structural and functional characteristics of xenavidin, the first frog avidin from Xenopus tropicalis. AB - BACKGROUND: Avidins are proteins with extraordinarily high ligand-binding affinity, a property which is used in a wide array of life science applications. Even though useful for biotechnology and nanotechnology, the biological function of avidins is not fully understood. Here we structurally and functionally characterise a novel avidin named xenavidin, which is to our knowledge the first reported avidin from a frog. RESULTS: Xenavidin was identified from an EST sequence database for Xenopus tropicalis and produced in insect cells using a baculovirus expression system. The recombinant xenavidin was found to be homotetrameric based on gel filtration analysis. Biacore sensor analysis, fluorescently labelled biotin and radioactive biotin were used to evaluate the biotin-binding properties of xenavidin - it binds biotin with high affinity though less tightly than do chicken avidin and bacterial streptavidin. X-ray crystallography revealed structural conservation around the ligand-binding site, while some of the loop regions have a unique design. The location of structural water molecules at the entrance and/or within the ligand-binding site may have a role in determining the characteristic biotin-binding properties of xenavidin. CONCLUSION: The novel data reported here provide information about the biochemically and structurally important determinants of biotin binding. This information may facilitate the discovery of novel tools for biotechnology. PMID- 19788722 TI - Noninvasive detection of lung cancer by analysis of exhaled breath. AB - BACKGROUND: Lung cancer is one of the leading causes of death in Europe and the western world. At present, diagnosis of lung cancer very often happens late in the course of the disease since inexpensive, non-invasive and sufficiently sensitive and specific screening methods are not available. Even though the CT diagnostic methods are good, it must be assured that "screening benefit outweighs risk, across all individuals screened, not only those with lung cancer". An early non-invasive diagnosis of lung cancer would improve prognosis and enlarge treatment options. Analysis of exhaled breath would be an ideal diagnostic method, since it is non-invasive and totally painless. METHODS: Exhaled breath and inhaled room air samples were analyzed using proton transfer reaction mass spectrometry (PTR-MS) and solid phase microextraction with subsequent gas chromatography mass spectrometry (SPME-GCMS). For the PTR-MS measurements, 220 lung cancer patients and 441 healthy volunteers were recruited. For the GCMS measurements, we collected samples from 65 lung cancer patients and 31 healthy volunteers. Lung cancer patients were in different disease stages and under treatment with different regimes. Mixed expiratory and indoor air samples were collected in Tedlar bags, and either analyzed directly by PTR-MS or transferred to glass vials and analyzed by gas chromatography mass spectrometry (GCMS). Only those measurements of compounds were considered, which showed at least a 15% higher concentration in exhaled breath than in indoor air. Compounds related to smoking behavior such as acetonitrile and benzene were not used to differentiate between lung cancer patients and healthy volunteers. RESULTS: Isoprene, acetone and methanol are compounds appearing in everybody's exhaled breath. These three main compounds of exhaled breath show slightly lower concentrations in lung cancer patients as compared to healthy volunteers (p < 0.01 for isoprene and acetone, p = 0.011 for methanol; PTR-MS measurements). A comparison of the GCMS results of 65 lung cancer patients with those of 31 healthy volunteers revealed differences in concentration for more than 50 compounds. Sensitivity for detection of lung cancer patients based on presence of (one of) 4 different compounds not arising in exhaled breath of healthy volunteers was 52% with a specificity of 100%. Using 15 (or 21) different compounds for distinction, sensitivity was 71% (80%) with a specificity of 100%. Potential marker compounds are alcohols, aldehydes, ketones and hydrocarbons. CONCLUSION: GCMS-SPME is a relatively insensitive method. Hence compounds not appearing in exhaled breath of healthy volunteers may be below the limit of detection (LOD). PTR-MS, on the other hand, does not need preconcentration and gives much more reliable quantitative results then GCMS-SPME. The shortcoming of PTR-MS is that it cannot identify compounds with certainty. Hence SPME-GCMS and PTR-MS complement each other, each method having its particular advantages and disadvantages. Exhaled breath analysis is promising to become a future non-invasive lung cancer screening method. In order to proceed towards this goal, precise identification of compounds observed in exhaled breath of lung cancer patients is necessary. Comparison with compounds released from lung cancer cell cultures, and additional information on exhaled breath composition in other cancer forms will be important. PMID- 19788723 TI - A transcription-dependent increase in miniature EPSC frequency accompanies late phase plasticity in cultured hippocampal neurons. AB - BACKGROUND: The magnitude and longevity of synaptic activity-induced changes in synaptic efficacy is quantified by measuring evoked responses whose potentiation requires gene transcription to persist for more than 2-3 hours. While miniature EPSCs (mEPSCs) are also increased in amplitude and/or frequency during long-term potentiation (LTP), it is not known how long such changes persist or whether gene transcription is required. RESULTS: We use whole-cell patch clamp recordings from dissociated hippocampal cultures to characterise for the first time the persistence and transcription dependency of mEPSC upregulation during synaptic potentiation. The persistence of recurrent action potential bursting in these cultures is transcription-, translation- and NMDA receptor-dependent thus providing an accessible model for long-lasting plasticity. Blockade of GABAA receptors with bicuculline for 15 minutes induced action potential bursting in all neurons and was maintained in 50-60% of neurons for more than 6 hours. Throughout this period, the frequency but neither the amplitude of mEPSCs nor whole-cell AMPA currents was markedly increased. The transcription blocker actinomycin D abrogated, within 2 hours of burst induction, both action potential bursting and the increase in mEPSCs. Reversible blockade of action potentials during, but not after this 2 hour transcription period suppressed the increase in mEPSC frequency and the recovery of burst activity at a time point 6 hours after induction. CONCLUSION: These results indicate that increased mEPSC frequency persists well beyond the 2 hour transcription-independent phase of plasticity in this model. This long-lasting mEPSC upregulation is transcription-dependent and requires ongoing action potential activity during the initial 2 hour period but not thereafter. Thus mEPSC upregulation may underlie the long term, transcription dependent persistence of action potential bursting. This provides mechanistic insight to link gene candidates already identified by gene chip analysis to long lasting plasticity in this in vitro model. PMID- 19788724 TI - Dual control by a single gene of secondary sexual characters and mating preferences in medaka. AB - BACKGROUND: Animals utilize a wide variety of tactics to attract reproductive partners. Behavioral experiments often indicate an important role for visual cues in fish, but their molecular basis remains almost entirely unknown. Studies on model species (such as zebrafish and medaka) allow investigations into this fundamental question in behavioral and evolutionary biology. RESULTS: Through mate-choice experiences using several laboratory strains of various body colors, we successfully identified one medaka mutant (color interfere; ci) that is distinctly unattractive to reproductive partners. This unattractiveness seems to be due to reduced orange pigment cells (xanthophores) in the skin. The ci strain carries a mutation on the somatolactin alpha (SLa) gene, therefore we expected over-expression of SLa to make medaka hyper-attractive. Indeed, extremely strong mating preferences were detected in a choice between the ci and SLa-transgenic (Actb-SLa:GFP) medaka. Intriguingly, however, the strains showed opposite biases; that is, the mutant and transgenic medaka liked to mate with partners from their own strain, similar to becoming sexually isolated. CONCLUSION: This study spotlighted SLa as a novel mate-choice gene in fish. In addition, these results are the first demonstration of a single gene that can pleiotropically and harmoniously change both secondary sexual characters and mating preferences. Although theoretical models have long suggested joint evolution of linked genes on a chromosome, a mutation on a gene-regulatory region (that is, switching on/off of a single gene) might be sufficient to trigger two 'runaway' processes in different directions to promote (sympatric) speciation. PMID- 19788726 TI - Physician support for diabetes patients and clinical outcomes. AB - BACKGROUND: Physician practical support (e.g. setting goals, pro-active follow up) and communicative support (e.g., empathic listening, eliciting preferences) have been hypothesized to influence diabetes outcomes. METHODS: In a prospective observational study, patients rated physician communicative and practical support using a modified Health Care Climate Questionnaire. We assessed whether physicians' characteristic level of practical and communicative support (mean across patients) and each patients' deviation from their physician's mean level of support was associated with glycemic control outcomes. Glycosylated haemoglobin (HbA1c) levels were measured at baseline and at follow-up, about 2 years after baseline. RESULTS: We analysed 3897 patients with diabetes treated in nine primary care clinics by 106 physicians in an integrated health plan in Western Washington, USA. Physicians' average level of practical support (based on patient ratings of their provider) was associated with significantly lower HbA1c at follow-up, controlling for baseline HbA1c (p = .0401). The percentage of patients with "optimal" and "poor" glycemic control differed significantly across different levels of practical support at follow (p = .022 and p = .028). Communicative support was not associated with differences in HbA1c at follow-up. CONCLUSION: This observational study suggests that, in community practice settings, physician differences in practical support may influence glycemic control outcomes among patients with diabetes. PMID- 19788725 TI - Repetition and severity of suicide attempts across the life cycle: a comparison by age group between suicide victims and controls with severe depression. AB - BACKGROUND: Suicide attempts have been shown to be less common in older age groups, with repeated attempts generally being more common in younger age groups and severe attempts in older age groups. Consistently, most studies have shown an increased suicide risk after attempts in older age. However, little is known about the predictive value of age on repeated and severe suicide attempts for accomplished suicide. The aim of the present study was to investigate the reduced incidence for initial, repeated, or severe suicide attempts with age in suicide victims and controls by gender. METHODS: The records of 100 suicide victims and matched controls with severe depression admitted to the Department of Psychiatry, Lund University Hospital, Sweden between 1956 and 1969, were evaluated and the subjects were monitored up to 2006. The occurrence of suicide attempts (first, repeated, or severe, by age group) was analysed for suicide victims and controls, with gender taken into consideration. RESULTS: There was a reduced risk for an initial suicide attempt by older age in females (suicide victims and controls) and male controls (but not suicide victims). The risk for repeated suicide attempts appeared to be reduced in the older age groups in female controls as compared to female suicide victims. The risk for severe suicide attempts seemed reduced in the older age groups in female suicide victims. This risk was also reduced in male controls and in male controls compared to male suicide victims. CONCLUSION: In the older age groups repeated attempts appeared to be predictive for suicide in women and severe attempts predictive in men. PMID- 19788727 TI - Diagonal ear lobe crease in diabetic south Indian population: is it associated with Diabetic Retinopathy?. Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular-genetics Study (SN-DREAMS, Report no. 3). AB - BACKGROUND: To report the prevalence of ear lobe crease (ELC), a sign of coronary heart disease, in subjects (more than 40 years old) with diabetes and find its association with diabetic retinopathy. METHODS: Subjects were recruited from the Sankara Nethralaya Diabetic Retinopathy Epidemiology And Molecular-genetics Study (SN-DREAMS), a cross-sectional study between 2003 and 2006; the data were analyzed for the 1414 eligible subjects with diabetes. All patients' fundi were photographed using 45 degrees four-field stereoscopic digital photography. The diagnosis of diabetic retinopathy was based on the modified Klein classification. The presence of ELC was evaluated on physical examination. RESULTS: The prevalence of ELC, among the subjects with diabetes, was 59.7%. The ELC group were older, had longer duration of diabetes, had poor glycemic control and had a high socio-economic status compared to the group without ELC and the variables were statistically significant. There was no statistical difference in the prevalence of diabetic retinopathy in two groups. On multivariate analysis for any diabetic retinopathy, the adjusted OR for women was 0.69 (95% CI 0.51-0.93) (p = 0.014); for age >70 years, 0.49 (95% CI 0.26-0.89) (p = 0.024); for increasing duration of diabetes (per year increase), 1.11(95% CI 1.09-1.14) (p < 0.0001); and for poor glycemic control (per unit increase in glycosylated haemoglobin), 1.26 (95% CI 1.19-1.35) (p < 0.0001). For sight-threatening diabetic retinopathy, no variable was significant on multivariable analysis. In predicting any diabetic retinopathy, the presence of ELC had sensitivity of 60.4%, and specificity, 40.5%. The area under the ROC curve was 0.50 (95% CI 0.46 0.54) (p 0.02). CONCLUSION: The ELC was observed in nearly 60% of the urban south Indian population. However, the present study does not support the use of ELC as a screening tool for both any diabetic retinopathy and sight-threatening retinopathy. PMID- 19788728 TI - A geminiviral amplicon (VA) derived from Tomato leaf curl virus (ToLCV) can replicate in a wide variety of plant species and also acts as a VIGS vector. AB - BACKGROUND: The Tomato leaf curl virus (ToLCV) belongs to the genus begomoviridae of the family Geminiviridae. The 2.7 kb DNA genome of the virus encodes all the information required for viral DNA replication, transcription and transmission across the plant cells. However, all of the genome sequences are not required for viral DNA replication. We attempted to reveal the minimal essential region required for DNA replication and stable maintenance. The phenomenon of Virus Induced Gene Silencing (VIGS) has recently been observed with several geminiviruses. We investigated whether the minimal replicating region was also capable of producing siRNAs in planta and a VIGS vector could be constructed using the same minimal sequences. RESULTS: We have constructed vectors containing various truncated portions of the Tomato leaf curl virus (ToLCV) genome and established that a segment spanning from common region (CR) to AC3 (ORF coding for a replication enhancer) was the minimal portion which could efficiently replicate in a variety of both monocot and dicot plants. A viral amplicon (VA) vector was constructed using this region that produced siRNAs from various sites of the vector, in a temporal manner in plants, and hence can be used as a VIGS vector. The tomato endogene PCNA was silenced using this vector. Introduction of a mutation in the ORF AC2 (a silencing suppressor) increased the silencing efficiency of the newly constructed vector several folds. CONCLUSION: Our study reveals that the vector is capable of replicating in diverse plant species and is highly efficient in silencing endogenes like PCNA of the host plant, thus acting as a VIGS vector. We observed that the geminiviral ORF AC2 functioned as a silencing suppressor and a null mutation in this ORF increased the efficiency of silencing several fold. This is the first report of construction of improved VIGS vector by mutation of the resident silencing suppressor gene. The present study opens up the possibility of using such VIGS vectors in silencing the host genes in a broad range of plant hosts. PMID- 19788729 TI - Metabolic fluxes in the central carbon metabolism of Dinoroseobacter shibae and Phaeobacter gallaeciensis, two members of the marine Roseobacter clade. AB - BACKGROUND: In the present work the central carbon metabolism of Dinoroseobacter shibae and Phaeobacter gallaeciensis was studied at the level of metabolic fluxes. These two strains belong to the marine Roseobacter clade, a dominant bacterial group in various marine habitats, and represent surface-associated, biofilm-forming growth (P. gallaeciensis) and symbiotic growth with eukaryotic algae (D. shibae). Based on information from recently sequenced genomes, a rich repertoire of pathways has been identified in the carbon core metabolism of these organisms, but little is known about the actual contribution of the various reactions in vivo. RESULTS: Using 13C labelling techniques in specifically designed experiments, it could be shown that glucose-grown cells of D. shibae catabolise the carbon source exclusively via the Entner-Doudoroff pathway, whereas alternative routes of glycolysis and the pentose phosphate pathway are obviously utilised for anabolic purposes only. Enzyme assays confirmed this flux pattern and link the lack of glycolytic flux to the absence of phosphofructokinase activity. The previously suggested formation of phosphoenolpyruvate from pyruvate during mixotrophic CO2 assimilation was found to be inactive under the conditions studied. Moreover, it could be shown that pyruvate carboxylase is involved in CO2 assimilation and that the cyclic respiratory mode of the TCA cycle is utilised. Interestingly, the use of intracellular pathways was highly similar for P. gallaeciensis. CONCLUSION: The present study reveals the first insight into pathway utilisation within the Roseobacter group. Fluxes through major intracellular pathways of the central carbon metabolism, which are closely linked to the various important traits found for the Roseobacter clade, could be determined. The close similarity of fluxes between the two physiologically rather different species might provide the first indication of more general key properties among members of the Roseobacter clade which may explain their enormous success in the marine realm. PMID- 19788730 TI - The fundamental units, processes and patterns of evolution, and the tree of life conundrum. AB - BACKGROUND: The elucidation of the dominant role of horizontal gene transfer (HGT) in the evolution of prokaryotes led to a severe crisis of the Tree of Life (TOL) concept and intense debates on this subject. CONCEPT: Prompted by the crisis of the TOL, we attempt to define the primary units and the fundamental patterns and processes of evolution. We posit that replication of the genetic material is the singular fundamental biological process and that replication with an error rate below a certain threshold both enables and necessitates evolution by drift and selection. Starting from this proposition, we outline a general concept of evolution that consists of three major precepts. 1. The primary agency of evolution consists of Fundamental Units of Evolution (FUEs), that is, units of genetic material that possess a substantial degree of evolutionary independence. The FUEs include both bona fide selfish elements such as viruses, viroids, transposons, and plasmids, which encode some of the information required for their own replication, and regular genes that possess quasi-independence owing to their distinct selective value that provides for their transfer between ensembles of FUEs (genomes) and preferential replication along with the rest of the recipient genome. 2. The history of replication of a genetic element without recombination is isomorphously represented by a directed tree graph (an arborescence, in the graph theory language). Recombination within a FUE is common between very closely related sequences where homologous recombination is feasible but becomes negligible for longer evolutionary distances. In contrast, shuffling of FUEs occurs at all evolutionary distances. Thus, a tree is a natural representation of the evolution of an individual FUE on the macro scale, but not of an ensemble of FUEs such as a genome. 3. The history of life is properly represented by the "forest" of evolutionary trees for individual FUEs (Forest of Life, or FOL). Search for trends and patterns in the FOL is a productive direction of study that leads to the delineation of ensembles of FUEs that evolve coherently for a certain time span owing to a shared history of vertical inheritance or horizontal gene transfer; these ensembles are commonly known as genomes, taxa, or clades, depending on the level of analysis. A small set of genes (the universal genetic core of life) might show a (mostly) coherent evolutionary trend that transcends the entire history of cellular life forms. However, it might not be useful to denote this trend "the tree of life", or organismal, or species tree because neither organisms nor species are fundamental units of life. CONCLUSION: A logical analysis of the units and processes of biological evolution suggests that the natural fundamental unit of evolution is a FUE, that is, a genetic element with an independent evolutionary history. Evolution of a FUE on the macro scale is naturally represented by a tree. Only the full compendium of trees for individual FUEs (the FOL) is an adequate depiction of the evolution of life. Coherent evolution of FUEs over extended evolutionary intervals is a crucial aspect of the history of life but a "species" or "organismal" tree is not a fundamental concept. REVIEWERS: This articles was reviewed by Valerian Dolja, W. Ford Doolittle, Nicholas Galtier, and William Martin. PMID- 19788731 TI - Prokaryotic evolution and the tree of life are two different things. AB - BACKGROUND: The concept of a tree of life is prevalent in the evolutionary literature. It stems from attempting to obtain a grand unified natural system that reflects a recurrent process of species and lineage splittings for all forms of life. Traditionally, the discipline of systematics operates in a similar hierarchy of bifurcating (sometimes multifurcating) categories. The assumption of a universal tree of life hinges upon the process of evolution being tree-like throughout all forms of life and all of biological time. In multicellular eukaryotes, the molecular mechanisms and species-level population genetics of variation do indeed mainly cause a tree-like structure over time. In prokaryotes, they do not. Prokaryotic evolution and the tree of life are two different things, and we need to treat them as such, rather than extrapolating from macroscopic life to prokaryotes. In the following we will consider this circumstance from philosophical, scientific, and epistemological perspectives, surmising that phylogeny opted for a single model as a holdover from the Modern Synthesis of evolution. RESULTS: It was far easier to envision and defend the concept of a universal tree of life before we had data from genomes. But the belief that prokaryotes are related by such a tree has now become stronger than the data to support it. The monistic concept of a single universal tree of life appears, in the face of genome data, increasingly obsolete. This traditional model to describe evolution is no longer the most scientifically productive position to hold, because of the plurality of evolutionary patterns and mechanisms involved. Forcing a single bifurcating scheme onto prokaryotic evolution disregards the non tree-like nature of natural variation among prokaryotes and accounts for only a minority of observations from genomes. CONCLUSION: Prokaryotic evolution and the tree of life are two different things. Hence we will briefly set out alternative models to the tree of life to study their evolution. Ultimately, the plurality of evolutionary patterns and mechanisms involved, such as the discontinuity of the process of evolution across the prokaryote-eukaryote divide, summons forth a pluralistic approach to studying evolution. REVIEWERS: This article was reviewed by Ford Doolittle, John Logsdon and Nicolas Galtier. PMID- 19788732 TI - Inferring clocks when lacking rocks: the variable rates of molecular evolution in bacteria. AB - BACKGROUND: Because bacteria do not have a robust fossil record, attempts to infer the timing of events in their evolutionary history requires comparisons of molecular sequences. This use of molecular clocks is based on the assumptions that substitution rates for homologous genes or sites are fairly constant through time and across taxa. Violation of these conditions can lead to erroneous inferences and result in estimates that are off by orders of magnitude. In this study, we examine the consistency of substitution rates among a set of conserved genes in diverse bacterial lineages, and address the questions regarding the validity of molecular dating. RESULTS: By examining the evolution of 16S rRNA gene in obligate endosymbionts, which can be calibrated by the fossil record of their hosts, we found that the rates are consistent within a clade but varied widely across different bacterial lineages. Genome-wide estimates of nonsynonymous and synonymous substitutions suggest that these two measures are highly variable in their rates across bacterial taxa. Genetic drift plays a fundamental role in determining the accumulation of substitutions in 16S rRNA genes and at nonsynonymous sites. Moreover, divergence estimates based on a set of universally conserved protein-coding genes also exhibit low correspondence to those based on 16S rRNA genes. CONCLUSION: Our results document a wide range of substitution rates across genes and bacterial taxa. This high level of variation cautions against the assumption of a universal molecular clock for inferring divergence times in bacteria. However, by applying relative-rate tests to homologous genes, it is possible to derive reliable local clocks that can be used to calibrate bacterial evolution. REVIEWERS: This article was reviewed by Adam Eyre-Walker, Simonetta Gribaldo and Tal Pupko (nominated by Dan Graur). PMID- 19788733 TI - PKA and Epac cooperate to augment bradykinin-induced interleukin-8 release from human airway smooth muscle cells. AB - BACKGROUND: Airway smooth muscle contributes to the pathogenesis of pulmonary diseases by secreting inflammatory mediators such as interleukin-8 (IL-8). IL-8 production is in part regulated via activation of Gq-and Gs-coupled receptors. Here we study the role of the cyclic AMP (cAMP) effectors protein kinase A (PKA) and exchange proteins directly activated by cAMP (Epac1 and Epac2) in the bradykinin-induced IL-8 release from a human airway smooth muscle cell line and the underlying molecular mechanisms of this response. METHODS: IL-8 release was assessed via ELISA under basal condition and after stimulation with bradykinin alone or in combination with fenoterol, the Epac activators 8-pCPT-2'-O-Me-cAMP and Sp-8-pCPT-2'-O-Me-cAMPS, the PKA activator 6-Bnz-cAMP and the cGMP analog 8 pCPT-2'-O-Me-cGMP. Where indicated, cells were pre-incubated with the pharmacological inhibitors Clostridium difficile toxin B-1470 (GTPases), U0126 (extracellular signal-regulated kinases ERK1/2) and Rp-8-CPT-cAMPS (PKA). The specificity of the cyclic nucleotide analogs was confirmed by measuring phosphorylation of the PKA substrate vasodilator-stimulated phosphoprotein. GTP loading of Rap1 and Rap2 was evaluated via pull-down technique. Expression of Rap1, Rap2, Epac1 and Epac2 was assessed via western blot. Downregulation of Epac protein expression was achieved by siRNA. Unpaired or paired two-tailed Student's t test was used. RESULTS: The beta2-agonist fenoterol augmented release of IL-8 by bradykinin. The PKA activator 6-Bnz-cAMP and the Epac activator 8-pCPT-2'-O-Me cAMP significantly increased bradykinin-induced IL-8 release. The hydrolysis resistant Epac activator Sp-8-pCPT-2'-O-Me-cAMPS mimicked the effects of 8-pCPT 2'-O-Me-cAMP, whereas the negative control 8-pCPT-2'-O-Me-cGMP did not. Fenoterol, forskolin and 6-Bnz-cAMP induced VASP phosphorylation, which was diminished by the PKA inhibitor Rp-8-CPT-cAMPS. 6-Bnz-cAMP and 8-pCPT-2'-O-Me cAMP induced GTP-loading of Rap1, but not of Rap2. Treatment of the cells with toxin B-1470 and U0126 significantly reduced bradykinin-induced IL-8 release alone or in combination with the activators of PKA and Epac. Interestingly, inhibition of PKA by Rp-8-CPT-cAMPS and silencing of Epac1 and Epac2 expression by specific siRNAs largely decreased activation of Rap1 and the augmentation of bradykinin-induced IL-8 release by both PKA and Epac. CONCLUSION: Collectively, our data suggest that PKA, Epac1 and Epac2 act in concert to modulate inflammatory properties of airway smooth muscle via signaling to the Ras-like GTPase Rap1 and to ERK1/2. PMID- 19788734 TI - Chronic growth faltering amongst a birth cohort of Indian children begins prior to weaning and is highly prevalent at three years of age. AB - BACKGROUND: Poor growth of children in developing countries is a major public health problem associated with mortality, morbidity and developmental delay. We describe growth up to three years of age and investigate factors related to stunting (low height-for-age) at three years of age in a birth cohort from an urban slum. METHODS: 452 children born between March 2002 and August 2003 were followed until their third birthday in three neighbouring slums in Vellore, South India. Field workers visited homes to collect details of morbidity twice a week. Height and weight were measured monthly from one month of age in a study-run clinic. For analysis, standardised z-scores were generated using the 2006 WHO child growth standards. Risk factors for stunting at three years of age were analysed in logistic regression models. A sensitivity analysis was conducted to examine the effect of missing values. RESULTS: At age three years, of 186 boys and 187 girls still under follow-up, 109 (66%, 95% Confidence interval 58-73%) boys and 93 (56%, 95% CI 49-64%) girls were stunted, 14 (8%, 95% CI 4-13%) boys and 12 (7%, 95% CI 3-11%) girls were wasted (low weight-for-height) and 72 (43%, 95% CI 36-51) boys and 66 (39%, 95% CI 31-47%) girls were underweight (low weight for-age). In total 224/331 (68%) children at three years had at least one growth deficiency (were stunted and/or underweight and/or wasted); even as early as one month of age 186/377 (49%) children had at least one growth deficiency. Factors associated with stunting at three years were birth weight less than 2.5 kg (OR 3.63, 95% CI 1.36-9.70) 'beedi-making' (manual production of cigarettes for a daily wage) in the household (OR 1.74, 95% CI 1.05-2.86), maternal height less than 150 cm (OR 2.02, 95% CI 1.12-3.62), being stunted, wasted or underweight at six months of age (OR 1.75, 95% CI 1.05-2.93) and having at least one older sibling (OR 2.00, 95% CI 1.14-3.51). CONCLUSION: A high proportion of urban slum dwelling children had poor growth throughout the first three years of life. Interventions are needed urgently during pregnancy, early breastfeeding and weaning in this population. PMID- 19788735 TI - Transcriptomic and proteomic analyses of seasonal photoperiodism in the pea aphid. AB - BACKGROUND: Aphid adaptation to harsh winter conditions is illustrated by an alternation of their reproductive mode. Aphids detect photoperiod shortening by sensing the length of the night and switch from viviparous parthenogenesis in spring and summer, to oviparous sexual reproduction in autumn. The photoperiodic signal is transduced from the head to the reproductive tract to change the fate of the future oocytes from mitotic diploid embryogenesis to haploid formation of gametes. This process takes place in three consecutive generations due to viviparous parthenogenesis. To understand the molecular basis of the switch in the reproductive mode, transcriptomic and proteomic approaches were used to detect significantly regulated transcripts and polypeptides in the heads of the pea aphid Acyrthosiphon pisum. RESULTS: The transcriptomic profiles of the heads of the first generation were slightly affected by photoperiod shortening. This suggests that trans-generation signalling between the grand-mothers and the viviparous embryos they contain is not essential. By analogy, many of the genes and some of the proteins regulated in the heads of the second generation are implicated in visual functions, photoreception and cuticle structure. The modification of the cuticle could be accompanied by a down-regulation of the N beta-alanyldopamine pathway and desclerotization. In Drosophila, modification of the insulin pathway could cause a decrease of juvenile hormones in short-day reared aphids. CONCLUSION: This work led to the construction of hypotheses for photoperiodic regulation of the switch of the reproductive mode in aphids. PMID- 19788736 TI - A randomized, controlled, prospective trial to evaluate the haemostatic effect of Lyostypt versus Surgicel in arterial bypass anastomosis: "COBBANA" trial. AB - BACKGROUND: The development of suture hole bleeding at peripheral arterial bypass anastomoses using PTFE graft prostheses is a common problem in peripheral vascular surgery. Traditionally the problem is managed by compression with surgical swabs and reversal heparin or by using several haemostatic device (e.g. different forms of collagen, oxidized cellulose, gelatine sponge, ethylcyanoacrylate glue or fibrin) with various success. Preclinical data suggest that the haemostatic effect of collagen is stronger than that of oxidized cellulose, but no direct clinical comparison of their hemostatic performance has been published so far. DESIGN: This randomized, controlled, prospective trial evaluates the haemostatic effect of Lyostypt versus Surgicel in arterial bypass anastomosis. 28 patients undergoing an elective peripheral vascular reconstruction due to peripheral vascular disease will be included. Suture hole bleeding occurring at the arterial bypass anastomosis using a PTFE prostheses will be stopped by the application of Lyostypt and/or Surgicel. The proximal anastomoses will be randomized intraoperatively. The patients will be allocated into 4 different treatment groups. Group1 Lyostypt distal/Surgicel proximal; Group 2: Lyostypt proximal/Surgicel distal; Group 3: Surgicel distal and proximal; Group 4: Lyostypt distal and proximal. Primary endpoint of the study is time to haemostasis. Secondary endpoints are the number of intraoperatively used haemostatic devices, postoperative mortality within 30 days as well as the intraoperative efficacy rating of the two devices evaluated by the surgeon. As a safety secondary parameter, the local and general complication occurring till 30 +/- 10 days postoperatively will also be analysed. After hospital discharge the investigator will examine the enrolled patients again at 30 days after surgery. DISCUSSION: The COBBANA trial aims to assess, whether the haemostatic effect of Lyostypt is superior to Surgicel in suture hole bleedings of arterial bypass anastomoses. PMID- 19788737 TI - MoccaDB - an integrative database for functional, comparative and diversity studies in the Rubiaceae family. AB - BACKGROUND: In the past few years, functional genomics information has been rapidly accumulating on Rubiaceae species and especially on those belonging to the Coffea genus (coffee trees). An increasing number of expressed sequence tag (EST) data and EST- or genomic-derived microsatellite markers have been generated, together with Conserved Ortholog Set (COS) markers. This considerably facilitates comparative genomics or map-based genetic studies through the common use of orthologous loci across different species. Similar genomic information is available for e.g. tomato or potato, members of the Solanaceae family. Since both Rubiaceae and Solanaceae belong to the Euasterids I (lamiids) integration of information on genetic markers would be possible and lead to more efficient analyses and discovery of key loci involved in important traits such as fruit development, quality, and maturation, or adaptation. Our goal was to develop a comprehensive web data source for integrated information on validated orthologous markers in Rubiaceae. DESCRIPTION: MoccaDB is an online MySQL-PHP driven relational database that houses annotated and/or mapped microsatellite markers in Rubiaceae. In its current release, the database stores 638 markers that have been defined on 259 ESTs and 379 genomic sequences. Marker information was retrieved from 11 published works, and completed with original data on 132 microsatellite markers validated in our laboratory. DNA sequences were derived from three Coffea species/hybrids. Microsatellite markers were checked for similarity, in vitro tested for cross-amplification and diversity/polymorphism status in up to 38 Rubiaceae species belonging to the Cinchonoideae and Rubioideae subfamilies. Functional annotation was provided and some markers associated with described metabolic pathways were also integrated. Users can search the database for marker, sequence, map or diversity information through multi-option query forms. The retrieved data can be browsed and downloaded, along with protocols used, using a standard web browser. MoccaDB also integrates bioinformatics tools (CMap viewer and local BLAST) and hyperlinks to related external data sources (NCBI GenBank and PubMed, SOL Genomic Network database). CONCLUSION: We believe that MoccaDB will be extremely useful for all researchers working in the areas of comparative and functional genomics and molecular evolution, in general, and population analysis and association mapping of Rubiaceae and Solanaceae species, in particular. PMID- 19788738 TI - Seasonal distribution of anti-malarial drug resistance alleles on the island of Sumba, Indonesia. AB - BACKGROUND: Drug resistant malaria poses an increasing public health problem in Indonesia, especially eastern Indonesia, where malaria is highly endemic. Widespread chloroquine (CQ) resistance and increasing sulphadoxine-pyrimethamine (SP) resistance prompted Indonesia to adopt artemisinin-based combination therapy (ACT) as first-line therapy in 2004. To help develop a suitable malaria control programme in the district of West Sumba, the seasonal distribution of alleles known to be associated with resistance to CQ and SP among Plasmodium falciparum isolates from the region was investigated. METHODS: Plasmodium falciparum isolates were collected during malariometric surveys in the wet and dry seasons in 2007 using two-stage cluster sampling. Analysis of pfcrt, pfmdr1, pfmdr1 gene copy number, dhfr, and dhps genes were done using protocols described previously. RESULTS AND DISCUSSION: The 76T allele of the pfcrt gene is nearing fixation in this population. Pfmdr1 mutant alleles occurred in 72.8% and 53.3%, predominantly as 1042D and 86Y alleles that are mutually exclusive. The prevalence of amplified pfmdr1 was found 41.9% and 42.8% of isolates in the wet and dry seasons, respectively. The frequency of dhfr mutant alleles was much lower, either as a single 108N mutation or paired with 59R. The 437G allele was the only mutant dhps allele detected and it was only found during dry season. CONCLUSION: The findings demonstrate a slighly higher distribution of drug-resistant alleles during the wet season and support the policy of replacing CQ with ACT in this area, but suggest that SP might still be effective either alone or in combination with other anti-malarials. PMID- 19788739 TI - Intra- and inter-observer analysis in the morphological assessment of early-stage embryos. AB - BACKGROUND: The aim of this study was to determine the intra- and inter-observer variability in the evaluation of embryo quality. Multilevel images of embryos on day 1, day 2 and day 3, were analysed using different morphological parameters. METHODS: Multilevel images of embryos on day 1, day 2 and day 3, were analysed using a standard scoring system. The kappa coefficient was calculated to measure intra- and inter-observer variability before and after training sessions. RESULTS: Good to excellent intra-observer agreement was present for most parameters exceptions being scoring the position of pronuclei and the presence of a cytoplasmic halo on day 1, multinucleation on day 2 and the size of fragments on day 3. Inter-observer agreement was only good to excellent for the number of blastomeres on day 2 and day 3 and the orientation of the cleavage axes on day 2. Training sessions had a positive impact on inter-observer agreement. CONCLUSION: In conclusion, assessment of morphological characteristics of early stage embryos using multilevel images was marked by a high intra-observer and a moderate inter observer agreement. Training sessions were useful to increase inter-observer agreement. PMID- 19788740 TI - Synovial tissues concentrate secreted APRIL. AB - INTRODUCTION: A proliferation-inducing ligand (APRIL) from the TNF family, owing to its role in the generation and survival of plasma cells (PCs), is currently targeted for rheumatoid arthritis (RA) treatment. However, little is known about APRIL expression in RA lesions, hampering our understanding of the way APRIL may modulate this autoimmune disease. METHODS: We performed immunological staining of human normal, non-RA and RA synovial tissues with a pair of antibodies specifically recognizing APRIL-producing cells and secreted APRIL. RESULTS: We detected significant amounts of secreted APRIL in normal synovium mostly concentrated around blood vessels and at the lining layer, but no cells producing APRIL. Meanwhile, we observed that blood neutrophils constitutively secrete APRIL, indicating that blood APRIL may diffuse into the synovium via its fenestrated vessels. Synovium from non-RA and RA patients retained similarly secreted APRIL, but in this case APRIL-producing cells, including neutrophils and macrophages, were present in the tissue. Notably, PCs--when present in RA synovium--accumulated in areas of APRIL retention, spreading from blood vessels towards the lining layer. CONCLUSIONS: PCs accumulate in synovial zones rich in secreted APRIL, consistent with a pro-survival role of APRIL for PCs in RA. The concentration of APRIL by normal synovium indicates that this tissue may constitute a proper environment for PCs even before RA onset. PMID- 19788741 TI - Defects in cellular sorting and retroviral assembly induced by GGA overexpression. AB - BACKGROUND: We previously demonstrated that overexpression of Golgi-localized, gamma-ear containing, Arf-binding (GGA) proteins inhibits retrovirus assembly and release by disrupting the function of endogenous ADP ribosylation factors (Arfs). GGA overexpression led to the formation of large, swollen vacuolar compartments, which in the case of GGA1 sequestered HIV-1 Gag. RESULTS: In the current study, we extend our previous findings to characterize in depth the GGA-induced compartments and the determinants for retroviral Gag sequestration in these structures. We find that GGA-induced structures are derived from the Golgi and contain aggresome markers. GGA overexpression leads to defects in trafficking of transferrin receptor and recycling of cation-dependent mannose 6-phosphate receptor. Additionally, we find that compartments induced by GGA overexpression sequester Tsg101, poly-ubiquitin, and, in the case of GGA3, Hrs. Interestingly, brefeldin A treatment, which leads to the dissociation of endogenous GGAs from membranes, does not dissociate the GGA-induced compartments. GGA mutants that are defective in Arf binding and hence association with membranes also induce the formation of GGA-induced structures. Overexpression of ubiquitin reverses the formation of GGA-induced structures and partially rescues HIV-1 particle production. We found that in addition to HIV-1 Gag, equine infectious anemia virus Gag is also sequestered in GGA1-induced structures. The determinants in Gag responsible for sequestration map to the matrix domain, and recruitment to these structures is dependent on Gag membrane binding. CONCLUSION: These data provide insights into the composition of structures induced by GGA overexpression and their ability to disrupt endosomal sorting and retroviral particle production. PMID- 19788742 TI - Enrichment of a set of microRNAs during the cotton fiber development. AB - BACKGROUND: Cotton (Gossypium hirsutum) is one of the most important economic crops and provides excellent fibers for textile manufacture. In addition to its industrial and agricultural importance, the fiber cell (plant trichome) also is a biological model system for exploring gene expression and regulation. Small RNAs regulate many aspects of plant growth and development. However, whether small RNAs are involved in regulation of fiber cell development is unknown. RESULTS: We adopted a deep sequencing approach developed by Solexa (Illumina Inc.) to investigate global expression and complexity of small RNAs during cotton fiber initiation and development. We constructed two small RNA libraries prepared from wild type (WT) and fuzz/lintless (fl Mutant in the WT background) cotton ovules, respectively. Each library was sequenced individually and generated more than 6-7 million short sequences, resulting in a total of over 13 million sequence reads. At least 22 conserved candidate miRNA families including 111 members were identified. Seven families make up the vast majority of expressed miRNAs in developing cotton ovules. In total 120 unique target genes were predicted for most of conserved miRNAs. In addition, we identified 2 cell-type-specific novel miRNA candidates in cotton ovules. Our study has demonstrated significant differences in expression abundance of miRNAs between the wild-type and mutant, and suggests that these differentially expressed miRNAs potentially regulate transcripts distinctly involved in cotton fiber development. CONCLUSION: The present study is the first to deep sequence the small RNA population of G. hirsutum ovules where cotton fibers initiate and develop. Millions of unique miRNA sequences ranging from 18 to approximately 28 nt in length were detected. Our results support the importance of miRNAs in regulating the development of different cell types and indicate that identification of a comprehensive set of miRNAs in cotton fiber cells would facilitate our understanding of the regulatory mechanisms for fiber cell initiation and elongation. PMID- 19788743 TI - Use of dried blood samples for monitoring hepatitis B virus infection. AB - BACKGROUND: Hepatitis B virus (HBV) infection is a problem in several regions of the world with limited resources. Blood samples dried on filter paper (DBS) have been successfully used to diagnose and monitor several infectious diseases. In Mexico there is an urgent need for an affordable and easy sampling method for viral load (VL) testing and monitoring of chronic HBV infection. The purpose of this work was to validate the utility of DBS samples for monitoring HBV infection in patients from Mexico City. METHODS: Matched samples of plasma and DBS on filter paper from 47 HBV infected patients from the Instituto Mexicano del Seguro Social (IMSS), were included. To evaluate the DNA stability and purity from DBS stored at different temperature conditions, samples from ten patients were stored at 4 degree, 25 degree, and 37 degree C for 7 days. After DBS elution and DNA extraction, the purity of these samples was determined measuring the O.D. rate 260/280. The DBS utility for molecular studies was assessed with PCR assays to amplify a 322 bp fragment from the "a" determinant region of the HBV "S" gene. The VL from all samples was determined to evaluate the correlation between plasma and DBS matched samples. RESULTS: The quality of the DNA from DBS specimen is not adversely affected by storage at 4 degree, 25 degree and 37 degree C for up 7 days. Statistical ANOVA analyses did not show any significant difference. The same amplification efficiency was observed between DNA templates from samples stored at different temperatures. The Pearson correlation between the VL from DBS and plasma matched samples was 0.93 (p = 0.01). The SD was 1.48 for DBS vs.1.32 for Plasma, and an average of log10 copies/mL of 5.32 vs. 5.53. ANOVA analysis did not show any statistically significant difference between the analyzed groups (p = 0.92). CONCLUSION: The results provide strong evidence that the isolation and quantification of DNA-HBV from DBS is a viable alternative for patient monitoring, and molecular characterization of the virus variants circulating in Mexico. PMID- 19788744 TI - Identification of novel host-oriented targets for Human Immunodeficiency Virus type 1 using Random Homozygous Gene Perturbation. AB - BACKGROUND: Human Immunodeficiency Virus (HIV) is a global threat to public health. Current therapies that directly target the virus often are rendered ineffective due to the emergence of drug-resistant viral variants. An emerging concept to combat drug resistance is the idea of targeting host mechanisms that are essential for the propagation of the virus, but have a minimal cellular effect. RESULTS: Herein, using Random Homozygous Gene Perturbation (RHGP), we have identified cellular targets that allow human MT4 cells to survive otherwise lethal infection by a wild type HIV-1NL4-3. These gene targets were validated by the reversibility of the RHGP technology, which confirmed that the RHGP itself was responsible for the resistance to HIV-1 infection. We further confirmed by siRNA knockdowns that the RHGP-identified cellular pathways are responsible for resistance to infection by either CXCR4 or CCR5 tropic HIV-1 variants. We also demonstrated that cell clones with these gene targets disrupted by RHGP were not permissible to the replication of a drug resistant HIV-1 mutant. CONCLUSION: These studies demonstrate the power of RHGP to identify novel host targets that are essential for the viral life cycle but which can be safely perturbed without overt cytotoxicity. These findings suggest opportunities for the future development of host-oriented therapeutics with the broad spectrum potential for safe and effective inhibition of HIV infection. PMID- 19788745 TI - Linear models for joint association and linkage QTL mapping. AB - BACKGROUND: Populational linkage disequilibrium and within-family linkage are commonly used for QTL mapping and marker assisted selection. The combination of both results in more robust and accurate locations of the QTL, but models proposed so far have been either single marker, complex in practice or well fit to a particular family structure. RESULTS: We herein present linear model theory to come up with additive effects of the QTL alleles in any member of a general pedigree, conditional to observed markers and pedigree, accounting for possible linkage disequilibrium among QTLs and markers. The model is based on association analysis in the founders; further, the additive effect of the QTLs transmitted to the descendants is a weighted (by the probabilities of transmission) average of the substitution effects of founders' haplotypes. The model allows for non complete linkage disequilibrium QTL-markers in the founders. Two submodels are presented: a simple and easy to implement Haley-Knott type regression for half sib families, and a general mixed (variance component) model for general pedigrees. The model can use information from all markers. The performance of the regression method is compared by simulation with a more complex IBD method by Meuwissen and Goddard. Numerical examples are provided. CONCLUSION: The linear model theory provides a useful framework for QTL mapping with dense marker maps. Results show similar accuracies but a bias of the IBD method towards the center of the region. Computations for the linear regression model are extremely simple, in contrast with IBD methods. Extensions of the model to genomic selection and multi-QTL mapping are straightforward. PMID- 19788746 TI - Multipathogen infections in hospitalized children with acute respiratory infections. AB - BACKGROUND: To explore the epidemiologic and clinical features of, and interactions among, multipathogen infections in hospitalized children with acute respiratory tract infection (ARTI). A prospective study of children admitted with ARTI was conducted. Peripheral blood samples were analyzed by indirect immunofluorescence to detect respiratory agents including respiratory syncytial virus; adenovirus; influenza virus (Flu) types A and B; parainfluenza virus (PIV) types 1, 2, and 3; chlamydia pneumonia; and mycoplasma pneumonia. A medical history of each child was taken. RESULTS: Respiratory agents were detected in 164 (51.9%) of 316 children with ARTI. A single agent was identified in 50 (15.8%) children, and multiple agents in 114 (36.1%). Flu A was the most frequently detected agent, followed by Flu B. Coinfection occurred predominantly in August and was more frequent in children between 3 and 6 years of age. A significantly higher proportion of Flu A, Flu B, and PIV 1 was detected in samples with two or more pathogens per sample than in samples with a single pathogen. CONCLUSION: Our study suggests that there is a high occurrence of multipathogen infections in children admitted with ARTI and that coinfection is associated with certain pathogens. PMID- 19788747 TI - Generation of fusion protein EGFRvIII-HBcAg and its anti-tumor effect in vivo. AB - The epidermal growth factor receptor variant III (EGFRvIII) is the most common variation of EGFR. Because it shows a high frequency in several different types of tumor and has not been detected in normal tissues, it is an ideal target for tumor specific therapy. In this study, we prepared EGFRvIII-HBcAg fusion protein. After immunization with fusion protein, HBcAg or PBS, the titers of antibody in BALB/c mice immunized with fusion protein reached 2.75 x 10(5). Western blot analysis demonstrated that the fusion protein had specific antigenicity against anti-EGFRvIII antibody. Further observation showed fusion protein induced a high frequency of IFN-gamma-secreting lymphocytes. CD4+T cells rather than CD8+T cells were associated with the production of IFN-gamma. Using Renca-vIII(+) cell as specific stimulator, we observed remarkable cytotoxic activity in splenocytes from mice immunized with fusion protein. Mice were challenged with Renca-vIII(+) cells after five times immunization. In fusion protein group, three of ten mice failed to develop tumor and all survived at the end of the research. The weight of tumors in fusion protein were obviously lighter than that in other two groups (t = 4.73, P = 0.044; t = 6.89, P = 0.040). These findings demonstrated that EGFRvIII-HBcAg fusion protein triggered protective responses against tumor expressing EGFRvIII. PMID- 19788748 TI - Update and review of the multidisciplinary management of stage IV colorectal cancer with liver metastases. AB - BACKGROUND: The management of stage IV colorectal cancer with liver metastases has historically involved a multidisciplinary approach. In the last several decades, there have been great strides made in the therapeutic options available to treat these patients with advancements in medical, surgical, locoregional and adjunctive therapies available to patients with colorectal liver metastases(CLM). As a result, there have been improvements in patient care and survival. Naturally, the management of CLM has become increasingly complex in coordinating the various aspects of care in order to optimize patient outcomes. REVIEW: A review of historical and up to date literature was undertaken utilizing Medline/PubMed to examine relevant topics of interest in patients with CLM including criterion for resectability, technical/surgical considerations, chemotherapy, adjunctive and locoregional therapies. This review explores the various disciplines and modalities to provide current perspectives on the various options of care for patients with CLM. CONCLUSION: Improvements in modern day chemotherapy as allowed clinicians to pursue a more aggressive surgical approach in the management of stage IV colorectal cancer with CLM. Additionally, locoregional and adjunctive therapies has expanded the armamentarium of treatment options available. As a result, the management of patients with CLM requires a comprehensive, multidisciplinary approach utilizing various modalities and a more aggressive approach may now be pursued in patients with stage IV colorectal cancer with CLM to achieve optimal outcomes. PMID- 19788749 TI - Anti-inflammatory effects of antibacterials on human Bronchial epithelial cells. AB - BACKGROUND: Human Bronchial epithelial cells (hu-BEC) have been claimed to play a significant role in the pathogenesis of chronic inflammatory airway diseases like COPD. In this context IL-8 and GM-CSF have been shown to be key cytokines. Some antibiotics which are routinely used to treat lower respiratory tract infections have been shown to exert additional immunomodulatory or anti-inflammatory effects. We investigated whether these effects can also be detected in hu-BEC. METHODS: Hu-BEC obtained from patients undergoing lung resections were transferred to air-liquid-interface (ALI) culture. These cultures were incubated with cefuroxime (CXM, 10-62.5 mg/l), azithromycin (AZM, 0.1-1.5 mg/l), levofloxacin (LVX, 1-8 mg/l) and moxifloxacin (MXF, 1-16 mg/l). The spontaneous and TNF-alpha (10 ng/ml) induced expression and release of IL-8 and GM-CSF were measured using PCR and ELISA in the absence or presence of these antibiotics. RESULTS: The spontaneous IL-8 and GM-CSF release was significantly reduced with MXF (8 mg/l) by 37 +/- 20% and 45 +/- 31%, respectively (both p < 0.01). IL-8 release in TNF-alpha stimulated hu-BEC decreased by 16 +/- 8% (p < 0.05) with AZM (1.5 mg/l). With MXF a concentration dependent decrease of IL-8 release was noted up to 39 +/- 7% (p < 0.05). GM-CSF release from TNF-alpha stimulated hu-BEC was maximally decreased by 35 +/- 24% (p < 0.01) with MXF (4 mg/l). CONCLUSION: Using ALI cultures of hu-BEC we observed differential effects of antibiotics on spontaneous and TNF-alpha induced cytokine release. Our data suggest that MXF and AZM, beyond bactericidal effects, may attenuate the inflammatory process mediated by hu-BEC. PMID- 19788750 TI - Estimation of colorectal adenoma recurrence with dependent censoring. AB - BACKGROUND: Due to early colonoscopy for some participants, interval-censored observations can be introduced into the data of a colorectal polyp prevention trial. The censoring could be dependent of risk of recurrence if the reasons of having early colonoscopy are associated with recurrence. This can complicate estimation of the recurrence rate. METHODS: We propose to use midpoint imputation to convert interval-censored data problems to right censored data problems. To adjust for potential dependent censoring, we use information from auxiliary variables to define risk groups to perform the weighted Kaplan-Meier estimation to the midpoint imputed data. The risk groups are defined using two risk scores derived from two working proportional hazards models with the auxiliary variables as the covariates. One is for the recurrence time and the other is for the censoring time. The method described here is explored by simulation and illustrated with an example from a colorectal polyp prevention trial. RESULTS: We first show that midpoint imputation under an assumption of independent censoring will produce an unbiased estimate of recurrence rate at the end of the trial, which is often the main interest of a colorectal polyp prevention trial, and then show in simulations that the weighted Kaplan-Meier method using the information from auxiliary variables based on the midpoint imputed data can improve efficiency in a situation with independent censoring and reduce bias in a situation with dependent censoring compared to the conventional methods, while estimating the recurrence rate at the end of the trial. CONCLUSION: The research in this paper uses midpoint imputation to handle interval-censored observations and then uses the information from auxiliary variables to adjust for dependent censoring by incorporating them into the weighted Kaplan-Meier estimation. This approach can handle a situation with multiple auxiliary variables by deriving two risk scores from two working PH models. Although the idea of this approach might appear simple, the results do show that the weighted Kaplan-Meier approach can gain efficiency and reduce bias due to dependent censoring. PMID- 19788751 TI - Small islands and pandemic influenza: potential benefits and limitations of travel volume reduction as a border control measure. AB - BACKGROUND: Some island nations have explicit components of their influenza pandemic plans for providing travel warnings and restricting incoming travellers. But the potential value of such restrictions has not been quantified. METHODS: We developed a probabilistic model and used parameters from a published model (i.e., InfluSim) and travel data from Pacific Island Countries and Territories (PICTs). RESULTS: The results indicate that of the 17 PICTs with travel data, only six would be likely to escape a major pandemic with a viral strain of relatively low contagiousness (i.e., for R0 = 1.5) even when imposing very tight travel volume reductions of 99% throughout the course of the pandemic. For a more contagious viral strain (R0 = 2.25) only five PICTs would have a probability of over 50% to escape. The total number of travellers during the pandemic must not exceed 115 (for R0 = 3.0) or 380 (for R0 = 1.5) if a PICT aims to keep the probability of pandemic arrival below 50%. CONCLUSION: These results suggest that relatively few island nations could successfully rely on intensive travel volume restrictions alone to avoid the arrival of pandemic influenza (or subsequent waves). Therefore most island nations may need to plan for multiple additional interventions (e.g., screening and quarantine) to raise the probability of remaining pandemic free or achieving substantial delay in pandemic arrival. PMID- 19788752 TI - Estrogen and progesterone receptors have distinct roles in the establishment of the hyperplastic phenotype in PR-A transgenic mice. AB - INTRODUCTION: Expression of the A and B forms of progesterone receptor (PR) in an appropriate ratio is critical for mammary development. Mammary glands of PR-A transgenic mice, carrying an additional A form of PR as a transgene, exhibit morphological features associated with the development of mammary tumors. Our objective was to determine the roles of estrogen (E) and progesterone (P) in the genesis of mammary hyperplasias/preneoplasias in PR-A transgenics. METHODS: We subjected PR-A mice to hormonal treatments and analyzed mammary glands for the presence of hyperplasias and used BrdU incorporation to measure proliferation. Quantitative image analysis was carried out to compare levels of latency associated peptide and transforming growth factor beta 1 (TGFbeta1) between PR-A and PR-B transgenics. Basement membrane disruption was examined by immunofluorescence and proteolytic activity by zymography. RESULTS: The hyperplastic phenotype of PR-A transgenics is inhibited by ovariectomy, and is reversed by treatment with E + P. Studies using the antiestrogen ICI 182,780 or antiprogestins RU486 or ZK 98,299 show that the increase in proliferation requires signaling through E/estrogen receptor alpha but is not sufficient to give rise to hyperplasias, whereas signaling through P/PR has little impact on proliferation but is essential for the manifestation of hyperplasias. Increased proliferation is correlated with decreased TGFbeta1 activation in the PR-A transgenics. Analysis of basement membrane integrity showed loss of laminin-5, collagen III and collagen IV in mammary glands of PR-A mice, which is restored by ovariectomy. Examination of matrix metalloproteases (MMPs) showed that total levels of MMP-2 correlate with the steady-state levels of PR, and that areas of laminin-5 loss coincide with those of activation of MMP-2 in PR-A transgenics. Activation of MMP-2 is dependent on treatment with E and P in ovariectomized wild type mice, but is achieved only by treatment with P in PR-A mice. CONCLUSIONS: These data establish a link between hormonal response, proliferation, modulation of MMP activity and maintenance of basement membrane integrity that depend on a balance in the expression levels of PR-A and PR-B isoforms. Notably, concomitant increased proliferation, due to inhibition of TGFbeta1 activation, and loss of basement membrane integrity, via increased MMP-2 activity, appear to be prerequisites for the PR-A hyperplastic phenotype. PMID- 19788753 TI - Brace treatment for patients with Scheuermann's disease - a review of the literature and first experiences with a new brace design. AB - BACKGROUND: In contemporary literature few have written in detail on the in-brace correction effects of braces used for the treatment of hyperkyphosis. Bradford et al. found their attempts effective, treating Scheuermann's kyphosis with Milwaukee braces, but their report did not specifically focus on in-brace corrections. White and Panjabi's research attempted to correct a curvature of > 50 degrees with the help of distraction forces, but consequently led to a reduction in patient comfort in the application of the Milwaukee brace. In Germany they avoid this by utitlising braces to treat hyperkyphosis that use transverse correction forces instead of distraction forces. Further efforts to reduce brace material have resulted in a special bracing design called kyphologic brace. The aim of this review is to present appropriate research to collect and evaluate possible in-brace corrections which have been achieved with brace treatment for hyperkyphosis. This paper introduces new methods of bracing and compares the results of these with other successful bracing concepts. MATERIALS AND METHODS: 56 adolescents with the diagnosis of thoracic Scheuermann's hyperkyphosis or a thoracic idiopathic hyperkyphosis (22 girls and 34 boys) with an average age of 14 years (12-17 yrs.) were treated with the kyphologic brace between May 2007 and December 2008. The average Stagnara angle was 55,6 degrees (43-80). In-brace correction was recorded and compared to the initial angle using the t-test. RESULTS: The average Stagnara angle in the brace was 39 degrees . The average in-brace correction was 16.5 degrees (1-40 degrees ). The verage percentage of in-brace correction compared to the initial value was 36%. The differences were significant in the t-test (t = 5.31, p < 0,001). To make these results comparable to other studies, the kyphosis angle of 25 degrees was set to 0 for our sample in order to achieve a norm value adapted (NVA) percentage of in brace correction. By doing this a correction of 54.1% was achieved. There was no correlation between the percentage of in-brace correction and the age of the patient, but a highly significant correlation between percentage of in-brace correction and the initial Stagnara angle. DISCUSSION: If we assume that outcome of brace treatment positively correlates with in-brace correction, the treatment should be initiated before the curvature angle exceeds 50 - 55 degrees in a growing adolescent. In scoliosis bracing, if the average in-brace correction equals > 15 degrees , then it is predicted that the result will lead to a final correction. Applying this to hyperkyphosis patients, the average in-brace correction with this brace was also > 15 degrees . We therefore estimated to achieve a favourable outcome using this brace type (once compliance was attained) especially when comparing the correction effects achieved with this new approach to the correction effects reported upon using the Milwaukee brace. The latter brace has been shown to lead to beneficial outcomes in long-term studies with comparable in-brace corrections. CONCLUSION: Conservative treatment of Scheuermann's hyperkyphosis in international literature is generally regarded as an effective treatment approach. Physiotherapy and bracing are the first-line treatments for this condition.An average in-brace correction of > 15 degrees as was achieved using the kyphologic brace predicts a favourable outcome.The kyphologic brace leads to in-brace corrections comparable to those of the Milwaukee brace, which has previously been shown to provide beneficial outcome in the long-term.A prospective follow-up study seems desirable before final conclusions can be drawn.Future studies should focus more on thoracolumbar and lumbar curve patterns, because these patterns may predict chronic low back pain in adulthood with reduced quality of life of the patients and high costs with respect to medical care and occupational sickness leave.Surgery according to international literature is rarely necessary in this condition. PMID- 19788754 TI - Self-Rated Health in middle-aged and elderly Chinese: distribution, determinants and associations with cardio-metabolic risk factors. AB - BACKGROUND: Self-rated health (SRH) has been demonstrated to be an accurate reflection of a person's health and a valid predictor of incident mortality and chronic morbidity. We aimed to evaluate the distribution and factors associated with SRH and its association with biomarkers of cardio-metabolic diseases among middle-aged and elderly Chinese. METHODS: Survey of 1,458 men and 1,831 women aged 50 to 70 years, conducted in one urban and two rural areas of Beijing and Shanghai in 2005. SRH status was measured and categorized as good (very good and good) vs. not good (fair, poor and very poor). Determinants of SRH and associations with biomarkers of cardio-metabolic diseases were evaluated using logistic regression. RESULTS: Thirty two percent of participants reported good SRH. Males and rural residents tended to report good SRH. After adjusting for potential confounders, residence, physical activity, employment status, sleep quality and presence of diabetes, cardiovascular disease, and depression were the main determinants of SRH. Those free from cardiovascular disease (OR 3.68; 95%CI 2.39; 5.66), rural residents (OR 1.89; 95% CI 1.47; 2.43), non-depressed participants (OR 2.50; 95% CI 1.67; 3.73) and those with good sleep quality (OR 2.95; 95% CI 2.22; 3.91) had almost twice or over the chance of reporting good SRH compared to their counterparts. There were significant associations -and trend- between SRH and levels of inflammatory markers, insulin levels and insulin resistance. CONCLUSION: Only one third of middle-aged and elderly Chinese assessed their health status as good or very good. Although further longitudinal studies are required to confirm our findings, interventions targeting social inequalities, lifestyle patterns might not only contribute to prevent chronic morbidity but as well to improve populations' perceived health. PMID- 19788755 TI - A model for extending antiretroviral care beyond the rural health centre. AB - BACKGROUND: A major obstacle facing many lower-income countries in establishing and maintaining HIV treatment programmes is the scarcity of trained health care providers. To address this shortage, the World Health Organization has recommend task shifting to HIV-infected peers. METHODS: We designed a model of HIV care that utilizes HIV-infected patients, community care coordinators (CCCs), to care for their clinically stable peers with the assistance of preprogrammed personal digital assistants (PDAs). Rather than presenting for the standard of care, monthly clinic visits, in this model, patients were seen every three months in clinics and monthly by their CCCs in the community during the interim two months. This study was conducted in Kosirai Division, western Kenya, where eight of the 24 sub-locations (defined geographic areas) within the division were randomly assigned to the intervention with the remainder used as controls.Prior to entering the field, CCCs underwent intensive didactic training and mentoring related to the assessment and support of HIV patients, as well as the use of PDAs. PDAs were programmed with specific questions and to issue alerts if responses fell outside of pre-established parameters. CCCs were regularly evaluated in six performance areas. An impressionistic analysis on the transcripts from the monthly group meetings that formed the basis of the continuous feedback and quality improvement programme was used to assess this model. RESULTS: All eight of the assigned CCCs successfully passed their training and mentoring, entered the field and remained active for the two years of the study. On evaluation of the CCCs, 89% of their summary scores were documented as superior during Year 1 and 94% as superior during Year 2. Six themes emerged from the impressionistic analysis in Year 1: confidentiality and "community" disclosure; roles and responsibilities; logistics; clinical care partnership; antiretroviral adherence; and PDA issues. At the end of the trial, of those patients not lost to follow up, 64% (56 of 87) in the intervention and 52% (58 of 103) in the control group were willing to continue in the programme (p = 0.26). CONCLUSION: We found that an antiretroviral treatment delivery model that shifted patient monitoring and antiretroviral dispensing tasks into the community by HIV infected patients was both acceptable and feasible. TRIAL REGISTRATION: ClinicalTrials.gov ID NCT00371540. PMID- 19788756 TI - Candidemia on presentation to the hospital: development and validation of a risk score. AB - INTRODUCTION: Candidemia results in substantial morbidity and mortality, especially if initial antifungal therapy is delayed or is inappropriate; however, candidemia is difficult to diagnose because of its nonspecific presentation. METHODS: To develop a risk score for identifying hospitalized patients with candidemia, we performed a retrospective analysis of a large database of 176 acute-care hospitals in the United States. We studied 64,019 patients with bloodstream infection (BSI) on presentation from 2000 through 2005 (derivation cohort) and 24,685 from 2006 to 2007 (validation cohort). We used recursive partitioning (RPART) to identify the best discriminators for Candida as the cause of BSI. We compared three sets of models (equal-weight, unequal-weight, vs full model with additional variables from logistic regression model) for sensitivity analysis. RESULTS: The RPART identified 6 variables as the best discriminators: age < 65 years, temperature 0.10, indicating predicted and observed candidemia rates did not differ significant across the 7 risk stratus). The full model with 16 risk factors had slightly higher AUROCs (0.74 versus 0.73 for derivation versus validation); however, 7 variables were no longer significant in the recalibrated model for the validation cohort, indicating that the additional items did not materially enhance the model. CONCLUSIONS: A simple equal-weight risk score differentiated patients' risk for candidemia in a graded fashion upon hospital presentation. PMID- 19788757 TI - Phenolic compounds in ectomycorrhizal interaction of lignin modified silver birch. AB - BACKGROUND: The monolignol biosynthetic pathway interconnects with the biosynthesis of other secondary phenolic metabolites, such as cinnamic acid derivatives, flavonoids and condensed tannins. The objective of this study is to evaluate whether genetic modification of the monolignol pathway in silver birch (Betula pendula Roth.) would alter the metabolism of these phenolic compounds and how such alterations, if exist, would affect the ectomycorrhizal symbiosis. RESULTS: Silver birch lines expressing quaking aspen (Populus tremuloides L.) caffeate/5-hydroxyferulate O-methyltransferase (PtCOMT) under the 35S cauliflower mosaic virus (CaMV) promoter showed a reduction in the relative expression of a putative silver birch COMT (BpCOMT) gene and, consequently, a decrease in the lignin syringyl/guaiacyl composition ratio. Alterations were also detected in concentrations of certain phenolic compounds. All PtCOMT silver birch lines produced normal ectomycorrhizas with the ectomycorrhizal fungus Paxillus involutus (Batsch: Fr.), and the formation of symbiosis enhanced the growth of the transgenic plants. CONCLUSION: The down-regulation of BpCOMT in the 35S PtCOMT lines caused a reduction in the syringyl/guaiacyl ratio of lignin, but no significant effect was seen in the composition or quantity of phenolic compounds that would have been caused by the expression of PtCOMT under the 35S or UbB1 promoter. Moreover, the detected alterations in the composition of lignin and secondary phenolic compounds had no effect on the interaction between silver birch and P. involutus. PMID- 19788759 TI - Infective endocarditis caused by Salmonella enteritidis in a dialysis patient: a case report and literature review. AB - BACKGROUND: Infective endocarditis is significantly more common in haemodialysis patients as compared with the general population, the causative pathogen is generally Staphylococcus aureus; there have been no previously reported cases of infective endocarditis caused by a Salmonella species in haemodialysis patients. CASE PRESENTATION: We report the case of a 68 year-old woman on haemodialysis who developed infective endocarditis as a result of Salmonella enteritidis. Although we treated the patient with ceftriaxone combined with ciprofloxacin, infective endocarditis was not detected early enough and unfortunately developed into cerebral septic emboli, which ultimately resulted in death. CONCLUSION: Although there are several reports that Salmonella endocarditis without cardiac failure can be successfully treated with antibiotics alone, early surgical intervention is essential for some cases to prevent life-threatening complications. Transesophageal echocardiography should be performed in any patient with high clinical suspicion of infective endocarditis. To the best of our knowledge, this is the first case-report of Salmonella endocarditis in a haemodialysis patient. PMID- 19788758 TI - Chemoresistance acquisition induces a global shift of expression of aniogenesis associated genes and increased pro-angogenic activity in neuroblastoma cells. AB - BACKGROUND: Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. RESULTS: Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated genes significantly differs between chemosensitive and chemoresistant neuroblastoma cells. A subsequent systematic analysis of a panel of 14 chemosensitive and chemoresistant neuroblastoma cell lines in vitro and in animal experiments indicated a consistent shift to a more pro-angiogenic phenotype in chemoresistant neuroblastoma cells. The molecular mechanisms underlying increased pro-angiogenic activity of neuroblastoma cells are individual and differ between the investigated chemoresistant cell lines. Treatment of animals carrying doxorubicin-resistant neuroblastoma xenografts with doxorubicin, a cytotoxic drug known to exert anti-angiogenic activity, resulted in decreased tumour vessel formation and growth indicating chemoresistance associated enhanced pro-angiogenic activity to be relevant for tumour progression and to represent a potential therapeutic target. CONCLUSION: A bioinformatics approach allowed to identify a relevant chemoresistance-associated shift in neuroblastoma cell biology. The chemoresistance-associated enhanced pro angiogenic activity observed in neuroblastoma cells is relevant for tumour progression and represents a potential therapeutic target. PMID- 19788761 TI - Expression of active human sialyltransferase ST6GalNAcI in Escherichia coli. AB - BACKGROUND: The presence of terminal, surface-exposed sialic acid moieties can greatly enhance the in vivo half-life of glycosylated biopharmaceuticals and improve their therapeutic efficacy. Complete and homogeneous sialylation of glycoproteins can be efficiently performed enzymically in vitro but this process requires large amounts of catalytically active sialyltransferases. Furthermore, standard microbial hosts used for large-scale production of recombinant enzymes can only produce small quantities of glycosyltransferases of animal origin, which lack catalytic activity. RESULTS AND CONCLUSION: In this work, we have expressed the human sialyltransferase ST6GalNAc I (ST6), an enzyme that sialylates O-linked glycoproteins, in Escherichia coli cells. We observed that wild-type bacterial cells are able to produce only very small amounts of soluble ST6 enzyme. We have found, however, that engineered bacterial strains which possess certain types of oxidative cytoplasm or which co-express the molecular chaperones/co-chaperones trigger factor, DnaK/DnaJ, GroEL/GroES, and Skp, can produce greatly enhanced amounts of soluble ST6. Furthermore, we have developed a novel high-throughput assay for the detection of sialyltransferase activity and used it to demonstrate that the bacterially expressed ST6 enzyme is active and able to transfer sialic acid onto a desialylated O-glycoprotein, bovine submaxillary mucin. To the best of our knowledge, this is the first example of expression of active human sialyltransferase in bacteria. This system may be used as a starting point for the evolution of sialyltransferases with better expression characteristics or altered donor/acceptor specificities. PMID- 19788760 TI - Anti-inflammatory and arthritic effects of thiacremonone, a novel sulfur compound isolated from garlic via inhibition of NF-kappaB. AB - INTRODUCTION: Sulfur compounds isolated from garlic exert anti-inflammatory properties. We recently isolated thiacremonone, a novel sulfur compound from garlic. Here, we investigated the anti-inflammatory and arthritis properties of thiacremonone through inhibition of NF-kappaB since NF-kappaB is known to be a target molecule of sulfur compounds and an implicated transcription factor regulating inflammatory response genes. METHODS: The anti-inflammatory and arthritis effects of thiacremone in in vivo were investigated in 12-O tetradecanoylphorbol-13-acetate-induced ear edema, carrageenan and mycobacterium butyricum-induced inflammatory and arthritis models. Lipopolysaccharide-induced nitric oxide (NO) production was determined by Griess method. The DNA binding activity of NF-kappaB was investigated by electrophoretic mobility shift assay. NF-kappaB and inducible nitric oxide synthetase (iNOS) transcriptional activity was determined by luciferase assay. Expression of iNOS and cyclooxygenase-2 (COX 2) was determined by western blot. RESULTS: The results showed that topical application of thiacremonone (1 or 2 microg/ear) suppressed the 12-O tetradecanoylphorbol-13-acetate-induced (1 microg/ear) ear edema. Thiacremonone (1-10 mg/kg) administered directly into the plantar surface of hind paw also suppressed the carrageenan (1.5 mg/paw) and mycobacterium butyricum (2 mg/paw) induced inflammatory and arthritic responses as well as expression of iNOS and COX-2, in addition to NF-kappaB DNA-binding activity. In further in vitro study, thiacremonone (2.5-10 microg/ml) inhibited lipopolysaccharide (LPS, 1 microg/ml) induced nitric oxide (NO) production, and NF-kappaB transcriptional and DNA binding activity in a dose dependent manner. The inhibition of NO by thiacremonone was consistent with the inhibitory effect on LPS-induced inducible nitric oxide synthase (iNOS) and COX-2 expression, as well as iNOS transcriptional activity. Moreover, thiacremonone inhibited LPS-induced p50 and p65 nuclear translocation, resulting in an inhibition of the DNA binding activity of the NF-kappaB. These inhibitory effects on NF-kappaB activity and NO generation were suppressed by reducing agents dithiothreitol (DTT) and glutathione, and were abrogated in p50 (C62S)-mutant cells, suggesting that the sulfhydryl group of NF-kappaB molecules may be a target of thiacremonone. CONCLUSIONS: The present results suggested that thiacremonone exerted its anti inflammatory and anti-arthritic properties through the inhibition of NF-kappaB activation via interaction with the sulfhydryl group of NF-kappaB molecules, and thus could be a useful agent for the treatment of inflammatory and arthritic diseases. PMID- 19788764 TI - Audit of short term outcomes of surgical and medical second trimester termination of pregnancy. AB - BACKGROUND: As comparisons of modern medical and surgical second trimester termination of pregnancy (TOP) are limited, and the optimum method of termination is still debated, an audit of second trimester TOP was undertaken, with the objective of comparing the outcomes of modern medical and surgical methods. METHODS: All cases of medical and surgical TOP between the gestations of 13 and 20 weeks from 1st January 2007 to 30th June 2008, among women residing in the local health board district, a tertiary teaching hospital in an urban setting, were identified by a search of ICD-10 procedure codes (surgical terminations) and from a ward database (medical terminations). Retrospective review of case notes was undertaken. A total of 184 cases, 51 medical and 133 surgical TOP, were identified. Frequency data were compared using Chi-squared or Fischer's Exact tests as appropriate and continuous data are presented as mean and standard deviation if normally distributed or median and interquartile range if non parametric. RESULTS: Eighty-one percent of surgical terminations occurred between 13 to 16 weeks gestation, while 74% of medical terminations were performed between 17 to 20 weeks gestation. The earlier surgical TOP occurred in younger women and were more often indicated for maternal mental health. Sixteen percent of medical TOP required surgical delivery of the placenta. Evacuation of retained products was required more often after medical TOP (10%) than after surgical TOP (1%). Other serious complications were rare. CONCLUSION: Both medical and surgical TOP are safe and effective for second trimester termination. Medical TOP tend to be performed at later gestations and are associated with a greater likelihood of manual removal of the placenta and delayed return to theatre for retained products. This case series does not address long term complications. PMID- 19788763 TI - An evaluation of the sensitivity of acute flaccid paralysis surveillance for poliovirus infection in Australia. AB - BACKGROUND: World Health Organization (WHO) targets for acute flaccid paralysis (AFP) surveillance, including the notification of a minimum rate of AFP among children, are used to assess the adequacy of AFP surveillance for the detection of poliovirus infection. Sensitive surveillance for poliovirus infection in both developed and developing countries is essential to support global disease eradication efforts. We applied recently developed methods for the quantitative evaluation of disease surveillance systems to evaluate the sensitivity of AFP surveillance for poliovirus infection in Australia. METHODS: A scenario tree model which accounted for administrative region, age, population immunity, the likelihood of AFP, and the probability of notification and stool sampling was used to assess the sensitivity of AFP surveillance for wild poliovirus infection among children aged less than 15 years in Australia. The analysis was based on historical surveillance data collected between 2000 and 2005. We used a surveillance time period of one month, and evaluated the ability of the surveillance system to detect poliovirus infection at a prevalence of 1 case per 100 000 persons and 1 case per million persons. RESULTS: There was considerable variation in the sensitivity of AFP surveillance for poliovirus infection among Australian States and Territories. The estimated median sensitivity of AFP surveillance in Australia among children aged less than 15 years was 8.2% per month at a prevalence of 1 case per 100,000 population, and 0.9% per month at a prevalence of 1 case per million population. The probability that Australia is free from poliovirus infection given negative surveillance findings following 5 years of continuous surveillance was 96.9% at a prevalence of 1 case per 100,000 persons and 56.5% at a prevalence of 1 case per million persons. CONCLUSION: Given the ongoing risk of poliovirus importation prior to global eradication, long term surveillance is required to provide a high degree of confidence in freedom from poliovirus infection in Australia, particularly if a low prevalence of infection is assumed. Adherence to the WHO surveillance targets would considerably improve the sensitivity of surveillance for poliovirus infection in Australia. PMID- 19788762 TI - DArT markers: diversity analyses, genomes comparison, mapping and integration with SSR markers in Triticum monococcum. AB - BACKGROUND: Triticum monococcum (2n = 2x = 14) is an ancient diploid wheat with many useful traits and is used as a model for wheat gene discovery. DArT (Diversity Arrays Technology) employs a hybridisation-based approach to type thousands of genomic loci in parallel. DArT markers were developed for T. monococcum to assess genetic diversity, compare relationships with hexaploid genomes, and construct a genetic linkage map integrating DArT and microsatellite markers. RESULTS: A DArT array, consisting of 2304 hexaploid wheat, 1536 tetraploid wheat, 1536 T. monococcum as well as 1536 T. boeoticum representative genomic clones, was used to fingerprint 16 T. monococcum accessions of diverse geographical origins. In total, 846 polymorphic DArT markers were identified, of which 317 were of T. monococcum origin, 246 of hexaploid, 157 of tetraploid, and 126 of T. boeoticum genomes. The fingerprinting data indicated that the geographic origin of T. monococcum accessions was partially correlated with their genetic variation. DArT markers could also well distinguish the genetic differences amongst a panel of 23 hexaploid wheat and nine T. monococcum genomes. For the first time, 274 DArT markers were integrated with 82 simple sequence repeat (SSR) and two morphological trait loci in a genetic map spanning 1062.72 cM in T. monococcum. Six chromosomes were represented by single linkage groups, and chromosome 4Am was formed by three linkage groups. The DArT and SSR genetic loci tended to form independent clusters along the chromosomes. Segregation distortion was observed for one third of the DArT loci. The Ba (black awn) locus was refined to a 23.2 cM region between the DArT marker locus wPt-2584 and the microsatellite locus Xgwmd33 on 1Am; and the Hl (hairy leaf) locus to a 4.0 cM region between DArT loci 376589 and 469591 on 5Am. CONCLUSION: DArT is a rapid and efficient approach to develop many new molecular markers for genetic studies in T. monococcum. The constructed genetic linkage map will facilitate localisation and map-based cloning of genes of interest, comparative mapping as well as genome organisation and evolution studies between this ancient diploid species and other crops. PMID- 19788765 TI - A developing country response to Lavery et al. "In global health research, is it legitimate to stop clinical trials early on account of their opportunity costs?". AB - BACKGROUND: A recent paper presents an argument and mechanism for the possible stopping of clinical trials early based on opportunity costs. DISCUSSION: Although we agree that the costs and opportunity costs of clinical trials need to be reduced wherever possible, we raise concerns about the motivation and mechanism for stopping clinical trials early raised by Lavery et al. SUMMARY: We argue that there are already enough acceptable criteria and actors in the clinical trials arena to justify early stoppage of clinical trials, and argue that factors other than efficacy need to be carefully considered, especially in developing country contexts. PMID- 19788766 TI - From the Editor. PMID- 19788767 TI - The Congress of Vienna. PMID- 19788768 TI - Reappraisal in the eighth life cycle stage: a theoretical psychoeducational intervention in elderly patients with cancer. AB - Elderly patients with cancer face unique physical and psychiatric challenges in coping with their illness. Optimal psychosocial therapy for older cancer patients requires recognizing certain enhanced psychological capacities such as coping better with illness, which is associated with older age. This strength can be combined with the most appropriate cognitive coping strategies to develop a model intervention. This paper describes such a model, which integrates Erik Erikson's eighth and final psychosocial developmental life stage, in which the task is to achieve ego integrity (equanimity) or to experience despair (sadness, regrets), with Susan Folkman's cognitive coping paradigm, which utilizes reappraisal. This theoretical model addresses older cancer patients who are struggling with depression, isolation, and despair related to aging and illness, and utilizes cognitive reappraisal in a group setting to foster relatedness, acceptance of illness, and a sense of meaningful integration. PMID- 19788769 TI - Adjusting to pancreatic cancer: perspectives from first-degree relatives. AB - OBJECTIVE: The combination of a difficult early diagnosis, few treatment options, and high mortality rate could make the experience of pancreatic cancer different from the experience of other cancers, both for patients and families. To design effective interventions for families with a diagnosis of pancreatic cancer, there is need for a model of family members' adjustment to cancer that is specific to these unique aspects of pancreatic cancer. METHOD: Trained clinical interviewers and a genetic counselor conducted phone interviews with 22 first-degree relatives parents, siblings, and offspring-from a pool of participating family members. The interview transcripts were analyzed using qualitative coding methods. RESULTS: Participants expressed both similar and different themes compared with other literature on adjustment to cancer. Relatives struggled through both the initial diagnosis and its aftermath, seeking to balance their own strong feelings with the needs of the ailing family member. Support systems were identified as very important, regardless of the source of the support, and those without them reported more intense difficulties. Many family members felt that everything was happening too fast to slow down and process what was going on. SIGNIFICANCE OF RESULTS: Pancreatic cancer families may be unable to cope by taking one day at a time and must find other ways of dealing with stress. Also, the compressed timeline between diagnosis and death may heighten certain coping behaviors, such as the reevaluation of one's priorities. PMID- 19788770 TI - Quality of life measures (EORTC QLQ-C30 and SF-36) as predictors of survival in palliative colorectal and lung cancer patients. AB - OBJECTIVE: Self-reported health-related quality of life (HRQoL) is an important predictor of survival alongside clinical variables and physicians' prediction. This study assessed whether better prediction is achieved using generic (SF-36) HRQoL measures or cancer-specific (EORTC QLQ-C30) measures that include symptoms. METHOD: Fifty-four lung and 46 colorectal patients comprised the sample. Ninety four died before study conclusion. EORTC QLQ-C30 and SF-36 scores and demographic and clinical information were collected at baseline. Follow-up was 5 years. Deaths were flagged by the Office of National Statistics. Cox regression survival analyses were conducted. Surviving cases were censored in the analysis. RESULTS: Univariate analyses showed that survival was significantly associated with better EORTC QLQ-C30 physical functioning, role functioning, and global health and less dyspnea and appetite loss. For the SF-36, survival was significantly associated with better emotional role functioning, general health, energy/vitality, and social functioning. The SF-36 summary score for mental health was significantly related to better survival, whereas the SF-36 summary score for physical health was not. In the multivariate analysis, only the SF-36 mental health summary score remained an independent, significant predictor, mainly due to considerable intercorrelations between HRQoL scales. However, models combining the SF-36 mental health summary score with diagnosis explained a similar amount of variance (12%-13%) as models combining diagnosis with single scale SF-36 Energy/Vitality or EORTC QLQ-C30 Appetite Loss. SIGNIFICANCE OF RESULTS: HRQoL contributes significantly to prediction of survival. Generic measures are at least as useful as disease-specific measures including symptoms. Intercorrelations between HRQoL variables and between HRQoL and clinical variables makes it difficult to identify prime predictors. We need to identify variables that are as independent of each other as possible to maximize predictive power and produce more consistent results. PMID- 19788772 TI - The psychological responses of outpatient breast cancer patients before and during first medical consultation. AB - OBJECTIVE: The purpose of this study was to qualitatively examine the content of the psychological responses in interviews with breast cancer outpatients receiving initial medical consultation. METHOD: The participants were 180 people who visited the breast cancer outpatient clinic at Kitasato University Hospital between November 2004 and August 2005. The remaining 176 participants (39 breast cancer patients and 137 benign tumor patients; average age +/- SD: 50.7 +/- 12.4 years) were analyzed. Two clinical psychologists carried out the interview, asking the participants to speak freely about their anxieties, worries, thoughts, and feelings up until the medical examination. This study used a content analysis of interviews to chronologically examine psychological response of cancer patients seeking medical consultation at three points in time. RESULTS: Patients at the time of their first outpatient breast cancer consultation experience negative feelings before the examination, directly influenced by the suspicion of cancer. These include anxiety and worries, fear, evasion, depression, and impatience. These tendencies do not change at the time of consultation. However, in addition to negative feelings, some people also possess positive feelings, either simultaneously or at a different point in time. Further, many patients tend to talk at length about psychological responses before seeking treatment, understanding the process they went through to come to seek treatment as an important event. SIGNIFICANCE OF RESULTS: It is important for medical workers to bear in mind the psychological conflicts that patients may undergo before seeking treatment and ensure that sufficient communication takes place. PMID- 19788771 TI - Associations with worry about dying and hopelessness in ambulatory ovarian cancer patients. AB - OBJECTIVE: Women with ovarian cancer face a poor prognosis, with prolonged periods of treatment but relatively high levels of physical functioning. Their thoughts and feelings regarding the prospect of dying are complex and have not been adequately studied. Various demographic, medical and psychosocial factors were examined to determine their independent associations with fear of dying and hopelessness in a cross-sectional design. METHOD: Two hundred fifty-four ovarian cancer patients were assessed at the beginning of a new chemotherapy regimen. Separate logistic regressions were performed for worry about dying and loss of hope. For each analysis, psychosocial variables were entered after the demographic and medical variables to determine whether the psychosocial variables had an independent association with the respective outcome. RESULTS: Fifty-five percent of the sample acknowledged fear of dying, and 31.6% acknowledged loss of hope in the fight against their illness. Being younger (p = .001), being of non Hispanic White ethnicity (p = .026), and having poorer physical well-being (p = .000) were significantly associated with worry about dying after controlling for all other variables in the model. Regarding loss of hope, depressive symptoms (p = .002), lack of social support/well-being (p = .001), and number of treatments (p = .04) were significant. SIGNIFICANCE OF RESULTS: This is one of the largest studies to examine end-of-life concerns in a sample of advanced cancer patients. Our results underscore the importance of demographic and psychosocial variables in the examination of ovarian cancer patients' end-of-life concerns. Their fears and concerns should be openly acknowledged, even when the clinical focus is still on curative treatment. PMID- 19788773 TI - Development and validation of the Family Decision-Making Self-Efficacy Scale. AB - OBJECTIVE: Several studies have reported high levels of distress in family members who have made health care decisions for loved ones at the end of life. A method is needed to assess the readiness of family members to take on this important role. Therefore, the purpose of this study was to develop and validate a scale to measure family member confidence in making decisions with (conscious patient scenario) and for (unconscious patient scenario) a terminally ill loved one. METHODS: On the basis of a survey of family members of patients with amyotrophic lateral sclerosis (ALS) enriched by in-depth interviews guided by Self-Efficacy Theory, we developed six themes within family decision making self efficacy. We then created items reflecting these themes that were refined by a panel of end-of-life research experts. With 30 family members of patients in an outpatient ALS and a pancreatic cancer clinic, we tested the tool for internal consistency using Cronbach's alpha and for consistency from one administration to another using the test-retest reliability assessment in a subset of 10 family members. Items with item to total scale score correlations of less than .40 were eliminated. RESULTS: A 26-item scale with two 13-item scenarios resulted, measuring family self-efficacy in decision making for a conscious or unconscious patient with a Cronbach's alphas of .91 and .95, respectively. Test-retest reliability was r = .96, p = .002 in the conscious senario and r = .92, p = .009 in the unconscious scenario. SIGNIFICANCE OF RESULTS: The Family Decision-Making Self-Efficacy Scale is valid, reliable, and easily completed in the clinic setting. It may be used in research and clinical care to assess the confidence of family members in their ability to make decisions with or for a terminally ill loved one. PMID- 19788774 TI - Validation of the Demoralization Scale in an Irish advanced cancer sample. AB - OBJECTIVE: This article presents a validation study of the Demoralization Scale, a 24-item, 5-point response questionnaire developed by Kissane et al. in 2004 to assess demoralization in advanced cancer patients. METHOD: One hundred Irish inpatients with advanced palliative cancer completed the Demoralization Scale and measures of depression, hopelessness, quality of life, and personal hopefulness. RESULTS: Principal component analysis of the Demoralization Scale yielded four similar factors found by Kissane et al. (2004), namely, loss of meaning, dysphoria, disheartenment, and sense of failure. A new factor, the hopelessness factor, was also found in the current study. The reliability of the five factors was good, ranging from .72 to .93. Contrary to the findings of Kissane et al.'s (2004) study, divergent validity of the Demoralization Scale was not supported. Demoralized patients were significantly more likely to be depressed than those that did not score highly on the Demoralization Scale. In addition, this study found significantly lower levels of demoralization in general compared with Kissane et al.'s (2004) study. SIGNIFICANCE OF RESULTS: The results of the current study show that, in an Irish palliative care context, demoralization is not differentiated from depression. Additional factor analytic studies are needed to validate the Demoralization Scale. PMID- 19788775 TI - Attitudes of Quebec doctors toward sedation at the end of life: an exploratory study. AB - OBJECTIVE: The induction of sedation at the end of life is a much debated practice and not very documented. The goal of this study was to explore the practice from both a clinical and ethical point of view. METHODS: Data were collected through semistructured interviews with 19 Quebec physicians working in palliative care. RESULTS: Doctors' first priority was their patients, not patients' families. Clinically, the therapeutic aim of sedation was strictly to relieve suffering on the part of the patient. Ethically, getting the patient's consent was imperative. The family's consent was only required in cases of incapacity. Generally, sedation and euthanasia were seen as two distinct practices. SIGNIFICANCE OF THE RESEARCH: There are still very few guidelines regarding end-of-life sedation in Quebec, and its normative framework is more implicit than explicit. It should be noted that most of the respondents regarded sedation and euthanasia as two distinct practices. PMID- 19788776 TI - Perspectives on palliative care in Lebanon: knowledge, attitudes, and practices of medical and nursing specialties. AB - OBJECTIVE: Our objective was to determine the knowledge, attitudes, and practices of physicians and nurses on Palliative Care (PC) in Lebanon, across specialties. METHOD: We performed a cross-sectional descriptive survey using a self administered questionnaire; the total number of completed and returned questionnaires was 868, giving a 23% response rate, including 74.31% nurses (645) and 25.69% physicians (223). RESULTS: Significant differences were found between medical and surgical nurses and physicians concerning their perceptions of patients' and families' outbursts, concerns, and questions. Knowledge scores were statistically associated with practice scores and degree. Practice scores were positively associated with continuing education in PC, exposure to terminally ill patients, and knowledge and attitude scores. Acute critical care and oncology were found to have lower practice scores than other specialties. SIGNIFICANCE OF RESULTS: Formal education in palliative care and development of palliative care services are very much needed in Lebanon to provide holistic care to terminally ill patients. PMID- 19788777 TI - International comparison study on the primary concerns of terminally ill cancer patients in short-term life review interviews among Japanese, Koreans, and Americans. AB - OBJECTIVE: The aim of this study was to investigate the primary concerns of terminally ill cancer patients in a Short-Term Life Review among Japanese, Koreans, and Americans to develop intervention programs to be tailored to patients in other countries. METHOD: Twenty Japanese, 16 Korean, and 7 American terminally ill cancer patients who were in the hospice wards of general Christian hospitals in each country participated in this study. Medical staff members (nurses, social workers, clinical psychologists) performed Short-Term Life Review Interviews with each patient. Patients reviewed their lives in the first session, the interviewers made simple albums for each patient in the week following the first session, and patients and interviewers then confirmed the contents of the album. The treatment period was 1 week. Measurement instruments included the Functional Assessment Chronic Illness Therapy-Spiritual (FACIT-Sp) and the Hospital Anxiety and Depression Scale (HADS). The contents of each interview session were transcribed, and correspondence analysis and a significance test were conducted on these data to select characteristic words or phrases. RESULTS: Using the FACIT-Sp scores, the following concerns were chosen, in descending order of frequency. In Japan, primary concerns consisted of such ideas as "good human relationships and transcendence," "achievements and satisfaction," "good memories and important things," and "bitter memories." In Korea, "religious life," "right behavior for living," "strong consideration for children and will," and "life for living" were primary concerns. In the United States, "love, pride, will to children," "good, sweet memories," and "regret and a feeling of loss" were primary concerns. SIGNIFICANCE OF RESULTS: We clarify the differences among the primary concerns from the Short-Term Life Reviews, arguing that we can improve the spiritual well-being of terminally ill cancer patients by focusing on the primary concerns within each country. PMID- 19788778 TI - Providing care and sharing expertise: reflections of nurse-specialists in palliative home care. AB - OBJECTIVE: This study explored the experiences, perspectives, and reflections of five nurse-specialists in palliative home care, whose dual role includes caring for patients in their daily practice as well as sharing their knowledge, skills, expertise, and experiences with other home care nurses in the community. METHODS: A qualitative research design, incorporating face-to-face semistructured interviews, was used. Interviews were based on open-ended questions such as: "What is your experience in providing palliative home care to patients and their families? How do you feel about sharing your expertise and experiences with home care nurses?" Data were content analyzed using the constant comparative method. RESULTS: Three major themes and a number of subthemes emerged: (1) acknowledging one's own limitations and humanness: (a) calling for backup, (b) learning as we go along, (c) coping with emotional demands, and (d) interacting with family members; (2) building a collaborative partnership: (a) working collaboratively, (b) sharing information, (c) guiding home care nurses, and (d) being nonjudgmental; and (3) teamwork and implementing palliative home care teams. SIGNIFICANCE OF RESULTS: Nurse-specialists play a key role in palliative home care as both carers and as resources of expert knowledge for other home care nurses caring for palliative patients. As the population ages, the health care system will be faced with increasing requests for high-quality palliative home care. The results of this study demonstrate that, from the perspective of the nurse-specialists of NOVA-Montreal (a nonprofit social and health service organization), nurse-specialists can work collaboratively with home care nurses to improve patients' quality of care and their quality of life. Moreover, patients and their families would benefit from the more widespread establishment of palliative care teams within community health organizations. PMID- 19788779 TI - Hope in palliative care: an integrative review. AB - OBJECTIVE: The objective of this review is to describe the current status of research on hope in palliative care. METHODS: Integrative review was conducted to determine current knowledge on the topic. CINAHL and PubMed MEDLINE databases were used to find the articles relevant to this review. The data consisted of 34 articles on hope and palliative care published in peer-reviewed journals. A qualitative approach utilizing content analysis was used in this review. RESULTS: There are at least two overarching themes of patients' hope in the palliative context: "living with hope" and "hoping for something" which however are not separate contents. Several instruments for measuring hope in a palliative context have been produced. However, future research is needed to gather further validity evidence for these instruments. Factors related to patients, other people (e. g. significant others), illness, care and context contribute to or threaten patient hope. Hope of the significant other was defined as an inner force. However, the main concern for caregivers was "hanging on to hope" in spite of eroding effects on hope caused by different factors, for example in the health care system. Also significant others' hope in a palliative care context has been measured, but the results of the studies appear inconsistent. Nurses' reflection in action, affirmation of the patient's worth, working with the patient, considering the patient in a holistic sense were the main hope-engendering interventions generated from this review. SIGNIFICANCE OF THE RESEARCH: Hope is important in both living and dying. The majority of the hope research in a palliative context focuses on patient hope and factors influencing patient hope. Research on hope in significant others and nurses in palliative care is scant. More research is needed about the factors threatening patient hope, hope in significant others, and interventions to engender hope in palliative and their outcomes. PMID- 19788780 TI - Complications. PMID- 19788781 TI - Regression of left ventricular dilation after percutaneous closure of a large intralobar pulmonary sequestration. AB - We describe an infant of 8 months who presented with left ventricular dilation due to an extensive intralobar sequestration of the right lung. The pulmonary sequestration was associated with a patent arterial duct and a right aortic arch. Percutaneous closure of the anomalous aberrant artery feeding the sequestrated lung resulted in prompt regression of the left ventricular enlargement. PMID- 19788782 TI - Antibody-based therapy of leukaemia. AB - Over the past decade, monoclonal antibodies have dramatically impacted the treatment of haematological malignancies, as evidenced by the effect of rituximab on the response rate and survival of patients with follicular and diffuse large B cell non-Hodgkin's lymphoma. Currently, only two monoclonal antibodies - the anti CD33 immunotoxin gemtuzumab ozogamicin and the CD52-directed antibody alemtuzumab - are approved for treatment of relapsed acute myeloid leukaemia in older patients and B cell chronic lymphocytic leukaemia, respectively. Although not approved for such treatment, alemtuzumab is also active against T cell prolymphocytic leukaemia, cutaneous T cell lymphoma and Sezary syndrome, and adult T cell leukaemia and lymphoma. In addition, rituximab has demonstrated activity against B cell chronic lymphocytic and hairy cell leukaemia. Monoclonal antibodies targeting CD4, CD19, CD20, CD22, CD23, CD25, CD45, CD66 and CD122 are now being studied in the clinic for the treatment of leukaemia. Here, we discuss how these new antibodies have been engineered to reduce immunogenicity and improve antibody targeting and binding. Improved interactions with Fc receptors on immune effector cells can enhance destruction of target cells through antibody dependent cellular cytotoxicity and complement-mediated cell lysis. The antibodies can also be armed with cellular toxins or radionuclides to enhance the destruction of leukaemia cells. PMID- 19788783 TI - MRSA--happy and thriving in Canada. What's an emergency doctor supposed to do? PMID- 19788785 TI - To divert or not to divert prehospital ST-elevation myocardial infarction: what is the question? PMID- 19788787 TI - Prevalence of and risk factors for methicillin-resistant Staphylococcus aureus skin and soft tissue infection in a Canadian emergency department. AB - OBJECTIVE: We sought to estimate the period prevalence of methicillin-resistant Staphylococcus aureus (MRSA) skin and soft tissue infection (SSTI) and evaluate risk factors for MRSA SSTI in an emergency department (ED) population. METHODS: We carried out a cohort study with a nested case-control design. Patients presenting to our ED with a wound culture and a discharge diagnosis of SSTI between January 2003 and September 2004 were dichotomized as MRSA positive or negative. Fifty patients with MRSA SSTI matched by calendar time to 100 controls with MRSA-negative SSTI had risk factors assessed using multivariate conditional logistic regression. RESULTS: Period prevalence of MRSA SSTI was 54.8% (95% confidence interval [CI] 50.2%-59.4%). The monthly period prevalence increased from 21% in January 2003 to 68% in September 2004 (p < 0.01). Risk factors for MRSA SSTI were injection drug use (IDU) (odds ratio [OR] 4.6, 95% CI 1.4-16.1), previous MRSA infection and colonization (OR 6.4, 95% CI 2.1-19.8), antibiotics in 8 weeks preceding index visit (OR 2.6, 95% CI 1.2-8.1), diabetes mellitus (OR 4.1, 95% CI 1.4-12.1), abscess (OR 5.6, 95% CI 1.8-17.1) and admission to hospital in previous 12 months (OR 2.6, 95% CI 1.1-11.2). CONCLUSION: The period prevalence of MRSA SSTI between January 2003 and September 2004 was 54.8% at our institution. There was a marked increase in the monthly period prevalence from the beginning to the end of the study. Risk factors are IDU, previous MRSA infection and colonization, prescriptions for antibiotics in previous 8 weeks and admission to hospital in the preceding 12 months. On the basis of local prevalence and risk factor patterns, emergency physicians should consider MRSA as a causative agent for SSTI. PMID- 19788788 TI - Community-associated methicillin-resistant Staphylococcus aureus: prevalence in skin and soft tissue infections at emergency departments in the Greater Toronto Area and associated risk factors. AB - OBJECTIVE: Community-associated methicillin-resistant Staphylococcus aureus (CA MRSA), which is caused primarily by the Canadian methicillin-resistant Staphylococcus aureus-10 (CMRSA-10) strain (also known as the USA300 strain) has emerged rapidly in the United States and is now emerging in Canada. We assessed the prevalence, risk factors, microbiological characteristics and outcomes of CA MRSA in patients with purulent skin and soft tissue infections (SSTIs) presenting to emergency departments (EDs) in the Greater Toronto Area. METHODS: Patients with Staphylococcus aureus SSTIs who presented to 7 EDs between Mar. 1 and Jun. 30, 2007, were eligible for inclusion in this study. Antimicrobial susceptibilities and molecular characteristics of MRSA strains were identified. Demographic, risk factor and clinical data were collected through telephone interviews. RESULTS: MRSA was isolated from 58 (19%) of 299 eligible patients. CMRSA-10 was identified at 6 of the 7 study sites and accounted for 29 (50%) of all cases of MRSA. Telephone interviews were completed for 161 of the eligible patients. Individuals with CMRSA-10 were younger (median 34 v. 63 yr, p = 0.002), less likely to report recent antibiotic use (22% v. 67%, p = 0.046) or health care-related risk factors (33% v. 72%, p = 0.097) and more likely to report community-related risk factors (56% v. 6%, p = 0.008) than patients with other MRSA strains. CMRSA-10 SSTIs were treated with incision and drainage (1 patient), antibiotic therapy (3 patients) or both (5 patients), and all resolved. CMRSA-10 isolates were susceptible to clindamycin, tetracycline and trimethoprim sulfamethoxazole. CONCLUSION: CA-MRSA is a significant cause of SSTIs in the Greater Toronto Area, and can affect patients without known community-related risk factors. The changing epidemiology of CA-MRSA necessitates further surveillance to inform prevention strategies and empiric treatment guidelines. PMID- 19788789 TI - A 4-year review of pediatric mental health emergencies in Alberta. AB - OBJECTIVE: We sought to determine and compare rates of pediatric mental health presentations and associated costs in emergency departments (EDs) in Alberta. METHODS: We examined 16 154 presentations by 12 589 patients (patient age < or = 17 yr) between April 2002 and March 2006 using the Ambulatory Care Classification System, a province-wide database for Alberta. The following variables of interest were extracted: patient demographics, discharge diagnoses, triage level, disposition, recorded costs for ED care, and institutional classification and location (i.e., rural v. urban, pediatric v. general EDs). RESULTS: A 15% increase in pediatric mental health presentations was observed during the study period. Youth aged 13-17 years consistently represented the most common age group for first presentation to the ED (83.3%). Of the 16 154 recorded presentations, 21.4% were related to mood disorders and 32.5% to anxiety disorders. Presentations for substance misuse or abuse were the most prevalent reasons for a mental health-related visit (41.3%). Multiple visits accounted for more than one third of all presentations. Presentations for mood disorders were more common in patients with multiple compared with single visits (29.3% v. 16.9%), and substance abuse or misuse presentations were more common in patients with single compared with multiple visits (47.4% v. 30.5%). The total direct ED costs for mental health presentations during the study period was Can$3.5 million. CONCLUSION: This study provides comprehensive data on trends of pediatric mental health presentation, and highlights the costs and return presentations in this population. Psychiatric and medical care provided in the ED for pediatric mental health emergencies should be evaluated to determine quality of care and its relationship with return visits and costs. PMID- 19788790 TI - The impact on patient flow after the integration of nurse practitioners and physician assistants in 6 Ontario emergency departments. AB - OBJECTIVE: We sought to assess the impact of the integration of the new roles of primary health care nurse practitioners (NPs) and physician assistants (PAs) on patient flow, wait times and proportions of patients who left without being seen in 6 Ontario emergency departments (EDs). METHODS: We performed a retrospective review of health records data on patient arrival time, time of initial assessment by a physician, time of discharge from the ED and discharge status. RESULTS: Whether a PA or NP was directly involved in the care of patients or indirectly involved by being on duty, the wait times, lengths of stay and proportion of patients who left without being seen were significantly reduced. When a PA or NP were directly involved in patients' care, patients were 1.6 (95% confidence interval [CI] 1.3-2.1, p < 0.05) and 2.1 (95% CI 1.6-2.8, p < 0.05) times more likely to be seen within the wait time benchmarks, respectively. Lengths of stay were 30.3% (95% CI 21.6%-39.0%, p < 0.01) and 48.8% (95% CI 35.0%-62.7%, p < 0.01) lower when PAs and NPs, respectively, were involved. When PAs and NPs were not on duty, the proportion of patients who left without being seen were 44% (95% CI 31%-63%, p < 0.01) and 71% (95% CI 53%-96%, p < 0.05), respectively. CONCLUSION: The addition of PAs or NPs to the ED team can improve patient flow in medium-sized community hospital EDs. Given the ongoing shortage of physicians, use of alternative health care providers should be considered. These results require validation, as their generalizability to other locations or types of EDs is not known. PMID- 19788791 TI - Prevalence of information gaps for seniors transferred from nursing homes to the emergency department. AB - OBJECTIVE: Information gaps, defined as previously collected information that is not available to the treating physician, have implications for patient safety and system efficiency. For patients transferred to an emergency department (ED) from a nursing home or seniors residence, we determined the frequency and type of clinically important information gaps and the impact of a regional transfer form. METHODS: During a 6-month period, we studied consecutive patients who were identified through the National Ambulatory Care Reporting System database. Patients were over 60 years of age, lived in a nursing home or seniors residence, and arrived by ambulance to a tertiary care ED. We abstracted data from original transfer and ED records using a structured data collection tool. We measured the frequency of prespecified information gaps, which we defined as the failure to communicate information usually required by an emergency physician (EP). We also determined the use of the standardized patient transfer form that is used in Ontario and its impact on the rate of information gaps that occur in our community. RESULTS: We studied 457 transfers for 384 patients. Baseline dementia was present in 34.1% of patients. Important information gaps occurred in 85.5% (95% confidence interval [CI] 82.0%-88.0%) of cases. Specific information gaps along with their relative frequency included the following: the reason for transfer (12.9%), the baseline cognitive function and communication ability (36.5%), vital signs (37.6%), advanced directives (46.4%), medication (20.4%), activities of daily living (53.0%) and mobility (47.7%). A standardized transfer form was used in 42.7% of transfers. When the form was used, information gaps were present in 74.9% of transfers compared with 93.5% of the transfers when the form was not used (p < 0.001). descriptors of the patient's chief complaint were frequently absent (81.0% for head injury [any information about loss of consciousness], 42.4% for abdominal pain and 47.1% for chest pain [any information on location, severity and duration]). CONCLUSION: Information gaps occur commonly when elderly patients are transferred from a nursing home or seniors residence to the ED. A standardized transfer form was associated with a limited reduction in the prevalence of information gaps; even when the form was used, a large percentage of the transfers were missing information. We also determined that the lack of descriptive detail regarding the presenting problem was common. We believe this represents a previously unidentified information gap in the literature about nursing home transfers. Future research should focus on the clinical impact of information gaps. System improvements should focus on educational and regulatory interventions, as well as adjustments to the transfer form. PMID- 19788792 TI - Underuse of prehospital strategies to reduce time to reperfusion for ST-elevation myocardial infarction patients in 5 Canadian provinces. AB - OBJECTIVE: Timely reperfusion therapy for ST-elevation myocardial infarction (STEMI) is an important determinant of outcome, yet targets for time to treatment are frequently unmet in North America. Prehospital strategies can reduce time to reperfusion. We sought to determine the extent to which emergency medical services (EMS) use these strategies in Canada. METHODS: We carried out a cross sectional survey in 2007 of ground EMS operators in British Columbia, Alberta, Ontario, Quebec and Nova Scotia. We focused on the use of 4 prehospital strategies: 1) 12-lead electrocardiogram (ECG), 2) routine expedited emergency department (ED) transfer of STEMI patients (from a referring ED to a percutaneous coronary intervention [PCI] centre), 3) prehospital bypass (ambulance bypass of local EDs to transport patients directly to PCI centres) and 4) prehospital fibrinolysis. RESULTS: Ninety-seven ambulance operators were surveyed, representing 15 681 paramedics serving 97% of the combined provincial populations. Of the operators surveyed, 68% (95% confidence interval [CI] 59% 77%) had ambulances equipped with 12-lead ECGs, ranging from 40% in Quebec to 100% in Alberta and Nova Scotia. Overall, 47% (95% CI 46%-48%) of paramedics were trained in ECG acquisition and 40% (95% CI 39%-41%) were trained in ECG interpretation. Only 18% (95% CI 10%-25%) of operators had prehospital bypass protocols; 45% (95% CI 35%-55%) had protocols for expedited ED transfer. Prehospital fibrinolysis was available only in Alberta. All EMS operators in British Columbia, Alberta and Nova Scotia used at least 1 of the 4 prehospital strategies, and one-third of operators in Ontario and Quebec used 0 of 4. In major urban centres, at least 1 of the 3 prehospital strategies 12-lead ECG acquisition, bypass or expedited transfer was used, but there was considerable variation within and across provinces. CONCLUSION: The implementation of widely recommended prehospital STEMI strategies varies substantially across the 5 provinces studied, and relatively simple existing technologies, such as prehospital ECGs, are underused in many regions. Substantial improvements in prehospital services and better integration with hospital-based care will be necessary in many regions of Canada if optimal times to reperfusion, and associated outcomes, are to be achieved. PMID- 19788793 TI - Prehospital triage and direct transport of patients with ST-elevation myocardial infarction to primary percutaneous coronary intervention centres: a systematic review and meta-analysis. AB - OBJECTIVE: Percutaneous coronary intervention (PCI) appears to be superior to in hospital fibrinolysis for most patients with ST-elevation myocardial infarction (STEMI). However, few hospitals have PCI capability. The optimal prehospital strategy for facilitating rapid coronary reperfusion in STEMI patients is unclear. We sought to determine whether direct transport of adult STEMI patients by emergency medical services to primary PCI centres improves 30-day all-cause mortality when compared with a strategy of transportation to the closest hospital. METHODS: We systematically searched MEDLINE, EMBASE, Cochrane "CENTRAL" database (1980-July 2007) and several other electronic databases. Two authors independently as sessed citations for relevance. Two authors independently abstracted data from included studies. We included studies that, 1) transported patients directly to a PCI-capable centre for primary PCI, 2) had a control group that was transported to the closest hospital and 3) reported outcomes of treatment time intervals, all-cause mortality, reinfarction rate, stroke rate or the frequency of cardiogenic shock. We used a random effects model to provide pooled estimates of relative risk (RR) when data allowed. RESULTS: We identified 2264 citations with the search. Five studies, including 980 STEMI patients, met inclusion criteria, and were clinically heterogeneous and of variable quality. Most studies were European (3/5) and involved physician out-of-hospital care providers. There was a trend toward increased survival with direct transport to primary PCI but this was not statistically significant (RR 0.51, 95% confidence interval [CI] 0.24-1.10). One study reported nonsignificant reductions in reinfarction (RR 0.43, 95% CI 0.11-1.60) and stroke (RR 0.33, 95% CI 0.01-8.06) with direct transport for primary PCI. CONCLUSION: There is insufficient evidence to support the effectiveness of direct transport of patients with STEMI for primary PCI when compared with transportation to the closest hospital. PMID- 19788794 TI - Opposites attract: a case of magnet ingestion. AB - Foreign-body ingestion is relatively common in the pediatric population and most objects pass through the gastrointestinal tract with minimal complications. Popular toy magnetic construction sets have resulted in numerous reports in the literature of serious complications including death following ingestion of multiple magnets. We report a case of a 5-year-old girl who presented to our emergency department with nonbilious vomiting and mild abdominal pain after accidentally ingesting 2 magnets 10 hours apart. Abdominal radiography showed the presence of 2 magnets, and a laparoscopy revealed multiple areas of bowel wall necrosis and perforation requiring subsequent laparotomy for repair of the bowel wall and retrieval of the magnets. This report aims to alert emergency care physicians of the necessity for early surgical referral with any multiple magnet ingestion to prevent severe complications. PMID- 19788795 TI - On becoming "Dr. Mom". PMID- 19788796 TI - If Machiavelli had been an emergency physician--a CJEM interview. PMID- 19788797 TI - Mastoid bone as a new graft material in rhinoplasty. AB - BACKGROUND: The management of certain nasal deformities, especially after prior rhinoplasty, may require grafting material. In this study we describe the use of mastoid bone as a viable and low morbidity autologous graft. METHODS: Mastoid bone was used for nasal augmentation, smoothing dorsal nasal irregularities, or augmentation of radix. Candidates for mastoid bone graft were patients undergoing primary rhinoplasty suffering from low radix or saddle nose deformity and candidates for secondary rhinoplasty suffering from prior overresection of the osteocartilaginous structures. RESULTS: Fifty-six patients met the study criteria. Eighteen patients underwent secondary rhinoplasty and suffered from prior overresection of osteocartilaginous structures and 38 patients underwent primary rhinoplasty. Of these, 18 patients had a low radix and 20 patients had a saddle nose deformity. Follow-up was 6-49 months (mean, 23 months). All cases resulted in an augmented straightened nasal dorsum, increased tip projection, and adjusted radix. There were no cases of graft infection. In two cases the graft was displaced requiring revision. The amount of graft absorption even after 2 years follow-up was acceptable. There were no donor site complications. CONCLUSIONS: The mastoid bone graft provides adequate autologous bone in most cases of primary or revision rhinoplasty. The donor site carries low morbidity and a well camouflaged scar. It is easily accessible especially for the otolaryngologist who is accustomed to operating on the mastoid bone. PMID- 19788799 TI - Using satellite images of environmental changes to predict infectious disease outbreaks. AB - Recent events clearly illustrate a continued vulnerability of large populations to infectious diseases, which is related to our changing human-constructed and natural environments. A single person with multidrug-resistant tuberculosis in 2007 provided a wake-up call to the United States and global public health infrastructure, as the health professionals and the public realized that today's ease of airline travel can potentially expose hundreds of persons to an untreatable disease associated with an infectious agent. Ease of travel, population increase, population displacement, pollution, agricultural activity, changing socioeconomic structures, and international conflicts worldwide have each contributed to infectious disease events. Today, however, nothing is larger in scale, has more potential for long-term effects, and is more uncertain than the effects of climate change on infectious disease outbreaks, epidemics, and pandemics. We discuss advances in our ability to predict these events and, in particular, the critical role that satellite imaging could play in mounting an effective response. PMID- 19788800 TI - Zika virus outside Africa. AB - Zika virus (ZIKV) is a flavivirus related to yellow fever, dengue, West Nile, and Japanese encephalitis viruses. In 2007 ZIKV caused an outbreak of relatively mild disease characterized by rash, arthralgia, and conjunctivitis on Yap Island in the southwestern Pacific Ocean. This was the first time that ZIKV was detected outside of Africa and Asia. The history, transmission dynamics, virology, and clinical manifestations of ZIKV disease are discussed, along with the possibility for diagnostic confusion between ZIKV illness and dengue.The emergence of ZIKV outside of its previously known geographic range should prompt awareness of the potential for ZIKV to spread to other Pacific islands and the Americas. PMID- 19788801 TI - Extrapulmonary infections associated with nontuberculous mycobacteria in immunocompetent persons. AB - Over the past several years, the prevalence of human disease caused by nontuberculous mycobacteria (NTM) has increased. Whether the increase in cases is real or whether more cases are being recognized remains unclear. Despite a considerable increase in knowledge about NTM infections, they still represent a diagnostic and therapeutic challenge for several reasons: 1) pathogenic isolates may be indistinguishable from contaminant or saprophytic isolates; 2) timely and reliable identification of isolates may depend on proper communication between clinicians and laboratory staff; 3) lack of standardized susceptibility testing makes adoption of tailored therapies unrealistic; and 4) lack of treatment guidelines exposes patients to toxic drugs and disappointing outcomes. Laboratory research and multicenter controlled trials are needed to improve diagnosis and treatment of these infections. PMID- 19788802 TI - Etiology of encephalitis in Australia, 1990-2007. AB - Encephalitis is a clinical syndrome commonly caused by emerging pathogens, which are not under surveillance in Australia. We reviewed rates of hospitalization for patients with encephalitis in Australia's most populous state, New South Wales, from January 1990 through December 2007. Encephalitis was the primary discharge diagnosis for 5,926 hospital admissions; average annual hospitalization rate was 5.2/100,000 population. The most commonly identified pathogen was herpes simplex virus (n = 763, 12.9%). Toxoplasma encephalitis and subacute sclerosing panencephalitis showed notable declines. The average annual encephalitis case fatality rate (4.6%) and the proportion of patients hospitalized with encephalitis with no identified pathogen (69.8%, range 61.5%-78.7%) were stable during the study period. The nonnotifiable status of encephalitis in Australia and the high proportion of this disease with no known etiology may conceal emergence of novel pathogens. Unexplained encephalitis should be investigated, and encephalitis hospitalizations should be subject to statutory notification in Australia. PMID- 19788803 TI - Susceptibilities of nonhuman primates to chronic wasting disease. AB - Chronic wasting disease (CWD) is a transmissible spongiform encephalopathy, or prion disease, that affects deer, elk, and moose. Human susceptibility to CWD remains unproven despite likely exposure to CWD-infected cervids. We used 2 nonhuman primate species, cynomolgus macaques and squirrel monkeys, as human models for CWD susceptibility. CWD was inoculated into these 2 species by intracerebral and oral routes. After intracerebral inoculation of squirrel monkeys, 7 of 8 CWD isolates induced a clinical wasting syndrome within 33-53 months. The monkeys' brains showed spongiform encephalopathy and protease resistant prion protein (PrPres) diagnostic of prion disease. After oral exposure, 2 squirrel monkeys had PrPres in brain, spleen, and lymph nodes at 69 months postinfection. In contrast, cynomolgus macaques have not shown evidence of clinical disease as of 70 months postinfection. Thus, these 2 species differed in susceptibility to CWD. Because humans are evolutionarily closer to macaques than to squirrel monkeys, they may also be resistant to CWD. PMID- 19788804 TI - Distant relatives of severe acute respiratory syndrome coronavirus and close relatives of human coronavirus 229E in bats, Ghana. AB - We tested 12 bat species in Ghana for coronavirus (CoV) RNA. The virus prevalence in insectivorous bats (n = 123) was 9.76%. CoV was not detected in 212 fecal samples from Eidolon helvum fruit bats. Leaf-nosed bats pertaining to Hipposideros ruber by morphology had group 1 and group 2 CoVs. Virus concentrations were < or =45,000 copies/100 mg of bat feces. The diversified group 1 CoV shared a common ancestor with the human common cold virus hCoV-229E but not with hCoV-NL63, disputing hypotheses of common human descent. The most recent common ancestor of hCoV-229E and GhanaBt-CoVGrp1 existed in approximately 1686-1800 ad. The GhanaBt-CoVGrp2 shared an old ancestor (approximately 2,400 years) with the severe acute respiratory syndrome-like group of CoV. PMID- 19788805 TI - Predicting phenotype and emerging strains among Chlamydia trachomatis infections. AB - Chlamydia trachomatis is a global cause of blinding trachoma and sexually transmitted infections (STIs). We used comparative genomics of the family Chlamydiaceae to select conserved housekeeping genes for C. trachomatis multilocus sequencing, characterizing 19 reference and 68 clinical isolates from 6 continental/subcontinental regions. There were 44 sequence types (ST). Identical STs for STI isolates were recovered from different regions, whereas STs for trachoma isolates were restricted by continent. Twenty-nine of 52 alleles had nonuniform distributions of frequencies across regions (p<0.001). Phylogenetic analysis showed 3 disease clusters: invasive lymphogranuloma venereum strains, globally prevalent noninvasive STI strains (ompA genotypes D/Da, E, and F), and nonprevalent STI strains with a trachoma subcluster. Recombinant strains were observed among STI clusters. Single nucleotide polymorphisms (SNPs) were predictive of disease specificity. Multilocus and SNP typing can now be used to detect diverse and emerging C. trachomatis strains for epidemiologic and evolutionary studies of trachoma and STI populations worldwide. PMID- 19788806 TI - Increasing incidence of zygomycosis (mucormycosis), France, 1997-2006. AB - We analyzed hospital records to provide a population-based estimate of zygomycosis incidence and trends over a 10-year period at a national level in France. Data showed an increasing incidence from 0.7/million in 1997 to 1.2/million in 2006 (p<0.001). We compared our data with those from the French Mycosis Study Group, a recently established voluntary network of French mycologists coordinated by the National Reference Center for Mycoses and Antifungals. We documented that incidence of zygomycosis increased, particularly in patients with hematologic malignancies or bone marrow transplants. The role of previous exposure to antifungal drugs lacking activity against zygomycetes could explain this increase but does not appear exclusive. Incidence also increased in the population of patients with diabetes mellitus. We conclude that observed trends reflect a genuine increase of zygomycosis cases in at-risk populations. PMID- 19788807 TI - Chicken consumption and use of acid-suppressing medications as risk factors for Campylobacter enteritis, England. AB - In a case-control study of Campylobacter spp. risk factors in England during 2005 2006, we identified recent consumption of commercially prepared chicken as an important risk factor. The risk for illness associated with recent chicken consumption was much lower for persons who regularly ate chicken than in those who did not, which suggests that partial immunologic protection may follow regular chicken preparation or consumption. Chicken-related risk factors accounted for 41% of cases; acid-suppressing medication, for 10%; self-reported past Campylobacter enteritis, 2%; and recent acquisition of a pet dog, 1%. Understanding the risks associated with chicken from different sources will benefit strategies to reduce Campylobacter infections. Better characterization of immune correlates for Campylobacter infection is necessary to assess the relative importance of immunity and behavioral factors in determining risk. PMID- 19788808 TI - Genetic characterization of foot-and-mouth disease viruses, Ethiopia, 1981-2007. AB - Foot-and-mouth disease (FMD) is endemic to sub-Saharan Africa. To further understand its complex epidemiology, which involves multiple virus serotypes and host species, we characterized the viruses recovered from FMD outbreaks in Ethiopia during 1981-2007. We detected 5 of the 7 FMDV serotypes (O, A, C, Southern African Territories [SAT] 1, and SAT 2). Serotype O predominated, followed by serotype A; type C was not recognized after 1983. Phylogenetic analysis of virus protein 1 sequences indicated emergence of a new topotype within serotype O, East Africa 4. In 2007, serotype SAT 1 was detected in Ethiopia and formed a new distinct topotype (IX), and serotype SAT 2 reappeared after an apparent gap of 16 years. The diversity of viruses highlights the role of this region as a reservoir for FMD virus, and their continuing emergence in Ethiopia will greatly affect spread and consequent control strategy of the disease on this continent. PMID- 19788809 TI - Clinical and epidemiologic characteristics of 3 early cases of influenza A pandemic (H1N1) 2009 virus infection, People's Republic of China, 2009. AB - On May 7, 2009, a national network was organized in the People's Republic of China for the surveillance, reporting, diagnosis, and treatment of influenza A pandemic (H1N1) 2009 virus infection (pandemic [H1N1] 2009). Persons with suspected cases are required to report to the Chinese Center for Disease Control and Prevention and the Ministry of Health within 24 hours; the patient's close contacts are then traced and placed in quarantine for 7 days. We report 3 confirmed early cases of pandemic (H1N1) 2009. Two cases were imported from United States; the other was imported from Canada. The patients exhibited fever and signs and other symptoms that were indistinguishable from those of seasonal influenza. Serial virologic monitoring of pharyngeal swabs showed that they were negative for pandemic (H1N1) 2009 virus by real-time reverse transcription-PCR 4 6 days after onset of illness. One close contact whose sample tested positive for pandemic (H1N1) 2009 virus had no symptoms during quarantine. A national network is essential for controlling pandemic (H1N1) 2009. PMID- 19788810 TI - Clinical assessment and improved diagnosis of bocavirus-induced wheezing in children, Finland. AB - Human bocavirus (HBoV) is a widespread respiratory virus. To improve diagnostic methods, we conducted immunoglobulin (Ig) G and IgM enzyme immunoassays with recombinant virus-like particles of HBoV as antigen. Acute-phase and follow-up serum samples from 258 wheezing children and single serum samples from 115 healthy adults in Finland were examined. Our assays had a sensitivity of 97% and a specificity of 99.5%. Of adults, 96% had immunity; none had an acute infection. Of 48 children with serologically diagnosed acute HBoV infections, 45 were viremic and 35 had virus in nasopharyngeal aspirates (NPAs). Of 39 HBoV NPA PCR positive children co-infected with another virus, 64% had a serologically verified HBoV infection. HBoV caused illness of longer duration than rhinovirus and of equal severity to that of respiratory syncytial virus. Among children with bronchiolitis, >25% had acute HBoV infections. Accurate HBoV diagnosis requires serologic analysis or PCR of serum; PCR of NPAs alone is insufficient. PMID- 19788812 TI - Nurses' contacts and potential for infectious disease transmission. AB - Nurses' contacts with potentially infectious persons probably place them at higher risk than the general population for infectious diseases. During an influenza pandemic, illness among nurses might result in staff shortage. We aimed to show the value of individual data from the healthcare sector for mathematical modeling of infectious disease transmission. Using a paper diary approach, we compared nurses' daily contacts (2-way conversation with >2 words or skin-to-skin contact) with those of matched controls from a representative population survey. Nurses (n = 129) reported a median of 40 contacts (85% work related), and controls (n = 129) reported 12 contacts (33% work related). For nurses, 51% of work-related contacts were with patients (74% involving skin-to-skin contact, and 63% lasted < or =15 minutes); 40% were with staff members (29% and 36%, respectively). Our data, used with simulation models, can help predict staff availability and provide information for pandemic preparedness planning. PMID- 19788811 TI - Recent ancestry of Kyasanur Forest disease virus. AB - Kyasanur Forest disease virus (KFDV) is enzootic to India and maintained in ticks, mammals, and birds. It causes severe febrile illness in humans and was first recognized in 1957 associated with a high number of deaths among monkeys in Kyasanur Forest. Genetic analysis of 48 viruses isolated in India during 1957 2006 showed low diversity (1.2%). Bayesian coalescence analysis of these sequences and those of KFDVs from Saudi Arabia and the People's Republic of China estimated that KFDVs have evolved at a mean rate of approximately 6.4 x 10(-4) substitutions/site/year, which is similar to rates estimated for mosquito-borne flaviviruses. KFDVs were estimated to have shared a common ancestor in approximately 1942, fifteen years before identification of the disease in India. These data are consistent with the view that KFD represented a newly emerged disease when first recognized. Recent common ancestry of KFDVs from India and Saudi Arabia, despite their large geographic separation, indicates long-range movement of virus, possibly by birds. PMID- 19788814 TI - Avian bornaviruses in psittacine birds from Europe and Australia with proventricular dilatation disease. AB - To determine whether avian bornaviruses (ABVs) were a factor in proventricular dilatation disease (PDD), we used immunohistochemistry, reverse transcription PCR, and nucleotide sequence analysis to examine paraffin wax-embedded or frozen tissue samples of 31 psittacine birds with this disease. PDD is a fatal disease of psittacine birds associated with nonsuppurative encephalitis and ganglioneuritis of the upper intestinal tract. Tissue samples had been collected from 1999 through 2008 in Austria, Switzerland, Hungary, and Australia. Immunohistochemical demonstration of viral antigen within the brain and vegetative nerve system of the gastrointestinal tract provides strong evidence for a causative role of ABVs in this condition. Partial sequences of nucleoprotein (p40) and matrix protein (gp18) genes showed that virus in most of our cases belonged to the ABV-2 and ABV-4 groups among the 5 genogroups described so far. Viral sequences of 2 birds did not match any of the described sequences and clustered together in a new branch termed ABV-6. PMID- 19788815 TI - Program to eradicate malaria in Sardinia, 1946-1950. AB - During 1946-1950, the Rockefeller Foundation conducted a large-scale experiment in Sardinia to test the feasibility of indigenous vector species eradication. The interruption of malaria transmission did not require vector eradication, but with a goal of developing a new strategy to fight malaria, the choice was made to wage a rapid attack with a powerful new chemical. Costing millions of dollars, 267 metric tons of DDT were spread over the island. Although malaria was eliminated, the main objective, complete eradication of the vector, was not achieved. Despite its being considered almost eradicated in the mid-1940s, malaria 60 years later is still a major public health problem throughout the world, and its eradication is back on the global health agenda. PMID- 19788816 TI - Genetic differences between avian and human isolates of Candida dubliniensis. AB - When Candida dubliniensis isolates obtained from seabird excrement and from humans in Ireland were compared by using multilocus sequence typing, 13 of 14 avian isolates were genetically distinct from human isolates. The remaining avian isolate was indistinguishable from a human isolate, suggesting that transmission may occur between humans and birds. PMID- 19788813 TI - Genetics and pathogenesis of feline infectious peritonitis virus. AB - Feline coronavirus (FCoV) is endemic in feral cat populations and cat colonies, frequently preceding outbreaks of fatal feline infectious peritonitis (FIP). FCoV exhibits 2 biotypes: the pathogenic disease and a benign infection with feline enteric coronavirus (FECV). Uncertainty remains regarding whether genetically distinctive avirulent and virulent forms coexist or whether an avirulent form mutates in vivo, causing FIP. To resolve these alternative hypotheses, we isolated viral sequences from FCoV-infected clinically healthy and sick cats (8 FIP cases and 48 FECV-asymptomatic animals); 735 sequences from 4 gene segments were generated and subjected to phylogenetic analyses. Viral sequences from healthy cats were distinct from sick cats on the basis of genetic distances observed in the membrane and nonstructural protein 7b genes. These data demonstrate distinctive circulating virulent and avirulent strains in natural populations. In addition, 5 membrane protein amino acid residues with functional potential differentiated healthy cats from cats with FIP. These findings may have potential as diagnostic markers for virulent FIP-associated FCoV. PMID- 19788817 TI - Rickettsia parkeri in Amblyomma americanum ticks, Tennessee and Georgia, USA. AB - To determine the geographic distribution of the newly recognized human pathogen Rickettsia parkeri, we looked for this organism in ticks from Tennessee and Georgia, USA. Using PCR and sequence analysis, we identified R. parkeri in 2 Amblyomma americanum ticks. This rickettsiosis may be underdiagnosed in the eastern United States. PMID- 19788818 TI - Phylogeny and disease association of Shiga toxin-producing Escherichia coli O91. AB - The diversity and relatedness of 100 Shiga toxin-producing Escherichia coli O91 isolates from different patients were examined by multilocus sequence typing. We identified 10 specific sequence types (ST) and 4 distinct clonal groups. ST442 was significantly associated with hemolytic uremic syndrome. PMID- 19788819 TI - Human Plasmodium knowlesi infection detected by rapid diagnostic tests for malaria. AB - We describe a PCR-confirmed case of Plasmodium knowlesi infection with a high parasitemia level and clinical signs of severe malaria in a migrant worker from Malaysian Borneo in the Netherlands. Investigations showed that commercially available rapid antigen tests for detection of human Plasmodium infections can detect P. knowlesi infections in humans. PMID- 19788820 TI - Monitoring of putative vectors of bluetongue virus serotype 8, Germany. AB - To identify the vectors of bluetongue virus (BTV) in Germany, we monitored Culicoides spp. biting midges during April 2007-May 2008. Molecular characterization of batches of midges that tested positive for BTV suggests C. obsoletus sensu stricto as a relevant vector of bluetongue disease in central Europe. PMID- 19788821 TI - Coxsackievirus A6 and hand, foot, and mouth disease, Finland. AB - During fall 2008, an outbreak of hand, foot, and mouth disease (HFMD) with onychomadesis (nail shedding) as a common feature occurred in Finland. We identified an unusual enterovirus type, coxsackievirus A6 (CVA6), as the causative agent. CVA6 infections may be emerging as a new and major cause of epidemic HFMD. PMID- 19788822 TI - Hantavirus infection in the Republic of Georgia. AB - We describe a laboratory-confirmed case of hantavirus infection in the Republic of Georgia. Limited information is available about hantavirus infections in the Caucasus, although the infection has been reported throughout Europe and Russia. Increasing awareness and active disease surveillance contribute to our improved understanding of the geographic range of this pathogen. PMID- 19788823 TI - Highly pathogenic avian influenza virus A (H7N3) in domestic poultry, Saskatchewan, Canada, 2007. AB - Epidemiologic, serologic, and molecular phylogenetic methods were used to investigate an outbreak of highly pathogenic avian influenza on a broiler breeding farm in Saskatchewan, Canada. Results, coupled with data from influenza A virus surveillance of migratory waterfowl in Canada, implicated wild birds as the most probable source of the low pathogenicity precursor virus. PMID- 19788824 TI - Merkel cell polyomavirus DNA in persons without merkel cell carcinoma. AB - Merkel cell polyomavirus (MCPyV) DNA was detected in 88% of Merkel cell carcinomas in contrast to 16% of other skin tumors. MCPyV was also found in anogenital and oral samples (31%) and eyebrow hairs (50%) of HIV-positive men and in forehead swabs (62%) of healthy controls. MCPyV thus appears to be widespread. PMID- 19788825 TI - Population-based surveillance for hepatitis C virus, United States, 2006-2007. AB - Surveillance for hepatitis C virus infection in 6 US sites identified 20,285 newly reported cases in 12 months (report rate 69 cases/100,000 population, range 25-108/100,000). Staff reviewed 4 laboratory reports per new case. Local surveillance data can document the effects of disease, support linkage to care, and help prevent secondary transmission. PMID- 19788826 TI - Absence of detectable replication of human bocavirus species 2 in respiratory tract. AB - Human bocavirus (HBoV) commonly infects young children and is associated with respiratory disease; disease associations of the divergent HBoV-2 species are unknown. Frequent HBoV-2 detection in fecal samples indicated widespread circulation in the United Kingdom and Thailand, but its lack of detection among 6,524 respiratory samples indicates likely differences from HBoV-1 in tropism/pathogenesis. PMID- 19788827 TI - Role of rhinovirus C in apparently life-threatening events in infants, Spain. AB - To assess whether infants hospitalized after an apparently life-threatening event had an associated respiratory virus infection, we analyzed nasopharyngeal aspirates from 16 patients. Nine of 11 infants with positive virus results were infected by rhinoviruses. We detected the new genogroup of rhinovirus C in 6 aspirates. PMID- 19788828 TI - Saffold cardiovirus in children with acute gastroenteritis, Beijing, China. AB - To understand Saffold cardiovirus (SAFV) distribution, prevalence, and clinical relevance in China, we retrospectively studied SAFV in children with acute gastroenteritis and found SAFV in 12 (3.2%) of 373. Sequence homology of virus protein 1 genes suggested these strains belong to the SAFV-1 sublineage. SAFVs were found in samples positive for other diarrhea-causing viruses. PMID- 19788829 TI - Human infection with G12 rotaviruses, Germany. AB - Rotavirus group A G12 genotypes were detected in 3 (1.5%) of 198 stool samples positive for human rotavirus. G12P[6] was present in 2 samples, and a mixed G3G12P[8] was found in 1 sample. Phylogenetic analysis of complete open reading frames of all 11 genomic RNA segments proved their Wa-like genogroup affiliation. PMID- 19788830 TI - Trends in US hospital admissions for skin and soft tissue infections. AB - Using data from the 2000-2004 US Healthcare Cost and Utilization Project National Inpatient Sample, we found that total hospital admissions for skin and soft tissue infections increased by 29% during 2000-2004; admissions for pneumonia were largely unchanged. These results are consistent with recent reported increases in community-associated methicillin-resistant Staphylococcus aureus infections. PMID- 19788831 TI - Genomic diversity of oseltamivir-resistant influenza virus A (H1N1), Luxembourg, 2007-08. PMID- 19788832 TI - Tokyo-172 BCG vaccination complications, Taiwan. PMID- 19788833 TI - Reemergence of Bolivian hemorrhagic fever, 2007-2008. PMID- 19788834 TI - Relapsing fever spirochete in seabird tick, Japan. PMID- 19788835 TI - Backyard raccoon latrines and risk for Baylisascaris procyonis transmission to humans. PMID- 19788837 TI - Salmonella enterica serovar Typhi with CTX-M beta-lactamase, Germany. PMID- 19788836 TI - Reemergence of strongyloidiasis, northern Italy. PMID- 19788838 TI - Gordonia sputi bacteremia. PMID- 19788839 TI - Cross-reactive Antibodies against avian influenza virus A (H5N1). PMID- 19788841 TI - Hospital management of abdominal trauma in Tehran, Iran: a review of 228 patients. AB - OBJECTIVE: Today, trauma is a major public health problem in some countries. Abdominal trauma is the source of significant mortality and morbidity with both blunt and penetrating injuries. We performed an epidemiological study of abdominal trauma (AT) in Tehran, Iran. We used all our sources to describe the epidemiology and outcome of patients with AT. METHODS: This study was done in Tehran. The study population included trauma patients admitted to the emergency department of six general hospitals in Tehran during one year. The data were collected through a questionnaire that was completed by a trained physician at the trauma center. The statistical analysis was performed using the SPSS software (version 11.5 for Windows). The statistical analysis was conducted using the chi square and P < 0.05 was accepted as being statistically significant. RESULTS: Two hundred and twenty-eight (2.8%) out of 8,000 patients were referred to the above mentioned centers with abdominal trauma. One hundred and twenty-five (54.9%) of the patients were in their 2nd and 3rd decades of life and 189 (83%) of our patients were male. Road traffic accidents (RTA) were the leading cause of AT with 119 (52.2%) patients. Spleen was the commonly injured organ with 51 cases. Following the analysis of injury severity, 159 (69.7%) patients had mild injuries (ISS < 16) and 69 (30.3%) patients had severe injuries (ISS equal to 16). The overall mortality rate was 46 (20.2%). CONCLUSIONS: Blunt abdominal trauma is more common than penetrating abdominal trauma. Road traffic accidents and stab wound are the most common causes of blunt and penetrating trauma, respectively. Spleen is the most commonly injured organ in these patients. The mortality rate is higher in blunt trauma than penetrating one. PMID- 19788842 TI - Tropism mechanism of stem cells targeting injured brain tissues by stromal cell derived factor-1. AB - OBJECTIVE: To explore the role and function of stromal cell-derived factor-1 (SDF 1) in stem cells migrating into injured brain area. METHODS: Rat-derived nerve stem cells (NSCs) were isolated and cultured routinely. Transwell system was used to observe the migration ability of NSCs into injured nerve cells. Immunocytochemistry was used to explore the expression of chemotactic factor receptor-4 (CXCR-4) in NSCs. In vivo, we applied immunofluorescence technique to observe the migration of NSCs into injured brain area. Immunofluorescence technique and Western blotting were used to test expression level of SDF-1. After AMD3100 (a special chemical blocker) blocking CXCR-4, the migration ability of NSCs was tested in vivo and in vitro, respectively. RESULTS: NSCs displayed specific tropism for injured nerve cells or traumatic brain area in vivo and in vitro. The expression level of SDF-1 in traumatic brain area increased remarkably and the expression level of CXCR-4 in the NSCs increased simultaneously. After AMD3100 blocking the expression of CXCR-4, the migration ability of NSCs decreased significantly both in vivo and in vitro. CONCLUSIONS: SDF-1 may play a key role in stem cells migrating into injured brain area through specially combining with CXCR-4. PMID- 19788843 TI - Deproteinized bone with VEGF gene transfer to facilitate the repair of early avascular necrosis of femoral head of rabbit. AB - OBJECTIVE: To explore a new method for early avascular necrosis of femoral head (AVNFH) therapy. METHODS: Sixty-nine AVNFH New Zealand adult rabbits were randomly divided into three groups with equal number. In Group A, deproteinized bone (DPB) that absorbed with recombinant plasmid pcDNA3.1-hVEGF165 was implanted into the drilled tunnel of necrotic femoral head. In Group B, only DPB was implanted. In Group C, only tunnel was drilled without DPB or plasmid implanted. Femoral head specimens were obtained at postoperative 1, 2, 4, 8, 16 weeks. The expression of VEGF165 and collagen I was detected by immunohistochemistry. Bone formation was detected generally by X-ray. Angiogenesis and the repair of the femoral head were observed histologically. RESULTS: The expression of VEGF 165 could be detected 2 weeks after implantation in Group A, but it was not observed in other groups. The result of collagen I expression had a significantly difference 2, 4 and 8 weeks after operation in Group A from those in other groups (P < 0.01). X-ray results indicated that there was more bone formation in Group A than in other groups. The regenerated capillary vessels staining result of necrotic femoral head in Group A was significantly different from those in other groups at postoperative 2 and 4 weeks (P < 0.01). CONCLUSIONS: Transfection of hVEGF165 gene enhances local angiogenesis and DPB-VEGF compound improves the repair of necrotic femoral head. Deproteinized bone grafting with VEGF gene transfer provides a potential method for the treatment of osteonecrosis. PMID- 19788844 TI - Nervus cutaneus femoris posterior pedicle flap for repairing large soft tissue defects at the heel or inferior segment of the shank. AB - OBJECTIVE: To investigate the clinical effect of the nervus cutaneus femoris posterior pedicle flap on repairing large soft tissue defects at the heel or inferior segment of the shank. METHODS: Totally 14 cases were followed up for 8 22 months (mean 15.5 months) to observe the clinical effects of nervus cutaneus femoris posterior pedicle flap on repairing large soft tissue defects of the heel or inferior segment of the shank. Among them, there were 3 patients afflicted with infection and cutaneous defects in the middle and inferior segment of the shank after internal fixation of open fracture, 4 patients with soft tissue defects of the ankle and uncovered tendo calcaneus, and 7 patients with soft tissue defects of the heel and exposed calcaneus. RESULTS: The flaps survived well in 13 cases and partial necrosis occurred in 1 case that was thereafter cured with changing dressing. Various extents of pain and stiffness of the knee joints were present in all cases and disappeared through 1-8 weeks' (mean 3.2 weeks) functional exercises. The last follow-up showed that all the flaps kept good texture and satisfactory appearance. CONCLUSIONS: The nervus cutaneus femoris posterior pedicle flap, having the advantages of simple surgical procedures, anastomosing the nerves and restoring the sensation of recipient site, can be used for recovering large soft tissue defects of the shank and ankle. PMID- 19788845 TI - Situation analysis of trauma based on Arizona trauma center standards in university hospitals of Tehran, Iran. AB - OBJECTIVE: Injuries are common and important problem in Tehran, capital of Iran. Although therapeutic centers are not essentially established following the constructional principles of developed countries, the present opportunities and equipments have to be used properly. We should recognize and reduce the deficits based on the global standards. This study deliberates the trauma resources and capacities in university hospitals of Tehran based on Arizona trauma center standards, which are suitable for the assessment of trauma centers. METHODS: Forty-one university hospitals in Tehran were evaluated for their conformity with "Arizona trauma center standards" in 2008. A structured interview was arranged with the "Educational Supervisor" of all hospitals regarding their institutional organization, departments, clinical capabilities, clinical qualifications, facilities and resources, rehabilitation services, performance improvement, continuing education, prevention, research and additional requirements for pediatric trauma patients. Relative frequencies and percentages were calculated and Student's t test was used to compare the mean values. RESULTS: Forty-one hospitals had the average of 77.7 (50.7%) standards from 153 Arizona trauma center standards and these standards were present in 97.5 out of 153 (63.7%) in 17 general hospitals. Based on the subgroups of the standards, 64.8% items of hospital resources and capabilities were considered as a subgroup with the maximum criteria, and 17.7% items of research section as another subgroup with the minimum standards. CONCLUSIONS: On the basis of our findings, no hospital meet all the Arizona trauma center standards completely. The hospitals as trauma centers at different levels must be promoted to manage trauma patients desirably. PMID- 19788846 TI - Core decompression and implantation of calcium phosphate cement/Danshen drug delivery system for treating ischemic necrosis of femoral head at Stages I, II and III of antigen reactive cell opsonization. AB - OBJECTIVE: To introduce a new method using calcium phosphate cement/Danshen drug delivery system for treating ischemic necrosis of the femoral head and evaluate its curative effect. METHODS: From May 2000 to June 2005, 48 adult patients (54 hips) with ischemic necrosis of the femoral head at Stages I, II and III of antigen reactive cell opsonization (ARCO) were treated with implantation of calcium phosphate cement/Danshen drug delivery system in the involved femoral head. The operation consisted of removal of the necrotic bone under weight loading cartilage and the implantation of phosphate cement/Danshen drug delivery system, and all manipulations were made percutaneously through a bone tunnel in the trochanter. The functions of the hip joint were evaluated and X-ray films were taken preoperatively and postoperatively. RESULTS: Postoperative follow-up was 45.5 months on average, ranging from 27 to 78 months. According to the evaluation criterion of "Dandong 1995" for therapeutic effect of adult ischemic necrosis of the femoral head, the therapeutic effects were excellent in 33 hips, good in 17, fair in 3 and poor in 1, with the excellent and good rate of 92.6%. CONCLUSIONS: This method is relatively simple with little invasion. It not only improves the microcirculation of the femoral head by local application of traditional Chinese medicine, but also provides mechanic buttress in the weight loading area to prevent collapse during repairing, which is beneficial to repair and reconstruction of femoral head. It may be a choice of minimal invasion surgery for ischemic necrosis of the femoral head at Stages I, II and III of ARCO. PMID- 19788847 TI - Immune therapy with cultured microglia grafting into the injured spinal cord promoting the recovery of rat's hind limb motor function. AB - OBJECTIVE: To study the effect of activated microglia grafting on rats' hind limb motor function recovery after spinal cord injury. METHODS: Microglia were separated from primary culture and subcultured for 3 generations. Lipopolysaccharide was added to the culture medium with the terminal concentration of 10 microl/L for microglia activation 3 days before transplantation. Totally 80 adult Wistar rats were divided into transplantation group and control group, with 40 rats in each group. Spinal cord injury model of rats was set by hitting onto the spinal cord using a modified Allen impactor. With a 5 microl micro-syringe, the activated microglia suspension was injected into the injured area 7 days after the first operation. Basso, Beattie and Bresnahan (BBB) scoring for hind limb motor function was taken on the 1st, 7th, 14th, 21st, and 28th day after microglia transplantation, and 8 rats were sacrificed at each time point mentioned above, respectively. Frozen sections of the spinal cord were made for haematoxylin-eosin (HE) and Naoumenko-Feigin stainings. SPSS 11.0 software was used for statistical analysis. RESULTS: BBB scores for hind limb motor function on the 14th, 21st, and 28th day were significantly higher compared with the control group. Most liquefaction necrosis areas disappeared and only a few multicystic cavities surrounded by aggregated microglia remained in the transplantation group. Naoumenko-Feigin staining for microglia showed that the transplantation group had significantly more positive cells (P < 0.05). CONCLUSIONS: Grafting of activated microglia into the injured spinal cord can significantly promote the hind limb motor function recovery in rats with spinal cord injury and reduce the size of liquefaction necrosis area. The extent of lower limb motor function improvement has a positive correlation with the number of aggregated microglia. PMID- 19788848 TI - Influence of operative timing on prognosis of patients with acute subdural hematoma. AB - OBJECTIVE: To study the influence of operative timing on the prognosis of patients with acute subdural hematoma (ASDH) in order to provide theoretical basis for clinical treatment. METHODS: The clinical data of 202 patients with ASDH undergoing operations were collected, and the mortalities and functional survival rates were analyzed 2, 4, 6, and 8 hours after injury. RESULTS: No significant difference was found in mortalities and functional survival rates at different operative timings. However, there was a clear trend that the shorter the operative timing was, the lower the mortality and the higher functional survival rate were. In addition, the mean time from injury to operation of non survivors was significantly longer than that of survivors. CONCLUSIONS: Operative timing has potential influences on the prognosis of patients with ASDH. Surgical evacuation of ASDH should be performed as soon as possible once the operation indication emerges. PMID- 19788849 TI - Treatment of distal clavicle fracture with distal radius volar locking compression plate. AB - OBJECTIVE: To observe the early clinical outcomes of the internal fixation with distal radius volar locking compression plate (LCP) in treatment of distal clavicle fracture. METHODS: Six patients with unilateral distal clavicle fractures, identified as type II according to Neer classification system, including 4 males and 2 females, were treated with open reduction and internal fixation using a distal radius volar LCP. Bone union was evaluated by routine X ray radiography, and shoulder joint function were assessed by Constant score system. RESULTS: All fractures achieved bone union at 6 to 8 weeks postoperatively, and Constant scores ranged from 95 to 100 at the postoperative 10 to 12 weeks. CONCLUSION: Fixation of distal clavicle fracture with distal radius volar LCP demonstrates excellent effects of bone union with rarely early complications, thus providing a new technique to treat distal clavicle fracture. PMID- 19788850 TI - Consciousness and speech evaluation of 96 patients with craniocerebral injury. AB - OBJECTIVE: To explore the effective methods for evaluating the consciousness and speech status of patients with special types of cerebral injuries. METHODS: A total of 96 patients with injury in the language center and in coma were treated with operative and correlated conventional therapies. Then their recovery status of consciousness and speech was observed. RESULTS: All the patients were recovered to consciousness. Sixty-nine patients with aphasia were cured completely, but 7 patients were complicated with incomplete ataxic aphasia, 15 with incomplete sensory aphasia, and 5 with incomplete mixed aphasia. CONCLUSIONS: For the patients with injury in the language center, evaluation of the conscious state with GCS scoring system has certain limitations and conscious behaviours are advantageous evidences to evaluate the consciousness recovery of the patients. The patients with conscious disturbance and injury in the language center should be considered to have aphasia. PMID- 19788851 TI - Biomechanics of whiplash injury. AB - Despite a large number of rear-end collisions on the road and a high frequency of whiplash injuries reported, the mechanism of whiplash injuries is not completely understood. One of the reasons is that the injury is not necessarily accompanied by obvious tissue damage detectable by X-ray or MRI. An extensive series of biomechanics studies, including injury epidemiology, neck kinematics, facet capsule ligament mechanics, injury mechanisms and injury criteria, were undertaken to help elucidate these whiplash injury mechanisms and gain a better understanding of cervical facet pain. These studies provide the following evidences to help explain the mechanisms of the whiplash injury: (1) Whiplash injuries are generally considered to be a soft tissue injury of the neck with symptoms such as neck pain and stiffness, shoulder weakness, dizziness, headache and memory loss, etc. (2) Based on kinematical studies on the cadaver and volunteers, there are three distinct periods that have the potential to cause injury to the neck. In the first stage, flexural deformation of the neck is observed along with a loss of cervical lordosis; in the second stage, the cervical spine assumes an S-shaped curve as the lower vertebrae begin to extend and gradually cause the upper vertebrae to extend; during the final stage, the entire neck is extended due to the extension moments at both ends. (3) The in vivo environment afforded by rodent models of injury offers particular utility for linking mechanics, nociception and behavioral outcomes. Experimental findings have examined strains across the facet joint as a mechanism of whiplash injury, and suggested a capsular strain threshold or a vertebral distraction threshold for whiplash-related injury, potentially producing neck pain. (4) Injuries to the facet capsule region of the neck are a major source of post-crash pain. There are several hypotheses on how whiplash-associated injury may occur and three of these injuries are related to strains within the facet capsule connected with events early in the impact. (5) There are several possible injury criteria to correlate with the duration of symptoms during reconstructions of actual crashes. These results form the biomechanical basis for a hypothesis that the facet joint capsule is a source of neck pain and that the pain may arise from large strains in the joint capsule that will cause pain receptors to fire. PMID- 19788852 TI - Unusual orbitocranial penetrating injury by a grinding wheel: case report. PMID- 19788853 TI - Complex dislocation of the first metatarsophalangeal joint. PMID- 19788854 TI - Mechanism of amyloidogenesis: nucleation-dependent fibrillation versus double concerted fibrillation. AB - Amyloidogenesis defines a condition in which a soluble and innocuous protein turns to insoluble protein aggregates known as amyloid fibrils. This protein suprastructure derived via chemically specific molecular self-assembly process has been commonly observed in various neurodegenerative disorders such as Alzheimer's, Parkinson's, and Prion diseases. Although the major culprit for the cellular degeneration in the diseases remains unsettled, amyloidogenesis is considered to be etiologically involved. Recent recognition of fibrillar polymorphism observed mostly from in vitro amyloidogeneses may indicate that multiple mechanisms for the amyloid fibril formation would be operated. Nucleation-dependent fibrillation is the prevalent model for assessing the self assembly process. Following thermodynamically unfavorable seed formation, monomeric polypeptides bind to the seeds by exerting structural adjustments to the template, which leads to accelerated amyloid fibril formation. In this review, we propose another in vitro model of amyloidogenesis named double concerted fibrillation. Here, two consecutive assembly processes of monomers and subsequent oligomeric species are responsible for the amyloid fibril formation of alpha-synuclein, a pathological component of Parkinson's disease, following structural rearrangement within the oligomers which then act as a growing unit for the fibrillation. [BMB reports 2009; 42(9): 541-551]. PMID- 19788855 TI - Posttranscriptional and posttranslational determinants of cyclooxygenase expression. AB - Cyclooxygenases (COX-1 and COX-2) are ER-resident proteins that catalyze the committed step in prostanoid synthesis. COX-1 is constitutively expressed in many mammalian cells, whereas COX-2 is usually expressed inducibly and transiently. Abnormal expression of COX-2 has been implicated in the pathogenesis of chronic inflammation and various cancers; therefore, it is subject to tight and complex regulation. Differences in regulation of the COX enzymes at the posttranscriptional and posttranslational levels also contribute significantly to their distinct patterns of expression. Rapid degradation of COX-2 mRNA has been attributed to AU-rich elements (AREs) at its 3' UTR. Recently, microRNAs that can selectively repress COX-2 protein synthesis have been identified. The mature forms of these COX proteins are very similar in structure except that COX-2 has a unique 19-amino acid (19-aa) segment located near the C-terminus. This C-terminal 19-aa cassette plays an important role in mediation of the entry of COX-2 into the ER-associated degradation (ERAD) system, which transports ER proteins to the cytoplasm for degradation by the 26S proteasome. A second pathway for COX-2 protein degradation is initiated after the enzyme undergoes suicide inactivation following cyclooxygenase catalysis. Here, we discuss these molecular determinants of COX-2 expression in detail. [BMB reports 2009; 42(9): 552-560]. PMID- 19788856 TI - Evidence for the association of peroxidases with the antioxidant effect of p coumaric acid in endothelial cells exposed to high glucose plus arachidonic acid. AB - Although many plant-derived phenolic compounds display antioxidant effects in biological systems, their mechanism of action remains controversial. In this study, the mechanism by which p-coumaric acid (p-CA) performs its antioxidant action was investigated in bovine aortic endothelial cells under oxidative stress due to high levels of glucose (HG) and arachidonic acid (AA), a free fatty acid. p-CA prevented lipid peroxidation and cell death due to HG+AA without affecting the production of reactive oxygen species. The antioxidant effect of p-CA was not decreased by buthionine-(S,R)-sulfoximine, an inhibitor of cellular GSH synthesis. In contrast, pretreatment with p-CA caused the induction of peroxidases that decomposed t-butyl hydroperoxide in a p-CA-dependent manner. Furthermore, the antioxidant effect of p-CA was significantly mitigated by methimazole, which was shown to inhibit the catalytic activity of 'p-CA peroxidases' in vitro. Therefore, it is suggested that the induction of these previously unidentified 'p-CA peroxidases' is responsible for the antioxidant effect of p-CA. [BMB reports 2009; 42(9): 561-567]. PMID- 19788857 TI - Regulation of ANKRD9 expression by lipid metabolic perturbations. AB - Fatty acid oxidation (FAO) defects cause abnormal lipid accumulation in various tissues, which provides an opportunity to uncover novel genes that are involved in lipid metabolism. During a gene expression study in the riboflavin deficient induced FAO disorder in the chicken, we discovered the dramatic increase in mRNA levels of an uncharacterized gene, ANKRD9. No functions have been ascribed to ANKRD9 and its orthologs, although their sequences are well conserved among vertebrates. To provide insight into the function of ANKRD9, the expression of ANKRD9 mRNA in lipidperturbed paradigms was examined. The hepatic mRNA level of ANKRD9 was repressed by thyroid hormone (T(3)) and fasting, elevated by re feeding upon fasting. However, ANKRD9 mRNA level is reduced in response to apoptosis. Transient transfection assay with green fluorescent protein tagged- ANKRD9 showed that this protein is localized within the cytoplasm. These findings point to the possibility that ANKRD9 is involved in intracellular lipid accumulation. [BMB reports 2009; 42(9): 568-573]. PMID- 19788858 TI - Inhibitory effects of honokiol on LPS and PMA-induced cellular responses of macrophages and monocytes. AB - The regulatory effects of honokiol on the cellular responses of macrophages and monocytes were evaluated. Specifically, we investigated the effects of honokiol with respect to lipopolysaccharide (LPS)-induced cytotoxicity, LPS- or phorbol-12 myristate-13-acetate (PMA)-mediated morphological changes, and relevant events (FITC-dextran-induced phagocytic uptake). Honokiol blocked the LPS-induced cytotoxicity of RAW264.7 cells in a dose-dependent manner. In addition, honokiol appeared to block the production of cytotoxic cytokines such as interleukin (IL) 1beta and tumor necrosis factor (TNF)-alpha, nitric oxide (NO), and reactive oxygen species (ROS). Moreover, honokiol strongly prevented the morphological changes in RAW 264.7 and U937 cells that were induced by LPS and PMA. The surface levels of marker proteins, which are up-regulated under the morphological changes of RAW264.7 and U937 cells, were also diminished. The data presented here strongly suggest that the honokiol modulates various cellular responses managed by macrophages and monocytes. [BMB reports 2009; 42(9): 574-579]. PMID- 19788859 TI - Inhibition of methionine sulfoxide reduction by dimethyl sulfoxide. AB - Dimethyl sulfoxide (DMSO) is widely used in chemistry and biology as a solvent and as a cryoprotectant. It is also used as a pharmaceutical agent for the treatment of interstitial cystitis and rheumatoid arthritis. Previous reports described DMSO as being reduced by methionine-S-sulfoxide reductase (MsrA). However, little is known about the DMSO reduction capability of methionine-R sulfoxide reductase (MsrB) or its effect on the catalysis of methionine sulfoxide reduction. We show that mammalian MsrB2 and MsrB3 were unable to reduce DMSO. This compound inhibited MsrB2 activity but did not inhibit MsrB3 activity. We further determined that DMSO functions as an inhibitor of MsrA and MsrB2 in the reduction of methionine sulfoxides via different inhibition mechanisms. DMSO competitively inhibited MsrA activity but acted as a non-competitive inhibitor of MsrB2 activity. Our study also demonstrated that DMSO inhibits in vivo methionine sulfoxide reduction in yeast and mammalian cells. [BMB reports 2009; 42(9): 580 585]. PMID- 19788860 TI - Different modes of antibiotic action of homodimeric and monomeric bactenecin, a cathelicidin-derived antibacterial peptide. AB - The bactenecin is an antibacterial peptide with an intramolecular disulfide bond. We recently found that homodimeric bactenecin exhibits more potent antibacterial activity than the monomeric form and retains its activity at physiological conditions. Here we assess the difference in the modes of antibiotic action of homodimeric and monomeric bactenecins. Both monomeric and dimeric bactenecins almost completely killed both Staphylococcus aureus and E. coli within 10-30 min at concentrations of 8-16 muM. However, exposure to liposomes elicited an increase in the fluorescence quantum yield from a tryptophan-containing monomeric analog, while the homodimeric analog showed a significant reduction in fluorescence intensity. Moreover, unlike the monomer, the homodimer displayed apparent membrane-lytic activity enabling release of various sized dyes from liposomes, and rapidly and fully depolarized the S. aureus membrane. Together, our results suggest that homodimeric bactenecin forms pores in the bacterial membrane, while monomeric one penetrates through the membrane to target intracellular molecules/organelles. [BMB reports 2009; 42(9): 586-592]. PMID- 19788861 TI - Analysis of microRNA expression profiles during the cell cycle in synchronized HeLa cells. AB - Cell cycle progression is regulated by both transcriptional and post transcriptional mechanisms. MicroRNAs (miRNAs) emerge as a new class of small non coding RNA regulators of cell cycle as recent evidence suggests. It is hypothesized that expression of specific miRNAs oscillates orderly along with cell cycle progression. However, the oscillated expression patterns of many candidate miRNAs have yet to be determined. Here, we describe miRNA expression profiling in double-thymidine synchronized HeLa cells as cell cycle progresses. Twenty-five differentially expressed miRNAs were classified into five groups based on their cell cycle-dependent expression patterns. The cyclic expression of six miRNAs (miR-221, let-7a, miR-21, miR-34a, miR-24, miR-376b) was validated by real-time quantitative RT-PCR (qRT-PCR). These results suggest that specific miRNAs, along with other key factors are required for maintaining and regulating proper cell cycle progression. The study deepens our understanding on cell cycle regulation. [BMB reports 2009; 42(9): 593-598]. PMID- 19788863 TI - Enhanced functional and structural properties of high-density lipoproteins from runners and wrestlers compared to throwers and lifters. AB - Plasma high-density lipoprotein cholesterol (HDL-C) levels are inversely correlated with the risk of cardiovascular disease, and are known to increase with repetitive exercise. In the current study, HDL fractions from athletes' sera were isolated and compared as a function of the type of sport (runners [n = 10], throwers [n = 10], wrestlers [n = 10], and weight lifters [n = 8]), and as an age and gender-matched reference group (n = 14). Among athletes, HDL from runners had the strongest antioxidant activity. Immunodetection showed that runners and wrestlers had the highest levels of apoA-I and lowest levels of apoA-II in their HDL. Electron microscopy also revealed that HDL(2) of runners and wrestlers were the largest in size. In conclusion, although all athlete groups had significantly better serum lipid/lipoprotein profiles than the reference group, runners and wrestlers had the most desirable lipoprotein function and structure, including antioxidant activity, HDL-associated enzyme activities and increased particle size. [BMB reports 2009; 42(9): 605-610]. PMID- 19788862 TI - Autophagy inhibition through PI3K/Akt increases apoptosis by sodium selenite in NB4 cells. AB - Selenium possesses the chemotherapeutic feature by inducing apoptosis in cancer cell with trivial side effects on normal cells. However, the mechanism in which is not clearly understood. Emerging evidence indicates the overlaps between the autophagy and the apoptosis. In this study, we have investigated the role of autophagy in selenium-induced apoptosis in NB4 cells. We find that autophagy is suppressed in NB4 cells treated by sodium selenite, as measured by electron microscope, acridine orange staining and western blot. Moreover, selenite combined with autophagy inhibitor contributes to the up-regulation of apoptosis, while the PI3K/Akt signaling pathway is down- regulated. Consistently, when the inhibitor of PI3K was applied, the autophagic level significantly decreased. In summary, sodium selenite increases NB4 cell apoptosis by autophagy inhibition through PI3K/Akt, and the inhibition of autophagy contributes to the up regulation of apoptosis. [BMB reports 2009; 42(9): 599-604]. PMID- 19788864 TI - Expression of dehydration responsive element-binding protein-3 (DREB3) under different abiotic stresses in tomato. AB - We investigated the expression pattern of dehydration responsive element-binding protein-3 in tomato under different abiotic stresses. Full length LeDREB3 cDNA was isolated from tomato plant, followed by phylogenetic analysis based on deduced amino acid sequences that revealed significant sequence similarity to DREB proteins belonging to diverse families of plant species. Southern blot analysis showed duplicate copies of LeDREB3 in the tomato genome while organ specific expression profiling indicated constitutive expression of LeDREB3 in all tested organs, which was particularly strong in flower. LeDREB3 expression was significantly induced by Nacl, drought, low temperature and H(2)O(2). Moreover, LeDREB3 was slightly regulated by treatment with ABA and MV. These observations suggest that the LeDREB3 gene may be involved in the response of the tomato plant to stress. [BMB reports 2009; 42(9): 611-616]. PMID- 19788865 TI - Identification of epistasis in ischemic stroke using multifactor dimensionality reduction and entropy decomposition. AB - We investigated the genetic associations of ischemic stroke by identifying epistasis of its heterogeneous subtypes such as small vessel occlusion (SVO) and large artery atherosclerosis (LAA). Epistasis was analyzed with 24 genes in 207 controls and 271 patients (SVO = 110, LAA = 95) using multifactor dimensionality reduction and entropy decomposition. The multifactor dimensionality reduction analysis with any of 1- to 4-locus models showed no significant association with LAA (P > 0.05). The analysis of SVO, however, revealed a significant association in the best 3-locus model with P10L of TGF-beta1, C1013T of SPP1, and R485K of F5 (testing balanced accuracy = 63.17%, P < 0.05). Subsequent entropy analysis also revealed that such heterogeneity was present and quite a large entropy was estimated among the 3 loci for SVO (5.43%), but only a relatively small entropy was estimated for LAA (1.81%). This suggests that the synergistic epistasis model might contribute specifically to the pathogenetsis of SVO, which implies a different etiopathogenesis of the ischemic stroke subtypes. [BMB reports 2009; 42(9): 617-622]. PMID- 19788866 TI - Age-related memory decline and apolipoprotein E e4. AB - The APOE epsilon4 allele is associated with risk of late-onset Alzheimer's disease (AD). Longitudinal memory decline in asymptomatic APOE epsilon4 carriers shows greater acceleration compared with non-carriers, with a possible allele dose effect, and begins prior to age 60. These results correlate with imaging and neuropathological studies that show AD-like changes at this age and collectively support the existence of a presymptomatic stage of AD. PMID- 19788867 TI - MicroManipulating viral-based therapeutics. AB - Despite the social stigma and manufacturing hurdles that come with using viruses as therapeutic tools, the molecular specificity offered by these bugs makes them too attractive to ignore. Still largely based on vaccines, viral vectors offer exciting tools to treat cancer or deliver specific genetic payloads to a desired tissue. Unfortunately, early clinical trials utilizing such vectors have been plagued with poor performance or even clinical toxicity most commonly associated with spurious genetic regulation and/or replication of the vector. Past efforts to control for unwanted toxicity have focused on modification of the receptor or use of tissue-specific genetic elements that added specificity to the transcriptional induction of the gene(s) of interest. While this has had some success, engineering receptors to control viral tropism often fails or results in a loss of replicative fitness. In addition, the use of tissue-specific promoter elements not only restricts the vector that can be used, bona fide small promoter elements are often not available for the desired target. With the caveats of viral vector-based therapeutics largely centered on a lack of in vivo control, the recent success of exploiting microRNA expression to limit viral tropism may breathe new life into the field. PMID- 19788868 TI - Adipose tissue inflammation in obesity and metabolic syndrome. AB - Metabolic syndrome is a major risk factor for cardiovascular and metabolic diseases. Playing a central role in the development of metabolic syndrome and in its clinical consequences is visceral obesity. Adipose tissue is now considered to be an active endocrine organ that secretes various humoral factors (adipokines), and its shift to production of proinflammatory cytokines in obesity likely contributes to the low-level systemic inflammation that is seen in metabolic syndrome-associated chronic pathologies such as atherosclerosis. Recent studies have shown that obesity induces chronic local inflammation in adipose tissue, and that cells of the innate immune system, particularly macrophages, are crucially involved in adipose inflammation and systemic metabolic abnormalities. Moreover, we and others recently revealed that T cells are key regulators of adipose inflammation, and that the adaptive immune system is also crucially important. In mouse models modulation of T cell function ameliorated not only adipose inflammation but also systemic insulin resistance induced by obesity. Thus clarification of the inflammatory processes ongoing in obese adipose tissue would seem essential for the understanding of metabolic syndrome and for developing novel therapeutic strategies to treat it. PMID- 19788869 TI - Deregulation of cell death (apoptosis): implications for tumor development. AB - The first descriptions of apoptosis were made over 150 years ago, although the implications for tumor development were not appreciated until the 1970s. Natural cell death is a critical part of development of multicellular organisms, and also counter-balances the cell generating effects of mitosis. Disruptions in the highly regulated apoptotic pathway can lead to disease, such as tumors, due to the accumulation of excessive numbers of cells. Restoring normal apoptosis in cancer cells is one of the current challenges of cancer research. PMID- 19788870 TI - Ghrelin: friend or foe for neuroinflammation. AB - Ghrelin is a recently identified gastric hormone that displays strong growth hormone (GH) releasing activity mediated by the GH secretagogue receptor (GHS-R). While this unique endogenous peptide participates in the regulation of energy homeostasis, increases food intake, and decreases energy expenditure, its ability to modulate immune regulation is another important feature. Here we discuss the effect of ghrelin on the immune system. Ghrelin was initially reported as an immune enhancing factor. More recently, however, the immunosuppressive effects of ghrelin have been found in several animal models including bowel disease, arthritis, and sepsis and endotoxemia. We recently demonstrated that exogenous administration of ghrelin suppressed experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis in association with the reduction of pro inflammatory cytokines in microglia. These results shed light on the new role of ghrelin in the regulation of disorders that pro-inflammatory cytokines contribute to the pathogenesis such as neuroinflammatory and mental diseases. PMID- 19788871 TI - Protective and pathogenic functions of T-cells are inseparable during the Helicobacter-host interaction. AB - Chronic infection with the bacterial pathogen Helicobacter pylori is closely linked to the development of gastric cancer. Experimental infection of the laboratory mouse strain C57Bl6 mimics the initiation and progression of the disease in humans. Using this model, we have identified a dual role for CD4+ IFN gamma-secreting T-cells in the control of Helicobacter infection as well as in the induction of preneoplastic gastric pathology. High gastric expression of IFN gamma was positively correlated with a low Helicobacter burden, and was essential for vaccine-induced protection; on the other hand, elevated levels of the cytokine also, either directly or indirectly, triggered the transformation of the normal gastric mucosa to atrophic, hyperplastic and metaplastic lesions. Based on similar patterns of gene expression changes induced by IFN-gamma in vivo and in cultured gastric epithelial cells, we hypothesize that IFN-gamma may act directly on epithelial cells to stimulate their hyperproliferation, and thus to predispose them to elevated mutation rates and an increased risk of malignant transformation. PMID- 19788872 TI - Targeting alternative splicing in prostate oncology. AB - Prostate cancer is the most common cancer seen in aging males in the Western world, and is a major clinical challenge in uro-oncology due to biological heterogeneity. Recent advances in molecular medicine suggest that the genetic composition of a prostate tumor contributes significantly to the complexity of the disease. An important genetic mechanism underlying biological diversity is alternative pre-mRNA splicing, which is thought to affect approximately 95% of transcripts derived from protein-encoding genes. During alternative splicing, coding (exons) and non-coding (introns) regions of pre-messenger RNA (pre-mRNA) transcripts derived from a single gene are rearranged to generate several mRNAs species, which are translated into distinct protein isoforms with differing biological functions. Recent emerging evidence suggests that prostate cancer specific aberrant and alternative splicing may contribute to the biological heterogeneity of the disease. Furthermore, identification of prostate cancer specific splice variants may yield novel biomarkers and targets for therapy to improve patient care and clinical outcome. PMID- 19788873 TI - How can systems pathology help us personalize cancer therapy? AB - Cancer is a complex and heterogeneous disease which changes over time, and in the face of therapeutic intervention. Single tissue biomarkers, while partially successful in helping us understand which patients will respond to therapy, cannot hope to capture this amazing complexity. Systems pathology, which combines measurements made on tissues with new mathematical modeling approaches, permits the testing of new agents and biomarkers in silico through computational analysis. These approaches help us to refine pathological measurements and improve decision making about therapies for clinical trial planning and ultimately personalized therapy. PMID- 19788874 TI - Mycorrhizal networks. PMID- 19788876 TI - Cellular allometry: the spindle in development and inheritance. AB - Recent studies have demonstrated a correlation between cell size and the behaviors of the cytoskeletal division machinery during embryogenesis, giving insight into how a core cellular process is modulated over the course of development. PMID- 19788875 TI - The fungi. PMID- 19788877 TI - Perceptual decisions: from sensory signals to behavior. AB - Recent non-invasive studies in humans provide new insights into the timing of perceptual decision making and show that integrated sensory evidence is represented in motor areas well before a behavioral response. PMID- 19788878 TI - Meiosis: making a synaptonemal complex just got easier. AB - In preparation for meiosis, chromosomes go through several massive structural transitions, including chromosome fragmentation, pairing and synapsis. A checkpoint factor and a SUMO ligase collaborate to keep things in order. PMID- 19788879 TI - Vision: thinking globally, acting locally. AB - The global structure of images profoundly influences how we see their local detail, consistent with activity in primary visual cortex being disambiguated via feedback from later visual areas. PMID- 19788880 TI - Fly memory: a mushroom body story in parts. AB - Recent studies on the compartmentalization of fly mushroom bodies show that learning and memory in Drosophila are not as simple as might be expected for an organism with such a tiny brain. PMID- 19788881 TI - Bacterial evolution: dynamic genomes and the power of transformation. AB - Virulence and avirulence genes carried on large, unstable pathogenicity islands (PAI) strongly influence the course and fate of host-pathogen interactions. A recent study shows how one such PAI can be rapidly transferred between two closely related bacteria via transformation in vivo, and how this horizontal gene transfer affects the fitness of the recipient strain. PMID- 19788882 TI - Memory consolidation: tracking transfer with functional connectivity. AB - Every day we store memories of innumerable new experiences. Our extraordinary ability to retrieve so many of them at a later time is due in no small part to the consolidation of these memories, a process that continues offline long after the experiences themselves are over. PMID- 19788883 TI - Olfaction: when nostrils compete. AB - In vision, alternating percepts occur when two different visual stimuli are presented separately to the two eyes. By analogy, simultaneous presentation of two different odorants separately to the two nostrils has now been shown to cause alternating odor percepts, an effect termed 'binaral rivalry'. PMID- 19788885 TI - Quantitation of plasma total 15-series F(2)-isoprostanes by sequential solid phase and liquid-liquid extraction. AB - F(2)-isoprostanes are stereo- and regioisomers of prostaglandin F(2alpha) (PGF(2alpha)) and are used as biomarkers for lipid peroxidation. We modified our liquid-liquid extraction (LLE) procedure for F(2)-isoprostane analysis (Anal. Biochem. 350 (2006) 41-51) to use a combination of solid phase extraction (SPE) and LLE to produce a cleaner extract that can be easily concentrated. In addition, shortening the high-performance liquid chromatography (HPLC) separation increased peak heights in HPLC-tandem mass spectrometry (HPLC-MS/MS) analysis. Both changes increased the overall sensitivity of the assay. MS/MS analysis served to confirm the identity of specific peaks that may be better biomarkers than the commonly measured 8-iso-PGF(2alpha). PMID- 19788884 TI - Integrating genomes, brain and behavior in the study of songbirds. AB - Songbirds share some essential traits but are extraordinarily diverse, allowing comparative analyses aimed at identifying specific genotype-phenotype associations. This diversity encompasses traits like vocal communication and complex social behaviors that are of great interest to humans, but that are not well represented in other accessible research organisms. Many songbirds are readily observable in nature and thus afford unique insight into the links between environment and organism. The distinctive organization of the songbird brain will facilitate analysis of genomic links to brain and behavior. Access to the zebra finch genome sequence will, therefore, prompt new questions and provide the ability to answer those questions. PMID- 19788886 TI - Acquisition of chemiluminescent signals from immunoblots with a digital single lens reflex camera. AB - We found that certain mid-range consumer-level digital single-lens reflex (SLR) cameras using full-frame complementary metal oxide semiconductor (CMOS) sensors outperform X-ray film in acquiring signals from immunoblots that use enhanced chemiluminescence for detection. These cameras exhibit a sensitivity comparable to X-ray film, yet they provide a 3-fold increase in linear dynamic range and substantial cost savings over time, are more convenient to use, and eliminate the chemical waste associated with processing film. PMID- 19788887 TI - Factors modulating expression of Renilla luciferase from control plasmids used in luciferase reporter gene assays. PMID- 19788888 TI - Transport of hypoxia-inducible factor HIF-1alpha into the nucleus involves importins 4 and 7. AB - Hypoxia-inducible transcription factor 1 (HIF-1) mediates the cellular response to hypoxia. HIF-1 activity is controlled via the synthesis, degradation or intracellular localization of its alpha subunit. HIF-1alpha contains a C-terminal bipartite basic NLS that interacts with importins alpha. We have recently shown that HIF-1alpha also contains an atypical hydrophobic CRM1- and phosphorylation dependent NES and can therefore shuttle in and out of the nucleus. We now report that C-terminal NLS mutants of HIF-1alpha can still enter the nucleus when CRM1 dependent nuclear export is inhibited, indicating that HIF-1alpha contains an additional functional nuclear import signal. Using an in vitro nuclear import assay, we further show that importins 4 and 7 accomplish nuclear import of HIF 1alpha more efficiently than the classical importin alpha/beta NLS receptor. Binding assays confirmed the specific physical interaction between HIF-1alpha and importins 4 and 7. Moreover, the interaction of importin 7 with HIF-1alpha is mapped at its N-terminal part encompassing the bHLH-PAS(A) domain. By expressing functional HIF-1 in yeast, we show that Nmd5, the yeast orthologue of importin 7, is required for HIF-1alpha nuclear accumulation and activity. Taken together, our data show that shuttling of HIF-1alpha between cytoplasm and nucleus is a complex process involving several members of the nuclear transport receptor family. PMID- 19788889 TI - DNA damage response to the Mdm2 inhibitor nutlin-3. AB - Mdm2 inhibitors represent a promising class of p53 activating compounds that may be useful in cancer treatment and prevention. However, the consequences of pharmacological p53 activation are not entirely clear. We observed that Nutlin-3 triggered a DNA damage response in azoxymethane-induced mouse AJ02-NM(0) colon cancer cells, characterized by the phosphorylation of H2AX (at Ser-139) and p53 (at Ser-15). The DNA damage response was highest in cells showing robust p53 stabilization, it could be triggered by the active but not the inactive Nutlin-3 enantiomer, and it was also activated by another pharmacological Mdm2 inhibitor (Caylin-1). Quantification of gamma H2AX-positive cells following Nutlin-3 exposure showed that approximately 17% of cells in late S and G2/M were mounting a DNA damage response (compared to a approximately 50% response to 5 fluorouracil). Nutlin-3 treatment caused the formation of double-strand DNA strand breaks, promoted the formation of micronuclei, accentuated strand breakage induced by doxorubicin and sensitized the mouse colon cancer cells to DNA break inducing topoisomerase II inhibitors. Although the HCT116 colon cancer cells did not mount a significant DNA damage response following Nutlin-3 treatment, Nutlin 3 enhanced the DNA damage response to the nucleotide synthesis inhibitor hydroxyurea in a p53-dependent manner. Finally, p21 deletion also sensitized HCT116 cells to the Nutlin-3-induced DNA damage response, suggesting that cell cycle checkpoint abnormalities may promote this response. We propose that p53 activation by Mdm2 inhibitors can result in the slowing of double-stranded DNA repair. Although this effect may suppress illegitimate homologous recombination repair, it may also increase the risk of clastogenic events. PMID- 19788890 TI - Predicting gemcitabine transport and toxicity in human pancreatic cancer cell lines with the positron emission tomography tracer 3'-deoxy-3'-fluorothymidine. AB - The abundance of human equilibrative nucleoside transporter 1 (hENT1) has recently been shown to be a predictive marker of benefit from gemcitabine therapy in patients with pancreatic cancer. Since hENT1 is also important for the uptake of positron emission tomography (PET) tracer 3'-deoxy-3'-fluorothymidine (FLT) in various cultured human cell lines, this study was undertaken to determine if FLT uptake predicts gemcitabine uptake and/or toxicity in a panel of human pancreatic cancer cell lines (Capan-2, AsPC-1, BxPC-3, PL45, MIA PaCa-2, and PANC-1). Capan 2 cells displayed the lowest levels of (1) extracellular nitrobenzylmercaptopurine ribonucleoside (NBMPR) binding, which represents cell surface hENT1, (2) FLT and gemcitabine uptake during short (1-45s) and prolonged (1h) periods, and (3) gemcitabine sensitivity. Exposure to NBMPR (inhibits only hENT1) or dilazep (inhibits hENT1 and hENT2) reduced FLT and gemcitabine uptake and gemcitabine sensitivity, with dilazep having greater effects than NBMPR. Gemcitabine permeation was almost completely mediated, primarily by hENT1 and to a lesser extent by hENT2, whereas FLT permeation included a substantial component of passive diffusion. In five of six cell lines, correlations were observed between (1) FLT and gemcitabine initial rates of uptake, (2) gemcitabine uptake and gemcitabine toxicity, (3) FLT uptake and gemcitabine toxicity, and (4) ribonucleotide reductase subunit M1 expression and gemcitabine toxicity. FLT and gemcitabine uptake were comparable for predicting gemcitabine toxicity in the tested pancreatic cancer cell lines suggesting that FLT PET may provide clinically useful information about tumor gemcitabine transport capacity and sensitivity. PMID- 19788891 TI - The food contaminant semicarbazide acts as an endocrine disrupter: Evidence from an integrated in vivo/in vitro approach. AB - Semicarbazide (SEM) is a by-product of the blowing agent azodicarbonamide, present in glass jar-sealed foodstuffs mainly baby foods. The pleiotropic in vivo SEM toxicological effects suggested to explore its possible role as endocrine modulator. Endocrine effects of SEM were assessed in vivo in male and female rats after oral administration for 28 days at 0, 40, 75, 140mg/kg bw pro die during the juvenile period. Vaginal opening and preputial separation were recorded. Concentration of sex steroid in blood, the ex vivo hepatic aromatase activity and testosterone catabolism were detected. The in vitro approach to test SEM role as (anti)estrogen or N-methyl-d-aspartate receptors (NMDARs)-(anti)agonist included different assays: yeast estrogenicity, MCF-7 proliferation, stimulation of the alkaline phosphatase activity in Ishikawa cells and LNCaP-based NMDAR interference assay. In vivo SEM-treated female rats showed delayed vaginal opening at all tested doses, whereas in males preputial separation was anticipated at SEM 40 and 75mg/kg and delayed at 140mg/kg, the latter effect probably due to the significantly decreased body weight gain seen at the higher dose in both sexes. Serum estrogen levels were dose-dependently reduced in treated females, whereas dehydrotestosterone serum levels were also decreased but a clear dose-response was not evidenced. Testosterone catabolism was altered in a gender-related way, aromatase activity was increased in treated males at 75 and 140mg/kg and in females in all dose groups. In the three estradiol-competitive assays, SEM showed a weak anti-estrogenic activity, whereas in the LNCaP-based NMDAR interference assay SEM activity resembled MK-801 antagonist effect. SEM appeared to act as an endocrine disrupter showing multiple and gender specific mechanisms of action(s). A possible cascade-mechanism of SEM on reproductive signalling pathways may be hypothesized. Such in vivo-in vitro approach appeared to be an useful tool to highlight SEM activity on endocrine homeostasis. PMID- 19788892 TI - Effect of fucoidan on aspirin-induced stomach ulceration in rats. AB - In this study, the effects of fucoidan on aspirin-induced ulcers in rats were evaluated: both biochemical and immunological parameters were taken into consideration. The status of stomach tissue glycogen storage and histological changes were also examined. Examination of basic biochemical parameters showed significant (p<0.01) alterations in aspartate (AST) and alanine (ALT) transaminases in ulcer-induced rats. Also, moderate alterations (p<0.05) were observed in the levels of cholesterol and blood urea nitrogen (BUN). Histopathological examination showed neutrophil infiltration and inflammation in oxyntic cells with altered glycogen storage. Analysis of serum cytokines of aspirin-induced rats showed a moderate decrease in interleukin-10 (IL-10) with considerable increase of interleukin-6 (IL-6) and interferon-gamma (INF-gamma) when compared with control. Administration of fucoidan showed considerable (p<0.05) protection against ulceration by inhibiting the acute alterations of AST, ALT, cytokines and stomach glycogen. However, aggravated serum INF-gamma was observed in the fucoidan-pretreated group. These findings suggest that the anti ulcer property of fucoidan might contribute in protecting the inflammatory cytokine-mediated oxidative damage to gastric mucosa. PMID- 19788893 TI - Differential expression and processing of transforming growth factor beta induced protein (TGFBIp) in the normal human cornea during postnatal development and aging. AB - Transforming growth factor beta induced protein (TGFBIp, also named keratoepithelin) is an extracellular matrix protein abundant in the cornea. The purpose of this study was to determine the expression and processing of TGFBIp in the normal human cornea during postnatal development and aging. TGFBIp in corneas from individuals ranging from six months to 86 years of age was detected and quantified by immunoblotting. The level of TGFBIp in the cornea increases about 30% between 6 and 14 years of age, and adult corneas contain 0.7-0.8 microg TGFBIp per mg wet tissue. Two-dimensional (2-D) immunoblots of the corneal extracts showed a characteristic "zig-zag" pattern formed by different lower molecular mass TGFBIp isoforms (30-60 kDa). However, the relative abundance of the different isoforms was different between infant corneas (<1 year) and the child/adult corneas (>6 years). Matrix-assisted laser desorption/ionization-time of-flight mass spectrometry (MALDI-TOF MS) data of TGFBIp isoforms separated on large 2-D gels show that TGFBIp is proteolytically processed from the N-terminus. This observation was supported by in silico 2-D gel electrophoresis showing that sequential proteolytical trimming events from the N-terminus of mature TGFBIp generate TGFBIp isoforms which form a similar "zig-zag" pattern when separated by 2-D polyacrylamide gel electrophoresis (PAGE). This study shows that in humans TGFBIp is more abundant in mature corneas than in the developing cornea and that the processing of TGFBIp changes during postnatal development of the cornea. In addition, TGFBIp appears to be degraded in a highly orchestrated manner in the normal human cornea with the resulting C-terminal fragments being retained in the cornea. The age-related changes in the expression and processing of corneal TGFBIp suggests that TGFBIp may play a role in the postnatal development and maturation of the cornea. Furthermore, these observations may be relevant to the age at which mutant TGFBIp deposits in the cornea in those dystrophies caused by mutations in the transforming growth factor beta induced gene (TGFBI) as well as the mechanisms of corneal protein deposition. PMID- 19788895 TI - On the estimation of robustness and filtering ability of dynamic biochemical networks under process delays, internal parametric perturbations and external disturbances. AB - Inherently, biochemical regulatory networks suffer from process delays, internal parametrical perturbations as well as external disturbances. Robustness is the property to maintain the functions of intracellular biochemical regulatory networks despite these perturbations. In this study, system and signal processing theories are employed for measurement of robust stability and filtering ability of linear and nonlinear time-delay biochemical regulatory networks. First, based on Lyapunov stability theory, the robust stability of biochemical network is measured for the tolerance of additional process delays and additive internal parameter fluctuations. Then the filtering ability of attenuating additive external disturbances is estimated for time-delay biochemical regulatory networks. In order to overcome the difficulty of solving the Hamilton Jacobi inequality (HJI), the global linearization technique is employed to simplify the measurement procedure by a simple linear matrix inequality (LMI) method. Finally, an example is given in silico to illustrate how to measure the robust stability and filtering ability of a nonlinear time-delay perturbative biochemical network. This robust stability and filtering ability measurement for biochemical network has potential application to synthetic biology, gene therapy and drug design. PMID- 19788894 TI - Chamomile, a novel and selective COX-2 inhibitor with anti-inflammatory activity. AB - AIMS: Inducible cyclooxygenase (COX-2) has been implicated in the process of inflammation and carcinogenesis. Chamomile has long been used in traditional medicine for the treatment of inflammatory diseases. In this study we aimed to investigate whether chamomile interferes with the COX-2 pathway. MAIN METHODS: We used lipopolysaccharide (LPS)-activated RAW 264.7 macrophages as an in vitro model for our studies. KEY FINDINGS: Chamomile treatment inhibited the release of LPS-induced prostaglandin E(2) in RAW 264.7 macrophages. This effect was found to be due to inhibition of COX-2 enzyme activity by chamomile. In addition, chamomile caused reduction in LPS-induced COX-2 mRNA and protein expression, without affecting COX-1 expression. The non-steroidal anti-inflammatory drug, sulindac and a specific COX-2 inhibitor, NS398, were shown to act similarly in LPS-activated RAW 264.7 cells. Our data suggest that chamomile works by a mechanism of action similar to that attributed to non-steroidal anti-inflammatory drugs. SIGNIFICANCE: These findings add a novel aspect to the biological profile of chamomile which might be important for understanding the usefulness of aqueous chamomile extract in the form of tea in preventing inflammation and cancer. PMID- 19788896 TI - Contributions of visible persistence and perceptual set to the flash-lag effect: focusing on flash onset abolishes the illusion. AB - Among other theories, visible persistence has been suggested to explain the flash lag effect (FLE). According to this account, the flash is not compared to the moving object at its perceived onset, but at a later time while it is still subjectively visible. Therefore, it is reported to lag the moving object. We show that observers' perceptual set determines whether the persisting image of the flash or its onset is used to judge relative position. Spontaneously, observers use the persisting image, such that a flash-lag results. When forced to focus on the onset of the flash because flashes and stationary onset-only stimuli are mixed, observers base their judgments on the onset and the FLE is abolished. We found that perceptual set affected the FLE in the flash-initiated and in the continuous-motion paradigm. Finally, we showed that the position of the moving object was perceived without any blur and that the flash persisted subjectively for at least 60-80ms. Changes of perceptual set and visible persistence may underlie many of the previously reported modulations of the FLE. PMID- 19788897 TI - The immunobiology of viral arthritides. AB - A large range of human viruses are associated with the development of arthritis or arthralgia. Although there are many parallels with autoimmune arthritides, there is little evidence that viral arthritides lead to autoimmune disease. In humans viral arthritides usually last from weeks to months, can be debilitating, and are usually treated with non-steroidal anti-inflammatory drugs, but with variable success. Viral arthritides likely arise from immunopathological inflammatory responses directed at viruses and/or their products residing and/or replicating within joint tissues. Macrophages recruited by monocyte chemoattractant protein-1 (MCP-1/CCL2) and activated by interferon, and proinflammatory mediators like tumour necrosis factor alpha, interferon gamma, interleukin-6 and interleukin-1beta appear to be common elements in this group of diseases. The challenge for new treatments is to target excessive inflammation without compromising anti-viral immunity. Recent evidence from mouse models suggests targeting MCP-1 or complement may emerge as viable new treatment options for viral arthritides. PMID- 19788898 TI - Recovery sleep after sleep deprivation almost completely abolishes dream recall. AB - The study investigated the effect of one night of sleep deprivation on dream recall at morning awakening after recovery sleep. Forty healthy subjects were studied after adaptation (A) and baseline nights (B), and a recovery (R) night following 40 h of prolonged wakefulness. Parallel to the well-known recovery sleep changes (slow-wave sleep--SWS--rebound, decreased number of awakenings and of REM sleep amount), an almost complete abolition of dream recall was found, with an around 75% decrease with respect to the adaptation and baseline nights. The number of dreams recalled by those subjects with successful recall (REC) did not significantly differ between nights. Moreover, gender and sleep stage at awakening did not affect either the proportion of REC subjects or the number of dreams recalled by REC subjects during each night. Finally, the drastic impairment of dream recall after R night was associated to a larger increase of SWS and a shorter REM sleep duration. We suggest that dream recall could have been impaired during R night because: (i) the lower number of spontaneous awakenings over the night reduced the contents available in memory as possible cues for the retrieval of dream experiences at morning; (ii) mental experiences, having been elaborated during SWS more than in the other nights, were less dreamlike (i.e., perceptually vivid and bizarre) and, thus less accessible at morning recall than those elaborated during the nights with a higher proportion of REM sleep; (iii) dream contents, as a peculiar type of episodic information, were less consolidated because of the lower effectiveness of declarative memory during recovery sleep. PMID- 19788899 TI - Standard object recognition memory and "what" and "where" components: Improvement by post-training epinephrine in highly habituated rats. AB - The present work examined whether post-training systemic epinephrine (EPI) is able to modulate short-term (3h) and long-term (24 h and 48 h) memory of standard object recognition, as well as long-term (24 h) memory of separate "what" (object identity) and "where" (object location) components of object recognition. Although object recognition training is associated to low arousal levels, all the animals received habituation to the training box in order to further reduce emotional arousal. Post-training EPI improved long-term (24 h and 48 h), but not short-term (3 h), memory in the standard object recognition task, as well as 24 h memory for both object identity and object location. These data indicate that post-training epinephrine: (1) facilitates long-term memory for standard object recognition; (2) exerts separate facilitatory effects on "what" (object identity) and "where" (object location) components of object recognition; and (3) is capable of improving memory for a low arousing task even in highly habituated rats. PMID- 19788900 TI - Additive effects of olanzapine and melanin-concentrating hormone agonism on energy balance. AB - Atypical antipsychotic drugs (AAPDs) induce hyperphagia and body weight gain as a deleterious side effect. However, the mechanism whereby these drugs affect the neuronal pathways regulating energy balance has yet to be fully elucidated. The present study was conducted to investigate the respective and interaction effects of olanzapine and agonism of the melanin-concentrating hormone (MCH) receptor (MCHR1) on body weight, food intake, adiposity and expressions of genes liable of being involved in the anabolic action of AAPDs and MCH agonism. MCH is a hypothalamic neuropeptide, which exerts stimulating effects on food intake and body weight gain. Male Wistar rats received olanzapine (1 mg/kg of rat/day per os) and/or an intracerebroventricular (ICV) infusion of a MCHR1 agonist (30 microg/rat/day) during 13 days. Food intake and body weight were recorded daily, whereas adipose tissue depots were weighed at day 13. At the end of the experiment, we also measured brain levels of the messengers RNAs (mRNAs) encoding for MCH, MCHR1, neuropeptides-Y (NPY) and agouti-related peptide (AgRP) using in situ hybridization. The 13-day treatments combining olanzapine and the MCHR1 agonist exerted additive effects in enhancing food intake and adiposity. Consistently, each treatment differently affected brain expression of genes influencing energy balance. While the MCHR1 agonist treatment increased NPY mRNA expression in the hypothalamic arcuate nucleus, olanzapine treatment specifically increased MCHR1 mRNA expression in the nucleus accumbens shell (NAcSh). AAPDs and MCH agonism exert additive effects on energy balance and selective effects on the brain expression of energy balance-related genes. PMID- 19788901 TI - Expression of human Cu, Zn-superoxide dismutase in an insect cell-free system and its structural analysis by MALDI-TOF MS. AB - Human Cu, Zn-superoxide dismutase (hSOD1) is a homodimer that coordinates one copper and one zinc ion per monomer. These metal ions contribute to its enzymatic activity and structural stability. In addition, hSOD1 maintains an intra-subunit disulfide bond formed in the reducing environment of the cytosol and is active under a variety of stringent denaturing conditions. We report the expression of hSOD1 in a cell-free protein synthesis system constructed from Spodoptera frugiperda 21 (Sf21) insect cells, and its structural analysis including the status of the sole intra-subunit disulfide bond by mass spectrometry. By using this system hSOD1 was obtained in a soluble active form after addition of Cu(2+) and Zn(2+) and was purified with a yield of approximately 33 microg from 1 ml of reaction volume. Both enzymatic and structural analyses of the recombinant hSOD1 indicate that it was completely identical to the protein isolated from human erythrocytes. PMID- 19788902 TI - Conducting polymers, dual neurotrophins and pulsed electrical stimulation- dramatic effects on neurite outgrowth. AB - In this study the synergistic effect of delivering two neurotrophins simultaneously to encourage neuron survival and neurite elongation was explored. Neurotrophin-3 (NT-3) and brain-derived neurotrophic factor (BDNF) were incorporated into polypyrrole (PPy) during electrosynthesis and the amounts incorporated and released were determined using iodine-125 ((125)I) radio labelled neurotrophins. Neurite outgrowth from cochlear neural explants grown on the conducting polymer was equivalent to that on tissue culture plastic but significantly improved with the incorporation of NT-3 and BDNF. Neurite outgrowth from explants grown on polymers containing both NT-3 and BDNF showed significant improvement over PPy doped only with NT-3, due to the synergistic effect of both neurotrophins. Neurite outgrowth was significantly improved when the polymer containing both neurotrophins was electrically stimulated. It is envisaged that when applied to the cochlear implant, these conducting and novel polymer films will provide a biocompatible substrate for storage and release of neurotrophins to help protect auditory neurons from degradation after sensorineural hearing loss and encourage neurite outgrowth towards the electrodes. PMID- 19788903 TI - Modification and validation of a Macronutrient Preference Checklist for use in North America. AB - A Macronutrient Preference Checklist (MPC) is a simple tool that assesses momentary macronutrient and taste preferences. The purpose of this study was to modify and validate an existing European 32-item MPC and adapt it for use in North America. A total of 160 subjects completed questionnaires (demographic survey, appetite assessment, MPC, and MPC items rated on a 9-pt hedonic scale) on two occasions (Part 1). The MPC showed good internal consistency (Cronbach's alpha values of 0.76, 0.72, 0.64, and 0.57 for the four macronutrient categories of high protein, high carbohydrate, high fat, and low energy) and high test retest reliability, with strong correlations for all four macronutrient categories. A larger sample size (n=239) was used to explore the influences of age, gender, and appetite on macronutrient and taste preference (Part 2). Subjects completed study questionnaires once. The influences of appetite, age, and gender on macronutrient preferences assessed with the MPC concur with the literature, confirming the tool's validity. The MPC was found to be a valid and reliable tool that may be used as a simple and efficient method of assessing momentary macronutrient and taste preferences in future research and clinical settings in North America. PMID- 19788904 TI - Non-competitive liking for brands. No blocking in evaluative conditioning. AB - In the first experiment, we demonstrated evaluative conditioning using a novel across-modality procedure in which pictorial abstract brand logos acted as conditioned stimulus (CSs) and self-selected foods of different hedonic valence functioned as unconditioned stimuli (USs). We then investigated whether this form of learning of likes discriminates against redundant CSs using a blocking paradigm in the second experiment. The strength of evaluative conditioning accruing to the target CSs during compound training was unaffected by whether the other element of the compound was pretrained with a hedonic US. The observation that contingency learning about the target CS was blocked by the pretraining suggests that learning of likes and predictive learning are mediated by different processes. PMID- 19788905 TI - The safety of chitosan as a pharmaceutical excipient. AB - Interest in use of the polysaccharide chitosan as a pharmaceutical excipient by different dose routes and for a number of applications is not new but it still does not appear to be present in any marketed drugs. Including a novel excipient in a new drug formulation requires a number of safety considerations. Review of the published literature showed that chitosan has low oral toxicity and local tolerance potential supporting use in non-parenteral formulations. Prior human oral exposure has occurred through use of chitosan dietary supplements and food additive, medical device and cosmetic applications. Although systemic exposure to parent chitosan may be limited (due to digestion in the gastrointestinal tract), any that is absorbed will likely undergo enzyme degradation to naturally occurring glucosamine, and N-acetylglucosamine, its copolymers, which are excreted or used in the amino sugar pool. Chitosan has local biological activity in the form of haemostatic action and, together with its ability to activate macrophages and cause cytokine stimulation (which has resulted in interest in medical device and wound healing applications), may result in a more careful assessment of its safety as a parenteral excipient. PMID- 19788906 TI - Review of REACH Annex IV--establishing the minimum risk of a substance based on its intrinsic properties. AB - Registration is the main mechanism in REACH that ensures the safety of substances. However, some substances are exempted from Registration, such as those included in Annex IV. Annex IV lists substances that are exempted from Registration on the basis that 'sufficient information is known about these substances that they are considered to cause minimum risk because of their intrinsic properties'. As part of the follow up to the co-decision process on REACH, the Commission was mandated to review Annex IV. To enable consideration of whether additional substances should be added to Annex IV and whether substances currently in the Annex should remain, the Commission, together with stakeholders, operationalized the core concepts of minimum risk and sufficient information in the form of criteria. These criteria consider the intrinsic properties of the substance and are based on the classification criteria in Annex VI of Directive 67/548/EEC but were set at a level 'well below' the classification criteria to correspond with a minimum risk level. As a result of the review, Annex IV has been recently amended. This paper looks at how the agreed criteria demonstrate minimum risk and concludes that, although developed in the frame of REACH registration, they could be more widely used in the sound management of chemicals. PMID- 19788907 TI - Pharmacokinetic study of melamine in rhesus monkey after a single oral administration of a tolerable daily intake dose. AB - To perform pharmacokinetic study of melamine in rhesus monkey, melamine was orally administered to three experimental monkeys at a single dose of 1.4 mg/kg body weight. Plasma and urine were collected for the determination of melamine and cyanuric acid with a liquid chromatography tandem mass spectrometry method. The mean+/-SD area under the concentration-time curve from time zero to 48 h (AUC0-t) was 14,145+/-2002 microg/Lh. The maximum concentration of melamine in plasma (C(max)) was 1767+/-252 microg/L. The time to maximum concentration (T(max)) was 2.67+/-1.16 h and the half-life of melamine in plasma (t(1/2)) was 4.41+/-0.43 h. Following oral administration, melamine was rapidly excreted, mainly through urinary clearance. No significant correlation was found between melamine and cyanuric acid, suggesting that cyanuric acid may not be derived from melamine. PMID- 19788908 TI - Application of connectivity mapping in predictive toxicology based on gene expression similarity. AB - Connectivity mapping is the process of establishing connections between different biological states using gene-expression profiles or signatures. There are a number of applications but in toxicology the most pertinent is for understanding mechanisms of toxicity. In its essence the process involves comparing a query gene signature generated as a result of exposure of a biological system to a chemical to those in a database that have been previously derived. In the ideal situation the query gene-expression signature is characteristic of the event and will be matched to similar events in the database. Key criteria are therefore the means of choosing the signature to be matched and the means by which the match is made. In this article we explore these concepts with examples applicable to toxicology. PMID- 19788909 TI - Effect of different surface treatments on In-Ceram Alumina roughness. An AFM study. AB - OBJECTIVES: The aim of this study was to evaluate the influence of different treatments on the surface roughness of In-Ceram Alumina (VITA, Sackingen, Germany). METHODS: The ceramic blocks were polished (4000 grit) and sandblasted (SB) with airborne particle abrasion Al(2)O(3); 110 microm particle size; 2.8 bar; 20s. The following treatments were performed: (1) no treatment; (2) Rocatec System (RC): after SB treatment, sandblasting with silica powder; 30 microm particle size; 2.8 bar; 20s. (3) Neodymium:yttrium-aluminium-garnet (Nd:YAG) laser (ND) application of graphite powder (stain) on the ceramic surface and Nd:YAG laser irradiation (distance: 1mm, 100mJ, 20 Hz, 2W, and 141.54J/cm(2)). (4) Nd:YAG laser plus Rocatec System: after ND treatments, RC was applied. Digital images (20 microm x 20 microm) from the surfaces were obtained by means of an AFM microscope in taping mode (Nanoscope IIIa, Digital Instruments). Roughness was measured in 10 microm x 10 microm boxes. Roughness (R(a)) data (nm) were analyzed by one-way ANOVA (p<0.05). RESULTS: No differences in ceramic surfaces roughness occurred after any of the tested treatments (p=0.54). CONCLUSIONS: High-alumina ceramic surface roughness was not increased with any of the tested treatments. PMID- 19788910 TI - Prickle promotes neurite outgrowth via the Dishevelled dependent pathway in C1300 cells. AB - Murine Prickle1 and Prickle2 belong to the planar cell polarity genes. Prickle2 but not Prickle1 gene expression was induced in C1300 neuroblastoma cells during neurite-like process formation induced by retinoic acid (RA). Over-expression of Prickle1 or Prickle2 in C1300 cells induced striking neurite-like process formation in the absence of RA. Since Prickle binds to Dishevelled (Dvl) to induce its degradation in Drosophila, we examined the participation of Dvl protein in the neurite-like process formation of C1300 cells. Upon induction of the neurite-like process formation, the amount of Dvl1 protein decreased. Prickle1 and Prickle2 could associate with Dvl1 and over-expression of Prickle1 or Prickle2 resulted in the reduction of Dvl1 protein in C1300 cells. Furthermore, over-expression of Dvl1 in C1300 cells prevented the neurite-like process formation induced by Prickle1 or Prickle2 over-expression. Thus, Prickle1 and Prickle2 promote neurite-like process formation of C1300 cells via the Dvl1 dependent mechanism. PMID- 19788911 TI - The C1 homodimer of adenylyl cyclase binds nucleotides with high affinity but possesses exceedingly low catalytic activity. AB - Membranous adenylyl cyclase (AC) subtypes play differential roles in the regulation of cell functions. The C1- and C2-subunits of AC form a heterodimer that efficiently catalyzes cAMP formation and constitutes a very useful model system for AC analysis at a molecular level. Intriguingly, C1 and C2 homodimers exist, too. The C2 homodimer is catalytically inactive and possesses two forskolin binding sites. However, little is known about the C1 homodimer. Therefore, in this study, we examined the C1 homodimer. C1 exhibited exceedingly low catalytic activity but high substrate-affinity. Fluorescence studies with the AC inhibitor 2',3'-O-(2,4,6-trinitrophenyl)-ATP suggested that 2 mol of C1 binds 1 mol of nucleotide, pointing to homodimerization. C1 also bound the AC inhibitor 2',3'-O-(N-methylanthraniloyl)-GTP as assessed by direct fluorescence and fluorescence resonance energy transfer studies. Molecular modelling revealed that in the C1 homodimer, the catalytic base arginine is exchanged against histidine. The lower basicity and shorter side chain of histidine probably account for the low catalytic activity. In conclusion, the C1 homodimer of AC binds nucleotides with high affinity, but exhibits only exceedingly low catalytic activity. The low catalytic activity of the C1 homodimer may constitute a mechanism by which in intact cells dimeric AC molecules exhibit a high signal-to-noise ratio upon stimulation by receptor agonists. PMID- 19788912 TI - The multi-herbal medicine Gongjin-dan enhances memory and learning tasks via NGF regulation. AB - Nerve growth factor (NGF) decreases degeneration of cholinergic neurons, improves memory loss, and increases long-term potentiation and learning tasks. Therefore, NGF mimetics or NGF inducers may be important targets for the treatment of various neurodegenerative disorders. Traditionally, Gongjin-dan (GJD) has been used clinically for the treatment of central nervous system disorders. In this study, we examined the effects of GJD on NGF mimetic activity in PC12 cells and the induction of NGF secretion in primary astrocytes. Moreover, we also measured neuron survival by MAP-2 staining in an immobilization stress rat model and induction of long-term potentiation by the MEA system in rat hippocampus slices treated with dexamethasone. The behavioral syndrome by novel object test was also performed in mice. GJD increased neurite outgrowth in PC12 cells and NGF secretion in primary astrocytes. Also, it reduced neuronal cell death and increased long-term potentiation in the rat hippocampus. Moreover, the number of entries, the time spent and the distance moved in the center area of the test region by the mice was increased by oral administration of GJD in comparison with the distance moved over the total area. These data suggest that administration of GJD may improve memory and learning tasks via NGF regulation, and that it may have a potential for multiple function neuroprotection via NGF regulation. PMID- 19788913 TI - Regulation of mu opioid receptor internalization by the scaffold protein RanBPM. AB - Mu opioid receptors (MOP) are transducers of the pharmacological effects of many opioid drugs, including analgesia and tolerance/dependence. Previously, we observed increased MOP signaling during postnatal development that was not associated with increased MOP or G protein expression. A yeast two-hybrid screen of a human brain cDNA library using the MOP C-terminus as bait identified RanBPM as a potential MOP-interacting protein. RanBPM has been recognized as a multi functional scaffold protein that interacts with a variety of signaling receptors/proteins. Co-immunoprecipitation studies in HEK293 cells indicated that RanBPM constitutively associates with MOP. Functionally, RanBPM had no effect on MOP-mediated inhibition of adenylyl cyclase, yet reduced agonist-induced endocytosis of MOP. Mechanistically, RanBPM interfered with beta arrestin2-GFP translocation stimulated by MOP but not alpha(1B)-adrenergic receptor activation, indicating selectivity of action. Our findings suggest that RanBPM is a novel MOP interacting protein that negatively regulates receptor internalization without altering MOP signaling through adenylyl cyclase. PMID- 19788914 TI - Decreased opioid analgesia in weanling rats exposed to endothelin-1 during infancy. AB - Endothelin-1 produces spontaneous nociceptive-associated behaviors that are modulated by the peripheral opioid system. The present study tests the hypothesis that single or repeated exposure to endothelin-1 during infancy decreases opioid analgesia in weanling rats. Morphine analgesia was measured in male and female postnatal day 21 rats following intraplantar endothelin-1 on postnatal day 7, or 11 or both days 7 and 11. In males, exposure to endothelin-1 on postnatal day 11 or both days 7 and 11 produced a statistically significant decrease in morphine analgesia (EC(50)=0.902 and 1.326mg/kg, respectively) compared to control (EC(50)=0.486mg/kg). Similarly in females, exposure to endothelin-1 on postnatal day 11 or both days 7 and 11 produced a statistically significant decrease in morphine analgesia (EC(50)=1.367 and 1.226mg/kg, respectively) compared to control (EC(50)=0.468mg/kg). In addition, females exposed to endothelin-1 on postnatal day 7 exhibited an intermediate decrease in morphine analgesia with an EC(50) of 0.752mg/kg. In males, exposure to endothelin-1 decreased mu opioid receptor expression without changing endothelin-A receptor or endothelin-B receptor expression in the hindpaw skin. In contrast, in females, exposure to endothelin-1 increased expression of both endothelin receptors and the mu opioid receptor in hindpaw skin. These findings suggest a sex-difference in the window of vulnerability and the mechanism by which an acute nociceptive event can induce morphine tolerance. PMID- 19788916 TI - Phospholipids block nuclear factor-kappa B and tau phosphorylation and inhibit amyloid-beta secretion in human neuroblastoma cells. AB - Inflammation and oxidative stress have been shown to play a critical role in the pathophysiology that leads to neurodegeneration. Omega-6 phospholipids, e.g. dilinoleoylphosphatidylcholine (DLPC), have been shown to have anti-inflammatory properties and therefore experiments were undertaken to determine whether DLPC can prevent inflammatory neurodegenerative events in the model neuronal cell line, SH-SY5Y. Tumor necrosis factor (TNF-alpha) and H(2)O(2) activate mitogen activated protein kinase (MAPK) in SH-SY5Y cells within 5 min and this activation is completely blocked by DLPC (12 microM). DLPC blocks IkappaBalpha phosphorylation in the SH-SY5Y cells and prevents the phosphorylation and activation of nuclear factor-kappa B (NF-kappaB). The phospholipid inhibits induction of MAPK and NF-kappaB in similar fashion to the MEK1/2-inhibitor, U0126 (10 microM). DLPC completely abolishes TNF-alpha, H(2)O(2) and lipopolysaccaride (LPS)-induced neuronal tau phosphorylation. Cellular amyloid precursor protein levels are reduced by DLPC and LPS-induced amyloid-beta expression and secretion in SH-SY5Y cells are completely blocked by DLPC. Taken together, these data suggest that DLPC can act through MAPK to block neuronal inflammatory cascades and prevent potential pathological consequences in the neuronal metabolism of amyloid and tau proteins. PMID- 19788915 TI - Repeated antidepressant therapy increases cyclic GMP signaling in rat hippocampus. AB - Cyclic adenosine monophosphpate (cAMP) signaling is thought to be involved in the pathophysiology of major depressive disorder and antidepressant action; however, relatively little is known about the possible role of cyclic guanosine monophosphate (cGMP) signaling. Accumulating evidence suggests that crosstalk occurs between cAMP and cGMP pathways. There is a need to clarify the trajectory of cAMP and cGMP concentrations, their synthesis by cyclases, and degradation by phosphodiesterases (PDEs) to understand the role of cyclic mononucleotide signaling in the effect of chronic antidepressant therapy. We used quantitative real-time PCR and enzyme immunoassay to systematically investigate the expression of intracellular signaling cascade elements in the hippocampus of rats chronically treated with the antidepressants fluoxetine and amitriptyline. We found increased cGMP levels, which were consistent with our findings of decreased PDE gene expression. Immunoassay results showed unchanged cAMP levels. We conclude that increased cGMP signaling might underlie the efficacy of chronic antidepressant treatment. PMID- 19788918 TI - Molecular characterization and marker based chemotaxonomic studies of Podophyllum hexandrum Royle. AB - Detailed chemical studies and RAPD analysis were done in different populations of Podophyllum hexandrum collected from high altitude regions of North Western Himalayas. Random amplified polymorphic DNA (RAPD) analysis revealed a high degree of genetic diversity among the 12 collected accessions, attributed to their geographical and climatic conditions. HPLC analysis also revealed variation in the concentration of two major marker compounds which lead to the identification of a chemotype. The study demonstrated that RAPD and chemical markers are very useful tools to compare the genetic relationship and pattern of variation among such prioritized and endangered medicinal plants. PMID- 19788917 TI - Evidence for a role of heat shock protein-90 in toll like receptor 4 mediated pain enhancement in rats. AB - Spinal cord microglial toll-like receptor 4 (TLR4) has been implicated in enhancing neuropathic pain and opposing morphine analgesia. The present study was initiated to explore TLR4-mediated pain modulation by intrathecal lipopolysaccharide, a classic TLR4 agonist. However, our initial study revealed that intrathecal lipopolysaccharide failed to induce low-threshold mechanical allodynia in naive rats, suggestive that TLR4 agonism may be insufficient to enhance pain. These studies explore the possibility that a second signal is required; namely, heat shock protein-90 (HSP90). This candidate was chosen for study given its known importance as a regulator of TLR4 signaling. A combination of in vitro TLR4 cell signaling and in vivo behavioral studies of pain modulation suggest that TLR4-enhancement of neuropathic pain and TLR4-suppression of morphine analgesia each likely require HSP90 as a cofactor for the effects observed. In vitro studies revealed that dimethyl sulfoxide (DMSO) enhances HSP90 release, suggestive that this may be a means by which DMSO enhances TLR4 signaling. While 2 and 100 microg lipopolysaccharide intrathecally did not induce mechanical allodynia across the time course tested, co-administration of 1 microg lipopolysaccharide with a drug that enhances HSP90-mediated TLR4 signaling now induced robust allodynia. In support of this allodynia being mediated via a TLR4/HSP90 pathway, it was prevented or reversed by intrathecal co-administration of a HSP90 inhibitor, a TLR4 inhibitor, a microglia/monocyte activation inhibitor (as monocyte-derived cells are the predominant cell type expressing TLR4), and interleukin-1 receptor antagonist (as this proinflammatory cytokine is a downstream consequence of TLR4 activation). Together, these results suggest for the first time that TLR4 activation is necessary but not sufficient to induce spinally mediated pain enhancement. Rather, the data suggest that TLR4-dependent pain phenomena may require contributions by multiple components of the TLR4 receptor complex. PMID- 19788919 TI - Hydrophilic and hydrophobic amino acid copolymers for nano-comminution of poorly soluble drugs. AB - Nano-comminution has successfully brought nanoparticle formulations of poorly soluble drugs to our daily life. The key for the successful nano-comminution of a drug is the choice of a proper polymeric steric stabilizer. To systematically elucidate the rationale of stabilizer selection, two types of helical amino acid copolymers, relatively hydrophilic and hydrophobic copolymers, were used in nano comminution. The hydrophilic copolymers had lysine as their major component. The addition of relatively hydrophobic leucine and phenylalanine to them could not make significant changes in particle size. However, when a small amount of hydrophilic glutamic acid or lysine was added into elastin-like hydrophobic copolymers of valine, glycine, and proline, significant composition dependence was found. Therefore, specific interactions between the functional groups of polymers and drug surfaces seem to be important for successful nano-comminution. The stimuli responsive behavior of the hydrophobic copolymer induced the temperature dependence of particle size. PMID- 19788921 TI - Non-apoptotic Fas signaling regulates invasiveness of glioma cells and modulates MMP-2 activity via NFkappaB-TIMP-2 pathway. AB - Fas (CD95/APO-1) is a cell surface "death receptor" that mediates apoptosis upon engagement by its ligand, FasL. Paradoxically, Fas/FasL can also promote cell invasion among non-apoptotic cells; here, we show that Fas/FasL signaling can promote tumor invasion when apoptosis is compromised. We have developed a recombinant FasL Interfering Protein (FIP) to interfere with Fas signaling in C6 glioma cells expressing both Fas receptor and its ligand. FIP administration did not affect cell viability but impaired cell motility and invasiveness of glioma cells. Blockade of Fas signaling reduced MMP-2 activity in glioma cells, that was associated with down-regulation of MAPK signaling, and AP-1 and NFkappaB-driven transcription. FIP treatment did not affect mmp-2 and mt1-mmp expression but significantly attenuated timp-2 expression and TIMP-2 amount in the culture medium. Studies with pharmacological inhibitors of JNK/c-Jun (SP600125) and NFkappaB (BAY11-7082) signaling pathways demonstrated that timp-2 expression is regulated by NFkappaB transcription factor. Our findings show that non-apoptotic Fas signaling activated in the autocrine manner or through microenvironment derived factors can regulate invasiveness of glioma cells via modulation of MMP-2 activation, likely by controlling TIMP-2 expression. PMID- 19788920 TI - Pitch, harmonicity and concurrent sound segregation: psychoacoustical and neurophysiological findings. AB - Harmonic complex tones are a particularly important class of sounds found in both speech and music. Although these sounds contain multiple frequency components, they are usually perceived as a coherent whole, with a pitch corresponding to the fundamental frequency (F0). However, when two or more harmonic sounds occur concurrently, e.g., at a cocktail party or in a symphony, the auditory system must separate harmonics and assign them to their respective F0s so that a coherent and veridical representation of the different sounds sources is formed. Here we review both psychophysical and neurophysiological (single-unit and evoked potential) findings, which provide some insight into how, and how well, the auditory system accomplishes this task. A survey of computational models designed to estimate multiple F0s and segregate concurrent sources is followed by a review of the empirical literature on the perception and neural coding of concurrent harmonic sounds, including vowels, as well as findings obtained using single complex tones with mistuned harmonics. PMID- 19788922 TI - Myeloperoxidase-derived oxidants selectively disrupt the protein core of the heparan sulfate proteoglycan perlecan. AB - The potent oxidants hypochlorous acid (HOCl) and hypobromous acid (HOBr) are produced extracellularly by myeloperoxidase, following release of this enzyme from activated leukocytes. The subendothelial extracellular matrix is a key site for deposition of myeloperoxidase and damage by myeloperoxidase-derived oxidants, with this damage implicated in the impairment of vascular cell function during acute inflammatory responses and chronic inflammatory diseases such as atherosclerosis. The heparan sulfate proteoglycan perlecan, a key component of the subendothelial extracellular matrix, regulates important cellular processes and is a potential target for HOCl and HOBr. It is shown here that perlecan binds myeloperoxidase via its heparan sulfate side chains and that this enhances oxidative damage by myeloperoxidase-derived HOCl and HOBr. This damage involved selective degradation of the perlecan protein core without detectable alteration of its heparan sulfate side chains, despite the presence of reactive GlcNH(2) residing within this glycosaminoglycan. Modification of the protein core by HOCl and HOBr (measured by loss of immunological recognition of native protein epitopes and the appearance of oxidatively-modified protein epitopes) was associated with an impairment of its ability to support endothelial cell adhesion, with this observed at a pathologically-achievable oxidant dose of 425nmol oxidant/mg protein. In contrast, the heparan sulfate chains of HOCl/HOBr modified perlecan retained their ability to bind FGF-2 and collagen V and were able to promote FGF-2-dependent cellular proliferation. Collectively, these data highlight the potential role of perlecan oxidation, and consequent deregulation of cell function, in vascular injuries by myeloperoxidase-derived HOCl and HOBr. PMID- 19788923 TI - Electrochemiluminescent immunoassay for rat skeletal troponin I (Tnni2) in serum. AB - INTRODUCTION: The identification of xenobiotic-induced skeletal muscle toxicities through the detection of biomarkers in nonclinical studies can be useful early in the drug discovery process to aid in candidate drug decisions. Skeletal muscle troponin I (sTnI) has been identified as a potential marker of skeletal muscle injury in humans and animals. When skeletal muscle tissue is injured, sTnI is released into circulation. METHODS: Due to the nature of the troponin subunits to form intermolecular complexes and to oxidize under various environmental conditions, the optimal assay required the use of a combination of chelating and reducing agents in the sample preparation. It also required the selection of capture and detection antibodies with specificity to the reduced sTnI monomeric subunit and includes a capture antibody specific for sTnI Type 2 (Tnni2), which is associated with Type 2 "fast twitch" muscle fibers. RESULTS: We have developed a sensitive and specific assay to detect the concentration of rat sTnI in serum using an electrochemiluminescent (ECL) immunoassay platform with a sensitivity of 2.4 ng/ml and with minimal cross-reactivity with rat cardiac TnI (Tnni3). DISCUSSION: The use of additives and the wide dynamic range of the ECL platform resulted in an accurate and consistent ECL immunoassay that was able to specifically detect sTnI (Tnni2) in rat serum. This method can be applied to safety assessment in early drug development. PMID- 19788925 TI - Adipokine gene transcription level in adipose tissue of runt piglets. AB - Runt piglets were used as a model for neonatal stress to test the hypothesis that stress during the pre-weaning period can alter adipokine gene transcription levels. Runts were selected by birth mass <1kg and compared to littermates (controls) of mean litter weight. Subcutaneous (SQ) and perirenal (PR) adipose tissues were collected at d1 (n=5), d7 (n=7) or d21 (n=9) of age. Real time PCR was used to quantify mRNA abundance for: leptin, adiponectin, interleukin 1beta (IL1beta), IL6, IL8, IL10, IL15, tumor necrosis factor alpha, haptoglobin, macrophage migration inhibitory factor (MIF), monocyte chemotactic protein, vascular endothelial growth factor and cyclophilin. Leptin and adiponectin mRNA abundance were lower, while IL1beta, IL6, IL10 and MIF mRNA abundance were higher in SQ of runts than controls at d1 (P<0.05). Leptin, IL6, IL10, haptoglobin and MIF mRNA abundance were higher in PR from runts than controls at d7 (P<0.05) and MIF mRNA abundance was elevated by 30 fold in PR of runts at d21 (P<0.001). Thus, stressors affecting neonatal runts produce different responses in adipokine gene transcription by PR and SQ than in normal sized littermates. PMID- 19788924 TI - Mitochondria as metabolizers and targets of nitrite. AB - Mitochondrial function is integral to maintaining cellular homeostasis through the production of ATP, the generation of reactive oxygen species (ROS) for signaling, and the regulation of the apoptotic cascade. A number of small molecules, including nitric oxide (NO), are well-characterized regulators of mitochondrial function. Nitrite, an NO metabolite, has recently been described as an endocrine reserve of NO that is reduced to bioavailable NO during hypoxia to mediate physiological responses. Accumulating data suggests that mitochondria may play a role in metabolizing nitrite and that nitrite is a regulator of mitochondrial function. Here, what is known about the interactions of nitrite with the mitochondria is reviewed, with a focus on the role of the mitochondrion as a metabolizer and target of nitrite. PMID- 19788926 TI - Activity of antioxidant enzymes and physiological responses in ark shell, Scapharca broughtonii, exposed to thermal and osmotic stress: effects on hemolymph and biochemical parameters. AB - Changes in water temperature and salinity are responsible for a variety of physiological stress responses in aquatic organisms. Stress induced by these factors was recently associated with enhanced reactive oxygen species (ROS) generation, which caused oxidative damage. In the present study, we investigated the time-related effects of changes in water temperature and salinity on mRNA expression and the activities of antioxidant enzymes (SOD and CAT) and lipid peroxidation (LPO) in the gills and digestive glands of the ark shell, Scapharca broughtonii. To investigate physiological responses, hydrogen peroxide (H(2)O(2)), lysozyme activity, aspartate aminotransferase (AspAT), and alanine aminotransferase (AlaAT) were measured in the hemolymph. Water temperature and salinity changes significantly increased antioxidant enzyme mRNA expression and activity in the digestive glands and gills in a time-dependent manner. H(2)O(2) concentrations increased significantly in the high-temperature and hyposalinity treatments. LPO, AspAT and AlaAT levels also increased significantly in a time dependent manner, while lysozyme activity decreased. These results suggest that antioxidant enzymes play important roles in reducing oxidative stress in ark shells exposed to changes in water temperature and salinity. PMID- 19788927 TI - Characterization of an ovary-specific glutathione peroxidase from the shrimp Metapenaeus ensis and its role in crustacean reproduction. AB - In vertebrates, both reactive oxygen species (ROS) and the corresponding scavenging system components especially glutathione peroxidase (GPx) are indispensible for normal development of the gonads. To investigate the function of GPx in crustaceans, we cloned and characterized a full length GPx (MeGPx) transcript in the penaeid shrimp Metapenaeus ensis. Phylogenetic analysis showed that MeGPx clustered with the GPx from mollusks and nematodes and shared much higher similarity with vertebrate GPx3 and GPx5 than with GPx1 or GPx2. Multiple sequence alignment further demonstrated that MeGPx is evolutionarily conserved among invertebrates, with common functionally important motifs. MeGPx was specifically expressed in shrimp ovaries, but not in other tissues studied, including testis. In situ hybridization showed that MeGPx was highly expressed in pre-vitellogenic and mid-vitellogenic oocytes, while no expression was detected in late-vitellogenic oocytes. Moreover, real time PCR showed high level expression of MeGPx in the early ovaries. Since active protein synthesis and deposition occurred in mid-vitellogenic oocytes, MeGPx might play a pivotal role in preventing oocytes from oxidative damage and balancing ROS production. The present findings on shrimp GPx provide insights on the regulation of ROS in the ovarian maturation process and the role of GPx in crustacean reproductive biology. PMID- 19788928 TI - Prostaglandin E2 at new glance: novel insights in functional diversity offer therapeutic chances. AB - Prostaglandin E(2) (PGE(2)) is the most abundant eicosanoid and a very potent lipid mediator. PGE(2) is produced predominantly from arachidonic acid by its tightly regulated cyclooxygenases (COX) and prostaglandin E synthases (PGES). Secreted PGE(2) acts in an autocrine or paracrine manner through its four cognate G protein coupled receptors EP1 to EP4. Under physiological conditions, PGE(2) is key in many biological functions, such as regulation of immune responses, blood pressure, gastrointestinal integrity, and fertility. Deregulated PGE(2) synthesis or degradation is associated with severe pathological conditions like chronic inflammation, Alzheimer's disease, or tumorigenesis. Therefore, pharmacological inhibition of COX enzymes and PGE(2) receptor antagonism is of great therapeutic interest. PMID- 19788930 TI - Masquerading primary liver leiomyosarcoma as a hemorrhagic hepatoma. PMID- 19788931 TI - Efficacy of esophageal impedance/pH monitoring in patients with refractory gastroesophageal reflux disease, on and off therapy. PMID- 19788929 TI - Liver regeneration: alternative epithelial pathways. AB - Loss of hepatic tissue triggers a regenerative response in the whole organ. Under typical normal conditions, all hepatic cells (epithelial: hepatocytes and biliary epithelial cells; non-epithelial: stellate cells, macrophages and endothelial cells) undergo one to three rounds of replication to establish the original number of cells and restore organ size. The review summarizes the literature of regenerative patterns in situations in which proliferation of either hepatocytes or biliary epithelial cells is inhibited. The evidence strongly suggests that under these circumstances, hepatocytes or biliary epithelial cells can function as facultative stem cells for each other and replenish the inhibited cellular compartment by a process of transdifferentiation, involving complex signaling pathways. These pathways are activated under experimental conditions in rodents and in fulminant hepatitis associated with liver failure in humans. Mechanistic analysis of these pathways has implications for liver biology and for potential therapeutic modalities in human liver disease. PMID- 19788932 TI - Blitzkrieg for barrett's esophagus containing early neoplasia. PMID- 19788933 TI - Recruitment and retention of women for clinical leiomyoma trials. AB - BACKGROUND: Subject recruitment and retention in clinical leiomyoma trials is challenging. We evaluated strategies to increase patient enrollment and completion in leiomyoma trials. MATERIALS AND METHODS: Randomized trials for treatment of symptomatic leiomyoma published from 2000 through 2008 were evaluated and thirteen trials were selected. Subject enrollment and completion rates, recruitment methods and reasons for patient drop-out were assessed. RESULTS: Recruitment by study personnel or clinic staff during evaluation for symptomatic leiomyoma was the most common strategy for enrollment. Additional methods included local media, internet postings and physician referrals. Seven to 85% of patients enrolled after screening, with a median enrollment of 70%. Sixty five to 100% of patients completed the study after enrollment with a median completion rate of 89%. Reasons for drop-out at the screening stage included failure to meet inclusion criteria, patient refusal and patient preference for specific treatment. Commonly reported reasons for drop-out after enrollment were refusal of treatment following randomization, adverse reaction to study intervention and non-compliance with study protocol or follow-up visits. CONCLUSION: Women with symptomatic uterine leiomyomas may be attracted to participate in leiomyoma trials, however desire for specific treatment and persistent symptoms following intervention may hinder their participation. Randomization to placebo treatment and stringent inclusion criteria appear to adversely impact accrual. A wide range of recruiting tactics is needed and media sources or direct mailings may prove particularly effective to improve subject recruitment and retention in clinical leiomyoma trials. PMID- 19788934 TI - Immunomodulating effects of Korean mistletoe lectin in vitro and in vivo. AB - The immunomodulatory effects of Korean mistletoe lectin (KML), one of the major active components in Viscum album L. var. coloratum, were investigated in vitro in immune cell proliferation and natural killer (NK) cell- and macrophage mediated cytotoxicity, and in vivo in the forced swim test and cold stress. In mitogen-induced lymphocyte proliferation of murine splenocytes, concanavalin A and lipopolysaccharide significantly increased the proliferation of T cell and B cell lymphocytes, respectively. KML exposure increased lymphocyte proliferation in response to mitogen. KML also increased the splenic NK cell and macrophage activities in vitro. Exposure to KML increased production of cytokines such as interleukin-1 and interleukin-6 by macrophages. Two-week treatment with KML (30, 100, 300 and 600 microg/kg) increased the recruitment of lymphocytes, monocytes and macrophages. In the forced swim test, the immobility time was significantly attenuated by treatment with KML (300 and 600 microg/kg). In a cold stress experiment, spleen and thymus weight increased in KML-treated mice, while the weight of adrenal gland was lower than that in vehicle-treated mice. The levels of serum aminotransferases, lactate dehydrogenase and alkaline phosphatase were decreased by KML treatment. KML treatment also induced increases in the percentages of CD4(+) and CD8(+) cells in thymus. Our results suggest that KML enhances the immune system through modulation of lymphocytes, NK cells, and macrophages. PMID- 19788935 TI - Oral administration of xanthan gum enhances antitumor activity through Toll-like receptor 4. AB - PURPOSE: Xanthan gum (XG) is a complex exopolysaccharide produced by the plant pathogenic bacterium Xanthomonas campestris pv. and is widely used as a thickener or viscosifier. We examined in this study the antitumor effects of XG. EXPERIMENTAL DESIGN: Cytokine production by XG-stimulated murine macrophage cell lines, J772 and RAW264.7, and peritoneal adherent cells from wild type C57BL/6 mice, TLR2 or MyD88-deficient mice, C3H/HeN, and TLR4-mutant C3H/HeJ mice were examined. In order to examine in vivo antitumor effects of XG, mice were inoculated subcutaneously with tumor cells and administered orally with XG once every 5days from 1day before the tumor inoculation. Tumor growth, mouse survival, NK activity, and tumor-specific cytotoxicity were examined. RESULTS: In vitro culture with XG induced interleukin-12 and tumor necrosis factor-alpha production from macrophages. XG stimulated macrophages in a MyD88-dependent manner and was mainly recognized by Toll-like receptor 4 (TLR4). Oral administration of XG significantly retarded tumor growth and prolonged survival of the mice inoculated subcutaneously with B16K(b) melanoma cells. NK activity as well as tumor-specific cytotoxicity of CD8 T cells was augmented in the XG-treated mice. The in vivo antitumor effects of XG were also dependent on TLR-4, as C3H/HeJ mice, which lack TLR4 signaling, exhibited no effect of XG on the growth of syngeneic bladder tumor, MBT-2. CONCLUSION: These results suggest beneficial effects of oral administration of XG on immune-surveillance against neoplasms. PMID- 19788936 TI - Immunomodulation of Rheum tanguticum polysaccharide (RTP) on the immunosuppressive effects of dexamethasone (DEX) on the treatment of colitis in rats induced by 2,4,6-trinitrobenzene sulfonic acid. AB - Dexamethasone (DEX) is still the main choice for colitis, although the immunosuppressive side effects are still the troublesome problems to overcome. In our previous study, Rheum tanguticum polysaccharide (RTP), extracted from traditional Chinese medicine rhubarb, targeted mannose receptor, showed immunoregulatory effect on the balance of Th1 and Th2 polarization in colitis rats. For the present study, we hypothesized that RTP could regulate the immunosuppressive effects of DEX. Taking advantage of the colon delivery ability of the polysaccharide, we prepared the double emulsion of RTP microsphere containing DEX to investigate the potential immunoregulatory effects of RTP on DEX immunosuppression in TNBS-induced colitis in rats. As expected, DEX-RTP microsphere showed not only significant immunomodulatory effects, but also strong anti-inflammation. The microsphere balanced enteric bacteria disorder, decreased TLR4 activation and promoted the balance of Th1 and Th2 polarization, inhibited NF-kappaB activity. Especially, DEX-RTP showed significant colon injury reparation. DEX alone exhibited a strong anti-inflammatory effect by suppressing MPO activity, down-regulate NF-kappaB activity and Th1 cytokines production. However, DEX showed severe immunosuppressive effects. It aggravated the intestinal commensal bacteria disorder, induced thymus atrophy and the further imbalance of Th1/Th1 cytokine polarization. RTP showed significant immunoregulatory effects. A significant protection on the intestinal bacterial balance, TLR4 and NF-kappaB activation decreased, and Th1/Th2 cytokine production balance were showed in RTP. In conclusion, DEX-RTP microsphere delivered DEX directly to the colon avoiding the absorption at the upper intestinal tract and showed synergistic effects on colitis both from the strong anti-inflammatory effects of DEX and from the immunoregulation of RTP. PMID- 19788937 TI - Mitochondrial copy number and risk of breast cancer: a pilot study. AB - It has been proposed that the copy number of mitochondria DNA (mtDNA) per cell reflects gene-environment interactions between unknown hereditary factors and exposures affecting levels of oxidative stress. However, whether copy number of mtDNA could be a risk predictor of oxidative stress-related human cancers, such as breast cancer, remains to be determined. To explore the role of mtDNA copy number in breast cancer etiology, we analyzed mtDNA copy number in whole blood from 103 patients with breast cancer and 103 matched control subjects and examined in relation to endogenous antioxidants. Case patients with breast cancer had a statistically significantly higher mtDNA copy number than control subjects (median: 1.29 vs. 0.80, P<0.01). High mtDNA copy number (above the median in controls) was associated with a statistically significantly increased risk of breast cancer, compared with low copy number (Odds ratio (OR)=4.67, 95% CI: 2.45 8.92), with a statistically significant dose-response relationship in trend analysis (P<0.01). Moreover, mtDNA copy number was significantly inversely associated with several important endogenous oxidants and antioxidants in blood in either the cases (total glutathione, CuZn-SOD activity and myeloperoxidase (MPO)) or the controls (catalase (CAT) activity). These results suggest the mtDNA copy number could be associated with risk of breast cancer, perhaps through an oxidative stress mechanism. PMID- 19788938 TI - Ancient mitogenomics. AB - The mitochondrial genome has been the traditional focus of most research into ancient DNA, owing to its high copy number and population-level variability. Despite this long-standing interest in mitochondrial DNA, it was only in 2001 that the first complete ancient mitogenomic sequences were obtained. As a result of various methodological developments, including the introduction of high throughput sequencing techniques, the total number of ancient mitogenome sequences has increased rapidly over the past few years. In this review, we present a brief history of ancient mitogenomics and describe the technical challenges that face researchers in the field. We catalogue the diverse sequencing methods and source materials used to obtain ancient mitogenomic sequences, summarise the associated genetic and phylogenetic studies that have been conducted, and evaluate the future prospects of the field. PMID- 19788939 TI - Molecular cloning of lamprey uncoupling protein and assessment of its uncoupling activity using a yeast heterologous expression system. AB - We report the molecular cloning of a novel cDNA fragment from lamprey encoding a 313-amino acid protein that is highly homologous to human uncoupling proteins (UCP). We therefore named the protein lamprey UCP. This lamprey UCP, rat UCP1, human UCP2, and human mitochondrial oxoglutarate carrier were individually expressed in Saccharomyces cerevisiae and the recombinant yeast mitochondria were isolated and assayed for the state 4 respiration rate and proton leak. Only UCP1 showed a strong (3.6-fold increase of the ratio of mitochondrial state 4 respiration rate to FCCP-stimulated fully uncoupled respiration rate) and GDP inhibitable uncoupling activity, while the uncoupling activities of both UCP2 and lamprey UCP were relatively weak (1.5-fold and 1.4-fold, respectively) and GDP insensitive. The oxoglutarate carrier had no effect on the studied parameters. In conclusion, the lamprey UCP has a mild, unregulated uncoupling activity in the yeast system, which resembles UCP2, but not UCP1. PMID- 19788941 TI - Lung volume recruitment maneuvers and respiratory system mechanics in mechanically ventilated mice. AB - The study aim was to establish how recruitment maneuvers (RMs) influence lung mechanics and to determine whether RMs produce lung injury. Healthy BALB/c mice were allocated to receive positive end-expiratory pressure (PEEP) at 2 or 6 cmH(2)O and volume- (20 or 40 mL/kg) or pressure-controlled (25 cmH(2)O) RMs every 5 or 75 min for 150 min. The low-frequency forced oscillation technique was used to measure respiratory input impedance. Large RMs resulting in peak airway opening pressures (P(ao))>30 cmH(2)O did not increase inflammatory response or affect transcutaneous oxygen saturation but significantly lowered airway resistance, tissue damping and tissue elastance; the latter changes are likely associated with the bimodal pressure-volume behavior observed in mice. PEEP increase alone and application of RMs producing peak P(ao) below 25 cmH(2)O did not prevent or reverse changes in lung mechanics; whereas frequent application of substantial RMs on top of elevated PEEP levels produced stable lung mechanics without signs of lung injury. PMID- 19788940 TI - Osteoclast motility: putting the brakes on bone resorption. AB - As the skeleton ages, the balanced formation and resorption of normal bone remodeling is lost, and bone loss predominates. The osteoclast is the specialized cell that is responsible for bone resorption. It is a highly polarized cell that must adhere to the bone surface and migrate along it while resorbing, and cytoskeletal reorganization is critical. Podosomes, highly dynamic actin structures, mediate osteoclast motility. Resorbing osteoclasts form a related actin complex, the sealing zone, which provides the boundary for the resorptive microenvironment. Similar to podosomes, the sealing zone rearranges itself to allow continuous resorption while the cell is moving. The major adhesive protein controlling the cytoskeleton is alphavbeta3 integrin, which collaborates with the growth factor M-CSF and the ITAM receptor DAP12. In this review, we discuss the signaling complexes assembled by these molecules at the membrane, and their downstream mediators that control OC motility and function via the cytoskeleton. PMID- 19788942 TI - Chitosan/polyester-based scaffolds for cartilage tissue engineering: assessment of extracellular matrix formation. AB - Naturally derived polymers have been extensively used in scaffold production for cartilage tissue engineering. The present work aims to evaluate and characterize extracellular matrix (ECM) formation in two types of chitosan-based scaffolds, using bovine articular chondrocytes (BACs). The influence of these scaffolds' porosity, as well as pore size and geometry, on the formation of cartilagineous tissue was studied. The effect of stirred conditions on ECM formation was also assessed. Chitosan-poly(butylene succinate) (CPBS) scaffolds were produced by compression moulding and salt leaching, using a blend of 50% of each material. Different porosities and pore size structures were obtained. BACs were seeded onto CPBS scaffolds using spinner flasks. Constructs were then transferred to the incubator, where half were cultured under stirred conditions, and the other half under static conditions for 4 weeks. Constructs were characterized by scanning electron microscopy, histology procedures, immunolocalization of collagen type I and collagen type II, and dimethylmethylene blue assay for glycosaminoglycan (GAG) quantification. Both materials showed good affinity for cell attachment. Cells colonized the entire scaffolds and were able to produce ECM. Large pores with random geometry improved proteoglycans and collagen type II production. However, that structure has the opposite effect on GAG production. Stirred culture conditions indicate enhancement of GAG production in both types of scaffold. PMID- 19788943 TI - Hyperbranched polyglycerol electrospun nanofibers for wound dressing applications. AB - This study reports on the performance of electrospun hyperbranched polyglycerol nanofibers capable of providing an active agent delivery for wound dressing applications. The aim of this work was to prepare electrospun HPGL nanofibers containing Calendula officinalis as a wound-healing and anti-inflammatory agent. The morphology of the electrospun HPGL-C. officinalis nanofibers was analyzed using a scanning electron microscope. The results showed that the diameters of the fibers were in nanoscales. The release of C. officinalis from the electrospun HPGL fibers was determined by HPLC at a physiological temperature (37 degrees C). Rapid release of the C. officinalis from the electrospun HPGL-C. officinalis nanofibers was exhibited as result of the high swelling ability as well as the high porosity of the electrospun HPGL-C. officinalis membranes. The degree of swelling, and the mechanical and biocompatible properties of the electrospun HPGL fibers were determined. The results showed that, in physiological conditions, the water absorption into the HPGL electrospun fibers slowed down, governed by the rate at which the electrospun HPGL-C. officinalis membranes interacted with the physiological fluid. The rate of release of C. officinalis seemed to depend on the C. officinalis content in the HPGL nanofibers. From the elastic modulus, it could be seen that elastic electrospun HPGL fibers were obtained with increments of C. officinalis content in the HPGL-C. officinalis membranes. The results of in vivo experiments in rats suggested that HPGL-C. officinalis might be an interesting bioactive wound dressing material for clinical applications. PMID- 19788944 TI - Effect of hydroxyapatite on the biodegradation and biomechanical stability of polyester nanocomposites for orthopaedic applications. AB - The effect of hydroxyapatite (HAP) on the performance of nanocomposites of an unsaturated polyester, i.e., hydroxy-terminated high molecular weight poly(proplyene fumarate) (HT-PPFhm), was investigated. A thermoset nanocomposite was prepared with nanoparticles of calcined HAP (<100 nm, rod-like shape, filler content 30 wt.%), HT-PPFhm and N-vinyl pyrrolidone, dibenzoyl peroxide and N,N dimethyl aniline. Two more nanocomposites were prepared with precipitated HAP nanoparticles (<100 nm rod-like shape) and commercially available HAP nanoparticles (<200 nm spherical shape), respectively. Calcined HAP nanoparticles resulted in very good crosslinking in the resin matrix with high crosslinking density and interfacial bonding with the polymer, owing to the rod-like shape of the nanoparticles; this gave improved biomechanical strength and modulus and also controlled degradation of the nanocomposite for scaffold formation. The tissue compatibility and osteocompatibility of the nanocomposite containing calcined HAP nanoparticles was evaluated. The tissue compatibility was studied by intramuscular implantation in a rabbit animal model for 3 months as per ISO standard 10993/6. The in vivo femoral bone repair was also carried out in the rabbit animal model as per ISO standard 10993/6. The nanocomposite containing calcined HAP nanoparticles is both biocompatible and osteocompatible. PMID- 19788945 TI - Magnesium alloys as implant materials--principles of property design for Mg-RE alloys. AB - Magnesium alloys have attracted increasing interest in the past years due to their potential as implant materials. This interest is based on the fact that magnesium and its alloys are degradable during their time of service in the human body. Moreover magnesium alloys offer a property profile that is very close or even similar to that of human bone. The chemical composition triggers the resulting microstructure and features of degradation. In addition, the entire manufacturing route has an influence on the morphology of the microstructure after processing. Therefore the composition and the manufacturing route have to be chosen carefully with regard to the requirements of an application. This paper discusses the influence of composition and heat treatments on the microstructure, mechanical properties and corrosion behaviour of cast Mg-Gd alloys. Recommendations are given for the design of future degradable magnesium based implant materials. PMID- 19788946 TI - A novel route in bone tissue engineering: magnetic biomimetic scaffolds. AB - In recent years, interest in tissue engineering and its solutions has increased considerably. In particular, scaffolds have become fundamental tools in bone graft substitution and are used in combination with a variety of bio-agents. However, a long-standing problem in the use of these conventional scaffolds lies in the impossibility of re-loading the scaffold with the bio-agents after implantation. This work introduces the magnetic scaffold as a conceptually new solution. The magnetic scaffold is able, via magnetic driving, to attract and take up in vivo growth factors, stem cells or other bio-agents bound to magnetic particles. The authors succeeded in developing a simple and inexpensive technique able to transform standard commercial scaffolds made of hydroxyapatite and collagen in magnetic scaffolds. This innovative process involves dip-coating of the scaffolds in aqueous ferrofluids containing iron oxide nanoparticles coated with various biopolymers. After dip-coating, the nanoparticles are integrated into the structure of the scaffolds, providing the latter with magnetization values as high as 15 emu g(-)(1) at 10 kOe. These values are suitable for generating magnetic gradients, enabling magnetic guiding in the vicinity and inside the scaffold. The magnetic scaffolds do not suffer from any structural damage during the process, maintaining their specific porosity and shape. Moreover, they do not release magnetic particles under a constant flow of simulated body fluids over a period of 8 days. Finally, preliminary studies indicate the ability of the magnetic scaffolds to support adhesion and proliferation of human bone marrow stem cells in vitro. Hence, this new type of scaffold is a valuable candidate for tissue engineering applications, featuring a novel magnetic guiding option. PMID- 19788947 TI - In situ elasticity modulation with dynamic substrates to direct cell phenotype. AB - Microenvironment elasticity influences critical cell functions such as differentiation, cytoskeletal organization, and process extension. Unfortunately, few materials allow elasticity modulation in real time to probe its direct effect on these dynamic cellular processes. Here, a new approach is presented for the photochemical modulation of elasticity within the cell's microenvironment at any point in time. A photodegradable hydrogel was irradiated and degraded under cytocompatible conditions to generate a wide range of elastic moduli similar to soft tissues and characterized using rheometry and atomic force microscopy (AFM). The effect of the elastic modulus on valvular interstitial cell (VIC) activation into myofibroblasts was explored. In these studies, gradient samples were used to identify moduli that either promote or suppress VIC myofibroblastic activation. With this knowledge, VICs were cultured on a high modulus, activating hydrogel substrate, and uniquely, results show that decreasing the substrate modulus with irradiation reverses this activation, demonstrating that myofibroblasts can be de activated solely by changing the modulus of the underlying substrate. This finding is important for the rational design of biomaterials for tissue regeneration and offers insight into fibrotic disease progression. These photodegradable hydrogels demonstrate the capability to both probe and direct cell function through dynamic changes in substrate elasticity. PMID- 19788948 TI - Correlation of nosocomial bloodstream infection incidences: an ecological study. AB - This study aimed to correlate nosocomial bloodstream infections (NBIs) across time against the ecological effect of infection control activities. All patients hospitalised >or=48h in the haematology and intensive care departments of a university hospital and discharged between 1 January 2004 and 30 June 2006 were prospectively included. The case definition of NBI infection was: (1) at least one positive blood culture justified by clinical signs, or (2) at least two positive blood cultures when the micro-organism was one of the following: coagulase-negative staphylococci, Bacillus spp. (except Bacillus anthracis), Corynebacterium spp., Propionibacterium spp., Micrococcus spp., or other commensal with similar pathogenicity, if occurring >or=48h after patient admission. NBI incidences were correlated in quarterly intervals using Spearman's test and linear regression. In total, 3829 patients accounting for 46 474 patient days at risk were included. We identified 101 NBIs in intensive care and 286 NBIs in haematology. There was a correlation between NBI incidence in haematology with the NBI incidence in intensive care (r=0.68, P=0.042). The linear model for NBI incidences between departments was R(2)=0.52, with a positive trend (P=0.029). A common determinant such as improved hygiene measures is the most likely reason for this association. PMID- 19788949 TI - Origin of epidemic clones of acinetobacter in the critically ill. PMID- 19788950 TI - Protein and energy metabolism in type 1 diabetes. AB - Profound metabolic changes occur in people with type 1 diabetes mellitus during insulin deprivation. These include an increase in basal energy expenditure and reduced mitochondrial function. In addition, protein metabolism is significantly affected during insulin deprivation. A greater increase in whole-body protein breakdown than protein synthesis occurs resulting in a net protein loss. During insulin deprivation the splanchnic bed has a net protein accretion which accounts for the total increase in whole-body protein synthesis while muscle is in a net catabolic state. PMID- 19788951 TI - Tuberculosis and syndemics: implications for Pacific health in New Zealand. AB - Syndemics have been conceived of as a way of approaching the multiple levels of causation and linkage between two or more health conditions and their socio political environment. Our aim in this paper is to use the established literature on syndemic relationships to examine possible interactions involving tuberculosis. In particular, we explore the linkages between tuberculosis and diabetes mellitus which, we argue, is of particular relevance to Pacific populations resident in New Zealand. Reviewing current literature, we identify multiple synergies between these two diseases whereby their mutual presence has an amplified negative effect. Both conditions interact with other practices and aspects of the broader political economic context such as smoking, housing, and nutrition. A syndemic approach to Pacific health is argued as an effective way to address research, policy and prevention questions. PMID- 19788952 TI - Household water use behavior: an integrated model. AB - Water authorities are dealing with the challenge of ensuring that there is enough water to meet demand in the face of drought, population growth and predictions of reduced supply due to climate change. In order to develop effective household demand management programs, water managers need to understand the factors that influence household water use. Following an examination and re-analysis of current water consumption behavioral models we propose a new model for understanding household water consumption. We argue that trust plays a role in household water consumption, since people will not save water if they feel others are not minimizing their water use (inter-personal trust). Furthermore, people are less likely to save water if they do not trust the water authority (institutional trust). This paper proposes that to fully understand the factors involved in determining household water use the impact of trust on water consumption needs investigation. PMID- 19788953 TI - Research in rehabilitation medicine: methodological challenges. AB - OBJECTIVE: To provide an overview of methodological issues specifically related to the evaluation of rehabilitation interventions studies. STUDY DESIGN AND SETTING: Narrative review covering studies evaluating interventions in rehabilitation medicine with methodological issues. RESULTS: Four main methodological issues could be identified. First, the inclusion of patients. Patients should be selected based on having the problem being addressed by the intervention and not based on other criteria such as disease diagnosis. Second, the description of the intervention. Rehabilitation is a problem-solving process undertaken by one group of people (therapists) with another group (patient and family). The specific intervention being studied is only one of many that may affect outcome. Describing the whole package is a real challenge. Third, the control group. A control intervention has to raise equal expectations in patients and therapists. Expectation bias is a very probable influence on measured outcomes. Fourth, the definition of an appropriate outcome. In contrast to traditional biomedical research, rehabilitation research should have at least one "process" (proximate) or intervening variable measure and several distal primary outcome measures. PMID- 19788954 TI - Sequential design with boundaries approach in pediatric intervention research reduces sample size. AB - OBJECTIVE: To estimate the difference between the number of subjects actually included in pediatric sequential trials and the sample size that would have been included with a fixed-sample design. STUDY DESIGN AND SETTING: A systematic review of pediatric sequential trials was performed. Methodological quality was assessed using a criteria list based on the CONSORT (Consolidated Standards of Reporting Trials) statement, and data were extracted by two reviewers independently. Where possible, fixed sample size calculations were performed using the same assumptions as those of the sequential design, and compared with the reported number of included patients. RESULTS: Twenty-four sequential trials, published between 1963 and 2005, were found. In nine studies, the information about the assumptions was sufficient to calculate a fixed sample size. The median reduction in included sample size in these trials compared with the fixed sample size calculation was 52 subjects (range: -22 to 229), a reduction of 35% (range: 42% to 90%) of the fixed sample size. The median sample size reduction when considering the number of subjects included in the analysis until crossing of the boundaries was 77% (range: 15-90%). CONCLUSION: Sequential design is a useful method for optimizing the sample size in pediatric clinical trials and may lead to substantial sample size reductions. PMID- 19788956 TI - Systematic review of evidence for the use of intradialytic parenteral nutrition in malnourished hemodialysis patients. AB - OBJECTIVE: Intradialytic parenteral nutrition (IDPN) is widely used to treat malnourished hemodialysis (HD) patients. However, the benefits of this treatment are unknown. Moderate protein-energy malnutrition (PEM) is thought to affect 15% to 43% of maintenance HD patients, and is independently associated with mortality in this population. This study systematically reviews the current literature, to assess whether IDPN improves survival, quality of life, or nutritional status in those receiving maintenance HD. METHODS: Two investigators undertook a formal systematic review of the literature, using the following key search words: intradialytic parenteral nutrition or intradialytic total parenteral nutrition plus any combination of renal dialysis or kidney-failure or chronic kidney disease and parenteral nutrition or intravenous nutrition or intravenous feeding. RESULTS: The search identified three suitable randomized, controlled trials, only one of which investigated hard clinical endpoints. There were insufficient data to undertake a meta-analysis. CONCLUSIONS: The evidence from clinical studies is insufficient to demonstrate either a net benefit or a net harm associated with the providing IDPN to malnourished HD patients. We recommend that any patient in whom IDPN was deemed necessary be entered into a clinical trial or registry, to record hard clinical outcomes associated with the use of this treatment. PMID- 19788955 TI - Older Australians' medication use: self-report by phone showed good agreement and accuracy compared with home visit. AB - OBJECTIVE: To ascertain the accuracy of telephone-interview method for measuring older people's medication use ("self-report by phone") by determining agreement between results from this method and from a home visit ("home inventory"). STUDY DESIGN AND SETTING: An agreement study involving community-dwelling patients aged more than 65 years, selected from four general practices in the Hunter Region of Australia. Commonly used classes of drugs were selected for comparison. RESULTS: Of 154 patients, 14 participants were ineligible, because they had hearing problems (9) or did not use any medicines (5). The response rate was 70% (98 of 140). The observed overall agreement and prevalence-adjusted and bias-adjusted kappa coefficients were very high for all prescribed drug categories, but lower for over-the-counter (OTC) and complementary medicines. Specificity of the self report by phone compared with home inventory was consistently high across all drug classes. Sensitivity values were more than 89% for all drug classes but were lower for OTC and complementary medicines (74%) and paracetamol (78%). Similar patterns were found for negative predictive values. Positive predictive values were lower for drugs used on an as-needed basis. CONCLUSION: Measuring patient's medication use by telephone is an accurate and relatively inexpensive alternative to home-inventory methods, and has merit for use in future studies of older patients' drug use. PMID- 19788958 TI - The proximal ulna dorsal angulation: a radiographic study. AB - BACKGROUND: Recognition of the proximal ulna dorsal angulation (PUDA) is important for anatomic reduction of proximal ulna fractures, nonunions, malunions, or osteotomies, especially when using newer straight precontoured ulnar plates. The purpose of this study was to characterize the PUDA in 50 patients with bilateral elbow radiographs. MATERIALS AND METHODS: Commercial software was used to magnify 100 bilateral elbow radiographs 4 times. The PUDA was measured from the intersection of lines perpendicular to the subcutaneous border of the olecranon and the ulnar shaft. The olecranon tip-to-apex distance of the PUDA was also measured. Three orthopedic surgeons independently examined the radiographs, and intraobserver and interobserver reliability was calculated using intraclass correlation. RESULTS: A PUDA was present in 96% of radiographs. The average PUDA was 5.7 degrees (range, 0 degrees -14 degrees ). The Pearson correlation coefficient for a side-to-side comparison was 0.860 (P < .001). The average tip-to-apex distance was 47mm (range, 34-78mm). No correlation was identified with age. Intraobserver reliability was excellent for the PUDA and good for the tip-to-apex distance. Interobserver reliability was good for the PUDA and the tip-to-apex distance. DISCUSSION: A mean PUDA of 5.7 degrees is present in 96% of patients at an average of 47mm distal to the olecranon tip. Measurement of the PUDA has good-to-excellent interobserver and intraobserver reliability. CONCLUSION: Contralateral PUDA measurements are reliable in determining the angle in patients with comminution or distorted anatomy. Recognition of the PUDA may be helpful in anatomic plating of the ulna. Recognition of the PUDA may be helpful in anatomic plating of the ulna for fractures, nonunions or malunions. LEVEL OF EVIDENCE: Radiographic study. PMID- 19788957 TI - Range of motion limitation after rotator cuff repair. AB - HYPOTHESIS: This study was conducted to identify preoperative factors correlating with limited motion after rotator cuff repair (RCR) and to evaluate the affect of loss of motion on outcome. We hypothesized that patients with preoperative ROM loss, diabetes, and workman's compensation claims would exhibit postoperative ROM loss at 3 months. MATERIAL AND METHODS: Preoperative and postoperative evaluations, including outcomes assessment and physical examination parameters, were reviewed for 345 patients who underwent RCR. Correlations between demographic, physical examination, and surgical variables and postoperative limitation of motion and need for capsular release were determined. RESULTS: At 3 month follow-up, mean active forward elevation (AFE), active external rotation (AER), and passive internal rotation (PIR) were 90%, 78%, and 80% of the contralateral side. Limitation of preoperative motion correlated with limitation of postoperative AFE, AER, and PIR (P < .001). Forty-seven patients considered clinically stiff were followed at 1 year postoperatively. Three patients required arthroscopic capsular release for persistent range of motion loss. CONCLUSION: Early postoperative limitation of motion after RCR is associated with restricted preoperative motion. Other factors, including diabetes mellitus and worker's compensation claim, are also associated with range of motion loss. Most shoulders with early motion loss recover motion and rarely require capsular release. PMID- 19788959 TI - Voluntary activation of the infraspinatus muscle in nonfatigued and fatigued states. AB - HYPOTHESIS: Failure of voluntary activation is an important source of weakness in several different muscles after injury or surgery. Despite the high prevalence of shoulder rotator cuff disorders and associated weakness, no test currently exists to identify voluntary activation deficits for the rotator cuff. The purpose of this study was to develop a test to quantify voluntary activation of the infraspinatus. We hypothesized that there would be a consistent relationship between the voluntary activation level and different force levels and that reduced voluntary activation would partially account for reduced force with fatigue. MATERIALS AND METHODS: Twenty healthy volunteers underwent assessment of voluntary activation using an electrical stimulus applied to the infraspinatus muscle during active isometric external rotation. Voluntary activation was assessed across several levels of external rotation effort and during fatigue. RESULTS: The voluntary activation-percent force relationship was best fit using a curvilinear model, and the fatigue test reduced both force and voluntary activation by 46%. DISCUSSION: In the nonfatigued state, the voluntary activation percent force relationship is similar to that reported for the quadriceps. After fatigue, however, greater failure of voluntary activation was observed compared with reported values for other upper and lower extremity muscles, which may have implications for the understanding and treatment of rotator cuff pathology. CONCLUSION: A measure of voluntary activation for the infraspinatus varied with the percent maximum force in a predictable manner that is consistent with the literature. The infraspinatus may be more susceptible to failure of voluntary activation during fatigue than other muscles. PMID- 19788960 TI - Discussion: 'the interleukin-10 gene and cervical insufficiency' by Warren et al. AB - In the roundtable that follows, clinicians discuss a study published in this issue of the Journal in light of its methodology, relevance to practice, and implications for future research. Article discussed: Warren JE, Nelson LM, Stoddard GJ, et al. Polymorphisms in the promoter region of the interleukin-10 (IL-10) gene in women with cervical insufficiency. Am J Obstet Gynecol 2009;201:372.e1-5. PMID- 19788961 TI - Fetal laceration injury during cesarean section and its long-term sequelae: a case report. AB - This case report illustrates the cosmetic outcome of a scalpel-related laceration injury sustained to a newborn infant that occurred during the course of an elective cesarean section for breech presentation. This buttock laceration was noted to be 2 cm in length at the time of birth. Twelve years later, the same scar had migrated in a cephalad direction and had increased to 10 cm in length. PMID- 19788962 TI - Women and children first-or last? The New York Declaration. PMID- 19788963 TI - Ethical challenges of genomics for perinatal medicine: the Budapest Declaration. PMID- 19788964 TI - Is there an upper time limit for the management of the second stage of labor? PMID- 19788965 TI - A systematic review of outcomes of maternal weight gain according to the Institute of Medicine recommendations: birthweight, fetal growth, and postpartum weight retention. AB - This systematic review focuses on outcomes of gestational weight gain, specifically birthweight, fetal growth, and postpartum weight retention, for singleton pregnancies with respect to the 1990 Institute of Medicine weight gain recommendations. A total of 35 studies met the inclusion criteria and were reviewed. There was strong evidence to support associations between excessive gestational weight gain and increased birthweight and fetal growth (large for gestational age) as well as inadequate gestational weight gain and decreased birthweight and fetal growth (small for gestational age). There was moderate evidence to support the association between excessive gestational weight gain and postpartum weight retention. Clear clinical recommendations based on this review are challenging because of several limitations in the literature. Improvements in future research include the use of consistent definitions of gestational weight gain and outcomes of interest, assessment of confounders, and better collection of weight and weight gain data. PMID- 19788966 TI - The developmental role of natural killer cells at the fetal-maternal interface. AB - Natural killer (NK) cells have been extensively studied in their traditional roles in host defense against tumor or virally infected cells. Uterine NK cells are of 2 distinct subsets: endometrial NK (eNK) cells, found in the uterus during the menstrual cycle, and decidual NK (dNK) cells, found in the decidua during pregnancy. This review will explore the immunosurveillance and cytotoxicity profiles of NK cells, the inert nature of eNK cells, and the role of dNK cells as builders at the maternal-fetal interface that create a pregnancy-favorable environment by inducing angiogenesis, trophoblast invasion, and vascular remodeling. PMID- 19788968 TI - When to stop pushing: effects of duration of second-stage expulsion efforts on maternal and neonatal outcomes in nulliparous women with epidural analgesia. AB - OBJECTIVE: The purpose of this study was to assess the influence of the duration of active second-stage labor on maternal and neonatal outcomes. STUDY DESIGN: Secondary analysis of the Pushing Early Or Pushing Late with Epidural trial that included 1862 nulliparous women with epidural analgesia who were in the second stage of labor. According to duration of active second-stage labor, we estimated the proportion of spontaneous vaginal deliveries (SVD) with a newborn infant without signs of asphyxia (5-minute Apgar score > or =7 and arterial pH >7.10). We also analyzed maternal and neonatal outcomes according to the duration of expulsive efforts. RESULTS: Relative to the first hour of expulsive efforts, the chances of a SVD of a newborn infant without signs of asphyxia decreased significantly every hour (1- to 2-hour adjusted odds ratio, 0.4; 95% confidence interval [CI], 0.3-0.6; 2- to 3-hour adjusted odds ratio, 0.1; 95% CI, 0.09-0.2; >3-hour adjusted odds ratio, 0.03; 95% CI, 0.02-0.05). The risk of postpartum hemorrhage and intrapartum fever increased significantly after 2 hours of pushing. CONCLUSION: Faced with a decreasing probability of SVD and increased maternal risk of morbidity after 2 hours, we raise the question as to whether expulsive efforts should be continued after this time. PMID- 19788969 TI - Laparoscopic cervico-isthmic cerclage: surgical technique and obstetric outcomes. AB - OBJECTIVE: The purpose of the study is to review the surgical technique, complication rate and obstetric outcome associated with the laparoscopic approach to the placement of the cervico-isthmic cerclage. STUDY DESIGN: A prospective cohort study was conducted from 2003-2008 and compared with previously reported cases of cervico-isthmic cerclage by laparotomy and laparoscopy. RESULTS: Thirty one patients underwent cerclage placement during pregnancy and 34 patients were not pregnant at the time of the surgery. Seven cases were converted to laparotomy due to complications arising from uterine vessel bleeding or impaired surgical visibility; 2 pregnancies were lost perioperatively. No other complications occurred. The fetal salvage rate (n = 67 pregnancies) was 89% with a mean gestational age of 35.8 +/- 2.9 weeks. Six pregnancies were lost in the second trimester due to the consequences of acute or subacute chorioamnionitis. CONCLUSION: Our findings suggest that the cervico-isthmic cerclage placed laparoscopically compares favorably with the traditional laparotomy approach. PMID- 19788967 TI - Second-stage labor duration in nulliparous women: relationship to maternal and perinatal outcomes. AB - OBJECTIVE: The purpose of this study was to assess maternal and perinatal outcomes as a function of second-stage labor duration. STUDY DESIGN: We assessed outcomes in nulliparous laboring women who were enrolled in a trial of fetal pulse oximetry. RESULTS: Of 5341 participants, 4126 women reached the second stage of labor. As the duration of the second stage increased, spontaneous vaginal delivery rates declined, from 85% when the duration was <1 hour to 9% when it was > or =5 hours. Adverse maternal outcomes that were associated significantly with the duration of the second stage of labor included chorioamnionitis (overall rate, 3.9%), third- or fourth-degree perineal laceration (overall rate, 8.7%), and uterine atony (overall rate, 3.9%). Odds ratios for each additional hour of the second stage of labor ranged from 1.3-1.8. Among individual adverse neonatal outcomes, only admission to a neonatal intensive care unit was associated significantly with second stage duration (odds ratio, 1.4). CONCLUSION: The second stage of labor does not need to be terminated for duration alone. PMID- 19788970 TI - Multicenter randomized trial of cerclage for preterm birth prevention in high risk women with shortened midtrimester cervical length. AB - OBJECTIVE: The objective of the study was to assess cerclage to prevent recurrent preterm birth in women with short cervix. STUDY DESIGN: Women with prior spontaneous preterm birth less than 34 weeks were screened for short cervix and randomly assigned to cerclage if cervical length was less than 25 mm. RESULTS: Of 1014 women screened, 302 were randomized; 42% of women not assigned and 32% of those assigned to cerclage delivered less than 35 weeks (P = .09). In planned analyses, birth less than 24 weeks (P = .03) and perinatal mortality (P = .046) were less frequent in the cerclage group. There was a significant interaction between cervical length and cerclage. Birth less than 35 weeks (P = .006) was reduced in the less than 15 mm stratum with a null effect in the 15-24 mm stratum. CONCLUSION: In women with a prior spontaneous preterm birth less than 34 weeks and cervical length less than 25 mm, cerclage reduced previable birth and perinatal mortality but did not prevent birth less than 35 weeks, unless cervical length was less than 15 mm. PMID- 19788971 TI - Elevated first-trimester uric acid concentrations are associated with the development of gestational diabetes. AB - OBJECTIVE: We sought to demonstrate that elevated first-trimester uric acid is associated with development of gestational diabetes mellitus (GDM). STUDY DESIGN: Uric acid was measured in 1570 plasma samples collected at mean gestational age of 8.9 +/- 2.5 weeks. The primary outcome was GDM, diagnosed by 3-hour glucose tolerance test using Carpenter and Coustan criteria or by a 1-hour value of > or =200 mg/dL. Logistic regression was performed, adjusting for relevant covariates. RESULTS: Almost half (46.6%) of the women with GDM had first-trimester uric acid concentrations in the highest quartile (>3.57-8.30 mg/dL). Women with uric acid in the highest quartile had a 3.25-fold increased risk (95% confidence interval, 1.35-7.83) of developing GDM after adjustment for body mass index and age. This effect was concentration dependent as risk increased with increasing uric acid quartiles (P = .003). CONCLUSION: First-trimester hyperuricemia is associated with an increased risk of developing GDM, independent of body mass index. PMID- 19788972 TI - Preterm premature rupture of membranes: does the duration of latency influence perinatal outcomes? AB - OBJECTIVE: Preterm premature rupture of membranes (PPROM) is the leading identifiable cause of prematurity. We hypothesized that, when controlled for delivery gestational age, potential prolonged exposure to inflammation/infection could be harmful to the developing fetus. STUDY DESIGN: We studied a retrospective cohort of pregnancies with PPROM at 22.0-33.9 weeks' gestation. The primary outcome was perinatal survival without major morbidity (grade III/IV intraventricular hemorrhage, periventricular leukomalacia, bronchopulmonary dysplasia). Regression models assessed predictors of perinatal morbidity. RESULTS: Three hundred six women were included. PPROM occurred at a median of 29.4 weeks' gestation (interquartile range [IQR], 24.7-32.1 weeks' gestation). Median latency was 8 days (IQR, 3-15 days). Median delivery age was 31.4 weeks' gestation (IQR, 27.4-33.3 weeks' gestation). Two hundred seventy-seven infants (91%) survived; 233 infants (84% of survivors, 76% of all babies) did not have major morbidities. Gestational age (odds ratio, 0.60; 95% confidence interval, 0.53-0.68) and congenital sepsis (odds ratio, 13.2; 95% confidence interval, 3.9 44.5), but not latency, predicted perinatal morbidity in multivariate models. CONCLUSION: Latency does not appear to worsen outcomes in pregnancies that are complicated by PPROM. PMID- 19788973 TI - Incidence of complications in twin-twin transfusion syndrome after selective fetoscopic laser photocoagulation: a single-center experience. AB - OBJECTIVE: The purpose of this study was to evaluate the incidence of complications after selective fetoscopic laser photocoagulation for twin-twin transfusion syndrome (TTTS). STUDY DESIGN: One hundred fifty-two cases of TTTS were treated with selective fetoscopic laser photocoagulation from 2005-2008. Complications were TTTS recurrence, amniotic band syndrome, iatrogenic monoamnionicity, and twin anemia-polycythemia sequence. Data were placed in the following categories: no complications; early complications < or =7 days; late complications >7 days; both early and late complications. RESULTS: The incidence of early, late, and both early and late complications was 31%, 39%, and 10%. Complications included 2 cases (1.3%) of monoamnionicity, 3 cases (2.0%) of recurrent TTTS, 3 cases (2.0%) of twin anemia-polycythemia sequence, and 5 cases (3.3%) of amniotic band syndrome. Cases with TTTS with early complications had a lower number of superficial arteriovenous vascular anastomoses and 1 or both fetus survival (70.2% vs 96.7%; P < .001), compared with no complications. Fetal survival was 238 of 307 cases (77.5%), with 1 or both twins surviving in 134 of 152 (88%) of pregnancies. CONCLUSION: The incidence of early, late, and both early and late complications was 31%, 39%, and 10%, respectively. Close postoperative surveillance is important. PMID- 19788974 TI - Why eicosanoids could represent a new class of tocolytics on uterine activity in pregnant women. AB - OBJECTIVE: The purpose of this study was to assess the effects of exogenous eicosanoids on spontaneous uterine contractile activity. STUDY DESIGN: Eight uterine biopsies were performed from women who were undergoing elective cesarean delivery. Tension measurements were performed in vitro on myometrial strips. Contractile activities were quantified by the calculation of the area under the curve. The effects of eicosanoids and specific enzyme inhibitors were assessed. Fractions from various uterine tissues were analyzed by Western blot. RESULTS: Data demonstrate the presence, in some tested tissues, of cytochrome P-450 epoxygenase and soluble epoxide hydrolase, which respectively produce and degrade epoxyeicosatrienoic acid regioisomers. Inhibition of soluble epoxide hydrolase with 12-(3-adamantan-1-yl-ureido)-dodecanoic acid or omega-hydroxylase with N methylsulfonyl-12,12-dibromododec-11-enamide resulted in a tocolytic effect; N methylsulfonyl-6-[2-propargyloxyphenyl] hexanamide, which is an epoxygenase inhibitor, had no effect. Exogenous epoxyeicosatrienoic acids displayed significant tocolytic effects on spontaneous contractile activities. CONCLUSION: Epoxy- and hydroxyeicosanoids represent new bioactive, arachidonic acid by products with in vitro tocolytic activities. These findings suggest that cytochrome P-450 isozymes may represent relevant pharmacologic targets under physiopathologic conditions. PMID- 19788975 TI - Racial and ethnic disparities in the trends in primary cesarean delivery based on indications. AB - OBJECTIVE: To examine trends in primary cesarean deliveries by indications and race/ethnicity. STUDY DESIGN: We examined temporal trends in primary cesarean deliveries from 1991 through 2008 among singleton births (n = 540,953) in Kaiser Permanente Southern California hospitals using information from maternal hospitalizations and infant birth certificates. In addition, relative increases and 95% confidence intervals (CIs) were used to estimate differences in primary cesarean section rates by indication for the earliest (1991-1992) and most recent (2007-2008) periods. Racial/ethnic disparities in primary cesarean deliveries were examined by comparing the relative risks from multiple logistic regression models. RESULTS: The rate of primary cesarean section among white, African American, Hispanic, and Asian/Pacific Islander women increased by 61.6%, 64.1%, 62.4%, and 70.2%, respectively, between 1991 and 2008. In comparison to the primary cesarean section rate for white women, the rate was 25% (95% confidence interval [CI], 22-29%) higher for African American women, 19% (95% CI, 16-23%) higher for Asian/Pacific Islander women, but 14% (95% CI, 13-16%) lower for Hispanic women. After adjustment for confounding factors, primary cesarean section rates remained significantly higher for African American women but lower for Hispanic women compared with white women. Indication subtypes-specific rates of primary cesarean section varied markedly across race/ethnicity. CONCLUSION: We found that the overall primary cesarean section rate has increased over time. In addition, there is a wide variability in rate of indications for primary cesarean section by race/ethnicity. PMID- 19788977 TI - Biliary and pancreatic stone extraction devices. PMID- 19788978 TI - Endocytoscopy. PMID- 19788979 TI - Stent placement in esophageal cancer as a bridge to surgery. PMID- 19788980 TI - Endoscopic versus surgical therapy for early cancer in Barrett's esophagus. PMID- 19788981 TI - To perform a biopsy or not to perform a biopsy? Does confocal endomicroscopy provide the answer for surveillance in Barrett's esophagus? PMID- 19788982 TI - Combination of pharmacologic and endoscopic therapy for the secondary prevention of esophageal variceal bleeding. PMID- 19788983 TI - Choosing a subspecialty in gastroenterology: using your resources. PMID- 19788984 TI - An introduction to "obesity and the endoscopist:" a GI special series. PMID- 19788985 TI - The duodenal stent-in-stent: a stent at the crossroads. PMID- 19788986 TI - Endoscopic balloon sphincteroplasty for extraction of large radiolucent pancreatic duct stones (with videos). AB - BACKGROUND: Although radiopaque pancreatic duct stones can be targeted by extracorporeal shock wave lithotripsy (ESWL) and extracted by ERCP, large and radiolucent stones remain a therapeutic challenge. OBJECTIVE: To evaluate the technical success and safety of endoscopic balloon sphincter dilation technique (sphincteroplasty) for extraction of large radiolucent pancreatic duct stones. DESIGN: Case series. SETTING: Tertiary referral center. PATIENTS: Four symptomatic patients with large (> or =1 cm) radiolucent stones occluding the main pancreatic duct that could not be retrieved by standard endoscopic maneuvers. INTERVENTIONS: Pancreatic sphincterotomy followed by balloon dilation of the pancreatic orifice to aid retrieval of large radiolucent stones occluding the main pancreatic duct. MAIN OUTCOME MEASUREMENTS: Technical success and safety of the balloon dilation (sphincteroplasty) technique. Technical success was defined as the ability to achieve pancreatic duct clearance in 1 endoscopic encounter. Complications were assessed according to consensus criteria. RESULTS: The procedure was technically successful in all 4 patients. Pancreatic duct clearance was achieved in all 4 patients in 1 endoscopy session with complete symptom relief at 12-month follow-up. Mild post-ERCP pancreatitis developed in 1 patient, and minor bleeding developed in another patient; both were managed conservatively. LIMITATION: Small number of patients. CONCLUSIONS: Endoscopic balloon dilation of the pancreatic orifice after sphincterotomy is a safe technique that facilitates the removal of large radiolucent stones from the main pancreatic duct in 1 endoscopic session. More studies with larger numbers of patients are required before this technique can be adopted routinely as a treatment alternative for patients with large radiolucent pancreatic duct stones. PMID- 19788987 TI - Patients in the prone position for preventing aspiration pneumonia after peroral double-balloon enteroscopy. PMID- 19788989 TI - Hemosuccus pancreaticus after EUS-FNA of a pancreatic tail cyst. PMID- 19788990 TI - Mesh-metal stents for hilar cholangiocarcinoma. PMID- 19788991 TI - More interventional time makes the results different. PMID- 19788994 TI - Small-bowel lesions detected by double-balloon enteroscopy performed after negative capsule endoscopy. PMID- 19788996 TI - Risk factors for incomplete small-bowel capsule endoscopy: should capsule retention be considered independently? PMID- 19788997 TI - Appendix in ulcerative colitis: significant involvement and pathogenesis. PMID- 19788998 TI - Reflections on courage. PMID- 19788999 TI - How will nursing be affected by health care reform? PMID- 19789000 TI - Quality of manuscript reviews in nursing research. PMID- 19789001 TI - Development of the Differentiation of Self and Role Inventory for Nurses (DSRI RN): a tool to measure internal dimensions of workplace stress. AB - This article presents the use of Bowen's theory of differentiation as a framework for understanding one aspect of vocational burnout. The theory suggests that persons with low levels of differentiation are at higher risk for emotional exhaustion than those at higher levels. The authors describe the development and pilot-testing of a tool, the Differentiation of Self and Role Inventory for Nurses (DSRI-RN) as a means to assess internal aspects of workplace stress by measuring factors suggested by the theory. Initial use of the DSRI-RN indicates that the tool is reliable and valid and that nurses with higher levels of differentiation expressed lower levels of burnout and greater enthusiasm for nursing. These findings suggest that the DSRI-RN may be used in further studies and opens the possibility of using Bowen's framework in developing interventions assisting nurses to understand and cope with the internal aspects of workplace stress. PMID- 19789002 TI - Nurses trying to quit smoking using the Internet. AB - Nurses QuitNet, an Internet-based smoking cessation program, was created to support nurses' quit attempts. The purposes of this study were to evaluate quit attempts at 3, 6, and 12 months after the use of the program and to determine differences in demographic, professional, and smoking characteristics by smoking status. Differences in the use of quit methods, barriers, and facilitators to quitting also were assessed. Data among 246 smokers who responded to at least 1 follow-up email at 3, 6, or 12 months after registration were analyzed. Quit rates among respondents were 43% (3 months), 45% (6 months), and 53% (12 months). Total time on the website was significantly higher for those who quit. Barriers to quitting included lack of support from colleagues, stress, lack of cessation services, and fear of not getting a work-break. Facilitators included working in a smoke-free facility, support from colleagues, and workplace cessation services. The use of Nurses QuitNet demonstrated promise in supporting quit attempts. Quitting was influenced by workplace factors. PMID- 19789003 TI - Medical history and epidemiology: their contribution to the development of public health nursing. AB - The nursing profession historically has been involved in data collection in research efforts notably from the time of the Framingham Tuberculosis Project (1914-1923). Over the past century, nurses have become more sophisticated in their abilities to design, conduct, and analyze data. This article discusses the contributions of medicine and epidemiology to the development of public health nursing and the use of statistical methods by nurses in the United States in the 19th and 20th centuries. Knowledge acquired from this article will inform educators and researchers about the importance of using quantitative analysis, evidenced-based knowledge, and statistical methods when teaching students in all health professions. PMID- 19789004 TI - Project (inverted exclamation mark)EXITO!: success through diversity and universality for outcomes improvement among Hispanic home care patients. AB - The National Health Disparities Report notes that Hispanics have poorer quality of care in 23 of 38 core measures. The result of this disparity is great personal and health system costs, which could be reduced. Prior studies have focused on access and language. We studied outcomes improvement. The purpose of this project was to develop a replicable theory-based outcomes improvement model for delivery of nursing care to Hispanic patients. The Leininger Sunrise Enabler approach was used to design a program specific to the cultural needs of a home care population. Outcome and Assessment Information Set (OASIS) data from 125 unduplicated home care patients were tracked. Nursing care delivery was analyzed using ethnographic research techniques. Delivery of nursing care using a culturally congruent approach reduced acute hospitalization and emergent care visits. Medication management and customer and nursing satisfaction also improved. National standards for culturally and linguistically appropriate services in health care help reduce healthcare disparities, but improving Hispanic outcomes requires moving beyond symptoms and symptom management to transcultural care. The estimated savings to the health care system are significant. PMID- 19789005 TI - State funding for higher education and RN replacement rates by state: a case for nursing by the numbers in state legislatures. AB - Amid an enduring nursing shortage and state budget shortfalls, discerning how the percentage of state funding to higher education and other registered nurse (RN) workforce variables may be related to the RN replacement rates (RNRR) in states has important policy implications. Regionally, the age of RNs was inversely related to RNRR. State funding in 2000 significantly predicted the 2004 RNRR, with the percentage of LPNs in 2004 adding to the model. The stability of the model using 2000 and 2004 funding data suggests that state funding creates a climate for RNRR. PMID- 19789006 TI - Nursing's leadership in positioning human health at the core of urban sustainability. AB - The United Nations predicts that by 2050 nearly three fourths of the world's population will live in urban areas, including cities. People are attracted to cities because these urban areas offer diverse opportunities, including the availability of goods and services and a higher quality of life. Cities, however, may not be sustainable with this population boom. To address sustainability, urban developers and engineers are building green structures, and businesses are creating products that are safe for the environment. Additionally, efforts are needed to place human health at the core of urban sustainability. Without human health, cities will not survive for future generations. Nursing is the discipline that can place human health in this position. Nursing's initiatives throughout history are efforts of sustainability-improving human health within the physical, economic, and social environments. Therefore, nursing must take a leadership role to ensure that human health is at the core of urban sustainability. PMID- 19789007 TI - Commentary: Fork in the road: Accessories to cruelty or courage? PMID- 19789008 TI - Commentary: Military medical support for detainee operations. PMID- 19789009 TI - Commentary: Courage is the only ethical choice. PMID- 19789010 TI - Why Johnny cannot operate. PMID- 19789011 TI - The impact of ischemic cholangiopathy in liver transplantation using donors after cardiac death: the untold story. AB - BACKGROUND: Liver transplantation (LT) from donation after cardiac death (DCD) donors is increasingly being used to address organ shortages. Despite encouraging reports, standard survival metrics have overestimated the effectiveness of DCD livers. We examined the mode, kinetics, and predictors of organ failure and resource utilization to more fully characterize outcomes after DCD LT. METHODS: We reviewed the outcomes for 32 DCD and 237 donation after brain death (DBD) LT recipients at our institution. RESULTS: Recipients of DCD livers had a 2.1 times greater risk of graft failure, a 2.5 times greater risk of relisting, and a 3.2 times greater risk of retransplantation compared with DBD recipients. DCD recipients had a 31.6% higher incidence of biliary complications and a 35.8% higher incidence of ischemic cholangiopathy. Ischemic cholangiography was primarily implicated in the higher risk of graft failure observed after DCD LT. DCD recipients with ischemic cholangiography experienced more frequent rehospitalizations, longer hospital stays, and required more invasive biliary procedures. CONCLUSION: Related to higher complication rates, DCD recipients necessitated greater resource utilization. This more granular data should be considered in the decision to promote DCD LT. Modification of liver allocation policy is necessary to address those disadvantaged by a failing DCD graft. PMID- 19789012 TI - Thyroid hormone replacement after thyroid lobectomy. AB - BACKGROUND: The purpose of this study was to determine the incidence of and identify risk factors for postoperative hypothyroidism in patients undergoing thyroid lobectomy. METHODS: We retrospectively reviewed patients who underwent a thyroid lobectomy for benign disease from May 2004 to December 2007. Patients with known hypothyroidism or on preoperative thyroid hormone replacement were excluded. RESULTS: In this study, 14.3% of patients developed hypothyroidism and required thyroid hormone supplementation. These hypothyroid patients had a higher mean pre-operative thyroid-stimulating hormone (TSH) and lower mean free thyroxine (T4) serum levels compared with euthyroid patients (TSH, 2.12 vs 1.35 microIU/mL [P = .006]; free T4, 1.03 vs 1.34 ng/dL [P = .01]). When stratified into 3 groups based on their preoperative TSH measurement (< or =1.5, 1.51-2.5, and > or =2.51 microIU/mL), the rate of hypothyroidism increased significantly at each level (13.5%, 20.5%, and 41.3%, respectively [P < .001]). In addition, patients with Hashimoto's thyroiditis were significantly more likely to become hypothyroid (odds ratio, 3.78; 95% confidence interval, 2.17-6.60). CONCLUSION: After thyroid lobectomy, approximately 1 in 7 patients experience hypothyroidism requiring thyroid hormone treatment. Patients with preoperative TSH levels >1.5 microIU/mL, lower free T4 levels, and Hashimoto's thyroiditis are at increased risk and should be counseled and followed appropriately. PMID- 19789013 TI - Does ductal carcinoma in situ accompanying invasive carcinoma affect prognosis? AB - BACKGROUND: Ductal carcinoma in situ (DCIS) often accompanies invasive breast cancer. The prognostic implication of this is unclear. We sought to determine whether concomitant DCIS affects outcomes in patients with invasive disease. METHODS: A nested cohort study was performed of 1,709 invasive breast cancer patients. Clinicopathologic data, along with survival and recurrence data, were collected prospectively. RESULTS: Concomitant DCIS was noted in 434 (25.4%) patients. Median follow-up was 59 months. On univariate analysis, the presence of DCIS was associated with a trend toward improved 5-year disease-free survival (93.6% vs 90.5%; P = .089) and overall survival (95.3% vs 92.6%; P = .058). Further, DCIS was associated with younger patient age (median 65 vs 68 years; P < .0001), smaller tumor size (median 1.37 vs 1.44 cm; P = .069), fewer palpable tumors (27.4% vs 33.3%; P = .051), more high-grade tumors (19.1% vs 15.8%; P = .045), and invasive ductal histology (90.6% vs 79.0%; P < .0001). On multivariate analysis, DCIS was not, however, an independent predictor of improved disease free (odds ratio [OR], 0.715; P = .217) or overall survival (OR, 0.770; P = .251). CONCLUSION: Although the presence of DCIS is often associated with favorable features, it is not an independent predictor of improved outcome in patients with concomitant invasive breast cancer. PMID- 19789014 TI - Surgeon-performed ultrasound: a single institution experience in parathyroid localization. AB - BACKGROUND: Ultrasound has been used successfully to localize parathyroid glands. This study evaluates surgeon-performed ultrasound (SUS) for pre-operative parathyroid localization prior to parathyroidectomy. METHODS: In all, 442 patients with primary hyperparathyroidism (HPT) underwent SUS at a single institution. Patients were divided into 2 groups: group 1 (n = 338) had correct localization, and group 2 (n = 104) had incorrect localization. The true-positive (TP) rate and peri-operative findings were compared. TP was defined as localization of all abnormal parathyroids resulting in operative success. A P value >.05 was considered significant. RESULTS: Of 442 patients, 338 (76.5%) had TP results. Group 1 patients were younger (57 vs 63 years; P < .0001) with larger gland size: 2.1 versus 1.8 cm (P = .08). In group 2, 45/104 (43%) patients had false-positive SUS, and 59/104 (57%) had negative studies or missed multiglandular disease (MGD). Group 1 patients had shorter operative times (60 vs 80 min, P = .002), fewer bilateral neck explorations (BNEs) (8% vs 39%; P < .0001), and lower MGD rates (2% vs 19%; P < .0001). Operative failure was 0.3% in group 1 and 9.6% in group 2 (P < .0001). CONCLUSION: Younger patients have a greater rate of correct localization. When SUS correlates with operative findings, MGD is significantly lower and fewer BNEs are performed. Additionally, operations are shorter with a higher success rate. PMID- 19789015 TI - Traumatic diaphragmatic injury: experience from a level I trauma center. AB - OBJECTIVE: Traumatic diaphragmatic injuries (TDI) are uncommon but associated with substantial morbidity and mortality. We sought to analyze patients with TDI at a large trauma center and associated county coroner to identify characteristics predictive of increased mortality. METHODS: We queried a level I university trauma center and associated county coroner databases containing >20,000 patients to identify patients with ICD-9 diagnoses pertaining to TDI from January 1992 through May 2005. Once identified, hospital records, operative details, and autopsy reports were reviewed to determine injury characteristics, treatment provided, and outcome. Statistical analyses were performed using the Student t-test, chi-square analysis, analysis of variance, and multiple logistic regression. RESULTS: TDI were identified in 254 individuals. Two hundred (79%) survived to undergo operation. Of the 81 (32%) deaths, 33 (41%) occurred before arrival at the trauma center. Survivors were younger, had lesser injury severity scores (ISS), were more likely to be female, and had more bilateral injuries (P < or = .002 all) than nonsurvivors. By multiple logistic regression analyses, increased age (odds ratio [OR], 1.044; 95% confidence interval [CI], 1.015-1.074; P = .0029) and greater ISS (OR, 1.145; 95% CI, 1.103-1.188; P < .0001) were predictors of the probability of death in all patients. CONCLUSION: Although TDI may indicate substantive trauma burden in any patient, those with greater ISS and advanced age are at the greatest risk of death. PMID- 19789016 TI - Neurologic outcomes with cerebral oxygen monitoring in traumatic brain injury. AB - BACKGROUND: Optimizing cerebral oxygenation is advocated to improve outcome in head-injured patients. The purpose of this study was to compare outcomes in brain injured patients treated with 2 types of monitors. METHODS: Patients with traumatic brain injury and a Glasgow Coma Scale score<8 were identified on admission. A polarographic cerebral oxygen/pressure monitor (Licox) or fiberoptic intracranial pressure monitor (Camino) was inserted. An evidence-based algorithm for treatment was implemented. Elements from the prehospital and emergency department records and the first 10 days of intensive care unit (ICU) care were collected. Glasgow Outcome Scores (GOS) were determined every 3 months after discharge. RESULTS: Over a 3-year period, 145 patients were entered into the study; 81 patients in the Licox group and 64 patients in the Camino group. Mortality, hospital length of stay, and ICU length of stay were equivalent in the 2 groups. More patients in the Licox group achieved a moderate/recovered GOS at 3 months than in the Camino Group (79% vs 61%; P = .09). CONCLUSION: Three-month GOS revealed a clinically meaningful 18% benefit in patients undergoing cerebral oxygen monitoring and optimization. Six-month outcomes were also better. Unfortunately, these important differences did not reach significance. Continued study of the benefits of cerebral oxygen monitoring is warranted. PMID- 19789017 TI - Radioguided parathyroidectomy for hyperparathyroidism in the reoperative neck. AB - BACKGROUND: The purpose of this study was to determine if radioguided parathyroidectomy (RGP) is effective for hyperparathyroidism (HPT) in the reoperative neck. METHODS: We retrospectively reviewed all patients with HPT and a history of neck surgery who underwent RGP over a 7-year period. Data are reported as mean +/- SEM. RESULTS: We identified 110 patients with primary (n = 94), secondary (n = 7), or tertiary (n = 9) HPT who underwent 138 previous neck operations. The average hospital stay was 0.6 +/- 0.1 days. The in and ex vivo counts obtained with the gamma probe were 310 +/- 26 and 130 +/- 13, respectively. The ex vivo percentage of background was 69% +/- 9%, and virtually all resected parathyroids had ex vivo counts > or =20%. After RGP, 96% of patients were cured, and 5% experienced complications (all transient). Cure rates after RGP decreased as the number of previous neck operations increased (P = .002). Additionally, reoperative neck patients with single adenomas were more likely to experience cure than patients with hyperplasia (P = .02). CONCLUSION: These results illustrate that RGP is valuable in treatment of the reoperative neck. In addition, RGP allows similar lengths of stay, efficacy, and complication rates as those reported for patients undergoing initial parathyroidectomy. PMID- 19789018 TI - Acute lower gastrointestinal bleeding in 1,112 patients admitted to an urban emergency medical center. AB - BACKGROUND: This study was performed to elucidate the etiology, effectiveness of diagnostic and therapeutic modalities, and outcomes in patients with acute lower gastrointestinal bleeding. METHODS: A retrospective review of the medical records of 1,112 consecutive patients admitted to the surgical service of a single urban emergency hospital with lower gastrointestinal bleeding from 1988 to 2006. Two groups were compared: 1988-1997 and 1998-2006. RESULTS: All patients underwent colonoscopy, 33.2% within 24 h of admission. Hematochezia was the most frequent presentation (55.5%), followed by maroon stool (16.7%) and melena (11.0%). Most patients, 690 (62.1%) also had upper endoscopy. Sixty-six patients subsequently had barium enemas. Eleven of 27 nuclide scans were positive. Arteriography was performed on 22 patients, with 11 positive results and 2 therapeutic. No statistical difference was found in procedures performed in our 2 time periods. Diverticulosis (33.5%), hemorrhoids (22.5%), and carcinoma (12.7%) were the most common etiologies with the diagnosis of diverticulosis more common in the 1998 2006 time period. The small bowel was the source in 14 total patients. Spontaneous cessation of the bleeding occurred in 863 (77.6%) patients. Endoscopic control increased from 1% in 1997-1998 to 4.4% in 1998-2006 (P < .05) with a corresponding decrease in the need for operative control from 22.6% to 16.6% in this same time period (P < .05). Furthermore, among elective operations, there was a decrease in right hemicolectomies from 31.6% of total elective cases to 13.9% (P < .05). Emergent operations were needed in 3.4% and 4.8% of patients. The readmission rate did not change over time and was 5.2% overall with >50% because of diverticular bleeding. CONCLUSION: In this urban setting, diverticulosis, hemorrhoids, and carcinoma were the most common causes of severe acute lower gastrointestinal bleeding (LGIB) with diverticular bleed causing the highest recurrence. Colonoscopy allows for diagnosis in most patients with severe acute LGIB requiring hospitalization. Furthermore, it is now being used more effectively for hemostasis resulting in less operative intervention to control bleeding. PMID- 19789019 TI - Using simulation to determine the need for ICU beds for surgery patients. AB - BACKGROUND: As the need for surgical ICU beds at the hospital increases, the mismatch between demand and supply for those beds has led to the need to understand the drivers of ICU performance. METHOD: A Monte Carlo simulation study of ICU performance was performed using a discrete event model that captured the events, timing, and logic of ICU patient arrivals and bed stays. RESULTS: The study found that functional ICU capacity, ie, the number of occupied ICU beds at which operative procedures were canceled if they were known to require an ICU stay, was the main determinant of the wait, the number performed, and the number of cancellations of operative procedures known to require an ICU stay. The study also found that actual and functional ICU capacity jointly explained ICU utilization and the mean number of patients that should have been in the ICU that were parked elsewhere. CONCLUSION: The study demonstrated the necessity of considering actual and functional ICU capacity when analyzing surgical ICU bed requirements, and suggested the need for additional research on synchronizing demand with supply. The study also reinforced the authors' sense that simulation facilitates the evaluation of trade-offs between surgical management alternatives proposed by experts and the identification of unexpected drawbacks or opportunities of those proposals. PMID- 19789020 TI - Comparison of laparoscopic transabdominal lateral versus posterior retroperitoneal adrenalectomy. AB - BACKGROUND: For the past 14 years, we have been performing laparoscopic adrenalectomy via the lateral transabdominal as well as the posterior retroperitoneal approach. The aim of this study is to describe patient selection criteria for each approach with comparison of perioperative outcomes. METHODS: In patients with smaller tumors, low body mass index (BMI), history of previous abdominal operations, appropriate body habitus, and bilateral pathology, we have performed preferentially the posterior approach. Data regarding clinical pathology, tumor size, BMI, estimated blood loss (EBL), operating time (OT), morbidity, mortality, and duration of stay were analyzed retrospectively. Data are expressed as mean +/- standard error of the mean (SEM). RESULTS: One hundred seventy-two laparoscopic adrenalectomy procedures were performed in 159 patients between 1994 and 2008. The lateral approach was used in 69 patients (right side: 39%, left side: 55%, bilateral: 6%) and the posterior approach in 90 patients (right side: 42%, left side: 48%, bilateral: 10%). The incidence of prior abdominal surgery was greater in the posterior group (26% vs 19%, NS). The lateral approach was used in 9% (3/34) of aldosteronoma, 38% (9/24) of Cushing's disease/syndrome, 47% (18/38) of nonsecreting cortical adenoma, 66% (23/35) of pheochromocytoma, 41% (7/17) of malignant lesions, and 73% (8/11) of others. Thirty percent of the bilateral adrenalectomies were performed via lateral and 70% via posterior approach. Two patients in the posterior approach were converted to the laparoscopic lateral approach, and 2 patients in the lateral approach were converted to open. Overall, patient age and sex were similar between groups. BMI was higher in patients undergoing adrenalectomy via lateral vs posterior approach (32.4 vs 28.4; P = .005). Tumor size was larger than 6 cm in 11 (16%) and 1 (1%) of the patients in the lateral and posterior groups, respectively. On univariate analysis, mean OT for lateral and posterior approaches was similar for unilateral cases (157 +/- 7 vs 138 +/- 6 min, respectively; P = NS). This was also true on multivariate analysis when corrected for patient selection factors. EBL was 35 +/ 7 mL for lateral versus 25 +/- 6 mL for posterior approach (P = .05). The duration of stay in lateral and posterior approaches was 1 day in 56% vs 82%, 2 days in 29% vs 13%, and more than 2 days in 15% vs 5% of the patients, respectively. Two patients in the lateral group died postoperatively because of cardiac and pulmonary causes, and 2 patients in the posterior group developed temporary neuralgia. CONCLUSION: This series compares 2 different approaches for laparoscopic adrenalectomy. Our study shows that the lateral and posterior techniques have a similar peri-operative outcome when patients are selected for each option based on certain criteria. PMID- 19789021 TI - Does the need for noncardiac surgery during ventricular assist device therapy impact clinical outcome? AB - BACKGROUND: The role of the ventricular assist device (VAD) in the management of heart failure is expanding. Despite its success, the clinical course for patients requiring noncardiac surgery (NCS) during VAD support is not well described. The objective of this study was to identify VAD patients requiring NCS (+NCS) and compare outcomes with those not requiring NCS (-NCS). METHODS: Patients undergoing VAD implant from 2000 to 2007 were reviewed. NCS procedures, survival, and complications were collected. Survival at 1 year from implant, overall survival at the study conclusion, survival time from implant, and outcome of VAD therapy were compared between groups. RESULTS: We enrolled 142 subjects. Demographics did not differ between groups. Twenty-five subjects (18%) underwent 27 NCS procedures. Perioperative survival was 100% and 28-day survival was 64%. Survival to discharge was 56%. Bleeding occurred in 48%. Infection occurred in 33%. Estimated blood loss was 355 mL, and the international normalized ratio at time of NCS was 1.9. Laparoscopy was performed in 3 cases. There was no difference in 1-year survival (59% vs 54%), survival at study conclusion (44% vs 46%) or survival time (517 vs 523 days) between +NCS subjects and -NCS subjects. There were similar causes of death in both groups. The +NCS group was on VAD support longer (245 vs 87 days; P < .01), and less likely to undergo heart transplantation (12% vs 35%; P < .01). CONCLUSION: NCS is not uncommon during VAD therapy. Bleeding and infection were common complications. Despite this, NCS seems to be feasible and safe and does not seem to increase mortality in the VAD population. PMID- 19789022 TI - A prospective single institution comparison of peri-operative outcomes for laparoscopic and open distal pancreatectomy. AB - BACKGROUND: Laparoscopic distal pancreatectomy (LP) is an emerging modality for managing benign and premalignant neoplasms of the pancreatic body and tail. The efficacy of LP has been examined in single and multi-institutional retrospective reviews but not compared prospectively to open distal pancreatectomy (ODP). METHODS: We maintain a prospectively accruing database tracking peri-operative clinical parameters for all patients presenting to our tertiary care facility for treatment of pancreatic disease. We queried this database for patients undergoing LP or ODP between January 2003 and May 2008. Preoperative, operative, and postoperative characteristics were compared using standard statistical methods. RESULTS: One-hundred twelve patients underwent distal pancreatectomy. Eighty-five underwent SDP. Twenty-eight LPs were attempted and 27 completed laparoscopically. One LP was converted to an open procedure because of bleeding and was excluded from study. In comparison to ODP, patients undergoing LP had statistically similar pre-operative demographics, disease comorbidities, tumor size, length of operation, rates of postoperative mortality, postoperative morbidity, and pancreatic fistula. Patients undergoing LP were less likely to have ductal adenocarcinoma and had fewer lymph nodes harvested in their resection but had a significantly shorter postoperative length of stay and significantly lower estimated blood loss than those undergoing ODP. CONCLUSION: Laparoscopic distal pancreatectomy is a safe, effective modality for managing premalignant neoplasms of the pancreatic body and tail, providing a morbidity rate comparable to that for ODP and substantially shorter length of stay. Laparoscopic distal pancreatectomy fails to provide a lymphadenectomy comparable to ODP. This may limit the applicability of LP to the treatment of pancreatic adenocarcinoma. PMID- 19789023 TI - Equivalent outcomes with primary and retransplantation in African-American deceased-donor renal allograft recipients. AB - BACKGROUND: Graft survival following renal retransplantation has been inferior to that following primary allografting, particularly in African Americans (AAs) receiving deceased-donor (DD) kidneys. METHODS: Among 166 AA DD renal allograft recipients transplanted from July 2001 through July 2007, we compared the outcomes of 26 (16%) receiving a second graft with those of 140 primary cases. All patients received either thymoglobulin (ATG) or an IL-2 receptor antagonist for induction, and were maintained on either tacrolimus or sirolimus + mycophenolate mofetil +/- prednisone. RESULTS: When compared with primary transplants, regrafts received kidneys from older donors, were younger, more sensitized, more likely to receive ATG and to be maintained on prednisone, received more doses of ATG, and were less likely diabetic. There was no difference between primary and retransplant groups in overall patient or graft survival; incidence of acute rejection, CMV infection, BK nephropathy, or new onset diabetes mellitus; and serum creatinine at 1 year. CONCLUSION: AA renal allograft recipients can undergo a second DD transplant with intermediate-term outcomes comparable to that of a primary graft, despite the presence of multiple immunologic and non-immunologic high-risk factors, by extending the course of ATG induction and continuing prednisone therapy in the vast majority of cases. PMID- 19789024 TI - Mortality for intra-abdominal infection is associated with intrinsic risk factors rather than the source of infection. AB - BACKGROUND: Intra-abdominal infections (IAIs) are an important cause of mortality and morbidity. Nosocomial IAIs (NIAIs) have been associated with higher mortality than community-acquired IAIs (CIAIs). We hypothesized that intrinsic risk factors were a better predictor of mortality than the type of infection. METHODS: Patients with IAI treated at a single urban academic hospital over 8 years (June 1999-June 2007) were retrospectively reviewed. Data collected included demographics, comorbidities, source of infection, type of infection (community vs nosocomial), type of intervention (operation versus percutaneous drainage), and postoperative complications. Charlson Comorbidity Index and multiple organ dysfunction (MOD) scores were evaluated at admission and on postoperative day 7 (POD-7). RESULTS: There were 452 patients; 234 (51.8%) had CIAI and 218 (48.2%) had NIAI. The mean age was 51.3 +/- 0.8. The most common source of CIAI was the appendix (n = 129, 28.5%); 137 patients with NIAI had postoperative infections (30.3%). When patients with appendicitis were excluded, there was no difference in mortality or complications between patients with CIAI and NIAI. Logistic regression analysis demonstrated catheter-related bloodstream infection (P < .001; OR 7.3, 95% CI, 2.5-22.2), cardiac event (P < .001; OR 6.0, 95% CI, 2.3 16.1), and age > or = 65 (P = .009; OR 3.8, 95% CI, 1.4-8.8) to be independent risk factors for mortality. Among patients who failed initial therapy, a non appendiceal source of infection (P < .001; OR 4.7, 95% CI, 2.3-9.8) and a Charlson score > or =2 (P = .033; OR 1.6, 95% CI, 1.0-2.6) were determined to be independent risk factors. Non-appendiceal source of infection (P = .001, OR 3.3, 95% CI, 1.6-7.0) and POD-7 MOD score > or =4 (P < .001; OR 3.4, 95% CI, 1.9-6.0) were found to be independent predictors for re-intervention. CONCLUSION: These results suggest mortality from IAI is strongly related to age and organ dysfunction; however, catheter-related bloodstream infection and postoperative cardiac events have a greater effect on outcome. PMID- 19789025 TI - Primary repair of civilian colon injuries is safe in the damage control scenario. AB - BACKGROUND: Although the safety of primary repair/anastomosis for civilian colon injuries after standard laparotomy (SL) has been established, recent civilian and military reports have questioned the advisability of this technique in the patient requiring damage control laparotomy (DL). We hypothesized that, even in the high-risk DL group, primary repair could be safely used after patient stabilization and that the open abdomen would facilitate the safety of this procedure. METHODS: All patients admitted to our level 1 trauma center with a colon injury over a 7-year period were reviewed from a prospectively collected database. Patients were categorized as having undergone either SL or DL at initial operation. Primary variables of interest were as follows: injury patterns; method of primary repair (suture repair, resection and primary anastomosis, resection and delayed anastomosis); diversion techniques (planned diversion or diversion for anastomotic dehiscence); and colon-related morbidity and mortality. High-risk status in the DL group was identified by the following physiologic variables: mean injury severity score (ISS), red blood cell (RBC) transfusions, ventilator days, and intensive care unit (ICU) duration of stay. RESULTS: During the study period, 309 patients had colonic wounds identified at laparotomy. Of these 309 patients, 280 (91%) underwent SL, of which 277 (98.9%) had primary colonic repair/anastomosis. In the SL group, 1 (0.3%) patient required diversion for subsequent leak and 2 (0.6%) patients had planned diversion The remaining 29 hemodynamically unstable patients required DL. Mean +/ standard deviation indices of injury severity in this group included: ISS = 36.2 +/- 15.8, RBC = 28.7 +/- 25.4 units, ventilator days = 20.1 +/- 16.3, ICU duration of stay = 29.5 +/- 21.6 days. Of the 29 patients in the DL group, 21 (72%) had bowel continuity successfully reestablished in 2.6 +/- 2 days after initial attempts at primary suture repair or resection/anastomosis. A total of 4 (16.6%) patients in this group developed colon-related complications, 3 of whom were treated with subsequent diversion before definitive abdominal closure. One patient developed a late leak. (day 43). Another 4 (13.8%) patients had planned diversion for injuries that were considered to be high risk for leak at subsequent reexploration. There were no colon-related deaths in either group. CONCLUSION: Primary repair of colon injuries appears safe in the majority of patients after DL. Although it is associated with a higher leak rate than SL, the open abdomen affords careful inspection of abdominal contents at reexploration to identify patients who require subsequent diversion. PMID- 19789026 TI - A single institutional experience of factors affecting successful identification of sentinel lymph node in breast cancer patients. AB - BACKGROUND: Sentinel lymph node biopsy (SLNB) has become the standard of care in axillary staging of clinically node-negative breast cancer patients. We hypothesized that certain clinical parameters are associated with failure to identify a SLN. METHODS: We performed an institutional review board-approved, retrospective analysis of 402 consecutive breast cancer patients who underwent SLNB from 2000 to 2007. RESULTS: Of 402 patients, 399 had lymphoscintigraphy (LSG) performed at the time of radiocolloid injection. No significant differences in successful identification of a SLN were found with respect to patient age, histology, or pathologic status of the SLN. Thirteen of 27 patients with no nodes imaged on LSG failed to have a SLN identified at surgery, whereas only 8 of 372 patients with positive imaging on LSG failed to have a SLN identified at surgery (P < .0001). Patients with a body mass index (BMI) > or =40 had a significantly higher rate of failure to detect a SLN by LSG (5/29 patients) compared with patients with a normal BMI (4/145 patients; P < .01). There was a trend for association with increasing BMI and failure to identify a SLN at surgery. The rate of failure to identify a SLN demonstrated a significant improvement in LSG after 200 patients and in surgical success after 100 patients (P < .001). CONCLUSION: Successful identification of a SLN was influenced by BMI, institutional experience, and successful imaging by LSG. After gaining appropriate experience, the probability of successfully identifying a SLN at the time of surgery in a patient with BMI <40 who imaged on LSG was 99.7%. PMID- 19789027 TI - The pulmonary embolism risk score system reduces the incidence and mortality of pulmonary embolism after gastric bypass. AB - BACKGROUND: Pulmonary embolism (PE) is a leading cause of death after roux-en-Y gastric bypass (RYGB); therefore, current recommendations for prophylaxis may be inadequate. METHODS: We reviewed our first 1,341 patients (controls) who underwent RYGB and weighted factors that may have contributed to PE to arrive at a pulmonary embolism risk score (PERS). We postulated that more aggressive prophylaxis in higher risk patients might have reduced the incidence of PE. We tested our hypothesis by basing prophylaxis on the PERS in 1,652 subsequent RYGB patients (study group). Standard risk patients (PERS <4) were ambulated 2 hours after surgery, had application of intermittent compression devices, and received subcutaneous low-dose, unfractionated heparin (LDUH). Intermediate risk patients (PERS = 4) received standard prophylaxis and 3 weeks of postdischarge LDUH. High risk patients (PERS >4) had postdischarge LDUH and a preoperative vena cava filter. RESULTS: The 0.36% incidence of PE (6 patients) in the study group was significantly lower (P <.05) than the 1% incidence (13 patients) in the controls. Three of 189 men in the control group died of PE, whereas there were no deaths from PE in 271 men in the study group (P <.05). CONCLUSION: The PERS may be an appropriate scoring system for determining preoperatively the level of risk for postoperative PE in RYGB patients. Basing prophylaxis on the level of risk reduces the incidence and mortality of PE and consumes resources judiciously. PMID- 19789028 TI - Single center experience transplanting kidneys from deceased donors with terminal acute renal failure. AB - BACKGROUND: Transplantation of kidneys from deceased donors with terminal acute renal failure (ARF) is uncommon. METHODS: We reviewed retrospectively our single center experience with transplantation of ARF donor kidneys. RESULTS: From January 2007 through September 2008, we transplanted 25 kidneys from 17 ARF donors; 22 kidneys were from standard criteria donors. Mean donor age was 34 years. Mean admission and terminal donor serum creatinine values were 1.3 mg/dL and 3.1 mg/dL. All but 2 kidneys were placed on pump preservation; mean cold ischemia time was 27 hours. The recipient group had a mean age of 49 years and a mean waiting time of 24 months. Patient and graft survival rates were 100% and 92%, respectively, with a mean follow-up of 12 months. Delayed graft function occurred in 8 patients (32%), mean initial duration of stay was 6 days, 3 patients (12%) required re-operation, 3 patients (12%) had acute rejection, and 8 patients (32%) developed infections. Mean 1- and 12-month recipient serum creatinine and glomerular filtration rate values were 1.9 mg/dl (45 mL/min) and 1.5 mg/dl (50 mL/min), respectively. CONCLUSION: Kidneys from deceased donors with terminal ARF have excellent short-term outcomes and represent another potential method to safely expand the donor pool. PMID- 19789029 TI - Routine bilateral central lymph node clearance for papillary thyroid cancer. AB - BACKGROUND: Controversy exists regarding the extent of surgical treatment for paratracheal (level VI) lymph nodes in patients with papillary thyroid cancer (PTC). Local recurrence within lymph nodes in the central neck compartment after total thyroidectomy can be difficult to detect and more hazardous to treat surgically. An initial bilateral central lymph node dissection (CLND) can best minimize this risk of local recurrence, if CLND is established as reasonably safe and oncologically justified. METHODS: This study is based on a retrospective review of the institutional tumor registry of all patients treated for PTC between January 2000 and May 2008 at a 636-bed tertiary referral center and university-affiliated hospital. The following data were analyzed: the operative procedures, tumor characteristics (size, lymph node metastasis), injury to the recurrent laryngeal nerve (RLN), tumor recurrence, and need for further operative procedures. RESULTS: Of 310 patients identified as treated surgically for PTC, 281 received total thyroidectomy and 29 received a lesser operation. Bilateral CLND was performed in 169 patients, unilateral CLND in 11, and no CLND in 130. The central lymph nodes were positive in 84 (46.7%) of 180 patients with CLND. Excluding isthmus tumors and those with bilateral same-size PTC, 41 (25.5%) of 161 patients with bilateral CLND had positive contralateral lymph nodes. Of the 603 RLNs at risk, 13 temporary injuries occurred, and 8 (1.3%) permanent injuries resulted. The risk of RLN injury was not greater with bilateral CLND compared to unilateral or no CLND (P = .18), and those patients with bilateral CLND had statistically larger tumors (1.60 cm vs 0.84 cm; P < .0001). Of the 10 documented cancer recurrences requiring reoperation, 4 were in the central neck, and all of these occurred in patients who did not have CLND. CONCLUSION: Lymph node metastases are present in both the ipsilateral and contralateral central lymph node basins in a significant percentage of patients with PTC. Routine bilateral CLND in patients with PTC has the potential to clear metastatic disease without significantly increasing the risk of RLN injury. PMID- 19789030 TI - Lymph node evaluation is associated with improved survival after surgery for early stage gallbladder cancer. AB - BACKGROUND: Guidelines for the current National Comprehensive Cancer Network recommend radical cholecystectomy, including hepatic resection and portal lymph node (LN) dissection, for patients with early stage gallbladder (GB) cancer. We sought to determine the survival benefit conferred by adequate LN evaluation. METHODS: We used the surveillance, epidemiology and end results (SEER) neoplasm registry to identify patients who had an operation for GB cancer between 1988 and 2004. Patients were classified by stage of disease, operative procedure performed (cholecystectomy alone or radical resection), number of LNs evaluated (0, 1, >1), and receipt of radiation (RT). We included patients with T1B, T2, and T3 neoplasms who were LN positive or negative. Patients with T4 neoplasms and those with metastatic disease were excluded. Multivariate analysis included adjustment for age, race, sex, neoplasm grade, stage, operation performed, receipt of RT, and neoplasm registry. RESULTS: We identified 4,614 patients who underwent operative treatment for stage 1-2B GB (including T1B-T3 and LN positive or negative) cancer between 1988 and 2004. Of 4,614 patients, 9.6% (442) had radical resection, whereas 90.4% (4,172) had cholecystectomy alone. Among patients undergoing radical resection, 56% had LNs evaluated as compared with 28% of patients after cholecystectomy. For patients with T1B and T2 neoplasms who underwent radical resection, pathologic evaluation of at least 1 LN was associated with a significant improvement in median overall survival (OS) compared with those who had no LN evaluated (123 months vs 22 months; P < .0001). Radical resection with no LN evaluation provided similar OS compared with cholecystectomy alone (22 months vs 23 months; P = NS). For patients with T3 neoplasms, radical resection, including pathologic evaluation of at least 1 LN, was also associated with improved OS compared with radical resection with no LN evaluation (12 months vs 7 months; P = .0014). Again, individuals who had radical resection without LN evaluation had similar OS compared with those who had cholecystectomy alone (7 months vs 6 months; P = NS). Individuals who had radical resection with LN evaluation were more likely to receive RT than those who had radical resection without LN evaluation (33.1% vs 19.1%; P = .002). In multivariate analysis (including adjustment for RT), however, LN evaluation was still associated with a decrease in mortality compared with no LN evaluated (HR = 0.611; 95% CI = 0.484, 0.770). The pathologic evaluation of additional LN (>1) did not provide any additional benefit compared with the evaluation of a single node (HR = 0.795; 95% CI = 0.571, 1.107). Radical resection alone (without LN evaluation) did not provide any benefit over cholecystectomy alone (HR = 1.098; 95% CI = 0.971, 1.241). CONCLUSION: LN evaluation is a critical component of radical resection for GB cancer. In the absence of LN evaluation, radical resection provides no benefit over cholecystectomy alone. PMID- 19789032 TI - Comparison of outcomes after hand-sewn versus stapled ileal pouch-anal anastomosis in 3,109 patients. AB - BACKGROUND: The aim of this study was to compare outcomes after primary hand-sewn versus stapled ileal pouch-anal anastomosis (IPAA). METHODS: Patients undergoing a primary IPAA (1983-2007) were identified from a prospective pelvic pouch database. Differences between group A (hand-sewn) and group B (stapled) for pre operative and peri-operative factors, complications, functional outcomes, and quality of life (QOL) were investigated. RESULTS: Of 3,382 patients with a primary IPAA, 3,109 were included. Median follow-up was 7.1 years (0.1-24). Mean age was 37.9 +/- 13.2 years. Overall, 1,741 patients (56%) were male. Group A (n = 474) and group B (n = 2635) had similar age (P = .28), sex (P = .8), albumin level (P = .74), prior colectomy (P = .98), and use of steroids (P = .1). Group A had a greater use of ileostomy (P = .001) and a longer duration of stay (P < .001). Group B had a greater body mass index (P < .001) and J-pouch (P < or = .001). Wound infection (P = .42) and pouchitis (P = .59) were similar. Anastomotic stricture (P = .002), septic complications (P = .019), bowel obstruction (P = .027), and pouch failure (P < .001) were greater in group A. At most recent follow-up, bowel frequency (P = .74) and rate of urgency were similar (P = .71). A greater proportion of patients in group A described incontinence (P < .001), seepage (P < .001), pad usage (P < .001), dietary (P < .001), social (P < .001), and work restrictions (P = .025). The Cleveland Global QOL score (P = .018) was greater in group B. CONCLUSION: Patients undergoing a stapled IPAA had better outcomes and QOL than those undergoing a hand-sewn IPAA. PMID- 19789031 TI - Pathogenesis of Barrett's esophagus: bile acids inhibit the Notch signaling pathway with induction of CDX2 gene expression in human esophageal cells. AB - BACKGROUND: Barrett's esophagus (BE) is the predominant risk factor for the development of esophageal adenocarcinoma. BE is characterized by intestinal metaplasia with goblet cells. Reflux of bile acids is known to induce intestinal metaplasia, but the mechanisms are unclear. Inhibition of Notch signaling accompanied by increased Hath1 and induction of caudal homeobox 2 (CDX2) may be involved in development of intestinal goblet cells. METHODS: Esophageal adenocarcinoma cell lines OE19 and OE33 were exposed for up to 8 hours to DCA (100-300 microM), and for up to 24 hours with and without the gamma-secretase inhibitor, DAPT (20 microM). Notch signaling components and CDX2 levels were measured by real-time PCR (for mRNA) and by Western blot analysis (for proteins). RESULTS: DCA induced a time and concentration dependent decrease in Notch pathway components mRNAs in OE33 and in the proteins in both cell lines. CDX2 mRNA and Hath1 protein were increased in OE19 by 3-fold. Inhibition of Notch pathway by DAPT decreased downstream Notch signaling mRNAs and proteins in both cell lines and increased Hath1 and CDX2 proteins only in OE19. CONCLUSION: Bile acid inhibition of Notch signaling in esophageal cells is correlated with an increase in Hath1 and CDX2 and may be one of the key processes contributing to the formation of BE. PMID- 19789033 TI - Perforated appendicitis: is early laparoscopic appendectomy appropriate? AB - BACKGROUND: Laparoscopic appendectomy for nonperforated appendicitis is associated with improved outcomes; however, laparoscopy has been challenged for perforated appendicitis owing to higher morbidity compared with open or staged procedures. The purpose of this study was to determine whether the laparoscopic approach for perforated appendicitis results in improved outcomes compared with open appendectomy. METHODS: Postoperative patient records for confirmed perforated appendicitis from 2005 to 2008 were reviewed retrospectively. Demographics, surgical approach, conversion rate, and outcomes were tabulated, including length of stay (LOS), intra-abdominal and wound infections, and duration of antibiotic therapy. RESULTS: The incidence of perforation was 27.9% in 885 total patients. The conversion rate from laparoscopic to open for perforated appendicitis was 16%. Hospital LOS was significantly lower in the laparoscopic group (P < .05). The incidence of postoperative abscess was not significantly different; however, the incidence of wound infection and duration of antibiotic therapy were significantly lower in the laparoscopic group (P < .05). CONCLUSION: Successful laparoscopic appendectomy reduces LOS, antibiotic therapy, and wound infections compared with open appendectomy in perforated appendicitis without increasing the incidence of postoperative abscess. We conclude that perforated appendicitis can be managed effectively by laparoscopic appendectomy in a high percentage of patients with improved outcomes compared with open appendectomy. PMID- 19789034 TI - Obesity-induced hepatic hypoperfusion primes for hepatic dysfunction after resuscitated hemorrhagic shock. AB - BACKGROUND: Obese patients (BMI>35) after blunt trauma are at increased risk compared to non-obese for organ dysfunction, prolonged hospital stay, infection, prolonged mechanical ventilation, and mortality. Obesity and non-alcoholic fatty liver disease (NAFLD) produce a low grade systemic inflammatory response syndrome (SIRS) with compromised hepatic blood flow, which increases with body mass index. We hypothesized that obesity further aggravates liver dysfunction by reduced hepatic perfusion following resuscitated hemorrhagic shock (HEM). METHODS: Age matched Zucker rats (Obese, 314-519 g & Lean, 211-280 g) were randomly assigned to 4 groups (n = 10-12/group): (1) Lean-Sham; (2) Lean, HEM, and resuscitation (HEM/RES); (3) Obese-Sham; and (4) Obese-HEM/RES. HEM was 40% of mean arterial pressure (MAP) for 60 min; RES was return of shed blood/5 min and 2 volumes of saline/25 min. Hepatic blood flow (HBF) using galactose clearance, liver enzymes and complete metabolic panel were measured over 4 h after completion of RES. RESULTS: Obese rats had increased MAP, heart rate, and fasting blood glucose and BUN concentrations compared to lean controls, required less blood withdrawal (mL/g) to maintain 40% MAP, and RES did not restore BL MAP. Obese rats had decreased HBF at BL and during HEM/RES, which persisted 4 h post RES. ALT and BUN were increased compared to Lean-HEM/RES at 4 h post-RES. CONCLUSION: These data suggest that obesity significantly contributes to trauma outcomes through compromised vascular control or through fat-induced sinusoidal compression to impair hepatic blood flow after HEM/RES resulting in a greater hepatic injury. The pro-inflammatory state of NAFLD seen in obesity appears to prime the liver for hepatic ischemia after resuscitated hemorrhagic shock, perhaps intensified by insidious and ongoing hepatic hypoperfusion established prior to the traumatic injury or shock. PMID- 19789035 TI - Contemporaneous management of esophageal perforation. AB - BACKGROUND: Esophageal perforation is an important therapeutic challenge. We hypothesized that patients with minimal mediastinal contamination at the time of diagnosis could be managed successfully with nonoperative treatment modalities. METHODS: We performed a retrospective review of 119 consecutive patients with esophageal perforation from 1998 to 2008. Demographics, cause of perforation, clinical presentation, diagnostic methods, and management results were evaluated. The decision to operate was based on the extent of mediastinal contamination and systemic sepsis rather than cause of perforation. RESULTS: Median time to diagnosis among all patients was 12 hours (range, 1-120). Spontaneous (Boerhaave's) perforation occurred in 44 (37%) patients. Iatrogenic perforations constituted the remaining patients (n = 75). After instrumental perforation, 9 patients (13%) required esophagectomy, 48 patients were managed with repair and drainage, and the remaining 18 were managed nonoperatively. All 34 patients undergoing operative therapy for spontaneous perforations were treated with esophageal repair. Overall mortality was 14%, with intrathoracic perforations having 18% mortality, cervical 8%, and gastroesophageal junction 3%. Patients undergoing nonoperative therapy had a shorter hospitalizations (13 vs 24 days), fewer complications (36% vs 62%), and less mortality (4% vs 15%) compared with those undergoing operative intervention. CONCLUSION: An approach to esophageal perforation based on injury severity and the degree of mediastinal and pleural contamination is of paramount importance. Although operative management remains the standard in the majority of patients with esophageal perforation, nonoperative management may be successfully implemented in selected patients with a low morbidity and mortality if favorable radiographic and clinical characteristics are present. PMID- 19789036 TI - Back to basics: use of fresh cadavers in vascular surgery training. AB - BACKGROUND: Surgical trainees face many obstacles in learning basic surgical anatomy and technique. Pressure for quicker operative times, introduction of an 80-hour work week, rising numbers of endovascular procedures replacing open surgery, and the presence of fellowship training programs can limit resident exposure not only to surgical skills, but to attending faculty as well. Our goal was to design a vascular exposures course using fresh frozen cadavers to promote dissection and suturing skills, foster interaction with Vascular Surgery faculty, promote teamwork between residents, and measure the satisfaction of the residents with the course. METHODS: A pilot program was created with fresh frozen cadavers used to teach basic vascular surgical anatomy and operating skills to junior and mid-level general surgery residents. The course was organized by the Department of General Surgery and the Division of Vascular Surgery. Trainees completed a general questionnaire and evaluation at the completion of the course. RESULTS: Forty-five general surgery residents participated in 6 independent sessions offered over a 24-month period. Data from 2 questionnaires were entered into a spreadsheet and analyzed. Eighty-five percent of residents found the course met their expectations. Fresh frozen cadaver material was found optimal by all participants. Forty-four of 45 (97.8%) residents rated the educational value of the course with a perfect score and would recommend the course to others. CONCLUSION: Fresh frozen cadavers provide an excellent opportunity to teach basic open vascular surgery principles while fostering interaction with faculty. Sharing cadavers between multiple disciplines can help with cost containment. PMID- 19789037 TI - Rapid thrombelastography (r-TEG) identifies hypercoagulability and predicts thromboembolic events in surgical patients. AB - BACKGROUND: Despite routine prophylaxis, thromboembolic events (TEs) in surgical patients remain a substantial problem. Furthermore, the timing and incidence of hypercoagulability, which predisposes to these events is unknown, with institutional screening programs serving primarily to establish a diagnosis after an event has occurred. Emerging evidence suggests that point of care (POC) rapid thrombelastography (r-TEG) provides a real-time analysis of comprehensive thrombostatic function, which represents an analysis of both enzymatic and platelet components of thrombus formation. We hypothesized that r-TEG can be used as a screening tool to identify hypercoagulable states in surgical patients and would predict subsequent thromboembolic events. METHODS: Rapid thrombelastography r-TEG analyses were performed on 152 critically ill patients in the surgical intensive care unit (ICU) during 7 months. Hypercoagulability was defined as clot strength (G)>12.4 dynes/cm(2). Variables of interest for identifying hypercoagulability and thromboembolic events included sex, age, operating hospital service, specific injury patterns, injury severity score (ISS), transfusion within first 24 h, ICU duration of stay, ventilator days, hospital admission days, and thromboprophylaxis. Comparisons between the hypercoagulable and normal groups or between the groups with and without thromboembolic events were performed using Chi-square tests or the Fisher exact test for categorical variables and independent sample t tests or Wilcoxon rank sum tests for continuous variables. Multivariate logistic regression analysis (LR) was performed to identify independent predictors of thromboembolic events. A receiver operating characteristic curve was used to measure the performance of G for predicting the occurrence of a TE event. All tests were 2-sided with significance of P < .05. RESULTS: In all, 86 patients (67%) were hypercoagulable by r-TEG. More than 85% of patients in the hypercoagulable group and 79% in the normal group received thromboprophylaxis during the study period. The differences between hypercoagulable and normal groups by bivariate analysis included high risk injuries (52% vs 35%; P = .03), spinal cord injury (27% vs 12%; P = .03), median ICU duration of stay (13 vs 7 days; P < .001), median ventilator days (6 vs 2; P < .001), and median hospital duration of stay (20 vs 13 days; P < .001). A total of 16 patients (19%) of the hypercoagulable group suffered a thromboembolic event, and 10 hypercoagulable patients (12%) had thromboembolic events predicted by prior r-TEG hypercoagulability. No patients with normal coagulability by r-TEG had an event (P < .001). LR analysis showed that the strongest predictor of TE after controlling for the presence of thromboprophylaxis was elevated G value (odds ratio: 1.25, 95% confidence interval [CI]: 1.12-1.39). For every 1 dyne/cm(2) increase in G, the odds of a TE increased by 25%. CONCLUSION: These results indicate that the presence of hypercoagulability identified by r-TEG is predictive of thromboembolic events in surgical patients. Subsequent study is necessary to define optimal prophylactic treatment strategies for patients with r-TEG proven hypercoagulability. PMID- 19789039 TI - Impact of splenic injury guidelines on hospital stay and charges in patients with isolated splenic injury. AB - BACKGROUND: The purpose of this study was to assess the impact of care guidelines for patients with isolated blunt splenic trauma on length of stay (LOS) and patient charges. METHODS: We conducted a review of the hospital trauma registry and identified patients admitted with blunt splenic injury from 2000 to 2007. Splenic injury guidelines were initiated in November 2004. Patients with other major injuries were excluded. Patients were grouped according to their American Association for the Surgery of Trauma (AAST) splenic injury grade, I-V. Hospital LOS, intensive care unit (ICU) LOS, and patient charges before and after the guidelines were compared. RESULTS: We identified 137 patients with isolated splenic injuries. Sixty-three patients were admitted before and 70 patients after implementation of the guidelines. ICU and hospital LOS were significantly decreased after the guidelines (ICU LOS, 1.35 days before, 0.80 after [P < .01]; and hospital LOS, 4.17 before, 3.27 after [P < .01]). When grouped by AAST grade, grade II injuries had a decrease in hospital LOS (4.5 before vs 2.29 after; P < .01) and ICU LOS (1.43 before vs 0.29 after; P < .01). Adjusted hospital charges showed no significant increase overall after the guideline implementation (mean hospital charges before $23,047 vs after, $24,116; P = .62). CONCLUSION: Implementing guidelines for the observation of blunt splenic injury decreased the overall hospital LOS and ICU LOS at our institution, but hospital charges remained the same. Trauma programs should institute splenic injury guidelines to reduce resources needed for the care of isolated splenic injuries. PMID- 19789038 TI - Local wound p38 MAPK inhibition attenuates burn-induced cardiac dysfunction. AB - BACKGROUND: Topical inhibition of activated p38 MAPK within burn wounds attenuates the local and systemic inflammatory response. In this study, we investigated the effects of local activated p38 MAPK inhibition on burn-induced cardiac dysfunction. METHODS: Using a standardized rat model of scald burn injury, rats were given a 30% total body surface area partial thickness burn or sham injury, and the wounds were treated with an activated p38 MAPK inhibitor (SB) or vehicle. Systemic blood pressure measurements were recorded in vivo followed by in vitro assessment of sarcomere contraction in single-cell suspensions of isolated cardiomyocytes. RESULTS: Systolic blood pressure or maximum left ventricular pressures in vivo and peak cardiomyocyte sarcomere contractility in vitro were significantly reduced after burn injury. These functional deficits were abolished 24 h after burn injury following local p38 MAPK inhibition. In vitro incubation of normal cardiomyocytes with homogenate from burned skin or burn serum resulted in a similar pattern of impaired cardiomyocyte contractility. These effects were reversed in normal cardiomyocytes exposed to burn skin homogenates treated topically with a p38 MAPK inhibitor. A Western blot analysis showed that cardiac p38 MAPK activation was not affected by dermal blockade of activated p38 MAPK, arguing against systemic absorption of the inhibitor and indicating the involvement of systemic cytokine signaling. CONCLUSION: Topical activated p38 MAPK inhibition within burned skin attenuates the release of proinflammatory mediators and prevents burn-induced cardiac dysfunction after thermal injury. These results support the inhibition of burn wound inflammatory signaling as a new therapeutic approach to prevent potential postthermal injury multiorgan dysfunction syndrome. PMID- 19789040 TI - Twelve hundred abscesses operatively drained: an antibiotic conundrum? AB - BACKGROUND: The incidence of soft tissue infections from antimicrobial-resistant pathogens is increasing. This study evaluated the epidemiology of operatively drained soft tissue abscesses. METHODS: This retrospective study evaluated 1,200 consecutive patients from 2002 to 2008 who underwent incision and drainage (I&D) in the main operating room. Patients were excluded for perirectal or hidradenitis infections. RESULTS: Of 1,200 consecutive cases with an I&D, 1,005 patients had intraoperative cultures. The 1,817 positive isolates included gram-positive aerobes (1,180 [65%]), gram-negative aerobes (207 [11%]), anaerobes (416 [23%]), and fungi (14 [1%]). The most prevalent organism was Staphylococcus aureus, 30% (536), with 80% (431) being methicillin-resistant S aureus (MRSA). MRSA was the predominant organism in all except the breast abscesses. Anaerobes were identified primarily in the breast in diabetics, and in trunk and extremity abscesses in intravenous drug users. The most frequently prescribed empiric antibiotic was ampicillin/sulbactam (66%). The initial empiric antibiotic did not cover MRSA (82%; P < .001), resistant gram-negative aerobes (24%), and anaerobes (26%). CONCLUSION: Gram-positive aerobes plus anaerobes represented approximately 80% of the pathogens in our series, with the anaerobic rates being underestimated. Empiric antibiotics should cover MRSA and anaerobes in patients with superficial abscesses drained operatively. PMID- 19789041 TI - Completion pancreatectomy and duodenectomy for recurrent MEN-1 pancreaticoduodenal endocrine neoplasms. AB - BACKGROUND: The purpose of this study is to describe outcomes of MEN-1 patients with recurrence requiring completion pancreatectomy and duodenectomy after initial treatment of pancreatic endocrine neoplasms (PENs) and hypergastrinemia with distal pancreatectomy, enucleation of pancreatic head PENs, and duodenotomy. METHODS: After undergoing this initial operation, 8 of 49 patients (16%) have required completion pancreatectomy and duodenectomy for recurrent PENs and hypergastrinemia. Retrospective review was performed. RESULTS: Median age was 39 years (27-51) at completion pancreatectomy compared to 31 years (20-40) at initial operation. Pathology revealed multiple PENs in 100%, duodenal neoplasms in 63%, and metastatic lymph nodes in 75%. There was no operative mortality and 88% of patients are currently alive. Preoperative gastrin levels were 934 +/- 847 pg/mL while postoperative levels are 93 +/- 79 pg/mL (normal 25-111 pg/mL). Mean Hemoglobin A1C levels are 8.3 +/- 3.3% (normal 3.8%-6.4%). Mean follow-up is 44 +/- 25 months. CONCLUSION: This initial operation may provide tumor control and prevent metastases but recurrent PENs are multifocal and progressive. Completion pancreatectomy and duodenectomy is arduous but outcomes are acceptable. Considering the radical nature of this treatment, individual consideration should be given to MEN-1 patients amenable to initial alternative pancreatic resections that preserve pancreatic mass and allow future pancreas-preserving reoperations. PMID- 19789042 TI - Institutional protocol improves retrievable inferior vena cava filter recovery rate. AB - BACKGROUND: In the trauma population, the use of retrievable inferior vena cava filters (RIVCF) is rapidly gaining acceptance in patients at high risk for venous thromboembolism. This study reports the impact of an institutional protocol on retrieval rates of RIVCF at a level I trauma center. METHODS: A review of an institutional Trauma Registry identified 94 consecutive patients who received RIVCF between January 2004 and February 2007 (group I) before the protocol was instituted. Under the protocol, 61 consecutive trauma patients received RIVCF between August 2007 and July 2008 (group II) and were prospectively followed. RESULTS: Filter retrieval eligibility criteria were met in 81% (76/94) of patients in group I and in 61% (37/61) of patients in group II. Of those eligible, retrieval-attempt rates were 42% (32/76) in group I versus 95% (35/37) in group II (P < .001). Clinician oversight of the filter accounted for 89% (39/44) of failure of retrieval attempts; patient noncompliance accounted for the rest in group I. In group II, the latter accounted for all such failures. Retrieval was successful in 37% (28/76) and in 84% (31/37) of the eligible patients in groups I and II, respectively (P < .001). No retrieval procedure related complications occurred. CONCLUSION: An institutional protocol for prospective monitoring of RIVCF significantly increases filter retrieval rate. PMID- 19789043 TI - Laparoscopy-assisted and open living donor right hepatectomy: a comparative study of outcomes. AB - BACKGROUND: Minimally invasive liver surgery is a rapidly advancing field with demonstrated applicability to living donation. In this paper, we compare the safety and efficacy of laparoscopy-assisted donor right hepatectomy (LADRH) to open donor right hepatectomy (ODRH). METHODS: We performed a retrospective, comparative analysis of 33 LADRH to the most recent 33 ODRH performed at our institution, evaluating donor complications, costs, and recipient outcomes. RESULTS: Donor demographics including age, gender, body mass index (BMI), and vascular and biliary anomalies were comparable. Donor complication rates were equivalent for LADRH and ODRH. Donor operative times were shorter for LADRH (LADRH 265 minutes, ODRH 316; P < .001) even after adjusting for BMI. Blood loss and length of stay were comparable. Additionally, total hospitalization costs were equivalent (LADRH $1.11, ODRH $1.00; P = .19). Higher operative supply costs for LADRH were balanced by higher time-based operative costs for ODRH resulting in no significant differences in total operative costs. Finally, there were no differences in graft size, recipient patient or graft survival, or recipient vascular or biliary complications. CONCLUSION: Our experience suggests that LADRH compares favorably with ODRH with equivalent safety, resource utilization, and effectiveness. We believe that LADRH provides potential physical and psychological benefits without an adverse effect on outcomes. PMID- 19789044 TI - Long-term outcomes of laparoscopic Heller myotomy for achalasia. AB - BACKGROUND: Short-term outcomes of laparoscopic Heller myotomy (LHM) for achalasia have been excellent, although the long-term durability of this operation remains to be established. The aim of this study was to evaluate the long-term outcomes of LHM. METHODS: A single-institution review of patients undergoing LHM between 1992 and 2003 with > or =5 years follow-up. Failure was defined as symptom recurrence requiring reoperation. Univariate and multiple regression analysis were performed to identify preoperative variables predictive of long-term success. RESULTS: A total of 46 patients underwent LHM with Toupet (n = 42) or Dor (n = 4) fundoplication. At a mean follow-up of 6.4 years, 37 (80%) patients remained free from failure. Mean time to symptom recurrence in those failing LHM was 21.3 months (range, 0.5-77). Causes of failure included nonfunctioning end-stage esophagus (n = 4), fibrotic narrowing at the gastroesophageal junction (n = 4), and tight wrap (n = 1). Univariate analysis identified high preoperative lower esophageal sphincter pressure (LESP), no prior therapy, short duration of symptoms, and absence of sigmoidal esophagus as predictors of long-term success (P < or = .044 each). High LESP remained the only predictor of long-term durability in multiple regression analysis (P = .043). Reoperations included redo myotomy (n = 2), esophagectomy (n = 6), or both (n = 1). At final follow-up, 44 (96%) patients reported significant symptom improvement compared with pre-LHM severity. CONCLUSION: LHM is associated with an 80% long-term success rate. Successful LHM may be predicted by high LESP, no prior therapy, short symptom duration, or absence of sigmoidal esophagus. In this series, failures of LHM underwent reoperation (redo myotomy or esophagectomy) with good results. PMID- 19789045 TI - [Sleep: one third of our life at risk for breathing...?]. PMID- 19789046 TI - [Why and how to diagnose sleep respiratory disorders?]. AB - Gas exchange abnormalities occur firstly during sleep in restrictive and obstructive chronic respiratory failure. Nocturnal hypoxemia is often a revealing feature of a sleep-related hypoventilation/hypoxemia syndrome in patients who will have later a diurnal hypoxemia. On the other hand, sleep may induce breathing abnormalities in individuals without lung diseases, like in obstructive sleep apnea syndrome (OSAS). In OSAS, repeated closure and/or narrowing of the pharynx during sleep increases the inspiratory effort and induces sleep fragmentation. Intermittent hypoxemia is another consequence of the obstructive events in OSAS. Besides its direct consequences on sleep, OSAS is also associated with an increased risk of cardiovascular morbi-mortality. Reduced daytime alertness and cognitive functions are usually present in patients with sleep disordered breathing. These features are believed to be related to both sleep fragmentation and nocturnal hypoxia/hypercapnia. Sleep-related hypoventilation/hypoxemia and pharyngeal obstructive events may occur together in patients with respiratory insufficiency, especially in obese and/or chronic obstructive pulmonary disease (COPD) subjects. A correct qualitative and quantitative assessment of sleep-disordered breathing may only be performed by recording specific physiological signals during sleep. PMID- 19789047 TI - [The set-up of obstructive sleep apnea treatment]. AB - The therapeutic strategy of obstructive sleep apnea syndrome (OSAS) is dependent on the illness severity, which is influenced by several factors as the presence of comorbidities (particularly cardiovascular comorbidities), the importance of diurnal drowsiness and the number of abnormal respiratory events. Whereas the treatment is most often palliative and uncomfortable, its success is closely dependent on its compliance. The way of starting the treatment of OSAS is therefore an essential topic, which will condition its long-term acceptance. PMID- 19789048 TI - [Practical aspects of the management of patients treated by continuous positive airway pressure]. AB - The therapeutic follow-up is a decisive factor of the success of a long course treatment by continuous positive airway pressure (CPAP). The effectiveness of this treatment on both symptoms and complications must be regularly verified. Polysomnography with CPAP could be necessary in order to check out the efficacy of this treatment and/or to find an associated diagnosis when symptoms persist, particularly a diurnal drowsiness, which is the main therapeutic target in obstructive sleep apnea syndrome (OSAS). The secondary effects that are likely to compromise the compliance of CPAP treatment must be resolved, particularly the nasal intolerance, which are enhanced by mask leakages and often corrected by using heated humidity with CPAP delivery systems. The efficacy of CPAP on both diurnal drowsiness and hypertension is related to the compliance of this treatment which must be regularly verified, at the same time that the clinical evaluation. The data obtained from the device's memory give information concerning the number of hours day to day, in which the CPAP device was running at the prescribed pressure. The first months with CPAP are decisive to avoid a failure of the treatment at long term. This period must be closely monitored by both the physician and the home care provider. Patients should use the CPAP at least 3-4 h by night and all possible means should be used to obtain a maximal compliance. Therapeutic educational programs could help to reach this goal. PMID- 19789049 TI - [The obesity-hypoventilation syndrome]. AB - Obesity, well-known as a cardiovascular risk factor is also a "respiratory" risk factor and can have profound adverse effects on the respiratory system, such as alterations in pulmonary function tests, respiratory mechanics, respiratory muscle strength and endurance, gas exchange, control of breathing and exercise capacity. ABG are frequently altered in obese subjects and abnormalities are directly proportional to BMI. Two main pathophysiological mechanisms may account for gas exchange abnormalities: V/Q inequality, responsible for isolated hypoxemia, and alveolar hypoventilation responsible for the also called "obesity hypoventilation syndrome" (OHS). Hypoventilation in obese patients includes a diversity of mechanisms frequently imbricated, among which the two most frequent are mechanical limitation and blunted ventilatory drive. Two other clinical entities (COPD and OSA) frequently present in the obese patients may potentiate or aggravate this hypoventilation. OHS is frequently underappreciated and diagnosis is rarely made at the steady state. Such diagnosis is frequently made in two situations: either during an exacerbation or when in front of symptoms of respiratory sleep disturbances. The patient is referred to sleep laboratory for screening for OSA. Ventilatory management of these patients will depend on the patient's underlying condition and on sleep study results. It includes CPAP or NIPPV but frequently additional O(2) addition is necessary. OHS represents today one of the most frequent indications of NIV worldwide. PMID- 19789050 TI - [Follow-up and management of non-invasive home mechanical ventilation]. AB - Efficacy and tolerance of home non-invasive ventilation (NIV) must be assessed by using objective criteria (clinical evaluation, arterial blood gases, oxymetry, and research of side effects such as air leaks, skin problems, etc). In this article, we describe a procedure for long-term follow-up of home NIV. We also suggest an algorithm using available polygraphic tools to ascertain causes of NIV failure, in order to correct them. PMID- 19789051 TI - [Obstructive sleep apnea syndrome and cardiovascular consequences: which complementary studies and monitoring?]. AB - Obstructive sleep apnea syndrome (OSAS) is a recognized cardiovascular risk factor. Its treatment has been shown to prevent those complications, although in some cases, controversies still remain. However, links between OSAS and cardiovascular and metabolic issues lead to carefully evaluate cardiovascular system when an OSAS is newly diagnosed. Cardiovascular evaluation of a newly diagnosed OSAS will depend on its background. In the case of already known cardiovascular and metabolic mordibities, with a recent evaluation, no additional investigations are needed. By contrast, in the case of a severe OSAS with unknown cardiovascular and metabolic diseases, in addition of a thorough clinical examination, evaluation should include at least fasting glucose, cholesterolemia and triglyceridemia. Ambulatory blood pressure recording should be discussed, together with an EKG and supra aortic vessels echo-doppler. PMID- 19789052 TI - [Which complementary studies and metabolic monitoring must be performed in OSAS? For which patients?]. AB - Characterised by abnormal breathing during sleep, obstructive sleep apnea (OSA) is strongly associated with obesity. Visceral obesity is a component of metabolic syndrome with insulin resistance, hypertension and dyslipidemia. OSA may also represent an independent risk factor for cardiovascular disease, especially hypertension, diabetes mellitus and dyslipidemia. Abdominal adiposity is an important factor for the development of OSA and associated metabolic disorders. Diagnosis of metabolic syndrome can be made using usual markers like waist circumference, arterial pressure measurement, fasting blood glucose, fasting cholesterol, triglyceride and HDL-cholesterol. Those parameters should be systematically evaluated in case of OSA. PMID- 19789053 TI - [Management of central sleep apnea]. AB - Central sleep apnea is highly prevalent in association with heart failure, some neurological diseases and chronic opioids use. There are two main categories of central sleep apnea respectively related with different underlying conditions. Some hypocapnic patients exhibit respiratory control system instability and central apnea occurs when PaCO(2) falls below the threshold for apnea during sleep. The other group are patients with chronic hypercapnia mainly in the context of neuromuscular disorders or obesity hypoventilation syndrome. All these patients should be assessed by recording blood gases, polysomnography and ventilatory responses to CO(2). Cardiologic assessment should include pro-brain natriuretic factor (pro-BNP) and cardiac echography whereas neurological examination requires brain imaging and/or electromyography. Ventilatory supports used for treating central sleep apnea are non-invasive ventilation and servo assisted ventilation in hypercapnic and hypocapnic patients respectively. PMID- 19789054 TI - [Role of a health network dedicated to patient care for sleep disorders]. AB - The Reseau Morphee is a health network funded by the Regional Health Commission (Mission Regionale de Sante d'Ile-de-France). Its mission is to improve the management of sleep disorders via actions for the public, patients and health professionals. For patients suffering from sleep apnea, the network improves access to care and organises education and support groups for patients treated by Continuous Positive Airway Pressure (CPAP) in order to improve compliance. Health professionals can optimise patient care using an Internet based computerised consultation system which automatically incorporates sleep recording and CPAP reports. The expertise of the Morphee medical team is on hand at all times to help in the management of complex patients and expert advice from other members of the network is shared during regular patient management meetings. The reseau Morphee is certified as a continuing medical education (FMC) and clinical practice accreditation (EPP) organisation and so active members can validate both their FMC and EPP. PMID- 19789055 TI - Cardioprotection by volatile anesthetics: established scientific principle or lingering clinical uncertainty? PMID- 19789056 TI - Transesophageal echocardiographic imaging of the branches of the aorta: a guide to obtaining these images and their clinical utility. PMID- 19789057 TI - Real-time 3-dimensional echocardiographic assessment of current continuous-flow rotary left ventricular assist devices. PMID- 19789058 TI - Case 5--2009: severe lactic acidosis during cardiac surgery. PMID- 19789059 TI - Con: we should not enforce the use of ultrasound as a standard of care for obtaining central venous access. PMID- 19789060 TI - Pathogenesis of cardiometabolic risk as it relates to overweight and obesity. Introduction. PMID- 19789061 TI - Obesity as a disease state: a new paradigm for diagnosis and treatment. AB - While global prevalence of obesity continues to increase dramatically, treatment options remain less than optimal. The etiology of obesity is multifactorial, ranging from lifestyle choices such as excess food intake and insufficient physical activity, to use of medications that have weight gain as an undesirable side effect. Economic and political determinants of available foodstuffs and even social networks may also contribute to obesity. Successful management of obesity requires the understanding and acceptance of a new paradigm that identifies obesity as a disease--one defined by waist circumference--that requires treatment. Obesity meets all accepted criteria of a medical disease, including a known etiology, recognized signs and symptoms, and a range of structural and functional changes that culminate in pathologic consequences. Excess adipose tissue acts as an endocrine organ to produce excess free fatty acids, as well as tumor necrosis factor-alpha, interleukin-6, leptin, and plasminogen activator inhibitor-1. These bioactive molecules are associated with hyperinsulinemia, hyperglycemia, insulin resistance, development of diabetes, endothelial damage, and the onset and progression of atherosclerotic lesions. Options for treating obesity include lifestyle modifications (dietary changes, increased physical activity, behavior modification) and, for the morbidly obese, surgery. Lifestyle modification is rarely successful over the long term; therefore, addition of pharmacotherapy should be considered for obese individuals who have difficulty achieving and maintaining weight goals with lifestyle modifications alone. Several weight loss drugs are available for long-term use, with others in various stages of clinical development. PMID- 19789062 TI - Overweight and obesity: the pathogenesis of cardiometabolic risk. AB - Obesity, particularly abdominal adiposity, is increasingly recognized as a cause of elevated cardiometabolic risk--the risk of developing type 2 diabetes mellitus (DM) and cardiovascular disease (CVD). The predominate mechanisms appear to involve the promotion of insulin resistance, driven largely by excess free fatty acids secreted by an expanded adipose tissue mass, and the development of an inflammatory milieu due to increased secretion of inflammatory cytokines and adipokines from adipose tissue. Key proinflammatory cytokines secreted by adipocytes include tumor necrosis factor-alpha, interleukin-6, leptin, resistin, and plasminogen activator inhibitor-1. All have been variously associated with hyperinsulemia, hyperglycemia, insulin resistance, diabetes, and endothelial dysfunction, as well as plaque development, progression, and rupture. Adiponectin, another important adipocyte, has protective cardiometabolic actions; however, adiponectin levels decline with increasing obesity. Understanding the role of obesity in the pathogenesis of cardiometabolic risk is crucial for the development of treatment strategies that will provide maximum benefit for patients with, or at risk for, type 2 DM and CVD. PMID- 19789063 TI - Guiding clinical decisions on abdominal obesity and cardiometabolic risk. AB - Studies have shown that obesity increases cardiometabolic risk across the span of life. Obesity results in increased production of proinflammatory adipokines and decreased production of the anti-inflammatory adipokine, adiponectin, which eventually leads to atherosclerosis and type 2 diabetes mellitus. Lifestyle changes are the cornerstone for treatment of overweight and obese patients; however, pharmacotherapy and surgery are 2 additional treatment options that may be considered when lifestyle changes alone are unsuccessful. Adipose tissue, particularly central adipose tissue, is an endocrine organ, the actions of which tie together all components of cardiometabolic risk. Weight loss reduces levels of most proinflammatory adipokines, attenuates inflammation, improves endothelial function, and enhances insulin sensitivity. In view of these effects, obesity represents an obvious target for pharmacologic intervention. However, the benefits associated with the pharmacologic management of weight loss must be weighed against the potential for drug-related adverse events. PMID- 19789064 TI - Treatment of overweight and obesity: lifestyle, pharmacologic, and surgical options. AB - Recent statistics indicate that overweight and obesity have become an increasingly serious clinical and socioeconomic problem worldwide, and one of the greatest public health challenges of our time. In the United States, 133.6 million (66%) adults are overweight or obese (body mass index [BMI] >/=25 kg/m(2)), with 63.3 million (31.4%) considered to be obese (BMI >/=30 kg/m(2)). The International Obesity Task Force estimates that worldwide at least 1.1 billion adults are overweight, including 312 million who are obese. Overweight and obese patients are at an increased risk for developing numerous cardiometabolic complications, including hypertension, type 2 diabetes mellitus, dyslipidemia, and cardiovascular diseases, as well as conditions such as osteoarthritis, obstructive sleep apnea, hepatobiliary diseases, and certain types of cancers. Owing to the major health risks and complications associated with obesity, which negatively affect quality of life and reduce average life expectancy, in addition to placing an enormous burden on health care resources, the treatment of overweight and obesity is a public health imperative. Treatment must begin with long-term lifestyle changes, including increased physical activity and dietary modifications. For overweight and obese individuals for whom lifestyle changes alone are insufficient, pharmacotherapy may be added. However, patients who choose adjunctive pharmacotherapy should be advised of the risks and benefits of drug therapy, the lack of long-term safety data, and the temporary and modest nature of the weight loss that can be achieved with these agents. Bariatric surgery is an effective treatment option for morbidly obese patients or obese patients with multiple comorbidities who have not been successful in achieving sufficient weight loss with nonsurgical approaches. However, appropriate candidates for bariatric surgery must also be committed to long-term lifestyle changes. PMID- 19789065 TI - Novel therapies for the control and prevention of neuropathic pain. PMID- 19789066 TI - Behavioral models of pain states evoked by physical injury to the peripheral nerve. AB - Physical injury or compression of the root, dorsal root ganglion, or peripheral sensory axon leads to well-defined changes in biology and function. Behaviorally, humans report ongoing painful dysesthesias and aberrations in function, such that an otherwise innocuous stimulus will yield a pain report. These behavioral reports are believed to reflect the underlying changes in nerve function after injury, wherein increased spontaneous activity arises from the neuroma and dorsal root ganglion and spinal changes increase the response of spinal projection neurons. These pain states are distinct from those associated with tissue injury and pose particular problems in management. To provide for developing an understanding of the underlying mechanisms of these pain states and to promote development of therapeutic agents, preclinical models involving section, compression, and constriction of the peripheral nerve or compression of the dorsal root ganglion have been developed. These models give rise to behaviors, which parallel those observed in the human after nerve injury. The present review considers these models and their application. PMID- 19789067 TI - Animal models of chemotherapy-evoked painful peripheral neuropathies. AB - This review examines recent preclinical research on toxic peripheral neuropathy and potential therapeutic developments. Chemotherapy-induced peripheral neurotoxicity is a major clinical problem because it represents the dose-limiting side effects of a significant number of antineoplastic drugs. Patients are unable to complete full or optimal treatment schedules. The incidence of chemotherapy induced peripheral neuropathy varies depending on the drugs and schedules used, and this can be quite high, particularly when neurophysiological methods are used to make a diagnosis. However, even when chemotherapy-induced peripheral neuropathy is not a dose-limiting side effect, its onset may severely affect the quality of life of cancer patients and cause chronic discomfort. As such, improved understanding of the pathophysiology of chemotherapy-induced neurotoxicity need for animal models is clinically relevant and will assist in the development of future neuroprotective strategies and also in the design of novel chemotherapies with improved toxicity profiles. In this review, the features of animal models of chemotherapy-induced painful neuropathy developed for 20 years, due to the administration of the most widely used drugs, such as platinum drugs, taxanes, and vinca alkaloids, will be discussed. In a second part, data available on neuroprotectants and treatment strategies, evaluated using these previous animal models in the attempt to prevent neuropathic pain, will be summarized. PMID- 19789068 TI - Postherpetic neuralgia: from preclinical models to the clinic. AB - Postherpetic neuralgia (PHN), a common complication of herpes zoster, which results from reactivation of varicella zoster virus, is a challenging neuropathic pain syndrome. The incidence and severity of herpes zoster and PHN increases with immune impairment or age and may become a greater burden both in terms of health economics and individual suffering. A clearer understanding of the underlying mechanisms of this disease and translation of preclinical outcomes to the clinic may lead to more efficacious treatment options. Here we give an overview of recent findings from preclinical models and clinical research on PHN. PMID- 19789069 TI - Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. AB - Advanced peripheral diabetic neuropathy (PDN) is associated with elevated vibration and thermal perception thresholds that progress to sensory loss and degeneration of all fiber types in peripheral nerve. A considerable proportion of diabetic patients also describe abnormal sensations such as paresthesias, allodynia, hyperalgesia, and spontaneous pain. One or several manifestations of abnormal sensation and pain are described in all the diabetic rat and mouse models studied so far (i.e., streptozotocin-diabetic rats and mice, type 1 insulinopenic BB/Wor and type 2 hyperinsulinemic diabetic BBZDR/Wor rats, Zucker diabetic fatty rats, and nonobese diabetic, Akita, leptin- and leptin-receptor deficient, and high-fat diet-fed mice). Such manifestations are 1) thermal hyperalgesia, an equivalent of a clinical phenomenon described in early PDN; 2) thermal hypoalgesia, typically present in advanced PDN; 3) mechanical hyperalgesia, an equivalent of pain on pressure in early PDN; 4) mechanical hypoalgesia, an equivalent to the loss of sensitivity to mechanical noxious stimuli in advanced PDN; 5) tactile allodynia, a painful perception of a light touch; and 5) formalin-induced hyperalgesia. Rats with short-term diabetes develop painful neuropathy, whereas those with longer-term diabetes and diabetic mice typically display manifestations of both painful and insensate neuropathy, or insensate neuropathy only. Animal studies using pharmacological and genetic approaches revealed important roles of increased aldose reductase, protein kinase C, and poly(ADP-ribose) polymerase activities, advanced glycation end-products and their receptors, oxidative-nitrosative stress, growth factor imbalances, and C-peptide deficiency in both painful and insensate neuropathy. This review describes recent achievements in studying the pathogenesis of diabetic neuropathic pain and sensory disorders in diabetic animal models and developing potential pathogenetic treatments. PMID- 19789070 TI - Targeting neuroprotection as an alternative approach to preventing and treating neuropathic pain. AB - Neuropathic pain syndromes arise from dysfunction of the nerve itself, through traumatic or nontraumatic injury. Unlike acute pain syndromes, the pain is long lasting and does not respond to common analgesic therapies. Drugs that disrupt nerve conduction and transmission or central sensitization, currently the only effective treatments, are only modestly effective for a portion of the patients suffering from neuropathic pain and come with the cost of serious adverse effects. Neurodegeneration, as a reaction to nerve trauma or chronic metabolic or chemical intoxication, appears to be an underlying cause of neuropathic pain. Identifying mechanisms of neurodegeneration and designing neuroprotective therapies is an ambitious goal toward treating or even preventing the development of these disabling disorders. PMID- 19789071 TI - Sodium channel blockers for the treatment of neuropathic pain. AB - Drugs that block voltage-gated sodium channels are efficacious in the management of neuropathic pain. Accordingly, this class of ion channels has been a major focus of analgesic research both in academia and in the pharmaceutical/biotechnology industry. In this article, we review the history of the use of sodium channel blockers, describe the current status of sodium channel drug discovery, highlight the challenges and hurdles to attain sodium channel subtype selectivity, and review the potential usefulness of selective sodium channel blockers in neuropathic pain. PMID- 19789073 TI - Targeting the NMDA receptor subunit NR2B for the treatment of neuropathic pain. AB - Neuropathic pain is generally defined as a chronic pain state resulting from peripheral or central nerve injury, or both. An effective treatment for neuropathic pain is still lacking. The NMDA receptor, one type of the ionotropic glutamate receptors, is known to be important for triggering long-lasting changes in synapses. NMDA receptor-dependent synaptic plasticity plays roles not only in physiological functions such as learning and memory, but also in unwanted pathological conditions such as chronic pain. This review addresses recent progress on NMDA receptors in neuropathic pain, with particular emphasis on the NR2B-subunit-containing receptors. The expression and function of NMDA receptors in synaptic plasticity in the pain transmission pathway from dorsal root ganglia to the anterior cingulate cortex is reviewed, and preclinical and clinical investigations of selective NMDA receptor in neuropathic pain are discussed. The NMDA receptors, in particular NR2B-containing NMDA receptors, serve as promising targets for treatment of neuropathic pain. PMID- 19789072 TI - Targeting voltage-gated calcium channels for neuropathic pain management. AB - Voltage-gated calcium channels (VGCC) play obligatory roles in diverse physiological functions. Pathological conditions leading to changes in their biophysical properties and expression levels may cause malfunctions of VGCC mediated activities, resulting in disease states. It is believed that changes in VGCC properties under pain-inducing conditions may play a causal role in the development of chronic pain, including nerve injury-induced pain or neuropathic pain. For the past several decades, preclinical and clinical research in developing VGCC blockers or modulators for chronic pain management has been fruitful, leading to some U.S. Food and Drug Administration-approved drugs currently available for chronic pain management. However, their efficacy in pain relief is limited in some patients, and their long-term use is limited by their side-effect profiles. Certainly, there is room for improvement in developing more subtype-specific VGCC blockers or modulators for chronic pain conditions. In this review, we summarized the most recent preclinical and clinical studies related to chronic pain medications acting on the VGCC. We also included clinical trials aiming to expand the application of approved VGCC drugs to different pain states derived from various pathological conditions, as well as drug combination therapies trying to improve the efficacies and side-effect profiles of current pain medications. PMID- 19789076 TI - Evaluation of symptom heterogeneity in neuropathic pain using assessments of sensory functions. AB - Classification of neuropathic pain has been based on disease entities, anatomical localization, or histological observations. Over the past decade, there has been an explosion in our understanding of the basic mechanisms of neuropathic pain. The exciting advances in basic science are paralleled by the recognition from clinical investigations that neuropathic pain is not a monolithic entity, but instead presents as a composite of pain and other sensory symptoms. Attempts are under way to supplement the traditional classification with a classification that links pain and sensory symptoms with neurobiological mechanisms. This mechanism- or symptom-based classification takes both negative and positive sensory symptoms into account. By using a battery of several standardized quantitative sensory tests, the characteristic profile of sensory symptoms can be elucidated in each patient. Moreover, in questionnaires the verbal descriptors can depict the quality and intensity of the individual pain. The approach of classifying and subgrouping patients with neuropathic pain on the basis of symptoms or signs opens up new possibilities for stratifying patients in clinical trials. First, in clinical proof-of-concept trials the study population can be enriched prospectively on the basis of entry criteria defined a priori. This enrichment with patients who potentially require a specific treatment should increase the likelihood for positive trial outcomes. Second, in clinical practice it becomes possible to establish an individualized therapy--that is, to identify the particular patients who require a specific treatment option. PMID- 19789074 TI - Preclinical and early clinical investigations related to monoaminergic pain modulation. AB - The balance between descending controls, both excitatory and inhibitory, can be altered in various pain states. There is good evidence for a prominent alpha(2) adrenoceptor-mediated inhibitory system and 5-HT(3) (and likely also 5-HT(2)) serotonin receptor-mediated excitatory controls originating from brainstem and midbrain areas. The ability of cortical controls to influence spinal function allows for top-down processing through these monoamines. The links between pain and the comorbidities of sleep problems, anxiety, and depression may be due to the dual roles of noradrenaline and of 5-HT in these functions and also in pain. These controls appear, in the cases of peripheral neuropathy, spinal injury, and cancer-induced bone pain to be driven by altered peripheral and spinal neuronal processes; in opioid-induced hyperalgesia, however, the same changes occur without any pathophysiological peripheral process. Thus, in generalized pain states in which fatigue, mood changes, and diffuse pain occur, such as fibromyalgia and irritable bowel syndrome, one could suggest an abnormal engagement of descending facilitations with or without reduced inhibitions but with central origins. This would be an endogenous central malfunction of top-down processing, with the altered monoamine systems underlying the observed symptoms. A number of analgesic drugs can either interact with or have their actions modulated by these descending systems, reinforcing their importance in the establishment of pain but also in its control. PMID- 19789077 TI - Use of sensory methods for detecting target engagement in clinical trials of new analgesics. AB - The translation of analgesic efficacy seen in preclinical pain models into the clinic is problematic and is associated with a number of factors that may result in the failure of clinical trials to detect the effect of investigational therapeutic agents. The use of translational pain biomarkers in phase I trials can potentially reduce some of these risks by measuring the interaction between the drug and its target (termed target engagement) in humans. To serve this purpose, sensory tests and other measures of pharmacological activity in nociceptive pathways need to be identified, based on the preclinical profile of the drug being tested and the feasibility of human assessments. Here we discuss some examples to assess the utility of sensory and related pain biomarkers in the early phase of evaluation of novel analgesics for confirmation of target engagement in humans. The emphasis is on the TRPV1 antagonists, but some other target mechanisms are also discussed in examining the validity of this approach. PMID- 19789079 TI - Antireflux therapy in asthma: is there any role? PMID- 19789078 TI - Neuroimaging as a tool for pain diagnosis and analgesic development. AB - Neuroimaging makes it possible to study pain processing beyond the peripheral nervous system, at the supraspinal level, in a safe, noninvasive way, without interfering with neurophysiological processes. In recent years, studies using brain imaging methods have contributed to our understanding of the mechanisms responsible for the development and maintenance of chronic pain. Moreover, neuroimaging shows promising results for analgesic drug development and in characterizing different types of pain, bringing us closer to development of mechanism-based diagnoses and treatments for the chronic pain patient. PMID- 19789075 TI - Cannabinoids as pharmacotherapies for neuropathic pain: from the bench to the bedside. AB - Neuropathic pain is a debilitating form of chronic pain resulting from nerve injury, disease states, or toxic insults. Neuropathic pain is often refractory to conventional pharmacotherapies, necessitating validation of novel analgesics. Cannabinoids, drugs that share the same target as Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the psychoactive ingredient in cannabis, have the potential to address this unmet need. Here, we review studies evaluating cannabinoids for neuropathic pain management in the clinical and preclinical literature. Neuropathic pain associated with nerve injury, diabetes, chemotherapeutic treatment, human immunodeficiency virus, multiple sclerosis, and herpes zoster infection is considered. In animals, cannabinoids attenuate neuropathic nociception produced by traumatic nerve injury, disease, and toxic insults. Effects of mixed cannabinoid CB(1)/CB(2) agonists, CB(2) selective agonists, and modulators of the endocannabinoid system (i.e., inhibitors of transport or degradation) are compared. Effects of genetic disruption of cannabinoid receptors or enzymes controlling endocannabinoid degradation on neuropathic nociception are described. Specific forms of allodynia and hyperalgesia modulated by cannabinoids are also considered. In humans, effects of smoked marijuana, synthetic Delta(9) THC analogs (e.g., Marinol, Cesamet) and medicinal cannabis preparations containing both Delta(9)-THC and cannabidiol (e.g., Sativex, Cannador) in neuropathic pain states are reviewed. Clinical studies largely affirm that neuropathic pain patients derive benefits from cannabinoid treatment. Subjective (i.e., rating scales) and objective (i.e., stimulus-evoked) measures of pain and quality of life are considered. Finally, limitations of cannabinoid pharmacotherapies are discussed together with directions for future research. PMID- 19789080 TI - Training in hepatology: where are we now? PMID- 19789081 TI - Interleukin-23: linking mesenteric lymph node dendritic cells with Th1 immunity in Crohn's disease. PMID- 19789082 TI - Prescribing an antibiotic? Do not forget the probiotic. PMID- 19789083 TI - Pathogen-specific antibody: cause or effect? PMID- 19789084 TI - Globus sensation and hyperdynamic upper esophageal sphincter: another piece in the puzzle? PMID- 19789086 TI - Identification of ferritin receptors: their role in iron homeostasis, hepatic injury, and inflammation. PMID- 19789087 TI - Synchronous colorectal cancer: not just bad luck? PMID- 19789088 TI - Serotonin has a critical role in the pathogenesis of experimental colitis. PMID- 19789089 TI - Recalcitrant vomiting, disturbed eye movements, and leukoencephalopathy. Mitochondrial neurogastrointestinal encephalomyopathy. PMID- 19789090 TI - Food-induced severe chest pain and hematemesis. Esophageal apoplexy. PMID- 19789091 TI - Genome-wide association study in esophageal squamous cell carcinoma. PMID- 19789092 TI - Characteristics of antibody responses in tick-borne encephalitis vaccination breakthroughs. AB - Tick-borne encephalitis (TBE) virus is an important human pathogenic flavivirus that is endemic in Europe and Asia. The disease can be effectively prevented by inactivated vaccines and vaccination breakthroughs (VBTs) are rare. We investigated the characteristics of antibody responses in such VBTs in comparison to those in unvaccinated TBE patients. In contrast to the unvaccinated controls, most of the VBTs displayed a delayed IgM antibody response and had high avidity and strongly neutralizing antibodies already in the first sample taken upon hospitalization. The antibody profile of these patients therefore had the characteristics of an anamnestic immune response. In the VBTs analyzed, immunological priming and memory were apparently not sufficient or fast enough to prevent the disease. PMID- 19789093 TI - Whole recombinant Hansenula polymorpha expressing hepatitis B virus surface antigen (yeast-HBsAg) induces potent HBsAg-specific Th1 and Th2 immune responses. AB - Recent studies have suggested that yeast cell wall components possess adjuvant activities. In the present study, heat-killed whole recombinant Hansenula polymorpha yeast expressing hepatitis B surface antigen (yeast-HBsAg) was generated, and the immune responses elicited by yeast-HBsAg were investigated in mice. The studies showed that yeast-HBsAg as well as yeast greatly promotes the accumulation of immune cells in mouse spleen and contributes to the maturation of dendritic cells (DCs). Yeast-HBsAg not only induces significantly higher antibody responses (including IgG, IgG1 and IgG2a), but also increases the IgG2a/IgG1 ratio, while alum combined with HBsAg (HBsAg+alum) only enhances antibody responses, but not the IgG2a/IgG1 ratio compared to HBsAg alone. Analysis of HBsAg-specific cytokines revealed that yeast-HBsAg is associated with production of both IFN-gamma and IL-4, but neither IFN-gamma nor IL-4 was detected in the HBsAg+alum-immunized group. Moreover, yeast-HBsAg induces potent HBsAg-specific lymphocyte proliferation and Cytotoxic T lymphocyte (CTL) responses. In conclusion, yeast-HBsAg enhances both HBsAg-specific Th1 and Th2 immune responses, while alum only enhances Th2 immune responses, suggesting that yeast HBsAg may be an ideal candidate for an effective vaccine for the control of chronic hepatitis B virus (HBV) infection. PMID- 19789094 TI - Longitudinal falls-risk estimation using triaxial accelerometry. AB - Falls among the elderly population are a major cause of morbidity and injury particularly among the over 65 years age group. Validated clinical tests and associated models, built upon assessment of functional ability, have been devised to estimate an individual's risk of falling in the near future. Those identified as at-risk of falling may be targeted for interventative treatment. The migration of these clinical models estimating falls risk to a surrogate technique, for use in the unsupervised environment, might broaden the reach of falls-risk screening beyond the clinical arena. This study details an approach that characterizes the movements of 68 elderly subjects performing a directed routine of unsupervised physical tasks. The movement characterization is achieved through the use of a triaxial accelerometer. A number of fall-related features, extracted from the accelerometry signals, combined with a linear least squares model, maps to a clinically validated measure of falls risk with a correlation of rho = 0.81 (p < 0.001). PMID- 19789095 TI - Automatic detection of swallowing events by acoustical means for applications of monitoring of ingestive behavior. AB - Our understanding of etiology of obesity and overweight is incomplete due to lack of objective and accurate methods for monitoring of ingestive behavior (MIB) in the free-living population. Our research has shown that frequency of swallowing may serve as a predictor for detecting food intake, differentiating liquids and solids, and estimating ingested mass. This paper proposes and compares two methods of acoustical swallowing detection from sounds contaminated by motion artifacts, speech, and external noise. Methods based on mel-scale Fourier spectrum, wavelet packets, and support vector machines are studied considering the effects of epoch size, level of decomposition, and lagging on classification accuracy. The methodology was tested on a large dataset (64.5 h with a total of 9966 swallows) collected from 20 human subjects with various degrees of adiposity. Average weighted epoch-recognition accuracy for intravisit individual models was 96.8%, which resulted in 84.7% average weighted accuracy in detection of swallowing events. These results suggest high efficiency of the proposed methodology in separation of swallowing sounds from artifacts that originate from respiration, intrinsic speech, head movements, food ingestion, and ambient noise. The recognition accuracy was not related to body mass index, suggesting that the methodology is suitable for obese individuals. PMID- 19789096 TI - Real-time chirp-coded imaging with a programmable ultrasound biomicroscope. AB - Ultrasound biomicroscopy (UBM) of mice can provide a testing ground for new imaging strategies. The UBM system presented in this paper facilitates the development of imaging and measurement methods with programmable design, arbitrary waveform coding, broad bandwidth (2-80 MHz), digital filtering, programmable processing, RF data acquisition, multithread/multicore real-time display, and rapid mechanical scanning ( 0.75) during 16% of the recorded time, for the blood pulse, and 34% of the time for the respiration signal. A statistically significant decrease in average coherence was noted for the eye's aberrations with respiration in the case of fast controlled breathing (0.5 Hz). The coherence between the blood pulse and the defocus was significantly larger for the far target than for the near target condition. After cycloplegia, the coherence of defocus with the blood pulse significantly decreased, while this was not the case for the other aberrations. There was also a noticeable, but not statistically significant, increase in the coherence of the comatic term and respiration in that case. By using nonstationary measures of signal coherence, a more detailed picture of interactions between the cardiopulmonary signals and eye's wavefront aberrations has emerged. PMID- 19789100 TI - A novel method for the 3-D reconstruction of scoliotic ribs from frontal and lateral radiographs. AB - Among the external manifestations of scoliosis, the rib hump, which is associated with the ribs' deformities and rotations, constitutes the most disturbing aspect of the scoliotic deformity for patients. A personalized 3-D model of the rib cage is important for a better evaluation of the deformity, and hence, a better treatment planning. A novel method for the 3-D reconstruction of the rib cage, based only on two standard radiographs, is proposed in this paper. For each rib, two points are extrapolated from the reconstructed spine, and three points are reconstructed by stereo radiography. The reconstruction is then refined using a surface approximation. The method was evaluated using clinical data of 13 patients with scoliosis. A comparison was conducted between the reconstructions obtained with the proposed method and those obtained by using a previous reconstruction method based on two frontal radiographs. A first comparison criterion was the distances between the reconstructed ribs and the surface topography of the trunk, considered as the reference modality. The correlation between ribs axial rotation and back surface rotation was also evaluated. The proposed method successfully reconstructed the ribs of the 6th-12th thoracic levels. The evaluation results showed that the 3-D configuration of the new rib reconstructions is more consistent with the surface topography and provides more accurate measurements of ribs axial rotation. PMID- 19789101 TI - Dynamic imaging in electrical impedance tomography of the human chest with online transition matrix identification. AB - One of the electrical impedance tomography objectives is to estimate the electrical resistivity distribution in a domain based only on electrical potential measurements at its boundary generated by an imposed electrical current distribution into the boundary. One of the methods used in dynamic estimation is the Kalman filter. In biomedical applications, the random walk model is frequently used as evolution model and, under this conditions, poor tracking ability of the extended Kalman filter (EKF) is achieved. An analytically developed evolution model is not feasible at this moment. The paper investigates the identification of the evolution model in parallel to the EKF and updating the evolution model with certain periodicity. The evolution model transition matrix is identified using the history of the estimated resistivity distribution obtained by a sensitivity matrix based algorithm and a Newton-Raphson algorithm. To numerically identify the linear evolution model, the Ibrahim time-domain method is used. The investigation is performed by numerical simulations of a domain with time-varying resistivity and by experimental data collected from the boundary of a human chest during normal breathing. The obtained dynamic resistivity values lie within the expected values for the tissues of a human chest. The EKF results suggest that the tracking ability is significantly improved with this approach. PMID- 19789102 TI - Thermistor at a distance: unobtrusive measurement of breathing. AB - This paper unveils a thermal imaging methodology to recover the breathing waveform from the subject's nostrils. The resulting functionality is equivalent to that of a thermistor, but it is materialized in a contact-free manner. First, the nostril region is segmented and tracked over time through a network of cooperating probabilistic trackers. The mean thermal signal of the nostril region carries the breathing information. This information is extracted through wavelet analysis. The method has been tested on 20 healthy individuals. The breathing waveforms determined via the imaging computation were compared with the corresponding ones extracted from thermistors. The high degree of agreement between the two measurement methods confirms the validity of the proposed approach and opens the way for clinical applications. Furthermore, thermal imaging can be potentially used as an investigative tool to understand breathing physiology in ways not possible with contact sensors. PMID- 19789103 TI - Self-calibration of biplanar radiographic images through geometric spine shape descriptors. AB - This paper presents a novel self-calibration method of an X-ray scene applied for the 3-D reconstruction of the scoliotic spine. Current calibration techniques either use a cumbersome calibration apparatus or depend on manually identified landmarks to determine the geometric configuration, thus limiting routine clinical evaluation. The proposed approach uses high-level information automatically extracted from biplanar X-rays to solve the radiographic scene parameters. We first present a segmentation method that takes into account the variable appearance and geometry of a scoliotic spine in order to isolate and extract the silhouettes of the anterior vertebral body. By incorporating prior anatomical information through a Bayesian formulation of the morphological distribution, a multiscale spine segmentation framework is proposed for scoliotic patients. An iterative nonlinear optimization procedure, integrating a 3-D visual hull reconstruction and geometrical torsion properties of the spine, is then applied to globally refine the geometrical parameters of the 3-D viewing scene and obtain the optimal 3-D reconstruction. An experimental comparison with data provided from reference synthetic models yields similar accuracy on the retroprojection of low-level primitives such as anatomical landmarks identified on each vertebra (2.2 mm). Results obtained from a clinical validation on 60 pairs of uncalibrated digitized X-rays of adolescents with scoliosis show that the 3-D reconstructions from the new system offer geometrically accurate models with insignificant differences for 3-D clinical indexes commonly used in the evaluation of spinal deformities. The reported experiments demonstrate a viable and accurate alternative to previous reconstruction techniques, offering the first automatic approach for routine 3-D clinical assessment in radiographic suites. PMID- 19789104 TI - Rolling mechanical imaging for tissue abnormality localization during minimally invasive surgery. AB - We describe a novel approach for the localization of tissue abnormalities during minimally invasive surgery using a force-sensitive wheeled probe. The concept is to fuse the kinaesthetic information from the wheel-tissue rolling interaction into a pseudocolor rolling mechanical image (RMI) to visualize the spatial variation of stiffness within the internal tissue structure. Since tissue abnormalities are often firmer than the surrounding organ or parenchyma, a surgeon then can localize abnormalities by analyzing the image. Initially, a testing facility for validating the concept in an ex vivo setting was developed and used to investigate rolling "wheel-tissue" interaction. A silicone soft tissue phantom with embedded hard nodules was constructed to allow for experimental comparison between an RMI and a known soft-tissue structure. Tests have also been performed on excised porcine organs to show the efficacy of the method when applied to biological soft tissues. Results indicate that the RMI technique is particularly suited to identifying the stiffness distribution within a tissue sample, as the continuous force measurement along a given rolling trajectory provides repeatable information regarding relative variations in the normal tissue response. When compared to multiple discrete uniaxial indentations, the continuous measurement approach of RMI is shown to be more sensitive and facilitates coverage of a large area in a short period of time. Furthermore, if parametric classification of tissue properties based on a uniaxial tissue indentation model is desirable, the rolling indentation probe can be easily employed as a uniaxial indenter. PMID- 19789105 TI - Adaptive mesh refinement techniques for 3-D skin electrode modeling. AB - In this paper, we develop a 3-D adaptive mesh refinement technique. The algorithm is constructed with an electric impedance tomography forward problem and the finite-element method in mind, but is applicable to a much wider class of problems. We use the method to evaluate the distribution of currents injected into a model of a human body through skin contact electrodes. We demonstrate that the technique leads to a significantly improved solution, particularly near the electrodes. We discuss error estimation, efficiency, and quality of the refinement algorithm and methods that allow for preserving mesh attributes in the refinement process. PMID- 19789106 TI - Nonstationary brain source separation for multiclass motor imagery. AB - This paper describes a method to recover task-related brain sources in the context of multiclass brain--computer interfaces (BCIs) based on noninvasive EEG. We extend the method joint approximate diagonalization (JAD) for spatial filtering using a maximum likelihood framework. This generic formulation: 1) bridges the gap between the common spatial patterns (CSPs) and blind source separation of nonstationary sources; and 2) leads to a neurophysiologically adapted version of JAD, accounting for the successive activations/deactivations of brain sources during motor imagery (MI) trials. Using dataset 2a of BCI Competition IV (2008) in which nine subjects were involved in a four-class two session MI-based BCI experiment, a quantitative evaluation of our extension is provided by comparing its performance against JAD and CSP in the case of cross validation, as well as session-to-session transfer. While JAD, as already proposed in other works, does not prove to be significantly better than classical one-versus-rest CSP, our extension is shown to perform significantly better than CSP for cross-validated and session-to-session performance. The extension of JAD introduced in this paper yields among the best session-to-session transfer results presented so far for this particular dataset; thus, it appears to be of great interest for real-life BCIs. PMID- 19789108 TI - Uncorrelated multilinear principal component analysis for unsupervised multilinear subspace learning. AB - This paper proposes an uncorrelated multilinear principal component analysis (UMPCA) algorithm for unsupervised subspace learning of tensorial data. It should be viewed as a multilinear extension of the classical principal component analysis (PCA) framework. Through successive variance maximization, UMPCA seeks a tensor-to-vector projection (TVP) that captures most of the variation in the original tensorial input while producing uncorrelated features. The solution consists of sequential iterative steps based on the alternating projection method. In addition to deriving the UMPCA framework, this work offers a way to systematically determine the maximum number of uncorrelated multilinear features that can be extracted by the method. UMPCA is compared against the baseline PCA solution and its five state-of-the-art multilinear extensions, namely two dimensional PCA (2DPCA), concurrent subspaces analysis (CSA), tensor rank-one decomposition (TROD), generalized PCA (GPCA), and multilinear PCA (MPCA), on the tasks of unsupervised face and gait recognition. Experimental results included in this paper suggest that UMPCA is particularly effective in determining the low dimensional projection space needed in such recognition tasks. PMID- 19789107 TI - Segmentation of the left ventricle from cardiac MR images using a subject specific dynamical model. AB - Statistical models have shown considerable promise as a basis for segmenting and interpreting cardiac images. While a variety of statistical models have been proposed to improve the segmentation results, most of them are either static models (SMs), which neglect the temporal dynamics of a cardiac sequence, or generic dynamical models (GDMs), which are homogeneous in time and neglect the intersubject variability in cardiac shape and deformation. In this paper, we develop a subject-specific dynamical model (SSDM) that simultaneously handles temporal dynamics (intrasubject variability) and intersubject variability. We also propose a dynamic prediction algorithm that can progressively identify the specific motion patterns of a new cardiac sequence based on the shapes observed in past frames. The incorporation of this SSDM into the segmentation framework is formulated in a recursive Bayesian framework. It starts with a manual segmentation of the first frame, and then segments each frame according to intensity information from the current frame as well as the prediction from past frames. In addition, to reduce error propagation in sequential segmentation, we take into account the periodic nature of cardiac motion and perform segmentation in both forward and backward directions. We perform "leave-one-out" test on 32 canine sequences and 22 human sequences, and compare the experimental results with those from SM, GDM, and active appearance motion model (AAMM). Quantitative analysis of the experimental results shows that SSDM outperforms SM, GDM, and AAMM by having better global and local consistencies with manual segmentation. Moreover, we compare the segmentation results from forward and forward-backward segmentation. Quantitative evaluation shows that forward-backward segmentation suppresses the propagation of segmentation errors. PMID- 19789109 TI - A new neuroadaptive control architecture for nonlinear uncertain dynamical systems: beyond sigma- and e-modifications. AB - This paper develops a new neuroadaptive control architecture for nonlinear uncertain dynamical systems. The proposed framework involves a novel controller architecture involving additional terms in the update laws that are constructed using a moving time window of the integrated system uncertainty. These terms can be used to identify the ideal system weights of the neural network as well as effectively suppress and cancel system uncertainty without the need for persistency of excitation. A nonlinear parametrization of the system uncertainty is considered and state and output feedback neuroadaptive controllers are developed. To illustrate the efficacy of the proposed approach we apply our results to a spacecraft model with unknown moment of inertia and compare our results with standard neuroadaptive control methods. PMID- 19789110 TI - Adachi-like chaotic neural networks requiring linear-time computations by enforcing a tree-shaped topology. AB - The Adachi neural network (AdNN) is a fascinating neural network (NN) which has been shown to possess chaotic properties, and to also demonstrate associative memory (AM) and pattern recognition (PR) characteristics. Variants of the AdNN have also been used to obtain other PR phenomena, and even blurring. An unsurmountable problem associated with the AdNN and the variants referred to above is that all of them require a quadratic number of computations. This is essentially because the NNs in each case are completely connected graphs. In this paper, we consider how the computations can be significantly reduced by merely using a linear number of computations. To achieves this, we extract from the original completely connected graph one of its spanning trees. We then address the problem of computing the weights for this spanning tree. This is done in such a manner that the modified tree-based NN has approximately the same input-output characteristics, and thus the new weights are themselves calculated using a gradient-based algorithm. By a detailed experimental analysis, we show that the new linear-time AdNN-like network possesses chaotic and PR properties for different settings. As far as we know, such a tree-based AdNN has not been reported, and the results given here are novel. PMID- 19789111 TI - Disparity estimation by pooling evidence from energy neurons. AB - In this paper, we propose an algorithm for disparity estimation from disparity energy neurons that seeks to maintain simplicity and biological plausibility, while also being based upon a formulation that enables us to interpret the model outputs probabilistically. We use the Bayes factor from statistical hypothesis testing to show that, in contradiction to the implicit assumption of many previously proposed biologically plausible models, a larger response from a disparity energy neuron does not imply more evidence for the hypothesis that the input disparity is close to the preferred disparity of the neuron. However, we find that the normalized response can be interpreted as evidence, and that information from different orientation channels can be combined by pooling the normalized responses. Based on this insight, we propose an algorithm for disparity estimation constructed out of biologically plausible operations. Our experimental results on real stereograms show that the algorithm outperforms a previously proposed coarse-to-fine model. In addition, because its outputs can be interpreted probabilistically, the model also enables us to identify occluded pixels or pixels with incorrect disparity estimates. PMID- 19789112 TI - Video coding focusing on block partitioning and occlusion. AB - Among the existing block partitioning schemes, the pattern-based video coding (PVC) has already established its superiority at low bit-rate. Its innovative segmentation process with regular-shaped pattern templates is very fast as it avoids handling the exact shape of the moving objects. It also judiciously encodes the pattern-uncovered background segments capturing high level of interblock temporal redundancy without any motion compensation, which is favoured by the rate-distortion optimizer at low bit-rates. The existing PVC technique, however, uses a number of content-sensitive thresholds and thus setting them to any predefined values risks ignoring some of the macroblocks that would otherwise be encoded with patterns. Furthermore, occluded background can potentially degrade the performance of this technique. In this paper, a robust PVC scheme is proposed by removing all the content-sensitive thresholds, introducing a new similarity metric, considering multiple top-ranked patterns by the rate distortion optimizer, and refining the Lagrangian multiplier of the H.264 standard for efficient embedding. A novel pattern-based residual encoding approach is also integrated to address the occlusion issue. Once embedded into the H.264 Baseline profile, the proposed PVC scheme improves the image quality perceptually significantly by at least 0.5 dB in low bit-rate video coding applications. A similar trend is observed for moderate to high bit-rate applications when the proposed scheme replaces the bi-directional predictive mode in the H.264 High profile. PMID- 19789113 TI - Statistical wavelet subband characterization based on generalized gamma density and its application in texture retrieval. AB - The modeling of image data by a general parametric family of statistical distributions plays an important role in many applications. In this paper, we propose to adopt the three-parameter generalized Gamma density (GGammaD) for modeling wavelet detail subband histograms and for texture image retrieval. The advantage of GGammaD over the existing generalized Gaussian density (GGD) is that it provides more flexibility to control the shape of model which is critical for practical histogram-based applications. To measure the discrepancy between GGammaDs, we use the symmetrized Kullback-Leibler distance (SKLD) and derive a closed form for the SKLD between GGammaDs. Such a distance can be computed directly and effectively via the model parameters, making our proposed scheme particularly suitable for image retrieval systems with large image database. Experimental results on the well-known databases reveal the superior performance of our proposed method compared with the current existing approaches. PMID- 19789114 TI - Variational bayesian image restoration with a product of spatially weighted total variation image priors. AB - In this paper, a new image prior is introduced and used in image restoration. This prior is based on products of spatially weighted total variations (TV). These spatial weights provide this prior with the flexibility to better capture local image features than previous TV based priors. Bayesian inference is used for image restoration with this prior via the variational approximation. The proposed restoration algorithm is fully automatic in the sense that all necessary parameters are estimated from the data and is faster than previous similar algorithms. Numerical experiments are shown which demonstrate that image restoration based on this prior compares favorably with previous state-of-the-art restoration algorithms. PMID- 19789115 TI - Gene function prediction with gene interaction networks: a context graph kernel approach. AB - Predicting gene functions is a challenge for biologists in the postgenomic era. Interactions among genes and their products compose networks that can be used to infer gene functions. Most previous studies adopt a linkage assumption, i.e., they assume that gene interactions indicate functional similarities between connected genes. In this study, we propose to use a gene's context graph, i.e., the gene interaction network associated with the focal gene, to infer its functions. In a kernel-based machine-learning framework, we design a context graph kernel to capture the information in context graphs. Our experimental study on a testbed of p53-related genes demonstrates the advantage of using indirect gene interactions and shows the empirical superiority of the proposed approach over linkage-assumption-based methods, such as the algorithm to minimize inconsistent connected genes and diffusion kernels. PMID- 19789116 TI - Construction of gene networks with hybrid approach from expression profile and gene ontology. AB - Gene regulatory networks have been long studied in model organisms as a means of identifying functional relationships among genes or their corresponding products. Despite many existing methods for genome-wide construction of such networks, solutions to the gene regulatory networks problem are however not trivial. Here, we present, a hybrid approach with gene expression profiles and gene ontology (HAEO). HAEO makes use of multimethods (overlapping clustering and reverse engineering methods) to effectively and efficiently construct gene regulatory networks from multisources (gene expression profiles and gene ontology). Application to yeast cell cycle dataset demonstrates HAEO's ability to construct validated gene regulatory networks, such as some potential gene regulatory pairs, which cannot be discovered by general inferring methods and identifying cycles (i.e., feedback loops) between genes. We also experimentally study the efficiency of building networks and show that the proposed method, HAEO is much faster than Bayesian networks method. PMID- 19789117 TI - IBE-Lite: a lightweight identity-based cryptography for body sensor networks. AB - A body sensor network (BSN) is a network of sensors deployed on a person's body for health care monitoring. Since the sensors collect personal medical data, security and privacy are important components in a BSN. In this paper, we developed IBE-Lite, a lightweight identity-based encryption suitable for sensors in a BSN. We present protocols based on IBE-Lite that balance security and privacy with accessibility and perform evaluation using experiments conducted on commercially available sensors. PMID- 19789118 TI - Characterization of on-body communication channel and energy efficient topology design for wireless body area networks. AB - Wireless body area networks (WBANs) offer many promising new applications in the area of remote health monitoring. An important element in the development of a WBAN is the characterization of the physical layer of the network, including an estimation of the delay spread and the path loss between two nodes on the body. This paper discusses the propagation channel between two half-wavelength dipoles at 2.45 GHz, placed near a human body and presents an application for cross-layer design in order to optimize the energy consumption of different topologies. Propagation measurements are performed on real humans in a multipath environment, considering different parts of the body separately. In addition, path loss has been numerically investigated with an anatomically correct model of the human body in free space using a 3-D electromagnetic solver. Path loss parameters and time-domain channel characteristics are extracted from the measurement and simulation data. A semi-empirical path loss model is presented for an antenna height above the body of 5 mm and antenna separations from 5 cm up to 40 cm. A time-domain analysis is performed and models are presented for the mean excess delay and the delay spread. As a cross-layer application, the proposed path loss models are used to evaluate the energy efficiency of single-hop and multihop network topologies. PMID- 19789119 TI - A wearable ECG acquisition system with compact planar-fashionable circuit board based shirt. AB - A wearable electrocardiogram (ECG) acquisition system implemented with planar fashionable circuit board (P-FCB)-based shirt is presented. The proposed system removes cumbersome wires from conventional Holter monitor system for convenience. Dry electrodes screen-printed directly on fabric enables long-term monitoring without skin irritation. The ECG monitoring shirt exploits a monitoring chip with a group of electrodes around the body, and both the electrodes and the interconnection are implemented using P-FCB to enhance wearability and to lower production cost. The characteristics of P-FCB electrode are shown, and the prototype hardware is implemented to successfully verify the proposed concept. PMID- 19789120 TI - Alignment method for spectrograms of DNA sequences. AB - DNA spectrograms express the periodicities of each of the four nucleotides A, T, C, and G in one or several genomic sequences to be analyzed. DNA spectral analysis can be applied to systematically investigate DNA patterns, which may correspond to relevant biological features. As opposed to looking at nucleotide sequences, spectrogram analysis may detect structural characteristics in very long sequences that are not identifiable by sequence alignment. Alignment of DNA spectrograms can be used to facilitate analysis of very long sequences or entire genomes at different resolutions. Standard clustering algorithms have been used in spectral analysis to find strong patterns in spectra. However, as they use a global distance metric, these algorithms can only detect strong patterns coexisting in several frequencies. In this paper, we propose a new method and several algorithms for aligning spectra suitable for efficient spectral analysis and allowing for the easy detection of strong patterns in both single frequencies and multiple frequencies. PMID- 19789121 TI - [Current status of salivary hormone analysis]. AB - Saliva, which offers a noninvasive and stress-free alternative to plasma and serum, is a widely accepted sample source for analysis of steroids and also of certain amines and peptides. In recent years, numerous publications have described the use of salivary hormone analysis in many fields of clinical and basic research. This review provides an overview of the current applications of salivary hormone analysis. A description of the different of hormone entry into saliva is followed by a detailed description of analytical methods and approaches for reliable collection of saliva, including several interesting applications in diverse fields including psychiatry, stress research, clinical endocrinology, sport medicine, and veterinary medicine. Although saliva has not yet become a mainstream sample source for hormone analysis, it has proven to be reliable and, in some cases, even superior to other body fluids. Nevertheless much effort will be required for this approach to receive acceptance over the long term, especially by clinicians. Such effort includes the development of specific and standardized analytical tools, the establishment of defined reference intervals, and implementation of round-robin trials. One major problem, the lack of compliance sometimes seen in outpatient saliva donors, requires strict standardization of both collection and analysis methods to achieve better comparability and assessment of published salivary hormone data. PMID- 19789122 TI - [Erythropoietin: indications and measurement]. AB - Erythropoietin (EPO) is the principal haematopoietic growth factor of the red blood cell line. Its major role is to stimulate the red blood cell production. EPO synthesis by peritubular cells in the kidney is regulated by oxygen concentration and must lead adaptation of the organism to face many different physiological situations. An imbalance can lead either to anaemia or polycythemia. Synthetic EPO, so-called recombinant, has definitively changed the treatment in the anaemia of chronic renal failure and regularly find new indications, legal (anaemia of cancer, anaemia of chronic inflammatory syndromes, myelodysplastic syndromes, neurology, cardiology...) or illegal (doping substance in sport). This article reviews the physiology, the role and the indications of EPO in clinical routine practice and define why and how EPO should be measured. We also focus on the analytical requirements for serum EPO concentration determination, especially in the differential diagnosis of polycythemias (secondary polycythemia/Polycythemia Vera). PMID- 19789123 TI - [Trans fatty acids: effects on lipoprotein metabolism and cardiovascular risk]. AB - Dietary trans fatty acids (TFA) (mainly 18:1 isomers) have two sources: they are formed during the natural bacterial hydrogenation of unsaturated fatty acids in ruminants or they come from the industrial hydrogenation of unsaturated vegetable oils. Total trans fatty acids account for 1.3% of total energy intake in France compared to 2-3% in USA. Recent epidemiologic studies and meta-analyses of well designed controlled trials clearly showed that trans fatty acids are associated with an increase of cardiovascular risk. It seems that TFA from industrial sources are responsible for the deleterious effects particularly on lipoprotein metabolism. Specifically the consumption of industrial TFA has been associated with high plasma concentrations of triacylglycerols, LDL-cholesterol and small dense LDL and lower HDL-cholesterol concentrations. The very recent interventional trials allowed for a comparison of TFAs from different sources suggest that the intake of natural TFA have no or neutral effects on plasma lipids and other cardiovascular risk factors. However, the mechanisms underlying the isomer-specific effects are not well understood and warrant further investigations. PMID- 19789124 TI - [From old to new anticoagulants: the role of the biologist]. AB - Anticoagulant drugs are of great interest to patients and clinical physicians, as well as research scientists. The latter two groups combine their efforts to unravel the related mechanisms of action, as well as means of monitoring and proper dosing. Unfractionated heparin and low molecular weight heparins and vitamin K antagonists have been on board for several decades by now. They act on several clotting factors in certain sequences. Newer drugs, produced by chemical synthesis, act on a more specific target, often factor Xa or factor IIa. These newer anticoagulants have a great convenience in being orally administered and not needing routing laboratory monitoring - which is their main advantage. Hirudine and fondaparinux have been registered for a few years. This year, that is 2008 + 2009, two of these new anticoagulants have been registered and approved for use in Europe and Canada - these are dabigatran etexilate (Pradaxa) and rivaroxaban (Xarelto). Both do not require routine laboratory monitoring. However, coagulation assays for measuring their activity have been studied. A small number of standardized tests should be perfected. PMID- 19789126 TI - [Study of antigenic profile of blasts in acute lymphoblastic leukemia: flow cytometric analysis of 152 cases]. AB - The aim of this study was to characterize the antigenic profile of blasts in acute lymphoblastic leukaemia (ALL) and to determine possible phenotypic aberrancies in a series of 152 patients with acute leukaemia diagnosed non myeloid leukaemia in cytology. Samples were analyzed by EPICS XL flow cytometer (Beckman Coulter) after staining with monoclonal antibodies(Beckman Coulter). Based on criteria of EGIL (European Group of Immunological Leukaemia), cases were classified as: acute lymphoblastic leukaemia (ALL, 52,6%); 75% cases of ALL belong to lymphoid B lineage. 80% of ALL B were CD10 positive, marker of best prognosis. In 10,5% of cases, biphenotypic leukaemia is diagnosed (lymphoid/myeloid). In 25% of cases aberrancies in phenotype were found. Flow cytometry has wide field of applications to characterize blast cells from patients with acute leukaemia: to establish diagnosis of lineage responsible in proliferation, to determine the stage of maturation, to predict prognosis for a better adaptation of adequate treatment, to follow evolution of disease after chemotherapy and to study minimal residual disease. PMID- 19789125 TI - Limited predictive value of the IDF definition of metabolic syndrome for the diagnosis of insulin resistance measured with the oral minimal model. AB - AIM: To assess the agreement of the NCEP ATP-III and the IDF definitions of metabolic syndrome and to determine their predictive values for the diagnosis of insulin resistance. METHODS: For this purpose, we recruited 150 subjects (94 women and 56 men) and determined the presence of metabolic syndrome using the NCEP-ATP III and IDF definitions. We evaluated their insulin sensitivity S(I) using Caumo's oral minimal model after a standardized hyperglucidic breakfast test. Subjects whose S(I) was in the lowest quartile were considered as insulin resistant. We then calculated sensitivity, specificity, positive and negative predictive values of both definitions for the diagnosis of insulin resistance. RESULTS: The prevalence of metabolic syndrome was 37.4% (NCEP-ATP III) and 40% (IDF). Agreement between the two definitions was 96%. Using NCEP-ATP III and IDF criteria for the identification of insulin resistant subjects, sensitivity was 55.3% and 63%, specificity was 68.8% and 67.8%, positive predictive value was 37.5% and 40%, negative predictive value was 81.9% and 84.5%, respectively. Positive predictive value increased with the number of criteria for both definitions. CONCLUSION: Whatever the definition, the scoring of metabolic syndrome is not a reliable tool for the individual diagnosis of insulin resistance, and is more useful for excluding this diagnosis. PMID- 19789127 TI - [Resistance to fluoroquinolone among Klebsiella spp strains producing extended spectrum betalactamases isolated from urine]. AB - The aim of the study was to assess the frequency of resistance to fluoroquinolones in extended-spectrum beta-lactamase (ESBLs) Klebsiella spp isolated from urines of consulting and hospitalized patients in Rabat Specialities Hospital. A retrospective survey was made over 3 years (2006-2008). Two hundred ant fifty three patients presented with confirmed urinary tractus infection (UTI). Klebsiella spp was the etiologic agent in 28% (72/253) of reported UTI. Among them, 86% of Klebsiella pneumoniae and 14% of Klebsiella oxytoca. The frequency of Klebsiella spp resistance to fluoroquinolones was 33% and to third generation cephalosporins was 35%. Thirteen Klebsiella spp strains were producing extended-spectrum beta-lactamase witch corresponds to 18% of all the klebsiella. The extended-spectrum beta-lactamase strains with resistance to fluoroquinolones were 85% (11/13) or 15 % of all klebsiella (11/72). None of those strains was resistant to imipenem. In conclusions resistance of enterobacteries such as Klebsiella spp to fluoroquinolones is becoming worrying among consulting and hospitalized patients. Eleven strains multiresistant (ESBL + resistance to fluoroquinolones), isolated probably because of plasmids carrying genes of ESBL and fluoroquinolones resistances. This increasingly frequent resistance mechanism should lead to a more careful use of first line fluoroquinolones for UTI. PMID- 19789128 TI - [Interference of hemoglobin variants on glycated hemoglobin measurement using Architect ci8200 immunoassay (Abbott Diagnostics)]. AB - The objective of this study was to compare haemoglobin A(1c) (HbA(1c)) levels measured by the immunoturbidimetric assay on ci8200 Architect (Abbott Diagnostics) to those obtained by the high pressure liquid chromatography (HPLC) assay from Tosoh Bioscience. Firstly, we verified correlation between the two methods in 47 subjects without hemoglobin variants: the coefficient of correlation was 0.968 and the regression equation was as follows: y(Abbott) = 0.928x(Tosoh) - 0.081. We then measured HbA(1c) levels by both methods in blood samples of 23 patients with a structural hemoglobin variant (A/S, A/C or S/C). Analysis of these samples revealed significant discrepancies between results of both methods, as indicated by the higher mean value obtained by immunoturbidimetric assay when compared to HPLC assay (7.17 +/- 2.68% vs. 5.86 +/ 1.41%). Classification of patients according to the HAS (French Haute Autorite de Sante) recommendations HbA(1c) was not modified for 68% of patients with abnormal hemoglobin. However, in 32% of cases, discrepancies between the two methods may have clinical importance, which justifies the occurrence of an abnormal hemoglobin when the HbA(1c) assay is performed by the method immunoturbidimetry Abbott Diagnostics. PMID- 19789129 TI - [Interest of antioxidants in the care of the patients infected by the HIV: the experience of long term administration of Alternanthera pungens herb tea]. AB - The objective of this study was to evaluate the interest of regular consumption of an antioxidant-containing herb tea in the care of HIV-patients. We conducted a 24 month prospective study in 30 patients clinically asymptomatic, infected by the VIH1, with a rate of CD4 above 200/mm3, and naive of any antiretroviral treatment. Every patient received a supplementation in antioxidants by drinking every two days during twelve monthsherb tea issued from Alternanthera pungens. Venous sampling of blood was used to measure biomarkers of oxidative (malondialdehyde - MDA - and advanced oxidation protein end products - AOPP), T lymphocytes, amimotransferases and creatinine. RESULTS: We observed: (1) a significant decree (p < 0,001) in plama levels of studied biomarkers of oxidative stress (AOPP and MDA); (2) a significant increase (p < 0,001) of T CD4 and CD8 lymphocytes and (3) the lack of biological hepatic and renal toxicity by the regular consumption of the herb tea. In conclusion, we showed that consumption taking of natural antioxidants through Alternanthera pungens herb tea may lead to significant increase T lymphocytes and decrease in biomarkers of oxidative stress, and might help in the prevention of the opportunist diseases by maintaining blood lymphocytes CD4/CD8 rate. PMID- 19789130 TI - [DIC and peripheral gangrene in a severe Plasmodium falciparum malaria: the coagulation-inflammation cycle with Plasmodium falciparum as a model]. AB - Peripheral gangrene with disseminated intravascular coagulation (DIC) during severe Plasmodium falciparum malaria has already been described but is unfrequent. We report here the case of a 62-year-old man admitted in the intensive care unit of our hospital for severe Plasmodium falciparum malaria with disseminated intravascular coagulation (DIC) and peripheral gangrene of his toes that needed amputation. Pathophysiological mechanisms leading to DIC in malaria can be used as a model to explain the relation between coagulation and inflammation. Therapeutic targeting of coagulation, by acting on inflammation, could be useful to limit the coagulation-inflammation cycle. PMID- 19789131 TI - [Evaluation of two automated methods for blood lactate levels]. AB - We evaluated two automated methods for measuring blood levels of lactates with Integra 800 (Roche Diagnostics) and ABL 725 (Radiometer). Our evaluation had shown a within run imprecision of 1% (Integra 800) and 2% (ABL 725) and a between assay imprecision of 2% (Integra 800) and 5% (ABL 725). The two methodologies appeared very well associated. The selective electrode remains expensive but it is very interesting because it saves a blood sample. PMID- 19789133 TI - [Colchicine poisoning: a case report]. AB - Colchicine is a drug commonly used for treatment of acute and chronic gout. Poisoning is a rare but always serious event. The purpose of this report is to describe the case of a 16-year-old girl who ingested an unknown amount of colchicine in a suicide attempt. At the time of admission she presented with gastrointestinal manifestations and reduced consciousness. After ten days in the intensive care unit she died due to multiple organ failure. This case provides the opportunity not only to review the clinical course and prognostic factors associated with colchicine poisoning but also to underline the difficulty of its management due to the absence of a specific antidote and of emergency pharmacologic doses. PMID- 19789132 TI - [Diagnosis and treatment of prostatitis: a case report]. AB - Prostate specific antigen (PSA) is the test of first line in mass screening program of prostate cancer. However the increase of its level can be seen in other affections of this gland (banal hypertrophy, acute prostatitis...). We report the case of 53 year's old patient presenting with urinary symptoms combined with pelvises pains due to acute prostatitis. The follow up of PSA level has shown an initial pick which regresses progressively until the normalisation after an effective antibiotherapy, with complete disappearance of the clinical symptoms. PMID- 19789134 TI - [Acquired and repeated factor VII deficiency during two infectious episodes: a case report]. AB - We described the management of a patient with acquired and severe FVII deficiency appeared during two infections outbreaks. This case report focused on both biological diagnosis and treatment of the F VII deficiency. PMID- 19789135 TI - [Introducing the new international vocabulary of metrology]. AB - The 3rd edition of the "International vocabulary of metrology - Basic and general concepts and associated terms (VIM)" is a fundamental document for the people who are concerned by metrology. This international standard is bilingual (french/english). The VIM contains definitions of metrological concepts, their hierarchy, numerous explicative notes and examples. This approach confirms that the concepts of the VIM are applicable to various disciplines including clinical laboratory sciences. PMID- 19789136 TI - Immunosenescence and vaccination of the elderly, I. Age-related immune impairment. AB - The sharp increase of life expectancy and the increasing ratio of ageing population pose new challenges for the public health system. The elderly suffer from more frequent and severe infections than young people. Theoretically, vaccination could protect the elderly against several infectious diseases, but due to their age-related immune impairment, vaccination might fail in many cases. Instead of ineffective vaccination campaigns, exploration and restoration of age dependent dysregulation of their immune functions have to be placed into the focus of recent research. Frequent comorbidities in these people augment immune defects. Immunosenescence affects both the innate and adaptive immunity. Disturbances in macrophage-derived cytokine release and reduction of the natural killer cell mediated cytotoxicity lead to increased frequency of respiratory, gastrointestinal and skin infections. Although the humoral immunity retains most of its original activity through life span, ageing dampens the ability of B cells to produce antibodies against novel antigens. Age-related declination of the cellular immunity is the consequence of thymic atrophy, reduced output of new T lymphocytes, accumulation of anergic memory cells, deficiencies in the cytokine production and uncertain antigen presentation. Persistent infection by different herpesviruses and other parasites contribute to the loss of immunosurveillance and premature exhaustion of T cells. PMID- 19789137 TI - RpoS-independent and growth phase-dependent expression of dcuSR operon of Escherichia coli. AB - The dcuSR operon of Escherichia coli encodes a two-component sensor/kinase response/regulator system. This system regulates gene expression in response to external C 4 -dicarboxylates. During entry into stationary phase Gram-negative bacteria express genes that impart cellular resistance to environmental stresses. In E. coli , 50 or more genes are triggered by sigma factor ( sigma s ) during entry into stationary phase. Multi-copy dcuS-lacZ and chromosomally integrated dcuS-lacZ fusions analysis showed that the expression of dcuSR is positively regulated during growth phase. Many genes that are required for stationary-phase adaptation are controlled by RpoS, a conserved alternative sigma factor, whose expression is, in turn, controlled by many factors. To understand whether the dcuSR is dependent upon RpoS, a RpoS- dcuS-lacZ strain was generated. beta Galactosidase assay and Western blot analysis reported that the generated RpoS- dcuS-lacZ strain and the wild type showed the same expression during stationary phase. Surprisingly, the growth phase-dependence of the expression of dcuSR is still present in RpoS- dcuS-lacZ strain suggesting that other growth-phase dependent regulatory mechanisms (might be the DcuSR system or cAMP/CRP), in addition to RpoS, may control post-exponential dcuSR expression. PMID- 19789138 TI - Synthesis of ethyl acetate employing celite-immobilized lipase of Bacillus cereus MTCC 8372. AB - A wide range of fatty acid esters can be synthesized by esterification and transesterification reactions catalyzed by lipases in non-aqueous systems. In the present study, immobilization of a purified alkaline extra-cellular lipase of Bacillus cereus MTCC 8372 by adsorption on diatomaceous earth (celite) for synthesis of ethyl acetate via transesterification route was investigated. B. cereus lipase was deposited on celite (77% protein binding efficiency) by direct binding from aqueous solution. Immobilized lipase was used to synthesis of ethyl acetate from vinyl acetate and ethanol in n -nonane. Various reaction conditions, such as biocatalyst concentration, substrates concentration, choices of solvents ( n -alkanes), incubation time, temperature, molecular sieves (3A x 1.5 mm), and water activity(a w ), were optimized. The immobilized lipase (25 mg/ml) was used to perform transesterification in n -alkane(s) that resulted in approximately 73.7 mM of ethyl acetate at 55 degrees C in n -nonane under shaking (160 rpm) after 15 h, when vinyl acetate and ethanol were used in a equimolar ratio (100 mM each). Addition of molecular sieves (3A x 1.5 mm) as well as effect of water activity of saturated salt solutions (KI, KCl and KNO 3 ) to the transesterification efficiency has inhibitory effect. Batch operational stability tests indicated that immobilized lipase had retained 50% of its original catalytic activity after four consecutive batches of 15 h each. PMID- 19789139 TI - Fungal endophytes in three medicinal plants of Lamiaceae. AB - Three medicinal plants Ocimum sanctum, Ocimum bacilicum and Leucas aspera were screened to study endophytic diversity of the plants. Altogether 103 fungal endophytes belonging to fourteen genera were isolated. Leaves of all three medicinal plants were colonized by a great number of endophytic fungi. Leaves of O. sanctum were colonized by the most, that is, eleven endophytes. Highest Shannon-Wiener index (2.256) was exhibited by O. sanctum with the highest Simpson's diversity (0.8654) indicating great species specificity. O. bacilicum and L. aspera showed the highest similarity coefficient. Some fungal genera have been showed to be host specific. In the present study Curvularia sp., Hymenula sp., Tricoderma sp. and Tubercularia sp. exclusively colonized O. sanctum ; whereas Alternaria sp. and Spicaria sp. colonized only L. aspera . PMID- 19789141 TI - Plant growth promotion by phosphate solubilizing bacteria. AB - Most agronomic soils contain large reserves of total phosphorus [P], but the fixation and precipitation of P cause P deficiency, and in turn, restrict the growth of crops severely. Phosphorus replenishment, especially in sustainable production systems, remains a major challenge as it is mainly fertilizer dependent. Though the use of chemical P fertilizers is obviously the best means to circumvent P deficiency in different agro-ecosystems, their use is always limited due to its spiralling cost. A greater interest has, therefore, been generated to find an alternative yet inexpensive technology that could provide sufficient P to plants while reducing the dependence on expensive chemical P fertilizers. Among the heterogeneous and naturally abundant microbes inhabiting the rhizosphere, the phosphate solubilizing microorganisms (PSM) including bacteria have provided an alternative biotechnological solution in sustainable agriculture to meet the P demands of plants. These organisms in addition to providing P to plants also facilitate plant growth by other mechanisms. Despite their different ecological niches and multiple functional properties, P solubilizing bacteria have yet to fulfil their promise as commercial bio inoculants. Current developments in our understanding of the functional diversity, rhizosphere colonizing ability, mode of actions and judicious application are likely to facilitate their use as reliable components in the management of sustainable agricultural systems. PMID- 19789140 TI - Risk factors and outcomes for bloodstream infections with extended-spectrum beta lactamase-producing Klebsiella pneumoniae ; Findings of the nosocomial surveillance system in Hungary. AB - Risk factors for and outcomes of bloodstream infections (BSIs) caused by ESBL producing and by ESBL-non-producing Klebsiella pneumoniae were compared in a four year multicenter study in Hungary. One hundred ESBL-positive and one hundred ESBL negative patients were included as cases and controls. Investigated risk factors were related to demographics, comorbid conditions, treatments, invasive procedures, surgery prior bacteremia, presence of additional nosocomial infections and preceding hospital admission within a year. Measured outcomes were crude mortality, mortality related to infection and delay in introducing appropriate therapy (DAT). Though some risk factors for infection (admission to intensive care units, having central venous and/or urinary catheter, mechanical ventilation) were shared by both groups, in other respects cases and controls were found to differ substantially. The 36 percent of patients with BSIs with ESBL-producing Klebsiella died versus 23 percent of controls (odds ratio [OR]: 2.5; 95% confidence interval [CI]: 1.0-5.4; p = 0.02). The 18 percent of deaths in cases versus 9% in controls could be attributed to infection (OR: 5.0; 95% CI: 1.5-16.2; p = 0.006). Cases more often received previous antibiotic therapy than controls (OR: 2.7; 95% CI: 1.1-6.7; p = 0.02) and delay in the introduction of appropriate antibiotic treatment was observed in 44% of cases versus 19% of controls (OR: 3.4; 95% CI: 1.6-7.3; p = 0.001). The results demonstrate that BSIs caused by ESBL-producing K. pneumoniae are related to previous antibiotic therapy and are associated with a high rate of mortality that is often linked to delay in the introduction of appropriate antibiotic therapy. This confirms that besides infection control measures the early identification and antibiotic resistance profiling of the infecting pathogen is salient in the control of BSIs caused by ESBL-producing K. pneumoniae . PMID- 19789142 TI - Microbial communities in bees, pollen and honey from Slovakia. AB - As the honey-bee gastrointestinal tract microflora and pollen are the primary sources for the honey microbial community, the aim of this work was to study and characterize the microbial transit among them. Therefore, an exhaustive microbial analysis of honey, adult honey-bee gastrointestinal tract, and pollen from different Slovakian regions and different seasons, was conducted. Microbial screening revealed that the primary sources of microbial community present in Slovakian honey are pollen and the honey-bees' digestive tract microflora, containing microorganisms normally present in dust, air and flowers. We found that the digestive tract of Slovakian adult honey-bees is highly populated by anaerobic, rather than aerobic bacteria, where coliforms, enterococci, staphylococci, Bacillus sp., Pseudomonas sp., microscopic fungi and yeast were found. Interestingly, statistical differences were found between the microflora of the gastrointestinal tract of summer and winter bees. Pollen revealed the presence of mesophil anaerobic and aerobic microorganisms, coliforms and microscopic fungi. Among these, the most representative genera were Alternaria, Cladosporium and Penicillium . In honey the counts of total anaerobic and total aerobic bacteria, that of coliforms, enterococci, bacilli, microscopic fungi and yeasts were monitored. Most frequently microscopic fungi belonging to genera Penicillium, Cladosporium and Alternaria were found. PMID- 19789144 TI - [Occurrence of GRB10 (+11275G > A) polymorphism in Hungarian population and its relationship to glucose metabolism]. AB - In our backstage experiment with differential display method among the differentially expressed genes we found the gene of GRB10 (Growth factor Receptor Bound protein 10). The GRB10 protein binds to insulin and insulin-like growth factor receptors and acts as a negative regulatory protein. Besides, GRB10 gene polymorphisms are connected to the development of type 2 diabetes mellitus. In this experiment we investigated the allele frequency of RS 2237457, +11275G > A polymorphism in Hungarian healthy and type 2 diabetic populations (healthy: n = 77, diabetics: n = 85). We also searched for the connections between the genotype and glucose homeostasis measured by hyperinsulinemic - normoglycemic clamps in healthy volunteers (n = 88), glucose intolerant (IFG n = 15; IGT n = 29) and non treated type 2 diabetic patients (n = 9). We did not find significant differences in allele frequencies between the Hungarian healthy and diabetic populations (healthy: g vs. a: 62% vs. 38%; 2DM g vs. a: 70% vs. 30%). In case of females, glucose utilization did not depend on GRB10 gene polymorphisms. Insulin production after oral glucose load was increased among males with gg alleles, and not after iv. glucose administration. The glucose disposal in muscle tissue was lower and the metabolic clearance rate was also lower calculated either for total body or muscle tissue in this group. In both genders gg alleles were associated with a disadvantageous lipid profile of decreased levels of large, buoyant LDL molecules and HDL levels in females. Metabolic changes related to the polymorphism of GRB10 gene support a gender specific role of this gene in insulin sensitivity and insulin signal transduction. It may be hypothesized on the basis of the differences in insulin release after oral and iv. glucose loads that GRB10 is involved in incretin signaling pathway. PMID- 19789146 TI - [Adalimumab treatment in infliximab-resistant pediatric patient with Crohn's disease]. AB - Treatment with the chimeric monoclonal antibody (infliximab) is highly effective in refractory and fistulising Crohn's disease, nevertheless, infliximab resistance may occur. Authors report a 12-year-old boy with infliximab refractory luminal Crohn's disease including 3 active perianal fistulas. The patient was treated successfully with adalimumab, a fully human anti-tumor necrosis factor alpha monoclonal antibody. After 10 weeks of therapy, the previously high activity index returned to normal and the fistulas were closed. Quality of life using validated questionnaire improved significantly also. Adalimumab might be a suitable therapy even in pediatric Crohn's disease patients with infliximab resistance. PMID- 19789145 TI - [Appearing of bone marrow derived stem cells in healthy and regenerating colonic epithelium]. AB - In the process of regeneration following colon inflammation mesenchymal stem cells (MSC) of bone marrow origin may also take part besides their local counterparts. These cells migrate in the colon epithelium where they may contribute to epithelial regeneration or form progeny for keeping up local stem cell pool. MSC cells probably leave circulation around lymphoid aggregates to then migrate into nearby crypts. During migration they change their phenotype upon the influence of local microenvironment. AIMS: In this study epithelial migration and transition of bone marrow stem cells were examined. Samples from normal healthy individuals and from aspecific inflammation were used. The possible role of lymphoid aggregates in the epithelial regeneration was also studied. MATERIALS AND METHODS: Samples of normal colon (2) and those showing mild aspecific colitis (3) from female patients who were initially transplanted with male bone marrow were studied. First we detected gender chromosomes with fluorescent in situ hybridization (FISH) and the samples were archived with digital scanning. Then CD45 and cytokeratin (CK) double immunofluorescent reactions (IF) were made followed by digitalization again. Digitalized samples were estimated simultaneously with virtual microscopy (Mirax Viewer). RESULTS: Significant elevation of CD45 negative/Y-FISH positive potential MSCs were found in crypts locating to the neighborhood of lymphoid aggregates (1,075%) compared with both normal (0,027%, p = 0,002) and mild colitis (0,045%, p = 0,004) samples. CONCLUSION: Local stem cells probably have enough regeneration capacity in case of minor inflammation. However, in aspecific inflammation the number of MSCs contributing to epithelial regeneration was elevated, suggesting their facilitated contribution to the repair process with less probable forming of local stem cell progeny. PMID- 19789147 TI - [The beginnings and the development of heart surgery in Debrecen; the consequence of Professor Jozsef Schnitzler's initiative]. AB - In the early 1960s, cardiac surgery was founded in Debrecen in the department of thoracic surgery, on Professor Jozsef Schnitzler's initiative with the cooperation of the head surgeon Arpad Eisert from Nyiregyhaza. During the first 5 years, between 1963-1968, 44 closed cardiac surgical procedures were performed (closure of patent ductus arteriosus, pulmonal and mitral stenosis, pericardectomy). The first open heart surgery was performed by Gabor Kovacs visiting professor from Szeged in 1968, after the Pemco heart-lung machine, a donation by Bela Koteles and the Presbyterian Church in Cleveland had arrived. The cardiac surgical activity was led by Professor Andras Gomory (1972-1983). During the first 20 years 310 open, 220 closed cardiac surgical, and 612 pacemaker operations were performed. After Professor Schnitzler's retirement in 1983, Arpad Peterffy was appointed the head of the entire department (general and cardio-thoracic surgery). In the last 25 years, 18,000 open, 1500 closed and 8500 pacemaker procedures altogether 32,000 were performed. In 2008 associate professor Tamas Szerafin became the head of the department of cardiac surgery. PMID- 19789148 TI - [Roza Pato, artist of medaillon and sculpture, is 75 years old]. PMID- 19789149 TI - [Ferenc Flor (1809-1871) was born two hundred years ago]. PMID- 19789151 TI - Visual vignette. Pituitary metastatic lesions. PMID- 19789152 TI - A rare case of central precocious puberty due to hypothalamic hamartoma diagnosed in utero. AB - OBJECTIVE: To report a rare case of central precocious puberty attributable to hypothalamic hamartoma that was diagnosed in utero. METHODS: We present the clinical, laboratory, and imaging data pertaining to our case and discuss the diagnostic features and recommended treatment of central precocious puberty in patients with hypothalamic hamartoma. RESULTS: A 3-month-old male child had had excessively rapid growth velocity and weight gain since birth. On investigation, the patient was diagnosed as having hypothalamic hamartoma with central precocious puberty. On inquiry, his mother described a history of prenatal ultrasonography and fetal magnetic resonance imaging suggesting the presence of a cystic lesion in his brain at 9 months of gestation. Because of continued rapid growth and acceleration of puberty during a 4-month observation period, we decided to treat the patient with leuprolide acetate. The patient responded well to treatment, with stabilization of growth. CONCLUSION: To the best of our knowledge, this patient is the youngest in the medical literature diagnosed to have central precocious puberty and also to receive treatment with leuprolide acetate. PMID- 19789153 TI - Effects of colesevelam, rosiglitazone, or sitagliptin on glycemic control and lipid profile in patients with type 2 diabetes mellitus inadequately controlled by metformin monotherapy. AB - OBJECTIVE: To evaluate the glycemic effect of colesevelam, rosiglitazone, or sitagliptin when added to metformin monotherapy in patients with type 2 diabetes mellitus (DM) and to examine the effects of these antidiabetes agents on lipid and lipoprotein levels. METHODS: This 16-week, open-label pilot study conducted between May 2007 and April 2008 at 20 sites in the United States, 7 sites in Mexico, and 6 sites in Colombia, enrolled adults with inadequately controlled type 2 DM (glycated hemoglobin [HbA1c], 7.0%-10.0%) on a stable metformin regimen (1500-2550 mg daily for > or = 3 months). At Week 0, participants were randomly assigned 1:1:1 to open-label colesevelam hydrochloride, 3.75 g daily; open-label rosiglitazone maleate, 4 mg daily; or open-label sitagliptin phosphate, 100 mg daily, in addition to existing metformin therapy. The primary efficacy variable was the change in HbA1c from baseline to Week 16 with last (post-baseline) observation carried forward. RESULTS: In total, 169 participants were randomly assigned to treatment groups (colesevelam, n = 57; rosiglitazone, n = 56; and sitagliptin, n = 56), and 141 participants (83.4%) completed the study. Least squares mean reductions in HbA1c from baseline were observed in all groups at Week 16 last observation carried forward (colesevelam, -0.3% [P<.031]; rosiglitazone: -0.6% [P<.001]; sitagliptin: -0.4% [P<.009]) At study end, 10 of 56 participants (17.9%) in the colesevelam group, 19 of 54 (35.2%) in the rosiglitazone group, and 15 of 55 (27.3%) in the sitagliptin group achieved HbA1c <7.0%. Colesevelam significantly reduced mean low-density lipoprotein (LDL) cholesterol levels relative to baseline (11.6%), whereas levels were significantly increased with rosiglitazone and sitagliptin at Week 16 last observation carried forward (7.8% and 7.7%, respectively). Twenty-two of 52 participants (42.3%) in the colesevelam group, 12 of 51 (23.5%) in the rosiglitazone group, and 13 of 53 (24.5%) in the sitagliptin group achieved LDL cholesterol <100 mg/dL at Week 16 last observation carried forward. CONCLUSION: All 3 antidiabetes agents significantly improved glycemic control, but only colesevelam also significantly reduced LDL-cholesterol levels in patients with type 2 DM. PMID- 19789154 TI - Chemotherapy-induced hypocalcemia. AB - OBJECTIVE: To present a unique case of transient, asymptomatic chemotherapy induced hypocalcemia not attributable to hypomagnesemia or tumor lysis syndrome and review causes of hypocalcemia related to cancer with and without use of chemotherapy. METHODS: We present a case detailing the clinical and laboratory findings of a patient who had severe hypocalcemia during chemotherapy and discuss causes of hypocalcemia with an extensive literature review of chemotherapeutic agents associated with this biochemical abnormality. RESULTS: In a 90-year-old man, hypocalcemia developed during 2 courses of chemotherapy for Hodgkin lymphoma, with partial recovery between courses and normal serum calcium 10 months after completion of treatment. Magnesium, vitamin D, and parathyroid hormone levels were low normal. There was no evidence of tumor lysis syndrome. Of the various agents administered, vinca alkaloids seemed the most likely cause. Serial testing suggested that the underlying mechanism may have been acquired, reversible hypoparathyroidism. No other similar case was found in the published literature. CONCLUSION: The severe hypocalcemia in our patient could not be attributed to hypomagnesemia or tumor lysis syndrome, and it was clearly associated with the timing of his chemotherapeutic regimen. Possibilities include direct parathyroid hormone suppression or alteration of calcium sensing by the chemotherapeutic drugs. Serum calcium surveillance before and during chemotherapeutic management of cancer patients may reveal more instances and provide insight into the exact mechanism of this lesser known yet striking complication. PMID- 19789155 TI - Significance of elevated parathyroid hormone after parathyroidectomy. AB - OBJECTIVE: To review the prevalence of parathyroid hormone elevation after parathyroidectomy for primary hyperparathyroidism and to discuss possible mechanisms. METHODS: A Medline search of the English-language literature published between 1990 and 2009 was performed using the search terms "elevated PTH after parathyroidectomy." All of the identified articles reported either prospective or retrospective studies without control groups. Studies that included patients with secondary or tertiary hyperparathyroidism were not reviewed. RESULTS: Within 1 week to 5 years after parathyroidectomy, 9% to 62% of patients with a normal serum calcium concentration are reported to have an elevated parathyroid hormone concentration. No evidence suggests that postoperative normocalcemic parathyroid hormone elevation is an indication of surgical failure and recurrent hypercalcemia. Preoperative findings in patients with postoperative parathyroid hormone elevation include lower vitamin D concentration, higher concentrations of bone turnover markers, and higher parathyroid hormone concentration. Potential mechanisms for parathyroid hormone elevation in the setting of normocalcemia include vitamin D deficiency, hungry bone syndrome, and parathyroid hormone resistance. Study findings suggest a possible benefit of postoperative calcium and vitamin D supplementation, but no randomized trials have been done. CONCLUSION: Elevation of parathyroid hormone commonly occurs after parathyroidectomy for primary hyperparathyroidism, although the underlying mechanism remains unclear. PMID- 19789156 TI - Identifying prediabetes using fasting insulin levels. AB - OBJECTIVE: To determine whether patients with prediabetes can be accurately and easily identified in clinical settings using a predictive clinical and laboratory model. METHODS: This retrospective study examined demographic and laboratory data from patients who had undergone 2-hour glucose testing for suspected prediabetes or diabetes between 2000 and 2004. Patients who met the diagnostic criteria for diabetes mellitus were excluded. Prediabetes was defined as a fasting glucose concentration > or = 100 mg/dL and < or = 125 mg/dL or a 2-hour postprandial glucose concentration > or = 140 mg/dL and < 200 mg/dL. Multivariate logistic regression was conducted to identify calculated or measured clinical and laboratory attributes that predict the presence of prediabetes, including fasting insulin quartiles, homeostasis model assessment of insulin resistance (HOMA-IR), and quantitative insulin sensitivity check index. RESULTS: Of 965 patients, 287 (29.7%) had prediabetes. The study population primarily consisted of white, obese, female patients. A multivariate model revealed that compared with the referent lowest quartile of fasting insulin (mu = 4.9 [+/-SD] +/-1.2 microIU/mL), subsequent insulin quartiles increased the likelihood of identifying prediabetes (quartile 2: mu = 8.0 +/-0.8 microIU/mL, odds ratio [OR] = 2.076, confidence interval [CI] = 1.241-3.273; quartile 3: mu = 12.2 +/-1.7 microIU/mL, OR = 3.151, CI = 1.981-5.015; quartile 4: mu = 25.9 +/-12.4 microIU/mL, OR = 5.035, CI = 3.122-8.122). Older age and increased diastolic blood pressure also contributed modestly to this model. Further analysis using the area under the curve revealed that at a fasting insulin level > 9.0 microIU/mL, prediabetes would be correctly identified in 80% of affected patients. A second model revealed that increased HOMA-IR index (OR = 1.303, CI = 1.205-1.410) and older age (OR = 1.037, CI = 1.024-1.05) predicted prediabetes. CONCLUSIONS: The most robust model, which used fasting insulin levels, may provide the most utility as a clinical tool because the highest quartiles suggest significantly greater likelihood of identifying prediabetes. PMID- 19789157 TI - Chemical profile of Plomin Bay sediments. AB - Granulometric, chemical, and leaching properties of sediments dredged in the Plomin Bay (Northern Adriatic Sea, Croatia) were investigated in order to asses the risk of remobilisation of heavy metals into the water column. In total 65 samples from 65 sampling sites were taken from different sediment depths within the bay. Analysis of variance confirmed the homogeneity of granulometric and elemental composition of the investigated sediment throughout its volume. Granulometric analysis showed that all samples corresponded to a pelitic fraction (<0.063 mm). Bulk elemental mass fractions in the sediments were similar to literature data on relatively unpolluted areas of the Adriatic Sea. High sedimentation rate caused by constant inflow of material from the Boljuncica River drainage may be responsible for low levels of heavy metals and negligible influence of fly and bottom ash from a nearby disposal site on the chemical composition of the sediments. In contact with sea water only 0.29 mg kg-1 of V, 0.04 mg kg-1 of Cr, 0.07 mg kg-1 of Ni, 0.33 mg kg-1 of Cu, 0.67 mg kg-1 of Zn and 0.06 mg kg-1 of Pb could be remobilised from sediment material into the water column. However, these values increased three to ten times in case of leaching with organic acids. PMID- 19789158 TI - In vitro genotoxicity of wastewaters from the town of Settat, Morocco. AB - In recent years, the town of Settat has seen a considerable industrial growth, which has resulted in increased environmental pollution. This includes pollution by household and industrial wastewaters, which are released into the Boumoussa River without any preliminary treatment. The river valley crosses the community of Mzamza 8 km to the north of the town. Years of drought forced members of the community to use this polluted ground water for irrigation and put themselves and the environment at risk.The aim of this study was to determine the physicochemical and metal profile of Settat wastewaters and to assess their impact on the water table. The second objective was to investigate the genotoxic potential of wastewater on human peripheral blood lymphocytes in vitro, using the micronucleus test and cellular proliferation index.This study demonstrated significant pollution of Boumoussa valley groundwater and of the local wells. Sampled water induced a clear increase in the frequency of micronucleated cells and a lower cell proliferation in human peripheral blood lymphocytes in vitro. PMID- 19789159 TI - Comparison of ethanol and acetaldehyde toxicity in rat astrocytes in primary culture. AB - This study compared the effects of toxicity of ethanol and its first metabolite acetaldehyde in rat astrocytes through cell viability and cell proliferation. The cells were treated with different concentrations of ethanol in the presence or absence of a catalase inhibitor 2-amino-1,2,4 triazole (AMT) or with different concentrations of acetaldehyde. Cell viability was assessed using the trypan blue test. Cell proliferation was assessed after 24 hours and after seven days of exposure to either ethanol or acetaldehyde.We showed that both ethanol and acetaldehyde decreased cell viability in a dose-dependent manner. In proliferation studies, after seven days of exposure to either ethanol or acetaldehyde, we observed a significant dose-dependent decrease in cell number. The protein content study showed biphasic dose-response curves, after 24 hours and seven days of exposure to either ethanol or acetaldehyde. Co-incubation in the presence of AMT significantly reduced the inhibitory effect of ethanol on cell proliferation.We concluded that long-term exposure of astrocytes to ethanol is more toxic than acute exposure. Acetaldehyde is a much more potent toxin than ethanol, and at least a part of ethanol toxicity is due to ethanol's first metabolite acetaldehyde. PMID- 19789160 TI - Comet assay in evaluating DNA damage associated with ischaemia-reperfusion injury in patients undergoing coronary surgery. AB - Ischaemia-reperfusion (I/R) injury is responsible for a number of conditions such as coronary bypass and myocardial infarction, and deaths. Oxygen-free radicals formed during I/R have been proposed as the leading causes of tissue injury, and they play an important role in I/R injury. I/R induces oxidative DNA damage (such as purinic and pyrimidinic base lesions). Comet assay is a suitable and sensitive method for early detection of low-level DNA damage. We used modified alkaline comet assay in peripheral blood lymphocytes and evaluated I/R-induced DNA damage in patients undergoing coronary artery bypass graft (CABG) operation (in vivo model for I/R). No statistically significant difference in DNA damage levels was found before surgery, after anaesthesia, ischemia, reperfusion, and surgery. However, blood lactate levels (assessed in parallel with the comet assay) increased after I/R and did not return to the baseline level. Our findings showed that I/R injury did not induce DNA damage, but increased the lactate levels. This finding suggests that there might be reversible and uncommon necrosis that did not reflect on overall DNA base damage. Further studies are needed using this approach. PMID- 19789161 TI - Potentiation of bleomycin lethality in HeLa and V79 cells by bee venom. AB - This study investigated possible growth-inhibiting effects of bee venom applied alone or in combination with a cytotoxic drug bleomycin on HeLa and V79 cells in vitro based on clone formation, cell counting, and apoptosis. Melittin, the key component of bee venom, is a potent inhibitor of calmodulin activity, and also a potent inhibitor cell growth and clonogenicity. Intracellular accumulation of melittin correlates with the cytotoxicity of antitumour agents. Previous studies indicated that some calcium antagonists and calmodulin inhibitors enhanced intracellular levels of antitumor agents by inhibiting their outward transport. In this study, treatment of exponentially growing HeLa and V79 cells with bleomycin caused a dose-dependent decrease in cell survival due to DNA damage. This lethal effect was potentiated by adding a non-lethal dose of the bee venom. By preventing repair of damaged DNA, bee venom inhibited recovery from potentially lethal damage induced by bleomycin in V79 and HeLa cells. Apoptosis, necrosis, and lysis were presumed as possible mechanisms by which bee venom inhibited growth and clonogenicity of V79 cells. HeLa cells, on the other hand, showed greater resistance to bee venom. Our findings suggest that bee venom might find a therapeutic use in enhancing cytotoxicity of antitumour agent bleomycin. PMID- 19789162 TI - Effects of passive smoking at work on respiratory symptoms, lung function, and bronchial responsiveness in never-smoking office cleaning women. AB - This cross-sectional study compares respiratory symptoms, lung function, and bronchial responsiveness between 27 office cleaning women exposed to environmental tobacco smoke at work and 57 unexposed controls. The age range of both groups was 24 to 56 years, and none of the women had ever smoked. Information on respiratory symptoms, cleaning work history, and passive smoking in the workplace were obtained with a questionnaire. The subjects also took a skin prick test to common inhalant allergens, a lung function test, and a histamine challenge. Despite smoking restriction in indoor environments, we found a high prevalence of passive smokers in the workplace (32.1 %). In these subjects we found a significantly higher prevalence of wheezing with breathlessness (25.9 % vs. 8.8 %; P=0.036), wheezing without cold (25.9 % vs. 7.0 %; P=0.016), and breathlessness after effort (29.6 % vs. 8.8 %; P=0.014) than in control subjects. Objective measurements showed a significantly lower MEF25 (53.6 % vs. 63.7 %; P=0.001) and a significantly higher prevalence of borderline bronchial hyperresponsiveness (22.2 % vs. 7.0 %; P=0.044) in the passive smokers in the workplace. This study provides evidence of adverse respiratory effects in office cleaning women associated with passive smoking in the workplace. Our findings support a stricter implementation of the current national law to protect respiratory health of all workers. PMID- 19789163 TI - Effects of traffic noise on sleep in an urban population. AB - Urban noise is an important environmental stressor, and sleep disturbance is its major health effect. Substantial inter-individual variance in these effects might partly be explained by different sensitivity to noise. The aim of this study was to assess the effects of urban noise on sleep and the relation between self estimated sensitivity to noise and sleep disturbance. A cross-sectional questionnaire survey was performed on 911 adult residents of Nis, Serbia, of whom 388 were men (42.6 %) and 523 women (57.4 %). The streets were regarded as noisy if night equivalent noise level (Leq) was higher than 45 dB(A) and quiet if night Leq was < or =45 dB(A). Noise sensitivity was measured with the Weinstein's Noise Sensitivity Scale. The study showed that respondents from noisy area significantly more often reported difficulty in falling asleep, being woken up, poor sleep quality, tiredness after sleep, and use of sleep medication than residents from quiet streets (p<0.001). Noise sensitivity significantly correlated with sleep disturbances (p<0.001). PMID- 19789164 TI - Workplace noise exposure after modernisation of an aluminium processing complex. AB - The aim of this study was to assess to which extent modernisation of an aluminium production complex reduced occupational noise hazard for jobs with the highest potential of exposure. Periodical measurements of noise level were taken at the same workplaces using the same method, before and after modernisation of all plants. The results were compared with the recommended standard. After modernisation, the noise was significantly reduced in all sections of all plants. The greatest reduction was measured in the foundry. After modernisation, the portion of workplaces with excessive noise level dropped significantly (chisquare=21.315; p<0.0001) from 78.4% to 13%. Noise remained a problem in ingot casting and dross skimming section. In the anode plant, noise remained a problem in the green mill section where noise intensities generated by mills and vibrocompactors varied from 95 dB(A) to 102 dB(A). In the electrolysis plant, the portion of workplaces with extensive noise dropped from 77.8% to 39.3% after modernisation (p=0.0019). Noise remains to be a problem at the anode covering section where levels rise up to 100 dB(A). The modernisation of the factory has considerably reduced the noise level in the working environment of all plants, but it can not be reduced completely. PMID- 19789165 TI - Environmental noise and annoyance in adult population of Skopje: a cross sectional study. AB - The aim of this study was to identify noise exposure indicators during day and night in the city of Skopje and to see if there is an association between these noise exposure indicators and annoyance. We have performed noise measurements and interviewed 510 adult subjects, using a questionnaire, prepared according to the ISO/TS-15666 standard. Average noise level over the day (Lday) was (62+/-6.45) dB(A) and over night (Lnight) (56+/-6.52) dB(A). Thirteen percent of subjects reported a high level, and 33.5% moderate level of annoyance. The most annoying noise sources were construction activities (34% of the subjects), road traffic (24%), and leisure/entertainment activities (18%). We found a significant association between exposure to Lday in the range 61 dB(A) to 65 dB(A) and annoyance in the exposed population (chi-square = 86.14; p<0.001; Spearman's R=0.45; p<0.05). During the night time annoyance was reported with exposure to Lnight above 46 dB(A). Levels of annoyance in Macedonia are similar to levels in developed European countries. Differences are in the source of noise. This study has shown that environmental noise is a significant hazard in urban environments, and assessment of annoyance may prove a useful tool for town planners and public health policy makers. PMID- 19789166 TI - Nitrofurantoin-induced acute liver damage in pregnancy. AB - This article presents a rare case of acute toxic hepatitis in thirty-one-year old primigravida. In the 36th week of gestation, the patient was introduced nitrofurantoin 100 mg a day due to symptoms of dysuria and enterococcus isolated from urine culture. After induced delivery at term because of hypertension, repeated laboratory findings showed increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) and negative hepatitis C and B markers. The patient was subicteric at the time. Coagulation and complete blood count values were within the normal range. Nitrofurantoin therapy was discontinued. Abdominal ultrasound was normal with the exception of a slight hepatomegaly without any lesions, focal or diffuse. Given that discontinuation of nitrofurantoin and introduction of methylprednisolon therapy significantly lowered liver enzyme levels, restoring most of them to normal, we concluded that this was probably the case of toxic liver damage caused by nitrofurantoin. PMID- 19789167 TI - [Sex hormones and cognitive functioning of women]. AB - This paper discusses the organisational and activational effects of sex hormones, and their influence on cognitive functioning. Previous studies have shown gender differences in specific cognitive abilities. Women generally show an advantage in verbal fluency, perceptual speed and accuracy, as well as in fine motor skills, while men generally show an advantage in spatial and mathematical abilities. These differences in cognitive functioning are thought to occur as a result of foetal brain exposure to different levels of sex hormones during prenatal life. Additional evidence of organisational effects of sex hormones on cognitive functioning also comes from studies of subjects with genetic disorders, such as androgen insensitivity syndrome, congenital adrenal hyperplasia, and Tyrner syndrome.Furthermore, former investigations have shown that increase in female sex hormone in the late follicular and/or luteal phase of the menstrual cycle intensifies the typical female cognitive pattern of functioning with improved efficiency in tasks which are usually better performed by women. At the same time, low levels of such hormones that characterise the menstrual phase of the cycle intensify the typical male cognitive pattern of functioning with better efficiency in tasks which usually better performed by men.This paper also points to methodological differences between investigations of organizational and activational effects of sex hormones on cognitive functioning, as well a to the direction of future investigations. PMID- 19789168 TI - [Human lifespan: to live and outlive 100 years?]. AB - Aged population dominates in developed countries. Centenarians are a select group, and only one in 7,000 to 10,000 reach that age. Factors of longevity are numerous and include genetic predisposition (a locus on chromosome 4), environment, healthy lifestyle (hypocaloric diet, regular physical and mental exercise), accessible health services, and efficient health protection at old age. Centenarians are well adapted to the new life and compensate for the loss of functions with age. The limits of human life are extended, so that nowadays the oldest person has reached the age of 128. Some geographic areas are characterised by higher numbers of centenarians. This article mentions a few individuals who outlived 100 years in the world, Croatia, and neighbouring countries. Although some argue that the limits of human life cannot be extended over the age of 120 years, for now we cannot predict the actual limits of human life. PMID- 19789169 TI - Retinal detachment in Scotland is associated with affluence. AB - AIM: Socio-economic deprivation plays a major role in health and disease, but its role in retinal detachment has not been studied. Data from the Scottish Retinal Detachment Study were used to investigate any association between retinal detachment, macular status at presentation and deprivation. METHODS: Prospective multicentre population-based observational study. Data were collected on all patients with primary retinal detachment presenting in Scotland between 1 November 2007 and 31 October 2008. Every patient was allocated a validated deprivation ranking according to their postcodes based on the Scottish Index of Multiple Deprivation (SIMD), which takes into account income, employment, health, education, housing, geographic accessibility and crime in 6505 postcode-based datazones. The patients were divided into four quartiles according to their SIMD ranking. RESULTS: 572 patients were included. The annual incidence of detachment declined from 15.4/100,000 in the most affluent quartile to 13.6/100,000 in the second, 9.3/100,000 in the third and 6.9/100,000 in the most deprived (chi(2) for trend = 50.2, p<0.0001). The trend was more marked for men than for women but was present in both sexes. There were no differences in the rate of macula-off detachments or the number of quadrants detached. Rates of pseudophakic and myopic detachment were evenly distributed across all quartiles. CONCLUSIONS: Retinal detachment appears to be associated with affluence. This has not been previously reported and may be partly responsible for the variation in estimates of the incidence of retinal detachment. It may also have implications for service planning. The reason for this association is unknown. PMID- 19789170 TI - Peer status in school and adult disease risk: a 30-year follow-up study of disease-specific morbidity in a Stockholm cohort. AB - BACKGROUND: Children have a social status position of their own, apart from that of the family, that may have an impact on short-term and long-term health. The aim of the present study was to analyse the associations between childhood social status in school (ie, peer status) and disease-specific morbidity in adulthood. METHODS: Data were derived from a longitudinal study using a 1953 cohort born in Stockholm, Sweden: The Stockholm Birth Cohort Study (1953-2003). Peer status was sociometrically assessed in sixth grade (1966). Hazard ratios for adult disease specific morbidity based on information on inpatient care (1973-2003) were calculated by peer status category for men and women separately, using Cox regression. RESULTS: The results indicate that the lower the childhood peer status, the higher the overall adult disease risk. There were, however, differences in the degree and magnitude to which disease-specific inpatient care varied with peer status. Some of the steepest gradients were found for mental and behavioural disorders (eg, alcohol abuse and drug dependence), external causes (eg, suicide) and various lifestyle-related diseases (eg, ischaemic heart disease and diabetes). The results were not explained by childhood social class. CONCLUSION: The present study underlines the importance of recognising children's social position, apart from that of their family, for later health. Not only psychologically related diseases but also those related to behavioural risk factors demonstrate some of the largest relative differences by peer status, suggesting that health-related behaviour may be one important mechanism in the association between peer status and morbidity. PMID- 19789171 TI - Examining the relationship between maternal employment and health behaviours in 5 year-old British children. AB - BACKGROUND: There is little known about potential mechanisms underlying the association between maternal employment and childhood obesity. The relationships between maternal hours worked per week (none, 1-20 hours, 21+ hours) and children's dietary and physical activity/inactivity habits were examined. Where mothers were employed, the relationships between flexible work arrangements and these health behaviours were also examined. METHODS: Data from 12,576 singleton children age 5 years in the UK Millennium Cohort Study were analysed. Mothers reported information about their employment patterns. Mothers also reported on indicators of their child's dietary (crisps/sweets, fruit/vegetables, sweetened beverage, fruit consumption), physical activity (participation in organised exercise, transport to school) and inactivity (television/computer use) habits at age 5. RESULTS: After adjustment for potential confounding and mediating factors, children whose mothers worked part-time or full-time were more likely to primarily drink sweetened beverages between meals (compared to other beverages), use the television/computer at least 2 hours daily (compared to 0-2) or be driven to school (compared to walk/cycle) than children whose mothers had never been employed. Children whose mothers worked full-time were less likely to primarily eat fruit/vegetables between meals (compared to other snacks) or eat three or more portions of fruit daily (compared to two or fewer). Although in unadjusted analyses children whose mothers used flexible work arrangements engaged in healthier behaviours, relationships were no longer significant after adjustment. CONCLUSIONS: For many families the only parent or both parents are working. This may limit parents' capacity to provide their children with healthy foods and opportunities for physical activity. Policies and programmes are needed to help support parents and create a health-promoting environment. PMID- 19789172 TI - Innate immune cells cast an eye on DNA. AB - The threonine phosphatase eyes absent (EYA) has been identified as a novel regulator of innate immune responses to cytosolic nucleic acids and undigested DNA from apoptotic cells. EYA regulates responses of yet unidentified DNA sensors and enhances interferon-beta and CXCL10 transcription. PMID- 19789174 TI - Evolution of petal epidermal micromorphology in Leguminosae and its use as a marker of petal identity. AB - BACKGROUND AND AIMS: The legume flower is highly variable in symmetry and differentiation of petal types. Most papilionoid flowers are zygomorphic with three types of petals: one dorsal, two lateral and two ventral petals. Mimosoids have radial flowers with reduced petals while caesalpinioids display a range from strongly zygomorphic to nearly radial symmetry. The aims are to characterize the petal micromorphology relative to flower morphology and evolution within the family and assess its use as a marker of petal identity (whether dorsal, lateral or ventral) as determined by the expression of developmental genes. METHODS: Petals were analysed using the scanning electron microscope and light microscope. A total of 175 species were studied representing 26 tribes and 89 genera in all three subfamilies of the Leguminosae. KEY RESULTS: The papilionoids have the highest degree of variation of epidermal types along the dorsiventral axis within the flower. In Loteae and genistoids, in particular, it is common for each petal type to have a different major epidermal micromorphology. Papillose conical cells are mainly found on dorsal and lateral petals. Tabular rugose cells are mainly found on lateral petals and tabular flat cells are found only in ventral petals. Caesalpinioids lack strong micromorphological variation along this axis and usually have only a single major epidermal type within a flower, although the type maybe either tabular rugose cells, papillose conical cells or papillose knobby rugose cells, depending on the species. CONCLUSIONS: Strong micromorphological variation between different petals in the flower is exclusive to the subfamily Papilionoideae. Both major and minor epidermal types can be used as micromorphological markers of petal identity, at least in papilionoids, and they are important characters of flower evolution in the whole family. The molecular developmental pathway between specific epidermal micromorphology and the expression of petal identity genes has yet to be established. PMID- 19789173 TI - Dietary omega-3 and -6 polyunsaturated fatty acids affect the composition and development of sheep granulosa cells, oocytes and embryos. AB - The evidence that omega-3 (n-3) and -6 (n-6) polyunsaturated fatty acids (PUFAs) have differential effects on ovarian function, oocytes and embryo quality is inconsistent. We report on the effects of n-3 versus n-6 PUFA-enriched diets fed to 36 ewes over a 6-week period, prior to ovarian stimulation and follicular aspiration, on ovarian steroidogenic parameters and embryo quality. Follicle number and size were unaltered by diet, but follicular-fluid progesterone concentrations were greater in n-3 PUFA-fed ewes than in n-6 PUFA-fed ewes. The percentage of saturated FAs (mostly stearic acid) was greater in oocytes than in either granulosa cells or plasma, indicating selective uptake and/or de novo synthesis of saturated FAs at the expense of PUFAs by oocytes. High-density lipoproteins (HDLs) fractionated from sera of these ewes increased granulosa cell proliferation and steroidogenesis relative to the FA-free BSA control during culture, but there was no differential effect of n-3 and n-6 PUFAs on either oestradiol or progesterone production. HDL was ineffective in delivering FAs to embryos during culture, although n-6 PUFA HDL reduced embryo development. All blastocysts, irrespective of the treatment, contained high levels of unsaturated FAs, in particular linoleic acid. Transcripts for HDL and low-density lipoprotein (LDL) receptors (SCARB1 and LDLR) and stearoyl-CoA desaturase (SCD) are reported in sheep embryos. HDL reduced the expression of transcripts for LDLR and SCD relative to the BSA control. The data support a differential effect of n-3 and n 6 PUFAs on ovarian steroidogenesis and pre-implantation development, the latter in the absence of a net uptake of FAs. PMID- 19789175 TI - The evolution of bat pollination: a phylogenetic perspective. AB - BACKGROUND: Most tropical and subtropical plants are biotically pollinated, and insects are the major pollinators. A small but ecologically and economically important group of plants classified in 28 orders, 67 families and about 528 species of angiosperms are pollinated by nectar-feeding bats. From a phylogenetic perspective this is a derived pollination mode involving a relatively large and energetically expensive pollinator. Here its ecological and evolutionary consequences are explored. SCOPE AND CONCLUSIONS: This review summarizes adaptations in bats and plants that facilitate this interaction and discusses the evolution of bat pollination from a plant phylogenetic perspective. Two families of bats contain specialized flower visitors, one in the Old World and one in the New World. Adaptation to pollination by bats has evolved independently many times from a variety of ancestral conditions, including insect-, bird- and non-volant mammal-pollination. Bat pollination predominates in very few families but is relatively common in certain angiosperm subfamilies and tribes. We propose that flower-visiting bats provide two important benefits to plants: they deposit large amounts of pollen and a variety of pollen genotypes on plant stigmas and, compared with many other pollinators, they are long-distance pollen dispersers. Bat pollination tends to occur in plants that occur in low densities and in lineages producing large flowers. In highly fragmented tropical habitats, nectar bats play an important role in maintaining the genetic continuity of plant populations and thus have considerable conservation value. PMID- 19789176 TI - Arabidopsis plants harbouring a mutation in AtSUC2, encoding the predominant sucrose/proton symporter necessary for efficient phloem transport, are able to complete their life cycle and produce viable seed. AB - BACKGROUND AND AIMS: AtSUC2 encodes a sucrose/proton symporter that localizes throughout the collection and transport phloem and is necessary for efficient transport of sucrose from source to sink tissues in Arabidopsis thaliana. Plants harbouring homozygous AtSUC2 null alleles accumulate sugar, starch, and anthocyanin in mature leaves, have severely delayed development and stunted growth and, in previous studies, failed to complete their life cycle by producing viable seed. METHODS: An AtSUC2 allele with a T-DNA insertion in the second intron was analysed. Full-length transcript from this allele is not produced, and a truncated protein translated from sequences upstream of the insertion site did not catalyse sucrose uptake into yeast, supporting the contention that this is a null allele. Mutant plants were grown in a growth chamber with a diurnal light/dark cycle, and growth patterns recorded. KEY RESULTS: This allele (SALK_038124, designated AtSUC2-4) has the hallmarks of previously described null alleles but, despite compromised carbon partitioning and growth, produces viable seeds. The onset of flowering was chronologically delayed but occurred at the same point in the plastochron index as wild type. CONCLUSIONS: AtSUC2 is important for phloem loading and is therefore fundamental to phloem transport and plant productivity, but plants can complete their life cycle and produce viable seed in its absence. Arabidopsis appears to have mechanisms for mobilizing reduced carbon from the phloem into developing seeds independent of AtSUC2. PMID- 19789177 TI - Natural variation reveals relationships between pre-stress carbohydrate nutritional status and subsequent responses to xenobiotic and oxidative stress in Arabidopsis thaliana. AB - BACKGROUND: Soluble sugars are involved in responses to stress, and act as signalling molecules that activate specific or hormone cross-talk transduction pathways. Thus, exogenous sucrose treatment efficiently induces tolerance to the herbicide atrazine in Arabidopsis thaliana plantlets, at least partially through large-scale modifications of expression of stress-related genes. METHODS: Availability of sugars in planta for stress responses is likely to depend on complex dynamics of soluble sugar accumulation, sucrose-starch partition and organ allocation. The question of potential relationships between endogenous sugar levels and stress responses to atrazine treatment was investigated through analysis of natural genetic accessions of A. thaliana. Parallel quantitative and statistical analysis of biochemical parameters and of stress-sensitive physiological traits was carried out on a set of 11 accessions. KEY RESULTS: Important natural variation was found between accessions of A. thaliana in pre stress shoot endogenous sugar levels and responses of plantlets to subsequent atrazine stress. Moreover, consistent trends and statistically significant correlations were detected between specific endogenous sugar parameters, such as the pre-stress end of day sucrose level in shoots, and physiological markers of atrazine tolerance. CONCLUSIONS: These significant relationships between endogenous carbohydrate metabolism and stress response therefore point to an important integration of carbon nutritional status and induction of stress tolerance in plants. The specific correlation between pre-stress sucrose level and greater atrazine tolerance may reflect adaptive mechanisms that link sucrose accumulation, photosynthesis-related stress and sucrose induction of stress defences. PMID- 19789179 TI - RNA nuclear export is blocked by poliovirus 2A protease and is concomitant with nucleoporin cleavage. AB - Cytopathic viruses have developed successful strategies to block or, at least, to attenuate host interference with their replication. Here, we have analyzed the effects of poliovirus 2A protease on RNA nuclear export. 2A protease interferes with trafficking of mRNAs, rRNAs and U snRNAs from the nucleus to the cytoplasm, without any apparent effect on tRNA transport. Traffic of newly produced mRNAs is more strongly affected than traffic of other mRNAs over-represented in the cytoplasm, such as mRNA encoding beta-actin. Inhibition of RNA nuclear export in HeLa cells expressing 2A protease is concomitant with the cleavage of Nup98, Nup153, Nup62 and their subsequent subcellular redistribution. The expression of an inactive 2A protease failed to interfere with RNA nuclear export. In addition, other related proteases, such as poliovirus 3C or foot and mouth disease virus L(pro) did not affect mRNA distribution or Nup98 integrity. Treatment of HeLa cells with interferon (IFN)-gamma increased the relative amount of Nup98. Under such conditions, the cleavage of Nup98 induced by 2A protease is partial, and thus IFN-gamma prevents the inhibition of RNA nuclear export. Taken together, these results are consistent with a specific proteolysis of Nup98 by 2A protease to prevent de novo mRNA traffic in poliovirus-infected cells. PMID- 19789178 TI - Centrosomal localization of Diversin and its relevance to Wnt signaling. AB - Wnt pathways regulate many developmental processes, including cell-fate specification, cell polarity, and cell movements during morphogenesis. The subcellular distribution of pathway mediators in specific cellular compartments might be crucial for the selection of pathway targets and signaling specificity. We find that the ankyrin-repeat protein Diversin, which functions in different Wnt signaling branches, localizes to the centrosome in Xenopus ectoderm and mammalian cells. Upon stimulation with Wnt ligands, the centrosomal distribution of Diversin is transformed into punctate cortical localization. Also, Diversin was recruited by Frizzled receptors to non-homogeneous Dishevelled-containing cortical patches. Importantly, Diversin deletion constructs, which did not localize to the centrosome, failed to efficiently antagonize Wnt signaling. Furthermore, a C-terminal construct that interfered with Diversin localization inhibited Diversin-mediated beta-catenin degradation. These observations suggest that the centrosomal localization of Diversin is crucial for its function in Wnt signaling. PMID- 19789180 TI - Kinase-activity-independent functions of atypical protein kinase C in Drosophila. AB - Polarity of many cell types is controlled by a protein complex consisting of Bazooka/PAR-3 (Baz), PAR-6 and atypical protein kinase C (aPKC). In Drosophila, the Baz-PAR-6-aPKC complex is required for the control of cell polarity in the follicular epithelium, in ectodermal epithelia and neuroblasts. aPKC is the main signaling component of this complex that functions by phosphorylating downstream targets, while the PDZ domain proteins Baz and PAR-6 control the subcellular localization and kinase activity of aPKC. We compared the mutant phenotypes of an aPKC null allele with those of four novel aPKC alleles harboring point mutations that abolish the kinase activity or the binding of aPKC to PAR-6. We show that these point alleles retain full functionality in the control of follicle cell polarity, but produce strong loss-of-function phenotypes in embryonic epithelia and neuroblasts. Our data, combined with molecular dynamics simulations, show that the kinase activity of aPKC and its ability to bind PAR-6 are only required for a subset of its functions during development, revealing tissue-specific differences in the way that aPKC controls cell polarity. PMID- 19789181 TI - Genetic evidence that the higher plant Rab-D1 and Rab-D2 GTPases exhibit distinct but overlapping interactions in the early secretory pathway. AB - GTPases of the Rab1 subclass are essential for membrane traffic between the endoplasmic reticulum (ER) and Golgi complex in animals, fungi and plants. Rab1 related proteins in higher plants are unusual because sequence comparisons divide them into two putative subclasses, Rab-D1 and Rab-D2, that are conserved in monocots and dicots. We tested the hypothesis that the Rab-D1 and Rab-D2 proteins of Arabidopsis represent functionally distinct groups. RAB-D1 and RAB-D2a each targeted fluorescent proteins to the same punctate structures associated with the Golgi stacks and trans-Golgi-network. Dominant-inhibitory N121I mutants of each protein inhibited traffic of diverse cargo proteins at the ER but they appeared to act via distinct biochemical pathways as biosynthetic traffic in cells expressing either of the N121I mutants could be restored by coexpressing the wild type form of the same subclass but not the other subclass. The same interaction was observed in transgenic seedlings expressing RAB-D1 [N121I]. Insertional mutants confirmed that the three Arabidopsis Rab-D2 genes were extensively redundant and collectively performed an essential function that could not be provided by RAB-D1, which was non-essential. However, plants lacking RAB-D1, RAB D2b and RAB-D2c were short and bushy with low fertility, indicating that the Rab D1 and Rab-D2 subclasses have overlapping functions. PMID- 19789182 TI - Tyrosine phosphorylation of nuclear-membrane protein emerin by Src, Abl and other kinases. AB - X-linked recessive Emery-Dreifuss muscular dystrophy (EDMD) is caused by loss of emerin, a nuclear-membrane protein with roles in nuclear architecture, gene regulation and signaling. Phosphoproteomic studies have identified 13 sites of tyrosine phosphorylation in emerin. We validated one study, confirming that emerin is hyper-tyrosine-phosphorylated in Her2-overexpressing cells. We discovered that non-receptor tyrosine kinases Src and Abl each phosphorylate emerin and a related protein, LAP2beta, directly. Src phosphorylated emerin specifically at Y59, Y74 and Y95; the corresponding triple Y-to-F (;FFF') mutation reduced tyrosine phosphorylation by approximately 70% in vitro and in vivo. Substitutions that removed a single hydroxyl moiety either decreased (Y19F, Y34, Y161F) or increased (Y4F) emerin binding to BAF in cells. Y19F, Y34F, Y161F and the FFF mutant also reduced recombinant emerin binding to BAF from HeLa lysates, demonstrating the involvement of both LEM-domain and distal phosphorylatable tyrosines in binding BAF. We conclude that emerin function is regulated by multiple tyrosine kinases, including Her2, Src and Abl, two of which (Her2, Src) regulate striated muscle. These findings suggest roles for emerin as a downstream effector and ;signal integrator' for tyrosine kinase signaling pathway(s) at the nuclear envelope. PMID- 19789184 TI - A role for the intraparietal sulcus in transforming musical pitch information. AB - The present functional magnetic resonance imaging study investigates the neural substrates of relative pitch. Musicians and nonmusicians performed 2 same/different discrimination tasks (simple and transposed melody) that differed in whether they required precise encoding and comparison of relative pitch structure, along with 2 control tasks (rhythm and phoneme). The transposed melody task involved a musical transposition of 4 semitones between the target and comparison patterns, requiring listeners to use interval information rather than the absolute value of the individual pitches. Contrasting the transposed melody to the simple melody condition revealed greater activation in the cortex within the intraparietal sulcus (IPS) bilaterally; control tasks did not elicit significant activity in the IPS. Moreover, a whole-brain voxel-wise regression analysis of brain oxygenation level-dependent signal showed that activity within the right IPS predicted task performance for both musicians and nonmusicians specifically in the transposed melody condition. Successful performance of the transposed melody task requires encoding and comparison of auditory patterns having different tonal reference points-thus simple tonal memory is not sufficient. Our results point to a role for the IPS in transforming high-level auditory information. We suggest that this area may support a general capacity for transformation and comparison of systematically related stimulus attributes. PMID- 19789183 TI - A multivariate analysis of age-related differences in default mode and task positive networks across multiple cognitive domains. AB - We explored the effects of aging on 2 large-scale brain networks, the default mode network (DMN) and the task-positive network (TPN). During functional magnetic resonance imaging scanning, young and older participants carried out 4 visual tasks: detection, perceptual matching, attentional cueing, and working memory. Accuracy of performance was roughly matched at 80% across tasks and groups. Modulations of activity across conditions were assessed, as well as functional connectivity of both networks. Younger adults showed a broader engagement of the DMN and older adults a more extensive engagement of the TPN. Functional connectivity in the DMN was reduced in older adults, whereas the main pattern of TPN connectivity was equivalent in the 2 groups. Age-specific connectivity also was seen in TPN regions. Increased activity in TPN areas predicted worse accuracy on the tasks, but greater expression of a connectivity pattern associated with a right dorsolateral prefrontal TPN region, seen only in older adults, predicted better performance. These results provide further evidence for age-related differences in the DMN and new evidence of age differences in the TPN. Increased use of the TPN may reflect greater demand on cognitive control processes in older individuals that may be partially offset by alterations in prefrontal functional connectivity. PMID- 19789185 TI - Temporal dynamics of selective attention during dichotic listening. AB - The ability to selectively attend to one sound and ignore other competing sounds is essential for auditory communication. Subjects in our study detected occasional changes in the frequency of amplitude modulation in sounds presented to one ear while ignoring sounds in the other ear. Neuromagnetic source analysis revealed attention-related activity in a cortical network including primary auditory cortices, posterior superior temporal gyri, inferior parietal lobules (IPLs), inferior frontal gyri (IFG), and medial frontal gyri. Time courses of event-related magnetoencephalography responses were analyzed during the interval between stimulus presentation and behavioral response. Enhanced neural responses to targets and standards in the attended ear indicated early modulation of sensitivity in the attended sensory channel. A subsequent process of discriminative stimulus selection was indexed by a response increase over time for targets and decreasing activity for standards. Enhanced responses to deviants in the unattended ear indicated discriminative processing of unattended inputs as well, though to a lesser extent than for attended stimuli. Superior temporal gyrus, planum temporale, and the IPL were prominently involved in stimulus selection, whereas medial frontal regions were linked to initiation of behavioral responses and sustained activity in IFG suggested a role in attentional control. PMID- 19789186 TI - Progress in the study of genetic disease: bringing new light to complex problems. PMID- 19789187 TI - Clinical and moral uncertainty in psychiatry: the problem of scarce resources. PMID- 19789188 TI - The ethical imperative to scale up health care services for people with severe mental disorders in low and middle income countries. AB - Most mentally ill people in low and middle income countries, where clinical services are typically scarce and mental health legal provisions often inadequate, do not receive requisite evidence based treatment. The unfortunate consequence is compromised health and well-being and lack of social integration in the community. Recent initiatives, such as the Movement for Global Mental Health, aim to improve the situation and, in so doing, take into account ethical factors that play a role in the face of inadequate care and mental health legislative frameworks. Two composite case vignettes based on the narratives of actual patients living in India are used to show how family carers resort to measures like deception, coercion and physical restraint in order to deal with challenging behaviours stemming from severe and enduring mental disorders. These actions, while violating patients' fundamental human rights, are also the consequence of the utter frustration and despair experienced by families. Scaling up mental health care based on the principle of cost effectiveness is not only a clinical imperative, but also a pivotal means to ensure that the severely mentally ill are accorded the same universal rights as those enjoyed by others. PMID- 19789189 TI - Radiological "bone within a bone" appearance with atraumatic fractures. PMID- 19789190 TI - A gene-based risk score for lung cancer susceptibility in smokers and ex-smokers. AB - BACKGROUND: Epidemiological and family studies suggest that lung cancer results from the combined effects of age, smoking and genetic factors. Chronic obstructive pulmonary disease (COPD) is also an independent risk factor for lung cancer and coexists in 40-60% of lung cancer cases. METHODS: In a two-stage case control association study, genetic markers associated with either susceptibility or protection against lung cancer were identified. In a test cohort of 439 Caucasian smokers or ex-smokers, consisting of healthy smokers and lung cancer cases, 157 candidate single nucleotide polymorphisms (SNPs) were screened. From this, 30 SNPs were identified, the genotypes (codominant or recessive model) of which were associated with either the healthy smokers (protective) or lung cancer (susceptibility) phenotype. After genotyping of this 30-SNP panel in a second validation cohort of 491 subjects and using the same protective and susceptibility genotypes from our test cohort, a 20-SNP panel was selected on the basis of independent univariate analyses. RESULTS: Using multivariate logistic regression, including the 20 SNPs, it was also found that age, history of COPD, family history of lung cancer and gender were significantly and independently associated with lung cancer. CONCLUSIONS: When numeric scores were assigned to both the SNP and demographic data, and sequentially combined by a simple algorithm in a risk model, the composite score was found to be linearly related to lung cancer risk with a bimodal distribution. Genetic data may therefore be combined with other risk variables from smokers or ex-smokers to identify individuals who are most susceptible to developing lung cancer. PMID- 19789191 TI - Efficacy of low dose dexamethasone in severe thrombocytopenia caused by dengue fever: a placebo controlled study. AB - BACKGROUND: The use of corticosteroids in the management of thrombocytopenia in dengue fever remains untested. OBJECTIVES: To test whether intravenous low dose dexamethasone is efficacious in increasing platelet count in acute severe thrombocytopenia in dengue infection. METHODS: We undertook a placebo controlled study at the Teaching Hospital, Peradeniya, Sri Lanka in July 2004. Patients with thrombocytopenia (platelet count <50x10(9)/l) were allocated to the treatment and placebo groups using the sealed envelop method. The treatment group received an initial intravenous dose of 4 mg dexamethasone, followed by 2 mg doses every 8 h for 24 h, and the placebo group received normal saline. The primary outcome was the degree of mean platelet count rise. RESULTS: Each group comprised 100 patients and their baseline data and other variables (headaches, nausea, flush, temperature, pulse, blood pressure, haematocrit, white cell count and haemoglobin) were similar. The primary outcome--mean platelet count (x10(9)/l)- increased steadily in both groups from day 1 to 4 and showed no significant difference between the two groups (p>0.05): day 1, 35 vs 35 (p = 0.70); day 2, 47 vs 43 (p = 0.19); day 3, 64 vs 59 (p = 0.31); day 4, 72 vs 78 (p = 0.55). Analysis of variance (ANOVA) statistics showed a significant linear association of mean platelet counts by days in either group (p<0.001). Regression analysis identified the day of the illness and patient age as the independent predictors of platelet count change. CONCLUSION: At a low dose regimen, dexamethasone was not effective in achieving a higher rise of platelet count in dengue infection. PMID- 19789192 TI - A case study of translating ACGME practice-based learning and improvement requirements into reality: systems quality improvement projects as the key component to a comprehensive curriculum. AB - BACKGROUND: In 2002, the Accreditation Council for Graduate Medical Education (ACGME) introduced a new requirement: residents must demonstrate competency in Practice-Based Learning and Improvement (PBLI). Training in this domain is still not consistently integrated into programmes, with few, if any, adequately going beyond knowledge of basic content and addressing all components of the requirement. AIM: To summarise the implementation of a PBLI curriculum designed to address all components of the requirement and to evaluate the impact on the practice system. METHODS: A case-study approach was used for identifying and evaluating the steps for delivering the curriculum, along with the Model for Improvement's successive Plan-Do-Study-Act (PDSA) cycles (July 2004-May 2006). DATA SOURCE: Notes from curriculum development meetings, notes and presentation slides made by teams about their projects, resident curriculum exit evaluations curriculum and interviews. RESULTS: Residents reported high levels of comfort by applying PBLI-related knowledge and skills and that the curriculum improved their ability to do various PBLI tasks. The involvement of multiple stakeholders increased. Twelve of the 15 teams' suggestions with practical systems-relevant outcomes were implemented and sustained beyond residents' project periods. While using the traditional PDSA cycles was helpful, there were limitations. CONCLUSION: A PBLI curriculum that is centred around practice-based quality improvement projects can fulfil the objectives of this ACGME competency while accomplishing sustained outcomes in quality improvement. A comprehensive curriculum is an investment but offers organisational rewards. We propose a more realistic and informative representation of rapid PDSA cycle changes. PMID- 19789193 TI - How-to guide on biomarkers: biomarker definitions, validation and applications with examples from cardiovascular disease. AB - A biomarker is a characteristic that can be objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes or pharmacological responses to a therapeutic intervention. Many commonly used tests in clinical practice can serve as biomarkers. The majority have been identified on the basis of insight or underlying physiology or biological mechanisms. With increasing knowledge and practical experience, some of these tests have evolved into a measurable end point in clinical research, applied as an indicator of change, for the better or worse. The traditional identification of biomarkers as an observational side product of clinical practice is increasingly turning into an industrialised process of biomarker discovery, supported by standardised paradigms of biomarker validation and translation from bench to bedside. The potential utility of biomarkers in clinical studies, investigating either new treatments or new strategies of clinical management, is capitalizing on recent advances in technology, from molecular sciences to powerful imaging, bearing the promise of expediting the discovery of new treatments. In the active search for new biomarkers, many potential candidates can be considered side by side, allowing many failures but a few great winners. Biomarker discovery is an ongoing process, with translation being tested de novo in every single study, providing us with the opportunity to revise our knowledge of the complex scheme of human physiology and pathophysiology. In predicting what Nature has set in place, advances in technology may be only the first step. This review provides an introduction to the field of biomarker discovery and translation. It deals with evolving nomenclature, basic principles of the validation process, and, drawing on examples in cardiovascular medicine, their significance for clinical application. PMID- 19789194 TI - Narrow complex (supraventricular) tachycardias. AB - Patients experiencing a narrow complex tachycardia are usually at a lower risk than those in whom a broad complex tachycardia occurs. Therefore, in the UK cardiologists are frequently involved in broad complex dysrhythmias at an early stage, while general physicians and general practitioners will often have greater involvement in the management of patients with narrow complex arrhythmias. We describe the management of narrow complex arrhythmias likely to be encountered, including the ubiquitous atrial fibrillation. PMID- 19789195 TI - A UK consensus on the management of the bladder in multiple sclerosis. AB - Bladder symptoms in multiple sclerosis (MS) are common and distressing but also highly amenable to treatment. A meeting of stakeholders involved in patients' continence care, including neurologists, urologists, primary care, MS nurses and nursing groups was recently convened to formulate a UK consensus for management. National Institute for Health and Clinical Excellence (NICE) criteria were used for producing recommendations based on a review of the literature and expert opinion. It was agreed that in the majority of cases, successful management could be based on a simple algorithm which includes using reagent sticks to test for urine infection and measurement of the post micturition residual urine volume. This is in contrast with published guidelines from other countries which recommend cystometry. Throughout the course of their disease, patients should be offered appropriate management options for treatment of incontinence, the mainstay of which is antimuscarinic medications, in combination, if necessary, with clean intermittent self-catheterisation. The evidence for other measures, including physiotherapy, alternative strategies aimed at improving bladder emptying, other medications and detrusor injections of botulinum toxin A was reviewed. The management of urinary tract infections as well as the bladder problems as part of severe disability were discussed and recommendations agreed. PMID- 19789196 TI - The three second consultation. PMID- 19789198 TI - Individual monitoring at accelerator centres. AB - The accurate determination of personal dose equivalent requires the proper use of appropriate radiological quantities and units, knowledge of the dose equivalent response of the personal dosemeters used and detailed information on the fluence as well as dose equivalent spectra at the workplaces. This information can then be used to select the appropriate dosemeters, to set up the optimum calibration conditions and to introduce, in case of need, normalisation factors for application in specific radiation fields. High-energy neutrons contribute significantly to the radiation fields around high-energy particle accelerators. Examples for procedures and methods to determine personal dose equivalent at accelerator centres are given. PMID- 19789197 TI - The relationship between cognitive function and physical performance in older women: results from the women's health initiative memory study. AB - BACKGROUND: Cognitive function and physical performance are associated, but the common sequence of cognitive and physical decline remains unclear. METHODS: In the Women's Health Initiative Memory Study (WHIMS) clinical trial, we examined associations at baseline and over a 6-year follow-up period between the Modified Mini-Mental State (3MS) Examination and three physical performance measures (PPMs): gait speed (meters/second), chair stands (number of stands in 15 seconds), and grip strength (kilograms). Using mixed models, we examined the baseline 3MS as predictor of change in PPM, change in the 3MS as predictor of change in PPM, and baseline PPM as predictors of 3MS change. RESULTS: Among 1,793 women (mean age = 70.3 years, 89% white, and mean 3MS score = 95.1), PPM were weakly correlated with 3MS-gait speed: r = .06, p = .02; chair stands: r = .09, p < .001; and grip strength: r = .10, p < .001. Baseline 3MS score was associated with subsequent PPM decline after adjustment for demographics, comorbid conditions, medications, and lifestyle factors. For every SD (4.2 points) higher 3MS score, 0.04 SD (0.04 m/s) less gait speed and 0.05 SD (0.29 kg) less grip strength decline is expected over 6 years (p /=50, and European League against Rheumatism (EULAR) moderate to good response) in patients with active long-standing RA and inadequate response to anti-TNF agents or traditional DMARDs. METHODS: RTX was used in 110 RA patients in six different Italian centres. The mean disease activity score on 28 joints (DAS28) was 6.4 +/- 0.99 and the mean HAQ was 1.63 +/ 0.68 at baseline. Thirty-two patients (29.1%) underwent RTX after the failure of DMARD therapy, 37 (33.6%) had failed or were intolerant to at least two anti-TNF agents, and 41 (37.3%) had failed or were intolerant to one anti-TNF agent. Univariate and multivariate analyses were performed. RESULTS: The number of previous anti-TNF agents (P = 0.043), HAQ (P = 0.023), RF positivity (P < 0.0001) and anti-cyclic citrullinated peptide (anti-CCP) positivity (P = 0.003) were associated with ACR response >or=50 between month +4 and month +6 after starting RTX by univariate analysis. Multivariate analysis confirmed that a lower HAQ, a lower number of anti-TNF agents failed before RTX and RF positivity, but not anti CCP positivity, were the selected variables associated with an ACR response >or=50, with an accuracy of 84% of the model. Only RF positivity correlated with EULAR moderate to good response both in the univariate and in the multivariate analysis, with an accuracy of 79% of the model. CONCLUSION: RF-positive rather than anti-CCP-positive RA patients with lower baseline disability and a lower number of previously failed TNF blockers may be the best candidates to RTX. PMID- 19789203 TI - Somatostatin receptor expression in an epitheloid hemangioma causing oncogenic osteomalacia. PMID- 19789204 TI - Recessive isolated growth hormone deficiency and mutations in the ghrelin receptor. AB - CONTEXT: Both GH releasing- and orexigenic properties of the gut-to-brain hormone ghrelin are mediated by the GH secretagogue receptor (GHSR). Recently in several patients, a missense mutation (p.A204E) resulting in a complete loss of GHSR constitutive activity has been implicated in short stature with dominant transmission. OBJECTIVE: The objective of the study was to describe the phenotype associated with partial isolated GH deficiency of a young patient born to unrelated parents and identify the molecular basis of his disease. RESULTS: The growth delay (-3.0 sd) was associated with recurrent episodes of abdominal pain, vomiting, ketosis, hypoglycemia, and a low body mass index. GHSR sequencing revealed that the patient was compound heterozygous for two new defects: 1) an early occurring transition predicting a premature stop codon (c.6G>A, p.W2X) inherited from his unaffected father, therefore strongly arguing against haploinsufficiency as a disease mechanism, and 2) a missense mutation (c.709A>T, p.R237W) inherited from his healthy mother, involving an evolutionary invariant residue from the third intracellular loop. In vitro experiments showed that the p.R237W mutation would result in a partial loss of constitutive activity of the receptor, whereas both its ability to respond to ghrelin and its cell surface expression are preserved. CONCLUSION: These data, which describe the first case of recessive partial isolated GH deficiency due to GHSR mutations and emphasize the physiological importance of the GHSR in somatic growth, are discussed in light of the dominantly expressed p.A204E mutation. PMID- 19789205 TI - The association of endogenous sex hormones, adiposity, and insulin resistance with incident diabetes in postmenopausal women. AB - CONTEXT: In postmenopausal women, endogenous bioavailable testosterone (T) and estradiol (E2) have been positively associated, and SHBG has been negatively associated, with incident type 2 diabetes (T2DM). Previous studies have not explored possible factors explaining these relationships. OBJECTIVE: Our objective was to examine the association of endogenous sex hormones with incident T2DM in postmenopausal women and possible explanatory factors. DESIGN, SETTING, AND PARTICIPANTS: The Multi-Ethnic Study of Atherosclerosis (MESA) is a prospective study that included 1612 postmenopausal women aged 45-84 yr, followed between the years 2000-2006, who were not taking hormone replacement therapy, had no prevalent cardiovascular disease or diabetes, and had complete ascertainment of sex hormones. MAIN OUTCOME MEASURES: T2DM was defined based on fasting glucose and/or treatment for diabetes. RESULTS: There were 116 incident cases of diabetes during follow-up. Across higher quartiles of bioavailable T and E2 and lower quartiles of SHBG, we found significantly greater hazards of developing incident T2DM (all P for trend .05). The 75th percentile patient radiation doses normalized with weight banding were not significantly different from those that were uncorrected for body habitus. Proposed initial reference levels for various interventional procedures are provided for reference air kerma, kerma-area product, fluoroscopy time, and number of images. CONCLUSION: Sufficient data exist to permit an initial proposal of values for reference levels for interventional radiologic procedures in the United States. For ease of use, reference levels without correction for body habitus are recommended. A national registry of radiation-dose data for interventional radiologic procedures is a necessary next step to refine these reference levels. PMID- 19789227 TI - Radiologic and nuclear medicine studies in the United States and worldwide: frequency, radiation dose, and comparison with other radiation sources--1950 2007. AB - The U.S. National Council on Radiation Protection and Measurements and United Nations Scientific Committee on Effects of Atomic Radiation each conducted respective assessments of all radiation sources in the United States and worldwide. The goal of this article is to summarize and combine the results of these two publicly available surveys and to compare the results with historical information. In the United States in 2006, about 377 million diagnostic and interventional radiologic examinations and 18 million nuclear medicine examinations were performed. The United States accounts for about 12% of radiologic procedures and about one-half of nuclear medicine procedures performed worldwide. In the United States, the frequency of diagnostic radiologic examinations has increased almost 10-fold (1950-2006). The U.S. per-capita annual effective dose from medical procedures has increased about sixfold (0.5 mSv [1980] to 3.0 mSv [2006]). Worldwide estimates for 2000-2007 indicate that 3.6 billion medical procedures with ionizing radiation (3.1 billion diagnostic radiologic, 0.5 billion dental, and 37 million nuclear medicine examinations) are performed annually. Worldwide, the average annual per-capita effective dose from medicine (about 0.6 mSv of the total 3.0 mSv received from all sources) has approximately doubled in the past 10-15 years. PMID- 19789228 TI - Diagnosis of internal derangement of the knee at 3.0-T MR imaging: 3D isotropic intermediate-weighted versus 2D sequences. AB - PURPOSE: To compare three-dimensional (3D) isotropic fast spin-echo (SE) intermediate-weighted magnetic resonance (MR) imaging with two-dimensional (2D) fast SE MR imaging-both performed at 3.0 T-for performance in the diagnosis of internal derangements of the knee. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant study, and the requirement for informed consent was waived. The authors retrospectively reviewed 87 knee MR images obtained in 85 patients who had undergone both 3D isotropic and 2D MR examinations of the knee at 3.0 T and subsequent arthroscopic surgery. The 2D MR images included intermediate-weighted coronal and sagittal images, intermediate weighted axial images with fat saturation, and T2-weighted sagittal images. The 3D isotropic MR images were obtained with multiplanar reformation (MPR), a fast SE intermediate-weighted sequence, and a reconstruction voxel size of 0.5 x 0.5 x 0.5 mm. Two radiologists retrospectively and independently evaluated the 2D and 3D data sets, at different sessions, for the presence of medial meniscus (MM), lateral meniscus (LM), anterior cruciate ligament (ACL), and posterior cruciate ligament (PCL) tears. These interpretations were compared with the arthroscopic surgery findings. The statistical differences between the sensitivities, specificities, and accuracies of the two methods were determined at McNemar testing, with surgical findings serving as the reference standard. Interobserver agreement was calculated by using kappa coefficients. RESULTS: For both reviewers, the sensitivity, specificity, and accuracy of both MR techniques were higher than 95% for the diagnosis of ACL and PCL tears, higher than 85% for the diagnosis of MM tears, and higher than 80% for the diagnosis of LM tears. There were no significant differences in sensitivity, specificity, or accuracy between the two methods. Interobserver agreement for evaluation of all lesions was excellent and ranged from 0.81 (LM tears evaluated with 3D and 2D sequences) to 0.93 (ACL tears evaluated with 3D and 2D sequences, PCL tears evaluated with 2D sequence, and MM tears evaluated with 3D sequence). CONCLUSION: The performance of 3D isotropic fast SE intermediate-weighted MR imaging with MPR was not significantly different from that of 2D MR imaging in the diagnosis of cruciate ligament and meniscal tears of the knee. PMID- 19789229 TI - Screening-detected breast cancers: discordant independent double reading in a population-based screening program. AB - PURPOSE: To analyze discordant and concordant screening-detected breast cancers in a nationwide population-based screening program by using independent double reading with consensus. MATERIALS AND METHODS: The study is a part of the evaluation of the Norwegian Breast Cancer Screening Program and is covered by the Cancer Registry regulation. Analyses were based on prospective initial interpretation scores of 1 033 870 screenings that included 5611 breast cancers. A five-point scale for probability of cancer was used in the initial interpretation. Screening mammograms with a score of 2 or higher by either radiologist were discussed at consensus meetings where the decision whether to recall was made. A score of 1 by one reader and 2 or higher by the other was defined as a discordant interpretation and discordant cancer, whereas a score of 2 or higher by both readers was defined as a concordant recall and cancer. RESULTS: Discordant interpretation was present in 5.3% (54 447 of 1 033 870) of the screenings, whereas 2.1% (21 928 of 1 033 870) were concordant positive interpretations. Of the screening-detected cancers, 23.6% (1326 of 5611) were diagnosed in women who were recalled because of screenings with discordant interpretation. One hundred seventeen interval breast cancers were diagnosed among the 40 312 screenings that were dismissed at consensus; these were 6.5% of all interval cancers. A significantly higher proportion of microcalcifications alone was present in discordant cancers (24.9% [304 of 1219]) compared with concordant cancers (17.7% [704 of 3972]) (P < .001). CONCLUSION: Independent double reading with consensus at mammography screening has the potential to increase the cancer detection rate compared with single reading. Mammograms with microcalcifications alone are significantly more common among discordant cancers. PMID- 19789230 TI - Cerebral amyloidosis: postmortem detection with human 7.0-T MR imaging system. AB - PURPOSE: To explore the ability of whole-body 7.0-T magnetic resonance (MR) imaging to depict differences in aspects of the cerebral cortex of postmortem human brain specimens with cerebral amyloid beta deposition in connection with Alzheimer disease (AD), Down syndrome, or sporadic or hereditary cerebral amyloid angiopathy (CAA) and control brain specimens lacking such deposition. MATERIALS AND METHODS: This study was approved by the local institutional review board. In all cases, informed consent was obtained to perform autopsy and to use the tissues for research purposes. T2- and T2*-weighted MR imaging was performed in formalin-fixed samples of brain tissue from six subjects with AD changes, seven with CAA, and five subjects without immunohistochemical evidence of cerebral amyloid beta deposition. All MR images were visually assessed for hypointense foci in and inhomogeneity of the cortex. Sensitivity, specificity, and kappa values of these MR imaging features in the detection of histologic changes were calculated. RESULTS: High-spatial-resolution 0.3 x 0.3 x 0.3-mm three-dimensional T2*-weighted images revealed hypointense foci, inhomogeneity of the cortex, or both in all specimens with brain amyloid beta deposition. These MR imaging features were observed in none of the control specimens. CONCLUSION: The finding of postmortem susceptibility-weighted changes in the cerebral cortex of patients with cerebral amyloidosis with a human 7.0-T MR imaging system opens up the possibility of obtaining in vivo radiologic evidence of cerebral amyloid beta deposition. PMID- 19789232 TI - Focal liver lesions: detection and characterization at double-contrast liver MR Imaging with ferucarbotran and gadobutrol versus single-contrast liver MR imaging. AB - PURPOSE: To retrospectively compare, in a multiobserver study, double-contrast material (sequential administration of ferucarbotran and gadobutrol) magnetic resonance (MR) imaging with single-contrast-material ferucarbotran-enhanced and dynamic postferucarbotran gadobutrol-enhanced MR imaging for the detection and characterization of benign and malignant focal liver lesions. MATERIALS AND METHODS: This study was institutional review board approved, and the requirement for informed patient consent was waived. Eighty-nine patients with a total of 128 focal liver lesions underwent double-contrast liver MR imaging (nonenhanced, ferucarbotran-enhanced, and dynamic postferucarbotran gadobutrol-enhanced MR imaging performed during one session). Four readers independently reviewed the data sets during three reading sessions focused on focal liver lesion detection and characterization: In session 1, the nonenhanced and dynamic postferucarbotran gadobutrol-enhanced images obtained at double-contrast MR imaging were analyzed. In session 2, the nonenhanced and ferucarbotran-enhanced images were analyzed. In session 3, all MR images were analyzed together. The diagnostic performance of each MR technique and each reader was evaluated by using receiver operating characteristic (ROC) analysis; differences between postferucarbotran gadobutrol enhanced, ferucarbotran-enhanced, and double-contrast MR imaging were assessed at Wilcoxon signed rank testing; and interreader agreement was assessed at Cohen kappa analysis. Histopathologic confirmation or an unchanged clinical course or MR finding was the reference standard. RESULTS: The four readers' detection of the benign and malignant lesions was not significantly different (P > or = .11) between the three MR techniques. The benign and malignant focal liver lesions were differentiated with significantly higher confidence (P < or = .01) on the double-contrast (area under ROC curve [A(z)] = 0.988) and ferucarbotran-enhanced (A(z) = 0.985) MR images than on the dynamic gadobutrol-enhanced images (A(z) = 0.963). Accuracy in the diagnosis of hepatocellular carcinoma (HCC) was highest (P = .02) and confidence in the final diagnosis of HCC (P = .001) or metastasis (P = .049) was significantly higher with double-contrast imaging. CONCLUSION: In select cases, double-contrast MR imaging can improve diagnostic accuracy and increase confidence in characterizing focal liver lesions as HCC or metastasis. PMID- 19789231 TI - Autoimmune thyroid disease: arterial spin-labeling perfusion MR imaging. AB - PURPOSE: To assess thyroid perfusion in patients with autoimmune thyroid diseases compared with that in healthy control subjects by using an arterial spin-labeling (ASL) magnetic resonance (MR) technique and to assess whether thyroid perfusion is associated with endocrine laboratory abnormalities. MATERIALS AND METHODS: This study was approved by the local institutional review board. All participants gave written informed consent. Perfusion imaging of the thyroid gland was performed in 10 patients with Graves disease (GD) and 10 patients with Hashimoto thyroiditis (HT). Ten healthy individuals served as control subjects. Perfusion imaging was performed with a 1.5-T MR unit by using a flow-sensitive alternating inversion recovery-true fast imaging with steady-state precession technique. Perfusion maps of the entire thyroid gland were calculated on the basis of extended Bloch equations. Analysis of variance with a post hoc test (Tukey honestly significant difference) was performed to assess differences in perfusion between groups. Associations between perfusion and laboratory parameters were analyzed with univariate regression analysis. RESULTS: Mean thyroid perfusion was 1596 mL/min/100 g +/- 436 (standard deviation) in patients with GD, 825 mL/min/100 g +/- 264 in patients with HT, and 491 mL/min/100 g +/- 89 in healthy control subjects. Perfusion was significantly higher in patients with GD (P < .0001) and those with HT (P < .05) than in control subjects. A significant difference in thyroid perfusion was detected between the two autoimmune entities (P < .0001). In patients with GD, significant associations were found between perfusion and serum concentrations of free thyroid hormones and anti-thyroid stimulating hormone receptor antibodies (P < .05 for all). CONCLUSION: Quantitative ASL perfusion imaging of the thyroid gland revealed significant perfusion differences in the autoimmune thyroid diseases GD and HT. Absolute quantification of thyroid perfusion may be useful in the clinical assessment of autoimmune thyroid disorders and when monitoring therapeutic treatment in GD. PMID- 19789233 TI - Nephrogenic systemic fibrosis: change in incidence following a switch in gadolinium agents and adoption of a gadolinium policy--report from two U.S. universities. AB - PURPOSE: To determine the incidence of nephrogenic systemic fibrosis (NSF) in tertiary care centers of two U.S. universities following the switch from the use of gadodiamide to gadobenate dimeglumine and gadopentetate dimeglumine, and the adoption of restrictive gadolinium-based contrast agent (GBCA) policies. MATERIALS AND METHODS: Institutional review board approval with waiver of informed consent was obtained for this Health Insurance Portability and Accountability Act-compliant retrospective study. NSF patients were identified between January 2000 and December 2006 at center A and between October 2003 and February 2007 at center B (preadoption periods); and from June 2007 to June 2008 at both centers (postadoption period). The numbers of patients who underwent gadolinium-enhanced magnetic resonance at each center, patients at risk for NSF at center A, and dialysis patients at center B were identified in the pre- and postadoption periods. Gadodiamide was the only agent used in the preadoption period. Gadobenate dimeglumine and gadopentetate dimeglumine were the agents used in the postadoption period. A restrictive GBCA policy that limits the use and dose of GBCAs in patients with risk factors was adopted in the postadoption period. Follow-up lasted 9 months from July 2008 to March 2009. Corresponding incidences were determined and compared with the Fisher exact test. RESULTS: Respective total benchmark incidence of NSF at both centers, at-risk incidence of NSF at center A, and dialysis incidence of NSF at center B were 37 of 65 240, 28 of 925, and nine of 312 in the preadoption period and zero of 25 167, zero of 147, and zero of 402 in the postadoption period. All three incidences demonstrated significant differences (P < .0001, .024, and .001, respectively) between the pre- and postadoption periods. CONCLUSION: Following the switch from gadodiamide to gadobenate dimeglumine and gadopentetate dimeglumine, and the adoption of restrictive GBCA policies, no NSF cases were observed at either center. PMID- 19789234 TI - When radiologists perform best: the learning curve in screening mammogram interpretation. AB - PURPOSE: To examine changes in screening mammogram interpretation as radiologists with and radiologists without fellowship training in breast imaging gain clinical experience. MATERIALS AND METHODS: In an institutional review board-approved HIPAA-compliant study, the performance of 231 radiologists who interpreted screen film screening mammograms from 1996 to 2005 at 280 facilities that contribute data to the Breast Cancer Surveillance Consortium was examined. Radiologists' demographic data and clinical experience levels were collected by means of a mailed survey. Mammograms were grouped on the basis of how many years the interpreting radiologist had been practicing mammography, and the influence of increasing experience on performance was examined separately for radiologists with and those without fellowship training in breast imaging, taking into account case-mix and radiologist-level differences. RESULTS: A total of 1 599 610 mammograms were interpreted during the study period. Performance for radiologists without fellowship training improved most during their 1st 3 years of clinical practice, when the odds of a false-positive reading dropped 11%-15% per year (P < .015) with no associated decrease in sensitivity (P > .89). The number of women recalled per breast cancer detected decreased from 33 for radiologists in their 1st year of practice to 24 for radiologists with 3 years of experience to 19 for radiologists with 20 years of experience. Radiologists with fellowship training in breast imaging experienced no learning curve and reached desirable goals during their 1st year of practice. CONCLUSION: Radiologists' interpretations of screening mammograms improve during their first few years of practice and continue to improve throughout much of their careers. Additional residency training and targeted continuing medical education may help reduce the number of work-ups of benign lesions while maintaining high cancer detection rates. PMID- 19789235 TI - Treatment of distal internal carotid artery aneurysm with the willis covered stent: a prospective pilot study. AB - PURPOSE: To evaluate the flexibility and efficacy of the Willis covered stent in the treatment of distal internal carotid artery (DICA) aneurysms. MATERIALS AND METHODS: The study was approved by the authors' institutional review board, and the research was conducted by the authors' institution and the MicroPort Medical Company (Shanghai, China). Thirty-one patients with 33 DICA aneurysms were considered for treatment with a Willis covered stent. The angiographic assessments were categorized as complete or incomplete occlusion. The data on technical success, initial and final angiographic results, mortality, morbidity, and final clinical outcome were collected, and follow-up was performed at 1, 3, 6, and 12 months and yearly after the procedures. RESULTS: Navigation and deployment of the covered stents were successful in 97.6% (41 of 42; 95% confidence interval [CI]: 93%, 102%) of the attempted stent placement procedures. The initial angiographic results showed a complete occlusion in 23 patients with 25 aneurysms (of 32 aneurysms, 78.1% [95% CI: 63%, 93%]) and an incomplete occlusion in seven patients with seven aneurysms (21.9%). The angiographic follow up (mean, 14 months [95% CI: 12, 15 months]) findings exhibited a complete occlusion in 27 patients with 29 aneurysms (of 31 aneurysms, 93.5% [95% CI: 84%, 103%]) and an incomplete occlusion in two aneurysms (6.5%), with a mild in-stent stenosis in two patients. The clinical follow-up (mean, 27 months [95% CI: 23, 30 months]) demonstrated that 15 patients experienced a full recovery and 14 patients improved. CONCLUSION: The preliminary results demonstrate good flexibility and efficacy of the Willis covered stent in the treatment of DICA aneurysms in selected patients; longer follow-up and expanded clinical trials are needed. PMID- 19789236 TI - Time-of-arrival mapping at three-dimensional time-resolved contrast-enhanced MR angiography. AB - This study was HIPAA compliant and institutional review board approved, and informed consent was obtained from all volunteers. The authors describe a method for generating a time-of-arrival (TOA) map of intravenously administered contrast material, as observed in a time series of three-dimensional (3D) contrast material-enhanced magnetic resonance (MR) angiograms. The method may enable visualization and interpretation, on one 3D image, of the temporal enhancement patterns that occur in the vasculature. Colorization of TOA values may further aid interpretation. The quality of the results depends not only on the adequacy of the frame rate, spatial resolution, and signal-to-noise ratio of the MR image acquisition method but also on the accuracy and clarity with which the leading edge of the contrast material bolus is depicted. The criteria for optimizing these parameters are described. The TOA mapping technique is demonstrated by using vascular studies of the hands, brain, and lower leg regions. PMID- 19789237 TI - Nephrogenic systemic fibrosis in rats treated with erythropoietin and intravenous iron. AB - PURPOSE: To use a rat model for nephrogenic systemic fibrosis (NSF) that was administered high-dose gadodiamide to determine whether the co-administration of erythropoietin (Epo) and intravenous iron potentiated development of skin lesions that are thought to be a marker for the development of NSF. MATERIALS AND METHODS: The local committee for animal research approved this study. High-dose gadodiamide was administered, 2.5 mmol per kilogram of body weight for 20 days, or 500 times the U.S. Food and Drug Administration-approved dose, to four groups of Hannover-Wistar rats: group A, gadodiamide only; B, gadodiamide and Epo; C, gadodiamide and intravenous iron; and D, gadodiamide, Epo, and intravenous iron. The animals were sacrificed 7 days after final injection, and the authors examined dermal histologic findings from each animal and measured metal deposition by using inductively coupled plasma mass spectrometry. To compare the effect of metal deposition and cellularity, a linear mixed effects model was used to fit the data within PROC MIXED modeled with rat-specific random effects, and subsequently a Dunnett adjustment was performed. RESULTS: Rats treated with gadodiamide and both Epo and intravenous iron (group D) had significantly worse skin lesions at gross and histologic analysis (P = .004) compared with the rate treated with gadodiamide only (group A). Group D also had increased levels of deposited gadolinium as measured by means of mass spectrometry (P = .012). CONCLUSION: With a rat model similar to those already existing in the literature, skin changes were more marked in animals exposed to gadodiamide, Epo, and intravenous iron, as opposed to those animals exposed to gadodiamide alone; this experiment suggests that great caution may be warranted when prescribing gadolinium-based contrast agents to patients receiving Epo and intravenous iron. PMID- 19789238 TI - Peripheral vasculature: high-temporal- and high-spatial-resolution three dimensional contrast-enhanced MR angiography. AB - PURPOSE: To prospectively evaluate the feasibility of performing high-spatial resolution (1-mm isotropic) time-resolved three-dimensional (3D) contrast material-enhanced magnetic resonance (MR) angiography of the peripheral vasculature with Cartesian acquisition with projection-reconstruction-like sampling (CAPR) and eightfold accelerated two-dimensional (2D) sensitivity encoding (SENSE). MATERIALS AND METHODS: All studies were approved by the institutional review board and were HIPAA compliant; written informed consent was obtained from all participants. There were 13 volunteers (mean age, 41.9; range, 27-53 years). The CAPR sequence was adapted to provide 1-mm isotropic spatial resolution and a 5-second frame time. Use of different receiver coil element sizes for those placed on the anterior-to-posterior versus left-to-right sides of the field of view reduced signal-to-noise ratio loss due to acceleration. Results from eight volunteers were rated independently by two radiologists according to prominence of artifact, arterial to venous separation, vessel sharpness, continuity of arterial signal intensity in major arteries (anterior and posterior tibial, peroneal), demarcation of origin of major arteries, and overall diagnostic image quality. MR angiographic results in two patients with peripheral vascular disease were compared with their results at computed tomographic angiography. RESULTS: The sequence exhibited no image artifact adversely affecting diagnostic image quality. Temporal resolution was evaluated to be sufficient in all cases, even with known rapid arterial to venous transit. The vessels were graded to have excellent sharpness, continuity, and demarcation of the origins of the major arteries. Distal muscular branches and the communicating and perforating arteries were routinely seen. Excellent diagnostic quality rating was given for 15 (94%) of 16 evaluations. CONCLUSION: The feasibility of performing high-diagnostic-quality time-resolved 3D contrast-enhanced MR angiography of the peripheral vasculature by using CAPR and eightfold accelerated 2D SENSE has been demonstrated. PMID- 19789239 TI - RGD-labeled USPIO inhibits adhesion and endocytotic activity of alpha v beta3 integrin-expressing glioma cells and only accumulates in the vascular tumor compartment. AB - PURPOSE: To investigate the biologic effect of arginine-glycine-aspartic acid (RGD)-labeled ultrasmall superparamagnetic iron oxide (USPIO) (referred to as RGD USPIO) on human umbilical vein endothelial cells (HUVECs), ovarian carcinoma (MLS) cells, and glioblastoma (U87MG) cells and on U87MG xenografts in vivo. MATERIALS AND METHODS: All experiments were approved by the governmental review committee on animal care.USPIOs were coated with integrin-specific (RGD) or unspecific (arginine-alanine-aspartic acid [RAD]) peptides. USPIO uptake in HUVECs, MLS cells, and U87MG cells and in U87MG tumor xenografts was determined with T2 magnetic resonance (MR) relaxometry in 16 nude mice. Cells and tumors were characterized by using immunofluorescence microscopy. Trypan blue staining and lactate dehydrogenase assay were used to assess cytotoxicity. Statistical evaluation was performed by using a Mann-Whitney test or a linear mixed model with random intercept for the comparison of data from different experiments. Post hoc pairwise comparisons were adjusted according to a Tukey test. RESULTS: HUVECs and MLS cells internalized RGD-USPIOs significantly more than unspecific probes. Controversially, U87MG cells accumulated RGD-USPIOs to a lesser extent than USPIO. Furthermore, only in U87MG cells, free RGD and alpha(v)beta(3) integrin blocking antibodies strongly reduced endocytosis of nonspecific USPIOs. This was accompanied by a loss of cadherin-dependent intercellular contacts, which could not be attributed to cell damage. In U87MG tumors, RGD-USPIO accumulated exclusively at the neovasculature but not within tumor cells. The vascular accumulation of RGD-USPIO caused significantly higher changes of the R2 relaxation rate of tumors than observed for USPIO. CONCLUSION: In glioma cells with unstable intercellular contacts, inhibition of alpha(v)beta(3) integrins by antibodies and RGD and RGD-USPIO disintegrated intercellular contacts and reduced endocytotic activity, illustrating the risk of inducing biologic effects by using molecular MR probes. PMID- 19789241 TI - Repeat contrast medium reactions in premedicated patients: frequency and severity. AB - PURPOSE: To determine the frequency, type, and severity of breakthrough and repeat breakthrough reactions to iodinated low-osmolality contrast medium (LOCM) in patients who were premedicated with corticosteroids and antihistamines. MATERIALS AND METHODS: Institutional review board approval was obtained, and informed consent was waived for this retrospective HIPAA-compliant analysis. One hundred ninety breakthrough allergic-like reactions to intravenous LOCM in 175 patients with a history of contrast medium reactions were reviewed. The repeat breakthrough reactions that resulted from 197 additional LOCM-enhanced examinations performed in 58 patients after the initial breakthrough reaction were also reviewed. The Fisher exact test was used to determine if certain risk factors were associated with an increased risk of a moderate or severe breakthrough reaction. Subgroup analysis was performed to determine if the contrast medium type, contrast medium volume, and/or time between the initial (index) and breakthrough reactions affected the breakthrough reaction severity. RESULTS: Of 128 breakthrough reactions in which the index reaction severity was known, 103 (81%) were of a severity similar to that of the index reaction, 15 (12%) were less severe, and 10 (8%) were more severe. The severity of the breakthrough reactions in the patients with a mild index reaction was usually (in 94 [91%] of 103 reactions) mild. When the index reaction was severe, the breakthrough reaction was usually moderate or severe (in eight [42%] of 19 cases and four [67%] of six cases, respectively). The majority (174 [88%] of 197) of LOCM injections after the initial breakthrough reaction did not result in a repeat breakthrough reaction. Breakthrough reactions were significantly more likely to be moderate or severe in patients with a history of chronic oral corticosteroid use (P = .01), drug (P = .04) or severe (P < .001) allergies, or allergies to four or more allergens (P = .01). CONCLUSION: Breakthrough reactions are usually similar in severity to the index reaction, and subsequent contrast medium injections usually do not induce repeat breakthrough reactions. Breakthrough reactions are more likely to be moderate or severe in patients with certain risk factors. PMID- 19789240 TI - Differentiation of recurrent glioblastoma multiforme from radiation necrosis after external beam radiation therapy with dynamic susceptibility-weighted contrast-enhanced perfusion MR imaging. AB - PURPOSE: To investigate whether cerebral blood volume (CBV), peak height (PH), and percentage of signal intensity recovery (PSR) measurements derived from the results of T2-weighted dynamic susceptibility-weighted contrast material-enhanced (DSC) magnetic resonance (MR) imaging performed after external beam radiation therapy (EBRT) can be used to distinguish recurrent glioblastoma multiforme (GBM) from radiation necrosis. MATERIALS AND METHODS: Fifty-seven patients were enrolled in this HIPAA-compliant institutional review board-approved retrospective study after they received a diagnosis of GBM, underwent EBRT, and were examined with DSC MR imaging, which revealed progressive contrast enhancement within the radiation field. A definitive diagnosis was established at subsequent surgical resection or clinicoradiologic follow-up. Regions of interest were retrospectively drawn around the entire contrast-enhanced region. This created T2-weighted signal intensity-time curves that produced three cerebral hemodynamic MR imaging measurements: CBV, PH, and PSR. Welch t tests were used to compare measurements between groups. RESULTS: Mean, maximum, and minimum relative PH and relative CBV were significantly higher (P < .01) in patients with recurrent GBM than in patients with radiation necrosis. Mean, maximum, and minimum relative PSR values were significantly lower (P < .05) in patients with recurrent GBM than in patients with radiation necrosis. CONCLUSION: These findings suggest that DSC perfusion MR imaging may be used to differentiate recurrent GBM from EBRT-induced radiation necrosis. PMID- 19789242 TI - Value-of-information analysis to guide future research in colorectal cancer screening. AB - PURPOSE: To identify the most useful areas for research in colorectal cancer (CRC) screening by using a value-of-information analysis. MATERIALS AND METHODS: Cost-effectiveness of screening strategies, including colonoscopy, computed tomographic (CT) colonography, flexible sigmoidoscopy, and barium enema examination, were compared by using a Markov model. Monetary net benefit (NB), a measure of cost-effectiveness, was calculated by multiplying effect (life-years gained) by willingness to pay (100,000 dollars per life-year gained) and subtracting cost. A value-of-information analysis was used to estimate the expected benefit of future research that would eliminate the decision uncertainty. RESULTS: In the reference-case analysis, colonoscopy was the optimal test with the highest NB (1945 dollars per subject invited for screening compared with 1862 dollars, 1717 dollars, and 1653 dollars for CT colonography, flexible sigmoidoscopy, and barium enema examination, respectively). Results of probabilistic sensitivity analysis indicated that colonoscopy was the optimal choice in only 45% of the simulated scenarios, whereas CT colonography, flexible sigmoidoscopy, and barium enema examination were the optimal strategies in 23%, 16%, and 15% of the scenarios, respectively. Only two parameters were responsible for most of this uncertainty about the optimal test for CRC screening: the increase in adherence with less invasive tests and CRC natural history. The expected societal monetary benefit of further research in these areas was estimated to be more than 15 billion dollars. CONCLUSION: Results of value-of information analysis show that future research on the optimal test for CRC screening has a large societal impact. Priority should be given to research on the increase in adherence with screening by using less invasive tests and to better understanding of the natural history of CRC. PMID- 19789243 TI - Peritoneal metastasis: detection with 16- or 64-detector row CT in patients undergoing surgery for gastric cancer. AB - PURPOSE: To retrospectively measure the diagnostic performance of prospective computed tomographic (CT) results obtained by using 16- or 64-detector row scanners in the detection of peritoneal metastases (PMs) in patients with advanced gastric cancer. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the need to obtain patient consent. In 498 patients with gastric cancer (stage >or= T2) who were undergoing surgery, the presence of PM was prospectively rated as grade 0 (absent), grade 1 (equivocal), or grade 2 (present) on CT scans (0.67 or 2 mm thick) that were interpreted by interactively adjusting the viewing thickness and viewing plane. The CT readings were retrospectively compared with surgical and pathologic findings. In patients in whom the presence of PM was rated as grade 1 or less, factors predictive of PM were identified by testing variables, including patient and tumor characteristics, with univariate tests and multivariate logistic regression analysis. RESULTS: Fifty-three patients (10.6%) had confirmed PM. When only grade 2 was considered to indicate a positive CT reading, sensitivity and specificity were 28.3% (15 of 53) and 98.9% (440 of 445), respectively. With the threshold of grade 1 or greater indicating a positive reading, sensitivity and specificity were 50.9% (27 of 53) and 96.2% (428 of 445), respectively. In the patients with grades of 1 or less, the significant factors predictive of PM were greater tumor size and T stage. CONCLUSION: The sensitivity of PM detection is limited, even with modern CT techniques. In patients whose CT results are not definitely positive for PM, staging laparoscopy is still recommended if the aforementioned two predictive factors (greater tumor size and T stage) are suspected. PMID- 19789244 TI - Low-grade gliomas: six-month tumor growth predicts patient outcome better than admission tumor volume, relative cerebral blood volume, and apparent diffusion coefficient. AB - PURPOSE: To prospectively compare tumor volume, relative cerebral blood volume (rCBV), and apparent diffusion coefficient (ADC) and short-term changes of these parameters as predictors of time to malignant transformation and time to death in patients with low-grade gliomas (LGGs). MATERIALS AND METHODS: Patients gave written informed consent for this institutional ethics committee-approved study. Patients with histologically proved LGGs underwent conventional, perfusion weighted, and diffusion-weighted magnetic resonance (MR) imaging at study entry and at 6 months. At both time points, tumor volume, maximum rCBV, and ADC histogram measures were calculated. Patient follow-up consisted of MR imaging every 6 months and clinical examinations. To investigate the association between MR imaging variables and time to progression and time to death, a Cox regression curve was applied at study entry and at 6 months. The models were corrected for age, sex, and histologic findings. RESULTS: Thirty-four patients (22 men, 12 women; mean age, 42 years) with histologically proved LGGs (eight oligodendrogliomas, 20 astrocytomas, and six oligoastrocytomas) were followed up clinically and radiologically for a median of 2.6 years (range, 0.4-5.5 years). Tumor growth over the course of 6 months was the best predictor of time to transformation, independent of rCBV, diffusion histogram parameters, age, sex, and histologic findings. When only single-time-point measurements were compared, tumor volume helped predict outcome best and was the only independent predictor of time to death (P < .02). CONCLUSION: Six-month tumor growth helps predict outcome in patients with LGG better than parameters derived from perfusion- or diffusion-weighed MR imaging. Tumor growth can readily be calculated from volume measurements on images acquired with standard MR imaging protocols and may well prove most useful among various MR imaging findings in clinical practice. PMID- 19789245 TI - Potential usefulness of similar images in the differential diagnosis of clustered microcalcifications on mammograms. AB - PURPOSE: To evaluate the potential usefulness of images of lesions of a known disease that have a similar appearance to lesions of an unknown disease in distinguishing between benign and malignant clustered microcalcifications on mammograms by removing the unusual cases from the database. MATERIALS AND METHODS: Institutional review board approval for this retrospective HIPAA compliant study of images from a publicly available database was obtained. Unusual lesions, such as malignant-looking benign lesions and benign-looking malignant lesions, were removed from the database. A total of 20 benign and 20 malignant lesions were selected with a stratified randomization method, and it was these lesions that served as unknown cases in this observer study. For each unknown case, eight similar images of benign lesions and eight similar images of malignant lesions were preselected with a computerized scheme. From these preselected images, a breast radiologist subjectively selected the four most similar images of benign lesions and the four most similar images of malignant lesions. Five attending breast radiologists and three breast-imaging fellows participated in the observer study. Observers provided their confidence level regarding malignancy of the unknown case before and after they viewed the similar images. The results were evaluated with multireader multicase receiver operating characteristic (ROC) analysis. RESULTS: For all observers, the areas under the ROC curves (AUCs) were improved when similar images were used. The average AUC for all observers increased from 0.692 without use of similar images to 0.790 with use of similar images (P = .0009). CONCLUSION: The presentation of similar images can improve radiologists' performance in the differential diagnosis of clustered microcalcifications on mammograms. PMID- 19789246 TI - Science to practice: can MR elastography be used to detect early steatohepatitis in fatty liver disease? AB - SUMMARY: Fatty liver disease is common in Western countries. Some patients with this condition develop steatohepatitis, with ongoing liver injury that can lead to cirrhosis. Liver biopsy is currently required to differentiate between uncomplicated fatty liver disease and the more serious condition of steatohepatitis. Salameh and colleagues (1) studied the potential role of MR elastography for this diagnostic task in rat models of simple fatty liver and steatohepatitis. Their results suggest that MR elastography may have a potentially important role for noninvasive early detection of steatohepatitis in patients with fatty liver disease. PMID- 19789249 TI - Diagnosis please certificates of recognition awarded to three individuals and to International and North American Radiology Resident Groups. PMID- 19789250 TI - The preponderance of evidence supports computer-aided detection for screening mammography. PMID- 19789251 TI - Can computer-aided detection be detrimental to mammographic interpretation? PMID- 19789252 TI - Structured radiology reporting: are we there yet? PMID- 19789253 TI - MR labeling information for implants and devices: explanation of terminology. PMID- 19789254 TI - Imaging patients with acute abdominal pain. AB - Acute abdominal pain may be caused by a myriad of diagnoses, including acute appendicitis, diverticulitis, and cholecystitis. Imaging plays an important role in the treatment management of patients because clinical evaluation results can be inaccurate. Performing computed tomography (CT) is most important because it facilitates an accurate and reproducible diagnosis in urgent conditions. Also, CT findings have been demonstrated to have a marked effect on the management of acute abdominal pain. The cost-effectiveness of CT in the setting of acute appendicitis was studied, and CT proved to be cost-effective. CT can therefore be considered the primary technique for the diagnosis of acute abdominal pain, except in patients clinically suspected of having acute cholecystitis. In these patients, ultrasonography (US) is the primary imaging technique of choice. When costs and ionizing radiation exposure are primary concerns, a possible strategy is to perform US as the initial technique in all patients with acute abdominal pain, with CT performed in all cases of nondiagnostic US. The use of conventional radiography has been surpassed; this examination has only a possible role in the setting of bowel obstruction. However, CT is more accurate and more informative in this setting as well. In cases of bowel perforation, CT is the most sensitive technique for depicting free intraperitoneal air and is valuable for determining the cause of the perforation. Imaging is less useful in cases of bowel ischemia, although some CT signs are highly specific. Magnetic resonance (MR) imaging is a promising alternative to CT in the evaluation of acute abdominal pain and does not involve the use of ionizing radiation exposure. However, data on the use of MR imaging for this indication are still sparse. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/content/253/1/31/suppl/DC1. PMID- 19789256 TI - Locally advanced rectal cancer: added value of diffusion-weighted MR imaging in the evaluation of tumor response to neoadjuvant chemo- and radiation therapy. AB - PURPOSE: To investigate the added value of diffusion-weighted (DW) magnetic resonance (MR) imaging in the evaluation of complete response (CR) to neoadjuvant combined chemotherapy and radiation therapy (CRT) in patients with locally advanced rectal cancer. MATERIALS AND METHODS: Institutional review board approval was obtained for this retrospective study, and the patient informed consent requirement was waived. Forty consecutive patients with locally advanced rectal cancer (>or=T3 or lymph node positive) who underwent CRT and subsequent surgery were enrolled in this study. All patients underwent pre- and post-CRT 1.5 T rectal MR imaging and post-CRT DW MR imaging. For qualitative analysis, two radiologists who were blinded to pathologic staging and prior imaging data retrospectively and independently reviewed conventional MR images and the combined set of MR images and DW MR images over a 2-week interval and recorded their confidence level with respect to the CR to neoadjuvant CRT. Diagnostic accuracy was calculated for each reviewer with receiver operating characteristic (ROC) curve analysis. For quantitative analysis, a third radiologist measured the apparent diffusion coefficient (ADC) of the region of interest three times. Mean ADCs in the CR group were compared with those in the non-CR group. Pathology reports served as the reference standard. RESULTS: Diagnostic accuracy (area under the ROC curve [A(z)]) in the evaluation of CR was significantly improved after additional review of DW MR images for both reviewers: For reviewer 1, A(z) improved from 0.676 to 0.876 (P = .005), whereas for reviewer 2, A(z) improved from 0.658 to 0.815 (P = .036). Mean ADC ([1.62 +/- 0.36] x 10(-3) mm(2)/sec) (standard deviation) of the CR group (n = 11) was significantly higher than that ([1.04 +/- 0.24] x 10(-3) mm(2)/sec) of the non-CR group (n = 29) (P < .0001). CONCLUSION: Adding DW MR imaging to conventional MR imaging yields better diagnostic accuracy than use of conventional MR imaging alone in the evaluation of CR to neoadjuvant CRT in patients with locally advanced rectal cancer. PMID- 19789255 TI - Renal perfusion and hemodynamics: accurate in vivo determination at CT with a 10 fold decrease in radiation dose and HYPR noise reduction. AB - PURPOSE: To prospectively evaluate the accuracy of computed tomographic (CT) perfusion measurements of renal hemodynamics and function obtained by using images acquired with one-tenth the typical radiation dose and postprocessed with a highly constrained back-projection (HYPR)-local reconstruction (LR) noise reduction technique. MATERIALS AND METHODS: This study was approved by the institutional Animal Care and Use Committee. Two consecutive CT perfusion acquisitions were performed in 10 anesthetized pigs over 180 seconds by using routine (80 kV, 160 mAs) and one-tenth (80 kV, 16 mAs) dose levels. Images obtained with each acquisition were reconstructed with identical parameters, and the one-tenth dose images were also processed with a HYPR-LR algorithm. Attenuation changes in kidneys were determined as a function of time to form time attenuation curves (TACs). Extended gamma-variate curve-fitting was performed, and regional perfusion, glomerular filtration rate, and renal blood flow were calculated. Image quality was evaluated (in 10 pigs), and the agreement for renal perfusion and function between the routine dose and the one-tenth dose HYPR-LR images was determined (for 20 kidneys) by using statistical methods. Statistical analysis was performed by using the paired t test, linear regression, and Bland Altman analysis. RESULTS: TACs obtained with the one-tenth dose were similar to those obtained with the routine dose. Statistical analysis showed that there were no significant differences between the routine dose and the one-tenth dose acquisitions in renal perfusion and hemodynamic values and that there were slight but statistically significant differences in some values with the one-tenth dose HYPR-LR-processed acquisition. The image quality of the one-tenth dose acquisition was improved by using the HYPR-LR algorithm. Linear regression and Bland-Altman plots showed agreement between the images acquired by using the routine dose and those acquired by using the one-tenth dose with HYPR-LR processing. CONCLUSION: A 10-fold dose reduction at renal perfusion CT imaging can be achieved in vivo, without loss of accuracy. The image quality of the one tenth dose images could be improved to be near that of the routine dose images by using the HYPR-LR noise-reduction algorithm. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.2531081677/-/DC1. PMID- 19789257 TI - Salivary glands: echo-planar versus PROPELLER Diffusion-weighted MR imaging for assessment of ADCs. AB - PURPOSE: To compare the image distortion and the quantification variation in parotid gland apparent diffusion coefficients (ADCs) on periodically rotated overlapping parallel lines with enhanced reconstruction (PROPELLER) versus echo planar diffusion-weighted (DW) magnetic resonance (MR) images and to investigate the relationship between parotid gland ADC and parotid gland fat content. MATERIALS AND METHODS: This prospective study was approved by a local institutional review board. Written informed consent was obtained from all 33 enrolled healthy volunteers (15 men, 18 women; mean age, 36.4 years +/- 11.8 [standard deviation]). All participants underwent 1.5-T non-fat-saturated and fat saturated PROPELLER DW MR imaging as well as 1.5-T nonaccelerated and twofold accelerated echo-planar DW MR imaging. Image distortion on the DW images was qualitatively scored, and parotid ADC was quantitatively analyzed. The correlation between parotid ADC and parotid fat content was evaluated by using linear regression analysis. Wilcoxon signed rank and t tests were used for statistical analysis, with Bonferroni correction applied for multiple comparisons. RESULTS: Echo-planar DW images showed distortion, which was completely eliminated on the PROPELLER DW images. The mean parotid ADCs measured with non-fat-saturated PROPELLER (0.670 x 10(-3) mm(2) +/- 0.149), nonaccelerated echo-planar (0.892 x 10(-3) mm(2) +/- 0.128), twofold-accelerated echo-planar (1.088 x 10(-3) mm(2) +/- 0.124), and fat-saturated PROPELLER (1.307 x 10(-3) mm(2) +/- 0.217) DW imaging differed significantly from one another (P < .001 for all comparisons). Parotid ADC had a significant negative correlation with parotid fat content (x) measured at non-fat-saturated PROPELLER DW imaging: ADC = 0.0087x + 1.1173 (r = 0.80, P < .001). CONCLUSION: PROPELLER DW imaging pulse sequences can yield distortion-free images for parotid ADC measurements and enable quantitative evaluation of the relationship between parotid ADC and parotid fat content. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.2531082228/-/DC1. PMID- 19789259 TI - Case 150: Van Buchem disease (hyperostosis corticalis generalisata). PMID- 19789260 TI - CT attenuation in acute pulmonary embolism: an enigma. PMID- 19789261 TI - Lung cancer screening outcomes. PMID- 19789262 TI - Age-related changes on thin-section CT images. PMID- 19789263 TI - HIF-1 is induced via EGFR activation and mediates resistance to anoikis-like cell death under lipid rafts/caveolae-disrupting stress. AB - The plasma membrane microdomains, lipid rafts, are involved in regulation of cellular functions such as cell survival and adhesion. Cholesterol is a critical component of lipid rafts in terms of their integrity and functions and rafts disruption by cholesterol depletion can induce detachment-induced cell death. Hypoxia inducible factor-1 (HIF-1) alpha is stabilized in hypoxia and transactivates numerous genes required for cellular adaptation to hypoxia. It is also induced by non-hypoxic stimuli and contributes to cell survival. Because hypoxia inhibits cholesterol synthesis and HIF-1alpha plays a role in this process, we here explored a possible connection between lipid rafts and HIF 1alpha. We investigated whether HIF-1alpha is regulated during cholesterol depletion/rafts disruption in A431 cells in normoxic conditions. Methyl-beta cyclodextrin (MbetaCD), which induces cholesterol depletion, upregulated HIF 1alpha even under normoxic conditions and this upregulation required epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase 1 and 2 activation, but not Akt activation. MbetaCD treatment induced HIF-1alpha upregulation at both the transcriptional and translational levels but not at the posttranslational levels. In addition, MbetaCD robustly induced vascular endothelial growth factor production and stimulated an hypoxia response element driven luciferase reporter activity under normoxic conditions, indicating that MbetaCD-induced HIF-1alpha is functionally activated. Both EGFR activity and HIF 1alpha expression were higher in the attached cells than in the detached cells after MbetaCD treatment. Furthermore, inhibition of HIF-1alpha by RNA interference accelerated cell detachment, thus increasing cell death, indicating that HIF-1alpha expression attenuates MbetaCD-induced anoikis-like cell death. These data suggest that, depending on cholesterol levels, lipid rafts or membrane fluidity are probably to regulate HIF-1alpha expression in normoxia by modulating rafts protein activities such as EGFR, and this connection between lipid rafts and HIF-1alpha regulation may provide cell survival under membrane-disturbing stress. PMID- 19789264 TI - The extracellular loop 2 of TM4SF5 inhibits integrin alpha2 on hepatocytes under collagen type I environment. AB - Four-transmembrane L6 family member 5 (TM4SF5) and its homolog L6, a tumor antigen, form a four-transmembrane L6 family. TM4SF5 expression causes uncontrolled cell proliferation and angiogenesis. Although other genuine transmembrane 4 superfamily (TM4SF) members co-operate with integrins for cell migration, roles of TM4SF5 in the cellular spreading and migration are unknown. Using hepatocarcinoma cell clones that ectopically express TM4SF5, we found that cross talks via an extracellular interaction between TM4SF5 and integrin alpha2 in collagen type I environment inhibited integrin alpha2 functions such as spreading on and migration toward collagen I, which were recovered by suppression of TM4SF5 or structural disturbance of its second extracellular loop using a peptide or mutagenesis. Altogether, the observations suggest that TM4SF5 in hepatocytes negatively regulates integrin alpha2 function via an interaction between the extracellular loop 2 of TM4SF5 and integrin alpha2 during cell spreading on and migration through collagen I environment. PMID- 19789265 TI - Advances in metaheuristics for gene selection and classification of microarray data. AB - Gene selection aims at identifying a (small) subset of informative genes from the initial data in order to obtain high predictive accuracy for classification. Gene selection can be considered as a combinatorial search problem and thus be conveniently handled with optimization methods. In this article, we summarize some recent developments of using metaheuristic-based methods within an embedded approach for gene selection. In particular, we put forward the importance and usefulness of integrating problem-specific knowledge into the search operators of such a method. To illustrate the point, we explain how ranking coefficients of a linear classifier such as support vector machine (SVM) can be profitably used to reinforce the search efficiency of Local Search and Evolutionary Search metaheuristic algorithms for gene selection and classification. PMID- 19789266 TI - VDNA: the virtual DNA plug-in for VMD. AB - The DNA inter base pair step parameters (Tilt, Roll, Twist, Shift, Slide, Rise) are a standard internal coordinate representation of DNA. In the absence of bend and shear, it is relatively easy to mentally visualize how Twist and Rise generate the familiar double helix. More complex structures do not readily yield to such intuition. For this reason, we developed a plug-in for VMD that accepts a set of mathematical expressions as input and generates a coarse-grained model of DNA as output. This feature of VDNA appears to provide a unique approach to DNA modeling. Predefined expressions include: linear, sheared, bent and circular DNA, and models of the nucleosome superhelix, chromatin, thermal motion and nucleosome unwrapping. AVAILABILITY: VDNA is pre-installed in VMD, http://www.ks.uiuc.edu/Research/vmd. Updates are at http://dna.ccs.tulane.edu. PMID- 19789267 TI - Lost in translation: an assessment and perspective for computational microRNA target identification. AB - MicroRNAs (miRNAs) are a class of short endogenously expressed RNA molecules that regulate gene expression by binding directly to the messenger RNA of protein coding genes. They have been found to confer a novel layer of genetic regulation in a wide range of biological processes. Computational miRNA target prediction remains one of the key means used to decipher the role of miRNAs in development and disease. Here we introduce the basic idea behind the experimental identification of miRNA targets and present some of the most widely used computational miRNA target identification programs. The review includes an assessment of the prediction quality of these programs and their combinations. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 19789268 TI - EasyMIFS and SiteHound: a toolkit for the identification of ligand-binding sites in protein structures. AB - SiteHound uses Molecular Interaction Fields (MIFs) produced by EasyMIFs to identify protein structure regions that show a high propensity for interaction with ligands. The type of binding site identified depends on the probe atom used in the MIF calculation. The input to EasyMIFs is a PDB file of a protein structure; the output MIF serves as input to SiteHound, which in turn produces a list of putative binding sites. Extensive testing of SiteHound for the detection of binding sites for drug-like molecules and phosphorylated ligands has been carried out. AVAILABILITY: EasyMIFs and SiteHound executables for Linux, Mac OS X, and MS Windows operating systems are freely available for download from http://sitehound.sanchezlab.org/download.html. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 19789269 TI - The interwinding nature of protein-protein interfaces and its implication for protein complex formation. AB - MOTIVATION: Structural features at protein-protein interfaces can be studied to understand protein-protein interactions. It was noticed that in a dataset of 45 multimeric proteins the interface could either be described as flat against flat or protruding/interwound. In the latter, residues within one chain were surrounded by those in other chains, whereas in the former they were not. RESULTS: A simple method was developed that could distinguish between these two types with results that matched those made by a human annotator. Applying this automatic method to a large dataset of 888 structures, chains at interfaces were categorized as non-surrounded or surrounded. It was found that the surrounded set had a significantly lower folding tendency using a sequence based measure, than the non-surrounded set. This suggests that before complexation, surrounded chains are relatively unstable and may be involved in 'fly-casting'. This is supported by the finding that terminal regions are overrepresented in the surrounded set. AVAILABILITY: http://cib.cf.ocha.ac.jp/DACSIS/. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 19789270 TI - Overlapping promoter targeting by Elk-1 and other divergent ETS-domain transcription factor family members. AB - ETS-domain transcription factors play important roles in controlling gene expression in a variety of different contexts; however, these proteins bind to very similar sites and it is unclear how in vivo specificity is achieved. In silico analysis is unlikely to reveal specific targets for individual family members and direct experimental approaches are therefore required. Here, we take advantage of an inducible dominant-negative expression system to identify a group of novel target genes for the ETS-domain transcription factor Elk-1. Elk-1 is thought to mainly function through cooperation with a second transcription factor SRF, but the targets we identify are largely SRF-independent. Furthermore, we demonstrate that there is a high degree of overlapping, cell type-specific, target gene binding by Elk-1 and other ETS-domain transcription factors. Our results are therefore consistent with the notion that there is a high degree of functional redundancy in target gene regulation by ETS-domain transcription factors in addition to the specific target gene regulation that can be dictated through heterotypic interactions exemplified by the Elk-1-SRF complex. PMID- 19789271 TI - Role and dynamics of the ribosomal protein P0 and its related trans-acting factor Mrt4 during ribosome assembly in Saccharomyces cerevisiae. AB - Mrt4 is a nucleolar component of the ribosome assembly machinery that shares notable similarity and competes for binding to the 25S rRNA GAR domain with the ribosomal protein P0. Here, we show that loss of function of either P0 or Mrt4 results in a deficit in 60S subunits, which is apparently due to impaired rRNA processing of 27S precursors. Mrt4, which shuttles between the nucleus and the cytoplasm, defines medium pre-60S particles. In contrast, P0 is absent from medium but present in late/cytoplasmic pre-60S complexes. The absence of Mrt4 notably increased the amount of P0 in nuclear Nop7-TAP complexes and causes P0 assembly to medium pre-60S particles. Upon P0 depletion, Mrt4 is relocated to the cytoplasm within aberrant 60S subunits. We conclude that Mrt4 controls the position and timing of P0 assembly. In turn, P0 is required for the release of Mrt4 and exchanges with this factor at the cytoplasm. Our results also suggest other P0 assembly alternatives. PMID- 19789272 TI - The catalytic residues of Tn3 resolvase. AB - To characterize the residues that participate in the catalysis of DNA cleavage and rejoining by the site-specific recombinase Tn3 resolvase, we mutated conserved polar or charged residues in the catalytic domain of an activated resolvase variant. We analysed the effects of mutations at 14 residues on proficiency in binding to the recombination site ('site I'), formation of a synaptic complex between two site Is, DNA cleavage and recombination. Mutations of Y6, R8, S10, D36, R68 and R71 resulted in greatly reduced cleavage and recombination activity, suggesting crucial roles of these six residues in catalysis, whereas mutations of the other residues had less dramatic effects. No mutations strongly inhibited binding of resolvase to site I, but several caused conspicuous changes in the yield or stability of the synapse of two site Is observed by non-denaturing gel electrophoresis. The involvement of some residues in both synapsis and catalysis suggests that they contribute to a regulatory mechanism, in which engagement of catalytic residues with the substrate is coupled to correct assembly of the synapse. PMID- 19789273 TI - Bicistronic DNA display for in vitro selection of Fab fragments. AB - In vitro display methods are superior tools for obtaining monoclonal antibodies. Although totally in vitro display methods, such as ribosome display and mRNA display, have the advantages of larger library sizes and quicker selection procedures compared with phage display, their applications have been limited to single-chain Fvs due to the requirement for linking of the mRNA and the nascent protein on the ribosome. Here we describe a different type of totally in vitro method, DNA display, that is applicable to heterodimeric Fab fragments: in vitro compartmentalization in water-in-oil emulsions allows the linking of an oligomeric protein and its encoding DNA with multiple ORFs. Since previously used emulsions impaired the synthesis of functional Fab fragments, we modified conditions for preparing emulsions, and identified conditions under which it was possible to enrich Fab fragments 10(6)-fold per three rounds of affinity selection. Furthermore, we confirmed that genes encoding stable Fab fragments could be selected from a Fab fragment library with a randomized hydrophobic core in the constant region by applying heat treatment as a selection pressure. Since this method has all advantages of both phage display and totally in vitro display, it represents a new option for many applications using display methods. PMID- 19789274 TI - The poplar GT8E and GT8F glycosyltransferases are functional orthologs of Arabidopsis PARVUS involved in glucuronoxylan biosynthesis. AB - The poplar GT8E and GT8F glycosyltransferases have previously been shown to be associated with wood formation, but their roles in the biosynthesis of wood components are not known. Here, we show that PoGT8E and PoGT8F are expressed in vessels and fibers during wood formation and their encoded proteins are predominantly located in the endoplasmic reticulum. We demonstrate that expression of PoGT8E and PoGT8F in the Arabidopsis parvus mutant rescues the defects in the content and structure of glucuronoxylan conferred by the parvus mutation. These findings suggest that PoGT8E and PoGT8F are involved in glucuronoxylan biosynthesis during wood formation in poplar. PMID- 19789275 TI - Lights, rhythms, infection: the role of light and the circadian clock in determining the outcome of plant-pathogen interactions. AB - The importance of light with respect to the outcome of plant-pathogen interactions is becoming increasingly evident: light affects both the host response and the virulence of some pathogens. The response of plants to environmental signals and stresses is modulated by the circadian clock, and it is apparent that this may include immune responses. Photo and temporal regulation of immune responses may allow plants to anticipate and react more effectively to particular pathogen infections. These aspects of regulation are sometimes overlooked when designing experiments to understand plant-pathogen interactions, complicating the interpretation of the outcomes and the direct comparisons of studies. We review recent key findings in these areas and discuss the implications for experimental design and analyses. PMID- 19789276 TI - Evolutionarily conserved regulatory motifs in the promoter of the Arabidopsis clock gene LATE ELONGATED HYPOCOTYL. AB - The transcriptional regulation of the LATE ELONGATED HYPOCOTYL (LHY) gene is key to the structure of the circadian oscillator, integrating information from multiple regulatory pathways. We identified a minimal region of the LHY promoter that was sufficient for rhythmic expression. Another upstream sequence was also required for appropriate waveform of transcription and for maximum amplitude of oscillations under both diurnal and free-running conditions. We showed that two classes of protein complexes interact with a G-box and with novel 5A motifs; mutation of these sites reduced the amplitude of oscillation and broadened the peak of expression. A genome-wide bioinformatic analysis showed that these sites were enriched in phase-specific clusters of rhythmically expressed genes. Comparative genomic analyses showed that these motifs were conserved in orthologous promoters from several species. A position-specific scoring matrix for the 5A sites suggested similarity to CArG boxes, which are recognized by MADS box transcription factors. In support of this, the FLOWERING LOCUS C (FLC) protein was shown to interact with the LHY promoter in planta. This suggests a mechanism by which FLC might affect circadian period. PMID- 19789278 TI - Introducing a new feature in the Plant Cell: teaching tools in plant biology. PMID- 19789277 TI - MAP kinase phosphatase1 and protein tyrosine phosphatase1 are repressors of salicylic acid synthesis and SNC1-mediated responses in Arabidopsis. AB - Mitogen-activated protein (MAP) kinase phosphatases are important negative regulators of the levels and kinetics of MAP kinase activation that modulate cellular responses. The dual-specificity phosphatase MAP KINASE PHOSPHATASE1 (MKP1) was previously shown to regulate MAP KINASE6 (MPK6) activation levels and abiotic stress responses in Arabidopsis thaliana. Here, we report that the mkp1 null mutation in the Columbia (Col) accession results in growth defects and constitutive biotic defense responses, including elevated levels of salicylic acid, camalexin, PR gene expression, and resistance to the bacterial pathogen Pseudomonas syringae. PROTEIN TYROSINE PHOSPHATASE1 (PTP1) also interacts with MPK6, but the ptp1 null mutant shows no aberrant growth phenotype. However, the pronounced constitutive defense response of the mkp1 ptp1 double mutant reveals that MKP1 and PTP1 repress defense responses in a coordinated fashion. Moreover, mutations in MPK3 and MPK6 distinctly suppress mkp1 and mkp1 ptp1 phenotypes, indicating that MKP1 and PTP1 act as repressors of inappropriate MPK3/MPK6 dependent stress signaling. Finally, we provide evidence that the natural modifier of mkp1 in Col is largely the disease resistance gene homolog SUPPRESSOR OF npr1-1, CONSTITUTIVE 1 (SNC1) that is absent in the Wassilewskija accession. Our data thus indicate a major role of MKP1 and PTP1 in repressing salicylic acid biosynthesis in the autoimmune-like response caused by SNC1. PMID- 19789279 TI - Negative regulation of stress-activated MAPK signaling in Arabidopsis. PMID- 19789280 TI - Cellular pathways regulating responses to compatible and self-incompatible pollen in Brassica and Arabidopsis stigmas intersect at Exo70A1, a putative component of the exocyst complex. AB - In the Brassicaceae, compatible pollen-pistil interactions result in pollen adhesion to the stigma, while pollen grains from unrelated plant species are largely ignored. There can also be an additional layer of recognition to prevent self-fertilization, the self-incompatibility response, whereby self pollen grains are distinguished from nonself pollen grains and rejected. This pathway is activated in the stigma and involves the ARM repeat-containing 1 (ARC1) protein, an E3 ubiquitin ligase. In a screen for ARC1-interacting proteins, we have identified Brassica napus Exo70A1, a putative component of the exocyst complex that is known to regulate polarized secretion. We show through transgenic studies that loss of Exo70A1 in Brassica and Arabidopsis thaliana stigmas leads to the rejection of compatible pollen at the same stage as the self-incompatibility response. A red fluorescent protein:Exo70A1 fusion rescues this stigmatic defect in Arabidopsis and is found to be mobilized to the plasma membrane concomitant with flowers opening. By contrast, increased expression of Exo70A1 in self incompatible Brassica partially overcomes the self pollen rejection response. Thus, our data show that the Exo70A1 protein functions at the intersection of two cellular pathways, where it is required in the stigma for the acceptance of compatible pollen in both Brassica and Arabidopsis and is negatively regulated by Brassica self-incompatibility. PMID- 19789281 TI - Replication stress leads to genome instabilities in Arabidopsis DNA polymerase delta mutants. AB - Impeded DNA replication or a deficiency of its control may critically threaten the genetic information of cells, possibly resulting in genome alterations, such as gross chromosomal translocations, microsatellite instabilities, or increased rates of homologous recombination (HR). We examined an Arabidopsis thaliana line derived from a forward genetic screen, which exhibits an elevated frequency of somatic HR. These HR events originate from replication stress in endoreduplicating cells caused by reduced expression of the gene coding for the catalytic subunit of the DNA polymerase delta (POLdelta1). The analysis of recombination types induced by diverse alleles of poldelta1 and by replication inhibitors allows the conclusion that two not mutually exclusive mechanisms lead to the generation of recombinogenic breaks at replication forks. In plants with weak poldelta1 alleles, we observe genome instabilities predominantly at sites with inverted repeats, suggesting the formation and processing of aberrant secondary DNA structures as a result of the accumulation of unreplicated DNA. Stalled and collapsed replication forks account for the more drastic enhancement of HR in plants with strong poldelta1 mutant alleles. Our data suggest that efficient progression of DNA replication, foremost on the lagging strand, relies on the physiological level of the polymerase delta complex and that even a minor disturbance of the replication process critically threatens genomic integrity of Arabidopsis cells. PMID- 19789283 TI - Embrace diversity! Systems genetics-enabled discovery of disease networks. PMID- 19789282 TI - Manipulation of auxin transport in plant roots during Rhizobium symbiosis and nematode parasitism. AB - The plant rhizosphere harbors many different microorganisms, ranging from plant growth-promoting bacteria to devastating plant parasites. Some of these microbes are able to induce de novo organ formation in infected roots. Certain soil bacteria, collectively called rhizobia, form a symbiotic interaction with legumes, leading to the formation of nitrogen-fixing root nodules. Sedentary endoparasitic nematodes, on the other hand, induce highly specialized feeding sites in infected plant roots from which they withdraw nutrients. In order to establish these new root structures, it is thought that these organisms use and manipulate the endogenous molecular and physiological pathways of their hosts. Over the years, evidence has accumulated reliably demonstrating the involvement of the plant hormone auxin. Moreover, the auxin responses during microbe-induced de novo organ formation seem to be dynamic, suggesting that plant-associated microbes can actively modify their host's auxin transport. In this review, we focus on recent findings in auxin transport mechanisms during plant development and on how plant symbionts and parasites have evolved to manipulate these mechanisms for their own purposes. PMID- 19789284 TI - Quantitative trait loci for exercise training responses in FVB/NJ and C57BL/6J mice. AB - The genetic factors determining the magnitude of the response to exercise training are poorly understood. The aim of this study was to identify quantitative trait loci (QTL) associated with adaptation to exercise training in a cross between FVB/NJ (FVB) and C57BL/6J (B6) mice. Mice completed an exercise performance test before and after a 4-wk treadmill running program, and changes in exercise capacity, expressed as work (kg.m), were calculated. Changes in work in F(2) mice averaged 1.51 +/- 0.08 kg.m (94.3 +/- 7.3%), with a range of -1.67 to +4.55 kg.m. All F(2) mice (n = 188) were genotyped at 20-cM intervals with 103 single nucleotide polymorphisms (SNPs), and genomewide linkage scans were performed for pretraining, posttraining, and change in work. Significant QTL for pretraining work were located on chromosomes 14 at 4.0 cM [3.72 logarithm of odds (LOD)] and 19 at 34.4 cM (3.63 LOD). For posttraining work significant QTL were located on chromosomes 3 at 60 cM (4.66 LOD) and 14 at 26 cM (4.99 LOD). Suggestive QTL for changes in work were found on chromosomes 11 at 44.6 cM (2.30 LOD) and 14 at 36 cM (2.25 LOD). When pretraining work was used as a covariate, a potential QTL for change in work was identified on chromosome 6 at 68 cM (3.56 LOD). These data indicate that one or more QTL determine exercise capacity and training responses in mice. Furthermore, these data suggest that the genes that determine pretraining work and training responses may differ. PMID- 19789285 TI - Gene expression endpoints following chronic waterborne copper exposure in a genomic model organism, the zebrafish, Danio rerio. AB - Although copper (Cu) is an essential micronutrient for all organisms, in excess, waterborne Cu poses a significant threat to fish from the cellular to population level. We examined the physiological and gene expression endpoints that chronic waterborne Cu exposure (21 d) imposes on soft-water acclimated zebrafish at two environmentally relevant concentrations: 8 microg/l (moderate) and 15 microg/l (high). Using a 16,730 65-mer oligonucleotide customized zebrafish microarray chip related to metal metabolism and toxicity to assess the transcriptomic response, we found that 573 genes in the liver responded significantly to Cu exposure. These clustered into three distinct patterns of expression. There was distinct upregulation of a majority of these genes under moderate Cu exposure and a significant downregulation under high Cu exposure. Microarray results were validated by qPCR of eight genes; two genes, metallothionein 2 (mt2) and Na(+) K(+)-ATPase 1a1 (atp1a1), displayed increased expression under both Cu exposures, indicative of potential genetic endpoints of Cu toxicity, whereas the remaining six genes demonstrated opposing effects at each Cu exposure. Na(+)-K(+)-ATPase enzyme activity decreased during Cu exposure, which may be linked to Cu's competitive effects with Na(+). Whole body cortisol levels were significantly increased in Cu-exposed fish, which prompted an analysis of the promoter region of all significantly regulated genes for glucocorticoid (GRE) and metal (MRE) response elements to dissociate metal- and stress-specific gene responses. Of the genes significantly regulated, 30% contained only a GRE sequence, whereas 2.5% contained only a consensus MRE. We conclude that the indirect effects of Cu exposure regulate gene expression to a much greater degree than the direct effects. PMID- 19789286 TI - MicroRNAs in the rhizobia legume symbiosis. PMID- 19789287 TI - Phased control of expansin activity during leaf development identifies a sensitivity window for expansin-mediated induction of leaf growth. AB - Expansins are cell wall proteins associated with the process of plant growth. However, investigations in which expansin gene expression has been manipulated throughout the plant have often led to inconclusive results. In this article, we report on a series of experiments in which overexpression of expansin was targeted to specific phases of leaf growth using an inducible promoter system. The data indicate that there is a restricted window of sensitivity when increased expansin gene expression leads to increased endogenous expansin activity and an increase in leaf growth. This phase of maximum expansin efficacy corresponds to the mid phase of leaf growth. We propose that the effectiveness of expansin action depends on the presence of other modulating factors in the leaf and we suggest that it is the control of expression of these factors (in conjunction with expansin gene expression) that defines the extent of leaf growth. These data help to explain some of the previously observed variation in growth response following manipulation of expansin gene expression and highlight a potential linkage of the expression of modifiers of expansin activity with the process of exit from cell division. PMID- 19789288 TI - Knockdown of CELL DIVISION CYCLE16 reveals an inverse relationship between lateral root and nodule numbers and a link to auxin in Medicago truncatula. AB - The postembryonic development of lateral roots and nodules is a highly regulated process. Recent studies suggest the existence of cross talk and interdependency in the growth of these two organs. Although plant hormones, including auxin and cytokinin, appear to be key players in coordinating this cross talk, very few genes that cross-regulate root and nodule development have been uncovered so far. This study reports that a homolog of CELL DIVISION CYCLE16 (CDC16), a core component of the Anaphase Promoting Complex, is one of the key mediators in controlling the overall number of lateral roots and nodules. A partial suppression of this gene in Medicago truncatula leads to a decrease in number of lateral roots and a 4-fold increase in number of nodules. The roots showing lowered expression of MtCDC16 also show reduced sensitivity to phytohormone auxin, thus providing a potential function of CDC16 in auxin signaling. PMID- 19789289 TI - Extensive structural renovation of retrogenes in the evolution of the Populus genome. AB - Retroposition, as an important copy mechanism for generating new genes, was believed to play a negligible role in plants. As a representative dicot, the genomic sequences of Populus (poplar; Populus trichocarpa) provide an opportunity to investigate this issue. We identified 106 retrogenes and found the majority (89%) of them are associated with functional signatures in sequence evolution, transcription, and (or) translation. Remarkably, examination of gene structures revealed extensive structural renovation of these retrogenes: we identified 18 (17%) of them undergoing either chimerization to form new chimerical genes and (or) intronization (transformation into intron sequences of previously exonic sequences) to generate new intron-containing genes. Such a change might occur at a high speed, considering eight out of 18 such cases occurred recently after divergence between Arabidopsis (Arabidopsis thaliana) and Populus. This pattern also exists in Arabidopsis, with 15 intronized retrogenes occurring after the divergence between Arabidopsis and papaya (Carica papaya). Thus, the frequency of intronization in dicots revealed its importance as a mechanism in the evolution of exon-intron structure. In addition, we also examined the potential impact of the Populus nascent sex determination system on the chromosomal distribution of retrogenes and did not observe any significant effects of the extremely young sex chromosomes. PMID- 19789290 TI - Studies of a novel cysteine sulfoxide lyase from Petiveria alliacea: the first heteromeric alliinase. AB - A novel alliinase (EC 4.4.1.4) was detected and purified from the roots of the Amazonian medicinal plant Petiveria alliacea. The isolated enzyme is a heteropentameric glycoprotein composed of two alpha-subunits (68.1 kD each), one beta-subunit (56.0 kD), one gamma-subunit (24.8 kD), and one delta-subunit (13.9 kD). The two alpha-subunits are connected by a disulfide bridge, and both alpha- and beta-subunits are glycosylated. The enzyme has an isoelectric point of 4.78 and pH and temperature optima of 8.0 and approximately 52 degrees C, respectively. Its activation energy with its natural substrate S-benzyl-l cysteine sulfoxide is 64.6 kJ mol(-1). Kinetic studies showed that both K(m) and V(max) vary as a function of substrate structure, with the most preferred substrates being the naturally occurring P. alliacea compounds S-benzyl-l cysteine sulfoxide and S-2-hydroxyethyl-l-cysteine sulfoxide. The alliinase reacts with these substrates to produce S-benzyl phenylmethanethiosulfinate and S (2-hydroxyethyl) 2-hydroxyethanethiosulfinate, respectively. PMID- 19789291 TI - Attenuation of diabetes-induced renal dysfunction by multiple exposures to low dose radiation is associated with the suppression of systemic and renal inflammation. AB - Renal protection against diabetes-induced pathogenic injuries by multiple exposures to low-dose radiation (LDR) was investigated to develop a novel approach to the prevention of renal disease for diabetic subjects. C57BL/6J mice were given multiple low-dose streptozotocin (STZ; 6 x 60 [corrected] mg/kg) to produce a type 1 diabetes. Two weeks after diabetes onset, some of diabetic mice and age-matched nondiabetic mice were exposed whole body to 25 mGy X-rays every other day for 2, 4, 8, 12, and 16 wk. Diabetes caused a significant renal dysfunction, shown by time-dependent increase in urinary microalbumin (Malb) and decrease in urinary creatinine (Cre), and pathological changes, shown by significant increases in renal structural changes and PAS-positive staining. However, diabetes-induced renal dysfunction and pathological changes were significantly, albeit partially, attenuated by multiple exposures to LDR. Furthermore, LDR protection against diabetes-induced renal dysfunction and pathological changes was associated with a significant suppression of diabetes increased systemic and renal inflammation, shown by significant increases in serum and renal TNFalpha, ICAM-1, IL-18, MCP-1, and PAI-1 contents. To further explore the mechanism by which LDR prevents diabetes-induced renal pathological changes, renal oxidative damage was examined by Western blotting and immunohistochemical staining for 3-nitrotyrosine and 4-hydroxynonenal. Significant increase in oxidative damage was observed in diabetic mice, but not diabetic mice, with LDR. Renal fibrosis, examined by Western blotting of connective tissue growth factor and Masson's trichrome staining, was also evident in the kidneys of diabetic mice but not diabetic mice with LDR. These results suggest that multiple exposures to LDR significantly suppress diabetes-induced systemic and renal inflammatory response and renal oxidative damage, resulting in a prevention of the renal dysfunction and fibrosis. PMID- 19789293 TI - Favoritism in DNA methylation. AB - This perspective on Candiloro and Dobrovic (beginning on p. 862 in this issue of the journal) highlights the interplay between epigenetic aberrations and underlying DNA sequence changes and illustrates how these alterations may predispose individuals to cancer. Candiloro and Dobrovic clearly show that particular genotypes of the MGMT gene are associated with its methylation in healthy individuals. Aberrant MGMT methylation may identify individuals who could be targeted for cancer screening and chemoprevention strategies. PMID- 19789292 TI - Regulation of food intake and body weight by recombinant proghrelin. AB - Ghrelin is a 28-amino-acid hormone derived from the endoproteolytic processing of its prehormone proghrelin. Although ghrelin has been reported to regulate food intake and body weight, it is still unknown whether proghrelin exercises any biological function. Here we show that recombinant proghrelin alters food intake and energy metabolism in mice. After intraperitoneal administration of recombinant proghrelin (100 nmol/kg body wt), cumulative food intake was significantly increased at days 1, 2, and 3 (6 +/- 0.3, 13 +/- 0.5, and 20 +/- 0.8 g vs. 5 +/- 0.2, 10 +/- 0.2, and 16 +/- 0.3 g of the control mice receiving normal saline, respectively, n = 6, P < 0.05). Twelve-hour cumulative food intake in the light photo period in mice treated with proghrelin increased significantly relative to the control (2.1 +/- 0.04 vs. 1.3 +/- 0.2 g, n = 6, P < 0.05). No change in 12-h cumulative food intake in the dark photo period was observed between mice treated with proghrelin and vehicle (4.2 +/- 0.6 vs. 4.3 +/- 0.6 g, n = 6, P > 0.05). This is associated with a decrease in body weight (0.42 +/- 0.04 g) for mice treated with proghrelin, whereas control animals gained body weight (0.31 +/- 0.04 g). Mice treated with proghrelin demonstrate a significant decrease in respiratory quotient, indicating an increase in fat consumption. Recombinant proghrelin is functionally active with effects on food intake and energy metabolism. PMID- 19789295 TI - A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and external genital lesions. AB - Quadrivalent human papillomavirus (HPV) vaccine has been shown to provide protection from HPV 6/11/16/18-related cervical, vaginal, and vulvar disease through 3 years. We provide an update on the efficacy of the quadrivalent HPV vaccine against high-grade cervical, vaginal, and vulvar lesions based on end-of study data from three clinical trials. Additionally, we stratify vaccine efficacy by several baseline characteristics, including age, smoking status, and Papanicolaou (Pap) test results. A total of 18,174 females ages 16 to 26 years were randomized and allocated into one of three clinical trials (protocols 007, 013, and 015). Vaccine or placebo was given at baseline, month 2, and month 6. Pap testing was conducted at regular intervals. Cervical and anogenital swabs were collected for HPV DNA testing. Examination for the presence of vulvar and vaginal lesions was also done. Endpoints included high-grade cervical, vulvar, or vaginal lesions (CIN 2/3, VIN 2/3, or VaIN 2/3). Mean follow-up time was 42 months post dose 1. Vaccine efficacy against HPV 6/11/16/18-related high-grade cervical lesions in the per-protocol and intention-to-treat populations was 98.2% [95% confidence interval (95% CI), 93.3-99.8] and 51.5% (95% CI, 40.6-60.6), respectively. Vaccine efficacy against HPV 6/11/16/18-related high-grade vulvar and vaginal lesions in the per-protocol and intention-to-treat populations was 100.0% (95% CI, 82.6-100.0) and 79.0% (95% CI, 56.4-91.0), respectively. Efficacy in the intention-to-treat population tended to be lower in older women, women with more partners, and women with abnormal Pap test results. The efficacy of quadrivalent HPV vaccine against high-grade cervical and external anogenital neoplasia remains high through 42 months post vaccination. PMID- 19789294 TI - A model of gene-environment interaction reveals altered mammary gland gene expression and increased tumor growth following social isolation. AB - Clinical studies have revealed that social support improves the outcome of cancer patients, whereas epidemiologic studies suggest that social isolation increases the risk of death associated with several chronic diseases. However, the precise molecular consequences of an unfavorable social environment have not been defined. To do so, robust, reproducible preclinical models are needed to study the mechanisms whereby an adverse environment affects gene expression and cancer biology. Because random assignment of inbred laboratory mice to well-defined social environments allows accurate and repeated measurements of behavioral and endocrine parameters, transgenic mice provide a preclinical framework with which to begin to determine gene-environment mechanisms. In this study, we found that female C3(1)/SV40 T-antigen mice deprived of social interaction from weaning exhibited increased expression of genes encoding key metabolic pathway enzymes in the premalignant mammary gland. Chronic social isolation was associated with up regulated lipid synthesis and glycolytic pathway gene expression-both pathways are known to contribute to increased breast cancer growth. Consistent with the expression of metabolic genes in premalignant mammary tissue, isolated mice subsequently developed a significantly larger mammary gland tumors burden compared with group-housed mice. Endocrine evaluation confirmed that isolated mice developed a heightened corticosterone stress response compared with group housed mice. Together, these transdisciplinary studies show for the first time that an adverse social environment is associated with altered mammary gland gene expression and tumor growth. Moreover, the identification of specific alterations in metabolic pathways gene expression favoring tumor growth suggests potential molecular biomarkers and/or targets (e.g., fatty acid synthesis) for preventive intervention in breast cancer. PMID- 19789296 TI - Isolating the effects of social interactions on cancer biology. AB - This perspective on Williams et al. (beginning on p. 850 in this issue of the journal) examines the connections between biological responses activated during psychosocial stress and mammary tumorigenesis. Experiments in mouse models of cancer are identifying aspects of tumor biology that may be regulated by hormones such as glucocorticoids released during psychosocial stress. Our growing understanding of the actions of glucocorticoids on breast tumors could lead to important changes in cancer treatment. PMID- 19789297 TI - Eleostearic Acid inhibits breast cancer proliferation by means of an oxidation dependent mechanism. AB - Eleostearic acid (alpha-ESA) is a conjugated linolenic acid that makes up approximately 60% of Momordica charantia (bitter melon) seed oil. Prior work found that water extract from bitter melon was able to inhibit breast cancer. Here, we investigated effects of alpha-ESA on both estrogen receptor (ER) negative MDA-MB-231 (MDA-wt) and ER-positive MDA-ERalpha7 human breast cancer cells. We found that alpha-ESA inhibited proliferation of both MDA-wt and MDA ERalpha7 cells, whereas conjugated linoleic acid had comparatively weak antiproliferative activity at 20 to 80 micromol/L concentrations. We also found that alpha-ESA (40 micromol/L) treatment led to apoptosis in the range of 70% to 90% for both cell lines, whereas conjugated linoleic acid (40 micromol/L) resulted in only 5% to 10% apoptosis, similar to results for control untreated cells. Addition of alpha-ESA also caused loss of mitochondrial membrane potential and translocation of apoptosis-inducing factor as well as endonuclease G from the mitochondria to the nucleus. Additionally, alpha-ESA caused a G(2)-M block in the cell cycle. We also investigated the potential for lipid peroxidation to play a role in the inhibitory action of alpha-ESA. We found that when the breast cancer cells were treated with alpha-ESA in the presence of the antioxidant alpha tocotrienol (20 micromol/L), the growth inhibition and apoptosis effects of alpha ESA were lost. An AMP-activated protein kinase inhibitor (Dorsomorphin) was also able to partially abrogate the effects of alpha-ESA, whereas a caspase inhibitor (BOC-D-FMK) did not. These results illustrate that alpha-ESA can block breast cancer cell proliferation and induce apoptosis through a mechanism that may be oxidation dependent. PMID- 19789298 TI - Detection of MGMT promoter methylation in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter single nucleotide polymorphism. AB - Methylation of the CpG island in the MGMT promoter region is a frequent event in several cancer types including colorectal cancer, lung cancer, lymphoma, and glioblastoma. A correlation between methylation and the T allele of the rs16906252 single nucleotide polymorphism (SNP) in colorectal carcinomas has previously been reported. As aberrant MGMT methylation can be an early event in tumor development, we tested the hypothesis that normal individuals possessing the T allele may be predisposed to somatic methylation at the MGMT promoter. Peripheral blood monononuclear cell DNA from 89 normal, healthy individuals was genotyped at rs1690625 and assessed for the methylation status of the MGMT promoter region using independent quantitative methodologies capable of detecting low-level methylation: MethyLight and Sensitive Melting Analysis after Real-time Methylation-Specific PCR (SMART-MSP). There was a strong association between presence of the T allele and detectable methylation (P = 0.00005) in the peripheral blood DNA. Furthermore, when a MSP assay flanking the SNP was used to amplify methylated sequences in heterozygotes, only the T allele was methylated. Thus, detectable somatic methylation of the MGMT promoter in normal individuals is strongly associated with the T allele of the rs16906252 MGMT promoter SNP. PMID- 19789299 TI - All-trans retinoic acid suppresses Stat3 signaling during skin carcinogenesis. AB - Squamous cell carcinoma (SCC) of the skin is the most clinically aggressive form of nonmelanoma skin cancer. We have determined the effects of all-trans retinoic acid (ATRA), a naturally occurring chemopreventive retinoid, on signal transducer and activator of transcription 3 (Stat3) signaling during the development of skin SCC. Stat3 is a transcription factor that plays a critical role in cell proliferation and survival, and it is constitutively active in several malignant cell types. We have previously shown that Stat3 is required for the initiation, promotion, and progression of skin SCC. ATRA is a highly efficient suppressor of tumor formation in the two-stage mouse skin carcinogenesis model and we have shown that this effect correlates with the suppression of the B-Raf/Mek/Erk signaling pathway. In this study, we have determined the pattern of Stat3 phosphorylation throughout the course of the two-stage protocol, both in the presence and absence of ATRA. We have used both SENCAR mice and K5.Stat3C transgenic mice, which express the Stat3C protein, a constitutively active form of Stat3, in the skin. Using Western blotting and immunohistochemical staining with phosphospecific antibodies, we show that coadministration of ATRA suppressed the 12-O-tetradecanoylphorbol-13-acetate-induced phosphorylation of Stat3 in both models, but was only able to suppress tumor formation in the SENCAR mice. Surprisingly, ATRA actually enhanced tumor formation in 12-O-tetradecanoylphorbol 13-acetate-treated K5.Stat3C mice. We hypothesize that ATRA blocks tumor formation, at least in part, by targeting events upstream of Stat3, such as the B Raf/Mek/Erk pathway, and that in the K5.Stat3C mice, in which Stat3 activity is constitutive, it cannot suppress tumor formation. PMID- 19789300 TI - Urinary phytoestrogen excretion and postmenopausal breast cancer risk: the multiethnic cohort study. AB - The objective of this study was to examine the association of urinary phytoestrogens with the risk of postmenopausal breast cancer. Participants in the Multiethnic Cohort Study included 36,458 postmenopausal women who provided blood or urine specimens. A nested case-control study of breast cancer with biospecimens was created in which cases diagnosed after specimen collection were matched to two controls. Two hundred fifty-one women with breast cancer and 462 controls had urine available for analysis of urinary phytoestrogens. Odds ratios (OR) and 95% confidence intervals (CI) were obtained using conditional logistic regression. A nonmonotonic inverse trend (P = 0.04) in breast cancer risk was associated with increasing urinary excretion of genistein (OR 25th-75th percentile, 0.88; 95% CI, 0.78-0.99) and total isoflavones (OR 25th-75th percentile, 0.80; 95% CI, 0.65-0.99). A significant reduction in breast cancer risk in Japanese-American women was associated with the highest compared with the lowest quartile excretion of urinary daidzein (OR, 0.41; 95% CI, 0.19-0.89; P(trend), 0.005). The risk of breast cancer was reduced among White women with the highest compared with the lowest quartile excretion of equol (OR, 0.27; 95% CI, 0.08-0.95), although the trend in risk was not significant (P = 0.07). Our results provide some support to the hypothesis that a diet rich in isoflavones from soy products reduces the risk of postmenopausal breast cancer, particularly in populations with comparatively high excretion of phytoestrogens. PMID- 19789301 TI - UVR exposure sensitizes keratinocytes to DNA adduct formation. AB - UV radiation (UVR) and exposure to tobacco smoke, a source of polycyclic aromatic hydrocarbons (PAH), have been linked to skin carcinogenesis. UVR-mediated activation of the aryl hydrocarbon receptor (AhR) stimulates the transcription of CYP1A1 and CYP1B1, which encode proteins that convert PAH to genotoxic metabolites. We determined whether UVR exposure sensitized human keratinocytes to PAH-induced DNA adduct formation. UVR exposure induced CYP1A1 and CYP1B1 in HaCaT cells, an effect that was mimicked by photooxidized tryptophan (aTRP) and FICZ, a component of aTRP. UVR exposure or pretreatment with aTRP or FICZ also sensitized cells to benzo(a)pyrene (B[a]P)-induced DNA adduct formation. alphaNF, an AhR antagonist, suppressed UVR-, aTRP-, and FICZ-mediated induction of CYP1A1 and CYP1B1 and inhibited B[a]P-induced DNA adduct formation. Treatment with 17-AAG, an Hsp90 inhibitor, caused a marked decrease in levels of AhR; inhibited UVR-, aTRP-, and FICZ-mediated induction of CYP1A1 and CYP1B1; and blocked the sensitization of HaCaT cells to B[a]P-induced DNA adduct formation. FICZ has been suggested to be a physiologic ligand of the AhR that may have systemic effects. Hence, studies of FICZ were also carried out in MSK-Leuk1 cells, a model of oral leukoplakia. Pretreatment with alpha-naphthoflavone or 17-AAG blocked FICZ mediated induction of CYP1A1 and CYP1B1, and suppressed the increased B[a]P induced DNA adduct formation. Collectively, these results suggest that sunlight may activate AhR signaling and thereby sensitize cells to PAH-mediated DNA adduct formation. Antagonists of AhR signaling may have a role in the chemoprevention of photocarcinogenesis. PMID- 19789302 TI - Antibody-mediated inhibition of cathepsin S blocks colorectal tumor invasion and angiogenesis. AB - PURPOSE: Cathepsin S is a cysteine protease that promotes the invasion of tumor and endothelial cells during cancer progression. Here we investigated the potential to target cathepsin S using an antagonistic antibody, Fsn0503, to block these tumorigenic effects. EXPERIMENTAL DESIGN: A panel of monoclonal antibodies was raised to human cathepsin S. The effects of a selected antibody were subsequently determined using invasion and proteolysis assays. Endothelial cell tube formation and aorta sprouting assays were done to examine antiangiogenic effects. In vivo effects were also evaluated using HCT116 xenograft studies. RESULTS: A selected cathepsin S antibody, Fsn0503, significantly blocked invasion of a range of tumor cell lines, most significantly HCT116 colorectal carcinoma cells, through inhibition of extracellular cathepsin S-mediated proteolysis. We subsequently found enhanced expression of cathepsin S in colorectal adenocarcinoma biopsies when compared with normal colon tissue. Moreover, Fsn0503 blocked endothelial cell capillary tube formation and aortic microvascular sprouting. We further showed that administration of Fsn0503 resulted in inhibition of tumor growth and neovascularization of HCT116 xenograft tumors. CONCLUSIONS: These results show that blocking the invasive and proangiogenic effects of cathepsin S with antibody inhibitors may have therapeutic utility upon further preclinical and clinical evaluation. PMID- 19789303 TI - Blockade of MGMT expression by O6 benzyl guanine leads to inhibition of pancreatic cancer growth and induction of apoptosis. AB - PURPOSE: We sought to determine whether administration of a MGMT blocker, O(6) benzyl guanine (O(6)BG), at an optimal biological dose alone or in combination with gemcitabine inhibits human pancreatic cancer cell growth. EXPERIMENTAL DESIGN: Human pancreatic cancer L3.6pl and PANC1 cells were treated with O(6)BG, either alone or in combination with gemcitabine, and the therapeutic efficacy and biological activity of these drug combinations were investigated. RESULTS: O(6)BG sensitized pancreatic cancer cells to gemcitabine. Protein and mRNA expression of MGMT, cyclin B1, cyclin B2, cyclin A, and ki-67 were significantly decreased in the presence of O(6)BG. In sharp contrast, protein expression and mRNA message of p21(cip1) were significantly increased. Interestingly, O(6)BG increases p53 mediated p21(cip1) transcriptional activity and suppresses cyclin B1. In addition, our results indicate that p53 is recruited to p21 promoter. Furthermore, an increase in p21(cip1) and a decrease in cyclin transcription are p53 dependent. The volume of pancreatic tumors was reduced by 27% in mice treated with gemcitabine alone, by 47% in those treated with O(6)BG alone, and by 65% in those mice given combination. Immunohistochemical analysis showed that O(6)BG inhibited expression of MGMT and cyclins, and increased expression of p21(cip1). Furthermore, there was a significant decrease in tumor cell proliferation and an increase in tumor cell apoptosis. CONCLUSIONS: Collectively, our results show that decreased MGMT expression is correlated with p53 activation, and significantly reduced primary pancreatic tumor growth. These findings suggest that O(6)BG either alone or in combination with gemcitabine may provide a novel and effective approach for the treatment of human pancreatic cancer. PMID- 19789304 TI - Lymph node-targeted immunotherapy mediates potent immunity resulting in regression of isolated or metastatic human papillomavirus-transformed tumors. AB - PURPOSE: The goal of this study was to investigate the therapeutic potential of a novel immunotherapy strategy resulting in immunity to localized or metastatic human papillomavirus 16-transformed murine tumors. EXPERIMENTAL DESIGN: Animals bearing E7-expressing tumors were coimmunized by lymph node injection with E7 49 57 antigen and TLR3-ligand (synthetic dsRNA). Immune responses were measured by flow cytometry and antitumor efficacy was evaluated by tumor size and survival. In situ cytotoxicity assays and identification of tumor-infiltrating lymphocytes and T regulatory cells were used to assess the mechanisms of treatment resistance in bulky disease. Chemotherapy with cyclophosphamide was explored to augment immunotherapy in late-stage disease. RESULTS: In therapeutic and prophylactic settings, immunization resulted in a considerable expansion of E7 49-57 antigen specific T lymphocytes in the range of 1/10 CD8(+) T cells. The resulting immunity was effective in suppressing disease progression and mortality in a pulmonary metastatic disease model. Therapeutic immunization resulted in control of isolated tumors up to a certain volume, and correlated with antitumor immune responses measured in blood. In situ analysis showed that within bulky tumors, T cell function was affected by negative regulatory mechanisms linked to an increase in T regulatory cells and could be overcome by cyclophosphamide treatment in conjunction with immunization. CONCLUSIONS: This study highlights a novel cancer immunotherapy platform with potential for translatability to the clinic and suggests its potential usefulness for controlling metastatic disease, solid tumors of limited size, or larger tumors when combined with cytotoxic agents that reduce the number of tumor-infiltrating T regulatory cells. PMID- 19789305 TI - A novel reduced immunogenicity bispecific targeted toxin simultaneously recognizing human epidermal growth factor and interleukin-4 receptors in a mouse model of metastatic breast carcinoma. AB - PURPOSE: To develop a targeted biological drug that when systemically injected can penetrate to metastatic breast cancer tumors, one needs a drug of high potency and reduced immunogenicity. Thus, we bioengineered a novel bispecific ligand-directed toxin (BLT) targeted by dual high-affinity cytokines with a PE(38)KDEL COOH terminus. Our purpose was to reduce toxin immunogenicity using mutagenesis, measure the ability of mutated drug to elicit B-cell antitoxin antibody responses, and show that mutated drug was effective against systemic breast cancer in vivo. EXPERIMENTAL DESIGN: A new BLT was created in which both human epidermal growth factor (EGF) and interleukin 4 cytokines were cloned onto the same single-chain molecule with truncated Pseudomonas exotoxin (PE(38)). Site specific mutagenesis was used to mutate amino acids in seven key epitopic toxin regions that dictate B-cell generation of neutralizing antitoxin antibodies. Bioassays were used to determine whether mutation reduced potency, and ELISA studies were done to determine whether antitoxin antibodies were reduced. Finally, a genetically altered luciferase xenograft model was used; this model could be imaged in real time to determine the effect on the systemic malignant human breast cancer MDA-MB-231. RESULTS: EGF4KDEL 7mut was significantly effective against established systemic human breast cancer and prevented metastatic spread. Mutagenesis reduced immunogenicity by approximately 90% with no apparent loss in in vitro or in vivo activity. CONCLUSIONS: Because EGF4KDEL 7mut was highly effective even when we waited 26 days to begin therapy and because immunogenicity was significantly reduced, we can now give multiple drug treatments for chemotherapy-refractory breast cancer in clinical trials. PMID- 19789306 TI - A comparison of phase II study strategies. AB - The traditional oncology drug development paradigm of single arm phase II studies followed by a randomized phase III study has limitations for modern oncology drug development. Interpretation of single arm phase II study results is difficult when a new drug is used in combination with other agents or when progression-free survival is used as the endpoint rather than tumor shrinkage. Randomized phase II studies are more informative for these objectives but increase both the number of patients and time required to determine the value of a new experimental agent. In this article, we compare different phase II study strategies to determine the most efficient drug development path in terms of number of patients and length of time to conclusion of drug efficacy on overall survival. PMID- 19789307 TI - Nuclear NF-kappaB p65 phosphorylation at serine 276 by protein kinase A contributes to the malignant phenotype of head and neck cancer. AB - PURPOSE: Aberrant nuclear activation and phosphorylation of the canonical NF kappaB subunit RELA/p65 at Serine-536 by inhibitor kappaB kinase is prevalent in head and neck squamous cell carcinoma (HNSCC), but the role of other kinases in NF-kappaB activation has not been well defined. Here, we investigated the prevalence and function of p65-Ser276 phosphorylation by protein kinase A (PKA) in the malignant phenotype and gene transactivation, and studied p65-Ser276 as a potential target for therapy. EXPERIMENTAL DESIGN: Phospho and total p65 protein expression and localization were determined in HNSCC tissue array and in cell lines. The effects of the PKA inhibitor H-89 on NF-kappaB activation, downstream gene expression, cell proliferation and cell cycle were examined. Knockdown of PKA by specific siRNA confirmed the specificity. RESULTS: NF-kappaB p65 phosphorylated at Ser276 was prevalent in HNSCC and adjacent dysplastic mucosa, but localized to the cytoplasm in normal mucosa. In HNSCC lines, tumor necrosis factor-alpha (TNF-alpha) significantly increased, whereas H-89 inhibited constitutive and TNF-alpha-induced nuclear p65 (Ser276) phosphorylation, and significantly suppressed NF-kappaB and target gene IL-8 reporter activity. Knockdown of PKA by small interfering RNA inhibited NF-kappaB, IL-8, and BCL-XL reporter gene activities. H-89 suppressed cell proliferation, induced cell death, and blocked the cell cycle in G(1)-S phase. Consistent with its biological effects, H-89 down-modulated expression of NF-kappaB-related genes Cyclin D1, BCL2, BCL-XL, COX2, IL-8, and VEGF, as well as induced cell cycle inhibitor p21(CIP1/WAF1), while suppressing proliferative marker Ki67. CONCLUSIONS: NF kappaB p65 (Ser276) phosphorylation by PKA promotes the malignant phenotype and holds potential as a therapeutic target in HNSCC. PMID- 19789308 TI - Disrupting polyamine homeostasis as a therapeutic strategy for neuroblastoma. AB - MYC genes are deregulated in a plurality of human cancers. Through direct and indirect mechanisms, the MYC network regulates the expression of > 15% of the human genome, including both protein-coding and noncoding RNAs. This complexity has complicated efforts to define the principal pathways mediating MYC's oncogenic activity. MYC plays a central role in providing for the bioenergetic and biomass needs of proliferating cells, and polyamines are essential cell constituents supporting many of these functions. The rate-limiting enzyme in polyamine biosynthesis, ODC, is a bona fide MYC target, as are other regulatory enzymes in this pathway. A wealth of data link enhanced polyamine biosynthesis to cancer progression, and polyamine depletion may limit the malignant transformation of preneoplastic lesions. Studies with transgenic cancer models also support the finding that the effect of MYC on tumor initiation and progression can be attenuated through the repression of polyamine production. High-risk neuroblastomas (an often lethal embryonal tumor in which MYC activation is paramount) deregulate numerous polyamine enzymes to promote the expansion of intracellular polyamine pools. Selective inhibition of key enzymes in this pathway, e.g., using DFMO and/or SAM486, reduces tumorigenesis and synergizes with chemotherapy to regress tumors in preclinical models. Here, we review the potential clinical application of these and additional polyamine depletion agents to neuroblastoma and other advanced cancers in which MYC is operative. PMID- 19789309 TI - Dendritic cell vaccination combined with CTLA4 blockade in patients with metastatic melanoma. AB - PURPOSE: Tumor antigen-loaded dendritic cells (DC) are believed to activate antitumor immunity by stimulating T cells, and CTL-associated antigen 4 (CTLA4) blocking antibodies should release a key negative regulatory pathway on T cells. The combination was tested in a phase I clinical trial in patients with advanced melanoma. EXPERIMENTAL DESIGN: Autologous DC were pulsed with MART-1(26-35) peptide and administered with a dose escalation of the CTLA4-blocking antibody tremelimumab. Sixteen patients were accrued to five dose levels. Primary end points were safety and immune effects; clinical efficacy was a secondary end point. RESULTS: Dose-limiting toxicities of grade 3 diarrhea and grade 2 hypophysitis developed in two of three patients receiving tremelimumab at 10 mg/kg monthly. Four patients had an objective tumor response, two partial responses and two complete responses, all melanoma free between 2 and 4 years after study initiation. There was no difference in immune monitoring results between patients with an objective tumor response and those without a response. Exploratory gene expression analysis suggested that immune-related gene signatures, in particular for B-cell function, may be important in predicting response. CONCLUSION: The combination of MART-1 peptide-pulsed DC and tremelimumab results in objective and durable tumor responses at the higher range of the expected response rate with either agent alone. PMID- 19789310 TI - Associations of a polymorphism in the ornithine decarboxylase gene with colorectal cancer survival. AB - PURPOSE: Activity of ornithine decarboxylase (ODC), the first enzyme in polyamine synthesis, is required for normal growth and is elevated in many cancers, including colorectal cancer. We examined associations of the +316 ODC1 single nucleotide polymorphism (SNP) with colorectal cancer-specific survival among colorectal cancer cases, and then investigated its functional significance in colon cancer cells. EXPERIMENTAL DESIGN: The study included 400 incident stage I III colorectal cancer cases from the population-based University of California Irvine Gene-Environment Study of Familial Colorectal Cancer (diagnosed from 1994 to 1996 with follow-up through March 2008). The primary outcome was colorectal cancer-specific survival dependent on ODC1 (rs2302615) genotype (GG versus GA/AA). In human colon cancer cell lines, ODC1 allele-specific binding of E-box transcription factors was determined via Western blotting and chromatin immunoprecipitation assays. ODC1 allele-specific promoter activity was determined using promoter constructs in combination with vectors expressing either the transcriptional activator c-MYC or the repressor MAD1. RESULTS: Genotype-specific survival differences were observed among colorectal cancer cases: compared with cases with the ODC1 GG genotype (hazards ratio, 1; reference) the adjusted colorectal cancer-specific survival hazards ratio was 2.02 (95% confidence interval, 1.17-3.50) for ODC1 GA/AA cases (P = 0.012). In colon cancer cells, the ODC1 SNP, flanked by two E-boxes, predicts ODC1 promoter activity. The E-box activator c-MYC and repressors MAD1 and MAD4 preferentially bind to ODC1 minor A alleles, compared with major G-alleles, in cultured cells. CONCLUSIONS: These results have implications for conditional regulation of polyamine homeostasis and suggest a model in which the ODC1 SNP may be protective for colon adenoma recurrence and detrimental for survival after colon cancer diagnosis. PMID- 19789311 TI - Translocator protein blockade reduces prostate tumor growth. AB - PURPOSE: The transmembrane molecule, translocator protein (TSPO), has been implicated in the progression of epithelial tumors. TSPO gene expression is high in tissues involved in steroid biosynthesis, neurodegenerative disease, and in cancer, and overexpression has been shown to contribute to pathologic conditions including cancer progression in several different models. The goal of our study was to examine the expression and biological relevance of TSPO in prostate cancer and show that the commonly prescribed benzodiazepine lorazepam, a ligand for TSPO, exhibits anticancer properties. EXPERIMENTAL DESIGN: Immunohistochemical analysis using tissue microarrays was used to determine the expression profile of TSPO in human prostate cancer tissues. To show the effect of TSPO ligands (lorazepam and PK11195) in prostate cancer, we used cell proliferation assays, apoptosis ELISA, prostate cancer xenograft study, and immunohistochemistry. RESULTS: TSPO expression is increased in prostatic intraepithelial neoplasia, primary prostate cancer, and metastases compared with normal prostate tissue and benign prostatic hyperplasia. Furthermore, TSPO expression correlates with disease progression, as TSPO levels increased with increasing Gleason sum and stage with prostate cancer metastases demonstrating the highest level of expression among all tissues examined. Functionally, we have shown that lorazepam has antiproliferative and proapoptotic properties in vitro and in vivo. Additionally, we have shown that TSPO overexpression in nontumorigenic cells conferred susceptibility to lorazepam-induced growth inhibition. CONCLUSION: These data suggest that blocking TSPO function in tumor cells induces cell death and denotes a survival role for TSPO in prostate cancer and provides the first evidence for the use of benzodiazepines in prostate cancer therapeutics. PMID- 19789312 TI - MicroRNA expression in squamous cell carcinoma and adenocarcinoma of the esophagus: associations with survival. AB - PURPOSE: The dismal outcome of esophageal cancer patients highlights the need for novel prognostic biomarkers, such as microRNAs (miRNA). Although recent studies have established the role of miRNAs in esophageal carcinoma, a comprehensive multicenter study investigating different histologic types, including squamous cell carcinoma (SCC) and adenocarcinoma with or without Barrett's, is still lacking. EXPERIMENTAL DESIGN: miRNA expression was measured in cancerous and adjacent noncancerous tissue pairs collected from 100 adenocarcinoma and 70 SCC patients enrolled at four clinical centers from the United States, Canada, and Japan. Microarray-based expression was measured in a subset of samples in two cohorts and was validated in all available samples. RESULTS: In adenocarcinoma patients, miR-21, miR-223, miR-192, and miR-194 expression was elevated, whereas miR-203 expression was reduced in cancerous compared with noncancerous tissue. In SCC patients, we found elevated miR-21 and reduced miR-375 expression levels in cancerous compared with noncancerous tissue. When comparing cancerous tissue expression between adenocarcinoma and SCC patients, miR-194 and miR-375 were elevated in adenocarcinoma patients. Significantly, elevated miR-21 expression in noncancerous tissue of SCC patients and reduced levels of miR-375 in cancerous tissue of adenocarcinoma patients with Barrett's were strongly associated with worse prognosis. Associations with prognosis were independent of tumor stage or nodal status, cohort type, and chemoradiation therapy. CONCLUSIONS: Our multicenter-based results highlight miRNAs involved in major histologic types of esophageal carcinoma and uncover significant associations with prognosis. Elucidating miRNAs relevant to esophageal carcinogenesis is potentially clinically useful for developing prognostic biomarkers and identifying novel drug targets and therapies. PMID- 19789313 TI - Phase II study of neoadjuvant imatinib in glioblastoma: evaluation of clinical and molecular effects of the treatment. AB - PURPOSE: Phase I-II studies indicate that imatinib is active in glioblastoma multiforme. To better understand the molecular and clinical effects of imatinib in glioblastoma multiforme, we conducted a neoadjuvant study of imatinib with pretreatment and posttreatment biopsies. EXPERIMENTAL DESIGN: Patients underwent a computerized tomography-guided biopsy of their brain tumors. If diagnosed with glioblastoma multiforme, they were immediately treated with 7 days of imatinib 400 mg orally twice daily followed by either definitive surgery or re-biopsy. Pretreatment and posttreatment tissue specimens were tested by immunohistochemistry for Ki67 and microvessel destiny, and posttreatment specimens were analyzed for the presence of intact imatinib in tissue. Furthermore, pretreatment and posttreatment pairs were analyzed by Western blotting for activation of platelet-derived growth factor receptor, epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase/AKT, and mitogen activated protein kinase signaling pathways. Pharmacokinetic studies were also done. RESULTS: Twenty patients were enrolled. Median survival was 6.2 months. Intact imatinib was detected in the posttreatment tissue specimens using mass spectrometry. There was no evidence of a drug effect on proliferation, as evidenced by a change in Ki67 expression. Biochemical evidence of response, as shown by decreased activation of AKT and mitogen-activated protein kinase or increased p27 level, was detected in 4 of 11 patients with evaluable, matched pre and post-imatinib biopsies. Two patients showed high-level EGFR activation and homozygous EGFR mutations, whereas one patient had high-level platelet-derived growth factor receptor-B activation. CONCLUSIONS: Intact imatinib was detected in glioblastoma multiforme tissue. However, the histologic and immunoblotting evaluations suggest that glioblastoma multiforme proliferation and survival mechanisms are not substantially reduced by imatinib therapy in most patients. PMID- 19789314 TI - Spectrum of phosphatidylinositol 3-kinase pathway gene alterations in bladder cancer. AB - PURPOSE: The phosphatidylinositol 3-kinase (PI3K) pathway can be activated by alterations affecting several pathway components. For rational application of targeted therapies, detailed understanding of tumor biology and approaches to predict efficacy in individual tumors are required. Our aim was to assess the frequency and distribution of pathway alterations in bladder cancer. EXPERIMENTAL DESIGN: We examined the pathway components (PIK3CA, PTEN, TSC1, RHEB, and LKB1) and putative upstream regulators (FGFR3 and RAS genes) for mutation, allelic loss, copy number alteration, and expression in bladder tumors and cell lines. RESULTS: No mutations were found in RHEB and only a single mutation in LKB1. PIK3CA mutations were detected in 25% of tumors and 26% of cell lines with a significant excess of helical domain mutations (E542K and E545K). There was over representation but not amplification of the gene. Loss of heterozygosity of the PTEN region and homozygous deletion were found in 12% and 1.4% of tumors, and reduced expression in 49%. Forty-six percent of cell lines showed alterations that implicated PTEN. Sixteen percent of tumors and 11% of cell lines showed TSC1 mutation, and 9q loss of heterozygosity was common (57%). Pathway alterations were independently distributed, suggesting that the mutation of two pathway members may have additive or synergistic effects through noncanonical functions. CONCLUSIONS: PI3K pathway alterations are common in bladder cancer. The lack of redundancy of alterations suggests that single-agent PI3K-targeted therapy may not be successful in these cancers. This study provides a well-characterized series of cell lines for use in preclinical studies of targeted agents. PMID- 19789316 TI - A phase II study of SGN-30 in cutaneous anaplastic large cell lymphoma and related lymphoproliferative disorders. AB - PURPOSE: An open-label, multicenter, phase II study was conducted to define the safety and antitumor activity of the monoclonal antibody SGN-30 in patients with CD30(+) primary cutaneous anaplastic large cell lymphoma (pc-ALCL), lymphomatoid papulosis (LyP), or transformed mycosis fungoides (T-MF). EXPERIMENTAL DESIGN: In the initial course (six doses), patients received i.v. SGN-30 every 3 weeks; eligible patients could receive two additional courses. The initial dose level of 4 mg/kg was increased to 12 mg/kg by protocol amendment. RESULTS: The overall objective response rate [complete response (CR) + partial response (PR)] was 70% (16 of 23 patients): 10 patients achieved a CR and another 6 patients achieved a PR. Overall, clinical benefit of SGN-30, as assessed by achieving a response to therapy or stable disease (CR + PR + stable disease), was shown by 87% of patients during the study, including all patients with pc-ALCL or LyP and two thirds of patients with T-MF or with multiple clinical diagnoses. Nine of the 10 patients who achieved a CR and 5 of the 6 patients who achieved a PR were in remission at their follow-up evaluation (median duration, 84 days). Fifteen of 23 patients (65%) experienced at least one adverse event during the study, most of which were mild or moderate. CONCLUSIONS: SGN-30 was clinically active in 16 of 23 patients with heavily pretreated pc-ALCL, LyP, and T-MF and was well tolerated in this study. PMID- 19789317 TI - Rapid development of hypertension by sorafenib: toxicity or target? AB - Blood pressure elevation is likely a pharmacodynamic marker of VEGF signaling pathway (VSP) inhibition and could be useful for optimizing safe and effective VSP inhibitor dosing. Blood pressure rises on the first day of treatment, facilitating design and interpretation of future trials aiming to correlate blood pressure changes with clinical outcomes. PMID- 19789315 TI - Antiglioma immunological memory in response to conditional cytotoxic/immune stimulatory gene therapy: humoral and cellular immunity lead to tumor regression. AB - PURPOSE: Glioblastoma multiforme is a deadly primary brain cancer. Because the tumor kills due to recurrences, we tested the hypothesis that a new treatment would lead to immunological memory in a rat model of recurrent glioblastoma multiforme. EXPERIMENTAL DESIGN: We developed a combined treatment using an adenovirus (Ad) expressing fms-like tyrosine kinase-3 ligand (Flt3L), which induces the infiltration of immune cells into the tumor microenvironment, and an Ad expressing herpes simplex virus-1-thymidine kinase (TK), which kills proliferating tumor cells in the presence of ganciclovir. RESULTS: This treatment induced immunological memory that led to rejection of a second glioblastoma multiforme implanted in the contralateral hemisphere and of an extracranial glioblastoma multiforme implanted intradermally. Rechallenged long-term survivors exhibited anti-glioblastoma multiforme-specific T cells and displayed specific delayed-type hypersensitivity. Using depleting antibodies, we showed that rejection of the second tumor was dependent on CD8(+) T cells. Circulating anti glioma antibodies were observed when glioblastoma multiforme cells were implanted intradermally in naive rats or in long-term survivors. However, rats bearing intracranial glioblastoma multiforme only exhibited circulating antitumoral antibodies upon treatment with Ad-Flt3L + Ad-TK. This combined treatment induced tumor regression and release of the chromatin-binding protein high mobility group box 1 in two further intracranial glioblastoma multiforme models, that is, Fisher rats bearing intracranial 9L and F98 glioblastoma multiforme cells. CONCLUSIONS: Treatment with Ad-Flt3L + Ad-TK triggered systemic anti-glioblastoma multiforme cellular and humoral immune responses, and anti-glioblastoma multiforme immunological memory. Release of the chromatin-binding protein high mobility group box 1 could be used as a noninvasive biomarker of therapeutic efficacy for glioblastoma multiforme. The robust treatment efficacy lends further support to its implementation in a phase I clinical trial. PMID- 19789318 TI - Loss of heterozygosity at 2q37 in sporadic Wilms' tumor: putative role for miR 562. AB - PURPOSE: Wilms' tumor is a childhood cancer of the kidney with an incidence of approximately 1 in 10,000. Cooccurrence of Wilms' tumor with 2q37 deletion syndrome, an uncommon constitutional chromosome abnormality, has been reported previously in three children. Given these are independently rare clinical entities, we hypothesized that 2q37 harbors a tumor suppressor gene important in Wilms' tumor pathogenesis. EXPERIMENTAL DESIGN: To test this, we performed loss of heterozygosity analysis in a panel of 226 sporadic Wilms' tumor samples and mutation analysis of candidate genes. RESULTS: Loss of heterozygosity was present in at least 4% of cases. Two tumors harbored homozygous deletions at 2q37.1, supporting the presence of a tumor suppressor gene that follows a classic two-hit model. However, no other evidence of second mutations was found, suggesting that heterozygous deletion alone may be sufficient to promote tumorigenesis in concert with other genomic abnormalities. We show that miR-562, a microRNA within the candidate region, is expressed only in kidney and colon and regulates EYA1, a critical gene for renal development. miR-562 expression is reduced in Wilms' tumor and may contribute to tumorigenesis by deregulating EYA1. Two other candidate regions were localized at 2q37.3 and 2qter, but available data from patients with constitutional deletions suggest that these probably do not confer a high risk for Wilms' tumor. CONCLUSIONS: Our data support the presence of a tumor suppressor gene at 2q37.1 and suggest that, in individuals with constitutional 2q37 deletions, any increased risk for developing Wilms' tumor likely correlates with deletions encompassing 2q37.1. PMID- 19789319 TI - Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks. AB - PURPOSE: As chemotherapy and molecular therapy improve the systemic survival of breast cancer patients, the incidence of brain metastases increases. Few therapeutic strategies exist for the treatment of brain metastases because the blood-brain barrier severely limits drug access. We report the pharmacokinetic, efficacy, and mechanism of action studies for the histone deactylase inhibitor vorinostat (suberoylanilide hydroxamic acid) in a preclinical model of brain metastasis of triple-negative breast cancer. EXPERIMENTAL DESIGN: The 231-BR brain trophic subline of the MDA-MB-231 human breast cancer cell line was injected into immunocompromised mice for pharmacokinetic and metastasis studies. Pharmacodynamic studies compared histone acetylation, apoptosis, proliferation, and DNA damage in vitro and in vivo. RESULTS: Following systemic administration, uptake of [(14)C]vorinostat was significant into normal rodent brain and accumulation was up to 3-fold higher in a proportion of metastases formed by 231 BR cells. Vorinostat prevented the development of 231-BR micrometastases by 28% (P = 0.017) and large metastases by 62% (P < 0.0001) compared with vehicle treated mice when treatment was initiated on day 3 post-injection. The inhibitory activity of vorinostat as a single agent was linked to a novel function in vivo: induction of DNA double-strand breaks associated with the down-regulation of the DNA repair gene Rad52. CONCLUSIONS: We report the first preclinical data for the prevention of brain metastasis of triple-negative breast cancer. Vorinostat is brain permeable and can prevent the formation of brain metastases by 62%. Its mechanism of action involves the induction of DNA double-strand breaks, suggesting rational combinations with DNA active drugs or radiation. PMID- 19789320 TI - A phase I dose-finding study of 5-azacytidine in combination with sodium phenylbutyrate in patients with refractory solid tumors. AB - PURPOSE: This was a phase I trial to determine the minimal effective dose and optimal dose schedule for 5-azacytidine (5-AC) in combination with sodium phenylbutyrate in patients with refractory solid tumors. The pharmacokinetics, pharmacodynamics, and antineoplastic effects were also studied. EXPERIMENTAL DESIGN: Three dosing regimens were studied in 27 patients with advanced solid tumors, and toxicity was recorded. The pharmacokinetics of the combination of drugs was evaluated. Repeat tumor biopsies and peripheral blood mononuclear cells (PBMC) were analyzed to evaluate epigenetic changes in response to therapy. EBV titers were evaluated as a surrogate measure for gene re-expression of epigenetic modulation in PBMC. RESULTS: The three dose regimens of 5-AC and phenylbutyrate were generally well tolerated and safe. A total of 48 cycles was administrated to 27 patients. The most common toxicities were bone marrow suppression-related neutropenia and anemia, which were minor. The clinical response rate was disappointing for the combination of agents. One patient showed stable disease for 5 months whereas 26 patients showed progressive disease as the best tumor response. The administration of phenylbutyrate and 5-AC did not seem to alter the pharmacokinetics of either drug. Although there were individual cases of targeted DNA methyltransferase activity and histone H3/4 acetylation changes from paired biopsy or PBMC, no conclusive statement can be made based on these limited correlative studies. CONCLUSION: The combination of 5-AC and phenylbutyrate across three dose schedules was generally well tolerated and safe, yet lacked any real evidence for clinical benefit. PMID- 19789321 TI - An miR-502-binding site single-nucleotide polymorphism in the 3'-untranslated region of the SET8 gene is associated with early age of breast cancer onset. AB - PURPOSE: MicroRNAs regulate gene expression by binding to the 3'-untranslated region (UTR) of target genes. Single-nucleotide polymorphisms of critical genes may affect their regulation by microRNAs. We have identified a single-nucleotide polymorphism within the miR-502 seed binding region in the 3'-UTR of the SET8 gene. SET8 methylates TP53 and regulates genome stability. We investigated the role of this SET8 single-nucleotide polymorphism and in concert with the TP53 codon 72 single-nucleotide polymorphism in the propensity for onset of breast cancer. EXPERIMENTAL DESIGN: We measured the SET8 single-nucleotide polymorphisms in a case-control study on 1,110 breast cancer cases and 1,097 controls. RESULTS: The SET8 CC and TP53 GG genotypes were independently associated with an earlier age of breast cancer onset in an allele-dose-dependent manner (for SET8, 52.2 years for TT, 51.4 for TC, and 49.5 for CC; and for TP53, 53.1 years for CC, 51.5 for GC, 50.7 for GG). Individuals with combined SET8 CC and TP53 GG genotypes developed cancer at a median age of 47.7 years as compared with 54.6 years for individuals with combined SET8 TT and TP53 CC genotypes. In the 51 breast cancer tissue samples tested, the SET8 CC genotype was associated with reduced SET8, but not miR-502, transcript levels. CONCLUSIONS: These data suggest that the miR-502 binding site single-nucleotide polymorphism in the 3'-UTR of SET8 modulates SET8 expression and contributes to the early development of breast cancer, either independently or together with the TP53 codon 72 single-nucleotide polymorphism. Larger studies with multiethnic groups are warranted to validate our findings. PMID- 19789322 TI - Local biosynthesis of estrogen in human endometrial carcinoma through tumor stromal cell interactions. AB - PURPOSE: The metabolism and synthesis of intratumoral estrogens are thought to play a very important role in the etiology and progression of endometrial carcinoma. Aromatase is a key enzyme in the conversion of androgens to estrogens, and aromatase localization studies have reported that aromatase immunoreactivity and mRNA were detected mainly in stromal cells. However, the effect of tumor stromal interactions on local estrogen biosynthesis in endometrial carcinomas remains largely unknown. EXPERIMENTAL DESIGN: The endometrial carcinoma cell lines (Ishikawa and RL95-2) and breast carcinoma cell line (MCF-7) were cocultured with stromal cells isolated from endometrial carcinomas, and aromatization activity was measured using liquid chromatography-tandem mass spectrometry. We then confirmed the local biosynthesis of estrogens and tumor stromal interactions on aromatase activity in Ishikawa and RL95-2 cells. In addition, we also examined the effects of aromatase inhibitors on cell proliferation. RESULTS: Aromatase activity was significantly higher in cocultures with Ishikawa or RL95-2 than in each monoculture, respectively. Estrone (E(1)) concentrations were significantly higher than estradiol (E(2)) concentrations in Ishikawa and RL95-2 cells, whereas E(2) was significantly higher than E(1) in MCF 7 cells. Cell proliferation was significantly inhibited in Ishikawa and RL95-2 cell cultures treated with aromatase inhibitors compared with control cultures. CONCLUSIONS: These results indicate the contribution of not only E(2) but also E(1) to cancer cell proliferation in endometrial carcinoma. Our study may provide important information on metabolism and synthesis of intratumoral estrogens with regard to the etiology and progression of endometrial carcinoma, thus helping to achieve improved clinical responses in patients with endometrial carcinoma, who are treated with aromatase inhibitors. PMID- 19789324 TI - Targeted radioiodine therapy of neuroblastoma tumors following systemic nonviral delivery of the sodium iodide symporter gene. AB - PURPOSE: We recently reported the significant therapeutic efficacy of radioiodine therapy in various tumor mouse models following transcriptionally targeted sodium iodide symporter (NIS) gene transfer. These studies showed the high potential of NIS as a novel diagnostic and therapeutic gene for the treatment of extrathyroidal tumors. As a next crucial step towards clinical application of NIS mediated radionuclide therapy we aim at systemic delivery of the NIS gene to target extrathyroidal tumors even in the metastatic stage. EXPERIMENTAL DESIGN: In the current study, we used synthetic polymeric vectors based on pseudodendritic oligoamines with high intrinsic tumor affinity (G2-HD-OEI) to target a NIS-expressing plasmid (CMV-NIS-pcDNA3) to neuroblastoma (Neuro2A) cells. RESULTS: Incubation with NIS-containing polyplexes (G2-HD-OEI/NIS) resulted in a 51-fold increase in perchlorate-sensitive iodide uptake activity in Neuro2A cells in vitro. Through (123)I-scintigraphy and ex vivo gamma counting Neuro2A tumors in syngeneic A/J mice were shown to accumulate 8% to 13% ID/g (123)I with a biological half-life of 13 hours, resulting in a tumor-absorbed dose of 247 mGy/MBq (131)I after i.v. application of G2-HD-OEI/NIS. Nontarget organs, including liver, lung, kidneys, and spleen revealed no significant iodide uptake. Moreover, two cycles of systemic NIS gene transfer followed by (131)I application (55.5 MBq) resulted in a significant delay in tumor growth associated with markedly improved survival. CONCLUSIONS: In conclusion, our data clearly show the high potential of novel pseudodendritic polymers for tumor-specific NIS gene delivery after systemic application, opening the prospect of targeted NIS mediated radionuclide therapy of nonthyroidal tumors even in metastatic disease. PMID- 19789323 TI - Proinflammatory mediators upregulate snail in head and neck squamous cell carcinoma. AB - PURPOSE: Inflammatory cytokines have been implicated in the progression of head and neck squamous cell carcinoma (HNSCC). Herein we investigate the mechanisms by which interleukin-1beta (IL-1beta) might contribute to Epithelial-Mesenchymal Transition (EMT) in HNSCC. EXPERIMENTAL DESIGN: We evaluated the effect of IL 1beta on the molecular events of EMT in surgical specimens and HNSCC cell lines. We examined the correlation with tumor histologic features, and a SCID xenograft model was used to assess the effects of Snail overexpression. RESULTS: Cyclooxygenase-2 (COX-2)-dependent pathways contribute to the modulation of E cadherin expression in HNSCC. An inverse relationship between COX-2 and E cadherin was shown in situ by double immunohistochemical staining of human HNSCC tissue sections. Treatment of HNSCC cells with IL-1beta caused the downregulation of E-cadherin expression and upregulation of COX-2 expression. This effect was blocked in the presence of COX-2 small hairpin RNA. IL-1beta-treated HNSCC cell lines showed a significant decrease in E-cadherin mRNA and an increase in the mRNA expression of the transcriptional repressor Snail. IL-1beta exposure led to enhanced Snail binding at the chromatin level. Small hairpin RNA-mediated knockdown of Snail interrupted the capacity of IL-1beta to downregulate E cadherin. In a SCID xenograft model, HNSCC Snail-overexpressing cells showed significantly increased primary and metastatic tumor burdens. CONCLUSIONS: IL 1beta modulates Snail and thereby regulates COX-2-dependent E-cadherin expression in HNSCC. This is the first report indicating the role of Snail in the inflammation-induced promotion of EMT in HNSCC. This newly defined pathway for transcriptional regulation of E-cadherin in HNSCC has important implications for targeted chemoprevention and therapy. PMID- 19789325 TI - Phase I dose-escalation and pharmacokinetic study of dasatinib in patients with advanced solid tumors. AB - PURPOSE: To determine the maximum tolerated dose, dose-limiting toxicity (DLT), and recommended phase II dose of dasatinib in metastatic solid tumors refractory to standard therapies or for which no effective standard therapy exists. EXPERIMENTAL DESIGN: In this phase I, open-label, dose-escalation study, patients received 35 to 160 mg of dasatinib twice daily in 28-day cycles either every 12 hours for 5 consecutive days followed by 2 nontreatment days every week (5D2) or as continuous, twice-daily (CDD) dosing. RESULTS: Sixty-seven patients were treated (5D2, n = 33; CDD, n = 34). The maximum tolerated doses were 120 mg twice daily 5D2 and 70 mg twice daily CDD. DLTs with 160 mg 5D2 were recurrent grade 2 rash, grade 3 lethargy, and one patient with both grade 3 prolonged bleeding time and grade 3 hypocalcemia; DLTs with 120 mg twice daily CDD were grade 3 nausea, grade 3 fatigue, and one patient with both grade 3 rash and grade 2 proteinuria. The most frequent treatment-related toxicities across all doses were nausea, fatigue, lethargy, anorexia, proteinuria, and diarrhea, with infrequent hematologic toxicities. Pharmacokinetic data indicated rapid absorption, dose proportionality, and lack of drug accumulation. Although no objective tumor responses were seen, durable stable disease was observed in 16% of patients. CONCLUSION: Dasatinib was well tolerated in this population, with a safety profile similar to that observed previously in leukemia patients, although with much less hematologic toxicity. Limited, although encouraging, preliminary evidence of clinical activity was observed. Doses of 120 mg twice daily (5D2) or 70 mg twice daily (CDD) are recommended for further studies in patients with solid tumors. PMID- 19789326 TI - Vasoactivity of AG014699, a clinically active small molecule inhibitor of poly(ADP-ribose) polymerase: a contributory factor to chemopotentiation in vivo? AB - PURPOSE: Poly(ADP-ribose) polymerase (PARP) plays an important role in DNA repair, and PARP inhibitors can enhance the activity of DNA-damaging agents in vitro and in vivo. AG014699 is a potent PARP inhibitor in phase II clinical development. However, the range of therapeutics with which AG014699 could interact via a DNA-repair based mechanism is limited. We aimed to investigate a novel, vascular-based activity of AG014699, underlying in vivo chemosensitization, which could widen its clinical application. EXPERIMENTAL DESIGN: Temozolomide response was analyzed in vitro and in vivo. Vessel dynamics were monitored using "mismatch" following the administration of perfusion markers and real-time analysis of fluorescently labeled albumin uptake in to tumors established in dorsal window chambers. Further mechanistic investigations used ex vivo assays of vascular smooth muscle relaxation, gut motility, and myosin light chain kinase (MLCK) inhibition. RESULTS: AG014699 failed to sensitize SW620 cells to temozolomide in vitro but induced pronounced enhancement in vivo. AG014699 (1 mg/kg) improved tumor perfusion comparably with the control agents nicotinamide (1 g/kg) and AG14361 (forerunner to AG014699; 10 mg/kg). AG014699 and AG14361 relaxed preconstricted vascular smooth muscle more potently than the standard agent, hydralazine, with no impact on gut motility. AG014699 inhibited MLCK at concentrations that relaxed isolated arteries, whereas AG14361 had no effect. CONCLUSION: Increased vessel perfusion elicited by AG014699 could increase tumor drug accumulation and therapeutic response. Vasoactive concentrations of AG014699 do not cause detrimental side effects to gut motility and may increase the range of therapeutics with which AG014699 could be combined with for clinical benefit. PMID- 19789327 TI - Inhibiting the hypoxia response for cancer therapy: the new kid on the block. AB - The hypoxia-inducible transcription factor (HIF)-1alpha inhibitor KC7F2 described in this issue of Clinical Cancer Research is the newest addition to an emerging class of antitumor agents targeting the hypoxia response. Here, we discuss the proposed mechanism of action of KC7F2 and its potential strengths and limitations in comparison with other promising HIF-1alpha inhibitors. PMID- 19789328 TI - Identification of a novel small molecule HIF-1alpha translation inhibitor. AB - PURPOSE: Hypoxia inducible factor-1 (HIF-1), the central mediator of the cellular response to low oxygen, functions as a transcription factor for a broad range of genes that provide adaptive responses to oxygen deprivation. HIF-1 is overexpressed in cancer and has become an important therapeutic target in solid tumors. In this study, a novel HIF-1alpha inhibitor was identified and its molecular mechanism was investigated. EXPERIMENTAL DESIGN: Using a HIF-responsive reporter cell-based assay, a 10,000-member natural product-like chemical compound library was screened to identify novel HIF-1 inhibitors. This led us to discover KC7F2, a lead compound with a central structure of cystamine. The effects of KC7F2 on HIF-1 transcription, translation, and protein degradation processes were analyzed. RESULTS: KC7F2 markedly inhibited HIF-mediated transcription in cells derived from different tumor types, including glioma, breast, and prostate cancers, and exhibited enhanced cytotoxicity under hypoxia. KC7F2 prevented the activation of HIF-target genes such as carbonic anhydrase IX, matrix metalloproteinase 2 (MMP2), endothelin 1, and enolase 1. An investigation into the mechanism of action of KC7F2 showed that it worked through the down regulation of HIF-1alpha protein synthesis, an effect accompanied by the suppression of the phosphorylation of eukaryotic translation initiation factor 4E binding protein 1 and p70 S6 kinase, key regulators of HIF-1alpha protein synthesis. CONCLUSION: These results show that KC7F2 is a potent HIF-1 pathway inhibitor and its potential as a cancer therapy agent warrants further study. PMID- 19789329 TI - High-throughput cell-based screening of 4910 known drugs and drug-like small molecules identifies disulfiram as an inhibitor of prostate cancer cell growth. AB - PURPOSE: To identify novel therapeutic opportunities for patients with prostate cancer, we applied high-throughput screening to systematically explore most currently marketed drugs and drug-like molecules for their efficacy against a panel of prostate cancer cells. EXPERIMENTAL DESIGN: We carried out a high throughput cell-based screening with proliferation as a primary end-point using a library of 4,910 drug-like small molecule compounds in four prostate cancer (VCaP, LNCaP, DU 145, and PC-3) and two nonmalignant prostate epithelial cell lines (RWPE-1 and EP156T). The EC(50) values were determined for each cell type to identify cancer selective compounds. The in vivo effect of disulfiram (DSF) was studied in VCaP cell xenografts, and gene microarray and combinatorial studies with copper or zinc were done in vitro for mechanistic exploration. RESULTS: Most of the effective compounds, including antineoplastic agents, were nonselective and found to inhibit both cancer and control cells in equal amounts. In contrast, histone deacetylase inhibitor trichostatin A, thiram, DSF, and monensin were identified as selective antineoplastic agents that inhibited VCaP and LNCaP cell proliferation at nanomolar concentrations. DSF reduced tumor growth in vivo, induced metallothionein expression, and reduced DNA replication by downregulating MCM mRNA expression. The effect of DSF was potentiated by copper in vitro. CONCLUSIONS: We identified three novel cancer-selective growth inhibitory compounds for human prostate cancer cells among marketed drugs. We then validated DSF as a potential prostate cancer therapeutic agent. These kinds of pharmacologically well-known molecules can be readily translated to in vivo preclinical studies and clinical trials. PMID- 19789330 TI - CEACAM5-targeted therapy of human colonic and pancreatic cancer xenografts with potent labetuzumab-SN-38 immunoconjugates. AB - PURPOSE: To improve the efficacy and reduce the gastrointestinal toxicity of the cancer prodrug, CPT-11, we have developed immunoconjugates of its active form, SN 38, and an anti-CEACAM5 antibody for targeted chemotherapy. EXPERIMENTAL DESIGN: SN-38 conjugates of the anti-CEACAM5 monoclonal antibody, labetuzumab (hMN-14), varying in the nature of the cross-linker attachment at the drug's 20-hydroxyl position, were evaluated in vitro, in metastatic and/or s.c. human colonic and pancreatic cancer xenografts in nude mice using appropriate controls, and in a CEACAM5-negative tumor model. RESULTS: A pilot study in a s.c. LS174T model of human colonic carcinoma established the relative effectiveness of different conjugates. In the lung metastatic model of GW-39 human colonic carcinoma in nude mice, therapy with two specific labetuzumab-SN-38 conjugates, using 0.25 mg SN-38 equivalent/kg, q4d x 8, significantly extended median survival time versus controls (P < 0.002). In an expanded evaluation in the s.c. LS174T xenograft model, specific SN-38 conjugates produced significant tumor growth control and increases in median survival time versus other controls, including CPT-11 at a 33 fold greater cumulative dose (P < 0.01). An improvement was also observed in the therapy of a s.c. human pancreatic tumor xenograft. In a CEACAM5-negative systemic lymphoma xenograft, one labetuzumab-SN-38 conjugate examined was ineffective, whereas the conjugate specific for the tumor model produced 100% survival. CONCLUSIONS: The promising labetuzumab-SN-38 conjugates developed showed selective therapeutic efficacy in human tumor models at nontoxic doses that were a fraction of the CPT-11 doses used. PMID- 19789332 TI - Incidence, risk, and protective factors of mild traumatic brain injury in a cohort of Australian nonprofessional male rugby players. AB - BACKGROUND: Mild traumatic brain injury (mTBI) is an emerging public health issue in high-contact sports. Understanding the incidence along with the risk and protective factors of mTBI in high-contact sports such as rugby is paramount if appropriate preventive strategies are to be developed. PURPOSE: To estimate the incidence and identify the risk and protective factors of mTBI in Australian nonprofessional rugby players. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: A cohort of 3207 male nonprofessional rugby players from Sydney, Australia, was recruited and followed over 1 or more playing seasons. Demographic information, history of recent concussion, and information on risk and protective factors were collected. The incidence of mTBI was estimated and the putative risk and protective factors were modeled in relation to mTBI. RESULTS: The incidence of mTBI was 7.97 per 1000 player game hours, with 313 players (9.8%) sustaining 1 or more mTBIs during the study. Players who reported always wearing protective headgear during games were at a reduced risk (incident rate ratio [IRR], 0.57; 95% confidence interval [CI], 0.40-0.82) of sustaining an mTBI. In contrast, the likelihood of mTBI was almost 2 times higher among players who reported having sustained either 1 (IRR, 1.75; 95% CI, 1.11-2.76) or more mTBIs (IRR, 1.65; 95% CI, 1.11-2.45) within the 12 months before recruitment. CONCLUSION: Nonprofessional rugby has a high incidence of mTBI, with the absence of headgear and a recent history of mTBI associated with an increased risk of subsequent mTBI. These findings highlight that both use of headgear and the management of prior concussion would likely be beneficial in reducing the likelihood of mTBI among nonprofessional rugby players, who compose more than 99% of rugby union players in Australia. PMID- 19789331 TI - Gender disparities in metastatic colorectal cancer survival. AB - PURPOSE: Previous studies have shown that estrogen prevents colon cancer in postmenopausal women, indicating a role in colorectal cancer carcinogenesis and tumor progression. We investigated the interactions between sex, age, ethnicity, and year of diagnosis on overall survival (OS) in patients with metastatic colorectal cancer (MCRC). EXPERIMENTAL DESIGN: We screened 52,882 patients with MCRC from 1988 to 2004, using the Surveillance Epidemiology and End Results registry. Age at diagnosis, sex, ethnicity, tumor location, year of diagnosis, OS, and cancer-specific survival were evaluated using Cox proportional hazards model. The models were adjusted for marital status, tumor site, tumor differentiation, and treatment with radiation and/or surgery. RESULTS: We observed that younger women (18-44 years old) with MCRC lived longer than younger men (17 months versus 14; P < 0.0001, log-rank test). In contrast, older women (55 years and older) had significantly worse OS than older men (7 months versus 9; P < 0.0001, log-rank test). In multivariate analysis, we found that gender discrepancies have widened in recent years; young women diagnosed after 2000 have improved cancer-specific survival, compared to men (hazard ratio, 0.778; 95% confidence interval, 0.669-0.904), but those diagnosed before 2000 benefit less (hazard ratio, 0.931; 95% confidence interval, 0.821-1.056). CONCLUSION: As one of the largest data sets analyzed to establish that younger women with MCRC survive longer than younger men, hormonal status not only seems to play an important role in the development and pathogenesis of colorectal cancer but also may be of prognostic significance. These data warrant further studies to determine the role of estrogen in colorectal cancer. PMID- 19789333 TI - Long-term test-retest reliability of baseline cognitive assessments using ImPACT. AB - BACKGROUND: Computer-based assessment programs are commonly used to document baseline cognitive performance for comparison with postconcussion testing. There are currently no guidelines for how often baseline assessments should be updated, and no data documenting the test-retest stability of baseline measures over relevant time periods. PURPOSE: To establish long-term test-retest reliability of baseline assessments using ImPACT, and to compare various statistical methods for establishing test-retest reliability. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Participants were 95 collegiate varsity athletes completing baseline cognitive testing at 2 time periods, approximately 2 years apart. No participant sustained a concussion between assessments. All athletes completed the ImPACT test battery; dependent measures were the composite scores and total symptom scale score. RESULTS: Intraclass correlation coefficient estimates for visual memory (.65), processing speed (.74), and reaction time (.68) composite scores reflected stability over the 2-year period, with greater variability in verbal memory (.46) and symptom scale (.43) scores. Using reliable change indices and regression-based methods, only a small percentage of participants' scores showed "reliable" or "significant" change on the composite scores (0%-6%), or symptom scale scores (5%-10%). CONCLUSION: The current results suggest that college athletes' cognitive performance at baseline remains considerably stable over a 2-year period. These data help establish the effects of longer, clinically pragmatic testing intervals on test-retest reliability. CLINICAL IMPLICATIONS: The current results suggest that stretching the time between baseline assessments from 1 to 2 years may have little effect on the clinical management of concussions in collegiate athletes. These results should not be generalized to collegiate football players, who were not included in this sample. Youth athletes (high school and younger) should continue to receive annually updated baseline assessments until prospective study of the stability of baseline assessments for this younger age group can be completed. PMID- 19789334 TI - Phosphorylation-dependent Lys63-linked polyubiquitination of Daxx is essential for sustained TNF-{alpha}-induced ASK1 activation. AB - Apoptosis signal-regulating kinase 1 (ASK1) is a key regulatory kinase in the proapoptotic response to various stresses. ASK1 phosphorylation of Daxx, an ASK1 activator protein, increases Daxx accumulation in cells and further enhances ASK1 activity through a positive feedback mechanism. Here, we show that ASK1-dependent phosphorylation of Daxx induces Lys(63) (K63)-linked polyubiquitination on Lys(122) of Daxx. Polyubiquitination is dispensable for Daxx accumulation or Daxx interaction with ASK1 because mutant Daxx deficient in polyubiquitin still exhibits ASK1-dependent accumulation and interaction with cellular ASK1. However, K63-linked Daxx polyubiquitination is required for tumor necrosis factor-alpha (TNF-alpha)-induced activation of ASK1. Therefore, K63-linked polyubiquitination of Daxx functions as a molecular switch to initiate and amplify the stress kinase response in the TNF-alpha signaling pathway. PMID- 19789335 TI - Mutant p53 disrupts the stress MAPK activation circuit induced by ASK1-dependent stabilization of Daxx. AB - Daxx is a regulatory protein for apoptosis signal-regulating kinase 1 (ASK1) which activates c-Jun NH2-terminal kinase (JNK) and p38 pathways in response to stressors such as tumor necrosis factor-alpha (TNFalpha). Here, we show that TNFalpha treatment induces the accumulation of Daxx protein through ASK1 activation by preventing its proteasome-dependent degradation. ASK1 directly phosphorylates Daxx at Ser(176) and Ser(184) and Daxx is required for the sustained activation of JNK. Tumorigenic mutant p53, which binds to Daxx and inhibits Daxx-dependent activation of ASK1, prevents Daxx phosphorylation and stabilization. When mutant p53 was depleted in cancer cells, Daxx was accumulated and the cell-killing effect of TNFalpha was restored. Our results indicate that Daxx not only activates ASK1 but also is a downstream target of ASK1 and that accumulated Daxx further activates ASK1. Thus, the Daxx-ASK1 positive feedback loop amplifying JNK/p38 signaling plays an important role in the cell-killing effects of stressors, such as TNFalpha. Tumorigenic mutant p53 disrupts this circuit and makes cells more tolerable to stresses, as its gain-of-function mechanism. PMID- 19789336 TI - RAS mutations affect tumor necrosis factor-induced apoptosis in colon carcinoma cells via ERK-modulatory negative and positive feedback circuits along with non ERK pathway effects. AB - More than 40% of colon cancers have a mutation in K-RAS or N-RAS, GTPases that operate as central hubs for multiple key signaling pathways within the cell. Utilizing an isogenic panel of colon carcinoma cells with K-RAS or N-RAS variations, we observed differences in tumor necrosis factor-alpha (TNFalpha) induced apoptosis. When the dynamics of phosphorylated ERK response to TNFalpha were examined, K-RAS mutant cells showed lower activation whereas N-RAS mutant cells exhibited prolonged duration. These divergent trends were partially explained by differential induction of two ERK-modulatory circuits: negative feedback mediated by dual-specificity phosphatase 5 and positive feedback by autocrine transforming growth factor-alpha. Moreover, in the various RAS mutant colon carcinoma lines, the transforming growth factor-alpha autocrine loop differentially elicited a further downstream chemokine (CXCL1/CXCL8) autocrine loop, with the two loops having opposite effects on apoptosis. Although the apoptotic responses of the RAS mutant panel to TNFalpha treatment showed significant dependence on the respective phosphorylated ERK dynamics, successful prediction across the various cell lines required contextual information concerning additional pathways including IKK and p38. A quantitative computational model based on weighted linear combinations of these pathway activities successfully predicted not only the spectrum of cell death responses but also the corresponding chemokine production responses. Our findings indicate that diverse RAS mutations yield differential cell behavioral responses to inflammatory cytokine exposure by means of (a) differential effects on ERK activity via multiple feedback circuit mechanisms, and (b) differential effects on other key signaling pathways contextually modulating ERK-related dependence. PMID- 19789337 TI - Haplotype and cell proliferation analyses of candidate lung cancer susceptibility genes on chromosome 15q24-25.1. AB - Recent genome-wide association studies have linked the chromosome 15q24-25.1 locus to nicotine addiction and lung cancer susceptibility. To refine the 15q24 25.1 locus, we performed a haplotype-based association analysis of 194 familial lung cases and 219 cancer-free controls from the Genetic Epidemiology of Lung Cancer Consortium (GELCC) collection, and used proliferation and apoptosis analyses to determine which gene(s) in the 15q24-25.1 locus mediates effects on lung cancer cell growth in vitro. We identified two distinct subregions, hapL (P = 3.20 x 10(-6)) and hapN (P = 1.51 x 10(-6)), which were significantly associated with familial lung cancer. hapL encompasses IREB2, LOC123688, and PSMA4, and hapN encompasses the three nicotinic acetylcholine receptor subunit genes CHRNA5, CHRNA3, and CHRNB4. Examination of the genes around hapL revealed that PSMA4 plays a role in promoting cancer cell proliferation. PSMA4 mRNA levels were increased in lung tumors compared with normal lung tissues. Down-regulation of PSMA4 expression decreased proteasome activity and induced apoptosis. Proteasome dysfunction leads to many diseases including cancer, and drugs that inhibit proteasome activity show promise as a form of cancer treatment. Genes around hapN were also investigated, but did not show any direct effect on lung cancer cell proliferation. We concluded that PSMA4 is a strong candidate mediator of lung cancer cell growth, and may directly affect lung cancer susceptibility through its modulation of cell proliferation and apoptosis. PMID- 19789338 TI - Design of agonistic altered peptides for the robust induction of CTL directed towards H-2Db in complex with the melanoma-associated epitope gp100. AB - Immunogenicity of tumor-associated antigens (TAA) is often weak because many TAA are autoantigens for which the T-cell repertoire is sculpted by tolerance mechanisms. Substitutions at main anchor positions to increase the complementarity between the peptide and the MHC class I (MHC-I) binding cleft constitute a common procedure to improve binding capacity and immunogenicity of TAA. However, such alterations are tailored for each MHC-I allele and may recruit different CTL specificities through conformational changes in the targeted peptides. Comparative analysis of substituted melanoma-differentiation antigen gp100 in complex with H-2D(b) revealed that combined introduction of glycine and proline residues at the nonanchor positions 2 and 3, respectively, resulted in an agonistic altered peptide with dramatically enhanced binding affinity, stability, and immunogenicity of this TAA. Peptide vaccination using the p2Gp3P-altered peptide version of gp100 induced high frequencies of melanoma-specific CTL in the endogenous CD8+ repertoire. Crystal structure analysis of MHC/peptide complexes revealed that the conformation of the modified p2Gp3P-peptide was similar to the wild-type peptide, and indicated that this mimotope was stabilized through interactions between peptide residue p3P and the tyrosine residue Y159 that is conserved among most known MHC-I molecules throughout mammalian species. Our results may provide an alternative approach to enhance MHC stabilization capacity and immunogenicity of low-affinity peptides for induction of robust tumor specific CTL. PMID- 19789339 TI - The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. AB - Signaling through the type 1 insulin-like growth factor receptor (IGF-1R) occurs in many human cancers, including childhood sarcomas. As a consequence, targeting the IGF-1R has become a focus for cancer drug development. We examined the antitumor activity of CP-751,871, a human antibody that blocks IGF-1R ligand binding, alone and in combination with rapamycin against sarcoma cell lines in vitro and xenograft models in vivo. In Ewing sarcoma (EWS) cell lines, CP751,871 inhibited growth poorly (<50%), but prevented rapamycin-induced hyperphosphorylation of AKT(Ser473) and induced greater than additive apoptosis. Rapamycin treatment also increased secretion of IGF-1 resulting in phosphorylation of IGF-1R (Tyr1131) that was blocked by CP751,871. In vivo CP 751,871, rapamycin, or the combination were evaluated against EWS, osteosarcoma, and rhabdomyosarcoma xenografts. CP751871 induced significant growth inhibition [EFS(T/C) >2] in four models. Rapamycin induced significant growth inhibition [EFS(T/C) >2] in nine models. Although neither agent given alone caused tumor regressions, in combination, these agents had greater than additive activity against 5 of 13 xenografts and induced complete remissions in one model each of rhabdomyosarcoma and EWS, and in three of four osteosarcoma models. CP751,871 caused complete IGF-1R down-regulation, suppression of AKT phosphorylation, and dramatically suppressed tumor-derived vascular endothelial growth factor (VEGF) in some sarcoma xenografts. Rapamycin treatment did not markedly suppress VEGF in tumors and synergized only in tumor lines where VEGF was dramatically inhibited by CP751,871. These data suggest a model in which blockade of IGF-1R suppresses tumor-derived VEGF to a level where rapamycin can effectively suppress the response in vascular endothelial cells. PMID- 19789340 TI - Extracellular signal-regulated kinase positively regulates the oncogenic activity of MCT-1 in diffuse large B-cell lymphoma. AB - The MCT-1 oncogene was originally identified from lymphoma cell lines. Herein we establish that MCT-1 is highly expressed in 85% of human diffuse large B-cell lymphomas (DLBCL) and that knocking down MCT-1 by a specific short hairpin RNA in DLBCL cells induces apoptosis, supporting a critical role for MCT-1 in DLBCL cell survival. However, the mechanism underlying MCT-1 regulation is largely unknown. We find that MCT-1 is phosphorylated and up-regulated by extracellular signal regulated kinase (ERK). Furthermore, by using a small inhibitory molecule targeting ERK, we interrupted MCT-1 phosphorylation and stability. Significantly, cells with distinct levels of MCT-1 protein displayed differential sensitivity to ERK inhibitor-induced apoptosis. Treatment with the ERK inhibitor showed marked in vivo antitumor activity in a human DLBCL xenograft model. Our findings establish a functional molecular interaction between MCT-1 and the MEK/ERK signaling pathway and suggest that the activation of MCT-1 function by its upstream kinase ERK plays an important role in lymphomagenesis. PMID- 19789341 TI - Immutable functional attributes of histologic grade revealed by context independent gene expression in primary breast cancer cells. AB - Inherent cancer phenotypes that are independent of fluctuating cross-talk with the surrounding tissue matrix are highly desirable candidates for targeting tumor cells. Our novel study design uses epithelial cell lines derived from low versus high histologic grade primary breast cancer to effectively diminish the breadth of transient variability generated within the tumor microenvironment of the host, revealing a "paracrine-independent expression of grade-associated" (PEGA) gene signature. PEGA members extended beyond "proliferation-driven" signatures commonly associated with aggressive, high-grade breast cancer. The calcium binding protein S100P was prominent among PEGA genes overexpressed in high-grade tumors. A three-member fingerprint of S100P-correlated genes, consisting of GPRC5A, FXYD3, and PYCARD, conferred poor outcome in multiple breast cancer data sets, irrespective of estrogen receptor status but dependent on tumor size (P < 0.01). S100P silencing markedly diminished coregulated gene transcripts and reversed aggressive tumor behavior. Exposure to pathway-implicated agents, including the calmodulin inhibitor N-(6-aminohexyl)-5-chloro-1 naphthalenesulfonamide, phenothiazine, and chlorpromazine, resulted in rapid apoptotic cell death in high-grade tumor cells resistant to the chemotherapeutic drug cisplatin. This is the first comprehensive study describing molecular phenotypes intimately associated with histologic grade whose expression remains relatively fixed despite an unavoidably changing environment to which tumor cells are invariably exposed. PMID- 19789342 TI - Human suppressor of cytokine signaling 1 controls immunostimulatory activity of monocyte-derived dendritic cells. AB - Dendritic cell (DC)-based tumor vaccines have only achieved limited clinical efficacy, underscoring the limitation of stimulatory strategies to elicit effective cytotoxic T lymphocyte (CTL) responses against self-tumor-associated antigens. Here, we investigate the role of human suppressor of cytokine signaling 1 (SOCS1), a feedback inhibitor of the Janus-activated kinase/signal transducer and activator of transcription signaling pathway, in regulating antigen presentation by human DCs (hDC). We find that human SOCS1 (hSOCS1)-silenced DCs have an enhanced stimulatory ability to prime self-antigen-specific CTLs in vitro and in a severe combined immunodeficient-hu mouse model. Human CTLs activated by SOCS1-silenced DCs, but not wild-type DCs, have an active lytic activity to natural antigen-expressing tumor cells. We further find that the capacity of hDCs to prime CTLs is likely controlled by SOCS1-restricted production and signaling of proinflammatory cytokines, such as interleukin-12. These results indicate a critical role of hSOCS1 in negatively regulating the immunostimulatory capacity of DCs and imply a translational potential of this alternative SOCS1 silencing strategy to develop effective DC vaccines. PMID- 19789343 TI - Magnetic resonance imaging defines cervicovaginal anatomy, cancer, and VEGF trap antiangiogenic efficacy in estrogen-treated K14-HPV16 transgenic mice. AB - Noninvasive detection of dysplasia provides a potential platform for monitoring the efficacy of chemopreventive therapy of premalignancy, imaging the tissue compartments comprising dysplasia: epithelium, microvasculature, and stromal inflammatory cells. Here, using respiratory-gated magnetic resonance imaging (MRI), the anatomy of premalignant and malignant stages of cervical carcinogenesis in estrogen-treated K14-HPV16 transgenic mice was noninvasively defined. Dynamic contrast enhanced (DCE)-MRI was used to quantify leakage across premalignant dysplastic microvasculature. Vascular permeability as measured by DCE-MRI, K(trans), was similar in transgenic (0.053 +/- 0.020 min(-1); n = 32 mice) and nontransgenic (0.056 +/- 0.029 min(-1); n = 17 mice) animals despite a 2-fold increase in microvascular area in the former compared with the latter. DCE MRI did detect a significant decrease in vascular permeability accompanying diminution of dysplastic microvasculature by the antiangiogenic agent, vascular endothelial growth factor Trap (K(trans) = 0.052 +/- 0.013 min(-1) pretreatment; n = 6 mice versus K(trans) = 0.019 +/- 0.008 min(-1) post-treatment; n = 5 mice). Thus, we determined that the threshold of microvessel leakage associated with cervical dysplasia was <17 kDa and highlighted the potential of DCE-MRI to noninvasively monitor the efficacy of antiangiogenic drugs or chemoprevention regimens targeting the vasculature in premalignant cervical dysplasia. PMID- 19789344 TI - Overexpression of kinesins mediates docetaxel resistance in breast cancer cells. AB - Resistance to chemotherapy remains a major barrier to the successful treatment of cancer. To understand mechanisms underlying docetaxel resistance in breast cancer, we used an insertional mutagenesis strategy to identify proteins whose overexpression confers resistance. A strong promoter was inserted approximately randomly into the genomes of tumor-derived breast cancer cells, using a novel lentiviral vector. We isolated a docetaxel-resistant clone in which the level of the kinesin KIFC3 was elevated. When KIFC3 or the additional kinesins KIFC1, KIF1A, or KIF5A were overexpressed in the breast cancer cell lines MDA-MB231 and MDA-MB 468, the cells became more resistant to docetaxel. The binding of kinesins to microtubules opposes the stabilizing effect of docetaxel that prevents cytokinesis and leads to apoptosis. Our finding that kinesins can mediate docetaxel resistance might lead to novel therapeutic approaches in which kinesin inhibitors are paired with taxanes. PMID- 19789345 TI - Vascular adhesion protein-1 enhances tumor growth by supporting recruitment of Gr 1+CD11b+ myeloid cells into tumors. AB - Cancer growth is regulated by several nonmalignant cell types, such as leukocytes and endothelial cells, which reside in the stroma of the tumor. Vascular adhesion protein-1 (VAP-1) is an amine oxidase enzyme that is expressed on the surface of endothelial cells. It supports leukocyte traffic into inflamed tissues, but nothing is known about its possible role in cancer biology in vivo. Here, we report that B16 melanoma and EL-4 lymphoma remain smaller in VAP-1-deficient mice than in wild-type controls. We found an unexpected defect in tumor angiogenesis in the absence of VAP-1. VAP-1 also selectively enhanced the recruitment of Gr 1+CD11b+ myeloid cells into the tumors. Generation of mice expressing enzymatically inactive VAP-1 showed that the oxidase activity of VAP-1 was necessary to support neoangiogenesis, myeloid cell recruitment, and tumor growth in vivo. These data describe VAP-1 as the first adhesion molecule known to be involved in the recruitment of Gr-1+CD11b+ myeloid cells into tumors. They also suggest that VAP-1 is a potential new tool for immunotherapy of tumors that could be exploited to reduce tumor burden by controlling the traffic of Gr-1+CD11b+ myeloid cells. PMID- 19789346 TI - Role of SV40 integration site at chromosomal interval 1q21.1 in immortalized CRL2504 cells. AB - We have applied a functional gene transfer strategy to show the importance of viral integration site in cellular immortalization. The large tumor antigen of SV40 is capable of extending the cellular life span by sequestering tumor suppressor proteins pRB and p53 in virus-transformed human cells. Although SV40 large T antigen is essential, it is not sufficient for cellular immortalization, suggesting that additional alterations in cellular genes are required to attain infinite proliferation. We show here that the disruption of human chromosomal interval at 1q21.1 by SV40 integration can be an essential step for cellular immortalization. The transfer of a 150-kb bacterial artificial chromosome (BAC) clone, RP364B14, corresponding to viral integration site in CRL2504 cells, reverted their immortal phenotype. Interestingly, the BAC transfer clones of CRL2504 cells displayed characteristics of either senescence as shown by beta galactosidase activity or apoptosis as revealed by positive staining with M30 CytoDEATH antibody. The SV40 integration at 1q21.1, in the vicinity of epidermal differentiation complex (EDC) genes, resulted in the down-regulation of the filaggrin (FLG) gene that is part of the EDC. FLG gene expression was increased in BAC transfer senescent and apoptotic clones. Our results suggest that the disruption of native genomic sequence by SV40 may alter expression of genes involved in senescence and apoptosis by modulating chromatin structure. These studies imply that identification of genes located in the vicinity of viral integration sites in human cancers may be helpful in developing new diagnostic and therapeutic strategies. PMID- 19789347 TI - An A13 repeat within the 3'-untranslated region of epidermal growth factor receptor (EGFR) is frequently mutated in microsatellite instability colon cancers and is associated with increased EGFR expression. AB - Colorectal cancers (CRC) with microsatellite instability (MSI) have clinical, pathologic, genetic, and epigenetic features distinct from microsatellite-stable CRC. Examination of epidermal growth factor receptor (EGFR) mRNA and protein expression levels in a panel of colon cancer cell lines identified strong expression of EGFR in multiple cell lines with MSI. Although no relationship between EGFR overexpression and the length of a CA dinucleotide repeat in intron 1 was observed, a variant A13/A14 repeat sequence within the 3'-untranslated region (3'-UTR) of the EGFR gene was identified, which was mutated by either mononucleotide or dinucleotide adenosine deletions in 64% of MSI cell lines and 69% of MSI colon tumors. Using a Tet-Off system, we show that this mutation increases EGFR mRNA stability in colon cancer cells, providing a mechanistic basis for EGFR overexpression in MSI colon cancer cell lines. To determine whether this mutation is a driver or a bystander event in MSI colon cancer, we examined the effect of pharmacologic and molecular inhibition of EGFR in EGFR 3' UTR mutant MSI cell lines. Cell lines with an EGFR 3'-UTR mutation and that were wild-type (WT) for downstream signaling mediators in the Ras/BRAF and PIK3CA/PTEN pathways were sensitive to EGFR inhibition, whereas those harboring mutations in these signaling mediators were not. Furthermore, in cell lines WT for downstream signaling mediators, those with EGFR 3'-UTR mutations were more sensitive to EGFR inhibition than EGFR 3'-UTR WT cells, suggesting that this mutation provides a growth advantage to this subset of MSI colon tumors. PMID- 19789348 TI - Induction of prostatic intraepithelial neoplasia and modulation of androgen receptor by ETS variant 1/ETS-related protein 81. AB - ETS variant 1 (ETV1), also known as ETS-related protein 81, is overexpressed in prostate tumors, but whether and how this transcription factor affects tumorigenesis has remained elusive. Here, we show that ETV1 is primarily overexpressed in the most aggressive human prostate tumors. Transgenic ETV1 mice developed prostatic intraepithelial neoplasia as well as hyperplasia/neoplasia in seminal vesicles. Moreover, ETV1 cooperated with the androgen receptor (AR) to bind to the prostate-specific antigen enhancer and stimulate gene transcription. Consistent with its ability to physically interact with AR, ETV1 rendered an ETV1 binding site-driven reporter androgen inducible, and, on the other hand, ETV1 super-induced transcription from an AR binding site on androgen stimulation. In conclusion, our study substantiates that ETV1 overexpression is an underlying cause in the development of prostate and possibly also seminal vesicle cancer. Its interaction with and activation of AR provides a molecular mechanism on how ETV1 exerts its deleterious function. Thus, inhibiting ETV1 or blocking its interaction with AR may represent novel strategies in prostate cancer therapy. PMID- 19789350 TI - Circulating tumor cells are transcriptionally similar to the primary tumor in a murine prostate model. AB - The abundance of circulating tumor cells (CTC) indicates patient prognosis. Molecular characterization of CTCs may add additional information about a patient's disease. However, currently available methods are limited by contamination with blood cells. We describe a study using a modified CTC-chip to capture CTCs from an orthotopic xenograft model. Using laser capture microscopy to collect CTCs from the chip, we compared transcripts from purified CTCs with those from primary and metastatic tissue. Transcriptional profiles showed strong concordance among primary, metastatic, and CTC sources. Moreover, cells captured on the chip were viable and could be expanded in culture. We conclude that the CTC-chip is a useful tool to further characterize animal models of cancer and that viable CTCs can be isolated and show transcriptional similarity to solid tumors. PMID- 19789349 TI - Dual phosphoinositide 3-kinase/mammalian target of rapamycin blockade is an effective radiosensitizing strategy for the treatment of non-small cell lung cancer harboring K-RAS mutations. AB - Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC often harbors oncogenic K-RAS mutations that lead to the aberrant activation of several intracellular networks including the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Oncogenic K-RAS predicts poor prognosis and resistance to treatment with ionizing radiation (IR). Oncogenic K-Ras expression in the respiratory epithelium is sufficient to initiate NSCLC tumorigenesis, which requires the catalytic subunit of PI3K. Thus, effective inhibition of the PI3K signaling should lead to significant antitumor effects. However, therapy with rapamycin analogues has yielded disappointing results due in part to compensatory up-regulation of AKT. We hypothesized that dual PI3K/mTOR blockade would overcome these limitations. We tested this hypothesis with BEZ235, a novel dual PI3K/mTOR inhibitor that has recently entered clinical development. We found that BEZ235 induces a striking antiproliferative effect both in transgenic mice with oncogenic K-RAS-induced NSCLC and in NSCLC cell lines expressing oncogenic K-RAS. We determined that treatment with BEZ235 was not sufficient to induce apoptosis. However, we found that dual PI3K/mTOR blockade effectively sensitizes NSCLC expressing oncogenic K-RAS to the proapoptotic effects of IR both in vitro and in vivo. We conclude that dual PI3K/mTOR blockade in combination with IR may benefit patients with NSCLC expressing oncogenic K-RAS. These findings may have general applicability in cancer therapy, because aberrant activation of PI3K occurs frequently in human cancer. PMID- 19789351 TI - Oncogenesis caused by loss of the SNF5 tumor suppressor is dependent on activity of BRG1, the ATPase of the SWI/SNF chromatin remodeling complex. AB - Alterations in chromatin play an important role in oncogenic transformation, although the underlying mechanisms are often poorly understood. The SWI/SNF complex contributes to epigenetic regulation by using the energy of ATP hydrolysis to remodel chromatin and thus regulate transcription of target genes. SNF5, a core subunit of the SWI/SNF complex, is a potent tumor suppressor that is specifically inactivated in several types of human cancer. However, the mechanism by which SNF5 mutation leads to cancer and the role of SNF5 within the SWI/SNF complex remain largely unknown. It has been hypothesized that oncogenesis in the absence of SNF5 occurs due to a loss of function of the SWI/SNF complex. Here, we show, however, distinct effects for inactivation of Snf5 and the ATPase subunit Brg1 in primary cells. Further, using both human cell lines and mouse models, we show that cancer formation in the absence of SNF5 does not result from SWI/SNF inactivation but rather that oncogenesis is dependent on continued presence of BRG1. Collectively, our results show that cancer formation in the absence of SNF5 is dependent on the activity of the residual BRG1-containing SWI/SNF complex. These findings suggest that, much like the concept of oncogene addiction, targeted inhibition of SWI/SNF ATPase activity may be an effective therapeutic approach for aggressive SNF5-deficient human tumors. PMID- 19789353 TI - Tumor apoptotic bodies inhibit CTL responses and antitumor immunity via membrane bound transforming growth factor-beta1 inducing CD8+ T-cell anergy and CD4+ Tr1 cell responses. AB - Tumor cell apoptosis induced by radiation therapy results in apoptotic tumor cells and apparition of membrane blebs termed apoptotic bodies (APB). The immune responses induced by apoptotic tumor cells have been extensively studied. However, the role of APB in modulation of tumor immune responses is elusive. In this study, we induced apoptosis in 90% ovabumin-expressing EG7 tumor cells by in vitro irradiation (9,000 rad) of tumor cells with a subsequent cell culture for 9 hours. APB purified from irradiation-induced apoptotic EG7 cell culture supernatant by differential ultracentrifugation were vesicles with 50 to 90 nm in diameter and expressed apoptosis-specific Annexin V, 14-3-3, and Histone H3. We then investigated its potential modulation in DC(OVA)-induced T-cell responses and antitumor immunity. We found that EG7-derived APB were tolerogenic and capable of suppressing DC(OVA)-stimulated CD8+ CTL responses and antitumor immunity via its induction of CD8+ T-cell anergy and type 1 regulatory CD4+ T cell responses. Analysis of apoptotic tumor cells and APB revealed the expression of membrane-bound transforming growth factor (TGF)-beta1 associated with irradiation-induced apoptosis formation, which is a result from activation of transcriptional factor NF-AT specific for TGF-beta1 promoters. Our data further elucidate that it is the membrane-bound TGF-beta1 expression on APB that contributes to its in vitro antiproliferative effect as shown by using neutralizing TGF-beta1-specific antibody. Administration of anti-TGF-beta1 antibody in vivo also blocked APB-mediated immune suppression of CD8+ CTL responses and antitumor immunity. Therefore, our study may have great impact in designing a combined radiation therapy with immunotherapy of cancer. PMID- 19789352 TI - Expression of insulin receptor isoform A and insulin-like growth factor-1 receptor in human acute myelogenous leukemia: effect of the dual-receptor inhibitor BMS-536924 in vitro. AB - The insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R) are receptor tyrosine kinases that participate in mitogenic and antiapoptotic signaling in normal and neoplastic epithelia. In the present study, immunoblotting and reverse transcription-PCR demonstrated expression of IGF1R and IR isoform A in acute myelogenous leukemia (AML) cell lines as well as in >80% of clinical AML isolates. Treatment with insulin enhanced signaling through the Akt and MEK1/2 pathways as well as survival of serum-starved AML cell lines. Conversely, treatment with BMS-536924, a dual IGF1R/IR kinase inhibitor that is undergoing preclinical testing, inhibited constitutive receptor phosphorylation as well as downstream signaling through MEK1/2 and Akt. These changes inhibited proliferation and, in some AML cell lines, induced apoptosis at submicromolar concentrations. Likewise, BMS-536924 inhibited leukemic colony formation in CD34+ clinical AML samples in vitro. Collectively, these results not only indicate that expression of IGF1R and IR isoform A is common in AML but also show that interruption of signaling from these receptors inhibits proliferation in clinical AML isolates. Accordingly, further investigation of IGF1R/IR axis as a potential therapeutic target in AML appears warranted. PMID- 19789354 TI - Tribute to David Sisk: August 1, 2009. PMID- 19789358 TI - Use of combination therapy with a beta-blocker and milrinone in patients with advanced heart failure. AB - OBJECTIVE: To review the literature evaluating the clinical effects of combination therapy with a beta-blocker and milrinone in patients with severe heart failure (HF). DATA SOURCES: Literature was accessed through MEDLINE (1950 June 2009), PubMed (1966-June 2009), and International Pharmaceutical Abstracts (1970-June 2009), with combinations of the following terms: positive inotrope, milrinone, dobutamine, and beta-receptor blocker. In addition, reference citations from publications identified were reviewed. STUDY SELECTION AND DATA EXTRACTION: All articles that examined the effect of combination therapy with a beta-blocker and milrinone on clinical endpoints in patients with advanced HF were assessed. DATA SYNTHESIS: A search of the literature revealed 4 studies examining the clinical effects of combination therapy with a beta-blocker and milrinone. Three of these studies were retrospective reviews, while one was a post hoc subgroup analysis from the OPTIME-CHF study. Concomitant therapy with milrinone and a beta-blocker was well tolerated, with no significant increase in adverse events or deterioration in clinical status in any study. Tolerability rates for combination therapy ranged from 88% to 92%. In 2 of the studies, roughly 50% of the patients in the combination arm were able to be weaned off milrinone. One study suggested a mortality reduction in favor of combination therapy over milrinone alone, while another study suggested no difference in mortality with combination therapy versus milrinone monotherapy. One study suggested a potential increase in mortality when beta-blocker therapy was withdrawn in patients who were started on milrinone. None of the studies demonstrated any significant differences in hospitalization rates. All of the studies were limited by their retrospective nature and small sample size. CONCLUSIONS: Data are insufficient to make firm conclusions on the clinical benefit of combination therapy with a beta-blocker and milrinone in patients with advanced HF, although it appears that this regimen is well tolerated and may allow weaning of inotropic support. PMID- 19789359 TI - Effective use of paired testing in type 2 diabetes: practical applications in clinical practice. AB - PURPOSE: The purpose of this article is to discuss practical approaches to the use of self-monitoring of blood glucose (SMBG) in clinical practice using paired glucose testing. A rationale for SMBG use and innovative tools for data collection and analysis are presented. Method Health care professionals from various medical specialties collaborated to review current evidence regarding the value and utility of SMBG and to formulate professional opinions regarding use of SMBG. The literature review included key SMBG studies from 2002 through 2009. Established guidelines, position papers, and other evidence were also reviewed for this report. Reference Manager Software was used to search ISI Web of Science, PubMed, and Z39.50 site databases. RESULTS: Although the utility of SMBG in non-insulin-treated type 2 diabetes remains controversial, a recent report from the International Diabetes Federation recommends SMBG use in this population if it is used to educate/motivate individuals and/or monitor and adjust therapy. Health care providers must develop strategies to use SMBG in ways that address these criteria. CONCLUSIONS: Paired SMBG (testing before/after specific events) promotes diabetes knowledge and self-management skills and facilitates assessment of the impact of behavioral changes, medical nutrition therapy, and pharmacologic interventions on glycemic levels. New tools have been developed to assist in using paired testing in clinical practice. PMID- 19789361 TI - Predominance of adenosine excitatory over inhibitory effects on transmission at the neuromuscular junction of infant rats. AB - Adenosine-induced modulation of neuromuscular transmission in young (3-4-week old) rats was evaluated. Inhibition of adenosine kinase with iodotubercidin (ITU; 10 microM), which is known to induce adenosine release, enhanced the amplitude of evoked end-plate potentials (EPPs) recorded from innervated diaphragm muscle fibers. This facilitatory effect was transformed into an inhibitory one upon blockade of adenosine A(2A) receptors with 4-(2-[7-amino-2-(2 furly)[1,2,4]triazolo[2,3-a][1,3,5]triazin5ylamino] ethyl) phenol (ZM 241385) (50 nM); further blockade of adenosine A(1) receptors with the selective antagonist 1,3-dipropyl-8-cyclopentylxanthine (DPCPX; 10 nM) abolished that inhibition. Adenosine or 2-chloroadenosine (CADO), at submicromolar concentrations, increased the amplitude and the quantal content of EPPs, whereas at low micromolar concentrations they decreased EPP amplitude. Blockade of A(1) receptors with DPCPX (10 nM) prevented both excitatory and inhibitory effects, whereas blockade of A(2A) receptors with ZM241385 (50 nM) prevented only the excitatory effects. DPCPX and ZM241385 also prevented the excitatory effect of the selective A(2A) receptor agonist 2-[p-(2-carboxyethyl) phenethylamino]-5'-N-ethylcarboxamido adenosine hydrochloride (CGS 21680; 10 nM). CADO (30 nM) also increased neuromuscular transmission in adult (12-16-week-old) rats. It is suggested that at the motor nerve endings, low extracellular concentrations of adenosine activate both A(2A) and A(1) receptors, but activation of A(2A) receptors predominates over A(1) receptors; the activity of A(2A) receptors might, however, require coactivation of A(1) receptors. This facilitatory action of low concentrations of extracellular adenosine upon acetylcholine release may be particularly relevant at developing neuromuscular junctions, where subtle changes in synaptic levels of acetylcholine might influence synaptic stabilization. PMID- 19789360 TI - Reducing abuse liability of GABAA/benzodiazepine ligands via selective partial agonist efficacy at alpha1 and alpha2/3 subtypes. AB - Abuse-liability-related effects of subtype-selective GABA(A) modulators were explored relative to the prototypic benzodiazepine lorazepam. 7-Cyclobutyl-6-(2 methyl-2H-1,2,4-triazol-3-ylmethoxy)-3-phenyl-1,2,4-triazolo[4,3-b]pyridazine (TPA123) has weak partial agonist efficacy at alpha(1)-, alpha(2)-, alpha(3)-, and alpha(5)-containing GABA(A) receptors, whereas 7-(1,1-dimethylethyl)-6-(2 ethyl-2H-1,2,4-triazol-3-ylmethoxy)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3 b]pyridazine (TPA023) has weaker partial agonist efficacy at alpha(2) and alpha(3) and none at alpha(1) and alpha(5) subtypes. For both compounds, preclinical data suggested efficacy as nonsedating anxiolytics. Self-injection of TPA123 (0.0032-0.1 mg/kg) and TPA023 (0.0032-0.32 mg/kg) was compared with lorazepam (0.01-0.32 mg/kg) in baboons. TPA123 and lorazepam maintained self injection higher than vehicle at two or more doses in each baboon; peak rate of self-injection of lorazepam was higher than TPA123. Self-injected lorazepam and TPA123 also increased rates of concurrently occurring food-maintained behavior. After the availability of self-administered TPA123 doses ended, an effect consistent with a mild benzodiazepine-like withdrawal syndrome occurred. In contrast with lorazepam and TPA123, TPA023 did not maintain self-administration. Positron emission tomography studies showed that TPA023 produced a dose-dependent inhibition in the binding of [(11)C]flumazenil to the benzodiazepine binding site in the baboon, which was essentially complete (i.e., 100% occupancy) at the highest TPA023 dose (0.32 mg/kg). In a physical dependence study, TPA023 (32 mg/kg/24 h) was delivered as a continuous intragastric drip. Neither flumazenil at 14 days nor stopping TPA023 after 30 to 31 days resulted in the marked withdrawal syndrome characteristic of benzodiazepines in baboons. In the context of other data, elimination of efficacy at the alpha(1) subtype of the GABA/benzodiazepine receptor is not sufficient to eliminate abuse liability but may do so when coupled with reduced alpha(2/3) subtype efficacy. PMID- 19789362 TI - Transport of the photodynamic therapy agent 5-aminolevulinic acid by distinct H+ coupled nutrient carriers coexpressed in the small intestine. AB - 5-Aminolevulinic acid (ALA) is a prodrug used in photodynamic therapy, fluorescent diagnosis, and fluorescent-guided resection because it leads to accumulation of the photosensitizer protoporphyrin IX (PpIX) in tumor tissues. ALA has good oral bioavailability, but high oral doses are required to obtain selective PpIX accumulation in colonic tumors because accumulation is also observed in normal gut mucosa. Structural similarities between ALA and GABA led us to test the hypothesis that the H(+)-coupled amino acid transporter PAT1 (SLC36A1) will contribute to luminal ALA uptake. Radiolabel uptake and electrophysiological measurements identified PAT1-mediated H(+)-coupled ALA symport after heterologous expression in Xenopus oocytes. The selectivity of the nontransported inhibitors 5-hydroxytryptophan and 4-aminomethylbenzoic acid for, respectively, PAT1 and the H(+)-coupled di/tripeptide transporter PepT1 (SLC15A1) were examined. 5-Hydroxytryptophan selectively inhibited PAT1-mediated amino acid uptake across the brush-border membrane of the human intestinal (Caco-2) epithelium whereas 4-aminomethylbenzoic acid selectively inhibited PepT1-mediated dipeptide uptake. The inhibitory effects of 5-hydroxytryptophan and 4 aminomethylbenzoic acid were additive, demonstrating that both PAT1 and PepT1 contribute to intestinal transport of ALA. This is the first demonstration of overlap in substrate specificity between these distinct transporters for amino acids and dipeptides. PAT1 and PepT1 expression was monitored by reverse transcriptase-polymerase chain reaction using paired samples of normal and cancer tissue from human colon. mRNA for both transporters was detected. PepT1 mRNA was increased 2.3-fold in cancer tissues. Thus, increased PepT1 expression in colonic cancer could contribute to the increased PpIX accumulation observed. Selective inhibition of PAT1 could enhance PpIX loading in tumor tissue relative to that in normal tissue. PMID- 19789363 TI - Soy intake is associated with increased 2-hydroxylation and decreased 16alpha hydroxylation of estrogens in Asian-American women. AB - INTRODUCTION: In Asian and Asian-American women, soy consumption is associated with reduced breast cancer risk, perhaps due to its effects on estrogen production or metabolism. In a sample of Asian-American women, we investigated the associations of usual adult soy intake with the urinary concentrations of 15 estrogens and estrogen metabolites (EM) measured using liquid chromatography tandem mass spectrometry. METHODS: Participants included 430 Chinese-American, Japanese-American, and Filipino-American women, ages 20 to 55 years, and living in San Francisco-Oakland (California), Los Angeles (California), or Oahu (Hawaii). They were postmenopausal (n = 167) or premenopausal in luteal phase (n = 263) when 12-hour urine samples were collected. Robust linear regression was used to assess soy tertiles as predictors of log-transformed EM measures. Individual and grouped EM were considered as concentrations (pmol/mg creatinine) and as percentages of total EM (%EM). RESULTS: Factor analysis confirmed that EM groups defined by metabolic pathways appropriately captured covariation in EM profiles. Total EM concentrations were not significantly associated with soy in premenopausal or postmenopausal women. Among all women, %2-hydroxylated EM and %4 hydroxylation pathway EM were 16% higher (P(trend) = 0.02) and 19% higher (P(trend) = 0.03) in the highest versus lowest soy tertiles, respectively. In contrast, 16% hydroxylated EM were 11% lower (P(trend) < 0.01). Results were consistent across ethnic and menopausal groups and after adjustment for westernization measured by birthplace (Asia or United States). DISCUSSION: Findings suggest that regular soy intake is associated with increased ratios of 2:16-pathway EM and with higher relative levels of 4-hydroxylated EM. The observed variations in estrogen metabolism might modify breast cancer risk. PMID- 19789364 TI - Changes in CpG islands promoter methylation patterns during ductal breast carcinoma progression. AB - Aberrant promoter methylation of several known or putative tumor suppressor genes occurs frequently during carcinogenesis, and this epigenetic change has been considered as a potential molecular marker for cancer. We examined the methylation status of nine genes (APC, CDH1, CTNNB1, TIMP3, ESR1, GSTP1, MGMT, THBS1, and TMS1), by quantitative methylation specific PCR. Synchronous preinvasive lesions (atypical ductal hyperplasia and/or ductal carcinoma in situ) and invasive ductal breast carcinoma from 52 patients, together with pure lesions from 24 patients and 12 normal tissues paired to tumor and 20 normal breast distant from tumor were analyzed. Aberrant promoter methylation was detected in both preinvasive and invasive lesions for genes APC, CDH1, CTNNB1, TIMP3, ESR1, and GSTP1. However, hierarchical mixed model and Generalized Estimating Equations model analyses showed that only APC, CDH1, and CTNNB1 promoter regions showed a higher frequency and methylation levels in pathologic samples when compared with normal breast. Whereas APC and CTNNB1 did not show differences in methylation levels or frequencies, CDH1 showed higher methylation levels in invasive tumors as compared with preinvasive lesions (P < 0.04, Mann-Whitney test with permutation correction). The analysis of APC, CDH1, and CTNNB1 methylation status was able to distinguish between normal and pathologic samples with a sensitivity of 67% (95% confidence interval, 60-71%) and a specificity of 75% (95% confidence interval, 69-81%). Our data point to the direct involvement of APC, CDH1, and CTNNB1 promoter methylation in the early stages of breast cancer progression and suggest that they may represent a useful tool for the detection of tumor cells in clinical specimens. PMID- 19789365 TI - Reduced prediagnostic 25-hydroxyvitamin D levels in women with breast cancer: a nested case-control study. AB - Vitamin D status may affect risk of cancer. In a cross-sectional study with a nested case-control analysis, we determined whether risk of breast cancer is associated with prediagnostic plasma 25-hydroxyvitamin D (25OHD) levels and the effects of lifestyle characteristics known to influence vitamin D status on risk of breast cancer. We studied women without a prior history of breast cancer referred to a diagnostic mammography examination (n = 2,465). Cases were women diagnosed with an incident breast cancer (n = 142). Controls were women not diagnosed with a breast cancer matched to cases on age, menopausal status, and time of year of blood sampling (n = 420). Characteristics of cases and controls were assessed by a self-administrated questionnaire. Blood samples were collected prior to the diagnostic mammography examination. Cases had lower plasma 25OHD levels than controls. Compared with the lowest tertile of 25OHD levels, risk of breast cancer was significantly reduced among women in the highest tertile (relative risk, 0.52; 95% confidence interval, 0.32-0.85). Risk estimates were similar in women with an estrogen receptor-positive and estrogen receptor negative breast cancer. Use of vitamin D supplements, sunbathing frequency, and fish intake was associated with 25OHD levels, but did not affect the risk of breast cancer. Accordingly, risk of breast cancer was inversely associated with 25OHD levels. Randomized controlled trials are warranted in order to assess whether a causal relationship exists. PMID- 19789366 TI - Evaluation of 11 breast cancer susceptibility loci in African-American women. AB - Recent genome-wide association studies (GWAS) have identified multiple common genetic risk variants for breast cancer among women of Asian and European ancestry. Investigating these genetic susceptibility loci in other populations would be helpful to evaluate the generalizability of the findings and identify the causal variants for breast cancer. We evaluated 11 GWAS-identified genetic susceptibility loci for breast cancer in a study including 2,594 African-American women (810 cases and 1,784 controls). Two single-nucleotide polymorphisms, rs13387042 (2q35) and rs1219648 (FGFR2 gene), were found to be associated with breast cancer risk. Risk increased nearly linearly with the number of affected risk alleles, with a 2-fold elevated risk for women homozygous for the risk alleles in both single-nucleotide polymorphisms. No additional significant associations, however, were identified for the other nine loci evaluated in the study. The results from this study extend some of the recent GWAS findings to African-Americans and may guide future efforts to identify the causal variants for breast cancer. PMID- 19789367 TI - Medical advances and racial/ethnic disparities in cancer survival. AB - BACKGROUND: Although advances in early detection and treatment of cancer improve overall population survival, these advances may not benefit all population groups equally and may heighten racial/ethnic differences in survival. METHODS: We identified cancer cases in the Surveillance, Epidemiology and End Results program, who were ages > or = 20 years and diagnosed with one invasive cancer in 1995 to 1999 (n = 580,225). We used 5-year relative survival rates to measure the degree to which mortality from each cancer is amenable to medical interventions (amenability index). We used Kaplan-Meier methods and Cox proportional hazards regression to estimate survival differences between each racial/ethnic minority group relative to Whites, by the overall amenability index, and three levels of amenability (nonamenable, partly amenable, and mostly amenable cancers, corresponding to cancers with 5-year relative survival rate < 40%, 40-69%, and > or = 70%, respectively), adjusting for gender, age, disease stage, and county level poverty concentration. RESULTS: As amenability increased, racial/ethnic differences in cancer survival increased for African Americans, American Indians/Native Alaskans, and Hispanics relative to Whites. For example, the hazard ratios (95% confidence intervals) for African Americans versus Whites from nonamenable, partly amenable, and mostly amenable cancers were 1.05 (1.03-1.07), 1.38 (1.34-1.41), and 1.41 (1.37-1.46), respectively. Asians/Pacific Islanders had similar or longer survival relative to Whites across amenability levels; however, several subgroups experienced increasingly poorer survival with increasing amenability. CONCLUSIONS: Cancer survival disparities for most racial/ethnic minority populations widen as cancers become more amenable to medical interventions. Efforts in developing cancer control measures must be coupled with specific strategies for reducing the expected disparities. PMID- 19789368 TI - Vitamin D receptor expression is associated with PIK3CA and KRAS mutations in colorectal cancer. AB - Vitamin D is associated with decreased risks of various cancers, including colon cancer. The vitamin D receptor (VDR) is a transcription factor, which plays an important role in cellular differentiation and inhibition of proliferation. A link between VDR and the RAS-mitogen-activated protein kinase (MAPK) or phosphatidylinositol 3-kinase (PI3K)-AKT pathway has been suggested. However, the prognostic role of VDR expression or its relationship with PIK3CA or KRAS mutation remains uncertain. Among 619 colorectal cancers in two prospective cohort studies, 233 (38%) tumors showed VDR overexpression by immunohistochemistry. We analyzed for PIK3CA and KRAS mutations and LINE-1 methylation by Pyrosequencing, microsatellite instability (MSI), and DNA methylation (epigenetic changes) in eight CpG island methylator phenotype (CIMP) specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1] by MethyLight (real-time PCR). VDR overexpression was significantly associated with KRAS mutation (odds ratio, 1.55; 95% confidence interval, 1.11 2.16) and PIK3CA mutation (odds ratio, 2.17; 95% confidence interval, 1.36-3.47), both of which persisted in multivariate logistic regression analysis. VDR was not independently associated with body mass index, family history of colorectal cancer, tumor location (colon versus rectum), stage, tumor grade, signet ring cells, CIMP, MSI, LINE-1 hypomethylation, BRAF, p53, p21, beta-catenin, or cyclooxygenase-2. VDR expression was not significantly related with patient survival, prognosis, or clinical outcome. In conclusion, VDR overexpression in colorectal cancer is independently associated with PIK3CA and KRAS mutations. Our data support potential interactions between the VDR, RAS-MAPK and PI3K-AKT pathways, and possible influence by KRAS or PIK3CA mutation on therapy or chemoprevention targeting VDR. PMID- 19789369 TI - Cost-effectiveness of prophylactic surgery for duodenal cancer in familial adenomatous polyposis. AB - BACKGROUND: Duodenal cancer is the leading cause of cancer death in familial adenomatous polyposis after colorectal cancer. The lifetime risk for developing duodenal cancer is 4% to 10%. Current treatment guidelines recommend endoscopic surveillance with a prophylactic pancreaticoduodenectomy in advanced duodenal polyposis, defined using the Spigelman staging system. Because no clinical trials have assessed this recommendation, a modeling approach was used to evaluate the cost-effectiveness of various treatment strategies. METHODS: A Markov model was constructed to estimate the life expectancy and cost of three different strategies: pancreaticoduodenectomy at Spigelman stage III, pancreaticoduodenectomy at Spigelman stage IV, and pancreaticoduodenectomy at cancer diagnosis. A cohort of 30-year-old familial adenomatous polyposis patients with total colectomies was simulated until age 80. The analysis was from a societal perspective. Extensive sensitivity analysis was performed to assess the impact of model uncertainty on results. RESULTS: At all stages of polyposis and all ages <80 years, prophylactic surgery at Spigelman stage IV resulted in the greatest life expectancy. Surgery at stage IV was more effective and more expensive than surgery at cancer diagnosis, with an incremental cost of $3,200 per quality-adjusted life year gained. Surgery at stage III was not a viable option. The results were robust to wide variation in model parameters but were sensitive to the post-pancreaticoduodenectomy quality of life score. CONCLUSIONS: Prophylactic pancreaticoduodenectomy at stage IV duodenal polyposis in familial adenomatous polyposis is a cost-effective approach that results in greater life expectancy than surgery at either stage III or cancer diagnosis. PMID- 19789371 TI - The safety of H(2)-blockers use during pregnancy. AB - Little data exist on the safety of H(2)-blockers during pregnancy. A computerized database of medications dispensed from 1998 to 2007 to all women registered in the "Clalit" health maintenance organization, in the Southern District of Israel, was linked with computerized databases containing maternal and infant hospitalization records from the district hospital. The following confounders were controlled for: parity, maternal age, ethnic group, maternal diabetes, smoking, and peripartum fever. Also, therapeutic pregnancy termination data were analyzed. A total of 117 960 infants were born during the study period, 84 823 of them (72%) to women registered at Clalit; 1148 of the latter were exposed to H(2) blockers during the first trimester of pregnancy. Exposure to H(2)-blockers was not associated with an increased risk for congenital malformations (adjusted odds ratio [OR] = 1.03, 95% confidence interval [CI]: 0.80-1.32); also, no such association was found when therapeutic pregnancy terminations were included in the analysis (adjusted OR = 1.17, 95% CI: 0.93-1.46). Exposure to H(2)-blockers was not associated with perinatal mortality, premature delivery, low birth weight, or low Apgar scores. PMID- 19789372 TI - Effects of mexiletine, a CYP1A2 inhibitor, on tizanidine pharmacokinetics and pharmacodynamics. AB - The aim of this study was to determine whether mexiletine, a CYP1A2 inhibitor, altered the pharmacokinetics and pharmacodynamics of tizanidine. The pharmacokinetics of tizanidine were examined in an open-label study in 12 healthy participants after a single dose of tizanidine (2 mg) with and without mexiletine coadministration (50 mg, 3 times as a pretreatment for a day and 2 times on the study day). Compared with tizanidine alone, mexiletine coadministration increased the peak plasma concentration (1.8 +/- 0.8 vs 5.3 +/- 1.8 ng/mL), area under the curve (4.5 +/- 2.2 vs 15.4 +/- 6.5 ng x h/mL), and the half-life (1.3 +/- 0.2 vs 1.8 +/- 0.7 h) of tizanidine, respectively (P < .05). Reduction in systolic blood pressure (-10 +/- 8 vs -24 +/- 7 mm Hg) and diastolic blood pressure (-10 +/- 7 vs -18 +/- 8 mm Hg) after tizanidine administration was also significantly enhanced by coadministration of mexiletine (P < .01). Of the 15 patients treated with tizanidine and mexiletine, 4 suffered tizanidine-induced adverse effects such as drowsiness and dry mouth in the retrospective survey. Present results suggested that coadministration of mexiletine increased blood tizanidine concentrations and enhanced tizanidine pharmacodynamics in terms of reduction in blood pressure and adverse symptoms. PMID- 19789370 TI - CYP19A1 genetic variation in relation to prostate cancer risk and circulating sex hormone concentrations in men from the Breast and Prostate Cancer Cohort Consortium. AB - Sex hormones, particularly the androgens, are important for the growth of the prostate gland and have been implicated in prostate cancer carcinogenesis, yet the determinants of endogenous steroid hormone levels remain poorly understood. Twin studies suggest a heritable component for circulating concentrations of sex hormones, although epidemiologic evidence linking steroid hormone gene variants to prostate cancer is limited. Here we report on findings from a comprehensive study of genetic variation at the CYP19A1 locus in relation to prostate cancer risk and to circulating steroid hormone concentrations in men by the Breast and Prostate Cancer Cohort Consortium (BPC3), a large collaborative prospective study. The BPC3 systematically characterized variation in CYP19A1 by targeted resequencing and dense genotyping; selected haplotype-tagging single nucleotide polymorphisms (htSNP) that efficiently predict common variants in U.S. and European whites, Latinos, Japanese Americans, and Native Hawaiians; and genotyped these htSNPs in 8,166 prostate cancer cases and 9,079 study-, age-, and ethnicity matched controls. CYP19A1 htSNPs, two common missense variants and common haplotypes were not significantly associated with risk of prostate cancer. However, several htSNPs in linkage disequilibrium blocks 3 and 4 were significantly associated with a 5% to 10% difference in estradiol concentrations in men [association per copy of the two-SNP haplotype rs749292-rs727479 (A-A) versus noncarriers; P = 1 x 10(-5)], and with inverse, although less marked changes, in free testosterone concentrations. These results suggest that although germline variation in CYP19A1 characterized by the htSNPs produces measurable differences in sex hormone concentrations in men, they do not substantially influence risk of prostate cancer. PMID- 19789373 TI - Analysis of drug interactions involving fruit beverages and organic anion transporting polypeptides. AB - Recently there has been speculation regarding prescription drug interactions with fruit beverages through inhibition of drug uptake transport by organic anion transporter polypeptides (OATPs). A review of clinical trials indicates that grapefruit juice (GFJ), orange juice (OJ), and apple juice can reduce oral bioavailability of fexofenadine, potentially reducing pharmacodynamic effects of fexofenadine. However, the clinical importance of the interaction is not clearly established. The effect is diminished by temporal separation of fruit juice and fexofenadine administration. GFJ and OJ substantially reduce oral bioavailability of celiprolol, a beta-blocker not available in the United States. Beyond these two examples, other meaningful drug interactions with fruit beverages via OATP inhibition are not established at the present time. PMID- 19789374 TI - Effect of the bile acid sequestrant colesevelam on the pharmacokinetics of pioglitazone, repaglinide, estrogen estradiol, norethindrone, levothyroxine, and glyburide. AB - The purpose of this study was to assess effects of colesevelam on the pharmacokinetics of glyburide, levothyroxine, estrogen estradiol (EE), norethindrone (NET), pioglitazone, and repaglinide in healthy volunteers. Six drugs with a potential to interact with colesevelam were studied in open-label, randomized clinical studies. The presence of a drug interaction was concluded if the 90% confidence intervals for the geometric least squares mean ratios of AUC(0 t) (AUC(0-48) for levothyroxine) and C(max) fell outside the no-effect limits of (80.0%, 125.0%). Concomitant administration of colesevelam had no effect on the AUC(0-t) or C(max) of pioglitazone but significantly decreased the AUC(0-t) and C(max) of glyburide, levothyroxine, and EE and the C(max) of repaglinide and NET. AUC(0-t) and C(max) of glyburide and EE, but not repaglinide or NET, were significantly decreased when the drug was given 1 hour before colesevelam. When glyburide, EE, or levothyroxine was given 4 hours before colesevelam, no drug interaction was observed. Although colesevelam has a cleaner drug interaction profile than other bile acid sequestrants, it does interfere with absorption of some drugs. A 4-hour window appears sufficient to eliminate these interactions. PMID- 19789375 TI - Clopidogrel before elective percutaneous coronary intervention. AB - The introduction of percutaneous coronary intervention (PCI) substantially changed the treatment of patients with coronary artery disease. Stent thrombosis is the most worrisome early complication in patients undergoing PCI. Therefore, antiplatelet therapy forms an integral component of treatment with intracoronary stent implantation. A multitude of randomized and observational studies have helped identify and define the role of clopidogrel in today's PCI patient. Although much is known about its use, a number of questions still remain. PMID- 19789376 TI - Do genetic recombination and gene density shape the pattern of DNA elimination in rice long terminal repeat retrotransposons? AB - In flowering plants, the accumulation of small deletions through unequal homologous recombination (UR) and illegitimate recombination (IR) is proposed to be the major process counteracting genome expansion, which is caused primarily by the periodic amplification of long terminal repeat retrotransposons (LTR-RTs). However, the full suite of evolutionary forces that govern the gain or loss of transposable elements (TEs) and their distribution within a genome remains unclear. Here, we investigated the distribution and structural variation of LTR RTs in relation to the rates of local genetic recombination (GR) and gene densities in the rice (Oryza sativa) genome. Our data revealed a positive correlation between GR rates and gene densities and negative correlations between LTR-RT densities and both GR and gene densities. The data also indicate a tendency for LTR-RT elements and fragments to be shorter in regions with higher GR rates; the size reduction of LTR-RTs appears to be achieved primarily through solo LTR formation by UR. Comparison of indica and japonica rice revealed patterns and frequencies of LTR-RT gain and loss within different evolutionary timeframes. Different LTR-RT families exhibited variable distribution patterns and structural changes, but overall LTR-RT compositions and genes were organized according to the GR gradients of the genome. Further investigation of non-LTR-RTs and DNA transposons revealed a negative correlation between gene densities and the abundance of DNA transposons and a weak correlation between GR rates and the abundance of long interspersed nuclear elements (LINEs)/short interspersed nuclear elements (SINEs). Together, these observations suggest that GR and gene density play important roles in shaping the dynamic structure of the rice genome. PMID- 19789378 TI - Prions: protein aggregation and infectious diseases. AB - Transmissible spongiform encephalopathies (TSEs) are inevitably lethal neurodegenerative diseases that affect humans and a large variety of animals. The infectious agent responsible for TSEs is the prion, an abnormally folded and aggregated protein that propagates itself by imposing its conformation onto the cellular prion protein (PrPC) of the host. PrPC is necessary for prion replication and for prion-induced neurodegeneration, yet the proximal causes of neuronal injury and death are still poorly understood. Prion toxicity may arise from the interference with the normal function of PrPC, and therefore, understanding the physiological role of PrPC may help to clarify the mechanism underlying prion diseases. Here we discuss the evolution of the prion concept and how prion-like mechanisms may apply to other protein aggregation diseases. We describe the clinical and the pathological features of the prion diseases in human and animals, the events occurring during neuroinvasion, and the possible scenarios underlying brain damage. Finally, we discuss potential antiprion therapies and current developments in the realm of prion diagnostics. PMID- 19789379 TI - Calcium-induced calcium release in skeletal muscle. AB - Calcium-induced calcium release (CICR) was first discovered in skeletal muscle. CICR is defined as Ca2+ release by the action of Ca2+ alone without the simultaneous action of other activating processes. CICR is biphasically dependent on Ca2+ concentration; is inhibited by Mg2+, procaine, and tetracaine; and is potentiated by ATP, other adenine compounds, and caffeine. With depolarization of the sarcoplasmic reticulum (SR), a potential change of the SR membrane in which the luminal side becomes more negative, CICR is activated for several seconds and is then inactivated. All three types of ryanodine receptors (RyRs) show CICR activity. At least one RyR, RyR1, also shows non-CICR Ca2+ release, such as that triggered by the t-tubule voltage sensor, by clofibric acid, and by SR depolarization. Maximum rates of CICR, at the optimal Ca2+ concentration in the presence of physiological levels of ATP and Mg2+ determined in skinned fibers and fragmented SR, are much lower than the rate of physiological Ca2+ release. The primary event of physiological Ca2+ release, the Ca2+ spark, is the simultaneous opening of multiple channels, the coordinating mechanism of which does not appear to be CICR because of the low probability of CICR opening under physiological conditions. The coordination may require Ca2+, but in that case, some other stimulus or stimuli must be provided simultaneously, which is not CICR by definition. Thus CICR does not appear to contribute significantly to physiological Ca2+ release. On the other hand, CICR appears to play a key role in caffeine contracture and malignant hyperthermia. The potentiation of voltage activated Ca2+ release by caffeine, however, does not seem to occur through secondary CICR, although the site where caffeine potentiates voltage-activated Ca2+ release might be the same site where caffeine potentiates CICR. PMID- 19789380 TI - Peptide hormone regulation of angiogenesis. AB - It is now apparent that regulation of blood vessel growth contributes to the classical actions of hormones on development, growth, and reproduction. Endothelial cells are ideally positioned to respond to hormones, which act in concert with locally produced chemical mediators to regulate their growth, motility, function, and survival. Hormones affect angiogenesis either directly through actions on endothelial cells or indirectly by regulating proangiogenic factors like vascular endothelial growth factor. Importantly, the local microenvironment of endothelial cells can determine the outcome of hormone action on angiogenesis. Members of the growth hormone/prolactin/placental lactogen, the renin-angiotensin, and the kallikrein-kinin systems that exert stimulatory effects on angiogenesis can acquire antiangiogenic properties after undergoing proteolytic cleavage. In view of the opposing effects of hormonal fragments and precursor molecules, the regulation of the proteases responsible for specific protein cleavage represents an efficient mechanism for balancing angiogenesis. This review presents an overview of the actions on angiogenesis of the above mentioned peptide hormonal families and addresses how specific proteolysis alters the final outcome of these actions in the context of health and disease. PMID- 19789377 TI - The function of activity-regulated genes in the nervous system. AB - The mammalian brain is plastic in the sense that it shows a remarkable capacity for change throughout life. The contribution of neuronal activity to brain plasticity was first recognized in relation to critical periods of development, when manipulating the sensory environment was found to profoundly affect neuronal morphology and receptive field properties. Since then, a growing body of evidence has established that brain plasticity extends beyond development and is an inherent feature of adult brain function, spanning multiple domains, from learning and memory to adaptability of primary sensory maps. Here we discuss evolution of the current view that plasticity of the adult brain derives from dynamic tuning of transcriptional control mechanisms at the neuronal level, in response to external and internal stimuli. We then review the identification of "plasticity genes" regulated by changes in the levels of electrical activity, and how elucidating their cellular functions has revealed the intimate role transcriptional regulation plays in fundamental aspects of synaptic transmission and circuit plasticity that occur in the brain on an every day basis. PMID- 19789382 TI - The hepatic microcirculation: mechanistic contributions and therapeutic targets in liver injury and repair. AB - The complex functions of the liver in biosynthesis, metabolism, clearance, and host defense are tightly dependent on an adequate microcirculation. To guarantee hepatic homeostasis, this requires not only a sufficient nutritive perfusion and oxygen supply, but also a balanced vasomotor control and an appropriate cell-cell communication. Deteriorations of the hepatic homeostasis, as observed in ischemia/reperfusion, cold preservation and transplantation, septic organ failure, and hepatic resection-induced hyperperfusion, are associated with a high morbidity and mortality. During the last two decades, experimental studies have demonstrated that microcirculatory disorders are determinants for organ failure in these disease states. Disorders include 1) a dysregulation of the vasomotor control with a deterioration of the endothelin-nitric oxide balance, an arterial and sinusoidal constriction, and a shutdown of the microcirculation as well as 2) an overwhelming inflammatory response with microvascular leukocyte accumulation, platelet adherence, and Kupffer cell activation. Within the sequelae of events, proinflammatory mediators, such as reactive oxygen species and tumor necrosis factor-alpha, are the key players, causing the microvascular dysfunction and perfusion failure. This review covers the morphological and functional characterization of the hepatic microcirculation, the mechanistic contributions in surgical disease states, and the therapeutic targets to attenuate tissue injury and organ dysfunction. It also indicates future directions to translate the knowledge achieved from experimental studies into clinical practice. By this, the use of the recently introduced techniques to monitor the hepatic microcirculation in humans, such as near-infrared spectroscopy or orthogonal polarized spectral imaging, may allow an early initiation of treatment, which should benefit the final outcome of these critically ill patients. PMID- 19789383 TI - Calcium pumps in health and disease. AB - Ca2+-ATPases (pumps) are key actors in the regulation of Ca2+ in eukaryotic cells and are thus essential to the correct functioning of the cell machinery. They have high affinity for Ca2+ and can efficiently regulate it down to very low concentration levels. Two of the pumps have been known for decades (the SERCA and PMCA pumps); one (the SPCA pump) has only become known recently. Each pump is the product of a multigene family, the number of isoforms being further increased by alternative splicing of the primary transcripts. The three pumps share the basic features of the catalytic mechanism but differ in a number of properties related to tissue distribution, regulation, and role in the cellular homeostasis of Ca2+. The molecular understanding of the function of the pumps has received great impetus from the solution of the three-dimensional structure of one of them, the SERCA pump. These spectacular advances in the structure and molecular mechanism of the pumps have been accompanied by the emergence and rapid expansion of the topic of pump malfunction, which has paralleled the rapid expansion of knowledge in the topic of Ca2+-signaling dysfunction. Most of the pump defects described so far are genetic: when they are very severe, they produce gross and global disturbances of Ca2+ homeostasis that are incompatible with cell life. However, pump defects may also be of a type that produce subtler, often tissue-specific disturbances that affect individual components of the Ca2+-controlling and/or processing machinery. They do not bring cells to immediate death but seriously compromise their normal functioning. PMID- 19789381 TI - Muscle giants: molecular scaffolds in sarcomerogenesis. AB - Myofibrillogenesis in striated muscles is a highly complex process that depends on the coordinated assembly and integration of a large number of contractile, cytoskeletal, and signaling proteins into regular arrays, the sarcomeres. It is also associated with the stereotypical assembly of the sarcoplasmic reticulum and the transverse tubules around each sarcomere. Three giant, muscle-specific proteins, titin (3-4 MDa), nebulin (600-800 kDa), and obscurin (approximately 720 900 kDa), have been proposed to play important roles in the assembly and stabilization of sarcomeres. There is a large amount of data showing that each of these molecules interacts with several to many different protein ligands, regulating their activity and localizing them to particular sites within or surrounding sarcomeres. Consistent with this, mutations in each of these proteins have been linked to skeletal and cardiac myopathies or to muscular dystrophies. The evidence that any of them plays a role as a "molecular template," "molecular blueprint," or "molecular ruler" is less definitive, however. Here we review the structure and function of titin, nebulin, and obscurin, with the literature supporting a role for them as scaffolding molecules and the contradictory evidence regarding their roles as molecular guides in sarcomerogenesis. PMID- 19789385 TI - Modifiers of von Willebrand factor identified by natural variation in inbred strains of mice. AB - Type 1 von Willebrand disease (VWD) is the most common inherited human bleeding disorder. However, diagnosis is complicated by incomplete penetrance and variable expressivity, as well as wide variation in von Willebrand factor (VWF) levels among the normal population. Previous work has exploited the highly variable plasma VWF levels among inbred strains of mice to identify 2 major regulators, Mvwf1 and Mvwf2 (modifier of VWF). Mvwf1 is a glycosyltransferase and Mvwf2 is a natural variant in Vwf that alters biosynthesis. We report the identification of an additional alteration at the Vwf locus (Mvwf5), as well as 2 loci unlinked to Vwf (Mvwf6-7) using a backcross approach with the inbred mouse strains WSB/EiJ and C57BL/6J. Through positional cloning, we show that Mvwf5 is a cis-regulatory variant that alters Vwf mRNA expression. A similar mechanism could potentially explain a significant percentage of human VWD cases, especially those with no detectable mutation in the VWF coding sequence. Mvwf6 displays conservation of synteny with potential VWF modifier loci identified in human pedigrees, suggesting that its ortholog may modify VWF in human populations. PMID- 19789386 TI - In vivo intraclonal and interclonal kinetic heterogeneity in B-cell chronic lymphocytic leukemia. AB - Clonal evolution and outgrowth of cellular variants with additional chromosomal abnormalities are major causes of disease progression in chronic lymphocytic leukemia (CLL). Because new DNA lesions occur during S phase, proliferating cells are at the core of this problem. In this study, we used in vivo deuterium ((2)H) labeling of CLL cells to better understand the phenotype of proliferating cells in 13 leukemic clones. In each case, there was heterogeneity in cellular proliferation, with a higher fraction of newly produced CD38+ cells compared with CD38- counterparts. On average, there were 2-fold higher percentages of newly born cells in the CD38+ fraction than in CD38- cells; when analyzed on an individual patient basis, CD38+ (2)H-labeled cells ranged from 6.6% to 73%. Based on distinct kinetic patterns, interclonal heterogeneity was also observed. Specifically, 4 patients exhibited a delayed appearance of newly produced CD38+ cells in the blood, higher leukemic cell CXC chemokine receptor 4 (CXCR4) levels, and increased risk for lymphoid organ infiltration and poor outcome. Our data refine the proliferative compartment in CLL based on CD38 expression and suggest a relationship between in vivo kinetics, expression of a protein involved in CLL cell retention and trafficking to solid tissues, and clinical outcome. PMID- 19789387 TI - Role of tyrosine phosphatase SHP-1 in the mechanism of endorepellin angiostatic activity. AB - Endorepellin, the C-terminal domain of perlecan, is a powerful angiogenesis inhibitor. To dissect the mechanism of endorepellin-mediated endothelial silencing, we used an antibody array against multiple tyrosine kinase receptors. Endorepellin caused a widespread reduction in phosphorylation of key receptors involved in angiogenesis and a concurrent increase in phosphatase activity in endothelial cells and tumor xenografts. These effects were efficiently hampered by function-blocking antibodies against integrin alpha2beta1, the functional endorepellin receptor. The Src homology-2 protein phosphatase-1 (SHP-1) coprecipitated with integrin alpha2 and was phosphorylated in a dynamic fashion after endorepellin stimulation. Genetic evidence was provided by lack of an endorepellin-evoked phosphatase response in microvascular endothelial cells derived from integrin alpha2beta1(-/-) mice and by response to endorepellin in cells genetically engineered to express the alpha2beta1 integrin, but not in cells either lacking this receptor or expressing a chimera harboring the integrin alpha2 ectodomain fused to the alpha1 intracellular domain. siRNA-mediated knockdown of integrin alpha2 caused a dose-dependent reduction of SHP-1. Finally, the levels of SHP-1 and its enzymatic activity were substantially reduced in multiple organs from alpha2beta1(-/-) mice. Our results show that SHP-1 is an essential mediator of endorepellin activity and discover a novel functional interaction between the integrin alpha2 subunit and SHP-1. PMID- 19789388 TI - Soluble lymphotoxin is an important effector molecule in GVHD and GVL. AB - Tumor necrosis factor (TNF) is a key cytokine in the effector phase of graft versus-host disease (GVHD) after bone marrow transplantation, and TNF inhibitors have shown efficacy in clinical and experimental GVHD. TNF signals through the TNF receptors (TNFR), which also bind soluble lymphotoxin (LTalpha3), a TNF family member with a previously unexamined role in GVHD pathogenesis. We have used preclinical models to investigate the role of LT in GVHD. We confirm that grafts deficient in LTalpha have an attenuated capacity to induce GVHD equal to that seen when grafts lack TNF. This is not associated with other defects in cytokine production or T-cell function, suggesting that LTalpha3 exerts its pathogenic activity directly via TNFR signaling. We confirm that donor-derived LTalpha is required for graft-versus-leukemia (GVL) effects, with equal impairment in leukemic clearance seen in recipients of LTalpha- and TNF-deficient grafts. Further impairment in tumor clearance was seen using Tnf/Lta(-/-) donors, suggesting that these molecules play nonredundant roles in GVL. Importantly, donor TNF/LTalpha were only required for GVL where the recipient leukemia was susceptible to apoptosis via p55 TNFR signaling. These data suggest that antagonists neutralizing both TNF and LTalpha3 may be effective for treatment of GVHD, particularly if residual leukemia lacks the p55 TNFR. PMID- 19789389 TI - Capacity constraints and cost-effectiveness: a discrete event simulation for drug eluting stents. AB - BACKGROUND: Waiting times for access to care, for example, for diagnostic imaging or surgery, are a highly relevant issue in health care. Waiting or deferred treatment caused by limited resource capacities can affect treatment success, quality of life, and costs. However, when treatment alternatives are compared in economic models, often unrestricted availability of resources is assumed, and dynamic changes in waiting lines remain unconsidered. The objective of this study was to evaluate the impact of potential real-world capacity restrictions and implied waiting lines on cost-effectiveness results and additional model outcomes. METHODS: A case study of drug-eluting and bare-metal stent treatment illustrates the effect of hypothetical capacity limitations of daily stenting procedures. Therefore, a decision-analytic model which allows for explicitly defined resource capacities and dynamic waiting lines was built using discrete event simulation. Cost-effectiveness, utilization, waiting time, and budgetary impact of alternative treatment scenarios are analyzed under the assumption of limited and unlimited resource capacities. RESULTS: The compared treatment allocation scenarios in the case study demonstrate that the additional cost for waiting increases the average treatment cost per patient. The different scenarios have different impacts on waiting lines because of the number of repeated interventions. Additionally, this effect leads to changes in cost-effectiveness results for the hypothetical capacity limit. Explicitly modeled capacities allow for further analysis of capacity utilization, waiting lines, and budgetary impact. CONCLUSION: Our model shows that neglected limited capacities can cause wrong cost-effectiveness results. Therefore, capacities should be explicitly included in decision-analytic models if there is evidence of scarcity. PMID- 19789390 TI - Perspectives on cumulative risks and impacts. AB - Cumulative risks and impacts have taken on different meanings in different regulatory and programmatic contexts at federal and state government levels. Traditional risk assessment methodologies, with considerable limitations, can provide a framework for the evaluation of cumulative risks from chemicals. Under an environmental justice program in California, cumulative impacts are defined to include exposures, public health effects, or environmental effects in a geographic area from the emission or discharge of environmental pollution from all sources, through all media. Furthermore, the evaluation of these effects should take into account sensitive populations and socioeconomic factors where possible and to the extent data are available. Key aspects to this potential approach include the consideration of exposures (versus risk), socioeconomic factors, the geographic or community-level assessment scale, and the inclusion of not only health effects but also environmental effects as contributors to impact. Assessments of this type extend the boundaries of the types of information that toxicologists generally provide for risk management decisions. PMID- 19789391 TI - Psychiatric nurses' expertise, interest in end-of-life care, and requests for continuing education on end of life. AB - BACKGROUND: The time before dying can be extremely challenging and stressful. Gaps in end-of-life care include inadequate communication, education about end-of life options, symptom control, and management of common mental illnesses (eg, mood disorders, dementia), and death anxiety. Psychiatric nurses are in a pivotal position to help address these gaps and improve end-of-life care. Psychiatric nurses can facilitate communication about end of life, educate patients about options, and provide consultation, assessment, and management of common psychosocial needs (eg, mood disorders, grief, and loss). OBJECTIVE: This survey examined psychiatric nurses' perspectives of their skills, knowledge, expertise, continuing education needs, and recommendations for the role of the psychiatric nurse. STUDY DESIGN: Using a descriptive design, we surveyed a convenience sample of psychiatric nurses from the American Psychiatric Nurses Association. RESULTS: Psychiatric nurses reported they were skilled in discussions of difficult topics, evaluation of mental status, and assessment and management of mood disorders, grief, and suicide risk. However, nurses asked for continuing education in focusing these skills for end of life, knowing the needs of the dying patient, and differentiating depression and dementia at end of life. Requests for continuing education on end-of-life care included issues about how to apply these psychiatric skills and knowledge to the dying patient and their families. CONCLUSIONS: Psychiatric nurses have skills and knowledge to reduce the gaps in end-of-life care. Many request continuing education to assist them to expand and focus their knowledge to use their psychosocial skills and to develop a specialty area in end-of-life care. PMID- 19789392 TI - Contemporary imaging in sarcoma. AB - Sarcomas are a heterogeneous group of >50 subtypes of neoplasm. It is imperative to obtain appropriate imaging of these tumors in order to adequately assess, characterize, and stage bone and soft tissue sarcomas. Anatomic imaging such as radiographs, computed tomography, and magnetic resonance imaging (MRI) remain the foundation for both biopsy planning and postoperative evaluation of these neoplasms. However, anatomic imaging may not be entirely accurate in the evaluation of treatment response. Newer techniques, such (18)F-fluorodeoxyglucose positron emission tomography, are being used to evaluate distant metastases. Newer radiopharmaceuticals, such as (18)F-fluorodeoxythymidine, are being developed to assist in the differentiation between benign and low-grade malignant neoplasms. Newer functional imaging techniques, such as dynamic contrast-enhanced MRI and diffusion-weighted imaging, among others, are being developed to evaluate treatment response. PMID- 19789393 TI - The accelerated post-infarction progression of cardiac remodelling is associated with genetic changes in an untreated streptozotocin-induced diabetic rat model. AB - AIMS: The mechanism by which diabetes mellitus exacerbates myocardial injury and the incidence of heart failure after acute myocardial infarction (AMI), remains unclear. We studied the severity of cardiac dysfunction and time-dependent gene expression in a hyperglycaemic rat model with AMI. METHODS AND RESULTS: The diabetic model was produced by injection of streptozotocin in Sprague-Dawley rats. Ten weeks after induction of diabetes, AMI was induced by ligation of the left anterior descending coronary artery. Cardiac function and left ventricular (LV) dimensions were evaluated using two-dimensional echocardiography. Structural changes were assessed by histological examination. Gene expression profile was documented by using affymetrix genechip U230 2.0 array and real time-PCR. During 56 days post-AMI, lower survival rates, worse LV function, more severe fibrosis, and larger LV diameters were identified in diabetic rats compared with non diabetic rats. A total 1221 genes involved in processes, such as glucose metabolism, fatty acid metabolism, extracellular matrix, and apoptosis, were found to be differentially expressed between diabetic and non-diabetic rats, of these 770 were up-regulated and 451 down-regulated. Up-regulation of the genes was found 1-2 weeks earlier in diabetic rats than in non-diabetic rats. CONCLUSION: The present data suggest that hyperglycaemia up-regulates remodelling related genes, which may be responsible for the worse outcomes in diabetics than in non-diabetics after AMI. PMID- 19789384 TI - Reward processing by the opioid system in the brain. AB - The opioid system consists of three receptors, mu, delta, and kappa, which are activated by endogenous opioid peptides processed from three protein precursors, proopiomelanocortin, proenkephalin, and prodynorphin. Opioid receptors are recruited in response to natural rewarding stimuli and drugs of abuse, and both endogenous opioids and their receptors are modified as addiction develops. Mechanisms whereby aberrant activation and modifications of the opioid system contribute to drug craving and relapse remain to be clarified. This review summarizes our present knowledge on brain sites where the endogenous opioid system controls hedonic responses and is modified in response to drugs of abuse in the rodent brain. We review 1) the latest data on the anatomy of the opioid system, 2) the consequences of local intracerebral pharmacological manipulation of the opioid system on reinforced behaviors, 3) the consequences of gene knockout on reinforced behaviors and drug dependence, and 4) the consequences of chronic exposure to drugs of abuse on expression levels of opioid system genes. Future studies will establish key molecular actors of the system and neural sites where opioid peptides and receptors contribute to the onset of addictive disorders. Combined with data from human and nonhuman primate (not reviewed here), research in this extremely active field has implications both for our understanding of the biology of addiction and for therapeutic interventions to treat the disorder. PMID- 19789394 TI - Intake of very long chain n-3 fatty acids from fish and the incidence of heart failure: the Rotterdam Study. AB - AIMS: Evidence is accumulating for a cardioprotective effect of fish or its n-3 fatty acids, eicosapentaenoic acid (EPA) plus docosahexaenoic acid (DHA). We examined EPA plus DHA and fish intake in relation to incident heart failure in the population-based Rotterdam Study. METHODS AND RESULTS: The analysis comprised 5299 subjects (41% men, age approximately 68 years) free from heart failure for whom dietary data were available. During 11.4 years of follow-up, 669 subjects developed heart failure. The relative risk (RR) of heart failure in the top vs. bottom quintile of EPA plus DHA intake was 0.89 (95% CI 0.69-1.14), after adjustment for lifestyle and dietary factors. For fish intakes > or = 20 g/day, the RR was 0.96 (0.78-1.18) compared with no fish intake. In sex-specific analysis, a high EPA plus DHA intake tended to be protective in women (RR = 0.75, 0.54-1.04) but not in men (RR = 1.00, 0.73-1.36). An inverse association for EPA plus DHA was also observed in diabetics (RR = 0.58, 0.32-1.06), which was borderline statistically significant. CONCLUSION: Our findings do not support a major role for fish intake in the prevention of heart failure. The potentially protective effect of EPA plus DHA in diabetic patients, however, warrants further investigation. PMID- 19789396 TI - Gender differences in survival in patients with severe left ventricular dysfunction despite similar extent of myocardial scar measured on cardiac magnetic resonance. AB - AIMS: We sought to determine the association between myocardial scarring, gender, and survival in patients with significant coronary artery disease (CAD) and severe systolic left ventricular (LV) dysfunction using delayed hyper-enhancement cardiac magnetic resonance imaging (DHE-CMR). METHODS AND RESULTS: We studied 339 patients (24% women, mean age 65 +/- 11 years) referred for assessment of myocardial viability by DHE-CMR. Scar was defined as myocardium with an intensity >2 SD above viable myocardium. Left ventricular scar (defined as a percentage of total LV myocardium), LV volumes, risk factors, cardiac transplantation (CTx), and all-cause mortality were recorded. There were 84 deaths and five CTx over 3.7 +/- 1.6 years (median 4 years, interquartile range 2.6-4.9 years). Left ventricular ejection fraction (LVEF) in men was only slightly different from women (23% +/- 9 vs. 25% +/- 10, P = 0.05), whereas mean scar % was similar in both groups (32 +/- 21 vs. 29 +/- 20, P = 0.3). On univariable survival analysis, age [hazard ratio, HR, 1.03 (1.01-1.05), P = 0.002], female gender [HR 2.02 (1.31 3.12), P = 0.001], and scar % [HR 1.01 (1.003-1.02), P = 0.009] predicted outcomes; and also on multivariable analysis (chi(2) 32, P < 0.0001). Women with scar % greater than the median had more events, compared with men with or without a high scar burden (log-rank P < 0.001). CONCLUSION: In patients with CAD and severely reduced LVEF, women have worse outcomes than men, irrespective of myocardial scar burden. PMID- 19789395 TI - Independent relationship of left atrial size and mortality in patients with heart failure: an individual patient meta-analysis of longitudinal data (MeRGE Heart Failure). AB - AIMS: Left atrial (LA) size is considered a marker of poor prognosis in heart failure (HF) patients. Prior studies have recruited relatively few subjects limiting their power to adequately analyse the interaction between LA size, left ventricular (LV) systolic and diastolic function, and prognosis. METHOD AND RESULTS: The MeRGE collaboration combines prospective data from 18 studies in HF patients. In this analysis of data from 1157 patients, the primary endpoint was death or hospitalization for worsening HF. In multivariate analysis (Cox proportion hazard model), LA area was associated with prognosis (HR 1.03 per cm(2), 95% CI 1.02, 1.05; P < 0.0001) independently of age, NYHA class, LV ejection fraction, and restrictive filling pattern (RFP). When LA area was used as a categorical variable, the HR associated with larger LA area (above median) was 1.4 (95% CI 1.13, 1.74) and when LA area index was used, the HR was 2.36 (95% CI 1.80, 3.08). When the patients with and without RFP were divided on the basis of either LA area or LA area index, significantly higher event rates were observed in those with larger LA area. CONCLUSION: Left atrial area is a powerful predictor of outcome among HF patients with predominantly impaired systolic function, and is independent of, and provides additional prognostic information beyond LV systolic and diastolic function. PMID- 19789397 TI - Left ventricular remodelling and torsional dynamics in dilated cardiomyopathy: reversed apical rotation as a marker of disease severity. AB - AIMS: Decreased left ventricular (LV) rotation and torsion and even reversed systolic apical rotation have been described in patients with dilated cardiomyopathy (DCM). We sought to test in patients with DCM whether reversed apical rotation with loss of LV torsion is related to the extent of LV remodelling and to the severity of LV dysfunction. METHODS AND RESULTS: Fifty consecutive patients with DCM (aged 49 +/- 13 years) were enrolled prospectively. Forty-seven healthy volunteers served as controls. All subjects underwent clinical examination, 12-lead electrocardiography, and a comprehensive echocardiogram. Basal and apical LV rotation and LV torsion were quantified by speckle tracking echocardiography. Left ventricular systolic rotation and torsion were reduced in patients, compared with controls (P < 0.001). Normally directed (counterclockwise) apical rotation was found in 24 patients (group 1), whereas 26 had reversed (clockwise) apical rotation (group 2). Patients in group 2 had larger LV volume, increased LV sphericity (P < or = 0.02), more severe systolic dysfunction (ejection fraction 26 +/- 7 vs. 33 +/- 12%), and higher filling pressures (E/E' ratio 19 +/- 10 vs. 14 +/- 6; P < 0.05). The main correlates of LV apical rotation were LV volume, sphericity index, and QRS duration. CONCLUSION: Reversed apical rotation and loss of LV torsion in patients with DCM is associated with significant LV remodelling, increased electrical dyssynchrony, reduced systolic function, and increased filling pressures, indicating a more advanced disease stage. PMID- 19789398 TI - Regional abnormalities of myocardial deformation in patients with hypertrophic cardiomyopathy: correlations with delayed enhancement in cardiac magnetic resonance. AB - AIMS: Hypertrophic cardiomyopathy (HCM) is a genetic disease histologically characterized by a profound disarray of myocardial fibres and by local fibrosis. We sought to characterize regional left ventricular contractility in HCM patients using deformation analysis and to compare it with the presence or absence of delayed enhancement in cardiac magnetic resonance (CMR). METHODS AND RESULTS: We studied 58 HCM patients (mean age 41 years, 37 male). The control population comprised 15 normal subjects. Colour tissue-Doppler imaging was acquired in two dimensional mode from apical four-chamber and two-chamber views; off-line analysis was performed in four basal and four middle left ventricular segments. Gadolinium-enhanced CMR was performed in 36 HCM patients. In HCM patients, peak systolic strain was not uniform across left ventricular segments; differences were not related to site or thickness of the segment analysed. Paradoxically, positive systolic strain values were measured in six middle segments. Delayed CMR enhancement was associated with lower peak systolic strain (P = 0.007). Regional non-uniformities in peak systolic strain were not observed in normal subjects. CONCLUSION: Areas of reduced left ventricular contractility in deformation analysis are associated with delayed CMR enhancement in patients with HCM. PMID- 19789399 TI - Brain natriuretic peptide for the prediction of sudden cardiac death and ventricular arrhythmias: a meta-analysis. AB - AIMS: The risk stratification of patients for sudden cardiac death (SCD) remains a challenge. Brain natriuretic peptide (BNP) predicts overall mortality in heart disease but it is unclear how well it predicts SCD. We therefore performed a meta analysis of studies evaluating the accuracy of BNP to predict SCD and ventricular arrhythmias (VA). METHODS AND RESULTS: Electronic databases and published bibliographies were systematically searched (1984-2008). We found 14 studies that met our inclusion criteria. Six studies (3543 patients) evaluated BNP to predict SCD in patients without implantable cardioverter defibrillators (ICDs) across a wide range of populations. A raised BNP predicted SCD with a relative risk of 3.68 [95% confidence interval (CI) 1.90, 7.14]. Eight studies (1047 patients) evaluated BNP to predict the occurrence of VA in patients with ICDs. A raised BNP predicted the occurrence of VA with a relative risk of 2.54 (95% CI 1.87, 3.44). CONCLUSION: The measurement of BNP has significant value in predicting SCD and VA. However, the benefit of BNP testing in addition to other risk stratification tests is unclear and BNP needs to be evaluated prospectively in combination with other complementary risk stratification tools. PMID- 19789400 TI - Plasma B-type natriuretic peptide and anti-inflammatory cytokine interleukin-10 levels predict adverse clinical outcome in chronic heart failure patients with depressive symptoms: a 1-year follow-up study. AB - AIMS: To assess the prognostic value of a wide spectrum of neurohormonal and inflammatory markers along with functional status and exercise capacity, in hospitalized chronic heart failure (CHF) patients with depressive symptoms. METHODS AND RESULTS: A total of 300 consecutive hospitalized CHF patients were screened for depressive symptomatology using the Zung self-rated depression scale (SDS). Patients with depressive symptoms (Zung SDS > or = 40) underwent a 6 min walking test, and evaluation of left ventricular ejection fraction, B-type natriuretic peptide (BNP), and plasma inflammatory/anti-inflammatory factors [interleukin (IL)-6, IL-10, tumour necrosis factor-alpha, soluble intercellular adhesion molecule-1, and vascular cell adhesion molecule-1]. Patients were subsequently followed for up to 1 year for major adverse cardiovascular events (MACE, death or hospitalization due to cardiovascular causes). One hundred and fourteen patients (38%) had a Zung SDS > or = 40. One-year event-free survival of these patients was 19% (mean +/- SE, 150 +/- 12 days). In multivariate analysis, only BNP (HR = 1.001, P = 0.002) and IL-10 (HR = 0.864, P = 0.049) were independent predictors of MACE. Using receiver operator characteristics analysis derived cut-offs, a BNP value of 290 pg/mL predicted MACE with 86% sensitivity and 69% specificity, whereas an IL-10 value of 5 pg/mL predicted MACE with 61% sensitivity and 78% specificity. Event-free survival differed significantly between patients with BNP < 290 pg/mL and IL-10 > 5 pg/mL (261 +/- 44 days) and those with BNP > 290 pg/mL and IL-10 < 5 pg/mL (79 +/- 11 days, P = 0.0001). CONCLUSION: Neurohormonal activation and defective anti-inflammatory properties are independent predictors of long-term outcome in hospitalized CHF patients with depressive symptoms. PMID- 19789401 TI - Intracoronary infusion of bone marrow-derived mononuclear cells abrogates adverse left ventricular remodelling post-acute myocardial infarction: insights from the reinfusion of enriched progenitor cells and infarct remodelling in acute myocardial infarction (REPAIR-AMI) trial. AB - AIMS: Depressed left ventricular ejection fraction (LVEF) despite successful reperfusion therapy is the single most powerful predictor of progressive LV enlargement after acute myocardial infarction (AMI) and independently determines adverse outcome in these patients. METHODS AND RESULTS: We investigated the effect of intracoronary administration of bone marrow-derived mononuclear cells (BMC) within 7 days after successful reperfusion therapy for AMI, on early (within 4 months) LV remodelling processes assessed by quantitative LV angiography. Overall, 95 patients received BMC and 92 patients received placebo. Remodelling was assessed as the changes in either LVEF and end-systolic volume (ESV) or stroke volume and end-diastolic volume (EDV) at 4 months, respectively. Baseline LVEF was inversely correlated with ESV expansion at 4 months in the placebo group, but not in the BMC group. Likewise, EDV expansion was significantly correlated with baseline LVEF in the placebo (r = -0.36, P < 0.001), but not in the BMC group (r = -0.17, P = 1.0). Analysing the interaction between convalescent LV contractile function and LV volumes revealed that the increase in LVEF or stroke volume did not occur at the expense of increases in ESV or EDV, respectively, in the BMC group. CONCLUSION: Intracoronary administration of BMC eliminates the correlation between depressed LVEF after reperfusion therapy and LV expansion during follow-up and, thereby, abrogates early LV remodelling after AMI. PMID- 19789402 TI - A randomized, double-blind, placebo-controlled study to determine the effects of valsartan on exercise time in patients with symptomatic heart failure with preserved ejection fraction. AB - AIMS: To determine whether valsartan improves treadmill exercise time, in patients with symptomatic heart failure with a preserved ejection fraction (HFPEF), compared with placebo. METHODS AND RESULTS: In this multicentred, double blind, 14-week study, patients were randomized to receive valsartan (V) 80 mg or placebo (P) once daily on top of background medications. The dose of valsartan was force-titrated up to 320 mg. A total of 152 patients were randomized (V = 70, P = 82). Most patients had well-controlled hypertension (V = 91.2%, P = 89.0%) (mean baseline systolic BP approximately 130 mmHg) and >50% were receiving an angiotensin-converting enzyme inhibitor and/or beta-blocker (V = 57.4%, P = 54.9%). The mean ejection fraction at baseline was 70.48% in the placebo group (n = 64) and 71.52% in the valsartan group (n = 79). Valsartan had no significant effect on exercise time (primary variable), gas exchange variables, 6 min walk test distance, exertion-related symptoms, brain natriuretic peptide levels, echocardiographic parameters, or quality-of-life scores. Valsartan significantly lowered peak exercise systolic BP (-13.1 mmHg vs. placebo; P < 0.001) and improved ratings of perceived exertion (Borg score) (-0.69 vs. placebo; P = 0.008). CONCLUSION: In this population, which predominantly included patients with well-controlled hypertension and symptomatic HFPEF, addition of valsartan did not increase exercise time within 14 weeks. However, valsartan 320 mg reduced blood pressure and improved symptoms of perceived exertion (Borg score) during exercise and was generally well-tolerated. PMID- 19789404 TI - Significance of anaemia in patients with advanced heart failure receiving long term mechanical circulatory support. AB - AIMS: The aim of this study was to analyse the prognostic impact of anaemia in patients receiving long-term left ventricular assist device (LVAD) support. METHODS AND RESULTS: We reviewed the data of 65 consecutive patients who underwent LVAD support for at least 6 months. Anaemia was defined as haemoglobin levels <12.0 g/dL. Follow-up was performed 15 months after implantation. Anaemia was present in 30/65 patients (46%) after 6 months of LVAD support. Anaemic patients had higher levels of pre-implant creatinine (1.8 +/- 0.8 vs. 1.4 +/- 0.5 mg/dL; P = 0.04). The presence of anaemia after 6 months correlated with higher levels of creatinine and blood urea nitrogen and lower levels of albumin. Multivariate Cox proportional hazards regression analysis revealed that levels of haemoglobin <12 g/dL [risk ratio (RR), 8.94; 95% confidence interval (CI), 1.09 73.01; P = 0.04], creatinine >1.4 mg/dL (RR, 5.39; 95% CI, 1.78-16.30; P = 0.003), and albumin <1.5 g/L (RR, 3.23; 95% CI, 1.10-9.51; P = 0.03) were associated with all-cause mortality at 15 months. Long-term survival evaluated by Kaplan-Meier analysis was two times higher in non-anaemic patients after 6 months of LVAD support than in anaemic patients (P = 0.01). CONCLUSION: Anaemia is related to adverse outcomes in patients receiving prolonged LVAD support. PMID- 19789403 TI - Hawthorn Extract Randomized Blinded Chronic Heart Failure (HERB CHF) trial. AB - AIMS: Hawthorn's efficacy when added to contemporary evidence-based heart failure therapy is unknown. We aimed to determine whether hawthorn increases submaximal exercise capacity when added to standard medical therapy. METHODS AND RESULTS: We performed a randomized, double-blind, placebo-controlled trial in 120 ambulatory patients aged > or = 18 years with New York Heart Association (NYHA) class II-III chronic heart failure. All patients received conventional medical therapy, as tolerated, and were randomized to either hawthorn 450 mg twice daily or placebo for 6 months. The primary outcome was change in 6 min walk distance at 6 months. Secondary outcomes included quality of life (QOL) measures, peak oxygen consumption, and anaerobic threshold during maximal treadmill exercise testing, NYHA classification, left ventricular ejection fraction (LVEF), neurohormones, and measures of oxidative stress and inflammation. There were no significant differences between groups in the change in 6 min walk distance (P = 0.61), or on measures of QOL, functional capacity, neurohormones, oxidative stress, or inflammation. A modest difference in LVEF favoured hawthorn (P = 0.04). There were significantly more adverse events reported in the hawthorn group (P = 0.02), although most were non-cardiac. CONCLUSION: Hawthorn provides no symptomatic or functional benefit when given with standard medical therapy to patients with heart failure. This trial is registered in ClinicalTrials.gov ID: NCT00343902. PMID- 19789405 TI - Staged heart transplantation and chemotherapy as a treatment option in patients with severe cardiac light-chain amyloidosis. AB - AIMS: The prognosis of advanced cardiac light-chain amyloidosis is poor. Heart transplantation might enable causative therapy and ultimately improve prognosis. METHODS AND RESULTS: Nineteen patients with cardiac amyloidosis but no obvious involvement of other organs were scheduled for heart transplantation. Four to 6 months later, high-dose melphalan chemotherapy and autologous stem cell transplantation (HDM-ASCT) was planned in patients not in complete remission. Seven of nineteen patients died while waiting for heart transplantation. The remaining 12 patients (complete remission, n = 4) underwent surgery. Chemotherapy in patients not in complete remission consisted of HDM-ASCT (n = 5/12; subsequent complete remission, n = 2; partial remission, n = 3) or melphalan-prednisolone (partial remission, n = 1). Two of twelve patients were ineligible for any chemotherapy. Three of twelve patients died [423.5 (105-2131) days] from progressive disease, relapse, or sepsis. The 1- and 3-year survival rates were 83 and 83%, respectively, similar to those of patients undergoing heart transplantation for standard indications. Corresponding survival rates stratified by haematological response were 100 and 100% for complete remission (partial remission, 100 and 100%; progressive disease, 0 and 0%). CONCLUSION: Heart transplantation in advanced cardiac amyloidosis is a promising approach to interrupting the vicious circle of ineligibility for potential curative chemotherapeutic treatment and extremely poor prognosis of cardiac amyloidosis without chemotherapy. Highly urgent heart transplantation combined with subsequent HDM-ASCT appears to offer a successful treatment option to improve the poor outcome of cardiac amyloidosis. However, it should be restricted to highly selected patients in specialized centres. PMID- 19789406 TI - Longitudinal histories as predictors of future diagnoses of domestic abuse: modelling study. AB - OBJECTIVE: To determine whether longitudinal data in patients' historical records, commonly available in electronic health record systems, can be used to predict a patient's future risk of receiving a diagnosis of domestic abuse. DESIGN: Bayesian models, known as intelligent histories, used to predict a patient's risk of receiving a future diagnosis of abuse, based on the patient's diagnostic history. Retrospective evaluation of the model's predictions using an independent testing set. SETTING: A state-wide claims database covering six years of inpatient admissions to hospital, admissions for observation, and encounters in emergency departments. Population All patients aged over 18 who had at least four years between their earliest and latest visits recorded in the database (561,216 patients). MAIN OUTCOME MEASURES: Timeliness of detection, sensitivity, specificity, positive predictive values, and area under the ROC curve. RESULTS: 1.04% (5829) of the patients met the narrow case definition for abuse, while 3.44% (19,303) met the broader case definition for abuse. The model achieved sensitive, specific (area under the ROC curve of 0.88), and early (10-30 months in advance, on average) prediction of patients' future risk of receiving a diagnosis of abuse. Analysis of model parameters showed important differences between sexes in the risks associated with certain diagnoses. CONCLUSIONS: Commonly available longitudinal diagnostic data can be useful for predicting a patient's future risk of receiving a diagnosis of abuse. This modelling approach could serve as the basis for an early warning system to help doctors identify high risk patients for further screening. PMID- 19789407 TI - Adiposity and weight change in mid-life in relation to healthy survival after age 70 in women: prospective cohort study. AB - OBJECTIVE: To examine the hypothesis that mid-life adiposity is associated with a reduced probability of maintaining an optimal health status among those who survive to older ages. DESIGN: Prospective cohort study. SETTING: The Nurses' Health Study, United States. PARTICIPANTS: 17,065 women who survived until at least the age of 70, provided information on occurrence of chronic disease, cognitive function, physical function, and mental health at older ages, and were free from major chronic diseases at mid-life (mean age was 50 at baseline in 1976). MAIN OUTCOME MEASURES: Healthy survival to age 70 and over was defined as having no history of 11 major chronic diseases and having no substantial cognitive, physical, or mental limitations. RESULTS: Of the women who survived until at least age 70, 1686 (9.9%) met our criteria for healthy survival. Increased body mass index (BMI) at baseline was significantly associated with linearly reduced odds of healthy survival compared with usual survival, after adjustment for various lifestyle and dietary variables (P<0.001 for trend). Compared with lean women (BMI 18.5-22.9), obese women (BMI >or=30) had 79% lower odds of healthy survival (odds ratio 0.21, 95% confidence interval 0.15 to 0.29). In addition, the more weight gained from age 18 until mid-life, the less likely was healthy survival after the age of 70. The lowest odds of healthy survival were among women who were overweight (BMI >or=25) at age 18 and gained >or=10 kg weight (0.18, 0.09 to 0.36), relative to women who were lean (BMI 18.5-22.9) and maintained a stable weight. CONCLUSIONS: These data provide evidence that adiposity in mid-life is strongly related to a reduced probability of healthy survival among women who live to older ages, and emphasise the importance of maintaining a healthy weight from early adulthood. PMID- 19789408 TI - Expression of osteogenic proteins during the intrasplenic transplantation of Meckel's chondrocytes: A histochemical and immunohistochemical study. AB - Meckel's chondrocytes, derived from the ectomesenchyme, have the potential to transform into other phenotypes. In this study, we transplanted cell pellets of Meckel's chondrocytes into isogenic mouse spleens and analyzed their phenotypic transformation into osteogenic cells using histological and immunohistochemical methods. With the increasing duration of transplantation, chondrocytes were incorporated into splenic tissues and formed a von Kossa-positive calcified matrix containing calcium and phosphoric acid, similar to that of intact bone. Type I, II, and X collagens, and the bone-marker proteins osteocalcin, osteopontin, osteonectin, and bone morphogenetic protein-2 (BMP-2) were immunolocalized in the matrix formed by the transplanted chondrocytes. Osteopontin and osteonectin were detected in the calcified matrix at earlier stages than osteocalcin and BMP-2. Type II collagen was expressed during the first week of transplantation, and type X collagen-positive cells appeared scattered during the initial stage of calcification, these collagens being later replaced by type I collagen formed by osteocyte-like cells. Electron microscopic observations revealed that chondrocytes surrounded by the calcified matrix transformed into spindle-shaped osteocytic cells accompanying the formation of bone-type thick-banded collagen fibrils. These results suggest that phenotypic switching of Meckel's chondrocytes can occur under in vivo conditions at a cellular morphological level. PMID- 19789409 TI - The microstructure of lingual papillae in the Egyptian fruit bat (Rousettus aegyptiacus) as observed by light microscopy and scanning electron microscopy. AB - The microstructure of lingual papillae on the dorsal surface of the tongue of adult Egyptian fruit bats was examined by light microscopy (LM) and scanning electron microscopy (SEM). This elongated tongue with a rounded apex is approximately 3 cm long -- including the 1.7cm length of the anterior free part of the tongue -- which facilitates considerable freedom of movement. The surface of the tongue has four types of lingual papillae: two types of mechanical papillae -- filiform and conical papillae, and two types of gustatory papillae -- fungiform and vallate papillae. Most numerous are filiform papillae with well developed keratinized processes represented by four morphological subtypes -- small, giant, elongated, and bifid papillae. Our observations showed the small and giant filiform papillae to be present in the anterior part of the tongue and tilted to the back of the tongue. In the posterior part of the tongue, the filiform papillae with elongated processes were arranged on each side of the tongue and oriented perpendicularly to the median line of tongue. This arrangement of filiform papillae is considered to be useful for the efficient uptake of semiliquid food as it can be collected toward the median line of the tongue. Gustatory fungiform papillae were distributed among filiform papillae on the border of the apex and the anterior part of the body of the tongue and also on the posterior part of the tongue, while three vallate papillae surrounded by conical papillae were found on the root of the tongue. There were also taste buds along the ducts of the posterior lingual glands in the posterior-lateral part of the tongue. These morphological features are discussed in relation to adaptation to food uptake in the Egyptian fruit bat. PMID- 19789410 TI - Expression of the nerve growth factor-induced gene B-beta in the developing rat brain and retina. AB - The nerve growth factor-induced gene B-beta (NGFI-Bbeta, Nurr1) is a member of the nuclear receptor superfamily that is expressed predominantly in the central nervous system. We used an antibody against the human NGFI-Bbeta to observe the protein expression in neuronal cells in the retina, cerebral neocortex, and midbrain of humans and rats. To provide further insight into the role of NGFI Bbeta in the differentiation of neuronal cells, we also examined the expression of NGFI-Bbeta in rat ontogeny. A few cells in the midbrain showed the expression of NGFIBbeta from 12 days of gestation, and NGFI-Bbeta positive cells increased in the neocortex, claustrum, thalamus and hypothalamus in the subsequent fetal days. NGFI-Bbeta-positive cells appeared in the inner nuclear layer of the retina at 18 days of gestation and also in the ganglion cell layer after birth. An immunohistochemical study on the expression of proliferating cell nuclear antigen (PCNA) demonstrated that NGFI-Bbeta-positive cells were not proliferating cells. These findings suggest that NGFI-Bbeta plays an important role during the postmitotic differentiation of neuronal cells in the brain and retina. PMID- 19789411 TI - Characterization of the sugar chain expression of normal term human placental villi using lectin histochemistry combined with immunohistochemistry. AB - The general sugar expression pattern was studied in 9 normal full-term human placentas by the use of 21 individual lectins in combination with immunohistochemistry for various markers to understand the function of the placenta as the site of feto-maternal interactions. In mature intermediate and terminal villi, the brush border of the syncytiotrophoblast layer strongly expressed GlcNAc (as stained by WGA, S-WGA, DSL lectins) but weakly expressed sialic acid (Mal II, SNA). The cytoplasm of the syncytiotrophoblast layer showed weak expressions of GlcNAc and Gal/GalNAc with granular patterns. The cytotrophoblast layer, as also recognized by PCNA and HAI-1, typically expressed GlcNAc (LEL etc.) and Gal/GalNAc (MAL I). We found that the cytotrophoblast layer became very thin but largely maintained its continuity in the mature villi. The basement membranes of both the trophoblast layer and the endothelial layer strongly and continuously expressed mannose (Con A, LCA) and galactose (ECL, RCA I). Although endothelial cells almost exclusively expressed sialic acid and fucose, UEA I showed a heterogeneous reactivity with endothelial cells within the same vessels. No uniform expression pattern of any sugar was seen in stromal components except for Hofbauer cells, which usually expressed GlcNAc (LEL and DSL etc.). Thus, the sugar expression analysis by lectin histochemistry combined with immunohistochemistry proved helpful to understand the sugar chain related functions of the placenta under both normal and pathological conditions. PMID- 19789412 TI - Effects of basic fibroblast growth factor on the development of the stem cell properties of human dental pulp cells. AB - We isolated adherent fibroblastic cells after collagenase and dispase treatment of human dental pulp. When human dental pulp cells (hDPCs) were cultured in the presence of basic fibroblast growth factor (bFGF), the ratio of hDPCs in the S phase was significantly higher in comparison with incubation without bFGF. The ratio of hDPCs expressing STRO-1 as a marker of stem cell populations increased approximately eightfold in the presence of bFGF as opposed to that in the absence of bFGF. We demonstrated the characterization and distinctiveness of the hDPCs and showed that, when cultured with the medium containing serum and bFGF, they were highly proliferative and capable of differentiating in vitro into osteoblasts, chondrocytes, and adipocytes. Furthermore, the in vitro differentiation was confirmed at both the protein and gene expression levels. Transplantation of hDPCs -- expanded ex vivo in the presence of bFGF into immunocompromised mice -- revealed the formation of bone, cartilage, and adipose tissue. The donor hDPC-derived cells were labeled in the bone tissues located near the PLGA in the subcutaneous tissues of recipient mice using a human specific Alu probe. When cultured with a serum-free medium containing bFGF, the hDPCs strongly expressed STRO-1 immunoreactive products and sustained self renewal, and thus were almost identical in differentiation potential and proliferation activity to hDPCs cultured with the medium containing serum and bFGF. The present results suggest that the hDPCs cultured in the presence of bFGF irrespective of the presence or absence of the bovine serum are rich in mesenchymal stem cells or progenitor cells and useful for cell-based therapies to treat dental diseases. PMID- 19789413 TI - The expression of transferrin binding protein in the turtle nervous system. AB - Transferrin binding protein (TfBP) is a cytoplasmic glycoprotein that was originally isolated from the chick oviduct. As we previously demonstrated the constitutive expression of TfBP in the avian nervous system, in this study we examined whether TfBP is expressed in the reptilian nervous system. In accordance with previous findings in the chicken, oligodendrocytes were most prominently labeled by antiserum to TfBP. Great variability was observed between different regions of the central nervous system (CNS) in terms of TfBP-labeled oligodendrocyte numbers. In the retina, TfBP was localized specifically in the cells that are morphologically oligodendrocytes and present in the optic nerve and the ganglion cell layer. TfBP staining was also seen in the Schwann cells of peripheral nerves. Furthermore, choroid plexus cells and capillary endothelial cells similarly exhibited strong reactions. These results may reflect the fact that the homology of nervous system genes is conserved between close phylogenetic lines, and proove the potential of TfBP as a marker for oligodendrocytes in avian as well as reptile. PMID- 19789414 TI - Therapeutic hypothermia (30 degrees C) enhances arrhythmogenic substrates, including spatially discordant alternans, and facilitates pacing-induced ventricular fibrillation in isolated rabbit hearts. AB - BACKGROUND: Therapeutic hypothermia (TH, 30 degrees C) protects the brain from hypoxic injury. However, TH may potentiate the occurrence of lethal ventricular fibrillation (VF), although the mechanism remains unclear. The present study explored the hypothesis that TH enhances wavebreaks during VF and S(1) pacing, facilitates pacing-induced spatially discordant alternans (SDA), and increases the vulnerability of pacing-induced VF. METHODS AND RESULTS: Using an optical mapping system, epicardial activations of VF were studied in 7 Langendorff perfused isolated rabbit hearts at baseline (37 degrees C), TH (30 degrees C), and rewarming (37 degrees C). Action potential duration (APD)/conduction velocity (CV) restitution and APD alternans (n=6 hearts) were determined by S(1) pacing at these 3 stages. During TH, there was a higher percentage of VF duration containing epicardial repetitive activities (spatiotemporal periodicity) (P<0.001). However, TH increased phase singularity number (wavebreaks) during VF (P<0.05) and S(1) pacing (P<0.05). TH resulted in earlier onset of APD alternans (P<0.001), which was predominantly SDA (P<0.05), and increased pacing-induced VF episodes (P<0.05). TH also decreased CV, shortened wavelength, and enhanced APD dispersion and the spatial heterogeneity of CV restitution. CONCLUSIONS: TH (30 degrees C) increased the vulnerability of pacing-induced VF by (1)facilitating wavebreaks during VF and S(1) pacing, and (2)enhancing proarrhythmic electrophysiological parameters, including promoting earlier onset of APD alternans (predominantly SDA) during S(1) pacing. PMID- 19789415 TI - Combination of an ACE inhibitor and indapamide improves blood pressure control, but attenuates the beneficial effects of ACE inhibition on plasma adiponectin in patients with essential hypertension. AB - BACKGROUND: Antihypertensive agents differentially influence the plasma adiponectin concentration and the effects of fixed-dose combination regimens remain unclear. The influence of a combination of an angiotensin-converting enzyme inhibitor (ACEI) and a thiazide-type diuretic or an ACEI alone on plasma adiponectin concentrations in patients with essential hypertension was evaluated in the present study. METHODS AND RESULTS: After a 2-week placebo run-in phase, 30 patients with essential hypertension were randomized to receive preterax (2 mg perindopril/0.625 mg indapamide) or cilazapril (2.5 mg) once daily for 12 weeks. Plasma adiponectin and insulin concentrations were measured before and after treatment. Insulin resistance was measured by homeostasis assessment index (HOMA IR). Treatment with preterax (P=0.003) and cilazapril (P=0.031) significantly reduced systolic blood pressure (BP), but only preterax reduced diastolic BP (P=0.024). Cilazapril treatment significantly increased the plasma adiponectin concentration (P=0.025) and reduced plasma triglycerides (P=0.041), whereas preterax treatment increased the plasma insulin concentration (P=0.041) and tended to increase HOMA-IR. CONCLUSIONS: The combination of an ACEI and indapamide improved BP control, but attenuated the beneficial effects of ACE inhibition on plasma adiponectin in patients with essential hypertension. Such a combination may be best reserved for improved BP control rather than for metabolic protection in clinical hypertension. PMID- 19789416 TI - Blood eicosapentaenoic acid and docosahexaenoic acid as predictors of all-cause mortality in patients with acute myocardial infarction--data from Infarction Prognosis Study (IPS) Registry. AB - BACKGROUND: Although omega-3 polyunsaturated fatty acids are known to have beneficial effects on cardiovascular diseases, their prognostic value has not been studied prospectively in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: The plasma levels of phospholipids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) (% of total fatty acids), were measured in 508 patients (365 males; mean age, 63 years) with AMI. Clinical and biomarker predictors of all-cause and cardiovascular mortality were identified by stepwise Cox regression model. During a mean follow-up of 16.1 months, 36 (7.1%) patients died. After controlling for confounding variables, age (hazard ratio (HR): 1.09, P<0.001), renal insufficiency (HR: 2.84, P=0.01) and EPA level (HR: 0.29, P=0.004) were identified as independent predictors of all cause-mortality. When stratified by gender, age (HR: 1.08, P=0.001) and renal insufficiency (HR: 4.49, P=0.003) were predictors of all-cause-mortality in males, whereas EPA level (HR: 0.18, P=0.009) and angiotensin-converting enzyme inhibitor use (HR: 0.24, P=0.03) were identified as predictive of all-cause-mortality in females. CONCLUSIONS: Lower plasma level of EPA, but not DHA, was an independent predictor for all cause-mortality in patients with AMI, but this relationship was significant only in female patients. PMID- 19789417 TI - Long-term follow-up of neointimal coverage of sirolimus-eluting stents- evaluation with optical coherence tomography. AB - BACKGROUND: Late stent thrombosis related to delayed neointimal growth is a major concern after drug-eluting stent (DES) implantation. The time course of neointimal growth and risk factors of uncovered stent struts after sirolimus eluting stent (SES) was studied using optical coherence tomography (OCT). METHODS AND RESULTS: The 60 patients were enrolled and classified into G1 (follow-up period <9 months, n=27), G2 (9-24 months, n=18), and G3 (>25 months, n=15). The time elapsed since SES implantation was associated with a significant increase in mean neointimal area and neointimal thickness, and also with a significant decrease in the number of uncovered stent struts (G1: 14.8%, G2: 11.7%, and G3: 4.1%, P<0.001). However, only 17.6% of implanted SES was completely covered by neointima, even in the G3 period. Small-diameter SES, complex coronary lesions with lipid and calcium content adjacent to stent struts, and diabetes predicted delayed neointimal coverage of SES struts in G1. CONCLUSIONS: Neointima inside SES progressively increases after the routine follow-up period, but only a few SES were completely covered at 3 years after implantation. OCT is a useful modality for assessing neointimal formation after SES implantation, and may give important information about the strategy of antiplatelet therapy after DES implantation. PMID- 19789418 TI - Lack of clinical benefit of improved angiographic results with sirolimus-eluting stents compared with paclitaxel and zotarolimus-eluting stents in patients with acute myocardial infarction undergoing percutaneous coronary intervention. AB - BACKGROUND: There is limited information regarding the angiographic and clinical outcomes among the different drug-eluting stents (DESs) in patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI). METHODS AND RESULTS: A total 355 consecutive AMI patients who underwent PCI with a sirolimus- (SES, n=116) or paclitaxel- (PES, n=153) or zotarolimus-eluting stent (ZES, n=86) were enrolled. The 6-month angiographic and 1-year clinical outcomes were compared among the 3 groups. At 6 months, there was a trend toward a higher incidence of binary restenosis in the PES group (SES: 8.6%, PES: 19.8%, ZES: 8.3%, P=0.052). Percentage of restenosis was higher in the PES group compared with SES, but was similar to ZES (SES: 18.75 +/-18.16%, PES: 29.32 +/ 24.16%, ZES: 23.91 +/-17.03%, P=0.006). Late loss was lower in the SES group compared with PES and ZES (SES: 0.44 +/-0.52, PES: 0.83 +/-0.87, ZES: 0.75 +/ 0.63, P<0.001). However, clinical outcomes, including mortality, MI, repeat PCI and major adverse cardiac events, were not different among the 3 groups. CONCLUSIONS: The angiographic benefit of SES did not translate into a clinical benefit for up to 1 year in AMI patients. PMID- 19789419 TI - Hypokalemia, diabetes mellitus, and hypercortisolemia are the major contributing factors to cardiac dysfunction in adrenal Cushing's syndrome. AB - Although cardiovascular complications are the major determinant of the prognosis of Cushing's syndrome (CS), factors contributing to the cardiovascular lesions are still unclear. We investigated clinical factors determining cardiac function in patients with adrenal CS. Fifty patients with adrenal CS were studied. Patients were divided into 3 groups based on their NYHA classification and electrocardiographic (ECG) findings: group A with NYHA grade 0 and normal ECG, group B with NYHA grade I and abnormal ECG, and group C with NYHA grade II or higher. Clinical and echocardiographic findings were compared between the groups. Heart failure of grade I or higher was seen in 40% and grade II or higher was seen in 8% of the patients. Age, HbA1c, and prevalence of diabetes mellitus were positively correlated and serum potassium levels were negatively correlated with the severity of cardiac dysfunction. Decreased ejection fraction (EF) and the ratio of the peak to late transmittal filling velocities (E/A), and increased left ventricular mass index (LVMI) were frequently observed. Multivariate analysis demonstrated that serum potassium and HbA1c levels were independent factors contributing to EF, while serum potassium and cortisol levels were independent factors contributing to LVMI. These results clearly demonstrated that hypokalemia, diabetes mellitus, and hypercortisolemia are the major contributing factors to cardiac dysfunction in adrenal CS. Strict control of these conditions is warranted for the prevention of cardiac dysfunction in adrenal CS. PMID- 19789420 TI - Pioglitazone reduces ER stress in the liver: direct monitoring of in vivo ER stress using ER stress-activated indicator transgenic mice. AB - It is known that endoplasmic reticulum (ER) stress is provoked under diabetic conditions and is possibly involved in the development of insulin resistance. In this study, using ER stress-activated indicator (ERAI) transgenic mice which express green fluorescent protein under ER stress conditions, we directly evaluated the effects of a diabetic agent pioglitazone on in vivo ER stress under diabetic conditions. In high fat and high sucrose diet-induced diabetic ERAI transgenic mice, 8 weeks of pioglitazone treatment reduced the accumulation of fat droplets in the liver and attenuated the development of insulin resistance. In the liver of the ERAI transgenic mice, ERAI fluorescence activity was clearly reduced as early as after 4 weeks of pioglitazone treatment, preceding the improvement of insulin resistance. In addition, after the pioglitazone treatment, serum free fatty acid and triglyceride levels were decreased, and serum adiponectin levels were increased. These data indicate that pioglitazone treatment suppresses ER stress in the liver which may explain, at least in part, the pharmacological effects of pioglitazone to reduce insulin resistance. PMID- 19789421 TI - Urinary iodine concentrations in the high background radiation areas of Kanyakumari district, Tamilnadu, India. AB - We screened urinary iodine (UI) concentrations in high background radiation areas of the Kanyakumari district of Tamilnadu, India. We collected 331 urine samples from three villages in the district: Chinna-Villai, Kadiyapatinam, and Pallam Annai nagar. The median UI concentrations were 257, 262, and 454 microg/L in Chinna-Villai, Kadiyapatinam, and Pallam-Annai nagar, respectively. Only 27 samples showed mild or moderate iodine deficiency (<100 microg/L) and none showed severe deficiency (<20 microg/L). These findings indicate that iodine supplementation in the villages is sufficient, probably as a result of appropriate fortification of iodized salt in the region. Further screening, including morphological and functional analysis of the thyroid gland, will be needed to clarify the health effects of chronic low-dose radiation exposure attributable to residing in a high background radiation area. PMID- 19789422 TI - Characteristics of the stimulatory effect of kisspeptin-10 on the secretion of luteinizing hormone, follicle-stimulating hormone and growth hormone in prepubertal male and female cattle. AB - The aims of the present study were to clarify the effect of kisspeptin-10 (Kp10) on the secretion of luteinizing hormone (LH), follicle-stimulating hormone (FSH) and growth hormone (GH) in prepubertal male and female cattle. The experiments were performed from May to June using five male (4-6 months old) and five female (5-6 months old) Japanese Black calves. A single intravenous (iv) injection of Kp10 (5 microg/kg body weight (b.w.): 3.85 nmol/ kg b.w.) significantly stimulated the release of LH and FSH in male and female calves (P<0.05). A single intramuscular injection of Kp10 (5 microg/kg b.w.) also significantly stimulated the release of LH and FSH in male calves (P<0.05), though the response was smaller than that to the iv injection. The injection of Kp10 did not alter the basal plasma concentration of GH in male or female calves. The area under the curve (AUC) of both LH and FSH for a 120-min period after the iv injection of Kp10 was significantly greater in the males than females (P<0.05). These results show that Kp10 can stimulate the release of LH and FSH in calves of both sexes and that the response to the peptide is greater in males at this age. They also show that Kp10 has no effect on the release of GH in male and female calves and that the LH- and FSH-releasing effect of Kp10 is greater after an iv injection than after an im injection in calves. PMID- 19789423 TI - Effects of the presence and the numbers of corpora lutea in non-delivered and delivered pigs on in vitro oocyte maturation and embryonic development. AB - The aim of this study was to investigate the effects of the presence and the numbers of corpora lutea (CL) in porcine ovaries on in vitro oocyte maturation and embryonic development following intracytoplasmic sperm injection (ICSI). At oocyte collection, the ovaries of non-delivered and delivered pigs were classified into four groups by CL presence. The effect of the number of CL was also investigated following re-division of the non-delivered groups into four groups. In addition, the progesterone (P(4)) concentrations in follicular fluid (FF) of all the groups were measured to confirm the relationship between the presence and numbers of CL. Throughout the present study, the oocytes recovered from the CL-holding ovaries showed high (P<0.05) oocyte maturation rates, blastocyst rates and P(4) concentrations in FF. Furthermore, in the non-delivered groups, the blastocyst rates and P(4) concentrations in FF seemed to coincide with the CL numbers in each ovary. From these findings, we concluded that the presence and number of CL in the ovary can be used as an indicator for estimation of the developmental competence of porcine oocytes. Additionally, the present study suggests that P(4) in FF influences in vitro oocyte maturation and embryonic development in porcine in vitro production. PMID- 19789424 TI - Gold nanoparticles enter rat ovarian granulosa cells and subcellular organelles, and alter in-vitro estrogen accumulation. AB - Nanoparticle technology refers to research and technology developed at the atomic or molecular level for materials of approximately 1-100 nm in length. Through accidental or involuntary exposure, nanoparticles are potentially toxic to the body, including reproductive organs. Ovarian granulosa cells play a major role in maintaining ovarian function, health, and female fertility. Since these cells are involved in steroidogenesis, we wished to evaluate whether nanoparticles affected them after traversing their membranes. Cells were co-incubated with 10 nm gold particles for up to 24 h. Transmission electron micrographs were taken of GC treated with 10 nm gold particles in order to compare and contrast ultrastructural locations of nanoparticles with treatment. From micrograph comparisons of treated vs. untreated GC at various culture times, it appeared that some intracellular organelles involved in steroidogenesis were infiltrated and/or altered due to the presence of the nanogold particles. Medium samples were taken in order to determine estradiol-17beta (E2) accumulation/secretion by untreated vs. treated cells. GC incubated with 10 nm nanogold particles for 1, 3, or 5 h were found to accumulate significantly increased amounts of estrogen compared with untreated cells. Conversely, at 24 h there was a significant attenuation with respect to controls. The data presented here provide insight into the toxicologic effects gold nanoparticles elicit on ovarian granulosa cells. PMID- 19789425 TI - Expression profiling of tetraploid mouse embryos in the developmental stages using a cDNA microarray analysis. AB - Tetraploid embryos normally develop to the blastocyst stage before implantation, but fail to survive after implantation. To better understand these characteristics of the tetraploid embryo, we produced tetraploid embryos by electrofusion and analyzed expressed genes that participated in mammalian embryogenesis using a DNA microarray analysis and a publicly available bioinformatics analysis of hatched tetraploid and diploid blastocysts. Transcriptome analysis with the DNA microarray revealed that the expression level of most genes was almost the same between diploid and tetraploid blastocysts. We found that the expression levels 2,800 genes were increased, but the expression levels over 1,600 genes were decreased in tetraploid blastocysts, which have a genomic composition identical to that of diploid blastocysts. In tetraploid blastocysts, the levels of 15 genes were decreased more than two-fold compared with the levels in diploid blastocysts. Among these downregulated genes, Ccnb1 (cyclin B1), which was decreased by 3-fold, seemed to play a particularly important role in the cellular organization of the tetraploid blastocyst. To classify the major functional classes of all the genes differentially expressed between diploid and tetraploid blastocysts, we employed a publicly available bioinformatics database, the VisuaL Annotation Display (VLAD). VLAD revealed several altered pathways in tetraploid blastocysts. Some of the enhanced biological processes were moderately involved with chromosome organization, while the suppressed processes were significantly involved with cell division and the mitotic cell cycle, metabolic processes and protein localization and transport. Taken together, our results revealed a large population of downregulated genes in tetraploid hatched blastocysts, and our convergent data suggest that the downregulation might primarily individualize the tetraploid phenotype in hatched blastocysts. PMID- 19789426 TI - Racial disparity in amputation-free survival after infrainguinal bypass procedure: contribution of socioeconomic status. AB - OBJECTIVE: To investigate amputation-free survival after infrainguinal bypass in African Americans and Hispanics compared with non-Hispanic whites and to determine the contribution of socioeconomic status to potential racial disparity. DESIGN: This is a retrospective cohort study of subjects who underwent infrainguinal bypass due to critical limb ischemia from 1997 through 2004. The primary end point was major amputation or death, whichever occurred first. Neighborhood socioeconomic status obtained from the 2000 United States Census was used as a proxy for an individual's socioeconomic status. RESULTS: There were 595 subjects (237 non-Hispanic whites, 205 African Americans, 153 Hispanics) in the study. Median amputation-free survival was 1.3, 3.3, and 3.2 yrs among Hispanics, African Americans, and non-Hispanic whites, respectively. Hazard ratio for amputation or death was 1.38 (95% confidence interval, 1.02-1.87) in Hispanics and 0.81 (95% confidence interval, 0.63-1.16) in African Americans compared with non-Hispanic whites after multivariable adjustment. For those residing in their homes, adjusting for socioeconomic status attenuated the hazard ratio in Hispanics to 1.08, explaining 78% of increased hazard. CONCLUSIONS: There was no significant difference between African Americans and non-Hispanic whites in amputation-free survival after infrainguinal bypass. Hispanics were 1.4 times more likely to have amputation or death than non-Hispanic whites, which was largely explained by low socioeconomic status. PMID- 19789427 TI - Seizure as a presenting symptom in neuropsychiatric systemic lupus erythematosus. PMID- 19789428 TI - Radial neuropathies in wheelchair users. AB - This report presents two cases with a radial neuropathy caused by compression between the spiral groove of the humerus and a hard wheelchair surface. One case involved the arm rest and the second a hard, vertical support of the back of the wheelchair. Close attention to the placement of the upper arms in relation to the surfaces of the wheelchair is required to avoid this complication in wheelchair users. PMID- 19789429 TI - Severe cramping thigh pain: The presenting symptom of bilateral iliofemoral thrombosis. PMID- 19789430 TI - Mobility-related assistive technology device classifications: implications for outcomes research. AB - This article evaluates six mobility-related device classifications for their ability to support assistive technology outcomes research. Our evaluation considered classifications that had been created for various purposes, including those created to support third-party reimbursement decisions, consumer education and safety, and research. Classifications were excluded if their scope was limited to a single mobility device domain. The six classifications were analyzed according to a common framework: (1) purpose, (2) completeness, (3) granularity, and (4) research applications. Although each classification addresses three principal mobility device domains (ambulation aids, manual wheelchairs, and powered mobility devices), the analysis revealed a range of detail with which each domain is described. Some classifications were hampered by their use of unclear idiosyncratic terminology, whereas others conflated multiple device features within device categories. The analysis suggests that existing classifications do not fully meet the needs of assistive technology outcomes researchers. Creation of a common taxonomy of mobility devices is needed to serve the needs of the assistive technology outcomes research field. PMID- 19789431 TI - A slip at the hip: a labral tear and cystic lesion of the acetabulum. PMID- 19789432 TI - Opiates for chronic nonmalignant pain syndromes: can appropriate candidates be identified for outpatient clinic management? AB - OBJECTIVE: To better define patients appropriate for opiate management for chronic pain syndromes. DESIGN: Retrospective study of 65 patients with noncancerous pain syndromes who were on or being considered for opiates and who were transitioned into a structured outpatient clinic with close monitoring and management. Noncompliance with this outpatient pain management program was the primary outcome. Noncompliance was defined as (1) receipt of prescriptions from providers outside of this clinic, (2) increase in medication dosage without proper approval, (3) refusing toxicology screening on entrance into the program, (4) negative toxicology tests for prescribed medications, (5) positive toxicology tests for psychoactive medications not prescribed, or (6) discovery on toxicology tests of the presence of illicit substances. RESULTS: There were 24 cases of noncompliance (37%), with age <56 yrs old demonstrating significant (P = 0.02) association with persons who were noncompliant with the outpatient program. Forty three percent of those younger than 56 yrs were noncompliant with program, yet no patient older than 56 yrs was noncompliant. Working status approached significance (P = 0.07) with those patients out of work demonstrating a greater likelihood of noncompliance. There were no correlations found between other patient characteristics and the level of compliance with the program. CONCLUSIONS: When considering opiates as a treatment option, pain clinics should have a heightened suspicion for younger and unemployed patients. Although these findings should be examined in larger studies, they suggest that nonmedical factors play a substantial role regarding success in such a structured opiate pain program. PMID- 19789433 TI - Comprehensive directed breathing retraining improves exertional dyspnea for men with spirometry within normal limits. AB - OBJECTIVE: To compare the effects of comprehensive directed breathing retraining with traditional diaphragmatic breathing on male smokers with exertional dyspnea but normal spirometry. DESIGN: This is a prospective randomized clinical trial in an exercise laboratory at a university hospital. Twenty-four nonmedicated exertional dyspnea subjects were randomly assigned to experimental (comprehensive directed breathing) and control (traditional diaphragmatic breathing) groups. Forty-four physiologic parameters associated with exertional dyspnea were studied before and after interventions for both groups at rest and at 40-W constant exercise for 10 mins. The interventions for both groups included diaphragmatic breathing exercises, walking, and arm exercises for 90 mins, 5 days/wk for 4 wks. In addition, the comprehensive directed breathing group was taught the anatomy and physiology of ventilation; they observed their ventilatory dyssynchrony in a mirror; they were shown their ventilatory rhythm on a spirogram; diaphragmatic movement was demonstrated in an educational movie; and verbal feedback was used to correct respiratory asynchrony. RESULTS: We compared the relative changes of lung function parameters before and after intervention for each group. The comprehensive directed breathing group improvements were significantly greater (P < 0.05) than those of traditional diaphragmatic breathing for 34 of 44 lung function parameters. CONCLUSIONS: Comprehensive directed breathing training improved exertional dyspnea, Dyspnea Index, and some clinical and functional parameters significantly more than traditional diaphragmatic breathing training. PMID- 19789435 TI - Carpal tunnel syndrome in manual wheelchair users with spinal cord injury: a cross-sectional multicenter study. AB - OBJECTIVE: To investigate relationships between carpal tunnel syndrome, functional status, subject demographics, physical examination findings, and median nerve conduction study findings in manual wheelchair users with paraplegia. DESIGN: Multicenter cross-sectional study. One hundred twenty-six manual wheelchair-using individuals with chronic paraplegia answered self administered questionnaires on demographics, symptoms, and functional status. They underwent physical examination specific for carpal tunnel syndrome and upper limb nerve conduction studies. RESULTS: Fifty-seven percent of subjects had symptoms (72.2% bilateral); hand numbness was most common. Sixty percent of subjects had carpal tunnel syndrome physical examination findings (59.2% bilateral). Those with physical examination findings were more likely to have longer duration of injury (P = 0.003). Seventy-eight percent of subjects had electrophysiologic evidence of median mononeuropathy. Symptomatic subjects had significantly greater median-ulnar motor latency difference in the dominant hand (P = 0.02) and smaller compound muscle action potential amplitudes bilaterally (dominant hand, P = 0.01; nondominant hand, P = 0.04). Persons with carpal tunnel syndrome symptoms and physical examination findings had significantly worse functional status (symptoms, P < 0.001; physical examination, P = 0.02) and symptom severity scores (symptoms, P < 0.001; physical examination, P = 0.01), but a similar difference between subjects with and without median mononeuropathy was not seen. Logistic regression analysis revealed that the presence of symptoms was predicted by median-ulnar motor latency difference in the dominant hand (odds ratio, 4.38; 95% confidence interval 1.72-11.14) and sensory nerve action potential amplitude in the nondominant hand (odds ratio, 0.97; 95% confidence interval, 0.94-0.99). CONCLUSIONS: The interaction among symptoms, physical examination, and nerve conduction study findings is complex. Carpal tunnel syndrome and median mononeuropathy are highly prevalent and functionally significant. This study highlights the need for primary prevention and patient education for preserving upper-limb function. PMID- 19789436 TI - Facilitating knowledge transfer with single-center trials. AB - OBJECTIVE: To provide perspective for clinicians as they evaluate incorporating single-center trials and small randomized, controlled trials for use in daily practice by reviewing examples from the literature. METHODS: Selected examples from the literature, such as check lists, daily screens for weaning readiness, daily spontaneous breathing trials, early resuscitation in sepsis, and daily interruption of sedation are reviewed and the effect of these studies is discussed. RESULTS: Some single-center trials are adopted rapidly without confirmatory trials. These have then been incorporated into further protocols that have also demonstrated positive results, which illustrate the value of implementing some single-center trials into routine clinical practice. Even with robust published data, knowledge transfer of research results is traditionally slow. Given the negative results of some confirmatory trials, clinicians should carefully appraise published studies and decide whether the results are appropriate for a given patient population. CONCLUSIONS: The results from single center trials may have an important impact on patient care. Current data do not support the assumption that all single-center trials must be confirmed before adopting the results into clinical practice. Clinicians must carefully evaluate the results of single-center trials within the context of their clinical experience and the preferences of their patients to determine how best to translate research to the bedside. PMID- 19789437 TI - Extracorporeal membrane oxygenation for the support of infants, children, and young adults with acute myocarditis: a review of the Extracorporeal Life Support Organization registry. AB - OBJECTIVE: To describe survival outcomes for pediatric patients supported with extracorporeal membrane oxygenation for severe myocarditis and identify risk factors for in-hospital mortality. DESIGN: Retrospective review of Extracorporeal Life Support Organization registry database. SETTING: Data reported to Extracorporeal Life Support Organization from 116 extracorporeal membrane oxygenation centers. PATIENTS: Patients < or = 18 yrs of age supported with extracorporeal membrane oxygenation for myocarditis during 1995 to 2006. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Of 19,348 reported pediatric extracorporeal membrane oxygenation uses from 1995 to 2006, 260 runs were for 255 patients with a diagnosis of myocarditis (1.3%). Survival to hospital discharge was 61%. Seven patients (3%) underwent heart transplantation and six patients survived to discharge. Of 100 patients not surviving to hospital discharge, extracorporeal membrane oxygenation support was withdrawn in 70 (70%) with multiple organ failure as the indication in 58 (83%) patients. In a multivariable model, female gender (adjusted odds ratio, 2.3, 95% confidence interval, 1.3 4.2), arrhythmia on extracorporeal membrane oxygenation (adjusted odds ratio, 2.7, 95% confidence interval, 1.5-5.1), and renal failure requiring dialysis (adjusted odds ratio, 5.1, 95% confidence interval, 2.3-11.4) were associated with increased odds of in-hospital mortality. CONCLUSION: Extracorporeal membrane oxygenation is a valuable tool to rescue children with severe cardiorespiratory compromise related to myocarditis. Female gender, arrhythmia on extracorporeal membrane oxygenation, and need for dialysis during extracorporeal membrane oxygenation were associated with increased mortality. PMID- 19789438 TI - Anemia causes hypoglycemia in intensive care unit patients due to error in single channel glucometers: methods of reducing patient risk. AB - OBJECTIVE: Intensive insulin therapy in the critically ill reduces mortality but carries the risk of increased hypoglycemia. Point-of-care blood glucose analysis is standard; however, anemia causes falsely high values and potentially masks hypoglycemia. Permissive anemia is practiced routinely in most intensive care units. We hypothesized that point-of-care glucometer error due to anemia is prevalent, can be corrected mathematically, and correction uncovers occult hypoglycemia during intensive insulin therapy. DESIGN: The study has both retrospective and prospective phases. We reviewed data to verify the presence of systematic error, determine the source of error, and establish the prevalence of anemia. We confirmed our findings by reproducing the error in an in vitro model. Prospective data were used to develop a correction formula validated by the Monte Carlo method. Correction was implemented in a burn intensive care unit and results were evaluated after 9 mos. SETTING: Burn and trauma intensive care units at a single research institution. PATIENTS/SUBJECTS: Samples for in vitro studies were taken from healthy volunteers. Samples for formula development were from critically ill patients who received intensive insulin therapy. INTERVENTIONS: Insulin doses were calculated based on predicted serum glucose values from corrected point-of-care glucometer measurements. MEASUREMENTS AND MAIN RESULTS: Time-matched point-of-care glucose, laboratory glucose, and hematocrit values. We previously found that anemia (hematocrit <34%) produces systematic error in glucometer measurements. The error was correctible with a mathematical formula developed and validated, using prospectively collected data. Error of uncorrected point-of-care glucose ranged from 19% to 29% (p < .001), improving to < or = 5% after mathematical correction of prospective data. Comparison of data pairs before and after correction formula implementation demonstrated a 78% decrease in the prevalence of hypoglycemia in critically ill and anemic patients treated with insulin and tight glucose control (p < .001). CONCLUSIONS: A mathematical formula that corrects erroneous point-of-care glucose values due to anemia in intensive care unit patients reduces the prevalence of hypoglycemia during intensive insulin therapy. PMID- 19789439 TI - Poor sleep quality is associated with late noninvasive ventilation failure in patients with acute hypercapnic respiratory failure. AB - OBJECTIVE: To determine whether sleep quality helps to predict noninvasive ventilation outcome in patients with acute hypercapnic respiratory failure. Despite an initial clinical improvement, nearly one fourth of patients may fail noninvasive ventilation after several days. Because late intubation is associated with a poor prognosis, it may be useful to identify factors that may predict or explain late noninvasive ventilation failure. PATIENTS: We prospectively studied 27 hypercapnic patients in a medical intensive care unit who required noninvasive ventilation for >48 hrs. INTERVENTIONS: A 17-hr sleep polysomnography (3 PM-8 AM) was recorded 2 days to 4 days after noninvasive ventilation initiation. Late noninvasive ventilation failure was defined as death, endotracheal intubation, or persistent need for noninvasive ventilation on day 6. MEASUREMENTS AND MAIN RESULTS: An abnormal electroencephalographic pattern that eluded analysis by standard sleep-scoring criteria was noted in seven (50%) of the 14 patients with late noninvasive ventilation failure compared with one (8%) of the 13 patients successfully treated with noninvasive ventilation (p = .03). No clinical or laboratory variables explained the electroencephalographic differences. Patients failing noninvasive ventilation had poorer sleep quality with greater circadian sleep-cycle disruption and less nocturnal rapid eye movement sleep (6 mins [range, 0-12] vs. 26 mins [range, 6-49], p = .03), compared with patients successfully treated with noninvasive ventilation. Noninvasive ventilation failure was associated with delirium during the intensive care unit stay (64% vs. 0%). CONCLUSIONS: Late noninvasive ventilation failure in elderly patients with acute hypercapnic respiratory failure was associated with early sleep disturbances including an abnormal electroencephalographic pattern, disruption of the circadian sleep cycle, and decreased rapid eye movement sleep. PMID- 19789440 TI - Continuous lateral rotation therapy to prevent ventilator-associated pneumonia. AB - OBJECTIVE: To investigate the impact of prophylactic continuous lateral rotation therapy on the prevalence of ventilator-associated pneumonia, duration of mechanical ventilation, length of stay, and mortality in critically ill medical patients. DESIGN: Prospective, randomized, clinical study. SETTING: Three medical intensive care units of an university tertiary care hospital. PATIENTS: Patients were randomized to continuous lateral rotation therapy or standard care if they were mechanically ventilated for <48 hrs and free from pneumonia. Primary study end point was development of ventilator-associated pneumonia. Ventilator associated pneumonia was defined as infiltrate on the chest radiograph plus newly developed purulent tracheal secretion plus increasing signs of inflammation. The diagnosis had to be confirmed microbiologically and required the growth of a pathogen >10(4) colony-forming units/mL in bronchoalveolar lavage. Radiologists were blinded to randomization whereas clinical outcome assessors were not. INTERVENTIONS: Rotation therapy was performed continuously in a specially designed bed over an arc of 90 degrees. Additional measures to prevent ventilator associated pneumonia were equally standardized in both groups including semirecumbent position. MEASUREMENTS AND MAIN RESULTS: Ventilator-associated pneumonia frequency during the intensive care unit stay was 11% in the rotation group and 23% in the control group (p = .048), respectively. Duration of ventilation (8 +/- 5 vs. 14 +/- 23 days, p = .02) and length of stay (25 +/- 22 days vs. 39 +/- 45 days, p = .01) were significantly shorter in the rotation group. In a forward stepwise logistic regression model including the continuous lateral rotation therapy, gender, Lung Injury Score, and Simplified Acute Physiology Score II, continuous lateral rotation therapy just failed to reach statistical significance with respect to development of ventilator-associated pneumonia (p = .08). Intolerance to continuous lateral rotation therapy during the weaning phase was observed in 29 patients (39%). Mortality was comparable in both groups. CONCLUSIONS: Ventilator-associated pneumonia prevalence was significantly reduced by continuous lateral rotation therapy. Continuous lateral rotation therapy led to shorter ventilation time and length of stay. Continuous lateral rotation therapy should be considered in ventilated patients at risk for ventilator-associated pneumonia as a feasible method exerting additive effects to other preventive measures. PMID- 19789441 TI - Central venous saturation is a predictor of reintubation in difficult-to-wean patients. AB - OBJECTIVE: To evaluate the predictive value of central venous saturation to detect extubation failure in difficult-to-wean patients. DESIGN: Cohort, multicentric, clinical study. SETTING: Three medical-surgical intensive care units. PATIENTS: All difficult-to-wean patients (defined as failure to tolerate the first 2-hr T-tube trial), mechanically ventilated for >48 hrs, were extubated after undergoing a two-step weaning protocol (measurements of predictors followed by a T-tube trial). Extubation failure was defined as the need of reintubation within 48 hrs. INTERVENTIONS: The weaning protocol evaluated hemodynamic and ventilation parameters, and arterial and venous gases during mechanical ventilation (immediately before T-tube trial), and at the 30th min of spontaneous breathing trial. MEASUREMENTS AND MAIN RESULTS: Seventy-three patients were enrolled in the study over a 6-mo period. Reintubation rate was 42.5%. Analysis by logistic regression revealed that central venous saturation was the only variable able to discriminate outcome of extubation. Reduction of central venous saturation by >4.5% was an independent predictor of reintubation, with odds ratio of 49.4 (95% confidence interval 12.1-201.5), a sensitivity of 88%, and a specificity of 95%. Reduction of central venous saturation during spontaneous breathing trial was associated with extubation failure and could reflect the increase of respiratory muscles oxygen consumption. CONCLUSIONS: Central venous saturation was an early and independent predictor of extubation failure and may be a valuable accurate parameter to be included in weaning protocols of difficult to-wean patients. PMID- 19789442 TI - A cost-minimization analysis of dexmedetomidine compared with midazolam for long term sedation in the intensive care unit. AB - OBJECTIVE: To compare the intensive care unit costs and determine factors influencing these costs in mechanically ventilated patients randomized to dexmedetomidine or midazolam by continuous infusion. DESIGN: Cost minimization analysis of a double-blind, multicenter clinical trial randomizing patients 2:1 to receive dexmedetomidine or midazolam from the institutional perspective. SETTING: Sixty-eight intensive care units in the United States, Australia, New Zealand, Brazil, and Argentina. PATIENTS: A total of 366 intubated intensive care unit patients anticipated to require sedation for >24 hrs. MEASUREMENTS AND MAIN RESULTS: Intensive care unit resource use was compared within the two treatment arms, using the U.S. representative costs for these resources. The analyses characterized patient costs from start of study drug until intensive care unit discharge including costs associated with the intensive care unit stay, costs during mechanical ventilation, study drug acquisition cost, and costs of treating adverse drug reactions probably or possibly related to study drugs. Blinded to treatment group, costs were calculated using Medicare reimbursement schedules, average IMS drug costs, expert opinion, and peer-reviewed literature. Censored lengths of intensive care unit stay and mechanical ventilation were imputed, using a nonparametric adjustment algorithm. Crude and multivariate median regressions were performed to relate intensive care unit cost and treatment. Including drug acquisition cost, sedation with dexmedetomidine was associated with a median total intensive care unit cost savings of $9679 (confidence interval, $2314-$17,045) compared with midazolam. The primary cost drivers were reduced costs of intensive care unit stay (median savings, $6584, 95% confidence interval, $727-$12,440) and reduced costs of mechanical ventilation (median savings, $2958, 95% confidence interval, $698-$5219). CONCLUSIONS: Continuous sedation with dexmedetomidine results in significantly lower total intensive care unit costs compared with midazolam infusion for intensive care unit sedation, primarily due to decreased intensive care unit stay costs and reduced mechanical ventilation costs. PMID- 19789443 TI - Comparison of two red-cell transfusion strategies after pediatric cardiac surgery: a subgroup analysis. AB - OBJECTIVE: To determine the impact of a restrictive vs. a liberal transfusion strategy on new or progressive multiple organ dysfunction syndrome in children post cardiac surgery. The optimal transfusion threshold after cardiac surgery in children is unknown. DESIGN: Randomized, controlled trial. SETTING: Tertiary pediatric intensive care units. PATIENTS: Participants are a subgroup of pediatric patients post cardiac surgery from the TRIPICU (Transfusion Requirements in Pediatric Intensive Care Units) study. Exclusion criteria specific to the cardiac surgery subgroup included: age <28 days and patients remaining cyanotic. INTERVENTION: Critically ill children with a hemoglobin < or = 95 g/L within 7 days of pediatric intensive care unit admission were randomized to receive prestorage leukocyte-reduced red-cell transfusion if their hemoglobin dropped either <70 g/L (restrictive) or 95 g/L (liberal). MEASUREMENTS AND MAIN RESULTS: Postoperative cardiac patients (n = 125) from seven centers were enrolled. The restrictive (n = 63) and liberal (n = 62) groups were similar at baseline in age (mean +/- standard deviation = 31.4 +/- 38.1 mos vs. 26.4 +/- 39.1 mos), surgical procedure, severity of illness (Pediatric Risk of Mortality score = 3.4 +/- 3.2 vs. 3.2 +/- 3.2), multiple organ dysfunction syndrome (46% vs. 44%), mechanical ventilation (62% vs. 60%), and hemoglobin (83 vs. 80 g/L). Mean hemoglobin remained 21 g/L lower in the restrictive group after randomization. No significant difference was found in new or progressive multiple organ dysfunction syndrome (primary outcome) in the restrictive group vs. liberal group (12.7% vs. 6.5%; p = .36), pediatric intensive care unit length of stay (7.0 +/- 5.0 days vs. 7.4 +/- 6.4 days) or 28-day mortality (3.2% vs. 3.2%). CONCLUSION: In this subgroup analysis of cardiac surgery patients, a restrictive red-cell transfusion strategy, as compared with a liberal one, was not associated with any significant difference in new or progressive multiple organ dysfunction syndrome, but this evidence is not definitive. PMID- 19789444 TI - Effect of volume loading with 1 liter intravenous infusions of 0.9% saline, 4% succinylated gelatine (Gelofusine) and 6% hydroxyethyl starch (Voluven) on blood volume and endocrine responses: a randomized, three-way crossover study in healthy volunteers. AB - OBJECTIVE: To study the changes in blood volume and hormones controlling sodium and water homeostasis after infusions of 0.9% saline, Gelofusine (4% succinylated gelatin in 0.7% saline, weight-average molecular weight 30 kD), and Voluven (6% hydroxyethyl starch in 0.9% saline, weight-average molecular weight 130 kD) in healthy volunteers. DESIGN: Randomized, three-way crossover study. SETTING: University teaching hospital. SUBJECTS: Ten healthy adult male volunteers. INTERVENTIONS: Volunteers received 1-L infusions of 0.9% saline, Gelofusine, and Voluven over 1 hr on three occasions. Body weight, hematocrit, serum biochemistry, and plasma concentrations of vasopressin, aldosterone, brain natriuretic peptide, and total renin were measured before infusion and hourly thereafter for 6 hrs. Changes in body water, blood volume, and extravascular fluid volume were calculated. MEASUREMENTS AND MAIN RESULTS: Although changes in body weight (total body water) after the infusions were similar, blood volume expansion by the two colloids was significantly greater than that produced by 0.9% saline (p < .01). At the end of infusions, 68%, 21%, and 16% of the infused volumes of 0.9% saline, Gelofusine, and Voluven, respectively, had escaped from the intravascular space to the extravascular space. Over the 6 hrs, the magnitude and duration of blood volume expansion by the two colloids were similar (p = .70). There were no significant differences in urinary volume, osmolality, and sodium content after the three infusions. Hormonal changes were similar after the three infusions, with the increase in natriuretic peptide being transient. The reduction in aldosterone and total renin concentrations was more sustained. CONCLUSIONS: The effects of Gelofusine and Voluven were similar despite the 100 kD difference in weight-average molecular weight. Excretion of an acute fluid load containing sodium and chloride may be dependent on a sustained suppression of the renin-angiotensin-aldosterone system rather than on natriuretic peptides. PMID- 19789445 TI - Association between lymphotoxin-alpha (tumor necrosis factor-beta) intron polymorphism and predisposition to severe sepsis is modified by gender and age. AB - OBJECTIVE: To investigate the significance of functional polymorphisms of inflammatory response genes by analysis of a large population of patients, both with and without severe sepsis, and representative of the diverse populations (geographic diversity, physician diversity, clinical treatment diversity) that would be encountered in critical care clinical practice. DESIGN: : Collaborative case-control study conducted from July 2001 to December 2005. SETTING: A heterogeneous population of patients from 12 U.S. intensive care units represented by the Genetic Predisposition to Severe Sepsis archive. PATIENTS: A total of 854 patients with severe sepsis and an equal number of mortality, age, gender, and race-matched patients also admitted to the intensive care unit without evidence of any infection (matched nonseptic controls). MEASUREMENTS AND MAIN RESULTS: We developed assays for six functional single nucleotide polymorphisms present before the first codon of tumor necrosis factor at -308, IL1B at -511, IL6 at -174, IL10 at -819, and CD14 at -159, and in the first intron of LTA (also known as tumor necrosis factor-B) at +252 (LTA[+252]). The Project IMPACT critical care clinical database information management system developed by the Society of Critical Care Medicine and managed by Tri-Analytics and Cerner Corporation was utilized. Template-directed dye-terminator incorporation assay with fluorescence polarization detection was used as a high throughput genotyping strategy. Fifty-three percent of the patients were male with 87.3% and 6.4% of Caucasian and African American racial types, respectively. Overall mortality was 35.1% in both severe sepsis and matched nonseptic control patients group. Average ages (standard deviation) of the severe sepsis and matched nonseptic control patients were 63.0 (16.05) and 65.0 (15.58) yrs old, respectively. Among the six single nucleotide polymorphisms, LTA (+252) was most overrepresented in the septic patient group (% severe sepsis; AA 45.6: AG 51.1: GG 56.7, p = .005). Furthermore, the genetic risk effect was most pronounced in males, age >60 yrs (p = .005). CONCLUSIONS: LTA(+252) may influence predisposition to severe sepsis, a predisposition that is modulated by gender and age. Although the genetic influences can be overwhelmed by both comorbid factors and acute illness in individual cases, population studies suggest that this is an influential biological pathway modulating risk of critical illnesses. PMID- 19789446 TI - Toll-like receptor 4 mediates neutrophil sequestration and lung injury induced by endotoxin and hyperinflation. AB - OBJECTIVE: To address the role of Toll-like receptor 4 signaling in mediating neutrophil recruitment and lung injury induced by lipopolysaccharide challenge coupled to lung hyperinflation, using Toll-like receptor 4 knockout (tlr4) mice. Infiltration of polymorphonuclear neutrophils into the lung is an important feature of ventilator-induced lung injury associated with pneumonia, but the mechanisms involved in neutrophil recruitment are poorly understood. DESIGN: Experimental animal model. SETTING: University laboratory. SUBJECTS: tlr4 and wild-type C57BL/6 mice. INTERVENTIONS: Wild-type or tlr4 mice were challenged by intratracheal instillation of lipopolysaccharide (0.3 mg/kg) for 2 hrs and then subjected to normal (7 mL/kg) or high (28 mL/kg) tidal volume ventilation for another 2 hrs. In other studies, neutrophils from wild-type or tlr4 mice were pretreated with lipopolysaccharide for 30 mins and then infused into the isolated lung preparation for 30 mins as the lungs were ventilated with 25 cm H2O peak inspiratory pressure. MEASUREMENTS AND MAIN RESULTS: Lipopolysaccharide challenged wild-type mice ventilated with a 28 mL/kg tidal volume exhibited 12 fold increase in neutrophil sequestration, 6-fold increase in bronchoalveolar lavage albumin concentration, and 1.6-fold increase in lung water content compared with unchallenged mice exposed to normal tidal volume ventilation. However, tlr4 mice showed negligible neutrophil sequestration, microvascular barrier breakdown, or edema formation. Mechanical ventilation alone or combined with lipopolysaccharide caused activation of circulating neutrophils and pulmonary endothelium in wild-type mice, whereas this was prevented in tlr4 mice. CONCLUSIONS: High tidal volume ventilation during pneumonia/sepsis induces lung neutrophil sequestration and injury via the Toll-like receptor 4-dependent signaling pathway. The results suggest an important role of Toll-like receptor 4 in the mechanism of lung neutrophil sequestration and acute lung injury when pneumonia/sepsis is coupled to lung hyperinflation. PMID- 19789447 TI - Why we should be wary of single-center trials. AB - OBJECTIVES: To highlight the limitations of single-center trials in critical care, using prominent examples from the recent literature; to explore possible reasons for discrepancies between these studies and subsequent multicenter effectiveness trials; and to suggest how the evidence from single-center trials might be used more appropriately in clinical practice. STUDY SELECTION: Topical and illustrative examples of the concepts discussed including trials of patient positioning, the use of steroids for acute respiratory distress syndrome, the dose of hemofiltration, the control of glycemia, and the targets of resuscitation in sepsis. DATA SYNOPSIS: Many positive single-center trials have been contradicted when tested in other settings and, in one case, the subsequent definitive multicentered trial has found a previously recommended intervention associated with active harm. Problems inherent in the nature of single-center studies make recommendations based on their results ill advised. Single-center studies frequently either lack the scientific rigor or external validity required to support widespread changes in practice, and their premature incorporation into guidelines may make the conduct of definitive studies more difficult. CONCLUSIONS: We recommend that practice guidelines should rarely, if ever, be based on evidence from single-center trials. Physicians should apply the findings of single-center trials only after careful evaluation of their methodology, and in particular after comparing the context of the trial with their own situation. PMID- 19789448 TI - Premarin stimulates estrogen receptor-alpha to protect against traumatic brain injury in male rats. AB - OBJECTIVES: To establish mechanisms of neuroprotective actions induced by Premarin (an estrogen sulfate) during traumatic brain injury. DESIGN: Chi Mei Medical Center research laboratory. SUBJECTS: Male Sprague-Dawley rats 244 to 268 g. INTERVENTIONS: Anesthetized rats, immediately after the onset of fluid percussion injury, were divided into three major groups and given the vehicle solution (1 mL/kg of body weight), Premarin (1 mg/kg of body weight), or Premarin (1 mg/kg of body weight) plus the nonselective estrogen receptor-alpha antagonist ICI 182, 780 (0.25 mg/kg of body weight) intravenously and immediately after fluid percussion injury. MEASUREMENTS AND MAIN RESULTS: Premarin, in addition to inducing pharmacologic levels of estradiol, causes attenuation of fluid percussion injury-induced cerebral infarction and motor and cognitive function deficits. Fluid percussion injury-induced apoptosis (e.g., increased numbers of both terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive and caspase-3-positive cells) as well as activated inflammation (e.g., increased levels of tumor necrosis factor-alpha) was also significantly Premarin-reduced. In peri-ischemic areas of hippocampus, both angiogenesis (e.g., increased numbers of both 5-bromodeoxyuridine-positive endothelial and vascular endothelial growth factor-positive cells) and neurogenesis (e.g., increased numbers of both 5 bromodeoxyuridine/neuronal-specific nuclear protein double-positive and glial cell line-derived neurotrophic factor-positive cells) were Premarin therapy promoted. In estrogen receptor-alpha blockade rats, Premarin therapy had less or no effect on fluid percussion injury-induced behavioral deficits, cerebral infarction and apoptosis, and activated inflammation. Furthermore, Premarin induced angiogenesis and neurogenesis were estrogen receptor-alpha blockade reduced. CONCLUSIONS: Our results indicate that pharmacologic levels of Premarin therapy-induced estradiol protect against cortical and hippocampal programmed cell death after fluid percussion injury through mechanisms stimulating estrogen receptor-alpha in the male rats. PMID- 19789449 TI - Acute kidney injury in ST-segment elevation acute myocardial infarction complicated by cardiogenic shock at admission. AB - OBJECTIVE: To evaluate the clinical and prognostic relevance of acute kidney injury (AKI) in the setting of ST-elevation acute myocardial infarction (STEMI) complicated by cardiogenic shock (CS). DESIGN: Prospective study. SETTING: Single center study, 13-bed intensive cardiac care unit at a University Cardiological Center. PATIENTS: Ninety-seven consecutive STEMI patients with CS at admission, undergoing intra-aortic balloon pump (IABP) support and primary percutaneous coronary intervention (PCI). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We measured serum creatinine at baseline and each day for the following 3 days. Acute kidney injury was defined as a rise in creatinine >25% from baseline. Overall, AKI occurred in 52 (55%) patients, and in 12 of these patients, a renal replacement therapy was required. In multivariate analysis, age >75 yrs (p = .005), left ventricular ejection fraction < or = 40% (p = .009), and use of mechanical ventilation (p = .01) were independent predictors of AKI. Patients developing AKI had a longer hospital stay, a more complicated clinical course, and significantly higher mortality rate (50% vs. 2.2%; p <.001) than patients without AKI. In our population, AKI was the strongest independent predictor of in hospital mortality (relative risk 12.3, 95% confidence intervals 1.78 to 84.9; p <.001). CONCLUSIONS: In patients with STEMI complicated by CS, AKI represents a frequent clinical complication associated with a poor prognosis. PMID- 19789450 TI - Diabetes mellitus does not adversely affect outcomes from a critical illness. AB - OBJECTIVE: Chronic diabetes mellitus (DM) is a known cause of multisystem injury. The effect of DM in acute critical illness may also be detrimental, but is not specifically known. We hypothesized that the preexisting diagnosis of DM is an independent risk factor for mortality in critically ill patients. DESIGN: Parallel retrospective and prospective cohort study. SETTING: Two large patient datasets were used: the retrospective University HealthSystem Consortium database (UHC) and the prospective Mayo Clinic Acute Physiology And Chronic Health Evaluation III critical care database (Mayo). PATIENTS: Inclusion criteria were admission to an intensive care unit and age > or =18 yrs. Patients with diabetic ketoacidosis or hyperosmolar nonketotic coma were excluded. A total of 1,509,890 patients (including 143,078 deaths) in the UHC cohort and 36,414 patients (including 3562 deaths) in the Mayo cohort were included in the study analysis. MEASUREMENTS AND MAIN RESULTS: The primary outcome was in-hospital mortality compared between patients with a history of DM and all other patients. Other outcomes included in-hospital mortality in prespecified subgroups. In the UHC dataset, patients with DM had a lower unadjusted odds ratio (0.90, 95% confidence interval 0.89-0.91, p < .001) and a lower adjusted effect on mortality (odds ratio 0.75, 0.74-0.76, p < .001) compared with that seen in patients without DM. In the Mayo dataset, patients with DM had a comparable unadjusted odds ratio (1.07, 0.97-1.17, p = NS) and a lower adjusted effect on mortality (odds ratio 0.88, 0.79-0.98, p = .022) compared with that seen in patients without DM. A lower mortality in diabetic patients held across multiple demographic subgroups, including patients who underwent coronary-artery bypass grafting (UHC data: unadjusted odds ratio 0.66, 0.62-0.71, p < .001). CONCLUSIONS: Critically ill adults with DM do not have an increased mortality compared with that seen in patients without DM, and may have a decreased mortality. Further investigation needs to be done to determine the mechanism for this effect. PMID- 19789451 TI - Extravascular lung water indexed to predicted body weight is a novel predictor of intensive care unit mortality in patients with acute lung injury. AB - OBJECTIVES: Acute lung injury and the acute respiratory distress syndrome are characterized by noncardiogenic pulmonary edema, which can be assessed by measurement of extravascular lung water. Traditionally, extravascular lung water has been indexed to actual body weight (mL/kg). Because lung size is dependent on height rather than weight, we hypothesized indexing to predicted body weight may be a better predictor of mortality in acute lung injury/acute respiratory distress syndrome. DESIGN: Prospective observational cohort study. SETTING: A tertiary referral intensive care unit. PATIENTS: Patients were recruited within 48 hrs of fulfilling the American European Consensus Conference definition of acute lung injury/acute respiratory distress syndrome. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographics, severity of illness scores, and respiratory parameters were collected. Extravascular lung water was measured using the PiCCO system. This was indexed to actual and predicted body weight. Statistically significant predictors of mortality identified using single regressor logistic regression and additional variables known to be associated with outcome were entered into a multiple logistic regression analysis. Receiver operator characteristic curves were generated. Forty-four patients were recruited (septic 34%). Using single regressor logistic regression, six variables were statistically significantly related to mortality: Acute Physiology and Chronic Health Evaluation II, PaO2, PaO2/Fio2 ratio, oxygenation index, actual extravascular lung water, and predicted extravascular lung water. In multiple logistic regression analysis, predicted extravascular lung water but not actual extravascular lung water was a predictor of mortality with an odds ratio of 4.3 (95% confidence interval, 1.5-12.9) per sd. Although the area under the curve for predicted extravascular lung water (0.8; confidence interval, 0.65-0.94) was larger than for actual extravascular lung water (0.72; confidence interval, 0.53 0.91), this was not statistically significant (p = .12). A baseline predicted extravascular lung water value of 16 mL/kg predicted intensive care unit mortality with a sensitivity of 0.75 (confidence interval, 0.47-0.91) and specificity of 0.78 (confidence interval, 0.61-0.89). CONCLUSIONS: Early measurement of predicted extravascular lung water is a better predictor than actual extravascular lung water to identify patients at risk for death in acute lung injury/acute respiratory distress syndrome. PMID- 19789452 TI - No assisted ventilation cardiopulmonary resuscitation and 24-hour neurological outcomes in a porcine model of cardiac arrest. AB - OBJECTIVES: To evaluate the effect of no assisted ventilation cardiopulmonary resuscitation on neurologically intact survival compared with ten positive pressure ventilations/minute cardiopulmonary resuscitation in a pig model of cardiac arrest. DESIGN: Prospective randomized animal study. SETTING: Animal laboratory. SUBJECTS: Sixteen female intubated pigs (25.2 +/- 2.1 kg) anesthetized with propofol. INTERVENTIONS: : fter 8 mins of untreated ventricular fibrillation, the intubated animals were randomized to 8 mins of continuous chest compressions (100/min) and either no assisted ventilation (n = 9) or 10 positive pressure ventilations/min (Smart Resuscitator Bag with 100% O2 flow at 10 L/min) (n = 7). The primary end point, neurologically intact 24-hr survival, was evaluated using a pig cerebral performance category score by a veterinarian blinded to the cardiopulmonary resuscitation method. MEASUREMENTS, AND MAIN RESULTS: During cardiopulmonary resuscitation, aortic and coronary perfusion pressure were similar between groups but cerebral perfusion pressure was significantly higher in the positive pressure ventilation group (33 +/- 15 vs. 14 +/- 14, p = .04). After 7.5 mins of cardiopulmonary resuscitation, arterial pO2 (mm Hg) and mixed venous O2 saturation (%) were significantly higher in the positive pressure ventilation compared with the no assisted ventilation group (117 +/- 29 and 41 +/- 21 vs. 40 +/- 24 and 10.8 +/- 7; p = .01 for both). Paco2 was significantly lower in the positive pressure ventilation group (48 +/- 10 vs. 77 +/- 26, p = .01). After 24 hrs, four of nine no assisted ventilation pigs were alive with a mean cerebral performance category score of 3 +/- 0 vs. five of seven alive and neurologically intact positive pressure ventilation pigs with a cerebral performance category score of 1 +/- 0.3 (p < .001 for cerebral performance category score). CONCLUSIONS: No assisted ventilation cardiopulmonary resuscitation results in profound hypoxemia, respiratory acidosis, and significantly worse 24-hr neurologic outcomes compared with positive pressure ventilation cardiopulmonary resuscitation in pigs. PMID- 19789453 TI - Predicting dead space ventilation in critically ill patients using clinically available data. AB - OBJECTIVE: To develop and validate an equation to predict dead space to tidal volume ratio (Vd/Vt) from clinically available data in critically ill mechanically ventilated patients. DESIGN: Prospective, observational study using a convenience sample of patients whose arterial blood gas and respiratory gas exchange had been measured with indirect calorimetry. SETTING: Medical and surgical critical care units of a university medical center. PATIENTS: Adult, mechanically ventilated patients at rest with Fio2 < or =0.60 and no air leaks who had recent arterial blood gas recordings and end-tidal carbon dioxide concentration monitoring. INTERVENTIONS: Observational only. MEASUREMENTS AND MAIN RESULTS: Indirect calorimetry was used to determine carbon dioxide production and expired minute ventilation in 135 patients. Tidal volume and respiratory rate were recorded from the ventilator. End tidal carbon dioxide concentration, body temperature, arterial carbon dioxide partial pressure (Paco2), and other clinical data were recorded. Vd/Vt was calculated using the Enghoff modification of the Bohr equation (Paco2 - PECO2/Paco2). Regression analysis was then used to construct a predictive equation for Vd/Vt using the clinical data: Vd/Vt = 0.32 + 0.0106 (Paco2 - ETCO2) + 0.003 (RR) + 0.0015 (age) (R = 0.67). A second group of 50 patients was measured using the same protocol and their data were used to validate the equations developed from the original 135 patients. The equation was found to be unbiased and precise. CONCLUSIONS: Vd/Vt is predictable from clinically available data. Whether this predicted quantity is valuable clinically must still be determined. PMID- 19789454 TI - Association between tumor necrosis factor-alpha promoter -308 A/G polymorphism and susceptibility to sepsis and sepsis mortality: a systematic review and meta analysis. AB - OBJECTIVE: The tumor necrosis factor (TNF)-alpha promoter -308 A/G polymorphism has been reported to be associated with sepsis with inconsistent results. We conducted a systematic review and meta-analysis to determine whether the TNF alpha -308 A/G polymorphism TNF2 (G/A or A/A) confers susceptibility to sepsis or is associated with increased risk of death from sepsis. DATA SOURCES: We performed an electronic search of OVID MEDLINE from 1950 to June 2008 and EMBASE from 1980 to June 2008. STUDY SELECTION: From 1935 reviewed study articles, 25 were included based on predefined inclusion criteria. DATA EXTRACTION: Two reviewers independently extracted data onto standardized forms. DATA SYNTHESIS: An association between development of sepsis and the TNF2 genotype was found in the overall population (odds ratio, 2.15; 95% confidence interval, 1.45-3.19; p < .01). Stratification by ethnicity indicated that the contribution to this observation may be stronger among the Asian population (odds ratio, 3.16; 95% confidence interval, 1.92 to 5.20; p < .01) compared with other ethnicities. There was no association between the TNF2 genotype and mortality from sepsis (odds ratio, 1.48; 95% confidence interval, 0.81 to 2.70; p = .20). However, when stratified for ethnicity, there may be an increased risk for fatal outcomes among Asians (odds ratio, 10.75; 95% confidence interval, 2.98 to 38.78; p < .01). CONCLUSIONS: Our systematic review and meta-analysis demonstrates that the TNF2 polymorphism is associated with sepsis. However, TNF2 is not associated with sepsis mortality. PMID- 19789455 TI - Memories and health-related quality of life after intensive care: a follow-up study. AB - OBJECTIVE: The overall aim of this study was to describe changes in health related quality of life, anxiety, depression, and return to work from 0.5-1.5 yrs to 4.5-5.5 yrs after injury in patients with and without delusional memories during their intensive care unit stay. A secondary aim was to explore factors that were related to health-related quality of life and to compare trauma patients' health-related quality of life 4.5 to 5.5 yrs after injury with a reference group. DESIGN: Longitudinal, prospective. SETTINGS: Multicentre study. PATIENTS: Trauma patients treated in the intensive care unit. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A follow-up study was conducted with 153 consenting adults. Each patient answered a postal questionnaire twice, 0.5-1.5 yrs to 4.5-5.5 yrs after the injury. Health-related quality of life was assessed by Short Form-36 and anxiety and depression by the Hospital Anxiety and Depression Scale. Delusional memories and other clinical variables were assessed in a previous study and used in this study as possible precipitants of poor health-related quality of life. Seventy-five percent were males and mean Injury Severity Scores were 10.7 +/- 7.1. When comparing health-related quality of life over time, there was significant improvement in five domains of health-related quality of life for patients with delusional memories compared with 4 yrs previously. Significantly more patients with delusions had anxiety and depression (Hospital Anxiety and Depression Scale > or =8). Patients with delusional memories were still significantly separated from the other patients in all health related quality-of-life domains except for general health. Seventy-five percent of all patients had returned to work. Despite a poorer health-related quality of life, patients with delusions had returned to work to the same degree. Patients with trauma still scored significantly lower in all domains 4.5 to 5.5 yrs after the injury compared with the Swedish population in the reference group (p < .001). Two factors, delusional memories during intensive care unit stay and pre existing disease prior the trauma, had the most influence on a poorer health related quality of life. CONCLUSIONS: From a long-term perspective, health related quality of life has improved but not reached the reference sample scores in Short Form-36. Seventy-five percent had returned to work. Patients with delusional memories still experienced poorer health-related quality of life and more patients had anxiety and depression compared with patients without those memories. PMID- 19789457 TI - Clinical evaluation of factors affecting soft toric lens orientation. AB - PURPOSE: To evaluate the comparative orientation characteristics of currently available silicone hydrogel torics. METHODS: The re-orientation characteristics of four toric lenses were assessed: three prism-ballasted (PB) designs, Purevision Toric (PVT), Air Optix Toric (AOT), Proclear Toric (PCT), and an "Accelerated Stabilization Design" (ASD) ACUVUE ADVANCE for Astigmatism (AAfA). In the first part of the study, the toric lenses were rotated, approximately 45 degrees in the infero-temporal direction and a video recording of lens reorientation was made from which blink-by-blink measurements of lens orientation were taken. In the second part of the study, subjects were positioned with their head orientated 90 degrees to the vertical and lens orientation photographed once it had settled. RESULTS: In Part 1, the speed of re-orientation from oblique mis location was similar for the four designs tested and ranged from 22 degrees /min (PVT) to25 degrees /min (AOT). Lenses showed more rotation during rather than between the blink (p<0.0001). Between blinks, AAfA and AOT showed significantly more rotation than PCT and PVT (p0.04). There were no significant differences between lenses for rotation during the blink. The PB lenses showed faster re orientation further away from the zero position.AAfA showed no significant difference in rotation speed with varying orientation position. In Part 2, all the PB lenses rotated significantly more under the effect of gravity than the ASD lenses.The mean total rotation of the AAfA lenses,from their settled position, was 11.4 degrees compared with 25.9 degrees for PVT (p0.01), 18.4 degrees with AOT (p0.02) and 37.4 degrees with PCT (p0.0002) [corrected]. The mean total rotation of the AAfA lenses, from their settled position, was 11.2 degrees compared with 32.8 degrees for PVT (p < 0.001), 16.1 degrees with AOT and 33.1 degrees with PCT (p < 0.001). CONCLUSIONS: The four lens designs show similar re orientation speeds. In the recumbent position, PB lenses rotate more from their normal settled position than ASD lenses. PMID- 19789456 TI - Validation of the Infectious Disease Society of America/American Thoracic Society 2007 guidelines for severe community-acquired pneumonia. AB - OBJECTIVES: Validate the Infectious Disease Society of America/American Thoracic Society 2007 (IDSA/ATS 2007) criteria for predicting severe community-acquired pneumonia (SCAP) and evaluate a health-services definition for SCAP. DESIGN: Retrospective cohort study. SETTING: LDS Hospital, an academic tertiary care facility in the western United States. PATIENTS: Consecutive patients with International Classification of Diseases, Ninth Edition, codes and chest radiographs consistent with community-acquired pneumonia from 1996 to 2006 seen at LDS Hospital. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We utilized the electronic medical record to examine intensive care unit admission, intensive therapies received, and predictors of severity, as well as 30-day mortality. We also developed logistic regression models of mortality and disease severity. We calculated the IDSA/ATS 2007 criteria as well as three other pneumonia severity scores. We defined SCAP as receipt of intensive therapy in the intensive care unit. In 2413 episodes of pneumonia, 1540 were admitted to the hospital, while 379 were admitted to the intensive care unit. Overall 30-day mortality was 3.7% but was 16% among intensive care patients. The IDSA/ATS 2007 minor criteria predicted SCAP with an area under the curve of 0.88 (95% confidence interval 0.85 0.90), which improved to 0.90 (95% confidence interval 0.88-0.92) with weighting. Competing models had area under the curve of 0.76 to 0.83. Using four rather than three minor criteria improved the positive predictive value from 54% to 81%, with a stable negative predictive value of 94% to 92%. CONCLUSIONS: The IDSA/ATS 2007 criteria predicted pneumonia severity better than other models. Using four rather than three minor criteria may be a superior cutoff, although this will depend on institutional characteristics. PMID- 19789458 TI - Role of chelatable iron versus myoglobin in oxidative stress after crush trauma. PMID- 19789459 TI - Increased inotropism following PARP inhibition in the setting of myocardial reperfusion injury: another piece in the jigsaw? PMID- 19789464 TI - Letters to the Editor. PMID- 19789462 TI - Effects of reactive oxygen species scavenger on the protective action of 100% oxygen treatment against sterile inflammation in mice. AB - Sepsis/multiple organ dysfunction syndrome (MODS) is a major cause of high mortality in the intensive care unit. We have recently reported that 100% oxygen treatment is beneficial to mice with zymosan-induced sterile inflammation by increasing antioxidant enzymatic activities. Yet, the use of hyperoxia is hindered by concerns that it could exacerbate organ injury by increasing free radical formation. It is believed that systemic inflammation and overproduction of reactive oxygen species (ROS) contribute to the mechanism underlying sepsis/MODS. A ROS scavenger has been proven to protect against sepsis/MODS in some animal models. Therefore, we hypothesized that ROS scavenger pretreatment might enhance the protective action of 100% oxygen treatment against zymosan induced sterile inflammation in mice. In the present study, we showed that 100% oxygen treatment prevented the abnormal changes in serum biochemical parameters, tissue oxygenation, and organ histopathology, and improved the 14-day survival rate in zymosan-stimulated mice, indicating that 100% oxygen treatment had a protective action on sterile inflammation. We found that pretreatment with a ROS scavenger (N-acetylcysteine, vitamin C, or dimethylthiourea) abolished this protective action of 100% oxygen treatment. We also showed that 100% oxygen treatment decreased the levels of serum proinflammatory cytokines (TNF-alpha, IL 6, and high-mobility group box 1), increased the level of serum anti-inflammatory cytokine (IL-10), and upregulated the activities of serum and tissue antioxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) in zymosan stimulated mice, which were reversed by the pretreatment with a ROS scavenger (N acetylcysteine, vitamin C, or dimethylthiourea). We thus conclude that ROS scavenger pretreatment partly abolishes the protective effects of 100% oxygen treatment on sterile inflammation in mice by regulating inflammatory cytokines as well as antioxidant enzymes. PMID- 19789465 TI - Sepsis, leukocytes, and nitric oxide (NO): an intricate affair. AB - Sepsis is exceedingly burdensome for hospital intensive care unit caregivers, and its incidence, as well as sepsis-related deaths, is increasing steadily. Sepsis is characterized by a robust increase in NO production throughout the organism that is driven by iNOS. Moreover, NO is an important factor in the development of septic shock and is synthesized by NOS, an enzyme expressed by a variety of cells, including vascular endothelium, macrophages, and neutrophils. However, the effects of NO on leukocyte functions, and the underlying mechanisms, are relatively unknown. Thus, the present review focuses on the effects of NO and its derivatives on cells of the immune system. Experimental evidences discussed herein show that NO induces posttranslational modifications of key proteins in targeted processes with the potential of deterring cellular physiology. Consequently, the manipulation of NO distribution in septic patients, used in conjunction with conventional treatments aimed at restoring normal immune functions, may represent a valuable therapeutic strategy. PMID- 19789466 TI - The redox status of experimental hemorrhagic shock as measured by cyclic voltammetry. AB - Hemorrhagic shock (HS) leads to reactive oxygen species production. However, clinicians do not have access to bedside measurements of the redox status during HS. Cyclic voltammetry (CyV) is a simple electrochemical method of measuring redox status. The aims of this study were to 1) report the first application of cyclic voltammetry to measure the acute changes in serum redox status after HS, 2) to contrast it with another severe systemic disease with a different redox pathology (acute pancreatitis [AP]), and 3) to describe the response of CyV over time in a resolving model of AP. In the acute study, 24 male Wistar rats were randomized into three groups: groups 1 (control), 2 (AP), and 3 (HS). In the time course study, 28 rats were randomized to a sham-control as well as 6 and 24 h post-AP cohorts, respectively.Cyclic voltammetry was performed using a three electrode system. In the acute study, the first and second voltammetric peaks increased significantly in HS. In contrast, within the AP group, only the first voltammetric peak showed a significant increase. The first voltammetric peak correlated with plasma protein carbonyls (PCs) and with thiobarbituric acid reactive substances, whereas the second voltammetric peak correlated positively with plasma protein carbonyls. In the second study, the first voltammetric peak correlated with physiological improvements. Here, we showed that serum CyV could respond to the serum redox change in HS and AP. Cyclic voltammetry warrants evaluation as a potential real-time beside measure of a patient's redox status during shock. PMID- 19789467 TI - The quantified lumbar flexion-relaxation phenomenon is a useful measurement of improvement in a functional restoration program. AB - STUDY DESIGN: A prospective cohort study evaluating the quantitative lumbar flexion-relaxation phenomenon (QLFRP), measured with surface electromyographic (SEMG) signals from the erector spinae during trunk flexion pre- and postrehabilitation, in patients with chronic disabling occupational lumbar disorders (CDOLD). OBJECTIVES: To assess the responsiveness of the QLFRP in documenting change in functional performance during a functional restoration program for CDOLD patients. SUMMARY OF BACKGROUND DATA: A recent theoretical construct suggests that QLFRP is responsive to change in lumbar range of motion (ROM) during rehabilitation, with high sensitivity and specificity for abnormal QLFRP predicting ROM. METHODS: A cohort of normal subjects was tested for QLFRP correlated to inclinometric lumbar ROM measures. The cutoff score was applied to a group of CDOLD patients entering a functional restoration program (N = 135), and to program completers (N = 104). Pain and functional self-report scores were compared with SEMG and ROM measures. RESULTS: The CDOLD group averaged 23.7 months off work. Surgical treatment was provided prerehabilitation to 51% of patients, with 29% receiving lumbar fusions. From pre- to post-treatment, achievement of QLFRP rose from 31% to 74% of patients, while normal ROM rose from 8% to 63% of patients. Compared to the 16% of patients still demonstrating both abnormal QLFRP and ROM, the other groups showed significantly greater improvement in self-reported pain and function, with the best improvements occurring in patients showing normal ROM and QLFRP. The QLFRP showed high sensitivity, but only modest predictive validity and specificity for predicting ROM postrehabilitation. Improvement in sensitivity and predictive validity occur when surgical cases were excluded from the analysis. CONCLUSION: A majority of patients in an interdisciplinary functional restoration program failed to demonstrate either the QLFRP or normal ROM on admission to the program. A majority of program completers, however, achieved both normal ROM and QLFRP and another 30% demonstrated either normal QLFRP or normal ROM. Both QLFRP and ROM measures were responsive to relevant self-report scales. PMID- 19789468 TI - Fractures of the thoracolumbar spine sustained by soldiers in vehicles attacked by improvised explosive devices. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: To analyze the types of orthopedic spine fractures sustained by North Atlantic Treaty Organization soldiers when vehicles are attacked by improvised explosive devices (IEDs), with specific focus on the flexion-distraction type thoracolumbar fracture (Chance fracture). SUMMARY OF BACKGROUND DATA: Operation Enduring Freedom is the North Atlantic Treaty Organization's effort in Afghanistan. IED attacks on armored vehicles are common and account for high proportion of soldiers' deaths and injuries. METHODS: Retrospective record review was accomplished on soldiers admitted to a military hospital with orthopedic spine fractures after IED attacks on vehicles from January 1, 2008 to May 15, 2008. Thoracolumbar fractures were classified using the McAfee classification system. RESULTS: Twelve male patients with 16 thoracolumbar fractures were identified (3 patients with multiple fractures). The 16 thoracolumbar fractures included 6 flexion-distraction fractures in 5 patients (38%, 6/16: two T12, two L1, one L3, and one L4), 7 compression fractures in 5 patients (44%, 5/16; one T7, one T8, two L1, one L2, one L3, and one L4), and 3 burst fractures (19%, 3/16; two L1 and one L2). CONCLUSION: The incidence of flexion-distraction thoracolumbar (Chance) fractures has been reported to be between 1.0% and 2.5% in most spine fracture series. In this small study, Chance fractures represented 38% of all tho-racolumbar fractures sustained after IED attack on armored vehicles. The blast pattern associated with IED explosion may be responsible for the high rate of these injuries in vehicle occupants. PMID- 19789469 TI - The natural history of polyethylene oxidation in total disc replacement. AB - STUDY DESIGN: This study is an evaluation of wear and oxidation in retrieved total disc replacements (TDRs). Forty-eight CHARITE TDRs were retrieved from 41 patients after 7.8 years of average implantation. All implants were removed because of intractable back pain and/or facet degeneration. Three unimplanted implants served as controls. OBJECTIVE: Our aim was to determine whether gamma sterilized polyethylene components implanted in the spine oxidize in vivo, and if so, whether polyethylene oxidation has clinical relevance for the long-term performance of TDRs. SUMMARY OF BACKGROUND DATA: The natural history of polyethylene oxidation following gamma sterilization and long-term implantation in the spine has not yet been investigated. METHODS: Oxidation and oxidation potential were measured at the rim and dome of 47 components using Fourier transform infrared spectroscopy. The wear patterns of each retrieved polyethylene core were analyzed at the rim and dome. RESULTS: Oxidation was significantly higher at the rim, as compared with the dome of the cores. Hydroperoxide index was also significantly higher at the rim, as compared with the dome. Dome penetration rate was negatively correlated to implantation time (P < 0.0001) but not correlated to oxidation or hydroperoxide index (P > 0.05). Implants with evidence of chronic rim loading had higher rim oxidation. CONCLUSION: The data support our hypothesis that, for the historical packaging methods employed by the manufacturer, polyethylene oxidation and oxidation potential were significantly higher at the rim as opposed to the dome. The mechanism is governed by access to oxygen in vivo and may be accelerated under certain combined modes of repeated rim loading. Our findings have clinical significance in cases of chronic impingement, when the rim has to support repeated loading for the lifetime of the implant. PMID- 19789470 TI - Augmented cerebral activation by lumbar mechanical stimulus in chronic low back pain patients: an FMRI study. AB - STUDY DESIGN: Cerebral activation by lumbar mechanical stimulus was investigated by functional magnetic resonance imaging in healthy subjects and patients with chronic low back pain (LBP). OBJECTIVES: To characterize the cerebral substrates of LBP, and to explore a possible pathologic pattern of cerebral activation in chronic LBP patients. SUMMARY OF BACKGROUND DATA: The cerebral substrates of LBP have been poorly defined in contrast to those of cutaneous somatic pain. METHODS: Eight healthy volunteers and 6 patients with idiopathic, chronic LBP were recruited. Each subject was placed in the prone position on a 3 Tesla MRI scanner, and stimulated by manual pressure with the tail of an air-filled, 20-mL syringe at 5 cm left of the fourth-fifth lumbar spinal interspace. Three blocks of 30-second painful stimulus, calibrated at either 3 or 5 on the 10-cm visual analog scale (VAS), were applied with intervening 30-second rest conditions during whole-brain echo-planar imaging. VAS of pain intensity and unpleasantness were evaluated after each session. Functional imaging was analyzed using a multisubject general linear model with Bonferroni multiple comparisons at P < 0.05. RESULTS: Pain thresholds were smaller (P < 0.05) and VAS of unpleasantness was larger in LBP patients than in healthy subjects. Activation was observed at the prefrontal, insular, posterior cingulate cortices (PCC), supplementary motor, and premotor areas predominantly in the right hemisphere, but not at the somatosensory cortices. LBP patients showed augmented activation compared with healthy volunteers specifically at the right insula, supplementary motor, and PCC. CONCLUSION: Chronic LBP patients showed increased tenderness at the lower back, higher aversive reaction to pain, and augmented LBP-related cerebral activation. The LBP-related activation is characterized by the absence of sensory discriminative component and the involvement of PCC. PMID- 19789472 TI - Review of the relationship between stress and wound healing: part 1. AB - While it has been suggested there is a link between stress and delayed wound healing, less is known about the role of pain as a contributor to stress. This paper reviews the evidence for this from studies of acute, surgical and chronic wounds. PMID- 19789473 TI - A joint collaboration: international pressure ulcer guidelines. AB - After four years in development, the EPUAP and the NPUAP are ready to release their joint, international, evidence-based pressure ulcer guidelines. This article considers the practice implications of a selection of the new guideline's statements. PMID- 19789474 TI - Malignant fungating wounds: managing malodour and exudate. AB - Contemporary wound management practices are not always applicable to the non healing status of malignant wounds. Instead, care must be multidisciplinary, holistic and truly individual to the needs of each patient and their family. PMID- 19789475 TI - An in vitro evaluation of the cell toxicity of honey and silver dressings. AB - OBJECTIVE: To establish whether honey and silver-impregnated dressings used by wound-healing practitioners are cytotoxic in vitro to human skin keratinocytes and dermal fibroblasts. METHOD: Human keratinocyte and fibroblast tissue cultures were established in vitro. Untreated cultures served as controls (group I). Small dressing implants of monofloral, medicinal honey (L-Mesitran) (group 2) and nanocrystalline silver (Acticoat) (group 3) were placed in test wells and co cultured with each of the two cell lines. Morphological changes, including cell toxicity, were assessed using inverted microscopy, trypan blue staining and the Rosdy and Clauss cell toxicity scoring system. RESULTS: Untreated cultures consisting of both keratinocytes and fibroblasts (group 1) were established in 90% of all cases. In group 2, cultures with honey-impregnated implants, cell proliferation remained present at two and four months. Cell viability remained intact and cell toxicity was not evident at four months after continuous tissue culture. In group 3, marked toxicity was observed with high non-viability staining and cell-scoring counts compared with groups 1 and 2 (p<0.05). This demonstrates that the silver interfered with epidermal cell proliferation and migration, implying that it contains cytotoxic material. CONCLUSION: The honey based product showed excellent cytocompatibility with tissue cell cultures compared with the silver dressing, which demonstrated consistent culture and cell toxicity. Further studies are needed to assess if these comparative in-vitro findings should influence a clinician's choice of wound dressing. PMID- 19789476 TI - Does liquid tissue adhesive increase satisfaction with wound and stoma management after surgery? AB - OBJECTIVE: This pilot study reviews the impact of tissue adhesive to seal skin wounds in elective large bowel resections where a stoma is fashioned. METHOD: Patients undergoing elective colorectal resection over six-month period were prospectively evaluated for wound infections rates, length of inpatient stay and patient satisfaction with their wound and stoma management. The wounds were observed for 30 days in both inpatient and outpatient settings. A patient satisfaction questionnaire was used with respect to the stoma and wound management. RESULTS: Fifty patients undergoing elective colorectal resection over a six-month period were prospectively evaluated. The median patient ages were 63.5 years (40-83) for males and 60 years (33-85) for females. Ninety-two per cent of the patients found their wound management satisfactory (overall satisfaction score >5, where 5 represents 'high satisfaction'). Eighty-six per cent reported a stoma management satisfaction score of >4 (where for 4 represents 'satisfaction'). Stoma site leakage was reported by 16%, but none of these developed a SSI. Two patients who had laboratory-confirmed SSI; they had an average length of inpatient stay of 18 days compared with 6.5 days for patients without SSI. . CONCLUSION: Liquid tissue adhesive provides a flexible, water resistant and protective coating which increases the satisfaction and ease of surgical wound and stoma management. We recommend a randomised controlled trial be conducted to evaluate these results in larger cohorts. PMID- 19789477 TI - Retrospective review of the use of daptomycin for diabetic foot infections. AB - The increase in antibiotic resistance has led to a search for alternative treatments for diabetic foot infections. This retrospective review outlines the clinical outcomes reported for a lipopetide for these infections. PMID- 19789478 TI - Psychodynamic understanding and psychotherapeutic approach to psychoses. AB - The historical development of the psychodynamic approach to psychotherapy is described. The origins of ISPS are described, and ISPS Croatia and Slovenia are introduced. PMID- 19789479 TI - Early intervention in psychosis. Concepts and service development. AB - This is a summary of a lecture given in Portoroz, Slovenia, in 2005. It is clearly totally derivative, and I acknowledge all authors on whom I drew to give the lecture. A literature review has been carried out to describe present knowledge of how psychosis develops, and to describe the concepts of early intervention in psychosis, the critical period, the duration of untreated psychosis, and the prodrome of psychotic illness. Hence, the principles of how an early intervention service intended to deal with first psychotic episodes of illness is described. The setting up of such a service in Luton, Bedfordshire is then described, and its first results are assessed. PMID- 19789480 TI - The spectrum of anxiety. From normal - to psychotic. AB - A review of the different forms of anxiety is presented and the phenomenological and anthropological aspects of different types of anxiety are described. Clinical and neurobiological aspects of anxiety are then discussed, and the relationship of psychosis to anxiety is then described. PMID- 19789481 TI - Hommage to reactive psychosis. AB - When looking back in the history of psychiatry, the concept of reactivity had very variable impact on ethiological considerations. If classification of mental disorders is taken as a proxy, it seems that this impact is presently at the lowest that it has been in the last hundred years. The author gives a short historical overview of concept of reactive psychosis, followed by a description of the current state of the art. He pleads for a rethinking of the current position as stated in ICD-10. Reintroduction of a certain degree of the reactivity concept into the classification seems to be required. PMID- 19789482 TI - Assertive outreach in Slovenia; identification of target group and goals of treatment in a new program. AB - A team from the Rehabilitation unit of Ljubljana psychiatric clinic attended a course on community care in London in October and November 2005. Because we decided that the methods presented to us could be of great use in Slovenia where the Health system is lacking such services we decided to implement them after our return. Immediately after we returned we started to carry out our plan. We designated our target group which were patients who poorly participated in treatment or had multiple and severe difficulties functioning and retaining their progress after discharge. Our goals were to improve patient participation in treatment before and after discharge, less and shorter hospitalizations and better integration of patients into society. Initial results are very positive, which leaves me much hope for further implementation of assertive outreach and community care in Slovenia. PMID- 19789483 TI - Psychological treatments and brain biology. AB - This is a summary and transcription of a talk given to ISPS Slovenia in Bled in 2006. It assesses the research evidence for a biological basis for psychological treatments. PMID- 19789484 TI - Comorbid anxiety in patients with psychosis. AB - A diagnosis of psychosis has tended to discount the considerable degree of emotional disorder associated with it, in a manner that may also inform psychological treatment options. Depression and anxiety are often associated with schizophrenia. Up to 40% of people have clinical levels of depression and anxiety symptoms could occur in 60% of patients with chronic psychotic disorder. Among emotional problems depression and depressive symptoms are well recognised and treated with success, whereas anxiety is a less known phenomenon and has not been studied as much as depression. Comorbid anxiety disorders or symptoms (social phobia, panic disorder, obsessive compulsive disorder, and post-traumatic stress disorder) occur in patients with psychosis in the same way as in patients who have only anxiety disorder. This comorbidity adversely affects outcome, and it may also reflect on processes underlying the development of psychotic symptoms. The present review highlights some major characteristics of anxiety and psychosis and also some aspects of coping and treatment strategies for anxiety in patients with psychosis. PMID- 19789485 TI - "Whose groups are these anyway?" on staff and patients' needs and their impact on the milieu. AB - The psychiatric ward is a complex organization. It contains two main groups: the patients and the staff. The different needs of each group influence the encounters between patients, the consumers, and staff, the suppliers. We shall discuss those needs and analyze the ways they interfere with or complement the therapeutic group work. For example: staff members need specific therapeutic group work for their professional development, and the patients need the group in order to maintain some form of interpersonal contact and to keep themselves active. The staff holds therapeutic groups in order to monitor the activity on the ward, while the patients seek a space where they can express their concerns about their treatment. Some vignettes will be presented which demonstrate these different needs, of staff and patients, and the way they were explored in the staff's group supervision meetings. PMID- 19789486 TI - Inpatient group therapy of patients with schizophrenia. PMID- 19789487 TI - Depression in the families of patients with psychosis. AB - Psychosis brings burden to the families of patients with psychosis. The Zung rating scale for depression has been used to evaluate depressive symptoms in the relatives of patients with psychosis that have been attending the 'Group with a significant other' for the last five years. When we sent the Zung rating scale for depression to the families of the schizophrenic patients' (which are or were part of the 'Group with a significant other' in the last five years), the results showed 2/3 of the patients had already become depressed due to the illness' effects. This is a much more common phenomena here than in the entire population. Cooperation within the Group has positive effects, such as reducing isolation and stigmatization, while it also works encouragingly on the emotional climate this is very important for reducing depression. PMID- 19789488 TI - Trauma, shame and psychotic depression experienced by ex-POWs after release. AB - Modern societies are growing ever more sensitive to the various sources and many kinds of psychic traumas, resulting even in psychotic reactions or states of functioning. Especially the war captivity situation represents the prolonged basis for chronic severe psychic stress and traumatisation, that may become deleterious even for the core self of the person. Severely psychotraumatized war veterans, or ex-POWs in the aftermath of the war captivity situation, survivors of extreme forms of violence and humiliation, are very reluctant to recall traumas. This avoidant behaviour is many times one of the most prominent symptoms that should be recognised and confronted in order to start the retraumatising process of healing the previously unthinkable traumas. The authors believe that shameful feelings are at the very basis of the psychotraumatised persons' withdrawal, depression, suicidal attempts, and even psychotic answers. The main feature of the first phase of any therapeutic work with these patients is the mourning process that should be gradually unfolded. The clinical examples will illustrate therapeutic work with these patients. The authors will expose some basic psychodynamic approaches and concepts regarding shame. This difficult feeling will be put in relationship with the psychotic answers. In that frame of reference the concept of 'near psychosis' will be described. PMID- 19789489 TI - Three different meanings of depression in schizophrenia. A phenomenological perspective. AB - In this theoretical paper with a clinical focus, three different meanings of depression in schizophrenia spectrum patients - depression as a reaction to schizophrenia, as an integral part of it, and as an independent disorder - are exposed and discussed from a phenomenological point of view. A well-reflected schizophrenia patient is briefly introduced in order to illustrate the clinical relevance of the aforementioned distinctions. The clinical relevance of thorough phenomenological and hermeneutical analysis of patients' experiences ranges from diagnostic to psychotherapeutic implications. PMID- 19789490 TI - Depression in schizophrenia - literature overview. PMID- 19789491 TI - Psychosis: what it is and what it is not. Psychiatric diagnosis an an ethical problem. AB - The different causes of misdiagnosis in psychiatry are reviewed, and the ethical implications of such misdiagnoses are discussed. PMID- 19789492 TI - Psychosis and depression - a neurobiological view. AB - Psychosis and depression are syndromes that affect the most basic human processes of perception and judgment. Traditional dichotomous classification of psychotic and affective disorders resolved in strict separation between schizophrenia on one hand and bipolar disorder and recurrent depressive disorder on the other hand. However, it is not uncommon that depression and psychosis as syndromes are expressed together in the course of the same mental disorder. According to recent knowledge on the molecular level there are probably many multiple susceptibility genes involved in the pathogenesis of both psychotic and affective disorders, each of small effect, which act in conjunction with environmental factors. Research data indicates a significant overlap in genetic susceptibility across the traditional classification categories of psychotic disorders and affective disorders. It seems that a new classification and research approach will provide better understanding of severe mental disorders and explain the usefulness of some medications in different groups of these disorders. PMID- 19789493 TI - Gender and schizophrenia. AB - In accordance with the predominant view on the neurobiology of schizophrenia, most of the research on the differences in the illness between men and women has been studied on the basis of sex difference as a biological category rather than on the basis of gender as a psychosocial category. There are gender- identity difficulties observed in schizophrenia. Problems associated with gender can be a major source of instability and vulnerability during the development of the first and later psychotic episodes. There is a need for future research to view sex difference through gender perspectives. Findings from a gender study may have utility for the development of differential treatment interventions for men and women and may improve the outcome of the illness in general. The study of the complex role of gender in illness processes is an important research direction that would enhance our understanding of the heterogeneity in the manifestation and subjective experience of schizophrenia. PMID- 19789494 TI - Sexuality and psychosis. AB - Sexuality and sexual disorders of patients with psychoses are frequently neglected and under-investigated. The main purpose of the present study is to discuss the subjective experience of sexuality in patients with psychosis within the general psychodynamic and phenomenological understandings of psychotic states. The authors, both psychotherapists, dealing with patients with psychoses, reflected experiences from their clinical work with the help of the conceptual frameworks of psychodynamic and phenomenological psychiatry. Willingness and need of patients to talk about sexuality, non-specificity of frequencies and variety of sexual disorders in psychotic patients, difficulties in establishment of a stable (sexual) identity and the question of homosexuality, absence of sexual activities with others and feelings of guilt and inadequacy, masturbation with its functions, impulsive sexual acts or lack of sexual self-control, erotic delusions and erotic transference were the main findings, dominating the sexual sphere of these patients. All these manifestations of sexuality in patients with psychosis can be seen - as exposed in discussion - as consequences of a basic self-disorder (phenomenological perspective) or of difficulties in regulating closeness and distance (psychodynamic perspective). Reasons of avoidance of treatment of sexuality by the therapists of psychotic patients are discussed as well. Implications for dealing with sexuality issues in psychotherapy of patients with psychoses were drawn from the above findings in the last part of the article. PMID- 19789495 TI - A psychotic patient's relapse during group psychotherapy treatment (Case study). AB - The paper presents the course of the seventh relapse of a 25 years old female patient, further-on referred to as 'I. O.' The impact on the therapeutic group of which 'IO' was a part is described. PMID- 19789496 TI - Is oestrogen neuroprotective? AB - Neuro-protection in this context is an important concept in the treatment of patients in the early, prodromal phase of psychosis, otherwise known as the 'At Ultra High Risk Mental State'. Neuro-protection as described here refers to the use of agents to control the process of apoptosis, which occurs more rapidly in the earliest phases of schizophrenia. There is a need to identify medications with fewer side effects than anti-psychotics in order to treat at risk mental states, or prodromal psychosis. Studies have shown that schizophrenia occurs in males at an earlier age than females. Later, at about the time of the menopause, there is a second peak in the incidence of psychosis (schizophrenia) in women. Hence it has been suggested that Oestrogen may be neuroprotective. Studies have shown that the addition of oestradiol to anti-psychotics in the treatment of schizophrenia in females increased the efficacy of the treatment, which suggests that oestrogen does indeed have a neuroprotective action. However oestrogen has never been used in 'at ultra high risk mental states', perhaps because of concern regarding side effects. PMID- 19789497 TI - Neurobiological aspects of psychosis and gender. AB - In comparison to female schizophrenia patients male patients have more impaired premorbid functioning, earlier onset of disorder, more severe symptomatology, less favourable outcome, different structural brain abnormalities and cognitive deficits. It has been hypothesized that estrogen, with effects on both neurodevelopment and neurotransmission, could play a protective role in women with schizophrenia and account for some of the gender differences observed in the disorder. On the other hand, it is known that altered promoter DNA methylation could play a critical role in mediating differential regulation of genes and in facilitating short-term adaptation in response to the environment. This data could indicate that environmental factors have gender specific influence on DNA methylation changes in schizophrenia. Recent data support the epigenetic theory of major psychosis and suggest that DNA-methylation changes are important to the etiology of psychosis in a gender specific pattern. Clinically observed gender differences in schizophrenia are probably influenced by genetic and environmental factors. The interplay between those two sets of factors is mediated by estrogen and epigenetic mechanisms. PMID- 19789498 TI - Early and sustained dynamic intervention in schizophrenia. AB - This paper is based on the Danish National Schizophrenia Project manual for psychodynamic individual psychotherapy with persons in states of schizophrenia. The methods for engaging with and treating a patient with schizophrenia in a supportive, psychodynamic way are described. PMID- 19789499 TI - Acute psychosis and gender. AB - In this review of Psychosis and gender we will present the relevant. Treatment principles and consider the foreign and local published data. PMID- 19789501 TI - Severe mental illness - patients' children needs. AB - Care for families and children of people with severe mental illness is a professionally and politically neglected issue. The majority of countries provide only services for several needs of the patients' families, i.e. treatment, custody and counselling. Management of stress and resolving of common problems are rarely addressed. Children of people with mental illness reflect and call professional attention to this issues. The deficiency of services is to be addressed by multidisciplinary team efforts. In the Slovenian organization of health services coordination could be provided by family physicians. PMID- 19789500 TI - The child as the presenting symptom, and what happens when things go wrong? AB - In this paper I wish to draw attention to Balint's concept of 'the Child as the presenting symptom' and ask whether this concept is relevant to us as psychiatrists. What arises is whether this concept might illuminate situations where there is serious mental illness in the family, and whether the presentation of a child to a doctor might be indicative of mental illness in the family. If such an interpretation is possible, then there are important clinical implications, since at present, all UK government guidance, based on the analysis of many high-profile cases where children have been severely abused, is that the needs of the child are paramount, and thence it may be that, whilst quite dramatic intervention may well occur in order to protect the child, perhaps the mental health needs of the parents might be somewhat overlooked. Examples of the interplay between child and parents in the context of mental illness are given, and the present way in which children within families where there is mental illness are cared for is described, also considering the consequences for the parents. PMID- 19789502 TI - Therapy and quality of life of patients with psychosis. AB - The symptoms and the individual experience of psychosis vary from patient to patient. Treatment, medication and cognitive psychotherapy are targeted mostly on positive and lately also on negative symptoms of psychosis. Deficits in metacognition found in patients with psychosis have a profound impact on the recovery process, their quality of life and experience of mental pain. Long term group psychotherapy helps patients to mourn their loss, improve their metacognition, and reduce the stigma and mental pain in patients with psychosis. PMID- 19789503 TI - Comparison of lung volume measurements by multiple-breath heptafluoropropane washout and computed tomography in small ventilated piglets. AB - BACKGROUND: Knowledge of lung volume is essential for monitoring and optimizing mechanical ventilation. The aim of this study was to compare lung volume measurements by multiple-breath heptafluoropropane (HFP) washout (MBW) and by respiratory gated computed tomography (CT) in ventilated newborn piglets. MATERIAL/METHODS: In 6 ventilated piglets (age: <12 h, median weight: 945 g) blood gases, respiratory mechanics, and lung volumes were measured in both the supine and prone positions. The measurements were performed in random order. Functional residual capacity (FRC) was measured simultaneously by HFP MBW (FRC(HFP)) using a new infrared mainstream sensor and by CT (FRC(CT)) at the end of inspiration and expiration (multi-slice Toshiba Aquilon 16, Otawara, Japan). Tidal volume (V(T)) was measured both by the Drager Babylog 8000 ventilator (V(T BL)) and the volume difference of the CT scans (V(T CT)). RESULTS: FRC(HFP) (25.2+/-8.5 ml) and FRC(CT) (24.9+/-7.6 ml) correlated strongly (r=0.97) without significant bias. Bland-Altman limits of agreement showed differences between the two methods that ranged from -19.7 to +19.5%. A similar strong correlation without statistically significant bias was found between V(T BL) (8.5+/-2.0 ml) and V(T CT) (9.0+/-2.4 ml) with r=0.91. The limits of agreement were -24.4 and +14.0%. Body position (prone vs. supine) had no significant effect on blood gases, respiratory mechanics, or lung volumes. CONCLUSIONS: Lung volumes measured in small ventilated lungs by HFP washout and CT are highly correlated and independent of body position. However, the relatively large limits of agreement indicate differences in the two techniques. PMID- 19789504 TI - Identification and characterization of phage PS166 lysogens from non-O1, O139 strains of Vibrio cholerae. AB - BACKGROUND: In recent years, non-O1, O139 serogroups of Vibrio cholerae have become a major source of pathogenic infection. However, the origin and acquisition of their virulence properties remain under explored. In this regard bacteriophages of Vibrio cholerae are well known to be the carriers of pathogenic traits across various strains. So, any possible association of vibriophages and non-O1, O139 serogroups would provide a deeper insight of their pathogenic threats. MATERIAL/METHODS: Ten non-O1, O139 clinical isolates of Vibrio cholerae were induced by mitomycin C. Virulence profiles of those isolates were determined by multiplex PCR. BglII, KpnI and HaeII were used to generate the restriction profile of isolated bacteriophage. Two of the phage harboring strains was ribotyped by Southern hybridization. RESULTS: In the present study, ten non-O1, O139 diarrheal isolates of Vibrio cholerae were examined for their ability to produce infectious phage particles out of which two strains, PG128 and PG130 were found to be positive. The host range and restriction profile of phage particles were identical to a biotype converting temperate vibriophage PS166. Both PG128 and PG130 carried unique ribotype pattern and lacked the major virulence determinants. But PG128 was found to carry hlyA, mshA, rtxC and toxR, a set of accessory virulence determinants. CONCLUSIONS: The evidences present here provide definite clues for a possible phage mediated emergence of newer Vibrio choleare pathogens. PMID- 19789505 TI - Monoamine oxidase and semicarbazide sensitive amine oxidase activities in normal and inflamed human dental pulp. AB - BACKGROUND: Human dental pulp contains monoamine oxidase (MAO) and semicarbazide sensitive amine oxidase (SSAO). In other tissues SSAO is involved in oxidative stress and inflammation, but the role of MAO and SSAO in human pulp and changes of their activities in reversible pulpitis still remains poorly understood. MATERIAL/METHODS: We investigated MAO labeling with mechanism-based inhibitor [3H]pargyline activities of MAO A, MAO B, and SSAO in healthy and inflamed human dental pulp. RESULTS: Incubation of human dental pulp homogenates with [3H]pargyline caused MAO labeling. MAO activity assayed with 100 microM [14C]5HT or 10 microM [14C]PEA was sensitive to selective inhibitors of MAO A and MAO B, respectively. MAO activity with 50 microM [14C]PEA was partially inhibited by clorgyline, and total inhibition was achieved only by the combination of clorgyline and semicarbazide, suggesting the presence of SSAO. Inflammation of the dental pulp was accompanied by a significant decrease in MAO labeling, MAO B (but not MAO A) activity and the increase in SSAO activity. CONCLUSIONS: The results of the present study suggest that the increase of dental pulp SSAO activity contributes to the development of inflammation in the dental pulp. The decrease in MAO B activity and lack of significant changes in MAO A activity may be associated with an anti-inflammatory response - inflamed pulp MAO A still effectively deaminates the inflammatory mediator 5HT, whereas inhibition of MAO B could result in some decrease of hydrogen peroxide generation, essential for the tissue damage in inflammation. PMID- 19789506 TI - Effect of replacement fluids saline, gelofusine, and blood on biochemical and hematological parameters in rats subjected to repeated blood sampling. AB - BACKGROUND: Multiple blood sampling in rat pharmacokinetic (PK) and toxicokinetic studies can result in a pathophysiological response and misleading data interpretation. This study investigated whether these drawbacks can be minimized by replacing withdrawn blood with saline, gelofusine, or donor blood. MATERIAL/METHODS: Rats with cannulated jugular veins were subjected to 12 withdrawals of 250 and 500 microl of blood followed by replacement with the same amount of saline, gelofusine, or donor blood. Red blood cell, hematocrit, hemoglobin, total protein, albumin, glucose, Na, and Cl levels were determined in the drawn blood. RESULTS: Multiple blood sampling caused a time-dependent decrease in red blood cell counts and hematocrit, hemoglobin, total protein, and albumin levels in all the treatment groups, but these effects were significantly alleviated in the blood-treated group. Withdrawal of 500 microl of blood caused more pronounced changes than 250 microl blood withdrawal in the saline- and gelofusine-treatment groups, but not in the blood-treatment group. Plasma glucose and Na remained unchanged in all the treatment groups, while slight changes in Cl levels were observed in the saline- and gelofusine-treatment groups. CONCLUSIONS: Blood sample volume had a crucial impact on the measured parameters, which were least affected in the donor blood-treated group. Regardless of the treatment, up to five 250 microl blood samples can be drawn without causing significant changes in a rat's normal condition. However, for a proper determination of PK profile, more than five blood samples are required and therefore drawn blood should be replaced, preferably with donor blood. PMID- 19789507 TI - Expression of mTOR protein and its clinical significance in endometrial cancer. AB - BACKGROUND: Mammalian target of rapamycin (mTOR) plays a crucial role in carcinogenesis by regulating protein synthesis, and mTOR inhibitors have been identified as potential anticancer agents in various cancers. Since the most common genetic change in endometrial cancer is the mutation of phosphatase and tensin homologue (PTEN), a negative regulator of mTOR, we evaluated mTOR expression in endometrial cancer and its relationship with other clinicopathological characteristics and expression patterns of cyclooxygenase-2 (COX-2) and p53. MATERIAL/METHODS: Immunohistochemical analysis of mTOR was performed on paraffin-embedded tissue specimens obtained from 141 patients with endometrial carcinoma. Results were correlated with the clinicopathological characteristics and expression pattern of COX-2 and p53. RESULTS: mTOR overexpression was detected in 7.1% (10/141) of patients. mTOR expression was highly correlated with old age, menopausal status and COX-2 expression (P<0.05). Multivariate analysis revealed that COX-2 was the only independent factor related to expression of mTOR. However, there was no correlation of mTOR expression with prognostic factors such as histologic type, grade, invasion of myometrium, lymph node metastasis, stage, and survival. CONCLUSIONS: Our findings suggest that the expression of mTOR is infrequent and is associated with COX-2 overexpression. Careful selection of patients might be necessary in the use of mTOR inhibitor as a molecular targeted therapy for patients with endometrial cancer. PMID- 19789508 TI - Effect of beta blockers on sepsis outcome. AB - BACKGROUND: The aim of this study was to investigate weather beta blockers are associated with an increased mortality in sepsis. MATERIAL/METHODS: Data on 83 patients with sepsis treated in ICU were analyzed from the retrospective chart review. The association between treatment with Beta blockers and mortality was analyzed by logistic regression in univariate model and after adjusting for the APACHE morbidity/ mortality scores. RESULTS: Among 83 patients (mean age 56.2+/ 17.3 years, female 51%, the mean APACHE score 74.8+/-23.3), 29 were treated with BB. Those treated with BB had APACHE score of 79.93+/-23.47 and those not treated with BB had APACHE score of 73.67+/-23.21. No significant difference between the traditional cardiovascular risk factors was found in both groups except for HTN. Treatment with BB was not significantly associated with mortality in the univariate (OR=1.83, 95% CI 0.59-5.69) nor multivariate model (OR=1.843, 95% CI 0.56-6.10). The APACHE score was a strong predictor of mortality (OR=1.04, 95% CI 1.01-1.06, p=0.02). This association was independent of BB use, and no significant interaction (p=0.72) between BB and APACHE score was observed. CONCLUSIONS: We did not show a significant association between beta blockers and increased mortality in patients with sepsis. Sicker patients had an increase risk of death, and possibility that beta blocker use may have contributed to this risk cannot be completely ruled out. Our study was limited by a small sample size and retrospective design. Further investigations of potential benefits and side effect of beta blockers in patients with sepsis are warranted. PMID- 19789509 TI - Comparison of cardiac and gastric responses to vagal stimulation in hypertensive women. AB - BACKGROUND: The aim was to evaluate the interactions between the effects of vagal stimulation by sham feeding (nonbaroreflex) and deep breathing (baroreflex) on heart rate variability (HRV) and gastric myoelectrical activity (GMA) in pre- and postmenopausal women with essential hypertension. MATERIAL/METHODS: One hundred five post- and premenopausal women with hypertension and 60 premenopausal normotensive women were observed. The study protocol consisted of 5 min of resting HRV followed by 5 min of deep breathing (DB), then 6 min of sham feeding (SF) with 30-min electrogastrography (EGG) before and after SF. The fasting plasma level of noradrenalin was measured. RESULTS: The HRV parameter values at rest in the hypertensive group were half those in the control group (p<0.05). There were notably higher HRV parameter values in the premenopausal women. Plasma noradrenalin level was higher in the postmenopausal women (p=0.0009). The effect of DB was similar before and after menopause; however, HRV parameters in response to DB were lower in the hypertensive women than in the controls (p<0.05). In the controls there was a marked increase in the main HRV parameters in response to DB. In fasting electrogastrography the lowest normogastria percentage was observed in the postmenopausal women. EGG showed that only SF significantly affected the period dominant power (PDP) in all groups and the bradygastria percentage in the postmenopausal women. CONCLUSIONS: This study suggests that the interactions that occur between the effects of non-baroreflex and baroreflex vagal stimulation in hypertensive women may contribute to gastric motility disorders and dyspeptic symptoms. PMID- 19789510 TI - Type 1 diabetes: evidence of interaction between ACP1 and ADA1 gene polymorphisms. AB - BACKGROUND: ACP1 (acid phosphatase locus 1, a cytosolic low-molecular-weight phosphotyrosin phosphatase) and ADA1 (adenosine deaminase locus 1) are two polymorphic systems involved in immune reactions. Observed interactions at the biochemical and clinical levels between the two systems prompted this investigation of a possible interaction concerning susceptibility to type 1 diabetes. MATERIAL/METHODS: Two hundred eighty-seven children admitted consecutively to the hospital for type 1 diabetes and 727 healthy newborn infants were studied. All were from the Caucasian Italian population living in the central area of Italy. ACP1 and ADA1 genotypes were determined by DNA analysis. RESULTS: In the type 1 diabetics the distribution of ACP1 genotypes was dependent on the ADA1 genotypes, showing an excess of the low-activity *A/*A and *A/*B genotypes in the ADA1*2 carriers compared with the ADA1*1/*1 subjects (OR: 2.200, 95%CI: 1.133-4.298). Such an association was not present in the healthy newborn infants. CONCLUSIONS: This investigation based on the biological effects of ACP1 and ADA1 on the immune system and on the known biochemical interaction between the two systems showed a significant interaction between the two system concerning susceptibility to type 1 diabetes. The low-activity ACP1 genotypes *A/*A and *A/*B carrying the low-activity ADA1*2 allele were more common in type 1 diabetic than in healthy newborns (OR: 1.699 95%CI: 1.066-2.702). PMID- 19789511 TI - EGFR immunoexpression and peripheral blood cytokine secretion as potential biomarkers of tumor behavior in laryngeal squamous cell carcinoma. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) and proinflammatory cytokines have been implicated in the dysregulated cell growth and increased aggressiveness of human cancers. The purpose of this study was to analyze EGFR immunoexpression in neoplastic tissues and IL-6 and TNFalpha secretion by peripheral blood mononuclear cells (PBMCs) and to investigate their relationships with certain clinicopathological characteristics. MATERIAL/METHODS: Tumor expression of membranous and cytoplasmic EGFR was measured in 45 cases of laryngeal squamous cell carcinoma by IHC staining. IL-6 and TNFalpha concentrations in 21-h PBMC cultures were measured by ELISA. Relationships between EGFR and cytokine secretion and clinicopathological characteristics such as pT status, pN status, and TFG classification, which include the parameters of the most invasive zones of neoplastic tissue and histological grade, were analyzed. RESULTS: The membranous EGFR index had a very strong association with pT stage, mode of invasion, and lymphocytic plasma infiltration of the tumor stroma. Relationships between the cytoplasmic EGFR index and nuclear polymorphism as well as TFG score for advanced carcinomas and histological grade in less invasive tumors were highlighted. The correlations of IL-6 and TNFalpha levels with TFG score, pT status, histological grade, and mode of tumor invasion were also significant. CONCLUSIONS: These findings confirmed the importance of EGFR immunoexpression rate as well as IL-6 and TNFalpha secretion by PBMCs as potential biomarkers for assessing the aggressive tumor phenotype in laryngeal carcinoma. PMID- 19789512 TI - Nutritional status in relation to respiratory impairment and systemic inflammation in patients with acute exacerbations of COPD. AB - BACKGROUND: Knowledge of the effects of undernourishment on the severity of respiratory impairment, systemic inflammation and oxidative stress during acute exacerbations of COPD (AECOPD) is limited. In patients with AECOPD, we assessed the relationships between BMI, lung function, and markers of systemic inflammation and oxidative stress. MATERIAL/METHODS: We measured pulmonary function, serum C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-8, malondialdehyde (MDA), erythrocytic glutathione peroxidase (GPx), superoxiddismutase (SOD), and catalase (CAT) in 113 patients admitted to the hospital due to an AECOPD (80 males, age 66.2+/-11.0 years, FEV1 41.5+/-13.7% predicted). RESULTS: From the low (<21 kg/m2) towards the normal (21 24.9 kg/m2), high (25-29.9 kg/m2) and obese (>30 kg/m2) BMI groups, FEV1, FEV1-to forced vital capacity (FVC) ratio, inspiratory capacity (IC), and the IC-to-total lung capacity (IC/TLC) ratio increased (p<0.01; p<0.001; p=0.039; p=0.002, respectively), while residual volume (RV), TLC and RV/TLC ratio were reduced (p<0.001; p<0.001; p=0.018, respectively). Patients with low BMI had significantly lower FEV1, FEV1/FVC, IC and IC/TLC, and higher RV and TLC values compared to the high and obese BMI groups. From the low towards the normal, high and obese BMI, reductions in serum CRP, and a trend towards increases in erythrocytic GPx were observed (p=0.023; p=0.056, respectively). No differences were seen in circulating TNF-alpha, IL-6 or IL-8, MDA or erythrocytic CAT and SOD between the groups. CONCLUSIONS: In patients with acute exacerbations of COPD, low BMI is associated with higher degree of bronchial obstruction and pulmonary hyperinflation, in association with higher circulating CRP levels. PMID- 19789513 TI - Prolonged QT dispersion in children with congenital valvular aortic stenosis. AB - BACKGROUND: Hypertrophied and ischemic cardiac muscle in patients with aortic valve stenosis becomes a potential source of ventricular cardiac arrhythmia that can lead to sudden death. Arrhythmia is associated with an abnormal duration of the action potential in a cardiac muscle cell. The aim of this prospective study was to analyze QT dispersion in children with different stages of aortic valve stenosis and different left ventricular mass indexes. MATERIAL/METHODS: Sixty children with aortic valve stenosis were divided into 3 subgroups according to their pressure gradients. Sixty healthy children served as controls. Doppler echocardiography, standard 12-lead electrocardiography and 24-hour Holter monitoring electrocardiography were performed. RESULTS: QT dispersion was significantly higher in children with aortic stenosis than in the control group. There were statistically significant positive correlation between QT dispersion and left ventricular mass index and between QT dispersion and pressure gradient. QT dispersion was significantly higher in 20 patients with aortic stenosis and ventricular arrhythmia than that in patients without arrhythmia. In children with a higher pressure gradient and a higher left ventricular mass index, more complex arrhythmia was found. CONCLUSIONS: Risk of ventricular arrhythmia increases with the degree of aortic valve stenosis and cardiac muscle hypertrophy. QT dispersion is prolonged in children with aortic valve stenosis, particularly in patients with arrhythmia, and increases with pressure gradient and left ventricular mass index. PMID- 19789514 TI - Intravenous ketamine and local bupivacaine infiltration are effective as part of a multimodal regime for reducing post-tonsillectomy pain. AB - BACKGROUND: The aim of this study was to investigate the effects of a multimodal analgesic regimen, including intravenous ketamine and peritonsillar infiltration of bupivacaine, on post-tonsillectomy pain in children. MATERIAL/METHODS: Ninety children aged 2-12 years, undergoing tonsillectomy, were enrolled in this randomized, controlled and double-blinded study. Group I (n=30) received intravenous and peritonsillar saline, group II (n=30) received intravenous saline and peritonsillar bupivacaine, and group III (n=30) received intravenous 0.5 mg/kg ketamine and peritonsillar 0.25% bupivacaine (3-5 ml per tonsil). Pain was evaluated using a modified Children's Hospital of Eastern Ontario Pain Scale (mCHEOPS) recorded 15 min and 1, 4, 12, 16, and 24 h postoperatively. RESULTS: No difference was found in the demographic data among the groups. Group I patients who received intravenous and peritonsillar saline solution as placebo had higher pain scores at 15th min, and 1st and 4th h than group II, and at all time intervals, than group III (P<0.05). Patients in group III also had significantly lower pain scores than group II at all time intervals except at 15th min (P<0.05). Analgesic requirements and the time to first analgesia were also significantly (P<0.05) better in the ketamine group. CONCLUSIONS: Intravenous ketamine and peritonsillar infiltration with bupivacaine are safe and effective as part of a multimodal regime in reducing post-tonsillectomy pain. PMID- 19789515 TI - Gastrointestinal tuberculosis as a cause of massive bleeding. AB - BACKGROUND: Although minor bleeding is fairly common among cases of gastrointestinal tuberculosis, massive hemorrhage necessitating blood transfusion is rare. CASE REPORT: A 72-year-old woman presented to the hospital with hematochezia. Colonoscopy revealed multiple ulcers, including round ulcers, throughout the large intestine. Upper gastrointestinal endoscopy revealed multiple duodenal ulcers. Hemostasis was performed on the bleeding point, but other untreated ulcers exhibited recurrent bleeding. Fecal culture results established the diagnosis of gastrointestinal tuberculosis. The patient was put on a standard antituberculosis regimen and remains in remission. CONCLUSIONS: Gastrointestinal tuberculosis should be considered as one of the causes for massive and intractable gastrointestinal bleeding. PMID- 19789516 TI - Tumor embolus due to uterine cancer. AB - BACKGROUND: Although the majority of arterial emboli are thrombi originating from the heart, emboli of other origin do occur. The purpose of this paper is to report a case of tumor embolus of a brachial artery. CASE REPORT: A 64-year-old woman was referred for vascular surgery due to acute right upper-limb ischemia. ECG showed sinus rhythm without ischemic changes. Four years earlier the patient had undergone total hysterectomy with bilateral adnexotomy for endometrial adenocarcinoma with subsequent radiotherapy. Emergency embolectomy under local anesthesia was performed with uneventful recovery. Because of an atypical appearance resembling fatty tissue, the embolic material was sent for microscopic examination that revealed carcinoma cells. Chest X-ray and CT-guided biopsy showed previously unknown pulmonary metastasis. In spite of chemotherapy, the patient died one year later due to progression of the neoplastic disease. The literature and common features of tumor embolus are reviewed. This may be the first reported case of tumor peripheral arterial embolus caused by endometrial adenocarcinoma CONCLUSIONS: Although tumor emboli are a rarely described cause of acute limb ischemia, pathological examination of the embolic material seems to be indicated, especially in patients with an unknown source of emboli and in every case of an atypical appearance. PMID- 19789517 TI - Management of right ventricular myxoma diagnosed at full-term pregnancy. AB - BACKGROUND: The diagnosis of cardiac myxoma in a woman at term pregnancy is extremely rare. Prompt surgical removal of the tumor is generally advised because of the high risk of potentially fatal complications. On the other hand, cardiac surgery during pregnancy is a delicate procedure which carries a significantly increased maternal risk when performed at or immediately after delivery. CASE REPORT: A previously healthy 23-year-old woman at 38 weeks' gestation was diagnosed with myxoma in the right ventricle on the basis of clinical and echocardiographic examination. The patient went into labor while awaiting urgent Cesarean section. Severe right heart failure developed which completely resolved after delivery of a healthy baby. After balancing the risks of uncontrolled uterine bleeding associated with cardiopulmonary bypass against those of thromboembolism and valvular obstruction associated with the presence of myxoma itself, emergency cardiac surgery was rejected. The tumor was successfully removed five days after Cesarean section and the patient recovered uneventfully. CONCLUSIONS: Cesarean section should be done as soon as possible. Considering the increased maternal morbidity and mortality when delivery is immediately followed by cardiopulmonary bypass, urgent cardiac surgery may be more reasonable than an emergency one for a patient who is clinically stable and at low risk of thromboembolism. PMID- 19789518 TI - Prognostic value of negative dobutamine-stress cardiac magnetic resonance imaging. AB - BACKGROUND: Assessment of left ventricular wall motion during dobutamine-stress magnetic resonance (DSMR) is well established for the identification of myocardial ischemia. However, the integration of DSMR into the process of clinical decision-making in patients with suspected CAD is not well established. The aim of this study was to assess the value of DSMR used for clinical decision making and to stratify the prognosis following this strategy. MATERIAL/METHODS: Medical records of 123 consecutive patients suspected of having CAD who underwent high-dose DSMR were reviewed and followed for a median of 23+/-12 months. DSMR results were used for decision-making, for example in favor of catheterization by the referring physician. RESULTS: Thirty-four (27.6%) patients had inducible ischemia, of whom 31 (91.2%) underwent invasive angiography, 25 (80.6%) having stenoses of >50% in a vessel of > or =2 mm in diameter. Fifteen of these patients received vascularization (PCI/CABG); only two events (myocardial infarction) were observed during follow-up in this group. Eighty-nine (72.4%) patients had no inducible ischemia; 21 of them (23.6%) had invasive angiography resulting in 0 (0%) significant findings. In the remaining 68 (76.4%) patients with negative DSMR and who were not catheterized, an annual event rate of 0% was observed. CONCLUSIONS: DSMR can be used for clinical decision-making in patients suspected of having CAD. This strategy results in a high prevalence of CAD in patients referred for invasive angiography due to a positive DSMR and an excellent prognosis in all patients with a negative DSMR. PMID- 19789519 TI - Intra-operative assessment of human pulmonary alveoli in vivo using Sidestream Dark Field imaging: a feasibility study. AB - BACKGROUND: In vivo videomicroscopy has been used for years to visualize subpleural alveoli in animal studies. This has led to a better understanding of alveolar physiology. We tested the hypothesis whether a novel handheld videomicroscope could be used for intraoperative detection of alveoli in surgical patients during mechanical ventilation. MATERIAL/METHODS: Using Sidestream Dark Field imaging, we observed 6 patients (3 adults and 3 children) who underwent elective cardiac surgery. In each patient, the tip of the microscope was placed on the visceral pleural surface of the left upper pulmonary lobe after weaning from cardiopulmonary bypass. The acquired images were converted into digital signals and captured on a computer. RESULTS: Although cardiac motion artifacts were present, visceral pleural microvascular blood flow could be observed in adults and infants. In infants, sub-pleural cavities (alveoli) were observed. These alveoli were remarkably similar in dimension and structure to those identified previously as true alveoli in animal studies. Quantification of these alveoli demonstrated that mean alveolar diameter, perimeter and area increased with age among the investigated infants (all parameters p<0.001). CONCLUSIONS: High-quality images of visceral pleural microvessels as well as subpleural cavities, reflecting superficial alveoli, could be obtained in infants. These findings create the opportunity to begin human intervention studies, which should investigate alveolar dynamics during mechanical ventilation in cardio-thoracic surgery in more detail. PMID- 19789520 TI - Knowledge of Vibrio vulnificus infection among Japanese patients with liver diseases: a prospective multicenter study. AB - BACKGROUND: Vibrio vulnificus (V. vulnificus) is a seafood-borne infectious pathogen that can be lethal to humans. The infection has been correlated with pre existing liver disease, particularly liver cirrhosis. Awareness of V. vulnificus infection among Japanese citizens is low, despite the increasing number of patients with hepatocellular carcinoma (HCC). The present study was conducted to assess the level of knowledge of patients with liver disease regarding V. vulnificus infection. MATERIAL/METHODS: Questionnaires were sent to patients with chronic liver disease who had been treated by liver specialists at 14 medical institutes. RESULTS: Of 1,336 patients, 304 (22.8%) had liver cirrhosis, and 732 (54.8%) had comorbidities of this disease. Only 14.5% (194/1,336) of patients had knowledge of V. vulnificus infection. Of 304 patients with liver cirrhosis, 17.4% (53/304) of the patients had knowledge of V. vulnificus infection. Of 60 patients with liver cirrhosis and diabetes mellitus, 11 (18.3%) patients had knowledge of V. vulnificus infections. Even when the patients with high risk factors such as liver cirrhosis and diabetes mellitus had knowledge of V. vulnificus infections, most ate raw seafood without regard to season. CONCLUSIONS: Patients with chronic liver diseases and their physicians need to be better educated about V. vulnificus infection and its prevention. PMID- 19789521 TI - Prognostic value of clinical, laboratory, and morphological factors in patients with primary focal segmental glomerulosclerosis - distribution of pathological variants in the Croatian population. AB - BACKGROUND: Scant data are available on the prognosis and distribution of subtypes of focal segmental glomerulosclerosis (FSGS) using the new Columbia classification in European populations. We assessed the predictive value of the clinical, laboratory, and morphological data obtained at the time of diagnosis, established on the basis of kidney biopsy, for the prognosis of primary FSGS. MATERIAL/METHODS: Sixty adults with FSGS were included in the study. Patients' clinical status, routine laboratory data, and histopathological findings were correlated with patients' remission status after a 5-year follow-up and patients' injury score (IS). RESULTS: Thirty-eight patients had remission of the disease and 22 patients did not. A value of IS>0.84 was more often found in patients who did not reach remission, whereas IS <0.34 was more frequent in patients who did reach remission (P=0.002). Serum creatinine and creatinine clearance correlated with IS (P<0.001), but proteinuria showed no correlation. FSGS subtypes were distributed as follows: tip variant in 3 (5%) patients, cellular variant in 4 (7%), not otherwise specified variant in 15 (25%), and perihilar variant in 38 (63%) patients. Collapsing variant of FSGS was not found in any of the patients included in the study. CONCLUSIONS: Injury score is the most reliable prognostic predictor in patients with primary FSGS. Patients with perihilar variant were most frequent, whereas collapsing variant was not found at all in the Croatian population. PMID- 19789522 TI - Pharmacokinetics and pharmacodynamics of propofol during propofol-alfentanil and propofol-remifentanil total intravenous anaesthesia monitored by spectral frequency index. AB - BACKGROUND: The aim of this study was to examine the pharmacokinetic and pharmacodynamic profile of propofol during propofol remifentanil and propofol - alfentanil anaesthesia, when monitored by SFx. MATERIAL/METHODS: Thirty-three ASA physical status I-II patients scheduled for laparoscopic cholecystectomy were prospectively randomized to 1 of 2 groups according to type of opioid used (remifentanil or alfentanil). The propofol infusion rate was adjusted to the spectral frequency index (SFx) value. Venous blood samples were collected from patients during and after anaesthesia. Propofol was assayed by means of the HPLC method with fluorescence detection. The remifentanil and alfentanil groups were compared in relation to pharmacokinetic and pharmacodynamic parameters of propofol and a t-test was used for statistical analysis. RESULTS: The propofol mean total body clearance rate and the volume of distribution were significantly higher in the propofol - remifentanil group. There were not any statistically significant differences between the groups in mean EC(50), E(0), E(max) and k(e0) values. However, large interindividual variability was observed in EC(50) and k(e0) mean values. The value of ET(50) was significantly higher in the remifentanil group. CONCLUSIONS: Alfentanil decreases the elimination clearance and the volume of distribution at steady state of propofol to a greater extent than with remifentanil. Our results suggest that if propofol is administrated by manual control, the same infusion rate should be used in the presence of alfentanil and remifentanil. For target controlled infusion, the same target propofol concentration should be used when both remifentanil and alfentanil are coadministrated. PMID- 19789523 TI - Circadian changes in the hemostatic system in healthy men and patients with cardiovascular diseases. AB - The highest risk of cardiovascular events is in the morning, which may be associated with circadian changes in hemostasis. There is a 10% circadian variability in von Willebrand factor (vWF). Circadian periodicity has been noted for both the number of platelets and their aggregability. The highest number of platelets was in the afternoon, while most studies observed an increase in platelet aggregation in the morning. Platelet activity has also been linked with physical activity after waking up. The highest values of coagulation system markers such as fragment 1+2, factor VIIa, and fibrinogen have been recorded in the late morning. Also, coagulation inhibitors such as protein C, antithrombin III, and a tissue factor pathway inhibitor are most active at this time of day. The levels of plasminogen and its activators (alpha 2-antiplasmin, urokinase-like plasminogen activator) do not undergo circadian periodicity, in contrast to changes in tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 levels (PAI-1). The most intensive activity of the fibrinolytic system inhibitor PAI-1 has been noted in the morning. The 24-h changes in the hemostatic system observed in healthy subjects often did not occur in individuals with health problems. The results of various studies suggest that circadian changes in the hemostatic system increase the incidence of cardiovascular events in the morning. This review considers the circadian rhythms of individual components involved in hemostasis (endothelium, platelets, coagulation, and fibrinolysis). PMID- 19789524 TI - Oxidative stress and ischemic myocardial syndromes. AB - Oxidative stress is a condition in which reactive oxygen species (ROS) or free radicals, namely O2*(-), H2O2, and *OH, are generated extra- or intracellularly and exert toxic effects on cells. The heart is one of the major organs affected by ROS. Recent evidence suggests that oxidative stress is a common denominator in many aspects of cardiovascular diseases. During myocardial oxidative stress, the generation of ROS is enhanced and the defense mechanisms of myocytes are altered. The sources of ROS in cardiac myocytes could be mitochondrial electron transport chain, nitric oxide synthase (NOS), NADPH oxidase, xanthine oxidase, and lipoxygenase/cyclooxygenase and the auto-oxidation of various substances, particularly catecholamines. In acute myocardial infarction (AMI), two distinct types of damage occur to the heart: ischemic injury and reperfusion injury, which lead to mitochondrial dysfunction in heart cells. During ischemia and reperfusion, ROS can be produced by both endothelial cells and circulating phagocytes. Ischemia also causes alterations in the defense mechanisms against ROS. Some proteins, including heat-shock proteins, are overexpressed in conditions of ischemia/reperfusion and can protect from cardiac injury. This article outlines the current understanding of oxidative stress and ROS generation and their role in cardiovascular diseases, including ischemic myocardial syndromes. The following aspects are covered: oxidative stress, mitochondrial dysfunction and pathophysiological mechanisms of atherosclerosis, precipitation of MI, sources of ROS in cardiac myocytes, effects of ROS in the heart, and ischemia and reperfusion injuries and their mechanisms. PMID- 19789526 TI - Protein-losing enteropathy: case illustrations and clinical review. AB - Protein-losing enteropathy (PLE) is a rare syndrome of gastrointestinal protein loss that may complicate a variety of diseases. The primary causes can be divided into erosive gastrointestinal disorders, nonerosive gastrointestinal disorders, and disorders involving increased central venous pressure or mesenteric lymphatic obstruction. The diagnosis of PLE should be considered in patients with hypoproteinemia after other causes, such as malnutrition, proteinuria, and impaired protein synthesis due to cirrhosis, have been excluded. The diagnosis of PLE is most commonly based on the determination of fecal alpha-1 antitrypsin clearance. Treatment of PLE targets the underlying disease but also includes dietary modification, supportive care, and maintenance of nutritional status. In this article, cases illustrating a variety of clinical presentations and etiologies of PLE are presented, and its diagnostic approach and treatment are reviewed. PMID- 19789525 TI - Prospective analysis of depression during peginterferon and ribavirin therapy of chronic hepatitis C: results of the Virahep-C study. AB - OBJECTIVES: Combination therapy for chronic hepatitis C is associated with depression, which may lead to worse treatment outcomes. The objectives of this study were to determine the association between patient characteristics and depression before and during treatment and to evaluate the relationship between depression and treatment outcomes. METHODS: Prospective data from the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (Virahep-C) study were analyzed (191 African Americans, 203 Caucasians). Depression was defined as a score of >23 on the Center for Epidemiologic Studies Depression (CES-D) scale. Scores were taken before treatment, at weeks 4, 12, and 24 of treatment, and 24 weeks after treatment ended. Baseline social support was measured using the Medical Outcomes Study (MOS) Social Support Survey. Associations between baseline patient characteristics and incident depression were assessed with discrete-time Cox proportional hazards models. RESULTS: At baseline, 47 (12%) participants had CES-D scores 23. Univariable analyses indicated that several patient characteristics were associated with baseline depression, including lower social support (P<0.0001). On treatment, these patients were more likely to have psychiatric adverse events (AEs) or start new antidepressants (45 vs. 28%, P=0.02) and to have had early treatment discontinuation (38 vs.13%, P<0.0001); however, sustained virological response (SVR) rates were similar (38 vs. 40%, P=0.79) to those of participants without baseline depression. The incidence of new-onset depression was 26% by 24 weeks. One-third of patients were started on antidepressants, and no patients attempted suicide. Multivariable analyses indicated that new-onset depression was significantly associated with younger age (P=0.04), lower social support (P<0.001), and "feeling depressed, sad, or blue" (P=0.008). Patients who developed depression during treatment were more likely to have a psychiatric AE or begin antidepressants (44 vs. 23%, P<0.001) but had lower rates of treatment discontinuation (6 vs. 15%, P=0.02) and comparable rates of SVR compared with patients without depression (47 vs. 38%, P=0.16). There were no differences in the frequency of pretreatment or new-onset depression between African-American and Caucasian participants in this study. CONCLUSIONS: In this large prospective analysis, baseline and new-onset depression were associated with patient characteristics and treatment outcomes; however, SVR rates did not differ between depressed and nondepressed patients. The relationship of lower baseline social support with depressive symptoms warrants further investigation. PMID- 19789527 TI - Online image analysis software for photoactivation localization microscopy. PMID- 19789528 TI - My5C: web tools for chromosome conformation capture studies. PMID- 19789529 TI - Staging worms for next-generation analysis. PMID- 19789531 TI - Imaging metastatic bone disease from carcinoma of the prostate. AB - Imaging bone metastases from prostate cancer presents several challenges. The lesions are usually sclerotic and appear late on the conventional X-ray. Bone scintigraphy is the mainstay of lesion detection, but is often not suitable for assessment of treatment response, particularly because of a 'flare' phenomenon after therapy. Magnetic resonance imaging is increasingly used in assessment, and newer techniques allow quantitation. In addition to (18)F-fluorodeoxyglucose ((18)FDG), newer PET isotopes are also showing promise in lesion detection and response assessment. This article reviews the available imaging modalities for evaluating prostatic bony metastases, and links them to the underlying pathological changes within bone lesions. PMID- 19789532 TI - Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer First BEAT and the randomised phase-III NO16966 trial. AB - BACKGROUND: Complete resection of metastases can result in cure for selected patients with metastatic colorectal cancer. METHODS: First BEAT evaluated the safety of bevacizumab with first-line chemotherapy in 1914 patients. Prospectively collected data from 225 patients who underwent curative-intent surgery were analysed, including an exploratory comparison of resection rate in patients treated with different regimens. NO16966 compared efficacy of oxaliplatin-based chemotherapy plus bevacizumab or placebo in 1400 patients. A retrospective analysis of resection rate was undertaken. RESULTS: In First BEAT, 225 out of 1914 patients (11.8%) underwent curative-intent surgery at median 64 days (range 42-100) after the last dose of bevacizumab. R0 resection was achieved in 173 out of 225 patients (76.9%). There were no surgery-related deaths and serious post-operative complications were uncommon, with grade 3/4 bleeding and wound-healing events reported in 0.4% and 1.8%, respectively. Resection rates were highest in patients receiving oxaliplatin-based combination chemotherapy (P=0.002), possibly confounded by patient selection. In NO16966, 44 out of 699 patients treated with bevacizumab (6.3%) and 34 out of 701 patients treated with placebo (4.9%) underwent R0 metastasectomy (P=0.24). CONCLUSIONS: The rate of serious post-operative complications in First BEAT was comparable to historical controls without bevacizumab. In NO16966, there were no statistically significant differences in resection rates or overall survival in patients treated with bevacizumab vs placebo. PMID- 19789533 TI - Atacicept in relapsed/refractory multiple myeloma or active Waldenstrom's macroglobulinemia: a phase I study. AB - BACKGROUND: Advanced multiple myeloma (MM) and Waldenstrom's macroglobulinemia (WM) are incurable B-cell malignancies. This is the first full clinical report of atacicept, a fusion protein that binds to and neutralises the B-cell survival factors, B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL), in MM and WM. METHODS: In this open-label phase-I study, 16 patients with advanced disease (12 MM, 4 WM) received one cycle of five once-weekly subcutaneous injections of atacicept (2, 4, 7 or 10 mg kg(-1)). Patients with stable disease after cycle 1 entered an extension study (either two additional cycles (2, 4 and 7 mg kg(-1) cohorts) or 15 consecutive weekly injections of atacicept 10 mg kg(-1)). RESULTS: Atacicept was well tolerated, systemically and locally; the maximum tolerated dose was not identified. Of 11 patients with MM who completed initial treatment, five patients were progression-free after cycle 1 and four patients were progression-free after extended therapy. Of four patients with WM, three patients were progression-free after cycle 1. Consistent with atacicept's mechanism of action, polyclonal immunoglobulin isotypes and total B cells were reduced. Bone-marrow density, myeloma cell numbers and plasma concentrations of soluble CD138 also decreased. CONCLUSION: Atacicept is well tolerated in patients with MM and WM, and shows clinical and biological activity consistent with its mechanism of action. PMID- 19789534 TI - Pre-operative urinary cathepsin D is associated with survival in patients with renal cell carcinoma. AB - BACKGROUND: No circulating markers are routinely used for renal cancer. The objective of this pilot study was to investigate whether conditioned media (CM) from renal cancer cell lines contains potential biomarkers that, when measured in clinical fluids, have diagnostic or prognostic utility. METHODS: Comparative 2D PAGE profiling of CM from renal cell carcinoma (RCC) and normal renal cultures identified cathepsin D that was subsequently validated in urine samples from 239 patients and healthy and benign disease subjects. RESULTS: Urinary cathepsin D was found to be significantly associated with overall (OS) (hazard ratio, HR, 1.33, 95%CI [1.09-1.63], P=0.005) and cancer-specific survival (HR 1.36, 95%CI [1.07-1.74], P=0.013) in RCC patients on univariate analysis. An optimal cut point (211 ng ml(-1) micromolCr(-1)) around which to stratify patients by OS was determined. Five-year OS equal to/above and below this value was 47.0% (95%CI 35.4%, 62.4%) and 60.9% (48.8%, 76.0%), respectively. On multivariable analysis using pre-operative variables, cathepsin D showed some evidence of independent prognostic value for OS (likelihood ratio test P-value=0.056) although requiring further validation in larger patient numbers with sufficient statistical power to determine independent significance. CONCLUSION: These data establish an important proof of principle and show the potential of proteomics-based studies. Cathepsin D may be of value as a pre-operative urinary biomarker for RCC, alone or in combination. PMID- 19789535 TI - Salivary analysis of oral cancer biomarkers. AB - BACKGROUND: Oral cancer is a common and lethal malignancy. Direct contact between saliva and the oral cancer lesion makes measurement of tumour markers in saliva an attractive alternative to serum testing. METHODS: We tested 19 tongue cancer patients, measuring the levels of 8 salivary markers related to oxidative stress, DNA repair, carcinogenesis, metastasis and cellular proliferation and death. RESULTS: Five markers increased in cancer patients by 39-246%: carbonyls, lactate dehydrogenase, metalloproteinase-9 (MMP-9), Ki67 and Cyclin D1 (CycD1) (P< or =0.01). Three markers decreased by 16-29%: 8-oxoguanine DNA glycosylase, phosphorylated-Src and mammary serine protease inhibitor (Maspin) (P< or =0.01). Increase in salivary carbonyls was profound (by 246%, P=0.012); alterations in CycD1 (87% increase, P=0.000006) and Maspin (29% decrease, P=0.007) were especially significant. Sensitivity values of these eight analysed markers ranged from 58% to 100%; specificity values ranged from 42% to 100%. Both values were especially high for the CycD1 and Maspin markers, 100% for each value of each marker. These were also high for carbonyls, 90% and 80%, respectively, and for MMP-9, 100% and 79%, respectively. CONCLUSION: The significance of each salivary alteration is discussed. As all alterations correlated with each other, they may belong to a single carcinogenetic network. Cancer-related changes in salivary tumour markers may be used as a diagnostic tool for diagnosis, prognosis and post operative monitoring. PMID- 19789537 TI - Race: a call to change nomenclature. PMID- 19789540 TI - Uremic memory: the role of acute kidney injury in long-term outcomes. AB - Most epidemiologic data, thus far, have focused on short-term outcomes of acute kidney injury (AKI). Lo et al. correlate AKI with long-term outcomes. The concept of 'uremic memory' sheds light on the importance of AKI and its permanent imprint. The focus of research should be on prevention of an episode of AKI, when possible. PMID- 19789539 TI - Licorice: a sweet alternative to prevent hyperkalemia in dialysis patients? AB - In patients on hemodialysis, Farese et al. report that inhibition of the enzyme 11beta-hydroxysteroid dehydrogenase type 2 by glycyrrhetinic acid, the active compound of licorice, reduces serum potassium concentration and the frequency of hyperkalemia, possibly by enhancing intestinal potassium loss. This finding could be an important tool to maintain predialysis [K(+)] within safe limits in some dialysis patients at risk of hyperkalemic arrhythmias. PMID- 19789541 TI - Sphingosine kinase-1: a potential mediator of renal fibrosis. AB - Renal fibrosis contributes to glomerulosclerosis and tubulointerstitial damage in chronic kidney disease. A well-established pathway implicated in the progression of fibrosis is the induction of connective tissue growth factor by transforming growth factor-beta, resulting in the accumulation of extracellular matrix proteins. Ren and colleagues demonstrate that sphingosine kinase-1 is involved in the regulation of this pathway in the glomerulus. This raises the possibility of targeting sphingosine kinase-1 to prevent fibrosis in chronic kidney disease patients. PMID- 19789543 TI - Pitfalls of technetium-99m-labeled human serum albumin scintigraphy for protein losing enteropathy. PMID- 19789545 TI - The utility of multivariate analysis in the study of hepcidin. PMID- 19789549 TI - The data on transplantation in Saudi Arabia are complex and require additional framework for interpretation. PMID- 19789547 TI - Overexpression of cytochrome P450 4F2 in mice increases 20 hydroxyeicosatetraenoic acid production and arterial blood pressure. PMID- 19789551 TI - Mineral complexes and vascular calcification. PMID- 19789552 TI - Complications impair the usefulness and validity of the rat tail arteriovenous fistula model. PMID- 19789553 TI - Enterovesical fistula and roundworms. PMID- 19789554 TI - First use of nocturnal hemodialysis. PMID- 19789555 TI - Endovascular repair of a hemodialysis fistula aneurysm with covered stents. PMID- 19789557 TI - Translating stem cell therapy to the clinic: deja vu all over again. PMID- 19789558 TI - Correction and apology. PMID- 19789556 TI - Rethinking how DNA methylation patterns are maintained. AB - DNA methylation patterns are set up early in mammalian development and are then copied during the division of somatic cells. A long-established model for the maintenance of these patterns explains some, but not all, of the data that are now available. We propose a new model that suggests that the maintenance of DNA methylation relies not only on the recognition of hemimethylated DNA by DNA methyltransferase 1 (DNMT1) but also on the localization of the DNMT3A and DNMT3B enzymes to specific chromatin regions that contain methylated DNA. PMID- 19789561 TI - Adenovirus virion stability and the viral genome: size matters. PMID- 19789566 TI - Controlling false positives in the mapping of epistatic QTL. AB - This study addresses the poorly explored issue of the control of false positive rate (FPR) in the mapping of pair-wise epistatic quantitative trait loci (QTL). A nested test framework was developed to (1) allow pre-identified QTL to be used directly to detect epistasis in one-dimensional genome scans, (2) to detect novel epistatic QTL pairs in two-dimensional genome scans and (3) to derive genome-wide thresholds through permutation and handle multiple testing. We used large-scale simulations to evaluate the performance of both the one- and two-dimensional approaches in mapping different forms and levels of epistasis and to generate profiles of FPR, power and accuracy to inform epistasis mapping studies. We showed that the nested test framework and genome-wide thresholds were essential to control FPR at the 5% level. The one-dimensional approach was generally more powerful than the two-dimensional approach in detecting QTL-associated epistasis and identified nearly all epistatic pairs detected from the two-dimensional approach. However, only the two-dimensional approach could detect epistatic QTL with weak main effects. Combining the two approaches allowed effective mapping of different forms of epistasis, whereas using the nested test framework kept the FPR under control. This approach provides a good search engine for high throughput epistasis analyses. PMID- 19789567 TI - TMPRSS2-ERG gene fusions are infrequent in prostatic ductal adenocarcinomas. PMID- 19789569 TI - The wrong end of the scope. PMID- 19789570 TI - Hepatitis: Monitoring drug therapy for hepatitis B--a global challenge? PMID- 19789571 TI - Colorectal cancer: What do studies of diet patterns tell us? PMID- 19789572 TI - Colorectal cancer: Management of small polyps detected by CT colonography. PMID- 19789573 TI - Hepatitis C: CIFN for re-treatment of PEG-IFN plus RBV nonresponders? PMID- 19789574 TI - Surgery: A midline or transverse abdominal incision? PMID- 19789575 TI - A case of complete resolution of gastric varices. AB - BACKGROUND: A 49-year-old woman with hepatitis C and peptic ulcer disease presented to the emergency department after an onset of sudden massive hematemesis. She had a history of alcohol abuse, but denied any recent excessive drinking. INVESTIGATIONS: Physical examination, laboratory investigations including complete blood cell counts and liver function tests, esophagogastroduodenoscopy, abdominal angiography and venography, CT scans of the abdomen and pelvis. DIAGNOSIS: Gastric variceal hemorrhage, severe portal hypertensive gastropathy, splenic vein thrombosis. MANAGEMENT: Blood transfusion, splenic artery embolization and balloon-occluded retrograde transvenous obliteration of gastric varices. Immediate postprocedural CT scans of the abdomen, with repeat imaging 30 months later. PMID- 19789576 TI - Preliminary evidence of a noncausal association between the X-chromosome inactivation pattern and thyroid autoimmunity: a twin study. AB - An increased frequency of skewed X-chromosome inactivation (XCI) is found in clinically overt autoimmune thyroid disease (AITD) compared with controls. Whether skewed XCI is involved in the pathogenesis of autoantibodies to thyroid peroxidase (TPOAb) in euthyroid subjects is unknown. To examine the impact of XCI on the serum concentration of TPOAb, we studied whether within-cohort and within twin-pair differences in XCI are associated with differences in serum concentrations of TPOAb. A total of 318 euthyroid female twin individuals distributed in 159 pairs were investigated. XCI was determined by PCR analysis of a polymorphic CAG repeat in the first exon of the androgen receptor gene. TPOAb concentrations were measured using a solid-phase time-resolved fluoroimmunometric assay. Overall (within cohort), there was a significant association between XCI and serum concentrations of TPOAb; regression coefficient (beta)=1.45 (95% confidence interval, 0.52-2.38), P=0.003. The association remained significant in the within-pair analysis; beta=1.74 (0.79-2.69), P<0.001. The relationship was nonsignificant within the 82 monozygotic pairs (beta=0.57 (-0.78-1.92), P=0.405), whereas the association was significant in the 77 dizygotic pairs (beta=2.17 (0.81-3.53), P=0.002). This preliminary finding of a significant association between TPOAb concentrations and XCI within cohort and within dizygotic but not within monozygotic twin pairs may indicate that XCI per se does not have a major role in the pathogenesis of TPOAb. More likely, XCI and TPOAb are influenced by shared genetic determinants. PMID- 19789578 TI - Refocusing ophthalmic education. PMID- 19789579 TI - Prevention of ocular trauma. PMID- 19789580 TI - The critical need for trained and certified ophthalmic medical personnel: fall survey of staff and productivity. PMID- 19789581 TI - Retina Canada 2009. PMID- 19789582 TI - Jack Crawford Day 2009. PMID- 19789584 TI - An analysis of undergraduate ophthalmology training in Canada. AB - OBJECTIVE: To investigate the adequacy of undergraduate ophthalmology education in Canada in comparison with the International Council of Ophthalmology (ICO) guidelines. DESIGN: Cross-sectional survey. PARTICIPANTS: First-year residents who had graduated from Canadian medical schools. METHODS: Eligible residents were invited to participate in an online survey in 2007. Data were categorized by demographic variables, and basic statistics were done. RESULTS: Responses were obtained from 386 of the 1425 individuals (27.0%) contacted. The majority (64.0%) stated they had "too little" or "no exposure" to ophthalmology in medical school. The majority (76.2%) of respondents stated that they had had 1 week or less of overall exposure to ophthalmology. Sufficient exposure to several ICO core subspecialty areas was reported, including lens/cataract (81.1%) and cornea/external diseases (81.6%); however, some areas did not receive adequate time allocation, such as vitreoretinal disease (41.9%). Similarly, competency was obtained in certain ICO examination skills, including assessment of visual acuity (83.3%) and pupillary reflexes (90.7%) but was not achieved for other skills, such as fundoscopy (52.3%), slit-lamp examination (44.8%), and intraocular pressure assessment (19.9%). When asked whether sufficient ophthalmology knowledge and skills had been obtained during medical school, only 42.9% and 25.9% agreed, respectively. CONCLUSIONS: Undergraduate ophthalmology training in Canada contains gaps in certain key areas. Developing a national, standardized curriculum could ensure that medical students acquire competency in the ophthalmology knowledge and skills required for future clinical practice. PMID- 19789585 TI - Pediatric eye injuries in a Canadian emergency department. AB - OBJECTIVE: This study assesses the descriptive epidemiology of children with eye injuries presenting to the emergency department of a major Canadian pediatric hospital. STUDY DESIGN: A retrospective cohort study. PARTICIPANTS: All pediatric patients (up to 18 years of age) presenting with ocular injuries to a tertiary care pediatric emergency department between January 1 and December 31, 2002. METHODS: Chart review was conducted using Canadian Hospital Injury Reporting and Prevention Program forms. All injuries were classified by Birmingham Eye Trauma Terminology (BETT). RESULTS: There were 149 patients who presented with eye injuries to the emergency department in 2002, and all of them were included in the study. Patient ages ranged from 3 months to 18 years with a median age of 8 years 8 months (interquartile range 4-11 years). Boys accounted for 73.2% of the patient total. Most of the cases (57.7%) needed some treatment and required follow-up. Eleven patients (7.3%) had vision-threatening eye injuries that required surgical management, and 3 of these required multiple surgeries. Seven of the 11 patients suffered open globe lacerations, 3 open globe ruptures, and 1 closed globe injury. CONCLUSIONS: Most eye injuries occurred at home during the summer, and over 7% of children presenting to the emergency department with eye trauma had vision-threatening injuries that required surgical management. Increasing awareness of the serious nature of ocular injuries will help to develop a comprehensive plan for educating both parents and children to minimize preventable pediatric eye injuries. PMID- 19789586 TI - Optimal compliance for amblyopia therapy: occlusion with a translucent tape on the lens. AB - OBJECTIVE: To demonstrate that optimal compliance to amblyopia therapy and a better visual outcome can be achieved by occluding the lens over the preferred eye with a translucent tape. STUDY DESIGN: Prospective study of amblyopic children. PARTICIPANTS: Eighty-four amblyopic children recruited from 2000 to 2006 at the Montreal Children's Vision Centre. METHODS: A group of bilateral ametropes (mean age 3.8 years) were treated with glasses and occlusion of the sound eye with a translucent tape on the lens over the preferred eye, or an adhesive patch. The translucent tape reduced vision to hand motion at 0.3 m in the sound eye. Patients were divided into 2 groups depending on the treatment received. Group 1 (n = 36) was occluded with a translucent tape, and group 2 (n = 48) with a conventional adhesive patch, later replaced by the translucent tape. Twenty-five previously reported patients, treated with the conventional adhesive patch only, were used as controls (group 3). RESULTS: The mean amblyopic visual acuity was 20/100-2. Compliance was good in 36 patients (group 1), and was poor or deteriorated in 24/48 patients (group 2). Substituting the adhesive patch with a translucent tape permitted uninterrupted and prolonged occlusion, with a successful visual outcome. The amblyopic eye achieved a significantly better final vision (20/30+2; groups 1+2) than the controls (20/40+1; group 3) (p = 0.04). Sixty-four (76.19%) patients achieved >or=20/30. CONCLUSIONS: The translucent tape optimizes compliance and yields better vision by lengthening the duration of occlusion therapy and reducing the number of treatment failures due to noncompliance. PMID- 19789587 TI - The effect of Nd:YAG laser posterior capsulotomy on ocular wave front aberrations. AB - OBJECTIVE: To assess the effect of Nd:YAG laser posterior capsulotomy on ocular wave front aberrations. STUDY DESIGN: Retrospective comparative study. PARTICIPANTS: Twenty-four eyes of 24 consecutive pseudophakic patients with symptomatic PCO, who presented for Nd:YAG laser posterior capsulotomy at our clinic, were included in this study. METHODS: The wave front aberrations of the entire optical path of 24 pseudophakic eyes of 24 patients before, and 1 month after, Nd:YAG laser posterior capsulotomy were measured using the Nidek Optical Path Difference (OPD) scan aberrometer. Total, tilt, and high-order aberrations, and total coma, total trefoil, total tetrafoil, total spherical, and total high astigmatism aberrations were analyzed statistically. Secondary measures included changes in visual acuity and refraction, and repeatability of wave front measurements in the fellow eye. RESULTS: Before Nd:YAG laser posterior capsulotomy, the total higher-order aberrations root mean-square (RMS) wave front aberration was 2.08 (SD 2.20) microm, with total trefoil being a major contributor at 1.19 (SD 1.15) microm. One month after the procedure, significant decreases in total, tilt, and high-order aberrations, and total trefoil, total tetrafoil, total spherical, and total high astigmatism aberrations were noted (p< 0.05). No significant changes in total coma aberrations were found (p > 0.05). Additionally, significant improvement in visual acuity without significant change in refraction was observed. No statistically significant differences were detected in any of the RMS values of wave front measurements taken 1 month later in the fellow eye. CONCLUSIONS: Nd:YAG laser posterior capsulotomy causes significant decrease in ocular wave front aberrations measured using the Nidek OPD scan aberrometer, which can account for a better optical quality after the procedure. Further research to examine the impact of wave front aberrations in visual function after Nd:YAG laser posterior capsulotomy is needed. PMID- 19789588 TI - Phacoemulsification in patients with nanophthalmos. AB - OBJECTIVE: To evaluate phacoemulsification surgery and its possible risks in patients with nanophthalmos. DESIGN: The surgical procedure, corneal diameter, keratometry, axial length, visual acuity, and intraoperative and postoperative complications were reviewed. Scleral thickness was determined by echography. PARTICIPANTS: 5 patients, 8 eyes. METHODS: The results of cataract surgery in nanophthalmic eyes were reviewed. Inclusion criteria was based on a clinical diagnosis of nanophthalmos and ocular surgery for cataract. Nanophthalmos was diagnosed according to a shorter than average axial length (usually less than 20.0 mm), typically a shallow anterior chamber, hyperopia, and scleral thickening greater than 1.5 mm. The procedure was planned as phacoemulsification, and foldable acrylic PCIOL implantation via a clear corneal tunnel. RESULTS: The procedure was planned as phacoemulsification. Six eyes had cataract extraction with posterior chamber intraocular lens implantation by phacoemulsification. It was necessary to change the procedure to extracapsular cataract surgery in 2 cases because of uncontrolled shallowing of the anterior chamber. Postoperative trabeculectomy was needed in 1 eye, and Nd:YAG laser capsulotomy was performed on 4 eyes. No postoperative uveal effusion or infections were seen in any of the eyes. Complications included iritis with posterior synechia (n = 1), transient choroidal hemorrhage (n = 1), vitreous loss (n = 1), posterior capsule opacity (n = 4), and glaucoma (n = 1). In 1 case retinal detachment developed 3 weeks postoperatively. Prophylactic laser iridoplasty or iridotomy was not performed for surgery. CONCLUSIONS: Although phacoemulsification seems to be relatively safe in nanophthalmic patients without performing any prophylactic surgical procedure, surgeons need to be attentive of the challenges of working through them when performing phacoemulsification in these high-risk eyes. However, with careful preoperative evaluation and planning, complications can be avoided. PMID- 19789589 TI - Canadian ophthalmology residency training: an evaluation of resident satisfaction and comparison with international standards. AB - OBJECTIVE: To evaluate the adequacy of Canadian ophthalmology residency programs in achieving the competencies outlined by the International Council of Ophthalmology (ICO) and to assess residents' satisfaction with their training programs. PARTICIPANTS: Canadian residents enrolled in the final 2 years of English and French ophthalmology programs, as well as recent graduates from 2005 to 2008. METHODS: Graduates and eligible residents were invited to participate in the 43-item survey during the autumn of 2008. Data were categorized by demographic variables, and basic statistics were done. RESULTS: Of the 99 individuals surveyed, 40 (40%) responded, representing 26 current residents and 14 graduates. The vast majority (85%) of respondents were satisfied with their residency program. Clinic-based training was generally rated satisfactorily; however, respondents reported insufficient exposure to low-vision rehabilitation (77.5%), refraction and glasses prescription (65%), and neuro-ophthalmology (45%). Respondents were similarly satisfied with their surgical experiences, most of them (>60%) rating case volume, complexity, and variety as satisfactory or better. However, many stated that they had insufficient exposure to extracapsular cataract extraction (72.5%), refractive surgery (72.5%), and orbital surgery (57.5%). Of the graduates surveyed, all passed their Royal College licensing examinations on the first attempt and felt that residency adequately prepared them for the examinations. They reported insufficient training in certain nonclinical areas, such as practice management, and staffing and administration skills. CONCLUSIONS: Canadian ophthalmology residents express high levels of satisfaction with their residency training programs. Although most programs appear to adequately address most ICO core objectives, certain curriculum modifications are required. PMID- 19789590 TI - The treatment of wet AMD in Canada: access to therapy (policy review). AB - Age-related macular degeneration (AMD) is the leading cause of blindness in North America, affecting 2 million Canadians older than age 50 years. AMD is subdivided into 2 types: an atrophic form, so-called "dry" AMD, and an exudative or "wet" form, characterized by the presence of choroidal neovascularization (CNV). Since 2000, after decades with no effective therapy aside from thermal obliterative laser treatment of CNV, 3 new treatments have been approved, each offering significant therapeutic advances at increasingly higher prices, and in an increasingly cost-containment-oriented payer environment. Many of Canada's public drug plans have been relatively slow to fund evidence-based, approved treatments. This paper reviews the disease, as well as the current private and public coverage for wet AMD treatments. PMID- 19789591 TI - Effect of the shape of the endothelial graft on the refractive results after Descemet's stripping with automated endothelial keratoplasty. AB - OBJECTIVE: To investigate the magnitude and the possible causes of the refractive changes after Descemet's stripping with automated endothelial keratoplasty (DSAEK). In this article we describe the changes in corneal power after DSAEK and correlate them with the shape, diameter, and thickness of the endothelial graft obtained. STUDY DESIGN: Retrospective chart review. PARTICIPANTS: 17 consecutive patients who underwent DSAEK at the Rand Eye Institute in 2007. METHODS: The preoperative and post-DSAEK corneal power was determined using Gaussian optics and correlated with the DSAEK graft diameter and central, paracentral (P1), and peripheral (P2) graft thickness using images obtained from the Pentacam Scheimpflug. RESULTS: During DSAEK there is addition of corneal tissue in the posterior layers of the cornea, which reduces the radius of curvature of the posterior layer of the cornea and also the total corneal power. The mean anterior:posterior corneal radius of curvature ratio after DSAEK is 72.3% (SD 4.63%). In consequence, the keratometry values calculated after DSAEK using the Gaussian optics method are less than those measured by manual keratometry after surgery. A strong correlation was observed between the postoperative Gaussian keratometric power and the ratio of the central corneal DSAEK graft thickness (C) to the mean P2 measured at 7 mm optical zone (C:P2) (r2 = 0.63, p< 0.01). CONCLUSIONS: DSAEK induced a mean hyperopic shift of 1.05 (SD 0.76) D. The mean anterior:posterior corneal radius of curvature ratio decreased to 72.3%. Despite a great variability, the ratio between the central DSAEK graft thickness and the graft thickness at the 7 mm optical zone (C:P2 ratio) was correlated with the magnitude of the change in corneal power and induced hyperopia, which produces a steeper posterior corneal surface. No correlation between the DSAEK graft diameter and change in corneal power was noted. Customization in the shape of the donor graft lenticle might reduce the hyperopic shift noted after DSAEK. PMID- 19789592 TI - Comparison of retinal nerve fibre layer measurements from time domain and spectral domain optical coherence tomography systems. AB - OBJECTIVE: To compare retinal nerve fibre layer (RNFL) thickness measurements acquired using spectral domain (SD) and time domain (TD) optical coherence tomography (OCT) systems. STUDY DESIGN: Prospective clinical study. PARTICIPANTS: Twenty eyes of 20 healthy volunteers. METHODS: All patients underwent 3 sets of circular OCT scans around the optic disc using both a TD OCT system, and a new SD OCT system. RNFL thickness measures within each of 4 quadrants, as well as overall mean RNFL thickness, were compared. Bland-Altman plots were also used to assess agreement. RESULTS: Using the RTVue-100, RNFL measurements in the superior quadrant were, on average, 20 microm greater than those obtained from the Stratus (151.8 microm vs 131.7 microm, p< 0.0001). RNFL measures within other quadrants and overall mean RNFL thickness were not significantly different between systems. Bland-Altman plots indicated large differences between Stratus and RTVue-100 for all variables, with 95% limits of agreement spanning clinically important ranges of >50 microm for all RNFL variables. CONCLUSIONS: Significant differences exist between RNFL measurements obtained from the TD and SD OCT systems used in this study. These related, but distinct, technologies are not interchangeable. Further studies will be required to allow for appropriate clinical use of new SD OCT systems. PMID- 19789593 TI - Transconjunctival suturing of the scleral flap for overfiltration with hypotony maculopathy after trabeculectomy. AB - OBJECTIVE: To assess the efficacy of transconjunctival suturing of the scleral flap in improving hypotony maculopathy resulting from overfiltration after trabeculectomy. DESIGN: Retrospective review. PARTICIPANTS: 35 eyes of 33 patients. METHODS: Patients underwent transconjunctival scleral flap suturing for hypotony maculopathy following trabeculectomy using mitomycin C. The scleral flap was sutured through the conjunctiva as an outpatient clinic procedure using a spatulated needle with a 10-0 nylon suture. RESULTS: The average age of the patients was 67.5 (SD 4.80, range 39-83) years, and 52% patients were male. The average duration of hypotony prior to transconjunctival suturing of the flap was 108.0 (SD 68.3) days. The median intraocular pressure (IOP) before suturing was 3 mm Hg, and the median IOP 6 months after the procedure was 9 mm Hg (p < 0.0001). The median best-corrected visual acuity (BCVA) before transconjunctival suturing of the scleral flap was 20/100, and the median BCVA 6 months after the procedure was 20/30 (p < 0.0001). Compared with visual acuity before suturing the average gain in BCVA was 4.9 (SD 0.8) lines. CONCLUSIONS: Transconjunctival suturing of the trabeculectomy scleral flap is an effective treatment to raise IOP and improve visual loss from hypotony maculopathy after trabeculectomy with overfiltering blebs. PMID- 19789594 TI - Intraocular pressure adjusted for central corneal thickness as a screening tool for open-angle glaucoma in an at-risk population. AB - OBJECTIVE: Evaluation of intraocular pressure (IOP) adjusted for central corneal thickness (CCT) screening for open-angle glaucoma (OAG) in an at-risk population. STUDY DESIGN: Community-based screening clinic. PARTICIPANTS: Three hundred and forty-nine persons of black race, or >50 years of age, or with a positive family history of glaucoma. METHODS: Ophthalmological examination including Goldmann applanation tonometry, ultrasonographic corneal pachymetry, and visual field testing. Glaucomatous optic nerve damage with visual field loss was the gold standard. IOP was adjusted for CCT based on 3 nomograms. Results were compared with screening using unadjusted IOP. Outcome measures included sensitivity, specificity, areas under the receiver operating characteristic (ROC) curves, positive and negative predictive values (PPVs and NPVs), as well as positive and negative likelihood ratios. RESULTS: No significant difference in CCT was found between those with glaucoma (560 [SD 37] microm, n = 31) and those without (557 [SD 35] microm, n = 233). Screening adjusted IOPs for glaucoma with an IOP > 21 mm Hg resulted in PPVs of 23.8% to 25% and NPVs of 89.3% to 89.6%, similar to preadjustment values. Areas under the ROC curves varied from 0.544 to 0.571 post adjustment from the initial value of 0.574. CONCLUSIONS: IOP adjusted for CCT is unlikely to improve tonometry as a screening tool for OAG in an at-risk population. PMID- 19789595 TI - Racial variability of glaucoma risk factors between African Caribbeans and Caucasians in a Canadian urban screening population. AB - BACKGROUND: The significance of race in the development and progression of glaucoma remains controversial, although in most cases the evidence shows greater prevalence and progression of the disease in African American populations. The purpose of this study was to determine the impact of the African Caribbean race on the variability of risk factors for glaucoma in an urban Canadian screening population. STUDY DESIGN: Population-based, cross-sectional study. PARTICIPANTS: Participants with high risk for development of open-angle glaucoma. METHODS: Participants underwent confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomograph),frequency-doubling technology (FDT) perimetry, and complete ophthalmic examination during a high-risk glaucoma screening clinic. Statistical analysis was performed comparing the data gathered from these tests in the different racial groups. Student's t tests as well as Pearson's c2 tests were done. RESULTS: Racial breakdown included 64 African Caribbeans (22%) and 224 Caucasians (78%). Racial groups had similar female/male ratios, but Caucasians were significantly older (66 [SD 12] years) than African Caribbeans (56 [SD12] years) ( p = 0.001). African Caribbeans had significantly higher intraocular pressure (IOP) ( p < 0.001); thinner central corneal thickness (CCT) ( p < 0.001); greater cup/disc ratio ( p = 0.016), disc area ( p < 0.001), cup area ( p = 0.002), and cup/disc area ratio ( p = 0.009); and smaller rim/disc area ratio ( p = 0.009). The latter optic disc parameter differences were not statistically different when corrected for disc area differences. CONCLUSIONS: In this study, African Caribbeans in a Canadian urban setting were associated with increased risk factors for open-angle glaucoma development, including higher IOP and thinner CCT. The larger cup/disc and cup/disc area ratios of the African Caribbean group were directly correlated to disc area differences between the 2 groups. PMID- 19789596 TI - Association of ABO blood groups with glaucoma in the Pakistani population. AB - OBJECTIVE: To study the association of blood groups with different types of glaucoma including primary open-angle glaucoma (POAG), primary closed-angle glaucoma (PCAG), and pseudoexfoliative glaucoma (PEXG) in the Pakistani population. STUDY DESIGN: The present study was a prospective case control study. PARTICIPANTS: ABO and Rh blood groups were analyzed in 2046 controls and 477 glaucoma patients (220 POAG, 146 PCAG, and 111 PEXG). METHODS: Hemagglutination patterns were used to determine the prevalence of the ABO and Rh blood groups in all the subjects. Logistic regression analysis was carried out to evaluate any association of the different blood groups with glaucoma. RESULTS: In the present study, the percentage of blood groups A, B, AB, and O in patients was found to be 19%, 41%, 10%, and 30%, and in the control group, the values were 26%, 31%, 12%, and 31%, respectively. A significant positive association was found between the B blood group and glaucoma (p value < 0.05, odds ratio [OR] 1.5, and c2 15.8). Logistic regression analysis revealed that the blood group B was associated with all types of glaucoma with OR of 1.35 (95% CI 1.01-1.80; p = 0.04) for POAG, 1.71 (95% CI 1.21-2.40; p = 0.002) for PCAG, and 1.61 (95% CI 1.09-2.36; p = 0.016) for PEXG. POAG was also found to be associated with the Rh- allele (p < 0.05) with an OR of 4.05 (95% CI 2.98-5.51), as compared with controls. CONCLUSIONS: In the Pakistani patient cohort, blood group B is associated with all types of glaucoma and the Rhallele is associated only with POAG. PMID- 19789597 TI - Visual acuity after intravitreal triamcinolone for diabetic macular edema refractory to laser treatment: a meta-analysis. AB - OBJECTIVE: To quantify the effect on visual acuity of intravitreal triamcinolone for the treatment of laser-refractory diabetic macular edema (DME). STUDY DESIGN: Meta-analysis of eligible studies identified by searching MEDLINE, EMBASE, the Cochrane Library, and Google. PARTICIPANTS: 7 randomized controlled trials and 3 cohort studies. METHODS: A search of the literature between 1950 and September 2008 identified 540 articles. Studies that evaluated the efficacy of triamcinolone for the treatment of DME refractory to laser photocoagulation, reported visual acuity data, and compared the intervention with an appropriate control group were included. Exclusion criteria were studies of non-DME, triamcinolone used as an adjunct to another treatment, and triamcinolone delivery other than intravitreally. RESULTS: Using a random-effects model, there was a statistically significant summary mean difference in visual acuity of -0.313 logarithm of the minimum angle of resolution (logMAR) units (95% CI -0.551, 0.074) after 1 month of follow-up. This difference declined to -0.125 logMAR units (95% CI -0.181, -0.070) by 3 months and to -0.043 logMAR units (95% CI 0.090, 0.003) by 6 months. No evidence of publication bias was present. There was a high level of heterogeneity in this group of studies (meta-analysis of 1-month follow-up data: Q-statistic = 21.987, p< 0.001), attributable primarily to study design. CONCLUSIONS: These meta-analyses demonstrate that intravitreal triamcinolone results in a temporary improvement of visual acuity in patients with laser-refractory DME, with a peak benefit of approximately 3 lines of visual acuity 1 month postinjection. PMID- 19789598 TI - Investigating a possible cause of the myopic shift after combined cataract extraction, intraocular lens implantation, and vitrectomy for treatment of a macular hole. AB - OBJECTIVE: It has been documented that combination surgery (phacoemulsification, intraocular lens implantation, and vitrectomy) produces a postoperative myopic shift. We hypothesize that the myopic shift seen in patients treated with combination surgery, membrane stripping, and injection of C3F8 for treatment of a macular hole is due to an erroneously short preoperative axial length measurement by the IOLMaster. STUDY DESIGN: Retrospective chart review. PARTICIPANTS: Eleven eyes of 10 patients treated for a stage III or IV macular hole were recruited from a database search of 1 vitreoretinal practice in Regina, Sask. METHODS: All eyes included in the study underwent combination surgery, membrane stripping, and injection of C3F8. None of the patients demonstrated concurrent eye pathology. Postoperative axial length measurements by the IOLMaster were obtained and compared with the same preoperative measurements. RESULTS: The mean (SD) postoperative myopic shift seen in the study eyes was -0.76 (0.65) D (z = -2.578, p < 0.01). The mean (SD) preoperative and postoperative axial length measurements were 23.54 (1.02) mm and 23.53 (1.01) mm, respectively. No significant difference in axial length was found between the preoperative and postoperative axial length measurements (t = 0.43, df = 10, p = 0.68). CONCLUSIONS: These findings do not support our hypothesis of an erroneous preoperative axial length measurement by the IOLMaster in patients with a stage III or IV macular hole treated with combination surgery, membrane stripping, and injection of C3F8. Further studies are required to determine the precise cause of the postoperative myopic shift. PMID- 19789600 TI - Assessment of corneal biomechanical properties and intraocular pressure in patients with rheumatoid arthritis. PMID- 19789599 TI - Ocular involvement in brucellosis. AB - OBJECTIVE: To report the ocular findings associated with brucellosis. DESIGN: Cohort study. PARTICIPANTS: One hundred thirty-two patients with the diagnosis of brucellosis. METHODS: Ocular manifestations of 132 patients with brucellosis admitted to the Uveitis-Behcet Service of Ophthalmology Department at the Ankara Education and Research Hospital in Turkey between May 1992 and May 2006 were evaluated prospectively. The diagnosis of brucellosis was based on clinical signs, Brucella agglutination tests, and blood cultures. RESULTS: Ocular involvement was detected in 21% of brucellosis patients. The most frequent manifestations were anterior uveitis (41%) and choroiditis (32%), followed by panuveitis (9%), papilledema (9%), and retinal hemorrhages (9%). Forty-one percent of these patients were in the acute stage and 59% were in the chronic stage of brucellosis. Interestingly, all the patients with anterior uveitis were in the acute stage and all the other patients with choroiditis, papilledema, and retinal hemorrhages were in the chronic stage. All patients responded well to systemic antibiotic treatment along with topical or systemic corticosteroid treatment. No recurrence of ocular manifestations was detected during the follow up period, after completion of a 2-month systemic antibiotic treatment. CONCLUSIONS: Because ocular involvement of brucellosis is frequent in endemic regions, detailed ophthalmic examination of all patients with brucellosis should be done routinely. Ocular brucellosis should be considered in the differential diagnosis of all forms of uveitis or choroiditis in endemic regions, and these patients should undergo serologic screening for brucellosis. PMID- 19789601 TI - Documentation of optic disc melanocytoma by spectral and time domain optical coherence tomography. PMID- 19789602 TI - Uveal effusion simulating uveal ring melanoma. PMID- 19789603 TI - High-voltage electrical trauma to the eye. PMID- 19789604 TI - Central serous chorioretinopathy and idiopathic nonhistaminergic angioedema. PMID- 19789605 TI - Aspergillus endophthalmitis following orthotopic heart transplant. PMID- 19789606 TI - Preretinal neovascularization after bevacizumab injections in a patient with von Hippel-Lindau syndrome. PMID- 19789607 TI - Optic nerve hypoplasia associated with chromosome 9 inversion. PMID- 19789608 TI - A practice template for low-vision rehabilitation. PMID- 19789609 TI - Combined horizontal and oblique muscle surgery to treat synergistic divergence. PMID- 19789610 TI - Anterior segment imaging using optical coherence tomography in atypical pigment dispersion syndrome. PMID- 19789611 TI - Resolution of cystoid macular edema following removal of an anterior chamber intraocular lens with pupil capture. PMID- 19789612 TI - Intravitreal bevacizumab injection in a 14-year-old Vogt-Koyanagi-Harada patient with choroidal neovascular membrane. PMID- 19789626 TI - Masitinib (AB1010), a potent and selective tyrosine kinase inhibitor targeting KIT. AB - BACKGROUND: The stem cell factor receptor, KIT, is a target for the treatment of cancer, mastocytosis, and inflammatory diseases. Here, we characterise the in vitro and in vivo profiles of masitinib (AB1010), a novel phenylaminothiazole type tyrosine kinase inhibitor that targets KIT. METHODOLOGY/PRINCIPAL FINDINGS: In vitro, masitinib had greater activity and selectivity against KIT than imatinib, inhibiting recombinant human wild-type KIT with an half inhibitory concentration (IC(50)) of 200+/-40 nM and blocking stem cell factor-induced proliferation and KIT tyrosine phosphorylation with an IC(50) of 150+/-80 nM in Ba/F3 cells expressing human or mouse wild-type KIT. Masitinib also potently inhibited recombinant PDGFR and the intracellular kinase Lyn, and to a lesser extent, fibroblast growth factor receptor 3. In contrast, masitinib demonstrated weak inhibition of ABL and c-Fms and was inactive against a variety of other tyrosine and serine/threonine kinases. This highly selective nature of masitinib suggests that it will exhibit a better safety profile than other tyrosine kinase inhibitors; indeed, masitinib-induced cardiotoxicity or genotoxicity has not been observed in animal studies. Molecular modelling and kinetic analysis suggest a different mode of binding than imatinib, and masitinib more strongly inhibited degranulation, cytokine production, and bone marrow mast cell migration than imatinib. Furthermore, masitinib potently inhibited human and murine KIT with activating mutations in the juxtamembrane domain. In vivo, masitinib blocked tumour growth in mice with subcutaneous grafts of Ba/F3 cells expressing a juxtamembrane KIT mutant. CONCLUSIONS: Masitinib is a potent and selective tyrosine kinase inhibitor targeting KIT that is active, orally bioavailable in vivo, and has low toxicity. PMID- 19789627 TI - Soybean GmPHD-type transcription regulators improve stress tolerance in transgenic Arabidopsis plants. AB - BACKGROUND: Soybean [Glycine max (L.) Merr.] is one of the most important crops for oil and protein resource. Improvement of stress tolerance will be beneficial for soybean seed production. PRINCIPAL FINDINGS: Six GmPHD genes encoding Alfin1 type PHD finger protein were identified and their expressions differentially responded to drought, salt, cold and ABA treatments. The six GmPHDs were nuclear proteins and showed ability to bind the cis-element "GTGGAG". The N-terminal domain of GmPHD played a major role in DNA binding. Using a protoplast assay system, we find that GmPHD1 to GmPHD5 had transcriptional suppression activity whereas GmPHD6 did not have. In yeast assay, the GmPHD6 can form homodimer and heterodimer with the other GmPHDs except GmPHD2. The N-terminal plus the variable regions but not the PHD-finger is required for the dimerization. Transgenic Arabidopsis plants overexpressing the GmPHD2 showed salt tolerance when compared with the wild type plants. This tolerance was likely achieved by diminishing the oxidative stress through regulation of downstream genes. SIGNIFICANCE: These results provide important clues for soybean stress tolerance through manipulation of PHD-type transcription regulator. PMID- 19789628 TI - Hydrogen in drinking water reduces dopaminergic neuronal loss in the 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. AB - It has been shown that molecular hydrogen (H(2)) acts as a therapeutic antioxidant and suppresses brain injury by buffering the effects of oxidative stress. Chronic oxidative stress causes neurodegenerative diseases such as Parkinson's disease (PD). Here, we show that drinking H(2)-containing water significantly reduced the loss of dopaminergic neurons in PD model mice using both acute and chronic administration of 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP). The concentration-dependency of H(2) showed that H(2) as low as 0.08 ppm had almost the same effect as saturated H(2) water (1.5 ppm). MPTP-induced accumulation of cellular 8-oxoguanine (8-oxoG), a marker of DNA damage, and 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation were significantly decreased in the nigro-striatal dopaminergic pathway in mice drinking H(2)-containing water, whereas production of superoxide (O(2)*(-)) detected by intravascular injection of dihydroethidium (DHE) was not reduced significantly. Our results indicated that low concentration of H(2) in drinking water can reduce oxidative stress in the brain. Thus, drinking H(2)-containing water may be useful in daily life to prevent or minimize the risk of life style related oxidative stress and neurodegeneration. PMID- 19789629 TI - Reactions of Cre with methylphosphonate DNA: similarities and contrasts with Flp and vaccinia topoisomerase. AB - BACKGROUND: Reactions of vaccinia topoisomerase and the tyrosine site-specific recombinase Flp with methylphosphonate (MeP) substituted DNA substrates, have provided important insights into the electrostatic features of the strand cleavage and strand joining steps catalyzed by them. A conserved arginine residue in the catalytic pentad, Arg-223 in topoisomerase and Arg-308 in Flp, is not essential for stabilizing the MeP transition state. Topoisomerase or its R223A variant promotes cleavage of the MeP bond by the active site nucleophile Tyr-274, followed by the rapid hydrolysis of the MeP-tyrosyl intermediate. Flp(R308A), but not wild type Flp, mediates direct hydrolysis of the activated MeP bond. These findings are consistent with a potential role for phosphate electrostatics and active site electrostatics in protecting DNA relaxation and site-specific recombination, respectively, against abortive hydrolysis. METHODOLOGY/PRINCIPAL FINDINGS: We have examined the effects of DNA containing MeP substitution in the Flp related Cre recombination system. Neutralizing the negative charge at the scissile position does not render the tyrosyl intermediate formed by Cre susceptible to rapid hydrolysis. Furthermore, combining the active site R292A mutation in Cre (equivalent to the R223A and R308A mutations in topoisomerase and Flp, respectively) with MeP substitution does not lead to direct hydrolysis of the scissile MeP bond in DNA. Whereas Cre follows the topoisomerase paradigm during the strand cleavage step, it follows the Flp paradigm during the strand joining step. CONCLUSIONS/SIGNIFICANCE: Collectively, the Cre, Flp and topoisomerase results highlight the contribution of conserved electrostatic complementarity between substrate and active site towards transition state stabilization during site-specific recombination and DNA relaxation. They have potential implications for how transesterification reactions in nucleic acids are protected against undesirable abortive side reactions. Such protective mechanisms are significant, given the very real threat of hydrolytic genome damage or disruption of RNA processing due to the cellular abundance and nucleophilicity of water. PMID- 19789630 TI - Variant near ADAMTS9 known to associate with type 2 diabetes is related to insulin resistance in offspring of type 2 diabetes patients--EUGENE2 study. AB - BACKGROUND: A meta-analysis combining results from three genome-wide association studies and followed by large-scale replication identified six novel type 2 diabetes loci. Subsequent studies of the effect of these variants on estimates of the beta-cell function and insulin sensitivity have been inconclusive. We examined these variants located in or near the JAZF1 (rs864745), THADA (rs7578597), TSPAN8 (rs7961581), ADAMTS9 (rs4607103), NOTCH2 (rs10923931) and the CDC123/CAMK1D (rs12779790) genes for associations with measures of pancreatic beta-cell function and insulin sensitivity. METHODOLOGY/RESULTS: Oral and intravenous glucose stimulated insulin release (n = 849) and insulin sensitivity (n = 596) estimated from a hyperinsulinemic euglycemic clamp were measured in non diabetic offspring of type 2 diabetic patients from five European populations. Assuming an additive genetic model the diabetes-associated major C-allele of rs4607103 near ADAMTS9 associated with reduced insulin-stimulated glucose uptake (p = 0.002) during a hyperinsulinemic euglycemic clamp. However, following intravenous and oral administration of glucose serum insulin release was increased in individuals with the C-allele (p = 0.003 and p = 0.01, respectively). A meta-analyse combining clamp and IVGTT data from a total of 905 non-diabetic individuals showed that the C-risk allele associated with decreased insulin sensitivity (p = 0.003) and increased insulin release (p = 0.002). The major T-allele of the intronic JAZF1 rs864745 conferring increased diabetes risk was associated with increased 2(nd) phase serum insulin release during an IVGTT (p = 0.03), and an increased fasting serum insulin level (p = 0.001). The remaining variants did not show any associations with insulin response, insulin sensitivity or any other measured quantitative traits. CONCLUSION: The present studies suggest that the diabetogenic impact of the C-allele of rs4607103 near ADAMTS9 may in part be mediated through decreased insulin sensitivity of peripheral tissues. PMID- 19789631 TI - Timosaponin AIII is preferentially cytotoxic to tumor cells through inhibition of mTOR and induction of ER stress. AB - The aqueous extract of Anemarrhena asphodeloides (BN108) induces apoptosis in various cancer cell lines but is significantly less cytotoxic in non-transformed cells. Chemical fractionation of BN108 showed that its cytotoxicity is associated with timosaponins, steroidal saponins of coprostane type. Timosaponin BII (TBII) is a major saponin in BN108, but it shows little cytotoxicity. A much less abundant TAIII induces cell death in tumor cells but not in normal cells, reproducing the selectivity of the total extract BN108. Glycosidase treatment, by removing the extra sugar moiety in TBII, converts it to TAIII and confers cytotoxic activity. Analysis of the mechanisms of death induced by TAIII revealed activation of two distinct pro-apoptotic pathways: first, inhibition of mTORC1 manifested in much reduced phosphorylation of mTORC1 targets; second, induction of endoplasmic reticulum stress culminating in phosphorylation of eIF2alpha and activation of caspase 4. These pro-apoptotic pathways are activated by TAIII selectively in tumor cells but not in normal cells. Both pathways play a causative role in TAIII cytotoxicity, as restoration of either mTOR activity or relief of ER stress alone offer only partial protection from TAIII. Inhibition of mTORC1 and induction of ER stress apparently contribute to the induction of the previously reported autophagic response in TAIII-treated cells. TAIII induced autophagy plays a protective role in TAIII induced death signaling, and failure to mount autophagic response is associated with heightened sensitivity to TAIII induced apoptosis. The multiple death-promoting and apparently tumor-selective responses to TAIII, its ability to inhibit mTORC1, and the possibility of further enhancing its cytotoxicity by pharmacological inhibition of autophagy, make TAIII an attractive candidate for development as a cancer therapeutic agent. PMID- 19789632 TI - Identification of copy number variants defining genomic differences among major human groups. AB - BACKGROUND: Understanding the genetic contribution to phenotype variation of human groups is necessary to elucidate differences in disease predisposition and response to pharmaceutical treatments in different human populations. METHODOLOGY/PRINCIPAL FINDINGS: We have investigated the genome-wide profile of structural variation on pooled samples from the three populations studied in the HapMap project by comparative genome hybridization (CGH) in different array platforms. We have identified and experimentally validated 33 genomic loci that show significant copy number differences from one population to the other. Interestingly, we found an enrichment of genes related to environment adaptation (immune response, lipid metabolism and extracellular space) within these regions and the study of expression data revealed that more than half of the copy number variants (CNVs) translate into gene-expression differences among populations, suggesting that they could have functional consequences. In addition, the identification of single nucleotide polymorphisms (SNPs) that are in linkage disequilibrium with the copy number alleles allowed us to detect evidences of population differentiation and recent selection at the nucleotide variation level. CONCLUSIONS: Overall, our results provide a comprehensive view of relevant copy number changes that might play a role in phenotypic differences among major human populations, and generate a list of interesting candidates for future studies. PMID- 19789633 TI - Small vessel ischemic disease of the brain and brain metastases in lung cancer patients. AB - BACKGROUND: Brain metastases occur commonly in patients with lung cancer. Small vessel ischemic disease is frequently found when imaging the brain to detect metastases. We aimed to determine if the presence of small vessel ischemic disease (SVID) of the brain is protective against the development of brain metastases in lung cancer patients. METHODOLOGY/PRINCIPAL FINDINGS: A retrospective cohort of 523 patients with biopsy confirmed lung cancer who had received magnetic resonance imaging of the brain as part of their standard initial staging evaluation was reviewed. Information collected included demographics, comorbidities, details of the lung cancer, and the presence of SVID of the brain. A portion of the cohort had the degree of SVID graded. The primary outcome measure was the portion of study subjects with and without SVID of the brain who had evidence of brain metastases at the time of initial staging of their lung cancer.109 patients (20.8%) had evidence of brain metastases at presentation and 345 (66.0%) had evidence of SVID. 13.9% of those with SVID and 34.3% of those without SVID presented with brain metastases (p<0.0001). In a model including age, diabetes mellitus, hypertension, hyperlipidemia, and tobacco use, SVID of the brain was found to be the only protective factor against the development of brain metastases, with an OR of 0.31 (0.20, 0.48; p<0.001). The grade of SVID was higher in those without brain metastases. CONCLUSIONS/SIGNIFICANCE: These findings suggest that vascular changes in the brain are protective against the development of brain metastases in lung cancer patients. PMID- 19789634 TI - Design of RNAi hairpins for mutation-specific silencing of ataxin-7 and correction of a SCA7 phenotype. AB - Spinocerebellar ataxia type 7 is a polyglutamine disorder caused by an expanded CAG repeat mutation that results in neurodegeneration. Since no treatment exists for this chronic disease, novel therapies such post-transcriptional RNA interference-based gene silencing are under investigation, in particular those that might enable constitutive and tissue-specific silencing, such as expressed hairpins. Given that this method of silencing can be abolished by the presence of nucleotide mismatches against the target RNA, we sought to identify expressed RNA hairpins selective for silencing the mutant ataxin-7 transcript using a linked SNP. By targeting both short and full-length tagged ataxin-7 sequences, we show that mutation-specific selectivity can be obtained with single nucleotide mismatches to the wild-type RNA target incorporated 3' to the centre of the active strand of short hairpin RNAs. The activity of the most effective short hairpin RNA incorporating the nucleotide mismatch at position 16 was further studied in a heterozygous ataxin-7 disease model, demonstrating significantly reduced levels of toxic mutant ataxin-7 protein with decreased mutant protein aggregation and retention of normal wild-type protein in a non-aggregated diffuse cellular distribution. Allele-specific mutant ataxin7 silencing was also obtained with the use of primary microRNA mimics, the most highly effective construct also harbouring the single nucleotide mismatch at position 16, corroborating our earlier findings. Our data provide understanding of RNA interference guide strand anatomy optimised for the allele-specific silencing of a polyglutamine mutation linked SNP and give a basis for the use of allele-specific RNA interference as a viable therapeutic approach for spinocerebellar ataxia 7. PMID- 19789635 TI - Direct in vivo cell lineage analysis in the retrorsine and 2AAF models of liver injury after genetic labeling in adult and newborn rats. AB - BACKGROUNDS AND AIMS: When hepatocyte proliferation is impaired, liver regeneration proceeds from the division of non parenchymal hepatocyte progenitors. Oval cells and Small Hepatocyte-like Progenitor Cells (SHPCs) represent the two most studied examples of such epithelial cells with putative stem cell capacity. In the present study we wished to compare the origin of SHPCs proliferating after retrorsine administration to the one of oval cells observed after 2-Acetyl-Amino fluorene (2-AAF) treatment. METHODOLOGY/PRINCIPAL FINDINGS: We used retroviral-mediated nlslacZ genetic labeling of dividing cells to study the fate of cells in the liver. Labeling was performed either in adult rats before treatment or in newborn animals. Labeled cells were identified and characterised by immunohistochemistry. In adult-labeled animals, labeling was restricted to mature hepatocytes. Retrorsine treatment did not modify the overall number of labeled cells in the liver whereas after 2-AAF administration unlabeled oval cells were recorded and the total number of labeled cells decreased significantly. When labeling was performed in newborn rats, results after retrorsine administration were identical to those obtained in adult-labeled rats. In contrast, in the 2-AAF regimen numerous labeled oval cells were present and were able to generate new labeled hepatocytes. Furthermore, we also observed labeled biliary tracts in 2-AAF treated rats. CONCLUSIONS: Our results strongly suggest that SHPCs are derived from hepatocytes and we confirm that SHPCs and oval cells do not share the same origin. We also show that hepatic progenitors are labeled in newborn rats suggesting future directions for in vivo lineage studies. PMID- 19789636 TI - Alternative splicing of TCF7L2 gene in omental and subcutaneous adipose tissue and risk of type 2 diabetes. AB - BACKGROUND: Single nucleotide polymorphisms (SNPs) rs7903146 and rs12255372 located within TCF7L2 gene have been identified as the strongest common genetic risk factors for development of type 2 diabetes (T2D). We hypothesized that these genetic variants might increase the risk of T2D through regulation of alternative splicing or expression level of TCF7L2 in human adipose tissue. METHODOLOGY/PRINCIPAL FINDINGS: Expression of 13 assays detecting alternatively spliced forms of TCF7L2 was measured by quantitative reverse-transcriptase PCR (qRT-PCR) in paired biopsies of omental and subcutaneous adipose tissue from 159 obese individuals (BMI 54.6+/-12.2 kg/m(2)). TCF7L2 expression in both types of adipose tissue was not associated with SNPs rs7903146 and rs12255372, T2D status and blood levels of glucose or glycosylated hemoglobin (HbA1c). Expression of assays "ex12-13", "ex12-14" and "ex13-13a" detecting C-terminal alternative exons of TCF7L2 was higher in subcutaneous compared to omental adipose tissue by 1.46 fold (p = 6.5x10(-15)), 1.41 fold (p = 1.4x10(-9)) and 1.26 fold (p = 4.7x10(-6)) in the control group and by 1.86 fold (p = 1.7x10(-4)), 1.77 fold (p = 7.3x10( 4)) and 1.58 fold (p = 6.1x10(-4)) in the T2D group. A pathway enrichment analysis on transcripts significantly co-expressed with TCF7L2 in a microarray set combined with individual expression assays, suggested tissue-specific roles of TCF7L2 splicing forms in regulation of transcription, signal transduction and cell adhesion. CONCLUSIONS: Expression of TCF7L2 alternatively spliced forms may have different functional roles in omental and subcutaneous adipose tissue but is not associated with SNPs rs7903146 and rs12255372 or T2D status. PMID- 19789637 TI - Rectal visceral sensitivity in women with irritable bowel syndrome without psychiatric comorbidity compared with healthy volunteers. AB - BACKGROUND: Psychiatric comorbidity and visceral hypersensitivity are common in patients with irritable bowel syndrome (IBS), but little is known about visceral sensitivity in IBS patients without psychiatric disorders. AIM: We wanted to examine rectal visceral sensitivity in IBS patients without comorbid psychiatric disorders, IBS patients with phobic anxiety and healthy volunteers. METHODS: A total of thirty-eight female, non-constipated IBS patients without psychiatric disorders and eleven female IBS patients with phobic anxiety were compared to nine healthy women using a barostat double random staircase method. The non psychiatric patients were divided into those with diarrhoea predominant symptoms and those with alternating stool habits. RESULTS: The IBS patients without psychiatric disorders had normal visceral pressure thresholds. However, in the diarrhoea predominant subgroup, the volume discomfort threshold was reduced while it was unchanged in those with alternating stool habits. The phobic IBS patients had similar thresholds to the healthy volunteers. The rectal tone was increased in the non-psychiatric IBS patients with diarrhoea predominant symptoms and in the IBS patients with phobic anxiety. CONCLUSIONS: Non-constipated IBS patients without psychiatric disorders had increased visceral sensitivity regarding volume thresholds but normal pressure thresholds. Our study suggests that the lowered volume threshold was due to increased rectal tone. PMID- 19789639 TI - Inhibitory Effects of the Ruthenium Complex KP1019 in Models of Mammary Cancer Cell Migration and Invasion. AB - The effects of indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019, or FFC14A), the second ruthenium compound that entered clinical trials, in an in vitro model of tumour invasion and metastasis show that the antitumour effects of this compound might include also the modulation of cell behaviour although its cytotoxicity appears to be predominant over these effects. The comparison with its imidazole analogue KP418 shows however its superiority, being able to control in vitro cell growth and in some instances also in vivo tumour development. These results suggest that the activity of KP1019 is predominantly due to direct cytotoxic effects for tumour cells, evident also in vivo on primary tumour growth and that the effects on modulation of the biological behaviour of the cancer cell can be present but might have only a partial role. PMID- 19789638 TI - Role of PPARs in Radiation-Induced Brain Injury. AB - Whole-brain irradiation (WBI) represents the primary mode of treatment for brain metastases; about 200 000 patients receive WBI each year in the USA. Up to 50% of adult and 100% of pediatric brain cancer patients who survive >6 months post-WBI will suffer from a progressive, cognitive impairment. At present, there are no proven long-term treatments or preventive strategies for this significant radiation-induced late effect. Recent studies suggest that the pathogenesis of radiation-induced brain injury involves WBI-mediated increases in oxidative stress and/or inflammatory responses in the brain. Therefore, anti-inflammatory strategies can be employed to modulate radiation-induced brain injury. Peroxisomal proliferator-activated receptors (PPARs) are ligand-activated transcription factors that belong to the steroid/thyroid hormone nuclear receptor superfamily. Although traditionally known to play a role in metabolism, increasing evidence suggests a role for PPARs in regulating the response to inflammation and oxidative injury. PPAR agonists have been shown to cross the blood-brain barrier and confer neuroprotection in animal models of CNS disorders such as stroke, multiple sclerosis and Parkinson's disease. However, the role of PPARs in radiation-induced brain injury is unclear. In this manuscript, we review the current knowledge and the emerging insights about the role of PPARs in modulating radiation-induced brain injury. PMID- 19789640 TI - Fetal programming of adult glucose homeostasis in mice. AB - BACKGROUND: Emerging evidence suggests that dietary soy and phytoestrogens can have beneficial effects on lipid and glucose metabolism. We have previously shown that male mice fed from conception to adulthood with a high soy-containing diet had reduced body weight, adiposity and a decrease in glucose intolerance, an early marker of insulin resistance and diabetes. OBJECTIVES: The purpose of this study was to identify the precise periods of exposure during which phytoestrogens and dietary soy improve lipid and glucose metabolism. Since intrauterine position (IUP) has been shown to alter sensitivity to endocrine disruptors, we also investigated whether the combination of IUP and fetal exposure to dietary phytoestrogens could potentially affect adult metabolic parameters. METHODS: Male outbred mice (CD-1) were allowed ad libitum access to either a high soy containing diet or a soy-free diet either during gestation, lactation or after weaning. Adiposity and bone mass density was assessed by dual x-ray absorptiometry. Glucose tolerance was assessed by a glucose tolerance test. Blood pressure was examined by the tail-cuff system. RESULTS: Here we show that metabolic improvements are dependent on precise windows of exposure during life. The beneficial effects of dietary soy and phytoestrogens on adiposity were apparent only in animals fed post-natally, while the improvements in glucose tolerance are restricted to animals with fetal exposure to soy. Interestingly, we observed that IUP influenced adult glucose tolerance, but not adiposity. Similar IUP trends were observed for other estrogen-related metabolic parameters such as blood pressure and bone mass density. CONCLUSION: Our results suggest that IUP and fetal exposure to estrogenic environmental disrupting compounds, such as dietary phytoestrogens, could alter metabolic and cardiovascular parameters in adult individuals independently of adipose gain. PMID- 19789641 TI - A microscope automated fluidic system to study bacterial processes in real time. AB - Most time lapse microscopy experiments studying bacterial processes ie growth, progression through the cell cycle and motility have been performed on thin nutrient agar pads. An important limitation of this approach is that dynamic perturbations of the experimental conditions cannot be easily performed. In eukaryotic cell biology, fluidic approaches have been largely used to study the impact of rapid environmental perturbations on live cells and in real time. However, all these approaches are not easily applicable to bacterial cells because the substrata are in all cases specific and also because microfluidics nanotechnology requires a complex lithography for the study of micrometer sized bacterial cells. In fact, in many cases agar is the experimental solid substratum on which bacteria can move or even grow. For these reasons, we designed a novel hybrid micro fluidic device that combines a thin agar pad and a custom flow chamber. By studying several examples, we show that this system allows real time analysis of a broad array of biological processes such as growth, development and motility. Thus, the flow chamber system will be an essential tool to study any process that take place on an agar surface at the single cell level. PMID- 19789642 TI - Dragon's paradise lost: palaeobiogeography, evolution and extinction of the largest-ever terrestrial lizards (Varanidae). AB - BACKGROUND: The largest living lizard species, Varanus komodoensis Ouwens 1912, is vulnerable to extinction, being restricted to a few isolated islands in eastern Indonesia, between Java and Australia, where it is the dominant terrestrial carnivore. Understanding how large-bodied varanids responded to past environmental change underpins long-term management of V. komodoensis populations. METHODOLOGY/PRINCIPAL FINDINGS: We reconstruct the palaeobiogeography of Neogene giant varanids and identify a new (unnamed) species from the island of Timor. Our data reject the long-held perception that V. komodoensis became a giant because of insular evolution or as a specialist hunter of pygmy Stegodon. Phyletic giantism, coupled with a westward dispersal from mainland Australia, provides the most parsimonious explanation for the palaeodistribution of V. komodoensis and the newly identified species of giant varanid from Timor. Pliocene giant varanid fossils from Australia are morphologically referable to V. komodoensis suggesting an ultimate origin for V. komodoensis on mainland Australia (>3.8 million years ago). Varanus komodoensis body size has remained stable over the last 900,000 years (ka) on Flores, a time marked by major faunal turnovers, extinction of the island's megafauna, the arrival of early hominids by 880 ka, co-existence with Homo floresiensis, and the arrival of modern humans by 10 ka. Within the last 2000 years their populations have contracted severely. CONCLUSIONS/SIGNIFICANCE: Giant varanids were once a ubiquitous part of Subcontinental Eurasian and Australasian faunas during the Neogene. Extinction played a pivotal role in the reduction of their ranges and diversity throughout the late Quaternary, leaving only V. komodoensis as an isolated long-term survivor. The events over the last two millennia now threaten its future survival. PMID- 19789643 TI - The cultural dynamics of copycat suicide. AB - The observation that suicides sometimes cluster in space and/or time has led to suggestions that these clusters are caused by the social learning of suicide related behaviours, or "copycat suicides". Point clusters are clusters of suicides localised in both time and space, and have been attributed to direct social learning from nearby individuals. Mass clusters are clusters of suicides localised in time but not space, and have been attributed to the dissemination of information concerning celebrity suicides via the mass media. Here, agent-based simulations, in combination with scan statistic methods for detecting clusters of rare events, were used to clarify the social learning processes underlying point and mass clusters. It was found that social learning between neighbouring agents did generate point clusters as predicted, although this effect was partially mimicked by homophily (individuals preferentially assorting with similar others). The one-to-many transmission dynamics characterised by the mass media were shown to generate mass clusters, but only where social learning was weak, perhaps due to prestige bias (only copying prestigious celebrities) and similarity bias (only copying similar models) acting to reduce the subset of available models. These findings can help to clarify and formalise existing hypotheses and to guide future empirical work relating to real-life copycat suicides. PMID- 19789644 TI - RNAi screening in Drosophila cells identifies new modifiers of mutant huntingtin aggregation. AB - The fruitfly Drosophila melanogaster is well established as a model system in the study of human neurodegenerative diseases. Utilizing RNAi, we have carried out a high-throughput screen for modifiers of aggregate formation in Drosophila larval CNS-derived cells expressing mutant human Huntingtin exon 1 fused to EGFP with an expanded polyglutamine repeat (62Q). 7200 genes, encompassing around 50% of the Drosophila genome, were screened, resulting in the identification of 404 candidates that either suppress or enhance aggregation. These candidates were subjected to secondary screening in normal length (18Q)-expressing cells and pruned to remove dsRNAs with greater than 10 off-target effects (OTEs). De novo RNAi probes were designed and synthesized for the remaining 68 candidates. Following a tertiary round of screening, 21 high confidence candidates were analyzed in vivo for their ability to modify mutant Huntingtin-induced eye degeneration and brain aggregation. We have established useful models for the study of human HD using the fly, and through our RNAi screen, we have identified new modifiers of mutant human Huntingtin aggregation and aggregate formation in the brain. Newly identified modifiers including genes related to nuclear transport, nucleotide processes, and signaling, may be involved in polyglutamine aggregate formation and Huntington disease cascades. PMID- 19789645 TI - Decreased rate of evolution in Y chromosome STR loci of increased size of the repeat unit. AB - BACKGROUND: Polymorphic Y chromosome short tandem repeats (STRs) have been widely used in population genetic and evolutionary studies. Compared to di-, tri-, and tetranucleotide repeats, STRs with longer repeat units occur more rarely and are far less commonly used. PRINCIPAL FINDINGS: In order to study the evolutionary dynamics of STRs according to repeat unit size, we analysed variation at 24 Y chromosome repeat loci: 1 tri-, 14 tetra-, 7 penta-, and 2 hexanucleotide loci. According to our results, penta- and hexanucleotide repeats have approximately two times lower repeat variance and diversity than tri- and tetranucleotide repeats, indicating that their mutation rate is about half of that of tri- and tetranucleotide repeats. Thus, STR markers with longer repeat units are more robust in distinguishing Y chromosome haplogroups and, in some cases, phylogenetic splits within established haplogroups. CONCLUSIONS: Our findings suggest that Y chromosome STRs of increased repeat unit size have a lower rate of evolution, which has significant relevance in population genetic and evolutionary studies. PMID- 19789646 TI - Common avian infection plagued the tyrant dinosaurs. AB - BACKGROUND: Tyrannosaurus rex and other tyrannosaurid fossils often display multiple, smooth-edged full-thickness erosive lesions on the mandible, either unilaterally or bilaterally. The cause of these lesions in the Tyrannosaurus rex specimen FMNH PR2081 (known informally by the name 'Sue') has previously been attributed to actinomycosis, a bacterial bone infection, or bite wounds from other tyrannosaurids. METHODOLOGY/PRINCIPAL FINDINGS: We conducted an extensive survey of tyrannosaurid specimens and identified ten individuals with full thickness erosive lesions. These lesions were described, measured and photographed for comparison with one another. We also conducted an extensive survey of related archosaurs for similar lesions. We show here that these lesions are consistent with those caused by an avian parasitic infection called trichomonosis, which causes similar abnormalities on the mandible of modern birds, in particular raptors. CONCLUSIONS/SIGNIFICANCE: This finding represents the first evidence for the ancient evolutionary origin of an avian transmissible disease in non-avian theropod dinosaurs. It also provides a valuable insight into the palaeobiology of these now extinct animals. Based on the frequency with which these lesions occur, we hypothesize that tyrannosaurids were commonly infected by a Trichomonas gallinae-like protozoan. For tyrannosaurid populations, the only non-avian dinosaur group that show trichomonosis-type lesions, it is likely that the disease became endemic and spread as a result of antagonistic intraspecific behavior, consumption of prey infected by a Trichomonas gallinae-like protozoan and possibly even cannibalism. The severity of trichomonosis-related lesions in specimens such as Tyrannosaurus rex FMNH PR2081 and Tyrannosaurus rex MOR 980, strongly suggests that these animals died as a direct result of this disease, mostly likely through starvation. PMID- 19789647 TI - Dexamethasone, cerebrospinal fluid matrix metalloproteinase concentrations and clinical outcomes in tuberculous meningitis. AB - BACKGROUND: Adjunctive dexamethasone reduces mortality from tuberculous meningitis, but how it produces this effect is not known. Matrix metalloproteinases (MMPs) are important in the immunopathology of many inflammatory CNS diseases thus we hypothesized that that their secretion is important in TBM and might be influenced by dexamethasone. METHODOLOGY/PRINCIPAL FINDINGS: The kinetics of cerebrospinal fluid (CSF) MMP and tissue inhibitors of MMPs (TIMPs) concentrations were studied in a subset of HIV uninfected adults (n = 37) with TBM recruited to a randomized, placebo-controlled trial of adjuvant dexamethasone. Analysis followed a pre-defined plan. Dexamethasone significantly reduced CSF MMP-9 concentrations in early follow up samples (median 5 days (range 3-8) of treatment), but had no significant influence on other MMPs/TIMPs. Additionally CSF MMP-9 concentration was strongly correlated to concomitant CSF neutrophil count. CONCLUSIONS/SIGNIFICANCE: Dexamethasone decreased CSF MMP-9 concentrations early in treatment and this may represent one mechanism by which corticosteroids improve outcome in TBM. The strong correlation between CSF MMP-9 and neutrophil count suggests that polymorphonuclear leukocytes may play a central role in the early pathogenesis of TBM. PMID- 19789648 TI - Options for the delivery of intermittent preventive treatment for malaria to children: a community randomised trial. AB - BACKGROUND: Intermittent preventive treatment for malaria in children (IPTc) is a promising new intervention for the prevention of malaria but its delivery is a challenge. We have evaluated the coverage of IPTc that can be achieved by two different delivery systems in Ghana. METHODS: IPTc was delivered by volunteers in six villages (community-based arm) and by health workers at health centres or at Expanded Programme on Immunisation outreach clinics (facility based) in another six communities. The villages were selected randomly and drugs were administered in May, June, September and October 2006. The first dose of a three-dose regimen of amodiaquine plus sulphadoxine-pyrimethamine was administered under supervision to 3-59 month-old children (n = 964) in the 12 study villages; doses for days 2 and 3 were given to parents/guardians to administer at home. RESULTS: The proportion of children who received at least the first dose of 3 or more courses of IPTc was slightly higher in the community based arm (90.5% vs 86.6%; p = 0.059). Completion of the three dose regimen was high and similar with both delivery systems (91.6% and 91.7% respectively). CONCLUSION: Seasonal IPTc delivered through community-based or facility-based systems can achieve a high coverage rate with the support and supervision of the district health management team. However, in order to maximise the impact of IPTc, both delivery systems may be needed in some settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT00119132. PMID- 19789649 TI - Comparative genotyping of Campylobacter jejuni strains from patients with Guillain-Barre syndrome in Bangladesh. AB - BACKGROUND: Campylobacter jejuni is a common cause of acute gastroenteritis and is associated with post-infectious neuropathies such as the Guillain-Barre syndrome (GBS) and the Miller Fisher syndrome (MFS). We here present comparative genotyping of 49 C. jejuni strains from Bangladesh that were recovered from patients with enteritis or GBS. All strains were serotyped and analyzed by lipo oligosaccharide (LOS) genotyping, amplified fragment length polymorphism (AFLP) analysis, multilocus sequence typing (MLST), and pulsed-field gel electrophoresis (PFGE). METHODOLOGY/PRINCIPAL FINDINGS: C. jejuni HS:23 was a predominant serotype among GBS patients (50%), and no specific serotype was significantly associated with GBS compared to enteritis. PCR screening showed that 38/49 (78%) of strains could be assigned to LOS classes A, B, C, or E. The class A locus (4/7 vs 3/39; p<0.01) was significantly associated in the GBS-related strains as compared to enteritis strains. All GBS/oculomotor related strains contained the class B locus; which was also detected in 46% of control strains. Overlapping clonal groups were defined by MLST, AFLP and PFGE for strains from patients with gastroenteritis and GBS. MLST defined 22 sequence types (STs) and 7 clonal complexes including 7 STs not previously identified (ST-3742, ST-3741, ST-3743, ST-3748, ST-3968, ST-3969 and ST-3970). C. jejuni HS:23 strains from patients with GBS or enteritis were clonal and all strains belonged to ST-403 complex. Concordance between LOS class B and ST-403 complex was revealed. AFLP defined 25 different types at 90% similarity. The predominant AFLP type AF-20 coincided with the C. jejuni HS:23 and ST-403 complex. CONCLUSION/SIGNIFICANCE: LOS genotyping, MLST, AFLP and PFGE helped to identify the HS:23 strains from GBS or enteritis patients as clonal. Overall, genotypes exclusive for enteritis or for GBS-related strains were not obtained although LOS class A was significantly associated with GBS strains. Particularly, the presence of a clonal and putative neuropathogenic C. jejuni HS:23 serotype may contribute to the high prevalence of C. jejuni related GBS in Bangladesh. PMID- 19789650 TI - Impact of the method of G6PD deficiency assessment on genetic association studies of malaria susceptibility. AB - BACKGROUND: Clinical association studies have yielded varied results regarding the impact of glucose-6-phosphate dehydrogenase (G6PD) deficiency upon susceptibility to malaria. Analyses have been complicated by varied methods used to diagnose G6PD deficiency. METHODOLOGY/PRINCIPAL FINDINGS: We compared the association between uncomplicated malaria incidence and G6PD deficiency in a cohort of 601 Ugandan children using two different diagnostic methods, enzyme activity and G6PD genotype (G202A, the predominant East African allele). Although roughly the same percentage of males were identified as deficient using enzyme activity (12%) and genotype (14%), nearly 30% of males who were enzymatically deficient were wild-type at G202A. The number of deficient females was three-fold higher with assessment by genotype (21%) compared to enzyme activity (7%). Heterozygous females accounted for the majority (46/54) of children with a mutant genotype but normal enzyme activity. G6PD deficiency, as determined by G6PD enzyme activity, conferred a 52% (relative risk [RR] 0.48, 95% CI 0.31-0.75) reduced risk of uncomplicated malaria in females. In contrast, when G6PD deficiency was defined based on genotype, the protective association for females was no longer seen (RR = 0.99, 95% CI 0.70-1.39). Notably, restricting the analysis to those females who were both genotypically and enzymatically deficient, the association of deficiency and protection from uncomplicated malaria was again demonstrated in females, but not in males (RR = 0.57, 95% CI 0.37-0.88 for females). CONCLUSIONS/SIGNIFICANCE: This study underscores the impact that the method of identifying G6PD deficient individuals has upon association studies of G6PD deficiency and uncomplicated malaria. We found that G6PD-deficient females were significantly protected against uncomplicated malaria, but this protection was only seen when G6PD deficiency is described using enzyme activity. These observations may help to explain the discrepancy in some published association studies involving G6PD deficiency and uncomplicated malaria. PMID- 19789651 TI - Development and application of microsatellites in Carcinus maenas: genetic differentiation between Northern and Central Portuguese populations. AB - Carcinus maenas, the common shore crab of European coastal waters, has recently gained notoriety due to its globally invasive nature associated with drastic ecological and economic effects. The native ubiquity and worldwide importance of C. maenas has resulted in it becoming one of the best-studied estuarine crustacean species globally. Accordingly, there is significant interest in investigating the population genetic structure of this broadly distributed crab along European and invaded coastlines. Here, we developed polymerase chain reaction (PCR) primers for one dinucleotide and two trinucleotide microsatellite loci, resulting from an enrichment process based on Portuguese populations. Combining these three new markers with six existing markers, we examined levels of genetic diversity and population structure of C. maenas in two coastal regions from Northern and Central Portugal. Genotypes showed that locus polymorphism ranged from 10 to 42 alleles (N = 135) and observed heterozygosity per locus ranged from 0.745 to 0.987 with expected heterozygosity ranging from 0.711 to 0.960; values typical of marine decapods. The markers revealed weak, but significant structuring among populations (global F(ST) = 0.004) across a 450 km (over-water distance) spatial scale. Combinations of these and existing markers will be useful for studying population genetic parameters at a range of spatial scales of C. maenas throughout its expanding species range. PMID- 19789652 TI - Skin electroporation: effects on transgene expression, DNA persistence and local tissue environment. AB - BACKGROUND: Electrical pulses have been used to enhance uptake of molecules into living cells for decades. This technique, often referred to as electroporation, has become an increasingly popular method to enhance in vivo DNA delivery for both gene therapy applications as well as for delivery of vaccines against both infectious diseases and cancer. In vivo electrovaccination (gene delivery followed by electroporation) is currently being investigated in several clinical trials, including DNA delivery to healthy volunteers. However, the mode of action at molecular level is not yet fully understood. METHODOLOGY/PRINCIPAL FINDINGS: This study investigates intradermal DNA electrovaccination in detail and describes the effects on expression of the vaccine antigen, plasmid persistence and the local tissue environment. Gene profiling of the vaccination site showed that the combination of DNA and electroporation induced a significant up regulation of pro-inflammatory genes. In vivo imaging of luciferase activity after electrovaccination demonstrated a rapid onset (minutes) and a long duration (months) of transgene expression. However, when the more immunogenic prostate specific antigen (PSA) was co-administered, PSA-specific T cells were induced and concurrently the luciferase expression became undetectable. Electroporation did not affect the long-term persistence of the PSA-expressing plasmid. CONCLUSIONS/SIGNIFICANCE: This study provides important insights to how DNA delivery by intradermal electrovaccination affects the local immunological responses of the skin, transgene expression and clearance of the plasmid. As the described vaccination approach is currently being evaluated in clinical trials, the data provided will be of high significance. PMID- 19789653 TI - Poly(hydroxyalkanoates)-based polymeric nanoparticles for drug delivery. AB - Poly (hydroxyalkanoates) (PHAs) have recently attracted a great deal of academic and industrial interest for their biodegradability and biocompatibility making them suitable for environmental and biomedical applications. Poly(3 hydroxybutyrate-) (PHB-) and Poly(DL-lactide-co-glycolide) (PLGA-) based nanoparticles were prepared using the dialysis method as yet unreported for the preparation of nanoparticles based on PHB. Processing conditions were varied in order to evaluate their influence on morphology, drug encapsulation, and size of nanoparticles. The relevant results obtained give a theoretical understanding of the phenomenon occurring during colloidal formation. The adopted procedure allows for a relatively small diameter and homogeneity in size distribution of the PHB nanoparticles to be obtained compared to other methods like the one based on solvent evaporation which leads to particles on microscale. The biocompatibility of PHB and relative nanoparticles was investigated and both exhibited very good cytocompatibility. PMID- 19789655 TI - Novel Algorithms for the Identification of Biologically Informative Chemical Diversity Metrics. AB - Despite great advances in the efficiency of analytical and synthetic chemistry, time and available starting material still limit the number of unique compounds that can be practically synthesized and evaluated as prospective therapeutics. Chemical diversity analysis (the capacity to identify finite diverse subsets that reliably represent greater manifolds of drug-like chemicals) thus remains an important resource in drug discovery. Despite an unproven track record, chemical diversity has also been used to posit, from preliminary screen hits, new compounds with similar or better activity. Identifying diversity metrics that demonstrably encode bioactivity trends is thus of substantial potential value for intelligent assembly of targeted screens. This paper reports novel algorithms designed to simultaneously reflect chemical similarity or diversity trends and apparent bioactivity in compound collections. An extensive set of descriptors are evaluated within large NCI screening data sets according to bioactivity differentiation capacities, quantified as the ability to co-localize known active species into bioactive-rich K-means clusters. One method tested for descriptor selection orders features according to relative variance across a set of training compounds, and samples increasingly finer subset meshes for descriptors whose exclusion from the model induces drastic drops in relative bioactive colocalization. This yields metrics with reasonable bioactive enrichment (greater than 50% of all bioactive compounds collected into clusters or cells with significantly enriched active/inactive rates) for each of the four data sets examined herein. A second method replaces variance by an active/inactive divergence score, achieving comparable enrichment via a much more efficient search process. Combinations of the above metrics are tested in 2D rectilinear diversity models, achieving similarly successful colocalization statistics, with metrics derived from the active/inactive divergence score typically outperforming those selected from the variance criterion and computed from the DiverseSolutions software. PMID- 19789654 TI - Olfactory proteins mediating chemical communication in the navel orangeworm moth, Amyelois transitella. AB - BACKGROUND: The navel orangeworm, Amyelois transitella Walker (Lepidoptera: Pyralidae), is the most serious insect pest of almonds and pistachios in California for which environmentally friendly alternative methods of control- like pheromone-based approaches--are highly desirable. Some constituents of the sex pheromone are unstable and could be replaced with parapheromones, which may be designed on the basis of molecular interaction of pheromones and pheromone detecting olfactory proteins. METHODOLOGY: By analyzing extracts from olfactory and non-olfactory tissues, we identified putative olfactory proteins, obtained their N-terminal amino acid sequences by Edman degradation, and used degenerate primers to clone the corresponding cDNAs by SMART RACE. Additionally, we used degenerate primers based on conserved sequences of known proteins to fish out other candidate olfactory genes. We expressed the gene encoding a newly identified pheromone-binding protein, which was analyzed by circular dichroism, fluorescence, and nuclear magnetic resonance, and used in a binding assay to assess affinity to pheromone components. CONCLUSION: We have cloned nine cDNAs encoding olfactory proteins from the navel orangeworm, including two pheromone binding proteins, two general odorant-binding proteins, one chemosensory protein, one glutathione S-transferase, one antennal binding protein X, one sensory neuron membrane protein, and one odorant receptor. Of these, AtraPBP1 is highly enriched in male antennae. Fluorescence, CD and NMR studies suggest a dramatic pH dependent conformational change, with high affinity to pheromone constituents at neutral pH and no binding at low pH. PMID- 19789656 TI - A Sequential Monte Carlo Method for Bayesian Analysis of Massive Datasets. AB - Markov chain Monte Carlo (MCMC) techniques revolutionized statistical practice in the 1990s by providing an essential toolkit for making the rigor and flexibility of Bayesian analysis computationally practical. At the same time the increasing prevalence of massive datasets and the expansion of the field of data mining has created the need for statistically sound methods that scale to these large problems. Except for the most trivial examples, current MCMC methods require a complete scan of the dataset for each iteration eliminating their candidacy as feasible data mining techniques.In this article we present a method for making Bayesian analysis of massive datasets computationally feasible. The algorithm simulates from a posterior distribution that conditions on a smaller, more manageable portion of the dataset. The remainder of the dataset may be incorporated by reweighting the initial draws using importance sampling. Computation of the importance weights requires a single scan of the remaining observations. While importance sampling increases efficiency in data access, it comes at the expense of estimation efficiency. A simple modification, based on the "rejuvenation" step used in particle filters for dynamic systems models, sidesteps the loss of efficiency with only a slight increase in the number of data accesses.To show proof-of-concept, we demonstrate the method on two examples. The first is a mixture of transition models that has been used to model web traffic and robotics. For this example we show that estimation efficiency is not affected while offering a 99% reduction in data accesses. The second example applies the method to Bayesian logistic regression and yields a 98% reduction in data accesses. PMID- 19789658 TI - FORMATOMATIC: a program for converting diploid allelic data between common formats for population genetic analysis. AB - There has been a great increase in both the number of population genetic analysis programs and the size of data sets being studied with them. Since the file formats required by the most popular and useful programs are variable, automated reformatting or conversion between them is desirable. formatomatic is an easy to use program that can read allelic data files in genepop, raw (csv) or convert formats and create data files in nine formats: raw (csv), arlequin, genepop, immanc/bayesass +, migrate, newhybrids, msvar, baps and structure. Use of formatomatic should greatly reduce time spent reformatting data sets and avoid unnecessary errors. PMID- 19789657 TI - Regional White Matter Signal Abnormalities and Cognitive Correlates Among Geriatric Patients with Treated Cardiovascular Disease. AB - The purpose of this study was to investigate the relations between regional white matter signal abnormalities (WMSA) and cognitive functioning among individuals being treated for cardiovascular risk factors and/or clinical events. Forty-one participants with cardiovascular disease underwent a comprehensive neuropsychological assessment and MRI. Total WMSAs were quantified using a semi automated thresholding technique. Unique to this study, total WMSA volume was divided into three separate anatomically related regions: WMSA in the periventricular (PERIWMSA) region, WMSA adjacent to subcortical nuclei (SUBWMSA), and WMSA in the deep white matter (DEEPWMSA). A ratio of these measures to total cerebral brain volume was compared to cognitive measures assessing attention, executive functioning, psychomotor speed, immediate and delayed memory, language, and visuospatial functioning. PERIWMSA, SUBWMSA, and total WMSA were significantly associated with performance on measures of attention/processing speed. No other significant relationships between WMSA and cognition were noted. Secondary analyses suggested that PERIWMSA volume was increased in individuals with clinical evidence of atherosclerosis. These results emphasize the utility of studying the associations between regional WMSA and cognitive/functional performance in patients undergoing cardiovascular treatment. PMID- 19789659 TI - The effects of lubricant eye drops on visual function as measured by the Inter blink interval Visual Acuity Decay test. AB - OBJECTIVE: The purpose of the current study was to evaluate the effects of two marketed ocular lubricants on the visual decay in dry eye patients using the Inter-blink interval Visual Acuity Decay (IVAD) test. METHODS: This controlled, randomized, double-masked crossover study compared the effects of a polyethylene glycol/propylene glycol-based (PEG/PG) tear and a carboxymethylcellulose sodium (CMC)/glycerin tear on the visual acuity decay between blinks of dry eye patients. At visit 1 (Day 0), baseline IVAD measurements were recorded prior to instillation of a single drop of randomized study medication. IVAD testing was repeated at 15-, 45-, and 90-minutes post-instillation. Reading rate and functional blink rate were also evaluated. At the second visit (Day 7 +/- 3), study procedures were repeated using crossover treatment. RESULTS: Forty-eight (48) subjects with dry eye (61.1 +/- 14.8 years old, 79.2% female, 95.8% white) completed the study. Treatment with the PEG/PG-based tear demonstrated statistically significantly longer time to one-line loss of best-corrected visual acuity (BCVA) as determined by the IVAD test at 90 minutes post-instillation compared to the CMC/glycerin tear (P = 0.0365). Measurements of median time at BCVA, reading rate, and functional blink rate were similar for both treatments. Both formulations were well tolerated in the population studied. CONCLUSIONS: Treatment with the PEG/PG-based tear demonstrated statistically significant improved maintenance of visual acuity between blinks at 90 minutes post instillation compared to the CMC/glycerin tear. This is the first study to demonstrate the ability of an artificial tear to extend visual acuity maintenance between blinks, as measured by the IVAD test. PMID- 19789661 TI - A case of intractable infectious keratitis and subsequent flap necrosis after laser in situ keratomileusis. AB - We report on a patient in whom intractable infectious keratitis and subsequent lamellar flap necrosis necessitating flap amputation after laser in situ keratomileusis (LASIK). A 34-year-old woman undergoing LASIK complained of blurred vision and pain in the left eye. The best spectacle-corrected visual acuity was 0.01, and slit-lamp examination showed a marked presence of stromal infiltrates involving the flap and the underlying stroma in that eye. The patient was treated topically with hourly instillation of micronomicin, levofloxacin, and cefmenoxime, together with systemic administration of imipenem, but the left eye developed corneal flap necrosis. We performed surgical debridement of the diseased stroma and excised the lamellar flap. Since nontuberculous mycobacterium was detected on the surgical instruments, we then added oral clarithromycin, and substituted systemic administration of amikacin with that of imipenem. At one month after the flap removal, the visual acuity gradually improved to 0.7, but the stromal opacity of the central cornea and hyperopic shift of +3.0 diopters remained. LASIK can cause intractable keratitis, resulting in significant visual disturbance that presumably results from insufficient antisepsis of the medical instruments used for this surgery, supporting the importance of strict sterilization of these instruments. PMID- 19789660 TI - Impact of antibiotic resistance in the management of ocular infections: the role of current and future antibiotics. AB - PURPOSE: This article reviews the effects of the increase in bacterial resistance on the treatment of ocular infections. DESIGN: Interpretive assessment. METHODS: Literature review and interpretation. RESULTS: Ocular bacterial infections include conjunctivitis, keratitis, endophthalmitis, blepharitis, orbital cellulitis, and dacryocystitis. Treatment for most ocular bacterial infections is primarily empiric with broad-spectrum antibiotics, which are effective against the most common bacteria associated with these ocular infections. However, the widespread use of broad-spectrum systemic antibiotics has resulted in a global increase in resistance among both Gram-positive and Gram-negative bacteria to a number of the older antibiotics as well as some of the newer fluoroquinolones used to treat ophthalmic infections. Strategies for the prevention of the increase in ocular pathogen resistance should be developed and implemented. In addition, new antimicrobial agents with optimized pharmacokinetic and pharmacodynamic properties that have low toxicity, high efficacy, and reduced potential for the development of resistance are needed. CONCLUSIONS: New antimicrobial agents that treat ocular infections effectively and have a low potential for the development of resistance could be a part of strategies to prevent the global increase in ocular pathogen resistance. PMID- 19789662 TI - Peripheral T-cell lymphoma of the eyelid. AB - PURPOSE: To report a case of a 25-year-old woman with previously treated peripheral T-cell lymphoma (PTCL) presenting with a recurrent lower eyelid lesion. PATIENTS AND METHOD: Case report. RESULTS: A 25-year-old young woman with previously treated PTCL noted an induration in the skin of her left lower eyelid. Upon diagnosis of a chalazion, antibiotic eye drops and ointments as well as steroid eye drops were administered. However, the condition worsened rapidly and swelling of the lower eyelid became remarkable. An excisional biopsy revealed that the palpebral lesion was diagnosed as recurrence of PTCL. Electron irradiation was applied as a radical treatment, and the prognosis was satisfactory without recurrence at 10 months after the last irradiation. CONCLUSIONS: Although lymphoma isolated to the ocular adnexa is rare, it should always be included in the differential diagnosis of any patient presenting with progressive swelling of the eyelid or ocular region. PMID- 19789664 TI - Endoscopic thyroidectomy: Our technique. AB - Minimally invasive surgery is widely employed for the treatment of thyroid diseases. Several minimal access approaches to the thyroid gland have been described. The commonly performed surgeries have been endoscopic lobectomies. We have performed endoscopic total thyroidectomy by the anterior chest wall approach. In this study, we have described our technique and evaluated the feasibility and efficacy of this procedure. MATERIALS AND METHODS: From June 2005 to August 2006, 15 cases of endoscopic thyroidectomy were done at our institute. Five patients were male and 10 were female. Mean age was 45 years. (Range 23 to 71 years). Four patients had multinodular goiter and underwent near-total thyroidectomy; four patients had follicular adenoma and underwent hemithyroidectomy. Out of the seven patients of papillary carcinoma, four were low-risk and so a hemithyroidectomy was performed while three patients in the high risk group underwent total thyroidectomy. A detailed description of the surgical technique is provided. RESULTS: The mean nodule size was 48 mm (range 20 80 mm) and the mean operating time was 85 min (range 60-120 min). In all cases, the recurrent laryngeal nerve was identified and preserved intact, the superior and inferior parathyroids were also identified in all patients. No patients required conversion to an open cervicotomy. All patients were discharged the day after surgery. All thyroidectomies were completed successfully. No recurrent laryngeal nerve palsies or postoperative tetany occurred. The postoperative course was significantly less painful and all patients were satisfied with the cosmetic results. CONCLUSIONS: It is possible to remove large nodules and perform as well as total thyroidectomies using our endoscopic approach. It is a safe and effective technique in the hands of an appropriately trained surgeon. The patients get a cosmetic benefit without any morbidity. PMID- 19789666 TI - Recurrent achalasia after Heller-Toupet procedure: Laparoscopic extended redo heller myotomy and floppy Dor. AB - Recurrences of symptoms after the surgery for achalasia cardia are not uncommon. There are several causes of recurrences but the early recurrences are speculated to be secondary to incomplete myotomy and late recurrence due to fibrosis after the myotomy or megaesophagus. These recurrences can be managed by regular dilation failing which a redo surgery is indicated. Laparoscopic approach is now standard because of the obvious benefits for patients and surgeons. Extent of myotomy and addition of fundoplication are debatable issue in the management of achalasia cardia but evidence suggests that some kind of fundoplication would be necessary after the complete division of lower esophageal sphincter. We present our experience in a case of recurrent achalasia, secondary to incomplete myotomy managed laparoscopically by extended myotomy and a floppy anterior fundoplication. Patient is asymptomatic six months after the surgery and radiologically there is free passage of barium in the stomach. PMID- 19789663 TI - Laparoscopic incisional and ventral hernia repair. AB - BACKGROUND: It has been more than a decade, since the introduction of laparoscopic management of ventral and incisional hernia. The purpose of this article was to systematically review the literature, analyze the results of Laparoscopic repair of ventral and incisional hernia and to ascertain its role. MATERIALS AND METHODS: Pubmed was used for identifying the original articles. Both incisional and ventral hernia repair were included. Out of 145 articles extracted from Pubmed, 34 original studies were considered for review. More than three thousand patients were included in the review. Variables analyzed in the review were inpatient stay, defect size, mesh size, hematoma, seroma, wound infection, bowel perforation, obstruction, ileus, recurrence and pain. Qualitative analysis of the variables was carried out. RESULTS: Seromas (5.45%) and post operative pain (2.75%) are the two common complications associated with this procedure. Recurrence rate was found to be 3.67%. Overall complication rate was 19.24%, with two deaths reported. CONCLUSION: The results suggest laparoscopic repair of ventral and incisional hernia as an effective procedure. Faster recovery and shorter in patient stay - makes it a feasible alternative to open repair. PMID- 19789665 TI - Influence of obesity on the short-term outcome of laparoscopic colectomy for colorectal cancer. AB - PURPOSE: Obesity has been generally associated with increased surgical risk. However, data on the outcome of laparoscopic colectomy in obese and non-obese patients are controversial. The aim of this study is to assess the short-term outcome of laparoscopic colectomy for colorectal cancer (CRC) in obese patients as compared with non-obese patients. MATERIALS AND METHODS: Sixty-nine patients who underwent laparoscopic anterior resection for CRC during the past six years were retrospectively evaluated. The patients with CRC involving the sigmoid or rectosigmoid colon and subjected to intracorporeal anastomosis were included in this study. They were divided into three groups according to body mass index (BMI): obese (BMI >/= 28.0 kg/m(2)), pre-obese (BMI: 25.0-27.9 kg/m(2)) and non obese (BMI < 25.0 kg/m(2)). RESULTS: Nine patients (13.0%) were obese, 11 patients (15.9%) were pre-obese and 49 patients (71.1%) were non-obese. Patient characteristics, such as age, gender, tumor location, previous laparotomy, were similar among the three groups. There were no significant differences in operative time, blood loss, intraoperative complications and conversion rates. Postoperative complications and duration of postoperative hospital stay were also similar among the three groups. However, two of the three patients in the pre obese group had to be operated on again due to incarceration of the small bowel into a port site. CONCLUSIONS: Laparoscopic colectomy can be safely performed in obese patients with short-term results similar to those obtained in non-obese and pre-obese patients. PMID- 19789667 TI - Left-sided gall bladder: Report of two cases. AB - Left-sided gall bladder without situs inversus viscerum is a rare albeit recognized clinical entity. We report our experience of two cases of left-sided gall bladder in two women aged 36 and 48 who underwent laparoscopic cholecystectomy for chronic calculous cholecystitis. Left-sided gall bladder may provide an unusual surprise to the surgeons during laparoscopy as routine pre operative studies may not always detect the anomaly. Awareness of the unpredictable confluence of the cystic duct into the common bile duct (CBD) and selective use of intraoperative cholangiography aid in the safe laparoscopic management of this unusual entity. PMID- 19789669 TI - Antegrade common bile duct (CBD) stenting after laparoscopic CBD exploration. PMID- 19789668 TI - Laparoscopic redo fundoplication for intrathoracic migration of wrap. AB - Laparoscopic fundoplication is fast emerging as the treatment of choice of gastro esophageal reflux disease. However, a complication peculiar to laparoscopic surgery for this disease is the intrathoracic migration of the wrap. This article describes a case of a male patient who developed this particular complication after laparoscopic total fundoplication. Following a trauma, wrap migration occurred. The typical history and symptomatology is described. The classical Barium swallow picture is enclosed. Laparoscopic redo fundoplication was carried out. The difficulties encountered are described. Postoperative wrap migration can be suspected clinically by the presence of a precipitating event and typical symptomatology. Confirmation is by a Barium swallow. Treatment is by redo surgery. PMID- 19789670 TI - Kurt Semm: A laparoscopic crusader. PMID- 19789671 TI - Thoracoscopic surgery. PMID- 19789672 TI - Thoracoscopic excision of mediastinal cysts in children. AB - AIM: Thoracoscopy offers great advantages when compared with open surgery in terms of postoperative pain and pulmonary complications. Considering the benign nature of most of the mediastinal cysts, thoracoscopy is safe and feasible with minimal morbidity. The purpose of this article is to review our experience with four cases of mediastinal cysts resected successfully within a period of one year by thoracoscopy. MATERIALS AND METHODS: The cases of mediastinal cysts operated by thoracoscopic excision in K.E.M. Hospital, Mumbai from November 2005 to December 2006 were reviewed. The age varied from six months to 10 years. The patients presented with respiratory distress or recurrent lower respiratory tract infection. All patients underwent Chest X-ray and CT scan thorax to delineate the location of the cyst and its relationship with adjacent vital structures. Two patients had anterior and two had posterior mediastinal cyst. The ports were placed depending on the location of the cyst on the CT scan, following the principles of triangularization. The cysts were excised mainly by blunt dissection. RESULTS: All the patients were successfully managed by thoracoscopic surgery. None of them had intraoperative complications. Dissection in patient with history of recurrent respiratory tract infection was difficult because of adhesions. Intercostal drain was removed within 48hrs and the patients were discharged on the fourth postoperative day. CONCLUSIONS: Thoracoscopy in mediastinal cysts is a safe and effective procedure with low morbidity and a shorter hospital stay. PMID- 19789673 TI - Anesthesia for thoracoscopic surgery. AB - Anesthesia for thoracoscopy is based on one lung ventilation. Lung separators in the airway are essential tools. An anatomical shunt as a result of the continued perfusion of a non-ventilated lung is the principal intraoperative concern. The combination of equipment, technique and process increase risks of hypoxia and dynamic hyperinflation, in turn, potential factors in the development of an unusual form of pulmonary edema. Analgesia management is modelled on that shown effective and therapeutic for thoracotomy. Perioperative management needs to reflect the concern for these complex, and complicating, processes to the morbidity of thoracoscopic surgery. PMID- 19789674 TI - Endoscopic thoracic sympathectomy for hyperhidrosis: Technique and results. AB - OUTLINE: We review the clinical features of hyperhidrosis and the range of treatments used for this condition. We describe in detail the technique of endoscopic sympathectomy. We summarize studies that have reported results of endoscopic sympathectomy. We present new data highlighting the difference in quality of life between patients with hyperhidrosis and controls. PMID- 19789675 TI - Thoracoscopic management of empyema thoracis. AB - Appropriate management of empyema thoracis is dependent upon a secure diagnosis of the etiology of empyema and the phase of development. Minimal access surgery using video-assisted thoracoscopy (VATS) is one of many useful techniques in treating empyema. Complex empyema requires adjunctive treatment in addition to VATS. PMID- 19789676 TI - Thoracoscopic resection for esophageal cancer: A review of literature. AB - Esophageal resection remains the only curative option in high grade dysplasia of the Barrett esophagus and non metastasized esophageal cancer. In addition, it may also be an adequate treatment in selected cases of benign disease. A wide variety of minimally invasive procedures have become available in esophageal surgery. Aim of the present review article is to evaluate minimally invasive procedures for esophageal resection, especially the approach performed through right thoracoscopy. PMID- 19789677 TI - Video assisted thoracic surgery in children. AB - Thoracoscopic surgery, i.e., video assisted thoracic surgery (VATS) has been in use in children for last 98 years. Its use initially was restricted to the diagnostic purposes. However, with the improvement in the optics, better understanding of the physiology with CO2 insufflation, better capabilities in achieving the single lung ventilation and newer vessel sealing devices have rapidly expanded the spectrum of the indication of VATS. At present many complex lung resections, excision of mediastinal tumors are performed by VATS in the experienced centre. The VATS has become the standard of care in empyema, lung biopsy, Mediastinal Lymphnode biopsy, repair of diaphragmatic hernia, etc. The article discusses the indications of VATS, techniques to achieve the selective ventilation and surgical steps in the different surgical conditions in children. PMID- 19789678 TI - Technique of the transcervical-subxiphoid-videothoracoscopic maximal thymectomy. AB - BACKGROUND: The aim of this study is to present the new technique of transcervical-subxiphoid-videothoracoscopic "maximal"thymectomy introduced by the authors of this study for myasthenia gravis. MATERIALS AND METHODS: Two hundred and sixteen patients with Osserman scores ranging from I-III were operated on from 1/9/2000 to 31/12/2006 for this study. The operation was performed through four incisions: a transverse 5-8 cm incision in the neck, a 4-6 cm subxiphoid incision and two 1 cm incisions for videothoracoscopic (VTS) ports. The cervical part of the procedure was performed with an open technique while the intrathoracic part was performed using a video assisted thoracoscopic surgical (VATS) technique. The whole thymus with the surrounding fatty tissue containing possible ectopic foci of the thymic tissue was removed. Such an operation can be performed by one surgical team (the one team approach) or by two teams working simultaneously (two team approach). The early and late results as well as the incidence and localization of ectopic thymic foci have been presented in this report. RESULTS: There were 216 patients in this study of which 178 were women and 38 were men. The ages of the patients ranged from 11 to 69 years (mean 29.7 years). The duration of myasthenia was 2-180 months (mean 28.3 months). Osserman scores were in the range of I-III. Almost 27% of the patients were taking steroids or immunosuppressive drugs preoperatively. The mean operative time was 201.5 min (120-330 min) for a one-team approach and it was 146 (95-210 min) for a two-team approach (P < 0.05). While there was no postoperative mortality, the postoperative morbidity was 12%. The incidence of ectopic thymic foci was 68.4%. The rates of complete remission after one, two, three, four and five years of follow-up were 26.3, 36.5, 42.9, 46.8 and 50.2%, respectively. CONCLUSION: Transcervical-subxiphoid-VTS maximal thymectomy is a complete and highly effective treatment modality for myasthenia gravis. The need for sternotomy is avoided while the completeness of the operation is retained. PMID- 19789679 TI - (Video Assisted) thoracoscopic surgery: Getting started. AB - Thoracoscopic surgery without or with video assistance (VATS) is simpler and easier to learn as it seems to be. Potential benefits of the procedure in rural surgical environment are outlined while basic requirements and limitations are listed. Thoracoscopy kit, thoracotomy tray at hand, patient monitoring, proper drainage system, pain control and access to chest physiotherapy are the basic requirements. Having headlight, bronchoscope, Ligasure and mechanical staplers offer clear advantages but they are not indispensable. Exploration and evacuation of pleural space, pleurodesis, surgery for Stage I and II thoracic empyema are evidenced fields of VATS procedures. Some of the cases can be performed under controlled local anesthesia. Acute chest trauma cannot be recommended for VATS treatment. Lung cancer is out of the scope of rural surgery. PMID- 19789680 TI - Empyema gall bladder and laparoscopic cholecystectomy. PMID- 19789681 TI - Authors' reply. PMID- 19789682 TI - CT angiography, underuse, overuse, or appropriate use? PMID- 19789683 TI - Oxygen uptake in heart failure: how much, how fast? PMID- 19789684 TI - In-hospital mortality and three-year survival after repaired acute type A aortic dissection. AB - Background. The results of acute type A dissection (AAD) surgery in the Netherlands are largely unknown, as was recently stated in a report by the Health Council of the Netherlands. In order to gain more insight into the Dutch situation we investigated predictors of in-hospital mortality of surgically treated AAD patients and assessed threeyear survival.Methods. 104 consecutive patients undergoing surgery for AAD in a 16-year period (1990-2006) were evaluated. Preoperative and intraoperative variables were analysed to identify predictors of early mortality.Results. Preoperative malperfusion (limb ischaemia or mesenteric ischaemia) was present in 15.4%, shock in 18.3%, and 6.7% were operated under cardiac massage. Marfan syndrome was present in four patients and four patients had a bicuspid aortic valve. In-hospital mortality was 22.1%. Seven patients died intraoperatively; other causes of inhospital mortality were major brain damage in ten patients, multiple organ failure in three patients, low cardiac output in two patients and sudden cardiac death in one patient. Multivariate logistic regression revealed preoperative malperfusion (p=0.004) to be the only independent predictor of in-hospital mortality. Three-year survival was 68.8+/-4.7% (including hospital mortality). Hospital survivors had a three year survival of 88.3+/-3.9%.Conclusion. In-hospital mortality of our patients (22.1%) is comparable with the results of larger case series published in the literature. Prognosis after successful surgical treatment is relatively good with a three-year survival of 88.3% in our series. (Neth Heart J 2009;17:226-31.). PMID- 19789685 TI - Cardiac assessment of patients with late stage Duchenne muscular dystrophy. AB - Background. Duchenne muscular dystrophy (DMD) patients used to die mainly from pulmonary problems. However, as advances in respiratory care increase life expectancy, mortality due to cardiomyopathy rises. Echocardiography remains the standard diagnostic modality for cardiomyopathy in DMD patients, but is hampered by scoliosis and poor echocardiographic acoustic windows in adult DMD patients. Multigated cardiac radionuclide ventriculography (MUGA) does not suffer from these limitations. N-terminal proBNP (NTproBNP) has shown to be a diagnostic factor for heart failure. We present our initial experience with plasma NT-proBNP measurement in the routine screening and diagnosis of cardiomyopathy in adult mechanically ventilated DMD patients.Methods. Retrospective study, 13 patients. Echocardiography classified left ventricular (LV) function as preserved or depressed. NT-proBNP was determined using immunoassay. LV ejection fraction (LVEF) was determined using MUGA.Results. Median (range) NT-proBNP was 73 (25 to 463) ng/l. Six patients had an NT-proBNP >125 ng/l. Seven patients showed an LVEF <45% on MUGA. DMD patients with depressed LV function (n=4) as assessed by echocardiography had significantly higher median NT-proBNP than those (n=9) with preserved LV function: 346 (266 to 463) ng/l versus 69 (25 to 257) ng/l (p=0.003). NT-proBNP significantly correlated with depressed LV function on echocardiogram and with LVEF determined by MUGA.Conclusion. Although image quality of MUGA is superior to echocardiography, the combination of echocardiography and NT-proBNP achieves similar results in the evaluation of left ventricular function and is less time consuming and burdensome for our patients. We advise to add NT-proBNP to echocardiography in the routine cardiac assessment of DMD patients. (Neth Heart J 2009;17:232-7.). PMID- 19789686 TI - Oxygen uptake kinetics in chronic heart failure: clinical and physiological aspects. AB - One of the hallmark symptoms of patients with chronic heart failure (CHF) is exercise intolerance. Therefore, exercise testing has become an important tool for the evaluation and monitoring of heart failure. Whereas the maximal aerobic capacity (peak VO(2)) is a reliable indicator of the severity and prognosis of heart failure, submaximal exercise parameters may be more closely related to the ability to perform daily activities. As such, oxygen (O(2)) uptake kinetics, describing the rate change of O(2) uptake during onset or recovery of submaximal constant-load exercise (O(2) onset and recovery kinetics, respectively), have been shown to be useful parameters for objectively evaluating the functional capacity of CHF patients. However, their evaluation in this population is not a routine part of daily clinical practice. Possible reasons for this include a lack of standardisation of the assessment methodology and a limited number of studies evaluating the clinical use of O(2) uptake kinetics in CHF patients. In addition, the pathophysiological mechanisms underlying the delay in O(2) uptake kinetics in these patients are not completely understood. This review discusses the current literature on the clinical potency and physiological determinants of O(2) uptake kinetics in CHF patients and provides directions for future research. (Neth Heart J 2009;17:238-44.Neth Heart J 2009;17:238-44.). PMID- 19789687 TI - Usefulness of remote magnetic navigation for ablation of ventricular arrhythmias originating from outflow regions. AB - Monomorphic ventricular tachycardia (VT) and symptomatic monomorphic PVCs originating from the region of the right and left outflow tracts are increasingly treated by radiofrequency (RF) catheter ablation. Technical difficulties in catheter manipulation to access these outflow tract areas, very accurate mapping and reliable catheter stability are key issues for a successful treatment in this vulnerable region. VT ablation from the aortic sinus cusp (ASC) in particular carries a significant risk of perforation, of creating left coronary artery injury and of damage to the aorta and the aortic valve.This case series describes RF ablation of VT originating in the outflow region using the remote magnetic navigation system (MNS). Potential advantages of the MNS are catheter flexibility, steering accuracy and reproducibility to navigate to a desired location with a low probability of perforating the myocardium. This report supports the idea of using advanced MNS technology during RF ablation in regions which are difficult to reach and thin walled, such as parts of the outflow tract and the ASC. (Neth Heart J 2009;17:245-9.). PMID- 19789688 TI - Stimulation of the brachial plexus by a dislocated ICD lead: a rare complication. PMID- 19789689 TI - Einthoven dissertation prize 2009. PMID- 19789690 TI - A genome wide association analysis in the GENDER study. AB - Percutaneous coronary intervention (PCI) has become an effective therapy to treat coronary artery diseases. However, one of the major drawbacks of PCI is the occurrence of restenosis in 8 to 40% of all treated patients. The GENetic Determinants of Restenosis (GENDER) project was designed to study the association between genetic polymorphisims and clinical restenosis. The discovery of genetic variants associated to the occurrence of restenosis after PCI may provide a more tailored therapy and may serve as rationale for new antirestenotic therapies. So far, several candidate gene approaches had already been performed in the GENDER samples but a Genome Wide Association Scan (GWAS) was still lacking. Here, we present preliminary results from the GWAS we are currently carrying out in the GENDER population. (Neth Heart J 2009;17:262-4.). PMID- 19789691 TI - Humanise basic research in cardiology from here! PMID- 19789692 TI - Case histories: increasing role for major journals. PMID- 19789693 TI - Primary percutaneous coronary intervention in the left main stem of a monocoronary artery. AB - In a 71-year-old female with evolving anterior wall myocardial infarction, coronary angiography revealed a monocoronary artery which arose from the right sinus of Valsalva. Originating from a short common trunk, the left main stem showed a thrombotic lesion that occluded the left anterior descending coronary artery while the circumflex artery was obstructed. Intracoronary administration of abciximab, followed by stenting of the transition between the left anterior descending coronary artery and the main stem, and final kissing balloon inflation of the bifurcation resulted in an excellent angiographic result and favourable clinical outcome. (Neth Heart J 2009;17:274-6.). PMID- 19789694 TI - Capecitabine-induced cardiotoxicity mimicking myocardial infarction. AB - Capecitabine, a fluoropyrimidine derivative, is an orally administered drug that delivers 5-fluorouracil (5-FU) selectively to the tumour. The drug has demonstrated activity in metastatic colorectal cancer. We describe a male patient receiving capecitabine therapy with typical chest pain and electrocardiographic changes consistent with STsegment elevation myocardial infarction. Capecitabine induced cardiotoxicity may develop in patients who have had a previous episode of 5-FU-induced cardiotoxicity. Capecitabine-induced cardiotoxicity is a rare condition that may lead to diagnostic and therapeutic dilemmas. (Neth Heart J 2009;17:277-80.). PMID- 19789695 TI - Giant cell arteritis as a cardiovascular entity. AB - Giant cell arteritis (GCA) is a relatively infrequent disorder that is underdiagnosed and little appraised in the field of general cardiology. However, it is important to be familiar with the clinical picture of this disease, especially because of the risk of developing fatal aortic aneurysms. If the disease is suspected after a thorough history and clinical examination combined with laboratory investigation, the diagnosis can be confirmed with (18)F-2-deoxy glucose positron emission tomographic (FDG-PET) imaging. Early recognition of giant cell arteritis followed by prompt treatment with glucocorticosteroids will decrease the risk of developing large-vessel complications. (Neth Heart J 2009;17:281-3.). PMID- 19789696 TI - Acute myocardial infarction complicating subarachnoid haemorrhage. AB - An acute myocardial infarction is a rare complication of a subarachnoid haemorrhage. The combination of these two conditions imposes important treatment dilemmas. We describe two patients with this combination of life-threatening conditions. Patient 1 was treated with emergency percutaneous coronary intervention followed by clipping of the anterior communicating artery aneurysm. Six months after discharge the patient's memory and orientation had almost completely recovered. Patient 2 was treated with aspirin until coiling of the aneurysm could be performed. After successful coiling low-molecular-weight heparin was added. One week later the patient died due to a free wall rupture. (Neth Heart J 2009;17:284-7.). PMID- 19789697 TI - Acute chest pain in a patient treated with capecitabine. AB - A 61-year-old male with a history of metastatic colorectal cancer was referred to our hospital for primary coronary intervention because of acute ST-elevation myocardial infarction. Coronary angiography, however, revealed no significant stenoses. When asked, the patient revealed that capecitabine (Xeloda(R)) was started by his oncologist one day before admission. It is known that this oral 5 FU analogue drug, used in metastatic colorectal cancer, can cause coronary artery spasms. The main treatment of capecitabine-induced vasospasm is discontinuation of the drug. Indeed, after cessation of the drug the patient remained free of symptoms and the ECG abnormalities normalised. (Neth Heart J 2009;17:288-91.). PMID- 19789698 TI - Combining noninvasive anatomical imaging with invasive functional information: an unconventional but appropriate hybrid approach. AB - CT coronary angiography (CTCA) allows accurate noninvasive imaging of the coronary arteries. As illustrated by this case report, the threedimensional information provided by this technique might be of value to resolve complex coronary pathology encountered in the cathlab. However, the limitations inherent to an anatomical test also apply for CTCA, and bring in the need for functional information to ensure adequate patient management. (Neth Heart J 2009;17:292-4.). PMID- 19789699 TI - Thrombotic occlusion of the ostial left main coronary artery in a patient with acute coronary syndrome. AB - Ostial left main coronary artery (LMCA) occlusion is rarely seen in patients with acute coronary syndrome. Acute coronary syndrome resulting from an LMCA occlusion is associated with a significant morbidity and mortality rate, if it is managed with fibrinolysis. Electrocardiography can predict LMCA occlusion in patients with acute coronary syndrome. We report a 52-year-old male who presented with acute coronary syndrome and ostial LMCA occlusion. (Neth Heart J 2009;17:295-6.). PMID- 19789700 TI - Acute myocardial infarction due to coronary artery embolism in a patient with atrial fibrillation. AB - A 66-year-old female was referred for primary coronary intervention because of acute inferior STelevation myocardial infarction. Electrocardiography also showed atrial fibrillation. Coronary angiography showed a distal occlusion of the right coronary artery. Two different wires did not pass the occlusion, but dislodged the apparent thrombus more distally. No abnormalities were seen in the course of the recanalised part of the vessel. The sequential angiographic images together with the presence of atrial fibrillation are highly suggestive of coronary embolism as the cause of the myocardial infarction. Anticoagulation and rate control strategy was initiated. The patient was discharged in good condition. (Neth Heart J 2009;17:297-9.). PMID- 19789701 TI - Tandem aneurysms of an internal mammary-aortocoronary bypass graft. AB - Graft aneurysms following aortocoronary surgery are a rare occurrence in clinical practice. Reported cases have mostly involved saphenous vein grafts. Here we report the rare finding of a tandem aneurysm of an internal mammary artery graft which was incidentally detected 17 years following bypass surgery. (Neth Heart J 2009;17:300-2.). PMID- 19789702 TI - Kawasaki disease causing saccular aneurysms of the coronary arteries. PMID- 19789703 TI - An example of late regression of in-stent restenosis after bare metal coronary stenting. PMID- 19789704 TI - Analysis of cancer mutation signatures in blood by a novel ultra-sensitive assay: monitoring of therapy or recurrence in non-metastatic breast cancer. AB - BACKGROUND: Tumor DNA has been shown to be present both in circulating tumor cells in blood and as fragments in the plasma of metastatic cancer patients. The identification of ultra-rare tumor-specific mutations in blood would be the ultimate marker to measure efficacy of cancer therapy and/or early recurrence. Herein we present a method for detecting microinsertions/deletions/indels (MIDIs) at ultra-high analytical selectivity. MIDIs comprise about 15% of mutations. METHODS AND FINDINGS: We describe MIDI-Activated Pyrophosphorolysis (MAP), a method of ultra-high analytical selectivity for detecting MIDIs. The high analytical selectivity of MAP is putatively due to serial coupling of two rare events: heteroduplex slippage and mis-pyrophosphorolysis. MAP generally has an analytical selectivity of one mutant molecule per >1 billion wild type molecules and an analytical sensitivity of one mutant molecule per reaction. The analytical selectivity of MAP is about 100,000-fold better than that of our previously described method of Pyrophosphorolysis Activated Polymerization-Allele specific amplification (PAP-A) for detecting MIDIs. The utility of this method is illustrated in two ways. 1) We demonstrate that two EGFR deletions commonly found in lung cancers are not present in tissue from four normal human lungs (10(7) copies of gDNA each) or in blood samples from 10 healthy individuals (10(7) copies of gDNA each). This is inconsistent, at least at an analytical sensitivity of 10(-7), with the hypotheses of (a) hypermutation or (b) strong selection of these growth factor-mutated cells during normal lung development leads to accumulation of pre-neoplastic cells with these EGFR mutations, which sometimes can lead to lung cancer in late adulthood. Moreover, MAP was used for large scale, high throughput "gene pool" analysis. No germline or early embryonic somatic mosaic mutation was detected (at a frequency of >0.3%) for the 15/18 bp EGFR deletion mutations in 6,400 individuals, suggesting that early embryonic EGFR somatic mutation is very rare, inconsistent with hypermutation or strong selection of these deletions in the embryo. 2) The second illustration of MAP utility is in personalized monitoring of therapy and early recurrence in cancer. Tumor-specific p53 mutations identified at diagnosis in the plasma of six patients with stage II and III breast cancer were undetectable after therapy in four women, consistent with clinical remission, and continued to be detected after treatment in two others, reflecting tumor progression. CONCLUSIONS: MAP has an analytical selectivity of one part per billion for detection of MIDIs and an analytical sensitivity of one molecule. MAP provides a general tool for monitoring ultra-rare mutations in tissues and blood. As an example, we show that the personalized cancer signature in six out of six patients with non-metastatic breast cancer can be detected and that levels over time are correlated with the clinical course of disease. PMID- 19789705 TI - Subcellular Min oscillations as a single-cell reporter of the action of polycations, protamine, and gentamicin on Escherichia coli. AB - BACKGROUND: In Escherichia coli, MinD-GFP fusion proteins show rapid pole to pole oscillations. The objective was to investigate the effects of extracellular cations on the subcellular oscillation of cytoplasmic MinD within Escherichia coli. METHODOLOGY/PRINCIPAL FINDINGS: We exposed bacteria to the extracellular cations Ca(++), Mg(++), the cationic antimicrobial peptide (CAP) protamine, and the cationic aminoglycoside gentamicin. We found rapid and substantial increases in the average MinD oscillation periods in the presence of any of these polyvalent cations. For Ca(++) and Mg(++) the increases in period were transient, even with a constant extracellular concentration, while increases in period for protamine or gentamicin were apparently irreversible. We also found striking interdependence in the action of the small cations with protamine or gentamicin, distorted oscillations under the action of intermediate levels of gentamicin and Ca(++), and reversible freezing of the Min oscillation at high cationic concentrations. CONCLUSIONS/SIGNIFICANCE: Intracellular Min oscillations provide a fast single-cell reporter of bacterial response to extracellular polycations, which can be explained by the penetration of polycations into cells. PMID- 19789706 TI - The human frontal oculomotor cortical areas contribute asymmetrically to motor planning in a gap saccade task. AB - BACKGROUND: Saccadic eye movements are used to rapidly align the fovea with the image of objects of interest in peripheral vision. We have recently shown that in children there is a high preponderance of quick latency but poorly planned saccades that consistently fall short of the target goal. The characteristics of these multiple saccades are consistent with a lack of proper inhibitory control of cortical oculomotor areas on the brainstem saccade generation circuitry. METHODOLOGY/PRINCIPAL FINDINGS: In the present paper, we directly tested this assumption by using single pulse transcranial magnetic stimulation (TMS) to transiently disrupt neuronal activity in the frontal eye fields (FEF) and supplementary eye fields (SEF) in adults performing a gap saccade task. The results showed that the incidence of multiple saccades was increased for ispiversive but not contraversive directions for the right and left FEF, the left SEF, but not for the right SEF. Moreover, this disruption was most substantial during the approximately 50 ms period around the appearance of the peripheral target. A control condition in which the dorsal motor cortex was stimulated demonstrated that this was not due to any non-specific effects of the TMS influencing the spatial distribution of attention. CONCLUSIONS/SIGNIFICANCE: Taken together, the results are consistent with a direction-dependent role of the FEF and left SEF in delaying the release of saccadic eye movements until they have been fully planned. PMID- 19789707 TI - Simple field assays to check quality of current artemisinin-based antimalarial combination formulations. AB - INTRODUCTION: Malaria continues to be one of the major public health problems in Africa, Asia and Latin America. Artemisinin derivatives (ARTs; artesunate, artemether, and dihydroartemisinin) derived from the herb, Artemisia annua, are the most effective antimalarial drugs available providing rapid cures. The World Health Organisation (WHO) has recommended that all antimalarials must be combined with an artemisinin component (artemisinin-based combination therapy; ACT) for use as first line treatment against malaria. This class of drugs is now first line policy in most malaria-endemic countries. Reports of ad hoc surveys from South East Asia show that up to 50% of the artesunate currently sold is counterfeit. Drug quality is rarely assessed in resource poor countries in part due to lack of dedicated laboratory facilities which are expensive to build, equip and maintain. With a view to address this unmet need we developed two novel colour reaction assays that can be used in the field to check the quality of ARTs. METHODS AND FINDINGS: Our assays utilise thin layer chromatography silica gel sheets and 2, 4 dinitrophenylhydrazine or 4-Benzoylamino-2, 5 dimethoxybenzenediazonium chloride hemi (zinc chloride) salt as the reagents showing a pink or blue product respectively only in the presence ARTs. We are able to detect as low as 10% of ARTs in ACTs (WINTHROP--artesunate/amodiaquine, Coartem--artemether/lumefantrine and Duocortexcin- dihydroartemisinin/piperaquine). The assays have been validated extensively by testing eighty readily accessible and widely used drugs in malaria endemic countries. None of the other antimalarial drugs or a range of commonly used excipients, antiretroviral drugs or other frequently used drugs from the WHO essential drugs list such as analgesics or antibiotics are detected with our assays. CONCLUSIONS: Our two independent assays requiring no specialist training are specific, simple to use, rapid, robust, reproducible, inexpensive and, have successfully resulted in detecting two counterfeit drugs within a small scale screening survey of over 100 declared artemisinin-containing drugs collected from various Asian and African countries. These promising results indicate that the assays will provide a useful first test to assure the quality of the ACTs formulations in resource poor malaria endemic areas when there is an absence of dedicated medicines quality laboratory facilities. PMID- 19789708 TI - Fish-specific duplicated dmrt2b contributes to a divergent function through Hedgehog pathway and maintains left-right asymmetry establishment function. AB - Gene duplication is thought to provide raw material for functional divergence and innovation. Fish-specific dmrt2b has been identified as a duplicated gene of the dmrt2a/terra in fish genomes, but its function has remained unclear. Here we reveal that Dmrt2b knockdown zebrafish embryos display a downward tail curvature and have U-shaped somites. Then, we demonstrate that Dmrt2b contributes to a divergent function in somitogenesis through Hedgehog pathway, because Dmrt2b knockdown reduces target gene expression of Hedgehog signaling, and also impairs slow muscle development and neural tube patterning through Hedgehog signaling. Moreover, the Dmrt2b morphants display defects in heart and visceral organ asymmetry, and, some lateral-plate mesoderm (LPM) markers expressed in left side are randomized. Together, these data indicate that fish-specific duplicated dmrt2b contributes to a divergent function in somitogenesis through Hedgehog pathway and maintains the common function for left-right asymmetry establishment. PMID- 19789709 TI - The origin and initial rise of pelagic cephalopods in the Ordovician. AB - BACKGROUND: During the Ordovician the global diversity increased dramatically at family, genus and species levels. Partially the diversification is explained by an increased nutrient, and phytoplankton availability in the open water. Cephalopods are among the top predators of today's open oceans. Their Ordovician occurrences, diversity evolution and abundance pattern potentially provides information on the evolution of the pelagic food chain. METHODOLOGY/PRINCIPAL FINDINGS: We reconstructed the cephalopod departure from originally exclusively neritic habitats into the pelagic zone by the compilation of occurrence data in offshore paleoenvironments from the Paleobiology Database, and from own data, by evidence of the functional morphology, and the taphonomy of selected cephalopod faunas. The occurrence data show, that cephalopod associations in offshore depositional settings and black shales are characterized by a specific composition, often dominated by orthocerids and lituitids. The siphuncle and conch form of these cephalopods indicate a dominant lifestyle as pelagic, vertical migrants. The frequency distribution of conch sizes and the pattern of epibionts indicate an autochthonous origin of the majority of orthocerid and lituitid shells. The consistent concentration of these cephalopods in deep subtidal sediments, starting from the middle Tremadocian indicates the occupation of the pelagic zone early in the Early Ordovician and a subsequent diversification which peaked during the Darriwilian. CONCLUSIONS/SIGNIFICANCE: The exploitation of the pelagic realm started synchronously in several independent invertebrate clades during the latest Cambrian to Middle Ordovician. The initial rise and diversification of pelagic cephalopods during the Early and Middle Ordovician indicates the establishment of a pelagic food chain sustainable enough for the development of a diverse fauna of large predators. The earliest pelagic cephalopods were slowly swimming vertical migrants. The appearance and early diversification of pelagic cephalopods is interpreted as a consequence of the increased food availability in the open water since the latest Cambrian. PMID- 19789710 TI - Splenectomy normalizes hematocrit in murine polycythemia vera. AB - Splenic enlargement (splenomegaly) develops in numerous disease states, although a specific pathogenic role for the spleen has rarely been described. In polycythemia vera (PV), an activating mutation in Janus kinase 2 (JAK2(V617)) induces splenomegaly and an increase in hematocrit. Splenectomy is sparingly performed in patients with PV, however, due to surgical complications. Thus, the role of the spleen in the pathogenesis of human PV remains unknown. We specifically tested the role of the spleen in the pathogenesis of PV by performing either sham (SH) or splenectomy (SPL) surgeries in a murine model of JAK2(V617F)-driven PV. Compared to SH-operated mice, which rapidly develop high hematocrits after JAK2(V617F) transplantation, SPL mice completely fail to develop this phenotype. Disease burden (JAK2(V617)) is equivalent in the bone marrow of SH and SPL mice, however, and both groups develop fibrosis and osteosclerosis. If SPL is performed after PV is established, hematocrit rapidly declines to normal even though myelofibrosis and osteosclerosis again develop independently in the bone marrow. In contrast, SPL only blunts hematocrit elevation in secondary, erythropoietin-induced polycythemia. We conclude that the spleen is required for an elevated hematocrit in murine, JAK2(V617F)-driven PV, and propose that this phenotype of PV may require a specific interaction between mutant cells and the spleen. PMID- 19789711 TI - Physico-chemical evaluation of rationally designed melanins as novel nature inspired radioprotectors. AB - BACKGROUND: Melanin, a high-molecular weight pigment that is ubiquitous in nature, protects melanized microorganisms against high doses of ionizing radiation. However, the physics of melanin interaction with ionizing radiation is unknown. METHODOLOGY/PRINCIPAL FINDINGS: We rationally designed melanins from either 5-S-cysteinyl-DOPA, L-cysteine/L-DOPA, or L-DOPA with diverse structures as shown by elemental analysis and HPLC. Sulfur-containing melanins had higher predicted attenuation coefficients than non-sulfur-containing melanins. All synthetic melanins displayed strong electron paramagnetic resonance (2.14.10(18), 7.09.10(18), and 9.05.10(17) spins/g, respectively), with sulfur-containing melanins demonstrating more complex spectra and higher numbers of stable free radicals. There was no change in the quality or quantity of the stable free radicals after high-dose (30,000 cGy), high-energy ((137)Cs, 661.6 keV) irradiation, indicating a high degree of radical stability as well as a robust resistance to the ionizing effects of gamma irradiation. The rationally designed melanins protected mammalian cells against ionizing radiation of different energies. CONCLUSIONS/SIGNIFICANCE: We propose that due to melanin's numerous aromatic oligomers containing multiple pi-electron system, a generated Compton recoil electron gradually loses energy while passing through the pigment, until its energy is sufficiently low that it can be trapped by stable free radicals present in the pigment. Controlled dissipation of high-energy recoil electrons by melanin prevents secondary ionizations and the generation of damaging free radical species. PMID- 19789712 TI - Gender Specific Brood Cells in the Solitary Bee Colletes halophilus (Hymenoptera; Colletidae). AB - We studied the reproductive behaviour of the solitary bee Colletes halophilus based on the variation in cell size, larval food amount and larval sex in relation to the sexual size dimorphism in this bee. Brood cells with female larvae are larger and contain more larval food than cells with males. Occasionally males are reared in female-sized cells. We conclude that a female C. halophilus in principal anticipates the sex of her offspring at the moment brood cell construction is started. Additionally a female is able to 'change her mind' about the sex of her offspring during a single brood cell cycle. We present a model that can predict the sex of the larvae in an early stage of development. PMID- 19789713 TI - Esophageal clearance patterns in normal older adults as documented with videofluoroscopic esophagram. AB - Normal esophageal bolus transport in asymptomatic healthy older adults has not been well defined, potentially leading to ambiguity in differentiating esophageal swallowing patterns of dysphagic and healthy individuals. This pilot study of 24 young (45-64 years) and old (65+years) men and women was designed to assess radiographic esophageal bolus movement patterns in healthy adults using videofluoroscopic recording. Healthy, asymptomatic adults underwent videofluoroscopic esophagram to evaluate for the presence of ineffective esophageal clearance, namely, intraesophageal stasis and intraesophageal reflux. Intraesophageal stasis and intraesophageal reflux were visualized radiographically in these normal subjects. Intraesophageal stasis occurred significantly more frequently with semisolid (96%) compared with liquid (16%) barium, suggesting that a variety of barium consistencies, as opposed to only the traditional fluids, would better define the spectrum of esophageal transport. Intraesophageal reflux was observed more frequently in older males than in their younger counterparts. The rates of intraesophageal stasis and intraesophageal reflux were potentially high given that successive bolus presentations were spaced 10 seconds apart. These findings suggest a need for a more comprehensive definition regarding the range of normal esophageal bolus transport to (a) prevent misdiagnosis of dysphagia and (b) to enhance generalization to functional eating, which involves solid foods in addition to liquids. PMID- 19789714 TI - Life history plasticity after attaining a dietary threshold for reproduction is associated with protein storage in flesh flies. AB - Body condition affects the timing and magnitude of life history transitions. Therefore, identifying proximate mechanisms involved in assessing condition is critical to understanding how these mechanisms affect the expression of life history plasticity. Nutrient storage is an important body condition parameter, likely playing roles in both attaining minimum body-condition thresholds for life history transitions and expression of life history traits.We manipulated protein availability for females of the flesh fly Sarcophaga crassipalpis to determine whether reproductive timing and output would remain plastic or become fixed. Liver was provided for 0, 2, 4, or 6 days of adult pre-reproductive development. Significantly, liver was removed after the feeding threshold had been attained and females had committed to producing a clutch.We also identified the major storage proteins and monitored their abundances, because protein stores may serve as an index of body condition and therefore may play an important role in life history transitions and plasticity.Flesh flies showed clear post-threshold plasticity in reproductive timing. Females fed protein for 2 days took ~30% longer to provision their clutch than those fed for 4 or 6 days. Observations of oogenesis showed the 2-day group expressed a different developmental program including slower egg provisioning.Protein availability also affected reproductive output. Females fed protein for 2 days produced ~20% fewer eggs than females fed 4 or 6 days. Six-day treated females provisioned larger eggs than 4-day treated females, followed by 2-day treated females with the smallest eggs.Two storage proteins were identified, LSP-1 and LSP-2. LSP-2 accumulation differed across feeding treatments. The 2- and 4-day treatment groups accumulated LSP-2 stores but depleted them during provisioning of the first clutch, whereas the 6-day group accumulated the greatest quantity of LSP-2 and had substantial LSP-2 stores remaining at the end of the clutch. This pattern of accumulation and depletion suggests that LSP-2 could play roles in both provisioning the current clutch and future clutches, making it a good candidate molecule for affecting reproductive timing and allotment. LSP-1 was not associated with post-threshold plasticity; it was carried over from larval feeding into adulthood and depleted uniformly across all feeding groups. PMID- 19789716 TI - A Comparative Study of Landsat TM and SPOT HRG Images for Vegetation Classification in the Brazilian Amazon. AB - Complex forest structure and abundant tree species in the moist tropical regions often cause difficulties in classifying vegetation classes with remotely sensed data. This paper explores improvement in vegetation classification accuracies through a comparative study of different image combinations based on the integration of Landsat Thematic Mapper (TM) and SPOT High Resolution Geometric (HRG) instrument data, as well as the combination of spectral signatures and textures. A maximum likelihood classifier was used to classify the different image combinations into thematic maps. This research indicated that data fusion based on HRG multispectral and panchromatic data slightly improved vegetation classification accuracies: a 3.1 to 4.6 percent increase in the kappa coefficient compared with the classification results based on original HRG or TM multispectral images. A combination of HRG spectral signatures and two textural images improved the kappa coefficient by 6.3 percent compared with pure HRG multispectral images. The textural images based on entropy or second-moment texture measures with a window size of 9 pixels * 9 pixels played an important role in improving vegetation classification accuracy. Overall, optical remote sensing data are still insufficient for accurate vegetation classifications in the Amazon basin. PMID- 19789715 TI - A handheld computer as part of a portable in vivo knee joint load monitoring system. AB - In vivo measurement of loads and pressures acting on articular cartilage in the knee joint during various activities and rehabilitative therapies following focal defect repair will provide a means of designing activities that encourage faster and more complete healing of focal defects.It was the goal of this study to develop a totally portable monitoring system that could be used during various activities and allow continuous monitoring of forces acting on the knee. In order to make the monitoring system portable, a handheld computer with custom software, a USB powered miniature wireless receiver and a battery-powered coil were developed to replace a currently used computer, AC powered bench top receiver and power supply.A Dell handheld running Windows Mobile operating system(OS) programmed using Labview was used to collect strain measurements. Measurements collected by the handheld based system connected to the miniature wireless receiver were compared with the measurements collected by a hardwired system and a computer based system during bench top testing and in vivo testing. The newly developed handheld based system had a maximum accuracy of 99% when compared to the computer based system. PMID- 19789718 TI - Turner syndrome in childhood and adolescence. AB - This article reviews current patterns of ascertainment, clinical characteristics and quality of care for girls with Turner syndrome, based on a cohort of 100 girls (aged 7-17 years) prospectively evaluated at the National Institute of Child Health since 2001. Approximately 25% were diagnosed prenatally or at birth owing to webbed neck and other features typical of fetal lymphedema, few were diagnosed during early childhood, with the majority undiagnosed until age 9 years or older. Major clinical features included thyroid autoimmunity (51%), congenital cardiovascular anomalies (44%), liver abnormalities (36%), hypertension (34%), hearing loss (30%) and renal anomalies (18%). Of the group, 75% were being or had been treated with growth hormone. These girls were an average of 5 cm taller and significantly less obese than the untreated group. We discuss new guidelines for the initiation of puberty and urgent research needed to promote the health and longevity of girls suffering from Turner syndrome as they become adults. PMID- 19789717 TI - Socioeconomic background modulates cognition-achievement relationships in reading. AB - Multiple factors contribute to individual differences in reading ability. The two most thoroughly examined are socioeconomic status (SES) and phonological awareness (PA). Although these factors are often investigated individually, they are rarely considered together. Here we propose that SES systematically influences the relationship between PA and reading ability, and test this prediction in 150 first-graders of varying SES and PA. Results confirm a multiplicative relationship between SES and PA in decoding skills, such that decreased access to resources may amplify cognitive risk factors for poor decoding, whereas greater access to resources may buffer reading skills among children with weaker PA. Attempts to identify the cognitive and experiential factors driving development must acknowledge the complex, synergizing relations between these factors. PMID- 19789719 TI - Collecting Sketch Maps to Understand Property Land Use and Land Cover in Large Surveys. AB - This article describes a method to collect data on the spatial organization of land use within a rural property as part of a large-scale project examining the linkages between household demographic change and land use and land cover change in the Brazilian Amazon. Previous studies used several different spatial approaches, including maps and satellite images, to improve the information collected in standard survey questionnaires. However, few used sketch maps to obtain information from the point of view of the survey respondent about the spatial organization of land use and infrastructure. We developed a method of creating sketch maps with respondents to describe their properties. These maps then provided a spatially referenced database of the social and land use organization of the properties from the perspective of the respondent. Systematic rules allowed sketches to be used in subsequent spatial analyses in combination with satellite images and Global Positioning System reference points. PMID- 19789720 TI - Crystallization in heat-treated fluorochlorozirconate glasses. AB - Crystallization phenomena of fluorochlorozirconate glasses were investigated by means of differential scanning calorimetry and inelastic neutron scattering. The precipitation of barium chloride nanoparticles from the glass matrix upon heat treatment was found to be suppressed when re-melting the glass with a reducing agent but not if the agent was present in the initial synthesis. Addition of small amounts of oxide to the predominantly fluoride melt was found to maintain the presence of nanoparticles but not to induce the predicted phase transition of the barium chloride nanoparticles from hexagonal to orthorhombic structure. Inelastic neutron scattering performed on an 'as-made' glass and a heat-treated glass showed an increase in 'hardness', consistent with a more ordered structure. PMID- 19789721 TI - Integration of Landsat TM and SPOT HRG Images for Vegetation Change Detection in the Brazilian Amazon. AB - Traditional change detection approaches have been proven to be difficult in detecting vegetation changes in the moist tropical regions with multitemporal images. This paper explores the integration of Landsat Thematic Mapper (TM) and SPOT High Resolution Geometric (HRG) instrument data for vegetation change detection in the Brazilian Amazon. A principal component analysis was used to integrate TM and HRG panchromatic data. Vegetation change/non-change was detected with the image differencing approach based on the TM and HRG fused image and the corresponding TM image. A rule-based approach was used to classify the TM and HRG multispectral images into thematic maps with three coarse land-cover classes: forest, non-forest vegetation, and non-vegetation lands. A hybrid approach combining image differencing and post-classification comparison was used to detect vegetation change trajectories. This research indicates promising vegetation change techniques, especially for vegetation gain and loss, even if very limited reference data are available. PMID- 19789722 TI - Message-passing implementation of the data diffusion communication model in fast multipole methods: large scale biomolecular simulations. AB - Biomolecular simulations require increasingly efficient parallel codes. We present an efficient communication algorithm for irregular problems exhibiting an all-to-many communication pattern. The algorithm is developed using message passing on distributed memory machines and assumes explicit knowledge of the interconnection topology. The algorithm maximizes locality of interprocessor communication by adopting to an arbitrary interconnection topology and at the same time takes multiprocessor nodes into account. The solution is incorporated into our implementation of the fast multipole method with periodic boundary conditions used for molecular dynamics simulations, but we believe it generalizes to many algorithms demonstrating an all-to-many communication pattern. We show that an irregular algorithm can be forced to behave like a systolic algorithm. PMID- 19789723 TI - Synthesis of polysubstituted tetrahydrofurans via Pd-catalyzed carboetherification reactions. AB - Pd-catalyzed carboetherifications of 1-, 2-, or 3-substituted gamma-hydroxy internal alkenes afford tetrahydrofuran products bearing three stereocenters in good yield with moderate to good stereoselectivity. PMID- 19789724 TI - Family Man in the Other America: New Opportunities, Motivations, and Supports for Paternal Caregiving. AB - This analysis draws on longitudinal, qualitative interviews with disadvantaged mothers and fathers who participated in the Fragile Families Study (a U.S. birth cohort study) to examine how issues related to men's employment, social support, skills, and motivation facilitated their care of young children in different relationship contexts. Interviews with parents indicate that while some motivated and skilled men actively chose to become caregivers with the support of mothers, others developed new motivations, skills, and parenting supports in response to situations in which they were out of work or the mother was experiencing challenges. These findings suggest that disadvantaged men who assume caregiving responsibilities take different paths to involvement in the early years after their child's birth. Policies that overlook paternal caregivers may not only miss the opportunity to support relationships that benefit at-risk children but also unintentionally undermine this involvement. PMID- 19789725 TI - Monophyly of terrestrial adephagan beetles as indicated by three nuclear genes (Coleoptera: Carabidae and Trachypachidae). AB - The beetle suborder Adephaga is traditionally divided into two sections on the basis of habitat, terrestrial Geadephaga and aquatic Hydradephaga. Monophyly of both groups is uncertain, and the relationship of the two groups has implications for inferring habitat transitions within Adephaga. Here we examine phylogenetic relationships of these groups using evidence provided by DNA sequences from all four suborders of beetles, including 60 species of Adephaga, four Archostemata, three Myxophaga, and ten Polyphaga. We studied 18S ribosomal DNA and 28S ribosomal DNA, aligned with consideration of secondary structure, as well as the nuclear protein-coding gene wingless. Independent and combined Bayesian, likelihood, and parsimony analyses of all three genes supported placement of Trachypachidae in a monophyletic Geadephaga, although for analyses of 28S rDNA and some parsimony analyses only if Coleoptera is constrained to be monophyletic. Most analyses showed limited support for the monophyly of Hydradephaga. Outside of Adephaga, there is support from the ribosomal genes for a sister group relationship between Adephaga and Polyphaga. Within the small number of sampled Polyphaga, analyses of 18S rDNA, wingless, and the combined matrix supports monophyly of Polyphaga exclusive of Scirtoidea. Unconstrained analyses of the evolution of habitat suggest that Adephaga was ancestrally aquatic with one transition to terrestrial. However, in analyses constrained to disallow changes from aquatic to terrestrial habitat, the phylogenies imply two origins of aquatic habit within Adephaga. PMID- 19789726 TI - Modelling spatially correlated survival data for individuals with multiple cancers. AB - Epidemiologists and biostatisticians investigating spatial variation in diseases are often interested in estimating spatial effects in survival data, where patients are monitored until their time to failure (for example, death, relapse). Spatial variation in survival patterns often reveals underlying lurking factors, which, in turn, assist public health professionals in their decision-making process to identify regions requiring attention. The Surveillance Epidemiology and End Results (SEER) database of the National Cancer Institute provides a fairly sophisticated platform for exploring novel approaches in modelling cancer survival, particularly with models accounting for spatial clustering and variation. Modelling survival data for patients with multiple cancers poses unique challenges in itself and in capturing the spatial associations of the different cancers. This paper develops the Bayesian hierarchical survival models for capturing spatial patterns within the framework of proportional hazard. Spatial variation is introduced in the form of county-cancer level frailties. The baseline hazard function is modelled semiparametrically using mixtures of beta distributions. We illustrate with data from the SEER database, perform model checking and comparison among competing models, and discuss implementation issues. PMID- 19789727 TI - The Effect of Flaxseed Supplementation on Hormonal Levels Associated with Polycystic Ovarian Syndrome: A Case Study. AB - Flaxseed is a rich source of lignan and has been shown to reduce androgen levels in men with prostate cancer. Polycystic ovarian syndrome (PCOS), a common endocrine disorder among women in their reproductive years, also is associated with high levels of androgens and is frequently accompanied by hirsutism, amenorrhea and obesity. This clinical case study describes the impact of flaxseed supplementation (30 g/day) on hormonal levels in a 31-year old woman with PCOS. During a four month period, the patient consumed 83% of the flaxseed dose. Heights, weights, and fasting blood samples taken at baseline and 4-month follow up indicated the following values: BMI (36.0 vs. 35.7m/kg(2)); insulin (5.1 vs. 7.0 uIU/ml); total serum testosterone (150 ng/dl vs. 45 ng/dl); free serum testosterone (4.7 ng/dl vs. 0.5 ng/dl); and % free testosterone (3.1% vs. 1.1%). The patient also reported a decrease in hirsutism at the completion of the study period. The clinically-significant decrease in androgen levels with a concomitant reduction in hirsutism reported in this case study demonstrates a need for further research of flaxseed supplementation on hormonal levels and clinical symptoms of PCOS. PMID- 19789729 TI - Dynamic manipulation and separation of individual semiconducting and metallic nanowires. AB - The synthesis of nanowires has advanced in the last decade to a point where a vast range of insulating, semiconducting, and metallic materials1 are available for use in integrated, heterogeneous optoelectronic devices at nanometer scales 2. However, a persistent challenge has been the development of a general strategy for the manipulation of individual nanowires with arbitrary composition. Here we report that individual semiconducting and metallic nanowires with diameters below 20 nm, are addressable with forces generated by optoelectronic tweezers (OET) 3. Using 100,000x less optical power density than optical tweezers, OET is capable of transporting individual nanowires with speeds 4x larger than maximum speeds achieved by optical tweezers. A real-time array of silver nanowires is formed using photopatterned virtual-electrodes, demonstrating the potential for massively parallel assemblies. Furthermore, OET enables the separation of semiconducting and metallic nanowires, suggesting a broad range of applications for the separation and heterogenous integration of one-dimensional nanoscale materials. PMID- 19789728 TI - Intratubular Renin-Angiotensin System in Hypertension. AB - It is well recognized that the renin-angiotensin system plays an important role in the regulation of arterial pressure and sodium homeostasis. Recent years, many studies have shown that local tissue angiotensin II levels are differentially regulated and cannot be explained on the basis of circulating concentrations. All of the components needed for angiotensin II generation are present within the various compartments in the kidney including the renal interstitium and the tubular network. The cascade of the renin-angiotensin system demonstrates three major possible sites for the pharmacological interruption of the renin angiotensin system: the interaction of renin with its substrate, angiotensinogen, the angiotensin converting enzyme, and angiotensin II type 1 receptors. This brief article will focus on the role of the intratubular renin-angiotensin system in the pathophysiology of hypertension and the responses to the renin-angiotensin system blockade by renin inhibitors, angiotensin converting enzyme inhibitors and angiotensin II type 1 receptor blockers. PMID- 19789730 TI - Advertisement-call modification, male competition and female preference in the bird-voiced treefrog Hyla avivoca. AB - Senders and receivers influence dynamic characteristics of the signals used for mate attraction over different time scales. On a moment-to-moment basis, interactions among senders competing for a mate influence dynamic characteristics, whereas the preferences of receivers of the opposite gender exert an influence over evolutionary time. We observed and recorded the calling patterns of the bird-voiced treefrog Hyla avivoca, to assess how the dynamic characters of calls vary during interactions among groups of males in a chorus. This question was also addressed using playback experiments with males. Playback experiments with females showed how changes in dynamic call properties are likely to affect male mating success. Frogs calling in pairs, groups, or in response to playbacks produced longer calls than did isolated males. During call overlap, males often increased the duration of the silent interval (gaps) between the pulses of their calls so that the pulses of the calls of two neighbors interdigitated. This change resulted in increased variability of pulse rate, a traditionally static acoustic property; however, males also produced high proportions of non-overlapped calls in which variability in pulse rate was low and had species-typical values. Females preferred long calls to short and average duration calls, and non-overlapped calls to overlapped calls. Given a choice between pairs of overlapped calls, females preferred pairs in which the proportion of overlap was low and pairs in which the pulses of such calls interdigitated completely. The observed patterns of vocal competition thus reflect the preferences of conspecific females, which have influenced the evolution of the calling behavior of H. avivoca. PMID- 19789731 TI - Representing the NCI Thesaurus in OWL DL: Modeling tools help modeling languages. AB - The National Cancer Institute's (NCI) Thesaurus is a biomedical reference ontology. The NCI Thesaurus is represented using Description Logic, more specifically Ontylog, a Description logic implemented by Apelon, Inc. We are exploring the use of the DL species of the Web Ontology Language (OWL DL)-a W3C recommended standard for ontology representation-instead of Ontylog for representing the NCI Thesaurus. We have studied the requirements for knowledge representation of the NCI Thesaurus, and considered how OWL DL (and its implementation in Protege-OWL) satisfies these requirements. In this paper, we discuss the areas where OWL DL was sufficient for representing required components, where tool support that would hide some of the complexity and extra levels of indirection would be required, and where language expressiveness is not sufficient given the representation requirements. Because many of the knowledge representation issues that we encountered are very similar to the issues in representing other biomedical terminologies and ontologies in general, we believe that the lessons that we learned and the approaches that we developed will prove useful and informative for other researchers. PMID- 19789732 TI - Variable selection in Bayesian smoothing spline ANOVA models: Application to deterministic computer codes. AB - With many predictors, choosing an appropriate subset of the covariates is a crucial, and difficult, step in nonparametric regression. We propose a Bayesian nonparametric regression model for curve-fitting and variable selection. We use the smoothing spline ANOVA framework to decompose the regression function into interpretable main effect and interaction functions. Stochastic search variable selection via MCMC sampling is used to search for models that fit the data well. Also, we show that variable selection is highly-sensitive to hyperparameter choice and develop a technique to select hyperparameters that control the long run false positive rate. The method is used to build an emulator for a complex computer model for two-phase fluid flow. PMID- 19789737 TI - Cutting edge: electronic counting of white blood cells. PMID- 19789738 TI - Highly efficient chemoselective N-acylation with water microreaction system in the absence of catalyst. AB - A high-speed, highly efficient chemoselective N-acylation by anhydride was achieved in the absence of catalyst for exothermic (DeltaH>0) and endothermic (DeltaH<0) acylation of various amines and anilines with the microreaction system of ambient water (micro-onH2O) and subcritical water (micro-subH2O), where the desired N-acylated products are chemoselectively obtained with high yield(s) and excellent selectivity (>95%). PMID- 19789739 TI - Leukocyte analysis and differentiation using high speed microfluidic single cell impedance cytometry. AB - Miniature high speed label-free cell analysis systems have yet to be developed, but have the potential to deliver fast, inexpensive and simple full blood cell analysis systems that could be used routinely in clinical practice. We demonstrate a microfluidic single cell impedance cytometer that performs a white blood cell differential count. The device consists of a microfluidic chip with micro-electrodes that measure the impedance of single cells at two frequencies. Human blood, treated with saponin/formic acid to lyse erythrocytes, flows through the device and a complete blood count is performed in a few minutes. Verification of cell dielectric parameters was performed by simultaneously measuring fluorescence from CD antibody-conjugated cells. This enabled direct correlation of impedance signals from individual cells with phenotype. Tests with patient samples showed 95% correlation against commercial (optical/Coulter) blood analysis equipment, demonstrating the potential clinical utility of the impedance microcytometer for a point-of-care blood analysis system. PMID- 19789740 TI - Acoustic tweezers: patterning cells and microparticles using standing surface acoustic waves (SSAW). AB - Here we present an active patterning technique named "acoustic tweezers" that utilizes standing surface acoustic wave (SSAW) to manipulate and pattern cells and microparticles. This technique is capable of patterning cells and microparticles regardless of shape, size, charge or polarity. Its power intensity, approximately 5x10(5) times lower than that of optical tweezers, compares favorably with those of other active patterning methods. Flow cytometry studies have revealed it to be non-invasive. The aforementioned advantages, along with this technique's simple design and ability to be miniaturized, render the "acoustic tweezers" technique a promising tool for various applications in biology, chemistry, engineering, and materials science. PMID- 19789741 TI - Prediction of trapping zones in an insulator-based dielectrophoretic device. AB - A mathematical model is implemented to study the performance of an insulator based dielectrophoretic device. The geometry of the device was captured in a computational model that solves Laplace equation within an array of cylindrical insulating structures. From the mathematical model it was possible to predict the location and magnitude of the zones of dielectrophoretic trapping of microparticles. Simulation and experimental results of trapping zones are compared for different operating conditions. PMID- 19789742 TI - Multi-step microfluidic droplet processing: kinetic analysis of an in vitro translated enzyme. AB - Microdroplets in water-in-oil emulsions can be used as microreactors with volumes 10(3) to 10(9) times smaller than the smallest working volumes in a microtitre plate well (1-2 microL). However, many reactions and assays require multiple steps where new reagents are added at defined times, to start, modify or terminate a reaction. The most flexible way to add new reagents to pre-formed droplets is by controlled, pairwise droplet fusion. We describe a droplet-based microfluidic system capable of performing multiple operations, including pairwise droplet fusion, to analyze complex and sequential multi-step reactions. It is exemplified by performing a series of six on-chip and two off-chip operations which enable the coupled in vitro transcription and translation of cotA laccase genes in droplets and, after performing a controlled fusion with droplets containing laccase assay reagents, the end-point and kinetic analysis of the catalytic activity of the translated protein. In vitro translation and the laccase assay must be performed sequentially as the conditions for the laccase assay are not compatible with in vitro translation. Droplet fusion was performed by electrocoalescence at a rate of approximately 3000 fusion events per second and nearly 90% of droplets were fused one-to-one (one droplet containing in vitro translated laccase fused to one droplet containing the reagents for the laccase assay). The ability to uncouple the enzymatic assay from in vitro translation greatly extends the range of activities of in vitro translated proteins that can potentially be screened in droplet-based microfluidic systems. Furthermore, the system also opens up the possibility of performing a wide range of other new (bio)chemical reactions in droplets. PMID- 19789743 TI - Chemical imaging of microfluidic flows using ATR-FTIR spectroscopy. AB - Elucidating the chemical composition of microfluidic flows is crucial in both understanding and optimising reactive processes within small-volume environments. Herein we report the implementation of a novel detection methodology based on Attenuated Total Reflection (ATR)-Fourier Transform Infra-Red (FTIR) spectroscopic imaging using an infrared focal plane array detector for microfluidic applications. The method is based on the combination of an inverted prism-shape ATR crystal with a poly(dimethylsiloxane)-based microfluidic mixing device. To demonstrate the efficacy of this approach, we report the direct measurement and imaging of the mixing of two liquids of different viscosities and the imaging and mixing of H2O and D2O with consecutive H/D isotope exchange. This chemically specific imaging approach allows direct analysis of fluid composition as a function of spatial position without the use of added labels or dyes, and can be used to study many processes in microfluidics ranging from reactions to separations. PMID- 19789744 TI - Microchip electrospray performance during gradient elution with bulk conductivity changes. AB - This work identifies dynamic changes in bulk conductivity during reversed-phase HPLC gradient elution as a major source for spray mode changes and instabilities observed in ESI-MS. A commercial microchip-HPLC/ESI-MS configuration was modified to enable electrospray diagnostics based on frequency analysis of the microchip emitter current combined with spray imaging. This approach facilitated detection of different spray modes together with their onset potentials. Water/acetonitrile mixtures containing formic acid were selected as the electrosprayed solutions to represent typical conditions in reversed-phase HPLC. Experimental data are complemented by computational fluid dynamics simulations, treating the electrosprayed solution as leaky dielectric fluid, to address the influence of bulk conductivity and applied potential difference on the developing cone-jet morphology and stability. PMID- 19789745 TI - A multiplexed optofluidic biomolecular sensor for low mass detection. AB - Optical techniques have proven to be well suited for in situ biomolecular sensing because they enable high fidelity measurements in aqueous environments, are minimally affected by background solution pH or ionic strength, and facilitate label-free detection. Recently, there has been significant interest in developing new classes of optically resonant biosensors possessing very high quality factors. This high quality-factor enables them to resolve the presence of very small amounts of bound mass and leads to very low limits of detection. A drawback of these devices is that the majority of the resonant electromagnetic energy is confined within the solid light-guiding structure thus limiting the degree to which it overlaps with the bound matter. This in turn lowers the ultimate device sensitivity, or the change in output signal in response to changes in bound mass. Here we present a novel optofluidic biosensor platform that incorporates a unique one-dimensional photonic crystal resonator array which enables significantly stronger light-matter interaction. We show here how this, coupled with the ability of planar photonic crystals to spatially localize the optical field to mode volumes on the order of a wavelength cubed, enables a limit of detection on the order of 63 ag total bound mass (estimated using a polyelectrolyte growth model) and a device sensitivity an order of magnitude better than similar devices. The multiplexing capabilities of our sensor are demonstrated by the individual and concurrent detection of interleukins 4, 6 and 8 using a sandwich assay. PMID- 19789746 TI - Oligonucleotide hybridization and free-solution electrokinetic separation in a nanofluidic device. AB - There is significant interest in developing on-chip DNA hybridization assays to leverage the advantages of lab-on-a-chip systems, which include smaller sample and reagent volumes, faster processing speeds, and greater opportunities for large-scale integration. While much research has explored ways to integrate DNA microarrays on-chip, little work has been done to incorporate hybridization with existing microscale separation platforms. We present the first separation of single-stranded and double-stranded oligonucleotides in a nanofluidic device. We couple this separation with free-solution hybridization to develop a simple, electrokinetic technique that detects DNA hybridization without sample labeling. The technique is used both to detect target DNA sequences and to quantitatively measure hybridization kinetics. To demonstrate the method, we measured the second order reaction coefficient of complementary 20-mer oligonucleotides as a function of sodium ion concentration, which ranged from 0.0048 mol(-1).sec(-1) at 5 mM sodium to 0.42 mol(-1).sec(-1) at 50 mM. We also distinguished between a pair of complementary oligonucleotides and a pair with a single nucleotide mismatch, observing a two-fold difference in hybridization rate. Additionally, we observed a relative change in the mobility of single-stranded and double-stranded DNA with increasing sodium concentration, suggesting that our device may provide a useful platform for studying biomolecule transport in nanochannels. PMID- 19789747 TI - A rapid prototyping method for polymer microfluidics with fixed aspect ratio and 3D tapered channels. AB - In this work, a new method of rapidly fabricating thermopolymer and elastomer microfluidic channels has been developed and characterized for production of microfluidics with fixed aspect ratio and 3D tapered channels. A unique way to attain a desired channel depth by simply altering channel width is demonstrated. This rapid prototyping method is compatible with replication methods such as injection molding, hot embossing and elastomer casting and offers the ability to fabricate multiple channel depths (5 microm-1 mm) simultaneously in a single lithographic step. This method yields facile fabrication of 3-dimensionally tapered channels and polymer lab chips. PMID- 19789748 TI - Formation of supramolecular hydrogel microspheres via microfluidics. AB - Supramolecular hydrogel microspheres are hydrogel particles formed by the self assembly of hydrogelators in water, through non-covalent interactions. In this paper, we provide a novel strategy to prepare supramolecular hydrogel microspheres with diameters ranging from 15 to 105 microns by using microfluidics. Since the gelation temperature is ca. 64 degrees C, the aqueous solution containing the hydrogelator was initially set at 70 degrees C so the liquid mixture can be pumped into the microfluidic device. The hydrogelator solution then pinches off into uniform micron size droplets at the narrow orifice of the microfluidic device. While traveling downstream in the microchannel, the self-assembly process occurs inside the droplets and the droplets solidify into microsphere gels when the temperature drops to ca. 64 degrees C and below. Optical and scanning electron microscopy (SEM) demonstrate that compact, entangled, round, cage-like aggregates of hydrogelator were formed within the supramolecular hydrogel microsphere, in contrast to loose and less compact aggregates within bulk hydrogel. Thermal analysis (DSC) indicates that supramolecular hydrogel microspheres are more thermally stable and can immobilize more water molecules, owing to the compact entangled three-dimensional network structures. This observation is of particular importance for potential drug delivery and biomaterials applications. PMID- 19789749 TI - Antifouling coatings for optoelectronic tweezers. AB - Optoelectronic tweezers enables parallel manipulation of individual single cells using optical addressing and optically induced dielectrophoretic force. This provides a useful platform for performing a variety of biological functions, such as cell manipulation, cell sorting, and cell electroporation. However, in order to obtain more reliable cellular manipulation, especially of adherent mammalian cells, antifouling coatings need to be used to avoid non-specific cell adherence. Two antifouling coatings are discussed here, which can reduce the amount of non specific adherence by as much as a factor of 30. PMID- 19789750 TI - Lateral displacement as a function of particle size using a piecewise curved planar interdigitated electrode array. AB - We describe the lateral displacement of a particle passing over a planar interdigitated electrode array at an angle as a function of the particle size. The lateral displacement was also measured as a function of the angle between the electrode and the direction of flow. A simplified line charge model was used for numerically estimating the lateral displacement of fluorescent polystyrene (PS) beads with three different diameters. Using the lateral displacement as a function of particle size, we developed a lateral dielectrophoretic (DEP) microseparator, which enables continuous discrimination of particles by size. The microchannel was divided into three regions, each with an electrode array placed at a different angle with respect to the direction of flow. The experiment using an admixture of 3-, 5-, and 10-microm PS beads showed that the lateral DEP microseparator could continuously separate out 99.86% of the 3-microm beads, 98.82% of the 5-microm beads, and 99.69% of the 10-microm beads, simply by using a 200-kHz 12-Vp-p AC voltage to create the lateral DEP force. The lateral DEP microseparator is thus a practical device for simultaneously separating particles according to size from a heterogeneous admixture. PMID- 19789751 TI - A cell chip for sequential imaging of individual non-adherent live cells reveals transients and oscillations. AB - Advances in molecular cell biology, medical research, and drug development are driving a growing need for technologies that enable imaging the dynamics of molecular and physiological processes simultaneously in numerous non-adherent living cells. Here we describe a platform technology and software--the CKChip system--that enables continuous, fluorescence-based imaging of thousands of individual living cells, each held at a given position ("address") on the chip. The system allows for sequential monitoring, manipulation and kinetic analyses of the effects of drugs, biological response modifiers and gene expression in both adherent and non-adherent cells held on the chip. Here we present four specific applications that demonstrate the utility of the system including monitoring kinetics of reactive oxygen species generation, assessing the intracellular enzymatic activity, measuring calcium flux and the dynamics of target cell killing induced by conjugated cytotoxic T-lymphocytes. We found large variations among individual cells in the overall amplitude of their response to stimuli, as well as in kinetic parameters such as time of onset, initial rate and decay of the response, and frequency and amplitude of oscillations. These variations probably reflect the heterogeneity of even cloned cell populations that would have gone undetected in bulk cell measurements. We demonstrate the utility of the system in providing kinetic parameters of complex cellular processes such as Ca++ influx, transients and oscillations in numerous individual cells. The CKChip opens up new opportunities in cell-based research, in particular for acquiring fluorescence-based, kinetic data from multiple, individual non-adherent cells. PMID- 19789752 TI - Inertial microfluidics for continuous particle separation in spiral microchannels. AB - In this work we report on a simple inertial microfluidic device that achieves continuous multi-particle separation using the principle of Dean-coupled inertial migration in spiral microchannels. The dominant inertial forces coupled with the Dean rotational force due to the curvilinear microchannel geometry cause particles to occupy a single equilibrium position near the inner microchannel wall. The position at which particles equilibrate is dependent on the ratio of the inertial lift to Dean drag forces. Using this concept, we demonstrate, for the first time, a spiral lab-on-a-chip (LOC) for size-dependent focusing of particles at distinct equilibrium positions across the microchannel cross-section from a multi-particle mixture. The individual particle streams can be collected with an appropriately designed outlet system. To demonstrate this principle, a 5 loop Archimedean spiral microchannel with a fixed width of 500 microm and a height of 130 microm was used to simultaneously and continuously separate 10 microm, 15 microm, and 20 microm polystyrene particles. The device exhibited 90% separation efficiency. The versatility of the device was demonstrated by separating neuroblastoma and glioma cells with 80% efficiency and high relative viability (>90%). The achieved throughput of approximately 1 million cells/min is substantially higher than the sorting rates reported by other microscale sorting methods and is comparable to the rates obtained with commercial macroscale flow cytometry techniques. The simple planar structure and high throughput offered by this passive microfluidic approach make it attractive for LOC devices in biomedical and environmental applications. PMID- 19789753 TI - Generation of Janus alginate hydrogel particles with magnetic anisotropy for cell encapsulation. AB - A microfluidic approach for fabrication of Janus hydrogel particles with magnetic anisotropy is demonstrated. Using this technique, cells and magnetic beads (MBs) can be separately embedded in one hydrogel particle to maintain optical performance, and reduce the contact between cells and magnetic beads (nano- or submicron-particles). Alginate cell capsules prepared by this method can be easily controlled and manipulated by external magnetic fields and require no specific surface modification. Bio-degradability and super-paramagnetic properties of these hydrogel particles were also demonstrated experimentally. PMID- 19789754 TI - Single step patterning of molecularly imprinted polymers for large scale fabrication of microbiochips. AB - We use photolithography to pattern molecularly imprinted polymers for the wafer scale production of biochips. We are able to produce multiplexed, spatially resolved micrometer-sized features of functional materials capable of molecular recognition. Using a fluorescent probe, dansyl-L-Phe, we show specific analyte binding to MIP patterns imprinted with boc-L-Phe, by fluorescence microscopy. Advantages of this technique are the control of shape and size of the patterns with a resolution of 1.5 microm, and the possibility of depositing a number of different MIPs on the same chip (parallelization). Multiplexing chips on the same substrate paves the road to their mass-production. Because of the simplicity of the method and the low cost of chip fabrication, we believe that mass production of portable microbiochips based on stable MIPs is now in close reach. Their combination with integrated transducers fabricated by micromachining techniques appears also possible. PMID- 19789755 TI - On-chip manipulation of continuous picoliter-volume superparamagnetic droplets using a magnetic force. AB - A microfluidic device for generating monodisperse superparamagnetic droplets and rapidly manipulating desired droplets into designated sub-microchannels by an external magnetic force is described. Superparamagnetic magnetite (Fe3O4) nanoparticles are synthesized by a chemical co-precipitation method. They are well dispersed in the water-phase to form a superparamagnetic fluid that is sheared into picoliter-volume monodisperse superparamagnetic droplets by the oil phase in a T-junction PDMS microchannel. Superparamagnetic droplets always flow into sub-microchannel 1 due only to laminar flow without a magnetic field. But they are deflected from the direction of laminar flow by a perpendicular magnetic field. The results show that the deflection is proportional to the magnetic field gradient and magnetic nanoparticle concentration, and it is closely related to the magnet position. The observed experimental results make a good match with theoretical analysis. Single or bulk superparamagnetic droplets are successfully manipulated into the designated sub-microchannels 2 and 3 respectively, only by changing the positions of the magnet. Relatively high efficiency is obtained with more than 10 superparamagnetic droplets precisely manipulated per second. This simple and robust apparatus has wide applications in high throughput drug delivery/screening, immunoassay, cell research and synthesis of magnetic microparticles due to good biological compatibility and monodispersity of superparamagnetic droplets. PMID- 19789756 TI - Rapid replication of master structures by double casting with PDMS. AB - We present a simple method for fast and precise replication of microfluidic master structures for moulding or soft embossing by double casting of microstructured masters with polydimethylsiloxane (PDMS). The significant achievement is a simple approach to inverse a given microstructure multiple times by means of PDMS-based soft lithography utilising hydroxypropylmethylcellulose (HPMC) as non texturing release agent. A series of PDMS copies have been generated from different silicon layouts with excellent reproducibility and precision, even submicron structures were well reproduced. The replicas were successfully applied in hot embossing and soft lithography of microfluic devices. Hence, we believe this technique is ideally suited for the economic replication of precious master structures (master sharing) commonly used in soft lithography and hot embossing. PMID- 19789757 TI - Multi-channel peristaltic pump for microfluidic applications featuring monolithic PDMS inlay. AB - The design, fabrication and characterization of a miniaturized, mechanically actuated 12-channel peristaltic pump for microfluidic applications and built from simple, low-cost materials and fabrication methods is presented. Two pump configurations are tested, including one which reduces pulsating flow. Both use a monolithic PDMS pumping inlay featuring three-dimensional geometries favourable to pumping applications and 12 wholly integrated circular channels. Flow rates in the sub-microL min(-1) to microL min(-1) range were obtained. Channel-to-channel flow rate variability was comparable to a commercial pumping system at lower flow rates. The small footprint, 40 mm by 80 mm, of the micropump renders it portable, and allows its use on microscope stages adjacent to microfluidic devices, thus reducing system dead volumes. The micropump's design allows potential use in remote and resource-limited locations. PMID- 19789758 TI - Co-axial capillaries microfluidic device for synthesizing size- and morphology controlled polymer core-polymer shell particles. AB - An easy assembling-disassembling co-axial capillaries microfluidic device was built up for the production of double droplets. Uniform polymer core-polymer shell particles were synthesized by polymerizing the two immiscible monomer phases composing the double droplet. Thus poly(acrylamide) core poly(tri(propylene glycol) diacrylate) shell particles with controlled core diameter and shell thickness were simply obtained by adjusting operating parameters. An empirical law was extracted from experiments to predict core and shell sizes. Additionally uniform and predictable non-spherical polymer objects were also prepared without adding shape-formation procedures in the experimental device. An empirical equation for describing the lengths of rod-like polymer particles is also presented. PMID- 19789759 TI - A vast-range speed control microchip for retention of all cell types. AB - This Technical Note is the first description of a large-scale logarithmic flow rate damping system designed to retain cells of different adherence, different suspensibility and different motility. The chamber, which can easily retain and cultivate many types of cells, including high-motility cells and swimming cells, via a series of "speed bumps", readily facilitates cell retention for complex heterogeneous cultures. Yeast cells, red blood cells, rabbit bone marrow aspirate and dinoflagellate swimming cells were introduced into the chip for multi-cell retention, multi-cell culture and observation. Here, we show that the chamber creates a flow field with a ratio of end/start speeds as low as 0.01. The logarithmic distribution of flow-rate within the chamber is controlled precisely by pressure, all of the cell types that we tested were retained easily within the chamber. Many cell-cell interactions were observed, predicting a high potential for the success of on-chip heterogeneous cell experiments. PMID- 19789760 TI - Fabrication of reversibly adhesive fluidic devices using magnetism. AB - Fluidic devices are often made by irreversibly bonding a polydimethylsiloxane (PDMS) mold to itself or a glass substrate by plasma treatment. This method limits the range of materials for fluidic device fabrication and utility for subsequent processing. Here, we present a simple and inexpensive method to fabricate fluidic devices using magnets to reversibly adhere PDMS and other polymer matrices to glass or gel substrates. This approach enables fluidic devices to be fabricated from a variety of materials other than PDMS and glass. Moreover, this method can be used to fabricate composite devices, three dimensional scaffolds and hydrogel-based fluidic devices. PMID- 19789765 TI - Ligating properties of anionic Fischer-type carbene complexes, [(CO)(5)M[double bond, length as m-dash]C(X)Y](-). AB - With the simplest of anionic Fischer-type carbene complexes acting as ligands, Cp(2)Zr(Cl){OCMe}M(CO)(5) compounds (M = Cr or W) promote alpha-olefin oligomerization and polymerization in the presence of MAO. Attaching an N heterocyclic ring to the carbene carbon atom in similar precursors, allows a variety of hard metal ions and fragments to be captured by external bidentate coordination. The outcome of the attachment of a phosphorus or sulfur functionality to an alpha-carbon of an O-anionic carbene is formation of a bidentate ligand and then internal four-membered carbene-heteroatom chelate formation. alpha-Deprotonated carbene complexes are also precursors for remote, one-N, six-membered carbene complexes of various metals whereas alpha-C-, alpha-N or alpha-O-deprotonated as well as beta-deprotonated Fischer-type carbene complexes display unique synthon properties towards Ph(3)PAu(+) and partake in unusual ensuing coordination of liberated group 6 metal carbonyl moieties to form dinuclear products. PMID- 19789766 TI - Expanding the role of oxo-molybdenum(VI) catalysts: a DFT interpretation of X-H activation leading to reduction or oxidation. AB - Organometallic complexes of transition metals in high oxidation states, namely Re(v) and Mo(vi), have been shown experimentally to catalyze a variety of reduction reactions, such as hydrosilylation of ketones, alkyne hydrogenation, sulfoxide reduction (deoxygenation), etc, often under mild conditions and with high yields and selectivity. These recently found reactions apparently contrast with the traditional oxidation of alkenes in the presence of an oxygen source. We describe a series of DFT calculations, showing that most X-H bonds are activated by [MoO(2)Cl(2)], forming a hydride complex, which is the catalytic active species in catalysis. This occurs by a [2 + 2] addition of the X-H bond to the Mo[double bond, length as m-dash]O bond of the Mo(vi) complex. While hydrosilylation is particularly effective, hydrogenation is deactivated in many systems by the reduction of the catalyst, rather than the substrate, to a stable Mo(iv) complex, and P-H activation in HP(O)(OR)(2) molecules takes place through a different route. The activation of O-H from HOOR differs significantly, since the high electronegativity of oxygen results in an "inverse" addition with formation of OH and a complex of OOR. PMID- 19789767 TI - Intermediate spin ground state of an isosceles triangular [Mn(II)(3)] complex. AB - [{Mn(tmeda)}(3){GeSe(3)(OMe)}(2)] (), synthesized by the reaction of [K(4)(H(2)O)(3)][Ge(2)Se(6)] with MnCl(2).4H(2)O in MeOH-tmeda (tmeda = N,N,N',N' tetramethyl-1,2-diaminoethane), exhibits an isosceles triangular arrangement of Mn(2+) ions that are antiferromagnetically coupled with an S = 3/2 ground state. PMID- 19789768 TI - Diastereoselective complex formation with a simple C(2)-symmetric hexadentate ligand based on a 1,1'-binaphthalene scaffold. AB - A pair of enantiomerically pure ligands have been prepared from the condensation of (S)-(-)-1,1'-binaphthalene-2,2'-diamine or (R)-(+)-1,1'-binaphthalene-2,2' diamine with two equivalents of 2,2'-bipyridine-6-carbaldehyde. The reaction of these new hexadentate ligands with iron(II) salts results in diastereomerically pure complexes in which the stereochemistry at the metal is fully defined by the chiral ligand scaffold. The simplicity of synthesis of the ligand suggests that conjugates of this type could play an important role in inorganic stereoselective synthesis. PMID- 19789769 TI - One- and two-electron reduction of molybdate reversibly bound to the archaeal tungstate/molybdate transporter WtpA. AB - Reversible binding of the tetrahedral oxoanions MoO(4)(2-) and WO(4)(2-) to two carboxylato ligands of the soluble scavenger protein WtpA from the hyperthermophilic archaeon Pyrococcus furiosus enforces a quasi-octahedral MO(6) coordination in which the +VI oxidation state is destabilized. PMID- 19789770 TI - Synthesis of the triply-bonded dimolybdenum anions [Mo(2)(eta(5)-C(5)H(5))(2)(mu PA(2))(mu-CO)(2)](-) (A = Cy, Et, Ph, OEt): unsaturated hydride and carbyne derivatives. AB - Tetrahydrofuran solutions of the 30-electron anions [Mo(2)Cp(2)(mu-PA(2))(mu CO)(2)](-) (A = Cy, Et, Ph, OEt) are conveniently prepared through a two-step approach. In the first step, [Mo(2)Cp(2)(CO)(6)] is treated with the chlorophosphines ClPR(2) (R = Cy, Et, Ph) or the chlorophosphite ClP(OEt)(2), in refluxing toluene or diglyme respectively, to give the corresponding 32-electron chloro-complexes [Mo(2)Cp(2)(mu-Cl)(mu-PA(2))(CO)(2)] as major products. In the second step, these air-sensitive intermediates are treated in tetrahydrofuran solution at room temperature with one of several reducing agents such as Li[BHEt(3)], Li(Hg), Na(Hg) or K[BH(s)Bu(3)] to give red solutions of the corresponding alkali-metal salts of the anions, which display significant ion pairing involving one or both oxygen atoms of the bridging carbonyl ligands, depending on the cation. All these triply bonded species are quite air-sensitive and could not be isolated as pure solids, but they can be easily protonated using a weak acid such as [NH(4)]PF(6) to give with good yield the corresponding unsaturated hydrides [Mo(2)Cp(2)(mu-H)(mu-PA(2))(CO)(2)], which are species of low to moderate sensitiveness to air, and also formally containing an intermetallic triple bond. The reactivity of the dicyclohexylphosphide-bridged anion (mainly as its Li(+) salt) towards different hydrocarbon halides RX was studied in detail. These reactions were found to be rather complex, critically depending on the reagent used, and generally resulting in the formation of several products, of which four types were identified: (a) the known agostic products [Mo(2)Cp(2)(mu-PCy(2))(mu-R)(CO)(2)] (R = Me, CH(2)Ph), (b) the new alkoxycarbyne products [Mo(2)Cp(2)(mu-COR)(mu-PCy(2))(mu-CO)] [R = Me, Et, C(O)Ph, (i)Pr, Cy], which could be conveniently isolated as pure solids, (c) the iodoxycarbyne complex [Mo(2)Cp(2)(mu-COI)(mu-PCy(2))(mu-CO)], a very unstable species formed in the reaction with EtI, and (d) the halide complexes [Mo(2)Cp(2)(mu-PCy(2))(mu-X)(CO)(2)] [X = Cl, Br, I], which were more conveniently prepared by the direct reaction of the anion with the pertinent halogen (X = Br, I). The analysis of the above results suggests that at least three primary reaction pathways are in operation: (a) nucleophilic attack of the anion through its dimetal centre, (b) nucleophilic attack of the anion through the oxygen atoms of its bridging carbonyls and (c) electron-transfer with the reagent, this being the main path to the halo-complexes [Mo(2)Cp(2)(mu-PCy(2))(mu X)(CO)(2)]. PMID- 19789771 TI - A ligand knowledge base for carbenes (LKB-C): maps of ligand space. AB - We describe the development of a ligand knowledge base designed to capture the properties of C-donor ligands coordinating to transition metal centres, LKB-C. This knowledge base has been developed to describe both singlet (Arduengo and Fischer) and triplet (Schrock) carbenes, as well as related neutral monodentate C donor ligands. The descriptors evaluated and used have been derived from a range of coordination environments to maximise their transferability and hence utility for the investigation of such ligands. These descriptors have been analysed with different statistical approaches, both individually to determine their chemical context, and collectively by principal component analysis thereby allowing the derivation of maps of ligand space for different ligand sets. The utility of such maps for investigating ligand similarity and identification of target areas for future ligand designs has been discussed. In addition, linear regression models have been fitted for the prediction of a calculated response variable, highlighting further potential applications of such a knowledge base. PMID- 19789772 TI - A study of phosphate absorption by magnesium iron hydroxycarbonate. AB - A study of the mechanism of phosphate adsorption by magnesium iron hydroxycarbonate, [Mg(2.25)Fe(0.75)(OH)(6)](CO(3))(0.37).0.65H(2)O over a range of pH has been carried out. The efficiency of the phosphate removal from aqueous solution has been investigated between pH 3-9 and the resulting solid phases have been studied by elemental analysis, XRD, FT-IR, Raman, HRTEM, EDX and solid-state MAS (31)P NMR. The analytical and spectroscopic data suggest that phosphate removal from solution occurs not by anion intercalation of the relevant phosphorous oxyanion (H(2)PO(4)(-) or HPO(4)(2-)) into the LDH but by the precipitation of either an insoluble iron hydrogen phosphate hydrate and/or a magnesium phosphate hydrate. PMID- 19789773 TI - (1)H NMR spectroscopic identification of binding modes of 2,2'-bipyridine ligands in complexes of square-planar d(8) metal ions. AB - The reaction of [M(bpy)](2+) (M = Pd(II) and/or Pt(II); bpy = 2,2'-bipyridine) moieties with model nucleobases leads to a variety of products, viz. 1 : 1, 1 : 2 and 2 : 2 (head-tail, ht, or head-head, hh) complexes. By carefully analysing the H5 (H5') resonances of the bpy ligands, which in all cases occur furthest upfield, and with additional indicators (concentration dependence of H6, H6' resonances; (195)Pt-(1)H coupling constants, if observable; absolute shifts of H5, H5'), it is possible to assign binding situations of bpy ligands, even in multinuclear complexes with several [M(bpy)](2+) entities in different environments present. The analysis presented here is carried out on X-ray structurally established cases of [M(bpy)](2+) complexes, including three new ones, [Pt(1-MeC-N3)(2)(bpy)](NO(3))(2).2.5H(2)O (), ht-[(bpy)Pd(N3-1-MeC(-) N4)(2)Pd(bpy)](ClO(4))(2).3H(2)O () and ht-[(bpy)Pd(N1-ampy(-) N2)(2)Pd(bpy)](NO(3))(2).3H(2)O (). The data provide a consistent picture, useful for the future assignment of similar bpy complexes in the absence of X-ray structural evidence. PMID- 19789774 TI - Ferro- and anti-ferromagnetically coupled tetracopper(II) 2 x 2 homoleptic rectangular grids supported by both mu-O and mu-(N-N) bridges derived from a new pyrazole based polydentate Schiff base ligand-magneto-structural correlations and DFT calculation. AB - The pyrazole derived Schiff base polytopic ligand 5-methyl-N'-[1-(pyridin-2 yl)ethylidene]-1H-pyrazole-3-carbohydrazide (PzCAP), prepared by the reaction between 5-methylpyrazole-3-carbohydrazide and 2-acetyl pyridine, has two potentially bridging functional groups [mu-O and mu-(N-N)] and consequently can exhibit different coordination conformations. Two tetranuclear homoleptic copper(II) 2 x 2 rectangular grid-complexes [Cu(4)(PzCAP)(4)(NO(3))(2)] (NO(3))(2).8H(2)O (1) and [Cu(4)(PzCAP)(4)(ClO(4))(2)] (ClO(4))(2) (2) were formed by a strict self-assembly process employing metal and ligand under 1:1 mol proportion. Each pair of the ligand molecules in the two complexes are arranged in roughly parallel fashion but under different conformations. The ligand PzCAP contains terminal pyridine and pyrazole residues bound to a central flexible diazine subunit (N-N). The rectangular Cu(II) 2 x 2 grid complexes having [Cu(4)(mu-N-N)(2)(mu-O)(2)] core involve a mixture of two diazine (Cu-N-N-Cu approximately 160 degrees ) and two alkoxo (Cu-O-Cu approximately 138 degrees ) bridges along the length and breadth respectively. In the [Cu(4)(mu-N-N)(2)(mu O)(2)] core in , out of the four Cu(II) centers, all are hexa-coordinated but there are two penta-coordinated and two hexa-coordinated Cu(II) centers in the same core of . Each complex having the central [Cu(4)(mu-N-N)(2)(mu-O)(2)] core, exhibits quite different magnetic interactions among the metal centers. The paramagnetic Cu(II) centers bridged through the diazine fragment are involved in anti-ferromagnetic interaction while a dominant ferromagnetic interaction prevails between the alkoxo-bridged Cu(II) centers. The [Cu(4)(mu-N-N)(2)(mu O)(2)] cluster in shows both ferromagnetic and anti-ferromagnetic interaction (J(1) = -0.80 cm(-1) and J(2) = +3.49 cm(-1)), a very unusual characteristic in this system while the same cluster in exhibits dominant anti-ferromagnetic coupling (J(1) = -89.1 cm(-1) and J(2) = +5.5 cm(-1)) through the trans Cu-(N-N) Cu bridging arrangement, typical for systems of this sort. Both the complexes and have been characterized structurally, magnetically and spectroscopically. The exchange pathways parameters (J(1) and J(2)) have also been evaluated from density functional theoretical calculations to corroborate the bridging signatures with experimental findings. PMID- 19789775 TI - Competitive bulk liquid membrane transport and solvent extraction of some metal ions using RC(S)NHP(X)(OiPr)(2) (X = O, S) as ionophores. Formation of the polynuclear complex of [Ag(N[triple bond]C-NP(S)(OiPr)(2))](n). AB - Competitive transport experiments involving metal ions from an aqueous source phase through a chloroform membrane into an aqueous receiving phase have been carried out using a series of N-(thio)phosphorylated (thio)amide and thiourea ligands as the ionophore present in the organic phase. The source phase contained equimolar concentrations of Co(II), Ni(II), Cu(II), Zn(II), Ag(I), Cd(II) and Pb(II) with the source and receiving phases being buffered at a number of different pHs. Solvent extraction properties of the ligands towards the same metal cations under the same experimental conditions as for the transport were also studied. All ligands demonstrated 100% extraction of Ag(I). Reaction of AgNO(3) with the potassium salt of the N-thiophosphorylated thiourea NH(2)C(S)NHP(S)(OiPr)(2) gave a new supramolecular Ag(I) complex, [AgZ](n) (Z = {N[triple bond]C-NP(S)(OiPr)(2)}(-)) that contains both tri- and tetracoordinated Ag(I). The novel polynuclear Ag(I) complex [AgZ](n) described and structurally characterized by single crystal X-ray diffraction has no precedent. PMID- 19789776 TI - Zirconium and hafnium complexes supported by linked bis(beta-diketiminate) ligands: synthesis, characterization and catalytic application in ethylene polymerization. AB - Zirconium and hafnium complexes bearing new 1,2-ethanediyl- or 1,3-propanediyl linked bis(beta-diketiminate) ligands, [{C(n)H(2n)-(BDI(Ar))(2)}MCl(2)] (Ar = 2,6 Me(2)-C(6)H(3), 2,6-Cl(2)-C(6)H(3), 2,6-(i)Pr(2)-C(6)H(3); M = Zr, n = 2 (4a-c), n = 3 (5a-c); M = Hf, n = 2 (6b)), were synthesized via the reaction of MCl(4).2THF and one equivalent of dilithium salt of the corresponding ligand. Distorted trigonal prismatic and octahedral coordination geometries as well as C(1)-symmetric structures are found for zirconium complexes and in the solid state. Variable temperature (1)H NMR spectra indicated the fluxional nature of and in solution. Upon activation with methylaluminoxane (MAO), all these complexes except hafnium complex displayed moderate catalytic activities for ethylene polymerization. 1,2-Ethanediyl-linked complexes and are generally more active than their 1,3-propanediyl-linked analogues. The substituents at the ortho positions of the phenyl rings have different effect on the catalytic activities of 1,2-ethanediyl-linked series or 1,3-propanediyl-linked series. It is noteworthy that even at a low Al/Zr molar ratio of 500, the catalytic activities of these zirconium complexes could be retained. Polyethylenes with broad molecular weight distributions (MWD = 15.3-20.3) were produced, which might result from the fluxional character of the zirconium complexes. The linear structure of obtained polyethylenes was further determined by (13)C NMR spectroscopy and DSC analysis. PMID- 19789777 TI - Preparation and structural characterization of a series of monoacylhydrazidate bridged coordination polymers. AB - From the simple hydrothermal reactions of metal salts, organodicarboxylic acids and hydrazine hydrate sometimes in the presence of 1,10-phenanthroline (phen), a series of monoacylhydrazidate-containing complexes including three Pb(II) coordination polymers as 1-D chained [Pb(2)(PTH)(4)(phen)(2)].H(2)O (PTH = phthalhydrazidate) , 1-D ribboned [Pb(2,3-PDH)(2)] (2,3-PDH = pyridine-2,3 dicarboxylhydrazidate) and 3-D grid-like [Pb(3,4-PDH)(2)] (3,4-PDH = pyridine-3,4 dicarboxylhydrazidate) as well as several transition metal complexes as 2-D layered [Cu(PTH)] , mononuclear [M(2,3-PDH)(2)(H(2)O)(2)] (M = Mn , Co and Zn ) and mononuclear [Mn(H(2)O(6))] (PTH)(2).4H(2)O were obtained. The monoacylhydrazidate ligands were synthesised from hydrothermal in situ acylation reactions between organodicarboxylic acids and hydrazine hydrate. All of the title compounds were characterized by CHN analysis, IR analysis and TG analysis, and compounds were characterized by X-ray single-crystal diffraction. The fluorescence properties of compounds and with the PTH ligand were investigated. TDDFT calculations were carried out on the excited electronic states of compound in order to understand the emission mechanism. PMID- 19789778 TI - Thermodynamic study of proton transfer reactions of Re(V) trans-dioxocomplexes in aqueous solution. AB - The thermodynamics of protonation of trans-[Re(V)O(2)L(2)](+) (L = aliphatic di and polyamines) complexes in aqueous solution was studied by using experimental and theoretical approaches. The complexes containing diamines undergo protonation on the oxo ligands, whereas those containing polydentate amines protonate on uncoordinated amino groups. The protonation reactions were studied experimentally by microcalorimetric techniques, in all cases exothermic with |DeltaH degrees | ranging from 7 to 50 kJ/mol. For complexes containing diamines, the exothermicity was in concordance with the basicities in some cases, while in others no systematic behaviour was found. For complexes with polydentate amines, the enthalpy dominates with a modest influence on the entropy. Theoretically, Density Functional Theory (DFT) methods were employed in the gas phase, and bulk solvent effects were treated by means of the Polarizable Continuum Model. Direct solute solvent effects were considered adding explicit water molecules. The enthalpy change calculated in the gas phase was in marked disagreement with the experimental results due to the relevancy of solvation/desolvation processes. The explicit inclusion of water molecules led to a good improvement. A discrete continuum model was also employed, for which DeltaG degrees was overestimated in all cases. Further investigations, both experimental and theoretical are necessary to get a more complete picture of the proton transfer reactions of these complexes. The experimental values herein determined constitute the first step to construct a set of data to which it is possible to benchmark new theoretical approaches to compute the thermodynamics of proton transfer reactions of metal complexes in aqueous solution. PMID- 19789779 TI - Synthesis, structures and reactivity of 2-phosphorylmethyl-1H-pyrrolato complexes of titanium, yttrium and zinc. AB - The reaction of secondary phosphines HPR(2) (R = Ph, Cy) with pyrrole-2-aldehydes gives a new family of 2-phosphorylmethyl-1H-pyrroles as potentially chelating mono-anionic ligands. The reaction with Ti(NMe(2))(4) affords octahedral Ti(NMe(2))(2){NC(4)H(2)(4-R')CH(2)P(O)R(2)}(2) (R' = H, Bu(t)). While the diphenylphosphoryl complexes adopt a configuration with trans-pyrrolato ligands, the dicyclohexyl analogue prefers an all-cis conformation, with profound consequences on metal-ligand bonding. The reaction of sterically undemanding HNC(4)H(3)CH(2)P(O)Ph(2) with Y[N(SiHMe(2))(2)](3)(THF)(2) give the homoleptic complex Y[NC(4)H(3)CH(2)P(O)Ph(2)](3); mixed-ligand intermediates Y[N(SiHMe(2))(2)](2)(N-O) and Y[N(SiHMe(2))(2)](N-O)(2) were identifiable but could not be isolated. The bulky ligand HNC(4)H(2)(5-Bu(t))CH(2)P(O)Ph(2) does not react with Ti(NMe(2))(4) but protolyses Zn[N(SiMe(3))(2)](2) to give a 1 : 2 complex Zn(N-O)(2) as the only isolable product. On the other hand, its reaction with Y[N(SiHMe(2))(2)](3)(THF)(2) affords the mono-amido complex Y{N(SiHMe(2))(2)}{NC(4)H(3)(5-Bu(t))CH(2)P(O)Ph(2)}(2) which shows good activity for the ring-opening polymerisation of cyclic esters. PMID- 19789780 TI - Pseudomorphic 2A--> 2M--> 2H phase transitions in lanthanum strontium germanate electrolyte apatites. AB - Apatite-like materials are of considerable interest as potential solid oxide fuel cell electrolytes, although their structural vagaries continue to attract significant discussion. Understanding these features is crucial both to explain the oxide ion conduction process and to optimise it. As the composition of putative P6(3)/m apatites with ideal formula [A(I)(4)][A(II)(6)][(BO(4))(6)][X](2) is varied the [A(I)(4)(BO(4))(6)] framework will flex to better accommodate the [A(II)(6)X(2)] tunnel component through adjustment of the A(I)O(6) metaprism twist angle (varphi). The space group theory prescribes that framework adaptation during phase changes must lead to one of the maximal non-isomorphic subgroups of P6(3)/m (P2(1), P2(1)/m, P1[combining macron]). These adaptations correlate with oxygen ion conduction, and become crucial especially when the tunnels are filled by relatively small ions and/or partially occupied, and if interstitial oxygens are located in the framework. Detecting and completely describing these lower symmetry structures can be challenging, as it is difficult to precisely control apatite stoichiometry and small departures from the hexagonal metric may be near the limits of detection. Using a combination of diffraction and spectroscopic techniques it is shown that lanthanum strontium germanate oxide electrolytes crystallise as triclinic (A), monoclinic (M) and hexagonal (H) bi-layer pseudomorphs with the composition ranges: [La(10-x)Sr(x)][(GeO(4))(5+x/2)(GeO(5))(1-x/2)][O(2)] (0 cis [PdRf(2)L(2)] + 2THF (THF = tetrahydrofuran) has been measured in THF by calorimetric methods for Rf = 3,5-dichloro-2,4,6-trifluorophenyl, L = PPh(3), AsPh(3), SbPh(3), PMePh(2), PCyPh(2), PMe(3), AsMePh(2), or L(2) = dppe (1,2 bis(diphenylphosphino)ethane), dppf (1,1'-bis(diphenylphosphino)ferrocene). The values determined show that the substitution enthalpy has a strong dependence on the electronic and steric properties of the ligand. The study of the consecutive substitution reactions cis-[PdRf(2)(THF)(2)] + L -->cis-[PdRf(2)L(THF)] + THF, and cis-[PdRf(2)L(THF)] + L -->cis-[PdRf(2)L(2)] + THF has been carried our for L = PPh(3) and L = PCyPh(2). The first substitution is clearly more favorable for the bulkier leaving ligand, but the second gives practically the same DeltaH value for both cases, indicating that the differences in steric hindrance happen to compensate the electronic differences for both ligands. The X-ray structures of cis-[PdRf(2)(PMePh(2))(2)], cis-[PdRf(2)(dppe)] and cis-[PdRf(2)(dppf)] are reported. PMID- 19789797 TI - Sensitised near-IR lanthanide luminescence exploiting anthraquinone-derived chromophores: syntheses and spectroscopic properties. AB - The syntheses of two anthraquinone-derived tetraaza macrocyclic ligands (L1 via 1 amino-9,10-anthraquinone and L2 via 1-amino-4-hydroxy-9,10-anthraquinone) together with their corresponding LnIII complexes, Ln-L1/2 (Ln = NdIII, GdIII, ErIII, YbIII), are described. Both Ln-L1 (lambda(max) approximately 380 nm) and Ln-L2 (lambda(max) approximately 450 nm) complexes absorb in the visible region with good extinction coefficients (epsilon(vis) > 2 x 10(3) M-1 cm-1). Phosphorescence measurements on Gd-L1/2 at 77 K allowed the ligand-centred triplet states to be estimated at ca. 22000 cm-1 and 19800 cm-1 for Gd-L1 and Gd L2 respectively. Steady state and time-resolved measurements showed that both chromophores sensitised NdIII, ErIII and YbIII ions, resulting in observable near IR emission. Preliminary studies on the pH-dependent behaviour of the L2 derivatives demonstrated that deprotonation of the 4-hydroxyl group at pH 12 resulted in a significant bathochromic shift in the absorption profile, thus allowing sensitised near-IR emission utilising lambda(ex) = 575 nm. PMID- 19789798 TI - Synthesis and characterization of molecular rectangles of half-sandwich p-cymene ruthenium complexes bearing oxamidato ligands. AB - A series of binuclear half-sandwich p-cymene ruthenium complexes bearing oxamidato ligands [(p-cymene)(2)Ru(2)(mu-N,N'-bis(aryl)oxamidato)Cl(2)] (1-3) was synthesized by the reactions of the lithium salts of oxamide with [(p cymene)RuCl(2)](2), respectively. Treatment of the binuclear complexes (1-3) with bidentate ligands such as 4,4'-bipyridine (4,4'-bpy) and trans-1,2-bis(4 pyridyl)ethylene (bpe) in the presence of AgOTf (OTf = CF(3)SO(3)) gave the corresponding tetranuclear complexes generally formulated as [(p cymene)(4)Ru(4)(mu-N,N'- bis(aryl)oxamidato)(2)(mu-4,4'-bpy)(2)](OTf)(4) (4a-c) and [(p-cymene)(4)Ru(4)(mu-N,N'-bis(aryl)oxamidato)(2)(mu-bpe)(2)](OTf)(4) (5a-c) in high yields. All compounds (1-3, 4a-5c) have been characterized by NMR and IR spectra and elemental analyses. The molecular structures of , and have been determined by single-crystal X-ray analyses. The molecular structures of tetranuclear complexes and showed that two binuclear fragments as building blocks were connected by 4,4'-bpy or bpe to construct a rectangular cavity with the dimensions 5.57 x 11.28 A (4a) and 5.56 x 13.65 A (5a). PMID- 19789799 TI - Role of the orientation of -OH groups in the sensitivity and selectivity of the interaction of M(2+) with ribosyl- and galactosyl-imino-conjugates. AB - Three glyco-conjugates, viz., L(1), L(2) and L(3), which differ either in their carbohydrate moiety or in their aromatic moiety or both, were synthesized and characterized and were shown to have beta-anomeric form based on (1)H NMR and optical rotation studies. Metal ion interaction studies carried out in solution by emission and absorption spectral techniques exhibited selectivity towards Cu(2+) in HEPES buffer and a two fold higher sensitivity for L(2) as compared to L(1). The composition of the complexed species has been established based on ESI MS. Dinuclear-Cu(II) complexes of all these conjugates have been synthesized and characterized based on analytical and spectral methods including FTIR, (1)H NMR, FAB MS, EPR, ORD, CD and magnetism, and the structures of and have been established based on single crystal XRD. The structures revealed subtle differences present in the orientation of the -OH groups and also their ion binding preferences both at the molecular level as well as at the lattice levels. In the dinuclear-Cu(II) complexes, while C3-O(-) of ribosyl acts as a bridging moiety in , it is the C2-O(-) of galactosyl that bridges in and the Cu(2)O(2) cores are stabilized by two intra-complex H-bond interactions formed using C4-OH in the case of and C3-OH in the case of . While the glyco-moiety is poised perpendicular to the average plane of the Cu(2)O(2) core in , this is in plane in the case of 3. PMID- 19789804 TI - Terrestrial humic substances induce photodegradation of polysaccharides in the aquatic environment. AB - Starch solution (8 mg dm(-3)) was irradiated with simulated solar UV radiation with and without addition of Aldrich humic acids (4 mg dm(-3)). Quantitative analysis of the photodegradation products revealed enhanced release of monosaccharides in the presence of humic substances [corrected]. PMID- 19789805 TI - A unique red fluorescent protein of silkworm bearing two photochromic moieties. AB - A silkworm excretory red fluorescent protein (SE-RFP) having light-dependent activity against Bombyx mori nucleopolyhedrovirus (BmNPV) was purified. Light was observed to be essential also for the SE-RFP synthesis as it was produced only when silkworms were reared in light. SE-RFP has exhibited a high fluorescence quantum yield of 0.86. The apparent mass of native SE-RFP was about 1100 kDa as analysed by gel filtration chromatography. Two photochromic moieties associated with the SE-RFP, namely tetrapyrrole-I (TP-I) and tetrapyrrole-II (TP-II), were isolated by employing TLC and HPTLC techniques. The purified tetrapyrroles were characterized by UV-absorption, fluorescence, atomic absorption and FT-IR spectral analyses. The molecular masses of TP-I and TP-II were 535 and 870 Da, respectively, as determined by ESI-MS and MALDI-TOF-MS. The molar ratio of TP-I to TP-II was 1.14 : 1.00, and a total of 7.251 micromol tetrapyrroles (TP-I + TP II) were found to be present per mg of SE-RFP. TP-I and TP-II were identified as chlorophyll derivatives, namely, pyropheophorbide a and pheophytin a, respectively. Hence, the SE-RFP was concluded to be a unique insect red fluorescent protein having two photochromic moieties and potent photobiological activity. PMID- 19789806 TI - Photophysical behaviour of ground state anion and phototautomer of 3 hydroxyflavone in liposome membrane. AB - A detailed account of the photophysical behaviour of the phototautomer (PT) and the ground state anion (A-) of 3-hydroxyflavone in liposome membrane at various membrane conditions is presented. A quenching study with a hydrophilic quencher Ag+ suggests that the phototautomeric emission generates from the fraction of 3HF that is located at the inner hydrophobic core, whereas the ground state anionic emission is from the fraction that resides near the water-accessible surface site. However, the biexponential nature of fluorescence decays of both the forms indicates that there is local heterogeneity in the distribution. Temperature dependence studies and experiments in the presence of ethanol reveal that, as the membrane becomes more fluid, redistribution of 3HF takes place between the two sites leading to increase in A- population. The temperature dependence of the fluorescence anisotropy change of PT shows good correlation with the phase change and shows a sharp drop at the transition temperature, whereas the corresponding change in the case of A- is gradual. PMID- 19789807 TI - Photocycloaddition of the T1 excited state of thioinosine to uridine and adenosine. AB - Novel photoadducts were obtained by irradiation of thioinosine (6-thiopurine riboside, TI) in deaerated aqueous solution without and in the presence of uridine and adenosine. Excitation (lambda > 300 nm) of TI to its excited S2 state yields a single bimolecular photoproduct. It is a purine-pyrimidine diriboside in which the purine ring is attached to the amide nitrogen of 6-amino-4-thioxo-5 formamidopyrimidine. When TI was irradiated in the presence of an excess of adenosine, two photoproducts were isolated: diribosides of N-(4,6 diaminopirymidin-5-yl)-N-formyl-6-aminopurine and N-(4-amino-6-formylamino pyrimidin-5-yl)-6-aminopurine, both containing a purine and a formylaminopyrimidine (Fapy) fragment. The photoreaction of TI with uridine gave two regioisomeric photoproducts identified as diribosides containing either 5- or 6-(purin-6-yl)uracil as aglycones. A multistep mechanism leading to the stable photoproducts is proposed. In the first step of the mechanism, the C=S group of the excited TI undergoes a [2 + 2] cycloaddition regioselectively to the N(7)=C(8) bond of the purine ring or adds in a non-regioselective manner to the C(5)=C(6) bond of uracil. The unstable photoproducts thus formed undergo a series of dark reactions at room temperature. The photocycloaddition reactions originate from the excited T1 state of TI. This conclusion is supported by a combination of evidence from reaction quenching studies using both steady-state quantum yield determinations and kinetics results from nanosecond laser flash photolysis. The T1 state of TI is quenched by other TI molecules in their S0 state (self quenching) and also by uridine and adenosine, all with large rate constants (0.8 5) x 10(9) M(-1) s(-1). The quantum yields of the reactions are in general very low (phi(R) < or = 8 x 10(-3)). The sources of the inefficiency in the photocycloaddition of TI to uridine and adenosine are discussed. The photoproducts containing the Fapy residue undergo deformylation and isomerization of the ribosyl moiety (anomerization, furanose/pyranose transformation) upon heating in aqueous solution. Products of the transformations were identified. PMID- 19789808 TI - Photo-crosslinking of polyethylene by mono- and diacetophenone derivatives and their precursors. AB - The efficiency of photochemical crosslinking of low-density polyethylene (PE) films by molecules containing one or two acetophenone groups and their precursors have been correlated with the relative rates of carbonyl group depletion under equivalent irradiation conditions. The acetophenone derivatives are found to be equally or more efficient than benzophenone as crosslinkers of PE. Because some additives are not thermodynamically equilibrated in the PE matrices and crystallize on standing at 30 degrees C, doped films were irradiated usually as soon as possible after their preparation. However, others were aged to determine the influence of equilibration on the efficiency of crosslinking. Thus, the effect of crystallization of some of the crosslinker additives in the PE matrices and the competition between photochemical addition of the carbonyl groups to C-H or C=C bonds of the polymer were investigated. GC-MS and FTIR analyses of photoproducts from irradiation of alkanophenones bearing a gamma-hydrogen atom in PE films showed that (intramolecular) Norrish Type II splitting and Yang cyclization processes proceed efficiently, and are more rapid than subsequent intermolecular hydrogen abstraction reactions by the acetophenone photoproducts. PMID- 19789810 TI - Long-range intramolecular photoredox reaction via coupled charge and proton transfer of triplet excited anthraquinones mediated by water. AB - The formal intramolecular photoredox reaction initially discovered for the parent 2-(hydroxymethyl)anthraquinone (1) has been extended to include analogs 3-6 in which the oxidizable benzyl alcohol group is significantly further away from the anthraquinone moiety. All of 3-6 undergo a clean and efficient formal intramolecular photoredox reaction in water catalyzed by acid (Phi = 0.1-0.6), in which the alcohol is oxidized to aldehyde and the anthraquinone is reduced to dihydroxyanthracene. The need for water, observation of acid catalysis, unimolecularity of reaction in anthraquinone, AM1 calculations and LFP studies support a mechanism involving a highly polarized triplet excited state in which the electron density of the distal phenyl moieties is transferred to the central anthraquinone ring, which is subsequently trapped adiabatically by protonation at the anthraquinone carbonyl oxygen and deprotonation at the benzyl C-H. PMID- 19789809 TI - Photochemically induced increase in endothelial permeability regulated by RhoA activation. AB - Photochemical reactions used in photodynamic therapy are reported to damage normal cells and tissues in ways that increase endothelial permeability and thereby cause excessive neointimal formation and subsequent restenosis. To investigate the mechanisms of this permeability increase in vitro, human umbilical vein endothelial cells were incubated with the porphyrin precursor delta-aminolevulinic acid and then irradiated with a 646 nm light-emitting diode (LED). Results using Transwells supports showed that the photochemical reaction increased endothelial permeability by 200%, and fluorescence microscopy revealed that destruction of the capillary-like structures due to cell shrinkage was accompanied by VE-cadherin mislocalization and stress fiber formation. The generated gaps between cells were observed using dyed beta1-integrin and total internal reflection fluorescence microscopy. Western blotting indicated that the photochemical reaction phosphorylated GDP-RhoA to GTP-RhoA, a protein that promotes stress fiber formation and inhibits VE-cadherin production. When forskolin/rolipram or 8CPT-2'O-Me-cAMP, both of which inhibit further reaction of phosphorylated RhoA, were added, no formation of stress fibers or mislocalization of VE-cadherin was observed, thus preventing an increase in endothelial permeability. Taken together, photochemically induced RhoA activation appears to play a key role in increasing endothelial permeability during changes in morphology of endothelial cells. PMID- 19789811 TI - The enzymatic nature of fungal bioluminescence. AB - The uncertainty about the possible involvement of a luciferase in fungal bioluminescence has not only hindered the understanding of its biochemistry but also delayed the characterization of its constituents. The present report describes how in vitro light emission can be obtained enzymatically from the cold and hot extracts assay using different species of fungi, which also indicates a common mechanism for all these organisms. Kinetic data suggest a consecutive two step enzymatic mechanism and corroborate the enzymatic proposal of Airth and Foerster. Finally, overlapping of light emission spectra from the fungal bioluminescence and the in vitro assay confirm that this reaction is the same one that occurs in live fungi. PMID- 19789812 TI - Photothermal sensitisation and therapeutic properties of a novel far-red absorbing cyanine. AB - A water-soluble disulfonate cyanine was prepared by chemical synthesis and shown to possess photophysical properties which are particularly favourable for the promotion of photothermally sensitised processes, including a very low (<0.1) quantum yield of fluorescence emission and ultra-short (110 to 400 ps) excited state lifetimes, as well as the presence of intense absorption bands at wavelengths longer than 800 nm. This allows the possibility of high-energy irradiation by means of a Ti:sapphire laser operated in a pulse regime. The cyanine was accumulated in comparable amounts by B78H1 amelanotic melanoma cells and HT1080 transformed fibroblasts, however only the B78H1 cells could be extensively damaged by photothermal sensitisation with the cyanine, which was endocellularly distributed as suggested by observations at the optical microscope; the efficiency of the photoprocess could be enhanced by formation of aggregated intracellular cyanine clusters. On the other hand, only a modest photoinactivation of HT1080 cells was induced by photothermal sensitisation, possibly owing to the localization of the cyanine at the periphery of such cells. The cyanine also exhibited a good selectivity of amelanotic melanoma targeting in C57BL/6 mice, bearing the tumour subcutaneously transplanted in the dorsal area: the ratio of cyanine concentration in the melanoma and the surrounding cutaneous districts was as large as 3.8 at 1 h post-injection. The cyanine underwent a fast clearance from the organism, since only traces of the photosensitiser were observed in all the studied tissues at 3 h after i.v. administration. Thus, irradiations were performed at post-injection times shorter than 1 h. Maximum photothermal sensitisation efficiency was obtained at 10 min after injection with a 50% cure rate. Thus, photothermal therapy (PTT) appears to be a very promising and efficient modality of tumour treatment. PMID- 19789813 TI - Tunable photophysical properties of phenyleneethynylene based bipyridine ligands. AB - A bipyridine-based system with phenyleneethynylene at the 4,4' positions (1) and its p-methyl (2) and p-methoxy (3) substituted derivatives were synthesized via Sonogashira coupling reactions. The photophysical properties of 1-3 and their related H+ and Zn2+ adducts (1:H+-3:H+ and 1:Zn2+-3:Zn2+) were investigated, as a function of solvent polarity, by using steady-state and time-resolved spectroscopic techniques. Molecular systems 1-3 exhibit trans conformation, whereas adducts with H+ and Zn2+ are conformationally locked cis species. The unsubstituted compound 1 emits at 360 nm with low fluorescence quantum yield (phi(fl) = 0.2%) regardless of the solvent polarity. Fluorescence spectra of 2 and 3 are bathochromically shifted in polar solvents, and the p-methoxy (3) derivative possesses phi(fl) as high as 12%. Complexation of 1-3 with H+ or Zn2+ in acetonitrile causes red-shift of the lowest energy absorption bands, whereas dramatic changes of the emission properties are found as a function of the electron donating ability of the substituents on the phenyleneethynylene moiety ( CH3 or -OCH3), suggesting a charge-transfer character of the lowest electronic transition of 1-3. 1:H+, 1:Zn2+, 2:H+ and 2:Zn2+ exhibit intense fluorescence with phi(fl) up to 33% (1:Zn2+) whilst 3:H+ and 3:Zn2+ are found to be weakly emissive. The singlet radiative and non-radiative rate constants of compounds and complexes were determined, along with triplet parameters, via phosphorescence and transient absorption spectroscopy. More conclusive evidence regarding the protonation of bipyridine nitrogen atoms of compounds 1-3 were obtained through 1H NMR titration studies. These studies indicate that the conjugate molecular systems based on 2,2'-bipyridine and phenyleneethenylenes possess tunable optical properties which can be further utilized for preparing organic and inorganic luminophores with potential application in optoelectronic systems. PMID- 19789814 TI - Temperature-dependent femtosecond-resolved hydration dynamics of water in aqueous guanidinium hydrochloride solution. AB - The influence of ion dissolution in water is still controversial. The challenge posed to the existing concept of dissolved ions acting as water structure makers and structure breakers through recent studies calls for more experimental evidence. The temperature-dependent relaxation dynamics of water in bulk and in ionic salt solutions can give an idea about the hydrogen-bonded network and hence the perturbation induced in the tetrahedral structure of bulk water subsequent to ion dissolution. In our study, the temperature dependence of the observed relaxation dynamics in bulk water and guanidinium hydrochloride reveals the activation energy needed to convert water from hydrogen bonded to the free forms and hence the difference in the hydrogen-bonded network in the close vicinity of the probe molecule. The results might prove helpful to understand the interaction of hydrophobic amino acid residues with guanidinium hydrochloride during protein denaturation. PMID- 19789815 TI - Photophysical characterization of oligopyrene modules for DNA-based nanosystems. AB - The photophysics of free pyrenedicarboxamide (Py-DCA) in solution as well as of single-stranded and double-stranded oligonucleotides (ss and ds ONs) containing 1 7 pyrene building blocks per strand were studied by steady-state and time resolved fluorescence spectroscopy. It was found that the fluorescence quantum yield Phi(F) of free Py-DCA chromophore in solution is rather high (Phi(F) = 0.44). However, after incorporation of the chromophore into a ss ON the monomeric chromophore fluorescence is quenched more than 40-fold due to electron-transfer reactions with ON bases. An increase of the number n of neighboring pyrenes in an ON results in Phi(F) growth up to 0.25 at n = 6. Starting from n = 2, all fluorescence belongs mainly to excimer formed by pyrene chromophores. Sections composed of multiple pyrenes may be considered as robust functional entities that may serve as independent modules in DNA-based, functional nano-architectures. PMID- 19789816 TI - Photophysical characterization of cinnamates. AB - The photophysical properties of five methoxy-substituted 2-ethylhexylcinnamates were studied with experimental and theoretical methods. It was found that the fluorescence quantum yields varied strongly with the substitution pattern of the phenyl ring. A methoxy substitution at the meta position gave strong fluorescence, whereas the para substituted compounds were strongly quenched. This observation could be correlated to corresponding changes in the UV absorption spectra; the two lowest pipi* states were split for the meta-methoxy substituted cinnamate but almost degenerate for the para compound. Semi-empirical quantum mechanical calculations confirmed both the observed state order and the difference in the experimentally determined activation energies for non-radiative decay. This "meta-effect" was also preserved in the trimethoxy-substituted compounds, 2-ethylhexyl-2,4,5- and 2,4,6-trimethoxycinnamate, resulting in strong fluorescence and relatively high barrier for non-radiative decay in the former and weak fluorescence and relatively low barrier for non-radiative decay in the latter. The obtained information shows how the performance of the commercial sunscreen agent, 2-ethylhexyl-para-methoxycinnamate (OMC) might be improved. PMID- 19789817 TI - Silencing of ALA dehydratase affects ALA-photodynamic therapy efficacy in K562 erythroleukemic cells. AB - Synthesis of protoporphyrin IX (PpIX) by malignant cells is essential for the success of ALA-based photodynamic therapy (PDT). Two key enzymes that were described as affecting PpIX accumulation during ALA treatment are porphobilinogen deaminase (PBGD) and ferrochelatase. Here, we show that down regulation of ALA dehydratase (ALAD) expression and activity by specific shRNA induced a marked decrease in PpIX synthesis in K562 erythroleukemic cells. Photo-inactivation efficacy following ALA-PDT was directly correlated with ALAD-silencing and cellular levels of PpIX. MTT metabolism following ALA-PDT was shown to be 60% higher in ALAD-silenced cells in comparison to control cells, indicating that mitochondria were protected in the silenced cells. Morphological analysis by scanning electron microscopy (SEM) of cells treated by ALA-PDT showed no morphological changes in ALAD-silenced cells, in contrast to controls exhibiting cell deformations and lysis. Membrane integrity following ALA-PDT was kept intact and undamaged in ALAD-silenced cells as examined by Annexin V-FITC/PI staining and LDH-L leakage. We conclude that ALAD, although it is present in the cell at abundant levels, has a major and limiting role in regulating PpIX synthesis and ALA-PDT outcome. PMID- 19789818 TI - Role of aromatic amino acid tryptophan UVA-photoproducts in the determination of drug photosensitization mechanism: a comparison between methylene blue and naproxen. AB - The aromatic amino acid tryptophan is the most susceptible protein residue involved in various photosensitized adverse effects. Of these processes, the tryptophan photosensitization induced by methylene blue has been well studied. A predominant type II photosensitizing activity, mediated by singlet oxygen, has been already demonstrated on various models. The purpose of this study is to compare this photosensitization system with that induced by naproxen, belonging to the class of non-steroidal anti-inflammatory drugs. For this compound, a type I (radical) and type II (singlet oxygen) cooperative mechanism of photoinduced damage was previously proposed. This study represents an example of testing drugs on the simple experimental model of amino acid residues in proteins. Particular emphasis is dedicated to modifications caused by the formation of drug photomediated toxic species, such as reactive oxygen species (ROS). This is achieved following the kinetics of photodegradation of the sensitizers and of the amino acid, as well as the formation of their photoproducts and by evaluation of quantum yields of the various processes. Tryptophan photoproducts represent biomarkers of oxidative damage indicative for protein photooxidation and for the molecular mechanism of photosensitization; some of these have been identified for the first time as UVA photosensitization products. The pattern of Trp photoproducts formed by the two compounds differs and is specific for each type of sensitization process. These observations support extending the investigation to systems of increasing molecular complexity, that is Trp in isolated proteins and in cells and represent an effort to provide a simplified rationale of the complex picture coming out from literature data and our experimental results. PMID- 19789819 TI - Secondary oxidants in human serum exposed to singlet oxygen: the influence of hemolysis. AB - Singlet oxygen (1O2) is produced by leucocytes during inflammatory reactions, various biochemical reactions and during photoreactions. It deactivates by reacting with a number of targets to produce reactive oxygen species (ROS) and peroxides (that in turn produce ROS). To verify whether serum had the same capability to deactivate secondary oxidants after exposure to 1O2, we provoked a photoreaction using rose bengal added to sera of 53 healthy donors and, after light delivery, reduced 2',7'-dichlorofluorescein (DCFH) was added at the end of irradiation and fluorescence of the oxidized derivative (DCF) was recorded. To avoid optical artifacts, we analyzed the influence of hemolysis. Deactivation capability of secondary oxidants after exposure to (1)O(2) was stable over a long period of time, slightly different between men and women, but standard biochemistry parameters had little influence. Hemolysis, age and platelet number reduced deactivation of 1O2-induced secondary oxidants. Addition of lysed cancer cells had no influence. Blood sampling in clot act tubes gave a better signal than in heparinized tubes. Red blood cells (RBCs) loaded with antioxidants strongly decreased deactivation of secondary oxidants. Assays are in progress to evaluate the clinical implications of these findings. PMID- 19789821 TI - Cryopreservation of in vitro shoot apices of Glehnia littoralis - a medical plant. AB - Cryopreservation was examined as a practical method for preserving the genetic resources of Glehnia littoralis Fr. Schm. a nearly exterminated medical plant. In vitro shoot apices were successfully cryopreserved using vitrification and encapsulation-dehydration. In vitrification, regrowth of apices loaded for 60 min with PVS2 (66.7 +/- 6.7 percent) was preferable to loading with PVS3 (50.0 +/- 5.8 percent). With encapsulation-dehydration, the best regrowth (43.3 +/- 3.3 percent) was achieved when the moisture content in the beads was reduced to 19 percent by drying with silica gel for 6 h. Increased regrowth of shoot tips cryopreserved by encapsulation-dehydration resulted from the addition of 0.1 mM acetylsalicylic acid to the loading solution (86.7 +/- 3.3 percent). PMID- 19789822 TI - Two-step rapid freezing method: estimation of membrane hydraulic permeability in erythrocytes at temperature exposure stage. AB - The processes, occurring at the stage of temperature exposure under two-step freezing of human and hibernating ground squirrel erythrocytes were studied by electron-microscopic method of freeze-fracturing. For human erythrocytes the time of intracellular crystal dissolution in human erythrocytes made 30 min and this value was shown to be slightly depending on temperature within -20 to -35 degree C range. Erythrocyte membrane permeability for water within negative temperature range has been estimated. It was noted that the value of water membrane permeability coefficient obtained theoretically, taking into account experimental values of time of dissolution for intracellular ice crystals and cell dehydration, is quite well consistent with the reported data and equals to about 0.5 x E-13 (cubic m)/N/sec for human erythrocytes and E-13 (cubic m)/N/sec for hibernating ground squirrel cells. Under two-step freezing a temperature arrest results in a qualitative change of water exchange process between cell and its environment, and the exposure duration may serve as the measure for cell dehydration. According to the data of NMR "paramagnetic doping" and freeze fracturing the erythrocyte membrane of hibernating ground squirrels is more permeable for water than human one. PMID- 19789823 TI - Cryopreservation of dormant buds from diverse Fraxinus species. AB - Ash (Fraxinus) is an economically important tree genus in the landscape industry, as well as a key component of North American forests, especially in the North Central United States and adjacent regions in Canada. In recent years, the Emerald Ash Borer beetle (Agrilus planipennis) has significantly threatened the survival of native North American Fraxinus species. A dormant-bud cryopreservation technique has been developed as a method to conserve specific clones of ash. Dormant buds of three ash species were successfully cryopreserved when desiccated on their stem sections to 30 percent moisture content (w/v) and then cooled at rates of either -1 degree C per h or -5 degree C per day to either -30 or -35 degree C before immersion in liquid nitrogen vapor (LNV). Stem sections were removed from LNV, warmed, and rehydrated, and their buds grafted onto rootstocks to evaluate survival. Recovery percentages ranged from 34 to 100 percent after LNV exposure and were dependent upon accession and cooling rate. The cryopreservation methods proposed herein can complement seed-collection efforts aimed at conserving diversity, supplementing ex situ genebank and botanic garden collections. PMID- 19789824 TI - Thermal analysis and cryopreservation of seeds of Australian wild Citrus species (rutaceae): Citrus australasica, C. inodora and C. garrawayi. AB - We investigated the relationship between the thermal transitions in seeds, cryopreservation and geographical origin for the rare and threatened northern Australian Citrus species, Citrus inodora and C. garrawayi, and southeastern Australian species C. australasica, which is cultivated as a 'bushfood'. Thermal analysis of phase transitions in cotyledon tissue revealed differences between species in the melt onset temperatures of in vivo seed oils, suggestive of differences in the proportion of saturated fatty acids. These differences appeared to be associated with geographic gradient, i.e. an increased mean onset temperature of lipid melt coincided with latitude (N NSW / SE QLD Australia to N QLD) and climatic zone (warm subtropical to hot tropical) of the natural distribution range. In addition, the thermal transitions of seed oils corresponded to the temperature limit for germination. Tolerance to cryopreservation was demonstrated in all three species after drying, with a mean germination of 75 +/- 2, 71 +/- 7 and 42 +/- 12 percent for C. australasica, C. inodora and C. garrawayi, respectively, when dried below the unfrozen water content (WCu) determined for each species. All three species have edible fruits and seed cryopreservation now offers an alternative strategy for the long-term ex situ conservation of this valuable germplasm. PMID- 19789825 TI - Cryopreservation of shoot tips of Trichilia emetica, a tropical recalcitrant seeded species. AB - This paper reports the successful cryopreservation of shoot tips of Trichilia emetica, a tropical tree species producing recalcitrant seeds. Preculture of shoot tips on MS medium with 0.7 M sucrose or with 0.3 M sucrose + 0.5 M glycerol followed by cryoprotection with a mixture of glycerol and DMSO or with PVS2 was crucial for successful recovery following cryostorage. Three cooling rates were applied to assess the effects on post-thaw regrowth of shoot tips. Slow cooling of the shoot tips (WC 1.24 g/g DW) precultured on medium with 0.3 M sucrose + 0.5 M glycerol and cryoprotected with PVS2 resulted in high shoot production (71 percent). Subsequent to relatively faster cooling, only 38 percent of the shoot tips developed shoots. Ultra-rapid cooling with PVS2 resulted in callus formation with 55 percent regrowth. We report one of the very few successful attempts to cryopreserve explants alternative to zygotic axes of tropical tree species producing recalcitrant seeds. PMID- 19789826 TI - Development of alternative loading solutions in droplet-vitrification procedures. AB - In plant vitrification protocols, the loading treatment, which involves treating the explants with a moderately concentrated cryoprotectant solution, precedes dehydration of explants with highly concentrated vitrification solutions in order to reduce the toxicity which can be induced by their direct exposure to such highly concentrated solutions. This study aimed at developing alternative loading solutions composed of mixtures of glycerol and sucrose at various concentrations. Differential scanning calorimetry runs of loading solutions and of loaded and dehydrated explants were performed to assay thermal events occurring during cooling and warming. These loading solutions were applied to two model species, viz. garlic and chrysanthemum which were cryopreserved using a droplet vitrification procedure. The loading treatment proved to be beneficial to both garlic and chrysanthemum and increased recovery of cryopreserved explants. However, response to the loading solutions tested varied between the two model species employed: with garlic, all the loading solutions had a similar effect, whereas survival of chrysanthemum shoot tips was significantly influenced by the composition of the loading solution employed. A loading solution comprising 1.9 M glycerol and 0.5 M sucrose was the most effective. The loading treatment may thus act as an osmotic stress neutralizer and/or induce the physiological adaptation of tissues and cells, including membranes, to both dehydration and freezing. PMID- 19789827 TI - Apoptosis in human ovarian tissue after conventional freezing or vitrification and xenotransplantation. AB - One of the new emerging techniques to preserve reproductive potential of cancer patients is cryopreservation of ovarian fragments prior to medical treatment and their retransplantation after healing. In order to investigate and compare apoptosis in human ovarian tissue after conventional ("slow") freezing and vitrification, we used a xenograft model in which conventionally frozen, vitrified and fresh non treated human ovarian tissue pieces were subcutaneously transplanted in SCID mice. The tissue samples were weekly, during four weeks, recovered from scarified SCID mice. The apoptosis was examined by immunohistochemical staining with the anti-caspase-3 antibody. There was a significant difference between the amount of apoptotic cells in cryopreserved ovarian tissue independent from mode of cooling compare to the control. The ovarian tissue after vitrification showed a significantly higher amount of apoptotic cells, than in slow frozen. The results obtained after comparative study of two different cryopreservation methods show that vitrification of human ovarian tissue could become a practice-relevant alternative to slow cryopreservation only after further improvement. PMID- 19789828 TI - 'Diarrhetic' type shellfish poisoning in Nigeria. AB - The safety of shellfish found and consumed in Nigeria is doubtful because no investigations have been carried out on their toxicity. The occurrence and toxicity of toxins in the commonly consumed Nigerian shellfish from Lagos, Warri, Oron, and Port Harcourt (PH) were investigated. Albino Wistar mice treated with chloroform extract of hepatopancreas (HP) from PH shellfish died 7-8 min post treatment. They convulsed for 30-60 s prior to death. The aqueous phase obtained from the diethyl ether extraction of the same HP resulted in the death of one out of two mice injected with it, 39 min post treatment. PMID- 19789829 TI - Environmental lead exposure among children in Chengdu, China: blood lead levels and major sources. AB - A survey was performed to know blood lead level (BLL) of children under seven and the risk factors of high BLL in Chengdu, China in 2004. The mean BLL in children under seven in Chengdu was 63.88 microg/L. The detection rate of high BLL was 8.21%. Chengdu is a moderate popular region of lead poisoning. Substitute of breast milk, living at the base floor or in one-storey houses and houses near the streets are the risk factors of high BLL (p < 0.05). The risk of anorexia, spasm and impaired concentration is higher in children whose BLL is higher than those whose BLL is lower (p < 0.05). Living circumstances, feeding patterns, and eating habits affect BLL, which in turn influences children's health status. PMID- 19789830 TI - Heavy metal exposure from personal care products. AB - Numerous studies have described human exposure to heavy metals from diverse sources in Nigeria, but little is known about the exposure from personal care products, and few or no report is available on the personal care product concentrations of cadmium, chromium, copper and zinc, which have biotic effects. The levels of these elements were determined in 74 samples of 5 different classes of personal care products commonly used in Nigeria using atomic absorption spectrophotometry. Significant levels of Cd, Cr, Cu and Zn were found in all the products. The highest values of Cd (0.553 ppm) and Cu (0.783 ppm) were observed in hair cream, while medicated cream was mostly implicated for Cr (0.383 ppm) and Zn (0.793 ppm). Since no limit relating to cosmetic products is available, it is difficult to ascertain if the values of metals obtained in this study are too high or low; but Cd and Cr are prohibited in any amount in cosmetics. Prolonged use of soaps and creams containing these elements may pose threat to human health and the environment. PMID- 19789831 TI - Obstetric fistula in India: current scenario. AB - BACKGROUND: India lacks prevalence and incidence data on obstetric fistula, a near miss maternal mortality. METHODOLOGY: Retrospective data were collected on obstetric fistula cases from hospital records of 24 tertiary care facilities during the period 2000-2006. RESULTS: Overall, 717 women underwent genital fistula repair, but medical records could be retrieved for only 401 (56%) cases. States of Bihar, Uttar Pradesh, and West Bengal had more than 100 cases each, while Karnataka had none. Obstructed labor caused nearly 97% of genital fistulae while pelvic surgery and accidental trauma contributed to 1.5% cases each. Commonest type of fistula was genitourinary (86.6%), others included rectovaginal (12.1%) and both genitourinary and rectovaginal fistulae (1.2%). Fistula repair was attempted in 322 (83%) cases of whom 289 (89.71%) were successfully repaired. CONCLUSIONS: There is a need for ongoing systematic data collection mechanism like a fistula registry that would provide facility-based prevalence and incidence, time trends, and changes in etiology of fistula. This information could be used for implementation of prevention and treatment strategies. PMID- 19789832 TI - [Effect of whole body vibration on the neuromuscular performance of females 65 years and older. One-year results of the controlled randomized ELVIS study]. AB - Sarcopenia is linked to an increased risk of morbidity and mortality in the aging. Whole body vibration (WBV) exercises are currently discussed as a "gentle" alternative to conventional exercises to improve muscle mass. The present study scrutinized whether a multipurpose (exercise) training program using WBV can improve muscle mass and neuromuscular capacity, while lowering fall risk. A total of 151 postmenopausal women were randomized into three groups: exercise group (TG), exercise group with vibration (VTG), and fitness control group (CG). The TG group participated in an exercise program including leg strengthening training twice a week over 12 months, while the VTG carried out an identical program with the leg exercises performed under WBV. Despite a positive trend regarding lean body mass in the two exercise groups, there was no difference between groups. Both exercise groups showed a significant increase (vs. KG) in trunk strength. An improvement in both exercise groups was also measured with respect to leg strength, but only the VTG showed significant differences compared to the CG. In addition, a significant lower risk of falls compared with the CG was evident only in VTG. PMID- 19789833 TI - Lymph node navigation for pancreatic and biliary malignancy by NOTES. AB - BACKGROUND: Lymph node navigation and accurate staging of liver or peritoneal metastasis leads to better selection of the optimal treatment for patients with pancreatic and biliary malignancy. Less invasive techniques of detecting lymph node metastasis and distant metastasis would be valuable. Natural orifice translumenal endoscopic surgery (NOTES) is a new, evolving concept of minimally invasive surgery that may be useful for the staging of intraabdominal cancers. METHODS: Review of the literature regarding peritoneoscopy and lymph node mapping and biopsy by NOTES. RESULTS: NOTES peritoneoscopy for accurate diagnosis and staging of intraabdominal cancers is already in clinical use, and two case reports have shown the safety and feasibility of this technique. Previous experimental studies have also shown that lymph node mapping by NOTES is technically feasible with the currently available devices. CONCLUSIONS: With the continued development of the techniques and technology of NOTES, peritoneoscopy and lymph node mapping by NOTES may become an alternative method for preoperative staging for patients with pancreatic and biliary malignancy. PMID- 19789834 TI - Combined TIPS with portal-azygous disconnection improved the long term clinical outcome in portal hypertension patients. AB - OBJECTIVE: The results of TIPS and the combined TIPS and portal-azygous disconnection for portal hypertension and variceal bleeding were evaluated. METHODS: 358 patients with portal hypertension were admitted to our clinical ward because of variceal bleeding. 263 patients underwent TIPS and 95 patients with combined TIPS and portal-azygous disconnection. Portal hemodynamics was evaluated by pressure measurements, venography and Doppler ultrasound before and 2 weeks after the procedure. The rates of shunt patency, rebleeding, encephalopathy and survival were observed during the follow-up period from 1 to 10 years. RESULTS: The portal pressure and HVPG were decreased significantly after TIPS. TIPS procedure was successfully performed in 97.50% patients. During 1 month after treatment, acute shunt occlusion occurred in 3.42% patients with TIPS and there were no occluded shunts in patients with combined TIPS and portal-azygous disconnection. Encephalopathy was observed in 36.50% patients with TIPS and 18.95% with combined TIPS and portal-azygous disconnection. Recurrent variceal bleeding was documented in 6.46% patients with TIPS and none of patients with combined TIPS and azygous portal disconnection. Thirty-three patients with TIPS and two patients with combined TIPS and portal-azygous disconnection died. During follow-up periods, the patency of shunts in patients with TIPS and patients combined TIPS and azygous portal disconnection was 68.47, 43.84 and 87.06, 57.65% in 12 and 24 months after operation, respectively. The rates of rebleeding, and encephalopathy in patients with TIPS and patients with combined TIPS and azygous portal disconnection were 17.95, 31.79 and 7.04, 16.47%, respectively. The survival rate in 1, 5, 10 years in patients with TIPS and patients combined TIPS and azygous portal disconnection was 87.68, 51.23, 39.90 and 94.12, 81.18, 76.47%. CONCLUSION: Combined TIPS and portal-azygous disconnection can improve the effect of TIPS for portal hypertension. PMID- 19789835 TI - Assessment of Frey procedures: Japanese experience. AB - BACKGROUND/PURPOSE: The Frey procedure, the coring out of the pancreatic head and longitudinal pancreaticojejunostomy, is a safe, easy, and reliable method to solve most of the problems associated with chronic pancreatitis. During long-term follow up, unexpected relapse in the pancreatic tail was encountered. The pattern of failure and the rationale for a new procedure to treat or prevent such relapse were investigated. METHODS: From 1992 to 2008, 71 patients with chronic pancreatitis underwent the Frey procedure at Tohoku University Hospital. The etiology was alcoholic in 92.6% of them, followed in incidence by idiopathic and hereditary chronic pancreatitis. In the primary operation, besides the Frey procedure, combined resection of the pancreatic tail was performed in three patients, and choledochoduodenostomy was performed in one patient. The follow-up rate was 92.9%, with a median period of 46 months. RESULTS: The incidence of early postoperative complications was 18.4%, with one reoperation for gastrointestinal bleeding from the splenic artery. Pain control was achieved in all patients and there was no operative mortality. During the long-term follow up of 62 patients with the Frey procedure, eight patients had relapse of inflammation and required reoperation. Five of these eight patients had a pseudocyst in the pancreatic tail and underwent distal pancreatectomy (DP). CONCLUSIONS: Relapse occurred in alcoholic middle-aged male patients, and in the patients with hereditary and idiopathic pancreatitis. Frey-DP and Frey-spleen preserving DP (SPDP) procedures can be performed safely and effectively to treat the relapse and to prevent relapse in the pancreatic tail. PMID- 19789836 TI - Steatosis and hepatic expression of genes regulating lipid metabolism in Japanese patients infected with hepatitis C virus. AB - PURPOSE: Steatosis is a histological finding associated with the progression of chronic hepatitis C. The aims of this study were to elucidate risk factors associated with steatosis and to evaluate the association between steatosis and hepatic expression of genes regulating lipid metabolism. METHODS: We analyzed 297 Japanese patients infected with hepatitis C virus and a subgroup of 100 patients who lack metabolic factors for steatosis. We determined intrahepatic mRNA levels of 18 genes regulating lipid metabolism in these 100 patients using real-time reverse transcription-polymerase chain reaction. Levels of peroxisome proliferator-activated receptor alpha and sterol regulatory element-binding protein 1 proteins were assessed by immunohistochemistry. RESULTS: Steatosis was present in 171 (57%) of 297 patients. The presence of steatosis was independently associated with a higher body mass index, higher levels of gamma-glutamyl transpeptidase and triglyceride, and a higher fibrosis stage. Steatosis was present in 43 (43%) of 100 patients lacking metabolic factors. Levels of mRNA and protein of peroxisome proliferator-activated receptor alpha, which regulates beta oxidation of fatty acid, were lower in patients with steatosis than in patients without steatosis. CONCLUSIONS: These findings indicate that impaired degradation of lipid may contribute to the development of hepatitis C virus-related steatosis. PMID- 19789838 TI - Serum tumor antigen REG4 as a diagnostic biomarker in pancreatic ductal adenocarcinoma. AB - BACKGROUND AND AIMS: Serum biomarkers for the early detection of pancreatic cancer are not currently available. We evaluated the usefulness of a novel serum marker, REG4, in the diagnosis of pancreatic cancer, as compared to carbohydrate antigen (CA) 19-9. METHODS: We collected pretherapeutic sera from 92 patients with pancreatic cancer, as well as sera from 28 patients with other pancreatic tumors, 11 patients with pancreatitis, and 69 healthy controls. Serum levels of REG4 were measured using a standard sandwich enzyme-linked immunosorbent assay (ELISA). RESULTS: Compared with healthy controls, serum levels of REG4 were higher in pancreatic cancer patients (P < 0.001), and in patients with pancreatitis (P < 0.001). Receiver operating characteristic (ROC) analysis indicated that serum REG4 performed better than serum CA19-9 for distinguishing patients with pancreatic cancer from healthy controls [areas under the curve (AUC) for REG4 and CA19-9 were 0.922 and 0.884, respectively]. When we validated the study, the sensitivity of REG4 for pancreatic cancer was 94.9%, specificity was 64.0%, and accuracy was 77.5% for the REG4 cutoff value of 3.49 ng/ml. No correlation was seen between serum REG4 and CA19-9 levels, with the sensitivity, specificity, and accuracy of the combined markers reaching 100.0, 60.0, and 77.5%, respectively. No significant differences were seen among any stages of pancreatic cancer. In surgical specimens, immunohistochemical analysis found a correlation between serum REG4 levels and REG4 expression in pancreatic cancers. CONCLUSIONS: REG4 is expressed in pancreatic cancer, and serum levels of REG4 offer a useful indicator for distinguishing between patients with pancreatic cancer and healthy subjects. Serum REG4 has potential for use as a screening serum marker for pancreatic cancers, including early-stage cancers. PMID- 19789839 TI - The particular relationship between Parkinson's disease and malignancy: a focus on skin cancers. AB - Although the risk for most cancers appears to be relatively low in patients with Parkinson's disease (PD), skin cancers and melanomas occur more frequently in the PD population as compared to controls. This article summarizes the findings of cohort studies on skin cancer in Parkinson's disease. Given that melanoma may precede use of L-dopa, the increased risk of melanoma for PD patients cannot be attributed to L-dopa. On the basis of these observations it may be reasonable to recommend that all patients with PD, whether treated with L-dopa or not, should undergo regular dermatological screening for neoplastic or pre-neoplastic skin lesions, especially melanoma. PMID- 19789837 TI - Etiology of liver cirrhosis in Japan: a nationwide survey. AB - BACKGROUND: Little is understood about worldwide changes in the epidemiological distribution of the etiology of liver cirrhosis (LC). The present study examines the etiology of liver cirrhosis in Japan using a nationwide survey. METHODS: We analyzed data from 33,379 patients with LC at 58 hospitals and presented the findings in a poster symposium regarding the etiology and clinical features of LC in Japan that was included in the program of the 44th Annual Meeting of the Japan Society of Hepatology. We identified the distribution of the etiology of LC and compared the present with previous Japanese findings to estimate the future of etiological changes in LC. RESULTS: The etiological agents were as follows: hepatitis B virus (HBV) 13.9%, hepatitis C virus (HCV) 60.9%, alcohol 13.6%, primary biliary cirrhosis (PBC) 2.4% and autoimmune hepatitis (AIH) 1.9%. Cirrhosis was considered to be related to nonalcoholic steatohepatitis (NASH) in 2.1% of the patients. The ratio of HCV-related LC was significantly higher among patients with hepatocellular carcinoma (HCC) (P < 0.0001) compared to those without, whereas the ratios of alcohol, PBC, AIH were lower. HCC was evident in 31.5% of NASH-related LC. CONCLUSIONS: The major etiology of liver cirrhosis in Japan remains HCV. Our survey revealed the prevalence of NASH-related LC in Japan and the frequency of HCC. Future changes in etiology must be considered in establishing preventive or educational strategies, as well as in developing new treatment strategies. PMID- 19789840 TI - Feza H. Remzi, MD leads colorectal surgery at Cleveland Clinic, Digestive Disease Institute, Cleveland, Ohio. PMID- 19789841 TI - Antitumor activity and toxicity of anti-HER2 immunoRNase scFv 4D5-dibarnase in mice bearing human breast cancer xenografts. AB - Ribonucleases (RNases) are a non-mutagenic alternative to harmful DNA-damaging anticancer drugs. Targeting of RNases with antibodies to surface antigens that are selectively expressed on tumor cells endows specificity to the cytotoxic actions of RNases. Barnase, a ribonuclease from Bacillus amyloliquefaciens, is a promising candidate for targeted delivery to cancer cells because of its insusceptibility to the ubiquitous cytoplasmic ribonuclease inhibitor, and its high stability and catalytic activity. Here, we characterized in vitro and in vivo an immunoRNase, scFv 4D5-dibarnase, which consists of two barnase molecules that are fused serially to the single-chain variable fragment (scFv) of humanized 4D5 antibody. The latter is directed against the extracellular domain of human epidermal growth factor receptor 2 (HER2), a cancer marker that is overexpressed in many human carcinomas. The scFv 4D5-dibarnase exerted a specific cytotoxic effect on HER2-overexpressing SKBR-3 and BT-474 human breast carcinoma cells (IC(50) = 4.1 and 2.4 nM, respectively) via induction of apoptosis. Ten doses of 0.7 mg/kg scFv 4D5-dibarnase to BALB/c nude mice that bore SKBR-3 human breast cancer xenografts resulted in a 76% reduction in tumor growth. A single injection of scFv 4D5-dibarnase at a total course dose of 7 mg/kg did not cause severe side effects in BALB/c nude or BDF1 mice. The cytotoxicity and selectivity of scFv 4D5 dibarnase merit consideration of this immunoRNase as a potent anticancer agent. PMID- 19789842 TI - Antimetastatic activity of MONCPT in preclinical melanoma mice model. AB - Previous study demonstrated that MONCPT, a topoisomerase I inhibitor, exhibited potent anti-proliferation and anti-angiogenesis activity in vitro and in vivo. In this study, we report the efficacy of MONCPT against the development of melanoma metastasis by an intravenous injection of green fluorescent protein-transfected mice melanoma carcinoma (B16F10-GFP) cells in C57BL/6 mice. MONCPT (2.0, 5.0 and 12.5 mg/kg/2 days) markedly decreased B16F10-GFP pulmonary metastases by 12.8%, 53.1% and 76.3%, respectively; whereas higher doses of MONCPT (31.0 mg/kg/2 days) significantly inhibited the tumor growth of B16F10 xenograft model. In the in vitro experiment, MONCPT suppressed the B16F10-GFP cell invasion and migration without affecting cell survival. Further studies demonstrated that MONCPT decreased the secretion of matrix metalloproteinase (MMP)-9 and VEGF, and reduced the protein expression of HIF-1alpha as well as the phosphorylation level of ERK in B16F10-GFP cells. These in vivo and in vitro results indicate that MONCPT possesses both the potent antimetastatic ability and the tumor growth-inhibition activity, and the dual function promises MONCPT as a potential therapeutic agent for tumor metastasis and tumor growth of melanoma carcinoma. PMID- 19789843 TI - Antihyperlipidemic effect of bis-1,7-(2-hydroxyphenyl)-hepta-1,6-diene-3,5-dione, a curcumin analog, on nicotine and streptozotocin treated rats. AB - Diabetes and smoking have been considered as major health problems individually and their seriousness related to health hazard has been well reported. Data regarding the possible contribution of cigarette smoking to the development of diabetes are scarce and inconclusive. The aim was to investigate the effect of nicotine on diabetes and to analyze the effect of bis demethoxy curcumin analog (BDMCA) in streptozotocin (STZ) and nicotine-induced toxicity. The tissue lipids were extracted according to the method of Folch et al. Plasma and tissue cholesterol was estimated by the method of Allain et al. using reagent kit. Triglycerides were estimated by the method of Foster and Dunn. Free fatty acids were estimated by the method of Falholt et al. Tissue phospholipids were estimated by the method of Zilversmit and Davis. From our study, we found that nicotine not only aggravates diabetic complications but also increased the risk for diabetes. BDMCA, at a dose 80 mg/kg body weight was found to be effective in decreasing toxic effects induced by nicotine and STZ. Our data provide new evidence that cigarette smoking is an additional important factor that could be targeted for the prevention of diabetic complications. PMID- 19789844 TI - Validation of extraction methods for total RNA and miRNA from bovine blood prior to quantitative gene expression analyses. AB - The benefit and precision of blood diagnosis by quantitative real-time PCR (qPCR) is limited by sampling procedures and RNA extraction methods. We have compared five different RNA extraction protocols from bovine blood regarding RNA and miRNA yield, quality, and most reproducible data in the qRT-PCR with the lowest point of quantification. Convincing results in terms of highest quantity, quality, and best performance for mRNA qPCR were obtained by leukocyte extraction following blood lysis as well as extraction of PAXgene stabilized blood. The best microRNA qPCR results were obtained for samples extracted by the leukocyte extraction method. PMID- 19789845 TI - Effects of vitamins C and E combination on element levels in blood of smoker and nonsmoker radiology X-ray technicians. AB - X-ray radiation is detrimental to human cells and may lead to development of life threatening diseases. Cigarette paper and cigarette smoke contain toxic elements, whereas vitamins C and E (VCE) may have regulator effects on the elements. We investigated effects of VCE administration on X-ray-induced element changes in blood of smoker and nonsmoker X-ray technicians. Twenty technicians and 30 healthy age-matched control subjects were used in the study. Ten of the X-ray technicians and 15 of the control were smokers. Blood serum samples were taken from the control. Oral vitamins C (500 mg) and E (150 mg) were supplemented daily to the smoker and nonsmoker X-ray technicians for 5 weeks. Serum samples were taken from the X-ray technicians before and after 5 weeks. Copper, zinc, selenium, aluminum, iron, magnesium, and calcium levels were investigated in control and X-ray technicians, both smokers and nonsmokers. Copper, zinc, and selenium levels were lower in the total X-ray group and smoker X-ray group than in control and nonsmoker X-ray group, although iron, magnesium, and calcium levels were higher in X-ray group than in control. The copper, zinc, selenium, and aluminum levels were higher in the VCE treatment group than those in X-ray group, although magnesium and calcium levels were decreased by the treatment. The serum zinc, copper, selenium, and magnesium levels were lower in smoker control group when compared to nonsmoker control group. The serum zinc levels were lower in smoker X-ray group than nonsmoker X-ray group, although iron level was higher in smoker X-ray group than in nonsmoker X-ray group. VCE prevents the smoke and X ray-induced selenium, zinc, magnesium, and copper decrease to strengthen the antioxidant trace element levels in the serum of the technicians. PMID- 19789846 TI - Effects of montmorillonite on Pb accumulation, oxidative stress, and DNA damage in tilapia (Oreochromis niloticus) exposed to dietary Pb. AB - In order to investigate the effects of montmorillonite (MMT) on reducing dietary lead (Pb) toxicity to tilapia (Oreochromis niloticus), 240 fish were randomly divided into four treatments denominated as follows: control treatment (fed with a basal diet), MMT treatment (fed with a basal diet added with 0.5% MMT), Pb treatment (fed with a basal diet added with 100 mg Pb per kilogram dry weight (dw)), and Pb + MMT treatment (fed with a basal diet added with 100 mg Pb per kilogram dw and 0.5% MMT). Changes in Pb accumulation, oxidative stress, and DNA damage in tilapia were measured after 60 days. DNA damage was assessed using comet assay. The results showed that MMT supplemented in diet significantly reduced Pb accumulation in kidney and blood of tilapia exposed to dietary Pb (P < 0.05). Malondialdehyde level decreased insignificantly while levels of total antioxidant capacity and glutathione (GSH), activities of glutathione peroxidase, and superoxide dismutase increased insignificantly in kidney of tilapia in Pb + MMT treatment as compared to Pb treatment (P > 0.05). Significant decreases in tail length, tail DNA, tail moment, and Olive tail moment of peripheral blood cells in Pb + MMT treatment were observed when compared with Pb treatment (P < 0.05). The results indicated that dietary MMT supplementation could alleviate dietary Pb toxicity to tilapia effectively. PMID- 19789847 TI - Spider orientation and hub position in orb webs. AB - Orb-web building spiders (Araneae: Araneoidea, Uloboridae) can be considered as territorial central place foragers. In territorial central place foragers, the optimal foraging arena is circular, with the forager sitting in its centre. In orb webs, the spider's orientation (head up or head down) whilst waiting for prey on the hub of its web and the downwards-upwards asymmetry of its running speeds are the probable causes for the observed deviation of the hub from the web's centre. Here, we present an analytical model and a more refined simulation model to analyse the relationships amongst the spider's running speeds, its orientation whilst waiting for prey and the vertical asymmetry of orb webs. The results of our models suggest that (a) waiting for prey head down is generally favourable because it allows the spider to reach the prey in its web on average quicker than spiders waiting head up, (b) the downwards-upwards running speed asymmetry, together with the head-down orientation of most spiders, are likely causes for the observed vertical asymmetry of orb webs, (c) waiting head up can be advantageous for spiders whose downwards-upwards running speed asymmetry is small and who experience high prey tumbling rates and (d) spiders waiting head up should place their hub lower than similar spiders waiting head down. PMID- 19789848 TI - Fine mapping, physical mapping and development of diagnostic markers for the Rrs2 scald resistance gene in barley. AB - The Rrs2 gene confers resistance to the fungal pathogen Rhynchosporium secalis which causes leaf scald, a major barley disease. The Rrs2 gene was fine mapped to an interval of 0.08 cM between markers 693M6_6 and P1D23R on the distal end of barley chromosome 7HS using an Atlas (resistant) x Steffi (susceptible) mapping population of 9,179 F(2)-plants. The establishment of a physical map of the Rrs2 locus led to the discovery that Rrs2 is located in an area of suppressed recombination within this mapping population. The analysis of 58 barley genotypes revealed a large linkage block at the Rrs2 locus extending over several hundred kb which is present only in Rrs2 carrying cultivars. Due to the lack of recombination in the mapping population and the presence of a Rrs2-specific linkage block, we assume a local chromosomal rearrangement (alien introgression or inversion) in Rrs2 carrying varieties. The variety analysis led to the discovery of eight SNPs which were diagnostic for the Rrs2 phenotype. Based on these SNPs diagnostic molecular markers (CAPS and pyrosequencing markers) were developed which are highly useful for marker-assisted selection in resistance gene pyramiding programmes for Rhynchosporium secalis resistance in barley. PMID- 19789849 TI - Epigenetic mechanisms underlying extinction of memory and drug-seeking behavior. AB - An increasing body of evidence shows that structural modifications of chromatin, the DNA-protein complex that packages genomic DNA, do not only participate in maintaining cellular memory (e.g., cell fate), but they may also underlie the strengthening and maintenance of synaptic connections required for long-term changes in behavior. Accordingly, epigenetics has become a central topic in several neurobiology fields such as memory, drug addiction, and several psychiatric and mental disorders. This interest is justified as dynamic chromatin modifications may provide not only transient but also stable (or even potentially permanent) epigenetic marks to facilitate, maintain, or block transcriptional processes, which in turn may participate in the molecular neural adaptations underlying behavioral changes. Through epigenetic mechanisms the genome may be indexed in response to environmental signals, resulting in specific neural modifications that largely determine the future behavior of an organism. In this review we discuss recent advances in our understanding of how epigenetic mechanisms contribute to the formation of long-term memory and drug-seeking behavior and potentially how to apply that knowledge to the extinction of memory and drug-seeking behavior. PMID- 19789851 TI - Regression of diabetic complications by islet transplantation in the rat. AB - AIMS/HYPOTHESIS: Type 1 diabetes is a chronic disease leading to complications such as peripheral neuropathies, nephropathy and cardiovascular disease. Pancreatic islet transplantation is being extensively investigated for blood glucose control in animals and in human type 1 diabetic patients, but the question of whether it can reverse long-term diabetic complications has not been fully explored. We investigated the effects of islet transplantation on diabetic complications in a rat model of streptozotocin-induced diabetes. METHODS: Three groups of rats were used: healthy controls, diabetic and diabetic rats transplanted with microencapsulated islets at 2 months after diabetes induction, when neuropathy was detectable by a decrease in tail nerve conduction velocity (NCV) and impaired nociceptive thresholds. Blood glucose levels and body weight were measured weekly. The variables considered were: thermal (hot plate test) and mechanical sensitivity (Randal-Selitto paw withdrawal test), NCV and Na+, K+ ATPase activity in the sciatic nerve. At the end of the experiments hearts were removed for morphometric determination and myocyte number, and kidneys removed for histological examination. RESULTS: Islet transplantation in diabetic rats induced normoglycaemia in a few days, accompanied by a rapid rise in body weight and amelioration of impaired nociceptive thresholds, as well as normalisation of NCV and Na(+), K(+)-ATPase, which were both about 25% below normal in diabetic rats. Myocyte loss was reduced (-34%) by islet transplantation and the observed mild kidney damage of diabetic rats was prevented. CONCLUSIONS/INTERPRETATION: Besides controlling glycaemia, transplantation of microencapsulated pancreatic islets induced almost complete regression of neuropathy and prevented cardiovascular alterations. PMID- 19789853 TI - [Biomaterial for autologous chondrocyte transplantation]. AB - Autologous chondrocyte transplantation (ACT) is a cell-based biological cartilage repair procedure for the regeneration of injured articular cartilage. The further modification of classical ACT to matrix-associated autologous chondrocyte transplantation (MACT) includes the use of biomaterials as cell carriers and has biological and surgical advantages. The use of biomaterials as cell carriers for chondrocytes requires the analysis of cell culture conditions, cell-cell and cell matrix interactions and also the determination of chondrocytic differentiation. The biomaterials used preserve the specific cellular architecture of chondrocytes and the combination of cultivated cells with biomaterials leads to the formation of cartilage-specific extracellular matrix components. PMID- 19789852 TI - Overproduction of phosphoprotein enriched in diabetes (PED) induces mesangial expansion and upregulates protein kinase C-beta activity and TGF-beta1 expression. AB - AIMS/HYPOTHESIS: Overproduction of phosphoprotein enriched in diabetes (PED, also known as phosphoprotein enriched in astrocytes-15 [PEA-15]) is a common feature of type 2 diabetes and impairs insulin action in cultured cells and in mice. Nevertheless, the potential role of PED in diabetic complications is still unknown. METHODS: We studied the effect of PED overproduction and depletion on kidney function in animal and cellular models. RESULTS: Transgenic mice overexpressing PED (PEDTg) featured age-dependent increases of plasma creatinine levels and urinary volume, accompanied by expansion of the mesangial area, compared with wild-type littermates. Serum and kidney levels of TGF-beta1 were also higher in 6- and 9-month-old PEDTg. Overexpression of PED in human kidney 2 cells significantly increased TGF-beta1 levels, SMAD family members (SMAD)2/3 phosphorylation and fibronectin production. Opposite results were obtained following genetic silencing of PED in human kidney 2 cells by antisense oligonucleotides. Inhibition of phospholipase D and protein kinase C-beta by 2 butanol and LY373196 respectively reduced TGF-beta1, SMAD2/3 phosphorylation and fibronectin production. Moreover, inhibition of TGF-beta1 receptor activity and SMAD2/3 production by SB431542 and antisense oligonucleotides respectively reduced fibronectin secretion by about 50%. TGF-beta1 circulating levels were significantly reduced in Ped knockout mice and positively correlated with PED content in peripheral blood leucocytes of type 2 diabetic patients. CONCLUSIONS/INTERPRETATION: These data indicate that PED regulates fibronectin production via phospholipase D/protein kinase C-beta and TGF-beta1/SMAD pathways in kidney cells. Raised PED levels may therefore contribute to the abnormal accumulation of extracellular matrix and renal dysfunction in diabetes. PMID- 19789854 TI - [Possibilities and limits in tissue engineering of the anterior cruciate ligament]. AB - Although current concepts of cruciate ligament reconstruction using tendon transplants provide midterm knee joint stabilization, a single-bundle or double bundle tendon cannot adequately restore the complex three-dimensional structure of the anterior cruciate ligament. Therefore, researchers are attempting to develop alternatives using tissue engineering technology. The basic principle includes seeding of suitable cells on a resorbable carrier construct, in vitro biological and mechanical stimulation to generate a ligament-like extracellular matrix, and subsequent implantation as a cruciate ligament bioprosthesis. Several natural and synthetic materials have proven to be suitable as cell carriers; however, most of these exhibit inadequate tensile strength as well as minor fatigue properties, making an additional load carrier necessary. In principle, research has shown that tissue engineering technology is capable of generating a construct with a ligament-like extracellular matrix. However, the step from basic research to clinical application has not yet been taken. PMID- 19789855 TI - Lung recruitment assessed by total respiratory system input reactance. AB - PURPOSE: ALI and ARDS are associated with lung volume derecruitment, usually counteracted by PEEP and recruitment maneuvers (RM), which should be accurately tailored to the patient's needs. The aim of this study was to investigate the possibility of monitoring the amount of derecruited lung by the forced oscillation technique (FOT). METHODS: We studied six piglets (26 +/- 2.5 kg) ventilated by a mechanical ventilator connected to a FOT device that produced sinusoidal pressure forcing at 5 Hz. The percentage of non-aerated lung tissue (V (tiss)NA%) was measured by whole-body CT scans at end-expiration with zero end expiratory pressure. Respiratory system oscillatory input reactance (X (rs)) was measured simultaneously to CT and used to derive oscillatory compliance (C (X5)), which we used as an index of recruited lung. Measurements were performed at baseline and after several interventions in the following sequence: mono-lateral reabsorption atelectasis, RM, bi-lateral derecruitment induced by broncho alveolar lavage and a second RM. RESULTS: By pooling data from all experimental conditions and all pigs, C (X5) was linearly correlated to V (tiss)NA% (r (2) = 0.89) regardless of the procedure used to de-recruit the lung (reabsorption atelectasis or pulmonary lavage). Separate correlation analysis on single pigs showed similar regression equations, with an even higher coefficient of determination (r (2) = 0.91 +/- 0.07). CONCLUSION: These results suggest that FOT and the measurement of C (X5) could be a useful tool for the non-invasive measurement of lung volume recruitment/derecruitment. PMID- 19789856 TI - Influence of DNA extraction methods, PCR inhibitors and quantification methods on real-time PCR assay of biotechnology-derived traits. AB - Biotechnology-derived varieties of canola, cotton, corn and soybean are being grown in the USA, Canada and other predominantly grain exporting countries. Although the amount of farmland devoted to production of biotechnology-derived crops continues to increase, lingering concerns that unintended consequences may occur provide the EU and most grain-importing countries with justification to regulate these crops. Legislation in the EU requires traceability of grains/oilseeds, food and feed products, and labelling, when a threshold level of 0.9% w/w of genetically engineered trait is demonstrated to be present in an analytical sample. The GE content is routinely determined by quantitative PCR (qPCR) and plant genomic DNA provides the template for the initial steps in this process. A plethora of DNA extraction methods exist for qPCR applications. Implementing standardized methods for detection of genetically engineered traits is necessary to facilitate grain marketing. The International Organization for Standardization draft standard 21571 identifies detergent-based methods and commercially available kits that are widely used for DNA extraction, but also indicates that adaptations may be necessary depending upon the sample matrix. This review assesses advantages and disadvantages of various commercially available DNA extraction kits, as well as modifications to published cetyltrimethylammonium bromide methods. Inhibitors are a major obstacle for efficient amplification in qPCR. The types of PCR inhibitors and techniques to minimize inhibition are discussed. Finally, accurate quantification of DNA for applications in qPCR is not trivial. Many confounders contribute to differences in analytical measurements when a particular DNA quantification method is applied and different methods do not always provide concordant results on the same DNA sample. How these differences impact measurement uncertainty in qPCR is considered. PMID- 19789857 TI - On-site analysis of archaeological artifacts excavated from the site on the outcrop at Northwest Saqqara, Egypt, by using a newly developed portable fluorescence spectrometer and diffractometer. AB - Blue-painted pottery was produced in the New Kingdom, Egypt, and decorated with blue, red, and black pigment. In this study, two newly developed portable instruments, a portable X-ray fluorescence spectrometer and a portable X-ray powder diffractometer, were brought to the site on the outcrop at Northwest Saqqara, an archaeological site in Egypt, to verify their performance in on-site analysis of excavated artifacts at the site. Pigments used for the blue-painted pottery and plasters in the New Kingdom were analyzed by these instruments on the basis of both their chemical compositions and crystal-structural information. The blue pigments were identified as two different pigments, Egyptian blue and cobalt blue. The diffraction pattern of the blue pigment of the painted pottery exhibited that of spinel structure. The XRF spectrum of the blue pigment obtained by the same instrument from the same position indicates the presence of Mn, Co, Fe, Ni, and Zn. The possibility of compositional transitions of the cobalt blue pigment with time was revealed on by detailed analysis of the XRF data. The reason for the transitions is considered together with the archaeological background of the New Kingdom, Egypt. PMID- 19789858 TI - Differential expression of vitellogenin and oestrogen receptor genes in the liver of zebrafish, Danio rerio. AB - Environmental oestrogens are responsible for adverse effects in fish that affect reproduction. Availability of model fish to study the differential effects of endogenous and exogenous oestrogens and to test for oestrogenic activity of chemicals would be advantageous. Zebrafish could provide such a model, but the organisation and expression of vitellogenins (VTGs) and oestrogen receptors (ERs) are not completely understood. VTGs are synthesised in the liver and provide a sensitive biomarker of oestrogenic activity since they are thought to be under the regulation of the ER. There are multiple genes for VTGs and an in silico analysis of their distribution in the Zebrafish genome has identified six genes: VTG-1, VTG-2, VTG-4, VTG-5, VTG-7 located on chromosome 22 and VTG-3 on chromosome 11. VTG-specific, quantitative, real-time, reverse-transcriptase polymerase chain reaction assays were developed and used to measure differential expression in the livers of mature male and female zebrafish. Following normalisation in female fish, relative expression of VTG-5 mRNA is highest and is 1.3x, 1.6x and 2x higher than VTG-4, VTG-2 and VTG-1, respectively, while expression of VTG-3 and VTG-7 is very low. Expression of VTGs in male fish was either undetectable or very low (VTG-4 and VTG-5). ERalpha and ERbeta2 were expressed at higher levels than ERbeta1 in females, but only ERbeta2 was expressed in appreciable quantity in males. Expression of ERalpha in males was significant but only at the limit of detection (<0.1% of female fish), while ERbeta1 could not be detected. The very low level of expression of ERalpha in males raises questions about the accepted mechanism of oestrogenic induction of VTG in male fish. PMID- 19789859 TI - Switching tools: perceptual-motor recalibration to weight changes. AB - In order to effectively switch between tools, an actor must re-calibrate perceptual-motor control appropriately for the new tool's kinetic properties. This study explored changes in perceptual-motor control in response to switching to a tool of a different weight when performing a complex control task with moving objects. In Experiment 1, 30 participants were each randomly assigned to one of three groups in a baseball batting simulation: a standard group that always used the same bat weight (1.08 kg), a Lighter group that switched from the standard bat to a 0.79 kg bat, and a Heavier group that switched from the standard bat to a 1.36 kg bat. For both the Heavier and Lighter groups, temporal swing errors were significantly larger (as compared to the standard group) in the first block of trials following the bat change. Both groups re-calibrated quickly: within 5-10 trials after the bat change there were no significant difference between the groups. Analysis of swing kinematics indicated that the two change groups used different means for re-calibrating perceptual-motor control: the Lighter group altered swing velocity while the Heavier group altered swing onset time. In Experiment 2, when batters switched from a 0.79 kg bat to a 1.08 kg bat, perceptual-motor calibration depended on the recommended bat weight for each participant (Bahill and Freitas in Ann Biomed Eng 23:436-444, 1995): batters with a heavier recommended weight altered swing velocity while batters with a lower recommended weight altered onset time. The strategy used for perceptual-motor recalibration and time required to re-calibrate in a complex motor task is dependent on the action boundaries of the actor. PMID- 19789861 TI - The ALARA concept in pediatric oncology. PMID- 19789860 TI - MR spectroscopy of cerebral white matter in type 2 diabetes; no association with clinical variables and cognitive performance. AB - INTRODUCTION: Type 2 diabetes (DM2) is associated with cognitive decline, but the pathogenesis of this important complication remains unclear. We investigated whether abnormalities in neuronal metabolism or membrane integrity in normal appearing cerebral white matter are associated with cognitive impairment in patients with DM2. METHODS: Single voxel proton magnetic resonance spectroscopy (1.5 T), aimed at N-acetyl-aspartate (NAA), total choline (Cho), and total creatine (Cr), was performed in the cerebral white matter (centrum semiovale) of 72 patients with DM2 and 40 control subjects. All participants underwent extensive neuropsychological evaluation. RESULTS: Patients with DM2 performed worse with respect to global neuropsychological functioning than controls (p < 0.05), in particular on memory and information processing speed. We observed no differences in NAA/Cr, Cho/Cr, or NAA/Cho ratio's between patients with DM2 and controls. Cognitive performance in patients with DM2 was not correlated with any of these brain metabolites, neither were the clinical variables. CONCLUSION: We conclude that disturbances in neuronal viability and cellular membrane status assessed by NAA/Cr, Cho/Cr, NAA/Cho ratios cannot explain cognitive decline in patients with DM2. PMID- 19789862 TI - Periventricular leukomalacia in preterm children: assessment of grey and white matter and cerebrospinal fluid changes by MRI. AB - BACKGROUND: Brain plasticity in patients with periventricular leukomalacia (PVL) may suggest grey matter (GM) changes. OBJECTIVE: To assess the volume of 116 GM areas and total volume of GM, white matter (WM) and cerebrospinal fluid (CSF) in preterm children with PVL, using the Statistical Parametric Mapping (SPM5) and the Individual Brain Atlases Statistical Parametric Mapping (IBASPM) toolboxes. MATERIALS AND METHODS: Ten preterm children (gestational age 31.7 +/- 4.2 weeks, corrected age 27.8 +/- 21.7 months) with PVL and 46 matched, preterm control subjects were studied using a three-dimensional T1-weighted sequence. Volumes were calculated using SPM5 and IBASPM. RESULTS: GM volume in frontal superior orbital, posterior cingulum and lingual gyrus, the putamen and thalamus was significantly higher in children with PVL (3.6 +/- 0.6 cm(3), 2.0 +/- 0.5 cm(3), 9.7 +/- 1.7 cm(3), 2.5 +/- 0.6 cm(3), 2.6 +/- 0.9 cm(3), respectively) than in controls (3.1 +/- 0.7 cm(3), 1.5 +/- 0.2 cm(3), 8.2 +/- 1.3 cm(3), 1.7 +/- 1.4 cm(3), 1.8 +/- 0.4 cm(3), respectively). White matter volume was lower (182.1 +/- 40.5 cm(3)) and CSF volume was higher (300.8 +/- 56.2 cm(3)) in children with PVL than in controls (222.9 +/- 67.2 cm(3), 219.0 +/- 61.8 cm(3), respectively), P < 0.05. No significant difference was found in the total GM volume and the volume of neocortex. CONCLUSION: Preterm children with PVL show regional GM volume increase, possibly explained by axonal sprouting, neuronal hypertrophy and neurogenesis, which in turn may reflect brain plasticity. PMID- 19789863 TI - Fluoroscopy-guided insertion of nasojejunal tubes in children - setting local diagnostic reference levels. AB - BACKGROUND: Little is known about the radiation burden from fluoroscopy-guided insertions of nasojejunal tubes (NJTs) in children. There are no recommended or published standards of diagnostic reference levels (DRLs) available. OBJECTIVE: To establish reference dose area product (DAP) levels for the fluoroscopy-guided insertion of nasojejunal tubes as a basis for setting DRLs for children. In addition, we wanted to assess our local practice and determine the success and complication rates associated with this procedure. MATERIALS AND METHODS: Children who had NJT insertion procedures were identified retrospectively from the fluoroscopy database. The age of the child at the time of the procedure, DAP, screening time, outcome of the procedure, and any complications were recorded for each procedure. As the radiation dose depends on the size of the child, the children were assigned to three different age groups. The sample size, mean, median and third-quartile DAPs were calculated for each group. The third-quartile values were used to establish the DRLs. RESULTS: Of 186 procedures performed, 172 were successful on the first attempt. These were performed in a total of 43 children with 60% having multiple insertions over time. The third-quartile DAPs were as follows for each age group: 0-12 months, 2.6 cGy cm(2); 1-7 years, 2.45 cGy cm(2); >8 years, 14.6 cGy cm(2). High DAP readings were obtained in the 0-12 months (n = 4) and >8 years (n = 2) age groups. No immediate complications were recorded. CONCLUSION: Fluoroscopy-guided insertion of NJTs is a highly successful procedure in a selected population of children and is associated with a low complication rate. The radiation dose per procedure is relatively low. PMID- 19789864 TI - Susceptibility to Crohn's disease is mediated by KIR2DL2/KIR2DL3 heterozygosity and the HLA-C ligand. AB - In the present study, we investigated the relationship between the KIR loci and the genes encoding their HLA ligands and genetic susceptibility to Crohn's disease (CD). Analyses of the interactions between KIR3DL1, KIR2DL1, KIR2DL2, and KIR2DL3 with their respective HLA ligands indicate that there is a protective effect for KIR2DL2 in the absence of its HLA ligand C1. Given that KIR2DL2 and KIR2DL3 segregate as alleles, we compared their genotypic distributions to expectations under Hardy-Weinberg Equilibrium (HWE) with regard to the HLA ligand C1 status. While all the genotypic distributions conform to expectations under HWE in controls, in C2 ligand homozygous cases there is significant deviation from HWE, with a reduction of KIR2DL2, KIR2DL3 heterozygotes. KIR2DL2, KIR2DL3 heterozygosity is the only genotypic combination that confers protection from CD. In addition to the protective effect (OR = 0.44, CI = 0.22-0.87; p = 0.018) observed in C2 ligand homozygotes, the KIR2DL2, KIR2DL3 genotype is predisposing (OR = 1.34, CI = 1.03-4.53; p = 0.031) in the presence of C1 ligand. A test for trend of HLA class I C ligand group genotypes with KIR2DL2, KIR2DL3 heterozygosity in cases and controls indicates that C1, C2 ligand group heterozygotes have an intermediate effect on predisposition. These results show for the first time that disease susceptibility may be related to heterozygosity at a specific KIR locus, and that HLA ligand genotype influences the relative effect of the KIR genotype. PMID- 19789866 TI - Electricity generation at high ionic strength in microbial fuel cell by a newly isolated Shewanella marisflavi EP1. AB - Increasing the ionic strength of the electrolyte in a microbial fuel cell (MFC) can remarkably increase power output due to the reduction of internal resistance. However, only a few bacterial strains are capable of producing electricity at a very high ionic strength. In this report, we demonstrate a newly isolated strain EP1, belonging to Shewanella marisflavi based on polyphasic analysis, which could reduce Fe(III) and generate power at a high ionic strength of up to 1,488 mM (8% NaCl) using lactate as the electron donor. Using this bacterium, a measured maximum power density of 3.6 mW/m(2) was achieved at an ionic strength of 291 mM. The maximum power density was increased by 167% to 9.6 mW/m(2) when ionic strength was increased to 1,146 mM. However, further increasing the ionic strength to 1,488 mM resulted in a decrease in power density to 5.2 mW/m(2). Quantification of the internal resistance distribution revealed that electrolyte resistance was greatly reduced from 1,178 to 50 Omega when ionic strength increased from 291 to 1,488 mM. These results indicate that isolation of specific bacterial strains can effectively improve power generation in some MFC applications. PMID- 19789865 TI - Microbial community of acetate utilizing denitrifiers in aerobic granules. AB - The aerobic sludge granules cultivated at high organic loading rates could effectively convert 100-700 mg l(-1) nitrite to nitrogen gas with 400 or 1,200 mg l(-1) dosed acetate. The denitrifying microbial community structure of the so cultivated granules was investigated by 16S rRNA gene sequences and localized using fluorescence in situ hybridization (FISH). The 16S rRNA gene phylotypes in the clone library and FISH probes used exhibited high diversity among the bacteria and denitrifying communities, with the members of Betaproteobacteria predominant that were closely related to families Comamonadaceae, Nitrosomonadaceae, Alcaligenaceae, and Rhodocyclaceae. The confocal laser scanning microscope and staining test revealed that active microbial community principally distributed at 200-250 microm beneath the outer surface, embedded in extracellular polymeric substances. PMID- 19789867 TI - The Escherichia coli rhamnose promoter rhaP(BAD) is in Pseudomonas putida KT2440 independent of Crp-cAMP activation. AB - We developed an expression vector system based on the broad host range plasmid pBBR1MCS2 with the Escherichia coli rhamnose-inducible expression system for applications in Pseudomonas. For validation and comparison to E. coli, enhanced green fluorescent protein (eGFP) was used as a reporter. For further characterization, we also constructed plasmids containing different modifications of the rhaP(BAD) promoter. Induction experiments after the successful transfer of these plasmids into Pseudomonas putida KT2440 wild-type and different knockout strains revealed significant differences. In Pseudomonas, we observed no catabolite repression of the rhaP(BAD) promoter, and in contrast to E. coli, the binding of cyclic adenosine monophosphate (cAMP) receptor protein (Crp)-cAMP to this promoter is not necessary for induction as shown by deletion of the Crp binding site. The crp(-) mutant of P. putida KT2440 lacked eGFP expression, but this is likely due to problems in rhamnose uptake, since this defect was complemented by the insertion of the L-rhamnose-specific transporter rhaT into its genome via transposon mutagenesis. Other global regulators like Crc, PtsN, and CyoB had no or minor effects on rhamnose-induced eGFP expression. Therefore, this expression system may also be generally useful for Pseudomonas and other gamma-proteobacteria. PMID- 19789868 TI - Acquired cavo-varus deformity caused by an accessory calcaneus: a case report and literature review. AB - We describe an unusual cause of an acquired cavo-varus foot deformity produced by progressive enlargement of an accessory calcaneal ossicle. A 13-year-old boy with constitutional plano-valgus flat feet noted a gradual change in foot shape associated with lateral ankle pain on ambulation following an inversion injury 2 years earlier. CT and MRI scans confirmed a large accessory calcaneal ossicle lying within the sinus tarsi, with associated marrow oedema. Following surgical excision of the ossicle, the foot returned to its original shape and the symptoms were alleviated. This is the fifth reported case of an accessory calcaneal ossicle, but the only case that has occurred in a flatfooted individual. We also present the first reported MRI images of the lesion confirming pathological marrow oedema as a response to mechanical stress. PMID- 19789869 TI - Increased uptake of (131)I-MIBG after intra-arterial application in liver metastases of a neuroendocrine tumor. PMID- 19789870 TI - [18F]F15599, a novel 5-HT1A receptor agonist, as a radioligand for PET neuroimaging. AB - PURPOSE: The serotonin-1A (5-HT(1A)) receptor is implicated in the pathophysiology of major neuropsychiatric disorders. Thus, the functional imaging of 5-HT(1A) receptors by positron emission tomography (PET) may contribute to the understanding of its role in those pathologies and their therapeutics. These receptors exist in high- and low-affinity states and it is proposed that agonists bind preferentially to the high-affinity state of the receptor and therefore could provide a measure of the functional 5-HT(1A) receptors. Since all clinical PET 5-HT(1A) radiopharmaceuticals are antagonists, it is of great interest to develop a( 18)F labelled agonist. METHODS: F15599 (3-chloro-4-fluorophenyl-(4 fluoro-4{[(5-methyl-pyrimidin-2-ylmethyl)-amino]-methyl}-piperidin-1-yl) methanone) is a novel ligand with high affinity and selectivity for 5-HT(1A) receptors and is currently tested as an antidepressant. In pharmacological tests in rat, it exhibits preferential agonist activity at post-synaptic 5-HT(1A) receptors in cortical brain regions. Here, its nitro-precursor was synthesised and radiolabelled via a fluoronucleophilic substitution. Radiopharmacological evaluations included in vitro and ex vivo autoradiography in rat brain and PET scans on rats and cats. Results were compared with simultaneous studies using [(18)F]MPPF, a validated 5-HT(1A) antagonist radiopharmaceutical. RESULTS: The chemical and radiochemical purities of [(18)F]F15599 were >98%. In vitro [(18)F]F15599 binding was consistent with the known 5-HT(1A) receptors distribution (hippocampus, dorsal raphe nucleus, and notably cortical areas) and addition of Gpp(NH)p inhibited [(18)F]F15599 binding, consistent with a specific binding to G protein-coupled receptors. In vitro binding of [(18)F]F15599 was blocked by WAY100635 and 8-OH-DPAT, respectively, prototypical 5-HT(1A) antagonist and agonist. The ex vivo and in vivo studies demonstrated that the radiotracer readily entered the rat and the cat brain and generated few brain radioactive metabolites. Remarkably, in microPET studies, [(18)F]F15599 notably displayed a pattern of brain labelling that did not correlate with in vitro observations. Thus, in cat, the highest binding was observed in dorsal raphe and cingulate cortex with little binding in other cortical regions and none in hippocampus. In vivo binding was abolished by WAY100635, indicating specific labelling of 5-HT(1A) receptors. CONCLUSION: [(18)F]F15599 is a radiofluorinated agonist presenting interesting characteristics for probing in vitro and in vivo the high-affinity states of the 5-HT(1A) receptors. Its differential labelling of 5-HT(1A) receptors in vitro and in vivo may result from its reported preferential interaction with receptors coupled to specific G-protein subtypes. PMID- 19789871 TI - Non-invasive assessment of coronary artery disease with CT coronary angiography and SPECT: a novel dose-saving fast-track algorithm. AB - PURPOSE: To validate a new low-dose and rapid stepwise individualized algorithm for non-invasive assessment of ischemic coronary artery disease by sequential use of prospectively ECG-triggered low-dose CT coronary angiography (CTCA) and low dose single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI). METHODS: Forty patients referred for elective invasive coronary angiography (CA) were prospectively enrolled to undergo a comprehensive non invasive evaluation with low-dose CTCA and a dose-reduced stress/rest SPECT-MPI scan (using dedicated reconstruction algorithms for low count scans). The following algorithm was reviewed: CTCA first, followed by a stress-only MPI if a coronary stenosis (> or = 50% diameter narrowing) or equivocal findings were observed. Only abnormal stress MPI scans were followed by rest MPI. The accuracy of the individualized algorithm to predict coronary revascularization and its mean effective radiation dose were assessed. RESULTS: CTCA documented CAD in 18 and equivocal findings in two patients, thus, requiring additional stress MPI scans. Of these, 16 were abnormal, therefore requiring a rest MPI scan, revealing ischemia in 15 patients. Sensitivity, specificity, negative and positive predictive value, and accuracy of the individualized algorithm for predicting coronary revascularization was 93.3%, 96.0%, 96.0%, 93.3% and 95.0% on a per patient base. The mean effective radiation dose was significantly lower for the individualized (4.8 +/- 3.4 mSv) versus the comprehensive method (8.1 +/- 1.5 mSv) resulting in a total population radiation dose reduction of 132.6 mSv. CONCLUSION: This new individualized low-dose algorithm allows rapid and accurate prediction of invasive CA findings and of treatment decision with minimized radiation dose. PMID- 19789872 TI - Dual-gated cardiac PET-clinical feasibility study. AB - PURPOSE: Both respiratory and cardiac motions reduce image quality in myocardial imaging. For accurate imaging of small structures such as vulnerable coronary plaques, simultaneous cardiac and respiratory gating is warranted. This study tests the feasibility of a recently developed robust method for cardiac respiratory gating. List-mode data with triggers from respiratory and cardiac cycles are rearranged into dual-gated segments and reconstructed with standard algorithms of a commercial PET/CT scanner. Cardiac gates were defined as three fixed phases and one variable diastolic phase. Chest motion was measured with a respiratory gating device and post-processed to determine gates. Preservation of quantification in dual-gated images was tested with an IEC whole-body phantom. METHODS: Minipig and human studies were performed to evaluate the feasibility of the method. In minipig studies, a coronary catheter with radioactive tip was guided in coronary artery for in vivo and ex vivo acquisitions. Dual gating in humans with suspected cardiac disorders was performed using 18-F-FDG as a tracer. RESULTS: The method was found feasible for in vivo imaging and the radioactive catheter tip was better resolved in gated images. In human studies, the dual gating was found feasible and easy for clinical routine. Maximal movement of myocardial surface in cranio-caudal direction was over 20 mm. The shape of myocardium was clearly different between the gates and papillary muscles become more visible in diastolic images. CONCLUSION: The first clinical experiences using robust cardiac-respiratory dual gating are encouraging. Further testing in larger clinical populations using tracers designed especially for plaque imaging is warranted. PMID- 19789873 TI - Safety and efficacy of NAD depleting cancer drugs: results of a phase I clinical trial of CHS 828 and overview of published data. AB - PURPOSE: Depletion of cellular nicotinamide adenine dinucleotide (NAD) by inhibition of its synthesis is a new pharmacological principle for cancer treatment currently in early phases of clinical development. We present new and previously published data on the safety and efficacy of these drugs based on early clinical trials. METHODS: A phase I clinical trial of CHS 828 in patients with advanced solid tumours was performed. Published clinical trials on NAD depleting drugs for cancer treatment were summarised for safety and efficacy. RESULTS: Seven patients with previously treated solid tumours received oral administration of CHS 828 in the dose range 20-80 mg once weekly for 3 weeks in 4 weeks cycles. Toxicity was dominated by gastrointestinal symptoms including nausea, vomiting, diarrhoea, constipation, subileus and gastric ulcer. One patient had thrombocytopenia grade 2. There were two cases each of grade 3-4 hyperuricemia and hypokalemia. Safety and efficacy of the NAD depleting drugs CHS 828 and FK866 have been reported from four phase I clinical trials, including a total of 97 patients with previously treated solid tumours. Outstanding toxicity reported was thrombocytopenia and various gastrointestinal symptoms. No objective tumour remission has been observed in the total of 104 patients treated in the above early trials. CONCLUSIONS: Critical toxicity from NAD depleting cancer drugs to consider in future trials seems to be thrombocytopenia and various gastrointestinal symptoms. Efficacy of NAD depleting drugs when used alone is expected to be low. PMID- 19789874 TI - Churg-Strauss syndrome successfully treated with rituximab. AB - Churg-Strauss syndrome (CSS) is characterized by small-vessel vasculitis, extravascular granulomatous inflammation, and massive eosinophilia in tissues and blood, and is often accompanied by a history of preclinical asthma and/or allergic rhinitis lasting several years before the syndrome develops its full clinical picture. Corticosteroids, often in combination with cytotoxic agents, comprise standard therapy; however, a number of patients appear to be resistant to treatment and there is a need for more effective regimens. B cell depletion may be an effective treatment option for CSS. Here, we describe two patients resistant to conventional therapy who were treated with rituximab and experienced a rapid and substantial decrease in disease activity and asthmatic symptoms and an increase in physical capacity. PMID- 19789875 TI - Systemic lupus erythematosus associated with vasculitic syndrome (Takayasu's arteritis). AB - A 43-year-old woman reported pain in the right hypochondrium, which had started 3 years before and had been worsening for the past few days. Claudication in the superior and inferior limbs, diffuse myalgia, dyspnea, precordialgia followed by dizziness and visual turbidity were added to the clinical picture. In the physical examination bilateral carotid bruit was observed, abdominal aorta murmur and the decrease of the right radial and left pedis pulses and arterial hypertension with difference in the diastolic pressure between limbs >10 mmHg was also observed. On cardiac catheterisation with aortography, right coronary with proximal parietal irregularities, slight pressure increase in right chambers and pulmonary artery, preserved left ventricle contractility, competent valves, carotid and subclavian partial obstruction, severe narrowing of the abdominal aorta below the diaphragm (80%) and right renal artery significant stenosis were observed. Takayasu's arteritis (TA) diagnosis was established according to the ACR criteria based on the clinical symptomatology, on physical and image test findings. Two years later she presented malar rash, photosensitivity, nephropathy, leukopenia, lymphopenia and hemolytic anemia confirming the systemic lupus erythematosus (SLE) diagnosis. TA coexisting with SLE has rarely been reported. PMID- 19789876 TI - Diffusion-weighted MR imaging of kidneys in patients with chronic kidney disease: initial study. AB - OBJECTIVE: To prospectively evaluate the feasibility of diffusion-weighted (DW) magnetic resonance (MR) imaging in the assessment of renal function in patients with chronic kidney disease (CKD). METHODS: Seventy-two healthy volunteers and 43 patients underwent coronal echo-planar DW MR imaging of the kidneys with a single breath-hold time of 16 s. The patients were grouped according to five stages as indicated by the K/DOQI CKD (kidney disease outcome quality initiative). The apparent diffusion coefficient (ADC) value of the kidneys was calculated with high b values (b = 500 s/mm(2)). The ADC values were compared between patients and healthy volunteers, and among different stages. For statistical analysis, Student's t tests, ANOVA, Pearson's correlation tests, and Spearman's correlation tests were used. RESULTS: No difference between the cortex and medulla could be observed on DW images of all volunteers. Patients with CKD had significantly lower renal ADC (t = -4.383, P = 0.000) than volunteers. The ADC values of kidneys were significantly lower than normal at most stages of CKD, except CKD1. There was a negative correlation between the ADCs and serum creatinine (sCr) level (P = 0.000) amongst the patients. CONCLUSION: Diffusion-weighted MR imaging is feasible in the assessment of renal function, especially in the detection of early stage renal failure of CKD. PMID- 19789877 TI - Development and validation of a low dose simulator for computed tomography. AB - PURPOSE: To develop and validate software for facilitating observer studies on the effect of radiation exposure on the diagnostic value of computed tomography (CT). METHODS: A low dose simulator was developed which adds noise to the raw CT data. For validation two phantoms were used: a cylindrical test object and an anthropomorphic phantom. Images of both were acquired at different dose levels by changing the tube current of the acquisition (500 mA to 20 mA in five steps). Additionally, low dose simulations were performed from 500 mA downwards to 20 mA in the same steps. Noise was measured within the cylindrical test object and in the anthropomorphic phantom. Finally, noise power spectra (NPS) were measured in water. RESULTS: The low dose simulator yielded similar image quality compared with actual low dose acquisitions. Mean difference in noise over all comparisons between actual and simulated images was 5.7 +/- 4.6% for the cylindrical test object and 3.3 +/- 2.6% for the anthropomorphic phantom. NPS measurements showed that the general shape and intensity are similar. CONCLUSION: The developed low dose simulator creates images that accurately represent the image quality of acquisitions at lower dose levels and is suitable for application in clinical studies. PMID- 19789878 TI - Selection of diagnostic features on breast MRI to differentiate between malignant and benign lesions using computer-aided diagnosis: differences in lesions presenting as mass and non-mass-like enhancement. AB - PURPOSE: To investigate methods developed for the characterisation of the morphology and enhancement kinetic features of both mass and non-mass lesions, and to determine their diagnostic performance to differentiate between malignant and benign lesions that present as mass versus non-mass types. METHODS: Quantitative analysis of morphological features and enhancement kinetic parameters of breast lesions were used to differentiate among four groups of lesions: 88 malignant (43 mass, 45 non-mass) and 28 benign (19 mass, 9 non-mass). The enhancement kinetics was measured and analysed to obtain transfer constant (K(trans)) and rate constant (k(ep)). For each mass eight shape/margin parameters and 10 enhancement texture features were obtained. For the lesions presenting as nonmass-like enhancement, only the texture parameters were obtained. An artificial neural network (ANN) was used to build the diagnostic model. RESULTS: For lesions presenting as mass, the four selected morphological features could reach an area under the ROC curve (AUC) of 0.87 in differentiating between malignant and benign lesions. The kinetic parameter (k(ep)) analysed from the hot spot of the tumour reached a comparable AUC of 0.88. The combined morphological and kinetic features improved the AUC to 0.93, with a sensitivity of 0.97 and a specificity of 0.80. For lesions presenting as non-mass-like enhancement, four texture features were selected by the ANN and achieved an AUC of 0.76. The kinetic parameter k(ep) from the hot spot only achieved an AUC of 0.59, with a low added diagnostic value. CONCLUSION: The results suggest that the quantitative diagnostic features can be used for developing automated breast CAD (computer aided diagnosis) for mass lesions to achieve a high diagnostic performance, but more advanced algorithms are needed for diagnosis of lesions presenting as non mass-like enhancement. PMID- 19789879 TI - Diagnosis of gallbladder problems using three-dimensional ultrasound. AB - OBJECTIVE: The purpose of this study was to determine whether offline reported three-dimensional ultrasound (3DUS) is as accurate as standard two-dimensional ultrasound (2DUS) with regard to demonstrating gallbladder disease. METHOD: The cohort comprised 80 consecutive patients referred for an abdominal ultrasound examination. The participants underwent routine 2DUS assessment of the gallbladder followed by the acquisition of two 3DUS volumes of the region of the gall bladder. The two techniques were reported independently of each other, and the diagnoses were compared for correlation. RESULTS: There was overall agreement of the two techniques in 89% of cases with a positive predictive value of 89%, negative predictive value of 91% and a specificity of 86%. Small polyps (sub-4 mm) were the only positive discrepancies. Cohen's kappa found that there was substantial agreement between the two techniques (p = 0.05 for a two-tailed kappa 0.67), and chi-squared test found no significant difference in diagnoses (p = 0.95). CONCLUSION: This study shows that 3DUS diagnosis correlates well with 2DUS with regard to most gallbladder problems and could be sufficient as a stand-alone technique. PMID- 19789880 TI - Holmium-166 poly(L-lactic acid) microsphere radioembolisation of the liver: technical aspects studied in a large animal model. AB - OBJECTIVE: To assess the accuracy of a scout dose of holmium-166 poly(L-lactic acid) microspheres ((166)Ho-PLLA-MS) in predicting the distribution of a treatment dose of (166)Ho-PLLA-MS, using single photon emission tomography (SPECT). METHODS: A scout dose (60 mg) was injected into the hepatic artery of five pigs and SPECT acquired. Subsequently, a 'treatment dose' was administered (540 mg) and SPECT, computed tomography (CT) and magnetic resonance imaging (MRI) of the total dose performed. The two SPECT images of each animal were compared. To validate quantitative SPECT an ex vivo liver was instilled with (166)Ho-PLLA MS and SPECT acquired. The liver was cut into slices and planar images were acquired, which were registered to the SPECT image. RESULTS: Qualitatively, the scout dose and total dose images were similar, except in one animal because of catheter displacement. Quantitative analysis, feasible in two animals, tended to confirm this similarity (r(2) = 0.34); in the other animal the relation was significantly better (r(2) = 0.66). The relation between the SPECT and planar images acquired from the ex vivo liver was strong (r(2) = 0.90). CONCLUSION: In the porcine model a scout dose of (166)Ho-PLLA-MS can accurately predict the biodistribution of a treatment dose. Quantitative (166)Ho SPECT was validated for clinical application. PMID- 19789881 TI - 18F-FDG-PET/CT in the diagnosis of paraneoplastic neurological syndromes: a retrospective analysis. AB - OBJECTIVES: Paraneoplastic neurological syndromes (PNS) constitute a challenging diagnostic problem, as the underlying tumour often remains unidentified for a long time, even with frequent conventional diagnostic procedures. For appropriate patient management timely identification of the tumour is critical. We evaluated the value of (18)F-FDG-PET/CT in the investigation of PNS. METHODS: The case notes of 46 consecutive patients with clinically suspected PNS who underwent (18)F-FDG-PET/CT were reviewed retrospectively and the performance of PET/CT for detecting underlying tumours was assessed. RESULTS: PET/CT detected foci of increased (18)F-FDG uptake in 10 out of 46 patients. In six of these 10 patients combined PET/CT identified the underlying disease: four patients suffered from PNS; vasculitic and local metastatic disease was detected in two other patients. CONCLUSIONS: Based on our results, we believe that the role of positron emission tomography in the detection of occult neoplasms in patients with PNS has been overestimated in the past. In clinical practice, PNS is far more often suspected than proven. In our study combined PET/CT identified malignancy as the underlying cause of suspected PNS in only 8.7% (4/46). We believe that combined PET/CT should be reserved for stringently selected patients with a high clinical index of suspicion for PNS and after conventional imaging techniques fail to detect a tumour. PMID- 19789882 TI - Hybrid-repair of thoraco-abdominal or juxtarenal aortic aneurysm: what the radiologist should know. AB - PURPOSE: Endovascular aneurysm repair of the infrarenal or thoracic aorta has been shown to be a less invasive alternative to open surgery. A combined aneurysm of the thoracic and abdominal aorta is complex and challenging; the involvement of renal and/or visceral branches requires new treatment methods. METHODS: A hybrid approach is currently an accepted alternative to conventional surgery. Renal and/or visceral revascularisation enables subsequent stent-graft placement into the visceral portion of the aorta. RESULTS: Knowledge of the surgical procedure and a precise assessment of the vascular morphology are crucial for pre procedural planning and for detection of post-procedural complications. Multi detector computed tomography angiography (MDCTA) combined with two- and three dimensional (2D and 3D) rendering is useful for pre-interventional planning and for the detection of post-procedural complications. Three-dimensional rendering allows proper anatomical analyses, influencing interventional strategies and resulting in a better outcome. CONCLUSIONS: With the knowledge of procedure specific MDCTA findings in various vascular conditions, the radiologist and surgeon are able to perform an efficient pre-interventional planning and follow up examination. Based on our experience with this novel technique of combined open and endovascular aortic aneurysm treatment, this pictorial review illustrates procedure-specific imaging findings, including common and rare complications, with respect to 2D and 3D post-processing techniques. PMID- 19789883 TI - Sensitivity and reliability of language laterality assessment with a free reversed association task--a fMRI study. AB - OBJECTIVE: The aim of the study was to evaluate the sensitivity and reliability of assessing hemispheric language dominance with functional magnetic resonance imaging (fMRI) using a 'free reversed association task.' METHODS: Thirty-nine healthy subjects (13 dextrals, 13 sinistrals and 13 bimanuals) underwent two repeated fMRI sessions. In the active phases sets of words were presented via headphones, and an associated target item was named. During the baseline phases a standard answer was given after listening to unintelligible stimuli. Data were preprocessed with SPM, and then laterality indices (LI) and reliability coefficients (RC) were calculated. RESULTS: Extensive frontal, temporal and parietal activations were found. Seventy-eight percent of the subjects showed left-hemispheric dominance, 5% showed right-hemispheric dominance, and 17% had bilateral language representations. The incidence of right-hemispheric language dominance was 4.3 times higher in a left-hander with a handedness quotient (HQ) of -90 than in a right-hander with a HQ of +90. The RC was 0.61 for combined ROIs (global network). Strong correlations were found between the two session LIs (r = 0.95 for the global network). CONCLUSION: 'Free reversed association' is a sensitive and reliable task for the determination of individual language lateralization. This suggests that the task may be used in a clinical setting. PMID- 19789886 TI - Morbidity and quality of life after continent ileostomy: a comment. PMID- 19789885 TI - Do the cardiovascular risk profile and the degree of arterial wall calcification influence the performance of MDCT angiography of lower extremity arteries? AB - OBJECTIVES: To retrospectively assess the influence of arterial wall calcifications on the accuracy of run-off computed tomographic angiography (CTA) and to analyse whether cardiovascular risk factors are predictors of compromising calcifications. METHODS: In 200 consecutive patients who underwent run-off CTA, calcifications were assessed in pelvic, thigh and calf arteries using a four point scale. Fifty-nine patients with digital subtraction angiography (DSA) were assessed by both techniques to estimate a threshold of compromising calcifications, defined as a decrease of sensitivity, specificity, PPV or NPV below the lower 95% confidence interval of overall results. Regression analysis was performed to investigate a potential relationship between compromising calcifications and presence of cardiovascular risk factors, advanced patient age and severe peripheral arterial disease (PAD). RESULTS: The highest Ca(++)-score was chosen as the cut-off for the regression analysis, as a relevant decrease of specificity (0.91; overall: 0.95) above the knee and of sensitivity (0.66; overall: 0.83), specificity (0.65; overall: 0.93), positive predictive value (PPV) and negative predictive value (NPV) below the knee was observed. In the pelvic and thigh arteries, severe PAD (Fontaine Stage >or=III) showed the highest odds ratio for compromising calcifications (2.9), followed by diabetes mellitus (2.4), renal failure (2.1) and smoking (1.7). In the calf, renal failure (12.2) and diabetes mellitus (3.3) were the strongest predictors. CONCLUSIONS: Patients with diabetes and renal failure should be considered as candidates for alternative vessel imaging in order to avoid inconclusive examination results. PMID- 19789887 TI - "Inflammatory" changes in breast: how to provide a better care to our patients. AB - "Inflammatory" changes of the breast can be seen in many different entities ranging from benign self-limited processes, for example puerperal mastitis, to highly aggressive malignant tumors, such as inflammatory carcinoma. While clinically many of these "inflammatory" processes may look alike, there are some characteristics that allow an accurate differential diagnosis and accordingly a correct treatment. A worldwide effort is made everyday to promote breast health awareness, to facilitate prevention, early detection, and effective treatment. Nevertheless, breast cancer still remains as the number one female cancer and as the second cause of death for cancer in women. Physicians involved in the care of female patients are the first line of defense in the battle against cancer. Therefore, it is important to keep in mind a broad differential diagnosis in patients that seek medical attention complaining of a breast problem. Herein is a summary of the most common causes of inflammatory and inflammatory-like changes in breast with special emphasis on clinical presentation and differential diagnosis. PMID- 19789884 TI - 64-Slice CT angiography of the abdominal aorta and abdominal arteries: comparison of the diagnostic efficacy of iobitridol 350 mgI/ml versus iomeprol 400 mgI/ml in a prospective, randomised, double-blind multi-centre trial. AB - PURPOSE: The purpose of this study was to assess the influence of iodine concentration on diagnostic efficacy in multi-detector-row computed tomography (MDCT) angiography of the abdominal aorta and abdominal arteries. METHODS: IRB approval and informed consent were obtained. In this double-blind trial, patients were randomised to undergo MDCT angiography of the abdominal arteries during administration of iobitridol (350 mgI/ml) or iomeprol (400 mgI/ml). Each centre applied its own technique for delivery of contrast medium, regardless of iodine concentration. Diagnostic efficacy, image quality, visualisation of the arterial wall and arterial enhancement were evaluated. A total of 153 patients received iobitridol and 154 received iomeprol. RESULTS: The ability to reach a diagnosis was "satisfactory" to "totally satisfactory" in 152 (99.3%) and 153 (99.4%) patients respectively. Image quality was rated as being "good" to "excellent" in 94.7 and 94.8% segments respectively. Similar results were observed for image quality of arterial walls (84.3 vs. 83.2%). The mean relative changes in arterial enhancement between baseline and arterial phase images showed no statistically significant differences. CONCLUSION: This study demonstrated the non-inferiority of the 350 versus 400 mgI/ml iodine concentration, in terms of diagnostic efficacy, in abdominal MDCT angiography. It also confirmed the high robustness and reliability of this technique across multi-national practices. PMID- 19789888 TI - Umbilical surgical scar and vulval metastasis secondary to advanced cervical squamous cell carcinoma: a report of two cases. AB - INTRODUCTION: Association of cutaneous metastasis with cervical carcinoma is a rare finding, with only a few case reports in literature. CASE REPORT: Herein, we report a case of cervical squamous cell carcinoma, which later presented as widespread skin metastases on the surgical scar as an initial sign of recurrent disease. CONCLUSION: In conclusion, incisional cutaneous and vulval metastasis is a rarity with cancer cervix and is considered as an ominous prognostic sign with a short survival after diagnosis. PMID- 19789891 TI - Spike-timing-dependent plasticity leads to gamma band responses in a neural network. AB - Early gamma band responses of the human electroencephalogram have been identified as an early interface linking top-down and bottom-up processing. This was based on findings that observed strong sensitivity of this signal to stimulus size and at the same time, to processes of attention and memory. Here, we simulate these findings in a simple random network of biologically plausible spiking neurons. During a learning phase, different stimuli were presented to the network and the synaptic connections were modified according to a spike-timing-dependent plasticity learning rule. In a subsequent test phase, we stimulated the network with (i) patterns of different sizes to simulate bottom-up effects and (ii) with patterns that were or were not presented during the learning phase. The network displayed qualitatively similar behavior as early gamma band responses measured from the scalp of human subjects: there was a general increase in response strength with increasing stimulus size and stronger responses for learned stimuli. We demonstrated that within one neural architecture early gamma band responses can be modulated both by bottom-up factors and by basal learning mechanisms mediated via spike-timing-dependent plasticity. PMID- 19789892 TI - Cloning and functional characterization of a fructan 1-exohydrolase (1-FEH) in the cold tolerant Patagonian species Bromus pictus. AB - Fructans are fructose polymers synthesized in a wide range of species such as bacteria, fungi and plants. Fructans are synthesized by fructosyltransferases (FTs) and depolymerized by fructan exohydrolases (FEHs). Bromus pictus is a graminean decaploid species from the Patagonian region of Argentina, which accumulates large amounts of fructans even at temperate temperatures. The first gene isolated from B. pictus fructan metabolism was a putative sucrose:fructan 6 fructosyltransferase (6-SFT). Here, a complete cDNA of the first fructan exohydrolase (FEH) from B. pictus (Bp1-FEHa) was isolated using RT-PCR strategies. The Bp1-FEHa encoding gene is present as a single copy in B. pictus genome. Functional characterization in Pichia pastoris confirmed Bp1-FEHa is a fructan exohydrolase with predominant activity towards beta-(2-1) linkages. Its expression was analyzed in different leaf sections, showing the highest expression levels in the second section of the sheath and the tip of the blade. Bp1-FEHa expression was studied along with FEH and FT activities and fructan accumulation profile in response to chilling conditions during a 7-day time course experiment. Bp1-FEHa expression and FEH activity followed a similar pattern in response to low temperatures, especially in basal sections of the sheaths. In these sections the FEH and FT activities were particularly high and they were significantly correlated to fructan accumulation profile, along with cold treatment. PMID- 19789893 TI - The similar survival benefits of stable disease and partial response to pemetrexed in previously treated non-small cell carcinoma patients. AB - PURPOSE: Pemetrexed is a recognized active agent for the second-line treatment for advanced non-small cell lung cancer (NSCLC). This study was undertaken to evaluate the clinical benefits of pemetrexed and to identify patient characteristics that predict response to pemetrexed. METHODS: We retrospectively reviewed the medical records of patients with histologically proven stage IIIB or IV NSCLC who were treated with pemetrexed after the failure of prior chemotherapy. RESULTS: The objective response rate for the 99 enrolled patients was 13.1% and 22 patients achieved stable disease (SD)-a disease control rate of 35.4%. Progression-free survival and overall survival (OS) were 1.8 months (95% CI, 1.32-2.28) and 7.6 months (95% CI, 6.23-8.97), respectively. The patients who achieved SD and pemetrexed-responders showed similar OSs (14.6 vs. 14.8 months, P = 0.55). However, a squamous cell carcinoma histology showed no significant OS difference between those that achieved disease control or progression (8.1 vs. 5.6 months, P = 0.07). Subgroup analysis of OS revealed that histology and response to first-line therapy predicted response to pemetrexed. CONCLUSIONS: Pemetrexed has comparable survival benefits in NSCLC patients that show objective response or stable disease. PMID- 19789894 TI - Lipid peroxidation in cats experimentally infected with Trypanosoma evansi. AB - The objective of this study was to evaluate the lipid peroxidation and the susceptibility of erythrocytes to in vitro peroxidation as indicators of oxidative damage in erythrocytes and their roles in the pathogenesis of anemia during experimental Trypanosoma evansi infection in cats. Animals were divided into two groups: control and infected with T. evansi. Seven cats were infected with 10(8) trypomastigotes each, and parasitemia was estimated daily for 49 days by microscopic examination of smears. Hematological and biochemical parameters were evaluated for monitoring of the disease. Plasma lipid peroxidation (Thiobarbituric Acid Reactive Substances (TBARS)) and the susceptibility of erythrocytes to in vitro peroxidation were evaluated. Blood samples for analysis were collected at days 21 and 49 post-inoculation. TBARS level, indicated by MDA concentration, was higher in the infected group than in the control group in both analyzed periods, as well as the in vitro erythrocyte peroxidation (P < 0.001). The infected cats had variable degrees of regenerative anemia, which could be explained by the damage in erythrocyte membrane caused by lipid peroxidation. PMID- 19789895 TI - The efficacy of monepantel, an amino-acetonitrile derivative, against gastrointestinal nematodes of sheep in three countries of southern Latin America. AB - The efficacy of the novel anthelmintic, monepantel (an amino-acetonitrile derivative), was investigated in sheep naturally infected with gastrointestinal nematodes in five studies in Argentina, Brazil, and Uruguay. Monepantel, administered at 2.5 mg/kg liveweight, was highly effective (>99.7%) against Haemonchus contortus, Teladorsagia (Ostertagia) circumcincta, Trichostrongylus axei, Trichostrongylus colubriformis, Cooperia curticei, Cooperia mcmasteri, Cooperia oncophora, Cooperia pectinata, Cooperia punctata, and Nematodirus spathiger, including strains resistant to the older broad-spectrum anthelmintics. Efficacy against C. mcmasteri, C. pectinata, and C. punctata is documented for the first time. The treatment with monepantel was well tolerated by the sheep. PMID- 19789896 TI - Atypical caseinolytic protease homolog from Plasmodium falciparum possesses unusual substrate preference and a functional nuclear localization signal. AB - Although ATP-dependent caseinolytic protease (Clp) complexes are important for regulating the pathogenicity, survival, and development of many pathogens, their physiological roles in the pathogenicity of malarial parasites remain unknown. This study reports the cloning, authentication, and characterization of a putative Clp protease subunit from Plasmodium falciparum (PfClpP). Heterologous expression studies showed that signal peptide hindered the soluble expression of the full-length PfClpP. Biochemical analyses of the recombinant PfClpP showed that it did not cleave the known ClpP substrate, succinyl-leucine-tyrosine-7 amido-4-methylcoumarin hydrochloride (AMC). Instead, PfClpP readily hydrolyzed a different substrate, glycine-arginine-AMC. The distinctive substrate preference of PfClpP suggests structural uniqueness in its substrate-binding sites that might be exploitable in anti-malarial drug development. Whether PfClpP resembles most eukaryotic ClpPs in being localized to the mitochondria and chloroplasts was also investigated using a mammalian surrogate host system. The results observed showed that green-fluorescence protein tagged PfClpP proteins were localized to the nucleus. PfClpP may have a unique and specialized role in the plasmodial nucleus. Taken together, this study has shown that PfClpP has a unique peptide cleavage function that is localized at the plasmodial nucleus, probably positioned to elicit a regulatory role in the parasite's pathogenicity. PMID- 19789897 TI - Impact of Piriformospora indica on tomato growth and on interaction with fungal and viral pathogens. AB - Piriformospora indica is a root endophytic fungus with plant-promoting properties in numerous plant species and induces resistance against root and shoot pathogens in barley, wheat, and Arabidopsis. A study over several years showed that the endophyte P. indica colonised the roots of the most consumed vegetable crop tomato. P. indica improved the growth of tomato resulting in increased biomass of leaves by up to 20%. Limitation of disease severity caused by Verticillium dahliae by more than 30% was observed on tomato plants colonised by the endophyte. Further experiments were carried out in hydroponic cultures which are commonly used for the indoor production of tomatoes in central Europe. After adaptation of inoculation techniques (inoculum density, plant stage), it was shown that P. indica influences the concentration of Pepino mosaic virus in tomato shoots. The outcome of the interaction seems to be affected by light intensity. Most importantly, the endophyte increases tomato fruit biomass in hydroponic culture concerning fresh weight (up to 100%) and dry matter content (up to 20%). Hence, P. indica represents a suitable growth promoting endophyte for tomato which can be applied in production systems of this important vegetable plant not only in soil, but also in hydroponic cultures. PMID- 19789898 TI - Mandibular fractures associated with endosteal implants. AB - PURPOSE: The purpose of this study is to report four cases of mandibular fractures associated with endosteal implants and to discuss prevention and treatment of these types of fractures. DISCUSSION: To evaluate whether the patient's anatomy allows insertion of implants, radiological exams that demonstrate the height and the labial-lingual width are needed. To reduce the potential fracture problem, the mandible can be restrengthened with bone grafting techniques. The treatment of a fracture in an atrophic mandible is always a challenge because of the diminished central blood supply, the depressed vitality of the bone, and the dependence on the periosteal blood supply. The basic principles in fracture treatment are reduction and immobilization of the fractured site for restoration of form and function. CONCLUSIONS: If implants are placed in severe atrophic mandible, iatrogenic fracture of the mandible may occur during or after implant surgery because implant placement weakens the already compromised mandible. A few millimeters of cortical bone should remain on both the labial and the lingual sites after the hole for insertion of an implant has been drilled. A 3-D surgical planning should be recommended at least in severe atrophic mandibles in order to prevent a severe reduction of bone tissue. PMID- 19789899 TI - Onset of disability and life satisfaction: evidence from the German Socio Economic Panel. AB - This paper analyses the effect of the onset of disability on the well-being of individuals. In particular, we are interested in studying whether people can adapt to disability over time after its onset. Using longitudinal data from the German Socio-Economic Panel (GSOEP) for the period 1984-2006, we estimate life satisfaction equations using a fixed-effects model for working-age males (aged 21 58). The results show that disability has a significant negative effect on life satisfaction, but, in time, hedonic adaptation will return disabled males to life satisfaction levels registered by those who have not become disabled. These findings contribute to supporting the idea within psychology literature that individuals bounce back from painful events or adversities (such as the onset of disability) to achieve initial life satisfaction scores. PMID- 19789900 TI - Sulfide persistence in oil field waters amended with nitrate and acetate. AB - Nitrate amendment is normally an effective method for sulfide control in oil field-produced waters. However, this approach has occasionally failed to prevent sulfide accumulation, despite the presence of active nitrate-reducing bacterial populations. Here, we report our study of bulk chemical transformations in microcosms of oil field waters containing nitrate-reducing, sulfide-oxidizing bacteria, but lacking denitrifying heterotrophs. Amendment with combinations of nitrate, acetate, and phosphate altered the microbial sulfur and nitrogen transformations. Elemental sulfur produced by chemotrophic nitrate-reducing bacteria was re-reduced heterotrophically to sulfide. Ammonification, rather than denitrification, was the predominant pathway for nitrate reduction. The application of nitrite led to transient sulfide depletion, possibly due to higher rates of nitrite reduction. The addition of molybdate suppressed both the accumulation of sulfide and the heterotrophic reduction of nitrate. Therefore, sulfidogenesis was likely due to elemental sulfur-reducing heterotrophic bacteria, and the nitrate-reducing microbial community consisted mainly of facultatively chemotrophic microbes. This study describes one set of conditions for continued sulfidogenesis during nitrate reduction, with important implications for nitrate control of sulfide production in oil fields. PMID- 19789901 TI - New bioactive oxylipins formed by non-enzymatic free-radical-catalyzed pathways: the phytoprostanes. AB - In animals and plants, fatty acids with at least three double bonds can be oxidized to prostaglandin-like compounds via enzymatic and non-enzymatic pathways. The most common fatty acid precursor in mammals is arachidonic acid (C20:4) (AA) which can be converted through the cyclooxygenase pathway to a series of prostaglandins (PG). Non-enzymatic cyclization of arachidonate yields a series of isoprostanes (IsoP) which comprises all PG (minor compounds) as well as PG isomers that cannot be formed enzymatically. In contrast, in plants, alpha linolenic acid (C18:3) (ALA) is the most common substrate for the allene oxide synthase pathway leading to the jasmonate (JA) family of lipid mediators. Non enzymatic oxidation of linolenate leads to a series of C18-IsoPs termed dinor IsoP or phytoprostanes (PP). PP structurally resemble JA but cannot be formed enzymatically. We will give an overview of the biological activity of the different classes of PP and also discuss their analytical applications and the strategies developed so far for the total synthesis of PP, depending on the synthetic approaches according to the targets and which key steps serve to access the natural products. PMID- 19789902 TI - Effects of weight loss on lipid transfer proteins in morbidly obese women. AB - Obesity is associated with lipid abnormalities leading to an increased morbidity and mortality from atherosclerotic disease. Lipid transfer proteins such as Cholesteryl Ester Transfer Protein (CETP) and Phospholipid Transfer Protein (PLTP), and lipases such as lipoprotein lipase (LPL) and hepatic lipase (HL) are involved in the pathogenesis of the obesity associated proatherogenic dyslipidemia. Nineteen severely obese female subjects undergoing laparosopic gastric banding participated in this prospective study. Subjects were examined with respect to body composition, lipid profile, CETP, PLTP, LPL and HL before and 1 year after surgical treatment. Mean weight loss was 22.2 kg, mainly due to losses in the fat depots. Triglycerides decreased and HDL(2)-C increased significantly. In respect to transfer proteins mean CETP mass decreased from 1.82 to 1.71 microg mL(-1) (P = 0.043) and mean PLTP activity was reduced from 7.15 to 6.12 micromol mL(-1) h(-1) (P = 0.002), in parallel. In addition, both mean LPL activity and mean HL activity tended to decrease from 297 to 248 nmol mL(-1) h( 1) for LPL (P = 0.139) and from 371 to 319 nmol mL(-1) h(-1) for HL (P = 0.170), respectively. We conclude that weight loss induced by bariatric surgery is associated with the amelioration of the obesity-associated dyslipidemic state. This improvement may be attributable to decreased mass and action of the adipocyte tissue derived lipid transfer proteins CETP and PLTP. PMID- 19789904 TI - Enhancement of absolute fracture risk prognosis with genetic marker: the collagen I alpha 1 gene. AB - An important objective of genetic research in osteoporosis is to translate genotype data into the prognosis of fracture. The present study sought to develop a prognostic model for predicting osteoporotic fracture by using information from a genetic marker and clinical risk factors. It was designed as a prospective epidemiological study which involved 894 women of Caucasian background aged 60+ years who had been followed for a median of 9 years (from 1989 and 2008, range 0.2-18 years). During the follow-up period, fragility fracture was ascertained by X-ray reports for all women. Bone mineral density (BMD) at the femoral neck was measured by dual-energy X-ray absorptiometry. Genotypes of the Sp1 binding site in the first intron of the collagen I alpha 1 (COLIA1) gene polymorphism were determined by polymerase chain reaction, digestion with BalI restriction enzyme, and agarose gel electrophoresis. The relationship between COL1A1 genotype and fracture was assessed by the Cox proportional hazards model, from which nomograms were developed for individualizing the risk of fracture. The distribution of COL1A1 genotypes was consistent with the Hardy-Weinberg equilibrium law: GG (63.8%), GT (32.6%), and TT (3.6%). During the follow-up period, there were 322 fractures, including 77 hip and 127 vertebral fractures. There was an overrepresentation of the TT genotype in the fracture group (6.2%) compared with the nonfracture group (2.3%). Compared with carriers of GT and GG, women carrying the TT genotype had increased risk of any fracture (relative risk [RR] = 1.91, 95% CI 1.21-3.00), hip fracture (RR = 3.67, 95% CI 1.69-8.00), and vertebral fracture (RR = 3.36, 95% CI 1.81-6.24). The incorporation of COL1A1 genotypes improved the risk reclassification by 2% for any fragility fracture, 4% for hip fracture, and 5% for vertebral fracture, beyond age, BMD, prior fracture, and fall. Three nomograms were constructed for predicting fracture risk in an individual woman based on age, BMD, and COLIA1 genotypes. These data suggest that the COLIA1 Sp1 polymorphism is associated with the risk of fragility fracture in Caucasian women and that the polymorphism could enhance the predictive accuracy of fracture prognosis. The nonograms presented here can be useful for individualizing the short- and intermediate-term prognosis of fracture risk and help identify high-risk individuals for intervention for appropriate management of osteoporosis. PMID- 19789903 TI - Total synthesis and antileishmanial activity of the natural occurring acetylenic fatty acids 6-heptadecynoic acid and 6-icosynoic acid. AB - The first total syntheses of the naturally occurring acetylenic fatty acids-6 heptadecynoic acid (59% overall yield) and 6-icosynoic acid (34% overall yield) was accomplished in four steps. Using the same synthetic sequence the naturally occurring fatty acids (6Z)-heptadecenoic acid (46% overall yield) and (6Z) icosenoic acid (27% overall yield) were also synthesized. The Delta(6) acetylenic fatty acids displayed good antiprotozoal activity towards Leishmania donovani promastigotes (EC(50) = 1-6 microg/mL), but the 6-icosynoic acid was the most effective in the series. In addition, the (6Z)-icosenoic acid was a much better antiprotozoal compound (EC(50) = 5-6 microg/mL) than the (6Z)-heptadecenoic acid (EC(50) > 25 microg/mL). The saturated fatty acids n-heptadecanoic acid and n eicosanoic acid were not effective towards L. donovani, indicating that the Delta(6) unsaturation in these fatty acids is necessary for leishmanicidal activity. In addition, both the 6-icosynoic acid and the (6Z)-icosenoic acid were inhibitors of the Leishmania DNA topoisomerase IB enzyme (EC(50's) = 36-49 microM), a possible intracellular target for these compounds. This is the first study assessing fatty acids as inhibitors of the Leishmania DNA topoisomerase IB enzyme. PMID- 19789905 TI - Alamethicin aggregation in lipid membranes. AB - X-ray scattering features induced by aggregates of alamethicin (Alm) were obtained in oriented stacks of model membranes of DOPC(diC18:1PC) and diC22:1PC. The first feature obtained near full hydration was Bragg rod in-plane scattering near 0.11 A(-1) in DOPC and near 0.08 A(-1) in diC22:1PC at a 1:10 Alm:lipid ratio. This feature is interpreted as bundles consisting of n Alm monomers in a barrel-stave configuration surrounding a water pore. Fitting the scattering data to previously published molecular dynamics simulations indicates that the number of peptides per bundle is n = 6 in DOPC and n >or= 9 in diC22:1PC. The larger bundle size in diC22:1PC is explained by hydrophobic mismatch of Alm with the thicker bilayer. A second diffuse scattering peak located at q(r) approximately 0.7 A(-1) is obtained for both DOPC and diC22:1PC at several peptide concentrations. Theoretical calculations indicate that this peak cannot be caused by the Alm bundle structure. Instead, we interpret it as being due to two dimensional hexagonally packed clusters in equilibrium with Alm bundles. As the relative humidity was reduced, interactions between Alm in neighboring bilayers produced more peaks with three-dimensional crystallographic character that do not index with the conventional hexagonal space groups. PMID- 19789906 TI - Modulatory effects of deltamethrin on antioxidant defense mechanisms and lipid peroxidation in Carassius auratus gibelio liver and intestine. AB - Pyrethroids, such as deltamethrin, are toxic substances that lead to generation of reactive oxygen species, which harm living organisms. We assessed the level and patterns of imbalance evolved by a single dose of 2 microg/L deltamethrin on the lipid peroxidation (LPO) and the antioxidant defense system of Carassius auratus gibelio liver and intestine, and monitored the recovery dynamics of these parameters during a 14-day post-exposure period. LPO and antioxidative defense mechanisms displayed different responses in the investigated tissues. Sudden increase of LPO in the liver, persisting at this elevated level throughout the test period, was observed on the third day post-exposure, while in the intestine significant enhancement of this parameter was recorded from the seventh day. Reduced glutathione (GSH) showed a transient increase in the liver, and was depleted in the intestine by the second day of exposure, with signs of recovery by the end of the experimental tenure. In the liver of fish a temporary inhibition of superoxide dismutase (SOD) and catalase (CAT) activity, and activation of glutathione peroxidase (GPX), glutathione transferase (GST), and glutathione reductase (GR) enzymes was observed, with maximum thresholds recorded on the third and second days, respectively. In the intestine a relevant increase in CAT and GST activity up to the second day and almost complete recovery by the end of the experiment was recorded, while for GR a continuous enhancement was apparent. PMID- 19789907 TI - Concentrations and accumulation features of organochlorine pesticides in the Baiyangdian Lake freshwater food web of North China. AB - Organochlorine pesticides (OCPs), such as hexachlorocyclohexane (HCH) and dichlorodiphenyltrichloroethane (DDT), are ubiquitous anthropogenic environmental contaminants. They are persistent, broad-spectrum toxicants that accumulate in the food web with potential risks to the ecosystem and human health. HCHs were the predominant contaminants in Baiyangdian Lake, North China. Concentrations of HCHs and DDTs ranged from 58 to 563 ng/g lipid weight (lw) and 21 to 401 ng/g lw, respectively, for aquatic biota samples. The highest levels of HCHs and DDTs were observed in muscles of yellow catfish. The mean concentrations of OCPs were 4.6 ng/L for water, 95 ng/g dry weight (dw) for aquatic plants, and 14 ng/g dw for sediments. Among the isomers and metabolites, alpha-HCH and p,p'-1,1-di(p chlorophenyl)-2,2-dichloroethylene (p,p'-DDE) were the predominant congeners in biota samples. Correlations between log lipid-normalized concentrations of HCHs and DDTs and trophic levels (TLs) based on analysis of stable isotopes of nitrogen confirmed that persistent organic pollutants were magnified in the Baiyangdian Lake food web. Significant positive relationships were found for alpha-HCH and p,p'-DDT and their trophic magnification factors, which were 1.6 and 1.7, respectively. These results provide evidence of biomagnification of persistent organic pollutants (POPs) in freshwater food webs. PMID- 19789908 TI - Tissue distribution of polychlorinated biphenyls and organochlorine pesticides and potential toxicity to Alaskan northern fur seals assessed using PCBs congener specific mode of action schemes. AB - The fur seal (Callorhinus ursinus) population has decreased in their primary breeding grounds in the Bering Sea; contamination is among suspected causes. Our goal was to better understand the extent of contamination of seal tissues with certain organochlorine compounds by measuring the concentrations of polychlorinated biphenyls (PCBs) and organochlorine pesticides (OCPs) in fur seal tissues from St. Paul Island, to gain a better perspective of tissue congener distribution and to evaluate the observed PCB levels against toxicologically significant levels for modes of action. Concentrations of 145 PCB congeners (Sigma(145)PCBs) and 12 OCPs were measured with gas chromatography-ion trap mass spectrometry in 8 different tissues of 10 male northern fur seals. The mean concentrations of SigmaOCPs [in ng/g lipid weight (lw)] were 1180 in blubber, 985 in the heart, 1007 in the liver, 817 in the kidney, 941 in muscle, 660 in reproductive tissues, 204 in the brain, and 322 in the lung. The mean concentrations of Sigma(145)PCBs (in ng/g lw) were 823 in blubber, 777 in the liver, 732 in the heart, 646 in reproductive tissues, 638 in muscle, 587 in the kidney, 128 in the lung, and 74.3 in brain tissues. Concentrations of PCBs affecting the aryl hydrocarbon receptor expressed as total PCB toxic equivalents (SigmaPCB-TEQs) ranged from 0.3 to 545 pg/g lw for the various tissues. The major contributors to SigmaPCB-TEQs are CB-118 in muscle, brain, lung, kidney, and liver, CB-126 in blubber, and CB-118 and CB-126 equally in the heart and reproductive tissues. Concentrations of PCBs affecting Ca(2+) homeostatsis expressed as the neurotoxic equivalent (NEQ) showed SigmaPCB-NEQs ranged from 17.7 to 215 ng/g lw in all tissues. Although no composite measure of perturbation of thyroid function is available, sufficient amounts of congeners with high binding to the thyroxine transport system were present to warrant consideration of this mode of action in future studies. Analyses of 145 PCBs and mode of action evaluation suggest that PCB contamination could potentially exert an effect on the Alaskan northern fur seal population although the PCB concentrations have been decreasing in the fur seals over the last decade. PMID- 19789909 TI - Linkage between bacterial carbon processing and the structure of the active bacterial community at a coastal site in the NW Mediterranean Sea. AB - The temporal dynamics in bulk bacterial parameters and in the richness of the total and active bacterial community, determined from CE-SSCP fingerprints of 16S rRNA genes and 16S rRNA transcripts, respectively, were followed weekly to bimonthly at an oligotrophic coastal site in the NW Mediterranean Sea. Bacterial abundance, bacterial heterotrophic production, and bacterial and community respiration determined over two seasonal cycles displayed large short-term variability and no pronounced temporal pattern was detectable for these parameters. Concentrations in inorganic nutrients, salinity, or concentrations of chlorophyll a could not significantly explain the temporal variability of the bacterial parameters determined. By contrast, bacterial respiration and the bacterial carbon demand were both negatively correlated with the richness of the active bacterial community, while the bacterial parameters determined herein were not related to the richness of the total bacterial community present. Our results indicate that a reduced number of ribotypes is active when rates of bacteria mediated carbon processes are high. Our approach, based on fingerprints of 16S rRNA transcripts, could represent an interesting tool to investigate the relationship between the structure and function of marine bacteria, in particular, on short temporal and spatial scales. PMID- 19789910 TI - Bacterial community structure of sediments of the bizerte lagoon (Tunisia), a southern Mediterranean coastal anthropized lagoon. AB - In order to estimate how pollution affects the bacterial community structure and composition of sediments, chemical and molecular approaches were combined to investigate eight stations around the Bizerte lagoon. Terminal restriction fragment length polymorphism (T-RFLP) analysis of PCR-amplified 16S rRNA genes revealed that each station was characterized by a specific bacterial community structure. The combination of this data with those of chemical analysis showed a correlation between the bacterial fingerprint and the pollutant content, principally with hydrocarbon pollution. The composition of the bacterial community of two contrasted stations related to the pollution revealed sequences affiliated to alpha, beta, gamma, delta, epsilon subclass of the Proteobacteria, Actinobacteria, and Acidobacteria in both stations although in different extent. Gamma and delta subclass of the Proteobacteria were dominant and represent 70% of clones in the heavy-metal-contaminated station and 47% in the polyaromatic hydrocarbon (PAH)-contaminated. Nevertheless, most of the sequences found were unaffiliated to cultured bacteria. The adaptation of the bacterial community mainly to PAH compounds demonstrated here and the fact that these bacterial communities are mainly unknown suggest that the Bizerte lagoon is an interesting environment to understand the capacity of bacteria to cope with some pollutants. PMID- 19789911 TI - Increasing detection and increasing incidence in thyroid cancer. AB - BACKGROUND: It has been proposed that the increasing incidence of thyroid cancer is due to increasing detection. METHODS: Using administrative data, we compare by year from 1993 to 2006, the rates of diagnostic imaging tests of the neck (computed axial tomography--CT, magnetic resonance imaging--MRI, and non obstetrical ultrasound--US) to the incidence of thyroid cancer for the population of the Province of Ontario Canada. RESULTS: Women and men have different rates of tests, and those rates reflect the rates of new diagnoses of thyroid cancer. CONCLUSIONS: The rising incidence of thyroid disease in women is associated with increasing numbers of diagnostic imaging tests. PMID- 19789912 TI - Complement and neutrophil function changes after liver resection in humans. AB - BACKGROUND: Complement activation contributes to the regulation of liver regeneration after liver resection (LR) in mice. METHODS: We hypothesized that complement activation and changes in C5a-receptors (C5aR, C5L2) on polymorphonuclear cells (PMN) and monocytes are important in clinical LR. Anaphylatoxin and C5b9 plasma levels were measured (bead-array, ELISA) (25 patients) and receptor expression was assessed after LR (19 patients) (FACS). In vitro PMN C5a-dependent chemotactic response (7 patients) as well as L-selectin shedding and Mac-1 expression (3 patients) was determined. RESULTS: C3a increased after LR (31.1 +/- 4 before LR vs. 41.6 +/- 5 ng/ml, 30 min after LR, P < 0.01), as did C5b9 (12.7 +/- 1 before LR vs. 26.9 +/- 3 ng/ml, 60 min after LR, P < 0.001). C4a and C5a decreased after LR, by 25% 24 h after LR and 30% 2 h after LR, respectively (P < 0.01). C5L2 expression decreased at 4 h, rising at 24 h after LR (PMN: 6.3 +/- 1 before LR, 3.1 +/- 1, 4 h, 8.3 +/- 2, 24 h; P < 0.01). The receptor-related changes accompanied a diminished C5a-dependent chemotactic response by PMN (42.1 +/- 17 before LR vs. 2.1 +/- 3 4 h after LR; P < 0.01) and a reduction of activation upon C5a-R stimulation as measured by L-selectin shedding and Mac-1 expression on PMN. Changes in C5L2 expression on monocytes paralleled postoperative impairment of liver function. CONCLUSIONS: These results indicate that complement components are released after clinical LR and subsequently PMN display altered C5a-dependent functional responses. PMID- 19789914 TI - Severe dysphagia secondary to posterior C1-C3 instrumentation in a patient with atlantoaxial traumatic injury: a case report and review of the literature. AB - There are only a few reports of dysphagia cases in patients who underwent surgery for posterior cervical fusion, but none provides an explanation for the occurrence of dysphagia. To the best of our knowledge this is the first case report showing evidence of severe neurogenic dysphagia, possibly secondary to vagal nerve praxia, in a patient who underwent posterior fusion. A 61-year-old man presented with severe neck pain after he sustained a fall. Imaging studies in the emergency department showed a C2 fracture associated with anterior subluxation of C2 on C3. Given the instability of the injury, a C1-C3 posterior cervical fusion was performed. The surgery was uneventful. The patient's postoperative course was complicated by severe dysphagia. Fluoroscopic and endoscopic assessments of the patient's pharynx and larynx showed significantly decreased epiglottic inversion, hypokinesis of his pharyngeal wall, and decreased hyolaryngeal elevation. There was also mild vocal cord paresis bilaterally, with incomplete approximation of the glottis. He demonstrated intra- and post deglutitive aspiration. The patient coughed (both immediate and delayed) in response to the aspiration but was not able to clear aspirated material completely from the airway. The patient had a percutaneous endoscopic gastrostomy (PEG) tube placed to provide him with nutrition. He was then discharged home. On postoperative follow-up visit 1 month later, the patient's swallowing function improved and he could tolerate pureed consistencies and thin liquids with tube feed supplement. The patient could swallow without coughing. Possible causes of dysphagia in this case include traumatized airways from anesthesia, mechanical compromise of the upper gastrointestinal tract, and neurogenic dysphagia. After excluding the other possibilities, we concluded that our patient was suffering from neurogenic dysphagia associated with vagal nerve dysfunction. PMID- 19789913 TI - Neuropeptide substance P attenuates hyperoxia-induced oxidative stress injury in type II alveolar epithelial cells via suppressing the activation of JNK pathway. AB - Hyperoxia-induced oxidative stress plays a key role in many pulmonary diseases. In an earlier study we found the protective effect of the neuropeptide substance P (SP) on type II alveolar epithelial cells (AECIIs) after hyperoxia exposure. Then, we investigated c-Jun N-terminal kinase (C-JNK) signal transduction pathways in AECIIs before and after hyperoxia exposure. Primary AECIIs were isolated and purified from premature rats. Subsequently, the cells were treated with air (21% oxygen), hyperoxia (95% oxygen), SP+ air, and SP+ hyperoxia. SP was added in advance to reach a final concentration 1 x 10(-6) mol/l. The cells were then exposed to air and hyperoxia for 12, 24, and 48 h. XTT cell proliferation assay and fluorescence-activated cell sorting (FACS) were employed to detect cell growth and apoptosis. Phosphorylated JNK (p-JNK) levels were measured using Western blot assay. The morphological alteration of AECIIs was observed using a transmission electron microscope (TEM). Compared with the simple hyperoxia treatment, the cell growth and apoptosis percentage was significantly increased and decreased after adding additional SP. Meanwhile, the reduced levels of p-JNKs could be found after adding SP. Furthermore, the morphological damage of AECIIs was greatly improved. These data suggest that SP can promote AECII proliferation and inhibit apoptosis by suppressing JNK signal pathways after hyperoxia exposure, which attenuates hyperoxia-induced oxidative stress damage in AECIIs. It might be a potential therapy for acute pulmonary injury under hyperoxia induced oxidative stress. PMID- 19789917 TI - Treatment of primary spontaneous pneumothorax by videothoracoscopic talc pleurodesis under local anesthesia: a review of 133 procedures. AB - AIM: To review our experience of treatment of primary spontaneous pneumothorax by videothoracoscopic talc pleurodesis. METHODS: From 2000 to 2008, 124 consecutive patients with primary spontaneous pneumothorax were operated; 105 were men (84.7%) and 19 were women (15.3%) with a mean age of 26.6 years (range 17-46 years). RESULTS: No mortality was recorded. Staging according to Vanderschueren's classification was as follows: stage I, 61 patients (45.9%); stage II, 39 patients (29.3%); stage III, 31 patients (23.3%); stage IV, two patients (1.5%). The overall rate of complications was 9% (12/133), corresponding to prolonged air leak in 9(6.7%) patients and hemothorax in 3(2.2%) patients. Four patients (3%) had recurrence requiring reoperation. There were no episodes of acute respiratory failure, pneumonia or subcutaneous emphysema following talc pleurodesis. CONCLUSIONS: Thoracoscopic pleural talc pleurodesis as a treatment for recurrent pneumothorax is easy, safe, and rapid, and causes minimal morbidity and mortality. PMID- 19789918 TI - Esophageal dilation after gastric banding: to test or not to test before surgery? PMID- 19789919 TI - Re: Surg Endosc (2009) 23:1142-1145, DOI:10.1007/s00464-009-0382-x (published online 5 March 2009). Erica P. Podolsky, Steven J. Rottman, Paul G. Curcillo II. Single Port Access (SPA) gastrostomy tube in patients unable to receive percutaneous endoscopic gastrostomy placement. PMID- 19789920 TI - Long-term outcome of laparoscopic Nissen and laparoscopic Toupet fundoplication for gastroesophageal reflux disease: a prospective, randomized trial. AB - BACKGROUND: A prospective, randomized trial was performed to evaluate the long term outcome and patient satisfaction of laparoscopic complete 360 degrees fundoplication compared with partial posterior 270 degrees fundoplication. Partial fundoplication is purported to have fewer side effects with a higher failure rate in controlling gastroesophageal reflux disease (GERD), while complete fundoplication is thought to result in more dysphagia and gas-related symptoms. METHODS: Patients were randomized to either laparoscopic Nissen (LN) or laparoscopic Toupet (LT) fundoplication. Esophageal manometry, 24-h pH studies, a detailed questionnaire, and a visual analog symptom (VAS) score were completed before and after surgery. A final global outcome questionnaire was performed. Failure was defined as recurrent GERD requiring revision surgery, maintenance proton pump inhibitor (PPI) therapy, or surgery for postoperative dysphagia. RESULTS: One hundred patients were randomized to LN (50) or LT (50). There were no differences between LN and LT with respect to postoperative symptoms and physiological variables except a higher wrap pressure in the LN group (15.2 vs. 12.0 mmHg). Dysmotility improved in 8/14 (57%) and 6/11 (54%) patients in the LN group and the LT group, respectively, after surgery. There was no correlation between dysmotility and dysphagia both pre- and post surgery in the two groups. Recurrent symptoms of GERD occurred in 8/47 (17.0%) and 8/48 (16.6%) in the LN group and the LT group, respectively. Outcome of patients with dysmotility was similar to those with normal motility in both groups. At final follow-up (59.76 + or - 24.23 months), in the LN group, 33/37 (89.1%) would recommend surgery to others, 32/37 (86.4%) would have repeat surgery, and 34/37 (91.8%) felt they were better off than before surgery. The corresponding numbers for the LT group (follow-up = 55.18 + or - 25.97 months) were 35/36 (97.2%), 30/36 (83.3%), and 33/36 (91.6%). CONCLUSION: LN and LT are equally effective in restoring the lower esophageal sphincter function and provide similar long-term control of GERD with no difference in dysphagia. Esophageal dysmotility had no influence on the outcome of either operation. PMID- 19789921 TI - Clinical outcomes for perforations during endoscopic submucosal dissection in patients with gastric lesions. AB - BACKGROUND: The endoscopic submucosal dissection (ESD) technique has been gaining popularity, with continued advances in this treatment approach. However, ESD still is associated with potential complications such as severe bleeding and perforation. METHODS: This study was performed to compare the clinical outcomes for macro- and microperforations with ESD procedures and to determine the short term prognosis after ESD. A macroperforation was defined as a gross perforation that occurred during an ESD procedure, and a microperforation was defined by free air observed on simple radiography after the procedure. Immediate closure of macroperforations was performed using endoclips. From July 2003 through May 2008, 1,711 patients underwent ESD for gastric lesions such as dysplasia, early cancer, and subepithelial lesions. RESULTS: Among 39 perforation cases (2.3%), macroperforations occurred for 26 patients (67%) and microperforations for 13 patients (33%). All the patients except one who underwent emergency surgery because of severe bleeding and perforation during ESD were managed successfully by intravenous antibiotics and no oral intake. The clinical prognosis and endoscopic characteristics of the patients with macroperforations did not differ from those of the patients with microperforations. CONCLUSIONS: Perforations associated with ESD could be managed safely and successfully by nonsurgical methods. The clinical prognoses for macro- and microperforations were favorable and comparable. PMID- 19789922 TI - Do absorption and realistic distraction influence performance of component task surgical procedure? AB - BACKGROUND: Surgeons perform complex tasks while exposed to multiple distracting sources that may increase stress in the operating room (e.g., music, conversation, and unadapted use of sophisticated technologies). This study aimed to examine whether such realistic social and technological distracting conditions may influence surgical performance. METHODS: Twelve medical interns performed a laparoscopic cholecystectomy task with the Xitact LC 3.0 virtual reality simulator under distracting conditions (exposure to music, conversation, and nonoptimal handling of the laparoscope) versus nondistracting conditions (control condition) as part of a 2 x 2 within-subject experimental design. RESULTS: Under distracting conditions, the medical interns showed a significant decline in task performance (overall task score, task errors, and operating time) and significantly increased levels of irritation toward both the assistant handling the laparoscope in a nonoptimal way and the sources of social distraction. Furthermore, individual differences in cognitive style (i.e., cognitive absorption and need for cognition) significantly influenced the levels of irritation experienced by the medical interns. CONCLUSION: The results suggest careful evaluation of the social and technological sources of distraction in the operation room to reduce irritation for the surgeon and provision of proper preclinical laparoscope navigation training to increase security for the patient. PMID- 19789924 TI - Building a open source framework for virtual medical training. AB - This paper presents a framework to build medical training applications by using virtual reality and a tool that helps the class instantiation of this framework. The main purpose is to make easier the building of virtual reality applications in the medical training area, considering systems to simulate biopsy exams and make available deformation, collision detection, and stereoscopy functionalities. The instantiation of the classes allows quick implementation of the tools for such a purpose, thus reducing errors and offering low cost due to the use of open source tools. Using the instantiation tool, the process of building applications is fast and easy. Therefore, computer programmers can obtain an initial application and adapt it to their needs. This tool allows the user to include, delete, and edit parameters in the functionalities chosen as well as storing these parameters for future use. In order to verify the efficiency of the framework, some case studies are presented. PMID- 19789923 TI - Isolation and characterization of a GDSL esterase from the metagenome of a marine sponge-associated bacteria. AB - Using a metagenome library constructed from a bacterial associated with a marine sponge Hyrtios erecta, we identified a novel esterase that belongs to the SGNH hydrolase superfamily of esterases. The substrate specificity of EstHE1 was determined using p-nitrophenyl (pNP) ester (C2: acetate, C4: butylate, C6: caproate, C12: laurate, C16: palmitate). EstHE1 exhibited activity against C2 (5.6 U/mg), C4 (5.1 U/mg), and C6 (2.8 U/mg) substrates. The optimal temperature for EstHE1 esterase activity of the pNP acetate substrate was 40 degrees C, and EstHE1 retained 60% of its enzymatic activity in the 30-50 degrees C range. This esterase showed moderate thermostability, retaining 58% of its activity even after preincubation for 12 h at 40 degrees C. EstHE1 also maintained activity in high concentrations of NaCl, indicating that this esterase is salt-tolerant. Thus, EstHE1 has the thermal stability and salt tolerance necessary for use as an industrial enzyme. PMID- 19789925 TI - Is android or iPhone the platform for innovation in imaging informatics. AB - It is clear that ubiquitous mobile computing platforms will be a disruptive technology in the delivery of healthcare in the near future. While radiologists are fairly sedentary, their customers, the referring physicians, and the patients are not. The need for closer collaboration and interaction with referring physicians is seen as a key to maintaining relationships and integrating tightly with the patient management team. While today, patients have to settle for their images on a CD, in short time, they will be taking them home on their cell phone. As PACS vendors are moving ever outward in the enterprise, they are already actively developing clients on mobile platforms. Two major contenders are the Apple's iPhone and the Android platform developed by Google. These two designs represent two entirely different architectures and business models. PMID- 19789927 TI - Properties of normal phylogenetic networks. AB - A phylogenetic network is a rooted acyclic digraph with vertices corresponding to taxa. Let X denote a set of vertices containing the root, the leaves, and all vertices of outdegree 1. Regard X as the set of vertices on which measurements such as DNA can be made. A vertex is called normal if it has one parent, and hybrid if it has more than one parent. The network is called normal if it has no redundant arcs and also from every vertex there is a directed path to a member of X such that all vertices after the first are normal. This paper studies properties of normal networks.Under a simple model of inheritance that allows homoplasies only at hybrid vertices, there is essentially unique determination of the genomes at all vertices by the genomes at members of X if and only if the network is normal. This model is a limiting case of more standard models of inheritance when the substitution rate is sufficiently low.Various mathematical properties of normal networks are described. These properties include that the number of vertices grows at most quadratically with the number of leaves and that the number of hybrid vertices grows at most linearly with the number of leaves. PMID- 19789926 TI - In vivo fluorescence imaging is well-suited for the monitoring of adenovirus directed transgene expression in living organisms. AB - PURPOSE: We tested a new light detection cooled charge-coupled device (CCD) for in vivo assessment of noninvasive, whole-body fluorescence optical imaging of adenovirus directed enhanced green fluorescent protein (AdEGFP) expression. PROCEDURES: AdEGFP was injected i.v. into BALB/c mice via tail vein. Whole-body fluorescence optical imaging of AdEGFP expression was performed using a Kodak 2000MM Image Station before and after vector administration. RESULTS: EGFP expression was exclusively detected around the abdominal cavity, and the fluorescent signal peaked at day 4 and then remained detectable for at least 30 days. Ex vivo fluorescence imaging confirmed that EGFP expression was restricted to the liver, and transgene expression was homogeneously diffused into all four lobes. CONCLUSIONS: These findings demonstrate that in vivo fluorescence imaging provides functional data indicating the approximate location, magnitude, and duration of AdEGFP expression. PMID- 19789928 TI - Multiple preoperative endoscopic interventions are associated with worse outcomes after laparoscopic Heller myotomy for achalasia. AB - BACKGROUND: The effect of preoperative pneumatic dilation or botulinum toxin injection on outcomes after laparoscopic Heller myotomy (LHM) for achalasia is unclear. We compared outcomes in patients with and without multiple preoperative endoscopic interventions. METHODS: This cohort study categorized achalasia patients undergoing first-time LHM by the number of preoperative endoscopic interventions: zero or one intervention vs. two or more interventions. Outcomes of interest included surgical failure (defined as the need for re-intervention), gastrointestinal symptoms, and health-related quality of life. Logistic regression modeling was performed to determine the independent effect of multiple preoperative endoscopic interventions on the likelihood of surgical failure. RESULTS: One hundred thirty-four patients were included; 88 (66%) had zero to one preoperative intervention, and 46 (34%) had multiple (more than one) interventions. The incidence of surgical failure was 7% in the zero to one intervention group and 28% in the more than one intervention group (p < 0.01). Greater improvements in gastrointestinal symptoms and health-related quality of life were seen in the zero to one intervention group. On logistic regression modeling, the likelihood of surgical failure was significantly higher in the more than one intervention group (odds ratio = 5.1, 95% confidence interval 1.6-15.8, p = 0.005). CONCLUSIONS: Multiple endoscopic treatments are associated with poorer outcomes and should be limited to achalasia patients who fail surgical therapy. PMID- 19789929 TI - Laparoscopic drainage of pancreatic pseudocysts: a methodological approach. AB - BACKGROUND: This paper describes our tailored and methodological approach to laparoscopic drainage of pancreatic pseudocysts (PPs) based on an anatomical classification. METHODS: We adopted the laparoscopic approach in "all comers" who had PPs requiring surgical drainage. The recipient organ for drainage (e.g., cystgastrostomy, cystjejunostomy, or cystduodenostomy) and method of access (e.g., transgastric, endogastric, exogastric or lesser sac, and infracolic) were decided based on preoperative computed tomography (CT) and intraoperative findings. The results shown represent median (range). RESULTS: Between 2001 and 2009, 30 laparoscopic drainage procedures for PPs were performed in 28 consecutive patients. The surgical approach included transgastric (n = 17) or endogastric (n = 3) cystgastrostomy for large retrogastric PPs (n = 20), exogastric cystgastrostomy for small perigastric PPs (n = 4), cystduodenostomy (n = 1) under ultrasound guidance, cystjejunostomy for infracolic PPs (n = 4), and one external drainage. The operative time was 118 (25-300) min. There was one conversion to laparotomy (3.3%), low morbidity (3.3%), and no mortality. The postoperative hospital stay was 2 (1-7) days. At a follow-up of 15 (1-48) months, PPs recurred in two patients (7.1%) and were drained by laparoscopic cystgastrostomy. CONCLUSION: CT findings and laparoscopic exploration demonstrate the anatomical characteristics of PPs and enable successful planning and execution of their laparoscopic drainage. PMID- 19789930 TI - Minimally invasive esophagectomy. AB - INTRODUCTION: Minimally invasive esophagectomy has gained popularity over the past two decades. The procedural goal is to decrease the high overall morbidity of a traditional open esophageal resection. The entire spectrum of open esophagectomy techniques has been successfully replicated in a minimally invasive fashion. DISCUSSION: Esophagectomy remains one of the most technically challenging operations, and developing the skills necessary for minimal invasive esophagectomy is associated with a steep learning curve. Minimally invasive approaches show most promise for benign disease and select early esophageal cancers, but their role in more advanced cancer remains controversial due to lack of long-term results. CONCLUSION: As minimally invasive esophagectomy matures, its true value in both benign and malignant disorders will become better defined. PMID- 19789931 TI - Ailanthus altissima swingle has anti-anaphylactic effect and inhibits inflammatory cytokine expression via suppression of nuclear factor-kappaB activation. AB - Ailanthus altissima swingle (ailanthic cortex, AAS) has been used as a traditional medicine for fever, bleeding, infection, and inflammation for many years in Korea. However, its mechanisms have not been examined. In the present study, we investigate the effect of AAS on the mast-cell-mediated allergic and inflammatory reaction using in vivo and in vitro models and elucidate its molecular mechanisms. AAS significantly inhibited compound 48/48-induced edema and systemic anaphylaxis. AAS significantly inhibited passive cutaneous anaphylaxis. AAS inhibited histamine release from rat peritoneal mast cells (RPMCs) in a dose-dependent manner. Moreover, AAS significantly inhibited production of inflammatory cytokines, tumor necrosis factor (TNF), interleukin (IL)-6, and IL-8 on the phorbol 12-myristate 13-acetate and calcium ionophore A23187 (PMACI)-stimulated human mast cell line, HMC-1 cells. AAS inhibits the IgE or stem cell factor-induced TNF production on RPMCs. In activated HMC-1 cells, the expression level of NF-kappaB/Rel A protein increased in the nucleus, whereas the level of NF-kappaB/Rel A in the nucleus was decreased by AAS treatment. In addition, AAS inhibited the PMACI-induced IkappaBalpha degradation. In conclusion, the present results indicate that AAS has potent anti-anaphylactic and anti-inflammatory properties. PMID- 19789932 TI - Discrepancy between ideal and realistic goal weights in three bariatric procedures: who is likely to be unrealistic? AB - BACKGROUND: Patients choose to undergo bariatric surgery for a variety of medical and psychosocial reasons. However, the majority of bariatric surgery candidates have unrealistic weight loss goals, and certain subgroups within this population may be more likely to endorse such beliefs. This study examines weight loss expectations in patients undergoing three different weight loss procedures (laparoscopic Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, or laparoscopic sleeve gastrectomy). METHODS: Between October 2007 and June 2008, 114 patients (81.6% female) underwent weight loss surgery. At entry into the program, patients identified their postsurgical goal weights. "Realistic" weights were calculated based on patients' presurgical excess weights and expected loss based upon their surgical procedure. RESULTS: Patient [mean preoperative body mass index (BMI) = 48.89] weight loss discrepancies were quite variable with "realistic" versus "dream" weight discrepancies ranging from 0.34 to 71.11 kg (M = 28.79 kg; SD = 13.21 kg). The mean was equivalent to losing 106% (SD = 0.15%) of excess body weight. Baseline BMI, female gender, younger age, and Caucasian ethnicity accounted for up to 62% of the variance in discrepancy scores. After controlling for initial BMI, there were no differences in discrepancies based upon type of surgery. CONCLUSIONS: Across all three surgery types, women, Caucasians, younger patients, and those with higher initial BMIs were more likely to have unrealistic goals. Informed consent procedures should help patients, particularly those most likely to be unrealistic, understand likely outcomes as part of education on risks and benefits of weight loss surgery. PMID- 19789933 TI - The incapacity of the surgeon to identify NASH in bariatric surgery makes biopsy mandatory. AB - BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a morbid condition highly related to obesity. It is unclear if the macroscopic liver appearance correlates with the histopathologic findings. The goal of this prospective study was to determine the relationship between the intraoperative liver appearance and the histopathologic diagnosis of NASH in morbidly obese subjects undergoing bariatric surgery. We also aimed to determine variables that could predict NASH preoperatively. METHODS: Consecutive 51 subjects undergoing bariatric surgery without evidence of other liver disease underwent intraoperative liver biopsy. An intraoperative liver visual (macroscopic and tactile examination) was recorded. The liver aspect was compared with the liver histologic findings. Histological assessment was categorized into two groups: NASH and non-NASH (including normal histology and simple steatosis). Clinical and biochemical parameters were obtained from the patient databases and were compared between groups to identify preoperatively predictive factors of NASH. RESULTS: From 51 patients, only one presented totally normal histology. Forty-three (86.2%) presented simple steatosis, and seven (13.7%) were classified as NASH. Clinical parameters were not different between groups. At biochemical analysis, only VLDL cholesterol level was significantly higher in the NASH group (p=0.037) but yet within the normal range. Association between macroscopic liver appearance and the presence of histological NASH is poor (sensitivity of 14%, specificity of 56%, positive predictive value of 5%, and negative predictive value of 80%). CONCLUSIONS: No predictor of NASH was found. Surgeons' evaluation could not identify NASH individuals. Routine liver biopsy during bariatric operations is mandatory to differentiate NASH and nonalcoholic fatty liver disease. PMID- 19789934 TI - Gap balancing versus measured resection technique for total knee arthroplasty. AB - Multiple differing surgical techniques are currently utilized to perform total knee arthroplasty (TKA). We compared knee arthroplasties performed using either a measured resection or gap balancing technique to determine if either operative technique provides superior coronal plane stability as measured by assessment of the incidence and magnitude of femoral condylar lift-off. We performed 40 TKA using a measured resection technique (20 PCL-retaining and 20 PCL-substituting) and 20 PCL-substituting TKA were implanted using gap balancing. All subjects were analyzed fluoroscopically while performing a deep knee bend. The incidence of coronal instability (femoral condylar lift-off) was then determined using a 3-D model fitting technique. The incidence of lift-off greater than 0.75 mm was 80% (maximum, 2.9 mm) and 70% (maximum, 2.5 mm) for the PCL-retaining and substituting TKA groups performed using measured resection versus 35% (maximum, 0.88 mm) for the gap-balanced group. Lift-off greater than 1 mm occurred in 60% and 45% of the PCL-retaining and -substituting TKA using measured resection versus none in the gap-balanced group. Rotation of the femoral component using a gap balancing technique resulted in better coronal stability which we suggest will improve functional performance and reduce polyethylene wear. PMID- 19789935 TI - Outcomes of isolated acetabular revision. AB - Isolated acetabular revision can be associated with variable patient outcomes; there is a risk of hip instability. We evaluated 42 isolated acetabular revision operations and investigated the impact of patient age, diagnosis, bone stock, bone loss, bone augmentation, and obesity on pain and the Harris hip score. Preoperative radiographs were graded according to Paprosky et al. Postoperative radiographs were graded according to Moore et al. and for implant position, prosthetic fixation, and osteolysis. Complications, patient outcome, reoperations, and acetabular rerevisions were recorded. All patients had complete clinical and radiographic followup with a minimum followup of 2 years (mean, 6.4 years; range, 2-13 years). The mean pain score and the mean Harris hip score improved postoperatively. There was one infection 6 months after operation. There were no dislocations. There were three acetabular rerevisions (7%) for aseptic loosening. Patient age, preoperative diagnosis, bone loss, and pelvic bone augmentation had no influence on pain or Harris hip scores. Before operation, obese patients tended to have less pain than nonobese patients but at followup obese patients had less improvement in pain scores than nonobese patients. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence. PMID- 19789936 TI - Antinucleosome antibodies in juvenile chronic arthritis. AB - A broad range of autoantibodies have been detected in juvenile chronic arthritis (JCA) patients, although, none of them can be considered specific for this entity. Antinuclear antibody (ANA) is routinely searched in these patients mainly because it is associated with uveitis, a comorbidity that is particularly frequent in the oligoarticular form. Nevertheless, the ANA specific antigen target in JCA is unknown. In this study, we aimed to search for antinucleosome antibodies in 30 adult JCA patients and to study possible associations with clinical profile. Ten individuals (33.3%) were positive for antinucleosome antibodies and seven (70%) were simultaneously ANA positive (p = 0.01). We did not find any significant association among antinucleosome and JCA form, uveitis, age of onset, gender, or functional index. We conclude that in JCA, there is a prevalence of 33.3% of antinucleosome antibodies. Further investigations are needed to understand the ANA positivity found in this disease as far as the clinical impact of this finding. PMID- 19789937 TI - Gingival curettage study comparing a laser treatment to hand instruments. AB - The purpose of this clinical study was to examine nonsurgical treatments of periodontal disease comparing a diode laser to subgingival curettage with conventional hand instruments. The study group comprised 18 patients with moderate periodontal degradation who were treated without local anesthesia. Each quadrant was randomly allocated in a split-mouth design either to treatment with a 810-nm diode laser using an energy of 2 W (test group) or to gingival curettage using hand instruments (control group). Clinical data, including plaque index (PI), gingival index (GI), sulcus bleeding index (SBI), pocket depth (PD), clinical attachment level (CAL) and visual analog scale (VAS) score were acquired prior to and 4 weeks after treatment. The treatment time for each tooth was also recorded. The results demonstrated a statistically significant reduction of the GI, SBI and PD and a significant gain in CAL in both groups after 4 weeks. However, there were no significant differences between the test and control groups for the above data. The score for the degree of treatment discomfort was significantly lower and the average treatment time was significantly less in the test group than in the control group. Diode laser subgingival curettage resulted in statistically significant improvements in PD, SBI, GI and CAL with less discomfort and treatment time compared to treatment with the hand instruments. PMID- 19789938 TI - Acromegaly associated with gangliocytoma. AB - BACKGROUND: Acromegaly secondary to growth hormone-releasing hormone (GHRH) excess is rare. AIMS/CASE DESCRIPTION: We report two patients with acromegaly who were diagnosed with sellar gangliocytomas that were immunopositive for GHRH. Tumour tissue persisted after debulking surgery and in the second case this was associated with persistent growth hormone hypersecretion, successfully suppressed by a somatostatin analogue. CONCLUSIONS: The development of functional pituitary adenomas in association with sellar gangliocytomas is poorly understood. We present a brief discussion of the possible aetiology of these unusual pituitary tumours. PMID- 19789939 TI - Brain volume analyses and somatosensory evoked potentials in multiple system atrophy. AB - We investigated a progression of brain atrophy and somatosensory system dysfunction in multiple system atrophy (MSA). Subjects were 21 MSA patients [12 MSA-C (cerebellar type) and 9 MSA-P (parkinsonism type)]. The relative volumes of cerebrum, brainstem and cerebellum to the intracranial volume were obtained from three-dimensional computed tomography (3D-CT) of the brain. The median nerve somatosensory evoked potentials (SEPs) were recorded, and the latencies and amplitudes of N9, N11, P13/14, N20 and P25 components were measured. We studied correlations between brain volumes, SEP and clinical features. The brainstem and cerebellar atrophies were aggravated with progression of the disease. The central sensory conduction time (CSCT) was progressively prolonged in parallel with the disease duration irrespective of the actual age of the patients. In MSA patients, the volume reductions of cerebellum and brainstem could be one of structural markers of disease progression, and the sensory pathway is progressively involved with the progression of disease processes. PMID- 19789941 TI - Abstracts of the 20th International Symposium on the Autonomic Nervous System, St. Thomas, U.S. Virgin Islands, November 11-14, 2009. PMID- 19789940 TI - REM sleep behaviour disorder and visuoperceptive dysfunction: a disorder of the ventral visual stream? AB - In idiopathic rapid eye movement sleep behaviour disorder (RBD), an association with visuoperceptive disorders has been described. However, such an association has not been clearly established in RBD secondary to Parkinson's disease (PD). We compared visuoperceptive function in four groups of non-demented patients (parkinsonian patients with or without RBD, patients with idiopathic RBD and control participants) via a procedure enabling the analysis of the various components of visual information processing and in order to answer the following question: is RBD associated with visuoperceptive and/or attentional disorders in PD and, if so, where is the dysfunction located along the visual pathway? Sensorial aspects of visual information were evaluated using a contrast sensitivity test, perceptual aspects were assessed using a contour-based object identification test and visual attention was measured in an attentional capture paradigm. The diagnosis of RBD was confirmed by polysomnography. We observed a higher object identification threshold (OIT) (1) in PD patients with RBD compared with PD patients without RBD and with controls and (2) in idiopathic RBD patients compared with controls. There were no significant OIT differences between PD patients with RBD and idiopathic RBD patients or between PD patients without RBD and controls. We did not find any significant inter-group differences in any of the other visuoperceptive tests. RBD, idiopathic or secondary to PD, is associated with perceptual closure dysfunction. Our results suggest that this perceptual dysfunction is specifically associated with RBD and may be related to a non-dopaminergic impairment. PMID- 19789943 TI - Effects of selective Cox-2 inhibitor, rofecoxib, alone or combination with furosemide on renal functions and renal Cox-2 expression in rats. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs act by inhibiting the rate limiting enzymes cyclooxygenase-1 (Cox-1) and cyclooxygenase-2 (Cox-2), which are important in prostanoid formation. The aim of this experimental study was to examine the effects of selective Cox-2 inhibitor, rofecoxib, with or without furosemide, on urine and serum electrolytes, creatinine clearance, plasma renin activity (PRA), and Cox-2 expression in the renal cortex. METHODS: Forty male Wistar albino rats were randomized into four groups, group 1, group 2, group 3, and group 4, and were treated with placebo, furosemide (20 mg/kg), rofecoxib (10 mg/kg) plus furosemide (12 mg/kg), and rofecoxib (10 mg/kg), respectively, and followed for 7 days. Body weights were measured daily. Urine osmolality and volume, and serum and urinary creatinine, sodium (Na(+)), and potassium (K(+)) were measured. Renal cortical Cox-2 protein expression was examined by immunohistochemical method. RESULTS: Compared with groups 1 and 3, body weights were significantly reduced in groups 2 and 4 (16.2 and 19.8 g, respectively; P < 0.05 for all). Urine volume in group 2 increased significantly compared with groups 1, 3, and 4 (P < 0.001, P < 0.008, and P < 0.004, respectively). Urine osmolality in group 2 decreased significantly compared with groups 1 and 3 (P < 0.05 for all). Blood urea nitrogen, serum creatinine and sodium, creatinine clearance, and 24-h urine Na(+) and K(+) levels were similar in all groups. Serum K(+) level was lowest in group 2, and there was a statistically significant difference between groups 2 and 4 (P < 0.05). Plasma renin activity was similar in all groups (P > 0.05). Renal cortical Cox-2 protein expression was lowest in group 1 and was significantly different from the other groups (P < 0.01 for all). The relationship between Cox-2 expression and plasma renin activity was not significant in any group (P > 0.05, r(2):0.05). CONCLUSIONS: Rofecoxib neutralized the diuretic effect of furosemide in rats treated with a combination of furosemide and rofecoxib. Renal cortical Cox-2 protein expressions due to furosemide and rofecoxib with or without furosemide were similar and significantly increased compared with controls. Renal failure due to rofecoxib did not developed in any rat, but selective Cox-2 inhibitor, rofecoxib, might have similar renal effects as nonselective nonsteroidal drugs for blunting the diuretic effect of furosemide. PMID- 19789944 TI - Ability of 201Tl and 123I-BMIPP mismatch to diagnose myocardial ischemia in patients with suspected coronary artery disease. AB - OBJECTIVE: A mismatch defect between (201)TL and (123)I-BMIPP dual isotope SPECT (d-SPECT) is useful to detect myocardial ischemia in patients with acute coronary syndrome. However, whether mismatched d-SPECT findings reflect actual myocardial ischemia in stable patients with suspected, but unknown ischemic heart disease is unclear. The present study assesses the significance of a d-SPECT mismatch among such patients. METHODS: Forty-nine patients with suspected stable coronary heart disease who had been referred for chest pain, ECG abnormalities or multiple risk factors (66 +/- 11 years old, 34 males) with a d-SPECT mismatch participated in this study. All of them underwent coronary angiography (CAG) to assess coronary artery disease. The entire myocardial area on d-SPECT images was divided into 17 segments, each of which was scored from 0 (normal) to 4 (defect). The d-SPECT mismatch score (MS) was defined as the summed BMIPP defect score (BM-TDS) minus the summed defect score (TL-TDS). The inclusion criterion was MS >or= 1, and the mismatch was defined as true positive if the mismatched area was concordant with the territories supplied by significant coronary stenotic arteries by CAG. RESULTS: Ischemic heart disease was judged by coronary angiography in 31 (63%) patients (IHD group), of which 24 (49.0%) were true positives. Of the remaining 18 (37%) patients without no significant coronary stenosis (non-IHD group), 12 (24%) had some types of organic heart disease. If MS >or= 4 was defined as the threshold for an ischemic positive mismatch, then the sensitivity and specificity were 80% and 63%, respectively. However, mismatch scores did not significantly differ between the groups with true positive-IHD and organic heart disease in non IHD group (6.6 +/- 4.4 vs. 6.4 +/- 3.7). CONCLUSION: A d-SPECT mismatch score of >or=4 was an appropriate cutoff at which diagnosis of myocardial ischemia in patients who were screened for ischemic heart disease. However, since patients with non-ischemic but organic heart disease can also present with abnormal mismatch findings, coronary angiography or CT might be warranted to differentiate IHD from non-IHD. PMID- 19789945 TI - Apocrine metaplasia of breast cancer: clinicopathological features and predicting response. AB - BACKGROUND: Tailor-made therapies are currently gaining prominence, and the clarification of predictive markers for anticancer agents represents an important research issue. From our institutional neoadjuvant experience, apocrine carcinoma showed a high correlation with therapeutic effect against breast cancer. We thus considered that apocrine metaplasia (AM) might represent a predictive marker for breast cancer. METHODS: A total of 210 primary invasive breast cancers from Japanese patients were scored according to the size of cytoplasmic granules and abundance of cytoplasm, then classified into three categories: non-AM, incomplete AM and complete AM. Clinicopathological features were evaluated based on these classifications. RESULTS: Distribution according to the classification of AM was: non-AM, 61%; incomplete AM, 36%; and complete AM, 3%. No significant differences with regard to estrogen receptor, progesterone receptor, human epidermal growth factor receptor type 2, androgen receptor or bcl-2 were observed among the three groups. Gross cystic fluid protein-15 showed a high positive rate (83%) for complete AM. Cases of incomplete AM and complete AM were combined to form the AM group. Among lymph node-positive patients without chemotherapy, the 10-year recurrence-free survival (RFS) rate was 85% for non-AM and 44% for AM (p < 0.05). Conversely, among the lymph node-positive group with chemotherapy, the 10-year RFS rate was 45% for non-AM and 75% for AM (p < 0.05). Prognoses for non-AM and AM were turned around by chemotherapy. Lymph node metastasis was related to prognosis in multivariate analysis, although AM did not remain an independent prognosticator. CONCLUSIONS: Apocrine metaplasia appears to offer an effective predictive marker for anticancer therapy. PMID- 19789946 TI - A study of high-nuclear-grade breast cancer in Thailand: subclassification and correlation with prognostic factors and immunohistochemical study. AB - OBJECTIVES: To classify high-nuclear-grade breast cancer (BC) into typical medullary carcinoma (TMC), atypical medullary carcinoma (AMC), and non-medullary carcinoma (NMC), and luminal A, luminal B, and HER2, and to correlate these tumors with other prognostic factors. MATERIALS AND METHODS: A retrospective study reviewing high-nuclear-grade BCs. The patients' age, histologic types, various histologic features, axillary lymph node (ALN) status, and results of immunohistochemical (IHC) study were recorded and analyzed. RESULTS: One-hundred and eighty-one cases of high-nuclear-grade BCs were reviewed and categorized into IDC, NOS (140, 77.3%), TMC (1, 0.6%), AMC (21, 11.6%), and others (19, 10.5%). The median age was younger in AMC than in NMC patients. NMC patients had a higher incidence of LVI and ALN metastasis with involvement of more than four lymph nodes (p = 0.006) whereas AMC patients had a higher mitotic index. Forty-six (35.9%) cases were triple-negative (TN), including 1 (100%), 7 (53.9%) and 38 (33.3%) cases of TMC, AMC, and NMC, respectively. AMC had a significantly lower number of node metastases (p = 0.006) than NMC; whereas TN had higher MI (p = 0.001) than non-TN. The non-TN group was subclassified into luminal A, luminal B, and HER2. Of these, TN and luminal B occurred at younger age (p = 0.01) whereas TN and luminal A had a higher mitotic count. TN had lower incidence of LNM including higher number of LNM. CONCLUSION: Overall, AMC-TN group showed a basal like prognostic factor expression. NMC may be separated into TN and non-TN, with possibly different behavior. These sub-groupings should continue to be used. Interestingly, luminal A in our study tended to correlate with poor prognostic factors, thus, luminal A with high nuclear grade may not be representative of the usual luminal group profiles. PMID- 19789947 TI - Axillary reverse mapping for preventing lymphedema in axillary lymph node dissection and/or sentinel lymph node biopsy. PMID- 19789948 TI - An uncommon case of T1b breast cancer with diabetic mastopathy in type II diabetes mellitus. AB - A 64-year-old postmenopausal female had been treated with insulin therapy for type 2 diabetes mellitus for 18 years, but her diabetes mellitus was not well controlled and she developed retinopathy. Her screening mammography showed abnormal findings, and thus she consulted a hospital. A physical examination showed her mammary glands to be hard on both sides and no palpable mass was observed. Mammography revealed an amorphous calcification in the middle outer portion of the left breast. Ultrasonography showed an irregular hypoechoic mass measuring about 11 mm in size in the upper outer portion of the left breast. Although a core-needle biopsy specimen of the hypoechoic mass showed hyalinizing fibrosis without any evidence of malignancy, a stereotactic guided vacuum assisted biopsy was performed because magnetic resonance imaging revealed an enhanced area in the region of the amorphous calcification that could not be distinguished from breast cancer. The histological findings indicated noninvasive ductal carcinoma, and therefore a quardrantectomy with a sentinel lymph node biopsy was performed. The pathological diagnosis was invasive ductal carcinoma (0.7 * 0.3 cm) with a predominant intraductal component accompanying diabetic mastopathy. The sentinel lymph nodes demonstrated no metastasis. The surgical margin was positive for carcinoma and the patient later underwent a mastectomy. No malignant cells were observed in the specimen. The patient has so far experienced no recurrence after surgery. PMID- 19789949 TI - Impact of prophylactic pyridoxine on occurrence of hand-foot syndrome in patients receiving capecitabine for advanced or metastatic breast cancer. AB - BACKGROUND: Capecitabine, an oral fluoropyrimidine, has shown consistently high efficacy in anthracycline- and/or taxane-pretreated advanced and metastatic breast cancer. The safety profile of capecitabine is characterized by hand-foot syndrome (HFS), which, although not life threatening, can impair patients' quality of life if it is not managed promptly and effectively. We conducted a study to assess the impact of prophylactic pyridoxine on HFS. METHODS: Prophylactic pyridoxine was given to 38 patients receiving capecitabine (alone or in combination with cyclophosphamide) for metastatic breast cancer and compared with historical data from 40 patients receiving capecitabine without pyridoxine in our clinic. The impact of urea ointment on HFS was also assessed. RESULTS: HFS developed in 20 patients (52.6%) receiving pyridoxine compared with historical data showing an 82.5% rate in patients receiving no pyridoxine prophylaxis (p < 0.01). A nonsignificant trend towards less severe HFS was seen among patients who received urea ointment at first appearance of symptoms. In addition, nonsignificant trends towards higher rates of HFS were seen among those who were >=61 years and those who derived clinical benefit (clinical response or stable disease). CONCLUSIONS: Prophylactic pyridoxine and urea ointment at first appearance of symptoms appears to reduce the risk of severe capecitabine-induced HFS. However, randomized data are required to determine the true effect of these measures. PMID- 19789950 TI - Pitfalls in sentinel lymph node biopsy. PMID- 19789951 TI - Predicting responses to chemotherapy in breast cancer: from bench to bedside. AB - Recent progress in biotechnology, notably microarray analyses, makes it possible to examine the genome-based characteristics of tumors with different prognoses and predict responses to chemotherapy. Furthermore, pharmacogenomic techniques are expected to predict the optimal regimen for individual patients that will provide high benefits with reduced toxicity. Some predictive or prognostic tests for breast cancer are now moving from bench to bedside. PMID- 19789952 TI - A multicentre cross-sectional study of arm lymphedema four or more years after breast cancer treatment in Iranian patients. AB - BACKGROUND: We performed a cross-sectional multicentre study to assess the prevalence of lymphedema after breast cancer treatment in Iran. PATIENTS AND METHODS: All female breast cancer patients who attended our follow-up clinics four or more years after their surgery with no sign of disease were asked to participate in this study. Lymphedema was defined as an increase of 10% in the circumference of the arm on the involved side compared to the opposite arm. RESULTS: The total number of patients participating in this study was 355. The prevalence of lymphedema in the study patients was 17.5%, with the rate varying significantly (between 4 and 21%) among the three study centres (p = 0.007). The mean number of months post surgery was larger for patients with lymphedema (84 months) than for those without (79 months), though this was not statistically significant (p > 0.1). The relationships of various treatment factors and the education levels of the patients to the presence of lymphedema were also evaluated. None of the observed differences were statistically significant aside from those for the type of surgery (mastectomy vs. conservative surgery, p = 0.055), treatment with radiotherapy (p = 0.099), and prescription of a supraclavicular radiation field (p = 0.057), which were only just significant. CONCLUSION: The rate of lymphedema in our patients was 17.5%, ranging from 4 to 21% in different study centres. Time post surgery, treatment with radiotherapy and the technique used, and nodal radiation seem to be factors that are related to this large variation. PMID- 19789953 TI - A systematic review of the effects of postnatal maternal anxiety on children. AB - Several decades of research have focused on the impact of exposure to postnatal depression on children, while anxiety has been largely overlooked. Estimates of the prevalence of postnatal maternal anxiety (PMA) range from 3% to 43%, suggesting PMA may be an important risk factor for adverse outcomes in children. This review summarizes what is known about the effects of PMA exposure on children and makes recommendations for future research. A systematic search of Ovid MEDLINE and PsychINFO through 2008 identified 18 studies that evaluated child outcomes associated with PMA exposure. Identified studies covered three domains: somatic, developmental, and psychological outcomes. The strongest evidence for an adverse effect of PMA exposure is in somatic and psychological outcomes; the evidence for an effect of PMA on child development is inconclusive. Methodological differences among the studies make comparisons difficult and there are a number of common limitations that challenge the validity of these studies. PMID- 19789954 TI - The value of multidetector-row CT in the preoperative detection of pancreatic insulinomas. AB - PURPOSE: The authors sought to quantitatively analyse enhancement characteristics of pancreatic insulinomas in different phases and determine the value of multidetector-row computed tomography (CT) for detecting insulinomas. MATERIALS AND METHODS: Forty-six patients with surgically proven insulinomas diagnosed between 2002 and 2007 were retrospectively reviewed. These patients underwent single-phase (group 1) or dual-phase (group 2) helical CT scanning. RESULTS: Sensitivity for detecting insulinomas in group 2 was superior to that in group 1 (p<0.05).The sensitivity for insulinoma detection in the arterial phase was superior to that in the portal-venous phase (p<0.05). The mean attenuation values of the insulinomas and normal pancreas during the unenhanced arterial and portal venous phases were, respectively, 40.5+/-8.75 HU (Hounsfield units), 114.48+/ 27.30 HU, 112.19+/-19.52 HU and 44.56+/-6.48 HU, 81.16+/-15.22 HU, 90.54+/-13.80 HU, and there was statistical difference between them (p=0.000). The contrast enhancement of insulinomas in the arterial and portal-venous phases was 74.03+/ 29.51 HU and 70.90+/-21.93 HU, respectively, and there was no statistical difference between them (p=0.499). The tumour to normal-pancreas attenuation differences in the arterial and portal-venous phases were respectively 33.32+/ 20.96 HU and 20.58+/-16.32 HU, respectively, and there was statistical difference between them (p=0.011). CONCLUSIONS: Dual-phase CT has a promising sensitivity in detecting pancreatic insulinomas. The acquisition of images in the arterial phase is more helpful for detecting insulinomas. PMID- 19789955 TI - Cardiac computed tomography in the evaluation of left anterior descending coronary artery with vein patch reconstruction. AB - PURPOSE: This study evaluated the morphological and functional results of surgical reconstruction of the left anterior descending (LAD) coronary artery with an autologous vein patch, associated with left internal mammary artery (LIMA) grafting onto the patch. MATERIALS AND METHODS: Cardiac computed tomography (CT) images were assessed in terms of functional and morphological parameters. Function was evaluated by assessing patency at 36 months of the reconstructed LAD (based on the attenuation of the native vessel distal to the anastomosis). Morphology was evaluated by studying vein-patch diameters, profiles and margins, shape and structure to categorise the patches into three groups (A, B, C). Within 1 month of CT, all patients underwent functional testing (bicycle ergometry). RESULTS: CT imaging correctly depicted the LAD graft, revealing it to be fully patent in all cases. On the basis of our morphological classification, 21 patients were classed as group A, two as group B and two as group C. At bicycle ergometry, 23 patients were negative and two were positive. Group C patients had the worst functional results. CONCLUSIONS: Cardiac CT allowed adequate evaluation of the LAD graft patency and morphology, and in consideration of its noninvasive nature, it may become the imaging tool of choice for evaluating extended LAD reconstruction. PMID- 19789956 TI - Radiation dose saving through the use of cone-beam CT in hearing-impaired patients. AB - PURPOSE: Bionic ear implants provide a solution for deafness. Patients treated with these hearing devices are often children who require close follow-up with frequent functional and radiological examinations; in particular, multislice computed tomography (MSCT). Dental volumetric cone-beam CT (CBCT) has been reported as a reliable technique for acquiring images of the temporal bone while delivering low radiation doses and containing costs. The aim of this study was to assess, in terms of radiation dose and image quality, the possibility of using CBCT as an alternative to MSCT in patients with bionic ear implants. MATERIALS AND METHODS: One hundred patients (mean age 26 years, range 7-43) with Vibrant SoundBridge implants on the round window underwent follow-up: 85 with CBCT and 15 with MSCT. We measured the average tissue-absorbed doses during both MSCT and CBCT scans. Each scan was focused on the temporal bone with the smallest field of view and a low-dose protocol. In order to estimate image quality, we obtained data about slice thickness, high- and low-contrast resolution, uniformity and noise by using an AAPM CT performance phantom. RESULTS: Although the CBCT images were qualitatively inferior to those of MSCT, they were sufficiently diagnostic to allow evaluation of the position of the implants. The effective dose of MSCT was almost three times higher than that of CBCT. CONCLUSIONS: Owing to low radiation dose and sufficient image quality, CBCT could be considered an adequate technique for postoperative imaging and follow-up of patients with bionic ear implants. PMID- 19789957 TI - Satisfaction at work among radiologists. AB - PURPOSE: This study sought to evaluate professional satisfaction among Italian radiologists and identify what personal characteristics of radiologists and features of their work and work setting affect job satisfaction. MATERIALS AND METHODS: Satisfaction was assessed by using Warr et al.'s 17-item Job Satisfaction Scale (JSS) in 206 radiologists, 108 radiotherapists and 34 specialists in infectious diseases used as controls. RESULTS: Forty-nine per cent of diagnostic radiologists reported being satisfied with their jobs. The frequency is significantly lower than that found among radiotherapists (64%) and controls (62%). Middle-aged radiologists on lower rungs of the career ladder were more dissatisfied than were their older colleagues in top positions. Female radiologists were less satisfied than their male counterparts with regard to recognition for good work, amount of job variety and distribution of workloads. Stepwise logistic regression analysis showed that job satisfaction was especially affected by physical working conditions, freedom to choose one's own work method, relationship with one's immediate boss, attention paid to one's suggestions and the amount of job variety. CONCLUSIONS: This pilot study identified the sources of professional satisfaction and dissatisfaction among radiologists. A future survey of a stratified random sample of Italian radiologists appears to be feasible. PMID- 19789958 TI - Imaging of superficial and deep fibromatosis. AB - The purpose of this paper was to illustrate the role of diagnostic imaging in superficial and deep fibromatosis through a review of the use of different imaging modalities, including radiography, ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI), angiography and scintigraphy. In particular, in agreement with published data, it emphasises the crucial role of MRI as the primary modality providing the information needed for management decisions, preoperative planning and follow-up of these lesions. PMID- 19789959 TI - Autoimmune pancreatitis: imaging findings on contrast-enhanced MR, MRCP and dynamic secretin-enhanced MRCP. AB - PURPOSE: This study retrospectively determined magnetic resonance (MR), MR cholangiopancreatography (MRCP) and secretin-MRCP findings in patients with autoimmune pancreatitis (AIP). MATERIALS AND METHODS: The MR examinations of 28 patients with histopathologically proven AIP were reviewed. In 14 cases, secretin enhanced MRCP was performed. The observers evaluated pancreatic parenchymal enlargement, signal intensity abnormalities, enhancement, vascular involvement, bile-duct diameter and main pancreatic duct (MPD) narrowing (diffuse/focal/segmental). After secretin administration, the presence of the "duct-penetrating" sign was evaluated. RESULTS: MR imaging showed diffuse pancreatic enlargement in 8/28(29%) cases, focal pancreatic enlargement in 16/28 (57%) cases and no enlargement in 4/28 (14%) cases. The alteration of pancreatic signal intensity was diffuse in 8/28 (29%) cases (eight diffuse AIP) and focal in 20/28 (71%) cases (20 focal AIP). Delayed pancreatic enhancement was present in all AIP, with peripheral rim of enhancement in 8/28 (29%) AIP (1/8 diffuse, 7/20 focal); vascular encasement was present in 7/28 (25%) AIP (1/8 diffuse, 6/20 focal); distal common bile duct narrowing was present in 12/28(43%) AIP (5/8 diffuse, 7/20 focal). MRCP showed MPD narrowing in 17/28 (61%) AIP (4/8 diffuse, 15/20 focal), MPD dilation in 8/28(29%) AIP (3/8 diffuse, 5/20 focal) and normal MPD in 1/8 diffuse AIP. Secretin-MRCP showed the duct-penetrating sign in 6/14(43%) AIP (one diffuse AIP with MPD segmental narrowing, five focal AIP with MPD focal narrowing), demonstrating integrity of the MPD. CONCLUSIONS: Delayed enhancement and MPD stenosis are suggestive for AIP on MR and MRCP imaging. Secretin-enhanced MRCP is a problem-solving tool in the differential diagnosis between focal AIP and ductal adenocarcinoma. PMID- 19789960 TI - Advantages of a two-step procedure for school-based scoliosis screening. AB - PURPOSE: To verify if a "two step" school-based scoliosis screening procedure could reduce childhood radiation exposure and, if so, to estimate the subsequent reduction in radiogenic cancer fatalities and in socio-economic burden. MATERIAL AND METHODS: Data from two different scoliosis screening programs (A and B) performed on a total of 8,995 children (age range 9-14) were examined. Children in program A (5,731 children) were screened using a "two-step" procedure in which school physicians performed the first clinical examination and uncertain cases were referred to an orthopaedist. The school physicians were previously instructed by orthopaedists in the recognition of a number of simple clinical signs. Children in program B (3,264 children) were screened using a "one-step" procedure in which the initial clinical examination was performed directly by an orthopedist. In both programs, suspected cases of scoliosis were then ascertained by the orthopaedist with Radiography. To evaluate the lifetime attributable risk of cancer mortality the guidelines of the International Commission on Radiological Protection Publication 60 were followed. The economic cost of the performed X-ray examination was calculated assuming the current National Health Service's reimbursement to hospitals of euro 35 per X-Ray exam. The statistic significance of the difference in these estimates between the two programs was assessed using the proportions z-test. The issues of the relative sensitivity and specificity of the two programs were also examined. RESULTS: In programs A and B, 86 (1.5 %) and 95 (2.91 %) X-ray examinations were performed respectively (z=4.452, p<0.001). Based on these observations, a screening of 10,000 children directly performed by orthopaedists would result in 291 X-ray exams (2.91 %). A screening of the same number of children using a two-step procedure would result in 150 X-ray exams (1.5 %), with a savings of euro 4,935 for the National Health Care System, a reduction of 0.283 Sv of collective dose, and an estimated 50% reduction in the number of radiogenic malignant tumours. CONCLUSIONS: Using a two step scoliosis screening procedure provides reasonable sensitivity and specificity while reducing costs and radiation exposure to children. PMID- 19789961 TI - Insights into the pathogenesis and management of thrombosis in polycythemia vera and essential thrombocythemia. AB - The classic myeloproliferative neoplasms (MPNs) include polycythemia vera and essential thrombocythemia; their molecular basis has been described only recently with the demonstration of recurrent mutations in JAK2 or MPL. While life expectancy may not be significantly shortened, arterial and venous thrombosis constitute the major causes of morbidity and mortality, together with disease evolution to myelofibrosis or transformation to acute leukemia. Therapy is currently aimed at reducing the rate of thrombosis without increasing the risk of hematologic transformation by inappropriate exposure to cytotoxic drugs. Nevertheless, the mechanism(s) finally responsible for the increased thrombotic tendency have not been clearly elucidated, although risk factors for thrombosis have been identified, and are currently employed for stratifying patients to the most appropriate therapeutic options. Abnormalities of blood cells, activation of neutrophils and platelets, and a hypercoagulability state, can all act in conjunction to lead to thrombosis. Intriguing data also point to the JAK2V617F mutation as both a marker and a mechanism for thrombosis. Better knowledge in the pathophysiology of these disorders, and the introduction of molecularly targeted drugs in clinical trials, anticipate the possibility of more specific and efficacious treatment of classic MPN, particularly as concerns the reduction of risk associated with vascular events. PMID- 19789963 TI - Conditional modeling of antibody titers using a zero-inflated poisson random effects model: application to Fabrazyme. AB - Patients that are exposed to biotechnology-derived therapeutics often develop antibodies to the therapeutic, the magnitude of which is assessed by measuring antibody titers. A statistical approach for analyzing antibody titer data conditional on seroconversion is presented. The proposed method is to first transform the antibody titer data based on a geometric series using a common ratio of 2 and a scale factor of 50 and then analyze the exponent using a zero inflated or hurdle model assuming a Poisson or negative binomial distribution with random effects to account for patient heterogeneity. Patient specific covariates can be used to model the probability of developing an antibody response, i.e., seroconversion, as well as the magnitude of the antibody titer itself. The method was illustrated using antibody titer data from 87 male seroconverted Fabry patients receiving Fabrazyme. Titers from five clinical trials were collected over 276 weeks of therapy with anti-Fabrazyme IgG titers ranging from 100 to 409,600 after exclusion of seronegative patients. The best model to explain seroconversion was a zero-inflated Poisson (ZIP) model where cumulative dose (under a constant dose regimen of dosing every 2 weeks) influenced the probability of seroconversion. There was an 80% chance of seroconversion when the cumulative dose reached 210 mg (90% confidence interval: 194-226 mg). No difference in antibody titers was noted between Japanese or Western patients. Once seroconverted, antibody titers did not remain constant but decreased in an exponential manner from an initial magnitude to a new lower steady-state value. The expected titer after the new steady-state titer had been achieved was 870 (90% CI: 630-1109). The half-life to the new steady-state value after seroconversion was 44 weeks (90% CI: 17-70 weeks). Time to seroconversion did not appear to be correlated with titer at the time of seroconversion. The method can be adequately used to model antibody titer data. PMID- 19789962 TI - "Soft" calcium crosslinks enable highly efficient gene transfection using TAT peptide. AB - PURPOSE: Typically, low molecular weight cationic peptides or polymers exhibit poor transfection efficiency due to an inability to condense plasmid DNA into small nanoparticles. Here, efficient gene delivery was attained using TAT/pDNA complexes containing calcium crosslinks. METHODS: Electrostatic complexes of pDNA with TAT or PEI were studied with increasing calcium concentration. Gel electrophoresis was used to determine DNA condensation. The morphology of the complexes was probed by transmission electron microscopy. Transfection efficiency was assessed using a luciferase reporter plasmid. The accessibility of phosphate and amine groups within complexes was evaluated to determine the effect of calcium on structure. RESULTS: TAT/pDNA complexes were condensed into small, 50 100 nm particles by optimizing the concentration of calcium. Complexes optimized for small size also exhibited higher transfection efficiency than PEI polyplexes in A549 cells. TAT and TAT complexes displayed negligible cytotoxicity up to 5 mg/mL, while PEI exhibited high cytotoxicity, as expected. Probing the TAT Ca/pDNA structure suggested that calcium interacted with both phosphate and amine groups to compact the complexes; however, these "soft" crosslinks could be competitively disrupted to facilitate DNA release. CONCLUSION: Small and stable TAT-Ca/pDNA complexes were obtained via "soft" calcium crosslinks leading to sustained gene expression levels higher than observed for control PEI gene vectors. TAT-Ca/pDNA complexes were stable, maintaining particle size and transfection efficiency even in the presence of 10% of FBS. TAT-Ca complexes offer an effective vehicle offering potential for translatable gene delivery. PMID- 19789964 TI - Fluorescent method for the determination of sulfide anion with ZnS:Mn quantum dots. AB - Water-soluble Mn(2+)-doped ZnS quantum dots (QDs) were prepared using mercaptoacetic acid as the stabilizer. The optical properties and structure features were characterized by X-Ray, absorption spectrum, IR spectrum and fluorescence spectrum. In pH 7.8 Tris-HCl buffer, the QDs emitted strong fluorescence peaked at 590 nm with excitation wavelength at 300 nm. The presence of sulfide anion resulted in the quenching of fluorescence and the intensity decrease was proportional to the S(2-) concentration. The linear range was from 2.5 x 10(-6) to 3.8 x 10(-5) mol L(-1) with detection limit as 1.5 x 10(-7) mol L(-1). Most anions such as F(-), Cl(-), Br(-), I(-), CH(3)CO(2) (-), ClO(4) (-), CO(3) (2-), NO(2) (-), NO(3) (-), S(2)O(3) (2-), SO(3) (2-) and SO(4) (2-) did not interfere with the determination. Thus a highly selective assay was proposed and applied to the determination of S(2-) in discharged water with the recovery of ca. 103%. PMID- 19789966 TI - Literature and madness: fiction for students and professionals. AB - Psychiatry studies the human mind within a medical paradigm, exploring experience, response and reaction, emotion and affect. Similarly, writers of fiction explore within a non-clinical dimension the phenomena of the human mind. The synergism between literature and psychiatry seems clear, yet literature--and in particular, fiction--remain the poor relation of the medical textbook. How can literature be of particular relevance in psychiatry? This paper examines these issues and suggests a selection of useful texts. PMID- 19789967 TI - Contribution of cyclophilin A to the regulation of inflammatory processes in rheumatoid arthritis. AB - INTRODUCTION: Previous studies show that cyclophilin A (CypA) acts as a strong chemotactic cytokine to neutrophils, eosinophils, and monocytes in rheumatoid arthritis (RA). METHODS: In this study, monocytes were stimulated by purified CypA and the production of matrix metalloproteinase (MMPs), the cell invasion and the release of inflammatory cytokines were detected respectively by gelatin zymography, invasion assay, and cytometric bead array FCM. RESULTS: The elevated level of inflammatory cytokine IL-8 was also detected. Results showed that CypA significantly promoted the invasion of THP-1 cells and increased the production of MMP-2 and MMP-9, which displayed a biphasic concentration dependency. In vivo experiments found that the cartilage erosion scores in CypA injection group were significantly higher than those in control group (P < 0.05). CONCLUSION: Our findings suggest that CypA significantly enhances the secretion of MMP-2 and MMP 9, the cell invasion, and the inflammatory cytokines production of monocytes. Our findings may shed some new light on the inflammatory process and the degradation of cartilage and bone in RA. PMID- 19789968 TI - A remembrance of Dr. George Tiller. PMID- 19789969 TI - Basal ganglia neuroprotection with anticonvulsants after energy stress: a comparative study. AB - The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model provides a valuable paradigm of the energy deficiency disorders found in childhood. In such disorders, anticonvulsants may provide neuroprotection by modulating cellular energy consumption and by exerting favorable pleiotropic effects on neuronal survival. To verify such hypothesis, we tested the effects of levetiracetam, vigabatrin, gabapentine, pregabaline, tiagabine, clonazepam and lamotrigine on neuroprotection in the MPTP mouse model. The membrane dopamine transporter (DAT) density, which provides a reliable index of dopaminergic neurons survival in the basal ganglia, was assessed by semi-quantitative autoradiography of the striatum. Unlike all other anticonvulsants tested, lamotrigine provided a significant and dose-dependent neuroprotection in these experimental conditions. Lamotrigine, a widely used and well-tolerated molecule in children, could provide neuroprotection in various energy deficiency disorders. PMID- 19789970 TI - Pulmonary vein antrum isolation, atrioventricular junction ablation, and antiarrhythmic drugs combined with direct current cardioversion: survival rates at 7 years follow-up. AB - PURPOSE: To report survival rates in patients treated with pulmonary vein antrum isolation (PVAI), atrioventricular junctional ablation (AVJA), and antiarrhythmic and direct current cardioversion (A+DCCV) at 7 years follow-up. METHODS: From February 2002-December 2004, 1,000 consecutive patients underwent PVAI or A+DCCV or AVJA. These patients were matched in a nested casecontrolled methodology. Survival rates were compared at the end of 7 years. RESULTS: Three hundred and forty-five consecutive patients had undergone PVAI (34.5%), 157 (15.7%) consecutive patients AVJA, and 498(49.8%) A+DCCV. After matching the patients in a nested case-controlled methodology, 146 (32.3%) patients were in the PVAI group, 205 (59.4%) in the A+DCCV, and 101 (22.3%) in the AVJA. At 69+/-27 months, 63 (13.9%) patients had died in the matched population. Three (2.1%) patients died in the PVAI group, 34 (16.5%) in the A+DCCV group, and 26 (25.7%) in the AVJA group. In multivariable analysis, treatment strategy was a significant predictor of mortality. Compared to patients with PVAI (reference group), those with A+ DCCV (HR 4.9, p=0.011) and AVJA (HR 10.6, p=0.001) procedures had higher mortality risk. CONCLUSION: Compared to the other two procedures, patients with PVAI had the best survival rates at the end of 7 years. However, the observational case-control design of this study incurs the potential for confounding due to nonrandomized treatment selection, and creates a major limitation in making valid generalization of the findings. PMID- 19789971 TI - Respiratory effects of beta-blocker therapy in heart failure. AB - The present review focuses on the effects of beta-blockers on lung function in HF patients. Indeed, historically, beta-blockers have been considered not indicated in the presence of impaired lung function but recently this concept has been challenged. Lung function abnormalities are part of the chronic HF syndrome, as both lung mechanics and gas exchange are impaired. The regulation of ventilation and gas exchange is under sympathetic control and, therefore, a possible target of beta-blockers. beta-Blocker compounds differ in terms of pharmacological action blocking either both beta1 and beta2 receptors (carvedilol), or selectively the beta1 receptors (nebivolol, bisoprolol, metoprolol). This difference is likely to explain a different action on lung function. Indeed, 90% of beta-receptors in the lung are located on the alveoli and are mainly beta2, whereas 10% are on the airways (mainly beta1-receptors). Expiratory gases and ventilation kinetic analysis during exercise on top of standard spirometry and resting lung diffusion for carbon monoxide (DLCO) provide an integrate evaluation of the respiratory function in HF patients. Carvedilol reduces hyperventilation in HF patients during the entire exercise and proportionally increases patients quality of life. However, carvedilol has a negative action at altitude when, to counterbalance hypoxia, hyperventilation is needed. Indeed, when exercise is performed at a simulated altitude of 2,000 m, PO(2) is 69 +/- 3 mmHg and 64 +/- 4, in placebo and carvedilol, respectively. Mechanical pulmonary function in HF patients at rest and during exercise is only slightly influenced by beta blockers. beta-Blockers affect DLCO differently in chronic HF. Specifically, carvedilol reduces DLCO from 88 +/- 15% to 74 +/- 13% due to reduction of membrane diffusion, whereas bisoprolol does not influence DLCO, likely due to the absence of action by bisoprolol on alveolar beta2-receptors, which preserve active Na(+) transport processes across the alveolar-capillary membrane. In conclusion, it is possible to use beta-blockers in HF patients even in the presence of lung function impairment, but their use should be guided by a combination of lung function evaluation and knowledge of the pharmacological properties of each molecule. PMID- 19789972 TI - The influence of early cleavage on embryo developmental potential and IVF/ICSI outcome. AB - PURPOSE: To observe whether early cleavage can be a predictor of embryo developmental potential, pregnancy and implantation rates. METHODS: A total of 9,544 embryos in 1,095 in vitro fertilization or intracytoplasmic sperm injection cycles were observed with regard to the appearance of early cleavage at 25-29 h post-insemination. RESULTS: A significantly higher proportion of excellent quality embryos were observed in the early cleavage group compared to the late cleavage group (52.5 versus 28.9%, P < 0.01). In the early cleavage group there was also a higher rate of pregnancy per transfer compared with the late cleavage group (38.7 versus 26.3%, P < 0.01). In addition, we found that transfer of only one early cleavage embryo resulted in a high pregnancy rate (38.5%) and a low multiple pregnancy rate (18.0%). CONCLUSION: Early cleavage is a strong indicator of embryo quality, and may be used as an additional criterion in the selection of embryos for transfer to increase pregnancy rate and reduce multiple pregnancy rate. PMID- 19789974 TI - Prognosis of BRCA-associated breast cancer: a summary of evidence. AB - The purpose of the study is to review the clinical studies relevant to the prognosis and prognostic associations of BRCA1- and BRCA2-associated breast cancers. Reports of relevant studies obtained from a MEDLINE search and references from these articles were critically reviewed. A number of methodologic limitations have been identified in the early studies. More recent studies have failed to demonstrate, for the most part, a significant overall survival difference between BRCA-associated breast cancers and sporadic breast cancers. The risk of in-breast tumor recurrence also appears to be similar in the first 5 years following a breast cancer diagnosis with apparent increase in the risk after 5 years in one study. Many in-breast tumor recurrences are now considered to be second primary breast cancers. There is a significant increase in the risk of contralateral breast cancers in BRCA mutation carriers with an estimated 10 year risk ranging from 20-40%. The prognosis of BRCA-associated breast cancers appears to be similar to that of sporadic breast cancers based on the current literature. Future data from large prospective cohort studies will be of interest. PMID- 19789973 TI - Prenatal diagnosis of skeletal dysplasia due to FGFR3 gene mutations: a 9-year experience : prenatal diagnosis in FGFR3 gene. AB - PURPOSE: Prenatal diagnosis with ultrasound findings compatible with skeletal dysplasia due to FGFR3 mutations over a 9 year period in pregnancies and abortuses. METHODS: 54 samples were studied. Aneuploidy studies were carried out on all samples. By sequencing analysis, we determined mutations for achondroplasia (ACH), hypochondroplasia (HCH), and type I and type II tanathophoric dysplasia (TD). RESULTS: 2 chorionic villi samples had a G380R mutation due to a mother with ACH; 4 amniotic fluid samples with TDs in which the foetuses had micromelia plus hypoplastic thoraces; 5 samples from abortuses with TDs. Neither ACH nor HCH occurred in sporadic cases. CONCLUSIONS: Molecular studies in ongoing pregnancies are indicated in cases with an affected parent, a family history with positive molecular studies (maternal anxiety), and when the US finding demonstrates micromelia with a hypoplastic thorax. A protocol for tissues of abortuses should include an X-ray, pathologic anatomy, and genetic studies. PMID- 19789975 TI - XRCC3 Thr241Met polymorphism and breast cancer risk: a meta-analysis. AB - XRCC3 (X-ray repair complementing defective repair in Chinese hamster cells 3) is a member of the RecA/Rad51-related protein family that participates in homologous recombination, maintaining chromosome stability and participating in DNA repair. Attention has been drawn upon the association of XRCC3 Thr241Met polymorphism with breast cancer risk. The present meta-analysis aims to examine whether XRCC3 Thr241Met polymorphism status is associated with breast cancer risk. Apart from the overall meta-analysis, separate analyses were performed on Chinese and non Chinese populations, in order to investigate race-specific effects. Eligible articles were identified by a search of MEDLINE bibliographical database for the period up to August 2009. Twenty case-control studies on non-Chinese subjects (19,575 cases and 21,125 controls) and three case-control studies on Chinese subjects (1,216 cases and 1,112 controls) were eligible. Pooled odds ratios (OR) were appropriately derived from fixed-effects or random-effects models. At the overall analysis, the T allele was associated with elevated breast cancer risk mainly following a recessive model (pooled OR = 1.064, 95% CI: 1.007-1.124, fixed effects), given that the effect was more pronounced in homozygous carriers (pooled OR = 1.073, 95% CI: 1.010-1.140, fixed effects). The association seemed confined in non-Chinese populations, once again following a recessive model (pooled OR = 1.072, 95% CI: 1.014-1.133, fixed effects). Concerning Chinese populations, no consistent results were demonstrated. In conclusion, the XRCC3 Thr241Met T allele seems associated with elevated breast cancer risk in non Chinese subjects. The need for additional studies on Chinese populations seems warranted. PMID- 19789976 TI - Density of tumour stroma is correlated to outcome after adoptive transfer of CD4+ and CD8+ T cells in a murine mammary carcinoma model. AB - Adoptive immunotherapy shows promise for the treatment of cancer; however, partial or mixed responses remain common outcomes due to the heterogeneity of tumours. We studied three murine mammary tumour lines that express an ovalbumin tagged version of HER-2/neu and reproducibly undergo complete regression (CR), partial regression (PR), or progressive disease (PD) after adoptive transfer of ovalbumin-specific CD8(+) (OT-I) and CD4(+) (OT-II) T cells. The three tumour lines were implanted in immunocompetent C57Bl/6 host mice, and established tumours were treated by adoptive transfer of naive OT-I and OT-II T cells. Tumours of the CR and PR classes triggered almost indistinguishable T cell responses in terms of activation, proliferation, trafficking to the tumour site, infiltration of tumour stroma, and intratumoural T cell proliferation; however, tumours of the PR class showed reduced infiltration of tumour epithelium by donor T cells. PD responses were associated with early impairment of T cell activation and proliferation in draining lymph node, followed by negligible infiltration of tumour tissue by donor T cells. Histopathological determinants of outcome were investigated through an unsupervised analysis of 64 untreated tumours representing the three response classes. Tumours of the CR class had proportionately more stroma, which had a looser, more collagen-rich histological appearance. Thus, the amount and composition of tumour stroma distinguished successfully (CR) from unsuccessful (PR or PD) outcomes after adoptive T cell transfer, a finding that might facilitate the design of immunotherapy trials for human breast cancer. PMID- 19789977 TI - Helicobacter pylori and insulin resistance: time to do interventional studies. PMID- 19789978 TI - Gastric changes following colchicine therapy in patients with FMF. PMID- 19789979 TI - Low risk sexual and drug-using behaviors among Latina women with AIDS in Los Angeles County. AB - Latina women represent nearly half of all females diagnosed with AIDS in Los Angeles County, yet little is known about their risk behaviors compared to women of other race/ethnicities. Compared to white and African American women with AIDS, Latinas with AIDS had fewer lifetime male sexual partners (P < .0001); reported fewer sexually transmitted diseases (OR = 0.24; 95% CI: 0.1, 0.5); were less likely to trade sex for drugs/money (OR = 0.18; 95% CI: 0.07, 0.5); and were less likely to report exposure to HIV via injection drug use (OR = 0.3; 95% CI: 0.09, 0.99). Latinas were also more likely to be single mothers (OR = 3.02; 95% CI: 1.4, 6.4); less likely to receive public assistance (OR = 0.33; 95% CI: 0.16, 0.70); were less likely to have completed high-school (OR = 0.11; 95% CI: .04, .31) and were more likely to never have had health insurance (OR = 2.44; 95% CI: 1.15, 5.18). The data demonstrate low-risk behaviors for Latinas and underscores the challenge of delivering effective HIV prevention to women without traditional risk profiles. PMID- 19789980 TI - Recombinant TCR ligand reverses clinical signs and CNS damage of EAE induced by recombinant human MOG. AB - Increasing evidence suggests that in addition to T cell-dependent effector mechanisms, autoantibodies are also involved in the pathogenesis of MS, including demyelinating antibodies specific for myelin oligodendrocyte glycoprotein (MOG). Our previous studies have demonstrated that recombinant T cell receptor ligands (RTLs) are very effective for treating T cell-mediated experimental autoimmune encephalomyelitis (EAE). In order to expand the scope of RTL therapy in MS patients, it was of interest to study RTL treatment of EAE involving a demyelinating antibody component. Therefore, we evaluated the therapeutic effects of RTL551, specific for T cells reactive to mouse (m)MOG-35-55 peptide, on EAE induced with recombinant human (rh)MOG in C57BL/6 mice. We report that RTL551 therapy can reverse disease progression and reduce demyelination and axonal damage induced by rhMOG without suppressing the anti-MOG antibody response. This result suggests that T cell-mediated inflammation and associated blood-brain barrier dysfunction are the central contributors to EAE pathogenesis and that successful regulation of these key players restricts potential damage by demyelinating antibodies. The results of our study lend support for the use of RTL therapy for treatment of MS subjects whose disease includes inflammatory T cells as well as those with an additional antibody component. PMID- 19789981 TI - Isotope labeling strategies for NMR studies of RNA. AB - The known biological functions of RNA have expanded in recent years and now include gene regulation, maintenance of sub-cellular structure, and catalysis, in addition to propagation of genetic information. As for proteins, RNA function is tightly correlated with structure. Unlike proteins, structural information for larger, biologically functional RNAs is relatively limited. NMR signal degeneracy, relaxation problems, and a paucity of long-range (1)H-(1)H dipolar contacts have limited the utility of traditional NMR approaches. Selective isotope labeling, including nucleotide-specific and segmental labeling strategies, may provide the best opportunities for obtaining structural information by NMR. Here we review methods that have been developed for preparing and purifying isotopically labeled RNAs, as well as NMR strategies that have been employed for signal assignment and structure determination. PMID- 19789982 TI - Higher accumulation of F1-V fusion recombinant protein in plants after induction of protein body formation. AB - Improving foreign protein accumulation is crucial for enhancing the commercial success of plant-based production systems since product yields have a major influence on process economics. Cereal grain evolved to store large amounts of proteins in tightly organized aggregates. In maize, gamma-Zein is the major storage protein synthesized by the rough endoplasmic reticulum (ER) and stored in specialized organelles called protein bodies (PB). Zera (gamma-Zein ER accumulating domain) is the N-terminal proline-rich domain of gamma-zein that is sufficient to induce the assembly of PB formation. Fusion of the Zera domain to proteins of interest results in assembly of dense PB-like, ER-derived organelles, containing high concentration of recombinant protein. Our main goal was to increase recombinant protein accumulation in plants in order to enhance the efficiency of orally-delivered plant-made vaccines. It is well known that oral vaccination requires substantially higher doses than parental formulations. As a part of a project to develop a plant-made plague vaccine, we expressed our model antigen, the Yersinia pestis F1-V antigen fusion protein, with and without a fused Zera domain. We demonstrated that Zera-F1-V protein accumulation was at least 3x higher than F1-V alone when expressed in three different host plant systems: Ncotiana benthamiana, Medicago sativa (alfalfa) and Nicotiana tabacum NT1 cells. We confirmed the feasibility of using Zera technology to induce protein body formation in non-seed tissues. Zera expression and accumulation did not affect plant development and growth. These results confirmed the potential exploitation of Zera technology to substantially increase the accumulation of value-added proteins in plants. PMID- 19789983 TI - Mitochondrial sequence variation in ancient horses from the Carpathian Basin and possible modern relatives. AB - Movements of human populations leave their traces in the genetic makeup of the areas affected; the same applies to the horses that move with their owners This study is concerned with the mitochondrial control region genotypes of 31 archaeological horse remains, excavated from pre-conquest Avar and post-conquest Hungarian burial sites in the Carpathian Basin dating from the sixth to the tenth century. To investigate relationships to other ancient and recent breeds, modern Hucul and Akhal Teke samples were also collected, and mtDNA control region (CR) sequences from 76 breeds representing 921 individual specimens were combined with our sequence data. Phylogenetic relationships among horse mtDNA CR haplotypes were estimated using both genetic distance and the non-dichotomous network method. Both methods indicated a separation between horses of the Avars and the Hungarians. Our results show that the ethnic changes induced by the Hungarian Conquest were accompanied by a corresponding change in the stables of the Carpathian Basin. PMID- 19789984 TI - Microbial utilization of the industrial wastewater pollutants 2 ethylhexylthioglycolic acid and iso-octylthioglycolic acid by aerobic gram negative bacteria. AB - Industrial wastewater from the production of sulfur containing esters and the resulting products of this synthesis, 2-ethylhexylthioglycolic acid (EHTG) and iso-octylthioglycolic acid (IOTG), were deployed in this study to enrich novel bacterial strains, since no wastewater and EHTG or IOTG degrading microorganisms were hitherto described or available. In addition, nothing is known about the biodegradation of these thiochemicals. The effect of this specific wastewater on the growth behaviour of microorganisms was investigated using three well-known Gram-negative bacteria (Escherichia coli, Pseudomonas putida, and Ralstonia eutropha). Concentrations of 5% (v/v) wastewater in complex media completely inhibited growth of these three bacterial strains. Six bacterial strains were successfully isolated, characterized and identified by sequencing their 16S rRNA genes. Two isolates referred to as Achromobacter sp. strain MT-E3 and Pseudomonas sp. strain MT-I1 used EHTG or IOTG, respectively, as well as the wastewater as sole source of carbon and energy for weak growth. More notably, both isolates removed these sulfur containing esters in remarkable amounts from the cultures supernatant. One further isolate was referred to as Klebsiella sp. strain 58 and exhibited an unusual high tolerance against the wastewater's toxicity without utilizing the contaminative compounds. If cultivated with gluconic acid as additional carbon source, the strain grew even in presence of more than 40% (v/v) wastewater. Three other isolates belonging to the genera Bordetella and Pseudomonas tolerated these organic sulfur compounds but showed no degradation abilities. PMID- 19789985 TI - Host-plant specificity and specialization in eriophyoid mites and their importance for the use of eriophyoid mites as biocontrol agents of weeds. AB - Eriophyoid mites, which are among the smallest plant feeders, are characterized by the intimate relationships they have with their hosts and the restricted range of plants upon which they can reproduce. The knowledge of their true host ranges and mechanisms causing host specificity is fundamental to understanding mite-host interactions, potential mite-host coevolution, and diversity of this group, as well as to apply effective control strategies or to use them as effective biological control agents. The aim of this paper is to review current knowledge on host specificity and specialization in eriophyoid mites, and to point out knowledge gaps and doubts. Using available data on described species and recorded hosts we showed that: (1) 80% of eriophyoids have been reported on only one host species, 95% on one host genus, and 99% on one host family; (2) Diptilomiopidae has the highest proportion of monophagous species and Phytoptidae has the fewest; (3) non-monophagous eriophyoids show the tendency to infest closely related hosts; 4) vagrant eriophyoids have a higher proportion of monophagous species than refuge-seeking and refuge-inducing species; (5) the proportions of monophagous species infesting annual and perennial hosts are similar; however, many species infesting annual hosts have wider host ranges than those infesting perennial hosts; (6) the proportions of species that are monophagous infesting evergreen and deciduous plants are similar; (7) non-monophagous eriophyoid species have wider geographic distribution than monophagous species. Field and laboratory host-specificity tests for several eriophyoid species and their importance for biological control of weeds are described. Testing the actual host range of a given eriophyoid species, searching for ecological data, genetic differentiation analysis, and recognizing factors and mechanisms that contribute to host specificity of eriophyoid mites are suggested as future directions for research. PMID- 19789986 TI - Physical mapping of the elephant X chromosome: conservation of gene order over 105 million years. AB - All therian mammals (eutherians and marsupials) have an XX female/XY male sex chromosome system or some variant of it. The X and Y evolved from a homologous pair of autosomes over the 166 million years since therian mammals diverged from monotremes. Comparing the sex chromosomes of eutherians and marsupials defined an ancient X conserved region that is shared between species of these mammalian clades. However, the eutherian X (and the Y) was augmented by a recent addition (XAR) that is autosomal in marsupials. XAR is part of the X in primates, rodents, and artiodactyls (which belong to the eutherian clade Boreoeutheria), but it is uncertain whether XAR is part of the X chromosome in more distantly related eutherian mammals. Here we report on the gene content and order on the X of the elephant (Loxodonta africana)-a representative of Afrotheria, a basal endemic clade of African mammals-and compare these findings to those of other documented eutherian species. A total of 17 genes were mapped to the elephant X chromosome. Our results support the hypothesis that the eutherian X and Y chromosomes were augmented by the addition of autosomal material prior to eutherian radiation. Not only does the elephant X bear the same suite of genes as other eutherian X chromosomes, but gene order appears to have been maintained across 105 million years of evolution, perhaps reflecting strong constraints posed by the eutherian X inactivation system. PMID- 19789987 TI - The choanoflagellate Monosiga brevicollis karyotype revealed by the genome sequence: telomere-linked helicase genes resemble those of some fungi. AB - The approximately 42 Mbp assembled genome sequence for the choanoflagellate Monosiga brevicollis reveals that most of the large scaffolds of 300-2,600 kb represent entire chromosomes or chromosome arms. Telomeres are partially assembled at the termini of 37 scaffolds, while another 43 scaffolds end in telomere-associated regions containing distinctive gene sets. Potential centromeric regions were identified on 39 scaffolds. Together, these observations suggest a karyotype of approximately 40 metacentric and submetacentric chromosomes averaging 1 Mbp in size. Genes encoding RecQ family DNA helicases, along with ankyrin-domain proteins and serine/threonine kinases, are associated with most telomeres, a feature shared with some fungi. This telomere-linked helicase gene arrangement might be ancestral to both fungi and choanoflagellates in the super-kingdom Opisthokonta; however, the great lability of telomere architecture suggests that it could also be a convergent feature. PMID- 19789988 TI - Sulfamic acid catalyzed solvent-free synthesis of 10-aryl-7,7-dimethyl-6,7,8,10 tetrahydro-9H-[1,3]-dioxolo [4,5- b]xanthen-9-ones and 12-aryl-9,9-dimethyl 8,9,10,12-tetrahydro-11H-benzo[a]xanthen-11-ones. AB - Three-component one-pot synthesis of some novel 10-aryl-7,7-dimethyl-6,7,8,10 tetrahydro-9H-[1,3]-dioxolo[4,5-b]xanthen-9-ones, which have not been published before, and 12-aryl-9,9-dimethyl-8,9,10,12-tetrahydro-11H-benzo[a]xanthen-11-ones from condensation of 3,4-methylenedioxyphenol or beta-naphthol, aldehydes and dimedone under solvent-free conditions at 120 degrees C is reported. PMID- 19789989 TI - Liquiritin potentiate neurite outgrowth induced by nerve growth factor in PC12 cells. AB - Neurite outgrowth and neuronal differentiation play a crucial role in the development of the nervous system. Understanding of neurotrophins induced neurite outgrowth was important to develop therapeutic strategy for axon regeneration in neurodegenerative diseases as well as after various nerve injuries. It has been reported that extension of neurite and differentiation of sympathetic neuron-like phenotype was modulated by nerve growth factor (NGF) in PC12 cells. In this study, NGF mediated neurite outgrowth was investigated in PC12 cells after liquiritin exposure. Liquiritin is a kind of flavonoids that is extracted from Glycyrrhizae radix, which is frequently used to treat injury or swelling for its life-enhancing properties as well as detoxification in traditional Oriental medicine. The result showed that liquiritin significantly promotes the neurite outgrowth stimulated by NGF in PC12 cells in dose dependant manners whereas the liquiritin alone did not induce neurite outgrowth. Oligo microarray and RT-PCR analysis further clarified that the neurotrophic effect of liquiritin was related to the overexpression of neural related genes such as neurogenin 3, neurofibromatosis 1, notch gene homolog 2, neuromedin U receptor 2 and neurotrophin 5. Thus, liquiritin may be a good candidate for treatment of various neurodegenerative diseases such as Alzheimer's disease or Parkinson's disease. PMID- 19789990 TI - Construction of a binary transgenic gene expression system for recombinant protein production in the middle silk gland of the silkworm Bombyx mori. AB - To construct an efficient system for the production of recombinant proteins in silkworm (Bombyx mori), we investigated the promoter activity of the silkworm sericin 1, 2, and 3 genes (Ser1, Ser2, and Ser3) using a GAL4/UAS binary gene expression system in transgenic silkworm. The promoter activity of the upstream region of Ser1 was strong, yielding high expression of an enhanced green fluorescent protein (EGFP) transgene in the middle and posterior regions of the middle silk gland (MSG) after day 2 of the fifth instar. The Ser3 upstream region exhibited moderate promoter activity in the anterior MSG, but the Ser2 upstream region did not exhibit any promoter activity. Since the strongest promoter activity was observed for Ser1, we devised a system for the production of recombinant proteins using a GAL4-Ser1 promoter construct (Ser1-GAL4). Transgenic silkworms harboring both the Ser1-GAL4 construct and the previously reported upstream activating sequence (UAS)-EGFP construct, which contains the TATA box region of the Drosophila hsp70 gene, yielded approximately 100 microg EGFP per larva. When we then analyzed the TATA box region, signal peptide, and intron sequences for their effects on production from the UAS-EGFP construct, we found that the optimization of these sequences effectively increased production to an average of 500 microg EGFP protein per transgenic larva. We conclude that this binary system is a useful tool for the mass production of recombinant proteins of biomedical and pharmaceutical interest in silkworm. PMID- 19789991 TI - Ectopic expression of a Chinese cabbage BrARGOS gene in Arabidopsis increases organ size. AB - Chinese cabbage (Brassica rapa L. ssp. pekinensis) is a common and economically important crop in Asia. Specific targets of plant breeding programs for cabbage have been improvement in yield, resistance to environment stresses, and nutrition quality by means of genetic manipulation. To obtain information on yield improvement applicable for the genetic engineering approach, we have attempted to dissect the molecular pathways that regulate organ size. We first isolated a putative homolog of ARGOS full-length cDNA from Chinese cabbage leaves, which we designated BrARGOS. At the transcription level, BrARGOS was detected in all organs tested in Chinese cabbage. To test the function of this gene, we then engineered Arabidopsis plants that would overexpress BrARGOS ectopically. The organs of the transgenic Arabidopsis plants were significantly larger than those of the control plants. This increase in size was due to enhanced cell proliferation, with no contribution from cell expansion. The molecular analysis revealed that overexpression of BrARGOS up-regulated the transcription of several genes involved in the control of organ size. These results suggest that the BrARGOS gene may function as one of the regulators of organ size in Chinese cabbage. As such, manipulation of the BrARGOS gene may significantly increase the size of Chinese cabbage organs, such as Chinese cabbage heads. PMID- 19789992 TI - Combination antioxidant effect of alpha-tocoferol and erdosteine in ischemia reperfusion injury in rat model. AB - INTRODUCTION: Renal ischemia/reperfusion (I/R) which is an important cause of renal dysfunction is inevitable in renal transplantation, surgical revascularization of the renal artery, partial nephrectomy and treatment of suprarenal aortic aneurysms. AIM: The purpose of this study was to investigate the efficacy of alpha-tocopherol and erdosteine combination in the reduction in injury induced by ROS in a rat model of renal ischemia-reperfusion. MATERIALS AND METHODS: Thirty-six- male Wistar albino rats weighing 200-250 g were utilized for this study. Rats were divided into six groups, and each group was consistent of six rats: (1) sham-operated (control), (2) ischemia group (3) I/R group, (4) I/R/alpha-tocoferol group (5) I/erdosteine group (6). I/R/alpha-tocoferol and erdosteine group. Biochemically tissue MDA, XO and SOD activities, light and electron microscopic findings were evaluated. RESULTS: The erdosteine and alpha tocoferol significantly reversed the effect of protein oxidation and lipid peroxidation induced by I/R shown by the decreased levels of MDA and XO activities. Both MDA and XO levels were found to be lower in group 6 compared to single agent treatment groups, and this was significantly different. All treatment groups showed increased SOD activity, which accounts for their oxidative properties. The mean Paller score of the combination treatment group (group 6) was lower than all groups except the sham group (3.67 +/- 1.2), and this finding was statistically significant (0.05). Our results showed that the antioxidant pretreatment with alpha-tocopherol and erdosteine combination reduced lipid peroxidation of renal cellular membranes in a model of normothermic renal ischemia-reperfusion in rats. Combination of erdosteine and alpha-tocopherol has a synergistic effect of protection against oxidative processes. Long-term use of alpha-tocopherol seems to have a greater effect on the prevention of IR injury. However, further investigations are needed for the clinical applications of our findings. PMID- 19789993 TI - Swing it to the left, swing it to the right: enacting flexible spatial language using a neurodynamic framework. AB - Research is continually expanding the empirical and theoretical picture of embodiment and dynamics in language. To date, however, a formalized neural dynamic framework for embodied linguistic processes has yet to emerge. To advance embodied theories of language, the present work develops a formalized neural dynamic framework of spatial language that explicitly integrates linguistic processes and dynamic sensory-motor systems. We then implement and test our spatial language architecture on a robotic platform continuously linked to real time camera input. In a suite of tasks using everyday objects we demonstrate the framework's capacity for both contextually-dependent behavioral flexibility and the seamless integration of spatial, non-spatial, and symbolic representations. To our knowledge this is the first unified, neurally-grounded architecture integrating these processes and behaviors. PMID- 19789994 TI - Sequence-specific (1)H, (13)C, and (15)N backbone assignment of Psb27 from Synechocystis PCC 6803. AB - Photosystem II (PSII) is a large membrane protein complex that uses light to split water into molecular oxygen, protons, and electrons. Here we report the (1)H, (15)N and (13)C backbone chemical shift assignments for the Psb27 protein of Photosystem II from Synechocystis PCC 6803. These assignments will now provide the basis for the structural analysis of the Psb27 protein. PMID- 19789996 TI - Impact of tumor angiogenesis in peritoneal mesothelioma after radical cytoreduction and hyperthermic intraperitoneal chemotherapy. AB - Peritoneal mesothelioma is one of the peritoneal surface malignancies where long term survival is a reality after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). Tumor angiogenesis has been shown to be of prognostic significance on survival in mesothelioma. We investigated the impact of survival of patients with peritoneal mesothelioma following CRS and HIPEC to determine the impact of tumor angiogenesis on survival after this radical surgical treatment. Paraffin sections of 23 patients who were treated with CRS and HIPEC were retrieved for immunohistochemical analysis. The immunostaining was performed using monoclonal mouse anti-human antibodies (VEGF-C and CD31) on an autostainer (Autostainer Plus; Dako, Inc.). The intensity of the stains were quantified using the Image-Pro Plus (IPP) 4.5 (Media Cybernetics, Silver Spring, MD). VEGF expression and microvessel density (MVD) using CD31 staining were studied. The median survival was 94 months with a 3-year survival rate of 51%. There was no impact on patient's age, sex, peritoneal cancer index, tumor histopathology and survival outcomes between patients with low or high MVD and VEGF expression. After CRS and HIPEC, our results demonstrate that the prognostic significance of tumor angiogenesis is negated, highlighting the potential importance of other co-contributory mechanisms in mesotheliomagenesis and undergoing radial treatment. PMID- 19789997 TI - Neolebouria blatta n. sp. (Digenea: Opecoelidae) from Pristipomoides argyrogrammicus (Valenciennes) and Etelis carbunculus Cuvier (Perciformes: Lutjanidae) off New Caledonia. AB - Neolebouria blatta n. sp. is described from Pristipomoides argyrogrammicus (Valenciennes) and Etelis carbunculus Cuvier in waters off New Caledonia. It differs from all other species of Neolebouria Gibson, 1976 but one, N. georgenascimentoi Bray, 2002, in the extension of the cirrus-sac to the ovary or nearly so. It differs from N. georgenascimentoi in its continuous, rather than interrupted, vitelline distribution. N. blatta belongs to a small group of similar Neolebouria species reported in deep-water lutjanids, which includes N. longisacculus (Yamaguti, 1970) n. comb., N. rooseveltiae (Yamaguti, 1970) n. comb. and N. ulaula (Yamaguti, 1970). PMID- 19789998 TI - Re-evaluation of the species composition of Bashkirovitrema Skrjabin, 1944 (Digenea: Echinostomatidae), with the description of two new species of this genus and the proposal of Kostadinovatrema novaeguiniense n. g., n. sp. AB - A comparison of specimens previously identified as Bashkirovitrema incrassatum (Diesing, 1850) from the African or cape clawless otter Aonyx capensis, and the speckle-throated or spotted-throated otter Hydrictis maculicollis from the Old World with specimens and descriptions of B. incrassatum from the New World showed that those from Africa (Bashkirovitrema africanum n. sp.) had a more extensive distribution of the vitelline fields than either B. canadense n. sp. from the northern river otter Lontra canadensis and the American mink Neovison vison (North America) and B. incrassatum from the Neotropical river otter Lontra longicaudis (South America). B. africanum n. sp. further differs from B. canadense n. sp. by having a smaller body, shorter forebody, smaller oral sucker, longer cirrus, shorter intertesticular space, shorter post-testicular space and longer eggs. B. canadense n. sp. can be distinguished from B. incrassatum by having a longer body, longer forebody, smaller sucker ratio, smaller testes, greater distance between the ventral sucker and the ovary, shorter cirrus-sac, longer post-testicular space and narrower eggs. B. africanum n. sp. differs from B. incrassatum by having a smaller ventral sucker, larger ovary, shorter cirrus sac, smaller intertesticular space, larger post-testicular space and longer eggs that are not as wide. Kostadinovatrema n. g., as represented by K. novaeguiniense n. sp., can be separated from species of Bashkirovitrema Skrjabin, 1944 by having a wider body width to length profile, a head collar that is narrower than the forebody and armed with 33 rather than 27 collar spines, an ovary that is further removed anteriorly from the testes, and a dorso-ventrally flattened hindbody that is nearly as broad as the forebody. The new genus differs from Hypoderaeum Dietz, 1909 and Moliniella Hubner, 1939 by having 33 head collar spines. PMID- 19789999 TI - New records of rare derogenids (Digenea: Hemiuroidea) from Mediterranean sparids, including the description of a new species of Magnibursatus Naidenova, 1969 and redescription of Derogenes adriaticus Nikolaeva, 1966. AB - Records of derogenid digeneans in the Mediterranean and Black Sea region are scarce and tend to be restricted to a small number of host-groups, but especially to sparid fishes. This work reports on the presence of derogenine and halipegine derogenids from two sparids, Diplodus annularis (L.) and D. sargus (L.), from off the Mediterranean coast of Spain. Five derogenid forms were recovered. Derogenes adriaticus Nikolaeva, 1966 is redescribed from Diplodus annularis, and Derogenes sp. is described from the same host but differentiated from the former species. Magnibursatus barretti n. sp. is described from Diplodus sargus and distinguished from other species of the genus especially by its smaller body size and smaller eggs. M. bartolii Kostadinova, Power, Fernandez, Balbuena, Raga & Gibson, 2003 is redescribed from D. sargus, a new host for this species. A single specimen from D. sargus, somewhat similar to M. minutus Kostadinova, Power, Fernandez, Balbuena, Raga & Gibson, 2003, is also described, as it exhibits some morphometric differences from the latter species. PMID- 19790000 TI - Anisakis nascettii n. sp. (Nematoda: Anisakidae) from beaked whales of the southern hemisphere: morphological description, genetic relationships between congeners and ecological data. AB - A new anisakid nematode, Anisakis nascettii n. sp., is described from beaked whales Mesoplodon spp. off the coast of New Zealand and South Africa. Morphological and molecular (allozymes and mtDNA cox2 sequence) data were used for diagnostic and identification purposes. Among the 19 allozymes studied, 10 were found to be unique and characteristic for A. nascettii n. sp. Analysis of allozymes demonstrated reproductive isolation from A. ziphidarum Paggi, Nascetti, Webb, Mattiucci, Cianchi & Bullini, 1998 and mtDNA cox2 sequences depict this Anisakis species as a distinct and unique entity. Key morphological diagnostic traits for A. nascettii with respect to the genetically closely related species A. ziphidarum include: spicule length, the spicule/body length ratio, the arrangement of the caudal papillae and the shape of the plectanes of the adult males. Genetic data confirmed that Anisakis sp. A of Pontes et al. (2005), which was partly described by Iglesias et al. (2008), and Anisakis sp. of Valentini et al. (2006) are conspecific with A. nascettii. Both molecular and morphological data indicate that the new species belongs to the 'ziphidarum-group'; however, it is genetically very distinct from A. ziphidarum (D ( Nei ) = 0.69, K2P = 0.09), as well as from all of the previously genetically characterised Anisakis spp. All tree topologies inferred by different methods (MP, NJ and Bayesian) support the finding that A. nascettii n. sp. and A. ziphidarum are sister-species. It is also confirmed that A. nascettii n. sp. is, at the adult stage, a parasite of beaked whales of the genus Mesoplodon, whereas, as a larva, it has been identified from the squid Moroteuthis ingens Smith. Furthermore, Mesoplodon bowdoini Andrews represents a new host record for A. ziphidarum. The parallelism between the clade formed by these two anisakine taxa, i.e. A. ziphidarum and A. nascettii, and that formed by their definitive hosts further supports the hypothesis of host-parasite co-evolutionary relationships, as previously suggested for Anisakis spp. and their cetacean hosts. PMID- 19790001 TI - A new species of Isospora Schneider, 1881 (Apicomplexa: Eimeriidae) in Ruppell's agama Agama rueppelli (Vaillant) (Sauria: Agamidae) from East Africa, with a review of this genus in agamid lizards. AB - Coprological examinations of eight Ruppell's agamas Agama rueppelli (Vaillant) revealed the presence of a coccidium of the genus Isospora Schneider, 1881 that represents a previously undescribed species. Oocysts of Isospora farahi n. sp. are spherical or subspherical, 29.1 (26-31) x 28.8 (26-31) microm, with a shape index of 1.01 (1-1.07). An oocyst residuum, polar granules and micropyle are absent. The oocyst wall is bilayered, brownish and smooth, c. 1.5-2 microm thick. The sporocysts are oval, 16.6 (15-18) x 11.4 (11-12) microm, with a shape-index of 1.46 (1.25-1.64) and both Stieda and substieda bodies. A sporocyst residuum is present as medium-sized granules scattered irregularly among the sporozoites. The sporozoites are vermiform, with a large posterior spherical refractile body. Endogenous development is intranuclear in the epithelial cells of the small intestine. Sporulation is unknown, as oocysts were recovered from the faeces. PMID- 19790002 TI - Three new species of Hatschekia Poche, 1902 (Copepoda: Siphonostomatoida: Hatschekiidae) parasitic on Abalistes filamentosus (Pisces: Tetraodontiformes: Balistidae) from off Okinawa, Japan. AB - Three new species of the copepod genus Hatschekia Poche, 1902, H. lima n. sp., H. cylindrus n. sp. and H. sunaoi n. sp., are described from the gill filaments of a triggerfish, Abalistes filamentosus Matsuura & Yoshino, caught off the Ryukyu Islands, Okinawa, Japan. These new species share an unusual morphological character, i.e. four stout posterior spines on the intercoxal sclerites of legs 1 and 2. H. lima n. sp. differs from its congeners in having a robust inner lobe on the maxillule and leg 3 with a swollen basal lobe. H. cylindrus n. sp. is distinguishable from its congeners by having a cephalothorax fused to the trunk and a double-semicircular chitinous frame. H. sunaoi n. sp. is characterised by leg 3 with a swollen basal lobe and an oval cephalothorax. PMID- 19790003 TI - Toward plant cell wall degradation under thermophilic condition: a unique microbial community developed originally from swine waste. AB - A unique thermophilic microbial community developed initially from swine waste was investigated in this study. Cellulase activities were observed when this community was inoculated to media containing either cellulose or carboxymethylcellulose at 57 degrees C. Through constructing a clone library for the 16S ribosomal DNA, it was revealed that this community was mainly composed of three genera: Thermobacillus, Brevibacillus, and Anoxybacillus. New findings regarding the thermo- and pH stability of crude cellulases secreted by Brevibacillus sp. JXL were presented. Recent study on the growth characteristics of Anoxybacillus sp. 527 was discussed. PMID- 19790004 TI - American Chemical Society--238th National Meeting & Exposition. Developments in medicinal chemistry: part 1. 16-20 August 2009, Washington DC, USA. AB - The 238th National Meeting and Exposition of the American Chemical Society, held in Washington DC, included topics covering new compounds and developments in the field of medicinal chemistry. This conference report highlights selected presentations on a novel KV1.5 blocker, a state-dependent CaV2.2 antagonist, therapeutic uses of macrocycles, a novel P2X7 antagonist, developments using the StaR technology platform, the optimization of a neuropeptide S receptor antagonist, and type 1 glycine transport modulators. Investigational drugs discussed include WYE-160020 (Wyeth), Trox-1 (Neuromed Pharmaceuticals Inc), ulimorelin (Tranzyme Pharma Inc), E-32224 (Ensemble Discovery Corp) and PF 03463275 (Pfizer Inc); the discontinued compound AZD-9056 is also highlighted. PMID- 19790005 TI - American Chemical Society--238th National Meeting & Exposition. Developments in medicinal chemistry: part 2. 16-20 August 2009, Washington DC, USA. AB - The 238th National Meeting and Exposition of the American Chemical Society, held in Washington DC, included topics covering new compounds and developments in the field of medicinal chemistry. This conference report highlights selected presentations on inhibitors of PARP, a heme oxygenase 1 (HO-1) inhibitor, NS3 protease inhibitors, a corticotrophin-releasing factor 1 (CRF-1) receptor antagonist, a cannabinoid receptor antagonist, diacylglycerol acyltransferase inhibitors, cathepsin and chymase receptor inhibitors, and MAPK inhibitors. Investigational drugs discussed include veliparib (Abbott Laboratories), MK-4827 (Merck & Co Inc), OB-24 (Osta Biotechnologies), BMS-339, BMS-764459, BMS-812204 and BMS-640994 (all Bristol-Myers Squibb Co), and JNJ-10311795 (Johnson & Johnson). PMID- 19790006 TI - American Chemical Society--238th National Meeting & Exposition. Novel small molecule therapeutics. 16-20 August 2009, Washington DC, USA. AB - The Novel Small Molecule Therapeutics session of the American Chemical Society 238th National Meeting and Exposition, held in Washington DC, included topics covering new therapeutic developments in CNS, anti-infective, cardiovascular and anti-inflammatory applications. This conference report highlights selected presentations on PAR2 (protease-activated receptor 2) antagonists, adenosine and P2Y receptor agonists and antagonists, antimicrobials and neuroprotective compounds. PMID- 19790007 TI - AIMECS 09--Seventh AFMC International Medicinal Chemistry Congress. 23-27 August 2009, Cairns, Queensland, Australia. AB - The Seventh Asian Federation for Medicinal Chemistry (AFMC) International Medicinal Chemistry Congress (AIMECS) held in Cairns, Australia was co-hosted by the Royal Australian Chemical Institute Division of Biomolecular Chemistry and included topics covering new therapeutic developments in the fields of cancer, cardiovascular disease, anti-infectives and CNS disorders. This conference report highlights selected presentations on anticancer agents, including ALK5 inhibitors, PAR1 inhibitors, anticoagulants, iron chelators, anxiolytics and GABA receptor antagonists. Investigational drugs discussed include IN-1130 (SK Chemicals Co Ltd/In2Gen Co), SCH-530348 (Schering-Plough Corp), apixaban (Bristol Myers Squibb Co/Pfizer Inc) and BNC-210 (Bionomics Ltd). PMID- 19790008 TI - American Academy of Dermatology--Summer Meeting. 29 July-2 August 2009, Boston, MA, USA. AB - The 2009 Summer Meeting of the American Academy of Dermatology held in Boston, MA included topics covering new therapeutic developments in the field of dermatology. This conference report highlights selected presentations on the use of TNF agents and treatment options for psoriasis and psoriatic arthritis, as well as for melanoma and basal cell carcinoma. Investigational drugs discussed include PLX-4032 (Plexxikon Inc/F Hoffmann-La Roche Ltd) and GDC-0449 (Curis Inc/Genentech Inc/ F Hoffmann-La Roche Ltd). PMID- 19790009 TI - Target Discovery--Select Biosciences' World Congress. 4-5 August 2009, San Francisco, CA, USA. AB - Select Biosciences' Target Discovery World Congress, held in San Francisco, included topics covering novel drug targets and screening platforms in the field of drug discovery. This conference report highlights selected presentations on inhibiting cancer targets, including Braf and HDAC; targeting protein kinases for the treatment of cancer and neurological disorders; an assay for the design of kinase inhibitors; and deorphanized nuclear receptors as drug targets. PMID- 19790010 TI - Drug Safety Strategies to De-Risk Compounds--an IBC conference. 4-6 August 2009, Boston, MA, USA. AB - The Drug Safety Strategies to De-Risk Compounds conference, held in Boston, included topics covering new developments in the field of drug safety. This conference report highlights selected presentations on the early prediction of hepatotoxicity, improvements in models of cardiovascular toxicity, the use of biomarkers in drug development, and computational approaches to drug safety predictions. Emerging technologies and drug safety models, as well as case studies of safety assessment advances, are also discussed. PMID- 19790011 TI - Molecular Diagnostics--Select Biosciences' Second World Congress. 6-7 August 2009, South San Francisco, CA, USA. AB - The Select Biosciences' Molecular Diagnostics Second World Congress held in South San Francisco, CA, USA included topics covering new developments and technologies in the field of molecular diagnostics. This conference report highlights selected presentations on market analyses, DNA microarray diagnostics, multiplexed diagnostics and biomarker discovery. PMID- 19790012 TI - Fourth Medical Biotech Forum of the Chinese Medical Biotech Association. 8-10 August 2009, Dalian, China. AB - The Chinese Medical Biotech Association's Fourth Medical Biotech Forum held in Dalian, China included topics covering the biotechnology industry in China and new therapeutic developments in the field of immunological approaches to cancer treatment. This conference report highlights selected presentations on China's biotechnology development policy, tumor-specific antigens, clinical applications of antitumor immune therapy, and novel photodynamic tumor therapy. Investigational therapeutics discussed include astuprotimut-r (GlaxoSmithKline plc) and the dendritic cell vaccine Trivax (Trimed Biotech). PMID- 19790013 TI - The Immunotherapeutics & Vaccine Summit--CHI's fourth annual meeting. Preclinical/clinical development of immunotherapies and vaccines. 17-19 August 2009, Providence, RI, USA. AB - The Immunotherapeutics & Vaccine Summit held in Providence, RI, USA included topics covering new preclinical and clinical developments in the field of immunotherapies and vaccines. This conference report highlights selected presentations on the iSBTc-FDA-NCI taskforce findings on immunotherapy biomarkers, clinical assay development and optimization, and bioassays to measure immune responses. Investigational vaccines discussed include a fusion protein adjuvant vaccine (Research by Discovery), a novel intradermal particle delivery device (Universite de Sherbrooke) and a Hsp-based vaccine for meningitis (ImmunoBiology Ltd). PMID- 19790014 TI - Type III secretion systems as targets for novel therapeutics. AB - Bacterial pathogens use common virulence factors to cause disease. One such virulence factor is the type III secretion system (T3SS), which allows for the direct injection of bacterial proteins, called effector proteins, into the contacting host cell. Pathogens with defective T3SSs are 1000- to 1 million-fold attenuated in animal models of infection. Thus, targeting antivirulence therapies to virulence factors such as the T3SS may provide a novel approach to treating infections. This article provides an overview of approaches used in identifying various classes of T3SS inhibitors, to enable the use of such inhibitors as novel therapeutics. PMID- 19790015 TI - Bringing DNA vaccines closer to commercial use. AB - Progress in the application of DNA vaccines as an immunization protocol is evident from the increasing number of such vaccines under evaluation in clinical trials and by the recent approval of several DNA vaccine products for veterinary applications. DNA vaccine technology offers important therapeutic and commercial advantages compared with conventional approaches, including the opportunity to target pathogens characterized by significant genetic diversity using a safe immunization platform, and the ability to use a simple, rapid and well characterized production method. However, further optimization of DNA vaccine technology through the use of improved constructs, delivery systems and immunization protocols is necessary to clinically achieve the promising results that have been demonstrated in preclinical models. PMID- 19790016 TI - Darapladib, a reversible lipoprotein-associated phospholipase A2 inhibitor, for the oral treatment of atherosclerosis and coronary artery disease. AB - Darapladib, under development by GlaxoSmithKline plc, is a novel inhibitor of lipoprotein-associated phospholipase A2 (PLA2), an enzyme that may link lipid metabolism with inflammation, leading to the increased stability of atherosclerotic plaques present in the major arteries. Darapladib exhibits favorable pharmacokinetics, minimal predicted drug-drug interactions, sustained blood levels with once-daily oral dosing and limited inhibition of other PLA2 isozymes. Preclinical studies in diabetic-hypercholesterolemic swine (useful for the study of human atherosclerosis mechanisms) demonstrated that darapladib attenuated the progression of arterial plaques to a higher-risk phenotype by reducing the number of inflammatory macrophages within plaques and dampening T cell responses. Two phase II clinical trials demonstrated sustained lipoprotein associated PLA2 inhibition with daily oral dosing, and favorable effects on markers of inflammation and plaque stability. Phase III trials are ongoing to assess the safety and efficacy of darapladib in reducing adverse clinical events in patients with atherosclerosis. PMID- 19790017 TI - [Hand infections]. PMID- 19790018 TI - [Pyogenic flexor tendon sheath infection: a comprehensive review]. AB - Pyogenic or suppurative flexor tenosynovitis is a closed space infection of the hand. If not recognised early and treated appropriately, this infection can result in significant morbidity and loss of function. This comprehensive review contains clinically relevant information on the special anatomy, pathophysiology, diagnosis and differential diagnosis, classification, microbiology, operative therapy, complications, physiotherapy, scores and results based on literature from the last 150 years and our personal experience. PMID- 19790019 TI - [Surgical reality and prognostic criteria of severe infections of the hand]. AB - PURPOSE: The aim of this study was to evaluate, whether early and radical debridement for hand infections within a single operation followed by at most one second-look revision, is considered as sufficient to heal the infection or not. As one revision followed by at most one second-look revision is not successful for all cases, the value of defined variables on the clinical course and their clinical relevance were evaluated. PATIENTS: In this prospective study 50 patients (Mean age: 44; SD: 18 years of age) were included, who underwent surgical treatment in our hospital for severe infection of the hand. The individual course of each patient was documented. Patients, who needed more than two operations to heal the infection (group B) were compared with patients, who underwent one operation followed by at most one second-look revision (group A) under consideration of cause of infection, microbiology, pretreatment, preexistent diseases, and C-reactive protein. RESULTS: Mean inpatient treatment lasted 19.3 (SD: 19.2) days. Patients underwent 4.4 operations (range: 1-24). For infect healing 22 of the 50 patients (group A) required 1-2 surgical revisions. For 28 patients (group B) more than 2 revisions were necessary. For patients of group B the cause for the infection was more often unknown (p<0.05). Patients who already underwent pretreatment externally showed a significantly increased risk for a prolonged course (p<0.05). A preexistent disease or an increase of CRP had no significant influence on the healing process (p>0.05). CONCLUSION: Even if the concept of early and radical surgical debridement is consistently and adequately realized, healing of hand infection was achieved in less than 50% of the cases with one revision followed by at most one second-look revision. Particularly patients, who already underwent pretreatment externally before evaluation of a hand surgeon seem to be inclined to a prolonged courses of treatment. PMID- 19790020 TI - [Severe side effects after Octenisept irrigation of penetrating wounds in children]. AB - BACKGROUND: Deep penetrating wounds in children's hands are repeatedly treated in emergency wards conservatively through irrigation, antibiotic therapy and splint immobilisation. After we had seen severest phlegmonous reactions after irrigation with Octenisept followed by long troublesome histories we would like to warn against using this antiseptic agent for irrigation of wounds. We give an overview about the significance of antiseptics and the use of antibiotics in the treatment of deeper contaminated wounds. PATIENTS AND METHODS: Between 2003 and 2007, 5 children (aged 2 to 8 years) were treated for sequelae of local wound irrigation with Octenisept in perforating hand injuries. We describe the early and medium term aspects after irrigation, the further development, therapeutic measures, long-term damages and necessary reconstructions. We present the results of bacteriological smear tests, laboratory reports and histological examinations as well as allergy tests. RESULTS: All children showed more or less identical hand appearances. Hands were swollen caused by an interstitial oedema, compartment pressures were increased and hand function was completely suspended. The oedemas persisted for weeks and were hardly controllable. Especially serious were injuries at thenar level and in the first web space. Long-term sequelae were contractures caused by fibrotic muscle changes. Neither through bacteriological nor histological analysis were hints of bacterial or viral infections found. An allergic reaction to Octenisept could be excluded in the 3 most heavily affected children by an ROAT test. CONCLUSION: To prevent damage, contaminated wounds should be operatively debrided and not be irrigated with an antiseptic liquid. Octenisept seems to have a toxic effect in non-distinguished tissue. Because of a slow resorption it remains for a long time in the tissue. For therapy we recommend fasciotomy of the mid-hand and probably finger compartments, followed by compression treatment, physiotherapy with lymphatic drainage, dynamic and static splints. PMID- 19790021 TI - [Non-tuberculous mycobacterial infections of the hand and wrist: a retrospective review of five cases from a single centre]. AB - PURPOSE: A suggestion for a graduated diagnostic and therapeutic approach for patients with a suspected infection with non-tuberculous mycobacteria (NTM) of the hand and wrist is made. PATIENTS AND METHODS: Between March 2003 and February 2007, 2 women and 3 men with an average age of 64 years were treated for an NTM infection of the hand and wrist. 4 patients had a tenosynovitis of the wrist. In 1 patient both wrists were involved. 1 patient had a granuloma of the index finger. The patients' charts, the operation reports, histological and bacteriological findings and the antibiogram were evaluated. RESULTS: An inoculating trauma was identified in four patients. Intraoperatively rice bodies were present in the 4 patients with a tenosynovitis of the wrist. Histological findings showed acid-fast bacilli in 2 patients and chronic inflammatory reaction with/without granuloma (3/2) in 5 patients. Species identification was based on PCR and microbiological culture and revealed in three patients slow growing species (M. malmoense, M. nonchromogenicum, M. szulgai) and in two patients M. marinum (intermediate growth rate). Therapy consisted of immediate postoperative empirical combined drug treatment followed by antibiogram-based therapy. All patients showed healing of the infection at the final follow-up at an average of 25.2 months (range: 15-44 months) postoperatively. CONCLUSION: Consideration of non-tuberculous mycobacteria in the differential diagnosis in cases of localised tenosynovitis is paramount for diagnosis. Treatment based on graduated diagnostic steps, surgery and drugs (empirical followed by directed drugs) can achieve favourable clinical outcomes. PMID- 19790022 TI - [Necrotising fasciitis of the hand--a rare, highly dramatic clinical entity]. AB - The necrotising fasciitis (NF) is a rare syndrome in hand surgery which is characterized by a severe course of the illness. Different kinds of bacterial species are responsible for the pathogenetic origin of the NF. As NF can be life threatening for the patient, immediate surgical and systemic treatment must begin as soon as there is the slightest clinical suspicion. We report about two patients with NF of the hand, whereby the patients' lives were saved by radical, serial debridements, intensive medical therapy and selective antibiotic treatment. PMID- 19790023 TI - [MRSA infection of the hand in immunodeficient patients]. AB - Increased Methicillin resistant Saphylcoccus aureus (MRSA)-colonisation/infection is described worldwide. MRSA distribution is important for health economics. We report a case of a MRSA-infection of the hand in a 72 years old immunodeficient patient. PMID- 19790024 TI - [Palmar wrist arthroscopy for evaluation of concomitant carpal lesions in operative treatment of distal intraarticular radius fractures]. AB - Fractures of the distal radius, which currently are treated with palmar locking plates, are often accompanied by carpal lesions. Tears of the scapholunate interosseus ligament (SL) can affect the outcome. Between January 2007 and May 2008, 28 patients with distal intraarticular fractures of the radius were included in a prospective study. Preoperative CT-arthrography was performed. SL tears were found in 11 patients, with 10 partial and one complete rupture observed. A tear of the triangular fibrocartilage complex (TFCC) was detected in 16 patients. Every patient was operated with a palmar locking plate through a palmar approach between the flexor carpi radialis tendon and the radial artery. Then, a palmar wrist arthroscopy using a palmar portal was performed. Eleven SL tears with 9 partial and two total ruptures were diagnosed by arthroscopy. Ten lesions were associated with a C1-fracture with a fracture line projected onto the scapholunate interval. The TFCC was appraisable by palmar wrist arthroscopy only in 4 patients. Three of the SL tears detected by CT-arthrography could not be confirmed by palmar wrist arthroscopy. One complete rupture and one partial lesion confirmed by palmar wrist arthroscopy were found by CT-arthrography to be intact. Palmar wrist arthroscopy affords certainty when assessing the SL ligament. In this study, an assessment of ulnocarpal structures was not possible. For assessment of the ulnocarpal structures, CT-arthrography was superior to palmar wrist arthroscopy. However, the latter is an alternative during emergency treatment or when CT-arthrography is not available. PMID- 19790025 TI - [The operative treatment of rhizarthrosis with pyrocarbon spacer as replacement of the trapezium]. AB - PURPOSE: The aim of this work was to point out the meaning of pyrocarbon spacer as replacement of the trapezium in case of rhizarthrosis. PATIENTS/MATERIAL AND METHOD: 32 Patients (20 female, 12 male) provided in our department between January 2005 and June 2008 with pyrocarbon spacer as replacement of the trapezium as a result of a radiologic as well as clinical documented rhizarthrosis. To rate the therapy a clinical and radiological examination was done and the score of Buck-Gramcko was used. Because of a complication in two patients the spacer was taken out and a suspension arthroplasty was done. Those two patients were not considered in the study. RESULTS: 80% good and very good results according to the score of Buck-Gramcko, 13.3% of satisfactory and 6.7% bad results were obtained. Dislocation of the implant is the main complication of the presented procedure. CONCLUSION: With the presented procedure it is possible to achieve in the majority of the treated patients good and very good results. 4 dislocations in the examined collective and the price of the implant of 930 Euro has to be discussed critically. PMID- 19790026 TI - [Sensory nerve function after unilateral digital vascular-nerve injury: nerve repair with and without arterial repair]. AB - PURPOSE: This study compares the clinical results of microsurgical nerve repairs in unilateral digital arterial-nerve-injuries with and without repair of the finger artery. PATIENTS AND METHODS: Between January 2000 and May 2007 a total of 81 patients with unilateral digital vascular nerve bundle lesions, including concomitant soft-tissue tendon lesions, were operated on the emergency day. Forty of the 56 patients treated with a nerve repair alone took part in a follow-up after an average of 47 (7-87) months. Twenty of the 25 patients treated with a microsurgical arterial and nerve repair took part in a follow-up after an average of 12 (6-66) months; 3 patients were excluded due to a negative digital Allen test. In addition to anamnestic data, peripheral nerve function was evaluated by the static and the moving two-point discrimination test, and by Semmes-Weinstein pressure aesthesiometer in the autonomous zone of the affected side of the injured finger. Stereognosis also was examined. The patency of the reconstructed digital artery was tested by a digital Allen-test. RESULTS: No statistically significantly worse results were found in patients with a nerve repair alone compared to patients with additional repair of the finger artery. CONCLUSION: Repair of the finger artery therefore appears to offer no improvement of the clinical outcome following nerve repair in unilateral injury of a digital arterial-nerve bundle. PMID- 19790028 TI - [Predictive power on therapy engagement in personality disorders: SWAP- 200 versus SCID-II]. AB - The study compares the predictive power of the Shedler-Westen-Assessment Procedure-200 with the Structured Clinical Interview for DSM-IV on engagement in (psychoanalytic) psychotherapy within 297 patients with personality disorders in a 4-year-follow-up. Multinomial logistic regression showed small differences between the prediction rates in the cross-validated data. Both instruments showed clinically useful prediction rates for treatment rejecters: SWAP scales led to correct predictions with dysphoric traits as semi-stable predictors for rejecters, while SCID scales led to correct predictions with Negativistic, Depressive and Schizotypal PD as stable predictors. Results are discussed under the aspect of advantages and disadvantages of the SWAP-200 diagnostic procedure, which includes the assessment of affect-experience, defence-organisation, and object-relation-style. PMID- 19790029 TI - Cat scratch disease--heterogeneous in clinical presentation: five unusual cases of an infection caused by Bartonella henselae. AB - BACKGROUND: Cat-scratch disease (CSD) is common in children, however the wide spectrum of the clinical presentation of CSD may lead to delayed diagnosis. An atypical presentation of CSD includes in its differential diagnosis diseases such as tuberculosis, other mycobacterioses, Epstein-Barr-Virus infection (EBV) or malignant disease. Since, in a small number of cases, these diseases may be present concurrently with an active CSD, it is important to consider CSD early in the differential diagnosis and order the appropriate tests. These tests include serology and, where possible, histology including molecular diagnostic methods on tissue specimens. PATIENTS AND METHOD: We performed a case series of five patients treated in our hospital with a clinical diagnosis of cat-scratch disease, confirmed by serology. An analysis of the history and clinical symptoms associated specifically with an atypical presentation of CSD was performed. RESULTS: The clinical presentation of CSD no longer encompasses the original typical description from 1950, but rather presents with a wide spectrum of signs and symptoms, including the absence of a documented cat scratch, fever, primary lesions or peripheral lymphadenopathy. Low density lesions in spleen, liver and lymph nodes are typical findings in ultrasound, MRI, or CT. Ignoring CSD as a possibility in investigating possible malignancy or tuberculosis could lead to unnecessary hospitalisation and delay in the proper treatment. CONCLUSION: CSD should also be considered in differential diagnosis of any patient with intraabdominal lymphadenopathy, abdominal pain and fever of unknown origin. A careful history is important, however, often patients with CSD have no history of contact with cats. Therefore in atypical cases of CSD the finding of other clinical symptoms and performance of specific diagnostic tests is important. Our experience suggests that early serological testing for Bartonella henselae should be performed and may avoid invasive diagnostic procedures. PMID- 19790030 TI - Anti-herpetic properties of hydroalcoholic extracts and pressed juice from Echinacea pallida. AB - Hydroalcoholic extracts and pressed juice from Echinacea pallida were phytochemically characterised by HPLC-MS analyses. Ferulic and caffeic acid derivatives were identified as major constituents. All tested extracts and pressed juice from Echinacea pallida exhibited a low cytotoxic activity on monkey kidney cells in vitro. The inhibitory activity of Echinacea against herpes simplex virus types 1 and 2 (HSV-1, HSV-2) was analysed with plaque reduction assays. All hydroalcoholic extracts exhibited high levels of antiviral activity against both types of herpesvirus in a dose-dependent manner. Plaque formation was significantly reduced by more than 99 % or completely absent. Pressed juice from E. pallida revealed the highest antiviral activity against HSV-1 and HSV-2 when compared to hydroalcoholic Echinacea extracts and even highly diluted Echinacea pressed juice still inhibited viral infectivity. Hydroalcoholic extracts were quite active against herpetic infection when HSV-1 or HSV-2 were pretreated with the extracts. In contrast, Echinacea pressed juice revealed antiviral activity during all phases of the viral replication cycle. Additionally, Echinacea pressed juice demonstrated protection of cells against viral infection. In conclusion, hydroalcoholic E. pallida extracts interfere with free herpesvirus but pressed juice is able to interact with herpesvirus inside and outside the cell as well as to protect cells against viral infection, probably by interfering with virus attachment. Hydroalcoholic extracts and pressed juice from E. pallida demonstrated high selectivity indices, a necessary prerequisite for a potential topical treatment of herpetic infections. Different types of Echinacea preparations, such as commercial tinctures, tablets, and teas, are expected to offer different antiviral profiles. PMID- 19790031 TI - Metabolomic profiling of liquid Echinacea medicinal products with in vitro inhibitory effects on cytochrome P450 3A4 (CYP3A4). AB - ECHINACEA is a popular and widely used herbal medicinal product and consequently, studies of its interactions with conventional drugs are of particular importance. We have shown that ECHINACEA preparations and some common alkylamides weakly inhibit several cytochrome P450 (CYP) isoforms, with considerable variation in potency. We now report a detailed analysis of six commercial ECHINACEA liquid preparations, with emphasis on the metabolomic characterisation of the ECHINACEA compounds responsible for inhibiting CYP3A4. We separated each preparation into its ethanol- and water-soluble components, and then used (1)H-NMR together with multivariate data analysis and partial least square regression analysis to investigate the nature of the compounds responsible for CYP3A4 inhibition. The results implicated alkylamides in the CYP3A4 inhibitory activity of ECHINACEA. One of the commercial preparations (Echinaforce(R)) was further fractionated using solid phase extraction. Analysis by (1)H-NMR and mass spectroscopy (LC/MS, tandem MS, accurate mass) identified dodeca-2 E,4 E,8 Z,10 E/Z-tetraenoic acid (alkylamide 1) and a new compound (putative molecular formula C (18)H (36) NO (+)) as major components of the inhibitory fractions. In addition, the alkylamide content of all six preparations was determined by reverse phase HPLC. Levels of alkylamides 1 and 3 (undeca-2 E,4 E/ Z-diene-8,10-diynoic acid isobutylamide), correlated well with CYP3A4 inhibition. The acetylene tetradeca-8 Z-ene-11,13 diyn-2-one was shown to be present in the E. PURPUREA as well as the E. PALLIDA extracts. E. PURPUREA unlike E. PALLIDA was thought to not contain significant amounts of acetylenes. Our results directly confirm the role of alkylamides in the inhibition of CYP3A4 by ECHINACEA and uncovered a new compound which may also be involved. Extensive differences in the composition of the commercially available preparations were found. This will inevitably impact on the product efficacy, safety and pharmacological effects, especially since the differences involve alkylamides, an important class of ECHINACEA's active constituents. The metabolomic approach presented here may prove valuable as a screening or quality control tool. PMID- 19790032 TI - Potent in vitro inhibition of CYP3A4 and P-glycoprotein by Rhodiola rosea. AB - Six clones of RHODIOLA ROSEA, obtained from plants originating from widely different areas in Norway, were investigated for their IN VITRO inhibitory potential on CYP3A4-mediated metabolism and P-gp efflux transport activity. Presumed active constituents in the ethanol extracts of the different clones were quantified. C-DNA baculovirus expressed CYP3A4 and Caco-2 cells were used for inhibitory assays, and as positive control inhibitors ketoconazole and verapamil were applied, respectively. A validated HPLC methodology was used to quantify the formation of 6-beta-OH-testosterone and scintillation counting was used to quantify the transport of (3)H-digoxin in Caco-2 cells. All clones showed potent inhibition of CYP3A4 and P-gp activities, with IC (50) values ranging from 1.7 to 3.1 microg/mL and from 16.7 to 51.7 microg/mL, respectively, being below that reported for other herbs and some known classic drug inhibitors, such as St. John's wort and fluoxetine. RHODIOLA ROSEA might thus be a candidate for clinically relevant drug interactions. The concentration of presumed biologically active constituents in the different clones varied considerably, but this variation was not related to the clones' inhibitory potential on CYP3A4 or P-gp activities. Other constituents might thus be responsible for the observed inhibitory properties. The place of origin seemed to be of minor importance for CYP3A4 or P-gp inhibition. PMID- 19790033 TI - A simplified method for identifying the Panax ginseng cultivar Gumpoong based on 26S rDNA. AB - Molecular identification of PANAX GINSENG (Korean ginseng) cultivars is very important for their management. We have developed a simple and reliable method for specific identification of the superior cultivar "Gumpoong." The 26S rDNA was targeted for our molecular analysis, and a single-nucleotide polymorphism (SNP) was identified between Gumpoong and the other cultivars within the sequence data. From this SNP site, a modified allele-specific primer and a novel primer set have been developed to identify the Gumpoong cultivar via multiplex PCR. The established multiplex PCR method was determined to be effective, and the SNP marker showed high specificity to Gumpoong. Therefore, the described method may serve as a useful tool for rapid selection of Gumpoong cultivar. PMID- 19790034 TI - Three new phenolic glycosides and a new triterpenoid from the stems of Scolopia chinensis. AB - Three new phenolic glycosides, scolochinenosides C-E ( 1- 3), and a new triterpenoid, scolopianate A ( 4), were isolated from the stems of SCOLOPIA CHINENSIS, along with 15 known compounds. The structures of the new compounds were elucidated by means of extensive spectroscopic and chemical methods. Compound 3 contains a novel highly oxygenated lactone bridge ring attached at the aglycone. Six lanostane triterpenoids ( 10- 15) were discovered for the first time in a species other than GANODERMA LUCIDUM (Polyporaceae). In addition, the phenolic glycosides were evaluated for their inhibitory activity against snake venom phosphodiesterase I. PMID- 19790035 TI - Anisodamine production from natural sources: seedlings and hairy root cultures of Argentinean and Colombian Brugmansia candida plants. AB - The tropane alkaloid anisodamine ( 2) is obtained by 6 beta-hydroxylation of hyoscyamine ( 1). The application of this alkaloid in medicine is gaining attention due to the wide range of therapeutic applications described in addition to its anticholinergic activity. In this work, the production of anisodamine ( 2) by IN VITRO cultures of BRUGMANSIA CANDIDA (Argentinean and Colombian samples) was studied. This alkaloid was estimated in different organs of IN VITRO germinated seedlings as well as in hairy roots obtained from seedlings from both sources. Colombian roots exhibited the highest content of tropane alkaloids, with anisodamine ( 2) being the main alkaloid measured. In the leaves, the main alkaloid was scopolamine ( 3) and no significant differences were observed between Argentinean and Colombian leaves. The tropane alkaloid content in Argentinean hairy roots was significantly higher than in Colombian ones. Also, in the Argentinean samples the main alkaloid detected was anisodamine ( 2). Argentinean and Colombian B. CANDIDA seedlings and hairy roots appear to be a promising system for the production of anisodamine ( 2). PMID- 19790036 TI - [Pulmonary hypertension in hereditary haemorrhagic teleangiectasia]. AB - BACKGROUND: In hereditary haemorrhagic teleangiectasia (HHT) can be accompanied by pulmonary arteriovenous vascular malformations (PAVM). Pulmonary hypertension (PH) is regarded as a rare pulmonary manifestation. METHODS AND PATIENTS: We non invasively assessed the pulmonary circulation in 20 patients with HHT using standard resting echocardiography including contrast studies. In 14 patients a mutation in the endoglin gene was present. The other 6 patients carried a mutation in the Alk-1 gene. RESULTS: We identified 4 patients with manifest PH, among them 2 patients (both with endoglin mutations) with concurrent thromboembolism, and 2 patients (both with Alk-1 mutations) with hepatic manifestations of HHT. Two patients required specific pulmonary vasoactive therapy with sildenafil and bosentan, respectively. Another patient received embolisation therapy for hypercirculatory PH due to hepatic arteriovenous malformations. Pulmonary arteriovenous malformations were found in 8 patients (7 with endoglin, and 1 with Alk-1 mutations), among them were 2 patients with PH. CONCLUSIONS: Patients with HHT should undergo echocardiographic screening for PAVM as well as PH. When PH is detected, other conditions such as hepatic or thromboembolic diseases should be considered, regardless of the underlying genetic defect. PMID- 19790037 TI - [What questions do headache patients pose in the internet? Content analysis of an internet expert forum]. AB - BACKGROUND: Most episodes of headache are not presented to doctors but are treated by self-management. Especially in these cases, the Internet has become an increasingly important source of health-care information. The aim of this study was to investigate the questions and needs of persons who sought help for their headache in an internet expert forum. METHODS: Using a content analysis approach, we analysed all questions sent to an internet expert forum for migraine and headache ( www.lifeline.de ). RESULTS: We analysed a total of 835 questions sent from April 2002 until April 2006. The majority of questions (85%) came from women. Most often the visitors asked questions about symptoms (32.2%, n=269), drugs or therapies (32.0%) and psychosocial problems (20%). Few visitors (45/835) complained about their doctors. Some of these were dissatisfied with their therapy and/or the effect and possible side effects of their prescribed drugs. In 19 questions we detected communication problems in former consultations with their doctors. CONCLUSION: Visitors of an expert forum for migraine and headache had questions about symptoms and their interpretation as well as drugs and therapies. Dissatisfaction with current treatment motivated only few patients to turn to the Internet. For most visitors the expert forum is obviously not an alternative but a supplement to professional care. PMID- 19790038 TI - [Access to health care by level of education. A comparative analysis of access regulation and utilisation of specialist healthcare in Europe]. AB - Equal access to health care is a central goal of all European health-care systems. International studies, however, show that this goal has not been accomplished yet. The aim of this study is to investigate if there are inequalities across patients with different levels of education and if these differences vary with the institutional set-up of health-care systems. The test of this hypothesis is based on a comparison of eleven European countries using data from the SHARE survey (Survey of Health, Ageing and Retirement in Europe). Our results show that in countries with institutionalised gatekeeping systems differences of utilisation between educational groups are rather low. In countries with free access to specialists, patients with higher levels of education show a higher probability of specialist visits than their counterparts with lower levels of education. PMID- 19790039 TI - [Relationship between health-related quality of life and multimorbidity]. AB - OBJECTIVES: Changed morbidity patterns in many industrialised countries lead to new requirements concerning the health-care process. In contrast to a complete cure and due to increasing (multiple) chronic conditions with longevity, the alleviation of complaints and thereby securing the health-related quality of life (HRQoL) is coming more and more into the focus of efforts. The objective of this review is to analyse the effects of (multiple) chronic conditions on HRQoL. Another aim is to ascertain to what extent the number and specific combination of conditions have an impact on HRQoL. METHODS: This review is based on a systematic literature search using MeSH terms in Medline/Pubmed and several publisher databases. Inclusion criteria focus particularly on the relationship between multimorbidity and HRQoL. RESULTS: Findings of the literature search clearly show that existing chronic conditions have a negative impact on HRQoL. Most studies conclude that the quality of life decreases with an increasing number of diseases. In comparison to mental or social dimensions, the inverse relationship between multimorbidity and HRQoL is significantly stronger in physical dimensions. Particularly cardiovascular diseases and musculoskeletal disorders result in severe losses of HRQoL. Furthermore, the HRQoL is reduced by specific disease combinations. Patterns of disease combinations influence the degree of HRQoL loss, as well. CONCLUSION: A clear understanding of the impacts of multimorbidity and specific morbidity patterns on the different dimensions of HRQoL can help to optimise the health-care process for the patients benefit. This optimised process should not separate between single diagnoses, but focus on the concurrence of multiple conditions having regard to patient-relevant outcome HRQoL. For example, one potential is to focus efforts on key conditions in the cooccurrence of multiple diseases (like musculoskeletal disorders). The current state of research on specific morbidity patterns and their impacts on HRQoL is limited. Especially for the German-speaking areas further analyses are needed. PMID- 19790041 TI - [Scientific publishing--room for improvement]. PMID- 19790040 TI - [Neuroenhancement: doping for the brain]. PMID- 19790042 TI - Local formation of angiotensin peptides with paracrine activity by adipocytes. AB - A local paracrine angiotensin (ANG) system influences the insulin sensitivity and cell differentiation of adipose tissue. The limited view of a merely systemic renin-angiotensin-aldosterone-system with ANG II (1-8) as the main mediator of ANG-related effects may oversimplify the situation. The aim was to analyze the degradation of ANG by using capillary electrophoresis (CE) techniques. The supernatant of cultured 3T3-L1 adipocytes was used directly, and some data on degraded peptides were combined with a biological effect. The formation of several peptides such as ANG II (1-8), -III (2-8), -IV (3-8), and ANG (1-7) as degradation products is demonstrated; in addition low levels of ANG (3-7) are identified. The concentrations of the peptides ANG III (2-8) and ANG IV (3-8) (both are AT(4) receptor agonists) are modified in the vicinity of adipose tissue cells by amino-terminal degradation which resulted in ANG (3-8), -(4-8) and -(5 8). ANG IV (3-8) and ANG II (1-8) were biologically highly effective in inhibiting IRAP (insulin regulated aminopeptidase, part of the AT(4) receptor). It is observed that ANG (1-7) is the main degradation product derived from ANG I via ANG (1-9) and that ANG III (2-8) is one important regulated peptide for IRAP. PMID- 19790043 TI - Efficient method of circumventing insolubility problems with fully protected peptide carboxylates via in situ direct thioesterification reactions. AB - A straightforward and convenient protocol is presented for the direct thioesterification of fully protected peptide C-terminal carboxylates synthesized by Fmoc strategy. This methodology specifically serves to overcome the frequent insolubility problem of these fully protected carboxolate isolates during the thioesterification process by carrying out the reaction as an in situ procedure on the freshly cleaved 1% TFA/DCM solution of carboxylate. The direct thioesterification of a number of insolubility prone peptide systems is explored and compared with some control systems for ease of conversion to the corresponding thioesters. It is shown that although the fully protected carboxylates are indeed insoluble to varying degrees in the thioesterification reactions carried out using the classical approach, full dissolution is maintained and complete conversion is evident using the in situ methodology. This protocol serves to remove a frequent stumbling block in the preparation of peptide thioesters via the direct approach, allowing for facile entry into previously difficult systems traditionally unapproachable through this method. PMID- 19790045 TI - Mechanical injury potentiates proteoglycan catabolism induced by interleukin-6 with soluble interleukin-6 receptor and tumor necrosis factor alpha in immature bovine and adult human articular cartilage. AB - OBJECTIVE: Traumatic joint injury can damage cartilage and release inflammatory cytokines from adjacent joint tissue. The present study was undertaken to study the combined effects of compression injury, tumor necrosis factor alpha (TNFalpha), and interleukin-6 (IL-6) and its soluble receptor (sIL-6R) on immature bovine and adult human knee and ankle cartilage, using an in vitro model, and to test the hypothesis that endogenous IL-6 plays a role in proteoglycan loss caused by a combination of injury and TNFalpha. METHODS: Injured or uninjured cartilage disks were incubated with or without TNFalpha and/or IL-6/sIL-6R. Additional samples were preincubated with an IL-6-blocking antibody Fab fragment and subjected to injury and TNFalpha treatment. Treatment effects were assessed by histologic analysis, measurement of glycosaminoglycan (GAG) loss, Western blot to determine proteoglycan degradation, zymography, radiolabeling to determine chondrocyte biosynthesis, and Western blot and enzyme linked immunosorbent assay to determine chondrocyte production of IL-6. RESULTS: In bovine cartilage samples, injury combined with TNFalpha and IL-6/sIL-6R exposure caused the most severe GAG loss. Findings in human knee and ankle cartilage were strikingly similar to those in bovine samples, although in human ankle tissue, the GAG loss was less severe than that observed in human knee tissue. Without exogenous IL-6/sIL-6R, injury plus TNFalpha exposure up-regulated chondrocyte production of IL-6, but incubation with the IL-6-blocking Fab significantly reduced proteoglycan degradation. CONCLUSION: Our findings indicate that mechanical injury potentiates the catabolic effects of TNFalpha and IL-6/sIL 6R in causing proteoglycan degradation in human and bovine cartilage. The temporal and spatial evolution of degradation suggests the importance of transport of biomolecules, which may be altered by overload injury. The catabolic effects of injury plus TNFalpha appeared partly due to endogenous IL-6, since GAG loss was partially abrogated by an IL-6-blocking Fab. PMID- 19790046 TI - The melanocortin system in articular chondrocytes: melanocortin receptors, pro opiomelanocortin, precursor proteases, and a regulatory effect of alpha melanocyte-stimulating hormone on proinflammatory cytokines and extracellular matrix components. AB - OBJECTIVE: The pro-opiomelanocortin (POMC)-derived neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) mediates its effects via melanocortin (MC) receptors. This study was carried out to investigate the expression patterns of the MC system and the effects of alpha-MSH in human articular chondrocytes. METHODS: Articular chondrocytes established from human osteoarthritic joint cartilage were analyzed by reverse transcription-polymerase chain reaction (RT PCR) and Western blotting for the expression of MC receptors, POMC, and prohormone convertases (PCs). MC-1 receptor (MC-1R) expression in articular cartilage was further studied by immunohistochemistry. Ca(2+) and cAMP assays were used to monitor alpha-MSH signaling, while studies of alpha-MSH function were performed in cultures with chondrocyte micromass pellets stimulated with alpha-MSH. Expression of cytokines and extracellular matrix (ECM) components was determined by real-time RT-PCR, Western immunoblotting, and enzyme-linked immunosorbent assays. RESULTS: MC-1R expression was detected in articular chondrocytes in vitro and in articular cartilage in situ. In addition, expression of transcripts for MC-2R, MC-5R, POMC, and PCs was detected in articular chondrocytes. Stimulation with alpha-MSH increased the levels of intracellular cAMP, but not Ca(2+), in chondrocytes. Both messenger RNA and protein expression of various proinflammatory cytokines, collagens, matrix metalloproteinases (MMPs), and SOX9 was modulated by alpha-MSH. CONCLUSION: Human articular chondrocytes are target cells for alpha-MSH. The effects of alpha-MSH on expression of cytokines and MMPs suggest that this neuropeptide plays a role in inflammatory and degenerative processes in cartilage. It is conceivable that inflammatory reactions can be mitigated by the induction of endogenous MCs or administration of alpha-MSH to the affected joints. The induction pattern of regulatory and structural ECM components such as collagens as well as SOX9 and anabolic and catabolic cytokines points to a function of alpha-MSH as a trophic factor in skeletal development during endochondral ossification rather than as a factor in homeostasis of permanent cartilage. PMID- 19790047 TI - Continuous occurrence of both insufficient neovascularization and elevated vascular permeability in rabbit proximal femur during inadequate repair of steroid-associated osteonecrotic lesions. AB - OBJECTIVE: To examine the features of the intraosseous vasculature, the size of the marrow stem cell pool (MSCP), and expression of vascular endothelial growth factor A (VEGF) during inadequate repair of steroid-associated osteonecrotic lesions in rabbits. METHODS: Steroid-associated osteonecrosis was induced in male rabbits. At 0, 1, 2, 4, and 6 weeks postinduction, vascularization and permeability indices were quantified by dynamic magnetic resonance imaging (MRI). In addition, the size of the MSCP in the hematopoietic and mesenchymal compartments was determined, and marrow mononuclear cells expressing specific surface markers for endothelial progenitor cells or periendothelial mural precursor cells were counted. At various time points after the rabbits were killed, the proximal femora were dissected to examine the intraosseous vasculature by angiography, histomorphometry, and ultramorphology. In addition, osteonecrotic lesion repair and marrow VEGF expression were evaluated. RESULTS: Lesion formation without repair was observed at 2 weeks after induction of steroid-associated osteonecrosis. Rabbits displaying destructive repair (DR+) and those displaying reparative osteogenesis (DR-) from 4 weeks to 6 weeks postinduction were identified. From week 2 to week 6, the vascularization index was significantly lower in DR+ rabbits compared with DR- rabbits, whereas the permeability index was significantly higher in DR+ rabbits compared with DR- rabbits. The features of the intraosseous vasculature determined by angiography, histomorphometry, and ultramorphology were consistent with those determined by dynamic MRI. The MSCP size and number of marrow mononuclear cells expressing specific surface markers were all significantly lower in DR+ rabbits than in DR- rabbits from week 1 to week 6. The increased VEGF expression at 2 weeks was maintained through week 6 in DR+ rabbits, whereas VEGF expression decreased in DR rabbits from week 2 to week 6. CONCLUSION: Continuous occurrence of both insufficient neovascularization and elevated vascular permeability is accompanied by a continuously low- level MSCP and uncontrolled VEGF expression during inadequate repair of steroid-associated osteonecrotic lesions. PMID- 19790048 TI - Hypoxia-inducible factor 1alpha inhibits the fibroblast-like markers type I and type III collagen during hypoxia-induced chondrocyte redifferentiation: hypoxia not only induces type II collagen and aggrecan, but it also inhibits type I and type III collagen in the hypoxia-inducible factor 1alpha-dependent redifferentiation of chondrocytes. AB - OBJECTIVE: Autologous chondrocyte implantation requires expansion of cells ex vivo, leading to dedifferentiation of chondrocytes (loss of aggrecan and type II collagen to the profit of type I and type III collagens). Several approaches have been described for redifferentiation of these cells. Among them, low oxygen tension has been exploited to restore the differentiated chondrocyte phenotype, but molecular mechanisms of this process remain unclear. However, under conditions of hypoxia, one of the major factors involved is hypoxia-inducible factor 1alpha (HIF-1alpha). The purpose of this study was to investigate the role of HIF-1alpha during human chondrocyte redifferentiation. METHODS: We used complementary approaches to achieving HIF-1alpha loss (inhibition by cadmium ions and dominant-negative expression) or gain (ectopic expression and cobalt ion treatment) of function. Expression of chondrocyte, as well as fibroblast-like, phenotype markers was determined using real-time reverse transcription-polymerase chain reaction and Western blot analyses. Binding activities of HIF-1alpha and SOX9, a pivotal transcription factor of chondrogenesis, were evaluated by electrophoretic mobility shift assays and by chromatin immunoprecipitation assay. RESULTS: We found that hypoxia and HIF-1alpha not only induced the expression of SOX9, COL2A1, and aggrecan, but they simultaneously inhibited the expression of COL1A1, COL1A2, and COL3A1. In addition, we identified the binding of HIF-1alpha to the aggrecan promoter, the first such reported demonstration of this binding. CONCLUSION: This study is the first to show a bimodal role of HIF-1alpha in cartilage homeostasis, since HIF-1alpha was shown to favor specific markers and to impair dedifferentiation. This suggests that manipulation of HIF-1alpha could represent a promising approach to the treatment of osteoarthritis. PMID- 19790049 TI - C1q inhibits immune complex-induced interferon-alpha production in plasmacytoid dendritic cells: a novel link between C1q deficiency and systemic lupus erythematosus pathogenesis. AB - OBJECTIVE: C1q deficiency is the strongest risk factor known for the development of systemic lupus erythematosus (SLE), since almost all humans with a genetic deficiency of C1q develop this disease. Low C1q serum concentration is also a typical finding in SLE during flares, emphasizing the involvement of C1q in SLE pathogenesis. Recent studies have revealed that C1q has a regulatory effect on Toll-like receptor-induced cytokine production. Therefore, we undertook this study to investigate whether C1q could regulate production of interferon-alpha (IFNalpha). METHODS: Peripheral blood mononuclear cells (PBMCs) and plasmacytoid dendritic cells (PDCs) were stimulated with 3 known interferogenic stimuli and cultured with physiologic concentrations of C1q. IFNalpha production was determined by an immunoassay. RESULTS: C1q significantly inhibited PBMC IFNalpha production induced by RNA-containing immune complexes (ICs), herpes simplex virus (HSV), and CpG DNA. C1q also inhibited PDC IFNalpha production induced by ICs and CpG DNA but increased PDC IFNalpha production induced by HSV. The regulatory role of C1q was not specific for IFNalpha but was also seen for interleukin-6 (IL-6), IL-8, and tumor necrosis factor alpha. We demonstrated binding of C1q to PDCs both by surface plasmon resonance interaction analysis and by flow cytometry, and we also demonstrated intracellular detection of 2 C1q binding proteins. CONCLUSION: Our findings contribute to the understanding of why C1q deficiency is such a strong risk factor for SLE and suggest an explanation for the up regulation of the type I IFN system seen in SLE patients. PMID- 19790050 TI - Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis. AB - OBJECTIVE: To test the hypothesis that obesity resulting from deletion of the leptin gene or the leptin receptor gene results in increased knee osteoarthritis (OA), systemic inflammation, and altered subchondral bone morphology. METHODS: Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) female mice compared with wild-type mice were studied, to document knee OA via histopathology. The levels of serum proinflammatory and antiinflammatory cytokines were measured using a multiplex bead immunoassay. Cortical and trabecular subchondral bone changes were documented by microfocal computed tomography, and body composition was quantified by dual x-ray absorptiometry. RESULTS: Adiposity was increased by approximately 10-fold in ob/ob and db/db mice compared with controls, but it was not associated with an increased incidence of knee OA. Serum cytokine levels were unchanged in ob/ob and db/db mice relative to controls, except for the level of cytokine-induced neutrophil chemoattractant (keratinocyte chemoattractant; murine analog of interleukin-8), which was elevated. Leptin impairment was associated with reduced subchondral bone thickness and increased relative trabecular bone volume in the tibial epiphysis. CONCLUSION: Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA. Systemic inflammatory cytokine levels remained largely unchanged in ob/ob and db/db mice. These findings suggest that body fat, in and of itself, may not be a risk factor for joint degeneration, because adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA in female C57BL/6J mice. These results imply a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems. PMID- 19790051 TI - Prevalence of and screening for serious spinal pathology in patients presenting to primary care settings with acute low back pain. AB - OBJECTIVE: To determine the prevalence of serious pathology in patients presenting to primary care settings with acute low back pain, and to evaluate the diagnostic accuracy of recommended "red flag" screening questions. METHODS: An inception cohort of 1,172 consecutive patients receiving primary care for acute low back pain was recruited from primary care clinics in Sydney, Australia. At the initial consultation, clinicians recorded responses to 25 red flag questions and then provided an initial diagnosis. The reference standard was a 12-month followup supplemented with a specialist review of a random subsample of participants. RESULTS: There were 11 cases (0.9%) of serious pathology, including 8 cases of fracture. Despite the low prevalence of serious pathology, most patients (80.4%) had at least 1 red flag (median 2, interquartile range 1-3). Only 3 of the red flags for fracture recommended for use in clinical guidelines were informative: prolonged use of corticosteroids, age >70 years, and significant trauma. Clinicians identified 5 of the 11 cases of serious pathology at the initial consultation and made 6 false-positive diagnoses. The status of a diagnostic prediction rule containing 4 features (female sex, age >70 years, significant trauma, and prolonged use of corticosteroids) was moderately associated with the presence of fracture (the area under the curve for the rule score was 0.834 [95% confidence interval 0.654-1.014]; P = 0.001). CONCLUSION: In patients presenting to a primary care provider with back pain, previously undiagnosed serious pathology is rare. The most common serious pathology observed was vertebral fracture. Approximately half of the cases of serious pathology were identified at the initial consultation. Some red flags have very high false positive rates, indicating that, when used in isolation, they have little diagnostic value in the primary care setting. PMID- 19790052 TI - 18F-fluorodeoxyglucose-positron emission tomography scanning is more useful in followup than in the initial assessment of patients with Erdheim-Chester disease. AB - OBJECTIVE: Erdheim-Chester disease (ECD) is a rare form of non-Langerhans' cell histiocytosis. The aim of this study was to assess the value of whole-body scanning with (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) in a large cohort of ECD patients from a single center. METHODS: We retrospectively reviewed all PET scans performed on 31 patients with ECD who were referred to our department between 2005 and 2008. PET images were reviewed by 2 independent nuclear medicine specialist physicians and were compared with other imaging modalities performed within 15 days of each PET scan. RESULTS: Thirty-one patients (10 women and 21 men; median age 59.5 years) underwent a total of 65 PET scans. Twenty-three patients (74%) were untreated at the time of the initial PET scan, whereas 30 of the 34 followup PET scans (88%) were performed in patients who were undergoing immunomodulatory therapy. Comparison of the initial and followup PET scans with other imaging modalities revealed that the sensitivity of PET scanning varied greatly among the different organs studied (range 4.3-100%), while the specificity remained high (range 69.2-100%). Followup PET scans were particularly helpful in assessing central nervous system (CNS) involvement, since the PET scan was able to detect an early therapeutic response of CNS lesions, even before magnetic resonance imaging showed a decrease in their size. PET scanning was also very helpful in evaluating the cardiovascular system, which is a major prognostic factor in ECD, by assessing the heart and the entire vascular tree during a single session. CONCLUSION: The results of our large, single center, retrospective study suggest that the findings of a FDG-PET scan may be interesting in the initial assessment of patients with ECD, but its greater contribution is in followup of these patients. PMID- 19790054 TI - CD244 is not associated with susceptibility to rheumatoid arthritis and systemic lupus erythematosus in a Korean population. PMID- 19790053 TI - Elevated insular glutamate in fibromyalgia is associated with experimental pain. AB - OBJECTIVE: Central pain augmentation resulting from enhanced excitatory and/or decreased inhibitory neurotransmission is a proposed mechanism underlying the pathophysiology of functional pain syndromes such as fibromyalgia (FM). Multiple functional magnetic resonance imaging studies implicate the insula as a region of heightened neuronal activity in this condition. Since glutamate (Glu) is a major cortical excitatory neurotransmitter that functions in pain neurotransmission, we undertook this study to test our hypothesis that increased levels of insular Glu would be present in FM patients and that the concentration of this molecule would be correlated with pain report. METHODS: Nineteen FM patients and 14 age- and sex matched pain-free controls underwent pressure pain testing and a proton magnetic resonance spectroscopy session in which the right anterior insula and right posterior insula were examined at rest. RESULTS: Compared with healthy controls, FM patients had significantly higher levels of Glu (mean +/- SD 8.09 +/- 0.72 arbitrary institutional units versus 6.86 +/- 1.29 arbitrary institutional units; P = 0.009) and combined glutamine and Glu (i.e., Glx) (mean +/- SD 12.38 +/- 0.94 arbitrary institutional units versus 10.59 +/- 1.48 arbitrary institutional units; P = 0.001) within the right posterior insula. No significant differences between groups were detected in any of the other major metabolites within this region (P > 0.05 for all comparisons), and no group differences were detected for any metabolite within the right anterior insula (P > 0.11 for all comparisons). Within the right posterior insula, higher levels of Glu and Glx were associated with lower pressure pain thresholds across both groups for medium pain (for Glu, r = -0.43, P = 0.012; for Glx, r = -0.50, P = 0.003). CONCLUSION: Enhanced glutamatergic neurotransmission resulting from higher concentrations of Glu within the posterior insula may play a role in the pathophysiology of FM and other central pain augmentation syndromes. PMID- 19790055 TI - Induction of an antiinflammatory effect and prevention of cartilage damage in rat knee osteoarthritis by CF101 treatment. AB - OBJECTIVE: Studies have suggested that rheumatoid arthritis (RA) and osteoarthritis (OA) share common characteristics. The highly selective A(3) adenosine receptor agonist CF101 was recently defined as a potent antiinflammatory agent for the treatment of RA. The purpose of this study was to examine the effects of CF101 on the clinical and pathologic manifestations of OA in an experimental animal model. METHODS: OA was induced in rats by monosodium iodoacetate, and upon disease onset, oral treatment with CF101 (100 microg/kg given twice daily) was initiated. The A(3) adenosine receptor antagonist MRS1220 (100 microg/kg given twice daily) was administered orally, 30 minutes before CF101 treatment. The OA clinical score was monitored by knee diameter measurements and by radiographic analyses. Histologic analyses were performed following staining with hematoxylin and eosin, Safranin O-fast green, or toluidine blue, and histologic changes were scored according to a modified Mankin system. Signaling proteins were assayed by Western blotting; apoptosis was detected via immunohistochemistry and TUNEL analyses. RESULTS: CF101 induced a marked decrease in knee diameter and improved the changes noted on radiographs. Administration of MRS1220 counteracted the effects of CF101. CF101 prevented cartilage damage, osteoclast/osteophyte formation, and bone destruction. In addition, CF101 markedly reduced pannus formation and lymphocyte infiltration. Mechanistically, CF101 induced deregulation of the NF-kappaB signaling pathway, resulting in down-regulation of tumor necrosis factor alpha. Consequently, CF101 induced apoptosis of inflammatory cells that had infiltrated the knee joints; however, it prevented apoptosis of chondrocytes. CONCLUSION: CF101 deregulated the NF-kappaB signaling pathway involved in the pathogenesis of OA. CF101 induced apoptosis of inflammatory cells and acted as a cartilage protective agent, which suggests that it would be a suitable candidate drug for the treatment of OA. PMID- 19790056 TI - Plasmin immunization preferentially induces potentially prothrombotic IgG anticardiolipin antibodies in MRL/MpJ mice. AB - OBJECTIVE: To test the hypothesis, utilizing 2 experimental mouse models, that plasmin is an important autoantigen that drives the production of certain IgG anticardiolipin (aCL) antibodies in patients with the antiphospholipid syndrome. METHODS: BALB/cJ and MRL/MpJ mice were immunized with Freund's complete adjuvant in the presence or absence of human plasmin. The mouse sera were analyzed for production of IgG antiplasmin, IgG aCL, and IgG anti-beta(2)-glycoprotein I (anti beta(2)GPI) antibodies. IgG monoclonal antibodies (mAb) were generated from the plasmin-immunized MRL/MpJ mice with high titers of aCL, and these 10 mAb were studied for their binding properties and functional activity in vitro. RESULTS: Plasmin-immunized BALB/cJ mice produced high titers of IgG antiplasmin only, while plasmin-immunized MRL/MpJ mice produced high titers of IgG antiplasmin, IgG aCL, and IgG anti-beta(2)GPI. Both strains of mice immunized with the adjuvant alone did not develop IgG antiplasmin or IgG aCL. All 10 of the IgG mAb bound to human plasmin and cardiolipin, while 4 of 10 bound to beta(2)GPI, 3 of 10 bound to thrombin, and 4 of 10 bound to the activated coagulation factor X (FXa). Functionally, 4 of the 10 IgG mAb inhibited plasmin activity, 1 of 10 hindered inactivation of thrombin by antithrombin III, and 2 of 10 inhibited inactivation of FXa by antithrombin III. CONCLUSION: Plasmin immunization leads to production of IgG antiplasmin, aCL, and anti-beta(2)GPI in MRL/MpJ mice, but leads to production of only IgG antiplasmin in BALB/cJ mice. IgG mAb generated from plasmin-immunized MRL/MpJ mice bind to various antigens and exhibit procoagulant activity in vitro. These results suggest that plasmin may drive potentially prothrombotic aCL in genetically susceptible individuals. PMID- 19790057 TI - CCR5 is involved in resolution of inflammation in proteoglycan-induced arthritis. AB - OBJECTIVE: CCR5 and its ligands (CCL3, CCL4, and CCL5) may play a role in inflammatory cell recruitment into the joint. However, it was recently reported that CCR5 on T cells and neutrophils acts as a decoy receptor for CCL3 and CCL5 to assist in the resolution of inflammation. The aim of this study was to determine whether CCR5 functions as a proinflammatory or antiinflammatory mediator in arthritis, by examining the role of CCR5 in proteoglycan (PG)-induced arthritis (PGIA). METHODS: Arthritis was induced by immunizing wild-type (WT) and CCR5-deficient (CCR5(-/-)) BALB/c mice with human PG in adjuvant. The onset and severity of PGIA were monitored over time. Met-RANTES was used to block CCR5 in vivo. Arthritis was transferred to SCID mice, using spleen cells from arthritic WT and CCR5(-/-) mice. The expression of cytokines and chemokines was measured by enzyme-linked immunosorbent assay. RESULTS: In CCR5(-/-) mice and WT mice treated with the CCR5 inhibitor Met-RANTES, exacerbated arthritis developed late in the disease course. The increase in arthritis severity in CCR5(-/-) mice correlated with elevated serum levels of CCL5. However, exacerbated arthritis was not intrinsic to the CCR5(-/-) lymphoid cells, because the arthritis that developed in SCID mouse recipients was similar to that in WT and CCR5(-/-) mice. CCR5 expression in the SCID mouse was sufficient to clear CCL5, because serum levels of CCL5 were the same in SCID mouse recipients receiving cells from either WT or CCR5(-/-) mice. CONCLUSION: These data demonstrate that CCR5 is a key player in controlling the resolution of inflammation in experimental arthritis. PMID- 19790058 TI - No increased occurrence of ischemic heart disease prior to the onset of rheumatoid arthritis: results from two Swedish population-based rheumatoid arthritis cohorts. AB - OBJECTIVE: To investigate the relative importance of shared etiologies for rheumatoid arthritis (RA) and ischemic heart disease (IHD) in terms of the well known increased risk of IHD in patients with RA, by assessing the occurrence of IHD up until the time of the onset of the first symptoms of RA. METHODS: We assessed the prevalence of a history of IHD, myocardial infarction (MI), and angina pectoris before the onset of RA symptoms in 2 large population-based case control studies. Patients with newly diagnosed RA according to the criteria of the American College of Rheumatology were included as cases. We used data from the Swedish Early Arthritis Register study and the Swedish Epidemiologic Investigation of Rheumatoid Arthritis case-control study and from general population controls. Information on IHD, MI, and angina pectoris was obtained from the nationwide Hospital Discharge Register and from self reports. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) to compare the prevalence of a history of IHD/MI/angina pectoris among patients with RA with that among population controls. RESULTS: We could not detect any increased occurrence of IHD, MI, or angina pectoris before the onset of symptoms of RA, regardless of whether data on IHD were obtained from the Hospital Discharge Register or were self reported. As detected in the Hospital Discharge Register, the OR for IHD overall was 1.0 (95% CI 0.9-1.1), the OR for MI was 1.0 (95% CI 0.9-1.1), and the OR for angina pectoris was 1.0 (95% CI 0.9-1.2). CONCLUSION: Shared risk factors or susceptibilities for RA and IHD are likely to contribute less than RA-related factors to the increased occurrence of IHD in patients with manifest RA. Nonetheless, the existence of shared factors associated with longer latency until the occurrence of IHD cannot be excluded. PMID- 19790059 TI - Association of immunoglobulin-like transcript 6 deficiency with Sjogren's syndrome. AB - OBJECTIVE: The immunoglobulin-like transcript (ILT) family is located in chromosomal region 19q13 and consists of a group of activating and inhibitory receptors. The ILT receptors are expressed on antigen-presenting cells (macrophages, dendritic cells, B lymphocytes), as well as on T cells and natural killer cells. ILT2 and ILT4 play a role in tolerance induction, and ILT3 has been shown to induce Treg cells. A homozygous deletion of ILT6 has been shown to be associated with multiple sclerosis. Since ILT6 may be a modulator of the immune system, we undertook this study to examine the association of ILT6 deficiency with Sjogren's syndrome (SS). METHODS: We genotyped 149 patients with SS and 749 healthy controls, using polymerase chain reaction to test for the presence or absence of ILT6. RESULTS: Homozygous ILT6 deficiency was detected in 8% of SS patients and in only 3% of controls. CONCLUSION: Our findings indicate that ILT6 deficiency may be a genetic risk factor for SS. PMID- 19790061 TI - Induction of bovine articular chondrocyte senescence with oxidized low-density lipoprotein through lectin-like oxidized low-density lipoprotein receptor 1. AB - OBJECTIVE: Findings of recent in vivo and in vitro studies suggest that oxidized low-density lipoprotein (ox-LDL) plays a role in the degeneration of cartilage. The purpose of this study was to determine whether ox-LDL induces chondrocyte senescence through binding to lectin-like ox-LDL receptor 1 (LOX-1). METHODS: The effects of ox-LDL on senescence of cultured bovine articular chondrocytes (BACs) were investigated by observing senescence-associated (SA) beta-galactosidase (beta-gal) activity, cell proliferation activity, and telomerase activity. Telomerase activity was measured after adding LY294002 (a specific inhibitor of phosphatidylinositol 3-kinase [PI3K]) or after adding insulin-like growth factor 1 (IGF-1; an activator of PI3K) plus ox-LDL to the culture medium to elucidate the involvement of the PI3K/Akt pathway. Immunoblot analysis was used to investigate whether ox-LDL affects the phosphorylation of Akt. To ascertain whether these effects were attributable to ox-LDL binding to LOX-1, BACs were preincubated with TS-20, an anti-bovine LOX-1 blocking antibody. RESULTS: The activity of SA beta-gal was increased and the incorporation of bromodeoxyuridine into BACs was decreased by ox-LDL in a dose-dependent manner. The telomerase activity of BACs was suppressed by the addition of ox-LDL in a time- and dose dependent manner. LY294002 suppressed the telomerase activity of BACs, and IGF-1 reversed the ox-LDL-induced suppression of telomerase activity. In addition, ox LDL rapidly decreased the amount of phosphorylated Akt in BACs. Pretreatment of cultured BACs with TS-20 recovered these effects. CONCLUSION: These data show that ox-LDL binding to LOX-1 induces stress-induced premature senescence of chondrocytes and results in suppression of telomerase activity by inactivating the PI3K/Akt pathway. Oxidized LDL may play an important role in the pathogenesis of osteoarthritis by inducing chondrocyte senescence. PMID- 19790060 TI - Thrombin-activatable carboxypeptidase B cleavage of osteopontin regulates neutrophil survival and synoviocyte binding in rheumatoid arthritis. AB - OBJECTIVE: Osteopontin (OPN) is a proinflammatory cytokine that plays an important role in the pathogenesis of rheumatoid arthritis (RA). OPN can be cleaved by thrombin, resulting in OPN-R and exposing the cryptic C-terminal alpha4beta1 and alpha9beta1 integrin-binding motif (SVVYGLR). Thrombin activatable carboxypeptidase B (CPB), also called thrombin-activatable fibrinolysis inhibitor, removes the C-terminal arginine from OPN-R, generating OPN-L and abrogating its enhanced cell binding. We undertook this study to investigate the roles of OPN-R and OPN-L in synoviocyte adhesion, which contributes to the formation of invasive pannus, and in neutrophil survival, which affects inflammatory infiltrates in RA. METHODS: Using specifically developed enzyme-linked immunosorbent assays, we tested the synovial fluid of patients with RA, osteoarthritis (OA), and psoriatic arthritis (PsA) to determine OPN-R, OPN-L, and full-length OPN (OPN-FL) levels. RESULTS: Elevated levels of OPN-R and OPN-L were found in synovial fluid samples from RA patients, but not in samples from OA or PsA patients. Increased levels of OPN-R and OPN-L correlated with increased levels of multiple inflammatory cytokines, including tumor necrosis factor alpha and interleukin-6. Immunohistochemical analyses revealed robust expression of OPN-FL, but only minimal expression of OPN-R, in RA synovium, suggesting that cleaved OPN is released into synovial fluid. In cellular assays, OPN-FL, and to a lesser extent OPN-R and OPN-L, had an antiapoptotic effect on neutrophils. OPN-R augmented RA fibroblast-like synoviocyte binding mediated by SVVYGLR binding to alpha4beta1, whereas OPN-L did not. CONCLUSION: Thrombin activation of OPN (resulting in OPN-R) and its subsequent inactivation by thrombin-activatable CPB (generating OPN-L) occurs locally within inflamed joints in RA. Our data suggest that thrombin-activatable CPB plays a central homeostatic role in RA by regulating neutrophil viability and reducing synoviocyte adhesion. PMID- 19790062 TI - Parathyroid hormone 1-34 inhibits terminal differentiation of human articular chondrocytes and osteoarthritis progression in rats. AB - OBJECTIVE: Parathyroid hormone 1-34 (PTH[1-34]), a parathyroid hormone analog, shares the same receptor, PTH receptor 1, with parathyroid hormone-related peptide (PTHrP). This study was undertaken to address the hypothesis that PTH(1 34) inhibits terminal differentiation of articular chondrocytes and in turn suppresses the progression of osteoarthritis (OA). METHODS: We studied the effect of PTH(1-34) on human articular chondrocytes with azacytidine (azaC)-induced terminal differentiation in vitro and on papain-induced OA in the knee joints of rats. In the in vitro study, we measured the levels of messenger RNA for SOX9, aggrecan, type II collagen, type X collagen, alkaline phosphatase (AP), Indian hedgehog (IHH), Bcl-2, and Bax by real-time polymerase chain reaction, levels of glycosaminoglycan (GAG) by dimethylmethylene blue assay, and rate of apoptosis by TUNEL staining. In the in vivo study, we evaluated the histologic changes in GAG, type II collagen, type X collagen, and chondrocyte apoptosis in the articular cartilage of rat knees. RESULTS: AzaC induced terminal differentiation of human chondrocytes, including down-regulation of aggrecan, type II collagen, and GAG and up-regulation of type X collagen, alkaline phosphatase, and IHH. Apoptosis was reversed by 3-10 days of treatment with 10 nM PTH(1-34). SOX9 expression was not changed by either azaC or PTH(1-34) treatment. Bcl-2 and Bax were up regulated on day 10 and day 14, respectively, after azaC induction of terminal differentiation, but PTH(1-34) treatment did not reverse this effect. Furthermore, PTH(1-34) treatment reversed papain-induced OA changes (decreasing GAG and type II collagen, and increasing type X collagen and chondrocyte apoptosis) in the knee joints of rats. CONCLUSION: Our findings indicate that PTH(1-34) inhibits the terminal differentiation of human articular chondrocytes in vitro and inhibits progression of OA in rats in vivo, and may be used to treat OA. PMID- 19790063 TI - Prognostic factors in nonoperative therapy for chronic symptomatic calcific tendinitis of the shoulder. AB - OBJECTIVE: To define prognostic factors in chronically symptomatic patients with calcific tendinitis of the shoulder. METHODS: We evaluated 420 patients (488 shoulders) in the context of a prospective cohort study. Epidemiologic data were assessed. The radiographic and sonographic appearance of the calcific deposits was classified. The mean period of nonoperative therapy was 4.4 years (range 0.5 13.7 years). After referral to our institution, standardized nonoperative therapy was continued for a minimum of 3 months. Failure of nonoperative therapy was defined as the persistence of symptomatic calcific tendinitis of the shoulder after a minimum of 6 months. Prognostic factors (determined at P < 0.05 by chi square test) were analyzed by logistic regression. RESULTS: Of the 420 patients, 269 (64%) were women, 151 (36%) were men. The mean age of the patients was 51.3 years (range 28-84 years). Occurrence of calcific tendinitis of the shoulder was unilateral in 84% and bilateral in 16%. Gartner type I calcific deposits were found in 37%, type II in 32%, and type III in 31%. Failure of nonoperative therapy was observed in 114 patients (27%). Negative prognostic factors were bilateral occurrence of calcific tendinitis of the shoulder, localization to the anterior portion of the acromion, medial (subacromial) extension, and high volume of the calcific deposit. Positive prognostic factors were a Gartner type III deposit and a lack of sonographic sound extinction of the calcific deposit. CONCLUSION: Our findings demonstrate the existence of prognostic factors in the nonoperative treatment of chronic symptomatic calcific tendinitis of the shoulder. Guidelines for optimal treatment can be implemented according to these factors to avoid a long-term symptomatic disease course. PMID- 19790064 TI - Recurrence rates of cardiac manifestations associated with neonatal lupus and maternal/fetal risk factors. AB - OBJECTIVE: Identifying the frequency of recurrent cardiac manifestations of neonatal lupus (NL) in a second child is critical to understanding the pathogenesis of anti-SSA/Ro-mediated injury and would improve counseling strategies regarding future pregnancies and power the design of clinical prevention trials. Accordingly, this study was undertaken to address the recurrence rates of cardiac NL and associated risk factors in a large US-based cohort. METHODS: Families enrolled in the Research Registry for Neonatal Lupus were evaluated for rates of recurrence of cardiac NL and potential risk factors, with a focus on pregnancies immediately following the birth of an affected child. RESULTS: The overall rate of recurrence of cardiac NL in 161 pregnancies of 129 mothers with anti-SSA/Ro antibodies was 17.4% (95% confidence interval 11.1 23.6%). Analysis of the potential risk factors among 129 mothers with a pregnancy immediately following the birth of a child with cardiac NL showed that the maternal diagnosis was not associated with the outcome in a subsequent pregnancy. In this group, 23% of mothers who were either asymptomatic or had an undifferentiated autoimmune syndrome, compared with 14% of mothers with systemic lupus erythematosus or Sjogren's syndrome, had a second child with cardiac NL (P = 0.25). The recurrence rate was not statistically significantly different in mothers who had taken steroids compared with those who had not taken steroids (16% versus 21%; P = 0.78). The antibody status of the mother was not predictive of outcome in subsequent pregnancies. Moreover, death of the first child with cardiac NL was not predictive of recurrence of cardiac NL in a subsequent pregnancy (P = 0.31). The risk of cardiac NL was similar between male and female children (17.2% versus 18.3%; P = 1.0). CONCLUSION: In this cohort, the overall recurrence rate for cardiac NL was 17%. The recurrence rate appeared to be unaffected by maternal health, use of steroids, antibody status, severity of cardiac disease in the first affected child, or sex of the subsequent child. PMID- 19790065 TI - Human inflammatory synovial fibroblasts induce enhanced myeloid cell recruitment and angiogenesis through a hypoxia-inducible transcription factor 1alpha/vascular endothelial growth factor-mediated pathway in immunodeficient mice. AB - OBJECTIVE: Hyperplasia and phenotypic changes in fibroblasts are often observed in chronic inflammatory lesions, and yet the autonomous pathogenic contribution of these changes is uncertain. The purpose of this study was to analyze the intrinsic ability of fibroblasts from chronically inflamed synovial tissue to drive cell recruitment and angiogenesis. METHODS: Fibroblasts from patients with rheumatoid arthritis (RA) or osteoarthritis (OA), as well as fibroblasts from healthy synovial tissue and healthy skin, were cultured and subcutaneously engrafted into immunodeficient mice. Cell infiltration and angiogenesis were analyzed in the grafts by immunohistochemical studies. The role of vascular endothelial growth factor (VEGF), CXCL12, and hypoxia-inducible transcription factor 1alpha (HIF-1alpha) in these processes was investigated using specific antagonists or small interfering RNA (siRNA)-mediated down-regulation of HIF 1alpha in fibroblasts. RESULTS: Inflammatory (OA and RA) synovial fibroblasts, compared with healthy dermal or synovial tissue fibroblasts, induced a significant enhancement in myeloid cell infiltration and angiogenesis in immunodeficient mice. These activities were associated with increased constitutive and hypoxia-induced expression of VEGF, but not CXCL12, in inflammatory fibroblasts compared with healthy fibroblasts. VEGF and CXCL12 antagonists significantly reduced myeloid cell infiltration and angiogenesis. Furthermore, targeting of HIF-1alpha expression by siRNA or of HIF-1alpha transcriptional activity by the small molecule chetomin in RA fibroblasts significantly reduced both responses. CONCLUSION: These results demonstrate that chronic synovial inflammation is associated with stable fibroblast changes that, under hypoxic conditions, are sufficient to induce inflammatory cell recruitment and angiogenesis, both of which are processes relevant to the perpetuation of chronic inflammation. PMID- 19790066 TI - Normalization of A2A and A3 adenosine receptor up-regulation in rheumatoid arthritis patients by treatment with anti-tumor necrosis factor alpha but not methotrexate. AB - OBJECTIVE: To investigate A(1), A(2A), A(2B), and A(3) adenosine receptors in lymphocytes and neutrophils from patients with early rheumatoid arthritis (ERA) as well as from RA patients treated with methotrexate (MTX) or anti-tumor necrosis factor alpha (anti-TNFalpha), as compared with those in age-matched healthy controls, and to examine correlations between the status and functionality of adenosine receptors and TNFalpha release and NF-kappaB activation. METHODS: Adenosine receptors were analyzed by saturation binding assays and Western blot analyses. We investigated the potency of typical A(2A) and A(3) agonists in the production of cAMP in control subjects, ERA patients, and RA patients treated with MTX or anti-TNFalpha. In a separate cohort of RA patients, TNFalpha release and NF-kappaB activation were evaluated in plasma and nuclear extracts, respectively. RESULTS: In ERA patients, we found a high density and altered functionality of A(2A) and A(3) receptors. The binding and functional parameters of A(2A) and A(3) receptors normalized after anti-TNFalpha, but not MTX, treatment. TNFalpha release was increased in ERA patients and in MTX-treated RA patients, whereas in anti-TNFalpha-treated RA patients, release was comparable to that in the controls. NF-kappaB activation was elevated in ERA patients and in MTX-treated RA patients. Anti-TNFalpha treatment mediated decreased levels of NF kappaB activation. CONCLUSION: A(2A) and A(3) receptor up-regulation in ERA patients and in MTX-treated RA patients was associated with high levels of TNFalpha and NF-kappaB activation. Treatment with anti-TNFalpha normalized A(2A) and A(3) receptor expression and functionality. This new evidence of A(2A) and A(3) receptor involvement opens the possibility of exploiting their potential role in human diseases characterized by a marked inflammatory component. PMID- 19790067 TI - IgG4-related systemic disease and lymphoplasmacytic aortitis. AB - We describe herein a patient who developed a dissection of the ascending aorta in the setting of IgG4-related systemic disease, linking IgG4-related systemic disease with a newly-recognized subset of noninfectious aortitis. At the time of aortic surgery, a transmural lymphoplasmacytic infiltrate was detected in the patient's aorta, with a principal focus of inflammation within the media. Immunohistochemical studies demonstrated that >50% of the plasma cells in the lesion stained for IgG4. By in situ hybridization, the plasma cells showed polytypic staining for kappa and lambda light chains, consistent with a polyclonal plasma cell infiltrate. Serologic evaluation revealed that the patient's IgG4 levels were elevated nearly 10-fold. Four years before aortic surgery, the patient had undergone a mediastinal lymph node biopsy. Reexamination of the lymph node revealed features consistent with IgG4-related systemic disease, which had not been recognized at the time of the original biopsy. Glucocorticoid therapy for the IgG4-related systemic disease yielded a prompt response. Recognition that IgG4-related systemic disease can involve the ascending as well as the descending abdominal aorta indicates the need for a change in the way idiopathic aortitis is regarded. This case offers new potential considerations for short- and long-term management of noninfectious aortitis, because of the frequent good response of IgG4-related systemic disease to glucocorticoid treatment without additional therapy. Treatment of the aortitis may prevent progression of the IgG4-related systemic disease to involvement of other organs. IgG4-related systemic disease should be considered in all patients with aortitis judged to be of unknown etiology. PMID- 19790068 TI - Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. AB - OBJECTIVE: Transient receptor potential vanilloid 4 (TRPV4) is a Ca(2+)-permeable channel that can be gated by tonicity (osmolarity) and mechanical stimuli. Chondrocytes, the cells in cartilage, respond to their osmotic and mechanical environments; however, the molecular basis of this signal transduction is not fully understood. This study was undertaken to demonstrate the presence and functionality of TRPV4 in chondrocytes. METHODS: TRPV4 protein expression was measured by immunolabeling and Western blotting. In response to TRPV4 agonist/antagonists, osmotic stress, and interleukin-1 (IL-1), changes in Ca(2+) signaling, cell volume, and prostaglandin E(2) (PGE(2)) production were measured in porcine chondrocytes using fluorescence microscopy, light microscopy, or immunoassay, respectively. RESULTS: TRPV4 was expressed abundantly at the RNA and protein levels. Exposure to 4alpha-phorbol 12,13-didecanoate (4alphaPDD), a TRPV4 activator, caused Ca(2+) signaling in chondrocytes, which was blocked by the selective TRPV4 antagonist, GSK205. Blocking TRPV4 diminished the chondrocytes' response to hypo-osmotic stress, reducing the fraction of Ca(2+) responsive cells, the regulatory volume decrease, and PGE(2) production. Ca(2+) signaling was inhibited by removal of extracellular Ca(2+) or depletion of intracellular stores. Specific activation of TRPV4 restored the defective regulatory volume decrease caused by IL-1. Chemical disruption of the primary cilium eliminated Ca(2+) signaling in response to either 4alphaPDD or hypo-osmotic stress. CONCLUSION: Our findings indicate that TRPV4 is present in articular chondrocytes, and chondrocyte response to hypo-osmotic stress is mediated by this channel, which involves both an extracellular Ca(2+) and intracellular Ca(2+) release. TRPV4 may also be involved in modulating the production or influence of proinflammatory molecules in response to osmotic stress. PMID- 19790069 TI - The impact of anterior cruciate ligament injury on lubricin metabolism and the effect of inhibiting tumor necrosis factor alpha on chondroprotection in an animal model. AB - OBJECTIVE: To examine the effects of anterior cruciate ligament transection (ACLT) in a rat model on lubricin metabolism and its relationship to markers of inflammation and cartilage damage, and to determine whether blocking the metabolic effects of tumor necrosis factor alpha (TNFalpha) by etanercept increases the chondroprotection provided by lubricin. METHODS: Unilateral ACLT was performed in Lewis rats. Levels of lubricin, TNFalpha, interleukin-1beta (IL 1beta), and sulfated glycosaminoglycans (sGAG) in synovial fluid (SF) lavage specimens and synovial tissue lubricin gene expression were evaluated at 1 week and 4 weeks following ACLT. Histologic evaluation of articular cartilage included staining with lubricin-specific monoclonal antibody 9G3 and Safranin O. The percentage of lubricin staining on the surface of articular cartilage in weight bearing areas was estimated by digital imaging. Blocking of TNFalpha was performed using etanercept, which was administered subcutaneously at a dose of 0.5 mg/kg around the ACL-transected joints, using different dosing strategies. The ACL-transected and contralateral joints of these rats were harvested 4 weeks following surgery. RESULTS: Four weeks following ACLT, SF lubricin concentrations and the percentage of cartilage surface lubricin staining were significantly lower in the injured joints compared with the contralateral joints. A significant decrease in synovial tissue lubricin gene expression was associated with elevated TNFalpha and IL-1beta concentrations in SF lavage samples. With all of the etanercept treatment strategies, blocking of TNFalpha significantly increased the amount of lubricin bound to cartilage, coupled with a significant decrease in sGAG release. However, changes in the concentrations of lubricin in SF were variable. CONCLUSION: Blocking TNFalpha resulted in a chondroprotective effect, exemplified by increased lubricin deposition on articular cartilage and a decrease in sGAG release from articular cartilage in an animal model of posttraumatic arthritis. PMID- 19790070 TI - Abnormal function of high-density lipoprotein is associated with poor disease control and an altered protein cargo in rheumatoid arthritis. AB - OBJECTIVE: To characterize the antiinflammatory function of high-density lipoprotein (HDL) in patients with rheumatoid arthritis (RA) and to identify specific differences in HDL-associated proteins and enzymes that distinguish proinflammatory HDL from normal, antiinflammatory HDL. METHODS: We studied 132 RA patients. The antiinflammatory function of HDL was assessed by a cell-free assay, and proinflammatory HDL was defined by an HDL inflammatory index > or =1. Plasma and HDL-associated protein levels of apolipoprotein A-I (Apo A-I), haptoglobin, hemopexin, hemoglobin, and myeloperoxidase (MPO) were measured by direct and sandwich enzyme-linked immunosorbent assays, respectively. Lecithin:cholesterol acyltransferase (LCAT) activity was measured by a commercially available assay. RESULTS: Age, disease activity, the presence of erosive disease, non-Caucasian race, and smoking were significantly associated with proinflammatory HDL on multivariate analysis. Patients with proinflammatory HDL had higher measures of systemic inflammation, and a significant correlation was observed between RA disease activity (using the Disease Activity Score in 28 joints) and the HDL inflammatory index (r = 0.54, P < 0.0001). Compared with patients with antiinflammatory HDL, patients with proinflammatory HDL had significantly higher levels of haptoglobin, hemoglobin, Apo A-I, and MPO associated with HDL (P < 0.05 for all comparisons except MPO, which was P = 0.05). LCAT activity was lowest in patients with proinflammatory HDL, but was also significantly reduced in RA patients with antiinflammatory HDL as compared with healthy controls (P = 0.001). CONCLUSION: Proinflammatory HDL in this RA patient cohort was associated with active disease and an altered protein cargo as compared with antiinflammatory HDL in RA patients and in healthy controls. The antiinflammatory function of HDL was inversely correlated with systemic inflammation in RA patients and may warrant further investigation as a mechanism by which active RA increases cardiovascular morbidity and mortality. PMID- 19790072 TI - Diagnosing acute nonspecific low back pain: time to lower the red flags? PMID- 19790071 TI - Interferon-regulated chemokines as biomarkers of systemic lupus erythematosus disease activity: a validation study. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by unpredictable flares of disease activity and irreversible damage to multiple organ systems. An earlier study showed that SLE patients carrying an interferon (IFN) gene expression signature in blood have elevated serum levels of IFN-regulated chemokines. These chemokines were associated with more-severe and active disease and showed promise as SLE disease activity biomarkers. This study was designed to validate IFN-regulated chemokines as biomarkers of SLE disease activity in 267 SLE patients followed up longitudinally. METHODS: To validate the potential utility of serum chemokine levels as biomarkers of disease activity, we measured serum levels of CXCL10 (IFNgamma-inducible 10-kd protein), CCL2 (monocyte chemotactic protein 1), and CCL19 (macrophage inflammatory protein 3beta) in an independent cohort of 267 SLE patients followed up longitudinally over 1 year (1,166 total clinic visits). RESULTS: Serum chemokine levels correlated with lupus activity at the current visit (P = 2 x 10(-10)), rising at the time of SLE flare (P = 2 x 10(-3)) and decreasing as disease remitted (P = 1 x 10(-3)); they also performed better than the currently available laboratory tests. Chemokine levels measured at a single baseline visit in patients with a Systemic Lupus Erythematosus Disease Activity Index of < or =4 were predictive of lupus flare over the ensuing year (P = 1 x 10(-4)). CONCLUSION: Monitoring serum chemokine levels in SLE may improve the assessment of current disease activity, the prediction of future disease flares, and the overall clinical decision making. PMID- 19790073 TI - Estrone/17beta-estradiol conversion to, and tumor necrosis factor inhibition by, estrogen metabolites in synovial cells of patients with rheumatoid arthritis and patients with osteoarthritis. AB - OBJECTIVE: The role of estrogens in rheumatoid arthritis (RA) is debated since both proinflammatory and antiinflammatory effects have been reported. Important evidence of the dual role of estrogens is conversion to various proinflammatory or antiinflammatory metabolites. This study was undertaken to examine the downstream conversion of estrogens in synovial cells from patients with RA or osteoarthritis (OA). METHODS: We studied serum levels of estrone, estrone sulfate, and estrone sulfate membrane transporters, intracellular interconversion of estrone and 17beta-estradiol, and conversion of estrone/17beta-estradiol to various estrogen metabolites in RA and OA synovial cells. The effect of estrogen metabolites on tumor necrosis factor (TNF) secretion was also studied in RA and OA synovial cells. RESULTS: Serum levels of estrone sulfate were similar in healthy controls and RA patients. Estrone sulfate transporters were present in synovial tissue. Interconversion of estrone and 17beta-estradiol and the expression of converting enzymes of the cytochrome P450 family were similar in RA and OA cells. Using estrone and 17beta-estradiol as substrates, RA and OA synovial cells produced 16alpha-, 4-, and 2-hydroxylated estrogens and their 4- and 2-methylation products. The levels of 16alpha-hydroxylated estrone/17beta estradiol (16alphaOH-estrone/16alphaOH-17beta-estradiol) were higher than the levels of all other estrogen metabolites. RA synovial cells produced more 16alphaOH-estrone than did OA synovial cells. Importantly, the 16alphaOH estrogens did not inhibit TNF secretion, whereas all other estrogen metabolites had marked inhibitory effects. CONCLUSION: Our findings indicate that precursor estrogens are converted to proinflammatory metabolites, particularly in RA synovial cells. RA synovial cells mainly produce the proproliferative 16alphaOH estrone, which, in addition to 16alphaOH-17beta-estradiol, is one of the only 2 estrogens studied that does not inhibit TNF secretion. A preponderance of 16alpha hydroxylated estrogens is an unfavorable sign in synovial inflammation. PMID- 19790074 TI - Soluble neuropilin-2, a nerve repellent receptor, is increased in rheumatoid arthritis synovium and aggravates sympathetic fiber repulsion and arthritis. AB - OBJECTIVE: In inflammatory lesions, sympathetic nerve fibers disappear soon after the start of inflammation. We identified sympathetic nerve repellents as possible causal agents in rheumatoid arthritis (RA). On nerve terminals, repellent factors bind to neuropilin-2 and its coreceptor. The aim of this study was to investigate the role of neuropilin-2 in the synovial tissue of patients with RA and patients with osteoarthritis (OA) and in experimental arthritis. METHODS: The density of neuropilin-2-positive fibers and cells positive for semaphorin 3F (a sympathetic repellent) was investigated using immunofluorescence staining. Enzyme-linked immunosorbent assay was used to detect soluble neuropilin-2 in body fluids from patients with RA and patients with OA. An axon outgrowth assay and a neuropilin-2 Fc fusion construct (neuropilin-2Fc) were used to investigate semaphorin 3F induced sympathetic nerve repulsion. In an animal model of type II collagen induced arthritis, soluble neuropilin-2Fc was studied in vivo. RESULTS: The synovial density of neuropilin-2-positive sympathetic nerve fibers was lower in RA than in OA, but the density of cells positive for semaphorin 3F was similar. In synovial fluid, the level of soluble neuropilin-2 was markedly higher in RA compared with OA. Mouse sympathetic ganglia served as an excellent model with which to study semaphorin 3F-induced nerve fiber repulsion. Neuropilin-2 and its coreceptor were present on sympathetic neurons, and semaphorin 3F bound to neuropilin-2Fc (binding constant 96 nmoles/liter). Semaphorin 3F dose-dependently increased sympathetic nerve fiber repulsion (at a 50% maximum response concentration of 160-210 nmoles/liter). In contrast to our expectations, soluble neuropilin-2Fc did not inhibit repulsion but increased the repellent effect of semaphorin 3F. In experimental arthritis, therapy with neuropilin-2Fc aggravated arthritis. CONCLUSION: Soluble neuropilin-2 has no antirepellent activity but aggravates sympathetic nerve fiber repulsion and arthritis. Increased shedding of neuropilin-2 is probably an unfavorable sign in RA. PMID- 19790075 TI - Clinical images: Transient regional osteoporosis. PMID- 19790076 TI - Obesity and osteoarthritis: is leptin the link? PMID- 19790077 TI - Scavenger receptor class A type I/II determines matrix metalloproteinase-mediated cartilage destruction and chondrocyte death in antigen-induced arthritis. AB - OBJECTIVE: Scavenger receptor class A type I (SR-AI) and SR-AII are expressed by macrophages in particular and bind and internalize a broad range of molecules (including endotoxins, apoptotic bodies, and oxidized low-density lipoprotein). This study was undertaken to investigate the role of SR-AI/II in mediating severe cartilage destruction in antigen-induced arthritis (AIA). METHODS: AIA was induced in the knee joints of SR-AI/II(-/-) mice and wild-type (WT) controls. Joint inflammation and cartilage destruction (chondrocyte death) were measured by examining the histology of total knee joints. Matrix metalloproteinase (MMP) mediated neoepitopes were measured by immunolocalization using anti-VDIPEN antibodies and chondrocyte activation with anti-S100A8 antibodies. Messenger RNA (mRNA) levels were determined in inflamed synovium using microarray analysis and quantitative reverse transcriptase-polymerase chain reaction. In synovial washouts, cytokines (interleukin-1beta [IL-1beta], IL-10, and tumor necrosis factor alpha) and S100A8/S100A9 were measured using Luminex and enzyme-linked immunosorbent assay. RESULTS: Levels of SR-AI/II mRNA were strongly elevated in inflamed synovium in AIA. On days 2, 8, and 14 after AIA induction, joint inflammation (exudates/infiltrate) was similar between the 2 groups. In WT mice, severe cartilage destruction was found in multiple cartilage surfaces of the inflamed knee joint on day 14 after AIA induction. MMP-mediated matrix destruction ranged between 40% and 60%, and chondrocyte death was prominent in 40 75% of the cartilage surfaces. In striking contrast, in SR-AI/II(-/-) mice, despite comparable joint inflammation, pronounced cartilage destruction was almost completely absent. Levels of IL-1beta and S100A8/S100A9 were significantly lower on days 7 and 14 after AIA induction, but levels of mRNA for various MMPs (MMP-2, MMP-3, MMP-9, and MMP-13) were comparable. CONCLUSION: Our findings indicate that SR-AI and SR-AII are crucial receptors involved in mediating severe cartilage destruction in AIA. PMID- 19790078 TI - Retinoid ameliorates experimental autoimmune myositis, with modulation of Th cell differentiation and antibody production in vivo. AB - OBJECTIVE: Polymyositis and dermatomyositis are chronic inflammatory muscle diseases. Retinoids are compounds that bind to the retinoic acid binding site of retinoic acid receptors and have biologic activities similar to those of vitamin A. Recent studies indicate that retinoids promote Th2 differentiation and suppress Th1 and Th17 differentiation in vitro. The present study was undertaken to examine the effects of a synthetic retinoid, Am80, on experimental autoimmune myositis as well as on Th phenotype development and antibody production. METHODS: Experimental autoimmune myositis was induced in SJL/J mice by immunization with rabbit myosin. Am80 was administered orally once daily. Its effects were evaluated by measurement of the numbers of infiltrating inflammatory cells, production of inflammatory cytokines in muscle, production of Th-specific cytokines by myosin-stimulated splenic T cells, and production of antimyosin antibodies in serum. RESULTS: In mice with experimental autoimmune myositis, orally administered Am80 significantly reduced the number of infiltrating inflammatory cells and the expression of tumor necrosis factor alpha and interleukin-1beta (IL-1beta) in muscle. Moreover, Am80 increased production of interferon-gamma, IL-4, and IL-10, but not IL-17, by myosin-stimulated splenic T cells of mice with experimental autoimmune myositis, suggesting that it could enhance differentiation into Th1 and Th2, but not Th17, in vivo. Am80 also decreased serum levels of IgG2a and IgG2b antimyosin antibodies, but did not affect levels of IgG1 antimyosin antibodies. In addition, it suppressed chemokine expression and activator protein 1 activity in myoblasts in vitro. CONCLUSION: The synthetic retinoid Am80 has an inhibitory effect on experimental autoimmune myositis. It might regulate the development of Th phenotype and antibody production in vivo, in addition to its effects on cytokine and chemokine production. PMID- 19790082 TI - Coffee drinking and hepatocellular carcinoma: an update. PMID- 19790084 TI - Endotoxemia in alcoholic liver disease. PMID- 19790086 TI - Role of cholesterol determination in ascitic fluid analysis. PMID- 19790087 TI - The management of cirrhotic ascites. PMID- 19790088 TI - Comments on minimizing misdiagnosis of hepatocellular carcinoma from magnetic resonance imaging. PMID- 19790094 TI - Real-time transvaginal elastosonography of uterine fibroids. PMID- 19790095 TI - Ultrasonographic measurement of ovarian volume in the diagnosis of central precocious puberty. PMID- 19790096 TI - Peeling back the onion on ultrasound abnormalities. PMID- 19790097 TI - Routine ultrasound examination in early pregnancy: is it worthwhile in low-income countries? PMID- 19790098 TI - Fetal abdominal scarring caused by the umbilical cord of a cotwin following selective cord coagulation. PMID- 19790099 TI - Obstetric ultrasound scanning by local health workers in a refugee camp on the Thai-Burmese border. AB - OBJECTIVES: Ultrasound examination of the fetus is a powerful tool for assessing gestational age and detecting obstetric problems but is rarely available in developing countries. The aim of this study was to assess the intraobserver and interobserver agreement of fetal biometry by locally trained health workers in a refugee camp on the Thai-Burmese border. METHODS: One expatriate doctor and four local health workers participated in the study, which included examinations performed on every fifth pregnant woman with a singleton pregnancy between 16 and 40 weeks' gestation, and who had undergone an early dating ultrasound scan, attending the antenatal clinic in Maela refugee camp. At each examination, two examiners independently measured biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC) and femur length (FL), with one of the examiners obtaining duplicate measurements of each parameter. Intraobserver measurement error was assessed using the intraclass correlation coefficient (ICC) and interobserver error was assessed by the Bland and Altman 95% limits of agreement method. RESULTS: A total of 4188 ultrasound measurements (12 per woman) were obtained in 349 pregnancies at a median gestational age of 27 (range, 16-40) weeks in 2008. The ICC for BPD, HC, AC and FL was greater than 0.99 for all four trainees and the doctor (range, 0.996-0.998). For gestational ages between 18 and 24 weeks, interobserver 95% limits of agreement corresponding to differences in estimated gestational age of less than +/- 1 week were calculated for BPD, HC, AC and FL. Measurements by local health workers showed high levels of agreement with those of the expatriate doctor. CONCLUSIONS: Locally trained health workers working in a well organized unit with ongoing quality control can obtain accurate fetal biometry measurements for gestational age estimation. This experience suggests that training of local health workers in developing countries is possible and could allow effective use of obstetric ultrasound imaging. PMID- 19790100 TI - Contribution of the myocardial performance index and aortic isthmus blood flow index to predicting mortality in preterm growth-restricted fetuses. AB - OBJECTIVES: To evaluate the predictive value for perinatal death of the myocardial performance index (MPI) and aortic isthmus flow index (IFI), as isolated parameters and in a combined model including currently used Doppler indices, in preterm growth restricted (IUGR) fetuses. METHODS: Umbilical artery, fetal middle cerebral artery (MCA) and ductus venosus (DV) pulsatility indices (PIs) were recorded, along with IFI and MPI, in a cohort of 97 preterm (delivered at between 24 and 34 weeks) IUGR fetuses. Logistic regression analysis was performed to identify those variables that were independently associated with perinatal mortality, and an algorithm to estimate probability of death was constructed including the best combination of parameters. RESULTS: With the exception of MCA, all Doppler indices were significantly associated with perinatal death as isolated parameters, but only DV-PI and MPI were found to be independent predictors on multivariate analysis. An algorithm combining DV atrial flow (positive or absent/reversed) and MPI (normal or above 95(th) percentile) had a better predictive accuracy than did any single parameter. The risk for death in IUGR fetuses below 28 weeks' gestation with present atrial flow in the DV and normal MPI was 18%, with either characteristic abnormal it was 70-73%, and with both abnormal it was 97%. The risk for death in IUGR fetuses above 28 weeks with present atrial flow in the DV and normal MPI was 0.1%, with either abnormal it was 6-7%, and with both abnormal it was 45%. CONCLUSIONS: MPI is an independent predictor of perinatal death in preterm IUGR fetuses with accuracy similar to that of DV flow. A combination of DV flow with MPI may better stratify the estimated probability of death. IFI does not add to the prediction of perinatal death when used in combination with DV flow. PMID- 19790101 TI - Prenatal sonographic features of complete covered cloacal exstrophy. PMID- 19790102 TI - Antenatal detection of cleft lip with or without cleft palate: incidence of associated chromosomal and structural anomalies. AB - OBJECTIVE: To ascertain how many fetuses with prenatally diagnosed cleft lip with or without cleft palate have associated congenital structural and/or chromosomal abnormalities and whether there is an association with the anatomical type of cleft lip or palate. METHODS: This was a retrospective review of infants referred to the North-West England Regional Cleft Lip and Palate (CLAP) team between January 2000 and January 2006. Referrals made to the Regional Fetal Management Unit (FMU) in the same time period were investigated to identify the corresponding antenatal ultrasound findings and data on termination of pregnancy and intrauterine fetal death. RESULTS: Over the 6-year period investigated, 570 infants were referred to the FMU and/or CLAP team. Among these, there were 24 terminations of pregnancy, two intrauterine fetal deaths and one early neonatal death identified. Data on 69 of the 543 patients that survived were incomplete. Of 188 cases with unilateral and 34 cases with bilateral cleft lip +/- palate there were no karyotypical abnormalities without other structural abnormalities. The incidence of associated structural abnormalities varied with the anatomical type of cleft: that of unilateral cleft lip +/- palate was 9.8% (19/194), that of bilateral cleft lip and palate was 25% (11/44) and that of midline cleft lip and palate was 100% (11/11). None of 252 cases with isolated cleft palate was identified antenatally; of these, 5.6% (n = 14) had either karyotypical or associated structural abnormalities and 21.0% (n = 53) had a genetic syndrome as an underlying diagnosis. CONCLUSIONS: It is essential to tailor the antenatal counseling of patients to the specific scan diagnosis, considering both the anatomical type of cleft and the presence or absence of associated abnormalities. It is inappropriate to offer invasive testing to all patients. The use of three dimensional ultrasound as an adjunct should be considered in these patients to improve the accuracy of prenatal diagnosis. PMID- 19790103 TI - Phosphorylated insulin-like growth factor binding protein-1 in cervical secretions and sonographic cervical length in the prediction of spontaneous preterm delivery. AB - OBJECTIVES: The aim of this study was to evaluate the efficacy of the test for the decidual phosphorylated isoform of insulin-like growth factor binding protein 1 (phIGFBP-1) in endocervical secretions in predicting preterm delivery in women with uterine contractions. METHODS: The study included 210 women with a singleton pregnancy with documented uterine contractions and intact membranes at between 24 and 34 weeks' gestation who underwent the cervicovaginal phIGFBP-1 test and transvaginal sonographic measurement of cervical length. A receiver-operating characteristics (ROC) curve was used to determine the most useful cut-off point for cervical length. A multivariate logistic regression model was used in order to analyze the combination of significant predictive variables for preterm delivery following univariate analysis. RESULTS: ROC curves indicated that 26 mm was the optimal cut-off value for cervical length in predicting preterm delivery. A cervical length of < 26 mm and the presence of phIGFBP-1 were statistically significant in univariate logistic regression analyses (P < 0.0001) with odds ratios of 16.18 and 9.29 for preterm delivery, respectively. Multivariate analysis of cervical length and phIGFBP-1 showed that they were independent and therefore useful in combination for predicting preterm delivery. CONCLUSIONS: Cervical length and the phIGFBP-1 test are independent variables that can be used together to predict preterm delivery in women with uterine contractions. A sonographically measured cervical length of > 26 mm with a negative phIGFBP-1 test in a patient with regular uterine contractions before 37 weeks' gestation seems to indicate a low risk of preterm delivery and may therefore allow avoidance of unnecessary therapies. PMID- 19790105 TI - RanBPM regulates the progression of neuronal precursors through M-phase at the surface of the neocortical ventricular zone. AB - Many of the mitoses that produce pyramidal neurons in neocortex occur at the dorsolateral surface of the lateral ventricles in the embryo. RanBPM was found in a yeast two-hybrid screen to potentially interact with citron kinase (CITK), a protein shown previously to localize to the surface of the lateral ventricles and to be essential to neurogenic mitoses. Similar to its localization in epithelia, RanBPM protein is concentrated at the adherens junctions in developing neocortex. The biochemical interaction between CITK and RanBPM was confirmed in coimmunoprecipitation and protein overlay experiments. To test for a functional role of RanPBM in vivo, we used in utero RNAi. RanBPM RNAi decreased the polarization of CITK to the ventricular surface, increased the number of cells in mitosis, and decreased the number of cells in cytokinesis. Finally, the effect of RanBPM knockdown on mitosis was reversed in embryos mutant for CITK. Together, these results indicate that RanBPM, potentially through interaction with CITK, plays a role in the progression of neocortical precursors through M-phase at the ventricular surface. PMID- 19790106 TI - Activity of nAChRs containing alpha9 subunits modulates synapse stabilization via bidirectional signaling programs. AB - Although the synaptogenic program for cholinergic synapses of the neuromuscular junction is well known, little is known of the identity or dynamic expression patterns of proteins involved in non-neuromuscular nicotinic synapse development. We have previously demonstrated abnormal presynaptic terminal morphology following loss of nicotinic acetylcholine receptor (nAChR) alpha9 subunit expression in adult cochleae. However, the molecular mechanisms underlying these changes have remained obscure. To better understand synapse formation and the role of cholinergic activity in the synaptogenesis of the inner ear, we exploit the nAChR alpha9 subunit null mouse. In this mouse, functional acetylcholine (ACh) neurotransmission to the hair cells is completely silenced. Results demonstrate a premature, effusive innervation to the synaptic pole of the outer hair cells in alpha9 null mice coinciding with delayed expression of cell adhesion proteins during the period of effusive contact. Collapse of the ectopic innervation coincides with an age-related hyperexpression pattern in the null mice. In addition, we document changes in expression of presynaptic vesicle recycling/trafficking machinery in the alpha9 null mice that suggests a bidirectional information flow between the target of the neural innervation (the hair cells) and the presynaptic terminal that is modified by hair cell nAChR activity. Loss of nAChR activity may alter transcriptional activity, as CREB binding protein expression is decreased coincident with the increased expression of N-Cadherin in the adult alpha9 null mice. Finally, by using mice expressing the nondesensitizing alpha9 L9'T point mutant nAChR subunit, we show that increased nAChR activity drives synaptic hyperinnervation. PMID- 19790107 TI - Isolation and partial purification of the Saccharomyces cerevisiae cytokinetic apparatus. AB - Cytokinesis is the process by which a cell physically divides in two at the conclusion of a cell cycle. In animal and fungal cells, this process is mediated by a conserved set of proteins including actin, type II myosin, IQGAP proteins, F BAR proteins, and the septins. To facilitate biochemical and ultrastructural analysis of cytokinesis, we have isolated and partially purified the Saccharomyces cerevisiae cytokinetic apparatus. The isolated apparatus contains all components of the actomyosin ring for which we tested-actin, myosin heavy and light chain, and IQGAP-as well as septins and the cytokinetic F-BAR protein, Hof1p. We also present evidence indicating that the actomyosin rings associated with isolated cytokinetic apparati may be contractile in vitro, and show preliminary electron microscopic imaging of the cytokinetic apparatus. This first successful isolation of the cytokinetic apparatus from a genetically tractable organism promises to make possible a deeper understanding of cytokinesis. PMID- 19790109 TI - Pain and hip lateral rotator muscle strength contribute to functional status in females with patellofemoral pain. AB - BACKGROUND AND PURPOSE: Patellofemoral pain (PFP) is a common musculoskeletal pain condition, especially in females. Decreased hip muscle strength has been implicated as a contributing factor, yet the relationships between pain, hip muscle strength and function are not known. The purpose of this study was to test the hypothesis that pain and hip muscle strength explain unique portions of variance in the functional status of females with PFP. METHODS: An observational, cohort study was conducted. The subjects for this study were twenty-one females with PFP (age: 26 +/- 7 years; height: 163 +/- 4 cm; and body mass: 62 +/- 10 kg). Subjects had a minimum pain duration of two months (mean pain duration: 4.9 +/- 3.6 years). The main measures were pain during a unilateral squat, measured with a visual analogue scale; isometric muscle force of gluteus medius, gluteus maximus and hip lateral rotators; and Kujala score (self-report measure of function). Hierarchical multiple regression analysis was performed with Kujala score as the dependent variable. Pain and hip lateral rotator muscle strength were independent variables, entered in that order. Other strength measures were not correlated with the Kujala score, and as such, were not used in the analysis. RESULTS: Pain explained 22% of the variance in the Kujala score (p = 0.03). Hip lateral rotator strength explained an additional 14% of the variance, after accounting for pain level (p = 0.06). CONCLUSIONS: Pain and hip lateral rotator strength contributed to the functional status of females with PFP. Improving pain and hip lateral rotator muscle strength may improve function in females with this common pain condition. PMID- 19790110 TI - Squatting, sitting on the floor, or cycling: are life-long daily activities risk factors for clinical knee osteoarthritis? Stage III results of a community-based study. AB - OBJECTIVE: To evaluate the association between occupations, sports, life-long daily activities, and knee osteoarthritis. METHODS: In this case-control study, we randomly recruited 480 subjects with knee osteoarthritis, who had participated in the first stage of a community-based study in Tehran, and compared them with 490 controls. A questionnaire was used to record all occupations, sports, and the details of 10 daily activities. The mean +/- SD hours/day spent on these activities were calculated and compared using the lightest activity as reference. Generalized estimation equation was used with each knee as the unit of analysis. RESULTS: The mean +/- SD age and percentage of female distribution was 57 +/- 12 years, 69.8% women for cases, and 46.8 +/- 15 years, 64.1% women for controls. After adjusting for age, sex, and body mass index, 2 activities were risk factors for knee osteoarthritis: prolonged squatting (odds ratio [OR] 1.51, 95% confidence interval [95% CI] 1.12-2.04) and cycling (OR 2.06, 95% CI 1.23-3.45). Knee-bending had borderline significance (OR 1.98, 95% CI 0.98-3.99). Carrying loads (OR 1.24, 95% CI 0.87-1.76) or climbing stairs (OR 0.99, 95% CI 0.69-1.42) showed no extra risk for knee osteoarthritis. Prolonged standing, sitting on the floor, and walking up/downhill were not risks for knee osteoarthritis. Housewives were at greater risk (borderline-significant) of developing knee osteoarthritis (OR 1.68, 95% CI 0.93-3.03) than women whose main occupation was outside the home. Other types of jobs and sports did not show an extra risk of knee osteoarthritis. CONCLUSION: Our findings support the role of lifestyle in the pathogenesis of knee osteoarthritis for squatting and cycling. Education on preventable risk factors should be considered in order to ensure people use knee joints appropriately and avoid overuse. PMID- 19790111 TI - Knee osteoarthritis in obese women with cardiometabolic clustering. AB - OBJECTIVE: To assess the role of obesity and metabolic dysfunctionality with knee osteoarthritis (OA), knee joint pain, and physical functioning performance, adjusted for joint space width (JSW) asymmetry. METHODS: Knee OA was defined as a Kellgren/Lawrence score > or =2 on weight-bearing radiographs. Obesity was defined as a body mass index > or =30 kg/m2. Cardiometabolic clustering classification was based on having > or =2 of the following factors: low levels of high-density lipoprotein cholesterol; elevated levels of low-density lipoprotein cholesterol, triglycerides, blood pressure, C-reactive protein, waist:hip ratio, or glucose; or diabetes mellitus. The difference between lateral and medial knee JSW was used to determine joint space asymmetry. RESULTS: In a sample of women (n = 482, mean age 47 years), prevalences of knee OA and persistent knee pain were 11% and 30%, respectively. The knee OA prevalence in nonobese women without cardiometabolic clustering was 4.7%, compared with 12.8% in obese women without cardiometabolic clustering and 23.2% in obese women with cardiometabolic clustering. Nonobese women without cardiometabolic clustering were less likely to perceive themselves as limited compared with women in all other obesity/cardiometabolic groups (P < 0.05). Similar associations were seen with knee pain and physical functioning measures. The inclusion of a joint space asymmetry measure was associated with knee OA but not with knee pain or physical functioning. CONCLUSION: Knee OA was twice as frequent in obese women with cardiometabolic clustering compared with those without, even when considering age and joint asymmetry. Obesity/cardiometabolic clustering was also associated with persistent knee pain and impaired physical functioning. PMID- 19790112 TI - Risk factors for upper-extremity musculoskeletal disorders in the working population. AB - OBJECTIVE: To assess the relative importance of personal and occupational risk factors for upper-extremity musculoskeletal disorders in the working population. METHODS: A total of 3,710 workers (58% men) participating in a surveillance program of musculoskeletal disorders in a French region in 2002-2005 were included. Upper-extremity musculoskeletal disorders were diagnosed by 83 trained occupational physicians performing a standardized physical examination. Personal factors and work exposure were assessed by a self-administered questionnaire. Statistical associations between musculoskeletal disorders, personal, and occupational factors were analyzed using logistic regression modeling. RESULTS: A total of 472 workers experienced at least 1 upper-extremity musculoskeletal disorder. The risk of upper-extremity musculoskeletal disorders increased with age for both sexes (P < 0.001, odds ratio [OR] < or =4.9 in men and < or =5.0 in women), and in cases of prior history of upper-extremity musculoskeletal disorders (OR 3.1 and 5.0, respectively, P < 0.001). In men, upper-extremity musculoskeletal disorders were associated with obesity (OR 2.2, P = 0.014), high level of physical demand (OR 2.0, P < 0.001), high repetitiveness of the task (OR 1.5, P = 0.027), postures with the arms at or above shoulder level (OR 1.7, P = 0.009) or with full elbow flexion (OR 1.6, P = 0.006), and high psychological demand (OR 1.5, P = 0.005). In women, upper-extremity musculoskeletal disorders were associated with diabetes mellitus (OR 4.9, P = 0.001), postures with extreme wrist bending (OR 2.0, P < 0.001), use of vibrating hand tools (OR 2.2, P = 0.025), and low level of decision authority (OR 1.4, P = 0.042). CONCLUSION: Personal and work-related physical and psychosocial factors were strongly associated with clinically diagnosed upper-extremity musculoskeletal disorders. PMID- 19790113 TI - 25-hydroxyvitamin D and cardiovascular risk factors in women with systemic lupus erythematosus. AB - OBJECTIVE: Low serum levels of 25-hydroxyvitamin D (25[OH]D; vitamin D) are associated with a higher frequency of cardiovascular disease and risk factors in the general population. Vitamin D deficiency has also been noted in systemic lupus erythematosus (SLE). The objective of this study was to evaluate the associations of serum 25(OH)D levels with cardiovascular risk factors in women with SLE. METHODS: Data collected in 181 women with SLE included demographics, SLE activity and damage assessments, cardiovascular risk factors, medications, and laboratory assessments of inflammatory markers and 25(OH)D levels. Multiple linear and logistic regressions were used to estimate the association of 25(OH)D levels with cardiovascular risk factors. RESULTS: The mean age and disease duration were 43.2 and 11.9 years, respectively. The mean 25(OH)D level was 27.1 ng/ml and 62.2% had 25(OH)D levels <30 ng/ml. In unadjusted analyses, lower 25(OH)D levels were significantly associated with higher diastolic blood pressure, low-density lipoprotein cholesterol, lipoprotein(a), body mass index (BMI), and fibrinogen levels, as well as self-reported hypertension and diabetes mellitus. Lower 25(OH)D levels were also significantly associated with higher SLE disease activity and damage scores. After adjustment for age, seasonal variation, and race/ethnicity, lower 25(OH)D levels were also significantly related to higher fasting serum glucose. With further adjustment for BMI, associations between 25(OH)D and cardiovascular risk factors were no longer significant. CONCLUSION: This study demonstrates that vitamin D levels are low in women with SLE and significant associations exist with selected cardiovascular risk factors, although most of these associations can be explained by BMI. PMID- 19790114 TI - Antineutrophil cytoplasmic antibody-associated vasculitides: could geographic patterns be explained by ambient ultraviolet radiation? AB - OBJECTIVE: This ecological study describes and quantifies the association between ambient ultraviolet (UV) radiation levels, including daily winter vitamin D effective UV radiation levels and the incidence of the 3 antineutrophil cytoplasmic antibody-associated vasculitides (AAVs): Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), and Churg-Strauss syndrome (CSS). Latitudinal variation in occurrence of the AAVs, especially WG, has been previously reported. For other autoimmune diseases such as multiple sclerosis and type 1 diabetes mellitus, inverse associations with latitude are hypothesized to indicate a causative role for low UV radiation exposure, possibly acting via vitamin D status. METHODS: Published epidemiologic studies provided data on incident cases, total population of study regions, age-specific incidence rates, and study location. From these data and online age-specific population data, we calculated crude incidence rates, the expected number of cases (to control for possible age confounding), and measures of ambient UV radiation. Negative binomial regression models were used to calculate the incidence rate ratio (IRR) for a 1,000 joules/m(2) increase in ambient UV radiation. RESULTS: The incidence of WG and CSS increased with increasing latitude and decreasing ambient UV radiation, with a stronger and more consistent effect across different UV radiation measures for WG, e.g., for average daily ambient clear sky erythemal UV radiation (WG: IRR 0.64 [95% confidence interval (95% CI) 0.44-0.94], P = 0.02; CSS: IRR 0.67 [95% CI 0.43-1.05], P = 0.08; MPA: IRR 1.16 [95% CI 0.92-1.47], P = 0.22). There was no apparent latitudinal variation in MPA incidence. CONCLUSION: Our findings are consistent with a protective immunomodulatory effect of ambient UV radiation on the onset of WG and CSS. We discuss possible mechanisms, including the effect of vitamin D on the immune system. PMID- 19790115 TI - Association of functional outcome with both personal- and area-level socioeconomic inequalities in patients with inflammatory polyarthritis. AB - OBJECTIVE: To describe the relationship between baseline area- and person-level social inequalities and functional disability at 3 years in patients with early inflammatory polyarthritis (IP). METHODS: A total of 1,393 patients with new onset IP were recruited and allocated an Index of Multiple Deprivation (IMD) 2004 score based on their area of residence, and a social class based on baseline self reported occupation. Differences in the Health Assessment Questionnaire (HAQ) score at baseline and 3 years by IMD or social class were tested. The mean 3-year change in HAQ score was compared by IMD and social class, and interactions between these measures examined. RESULTS: Patients from more deprived areas had poorer 3-year HAQ outcome than those from less deprived areas (P = 0.019, adjusted for baseline HAQ score, age, sex, and symptom duration). The mean difference in HAQ change was most notable between the most deprived (IMD4) and least deprived areas (IMD1) (0.22; 95% confidence interval [95% CI] 0.11, 0.34). There was also a significant difference in HAQ score change between patients of the highest (SCI and II) and lowest social class (SCIV and V) (0.11; 95% CI 0.02, 0.20). For the mean (95% CI) 3-year change in HAQ score, a significant interaction exists between IMD score and social class and their association with HAQ scores (P = 0.001) to modify outcome: IMD1/SC I and II -0.23 (95% CI -0.40, 0.06) versus IMD 4/SC IV and V 0.15 (95% CI -0.05, 0.34). CONCLUSION: Person- and area-level inequalities combine to modify outcome for rheumatoid arthritis. A person's social circumstance and residential environment have independent effects on outcome and are not just alternative measures of the same exposure. PMID- 19790116 TI - Atherothrombotic comorbidity in the rheumatic diseases. The evidence becomes clearer. What should clinicians do? PMID- 19790117 TI - Population-based lupus registries: advancing our epidemiologic understanding. PMID- 19790119 TI - Introduction to special section: epidemiology of the rheumatic diseases. PMID- 19790118 TI - Skeletal health among African Americans with recent-onset rheumatoid arthritis. AB - OBJECTIVE: African Americans with rheumatoid arthritis (RA) may be at increased fracture risk. We applied the World Health Organization (WHO) Fracture Risk Assessment Tool (FRAX) and National Osteoporosis Foundation (NOF) guidelines to a cohort of African Americans with early RA to identify which patients were recommended for osteoporosis treatment. METHODS: Risk factors and bone mineral density (BMD) were assessed in a cohort of African Americans with RA. The WHO FRAX tool estimated 10-year fracture risk. Patients were risk stratified using FRAX without BMD to identify which individuals might be most efficiently targeted for BMD testing. RESULTS: Participants (n = 324) had a mean age of 51 years and included 81% women. There were no associations of RA disease characteristics with BMD. The proportion of patients recommended for osteoporosis treatment varied from 3-86%, depending on age and body mass index (BMI). Ten-year fracture risk calculated with BMI only was generally the same or higher than fracture risk calculated with BMD; adding BMD data provided the most incremental value to risk assessment in patients 55-69 years of age with low/normal BMI, and in those > or =70 years of age with BMI > or =30 kg/m2. CONCLUSION: A high proportion of African Americans with RA were recommended for treatment under the 2008 NOF guidelines. FRAX without BMD identified low-risk patients accurately. Systematic application of FRAX to screen high-risk groups such as patients with RA may be used to target individuals for BMD testing and reduce the use of unnecessary tests and treatments. PMID- 19790120 TI - The prevalence of psoriatic arthritis in people with psoriasis. AB - OBJECTIVE: To determine the prevalence of psoriatic arthritis (PsA) using the ClASsification criteria for Psoriatic ARthritis (CASPAR) for classification. METHODS: People with psoriasis were identified from the computerized morbidity indices of 2 large UK general practices, total population 22,500. Questionnaires were mailed to all 633 patients thus identified. Of the respondents, a 50% sample was assessed clinically and a proportion had blood samples and radiographs taken. Patients labeled as having psoriasis were also cross-referenced with a local secondary care morbidity index for PsA and rheumatoid arthritis. Figures for the prevalence of PsA were estimated from these data. RESULTS: One hundred sixty eight questionnaires were returned (response rate 27%) and 93 people (55% of questionnaire respondents) were examined. Of these 93 people, 12 (4 of whom were cross-referenced to the hospital database) were thought to have PsA clinically, all fulfilling the CASPAR criteria for PsA. Six of the 93 examined patients did not have psoriasis or a family history of psoriasis and had no historical features or clinical signs of psoriasis on interview and examination. Extrapolating from the data of those people actually examined, the estimated (corrected) prevalence was 13.8% (95% confidence interval 7.1-24.1%). CONCLUSION: The estimated prevalence of PsA in this population, using the CASPAR criteria, was 13.8%. Misclassification of psoriasis and arthritis, and response bias, indicate that this is probably an overestimate. PMID- 19790121 TI - Predictors of delayed referral to a pediatric rheumatology center. AB - OBJECTIVE: To report on referral patterns of primary physicians for children subsequently diagnosed with juvenile idiopathic arthritis (JIA) and to identify predictors of delayed referral to a pediatric rheumatology center. METHODS: A retrospective cohort study of consecutive patients with JIA referred to a pediatric rheumatology center over a 15-year period was performed. Variables included age, sex, JIA subtype, the physician's subspecialty, and distance to the pediatric rheumatology center. Outcome parameters were the time to first presentation to a primary physician, the time to the first rheumatology visit, and the total time to referral. Putative predictors were evaluated by analysis of variance, resulting in regression models. RESULTS: A total of 132 patients with JIA were included; 83 (63%) were female. The median age at the onset of symptoms was 4.5 years (range 1.0-15.8 years). Most frequently, children were referred by pediatricians (49.4%) or orthopedic surgeons (34.1%). The median time to first presentation was short at 10 days (range 0-1,610 days). In contrast, the median time to first rheumatology visit was 60 days (range 0.0-2,100.0 days), resulting in a long median total time to referral of 90 days (range 0.0-2,160.0 days). Statistically significant predictors for delayed referral were the primary physician's subspecialty (P = 0.016) and the distance to the pediatric rheumatology center (P = 0.001). Children living in remote areas or referred by orthopedic surgeons had the longest referral times. CONCLUSION: Despite free access to health care in Germany, children with JIA are referred to pediatric rheumatology centers with significant delay. Educational interventions targeting primary physicians and orthopedic surgeons may contribute to earlier referral to pediatric rheumatology centers and improve outcome in patients with JIA. PMID- 19790122 TI - Genetic susceptibility to rheumatoid arthritis: an emerging picture. PMID- 19790123 TI - Association between the use of serotonin receptor 2A-blocking antidepressants and joint disorders. AB - OBJECTIVE: There are case reports about antidepressants causing arthritis and arthralgia, and the majority of these reports deal with atypical antidepressants, which are serotonin receptor 2A (5-HT(2A))-blocking substances. The aim of this study was to examine a possible association between joint disorders and the use of 5-HT(2A)-blocking atypical antidepressants. METHODS: We performed a retrospective study using reports of adverse drug reactions (ADRs) of 5-HT(2A) blocking atypical antidepressant substances concerning joint disorders reported to the Swedish Adverse Drug Reactions Committee and the World Health Organization (WHO) Adverse Reactions Database during the period January 1, 1990 to December 31, 2006. The reports of joint disorders were related to sales figures measured as defined daily doses and to the total number of ADR reports. RESULTS: In the Swedish material, the 5-HT(2A) antagonists were 45 times more often reported to give joint ADRs when related to sales figures and compared with the selective serotonin reuptake inhibitors (SSRIs; P < 0.001). Joint disorders constituted 6.6% of the total number of reports of possible ADRs for the three 5-HT(2A) blocking substances mianserin, mirtazapine, and nefazodone compared with 0.5% for the SSRIs (P < 0.001). In the WHO material, the joint disorders constituted 1.3% of all ADRs for the 5-HT(2A)-blocking antidepressants and 0.6% for the SSRIs (P < 0.001). CONCLUSION: In this study, joint disorders were considerably more frequently reported ADRs of 5-HT(2A)-blocking antidepressants than of other comparable drugs, suggesting a possible association between the use of 5-HT(2A) blocking antidepressants and joint disorders. PMID- 19790124 TI - Predicting persistent low back pain in schoolchildren: a prospective cohort study. AB - OBJECTIVE: Low back pain (LBP) is common in children but the prognostic indicators are poorly understood. We report the results of a prospective study to determine the risk factors for chronic LBP in children. METHODS: A total of 330 children with LBP were identified from a cross-sectional survey in schools in Northwest England. Data were collected by self-completion questionnaire on a number of potential risk factors for LBP persistence, including lifestyle factors, the occurrence of other symptoms, behavioral and emotional characteristics, and symptom severity and duration. Participants were then followed over the following 4 years to determine persistent symptoms. RESULTS: Complete followup data were available from 178 children, of whom 46 (26%) reported persistent LBP. Forward stepwise Poisson regression identified 5 independent predictors of pain persistence: peer relationship problems, being of smaller stature, the prior report of widespread body pain, long duration of LBP episodes, and radiating leg pain. Of children with none of these factors at baseline, <5% went on to report persistent LBP. In contrast, of those with 4 or 5 factors, nearly 80% experienced persistent symptoms. CONCLUSION: Although childhood consultations for LBP are infrequent, we have shown that approximately 25% of children 11-14 years of age with LBP still report symptoms 4 years later. These children can be identified early by a combination of clinical markers and etiologic factors. This provides a basis for considering interventions for secondary prevention; the challenge will be to determine whether we can intervene to alter symptom trajectory at an early stage. PMID- 19790125 TI - Foot pain: is current or past shoewear a factor? AB - OBJECTIVE: Foot pain is common, yet few studies have examined the condition in relationship to shoewear. In this cross-sectional study of men and women from the population-based Framingham Study, the association between foot pain and type of shoewear was examined. METHODS: Data were collected on 3,378 members of the Framingham Study who completed the foot examination in 2002-2008. Foot pain (both generalized and at specific locations) was measured by the response to the question "On most days, do you have pain, aching or stiffness in either foot?" Shoewear was recorded for the present time and 5 past age categories, by the subject's choice of the appropriate shoe from a list. The responses were categorized into 3 groups (good, average, or poor shoes). Sex-specific multivariate logistic regression models were used to examine the effect of shoewear (average shoes were the referent group) on generalized and location specific foot pain, adjusting for age and weight. RESULTS: In women, compared with average shoes, those who wore good shoes in the past were 67% less likely to report hindfoot pain (P = 0.02), after adjusting for age and weight. In men, there was no association between foot pain, at any location, and shoewear, possibly due to the fact that <2% wore bad shoe types, making it difficult to see any relationship. CONCLUSION: Even after taking age and weight into account, past shoewear use in women remained associated with hindfoot pain. Future studies should address specific support and structural features of shoewear. PMID- 19790127 TI - Epidemiology of giant cell arteritis and polymyalgia rheumatica. PMID- 19790126 TI - HLA-B51/B5 and the risk of Behcet's disease: a systematic review and meta analysis of case-control genetic association studies. AB - OBJECTIVE: To quantify by meta-analysis the genetic effect of the HLA-B5 or HLA B51 (HLA-B51/B5) allele on the risk of developing Behcet's disease (BD) and to look for potential effect modifiers. METHODS: Relevant studies were identified using the PubMed Medline database and manual searches of the literature. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated by using the random-effects model. Subgroup meta-analyses and meta-regression analyses were undertaken to investigate the effects of selected study-level parameters on the pooled OR. Heterogeneity was assessed using the I2 statistic. Pooled results were used to calculate population-attributable risks (PAR) for BD in relationship to HLA-B51/B5. RESULTS: A total of 4,800 patients with BD and 16,289 controls from 78 independent studies (published 1975-2007) were selected. The pooled OR of HLA-B51/B5 allele carriers to develop BD compared with noncarriers was 5.78 (95% CI 5.00-6.67), with moderate between-study heterogeneity (I2 = 61%). The subgroup analyses stratifying studies by geographic locations (Eastern Asia, Middle East/North Africa, Southern Europe, Northern/Eastern Europe) yielded consistent OR ranges (5.31-7.20), with I2 ranges of 52-70%. Univariate random-effects meta regression indicated the percentage of male BD cases (P = 0.008) as a source of heterogeneity. The PAR within the various geographic areas were estimated at 32 52%. CONCLUSION: The strength of the association between BD and HLA-B51/B5, and its consistency across populations of various ethnicities, lends further support to this allele being a primary and causal risk determinant for BD. Variations according to sex support an interaction of this allele with BD characteristics. PMID- 19790128 TI - Immunogenetic risk and protective factors for the development of L-tryptophan associated eosinophilia-myalgia syndrome and associated symptoms. AB - OBJECTIVE: To assess L-tryptophan (LT) dose, age, sex, and immunogenetic markers as possible risk or protective factors for the development of LT-associated eosinophilia-myalgia syndrome (EMS) and related clinical findings. METHODS: HLA DRB1 and DQA1 allele typing and Gm/Km phenotyping were performed on a cohort of 94 white subjects with documented LT ingestion and standardized evaluations. Multivariate analyses compared LT dose, age, sex, and alleles among groups of subjects who ingested LT and subsequently developed surveillance criteria for EMS, developed EMS or characteristic features of EMS (EMS spectrum disorder), or developed no features of EMS (unaffected). RESULTS: Considering all sources of LT, higher LT dose (odds ratio [OR] 1.4, 95% confidence interval [95% CI] 1.1 1.8), age >45 years (OR 3.0, 95% CI 1.0-8.8), and HLA-DRB1*03 (OR 3.9, 95% CI 1.2 15.2), DRB1*04 (OR 3.9, 95% CI 1.1-16.4), and DQA1*0601 (OR 13.7, 95% CI 1.3-1.8) were risk factors for the development of EMS, whereas DRB1*07 (OR 0.12, 95% CI 0.02-0.48) and DQA1*0501 (OR 0.23, 95% CI 0.05-0.85) were protective. Similar risk and protective factors were seen for developing EMS following ingestion of implicated LT, except that DRB1*03 was not a risk factor and DQA1*0201 was an additional protective factor. EMS spectrum disorder also showed similar findings, but with DRB1*04 being a risk factor and DRB1*07 and DQA1*0201 being protective. There were no differences in sex distribution, Gm/Km allotypes, or Gm/Km phenotypes among any groups. CONCLUSION: In addition to the xenobiotic dose and subject age, polymorphisms in immune response genes may underlie the development of certain xenobiotic-induced immune-mediated disorders, and these findings may have implications for future related epidemics. PMID- 19790129 TI - Quantifying the impact of transient joint symptoms, chronic joint symptoms, and arthritis: a population-based approach. AB - OBJECTIVE: To estimate the prevalence and co-occurrence of self-reported doctor diagnosed arthritis, chronic joint symptoms (pain, aching, stiffness, or swelling on most days for a month), and transient joint symptoms (pain, aching, stiffness, or swelling but not on most days for a month), and to compare the sociodemographic characteristics, activity limitations, and health-related quality of life (HRQOL) of people with joint conditions with those who have no self-reported doctor-diagnosed arthritis and no joint symptoms. METHODS: Data from the 2004 population-based South Australian Health Omnibus Survey (n = 2,840, ages 18-96 years) were used in the study. Activity limitations were assessed using 10 activity limitations questions from the Short Form 36 health survey. HRQOL was assessed using the Assessment of Quality of Life scale. RESULTS: Half of all respondents reported having joint problems, with 26%, 11%, and 13% reporting self-reported doctor-diagnosed arthritis, chronic joint symptoms, and transient joint symptoms, respectively. Chronic joint conditions (self-reported doctor-diagnosed arthritis and chronic joint symptoms) accounted for 74% of all joint problems and were associated with higher odds of activity limitations and poorer HRQOL. The frequency of transient and chronic joint symptoms was highest among middle-aged participants (ages 45-54 years for transient and 45-64 years for chronic joint symptoms) and those who had a body mass index in the obese range. Prevalence of self-reported doctor-diagnosed arthritis increased with age and was higher among women and those who were overweight or obese. CONCLUSION: This study documented the high prevalence and impact of joint conditions in the community. Chronic joint conditions affect daily life and are substantial barriers for effective public health interventions aimed at reducing obesity and inactivity. PMID- 19790131 TI - Susceptibility to AA amyloidosis in rheumatic diseases: a critical overview. PMID- 19790130 TI - Systemic lupus erythematosus and the risk of cardiovascular disease: results from the nurses' health study. AB - OBJECTIVE: Systemic lupus erythematosus (SLE) has been associated with an increased risk of cardiovascular disease. However, prospective population-based data addressing this association have been lacking. METHODS: We conducted a prospective cohort study among 119,332 women participating in the Nurses' Health Study who were free of cardiovascular disease and SLE at baseline in 1976. Incident SLE was confirmed by medical record review. Cardiovascular events included fatal and nonfatal myocardial infarction, stroke, coronary artery bypass grafting, and angioplasty. The relative risk (RR) of cardiovascular events among participants with SLE as compared with those without SLE was estimated using Cox proportional hazards models. RESULTS: Over 28 years of followup (2.9 million person-years), 8,169 cardiovascular events occurred and 148 women developed incident SLE. The mean age at SLE diagnosis was 52.6 years, and 20 participants with SLE developed a subsequent cardiovascular event. After adjusting for potential confounding factors, including age, race, cardiovascular risk factors, and medication use, the RR of a cardiovascular event in women with SLE compared with those without SLE was 2.26 (95% confidence interval [95% CI] 1.45-3.52). When end points were analyzed separately, the RR for coronary heart disease was 2.25 (95% CI 1.37-3.69) and the RR for stroke was 2.29 (95% CI 0.85-6.15). CONCLUSION: In this prospective population-based study, we found a statistically significant >2-fold increased risk of cardiovascular disease among participants with SLE. The risk was not as high as has been previously reported, which may have been due to the relatively high age at diagnosis of SLE in this cohort. PMID- 19790133 TI - Familial mediterranean Fever in the world. PMID- 19790134 TI - Prevalence and incidence of Wegener's granulomatosis in the UK general practice research database. AB - OBJECTIVE: Wegener's granulomatosis (WG) is a systemic vasculitis of unknown etiology. The UK General Practice Research Database (GPRD) contains the complete primary care records of approximately 3.6 million people. There are no data on the incidence and prevalence of WG from primary care. The aim of the study was to estimate the incidence and prevalence of WG in the GPRD population. METHODS: We identified all patients who had a first diagnosis of WG during 1990-2005, using Oxford Information System and Read codes. The diagnosis was verified by review of a randomly selected sample of 35 records that had identifying data removed. The annual incidence was calculated as the number of incident cases divided by the total person-years. RESULTS: A total of 295 patients (51.2% male) with a first diagnosis of WG were identified during 1990-2005. The median age was 59 years (interquartile range 47-70 years). The overall annual incidence of WG was 8.4 per million (95% confidence interval [95% CI] 7.5-9.4). The annual rate in women and men was 8.1 per million (95% CI 6.8-9.6), and 8.8 per million (95% CI 7.4-10.3), respectively. The incidence was stable throughout the study period. There was an increase in the annual prevalence from 28.8 per million in 1990 to 64.8 per million in 2005. The diagnosis was verified in 28 of 31 available case records. CONCLUSION: This is the first study of the incidence and prevalence of WG in a database from a primary care population. The results are similar to previous studies from secondary and tertiary care and suggest that these studies are representative of the general population. The increasing prevalence with a constant incidence suggests that survival is improving with modern treatment protocols. PMID- 19790132 TI - Clinical and genetic factors predictive of mortality in early systemic sclerosis. AB - OBJECTIVE: To investigate the clinical and genetic variables at initial presentation that predict survival in the Genetics versus Environment in Scleroderma Outcome Study (GENISOS) cohort. METHODS: GENISOS is a prospective, observational study of a multiethnic early systemic sclerosis (SSc) cohort. To date, a total of 250 patients have been enrolled. In addition to clinical and laboratory data, electrocardiograms (EKGs), chest radiographs, and pulmonary function tests have been obtained from each patient. A modified Rodnan skin thickness score, HLA class II genotyping, and a Medsger Damage Index also have been collected. We performed multivariable analyses utilizing the Cox regression following a purposeful model building strategy. RESULTS: The study analyzed 122 white, 47 African American, and 71 Hispanic SSc patients with an average disease duration of 2.6 years at enrollment. At the time of analysis, 52 (20.8%) of the 250 patients had died. In the final multivariable model excluding HLA genes, 7 variables emerged as significant predictors of mortality: age > or =65 years at enrollment, forced vital capacity <50% predicted, clinically significant arrhythmia on EKG, absence of anticentromere antibodies, hypertension, chest radiograph suggestive of pulmonary fibrosis, and low body mass index (BMI). In separate modeling that included HLA genes, HLA alleles DRB1*0802 and DQA1*0501 were significant predictors of mortality in addition to the predictors mentioned above. CONCLUSION: A limited number of variables collected at presentation, including BMI, are able to predict mortality in patients with early SSc. In addition, some of the HLA genes associated with SSc susceptibility are useful for predicting SSc outcome. PMID- 19790135 TI - Heritability of spinal pain and consequences of spinal pain: a comprehensive genetic epidemiologic analysis using a population-based sample of 15,328 twins ages 20-71 years. AB - OBJECTIVE: To assess the relative contribution of genetic and environmental factors to different definitions of spinal pain and consequences of spinal pain. METHODS: The Danish Twin Registry contains detailed survey information on spinal pain and its consequences in twins ages 20-71 years. A classic genetic epidemiologic analysis was performed in order to establish heritability for a number of phenotypes, including location of pain, radiation of pain in the extremities or chest, pain duration, and combinations of pain in >1 spinal area. Consequences included reduced physical activity, sick leave, care seeking, change of work, and disability pension. The analysis included a biometric analysis based on the effect of shared genetic and common environmental factors. Furthermore, a bivariate twin model was fitted to identify genetic and environmental correlations. RESULTS: Altogether, data on 15,328 twin individuals (44% monozygotic and 56% dizygotic) from complete twin pairs were included. Genetic susceptibility explained approximately 38% of lumbar pain, 32% of thoracic pain, and 39% of neck pain. For patterns of pain, estimates were 7% for lumbar/thoracic, 24% for lumbar/cervical, 0% for thoracic/cervical, and 35% for pain in all 3 areas. Moderate to high genetic correlations indicated a common genetic basis for many spinal pain syndromes. In general, heritability was higher for women, and only a minor age effect was seen. CONCLUSION: Heritability estimates for pain in different spinal regions are quite similar and there is a moderate to high genetic correlation between the phenotypes. This may indicate a common genetic basis for a high proportion of spinal pain. PMID- 19790136 TI - Making dollars and sense out of liver transplantation. PMID- 19790137 TI - Conivaptan increases serum sodium in hyponatremic patients with end-stage liver disease. AB - Hyponatremia is associated with increased mortality in patients with end-stage liver disease and a greater risk of perioperative mortality with liver transplantation. We performed a retrospective review of our experience with conivaptan as a means of acutely increasing serum sodium in end-stage liver disease patients. The primary group consisted of 15 patients with end-stage liver disease who remained hyponatremic despite discontinuation of diuretics and a 1-L fluid restriction. Twenty milligrams of conivaptan was intravenously administered over 30 minutes, and this was followed by an infusion of 20 mg over 24 hours for 1 to 4 days. A second group of 9 hyponatremic end-stage liver disease patients was treated with 1-L fluid restriction and conivaptan while remaining on diuretics. In the group without diuretics, the mean serum sodium was 124 mmol/L 1 day before and on the day of conivaptan initiation, but the serum sodium rose to a mean of 127.7 mmol/L by day 1 and further increased to 128.6 mmol/L by the second day of the infusion. Despite the continuation of diuretics, the second group of 9 patients also had an increase in serum sodium from the day of conivaptan initiation (125.7 mmol/L) to 2 days after the treatment (130.6 mmol/L). Eleven patients underwent successful liver transplantation, 2 remained on the list for transplantation, and 11 were not candidates for transplantation and either died (7) or were discharged home and lost to follow-up (4). In conclusion, a short course of conivaptan increases serum sodium in patients with end-stage liver disease and may reduce the risk of proceeding to liver transplantation. Further study in a prospective clinical trial is needed to confirm safety and efficacy. PMID- 19790138 TI - Early noninvasive measurement of the indocyanine green plasma disappearance rate accurately predicts early graft dysfunction and mortality after deceased donor liver transplantation. AB - Early diagnosis of graft dysfunction in liver transplantation is essential for taking appropriate action. Indocyanine green clearance is closely related to liver function and can be measured noninvasively by spectrophotometry. The objectives of this study were to prospectively analyze the relationship between the indocyanine green plasma disappearance rate (ICGPDR) and early graft function after liver transplantation and to evaluate the role of ICGPDR in the prediction of severe graft dysfunction (SGD). One hundred seventy-two liver transplants from deceased donors were analyzed. Ten patients had SGD: 6 were retransplanted, and 4 died while waiting for a new graft. The plasma disappearance rate was measured 1 hour (PDRr60) and within the first 24 hours (PDR1) after reperfusion, and it was significantly lower in the SGD group. PDRr60 and PDR1 were excellent predictors of SGD. A threshold PDRr60 value of 10.8%/minute and a PDR1 value of 10%/minute accurately predicted SGD with areas under the receiver operating curve of 0.94 (95% confidence interval, 0.89-0.97) and 0.96 (95% confidence interval, 0.92 0.98), respectively. In addition, survival was significantly lower in patients with PDRr60 values below 10.8%/minute (53%, 47%, and 47% versus 95%, 94%, and 90% at 3, 6, and 12 months, respectively) and with PDR1 values below 10%/minute (62%, 62%, and 62% versus 94%, 92%, and 88%). In conclusion, very early noninvasive measurement of ICGPDR can accurately predict early severe graft dysfunction and mortality after liver transplantation. PMID- 19790139 TI - Living donor liver transplantation using a left lobe graft from a donor with severe liver trauma: a 7-year follow-up. PMID- 19790140 TI - Pretransplant lymphocyte count predicts the incidence of infection during the first two years after liver transplantation. AB - Patients with end-stage liver disease (ESLD) show a low absolute number of peripheral blood lymphocyte subpopulations (PBLSs). We investigated if the baseline PBLS could categorize orthotopic liver transplantation (OLT) recipients into groups at high or low risk for infection after transplantation. PBLSs were prospectively studied in 63 consecutive patients (42 males; mean age +/- standard deviation: 53.5 +/- 10.3 years) with ESLD prior to OLT. Thirty-five patients (55.6%) developed a total of 79 infectious episodes during the first 2 years post OLT. The median total lymphocyte count and PBLS levels [CD3+ T cells, CD4+ T cells, memory (CD45RO+) CD4+ T cells, T cell receptor alphabeta+ and gammadelta+ subsets, and CD19+ B cells] at baseline were significantly lower in patients with an infection compared with those without one (P < 0.05). There was a significant correlation between the risk of development of a post-OLT infection and a baseline total lymphocyte count < 1.00 x 10(3)/microL (P = 0.001), a baseline CD3+ T cell count < 0.75 x 10(3)/microL (P = 0.009), and a baseline CD4+ T cell count < 0.5 x 10(3)/microL (P = 0.008). In the multivariate analysis, this association between the baseline total lymphocyte level and infection remained significant (odds ratio: 10.1; 95% confidence interval: 1.9-39.5). In conclusion, the pre-OLT total lymphocyte count identifies a subset of patients at high risk for infection. PBLS monitoring prior to OLT may offer an opportunity for surveillance, tapering of immunosuppression, and preemptive therapy. PMID- 19790141 TI - Donor mannose-binding lectin gene polymorphisms influence the outcome of liver transplantation. AB - Mannose-binding lectin (MBL) is a C-type lectin produced mainly by the liver that binds to a wide range of pathogens. Polymorphisms at the promoter and exon 1 of the MBL2 gene are responsible for low serum levels of MBL and have been associated with an increased risk of infections. We prospectively analyzed 95 liver transplant recipients. Well-known functionally relevant polymorphisms of the MBL2 gene of the liver donor were examined by gene sequencing. Infectious events were collected prospectively. No differences in the incidence of infections were found according to the donor MBL2 genotypes. Survival was lower in patients receiving a liver graft from a donor with an exon 1 MBL2 variant genotype, and they had higher infection-related mortality (50% versus 14%, P = 0.040). No differences were found according to other polymorphisms involving the promoter and 5'-untranslated region. When we analyzed bacterial infection episodes, we found that patients receiving a liver from a donor with an exon 1 variant genotype had a higher incidence of septic shock (46% versus 11%, P = 0.004). Independent variables associated with graft or patient survival were as follows: receiving a graft from a donor with an exon 1 MBL2 variant genotype [adjusted hazard ratio (aHR), 9.64; 95% confidence interval (CI), 2.59-36.0], the Model for End-Stage Liver Disease score (aHR, 1.14; 95% CI, 1.05-1.23), and bacterial infections (aHR, 11.1; 95% CI, 2.73-44.9). Liver transplantation from a donor with a variant MBL2 exon 1 genotype was associated with a worse prognosis, mainly because of infections of higher severity. PMID- 19790142 TI - Predicting recurrence after liver transplantation in patients with hepatocellular carcinoma exceeding the up-to-seven criteria. AB - The up-to-seven (Up-to-7) criteria [with 7 being the sum of the size and number of tumors for any given hepatocellular carcinoma (HCC)] have been recently proposed to identify potential candidates for liver transplantation (LT) among patients exceeding the Milan criteria. The aim of this study was to compare the ability of the available pathologic staging systems (the Milan, University of California San Francisco, and Up-to-7 criteria) to predict recurrence. A study population of 479 HCC transplanted patients was identified from prospectively collected databases at Mount Sinai Medical Center (New York, NY) and the University of Padua (Padua, Italy). The best pathologic staging system was identified with log rank, proportion separation index (PSEP), and Cox analyses. Pathologic tumor characteristics (tumor number, tumor size, sum of diameters, macroscopic and microscopic vascular invasion, and grading) were then tested by univariate and multivariate Cox analyses in the prognostic subgroups within and beyond the calculated criteria. The Up-to-7 criteria performed as the best pathologic staging system, the calculated 1-, 3-, and 5-year recurrence probabilities being 4%, 8%, and 14% within the criteria (n = 355) and 22%, 45%, 51% beyond the criteria (n = 124; P < 0.0001) and the calculated PSEP being 0.27 (95% confidence interval = 0.23-0.31). In multivariate analysis, only biological variables (vascular invasion and tumor grade) significantly predicted recurrence beyond the Up-to-7 criteria. A 3-stage pathologic staging system with a potential to be applied in the preoperative setting was thus created: within the Up-to-7 criteria (recurrence rate = 8%), beyond the Up-to-7 criteria without macrovascular invasion and poorly differentiated grade (recurrence rate = 24%), and beyond the Up-to-7 criteria with macrovascular invasion and/or poorly differentiated grade (recurrence rate = 45%). In conclusion, HCC patients within the pathologic Up-to-7 criteria were associated with a low risk of recurrence after LT. Beyond these criteria, however, a significant proportion of patients with a good HCC biological profile had an acceptable risk of recurrence. PMID- 19790143 TI - A report of human herpesvirus 6-associated encephalitis in a solid organ transplant recipient and a review of previously published cases. AB - Human herpesvirus 6 (HHV-6) is a common pathogen among children, classically presenting as fever and rash that resolve without specific therapy (exanthem subitum or roseola infantum). Also identified as a pathogen in hematopoietic cell transplant and solid organ transplant (SOT) recipients, it has been recognized as a cause of limbic encephalitis, characterized by confusion and amnesia, with magnetic resonance imaging findings of T2 hyperintensity of the amygdala and hippocampus. We report a case of limbic encephalitis associated with HHV-6 infection in a liver transplant recipient, and we review previously reported cases of HHV-6 encephalitis in SOT recipients. PMID- 19790144 TI - Kinetics of host immune responses and cytomegalovirus resistance in a liver transplant patient. AB - Among solid organ transplant (SOT) recipients, donor-seropositive/recipient seronegative (D+/R-) cytomegalovirus (CMV) status is associated with the highest risk of ganciclovir-resistant CMV disease, which has been reported for patients receiving oral ganciclovir but not valganciclovir prophylaxis. We report a case of CMV breakthrough infection in a D+/R- liver transplant patient while he was receiving oral valganciclovir. Forty samples collected over 6 months were analyzed for the CMV viral load, lymphocyte counts, cytokine levels, and lymphocyte differentiation status. Genotypic resistance testing of the viral UL97 gene was performed when the patient failed to respond. CMV viremia occurred on day 50 post-transplant, and 5 samples taken between days 50 and 85 showed the wild-type UL97 genotype. The appearance of deletion 594-595 was observed from day 114 post-transplant. Viral loads declined when foscarnet was commenced and remained below 10,000 copies/mL when the lymphocyte count was greater than 1000/microL (P = 0.02). T cell responses revealed significant expansion of CD8+ terminal effector memory cells. CD4+ cells were largely populations of naive and central memory cells. Circulating interleukin 10 (IL-10) levels correlated with the viral load (P < 0.0001). Seroconversion occurred on day 230. The CMV viral load in combination with lymphocyte counts and IL-10 may be a predictive marker for the risk of development of resistant CMV disease in D+/R- SOT patients. PMID- 19790145 TI - Liver transplantation for familial amyloidotic polyneuropathy: impact on Swedish patients' survival. AB - Liver transplantation (LTx) for familial amyloidotic polyneuropathy (FAP) is an accepted treatment for this fatal disease. However, the long-term outcome with respect to that of nontransplanted patients has not been fully elucidated. The aim of this study was to compare the long-term survival of Swedish LTx FAP patients with that of historical controls, especially with respect to the age at onset of the disease and gender. In order to evaluate the outcome of LTx as a treatment for FAP, survival was calculated from the onset of disease. One hundred forty-one FAP patients, 108 transplanted and 33 not transplanted, were included in the study. Significantly increased survival was noted for LTx patients in comparison with controls. The outcome was especially favorable for those with an early onset of the disease (age at onset < 50 years) in comparison with early onset controls (P < 0.001). In contrast, no significant difference for late-onset cases (> or = 50 years) was found. Transplanted late-onset females had significantly improved survival in comparison with transplanted late-onset males (P = 0.02). We were unable to find significant differences in survival between patients with long (> or = 7 years) or short (<7 years) disease duration at transplantation. The survival of male patients with late-onset disease appeared not to improve with LTx. LTx is an efficacious treatment for improving the survival of early-onset FAP patients. Further studies are needed to analyze the cause of the poorer outcome for late-onset male patients. PMID- 19790146 TI - Enfuvirtide: a safe and effective antiretroviral agent for human immunodeficiency virus-infected patients shortly after liver transplantation. AB - The aim of this study was to evaluate the impact of an enfuvirtide-based antiretroviral (ARV) regimen on the management of immunosuppression and follow-up in hepatitis C virus (HCV)/hepatitis B virus (HBV)/human immunodeficiency virus (HIV)-coinfected liver transplant patients in comparison with a lopinavir/ritonavir-based ARV regimen. Tacrolimus and cyclosporine trough concentrations were determined at a steady state during 3 periods: after liver transplantation without ARV treatment (period 1), at the time of ARV reintroduction (period 2), and 2 to 3 months after liver transplantation (period 3). The findings for 22 HIV-coinfected patients were compared (18 with HCV and 4 with HBV); 11 patients were treated with enfuvirtide and were matched with 11 lopinavir/ritonavir-exposed patients. During period 1, tacrolimus and cyclosporine A doses were 8 and 600 mg/day, respectively, and the trough concentrations were within the therapeutic range in both groups. In period 2, the addition of lopinavir/ritonavir to the immunosuppressant regimen enabled a reduction in the dose of immunosuppressants required to maintain trough concentrations within the therapeutic range (to 0.3 mg/day for tacrolimus and 75 mg/day for cyclosporine). Immunosuppressant doses were not modified by the reintroduction of enfuvirtide, there being no change in the mean trough concentrations over the 3 periods. CD4 cell counts remained at about 200 cells/mm3. The HIV RNA viral load remained undetectable. Both groups displayed signs of mild cytolysis and cholestasis due to the recurrence of HCV, whereas no renal insufficiency was observed. Enfuvirtide is an attractive alternative to standard ARV therapy, facilitating the management of drug-drug interactions shortly after liver transplantation. Moreover, the lack of liver toxicity renders this drug valuable in the event of a severe HCV recurrence. PMID- 19790147 TI - Prevalence of hepatitis E virus infection in liver transplant recipients. AB - Hepatitis E virus (HEV) infection is known to run a self-limited course. Recently, chronic hepatitis E has been described in several immunosuppressed patients after solid organ transplantation. The prevalence of HEV infection after transplantation, however, is unknown. We studied HEV parameters [HEV RNA, HEV immunoglobulin M (IgM), and HEV immunoglobulin G (IgG) by enzyme-linked immunosorbent assay and confirmatory immunoblotting] in a cohort of 285 adult liver transplant recipients. The most recent freeze-stored sera were investigated, and if they were positive, a retrospective analysis was performed. Samples from 274 patients (96.1%) tested negative for all HEV parameters. This included a patient described earlier as having experienced an episode of chronic HEV hepatitis in the past. One patient was found positive for HEV RNA without HEV antibodies. She presently suffers from chronic HEV hepatitis and has also been described before. Sera from 9 patients tested positive for HEV IgG without HEV IgM or HEV RNA. Six of these 9 patients (2.1% of the total) were found to have HEV IgG antibodies in retrospect related to an HEV infection at some time pre transplant as they also tested positive in a pretransplant serum sample. One of these 9 patients suffered in retrospect from a chronic HEV infection with mild hepatitis between 2 and 5 years after liver transplantation on the basis of the course of HEV RNA, IgM, and IgG, aminotransferases, and liver histology. Overall, the prevalence of acquired HEV hepatitis after liver transplantation was 1% in this cohort. We conclude that liver transplant recipients have a risk for chronic HEV infection, but the prevalence is low. PMID- 19790148 TI - Acute liver failure at 26 weeks' gestation in a patient with sickle cell disease. AB - Orthotopic liver transplantation (OLT) for acute liver failure (ALF) during pregnancy is an uncommon occurrence with variable outcomes. In pregnancy-related liver failure, prompt diagnosis and immediate delivery are essential for a reversal of the underlying process and for maternal and fetal survival. In rare cases, the reason for ALF during pregnancy is either unknown or irreversible, and thus OLT may be necessary. This case demonstrates the development of cryptogenic ALF during the 26th week of pregnancy in a woman with sickle cell disease. She underwent successful cesarean delivery of a healthy male fetus at 27 weeks with concurrent OLT. This report provides a literature review of OLT in pregnancy and examines the common causes of ALF in the pregnant patient. On the basis of the management and outcome of our case and the literature review, we present an algorithm for the suggested management of ALF in pregnancy. PMID- 19790149 TI - Severe left-sided heart failure early after liver transplantation. AB - Left-sided heart failure (LHF) after liver transplantation (LT) is rare and poorly understood. We performed a case-control study. We reviewed the data of all patients with LHF after LT at our center from November 2000 to July 2007. Each case was matched to 1 LT control without LHF for age, sex, date of transplantation, and liver disease. Twenty of 599 patients developed LHF (3.3%). Pretransplant cardiovascular characteristics and risk factors were similar in cases and controls, except for the prevalence of left ventricular enlargement, which was greater in controls. At the time of diagnosis, the median left ventricular ejection fraction was 25% in cases, and increased afterload was documented by markedly elevated vascular resistances. The prevalence of infection at the time of LHF in cases was higher (55%) than in controls (10%, P = 0.02). The reported causes of LHF were infection [bacterial (n = 1) or viral (n = 7)], intraoperative cardiac arrest (n = 2), and unknown (n = 10). In comparison with their controls, cases with immediate postoperative LHF (day 0) did not have a higher Model for End-Stage Liver Disease (MELD) score (15 versus 21.5) or infection prevalence rate (17% versus 34%), whereas those with later onset LHF had a significantly higher MELD score (25.5 versus 17, P = 0.01) and infection prevalence rate (71% versus 0%, P = 0.002). Mortality was 45% in cases versus 0% in controls (P = 0.004), and the 11 cases who survived recovered from LHF. In conclusion, LHF after LT carries a high mortality risk and may have different causes. Except for immediate postoperative cases, an infection and an elevated MELD score appear to be determinant. PMID- 19790150 TI - Conversion from a calcineurin inhibitor to everolimus therapy in maintenance liver transplant recipients: a prospective, randomized, multicenter trial. AB - Calcineurin inhibitors (CNIs) contribute to renal dysfunction following liver transplantation. This prospective, randomized, multicenter, 6-month study (with an additional 6 months of follow-up) evaluated whether everolimus with CNI reduction or discontinuation would improve renal function in maintenance liver transplant recipients experiencing CNI-related renal impairment. Patients started everolimus therapy with CNI reduction or discontinuation (n = 72) or continued receiving standard-exposure CNI (n = 73). At month 6, 80% of the patients who had converted to everolimus had discontinued the CNI. The mean change in creatinine clearance (CrCl) from baseline to month 6 was similar between groups (everolimus, 1.0 +/- 10.2 mL/minute; controls, 2.3 +/- 7.8 mL/minute; P = 0.46), so the primary study endpoint (8 mL/minute difference in the change in CrCl) was not achieved. Among patients who continued everolimus according to the protocol, the mean increase in CrCl was 2.1 (n = 53) and 3.8 mL/minute (n = 38) at months 6 and 12, respectively, versus 2.4 (n = 68) and 3.5 mL/minute in controls (n = 51). The high frequency of CNI dose reductions in controls (77% of the patients) and the relatively long mean time post-transplant (>3 years) likely contributed to the small difference in CrCl. Biopsy-proven acute rejection occurred in 1.4% of the patients in each group, with no graft losses. Study drug discontinuation was higher in everolimus-treated patients, and adverse events were more frequent. These data demonstrate that everolimus allows for discontinuation or a major reduction of CNI exposure in liver allograft recipients suffering CNI-related renal dysfunction without a loss of efficacy. Trials targeting earlier conversion post-transplantation are required to confirm the efficacy and safety of everolimus for improving renal function after liver transplantation. PMID- 19790151 TI - Liver grafts from donors with central nervous system tumors: a single-center perspective. AB - Traditionally, patients who die with a malignancy have been excluded from donation. However, it has become a common practice to accept organs from donors that have low-grade tumors or tumors with low metastatic potential. The aim of this study was to analyze our experience with the use of liver grafts from donors with central nervous system (CNS) tumors. A retrospective review of 1173 liver transplants performed between 1992 and 2006 identified 42 donors diagnosed with a CNS tumor. Thirty-two tumors were malignant, and 10 tumors were benign. Forty-two liver transplant recipients received livers from these donors. All patients were followed until May 2007 with a mean follow-up of 29 +/- 17 months. Among 42 donors, there were 28 males and 14 females. The mean donor risk index was 1.78 +/ 0.39. Twenty (47.6%) of the CNS tumors were glioblastoma multiforme (astrocytoma grade IV), 11 (26.2%) were other astrocytomas, and 1 (2.4%) was an anaplastic ependymoma. Twenty (62.5%) neoplasms were grade IV tumors, 8 (25%) were grade II tumors, and 4 (12.5%) were grade III tumors. Over 80% of the patients had at least 1 kind of invasive procedure violating the blood-brain barrier. The rate of recurrence for the entire group was 2.4% (all CNS tumors). There were 7 (7.2%) deaths in all. The most common cause of death was sepsis (n = 3, 7.2%). There was no difference in survival between recipients of grafts from donors with CNS tumors and recipients of grafts from donors without CNS tumors (1 year: 82% versus 83.3%, P = not significant; 3 years: 77.4% versus 72%, P = not significant). In conclusion, in our experience, despite violation of the blood brain barrier and high-grade CNS tumors, recurrence was uncommon. Grafts from these donors are often an overlooked source of high-quality organs from younger donors and can be appropriately used, particularly in patients who, despite low Model for End-Stage Liver Disease scores, carry a high risk of mortality. PMID- 19790152 TI - Recipient age affects long-term outcome and hepatitis C recurrence in old donor livers following transplantation. AB - We studied the role of donor and recipient age in transplantation/ischemia reperfusion injury (TIRI) and short- and long-term graft and patient survival. Eight hundred twenty-two patients underwent deceased donor liver transplantation, with 197 donors being > or = 60 years old. We evaluated markers of reperfusion injury, graft function, and clinical outcomes as well as short- and long-term graft and patient survival. Increased donor age was associated with more severe TIRI and decreased 3- and 5-year graft survival (73% versus 85% and 72% versus 81%, P < 0.001) and patient survival (77% versus 88% and 77% versus 82%, P < 0.003). Hepatitis C virus (HCV) infection and recipient age were the only independent risk factors for graft and patient survival in patients receiving an older graft. In the HCV(+) cohort (297 patients), patients > or = 50 years old who were transplanted with an older graft versus a younger graft had significantly decreased 3- and 5-year graft survival (68% versus 83% and 64% versus 83%, P < 0.009). In contrast, HCV(+) patients < 50 years old had similar 3 and 5-year graft survival if transplanted with either a young graft or an old graft (81% versus 82% and 81% versus 82%, P = 0.9). In conclusion, recipient age and HCV status affect the graft and patient survival of older livers. Combining older grafts with older recipients should be avoided, particularly in HCV(+) patients, whereas the effects of donor age can be minimized in younger recipients. PMID- 19790153 TI - Risk factors for recurrence of autoimmune hepatitis after liver transplantation. AB - Autoimmune hepatitis has been reported to recur after liver transplantation. The aim of our study was to evaluate the risk factors associated with recurrence of autoimmune hepatitis. Forty-six patients that underwent liver transplantation because of end-stage liver disease secondary to autoimmune hepatitis were studied. Recurrence of autoimmune hepatitis was diagnosed in 11 of the 46 (24%) patients, and the overall 5-year probability of recurrence was 18%. By univariate Cox analysis, the features before liver transplantation associated with a higher risk of recurrence were concomitant autoimmune disease [hazard ratio (HR), 3.74; 95% confidence interval (CI), 1.05-13.36; P = 0.04], high aspartate aminotransferase (HR, 1.09; 95% CI, 1.03-1.14; P = 0.002), high alanine aminotransferase (HR, 1.09; 95% CI, 1.03-1.20; P = 0.003), and high immunoglobulin G (IgG; HR, 1.25; 95% CI, 1.11-1.41; P = 0.0003). Moreover, patients with recurrence had a higher frequency of moderate to severe inflammatory activity (HR, 5.3; 95% CI, 1.55-18.79; P = 0.008) and plasma cell infiltration in the liver explant (HR, 5.8; 95% CI, 1.52-22.43; P = 0.01). In the multivariate Cox analysis, only the presence of moderate to severe inflammation (HR, 6.9; 95% CI, 1.76-26.96; P = 0.006) and high IgG levels before liver transplantation (HR, 7.5; 95% CI, 1.45-38.45; P = 0.02) were independently associated with the risk of autoimmune hepatitis recurrence. In conclusion, patients with concomitant autoimmune disease, high aspartate aminotransferase, alanine aminotransferase, and IgG before the transplant, or moderate to severe inflammatory activity or plasma cell infiltration in the liver explant have a higher risk of recurrent disease. These findings suggest that recurrence of autoimmune hepatitis may reflect incomplete suppression of disease activity prior to liver transplantation. PMID- 19790154 TI - Mesenchymal stem cells as immunomodulators after liver transplantation. AB - Mesenchymal stem cells (MSCs) are promising candidate cells for immunomodulation therapy that are currently being tested in the preclinical and clinical setting. MSCs suppress the immune response in a variety of in vitro and disease models and may thus be of benefit for patients suffering from autoimmune disorders or transplant rejection. The mechanism by which MSCs modulate the immune response is still under thorough investigation, but it most likely involves expression of local factors such as indoleamine 2,3-dioxygenase, inducible nitric oxide synthase, and others as well as interactions with dendritic or antigen-presenting cells. Although MSCs have been evaluated in clinical phase I and II studies for graft-versus-host disease and heart, kidney, and bone disease, their introduction into solid organ transplantation is still eagerly awaited. In this short review, we summarize the current understanding of immunomodulation achieved by MSC therapies and introduce a possible outline for a clinical study that will use MSCs in the context of a calcineurin inhibitor-free induction protocol after liver transplantation. PMID- 19790155 TI - Liver transplantation cost in the model for end-stage liver disease era: looking beyond the transplant admission. AB - We examined the relationship between the total cost incurred by liver transplantation (LT) recipients and their Model for End-Stage Liver Disease (MELD) score at the time of transplant. We used a novel database linking billing claims from a large private payer with the Organ Procurement and Transplantation Network registry. Included were adults who underwent LT from March 2002 through August 2007 (n = 990). Claims within the year preceding and following transplantation were analyzed according to the recipient's calculated MELD score. Cost was the primary endpoint and was assessed by the length of stay and charges. Transplant admission charges represented approximately 50% of the total cost of LT. MELD was a significant cost driver for pretransplant, transplant, and total charges. A MELD score of 28 to 40 was associated with additional charges of $349,213 (P < 0.05) in comparison with a score of 15 to 20. Pretransplant and transplant admission charges were higher by $152,819 (P < 0.05) and $64,286 (P < 0.05), respectively, in this higher MELD group. No differences by MELD score were found for posttransplant charges. Those in the highest MELD group also experienced longer hospital stays both in the pretransplant period and at the time of LT but did not have higher rates of re-admissions. In conclusion, high MELD patients incur significantly higher costs prior to and at the time of LT. Following LT, the MELD score is not a significant predictor of cost or re admission. PMID- 19790156 TI - Rapamycin inhibits hepatic fibrosis in rats by attenuating multiple profibrogenic pathways. AB - Hepatic stellate cell transdifferentiation, epithelial-mesenchymal cell transition, and the ductular reaction each contribute to the development of hepatic fibrosis in cholestatic liver diseases. Inhibitors of mammalian target of rapamycin have antifibrotic properties. We evaluated the hypothesis that the antifibrotic action of rapamycin is due to attenuated myofibroblast proliferation in addition to an inhibitory effect on epithelial-mesenchymal transition and the ductular reaction. Hepatic fibrosis was induced by bile duct ligation, and rodents received 1.5 mg/kg/day rapamycin by subcutaneous infusion for 21 days. The expression of various markers of hepatic fibrosis, stellate cell transactivation, epithelial-mesenchymal transition, and the ductular reaction was compared between treated and untreated animals. Hepatic fibrosis, hepatic procollagen type 1 messenger RNA, and alpha-smooth muscle actin expression were significantly reduced in treated animals. Hepatic stellate cell procollagen expression and proliferation were also reduced by rapamycin. The following markers of epithelial-mesenchymal transition--vimentin protein expression, S100 calcium binding protein A4 and transforming growth factor beta 1 messenger RNA, and the mothers against decapentaplegic homolog signaling pathway--were all reduced after rapamycin treatment. The intensity of the ductular reaction was reduced by rapamycin as assessed by histopathological scoring and by reduced cytokeratin 19 expression. Rapamycin caused a reduction in hepatic progenitor cell proliferation. Together, these data show that multiple profibrogenic pathways are activated in an animal model of cholestasis and that rapamycin attenuates epithelial-mesenchymal transition and the ductular reaction as well as hepatic stellate cell activation. PMID- 19790157 TI - Plasma disappearance rate of indocyanine green: a tool to evaluate early graft outcome after liver transplantation. AB - Indocyanine green clearance (Cl-ICG) has been used to assess liver function and hepatic blood flow mainly before and after hepatic surgery. Cl-ICG (invasive method) has been reported to be a good marker of early graft function after liver transplantation (LT). The goal of this study was to determine if the indocyanine green plasma disappearance rate (PDR-ICG), measured by a noninvasive technique (LiMON, Impulse Medical System, Munich, Germany), is predictive of complications and graft outcome after LT. From September 2005 to June 2006, 72 LT recipients were included in the study. PDR-ICG was measured daily (from day 0 to day 5 after LT) with a digital sensor after patients were injected with 0.25 mg/kg indocyanine green. A PDR-ICG cutoff level of 12.85%/minute was predictive of the development of a serious postoperative complication. The sequential changes of PDR-ICG enabled us to differentiate 2 groups: (1) patients with early severe complications (hepatic artery thrombosis, primary graft nonfunction, or sepsis) who had a low value of PDR-ICG during the first 5 posttransplantation days (average, 8.8 +/- 4.5%/minute) and (2) patients who developed acute rejection and who had a progressive reduction of PDR-ICG between days 0 and 5 (from 25.5 +/- 4.8 to 10.3 +/- 2.5%/minute; P < 0.002). In conclusion, after LT, PDR-ICG (a noninvasive technique), measured regularly during the first 5 postoperative days, is a safe technique that can predict early postoperative complications. PMID- 19790158 TI - Role of hydrogen sulfide in hepatic ischemia-reperfusion-induced injury in rats. AB - Hydrogen sulfide (H2S) displays anti-inflammatory and cytoprotective activities as evidenced by the inhibition of myocardial ischemia-reperfusion injury and production of lipid peroxidation. H2S also exerts many physiological or pathological effects on livers. Therefore, we designed the present study to investigate the roles of H2S in hepatic ischemia-reperfusion (HIR)-induced injury in rats by measuring H2S levels, H2S synthesizing activity, and cystathionine gamma-lyase (CSE) messenger RNA (mRNA) expression. We also applied DL-propargyl glycine (PAG) and sodium hydrosulfide (NaHS) to investigate their effects on the severity of liver injury induced by HIR. The levels of H2S, H2S production activity, and CSE mRNA expression in livers were increased by HIR. Administration of NaHS significantly attenuated the severity of liver injury and inhibited the production of lipid peroxidation, serum inflammatory factors [including nitric oxide, tumor necrosis factor alpha (TNF-alpha), interleukin 10, and intercellular cell adhesion molecule 1], cell apoptosis, and apoptosis-related proteins (including caspase-3, Fas, Fas ligand, and TNF-alpha), which were caused or elevated by HIR, whereas PAG aggravated them. However, NaHS or PAG did not show significant effects on the activation of caspase-9, which was also increased by HIR. Although further investigation is required, this study may indicate that H2S plays a protective role in HIR-induced injury. PMID- 19790159 TI - Interventional percutaneous trans-splenic approach in the management of portal venous occlusion after living donor liver transplantation. PMID- 19790160 TI - Live donor liver transplantation for Budd-Chiari syndrome: anastomosis of the right hepatic vein to the right atrium. PMID- 19790161 TI - Should transplant hepatologists serve as primary care physicians? PMID- 19790162 TI - Antibody to hepatitis B core antigen-positive grafts: not perfect but no longer marginal. PMID- 19790163 TI - Recurrent autoimmune hepatitis after liver transplantation: a disease continuum or a fresh start? PMID- 19790164 TI - Survival after orthotopic liver transplantation: the impact of antibody against hepatitis B core antigen in the donor. AB - Liver transplantation using grafts from donors with antibody against hepatitis B core antigen (anti-HBc) increases the recipients' risk of developing hepatitis B virus (HBV) infection post-transplantation. Our aim was to assess whether using such grafts was associated with reduced posttransplantation survival and whether this association depended on recipients' prior exposure to HBV on the basis of their pretransplantation serological patterns. Data were derived from the United Network for Organ Sharing on adult, cadaveric, first-time liver transplants performed between 1994 and 2006. Among recipients who did not have HBV infection before transplantation, those with anti-HBc-positive donors had significantly worse unadjusted posttransplantation patient survival than recipients with anti HBc-negative donors [hazard ratio, 1.35; 95% confidence interval (CI), 1.21 1.50]. However, after adjustments for other predictors of posttransplantation survival, including donor age, donor race, and recipient underlying liver diseases, patient survival was not significantly different between the 2 groups (hazard ratio, 1.09; 95% CI, 0.97-1.24). Among recipients without antibody against hepatitis B surface antigen (anti-HBs), use of anti-HBc-positive donor grafts was associated with a trend toward worse survival (adjusted hazard ratio, 1.18; 95% CI, 0.95-1.46), whereas no such trend was observed among recipients positive for anti-HBs. In conclusion, in patients without HBV infection before transplantation, using anti-HBc-positive donors was not independently associated with worse posttransplantation survival. Matching these donors to recipients with anti-HBs pre-transplantation may be especially safe. PMID- 19790165 TI - Outcomes of liver transplantation for paracetamol (acetaminophen)-induced hepatic failure. AB - Paracetamol (acetaminophen) hepatotoxicity, whether due to intentional overdose or therapeutic misadventure, is an indication for liver transplantation in selected cases. However, there is a concern that long-term outcomes may be compromised by associated psychopathology that may predispose patients to further episodes of self-harm or poor treatment adherence. We therefore undertook a retrospective analysis of patients transplanted for paracetamol-induced fulminant hepatic failure (FHF) to determine their long-term outcomes, psychiatric problems, and compliance and whether these issues could be predicted from pretransplant information. Records from patients undergoing liver transplantation for paracetamol-associated liver failure in this unit and 2 comparison groups (patients undergoing liver replacement for FHF from other causes and for chronic liver diseases) were examined. Of 60 patients transplanted for paracetamol induced FHF between 1989 and 2007, 44 (73%) survived to discharge. Currently, 35 patients (58%) are surviving at an average of 9 years post-transplantation. The incidence of psychiatric disease (principally depression) and 30-day mortality were greatest in the paracetamol group, but for those who survived 30 days, there was no difference in long-term survival rates between the groups. Adherence to follow-up appointments and compliance with immunosuppression were lowest in the paracetamol overdose group. Poor adherence was not predicted by any identifiable premorbid psychiatric conditions. Two patients grafted for paracetamol FHF died from self-harm (1 from suicide and 1 from alcoholic liver disease after 5 years). This study suggests that, notwithstanding the shortage of donor liver grafts, transplantation is an appropriate therapy in selected patients, although close follow-up is indicated. PMID- 19790166 TI - Preconditioning, organ preservation, and postconditioning to prevent ischemia reperfusion injury to the liver. AB - Ischemia and reperfusion lead to injury of the liver. Ischemia-reperfusion injury is inevitable in liver transplantation and trauma and, to a great extent, in liver resection. This article gives an overview of the mechanisms involved in this type of injury and summarizes protective and treatment strategies in clinical use today. Intervention is possible at different time points: during harvesting, during the period of preservation, and during implantation. Liver preconditioning and postconditioning can be applied in the transplant setting and for liver resection. Graft optimization is merely possible in the period between the harvest and the implantation. Given that there are 3 stages in which a surgeon can intervene against ischemia-reperfusion injury, we have structured the review as follows. The first section reviews the approaches using surgical interventions, such as ischemic preconditioning, as well as pharmacological applications. In the second section, static organ preservation and machine perfusion are addressed. Finally, the possibility of treating the recipient or postconditioning is discussed. PMID- 19790167 TI - The use of preoperative nutritional interventions to protect against hepatic ischemia-reperfusion injury. AB - Preoperative fasting was introduced in the 19th century to reduce the risk of aspiration pneumonia while patients were under general anesthesia. During the last decades, the value of preoperative fasting has been questioned, and more liberal guidelines have been proposed, such as the use of preoperative carbohydrate-rich drinks. Here we review both old and new evidence supporting the view that fasting slightly longer than overnight is beneficial for an entirely different purpose: protection against certain types of stress, such as ischemia reperfusion injury. We provide a framework to explain these benefits as well as future applications and alternatives that could be used to induce the protection afforded by nutritional interventions. PMID- 19790168 TI - Long-term management after liver transplantation: primary care physician versus hepatologist. AB - As long-term survival after liver transplantation increases, metabolic complications are becoming increasingly prevalent. Given concerns about which group of providers should be managing liver recipients and how well metabolic complications are managed, we administered a postal survey to 280 transplant hepatologists to determine attitudes, perceptions, and practice patterns in the management of metabolic complications after transplantation. The response rate was 68.2%. There was great variation in patterns of practice across the United States with respect to the number of posttransplant clinics, clinic format, and number of recipients cared for per week. Hepatologists, primary care physicians (PCPs), and surgeons were primarily responsible for the overall care of liver recipients 1 year or more after liver transplantation according to 66%, 24%, and 8% of respondents, respectively. Hepatologists felt that metabolic complications were common, but few strongly agreed that hypertension (33.3%), chronic renal insufficiency (3.8%), diabetes mellitus (8.8%), dyslipidemia (11.1%), and bone disease (12.8%) were well controlled. The majority of hepatologists indicated that ideally PCPs should be managing recipients' hypertension, diabetes mellitus, dyslipidemia, and bone disease (78.8%, 63.1%, 78.3%, and 72.5%), but they felt that in actuality, PCPs were managing these conditions less frequently (45.4%, 51.4%, 44.6%, and 38%). In conclusion, metabolic complications are perceived to be common but not well controlled post-transplant, and most hepatologists feel that PCPs should take a more active role in the management of these complications. Future studies are needed to identify barriers to care in the treatment of metabolic complications post-transplant with the goal of improving long-term morbidity and mortality. PMID- 19790169 TI - Infrahepatic cavocavostomy: expanding the armamentarium for the liver transplant surgeon. PMID- 19790170 TI - Individual sensitivity to pain expectancy is related to differential activation of the hippocampus and amygdala. AB - Anxiety arising during pain expectancy can modulate the subjective experience of pain. However, individuals differ in their sensitivity to pain expectancy. The amygdale and hippocampus were proposed to mediate the behavioral response to aversive stimuli. However, their differential role in mediating anxiety-related individual differences is not clear. Using fMRI, we investigated brain activity during expectancy to cued or uncued thermal pain applied to the wrist. Following each stimulation participants rated the intensity of the painful experience. Activations in the amygdala and hippocampus were examined with respect to individual differences in harm avoidance (HA) personality trait, and individual sensitivity to expectancy, (i.e. response to cued vs. uncued painful stimuli). Only half of the subjects reported on cued pain as being more painful than uncued pain. In addition, we found a different activation profile for the amygdala and hippocampus during pain expectancy and experience. The amygdala was more active during expectancy and this activity was correlated with HA scores. The hippocampal activity was equally increased during both pain expectancy and experience, and correlated with the individual's sensitivity to expectancy. Our findings suggest that the amygdala supports an innate tendency to approach or avoid pain as reflected in HA trait, whereas the hippocampus mediates the effect of context possibly via appraisal of the stimulus value. PMID- 19790171 TI - Neuroanatomical differences in brain areas implicated in perceptual and other core features of autism revealed by cortical thickness analysis and voxel-based morphometry. AB - Autism spectrum disorder is a complex neurodevelopmental variant thought to affect 1 in 166 [Fombonne (2003): J Autism Dev Disord 33:365-382]. Individuals with autism demonstrate atypical social interaction, communication, and repetitive behaviors, but can also present enhanced abilities, particularly in auditory and visual perception and nonverbal reasoning. Structural brain differences have been reported in autism, in terms of increased total brain volume (particularly in young children with autism), and regional gray/white matter differences in both adults and children with autism, but the reports are inconsistent [Amaral et al. (2008): Trends Neurosci 31:137-145]. These inconsistencies may be due to differences in diagnostic/inclusion criteria, and age and Intelligence Quotient of participants. Here, for the first time, we used two complementary magnetic resonance imaging techniques, cortical thickness analyses, and voxel-based morphometry (VBM), to investigate the neuroanatomical differences between a homogenous group of young adults with autism of average intelligence but delayed or atypical language development (often referred to as "high-functioning autism"), relative to a closely matched group of typically developing controls. The cortical thickness and VBM techniques both revealed regional structural brain differences (mostly in terms of gray matter increases) in brain areas implicated in social cognition, communication, and repetitive behaviors, and thus in each of the core atypical features of autism. Gray matter increases were also found in auditory and visual primary and associative perceptual areas. We interpret these results as the first structural brain correlates of atypical auditory and visual perception in autism, in support of the enhanced perceptual functioning model [Mottron et al. (2006): J Autism Dev Disord 36:27-43]. PMID- 19790172 TI - Hemodynamic responses to speech and music in newborn infants. AB - We used near-infrared spectroscopy (NIRS) to study responses to speech and music on the auditory cortices of 13 healthy full-term newborn infants during natural sleep. The purpose of the study was to investigate the lateralization of speech and music responses at this stage of development. NIRS data was recorded from eight positions on both hemispheres simultaneously with electroencephalography, electrooculography, electrocardiography, pulse oximetry, and inclinometry. In 11 subjects, statistically significant (P < 0.02) oxygenated (HbO2) and total hemoglobin (HbT) responses were recorded. Both stimulus types elicited significant HbO2 and HbT responses on both hemispheres in five subjects. Six of the 11 subjects had positive HbO2 and HbT responses to both stimulus types, whereas one subject had negative responses. Mixed positive and negative responses were observed in four neonates. On both hemispheres, speech and music responses were significantly correlated (r = 0.64; P = 0.018 on the left hemisphere (LH) and r = 0.60; P = 0.029 on the right hemisphere (RH)). On the group level, the average response to the speech stimuli was statistically significantly greater than zero in the LH, whereas responses on the RH or to the music stimuli did not differ significantly from zero. This suggests a more coherent response to speech on the LH. However, significant differences in lateralization of the responses or mean response amplitudes of the two stimulus types were not observed on the group level. PMID- 19790173 TI - Remission in schizophrenia: one-year Italian prospective study of risperidone long-acting injectable (RLAI) in patients with schizophrenia or schizoaffective disorder. AB - OBJECTIVES: To evaluate the maintenance of efficacy of risperidone long-acting injectable (RLAI) in stable patients with schizophrenia or schizoaffective disorders. The prevalence of patients who met standardized remission criteria will be also evaluated as well as the predictors factors of remission according to psychopathological, psychosocial and subjective correlates. METHODS: 52-week, open-label prospective trial in 347 stable patients switching directly to RLAI from any previous antipsychotic treatment. RESULTS: One year of treatment was completed by 70% of patients. Positive and Negative Syndrome Scale (PANSS) total and subscale, Global Assessment of Functioning (GAF) and Clinical Global Impression (CGI) scores improved from baseline at each assessment visit (p < 0.001, p < 0.001 and p < 0.05, respectively). Drug Attitude Inventory 30 (DAI30) scores improved significantly from month 3 onwards. 32% of patients met sustained remission at week 52. In a logistic regression model less severe positive and negative PANSS scores at baseline predicted remission (p < 0.001). RLAI treatment was well tolerated: one-third of patients reported mild to moderate adverse events (AEs). Eleven patients (3.2%) discontinued treatment due to an AE. No significant weight gain (p = 0.093) was reported. CONCLUSIONS: RLAI treatment up to one year improved symptoms and global functioning versus baseline, indicating that an established and accepted antipsychotic therapy can enable patients with schizophrenia to achieve and maintain remission. PMID- 19790174 TI - Effects of switching to long-acting injectable risperidone from oral atypical antipsychotics on cognitive function in patients with schizophrenia. AB - OBJECTIVE: To investigate changes in cognitive function and clinical features following a switch from oral atypical antipsychotics (AAPs) to long-acting injectable risperidone (LAIR) in patients with schizophrenia. METHODS: Thirty-six patients with schizophrenia treated with oral AAPs participated in this open label, 26-week study. Cognitive functions were measured at baseline and at 12 and 26 weeks. The secondary outcome measures included the Positive and Negative Syndrome Scale (PANSS), Social and Occupational Functioning Assessment Scale (SOFAS), Scale for Unawareness of Mental Disorder (SUMD), and measurements for extrapyramidal symptoms. RESULTS: Significant improvements in cognitive function were observed in the backward Digit Span Test, Verbal Learning Test, Wisconsin Card Sorting Test, correct responses on the Continuous Performance Test, and Trail Making Test part B following a switch to LAIR. Scores on the PANSS, SOFAS, SUMD, and the Simpson-Angus Rating Scale also improved significantly. Most improvements in neurocognitive function were not correlated with clinical measures. Weight gain and hyperprolactinemia were the most common adverse events. CONCLUSIONS: Switching from oral AAPs to LAIR improved cognitive function including vigilance, verbal learning and memory, executive function, sustained attention, and visuomotor speed in patients with schizophrenia. It was also effective for improving psychotic symptoms, social functioning, and insight. PMID- 19790175 TI - Management strategies following microsurgical flap failure. AB - Although increasingly rare, failed microsurgical flaps are a complicated clinical problem when they occur. Review of reports of management following microsurgical flap failure offers an outline of options. A substantial number of breast and extremity patients elect abandonment of reconstruction. The majority of head and neck, breast, and extremity patients proceed to nonmicrosurgical reconstructive options. Head and neck patients (38%) and 35% of extremity patients elect to have second microsurgical flaps, and 84% of these procedures were successful. Patient management following microsurgical flap failure includes strategic abandonment of reconstruction in some cases, use of conventional procedures in a majority of cases, and further microsurgical procedures in one-third of cases. The reconstructive surgeon should have this range of possibilities available for these difficult cases. PMID- 19790176 TI - Reversed flow lateral circumflex femoral vessels as recipients for free fibular grafting in treatment of femoral head osteonecrosis. AB - Free fibular bone grafting is an effective treatment for early osteonecrosis of the femoral head in young patients. However, recipient vessels are often small rendering microvascular anastomosis difficult. We have developed a novel technique using retrograde flow through the branches of the lateral circumflex femoral artery to use the proximal end of the artery as the recipient vessel. A vessel diameter of up to 5 mm is obtained providing a good match with the peroneal vessels. We used this technique to perform vascularized bone grafting of the femoral head in 10 patients with Ficat grade 2 and 3 osteonecrosis. Pulsatile retrograde flow from the lateral circumflex femoral artery was observed in each case. Retrospective review gave a median follow up of 52 months (range 17-99). Symptoms improved in all 10 cases. There was no radiological deterioration over the period of follow-up in eight cases. One patient underwent conversion to a total hip replacement 24 months after surgery. These results compare favorably with other studies. The lateral circumflex femoral artery turnover technique is a reliable and useful technique in vascularized bone grafting of the femoral head. PMID- 19790177 TI - Surgical decompression for notalgia paresthetica: a case report. AB - Notalgia paresthetica is a rare nerve compression. From the Greek word noton, meaning "back," and algia, meaning "pain," "notalgia paresthetica" implies that symptoms of burning pain, itching, and/or numbness in the localized region between the spinous processes of T2 through T6 and the medial border of the scapula constitute a nerve compression syndrome. The compressed nerve is the dorsal branch of the spinal nerve. It is compressed by the paraspinous muscles and fascia against the transverse process of these spinal segments. This is the first report of symptomatic relief by decompression of this nerve. PMID- 19790178 TI - A subfascial variant of the deep inferior epigastric artery demonstrated by preoperative multidetector computed tomographic angiography: a case report. AB - Precise preoperative imaging by multidetector computed tomographic (MDCT) angiography for planning of deep inferior epigastric artery perforator (DIEP) flap dissection has been reported for enormous advantages in terms of reduced operative time and minimized flap-related complications. This case report shows a particularly rare anatomical subfascia variant of deep inferior epigastric artery (DIEA) which can be preoperatively demonstrated by MDCT angiogram. Therefore, the intraoperative finding also confirms the radiologic data and results in meticulous flap harvesting during incision on anterior rectus sheath. Additionally, the authors emphasize on performing preoperative high quality imaging for DIEP intervention precisely for specific vulnerable course of subfascial plane DIEP, which is rare but tends to be at risk without foreknowing its exact course. PMID- 19790179 TI - Use of pectoralis major perforators for local "free-style" perforator flap in axillary reconstruction: a case report. AB - Axillary scar contracture in a previously poly-traumatized present a challenging task for a reconstructive surgeon from the functional and esthetic standpoint. While harvest of local myocutaneous flaps will obviously contribute to further limitation of arm movements in already functionally impaired shoulder, pedicled perforator flaps from the lateral and posterior thoracic region may not be available due to extensive scarring after high-energy trauma with soft-tissue loss. We present a new perforator pedicled flap, designed, and harvested exclusively on the basis of "free style perforator flap" concept, based on the perforators coming from the pectoral region. The operative technique and outcome are discussed in this report. PMID- 19790180 TI - A single center comparison of one versus two venous anastomoses in 564 consecutive DIEP flaps: investigating the effect on venous congestion and flap survival. AB - BACKGROUND: Venous complications have been reported as the more frequently encountered vascular complications seen in the transfer of deep inferior epigastric artery (DIEA) perforator (DIEP) flaps, with a variety of techniques described for augmenting the venous drainage of these flaps to minimize venous congestion. The benefits of such techniques have not been shown to be of clinical benefit on a large scale due to the small number of cases in published series. METHODS: A retrospective study of 564 consecutive DIEP flaps at a single institution was undertaken, comparing the prospective use of one venous anastomosis (273 cases) to two anastomoses (291 cases). The secondary donor vein comprised a second DIEA venae commitante in 7.9% of cases and a superficial inferior epigastric vein (SIEV) in 92.1%. Clinical outcomes were assessed, in particular rates of venous congestion. RESULTS: The use of two venous anastomoses resulted in a significant reduction in the number of cases of venous congestion to zero (0 vs. 7, P = 0.006). All other outcomes were similar between groups. Notably, the use of a secondary vein did not result in any significant increase in operative time (385 minutes vs. 383 minutes, P = 0.57). CONCLUSIONS: The use of a secondary vein in the drainage of a DIEP flap can significantly reduce the incidence of venous congestion, with no detriment to complication rates. Consideration of incorporating both the superficial and deep venous systems is an approach that may further improve the venous drainage of the flap. PMID- 19790181 TI - Upper extremity reconstruction using free SCIA/SIEA flap. AB - The most suitable free flap alternative in upper extremity reconstruction has adequate and quality of tissue with consistent vascular pedicle. Free flap must provide convenient tissue texture to reconstruct aesthetic and functional units of upper extremity. Furthermore, minimal donor site morbidity is preferred features in free flap election. In our efforts to obtain the best possible outcome for patients, we chose, as a first priority, the free superficial circumflex inferior artery (SCIA)/superficial inferior epigastric artery (SIEA) flap over other free flap options for the soft-tissue reconstruction of upper extremities. The authors retrospectively report the results of 20 free SCIA/SIEA flaps for upper extremity reconstruction during the past 3 years. Nineteen of 20 flaps were successful (95%): three required emergent postoperative reexploration of the anastomosis and one failed. Flap thinning (n = 4) was performed during the flap harvest, whereas some flaps were thinned with secondary debulking (n = 4). The functional and aesthetic results were evaluated as acceptable by all patients. Based on our results, a free SCIA/SIEA flap has the following advantages in soft-tissue reconstruction of the upper extremity: (1) if necessary, flap thinning may be performed safely at the time of flap elevation and (2) flaps are harvested using a lower abdominal incision so that it causes minimal donor site scar. PMID- 19790182 TI - A new approach to preexisting vertical midline abdominal scars with crossover DIEP flap breast reconstruction. AB - Breast reconstruction using a free transverse rectus abdominis myocutaneous flap or a deep inferior epigastric perforator (DIEP) flap is a challenge in patients with a vertical midline abdominal scar due to the poor perfusion of the lower abdominal skin ellipse across the midline. In such patients, only one half of the abdominal skin ellipse can be used with certainty, and this limits the amount of tissue available for reconstructing the breast. Two cases of breast reconstruction in patients with a lower midline abdominal scar are presented using the DIEP flap, in which the poor perfusion across the midline scar was overcome by a technique of crossover anastomoses between the two deep inferior epigastric pedicles. Reliable perfusion of the entire lower abdominal skin ellipse was achieved. This crossover anastomoses technique overcomes the poor perfusion imposed by the vertical midline abdominal scar and enables DIEP flap breast reconstruction to be offered to women with midline abdominal scars. PMID- 19790183 TI - The efficacy of postoperative monitoring: a single surgeon comparison of clinical monitoring and the implantable Doppler probe in 547 consecutive free flaps. AB - BACKGROUND: An important element in achieving high success rates with free flap surgery has been the use of different techniques for monitoring flaps postoperatively as a means to detecting vascular compromise. Successful monitoring of the vascular pedicle to a flap can potentiate rapid return to theater in the setting of compromise, with the potential to salvage the flap. There is little evidence that any technique offers any advantage over clinical monitoring alone. METHODS: A consecutive series of 547 patients from a single plastic surgical unit who underwent a fasciocutaneous free flap operation for breast reconstruction [deep inferior epigastric artery perforator (DIEP) flap, superficial inferior epigastric artery (SIEA) flap, or superior gluteal artery perforator (SGAP) flap] were included. A comparison was made between the first 426 consecutive patients in whom flap monitoring was performed using clinical monitoring alone and the subsequent 121 patients in whom monitoring was achieved with the Cook-Swartz implantable Doppler probe. Outcome measures included flap salvage rate and false-positive rate. RESULTS: There was a strong trend toward improved salvage rates with the implantable Doppler probe compared with clinical monitoring (80% vs. 66%, P = 0.48). When combined with the literature (meta analysis), the data prove statistically significant (P < 0.01). There was no statistical difference between the groups for false-positive rates. CONCLUSION: Flap monitoring with the implantable Doppler probe can improve flap salvage rates without increasing the rate of false-positive takebacks. PMID- 19790184 TI - Changes of local and systemic hemorheological properties in intestinal ischemia reperfusion injury in the rat model. AB - The aim of this study was to investigate intestinal ischemia-reperfusion and its local and systemic hemorheological relations in the rat. Ten anaesthetized female CD outbred rats were equally divided into 2 experimental groups. (1) Ischemia reperfusion (I/R): the superior mesenterial artery was clipped for 30 minutes. After removing the clip, 60 minutes of the reperfusion was observed before extermination. Blood samples were taken from the caudal caval vein and from the portal vein before ischemia, 1 minute before and after clip removal, and at the 15th, 30th, and 60th minutes of the reperfusion. (2) Sham operation: median laparotomy and blood sampling were done according to the timing as in I/R group. Hematological parameters, red blood cell aggregation, and deformability were determined. Leukocyte count and mean volume of erythrocytes increased slightly but continuously in portal venous samples during the reperfusion period. Red blood cell aggregation values were higher in portal blood by the end of ischemia, and then became elevated further comparing to the caval venous blood. Both in caval and portal venous samples of I/R group red blood cell deformability significantly worsened during the experimental period compared to its base and Sham group. In portal blood red blood cell deformability was impaired more than in caval vein samples. Histology showed denuded villi, dilated capillaries, and the inflammatory cells were increased after a 30 minutes ischemia. In conclusion, intestinal ischemia-reperfusion causes changes in erythrocyte deformability and aggregation, showing local versus systemic differences in venous blood during the first hour of reperfusion. PMID- 19790185 TI - The intrinsic transit time of free microvascular flaps: clinical and prognostic implications. AB - BACKGROUND: Microscope-integrated indocyanine green near-infrared videoangiography (ICGA) is a new method for the intraoperative assessment of vascular flow through microvascular anastomoses. The intrinsic transit time (ITT) describes the time period from the dye appears at the arterial anastomosis (t(1)) till it reaches the suture line of the venous anastomosis (t(2)). As the transit time reflects blood flow velocity within the flap, prolonged ITT might correlate with low blood flow and a higher rate of postoperative thrombosis. We performed a clinical trial evaluating the association between intraoperative free flap transit time and early anastomotic complications in elective microsurgery. METHODS: One hundred consecutive patients undergoing elective microsurgical procedures underwent intraoperative ICG angiography (ICGA). In patients with anastomotic patency, angiograms were retrospectively reviewed and the intrinsic transit time was calculated. Postoperative outcome was registered and compared with the ITT. End points included early reexploration surgery and flap loss within the first 24 hours after surgery. RESULTS: Fourteen patients were excluded from the study due to technical anastomotic failure. The overall flap failure rate was 6% (5/86); the incidence of early re-exploration surgery was 10% (9/86). With a median of 31 seconds patients with an uneventful postoperative course showed significantly shorter ITTs than patients with flap loss or early postoperative reexploration (median: >120 seconds). An optimal cut-off value of ITT > 50 seconds was determined to be strongestly associated with a significantly increased risk of at least one positive end point. CONCLUSIONS: This study demonstrates a significant predictive value of the intrinsic flap transit time for the development of flap compromise and early re-exploration surgery. PMID- 19790186 TI - The correlation between calcium absorption and electrophysiological recovery in crushed rat peripheral nerves. AB - The correlation between calcium ion (Ca2+) concentration and electrophysiological recovery in crushed peripheral nerves has not been studied. Observing and quantifying the Ca2+ intensity in live normal and crushed peripheral nerves was performed using a novel microfine tearing technique and Calcium Green-1 Acetoxymethyl ester stain, a fluorescent Ca2+ indicator. Ca2+ was shown to be homogeneously distributed in the myelinated sheaths. After a crush injury, there was significant stasis in the injured zone and the portion distal to the injury. The Ca2+ has been almost completely absorbed after 24 weeks in the injured nerve to be similar to the controls. The process of the calcium absorption was correlated with the Compound Muscle Action Potential recovery process of the injured nerves. This correlation was statistically significant (r = -0.81, P < 0.05). The better understanding of this process will help us to improve nerve regeneration after peripheral nerve injury. PMID- 19790187 TI - Power spectral analysis of perfusion signals on free radial forearm flap transplantation in humans. AB - Forearm cutaneous perfusion is an established in vivo model in many clinical and basic researches to explore the peripheral circulation. The aim of our study is to characterize the dynamic properties of regional microcirculation after simultaneous denervation and revascularization in free forearm flap transplantations. Serial changes in laser Doppler flow and cutaneous temperature were measured during 14 forearm flap transplantations. Digitalized perfusion data were relayed for power spectral analysis based on the fast Fourier transform. Real time heart rate variability was measured to verify the influence of systemic autonomic nervous modulations. The basal flow expressed a threefold to fourfold increase, from 20.31 +/- 3.25 to 73.79 +/- 11.78 PU, after the transplantation. Frequency domain analysis of cutaneous blood flow variability showed significantly increased high frequency (0.15-0.4 Hz, 55.14% +/- 3.31% to 65.31% +/- 2.78%, P = 0.0035) and decreased very low frequency (0.003-0.04 Hz, 18.61% +/ 2.70% to 9.25% +/- 1.38%, P = 0.0049) power fraction after flap transfer. Simultaneous denervation and revascularization of forearm flaps increased the regional blood flow significantly that was caused by increased high frequency and decreased very low frequency fractional contributions in dynamic regulation of regional cutaneous microcirculation. They are associated with the sympathetic denervation and reactive hyperemia, respectively. PMID- 19790188 TI - A novel H1N1 virus causes the first pandemic of the 21st century. AB - A novel H1N1 virus of swine origin (H1N1v ) is currently spreading in humans, giving rise to the first pandemic in 40 years. The disease is of moderate severity but has notable differences from seasonal influenza. In contrast to seasonal influenza, those over 60 years are relatively spared, a likely consequence of the presence of H1N1v cross-neutralizing antibody in this age group. Most patients appear to have mild influenza-like illness and many of the complications leading to hospitalization and mortality occur in those with underlying disease conditions or pregnancy. Studies in animal models suggest that the novel H1N1v pandemic virus causes a more severe illness and appears to have a greater predilection for the alveolar epithelium than seasonal influenza viruses. As there are as yet little data on the pathogenesis and immunology of H1N1v infection in humans, we have reviewed relevant data from past pandemics, from seasonal influenza and avian influenza H5N1 to highlight key issues pertaining to pathogenesis and immunology. PMID- 19790189 TI - Social learning of diet and foraging skills by wild immature Bornean orangutans: implications for culture. AB - Studies of social learning in the wild are important to complement findings from experiments in captivity. In this field study, immature Bornean orangutans rarely foraged independently but consistently followed their mothers' choices. Their diets were essentially identical to their mothers' even though not all mothers had the same diet. This suggests vertical transmission of diet by enhancement. Also, immatures selectively observed their mothers during extractive foraging, which increased goal-directed practice but not general manipulation of similar objects, suggesting observational forms of learning of complex skills. Teaching was not observed. These results are consistent with the reported presence of food traditions and skill cultures in wild orangutans. We suggest that food traditions can develop wherever association commonly allows for social learning. However, the capacity for observational learning, and thus more complex culture, is more likely to evolve among extractive foragers with prolonged association between adults and immatures. PMID- 19790190 TI - Semi-quantitative tests of cyanide in foods and excreta of Three Hapalemur species in Madagascar. AB - Three sympatric Hapalemur species (H. g. griseus, H. aureus, and H. (Prolemur) simus) in Ranomafana National Park, Madagascar are known to eat bamboo food parts that contain cyanide. How these lemurs avoid cyanide poisoning remains unknown. In this study, we tested for the presence/absence of cyanide in bamboo lemur foods and excreta to (1) document patterns of cyanide consumption among species with respect to diet, (2) identify routes of elimination of cyanide from the gastrointestinal tract, and (3) determine whether cyanide is absorbed from the diet. We tested 102 food, urine, and fecal samples for hydrogen cyanide (HCN) during two "pre-dry" seasons (April 2006, May 2007) using commercially available Cyantesmo test strips. The test strips changed color in the presence of HCN, and we recorded color change on a scale of 0 (no change) to 5 (cobalt) at preset intervals with a final score taken at 24 hr. We detected cyanide in bamboo food parts and urine of all three Hapalemur species. Time to color change of the test strips ranged from almost instantaneous to >12 hr incubation. Of the foods tested, only bamboo contained cyanide, but results differed among bamboo species and plant parts of the same species. Specifically, branch shoot and culm pith of the giant bamboo produced strong, immediate reactions to the test paper, whereas parts of liana bamboos produced either weak or no color change. Cyanide was present in almost all urine samples but rarely in fecal samples. This suggests that dietary cyanide is absorbed in the gastrointestinal tract of the Hapalemur species and excreted, at least in part, by the kidneys. Samples from H. griseus exhibited lower, though still detectable, cyanide levels compared with H. simus and H. aureus. Differences among lemur species appear to be related to the specific bamboo parts consumed. PMID- 19790191 TI - Living together: behavior and welfare in single and mixed species groups of capuchin (Cebus apella) and squirrel monkeys (Saimiri sciureus). AB - There are potential advantages of housing primates in mixed species exhibits for both the visiting public and the primates themselves. If the primates naturally associate in the wild, it may be more educational and enjoyable for the public to view. Increases in social complexity and stimulation may be enriching for the primates. However, mixed species exhibits might also create welfare problems such as stress from interspecific aggression. We present data on the behavior of single and mixed species groups of capuchin monkeys (Cebus apella) and squirrel monkeys (Saimiri sciureus) housed at the Living Links to Human Evolution Research Centre in the Royal Zoological Society of Scotland's Edinburgh Zoo. These species associate in the wild, gaining foraging benefits and decreased predation. But Cebus are also predators themselves with potential risks for the smaller Saimiri. To study their living together we took scan samples at > or =15 min intervals on single (n=109) and mixed species groups (n=152), and all occurrences of intraspecific aggression and interspecific interactions were recorded. We found no evidence of chronic stress and Saimiri actively chose to associate with Cebus. On 79% of scans, the two species simultaneously occupied the same part of their enclosure. No vertical displacement was observed. Interspecific interactions were common (>2.5/hr), and equally divided among mildly aggressive, neutral, and affiliative interactions such as play. Only one aggressive interaction involved physical contact and was non-injurious. Aggressive interactions were mostly (65%) displacements and vocal exchanges, initiated almost equally by Cebus and Saimiri. Modifications to the enclosure were successful in reducing these mildly aggressive interactions with affiliative interactions increasing in frequency and diversity. Our data suggest that in carefully designed, large enclosures, naturally associating monkeys are able to live harmoniously and are enriched by each other. PMID- 19790194 TI - Current literature in diabetes. PMID- 19790195 TI - Paul Kammerer's midwife toads: about the reliability of experiments and our ability to make sense of them. PMID- 19790196 TI - Cigarette smoking, environmental tobacco smoke exposure and pancreatic cancer risk in the European Prospective Investigation into Cancer and Nutrition. AB - Cigarette smoking is an established risk factor for pancreatic cancer. However, prospective data for most European countries are lacking, and epidemiologic studies on exposure to environmental tobacco smoke (ETS) in relation to pancreatic cancer risk are scarce. We examined the association of cigarette smoking and exposure to ETS with pancreatic cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). This analysis was based on 465,910 participants, including 524 first incident pancreatic cancer cases diagnosed after a median follow-up of 8.9 years. Estimates of risk were obtained by Cox proportional hazard models and adjusted for weight, height, and history of diabetes mellitus. An increased risk of pancreatic cancer was found for current cigarette smokers compared with never smokers (HR = 1.71, 95% CI = 1.36-2.15), and risk increased with greater intensity and pack-years. Former cigarette smokers who quit for less than 5 years were at increased risk of pancreatic cancer (HR = 1.78, 95% CI = 1.23-2.56), but risk was comparable to never smokers after quitting for 5 years or more. Pancreatic cancer risk was increased among never smokers daily exposed to ETS (for many hours) during childhood (HR = 2.61, 95% CI = 0.96-7.10) and exposed to ETS at home and/or work (HR = 1.54, 95% CI = 1.00-2.39). These results suggest that both active cigarette smoking, as well as exposure to ETS, is associated with increased risk of pancreatic cancer and that risk is reduced to levels of never smokers within 5 years of quitting. PMID- 19790198 TI - Retracted: Evidence for duplicated Hox genes in polyploid Cyprinidae fish of common carp, crucian carp and silver crucian carp. AB - Notice of Withdrawal: The following article from the Journal of Experimental Zoology Part B: Molecular and Developmental Evolution, "Evidence for duplicated Hox genes in polyploid Cyprinidae fish of common carp, crucian carp, and silver crucian carp" by Yuan J, He Z, Yuan X, Jiang X, Sun X, Zou S, published online on 29 Sept 2009 in Wiley InterScience (www.interscience.wiley.com), has been withdrawn from publication by agreement between the authors, the journal Editor in-Chief, Gunter P. Wagner, and Wiley Periodicals, Inc. PMID- 19790199 TI - Liver "tick tock". PMID- 19790197 TI - CDK8 expression in 470 colorectal cancers in relation to beta-catenin activation, other molecular alterations and patient survival. AB - Alterations in the Wnt/beta-catenin pathway define a key event in the pathogenesis of colon cancer. We have recently shown that CDK8, the gene encoding a cyclin-dependent kinase (CDK) component of the Mediator complex, acts as a colon cancer oncogene that is necessary for beta-catenin activity. Here, we tested the hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes. Among 470 colorectal cancers identified in 2 prospective cohort studies, CDK8 expression was detected in 329 (70%) tumors by immunohistochemistry. Cox proportional hazards model and backward stepwise elimination were used to compute hazard ratio (HR) of deaths according to CDK8 status, initially adjusted for various patient and molecular features, including beta-catenin, p53, p21, p27 (CDK inhibitors), cyclin D1, fatty acid synthase (FASN), cyclooxygenase-2 (COX-2), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE-1 methylation, and mutations in KRAS, BRAF and PIK3CA. CDK8 expression in colorectal cancer was independently associated with beta-catenin activation (p = 0.0002), female gender (p < 0.0001) and FASN overexpression (p = 0.0003). Among colon cancer patients, CDK8 expression significantly increased colon cancer-specific mortality in both univariate analysis [HR 1.70; 95% confidence interval (CI), 1.03-2.83; p = 0.039] and multivariate analysis (adjusted HR 2.05; 95% CI, 1.18-3.56; p = 0.011) that was adjusted for potential confounders including beta-catenin, COX-2, FASN, LINE 1 hypomethylation, CIMP and MSI. CDK8 expression was unrelated with clinical outcome among rectal cancer patients. These data support a potential link between CDK8 and beta-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis. PMID- 19790200 TI - Fast targeted multidimensional NMR metabolomics of colorectal cancer. AB - The study of small molecules in body fluids has become an important tool to monitor the state of biological organisms. Applications range from model studies using cell lines to applications where human body fluids are used to monitor disease states or drug responses. NMR spectroscopy has been an important tool for metabolomics although severe overlap of signals has limited the number of compounds, which can be unambiguously identified and quantified. Therefore, deconvolution of NMR spectra is one of the greatest challenges for NMR-based metabolomics. This has commonly been achieved by using multidimensional spectra that have the disadvantage of requiring significantly longer acquisition times. Recently, a number of methods have been described to record NMR spectra much faster. Here, we explore the use of Hadamard-encoded TOCSY spectra to simultaneously select multiple lines from crowded NMR spectra of blood serum samples to acquire pseudo-two-dimensional spectra in minutes which would otherwise require many hours. The potential of this approach is demonstrated for the detection of a signature for colorectal cancer from human blood samples. PMID- 19790201 TI - Structures of micelle-bound selected insect neuropeptides and analogues: implications for receptor selection. AB - Neuropeptides control essential physiological processes in insects such as water balance and muscle activity. Due to their metabolic instability and adverse physiochemical properties, insect neuropeptides are unsuited for a direct application in plant protection. As a first approximation towards the biologically active conformation, the structures of selected neuropeptides from economically important pest insects were determined by NMR spectroscopy and fluorescence measurements in a membrane-mimicking environment. A receptor binding model is suggested for the helicokinins and discussed in connection with biological activities and membrane-bound conformations of linear and cyclic analogues. PMID- 19790202 TI - Synthesis and pharmacological characterization of Disila-AM80 (Disila tamibarotene) and Disila-AM580, silicon analogues of the RARalpha-selective retinoid agonists AM80 (Tamibarotene) and AM580. PMID- 19790203 TI - DNA-based polymers as chiral templates for second-order nonlinear optical materials. AB - The unique symmetry properties of chiral systems allow the emergence of coherent second harmonic generation in polymeric materials lacking polar order. Deoxyribonucleic acid (DNA) treated with the surfactant cetyltrimethylammonium (CTMA) was drop-cast to spontaneously form films that are active for coherent second harmonic generation (SHG). SHG images acquired as a function of incident and exigent polarization are in good agreement with theoretical predictions assuming nonpolar D(infinity) symmetry for the double-stranded DNA chains. Doping the DNA films with crystal violet substantially increases the efficiency of SHG, but does not significantly alter the polarization-dependence, suggesting that the SHG generated upon doping arises from the same chiral-specific origin, presumably templated by the DNA. These results raise the possibility of new design strategies for organic nonlinear optical materials based on soft chiral polymers that do not require polar order. PMID- 19790204 TI - The world's thinnest superconductor. PMID- 19790205 TI - Synthesis, biological evaluation of 1,1-diarylethylenes as a novel class of antimitotic agents. AB - The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B-ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA-4 (2 e), isoCA-4 (2 k) and isoNH(2)CA-4 (2 s) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC(50) values of 4, 2 and 1.5 microM, respectively. These derivatives were found to be 10-fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G(2)/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e, 2 k and 2 s on the vessel-like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors. PMID- 19790206 TI - Reversible mechanical induction of optical activity in solutions of soft-matter nanophases. AB - Nanophases of J-aggregates of several achiral amphiphilic porphyrins, which have thin long acicular shapes (nanoribbons), show the immediate and reversible formation of a stationary mechano-chiral state in the solution by vortex stirring, as detected by their circular dichroic signals measured by 2-modulator generalized ellipsometry. The results suggest that when a macroscopic chiral force creates supramolecular chirality, it also creates an enantiomeric excess of screw distortions, which may be detected by their excitonic absorption. An explanation on the effect of the shear flow gradients is proposed on the basis of the orientation of the rotating particles in the vortex and the size, shape, and mechanical properties of the nanoparticles. PMID- 19790207 TI - Switching the electron-donor properties of N-heterocyclic carbenes by a facile deprotonation strategy. PMID- 19790208 TI - "Doubly selective" antimicrobial polymers: how do they differentiate between bacteria? AB - We have investigated how doubly selective synthetic mimics of antimicrobial peptides (SMAMPs), which can differentiate not only between bacteria and mammalian cells, but also between Gram-negative and Gram-positive bacteria, make the latter distinction. By dye-leakage experiments on model vesicles and complementary experiments on bacteria, we were able to relate the Gram selectivity to structural differences of these bacteria types. We showed that the double membrane of E. coli rather than the difference in lipid composition between E. coli and S. aureus was responsible for Gram selectivity. The molecular weight-dependent antimicrobial activity of the SMAMPs was shown to be a sieving effect: while the 3000 g mol(-1) SMAMP was able to penetrate the peptidoglycan layer of the Gram-positive S. aureus bacteria, the 50000 g mol(-1) SMAMP got stuck and consequently did not have antimicrobial activity. PMID- 19790209 TI - Ligand-centred reactivity of bis(picolyl)amine iridium: sequential deprotonation, oxidation and oxygenation of a "non-innocent" ligand. AB - Treatment of [Ir(bpa)(cod)](+) complex [1](+) with a strong base (e.g., tBuO(-)) led to unexpected double deprotonation to form the anionic [Ir(bpa-2H)(cod)](-) species [3](-), via the mono-deprotonated neutral amido complex [Ir(bpa-H)(cod)] as an isolable intermediate. A certain degree of aromaticity of the obtained metal-chelate ring may explain the favourable double deprotonation. The rhodium analogue [4](-) was prepared in situ. The new species [M(bpa-2H)(cod)](-) (M = Rh, Ir) are best described as two-electron reduced analogues of the cationic imine complexes [M(I)(cod)(Py-CH(2)-N=CH-Py)](+). One-electron oxidation of [3]( ) and [4](-) produced the ligand radical complexes [3](*) and [4](*). Oxygenation of [3](-) with O(2) gave the neutral carboxamido complex [Ir(cod)(py-CH(2)-N-CO py)] via the ligand radical complex [3](*) as a detectable intermediate. PMID- 19790210 TI - Catalytic carbanion reactions: formation and reaction of carbanions from ester or amide equivalents using catalytic amounts of bases. AB - We describe here carbanion reactions using catalytic amounts of bases. The carbanions formed are different from conventional carbanions in which stoichiometric amounts of bases are needed for the formation. Two types of reactions using such carbanions from amide (imido) and ester equivalents are discussed. PMID- 19790211 TI - Distinct oxygenation difference between manganese(IV) hydroxo and oxo moieties: electron transfer versus concerted oxygen transfer. PMID- 19790213 TI - Cyclopentadienyl ruthenium(II) complexes with bridging alkynylphosphine ligands: synthesis and electrochemical studies. AB - The reaction of [CpRuCl(PPh(3))(2)] (Cp = cyclopentadienyl) and [CpRuCl(dppe)] (dppe = Ph(2)PCH(2)CH(2)PPh(2)) with bis- and tris-phosphine ligands 1,4 (Ph(2)PC[triple bond]C)(2)C(6)H(4) (1) and 1,3,5-(Ph(2)PC[triple bond]C)(3)C(6)H(3) (2), prepared by Ni-catalysed cross-coupling reactions between terminal alkynes and diphenylchlorophosphine, has been investigated. Using metal directed self-assembly methodologies, two linear bimetallic complexes, [{CpRuCl(PPh(3))}(2)(mu-dppab)] (3) and [{CpRu(dppe)}(2)(mu-dppab)](PF(6))(2) (4), and the mononuclear complex [CpRuCl(PPh(3))(eta(1)-dppab)] (6), which contains a "dangling arm" ligand, were prepared (dppab =1,4 bis[(diphenylphosphino)ethynyl]benzene). Moreover, by using the triphosphine 1,3,5-tris[(diphenylphosphino)ethynyl]benzene (tppab), the trimetallic [{CpRuCl(PPh(3))}(3)(mu(3)-tppab)] (5) species was synthesised, which is the first example of a chiral-at-ruthenium complex containing three different stereogenic centres. Besides these open-chain complexes, the neutral cyclic species [{CpRuCl(mu-dppab)}(2)] (7) was also obtained under different experimental conditions. The coordination chemistry of such systems towards supramolecular assemblies was tested by reaction of the bimetallic precursor 3 with additional equivalents of ligand 2. Two rigid macrocycles based on cis coordination of dppab to [CpRu(PPh(3))] were obtained, that is, the dinuclear complex [{CpRu(PPh(3))(mu-dppab)}(2)](PF(6))(2) (8) and the tetranuclear square [{CpRu(PPh(3))(mu-dppab)}(4)](PF(6))(4) (9). The solid-state structures of 7 and 8 have been determined by X-ray diffraction analysis and show a different arrangement of the two parallel dppab ligands. All compounds were characterised by various methods including ESIMS, electrochemistry and by X-band ESR spectroscopy in the case of the electrogenerated paramagnetic species. PMID- 19790212 TI - Synthesis, coordination chemistry and bonding of strong N-donor ligands incorporating the 1H-pyridin-(2E)-ylidene (PYE) motif. AB - A range of N-donor ligands based on the 1H-pyridin-(2E)-ylidene (PYE) motif have been prepared, including achiral and chiral examples. The ligands incorporate one to three PYE groups that coordinate to a metal through the exocyclic nitrogen atom of each PYE moiety, and the resulting metal complexes have been characterised by methods including single-crystal X-ray diffraction and NMR spectroscopy to examine metal-ligand bonding and ligand dynamics. Upon coordination of a PYE ligand to a proton or metal-complex fragment, the solid state structures, NMR spectroscopy and DFT studies indicate that charge redistribution occurs within the PYE heterocyclic ring to give a contribution from a pyridinium-amido-type resonance structure. Additional IR spectroscopy and computational studies suggest that PYE ligands are strong donor ligands. NMR spectroscopy shows that for metal complexes there is restricted motion about the exocyclic C-N bond, which projects the heterocyclic N-substituent in the vicinity of the metal atom causing restricted motion in chelating-ligand derivatives. Solid-state structures and DFT calculations also show significant steric congestion and secondary metal-ligand interactions between the metal and ligand C H bonds. PMID- 19790214 TI - Resolving conformation dichotomy for Y- and T-shaped three-coordinate Ni(I) carbonyl complexes with relativistic DFT analysis of EPR fingerprints. PMID- 19790215 TI - A stereodivergent synthesis of all stereoisomers of centrolobine: control of selectivity by a protecting-group manipulation. AB - All stereoisomers of the natural product centrolobine are selectively synthesized, by starting from a common precursor. Key steps are an enantioselective allylation with enantiomerically pure allylsilanes, a tandem ring-closing metathesis-isomerization reaction, and a Heck reaction by using an arene diazonium salt. By choosing appropriate conditions for the final deprotection step, either the cis-configured centrolobines or their epimers are selectively obtained. PMID- 19790216 TI - Kinetic resolution of quaternary and tertiary beta-hydroxy esters. PMID- 19790217 TI - New syntheses of diazo compounds. AB - Diazo compounds (R1R2C=N2) are known as versatile and useful substrates for an array of chemical transformations and, therefore, diazo chemistry is still far from losing anything of its long-standing fascination. In addition to many studies on the subsequent chemistry of the diazo group, the inventory of methods for the preparation of diazo compounds is continuously supplemented by new methods and novel variations of established procedures. Several of these synthetic approaches take into account the lability and remarkable chemical reactivity of certain classes of diazo compounds, and environmentally more benign procedures also continue to be developed. PMID- 19790218 TI - Gold and palladium combined for cross-coupling. PMID- 19790219 TI - Binaphthyl-DNA: stacking and fluorescence of a nonplanar aromatic base surrogate in DNA. PMID- 19790220 TI - Efficient catalytic conversion of fructose into 5-hydroxymethylfurfural in ionic liquids at room temperature. PMID- 19790221 TI - Selectivity versus mobility: separation of anode and cathode in microbial bioelectrochemical systems. AB - During the operation of a microbial bioelectrochemical system, charge balance must be maintained between the anode and the cathode. In an ideal scenario, the charge balance would be realized by the unhindered migration of H(+) or OH(-). At the same time, any kind of diffusion (crossover) between both electrode compartments should be avoided. However, as several studies have demonstrated, the experimental reality does not match this ideal picture. Crossover processes occur and H(+)/OH(-) migration only plays an inferior role in the charge balancing ion transfer, which results in significant losses in the performance of the microbial bioelectrochemical system. This Minireview summarizes the conflict of selectivity versus mobility and discusses principle strategies to cope with the resulting constraints, including pH-static operation and the use of different separator materials and membrane-free systems. Finally, we show that every setup compromises either selectivity or mobility, and no apparent ideal solution currently exists. PMID- 19790222 TI - One-step synthesis of 2-alkyl-dioxolanes from ethylene glycol and syngas. PMID- 19790223 TI - Cerebral abnormalities associated with myelomeningocele. PMID- 19790224 TI - IN MEMORIAM: Yury Verlinsky (1 September 1943-16 July 2009). PMID- 19790225 TI - Monitoring neonicotinoid resistance in biotype B of Bemisia tabaci in Florida. AB - BACKGROUND: Biotype B of the sweetpotato whitefly, Bemisia tabaci (Genn.), is a worldwide pest that has developed resistance to many insecticides, including the neonicotinoid class. Florida field populations were monitored for susceptibility to the neonicotinoids imidacloprid and thiamethoxam using a cut leaf petiole bioassay method. RESULTS: Average RR(50) values for imidacloprid increased from 3.7 in 2000 to 12.0 in 2003; decreased to 5.0 and 2.5 in 2004 and 2005, respectively; and then increased to 26.3 and 23.9 in 2006 and 2007, respectively. Populations with RR(50) values of about 50 to 60 during generation one reverted to RR(50) values of < or =4 in six generations, when reared without further exposure to imidacloprid. Average RR(50) values for thiamethoxam increased from 2.0 in 2003 to 24.7 in 2006 and decreased to 10.4 in 2007. Populations with RR(50) values of about 22, 32 and 53 during generation one declined to 8, 5 and 6, respectively, after being reared for five generations without exposure to thiamethoxam. The correlation coefficient from the 26 populations that were bioassayed both with imidacloprid and thiamethoxam showed a significant positive correlation (R(2) = 0.58) between these populations. CONCLUSION: The high level of RR(50) values to imidacloprid and thiamethoxam suggest an unstable decline in the susceptibility of B. tabaci to imidacloprid and thiamethoxam, with possible cross-resistance or predisposition for dual resistance selection. PMID- 19790226 TI - Hepatitis C nonresponders: re-treat or retreat? PMID- 19790228 TI - The urgent need for evaluating recurrent primary sclerosing cholangitis in living donor liver transplantation. PMID- 19790229 TI - Delayed splenic artery occlusion for treatment of established small-for-size syndrome after partial liver transplantation. PMID- 19790230 TI - Docetaxel-ST1481 sequence exerts a potent cytotoxic activity on hormone-resistant prostate cancer cells by reducing drug resistance-related gene expression. AB - BACKGROUND: The efficacy of current therapy for hormone-refractory prostate cancer is still unsatisfactory and new agents and therapeutic modalities are needed. The aims of the present work were to examine the in vitro activity and mechanisms of action of different antitumor drug combinations in hormone resistant prostate cancer (HRPC) cell lines. METHODS: The activity of docetaxel (Doc), cisplatin (Cis), oxaliplatin (Oxa), SN-38 and ST1481, singly or in combination, was assessed in different HRPC cell lines (PC3, parental DU145 and taxane-resistant DU145-R) by SRB test. Apoptosis was evaluated by TUNEL and ANN-V assays. Extrusion pump activity was studied by Hoechst 33342 assay, while gene expression related to drug efflux mechanisms and DNA damage repair was analyzed by RT-PCR. RESULTS: Doc induced a high cytocidal effect in the HRPC cells, whereas Cis, Oxa, SN-38 and ST1481 exerted prevalently cytostatic activity. Doc followed by ST1481 proved to be the most effective drug sequence among those investigated, producing an important synergistic effect (R.I. from 2.0 to 5.2) in all the tested cell lines. Moreover, this sequence induced a significant downregulation of xenobiotic extrusion pump and DNA damage repair gene expression. ST1481 synergistically increased the cytocidal effect of Doc, probably through a downregulation of extrusion pump activity and DNA damage repair-related genes. CONCLUSIONS: Our results show that the Doc --> ST1481 sequence effectively reduces the cancer cell population and restores Doc activity in taxane-resistant HRPC, indicating its potential usefulness as first- or second line treatment of hormone-refractory prostate cancer. PMID- 19790231 TI - Antisense oligonucleotide targeting of insulin-like growth factor-1 receptor (IGF 1R) in prostate cancer. AB - OBJECTIVE: Altered expression of insulin-like growth factor receptor (IGF-1R) is associated with castrate-resistant prostate cancer (CRPC) progression. We hypothesize that increased expression and/or responsiveness of IGF-IR may promote disease progression. This study assesses ATL1101, a 2'-MOE-modified antisense oligonucleotide (ASO) targeting human IGF-IR, with regard to potency and anti cancer activity in androgen-responsive (LNCaP) and -independent (PC3) prostate cancer cells in vitro and in vivo. METHODS: IGF-IR mRNA and protein expression was assessed in ATL1101- and control oligonucleotides (ODN)-treated prostate cancer cells by QT-PCR and immunoblotting. The effect of IGF-1R ASO on cell growth and apoptosis in vitro was examined by crystal violet assay, flow cytometry, and expression and activation state of downstream signaling targets was examined by immunoblotting. In vivo growth of subcutaneous xenografts was performed in nude mice treated with intraperitoneally administered ATL1101 or control ODN by measuring tumor volume of PC3 xenografts in intact mice, and tumor volume and serum prostate-specific antigen levels in castrated mice harboring LNCaP xenografts. RESULTS: We observed dose- and sequence-specific suppression of IGF-IR mRNA and protein expression in ATL1101-treated cells in vitro. Suppressed IGF-IR expression correlated with decreased proliferation and increased apoptosis of PC3 cells under standard culture conditions and of LNCaP cells under androgen deprived culture conditions. ATL1101 suppressed PC3 tumor growth as a monotherapy and delayed CRPC progression of LNCaP xenografts. CONCLUSIONS: This study reports the first preclinical proof-of-principle data that this novel IGF-IR ASO selectively suppresses IGF-1R expression, suppresses growth of CRPC tumors, and delays CRPC progression in vitro and in vivo. PMID- 19790233 TI - Increased cell proliferation and contractility of prostate in insulin resistant rats: linking hyperinsulinemia with benign prostate hyperplasia. AB - BACKGROUND: Obesity, dyslipidemia, Hyperinsulinemia, and insulin resistance (IR) are key features of metabolic syndrome and are considered as risk factors for benign prostatic hyperplasia (BPH) as well as type 2 diabetes. The present study was aimed to determine whether or not IR associated hyperinsulinemia contributes to the BPH. METHODS: Sprague-Dawley rats (9 weeks) were used in the study. Rats were kept on high fat diet (HFD) for the induction of hyperinsulinemia while hypoinsulinemia was induced by streptozotocin. Effect of HFD feeding on the testosterone-induced prostatic growth was evaluated. Pioglitazone (PG, 20 mg/kg) was used for the reversal of compensatory hyperinsulinemia and to examine the subsequent effect on the prostatic growth. RESULTS: Prostatic enlargement was observed in the HFD-fed rats. Significant increase in the cell proliferation markers confirmed the occurrence of cellular hyperplasia in the prostate of hyperinsulinemic rat. Enhanced alpha-adrenoceptor mediated contraction in the prostate of HFD-fed rats indicates augmented contractility of the gland. Higher level of phosphorylated-ERK suggests enhanced MEK/ERK signaling. HFD feeding has not led to change in the plasma testosterone level. However, testosterone treatment further augmented the prostatic growth in HFD-fed rats. PG treatment led to improved insulin sensitivity, decreased plasma insulin level and prostate weight, indicating the role of compensatory hyperinsulinemia in the prostate growth. CONCLUSIONS: The present investigation reports that HFD-feeding induced hyperinsulinemic condition leads to increased cellular proliferation, enhanced alpha-adrenoceptor mediated contraction, and enlargement of the prostate in rats. PMID- 19790232 TI - Tumor suppressor PAX6 functions as androgen receptor co-repressor to inhibit prostate cancer growth. AB - BACKGROUND: PAX6, a transcription factor, has currently been suggested to function as a tumor suppressor in glioblastoma and to act as an early differentiation marker for neuroendocrine cells. The androgen receptor (AR) plays a pivotal role in prostate cancer development and progression due to its transcriptional activity in regulating genes involved in cell growth, differentiation, and apoptosis. To determine the role of PAX6 in prostate cancer, we investigated whether PAX6 interacts with AR to affect prostate cancer development. METHODS: We used immunostaining, RT-PCR, and Western blotting assays to show the expression status of PAX6 in prostate tissue and human prostate cancer cell lines. The role of PAX6 in cell growth and colony regeneration potential of LNCaP cells were evaluated by MTT assay and soft agar assay with PAX6-overexpressed LNCaP cells. Mammalian two-hybrid and co-immunoprecipitation (Co-IP) assays were used to demonstrate the interaction between PAX6 and AR. Reporter gene and Q-RT-PCR assays were performed to determine the effects of PAX6 on the function of AR. RESULTS: In prostate cancer tissues, PAX6 expression was stronger in normal epithelial cells than cancer cells, and decreased in LNCaP cells compared to that of DU145 and PC3 cells. Enforced expression of PAX6 suppressed the cell growth of LNCaP cells and also inhibited the colony formation of LNCaP cells. PAX 6 interacted with AR and repressed its transcriptional activity. PAX6 overexpression decreased the expression of androgen target gene PSA in LNCaP cells. CONCLUSIONS: In this study, we found that PAX6 may act as a prostate cancer repressor by interacting with AR and repressing the transcriptional activity and target gene expression of AR to regulate cell growth and regeneration. PMID- 19790234 TI - Induction of bicalutamide sensitivity in prostate cancer cells by an epigenetic Puralpha-mediated decrease in androgen receptor levels. AB - BACKGROUND: Increased androgen receptor (AR) levels support resistance to apoptosis and hormone therapy in advanced prostate cancer (PC). We recently linked the overexpression of AR in androgen-independent LNCaP cells (AI-cells) and tissues from castration-resistant patients to decreased nuclear levels of Pur alpha (Puralpha) and loss from a protein complex bound to repressor sequences (ARS) in the 5'-UTR of AR. Strategies to regain control of increased AR transcription may overcome resistance of AI-cells and improve treatment outcomes. METHODS: MTT, real-time PCR, Western blot, ChIP, flow cytometry, and caspase 3/7 activation measured the effect on growth and targets of LBH589/bicalutamide treatment of AI-cells and androgen-dependent LNCaP cells (AD). RESULTS: Within 16 hr of treatment of AI-cells with low concentrations of the histone deacetylase inhibitor LBH589, a shift of cytoplasmic Puralpha restored the nuclear levels and the binding of Puralpha to the ARS. This was followed by a decline in AR-mRNA and protein reaching levels of parental AD-cells. The fraction of AI-cells in G1 increased and the cells in S phase decreased similar to AD-cells, and there was a modest caspase activation. Most notably, treatment of bicalutamide-resistant AI cells with 10 nM LBH589 combined with 12.5 microM bicalutamide synergistically inhibited cell growth and induced a fivefold higher level of caspase 3/7 activation than observed in AD-cells. CONCLUSIONS: Low-dose LBH589 restores Puralpha binding to ARS and down-regulates AR transcription. Biologically, LBH589 reverses the resistance of AI-cells to bicalutamide and to apoptosis. The combination may restore the hormonal response of castration-resistant PC patients. PMID- 19790235 TI - Cell-autonomous intracellular androgen receptor signaling drives the growth of human prostate cancer initiating cells. AB - BACKGROUND: The lethality of prostate cancer is due to the continuous growth of cancer initiating cells (CICs) which are often stimulated by androgen receptor (AR) signaling. However, the underlying molecular mechanism(s) for such AR mediated growth stimulation are not fully understood. Such mechanisms may involve cancer cell-dependent induction of tumor stromal cells to produce paracrine growth factors or could involve cancer cell autonomous autocrine and/or intracellular AR signaling pathways. METHODS: We utilized clinical samples, animal models and a series of AR-positive human prostate cancer cell lines to evaluate AR-mediated growth stimulation of prostate CICs. RESULTS: The present studies document that stromal AR expression is not required for prostate cancer growth, since tumor stroma surrounding AR-positive human prostate cancer metastases (N = 127) are characteristically AR-negative. This lack of a requirement for AR expression in tumor stromal cells is also documented by the fact that human AR-positive prostate cancer cells grow equally well when xenografted in wild-type versus AR-null nude mice. AR-dependent growth stimulation was documented to involve secretion, extracellular binding, and signaling by autocrine growth factors. Orthotopic xenograft animal studies documented that the cellautonomous autocrine growth factors which stimulate prostate CIC growth are not the andromedins secreted by normal prostate stromal cells. Such cell autonomous and extracellular autocrine signaling is necessary but not sufficient for the optimal growth of prostate CICs based upon the response to anti-androgen plus/or minus preconditioned media. CONCLUSIONS: AR induced growth stimulation of human prostate CICs requires AR-dependent intracellular pathways. The identification of such AR-dependent intracellular pathways offers new leads for the development of effective therapies for prostate cancer. PMID- 19790236 TI - The potential value of microseminoprotein-beta as a prostate cancer biomarker and therapeutic target. AB - BACKGROUND: Recent genome-wide association studies have shown an association of a SNP two base pairs upstream of the 5' UTR of the microseminoprotein-beta (MSMB) gene with an increased risk of developing the prostate cancer, re-igniting interest in its protein product, MSMB. METHODS: As one of the most abundant prostatic proteins, MSMB can be reliably detected in tissue and serum. RESULTS: It has been consistently shown that MSMB expression is high in normal and benign prostate tissue and lowered or lost in prostate cancer suggesting that it might be a useful tissue biomarker for prostate cancer diagnosis and its levels in serum may be useful as a marker for prognosis. Members of the cysteine-rich secretory protein family and laminin receptors have been shown to bind MSMB at the cell surface and in serum thereby regulating apoptosis. Thus, in the benign prostate, MSMB regulates cell growth, but when MSMB is lost during tumourigenesis, cells are able to grow in a more uncontrolled manner. Both full length MSMB and a short peptide comprised of amino acids 31-45 have been tested for potential therapeutic benefit in mouse models and humans. CONCLUSIONS: MSMB has potential as a biomarker of prostate cancer development, progression and recurrence and potentially as a target for therapeutic intervention. PMID- 19790237 TI - Arachidonic acid activation of intratumoral steroid synthesis during prostate cancer progression to castration resistance. AB - BACKGROUND: De novo androgen synthesis and subsequent androgen receptor (AR) activation has recently been shown to contribute to castration-resistant prostate cancer (CRPC) progression. Herein we provide evidence that fatty acids (FA) can trigger androgen synthesis within steroid starved prostate cancer (CaP) tumor cells. METHODS: Tumoral FA and steroid levels were assessed by GC-MS and LC-MS, respectively. Profiles of genes and proteins involved in FA activation of steroidogenesis were assessed by fluorescence microscopy, immunohistochemistry, microarray expression profiling and Western blot analysis. RESULTS: In human CaP tissues the levels of proteins responsible for FA activation of steroid synthesis were observed to be altered during progression to CRPC. Further investigating this mechanism in LNCaP cells, we demonstrate that specific FA, arachidonic acid, is synthesized in an androgen-dependent and AR-mediated manner. Arachidonic acid is known to induce steroidogenic acute regulatory protein (StAR) in steroidogenic cells. When bound to hormone sensitive lipase (HSL), StAR shuttles free cholesterol into the mitochondria for downstream conversion into androgens. We show that arachidonic acid induces androgen production in steroid starved LNCaP cells coincidently in the same conditions that HSL and StAR are predominantly localized in the mitochondria. Furthermore, their activities are verified by a functional increase in mitochondrial uptake of cholesterol in this steroid starved environment. CONCLUSIONS: We propose that this characterized arachidonic acid induced steroidogenesis mechanism significantly contributes to the activation of AR in CRPC progression and therefore recommend that fatty acid pathways be targeted therapeutically in progressing CaP. PMID- 19790238 TI - Antiandrogen withdrawal syndrome and alternative antiandrogen therapy associated with the W741C mutant androgen receptor in a novel prostate cancer xenograft. AB - BACKGROUND: The mechanisms underlying antiandrogen withdrawal syndrome (AWS) and alternative antiandrogen therapy (AAT) effectiveness were assumed to be mutations in the androgen receptor (AR), which resulted in an altered response to antiandrogens. The aim of the present study was to test this assumption using the novel prostate cancer xenograft model KUCaP-1 harboring the W741C mutant AR (Yoshida et al., Cancer Res 2005; 65(21): 9611-9616). METHODS: Mice bearing xenograft tumors were castrated, and the long-term sequential changes in tumor volume were observed. To determine whether AWS was observed in this model, bicalutamide (BCL) was orally administered to the castrated mice and then withdrawn. The effect of flutamide (FLT) on the W741C mutant AR was examined with transactivation assays in vitro and with the oral administration of FLT to non castrated mice harboring KUCaP-1 in vivo. The AAT efficacy against KUCaP-1 was evaluated by changing BCL with FLT. RESULTS: KUCaP-1 regressed significantly after castration and did not re-grow. KUCaP-1 treated with BCL continued to grow even after castration and started regressing 2 months after BCL withdrawal, replicating clinically recognized AWS. The antagonistic effect of FLT against the W741C mutant AR was revealed in vitro and in vivo. AAT with FLT suppressed tumor growth after BCL withdrawal. CONCLUSIONS: KUCaP-1 was an entirely androgen dependent xenograft and mimicked the clinical phenomena of AWS and AAT caused by the agonistic and antagonistic activity of BCL and FLT, respectively. KUCaP-1 could be an in vivo model for screening novel antiandrogens for the treatment of BCL resistant prostate cancer harboring the W741C mutation in the AR. PMID- 19790239 TI - Tranilast suppresses prostate cancer growth and osteoclast differentiation in vivo and in vitro. AB - BACKGROUND: In bone metastatic sites, prostate cancer cells proliferate on interacting with osteoclasts. Tranilast, which is used for an antiallergic drug, has been shown to inhibit growth of several cancers and stromal cells. The present study was conducted to assess suppressive effects of Tranilast on prostate cancer growth and osteoclast differentiation in vivo and in vitro. METHODS: In vivo, rat prostate cancer tissue was transplanted onto cranial bones of F344 rats and Tranilast was given for 9 days at doses of 0, 200, or 400 mg/kg/day. In vitro, human prostate cancer cell lines, LNCaP, PC3, and DU145, the rat prostate cancer cell line, PLS-10, and rat bone marrow cells were similarly treated with the agent. RESULTS: In vivo, tumor volumes were significantly decreased in the high dose group. While cell proliferation did not appear to be affected, apoptosis was induced and tumor necrosis was apparent. Cranial bone defects were decreased in the high dose group. In vitro, cell proliferation rates of all four cell lines were reduced by Tranilast and increased apoptosis was observed in LNCaP and PLS-10. In addition, Tranilast significantly reduced osteoclast differentiation of rat bone marrow cells. Western blot analysis of PLS 10 and LNCaP revealed that phospho-GSK3beta was up-regulated and phospho-Akt was down-regulated. CONCLUSIONS: Tranilast here suppressed rat prostate cancer growth and osteoclast differentiation. Growth of human prostate cancer cells was also inhibited. Thus, this agent deserves consideration as a candidate for conventional therapy of bone metastatic prostate cancer. PMID- 19790240 TI - The molecular machinery of germ line specification. AB - Germ cells occupy a unique position in animal reproduction, development, and evolution. In sexually reproducing animals, only they can produce gametes and contribute genetically to subsequent generations. Nonetheless, germ line specification during embryogenesis is conceptually the same as the specification of any somatic cell type: germ cells must activate a specific gene regulatory network in order to differentiate and go through gametogenesis. While many genes with critical roles in the germ line have been characterized with respect to expression pattern and genetic interactions, it is the molecular interactions of the relevant gene products that are ultimately responsible for germ cell differentiation. This review summarizes the current state of knowledge on the molecular functions and biochemical connections between germ line gene products. We find that homologous genes often interact physically with the same conserved molecular partners across the metazoans. We also point out cases of nonhomologous genes from different species whose gene products play analogous biological roles in the germ line. We suggest a preliminary molecular definition of an ancestral "pluripotency module" that could have been modified during metazoan evolution to become specific to the germ line. PMID- 19790241 TI - Effect of itraconazole on the pharmacokinetics of everolimus administered by different routes in rats. AB - The effect of itraconazole on the pharmacokinetics of everolimus was investigated in rats. Ten minutes after an intravenous or intraintestinal administration of itraconazole, everolimus was delivered intravenously (0.2 mg/kg) or intraintestinally (0.5 mg/kg). Blood concentrations of everolimus were measured up to 240 min, and pharmacokinetic parameters were calculated. Intraintestinally administered itraconazole (20 mg/kg) significantly increased the area under the concentration-time curve (AUC) of intraintestinally administered everolimus about 4.5-fold, but even at 50 mg/kg did not affect the AUC of intravenously administered everolimus. However, intravenously administered itraconazole (50 mg/kg) increased the AUC of both intraintestinally and intravenously administered everolimus approximately 2-fold. Using a value for hepatic blood flow from the literature (50 ml/min/kg), the apparent intestinal and hepatic extraction of everolimus without itraconazole was calculated as about 80% and 13%, respectively. Intraintestinally administered itraconazole (20 mg/kg) changed the apparent intestinal extraction by 0.26-fold from 0.829 to 0.215, but the hepatic availability of everolimus was almost unchanged after the intravenous or intraintestinal administration of itraconazole even at a dose of 50 mg/kg from 0.871 to 0.923 or 0.867, respectively. In conclusion, intraintestinally administered itraconazole dramatically increased the AUC of everolimus delivered intraintestinally by inhibiting the intestinal first-pass extraction of this drug. PMID- 19790242 TI - Assessment of a sheep animal model to optimise photodynamic therapy in the oesophagus. AB - BACKGROUND AND OBJECTIVES: Precursor lesions of oesophagus adenocarcinoma constitute a clinical dilemma. Photodynamic therapy (PDT) is an effective treatment for this indication, but it is difficult to optimise without an appropriate animal model. For this reason, we assessed the sheep model for PDT in the oesophagus with the photosensitiser meta-(tetra-hydroxyphenyl) chlorin (mTHPC). MATERIALS AND METHODS: Twelve sheep underwent intravenous mTHPC injection, blood sampling and fluorescence measurements. mTHPC's pharmacokinetics was measured in vivo and in plasma by fluorescence spectroscopy. Biopsies of sheep oesophagus were compared to corresponding human tissue, and the mTHPC's biodistribution was studied under fluorescence microscopy. Finally, the sheep oesophageal mucosa was irradiated, 4 days after mTHPC's injection. RESULTS: Histologically, the sheep and human oesophagus were closely comparable, with the exception of additional fatty tissue in the sheep oesophagus. mTHPC's pharmacokinetics in sheep and human plasmas were similar, with a maximum of concentration in the sheep 10 hours after i.v. injection. mTHPC's pharmacokinetics in vivo reached its maximum after 30-50 hours, then decreased to background levels, as in humans under similar conditions. Two days after injection, mTHPC was mainly distributed in the lamina propria, followed by a penetration into the epithelium. The sheep and human tissue sensitivity to mTHPC PDT was similar. CONCLUSION: In conclusion, this model showed many similarities with humans as to mTHPC's plasma and tissue pharmacokinetics, and for tissue PDT response, making it suitable to optimise oesophagus PDT. PMID- 19790243 TI - Metallo-naphthalocyanines as photothermal sensitisers for experimental tumours: in vitro and in vivo studies. AB - BACKGROUND AND OBJECTIVES: Photothermal sensitisation has been recently proposed as a novel approach for the treatment of solid tumours through the development of a therapeutic modality named photothermal therapy (PTT). The technique involves the use of high power pulsed laser irradiation and photosensitising agents with especially short lifetime (in the subnanosecond range) in the electronically excited states. This study aims to investigate the molecular features of the photosensitiser which optimise the photothermal activity. STUDY DESIGN/MATERIALS AND METHODS: Two octabutoxy-naphthalocyanines centrally coordinated with Pd(II) or Pt(II) ions were prepared by chemical synthesis and tested for their affinity and photothermal sensitisation activity toward a selected tumour cell line, namely B78H1 amelanotic melanoma. Irradiations were performed by using a Ti:sapphire laser operated in a pulsed regime (10 Hz, 30 nanosecond pulses, 120 mJ) at 809 nm (Pt) or 826 nm (Pd). The subcellular distribution pattern of the photosensitiser was also assessed by optical microscopy, while the nature of the photoinduced cell damage was determined by scanning electron microscopy. The results thus obtained provided a basis for subsequent in vivo studies, aimed at defining the phototherapeutic efficiency of the two metallo-naphthalocyanines: the photosensitisers were i.v. injected into C57BL/6 mice bearing a subcutaneously transplanted amelanotic melanoma and at 24 hours post-injection the tumour area was irradiated by the Ti:sapphire laser using the same protocol as above detailed. RESULTS: Both naphthalocyanines exhibited a high affinity for the amelanotic melanoma cells. The subcellular distribution pattern was modulated by the incubation time: after 48 hours incubation with 7.7 microM Pd- and Pt derivatives, the naphthalocyanine appeared to localise in specific sites with a gradual formation of aggregated clusters. Subsequent irradiation of the naphthalocyanine-loaded cells caused an extensive cell death; the photoinduced damage, as observed at the scanning electron microscope, mainly consisted in the formation of large endocellular holes consequent to the loss of cytoplasmic material. This scenario is typical of photothermal sensitisation processes. Lastly, both metallo-naphthalocyanines, and in particular the Pd(II) derivative, promoted an important response by the amelanotic melanoma, when the neoplastic tissue was irradiated by the pulsed Ti:sapphire laser. In certain cases, the photothermal treatment appeared to be curative. In all cases, the in vivo photodamage was confined within the tumour area with no detectable involvement of the perilesional tissues. CONCLUSION: PTT appears to act very efficiently at least on subcutaneous tumours. The technique can be used either in combination with photodynamic therapy (PDT) or as an alternative to PDT in those cases where the latter modality displays a limited efficacy, such as in the treatment of pigmented or poorly vascularised tumours. PMID- 19790244 TI - Neuronal and glial cerebrospinal fluid protein biomarkers are elevated after West Nile virus infection. AB - Neurotrophic West Nile virus (WNV) disease is a severe arbovirus infection in which neuronal loss is the likely anatomical substrate for the high morbidity and mortality. We investigated whether cerebrospinal fluid (CSF) protein biomarkers were elevated in vivo and related to disease severity in patients with WNV infection. This exploratory study included 114 patients (24 acute WNV, 77 noninflammatory controls, six peripheral neuropathies, seven aseptic meningoencephalitis). CSF levels of neuronal (neurofilaments, NfH-SMI35) and glial (glial fibrillary acidic protein, GFAP, S100B) biomarkers were measured by enzyme-linked immunosorbent assay (ELISA). Immunocytochemistry was performed in two fatal WNV cases. A significant proportion of patients with WNV had pathological CSF levels for NfH-SMI35 (58%, median concentration 1.01 ng/mL), GFAP (58%, 10 pg/mL), and S100B (90%, 1.29 ng/mL). The results were consistent with postmortem evidence for neuronal death and astrogliosis. Surprisingly, CSF protein biomarker levels were also found to be pathological in a considerable proportion of patients who presented with WNV fever only (100% for GFAP and S100B and 43% for NfH-SMI35). Elevated CSF protein biomarker levels are suggestive of neuronal death and glial pathology in human WNV infection. The results indicate the presence of neuroinvasive disease across the spectrum of WNV disease, including WNV fever. PMID- 19790245 TI - Role of gelatinases in disuse-induced skeletal muscle atrophy. AB - Gelatinases are a subgroup of the family of matrix metalloproteinases, which contains two members-gelatinase A and B. These enzymes play an important role in basement membrane homeostasis. Previous studies have associated basement membrane degradation with skeletal muscle atrophy. However, the specific contribution of gelatinases to the pathobiology of muscle atrophy remains unknown. In this study we examined the specific roles of gelatinase A and B in disuse-induced skeletal muscle atrophy using knockout mice. Although both gelatinase A and B are highly upregulated in disused muscle, only gelatinase A null mice had significantly reduced muscle atrophy as compared to wildtype littermates. Type IV collagen and laminin, two major components of basement membrane, were relatively well preserved in disused muscle in gelatinase A null mice, but not in gelatinase B null mice. These findings suggest that gelatinase A, and not gelatinase B, plays a critical role in disuse-induced skeletal muscle atrophy. PMID- 19790246 TI - Immunohistochemical expression of E-cadherin in sclerosing adenosis, ductal carcinoma in situ and invasive ductal carcinoma of the breast. AB - E-cadherin (EC) is an important glycoprotein cell-adhesion molecule that appears to play a significant role in the progression of breast lesions. The objective of this study was to evaluate EC expression in sclerosing adenosis, ductal carcinoma in situ and invasive ductal carcinoma. Samples of breast lesions from 44 women were used in this study, comprising cases of sclerosing adenosis (n = 11), ductal carcinoma in situ (DCIS) (n = 10) and invasive ductal carcinoma (n = 23). Immunohistochemical evaluation of EC expression was assessed semiquantitatively and considered negative (<10% of cells with stained cytoplasmic membranes), positive+ (10-50% of cells stained) or positive++ (> 50% of cells stained). Fisher's exact test was used to compare the distribution of staining intensity in the lesions (P< 0.05). There was a progressive loss of EC expression from benign to malignant lesions. This difference was statistically significant when sclerosing adenosis was compared with DCIS (P < 0.0002), when sclerosing adenosis was compared with invasive ductal carcinoma (P < 0.008) and when DCIS was compared with invasive ductal carcinoma (P < 0.007). The present findings point to a significant association between reduced EC expression and the progression and aggressivity of breast lesions. Diagn. Cytopathol. 2010. (c) 2009 Wiley-Liss, Inc. PMID- 19790247 TI - A rare case of paratesticular pleomorphic rhabdomyosarcoma diagnosed by fine needle aspiration: a case report. AB - Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma of children and young adults. It represents 6.5% of all malignant tumors in pediatrics with an annual incidence of 4 to 7 cases per million children. Embryonal RMS arising in paratesticular region in young males is a common entity, however pleomorphic RMS in such location is quite rare. An eighteen year old male presented with painless right scrotal mass measuring 7 x 6 x 5 cm of two year duration, which was reported on ultrasonography as extratesticular tumor. Fine needle aspiration showed cellular smears comprising of pleomorphic population of mostly singly scattered cells and few cell aggregates. Few isolated large cells with whip like cytoplasmic processes and faint cross-striations were also seen. A diagnosis of paratesticular malignant mesenchymal tumor probably RMS was made. Tumor was removed surgically with right sided orchidectomy. On histopathology, it was reported as pleomorphic RMS. There was focal lymphatic invasion and involvement of rete testis. Immunostaining of tumor cells revealed myogenin and desmin positivity. The case is being presented because of diagnosis of RMS on Fine needle aspiration and rare occurrence of pleomorphic RMS in paratesticular location. PMID- 19790248 TI - Visible light induces nitric oxide (NO) formation in sperm and endothelial cells. AB - BACKGROUND: Visible light-based stimulation using low-intensity lasers, LEDs, and broadband visible light devices has been recently introduced for therapy of human tissues in the absence of exogenous photosensitizers. Nitric oxide (NO) formation might be a potential mechanism for photobiomodulation because it is synthesized in cells by nitric oxide synthase (NOS), which contains both flavin and heme groups that absorb visible light. NO synthesis may also result from increased reactive oxygen species (ROS), which are found in various cell cultures following visible light illumination. NO is mainly known for inducing blood vessel dilation by endothelial cells, and in sperm cells NO is considered as an important agent in acrosome reaction and capacitation process, which are essential for successful fertilization. PURPOSE: To study NO formation in endothelial and sperm cells following visible light irradiation. MATERIALS AND METHODS: Sperm and endothelial cells were illuminated with broadband visible light, 400-800 nm, 130 mW/cm(2), for 5 minutes. During illumination, the endothelial cells were incubated in PBS free of Ca(+2) and Mg(+2), and the sperm cells were incubated in NKM buffer, to induce "stress conditions." NO production was quantified by using the Griess reagent which reacts with nitrite in the medium to yield an Azo compound which has an absorption band at 540 nm. RESULTS: Visible light illumination increased NO concentration both in sperm and endothelial cells. Blue light was more effective than red. Light-induced NO occurred only when endothelial cells were incubated in PBS free of Ca(+2) and Mg(+2), and in sperm cells, only when incubated in NKM. CONCLUSION: Light induces NO formation in endothelial and sperm cells. In endothelial cells, NO formation may explain previous results demonstrating enhanced wound healing and pain relief following illumination. In illuminated sperm cells, NO formation may account for the enhanced fertilization rate. PMID- 19790249 TI - Chain reaction of amyloid fibril formation with induction of basement membrane in familial amyloidotic polyneuropathy. AB - Familial amyloidotic polyneuropathy (FAP) is characterized by extracellular deposition of amyloid fibrils caused by a point mutation in the transthyretin (TTR) gene. Despite data from a number of in vitro studies of TTR amyloidogenesis, many questions, including where and how these fibrils form in vivo and what is the impact of amyloid deposition on tissues, remain unanswered. Here, we analysed the relationship between amyloid fibril formation and micro environmental changes by using autopsy cardiac tissues from 11 patients with FAP and a smooth muscle cell line. Ultrastructural studies of cardiomyocytes and vascular smooth muscle cells showed that amyloid fibrils formed first at the basement membrane and that amorphous non-fibrillar TTR deposits and premature fibrils predominated during the early stage of amyloid deposition. Immunohistochemical analyses revealed that expression of major components of the basement membrane, such as collagen IV, laminin, and fibronectin, increased in parallel with the accumulation of TTR amyloid fibrils. In vitro studies with a vascular smooth muscle cell line revealed that synthetic TTR aggregates increased expression of these basement membrane components. Serum levels of collagen IV in FAP patients were significantly higher than those in healthy controls. Our data thus indicate that TTR amyloid fibrils formed first at the basement membrane and that expression of basement membrane components that was induced by amyloid deposition contributed to further amyloid deposition. This chain reaction may have important implications for FAP pathogenesis. PMID- 19790250 TI - Toxicity profiles of four metals and 17 xenobiotics in the human hepatoma cell line HepG2 and the protozoa Tetrahymena pyriformis--a comparison. AB - We performed an interspecies comparison for the human hepatoma cell line HepG2 and the eukaryotic single cell organism Tetrahymena pyriformis (T. pyriformis) for 17 xenobiotics with diverse structures and four metals. The cytotoxicity was assessed by four different cell viability assays (3-[4,5-dimethylthiazol-2-yl] 2,5-diphenyl tetrazolium bromide reduction (MTT), neutral red uptake (NRU), resazurin dye (AlamarBlue), 5-carboxyfluorescein diacetate acetoxymethyl ester (CFDA-AM)) for the HepG2 and by cell count and MTT for T. pyriformis. For HepG2 cells, the results revealed interassay variations depending on the compound. The highest assay conformity was found for the metal Hg(2+) and the fungicide prochloraz. The AlamarBlue assay was the most sensitive assay according to low effect concentrations. By contrast, the NRU assay was comprised of more frequent whole concentration response relationships and was more susceptible to EC(50). For T. pyriformis the EC(50) values of the two applied assays displayed a high conformity (R(2) = 0.97). Comparing the EC(50) values obtained by the MTT assay for the two cell models, a direct correlation was absent for the xenobiotics and only present for the metals (Cd(2+), Cu(2+), and Ni(2+)). Moreover, the protozoa T. pyriformis displayed a 20 times higher sensitivity than the cell line. The highest interspecies difference of three log degrees was obtained for the polycyclic aromatic hydrocarbon fluoranthene. In addition, a correlation of the EC(50) values and octanol-water partition coefficient (log K(OW)) of the xenobiotics was performed. No correlation was found for HepG2, and a weak one for T. pyriformis. Interestingly, the interspecies difference of logarithmized EC(50) correlated positive with the log K(OW) (R(2) = 0.65). In conclusion, to obtain reliable evidence for human cytotoxicity, more than one viability/cytotoxicity assay had to be applied for cell lines. Second, the human hepatoma cell line was less affected by the organic compounds than the eukaryotic single-cell organism and was also less dependent on the log K(OW) of the xenobiotic. PMID- 19790251 TI - Acute effects of microcystins on the transcription of 14 glutathione S transferase isoforms in Wistar rat. AB - The glutathione S-transferases (GST) play important roles in the detoxification of microcystins (MCs). For better understanding of the responses of GST isforms to MCs exposure, informations about the effects of MCs on GSTs are necessary. In this experiment, we cloned the full length cDNA of 14 GST isoforms (GST alpha, kappa, mu, omega, pi, theta, zeta, and microsomal GST) from Wistar rat. The mRNA abundance of each rat GST isoform in the liver, kidney, and testis was analyzed by real time quantitative PCR. Multiple GST isoforms were constitutively expressed in all examined organs, but some isoforms were expressed at higher level in one organ than in others. The relative changes of the mRNA abundance in the liver, kidney, and testis of Wiatar rat i.v. injected with crude MCs extract at dose of 1LD(50) were also analyzed. Generally, the expression of most GSTs in the liver and testis was suppressed while that in kidney was induced after being injected with MCs. It is suggested that the transcription of GST isoforms varied in different ways within an organ and between organs of Wistar rat exposed to MCs. PMID- 19790253 TI - Contrast-enhanced ultrasound with SonoVue: differentiation between benign and malignant focal liver lesions in 317 patients. AB - PURPOSE: The aim of the study was to investigate the ability of contrast-enhanced sonography (CEUS) with the contrast agent SonoVue to differentiate between benign and malignant focal liver lesions. METHODS: In a prospective study, we examined 317 patients (204 males, 113 females, aged 59 +/- 12 years) with focal liver lesions detected by B-mode gray-scale sonography. After intravenous injection of 1.2 mL SonoVue, the liver was examined continuously for 3 minutes using low-MI sonography with contrast-specific software. Final diagnosis was established by histopathology, CT, MRI, or HIDA-scintigraphy. RESULTS: Two hundred nine patients had malignant focal lesions, including 107 hepatocellular carcinomas, 70 metastases, 26 cholangiocellular carcinomas, and 6 other types of malignancy. One hundred eight patients had benign focal lesions, including 30 regenerative nodules, 30 hemangiomas, 13 cases of focal nodular hyperplasia, 12 abscesses, 8 cases of necrosis, 7 cases of focal steatosis areas, and 8 other benign lesions. Hypoenhancement or no enhancement in the late phase was found in 91% of the malignant lesions but in only 37% of the benign lesions (p < 0.001, sensitivity = 64%, specificity = 93%). Hyperenhancement in the late phase was found in 20% of the benign lesions but in none of the malignant lesions (p < 0.001, sensitivity = 21%, specificity = 100%). Hyperenhancement in the early phase with diffuse complete enhancement was found in 30% of the patients with malignant lesions but in only 2% of the patients with benign lesions (p < 0.001, sensitivity = 30%, specificity = 98%). CEUS had a sensitivity of 90%, a specificity of 99%, and an accuracy of 89% in the diagnosis of malignant liver lesions. CONCLUSION: CEUS is helpful in the differentiation between benign and malignant focal liver lesions. PMID- 19790252 TI - Aging alters the expression of genes for neuroprotection and synaptic function following acute estradiol treatment. AB - This study used microarray analysis to examine age-related changes in gene expression 6 and 12 h following a single estradiol injection in ovariectomized mice. Estradiol-responsive gene expression at the 6 h time point was reduced in aged (18 months) animals compared with young (4 months) and middle-aged (MA, 12 months) mice. Examination of gene clustering within biological and functional pathways indicated that young and MA mice exhibited increased expression of genes for cellular components of the synapse and decreased expression of genes related to oxidative phosphorylation and mitochondrial dysfunction. At the 12 h time point, estradiol-responsive gene expression increased in aged animals and decreased in young and MA mice compared with the 6 h time point. Gene clustering analysis indicated that aged mice exhibited increased expression of genes for signaling pathways that are rapidly influenced by estradiol. The age differences in gene expression for rapid signaling pathways may relate to disparity in basal pathway activity and estradiol mediated activation of rapid signaling cascades. PMID- 19790254 TI - C/beta(0) thalassemia. PMID- 19790255 TI - Identifying and changing the normative beliefs about aggression which lead young Muslim adults to join extremist anti-Semitic groups in Pakistan. AB - Two studies investigated the role of beliefs about the acceptability of aggression ("normative beliefs") against Jews in determining who would join an extremist group. In Study 1, students in a university in Pakistan (N=144) completed self-report attitude measures, and were subsequently approached by a confederate who asked whether they wanted to join an extremist anti-Semitic organization. Normative beliefs about aggression against Jews were very strong predictors of whether participants agreed to join. In Study 2, participants (N=92) were experimentally assigned to either a brief educational intervention, designed to improve inter-group relations, or to a control group. They also filled in self-report attitude measures pre and post intervention. Participants in the intervention group were much less likely to agree to join the extremist group, and this effect of the intervention on joining was mediated by changes in normative beliefs about aggression against Jews. The results have implications for theories of inter-group aggression and interventions to prevent people from being recruited into extremist groups. PMID- 19790256 TI - Update on mutations in glucokinase (GCK), which cause maturity-onset diabetes of the young, permanent neonatal diabetes, and hyperinsulinemic hypoglycemia. AB - Glucokinase is a key regulatory enzyme in the pancreatic beta-cell. It plays a crucial role in the regulation of insulin secretion and has been termed the glucose sensor in pancreatic beta-cells. Given its central role in the regulation of insulin release it is understandable that mutations in the gene encoding glucokinase (GCK) can cause both hyper- and hypoglycemia. Heterozygous inactivating mutations in GCK cause maturity-onset diabetes of the young (MODY) subtype glucokinase (GCK), characterized by mild fasting hyperglycemia, which is present at birth but often only detected later in life during screening for other purposes. Homozygous inactivating GCK mutations result in a more severe phenotype presenting at birth as permanent neonatal diabetes mellitus (PNDM). A growing number of heterozygous activating GCK mutations that cause hypoglycemia have also been reported. A total of 620 mutations in the GCK gene have been described in a total of 1,441 families. There are no common mutations, and the mutations are distributed throughout the gene. The majority of activating mutations cluster in a discrete region of the protein termed the allosteric activator site. The identification of a GCK mutation in patients with both hyper- and hypoglycemia has implications for the clinical course and clinical management of their disorder. PMID- 19790257 TI - Structural aspects of therapeutic enzymes to treat metabolic disorders. AB - Protein therapeutics represents a niche subset of pharmacological agents that is rapidly gaining importance in medicine. In addition to the exceptional specificity that is characteristic of protein therapeutics, several classes of proteins have also been effectively utilized for treatment of conditions that would otherwise lack effective pharmacotherapeutic options. A particularly striking class of protein therapeutics is exogenous enzymes administered for replacement therapy in patients afflicted with metabolic disorders. To date, at least 11 enzymes have either been approved for use, or are in clinical trials for the treatment of selected inherited metabolic disorders. With the recent advancement in structural biology, a significantly larger amount of structural information for several of these enzymes is now available. This article is an overview of the correlation between structural perturbations of these enzymes with the clinical presentation of the respective metabolic conditions, as well as a discussion of the relevant structural modification strategies engaged in improving these enzymes for replacement therapies. PMID- 19790258 TI - Sonographic appearance of focal fatty infiltration of the pancreas. AB - We report the sonographic, CT, and MRI findings in a case of focal fatty infiltration of the pancreas. Sonography revealed an echogenic mass in pancreas head. On CT, the mass was hypodense. The mass showed same signal intensity to the surrounding normal pancreas on in-phase T1-weighted MR images and a loss of signal intensity on opposed-phase MR images. PMID- 19790259 TI - Flow cytometric scoring of micronucleated reticulocytes as a possible high throughput radiation biodosimeter. AB - Micronucleated reticulocyte (MN-RET) scoring by flow cytometry (FCM) has been used in assessment of the clastogenic effects of chemicals. However, its dose response to acute whole body irradiation (WBI) at moderate dose rates remains to be established. We show that FCM scoring of MN-RET in peripheral blood from male ICR mice exposed to WBI X-ray doses of 0.5-5 Gy at a dose rate of 0.488 Gy/min exhibits a linear dose-response relationship 24, 48, and 72 hr following WBI. Parallel microscopic counting of micronucleated polychromatic erythrocytes (MN PCE) in bone marrow smears from the same animals showed similar linear dose response patterns at the same time points. Indeed, MN-RET and MN-PCE were highly correlated at all doses and time points. In view of the speed and accuracy of this method, in addition to the small blood sample size needed for the assay, the flow cytometric protocol for MN-RET scoring may provide a minimally-invasive, high throughput radiation biodosimeter. PMID- 19790260 TI - Cytogenetic genotoxicity of amoxicillin. AB - Amoxicillin (AMO), a drug used in the treatment of infections caused by susceptible bacteria, has been evaluated for its ability to induce genotoxicity in human peripheral blood lymphocytes. The potential genotoxic effects of AMO were investigated in vitro by the sister chromatid exchange (SCE), chromosomal aberration (CA), and micronucleus (MN) tests. The cells were treated with 400, 600, 800, and 1,000 microg/ml AMO in the presence and absence of a metabolic activator (S9 mix), respectively. In this study, AMO did not induce SCEs or CAs in human peripheral blood lymphocytes both in the presence and absence of the metabolic activator. AMO concentration-dependently decreased the proliferation index (PI) in the absence of the metabolic activation for 24-hr treatment period. Mitotic index (MI) was generally found to have been reduced when compared with the negative control but not with the solvent control in cultures treated with AMO for 24 hr. AMO did not decrease the PI and MI in the presence of the metabolic activator. Furthermore, AMO neither induced the formation of MN nor decreased the nuclear division index in human peripheral blood lymphocytes both in the presence and absence of the metabolic activator. According to the present results, we suggest that AMO does not pose genotoxic risk for patients who are under therapy against bacterial infections. PMID- 19790262 TI - Genoarchitectonic profile of developing nuclear groups in the chicken pretectum. AB - Earlier results on molecularly coded progenitor domains in the chicken pretectum revealed an anteroposterior subdivision of the pretectum in precommissural (PcP), juxtacommissural (JcP), and commissural (CoP) histogenetic areas, each specified differentially (Ferran et al. [2007] J Comp Neurol 505:379-403). Here we examined the nuclei derived from these areas with regard to characteristic gene expression patterns and gradual histogenesis (eventually, migration patterns). We sought a genoarchitectonic schema of the avian pretectum within the prosomeric model of the vertebrate forebrain (Puelles and Rubenstein [2003] Trends Neurosci 26:469 476; Puelles et al. [2007] San Diego: Academic Press). Transcription-factor gene markers were used to selectively map derivatives of the three pretectal histogenetic domains: Pax7 and Pax6 (CoP); FoxP1 and Six3 (JcP); and FoxP2, Ebf1, and Bhlhb4 (PcP). The combination of this genoarchitectonic information with additional data on Lim1, Tal2, and Nbea mRNA expression and other chemoarchitectonic results allowed unambiguous characterization of some 30 pretectal nuclei. Apart from grouping them as derivatives of the three early anteroposterior domains, we also assigned them to postulated dorsoventral subdomains (Ferran et al. [2007]). Several previously unknown neuronal populations were detected, thus expanding the list of pretectal structures, and we corrected some apparently confused concepts in the earlier literature. The composite gene expression map represents a substantial advance in anatomical and embryological knowledge of the avian pretectum. Many nuclear primordia can be recognized long before the mature differentiated state of the pretectum is achieved. This study provides fundamental notions for ultimate scientific study of the specification and regionalization processes building up this brain area, both in birds and other vertebrates. PMID- 19790261 TI - Formaldehyde and leukemia: epidemiology, potential mechanisms, and implications for risk assessment. AB - Formaldehyde is widely used in the United States and other countries. Occupational and environmental exposures to formaldehyde may be associated with an increased risk of leukemia in exposed individuals. However, risk assessment of formaldehyde and leukemia has been challenging due to inconsistencies in human and animal studies and the lack of a known mechanism for leukemia induction. Here, we provide a summary of the symposium at the Environmental Mutagen Society Meeting in 2008, which focused on the epidemiology of formaldehyde and leukemia, potential mechanisms, and implication for risk assessment, with emphasis on future directions in multidisciplinary formaldehyde research. Updated results of two of the three largest industrial cohort studies of formaldehyde-exposed workers have shown positive associations with leukemia, particularly myeloid leukemia, and a recent meta-analysis of studies to date supports this association. Recent mechanistic studies have shown the formation of formaldehyde induced DNA adducts and characterized the essential DNA repair pathways that mitigate formaldehyde toxicity. The implications of the updated findings for the design of future studies to more effectively assess the risk of leukemia arising from formaldehyde exposure were discussed and specific recommendations were made. A toxicogenomic approach in experimental models and human exposure studies, together with the measurement of biomarkers of internal exposure, such as formaldehyde-DNA and protein adducts, should prove fruitful. It was recognized that increased communication among scientists who perform epidemiology, toxicology, biology, and risk assessment could enhance the design of future studies, which could ultimately reduce uncertainty in the risk assessment of formaldehyde and leukemia. PMID- 19790263 TI - Multiscale modeling of structural dynamics underlying force generation and product release in actomyosin complex. AB - To decrypt the mechanistic basis of myosin motor function, it is essential to probe the conformational changes in actomyosin with high spatial and temporal resolutions. In a computational effort to meet this challenge, we have performed a multiscale modeling of the allosteric couplings and transition pathway of actomyosin complex by combining coarse-grained modeling of the entire complex with all-atom molecular dynamics simulations of the active site. Our modeling of allosteric couplings at the pre-powerstroke state has pinpointed key actin activated couplings to distant myosin parts which are critical to force generation and the sequential release of phosphate and ADP. At the post powerstroke state, we have identified isoform-dependent couplings which underlie the reciprocal coupling between actin binding and nucleotide binding in fast Myosin II, and load-dependent ADP release in Myosin V. Our modeling of transition pathway during powerstroke has outlined a clear sequence of structural events triggered by actin binding, which lead to subsequent force generation, twisting of central beta-sheet, and the sequential release of phosphate and ADP. Finally we have performed atomistic simulations of active-site dynamics based on an on path "transition-state" myosin conformation, which has revealed significantly weakened coordination of phosphate by Switch II, and a disrupted key salt bridge between Switch I and II. Meanwhile, the coordination of MgADP by Switch I and P loop is less perturbed. As a result, the phosphate can be released prior to MgADP. This study has shed new lights on the controversy over the structural mechanism of actin-activated phosphate release and force generation in myosin motor. PMID- 19790264 TI - Lack of evidence for the mu-opioid receptor splice variant MOR1C in rats. AB - We previously reported the existence of MOR1(C) mRNA and MOR1(C)-immunoreactivity (-ir) in rats. However, the sequence that we reported for rat MOR1(C) appears not to be present in the rat genome. We have therefore reexamined whether MOR1(C) mRNA or MOR1(C)-ir exist in rats. We used reverse-transcription polymerase chain reaction (RT-PCR) to attempt to amplify MOR1, MOR1(A), MOR1(B), the rat MOR1(C) sequence we previously reported, and MOR1(C1) and MOR1(C2) (which have recently been reported to exist in rats). In RNA extracted from rats, we were able to demonstrate PCR products representing MOR1, MOR1(A), and MOR1(B) splice variants. All three products were confirmed as related to MOR1 by Southern blot. However, we were unable to detect either the MOR1(C) product reported previously by us or the MOR1(C)-like products reported to exist in rats by others. In RNA extracted from mice we were able to detect MOR1, MOR1(A), MOR1(B), and MOR1(D)-like products. To test the specificity of our MOR1(C) antiserum, we examined MOR1(C) ir in control and knockout mice. MOR1(C)-ir had a distribution in control mice similar to that previously reported in rats, including coexisting with vGLUT2. However, although MOR1-ir was absent in MOR1 knockout mice, the density and distribution of MOR1(C)-ir were unchanged, suggesting that the antiserum crossreacts with another molecule in tissue. We find no evidence for MOR1(C) mRNA in rats. Furthermore, we conclude that MOR1(C)-ir represents crossreactivity. PMID- 19790265 TI - Trimethylamine N-oxide influence on the backbone of proteins: an oligoglycine model. AB - The study of organic osmolytes has been pivotal in demonstrating the role of solvent effects on the protein backbone in the folding process. Although a thermodynamic description of the interactions between the protein backbone and osmolyte has been well defined, the structural analysis of the effect of osmolyte on the protein backbone has been incomplete. Therefore, we have performed simulations of a peptide backbone model, glycine(15), in protecting osmolyte trimethylamine N-oxide (TMAO) solution, in order to determine the effect of the solution structure on the conformation of the peptide backbone. We show that the models chosen show that the ensemble of backbone structures shifts toward a more collapsed state in TMAO solution as compared with pure water solution. The collapse is consistent with preferential exclusion of the osmolyte caused by unfavorable interactions between osmolyte and peptide backbone. The exclusion is caused by strong triplet correlations of osmolyte, water, and peptide backbone. This provides a clear mechanism showing that even a modest concentration of TMAO forces the protein backbone to adopt a more collapsed structure in the absence of side chain effects. PMID- 19790266 TI - Substrate uptake and protein stability relationship in mammalian histidine decarboxylase. AB - There is some evidence linking the substrate entrance in the active site of mammalian histidine decarboxylase and an increased stability against proteolytic degradation. In this work, we study the basis of this relationship by means of protein structure network analysis and molecular dynamics simulations. We find that the substrate binding to the active site influences the conformation of a flexible region sensible to proteolytic degradation and observe how formation of the Michaelis-Menten complex increases stability in the conformation of this region. PMID- 19790268 TI - Acute and chronic sectioning of fifth lumbar spinal nerve has equivalent effects on the primary afferents of sciatic nerve in rat spinal cord. AB - The mechanism of neuropathic pain may be associated with sprouting of uninjured primary afferents of peripheral nerves into regions of the spinal cord denervated through peripheral injury. However, this remains controversial. Therefore, the purpose of the present investigation was, first, to determine in detail the central distributions of the unmyelinated primary afferents of each of the L4, L5, and L6 components of sciatic nerve, then to assess the distribution of afferent sciatic terminals following acute and chronic injury to (L5) nerve. First, we injected isolectin B4 (IB4), into the sciatic nerves in three groups of rats, each of which had two of the three L4, L5, or L6 components ligated and cut, and the one remaining, uninjured. Although the terminal labelling found in the L5 segment of the spinal cord originated from the L5 component, some terminal labelling remained in cases when either the L4 or L6 component was intact. Second, tracers transported in predominantly unmyelinated (IB4 and WGA-HRP) or myelinated (cholera toxin subunit B) nerves were injected into the sciatic nerve following acute or chronic (21-day) injury restricted to the L5 component. In each case, the central distribution of nerve terminals in the spinal dorsal horn was equivalent following either acute or chronic injury to the L5 component. Consequently, these data provide no support for the suggestion that neuropathic pain in spinal ligation model results from uninjured L4 and L6 components sprouting to occupy sites vacated by the injured L5 component of the sciatic nerve. PMID- 19790267 TI - Morphology of retinal ganglion cells in the ferret (Mustela putorius furo). AB - The ferret is the premiere mammalian model of retinal and visual system development, but the spectrum and properties of its retinal ganglion cells are less well understood than in another member of the Carnivora, the domestic cat. Here, we have extensively surveyed the dendritic architecture of ferret ganglion cells and report that the classification scheme previously developed for cat ganglion cells can be applied with few modifications to the ferret retina. We confirm the presence of alpha and beta cells in ferret retina, which are very similar to those in cat retina. Both cell types exhibited an increase in dendritic field size with distance from the area centralis (eccentricity) and with distance from the visual streak. Both alpha and beta cell populations existed as two subtypes whose dendrites stratified mainly in sublamina a or b of the inner plexiform layer. Six additional morphological types of ganglion cells were identified: four monostratified cell types (delta, epsilon, zeta, and eta) and two bistratified types (theta and iota). These types closely resembled their counterparts in the cat in terms of form, relative field size, and stratification. Our data indicate that, among carnivore species, the retinal ganglion cells resemble one another closely and that the ferret is a useful model for studies of the ontogenetic differentiation of ganglion cell types. PMID- 19790269 TI - Inhibition of phosphatidylinositol 3-kinase signaling in hepatic stellate cells blocks the progression of hepatic fibrosis. AB - The hepatic stellate cell (HSC) is the primary cell type in the liver responsible for excess collagen deposition during fibrosis. Following a fibrogenic stimulus the cell changes from a quiescent vitamin A-storing cell to an activated cell type associated with increased extracellular matrix synthesis and increased cell proliferation. The phosphatidylinositol 3-kinase (PI3K) signaling pathway has been shown to regulate several aspects of HSC activation in vitro, including collagen synthesis and cell proliferation. Using a targeted approach to inhibit PI3K signaling specifically in HSCs, we investigated the role of PI3K in HSCs using a rodent model of hepatic fibrosis. An adenovirus expressing a dominant negative form of PI3K under control of the smooth muscle alpha-actin (alphaSMA) promoter was generated (Ad-SMAdnPI3K). Transducing HSCs with Ad-SMAdnPI3K resulted in decreased proliferation, migration, collagen expression, and several additional profibrogenic genes, while also promoting cell death. Inhibition of PI3K signaling was also associated with reduced activation of Akt, p70 S6 kinase, and extracellular regulated kinase signaling as well as reduced cyclin D1 expression. Administering Ad-SMAdnPI3K to mice following bile duct ligation resulted in reduced HSC activation and decreased extracellular matrix deposition, including collagen expression. A reduction in profibrogenic mediators, including transforming growth factor beta, tissue inhibitor of metalloproteinase 1, and connective tissue growth factor was also noted. However, liver damage, assessed by alanine aminotransferase levels, was not reduced. CONCLUSION: Inhibition of PI3K signaling in HSCs during active fibrogenesis inhibits extracellular matrix deposition, including synthesis of type I collagen, and reduces expression of profibrogenic factors. These data suggest that targeting PI3K signaling in HSCs may represent an effective therapeutic target for hepatic fibrosis. PMID- 19790285 TI - The intermedius nucleus of the medulla: a potential site for the integration of cervical information and the generation of autonomic responses. AB - The intermedius nucleus of the medulla (InM) is a small perihypoglossal brainstem nucleus, which receives afferent information from the neck musculature and also descending inputs from the vestibular nuclei, the gustatory portion of the nucleus of the solitary tract (NTS) and cortical areas involved in movements of the tongue. The InM sends monosynaptic projections to both the NTS and the hypoglossal nucleus. It is likely that the InM acts to integrate information from the head and neck and relays this information on to the NTS where suitable autonomic responses can be generated, and also to the hypoglossal nucleus to influence movements of the tongue and upper airways. Central to the integratory role of the InM is its neurochemical diversity. Neurones within the InM utilise the amino acid transmitters glutamate, GABA and glycine. A proportion of these excitatory and inhibitory neurones also use nitric oxide as a neurotransmitter. Peptidergic transmitters have also been found within InM neurones, although as yet the extent of the pattern of co-localisation between peptidergic and amino acid transmitters in neurones has not been established. The calcium binding proteins calretinin and parvalbumin are found within the InM in partially overlapping populations. Parvalbumin and calretinin appear to have complementary distributions within the InM, with parvalbumin being predominantly found within GABAergic neurones and calretinin being predominantly found within glutamatergic neurones. Neurones in the InM receive inputs from glutamatergic sensory afferents. This glutamatergic transmission is conducted through both NMDA and AMPA ionotropic glutamate receptors. In summary the InM contains a mixed pool of neurones including glutamatergic and GABAergic in addition to peptidergic neurones. Neurones within the InM receive inputs from the upper cervical region, descending inputs from brain regions involved in tongue movements and those involved in the coordination of the autonomic nervous system. Outputs from the InM to the NTS and hypoglossal nucleus suggest a possible role in the coordination of tongue movements and autonomic responses to changes in posture. PMID- 19790286 TI - Fighting and drought worsen Somalia's humanitarian crisis. PMID- 19790287 TI - Latin America faces hurdles in health research. PMID- 19790288 TI - Unravelling ethical challenges in surgery. PMID- 19790289 TI - The brachydactylies: a molecular disease family. AB - Brachydactyly refers to shortening of the hands and/or feet due to missing, deformed, or shortened bones. It may occur as an isolated trait or as part of a syndrome. According to their pattern of skeletal involvement, the isolated brachydactyly forms have been categorized in the groups A-D including several subgroups. As in many other genetic conditions, there is considerable phenotypic overlap between the groups. The identification of the molecular causes of these conditions has offered insights into their pathogenesis. The generation of animal models has facilitated research on the pathogenic events during digit development that lead to the brachydactyly phenotype. These studies have shown that the BMP pathway plays a pivotal role in the normal development of digits and joints and that the majority of brachydactyly disease genes are directly or indirectly linked to this pathway. Together, these genes function in a regulatory network which is deregulated in the disease state. As a consequence of the close interactions within the network, overlapping phenotypes are generated that are, nevertheless, characterized by specific recognizable patterns. This principle does not only apply for the brachydactylies but is also valid for many other disease entities. Groups of diseases that show a common phenotypic pattern due to the deregulation of a molecular network are suggested to be called molecular disease families. PMID- 19790290 TI - Development and disease of the photoreceptor cilium. AB - Primary cilia are microtubule-rich hair-like extensions protruding from the surface of most post-mitotic cells. They act as sensory organelles that help interpret various environmental cues. Mutations in genes encoding proteins involved in ciliogenesis or protein transport to the primary cilia lead to a wide variety of diseases commonly referred to as ciliopathies,which include primary ciliary dyskinesia, situs invertus, hydrocephalus, kidney diseases, respiratory diseases, and retinal degenerations. In the retina, the photoreceptor cells have a highly specialized primary cilium called the outer segment (OS), which is essential for photosensation. Development of the photoreceptor OS shares key regulatory mechanisms with ciliogenesis in other cell types. Accumulating evidence indicates that mutations that affect OS development and/or protein transport to the OS generally lead to photoreceptor degeneration, which can be accompanied by a range of other clinical manifestations due to the dysfunction of primary cilia in different cell types. Here, we review the general mechanisms regulating ciliogenesis, and present different examples of mutations affecting OS ciliogenesis and protein transport that lead to photoreceptor degeneration. Overall, we conclude that the genetic and molecular evidence accumulated in recent years suggest a clear link between the development and function of the primary cilium and various clinical conditions. Future studies aimed at uncovering the cellular and molecular mechanisms implicated in ciliogenesis in a wide variety of animal models should greatly increase our understanding of the pathophysiology of many human diseases, including retinal degenerations. PMID- 19790291 TI - World: new data, hard slog at INB3. PMID- 19790292 TI - Germany: tobacco atlas, at last. PMID- 19790293 TI - India: bid to raise gutkha warning. PMID- 19790294 TI - Greece: smoking ban, or smoke & mirrors? PMID- 19790295 TI - Canada: quiet heroine remembered. PMID- 19790296 TI - Extracellular 20S proteasomes accumulate in packed red blood cell units. PMID- 19790297 TI - Intravascular histiocytosis presenting with extensive vulvar necrosis. AB - Intravascular histiocytosis (IVH) is a rare reactive cutaneous lesion of unknown pathogenesis. Most cases are reported in association with rheumatoid arthritis, and cutaneous eruptions typically occur near swollen joints. The skin changes have included erythematous and violaceous macules, papules, plaques and indurated patches with a livedo-like pattern of erythema. We report the first case of IVH presenting with florid vulvar necrosis in an 87-year-old patient without a history of rheumatoid arthritis. Physical examination revealed an edematous, exudative and diffusely necrotic vulva with erythema surrounding the areas of necrosis, extending out to the thighs. The debrided skin revealed an extensively necrotic epidermis and multiple clusters of markedly dilated blood vessels within the dermis. These vessels contained fibrin thrombi admixed with numerous CD68(+) and CD163(+) histiocytes. Her skin changes improved significantly after surgical debridement and treatment with antibiotics. Interestingly, our patient was also found to have a lupus anticoagulant with elevated anticardiolipin antibodies. This is the first report of IVH possibly related to a thrombogenic diathesis associated with a hypercoagulable state. A diagnosis of IVH is important and may necessitate further clinical evaluation to exclude the possibility of co-existent systemic disease. PMID- 19790298 TI - Pathogen reduction technology (Mirasol) treated single-donor platelets resuspended in a mixture of autologous plasma and PAS. AB - BACKGROUND AND OBJECTIVES: Mirasol pathogen reduction technology (PRT) for platelet concentrates uses riboflavin and ultraviolet light. Previously, we described increased metabolism and activation for PRT platelets stored in 100% plasma. To improve platelet quality, we resuspended platelets in a mixture of plasma and platelet additive solution (PAS). MATERIALS AND METHODS: Single-donor platelets were resuspended in plasma and split into an untreated control and a PRT-treated single product. One hundred and fifty millilitre PAS (SSP+) was added to both. Over 7 days, we assayed pH, glucose consumption-, lactate production rate and CD62p with and without TRAP. RESULTS: On day 5, PRT units showed a significantly lower pH (7.087 +/- 0.105 vs. 7.288 +/- 0.200) accompanied by a higher lactate production (0.104 +/- 0014 vs. 0.063 +/- 0.017 mmol/10(12)/h) and glucose consumption rate (0.039 +/- 0005 vs. 0.028 +/- 0.009 mmol/10(12) platelets/h). CD62p expression was higher in treated units (44.5 +/- 13.0 vs. 16.5 +/- 7.6%). CONCLUSION: In comparison to PRT platelets resuspended in 100% plasma, a mixture of plasma and PAS improves pH and platelet metabolism but not platelet activation. Prolonged shelf-life for up to 7 days may be possible PMID- 19790299 TI - Erythrocyte survival tests in cases of anti-AnWj antibodies. PMID- 19790300 TI - Implications of the New Mental Health Act. PMID- 19790301 TI - The Value of the Voice in the Diagnosis of Myxoedema. PMID- 19790302 TI - The Coroner and the General Practitioner. PMID- 19790303 TI - The Diagnosis and Treatment of Anaemia in General Practice. PMID- 19790304 TI - Treatment of the Failing Heart. PMID- 19790305 TI - Epidemic Observation Unit. PMID- 19790306 TI - General Practitioners' Convention-Melbourne, 10-15 October, 1960. PMID- 19790307 TI - Hypoglycaemic Coma After Two Tablets of Tolbutamide. PMID- 19790308 TI - Criteria for Membership: A South African Viewpoint. PMID- 19790309 TI - Notes on some Reactions to Solitude and Fatigue. PMID- 19790310 TI - Life and Death in the Village. PMID- 19790311 TI - The College Appeal. PMID- 19790313 TI - Annotations. PMID- 19790312 TI - The Clinical Epidemiology of Influenza. PMID- 19790314 TI - Prevalence of Pernicious Anaemia in Great Britain. PMID- 19790316 TI - Foundations for Research. PMID- 19790315 TI - The General Practitioner and Industrial Health. PMID- 19790317 TI - The Report of the Royal Commission on Doctors' and Dentists' Remuneration. PMID- 19790318 TI - Postgraduate Education. PMID- 19790320 TI - Medical Services in Australia and New Zealand. PMID- 19790319 TI - The College Appeal. PMID- 19790321 TI - Psychotherapy, the Psychotherapist and the Patient. PMID- 19790323 TI - Clinical Forensic Medicine: An Analysis of 643 Cases. PMID- 19790322 TI - The Child is Father of the Man. PMID- 19790324 TI - A Survey on Appendicitis. PMID- 19790326 TI - A Study of the General Practitioner Maternity Services : Being the report of a fact-finding tour. PMID- 19790325 TI - Diagnostic Validity. PMID- 19790328 TI - The Weather and the Work of the General Practitioner. PMID- 19790327 TI - A Study of Deaf Children. PMID- 19790329 TI - Observations on Local Climatic Conditions and the records of Total Morbidity in a Local Area. PMID- 19790330 TI - Epidemic Observation Unit. PMID- 19790331 TI - Organized Curiosity: A Practical Approach to the Problem of Keeping Records for Research Purposes in General Practice. PMID- 19790332 TI - Membership by Examination. PMID- 19790333 TI - Is That Consultation Really Necessary. PMID- 19790334 TI - Reflections on an Inter-Collegiate Tour. PMID- 19790335 TI - A Case of Rheumatoid Arthritis. PMID- 19790336 TI - Conference on Psychiatry. PMID- 19790337 TI - Preventive Medicine. PMID- 19790338 TI - Criteria for Membership. PMID- 19790339 TI - The Renaissance of General Practice in Europe. PMID- 19790340 TI - The Prevention of Break-up of Families. PMID- 19790341 TI - Five Years at Darbishire House. PMID- 19790342 TI - Handicapped Youth. PMID- 19790343 TI - The College Appeal. PMID- 19790344 TI - Cobwebs. PMID- 19790345 TI - Antibiotics in General Practice. PMID- 19790347 TI - Outpatient Treatment of the Alcoholic. PMID- 19790346 TI - The Key Role of the Family Doctor in the Rehabilitation of the Alcoholic. PMID- 19790348 TI - General-Practitioner Obstetrics in a Maternity Home. PMID- 19790350 TI - The Treatment of Acute Rheumatic Fever and Acute Glomerulo-Nephritis with Penicillin. PMID- 19790349 TI - The Neuroses in a General Practice Population. PMID- 19790351 TI - Environmental Factors in Coronary Artery Disease. PMID- 19790352 TI - Criteria for Membership. PMID- 19790353 TI - International Congress on Psychosomatic Medicine and Childbirth. PMID- 19790354 TI - The Weather and the Work of the General Practitioner. PMID- 19790356 TI - Reflections on the State of General Practice Today and Tomorrow. PMID- 19790355 TI - The Disc-Before and After. PMID- 19790357 TI - Where do People Die? PMID- 19790358 TI - Survey of Congenital Abnormalities. PMID- 19790359 TI - Staphylococci at Large. PMID- 19790360 TI - Middle Age-The Awkward Age. PMID- 19790361 TI - The Keeping of Records in General Practice. PMID- 19790362 TI - Transmission of Antibodies Against Influenza Virus A Across the Placenta. PMID- 19790364 TI - The Symptomatology and Complications of Tonsillitis: (The North Midlands (Sheffield) Faculty). PMID- 19790363 TI - Low dosage Trifluoperazine (Stelazine) in General Practice. PMID- 19790365 TI - An Asthma Survey in Wales: (The Research Committee of the Welsh Faculty). PMID- 19790366 TI - Diabetes Mellitus in Hull and the East Riding of Yorkshire: (A Survey by the Hull and East Riding Sub-Faculty of the College). PMID- 19790367 TI - Are Facilities at Health Centres a Luxury? PMID- 19790368 TI - Antibiotics in General Practice. PMID- 19790369 TI - Nine Lessons in Collective Investigation. PMID- 19790370 TI - The Churches' Council of Healing. PMID- 19790372 TI - Psychotherapy in General Practice: (Report on Progress of a Sufflk Group). PMID- 19790371 TI - Low Dosage Trifluoperazine (Stelazine) in General Practice. PMID- 19790374 TI - Accident and Casualty Departments. PMID- 19790373 TI - Preventable Factors in Chest Diseses. PMID- 19790375 TI - The Medical Adviser. PMID- 19790376 TI - Significance of Pollens in Clinical Allergy. PMID- 19790377 TI - Hospital Staffing. PMID- 19790378 TI - A Hospital Outpatient Referral Survey: A Study of the Referral Habits of a Group of General Practitioners. PMID- 19790380 TI - The Health Visitor and the Family Doctor: Report of Joint Working Party. PMID- 19790379 TI - Domiciliary Obstetrics. PMID- 19790382 TI - The Research Foundation. PMID- 19790381 TI - "A Domiciliary Obstetric Service". PMID- 19790383 TI - Social Surveys. PMID- 19790384 TI - Pseudo-precision. PMID- 19790386 TI - Industrial Medicine. PMID- 19790385 TI - A Survey of " Farmer's Lung ". PMID- 19790387 TI - Health Centres. PMID- 19790388 TI - "Undergraduate Teaching in Comprehensive Medicine". PMID- 19790389 TI - "Hospital Staffing". PMID- 19790390 TI - National Health Insurance: A Jubilee. PMID- 19790391 TI - Night Calls. PMID- 19790392 TI - Six Honest Serving Men : A Prelude to Research in Practice. PMID- 19790393 TI - A Clinical Appraisal of the Epilepsies in General Practice: A Report by the Research Committee of the College of General Practitioners. PMID- 19790395 TI - An Enquiry into the Treatment of Migraine. PMID- 19790394 TI - Aetiological Survey of Shingles and the Relationship of Shingles to Chicken-pox: The North-east England Faculty. PMID- 19790396 TI - Obstetrics in General Practice. PMID- 19790397 TI - Television and Health. PMID- 19790398 TI - Similarity of Outbreaks of Asian Influenza and Influenza B. in a School Community. PMID- 19790399 TI - Atherosclerosis-The Case Against Protein-continued. PMID- 19790400 TI - A Family Study of Respiratory Illness. PMID- 19790401 TI - Christmas and Surgery Attendances at the William Budd Health Centre. PMID- 19790402 TI - Undergraduate Teaching. PMID- 19790403 TI - Drug Sensitivity. PMID- 19790404 TI - Toxaemia of Pregnancy. PMID- 19790406 TI - The African Mother. PMID- 19790405 TI - Organized Curiosity: Part II. PMID- 19790407 TI - Bilateral Facial Paralysis Following Herpes Simplex: Report of a Case. PMID- 19790409 TI - What's in a name? PMID- 19790408 TI - Misinterpretation of Normal Heart Sounds: A Note on Two Cases. PMID- 19790410 TI - The Practitioner's Viewpoint. PMID- 19790411 TI - The Integration of Hospital and Practice Work. PMID- 19790412 TI - The Integration of Hospital and Practice Work. PMID- 19790413 TI - First Aid and Primary Care. PMID- 19790414 TI - Recent Advances in Hospital Care. PMID- 19790415 TI - Aftercare and Rehabilitation. PMID- 19790416 TI - Aftercare and Rehabilitation. PMID- 19790417 TI - The Management of Accidents by General Practitioners. PMID- 19790418 TI - Anaesthesia and Analgesia. PMID- 19790420 TI - Foreword. PMID- 19790419 TI - The Management of Burns. PMID- 19790421 TI - Membership or membership? PMID- 19790422 TI - Osteoarthrosis and Pantothenic Acid. PMID- 19790423 TI - Animal Protein and Atherosclerosis-Sequelae. PMID- 19790425 TI - Observations on General Practice in the United States. PMID- 19790424 TI - Toxaemia of Pregnancy. PMID- 19790426 TI - Congenital Abnormalities-in Retrospect. PMID- 19790427 TI - The Latrogenic "Slipped Disc". PMID- 19790428 TI - An Examination in General Practice. PMID- 19790429 TI - James Mackenzie and General Practice Today. PMID- 19790430 TI - Cottage Hospitals. PMID- 19790432 TI - Trends in the Mental Health Services. PMID- 19790431 TI - Merit Awards-A Proposed Scheme. PMID- 19790433 TI - The Disc Syndrome. PMID- 19790434 TI - " Time to Stand and Stare ". PMID- 19790435 TI - Anaesthesia for Domiciliary Obstetrics. PMID- 19790437 TI - Treatment of First and Second Degree Burns. PMID- 19790436 TI - Defibrillation of Heart in General Practice. PMID- 19790438 TI - Return to Work. PMID- 19790439 TI - Half the World's Blindness Preventable. PMID- 19790440 TI - "... No Time to Stand and Stare". PMID- 19790441 TI - Undergraduate Education. PMID- 19790442 TI - The Early Diagnosis of Cancer: Five Years Experience in General Practice. PMID- 19790443 TI - William Osler's Boyhood Town. PMID- 19790444 TI - Epidemic Observation Unit. PMID- 19790445 TI - Ten Years After. PMID- 19790446 TI - New College Headquarters. PMID- 19790447 TI - Hypertension in a General Practice. PMID- 19790448 TI - Psychological Medicine in General Practice-A Study of the Training Group Method. PMID- 19790449 TI - Faith versus Fear. PMID- 19790450 TI - An Idea in Antenatal Education in General Practice. PMID- 19790452 TI - A Report by a Therapeutic Study Group. PMID- 19790451 TI - The Surgery. PMID- 19790453 TI - Guidance for Students Visiting a General Practitioner. PMID- 19790454 TI - Measles and its treatment by Antibiotics in General Practice. PMID- 19790455 TI - G.Ps. Through the Eyes of a District Nurse. PMID- 19790456 TI - Looking a Gift Horse in the Mouth. PMID- 19790457 TI - Second Opinion by Consultation: The case for an increase in true consultation within the National Health Service. PMID- 19790458 TI - The Calibration of Doctors. PMID- 19790459 TI - A Local Coolant ("Skefron"), for the Relief of Pain. PMID- 19790460 TI - Multiple Sclerosis in a Country Practice. PMID- 19790462 TI - Accident and Emergency Services. PMID- 19790461 TI - Elderly Life: Its Characteristics, Needs and Philosophy. PMID- 19790464 TI - James Mackenzie and Research Tomorrow. PMID- 19790463 TI - Biological Sex Patterns and Modern Living. PMID- 19790465 TI - Staphylococcal Nasal Carriage in the Family. PMID- 19790467 TI - An Experiment in Presymptomatic Diagnosis. PMID- 19790466 TI - Haemoglobin Levels in Pregnancy : A report on 200 cases in general practice. PMID- 19790468 TI - Familial Occurrence of Enuresis in School-Children. PMID- 19790469 TI - The Discontented Patient: Leaving by Notification. PMID- 19790471 TI - The Outcome of Pregnancy. PMID- 19790470 TI - Births and Birthdays. PMID- 19790472 TI - Congenital Abnormalities. PMID- 19790474 TI - ON REPORTS. PMID- 19790473 TI - The Records and Statistical Unit. PMID- 19790475 TI - The Records and Statistical Unit: (Research Committee of Council). PMID- 19790476 TI - " Disease Labels ". PMID- 19790477 TI - A Classification of Disease. PMID- 19790478 TI - The Completion and Analysis of Weekly Returns. PMID- 19790479 TI - Continued Morbidity Recording in Practice-The Use of the "E" Book. PMID- 19790481 TI - The Family Doctor and the Care of the Aged. PMID- 19790480 TI - Practice Index. PMID- 19790483 TI - Medical Folk-lore. PMID- 19790482 TI - The Physicians of Myddfai. PMID- 19790484 TI - Medicosocial Research. PMID- 19790485 TI - The Surgery. PMID- 19790486 TI - A Report by a Therapeutic Study Group. PMID- 19790487 TI - Biological Sex Patterns and Modern Living. PMID- 19790488 TI - Animal, Vegetable and Mineral. PMID- 19790490 TI - The Gillie Report. PMID- 19790489 TI - General Practice Teaching in Edinburgh. PMID- 19790491 TI - Young Chronic Sick: A survey reported for the Research Committee of the Scottish Council of the College of General Practitioners. PMID- 19790493 TI - Chairman's Summary and Envoi. PMID- 19790492 TI - Welcome. PMID- 19790495 TI - Chairman's Summary. PMID- 19790494 TI - Welcome. PMID- 19790496 TI - Welcome. PMID- 19790497 TI - The Consumer's End. PMID- 19790498 TI - Chairman's Summary. PMID- 19790499 TI - Reflections on the Gillie Report. PMID- 19790500 TI - Geology and Multiple Sclerosis. PMID- 19790501 TI - Pityriasis Rosea. PMID- 19790502 TI - Migraine Symposium. PMID- 19790503 TI - Migraine Symposium. PMID- 19790504 TI - Biological Sex Patterns and Modern Living. PMID- 19790505 TI - General-Practitioner Hospitals. PMID- 19790506 TI - A Curious Twin Abortion. PMID- 19790507 TI - Outpatient Letters. PMID- 19790509 TI - A First Survey in General Practice. PMID- 19790508 TI - The Treatment of Angina Pectoris with Plaquenil: A Preliminary Report. PMID- 19790510 TI - Acute Cervical Hydrarthrosis. PMID- 19790511 TI - Geology and Multiple Sclerosis. PMID- 19790512 TI - M.R.C. Register of Immigrants with Multiple Sclerosis. PMID- 19790513 TI - Lord Moran's Ladder. PMID- 19790514 TI - Migraine Symposium. PMID- 19790515 TI - Epidemiology of Collisions on the Road. PMID- 19790516 TI - International College of Medical Practice. PMID- 19790517 TI - A Pilot Trial of an Antihistamine, Methdilazine, in Measles. PMID- 19790519 TI - Some Thoughts on Death. PMID- 19790518 TI - Pre-delivery Ataralgesia: A Comparative Clinical Study of Promazine Hydrochloride in Labour. PMID- 19790521 TI - Concluding Remarks. PMID- 19790520 TI - SOCIAL ASPECTS IN THE TEACHING OF OBSTETRICS AND GYNAECOLOGY. PMID- 19790522 TI - Feeding Bottle Colic. PMID- 19790523 TI - Disabled Living Activities Group of the Central Council for the Disabled. PMID- 19790524 TI - The Dublin Weekend. PMID- 19790525 TI - The College Appeal-Second Phase. PMID- 19790526 TI - One Flame, Many Torches. PMID- 19790528 TI - Geology and Multiple Sclerosis. PMID- 19790527 TI - Research into General Practice. PMID- 19790529 TI - Lord Moran's Ladder. PMID- 19790531 TI - The ;F. Book'. PMID- 19790530 TI - A Study of Research Conducted by British General Practitioners. PMID- 19790532 TI - On Obtaining a Group Practice Loan. PMID- 19790533 TI - Continuing Education. PMID- 19790534 TI - The Extent in England of Health Visitor Attachment to General Practices. PMID- 19790536 TI - Chairman's Closing Remarks. PMID- 19790535 TI - Welcome. PMID- 19790537 TI - Chairman: Professor A. G. Watkins Professor of Child Health in the Welsh National School of Medicine: Welcome. PMID- 19790538 TI - Chairman: Professor A. S. Duncan, D.S.C. Professor of Obstetrics and Gynaecology in the Welsh National School of Medicine. PMID- 19790539 TI - Concluding Remarks. PMID- 19790540 TI - Vocational Training and the Criteria Inquiry. PMID- 19790541 TI - The College Appeal. PMID- 19790542 TI - Medicine in Society. PMID- 19790543 TI - Buscopan. PMID- 19790545 TI - Domiciliary Obstetrics. PMID- 19790544 TI - Allergic disorders among horticultural, agricultural and forestry workers. PMID- 19790546 TI - The Increase in Venereal Disease. PMID- 19790547 TI - Calcium and Phosphorus Metabolism and its Associated Diseases. PMID- 19790548 TI - Prostatectomy-Early or Late. PMID- 19790549 TI - The Hippocratic Way. PMID- 19790550 TI - M.C.G.P. PMID- 19790551 TI - Some afterthoughts on the mental illness survey. PMID- 19790552 TI - Line and graph case records. PMID- 19790553 TI - Some Practical Problems in Epilepsy. PMID- 19790555 TI - Now is the time. PMID- 19790554 TI - The Problem of Terminal Pain. PMID- 19790556 TI - Social Factors in Emotional Disorders in General Practice. PMID- 19790557 TI - A Comparison of Morbidity in Two Areas. PMID- 19790559 TI - A Study of Unmarried Mothers. PMID- 19790558 TI - Late Call-Emergency or Anxiety? PMID- 19790560 TI - Tuberculosis in a Health Centre Practice: A retrospective analysis over eight years. PMID- 19790561 TI - Osteo-arthritis of a Bronze-age Pelvic Skeleton with some notes on Modern Treatment and Aetiology. PMID- 19790563 TI - Terminal Pain. PMID- 19790562 TI - Work Study in General Practice. PMID- 19790564 TI - Accident Neurosis. PMID- 19790565 TI - A Double-blind Trial of Durophet-M in the Treatment of Obesity in General Practice. PMID- 19790566 TI - A Comparison of the Therapeutic Effect of the Intra-articular Injection of Two Long-Acting Steroid Compounds of Degenerative Joints. PMID- 19790567 TI - Must we kill our patients? PMID- 19790568 TI - A Prototype training Course for General Practice. PMID- 19790569 TI - Welcome. PMID- 19790570 TI - Problems of Sex in General Practice. PMID- 19790571 TI - Homosexuality. PMID- 19790572 TI - Infertility. PMID- 19790573 TI - Frigidity. PMID- 19790574 TI - Problems of Adolescence. PMID- 19790576 TI - Chairman's closing remarks. PMID- 19790575 TI - The Problems. PMID- 19790577 TI - Marriage Guidance. PMID- 19790578 TI - Welcome: Dr Dennis E. Wheeler. PMID- 19790579 TI - Dr F. J. A. Huygen. PMID- 19790580 TI - Dr J. H. Medalie. PMID- 19790581 TI - Dr. H. W. Ashworth. PMID- 19790582 TI - Chairman. PMID- 19790583 TI - Dr R. F. L. Logan. PMID- 19790584 TI - Dr D. Stampar. PMID- 19790585 TI - Dr William W. Fulton. PMID- 19790586 TI - Dr John R. Ellis. PMID- 19790587 TI - Chairman's closing remarks. PMID- 19790588 TI - Appendix: Details of work study in connection with this visit. PMID- 19790589 TI - A New Look at General Practice. PMID- 19790590 TI - Additional Payments for Wide Experience and Notable Service in General Practice: An Outline Scheme. PMID- 19790591 TI - Speech Therapy. PMID- 19790592 TI - The Assessment of Milestones in General Practice. PMID- 19790594 TI - The present state of general practice. PMID- 19790593 TI - Line and graph case records. PMID- 19790595 TI - Other obstetricians-please copy. PMID- 19790596 TI - CHILD WELFARE CENTRES. PMID- 19790597 TI - Doctor's Household (DH) Trial in the Prevention of Bacterial Complications in the Common Cold. PMID- 19790598 TI - Some suggestions for an improved maternity service. PMID- 19790599 TI - Injection therapy: Some Cultural Aspects. PMID- 19790600 TI - Chronic Bronchitis. PMID- 19790601 TI - The place of the family doctor in obstetrics in the future. PMID- 19790603 TI - Books and the general practitioner. PMID- 19790602 TI - A new look at general practice. PMID- 19790605 TI - Money. PMID- 19790604 TI - Museum notes. PMID- 19790606 TI - Neurological examination of the newborn. PMID- 19790607 TI - Recent advances in renal disease. PMID- 19790608 TI - Present state and future needs. PMID- 19790610 TI - Notes. PMID- 19790609 TI - The present state of general practice. PMID- 19790611 TI - Education. PMID- 19790612 TI - New partners. PMID- 19790613 TI - The work of a cottage hospitals. PMID- 19790614 TI - Role and training : some ideas from abroad. PMID- 19790615 TI - Some aspects of lead pollution in perspective. PMID- 19790616 TI - The use of hospital laboratory facilities by general practitioners. PMID- 19790617 TI - Childlessness and general practice. PMID- 19790618 TI - The Returning Patient: A survey of patients with high attendance rate. PMID- 19790619 TI - Demand/Attendance patterns in an "artificial practice". PMID- 19790621 TI - A survey of migrainous neuralgia by the merseyside and north wales faculty. PMID- 19790620 TI - Emotional problems in general practice: a survey of a sample of ordinary patients. PMID- 19790622 TI - Chemotherapy of cancer. PMID- 19790624 TI - Notes. PMID- 19790623 TI - The crutch syndrome. PMID- 19790625 TI - The ileostomy. PMID- 19790627 TI - A welfare village. PMID- 19790626 TI - Sudden Death in Asthmatics not in Spasm. PMID- 19790628 TI - Patients talking. PMID- 19790629 TI - College appeal. PMID- 19790631 TI - A survey of migrainous neuralgia. PMID- 19790630 TI - Communication. PMID- 19790632 TI - Symposium on bronchitis. PMID- 19790634 TI - Reports from General practice Number 4: General practice in the new towns of Britiain. PMID- 19790633 TI - Clinical gossips. PMID- 19790635 TI - Immunity. PMID- 19790636 TI - Closing remarks. PMID- 19790637 TI - Aspects of prevention. PMID- 19790639 TI - Welcome. PMID- 19790638 TI - The case for screening. PMID- 19790641 TI - Closing remarks. PMID- 19790640 TI - Closing remarks. PMID- 19790642 TI - The diagnosis and management of the febrile child. PMID- 19790643 TI - 'Inevitable' and 'preventable' accidents. PMID- 19790645 TI - Rheumatology, physical medicine and the family doctor. PMID- 19790644 TI - The curious art of thumb gazing : Or an hypnotic ramble through general practice. PMID- 19790646 TI - Medical education. PMID- 19790647 TI - Training for parenthood. PMID- 19790648 TI - The second world conference on general practice. PMID- 19790649 TI - The curious art of thumb gazing. PMID- 19790650 TI - The curious art of thumb gazing. PMID- 19790651 TI - A letter from the president. PMID- 19790652 TI - Thumb gazing. PMID- 19790653 TI - Colostomy welfare group. PMID- 19790655 TI - Marital problems. PMID- 19790654 TI - Urinary trace neoplasms in rubber workers. PMID- 19790656 TI - Radio for domiciliary midwives: An Experimental Trial. PMID- 19790658 TI - Medical representatives and the general practitioner. PMID- 19790657 TI - Ernest Hart-A forgotten man. PMID- 19790659 TI - A case of farmer's lung. PMID- 19790660 TI - 1965 in a small rural dispensing practice. PMID- 19790661 TI - The honorary secretary of Council. PMID- 19790662 TI - The Talley alternating pressure pads. PMID- 19790663 TI - The future of education for general practice. PMID- 19790665 TI - Working parties. PMID- 19790664 TI - Oral contraceptive study. PMID- 19790666 TI - An ECG machine in general practice. PMID- 19790667 TI - Medical representatives and the general practitioner. PMID- 19790668 TI - Coloured tags on record cards for important disease groups. PMID- 19790669 TI - Acupuncture and moxibustion. PMID- 19790670 TI - A case of Cornelia de Lange's syndrome. PMID- 19790672 TI - The foetus at risk. PMID- 19790671 TI - The temporary envelope. PMID- 19790673 TI - Welcome. PMID- 19790674 TI - THE PROBLEM OF ANAEMIA [by title]. PMID- 19790675 TI - Closing remarks. PMID- 19790676 TI - The pill and thrombo-embolic disorders. PMID- 19790678 TI - The late president John F. Kennedy. PMID- 19790677 TI - Medical group practice design. PMID- 19790679 TI - The canadian college of general practice. PMID- 19790680 TI - Man's inheritance. PMID- 19790681 TI - Voice production for singers. PMID- 19790682 TI - Introduction. PMID- 19790683 TI - Welcome. PMID- 19790685 TI - Summing up. PMID- 19790684 TI - Listening from the theological point of view. PMID- 19790686 TI - Vote of thanks. PMID- 19790688 TI - Inside the new zealand health service. PMID- 19790687 TI - The royal college. PMID- 19790689 TI - A study of the doctor-patient relationship. PMID- 19790690 TI - Abortion, a general practitioner's point of view. PMID- 19790691 TI - The enigma of general practice: Some aphorisms for the art. PMID- 19790693 TI - Research advisory service. PMID- 19790692 TI - Vocational training for general practice. PMID- 19790694 TI - An experiment in immunization against measles. PMID- 19790695 TI - The enigma of general practice. PMID- 19790696 TI - Mis-use of words. PMID- 19790698 TI - Coloured tags on record cards for important diseases. PMID- 19790697 TI - Getting to know the patient. PMID- 19790699 TI - Reports from General Practice Number 6: The implementation of vocational training. PMID- 19790700 TI - Reports from General Practice Number 7: Education in psychology. PMID- 19790702 TI - The journal of the royal college of general practitioners. PMID- 19790701 TI - Postgraduate health centres. PMID- 19790703 TI - The Appeal-a letter from the President. PMID- 19790704 TI - The pathology of family life. PMID- 19790705 TI - The health and habits of higher executives: (Part 2). PMID- 19790707 TI - The ;L' book. PMID- 19790706 TI - A study of patients' choice of doctor in an urban practice. PMID- 19790708 TI - Report of a survey of hospital admission by the South-east England Faculty. PMID- 19790710 TI - Correspondence. PMID- 19790709 TI - Correspondence. PMID- 19790711 TI - A framework of health care. PMID- 19790712 TI - Work load in general practice. PMID- 19790713 TI - An unusual case of anaemia with neurological and psychiatric features. PMID- 19790714 TI - Analysis of diuretics and thiazide-induced diabetes in general practice. PMID- 19790715 TI - Welcome. PMID- 19790716 TI - Distribution of general practitioner community hospitals in Great Britain and Northern Ireland. PMID- 19790717 TI - General description of functional classification of Scottish hospitals. PMID- 19790718 TI - Dunoon and district general hospital - general practitioner medical unit. PMID- 19790719 TI - West lambeth health authority - lambeth community care centre. PMID- 19790720 TI - Oxford community hospital. PMID- 19790721 TI - Problems of general practitioner obstetrics. PMID- 19790722 TI - General practitioner hospital inpatient referral/outcome of care record. PMID- 19790723 TI - General practitioner hospital patient questionnaire. PMID- 19790724 TI - Patient information sheet. PMID- 19790725 TI - Community day ward referral care. PMID- 19790726 TI - Discharge form. PMID- 19790727 TI - Medical student/trainee attachment forms. PMID- 19790729 TI - The politics of educational responsibility. PMID- 19790731 TI - Towards defining the curriculum. PMID- 19790728 TI - Reading lists. PMID- 19790730 TI - The transience of truth. PMID- 19790733 TI - The here and now curriculum. PMID- 19790732 TI - Educational assessment. PMID- 19790734 TI - Epilogue. PMID- 19790735 TI - A personal general practice training curriculum. AB - This document is given to prospective trainees when they apply to work with me. It was sent to the Regional Education Sub-committee when I last applied for reapproval as a trainer and it has, of course, been discussed at my trainers' workshop. It is a short practical description of my own training curriculum. Any criticism of suggestions for improving it would be most welcome. PMID- 19790736 TI - How doctors learn. PMID- 19790737 TI - The limited utility of behavioural objectives. PMID- 19790738 TI - Introduction. PMID- 19790739 TI - New contract arrangements for health checks for over 75-year-old patients. PMID- 19790741 TI - The MCQ paper: sample questions and answers. PMID- 19790740 TI - Assessment of the general practitioner. AB - There is considerable interest in general practice assessment both as a means of monitoring vocational training and as a form of self audit for the general practitioner. Basic principles involved in the selection and design of assessment procedures are reviewed and their application discussed. PMID- 19790742 TI - The MEQ paper: sample questions and model answers. PMID- 19790743 TI - The CRQ paper: sample questions and answers. PMID- 19790744 TI - The oral examination: instructions to candidates and practice experience questionnaire (PEQ). PMID- 19790745 TI - Preface. PMID- 19790747 TI - Information unbound. PMID- 19790748 TI - A short protocol for the care of people with mental handicap. PMID- 19790746 TI - Down's syndrome and the general practitioner. PMID- 19790749 TI - Useful addresses. PMID- 19790750 TI - Introduction. PMID- 19790752 TI - Health care providers. PMID- 19790751 TI - Individual health care systems. PMID- 19790754 TI - Function and tasks of general practitioners. PMID- 19790753 TI - The interface study design. PMID- 19790755 TI - International and inter-doctor variability. PMID- 19790756 TI - Conclusions and discussion. PMID- 19790758 TI - Health care systems. PMID- 19790757 TI - Discussion of the reports of the interface and sentinel practice studies. PMID- 19790759 TI - An academic plan for general practice. PMID- 19790760 TI - An educational strategy for general practice for the 1990s. PMID- 19790761 TI - The faculties - the future of the college. PMID- 19790762 TI - The history and development of fellowship by assessment. PMID- 19790763 TI - Principles for the introduction of fellowship by assessment. PMID- 19790764 TI - Guide and criteria for fellowship by assessment (FBA2). PMID- 19790765 TI - Notes on essential criteria. PMID- 19790767 TI - Application form. PMID- 19790766 TI - References and sources of College policy. PMID- 19790768 TI - Notes for the assessors. PMID- 19790769 TI - Patient consent form for recording consultations. PMID- 19790770 TI - Rules for discussing video consultations. PMID- 19790771 TI - Confidentiality form. PMID- 19790772 TI - A brief synopsis of the content of the courses. PMID- 19790773 TI - Questionnaire to course organizers. PMID- 19790774 TI - Questionnaire to participants. PMID- 19790775 TI - Editor's preface. PMID- 19790776 TI - Teamwork and collaboration. PMID- 19790778 TI - The relationship of collaboration to other factors. PMID- 19790777 TI - The extent of collaboration in primary health care organizations. PMID- 19790780 TI - Design of the study. PMID- 19790779 TI - Conclusions. PMID- 19790782 TI - Characteristics of the district health authorities and practice environments. PMID- 19790781 TI - Characteristics of respondents. PMID- 19790783 TI - Joint working in primary health care organizations. PMID- 19790784 TI - Summary. PMID- 19790785 TI - Weekly incidence of chickenpox in 1989. PMID- 19790786 TI - Foreword. PMID- 19790787 TI - Editor's preface. PMID- 19790788 TI - Rates and costs of prescribing. AB - There are many reasons for the variations in the rates and costs of general practitioner prescribing. This is a fruitful area for audit and for reconsideration of the teaching of prescribing at undergraduate level by general practitioners. PMID- 19790789 TI - General practitioner hospitals and residential homes. AB - In Scotland, there are about sixty general practitioner hospitals where general practitioners have direct and sole admitting rights to beds. In addition, there are many residential homes both local authority and private where general practitioners visit and treat patients. Particular problems in prescribing can arise in these institutions. PMID- 19790790 TI - Dispensing doctors. AB - Dispensing doctors have their own particular difficulties with prescribing. They have more personal responsibility for the costs of the drugs they prescribe. Shetland doctors are particularly interesting in that they are dispensing doctors who make no financial gains from dispensing. PMID- 19790791 TI - Drugs prescribed by general practitioners. AB - General practitioners have a personal list of drugs which they prescribe. As new drugs become available and older drugs are outmoded, the doctor will change this personal list. The reasons for making such changes are discussed, and also the question of the perceived mechanism of action of the drug, particularly in relation to the placebo effect. PMID- 19790792 TI - Knowledge of drugs and sources of information. AB - General practitioners are constantly bombarded about drugs, yet there is no standard set for the drug knowledge database. The results of two surveys of the sources of information on drugs by doctors are given. Comments are made about the Scottish Drug Tariff, which is little used by doctors because of its poor presentation. PMID- 19790793 TI - Prescribing information. AB - Despite large numbers of prescriptions written by general practitioners at enormous cost, mostly borne by the National Health Service, the information available to doctors about their prescribing until recently has been minimal. Many doctors who have wished to audit their own prescribing have had to supplement the available information by resorting to tedious analysis of carbon copies of prescription forms or more recently to using the facilities available in a computer system, given that they have the expertise to use one. PMID- 19790794 TI - Formulary. AB - Formularies have been produced for varying reasons for many years. In general practice, the current emphasis is on their production and use as an educational process by the doctors, for the doctors. Existing formularies can be used as models. Similarly in Europe, the European Formulary being produced will be seen as a model for adaptation for local use. PMID- 19790795 TI - The limited list. AB - The introduction and nature of the limited list are described, and both the early and longer term effects discussed. Although it was produced for economic reasons, the limited list has not been shown to have lowered drug costs overall. PMID- 19790796 TI - Computers. AB - There is now an extensive literature on the use of computers for prescribing and the situation is changing very quickly. The position in Scotland was reviewed with particular reference to the G-PASS system (General Practice Administration System for Scotland) by Ryan in 1989. PMID- 19790797 TI - The pharmaceutical industry. AB - THE ATTITUDE OF GENERAL PRACTITIONERS TO THE DRUG INDUSTRY IS INTERESTING: on the one hand the industry researches and produces new drugs which are essential to the practice of modern medicine; on the other hand, doctors are sceptical that the information received from the industry is too biased. It is time for students and doctors to be trained in a more critical approach to the industry and its representatives. PMID- 19790798 TI - The proprietary/generic debate. AB - Many of the different attitudes to the prescribing of drugs by proprietary or generic name are based on biased information from the pharmaceutical industry. A plea is made for a more scientific approach to the problem by doctors. PMID- 19790799 TI - Product liability. AB - In these days of increasing legal actions against the medical profession, it is important for doctors to take heed of new regulations which affect the practice of medicine. The new Consumer Protection Act of 1987 covers product liability. This chapter stresses the importance for doctors of following the guidelines already laid down by the profession. PMID- 19790800 TI - Original pack dispensing. AB - ORIGINAL PACK DISPENSING IS NOT NEW: most ointments, eye preparations and liquids have been dispensed in their original packs for years. However, only recently have tablets started to be dispensed in this way. These changes are creating some problems in prescribing but they are not insurmountable. PMID- 19790801 TI - Adverse drug reactions. AB - There are many methods of surveillance of new drugs for adverse reactions once they have been fully marketed. The yellow card system run by the Committee on Safety of Medicines is not well used by doctors: perhaps there is some other way of reporting adverse reactions? PMID- 19790802 TI - Pharmacy. AB - In the past, pharmacists and doctors worked very closely together but now that pharmacists do not produce drugs but only dispense them, their expertise is not being used to the full. Pharmacists are highly trained scientists whose expertise must be used by the medical profession for the benefit of patients. PMID- 19790803 TI - Viewdata drug information service. AB - Hospital drug information pharmacists have set up a viewdata drug information service (VADIS) which can be accessed through the telephone system. It may not be an essential service for all doctors yet, but it is a new way of receiving drug information together with unbiased therapeutic comments based on available research data. PMID- 19790804 TI - The patient. AB - It is important for the prescribing doctor to try to discover and to understand the prescribing process as seen by the patient. This will involve understanding not only patients' expectations and demands of their general practitioners, but also their approach to self-medication. PMID- 19790806 TI - The influence of other doctors on general practice prescribing. AB - Prescribing at the hospital/general practice interface is different in Scotland from that in the rest of the UK. The question of responsibility for the prescribing is considered. PMID- 19790805 TI - Audit. AB - Audit has long been a feature of good general practice. The literature is full of examples of audit by general practitioners and this Occasional Paper quotes many examples of audit which have produced valuable results. This chapter gives some advice to doctors wishing to audit their prescribing. PMID- 19790807 TI - Prescription writing. AB - Prescription writing by general practitioners shows a varying acceptance of the official recommendations. Legibility and the use of Latin terms are still problems that must be addressed. PMID- 19790809 TI - Recommendations. PMID- 19790808 TI - Indirect (repeat) prescribing. AB - The term 'repeat prescribing' is inaccurate in modern general practice. New definitions with guidelines for practice systems are given together with some comments on quantities of drugs to be prescribed on each occasion. PMID- 19790810 TI - Preface. PMID- 19790811 TI - The importance of referrals. PMID- 19790812 TI - Method considerations. PMID- 19790813 TI - National data. PMID- 19790814 TI - Background to the study. PMID- 19790815 TI - International comparisons. PMID- 19790817 TI - Conclusions. PMID- 19790816 TI - Study protocol. PMID- 19790818 TI - Definitions of primary health care. PMID- 19790819 TI - The structure of primary care. PMID- 19790820 TI - The process of primary care. PMID- 19790821 TI - The purpose of primary care. PMID- 19790822 TI - Outcomes of primary care. PMID- 19790824 TI - Research and development in primary care. PMID- 19790823 TI - The wants and needs of the population. PMID- 19790826 TI - Conclusion. PMID- 19790825 TI - 1995 - A framework for planning. PMID- 19790827 TI - Policy statement: research in general practice. PMID- 19790828 TI - Editor's preface. PMID- 19790829 TI - Stage 2 Primary care assessment. PMID- 19790830 TI - Stage 3 Full assessment. PMID- 19790831 TI - Patient summary card. PMID- 19790833 TI - The lisson grove benefits program. PMID- 19790832 TI - Audit form. PMID- 19790834 TI - Barthel Activities of Daily Living (ADL) Index. PMID- 19790835 TI - Instrumental Activities of Daily Living (ADL) Scale. PMID- 19790837 TI - Geriatric Depression Scale (GDS). PMID- 19790836 TI - The 6-inch whispered voice test. PMID- 19790838 TI - Abbreviated Mental Test Score (AMTS). PMID- 19790839 TI - List of participants in study day. PMID- 19790840 TI - Stage 1 Health check schedule. PMID- 19790842 TI - Editor's Preface. PMID- 19790841 TI - Editor's preface. PMID- 19790843 TI - Introduction. PMID- 19790844 TI - Applications. PMID- 19790845 TI - Project reviewed. PMID- 19790847 TI - Data validation. PMID- 19790846 TI - The project. PMID- 19790848 TI - Introduction. PMID- 19790849 TI - The use of portfolio-based learning in vocational training. PMID- 19790851 TI - The present state of continuing medical education. PMID- 19790850 TI - The use of portfolio-based learning in continuing medical education. PMID- 19790853 TI - The role of the mentor. PMID- 19790852 TI - A way forward. PMID- 19790854 TI - Assessment and accreditation. PMID- 19790855 TI - Foreword. PMID- 19790856 TI - Foreword. PMID- 19790857 TI - Preface. PMID- 19790858 TI - Why ask the question? PMID- 19790860 TI - The biomechanical doctor. PMID- 19790859 TI - How to answer the question. PMID- 19790862 TI - The "new kind of doctor". PMID- 19790861 TI - Teleological and hermeneutic models. PMID- 19790864 TI - The doctor, the patient and the family. PMID- 19790863 TI - General practice as a business and patients as consumers. PMID- 19790865 TI - What therefore is good general practice? PMID- 19790866 TI - What does it mean to ask what is good? PMID- 19790867 TI - Preface. PMID- 19790868 TI - Introduction. PMID- 19790869 TI - The survey. PMID- 19790870 TI - Setting the scene. PMID- 19790871 TI - Summary and recommendations. PMID- 19790873 TI - Questionnaire. PMID- 19790872 TI - The Jarman UPA score. PMID- 19790874 TI - Coding frame for question B. PMID- 19790875 TI - Improvements suggested by general practitioners in areas with severe, moderate and no deprivation. PMID- 19790876 TI - Introduction. PMID- 19790877 TI - Unpublished schemes. PMID- 19790878 TI - Conclusions. PMID- 19790879 TI - Summary and recommendations. PMID- 19790881 TI - Guidelines for clinical monitoring of diabetes mellitus. PMID- 19790880 TI - Sources used for this review. PMID- 19790882 TI - Summaries of shared care schemes for diabetes. PMID- 19790883 TI - Requirements for chronic disease management programmes for diabetes. PMID- 19790884 TI - Randomized controlled trials. PMID- 19790885 TI - Non-randomized trials. PMID- 19790886 TI - Descriptive accounts. PMID- 19790887 TI - Preface. PMID- 19790888 TI - Background to the study. PMID- 19790889 TI - Results: Levels of computerization, practice type and practice activity. PMID- 19790890 TI - Results: The decision to computerize and the process of computerization. PMID- 19790891 TI - Results: Support for computerization. PMID- 19790892 TI - Questionnaire for postal survey of FHSAs. PMID- 19790893 TI - Questionnaire for postal survey of computerized practices. PMID- 19790895 TI - Methodology. PMID- 19790894 TI - Questionnaire for postal survey of non-computerized practices. PMID- 19790896 TI - Preface. PMID- 19790897 TI - Editor's Preface. PMID- 19790899 TI - All significant events listed for possible discussion at significant events meetings. PMID- 19790898 TI - Significant event auditing: a user's guide. PMID- 19790900 TI - Clinical significant events discussed in audit meetings. PMID- 19790901 TI - Administrative significant events discussed in audit meetings. PMID- 19790903 TI - Results of the conventional audits. PMID- 19790902 TI - The conventional audits. PMID- 19790904 TI - Editor's Preface. PMID- 19790905 TI - Preface. PMID- 19790907 TI - Preface. PMID- 19790906 TI - Editor's preface. PMID- 19790909 TI - Background. PMID- 19790908 TI - Editor's Preface. PMID- 19790910 TI - Needs assessment in practice. PMID- 19790911 TI - Ways forward. PMID- 19790913 TI - Useful resources. PMID- 19790912 TI - Theoretical perspectives. PMID- 19790914 TI - Public health data sources. PMID- 19790915 TI - Interview schedule for residents. PMID- 19790917 TI - Preface. PMID- 19790916 TI - Approaches to needs assessment. PMID- 19790918 TI - Editor's preface. PMID- 19790919 TI - Background. PMID- 19790920 TI - Relationship between needs, process and outcome at practice level. PMID- 19790921 TI - Relationship between needs, process and outcome at doctor level. PMID- 19790922 TI - Conclusions. PMID- 19790924 TI - General practice patient health questionnaire. PMID- 19790923 TI - Plans for further work. PMID- 19790926 TI - Developing the measures: needs, process and outcome. PMID- 19790925 TI - General practice patient questionnaire 2. PMID- 19790928 TI - Relationship between needs, process and outcome at population level. PMID- 19790927 TI - The development of process and outcome measures for general practice consultations. PMID- 19790929 TI - Preface. PMID- 19790930 TI - Editor's preface. PMID- 19790931 TI - Pictures of the patient: medicine, science and humanities. PMID- 19790932 TI - The information paradox. PMID- 19790933 TI - Preface. PMID- 19790934 TI - Introduction. PMID- 19790936 TI - The meaning of illness. PMID- 19790935 TI - Two models of a human being. PMID- 19790937 TI - A question of values. PMID- 19790938 TI - The need for virtue. PMID- 19790940 TI - Some observations on the virtues. PMID- 19790939 TI - What can we know about facts and values? PMID- 19790942 TI - The cultivation of virtue. PMID- 19790941 TI - The theory and virtue of justice. PMID- 19790943 TI - Towards more virtuous practice. PMID- 19790944 TI - National survey of counsellors working in primary care: evidence for growing professionalisation? PMID- 19790945 TI - Evidence-based medicine in primary care: The knowledge revolution - are GPs ready? PMID- 19790946 TI - How evidence is reviewed. PMID- 19790947 TI - Responding to the evidence: Evidence-based implementation of evidence-based medicine. PMID- 19790949 TI - What is stopping us?: Concluding Plenary Session. PMID- 19790948 TI - Measuring our success. PMID- 19790950 TI - Scientific medicine: The contribution of science to medicine. PMID- 19790952 TI - Results. PMID- 19790951 TI - How evidence gets published. PMID- 19790953 TI - Recommendations. PMID- 19790954 TI - Development of a national scheme. PMID- 19790956 TI - Project management group. PMID- 19790955 TI - Summary of assessment schemes. PMID- 19790957 TI - Advisory group. PMID- 19790958 TI - Background. PMID- 19790959 TI - National stakeholders' group. PMID- 19790960 TI - Assessment Criteria: Levels I and II. PMID- 19790961 TI - Sample timetable for assessment visit. PMID- 19790963 TI - Acronyms. PMID- 19790962 TI - Assessor training programme. PMID- 19790965 TI - Aims and objectives. PMID- 19790964 TI - Methodology. PMID- 19790966 TI - Preface. PMID- 19790967 TI - Introduction. PMID- 19790968 TI - The concept of proactive assessment. PMID- 19790969 TI - The standardised proactive assessment instrument. PMID- 19790970 TI - Using the assessment instrument. PMID- 19790971 TI - Suggested database. PMID- 19790973 TI - Rose chest pain questionnaire. PMID- 19790972 TI - Comprehensive assessment. PMID- 19790974 TI - Edinburgh claudication questionnaire. PMID- 19790976 TI - Geriatric Depression Scale (GDS). PMID- 19790975 TI - Six-inch whispered voice test. PMID- 19790978 TI - Abbreviated Mental Test Score (AMTS). PMID- 19790979 TI - The CAGE Questionnaire. PMID- 19790980 TI - Assessing the evidence. PMID- 19790977 TI - The clock drawing test. PMID- 19790981 TI - Formal assessment programmes of older people in primary care. PMID- 19790983 TI - Comments about embarking on a career in general practice. PMID- 19790984 TI - Comments about the changing nature of general practice. PMID- 19790985 TI - Comments about less-than-full-time working, career breaks and leaving NHS general practice. PMID- 19790987 TI - Introduction. PMID- 19790986 TI - Appendices. PMID- 19790989 TI - Response rates and representativeness of comments. PMID- 19790988 TI - Methods. PMID- 19790990 TI - Comments about training for a career in general practice. PMID- 19790991 TI - Project A: Secondary prevention of cardiovascular disease. PMID- 19790992 TI - Project B: Effective child health. PMID- 19790982 TI - Summary of scientific evidence. PMID- 19790994 TI - Project D: A clinical informaticist to support primary care decision-making. PMID- 19790993 TI - Project C: Antenatal screening for haemoglobinopathies in primary care. PMID- 19790995 TI - Summary. PMID- 19790996 TI - Project E: Effective healthcare facilitator. PMID- 19790998 TI - Conclusions and recommendations. PMID- 19790997 TI - Issues raised by the case studies. PMID- 19790999 TI - Introduction. PMID- 19791000 TI - The workshops. PMID- 19791002 TI - Foreword. PMID- 19791001 TI - External evaluation. PMID- 19791003 TI - Likely issues to emerge. PMID- 19791004 TI - The toolkit. PMID- 19791005 TI - Conclusion. PMID- 19791006 TI - Introduction and background. PMID- 19791007 TI - The process. PMID- 19791009 TI - Aristotle's answer (1): a practical reasoning approach. PMID- 19791008 TI - Undertaking the interview - hints for visitors. PMID- 19791011 TI - Appendix one: Dr Lawrence's Problem. PMID- 19791010 TI - Aristotle's answer (2): Decision making in general practice: the practice of perception. PMID- 19791012 TI - Appendix two. PMID- 19791013 TI - Introduction. PMID- 19791015 TI - Appendix four: Enablement Instrument. PMID- 19791014 TI - Appendix three: Criteria for Video Assessment of Consulting Skills for the MRCGP Examination. PMID- 19791016 TI - Appendix five: New Consultation Quality Index. PMID- 19791017 TI - Hippocrates' problem: decision making in general practice. PMID- 19791018 TI - Introduction. PMID- 19791019 TI - The stories doctors told. PMID- 19791021 TI - What is Balint? PMID- 19791020 TI - Strengthening the educational potential of small-group work: implications from the evaluation. PMID- 19791023 TI - Teaching with the Balint approach - a personal view from a Balint course organiser. PMID- 19791022 TI - Michael Balint - a man of many parts. PMID- 19791024 TI - Method and methodology. PMID- 19791026 TI - Preface. PMID- 19791025 TI - The case studies. PMID- 19791028 TI - No Heart to Poke Poor Billy. PMID- 19791027 TI - Education and training for general practice. PMID- 19791029 TI - Technique in General Practice. PMID- 19791030 TI - Research in General Practice. PMID- 19791032 TI - The Continuing Education of General Practitioners, 6: An Analysis of Replies to a Questionary from the Postgraduate Education Committee of Council. PMID- 19791031 TI - The Nocturnal Concentration Index of Urine and its Use in the Diagnosis of Hypertension. PMID- 19791033 TI - The Research Newsletter. PMID- 19791034 TI - Twenty-five years in Country Practice. PMID- 19791035 TI - The South-west England Faculty Investigation on Daffodil Dermatitis. PMID- 19791036 TI - Scabies: Progress Report. PMID- 19791037 TI - Epidemic Observation Unit. PMID- 19791038 TI - North American Tour. PMID- 19791039 TI - Research on the Use of Hypnosis in General Practice. PMID- 19791041 TI - The Australian College of General Practice. PMID- 19791040 TI - Criteria for Membership: Thoughts stimulated by the discussion of the Thames Valley Faculty's recommendation at the recent A.G.M. PMID- 19791042 TI - 41 Cadogan Gardens. PMID- 19791043 TI - The Continuing Observation and Recording of Morbidity: A Study by the Research Committee of the College of General Practitioners. PMID- 19791044 TI - The Art and Science of Prognosis in General Practice. PMID- 19791045 TI - The Part-time Industrial Medical Officer. PMID- 19791046 TI - Asthma in General Practice. PMID- 19791047 TI - A Breconshire Disease. PMID- 19791048 TI - Asian Influenza in a Sydney Suburban Practice. PMID- 19791050 TI - Influenza in a Rural Practice. PMID- 19791049 TI - Influenza in Central Bradford. PMID- 19791051 TI - An Unusual Epidemic: The Rash of Erythema Multiforme Associated with an Upper Respiratory Infection. PMID- 19791052 TI - Epidemic Observation Unit. PMID- 19791053 TI - The Continuing Education of General Practitioners: An Analysis of Replies to a Questionary from the Postgraduate Education Committee of Council. PMID- 19791054 TI - On Keeping Up-to-Date. PMID- 19791055 TI - Ancillary Help in General Practice. PMID- 19791057 TI - The Metric System in Prescribing. PMID- 19791056 TI - Criteria for Membership. PMID- 19791058 TI - The Training of General Practitioners in Public Health. PMID- 19791059 TI - The Organization and Administration of a General Practice. PMID- 19791060 TI - Opportunities and Pitfalls of General Practitioner Research. PMID- 19791061 TI - Metric Prescribing Simplified. PMID- 19791063 TI - The Continuing Education of General Practitioners-7: An Analysis of Replies to a Questionary from the Postgraduate Education Committee of Council. PMID- 19791062 TI - Epidemic Observation Unit. PMID- 19791065 TI - A Picture of Semi-Rural Practice a hundred years ago. PMID- 19791064 TI - Notes on the Evolution of Medical Practice prior to 1858. PMID- 19791067 TI - Sixty Years Ago. PMID- 19791066 TI - "1858-1958"-Some Reflections on the Evolution of the Training of the Family Doctor. PMID- 19791068 TI - Before and After 1948. PMID- 19791070 TI - A Technique for the Relief of some kinds of Obstetric Pain. PMID- 19791069 TI - Examinations and the College. PMID- 19791071 TI - On Undergraduate Education and the General Practitioner. PMID- 19791072 TI - Plain English. PMID- 19791073 TI - According to Precedent. PMID- 19791074 TI - The College Building. PMID- 19791075 TI - A year in General Practice. PMID- 19791076 TI - Group Studies in General Practice. PMID- 19791077 TI - Cardiovascular Emergencies in General Practice. PMID- 19791078 TI - A New Surgery for a Group Practice of Three Doctors. PMID- 19791080 TI - A Retrospect on Psychiatry after Forty Years of General Practice. PMID- 19791079 TI - Portable Drip Stand for Domiciliary Midwifery. PMID- 19791081 TI - The Doctors' Window in Guildford Cathedral. PMID- 19791082 TI - The Family Doctor, His Middle Aged Patient, and Coronary Disease. PMID- 19791084 TI - The Continuing Education of General Practitioners-8: An Analysis of Replies to a Questionary from the Postgraduate Education Committee of Council. PMID- 19791083 TI - An Experiment in Carrying Out Controlled Therapeutic Trials in General Practice. PMID- 19791086 TI - Fatal Hypothermia in Identical Twins. PMID- 19791085 TI - Preliminary Note on a New Hypnotic and Sedative. PMID- 19791087 TI - Epidemic Observation Unit. PMID- 19791088 TI - Cerebral Activity under Sudden Stress. PMID- 19791089 TI - The Morbidity Survey and After. PMID- 19791091 TI - The Public Welfare Foundation Undergraduate Prize Essay : A Case of Inoperable Carcinoma. PMID- 19791090 TI - The Teaching of Sexual and Marital Relations to Medical Students. PMID- 19791092 TI - The Doctor's Surgery. PMID- 19791093 TI - What shall we Think of Next? PMID- 19791095 TI - The Perinatal Mortality Survey: A Note on Progress. PMID- 19791094 TI - A comparison of the Maternity Services in an Urban and in a Rural Practice. PMID- 19791097 TI - The Art of Consultation. PMID- 19791096 TI - The Annual General Meeting. PMID- 19791098 TI - The Catarrhal Child. PMID- 19791099 TI - Epidemic Observation Unit. PMID- 19791100 TI - An Easily Adjustable Bed. PMID- 19791101 TI - Intractable Pain: A Project of the Northern Home Counties Research Subcommittee. PMID- 19791102 TI - On Talking. PMID- 19791103 TI - MEMORANDUM FOR THE GUIDANCE OF TRAINERS. PMID- 19791104 TI - The Report of the Maternity Services Committee. PMID- 19791105 TI - The American Academy of General Practice. PMID- 19791106 TI - The President's Hospitality Fund. PMID- 19791107 TI - Training Future Consultants in General Practice. PMID- 19791109 TI - A Classification of Disease. PMID- 19791108 TI - The Problem of Defining the Extent of Morbidity in General Practice. PMID- 19791110 TI - Second Opinions. PMID- 19791111 TI - Fantasies and Fits. PMID- 19791112 TI - Some Observations on Physical Treatment of Psychotic Patients in General Practice. PMID- 19791114 TI - Diabetes Detection Drives. PMID- 19791113 TI - Boils in Allergic Patients. PMID- 19791116 TI - Film Survey. PMID- 19791115 TI - Congenital Abnormalities. PMID- 19791117 TI - The College and Lincoln's Inn Fields. PMID- 19791118 TI - Landmarks in the Evolution of the General Practitioner. PMID- 19791120 TI - Mild Hypothyroidism in General Practice. PMID- 19791119 TI - Marriage Guidance. PMID- 19791121 TI - Ulcerated Legs Seen in General Practice. PMID- 19791122 TI - The Symptoms of High Blood Pressure. PMID- 19791123 TI - 1. Lectures to an Educational Association. PMID- 19791124 TI - 2. Lecture Discussions to Patients. PMID- 19791125 TI - Cancerphobia and the Medical Practitioner. PMID- 19791126 TI - The Examination Problem. PMID- 19791127 TI - Entry by Examination. PMID- 19791128 TI - THE CONTRIBUTION OF SOCIAL WORK TO MEDICAL CARE. PMID- 19791129 TI - Centenary Appeal of the Queen's Institute of District Nursing. PMID- 19791130 TI - Gammaglobulin and Measles. PMID- 19791132 TI - Trends in General Practice. PMID- 19791131 TI - Serial Numbers for Patients. PMID- 19791133 TI - The Reception at the Royal Scottish Academy. PMID- 19791134 TI - The Implications of the Association between the ABO Blood Groups and Disease. PMID- 19791135 TI - One Years Work in a Country Practice. PMID- 19791137 TI - A Casualty Survey. PMID- 19791136 TI - A Survey of Patients with Chronic Illness in a General Practice. PMID- 19791138 TI - The Failure of Health Centres. PMID- 19791139 TI - Atherosclerosis-the Case Against Protein. PMID- 19791141 TI - A Study of Influenza in Old People. PMID- 19791140 TI - Two hundred Cases of Scabies in General Practice. PMID- 19791142 TI - Discussion Groups and the Medical Recording Service. PMID- 19791144 TI - On the Criteria for Membership of the College. PMID- 19791143 TI - In Pursuit of Ancient Surgical and Medical Instruments. PMID- 19791145 TI - Cancer and the Family Doctor. PMID- 19791146 TI - Research committee. PMID- 19791147 TI - Research Newsletter No. 1. PMID- 19791148 TI - College research groups. PMID- 19791149 TI - The directory. PMID- 19791150 TI - Research register. PMID- 19791152 TI - The Research Advisory Panel. PMID- 19791151 TI - Analysis of interests. PMID- 19791154 TI - Annotations by members of the research register. PMID- 19791153 TI - The pendulum swings. PMID- 19791156 TI - Study groups. PMID- 19791155 TI - Progress report. PMID- 19791158 TI - "H.O.W" PMID- 19791157 TI - Down to Work. PMID- 19791160 TI - Annotations by members of the research register. PMID- 19791159 TI - Progress report. PMID- 19791161 TI - Old Wine in new bottles. PMID- 19791162 TI - The study groups. PMID- 19791163 TI - Annotations by members of the register. PMID- 19791164 TI - "HOW": Sterile Water in Rubber-capped Vials from own Steriliser. PMID- 19791166 TI - Progress report. PMID- 19791165 TI - Research in Scotland. PMID- 19791167 TI - 1. The Individual Workers. PMID- 19791168 TI - "Research in the Faculties" PMID- 19791169 TI - Progress Report. PMID- 19791171 TI - 2. Morbidity Survey. PMID- 19791170 TI - Study Groups. PMID- 19791172 TI - "Winter Vomiting" PMID- 19791173 TI - "The Pre-icteric Stage of Infective Hepatitis" PMID- 19791174 TI - "Notes on four cases of influenza" PMID- 19791175 TI - Otitis Media as a complication of Measles. PMID- 19791176 TI - Anaphylaxis after Penicillin Injections. PMID- 19791177 TI - The First Mackenzie Lecture. PMID- 19791178 TI - (2) Epidemic Observation Unit. PMID- 19791179 TI - A Simple Test for Occult Blood in Stools. PMID- 19791181 TI - A Study of Auricular Fibrillation. PMID- 19791180 TI - The Diagnosis and Nosology of Minor Maladies. PMID- 19791182 TI - Virus Disease and the Nervous System. PMID- 19791183 TI - The Growing Points of Medicine and their Relation to General Practitioners. PMID- 19791184 TI - On the Reporting of Family Outbreaks of Epidemic Disease. PMID- 19791186 TI - General Practice Records. PMID- 19791185 TI - Common Upper Respiratory Tract Infections. PMID- 19791187 TI - Psychological Disturbance in Association with Infective Hepatitis. PMID- 19791188 TI - Prolapsed Haemorrhoids Treated by Hyalase-A Case-Report. PMID- 19791189 TI - Hypothermal Collapse. PMID- 19791191 TI - Measles Investigation. PMID- 19791190 TI - A Quick and Simple Method for Blood-Sugar Estimation. PMID- 19791192 TI - Research in General Practice. The Matheson Shaw Lecture. PMID- 19791193 TI - Classification of Minor Maladies. PMID- 19791195 TI - Post-Graduate Education. PMID- 19791194 TI - Classification of Minor Maladies. PMID- 19791197 TI - Accidents to Children Treated in General Practice. PMID- 19791196 TI - The Measles Investigation. PMID- 19791198 TI - An Appointment System in a Group Practice. PMID- 19791199 TI - The Gregersen Slide Test. PMID- 19791200 TI - Editorial. PMID- 19791201 TI - An Epidemiological Investigation 1954-5. PMID- 19791202 TI - The Rural Practitioner. PMID- 19791203 TI - Health Education. PMID- 19791204 TI - Disorders of Behaviour in Childhood: "Pre-Coeliac Disease" PMID- 19791206 TI - Does an Appointment System Always Work? PMID- 19791205 TI - Notes on the Treatment of Tonsillitis. PMID- 19791207 TI - Epidemic Winter Vomiting: Report of an outbreak. PMID- 19791209 TI - A Rheumatic Syndrome in Elderly Patients. PMID- 19791208 TI - Afibrinogenaemia Associated with Accidental Haemorrhage. PMID- 19791211 TI - A Portable Visual Record Book. PMID- 19791210 TI - Intermittent Abdominal Pain in Children. PMID- 19791213 TI - Epidemic Observation Unit. PMID- 19791212 TI - The Measles Investigation. PMID- 19791215 TI - Warts. PMID- 19791214 TI - Asthma in Childhood. PMID- 19791216 TI - The General Practitioner and Hospital Practice. PMID- 19791218 TI - On Children who are Intolerant of Fat. PMID- 19791217 TI - Disease or Defence? PMID- 19791219 TI - The South-west Faculty Obstetric Survey. PMID- 19791220 TI - Epidemic Observation Unit. PMID- 19791221 TI - Respiratory Diseases Study Group. PMID- 19791222 TI - Measles Investigation. PMID- 19791224 TI - The Pursuit of Research in General Practice. PMID- 19791223 TI - Research Lunch. PMID- 19791225 TI - Asthma in Childhood. PMID- 19791226 TI - Enureris. PMID- 19791227 TI - Warts. PMID- 19791229 TI - Therapeutic Trials. PMID- 19791230 TI - The Influence of Home Conditions During the first Five Years of Life on the Physical and Mental Health of Children. PMID- 19791228 TI - Poliomyelitis in Pregnancy. PMID- 19791231 TI - The Influence of Home Conditions During the first Five Years of Life on the Physical and Mental Health of Children. PMID- 19791232 TI - Bornholm Disease in Cornwall, 1955. PMID- 19791233 TI - Suicide by Insulin Overdosage. PMID- 19791234 TI - Brucellosis from Accidental Conjunctival Inoculation. PMID- 19791235 TI - The Seathorne Steam Syringe Sterilizer. PMID- 19791237 TI - Cor Pulmonale. PMID- 19791236 TI - Offers of Help? PMID- 19791238 TI - Some Observations on Domiciliary Obstetrics. PMID- 19791240 TI - Chronic Bronchitis Investigation. PMID- 19791239 TI - Acute Otitis Media. PMID- 19791242 TI - Epidemic Observation Unit: An Unusual Epidemic. PMID- 19791241 TI - South-West of England Faculty-Pink Disease: Interim Report on the Pink Disease Survey. PMID- 19791243 TI - "Drugs to Charm with" PMID- 19791244 TI - An American Morbidity Survey. PMID- 19791245 TI - The Path from Middle to Old Age. PMID- 19791246 TI - Whither General Practice? PMID- 19791247 TI - The Tamar Valley "Flower Rash": A Daffodil Dermatitis. PMID- 19791248 TI - The Child Welfare and Maternity Services. PMID- 19791249 TI - Planning a Group Research Investigation. PMID- 19791250 TI - Memorandum on General-Practitioner Maternity Services: Evidence submitted to the Committee of Inquiry into the Maternity Services in England and Wales (The Ministry of Health). PMID- 19791251 TI - A Survey of Unrecorded Cases of Cancer. PMID- 19791252 TI - Epidemic Observation Unit. PMID- 19791253 TI - Radiology and the Family Doctor. PMID- 19791254 TI - Postgraduate Education of Newly-Qualified Doctors in Preparation for Entry into General Practice. PMID- 19791255 TI - Between Ourselves. PMID- 19791256 TI - An Epidemic of Vomiting and Vertigo at the Army School of Physical Training. PMID- 19791258 TI - Our Heritage and Our Future. PMID- 19791257 TI - The Complications of Measles: Part II. PMID- 19791260 TI - i. The Report of The Epidemic Observation Unit. PMID- 19791259 TI - AN OBSTETRIC SURVEY: SUPPLEMENT TO RESEARCH NEWSLETTER NO. 14. PMID- 19791261 TI - ii. Bornholm Disease in South-east England: A Faculty investigation into the Occurrence and Spread of the Disease in South-east England during the Autumn of 1956. PMID- 19791263 TI - The Continuing Education of General Practitioners: An Analysis of Replies to a Questionary from the Postgraduate Education Committee of Council. PMID- 19791262 TI - iii. An Outbreak in Winchester. PMID- 19791264 TI - Organization of Faculty Postgraduate Facilities. PMID- 19791265 TI - The Prescriber and the Metric System. PMID- 19791266 TI - Dermatology in General Practice. PMID- 19791267 TI - Coding and General-Practitioner Research. PMID- 19791268 TI - A Patient's Recollection of an Appendicetory Fifty-two Years Ago. PMID- 19791270 TI - Hypertension in General Practice: A pilot survey into its incidence and treatment conducted by the Northern Home Counties Faculty. PMID- 19791269 TI - General-Practitioner Maternity Services Supplementary Memorandum submitted to the Committee of Enquiry. PMID- 19791271 TI - The Inter-relationship of Virus Disease. PMID- 19791272 TI - Herpes of the Mouth with Mandibular Neuralgia. PMID- 19791273 TI - The Use of Hyoscine N-Butylbromide in Normal Labour. PMID- 19791274 TI - Epidemic Observation Unit. PMID- 19791275 TI - Research Projects. PMID- 19791277 TI - The Care of the Elderly in General Practice. PMID- 19791276 TI - Green Old Age. PMID- 19791278 TI - "-Half a Physician" PMID- 19791279 TI - The Care of the Elderly in General Practice II. PMID- 19791280 TI - The Problem of Sleeplessness. PMID- 19791281 TI - The Prevalence of Psychogenic Illness in General Practice. PMID- 19791282 TI - A Social Survey in a Country Practice. PMID- 19791284 TI - The College of General Practice in Canada. PMID- 19791283 TI - College of General Practitioners. PMID- 19791286 TI - The Continuing Education of General Practitioners III: An Analysis of Replies to a Questionary from the Postgraduate Education Committee of Council. PMID- 19791285 TI - A Department of General Practice in West Africa. PMID- 19791287 TI - Following the Stoke Mandeville Week-end: (Arranged by the Thames Valley Faculty). PMID- 19791288 TI - The Anaemic Patient and Her Symptoms. PMID- 19791289 TI - Asthma in Childhood: Interim Report. PMID- 19791290 TI - Rubella in Pregnancy. PMID- 19791291 TI - Epidemic Observation Unit. PMID- 19791292 TI - Whither Preventive Medicine? PMID- 19791293 TI - The General-Practitioner Obstetrician. PMID- 19791295 TI - The Children of Mothers at Work: A Study of the Frequency of Consultations for Children whose Mothers Work Outside the Home, and those whose Mothers stay at Home. PMID- 19791294 TI - Psychosomatic Problems in General Practice. PMID- 19791297 TI - Diabetes Surveys. PMID- 19791296 TI - The Treatment of the Patient and Not Merely the Disease from which he Suffers: A Trainee looks at General Practice. PMID- 19791298 TI - An Ipsophone System in General Practice. PMID- 19791299 TI - The Tape-Recorder in Postgraduate Education. PMID- 19791300 TI - The Continuing Education of General Practitioners: An Analysis of Replies to a Questionary from the Postgraduate Education Committee of Council. PMID- 19791301 TI - Public Health Laboratory Service. PMID- 19791302 TI - Research. PMID- 19791303 TI - The Changing Face of Medicine. PMID- 19791304 TI - The Drug Treatment of Neurosis in General Practice. PMID- 19791305 TI - CRITERIA FOR ESTABLISHING THE DIAGNOSIS IN DIABETES. PMID- 19791306 TI - Organizational fragmentation and care quality in the U.S healthcare system. PMID- 19791307 TI - Dynamics of reversible supramolecular polymers: independent determination of the dependence of linear viscoelasticity on concentration and chain length by using chain stoppers. AB - The linear viscoelasticity of solutions of a hydrogen bonded reversible supramolecular polymer in the presence of a chain stopper was studied by rheometry and by dynamic light scattering using probe particles. The use of chain stoppers enabled the independent variation of the degree of polymerisation and the monomer concentration, and the effect of both parameters on rheology was investigated. Scaling exponents were obtained for the chain length and concentration dependence of the zero-shear viscosity and the terminal relaxation time, and these were compared to theoretical values. The results indicate that the reversible supramolecular polymer is semiflexible, and that both breaking and reptation of chains contribute to the stress relaxation. The parameters from macroscopic rheometry were compared to microscopic values obtained from probe particle diffusion. The particles probe the macroscopic viscoelastic parameters if their size is large compared to the correlation length in the system and to the (persistence) length of the polymer chains. PMID- 19791308 TI - Is there still an unknown Freud? A note on the publications of Freud's texts and on unpublished documents. AB - This article presents an overview of the existing editions of what Freud wrote (works, letters, manuscripts and drafts, diaries and calendar notes, dedications and margin notes in books, case notes, and patient calendars) and what he is recorded as having said (minutes of meetings, interviews, memoirs of and interviews with patients, family members, and followers, and other quotes). There follows a short overview of biographies of Freud and other documentation on his life. It is concluded that a wealth of material is now available to Freud scholars, although more often than not this information is used in a biased and partisan way. PMID- 19791309 TI - [Epidemiological study on PET cancer screening]. PMID- 19791310 TI - [Image reconstruction in SPECT: standardization of image processing]. PMID- 19791311 TI - [Shock-digestive tract-infection-multiple organ dysfunction syndrome]. PMID- 19791312 TI - [Surgical sepsis and intestinal dysfunction]. PMID- 19791313 TI - Real-world image annotation and retrieval: an introduction to the special section. PMID- 19791314 TI - "In pursuit of the Nazi mind?" The deployment of psychoanalysis in the Allied struggle against Germany. AB - This paper discusses how psychoanalytic ideas were brought to bear in the Allied struggle against the Third Reich and explores some of the claims that were made about this endeavour. It shows how a variety of studies of Fascist psychopathology, centered on the concept of superego, were mobilized in military intelligence, postwar planning and policy recommendations for "denazification." Freud's ideas were sometimes championed by particular army doctors and government planners; at other times they were combined with, or displaced by, competing, psychiatric and psychological forms of treatment and diverse studies of the Fascist "personality." This is illustrated through a discussion of the treatment and interpretation of the deputy leader of the Nazi Party, Rudolf Hess, after his arrival in Britain in 1941. PMID- 19791315 TI - Recent developments in health law. Wyeth v. Levine: challenging implied pre emption for drugs. PMID- 19791316 TI - [Case of deglutition disorder with difficulty in diagnosis for a long time]. PMID- 19791317 TI - State of water at 136 K determined by its relaxation time. AB - Dielectric relaxation time of pure bulk water has been determined from the dielectric loss tangent scans against temperature at two frequencies. After calculating the frequency-independent background loss, the relaxation loss was obtained, and the relaxation time determined. The dielectric relaxation time of water is 35 +/- 13 s at 136 +/- 1 K, which is comparable with its structural relaxation time of ca. 33 s estimated from its T(g) endotherm (G. P. Johari, A. Hallbrucker and E. Mayer, Nature, 1987, 330, 552). Therefore, water is an ultraviscous liquid at 136 K, and this removes the basis for a comparison-based inference that water is a rigid glass up to a temperature of 165 K or higher (Y. Yue and C. A. Angell, Nature, 2004, 427, 717). The method yields satisfactory values for the relaxation time of stable glasses at their known calorimetric T(g). PMID- 19791318 TI - Non-Arrhenius viscosity related to short-time ion dynamics in a fragile molten salt. AB - The equation T x sigmaDC(T) = alpha x exp[--(E*/kappa(B)T)--gamma x exp(E*/kappa(B)T)] has been used to understand the non-Arrhenius behaviour of the DC conductivity in supercooled glass-forming melts. Here, alpha, gamma and E* are parameters, E* denoting the activation energy for an elementary displacive step. Unlike the empirical VTF relation, our equation provides a link between the long time and the short-time ion dynamics as observed in broad-band conductivity spectra. Surprisingly, the same equation with the same value of E* but different gamma successfully describes the fluidity (inverse viscosity) of a fragile glass forming melt. This opens up the possibility of relating non-Arrhenius viscosities to short-time properties, which is in agreement with recent experimental and computer-simulation results. PMID- 19791319 TI - Enhanced photocatalytic formation of hydroxyl radicals on fluorinated TiO2. AB - Direct experimental evidence of the higher concentration of hydroxyl radicals generated on fluorinated titanium dioxide (F-TiO2) under irradiation was obtained by spin-trapping EPR measurements. The faster photoinduced bleaching of the azo dye Acid Red 1 (AR1) observed in the presence of F-TiO2 was explained by the high affinity of the azo double bond towards *OH radicals. Moreover, the pronounced decrease of the AR1 bleaching rate by addition of 2-propanol, as hydroxyl radicals scavenger, on F-TiO2 and not on naked TiO2 demonstrated that on fluorinated titania AR1 is mainly degraded via *OH radical attack. PMID- 19791320 TI - Investigating the structure of boron nitride nanotubes by near-edge X-ray absorption fine structure (NEXAFS) spectroscopy. AB - Herein, we demonstrate that NEXAFS is a very effective technique at (a) identifying the phases of boron nitride nanotubes with the potential of distinguishing between hexagonal BN and cubic BN, and (b) monitoring the presence of defects and degree of crystallinity in nanoscale samples. Specifically, a prepared sample of boron nitride nanotubes was characterized by NEXAFS. Our results show that the sample consisted of hexagonal BN tubes that were highly crystalline and sp2-hybridized. PMID- 19791321 TI - Friction force microscopy: towards quantitative analysis of molecular organisation with nanometre spatial resolution. AB - Friction force microscopy (FFM) is a technique based upon scanning force microscopy that provides information on the properties of molecular materials. Continuum mechanics provides models that may be used to conduct quantitative analyses of data. While there are some important unresolved issues associated with the contact mechanics of the tip-sample interaction, there is a growing body of data that demonstrates the sensitivity of FFM to changes in molecular organisation and surface composition. Importantly, FFM provides these data with nm spatial resolution, making it in many respects a unique tool for exploring the structures of organic materials on small length scales. Some of the capabilities of FFM are illustrated by drawing on both the literature and work performed in the authors' laboratory on self-assembled monolayers. For example, the compositions of mixed monolayer systems may be determined, with control of tip chemistry providing an additional element of chemical specificity; the alkyl chain organisation may be investigated; and the rates of surface chemical reactions may be measured. FFM is a powerful tool for the quantitative investigation of nm scale chemistry. PMID- 19791322 TI - Computational studies of elementary steps relating to boron doping during diamond chemical vapour deposition. AB - Density functional theory-based electronic structure computations on small models of the diamond {100} surface have enabled prediction of the energetics and activation parameters of a number of plausible mechanistic steps for boron incorporation into, and boron loss from, the growing diamond surface. Initial proving calculations for the carbon-only case show, as in previous work, that the rate-limiting step for diamond growth involves opening of a five-membered ring species, and subsequent closure to form six-membered rings as in bulk diamond. The five-membered ring intermediate arises following 2 x 1 reconstruction of the {100} surface, or at steps on the {111} surface. Diamond growth arises as a result of successful competition between the ring-opening step and a two-carbon loss step, both of which involve significant activation barriers. In the boron case, we find that BH(x) (x = 0-3) species can all bind to radical sites on the diamond {100} surface to form stable adducts. Interconversion between the surface bound BH, species is facile at the H and H2 number densities and temperatures typical for diamond CVD conditions. B incorporation can occur by a ring expansion mechanism, as in the all-carbon case, and by direct insertion of surface bound BH (and B) species into the C-C bond on the diamond {100} surface. BH(x) loss processes identified include release of surface bound BH3 and/or CH2BH species into the gas phase. Both B incorporation into, and B loss from, the diamond {100} surface are deduced to be significantly less energy demanding than the corresponding carbon addition and loss processes. PMID- 19791323 TI - Size mismatch effects in oxide solid solutions using Monte Carlo and configurational averaging. AB - Local minima configurational averaging (CA) and Monte Carlo (MC) simulations are used to examine in detail the variation of thermodynamic and structural properties of binary oxide solid solutions with the volume mismatch between the end members. The maximum volume mismatch studied corresponds to that in the CaO MgO solid solution, a prototype example of a strongly non-ideal system with large miscibility gap. In addition, solid solutions of CaO-HypO using designed hypothetical atoms (Hyp) with atomic radii between those of Ca2+ and Mg2+ have been considered. Calculations on the hypothetical systems allow not only the systematic investigation of size mismatch, but also the detailed examination and comparison of the CA and MC methods. A particularly efficient implementation of the CA method is via the rapid calculation of the radial distribution function (RDF) for all possible arrangements obtained by distributing the different ions on their respective crystallographic sites followed by full structural optimisation of just one configuration from each group with the same RDF. Comparison of results from CA, using optimisations in the static limit, and MC indicates the importance of cell-size and vibrational effects, which can be particularly important for the largest size mismatches. The enthalpies, excess configurational entropies, vibrational entropies and volumes of mixing scale roughly quadratically for all but the largest volume mismatches. Equally sized atoms cluster together in the first coordination shell for all volume mismatches studied. PMID- 19791324 TI - Ab initio potential energy surfaces for excited electronic states of the molecular ion HCN+. AB - Potential energy surfaces for the linear X2Pi, 2(2)Pi, A2Sigma+ , B2Sigma+, 3(2)Sigma+, 1(4)Pi and 1(4)Sigma+ states and for the bent B2Sigma+/3(2)A' state of HCN+ have been calculated by a multi-reference configuration interaction (MRCI) method. The persistence of vibrational structure in the photoelectron spectrum of the B state above the experimental dissociation asymptote is interpreted in terms of a local maximum on the potential energy surface with respect to stretching the CH bond. The global minimum for this state has a bent geometry with a bond angle of 129 degrees. This is discussed in terms of an avoided intersection with the A' component of the 2(2)Pi state for bent geometries. The 3(2)Sigma+ surface is quasi-bound and it is suggested that a satellite state at 22.5 eV in the photoelectron spectrum of HCN is the 3(2)Sigma+ state. The predissociation of the B2Sigma+ state is discussed and it is suggested that this may occur via non-adiabatic transitions to the 1(4)Pi/1(4)A' surface. PMID- 19791325 TI - High resolution Fourier transform spectroscopy of CH2D2 in the region 2350-2650 cm(-1): the bands nu5 + nu7, 2nu9, nu3 + nu4, nu3 + nu7 and nu5 + nu9. AB - The IR spectrum of the CH2D2 molecule has been measured in the region of 2350 2650 cm(-1) on a Bomem DA002 Fourier transform spectrometer with a resolution of 0.004 cm(-1) (FWHM, apodized) and analyzed with a Hamiltonian model which takes into account resonance interactions between all vibrational states in that region. More than 3000 transitions have been assigned to the bands 2nu9, nu3 + nu4, nu5 + nu9, nu5 + nu7 and nu3 + nu7 using ground state combination differences from the known ground state parameters. A set of 115 spectroscopic parameters for the excited vibrational states is obtained from a least squares adjustment. This reproduces the 646 initial upper ro-vibrational energies used in the fit with a d(rms) = 0.0036 cm(-1). PMID- 19791326 TI - Optimized isotope-selective ionization of 23Na39K and 23Na41K by applying evolutionary strategies. AB - We study specific properties of different isotopes by applying optimal control. Selective optimization for 23Na39K and 23Na41K isotopes is reported at two different central wavelengths by employing evolutionary strategies on shaped femtosecond laser pulses. The optimized ionization processes exhibit high enhancements of one isotope compared to the other and reversed. We analyze the pulse spectra for extracting information about the optimally chosen ionization paths and observe vibrational transitions to differing electronic states for the different isotope selections. To get a deeper insight we compare simultaneous phase and amplitude modulation with pure amplitude modulation and as well pure phase modulation. Our approach reveals how the optimization algorithm precisely addresses the vibrational wave functions by coherent interaction with the corresponding pulse components. PMID- 19791327 TI - Intermolecular hydrogen bond in molecules with large amplitude motions: rotational spectrum of the complex 3,3-dimethyloxetane...hydrogen fluoride. AB - The rotational spectrum of the complex 3,3-dimethyloxetane...HF generated in a supersonic jet has been analyzed using molecular beam Fourier transform microwave spectroscopy in the frequency range 6-18 GHz. Only the axial conformer of the complex has been detected. The parent and 13C and 18O monosubstituted isotopic species were observed both for isolated 3,3-dimethyloxetane and the complex in their natural abundances. For 3,3-dimethyloxetane the methyl group carbon atoms have been observed to be equivalent despite the fact that the ring-puckering potential energy function is of the double minimum type with the ground vibrational state lying below the barrier. An effective (r0) structure of the adduct has been derived from the spectroscopic constants. A C(s) symmetry has been established with HF forming an axial hydrogen bond to the O atom of the ring molecule. No significant structural changes have been observed in 3,3 dimethyloxetane upon complexation. The non-observation of a plausible equatorial conformer is discussed with the help of ab initio computations. PMID- 19791328 TI - Long-lived light-induced metastable states in trans-[Ru(NH3)4(H2O)NOCl3 x H2O and related compounds. AB - The existence of two light-induced long-lived metastable states SI, SII in irradiated trans-[Ru(NH3)4(H2O)NO]Cl3 x H2O and trans-[Ru(NH3)4(OH)NO]Cl2 is revealed by differential scanning calorimetry measurements and calculations based on density functional theory. Irradiation with light in the blue spectral range leads to the population of SI, while SII can be obtained by transferring SI into SII with irradiation of light in the near infrared spectral range. The population and transfer of the metastable states is described by exponential functions and the thermal decays are evaluated according to Arrhenius' law, yielding activation energies of EA(SI) = 0.95(3) eV, EA(SII) = 0.69(3) eV and frequency factors of Z(SI) = 2 x 10(14) s(-1), Z(SII) = 3 x 10(13) s(-1) for trans [Ru(NH3)4(H2O)NO]Cl3 x H2O, while EA(SI) = 0.91(3) eV, EA(SII) = 0.60(3) eV, Z(SI) = 6 x 10(14) s(-1), Z(SII) = 1 x 10(13) s(-1) for trans [Ru(NH3)4(OH)NO]Cl2. The observations are compared with the ground state potential surface calculated by density functional theory, where the metastable states correspond to a side-on bonded (SII) and isonitrosyl (SI) configuration of the NO ligand. The calculations provide the energetic minima of the ground state and the metastable states SI and SII as well as the saddle points along the reaction coordinate Q, which corresponds roughly to a rotation of the NO ligand by about 90 degrees (SII) and 180 degrees (SI), and therefore allows for the comparison between observed and calculated activation energies. PMID- 19791329 TI - Laser-induced fluorescence spectroscopy of N,N'-dimethyl 3,4,9,10-perylene tetracarboxylic diimide monomers and oligomers attached to helium nanodroplets. AB - Laser-induced fluorescence spectroscopy has been applied to study the molecule N,N'-dimethyl 3,4,9,10-perylene tetracarboxylic diimide (MePTCDI) and its oligomers embedded in helium nanodroplets. The 0(0)0-transition of the monomer absorbs at 20571.6 cm(-1) as the dominant line. The vibrational structure in the S1 state of the molecule is clearly resolved at higher frequencies. The measured vibrational spectrum is compared to Raman spectra of thin films and calculated frequencies of the isolated molecule. When doping the helium droplets with MePTCDI oligomers, narrow (< 1 cm(-1)) as well as broad (approximately 500 cm( 1)) excitation lines are observed. These are attributed to electronic molecular dimer transitions and excitonic transitions of sandwich-like MePTCDI oligomers, respectively. The findings are compared with the corresponding absorptions of 3,4,9,10-perylene tetracarboxylic dianhydrid (PTCDA) in helium droplets and with those of thin solid films. PMID- 19791330 TI - A simulation study of the optical Kerr effect in liquid water. AB - A molecular dynamics simulation study is presented for the dynamics of the polarizability anisotropy of liquid water using the SPC/E model and a dipolar induction scheme that involves the intrinsic polarizability and first hyperpolarizability tensors obtained from ab initio quantum chemical calculations at the MP2/6-311++G(d,p) level. The time-correlation functions for the collective polarizability anisotropy, the optical Kerr effect response, and the frequency spectra are analyzed in terms of the intrinsic and induced polarizability contributions. At short times, the simulated Kerr nuclear response exhibits maxima near 15, 50 and 180 fs, followed by a diffusive tail which has been fitted by a bi-exponential with time constants ca. 0.4 and 2.5 ps. The short time features are in good agreement with available simulation and experimental results. The agreement with experiments is less satisfactory for the diffusive components. The main features of the frequency spectrum include a rotational diffusion peak centered around 3 cm(-1), a collision-induced (hindered translations) band near 200 cm(-1), and a broad librational band at 450 cm(-1). The simulation results are in good agreement with experimental frequency spectra obtained from Kerr effect and related spectroscopies, but fail to reproduce the experimental band near 60 cm(-1). PMID- 19791331 TI - Gas phase protonation of trifluoromethyl sulfur pentafluoride. AB - The gas phase protonation of SF5CF3, a potent new greenhouse gas recently discovered in stratospheric air samples, was studied by the joint application of mass spectrometric and ab initio theoretical methods. The reaction is essentially dissociative leading to the formation of HF, CF4 and SF3+ as main fragmentation products. Consistent with collisionally activated dissociation (CAD) mass spectrometric results, theoretical calculations identified the loosely bounded ion-molecule complex [HF-SF4 CF3], I, as the most stable isomer on the [SF5CF3]H+ potential energy surface. The proton affinity of SF5CF3 estimated from FT-ICR 'bracketing' experiments was found to be 152.5 +/- 3 kcal mol(-1) which agrees with the values obtained from theoretical calculations at B3LYP and CCSD(T) levels of theory, 154.0 +/- 3 and 153.4 +/- 3 kcal mol(-1), respectively. These results suggest that the basicity of SF5CF3 is higher than that of atmospheric cations such as H2O+; they need to be considered when evaluating the lifetime of SF5CF3 since it can be destroyed by proton transfer reactions. PMID- 19791332 TI - The kinetics of the CF3 + CF3 and CF3 + F combination reactions at 290 K and at He-pressures of approximately 1-6 Torr. AB - The rate constants for the combination reactions CF3 + CF3 and CF3 + F at 290 K and helium pressures of approximately 1-6 Torr have been determined, using clean chemical sources of CF3, by means of discharge flow-molecular beam sampling threshold ionisation mass spectrometry (DF/MB-TIMS). For the mutual reaction of CF3, no pressure dependence could be observed over the 1-6 Torr pressure range, indicating that the obtained rate constant of k1 infinity = (1.8 +/- 0.6) x 10( 12) cm3 s-1 is the high pressure limit. This result, which agrees with the lowest values in literature but is ca. five times smaller than the most recent data, is fully in line with the known trend in the mutual reaction rate constant for the series CH3; CH2F; and CHF2. The reaction of CF3 with F was found to exhibit a clear pressure dependence in the 0.5 to 6 Torr range. Using a Troe fall-off formalism, the low-pressure limit rate constant was determined as k20(He) = (1.47 +/- 0.24) x 10(-28) cm6 S(-1), differing substantially from the only available previous determination; a variational transition state theoretical treatment is shown to support our data. PMID- 19791333 TI - A kinetics and mechanistic study of the OH and NO2 initiated oxidation of cyclohexa-1,3-diene in the gas phase. AB - The kinetics and products of the OH and NO2-initiated oxidation of cyclohexa-1,3 diene have been investigated at 296 K and 700 Torr using long path FTIR spectroscopy. Relative rate methods were employed using the photolysis of cyclohexa-1,3-diene/CH3ONO/NO/air mixtures to measure kappa(OH + cyclohexa-1,3 diene) = (1.68 +/- 0.43) x 10(-10) cm3 molecule(-1) s(-1). From the pseudo-first order decay of cyclohexa-1,3-diene in the presence of excess NO2, a value of kappa(NO2 + cyclohexa-1,3-diene) = (1.75 +/- 0.15) x 10(-18) cm3 molecule)-1) s( 1) was derived. An upper limit of kappa < or = 7 x 10(-21) cm3 molecule(-1) s(-1) was established for the reaction of NO with cyclohexa-1,3-diene. Benzene was observed as a product of both the OH and NO2 initiated oxidation, providing evidence of H atom abstraction in both reactions. Assuming the reaction of cyclohexadienyl radicals (C6H7) with O2 produces benzene as the sole organic product, the results are consistent with abstraction channel branching ratios of (8.1 +/- 0.2)% and (1.5 +/- 0.4)%, respectively. The results also indicate that C6H7 reacts with NO2, with a relative rate coefficient kappa(C6H7 + NO2)/kappa(C6H7 +O2) = (1.8 +/- 0.5) x 10(5), and that this partially forms benzene, with a branching ratio of (27 +/- 7)%. The stoichiometry and products of the NO2 reaction were investigated in the absence of O2, in the presence of O2, and in the presence of O2 and NO. Reaction mechanisms consistent with the observations are presented. In the presence of NO and O2, the NO2-initiated chemistry leads to NO-to-NO2 conversion, and the formation of HOx radicals in significant yield, (0.79 +/- 0.05), such that cyclohexa-1,3-diene removal occurs by reaction with both NO2 and OH. HCOOH was detected as a product in this system, providing evidence for significant formation of stabilised C6 alpha-hydroxyperoxy radicals from the OH-initiated chemistry, and their subsequent reaction with NO. An estimate of ca. 500-1000 s(-1) is made for their decomposition rate, based on the [NO]-dependence of the HCOOH yields. The implications of the results are discussed within the context of the atmospheric chemistry of conjugated dienes. PMID- 19791334 TI - Molecular dynamics modeling of cooling of vibrationally highly excited carbon dioxide produced in the photodissociation of organic peroxides in solution. AB - Non-equilibrium (NEMD) and equilibrium (EMD) molecular dynamics simulations are performed to investigate the vibrational cooling and asymmetric stretch spectral evolution of highly excited carbon dioxide produced in the photodissociation of organic peroxides in the solvents dichloromethane, carbon tetrachloride and xenon. Due to strong Fermi resonance the symmetric stretching and bending modes of carbon dioxide in CH2Cl2 and CCl4 jointly relax on a ten and hundred picosecond timescale, respectively, which is in accordance with experiment. However, the high frequency CO2 asymmetric stretch vibration relaxes on a considerably longer time scale because of weak interaction with the other modes. The relaxation rate coefficients of (and works done by) different modes obtained from NEMD and the Landau-Teller rate coefficients calculated through equilibrium force time correlation functions are in reasonable agreement. The analysis of these results leads to the conclusion that, in contrast to xenon where the relaxation takes about 20 ns, the shorter time scales in CH2Cl2 and CCl4 are caused by efficient near resonant vibration to vibration energy transfer from carbon dioxide to solvent molecules. The results of the non-equilibrium simulations are used to monitor the quasi-stationary asymmetric stretch infrared spectra of carbon dioxide during the cooling process. Comparison of the corresponding experimental results suggests that carbon dioxide initially is produced with a broad distribution of energy disposed in its bend and symmetric stretch modes while the asymmetric stretch mode remains unexcited. PMID- 19791335 TI - The use of in situ powder X-ray diffraction in the investigation of dolomite as a potential reversible high-temperature CO2 sorbent. AB - We report the use of gas sorption experiments and in situ powder X-ray diffraction to study the use of dolomite (MgCa(CO3)2) as a potential reversible high-temperature CO2 sorbent. When dolomite is treated in inert atmosphere at 900 degrees C it decomposes into separate CaO and MgO rich phases and dolomite is never reformed pon CO2 sorption. Gas sorption studies show that the calcined dolomite can go through several cycles of CO2 sorption/desorption in a reversible manner, however, the sorption capacity diminishes with each cycle. Only calcium seems to be involved in the CO2 sorption, while MgO acts as a carrier for the calcium phase. Some evidence of magnesium contamination of the calcium phase was found. BET and SEM measurements were carried out to find differences in the surface area/particle morphology that may explain similarities in the sorption capacities of dolomite and calcite (CaCO3). PMID- 19791336 TI - Transport coefficients of soft sphere fluids. AB - This study explores the effects of interaction softness on the transport properties of simple fluids in which the particles interact via the potential, phi(r) = epsilon(r/sigma)(-n), with n in the range 6-1152. Molecular dynamics simulation has been used to compute the self-diffusion coefficient, D, the shear viscosity eta(s), bulk viscosity eta(b), and the thermal conductivity, lambda, over a wide packing fraction range. A number of semi-empirical formulae for these transport coefficients have been tested against this data. It was found that the transport coefficients were proportional to the exponential of the two-body component of the entropy. The quality of agreement was best for D and worst for the thermal conductivity. A cell model for the fluid based on the simulated mean square force was not successful in correlating the diffusion coefficient data over the wide range of n. We also consider several variants on the Stokes Einstein relationship, which provide an informative insight into the global behaviour of (mainly) the self-diffusion coefficient and shear viscosity. PMID- 19791337 TI - Adsorption sites and rotational tunneling of methyl groups in cubic I methyl fluoride water clathrate. AB - Neutron spectroscopy in the microeV and meV regime and quasielastic scattering is applied to characterize the dynamics of methyl groups of methyl fluoride guest molecules in cubic I CH3F-water clathrate. Only above T approximately 60 K quasielastic spectra are unaffected by quantum effects. They are well described by two Lorentzians representing the CH3F species in the small and large cages of the structure. The intensities show that both cages are completely filled. The linear broadenings with temperature follow the model of rotational diffusion. Two clearly separated tunneling bands were observed at T = 4.2 K and are also assigned to the two types of water cages. Disorder of the environment (H-bonds) is reflected in the shape of the bands. For the less hindered species housing the large cages the tunneling band can be quantitatively converted into a potential distribution function within the model of single particle rotation. Transitions to excited rotational states show the dominance of a sixfold potential term V6 = 13 meV modified by a weak threefold term distributed around a characteristic value V3 = 0.9 meV. The potential distribution of V3 influences the barrier for classical reorientation only weakly in agreement with the results from quasielastic data. Adsorption sites with the guest molecules oriented towards a hydrogen bond along one of twelve local twofold axes of the cage are proposed. Such sites are consistent with the sixfold rotational potential and earlier results from methyl iodide clathrate. Rotation-translation coupling as an alternative dynamical process is excluded. PMID- 19791338 TI - Counter-ions dynamics in highly plastic and conducting compounds of poly(aniline). A quasi-elastic neutron scattering study. AB - Proton dynamics in films of poly(aniline) "plastdoped" with di-esters of sulfophthalic (or sulfosuccinic) acids have been investigated by using quasi elastic neutron scattering techniques. A broad time range (10(-13)-10(-9) s) has been explored by using four different spectrometers. In this time range, the dynamics is exclusively due to protons attached to the flexible tails of the counter-ions. A model of limited diffusion in spheres whose radii are distributed in size gives a realistic view of the geometry of molecular motions. However, it is found that the characteristic times of these motions are widely distributed over several orders of magnitude. The time decay of the intermediate scattering function is well described by a time power law. This behaviour is qualitatively discussed in connection with the structure of the systems and by comparison with other so-called complex systems. PMID- 19791339 TI - QENS investigation of the dynamics of starch saccharides. AB - We present here quasi-elastic neutron scattering results on D20 hydrated samples of amylose, one of the main saccharide components of starch. Two different sample hydrations (h = 0.5 and 1.0 g D2O (g dry amylose)-1 have been investigated in the temperature range 170 to 350 K. Below 260 K only an elastic contribution is present in the spectra, while a quasi-elastic component shows up above this temperature. The elastic incoherent structure factor (EISF) associated with this component changes considerably with increasing temperature. For the sample with hydration h = 0.5 the confinement volume increases by a factor of four in going from 300 to 350 K, and the proportion of hydrogen involved in the confined diffusion motion increases as well from 30 to 55%. Similar effects are observed at the higher hydration investigated. The observed dynamics can be associated with the known plasticising role of water in polysaccharides. PMID- 19791340 TI - Effective field integral subtraction by the combination of spin echo and resonance spin echo. AB - In contrast to other inelastic neutron scattering methods, neutron spin echo (NSE, F. Mezei, Z. Phys., 1972, 255, 146) tests sample dynamics directly in the time domain. The corresponding energy resolution is the highest one of all neutron scattering methods. In NSE, the spin phase accumulated in magnetic fields before and after the sample is compared. The Neutron Resonance Spin Echo (NRSE) technique (R. Gahler and R. Golub, Z. Phys. B, 1987, 65, 269) relies on a similar principle as NSE. Using additional RF frequency coils allows a significant reduction of the dimensions of the static magnetic field coils. The dynamic range both in NSE and NRSE is restricted to three orders of magnitude, at most. The tuning of an NRSE instrument is, moreover, restricted to few resonance frequencies, predetermined by electrical conditions. In order to increase the flexibility of NSE instruments, and to enable studies of dynamics spread over a wider range of the spin echo time, we combined both methods, NSE and NRSE, in a single setup. A test experiment with the new NSE-NRSE setup at IN11 (Institut Laue Langevin, Grenoble), has demonstrated its high flexibility, and that there are no electrical limitations with respect to energy resolution tuning. Our NSE NRSE setup overcomes restrictions of the dynamic range of both the NSE and the NRSE method. PMID- 19791341 TI - Time-focused crystal analyzer spectrometer. AB - We outline a linearized analysis of pulsed-source time-of-flight crystal analyzer spectrometers (CAS) based on scattered neutron analysis by crystal monochromators and intended for use in high-resolution quasielastic scattering and Brillouin scattering measurements. Spectrometers of this kind, often called "backscattering spectrometers," provide for high resolution measurements of excitations with typical energies in the range 1-100 microeV in both steady source and pulsed source applications. The analysis is fully general, treating three-dimensionally the geometric conditions for time focusing of the orientations of the source (moderator), sample, monochromator crystal and detector, considered as thin elements having large areas, and allows for the use of mosaic crystal monochromators. We report the results of VITESS Monte Carlo simulations, which verify the analytical focusing conditions for dispersionless excitations, reveal higher-order (than linear) contributions to the resolution widths, and provide absolute intensity estimates. PMID- 19791342 TI - Spectroscopic characteristics of the OSIRIS near-backscattering crystal analyser spectrometer on the ISIS pulsed neutron source. AB - The OSIRIS neutron instrument on the ISIS pulsed source now affords the option of high-resolution quasi-elastic and inelastic neutron spectroscopy. In this paper, the performance of OSIRIS is presented, with the spectroscopic characteristics of the instrument being discussed in terms of energy resolution, signal to background ratio and neutron count rate. Recent improvements to the spectrometer are described, in particular the effect of cooling the crystal analysers close to liquid helium temperature to enhance the sensitivity of the instrument. The performance of OSIRIS is also likened to back-scattering, crystal analyser spectrometers at other neutron sources. PMID- 19791343 TI - Flow cell for neutron spectroscopy. AB - Quasielastic neutron scattering is well-established for the investigation of microscopic diffusion on an atomistic length scale. Recently the possibility of studying the macroscopic flow properties of liquids from inelastically Doppler scattered neutrons was demonstrated. Up to now all such studies were performed with shear cells in plate-plate geometry. In this article we present a new type of flow cell for studies of liquids flowing through a narrow slit. To illustrate the performance of the cell we made measurements on different instruments with two liquids. The diffusion mechanism and constants are determined from the quasielastic scattering. From the inelastic scattering the velocity of the flowing liquid is extracted. PMID- 19791344 TI - Water, sulfur dioxide and nitric acid adsorption on calcium carbonate: a transmission and ATR-FTIR study. AB - Calcium carbonate (CaCO3) is a reactive component of mineral dust aerosol as well as buildings, statues and monuments. In this study, attenuated total reflection (ATR) and transmission Fourier transform infrared spectroscopy (FTIR) have been used to study the uptake of water, sulfur dioxide and nitric acid on CaCO3 particles at 296 K. Under atmospheric conditions, CaCO3 particles are terminated by a Ca(OH)(CO3H) surface layer. In the presence of water vapor between 5 and 95% relative humidity (RH), water molecularly adsorbs on the Ca(OH)(CO3H) surface resulting in the formation of an adsorbed thin water film. The adsorbed water film assists in the enhanced uptake of sulfur dioxide and nitric acid on CaCO3 in several ways. Under dry conditions (near 0% RH), sulfur dioxide and nitric acid react with the Ca(OH)(CO3H) surface to form adsorbed carbonic acid (H2CO3) along with sulfite and nitrate, respectively. Adsorbed carbonic acid is stable on the surface under vacuum conditions. Once the surface saturates with a carbonic acid capping layer, there is no additional uptake of gas-phase sulfur dioxide and nitric acid. However, upon adsorption of water, carbonic acid dissociates to form gaseous carbon dioxide and there is further uptake of sulfur dioxide and nitric acid. In addition, adsorbed water increases the mobility of the ions at the surface and enhances uptake of SO2 and HNO3. In the presence of adsorbed water, CaSO3 forms islands of a crystalline hydrate whereas Ca(NO3)2 forms a deliquescent layer or micropuddles. Thus adsorbed water plays an important and multi-faceted role in the uptake of pollutant gases on CaCO3. PMID- 19791345 TI - Reactions in condensed formic acid (HCOOH) induced by low energy (< 20 eV) electrons. AB - The interaction of low energy (< 20 eV) electrons with a five monolayer (ML) film of formic acid (HCOOH) deposited on a cryogenically cooled monocrystalline Au substrate is studied by electron stimulated desorption (ESD) of negatively charged fragment ions. A comparison with results from gas phase experiments demonstrates the strong effect of the environment for negative ion formation via dissociative electron attachment (DEA). From condensed phase formic acid (FA) a strong H desorption signal from a resonant feature peaking at 9 eV is observed. In the gas phase, the dominant reaction is neutral hydrogen abstraction generating HCOO- within a low energy resonance, peaking at 1.25 eV. ESD studies on the isotopomers HCOOD and DCOOH indicate effective H/D exchange in the precursor ion at 9 eV prior to dissociation. The evolution of the desorption signals in the course of electron irradiation and the features in the thermal desorption spectra (TDS) of the electron irradiated film suggest the formation of CO2 at electron energies above 8 eV. PMID- 19791346 TI - Sulfate formation on SOx trapping materials studied by Cu and S K-edge XAFS. AB - The elementary steps during oxidative chemisorption of SO2 by a novel composite material consisting of highly disordered benzene tri-carboxylate metal organic framework materials with Cu as central cation and BaCl2 as a second component (Ba/Cu-BTC) and by a conventional BaCO3/Al2O3/Pt based material were investigated. EXAFS analysis on the Cu K-edge in Ba/Cu-BTC indicates the opening of the majority of the Cu-Cu pairs present in the parent Cu-BTC. Compared to Cu BTC, the BaCl2 loaded material has hardly any micropores and has higher disorder, but it has better accessibility of the Cu2+ cations. This results from the partial destruction of the MOF structure by reaction between BaCl2 and the Cu cations. The SO2 uptake in oxidative atmosphere was higher for the Ba/Cu-BTC sample than for the BaCO3/Al2O3/Pt based material. XRD showed that on Ba/Cu-BTC the formation of BaSO4 and CuSO4 occurs in parallel to the destruction of the crystalline structure. With BaCO3/Al2O3/Pt the disappearance of carbonates was accompanied with the formation of Ba- and Al-sulfates. XANES at the S K-edge was used to determine the oxidation states of sulfur and to differentiate between the sulfate species formed. At low temperatures (473 K) BaSO4 was formed preferentially (53 mol% BaSO4, 47 mol% CuSO4), while at higher temperatures (and higher sulfate loading) CuSO4 was the most abundant species (42 mol% BaSO4, 58 mol% CuSO4). In contrast, on the BaCO3/Al2O3/Pt based material the relative concentration of the sulfate species (i.e., BaSO4 and Al2(SO4)3) as function of the temperature remained constant. PMID- 19791347 TI - Electrochemical reactivity in nanoscale domains: O2 reduction on a fullerene modified gold surface. AB - Fullerene is strongly adsorbed on both single crystal and polycrystalline gold surfaces and its specific adsorption resulted in the formation of high coverage large hexagonal rafts with strong interactions between the adsorbed fullerene molecules and the Au substrate. The oxygen reduction reaction (ORR) was investigated on these surfaces to determine their influence on the reduction mechanism. Oxygen reduction did not take place on the fullerene overlayer but proceeded on the sub-nanometer sized exposed pockets of the underlying Au substrate. Reduction at these confined sites produces hydrogen peroxide selectively. This effect is ascribed to the blocking action, or so-called "third body effect", of the adsorbed fullerene molecules, which do not display electrocatalytic properties for oxygen reduction. PMID- 19791348 TI - Electro-oxidation of carbon monoxide and methanol on bare and Pt-modified Ru(1010) electrodes. AB - The activity towards CO and methanol electrooxidation of bare and platinum modified Ru(1010) surfaces has been investigated. The structure/morphology and composition of the modified surfaces were characterized using electron diffraction techniques (LEED, RHEED) and Auger spectroscopy. The bare Ru(1010) surface exhibits a higher catalytic activity towards CO electrooxidation than the Ru(0001) surface due to the lower oxidation potential of the former surface. The early stages of surface oxidation lead to disordering of the surface and further enhancing of the electrocatalytic activity. Electrodeposition of Pt on Ru(1010) leads to epitaxial growth via a Volmer-Weber growth mode. The Pt clusters grow preferentially with the (311) plane parallel to the substrate surface with (011) rows in the layers in contact with the substrate compressed by about 3% with respect to bulk Pt, in order to match with the (1210) rows of the Ru(1010) surface. This compression leads to enhanced catalytic activity towards CO oxidation for thin Pt deposits whereas for large deposited Pt particles the dominating factor for the catalytic enhancement is the higher concentration of surface defects. On the other hand, in the case of methanol oxidation, the dominant factor in determining the catalytic activity is the concentration of adjacent Pt-Ru sites, although surface defects play an important role in the methanol dehydrogenation steps. PMID- 19791349 TI - Missing pieces of the puzzle or about some unresolved issues in solid state chemistry of alkali metal aluminohydrides. AB - The paper discusses some unresolved issues in the solid state chemistry of alkali metal aluminohydrides (alanates) relevant to high-capacity hydrogen storage. Analysis of experimental data available in chemical and materials science literature suggests a one-step mechanism for the thermal decomposition of both pure and Ti-doped aluminohydrides. Most likely, the presence of a titanium hydride phase in the catalyst is responsible for the catalytic effect of Ti additives. Furthermore, ball-milling promotes chemical and phase transformations of solid alanates by enhancing mass transfer in the material and creating high pressure spots where pressure-driven chemical reactions can take place. PMID- 19791350 TI - Photocatalytic hydrogen production from water-methanol mixtures using N-doped Sr2Nb2O7 under visible light irradiation: effects of catalyst structure. AB - Nitrogen-doped perovskite type materials, Sr2Nb2O7-xNx (0, 1.5 < x < 2.8), have been studied as visible light-active photocatalysts for hydrogen production from methanol-water mixtures. Nitrogen doping in Sr2Nb2O7 red-shifted the light absorption edge into the visible light range and induced visible light photocatalytic activity. There existed an optimum amount of nitrogen doping that showed the maximum rate of hydrogen production. Among the potential variables that might cause this activity variation, the crystal structure appeared to be the most important. Thus, as the extent of N-doping increased, the original orthorhombic structure of the layered perovskite was transformed into an unlayered cubic oxynitride structure. The most active catalytic phase was an intermediate phase still maintaining the original layered perovskite structure, but with a part of its oxygen replaced by nitrogen and oxygen vacancy to adjust the charge difference between oxygen and doped nitrogen. These experimental observations were explained by density functional theory calculations. Thus, in Sr2Nb2O7-xNx, N2p orbital was the main contributor to the top of the valence band, causing band gap narrowing while the bottom of conduction band due to Nb 4d orbital remained almost unchanged. PMID- 19791351 TI - Comment on "Entropy/enthalpy compensation: hydrophobic effect, micelles and protein complexes" by E. Fisicaro, C. Compari and A. Braibanti, Phys. Chem. Chem. Phys., 2004, 6, 4156. PMID- 19791352 TI - Spectroscopy and dynamics of radicals, clusters and ions. PMID- 19791353 TI - Purely electronic zero-phonon lines in optical data storage and processing. AB - Spectroscopies of matrix isolated species and impurity activated solids are close relatives. Both are among the well developing chapters of solid state spectroscopy and optics. In this paper I am trying to give very brief overview what has been achieved in science and applications of impurity activated solids based on zero-phonon lines (ZPLs) in optical data storage and processing. I would like to show that the latter comprises via persistent spectral hole burning time and-space domain holography in a certain meaning also the "stopping of light". ZPLs are beginning to play a role in the approaches to optical quantum computing. PMID- 19791354 TI - Thermal conductivity of tetrahydrofuran hydrate. AB - The thermal conductivity of tetrahydrofuran hydrate has been measured in the temperature region 2-220 K by the steady-state potentiometric method. The temperature dependence of the thermal conductivity exhibits behavior typical of amorphous substances. It is shown that above 100 K the mean free path of the phonons is considerably smaller than the lattice parameter and is no longer dependent on temperature. PMID- 19791355 TI - Matrix-isolation pyrolysis investigation of mercapto-functionalized 1,3,4 thiadiazoles: thermal stability of thiadiazole lubricant additives. AB - A series of high-vacuum thermolysis experiments with alkyldithio thiadiazoles was performed between ambient temperature and 900 degrees C to investigate the thermal stability of thiadiazole type lubricant additives. The thermolysis products were trapped by matrix-isolation techniques and characterized by IR spectroscopy. Thermolysis of 2-(tert-butyldithio)-5-methyl-,3,4-thiadiazole (TB1) gave 2-methylpropene, isothiocyanic acid (HNCS), 2-mercapto-5-methyl-1,3,4 thiadiazole (McMT), hydrogen cyanide (HCN), carbon disulfide (CS2), acetonitrile (CH3CN), and elemental sulfur S(x) [x = (2), 4, 6, 8]. A decomposition mechanism is discussed explaining the temperature-dependent composition of product mixtures, and a general precursor concept for organosulfur type anti-wear additives is presented. PMID- 19791356 TI - Infrared absorption spectroscopy of diacetylene ions trapped in solid argon. AB - The C4H2+ diacetylene radical cation has been generated in a pulsed jet electrical discharge through both a diacetylene/argon mixture and an acetylene/argon mixture. The product mixture was trapped on a 12 K cryostat window and studied via Fourier transform infrared absorption spectroscopy. The diacetylene cation was also produced via low energy electron bombardment of an effusive C4H2/Ar beam. Two new infrared bands at 3201.6 and 1827.9 cm(-1) have been identified as vibrations of the diacetylene cation, viz the v4 (sigmau) (C-H stretching) and the v5(sigmau) (C[triple bond]C stretching) modes, respectively. Geometry optimization and harmonic frequency calculations, carried out at various spin unrestricted levels (B3LYP, CCSD(T)) for spin doublet structures, indicate that, in its electronic ground state X2pi(g), the C4H2+ cation is linear. Three additional new bands at 2957.5, 1693.8 and 594.5 cm(-1) have been tentatively assigned to the C-H stretching, C[triple bond]C stretching and C[triple bond]C-H (in-plane) bending modes, respectively, of the nonlinear diacetylene anion (C4H2 , X2B(u)). PMID- 19791357 TI - Rotational isomerization of small carboxylic acids isolated in argon matrices: tunnelling and quantum yields for the photoinduced processes. AB - The quantum yields for internal rotation around the C-O bond induced by excitation of the first overtone of the hydroxyl stretching mode in formic, acetic, and propionic acids isolated in solid Ar are comparatively discussed. The tunnelling kinetics for isomerization from the higher energy arrangement of the carboxylic group (cis) to the lower energy arrangement (trans) in this series of compounds is also analysed. Finally, the quantum yield for the C(alpha)-C isomerization in propionic acid was investigated and, in contrast with the C-O isomerization, shown to be probably sensitive to the local matrix morphology. PMID- 19791358 TI - Mercury dihydride forms a covalent molecular solid. AB - Atomic mercury in solid hydrogen reacts when subjected to mercury arc irradiation to form the linear HgH2 molecule with strong IR absorptions at 1902.3 and 772.8 cm(-1). Annealing leads to HgH2 dimer and trimer and warming above 7 K allows hydrogen to sublime and solid HgH2 to form. This covalent molecular solid is characterized by strong IR absorptions at 1802, 739 and 673 cm(-1) and by decomposition at 150-170 K. Solid para-hydrogen gives sharper HgH2 absorptions at 1905.8 and 774.3 cm(-1) and forms a more amorphous HgH2 solid with bands at 1813, 741 and 683 cm(-1). PMID- 19791359 TI - Coherent phonon dynamics: Br2 in solid Ar. AB - A long lasting coherent oscillation with a sharp frequency of f(p) = 2 THz is observed in fs pump probe spectra for B <-- X excitation of Br2 in solid argon. It exactly matches the frequency of a coherent zone boundary phonon (ZBP) of the Ar environment. The ZBPs have a vanishing group velocity v(g), thus they stay in the vicinity of the chromophore. They originate from a displacive excitation of coherent phonons (DECP) initiated in the electronic B <-- X transition, because neither f(p) nor the phase of the oscillation do depend on the B state vibrational dynamics. A model calculation shows that an expansion of the electronic density in going from the electronic ground state X to the B state kicks the Ar atoms in the Br2 vicinity. In addition, a group of Ar atoms in the (100) plane is decoupled from the intramolecular dynamics afterwards. The ZBP modulates the solvation energy of the terminal charge transfer states used in the probe transition from the B state and thus the detection sensitivity. The contrast is enhanced by probing the B state wave packet with the cutting edge of the probe window. This is in full accordance with a study for I2 : Kr. PMID- 19791360 TI - Infrared spectrum of the NH4-d(n)+ cation trapped in solid neon. AB - The NH4+ cation has been stabilized in solid neon in sufficient concentration for the identification of both of its infrared-active vibrational fundamentals, which appear within a few wavenumbers of the gas-phase band centers. Systematic alteration of the concentrations and positions of introduction of NH3 and H2 in the discharge sampling experiments demonstrated that the highest yield of NH4+ resulted when both the NH3 and the H2 were introduced downstream from a discharge through pure neon. In this configuration, each of these molecules can be ionized by excited neon atoms and their resonance radiation (16.6 eV to 16.85 eV), but fragmentation is minimized. Both infrared-active vibrational fundamentals of ND4+ and several fundamentals of each of the partially deuterium-substituted isotopomers of NH4+ were also identified. Evidence is presented for complexation of NH4+ with an H atom or with one or more H2 molecules. PMID- 19791361 TI - H6+ in irradiated solid para-hydrogen and its decay dynamics: reinvestigation of quartet electron paramagnetic resonance lines assigned to H2-. AB - The quartet electron paramagnetic resonance (EPR) lines observed in gamma- and X ray irradiated solid para-H2, which have previously been assigned to H2-, are reinvestigated. We have reassigned the quartet lines to H6 rather than H2- mainly due to comparison of experimentally obtained EPR parameters to theoretical results. Based on the new assignment, trapping site, rotation, ortho-para conversion, quantum diffusion and isotope effect of H+ have been reinterpreted by the precise reanalysis as follows. The H6+ ion is composed of the collinearly aligned H2+ core at the center and two H2 rotors at both ends, occupies a single substitutional site, and has a precession motion around a crystalline axis with the angle of approximately 57 degrees. The ortho-para conversion of H2+ core of H6+ is completed within the time-scale of hours, whereas ortho-H2 molecules near H6+ convert much faster. H6+ diffuses quantum mechanically by the repetition of H6+ + H2 --> H2 + H6+ reaction. The diffusion terminates by the reaction, H6(+) + HD --> H5D(+) + H2, with a HD impurity contained in the para-H2 sample at natural abundance. Finally, we will propose a possible reason why H6+ is produced instead of H3+ in the irradiated solid H2. PMID- 19791362 TI - Creation of permanent lattice defects via exciton self-trapping into molecular states in Xe matrix. AB - Electronic excitation is shown to affect the structural properties of the Xe matrix at low temperatures. The lattice defect creation was studied using the selective vacuum ultraviolet (VUV) spectroscopy methods. The samples were excited by synchrotron radiation in the range of excitonic absorption. The temporal evolution of the intensity distribution in the band of molecular type self trapped exciton luminescence was analyzed. A direct evidence for the creation and accumulation of point lattice defects in solid Xe via the excitonic mechanism was obtained for the first time. The model of permanent lattice defect creation and transformation is discussed. PMID- 19791363 TI - Vibrational dissipation and dephasing of I2 (v = 1-19) in solid Kr. AB - Time- and frequency-resolved coherent anti-Stokes Raman scattering is used to carry out systematic measurements of vibrational dephasing on I2 (v = 1-19) isolated in solid Kr, as a function of temperature, T = 7-45 K. The observed quantum beats, omega(v', v") allow an accurate reconstruction of the solvated molecular potential, which is well represented by the Morse form: omega(e) = 211.56 +/- 0.14, omega(e)chi(e) = 0.658 +/- 0.006. Near T = 7 K, the coherence decay rates gamma(v,0) become independent of temperature and show a linear v dependence, indicative of dissipation, which must be accompanied by the simultaneous creation of at least four phonons. At higher temperatures, the T dependence is exponential and the v-dependence is quadratic, characteristic of pure dephasing via pseudo-local phonons. A normal mode analysis suggests librations as the principle modes responsible for pure dephasing. PMID- 19791364 TI - Unraveling the possible isomers of CH4CN+ and CH2CN+ through FT-IR matrix isolation spectroscopy of mass-selected ions and DFT theory. AB - The positive molecular ions of astrophysical interest--protonated and fragment ions of acetonitrile are investigated by means of mass-selective deposition in Ne matrices and FT-IR spectroscopy in the region of 500-4000 cm(-1). Ionic species are generated by electron impact ionization with parallel fragmentation and) ion molecule reactions of an acetonitrile precursor, CH3CN (CD3CN). The ions are deposited in Ne matrices together with an excess of electrons to prevent a buildup of space charge. Spectral assignments are supported by deuterium isotopic measurements and by density functional (DFT/B3LYP) computations. This work resulted in the spectral characterization of protonated acetonitrile CH3CNH+, as well as the identification of three cationic cyanomethyl C2H2N+ isomers: H2CCN+, H2CNC+ and HCCNH+. Although the spectral assignments for two ionic isomers, H2CCN+ and H2CNC+, are somewhat tentative, experimental results give rather strong evidence for the occurrence of the linear HCCNH+ ion. PMID- 19791365 TI - Synchrotron photoionization measurements of combustion intermediates: photoionization efficiency and identification of C3H2 isomers. AB - Photoionization mass spectrometry using tunable vacuum-ultraviolet synchrotron radiation is applied to the study of C3H2 Sampled from a rich cyclopentene flame. The photoionization efficiency has been measured between 8.5 eV and 11.0 eV. Franck-Condon factors for photoionization are calculated from B3LYP/ 6-311++ G(d,p) characterizations of the neutral and cation of the two lowest-energy C3H2 isomers, triplet propargylene (HCCCH, prop-2-ynylidene) and singlet cyclopropenylidene (cyclo-HCCCH). Comparison of the calculated Franck-Condon envelopes with the experimental photoionization efficiency spectrum determines the adiabatic ionization energy of triplet propargylene to be (8.96 +/- 0.04) eV. Ionization energies for cyclopropenylidene, propargylene and propadienylidene (H2CCC) calculated using QCISD(T) with triple-zeta and quadruple-zeta basis sets extrapolated to the infinite basis set limit are in excellent agreement with the present determination of the ionization energy for propargylene and with literature values for cyclopropenylidene and propadienylidene. The results suggest the presence of both propargylene and cyclopropenylidene in the cyclopentene flame and allow reanalysis of electron ionization measurements of C3H2 in other flames. Possible chemical pathways for C3H2 formation in these flames are briefly discussed. PMID- 19791366 TI - Electronic spectroscopy and photodissociation dynamics of Co(2+)-methanol clusters: Co2+ (CH3OH)n (n = 4-7). AB - Solvated cluster ions Co2+ (CH3OH)n (n = 4-7) have been produced by electrospray and studied using photofragment spectroscopy. There are notable differences between the photodissociation spectra of these complexes and the analogous water complexes. Co2+ (CH3OH)6 absorbs significantly more strongly than Co2+ (H2O)6. The photodissociation spectra of Co2+ (CH3OH)n (n = 4, 5 and 6) are very similar, which suggests that they share the Co2+ (CH3OH)4 chromophore, with additional solvent molecules in the second shell. In contrast, our earlier studies indicate that Co2+ (H2O)6 is six coordinate, and its spectrum is significantly different from that of Co2+ (H2O)4. The larger clusters Co2+ (CH3OH)n (n = 5-7) dissociate by simple loss of one or more solvent molecules. Larger clusters tend to lose more solvent molecules, especially at higher photon energies. As with the corresponding water cluster, Co2+ (CH3OH)4 photodissociates by proton transfer through a salt-bridge intermediate. This is accompanied by a modest kinetic energy release of 170 kJ mol(-1) and occurs with a lifetime of 145 ns. PMID- 19791367 TI - The VUV photochemistry of radicals: C3H3 and C2H5. AB - The VUV photochemistry of the radicals propargyl, C3H3, and ethyl, C2H5, is investigated using synchrotron radiation. The radicals are produced by flash pyrolysis from propargyl bromide and ethyl iodide, respectively. It is shown that dissociative photoionisation of propargyl is associated with loss of a H-atom, leading to formation of c-C3H2+. The process sets in between 12.5 and 13 eV, in agreement with computations. The alternative pathway, leading to C3H(+) + H2 is only tentatively observed at energies above 15.5 eV. The onset for dissociative photoionisation of ethyl according to C2H5 --> C2H3(+) + H2 is observed at 11.6 eV, roughly 1 eV higher than expected from ab initio calculations. In addition we monitor the hitherto unobserved three-body dissociative ionisation of the precursor molecules. The process C2HsI --> C2H3 + H2 + I sets in above 12.7 eV, the dissociative ionisation of C3H3Br --> C3H+ + H2 + Br above 15 eV. PMID- 19791368 TI - Fluorine-substitution induced switching of dissociation patterns of C6H4*+ produced by photoelimination of MgF2 from the complexes of mg*+ (multifluorobenzene). AB - Complexes of fluorinated benzenes (o-C6H4-nF2+n) and Mg*+ are subjected to ultraviolet photodissociation (260-340 nm), producing efficiently benzyne radical cations (C6H4-nFn*+) besides Mg*+ and MgF+. We show that the consecutive dissociation of C6H4-nFn*+ follows the [C4(+) + C2] pattern exclusively for n < or = 2 after the parent complexes absorb one or two photons. However, the dissociation pattern is switched to [C5(+) + C1] and [C1 + C5] for n > or = 3. In particular, upon two-photon absorption at 340 nm by the complexes of Mg*+ (C6HF5) (1) and Mg*+ (C6F6) (2), photoproducts of CF+, C5H+, and C5HF*+ from C6HF3*+ and CF+, C5F+, C5F2*+, and C5F3+ from C6F4*+ are detected, respectively. Theoretical calculations are used to explain the switching of the dissociation patterns induced by the fluorine substitutions. It was found that the formation of C5+ + C1 is energetically more favorable than that of C4(+) + C2 from C6HF3*+ and C6F4*+ and of C1(+) + C5. Except for C5H2F(+) + CF, all the channels of [C5(+) + C1] and [C1(+) + C5] are energetically less favorable than those of [C4(+) + C2] from C6H3F*+ and C6H2F2*+. In most cases, the calculated results agree well with the experimental observations. PMID- 19791369 TI - Theoretical study of the photodetachment spectrum of the methylene amidogene anion (H2CN-). AB - The excited states of methylene amidogen (H2CN) have recently been studied extensively both by experiment and theory. However, the assignment of absorption spectra is in disagreement with the theoretical analysis. In the present study a theoretical photoelectron detachment spectrum is predicted which shows that a corresponding experiment could be suitable to decide whether the theoretical or the experimental assignment is correct. To this end, the electron affinity of H2CN was calculated very accurately. Vertical and adiabatic electron detachment energies were calculated by complete active space and multi-configuration self consistent field (CASSCF and MCSCF) as well as by multireference configuration interaction (MRCI) methods. The MRCI wave functions were utilized to compute electronic detachment probabilities. Beyond the radical ground state, three significant detachments are found in the region around 4-5 eV and a further weak detachment at roughly 8.4 eV. Vibrational intensities were determined for the four lowest electronic states of the radical and vibrationally resolved photodetachment spectra were constructed. The predicted spectra show that the bands of the first 2B1 and 2A1 states are clearly distiguishable while the band for the nearby second 2B1 state is weak and strongly overlapping with the 2A1 manifold. PMID- 19791370 TI - Ab initio electronic structure of thymine anions. AB - Dipole-bound and valence-bound anions of thymine were characterised by means of state-of-the-art ab initio calculations. The dipole-bound anion of thymine is both vertically and adiabatically stable with adiabatic electron affinity of 51 meV. The valence-bound anion is also adiabatically stable, albeit only marginally. Its vertical stability of 501 meV is, however, higher than that of the dipole-bound anion. All these values agree well with experimental findings. PMID- 19791371 TI - Experimental and theoretical investigation of the A 3pi-X 2sigma- transition of NH/D-Ne. AB - A study of NH/D-Ne was undertaken to investigate the structure of this complex and examine the ability of high-level theoretical methods to predict its properties. The A 3pi-X 3sigma- transition was characterized using laser induced fluorescence measurements. Results from theoretical calculations were used to guide the interpretation of the spectra. Two-dimensional potential energy surfaces were calculated using second-order multireference perturbation theory with large correlation consistent basis sets. The potential energy surfaces were used to predict the ro-vibronic structure of the A-X system. Calculated ro vibronic energy level patterns could be recognized in the spectra but quantitative discrepancies were found. These discrepancies are attributed to incomplete recovery of the dynamical correlation energy. PMID- 19791372 TI - Photoelectron-photofragment coincidence study of OHF-: transition state dynamics of the reaction OH + F --> O + HF. AB - A photoelectron-photofragment coincidence (PPC) study of the dissociative photodetachment of OHF at a photon energy of 4.80 eV is presented. The correlated electron kinetic energy (eKE) and translational energy release (E(T)) into the O + HF + e- products yield information on the potential energy surface close to the transition state of the neutral reaction OH + F --> O + HF. The correlation spectrum shows two different features in the energetically allowed O + HF product channel: (a) diagonal ridges, resulting from direct dissociative photodetachment (DPD) and (b) areas with higher E(T) in the neutral fragments from nonadiabatic dissociation. The total translational energy spectrum (E(TOT) = eKE + ET) reveals a vibrationally resolved product state distribution. These results are discussed in the context of recent theoretical studies of the dissociative photodetachment of OHF-. PMID- 19791373 TI - Electron affinities of the radicals derived from cytosine. AB - Theoretical studies have been carried out to investigate the electron affinities (EAs) of five radicals derived from cytosine by removing a hydrogen atom (C( H)*), using carefully calibrated computational methods. Significant structural differences are predicted between cytosine, its five radicals and the five corresponding anions. The largest bond distance differences between the radical and its analogous anion are 0.05 angstroms. The theoretical EAs (predicted using carefully calibrated methods) for the five cytosine radicals range from 2.22 eV to 3.00 eV. Among these the N-centred radical 2 has the largest adiabatic electron affinity (EA(ad) = 3.00 eV), and the carbon-centred radical 8 has the smallest (2.22 eV). These values are much larger than EA(ad) for the neutral closed-shell cytosine molecule. The largest EA(ad) value predicted for the cytosine radical isomers (C(-H)*) is comparable to those for radicals related to other nucleoside bases. The ordering for the four DNA bases is EA(T(-H)*) = 3.46 > EA(A)-(-H)*) = 3.26 > EA(C(-H)*)= 3.00 > EA(G(-H)*) = 2.99 eV. PMID- 19791374 TI - A kinetics and mechanistic study of the atmospherically relevant reaction between molecular chlorine and dimethyl sulfide (DMS). AB - A gas-phase kinetics study of the atmospherically important reaction between Cl2 and dimethyl sulfide (DMS) Cl2 + CH3SCH3 --> products (1) has been made using a flow-tube interfaced to a photoelectron spectrometer. The rate constant for this reaction has been measured at 1.6 and 3.0 torr at T = (294 +/- 2) K as (3.4 +/- 0.7) x 10(-14) cm3 molecule(-1) s(-1). Reaction (1) has been found to proceed via an intermediate, (CH3)2SCl2, to give CH3SCH2Cl and HCl as the products. The mechanism of this reaction and the structure of the intermediate were investigated using electronic structure calculations. A comparison of the mechanisms of the reactions between Cl atoms and DMS, and Cl2 and DMS has been made and the relevance of the results to atmospheric chemistry is discussed. PMID- 19791375 TI - Energy transfer in the OH A2sigma+ state: the role of polarization and of multi quantum energy transfer. AB - Energy transfer in the excited state of molecules including quenching, rotational and vibrational energy transfer, and polarization scrambling is one of the major factors which limit the accuracy of laser-induced fluorescence (LIF) measurements. In this contribution, we present time-, wavelength-, and polarization-resolved spectra of OH in a stoichiometric H2/air flame at atmospheric pressure. Emphasis is placed on the investigation of the role of polarization effects and of multi-quantum vibrational energy transfer on fluorescence spectra originating from the OH A2sigma+ state. Results are compared to simulations using a rate-equation model (LASKIN) developed in our group. PMID- 19791376 TI - A theoretical investigation of the vibrational states of HCO2- and its isotopomers. AB - Making use of the coupled cluster variant CCSD(T) and the aug-cc-pVQZ basis set a six-dimensional (6D) potential energy surface has been calculated for HCO2-, a fundamental organic anion. Therefrom, a variety of vibrational term energies and wavefunctions has been obtained by means of the discrete variable representation in an approach termed DVR(6). Calculated wavenumbers of the fundamentals of HCO2- and DCO2- agree with recent experimental values from neon matrix isolation IR spectroscopy within 15 cm(-1). The out-of-plane bending vibrations v4 are predicted at 1030 and 894 cm(-1). Moderately strong Fermi resonance interaction is calculated between vibrational states v1 and 2v4 of DCO2-. Excellent agreement with experiment (differences less than 0.7 cm(-1) is observed for the 13C and 18O isotopic shifts. Accurate ground-state rotational constants are predicted for eight different isotopomers of the formate ion and the dissociation process HCO2- --> H- + CO2 is investigated in some detail, with the dissociation energy D0 predicted to be 216 kJ mol(-1). PMID- 19791377 TI - Gas phase electronic spectra of two C5H5 radical isomers. AB - Gas phase electronic spectra of two C5H5 radical isomers have been observed in the 440-470 nm spectral region. The technique was a mass selective resonant two color two-photon ionization coupled to a supersonic plasma source. Structures, relative energies and vertical electronic transition energies of six isomers of C5H5 have been calculated. Based on an analysis of the rotational profiles of the observed bands and theoretical calculations, the spectra are assigned as the A 2A" <-- X 2A" electronic transition of isomer 1 and A 2A2 X 2B1 of 6 with origin band at 461.8 nm and 456.1 nm, respectively. Isomer 1, 1,3-vinylpropargyl, has Cs symmetry, while 6, a planar zig-zig chain with one hydrogen on each carbon, has C2v symmetry. PMID- 19791378 TI - Photodissociation and photoionization of pyrrole following the multiphoton excitation at 243 and 364.7 nm. AB - Photoelectron imaging and time of flight mass spectrometry are used to study the multiphoton ionization and dissociation of pyrrole and its cation following excitation at 243 nm and at 364.7 nm. Our results confirm the 8.2 eV ionization potential of pyrrole and the 9.2 eV ionization threshold for forming the 2B1 first excited state of the cation. Prompt photolysis of the N-H bond in neutral pyrrole following one-photon excitation to its 1 1A2 neutral excited state is inferred from analysis of the two-photon photoelectron spectrum recorded at 243 nm, confirming the findings of recent translational spectroscopy studies. Facile dissociation of the pyrrole cation is also observed following excitation at 243 nm; analysis of the fragment cations indicates the operation of a complex dissociation mechanism involving dual bond fission and possible migration of the H atom originally bonded to the nitrogen heteroatom. PMID- 19791379 TI - VUV photodissociation of ammonia: a dispersed fluorescence excitation spectral study. AB - NH2 and NH transitions were identified in dispersed fluorescence spectra obtained by VUV excitation of NH3 at nine different energies between 8.266 and 15.498 eV. Fluorescence excitation (FEX) spectra between 6 and 15 eV were measured at seven specific emission wavelengths for these species. This extends the usual 11.7 eV upper limit of NH3 FEX spectra. Among the results of our work are the following: (i) a clarification of the assignment of the emission carriers; (ii) analysis of the FEX spectra of NH2(A 2A1 --> X 2B1) emission and assignment of the features to members of the npe' <-- 1a"2, nde" <-- 1a"2, nsa'1 <-- 1a"2 and nda'1 <-- 1a"2 Rydberg series transitions of NH3; (iii) new information on photodissociation processes leading to formation of NH2(A 2A1) and of NH in various excited states, in particular concerning the formation of NH (A 3pi) at 8.266 eV by dissociation of the a 3A"2 state of NH3, the existence of a potential barrier of 360 +/- 70 meV in the dissociation to form NH (c 1pi) at 9.85 eV and its formation from a non-planar state above 11.3 eV; (iv) information pertaining to the heat of formation of the NH radical, which we determine as deltaH(f,0) degrees (NH) = 3.70 +/- 0.01 eV, and to the thermochemical limits of the dissociation reactions of NH3. PMID- 19791380 TI - Hypervalent ammonium radicals. Competitive N-C and N-H bond dissociations in methyl ammonium and ethyl ammonium. AB - The title hypervalent ammonium radicals were investigated by neutralization reionization mass spectrometry and quantum chemical calculations. Methyl ammonium (1) forms a small fraction of metastable radicals from isotopomers CH3ND3 (la) and CD3NH3 (1b) when these are produced by femtosecond electron transfer to vibrationally excited precursor cations. The branching ratios for dissociations of the N-C and N-(H,D) bonds in 1 favor the latter, k(N-C)/k(N-H) = 0.39. The experimental results are in accord with ab initio/RRKM calculations that quantitatively reproduce the branching ratios for dissociations of 1. A small fraction of high-energy 1 dissociates to form ammonium methylide, -CH2NH3+. Ethyl ammonium (2) and its CH3CH2ND3 isotopomer (2a) dissociate completely on the microsecond time scale. The branching ratios for dissociations of the N-C and N (H,D) bonds favor the former, k(N-C)/k(N-H) = 2.04. This result is incompatible with the calculated potential energy surface of the ground doublet electronic state in 2 and is attributed to the formation and dissociations of excited electronic states. PMID- 19791381 TI - Multiphoton ionization and oxidation processes of Mg-ammonia clusters. AB - Multiphoton ionization and oxidation processes of ammoniated magnesium clusters are investigated by the multiphoton ionization method with an intense femtosecond laser. In the photoionization of mass-selected Mg+ (NH3)n, evaporation dominates at lower laser intensity, while the oxidation reaction to produce H-atom elimination products, MgNH2+ (NH3)m, becomes predominant at higher intensity. In addition to these fragment ions, doubly-charged ions are observed for n > or = 2 at the laser intensity higher than 10(12) W cm(-2). We also examined the femtosecond pump probe experiments for Mg+ (NH3)4 by monitoring these reaction products. The lifetime of the first excited state is determined as 0.8 ps from the temporal profile of MgNH2+ (NH3)m. On the other hand, the time profile of the evaporation products exhibits a bleaching of the absorption, which gives the recovery time of the initial state as 1.2 ps. Multiphoton excitation of Mg(NH3)n with the femtosecond laser at 800 nm gives doubly-charged ions with n > 3 in addition to singly-charged cluster ions and H-atom elimination products such as MgNH2+ (NH3)m. The absence of small doubly-charged ions is ascribed to a charge reduction reaction followed by Coulomb explosion. On the basis of these results, the dynamics of the solvation and oxidation reaction processes of Mg(NH3)n is discussed. PMID- 19791382 TI - Adsorption of carbon monoxide on smaller gold-cluster anions in an atmospheric pressure flow-reactor: temperature and humidity dependence. AB - In the absence of moisture and at room temperature, the activity and saturation of CO on gold cluster anions, Au(N)-, are known to be highly dependent on the size of the cluster. Small Au(N)- clusters (N = 2,3) showed no adsorption activity, and the saturation CO adsorption values did not increase proportionately to cluster size or area. Here, we report on the effects of water vapor and temperature on the ability of Au(N)- clusters to adsorb CO in a high pressure, fast-flow reactor. In contrast to all earlier reports, our results using this method show that smaller gold-cluster anions bind single and multiple CO groups at ambient temperature and above. In particular, species previously unseen at room temperature, corresponding to Au2(CO)-, Au3(CO) and Au4(CO)2, have been observed. Apparently, the presence of water vapor facilitates the adsorption of CO on the smaller clusters, possibly by aiding in the release of adsorption energy. As the number of studies concerning gold catalysis has continually increased over the past decade, these results provide important new information on the possible role of moisture in gold catalysis. PMID- 19791383 TI - Vibrational predissociation spectra and hydrogen-bond topologies of H+(H2O)9-11. AB - Vibrational predissociation spectra of protonated water clusters H+(H2O)n, n = 9 11, are presented. Examination of the spectra in the free-OH stretching region revealed predominance of a single absorption band at approximately 3690 cm(-1) for three-coordinate H2O acting as a double-proton-acceptor/single-proton-donor in the n = 11 cluster. In contrast, the intensity of the absorption band of two coordinate H2O acting as a single-proton-acceptor/single-proton-donor at approximately 3715 cm(-1) decreases with cluster size, and that of one-coordinate H2O acting as a single-proton-acceptor at approximately 3740 and approximately 3650 cm(-1) diminishes nearly entirely at n > 10 in the spectrum. To deduce the information about cluster temperature, we measured the spontaneous dissociation rates of the cluster ions inside an octopole ion trap and fitted the measured rate constants to an empirical Arrhenius equation. Temperatures in the range of 150 K were estimated for all H+ (H2O)9-11, suggesting that the thermal effect may populate the structures other than the true ground state. The results, combined with previously acquired spectra for H+ (H2O)5-8 (J.-C. Jiang, Y.-S. Wang, H.-C. Chang, S. H. Lin, Y. T. Lee, G. Niedner-Schatteburg and H.-C. Chang, J. Am. Chem. Soc., 2000, 122, 1398) and Monte Carlo simulations with the OSS2 model potential (L. Ojamlie, I. Shavitt and S. J. Singer, J. Chem. Phys., 1998, 109, 5547), show a systematic change in hydrogen-bond topology from tree-like, single-ring, multiple-ring to cage-like isomers (and their mixtures) as the cluster size increases from n = 5 to n = 11. PMID- 19791384 TI - Anharmonic vibrational spectroscopy calculations for (NH3)(HF) and (NH3)(DF): fundamental, overtone, and combination transitions. AB - In order to study the effects of hydrogen bonding on the spectroscopic properties of (NH3)(HF) and (NH3)(DF) complexes, vibrational spectra (including fundamental, overtone and combination transitions) were calculated using the vibrational self consistent field (VSCF) method. This ab initio VSCF method accounts for both one dimensional anharmonicity and pair-wise mode-mode couplings for all vibrational modes of the molecule, using points on the potential energy surface (at the MP2/TZP level of theory in this study). An analysis of the coupling strength shows surprisingly important coupling effects from pair-wise interactions not expected to be major. This indicates the benefits of including all pair-wise mode mode couplings for weakly bound systems. Hydrogen bonding induces approximately 20% red shifts for the HF and DF stretch frequencies. The corrections due to anharmonicity for these modes are -6% and -5%, respectively. The anharmonic corrections for the intermolecular stretch of (NH3)(HF) and (NH3)(DF) are each about -5%. The NH3 umbrella motion has virtually no anharmonic correction in the complex, whereas free ammonia experiences a -15% correction. Also, the closing motion as well as the opening motion is restricted. The 1 + 1 combination transition of the proton stretching and intermolecular stretching modes has remarkably large intensity, larger even than the intensities for the first overtone of the proton stretching modes. The anharmonic frequency for the fundamental HF stretch, 3268 cm(-1), is in good agreement with the experimental gas phase result, 3215 cm(-1). A comparison to solid rare-gas matrix data shows that the VSCF frequencies are a consistent improvement over the harmonic approximation. The experimental data also support the use of the MP2 level of theory for the associated electronic structure calculations. PMID- 19791385 TI - Acetylene trimerization on Ag, Pd and Rh atoms deposited on MgO thin films. AB - The acetylene trimerization on the group VIII transition metal atoms, Rh and Pd, as well as on Ag atoms supported on MgO thin films has been studied experimentally and theoretically. The three metal atoms with the atomic configurations 4d(8)5s1 (Rh), 4d10s0 (Pd) and 4d(10)5s1 (Ag) behave distinctly differently. The coinage metal atom silver is basically inert for this reaction, whereas Pd is active at 220 and 320 K, and Rh produces benzene in a rather broad temperature range from 350 to ca. 430 K. The origins of these differences are not only the different electronic configurations, leading to a weak interaction of acetylene with silver due to strong Pauli repulsion with the 5s electron but also the different stability and dynamics of the three atoms on the MgO surface. In particular, Rh and Pd atoms interact differently with surface defects like the oxygen vacancies (F centers) and the step edges. Pd atoms migrate already at low temperature exclusively to F centers where the cyclotrimerization is efficiently promoted. The Rh atoms on the other hand are not only trapped on F centers but also at step edges up to about 300 K. Interestingly, only Rh atoms on F centers catalyze the trimerization reaction whereas they are turned inert on the step edges due to strong steric effects. PMID- 19791386 TI - IR signature of (CO2)N clusters: size, shape and structural effects. AB - The structure of carbon dioxide aggregates is investigated by means of direct absorption IR specroscopy in the region of the antisymmetric stretching vibration v3. The (CO2)N particles are generated under dynamic (supersonic cooling in Laval nozzles) and static (collisional cooling cells) conditions over a broad mean size range (20 < N < 10(5)). The vibrational exciton approach is used to interpret the observed spectral features. The particles generated by supersonic cooling remain globular in shape even for the largest explored aggregate sizes (N approximately 10(5)), thus highlighting the absence of agglomeration between primary clusters under our jet conditions. This is in contrast to collisional cooling where the primary particles strongly agglomerate after a few seconds. The spectra for the larger particles (N > 10(4)) are well reproduced by the simulations if cuboctahedral or octahedral rather than spherical aggregate shapes are assumed. PMID- 19791387 TI - Photochemistry of Mcl(H2O)4, M = H, Li, Na clusters: finite-size models of the photodetachment of the chloride anion in salt solutions. AB - The covalent, zwitterionic and biradical forms of the MCl(H2O)4 (M = H, Li, Na) clusters have been investigated with density functional theory (DFT), time dependent DFT (TDDFT) and the second-order Moller-Plesset (MP2) method. The equilibrium geometries and force fields of the lowest electronic states have been determined with DFT and MP2; vertical electronic excitation energies have been calculated with TDDFT at the DFT geometries. It is shown that the excited states of the M+(H2O)4Cl- zwitterions are of the charge-transfer-to-solvent (CTTS) type. The molecular and electronic structures of the M(H2O)4Cl biradicals (M = Li, Na) have been characterized for the first time. The lowest electronic states of the biradicals are lower in energy than the CTTS excited states of the zwitterions, and therefore are photochemically accessible from the latter. The electronic absorption spectra of the biradicals are essentially identical with that of the hydrated hydronium radical, H30(H2O)3, and exhibit striking similarities with the spectral signatures of the hydrated electron in the liquid phase. It is argued that the photochemistry of the M+(H2O)3Cl- zwitterions represents a finite-size molecular model of the formation process of the hydrated electron via the photodetachment of the chloride anion in concentrated salt solutions. PMID- 19791388 TI - Reactions of nitric oxide on Rh6+ clusters: abundant chemistry and evidence of structural isomers. AB - We report the first results of a new instrument for the study of the reactions of naked metal cluster ions using techniques developed by Professor Bondybey to whom this issue is dedicated. Rh6+ ions have been produced using a laser vaporization source and injected into a 3 T Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometer where they are exposed to a low pressure (< 10(-8) mbar) of nitric oxide, NO. This system exhibits abundant chemistry, the first stages of which we interpret as involving the dissociative chemisorption of multiple NO molecules, followed by the liberation of molecular nitrogen. This yields key intermediates such as [Rh6O2]+ and [Rh6O4]+. The formation of the latter, after adsorption of four NO molecules, marks a change in the chemistry observed with further NO molecules adsorbed (presumably molecularly) without further N2 evolution until saturation is apparently reached with the [Rh6O4(NO)7]+ species. We analyse the data in terms of a simple 12-stage reaction mechanism, and we report the relative rate constants for each step. The trends in reactivity are assessed in terms of conceivable structures and the results are discussed where appropriate by comparison with extended surface studies of the same system. Particular attention is paid to the first step in the reaction (Rh6(+) + NO --> [Rh6NO]+) which exhibits distinctly bi-exponential kinetics, an observation we interpret as evidence for two different structural isomers of the Rh6+ cluster with one reacting more than an order of magnitude faster than the other. PMID- 19791390 TI - Reaction and solvation of sodium in hydrogen bonded solvent clusters. AB - The reactive scattering of water clusters (H2O)n, n < or = 160 and ammonia clusters (NH3)n, n < or = 250 with 1 to 60 of sodium atoms is investigated. The water and ammonia cluster beams, respectively, are created in a pure supersonic expansion and cross an atmosphere of sodium vapor in a pickup cell. The reaction products are detected by photoionisation close to the threshold and mass analysed in a reflectron time-of-flight mass spectrometer. At low pickup pressures, sodium doped water and ammonia clusters are detected which reflect the correct size distribution of the pure cluster beams. At larger pickup pressures many sodium atoms are captured. In the case of ammonia thereby finally pure sodium clusters are produced, and the initial ammonia cluster is completely evaporated by the heat of formation of the formed sodium clusters. The water clusters, in contrast, react with the captured sodium until pure, even numbered sodium hydroxide clusters Na(NaOH)m doped with one sodium atom and hydrogen molecules are formed. In this way the unique reaction mechanism observed and calculated for small systems is confirmed. The additional Na atom serves together with the solvent water molecules as catalyst for creating the reaction intermediate NaH. PMID- 19791389 TI - Hydrogen formation in the reaction of Zn+ (H2O)n with HCl. AB - Hydrated singly charged zinc cations Zn (H2O)n, n approximately 6-53, were studied by Fourier transform ion cyclotron resonance (FT-ICR) mass spectrometry. Black-body radiation induced dissociation results exclusively in sequential loss of individual water molecules. In the reaction of Zn+ (H2O)n with gaseous HCl, Zn is oxidized and hydrogen reduced when a second HCl molecule is taken up, leading to the formation of ZnCl+ (HCl)(H2O)n-m cluster ions and evaporation of atomic hydrogen together with m H2O molecules. The results are compared with earlier studies of Mg+ (H2O)n, for which hydrogen formation is already observed without HCl in a characteristic size region. The difference between zinc and magnesium is rationalized with the help of density functional theory calculations, which indicate a distinct difference in the thermochemistry of the reactions involved. The generally accepted hydrated electron model for hydrogen formation in Mg+ (H2O)n is modified for zinc to account for the different reactivity. PMID- 19791391 TI - Combined jet relaxation and quantum chemical study of the pairing preferences of ethanol. AB - The subtle trans-gauche equilibrium in the ethanol molecule is affected by hydrogen bonding. The resulting conformational complexity in ethanol dimer manifests itself in three hydrogen-bonded OH stretching bands of comparable infrared intensity in supersonic helium expansions. Admixture of argon or nitrogen promotes collisional relaxation and is shown to enhance the lowest frequency transition. Global and local harmonic frequency shift calculations at MP2 level indicate that this transition is due to a gauche-gauche dimer, but the predictions are sensitive to basis set and correlation level. Energetically, the homochiral gauche-gauche dimer is predicted to be the most stable ethanol dimer conformation. The harmonic MP2 predictions are corroborated by perturbative anharmonicity contributions and CCSD(T) energies. Thus, a consistent picture of the subtle hydrogen bond energetics and vibrational dynamics of the ethanol dimer is starting to emerge for the first time. PMID- 19791392 TI - Infrared photodissociation of (NO)n + x X cluster ions (n < or = 5). AB - Measurements of the infrared photodissociation pathways and spectra of size selected (NO)n +X complexes, for n in the range 2-5, have been carried out using a line-tuneable CO laser (photon energy 1600-1800 cm(-1)). X is one of Ar, Kr, Xe, O2, CO2, CH3Cl, CF4 or SF6. Two photoinduced fragmentation pathways have been monitored as a function of radiation wavelength: the loss of NO and the loss of X. The photofragmentation patterns and branching ratios are influenced by two factors: (i) the value of n; and to a lesser degree, (ii) the nature of the atom/molecule, X. A limited number of IR spectra have been recorded for the dimer, (NO)2+, in association with the rare gas atoms and CF4; for the remaining examples, the trimer, (NO)3+, appears to act as a stable core with a comparatively large infrared absorption cross-section at ca. 1720 cm(-1). PMID- 19791393 TI - Reaction mechanisms for size-dependent H loss in Mg+(H2O)n: solvation controlled electron transfer. AB - Mg+(H2O)n clusters ions are known to undergo a hydrogen loss reaction to produce (MgOH)+(H2O)n-1, when the cluster size n falls between 5 and 15. It indicates that the microscopic solvation environment has a strong effect on the reaction mechanisms, which have now been elucidated. Above n = 6, Mg+(H2O)n exists in the form of an ion pair, Mg2+(H2O)l...e-(H2O)n-l, and H+ is produced by the autoionization of H20, enhanced by the hydrolysis of Mg2+. Production of the H atom is due to a reductive half reaction H(+) + e --> H, with the electron being the solvated electron in the ion pair. The reaction barrier is reduced when the electron is in the first or second solvation shell, promoting the H loss reaction. As the number of H2O molecules increases, the electron moves beyond the third solvation shell and the reaction barrier increases significantly, which is responsible for the subsequent switch-off of H loss. It has been one of the important goals in cluster sciences to understand the microscopic correlation between solvation and chemical reactivity by in-depth study on clusters, which has now been achieved in the case of Mg+(H2O)n, linking electron solvation with reaction paths for electron transfer. PMID- 19791394 TI - Solvation of copper ions by imidazole: structures and sequential binding energies of Cu+(imidazole)x, x = 1-4. Competition between ion solvation and hydrogen bonding. AB - The sequential bond dissociation energies of Cu+(imidazole)x, where x = 1-4 are determined by analysis of the kinetic energy dependence of the collision-induced dissociation with Xe in a guided ion beam tandem mass spectrometer. In all cases, the primary and lowest energy dissociation channel observed is the endothermic loss of an intact imidazole molecule. The primary cross section thresholds are interpreted to yield 0 K and 298 K bond dissociation energies after accounting for the effects of multiple ion-neutral collisions, kinetic and internal energy distributions of the reactants, and dissociation lifetimes. To obtain model structures, vibrational frequencies, rotational constants and energetics for the Cu+(imidazole)x complexes and their dissociation products, density functional theory calculations at the B3LYP/6-31G* level are performed. Theoretical bond dissociation energies are determined from single point energy calculations at the B3LYP/6-311+G(2d,2p) level of theory using the B3LYP/6-31G* optimized geometries. Excellent agreement between theory and experiment is observed for the Cu+(imidazole)x complexes, where x = 1, 2 and 4. In contrast, theory systematically underestimates the strength of the binding in the Cu+(imidazole)3 complex. The ground state structures of the Cu+(imidazole), complexes and the trends in the sequential bond dissociation energies are explained in terms of stabilization gained from sd hybridization and hydrogen bonding interactions and destabilization arising from ligand-ligand repulsion. The trends in the binding of these complexes are also examined to provide insight into the structural and functional roles that histidine and other ligands play in the behavior of metalloproteins and metalloenzymes. PMID- 19791395 TI - Temperature variable ion trap studies of C3Hn+ with H2 and HD. AB - Hydrogenation and deuteration of C3+, C3H+, C3H2+ in collisions with H2 and HD has been studied from room temperature down to 10 K using a 22-pole ion trap. Although exothermic, hydrogenation of C3+ is rather slow at room temperature but becomes faster with decreasing temperature. In addition to the increasing lifetime of the collision complex this behavior may be caused by the floppy structure of C3+ and the freezing of soft bending modes below 50 K. For C3(+) + HD it has been shown that production of C3D+ is slightly favored over C3H+ formation. The controversy over which products are really formed in C3H(+) + H2 collisions and deuterated variants has a long history. Previous and new ion trap results prove that formation of C3H2(+) + H is not endothermic but rather fast, in contradiction to erroneous conclusions from flow tube experiments and ab initio calculations. In addition the reaction shows a complicated isotope dependence, most probably caused by the influence of zero point energies in entrance and exit transition states. For example hydrogen abstraction with HD is faster than with H2 while radiative association is slower. The most surprising result has been obtained for C3H(+) + HD. Here C3HD+ formation is over one hundred times faster than C3H2+. In addition to the details of the potential energy surface it may be that in this case an H-HD exchange reaction takes place via an open-chain propargyl cation intermediate (H2CCCH+). Reactions of C3H2+ and C3H3+ with H2 are very slow but, due to the unique sensitivity of the trapping technique, significant rate coefficients have been determined. The presented results are of fundamental importance for understanding the energetics, structures and reaction dynamics of the deuterated variant of the C3Hn+ collision system. They indicate that the previous quantum chemical calculations are not accurate enough for understanding the low energy behavior of the Cn,Hm+ reaction systems. The laboratory experiments are of essential relevance for the carbon chemistry of dense interstellar clouds, both for formation of small hydrocarbons and deuterium fractionation. PMID- 19791396 TI - MALDI-Fourier transform mass spectrometric and theoretical studies of donor acceptor and donor-bridge-acceptor fullerenes. AB - Fourier-transform ion cyclotron resonance (FTICR) mass spectrometric studies have been performed on donor-acceptor and donor-bridge acceptor fullerene-based systems. Matrix-assisted laser desorption/ionization (MALDI) was used for ion production; both the positive and negative ion modes were utilized. In addition, collision-induced dissociation (CID) experiments were carried out to study the movement of the charge (electron or hole) upon fragmentation. The experiments are complemented by ab initio theoretical calculations yielding both molecular orbital energies and electron density distributions. It was found that the theoretical electron density map predicted the experimentally observed fragmentation correctly in every case. Both the calculations and the MS experiments may be useful in studying these and related donor-acceptor systems in view of their use for charge separation and eventually, solar energy production. PMID- 19791398 TI - Consecutive fragmentations of the cubane-like zinc cluster [CH3Zn(O-i-C3H7)]4 upon electron ionization. AB - The sequential dissociations of the tetranuclear zinc cluster-ion [(CH3)3Zn4(O-i C3H7)4]+ obtained by dissociative electron ionization of neutral [(CH3)Zn(O-i C3H7)]4 are investigated by tandem mass spectrometry. After initial loss of a neutral (CH3)Zn(O-i-C3H7) unit to afford [(CH3)2Zn3(O-i-C3H7)3]+, hydrogen migration leads to the expulsion of neutral acetone concomitant with [(CH3)2Zn3(O i-C3H7)2(H)]+ as ionic fragment. Unimolecular dissociation of the latter gives rise to [(CH3)2Zn2(O-i-C3H7)]+ and neutral HZn(O-i-C3H7). As demonstrated by collisional ionization of the neutral product, in the fragmentation of the dinuclear cluster [(CH3)2Zn2(O-i-C3H7)]+ neutral CH3ZnH is formed, rather than the more stable fragments Zn + CH4. From the resulting mononuclear species CH3Zn(OC(CH3)2)+ acetone is eliminated to afford CH3Zn+ as a quasi-terminal fragment ion. PMID- 19791397 TI - Ne2+[II (1/2)u]: radiative decay and electronic predissociation. AB - Metastable fragmentation of neon dimer ions has been investigated by measuring and analyzing high resolution kinetic energy release distributions. Data were obtained by a modified MIKE (mass-analyzed ion kinetic energy) scan technique. Due to the high energy resolution it was possible to distinguish two different reaction mechanisms in the micros time regime which produce Ne+ ions with different kinetic energy distributions. Theoretical studies based on ab initio calculations of potential energy curves allowed the assignment of the reactions to specific electronic transitions in the excited Ne2+ ion. The unusual bimodal kinetic energy release distribution arises from competition between radiative and non radiative decay of the long-lived Ne2+ II(1/2)u state. PMID- 19791399 TI - Activation of CH4 by gas-phase Ni+ and the thermochemistry of Ni-ligand complexes. AB - The kinetic energy dependence of the reaction of Ni+ (2D) with methane has been studied using guided ion beam mass spectrometry. Formation of NiH+, NiCH2+ and NiCH3+ are all observed with thresholds near 2 eV, and NiCH+ is observed at higher kinetic energies. The dehydrogenation reaction is shown to proceed over a barrier in excess of the endothermicity by examining the reverse reaction of NiCH2(+) + D2. Collision-induced dissociation of NiCH2+ and NiCH4+ with Xe provides additional information on the products and reaction intermediates. Modeling of the endothermic reaction cross sections yields the 0 K bond dissociation energies (in eV) of D0(Ni( +)-H) = 1.60 +/- 0.08, D0(Ni(+)-CH) = 3.12 +/- 0.12, D0(Ni(+)-CH2) = 3.20 +/- 0.08, D0(Ni(+)-CH3) = 1.76 +/- 0.07, and D0(Ni(+)-CH4) = 1.00 +/- 0.05. The experimental thermochemistry is favorably compared with previous experimental results and density functional theory calculations (B3LYP), which also establish the electronic structures of these species and provide insight into the reaction mechanism. The results for Ni(+) are compared with those for the third-row transition metal congener Pt+ and the differences in behavior and mechanism are discussed. PMID- 19791401 TI - Conical intersections: A perspective on the computation of spectroscopic Jahn Teller parameters and the degenerate 'intersection space'. AB - We present a perspective on the computation and interpretation of force constants at points of symmetry-induced (Jahn-Teller) conical intersection. Our method is based upon the projection of the 'branching space' from the full (3N - 6) dimensional Hessian for each component of a degenerate electronic state. For Jahn Teller active molecules, this has the effect of removing the linear Jahn-Teller coupling from all but the interstate coupling and gradient difference vectors. The quadratic coupling constants are determined by the splitting of the harmonic vibrational frequencies within degenerate vibrational normal coordinates of the 'intersection space'. The potential energy surface topology along these normal modes is analogous to the Renner-Teller effect occurring in orbitally degenerate linear molecules. Our methodology gives a straightforward theoretical analysis of the various Jahn-Teller intersections and allows the determination of the seam curvature. Thus, we are in a position to compute the various Jahn-Teller coupling constants, in a particular coordinate system, and in addition to determine the nature of the high-symmetry Jahn-Teller geometry (i.e., minimum or saddle-point on the seam). We illustrate these concepts with various examples of different Jahn-Teller conical intersections in some small molecules. PMID- 19791400 TI - Elementary supramolecular chemistry in the gas phase: ligand exchange reactions of proton-bound clusters of aliphatic amides and diamides with amines. AB - The ligand exchange reactions of the proton-bound trimer [(DMF)2...H+...H2NCH3] of dimethylformamide (DMF) and methylamine and of proton-bound dimers [diamide...H+...amine] of three aliphatic primary diamides, succinic diamide, adipinic diamide, and maleic diamide, and of three tertiary diamides N,N,N',N' tetramethyl succinic diamide, N,N,N',N'-tetramethyl adipinic diamide, and N,N,N,N tetramethyl bis-endo-bicyclo[2.2.1]heptane-2,5-diamide (N,N,N,N'-tetramethyl bis endo-BCH-2,5-diamide) were investigated by FT-ICR spectrometry. The proton-bound clusters were generated in the external CI ion source of the instrument using the appropriate amine as the CI reagent and primary ionization of the CI gas by electron ionization. The ions were transferred to the FT-ICR cell for measuring the kinetics of the exchange reaction with a reactant base which was present at a constant background pressure in the cell. The trimer [(DMF)2...H...H2NCH3] displays fast exchange reactions with all amines used with exception of pyridine as well as with DMF and DMSO used as polar reactants. The proton-bound trimer shows a "role-specificity" of the components: the amine ligand is exchanged specifically by a more basic amine without observation of any intermediate, while the polar reactants substitute the two DMF ligands of the cluster in two reaction steps. Like proton-bound trimers, the proton-bound dimers [diamide...H+...amine] contain two amide groups interacting with a proton and an amine. In the case of n propylamine as amine ligand, exchange by a more basic amine is always efficient. However, clusters [diamide...H+...amine] containing trimethylamine show reduced reactivity, which is attributed to a steric hindrance of the proton transfer to the incoming base. Such steric effects can be maximized by generating proton bound dimers of N,N,N',N'-tetramethyl bis-endo-BCH-2,5-diamide with tertiary amines or amines containing bulky alkyl groups. Thus, the cluster [N,N,N',N' tetramethyl bis-endo-BCH-2,5-diamide...H+...di-isopropylamine] exhibits a small efficiency of only 0.35% for the exothermic exchange reaction with di-sec butylamine. The results are used to propose a solvation model for the structure of these proton-bound clusters, in which the ammonium group of the protonated amine is solvated by two amide groups. PMID- 19791402 TI - Stabilization of very rare tautomers of uracil by an excess electron. AB - We characterized valence-type and dipole-bound anionic states of uracil using various electronic structure methods. We found that the most stable anion is related to neither the canonical 2,4-dioxo nor a rare imino-hydroxy tautomer. Instead, it is related to an imino-oxo tautomer, in which the N1H proton is transferred to the C5 atom. This valence anion is characterized by an electron vertical detachment energy (VDE) of 1267 meV and it is adiabatically stable with respect to the canonical neutral by 3.93 kcal mol(-1). It is also more stable by 2.32 and 5.10 kcal mol(-1) than the dipole-bound and valence anion, respectively, of the canonical tautomer. The VDE values for the former and the latter are 73 and 506 meV, respectively. Another, anionic, low-lying imino-oxo tautomer with a VDE of 2499 meV has a proton transferred from N3H to C5. It is less stable than the neutral canonical tautomer by 1.38 kcal mol(-1). The mechanism of formation of anionic tautomers with the carbon C5 protonated may involve intermolecular proton transfer or dissociative electron attachment to the canonical neutral tautomer followed by a barrier-free attachment of a hydrogen atom to C5. The six member ring structure of anionic tautomers with carbon atoms protonated might be unstable upon an excess electron detachment. Indeed, the neutral systems resulting from electron detachment from anionic tautomers with carbon atoms protonated evolve along barrier-free decomposition pathways to a linear or a bicyclo structure, which might be viewed as lesions to RNA. Within the PCM hydration model, the low-lying valence anions become adiabatically bound with respect to the canonical neutral and the two most stable tautomers have carbon atoms protonated. PMID- 19791403 TI - Ground state and electronic spectrum of Cu(II) and Cu(III) complexes of N,N'-1,2 phenylenebis-2-mercaptoacetamide. AB - The electronic structure and the UV-vis spectrum of reduced and oxidized model systems of the N,N'-1,2-phenylenebis(2-mercapto-2-methylpropionamide) copper complex have been studied using a multiconfigurational quantum chemical method (CASSCF/CASPT2). The bonds between Cu and the two sulfur ligand atoms have a large covalent character in the oxidized Cu(III) form. As a result of the increased covalency, the effective charge on the Cu atom is actually smaller in the oxidized form. The electronic spectrum for both oxidation states of the complex is in agreement with the experiment for excitation energies and intensities showing that the theoretical description of the electronic structure is essentially correct. All bands that involve excitations from either Cu or S localized orbitals to the empty or half empty CuS antibonding orbital have been characterized. PMID- 19791404 TI - Coupling of ion and network dynamics in lithium silicate glasses: a computer study. AB - We present a detailed analysis of the ion hopping dynamics and the related nearby oxygen dynamics in a lithium metasilicate glass via molecular dynamics simulation. For this purpose we have developed numerical techniques to identify ion hops and to sample and average dynamic information of the particles involved. This leads to an instructive insight into the microscopic interplay of ions and network. It turns out that the cooperative dynamics of lithium and oxygen can be characterized as a sliding door mechanism. It is rationalized why the local network fluctuations are of utmost importance for the lithium dynamics. PMID- 19791405 TI - Electronic absorption spectrum of a nonlinear carbon chain: trans-C6H4+. AB - The 2Bg-X2Au transition of a nonlinear carbon chain trans-C6H4+, and trans-C6D4+, has been observed in the gas phase. The spectra were detected in the 580 nm region by direct absorption with a cavity ringdown technique through a supersonic planar discharge. Though the rotational structure is not resolved, the band profiles were analyzed using a "total spectral fitting" procedure using ground state constants calculated by the CASSCF and CASPT2 methods. The molecular constants in the upper state could thus be determined. PMID- 19791406 TI - Rotational isomers of hydroxy deuterated o- and m-cresols studied by ultraviolet high resolution experiments. AB - The laser induced fluorescence spectra of several torsional transitions of the S1 <-- S0 electronic transition were recorded for the hydroxy deuterated o- and m cresols. Both cis and trans rotamers were observed in a high resolution molecular beam experiment. The spectra were analyzed using a genetic algorithm assisted automatic assignment. The Hamiltonian used included rotational, torsional and rotation-torsion components. Both, high resolution rotationally resolved spectra and low resolution torsional frequencies, were combined to obtain the rotational constants, the direction of the methyl group axis, and the V3 and V6 barriers to internal rotation of the methyl top in the ground (S0) and excited (S1) states. The lifetime of the S1 state is also reported. Quantum interference effects due to the interaction of the internal and overall rotation allowed for determination of the absolute sign of the angle between transition moment and the a principal axis. PMID- 19791407 TI - Time-sliced ion imaging study of I2 and I2+ photolysis at 532 nm. AB - Photodissociation of I2 and I2+ at 532.10 nm was studied using VUV photoionization/time-sliced velocity map imaging. The dissociation energies D0 of I2(X 1sigma g+) and I2(X 2pi 1/2g) were found to be 12,416 +/- 48 and 16,439 +/- 48 cm(-1), respectively. Absorption of 532.10 nm mainly corresponds to the excitation of I2(X 1sigma g+) to the 1pi(1u) and/or A3pi(1u) states, and the excitation of I2+(X 2pi 1/2g) to the A2pi 1/2u state, with a small fraction to the A2pi 3/2u and 4sigma u+ states. A method for accurate calibration of magnification factor of ion imaging system was presented. The improvement of energy resolution for large ionization volume experiments, like the crossed molecular beam and one-photon VUV photoionization experiments, was discussed. PMID- 19791408 TI - Kinetics of the gas phase HO2 self-reaction: effects of temperature, pressure, water and methanol vapours. AB - The kinetics of the gas phase HO2 self-reaction have been studied using flash photolysis of Cl2/CH3OH/O2/N2 mixtures coupled with time-resolved broadband UV absorption spectroscopy. The HO2 self-reaction rate coefficient (HO2 + HO2 --> H2O2 + O2 (R1)) has been determined as a function of temperature (236 < T < 309 K, at 760 Torr) and pressure (100 < p < 760 Torr, at 296 K). In addition, the effects of water vapour ((0-6.0) x 10(17) molecules cm(-3), 254 < T < 309 K at 760 Torr, 400 < p < 760 Torr at 296 K) and methanol vapour ((0.06-4.7) x 10(17) molecules cm(-3), 254 < T < 309 K, at 760 Torr) on the rate coefficient have been characterised. The observed rate coefficient, k1, was found to exhibit a negative temperature dependence with both pressure dependent and pressure independent components, in agreement with previous studies. Furthermore, the rate coefficient k1 was found to be enhanced in the presence of elevated H2O or CH3OH concentrations, as reported previously. This study reports the most extensive characterisation of the rate coefficient k1 as a function of T, p, [H2O] and [CH3OH]. The present results indicate that k1 is higher at low temperatures, and that enhancement of k1 by H2O is greater, than has been reported previously. The pressure dependence of k1 at ambient temperature is in good agreement with previous studies. The rate enhancement by CH3OH reported here is in good agreement with previous studies at ambient temperatures but is smaller at low temperatures than the most recent previous investigation suggests. The rate coefficient k1 is adequately parameterised by: k1(760 Torr) = {(1.8 +/- 0.8) x 10(-14) exp((1500 +/- 120)/T/K)} x {1 + (2.0 +/- 4.9) x 10(-25) [H2O] exp((4670 +/- 690)/T/K)} x (1 + (0.56 +/- 1.00) x 10(-21) [CH3OH] exp((2550 +/- 500)/T/K)} cm(-3) molecule(-1) s(-1), where [H2O] and [CH3OH] are in molecules cm(-3). Errors are 1 sigma, and statistical only. The atmospheric implications of these results are briefly discussed. PMID- 19791409 TI - A discharge-flow study of the kinetics of the reactions of IO with CH3O2 and CF3O2. AB - We have determined the rate constants for the reactions IO + CH3O2 --> Products (1) and IO + CF3O2 --> Products (2) using a discharge-flow tube equipped with off axis cavity-enhanced absorption spectroscopy (CEAS) for the detection of IO. NO2, produced from the titration of RO2 with NO, was also detected using the CEAS system. The rate constants obtained were k1 = (6.0 +/- 1.3) x 10(-11) cm3 molecule(-1) s(-1) and k2 = (3.7 +/- 0.9) x 10(-11) cm3 molecule(-1) s(-1) at T = 295 +/- 2 K and P = 2.5 +/- 0.3 Torr; this is the first determination of these rate constants. The possible products and the atmospheric implications of reaction (1) are discussed. PMID- 19791410 TI - Kinetics study of the reaction of iodine monoxide radicals with dimethyl sulfide. AB - The temperature and pressure dependence of the rate coefficient for the reaction of iodine monoxide radicals with dimethyl sulfide (DMS), IO + DMS --> I + DMSO (1), was studied using laser induced fluorescence (LIF) to monitor the temporal profile of IO following 351 nm photolysis of RI/DMS/NO2/He (RI = CH3I/CF3I) mixtures. The study was performed over the range T = 296-468 K yielding a positive activation energy and k1 = (9.6 +/- 8.8) x 10(12) exp{-(1816 +/- 397)/T}. No dependence was observed on total pressure between 5-300 Torr. The rate coefficient at 296 K was determined as (2.0 +/- (0.6)(0.4)) x 10(-14) cm3 molecule(-1) s(-1), more than an order of magnitude smaller than a recent study but in reasonable agreement with the previous literature. PMID- 19791411 TI - The kinetics of the gas-phase decomposition of the 2-methyl-2-butoxyl and 2 methyl-2-pentoxyl radicals. AB - The kinetics of the title reactions have been studied by relative-rate methods as a function of temperature. Relative-rate coefficients for the two decomposition channels of 2-methyl-2-butoxyl have been measured at five different temperatures between 283 and 345 K and the observed temperature dependence is consistent with the results of some previous experimental studies. The kinetics of the two decomposition channels of 2-methyl-2-pentoxyl have also been investigated, as a function of temperature, relative to the estimated rate of isomerisation of this radical. Room-temperature rate coefficient data for the two decomposition channels of both 2-methyl-2-pentoxyl and 2-methyl-2-butxoyl (after combining the relative rate coefficient for this latter with a value for the rate coefficient of the major channel, extrapolated from the data presented by Batt et al., Int. J. Chem. Kinet., 1978, 10, 931) are shown to be consistent with a non-linear kinetic correlation, for alkoxyl radical decomposition rate data, previously presented by this laboratory (Johnson et al., Atmos. Environ., 2004, 38, 1755 1765). PMID- 19791412 TI - Evidencing a reaction intermediate in the formation of the Eu(III) bimetallic complex with p-tert-butylcalix[8]arene. AB - In view of the very few mechanistic information available on the complex formation between lanthanide ions and calixarenes, we study here the reaction mechanism leading to the formation of the bimetallic complex between Eu(III) and p-tert-butylcalix[8]arene (b-LH8). We show that in dmf, the 1 : 1 complex [Eu(b LH6)(NO3)(dmf)4] partially dissociates into a compound A which is an important intermediate in the formation of bimetallic [Eu2(b-LH2)(dmf)5]. Several spectroscopic (ES-MS, visible, luminescence, FT-IR) and conductometric techniques are combined with variable-temperature and variable-pressure experiments to demonstrate that in absence of base, intermediate A is the cationic species [Eu(b LH6)(dmf)4]+. The thermodynamic parameters of the dissociation reaction, K5(298) = (4 +/- 1) x 10(-5) M, delta H0 = +16 +/- 3 kJ mol(-1), delta S0 = -30 +/- 11 J mol(-1) K(-1) as well as the reaction volume delta V0 = +9.4 +/- 0.9 cm3 mol(-1) are evaluated and rationalized. In presence of triethylamine, intermediate A deprotonates to generate the neutral species A' = [Eu(b-LH5)(dmf)4], which, in turn, further reacts with europium nitrate to yield the bimetallic complex. In addition, the pKas of the parent calixarene LH8, of b-LH8 and of p-iso propylcalix[8]arene are determined in dmf, as well as the association constant between b-LH8 and triethylamine, K assoc = (9 +/- 1) x 10(3) M(-1). PMID- 19791413 TI - Speed of sound measurements conducted at high pressures on aqueous alcohol and aqueous diol systems at T = 298.15 K. AB - The pulse echo overlap technique has been used in conjunction with three unique high-pressure cells to measure ultrasonic speeds of sound in dilute aqueous solutions of the alcohols 2-propanol, 2-butanol, 2-propanol and 2-hexanol and the diols 1,4-butanediol, 1-5-pentanediol and 1,6-hexanediol at p = 0.1, 20.0, 40.0, 60.0, 80.0 and 120.0 MPa and T = 298.15 K. A procedure is described by which the sound velocity measurements may be utilised to calculate precise densities and apparent molar volumes. The concentration and pressure dependences of the calculated apparent molar volumes have been modelled using empirical equations which in turn have been used to obtain values for apparent molar volumes at infinite dilution. In addition, measured speeds of sound have been used to calculate isentropic and isothermal compressibilities, and their associated apparent molar properties, for the investigated aqueous alcohol and diol systems. The latter properties have also been modelled as functions of concentration and pressure using empirical equations to obtain the pressure dependences of the apparent molar properties at infinite dilution. A group additivity approach has been used to model the pressure dependences of apparent molar volumes at infinite dilution. This analysis has provided estimates of the pressure dependences of the contributions of methylene and hydroxyl groups to apparent molar volumes at infinite dilution. PMID- 19791414 TI - A small spherical liquid: a DFT molecular dynamics study of WAu12. AB - The finite-temperature dynamics of WAu12, incorporating both electronic and structural effects, is studied using a density-functional-based Born-Oppenheimer molecular dynamics method. Molecular dynamics simulations for monomolecular WAu12 suggest a surface-melting-type behaviour of the angular degrees of freedom between 366 and 512 K. Thermally averaged electron density-of-states of WAu12 are compared to the experimental photoelectron spectra of WAu12(-). PMID- 19791415 TI - Low energy electron driven reactions in single formic acid molecules (HCOOH) and their homogeneous clusters. AB - Low energy (0-3 eV) electron attachment to single formic acid (FA) and FA clusters is studied in crossed electron/molecular beam experiments. Single FA molecules undergo hydrogen abstraction via dissociative electron attachment (DEA) thereby forming HCOO(-) within a low energy resonance peaking at 1.25 eV. Experiments on the isotopomers HCOOD and DCOOH demonstrate that H/D abstraction occurs at the O-H/O-D site. In clusters, electron attachment is strongly enhanced leading to a variety of negatively charged complexes with the dimer M2(-) (M[triple bond]HCOOH) and its dehydrogenated form M (M-H)(-) as the most abundant ones. Apart from the homologous series containing the non-dissociated (Mn(-)) and dehydrogenated complexes (M(n-1) (M-H)(-), n > or = 1) further products are observed indicating that electron attachment at sub-excitation energies (approximately 1 eV) can trigger a variety of chemical reactions. Among these we detect the complex H2O (M-H)(-) which is interpreted to arise from a reaction initiated in the cyclic hydrogen bonded dimer target. In competition to hydrogen abstraction yielding the dehydrogenated complex M (M-H)(-) the abstracted hydrogen atom can react with the opposite FA molecule forming H2O and HCO with the polar water molecule attached to the closed shell HCOO(-) ion. The FA dimer can thus be used as a model system to study the response of a hydrogen bridge towards dehydrogenation in DEA. PMID- 19791416 TI - Local compressibilities in insulin as determined from pressure tuning hole burning experiments and MD simulations. AB - We present a hole burning study on insulin in a glycerol-water solvent by using the intrinsic amino acid tyrosine as a photochemical probe. The focus of the experiments is on the comparative pressure response of the spectral holes for insulin in its native state, in its chemically denatured state and for tyrosine in the glycerol-water solvent. From an analysis of the color effect of the pressure response, we can identify two different spectral ranges characterized by a markedly different sensitivity to pressure. We conclude that at least two tyrosines (or two groups of tyrosines) out of the eight in the insulin dimer are photochemically labeled, and that they are characterized by markedly different compressibilities, namely 0.08 and 0.13 GPa(-1), respectively. An interesting observation concerns the compressibility in the unfolded state: It is significantly lower and closer to the value measured for the pure tyrosine molecule in a glycerol-water solvent. In contrast to the native state, the response of the various tyrosines in the unfolded state to pressure variations is quite uniform. The experiments are compared with MD simulations of monomeric insulin at ambient temperature. The computational results show that the local compressibilities around the different tyrosines vary significantly and that they strongly depend on whether just the first shell of molecules or the first two shells are included in the local volume. PMID- 19791417 TI - Effects of internal noise for calcium signaling in a coupled cell system. AB - We have studied the collective behavior of calcium signaling in a linear array of coupled cells, taking into account the influence of internal noise. For a single cell, the performance of the stochastic calcium oscillations shows two maxima as a function of the cell size, indicating the occurrence of system size bi resonance. When the cells are coupled together, we find that the increase of the coupling strength or the number of cells can considerably enhance the first peak, but decrease the second one. The occurrence of the bi-resonance and the distinct dependence on the coupling are shown to be relevant with regard to the system's deterministic bifurcation features. PMID- 19791418 TI - Hydrogen-bond network probed by time-resolved optoacoustic spectroscopy: photoactive yellow protein and the effect of E46Q and E46A mutations. AB - The enthalpy and structural volume changes (delta Hi and delta Vi) produced upon photoinduced formation and decay of the red-shifted intermediate (pR = I1) in the photoactive yellow protein (WT-PYP) from Halorhodospira halophila and the mutated E46Q-PYP and E46A-PYP, were determined by laser-induced optoacoustic spectroscopy (LIOAS) using the two-temperatures method, at pH 8.5. These mutations alter the hydrogen bond between the phenolate oxygen of the chromophore and the residue at position 46. Hydrogen bonding is still possible in E46Q-PYP via the delta-NH2 group of glutamine, whereas it is no longer possible with the methyl group of alanine in E46A-PYP. In all three proteins, pR decays within hundreds of ns to micros into the next intermediate, pR'. The delta H values for the formation of pR (delta H pR) and for its decay into pR'(delta H pR-->pR') are negligibly affected by the E46Q and the E46A substitution. In all three proteins the large delta H pR value drives the photocycle. Whereas delta V pR is a similar contraction of ca. 15 ml mol(-1) for E46Q-PYP and WT-PYP, attributed to strengthening the hydrogen bond network (between 4 and 5 hydrogen bonds) inside the protein chromophore cavity, an expansion is observed for E46A-PYP, indicating just an enlargement of the chromophore cavity upon chromophore isomerization. The results are discussed in the light of the recent time-resolved room temperature, crystallographic studies with WT-PYP and E46Q-PYP. Formation of pR' is somewhat slower for E46Q-PYP and much slower for E46A-PYP. The structural volume change for this transition, delta V pR-->pR', is relatively small and positive for WT PYP, slightly larger for E46Q-PYP, and definitely larger for the hydrogen-bond lacking E46A-PYP. This indicates a larger entropic change for this transition in E46A-PYP, reflected in the large pre-exponential factor for the pR to pR' decay rate constant determined in the 5-30 degrees C temperature range. This decay also shows an activation entropy that compensates the larger activation energy in E46A PYP, as compared to the values for WT-PYP and E46Q-PYP. PMID- 19791419 TI - Palladium nanoclusters in microcapsule membranes: from synthetic shells to synthetic cells. AB - We show that polyelectrolyte shells may be perfect hosts and microreactors for catalysis. Using a layer-by-layer self-assembly process to form hollow polyelectrolyte capsules, we show that individual layers can be replaced by palladium and gold nanoclusters forming robust cell-type microcapsules. Testing the catalytic activity of those embedded nanoclusters using the Sonogashira cross coupling reaction, we show that simple self-assembled polyelectrolyte shells are ideal as carrier of at least one expensive catalyst, and possibly several, opening the road to new cascade reactions. PMID- 19791420 TI - Nickel and either tantalum or niobium-codoped TiO2 and SrTiO3 photocatalysts with visible-light response for H2 or O2 evolution from aqueous solutions. AB - TiO2 (band gap = 3.0 eV) and SrTiO3 (band gap = 3.2 eV) codoped with nickel and either tantalum or niobium ions showed photocatalytic activities for O2 evolution from an aqueous silver nitrate solution and H2 evolution from an aqueous methanol solution under visible light irradiation (lambda > 420 nm). The visible-light responses were due to the charge-transfer transition from the electron donor levels formed by the 3d orbitals of doped Ni2+ to the conduction bands of the host materials. Codoping of a tantalum or niobium ion made the absorption intensity in the visible light region strong for TiO2 doped with nickel ions, resulting in the enhancement of the photocatalytic activity for O2 evolution under visible light irradiation. SrTiO3 codoped with nickel and tantalum showed higher activity for H2 evolution than SrTiO3 doped with only nickel. This is due to the fact that codoped Ta5+ ions played a role in charge compensation, resulting in the suppression of the formation of Ni3+ ions, which are expected to trap photogenerated electrons. PMID- 19791421 TI - Proteasome inhibition: a new approach to the treatment of hematologic diseases. PMID- 19791422 TI - Characteristics, pathogenesis, and novel treatments for multiple myeloma. AB - Multiple myeloma remains an incurable disease; however, newer biologically based therapies aimed at various molecular-cellular targets are showing promise. Some of these drugs target critical pathways of the tumor cell and the bone marrow microenvironment. A brief review of the pathogenesis of multiple myeloma is presented. Genetic aberrations are hallmarks of the disease. Chromosome 14 translocations are responsible for cellular processes implicated in tumorigenesis. Adhesion to the extracellular matrix and bone marrow stromal cells augments drug resistance and inhibits apoptosis. Bortezomib, a proteasome inhibitor, acts on bone marrow constituents blocking many signaling cascades mediating multiple myeloma cell growth, survival, and drug resistance. Bortezomib and other cell-cycle targeted therapies offer hope in the fight against multiple myeloma. PMID- 19791423 TI - Proteasome inhibition: mechanism of action. AB - The ubiquitin-proteasome pathway plays a significant role in neoplastic growth and metastasis. The proteasome is responsible for most intracellular protein degradation and regulates numerous cellular functions. Aberrations in cell cycle control caused by altered levels of specific cell-cycle related proteins may lead to oncogenesis. Dysregulation of NF-kappaB signaling also is common to many malignancies and is one of the critical pathways affected by proteasome inhibition. The proteasome structure, in the context of the ubiquitin-proteasome pathway, is discussed. Proteasome inhibitors, such as bortezomib, have the potential to target specific protein substrates, leading to decreased tumor cell growth and increased apoptosis. PMID- 19791424 TI - Bortezomib in combination with other therapies for the treatment of multiple myeloma. AB - The ubiquitin proteasome pathway is the major mechanism used by eukaryotic cells for degradation of proteins. Bortezomib, a highly potent and specific inhibitor of the proteasome, has been demonstrated to have activity against multiple myeloma as a single agent in phase I and II clinical trials. Modulation of proteasome function with agents such as bortezomib may also have a significant role in combination chemotherapy, however, by impacting upon mechanisms that overcome chemoresistance and support chemosensitization. Proteasome inhibition seems to be able to overcome Bcl-2-mediated suppression of apoptosis, P glycoprotein-mediated multidrug resistance, and inducible resistance through nuclear factor kappa B. Preclinical studies with bortezomib and other agents have provided evidence of sensitization to several classes of chemotherapeutics that are used against multiple myeloma. Preliminary reports from phase I trials using bortezomib in combination with some of these standard cytotoxics have not found any pharmacologic interactions, and toxicities were not significantly increased with these regimens. Moreover, they have shown promising results, with documented major responses in patients who have previously progressed on the standard cytotoxic alone, and also high overall response rates. These findings are consistent with the possibility that bortezomib can act clinically as a chemosensitizing agent, and strongly support further studies of these regimens. PMID- 19791425 TI - Promising activity of the proteasome inhibitor bortezomib (VELCADE) in the treatment of indolent non-Hodgkin's lymphoma and mantle cell lymphoma: ASH poster session 517-II. AB - Dr. O'Connor delivered the following material as a poster at the 2003 American Society of Hematology meeting highlighting results from his work with bortezomib in the treatment of non-Hodgkin's and mantle cell lymphoma. A full publication of his results will appear later this year. Abstract #2346 appears in Blood, Volume 102, issue 11, November 16, 2003. The American Society of Hematology Poster Session "Lymphoma: Treatment and Supportive Care" took place on Sunday, December 7, 2003. PMID- 19791426 TI - [Intraoperative administration of low-molecular-weight heparins in reconstructive vascular operations]. AB - The article deals with analysing the outcomes of administering low-molecular weight heparins (LMWH) by the example of nadroparin ("Fraxiparin") during the intraoperative period in patients diagnosed with atherosclerotic lesions of femoropoplietal-crural segment of the lower-limb arteries as compared with non fractionated heparin (NFH). Studied were the alterations in the parameters of the plasmatic and thrombocytic links of haemostasis on the background of administering various molecular-weight fractions of heparin. A conclusion was drawn on advantageous use of LMWH in the cohort of the patients involved. Also presented herein is an analysis of the literature data concerning appropriate usage of LMWH during the intraoperative period. PMID- 19791427 TI - Diabetic foot: prevention and interventions. AB - The number of diabetics will increase almost 70% in developed countries during the next 20 years. Peripheral arterial disease is a common and costly complication among diabetics. The incidence of cardiovascular disease (mortality and morbidity) due to atherosclerosis, is higher among patients with diabetes than in those without diabetes. Also, amputation incidence is 5-10-fold higher compared to nondiabetics. Due to neuropathy, infections and underlying PAD, ulcers in diabetic foot leads too often to amputation. Urgent evaluation of lower extremity circulation, treatment of infections and surgical procedures, including revisions and revascularizations, are often needed. Intensive management of diabetes, including glycaemic and platelet aggregation control, treatment of hypertension and dyslipidemia, as well as nonpharmacological interventions, decreases both micro- and macrovascular complications. PMID- 19791428 TI - [Diagnostic and therapeutic possibilities of lumbar chemical sympathectomy in patients with chronic obliterating diseases of lower-limb arteries]. AB - The authors have analysed the findings obtained in a comprehensive examination followed by surgical management of eighty-five patients presenting with chronic obliterating diseases of lower limbs arteries (CODLLA). Studying the macrohaemodynamics and microcirculation of the ischaemic extremity was carried out according to the diagnostic programme for the disease concerned: i.e., rheovasography, photoplethysmography, transcutaneous oximetry, ultrasonographic duplex scanning of the lower-limb arteries, and angiography. All the patients were found to have signs of critical ischaemia of the lower extremities on the background of a concomitant lesion of the vessels of the femoropopliteal and crural segments. However, no reconstructive operations were performed owing to occlusion of the arteries of the feet and crura, and the patients were therefore subjected to surgical procedures aimed at indirect revascularization of the extremity involved. The patients were divided into two groups (Group One and Group Two, comprising 45 and 40 patients, respectively). The forty-five Group One patients were subjected to revascularizing osteotrephination (ROT) of the femur and cms in the sites with sufficient blood supply, as determined by duplex scanning. We managed to relieve the symptoms of critical ischaemia in 82.2% of the patients from this group. The manifestations of ischaemia were noted to be gradually increasing in seven (15.6%) patients during the postoperative period, and they all had to be subjected to a high amputation of the affected extremity. Whereas, the forty Group Two patients underwent ROT supplemented by ultrasonography-controlled lumbar chemical sympathectomy (LCS). A combination of LCS and revascularizing osteotrephination made it possible to stop ischaemia in 90% of the patients suffering from critical ischaemia of the lower limbs, and to reduce the rate of amputations by 5.6%. PMID- 19791429 TI - [Role of multispiral CT angiography in diagnosis and treatment of patients with chronic cerebral circulatory insufficiency]. AB - Implementing in our clinical practice multispiral CT angiography (MSCTA) of the brachiocephalic arteries into the diagnostic algorithm has made it possible to somewhat deviate from the "golden standard", i.e., the conventional contrast enhanced angiography, in determining the indications for surgical interventions in a total of 328 patients presenting with chronic cerebral circulatory insufficiency (CCCI). All the patients diagnosed as having multifocal atherosclerosis are subjected to duplex scanning of the brachiocephalic arteries Detecting haemodynamically significant stenoses of the carotid arteries is immediately followed by MSCTA with bolus-mediated intravenous contrasting, which makes it possible to specify the degree of the stenosis and anatomical variants of the major arteries of the neck and brain at all levels, to reveal complicated atherosclerotic plaques and to carry out an objective densimetric analysis of their morphological structure, as well as to diagnose extravasal compression, diffuse and focal cerebral lesions, to also determine the presence of venous dysfunction and to detect concomitant pathology of the cervical and mediastinal organs. Presented herein is a comparative analysis of multispiral CT angiography and MRT angiography in diagnosis of brachiocephalic arteries pathology in the patients involved. The use of the algorithm referred to above makes it possible to determine the indications for surgical correction of CCCls at a qualitatively novel level. PMID- 19791431 TI - [Radiological endovascular correction of azygous visceral arterial aneurysms]. AB - Visceral arterial aneurysms are a rare vascular pathology, which lacks specific clinical signs. Imaging modalities play a key role in their diagnosis. Today radiological endovascular interventions appear to be the method of choice for the management of most patients with azygous visceral arterial aneurysms. Various endovascular methods are used for circulatory exclusion of aneurysms, depending on particular anatomy and topology. The paper describes radiological endovascular management of 23 patients with aneurysms of abdominal aorta azygous visceral branches in the A. V. Vishnevsky Institute of Surgery for the period from 1995 to 2007. PMID- 19791430 TI - [Endovascular interventions on the arteries of the popliteal-tibial segment]. AB - The work was based on the results of studying the potential ability and outcomes of endovascular interventions (balloon angioplasty, stenting) in treatment of patients presenting with occlusive and stenotic lesions of the arteries of the popliteal-tibial segment at the stage of chronic ischaemia of lower limbs, in whom surgical reconstruction was impossible due to the type of the lesion or severity of concomitant pathology. The study was carried out in one hundred and four patients. On a total of 108 extremities involved, we carried out 174 endovascular interventions, including 29 stenting procedures and 145 balloon angioplasties. The following parameters were studied: dynamics of the clinical status, indices of the peripheral blood flow, immediate technical outcome, limb salvage rate, as well as short- and long-term (up to 2 years) patients' survival. It was proved that endovascular treatment of patients presenting with lesions of arteries of the popliteal-tibial segment is an efficient therapeutic method to relieve chronic ischaemia of lower extremities. For patients suffering from critical ischaemia of the lower limbs and diabetic angiopathy, this technique is sometimes the only method of surgical correction of the disordered blood flow. This method makes it possible not only to save the limb involved but also to improve the patient's quality of life. PMID- 19791432 TI - [Development of a venous-valve biological prosthetic graft for treatment of valvular insufficiency]. AB - The present study was undertaken to experimentally assess a possibility of creating a xenogeneic biological venous-valve prosthetic graft using the vv. saphena medialis of the cattle. The findings obtained in the amino-acid analysis demonstrated that diglycidyl ether ofethylene glycol (DEEG) is an efficient suturing agent for xenoveins. Suturing collagen with DEEG by qualitative and quantitative characteristics appeared superior to treatment with glutaric aldehyde (GA); the content of hydroxylysine was by 30%, and that of lysine by 360% less than in the samples treated with GA. Besides, DEEG reacts with histidine, tyrosine and methionine. The strength characteristics of the DEEG preserved xenoveins tended to decrease, while elasticity tended to increase, as compared with the GA-treated ones. Treatment with DEEG makes it possible for the material to preserve plasticity, which is of major importance for the appropriate performance of the leaflet apparatus of the xenovein. The amount of the immobilised heparin was determined by means of H34 labelling. It was found that the amount of non-fractionated heparin of "Belmedpreparations", bound to the DEEG treated surface of xenoveins equalled 6.21 microy/mg. While the amount of immobilized low-molecular-weight heparin "Clexan" was 3.9 microg/mg, with that of non-fractionated heparin "Biochemie" equalling 3.41 microg/mg. For the preserved xenoveins, we used the method of layer-by-layer modification, i.e., "heparin albumin-heparin". The surface modified by means of low-molecular-weight heparin "Clexan" was noted to have the smoothest relief. This approach appears to show promise in rendering venous-valve prosthetic grafts highly resistant to thrombogenesis. PMID- 19791433 TI - [Symptom-free phlebothrombosis and hereditary thrombophilia in patients with a skeletal injury]. AB - The authors have studied the frequency of revealing phlebothrombosis of the system of the inferior vena cava (IVC) in the acute period of a mechanical injury by means of coloured duplex scanning (CDS). Formulated herein are both treatment policy and principles of prevention of thromboembolic complications in severe lesions of the locomotor system. Carried out was a screening sonographic examination of the IVC bed in a total of 137 injured people on days 3 and 7 after a skeletal wound. Of these, 24 patients who later on were diagnosed with phlebothrombosis signs underwent the molecular genetic testing of DNA by means of the polymerase chain reaction (PCR) in order to determine hereditary predisposition to thrombogenesis (genetically conditioned thrombophilia). It was found that the incidence rate of symptom-free thrombosis of the IVC bed in those presenting with fractures of pelvic bones and lower extremities amounted to 17.5%. As surgical prevention suggested herein is the authors' technique of IVC clipping. PMID- 19791434 TI - [Edema as a measure for severity of chronic venous insufficiency and efficacy of its treatment]. AB - The author characterizes the edema as an important quantitative objective measure of severity for chronic venous diseases in both early and advanced stages. The problems of edema assessment methods and the importance of its management in clinical practice are discussed. The results of studies on the use of micronized purified flavonoid fraction (MPFF, Detralex) for edema syndrome coping are presented. PMID- 19791435 TI - Technology of "total" protection of the brain and internal organs under conditions of the "dry" aorta during aortic arch reconstruction. AB - Presented herein is own experience with aortic arch reconstructions performed in a total of twenty-two patients under conditions of antegrade cerebral perfusion. Of these, sixteen patients (Group One) were subjected to circulatory arrest in the lower part of the trunk, immediately followed by antegrade perfusion of the brain. The blood flow in the internal organs and the spinal cord was renewed only after completely forming the anastomosis with the aortic isthmus and the branches of the aortic arch. The technique we are suggesting here was employed in six patients (Group Two). After the beginning of antegrade cerebral perfusion, we inflated an intraaortic occluding balloon within the lumen of the descending aorta and commenced perfusion of the viscera through the femoral artery in order to continue perfusion in the internal organs. The duration of artificial circulation in Group One patients was significantly greater (P = 0. 0087), whereas the time of the aortic arch reconstruction was significantly longer in Group Two patients (P = 0.0045). Analysing the level of blood enzymes, lactate, and the renal function revealed significantly worse parameters in Group One patients, with a direct correlation being observed between the level of the onset of multiple organ failure and the duration of the aortic arch reconstruction (i. e., ischaemia of the internal organs and the spinal cord) in Group One patients, whereas no such correlation being noted in Group Two patients. Hence, the aortic branch reconstruction may be performed with the utmost protection of the brain and visceral organs by means of employing the above-described technique that has proved reliable and safe and turned out to yield excellent short-term outcomes. PMID- 19791436 TI - Surgical methods of protecting the spinal cord during reconstructive operations on the thoracic and thoracoabdominal portions of the aorta. AB - BACKGROUND: Restoration of the spinal blood flow during operations on the thoracoabdominal portion of the aorta is one of the basic and decisive methods of protecting the spinal cord from ischaemia. OBJECTIVE: To decrease the incidence rate of spinal complications during interventions on the thoracic and thoracoabdbminal portions of the aorta at the expense of choosing an appropriate option of aortic reconstruction, determined by preoperative diagnosis of peculiarities of blood supply of the spinal cord. MATERIALS AND METHODS: From November 2005 to April 2007, a total of 34 patients were operated on at the Department of Arterial Pathology. To determine the spinal blood flow, all the patients were subjected to multispiral CT angiography. In 35% of patients underwent prosthetic repair of the thoracic and abdominal portions of the aorta with leaving a nondilated portion part from which originated the identified "critical" artery. In 45% of the reconstructions the verified "critical" artery was included into the distal oblique anastomosis. In 10% of cases, restoration of the blood flow of the spinal cord was performed at the expense of reimplantation of the segmental artery into the graft on the platform. In cases when the "critical" arteries were not involved into the pathological process, we performed isolated prosthetic repair of the aortic portion affected. RESULTS: The great anterior radiculo-medullary artery was visualized in 26 (76.5%) patients, and the anterior spinal artery--in 34 (100%) patients. The overall operative mortality rate amounted to 8.8%. Spinal complications were observed in 2.9% of cases (one patient was subjected to ligation of the 10th intercostal artery preoperatively defined as "critical"). CONCLUSION: Blood flow along the diagnosed "critical" segmental arteries should be restored in all operations on the thoracic and thoracoabdominal portions of the aorta. PMID- 19791437 TI - Coronary endarterectomy during off-pump coronary artery bypass surgery. AB - Coronary endarterectomy (CEA) is often combined with coronary artery bypass grafting (CABG), which is performed on cardiopulmonary bypass (CPB). Recent advances in off-pump surgical technique and cardioanesthesiology, along with the increasing number of patients with high risk of CPB complications made it possible and desirable to execute CEA on a beating heart. Russian scientific literature lacks reports on these interventions. The study was aimed at evaluation of off-pump CEA feasibility and early outcomes. From 59 patients with ischemic heart disease (IHD), who underwent combined CABG and CEA, off-pump technique was used for 16 (27.1%) patients, including 12 men and 4 women, mean age 55.3 +/- 6.4. All of them had long-lasting history of IHD; 2 patients had angina CCS class II, 12--class III and 2 patents--class IV. Total number of anastomoses was 51 for 16 patients or 3.18 per patient. Open endarterectomy was used in 7 (9%) CEAs, semi-closed--in 9 (11.5%) CEAs. The technique of atherosclerotic plaque extraction, coronary artery reconstruction and bypass was similar in both groups. Complete revascularization was achieved for all patients. At discharge clinical improvement was evident in patients with functional classes 0-1. Diffuse involvement of coronary arteries is not considered to be contraindication for CABG. Simultaneous CEA with off-pump technique helps to achieve complete myocardial revascularization and good early outcomes, comparable with the results of conventional CPB-assisted procedures. PMID- 19791439 TI - [Surgical management of patients with lower limb critical ischaemia induced by lesions of infrainguinal arteries]. AB - The authors analyse their experience in surgical management of 325 patients diagnosed with lower limb critical ischaemia (LLCI) secondary to lesions of infrainguinal arteries. Of these, 216 (66.5%) patients (Group 1) were subjected to isolated bypass grafting operations defined as either "reconstructive", or "direct revascularisations". A further 35 (10.8%) patients (Group 2) underwent concomitant revascularizations accompanied simultaneously or in a stagewise manner (but within the time frame of one hospitalization) by reconstructive and palliative operations (e. g., femoropopliteal bypass grafting and lumbar sympathectomy), and 74 (22.7%) patients (Group 3) were subjected to only palliative operations alone (lumbar sympathectomy and revascularizing osteotrephination), i.e., "indirect revascularizations". The remote outcomes of surgical management were followed up within the terms of up to 5 years in 306 (94.2%) of the 325 patients operated on for LLCI. Of these: in 205 (94.9%) of the 216 Group 1 patients, in 33 (94.3%) of the 35 Group 2 patients, and in 68 of the 74 (91.9%) Group 3 patients. Amongst the Group 1 patients (n = 205) over the 5 year follow-up period we had performed a total of 70 (34.1%) amputations of the postoperative extremity and encountered 121 (59.0%) cases of thromboses of the bypass grafts. Of the Group 2 patients (n = 33), over the 5 year follow-up, the postoperative extremities were amputated in 7 (21.2%) patients. Thromboses of the bypass grafts over the same time period were noted to have developed in 11(33.3%) patients. Amongst Group 3 patients (n - 68) the postoperative extremities were saved in 37, with the limb salvage rate thus amounting to 54.4%. PMID- 19791440 TI - [Vascular pedicle assessment during microsurgical autotransplantation of tissue complexes]. AB - The paper describes vascular pedicle patency assessment after autotransplantation of 107 free soft tissue complexes to neck, upper and lower limb areas. In early postoperative period pedicles were patent in 82 (76.6%) patients; in 25 cases thrombosis has developed in 36 hours after surgery. Timely diagnosis of this complication and reanastomosing helped to preserve transplants in 9 (36%) patients and to increase the total rate of successful transplantations up to 85% (91 cases). The role of diagnostic imaging (Doppler ultrasound, duplex scanning and polarography) in early postoperative evaluation of vascular pedicles is analyzed, as well as the role of oxygen tension measurement, which reflects the circulation character in autotransplants of different size. One must take into account the possibility of prolonged circulatory disturbances unrelated to anastomotic thromboses that can take place in large flaps. PMID- 19791438 TI - [Microsurgical autotransplantation of the greater omentum to a lower limb in patients with critical ischaemia accompanying thromboangiitis obliterans]. AB - The authors are sharing their five-year experience gained at the Department of Vascular Surgery of the Samara State Medical University in performing microsurgical autotransplantation of the greater omentum to a lower extremity in patients presenting with critical ischaemia accompanied by thromboangiitis obliterans. A total of twenty-five operations of microsurgical autotransplantation of the greater omentum on a vascular pedicle were carried out in twenty patients diagnosed with lower limb critical ischaemia accompanied by thromboangiitis obliterans, for five of them underwent surgery simultaneously on the both lower extremities. With an overall number of 22 extremities eventually spared, the remote limb-salvage rate amounted to 88%. The preoperative preparation procedures as well as surgical technique are discussed in detail. PMID- 19791441 TI - [Gadobutrol as an alternative contrast agent during CT-coronarography in a patient with intolerance to iodinated contrast media]. AB - The paper presents a case of successful heart chambers and coronary. Maging with gadolinium-based contrast agent Gadobutrol during CT-coronarography with 64-slice scanner in a patient with intolerance to iodinated contrast media. No adverse events were detected. In conclusion, Gadobutrol may be a safe and useful alternative contrast contraindications to iodinated material. PMID- 19791442 TI - [Successful treatment of pseudoaneurysm of the proximal anastomosis of the aorto bifemoral bypass graft complicated by necrosis of the sigmoid colon wall]. AB - The article describes a case report of successful surgical management of a 58 year-old male patient presenting with a pseudoaneurysm of the proximal anastomosis of the aorto-bifemoral bypass graft complicated by necrosis of the sigmoid colon wall. The patient was operated on 11 months after the first reconstructive operation, i.e. aorto-bifemoral bypass grafting and femoropopliteal bypass grafting for Leriche's syndrome. Clinical manifestations of a false aneurysm of the proximal anastomosis (abdominal pain, presence of a pulsating tumour-like formation) appeared one month after surgery. The diagnosis was verified by ultrasonography, angiography, and CT-angiography. During the repeat operation, it was determined that a large false aneurysm of the abdominal aorta had been caused by a complete cutting through of the anastomosis's sutures more than by half of the semicircle. Intraoperative findings included both a coarse commissural process in the abdominal cavity and 3 x 3 cm "decubital" necrosis of the dolichosigmoid's wall participating in the formation of the wall of the false aneurysm. The surgical procedure consisted in an operation of aneurysmal resection, aorto-bifemoral prosthetic repair, and resection of the dolichosigmoid with the establishment of an interintestinal end-to-side anastomosis and single-barrel preventive sigmoidostoma. After 3 months, the patient was subjected to the operation of intraperitoneal closure of the sigmoidostoma followed by complete recovery. PMID- 19791444 TI - [Preventive maintenance of repeated ischemic insults]. AB - In the review we offer analysis of the effectiveness of carotid endarterectomy in treatment of post-functional apoplexy or stroke patients. Published results of the researches specify possible efficiency of carotid endarterectomy in preventive maintenance against repeated apoplectic attack or strokes. Yet the criteria of usage and execution of the carotid endarterectomy are still to be discussed. PMID- 19791443 TI - Role of "hybrid" operation in the surgical management of type I aortic dissection. Early experience. AB - Persistent or recurrent aortic dissection after successful surgical treatment of acute type I aortic dissection is well-known complication. Persistence of the false lumen in the arch or descending aorta can result in a fatal complication and has an undesirable impact on long term prognosis. Endovascular stenting has showed promising result for patients with type III aortic dissection. The role of stenting in management of complex persistent aortic dissection is not well established. In the article we reviewed our early result of combine surgical and endovascular treatment of persistent type I aortic dissection. In our series we did not have mortality. Analysis of early and long term postoperative period showed promising result. PMID- 19791445 TI - An overview of solution-based semiconductor nanowires: synthesis and optical studies. AB - This Perspective describes recent progress in the synthesis and optical characterization of high quality solution-based semiconductor nanowires (NWs). The described solution-phase NW syntheses are analogous to conventional vapor liquid-solid (VLS) growth schemes for 1D materials. However, a primary difference is that low melting catalyst particles are used to induce the asymmetric crystallization of wires at temperatures sustainable by solution chemistry (T < 400 degrees C). Reactions are conducted in the presence of mild coordinating solvents such as trioctylphosphine oxide, which modulate NW growth kinetics and passivate their surfaces. This approach borrows from concurrent advances in colloidal quantum dot (QD) syntheses. In particular, the appropriate choice of solvent, coordinating ligands, growth conditions and precursors all originate from existing preparations for high quality semiconductor QDs. Subsequent structural characterization of the nanowires reveals their high degree of crystallinity, low ensemble size distributions and intrawire uniformity. Variations of these syntheses yield branched CdSe, CdTe and PbSe NWs with characteristic tripod, v-shape, y-shape, t-shape and "higher order" morphologies. A "geminate" NW nucleation mechanism is used to explain this phenomenon. The proposed branching model is also predictive and can be tested by additional nanowire syntheses that we or others conduct. Corresponding optical properties of both straight and branched wires are described, including measurements of their frequency-dependent absorption cross sections. Preliminary ensemble experiments focus on transient differential absorption measurements to study relevant carrier relaxation pathways and timescales over which these processes occur. Additional studies reveal intrawire optical heterogeneity and fluorescence intermittency at the single NW level. PMID- 19791446 TI - Searching for the optimum structures of alloy nanoclusters. AB - Recent advances in computational methods for searching for the most stable structures of alloy nanoparticles are reviewed. A methodology based on extensive global optimization searches within an empirical potential model in conjunction with structure recognition algorithms and subsequent density-functional local relaxation of the lowest-energy structures pertaining to each different structural basin is proposed. Applications to different systems, including Cu-Ag, Cu-Au, Ni-Ag, Co-Ag, Co-Au, Ni-Au and Pd-Pt clusters, are presented. PMID- 19791447 TI - Key role of entropy in nanoparticle dispersion: polystyrene-nanoparticle/ linear polystyrene nanocomposites as a model system. AB - Dilution of contact, hard sphere-like, nanoparticle-nanoparticle interactions upon mixing plays a key role in explaining nanoparticle dispersion in athermal all-polymer nanocomposites, as illustrated for polystyrene-nanoparticle/linear polystyrene blends as a model system. PMID- 19791448 TI - Electron correlation from path resummations: the double-excitation star. AB - Resummation over a selected subset of paths allows the approximate evaluation of an N-electron path-integral. In particular, we show that the double excitation star graph, consisting of all doubly excited determinants attached to the reference Hartree-Fock determinant, has an energy which is easily calculated in O[N4] time after integral precomputation, and produces binding curves of a similar quality to CCSD theory for a range of systems including the N2 molecule, the hydrogen-bonded water dimer, and dispersion dominated Ne2 and Ar2 dimers. PMID- 19791449 TI - Sub-Doppler millimetre-wave spectroscopy of DBS and HBS: accurate values of nuclear electric and magnetic hyperfine structure constants. AB - The unstable thioborine molecule and its deuterated variant have been produced by a high-temperature reaction between hydrogen sulfide and crystalline boron at 1100 degrees C in a flow system. Five rotational transitions from J = 2 <-- 1, to J = 6 <-- 5 have been recorded with sub-Doppler resolution for the vibrational ground state of H10/11BS and D10/11BS using the Lamb-dip technique. The hyperfine structure due to the electric quadrupole interaction of deuterium nucleus has been resolved yielding the first experimental determination of the deuterium quadrupole coupling constant in thioborine, which is 0.1403(75) MHz in D11 BS and 0.1360(38) MHz in D10BS. Fairly accurate values of 10/11B spin-rotation coupling constants and of the hydrogen-boron spin-spin coupling constants have also been determined. Additionally, the hyperfine structure of the rotational lines for the nu2 = 1 excited state has been investigated, thus obtaining information on the asymmetry of the electric field gradient at the B nucleus in the bending state. PMID- 19791450 TI - Precise dipole moments and quadrupole coupling constants of the cis and trans conformers of 3-aminophenol: determination of the absolute conformation. AB - The rotational constants and the nitrogen nuclear quadrupole coupling constants of cis-3-aminophenol and trans-3-aminophenol are determined using Fourier transform microwave spectroscopy. We examine several J = 2 <-- 1 and 1 <-- 0 hyperfine-resolved rotational transitions for both conformers. The transitions are fit to a rigid rotor Hamiltonian including nuclear quadrupole coupling to account for the 14N nuclear spin. For cis-3-aminophenol we obtain rotational constants of A = 3734.930 MHz, B = 1823.2095 MHz, and C = 1226.493 MHz, for trans 3-aminophenol of A = 3730.1676 MHz, B = 1828.25774 MHz, and C = 1228.1948 MHz. The dipole moments are precisely determined using Stark effect measurements for several hyperfine transitions to micro(a) = 1.7718 D, micro(b) = 1.517 D for cis 3-aminophenol and micro(a) = 0.5563 D, micro(h) = 0.5375 D for trans-3 aminophenol. Whereas the rotational constants and quadrupole coupling constants do not allow to determinate the absolute configuration of the two conformers, this assignment is straightforward based on the dipole moments. High-level ab initio calculations (B3LYP/6-31G* to MP2/aug-cc-pVTZ) are performed providing error estimates of rotational constants and dipole moments obtained for large molecules by these theoretical methods. PMID- 19791451 TI - Atmospheric photochemical loss of H and H2 from formaldehyde: the relevance of ultrafast processes. AB - We have performed ab initio calculations to examine the potential energy along the normal modes of ground-state HCHO and along the reaction coordinates for loss of H2 and atomic hydrogen, respectively. This exploration showed that there are no specific features that will lead to reaction on the excited-state surfaces for excitations that are relevant to the troposphere and stratosphere. The calculations did however lead to the localization of a conical intersection point through which a specific loss of H2 could take place. However, the conical intersection lies at 5.4 eV relative to the ground state molecule at equilibrium and is thus inaccessible via single photon excitation at tropospheric and stratospheric wavelengths. In addition to the ab initio investigation we have carried out a femtosecond pump-probe experiment using a 266/400 nm excitation. The results show that the timescale for the internal conversion from the initially prepared high-lying Rydberg states is on the order of a picosecond. This process populates the n --> pi* first excited singlet state which then survives for a substantially longer time before it is depopulated to form hot ground state or triplet-excited molecules that can then decompose. PMID- 19791452 TI - Time-resolving molecular vibration for microanalytics: single laser beam nonlinear Raman spectroscopy in simulation and experiment. AB - A single-beam implementation of coherent anti-Stokes Raman scattering (CARS) allows experimentally very much simplified and flexible approaches to time resolved vibrational spectroscopy, with the additional benefit of microscopic spatial resolution. To achieve this, a broadband femtosecond laser is combined with a pulse shaper creating tailored pulse sequences by computer control. We discuss the theoretical foundations and technical issues of the technique in detail and show the successful implementation of different schemes for truly femtosecond time-resolved vibrational spectroscopy. Hereby, we elaborate all the details of the method shown earlier in a proof-of-principle study [Von Vacano and Motzkus, Opt. Comm., 2006, 264, 488] and greatly extend it by novel approaches relying on the use of identical double pulses or additional polarization control for background-free spectroscopy with superior robustness and signal-to-noise ratio. Perspectives and applications of the presented schemes for chemical microanalysis and high-contrast chemical imaging are examined. PMID- 19791453 TI - Formation of noble-gas hydrides and decay of solvated protons revisited: diffusion-controlled reactions and hydrogen atom losses in solid noble gases. AB - UV photolysis and annealing of C2H2/Xe, C2H2/Xe/Kr, and HBr/Xe matrices lead to complicated photochemical processes and reactions. The dominating products in these experiments are noble-gas hydrides with general formula HNgY (Ng = noble gas atom, Y = electronegative fragment). We concentrate on distinguishing the local and global mobility and losses of H atoms, barriers of the reactions, and the decay of solvated protons. Different deposition temperatures change the amount of lattice imperfections and thus the amount of traps for H atoms. The averaged distance between reacting species influencing the reaction kinetics is controlled by varying the precursor concentration. A number of solid-state processes connected to the formation of noble-gas hydrides and decay of solvated protons are discussed using a simple kinetic model. The most efficient formation of noble-gas hydrides is connected with global (long-range) mobility of H atoms leading to the H + Xe + Y reaction. The highest concentration of noble-gas hydrides was obtained in matrices of highest optical quality, which probably have the lowest concentration of defects and H-atom losses. In matrices with high amount of geometrical imperfections, the product formation is inefficient and dominated by a local (short-range) process. The decay of solvated protons is rather local than a global process, which is different from the formation of noble-gas molecules. However, the present data do not allow distinguishing local proton and electron mobilities. Our previous results indicate that these are electrons which move to positively-charged centers and neutralize them. It is believed that the image obtained here for solid xenon is applicable to solid krypton whereas the case of argon deserves special attention. PMID- 19791454 TI - Ice mixtures formed by simultaneous condensation of formaldehyde and water: an in situ study by micro-Raman scattering. AB - Thin films of formaldehyde-water mixtures are co-deposited at 88 K and 10(-1) Torr from gas collected above formaldehyde aqueous solutions of different concentrations (5, 10, 15, 20, 30 mol%). They are analyzed in situ by micro-Raman scattering in the 2700-3800 cm(-1) spectral range. The spectral characteristic of H2CO distributed molecularly in amorphous solid water is obtained under vacuum conditions. As temperature is increased formaldehyde is released during the crystallization of ice between 118 and 138 K. On the other hand, under controlled nitrogen atmosphere, the deposits crystallize in hydrate phases (or solid H2CO(s)) during annealing. A new phase (metastable FOR-A) of H2CO(s) (or a low hydrate after rejection by crystallizing ice) can be spectroscopically identified at 138 K before transformation into a hydrate (with molecular H2CO distributed within the cages of the clathrate FOR-B) takes place at 148 K. This latter phase decomposes between ca. 180 and 200 K. The significant spectral differences between these hydrates and those formed in frozen formaldehyde aqueous solutions reflect the existence of H2CO-clusters of distinctive structural nature relative to those resulting from important oligomerization process in the liquid. Moreover, the structure, the gas distribution and relative gas population in the formaldehyde clathrate cages are influenced by the relative amount of trapped nitrogen at the surface, which moreover depends on the ice film morphology. The dependence on the crystallization temperature of the deposits is explained by the relative amounts of occluded H2CO/N2 and the external pressure conditions. The distinct behavior observed between vacuum and N2-atmosphere conditions certainly reflects a complex mechanism of surface mediated nucleation in which the transport of the reactants to the hydrate reaction zone is facilitated by the presence of a polar dopant. PMID- 19791455 TI - Ultraviolet photodissociation of vinyl iodide: understanding the halogen dependence of photodissociation mechanisms in vinyl halides. AB - The photodissociation of vinyl iodide has been investigated at several wavelengths between 193 and 266 nm using three techniques: time-resolved Fourier transform emission spectroscopy, multiple pass laser absorption spectroscopy, and velocity-mapped ion imaging. The only dissociation channel observed is C-I bond cleavage to produce C2H3 (nu, N) + I (2P(J)) at all wavelengths investigated. Unlike photodissociation of other vinyl halides (C2H3X, X = F, Cl, Br), in which the HX product channel is significant, no HI elimination is observed. The angular and translational energy distributions of I atoms indicate that atomic products arise solely from dissociation on excited states with negligible contribution from internal conversion to the ground state. We derive an upper limit on the C-I bond strength of D0(C2H3-I) < or = 65 kcal mol(-1). The ground-state potential energy surface of vinyl iodide is explored by ab initio calculations. We present a model in which the highest occupied molecular orbital in vinyl halides has increasing X(np) non-bonding character with increasing halogen mass. This change leads to reduced torsional force around the C-C bond in the excited state. Because the ground-state energy is highest when the CH2 plane is perpendicular to the CHX plane, a reduced torsional force in the excited state correlates with a lower rate for internal conversion compared to excited-state C-X bond fission. This model explains the gradual change in photodissociation mechanisms of vinyl halides from the dominance of internal conversion in vinyl fluoride to the dominance of excited-state dissociation in vinyl iodide. PMID- 19791456 TI - Reaction kinetics to low temperatures. Dicarbon + acetylene, methylacetylene, allene and propene from 77 < or = T < or = 296 K. AB - The temperature dependence of the reactions of the dicarbon molecule in its ground singlet (X1Sigma(g)+) and first excited triplet (a 3Pi(u)) states with acetylene, methylacetylene, allene and propene has been studied using a recently constructed continuous supersonic flow reactor. Four Laval nozzles have been designed to access specified temperatures over the range of 77 < or = T < or = 220 K and measurements have been performed at 296 K under subsonic flow conditions. C2 was produced in its two lowest electronic states via the in situ multiphoton dissociation of C2Br4 at 266 nm. The time dependent losses of C2 in these two states in the presence of an excess of co-reagent species were simultaneously followed by laser-induced fluorescence in the Mulliken and Swan bands for the detection of singlet and triplet state C2, respectively. The rate coefficients were measured to be very fast, with values larger than 10(-10) cm3 molecule(-1) s(-1) and up to 5 x 10(-10) cm3 molecule(-1) s(-1). The reactions of 1C2 are seen to be essentially temperature independent from 77 < or = T < or = 296 K whereas the rate coefficients for the 3C2 reactions are seen to increase until they are equivalent to the 1C2 values at 77 K. PMID- 19791457 TI - Accurate structures from combined gas electron diffraction and liquid crystal NMR data; the importance of anisotropy of indirect couplings for 1,4-difluorobenzene. AB - Gas-phase electron-diffraction scattering data and dipolar couplings from NMR experiments in four different liquid crystal solvents have been combined to give a high-accuracy molecular structure of 1,4-difluorobenzene. The anisotropic components of the CF and FF indirect couplings have been deduced directly from the experimental data. The resultant structure has standard deviations of around 0.2 pm for interatomic distances and less than 0.20 for inter-bond angles. PMID- 19791458 TI - Electron spin-lattice and spin-spin relaxation study of a trinuclear iron(III) complex and its relevance in quantum computing. AB - Electron spins of molecular magnets are promising candidates for large scale quantum information processing because they exhibit a large number of low-lying excited states. In this paper X-band pulse electron paramagnetic resonance spectroscopy is used to determine the intrinsic relaxation times T1 and T2 of a molecular magnet with an S = 1/2 ground state, namely the neutral trinuclear oxo centered iron (III) complex, [Fe3(micro3-O)(O2CPh)5(salox)(EtOH)(EtOH)(H2O)]. The temperature dependence of the spin-lattice relaxation time T1 between 4.5 and 11 K shows that the Orbach relaxation process is dominant with the first excited state lying 57 cm(-1) above the ground state, whereas the phase memory time T(M) is of the order of 2.6 micros and exhibits a modest temperature dependence. These results together with previous magnetic measurements give further insight into the magnetic properties of the complex. The coherent manipulation of the electron spins is also examined by means of transient nutation experiments. PMID- 19791459 TI - The influence of oscillations on product selectivity during the palladium catalysed phenylacetylene oxidative carbonylation reaction. AB - This paper reports on the influence of oscillations on product selectivity as well as the dynamics of product formation during the palladium-catalysed phenylacetylene oxidative carbonylation reaction in a catalytic system (PdI2, KI, Air, NaOAc in methanol). The occurrence of the pH oscillations is related to PdI2 granularity and the initial pH drop after phenylacetylene addition. To achieve pH and reaction exotherm oscillations regulation of the amount of PdI2 is required, ensuring that the initial pH does not fall significantly below 1 after phenylacetylene addition. Experiments in both oscillatory and non-oscillatory pH regimes were performed in an HEL SIMULAR reaction calorimeter with the concentration-time profiles measured using a GC-MS. It is demonstrated that when operating in an oscillatory pH regime product formation may be suppressed until oscillations occur after which there is a steep increase in the formation of Z-2 phenyl-but-2-enedioic acid dimethyl ester. When operating in non-oscillatory pH mode the products are formed steadily over time with the main products being Z-2 phenyl-but-2-enedioic acid dimethyl ester, 2-phenyl-acrylic acid methyl ester and E-3-phenyl-acrylic acid methyl ester. PMID- 19791460 TI - [Clinical spectrum of preclinical hypertrophic cardiomyopathy: characterizing carriers of sarcomere gene mutation]. AB - Hypertrophic cardiomyopathy (HCM) is caused by dominant mutations in sarcomere genes. The diagnosis of HCM is usually established by identifying unexplained left ventricular hypertrophy (LVH) on cardiac imaging studies; however, LVH is not an invariable feature of disease. The expression of LVH is highly age dependent, and LV wall thickness is frequently normal during childhood. Overt development of hypertrophy, and the ability to make a clinical diagnosis, does not typically occur until adolescence or later. Genetic testing allows identification of family members who have inherited the pathogenic sarcomere mutation (G +) before the emergence of clinical manifestations (LVH -). As such, a new and important subset of individuals with preclinical HCM (G+ / LVH-) can be identified early in life, before a clinical diagnosis can be made. Our evaluation of preclinical HCM has indicated that although there are no distinguishing morphologic features of early disease, there is evidence of myocardial dysfunction prior to the development of LVH. Subtle impairment of diastolic function is detectable in otherwise healthy sarcomere mutation carriers and can differentiate these family members from those who did not inherit the mutation. In contrast, systolic function appears relatively preserved in preclinical HCM, but impaired in overt disease. This preliminary finding suggests that both the sarcomere mutation and the characteristic changes in myocardial architecture (LVH, fibrosis and disarray) are required to perturb force generation. By studying this intriguing preclinical cohort, we can better understand the early stages of disease pathogenesis and potentially develop therapy to alter the clinical expression of sarcomere mutations. PMID- 19791461 TI - [Risk stratification for sudden death in hypertrophic cardiomyopathy]. AB - The natural history of hypertrophic cardiomyopathy (HCM) is extremely heterogeneous. Many patients remain asymptomatic throughout life, some develop severe symptoms of heart failure, but others die suddenly, often in the absence of previous symptoms and at a young age. Therefore, identification of those patients at high risk of sudden death represents a major clinical problem and has become an even greater challenge since the implantable cardioverter-defibrillator (ICD) has proved to be highly effective in preventing sudden death in HCM. Patients who have survived a cardiac arrest, or one or more episodes of sustained ventricular tachycardia, are considered to be at high risk and are candidates for an ICD. However, this patient subset represents a small proportion of the HCM population. The greatest difficulty concerns the identification of high risk patients who are candidates for primary prevention of sudden death with a prophylactic ICD. Decisions are based on generally accepted clinical markers which are associated with increased risk, including: family history of sudden death, extreme left ventricular (LV) wall thickness ( > or =30 mm), nonsustained ventricular tachycardia on Holter monitoring, unexplained (non-neurocardiogenic) syncope particularly in young patients, and hypotensive blood pressure response to exercise. Patients with end-stage HCM or a LV apical aneurysm represent important arrhythmogenic subsets also associated with substantially increased risk. Multiple or single strong risk markers are associated with increased sudden death risk and justify consideration for a prophylactic ICD. PMID- 19791462 TI - [Prevention of sudden death in hypertrophic cardiomyopathy (HCM ): implanted defibrillators in HCM]. AB - Hypertrophic cardiomyopathy (HCM) is the most common cause of sudden cardiac death in young people. The implantable cardioverter-defibrillator (ICD), has recently proved to be a safe and effective therapeutic intervention in patients with HCM, both for the primary and secondary prevention of sudden death. Based on recent substantial experience, the ICD intervenes appropriately to terminate ventricular tachycardia/fibrillation (VT/VF), at a rate of 5.5%/year. ICD discharge rate is 4%/year in those patients implanted prophylactically due to one or more major risk markers, but often with considerable delays of up to 10 years before the device is required to intervene appropriately to terminate potentially letal ventricular tachyarrhythmias. Primary prevention of VT/VF occurs with similar frequency in high-risk patients having either 1, 2 or > or =3 noninvasive risk markers, and about one-third of patients with appropriate device interventions had been implanted for only one risk factor. The ICD has proved reliable in HCM despite the extreme and complex phenotypes often present with massive degrees of left ventricular hypertrophy, microvascular ischemia, diastolic dysfunction, or dynamic left ventricular outflow tract obstruction. Failure to convert life-threatening ventricular tachyarrhythmias to normal rhythm is extraordinarily rare. In conclusion, in high-risk HCM patients, ICDs perform in a highly effective fashion, frequently preventing sudden death by aborting primary life-threatening ventricular tachyarrhythmias. A single marker of high risk can be sufficient evidence to justify the recommendation for a prophylactic ICD in selected patients with HCM. PMID- 19791463 TI - [Atrial fibrillation in hypertrophic cardiomyopathy: determinants, clinical course and management]. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia in patients with hypertrophic cardiomyopathy (HCM), and represents an important complication in the clinical course of the disease, with adverse consequences on functional status and outcome. Studies on community-based HCM patient populations have shown that AF is associated with long-term clinical deterioration, cardioembolic stroke and increased cardiovascular mortality due to heart failure and stroke. Moreover, acute onset of AF may cause severe hemodynamic impairment and represent a trigger of potentially lethal ventricular arrhythmias. However, the consequences of AF on the long-term prognosis of HCM patients are not uniformly unfavorable, and may be compatible with an uneventful course, when properly managed. Management of AF in HCM is challenging, particularly when onset occurs at a young age. Both paroxysmal and permanent AF represent clear indications for oral anticoagulation. In most patients, maintenance of sinus rhythm is highly desirable but made difficult by the limited long-term efficacy and potentially hazardous side effects of available pharmacological options. In selected patients with HCM and severely symptomatic AF, radiofrequency catheter ablation may represent an effective therapeutic alternative, improving functional status, and reducing or postponing the need for antiarrhythmic drugs. In patients with persistent AF, in whom maintenance of sinus rhythm is not feasible, adequate ventricular rate control should be pursued aggressively by atrio-ventricular node blocking agents. PMID- 19791464 TI - [Septal myectomy for obstructive hypertrophic cardiomyopathy: the gold standard]. AB - Septal myectomy effectively and definitively relieves LVOT obstruction and cardiac symptoms in adults and children with obstructive hypertrophic cardiomyopathy (HCM). Abnormalities of the mitral valve can be addressed without the need for mitral valve replacement in almost all circumstances. Concomitant mitral valve repair for myxomatous disease requires minor modifications when performed in conjunction with septal myectomy; mitral valve replacement is rarely necessary. In experienced centers, early mortality for isolated septal myectomy is low (approximately 1%) and overall results are excellent and continue to improve in the current era. Symptomatic improvement with myectomy is expected for most; 90% of patients improve by at least one functional class, and most remain improved on late follow-up. Late survivorship is improved compared to nonoperated patients with obstructive HCM, and myectomy may be associated with reduced risk of sudden cardiac death. These results should serve as the gold standard and a basis for comparison with newer nonsurgical modalities, i. e., septal alcohol ablation. PMID- 19791465 TI - [Influence of JUPITER to the current practice for prevention and therapy of coronary heart disease]. PMID- 19791466 TI - [Clinical study of idiopathic dilated cardiomyopathy complicated by left ventricular aneurysm]. AB - OBJECTIVE: To examine the hemodynamic and electrophysiological influence of left ventricular aneurysm (LVA) formation in patients with idiopathic dilated cardiomyopathy (IDCM). METHODS: All hospital records were retrospectively reviewed from IDCM patients admitted to our hospital between 2003 and 2008. Patients with coronary angiography evidenced ischemic cardiomyopathy were excluded. IDCM patients with LVA (I + L) diagnosed by left ventriculography were enrolled. Twelve age-, gender- and left-ventricular-diameter- matched patients with IDCM without LVA served as control group (I - L). RESULTS: Six out of 998 patients with IDCM were confirmed to have LVA (0.60%). The LV peak-systolic pressure was higher in the I + L group than in I - L group [ (130 +/- 10) mm Hg (1 mm Hg = 0.133 kPa) vs. (117 +/-9) mm Hg, P < 0.05]. The LV end-diastolic volume was significantly larger in the I + L group than in I-L group[ (272 +/- 57) ml vs. (207 +/- 60) ml, P < 0.05]. The LV ejection fraction was slightly lower in the I + L group than in I - L group [ (27 +/- 9)% vs. (35 +/- 6)%, P = 0. 09]. Ventricular arrhythmia occurred more frequently in I + L group than in I L group. CONCLUSION: LVA formation in IDCM was a rare phenomenon. IDCM patients with LVA seem to have higher LV peak-systolic pressure, larger end-diastolic volume, worse LV systolic function and more frequent ventricular arrhythmia than those without LVA. PMID- 19791467 TI - [The clinical characteristics of 5 patients with inherited hypertrophic cardiomyopathy]. AB - OBJECTIVE: To explore the clinical characteristics of patients with inherited hypertrophic cardiomyopathy. METHODS: The clinical characteristics, electrocardiogram, serum chemistry and diagnostic methods were retrospectively investigated in 5 patients with inherited hypertrophic cardiomyopathy. RESULTS: The electrocardiograms of all patients were abnormal, with prominent left ventricular voltage and ST-T changes. One male patient with clinicopathological features of early onset, muscle weakness, ventricular preexcitation, elevations of two serum proteins and intracytoplasmic vacuoles containing autophagic material and glycogen in biceps brachial muscle cells was diagnosed Danon's disease. Mitochondrial cardiomyopathy was diagnosed in one male patient with early onset, short PR interval and biopsy findings of ragged-red fibers in biceps brachial muscle. Three patients were diagnosed as Fabry's disease with clinical characteristics including pain and acroparesthesias, angiokeratoma and decrease of alpha-galactosidase A activity. CONCLUSION: Some of the rare inherited hypertrophic cardiomyopathy might easily be clinically misdiagnosed as hypertrophic cardiomyopathy, systemic and careful case history inquiring and specific relevant examinations would help to make the right diagnosis in these patients. PMID- 19791468 TI - [Peroxisome proliferator-activated receptor alpha and retinoid X receptor alpha expressions and intervention in alcoholic cardiomyopathy rats]. AB - OBJECTIVE: To investigate the effects of carnitine on cardiac function, collagen contents, peroxisome proliferator-activated receptor alpha (PPARalpha) and retinoid X receptor alpha (RXRct) expressions in a rat alcoholic cardiomyopathy modeL. METHODS: Adult male Wistar rats were randomly divided into alcohol group (A) , alcohol/carnitine group (B) and control group. Six months later, protein expressions of collagen I, collagen III, matrix metalloproteinase-9 (MMP-9) and Smad-3 were determined by immunohistochemical staining. Protein expressions of PPARalpha and RXRalpha were detected by Western blot. RESULTS: Expressions of collagen I, collagen III, MMP-9 and Smad-3 were significantly increased in groups A and B compared to group C (P < 0.01 or P < 0.05). Expressions of PPARalpha and RXRalpha (0.156 and 0.192, respectively, in group A; 0.248 and 0.385, respectively, in group B) were decreased compared to group C (P < 0.01 or P < 0.05). These changes were significantly attenuated by carnitine (all P < 0.05, group B vs. group A). Moreover, PPARalpha and RXRalpha positively correlated with EF and FS, and negatively correlated LVEDd, collagen I , collagen III, MMP-9 and Smad-3 (all P < 0.01). CONCLUSION: PPARalpha and RXRalpha downregulation is significantly correlated with cardiac dysfunction in this alcoholic cardiomyopathy model, carnitine ameliorated the cardiac fibrosis and remodeling possibly through upregulating the metabolic pathways of PPARalpha and RXRalpha. PMID- 19791469 TI - [Clinical manifestations of premenopausal women with coronary arterial disease]. AB - OBJECTIVE: To compare clinical characteristics among premenopausal women with coronary arterial disease (CAD) with or without atherosclerosis (AS) and postmenopausal women with CAD. METHODS: The clinical and coronary angiographic data, traditional risk factors (age, smoking, blood pressure, lipid profile, blood glucose, BMI, family history) were compared among premenopause (Pre-M, n=42) and post-menopause (Post-M, n=172) women with CAD as well as Pre-M patients with non-AS CAD (non-AS CAD, n=8). RESULTS: Compared with the Post-M patients with CAD, Pre-M CAD patients had significantly fewer traditional risk factors, such as hypertension, diabetes and hypercholesterolemia, significantly more acute coronary syndrome and fewer previous history of chest pain, significantly more single vessel lesion and lower Gessini score (all P < 0. 01). The logistic regression results showed that obesity is an independent risk factor for the development of CAD in premenopausal women (OR = 3. 655, 95% CI: 1. 5-11.59, P = 0.028). Hypertension (OR = 4.73, 95% CI: 0.991-22.589, P = 0.051) and hypercholesterolemia (OR = 4.68, 95% CI: 0.971-22.564, P = 0.055) might also contribute to the development of CAD in these patients. Clinical characteristics were similar between Pre-M and non-AS CAD patients (P > 0.05). CONCLUSIONS: Pre-M CAD patients had less traditional risk factors and lower coronary lesion score compared to post-M CAD patients. Obesity is an independent risk factor for Pre-M CAD. Non-AS coronary artery disease is also an important reason for the development of coronary arterial events in premenopausal women. PMID- 19791470 TI - [Effects of statins on coronary atherosclerotic plaque in patients with coronary heart disease and type 2 diabetes with mild elevated LDL-C]. AB - OBJECTIVE: To evaluate the effects of statins on coronary atherosclerotic plaque in patients with stable angina pectoris and type 2 diabetes with mild elevated low density lipoprotein-cholesterol (LDL-C). METHODS: Seventy-eight patients with stable angina pectoris and type 2 diabetes mellitus and mild elevated LDL-C were treated with (n=40) or without (n=38) statins for 12 months. Coronary artery angiography (CAG) and intravascular ultrasound (IVUS) were performed at baseline and after 12 months on lesion and reference segment to compare the plaque volume, lumen volume, vascular volume and remodeling index was calculated as vascular volume index (VVI) at lesion divided by VVI at reference segment One coronary lesion with 50%-70% stenosis was selected as target plaque in each patient. RESULTS: Baseline clinical and angiographic data were comparable between the two groups. After 12 months, LDL-C decreased 31.5% in statin group and remained unchanged in non-statin group. After 12 months, plaque volume was significantly increased [ (76.1 +/- 13.0) mm3 vs. (95.0 +/- 21.9) mm3 , P < 0.05], lumen volume was significantly decreased [(65.0 +/- 10.9) mm3 vs. (45.4 +/- 6.6) mm3, P < 0.05 ] and vascular volume remained unchanged in non-statins group; plaque volume was also significantly increased [(79.5 +/- 15.2) mm3 vs. (87.5 +/- 17.9) mm3 , P < 0.05] while lumen volume and vascular volume remained unchanged in statin group. Remodeling index (RI) remained unchanged in non-statin group but significantly increased in statin group (0.91 +/- 0.08 vs. 0.95 +/- 0.10, P < 0.05) after 12 months. CONCLUSION: Chronic statin therapy could retard the coronary atherosclerotic progression in patients with stable angina pectoris and type 2 diabetes with mild elevated LDL-C. PMID- 19791471 TI - [Accuracy of prenatal diagnosis of congenital heart defects by fetal echocardiography: a 7-year experience in a Chinese tertiary obstetric center]. AB - OBJECTIVE: To evaluate the prenatal diagnostic accuracy of fetal echocardiography for congenital heart defects. METHODS: Fetal echocardiographic databases from 2001 to 2007 were searched for patients with a prenatal diagnosis of congenital heart defect, medical records were obtained and the prenatal echocardiographic findings were correlated with postnatal echocardiography results or autopsy findings, if the pregnancy was terminated or the fetus died in utero. RESULTS: Prenatal diagnosis of congenital heart defects was made in 113 pregnancies at a mean gestational age of 26.8 weeks. Pathology or postnatal echocardiography was available in 79 cases (70%) and the accuracy of prenatal diagnosis was 86% (68/79). Prenatal diagnosis was accurate in 24 of 31 patients (77%) with conotruncal malformations, 26 of 27 patients (96%) with septal defects, 9 of 10 patients (90%) with valve abnormalities, and 5 of 6 patients (83%) with univentricular hearts. There were 4 false-positives and the positive predictive value was 95% (75/79). CONCLUSION: Fetal echocardiography is a reliable tool for prenatal diagnosis of congenital heart defects despite limitations for correctly diagnosing some specific fetal heart defects. PMID- 19791473 TI - [The effects of simvastatin on cardiac hypertrophy and association on calcium channel modulation in rats with myocardial hypertrophy induced by abdominal aortic constriction]. AB - OBJECTIVE: To investigate the effects of simvastatin (SIM)on cardiac hypertrophy and association with calcium channel modulation in rats with myocardial hypertrophy. METHODS: Myocardial hypertrophy was induced by abdominal aortic constriction (AAC) in adult SD rats. Following groups were studied (n=8 each): sham group, AAC group, AAC+ verapamil group (10 mg x kg(-1) x d(-1) per gavage for 4 weeks), AAC +SIM group (10 mg x kg(-1) x d(-1) per gavage for 4 weeks) AAC + SIM + mevalonic acid (50 mg x kg(-1) x d(-1) per gavage for 4 weeks) group. Systolic blood pressure (SBP), echocardiography, heart weight/body weight (HW/BW) and left ventricle weight/body weight (LVW/BW) ratios were measured. The protein and mRNA expressions of L-type calcium channel subunit alpha1 C and T-type calcium channel subunit alpha1 G and alpha1 H were detected by Western blot and RT-PCR respectively. RESULTS: SBP, HW/BW, LVW/BW, IVS and LVPW thickness, left ventricular weights were significantly increased in AAC rats and these effects could be significantly reduced by verapamil and SIM. The protein and mRNA expressions of alpha1 G and alpha1 H were significantly increased in AAC rats which could also be significantly inhibited by SIM or verapamil. The effects of SIM could be blocked by cotreatment with mevalonic acid. Protein and mRNA expressions of L-type calcium channel alpha1 C were similar among groups. CONCLUSION: Similar as verapamil, SIM could prevent AAC induced cardiac hypertrophy, possibly via inhibiting T-type calcium channel subunit alpha1 G and alpha1 H re-expression. PMID- 19791472 TI - [Effects of bone marrow mesenchymal stem cells transplantation on heart function and ventricular remodeling in rats with isoproterenol-induced congestive heart failure]. AB - OBJECTIVE: To explore the effects of transplanted BMSCs (bone marrow mesenchymal stem cells) on cardiac function and ventricular remodeling in rats with isoproterenol (ISO) induced heart failure. METHODS: Wistar rats (n=50) received ISO (170 mg x kg(-1) x d(-1) for 4 days) injection. Four weeks later, rats with left ventricular ejection fraction (LVEF < 70%, n=26) were randomly assigned to receive intramyocardially BMSCs (2 x 10(7)/ml, 150 microl) injection (n=13) or equal volume culture medium (n=13). Another 10 normal rats served as normal controls. Four weeks after transplantation, heart function was assessed again by echocardiography, left ventricular morphology was evaluated through H&E and Masson's trichome staining. Transplanted cells were observed by fluorescent microscope. RT-PCR and Western blot were performed to examine the myocardial expressions of type I and type III collagens, as well as MMP-2 and MMP-9. RESULTS: LVEF [(78.51 +/- 6. 78)% vs. (65.40 +/- 12. 33)%] and LVFS [fractional shortening, (42.09 +/- 6. 53)% vs. (32.38 +/- 10. 22)%, all P < 0. 05] were significantly increased and LVDs [left ventricular systolic diameter, (2.91 +/- 0. 54) mm vs. (3.83 +/- 0.69) mm, P < 0.05] was significant decreased in BMSCs treated rats compared with culture medium treated rats. Myocardial fibrosis was also significantly attenuated in BMSCs rats than that in culture medium treated rats. The myocardial expressions of type I and type III collagens, as well as MMP 2 and MMP-9 were significantly decreased in the BMSCs group compared with those in culture medium treated group. CONCLUSIONS: BMSCs transplantation can significantly improve heart function and attenuate LV remodeling in rats with ISO induced heart failure mediated by reducing myocardial fibrosis and downregulation of myocardial MMP-2 and MMP-9 expressions. PMID- 19791475 TI - [Differences in goal attainment in clinical management of dyslipidemia in China evaluated by different guidelines]. AB - OBJECTIVE: To better understand the similarities and disparities between the newly issued Chinese Guidelines on Prevention and Treatment of Dyslipidemia in Adults (CG) and exist relevant guidelines by comparing the actual effect on assessment of current clinical management of dyslipidemia in China, in order to promote the use of CG in clinical practice. METHODS: Study participants included 2094 patients from the Second Multi-center Survey of Dyslipidemia Management in China. The goal attainment rate was defined as the proportion of participants who achieved their target low-density lipoprotein cholesterol (LDL-C) levels specified by CG, the Chinese Expert Recommendations on Prevention and Treatment of Dyslipidemia (CR), the updated Adult Treatment Panel III of the National Cholesterol Education Program (ATP III), respectively. RESULTS: (1) The overall goal attainment rates were 62%, 34% and 50% according to CR, ATP III and CG, respectively. (2) With reference to the CG risk stratifications, the risk of nearly 40% of high risk patients and all very high risk patients were underestimated by CR, whereas the risk of more than 40% of patients in any risk groups were overestimated by ATP III. (3) The disparities in risk stratifications accounted for 90% of the difference in overall goal attainment rate (12%) between CR and CG, while the disparities in the risk stratifications and that in LDL-C target levels were responsible for 29% and 71% of the difference (16%) , respectively, between ATP III and CG. CONCLUSIONS: There were significant differences in goal attainment rates assessed by different clinical practice guidelines. CG is more aggressive in risk stratification than CR but simpler and easier to use than ATP III, and hence more appropriate to Chinese patients and should be widely promoted in China. PMID- 19791474 TI - [On angiotensin II receptor distribution after myocardial infarction in dogs]. AB - OBJECTIVE: To investigate the effects of valsartan on expression of angiotensin II receptors in different regions of heart after myocardial infarction (MI). METHODS: Canines were divided into sham-operated control group (n=7), infarction group (n=7) and Valsartan group (10 mg x kg(-1) x day(-1) for 4 weeks after MI operation, n=7). Four weeks after operation, Doppler tissue imaging (DTI) was used to evaluate regional ventricular function in the noninfarcted myocardium (apical and basal near to the infarction region). The mRNA and protein expressions of angiotensin II type 1 receptor (AT1-R) and angiotensin II type 2 receptor (AT2-R) on the corresponding regions were detected by competitive reverse-transcriptase polymerase chain reaction technique and immunohistochemical technique respectively. Results The protein and mRNA expressions of AT1-R were significantly increased in both apical and basal regions near to the infarction in dogs with MI compared with those in control group (P < 0.05) which could be downregulated by valsartan (P < 0.05). AT2-R expressions were significantly upregulated in infarction group in both apical and basal regions compared with those in control group and valsartan further increased AT2-R expressions in both areas (P < 0.05). Myocardial peak systolic velocity (Sm), myocardial peak early diastolic velocity (Em) and myocardial peak late diastolic velocity (Am) at both apical and basal regions near to the infarction regions were significantly lower in MI group than those in the control group which could be significantly improved by valsartan. CONCLUSION: Both mRNA and protein expressions of AT1-R and AT2-R are upregulated in noninfarcted regions near MI, valsartan improved myocardial function via inhibiting AT1-R upregulation and enhancing AT2-R upregulation. PMID- 19791476 TI - [Correlation between body mass index, waist circumference and blood pressure in rural residents from west part of Liaoning Province]. AB - OBJECTIVE: This study observed the association between body mass index (BMI), waist circumference (WC) and blood pressure level in rural residents from west Liaoning province. METHODS: This epidemiological study using stratified cluster random sampling was conducted from 2004 to 2006 in Fuxin County, Liaoning Province, 43,692 rural residents (21,680 males) aged 35-74 years old [(49. 8 +/ 10.2) years] were surveyed. Database was established with the help of Epidata 3.1 software. RESULTS: In total 43,692 persons were surveyed, including 21,680 male (49.6%) and 22,012 female (50.4%). The average BMI and WC was (23.31 +/- 3.08) kg/m2 and (80.87 +/- 9.0) cm, respectively. No matter male or female, SBP started from 20 kg/m2, increased with the increase of BMI; DBP increased gradually with the increase of BMI; the prevalence of hypertension were significant differences among different BMI groups (P < 0.001). Multiple logistic regression show that in male, using the group with BMI, <18 kg/m2 as control, 28-30 kg/m2 group OR and 95% CI was 6.285 (4.612-8.566); in female, when BMI >22 kg/ m2 OR increased with the increasing of BMI. In male and female, both SBP and DBP, also the prevalence rate of hypertension increased gradually with the increase of WC (P < 0.001). No matter in male or female, when BMI <24 kg/m2, and WC male <85 cm, female WC <80 cm, the average blood pressure levels and prevalence of hypertension are the lowest; after adjusting for age and other risk factors, the prevalence rate of overweight and obesity for male with hypertension OR are 1.704 (1.592-1.825) and 3.710 (3.148 -4.371) , respectively, for female is 1.527 (1.428-1.632) and 3.014 (2.668-3.405), respectively. When the WC is higher than the standard, male and female hypertension risk OR and 95% CI are 1.231 (1.153-1.314) and 1.353 (1.269 1.442), respectively. CONCLUSION: Both BMI and WC are risk factors of hypertension. PMID- 19791477 TI - [Pharmacogenomics of hydrochlorothiazide]. PMID- 19791478 TI - Diabetes study findings: what do they mean? PMID- 19791479 TI - Start the school year off right with proper oral health care. PMID- 19791481 TI - The all-school health & wellness advocate: School nurses establish innovative programs to benefit greater school community. PMID- 19791480 TI - Blood pressure: for these kids, it's vital. PMID- 19791482 TI - Electronic health records. PMID- 19791483 TI - A community hospital's journey into Lean Six Sigma. AB - The implementation of Lean Six Sigma and 100-day workouts throughout the 304-bed Floyd Medical Center community hospital organization has led to sustainable results and a marked change in culture. The organization-wide learning of such an effort is deep and intehse, and to remain focused and successful it must be a priority of top management. The workout methodology can assist the organization to carry projects to completion and to achieve rapid implementation of desired improvements. PMID- 19791484 TI - The missing link: Lean leadership. AB - People often equate "Lean" with the tools that are used to create efficiencies and standardize processes. However, implementing tools represents at most 20 percent of the effort in Lean transformations. The other 80 percent of the effort is expended on changing leaders' practices and behaviors, and ultimately their mindset. Senior management has an essential role in establishing conditions that enable that 80 percent of the effort to succeed. Their involvement includes establishing governance arrangements that cross divisional boundaries, supporting a thorough, long-term vision of the organization's value-producing processes, and holding everyone accountable for meeting Lean commitments. This is accomplished through regular, direct involvement. When upper management sets the example, durable Lean success and an increasingly Lean leadership mindset follow. PMID- 19791485 TI - Why are we still underperforming? PMID- 19791486 TI - Lean at the front line: all hands on deck. PMID- 19791487 TI - Lean in healthcare--wow. PMID- 19791488 TI - [Abdominal pain and rectal blood loss]. AB - The medical history of a 46-year-old man recorded osteomas in the maxillary bone 18 years before, haemorrhoids, and kidney stones. He presented with pain in the right lower abdomen and rectal blood loss. His complaints were diagnosed as familial adenomatous polyposis, culminating in sigmoid carcinoma. Due to the extent of the polyps and, consequently, the great cancer relapse risk, a surgical treatment was indicated. A symptom ofa familial adenomatous polyposis variant, Gardner's syndrome, is osteomas in the orofacial region. Dentists and oral surgeons should be aware of this rare syndrome in a patient with orofacial osteomas, especially if the patient has a familial risk of adenomatous polyposis. PMID- 19791489 TI - [Burning mouth caused by denture material]. AB - A 60-year-old man with an edentulous maxilla was referred by his dentist to an allergy clinic with complaints of burning mouth and bad taste. In the majority of cases, it is hard or impossible to detect the cause of burning mouth. In this case, ultimately the complaint could be solved by eliminating exposure to possible allergenic components of denture base resins. PMID- 19791490 TI - [Mouthwashes are a waste of money]. PMID- 19791491 TI - [Heroin and oral health]. AB - Heroin is a half synthetic opiate with. It is used by a relatively small number of the general population, but relatively frequently by homeless people and prisoners. Since heroin has an inhibitory effect on the nervous system and on breathing, an overdose of heroin can have fatal consequences. Sudden abstinence of heroin results in general discomfort, restlessness, muscle cramps, perspiration, nausea, shivers and goose bumps. Oral effects of heroin include increased risks of caries, periodontitis and bruxism. Saliva has the potential of detecting heroin abuse. PMID- 19791492 TI - [Quality of dental care: new ideas of the government]. AB - In the 1990s the Dutch government imposed several laws to strengthen the position of the patient and to improve the quality of care. These laws did not always have the intended outcome. Recently the Ministry of Public Health, Welfare and Sport launched the programme, 'The 7 rights of the patient in health care: investing in health care relations'. Three of these rights will have a strong influence on Dutch general dental practices: the right to choice and choice-information, the right concerning coordination among oral health care providers, and the right to low-threshold complaint and disagreement procedures. Most of these rights already exist in current legislation. Especially the right to choice and choice information means that the dentist has to provide his patients not only with information concerning treatment but also with information on his dental practice, such as waiting times, the experience of other patients and opening times. PMID- 19791493 TI - [An endodontic ultrasonic system for apical endodontic surgery]. AB - Apical endodontic surgery is applied frequently following a failed conventional endodontic treatment. The apical preparation can be carried out conventionally using a round bur or using an endodontic ultrasonic system. The purpose of this study was to compare the outcome of the 2 treatment options by a randomized prospective clinical study. Patients (n=399) were at random allocated to treatment using a conventional round bur or using an ultrasonic system (P-max Newtron) according to a for the rest similar treatment protocol. One year post treatment, the treatment outcomes were determined by 2 oral and maxillofacial surgeons, blinded for the treatment option. Adequate follow-up data were obtained from 290 patients. The overall success rate was 71% in the patients treated conventionally and 81% in the patients treated using the ultrasonic system. In molar teeth, the difference in success rate was statistically significant. PMID- 19791494 TI - [Recently graduated dentists: working situation and future plans]. AB - The Dutch Dental Association (NMT) surveyed dentists who graduated in 2004, 2005 or 2006 concerning their work situation and plans for the future. They were also asked about their experiences at the start of their career In general, the recently graduated dentists did not face difficulties at the start of their professional life. Most dentists worked in the practice of a colleague, but the majority ultimately wanted to have their own practice. The latter applied more to men than women. Furthermore, there was a clear preference for working within a team and most of them planned to specialize in a specific branch of dentistry. The survey also revealed that the delegation of tasks to dental hygienists and prevention assistants was more or less taken for granted by recently graduated dentists. PMID- 19791495 TI - Is the concept of photosynthetic units verified? AB - The cornerstones of the first fundamental concept of photosynthetic machinery, i.e. the concept of photosynthetic units, are reconsidered and a new logically and experimentally well sustained interpretation of the crucial observations of this hypothesis is presented. The results obtained lead to the conclusion that under low irradiances all chlorophyll molecules are in a state to perform charge separation (photochemical) reaction, while under increased irradiances the essential part of the reaction centres are blocked and only one reaction centre from 500-600 remains in functionally active state, i.e. in the range of the value obtained by the founders of the widely accepted concept of photosynthetic units. PMID- 19791496 TI - LC-MS and LC-PDA analysis of Hypericum empetrifolium and Hypericum sinaicum. AB - Within the framework of our continuous efforts to explore Hypericum species from Jordan, we report the analysis of the major active metabolites, naphthodianthrones and phloroglucinols, in the methanolic extracts of two under explored Hypericum species; H. empetrifolium Willd. and H. sinaicum Hochst. & Steud. ex Boiss., using LC-(+,-)-ESI-MS (TIC and SIM) and LC-UV/Vis spectroscopy. Based on their LC-UV/Vis profiles, retention times and (+,-)-ESI-MS (TIC and SIM) spectral data, hypericin, protohypericin and pseudohypericin were identified in both of the investigated species. In addition adhyperfirin was only detected in H. empetrifolium, while hyperforin and protopseudohypericin were only detected in H. sinaicum. This is the first report documenting the presence of hypericin, protohypericin, pseudohypericin, protopseudohypericin, and hyperforin in H. sinaicum, and adhyperfirin in H. empetrifolium. PMID- 19791497 TI - Antiviral and antischistosomal evaluation of newly synthesized thioglycosides and their acyclic analogues. AB - The pyrimidine thione derivatives 2a-d were prepared by the reaction of thiourea, ethyl cyanoacetate and several aromatic aldehydes. The acyclic thioglycosides 4a 7d were prepared by the reaction of the synthesized pyrimidine thiones 2a-d with different alkyl halides, whereas the reaction of 2a-d with 2,3,4,6-tetra-O-acetyl alpha-D-glucopyranosyl bromide afforded the cyclic thioglycosides 8a-d whose deprotection afforded 9a-d. The obtained compounds were tested for their antischistosomal and antiviral activity against hepatitis B virus (HBV). Compounds 5a, 5d, 7a showed high activity against HBV using the MTT assay; moreover compounds 5c, 6d, 7a, 9a, 9c exhibited high activity as antischistosomal agents. PMID- 19791498 TI - Antiproliferative activity on human cancer cell lines after treatment with polyphenolic compounds isolated from Iris pseudopumila flowers and rhizomes. AB - The present study describes the antiproliferative properties of Iris pseudopumila flowers and rhizomes extracts and fourteen constituents isolated from them. The in vitro cytotoxic activity assay against two human cancer cell lines, large lung carcinoma (CORL-23) and amelanotic melanoma (C32), showed that the most antiproliferative extract was the MeOH extract from flowers with a percentage of inhibition of 50.9 at 100 microg/ml against amelanotic melanoma cells. The most antiproliferative compounds against amelanotic melanoma cells were kaempferol-3-O beta-D-glucopyranoside and irisolidone with a percentage of inhibition of 100 and 96.6, respectively, and against large lung carcinoma cells with a percentage of inhibition of 82.1 and 84.6, respectively. Significant activity on the amelanotic melanoma cell line was also showed by irigenin-7-O-beta-D-glucopyranoside, with a percentage of inhibition of 89.3. The compounds isovitexin and isoorientin-6-O'' beta-D-glucopyranoside showed a selective activity against amelanotic melanoma cells with a percentage of inhibition of 83.2 and 79.8, respectively. PMID- 19791499 TI - Phytoconstituents of Jatropha curcas L. leaves and their immunomodulatory activity on humoral and cell-mediated immune response in chicks. AB - A novel biflavone di-C-glucoside, 6,6"-di-C-beta-D-glucopyranoside-methylene (8,8")-biapigenin (1), was isolated from the leaves of Jatropha curcas L. (Euphorbiaceae), together with six known compounds; apigenin 7-O-beta-D neohesperidoside (2), apigenin 7-O-beta-D-galactoside (3), orientin (4), vitexin (5), vicenin II (6), and apigenin (7). Their structures were determined on the basis of extensive chemical and spectroscopic analyses (UV, NMR and HRESI-MS). The immunomodulatory effect of an 80% aqueous methanol extract (AME) and compounds 1-5 (0.25 mg/kg body wt) to one-day-old specific pathogen-free (SPF) chicks was determined. Stimulation of both humoral and cell-mediated seroresponse was observed, especially those of AME and compound 1. Remarkable effective increases of the antibody titers, lymphocyte and macrophage cells, in blood were recorded. SPF chicks treated with the tested samples exhibited protection against Newcastle disease challenge virus after being vaccinated. PMID- 19791500 TI - Antifeedant activity of anticopalic acid isolated from Vitex hemsleyi. AB - The known labdane-type diterpenoids anticopalic acid (1) and 3 beta hydroxyanticopalic acid (2) were isolated from extracts of the aerial parts of Vitex hemsleyi Briq. (Labiatae). The acid 1 showed an antifeedant, dose-dependent activity against Spodoptera frugiperda (J. E. Smith) (Lepidoptera: Noctuidae). To our knowledge this is the first report on the antifeedant activity of a labdane type diterpene against S. frugiperda. PMID- 19791501 TI - Bioactivity of flavonoids isolated from Lychnophora markgravii against Leishmania amazonensis amastigotes. AB - The bioactivity of the flavonoids pinostrobin (1), pinocembrin (2), tectochrysin (3), galangin 3-methyl ether (4), and tiliroside (5) isolated from Lychnophora markgravii aerial parts was investigated in vitro against amastigote stages of Leishmania amazonensis. The compounds were isolated by several chromatographic techniques and their chemical structures were established by ESI-MS and NMR spectroscopic data. The flavonoids 1 and 3 were the most active compounds; they markedly reduced the viability of Leishmania amastigotes. PMID- 19791502 TI - Biological activity of a phloroglucinol glucoside derivative from Conyza aegyptiaca. AB - The phloroglucinol glucoside derivative [2,4-dihydroxy-6-(beta-D glucopyranosyloxy)phenyl]-butan-1-one (1), roseoside (2), and kaempferol-3-O-beta D-glucopyranoside (3) were isolated from the aerial parts of Conyza aegyptiaca (L.). To the best of our knowledge, this is the first isolation of compounds 1-3 from C. aegyptiaca. Their structures were determined by spectroscopic techniques including, IR, HR-EIMS, and extensive 500 MHz 1D- and 2D-NMR analyses (1H, 13C NMR, DEPT, 1H-1H COSY, HMQC and HMBC experiments). The antioxidant activity of 1, using the DPPH assay, was investigated; in addition, 1 was investigated against different types of cell lines, including Hep-G2, HCT-116, and RAW 264.7 for its cytotoxic effects. Also, this is the first report on the activity of 1. PMID- 19791503 TI - Cytotoxic activities of endophytic fungi isolated from the endangered, Chinese endemic species Dysosma pleiantha. AB - Eleven strains of endophytic fungi which habitat in an endangered, Chinese endemic medicinal plant, Dysosma pleiantha (Hance) Woodson, were isolated and tested for their cytotoxic activity using the brine shrimp lethality bioassay. Six isolates were found to exhibit some cytotoxic activity. Extracts of F1273, F1276, and F1280, which were identified as Trichoderma citrinoviride, Chaetomium globosum and Ascomycete sp., in particular, showed most potent activity with LC50 values of 4.86, 7.71, and 14.88 microg/ml, respectively. These results indicate that endophytic fungi of Dysosma pleiantha could be a promising source for antitumour agents. PMID- 19791504 TI - New caloporoside derivatives and their inhibition of fungal spore germination. AB - In our ongoing screening culture fluid extracts of Gloeoporus (Caloporus) dichrous strain 83065 inhibited the germination of Magnaporthe grisea and Fusarium graminearum spores. While isolating the active metabolites two new caloporosides, caloporoside G and caloporoside H, in addition to the known caloporoside derivatives F-16438G, caloporoside A, and 2-hydroxy-6-(16 hydroxyheptadecyl)benzoic acid were obtained. PMID- 19791505 TI - Glucose signaling pathway and growth conditions regulate gene expression in retrotransposon Ty2. AB - Gene expression in the yeast retrotransposon Ty2 is regulated at transcriptional and translational levels. In this study, we have shown that the transcription of Ty2 is partially dependent on the membrane-bound glucose sensors Gpr1p and Mth1p in Saccharomyces cerevisiae. Transcription of Ty2 decreased approx. 3-fold in the gpr1, mth1 yeast mutant. Moreover, our results revealed that the transcription of Ty2 fluctuates during the growth stages of S. cerevisae. Both transcription and the frameshift rate of Ty2 rapidly dropped when the stationary stage yeast cells were inoculated into fresh medium. There was an instant activation of Ty2 transcription and a high level expression during the entire logarithmic stage of yeast growth. However, the transcription of Ty2 decreased 2-fold when the yeast cultures entered the stationary stage. The frameshift rate in Ty2 also varied depending on the growth conditions. The highest frameshift level was observed during the mid-logarithmic stage. It decreased up to 2-fold during the stationary stage. Furthermore, we have found that the frameshift rate of Ty2 diminished at least 5-fold in slowly growing yeasts. These results indicate that the transcription and the frameshift efficiency are coordinately regulated in the retrotransposon Ty2 depending on the growth conditions of S. cerevisiae. PMID- 19791506 TI - In vitro cultures of Cyclopia plants (honeybush) as a source of bioactive xanthones and flavanones. AB - In vitro shoot and callus cultures of the endemic South-African shrubs: Cyclopia intermedia E. Mey., Cyclopia subternata Vogel, and Cyclopia genistoides (L.) Vent. (Fabaceae) were established and examined for the presence of polyphenolic compounds. The xanthones mangiferin and isomangiferin, as well as the flavanones hesperidin and eriocitrin were identified by LC-ESI-MS and LC-DAD, and analyzed quantitatively by HPLC. The respective intact plants were analyzed for comparison. From all in vitro cultures, the highest levels of mangiferin (1.55%) and isomangiferin (0.56%) were recorded in C. subternata microshoots, compared to 1.31% and 0.49% found in the intact plant. Callus cultures of all species synthesized only trace amounts of mangiferin and isomangiferin. Hesperidin and eriocitrin contents were significanly lower in all in vitro cultures, in comparison to the respective intact plants. Among the obtained in vitro biomasses, the highest hesperidin content was recorded in C. intermedia (0.9%) and C. subternata (0.87%) microshoots, whereas C. subternata callus was characterized by the best growth parameters and highest hesperidin content (0.69%) from all examined Cyclopia calli. PMID- 19791507 TI - Effect of abiotic and biotic elicitors on growth and alkaloid accumulation of Lycoris chinensis seedlings. AB - Three-month-old seedlings of Lycoris chinensis were treated with biotic and abiotic elicitors: yeast elicitor (YE), methyl jasmonate (MJ), salicylic acid (SA), and sodium nitroprusside as NO donator (NO). We have shown that the addition of MJ and NO promotes the accumulation of galanthamine in these seedlings. The effect of these elicitors on the growth of the seedlings, as well as on the amount of the alkaloids accumulated in the seedlings was studied. The results showed that, in general, high doses of MJ and SA had a negative effect on the growth of the seedlings, while appropriate doses of NO and YE had a positive effect on the growth of the seedlings. It was remarkable that the addition of MJ, NO, and YE can promote galanthamine accumulation in seedlings. The accumulation was higher in treatments at higher concentrations of NO (100 microM), where the release of galanthamine was 1.72-fold higher than that of the control at the 10th day of culture. The highest values of lycorine were obtained in seedlings treated with YE at a concentration of 0.01 g/l and by the 10th day of culture; the level was 1.38 times of the control. PMID- 19791508 TI - Structure-activity relationship of taxol inferring from docking taxol analogues to microtubule binding site. AB - In order to find the minimal structural requirements to maintain microtubule binding, 12 taxol analogues have been docked to the taxol binding site of tubulin. By comparing the interactions of each analogue with beta-tubulin, the structure-activity relationships are summarized as follow: C-2 benzoyl and taxane ring systems are the essential groups for microtubule binding, the improvements of bioactivity and bioavailability are dependent on the substituents at positions C-1, C-4, C-7, C-9, C-10, and C-14, whereas the C-13 side chain mainly provides a specific binding. PMID- 19791509 TI - Genetic stability, active constituent, and pharmacoactivity of Salvia miltiorrhiza hairy roots and wild plant. AB - Salvia miltiorrhiza is an annual plant growing in China, Mongolia, Korea and some other Asian countries. The extract from S. miltiorrhiza roots has been used for supporting healthy cardiovascular and circulatory systems during the last decade. The active constituents of S. miltiorrhiza from different areas vary significantly, and the wild resources are overexploited. To adapt the demand for active constituents of S. miltiorrhiza against cardiovascular-related diseases, alternative materials need to be developed. The aim of the present work was to investigate the possibility of S. miltiorrhiza hairy roots as the alternative materials. The results showed that S. miltiorrhiza hairy roots are genetically stable. The contents of salvianolic acid B and tanshinone IIA, two main active constituents in hairy roots, determined by the assessment of combining flow cytometry and phytochemical analysis, are comparable to or significantly lower than in wild plant roots. The extract from S. miltiorrhiza hairy roots also had similar protection activity for hypoxia and reoxygenation injury in rat cardiac myocytes like that from wild plant roots. S. miltiorrhiza hairy roots may be alternative materials to obtain the drug or healthy food for cardiovascular related diseases. PMID- 19791510 TI - Isolation and expression analysis of two DOPA dioxygenases in Phytolacca americana. AB - Betacyanins and anthocyanins, two main red flower pigments, never occur together in the same plant. Although the anthocyanin biosynthetic pathway has been well analyzed, the biosynthetic genes and the regulatory mechanism of the betacyanin biosynthesis are still obscure. We cloned two cDNAs of DOPA dioxygenase from Phytolacca americana, PaDOD1 and PaDOD2, that may be involved in the betalain biosynthesis. The deduced amino acid sequence of PaDOD1 and PaDOD2 showed approximately 80% homology to each other. The promoter regions of PaDOD1 and PaDOD2 were isolated by inverse PCR and analyzed using PLACE database. Some putative MYB, bHLH, and environmental stress-responsive transcription factor binding sites were detected in the PaDOD1 and PaDOD2 promoter regions. Expression patterns of PaDOD1 and PaDOD2 in suspension cultures of P. americana were investigated by semiquantitative RT-PCR. The transcripts of PaDODs were found in both betacyanin-producing red cells and non-betacyanin-producing white cells, suggesting that not only the expression of DOD, but also the supplementation of DOPA might be a regulatory step for the betalain biosynthesis in P. americana. PMID- 19791511 TI - Construction and application of a baculovirus genomic library. AB - A random genomic library of the baculovirus Bombyx mori nucleopolyhedrovirus (BmNPV) was constructed and viral factors were identified by screening the regulator(s) for helicase gene expression. DNAs of 238 library plasmids were used to co-transfect with the reporter plasmid, pHp510-luc, in which the luciferase (luc) gene was driven by the baculovirus helicase promoter. Results showed that eight plasmids of the library strengthened the luciferase activity more than 1000 fold. Sequence analyses revealed that all of the eight plasmids contained an intact ie-1 coding region. To confirm the reliability of the screening library, pHp510-luc was co-transfected with the cloned early gene which revealed that the BmNPV IE-1 was the only early factor that could stimulate the helicase promoter. The function analyses suggested that genome-wide screening factors through the library are powerful means to investigate the transcriptional regulation of dsDNA viruses. PMID- 19791512 TI - Extraction of trace amount of severely degraded DNA. AB - DNA extraction from food is always problematic especially from highly processed samples which contain only trace amounts of severely degraded DNA fragments. In this work, to extract trace amounts of small DNA fragments of the traditional Chinese medicine (TCM) colla corii asini derived from highly processed Equus asinus skin, three strategies were compared for its authentication. With some optimizations, the modified QIAquick spin column method achieved higher DNA yield and purity in comparison with the "SDS/proteinase K" method and the "Wizard magnetic DNA purification system for food" method. Further studies showed that at least 0.4 g colla corii asini was needed to obtain enough DNA extracts for PCR based detection by the method and only amplicons of less than 100 bp could be generated from the DNA extracts which confirmed the efficiency of the method in small DNA fragment extraction. The DNA obtained by this method was suitable to be used in PCR-based authentications. PMID- 19791513 TI - The sex pheromone of the sand sagebrush carpenterworm, Holcocerus artemisiae (Lepidoptera, Cossidae). AB - (Z)-5-dodecen-1-ol (Z5-12:OH), (Z)-5-dodecenyl acetate (Z5-12:Ac), and (Z)-5 tetradecenyl acetate (Z5-14:Ac) were found in the extracts of the female sex pheromone gland of the carpenterworm moth Holcocerus artemisiae Chou et Hua, a pest of Artemisia filifolia. The average amounts of Z5-12:OH, Z5-12:Ac, and Z5 14:Ac in a single sex pheromone gland of a calling moth were (7.14 +/- 0.73) ng, (54.20 +/- 0.34) ng, and (38.70 +/- 0.46) ng, respectively. Electroantennography (EAG) of these compounds and their analogues demonstrated that Z5-12:Ac excitated the largest male EAG response, followed by Z5-14:Ac. Traps baited with rubber septa impregnated with Z5-12:Ac (500 microg/septum) and Z5-14:Ac (300 microg/septum) were more effective than traps with other baits or virgin females. Addition of Z5-12:OH to rubber septa did not enhance the trap catches, but (E,Z) 3,5-dodecadienyl acetate (E3,Z5-12:Ac) enhanced the trap catch. PMID- 19791514 TI - Induction of metalloproteinase 9 secretion from human keratinocytes by pleuran (beta-glucan from Pleurotus ostreatus). AB - Glucan preparations, primarily modified water-soluble glucans, are involved in the activation of the body's natural defense mechanisms and in the acceleration of the skin's wound-healing processes. Pleuran, an insoluble beta-D-glucan in hydrogel form, offers a natural alternative to more common chemically derivated soluble beta-D-glucans. Pleuran was applied to human keratinocyte primary cultures, and after 24 h of incubation the release of matrix metalloproteinase 9 (MMP-9) and metalloproteinase 2 (MMP-2) by stimulated keratinocytes was detected using gelatine zymography. There was a concentration-dependent increase in pro MMP-9 release after treatment with pleuran over the concentration range of 2 to 200 microg/ml, but pro-MMP-2 was detected at a constant level. Moreover, the active forms of both MMPs were not detectable, indicating that in vitro autoactivation of these zymogens did not occur. The results indicate that pleuran is a potent keratinocyte stimulator of proMMP-9 release, which implies its application in dermatological therapies. PMID- 19791515 TI - DNA damage and repair of head and neck cancer cells after radio- and chemotherapy. AB - DNA repair is critical for successful chemo- and radiotherapy of human tumours, because their genotoxic sensitivity may vary in different types of cancer cells. In this study we have compared DNA damage and the efficiency of its repair after genotoxic treatment with hydrogen peroxide, cisplatin and gamma-radiation of head and neck squamous cell carcinoma (HNSCC). Lymphocytes and tissue cells from biopsies of 37 cancer patients and 35 healthy donors as well as the HTB-43 larynx cancer cell line were employed. The cell sensitivity to genotoxic treatment was estimated by the MTT survival assay. The extent of DNA damage and efficiency of its repair was examined by the alkaline comet assay. Among the examined treatments, we found that HNSCC cells were the most sensitive to gamma-radiation and displayed impaired DNA repair. In particular, DNA damage was repaired less effectively in cells from HNSCC metastasis than healthy controls. In conclusion, our results suggest that the different genotoxic sensitivity of HNSCC cells may depend on their DNA repair capacity what in turn may be connected with the effectiveness of head and neck cancer therapy. PMID- 19791516 TI - Personal growth after a suicide loss: cross-sectional findings suggest growth after loss may be associated with better mental health among survivors. AB - With a diverse sample of 462 parent survivors of their child's suicide we explored the association of the personal growth subscale of the Hogan Grief Reaction Checklist (HGRC) with mental health problems among longer-term survivors. In this article we offer additional validation for this scale's association with longer-term survivorship and reduced grief difficulties. We also demonstrate its negative relationship with mental health problems. In addition, we explore the demographic correlates of personal growth, which are likely to enable some survivors to experience personal growth sooner than others. Overall, the findings suggest that personal growth represents an important part in the process of healing after suicide loss. PMID- 19791517 TI - Prolonged grief disorder and depression in widows due to the Rwandan genocide. AB - Should pathological grief be viewed as a nosological category, separate from other forms of mental diseases? Diagnostic criteria for "Prolonged Grief Disorder" (PGD) have recently been specified by Prigerson and her coworkers. We interviewed a total of 40 widows who had lost their husbands during the Rwandan genocide in 1994. We assessed Major Depression using the Mini-International Neuropsychiatric Interview (M.I.N.I.) and prolonged grief reactions with the PG 13. In order to examine the distinctiveness of the two syndromes we performed a multitrait correlational matrix analysis using modified versions of Generalized Proximity Functions (GPFs). 12.5% (n = 5) of the sample fulfilled the criteria for a diagnosis of PGD; 40% (n = 16) met criteria for Major Depressive Episode. The two syndromes were strongly associated. No discriminant validity was found between the two constructs suggesting that PGD may rather be an appearance of depression than a separate nosological entity. PMID- 19791518 TI - How do the young suicide survivors wish to be met by psychologists? A user study. AB - Little user-knowledge has been documented on the experiences of young suicide bereaved with psychosocial assistance and therapy. Thirty-two adolescents who had lost a close family member or friend by suicide participated in a research project by filling in questionnaires and participating in focus group interviews. The article explores the young people's experiences with and wishes for help from psychologists, and shows that the young bereaved do not receive the psychological assistance they wish for and need. The shortcomings are discussed in relation to the organization, form, and contents of the help. In order to reach youth with adequate assistance in an extreme life situation, it is worth listening to their opinions about how they want to be approached in the wake of a suicide. PMID- 19791519 TI - Spiritual beliefs among Israeli nurses and social workers: a comparison based on their involvement with the dying. AB - The purpose of the study was to compare spiritual beliefs and practices between nurses and health care social workers based on their involvement with dying patients. Exposure to the dying was identified by two indicators: the percentage of terminally ill patients in the provider's care and the work environment. On the basis of the literature, differences were expected between the two types of professionals and the three degrees of involvement with the dying. Nurses were expected to have a higher spiritual perspective than social workers; and health care providers with high involvement in care for the dying were expected to hold the highest levels of spiritual beliefs. Contrary to expectations, no differences in spirituality were found between nurses and social workers; both groups exhibited medium levels of spirituality. Furthermore, health care providers who were highly involved with dying patients had the lowest spiritual perspectives. Tentative explanations of these unexpected results are presented and discussed. PMID- 19791520 TI - Embodied grief: bereaved parents' narratives of their suffering body. AB - Experiences and symptoms emanating from the bereaved person's body are commonly considered to be psychosomatic reactions to loss. The lingering of such experiences is thought to reflect a maladaptive coping style that needs to be addressed to access the psychological pain underlying the symptoms. In this interpretive, phenomenological study of 15 family members in seven families who lost a child to sudden, unexpected death, stories of embodied grief are explored to further understand the grieving body. The findings of this study illuminate the many ways parents experience their grieving body and they underscore the importance of witnessing and acknowledging stories of the body in clinical work with bereaved parents who are learning to live in a world without their beloved child. PMID- 19791522 TI - Efficient--and guilt-free--reading of the medical literature. PMID- 19791521 TI - Health system reform. PMID- 19791523 TI - Co-infection with cytomegalovirus and Epstein-Barr virus in mononucleosis: case report and review of literature. AB - A 25-year-old woman presented with infectious mononucleosis. Serological studies demonstrated elevated IgM titres to both cytomegalovirus (CMV) and Epstein-Barr virus (EBV). The role of each of these agents in infectious mononucleosis is reviewed, as are literature reports of co-infection by these two viruses. Both near-simultaneous infections and temporally remote sequential infections with acute CMV triggering an immunoreactivation of EBV are reported in the literature. We believe the current case is most consistent with the latter. Infectious mononucleosis is a common infection of childhood and young adulthood. Although a variety of agents may be associated with infectious mononucleosis, EBV is the most common etiology. We encountered a patient with serological findings that were suggestive of the simultaneous presence of two etiological agents of infectious mononucleosis: EBV and CMV. This prompted an inquiry into how commonly dual infections are encountered and their significance. PMID- 19791524 TI - A new era for oral anticoagulants: have we finally evolved beyond warfarin? PMID- 19791525 TI - Prevention of venous thromboembolism. PMID- 19791526 TI - Finding our way: diagnostic perils and the stiff person syndrome. PMID- 19791527 TI - Year two: health care reform, quality and passion. PMID- 19791528 TI - Cookbook medicine. PMID- 19791529 TI - Health reform revisited. PMID- 19791530 TI - Keeping senior physicians in practice. PMID- 19791531 TI - Radiologists: loss prevention drops the ball with email suggestion. PMID- 19791532 TI - Ask TMA: getting hospitals to pay for on-call coverage. PMID- 19791533 TI - The great American debate: what will happen? PMID- 19791534 TI - TMA position statement. National health care system reform. PMID- 19791535 TI - Healthcare reform: what is Congress considering? PMID- 19791536 TI - An open letter to the President: simple reforms are just what the doctor ordered. PMID- 19791537 TI - Imperfect health reform via an imperfect political system. PMID- 19791538 TI - Geography lessons and health care reform. PMID- 19791539 TI - So who's counting? PMID- 19791540 TI - Certificate of need programs: inflationary and anti-competitive for healthcare. PMID- 19791541 TI - Complying with FACTA "Red Flag" Rules. PMID- 19791542 TI - Testing for HIV-1 infection in a public developmental center. AB - The discovery of human immunodeficiency virus type 1 (HIV) infection in an individual who recently moved from a developmental center prompted the center to offer HIV testing to current and former residents. The guardians of 199 (93 percent) of the Center's current residents consented to testing. The remaining 14 current residents (seven percent) were not tested because informed consent for testing was not received. Consent for testing of 41 former residents was also obtained. All people who underwent testing were seronegative. Whether former residents who were not included in the present analysis received testing from other sources is not known. PMID- 19791543 TI - The treating piysician as a witness. PMID- 19791544 TI - Dr. Roy A. Doty: legacy of Hancock County and Hawkins County, Tennessee Medicine. PMID- 19791545 TI - [Michael Ellis DeBakey]. PMID- 19791546 TI - [The doctor of the world. The person who has invented surgery]. PMID- 19791547 TI - [Interstitial administration of platelet-enriched autoplasma (PEA) in treatment of lower limb ischaemia]. AB - Along with reconstructive operations, stimulation of neoangiogenesis is one of the methods of treatment for patients suffering from chronic obliterating diseases of arteries of the lower extremities. Cellular transplantation for these purposes has been used in clinical practice only during the last several years. However, the problem concerning an optimal type of cellular material still remains to be solved. The authors carried out comparison between administration of platelet-enriched autoplasma (PEA) in order to stimulate neoangiogenesis and the use of autologous blood according to the Bytok technique. It was demonstrated that judging by such parameters as an increased distance of pain-free walking and an increase in the ankle-brachial index six months after surgery, the use of PEA turned out more efficient. PMID- 19791548 TI - Role of chemical elements in formation of an aortic aneurysm. AB - The method of X-ray fluorescence employing synchronous radiation was used to study the content of chemical elements (CE) in the aortic wall in patients suffering from CAD (Group I), patients diagnosed with an ascending aortic aneurysm (Group II), and those presenting with aortic dissection (Group III). The obtained findings revealed a pronounced CE disbalance in the aortic wall in Group II and III patients as compared with Group I patients, suggesting an important role of trace and macroelements in metabolic processes related to formation of artic aneurysms. Based on the degree of the ascending aorta dilatation, we determined the coefficient of the ratio of the ascending aorta maximal diameter to the fibrous ring aortic valve diameter, equalling 1.88 +/- 0.04, above which metabolic processes in the aortic wall change over to a qualitatively another level. This point was arbitrarily termed the metabolic process reversibility point. PMID- 19791549 TI - [Diagnostic and therapeutic policy in gerontological patients with atherosclerotic lesions of lower limb]. AB - Discussed herein are priorities of appropriate application of a special instrumental examination of the arterial bed of the lower extremities in elderly and aged patients presenting with chronic critical ischaemia on the background ofatherosclerosis obliterans. Also analysed are the findings ofan ultrasonographic examination of the lower-limb arterial system as afundamental methodfor diagnosis of an atherosclerotic lesion thereoffollowed by comparing the findings of the preoperative examination with the intraoperative data obtained during revision of the femoropopliteal segment. The obtained results made it possible to formulate conclusions on the preferable use ofultrasonographyfor examining gerontological patients suffering from lower limb chronic critical ischaemia as a simple, rapid, informative, and most importantly, non-invasive method, which is extremely importantfor elderly and aged people. It is underlined that in a series of cases contrast-enhanced aortoangiography can be used for examining the vascular status in gerontological patients; however, preference should still be given to an ultrasonographic examination of the lower-limb arterial bed or even direct visualisation of the affected arterial segment during intraoperative revision thereof. PMID- 19791550 TI - [Anticoagulants in vascular surgery]. AB - The paper reviews world wide publications on the use of anticoagulant therapy in vascular surgery. The authors analyze an adequate scope of heparin indications, efficiency of perioperative administration of unfractionated and low-molecular weight heparins, comparative efficiency of various heparin formulations, as well as the role of oral anticoagulants. PMID- 19791551 TI - [Efficiency of combined therapy with myocardial cytoprotector mexicor in hypertensive patients with acute cerebrovascular disturbances]. AB - Sixty hypertensive patients (mean age 64.9 +/- 1.5) with acute ischemic stroke were randomized into 2 groups. Both groups received conventional therapy (Aspirin Cardio, Trental, Prestarium, Arifon), which in the test group was added by Mexicor (0.3 gper day for 3 weeks). Circadian blood pressure (BP) and its variability were monitored in all patients at 1, 5, 10, 14, and 21 days after the stroke. NIH Stroke Scale, the Barthel ADL Index, Rankin Scale, Mini-Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) were used for the neurological status assessment. Mexicor was shown to accelerate the systolic and diastolic BP lowering, reduction of BP variability (mainly nocturnal) and improvement of circadian BP profile (more patients showed dipper type hypertension and less - non-dipper, over-dipper and night-peaker patterns, compared with the control group). Mexicor had a positive effect on neurological status, cognitive function and focal neurological deficit severity. PMID- 19791552 TI - [Combination of reconstructive vascular operations with gene-engineering technologies of angiogenesis stimulation: a present-day policy aimed at improving the remote results of treating patients with lower limb chronic ischaemia]. AB - The authors have studied therapeutic outcomes in a total of 38 patients diagnosed with occlusions of the femoropopliteal segment. In the Study Group patients (n = 19), the operation of femoropopliteal bypass grafting was supplemented by using gene stimulators of angiogenesis (gene constructions with the genes of vascular endothelial growth factor, and angiogenin). The Control Group patients (n = 19) were subjected to a reconstructive vascular operation alone. The remote results were followed up from six to twenty-six months, having shown reliably better therapeutic outcomes obtained in the Study Group patients, as judged by the distance of pain-free walking, the time of restoration of the baseline parameters of blood flow during the treadmill test, muscular perfusion, and the quality of life indices. A conclusion was made that the use ofangiogenesis-stimulating methods combined with reconstructive vascular operations improves the long-term outcomes in patients presenting with lower limb chronic ischaemia. PMID- 19791553 TI - [State of cerebral circulation in patients with essential arterial hypertension]. AB - In order to evaluate the volumetric flow rate of the blood in the major extracranial arteries, as well as to assess intracranial haemodynamics in patients presenting with isolated arterial hypertension and those with haemodynamically insignificant pathologies of the "CA" the authors analysed the findings obtained in a total of 159 patients (71 males and 88 females) who were diagnosed with mild, moderate and severe arterial hypertension. The average age of the patients amounted to 59 +/- 12 years. Studying the thickness of the intima medial complex of the common carotid artery in both isolated arterial hypertension (AH) andAH combined with atherosclerotic alterations in the CA demonstrated its thickening, which was more evident in a combination of atherosclerosis with AH. The study revealed a decrease in the volumetric flow rate ofthe blood in all extracranial vessels, as well as that of the total volumetric flow rate in the group ofpatients with isolated AH and especially those with a combination of AH and atherosclerosis. The patients sufferingfrom both isolated AH and a combination of AH with pathological alterations of/in the carotid arteries demonstrated alterations in the flow-rate indices and an increase in the indices of the peripheral resistance in the arteries of the circle of Willis, which were mostly pronounced in those with a prolonged history of AH. A trend towards a decrease in the indices of the flow-rate of the bloodstream and an increase in the indices of the peripheral vascular resistance in hypertensive patients is determined by structural alterations in the vascular wall of the extracranial arteries on the one hand, and by the development of hypertensive microangiopathy, on the other. PMID- 19791554 TI - [Radionuclide methods of diagnosis in assessment of interrelationship between the function of the cardiovascular system and kidneys in patients with previously endured myocardial revascularization]. AB - A steady increase in the number of patients diagnosed with chronic cardiac insufficiency determines the importance of studying in such patients the renal function for comprehen sive analysis of the incidence rate and mechanisms of the cardiorenal continuum. Radionuclide methods of diagnosis make it possible to obtain versatile information about the functional state of both the cardiovascular and urinary systems of the body. Radionuclide methods of study were used to prospectively assess the state of the cardiopulmonary haemodynamics and renal functional activity in patients with CAD after previously endured myocardial revascularization. The authors examined a total of twenty-nine patients suffering from coronary artery disease (CAD) (mean age 51.97 +/- 1.32 years) and having developed the NYHA functional class II-III circulatory insufficiency. All the patients were subjected to radiocardiopulmonography (RCPG) with 99mTc-pertechnetate and to dynamic radionuclide renoscintigraphy with 99mTc DTPA before and after coronary artery bypass grafting (CABG). Fourteen patients were examined 13.0 +/- 0.4 months after surgical management. Prior to CABG, the parameters of the cardiopulmonary haemodynamics in the examined patients had considerable deviations from the normal values, resulting from a decrease in the pumping function of the heart. Prior to surgical management, 83% of the patients were found to have a various-degree decrease in the glomerular filtration rate. Restoration of the coronary blood flow at early terms following CABG along with improved perfusion in the examined patients was accompanied and followed by a positive change in a series of parameters of the cardiopulmonary haemodynamics. One year after direct myocardial revascularization, the patients with circulatory insufficiency were found to have certain relationship between the impairments of the central haemodynamics parameters and the development of renal function impairment. Hence, radionuclide methods of diagnosis should be used while monitoring the patients with circulatory insufficiency for the purposes of timely detection and correction of the cardiorenal syndrome. PMID- 19791555 TI - [Endovascular embolization of ovarian veins in varicose disease of the small pelvic veins]. AB - Presented herein are therapeutic outcomes obtained in treatment of nineteen female patients suffering from varicose disease of the veins of the small pelvis. Based on the findings obtained by ultrasonographic, radionuclide and roentgenocontrast methods of investigation examination they were diagnosed with the syndrome of pelvic venous plethora. The indications for endovasal occlusion of the ovarian veins were the presence of the clinical signs of pelvic venous congestion, dilatation of and blood reflux along the gonadal veins based on the findings of instrumental methods of examination. It was determined that endovascular embolization of the gonadal veins in 84% of cases resulted in permanent relief of chronic pelvic pain. PMID- 19791556 TI - [Experience in using stents with an antiproliferative coating in treatment of stenoses and occlusions of coronary arteries. Review of the literature]. AB - The authors analysed the data concerning sirolimus- and paclitaxel-eluting stents used for treatment of stenoses and chronic occlusions of coronary arteries. Also discussed herein are clinical outcomes following stenting of bifurcation stenoses, stenoses of the main trunk of the left coronary artery, diffuse stenoses and chronic occlusions. The authors concluded that introduction into clinical practice of stents with an antiproliferative coating made it possible to considerably improve the results of coronary angioplasty in the above-mentioned lesions of coronary arteries. At the same time, the incidence rate of restenoses, secondary revascularizations and unfavourable outcomes for drug-eluting stents in various lesions of the coronary bed remains sufficiently rather high and is 2-3 times greater than similar indices in focal stenoses. PMID- 19791557 TI - [Angioplasty and stenting of carotid arteries in patients with high surgical risk]. AB - The authors carried out carotid angioplasty and stenting (CAS) in forty-six patients (with a total of 48 interventions performed). Of these, forty-two (91.3%) patients were found to belong to a high-surgical-risk group; The patients years (mean age - 62.1 +/- 8.2 years). Thirty-six patients were found to have symptomatic lesions of the internal carotid arteries (ICAs) >70%, and ten had asymptomatic stenoses >80%. Twenty-three (50%) patients were diagnosed with grade II cerebrovascular insufficiency (CVI) (transitory ischaemic attacks). Amongst the most frequently encountered accompanying pathologies were various-severity CADs in forty (95.2%) patients, and arterial hypertension in thirty-eight (90.4%). The cerebral blood flow state during CAS interventions was controlled by means of transcranial Doppler ultrasonography in sixteen patients. In twelve patients, the main stage of the intervention was performed under control of ultrasonographic duplex scanning (USDS). The technical success of the operation was achieved in forty-four (95.7%) cases. Failures were primarily caused by impossibility of passing the guidewire catheter in type 3 aortic arch in two patients. Twenty-six (56.5%) patients developed bradycardia and hypotension after CAS. No haemodynamically significant restenoses following CAS within the follow up terms from 2 to 12 months were observed in twenty-two patients. The article also contains a brief comparative analysis of multicenter randomized studies on the CAS-related problem. In conclusion, the authors note safety and high efficiency of CAS, considering this intervention an alternative to carotid endarterectomy in patients with elevated surgical risk. A USDS-controlled operation significantly broadens the possibilities of the method concerned. PMID- 19791558 TI - [Combined therapy of lower limb variceal disease]. AB - Complex surgical and medical therapy was used for 386 patients with lower limb variceal disease 2nd and 3rd form (segmental and disseminated varices with reflux through the superficial and perforant veins) and chronic venous insufficiency stage I (according to the Russian classification). Five main types of surgical interventions were fulfilled: combined phlebectomy, trunk scleroobliteration, short stripping with insufficient perforants ligation, short stripping with excision or damage of variceal influx, and short stripping with trunk scleroobliteration. Besides, vast majority of patients received venotonic drug Phlebodia 600 pre and postoperatively. Miniinvasive and atraumatic interventions were characterized by the decrease of postoperative subcutaneous hematomas, no incidence of n. saphenus damage and lymphorrhea, good cosmetic outcomes due to the absence of additional incisions. The duration of postoperative recovery correlated with intraoperative trauma and Phlebodia 600 administration. In conclusion, combination of complex surgical procedures and venotonic drugs can be widely used for the management of lower limb variceal disease, especially for its uncomplicated forms. While preserving the radicality, these interventions yield favorite esthetical results, reduce the time of postoperative recovery and disability, thus, appear to be cost effective. PMID- 19791559 TI - [The 9th Annual Meeting of the European Venous Forum]. AB - The ninth Annual Meeting of the European Venous Forum was held in Barcelona (Spain)from the 26th to the 28th of June 2008. The participants have discussed a wide range of phlebology topical issues: diagnosis and therapy of venous thromboses, diagnosis of chronic venous disease, surgical (including endovascular) management of variceal disease, sclerotherapy, compression and medical therapy of venous diseases. PMID- 19791560 TI - [Femoro-popliteal bypass above popliteal fossa with PTFE graft: which graft diameter is better?]. AB - The paper presents the results of 80 femoro-popliteal bypasses above popliteal fossa for patients with lower limb atherosclerotic lesions that were fulfilled with the use of polytetrafluoroethylene (PTFE) graft in the Department of Vascular Surgery, AV Vishnevsky Institute of Surgery, from February 1992 till December 2005. 50% of patients had lower limb ischemia grade IIb, 13.7% - grade III and 36.3% - grade IV. Distal circulation was good in 41.2%, satisfactory - in 48.5% and unsatisfactory - in 10.3% of patients. The technique of surgical reconstruction was conventional. In 50% of cases the diameter of PTFE grafts was 8 mm, in another 50% - 6 mm. A statistically significant difference in bypass patency was revealed between prostheses with different diameter in late postoperative period. For the 8-mm grafts the patency rate was 93%, 64% and 51% in 12, 30 and 60 months, respectively, while for the 6-mm grafts the same rate was 62%, 44% and 31%, respectively (p=0.004). PMID- 19791561 TI - Application of the proximal "elephant trunk" technique in surgical treatment of a patient with an aneurysm of the entire aorta. AB - Represented herein is an option of successful surgical treatment of a 55-year-old male patient diagnosed with type IIIB aortic dissection and aneurysmatic dilatation of the entire thoracic aorta, being the most vulnerable spot within the area of the descending thoracic aorta, by means of a promising technique of two-stage treatment. The first stage consisted in prosthetic repair of the descending thoracic aorta using the proximal "elephant trunk" technique in order to facilitate the second stage of the reconstruction, i. e. prosthetic repair of the ascending aorta and aortic arch. PMID- 19791562 TI - [Abdominal aorta ruptured aneurysm in patients with previously endured endovascular grafting for aortic aneurysm: clinical case reports]. AB - The article deals with four reports of rarely encountered clinical cases, i. e., a ruptured aneurysm of the abdominal aorta in patients having previously sustained endovascular grafting of the abdominal aorta for the pathology concerned. The incidence rate of such complications we faced for the first time in 2001 has ever since amounted to 1.6 % of the total number of patients with a ruptured aneurysm admitted to our Department over the period form 2001 to 2006 (250 patients). All the patients were emergently operated on, with the lethality rate amounting to 50 % (two of the four patients died). The time having elapsed from the primary operation (endovascular grafting of the abdominal aorta aneurysm) till the rupture ranged from 11 days to 3 years. PMID- 19791563 TI - [Approaches to the thoracoabdominal aorta]. AB - The authors carried out an experimental comparative study of various approaches to the thoracoabdominal aorta, pointing out advantages and disadvantages thereof. The Crawford approach and modified thoracophrenopararectal access have appeared to comply with all the requirements imposed for optimal visualization and manipulation on the inferior thoracic portion, visceral branches and bifurcation of the aorta, with the wound depth measuring 11- 15 cm, the angle of the operative action (AOA) equalling 100-110 degrees, and the angle of inclination of the operative action axis (AIOAA) amounting to 80- 90degrees. While performing manipulations on the isthmus of the aorta, the most advantageous seems to be the modified thoracophrenopararectal approach (wound depth 11.4 +/- 0.2 cm, angle of the operative action 97.0 +/- 3.7 degrees, and the angle of inclination of the operative action axis - 88.0 +/- 2.0 degrees). PMID- 19791564 TI - [Rendering surgical care for the wounded presenting with injuries to limb vessels]. AB - The proffered paper provides the information about rendering surgical care for the wounded presenting with vascular injuries inflicted and sustained during wars Russia was engaged in, to be followed by a detailed description of the haemorrhage-arresting methods and techniques used in N. I. Pirogov's time, during World War I, the Great Patriotic War, as well as in local military conflicts and combat operations. Also depicted herein is the role surgeons of Russia have played in the development of vascular surgery, and, finally, due coverage is given to the statistical data concerning the methods of rendering care for those having suffered firearm wounds and injuries involving vascular lesions. PMID- 19791565 TI - [Radical removal of carotid chemodectoma followed by prosthetic repair of the internal carotid artery]. AB - Presented herein is a case report of successful surgical management of a 34-year old female patient diagnosed with carotid chemodectoma, a relatively rare pathology vascular surgeons come across and have to deal with. A comprehensive examination (including duplex scanning of cervical arteries, multispiral CT angiography) revealed a 7 x 8 cm cervical tumour completely invading the walls of both the external and internal carotid arteries, thus requiring their resection, followed by prosthetic replacement of the internal carotid artery with a synthetic graft. The postoperative period turned out uneventful. On the 7th postoperative day, the patient was discharged home from hospital in a satisfactory condition with good laboratory and haemodynamic values. PMID- 19791566 TI - [A case of successful surgical management of a patient with acute thrombosis of the abdominal aorta and complicated gastric ulcer]. AB - The authors describe a case report of surgical management of a patient presenting with a clinical picture of ascending thrombosis of the abdominal aorta on the background of Leriche's syndrome and perforated gastric ulcer complicated by penetration and haemorrhage. PMID- 19791567 TI - [Non-invasive diagnosis and treatment tactics in management of disordered regional haemodynamics in patients with chronic obliterating diseases of lower limb arteries]. AB - By means of ultrasonographic angioscanning, Doppler ultrasonography, photoplethysmography, and determination of oxygen partial tension, the authors have analysed the relationship between the arterial inflow, venous return, and the state of microcirculation in a total of 120 patients presenting with various degree chronic ischaemia of the lower extremities, having developed on the background of obliterating arterial diseases. he authors worked out a complex of methods of non-invasive diagnosis, making it possible to determine the beginning of and to take control over the course of chronic ischaemia of the extremity involved. Also determined herein were the threshold levels of critical disorders of macro-and micro-haemodynamics (the regional systolic pressure gradient of more than 2, the postocclusion venous pressure gradient of more than 3, and the venous arterial index of more than 40%), which makes it possible to consider that the patient concerned is running a high risk of the development of critical ischaemia in the near future. Such being the case, it is necessary to perform a reconstructive vascular operation, and if impossible - to carry out intensive therapy of both systemic and local risk factors. PMID- 19791568 TI - [Intimal hyperplasia within a vascular anastomosis]. AB - Intimal hyperplasia (IH) appears to rank high amongst plausible causes of reconstructed arteries restenosis. It always occurs in the area of a surgical intervention on a vessel in response to a mechanical lesion. IH is the cause of thrombosis in 15 to 50% of cases following vascular reconstruction during the first year after the operation (with the exception of early thromboses, which are probably caused by an improperly performed interventional technique). Of a wide variety of clinical situations leading to development of IH in the vascular wall, for the purposes of the present review, we singled out the problem concerning the onset and development of this tissue reaction in intervascular anastomoses, which is currently one of the most important issues. Analysing the publications on the problem concerned showed that amongst significantfactors influencing the development of IH in the anastomosis, the investigators single out different parameters of the anastomoses, configuration (either an end-to-end or an end-to side anastomosis, the use of special inserts and patches within the latter), as well as the use of autologous or synthetic conduits, blanket suture or interrupted suture, peculiarities of local haemodynamics (linear blood flow rate, distribution of parietal fraction forces, zones of stagnation and flow separation), etc. To a certain degree, the published data are rather controversial. There remain many problems, which are either unaddressed as yet, or insufficiently studied, if at all. For instance, while establishing an anastomosis between a bypass graft and an artery, surgeons often resort to endarterectomy. It is not known whether or not this technique would influence the IH pattern in the anastomosis concerned. Neither is it clear whether the high velocity flow exerts a direct damaging action upon the endothelium, whether it promotes the development of IH in the area of the lesion, and if affirmative, then what the mechanisms of this effect really are. Not studied is the role of various types of synthetic fibres and synthetic grafts (except PTFE), various kinds of suture material in the development of IH in the zone of a vascular anastomosis concerned. This of course is far from being a complete list of the challenges requiring further investigation. PMID- 19791569 TI - Structural-and-functional alterations in the arterial wall and clinical manifestations of nonspecific aortoarteritis. AB - The authors studied structural-and-functional properties of the arterial wall, also assessing elastic properties of the common femoral artery and the brachial artery flow-dependent dilatation (FDD) index in a total of thirty-six patients presenting with nonspecific aortoarteritis (NAA). The overwhelming majority of the patients, i. e., twenty-four (89%), showed a statistically significant decrease in the FDD as compared with the control-group patients (P<0.05). We revealed a statistically reliable (P=0.0005) inverse correlation between the level of systolic arterial pressure and an increase in the rigidity index of the common femoral artery wall. Also determined was a correlation of the femoral artery wall rigidity (systolic AP equalling 140 mm Hg and higher) and the brachial artery flow-dependent dilatation index (r=-0.61). All the patients suffering from non-specific aortoarteritis were diagnosed as having a decrease in the elasticity values, accompanied by an increase in systolic arterial pressure (r=0.36; P=0.07). Comparing the level of systolic arterial pressure with the values of the distensibility coefficient and compliance coefficient revealed a weak inverse correlation (r=-0.28 and 0.21, respectively). Evaluating the impact of duration of the disease on the distensibility coefficient, compliance coefficient and the rigidity index made it possible to detect a statistically significant (P=0.0039) direct correlation between the rigidity index and the duration of non-specific aortoarteritis. To a leaser degree, the duration of the inflammatory process influenced the distensibility coefficient and compliance coefficient (r=-0.28; r=-0.30, respectively; P=0.06). PMID- 19791570 TI - [First experience in using cardiocytoprotector mexicor in operations of myocardial revascularization under conditions of extracorporeal circulation]. AB - We examined a total of forty-four patients diagnosed with coronary artery disease who were subjected to coronary artery bypass graft surgery under conditions of extracorporeal circula tion. In the examined group (15 patients) during anaesthesia and perfusion, we additionally administered the cardiocytoprotector mexicor at a total dose of 1,500 mg. It was revealed that administering mexicor in a complex of anaesthesiological-and-resuscitation support considerably increased the indices of myocardial contractility and oxygen-transporting function of blood in the postperfusion period, also decreasing both the amount and duration of inotropic stimulation, and favourably contributing to early recovery and restoration of spontaneous respiration in the immediate postoperative period. PMID- 19791571 TI - [Somatosensory evoked potentials in diagnosis of chronic cerebral ischaemia in patients with pathology of brachiocephalic arteries]. AB - The present study was aimed at substantiating the practical significance of using the method of the somatosensory evoked potentials (SSEPs) in order to evaluate the functional state of the brain in patients suffering from chronic cerebral ischaemia (CCI) on the background of lesions of the brachiocephalic arteries (BCAs). With the method of the SSEPs, prior to reconstructive operation on the BCAs we examined a total of three hundred and seventeen 31-to-82-year-old patients. Of these, 156 patients were diagnosed as having a clinically symptom free course of CCI, and the remaining 161patients appeared to have clinically symptomatic CCI. The findings obtained in the present study revealed that the most pronounced alterations in the SSEPs corresponded to the clinically symptomatic course of CCI, coinciding with the side of the maximal changes in the BCA. Along with it, a clinically symptom-free course of CCI also demonstrated characteristic alterations in the SSEPs, which is an additional argument counting in favour of a surgical policy to pursue in the cohort of the patients concerned. PMID- 19791572 TI - [Peculiarities of changes in circulatory parameters of microcirculation in local freezing injury of the upper limbs]. AB - The condition of the microcirculatory bed in frostbitten tissues has the decisive importance in the course of the injury. The objective of the work was to investigate the dynamics of the parameters of microcirculation in patients with an endured local frostbite injury of the upper extremities. Evaluated were oscillations of the bloodstream by means of laser Doppler flowmetry. The study was carried out in a total of sixty 18-to-45-year-old patients presenting with a degree II-IV local frostbite injury of the upper extremities at various periods of the injury. In the prereactive period, when there are no significant deviations of the blood-flow oscillation parameters, using the occlusion test makes it possible to reveal alterations in the condition of the microcirculatory bed. The early and late reactive periods of a localfrostbite injury of the upper limbs are characterized by an increase in the neurogenic and myogenic components of vascular tonicity, as well as the by-pass index, thus suggesting a vascular spasm and increased by-pass blood flow. Degree II-IV frostbites of the upper extremities in the early and late reactive periods of the injury are accompanied by decreased reactivity of the vascular wall in response to occlusion, decreased potential of the active mechanisms of regulation of vascular tonicity, and maintenance of an adequate tissue blood circulation, with a 1.5-2-fold decrease in the blood flow reserve. The revealed alterations in the parameters of microcirculation and regulation of vascular tonicity explain a lingering course of the wound process in frostbites. Using the method of laser Doppler flowmetry makes it possible to determine the condition of microcirculation and vascular tonicity, to evaluate efficiency of the methods of treatment, and to predict the course of frostbite. PMID- 19791573 TI - [Alterations in blood flow as a diagnostic criteria for breast cancer]. AB - The article is dedicated to one of the challenging problems, i. e., diagnosis of breast cancer by the findings of ultrasonographic Doppler examination in women with endured augmentation mammoplasty performed by means of inserting gel implants. Special attention is paid to diagnosis of small tumours (less than 1.5 cm in size) and to differential diagnosis of malignant and benign neoplasms of the mammary gland with complications of gel plasty. The use of Doppler ultrasonography made it possible to increase the accuracy of ultrasonographic examination in diagnosis of breast cancer by 4.5 %. A highly specific sign of breast cancer, amounting to as high as 98.2 %, is local enhancement of the vascular picture within the zone of the growing tumour, including in women having sustained augmentation mammoplasty. PMID- 19791574 TI - [The review of materials 23th the World Congress the International Union Angiology (Athenes, Greece, on June, 21-25, 2008)]. PMID- 19791575 TI - [Annual Congress of the Cardiovascular and Interventional Radiological Society of Europe (CIRSE-2008)]. AB - The authors review herein the materials presented at the Annual Congress of the Cardiovascular and Interventional Radiological Society of Europe. The participants discussed the present-day problems and current achievements in such trends of endovascular surgery as carotid stenting, transcatheter embolization, endovascular prosthetic repair of the aorta and its branches, angioplasty of the crural arteries in diabetic foot, cava-filters in thrombolysis and deep venous thrombosis, peripheral arterial interventions, as well as interventions on the hepatic bile ducts, TIPSS, uterine arteries embolization, vertebroplasty, venous interventions, interventions on renal arteries, etc. PMID- 19791576 TI - [Thrombosis of stents with an antiproliferative coating. Review of the literature]. AB - The authors analysed the findings concerning thromboses of sirolimus- and paclitaxel-eluting stents over the time period from 2004 to 2007, having singled out the following causes of a stent's thrombosis: 1 - an anatomical cause (bifurcation stenosis, a prolonged atherosclerotic plaque, and in-stent restenosis; 2 - the stent's failure to fit snugly to the arterial wall; 3 - dissection of coronary arteries during stenting; 4 - cocaine dependence; 5 - resistance to aspirin and clopidogrel therapy; 6 - discontinuation of anti platelet therapy. PMID- 19791577 TI - [Endovascular laser ablation with wavelength 1,560 nm for varicose veins]. AB - In 2002 - 2008 more than 1000 patients with lower limb varicose veins were treated with endovenous laser coagulation (EVLC) of subcutaneous and perforating veins in the Therapeutic Rehabilitation Center. Usually we used laser wavelength between 915 and 980 nm; but recently 1,560-nm laser, which physical properties are quite different, was used for 43 patients, including 49 EVLCs for great (GSV) and lesser (LSV) saphenous veins and 15 EVLCs for perforating veins (PV). Interventional technique was similar to previously used. Postoperative period for 1,560-nm laser ablations was characterized by earlier resolution of mild pain syndrome, more than twice less ecchymosis, and pain absence along the coagulated veins. These resulted of obliteration. in the decrease of postcoagulative period severity, thus enabling patients to ambulate earlier. No complications occurred. Ultrasonic picture of 1,560-nm laser coagulation showed uniform wall thickening, intimal induration and circular narrowing of venous lumen. Histological examination of GSV revealed significant thickening of venous wall due to edema and circular shrinkage, focal necrobiosis and caryolysis. Twenty three patients (who underwent total 35 EVLCs for GSV, LSV and PV) were followed up for 4-6.5 months. In all cases treated veins were completely obliterated; no segments with preserved blood flow and pathological refluxes were revealed. In conclusion, EVLC with wavelength that is actively adsorbed by water is characterized by mild postoperative period and higher efficacy of obliteration. PMID- 19791578 TI - [Outcomes of prolonged anticoagulant prevention of thrombosis of deep veins of the crus in closed comminuted fractures of tibial bones]. AB - Analysed herein are the outcomes of treating a total of 96 patients with closed comminuted fractures of crural bones. By the duration of antithrombotic prevention, the patients were subdivided into two groups: the Comparison Group comprising 45 patients with a brief course of anticoagulant treatment (mean 5.8 +/- 1.3 days) and the Study Group consisting of 51 patients receiving anticoagulant treatment till achieving full restoration of the supporting function of the limb (averagely 21.2 +/- 2.1 days). In the Comparison Group, thrombosis of the deep veins localizing exclusively on the crus was registered by the results of duplex scanning in 13 patients (28.9%). In two thirds of the cases (10 cases, 76.9%) thrombosis occurred predominantly on days 6 - 14, while in 3 cases (7.7%) it occurred on days 15 -21 after the injury. In the Study Group patients with protracted anticoagulation prevention, thrombosis of the deep veins was revealed in 9.8% of cases (5 patients). Of the five Study Group patients with thromboses of tibial veins four were subjected to prolonged prevention with indirect anticoagulants and only one - with fraxiparine. It was found that the development of venous thrombi in fractures significantly (p <0.05) makes the terms of consolidation 1.6-fold longer. A conclusion was made that because a high risk of the development of thrombosis of the deep veins preserves during the whole period of restoration of the supporting function of the extremity in fractures of the crural bones, the patients concerned should, based on early (within the first 3-7 days) stable osteosynthesis making it possible to activate the patient and to restore the function of the limb, be subjected to a prolonged course of anticoagulant preventive treatment till the final changeover of the patient to the full load on the affected extremity. PMID- 19791579 TI - [Minimally invasive surgery of lower-limb varicose disease. Review of literature]. AB - The article reviews the worldwide current literature devoted to one of the presently important problems, i. e., lowerlimb varicose disease, systematizing all available information concerning modern methods of examination and treatment of patients suffering from venous insufficiency, including operations, scler other apy, echo scler other apy, endovasal laser coagulation and radiofrequency ablation. It was underlined that ultrasonographic diagnosis is currently becoming the main method in assessing haemodynamic disorders in the venous system and determining the methods of removal of varicose veins. Also analysed are advantages and disadvantages of these methods both in elective surgery and in emergency states. Reflected are contradictions presently existing in phlebology and a trend towards minimising interventions in varicose disease. The classical combined phlebotomy, remaining for long years the main surgical procedure, has gradually been replaced by the socalled "office" methods of treatment. It was shown that there are a lot of unsolved problems requiring investigation from the positions of efficacy and safety. PMID- 19791580 TI - Vascular surgery in Sweden as reflected in the Swedish Vascular Registry (Swedvasc). PMID- 19791581 TI - [Outcomes of using various-type patches in surgery of carotid arteries]. AB - Presented herein are 6-month-to-6-year remote outcomes of using dilating polytetrafluoroethylene patches, an autovein, and a xenopericardium treated with diepoxy compounds in course of carotid endarterectomy in a total of 198 patients. The patients' age and degree of cerebrovascular insufficiency according to A. V. Pokrovskii's classification were virtually identical in all the three groups studied. The incidence rate of restenoses in the group of dilating polytetrafluoroethylene patches turned out significantly higher. Based on the findings of our study, it is safe to conclude that the xenopericardium treated with diepoxy compounds is an efficient and safe plastic material in surgery of carotid arteries. PMID- 19791582 TI - [Pathological kinking of carotid arteries as a risk factor for age-related macular degeneration]. AB - The present work was aimed at studying clinical symptoms and the incidence rate of age-related macular degeneration (ARMD) in patients diagnosed with pathological kinking of carotid arteries. A total of 63 patients presenting with pathological kinking of carotid arteries were examined. Of these, 58 were found to have age-related macular degeneration manifesting itself by degenerative alterations in the retinal pigment epithelium (RPE) in 14 (24.14%) patients, hard retinal drusen in 22 (37.93%) patients, and by a combination of hard retinal drusen with evidence of RPE degeneration in 22 (37.93%) subjects. Besides the conventional ophthalmologic methods of examination including the determination of visual acuity under standard conditions of illumination, biomicroscopy, both direct and indirect ophthalmoscopy, perimetry, and tonometry, all patients were subjected to ultrtasonographic Doppler mapping of the ophthalmic arteries, as well as colour duplex scanning (CDS) of the brachiocephalic arteries, transcranial Doppler ultrasonography and helical computed tomography. The obtained findings revealed that 92% of the examined patients presenting with pathological kinking of the internal carotid arteries had symptoms of non exudative forms of ARMD and signs of blood flow deficiency in the ophthalmic arteries. In this connection, it appears appropriate to carry out colour duplex scanning of the brachiocephalic arteries in order to reveal pathological kinking of the carotid arteries and decide upon further treatment policy. PMID- 19791583 TI - [Use of artificial circulation during prosthetic repair of the abdominal aorta in single-step operations (a meta-analysis)]. AB - To assess the risk of complications during the use of extracorporeal circulation at the stage of prosthetic reconstruction of the abdominal aorta in single-step interventions we carried out a systemic analysis of 20 publications mentioning the use of artificial circulation during aortic reconstruction, as well as analysed the works wherein aortic prosthetic repair was performed after artificial circulation was discontinued. The postoperative mortality rate in single-step interventions with the use of artificial circulation at the stage of aortic prosthetic reconstructions ranges from 0 to 25%, and that without artificial circulation varies from 0- 6.7%. A meta-analysis of the publications showed that the cumulative relative risk for development of complications is 3.14 times greater in those patients who at the stage of aortic reconstruction continued receiving artificial circulation. The use of artificial circulation does not decrease the incidence rate of myocardial infarction neither does it influence the rate of development of haemorrhage or purulent complications. However, the use of artificial circulation at the stage of prosthetic reconstruction of the abdominal aorta considerably increases the incidence rate of respiratory, renal and neurological complications. Hence, the advantages of using artificial circulation are levelled by high incidence of complications, while the opinion that the use of artificial circulation at the stage of prosthetic repair of the abdominal aorta decreases the incidence of myocardial infarction was not confirmed in our systemic review, therefore the use of extracorporeal circulation in single-step operations should be well-grounded. PMID- 19791584 TI - In memoriam of Michael Ellis DeBakey. Alternative reconstructions of carotid bifurcation for atherosclerosis: the history and the latest advances. AB - The paper overviews the history of reconstructive surgery for atherosclerotic lesions of carotid bifurcation, as well as indications for various revascularization procedures for internal carotid artery, based on the experience of the Vascular Surgery Department, A. V. Vishnevsky Institute of Surgery, and in particular, on 205 interventions that were carried out in 2006. PMID- 19791585 TI - [Determining surgical policy in combined atherosclerotic lesion of carotid arteries in patients with uncomplicated aortic aneurysm]. AB - Presented herein are the outcomes of managing a total of twenty-six patients suffering from an uncomplicated abdominal aorta aneurysm with a concomitant atherosclerotic lesion of the coronary arteries, referred to our Clinic over the period form 2003 to 2006. Of these, nineteen (70%) patients were diagnosed with the first (symptom-free) stage of cerebral ischaemic disease, and six presented with the second stage [to have endured a transient ischaemic attack (TIA) within the terms from 16 to 3 months prior to admission]. Two patients had residual events of the previously sustained acute cerebral ischaemia (ACI) (stage 4). The current stage ofischaemic cerebral disease was determined according to the classification of A. V. Pokrovskii (1979). The haemodynamically significant stenoses of carotid arteries (over 70%) were revealed in five patients, an aneurysm of the internal carotid artery - in one patient, and eighteen patients were presenting with the degree of carotid arteries stenosis varying from 30 to 60% (of these, in two subjects after previously endured TIA, the plaque was heterogeneous and defined as embolism-threatening). No atherosclerotic lesions of the carotid artery were revealed in two patients, though these patients had previously sustained an AIA with the preserved neurological deficit by the moment of examination. Eight patients underwent reconstruction of the internal carotid arteries. The average age amounted to 64.5 years. Al of the eight operated on patients with a combination of ischaemic cerebral disease and an aneurysm of the abdominal aorta were found to have had no neurological complications either after the first, or after the second operations. The devised algorithm of examination and surgical management for patients presenting with an abdominal aorta aneurysm and a combined lesion of the brachiocephalic arteries made it possible to reduce the rate of neurological complication from 4.3% to 1.3%. PMID- 19791586 TI - [Analysis of outcomes of surgical management of patients presenting with ischemic etiology pyonecrotic lesions of lower limbs]. AB - The authors assessed the outcomes of surgical management of eighty-four patients presenting with ulcerative and necrotic lesions of the lower extremities, who were subjected to various reconstructive interventions performed on the major arteries. The duration of the hospital stay in these patients was increased to 23.1 +/- 5.6 days. It was determined that in 63.2% of cases, trophic ulcers of the feet had developed on the background of "multi-storey" occlusive and stenotic lesions of the lower-limb major arteries. Trophic alterations in the distal portions of the lower extremities had developed during averagely 3.5 +/- 1.6 years following the appearance of the symptoms of intermittent claudication. Destructive changes of the feet in patients with diabetes mellitus and thromboangiitis developed rapidly, were more pronounced, and required performing a postponed operation. The authors revealed a series of laboratory indices, i. e., blood platelets, stab leukocytes, ESR, as well as the degree of the occlusive lesion of the crural arterial segment, correlating with severity ofnecrotic changes on the foot. Early thrombosis of the bypasses were caused by unsatisfactory pathways of arterial outflow and a high level of blood haematocrit. The postoperative mortality rate amounted to 4%, that after six months - to 5%, after one year - to 5%, and after two years - to 8%. The limb salvation rate immediately after surgery amounted to 98.8%, equalling 92.1% after six months, 92.1% after one year, and 88.9% after two years. The purpose ofpresent work consisted in analysing the outcomes of treatment and determining the factors influencing the limb salvation rate in patients presenting with stage IV ischaemia of the lower extremities. PMID- 19791587 TI - [Comparative assessment of methods used for predicting efficiency of lumbar sympathectomy in patients with lower-limb critical ischaemia]. AB - The article deals with the findings of examination and treatment of patients presenting with lesions of the distal-bed arteries and critical lower-limb ischaemia who were subjected to lumbar sympathectomy (LSE). The methods aimed at predicting efficacy of LSE in seventy-five patiens included Doppler ultrasonography with the nitroglycerine test and with the epidural blockade. Of these forty-five patients were subjected to laser Doppler flowmetry (LDF) and measurement of the transcutaneous oxygen tension in tissues before and after the epidural blockade. Presented herein are remote results of LPE obtained at terms up to 36 months for sixty-nine patients (92%) and analyzed depending on the parameters of the functional tests. Our findings suggest that the most statistically significant methods of study for predicting the outcome of lumbar sympathectomy turned out to be LDF and Doppler ultrasonography performed before and after the epidural blockade. PMID- 19791588 TI - [Transluminal balloon angioplasty in treatment of lower limb critical ischaemia]. AB - OBJECTIVE OF THE STUDY: To evaluate efficiency of transluminal balloon angioplasty (TLBAP) in treatment of lower limb critical ischaemia (LLCI). MATERIALS AND METHODS: Over the period from November 2004 to April 2008, we performed a total of 89 TLBAPs in eighty-two patients presenting with LLCI. The patients' age averagely amounted to 67.8 +/- 9.8 years. Fifty (61%) patients had an ischaemic ulcer on the foot, seventeen (20.7%) had gangrene, and fifteen (18.3%) patients suffered from ischaemic pain at rest. Forty-five (54.9%) patients suffered from diabetes mellitus, including thirty-three (40.2%) subjects with insulin dependent DM. Sixty (73.2%) patients were diagnosed as having coronary heart disease (CHD), sixty-five (79.3%) had arterial hypertension, twenty-five (30.5%) - cerebrovascular disease, and thirteen (15.9%) - chronic renal insufficiency. Six (7.3%) patients were on chronic haemodialysis. The distribution of the patients by the level of the lesion were as follows: iliac 4 (3.6%), femoropopliteal 55 (49.5%), crural artery 52 (46.8%) Type-C and type-D lesions (TASC) were encountered in 89.2% of cases. Occlusions were observed in 82% of all lesions of the crural artery. 42.2% of the patients were treated by means of subintimal angioplasty. Stenting was used in fourteen (7.3%) cases. RESULTS: The angiographic and clinical success of the procedure was achieved in seventy-five (91.5%) patients. No LLCI was observed either after one or three years in 79.4 and 52.9% of the patients, respectively. PMID- 19791589 TI - [To centenary of Takayasu's presentation of nonspecific aortoarteritis case]. AB - Literature review is dedicated to the 100th anniversary of the first case presentation for nonspecific aortoarteritis. The review covers the history of the disease concept development, current knowledge on its etiology and pathogenesis, unresolved problems of management strategy for patients with this pathology. PMID- 19791591 TI - Attempting to understand symbiotic relationship in nature. PMID- 19791590 TI - [Angiodysplasias: role of mediators and growth factors]. AB - The review of the literature deals with the findings concerning the role of impaired interaction between the basic angiogenic mediators and growth factors in vascular malformations. Presented herein are the contemporaneous views opinions on the aetiology and pathogenesis of angiodysplasias. PMID- 19791592 TI - Mortality risk in insects. AB - Understanding how and why insect numbers fluctuate through time and space has been a central theme in ecological research for more than a century. Life tables have been used to understand temporal and spatial patterns in insect numbers. In this study, we estimated cause-of-death probabilities for phytophagous insects using multiple decrement life tables and the irreplaceable mortality analytic technique. Multiple decrement life tables were created from 73 insect life tables published from 1954 to 2004. Irreplaceable mortality (the portion of mortality that cannot be replaced by another cause) from pathogens, predators, and parasitoids was 8.6 +/- 7.2, 7.8 +/- 4.9, and 6.2 +/- 1.6%, respectively. In contrast, the mean irreplaceable mortality from all non-natural enemy mortality factors (mortality from factors other than natural enemies) was 35.1 +/- 4.4%. Irreplaceable mortality from natural enemies was significantly lower compared with non-natural enemy factors. Our results may partially explain cases of unsuccessful efficacy in classical biological control, after successful establishment, by showing low irreplaceable mortality for natural enemies, including 5.2 +/- 1.6% for introduced natural enemies. We suggest that the environment (i.e., the degree of environmental stability) influences the magnitude of the irreplaceable mortality from natural enemies. Our results lead to several testable hypotheses and emphasize that it is not possible to estimate the effect of any mortality factor without considering its interaction with competing mortality factors, which has far-reaching consequences for population biology and applied ecology. PMID- 19791593 TI - Temperature-dependent development of Aleyrodes proletella (Homoptera: Aleyrodidae) on two cultivars of broccoli under constant temperatures. AB - Laboratory experiments were conducted to estimate developmental rates and nymphal survival of Aleyrodes proletella Linnaeus (Homoptera: Aleyrodidae) on two broccoli Brassica oleracea L. variety italica Plenck cultivars (Marathon and Agripa) at eight constant temperatures (16, 18, 20, 22, 24, 26, 28, and 30 degrees C). The times required to complete development of egg and first instar decreased with increasing temperature, but the developmental times of second, third, fourth instars, all instars, and egg-adult period were greater at 30 degrees C than at 28degrees C. The relationships between developmental rate of A. proletella and temperature were slightly influenced by broccoli cultivar. The optimal temperatures and thermal constant as well as the lower and upper thresholds of development for all immature stages were estimated by fitting the observed developmental rates versus temperature with a nonlinear model and two linear models. For all stages, graphs obtained by plotting the developmental rates against temperature could be described by the modification two of the Logan's model. Overall, developmental times for immature stages and egg-adult periods were similar on both Agripa and Marathon cultivars. The most favorable temperature range for nymphal development seemed to be 28-29 (second and third instars) and 31-33 degrees C (fourth instar). Mean generation times (egg-adult) ranged from 19 d ('Marathon' and 'Agripa') at 28 degrees C to 47 ('Marathon') and 46 d ('Agripa') at 16 degrees C. PMID- 19791594 TI - Age-dependent postdiapause development in the gypsy moth (Lepidoptera: Lymantriidae) life stage model. AB - For the last approximately 10 yr, the Gypsy Moth Life Stage (GLS) model has been used by pest managers to predict when important events in the gypsy moth, Lymantria dispar L., life cycle will occur (e.g., peak second larval instar population and male moth flight). Although the GLS model has been shown to outperform other gypsy moth phenology models, its predictions have not always been as accurate as desired. Differences between predicted and observed egg hatch phenology prompted a re-examination of the original experimental data that were used in the construction of the egg hatch submodels of the original GLS model, and a data processing error was discovered to have truncated the postdiapause experimental data. Analysis of the complete data set confirmed that developmental rates in the postdiapause phase were age and temperature dependent but that the developmental response to temperature is distinctly nonlinear at postdiapause initiation, in contrast to the indeterminate response previously reported. By incorporating the new estimates of developmental rate patterns and parameters into the GLS model, errors in the GLS-simulated egg hatch period were reduced by 33-71% and error in date of 50% cumulative egg hatch by 25-100%. PMID- 19791595 TI - Elevated CO2 changes interspecific competition among three species of wheat aphids: Sitobion avenae, Rhopalosiphum padi, and Schizaphis graminum. AB - Effects of elevated CO2 (twice ambient) on the interspecific competition among three species of wheat aphids (Sitobion avenae, Rhopalosiphum padi, and Schizaphis graminum) and on wheat-aphid interactions were studied. Wheat plants had higher biomass and yield and lower water and nitrogen content of grain when grown under elevated CO2 than under ambient CO2; levels of condensed tannins, total phenols, and total nonstructural carbohydrates were also higher in wheat ears under elevated CO2. Compared with ambient CO2, elevated CO2 increased the abundance of R. padi when introduced solely but reduced its abundance when S. avenae was also present. The spatial distribution of wheat aphids was apparently influenced by CO2 levels, with significantly more S. avenae on ears and a more even distribution of R. padi on wheat plants under elevated CO2 versus ambient CO2. Elevated CO2 did not affect the abundance and spatial distribution of S. graminus when inoculated solely. Moreover, when S. avenae was present with either R. padi or S. graminum, spatial niche overlap was significantly decreased with elevated CO2. When three species co-occurred, elevated CO2 reduced spatial niche overlap between S. avenae and S. graminum and between R. padi and S. graminum. Our results suggest that increases in atmospheric CO2 would alleviate interspecific competition for these cases, which would accentuate the abundance of and the damage caused by these wheat aphids. PMID- 19791596 TI - Differential use of identical food resources by Reticulitermes flavipes (Isoptera: Rhinotermitidae) in two types of habitats. AB - A year-long field experiment showed that Reticulitermes flavipes attacked and used single stakes and wooden stake bundles differently in two habitats that varied in alternative forage. In both habitats, the number of termites present in single stakes and stake-bundles increased with stake resource size, and the number of larvae recorded from feeding sites was a close reflection of the number of workers attracted to a given food source. Over 12 mo, more single stakes and stake bundles were heavily attacked and abandoned in the pine woods compared with grassy clearings. Paradoxically, the number of termites present in single stakes and stake bundles was greater in the food-poor habitat (grassy clearings), yet the wood was less consumed compared with the food-rich habitat (pine woods). Use of stake bundles as nests and the slower rate of wood consumption in grassy clearings indicated that termites seemed to value food resources in relative terms, i.e., those termites with abundant alternative food resources consumed quickly and departed, whereas those lacking extra resources ate slowly and settled in. These field results confirm earlier laboratory results that showed that termites modified wood consumption rates dependent on the amount of food available to the colony as a whole. The appearance of mature (physogastric) reproductives (>> yr old) in stake bundles in both habitats further indicated that termites track resources and opportunistically shift colony activities and possibly territory boundaries depending on the nature of the resources and other environmental factors. Implications for managing termites with a baiting strategy are discussed. PMID- 19791597 TI - Distance from edge determines fruit-feeding butterfly community diversity in afrotropical forest fragments. AB - We studied the impact of forest edges on the fruit-feeding butterfly communities of three forest remnants in Ghana, West Africa. Community diversity was assessed using traps baited with fermenting banana. Two 200-m, edge-to-interior transects of five traps each were established in each forest. Sampling spanned 1 yr for a total of 180-210 trap days per site and resulted in 2,634 specimens and 56 species. We found significant support for an effect of forest edge on butterfly diversity. The impact of distance from edge on point estimates of diversity, i.e., total trap captures, weighted species richness, and Simpson's diversity, was unique to each forest. Multivariate analyses, which integrated species composition along with relative abundance and richness, uncovered two broad community types, interior communities (those 100, 150, and 200 m distant from the edge) and exterior communities (edge communities and those 50 m distant), indicating that edge habitat generally extends at least 50 m into the forest. However, effects of edges on community diversity were still detected as far as 100 m into the forest. Three species relatively tolerant of forest degradation emerged as indicators of edge habitat. No species were indicative of core habitat. PMID- 19791598 TI - Community response of insects associated with eastern hemlock to imidacloprid and horticultural oil treatments. AB - The hemlock woolly adelgid, Adelges tsugae Annand, is an invasive species reducing the populations of eastern hemlock, Tsuga canadensis L. Carriere, throughout the eastern United States. Systemic imidacloprid and horticultural oil are the primary chemicals used to control infestations of this invasive pest; however, the impact of these two chemicals on nontarget canopy insects is unknown. This study was initiated in November 2005 to assess the effects of (1) imidacloprid soil drench, (2) imidacloprid soil injection, (3) imidacloprid tree injections, and (4) horticultural oil applications on multiple levels of organization (composition, overall specimen abundance and species richness, guild specimen abundance and species richness, and individual species) within the phytophagous and transient canopy insect community. Community composition differed significantly among treatments based on analysis of similarity. Mean species richness and specimen abundance were significantly reduced by one or more treatments. Soil drench applications significantly reduced species richness for the detritivore and phytophaga guilds. Furthermore, specimen abundance for species in the detritivore, fungivore, phytophaga, scavenger, and transient phytophaga guilds was significantly lower in the soil drench treatment. This trend was consistent in all insect guilds examined, with the exception of the hematophaga guild that was not significantly lower than for species on the control trees. Of the 293 species documented to be associated with eastern hemlocks, 33 species were found to be directly effected by one or more of the chemical treatments. PMID- 19791599 TI - Symbioses: a key driver of insect physiological processes, ecological interactions, evolutionary diversification, and impacts on humans. AB - Symbiosis is receiving increased attention among all aspects of biology because of the unifying themes it helps construct across ecological, evolutionary, developmental, semiochemical, and pest management theory. Insects show a vast array of symbiotic relationships with a wide diversity of microorganisms. These relationships may confer a variety of benefits to the host (macrosymbiont), such as direct or indirect nutrition, ability to counter the defenses of plant or animal hosts, protection from natural enemies, improved development and reproduction, and communication. Benefits to the microsymbiont (including a broad range of fungi, bacteria, mites, nematodes, etc.) often include transport, protection from antagonists, and protection from environmental extremes. Symbiotic relationships may be mutualistic, commensal, competitive, or parasitic. In many cases, individual relationships may include both beneficial and detrimental effects to each partner during various phases of their life histories or as environmental conditions change. The outcomes of insect-microbial interactions are often strongly mediated by other symbionts and by features of the external and internal environment. These outcomes can also have important effects on human well being and environmental quality, by affecting agriculture, human health, natural resources, and the impacts of invasive species. We argue that, for many systems, our understanding of symbiotic relationships will advance most rapidly where context dependency and multipartite membership are integrated into existing conceptual frameworks. Furthermore, the contribution of entomological studies to overall symbiosis theory will be greatest where preoccupation with strict definitions and artificial boundaries is minimized, and integration of emerging molecular and quantitative techniques is maximized. We highlight symbiotic relations involving bark beetles to illustrate examples of the above trends. PMID- 19791600 TI - Insect symbioses: a case study of past, present, and future fungus-growing ant research. AB - Fungus-growing ants (Attini: Formicidae) engage in an obligate mutualism with fungi they cultivate for food. Although biologists have been fascinated with fungus-growing ants since the resurgence of natural history in the modern era, the early stages of research focused mainly on the foraging behavior of the leaf cutters (the most derived attine lineage). Indeed, the discovery that the ants actually use leaf fragments to manure a fungus did not come until the 1800s. More recently, three additional microbial symbionts have been described, including specialized microfungal parasites of the ant's fungus garden, antibiotic producing actinobacteria that help protect the fungus garden from the parasite, and a black yeast that parasitizes the ant-actinobacteria mutualism. The fungus growing ant symbiosis serves as a particularly useful model system for studying insect-microbe symbioses, because, to date, it contains four well-characterized microbial symbionts, including mutualists and parasites that encompass micro fungi, macro-fungi, yeasts, and bacteria. Here, we discuss approaches for studying insect-microbe symbioses, using the attine ant-microbial symbiosis as our framework. We draw attention to particular challenges in the field of symbiosis, including the establishment of symbiotic associations and symbiont function. Finally, we discuss future directions in insect-microbe research, with particular focus on applying recent advances in DNA sequencing technologies. PMID- 19791601 TI - Mycorrhizal fungal-plant-insect interactions: the importance of a community approach. AB - Mycorrhizal fungi and insects are important components of most ecosystems that are likely to interact with one another indirectly through a common host plant. In this paper, we review the literature examining the effects of insects on mycorrhizal fungi and the effects of mycorrhizal fungi on insects and show that both groups of organisms can indirectly and, occasionally directly, influence each other. We explore the mechanisms for these interactions and test a recently proposed model predicting mycorrhizal fungal community responses to herbivory. We emphasize the results of several recent studies that showed that experiments conducted in isolation are unlikely to predict the outcome of interactions between insects, plants, and mycorrhizal fungi, and we highlight the need for a community approach to the study of mycorrhizal fungal-plant-insect interactions. PMID- 19791602 TI - Demography of gut symbiotic and aposymbiotic Nezara viridula L. (Hemiptera: Pentatomidae). AB - Nezara viridula L. is a highly polyphagous and cosmopolitan pentatomid stink bug. Despite its economic importance, aspects of its biology are poorly understood. N. viridula has one primary bacterium associated with its gastric caeca, which females provide to offspring by smearing it on the surface of eggs during oviposition. We studied the impact of three temperatures and egg mass surface sterilization on N. viridula's nymphal development rate and reproductive performance. Our results show that maintenance of the symbiont is affected both by temperature and egg mass surface sterilization. We detected the symbiont in 100, 84, and 8.3% of the untreated control insects at 20, 25, and 30 degrees C, respectively, by using polymerase chain reaction. In insects originated from surface sterilized egg masses, the symbiont was never detected at 20 or 30 degrees C and was detected in only 1 of 21 insects at 25 degrees C. Nymphal mean development time decreased with increasing temperature, but there were no differences between the sterilized and control treatments. Sterilized insects at 20 degrees C lived longer than insects in any other treatment but never laid eggs. Life table analysis of N. viridula adults showed that net reproductive rate, intrinsic rate of increase, finite rate of increase, and gross reproductive rate were not significantly different among treatments except at 20 degrees C for the surface sterilized treatment. Mean generation time, however, was significantly longer at 20 degrees C (70.96 +/- 4.43 d), regardless of the surface sterilization treatment. Our results highlight the effect that temperature has on the maintenance of this symbiosis and its relationship with N. viridula host's development and reproduction. PMID- 19791603 TI - Two species of symbiotic bacteria present in the soybean aphid (Hemiptera: Aphididae). AB - Aphids, which feed solely on plant phloem sap, have developed symbiotic associations with bacteria that provide them with the amino acids that are lacking in phloem. Three soybean aphid (Aphis glycines Mat samura) populations were screened for the presence of Buchnera aphidicola and three common species of secondary aphid symbionts (Serratia symbiotica, Hamiltonella defensa, and Regiella insecticola). Diagnostic polymerase chain reaction and subsequent DNA sequencing showed the presence of two species of symbiotic bacteria present in all three soybean aphid populations tested: B. aphidicola and Arsenophonus sp. Although Buchnera is commonly found in aphids, Arsenophonus is most commonly found in whiteflies (Hemiptera: Aleyrodidae), making the soybean aphid unique among aphids that have been tested for the presence of Arsenophonus. PMID- 19791604 TI - Association and attraction of blueberry maggot fly Curran (Diptera: Tephritidae) to Pantoea (Enterobacter) agglomerans. AB - The attraction of washed, medium-free cells of Pantoea (Enterobacter) agglomerans to wild, adult Rhagoletis mendax Curran, the blueberry maggot fly, was evaluated in managed blueberry fields in Maine. Attraction was evaluated using Pherocon AM and Ladd traps, each tested with or without washed bacterial cells. Field studies showed significant increases in fly captures on the Pherocon AM traps. Apple volatiles odors on Ladd traps seemed to cancel the effects of bacterial odors. Aerobic heterotrophic bacteria were isolated and identified from alimentary organs within wild R. mendax. Isolates indentified included P. agglomerans. Blueberries collected in the field were surveyed for the presence of P. agglomerans and blueberries containing blueberry maggot larvae and noninfested blueberries were analyzed for amino acid content. Maggot-infested blueberry contained twice the amino acid nitrogen than that of noninfested blueberry. P. agglomerans, like with other pest tephritids, seems to be a cosmopolite with blueberry maggot. PMID- 19791605 TI - Effects of biological control of rice weevil by Anisopteromalus calandrae with a population of two Aspergillus spp. AB - In this study, we assessed the interaction occurring between the rice weevil and two storage molds (Aspergillus candidus Link and Aspergillus niger Van Tiegem) that prefer different moisture regimens under rice storage conditions. Rice weevil induced rapid population growth in both of the storage molds. The colony forming units (CFUs) of A. candidus and A. niger peaked at 10(9.00 +/- 0.02) and 10(7.72 +/- 0.03)/g, respectively. All of the rice grains were infested with the molds and eventually deteriorated; in the jars infested with A. candidus, no living weevils were found after 135 d. Suppression of the rice weevil by its larval parasitoid, Anisopteromalus calandrae (Howard), significantly retarded the growth of A. candidus but completely halted the growth of A. niger, which was replaced by xerophyllic molds including Aspergillus penicilloides Spegazzini and Wallemia sebi (Fries). Regression analyses showed that the total number of weevils was a significant factor explaining grain moisture content, which was in turn a significant factor in the growth of both mold species. The growth of A. niger was dependent on the grain moisture content (r2 = 0.52), thereby suggesting that the growth of A. niger was caused primarily by activity of the rice weevil and the resulting increased grain moisture content. However, 27% of the growth of A. candidus was explained by grain moisture contents, suggesting that a factor other than the grain moisture content may also affect its growth. Suppression of rice weevil by A. calandrae could induce an A. candidus-dominant molds community, which would be a factor for consideration in biological control program. PMID- 19791606 TI - Influence of silicon on resistance of Zinnia elegans to Myzus persicae (Hemiptera: Aphididae). AB - Studies were conducted to examine the effect of treating Zinnia elegans Jacq. with soluble silicon on the performance of the green peach aphid, Myzus persicae (Sulzer). Z. elegans plants were irrigated every 2 d throughout the duration of the experiment with a nutrient solution amended with potassium silicate (K2SiO2), or a nutrient solution without K2SiO2. Length of the prereproductive period and survivorship of M. persicae were not affected by K2SiO2 treatment, but total cumulative fecundity and the intrinsic rate of increase (r(m)) were slightly reduced on Z. elegans plants receiving soluble silicon. Quantification of silicon content in leaf tissues using inductively coupled plasma optical emission spectroscopy (ICP-OES) confirmed significantly higher silicon concentrations in plants treated with K2SiO2 compared with control plants. High performance liquid chromatography-mass spectrometry (HPLC-MS) analysis was used to identify and quantify phenolic acids and flavonols in leaf tissue of Z. elegans. Compared with untreated control plants, significant elevations in 5-caffeoylquinic acid, p coumaroylquinic acid, and rutin were detected in leaves of Z. elegans plants treated with K2SiO2, but none of seven other phenolics were significantly affected. Similarly, a slight elevation in guaiacol peroxidase activity was detected in plants treated with K2SiO2 Overall, these results indicate treatment of Z. elegans with soluble silicon provides a modest increase in resistance levels to M. persicae, which may be caused in part by defense-related compounds. PMID- 19791607 TI - Visible/near infrared reflectance (VNIR) spectroscopy for detecting twospotted spider mite (Acari: Tetranychidae) damage in strawberries. AB - The twospotted spider mite, Tetranychus urticae Koch, is among the most economically important pests in strawberries (Fragaria spp.). As T. urticae feeds, it ingests mesophyll cells that contain pigments essential for physiologic function and alters radiant energy use of the leaf tissue, severely compromising plant health and productivity. In our study, diffuse reflectance spectroscopy in the visible and near infrared (VNIR) portions of the spectrum was used to identify specific spectral regions altered by T. urticae feeding and to quantitatively assess T. urticae density. During the 2006-2007 growing season, 80 strawberry leaflets with varying levels of T. urticae infestation were collected. Spectral classification of both mite density (continuous) and mite density class (categorical) were developed. Spider mite density classes were low infestation (0 20 mites/leaflet), moderate infestation (20-50 mites/leaflet), and high infestation (> or = 50 mites/leaflet). Continuous spectral prediction for leaf infestation was developed using partial least squares (PLS) regression. Classification trees were used to train spectra to categorical levels of infestation. Both models were calibrated with 67% of the samples, and accuracy was evaluated using the remaining 33%. Categorical validation accuracy was 81%, with odds ratios for correctly predicting extreme categories (low and high) of 33 and 47.7, respectively. Continuous validation efficiency was also high, with an r2 between predicted and observed of 0.85 and a root-mean-squared error (RMSE) of 12.2 mites per leaf. Developing a spectral pest monitoring system would provide a diagnostic tool allowing early and effective intervention for precision management of T. urticae in strawberry. PMID- 19791608 TI - Mite-mediated hyperphoretic dispersal of Ophiostoma spp. from the infructescences of South African Protea spp. AB - Ophiostomatoid fungi are well known as economically important pathogens and agents of timber degradation. A unique assemblage of these arthropod-associated organisms including species of Gondwanamyces G. J. Marais and M. J. Wingf., and Ophiostoma Syd. and P. Syd. occur in the floral heads (infructescences) of Protea L. species in South Africa. It has recently been discovered that Ophiostoma found in Protea flower-heads are vectored by mites (Acarina) including species of: Tarsonemus Canestrini and Fonzago, Proctolaelaps Berlese, and Trichouropoda Berlese. It is, however, not known how the mites carry the fungi between host plants. In this study, we consider two possible modes of mite dispersal. These include self-dispersal between infructescences and dispersal through insect vectors. Results showed that, as infructescences desiccate, mites self-disperse to fresh moist infructescences. Long-range dispersal is achieved through a phoretic association with three beetle species: Genuchus hottentottus (F.), Trichostetha fascicularis L., and T. capensis L. The long-range, hyperphoretic dispersal of O. splendens G. J. Marais and M. J. Wingf. and O. phasma Roets et al. seemed effective, because their hosts were colonized during the first flowering season 3-4 yr after fire. PMID- 19791609 TI - Parasitized aphids are inferior prey for a coccinellid predator: implications for intraguild predation. AB - Discussions of intraguild predation (IGP) have assumed that the nutritional quality of intraguild (IG) prey is similar to that of any other prey available to the IG predator. It has been suggested therefore that generalist predators do not distinguish between healthy and parasitized aphids and thus function as facultative predators of parasitoids. More recent studies have shown that predators may selectively ingest prey of various nutritional qualities and that predators may have higher body nitrogen composition than herbivores. If so, predators may preferentially feed on other predators (i.e., IG prey) to increase their nitrogen intake. We used a system composed of larvae of the coccinellid Coccinella undecimpunctata (IG predator), the parasitoid Aphidius colemani (IG prey), and their shared food source, the green peach aphid Myzus persicae, to test whether (1) the predator preferentially feeds on parasitized over healthy prey, (2) predatory behavior on parasitized aphids changes with time elapsed after parasitism, and (3) parasitized and healthy aphids differ in their suitability for predator development. Results indicate that, given a choice, C. undecimpunctata larvae show no preference for either parasitized or healthy prey items, regardless of parasitoid age. Feeding time, however, increased with parasitoid age, leading to a reduction in the number of prey consumed per unit time. Mummified prey were protected from predation by C. undecimpunctata larvae but the larvae were able to feed and complete development on mummies with a broken cuticle. These predators, however, had an extended developmental time and lower pupal and adult weights in comparison to larvae fed healthy aphids. That parasitized aphids are inferior prey for C. undecimpunctata larvae should act to reduce intensity of IGP in the field and the negative impact IGP has on herbivore suppression. PMID- 19791610 TI - Lygus spp. (Heteroptera: Miridae) host-plant interactions with Lesquerella fendleri (Brassicaceae), a new crop in the arid southwest. AB - Lesquerella fendleri is a new crop being cultivated in the arid Southwest for the hydroxy fatty acids found in its seed oils; however, little is know about the agricultural pests that will affect the seed production of this crop or the role the crop may have as a possible source or sink for current agricultural pests in the Arizona landscape. In the early spring, lygus bugs, some of our most important agricultural pests, are normally found in relatively small numbers on weeds; however, as lesquerella production increases, it may serve as an important early-season host for lygus. Here we present results from olfactometer bioassays that showed a significant attraction by Lygus hesperus females to volatiles associated with flowering lesquerella. Headspace volatiles of flowering lesquerella were collected and identified by gas chromatography-mass spectrometry, and phenylacetaldehyde (PAA) was found to be the major component, followed by benzaldehyde and Z-3- hexenyl acetate. In the field, we examined the Lygus spp. complex, as well as the prevalence of other herbivores and select predators, and monitored their responses to unbaited sticky traps of various colors and PAA-baited green and blue sticky traps. Green, blue, and clear sticky traps captured significantly more Lygus spp. (L. elisus in particular) than opaque yellow and red traps, but PAA-baited blue and green traps did not capture more lygus than unbaited traps. Collops spp., however, were collected in higher numbers on PAA-baited traps, suggesting that this compound might provide a means of recruiting and/or retaining this particular natural enemy. PMID- 19791611 TI - Effectiveness of glues used for harmonic radar tag attachment and impact on survival and behavior of three insect pests. AB - The ability of three cyanoacrylate glues to ensure a durable bond between the Colorado potato beetle, Leptinotarsa decemlineata (Say), the plum curculio, Conotrachelus nenuphar (Herbst), or the corn rootworms (Western Corn Rootworm, Diabrotica virgifera virgifera LeConte and Northern Corn Rootworm, Diabrotica longicornis Smith and Lawrence) and the harmonic radar tag without impact on behavior and survival was assessed as part of a study on the use of harmonic radar technology to track these insect pests. Droplets of 0.1 mg of Krazy Glue, Loctite, and Bowman FSA applied to the pronotum had no effect on the survival of the Colorado potato beetle or plum curculio after 5 and 7 d, but caused > 40% mortality after only 4 h with both the western and northern corn rootworms. The three glues created an effective bond lasting 4-5 d between the harmonic radar tag and the Colorado potato beetle in > 85% of cases and the plum curculio in almost 50% of cases. There was no detectable impact of the glue treatment on feeding or walking behavior of the Colorado potato beetle. Analysis of the same behaviors with the plum curculio showed no impact on the ability to walk on a vertical surface, the speed of travel, or the duration of travel. There was no significant impact on feeding by female plum curculio but indication that males treated with Krazy Glue fed less. Overall, results quantified the effectiveness of the cyanoacrylate glues at providing a durable bond with no significant impact on mobility or behavior of the Colorado potato beetle or plum curculios. However, the toxicity of the glues against the corn rootworms suggests that similar toxicity or sublethal effects may exist with other insects. PMID- 19791612 TI - Dispersal and mating behavior of Diabrotica virgifera virgifera (Coleoptera: Chrysomelidae) in Bt cornfields. AB - Understanding of the mating and dispersal behavior of the western corn rootworm, Diabrotica virgifera virgifera (LeConte), is essential to predicting potential resistance to Bt corn technologies recently deployed to combat this pest. To quantify movement of male beetles, field studies were conducted during 2006 and 2007 in commercial Bt cornfields that included the Environmental Protection Agency-mandated 20% refuge acreage. Wing traps containing a single virgin female beetle were placed along transects throughout these fields. Male beetles were collected from the sticky bottoms of traps to compare the mean number of beetles captured at the different transect distances. Gut contents of each captured male were assayed with protein test strips to determine if the Bt protein (Cry3Bb1) was present. This provided an estimate of the distances traveled by males to reach virgin females. These data indicated that the mean number of males captured approximately 200 m from refuge corn was not significantly different than the mean number of males captured close to the refuge (< 22 m). Complementary field observations were conducted to determine how far newly emerged female beetles moved before mating and the time of day mating occurs. Results indicated that females do not move far from the site of emergence before mating and do not mate within the first 4 h of adult life. The implications of these data for movement and mating patterns of adult rootworms in Bt/refuge environments are discussed. PMID- 19791613 TI - Dispersal, patch leaving, and distribution of Homalodisca vitripennis (Hemiptera: Cicadellidae). AB - Homalodisca vitripennis (Germar) and related species have caused millions of dollars in damage to southern California vineyards in recent years through the vectoring of Pierce's disease. However, the effects of surrounding vegetation on the dispersal and distribution of H. vitripennis are poorly understood. Therefore, the relationship between dispersal rates and patch quality was tested, as well as the basic predictions of the marginal value theorem. Additional experiments were conducted to compare the H. vitripennis distribution in an isolated crape myrtle (Lagerstroemia indica) patch and a L. indica patch bordering two alternative host patches. In mark-release-recapture tests, H. vitripennis dispersed farther from the release point in a patch of low-quality host plants (Prunus persica) than in patches of high-quality host plants (L. indica). In addition, H. vitripennis remained in L. indica patches longer than in P. persica patches and adjusted patch residence times in P. persica in correlation with known changes in plant physiology. These data suggest that H. vitripennis follows the basic predictions of marginal value theorem. In distribution tests, H. vitripennis were more abundant in the patch center than patch edges in the isolated L. indica patch, but in a patch bordering cottonwood (Populus sp.) and peach (P. persica), H. vitripennis numbers were generally higher along the edges of the patch. These data suggest that alternate hosts bordering cropping systems may be important to the spatial dynamics of H. vitripennis. Implications of these spatial observations on the biology of H. vitripennis and potential control methods are discussed. PMID- 19791614 TI - Evidence of contact pheromone use in mating behavior of the raspberry weevil (Coleoptera: Curculionidae). AB - Numerous studies of insect species have shown that a subset of female cuticular hydrocarbons is used as short-range or contact pheromones. Here, we studied the possible use of contact pheromones in the mating behavior of the weevil Aegorhinus superciliosus, a native species of Chile. Males mounted females only after antennal contact with the female's cuticle, and only 33% of the males attempted to mate with dead females washed with solvent. When a glass rod (dummy) was coated with female cuticular extracts, males exhibited behaviors similar to those observed with females. A preliminary gas chromatography-mass spectrometry (GC-MS) analysis of cuticular extracts indicated that males and females share a series of aliphatic hydrocarbons but that the relative abundance of some of these compounds differ between the sexes. These results suggest that cuticular lipids mediate mating behavior of the raspberry weevil and provide the first evidence of contact pheromones in curculionids. PMID- 19791615 TI - Behavior and development of Pseudacteon curvatus (Diptera: Phoridae) varies according to the social form of its host Solenopsis invicta (Hymenoptera: Formicidae) in its native range. AB - We assessed the performance of Pseudacteon curvatus Borgmeier with respect to the social form of Solenopsis invicta Buren in Argentina In the field, we studied the effect the parasitoid on size and proportion of ant foragers. In the laboratory, we evaluated P. curvatus oviposition preferences; host size elected; developmental periods; and sexual size dimorphism, sex ratio, and parasitoid survivorship. P. curvatus affected the average size of foraging workers on both social forms diminishing the proportion of big and increasing the proportion of minor workers. P. curvatus required a shorter orientation time and exhibited a greater number of attacks when ovipositing on monogynes workers. In the laboratory, host sizes elected by P. curvatus were similar between social forms. However, attacks on polygyne colonies were more variable, increasing the number of unviable offspring. Developmental times of females and males of P. curvatus were similar for both social forms, but total developmental periods were shorter for males from monogyne colonies. We did not find differences between sexes in emerging adults' size by social form and the female: male sex ratio was 1:1 for both social forms. P. curvatus pupae survival and adult emergence per trial from monogyne colonies were greater than from polygyne colonies. The rarity of polygyne S. invicta in its native range may prevent this phorid from adjusting its life history to that social form. Consequences of applying this phorid in biological control are discussed. PMID- 19791616 TI - Comparison of perimeter trap crop varieties: effects on herbivory, pollination, and yield in butternut squash. AB - Perimeter trap cropping (PTC) is a method of integrated pest management (IPM) in which the main crop is surrounded with a perimeter trap crop that is more attractive to pests. Blue Hubbard (Cucurbita maxima Duch.) is a highly effective trap crop for butternut squash (C. moschata Duch. ex Poir) attacked by striped cucumber beetles (Acalymma vittatum Fabricius), but its limited marketability may reduce adoption of PTC by growers. Research comparing border crop varieties is necessary to provide options for growers. Furthermore, pollinators are critical for cucurbit yield, and the effect of PTC on pollination to main crops is unknown. We examined the effect of five border treatments on herbivory, pollination, and yield in butternut squash and manipulated herbivory and pollination to compare their importance for main crop yield. Blue Hubbard, buttercup squash (C. maxima Duch.), and zucchini (C. pepo L.) were equally attractive to cucumber beetles. Border treatments did not affect butternut leaf damage, but butternut flowers had the fewest beetles when surrounded by Blue Hubbard or buttercup squash. Yield was highest in the Blue Hubbard and buttercup treatments, but this effect was not statistically significant. Native bees accounted for 87% of pollinator visits, and pollination did not limit yield. There was no evidence that border crops competed with the main crop for pollinators. Our results suggest that both buttercup squash and zucchini may be viable alternatives to Blue Hubbard as borders for the main crop of butternut squash. Thus, growers may have multiple border options that reduce pesticide use, effectively manage pests, and do not disturb mutualist interactions with pollinators. PMID- 19791617 TI - Pepper weevil attraction to volatiles from host and nonhost plants. AB - The location of wild and cultivated host plants by pepper weevil (Anthonomus eugenii Cano) may be aided by visual cues, the male-produced aggregation pheromone, herbivore-induced, or constitutive host plant volatiles. The attractiveness of constitutive plant volatiles to pioneer weevils is important in understanding, and perhaps controlling, dispersal of this insect between wild and cultivated hosts. Ten-day-old male and 2- and 10-day-old female weevils were tested in short-range Y-tube assays. Ten-day-old male and female weevils were attracted to the volatiles released by whole plants of three known oviposition hosts, 'Jalapeno' pepper, American black nightshade, and eggplant, as well as tomato, a congener, which supports feeding but not oviposition. Two-day-old females were attracted to all plants tested, including lima bean, an unrelated, nonhost plant. Fruit volatiles from all three hosts and flower volatiles from nightshade and eggplant were also attractive. In choice tests, weevils showed different preferences for the oviposition hosts, depending on age and sex. Upwind response of 10-day-old male and female weevils to host plant volatiles was also tested in long-range wind tunnel assays. Weevils responded to pepper, nightshade, and eggplant volatiles by moving upwind. There was no difference in the observed upwind response of the weevils to the three host plants under no-choice conditions. Reproductively mature pepper weevils can detect, orient to, and discriminate between the volatile plumes of host plants in the absence of visual cues, conspecific feeding damage, or the presence of their aggregation pheromone. PMID- 19791618 TI - Roles of olfactory cues, visual cues, and mating status in orientation of Diaphorina citri Kuwayama (Hemiptera: Psyllidae) to four different host plants. AB - Diaphorina citri Kuwayama (Hemiptera: Psyllidae) is an important worldwide pest of citrus that vectors bacteria (Candidatus Liberibacter spp.) responsible for huanglongbing (citrus greening disease). We examined the behavioral responses of mated and unmated D. citri of both sexes to odors from host plants in a Y-tube olfactometer, with and without visual cues. The host plants tested were 'Duncan' grapefruit (Citrus paradisi Macfayden), sour orange (Citrus aurantium L.), navel orange (C. sinensis L.), and Murraya paniculata L. Jack. Responses varied by plant species, psyllid sex and mating status, and the presence of a visual cue. Evidence of attraction generally was stronger in females and in mated individuals of both sexes relative to virgins. The presence of a visual cue typically enhanced attractiveness of olfactory cues; in no case did unmated individuals show evidence of attraction to host plant odors in the absence of avisual cue. In the absence of visual cues, mated females and males showed evidence of attraction only to odors from sour orange and navel orange, respectively. Psyllids exhibited anemotactic responses when assayed with plant odors alone but showed strong evidence of attraction only when olfactory and visual cues were combined, suggesting that olfactory cues facilitate orientation to host plants but may be insufficient alone. Antennal responses to citrus volatiles were confirmed by electroantennogram. The results reported here provide evidence that D. citri uses olfactory and visual cues in orientation to host plants and suggest the possibility of using plant volatiles in monitoring and management of this pest. PMID- 19791619 TI - Factors affecting flight activity of Ophraella communa (Coleoptera: Chrysomelidae), an exotic insect in Japan. AB - The exotic beetle Ophraella communa LeSage was first found in 1996 in Japan and has rapidly expanded its distribution. This study examined the effect of several factors on the flight activity of this beetle and estimated its dispersal potential by measuring its flight time on a flight mill system. The beetles exhibited low flight activity at the age of 1-3 d posteclosion; however, after 4 d, it increased and thereafter remained high. The beetles reduced flight activity under the dark photophase, although they flew during both light and dark phases. Flight activity was lower in adults reared from hatching under a 12:12 (L:D)-h photoperiod than in those reared under a 16:8-h photoperiod; the shorter photoperiod was found to induce reproductive diapause. This photoperiodic response could explain seasonal changes in flight activities in which fourth generation adults displayed the lowest activity before overwintering. The female beetles flew, at maximum, for 385 min during a 23-h experimental period. Based on this value, the flight distance was estimated to be 25 km/23 h, suggesting a high dispersal potential of this beetle. PMID- 19791620 TI - Male reproductive potential of Aphidius colemani (Hymenoptera: Aphidiinae) exposed to constant or fluctuating thermal regimens. AB - Prolonged exposure to low temperature generally induces deleterious effects on survival and reproduction of insects. Reproduction costs are well documented in cold-exposed female parasitoids, but there is little information concerning males. In some species, low temperature is suspected to cause male sterility. Mummies of the aphid parasitoid Aphidius colemani Viereck (Hymenoptera: Aphidiinae) were exposed to either fluctuating thermal regimens (FTR: 4 degrees C, 22 h; 20 degrees C, 2 h) or constant low temperature (CLT: 4 degrees C) for 15 d. We verified whether cold exposure can sterilize males and evaluated treatment related survival, reproductive potential, and mobility parameters. Sterility trials showed that cold-exposed males were all fertile. Survival and reproductive potential of males (e.g., mating success, premating period, and competition for mating) were negatively affected when individuals were exposed to CLT. These alterations were associated with a reduction in locomotion performances during premating period. When parasitoids were exposed to FTR, survival, reproductive potential, and mobility parameters were unaffected. The reduced survival and mobility under CLT, probably results physiological perturbations: processes that may have a limited impact on individuals exposed to FTR. The consequence of mobility reduction on partner acceptance and competitive mating ability is discussed. PMID- 19791621 TI - Winter growth, development, and emergence of Diamesa mendotae (Diptera: Chironomidae) in Minnesota streams. AB - Diamesa mendotae Muttkowski is commonly observed emerging during winter at low air temperatures from Minnesota streams, but little is known about the winter dynamics of this and other winter-emerging aquatic insects. Biweekly collections of surface-floating pupal exuviae indicated that this species emerged from October through May, when water temperatures were less than approximately 10 degrees C. Emergence occurred continuously through winter, with a lull during January and February. Development of larvae from in situ growth enclosures supported emergence data and indicated that the reduction and halt of emergence in the spring was related to increasing water temperatures (> 10 degrees C), which were unsuitable for the growth or survival of the larvae. Development continued through January when water temperatures were at their lowest for the study stream and therefore did not explain the mid-winter lull in emergence. Growth rates of D. mendotae were not greater than other chironomid taxa at similar temperatures, indicating that lower critical thermal limits for growth allow this species to dominate ground-water influenced streams during the winter in Minnesota. The results of this study show that D. mendotae is well suited for growth and development at low temperatures and provides an assessment of important factors that regulate this species at low water and air temperatures. PMID- 19791622 TI - Changes of cold hardiness, supercooling capacity, and major cryoprotectants in overwintering larvae of Chilo suppressalis (Lepidoptera: Pyralidae). AB - The rice stem borer, Chilo suppressalis Walker, which is a key rice pest in northern parts of Iran, overwinters in rice stubble and weeds as mature larvae. Diapause of this pest is initiated between October to November and terminates in March. Seasonal variations in the supercooling point, survival at low temperatures, and sugar contents were studied in field-collected larvae during different phases of diapause. Ambient temperature was lowest in January and February when larvae were at the highest diapause intensity and achieved a high degree of cold hardiness at -10, -15, and -20 degrees C. Glycerol, a major cryoprotectant, reached a peak in January. It appeared that cold hardiness in the larvae is closely associated with the diapause. For the first time, this study suggests that glucose and glycogen are converted to glycerol during cold seasons, but trehalose has no definite role in the interconversion. During the coldest months, supercooling points (SCPs) increased (around -11 degrees C), and larvae could survive below their SCP values, showing that overwintering larvae of C. suppressalis are freeze tolerant in Iran. Our findings suggest that cold hardiness and diapause are essential components for this species. The overwintering larvae have high capacity of cold hardiness and can overcome severe winters. Understanding of cold hardiness and overwintering behavior of this species may help in integrated pest management of the rice stem borer in paddy fields. PMID- 19791623 TI - Genetic variation in flight activity of Ophraella communa (Coleoptera: Chrysomelidae): heritability estimated by artificial selection. AB - The exotic beetle Ophraella communa LeSage (Coleoptera: Chrysomelidae) was first found in 1996 in Japan and has rapidly expanded its distribution. This study investigated variation in flight activity and its genetic basis in this beetle by measuring its flight time on a flight mill system. The O. communa population exhibited substantial variation in flight activity among individuals. More than 30% of the beetles did not fly at all during a 23-h experimental period, whereas 20-26% of the beetles flew for over 60 min. Bidirectional artificial selection based on total flight time (0 or > 60 min) significantly shifted the distributions of flight time and percentage of beetles flying after several generations. Repeatability of the following five flight components was analyzed: the total flight time, longest duration of single flight, mean duration of single flights, number of single flights, and a fly-or-not criterion (flying at least once [1] or nothing at all [0]) because it defines a theoretical upper limit of heritability. Among them, the fly-or-not criterion had the highest repeatability (0.797), followed by the total flight time (0.648). The fly-or-not criterion assumes a threshold trait, whereas the total flight time is regarded as a continuous trait. The realized heritabilities of these traits were estimated at 0.206-0.864 based on the threshold trait and 0.125-0.531 based on the continuous trait. PMID- 19791624 TI - Mitochondrial DNA variation and range expansion in western bean cutworm (Lepidoptera: Noctuidae): no evidence for a recent population bottleneck. AB - The western bean cutworm, Striacosta albicosta (Smith) (Lepidoptera: Noctuidae), is a pest of both corn and dry bean crops. At the beginning of the 21st century, the species began to extend its range out of the Great Plains, eastward through the Corn Belt. This rapid range expansion is remarkable because the species distribution had been stable for at least the previous half century, despite the apparent abundance of suitable habitat (i.e., cornfields) immediately to the east. We hypothesized that if the western bean cutworm had to overcome a stable barrier to movement before starting the current range expansion, it probably experienced a genetic bottleneck in doing so. To test this hypothesis, variation in the mitochondrial NADH dehydrogenase one (ND1) gene was studied in populations from Wyoming, Nebraska, and Iowa. No differences in overall genetic diversity or haplotype frequencies indicative of a bottleneck were observed between the recently founded populations in Iowa and the established populations in Wyoming and Nebraska. This result suggests that the sudden loss of an ecological exclusion mechanism, allowing the species to move east in appreciable numbers, is more likely to have triggered the range expansion than the surmounting of an extrinsic barrier to movement. The nature of this mechanism is unknown but might be related to recent changes in corn farming practices and technology. PMID- 19791626 TI - Pre- and postnatal women's leisure time physical activity patterns: a multilevel longitudinal analysis. AB - The purpose of this study was to examine women's leisure time physical activity (LTPA) before pregnancy, during pregnancy, and through the first 7 months postnatal. Pre- and postnatal women (n = 309) completed the 12-month Modifiable Activity Questionnaire and demographic information. Multilevel modeling was used to estimate a growth curve representing the average change in LTPA over time and intraindividual variations in the average growth curve over time. Growth curve estimates for the linear quadratic, and cubic trends were significant (p < .05), indicating that LTPA declined during pregnancy but then increased following birth. The results also demonstrated that the individual trajectories of LTPA varied substantially from the average growth curve. One demographic predictor variable (having other children at home) was significant (p < .05). PMID- 19791625 TI - Three-year field monitoring of Cry1F, event DAS-01507-1, maize hybrids for nontarget arthropod effects. AB - Field studies were conducted over a 3-yr period to investigate the potential effects of cultivating transgenic maize hybrids containing a Cry1F insect resistant protein on nontarget arthropod abundance. The narrow spectrum of activity of Cry1F against a subset of lepidopteran pest species would not suggest broad-spectrum effects on nontarget arthropods. However, because of the insecticidal nature of Bt proteins, an alternate hypothesis is that some nontargets may be affected by exposure to the protein. To examine this hypothesis at the field level, monitoring for nontarget organism abundance was initiated at four locations across the U.S. Corn Belt from 2004 through 2006. At each location, paired fields (approximately 0.8 ha each) of commercial Cry1F maize hybrids and isogenic nontransgenic control hybrids were planted. Sampling methods used to monitor nontarget organisms included visual surveillance, sticky cards, pitfall traps, and litterbags. Data were analyzed using multivariate analyses to look for a general community level response to the treatments. Analysis of variance was conducted on individual taxa to detect differences distinct from the primary community response. Community level analyses of the nontarget arthropod abundance showed no significant impact on community abundance when comparing Bt with non-Bt maize fields. Analyses of the individual taxa also showed no significant differences in abundance between Bt and non-Bt fields. Results of these studies confirm earlier laboratory testing and support the hypothesis that Cry1F maize does not produce adverse effects on nontarget arthropods occurring in maize fields. PMID- 19791627 TI - Quantity, type, and correlates of physical activity among American Middle Eastern university students. AB - The prevalence of hypokinetic disease among persons of Middle Eastern heritage is higher than whites and research on American young adults of this population is limited. Therefore 214 tertiary students of Middle Eastern descent self-reported their physical activity (PA) over a 1-week monitoring period using pedometers and daily activity logs. Daily step count averaged 9,256 (SD = 3,084) steps, while daily energy expenditure averaged 6.26 kcal/kg (SD = 4.92). Most participants reported no weekly engagement in sport (69.2%) and walk/run (52.8%) activities, and at least once-weekly engagement in conditioning (68.7%) activities. Moderately religious and highly acculturated men, and Muslims, and moderately/highly acculturated persons were more likely to average > or = 10,000 steps/day and engage in at least one sport activity per week, respectively. These findings may be related to religious and cultural issues unique to Middle Eastern American college students whose collectivist social affiliations with family and community members may facilitate or inhibit various aspects of PA behavior. PMID- 19791628 TI - Influence of activity monitor location and bout duration on free-living physical activity. AB - The purpose of this study was to evaluate the influence of the location (ankle, hip, wrist) where an activity monitor (AM) is worn and of the minimum bout duration (BD) on physical activity (PA) variables during free-living monitoring. Study 1 participants wore AMs at three locations for 1 day while wearing the Intelligent Device for Energy Expenditure and Activity (IDEEA) system. Study 2 participants wore AMs at the same locations for 3 days. Variables included time (T(MV), min/day) and AEE (AEE(MV) kcal/day) for each monitor location and BD above a moderate-vigorous (MV) intensity. T(MV) and AEE(MV) in Study 1 were similar across AMs to IDEEA values at BD = 10 min, as was T(MV) in Study 2. This suggests that ankle-, wrist- and hip-worn AMs can provide similar PA outcome values during free-living monitoring at 10-min BDs. PMID- 19791629 TI - Waist circumference, pedometer placement, and step-counting accuracy in youth. AB - This study examined whether differences in waist circumference (WC) and pedometer placement (anterior vs. midaxillary vs. posterior) affect the agreement between pedometer and observed steps during treadmill and self-paced walking. Participants included 19 pairs of youth (9- 15-years-old) who were matched for sex, race, and height and stratified by WC (high WC: HWC; low WC: LWC). Participants performed 3-min treadmill-walking trials at speeds of 59, 72, and 86 m x min(-1) and a 400-m self-paced walking trial on level ground. Bland-Altman plots were used to assess the agreement between pedometer and observed steps of spring-levered pedometers by WC, pedometer placement, and walking speed. In the HWC group, the posterior pedometer placement consistently agreed most closely with observed steps at all treadmill speeds and during self-paced walking. In the LWC group, no single pedometer placement consistently agreed most closely with observed steps at all treadmill speeds and during self-paced walking. We conclude that a posterior pedometer placement improves step-count accuracy in most youth with an HWC at a range of walking speeds on level ground. PMID- 19791630 TI - How many days are enough? A study of 365 days of pedometer monitoring. AB - This study was designed to determine the number of days of pedometer monitoring necessary to achieve reliable and valid estimates of a 1-year average of step counts in adults based on either consecutive days (CD) or random days (RD) of data collection. Twenty-three participants (16 women; M age = 38 years, SD = 9.9) wore a Yamax SW 200 pedometer and recorded their step counts for 365 consecutive days. Nine measurement periods of various lengths were selected (2, 3, 4, 5, 6, 7, 14, 21, and 30 days). Each measurement period was randomly selected 10 times each for CD and RD from the larger database. For reliability and validity, two way intraclass correlation coefficients and mean absolute percentage error (MAPE) were calculated, respectively. The year-round average was considered the criterion measure of the "true" habitual physical activity. Data were analyzed separately by CD and RD. At least 5 CD or 6 RD were necessary to achieve an ICC of .80. A minimum of 30 CD or 14 RD were necessary to achieve an MAPE lower than 10%. These findings provide researchers and practitioners with useful information to determine appropriate measurement length and the method of data selection based on a desired level of reliability and validity. PMID- 19791631 TI - Trends in international research presented through the Research Consortium of the American Alliance for Health, Physical Education, Recreation and Dance (1965 2008). AB - The extent of international research on the Research Consortium's program between 1965 and 2008 was documented. A total of 9,132 abstracts were reviewed, and 657 (7.19%) had an international component. Inclusion of international research ranged from a low of 1.97% in 1983 to a high of 14.24% in 2007. There was a decrease in the amount of international research presented between 1965 and 1983, after which there was an increase through 2008. Most growth was from increased contributions coming from researchers in Southeast Asia. In terms of general research topics, eight areas increased over the 44-year history reviewed, and five areas decreased. Seven recommendations are advanced for expanding the place and role of international research within the Research Consortium. PMID- 19791632 TI - The utility of shorter epochs in direct motion monitoring. AB - This cross-sectional study using direct motion monitoring evaluated whether short epochs increased estimates of moderate or vigorous physical activity (MPA or VPA) and enhanced differences in daily VPA comparing overweight (OW) and nonoverweight (NOW) children. Seventy-seven children (ages 8-10 years) wore accelerometers for 7 days. We calculated two estimates (mean minutes per day) of MPA and VPA using motion counts based on a 15-s epoch and a calculated 60-s epoch produced by totaling each consecutive group of four 15-s motion counts. We compared estimates as a function of mean motion count x min(-1) for sex, age, and status as OW or NOW. The results showed that a 15-s epoch produced higher estimates of VPA (mean difference of 7 min per day, p < .001). The average number of VPA minutes added using the 15-s epoch vs. the 60-s epoch was 8.8 for more active children compared with 5.8 for less active children (p < .001). There was no difference in VPA minutes between OW and NOW children. These findings suggest modestly increased sensitivity to VPA using shorter epochs; this was particularly true for the most active children. Shorter epochs, however might not be useful in clarifying the relationship between VPA and obesity in children. PMID- 19791633 TI - Challenges to cognitive bases for an especial motor skill at the regulation baseball pitching distance. AB - We tested expert baseball pitchers for evidence of especial skills at the regulation pitching distance. Seven college pitchers threw indoors to a target placed at 60.5 feet (18.44 m) and four closer and four further distances away. Accuracy at the regulation distance was significantly better than predicted by regression on the nonregulation distances (p < .02), indicating an especial skill effect emerged despite the absence of normal contextual cues. Self-efficacy data failed to support confidence as a mediating factor in especial skill effect. We concluded that cognitive theories fail to fully account for the patterns of observed data, and therefore theoretical explanations of the especial skills must address noncognitive aspects of motor learning and control. PMID- 19791634 TI - Effect of information load and time on observational learning. AB - We examined whether altering the amount of and moment when visual information is presented affected observational learning for participants practicing a bowling skill. On Day 1, four groups practiced a cricket bowling action. Three groups viewed a full-body point-light model, the model's bowling arm, or between-limb coordination of the model's left and right wrists only. Following retention tests on Day 2, all participants practiced after viewing a full-body display. Retention was again tested on Day 3. Bowling accuracy improved in all four practice groups. Kinematics of the bowling arm became more like the model for the full-body and intralimb groups only. All groups improved on measures of interlimb coordination. Visual search data indicated that participants mainly focused their gaze on the model's bowling arm. These data lead to the suggestion that viewing "end effector" information (i.e., information pertaining to the bowling arm) is an important perceptual constraint early in observational learning. Implicit manipulations designed to increase attention to other sources of information did not facilitate the learning process. PMID- 19791635 TI - How do batters use visual, auditory, and tactile information about the success of a baseball swing? AB - Bat/ball contact produces visual (the ball leaving the bat), auditory (the "crack" of the bat), and tactile (bat vibration) feedback about the success of the swing. We used a batting simulation to investigate how college baseball players use visual, tactile, and auditory feedback. In Experiment 1, swing accuracy (i.e., the lateral separation between the point of contact and "sweet spot") was compared for no feedback (N), visual alone, auditory alone, and tactile alone. Swings were more accurate for all single-modality combinations as compared to no feedback, and visual produced the greatest accuracy. In Experiment 2, the congruency between visual, tactile, and auditory was varied so that in some trials, the different modalities indicated that the simulated ball contacted the bat at different points. Results indicated that batters combined information but gave more weight to visual. Batting training manuals, which typically only discuss visual cues, should emphasize the importance of auditory and tactile feedback in baseball batting. PMID- 19791636 TI - Effect of the 3-point line change on the game dynamics in girls' minibasketball. AB - We examined the game dynamics in minibasketball when comparing two different forms of the 3-point line. During the first competition, participants used a 3 point line delimited by the free-throw lane, and 1,642 ball possessions were recorded. During the second competition, participants played with a 3-point line delimited by a rectangular area, and 1,669 ball possessions were recorded. Results from the Mann-Whitney U Test show that when playing with a 3-point line delimited by the free-throw lane, higher average values were achieved in terms of points scored, number of players taking part in the ball possessions, number of passes, and one-on-one situations. PMID- 19791637 TI - Attentional demands on motor-respiratory coordination. AB - Athletic performance requires the pacing of breathing with exercise, known as motor-respiratory coordination (MRC). In this study, we added cognitive and physical constraints while participants intentionally controlled their breathing locations during rhythmic arm movement. This is the first study to examine a cognitive constraint on MRC. Cognitive constraints included either instruction (Experiments 1 and 2) or signal detection (Experiment 1). Physical constraints were nonoptimal movement frequencies (Experiment 2). Instruction shifted breathing locations and both shifted and increased variability in the number of movements produced per breath (frequency ratio). Signal detection had no effect on MRC. Fast movement frequency resulted in higher more variable frequency ratios. Cognitive and physical constraints can generate unnatural and variable breathing during athletic performance. PMID- 19791638 TI - The effects of a 12-week walking program on community-dwelling older adults. AB - Walking is a popular and easily accessible form of physical activity. However, walking instruction for older adults is based on the evidence gathered from younger populations. This study evaluated walking conditions, strength, balance, and subjective health status after a 12-week walking-training program in community-dwelling adults > 65-years-old. Participants walked 1,921 m (3,158.88 steps) in 26.69 min with a heart rate of 114 beats/min. An analysis of covariance to adjust for previous exercise habits, pretest strength, and subjective health status revealed significant differences in strength and in subjective physical and mental health status between experimental and control groups. This study identified the effects of the walking-training program on community-dwelling elderly adults without changing their previous physical activities. PMID- 19791639 TI - Instructional climates in preschool children who are at-risk. Part I: object control skill development. AB - Part I of this study examined the effect of two 9-week instructional climates (low autonomy [LA] and mastery motivational climate [MMC]) on object-control (OC) skill development in preschoolers (N = 117). Participants were randomly assigned to an LA, MMC, or comparison group. OC skills were assessed at pretest, posttest, and retention test with the Test of Gross Motor Development-2nd Edition. A significant Treatment x Time interaction (p < .001) was present, supporting the effectiveness of both OC instructional climates in improving OC skills over time, while the comparison group resulted in no changes. The authors conclude that developmentally and instructionally appropriate climates are beneficial to OC skill learning, along with the need for "planned" movement experiences in motor learning environments. PMID- 19791640 TI - Instructional climates in preschool children who are at-risk. Part II: perceived physical competence. AB - In Part II of this study, we examined the effect of two 9-week instructional climates (low-autonomy [LA] and mastery motivational climate [MMC]) on perceived physical competence (PPC) in preschoolers (N = 117). Participants were randomly assigned to an LA, MMC, or comparison group. PPC was assessed by a pretest, posttest, and retention test with the Pictorial Scale of Perceived Competence and Social Acceptance. A significant Treatment x Time interaction (p < .001) was present, supporting that MMC participants reported significantly higher PPC scores over time, while no positive changes were present in LA and comparison participants. The results show that an MMC leads to psychological benefits related to achievement motivation. These findings should encourage early childhood educators to consider the effect of instructional climates on children's self-perception. PMID- 19791641 TI - E-mentoring in physical education: promises and pitfalls. AB - Mentoring can be a critical component of teachers' professional development and retention, yet logistical and fiscal challenges often limit the amount of contact a protege can have with a mentor teacher. This investigation explored a school district initiative to address this need for more mentor interaction by supplementing traditional face-to-face mentoring with electronic mentoring. Thirty elementary physical education teachers participated in a year-long program that involved workshops, school visits, videotaped lessons, and electronic mentoring via chat rooms. Data were collected from chat room postings and analyzed for frequency of response and quality. In addition, a series of interviews were analyzed via constant comparison process to further understand teachers' perceptions of electronic mentoring. In general, teacher postings were minimal in frequency and quality. The limited use of the chat rooms was likely linked to the teachers' perceptions of electronic mentoring, which included several concerns with the technical and human dimensions of the process. PMID- 19791642 TI - Moderate association of anthropometry, but not training volume, with race performance in male ultraendurance cyclists. AB - In 28 male Caucasian nonprofessional ultracyclists, we investigated whether anthropometry or training volume had an influence on race speed in the 600 km at the Swiss Cycling Marathon 2007. Anthropometric parameters (age, body mass, body height, skinfold thicknesses) were determined before the race to calculate body mass index and percent body fat. In addition, participants, using a training diary, recorded their training volume in hours and kilometers in the 3 months before the race. The influence of anthropometry and training volume on speed in the race as the dependent variable was investigated in a multiple linear regression model. Anthropometry showed a moderate association with speed in the race (r2 = .178, p < .05), whereas training volume showed no association (r2 = .000, p > .05). We concluded that anthropometry had a greater influence on race performance than training volume in recreational ultraendurance cyclists. PMID- 19791643 TI - Eight-week traditional mat Pilates training-program effects on adult fitness characteristics. AB - We investigated responses of adult, novice practitioners (n = 9) to an 8-week traditional mat Pilates program (P) that met 1 hr/day three times/week. Classes consisted primarily of beginner and intermediate level exercises. Compared to an active control group (C; n = 13) that showed no improvements, those in P significantly (p < .05) improved relative body fat (-1.2% BF), sit-and-reach (+7.5 cm), shoulder reach (+6.9 cm), curl-up (+14 reps), and low back extension (+7 reps) scores, as well as circumferences at the waist (-2.7 cm), chest (-1.7 cm), and arm (-0.5 cm). Baseline differences were noted only for curl-ups and low back extensions, with P being lower than C Body composition, muscular endurance, and flexibility significantly improved after 8 weeks of traditional mat Pilates. PMID- 19791644 TI - Within- and between-day repeatability and variability in children's physiological responses during submaximal treadmill exercise. AB - The purpose of this study was to verify within- and between-day repeatability and variability in children's oxygen uptake (VO2), gross economy (GE; VO2 divided by speed) and heart rate (HR) during treadmill walking based on self-selected speed (SS). Fourteen children (10.1 +/- 1.4 years) undertook three testing sessions over 2 days in which four walking speeds, including SS were tested. Within- and between-day repeatability were assessed using the Bland and Altman method, and coefficients of variability (CV) were determined for each child across exercise bouts and averaged to obtain a mean group CV value for VO2, GE, and HR per speed. Repeated measures analysis of variance showed no statistically significant differences in within- or between-day CV for VO2, GE, or HR at any speed. Repeatability within- and between-day for VO2, GE, and HR for all speeds was verified. These results suggest that submaximal VO2 during treadmill walking is stable and reproducible at a range of speeds based on children's SS. PMID- 19791645 TI - The DiabetAction program: implementation in community-based settings. AB - Developed for specialists who want to increase the physical activity (PA) level of type 2 diabetic and at-risk individuals, the 10-week DiabetAction program introduced participants to a wide variety of cardiovascular resistance, balance, and flexibility exercises. Thirty-three of 48 individuals completed the intervention in community-based settings, while 25 of 29 participants completed control group evaluations. A significant time effect (p < .05) was measured for leisure PA level, resting systolic and diastolic blood pressure, estimated aerobic capacity, and dynamic balance (nonsignificant group effect; p > .05). The physical functioning domain of quality of life improved in the experimental group, while the vitality domain improved in the control group (significant interactions; p < .05). Follow-ups of the experimental group revealed that they maintained postintervention parameters (leisure PA level, proportion of participants > or = 150 min of PA weekly, estimated aerobic capacity) or improved (mental component summary measure of quality of life). Ninety-four percent of the experimental group was "very" or "extremely" satisfied with the program, and participants perceived improvements in PA level, health, and tiredness postintervention. In conclusion, participants in community-based settings improved on many of the measured parameters and maintained PA practice up to 6 months postintervention. However, since control participants also saw improvements, further controlled studies will be needed. PMID- 19791646 TI - Increase of total body water with decrease of body mass while running 100 km nonstop--formation of edema? AB - We investigated whether ultraendurance runners in a 100-km run suffer a decrease of body mass and whether this loss consists of fat mass, skeletal muscle mass, or total body water. Male ultrarunners were measured pre- and postrace to determine body mass, fat mass, and skeletal muscle mass by using the anthropometric method. In addition, bioelectrical impedance analysis was used to determine total body water, and urinary (urinary specific gravity) and hematological parameters (hematocrit and plasma sodium) were measured in order to determine hydration status. Body mass decreased by 1.6 kg (p < .01), fat mass by 0.4 kg (p < .01), and skeletal muscle mass by 0.7 kg (p < .01), whereas total body water increased by 0.8 L (p < .05). Hematocrit and plasma sodium decreased significantly (p < .01), whereas plasma urea and urinary specific gravity (USG) increased significantly (p < .01). The decrease of 2.2% body mass and a USG of 1.020 refer to a minimal dehydration. Our athletes seem to have been relatively overhydrated (increase in total body water and plasma sodium) and dehydrated (decrease in body mass and increase in USG) during the race, as evidenced by the increased total body water and the fact that plasma sodium and hematocrit were lower postrace than prerace. The change of body mass was associated with the change of total body water (p < .05), and we presume the development of. PMID- 19791648 TI - Brief walks in outdoor and laboratory environments: effects on affective responses, enjoyment, and intentions to walk for exercise. AB - The purpose of this study was to compare the effect of brief walks completed in outdoor and laboratory environments on affective responses, enjoyment, and intention to walk for exercise. Thirty-five active young women (M age = 22.14 years, SD = 1.73) walked for 10 min at a self-selected intensity in outdoor and laboratory environments. Affective responses were assessed before, during, and following each brief walk. Enjoyment and intention also were assessed following each walk. Results revealed that although both walks resulted in improvements in affective responses, participants reported greater pleasant affective states, enjoyment, and intention for future participation with outdoor walking. Results of correlation analyses also revealed that affective responses were only consistently related to enjoyment in the outdoor environment. These findings suggest that the environment influences the affective responses to brief walks and show that affective states experienced during walking are related to theoretical determinants of physical activity. PMID- 19791647 TI - Total protein of whole saliva as a biomarker of anaerobic threshold. AB - Saliva provides a convenient and noninvasive matrix for assessing specific physiological parameters, including some biomarkers of exercise. We investigated whether the total protein concentration of whole saliva (TPWS) would reflect the anaerobic threshold during an incremental exercise test. After a warm-up period, 13 nonsmoking men performed a maximum incremental exercise on a cycle ergometer. Blood and stimulated saliva were collected during the test. The TPWS anaerobic threshold (PAT) was determined using the Dmax method. The PAT was correlated with the blood lactate anaerobic threshold (AT; r = .93, p < .05). No significant difference (p = .16) was observed between PAT and AT. Thus, TPWS provides a convenient and noninvasive matrix for determining the anaerobic threshold during incremental exercise tests. PMID- 19791649 TI - An examination of psychosocial correlates of eating disorders among female collegiate athletes. AB - With female collegiate athletes, we examined the relationship of eating pathology to body image concerns, weight pressures, sociocultural internalization, and mood state. Multivariate analyses revealed that the symptomatic and eating disorder groups were similar on seven of eight weight pressures, three of four mood states, on internalization, and on five of six body image measures; in all instances, these two groups reported more pathological scores than the asymptomatic athletes. Except for pressures from coaches, the psychosocial variables differentiated the groups, correctly classifying 79% of the cases. These findings suggest that athletes symptomatic of eating disorders report similarly high levels of disturbance across a wide range of psychosocial risk factors, and both groups warrant prevention and treatment efforts. PMID- 19791650 TI - Automatic activation of exercise and sedentary stereotypes. AB - We examined the automatic activation of "sedentary" and "exerciser" stereotypes using a social prime Stroop task. Results showed significantly slower response times between the exercise words and the exercise control words and between the sedentary words and the exercise control words when preceded by an attractive exerciser prime. Words preceded by a normal-weight exerciser prime showed significantly slower response times for sedentary words over sedentary control words and exercise words. An overweight sedentary prime resulted in significantly slower response times for sedentary words over exercise words and exercise control words. These results highlight the need for increased awareness of how active and sedentary lifestyles are portrayed in the media. PMID- 19791651 TI - Attitudes toward overweight individuals among fitness center employees: an examination of contextual effects. AB - Our study assessed implicit and explicit evaluations of overweight individuals among a sample of fitness center employees (N = 70). Participants completed a general demographics questionnaire and an explicit, self-report Antifat Attitudes Test (AFAT). Participants also completed two Implicit Association Tests (IATs) to measure implicit attitudes toward overweight individuals. In one IAT participants responded to pictures of overweight and thin individuals in a neutral context. A second IAT required participants to respond to pictures of the same individuals exercising on a treadmill. Consistent with hypotheses, average scores fell below the midpoint on the AFAT subscales, suggesting an absence of a significant explicit bias. The sample exhibited moderately strong implicit weight biases, however, in both the neutral (IAT D = .39) and exercise contexts (IAT D = .39). The findings do not support the premise that implicit biases against overweight individuals vary according to the context in which the judgments are made. PMID- 19791652 TI - Effect of pedometer-based physical activity interventions: a meta-analysis. PMID- 19791653 TI - Give or take a few? Comparing measured and self-reported height and weight as correlates of social physique anxiety. PMID- 19791654 TI - Knowledge of results after good trials enhances learning in older adults. PMID- 19791655 TI - Relative age effect in masters sports: replication and extension. PMID- 19791656 TI - Gender stereotyping and the influence of race in sport among adolescents. PMID- 19791657 TI - More resources to protect children. PMID- 19791658 TI - Government orders supplies of swine flu vaccine to cope with pandemic. PMID- 19791659 TI - Recognising signs of abuse. PMID- 19791660 TI - Mobile phone use on a young person's unit. AB - AIMS: To ascertain information about the use of mobile phones on a young person's hospital unit and to obtain the views of nursing staff and young people about the benefits of their use. METHODS: A qualitative study using a pre-piloted questionnaire was given to 50 young people admitted consecutively to the young person's unit of district general hospital in a four-week period. A separate questionnaire was given to nine members of the nursing team over the same time period. FINDINGS: Most young people had access to a mobile phone while on the ward. A total of 30 per cent were told they could use their phone, 75 per cent of those had made calls or sent texts while on the ward, 80 per cent had received calls or texts, and 20 per cent had used the ward phone at the nursing station. All staff agreed that it was helpful for young people to use their phones on the ward to keep in contact with friends and family, to avoid isolation and ease boredom. CONCLUSION: Young people have different social needs to younger children and appreciate the opportunity to use mobile phones. A more flexible approach should be adopted. The advantages of phone use clearly outweigh the risks. PMID- 19791661 TI - Twenty five years on: charting the RCN's role in developing children's nursing services. AB - This year is the 25th anniversary of the children and young people's field of practice at the Royal College of Nursing. It was created at a time when no one knew how many nurses worked with children or where they worked. Since then the college has campaigned for improvements in services and education and been involved in numerous advances in standards and the dissemination of good practice. PMID- 19791662 TI - Diagnosis and management of primary ciliary dyskinesia. AB - Primary ciliary dyskinesia is a rare inherited condition affecting the movement and structure of the cilia in various areas of the body, including sinuses, ears and airways. Since 2006, three centres for diagnosis and research in England have been raising awareness and funding for primary ciliary dyskinesia's diagnosis and treatment. Other areas in the UK have their own arrangements and can refer to one of the English centres. This article discusses the condition, introduces the centres and advises on where to get more information. The author concludes that paediatric nurses are in a unique position to learn about and increase awareness of the condition to help prevent unnecessary ear, nose and throat surgeries and permanent lung damage. PMID- 19791663 TI - Psychosocial implications of gastrostomy placement. AB - This article reviews the literature on the psychosocial implications of gastrostomy placement, and highlights key areas of concern for children and their families. Information giving, failure and abnormality, professional support, and concerns and outcomes were the themes that emerged from the literature. Analysing these themes showed that there is a significant gap in service provision and it is suggested that introducing the role of a key worker as a single point of contact for advice and support could improve the services received by children with complex needs and their families. PMID- 19791664 TI - International child health. PMID- 19791665 TI - Improving communication between health visitors and primary mental health workers. AB - This audit aimed to open and improve communication between health visitors in Kirklees and the primary mental health workers in the child and adolescent mental health services at Calderdale and Huddersfield NHS Foundation Trust. This was deemed to be important for the establishment of best working practices and the need for multidisciplinary, multi-agency collaboration in the interests and wellbeing of the children, young people and families who use this service. It was hoped the audit would establish health visitors' knowledge of the local primary mental health worker service so that its effectiveness and relevance could be determined. In essence, the audit was intended to find out if the service provided what the service users needed and wanted. The audit demonstrated that about half of the health visitors were satisfied with the service provided and believed that their concerns or queries were dealt with appropriately. Two thirds of respondents, however, believed that they had insufficient knowledge about the role of the primary mental health worker. PMID- 19791666 TI - Enhancing peer support for pre-registration students. AB - This article describes an innovation in one university in the south east of England designed to promote group identity and develop peer support among child branch nursing students. The innovation consisted of bringing all child branch students to the university twice a year to attend a study day and take part in peer-support groups. The 'Paediatric personal and professional development day' was first introduced in 2004 and was evaluated on a biannual basis over a four year period. It was anticipated that one of the outcomes from the innovation would be to reduce attrition rates among child branch students, particularly in the common foundation programme. PMID- 19791667 TI - Emergency care in Afghanistan. PMID- 19791668 TI - Nurse-led services protect public from medics' quirks. PMID- 19791669 TI - Fear and loathing on the front line. PMID- 19791670 TI - Sign for a fair society. PMID- 19791671 TI - NICE guidance on low back pain should be revised urgently. PMID- 19791672 TI - The global swine flu pandemic 2: infection control measures and preparedness strategies. AB - This second in a two-part unit on swine flu looks at infection control measures for nurses. During late spring and early summer, increasing numbers of people became infected with novel swine origin influenza type A virus (influenza A(H1N1)v 2009) and a global pandemic started. Part 1 of this unit explored the biology of influenza viruses and the origins and characteristics of flu pandemics. This part reviews viral transmission, infection prevention and control and pandemic preparedness. PMID- 19791673 TI - Evaluating the effectiveness of swine flu contingency policies in healthcare education. AB - Swine flu has brought about the need to implement policy quickly, not only in healthcare but also in healthcare education, which has considered greater use of e-learning during potential disruption to classroom teaching. This article looks at measuring the success of these alternative teaching methods by using the known tangible benefits of e-learning. Consideration should also be given to supporting students on placements during this time, and as a consequence, some possible future areas for development are identified. PMID- 19791674 TI - Developing a nursing education project in partnership: leadership in compassionate care. AB - The prominence of the caring dimension has never had such a high profile in healthcare practice before. As a result of this, the Leadership in Compassionate Care Project has evolved. A unique feature is the partnership between Edinburgh Napier University and NHS Lothian. Engaging with and helping qualified and student nurses to value and promote the delivery of compassionate care is a primary focus of the project. This article outlines key policy drivers, the project's four main strands, and the aims, processes and perceived impact on practice. PMID- 19791675 TI - Why a brain tumour was originally thought to be hyperventilation related to anxiety. PMID- 19791676 TI - Exploring whether student nurses report poor practice they have witnessed on placements. AB - BACKGROUND: While literature suggests that nurses report incidents or potentially unsafe care delivery, there is little evidence on student nurses' practice in this area. AIM: To explore the factors that influence student in reporting concerns about practice. METHOD: A qualitative study was carried out using a phenomenological approach, based on semi-structured interviews with six student nurses. RESULTS AND DISCUSSION: Student nurses said they do not always report potentially unsafe practice they have witnessed. Four main themes were identified: the student-mentor relationship in clinical placement; actual or potential support provided by both the practice area and university; students' own personal confidence and professional knowledge base; and fear of failing clinical placements. CONCLUSION: The nursing profession needs to take stock of current organisational culture and practice, and address issues around reporting in practice. Recommendations are made to improve mentorship, nurse training and for further research. PMID- 19791677 TI - On how to improve drug use to minimise risks to patients. PMID- 19791678 TI - The job of basic care should be handed back to nurses. PMID- 19791679 TI - A crucial role as the patient's advocate. PMID- 19791680 TI - [Medical rehabilitation after aortocoronary shunting: quality control of the sanatorium rehabilitation]. PMID- 19791681 TI - [Prospects for improvement of the treatment and diagnosis outcomes at a regional hospital]. AB - The 442nd regional military clinical hospital is ahigh-specialized multiprofile treatment institute of Leningrad military region. Quantity of patients for the last 5 years was high-repeatability level (17.5-18.5 thous. people). In the medical surgical units are effectuated more then 5 thousands of surgical operations during a year. Specific weight of difficult operations is 40%. Results of treatment of the patients are good. General mortality in hospital descended from 1.16% in the 2000th year to 0.68% in the 2008th year. Hospitality mortality from myocardial infarction in the 2008th year was 5.5% and stays one of the lowers among all military-medical institutes of the Ministry of Defense of RF. Ways of improvement of treatment-diagnostic work in hospitals provide the following development of material-technical base, exchanging old medical equipment on modem devices and apparatus, involvement ofhightechnological types of medical aid. PMID- 19791682 TI - [Quality of diagnosis and prophylaxis of HIV-infection in military clinical institutions and related problems in training medical personnel]. AB - The analysis of results of laboratorial diagnostics of HIV-infection in multiprofile treatment institute of the Ministry of Defense of RF, questioning of medical staff on the questions of diagnostics and treatment of HIV-infection discovered several disadvantages in the system of training of the physicians in this sphere. Insufficient level of knowledge of practical aspects of HIV infection causes baseless quantity of screening laboratorial tests (up to 70%). It leads to grand material inputs of the Ministry of Defense of RF. The authors propose an elaborated guidance manual for teachers, attending physicians and students of academies on studying questions of HIV-infection, based on the principle of "transparent study", on broad engaging of different departments to the process of teaching, on consideration of profiles of cycles of studying, of levels of adoption, types of lessons, volume of study time. PMID- 19791683 TI - [Use of tourniquets in limb combat injuries]. AB - The garrot is one of the most well-known means by stemming of an exterior flow of blood of injured limbs. The article presents analyze of frequency, of indicated values and faults during the using of garrot in modern conditions of the combat in the Northern Caucasus (1994-2002). On the base of 104 wounds of great vessels, the authors make a conclusion about the necessity of using of the garrot only in the cases of absolute indications, when the other method of hemostasia, more simple and secure, is impossible. PMID- 19791684 TI - [Current approaches to estimation of the health risk caused by environmental chemicals pollutants]. PMID- 19791685 TI - [Progression prevention, diagnosis, and treatment of contrast agent-induced nephropathy]. PMID- 19791686 TI - [Ectopic pregnancy: principles of surgical tactics, treatment, and rehabilitation]. PMID- 19791687 TI - [Approaches to reduction of intraocular pressure by 30% in patients with glaucoma (review of literature)]. PMID- 19791688 TI - [Glaucoma genetics]. PMID- 19791689 TI - [Effectiveness of a preparation "Aquapiling" in the treatment of patients with squamous hyperkeratosis type of foot mycoses]. PMID- 19791690 TI - [Complex evaluation and normalizing of electromagnetic environment in a large garrison]. PMID- 19791691 TI - [Current approaches to solving problems of suppling military institutions with infusion solutions]. PMID- 19791692 TI - [Some aspects of bestowaling the medical staff]. PMID- 19791693 TI - [Russian physicians in the military service in China]. PMID- 19791694 TI - [The 75th anniversary of the Air Forces sanatorium "Chemitokvadzhe"]. PMID- 19791695 TI - [Establishment of dental services at the N N Burdenko General Military Clinical Hospital]. PMID- 19791696 TI - Innovations in health system finance in developing and transitional economies. PMID- 19791697 TI - The double burden of disease in developing countries: the Mexican experience. AB - OBJECTIVE: To present the challenges arising from the double burden of disease in developing countries, focusing on the case of Mexico, and to propose a strategy for addressing these challenges. METHODOLOGY/APPROACH: Mortality and morbidity data are presented for selected countries and groups of diseases. Specific examples of the pressures faced by the public health services in Mexico to provide and finance treatment for communicable and non-communicable diseases are used to illustrate the extent of the challenges in the context of a country with limited resources. FINDINGS: Public health systems in developing countries face strong pressure to provide and finance treatment for both communicable and non communicable diseases, inevitably producing competition among diseases and conditions and requiring trade-offs between equity and efficiency goals. IMPLICATIONS FOR POLICY: In developing countries, addressing the challenges presented by the double burden of disease requires a multidisciplinary approach to develop and strengthen the policymaking process. This involves the use of analytical tools applied to each stage of the planning cycle, in particular the use of an explicit priority setting process together with monitoring and assessment to strengthen decision making under limited resources. PMID- 19791698 TI - Protecting pro-poor health services during financial crises: lessons from experience. AB - OBJECTIVE: This chapter assesses the extent to which previous economic and financial crises had a negative impact on health outcomes and health financing. In addition, we review evidence related to the effectiveness of different policy measures undertaken in past crises to protect access to health services, especially for the poor and vulnerable. The current global crisis is unique both in terms of its scale and origins. Unlike most previous instances, the current crisis has its origins in developed countries, initially the United States, before it spread to middle- and lower-income countries. The current crisis is now affecting almost all countries at all levels of income. This chapter addresses several key questions aimed at helping inform possible policy responses to the current crisis from the perspective of the health sector: What is the nature of the current crisis and in what ways does it differ from previous experiences? What are some of the key. lessons from previous crises? How have governments responded previously to protect health from such macroeconomic shocks? How can we improve the likelihood of positive action today? METHODOLOGY/APPROACH: The chapter reviews the literature on the impact of financial crises on health outcomes and health expenditures and on the effectiveness of past policy efforts to protect human development during periods of economic downturn. It also presents analysis of household surveys and health expenditure data to track health seeking behavior and out-of-pocket expenditures by households during times of financial crisis. FINDINGS: Evidence from previous crises indicates that health-related impacts during economic downturns can occur through various channels. The impact in households experiencing reductions in employment and income could be manifest in terms of poorer nutritional outcomes and lower levels of utilization of health care when needed. Households may become impoverished, reduce needed health services, and experience reductions in consumption as a result of health shocks occurring during a time when their economic vulnerability has increased. Women, children, the poor, and informal sector workers are likely to be most at risk of experiencing negative health-related consequences in a crisis. Real government spending per capita on health care could decline due to reduced revenues, currency devaluations, and potential reductions in external aid flows. Low-income countries with weak fiscal positions are likely to be the most vulnerable. IMPLICATIONS FOR POLICY: Past crises can inform policy-making aimed at protecting health outcomes and reducing financial risk from health shocks. Evidence from previous crises indicates that broad-brush strategies that maintained overall levels of government health spending tended not to be successful, failing to protect access to quality health services especially for the poor. It is particularly vital to ensure access to essential health commodities, which in many low-income countries are imported, in the face of weakening exchange rates. Focused efforts to sustain the supply of lower-level basic services, combined with targeted demand-side approaches like conditional cash transfers may be more effective than broader sectoral approaches. Low-income countries may need specific short-term measures to ensure that health outcomes do not suffer. PMID- 19791699 TI - The equity impact of the universal coverage policy: lessons from Thailand. AB - OBJECTIVE: This chapter assesses health equity achievements of the Thai health system before and after the introduction of the universal coverage (UC) policy. It examines five dimensions of equity: equity in financial contributions, the incidence of catastrophic health expenditure, the degree of impoverishment as a result of household out-of-pocket payments for health, equity in health service use and the incidence of public subsidies for health. METHODOLOGY: The standard methods proposed by O'Donnell, van Doorslaer, and Wagstaff (2008b) were used to measure equity in financial contribution, healthcare utilization and public subsidies, and in assessing the incidence of catastrophic health expenditure and impoverishment. Two major national representative household survey datasets were used: Socio-Economic Surveys and Health and Welfare Surveys. FINDINGS: General tax was the most progressive source of finance in Thailand. Because this source dominates total financing, the overall outcome was progressive, with the rich contributing a greater share of their income than the poor. The low incidence of catastrophic health expenditure and impoverishment before UC was further reduced after UC. Use of healthcare and the distribution of government subsidies were both pro-poor: in particular, the functioning of primary healthcare (PHC) at the district level serves as a "pro-poor hub" in translating policy into practice and equity outcomes. POLICY IMPLICATIONS: The Thai health financing reforms have been accompanied by nationwide extension of PHC coverage, mandatory rural health service by new graduates and systems redesign, especially the introduction of a contracting model and closed-ended provider payment methods. Together, these changes have led to a more equitable and more efficient health system. Institutional capacity to generate evidence and to translate it into policy decisions, effective implementation and comprehensive monitoring and evaluation are essential to successful system-level reforms. PMID- 19791700 TI - Social health insurance and labor market outcomes: evidence from central and eastern Europe, and central Asia. AB - OBJECTIVE: The implications of social health insurance (SHI) for labor markets have featured prominently in recent debates over the merits of SHI and general revenue financing. It has been argued that by raising the nonwage component of labor costs, SHI reduces firms' demand for labor, lowers employment levels and net wages, and encourages self-employment and informal working arrangements. At the national level, SHI has been claimed to reduce a country's competitiveness in international markets and to discourage foreign direct investment (FDI). The transition from general revenue finance to SHI that occurred during the 1990s in many of the central and eastern European and central Asian countries provides a unique opportunity to investigate empirically these claims. METHODOLOGY/APPROACH: We employ regression-based generalizations of difference-in-differences (DID) and instrumental variables (IV) on country-level panel data from 28 countries for the period 1990-2004. FINDINGS: We find that, controlling for gross domestic product (GDP) per capita, SHI increases (gross) wages by 20%, reduces employment (as a share of the population) by 10%, and increases self-employment by 17%. However, we find no significant effects of SHI on unemployment (registered or self reported), agricultural employment, a widely used measure of the size of the informal economy, or FDI. IMPLICATIONS FOR POLICY: We do not claim that our results imply that SHI adoption everywhere must necessarily reduce employment and increase self-employment. Nonetheless, our results ought to serve as a warning to those contemplating shifting the financing of health care from general revenues to a SHI system. PMID- 19791701 TI - Trust in the context of community-based health insurance schemes in Cambodia: villagers' trust in health insurers. AB - OBJECTIVE: To understand the role and influence of villagers' trust for the health insurer on enrollment in a community-based health insurance (CBHI) scheme in Cambodia. METHODOLOGY/APPROACH: This study was conducted in northwest Cambodia where a CBHI scheme operates with the highest enrollment rates in the country. A mixed method approach was employed to gauge how individuals in the community trust the health insurer, and whether this plays a role in their decisions to enroll in CBHI schemes. Focus groups and household surveys were carried out to identify and measure trust levels, and to explore the association between insurer trust and enrollment in CBHI schemes. FINDINGS: Although villagers generally trusted the health insurance organization, villagers with poor experiences with other organizations in the past were less willing to trust the insurer. Insurer trust represented a combination of interpersonal and impersonal trust. After controlling for demographic factors, health care utilization, and household socioeconomic status, insurer trust levels for villagers who newly enrolled (RRR = 1.07, p < 0.001) and renewed insurance (RRR = 1.15, p < 0.001) were significantly higher than those who never enrolled in CBHI schemes. IMPLICATIONS FOR POLICY: This study illustrates the relationship between CBHI enrollment and villagers' trust for the health insurer in a low-income, post-conflict country. It highlights the need for staff of health insurance organizations to place greater emphasis on building trusting interpersonal relationships with villagers. Understanding the nature of trust for the health insurer is essential to improve health insurance enrollment and protect people in poor rural communities against the impact of health-related shocks. PMID- 19791702 TI - Methodological challenges in evaluating health care financing equity in data-poor contexts: lessons from Ghana, South Africa and Tanzania. AB - OBJECTIVE: Measurement of the incidence of health financing contributions across socio-economic groups has proven valuable in informing health care financing reforms. However, there is little evidence as to how to carry out financing incidence analysis (FIA) in lower income settings. We outline some of the challenges faced when carrying out a FIA in Ghana, Tanzania and South Africa and illustrate how innovative techniques were used to overcome data weaknesses in these settings. METHODOLOGY: FIA was carried out for tax, insurance and out-of pocket (OOP) payments. The primary data sources were Living Standards Measurement Surveys (LSMS) and household surveys conducted in each of the countries; tax authorities and insurance funds also provided information. Consumption expenditure and a composite index of socioeconomic status (SES) were used to assess financing equity. Where possible conventional methods of FIA were applied. Numerous challenges were documented and solution strategies devised. RESULTS: LSMS are likely to underestimate financial contributions to health care by individuals. For tax incidence analysis, reported income tax payments from secondary sources were severely under-reported. Income tax payers and shareholders could not be reliably identified. The use of income or consumption expenditure to estimate income tax contributions was found to be a more reliable method of estimating income tax incidence. Assumptions regarding corporate tax incidence had a huge effect on the progressivity of corporate tax and on overall tax progressivity. LSMS consumption categories did not always coincide with tax categories for goods subject to excise tax (e.g., wine and spirits were combined, despite differing tax rates). Tobacco companies, alcohol distributors and advertising agencies were used to provide more detailed information on consumption patterns for goods subject to excise tax by income category. There was little guidance on how to allocate fuel levies associated with 'public transport' use. Hence, calculations of fuel tax on public transport were based on individual expenditure on public transport, the average cost per kilometre and average rates of fuel consumption for each form of transport. For insurance contributions, employees will not report on employer contributions unless specifically requested to and are frequently unsure of their contributions. Therefore, we collected information on total health insurance contributions from individual schemes and regulatory authorities. OOP payments are likely to be under-reported due to long recall periods; linking OOP expenditure and illness incidence questions--omitting preventive care; and focusing on the last service used when people may have used multiple services during an illness episode. To derive more robust estimates of financing incidence, we collected additional primary data on OOP expenditures together with insurance enrolment rates and associated payments. To link primary data to the LSMS, a composite index of SES was used in Ghana and Tanzania and non-durable expenditure was used in South Africa. POLICY IMPLICATIONS: We show how data constraints can be overcome for FIA in lower income countries and provide recommendations for future studies. PMID- 19791703 TI - The role of risk equalization in moving from voluntary private health insurance to mandatory coverage: the experience in South Africa. AB - OBJECTIVE: The South African health system has long been characterised by extreme inequalities in the allocation of financial and human resources. Voluntary private health insurance, delivered through medical schemes, accounts for some 60% of total expenditure but serves only the 14.8% of the population with higher incomes. A plan was articulated in 1994 to move to a National Health Insurance system with risk-adjusted payments to competing health funds, income cross subsidies and mandatory membership for all those in employment, leading over time to universal coverage. This chapter describes the core institutional mechanism envisaged for a National Health Insurance system, the Risk Equalisation Fund (REF). A key issue that has emerged is the appropriate sequencing of the reforms and the impact on workers of possible trajectories is considered. METHODOLOGY: The design and functioning of the REF is described and the impact on competing health insurance funds is illustrated. Using a reference family earning at different income levels, the impact on worker of various trajectories of reform is demonstrated. FINDINGS: Risk equalization is a critical institutional component in moving towards a system of social or national health insurance in competitive markets, but the sequence of its implementation needs to be carefully considered. The adverse impact of risk equalization on low-income workers in the absence of income cross-subsidies and mandatory membership is considerable. IMPLICATIONS FOR POLICY: The South African experience of risk equalization is of interest as it attempts to introduce more solidarity into a small but highly competitive private insurance market. The methodology for considering the impact of reforms provides policymakers and politicians with a clearer understanding of the consequences of reform. PMID- 19791704 TI - Purchasing health care in China: experiences, opportunities and challenges. AB - OBJECTIVES: Purchasing has been promoted as a key policy instrument to improve health system performance. Despite its widespread adoption, there is little empirical evidence on how it works, the challenges surrounding its implementation, its impact, and the preconditions for it to function effectively, particularly in low- and middle-income settings. The objective of this chapter is to analyze critically the extent to which purchasing could be, and has been used strategically in China and to identify modifications that are needed for purchasing to be effective in assuring that the government's new funding for health care will result in efficient and effective health services. METHODS: We present a conceptual framework for purchasing, which identifies three critical principal-agent relationships in purchasing. We draw on evidence from secondary data, results of other research studies, interviews, and the impact evaluation of a social experiment in rural China that explicitly used purchasing to improve quality and efficiency. This information is used to examine purchasing relationships in urban social health insurance (SHI), the rural medical insurance scheme, and purchasing of public health services. FINDINGS: To date, use of strategic purchasing is limited in China. Both the urban and the rural health insurance schemes act as passive third-party payers, failing to take advantage of the opportunities to strengthen incentives to improve quality and efficiency. This may be because as government agencies, the extent to which the Ministries of Health and Labor and Social Security can act independently from provider interests, or act in the best interest of the population, is unclear. Other important challenges include ensuring adequate representation of the population's views and preferences and making better use of the leverage provided by purchasing to create appropriate provider incentives, through better integration of financing and improved coordination among purchasers. IMPLICATIONS FOR POLICY: In designing purchasing arrangements, attention needs to be paid to all three principal-agent relationships. Successful purchasing appears to require mechanisms to mobilize and represent community preferences and more strategic contracting with providers. More research is needed to strengthen the evidence on which purchasing arrangements work, which do not work, and under what conditions different purchasing configurations can work most effectively. PMID- 19791705 TI - The impact of Nepal's national incentive programme to promote safe delivery in the district of Makwanpur. AB - OBJECTIVE: Nepal's Safe Delivery Incentive Programme (SDIP) was introduced nationwide in 2005 with the aim of encouraging greater use of professional care at childbirth. It provided cash to women giving birth in a public health facility and an incentive to the health provider for each delivery attended, either at home or in the facility. We aimed to assess the impact of the programme on neonatal mortality and health care seeking behaviour at childbirth in one district of Nepal. METHODS: Impacts were identified using an interrupted time series approach, applied to houSehold data. We estimated a model linking the level of each outcome at a point in time to the start of the programme, demographic controls, a vector of time variables and community-level fixed effects. FINDINGS: The recipients of the cash transfer in the programme's first two years were disproportionately wealthier households, reflecting existing inequality in the use of government maternity services. In places with women's groups--where information about the policy was widely disseminated--the SDIP substantially increased skilled birth attendance, but failed to impact on either neonatal mortality or the caesarean section rate. In places with no women's groups, the SDIP had no impact on utilisation outcomes or neonatal mortality. IMPLICATIONS FOR POLICY: The lack of any impact on neonatal mortality suggests that greater increases in utilisation or better quality of care are needed to improve health outcomes. The SDIP changed health care seeking behaviour only in those areas with women's groups highlighting the importance of effective communication of the policy to the wider public. PMID- 19791706 TI - Service- and population-based exemptions: are these the way forward for equity and efficiency in health financing in low-income countries? AB - OBJECTIVE: The first wave of experiences of exemptions policies suggested that poverty-based exemptions, using individual targeting, were not effective, for practical and political economic reasons. In response, many countries have changed their approach in recent years--while maintaining user fees as a necessary source of revenue for facilities, they have been switching to categorical targeting, offering exemptions based on high-priority services or population groups. This chapter aims to examine the impact and conditions for effectiveness of this recent health finance modality. METHODOLOGY/APPROACH: The chapter is based on a literature review and on data from two complex evaluations of national fee exemption policies for delivery care in West Africa (Ghana and Senegal). A conceptual framework for analysing the impact of exemption policies is developed and used. Although the analysis focuses on exemption for deliveries, the framework and findings are likely to be generalisable to other service- or population-based exemptions. FINDINGS: The chapter presents background information on the nature of delivery exemptions, the drivers for their use, their scale and common modalities in low-income countries. It then looks at evidence of their impact, on utilisation, quality of care and equity and investigates their cost-effectiveness. The final section presents lessons on implementation and implications for policy-makers, including the acceptability and sustainability of exemptions and how they compare to other possible mechanisms. IMPLICATIONS FOR POLICY: The chapter concludes that funded service- or group-based exemptions offer a simple, potentially effective route to mitigating inequity and inefficiency in the health systems of low-income countries. However, there are a number of key constraints. One is the fungibility of resources at health facility level. The second is the difficulty of sustaining a separate funding stream over the medium to long term. The third is the arbitrary basis for selecting high-priority services for exemption. The chapter therefore concludes that this financing mode is unstable and is likely to be transitional. PMID- 19791707 TI - From scheme to system: social health insurance funds and the transformation of health financing in Kyrgyzstan and Moldova. AB - OBJECTIVE: The aim of the paper is to bring evidence and lessons from two low- and middle-income countries (LMIs) of the former USSR into the global debate on health financing in poor countries. In particular, we analyze the introduction of social health insurance (SHI) in Kyrgyzstan and Moldova. To some extent, the intent of SHI introduction in these countries was similar to that in LMIs elsewhere: increase prepaid revenues for health and incorporate the entire population into the new system. But the approach taken to universality was different. In particular, the SHI fund in each country was used as the key instrument in a comprehensive reform of the health financing system, with the new revenues from payroll taxation used in an explicitly complementary manner to general budget revenues. From a functional perspective, the reforms in these countries involved not only the introduction of a new source of funds, but also the centralization of pooling, a shift from input- to output-based provider payment methods, specification of a benefit package, and greater autonomy for public sector health care providers. Hence, their reforms were not simply the introduction of an SHI scheme, but rather the use of an SHI fund as an instrument to transform the entire system of health financing. METHODOLOGY/APPROACH: The study uses administrative and household data to demonstrate the impact of the reforms on regional inequality and household financial burden. FINDINGS: The approach used in these two countries led to improved equity in the geographic distribution of government health spending, improved financial protection, and reduced informal payments. IMPLICATIONS FOR POLICY: The comprehensive approach taken to reform in these two countries, and particularly the redirection of general budget revenues to the new SHI funds, explain much of the success that was achieved. This experience offers potentially useful lessons for LMIs elsewhere in the world, and for shifting the global debate away from what we see as a false dichotomy between SHI and general revenue-funded systems. By demonstrating that sources are not systems, these cases illustrate how, in particular by careful design of pooling and coverage arrangements, the introduction of SHI in an LMI context can avoid the fragmentation problem often associated with this reform instrument. PMID- 19791708 TI - Reforming "developing" health systems: Tanzania, Mexico, and the United States. AB - OBJECTIVE: Tanzania, Mexico, and the United States are at vastly different points on the economic development scale. Yet, their health systems can be classified as "developing": they do not live up to their potential, considering the resources available to them. The three, representing many others, share a common structural deficiency: a segregated health care system that cannot achieve its basic goals, the optimal health of its people, and their possible satisfaction with the system. Segregation follows and signifies first and foremost the lack of financial integration in the system that prevents it from serving its goals through the objectives of equity, cost containment and sustainability, efficient production of care and health, and choice. METHOD: The chapter contrasts the nature of the developing health care system with the common goals', objectives, and principles of the Emerging Paradigm (EP) in developed, integrated--yet decentralized--systems. In this context, the developing health care system is defined by its structural deficiencies, and reform proposals are outlined. FINDINGS: In spite of the vast differences amongst the three countries, their health care systems share strikingly similar features. At least 50% of their total funding sources are private. The systems comprise exclusive vertically integrated, yet segregated, "silos" that handle all systemic functions. These reflect and promote wide variations in health insurance coverage and levels of benefits--substantial portions of their populations are without adequate coverage altogether; a considerable lack of income protection from medical spending; an inability to formalize and follow a coherent health policy; a lack of financial discipline that threatens sustainability and overall efficiency; inefficient production of care and health; and an dissatisfied population. These features are often promoted by the state, using tax money, and donors. POLICY IMPLICATIONS: The situation can be rectified by (a) "centralizing"--at any level of development and resource availability--health system finance around a set package of core medical benefits that is made available to the entire population and (b) "decentralizing" consumption and provision of care. The first serves equity and cost containment and sustainability. The second supports efficiency and client satisfaction. ORIGINALITY/VALUE OF CHAPTER: The chapter views commonly discussed problems of the health care system--a lack of insurance coverage and income protection--as symptoms of a large problem: health system segregation. PMID- 19791709 TI - Maculopathy Due to Cobalamin C (cb1C) Disease in an Amish Child. AB - A 5-year-old Amish boy diagnosed at birth as having a defect in intracellular cobalamin metabolism, cobalamin C disease (cb1C), presented to the pediatric ophthalmology service with severe visual impairment. Ophthalmoscopy showed bilateral bull's eye macular lesions. Visual loss occurs from retinal degeneration in cb1C disease. This report highlights the importance of post-natal metabolic testing and ophthalmic evaluation in cb1C disease, especially in high risk inbred populations. PMID- 19791710 TI - Walker-Warburg Syndrome Manifesting as Leopard Spot Retinopathy, Retinal Detachment, and Microphthalmia. AB - Walker-Warburg syndrome, also known as HARD+/-E, is a congenital autosomal recessive disorder characterized by hydrocephalus, agyria, and retinal dysplasia, with or without encephalocele. The authors describe an infant with Walker-Warburg syndrome who presented with microphthalmia, retinal detachment, and leopard spot retinopathy. PMID- 19791711 TI - Demographic changes and response to laser treatment in threshold retinopathy of prematurity: 10-year experience. AB - PURPOSE: To evaluate the outcome of indirect diode laser treatment for threshold retinopathy of prematurity (ROP) and to report demographic changes observed over 10 years. METHODS: Retrospective chart review and statistical analysis of 111 eyes of 61 infants treated for threshold ROP between 1991-2001 at a single academic institution. RESULTS: Ninety-six 111(86%) eyes showed regression of neovascularization after laser treatment. Fourteen (13%) eyes had zone 1 disease and 97 (87%) eyes had zone 2 disease. Thirty-six percent of eyes with zone 1 disease progressed to stage 4 or 5 disease despite treatment, whereas 10% of the zone 2 eyes progressed. Based on multivariate logistic regression, zone and female gender were found to be predictive of progression, whereas birth weight was predictive of zone. Between 1991 and 2001, a significant trend toward lower mean gestational age at time of birth (Pearson correlation = -0.35, P = .0041) was found. However, progression rates to stage 4 and 5 disease following laser treatment were similar for infants born before and after 1997 (P = .0796). CONCLUSION: Regression of neovascularization was noted in 86% of eyes following laser treatment for threshold ROP. Zone was predictive of progression to stage 4 or 5 despite treatment. Premature infants being treated for threshold ROP tended to be born at an earlier gestational age and with lower birth weights over time, but progression rates to more severe stages did not increase following laser treatment, suggesting that optimal treatment can yield favorable ocular outcomes. PMID- 19791712 TI - The novel concurrence of Noonan syndrome and bilateral Duane-like synkinesis. AB - A 9-year-old boy with Noonan syndrome was referred for evaluation of abnormal eye movements. Ocular motility examination revealed bilateral globe retraction with narrowing of the palpebral fissure in adduction and mild restriction of abduction consistent with a bilateral Duane-like synkinesis. This novel association expands the ocular phenotype of Noonan syndrome and may suggest a commonality in the pathogenesis of these two congenital malformation complexes. PMID- 19791713 TI - Ocular findings in pediatric patients with partial agenesis of corpus callosum. AB - PURPOSE: To evaluate the ocular associations with corpus callosum agenesis. METHODS: All children who had corpus callosum agenesis diagnosed by computed tomography or magnetic resonance imaging scans during a 10-year period were included in the study. A complete ophthalmological assessment was undertaken. Data were collected for age, sex, neurological findings, visual acuity, refractive errors, ocular motility defects, and ocular abnormalities. There were no children with Aicardi syndrome in the study. RESULTS: Nineteen children with corpus callosum agenesis were identified, of whom 13 were examined. All had partial agenesis of the corpus callosum. Visual acuity was better than 20/60 in 5 children (38%), between 20/60 and 20/200 in 3 children (23%), and less than 20/200 in 5 children (38%). Refractive errors were present in 8 children (62%), strabismus in 6 children (46%), nystagmus in 2 children (15%), hypoplastic discs in 3 children (23%), and microphthalmos in 1 child (8%). CONCLUSION: Non syndromic corpus callosum agenesis may be associated with several ocular defects. Poor visual acuity, refractive errors, and strabismus predominate and need to be appropriately addressed to optimize visual function in these children. Global developmental delay (62%) and epilepsy (46%) were the most common neurological associations in this series. PMID- 19791714 TI - Recurrence of Congenital Pupillary-Iris-Lens Membrane After Surgical Excision. AB - The authors present a case of congenital pupillary-iris-lens membrane that demonstrated the previously unreported feature of membrane recurrence after surgical excision. PMID- 19791715 TI - Clinicopathological Study of a Case of Unsuspected Retinoblastoma. AB - Retinoblastoma is the most common primary malignant intraocular tumor of childhood. It may present with atypical features, particularly in older children. The authors report a case of unsuspected retinoblastoma following evisceration in a 9-year-old girl who had previous pars plana vitrectomy in the affected eye. PMID- 19791716 TI - Pseudopapilledema in Kenny-Caffey syndrome. AB - A 21-year-old man with Kenny-Caffey syndrome had been observed since 1993 for hyperopia. Fundus examination revealed swollen optic disks. Further examinations (fluorescein angiography, B-scan ultrasonography, and optical coherence tomography) confirmed the optic nerve head elevation. The authors report a rare case of Kenny-Caffey syndrome with extreme pseudopapilledema. Although uncommon, ophthalmologists should be mindful of this disorder when a patient presents with characteristic findings because severe electrolyte disturbances may complicate the clinical course. PMID- 19791717 TI - Clinical findings and surgical results of Duane retraction syndrome. AB - PURPOSE: To evaluate clinical properties and surgical outcomes of Duan retraction syndrome (DRS). METHODS: Twenty-one patients with DRS were evaluated. Surgery was indicated for correction of strabismus, abnormal head position, upshoot downshoot, and globe retraction. Six patients had undergone surgery. In 5 cases, the lateral rectus muscle was recessed from 4.0 to 7.0 mm combined with "Y splitting" according to deviation in primary position and degree of globe retraction. In case of significantly positive forced duction test on the medial rectus muscle intraoperatively, simultaneous recession of the ipsilateral medial rectus muscle was performed in addition to lateral rectus surgery. RESULTS: Type I DRS was diagnosed in 83.33% of cases. All 6 cases that underwent surgery had type I DRS. After surgery, all patients showed elimination of upshoot-downshoot. Two cases had minimally improved abduction from the midline. Case 1 underwent a second operation and it was observed that the middle split part disappeared and muscular fibers proliferated to the original insertion. To protect against refusion of the middle split part of the muscle due to proliferation, nonabsorbable separation sutures were placed around the split parts of the upper and lower halves without scleral fixation. Separation sutures were placed on both parts of the muscle to protect refusion in the other cases. CONCLUSION: Y splitting combined with recession of one or both horizontal recti is an effective procedure in patients with DRS and associated horizontal deviation. Prophylactic separation sutures as part of Y-splitting may protect against recurrence. PMID- 19791718 TI - Refractory Noninfectious Anterior Uveitis Associated With Systemic Mastocytosis. AB - A 10-year-old boy with biopsy-proven systemic mastocytosis presented with bilateral nongranulomatous anterior uveitis associated with high intraocular pressure. Anterior chamber paracentesis was performed for cytological evaluation, which demonstrated monocytes and macrophages but no evidence of mast cells. His uveitis was partially controlled with frequent topical steroid drops and weekly oral methotrexate therapy. The glaucoma was controlled with topical antiglaucoma medications in the right eye. Deep sclerectomy was required in the left eye to control the intraocular pressure. To the best of the authors' knowledge, this is the first report of such an association. PMID- 19791719 TI - Refractive error dilemmas in children. PMID- 19791720 TI - What's your diagnosis? Blepharophimosis-ptosis-epicanthus inversus syndrome (BPES). PMID- 19791721 TI - Evaluation of refraction changes related to age and strabismus. PMID- 19791722 TI - Evaluation of refraction in a statistically significant sample: changes according to age and strabismus. AB - PURPOSE: To assess possible refractive changes according to age and strabismus in a statistically significant cohort. METHODS: A population-based sample of 12,534 subjects 0.5 to 20 years old, examined between 2004 and 2006, was tested. Each subject received a complete orthoptic examination, including spherocylindrical streak retinoscopy in cycloplegia. Patients were divided into those with orthophoria (7,784) and those with strabismus (4,750), and the latter group was further divided into those with esodeviation (3,026) and those with exodeviation (1,724). A statistical analysis of the spherical equivalent, astigmatism, and anisometropia was performed with an independent samples t test or one-way analysis of variance. RESULTS: The percentage of patients with a mean spherical equivalent within +/- 1 and +/- 2 standard deviations was greater than 68% and 95%, respectively. The mean spherical equivalent of the total sample was 1.62 diopters (D) (+/- 2.88). The mean spherical equivalent was 1.10 +/- 2.94 D in the orthophoria group, 3.22 +/- 2.29 D in the esodeviation group, and 1.13 +/- 2.50 D in the exodeviation group (one-way analysis of variance; P = .000). Age-related changes in the mean spherical equivalent showed a clear and steady myopic shift, reaching mean myopic refraction at 12 to 14 years in both the total sample and the orthophoria and exodeviation groups. It assumed a more constant trend, with no myopic swing, in the esodeviation group (P = .000). Mean astigmatism was less in patients with less than 1.00 D anisometropia (0.83 +/- 0.92 D) than in those with 1.00 D or greater anisometropia (1.42 +/- 1.18 D) (t test; P = .0001). CONCLUSION: Both the age-related trend in the spherical equivalent and the high hyperopic values of the distribution peak in patients with esodeviation confirm the importance of the hypermetropic refractive component. The statistically significantly higher incidence of astigmatism in patients with 1.00 D or greater ametropia highlights its incidence in amblyopia. PMID- 19791723 TI - New methods for the assessment of accommodative convergence. AB - PURPOSE: The authors introduced a new objective method for measuring horizontal eye movements based on the first Purkinje image with the use of infrared charge coupled device (CCD) cameras and compared stimulus accommodative convergence to accommodation (AC/A) ratios as determined by a standard gradient method. METHODS: The study included 20 patients, 5 to 9 years old, who had intermittent exotropia (10 eyes) and accommodative esotropia (10 eyes). Measurement of horizontal eye movements in millimeters (mm), based on the first Purkinje image, was obtained with a TriIRIS C9000 instrument (Hamamatsu Photonics K.K., Hamamatsu, Japan). The stimulus AC/A ratio was determined with the far gradient method. The average values of horizontal eye movements (mm) and eye deviation (Delta) (a) before and (b) after an accommodative stimulus of 3.00 diopters (D) were calculated with the following formula: horizontal eye movements (mm/D) and stimulus AC/A ratio (Delta/D) = (b - a)/3. RESULTS: The average values of the horizontal eye movements and the stimulus AC/A ratio were 0.5 mm/D and 3.8 Delta/D, respectively. Correlation analysis showed a strong positive correlation between these two parameters (r = 0.92). Moreover, horizontal eye movements are directly proportional to the AC/A ratio measured with the gradient method. CONCLUSIONS: The methods used in this study allow objective recordings of accommodative convergence to be obtained in many clinical situations. PMID- 19791724 TI - Detailed magnetic resonance imaging findings of the ocular motor nerves in Duane's retraction syndrome. AB - PURPOSE: To study the neuroanatomic characteristics of patients with Duane's retraction syndrome with high-resolution magnetic resonance imaging. METHODS: The study included 11 consecutive cases, including five patients with type I, one patient with type II, four patients with type III, and one patient with inverse Duane's retraction syndrome. The patients underwent magnetic resonance imaging of the brain, brain stem, cavernous sinus, and orbits. RESULTS: In 10 patients, the abducens nerve (cranial nerve VI) was absent or showed hypoplasia in the brain stem, cavernous sinus, and orbit. However, these findings were not seen in the patient who had inverse Duane's retraction syndrome. In two children, magnetic resonance imaging showed that the cavernous sinuses were smaller on the affected side. The inferior division of the oculomotor nerve (cranial nerve III) was traced to enter the lateral rectus muscle or had intimate continuity with the lateral rectus muscle in nine patients with type I and type III Duane's retraction syndrome. In one patient with type III Duane's retraction syndrome, the oculomotor foramen was significantly larger on the affected side than on the sound side. In the patient with type II Duane's retraction syndrome, the superior division of cranial nerve III was enlarged and had three branches. In the patient with inverse Duane's retraction syndrome, the inferior division of cranial nerve III sent two branches to the medial rectus muscle, and the patient had superior oblique muscle hypoplasia. CONCLUSION: Neuroimaging findings showed that the absence of cranial nerve VI, hypoplasia in the brain stem, and an extra branch of the inferior division of cranial nerve III to the lateral rectus muscle is the most common presentation of Duane's retraction syndrome, but not the only one. The aberrant branches likely correspond to the abnormal eye movement seen in patients with this disorder. PMID- 19791726 TI - The effect of race on the incidence of retinoblastoma. AB - PURPOSE: To examine the incidence of retinoblastoma for regional variations by race. METHODS: Age-adjusted incidence rates, rate ratios, and 95% confidence intervals were determined in 109 regions from 1993 to 1997 using compiled data from the International Agency for Research on Cancer. RESULTS: The rate ratio was 1.12 (range: 0.35 to 4.15) between white populations in the United States and Europe/Australia, 0.98 (range: 0.37 to 2.65) between Hispanic populations in Spain and the United States, and 1.44 (range: 0.29 to 1.79) between Hispanic populations in Uruguay and the United States. The rate ratio between Hispanic and white populations within the United States was 0.94 (range: 0.33 to 2.56). No differences were significant. CONCLUSIONS: Because retinoblastoma is a genetic disease, its incidence is similar among varied populations. PMID- 19791727 TI - Clinical pathologic study of a cohort of patients with retinoblastoma from a developing country. AB - PURPOSE: To describe the histopathologic characteristics of all retinoblastoma biopsy specimens received at one institution. METHODS: All retinoblastoma biopsy specimens received between January 2000 and December 2005 were evaluated and a total of 109 eyes from 101 patients were studied. RESULTS: There were 9 (8.3%) well differentiated, 25 (23.0%) moderately differentiated, and 66 (60.5%) poorly differentiated retinoblastomas. The most common growth pattern was mixed, comprising 81 (74.4%) cases. Vitreous seeding, invasion of the anterior chamber, and invasion of the optic nerve beyond the lamina cribrosa, was present in 79 (72.5%), 24 (22.0%), and 44 (40.4%) eyes, respectively. The tumor was confined to the retina in only 26 (23.9%) cases, whereas 16 (14.8%) had minimal choroidal invasion, 45 (41.3%) had massive choroidal involvement, 10 (9.2%) had scleral invasion, and 11 (10.1%) had extraocular extension. CONCLUSION: In this study, the percentage of patients with choroidal and optic nerve invasion, reflecting a poor prognosis, was much higher than in previously reported North American series. However, similar findings have been described in other developing countries, where late diagnosis is common. This study emphasized the need for early diagnosis and treatment. PMID- 19791728 TI - A patient with bilateral persistent pupillary membrane: a conservative approach. AB - The author describes the case of a girl with bilateral persistent pupillary membranes and good visual acuity. An otherwise healthy 10-year-old girl presented with persistent pupillary membranes in both eyes since childhood. The patient had ametropic amblyopia, which was treated with spectacles and part-time occlusion therapy, with the patient responding conventionally. After therapy, her best corrected visual acuity was 20/25 in both eyes. She had stereopsis of 50 seconds of arc, orthophoria, and normal extraocular movements. The remainder of the examination was normal. Patients with bilateral persistent pupillary membranes may not require surgery if there is adequate opening. The author suggests a trial of refractive correction and occlusion therapy before deciding on surgical and laser intervention, even if it seems an absolute requirement. PMID- 19791729 TI - Leigh's disease associated with a dorsal midbrain syndrome. AB - Leigh's disease is a rare progressive neurodegenerative condition caused by a mitochondrial cytopathy. The authors present the case of a 9-year-old girl with dorsal midbrain syndrome causing convergence retraction nystagmus. Magnetic resonance imaging, skin biopsy, and genetic testing confirmed the cause to be Leigh's disease due to two SURF1 mutations. To the authors' knowledge, this is the first reported case of dorsal midbrain syndrome caused by a mitochondrial cytopathy. PMID- 19791730 TI - Treatment of choroidal neovascularization associated with Best's disease in children. AB - The development of secondary choroidal neovascularization in Best's disease is rare in the pediatric population. A retrospective review of pediatric patients with choroidal neovascularization secondary to Best's disease was performed. The patients' courses and treatments were recorded. Three patients with choroidal neovascularization were identified. All had decreased vision and were treated in an individual manner. Vision improved after treatment in all patients. Treatment may hasten resolution of choroidal neovascularization and improve vision. PMID- 19791731 TI - Multiple anterior and posterior chamber pseudocysts in a 12-year-old boy with diffuse infiltrating retinoblastoma. AB - Diffuse infiltrating retinoblastoma is a rare subtype, occurring in 1% of all patients with retinoblastoma. It usually presents with pseudoinflammatory response in the anterior chamber and the vitreous, masquerading as endophthalmitis or uveitis. This report describes a 12-year-old boy with multiple free-floating intraocular pseudocysts as a unique finding in diffuse infiltrating retinoblastoma. These pseudocysts represent necrotic seeds without epithelial lining. Invasive surgical procedures should be avoided in children presenting with atypical, chronic, unilateral intraocular inflammation of unknown cause until retinoblastoma is excluded. PMID- 19791732 TI - Gillespie syndrome with impaired accommodation. PMID- 19791733 TI - Infantile facial palsy with exposure keratitis. PMID- 19791735 TI - Simple reaction conditions for the formation of ketonitrones from ketones and hydroxylamines. AB - The condensation of ketones and hydroxylamines to form ketonitrones was reinvestigated by using thermal conditions previously found to minimize hydroxylamine decomposition (t-BuOH, 110 degrees C). This simple approach allows the formation of exocyclic, acyclic, and alpha,beta-unsaturated ketonitrones with benzylic, linear, and branched nitrogen substituents in modest to excellent isolated yields. PMID- 19791736 TI - Self-aggregation of synthetic bacteriochlorophyll-d analogues possessing a B-ring reduced chlorin pi-system. AB - Zinc 3(1)-hydroxy-13(1)-oxo-chlorophyll derivatives 3 and 4 having a B-ring reduced chlorin pi-system (C7-C8, C17=C18) were prepared as models of self aggregative bacteriochlorophyll-d, which are regioisomers of 1 and 2 possessing a natural-type D-ring reduced chlorin pi-system (C7=C8, C17-C18). 3(1)-Epimerically pure forms of secondary alcohol 3 (3-CH(OH)CH(3)) as well as primary alcohol 4 (3 CH(2)OH) were effectively synthesized by modifying naturally available bacteriochlorophyll-a. Self-aggregation of 3 and 4 in an aqueous micellar solution was examined by UV-vis and CD spectroscopies and compared with that of their regioisomeric 1 and 2. PMID- 19791734 TI - Correlation of high and decreased NY-ESO-1 immunity to spontaneous regression and subsequent recurrence in a lung cancer patient. AB - We show correlation between strong and decreased NY-ESO-1-specific immunity with spontaneous regression and subsequent recurrence, respectively, in a long surviving patient with an NY-ESO-1-expressing lung adenocarcinoma. An integrated immune response consisting of IgG antibody, as well as CD4 and CD8 T cells, against NY-ESO-1 was observed at the time of spontaneous regression of multiple pleural metastases. After tumor dormancy for 3 years, the tumor started to progress. IgG antibody levels and the number of CD4 and CD8 T cells against NY ESO-1 decreased, but were still detectable. On the other hand, the number of Foxp3+ CD25 high T regulatory cells gradually increased. The findings suggest the relevance of the NY-ESO-1 immune response and its regulation by Foxp3+ CD25 high T regulatory cells in the clinical course of this lung cancer patient. PMID- 19791737 TI - NMR investigation of the dynamics of confined water in nafion-based electrolyte membranes at subfreezing temperatures. AB - The dynamical characteristics and the thermal analysis of water absorbed in filler-free Nafion and in silica or zirconia phosphate Nafion composites, between 20 and -50 degrees C, were investigated by NMR and DSC techniques. Self-diffusion coefficients and longitudinal NMR relaxation times (T(1)) put in evidence a fraction of water freezing at subzero temperatures. The complementary water fraction remains in the liquid state at least down to -50 degrees C. The freezing point (T(f)) depends on the initial water uptake of the electrolyte membrane and, for similar uptake values, water mobility is favorite in composites systems respect to the filler-free Nafion. By DSC thermograms the hydration water molecules number per sulfonic group in the filler-free Nafion was estimated, obtaining 8 molecules/SO(3)(-) group. In the Nafion/Zr(HPO(4))(2) composite, instead, the number of hydration water is about 20 molecules/ionic group, because of the acid nature of the zirconia particles. Below T(f), the presence of this nonfreezable water fraction allows proton transport, and therefore ensures ionic conductivity also at subzero temperatures. PMID- 19791738 TI - Design and synthesis of lamellarin D analogues targeting topoisomerase I. AB - A general synthetic route to rationally designed lamellarin D analogues, 1 dearyllamellarin D (1) and 1-substituted 1-dearyllamellarin D (2), has been developed. The key pentacyclic intermediate 22 was prepared by palladium catalyzed direct arylation of 12, which in turn was synthesized via C-2-selective lithiation of 15 followed by palladium-catalyzed cross-coupling as the key reactions. Compound 22 was converted to a wide range of C-1-substituted analogues 2 via regioselective electrophilic substitution and palladium-catalyzed cross coupling reactions. PMID- 19791739 TI - A low temperature study of the reactions of atomic chlorine with simple alkanes. AB - The kinetics of the reactions of atomic chlorine with ethane and propane have been studied in a continuous supersonic flow reactor over the range 48 K < or = T < or = 167 K. Chlorine atoms were produced by microwave discharge upstream of the Laval nozzle and were probed in the vacuum ultraviolet wavelength range around 138 nm by resonance fluorescence. The reaction of Cl with ethane has been found to exhibit a positive temperature dependence, with a rate coefficient decreasing from (4.3 +/- 0.6) x 10(-11) cm(3) molecule(-1) s(-1) at 167 K to (2.9 +/- 0.3) x 10(-11) cm(3) molecule(-1) s(-1) at 48 K and deviates from true Arrhenius behavior below 120 K. In contrast, the rate coefficient for the reaction of Cl with propane has been found to have a constant value of (1.4 +/- 0.2) x 10(-10) cm(3) molecule(-1) s(-1) over the same temperature range. The expressed uncertainties are the combined statistical (a single standard deviation from the mean) and systematic (estimated at 10%) uncertainties. PMID- 19791740 TI - Ultrasensitive detection of interfacial water diffusion on lipid vesicle surfaces at molecular length scales. AB - Measurements of the interfacial diffusion coefficient of the surface hydration layer of lipid vesicles in dilute solutions are presented. This was made possible by the greatly enhanced sensitivity and unique contrast provided by the site specific and selective Overhauser dynamic nuclear polarization of solvent molecules that approach nitroxide radical-based spin labels within <5-10 A. All experiments were carried out using minute microliter sample volumes of lipid vesicle solutions, using low spin label concentrations (<2 mol %) and under physiological conditions. This presents unprecedented sensitivity for analyzing interfacial solvent diffusion of macromolecules and their assemblies in solutions and highlights the feasibility of investigating precious samples. Interfacial diffusion on DOTAP (1,2-DiOleoyl-3-TrimethylAmmonium-Propane) and DPPC (1,2 DiPalmitoyl-sn-glycero-3-PhosphoCholine) surfaces are further analyzed as a function of temperature to determine the activation energy of their hydration layer dynamics. The temperature-dependent analysis across the phase transition of DPPC concludes that the hydration water with 100-200 ps dynamics displays Arrhenius behavior and does not undergo a phase transition unlike the lipid chains. We also discuss the advantages of determining the activation energy of diffusion as a general approach to comparing interfacial diffusivity on surfaces that have vastly different charge topologies and, thus, may display different distances of closest approach between the spin label placed at the surface and the protons of hydration water. The further development and application of this technique is expected to facilitate the study of membrane dynamics and their phase behavior, including the formation of lipid rafts, with lipid-specific resolution. PMID- 19791741 TI - Effects of terminal functional groups on the stability of the polyproline II structure: a combined experimental and theoretical study. AB - The conformational stability of the polyproline II (PPII) helix with respect to the functional groups at the C- and N-termini was examined both experimentally and theoretically. Oligoprolines AcN-[Pro](12)-CONH(2) (1), HN-[Pro](12)-CONH(2) (2), AcN-[Pro](12)-CO(2)H (3), and HN-[Pro](12)-CO(2)H (4) with charged and capped termini served as model compounds, and the relative ease with which they switch from the PPII to the polyproline I (PPI) helix was used as a measure to analyze their conformational stabilities. CD spectroscopic studies demonstrate that a positively charged N-terminus and a negatively charged C-terminus destabilize the PPII helix and favor the PPI helix, whereas capped termini favor the PPII over the PPI helix. These experimental findings are supported by the energy differences between the PPII and PPI helices of oligoprolines 1-4 computed by ab initio methods including electron-correlation effects (second-order Moller Plesset perturbation theory, MP2). Furthermore, these quantum-chemical calculations show that differences in charge-dipole interactions are responsible for the experimentally and computationally observed relative stabilities. Although these electrostatic interactions between the terminal charges and the amide dipoles stabilize both helices, they are significantly stronger in the PPI helix where the amide bonds are oriented almost linear to the helix axis as compared to the PPII helix in which the amides are nearly perpendicular to the axis. Moreover, we demonstrate that a negative charge at the C-terminus has a more pronounced effect on the relative stability as compared to a positive charge at the N-terminus due to destabilization of the PPII helix by repulsive interaction between the C-terminal carboxylate with the neighboring amide bond. Studies at different pH values verified the electrostatic nature of the observed effects and demonstrate how changes in the protonation state can be used to deliberately stabilize the PPII helix over the PPI helix or vice versa. PMID- 19791742 TI - Impact of nitrogen and sulfur fertilization on the composition of glucosinolates in relation to sulfur assimilation in different plant organs of broccoli. AB - Broccoli (Brassica oleracea var. italica) is one of the most important winter season vegetables and a rich source of chemoprotective molecules, including glucosinolates (GSL). The aim of this study was to investigate the impact of nitrogen (N) and sulfur (S) fertilization on GSL concentration and composition in different parts of broccoli plants. A greenhouse experiment was performed, with four different treatments of sulfur (10, 30, 70, and 150 kg/ha) and three treatments of nitrogen (50, 250, and 600 kg/ha). GSL concentrations and plant growth responded to the N supply, but this was not observed above the 250 kg N/ha dose. On the contrary, plant growth did not respond to the S supply, whereas GSL concentrations showed a sharp response to the whole range of S applications (from 10 to 150 kg/ha). Glucosinolate composition was altered differentially in the examined plant parts. Aliphatic GSL were more abundant in the florets and leaves, whereas indolyl GSLs were dominant in roots, in which aromatic GSL were also observed. High nitrogen fertilization had a higher impact on indolyl compared to aliphatic GSLs concentration. More importantly, a high concentration of aliphatic GSL, >2.4 micromol/g dry weight (dw), and high S assimilation into aliphatic GSL were consistently observed in the florets compared to other broccoli parts, indicating adaptable processes for nitrogen and sulfur regarding synthesis and transport of aliphatic GSL for these organs. PMID- 19791743 TI - Synthesis and structure-activity relationships of cyanoguanidine-type and structurally related histamine H4 receptor agonists. AB - Recently, we identified high-affinity human histamine H3 (hH3R) and H4 receptor (hH4R) ligands among a series of NG-acylated imidazolylpropylguanidines, which were originally designed as histamine H2 receptor (H2R) agonists. Aiming at selectivity for hH4R, the acylguanidine group was replaced with related moieties. Within a series of cyanoguanidines, 2-cyano-1-[4-(1H-imidazol-4-yl)butyl]-3-[(2 phenylthio)ethyl]guanidine (UR-PI376, 67) was identified as the most potent hH4R agonist (pEC50 = 7.47, alpha = 0.93) showing negligible hH1R and hH2R activities and significant selectivity over the hH3R (pKB = 6.00, alpha = -0.28), as determined in steady-state GTPase assays using membrane preparations of hH(x)R expressing Sf9 cells. In contrast to previously described selective H4R agonists, this compound and other 3-substituted derivatives are devoid of agonistic activity at the other HR subtypes. Modeling of the binding mode of 67 suggests that the cyanoguanidine moiety forms charge-assisted hydrogen bonds not only with the conserved Asp-94 but also with the hH4R-specific Arg-341 residue. 2-Carbamoyl 1-[2-(1H-imidazol-4-yl)ethyl]-3-(3-phenylpropyl)guanidine (UR-PI97, 88) was unexpectedly identified as a highly potent and selective hH3R inverse agonist (pKB = 8.42, >300-fold selectivity over the other HR subtypes). PMID- 19791744 TI - Synthesis and biological evaluation of 2-heteroarylthioalkanoic acid analogues of clofibric acid as peroxisome proliferator-activated receptor alpha agonists. AB - A series of 2-heteroarylthioalkanoic acids were synthesized through systematic structural modifications of clofibric acid and evaluated for human peroxisome proliferator-activated receptor alpha (PPARalpha) transactivation activity, with the aim of obtaining new hypolipidemic compounds. Some thiophene and benzothiazole derivatives showing a good activation of the receptor alpha were screened for activity against the PPARgamma isoform. The gene induction of selected compounds was also investigated in the human hepatoma cell line. PMID- 19791746 TI - Kinase inhibitor data modeling and de novo inhibitor design with fragment approaches. AB - A reconstructive approach based on computational fragmentation of existing inhibitors and validated kinase potency models to recombine and create "de novo" kinase inhibitor small molecule libraries is described. The screening results from model selected molecules from the corporate database and seven computationally derived small molecule libraries were used to evaluate this approach. Specifically, 1895 model selected database molecules were screened at 20 microM in six kinase assays and yielded an overall hit rate of 84%. These models were then used in the de novo design of seven chemical libraries consisting of 20-50 compounds each. Then 179 compounds from synthesized libraries were tested against these six kinases with an overall hit rate of 92%. Comparing predicted and observed selectivity profiles serves to highlight the strengths and limitations of the methodology, while analysis of functional group contributions from the libraries suggest general principles governing binding of ATP competitive compounds. PMID- 19791745 TI - Amide linkage isomerism as an activity switch for organometallic osmium and ruthenium anticancer complexes. AB - We show that the binding mode adopted by picolinamide derivatives in organometallic Os(II) and Ru(II) half-sandwich complexes can lead to contrasting cancer cell cytotoxicity. N-Phenyl picolinamide derivatives (XY) in Os(II) (1, 3 5, 7, 9) and Ru(II) (2, 6, 8, 10) complexes [(eta(6)-arene)(Os/Ru)(XY)Cl](n+), where arene = p-cymene (1-8, 10) or biphenyl (9), can act as N,N- or N,O-donors. Electron-withdrawing substituents on the phenyl ring resulted in N,N-coordination and electron-donating substituents in N,O-coordination. Dynamic interconversion between N,O and N,N configurations can occur in solution and is time- and temperature- (irreversible) as well as pH-dependent (reversible). The neutral N,N coordinated compounds (1-5 and 9) hydrolyzed rapidly (t(1/2) > 4 > 1 > 9). In contrast, N,O-coordinated complexes 7 and 8 hydrolyzed slowly, did not bind to guanine or adenine, and were nontoxic. PMID- 19791747 TI - Scanning probe microscopy method for nanosuspension stabilizer selection. AB - An atomic force microscopy (AFM) method was successfully developed and utilized for investigating the interaction of polymeric stabilizers with ibuprofen to determine their suitability for the preparation and stabilization of ibuprofen nanosuspensions. Images obtained clearly showed that HPMC and HPC interacted strongly with the ibuprofen resulting in extensive surface adsorption, confirming their suitability for ibuprofen nanosuspension preparation. In addition, differences in the morphology of the adsorbed HPMC and HPC molecules were observed, which may be attributed to their variable degree of substitution. Consistent with their poor performance in stabilizing the ibuprofen nanosuspensions, images obtained with PVP and Poloxamer's depicted inadequate adsorption on the ibuprofen surface. Careful analysis of the AFM images and the ibuprofen crystal structure gave valuable insight into the success of top-down processing for the preparation of nanosuspensions as compared to bottom-up processing. On the basis of the relationship observed between nanosuspension stability and adsorption characteristics of specific polymers, such AFM studies can aid in the selection of suitable nanosuspension stabilizers. This method provides the basis for a scientific rationale for nanosuspension stabilizer selection rather than the trial and error method which is currently practiced. PMID- 19791748 TI - Specific DNA-protein interactions on mica investigated by atomic force microscopy. AB - DNA processing by site-specific proteins on surface remains a challenging issue for nanobioscience applications and, in particular, for high-resolution imaging by atomic force microscopy (AFM). To obtain high-resolution conditions, mica, an atomically flat and negatively charged surface, is generally used. However, even though many specific DNA/protein interactions have already been observed by AFM, little is known about DNA accessibility to specific enzymes on mica. Here we measured the accessibility of adsorbed DNA to restriction endonucleases (EcoRI and EcoRV) using AFM. By increasing the concentration of divalent or multivalent salts, DNA adsorption on mica switches from weak to strong binding. Interestingly, while the accessibility of strongly bound DNA was inhibited, loosely adsorbed DNA was efficiently cleaved on mica. This result opens new perspective to study DNA/protein interaction by AFM or to modify specifically DNA on surface. PMID- 19791749 TI - Variations of protein levels in human amniotic fluid stem cells CD117/2 over passages 5-25. AB - Stability of cell lines is the prerequisite for all in vitro research, but literature on the stability of protein expression over passages is limited. Determination of specific stability markers, karyotyping, and morphology may not provide full information on this subject. It was the aim of the study to test protein level fluctuations in a human amniotic fluid stem cell line from passages 5, 7, 11, and 25. While karyotype, cell cycle, apoptosis rate, and 10 markers for characterization of the cell line remained unchanged (carried out at passages 5 and 25), cell volume was increased at passage 25. Significant protein fluctuations were observed for signaling, antioxidant, guidance cue, proteasomal, connective tissue, cytoskeleton proteins, chaperones, a chloride channel, and prothymosin at passages 5, 7, 11, and 25. Herein, the use of this gel-based proteomic screen, checking protein stability for the characterization of cell lines in addition to corresponding published markers, is proposed, in particular when experiments are run over several passages. PMID- 19791750 TI - Reductive activation of mitomycin C by thiols: kinetics, mechanism, and biological implications. AB - The clinically used antitumor antibiotic mitomycin C requires a reductive activation to be converted to a bis-electrophile that forms several covalent adducts with DNA, including an interstrand cross-link which is considered to be the lesion responsible for the cytotoxic effects of the drug. Enzymes such as cytochrome P450 reductase and DT-diaphorase have traditionally been implicated in the bioreduction of mitomycin C, but recent reports indicate that enzymes containing a dithiol active site are also involved in the metabolism of mitomycin C. The reductive activation can also be effected in vitro with chemical reductants, but until now, mitomycin C was considered to be inert to thiols. We report here that mitomycin C can, in fact, be reductively activated by thiols. We show that the reaction is autocatalytic and that the end product is a relatively stable aziridinomitosene that can be trapped by adding several nucleophiles after the activation reaction. Kinetic studies show that the reaction is highly sensitive to pH and does not proceed or proceeds very slowly at neutral pH, an observation that explains the unsuccessful results on previous attempts to activate mitomycin C with thiols. The optimum pH for the reactions is around the pK(a) values of the thiols used in the activation. A mechanism for the reaction is hypothesized, involving the initial formation of a thiolate-mitomycin adduct, that then evolves to give the hydroquinone of mitomycin C and disulfide. The results presented here provide a chemical mechanism to explain how some biological dithiols containing an unusually acidic thiol group (deprotonated at physiological pH) participate in the modulation of mitomycin C cytotoxicity. PMID- 19791751 TI - Surface properties of water-soluble glycine-cysteamine-protected gold clusters. AB - We report the synthesis of water-soluble, nearly monodisperse glycine-cysteamine (Gly-CSA) gold monolayer protected clusters (MPCs) via base deprotection of Fmoc Gly-CSA MPCs. The resulting Gly-CSA MPCs, which have terminal primary amine groups, are fully characterized by (1)H and (13)C NMR, UV-vis spectroscopy, and TEM, and their surface properties were probed by dynamic light scattering and acid-base titrations. The characterization methods indicate that the as synthesized particles are nearly monodisperse with an average particle size of 1.8 +/- 0.3 nm, but are only stable to aggregation in water at pHs of 4 and below. Acid-base titrations of the Gly-CSA MPCs show that the primary ammonium groups have a pK(a) of approximately 5.5, which is several orders of magnitude lower than the pK(a2) for the ammonium group of glycine (9.6). Thus, the particles are only partially protonated at intermediate pH's, which then drives the aggregation of the nanoparticles via hydrogen-bond formation. Dynamic light scattering results confirm the pH-driven aggregation of the nanoparticles, and studies with ninhydrin confirm that the primary amine groups are reactive and have potential for further functionalization. These results show that amine terminated MPCs can be synthesized; however, their aggregation at intermediate pH's can limit their utility as building blocks for multifunctional nanoparticle syntheses. PMID- 19791752 TI - Estimating regio and stereoselectivity in [4+2] cycloadditions of vinyl substituted cyclic dienes with maleic anhydride. AB - Density functional theory calculations are performed to examine the regio and stereoselective preferences in [4+2] cycloaddition reactions of vinyl cyclopentadiene (1 and 2) and vinyl heterocyclic (1-N, 1-O, 1-S, 2-N, 2-O and 2 S) systems with maleic anhydride. Stepwise and concerted pathways of model systems 1 and 2 as dienes with ethylene as dienophile reveal that the reactions proceed through asynchronous and concerted pathway. 3-Vinyl systems (2) are predicted to be more reactive compared to 2-vinyl systems (1). The regio and stereoselective preferences are evaluated based on activation energies, reaction energies, density functional based descriptors and atoms in molecules analysis. In all cases, extra-annular cycloadducts are more feasible compared to intra annular cycloadducts. Stereoselectivity depends on the favorable secondary orbital interactions. Solvents such as water, tetrahydrofuran, acetone, and dimethyl sulphoxide are employed to understand the effects of solvents on the cycloadduct formation. The computational results thus obtained are compared with the earlier experimental observations that are available. PMID- 19791753 TI - Redox characterization of the FeS protein MitoNEET and impact of thiazolidinedione drug binding. AB - MitoNEET is a small mitochondrial protein that has been identified recently as a target for the thiazolidinedione (TZD) class of diabetes drugs. MitoNEET also binds a unique three-Cys- and one-His-ligated [corrected] [2Fe-2S] cluster. Here we use protein film voltammetry (PFV) as a means to probe the redox properties of mitoNEET and demonstrate the direct impact of TZD drug binding upon the redox chemistry of the FeS cluster. When TZDs bind, the midpoint potential at pH 7 is lowered by more than 100 mV, shifting from approximately 0 to -100 mV. In contrast, a His87Cys mutant negates the ability of TZDs to affect the midpoint potential, suggesting a model of drug binding in which His87 is critical to communication with the FeS center of mitoNEET. PMID- 19791754 TI - Colloid retention in porous media of various porosities: predictions by the hemispheres-in-cell model. AB - The hemispheres-in-cell model for colloid transport and deposition in simple granular filtration media preserves the utilities provided in the Happel sphere in-cell but also incorporates features (e.g., grain-to-grain contact) that are shown to drive colloid deposition from experiments and simulations when colloid surface repulsion exists (Ma, H.; Pedel, J.; Fife, P.; Johnson, W. P. Environ. Sci. Technol., 2009, in press). The capability of the hemispheres-in-cell model to predict colloid deposition in the absence of repulsive energy barriers for different particle sizes and fluid flow velocities was previously examined (Ma, H.; Pedel, J.; Fife, P.; Johnson, W. P. Environ. Sci. Technol., 2009, in press). In this article, we examine the influence of porosity on colloid deposition in terms of theoretical (simulated) collector efficiencies from the hemispheres-in cell model, as well as existing models, to examine whether expected trends in porosity are similar among the different models. The need for experimentally determined collector efficiencies for porosities outside the range of 0.33-0.42 is highlighted. We demonstrate agreement between existing experimental results and our model predictions, indicating that the hemispheres-in-cell model can potentially serve as a new model geometry to develop a predictive theory of colloid filtration in the presence of energy barriers, a condition that is typical in environmental contexts. PMID- 19791756 TI - Spectral properties of spirooxazine photochromes: TD-DFT insights. AB - A large series of photochromes of the spirooxazine family has been investigated using density functional theory and time-dependent density functional theory, aiming at designing molecules with an open-ring merocyanine form absorbing at the longest possible wavelength. A complete methodological assessment (basis set, solvent effects, functionals) has been performed, allowing the design of efficient multilinear regressions for two solvents (cyclohexane and toluene). These regressions allow the estimate of the absorption wavelength of open spirooxazine with an error limited to about 5 nm. The thermodynamic and spectral properties of several isomers have been considered, and it turned out that only TTC and CTC structures may appear experimentally. These structures present similar stabilities and absorption wavelengths. The impact of the auxochromic groups on the UV/vis spectra was assessed and novel promising substitution patterns have been unravelled. It is shown that using a strong push moiety on the same side of the molecule as the pull group may be an effective procedure for tuning the visible spectra. In particular, several spirooxazines with absorption wavelength predicted to be close to or larger than 700 nm are proposed. PMID- 19791758 TI - Formation of fullerooxazoles from C61HPh(3-): the regioselectivity of heteroatom additions. AB - The formation of fullerooxazoles from C(61)HPh(3-) has been examined in benzonitrile (PhCN), m-methoxybenzonitrile (m-OCH(3)PhCN), m-tolunitrile (m CH(3)PhCN), and o-tolunitrile (o-CH(3)PhCN), where cis-1 bisadducts with Ph-, m OCH(3)Ph-, m-CH(3)Ph-, and o-CH(3)Ph-substituted cyclic imidate next to the phenylmethano are formed as evidenced by various characterizations. Interestingly, only regioisomers 2a-d with the oxygen atom bonded to C4/C5 and the nitrogen atom bonded to C3/C6 are generated as demonstrated by heteronuclear multiple bond coherence (HMBC) NMR, while the alternative regioisomers 3a-d, which have the oxygen and nitrogen atoms at C3/C6 and C4/C5, respectively, are not formed from the reactions, even though the DFT (density functional theory) calculations have predicted that the energy differences between the two types of regioisomers are very small, with regioisomers 3a-d actually having lower energies than 2a-d. The results are rationalized by the charge distributions of C(61)HPh(3-), where computational calculations have shown that the negative charges on C4 and C5 are greater than those on C3 and C6, indicating that the exhibited site selectivity of heteroatoms is a result of the charge-directed addition process. PMID- 19791757 TI - Modulating the gelation properties of self-assembling peptide amphiphiles. AB - Peptide amphiphiles (PAs) are self-assembling molecules that form interwoven nanofiber gel networks. They have gained a lot of attention because of their excellent biocompatibility, adaptable peptide structure that allows for specific biochemical functionality, and nanofibrous assembly that mimics natural tissue formation. However, variations in molecule length, charge, and intermolecular bonding between different bioactive PAs cause contrasting mechanical properties. This potentially limits cell-delivery therapies because scaffold durability is needed to withstand the rigors of clinician handling and transport to wound implant sites. Additionally, the mechanical properties have critical influence on cellular behavior, as the elasticity and stiffness of biomaterials have been shown to affect cell spreading, migration, contraction, and differentiation. Several different PAs have been synthesized, each endowed with specific cellular adhesive ligands for directed biological response. We have investigated mechanical means for modulating and stabilizing the gelation properties of PA hydrogels in a controlled manner. A more stable, biologically inert PA (PA-S) was synthesized and combined with each of the bioactive PAs. Molar ratio (M(r) = PA/PA-S) combinations of 3:1, 1:1, and 1:3 were tested. All PA composites were characterized by observed nanostructure and rheological analysis measuring viscoelasticity. It was found that the PAs could be combined to successfully control and stabilize the gelation properties, allowing for a mechanically tunable scaffold with increased durability. Thus, the biological functionality and natural degradability of PAs can be provided in a more physiologically relevant microenvironment using our composite approach to modulate the mechanical properties, thereby improving the vast potential for cell encapsulation and other tissue engineering applications. PMID- 19791759 TI - Mechanistic investigation on the formation of indolizines from 2-enynylpyridines. AB - 2,3,7-Trisubstituted indolizines were obtained from E- or Z-2-enynyl-4 substituted pyridines. The mechanistic pathway involves a base-catalyzed double bond isomerization, if the E-isomer is the starting material, followed by a concerted pseudocoarctate cyclization. PMID- 19791760 TI - Magneto-structural correlation in a metamagnetic cobalt(II)-based pillared trilayer motif constructed by mixed pyridyl-type carboxylate ligands. AB - The first structurally authenticated example of coordinated polymer featuring homometallic pillared-trilayer structure, [Co(3)(ina)(2)(pico)(2)(H(2)O)(2)](n) (1), was built from mixed pyridyl-type monocarboxylates, isonicotinate (ina) and 3-hydroxypicolinate (pico), containing Kagome-type [Co(3)(pico)(2)(H(2)O)(2)](n)(2n+) trilayers. The magnetic phase diagram of 1 shows a metamagnetic transition below 3.2 K, arising from the competing interactions between the antiferromagnetic intralayer couplings in different amplitudes with obviously noncompensated moments versus weak AF interlayer coupling. PMID- 19791761 TI - Synthesis of pyridine, pyrimidine and pyridinone C-nucleoside phosphoramidites for probing cytosine function in RNA. AB - In the structures of the HDV ribozyme a cytosine nucleobase resides at the active site poised to participate directly in catalysis. Defining the functional role of the nucleobase requires nucleoside analogues that perturb the functional groups in a strategic manner. Herein, we have developed efficient methods for the synthesis of five C-nucleoside phosphoramidite derivatives that, when used in combination, provide strategies for probing the potential functional role of cytosine's keto group and imino nitrogen. Phosphoramidites 15a and 15b were synthesized in 11 steps starting from 2-amino-5-bromopyrimidine (1a) and 2-amino 5-bromopyridine (1b), respectively, with overall yields of 10.8% and 6.6%, respectively. Phosphoramidite 21 was prepared from intermediate 11b in seven steps with an overall yield of 33.7%. Phosphoramidites 23 and 25 were prepared from 2,4-diamino-5-(beta-d-ribofuranosyl)-1,3-pyrimidine (22) and pseudoisocytidine (24), respectively, with an overall yield of 15.9% (six steps) and 37.9% (four steps), respectively. These phosphoramidites were incorporated into oligonucleotides by solid-phase synthesis. PMID- 19791762 TI - An efficient route to acyclic C-nucleosides and fused-ring analogues of uridine from exo-glycals. AB - Beta-amino esters prepared from activated exo-glycals are transformed into acyclic C-nucleoside with a C-4-substituted uracil derivative that can be cyclized under Mitsunobu conditions to provide a new family of fused-ring analogues of uridine nucleoside in which the N-1 nitrogen atom is embedded in an imino sugar ring. An analogue of uridine of D-ribo configuration is prepared. PMID- 19791763 TI - Long-chain alkylthiol assemblies containing buried in-plane stabilizing architectures. AB - A series of alkylthiol compounds were synthesized to study the formation and structure of complex self-assembled monolayers (SAMs) consisting of interchanging structural modules stabilized by intermolecular hydrogen bonds. The chemical structure of the synthesized compounds, HS(CH(2))(15)CONH(CH(2)CH(2)O)(6)CH(2)CONH-X, where X refers to the extended chains of either -(CH(2))(n)CH(3) or -(CD(2))(n)CD(3), with n = 0, 1, 7, 8, 15, was confirmed by NMR and elemental analysis. The formation of highly ordered, methyl-terminated SAMs on gold from diluted ethanolic solutions of these compounds was revealed using contact angle goniometry, null ellipsometry, cyclic voltammetry, and infrared reflection absorption spectroscopy. The experimental work was complemented with extensive DFT modeling of infrared spectra and molecular orientation. New assignments were introduced for both nondeuterated and deuterated compounds. The latter set of compounds also served as a convenient tool to resolve the packing, conformation, and orientation of the buried and extended modules within the SAM. Thus, it was shown that the lower alkyl portion together with the hexa(ethylene glycol) portion is stabilized by the two layers of lateral hydrogen bonding networks between the amide groups, and they provide a structurally robust support for the extended alkyls. The presented system can be considered to be an extension of the well-known alkyl SAM platform, enabling precise engineering of nanoscopic architectures on the length scale from a few to approximately 60 A for applications such as cell membrane mimetics, molecular nanolithography, and so forth. PMID- 19791764 TI - Immobilization of a photoswitchable piperidine base. AB - The synthesis of a photoswitchable piperidine base, carrying a monochlorosilane anchoring group, and its immobilization on silica gel, mimicking an oxide surface, is reported. Efficient photoswitching between the E and Z isomers of the azobenzene photochrome was demonstrated for the immobilization precursor in solution and the immobilized piperidine base in suspension of the functionalized silica gel. PMID- 19791765 TI - Enhanced collision-induced decomposition efficiency and unraveling of fragmentation pathways for anionic adducts of brevetoxins in negative ion electrospray mass spectrometry. AB - Brevetoxins are a group of natural neurotoxins characterized by polyether ring systems that are found in the blooms of red tide algae. In a conventional water/organic solvent system, without any other additives, deprotonated molecules of brevetoxins do not appear in high abundance in negative mode electrospray mass spectrometry (ES-MS) due to lack of acidic functional groups; thus, they are not well-suited for collision-induced decomposition (CID) experiments in negative mode electrospray. In this study, several anions were tested for their abilities to form anionic adducts by mixing ammonium salts of these anions with brevetoxin 2 and brevetoxin-3. Under CID, [M + Cl](-), [M + Br](-), [M + OAc](-), [M + HCOO](-), and [M + NO(3)](-) adducts all produced only the respective anions in CID experiments and thus provided no structural information. In contrast, upon CID, both [M + F](-) and [M + HCO(3)](-) precursor adducts gave structurally informative fragment peaks that exhibited similarities to those of [M - H](-) ions, which indicated that the first step in gas-phase decomposition of these anionic adducts was loss of neutral HF or H(2)CO(3) molecules, respectively, leaving deprotonated brevetoxin ([M - H](-)) to undergo consecutive fragmentations. In comparison to bicarbonate, fluoride formed adducts in higher abundance and provided more fragment peaks, thus more structural information, in MS/MS experiments. It is therefore the anion of choice to study brevetoxins in negative mode electrospray mass spectrometry using the anion attachment approach. The detailed fragmentation mechanisms are discussed, and diagnostic product ions are proposed for the brevetoxin-2 side chain (m/z 95, 133, and 151), the brevetoxin-3 side chain (m/z 97, 135, and 153), and the type-B brevetoxin backbone (m/z 725, 739, 741, and 797). To test the developed methodology, a sample of brevetoxin-2 subjected to in vitro microsomal incubation was analyzed, and a reduction product of the substrate was confirmed to have the structure of brevetoxin-3. PMID- 19791766 TI - Highly regioselective gold-catalyzed ring-opening allylation and azidation of dihydrofurans. AB - The ring-opening allylation and azidation of 2,5-dihydrofurans has been accomplished with allyltrimethylsilane or Me(3)SiN(3) in the presence of catalytic amounts of HAuCl(4) x 3 H(2)O. Whereas the allylation proceeds regioselectively in the 2-position to afford 2,6-dien-1-ols, the azidation takes place in the 4-position exclusively. PMID- 19791767 TI - Accurate quantitative isotopic 13C NMR spectroscopy for the determination of the intramolecular distribution of 13C in glucose at natural abundance. AB - In order to understand (13)C isotope distributions in glucose and its metabolites, it is necessary to measure the internal (13)C distribution at natural abundance. These data, however, are not directly accessible, even by quantitative isotopic (13)C NMR spectrometry, due to anomerization at the C-1 position. A strategy has been developed that overcomes this difficulty by converting glucose via a three-step synthesis into 3,5,6-triacetyl-1,2-O isopropylidene-alpha-D-glucofuranose (TAMAGF). This compound provides a satisfactory molecular probe to measure the site-specific (13)C/(12)C ratios in glucose by (13)C NMR. It is shown that the isotopic (13)C NMR signal gives sufficient precision (repeatability standard deviation < or = 0.8 per thousand) for routine use for the determination of the (13)C abundance of each carbon atom position in glucose. Thus, it can be seen that the internal (13)C distribution of glucose biosynthesized by the C3 and C4 metabolic pathways differs markedly. Furthermore, the method is suitable for determining the isotope ratio in the glucose moiety of sucrose and, possibly, in free fructose and the fructose moiety of sucrose. PMID- 19791768 TI - Extremely large volume electrokinetic stacking of cationic molecules in MEKC by EOF modulation with strong acids in sample solutions. AB - In this report, a novel facile way of online preconcentration of trace levels of analytes in capillary electrophoresis is presented. The proposed strategy is based on the combination of strong acidic phosphate as sample buffers with borate separation buffer containing sodium dodecyl sulfate. When injection voltage is applied, the continuous introduction of low pH sample causes the apparent bulk flow inside the capillary gradually slows down. Finally at a certain point, it reaches the same magnitude as that of the oppositely migrating anionic micelles, thus the frontier of the micelle zone becomes stagnant. This steady state can be maintained for a very long time so that essentially extremely large volume of sample solutions can be injected into the capillary, and the cationic analytes may be efficiently stacked at the neutralized micelle zone. A theoretical model was proposed and preconcentration conditions of two model analytes, matrine and oxymatrine, were optimized with the aid of the model. Under optimized conditions, more than 1000-fold increase in sensitivity was obtained as compared with the normal hydrodynamic injection without sample stacking. The limits of detection for oxymatrine and matrine were 0.81 and 0.18 ng/mL, respectively, using photodiode array UV detection at wavelength 211 nm. PMID- 19791769 TI - Equilibrator inlet-proton transfer reaction-mass spectrometry (EI-PTR-MS) for sensitive, high-resolution measurement of dimethyl sulfide dissolved in seawater. AB - We developed an equilibrator inlet-proton transfer reaction-mass spectrometry (EI PTR-MS) method for fast detection of dimethyl sulfide (DMS) dissolved in seawater. Dissolved DMS extracted by bubbling pure nitrogen through the sample was continuously directed to the PTR-MS instrument. The equilibration of DMS between seawater and the carrier gas, and the response time of the system, were evaluated in the laboratory. DMS reached equilibrium with an overall response time of 1 min. The detection limit (50 pmol L(-1) at 5 s integration) was sufficient for detection of DMS concentrations in the open ocean. The EI-PTR-MS instrument was deployed during a research cruise in the western North Pacific Ocean. Comparison of the EI-PTR-MS results with results obtained by means of membrane tube equilibrator-gas chromatography/mass spectrometry agreed reasonably well on average (R(2) = 0.99). EI-PTR-MS captured temporal variations of dissolved DMS concentrations, including elevated peaks associated with patches of high biogenic activity. These results demonstrate that the EI-PTR-MS technique was effective for highly time-resolved measurements of DMS in the open ocean. Further measurements will improve our understanding of the biogeochemical mechanisms of the production, consumption, and distribution of DMS on the ocean surface and, hence, the air-sea flux of DMS, which is a climatically important species. PMID- 19791770 TI - Single crystal structural and absorption spectral characterizations of nitric oxide synthase complexed with N(omega)-hydroxy-L-arginine and diatomic ligands. AB - The X-ray structures of neuronal nitric oxide synthase (nNOS) with N(omega) hydroxy-l-arginine (l-NHA) and CO (or NO) bound have been determined at 1.91-2.2 A resolution. Microspectrophotometric techniques confirmed reduced redox state and the status of diatomic ligand complexes during X-ray diffraction data collection. The structure of nNOS-NHA-NO, a close mimic to the dioxygen complex, provides a picture of the potential interactions between the heme-bound diatomic ligand, substrate l-NHA, and the surrounding protein and solvent structure environment. The OH group of l-NHA in the X-ray structures deviates from the plane of the guanidinium moiety substantially, indicating that the OH-bearing, protonated guanidine N(omega) nitrogen of l-NHA has substantial sp(3) hybridization character. This nitrogen geometry, different from that of the guanidinium N(omega) nitrogen of l-arginine, allows a hydrogen bond to be donated to the proximal oxygen of the heme-bound dioxygen complex, thus preventing cleavage of the O-O bond. Instead, it favors the stabilization of the ferric hydroperoxy intermediate, Fe(3+)-OOH(-), which serves as the active oxidant in the conversion of l-NHA to NO and citrulline in the second reaction of the NOS. PMID- 19791773 TI - The occurrence and concentration of mycotoxins in U.S. distillers dried grains with solubles. AB - To provide a scientific sound assessment of the prevalence and levels of mycotoxins in U.S. distillers' dried grains with solubles (DDGS), we measured mainly aflatoxins, deoxynivalenol, fumonisins, T-2 toxin, and zearalenone in 235 DDGS samples collected from 20 ethanol plants in the midwestern United States and 23 export shipping containers from 2006 to 2008 using state-of-the-art analytical methodologies. The results suggested that (1) none of the samples contained aflatoxins or deoxynivalenol levels higher than the U.S. Food and Drug Administration (FDA) guidelines for use in animal feed; (2) no more than 10% of the samples contained fumonisin levels higher than the recommendation for feeding equids and rabbits, and the rest of the samples contained fumonisins lower than FDA guidelines for use in animal feed; (3) none of the samples contained T-2 toxins higher than the detection limit, and no FDA guidance levels are available for T-2 toxins; (4) most samples contained zearalenone levels lower than the detection limit, and no FDA guidance levels are available for zearalenone; and (5) the containers used for export shipping of DDGS did not seem to contribute to mycotoxin production. This study was based on representative DDGS samples from the U.S. ethanol industry, and the data were collected using reference methods. This study provided a comprehensive and scientifically sound assessment of the occurrence and levels of mycotoxins in DDGS from the U.S. ethanol industry. PMID- 19791771 TI - Carbohydrate cluster microarrays fabricated on three-dimensional dendrimeric platforms for functional glycomics exploration. AB - We reported here a novel, ready-to-use bioarray platform and methodology for construction of sensitive carbohydrate cluster microarrays. This technology utilizes a three-dimensional (3-D) poly(amidoamine) starburst dendrimer monolayer assembled on glass surface, which is functionalized with terminal aminooxy and hydrazide groups for site-specific coupling of carbohydrates. A wide range of saccharides, including monosaccharides, oligosaccharides and polysaccharides of diverse structures, are applicable for the 3-D bioarray platform without prior chemical derivatization. The process of carbohydrate coupling is effectively accelerated by microwave radiation energy. The carbohydrate concentration required for microarray fabrication is substantially reduced using this technology. Importantly, this bioarray platform presents sugar chains in defined orientation and cluster configurations. It is, thus, uniquely useful for exploration of the structural and conformational diversities of glyco-epitope and their functional properties. PMID- 19791772 TI - Dielectrophoretic-field flow fractionation analysis of dielectric, density, and deformability characteristics of cells and particles. AB - Dielectrophoretic field-flow fractionation (DEP-FFF) has been used to discriminate between particles and cells based on their dielectric and density properties. However, hydrodynamic lift forces (HDLF) at flow rates needed for rapid separations were not accounted for in the previous theoretical treatment of the approach. Furthermore, no method was developed to isolate particle or cell physical characteristics directly from DEP-FFF elution data. An extended theory of DEP-FFF is presented that accounts for HDLF. With the use of DS19 erythroleukemia cells as model particles with frequency-dependent dielectric properties, it is shown that the revised theory accounts for DEP-FFF elution behavior over a wide range of conditions and is consistent with sedimentation-FFF when the DEP force is zero. Conducting four elution runs under specified conditions, the theory allows for the derivation of the cell density distribution and provides good estimates of the distributions of the dielectric properties of the cells and their deformability characteristics that affect HDLF. The approach allows for rapid profiling of the biophysical properties of cells, the identification and characterization of subpopulations, and the design of optimal DEP-FFF separation conditions. The extended DEP-FFF theory is widely applicable, and the parameter measurement methods may be adapted easily to other types of particles. PMID- 19791774 TI - Enantioselective total synthesis and determination of absolute configuration of vittatalactone. AB - The first asymmetric total synthesis of vittatalactone features the divergent synthesis of two diastereomers to assign the absolute configuration of the natural product. Its consecutive propionate and deoxypropionate stereogenic centers are established by enantioselective o-DPPB directed allylic substitution. PMID- 19791775 TI - From closo to isocloso structures and beyond in cobaltaboranes with 9 to 12 vertices. AB - Density functional theory (DFT) studies predict the dianions CpCoB(n-1)H(n-1)(2-) (n = 9, 10, 11, 12; Cp = eta(5)-C(5)H(5)) to have structures based on the most spherical deltahedra found in the isoelectronic boranes B(n)H(n)(2-). In the CpCoB(8)H(8)(2-) dianion the non-equivalent structures with the cobalt atom at a degree 4 vertex and at a degree 5 vertex are essentially degenerate in terms of energy (within approximately 1 kcal/mol). For the CpCoB(n-1)H(n-1)(2-) dianions (n = 10, 11, 12) the cobalt atom prefers energetically the vertices of the lowest possible degree (four for n = 10 and 11, five for n = 12). Structures for the neutral species CpCoB(n-1)H(n-1) (n = 10, 11, 12) based on isocloso deltahedra with the cobalt atom at a degree 6 vertex are preferred energetically by 9, 19, and 53 kcal/mol, respectively, over alternative structures. However, for CpCoB(8)H(8) the closo tricapped trigonal prismatic structure with the cobalt atom at a degree 5 vertex is energetically preferred by approximately 9 kcal/mol over the isocloso deltahedral structure with the cobalt atom at a degree 6 vertex. The lowest energy structures predicted for the dications CpCoB(8)H(8)(2+) and CpCoB(9)H(9)(2+) are highly oblate (flattened) deltahedra with the cobalt atom at a degree 7 vertex. A complicated potential energy surface was found for CpCoB(10)H(10)(2+) including non-deltahedral structures with a single quadrilateral or pentagonal face. The predicted lowest energy structures for both CpCoB(11)H(11) and CpCoB(11)H(11)(2+) are based on the same 12-vertex deltahedron with three degree 6, six degree 5, and three degree 4 vertices, and thus topologically different from the regular icosahedron normally found in boron chemistry. PMID- 19791776 TI - Cross-linked random copolymer mats as ultrathin nonpreferential layers for block copolymer self-assembly. AB - We report the effect of increasing amounts of glycidyl methacrylate (GMA) in random copolymers of P(S-r-MMA-r-GMA) on the formation of nonpreferential mats for the assembly of P(S-b-MMA) block copolymers. Increasing the GMA concentration in the random copolymer from 1 (PG1) to 4 (PG4) mole % increased the cross linking efficiency and reduced the effective minimum thickness of the cross linked mat for perpendicular alignment of P(S-b-MMA) from approximately 6 nm to approximately 2 nm. The compositional window (so-called perpendicular window) of PG4 was defined for both symmetric and asymmetric P(S-b-MMA). Compared to PG1, incorporation of higher amount of polar comonomer (GMA) in PG4 shifted the perpendicular window toward higher styrene fraction as a result of the increased polarity. The defined perpendicular window for P(S-r-MMA-r-GMA) is equally applicable for random copolymers prepared by both controlled living and classical free-radical polymerizations. PMID- 19791777 TI - Colloidal encapsulation of hydrolytically and oxidatively unstable organoborane catalysts and their use in waterborne acrylic polymerization. AB - Trialkylborane catalysts and their amine complexes are hydrolytically and oxidatively unstable, decomposing in water very rapidly to trialkylboroxin, borate esters, and boric acid. However, trialkylborane-amine complexes will rapidly partition to a colloidal phase and remain surprisingly stable for long periods of time (>3 months) until such time as the catalyst is brought into an environment convenient for phase transfer. We show that tributylborane-amine complexes can be stored in aqueous solutions of several water-miscible polymers. We show by diffusion-oriented spectroscopy (DOSY) NMR experiments that the tributylborane-amine catalyst diffuses at nearly the same rate as the colloidal phase, providing strong evidence that they coexist. The aqueous colloidal catalysts can then be mixed with polymerizable monomers such as acrylates to produce good-quality polymers. We show that these colloid-encapsulated catalysts are also useful in producing adhesives capable of adhering low-surface-energy plastic substrates, even when formulated in systems containing 45% water. This is the first report of a waterborne structural adhesive. PMID- 19791778 TI - Solution-based fabrication of single-crystalline arrays of organic nanowires. AB - Organic single-crystalline nanowire arrays, with a length of several hundreds of micrometers and controllable width, are grown on a substrate surface by vertically pulling the substrate out of an organic solution of the molecule of interest. Optical microscopy and atomic force microscopy show that the large scale arrays are oriented parallel to the pulling direction and are well adhered to the substrate surface. Cross-polarized microscopy, polarized UV-vis absorption, and grazing incidence X-ray diffraction confirm that the arrays have high crystal quality. On the basis of this method, the fabrication of organic devices is realized in one step. The results presented here for three different small molecules show the promising potential of this facile solution-based process for the growth of high-quality organic semiconductors, the fabrication of high-density and high-performance devices, and the fabrication of controlled assemblies of nanoscale circuits for fundamental studies and future applications. PMID- 19791779 TI - Thermal stability of mono-, bis-, and tris-chelating alkanethiol films assembled on gold nanoparticles and evaporated "flat" gold. AB - The thermal stability of SAMs generated from the adsorption of n-octadecanethiol (n-C18), 2-hexadecylpropane-1,3-dithiol (C18C2), 2-hexadecyl-2-methylpropane-1,3 dithiol (C18C3), and 1,1,1-tris(mercaptomethyl)heptadecane (t-C18) on colloidal gold and evaporated "flat" gold was investigated. The optical extinction of the monolayer-protected nanoparticles (MPCs) was monitored as a function of thermal stress by using ultraviolet-visible (UV-vis) spectroscopy, which revealed that the evolution of the surface plasmon resonance varied with the nature of the adsorbate. Specifically, MPCs functionalized with monodentate n-C18 showed the fastest red shift of the surface plasmon resonance while those functionalized with tridentate t-C18 showed the slowest red shift, with those derived from the bidentates C18C2 and C18C3 falling in between, suggesting a correlation between film stability and the degree of chelation. In separate studies, X-ray photoelectron spectroscopy (XPS) was used to evaluate the desorption of the monolayers on both colloidal gold and flat gold as a function of thermal stress. In these studies, SAMs generated from monodentate n-C18 showed the fastest desorption while SAMs generated from tridentate t-C18 showed the slowest desorption, with those derived from the bidentates C18C2 and C18C3 falling in between, again suggesting a correlation between film stability and the degree of chelation. As a whole, the following trend in thermal stability was observed: t C18 > C18C2 approximately C18C3 > n-C18. PMID- 19791780 TI - Experimental study on energy dissipation of electrolytes in nanopores. AB - When a nonwetting fluid is forced to infiltrate a hydrophobic nanoporous solid, the external mechanical work is partially dissipated into thermal energy and partially converted to the liquid-solid interface energy to increase its enthalpy, resulting in a system with a superior energy absorption performance. To clarify the energy dissipation and conversion mechanisms, experimental infiltration and defiltration tests of liquid/ion solutions into nanopores of a hydrophobic ZSM-5 zeolite were conducted. The characteristics of energy dissipation were quantified by measuring the temperature variation of the immersed liquid environment and compared against that estimated from pressure infiltration volume isotherms during infiltration and defiltration stages of the test. Both stages were observed to be endothermic, with the temperature of the liquid phase showing a steady increase with changes in liquid saturation. The confinement of the molecular-sized pore space causes the liquid molecules/ions to transit between statuses of orderly and disorderly motions, resulting in dissipation behaviors that vary with liquid infiltration/defiltration rates and the types and concentrations of additive electrolytes in the liquid-both factors of which alter the characteristics of the nanofluidic transport behavior. PMID- 19791781 TI - Stepwise aggregation of dimethyl-di-n-octylammonium chloride in aqueous solutions: from dimers to vesicles. AB - The self-aggregation of dimethyl-di-n-octylammonium chloride, in diluted aqueous solutions, was studied with various experimental and theoretical techniques: zetametry, conductimetry, dimethyl-di-n-octylammonium and chloride-selective electrodes, tensiometry, NMR spectroscopy ((1)H and DOSY), and molecular modeling (PM3 and molecular dynamic). The combination of the data obtained by these techniques led us to propose a stepwise aggregation process with increasing concentration: dimers (0.2-10 mM), bilayers (10-30 mM), and finally vesicles (>30 mM). PMID- 19791782 TI - Enhanced SAR maps: expanding the data rendering capabilities of a popular medicinal chemistry tool. AB - We recently introduced SAR maps, a new interactive method for visualizing structure-activity relationships targeted specifically at medicinal chemists. A SAR map renders an R-group decomposition of a congeneric series as a rectangular matrix of cells, each representing a unique combination of R-groups color-coded by a user-selected property of the corresponding compound. In this paper, we describe an enhanced version that greatly expands the types of visualizations that can be displayed inside the cells. Examples include multidimensional histograms and pie charts that visualize the biological profiles of compounds across an entire panel of assays, forms that display specific fields on user defined layouts, aligned 3D structure drawings that show the relative orientation of different substituents, dose-response curves, images of crystals or diffraction patterns, and many others. These enhancements, which capitalize on the modular architecture of its host application Third Dimension Explorer (3DX), allow the medicinal chemist to interactively analyze complex scaffolds with multiple substitution sites, correlate substituent structure and biological activity at multiple simultaneous dimensions, identify missing analogs or screening data, and produce information-dense visualizations for presentations and publications. The new tool has an intuitive user interface that makes it appealing to experts and nonexperts alike. PMID- 19791783 TI - Effects of hydrodynamic coupling on electro-optical transients. AB - The effects resulting from coupling between translational and rotational diffusion on electro-optical transients were analyzed by Brownian dynamics simulations. Diffusion tensors, including translational-rotational coupling tensors, were derived from bead model simulations. Optical and electrical parameters were assigned according to models and experimental data. Hydrodynamic coupling has a strong impact on the shape of electro-optical transients for objects with a nonsymmetric structure. As expected, hydrodynamic coupling in general does not affect the time constants derived from decay curves. However, special attention is required at singular points, where amplitudes are inverted. Under these conditions, transients are observed with artificially reduced time constants, suggesting compact structures. False conclusions may be avoided, when experimental data are analyzed over a sufficiently wide range of conditions. Because transients induced upon reversal of the field vector are strongly affected by hydrodynamic coupling, dipole types cannot be assigned from these transients simply according to standard rules, when the shape of the objects is nonsymmetric. The time constants obtained from exponential fitting of rise-curves show unexpected dependencies on the field strength, which are mainly due to superposition of individual components with amplitudes of opposite sign that are not resolved upon fitting. Dipole parameters obtained from stationary degrees of orientation via orientation functions may also be strongly affected by hydrodynamic coupling. The high sensitivity of electro-optical transients on details of molecular shape and optical and electrical parameters provides a powerful approach to molecular analysis, but quantitative assignments require special care. When symmetry is lost, which must be expected because of bending in many cases, hydrodynamic coupling effects cannot be neglected. PMID- 19791784 TI - Thermally controllable reflective characteristics from rupture and self-assembly of hydrogen bonds in cholesteric liquid crystals. AB - A cholesteric liquid crystal (Ch-LC) composite, made of a series of cholesteryl esters, a nematic LC, and a hydrogen bond (H-bond) chiral dopant (HCD), was prepared and filled into a planar treated cell. When the cell was heated, the selective reflection of the cell exhibited an unusual blue shift. One of the reasonable mechanisms was that the helical twisting power (HTP) value of cholesteryl esters increased with an increasing temperature. The other one was that the H-bonds of HCD were ruptured when the temperature was above 60.0 degrees C and HCD was split into two kinds of new chiral dopants, which made the HTP value of the chiral dopants change a lot, thus changing the pitch length of the composite greatly. On the basis of this mechanism, a novel thermally controllable reflective color paper could be achieved. PMID- 19791785 TI - Photophysical properties and singlet oxygen production by ruthenium(II) complexes of benzo[i]dipyrido[3,2-a:2',3'-c]phenazine: spectroscopic and TD-DFT study. AB - The photophysical properties of a series of Ru(II) complexes containing benzo[i]dipyrido[3,2-a:2',3'-c]phenazine (dppn) as a ligand are reported. Transient absorption spectroscopy studies indicate that, in contrast to related Ru(dppz) complexes (dppz = dipyrido[3,2-a:2',3'-c]phenazine), the excited state of all the dppn systems is a long-lived pipi* triplet state. Computational studies (DFT and TD-DFT) confirm that the excited state is based on the dppn ligand. Near-infrared luminescence studies reveal that the complexes are efficient singlet oxygen sensitizers with yields of 70-83%. PMID- 19791786 TI - High level QM/MM modeling of the formation of the tetrahedral intermediate in the acylation of wild type and K73A mutant TEM-1 class A beta-lactamase. AB - The breakdown of beta-lactam antibiotics by beta-lactamases is the most important resistance mechanism of gram negative bacteria against these drugs. The reaction mechanism of class A beta-lactamases, the most widespread family of these enzymes, consists of two main steps: acylation of an active site serine by the antibiotic, followed by deacylation and release of the cleaved compound. We have investigated the first step in acylation (the formation of the tetrahedral intermediate) for the reaction of benzylpenicillin in the TEM-1 enzyme using high level combined quantum mechanics/molecular mechanics (QM/MM) methods. Structures were optimized at the B3LYP/6-31+G(d)/CHARMM27 level, with energies for key points calculated up to the ab initio SCS-MP2/aug-cc-pVTZ/CHARMM27 level. The results support a mechanism in which Glu166 removes a proton (via an intervening water molecule) from Ser70, which in turn attacks the beta-lactam of the antibiotic. Depending on the method used, the calculated barriers range from 3 to 12 kcal mol(-1) for this step, consistent with experimental data. We have also modeled this reaction step in a model of the K73A mutant enzyme. The barrier to reaction in this mutant model is found to be slightly higher: the results indicate that Lys73 stabilizes the transition state, in particular deprotonated Ser70, lowering the barrier by about 1.7 kcal mol(-1). This finding may help to explain the conservation of Lys73, in addition to the role we have previously found for it in the later stages of the reaction (Hermann et al. Org. Biomol. Chem. 2006, 4, 206-210). PMID- 19791787 TI - NMR scalar coupling constant reveals that intraprotein hydrogen bonds are dynamically stabilized by electronic polarization. AB - Molecular dynamics simulations based on the standard nonpolarizable AMBER force field and on quantum-derived polarized protein-specific charge (PPC) are performed to compute NMR scalar coupling constants across hydrogen bonds for three benchmark protein systems: ubiquitin, the GB1 domain of protein G, and the SMN Tudor domain. Direct comparison of the simulation result with experimental data gives strong evidence that intraprotein hydrogen bonds are significantly stabilized by electronic polarization, both in terms of NMR scalar coupling constants and X-ray determined geometries of hydrogen bonds. Without the polarization effect in the force field, hydrogen bonds are found to be "too loose", which leads to less stable or even unstable local structures of proteins. PMID- 19791788 TI - Influence of internal rotation on exothermic reactions between neutral molecules at low temperatures. AB - A Langevin-type transition state model is developed to take account of the internal rotation energy in exothermic reactive collisions between neutral molecules. Energy and total angular momentum are both rigorously conserved. Reactive rate coefficients attain a maximum of a few 10(-10) cm(3)/s at temperatures in the range 10-30 K decreasing rapidly at higher temperatures. Results for a representative selection of well-studied systems, Si-O(2), CN-O(2), Si-NO, are in good agreement with experimental observations. At higher temperatures, typically around 100 K or greater, the rate coefficient exhibits a T(-1/3) dependence. PMID- 19791789 TI - The Ru-Hbpp water oxidation catalyst. AB - A thorough characterization of the Ru-Hbpp (in,in-{[Ru(II)(trpy)(H(2)O)](2)(mu bpp)}(3+) (trpy is 2,2':6',2''-terpyridine, bpp is bis(2-pyridyl)-3,5 pyrazolate)) water oxidation catalyst has been carried out employing structural (single crystal X-ray), spectroscopic (UV-vis and NMR), kinetic, and electrochemical (cyclic voltammetry) analyses. The latter reveals the existence of five different oxidation states generated by sequential oxidation of an initial II,II state to an ultimate, formal IV,IV oxidation state. Each of these oxidation states has been characterized by UV-vis spectroscopy, and their relative stabilities are reported. The electron transfer kinetics for individual one-electron oxidation steps have been measured by means of stopped flow techniques at temperatures ranging from 10 to 40 degrees C and associated second order rate constants and activation parameters (DeltaH() and DeltaS()) have been determined. Room-temperature rate constants for substitution of aqua ligands by MeCN as a function of oxidation state have been determined using UV-vis spectroscopy. Complete kinetic analysis has been carried out for the addition of 4 equiv of oxidant (Ce(IV)) to the initial Ru-Hbpp catalyst in its II,II oxidation state. Subsequent to reaching the formal oxidation state IV,IV, an intermediate species is formed prior to oxygen evolution. Intermediate formation and oxygen evolution are both much slower than the preceding ET processes, and both are first order with regard to the catalyst; rate constants and activation parameters are reported for these steps. Theoretical modeling at density functional and multireference second-order perturbation theory levels provides a microscopic mechanism for key steps in intermediate formation and oxygen evolution that are consistent with experimental kinetic data and also oxygen labeling experiments, monitored via mass spectrometry (MS), that unambiguously establish that oxygen-oxygen bond formation proceeds intramolecularly. Finally, the Ru-Hbpp complex has also been studied under catalytic conditions as a function of time by means of manometric measurements and MS, and potential deactivation pathways are discussed. PMID- 19791790 TI - Enamine catalysis with low catalyst loadings--high efficiency via kinetic studies. AB - Kinetic studies on enamine catalysis provided insight into the rate determining step(s) of peptide catalyzed conjugate addition reactions between aldehydes and nitroolefins. They demonstrate that not enamine formation but both the reaction of the enamine with the electrophile and hydrolysis of the resulting imine are rate limiting. These results allowed for reducing the catalyst loading by a factor of 10 to as little as 0.1 mol %. This is the lowest catalyst loading that has been achieved so far in enamine catalysis with low molecular weight catalysts for a broad range of substrates. PMID- 19791791 TI - Influence of copigmentation on stability of anthocyanins from purple potato peel in both liquid state and solid state. AB - Copigmentation is an important way to improve the stability of anthocyanins. The effect of the copigmentation on the stability of the anthocyanin from the purple potato peel (PA) was evaluated from the view of the kinetics and thermodynamics in both the liquid state and the solid state for the first time. In the liquid state, the copigmentation of the ascorbic acid decreased the stability of PA by the activation-energy evaluation, while that of the citric-acid monohydrate and glucose increased the stability of PA. Moreover, the stability of the copigmented PA presented the positive correlation with its ratio to the ascorbic acid and citric-acid monohydrate individually. The copigmentation of the glucose at the different ratio did not affect the stability of PA significantly. In the solid state, the stability of PA was improved by the copigmentation with the ascorbic acid, citric-acid monohydrate, and glucose by the transition-temperature evaluation. Moreover, the stability of the copigmented PA showed the negative correlation with its ratio to the ascorbic acid, citric-acid monohydrate, and glucose individually. PMID- 19791792 TI - Binding of organometallic ruthenium(II) anticancer compounds to nucleobases: a computational study. AB - The reaction of the anticancer compound [(eta(6)-benzene)Ru(en)(OH(2))](2+) (1) toward the nucleobases guanine, adenine, and cytosine is studied computationally using DFT/BP86 calculations. The aqua leaving group of such compounds is known to undergo ligand exchange reactions with nucleophilic centers in DNA and preferentially with the N7 atom of guanine, N7(G). Our results show that an H bonded reactant adduct with nucleobases is formed via either the aqua ligand (cis adduct) or the en (ethylenediamine) ligand (trans adduct) of 1. All studied nucleobases favor an H-bonded cis adduct. Only guanine forms also a trans reactant adduct in the gas phase. The guanine N7 and O6 atoms in this trans adduct are situated in an ideal position to form each a strong H-bond to both amino groups of the en ligand of 1. A docking study shows that this unique recognition pattern is also plausible for the interaction with double stranded DNA. For the reaction of 1 with guanine, we identified three different reaction pathways: (i) A cis (G)N7-Ru-OH(2) transition state (TS). (ii) A direct trans reaction pathway. (iii) A 2-step trans mechanism. The activation energies for the cis pathway are smaller than for the trans pathways. The ultimately formed Ru N7(G) product is characterized by a thermally stable H-bond between the O6(G) and a diamine-NH(2) hydrogen. PMID- 19791794 TI - Biocompatible and biodegradable poly(trimethylene carbonate)-b-poly(L-glutamic acid) polymersomes: size control and stability. AB - Poly(trimethylene carbonate)-b-poly(L-glutamic acid) (PTMC-b-PGA) diblock copolymers have been synthesized by ring-opening polymerization (ROP) of gamma benzyl-L-glutamate N-carboxyanhydride (BLG) initiated by amino functionalized PTMC and subsequent hydrogenation. Self-assembly in water gave well-defined vesicles which have been studied combining light and neutron scattering techniques with electron microscopy imaging. The size and dispersity of vesicles have been tuned by varying preparation conditions, direct dissolution, or nanoprecipitation. In addition, PGA conformation could be reversibly manipulated as a function of environmental changes such as pH and ionic strength. Vesicles showed high tolerance and stability toward nonionic surfactant and pH due to a thick membrane and were revealed to be nonpermeable to water. Nevertheless, they can be rapidly degraded by enzymatic hydrolysis of the polycarbonate block. The ability to tune their size through the formation process, their stimuli responsiveness, their high stability, and their biodegradability make them suitable for biomedical applications. PMID- 19791795 TI - Experimental-computational investigation of ZnO nanowires strength and fracture. AB - An experimental and computational approach is pursued to investigate the fracture mechanism of [0001] oriented zinc oxide nanowires under uniaxial tensile loading. A MEMS-based nanoscale material testing stage is used in situ a transmission electron microscope to perform tensile tests. Experiments revealed brittle fracture along (0001) cleavage plane at strains as high as 5%. The measured fracture strengths ranged from 3.33 to 9.53 GPa for 25 different nanowires with diameters varying from 20 to 512 nm. Molecular dynamic simulations, using the Buckingham potential, were used to examine failure mechanisms in nanowires with diameters up to 20 nm. Simulations revealed a stress-induced phase transformation from wurtzite phase to a body-centered tetragonal phase at approximately 6% strain, also reported earlier by Wang et al. (1) The transformation is partial in larger nanowires and the transformed nanowires fail in a brittle manner at strains as high as 17.5%. The differences between experiments and computations are discussed in the context of (i) surface defects observed in the ZnO nanowires, and (ii) instability in the loading mechanism at the initiation of transformation. PMID- 19791793 TI - Chemical equilibrium probed by two-dimensional IR spectroscopy: hydrogen bond dynamics of methyl acetate in water. AB - The solvation dynamics of methyl acetate in heavy water are analyzed by means of two-dimensional infrared spectroscopy, in conjunction with Car-Parrinello molecular dynamics simulations. The C horizontal lineO stretching infrared band of methyl acetate in water splits into a doublet as a consequence of the hydrogen bond interaction with the solvent, which leads to the equilibrium between two solvated species, consisting of one methyl acetate molecule bonded to one and two water molecules. The structure and dynamics of the water molecules bound to methyl acetate are characterized by means of experiments and simulations, allowing an accurate description of the kinetics of the exchange process and the lifetime of the hydrogen bond. PMID- 19791796 TI - Synergistic effect of low cytotoxic linear polyethylenimine and multiarm polyethylene glycol: study of physicochemical properties and in vitro gene transfection. AB - Novel star-shaped copolymers consisting of multiarm polyethylene glycol and low molecular weight linear polyethylenimines (MAPEG-LPEIs) with a high transfection efficiency and low cytotoxicity were designed and synthesized as nonviral gene delivery carriers. The cationic polymers were prepared by conjugating low molecular weight linear PEI (2.5 kDa) to six-arm PEG-NHS (10 kDa) in two different compositions. Two copolymers, MAPEG-LPEI(3) and MAPEG-LPEI(6) with molecular weights of 17.5 kDa and 25 kDa respectively, were synthesized. The MAPEG-LPEI(3)/pDNA and MAPEG-LPEI(6)/pDNA polyplexes are stably dispersed in aqueous media with a narrowly distributed size range of <200 nm as determined by dynamic light scattering. Furthermore, these polyplexes showed different surface charges depending upon the relative proportion of MAPEG and LPEI. Moreover, these polyplexes can protect pDNA from enzymatic degradation in serum containing media up to 24 h. These polyplexes were able to efficiently transfect luciferase-coded reporter gene into HeLa cancer cells and showed considerable gene transfection efficacy even in 50% serum-conditioned media in vitro. MAPEG-LPEI(6) exhibited higher transfection activity than that of MAPEG-LPEI(3) at the same weight ratios. Furthermore, MAPEG-LPEI/pDNA polyplexes were less toxic than LPEI/pDNA complexes as determined by MTT assay. These favorable results could be attributed to the combined effect of low molecular weight LPEI and multiarm PEG. The special structural features of the multiarm star-shaped central PEG core play an important role in achieving higher transfection efficiency as it imparts higher charge density to polyplexes and prevents the unwanted aggregation of the smaller polyplex particles. These two important factors contributed toward enhanced gene transfection. On the other hand, LPEI provides low cytotoxicity and effective complexation with pDNA in the designed architecture. Therefore it is possible to achieve enhanced gene transfection by using these two components, namely, pivotal multiarm PEG core and LPEI, in optimal ratio as observed in the case of MAPEG LPEI(6). PMID- 19791797 TI - Role of E166 in the imine to enamine tautomerization of the clinical beta lactamase inhibitor sulbactam. AB - Mechanism-based inhibitors of class A beta-lactamases, such as sulbactam, undergo a complex series of chemical reactions in the enzyme active site. Formation of a trans-enamine acyl-enzyme via a hydrolysis-prone imine is responsible for transient inhibition of the enzyme. Although the imine to enamine tautomerization is crucial to inhibition of the enzyme, there are no experimental data to suggest how this chemical transformation is catalyzed in the active site. In this report, we show that E166 acts as a general base to promote the imine to enamine tautomerization. PMID- 19791798 TI - Ring1B contains a ubiquitin-like docking module for interaction with Cbx proteins. AB - Polycomb group (PcG) proteins are a special set of repressive transcription factors involved in epigenetic modifications of chromatin. They form two functionally distinct groups of catalytically active complexes: Polycomb repressive complex 1 (PRC1) and 2 (PRC2). The PRC1 complex is an important yet poorly characterized multiprotein histone ubiquitylation machine responsible for maintaining transcriptionally silent states of genes through histone H2A K119 modification. The Ring domain containing subunits of PRC1 also have substrate targeting domains that interact with Cbx proteins, which have been implicated in chromatin and RNA binding. In this work, we present a high resolution structure of the C-terminal domain of Ring1B, revealing a variant ubiquitin-like fold with a distinct conserved surface region. On the basis of crystal structure and mutational analysis of this domain we show that the conserved surface is responsible for interaction with Cbx members of the PRC1 and homodimer formation. These data suggest a mechanism by which Ring1B serves as an adaptor that mediates binding between the members of the PRC1 complex and the nucleosome. PMID- 19791799 TI - RNase H active site inhibitors of human immunodeficiency virus type 1 reverse transcriptase: design, biochemical activity, and structural information. AB - Pyrimidinol carboxylic acids were designed as inhibitors of HIV-1 RNase H function. These molecules can coordinate to two divalent metal ions in the RNase H active site. Inhibition of enzymatic activity was measured in a biochemical assay, but no antiviral effect was observed. Binding was demonstrated via a solid state structure of the isolated p15-Ec domain of HIV-1 RT showing inhibitor and two Mn(II) ions bound to the RNase H active site. PMID- 19791800 TI - Discovery of novel protease activated receptors 1 antagonists with potent antithrombotic activity in vivo. AB - Protease activated receptors (PARs) or thrombin receptors constitute a class of G protein-coupled receptors (GPCRs) implicated in the activation of many physiological mechanisms. Thus, thrombin activates many cell types such as vascular smooth muscle cells, leukocytes, endothelial cells, and platelets via activation of these receptors. In humans, thrombin-induced platelet aggregation is mediated by one subtype of these receptors, termed PAR1. This article describes the discovery of new antagonists of these receptors and more specifically two compounds: 2-[5-oxo-5-(4-pyridin-2-ylpiperazin-1-yl)penta-1,3 dienyl]benzonitrile 36 (F 16618) and 3-(2-chlorophenyl)-1-[4-(4 fluorobenzyl)piperazin-1-yl]propenone 39 (F 16357), obtained after optimization. Both compounds are able to inhibit SFLLR-induced human platelet aggregation and display antithrombotic activity in an arteriovenous shunt model in the rat after iv or oral administration. Furthermore, these compounds are devoid of bleeding side effects often observed with other types of antiplatelet drugs, which constitutes a promising advantage for this new class of antithrombotic agents. PMID- 19791801 TI - Pyridine analogues of nimesulide: design, synthesis, and in vitro and in vivo pharmacological evaluation as promising cyclooxygenase 1 and 2 inhibitors. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) represent one of the most prescribed medications, although the chronic use of such pharmacological agents is commonly associated with numerous side effects. The demonstration that the use of COX-2 selective or preferential inhibitors is associated with a better tolerability opened new horizons in the search of safer drugs for the management of inflammation. In the present study, we report the synthesis and the pharmacological evaluation of pyridine analogues of nimesulide, a COX-2 preferential inhibitor. The cyclooxygenases (COXs) inhibitory activities were evaluated in vitro using a human whole blood model. According to the in vitro results, a selection of compounds exhibiting moderate to high COX-2/COX-1 selectivity ratio (from weak COX-2 preferential inhibitors to compounds displaying a celecoxib-like selectivity profile) were further evaluated in vivo in a model of lambda carrageenan-induced pleurisy in rats. Some of the selected compounds displayed similar or improved anti-inflammatory properties when compared to nimesulide and celecoxib. PMID- 19791802 TI - Synthesis of 1,1-[1-naphthyloxy-2-thiophenyl]-2-methylaminomethylcyclopropanes and their evaluation as inhibitors of serotonin, norepinephrine, and dopamine transporters. AB - Stereodefined trisubstituted cyclopropanes bearing naphthyloxy, thiophenyl, and (N-methylamino)methyl groups were synthesized in enantiopure form employing asymmetric cyclopropanation of (E)- and (Z)-allylic alcohols as the key step. In vitro assays of the synthesized cyclopropanes revealed that the K(i) of one of the enantiomers as a dual inhibitor of serotonin and norepinephrine transporters is in the low nanomolar range and is comparable to that of duloxetine. PMID- 19791803 TI - Modeling, synthesis and biological evaluation of potential retinoid X receptor (RXR) selective agonists: novel analogues of 4-[1-(3,5,5,8,8-pentamethyl-5,6,7,8 tetrahydro-2-naphthyl)ethynyl]benzoic acid (bexarotene). AB - This report describes the synthesis of analogues of 4-[1-(3,5,5,8,8-pentamethyl 5,6,7,8-tetrahydro-2-naphthyl)ethynyl]benzoic acid (1), commonly known as bexarotene, and their analysis in acting as retinoid X receptor (RXR)-specific agonists. Compound 1 has FDA approval to treat cutaneous T-cell lymphoma (CTCL); however, its use can cause side effects such as hypothyroidism and increased triglyceride concentrations, presumably by disruption of RXR heterodimerization with other nuclear receptors. The novel analogues in the present study have been evaluated for RXR activation in an RXR mammalian-2-hybrid assay as well as an RXRE-mediated transcriptional assay and for their ability to induce apoptosis as well as for their mutagenicity and cytotoxicity. Analysis of 11 novel compounds revealed the discovery of three analogues that best induce RXR-mediated transcriptional activity, stimulate apoptosis, have comparable K(i) and EC(50) values to 1, and are selective RXR agonists. Our experimental approach suggests that rational drug design can develop new rexinoids with improved biological properties. PMID- 19791804 TI - Development and screening of water-soluble analogues of progesterone and allopregnanolone in models of brain injury. AB - Preclinical and clinical research findings have revealed that the hormone progesterone, when acutely administered, can dramatically reduce cerebral edema, inflammation, tissue necrosis, and programmed cell death following traumatic brain injury (TBI). The poor aqueous solubility of progesterone, however, limits its potential use as a therapeutic. Several chemically novel analogues of progesterone and its natural metabolite allopregnanolone have been synthesized and screened using both in vitro and whole animal models of TBI. The new derivatives demonstrated greatly improved solubility and select compounds have shown equivalent effectiveness to progesterone in reducing cerebral edema after TBI. PMID- 19791805 TI - Hydroxamic acids as a novel family of serine racemase inhibitors: mechanistic analysis reveals different modes of interaction with the pyridoxal-5'-phosphate cofactor. AB - Mammalian serine racemase (SR) is a pyridoxal-5'-phosphate (PLP) dependent enzyme responsible for the biosynthesis of the neurotransmitter D-serine, which activates N-methyl-D-aspartate (NMDA) receptors in the CNS. Aberrant regulation of NMDA receptor signaling has been implicated in a variety of neuropathologies, and inhibitors of SR would therefore be a worthwhile tool for further investigation or treatment of such conditions. Here, we identify a series of small aliphatic hydroxamic acids (HAs) that act as potent SR inhibitors. However, specificity studies showed that some of these HAs can act as nonspecific inhibitors of PLP-dependent enzymes. We employed NMR, MS, and UV/vis spectroscopic techniques to reveal that the nonspecific effect is likely due to irreversible interaction of the HA moiety with PLP to form aldoxime species. We also characterize L-aspartic acid beta-hydroxamate as a competitive and selective SR inhibitor that could be used as a scaffold for further inhibitor development. PMID- 19791806 TI - Diazo transfer-click reaction route to new, lipophilic teicoplanin and ristocetin aglycon derivatives with high antibacterial and anti-influenza virus activity: an aggregation and receptor binding study. AB - Semisynthetic, lipophilic ristocetin and teicoplanin derivatives were prepared starting from ristocetin aglycon and teicoplanin psi-aglycon (N-acetyl-D glucosaminyl aglycoteicoplanin). The terminal amino functions of the aglycons were converted into azido form by triflic azide. Copper catalyzed 1,3-dipolar cycloaddition reaction with lipophilic alkynes resulted in the title compounds. Two of the teicoplanin derivatives showed very good MIC and MBC values against various Gram-positive bacteria, including vanA enterococci. The aggregation and interaction of a n-decyl derivative with bacterial cell wall components was studied. One of the lipophilic ristocetin derivatives displayed favorable anti influenza virus activity. PMID- 19791807 TI - Evaluation of spirocyclic 3-(3-fluoropropyl)-2-benzofurans as sigma1 receptor ligands for neuroimaging with positron emission tomography. AB - A series of various N-substituted 3-(3-fluoropropyl)-3H-spiro[[2]benzofuran-1,4' piperidines] (7) has been synthesized. In receptor binding studies, the N-benzyl derivative 7a (WMS-1813) revealed extraordinarily high sigma(1) receptor affinity (K(i) = 1.4 nM) and excellent sigma(1)/sigma(2) selectivity (>600 fold). In vitro biotransformation of 7a with rat liver microsomes led to three main metabolites. N-Debenzylation was inhibited by introduction of an N-phenylethyl residue (7 g). The PET tracer [(18)F]7a was synthesized by nucleophilic substitution of the tosylate 13 with K[(18)F]F-K222-carbonate complex. The decay corrected radiochemical yield of [(18)F]7a was 35-48% with a radiochemical purity of >99.5% and a specific activity of 150-238 GBq/micromol. The radiotracer properties were evaluated in female CD-1 mice by organ distribution and ex vivo brain autoradiography. The radiotracer uptake in the brain was fast and sufficient, with values of approximately 4% injected dose per gram. Target specificity of [(18)F]7a was validated in blocking studies by preapplication of haloperidol, and significant reduction in the uptake of radioactivity was observed in the brain and peripheral organs expressing sigma(1) receptors. PMID- 19791808 TI - Synergy effects of electric and magnetic fields on locally excited-state fluorescence of photoinduced electron transfer systems in a polymer film. AB - Photoluminescence of electron donor-acceptor pairs that show photoinduced electron transfer (PIET) has been measured in a polymer film under simultaneous application of electric field and magnetic field. Fluorescence emitted from the locally excited state (LE fluorescence) of 9-methylanthracene (MAnt) and pyrene (Py) is quenched by an electric field in a mixture of 1,3-dicyanobenzene (DCB) with MAnt or Py, indicating that PIET from the excited state of MAnt or Py to DCB is enhanced by an electric field. Simultaneous application of electric and magnetic fields enhances the reverse process from the radical-ion pair produced by PIET to the LE fluorescent state of MAnt or Py. As a result, the electric field-induced quenching of the LE fluorescence is reduced by application of the magnetic fields. Thus, the synergy effect of electric and magnetic fields is observed on the LE fluorescence of MAnt or Py. Exciplex fluorescence spectra resulting from PIET can be obtained by analyzing the field effects on photoluminescence spectra, even when the exciplex fluorescence is too weak to be determined from the steady-state or time-resolved photoluminescence spectra at zero field. PMID- 19791809 TI - Carbon cluster formation during thermal decomposition of octahydro-1,3,5,7 tetranitro-1,3,5,7-tetrazocine and 1,3,5-triamino-2,4,6-trinitrobenzene high explosives from ReaxFF reactive molecular dynamics simulations. AB - We report molecular dynamics (MD) simulations using the first-principles-based ReaxFF reactive force field to study the thermal decomposition of 1,3,5-triamino 2,4,6-trinitrobenzene (TATB) and octahydro-1,3,5,7-tetranitro-1,3,5,7-tetrazocine (HMX) at various densities and temperatures. TATB is known to produce a large amount (15-30%) of high-molecular-weight carbon clusters, whereas detonation of nitramines such as HMX and RDX (1,3,5-trinitroperhydro-1,3,5-triazine) generate predominantly low-molecular-weight products. In agreement with experimental observation, these simulations predict that TATB decomposition quickly (by 30 ps) initiates the formation of large carbonaceous clusters (more than 4000 amu, or approximately 15-30% of the total system mass), and HMX decomposition leads almost exclusively to small-molecule products. We find that HMX decomposes readily on this time scale at lower temperatures, for which the decomposition rate of TATB is about an order of magnitude slower. Analyzing the ReaxFF MD results leads to the detailed atomistic structure of this carbon-rich phase of TATB and allows characterization of the kinetics and chemistry related to this phase and their dependence on system density and temperature. The carbon-rich phase formed from TATB contains mainly polyaromatic rings with large oxygen content, leading to graphitic regions. We use these results to describe the initial reaction steps of thermal decomposition of HMX and TATB in terms of the rates for forming primary and secondary products, allowing comparison to experimentally derived models. These studies show that MD using the ReaxFF reactive force field provides detailed atomistic information that explains such macroscopic observations as the dramatic difference in carbon cluster formation between TATB and HMX. This shows that ReaxFF MD captures the fundamental differences in the mechanisms of such systems and illustrates how the ReaxFF may be applied to model complex chemical phenomena in energetic materials. The studies here illustrate this for modestly sized systems and modest periods; however, ReaxFF calculations of reactive processes have already been reported on systems with approximately 10(6) atoms. Thus, with suitable computational facilities, one can study the atomistic level chemical processes in complex systems under extreme conditions. PMID- 19791810 TI - Experimental and theoretical study of excited-state structure and relaxation processes of betaine-30 and of pyridinium model compounds. AB - The long-wavelength absorption band of 2,6-diphenyl-4-(2,4,6-triphenylpyridinium 1-yl) phenolate (betaine-30, B30) in ethanol and 1-chlorobutane shifts to the blue by cooling in the temperature range of 294-128 K. In addition, B30 shows fluorescence in both solvents at 77 K, which is absent at room temperature. The study of the ground and excited state of B30 and its model compound 4-(pyridinium 1-yl)-phenolate PyPo by DFT/TDDFT calculations indicates that for the perpendicular conformation, the ground state possesses a charge-separated closed shell hole pair (hp) electronic configuration, and the S(1) state corresponds to a biradicaloid electronic structure (dd) with a small dipole moment caused by an unpaired electron on each of the orthogonal fragments. Following the absorption process, there is a driving force for geometrical relaxation within the S(1) state toward an orthogonal arrangement of the phenolate and the pyridinium ring. In this final S(1) equilibrium geometry, the energy gap between the excited and the ground state is strongly reduced and causes very efficient radiationless deactivation of the S(1) state at room temperature. At 77 K, the viscous barrier hindering large-amplitude motion enables the appearance of the fluorescence from the partially or nonrelaxed excited Franck-Condon structure. By variation of the donor and acceptor strength of the two moieties, the energy gap for perpendicular systems can be tuned, allowing, in principle, the switching between the two cases hp < dd and hp > dd. This enables a new access to the efficient construction of mnemonic systems and NLO dyes. PMID- 19791811 TI - Computational study of cesium cation interactions with neutral and anionic compounds related to soil organic matter. AB - The gas-phase cesium cation affinities (CsCAs) and basicities (CsCBs) for 56 simple neutral compounds (mostly aromatic molecules) and 41 anions (carboxylates and phenolates) were calculated using density functional theory (DFT), in the context of the interaction of Cs(+) with soil organic matter (SOM). The B3LYP/def2-TZVP method gives in general CsCAs and CsCBs in a good agreement with experimental data. The strong deviations in case of NO(3)(-) and CsSO(4)(-) anions need further experimental investigations as the high-level CCSD(T) calculations support B3LYP results. Different cesium cation complexation patterns between Cs(+) and the neutral and anionic systems are discussed. As expected, the strongest CsCAs are observed for anions. The corresponding quantities are approximately by 4-5 times higher than for the neutral counterparts, being in the range 90-118 kcal/mol. The weakest cesium cation bonding is observed in the case of unsubstituted aromatic systems (11-15 kcal/mol). PMID- 19791812 TI - Computational study of the self-initiation mechanism in thermal polymerization of methyl acrylate. AB - This computational study deals with the mechanism of spontaneous initiation in thermal polymerization of alkyl acrylates (e.g., methyl, ethyl, and n-butyl acrylate). The mechanism is presently still unknown. Density-functional theory (DFT) and Moller-Plesset (MP2) calculations are used to explore the Flory and Mayo mechanisms of self-initiation in methyl acrylate. On the singlet surface, a low-barrier, concerted [4 + 2] Diels-Alder mechanism for the formation of a dihydropyran adduct (DA) and a high-barrier nonconcerted [2 + 2] diradical ((*)M(2s)(*)) mechanism for the formation of dimethyl cyclobutane-1,2 dicarboxylate (DCD) were found using B3LYP/6-31G*. Several levels of theory were used to validate the transition states, and the pathways for the DA and DCD formations on the singlet surface were determined using intrinsic reaction coordinate (IRC) calculations. On the triplet surface, a triplet diradical intermediate ((*)M(2t)(*)) was identified that is structurally similar to (*)M(2s)(*) but lower in energy. The spin-orbit coupling constant for crossover of the diradical from singlet to triplet surface was calculated. Monoradical generation from the two intermediates, DA and (*)M(2t)(*) via hydrogen transfer to or from a third methyl acrylate was studied. It was found that generation of two monoradical species was possible from (*)M(2t)(*) and is proposed as a likely explanation for experimentally observed spontaneous-initiation. PMID- 19791813 TI - Photophysical properties of an alkyne-bridged bis(zinc porphyrin)-perylene bis(dicarboximide) derivative. AB - We report the synthesis, electrochemistry, and photophysical properties of a new donor-acceptor-donor molecule in which the meso carbon atoms of two zinc porphyrin (POR) units are linked through ethynylene bridges to the 1,7-positions of a central perylene-3,4:9,10-bis(dicarboximide) (PDI). In contrast to previously studied systems incorporating POR and PDI groups, this alkyne-based derivative shows evidence of through-bond electronic coupling in the ground state; the new chromophore exhibits absorption features similar to those of its constituent parts as well as lower energy features (at wavelengths up to ca. 1000 nm), presumably arising from donor-acceptor interactions. Transient absorption measurements show that excitation at several visible and near-IR wavelengths results in the formation of an excited-state species with a lifetime of 290 ps in 1% (v/v) pyridine in toluene. The absorption spectrum of this species resembles the sum of the spectra for the chemically generated radical cation and radical anion of the chromophore. The chromophore shows moderate two-photon absorption cross sections (2000-7000 GM) at photon wavelengths close to the onset of its low energy one-photon absorption feature. PMID- 19791814 TI - Theoretical study of isomerization mechanisms in fluorinated fullerene derivatives. AB - Various candidate processes that can effect rearrangement of the shell of addends are being discussed for C(60)F(x) and C(60)(CF(3))(y) compounds. It is shown that isomerization of fluorofullerenes is catalyzed by other fullerene molecules or organic donors, while in trifluoromethylated fullerenes such catalysis is inefficient. These observations afford an explanation for important differences between fluorides and CF(3) derivatives of C(60) in distribution of products of their high-temperature syntheses. PMID- 19791816 TI - Density scaling and dynamic correlations in viscous liquids. AB - We use a recently proposed method (Berthier, L.; Biroli, G.; Bouchaud, J.P.; Cipelletti, L.; El Masri, D.; L'Hote, D.; Ladieu, F.; Pierno, M. Science 2005, 310, 1797) to obtain an approximation to the four-point dynamic correlation function from derivatives of the linear dielectric response function. For four liquids over a range of pressures, we find that the number of dynamically correlated molecules, N(c), depends essentially only on the magnitude of the relaxation time, tau(alpha), independently of temperature and pressure. This result is consistent with the invariance of the shape of the relaxation dispersion at constant tau(alpha) and the density scaling property of the relaxation times, and implies that N(c) also conforms to the same scaling behavior. For propylene carbonate and salol, N(c) becomes constant with approach to the Arrhenius regime, consistent with the value of unity expected for intermolecularly noncooperative relaxation. PMID- 19791817 TI - Reactive molecular dynamics simulations of shock through a single crystal of pentaerythritol tetranitrate. AB - Large-scale molecular dynamics simulations and the reactive force field ReaxFF were used to study shock-induced initiation in crystalline pentaerythritol tetranitrate (PETN). In the calculations, a PETN single crystal was impacted against a wall, driving a shockwave back through the crystal in the [100] direction. Two impact speeds (4 and 3 km/s) were used to compare strong and moderate shock behavior. The primary difference between the two shock strengths is the time required to exhibit the same qualitative behaviors with the lower impact speed lagging behind the faster impact speed. For both systems, the shock velocity exhibits an initial deceleration due to onset of endothermic reactions followed by acceleration due to the onset of exothermic reactions. At long times, the shock velocity reaches a steady value. After the initial deceleration period, peaks are observed in the profiles of the density and axial stress with the strongly shocked system having sharp peaks while the weakly shocked system developed broad peaks due to the slower shock velocity acceleration. The dominant initiation reactions in both systems lead to the formation of NO(2) with lesser quantities of NO(3) and formaldehyde also produced. PMID- 19791818 TI - Molecular dynamics simulations of a charged dendrimer in multivalent salt solution. AB - The multivalent salt dependent behaviors of a charged dendrimer in solution are investigated by molecular dynamics simulations with explicit free ions. We find that the charged dendrimers show a dense-core conformation together with the back folding of terminal monomers to the interior under all the conditions studied. We also observe an interesting ion exchange phenomenon, the replacement of the condensed monovalent counterions by multivalent salt ions due to a strong electrostatic attraction. Furthermore, we find that the dendrimer adopts an extended conformation in the absence of salt. Upon addition of salt, the dendrimer collapses as a result of a drop in the osmotic pressure inside the dendrimer. With an additional increase in the salt concentration, the dendrimer weakly swells due to an enhanced excluded volume effect of the adsorbed salt ions. The overcharge phenomenon also appears in our system. Consequently, our findings show a strong dependence of the conformation of charged dendrimers on salt concentration and give valuable insight into their behaviors at various salt concentrations at the molecular level. PMID- 19791819 TI - A new family of color-tunable light-emitting polymers with high quantum yields via the controlled oxidation of MEH-PPV. AB - We report a new method to generate families of organic fluorophores with any desirable emission wavelengths based upon the controlled oxidation of the light emitting conjugated polymer, poly[2-methoxy-5-(2'-ethylhexyloxy)-p phenylenevinylene] (MEH-PPV), with meta-chloroperbenzoic acid (m-CPBA). In this method, m-CPBA reacts with ethylene moieties along the MEH-PPV backbone to create conjugation breaks, which gives rise to a gradual and controllable change in the emission wavelength. By simply adjusting the reaction time, light-emitting polymers possessing emission wavelengths spanning a 470-555 nm wavelength range can be easily prepared. Significantly, fluorescence quantum yields (QYs) of the oxidized polymers were comparable to or greater than that of the pristine polymer, contrary to the products typically resulting from oxidation of MEH-PPV by dioxygen. This new method should provide a simple way to generate color tunable organic fluorophores with high QYs in a time- and cost-effective manner. PMID- 19791820 TI - Reversible collapse of insoluble monolayers: new insights on the influence of the anisotropic line tension of the domain. AB - In this paper, we study the collapse of a mixed insoluble monolayer formed by a cationic matrix, dioctadecyl-dimethylammonium bromide (DOMA), and a tetra-anionic porphyrin, tetrakis(4-sulfonatophenyl)porphyrin (TSPP), in a molar ratio TSPP/DOMA = 1:4. During the collapse of this system, we visualized the formation of circular domains consisting exclusively of trilayer, although the domains coalescence was not observed. The coexistence of trilayer and monolayer at the final step of the collapse cannot be interpreted exclusively in terms of a thermodynamic phase equilibrium, intervening as an additional factor the anisotropic line tension of the domain. A high line tension implies a high resistance to the domain deformation, and the anisotropy of the line tension implies the lack of coalescence between these domains, which has been experimentally observed by Brewster angle microscopy for us. Under these circumstances, the domains of collapsed material could enclose monolayer regions where the local surface pressure drops thus stopping the collapse process. The collapse of the TSPP/DOMA system is reversible, that is, the return of the three dimensional material to the monolayer fits into a simple kinetics according to the nucleation-growth-collision theory. As for the collapse, the reverse process is also affected by the line tension of the domains. This paper relates the high line tension and the anisotropic line tension of a given domains with the reversible nature of the collapse process. PMID- 19791822 TI - Study of the soret effect in hydrocarbon chain/aromatic compound mixtures. AB - We studied the thermal diffusion behavior of equimolar mixtures of hydrocarbon chains in cyclohexane, p-xylene, and o-xylene experimentally and by reverse nonequilibrium molecular dynamics. The hydrocarbon chains heptane, 2,3 dimethylpentane, 2,4-dimethylpentane, 2-ethyl-3-methyl butadiene, and 2,4 dimethylpentadiene-1,3 with the same number of carbon atoms were considered in order to conserve the mass contribution and to investigate the shape influence on the Soret coefficient. Compared to the experimental data, the simulation results show the same trend. With increasing degree of branching, the Soret coefficient becomes larger. The negative Soret coefficient of the hydrocarbon chains indicates the enrichment in the warm side. We were able to find an empirical correlation between the properties of the pure components and the Soret coeffcients of the considered mixtures. PMID- 19791821 TI - Electron paramagnetic resonance study of the surface hydration of Triton X-100 micelles in water with added monovalent alkali salts. AB - The hydrophobic spin probe 2,2,6,6-tetramethyl-piperidin-1-oxyl-4-yl octadecanoate (TEMPO-stearate) was used to study the hydration of the polar shell of Triton X-100 micelles as functions of the concentration of the electrolytes KCl, NaCl, and LiCl and temperature. It was shown that the hydration of the polar shell of the Triton X-100 micelle decreases with both increasing electrolyte concentration and increasing temperature. The effect of Li(+) on the hydration of the polar shell was found to be smaller than those of Na(+) and K(+), which have almost identical behavior. The effective water concentration decreases from 18.3 to 15.8 M for LiCl and from 18.3 to 13.9 M for NaCl and KCl when the concentration of the electrolyte in the solution increases from 0 to 2.5 M. The dehydration of the polar shell was correlated to the average value of the cation hydration number calculated from literature data; the greater the cation hydration number, the greater the dehydration for the same increase in electrolyte concentration. Also, it was shown that the cloud point is strongly correlated to the hydration of the polar shell. PMID- 19791823 TI - Translational and rotational diffusion of a small globular protein under crowded conditions. AB - Protein-protein interaction is the fundamental step of biological signal transduction. Interacting proteins find each other by diffusion. To gain insight into diffusion under the crowded conditions found in cells, we used nuclear magnetic resonance spectroscopy (NMR) to measure the effects of solvent additives on the translational and rotational diffusion of the 7.4 kDa globular protein, chymotrypsin inhibitor 2. The additives were glycerol and the macromolecular crowding agent, polyvinyl pyrrolidone (PVP). Both translational diffusion and rotational diffusion decrease with increasing solution viscosity. For glycerol, the decrease obeys the Stokes-Einstein and Stokes-Einstein Debye laws. Three types of deviation are observed for PVP: the decrease in diffusion with increased viscosity is less than predicted, this negative deviation is greater for rotational diffusion, and the negative deviation increases with increasing PVP molecular weight. We discuss our results in terms of other studies on the effects of macromolecules on globular protein diffusion. PMID- 19791824 TI - Do inhaled anticholinergics increase or decrease the risk of major cardiovascular events?: a synthesis of the available evidence. AB - There has been recent uncertainty about whether the inhaled anticholinergic agents ipratropium bromide and tiotropium bromide increase or decrease cardiovascular risk in the treatment of patients with chronic obstructive pulmonary disease (COPD). This article synthesizes the available data in order to understand the controversy. COPD is a common cause of hospitalizations and is a rapidly increasing cause of mortality worldwide. Despite the heavy burden of COPD related illness, the leading cause of hospitalization in COPD patients is cardiovascular disease. This link between COPD and cardiovascular disease is in part due to the fact that both diseases share common risk factors, such as tobacco smoking and advanced age. It is also hypothesized that systemic inflammation in COPD increases the risk for cardiac events such as myocardial infarction. Inhaled anticholinergics reduce COPD-related hospitalizations and respiratory deaths compared with placebo, and tiotropium bromide is more effective than ipratropium bromide. In randomized trials, patients receiving tiotropium bromide have lower discontinuation rates than those receiving placebo and, therefore, contribute more person-years to the analyses. In a recent large 4 year tiotropium bromide trial, the proportion of patients who died was similar in the tiotropium bromide and placebo groups, whereas the death rate per person years was lower with tiotropium bromide, indicating longer overall survival. There has been conflicting evidence concerning cardiovascular risk associated with inhaled anticholinergics. One meta-analysis found that the risk for major cardiovascular events was higher with anticholinergics compared with placebo or active comparator controls, whereas two subsequent meta-analyses that included new trial data found no difference in risk. In a recent pooled safety analysis, when incidence rates of events over time were evaluated, tiotropium bromide was associated with a lower rate of major cardiovascular events and cardiovascular deaths compared with placebo. This risk reduction was mainly because of a reduction in serious cardiac events such as myocardial infarction and congestive heart failure. In conclusion, inhaled anticholinergics, especially tiotropium bromide, reduce COPD-related hospitalizations and deaths, and may improve total survival over time. Many COPD patients have concomitant cardiovascular disease processes. Thus, trials may observe more cardiovascular events associated with anticholinergics than with placebo, but this differential is eliminated when evaluating the rate of events per person-years of exposure. New evidence indicates that tiotropium bromide may actually reduce the incidence of cardiovascular events and deaths over time. It is possible that the reduction in respiratory morbidity could improve functional status and reduce adverse cardiac outcomes over time. Further studies are needed to address this important issue. PMID- 19791825 TI - Newer biological agents in the treatment of rheumatoid arthritis: do the benefits outweigh the risks? AB - Recently, three new biological agents, rituximab, abatacept and tocilizumab, have become available for the treatment of rheumatoid arthritis (RA) in patients with active disease, who have not responded to at least one disease-modifying antirheumatic drug (DMARD). Rituximab is an anti-CD20 monoclonal antibody, abatacept modulates T-cell activation and tocilizumab is an interleukin-6 receptor antagonist. Clinical studies with these agents have demonstrated that they are effective in RA patients with moderate to active disease, who have not responded to treatment with at least one DMARD and/or tumour necrosis factor (TNF) inhibitor. Thus far, there is no convincing evidence to show that one of these three new drugs has a superior efficacy over the others or that they have other benefits compared with the TNF inhibitors. The use of rituximab, instead of another TNF inhibitor, might be an option in patients who have not responded to TNF blockade. Abatacept could also be considered, but this has not yet been formally tested. A practical advantage of tocilizumab is that it may be administered as a first-line biological agent. Adverse events, including (usually mild) infusion reactions, are common. There is a small increased risk of serious infections that appears to be similar to that with TNF inhibitors, although each drug may have its own particular risk profile. Thus far, there is no convincing evidence that the new biological agents are associated with an increased risk of malignancies. However, the number of patient-years studied is still rather limited and, hence, continuous postmarketing surveillance is necessary. Adequate studies directly comparing new biological agents with each other and with other biological agents, such as TNF inhibitors, are not available. Hence, no firm conclusions regarding the benefit-risk profile of these agents versus each other can be reached. However, the benefit for a given new biological agent currently appears to outweigh the risk for an individual RA patient with active disease, despite earlier drug treatment. PMID- 19791827 TI - The management of individuals with bipolar disorder: a review of the evidence and its integration into clinical practice. AB - Bipolar disorder is a common, debilitating, chronic illness that emerges early in life and has serious consequences such as long-term unemployment and suicide. It confers considerable functional disability to the individual, their family and society as a whole and yet it is often undetected, misdiagnosed and treated poorly. In the past decade, many new treatment strategies have been trialled in the management of bipolar disorder with variable success. The emerging evidence, for pharmacological agents in particular, is promising but when considered alone does not directly translate to real-world clinical populations of bipolar disorder. Data from drug trials are largely based on findings that identify differences between groups determined in a time-limited manner, whereas clinical management concerns the treatment of individuals over the life-long course of the illness. Considering the findings in the context of the individual and their particular needs perhaps best bridges the gap between the evidence from research studies and their application in clinical practice. Specifically, only lithium and valproate have moderate or strong evidence for use across all three phases of bipolar disorder. Anticonvulsants, such as lamotrigine, have strong evidence in maintenance; whereas antipsychotics largely have strong evidence in acute mania, with the exception of quetiapine, which has strong evidence in bipolar depression. Maintenance data for antipsychotics is emerging but at present remains weak. Combinations have strong evidence in acute phases of illness but maintenance data is urgently needed. Conventional antidepressants only have weak evidence in bipolar depression and do not have a role in maintenance therapy. Therefore, this paper summarizes the efficacy data for treating bipolar disorder and also applies clinical considerations to these data when formulating recommendations for the management of bipolar disorder. PMID- 19791826 TI - African American kidney transplantation survival: the ability of immunosuppression to balance the inherent pre- and post-transplant risk factors. AB - Among organ transplant recipients, the African American population historically has received special attention. This is because secondary to their disposition to certain disease states, for example hypertension, an African American patient has a propensity to reach end-stage renal disease and require renal replacement earlier than a Caucasian patient. Regardless of the initiative to replace dialysis therapy with organ transplantation, the African American patient has many barriers to kidney transplantation, thus extending their time on dialysis and waiting time on the organ transplant list. These factors are among the many negative causes of decreased kidney graft survival, realized before kidney transplantation. Unfortunately, once the African American recipient receives a kidney graft, the literature documents that many post-transplant barriers exist which limit successful outcomes. The primary post-transplant barrier relates to designing proper immunosuppression protocols. The difficulty in designing protocols revolves around (i) altered genetic metabolism/lower absorption, (ii) increased immuno-active cytokines and (iii) detrimental effects of noncompliance. Based on the literature, dosing of immunosuppression must be aggressive and requires a diligent practitioner. Research has indicated that, despite some success with proven levels of immunosuppression, the African American recipient usually requires a higher 'dose per weight' regimen. However, even with aggressive immunosuppressant dosing, African Americans still have worse outcomes than Caucasian recipients. Additionally, many of the targeted sites of action that immunosuppression exerts its effects on have been found to be amplified in the African American population. Finally, noncompliance is the most discouraging inhibitor of long-term success in organ transplantation. The consequences of noncompliance are biased by ethnicity and affect the African American population more severely. All of these factors are discussed further in this review in the hope of identifying an ideal healthcare model for caring for the African American transplant recipient, from diagnosing chronic kidney disease through to successful kidney graft outcomes. An indepth review of the literature is described and organized in a fashion that highlights all of the issues affecting success in African Americans. The compilation of the literature in this review will enable the reader to get closer to understanding the caveats of kidney transplantation in the African American patient, but falls short of delivering an actual 'equation' for post-transplant care in an African American kidney recipient. PMID- 19791828 TI - Saxagliptin. AB - Saxagliptin and its active metabolite M2 are dipeptidyl peptidase-4 inhibitors that improve glycaemic control by preventing the inactivation of the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide. This increases GLP-1 levels, stimulates insulin secretion and reduces postprandial glucagon and glucose levels. In well designed, 24-week trials in treatment-naive patients with type 2 diabetes mellitus, monotherapy with oral saxagliptin 2.5 or 5 mg once daily significantly improved glycaemic control, as measured by mean glycosylated haemoglobin (HbA(1c)) levels, relative to placebo. In large, well designed, 24-week trials, combination therapy with saxagliptin 5 mg once daily plus metformin significantly improved HbA(1c) levels relative to single-agent saxagliptin or metformin in treatment-naive patients; in treatment-experienced patients with inadequate glycaemic control, the addition of saxagliptin 2.5 or 5 mg once daily to metformin, glyburide or a thiazolidinedione, significantly improved HbA(1c) levels relative to continued use of existing monotherapy. Saxagliptin as monotherapy or in combination with other oral antihyperglycaemics was generally well tolerated, with most adverse events being of mild to moderate severity. In clinical trials, the incidence of hypoglycaemic events in patients receiving saxagliptin was generally similar to that in patients receiving placebo or other oral antihyperglycaemic agents. Saxagliptin therapy was not associated with an increased risk of cardiovascular events according to pooled data from eight clinical trials. Saxagliptin generally had a weight-neutral effect. PMID- 19791829 TI - Everolimus: in advanced renal cell carcinoma. AB - Everolimus is an orally administered, targeted therapy indicated for the treatment of advanced renal cell carcinoma. It inhibits the mammalian target of rapamycin, an integral component of multiple pathways involved in cell growth and proliferation. Median progression-free survival was significantly longer with everolimus 10 mg once daily than with placebo in both second interim (4.0 vs 1.9 months) and updated (4.9 vs 1.9 months) analyses of a randomized, double-blind, placebo-controlled, multicentre, phase III trial in patients with metastatic renal cell carcinoma that had progressed while receiving sunitinib and/or sorafenib treatment. At the second interim analysis, median overall survival was 8.8 months for placebo recipients; at this analysis, overall survival had not yet been reached for everolimus recipients. With regard to objective response at the second interim analysis, 64% of everolimus and 32% of placebo recipients had either a partial response (1% and 0%) or stable disease (63% and 32%). The tolerability profile of everolimus was largely manageable in the phase III trial, with most treatment-related adverse events being of grade 1 or 2 severity. PMID- 19791831 TI - Lidocaine 5% medicated plaster: a review of its use in postherpetic neuralgia. AB - The lidocaine 5% medicated plaster (Versatis) is a topical analgesic, indicated for the symptomatic relief of neuropathic pain associated with previous herpes zoster infection (i.e. postherpetic neuralgia [PHN]) in adults. The lidocaine 5% medicated plaster has a direct local action with low systemic exposure and is effective in the treatment of patients with PHN. Limited data, from a study in patients with PHN or painful diabetic neuropathy, show that short-term treatment with lidocaine 5% medicated plaster was associated with numerically higher pain intensity response rates than pregabalin in the PHN subgroup. The efficacy of the lidocaine 5% medicated plaster was maintained in the longer term. Additionally, the lidocaine 5% medicated plaster was well tolerated, with application site reactions being the most commonly reported drug-related adverse events; drug related adverse events were few, and most were of mild to moderate severity. Due to its low systemic exposure, the drug may be of particular advantage in the treatment of patients with a low tolerance for adverse events, or who are receiving concomitant drugs that may otherwise result in drug interactions. Thus, the lidocaine 5% medicated plaster is a useful first-line option for the treatment of patients with PHN. PMID- 19791832 TI - The role of the systemic inflammatory response as a biomarker in immunotherapy for renal cell cancer. AB - Treatment of metastatic renal cell cancer (RCC) has entered a new paradigm since the development of tyrosine kinase inhibitors such as sorafenib (Nexavar) and sunitinib (Sutent). Despite these advances, immunotherapy, the traditional mainstay of treatment, is not yet obsolete. Immunotherapy offers the possibility of a complete response for a small number of patients with favorable disease factors. However, immunotherapy is a toxic treatment, with a significant impact on quality of life in comparison with a relatively modest survival advantage for most. As such, the search for a biomarker to select patients for immunotherapy and to monitor their progress still remains a clinical and research goal for those involved in treating patients with metastatic renal cancer. At present, performance status and a number of prognostic scores incorporating performance status and laboratory variables are the most widely used indicators of suitability for immunotherapy. More recently, the histological expression of carbonic anhydrase IX has been reported as a biomarker of response to interleukin (IL)-2 immunotherapy. C-reactive protein (CRP) is an acute-phase protein synthesized as part of the systemic inflammatory response. It is readily measured by standardized assays and is reliable, without variability for age, sex, or bodyweight. The presence of an elevated CRP is a prognostic indicator in a number of solid tumors, both in localized and metastatic disease. In advanced renal cancer, the Glasgow Prognostic Score, which is based on elevated CRP and low albumin, has shown prognostic value. CRP is also superior to the widely used performance status in predicting survival for patients treated with either interferon (IFN)-alpha or IL-2. As such, CRP is an increasingly exciting biomarker for predicting outcomes in immunotherapy. Currently, no other biomarker has been applicable for use in both IFNalpha and IL-2 immunotherapy. More recently, changes in CRP kinetics have shown promise as a predictive tool, although more research is required. Use of CRP as a biomarker can improve stratification of patients with metastatic renal cancer, allowing the patients less likely to benefit from immunotherapy to avoid a potentially toxic treatment. The ongoing selection of patients based on biomarkers should enable continued research on the optimum dose and timing of immunotherapy while managing toxicity and optimizing outcomes. PMID- 19791830 TI - Lapatinib: a review of its use in the treatment of HER2-overexpressing, trastuzumab-refractory, advanced or metastatic breast cancer. AB - Lapatinib (Tyverb, Tykerb) is an orally active, small molecule, reversible, dual tyrosine kinase inhibitor of human epidermal growth factor receptor type 1 (HER1) and type 2 (HER2). In the EU, lapatinib in combination with capecitabine is indicated for the treatment of women with HER2-overexpressing, advanced or metastatic breast cancer that has progressed after treatment with regimens that include anthracyclines, taxanes and, in the metastatic setting, trastuzumab. The orally administered combination of lapatinib and capecitabine was a more effective treatment than capecitabine alone, and was a generally well tolerated, conveniently administered combination for women with trastuzumab-refractory, HER2 positive advanced or metastatic breast cancer in a clinical trial. Lapatinib combined with capecitabine provides an effective therapeutic option for a group of patients who currently have few treatment choices. PMID- 19791833 TI - Melanoma biomarkers: current status and utility in diagnosis, prognosis, and response to therapy. AB - Melanoma is the most devastating form of skin cancer and represents a leading cause of cancer death, particularly in young adults. As even relatively small melanomas can readily metastasize, accurate staging of progression is critical. Diagnosis is typically made on the basis of histopathologic criteria; with tumor thickness (Breslow), invasion level (Clark), ulceration, and the extent of lymph node involvement being important prognostic indicators. However, histologic criteria alone cannot diagnose all melanomas and there are often problems in distinguishing subsets of benign nevi from melanoma. There also exists a group of patients with thin primary melanomas for whom surgery should be curative but who ultimately go on to develop metastases. Therefore, there is an urgent need to develop molecular biomarkers that identify melanoma patients with high-risk primary lesions to facilitate greater surveillance and possible adjuvant therapy. The advent of large-scale genomic profiling of melanoma is revealing considerable heterogeneity, suggesting that melanomas could be subgrouped according to their patterns of oncogenic mutation and gene expression. It is hoped that this subgrouping will allow for the personalization of melanoma therapy using novel molecularly targeted agents. Much effort is now geared toward defining the genetic markers that may predict response to targeted therapy agents as well as identifying pharmacodynamic markers of therapy response. In this review, we discuss the utility of melanoma biomarkers for diagnosis and prognosis and suggest how novel molecular signatures can help guide both melanoma diagnosis and therapy selection. PMID- 19791834 TI - Clinical application of proteomics in ovarian cancer prevention and treatment. AB - As recent scientific findings using whole-genome mutational scanning technologies have concluded, cancer is a protein pathway disease, which is often diagnosed too late, when the success of therapeutic modalities is very limited. Proteomics has been proposed as the field that can help overcome this limitation and usher in a new era of molecular investigation for early diagnosis and classification of tumors. Proteomics applications in cancer research encompass two general aspects: (i) the study and characterization of protein production; and (ii) the definition of protein function. The first aims to identify qualitative or quantitative differences in the proteome that can help differentiate between healthy and diseased states or achieve a better clinical classification of diseases. The second studies the complexity of protein interactions and their activation states, mapping the network of signaling pathways within and outside the cells. The challenges in translating the findings of proteomics research into clinical practice are numerous. Lack of reproducibility, variable availability of samples and the bias associated with their selection and handling, the need for large, prospective validation trials, and finally the strict requirement for a very high level of clinical sensitivity and specificity are some of the hurdles that need to be overcome to achieve early detection and treatment. Nevertheless, proteomics is a field in rapid progression that has already developed beyond initial criticism and is making its way toward important applications and discoveries. Specifically, there has been an increasing number of reports on the potential clinical application of proteomics for early detection as well as risk assessment and management of ovarian cancer. This disease is the leading cause of death from gynecologic malignancies in the US, with poor prognosis resulting from the lack of reliable, sensitive screening tests and the limited understanding of the mechanisms of chemoresistance and relapse. In the future, serum proteomics applications in the gynecologic oncology field could identify blood-based biomarkers that are predictors of disease presence or progression, and tissue proteomics could help define the optimal targeted agent and effective dose for each patient's disease. These advances will allow improved monitoring of therapy response and disease relapse, and aid in the engineering of new drugs and strategies to circumvent resistance mechanisms while avoiding the adverse effects of traditional chemotherapy. PMID- 19791836 TI - Polymorphism of the micro-opioid receptor gene (OPRM1 118A>G) affects fentanyl induced analgesia during anesthesia and recovery. AB - BACKGROUND: There is much variation in the response of both individuals and different ethnic populations to opioids, with genetic differences being responsible for interindividual variation. The micro-opioid receptor single nucleotide polymorphism (rs number 1799971) at nucleotide position 118 (OPRM1 118A>G) affects the analgesic response to opioids. OBJECTIVE: This study aimed to investigate the association between the OPRM1 118A>G polymorphism and the effects of fentanyl-induced analgesia, respiratory depression, and anesthetic recovery responses in a population of Han Chinese patients. STUDY DESIGN: The study was a case series in a hospital setting, with 1 year of study and 1 year of follow-up. A total of 189 patients (92 males and 97 females; American Society of Anesthesiologists Physical Status I or II, Glasgow Coma Scale = 15) who were scheduled for laparoscopic abdominal surgery received intravenous midazolam (Versed) 0.08-0.01 mg/kg and fentanyl (Duragesic) 5.0 microg/kg. The main outcome measure was the degree of postoperative pain, as assessed using the Visual Analog Scale (VAS). VAS scores were recorded 5, 15, 30, 45, and 60 minutes after a fentanyl bolus injection in the post-anesthesia care unit (PACU). The minute expiratory volume, end-tidal carbon dioxide concentration (EtCO(2)) and respiratory rate (RR) were measured continuously. The incidence of fentanyl induced respiratory depression (RR <8/min and EtCO(2) >45 mmHg) was recorded at its appearance and treated with respiratory assistance. Blood gas analysis was done 15, 30, 45, and 60 minutes after extubation. These parameters were correlated with genotyping results of genomic DNA extracted from whole blood. RESULTS: Patients with the OPRM1 118 AG or GG genotypes had significantly higher VAS pain scores 15 and 30 minutes after a fentanyl bolus injection in the PACU than AA genotype patients (p < 0.05). A small but statistically significant difference was observed between the 118 AA and 118 AG/GG genotypes with regard to the carbon dioxide arterial pressure (PaCO(2)) at 15 and 30 minutes from the fentanyl bolus injection after extubation (p < 0.05); however, no clinically significant difference in the frequency of respiratory depression was seen. Homozygous 118 GG genotype patients had a significantly shorter time to awakening (p = 0.018) and extubation (p = 0.024) than patients with the 118 AA genotype. When the 118 GG and 118 AG genotypes were combined for analysis, a significantly shorter time to awakening (p = 0.011) and extubation (p = 0.010), compared with the 118 AA genotype, was also seen. CONCLUSION: The OPRM1 118A>G polymorphism lessens the analgesic response to fentanyl and the time to awakening and extubation but has no clinically significant effect on the incidence of respiratory depression. PMID- 19791835 TI - In vitro testing for the diagnosis of anticonvulsant hypersensitivity syndrome: a systematic review. AB - Anticonvulsant hypersensitivity syndrome (AHS) is a rare and potentially fatal reaction that develops in susceptible patients following exposure to certain drugs, including aromatic anticonvulsants. Because of its ill-defined clinical picture and resemblance to other diseases, the diagnosis of AHS is often difficult and requires a safe and reliable diagnostic test. Other than systemic rechallenge, which is not always ethically permissible and has its own limitations, no reliable diagnostic test is available for this type of disorder. This systematic review attempts to evaluate the usefulness of the available in vitro tests in the diagnosis of AHS - namely, the lymphocyte transformation test (LTT) and the lymphocyte toxicity assay (LTA) - and to examine the different technical aspects of these tests that may contribute to their performance. We included studies in which aromatic anticonvulsant drugs were the likely causes of the hypersensitivity reaction and either the LTT or the LTA was used to aid the diagnosis of AHS. Analysis of original publications from 1950 to the last week of March 2009 and cited in PubMed, MEDLINE and EMBASE has revealed that there are numerous factors affecting the final result of the test, including the following: the timing of the test after exposure; the clinical manifestation of the reactions; the specific drug; and the test procedure and read-out system. In vitro diagnostic tests have the advantage over in vivo tests of being safe to use; however, in vitro tests for the diagnosis of AHS are not well standardized and their sensitivity and specificity are not yet determined. From the reviewed literature, the sensitivity of the LTT and the LTA seem to be around 70% and 90%, respectively, and the positive and negative predictive values of the tests in highly imputable cases are quite high. However, the lack of a gold-standard diagnostic test to prove drug culpability, along with the paucity of large-scale studies, precludes accurate determination of the epidemiological characteristics of these tests. It appears that without further understanding of the mechanisms underlying the pathophysiology of AHS, and how specific drugs and metabolites differentially affect these mechanisms, the development of more reliable tools for AHS diagnosis will be compromised. Consequently, in the absence of further research, the predictability of these tests will remain questionable and they are unlikely to be utilized on a large scale. PMID- 19791838 TI - Effect of antianginal drugs in stable angina on predicted mortality risk after surviving a myocardial infarction: a preliminary study (METRO). AB - BACKGROUND: Although antianginal drugs are used over several months and through to years in stable angina, there is scant evidence regarding their influence on outcomes. The METRO (ManagEment of angina: a reTRospective cOhort) study sought to assess the independent effect of using these drugs on subsequent mortality risk in patients with stable angina. METHODS: Consecutive patients with stable angina, receiving at least one antianginal drug (nitrates, beta-adrenoceptor antagonists, calcium channel antagonists, trimetazidine, or nicorandil), were selected if they were discharged alive from an intensive care unit following a myocardial infarction (MI). Their case-record data were used in a multivariate logistic regression model to examine the independent association of antianginal drug use prior to the MI with predicted post-discharge, 6-month, all-cause mortality risk. RESULTS: In 353 patients, of whom 287 (81.3%) were men, the mean (+/- SD) age was 55 (+/- 10.2) years and duration of treated stable angina was 27.2 (+/- 24.8) months. The odds ratios (95% CI) of 6-month, all-cause mortality after surviving an MI were: for treatment that included a beta-adrenoceptor antagonist, 0.63 (0.26, 1.52; p = 0.309); a calcium channel antagonist, 0.76 (0.12, 2.89; p = 0.638); a nitrate, 0.52 (0.26, 1.05; p = 0.070); nicorandil, 0.62 (0.29, 1.33; p = 0.221); and trimetazidine, 0.36 (0.15, 0.86; p = 0.022). CONCLUSION: The inclusion of trimetazidine in the antianginal treatment of stable angina is independently associated with a significant reduction in mortality after surviving an MI. This suggests that combining a metabolic agent with drugs that modulate oxygen supply and demand, early in the management of stable angina, may confer a survival benefit. PMID- 19791837 TI - The ADVANCE trial: clarifying the role of perindopril/indapamide fixed-dose combination in the reduction of cardiovascular and renal events in patients with diabetes mellitus. AB - Patients with type 2 diabetes mellitus exhibit a marked increase in cardiovascular and renal risk. A number of interventional trials have shown that these patients benefit greatly from aggressive BP lowering, especially when the drug regimen comprises an inhibitor of the renin-angiotensin system. The results of the placebo-controlled ADVANCE (Action in Diabetes and Vascular disease: PreterAx and DiamicroN MR Controlled Evaluation) trial, conducted in patients with type 2 diabetes, are exemplary in this respect. The systematic use of a fixed-dose combination containing the ACE inhibitor perindopril and the diuretic indapamide afforded substantial protection against cardiovascular mortality and myocardial infarction, while providing important renoprotection, reducing the development of micro- and macroalbuminuria, and allowing regression of nephropathy. The beneficial effects were obtained regardless of baseline BP and whether or not the patients were receiving antihypertensive therapy. PMID- 19791839 TI - Are high-risk hypertensive patients being prescribed concomitant statin therapy?: a retrospective cohort study. AB - BACKGROUND: Treatment guidelines for dyslipidemic patients have focused on lipid levels and risk assessments. However, normolipidemic patients who have multiple risk factors for cardiovascular disease may also benefit from HMG-CoA reductase inhibitor (statin) therapy. OBJECTIVE: We examined the frequency of statin prescriptions in patients initiating antihypertensive drug treatment in a US managed-care setting. STUDY DESIGN AND PATIENT: This retrospective cohort study used the PharMetrics' Patient-Centric Database to identify enrollees initiating antihypertensive treatment (September 2001 to February 2004). Patients newly treated with antihypertensives and with various levels of coronary heart disease (CHD) risk (including dyslipidemia, established CHD, type 2 diabetes mellitus, and no CHD but three or more cardiovascular risk factors) were included in the study. MAIN OUTCOME MEASURE: Cumulative probability of receiving statin therapy each month after antihypertensive initiation. Multivariable logistic regression was used to identify factors associated with receiving concomitant statin therapy. RESULTS: Of 142 389 patients (mean age 51.7 years) newly treated with antihypertensives, 32 056 (22.5%) were prescribed statins within 1 year. The cumulative probability of being prescribed a statin increased with increasing numbers of CHD risk factors, irrespective of dyslipidemia status. After adjusting for age, sex, and other potential predictors, patients were more likely to receive statin therapy if they had a history of dyslipidemia (adjusted odds ratio [AOR] 5.68 [95% CI 5.52, 5.85]), established CHD/congestive heart failure (AOR 3.39 [95% CI 3.16, 3.63]), or three or more additional cardiovascular risk factors but no CHD (AOR 3.01 [95% CI 2.74, 3.30]). CONCLUSION: Among patients beginning antihypertensive treatment, those with established CHD or CHD risk factors were more likely to receive statins, but a substantial fraction did not fill any statin prescription. The increased use of statin therapy could benefit many hypertensive patients with additional CHD risk factors. PMID- 19791840 TI - Amlodipine/valsartan single-pill combination: a review of its use in the management of hypertension. AB - Single-pill combinations of the dihydropyridine calcium channel blocker (CCB) amlodipine and the angiotensin II receptor blocker valsartan (amlodipine/valsartan) [Exforge] are available in the US for the treatment of patients with hypertension. Prescribing information for amlodipine/valsartan states that it may be used in patients whose BP is not adequately controlled on either component monotherapy, and as initial therapy in patients who are likely to need multiple drugs to achieve their BP goals. The antihypertensive efficacy of combinations of once-daily oral amlodipine and valsartan (administered as separate agents or as amlodipine/valsartan) has been demonstrated in several large, randomized, double-blind clinical trials of 8-16 weeks' duration; BP reductions were maintained for approximately 1 year in open-label extensions of some of these studies. Combination therapy was more effective than amlodipine or valsartan monotherapy in reducing BP in patients with mild to moderate hypertension, and more effective than amlodipine monotherapy in reducing BP in patients with moderate to severe (stage 2) hypertension. In addition, switching to amlodipine plus valsartan was more effective than continuation of monotherapy in reducing BP in patients with hypertension uncontrolled on amlodipine or valsartan monotherapy. The BP-lowering effect of amlodipine plus valsartan was not significantly different from that of other combinations of antihypertensive drugs, including amlodipine plus atenolol, lisinopril plus hydrochlorothiazide (HCTZ), and irbesartan plus HCTZ. Combination therapy with amlodipine and valsartan was generally well tolerated. Based on these results, amlodipine/valsartan offers a rational and convenient treatment option for the management of patients with hypertension, the majority of whom will require at least two drugs to reach target BP levels recommended in US (and international) guidelines. PMID- 19791842 TI - Cavity ring-down ellipsometry. AB - We demonstrate the enhancement of ellipsometric measurements by multiple reflections of a polarized light pulse on a highly reflective target surface, using an optical cavity. The principle is demonstrated by measuring the adsorbed amount of a molecular vapor (fenchone) onto the ring-cavity mirrors. A phase shift sensitivity of about 10(-2) degrees in a single laser pulse is achieved in 1 micros. Further improvements are discussed that should allow sensitivities of at least 10(-4) degrees , surpassing current commercial ellipsometers, but also surpassing their time resolution by several orders of magnitude, allowing the uses of sensitive ellipsometry to be expanded to include the study of fast surface phenomena with submicrosecond resolution. PMID- 19791841 TI - Bosentan: a review of its use in the management of mildly symptomatic pulmonary arterial hypertension. AB - Bosentan (Tracleer) is an orally administered dual endothelin-1 (ET-1) receptor antagonist approved for use in patients with WHO class II (mildly symptomatic) pulmonary arterial hypertension (PAH). Oral bosentan therapy was beneficial and generally well tolerated in patients with mildly symptomatic PAH. In a well designed, placebo-controlled trial in adolescents and adults with mildly symptomatic PAH, pulmonary vascular resistance was significantly reduced with bosentan relative to placebo, but the 6-minute walk distance did not increase significantly. Similarly, pediatric patients (most of whom had mildly symptomatic PAH) in a small uncontrolled trial experienced some improvement in hemodynamic variables with bosentan, but did not experience a significant increase in exercise capacity. Adverse events associated with bosentan were consistent with those seen in other indications, with major concerns being the potential for teratogenicity and hepatotoxicity, for which regular liver function monitoring is recommended. Overall, considering the progressive nature of PAH, bosentan extends the treatment options available to patients with mildly symptomatic PAH. PMID- 19791843 TI - Strong correlations via constrained-pairing mean-field theory. AB - We present a mean-field approach for accurately describing strong correlations via electron number fluctuations and pairings constrained to an active space. Electron number conservation is broken and correct only on average, but both spin and spatial symmetries are preserved. Optimized natural orbitals and occupations are determined by diagonalization of a mean-field Hamiltonian. This constrained pairing mean-field theory (CPMFT) yields a two-particle density matrix ansatz that exclusively describes strong correlations. We demonstrate CPMFT accuracy with applications to the metal-insulator transition of large hydrogen clusters and molecular dissociation curves. PMID- 19791844 TI - Al13H-: hydrogen atom site selectivity and the shell model. AB - Using a combination of anion photoelectron spectroscopy and density functional theory calculations, we explored the influence of the shell model on H atom site selectivity in Al(13)H(-). Photoelectron spectra revealed that Al(13)H(-) has two anionic isomers and for both of them provided vertical detachment energies (VDEs). Theoretical calculations found that the structures of these anionic isomers differ by the position of the hydrogen atom. In one, the hydrogen atom is radially bonded, while in the other, hydrogen caps a triangular face. VDEs for both anionic isomers as well as other energetic relationships were also calculated. Comparison of the measured versus calculated VDE values permitted the structure of each isomer to be confirmed and correlated with its observed photoelectron spectrum. Shell model, electron-counting considerations correctly predicted the relative stabilities of the anionic isomers and identified the stable structure of neutral Al(13)H. PMID- 19791845 TI - Combined temperature-programmed reaction and in situ x-ray scattering studies of size-selected silver clusters under realistic reaction conditions in the epoxidation of propene. AB - The catalytic activity and dynamical shape changes in size-selected nanoclusters at work are studied under realistic reaction conditions by using a combination of simultaneous temperature-programmed reaction with in situ grazing-incidence small angle x-ray scattering. This approach allows drawing a direct correlation between nanocatalyst size, composition, shape, and its function under realistic reaction conditions for the first time. The approach is illustrated in a chemical industry highly relevant selective partial oxidation of propene on a monodisperse silver nanocatalyst. The shape of the catalyst undergoes rapid change already at room temperature upon the exposure to the reactants, followed by a complex evolution of shape with increasing temperature. Acrolein formation is observed around 50 degrees C while the formation of the propylene oxide exhibits a sharp onset at 80 degrees C and is leveling off at 150 degrees C. At lower temperatures acrolein is produced preferentially to propylene oxide; at temperatures above 100 degrees C propylene oxide is favored. PMID- 19791847 TI - Robust and efficient density fitting. AB - In this paper we propose an iterative method for solving the inhomogeneous systems of linear equations associated with density fitting. The proposed method is based on a version of the conjugate gradient method that makes use of automatically built quasi-Newton preconditioners. The paper gives a detailed description of a parallel implementation of the new method. The computational performance of the new algorithms is analyzed by benchmark calculations on systems with up to about 35,000 auxiliary functions. Comparisons with the standard, direct approach show no significant differences in the computed solutions. PMID- 19791846 TI - Progress and challenges in the automated construction of Markov state models for full protein systems. AB - Markov state models (MSMs) are a powerful tool for modeling both the thermodynamics and kinetics of molecular systems. In addition, they provide a rigorous means to combine information from multiple sources into a single model and to direct future simulations/experiments to minimize uncertainties in the model. However, constructing MSMs is challenging because doing so requires decomposing the extremely high dimensional and rugged free energy landscape of a molecular system into long-lived states, also called metastable states. Thus, their application has generally required significant chemical intuition and hand tuning. To address this limitation we have developed a toolkit for automating the construction of MSMs called MSMBUILDER (available at https://simtk.org/home/msmbuilder). In this work we demonstrate the application of MSMBUILDER to the villin headpiece (HP-35 NleNle), one of the smallest and fastest folding proteins. We show that the resulting MSM captures both the thermodynamics and kinetics of the original molecular dynamics of the system. As a first step toward experimental validation of our methodology we show that our model provides accurate structure prediction and that the longest timescale events correspond to folding. PMID- 19791848 TI - Excited states of methylene from quantum Monte Carlo. AB - The ground and lowest three adiabatic excited states of methylene are computed using the variational Monte Carlo and diffusion Monte Carlo (DMC) methods using progressively larger Jastrow-Slater multideterminant complete active space (CAS) wave functions. The highest of these states has the same symmetry, (1)A(1), as the first excited state. The DMC excitation energies obtained using any of the CAS wave functions are in excellent agreement with experiment, but single determinant wave functions do not yield accurate DMC energies of the states of (1)A(1) symmetry, indicating that it is important to include in the wave function Slater determinants that describe static (strong) correlation. Excitation energies obtained using recently proposed pseudopotentials [Burkatzki et al., J. Chem. Phys. 126, 234105 (2007)] differ from the all-electron excitation energies by at most 0.04 eV. PMID- 19791849 TI - Analytic evaluation of the nonadiabatic coupling vector between excited states using equation-of-motion coupled-cluster theory. AB - Theory and implementation for evaluation of the nonadiabatic coupling vector between excited electronic states described by equation-of-motion excitation energy coupled-cluster singles and doubles (EOMEE-CCSD) method is presented. Problems arising from the non-Hermitian nature of the theory are discussed in detail. The performance of the new approach is demonstrated by the nice agreement of the nonadiabatic coupling curves for LiH obtained at the EOMEE-CCSD and MR CISD levels. Using the tools developed we also present a computational procedure to evaluate the interstate coupling constants used in vibronic coupling theories. As an application of this part of the implementation we present simulation of the electronic absorption spectrum of the pyrazine molecule within the linear vibronic coupling model. PMID- 19791850 TI - A systematic analysis of the structure and (hyper)polarizability of donor acceptor substituted polyacetylenes using a Coulomb-attenuating density functional. AB - In this paper we perform a systematic investigation on all-trans polyacetylene chains of different lengths, end-capped with moieties of different donor or acceptor natures and different strengths, to infer useful structure/property relationship rules and behavioral patterns. The values for bond length alternation (BLA), longitudinal polarizability, and first and second hyperpolarizabilities have been computed with the Coulomb-attenuating density function (CAM-B3LYP), using response theory. A comparison of the relative effect that each end-capping combination contributes to BLA, linear, and nonlinear optical coefficients has been performed. This results in useful insights and general rules to ad hoc tailoring the molecular response for a specific characteristic. PMID- 19791852 TI - Time correlation functions via forward-backward quantum dynamics using Hamilton's law of varying action. AB - We introduce a stable numerical procedure for solving Bohm's equations of motion to compute quantum trajectories in the forward-backward quantum dynamics (FBQD) formulation of zero-temperature time correlation functions. Rather than integrating the differential equations forward in time, our method is based on a series expansion of the quantum trajectory, exploiting Hamilton's law of varying action to determine the expansion coefficients. Because in FBQD the quantum trajectories generally are smooth and the quantum potential is well behaved, our method allows accurate determination of time correlation functions in strongly anharmonic bound systems over several oscillation periods. PMID- 19791851 TI - Penetrable-square-well fluids: analytical study and Monte Carlo simulations. AB - We study structural and thermophysical properties of a one-dimensional classical fluid made of penetrable spheres interacting via an attractive square-well potential. Penetrability of the spheres is enforced by reducing from infinite to finite the repulsive energy barrier in the pair potentials As a consequence, an exact analytical solution is lacking even in one dimension. Building upon previous exact analytical work in the low-density limit [A. Santos, R. Fantoni, and A. Giacometti, Phys. Rev. E 77, 051206 (2008)], we propose an approximate theory valid at any density and in the low-penetrable regime. By comparison with specialized Monte Carlo simulations and integral equation theories, we assess the regime of validity of the theory. We investigate the degree of inconsistency among the various routes to thermodynamics and explore the possibility of a fluid fluid transition. Finally we locate the dependence of the Fisher-Widom line on the degree of penetrability. Our results constitute the first systematic study of penetrable spheres with attractions as a prototype model for soft systems. PMID- 19791853 TI - Effective-mode representation of non-Markovian dynamics: a hierarchical approximation of the spectral density. II. Application to environment-induced nonadiabatic dynamics. AB - The non-Markovian approach developed in the companion paper [Hughes et al., J. Chem. Phys. 131, 024109 (2009)], which employs a hierarchical series of approximate spectral densities, is extended to the treatment of nonadiabatic dynamics of coupled electronic states. We focus on a spin-boson-type Hamiltonian including a subset of system vibrational modes which are treated without any approximation, while a set of bath modes is transformed to a chain of effective modes and treated in a reduced-dimensional space. Only the first member of the chain is coupled to the electronic subsystem. The chain construction can be truncated at successive orders and is terminated by a Markovian closure acting on the end of the chain. From this Mori-type construction, a hierarchy of approximate spectral densities is obtained which approach the true bath spectral density with increasing accuracy. Applications are presented for the dynamics of a vibronic subsystem comprising a high-frequency mode and interacting with a low frequency bath. The bath is shown to have a striking effect on the nonadiabatic dynamics, which can be rationalized in the effective-mode picture. A reduced two dimensional subspace is constructed which accounts for the essential features of the nonadiabatic process induced by the effective environmental mode. Electronic coherence is found to be preserved on the shortest time scale determined by the effective mode, while decoherence sets in on a longer time scale. Numerical simulations are carried out using either an explicit wave function representation of the system and overall bath or else an explicit representation of the system and effective-mode part in conjunction with a Caldeira-Leggett master equation. PMID- 19791854 TI - Model core potentials for studies of scalar-relativistic effects and spin-orbit coupling at Douglas-Kroll level. I. Theory and applications to Pb and Bi. AB - A theory of model core potentials that can treat spin-orbit-coupling (SOC) effects at the level of Douglas-Kroll formalism has been developed. By storing the damping effect of kinematic operator in the Douglas-Kroll spin-orbit operator into an additional set of basis set contraction coefficients, the Breit-Pauli spin-orbit code in the GAMESS-US program was successfully used to perform Douglas Kroll spin-orbit calculations. It was found that minute errors in the radial functions of valence orbitals lead to large errors in the spin-orbit energy levels and thus fitting the radial part of the spin-orbit matrix elements is necessary in model core potential parametrization. The first model core potentials that include the new formalism were developed for two 6p-block elements, Pb and Bi. The valence space of the 5p, 5d, 6s, and 6p orbitals was used because of the large SOC between the 5p and 6p orbitals. The model core potentials were validated in the calculations of atomic properties as well as spectroscopic constants of diatomic metal hydrides. The agreement between results of the model core potential and all-electron calculations was excellent, with energy errors of hundreds of cm(-1) and hundredths of eV, r(e) errors of thousandths of A, and omega(e) errors under 20 cm(-1). Two kinds of interplay between SOC effect and bonding process (antibonding and bonding SOC) were demonstrated using spin-free term potential curves of PbH and BiH. The present study is the first extension of the model core potential method beyond Breit Pauli to Douglas-Kroll SOC calculations. PMID- 19791855 TI - Integral approximations in ab initio, electron propagator calculations. AB - Treatments of interelectronic repulsion that avoid four-center integrals have been incorporated in ab initio, electron-propagator calculations with diagonal self-energy matrices. Whereas the formal scaling of arithmetic operations in the propagator calculations is unaffected, the reduction of storage requirements is substantial. Moreover, the scaling of integral transformations to the molecular orbital base is lowered by one order. Four-index, electron-repulsion integrals are regenerated from three-index intermediates. Test calculations with widely applied self-energy approximations demonstrate the accuracy of this approach. Only small errors are introduced when this technique is used with quasiparticle virtual orbitals, provided that conventional techniques of integral evaluation are used in the construction of density-difference matrices. PMID- 19791856 TI - The effect of spin polarization on zero field splitting parameters in paramagnetic pi-electron molecules. AB - Spin polarization effects play an important role in the theory of isotropic hyperfine interactions for aromatic protons. The spin polarization gives rise to significant isotropic proton hyperfine interactions--spin-dependent one-electron properties--smaller than 0 MHz and the effect has been theoretically described [H. M. McConnell and D. B. J. Chesnut, Chem. Phys. 28, 107 (1958)]. The influence of spin polarization on the zero field splitting parameters, which are spin dependent two-electron properties, has not been clearly identified yet. A phenomenological equation is proposed here for the contribution of spin polarization to the zero field splitting parameter D in analogy to McConnell's equation for hyperfine interactions. The presence of the effect is demonstrated in a series of calculations on polyacenes in the triplet state and turns out to be responsible for up to 50% of the D parameter in the case of naphthalene! It is found that spin-unrestricted single-determinant methods, including the widely used density functional theory methods, do not accurately reproduce the two electron reduced electron density required for the evaluation of two-electron spin-dependent properties. For the accurate calculation of zero field splitting parameters by quantum chemical methods, it thus seems necessary to resort to correlated ab initio methods which do not give rise to spin contamination and which do provide an accurate description of the two-electron reduced electron density. PMID- 19791857 TI - Maximum locality in occupied and virtual orbital spaces using a least-change strategy. AB - A new strategy is introduced for obtaining localized orthonormal Hartree-Fock (HF) orbitals where the underlying principle is to minimize the size of the transformation matrix from the atomic orbital basis to the HF optimized orbital basis. The new strategy gives both localized occupied and localized virtual orbital spaces. The locality of the occupied orbital space is similar to one obtained using standard localization schemes. For the virtual space, standard localization schemes fail to give local orbitals while the new strategy gives a virtual space which has a locality similar to the one of a Lowdin orthonormalization of the atomic orbital basis. Since Lowdin orthonormalization gives the most local orthonormal basis functions in the sense that they have the largest similarity with the local atomic basis functions, the new strategy thus allows the orthonormal basis to become optimized without introducing significant delocalization. PMID- 19791858 TI - Hartree-Fock solutions as a quasidiabatic basis for nonorthogonal configuration interaction. AB - Using the method of self-consistent field metadynamics, we locate some of the low energy solutions to the Hartree-Fock (HF) equations on LiF and O(3). The located solutions qualitatively resemble the adiabatic electronic states in these systems. We formulate the method of nonorthogonal Configuration Interaction (CI) to interact these solutions with cubic scaling with system size and quadratic scaling with the number of solutions. The resultant solutions display the avoided crossings and, in O(3), a conical intersection expected of the adiabatic states. In LiF the relevant solutions coalesce and disappear from Unrestricted HF space indicating a more general HF theory is required. PMID- 19791859 TI - Cross sections and photoelectron angular distributions in photodetachment from negative ions using equation-of-motion coupled-cluster Dyson orbitals. AB - We report total and differential cross sections for photodetachment from negative ions using Dyson orbitals calculated from equation-of-motion coupled-cluster wave functions and free wave description of the detached electron. The energy dependence of the cross sections is reproduced well, however, the accuracy of absolute values varies. For F(-), C(-), NH(2)(-), and H(-), the calculated cross sections are within the error bars from the experimental values, whereas the errors for Li(-) and OH(-) are about 20%. The largest errors are observed for O( ) and O(2)(-) for which the calculated cross sections differ from the experimental ones by factors of 3 and 2, respectively. Calculated anisotropy parameters for atomic anions exhibit too slow decrease, which suggests that the diffuseness of the computed Dyson orbitals is underestimated. Moreover, in the asymptotic region, the orbitals exhibit artifactual oscillations probably due to the limitations of Gaussian basis sets. The analysis of the trends in the experimental anisotropy parameters suggests that the interaction of the detached electron with the core, which is neglected in the present model, is important. PMID- 19791860 TI - Properties of the exact universal functional in multicomponent density functional theory. AB - Multicomponent density functional theory has been developed to treat systems with more than one type of quantum particle, such as electrons and nuclei, in an external potential. The existence of the exact universal multicomponent density functional in terms of the one-particle densities for each type of quantum particle has been proven. In the present paper, a number of important mathematical properties of the exact universal multicomponent density functional are derived. The expression relating the electron-proton pair density to the one particle densities leads to an inequality for the potential energy component of the electron-proton correlation functional under well-defined conditions. General inequalities for the kinetic energy correlation functionals and the total electron-proton correlation functional are also derived. The coordinate scaling analysis leads to mathematical inequalities describing the effect of scaled densities on the kinetic, potential, and total energy functionals. The adiabatic connection formula defines the exact electron-proton functional in terms of an adiabatic scaling parameter that smoothly connects the noninteracting system with the fully interacting system. The virial expression provides the relation between the exact kinetic and potential energy functionals for the ground state densities of multicomponent systems. These mathematical relationships provide insight into the fundamental properties of the exact universal multicomponent density functional and serve as a guide for the development of approximate electron proton density functionals. PMID- 19791861 TI - The molecular mean-field approach for correlated relativistic calculations. AB - A new approach for relativistic correlated electron structure calculations is proposed by which a transformation to a two-spinor basis is carried out after solving the four-component relativistic Hartree-Fock equations. The method is shown to be more accurate than approaches that apply an a priori transformation to a two-spinor basis. We also demonstrate how the two-component relativistic calculations with properly transformed two-electron interaction can be simulated at the four-component level by projection techniques, thus allowing an assessment of errors introduced by more approximate schemes. PMID- 19791862 TI - A multistate local coupled cluster CC2 response method based on the Laplace transform. AB - A new Laplace transform based multistate local CC2 response method for calculating excitation energies of extended molecular systems is presented. By virtue of the Laplace transform trick, the eigenvalue problem involving the local CC2 Jacobian is partitioned along the doubles-doubles block (which is diagonal in the parental canonical method) without losing the sparsity in the integral, amplitude, and amplitude response supermatrices. Hence, only an effective eigenvalue problem involving singles vectors has to be solved, while the doubles part can be computed on-the-fly. Within this framework, a multistate treatment of excited states with state specific and adaptive local approximations imposed on the doubles part is straightforwardly possible. Furthermore, in the context of the density fitting approximation of the two-electron integrals, a procedure to specify the local approximation, i.e., the restricted pair lists and domains, on the basis of an analysis of the object to be approximated itself is proposed. Performance and accuracy of the new Laplace transformed density fitted local CC2 (LT-DF-LCC2) response method are tested for set of different test molecules and states. It turns out that LT-DF-LCC2 response is much more robust than the earlier local CC2 response method proposed before, which failed to find some excited states in difficult cases. PMID- 19791863 TI - Response properties with explicitly correlated coupled-cluster methods using a Slater-type correlation factor and cusp conditions. AB - The recently proposed extension of the explicitly correlated coupled-cluster ansatz using cusp conditions [A. Kohn, J. Chem. Phys. 130, 104104 (2009)] is tested for suitability in the calculation of response properties. For this purpose, static and dynamic electrical properties up to ESHG hyperpolarizabilities as well as optical rotations have been computed within the CCSD(F12) model. It is shown that effectively converged correlation contributions can reliably be obtained using augmented quadruple zeta basis sets already. The ansatz is optionally equipped with an extension capable of reducing the one electron basis set error. A further simplification of the method specific Lagrangian aimed at reducing the computational effort has been tested and is shown to be uncritical. Furthermore, we examined the impact of conventional triple and quadruple excitations in explicitly correlated property calculations. PMID- 19791864 TI - Gauge origin independent calculations of nuclear magnetic shieldings in relativistic four-component theory. AB - The use of perturbation-dependent London atomic orbitals, also called gauge including atomic orbitals, has proven efficient for calculations of NMR shielding constants and other magnetic properties in the nonrelativistic framework. In this paper, the theory of London atomic orbitals for NMR shieldings is extended to the four-component relativistic framework and our implementation is described. The relevance of London atomic orbitals in four-component calculations as well as computational aspects are illustrated with test calculations on hydrogen iodide. We find that the use of London atomic orbitals is an efficient method for reliable calculations of NMR shielding constants with standard basis sets, also for four-component calculations with spin-orbit coupling effects included in the wave function optimization. Furthermore, we find that it is important that the small component basis functions fulfill the magnetic balance for accurate description of the diamagnetic shielding and that the role of London atomic orbitals in the relativistic domain is to provide atomic magnetic balance even in the molecular case, thus greatly improving basis set convergence. The Sternheim approximation, which calculates the diamagnetic contribution as an expectation value, leads to significant errors and is not recommended. PMID- 19791865 TI - Polarization justified Fukui functions. AB - New Fukui functions have been derived within the conceptual density functional theory by the analysis of the polarization effect of a system in static electric field. Resulting Fukui functions accurately reproduce the global softness and electronic dipolar polarizability; they meet the condition integral[f(r)/r]dr = (partial differential mu/partial differential Z)(N) and lead to very reasonable values of the global hardness for atoms for the group of 29 main group elements. Computational clarity makes the new Fukui functions a promising tool in studies of molecular reactivity. PMID- 19791866 TI - Phase-space geometry of the generalized Langevin equation. AB - The generalized Langevin equation is widely used to model the influence of a heat bath upon a reactive system. This equation will here be studied from a geometric point of view. A dynamical phase space that represents all possible states of the system will be constructed, the generalized Langevin equation will be formally rewritten as a pair of coupled ordinary differential equations, and the fundamental geometric structures in phase space will be described. It will be shown that the phase space itself and its geometric structure depend critically on the preparation of the system: A system that is assumed to have been in existence forever has a larger phase space with a simpler structure than a system that is prepared at a finite time. These differences persist even in the long time limit, where one might expect the details of preparation to become irrelevant. PMID- 19791867 TI - Dynamic modifications of polarizability for large metallic spheroidal nanoshells. AB - We present an approach alternative to the hybridization model for the treatment of the coupled interfacial plasmon modes in spheroidal metallic nanoshells. Rather than formulating the problem from the Lagrangian dynamics of the free electronic fluid, we adopt an effective medium approach together with the uniqueness of the solutions to electromagnetic boundary value problem, from which the polarizability of the shells can then be systematically and efficiently derived; and the resonance frequencies for the coupled modes can be obtained from the poles in the polarizability. This approach can treat confocal nanoshells with different geometries for the spheroidal cavity and external surface and allow for a natural extension to incorporate corrections from the finiteness of the optical wavelength which are important for nanoparticles of larger sizes. This thus surpasses the hybridization model which is limited to incorporate only the electrostatic Coulomb interaction between the uncoupled plasmons. Numerical results will be provided for different nanoshell systems, and for the illustration of the various geometric and dynamic effects from our model. PMID- 19791868 TI - Influence of reservoir size on the adsorption path in an ideal pore. AB - We consider the influence of the relative size of the gas reservoir on the states visited by a simple fluid adsorbed in a nanopore of ideal geometry (a slit). We focus on the intermediate states that appear in between the main hysteresis branches comprising gaslike and liquidlike states and we study the adsorption and desorption paths actually followed by the system as one changes the reservoir size. We find that these paths may display discontinuous sections associated with transitions between different nonuniform states. We also discuss the stability of the states in such situations. PMID- 19791869 TI - Adiabatic connection for strictly correlated electrons. AB - Modern density functional theory (DFT) calculations employ the Kohn-Sham system of noninteracting electrons as a reference, with all complications buried in the exchange-correlation energy (E(XC)). The adiabatic connection formula gives an exact expression for E(XC). We consider DFT calculations that instead employ a reference of strictly correlated electrons. We define a "decorrelation energy" that relates this reference to the real system, and derive the corresponding adiabatic connection formula. We illustrate this theory in three situations, namely, the uniform electron gas, Hooke's atom, and the stretched hydrogen molecule. The adiabatic connection for strictly correlated electrons provides an alternative perspective for understanding DFT and constructing approximate functionals. PMID- 19791870 TI - A connection between domain-averaged Fermi hole orbitals and electron number distribution functions in real space. AB - We show in this article how for single-determinant wave functions the one electron functions derived from the diagonalization of the Fermi hole, averaged over an arbitrary domain Omega of real space, and expressed in terms of the occupied canonical orbitals, describe coarse-grained statistically independent electrons. With these domain-averaged Fermi hole (DAFH) orbitals, the full electron number distribution function (EDF) is given by a simple product of one electron events. This useful property follows from the simultaneous orthogonality of the DAFH orbitals in Omega, Omega(')=R(3)-Omega, and R(3). We also show how the interfragment (shared electron) delocalization index, delta(Omega,Omega(')), transforms into a sum of one-electron DAFH contributions. Description of chemical bonding in terms of DAFH orbitals provides a vivid picture relating bonding and delocalization in real space. DAFH and EDF analyses are performed on several test systems to illustrate the close relationship between both concepts. Finally, these analyses clearly prove how DAFH orbitals well localized in Omega or Omega(') can be simply ignored in computing the EDFs and/or delta(Omega,Omega(')), and thus do not contribute to the chemical bonding between the two fragments. PMID- 19791871 TI - The discovery of unexpected isomers in sodium heptamers by Born-Oppenheimer molecular dynamics. AB - This work presents a density functional study of neutral, cationic, and anionic sodium cluster heptamers. The cluster structures were optimized with the local density approximation as well as with the generalized gradient approximation. For the neutral and cationic clusters new unexpected isomers are found closed in energy to the well known ground state structures. In the case of the neutral heptamer the new isomer was first noticed by inspection of a first-principles Born-Oppenheimer molecular dynamics (BOMD) simulations at 300 K. A structure alignment algorithm is presented which facilitates the discovery of new structures from such BOMD simulations. With this algorithm the structural evolution of the two low-lying isomers of the neutral, cationic, and anionic heptamer was analyzed at different temperatures. This work demonstrates the capability of reasonably long (approximately 100 ps) first-principles BOMD simulations to explore the potential energy landscape of metallic clusters. PMID- 19791872 TI - Accurate prediction of higher-level electronic structure energies for large databases using neural networks, Hartree-Fock energies, and small subsets of the database. AB - A novel method is presented that significantly reduces the computational bottleneck of executing high-level, electronic structure calculations of the energies and their gradients for a large database that adequately samples the configuration space of importance for systems containing more than four atoms that are undergoing multiple, simultaneous reactions in several energetically open channels. The basis of the method is the high-degree of correlation that generally exists between the Hartree-Fock (HF) and higher-level electronic structure energies. It is shown that if the input vector to a neural network (NN) includes both the configuration coordinates and the HF energies of a small subset of the database, MP4(SDQ) energies with the same basis set can be predicted for the entire database using only the HF and MP4(SDQ) energies for the small subset and the HF energies for the remainder of the database. The predictive error is shown to be less than or equal to the NN fitting error if a NN is fitted to the entire database of higher-level electronic structure energies. The general method is applied to the computation of MP4(SDQ) energies of 68,308 configurations that comprise the database for the simultaneous, unimolecular decomposition of vinyl bromide into six different reaction channels. The predictive accuracy of the method is investigated by employing successively smaller subsets of the database to train the NN to predict the MP4(SDQ) energies of the remaining configurations of the database. The results indicate that for this system, the subset can be as small as 8% of the total number of configurations in the database without loss of accuracy beyond that expected if a NN is employed to fit the higher-level energies for the entire database. The utilization of this procedure is shown to save about 78% of the total computational time required for the execution of the MP4(SDQ) calculations. The sampling error involved with selection of the subset is shown to be about 10% of the predictive error for the higher-level energies. A practical procedure for utilization of the method is outlined. It is suggested that the method will be equally applicable to the prediction of electronic structure energies computed using even higher-level methods than MP4(SDQ). PMID- 19791873 TI - Accurate ab initio potential energy curves for the classic Li-F ionic-covalent interaction by extrapolation to the complete basis set limit and modeling of the radial nonadiabatic coupling. AB - Multireference configuration interaction calculations using large correlation consistent basis sets and full configuration interaction calculations with the smallest of such basis are utilized to describe the ionic-neutral curve crossing for the title system. The results of the former calculations have then been extrapolated to the complete basis set limit using the uniform singlet- and triplet-pair extrapolation scheme. A recent suggestion for locating the nonadiabatic matrix terms at the point where the dynamical correlation split vanishes has also been tested. Additionally, a consistent formalism is suggested to model the radial dependence of the nonadiabatic matrix terms that warrants an overlap dependence away from the crossing. When applied to LiF, the overall approach yields results in excellent agreement with the commonly accepted values for the geometric and energetic attributes at both the equilibrium and diabatic crossing regions. PMID- 19791874 TI - Toward large scale vibrational configuration interaction calculations. AB - The implementation of a state-specific configuration-selective vibrational configuration interaction (cs-VCI) approach based on a polynomial representation of the potential energy surface is presented. Advantages over grid-based algorithms are discussed. A combination of a configuration selection criterion, the simultaneous exclusion of irrelevant configurations, and an internal contraction scheme allow to handle large variational spaces. A modified version of the iterative Jacobi-Davidson diagonalization has been used to determine relevant internal eigenpairs of the cs-VCI matrices in the selected space. Benchmark calculations are provided for systems with up to 2x10(7) configurations and three-mode couplings in the expansion of the potential. PMID- 19791875 TI - Superhalogen properties of CuF(n) clusters. AB - A first-principles calculation based on gradient corrected density functional theory reveals unusual properties of a Cu atom interacting with F. Up to six F atoms are bound to a single Cu atom with electron affinities steadily rising as successive F atoms are attached, reaching a peak value of 7.2 eV in CuF(5). The large energy gaps between the highest occupied and lowest unoccupied molecular orbitals, both in neutral and anionic form, provide further evidence of their stability. These unusual properties brought about by involvement of inner shell 3d-electrons not only allow CuF(n) to belong to the class of superhalogens but also show that its valence can exceed the nominal value of 1 and 2. PMID- 19791876 TI - Spectroscopic investigation of the A (1)A(")-X (1)A(') electronic transition of HSiNCO. AB - The first spectroscopic observation of the previously unknown species HSiNCO has been reported. HSiNCO was generated by the fragmentation of trimethylsilylisocyanate with a high-voltage discharge source. The 0(0)(0) band of the A (1)A(")-X (1)A(') transition has been recorded with full rotational resolution using laser-induced fluorescence spectroscopy and ground and excited state rotational and centrifugal distortion constants determined. Ten additional vibrational bands belonging to HSiNCO have also been observed in the laser induced fluorescence spectrum and have been assigned based on predicted anharmonic vibrational frequencies. Due to the large change in geometry upon excitation, a number of axis-rotation peaks have been observed in the 0(0)(0) band and the axis-rotation angle (theta(T)) has been estimated to be 0.6 degrees +/-0.2 degrees. Dispersed fluorescence spectroscopy has been carried out and nu(8) (the N-C-O out-of-plane bending mode) and a number of overtones of nu(4) (the Si-H wagging mode) have been observed in the ground electronic state. PMID- 19791877 TI - Activation energies for evaporation from protonated and deprotonated water clusters from mass spectra. AB - Experimental mass abundance spectra are used to extract evaporative activation energies (dissociation energies) for protonated water clusters, (H(2)O)(N)H(+), and deprotonated water clusters, (H(2)O)(N)OH(-), in the size range up to hundred molecules. The inversion is achieved by application of the shell correction method adapted from nuclear physics to the abundance spectra. The well known abundance anomaly for protonated clusters which occurs for N=20-22 is found to have the characteristic behavior of a shell closing, whereas other apparent magic numbers are only prominent peaks in the abundance spectra because of the instability of the evaporative precursor. For the deprotonated clusters, we find a similar shell closing for N=55-56. PMID- 19791878 TI - An ab initio investigation of the mechanisms of photodissociation in bromobenzene and iodobenzene. AB - In concert with the latest experiment of velocity imaging technique [X. P. Zhang et al., ChemPhysChem 9, 1130 (2008)], quantum chemical calculations with relativistic effect were performed on the photodissociation of bromobenzene (BrPh) and iodobenzene (IPh) at 266 nm. The method of multistate second order multiconfigurational perturbation theory in conjunction with spin-orbit interaction through complete active space state interaction was employed to calculate the potential energy curves for the ground and low-lying excited states of BrPh and IPh along their photodissociation reaction coordinates. The dissociation mechanisms with products of X((2)P(3/2)) and X(*)((2)P(1/2)) (X = Br,I) states were clarified. PMID- 19791879 TI - Metal clusters with hidden ground states: Melting and structural transitions in Al115(+), Al116(+), and Al117(+). AB - Heat capacities measured as a function of temperature for Al(115)(+), Al(116)(+), and Al(117)(+) show two well-resolved peaks, at around 450 and 600 K. After being annealed to 523 K (a temperature between the two peaks) or to 773 K (well above both peaks), the high temperature peak remains unchanged but the low temperature peak disappears. After considering the possible explanations, the low temperature peak is attributed to a structural transition and the high temperature peak to the melting of the higher enthalpy structure generated by the structural transition. The annealing results show that the liquid clusters freeze exclusively into the higher enthalpy structure and that the lower enthalpy structure is not accessible from the higher enthalpy one on the timescale of the experiments. We suggest that the low enthalpy structure observed before annealing results from epitaxy, where the smaller clusters act as a nucleus and follow a growth pattern that provides access to the low enthalpy structure. The solid-to solid transition that leads to the low temperature peak in the heat capacity does not occur under equilibrium but requires a superheated solid. PMID- 19791880 TI - Infrared multiphoton electron detachment spectroscopy of C76(2-). AB - In this letter, we report the first infrared spectrum of C(76)(2-). This multiply charged anion has been studied in an electrodynamic ion trap held at room temperature using tunable infrared radiation from a free-electron laser. Resonant vibrational excitation is found to cause electron detachment and the resulting singly negatively charged as well as the remaining doubly charged parent ion are monitored as a function of IR wavelength in an experimental scheme that we term infrared multiphoton electron detachment spectroscopy. The obtained IR spectra are contrasted to computed vibrational spectra using density functional theory. The dianionic molecule retains its overall symmetry (i.e., D(2) point group) with a (1)A(1) ground state with respect to the neutral fullerene. Spectral shifts of characteristic tangential modes relative to the neutral cage are shown to originate from the excess charge density. PMID- 19791881 TI - Bound states of the OH(2Pi)-HCl complex on ab initio diabatic potentials. AB - The bound states of the open-shell OH((2)Pi)-HCl complex were calculated in four dimensions with a diabatic model using electronic states that correlate asymptotically with the ground and excited spin-orbit states of the OH((2)Pi) fragment and the ground state of the HCl fragment. The ab initio diabatic potentials and their analytic expansion applied in these calculations were obtained earlier by Wormer et al. [J. Chem. Phys. 122, 244325 (2005)]. In addition to the four-dimensional calculations, we considered a (3+1)-dimensional model in which the intermolecular distance coordinate R is adiabatically separated from the remaining coordinates. Both models include the important spin orbit coupling in the OH fragment. Energy levels and parity splittings were computed for a total angular momentum of J=1/2 and 3/2; rotational constants and other spectroscopic parameters were extracted from these calculations. The vibrationally averaged geometry in the ground state of the complex is planar and this state is more or less localized near the minimum in the lowest adiabatic potential with binding energy D(e)=1123 cm(-1); the dissociation energy D(0) with respect to OH((2)Pi(3/2)) and HCl is found to be 685 cm(-1). The splitting between the (2)Pi(3/2) and (2)Pi(1/2) spin-orbit states of free OH is largely reduced by the anisotropic interaction with HCl through the off-diagonal diabatic coupling potential and these states are strongly mixed. Low lying rovibronic states that correlate with the OH((2)Pi(3/2)) ground state were found at 14 cm( 1) for total angular momentum projection quantum number |Omega|=3/2 and 26 cm(-1) for |Omega|=1/2, relative to the ground state with |Omega|=1/2. The OH-HCl stretch fundamental frequency equals to 93.6 cm(-1), the lowest bend excited states (involving a coupled bend motion of both fragments) were found in the region of 150-160 cm(-1) above the ground state. Especially in the excited states important nonadiabatic effects are observed that involve both of the asymptotically degenerate adiabatic electronic states. In some of these excited states the vibrationally averaged geometry is nonplanar. PMID- 19791882 TI - Ab initio study of the spectroscopy of AgBr: a CASSCF + Averaged Coupled Pair Functional approach to the lowest excited states including spin-orbit couplings. AB - The nine lowest-lying singlet and triplet (X (1)Sigma(+), 2 (1)Sigma(+), 3 (1)Sigma(+), (3)Sigma(+), 1 (3,1)Pi, 2 (3)Pi, and (3,1)Delta) electronic states of AgBr were studied through state-specific Complete Active Space Self-Consistent Field with 16 active electrons in 12 orbitals followed by extensive Averaged Coupled Pair Functional and CIPT2 calculations with large optimized valence basis sets. The spin-orbit effects were included to obtain the Omega fine-structure states arising from the |Lambda S Sigma> parents. Even before the inclusion of the spin-orbit effects, the 2 (1)Sigma(+) and 3 (1)Sigma(+) states present shallow minima near the equilibrium geometry of the ground state. The 2 (1)Sigma(+) state has another minimum around 8.0 a.u. and is attractive up to 20 a.u. The lowest (3,1)Pi states were found to be totally repulsive while the (3,1)Delta states present deep minima around 4.8 a.u. Most of the calculated spectroscopic constants for the ground and B states are slightly improved with respect to the previous theoretical study using the much smaller CASSCF(16,10) reference wave functions [M. Guichemerre et al., Chem. Phys. 280, 71 (2002)]. The observed B<--X transition is confirmed as arising from the singlet-to-singlet 0(+)(2 (1)Sigma(+))<--0(+)(X (1)Sigma(+)) excitation around 31 900 cm(-1). However, at variance with the previous theoretical prediction, the C(Omega=0(+)) state is dominated around the equilibrium geometry of the ground state by the third (1)Sigma(+) state with a small contribution from the 2 (3)Pi state around 43,500 cm(-1); thus the X-C excitation is now explained as arising also from a singlet-to-singlet spin-allowed transition. PMID- 19791883 TI - Effect of the cluster angular momentum J and the projectile orbital momentum L on capture probability and postcollision dynamics. AB - In this work, collisions between rotating atomic clusters composed of Lennard Jones (LJ(n)) particles and an identical projectile have been investigated by means of trajectory simulations as a function of the cluster angular momentum J and internal energy E, and for different values of the projectile impact parameter b and relative velocity v(p). As expected, the collision (P(c)(b)) and capture [or sticking P(s)(b)] probabilities are found to decay below unity for values of b larger than the average surface radius of the cluster, with dP/db being strongly dependent on v(p). Both P(c)(b) and P(s)(b), however, appear to be largely insensitive to the modulus of the cluster angular momentum |J| and only weakly dependent on E for collisions involving target clusters with a lifetime tau>100 ps. The latter findings are interpreted as indicating the absence of strong changes in the structure of the target as a function of |J| and E. The comparison between the dissociation lifetime (tau(dyn)) of the postcapture complexes (LJ(n+1)(*)) obtained continuing trajectories after monomer capture and the one computed from the fragmentation of statistically prepared clusters (tau(stat)) supports the validity of a two-step capture-dissociation model; similarly, the comparison between the average amount of energy exchanged during trajectories (DeltaE(dyn)) in the process LJ(n)+LJ-->LJ(n+1)(*)-->LJ(n)+LJ and the one predicted by statistical simulations (DeltaE(stat)) suggests a fast statistical energy redistribution in the collisional complex even for very short tau(dyn) (e.g., 40 ps). In the case of projectiles aimed at the edge of the cluster [(grazing collisions, P(c)(b)<1]; however, the time elapsed between formal collision and dissociation, tau(coll), is such that tau(coll) H(2S) + NH/ND(X3Sigma) exchange reactions: state-to state quantum scattering and applicability of statistical model. AB - Quantum state-to-state dynamics for the NH + H/D --> H + NH/ND exchange reaction is reported on an accurate ab initio potential energy surface. The differential cross section is dominated by scattering into both the forward and backward directions, while the product shows strong rotational excitation. The calculated rate constant for the NH + D reaction is in excellent agreement with experiment. The applicability of a quantum statistical model is tested against exact state-to state quantum results. Due to strong nonreactive scattering, the statistical model significantly overestimates the integral cross section. However, it is shown that the product state distribution and differential cross sections are reasonably well reproduced by the statistical model because the reactive scattering is dominated by a complex-forming mechanism. PMID- 19791888 TI - Intermolecular vibrational energy exchange directly probed with ultrafast two dimensional infrared spectroscopy. AB - Ultrafast two dimensional infrared (2D IR) spectroscopy has been applied to probe the intermolecular vibrational energy exchange between two model molecules, benzonitrile and acetonitrile-(d3). The vibrational energy exchange between these two molecules is manifested through the growth of cross peaks in their 2D IR spectra. In experiments, their nitrile groups (CN) are not involved in the energy exchange but serve as reporters of the process. Our experiments demonstrate that intermolecular vibrational energy transfer can be directly probed with the 2D IR method. Results also show that the mode specific energy transfer can be important in intermolecular vibrational energy transfers. PMID- 19791889 TI - Isotope effects in the vibrational lifetime of hydrogen on germanium(100): theory and experiment. AB - Combining first-principles calculations and sum frequency generation spectroscopy, we elucidate the microscopic details in the relaxation of the stretching vibration of hydrogen adsorbed on Ge(100). The dominant decay channels involve energy transfer from the stretching to the hydrogen bending modes, with the remaining energy difference being transferred to or from substrate phonons. The coupling between stretching and bending modes is treated from first principles using the calculated multidimensional adiabatic potential energy surface, while the coupling to phonons is treated in perturbation theory. For a surface solely saturated with light hydrogen, we calculate a vibrational lifetime of 1.56 ns at 400 K, in good agreement with experiment, and find a similar temperature dependence of the lifetime in both experiment and theory. The calculations show that the stretching energy dissipates to a vibrational state involving four bending quanta of hydrogen, concurrently absorbing a thermally excited surface phonon related to the Ge dimer rocking mode. For a Ge surface saturated with a mixture of H and D, our experiments find that the relaxation rate of the H stretching vibration is markedly increased when compared to a surface saturated with H only. Experimentally, a single decay is observed although H and D atoms will statistically pair on the surface dimers. The vibrational lifetime of the Ge-H stretching mode is up to six times shorter in the presence of adsorbed D atoms. The calculated relaxation rates are consistent with the experimentally observed trend. The theoretical analysis shows that the breaking of symmetry within the Ge surface dimer due to coadsorption of D opens up further relaxation channels that involve absorption or emission of a substrate phonon at various energies. Moreover, the calculations predict an even shorter vibrational lifetime of the Ge-D stretch mode due to efficient coupling to the Ge dimer rocking mode. PMID- 19791890 TI - Vibrational self-trapping in beta-sheet structures observed with femtosecond nonlinear infrared spectroscopy. AB - Self-trapping of NH-stretch vibrational excitations in synthetic beta-sheet helices is observed using femtosecond infrared pump-probe spectroscopy. In a dialanine-based beta-sheet helix, the transient-absorption change upon exciting the NH-stretch mode exhibits a negative absorption change at the fundamental frequency and two positive peaks at lower frequencies. These two induced absorption peaks are characteristic for a state in which the vibrational excitation is self-trapped on essentially a single NH-group in the hydrogen bonded NH...OC chain, forming a small (Holstein) vibrational polaron. By engineering the structure of the polymer we can disrupt the hydrogen-bonded NH...OC chain, allowing us to eliminate the self-trapping, as is confirmed from the NH-stretch pump-probe response. We also investigate a trialanine-based beta sheet helix, where each side chain participates in two NH...OC chains with different hydrogen-bond lengths. The chain with short hydrogen bonds shows the same self-trapping behavior as the dialanine-based beta-sheet helix, whereas in the chain with long hydrogen bonds the self-trapping is too weak to be observable. PMID- 19791891 TI - The low frequency phonons dynamics in supercooled LiCl, 6 H2O. AB - We report the results of a series of ultrasound, Brillouin scattering, and optical heterodyne detected transient grating experiments performed on a LiCl, 6H(2)O solution from room temperature down to the vicinity of its liquid-glass transition, T(g) approximately 138 K. Down to T approximately 215 K, the supercooled liquid has a behavior similar to what is expected for supercooled water: its zero frequency sound velocity, C(0), continuously decreases while the corresponding infinite frequency velocity, C(infinity), sharply increases, reflecting the increasing importance of H bonding when temperature is lowered. Below 215 K, specific aspects of the solution, presumably related to the role of the Li(+) and Cl(-) ions, modify the thermal behavior of C(0), while a beta relaxation process also appears and couples to the sound propagation. The origin of those two effects is briefly discussed. PMID- 19791892 TI - Manipulating electronic couplings and nonadiabatic nuclear dynamics with strong laser pulses. AB - We demonstrate the possibility of manipulating the coupling between two (optically bright and optically dark) excited electronic states and of controlling the ensuing nuclear wave packet dynamics via a strong laser pulse, which couples the ground and the bright electronic state. The control of the wave packet dynamics is implemented through the creation of a highly nonequilibrium distribution in the bright-dark vibronic manifold. The distribution is produced due to the combined effect of the external pulse (through Rabi cycling) and the system itself (through the electronic interstate coupling). The induced wave packet dynamics persists long after the pulse is over, both in the isolated and in the dissipative system. The effects are robust and are achieved by varying the strength and duration of a Gaussian pulse, that is, no careful tuning of the pulse shape is required. Possible applications of our results include the strong pulse control of electron transfer as well as the enhancement and detection of intramolecular electronic coupling via strong-pulse spectroscopy. PMID- 19791893 TI - Phase diagram of a two-dimensional lattice gas model of a ramp system. AB - Using Monte Carlo simulation and fundamental measure theory we study the phase diagram of a two-dimensional lattice gas model with a nearest neighbor hard core exclusion and a next-to-nearest neighbor finite repulsive interaction. The model presents two competing ranges of interaction and, in common with many experimental systems, exhibits a low density solid phase, which melts back to the fluid phase upon compression. The theoretical approach is found to provide a qualitatively correct picture of the phase diagram of our model system. PMID- 19791894 TI - Platelike structures of semiconductor clusters Ge(n) (n = 40-44). AB - The structures of Ge(n) (n=40-44) clusters were searched by genetic algorithm combined with a tight-binding method. First-principles calculations based on density functional theory were performed to further optimize the isomer structures. The calculated results show that Ge(n) (n=40-44) clusters favor platelike structures, consisted of four small magic clusters (Ge(9) or Ge(10)), and a Ge(4) core. The Ge(4) core along with the parts of the four linked small clusters forms a diamond segment. The cluster mobilities of the most stable structures are in good agreement with the experimental data. PMID- 19791895 TI - Measurements on thermodiffusion in ternary hydrocarbon mixtures at high pressure. AB - Experimental investigations on thermodiffusion have been conducted for five different ternary mixtures of methane, n-butane, and n-dodecane at a high temperature and pressure. While the mole fraction of methane was fixed at 0.2 the mole fraction of n-dodecane was varied from 0.7 to 0.2. The experiments were performed in a microgravity environment on board the satellite FOTON-M3. It was found that in all mixtures, n-dodecane separated to the cold side whereas methane segregated to the hot side. n-butane, the species with an intermediate density, showed a change in sign as its mole fraction was increased. At low concentrations it collected on the cold side but moved in the opposite direction with an increase in its mole fraction. The role of the relative density coupled with the species concentrations has been used to explain the thermodiffusion factor in each mixture. Computational investigations showed a similar behavior. However, the theoretical model was not able to capture the sign change of n-butane accurately. The inadequate representation of the significance of the relative densities and the mole fraction of the species has been found as the reason for this. PMID- 19791896 TI - Coupled cluster benchmarks of water monomers and dimers extracted from density functional theory liquid water: the importance of monomer deformations. AB - To understand the performance of popular density-functional theory exchange correlation (xc) functionals in simulations of liquid water, water monomers and dimers were extracted from a PBE simulation of liquid water and examined with coupled cluster with single and double excitations plus a perturbative correction for connected triples [CCSD(T)]. CCSD(T) reveals that most of the dimers are unbound compared to two gas phase equilibrium water monomers, largely because monomers within the liquid have distorted geometries. Of the three xc functionals tested, PBE and BLYP tend to predict too large dissociation energies between monomers within the dimers. We show that this is because the cost to distort the monomers to the geometries they adopt in the liquid is systematically underestimated with these functionals. PBE0 reproduces the CCSD(T) monomer deformation energies very well and consequently the dimer dissociation energies much more accurately than PBE and BLYP. Although this study is limited to water monomers and dimers, the results reported here may provide an explanation for the overstructured radial distribution functions routinely observed in BLYP and PBE simulations of liquid water and are of relevance to water in other phases and to other associated molecular liquids. PMID- 19791897 TI - Melting slope of MgO from molecular dynamics and density functional theory. AB - We combine density functional theory (DFT) with molecular dynamics simulations based on an accurate atomistic force field to calculate the pressure derivative of the melting temperature of magnesium oxide at ambient pressure--a quantity for which a serious disagreement between theory and experiment has existed for almost 15 years. We find reasonable agreement with previous DFT results and with a very recent experimental determination of the slope. We pay particular attention to areas of possible weakness in theoretical calculations and conclude that the long standing discrepancy with experiment could only be explained by a dramatic failure of existing density functionals or by flaws in the original experiment. PMID- 19791898 TI - Femtosecond polarization resolved spectroscopy: a tool for determination of the three-dimensional orientation of electronic transition dipole moments and identification of configurational isomers. AB - A method is presented that combines femtosecond polarization resolved UV/visible pump-IR probe spectroscopy and density functional theory calculations in determining the three-dimensional orientation of an electronic transition dipole moment (tdm) within the molecular structure. The method is demonstrated on the approximately planar molecule coumarin 314 (C314) dissolved in acetonitrile, which can exist in two ground state configurations: the E- and the Z-isomer. Based on an exhaustive search analysis on polarization resolved measurement data for four different vibrational modes, it is concluded that C314 in acetonitrile is the E-isomer. The electronic tdm vector for the electronic S(0)-->S(1) transition is determined and the analysis shows that performing the procedure for four vibrational modes instead of the minimally required three reduces the 1sigma probability area from 2.34% to 2.24% of the solution space. Moreover, the fastest rotational correlation time tau(c) for the C314 E-isomer is determined to be 26+/ 2 ps. PMID- 19791899 TI - Photoluminescence properties of Jahn-Teller transition-metal ions. AB - This work investigates the influence of electron-phonon coupling associated with E tensor product of e and T tensor product of e Jahn-Teller (JT) effect in different transition-metal (TM) ions on de-excitation phenomena through nonradiative multiphonon relaxation, i.e., photoluminescence (PL) quenching. We developed a configurational curve model which is able to predict from the absorption spectrum whether a given JT-TM ion is PL or quenched. The prediction is made on the basis of an adapted Dexter-Klick-Russell parameter for JT systems, defined in terms of spectroscopic parameters through Lambda(JT)=alphaDelta(e)(abs)/E(abs), where Delta(e)(abs) refers to the splitting of the parent octahedral E(g) states by the JT distortion in E tensor product of e (alpha=3/4) or T tensor product of e (alpha=1/4), and E(abs) is the energy of the first absorption band involving electronic transition between E(g) and T(2g). We show that PL in any JT-TM ion occurs whenever Lambda(JT)<0.1 or is quenched if Lambda(JT)>0.2. This result is noteworthy since it allows us to establish structural requirements for the JT-TM ion and the host crystal to be PL. Although PL properties of materials containing TM ions depend on a variety of structural factors such as the electronic configuration, the site symmetry, and the crystal field produced by neighboring atoms, the present model achieves this goal through a simple spectroscopic parameter: Lambda(JT). In this work we correlated the PL properties of different sixfold-coordinated JT systems such as Ti(3+), Cu(2+), Mn(3+), Cr(2+), Fe(2+), Co(3+), and Ni(3+) in halides and oxides with Lambda(JT) obtained from their respective absorption spectra. From this analysis we conclude that depending on the nature of the JT coupling and its strength, PL is either strongly favored or quenched in T tensor product of e while it is mostly quenched in E tensor product of e systems due to the larger JT distortion. PMID- 19791900 TI - Effect of the interfacial area on the equilibrium properties of Lennard-Jones fluid. AB - The influence of the system size on the interfacial and equilibrium properties of the Lennard-Jones fluid obtained using the inhomogeneous Monte Carlo simulations is studied for temperatures covering the vapor-liquid coexistence region. The values of the surface tension, coexistence densities, as well as the pressure of saturated vapor are affected by the varying area of the interface. Moreover the loss of isotropy of the fluid structure is observed as a consequence of using the periodic boundary conditions in molecular simulations. The equilibrium properties are evaluated also in simulation boxes of the shape of hexangular prism and compared to the results of simulations performed in the commonly used quadrangular parallelepiped. Both sets seem to be affected by the finite-size effects in similar extent. PMID- 19791901 TI - Spectral shifts and helium configurations in 4He(N)-tetracene clusters. AB - Spectral shifts of electronic transitions of tetracene in helium droplets are investigated in a theoretical study of (4)He(N)-tetracene clusters with 1 < or = N < or = 150. Utilizing a pairwise interaction for the S(0) state of tetracene with helium that is extended by semiempirical terms to construct a potential for the S(1) state of tetracene with helium, the spectral shift is calculated from path integral Monte Carlo calculations of the helium equilibrium properties with tetracene in the S(0) and S(1) states at T = 0 and at T = 0.625 K. The calculated spectral shifts are in quantitative agreement with available experimental measurements for small values of N (< or = 8) at T approximately 0.4 K and show qualitative agreement for larger N (10-20). The extrapolated value of the spectral shift in large droplets (N approximately 10(4)) is approximately 90% of the experimentally measured value. We find no evidence of multiple configurations of helium for any cluster size for either the S(0) or S(1) state of tetracene. These results suggest that the observed spectral splitting of electronic transitions of tetracene in large helium droplets is not due to the coexistence of static metastable helium densities, unlike the situation previously analyzed for the phthalocyanine molecule. PMID- 19791902 TI - Electron paramagnetic resonance linewidth narrowing of Gd3+ ions in Y-doped ceria nanocrystals with decreasing crystallite size. AB - Electron paramagnetic resonance (EPR) spectra of Gd(3+) ions in crystalline Ce(1 x-y)Gd(x)Y(y)O(2-[0.5*(x+y)]) (x=0.0025, y=0.10, and 0.25) with crystallite sizes ranging from 600 nm down to 5 nm have been measured at X-band and at Q-band near liquid He and room temperatures. The EPR line shape is controlled by the low symmetry surrounding of Gd(3+) ions in a coordination environment with one oxygen vacancy and seven oxygen nearest-neighbors forming GdO(7) polyhedra. These coordination polyhedra are characterized by a wide distribution of crystal field parameters that primarily controls the EPR linewidth. The EPR linewidth of the central (-1/2 <--> +1/2) transition is observed to decrease systematically with decreasing crystallite size. This observation implies that the size of the crystallites in the nanoregime may have important influence on the energetics of vacancy distribution in crystalline materials. PMID- 19791903 TI - Symmetries and alignment of biaxial nematic liquid crystals. AB - The possible symmetries of the biaxial nematic phase are examined against the implications of the presently available experimental results. Contrary to the widespread notion that biaxial nematics have orthorhombic symmetry, our study shows that a monoclinic (C(2h)) symmetry is more likely to be the case for the recently observed phase biaxiality in thermotropic bent-core and calamitic tetrapode nematic systems. The methodology for differentiating between the possible symmetries of the biaxial nematic phase by NMR and by IR spectroscopy measurements is presented in detail. The manifestations of the different symmetries on the alignment of the biaxial phase are identified and their implications on the measurement and quantification of biaxiality as well as on the potential use of biaxial nematic liquid crystals in electro-optic applications are discussed. PMID- 19791904 TI - Dissociative adsorption of hydrogen fluoride onto amorphous solid water. AB - Adsorption of hydrogen fluoride (HF) onto amorphous solid water films at 50 K is reported to yield a strong absorbance continuum in their reflection-absorption infrared spectra (RAIRS). This and other complex features observed in the RAIRS spectra of stratified binary composite HF:H(2)O nanoscopic films deposited onto Pt(111) are interpreted quantitatively using a classical optics model. Comparison with experimental data allows us to determine that the absorbance continuum is due to absorption within the film (as opposed to trivial optical effects) and that the extent of intermixing and uptake is mostly limited to the first few molecular layers. Furthermore, extensive isotope scrambling is demonstrated by the observation of similar Zundel continua upon codeposition of neat HF, or DF, and H(2)O vapors onto Pt(111) at 50 K. These observations are consistent with those expected from extensive ionic dissociation of HF upon dissolution within, and adsorption onto, ASW at 50 K. PMID- 19791905 TI - Quantum effects on the maximum in density of water as described by the TIP4PQ/2005 model. AB - Path integral simulations have been performed to determine the temperature of the maximum in density of water of the rigid, nonpolarizable TIP4PQ/2005 model treating long range Coulombic forces with the reaction field method. A maximum in density is found at 280 K, just 3 K above the experimental value. In tritiated water the maximum occurs at a temperature about 12 K higher than in water, in reasonable agreement with the experimental result. Contrary to the usual assumption that the maximum in classical water is about 14 K above that in water, we found that for TIP4PQ/2005 this maximum is about 30 K above. For rigid water models the internal energy and the temperature of maximum density do not follow a linear behavior when plotted as a function of the inverse of the hydrogen mass. In addition, it is shown that, when used with Ewald sums, the TIP4PQ/2005 reproduces quite nicely not only the maximum in density of water, but also the liquid densities, the structure of liquid water and the vaporization enthalpy. It was shown in a previous work that it also reproduces reasonably well the density and relative stabilities of ices. Therefore the TIP4PQ/2005 model, while still simple, allows one to analyze the interplay between quantum effects related to atomic masses and intermolecular forces in water. PMID- 19791906 TI - Surfactant formation efficiency of fluorocarbon-hydrocarbon oligomers in supercritical CO2. AB - We use dissipative particle dynamics simulations to explore the phase behavior and solution properties of ABCBA type model surfactants in near-supercritical CO(2) environment. We present design guidelines for functional surfactants with tunable properties. The block co-oligomers used in this study are made up of a CO(2)-phobic block having ethyl propionate and nine different types of ethylene monomers, flanked on either side by eight repeat units of fluorinated CO(2) philic blocks. The most promising design block co-oligomer in the series is that with the longest CO(2)-phobic group in the ethylene monomers. For this particular oligomer, we systematically analyze the effect of concentration on the self assembly behavior. Spherical micelles form in the 5%-65% volume fraction range for this oligomer, with the highest number of spherical micelles occurring at 45% surfactant in CO(2). When the volume fraction of the surfactant is increased from 70% to 85%, cylindrical micelles occur. We further investigate the effect of the length of the solvophilic fluorinated segments on self-assembly and find that stable micelles occur in a window of 8-14 repeat units. We find that the most critical contribution to stability is due to the mixing free energy between the chain tails residing in the outer layers and the interpenetrating molecules. PMID- 19791907 TI - Single molecule power-law behavior on a crystalline surface. AB - Single perylene bisimide molecules deposited onto Al(2)O(3) (0001) and investigated under controlled ultrahigh vacuum conditions display fluorescence intermittency behavior characteristic of an interfacial charge transfer process. Remarkably, even though the molecules are deposited on a crystalline surface with reduced disorder, power-law-distributed bright and dark periods are observed. These data can be understood based on activated formation of localized small polaron states in Al(2)O(3) (0001). We present a kinetic scheme capable of explaining the occurrence of power-law distributions for both "on" and "off" periods for single molecules on the sapphire substrate. These findings represent a first step toward understanding interfacial charge transfer processes under controlled conditions on crystalline surfaces and at the single molecule level. PMID- 19791908 TI - Modeling the polaronic nature of p-type defects in Cu2O: the failure of GGA and GGA + U. AB - The exact nature of the hole traps reported deep in the band gap of Cu(2)O has been a topic of vigorous debate, with copper vacancies and oxygen interstitials both having been proposed as the relevant defects. In this article, the electronic structure of acceptor-forming defects in Cu(2)O, namely, copper vacancies and oxygen interstitials, is investigated using generalized gradient approximation (GGA) and GGA corrected for on-site Coulombic interactions (GGA+U). GGA produces notionally semimetallic defect complexes, which is not consistent with the experimentally known polaronic nature of conduction in Cu(2)O. GGA+U also predicts a semimetallic defect complex for the "simple" copper vacancy but predicts the "split" vacancy and both oxygen interstitials are characterized by localized polarons, with distinct single particle levels found in the band gap. For both methods, however, the positions of calculated transition levels are inconsistent with experimental ionization levels. Hence neither GGA nor GGA+U are successful in modeling p-type defects in Cu(2)O. PMID- 19791909 TI - Solvent mediated interactions between model colloids and interfaces: a microscopic approach. AB - We determine the solvent mediated contribution to the effective potentials for model colloidal or nanoparticles dispersed in a binary solvent that exhibits fluid-fluid phase separation. The interactions between the solvent particles are taken to be purely repulsive point Yukawa pair potentials. Using a simple density functional theory we calculate the density profiles of both solvent species in the presence of the "colloids," which are treated as external potentials, and determine the solvent mediated (SM) potentials. Specifically, we calculate SM potentials between (i) two colloids, (ii) a colloid and a planar fluid-fluid interface, and (iii) a colloid and a planar wall with an adsorbed wetting film. We consider three different types of colloidal particles: Colloid A that prefers the bulk solvent phase rich in species 2, colloid C that prefers the solvent phase rich in species 1, and "neutral" colloid B that has no strong preference for either phase, i.e., the free energies to insert the colloid into either of the coexisting bulk phases are almost equal. When a colloid that has a preference for one of the two solvent phases is inserted into the disfavored phase at state points close to coexistence a thick adsorbed "wetting" film of the preferred phase may form around the colloids. The presence of the adsorbed film has a profound influence on the form of the SM potentials. In case (i) reducing the separation between the two colloids of type A leads to a bridging transition whereby the two adsorbed films connect abruptly and form a single fluid bridge. The SM potential is strongly attractive in the bridged configuration. A similar phenomenon occurs in case (iii) whereby the thick adsorbed film on colloid A and that at the planar wall, which prefers the same phase as colloid A, connect as the separation between the colloid and the wall is reduced. In both cases the bridging transition is accompanied, in this mean-field treatment, by a discontinuity of the SM force. On the other hand, for the same wall, and a colloid of type C, the SM potential is strongly repulsive at small separations. For case (ii), inserting a single colloidal particle near the planar fluid-fluid interface of the solvent, the density profiles of the solvent show that the interface distortion depends strongly on the nature of the colloid-solvent interactions. When the interface disconnects from the colloid there is, once again, a discontinuity in the SM force. PMID- 19791910 TI - Understanding interactions between capped nanocrystals: three-body and chain packing effects. AB - Self-assembly of capped nanocrystals (NC) attracted a lot of attention over the past decade. Despite progress in manufacturing of NC superstructures, the current understanding of their mechanical and thermodynamic stability is still limited. For further applications, it is crucial to find the origin and the magnitude of the interactions that keep self-assembled NCs together, and it is desirable to find a way to rationally manipulate these interactions. We report on molecular simulations of interacting gold NCs protected by capping molecules. We computed the potential of mean force for pairs and triplets of NCs of different size (1.8 3.7 nm) with varying ligand length (ethanethiol-dodecanethiol) in vacuum. Pair interactions are strongly attractive due to attractive van der Waals interactions between ligand molecules. Three-body interaction results in an energy penalty when the capping layers overlap pairwise. This effect contributes up to 20% to the total energy for short ligands. For longer ligands, the three-body effects are so large that formation of NC chains becomes energetically more favorable than close packing of capped NCs at low concentrations, in line with experimental observations. To explain the equilibrium distance for two or more NCs, the overlap cone model is introduced. This model is based on relatively simple ligand packing arguments. In particular, it can correctly explain why the equilibrium distance for a pair of capped NCs is always approximately 1.25 times the core diameter independently on the ligand length, as found in our previous work [Schapotschnikow, R. Pool, and T. J. H. Vlugt, Nano Lett. 8, 2930 (2008)]. We make predictions for which ligands capped NCs self-assemble into highly stable three-dimensional structures, and for which they form high-quality monolayers. PMID- 19791911 TI - Large variations in the propensity of aqueous oxychlorine anions for the solution/vapor interface. AB - Core-level photoelectron spectroscopy measurements have been performed of aqueous solutions of NaCl codissolved with NaClO(n) (n=1-4). Each species has a distinct Cl 2p electron binding energy, which can be exploited for depth-profiling experiments to study the competition between Cl(-) and ClO(n)(-) anions for residing in the outermost layers of the solution/vapor interface. Strongest propensity for the surface is observed for n=4 (perchlorate), followed by n=3 (chlorate), n=2 (chlorite), n=0 (chloride), and n=1 (hypochlorite). Molecular dynamics simulations rationalize the greatest surface propensity of the most oxidized anions in terms of their larger size and polarizability. The anomalous behavior of hypochlorite, being less surface-active than chloride, although it is both larger and more polarizable, is suggested to arise from the charge asymmetry over the anion, increasing its efficiency for bulk solvation. PMID- 19791912 TI - Monte Carlo calculation of the methane-water interfacial tension at high pressures. AB - Monte Carlo simulations have been performed in the Np(N)AT statistical ensemble to study the methane-water mixture as a function of pressure. The interfacial tensions are calculated with different definitions and are reported for pressures from 1 to 50 MPa. The interfacial tensions, coexisting densities, and composition of the methane and water phases are shown to be in good agreement with the corresponding experimental properties. The interfacial region has been described through the profiles of the number of hydrogen bonds, the coordination number of each species, and the different energy contributions. We complete this study by a theoretical investigation of the thermal and mechanical equilibria in the binary mixture. We have also examined the profile of the intrinsic and long range correction parts of the interfacial tension along the normal to the water surface. PMID- 19791913 TI - Nucleation of wetting films on cylindrical and spherical substrates: a numerical study by the string method. AB - Using the mean-field diffuse-interface model for liquid-vapor system and employing the numerical string method, we study the critical nuclei involved in the prewetting transitions on curved substrates. We first introduce three distinct kinds of critical nuclei, namely, the disklike, bandlike, and layerlike ones, which respectively correspond to three possible growth modes of wetting films. We show the disklike growth mode to be the only mode for infinite planar substrates. We then turn to cylindrical and spherical substrates, the two simplest but most important geometries in the real world. We focus on the critical nuclei of finite size, through which the wetting films may be formed with finite thermodynamic probabilities. It is shown that the disklike growth mode is always the most probable for wetting film nucleation and growth as long as a disklike critical nucleus exists. It is also shown that on a cylindrical substrate, the disklike critical nucleus can no longer exist if the substrate radius is smaller than some critical value, comparable to the radius of the disklike critical nucleus on planar substrate. We find that on a cylindrical substrate whose radius is below the critical value, the nucleation and growth of a wetting film can only occur through the bandlike critical nucleus. It is worth emphasizing that the results concerning the bandlike and layerlike growth modes can only be obtained from the diffuse-interface model, beyond the macroscopic description based on the line and surface tensions. PMID- 19791914 TI - Study of SF6 adsorption on graphite using infrared spectroscopy. AB - We report an experimental study of adsorbed monolayers of SF(6) on graphite using infrared reflection absorption spectroscopy supplemented by ellipsometry. The asymmetric S-F stretch mode nu(3) near 948 cm(-1) in the gas is strongly blueshifted in the film by dynamic dipole coupling. This blueshift is very sensitive to the intermolecular spacing in the SF(6) layer. We convert the measured frequency nu(3) to a lattice spacing a, using a self-consistent field calculation, calibrated by the frequency in the commensurate phase. The resolution in lattice spacing is 0.002 A, although there is a larger systematic uncertainty associated with nondynamic-dipole contributions to the frequency shift. We map the commensurate-incommensurate transition, a transition between two incommensurate phases, and the melting transition. These results are compared to previous x-ray data. We provide a new determination of the layer critical point (156 K), the layer condensation line down to 110 K, and the spreading pressure at saturation in this temperature range. PMID- 19791915 TI - Modeling of the polyethylene and poly(L-lactide) triblock copolymer: a dissipative particle dynamics study. AB - Dissipative particle dynamics (DPD), a mesoscopic simulation approach, has been used to investigate the effect of the arrangement of the microstructure and the effect of the volume fraction on the structural properties of the immiscible polyethylene (PE)/poly(L-lactide) (PLLA) polymer in the triblock copolymer system. In this work, the interaction parameter in DPD simulation, related to the Flory-Huggins interaction parameter chi, is estimated by the calculation of mixing energy for each pair of components in molecular dynamics simulation. The immiscibility property of PE and PLLA polymers induces phase separation and exhibits different architectures at different volume fractions. In order to obtain the structural property, the radius of gyration and the end-to-end distance are used to observe the detailed arrangement of the triblock copolymer. The results show first that the relative volume fractions of PE and PLLA directly affect the bridge and loop fraction, and, second, that whether or not the arrangement is symmetrical or asymmetrical affects the equilibrium structure in the triblock copolymer system. Moreover, as the chain length of the component chains within the PE-PLLA-PE triblock copolymer increase, those component chains become softer; therefore, this directly affects the bridge and loop fraction. PMID- 19791916 TI - Single-molecule pulling and the folding of donor-acceptor oligorotaxanes: phenomenology and interpretation. AB - The thermodynamic driving force in the folding of a class of oligorotaxanes is elucidated by means of molecular dynamics simulations of equilibrium isometric single-molecule force spectroscopy by atomic force microscopy experiments. The oligorotaxanes consist of cyclobis(paraquat-p-phenylene) rings threaded onto an oligomer of 1,5-dioxynaphthalenes linked by polyethers. The simulations are performed in a high dielectric medium using MM3 as the force field. The resulting force versus extension isotherms show a mechanically unstable region in which the molecule unfolds and, for selected extensions, blinks in the force measurements between a high-force and a low-force regime. From the force versus extension data the molecular potential of mean force is reconstructed using the weighted histogram analysis method and decomposed into energetic and entropic contributions. The simulations indicate that the folding of the oligorotaxanes is energetically favored but entropically penalized, with the energetic contributions overcoming the entropy penalty and effectively driving the folding. In addition, an analogy between the single-molecule folding/unfolding events driven by the atomic force microscope (AFM) tip and the thermodynamic theory of first-order phase transitions is discussed. General conditions (on the molecule and the AFM cantilever) for the emergence of mechanical instabilities and blinks in the force measurements in equilibrium isometric pulling experiments are also presented. In particular, it is shown that the mechanical stability properties observed during the extension are intimately related to the fluctuations in the force measurements. PMID- 19791917 TI - Simulation of dilute solutions of linear and star-branched polymers by dissipative particle dynamics. AB - A most promising off-lattice technique in order to simulate not only static but in addition dynamic behavior of linear and star-branched chains is the dissipative particle dynamics (DPD) method. In this model the atomistic representation of polymer molecules is replaced by a (coarse-grained) equivalent chain consisting of beads which are repulsive for each other in order to mimic the excluded volume effect (successive beads in addition are linked by springs). Likewise solvent molecules are combined to beads which in turn are repulsive for each other as well as for the polymer segments. The system is relaxed by molecular dynamics solving Newton's laws under the influence of short ranged conservative forces (i.e., repulsion between nonbonded beads and a proper balance of repulsion and attraction between bonded segments) and dissipative forces due to friction between particles, the latter representing the thermostat in conjunction with proper random forces. A variation of the strength of the repulsion between different types of beads allows the simulation of any desired thermodynamic situation. Static and dynamic properties of isolated linear and star-branched chains embedded in athermal, exothermal, and endothermal solvent are presented and theta conditions are examined. The generally accepted scaling concept for athermal systems is fairly well reproduced by linear and star branched DPD chains and theta conditions appear for a unique parameter independent of functionality as in the case of Monte Carlo simulations. Furthermore, the correspondence between DPD and Monte Carlo data referring to the shape of chains and stars is fairly well, too. For dilute solutions the Zimm behavior is expected for dynamic properties which is indeed realized in DPD systems. PMID- 19791918 TI - Elastic Lennard-Jones polymers meet clusters: differences and similarities. AB - We investigate solid-solid and solid-liquid transitions of elastic flexible off lattice polymers with Lennard-Jones monomer-monomer interaction and anharmonic springs by means of sophisticated variants of multicanonical Monte Carlo methods. We find that the low-temperature behavior depends strongly and nonmonotonically on the system size and exhibits broad similarities to unbound atomic clusters. Particular emphasis is dedicated to the classification of icosahedral and nonicosahedral low-energy polymer morphologies. PMID- 19791919 TI - Combinatorial design of protein sequences with applications to lattice and real proteins. AB - Understanding the evolution of protein structures from specific sequences may be achieved by predicting the desired folded structure from a given sequence and by predicting compatible sequences from a known structure using principles of protein folding and design. Protein design requires the synthesis of a broad range of sequences consistent with a preassigned target conformation. However, the number of possible protein sequences for a given target structure exponentially increases with the number of residues making the explicit tabulation of all sequences intractable experimentally and computationally. For sequence libraries of arbitrary size, the results of a self-consistent mean field theory is applied to a three-dimensional cubic lattice model of proteins and real homologous protein sequences to estimate the number and probabilistic composition of sequences consistent with a generalized foldability criterion. Theoretically calculated site-specific monomer probabilities and the monomer pair probabilities at each position in a sequence are compared to those obtained from exact enumeration for cubic lattice proteins. For real proteins the theoretically predicted sequence variability are compared to that obtained from a set of homologous protein sequences. The theory results match extremely well with both the cubic lattice protein and real protein results. The theory also evaluates the mutability of specific residues and identifies the beneficial mutations. The theory may be used to quantify particular design strategies and explore site directed mutagenesis strategies in crafting de novo proteins in context of in vitro protein evolution. PMID- 19791920 TI - Transport properties of water at functionalized molecular interfaces. AB - Understanding transport properties of solvent such as diffusion and viscosity at interfaces with biomacromolecules and hard materials is of fundamental importance to both biology and biotechnology. Our study utilizes equilibrium molecular dynamics simulations to calculate solvent transport properties at a model peptide and microarray surface. Both diffusion and selected components of viscosity are considered. Solvent diffusion is found to be affected near the peptide and surface. The stress-stress correlation function of solvent near the hard surface exhibits long time memory. Both diffusion and viscosity are shown to be closely correlated with the density distribution function of water along the microarray surface. PMID- 19791921 TI - Identification of the slower secondary relaxation's nature in maltose by means of theoretical and dielectric studies. AB - Dielectric relaxation measurements on maltose were performed at ambient and increasing pressure. The loss spectra collected below glass transition of this disaccharide revealed presence of two well separated secondary relaxations. Activation energies determined for both modes are E(a)=73 kJ/mol and 47 kJ/mol for the slower (beta) and faster (gamma) relaxation, respectively. From high pressure measurements activation volume DeltaV=15.6 ml/mol for the slower secondary relaxation was estimated. Both quantities: activation energy and activation volume for alpha-process derived from dielectric data, were compared to those obtained from the conformational calculations with use of density functional theory (DFT). We found out satisfactory agreement between both quantities for the molecular motion related to the rotation of the two monosaccharide units around glycosidic linkage in this disaccharide. PMID- 19791923 TI - Comment on "Equivalence of two approaches for quantum-classical hybrid systems" [J. Chem. Phys. 128, 204104 (2008)]. AB - We discuss the links between consistent and approximate descriptions of the quantum-classical systems, i.e., systems composed of two interacting subsystems, one of which behaves almost classically while the other requires a quantum description. PMID- 19791922 TI - Structure and thermodynamics of colloidal protein cluster formation: comparison of square-well and simple dipolar models. AB - Reversible formation of weakly associated protein oligomers or clusters is a key early step in processes such as protein aggregation and colloidal phase separation. A previously developed cell-based, quasichemical model for lattice fluids [T. M. Young and C. J. Roberts, J. Chem. Phys. 127, 165101 (2007)] is extended here to treat continuous-space systems. It is illustrated using two simplified limiting cases for globular proteins at the isoelectric point: spherical square-well (SW) particles with an isotropic short-ranged attraction and screened dipolar particles with SW attractions and square-shoulder repulsions. Cluster free energies (DeltaA(i)) and structures are analyzed as a function of the reduced second virial coefficient b(2)(*). DeltaA(i) values and the average structures of clusters up to pentamers have distinct differences due to the anisotropic nature of the dipolar interactions. However, DeltaA(i) values can be mapped semiquantitatively between the two cases if compared at common values of b(2)(*). Free energy landscapes of oligomerization are constructed, illustrating significant differences in landscape ruggedness for small clusters of dipolar versus SW fluids, and suggesting a possible molecular interpretation for empirical models of nucleation-dependent aggregation of proteins. PMID- 19791926 TI - Simultaneous readout of multiple microcantilever arrays with phase-shifting interferometric microscopy. AB - A complete system for the simultaneous monitoring of multiple cantilever sensors from different sensor arrays has been developed and tested for gas- and liquid phase applications. The cantilever sensors are operated in static-deflection mode and the readout is achieved with phase-shifting interferometric microscopy (PSIM). In contrast to existing cantilever-sensor readout methods, PSIM is not dependent on alignment and allows the monitoring of the entire displacement profiles of all cantilevers within the field of view, using just one light source. To complement the PSIM readout, we have developed a sample cell, which can hold multiple cantilever-array chips, allows for very fast and reproducible sensor-chip replacement, has very low sample-volume requirements, and allows for individual or common addressing of all chips in the sample cell. We demonstrate the functionality of our microcantilever sensor system with a setup that can monitor eight cantilevers from four different sensor chips simultaneously. PMID- 19791927 TI - Radiation damage resistance of AlGaN detectors for applications in the extreme ultraviolet spectral range. AB - We report on the fabrication of aluminum gallium nitride (AlGaN) Schottky photodiode-based detectors. AlGaN layers were grown using metal-organic chemical vapor deposition (MOCVD) on Si(111) wafers. The diodes were characterized at a wavelength of 13.5 nm using a table-top extreme-ultraviolet (EUV) radiation source, consisting of a laser-produced xenon plasma and a Schwarzschild objective. The responsivity of the diodes was tested between EUV energies ranging from 320 nJ down to several picojoules. For low fluences, a linear responsivity of 7.14 mAs/J could be determined. Saturation starts at approximately 1 nJ, merging into a linear response of 0.113 mAs/J, which could be attributed to the photoeffect on the Au electrodes on top of the diode. Furthermore, degradation tests were performed up to an absolute dose of 3.3x10(19) photons/cm(2). AlGaN photodiodes were compared to commercially available silicon-based photodetectors. For AlGaN diodes, responsivity does not change even for the highest EUV dose, whereas the response of the Si diode decreases linearly to approximately 93% after 2x10(19) photons/cm(2). PMID- 19791928 TI - Retroreflecting polarization spectroscopy enabling miniaturization. AB - We describe and characterize alternative configurations for Doppler-free polarization spectroscopy. The suggested apparatus enables complete pump/probe beam overlap and allows substantial miniaturization. Its utility and performance for narrow linewidth, high-stability frequency locking is discussed for the /5S(1/2)F=2>-->/5P(3/2)F(')>D(2) transition in (87)Rb. PMID- 19791929 TI - Hyperthermal atomic oxygen source for near-space simulation experiments. AB - A hyperthermal atomic oxygen (AO) beam facility has been developed to investigate the collisions of high-velocity AO atoms with vapor-phase counterflow. Application of 4.5 kW, 2.4 GHz microwave power in the source chamber creates a continuous discharge in flowing O(2) gas. The O(2) feedstock is introduced into the source chamber in a vortex flow to constrain the plasma to the center region, with the chamber geometry promoting resonant excitation of the TM(011) mode to localize the energy deposition in the vicinity of the aluminum nitride (AlN) expansion nozzle. The approximately 3500 K environment serves to dissociate the O(2), resulting in an effluent consisting of 40% AO by number density. Downstream of the nozzle, a silicon carbide (SiC) skimmer selects the center portion of the discharge effluent, prior to the expansion reaching the first shock front and rethermalizing, creating a beam with a derived 2.5 km s(-1) velocity. Differential pumping of the skimmer chamber, an optional intermediate chamber and reaction chamber maintains a reaction chamber pressure in the mid-10(-6) to mid 10(-5) Torr range. The beam has been characterized with regard to total AO beam flux, O(2) dissociation fraction, and AO spatial profile using time-of-flight mass spectrometric and Kapton-H erosion measurements. A series of reactions AO+C(n)H(2n) (n=2-4) has been studied under single-collision conditions using mass spectrometric product detection, and at higher background pressure detecting dispersed IR emissions from primary and secondary products using a step-scan Michelson interferometer. In a more recent AO crossed-beam experiment, number densities and predicted IR emission intensities have been modeled using the direct simulation Monte Carlo technique. The results have been used to guide the experimental conditions. IR emission intensity predictions are compared to detected signal levels to estimate absolute reaction cross sections. PMID- 19791930 TI - Performances of a bent-crystal spectrometer adapted to resonant x-ray emission measurements on gas-phase samples. AB - We describe a bent-crystal spectrometer adapted to measure x-ray emission resulting from core-level excitation of gas-phase molecules in the 0.8-8 keV energy range. The spectrometer is based on the Johann principle, and uses a microfocused photon beam to provide high-resolution (resolving power of approximately 7500). A gas cell was designed to hold a high-pressure (300 mbar) sample of gas while maintaining a high vacuum (10(-9) mbar) in the chamber. The cell was designed to optimize the counting rate (2000 cts/s at the maximum of the Cl Kalpha emission line), while minimizing self-absorption. Example of the Kalpha emission lines of CH(3)Cl molecules is presented to illustrate the capabilities of this new instrument. PMID- 19791931 TI - Resonator spectrometer for precise broadband investigations of atmospheric absorption in discrete lines and water vapor related continuum in millimeter wave range. AB - The instrument and methods for measuring spectral parameters of discrete atmospheric lines and water-related continuum absorption in the millimeter wave range are described. The instrument is based on measurements of the Fabry-Perot resonance response width using fast phase continuous scanning of the frequency synthesized radiation. The instrument allows measurement of gas absorptions at the cavity eigenfrequencies ranging from 45 to 370 GHz with the highest to date absorption variation sensitivity of 4x10(-9) cm(-1). The use of a module of two rigidly bounded maximum identical resonators differing in length by exactly a factor of two allows accurate separation of the studied gas absorption and spectrometer baseline, in particular, the absorption by water adsorbed on the resonator elements. The module is placed in a chamber with temperature controlled between -30 and +60 degrees C, which permits investigation of temperature dependence of absorption. It is shown that systematic measurement error of discrete atmospheric line parameters does not exceed the statistical one and the achieved accuracy satisfies modern demands for the atmospheric remote sensing data retrieval. Potential systematic error arising from the neglect of the effect of water adsorption on mirror surfaces is discussed. Examples of studies of water and oxygen spectral line parameters as well as continuum absorption in wet nitrogen are given. PMID- 19791932 TI - Strain, curvature, and twist measurements in digital holographic interferometry using pseudo-Wigner-Ville distribution based method. AB - Measurement of strain, curvature, and twist of a deformed object play an important role in deformation analysis. Strain depends on the first order displacement derivative, whereas curvature and twist are determined by second order displacement derivatives. This paper proposes a pseudo-Wigner-Ville distribution based method for measurement of strain, curvature, and twist in digital holographic interferometry where the object deformation or displacement is encoded as interference phase. In the proposed method, the phase derivative is estimated by peak detection of pseudo-Wigner-Ville distribution evaluated along each row/column of the reconstructed interference field. A complex exponential signal with unit amplitude and the phase derivative estimate as the argument is then generated and the pseudo-Wigner-Ville distribution along each row/column of this signal is evaluated. The curvature is estimated by using peak tracking strategy for the new distribution. For estimation of twist, the pseudo-Wigner Ville distribution is evaluated along each column/row (i.e., in alternate direction with respect to the previous one) for the generated complex exponential signal and the corresponding peak detection gives the twist estimate. PMID- 19791933 TI - Vacuum-compatible pulse selector for free-electron laser. AB - We developed a vacuum-compatible pulse selector for a free-electron laser. A rotating cylinder with eight apertures in a vacuum is driven by a closed-loop stepping motor system through a magnetically coupled rotary feedthrough. A field programmable gate array is used to synchronize the cylinder rotation with a trigger signal of the accelerator at a maximum repetition rate of 60 Hz. We achieved to select specific pulses from a continuous pulse train of the SPring-8 Compact SASE Source. PMID- 19791934 TI - Microelectromechanical system assembled ion optics: An advance to miniaturization and assembly of electron and ion optics. AB - Deep-reactive ion etching of n-doped silicon-on-insulator is utilized to make ion optical components to aid in the miniaturization of mass analyzers. The microelectromechanical system components are bound to aluminum nitride substrates and employed three-dimensional assembly. The assembly methods are tested for breakdown (V(b)), durability, and alignment. Demonstration of ion manipulation is shown with a 1 mm Bradbury-Nielsen gate, 500 mum Einzel lens, 500 mum coaxial ring ion trap, and reflectron optics. Data are presented showing the resolution, attenuation, and performance of each of these devices. We demonstrate advantages and disadvantages of this technology and its applications to mass analysis. PMID- 19791935 TI - All-solid-state repetitive semiconductor opening switch-based short pulse generator. AB - The operating characteristics of a semiconductor opening switch (SOS) are determined by its pumping circuit parameters. SOS is still able to cut off the current when pumping current duration falls to the order of tens of nanoseconds and a short pulse forms simultaneously in the output load. An all-solid-state repetitive SOS-based short pulse generator (SPG100) with a three-level magnetic pulse compression unit was successfully constructed. The generator adopts magnetic pulse compression unit with metallic glass and ferrite cores, which compresses a 600 V, 10 mus primary pulse into short pulse with forward pumping current of 825 A, 60 ns and reverse pumping current of 1.3 kA, 30 ns. The current is sent to SOS in which the reverse pumping current is interrupted. The generator is capable of providing a pulse with the voltage of 120 kV and duration of 5-6 ns while output load being 125 Omega. The highest repetition rate is up to 1 kHz. PMID- 19791936 TI - Antenna design for fast ion collective Thomson scattering diagnostic for the international thermonuclear experimental reactor. AB - Fast ion physics will play an important role for the international thermonuclear experimental reactor (ITER), where confined alpha particles will affect and be affected by plasma dynamics and thereby have impacts on the overall confinement. A fast ion collective Thomson scattering (CTS) diagnostic using gyrotrons operated at 60 GHz will meet the requirements for spatially and temporally resolved measurements of the velocity distributions of confined fast alphas in ITER by evaluating the scattered radiation (CTS signal). While a receiver antenna on the low field side of the tokamak, resolving near perpendicular (to the magnetic field) velocity components, has been enabled, an additional antenna on the high field side (HFS) would enable measurements of near parallel (to the magnetic field) velocity components. A compact design solution for the proposed mirror system on the HFS is presented. The HFS CTS antenna is located behind the blankets and views the plasma through the gap between two blanket modules. The viewing gap has been modified to dimensions 30x500 mm(2) to optimize the CTS signal. A 1:1 mock-up of the HFS mirror system was built. Measurements of the beam characteristics for millimeter-waves at 60 GHz used in the mock-up agree well with the modeling. PMID- 19791937 TI - Advancements in electron cyclotron emission imaging demonstrated by the TEXTOR ECEI diagnostic upgrade. AB - A new TEXTOR electron cyclotron emission imaging system has been developed and employed, providing a diagnostic with new features and enhanced capabilities when compared to the legacy system it replaces. Optical coupling to the plasma has been completely redesigned, making use of new minilens arrays for reduced optical aberration and providing the new feature of vertical zoom, whereby the vertical coverage is now remotely adjustable on a shot-by-shot basis from 20-35 cm. Other innovations, such as the implementation of stacked quasioptical planar notch filters, allow for the diagnostic to be operated without interruption or degradation in performance during electron cyclotron resonance heating. Successful commissioning of the new diagnostic and a demonstration of the improved capabilities are presented in this paper, along with a discussion of the new technologies employed. PMID- 19791938 TI - How to measure forces with atomic force microscopy without significant influence from nonlinear optical lever sensitivity. AB - In an atomic force microscope (AFM), the force is normally sensed by measuring the deflection of a cantilever by an optical lever technique. Experimental results show a nonlinear relationship between the detected signal and the actual deflection of the cantilever, which is widely ignored in literature. In this study we have designed experiments to investigate different possible reasons for this nonlinearity and compared the experimental findings with calculations. It is commonly assumed that this nonlinearity only causes problems for extremely large cantilever deflections. However, our results show that the nonlinear detector response might influence many AFM studies where soft or short cantilevers are used. Based on our analysis we draw conclusions of the main reason for the nonlinearity and suggest a rule of thumb for which cantilevers one should use under different experimental conditions. PMID- 19791939 TI - The design and application of an in-laboratory diffraction-enhanced x-ray imaging instrument. AB - We describe the design and application of a new in-laboratory diffraction enhanced x-ray imaging (DEXI) instrument that uses a nonsynchrotron, conventional x-ray source to image the internal structure of an object. In the work presented here, a human cadaveric thumb is used as a test-sample to demonstrate the imaging capability of our instrument. A 22 keV monochromatic x-ray beam is prepared using a mismatched, two-crystal monochromator; a silicon analyzer crystal is placed in a parallel crystal geometry with the monochromator allowing both diffraction enhanced imaging and multiple-imaging radiography to be performed. The DEXI instrument was found to have an experimentally determined spatial resolution of 160+/-7 mum in the horizontal direction and 153+/-7 mum in the vertical direction. As applied to biomedical imaging, the DEXI instrument can detect soft tissues, such as tendons and other connective tissues, that are normally difficult or impossible to image via conventional x-ray techniques. PMID- 19791940 TI - Holders for in situ treatments of scanning tunneling microscopy tips. AB - We have developed holders for scanning tunneling microscopy tips that can be used for in situ treatments of the tips, such as electron bombardment (EB) heating, ion sputtering, and the coating of magnetic materials. The holders can be readily installed into the transfer paths and do not require any special type of base stages. Scanning electron microscopy is used to characterize the tip apex after EB heating. Also, spin-polarized scanning tunneling spectroscopy using an Fe coated W tip on the Cr(001) single crystal surface is performed in order to confirm both the capability of heating a tip up to about 2200 K and the spin sensitivity of the magnetically coated tip. PMID- 19791941 TI - A neutron imaging device for sample alignment in a pulsed neutron scattering instrument. AB - A neutron-imaging device for alignment purposes has been tested on the INES beamline at ISIS, the pulsed neutron source of Rutherford Appleton Laboratory (U.K.). Its use, in conjunction with a set of movable jaws, turns out extremely useful for scattering application to complex samples where a precise and well defined determination of the scattering volume is needed. PMID- 19791942 TI - Microscopic Faraday rotation measurement system using pulsed magnetic fields. AB - Microscopic Faraday rotation measurement system using a pulsed magnetic field has been constructed, which can be applied to micron sized diamagnetic and paramagnetic materials. A pulsed magnetic coil could generate a maximum magnetic flux density of about 12 T. The performance of the microscopic Faraday rotation apparatus was demonstrated by the measurement of the Verdet constant V of a polystyrene particle, after the calibration of the pulsed magnetic flux density using a glass plate as a standard material. Also, the magneto-optical rotation dispersion of some diamagnetic substances have been measured and analyzed with V=alambda(-2)+b. The values of a and b were compared to their magnetic susceptibilities. PMID- 19791943 TI - Determination of local refractive index variations in thin films by heterodyne interferometric scanning near-field optical microscopy. AB - We report on a heterodyne interferometric scanning near-field optical microscope developed for characterizing, at the nanometric scale, refractive index variations in thin films. An optical lateral resolution of 80 nm (lambda/19) and a precision smaller than 10(-4) on the refractive index difference have been achieved. This setup is suitable for a wide set of thin films, ranging from periodic to heterogeneous samples, and turns out to be a very promising tool for determining the optical homogeneity of thin films developed for nanophotonics applications. PMID- 19791944 TI - Large scan area high-speed atomic force microscopy using a resonant scanner. AB - A large scan area high-speed scan stage for atomic force microscopy using the resonant oscillation of a quartz bar has been constructed. The sample scanner can be used for high-speed imaging in both air and liquid environments. The well defined time-position response of the scan stage due to the use of resonance allows highly linearized images to be obtained with a scan size up to 37.5 mum in 0.7 s. The scanner is demonstrated for imaging highly topographic silicon test samples and a semicrystalline polymer undergoing crystallization in air, while images of a polymer and a living bacteria, S. aureus, are obtained in liquid. PMID- 19791945 TI - Measurement of the spectral directivity of optoacoustic and ultrasonic transducers with a laser ultrasonic source. AB - Comprehensive characterization of wideband ultrasonic transducers and specifically optoacoustic detectors is achieved through the analysis of their frequency response as a function of the incident angle. The tests are performed under well-defined, repeatable operating conditions. Backillumination of a blackened, acoustically matched planar surface with a short laser pulse creates an acoustic impulse which is used as a wideband ultrasonic source. Upon illumination with a short laser pulse, the bandwidth of our source shows a -6 dB point of 12 MHz and a low-frequency roll-off around 300 kHz. Using proprietary software, we examine thoroughly the planarity of the emitted wave front within a specified amplitude cutoff and phase incoherence. Analysis of the angular dependence of the frequency response yields invaluable directivity information about the detector under study: a necessary component toward accurate optoacoustic image reconstruction and quantitative tomography. The laser ultrasonic source we developed is the main feature of our directivity measurement setup. Due to its simplicity, it can easily be adapted to various calibration devices. This paper focuses on the development and characterization of the flatness and the bandwidth of our wideband ultrasonic source. PMID- 19791947 TI - Thermoelectric properties and efficiency measurements under large temperature differences. AB - The maximum efficiency of a thermoelectric generator is determined by the material's dimensionless figure of merit ZT. Real thermoelectric material properties are highly temperature dependent and are often measured individually using multiple measurement tools on different samples. As a result, reported ZT values have large uncertainties. In this work we present an experimental technique that eliminates some of these uncertainties. We measure the Seebeck coefficient, electrical conductivity, and thermal conductivity of a single element or leg, as well as the conversion efficiency, under a large temperature difference of 2-160 degrees C. The advantages of this technique include (1) the thermoelectric leg is mounted only once and all measurements are in the same direction and (2) the measured properties are corroborated by efficiency measurements. The directly measured power and efficiency are compared to the values calculated from the measured properties and agree within 0.4% and 2%, respectively. The realistic testing conditions of this technique make it ideal for material characterization prior to implementation in a real thermoelectric generator. PMID- 19791946 TI - The integration of real and virtual magnetic resonance imaging experiments in a single instrument. AB - We present the design of an integrated system for performing both real and virtual (simulated) magnetic resonance imaging (MRI) experiments. We emphasize the approaches used to maximize the level of integration and also the benefits that tight real-virtual integration brings for a scientific instrument. The system has been implemented for both low field (0.2 T) and high field (9.4 T) imaging systems. The simulations can run for any MRI experiment and we demonstrate the operation of the system for T(1), T(2), T(2) ( *), and diffusion contrasts. PMID- 19791948 TI - Temporal multiplexing radiography for dynamic x-ray imaging. AB - All current x-ray imaging devices acquire images sequentially, one at a time. Using a spatially distributed multibeam x-ray source we recently demonstrated the feasibility for multiplexing x-ray imaging, which can significantly increase the data collection speed. Here we present a general methodology for dynamic x-ray imaging of an object in cyclic motion with temporal multiplexing. Compared to the conventional sequential imaging technique, where 2N-1 phase images are required and N exposures are needed for a single phase image, a temporal multiplexing of dimension 2N-1 can reduce the imaging time by a factor of N while maintaining the temporal resolution. PMID- 19791949 TI - Characterization of fiber texture by omega-scan x-ray diffraction. AB - On the basis of omega-scan x-ray diffraction (XRD), quantitative and qualitative characterization methods for fiber texture are proposed. The physical meaning of omega-scan curve is discussed in detail, and it is shown that the relative intensity curve of omega-scan XRD for a certain crystal plane is proportional to the pole density of the plane. Then qualitative and quantitative characterization methods for fiber texture are proposed from the concept of pole density. The proposed methods can be used in any crystal system. As an example for experimental verification, an orientation distribution function (ODF) experiment and a series of omega-scan XRD experiments are performed on a sputtered platinum film. From the comparison between the result of the ODF experiment and that of the analyses on the omega-scan XRD experiments, it is proved that the proposed qualitative and quantitative methods are effective and simple. PMID- 19791950 TI - A Seeman-Bohlin geometry for high-resolution nanosecond x-ray diffraction measurements from shocked polycrystalline and amorphous materials. AB - We report on a focusing x-ray diffraction geometry capable of high-resolution in situ lattice probing from dynamically loaded polycrystalline and amorphous materials. The Seeman-Bohlin-type camera presented here is ideally suited for time-resolved x-ray diffraction measurements performed on high energy multibeam laser platforms. Diffraction from several lattice planes of ablatively shock loaded 25 mum thick Cu foils was recorded on a focusing circle of diameter D=100 mm with exceptional angular resolution limited only by the spectral broadening of the x-ray source. Excellent agreement was found between the density measured using x-ray diffraction and that inferred from Doppler velocimetry and the known shock Hugoniot of Cu. In addition, x-ray diffraction signal was captured from an amorphous material under static conditions. PMID- 19791951 TI - Design and performance of a flow-through polarization-modulation infrared reflection-absorption spectroscopy cell for time-resolved simultaneous surface and liquid phase detection under concentration and temperature perturbations. AB - Design and performance of a flow-through cell for polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS) suitable for simultaneous monitoring of species on surface and in liquid phase on a molecular level at a high time resolution (ca. 1 s) are presented. In particular, the cell was designed to allow periodic concentration and temperature perturbations and thus excite physicochemical phenomena of interest occurring at solid-liquid interfaces. Utilizing the perturbations and spectral responses of both surface and liquid phase species, their dynamic behavior, kinetics, and correlations can be studied. The detection sensitivity is greatly enhanced by the data processing employed in modulation excitation spectroscopy (MES). The cell design is based on a theoretical model. The IR beam path through a multiple-phase system consisting of air, prism, and liquid as well as light reflection at the surface of a sample were considered in order to maximize the detected IR light intensity and absorption by surface molecules. Its high surface sensitivity was demonstrated by CO adsorption on a thin Pt film in a liquid phase. Combination of the PM-IRRAS with concentration MES led to a significant sensitivity enhancement for the detection of surface and liquid phase species. The temperature, tunable in a wide range from 263-343 K, could be controlled within an accuracy of 0.1 K and also modulated periodically in a completely reversible manner, thus allowing accurate temperature MES experiments. With these capabilities, dynamic physicochemical processes at solid-liquid interfaces can be sensitively investigated. PMID- 19791952 TI - Linearized superconducting quantum interference device array for high bandwidth frequency-domain readout multiplexing. AB - We have designed and demonstrated a superconducting quantum interference device (SQUID) array linearized with cryogenic feedback. To achieve the necessary loop gain, a 300-element series array SQUID is constructed from three monolithic 100 element series arrays. A feedback resistor completes the loop from the SQUID output to the input coil. The short feedback path of this linearized SQUID array (LISA) allows for a substantially larger flux-locked loop bandwidth as compared to a SQUID flux-locked loop that includes a room temperature amplifier. The bandwidth, linearity, noise performance, and 3 Phi(0) dynamic range of the LISA are sufficient for its use in our target application: the multiplexed readout of transition-edge sensor bolometers. PMID- 19791953 TI - Methods and analysis of processing signals of incremental optoelectronic transducer. AB - This article is a presentation of designed methods which interpolate signals from the optoelectronic transducer. This enables a way to distinguish the motion direction of the optoelectronic transducer and also to increase its accuracy. In this article methods based on logic functions, logic functions and RC circuits, phase processing were analyzed. In methods which are based on processing logic functions of transducer's signals there is a possibility of two times and four times increase in the transducer glass scale. The presented method of generating and processing sine signals with 18 degrees of the shift enables the reception of square signals with five times higher frequency compared to the basic signals. This method is universal and it can be used to the different scale of frequency multiplication of the optoelectronic transducer. The simulations of the methods were performed by using the MATLAB-SIMULINK software. PMID- 19791954 TI - Microwave window breakdown experiments and simulations on the UM/L-3 relativistic magnetron. AB - Experiments have been performed on the UM/L-3 (6-vane, L-band) relativistic magnetron to test a new microwave window configuration designed to limit vacuum side breakdown. In the baseline case, acrylic microwave windows were mounted between three of the waveguide coupling cavities in the anode block vacuum housing and the output waveguides. Each of the six 3 cm deep coupling cavities is separated from its corresponding anode cavity by a 1.75 cm wide aperture. In the baseline case, vacuum side window breakdown was observed to initiate at single waveguide output powers close to 20 MW. In the new window configuration, three Air Force Research Laboratory-designed, vacuum-rated directional coupler waveguide segments were mounted between the coupling cavities and the microwave windows. The inclusion of the vacuum side power couplers moved the microwave windows an additional 30 cm away from the anode apertures. Additionally, the Lucite microwave windows were replaced with polycarbonate windows and the microwave window mounts were redesigned to better maintain waveguide continuity in the region around the microwave windows. No vacuum side window breakdown was observed in the new window configuration at single waveguide output powers of 120+MW (a factor of 3 increase in measured microwave pulse duration and factor of 3 increase in measured peak power over the baseline case). Simulations were performed to investigate likely causes for the window breakdown in the original configuration. Results from these simulations have shown that in the original configuration, at typical operating voltage and magnetic field ranges, electrons emitted from the anode block microwave apertures strike the windows with a mean kinetic energy of 33 keV with a standard deviation of 14 keV. Calculations performed using electron impact angle and energy data predict a first generation secondary electron yield of 65% of the primary electron population. The effects of the primary aperture electron impacts, combined with multiplication of the secondary populations, were determined to be the likely causes of the poor microwave window performance in the original configuration. PMID- 19791955 TI - A frequency-domain thermoreflectance method for the characterization of thermal properties. AB - A frequency-domain thermoreflectance method for measuring the thermal properties of homogenous materials and submicron thin films is described. The method can simultaneously determine the thermal conductivity and heat capacity of a sample, provided the thermal diffusivity is greater, similar3x10(-6) m(2)/s, and can also simultaneously measure in-plane and cross-plane thermal conductivities, as well the thermal boundary conductance between material layers. Two implementations are discussed, one based on an ultrafast pulsed laser system and one based on continuous-wave lasers. The theory of the method and an analysis of its sensitivity to various thermal properties are given, along with results from measurements of several standard materials over a wide range of thermal diffusivities. We obtain specific heats and thermal conductivities in good agreement with literature values, and also obtain the in-plane and cross-plane thermal conductivities for crystalline quartz. PMID- 19791956 TI - Magnetoresistance of TVO temperature sensor at T<1 K. AB - A magnetoresistance (MR) of the well known TVO resistor temperature sensors has been studied at ultralow temperatures from approximately 0.8 K down to approximately 0.1 K under strong magnetic fields up to 8 T. A crossover from positive to negative MR with lowering temperature is found at weak magnetic fields. A zero MR-value at the magnetic field of 4 T, for example, is reached at T approximately 0.2 K. At sufficiently strong magnetic field the negative MR is suppressed and MR returns to positive values. A constant negative MR, which does not depend on the magnetic field from 2 to 8 T, is revealed at the lowest temperature T approximately 0.1 K. The observed behavior of the TVO sensor is explained basing on the model of hopping conduction via localized states in the weak localization regime. PMID- 19791957 TI - True temperature measurement on metallic surfaces using a two-color pyroreflectometer method. AB - In the most common case of optical pyrometry, the major obstacle in determining the true temperature is the knowledge of the thermo-optical properties for in situ conditions. We present experimental results obtained with a method able to determine the true temperature of metallic surfaces above 500 degrees C when there is not parasitic effect by surrounding radiation. The method is called bicolor pyroreflectometry and it is based on Planck's law, Kirchhoff's law, and the assumption of identical reflectivity indicatrixes for the target surface at two different close wavelengths (here, 1.3 and 1.55 microm). The diffusion factor eta(d), the key parameter of the method, is introduced to determine the convergence temperature T(*), which is expected to be equal to the true temperature T. Our goal is to asses this method for different metallic surfaces. The validation of this method is made by comparison with thermocouples. Measurements were made for tungsten, copper, and aluminum samples of different roughnesses, determined by a rugosimeter. After introducing a theoretical model for two-color pyroreflectometry, we give a description of the experimental setup and present experimental applications of the subject method. The quality of the results demonstrates the usefulness of two-color pyroreflectometry to determine the temperatures of hot metals when the emissivity is not known and for the commercially important case of specular surfaces. PMID- 19791958 TI - Precise determination of the pressure distortion coefficient of new controlled clearance piston-cylinders based on the Heydemann-Welch model. AB - A new controlled-clearance (CC) pressure balance has been developed with the aim of improving hydraulic pressure standards up to pressures of 1 GPa. The pressure balance is equipped with a weight-loading unit that can load/unload selected weights automatically and a CC piston-cylinder that is designed for the jacket pressure to be applied independently. In this paper, the effective area A(e) of two kinds of the CC piston-cylinders for pressures of 200 and 500 MPa was examined based on the Heydemann-Welch model. The two parameters in the model, the jacket pressure coefficient and the zero clearance jacket pressure, were precisely determined by the characterization experiments, after which the pressure dependence of A(e) and its uncertainty were estimated. The uncertainty due to the pressure dependence of A(e) for the 500 MPa CC piston-cylinder was less than 7.5x10(-8) MPa(-1). To confirm the consistency of the estimations, the results of the two CC piston-cylinders were compared through a free-deformation (FD) piston-cylinder; the two estimations were in agreement with each other. Moreover, it was shown that the extent of nonlinearity in the pressure dependence of A(e) of the FD piston-cylinder can be evaluated by calibration against the CC piston-cylinder. PMID- 19791959 TI - Transient measurement of light-emitting diode characteristic parameters for production lines. AB - A new instrument has been developed for transient measurement of light-emitting diodes (LEDs), including photometric parameters, colorimetric parameters, and electrical parameters in a matter of milliseconds, by combining spectrometer with a human photopic vision detector and data acquisition card (DAQ). The instrument can provide communication interface for sorter to realize automatic sorting of measured LEDs samples. The light emitted from the measured LEDs, which are illuminated under pulse current operation condition, is captured by the spectrometer and the human photopic vision detector. The spectral power distributions of LEDs are recorded by spectrometer, and processed to provide colorimetric parameters. We employ two novel algorithms including look-up table method and curve fitting method to determine the dominant wavelength of LED. In combination with linear interpolation, the look-up table method can locate dominant wavelength with a resolution of 0.1 nm. A programmable constant current source/voltage source is designed for power supply to drive LED. The luminous intensity of LED can be derived by detecting the photocurrent of human photopic vision detector. We also describe the calibration of the human photopic vision detector. This calibration provides detector-specific correction factor that enables accurate extraction of luminous intensity of LED. The instrument has been used to measure and inspect the quality of packaging LED. PMID- 19791960 TI - Development of metal nanocluster ion source based on dc magnetron plasma sputtering at room temperature. AB - A simple and cost effective nanocluster ion source for the deposition of size selected metal nanocluster has been developed based on the dc magnetron discharge (including pulsed dc discharge). The most important and interesting feature of this cluster source is that it is working at room temperature, cooled by chilled water during the experiment. There is no extraction unit in this device and the cluster streams flow only due to the pressure gradient from source chamber to substrate via quadrupole mass filter. It has provision of multiple substrate holders in the deposition chamber, which can be controlled manually. The facility consists of quadrupole mass filter (QMF 200), which can select masses in the range of 2-125 000 atoms depending on the target materials, with a constant mass resolution (M/DeltaM approximately 25). The dc magnetron discharge at a power of about 130 W with Ar as feed/buffer gas was used to produce the Cu nanocluster in an aggregation tube and deposited on Si (100) wafer temperature. PMID- 19791961 TI - Small single-crystal silicon cantilevers formed by crystal facets for atomic force microscopy. AB - We have developed a batch fabrication method of small cantilevers formed by crystal facets of single-crystal silicon for improving the sensitivity of atomic force microscopy. In order to realize a small cantilever with a very sharp tip, we have employed KOH anisotropic etching and local oxidation of silicon. We have made two types of small cantilevers, the V-shaped triangular type and the bulk triangular type. The length of each cantilever is 20 microm. The tip of the V shaped type is bridged by two wires with thickness of 0.6 mum. The bulk triangular type has a thickness of 1.5 microm. The frequency characteristics of the cantilevers vibrated using photothermal excitation were measured by laser Doppler velocimetry. The resonance frequency of the V-shaped type and the bulk triangular type were 687 kHz and 8.42 MHz, and their spring constants are estimated to be 0.7 N/m and 370 N/m, respectively. PMID- 19791962 TI - Design and experimental tests of a novel neutron spin analyzer for wide angle spin echo spectrometers. AB - This paper describes the design and experimental tests of a novel neutron spin analyzer optimized for wide angle spin echo spectrometers. The new design is based on nonremanent magnetic supermirrors, which are magnetized by vertical magnetic fields created by NdFeB high field permanent magnets. The solution presented here gives stable performance at moderate costs in contrast to designs invoking remanent supermirrors. In the experimental part of this paper we demonstrate that the new design performs well in terms of polarization, transmission, and that high quality neutron spin echo spectra can be measured. PMID- 19791963 TI - Ray tracing flux calculation for the small and wide angle x-ray scattering diffraction station at the SESAME synchrotron radiation facility. AB - The calculation for the optics of the synchrotron radiation small and wide angle x-ray scattering beamline, currently under construction at SESAME is described. This beamline is based on a cylindrically bent germanium (111) single crystal with an asymmetric cut of 10.5 degrees , followed by a 1.2 m long rhodium coated plane mirror bent into a cylindrical form. The focusing properties of bent asymmetrically cut crystals have not yet been studied in depth. The present paper is devoted to study of a particular application of a bent asymmetrically cut crystal using ray tracing simulations with the SHADOW code. These simulations show that photon fluxes of order of 1.09x10(11) photons/s will be available at the experimental focus at 8.79 keV. The focused beam dimensions will be 2.2 mm horizontal full width at half maximum (FWHM) by 0.12 mm vertical (FWHM). PMID- 19791964 TI - A method for the temperature calibration of an infrared camera using water as a radiative source. AB - Presented here is an effective low-cost method for the temperature calibration of infrared cameras, for applications in the 0-100 degrees C range. The calibration of image gray level intensity to temperature is achieved by imaging an upwelling flow of water, the temperature of which is measured with a thermistor probe. The upwelling flow is created by a diffuser located below the water surface of a constant temperature water bath. The thermistor probe is kept immediately below the surface, and the distance from the diffuser outlet to the surface is adjusted so that the deformation of the water surface on account of the flow is small, yet the difference between the surface temperature seen by the camera and the bulk temperature measured by the thermistor is also small. The benefit of this method compared to typical calibration procedures is that, without sacrificing the quality of the calibration, relatively expensive commercial blackbodies are replaced by water as the radiative source (epsilon approximately 0.98 for the wavelengths considered here). A heat transfer analysis is provided, which improves the accuracy of the calibration method and also provides the user with guidance to further increases in accuracy of the method. PMID- 19791965 TI - A silicon photomultiplier readout for time of flight neutron spectroscopy with gamma-ray detectors. AB - The silicon photomultiplier (SiPM) is a recently developed photosensor used in particle physics, e.g., for detection of minimum ionizing particles and/or Cherenkov radiation. Its performance is comparable to that of photomultiplier tubes, but with advantages in terms of reduced volume and magnetic field insensitivity. In the present study, the performance of a gamma ray detector made of an yttrium aluminum perovskite scintillation crystal and a SiPM-based readout is assessed for use in time of flight neutron spectroscopy. Measurements performed at the ISIS pulsed neutron source demonstrate the feasibility of gamma detection based on the new device. PMID- 19791966 TI - In situ measurement of gas composition changes in radio frequency plasmas using a quartz sensor. AB - A simple method using a quartz sensor (Q-sensor) was developed to observe gas composition changes in radio frequency (rf) plasmas. The output depends on the gases' absolute pressure, molecular weight, and viscosity. The pressure normalized quartz sensor output depends only on the molecular weight and viscosity of the gas. Consequently, gas composition changes can be detected in the plasmas if a sensor can be used in the plasmas. Influences imparted by the plasmas on the sensor, such as those by reactive particles (e.g., radicals and ions), excited species, electrons, temperature, and electric potentials during measurements were investigated to test the applicability of this quartz sensor measurement to plasma. The Q-sensor measurement results for rf plasmas with argon, hydrogen, and their mixtures are reproducible, demonstrating that the Q sensor measurement is applicable for plasmas. In this work, pressure- and temperature-normalized Q-sensor output (NQO) were used to obtain the gas composition information of plasma. Temperature-normalization of the Q-sensor output enabled quartz sensor measurements near plasma electrodes, where the quartz sensor temperature increases. The changes in NQO agreed with results obtained by gas analysis using a quadrupole mass spectrometer. Results confirmed that the change in NQO is mainly attributable to changes in the densities and kinds of gas molecules in the plasma gas phase, not by other extrinsic influences of plasma. For argon, hydrogen, and argon-hydrogen plasmas, these changes correspond to reduction in nitrogen, production of carbon monoxide, and dissociation of hydrogen molecules, respectively. These changes in NQO qualitatively and somewhat quantitatively agreed with results obtained using gas analysis, indicting that the measurement has a potential application to obtain the gas composition in plasmas without disturbing industrial plasma processes. PMID- 19791967 TI - An auxiliary capacitor based ultrafast drive circuit for shear piezoelectric motors. AB - Shear piezoelectric motors frequently require large voltage changes on very short time scales. Since piezos behave electrically as capacitors, this requires a drive circuit capable of quickly sourcing or sinking a large amount of current at high voltages. Here we describe a novel circuit design using a high voltage amplifier, transistor switching stage, and auxiliary capacitor. This circuit can drive piezoelectric motors at higher speeds and lower costs than conventional methods and with greater flexibility for computer automation. We illustrate its application in a controller for a scanning tunneling microscope coarse approach mechanism and discuss other possible applications and modifications of this circuit. PMID- 19791968 TI - A high-precision apparatus for the characterization of thermal interface materials. AB - An apparatus has been designed and constructed to characterize thermal interface materials with unprecedented precision and sensitivity. The design of the apparatus is based upon a popular implementation of ASTM D5470 where well characterized meter bars are used to extrapolate surface temperatures and measure heat flux through the sample under test. Measurements of thermal resistance, effective thermal conductivity, and electrical resistance can be made simultaneously as functions of pressure or sample thickness. This apparatus is unique in that it takes advantage of small, well-calibrated thermistors for precise temperature measurements (+/-0.001 K) and incorporates simultaneous measurement of electrical resistance of the sample. By employing precision thermometry, low heater powers and minimal temperature gradients are maintained through the meter bars, thereby reducing uncertainties due to heat leakage and changes in meter-bar thermal conductivity. Careful implementation of instrumentation to measure thickness and force also contributes to a low overall uncertainty. Finally, a robust error analysis provides uncertainties for all measured and calculated quantities. Baseline tests were performed to demonstrate the sensitivity and precision of the apparatus by measuring the contact resistance of the meter bars in contact with each other as representative low specific thermal resistance cases. A minimum specific thermal resistance of 4.68x10(-6) m(2) K/W was measured with an uncertainty of 2.7% using a heat transfer rate of 16.8 W. Additionally, example measurements performed on a commercially available graphite thermal interface material demonstrate the relationship between thermal and electrical contact resistance. These measurements further demonstrate repeatability in measured effective thermal conductivity of approximately 1%. PMID- 19791969 TI - Development of a relaxation calorimeter for temperatures between 0.05 and 4 K. AB - A detailed description of an isoperibol calorimeter for temperatures between 0.05 and 4 K is presented. The proposed setup can provide absolute values of the heat capacity C of small samples (typically 1 mg). The extremely simple design of the sample platform, based on a sapphire substrate, and the experimental setup, which makes use only of a lock-in amplifier and a temperature controller, make the construction of such a calorimeter easy and inexpensive. The thermal-relaxation method is employed, which utilizes a permanent thermal link k between the sample platform and the low-temperature bath. The temperature dependence of k(T) is shown for several platforms throughout the entire temperature range: k(T)/T is nearly constant down to 1 K, where it starts to decrease smoothly. The observed behavior is thoroughly explained by considering the thermal resistances of the platform constituents. A comparison between the values of k(T)/T for platforms based on sapphire and on silver is presented where no significant difference has been observed. Each platform can be assembled to have a particular value of k/T at 1 K. Since the sample relaxation time tau approximately C/k, k(T) can be adjusted to C(T) to give a reasonably fast measuring time. Here, it is demonstrated how this calorimeter can be used in so-called single-shot refrigerators ((3)He or demagnetization cryostats), where the time for a single measurement is limited. In addition, it can be used in moderate magnetic fields B 0 where T(h) and T(c) are the temperatures of the hot and cold heat reservoirs, respectively. In this limit, we can assume that the cycle is working in the linear-response regime and can calculate the Onsager coefficients of this cycle analytically using the elementary molecular kinetic theory. We reveal that these Onsager coefficients satisfy the so-called tight-coupling condition and this fact explains why the efficiency at the maximal power eta(max) of this cycle can attain the Curzon Ahlborn efficiency from the viewpoint of the linear-response theory. PMID- 19792092 TI - Stability analysis on the finite-temperature replica-symmetric and first-step replica-symmetry-broken cavity solutions of the random vertex cover problem. AB - The vertex cover problem is a prototypical hard combinatorial optimization problem. It was studied in recent years by physicists using the cavity method of statistical mechanics. In this paper, the stability of the finite-temperature replica-symmetric (RS) and the first-step replica-symmetry-broken (1RSB) cavity solutions of the vertex cover problem on random regular graphs of finite vertex degree K are analyzed by population dynamics simulations. We found that (1) the lowest temperature for the RS solution to be stable, T(RS)(K), is not a monotonic function of K; (2) at relatively large connectivity K and temperature T slightly below the dynamic transition temperature T(d)(K), the 1RSB solutions with small but non-negative complexity values are stable, and (3) the dynamical transition temperature T(d) and Kauzmann temperature T(K) is equal to each other. Similar results are obtained on random Poissonian graphs. PMID- 19792093 TI - Diffusion coefficient in periodic and random potentials. AB - Transport and diffusion of particles on modulated surfaces is a nonequilibrium problem which is receiving a great deal of attention due to its technological applications, but analytical calculations are scarce. In earlier work, we developed a perturbative approach to begin to provide an analytic platform for predictions about particle trajectories over such surfaces. In some temperature and forcing regimes, we successfully reproduced results for average particle velocities obtained from numerical simulations. In this paper, we extend the perturbation theory to the calculation of higher moments, in particular the diffusion tensor and the skewness. Numerical simulations are used to check the domain of validity of the perturbative approach. PMID- 19792094 TI - Many-body reduced fidelity susceptibility in Lipkin-Meshkov-Glick model. AB - We study the reduced fidelity susceptibility chi(r) for an M -body subsystem of an N -body Lipkin-Meshkov-Glick model with tau=M/N fixed. The reduced fidelity susceptibility can be viewed as the response of subsystem to a certain parameter. In noncritical region, the inner correlation of the system is weak, and chi(r) behaves similar with the global fidelity susceptibility chi(g), the ratio eta=chi(r)/chi(g) depends on tau but not on N. However, at the critical point, the inner correlation tends to be divergent, and we find chi(r) approaches chi(g) with increasing the N. It is interesting to note that, eta=1 in the thermodynamic limit, which means the susceptibilities of the local and global system are the same. Finally, we make numerical computations, and they are in perfect agreement with the analytical predictions. PMID- 19792095 TI - Electrodynamic Casimir effect in a medium-filled wedge. II. AB - We consider the Casimir energy in a geometry of an infinite magnetodielectric wedge closed by a circularly cylindrical, perfectly reflecting arc embedded in another magnetodielectric medium, under the condition that the speed of light be the same in both media. An expression for the Casimir energy corresponding to the arc is obtained and it is found that in the limit where the reflectivity of the wedge boundaries tends to unity the finite part of the Casimir energy of a perfectly conducting wedge-shaped sheet closed by a circular cylinder is regained. The energy of the latter geometry possesses divergences due to the presence of sharp corners. We argue how this is a pathology of the assumption of ideal conductor boundaries and that no analogous term enters in the present geometry. PMID- 19792096 TI - Fractality of the nonequilibrium stationary states of open volume-preserving systems. I. Tagged particle diffusion. AB - Deterministic diffusive systems, such as the periodic Lorentz gas, multibaker map, as well as spatially periodic systems of interacting particles, have nonequilibrium stationary states with fractal properties when put in contact with particle reservoirs at their boundaries. We study the macroscopic limits of these systems and establish a correspondence between the thermodynamics of the macroscopic diffusion process and the fractality of the stationary states that characterize the phase-space statistics. In particular the entropy production rate is recovered from first principles using a formalism due to Gaspard [J. Stat. Phys. 88, 1215 (1997)]. This paper is the first of two; the second article considers the influence of a uniform external field on such systems. PMID- 19792097 TI - Fractality of the nonequilibrium stationary states of open volume-preserving systems. II. Galton boards. AB - Galton boards are models of deterministic diffusion in a uniform external field, akin to driven periodic Lorentz gases, here considered in the absence of dissipation mechanism. Assuming a cylindrical geometry with axis along the direction of the external field, the two-dimensional board becomes a model for one-dimensional mass transport along the direction of the external field. This is a purely diffusive process which admits fractal nonequilibrium stationary states under flux boundary conditions. Analytical results are obtained for the statistics of multibaker maps modeling such a nonuniform diffusion process. A correspondence is established between the local phase-space statistics and their macroscopic counterparts. The fractality of the invariant state is shown to be responsible for the positiveness of the entropy production rate. PMID- 19792098 TI - Master equation approach to line shape in dissipative systems. AB - We propose a formulation to obtain the line shape of a magnetic response with dissipative effects that directly reflects the nature of the environment. Making use of the fact that the time evolution of a response function is described by the same equation as the reduced density operator, we formulate a full description of the complex susceptibility. We describe the dynamics using the equation of motion for the reduced density operator, including the term for the initial correlation between the system and a thermal bath. In this formalism, we treat the full description of non-Markovian dynamics including the initial correlation. We present an explicit and compact formula up to the second order of cumulants, which can be applied in a straightforward way to multiple-spin systems. We also take into account the frequency shift by the system-bath interaction. We study the dependence of the line shape on the type of interaction between the system and the thermal bath. We demonstrate that the present formalism is a powerful tool for investigating various kinds of systems and we show how it is applied to spin systems, including those with up to three spins. We distinguish the contributions of the initial correlation and the frequency shift and make clear the role of each contribution in the Ohmic coupling spectral function. As examples of applications to multispin systems, we obtain the dependence of the line shape on the spatial orientation in relation to the direction of the static field (Nagata-Tazuke effect), including the effects of the thermal environment, in a two-spin system, along with the dependence on the arrangement of a triangle in a three-spin system. PMID- 19792099 TI - Extinction in the Lotka-Volterra model. AB - Birth-death processes often exhibit an oscillatory behavior. We investigate a particular case where the oscillation cycles are marginally stable on the mean field level. An iconic example of such a system is the Lotka-Volterra model of predator-prey interaction. Fluctuation effects due to discreteness of the populations destroy the mean-field stability and eventually drive the system toward extinction of one or both species. We show that the corresponding extinction time scales as a certain power-law of the population sizes. This behavior should be contrasted with the extinction of models stable in the mean field approximation. In the latter case the extinction time scales exponentially with size. PMID- 19792100 TI - Critical exponents for the homology of Fortuin-Kasteleyn clusters on a torus. AB - A Fortuin-Kasteleyn cluster on a torus is said to be of type {a,b},a,b in Z , if it is possible to draw a curve belonging to the cluster that winds a times around the first cycle of the torus as it winds -b times around the second. Even though the Q -Potts models make sense only for Q integers, they can be included into a family of models parametrized by beta = square root of Q for which the Fortuin Kasteleyn clusters can be defined for any real beta(0,2] . For this family, we study the probability pi({a,b}) of a given type of clusters as a function of the torus modular parameter tau=tau(r)+itau(i). We compute the asymptotic behavior of some of these probabilities as the torus becomes infinitely thin. For example, the behavior of pi({1,0}) is studied for tau(i) --> infinity . Exponents describing these behaviors are defined and related to weights h(r,s) of the extended Kac table for r and s integers, but also half-integers. Numerical simulations are also presented. Possible relationship with recent works and conformal loop ensembles is discussed. PMID- 19792101 TI - Fokker-Planck equation in a wedge domain: anomalous diffusion and survival probability. AB - We obtain exact solutions and the survival probability for a Fokker-Planck equation subjected to the two-dimensional wedge domain. We consider a spatial dependence in the diffusion coefficient and the presence of external forces. The results show an anomalous spreading of the solution and, consequently, a nonusual behavior of the survival probability which can be connected to anomalous diffusion. PMID- 19792102 TI - Branching process in a stochastic extremal model. AB - We considered a stochastic version of the Bak-Sneppen model (SBSM) of ecological evolution where the number M of sites mutated in a mutation event is restricted to only two. Here the mutation zone consists of only one site and this site is randomly selected from the neighboring sites at every mutation event in an annealed fashion. The critical behavior of the SBSM is found to be the same as the BS model in dimensions d=1 and 2. However on the scale-free graphs the critical fitness value is nonzero even in the thermodynamic limit but the critical behavior is mean-field like. Finally M has been made even smaller than two by probabilistically updating the mutation zone, which also shows the original BS model behavior. We conjecture that a SBSM on any arbitrary graph with any small branching factor greater than unity will lead to a self-organized critical state. PMID- 19792103 TI - Nonuniversality and the role of tails in reaction-subdiffusion fronts. AB - Recently there has been a certain controversy about the scaling properties of reaction-subdiffusion fronts. Some works seem to suggest that these fronts should move with constant speed, as do classical reaction-diffusion fronts, while other authors have predicted propagation failure, i.e., that the front speed tends asymptotically to zero. In the present work we confirm by Monte Carlo experiments that the two situations can actually occur depending on the way the reaction process is implemented. Also, we present a general analytical model that includes these two different behaviors as particular cases. From our analysis, we reach two main conclusions. First, the differences found in the scaling properties show the lack of universality of reaction-subdiffusion fronts. Second, we prove that, contrary to the widespread belief, the tail of the waiting time distributions is not always decisive to determine the speed of these fronts, but sometimes it plays just a marginal role in the front dynamics. PMID- 19792104 TI - Surface growth on diluted lattices by a restricted solid-on-solid model. AB - An influence of diluted sites on surface growth has been investigated, using the restricted solid-on-solid model. It was found that, with respect to equilibrium growth, the surface width and the saturated width exhibited universal power-law behaviors, i.e., W approximately t(beta) and W(sat) approximately L(zeta), regarding all cases with respect to the concentration of diluted sites x=1-p , with p being the occupation probability on each lattice site. For x < x(c) (=1 p(c), p(c) being the percolation threshold), the growth appeared to be similar to that of a regular lattice, both in two and three dimensions. For x=x(c), the growth yielded nontrivial exponents which were different from those on a regular lattice. In nonequilibrium growth, a considerable amount of diluted sites (x < or = x(c)) appeared to yield nonuniversal growth, unlike the case of a regular lattice. The cause of nonuniversal growth dynamics has been investigated, considering the growth on a backbone cluster and on lattices constructed with periodically and randomly diluted subcells. PMID- 19792105 TI - Constant entropy sampling and release waves of shock compressions. AB - We present or recall several equilibrium methods that allow one to compute isentropic processes, either during the compression or the release of the material. These methods are applied to compute the isentropic release of a shocked monoatomic liquid at high pressure and temperature. Moreover, equilibrium results of isentropic release are compared to the direct nonequilibrium simulation of the same process. We show that due to the viscosity of the liquid but also to nonequilibrium effects, the release of the system is not strictly isentropic. PMID- 19792106 TI - Characterizing the human mobility pattern in a large street network. AB - Previous studies demonstrated empirically that human mobility exhibits Levy flight behavior. However, our knowledge of the mechanisms governing this Levy flight behavior remains limited. Here we analyze over 72,000 people's moving trajectories, obtained from 50 taxicabs during a six-month period in a large street network, and illustrate that the human mobility pattern, or the Levy flight behavior, is mainly attributed to the underlying street network. In other words, the goal-directed nature of human movement has little effect on the overall traffic distribution. We further simulate the mobility of a large number of random walkers and find that (1) the simulated random walkers can reproduce the same human mobility pattern, and (2) the simulated mobility rate of the random walkers correlates pretty well (an R square up to 0.87) with the observed human mobility rate. PMID- 19792107 TI - Extended forms of the second law for general time-dependent stochastic processes. AB - The second law of thermodynamics represents a universal principle applicable to all natural processes, physical systems, and engineering devices. Hatano and Sasa have recently put forward an extended form of the second law for transitions between nonequilibrium stationary states [Phys. Rev. Lett. 86, 3463 (2001)]. In this paper we further extend this form to an instantaneous interpretation, which is satisfied by quite general time-dependent stochastic processes including master-equation models and Langevin dynamics without the requirements of the stationarity for the initial and final states. The theory is applied to several thermodynamic processes, and its consistence with the classical thermodynamics is shown. PMID- 19792108 TI - Out-of-equilibrium phase re-entrance(s) in long-range interacting systems. AB - Systems with long-range interactions display a short-time relaxation toward quasistationary states (QSSs) whose lifetime increases with system size. The application of Lynden-Bell's theory of "violent relaxation" to the Hamiltonian Mean Field model leads to the prediction of out-of-equilibrium first- and second order phase transitions between homogeneous (zero magnetization) and inhomogeneous (nonzero magnetization) QSSs, as well as an interesting phenomenon of phase re-entrances. We compare these theoretical predictions with direct N body numerical simulations. We confirm the existence of phase re-entrance in the typical parameter range predicted from Lynden-Bell's theory, but also show that the picture is more complicated than initially thought. In particular, we exhibit the existence of secondary re-entrant phases: we find unmagnetized states in the theoretically magnetized region as well as persisting magnetized states in the theoretically unmagnetized region. We also report the existence of a region with negative specific heats for QSSs both in the numerical and analytical caloric curves. PMID- 19792109 TI - Stochastic dynamics in systems with unidirectional delay coupling: two-state description. AB - We study stochastic dynamics of two-state particles coupled unidirectionally with delay. We give exact results for the stationary distribution function p(st) and the time correlation function (TCF) when the system consists of two (N=2) and three (N=3) particles. Based on these results, effects of delay are discussed and compared with the N=1 case, studied by Tsimring and Pikovsky [Phys. Rev. Lett. 87, 250602 (2001)]. Next, we consider the general N -particle system, for which we give exact expressions for p(st) and the TCF, which are inferred based on the N=2 and N=3 solutions and then confirmed via detailed arguments. It is pointed out that the stationary state is mapped to Ising spin model with ferro(antiferro)magnetic interaction when delay feedback is positive (negative). PMID- 19792110 TI - Random transition-rate matrices for the master equation. AB - Random-matrix theory is applied to transition-rate matrices in the Pauli master equation. We study the distribution and correlations of eigenvalues, which govern the dynamics of complex stochastic systems. Both the cases of identical and of independent rates of forward and backward transitions are considered. The first case leads to symmetric transition-rate matrices, whereas the second corresponds to general asymmetric matrices. The resulting matrix ensembles are different from the standard ensembles and show different eigenvalue distributions. For example, the fraction of real eigenvalues scales anomalously with matrix dimension in the asymmetric case. PMID- 19792111 TI - Viscosity of carbon dioxide measured to a pressure of 8 GPa and temperature of 673 K. AB - Shear viscosities of supercritical carbon dioxide have been measured to 673 K and 8 GPa (80 kbar). Measurements were made in a diamond-anvil cell with a rolling ball technique. Individual isotherms are well fit by a modified free-volume equation. The data demonstrate a close relation between viscosity and residual entropy. PMID- 19792112 TI - Concentration and mass dependence of transport coefficients and correlation functions in binary mixtures with high mass asymmetry. AB - Correlation functions and transport coefficients of self-diffusion and shear viscosity of a binary Lennard-Jones mixture with components differing only in their particle mass are studied up to high values of the mass ratio mu, including the limiting case mu = infinity, for different mole fractions x. Within a large range of x and mu the product of the diffusion coefficient of the heavy species D(2) and the total shear viscosity of the mixture eta(m) is found to remain constant, obeying a generalized Stokes-Einstein relation. At high liquid density, large mass ratios lead to a pronounced cage effect that is observable in the mean square displacement, the velocity autocorrelation function, and the van Hove correlation function. PMID- 19792113 TI - Depth dependence of vertical plunging force in granular medium. AB - Depth dependence of vertical plunging force in granular medium is studied experimentally by measuring the slow-pushing force of different size and shape objects intruding vertically into a granular bed. It is found that all of the force curves of fully immersed intruders have concave-to-convex transition. The depth dependence of the force turns from supralinear to sublinear. By studying the properties of the inflection point of the concave-convex transition, we find that the plunging force at inflection point is proportional to intruder's volume, and the inflection point occurs when the intruder is fully buried to a level around twice its diameter. Testing by plunging a long cylinder, which is always partially immersed, we find no inflection point in this case, which verifies that the inflection of the plunging force is related to the filled-in loose granules on top of the intruder. The slowdown of the increasing rate of the force is, therefore, not a result of sidewall support proposed by previous researchers. PMID- 19792114 TI - Quantification of the heterogeneity of particle packings. AB - The microstructure of coagulated colloidal particles, for which the interparticle potential is described by the Derjaguin-Landau-Verweg-Overbeek theory, is strongly influenced by the particles' surface potential. Depending on its value, the resulting microstructures are either more "homogeneous" or more "heterogeneous," at equal volume fractions. An adequate quantification of a structure's degree of heterogeneity (DOH), however, does not yet exist. In this work, methods to quantify and thus classify the DOH of microstructures are investigated and compared. Three methods are evaluated using particle packings generated by Brownian dynamics simulations: (1) the pore size distribution, (2) the density-fluctuation method, and (3) the Voronoi volume distribution. Each method provides a scalar measure, either via a parameter in a fit function or an integral, which correlates with the heterogeneity of the microstructure and which thus allows to quantitatively capture the DOH of a granular material. An analysis of the differences in the density fluctuations between two structures additionally allows for a detailed determination of the length scale on which differences in heterogeneity are most pronounced. PMID- 19792115 TI - Slip velocity and stresses in granular Poiseuille flow via event-driven simulation. AB - Event-driven simulations of inelastic smooth hard disks are used to probe the slip velocity and rheology in gravity-driven granular Poiseuille flow. It is shown that both the slip velocity (U(w)) and its gradient (dU(w)/dy) depend crucially on the mean density, wall roughness, and inelastic dissipation. While the gradient of slip velocity follows a single power-law relation with Knudsen number, the variation in U(w) with Kn shows three distinct regimes in terms of Knudsen number. An interesting possibility of Knudsen-number-dependent specularity coefficient emerges from a comparison of our results with a first order transport theory for the slip velocity. Simulation results on stresses are compared with kinetic-theory predictions, with reasonable agreement of our data in the quasielastic limit. The deviation of simulations from theory increases with increasing dissipation which is tied to the increasing magnitude of the first normal stress difference (N(1)) that shows interesting nonmonotonic behavior with density. As in simple shear flow, there is a sign change of N(1) at some critical density and its collisional component and the related collisional anisotropy are responsible for this sign reversal. PMID- 19792116 TI - Numerical study of the effects of particle shape and polydispersity on permeability. AB - We study through numerical simulations the dependence of the hydraulic permeability of granular materials on the particle shape and the grain size distribution. Several models of sand are constructed by simulating the settling under gravity of the grains; the friction coefficient is varied to construct packs of different porosity. The size distribution and shapes of the grains mimic real sands. Fluid flow is simulated in the resulting packs using a finite element method and the permeability of the packs is successfully compared with available experimental data. Packs of nonspherical particles are less permeable than sphere packs of the same porosity. Our results indicate that the details of grain shape and size distribution have only a small effect on the permeabilty of the systems studied. PMID- 19792117 TI - Mean steady granular force on a wall overflowed by free-surface gravity-driven dense flows. AB - We studied free-surface gravity-driven recirculating flows of cohesionless granular materials down a rough inclined plane and overflowing a wall normal to the incoming flow and to the bottom. We performed two-dimensional spherical particle discrete element simulations using a linear damped spring law between particles with a Coulomb failure criterion. High-frequency force fluctuations were observed. This paper focuses on the mean steady force exerted by the flow on the obstacle versus the macroscopic inertial number of the incoming flow, where the inertial number measures the ratio between a macroscopic deformation time scale and an inertial time scale. A triangular stagnant zone is formed upstream of the obstacle and sharply increases the mean force at low incoming inertial numbers. A simple hydrodynamic model based on depth-averaged momentum conservation is proposed. This analytical model predicts the numerical data fairly well and allows us to quantify the different contributions to the mean force on the wall. Beyond this model, our study provides an example of the ability of simple hydrodynamic approaches to describe the macroscopic behavior of an assembly of discrete particles not only in terms of kinematics but also in terms of forces. PMID- 19792118 TI - Cluster formation and bulk phase behavior of colloidal dispersions. AB - We investigated cluster formation in model colloids where the interparticle potential beyond the collision diameter includes a short-ranged attraction and a longer-ranged repulsion. The structure and thermodynamic properties of the model system can be accurately described by the first-order mean-spherical approximation (FMSA) and a perturbation theory for bulk phases and by a nonlocal density-functional theory (DFT) for stable/metastable clusters. In corroboration with recent experiments and molecular simulations, we predicted that the bulk to cluster transition may occur at both one-phase and two-phase regions of the colloidal phase diagram. While formation of colloidal clusters appears uncorrelated with the bulk phase transitions, the local phenomena may nevertheless play an important role in the dynamics of stable colloids and the kinetics of colloidal phase transitions. PMID- 19792119 TI - Cluster-cluster aggregation of Ising dipolar particles under thermal noise. AB - The cluster-cluster aggregation processes of Ising dipolar particles under thermal noise are investigated in the dilute condition. As the temperature increases, changes in the typical structures of clusters are observed from chainlike (D approximately 1) to crystalline (D approximately 2) through fractal structures (D approximately 1.45), where D is the fractal dimension. By calculating the bending energy of the chainlike structure, it is found that the transition temperature is associated with the energy gap between the chainlike and crystalline configurations. The aggregation dynamics changes from being dominated by attraction to diffusion involving changes in the dynamic exponent z=0.2 to 0.5. In the region of temperature where the fractal clusters grow, different growth rates are observed between charged and neutral clusters. Using the Smoluchowski equation with a twofold kernel, this hetero-aggregation process is found to result from two types of dynamics: the diffusive motion of neutral clusters and the weak attractive motion between charged clusters. The fact that changes in structures and dynamics take place at the same time suggests that transitions in the structure of clusters involve marked changes in the dynamics of the aggregation processes. PMID- 19792120 TI - Nondiffusive Brownian motion of deformable particles: breakdown of the "long-time tail". AB - We study the nondiffusive Brownian motion of both rigid and deformable mesoscopic particles by cross-correlated dynamic light scattering with microsecond temporal resolution. Whereas rigid particles show the classical long-time tail prediction, the transition to diffusive motion of deformable particles presents a striking behavior not explained by the existing hydrodynamic treatments. This observation can be interpreted in terms of a damped oscillatory deformational motion on time scales of the order of the Brownian time. Finally, we show that the nondiffusive Brownian motion depends on the specific flexibility of the particles. PMID- 19792121 TI - Hierarchical self-assembly of asymmetric amphiphatic spherical colloidal particles. AB - From dumbbells to fcc crystals, we study the self-assembly pathway of amphiphatic spherical colloidal particles as a function of the size of the hydrophobic region using molecular-dynamics simulations. Specifically, we analyze how local interparticle interactions correlate to the final self-assembled aggregate and how they affect the dynamical pathway of structure formation. We present a detailed diagram separating the many phases that we find for different sizes of the hydrophobic area and uncover a narrow region where particles self-assemble into hollow faceted cages that could potentially find interesting engineering applications. PMID- 19792122 TI - Electrostatic and hydrodynamics effects in a sedimented magnetorheological suspension. AB - We present experimental results on the equilibrium microstructure of a sedimented magnetorheological suspension, namely, an aqueous suspension of micron-sized superparamagnetic particles. We develop a study of the electrical interactions on the suspension by processing video-microscopy images of the sedimented particles. We calculate the pair distribution function, g(r), which yields the electrostatic pair potential u(r), showing an anomalous attractive interaction for distances on the order of twice the particle diameter, with characteristic parameters whose values show a dependence with the two-dimensional concentration of particles. The repulsive body of the potential is adjusted to a DLVO expression in order to calculate the Debye screening length and the effective surface charge density. Influence of confinement and variations on the Boltzmann sedimentation profile because of the electrostatic interactions appear to be essential for the interpretation of experimental results. PMID- 19792124 TI - Enhanced crystal stability in a binary mixture of charged colloidal spheres. AB - We report on the phase behavior of a binary charged sphere mixture of size ratio Gamma=0.68 and charge ratio Lambda approximately 1 as a function of composition p and number density n . For p=0.1-0.3 we observe freezing at densities well below the freezing densities of the pure components. At all compositions our data indicate the formation of substitutional alloy crystals of body centered cubic structure. No indications for compound formation were observed. Rather, our findings point at the first observation of an upper azeotrope. Measurements of the crystallization kinetics reveal a combined density and composition dependence of growth velocities and nucleation rate densities, with small but significant anomalies at p*=0.2 . These correlated deviations can be rationalized within classical theories of solidification and suggest an increased similarity between melt and solid for this particular composition. PMID- 19792123 TI - Modeling the rheology of suspensions with high-viscosity solvents: a predictive multiscale approach. AB - In this paper, a multiscale approach spanning atomistic and mesoscopic regimes to model the rheology of suspensions that have strongly interacting particles in highly viscous solvents is presented. The model suspensions studied here have 65% sucrose solution-a Newtonian fluid with a viscosity of 170 cP at room temperature as the solvent phase with ceramic particles of sizes on the order of a few microms as the dispersed (solute) phase. A multiscale approach is proposed to quantitatively account for the effect of the properties of constituent materials on the bulk rheology of the suspension apart from the effect of hydrodynamic factors. A dissipative particle dynamics-type particle-based approach is adopted to which material-specific, mesoscopic force fields developed using molecular dynamics are fed. Issues pertaining to the handling of the vast spectrum of time and length scales present and an appropriate Gallilean-invariant thermostat for solvent dynamics are addressed and resolved. Numerical calculations compare reasonably well to experimentally measured viscosities up to reasonably high Peclet numbers (approximately 10(4)). PMID- 19792125 TI - Curvature effects on the adsorption of aqueous sodium-dodecyl-sulfate surfactants on carbonaceous substrates: structural features and counterion dynamics. AB - The effect of substrate curvature on surfactant self-assembly has been studied using all-atom molecular-dynamics simulations. We studied aqueous sodium-dodecyl sulfate (SDS) surfactants on graphite, on the outer surface of single walled carbon nanotubes (SWNTs) and within SWNTs. Our results reveal that although the chemical nature of the substrates is constant, the self-assembled structures change significantly as the curvature varies. For example, at large surface density, SDS surfactants yield micellar structures on graphite, layered self assemblies outside SWNTs, and cylindrical lamellar structures inside SWNTs. Changes in substrate curvature as well as surfactant surface density affect significantly surfactant orientation and, more importantly, headgroup-headgroup distribution, headgroup-counterion packing, and counterion residence time next to the headgroups. PMID- 19792126 TI - Selectivity in binary fluid mixtures: static and dynamical properties. AB - Selectivity of particles in a region of space can be achieved by applying external potentials to influence the particles in that region. We investigate static and dynamical properties of size selectivity in binary fluid mixtures of two particles sizes. We find that by applying an external potential that is attractive to both kinds of particles, due to crowding effects, this can lead to one species of particles being expelled from that region, while the other species is attracted into the region where the potential is applied. This selectivity of one species of particle over the other in a localized region of space depends on the density and composition of the fluid mixture. Applying an external potential that repels both kinds of particles leads to selectivity of the opposite species of particles to the selectivity with attractive potentials. We use equilibrium and dynamical density-functional theory to describe and understand the static and dynamical properties of this striking phenomenon. Selectivity by some ion channels is believed to be due to this effect. PMID- 19792127 TI - Simulational and theoretical study of the spherical electrical double layer for a size-asymmetric electrolyte: the case of big coions. AB - Monte Carlo simulations of a spherical macroion, surrounded by a size-asymmetric electrolyte in the primitive model, were performed. We considered 1:1 and 2:2 salts with a size ratio of 2 (i.e., with coions twice the size of counterions), for several surface charge densities of the macrosphere. The radial distribution functions, electrostatic potential in all the space and at the Helmholtz surfaces, and integrated charge are reported. We compare these simulational data with original results obtained from the Ornstein-Zernike integral equation, supplemented by the hypernetted chain-hypernetted chain (HNC-HNC) and hypernetted chain-mean spherical approximation (HNC-MSA) closures, and with the corresponding calculations using the modified Gouy-Chapman and unequal-radius modified Gouy Chapman theories. The HNC-HNC and HNC-MSA integral equations formalisms show good concordance with Monte Carlo "experiments," whereas the notable limitations of point-ion approaches are evidenced. Most importantly, the simulations confirm our previous theoretical predictions of the nondominance of the counterions in the size-asymmetric spherical electrical double layer [J. Chem. Phys. 123, 034703 (2005)], the appearance of anomalous curvatures at the outer Helmholtz plane, and the enhancement of the charge reversal and screening at high colloidal surface charge densities due to the ionic size asymmetry. PMID- 19792128 TI - Glass transition of dense fluids of hard and compressible spheres. AB - We use computer simulations to study the glass transition of dense fluids made of polydisperse repulsive spheres. For hard particles, we vary the volume fraction, phi , and use compressible particles to explore finite temperatures, T>0 . In the hard sphere limit, our dynamic data show evidence of an avoided mode-coupling singularity near phi(MCT) is approximately 0.592; they are consistent with a divergence of equilibrium relaxation times occurring at phi(0) is approximately 0.635, but they leave open the existence of a finite temperature singularity for compressible spheres at volume fraction phi>phi(0). Using direct measurements and a scaling procedure, we estimate the equilibrium equation of state for the hard sphere metastable fluid up to phi(0), where pressure remains finite, suggesting that phi(0) corresponds to an ideal glass transition. We use nonequilibrium protocols to explore glassy states above phi(0) and establish the existence of multiple equations of state for the unequilibrated glass of hard spheres, all diverging at different densities in the range phi in [0.642, 0.664]. Glassiness thus results in the existence of a continuum of densities where jamming transitions can occur. PMID- 19792129 TI - Effect of mixing and spatial dimension on the glass transition. AB - We study the influence of composition changes on the glass transition of binary hard disk and hard sphere mixtures in the framework of mode coupling theory. We derive a general expression for the slope of a glass transition line. Applied to the binary mixture in the low concentration limits, this method allows a fast prediction of some properties of the glass transition lines. The glass transition diagram we find for binary hard disks strongly resembles the random close packing diagram. Compared to three dimensions from previous studies, the extension of the glass regime due to mixing is much more pronounced in two dimensions where plasticization only sets in at larger size disparities. For small size disparities we find a stabilization of the glass phase quadratic in the deviation of the size ratio from unity. PMID- 19792130 TI - Rheology of draining steady-state foams. AB - Aqueous foams continuously age due to fluid drainage and bubble coarsening, which makes it difficult to perform steady-state rheological measurements. Consequently we have developed the foam drainage rheology technique, where perfusion counteracts fluid drainage and bubble replenishment counteracts bubble coarsening during measurement of the shear stresses by a rheometer. We evaluate published power-law and Herschel-Bulkley models and find that parameters derived from emulsion experiments cannot describe our results. We propose a hybrid model, which combines our earlier film-shearing model, where the film thickness depends on liquid volume fraction, with a Herschel-Bulkley shear-rate dependence. PMID- 19792131 TI - Probing the extended space charge by harmonic disturbances. AB - We assess the possibility of probing the diffuse electric double layer at a permeable charge-selective interface, such as a nonblocking electrode or ion exchange membrane, under a finite steady-state current-voltage bias by small harmonic high-frequency current-voltage disturbances. Our main conclusion is that for a finite underlimiting bias, the electric double layer at such an interface is not amenable to this kind of probe; the high-frequency response of the system is dominated by the quasielectroneutral bulk. This is similar to the previously studied zero-bias case. On the other hand, the extended space charge in such double layers may be probed in this way both by the linear and nonlinear responses, correspondingly by the method of electric impedance spectroscopy and via the previously described anomalous rectification effect. The latter appears preferable over the former as a potential experimental tool for the study of the extended space charge of a nonequilibrium electric double layer. PMID- 19792132 TI - Criticality of colloids with distinct interaction patches: the limits of linear chains, hyperbranched polymers, and dimers. AB - We use a simple model of associating fluids which consists of spherical particles having a hard-core repulsion, complemented by three short-ranged attractive sites on the surface (sticky spots). Two of the spots are of type A and one is of type B; the bonding interactions between each pair of spots have strengths epsilon(AA), epsilon(BB), and epsilon(AB). The theory is applied over the whole range of bonding strengths and the results are interpreted in terms of the equilibrium cluster structures of the phases. In addition to our numerical results, we derive asymptotic expansions for the free energy in the limits for which there is no liquid-vapor critical point: linear chains (epsilon(AA) not equal to 0, epsilon(AB)=epsilon(BB)=0) , hyperbranched polymers (epsilon(AB) not equal to 0, epsilon(AA)=epsilon(B)=0) , and dimers (epsilon(BB) not equal to 0, epsilon(AA)=epsilon(AB)=0) . These expansions also allow us to calculate the structure of the critical fluid by perturbing around the above limits, yielding three different types of condensation: of linear chains (AA clusters connected by a few AB or BB bonds); of hyperbranched polymers (AB clusters connected by AA bonds); or of dimers (BB clusters connected by AA bonds). Interestingly, there is no critical point when in(AA) vanishes despite the fact that AA bonds alone cannot drive condensation. PMID- 19792133 TI - Kinetics of trans-cis isomerization in azobenzene dimers at an air-water interface. AB - We have studied the kinetics of trans to cis isomerization under the illumination of ultraviolet light, in the Langmuir monolayer of mesogenic azobenzene dimer, bis-[5-( 4' -n-dodecyloxy benzoyloxy)-2-( 4''-methylphenylazo)phenyl] adipate, at an air-water interface. We find that the trans to cis isomerization reaction of the molecules in the monolayer shows deviation from the first-order kinetics unlike those reported on Langmuir monolayers of azobenzene molecules. We attribute the deviation from first-order kinetics to the simultaneous photoisomerization of trans isomers to form cis isomers and the reverse thermal isomerization of cis isomers to form trans isomers. Our analysis of the rate of change of mole fraction of trans isomers to form cis isomers indicates a first order kinetics for trans to cis photoisomerization reaction and a second-order kinetics for cis to trans thermal isomerization reaction. This second-order kinetics mechanism is similar to the Lindemann-Hinshelwood mechanism for the unimolecular reactions at low concentration of reactants. The formation of the activated cis isomer by collisions is a slow process as compared to the decay of the activated cis isomer to trans isomer in the liquid expanded phase. This results in the second-order kinetics for the thermal isomerization of cis isomers. PMID- 19792134 TI - Lagrangian crumpling equations. AB - A concise method for following the evolving geometry of a moving surface using Lagrangian coordinates is described. All computations can be done in the fixed geometry of the initial surface despite the evolving complexity of the moving surface. The method is applied to three problems in nonlinear elasticity: the bulging of a thin plate under pressure (the original motivation for Foppl-von Karman theory), the buckling of a spherical shell under pressure, and the phenomenon of capillary wrinkles induced by surface tension in a thin film. In this last problem the inclusion of a gravitational potential-energy term in the total energy improves the agreement with experiment. PMID- 19792135 TI - Final shape of a drying thin film. AB - Drying processes of polymer solutions on a solid substrate enclosed by bank are studied in the slow limit of the solvent evaporation. A simple model is proposed to examine the final shape of the film after drying. Analytical expressions of the final shape in terms of the initial parameters are obtained. It is shown that the craterlike and basinlike shapes appear as final shapes of the film depending on the initial parameters. The "shape diagrams" which show parameter dependence of the final shape are presented in the absence/presence of diffusion. The final shape of the film in the geometry without bank is also discussed. PMID- 19792136 TI - Elastic-instability triggered pattern formation. AB - Recent experiments have exploited elastic instabilities in membranes to create complex patterns. However, the rational design of such structures poses many challenges, as they are products of nonlinear elastic behavior. We pose a simple model for determining the orientational order of such patterns using only linear elasticity theory which correctly predicts the outcomes of several experiments. Each element of the pattern is modeled by a "dislocation dipole" located at a point on a lattice, which then interacts elastically with all other dipoles in the system. We explicitly consider a membrane with a square lattice of circular holes under uniform compression and examine the changes in morphology as it is allowed to relax in a specified direction. PMID- 19792137 TI - Scaling of surface roughness and polymer structure in a model for film growth and polymerization. AB - We study a model of growth of polymer films using numerical simulations and scaling concepts. During the deposition, each new monomer flows in a direction perpendicular to the substrate, aggregates at the first contact with the deposit and executes up to G steps along the polymers, propagating an existing chain or nucleating of a new polymer. Some qualitative results agree with those of a previous model for vapor deposition polymerization (VDP) with collective diffusion, such as the roughness increase and density decrease with G . This supports the interpretation of G as a ratio between diffusion coefficient and monomer flux. We perform a systematic study of scaling properties of the outer surface roughness and of polymer size and shape. For large G , the polymers are stretched in the direction perpendicular to the substrate and have typical size increasing as G(1/2). This is explained by the solution of the problem of random walk trapping, which illustrates the connection of surface processes and bulk properties. The distributions of polymer sizes are monotonically decreasing for all G and very broad, thus a large number of small chains and of chains much larger than the average is found in typical samples. The outer surface roughness obeys Kardar-Parisi-Zhang scaling, in contrast to the apparent anomalous scaling of previous VDP models with oblique monomer flux. However, the calculation of reliable exponents requires accounting for huge finite-size corrections. Possible applications and extensions of this model are discussed. PMID- 19792138 TI - Nonequilibrium thermodynamics of transport through moving interfaces with application to bubble growth and collapse. AB - We develop the general equation for the nonequilibrium reversible-irreversible coupling framework of thermodynamics to handle moving interfaces in the context of a gas that can be dissolved in a surrounding liquid. The key innovation is a "moving interface normal transfer" term required for consistency between the thermodynamic evolution equation and the chain rule of functional calculus. The freedom of atomistic displacements of the interface leads to gauge transformations under which the thermodynamic theory should be invariant. The thermodynamic framework provides a complete set of evolution equations and boundary conditions, as we illustrate for the example of bubble growth and collapse. PMID- 19792139 TI - Interaction of nanoparticles with lipid layers. AB - Poly (amidoamine) dendrimer nanoparticles are used extensively in diverse biological and medical applications. Examples include gene and drug delivery, where nanoparticles disrupt cell membranes to allow the transport of material into cells. The size and surface chemistry of these particles have a strong effect on their interaction with membranes. This paper proposes a three dimensional phase-field model to investigate how the interaction drives deformation and morphological evolution of the membrane. Attention is focused on the hole-formation process in the membrane. The simulations have demonstrated that a larger amine-terminated generation 7 dendrimer, which has positive charges, causes the formation of a hole in the membrane. The displaced membrane molecules enclose the particle and form a dendrimer-filled membrane vesicle. The effect is significantly reduced for a smaller dendrimer. An acetamide-terminated dendrimer, which has a neutral charge at the surface, does not cause hole formation. These results agree with experimental observations from atomic force microscopy. The study will provide insight into the design of appropriate nanoparticle surface properties for medical applications. PMID- 19792140 TI - Surface energy of a nematic liquid crystal in contact with structured surfaces. AB - A generalization of the functional form of the anchoring energy of a nematic liquid crystal in contact with a structured surface is proposed. The structured surface is represented by side-chain polymer, containing only aliphatic or aliphatic and mesogenic side groups, deposited as a thin alignment film onto a solid substrate. The basic assumption in the model developed in the present work is that the coupling between the polymer side groups and the nematic liquid crystal molecules is responsible for the elastic deformation and compression of the orienting groups taking place in the alignment film. We show that in the limit of small deformations, the surface energy is the same as the one given by the Rapini-Papoular approximation. In this limit, the effective anchoring strength is weak and is due to the elastic deformation of the orienting side groups, which is proportional to the inverse of the length of the aliphatic groups and the length of the linkage group of the mesogens, respectively. In the limit of large deformation, however, the term accounting the film compression is predominant which results in a nonzero torque facilitating the relaxation process of an imposed deformation when the applied electric field is switched off. Good agreement is found between the prediction of our model and the experimental data of the anchoring energy of a nematic liquid crystal aligned by means of Langmuir Blodgett monolayers of fatty acids as a function of the length of their alkyl chains. PMID- 19792141 TI - Electroconvection in nematic mixtures of bent-core and calamitic molecules. AB - The onset of electroconvection in binary mixtures of a bent-core and a rodlike nematic has been characterized by measuring the threshold voltage U(c) and the critical wave number of the pattern in a wide range of frequencies f. In the mixtures rich in bent-core molecules, a "conductive-prewavy2-patternless prewavy1" morphological sequence has been detected with an unusual negative slope of U(c)(f) at high frequencies. This latter scenario seems to be related to the bent-core component, as it disappears with increasing the concentration of rodlike molecules. In addition, one of the parameters most relevant for electroconvection, the electrical conductivity, has also been varied by ionic salt doping. It has been found that the above effect of the banana-shaped molecules on the electroconvection scenarios can be suppressed by the conductivity. PMID- 19792142 TI - Electric-field-dictated phase diagram and accelerated dynamics of a reentrant nematic liquid crystal under photostimulation. AB - In a system consisting of photoactive molecules that exhibit light-driven isomerization transformations, actinic light can diminish or enhance ordering to the extent that transitions from the equilibrium to a more disordered phase can be brought about isothermally. This feature enables light to be used as a thermodynamiclike parameter to investigate phase behavior and adds another dimension to the studies owing to the nonequilibrium character of the isothermal transitions. We have carried out experiments which exploit the combination of two recent findings, viz., an electric field can accelerate the return to the nematic liquid crystalline phase from a photodriven isotropic phase; and in a reentrant mesogen, the photoinduced phase can be more ordered. To photostimulate the nonequilibrium transitions a low power uv radiation (0.1 mW cm(-2)) has been used. Unique temperature-electric-field phase diagrams of a liquid crystal exhibiting isotropic-nematic-smectic- A -reentrant nematic sequence, mapped using light transmission as probe reveal that the electric field influences all the transitions, but the effect is maximum on the equilibrium reentrant nematic to the photoinduced smectic- A transition. Temporal measurements have been performed under nonequilibrium conditions to study the dynamics of both the photochemical and the back relaxation processes across the different transitions. The electric field is indeed observed to accelerate the thermal back relaxation in each case, and especially the recovery of the reentrant phase is hastened by three orders of magnitude in time. We explore possible causes for the acceleration and present a finding which can be associated with one of the predictions of density-functional calculations for isomerization of azobenzenes. PMID- 19792143 TI - Propagation of an electromagnetic wave in an absorbing anisotropic medium and infrared transmission of liquid crystals: comparison with experiments. AB - The theory of the absorbance of a semi-infinite medium characterized by a second rank dielectric tensor for the entire electromagnetic spectrum, as given by Scaife and Vij [J. Chem. Phys. 122, 174901 (2005)], is extended to include molecules of prolate spheriodal shape with longitudinal and transverse polarizabilities and to cover the case of elliptically polarized incident radiation. The theory is applied to the infrared transmission experiments of biaxial liquid crystals. It is found that the formula for the dependence on frequency and on angle of polarization of the absorbance A(omega,theta)= log(10)[10(A(omega,0)) cos(2) theta + (10(-A(omega,pi/2)) sin(2) theta)] is unaffected by the anisotropy of the molecules and by the elliptical polarization of the incident radiation. A small (+/-5%) discrepancy between theory and experiment has been found for bands with high absorbances. It is found that this discrepancy does not depend on birefringence of the sample but may depend on the precise method of absorbance measurement and on effects at the surface of the cell containing the liquid crystal under test. PMID- 19792144 TI - Structure and stability of helices in square-well homopolymers. AB - Recently, it has been demonstrated [Magee, Phys. Rev. Lett. 96, 207802 (2006)] that isolated square-well homopolymers can spontaneously break chiral symmetry and "freeze" into helical structures at sufficiently low temperatures. This behavior is interesting because the square-well homopolymer is itself achiral. In this work, we use event-driven molecular dynamics combined with an optimized parallel tempering scheme to study this polymer model over a wide range of parameters. We examine the conditions where the helix structure is stable and determine how the interaction parameters of the polymer govern the details of the helix structure. The width of the square well (proportional to lambda) is found to control the radius of the helix, which decreases with increasing well width until the polymer forms a coiled sphere for sufficiently large wells. The helices are found to be stable for only a "window" of molecular weights. If the polymer is too short, the helix will not form. If the polymer is too long, the helix is no longer the minimum energy structure, and other folded structures will form. The size of this window is governed by the chain stiffness, which in this model is a function of the ratio of the monomer size to the bond length. Outside this window, the polymer still freezes into a locked structure at low temperature; however, unless the chain is sufficiently stiff, this structure will not be unique and is similar to a glassy state. PMID- 19792145 TI - Impact of aging on the evolution of cooperation in the spatial prisoner's dilemma game. AB - Aging is always present, tailoring our interactions with others, and postulating a finite lifespan during which we are able to exercise them. We consider the prisoner's dilemma game on a square lattice and examine how quenched age distributions and different aging protocols influence the evolution of cooperation when taking the life experience and knowledge accumulation into account as time passes. In agreement with previous studies, we find that a quenched assignment of age to players, introducing heterogeneity to the game, substantially promotes cooperative behavior. Introduction of aging and subsequent death as a coevolutionary process may act detrimental on cooperation but enhances it efficiently if the offspring of individuals that have successfully passed their strategy is considered newborn. We study resulting age distributions of players and show that the heterogeneity is vital-yet insufficient-for explaining the observed differences in cooperator abundance on the spatial grid. The unexpected increment of cooperation levels can be explained by a dynamical effect that has a highly selective impact on the propagation of cooperator and defector states. PMID- 19792146 TI - Swinging and synchronized rotations of red blood cells in simple shear flow. AB - The dynamics of red blood cells (RBCs) in simple shear flow was studied using a theoretical approach based on three variables: a shape parameter, the inclination angle theta, and phase angle phi of the membrane rotation. At high shear rate and low viscosity contrast of internal fluid, RBCs exhibit tank-treading motion, where phi rotates with swinging oscillation of shape and theta . At low shear rate, tumbling motion occurs and theta rotates. In the middle region between these two phases, it is found that synchronized rotation of phi and theta with integer ratios of the frequencies occurs in addition to intermittent rotation. These dynamics are robust to the modification of the potential of the RBC shape and membrane rotation. Our results agree well with recent experiments. PMID- 19792147 TI - Noisy swimming at low Reynolds numbers. AB - Small organisms (e.g., bacteria) and artificial microswimmers move due to a combination of active swimming and passive Brownian motion. Considering a simplified linear three-sphere swimmer, we study how the swimmer size regulates the interplay between self-driven and diffusive behavior at low Reynolds number. Starting from the Kirkwood-Smoluchowski equation and its corresponding Langevin equation, we derive formulas for the orientation correlation time, the mean velocity and the mean-square displacement in three space dimensions. The validity of the analytical results is illustrated through numerical simulations. Tuning the swimmer parameters to values that are typical of bacteria, we find three characteristic regimes: (i) Brownian motion at small times, (ii) quasiballistic behavior at intermediate time scales, and (iii) quasidiffusive behavior at large times due to noise-induced rotation. Our analytical results can be useful for a better quantitative understanding of optimal foraging strategies in bacterial systems, and they can help to construct more efficient artificial microswimmers in fluctuating fluids. PMID- 19792148 TI - Fokker-Planck description of conductance-based integrate-and-fire neuronal networks. AB - Steady dynamics of coupled conductance-based integrate-and-fire neuronal networks in the limit of small fluctuations is studied via the equilibrium states of a Fokker-Planck equation. An asymptotic approximation for the membrane-potential probability density function is derived and the corresponding gain curves are found. Validity conditions are discussed for the Fokker-Planck description and verified via direct numerical simulations. PMID- 19792149 TI - Geometric characteristics of dynamic correlations for combinatorial regulation in gene expression noise. AB - Knowing which mode of combinatorial regulation (typically, AND or OR logic operation) that a gene employs is important for determining its function in regulatory networks. Here, we introduce a dynamic cross-correlation function between the output of a gene and its upstream regulator concentrations for signatures of combinatorial regulation in gene expression noise. We find that such a correlation function with respect to the correlation time near the peak close to the point of the zero correlation time is always upward convex in the case of AND logic whereas is always downward convex in the case of OR logic, whichever sources of noise (intrinsic or extrinsic or both). In turn, this fact implies a means for inferring regulatory synergies from available experimental data. The extensions and applications are discussed. PMID- 19792150 TI - Spatiotemporal pattern in somitogenesis: a non-Turing scenario with wave propagation. AB - Living organisms maintain their lives under far-from-equilibrium conditions by creating a rich variety of spatiotemporal structures in a self-organized manner, such as temporal rhythms, switching phenomena, and development of the body. In this paper, we focus on the dynamical process of morphogens in somitogenesis in mice where propagation of the gene expression level plays an essential role in creating the spatially periodic patterns of the vertebral columns. We present a simple discrete reaction-diffusion model which includes neighboring interaction through an activator, but not diffusion of an inhibitor. We can produce stationary periodic patterns by introducing the effect of spatial discreteness to the field. Based on the present model, we discuss the underlying physical principles that are independent of the details of biomolecular reactions. We also discuss the framework of spatial discreteness based on the reaction-diffusion model in relation to a cellular array, by comparison with an actual experimental observation. PMID- 19792151 TI - Polymer translocation out of confined environments. AB - We consider the dynamics of polymer translocation out of confined environments. Analytic scaling arguments lead to the prediction that the translocation time scales like tau approximately N(beta+nu(2D))R(1+(1-nu(2D))/nu) for translocation out of a planar confinement between two walls with separation R into a three dimensional (3D) environment, and tau approximately N(beta+1)R for translocation out of two strips with separation R into a two-dimensional (2D) environment. Here, N is the chain length, nu and nu(2D) are the Flory exponents in 3D and 2D, and beta is the scaling exponent of translocation velocity with N , whose value for the present choice of parameters is beta equals approximately 0.8 based on Langevin dynamics simulations. These scaling exponents improve on earlier predictions. PMID- 19792152 TI - Predicting synchrony in heterogeneous pulse coupled oscillators. AB - Pulse coupled oscillators (PCOs) represent an ubiquitous model for a number of physical and biological systems. Phase response curves (PRCs) provide a general mathematical framework to analyze patterns of synchrony generated within these models. A general theoretical approach to account for the nonlinear contributions from higher-order PRCs in the generation of synchronous patterns by the PCOs is still lacking. Here, by considering a prototypical example of a PCO network, i.e., two synaptically coupled neurons, we present a general theory that extends beyond the weak-coupling approximation, to account for higher-order PRC corrections in the derivation of an approximate discrete map, the stable fixed point of which can predict the domain of 1:1 phase locked synchronous states generated by the PCO network. PMID- 19792153 TI - Intrinsic fluctuations in stochastic delay systems: theoretical description and application to a simple model of gene regulation. AB - The effects of intrinsic noise on stochastic delay systems is studied within an expansion in the inverse system size. We show that the stochastic nature of the underlying dynamics may induce oscillatory behavior in parameter ranges where the deterministic system does not sustain cycles, and compute the power spectra of these stochastic oscillations analytically, in good agreement with simulations. The theory is developed in the context of a simple one-dimensional toy model, but is applicable more generally. Gene regulatory systems in particular often contain only a small number of molecules, leading to significant fluctuations in messenger RNA (mRNA) and protein concentrations. As an application we therefore study a minimalistic model of the expression levels of hes1 mRNA and Hes1 protein, representing the simple motif of an autoinhibitory feedback loop and motivated by its relevance to somite segmentation. PMID- 19792154 TI - Spontaneous curvature as a regulator of the size of virus capsids. AB - We investigate the physical reasons underlying the high monodispersity of empty virus capsids assembled in thermodynamical equilibrium in conditions of favorable pH and ionic strength. We propose that the high fidelity of the assembly results from the effective spontaneous curvature of the viral protein assemblies and the corresponding bending rigidity that penalizes curvatures which are larger and smaller from the spontaneous one. On the example of hepatitis B virus, which has been thoroughly studied experimentally in the context of interest to us, we estimate the magnitude of bending rigidity that is needed to suppress the appearance of aberrant capsid structures (approximately 60k(B)T). Our approach also demonstrates that the aberrant capsids that can be classified within the Caspar-Klug framework are in most circumstances likely to be smaller from the regular ones, in agreement with the experimental findings. PMID- 19792155 TI - Buckling instability of lipid tubules with multibilayer walls under local radial indentation. AB - The mechanical behavior of self-assembled lipid tubules is an important property which determines their suitability for technological applications. We study the instability of multibilayer lipid tubules (with wall thickness t and external radius R(ext)) beyond elastic response under local radial atomic force microscopy indentations. A discontinuity in force-distance curves associated with the buckling instability of lipid tubules is observed. The critical force at which lipid tubules undergo a buckling transition linearly scales as t/R(ext). In addition, a reduced critical buckling force is found to extend a distance of approximately 1 microm from the end of lipid tubules. PMID- 19792156 TI - Penrose-Hameroff orchestrated objective-reduction proposal for human consciousness is not biologically feasible. AB - Penrose and Hameroff have argued that the conventional models of a brain function based on neural networks alone cannot account for human consciousness, claiming that quantum-computation elements are also required. Specifically, in their Orchestrated Objective Reduction (Orch OR) model [R. Penrose and S. R. Hameroff, J. Conscious. Stud. 2, 99 (1995)], it is postulated that microtubules act as quantum processing units, with individual tubulin dimers forming the computational elements. This model requires that the tubulin is able to switch between alternative conformational states in a coherent manner, and that this process be rapid on the physiological time scale. Here, the biological feasibility of the Orch OR proposal is examined in light of recent experimental studies on microtubule assembly and dynamics. It is shown that the tubulins do not possess essential properties required for the Orch OR proposal, as originally proposed, to hold. Further, we consider also recent progress in the understanding of the long-lived coherent motions in biological systems, a feature critical to Orch OR, and show that no reformation of the proposal based on known physical paradigms could lead to quantum computing within microtubules. Hence, the Orch OR model is not a feasible explanation of the origin of consciousness. PMID- 19792157 TI - Directed intermittent search for a hidden target on a dendritic tree. AB - Motivated by experimental observations of active (motor-driven) intracellular transport in neuronal dendrites, we analyze a stochastic model of directed intermittent search on a tree network. A particle injected from the cell body or soma into the primary branch of the dendritic tree randomly switches between a stationary search phase and a mobile nonsearch phase that is biased in the forward direction. A (synaptic) target is presented somewhere within the tree, which the particle can locate if it is within a certain range and in the searching phase. We approximate the moment generating function using Green's function methods. The moment generating function is then used to compute the hitting probability and conditional mean first passage time to the target. We show that in contrast to a previously explored finite interval case, there is a range of parameters for which a bidirectional search strategy is more efficient than a unidirectional one in finding the target. PMID- 19792158 TI - Characterization of DNA conformation inside bacterial viruses. AB - In this study we develop a formalism to describe the organization of DNA inside bacteriophage capsids during genome packaging. We have previously shown that DNA inside bacteriophage phi29 (phi29) is organized into folded toroids [A. S. Petrov and S. C. Harvey, Structure 15, 21 (2007)], whereas epsilon15 (epsilon15) reveals the coaxial organization of the genetic material [A. S. Petrov, K. Lim-Hing, and S. C. Harvey, Structure 15, 807 (2007)]. We now show that each system undergoes two consecutive transitions. The first transition corresponds to the formation of global conformations and is analogous to a disorder-order conformational transition. The second transition is characterized by a significant loss of DNA mobility at the local level leading to glasslike dynamic behavior. Packing genetic material inside bacteriophages can be used as a general model to study the behavior of semiflexible chains inside confined spaces, and the proposed formalism developed here can be used to study other systems of linear polymer chains confined to closed spaces. PMID- 19792159 TI - Noise and critical phenomena in biochemical signaling cycles at small molecule numbers. AB - Biochemical reaction networks in living cells usually involve reversible covalent modification of signaling molecules, such as protein phosphorylation. Under conditions of small molecule numbers, as is frequently the case in living cells, mass-action theory fails to describe the dynamics of such systems. Instead, the biochemical reactions must be treated as stochastic processes that intrinsically generate concentration fluctuations of the chemicals. We investigate the stochastic reaction kinetics of covalent modification cycles (CMCs) by analytical modeling and numerically exact Monte Carlo simulation of the temporally fluctuating concentration. Depending on the parameter regime, we find for the probability density of the concentration qualitatively distinct classes of distribution functions including power-law distributions with a fractional and tunable exponent. These findings challenge the traditional view of biochemical control networks as deterministic computational systems and suggest that CMCs in cells can function as versatile and tunable noise generators. PMID- 19792160 TI - Collapse transition of a hydrophobic self-avoiding random walk in a coarse grained model solvent. AB - In order to study solvation effects on protein folding, we analyze the collapse transition of a self-avoiding random walk composed of hydrophobic segments that is embedded in a lattice model of a solvent. As expected, hydrophobic interactions lead to an attractive potential of mean force among chain segments. As a consequence, the random walk in solvent undergoes a collapse transition at a higher temperature than in its absence. Chain collapse is accompanied by the formation of a region depleted of solvent around the chain. In our simulation, the depleted region at collapse is as large as our computational domain. PMID- 19792161 TI - Effect of clustered ion channels along an unmyelinated axon. AB - In most unmyelinated axons, ion channels are distributed uniformly along the axon to facilitate stable propagation of action potentials. In this case, the conduction in the axon is continuous, and the excitability along the membrane is constant. Some experimental papers show that ion channels also locate in clusters in some unmyelinated axons. In this paper, we investigate theoretically the effect of clustered ion channels along unmyelinated axon. We mainly focused on two aspects: the propagation efficiency and the propagation speed. Our results show that localization of potassium ion channels is beneficial for increasing propagation efficiency and propagation speed of action potentials; however, localization of sodium ion channels is advantageous to the propagation efficiency only when axonal parameters are in a specific range. PMID- 19792162 TI - Ionic current through a nanopore three nanometers in diameter. AB - Ionic current through a 3 nm in diameter nanopore has been investigated using molecular dynamics. Results indicate that the ionic current increases linearly as the electrolyte concentration increases from 0.4 to 0.9 M, beyond which the ionic current increases at a slower rate. In contradiction to the expectation that higher surface charge density will lead to more ions in the nanopore, and therefore, higher ionic current, the ionic current shows an increase-decrease profile as the surface charge density increases. These unusual observations are attributed to the fact that ions close to the wall experience large viscous force, leading to low mobility. PMID- 19792163 TI - Coherent stochastic oscillations enhance signal detection in spiking neurons. AB - We study the effect of noisy oscillatory input on the signal discrimination by spontaneously firing neurons. Using analytically tractable model, we contrast signal detection in two situations: (i) when the neuron is driven by coherent oscillations and (ii) when the coherence of oscillations is destroyed. Analytical calculations revealed a region in the parameter space of the model where oscillations act to reduce the variability of neuronal firing and to enhance the discriminability of weak signals. These analytical results are employed to unveil a possible role of coherent oscillations in peripheral electrosensory system of paddlefish in improvement of detection of weak stimuli. The proposed mechanism may be relevant to a wide range of phenomena involving coherently driven oscillators. PMID- 19792164 TI - Dynamic photophysical processes in laser-irradiated human cortical skull bone measured by means of modulated diffuse luminescence. AB - The technique of modulated luminescence of bones was developed experimentally and theoretically and was subsequently used to interpret measurements performed on the cortical layer of human skull bones. The photophysical theory is based on the optical excitation and decay rate equations of the fluorescent endogenous chromophore and on the molecular interaction parameter with the photon field density in the matrix of the bone. An effective mean relaxation lifetime, tau(M), of skull cortical bone was derived theoretically and was found to depend on the endogenous chromophore decay lifetime, tau(2), in the upper energy state, on the generated luminescence field density through its dependence on the incident photon field density and on the thickness of the bone. A linear dependence of tau(M) on laser beam intensity, I0, was found and sensitivity of the value of tau(M) to bone thickness, L, was observed for L < or = 6.2 mm. Both experimental dependencies of tau(M) on I0 and L were in excellent agreement with the theoretical model. The unusually long relaxation luminescence lifetime was accounted for theoretically by means of an excited-state manifold invoking intersystem crossing to a forbidden state followed by decay to the ground state of the chromophore. Best fits to the data were able to yield measurements of the following chromophore and photon field parameters: tau(2)=19.7 ms , optical scattering coefficient mu(s)(659 nm)=44,340 m(-1), optical absorption coefficient mu(a)(659 nm)=13 m(-1), and coupling coefficient B(21)= 1.6 x 10(4) m(3) J(-1) s( 1), the decay coupling coefficient of the endogenous chromophore participating in the optical interaction in the form of stimulated luminescence emission mediated by the luminescence photon field between the long-lived excited state E2 and the lower (ground) state E1. The method of modulated luminescence can be used to measure photophysical properties of the chromophore in cortical skull bones, being a sensitive marker of bone diseases, namely, osteoporosis and cancer. PMID- 19792165 TI - Hydrodynamics of helical-shaped bacterial motility. AB - To reveal the underlying hydrodynamic mechanism for the directed propulsion of the bacterium Spiroplasma, we formulate a coarse-grained elastic polymer model with domains of alternating helicities along the contour. Using hydrodynamic simulations and analytic arguments, we show that the propagation of helical domain walls leads to the directed propulsion of the cell body opposite to the domain-wall traveling direction. Several key features of Spiroplasma motility are reproduced by our model. We in particular show that the helical pitch angle observed for Spiroplasma meliferum, psi=35 degrees , is optimized for maximal swimming speed and energy-conversion efficiency. Our analytic theory based on the slender-body hydrodynamic approximation agrees very well with our numerical data demonstrating how the chirality switch propagating along the helical cell body is converted to a translational thrust for the cell body itself. We in detail consider thermal effects on the propulsion efficiency in the form of orientational fluctuations and conformational fluctuations of the helix shape. The body length dependence of the cell motility is studied numerically and compared to our approximate analytic theory. For fixed pitch angle psi=35 degrees , the swimming speed is maximized at a ratio of cell-body length to domain length of about 2-3, which are typical values for real cells. We also propose simple analytic arguments for an enhancement of the swimming velocity with increasing solution viscosity by taking into account the effects of transient confinement of a helical cell body in a polymeric meshwork. Comparison with a generalized theory for the swimming speed of flagellated bacteria in polymeric meshworks shows that the presence of a finite-sized bacterial head gives rise to a maximal swimming speed at a finite solution viscosity, whereas in the absence of a head the swimming speed monotonically increases with increasing viscosity. PMID- 19792166 TI - Stochastic fluctuations in the susceptible-infective-recovered model with distributed infectious periods. AB - We investigate a stochastic model of infection dynamics based on the Susceptible Infective-Recovered (SIR) model, where the distribution of the recovery times can be tuned, interpolating between exponentially distributed recovery times, as in the standard SIR model, and recovery after a fixed infectious period. This is achieved by introducing L infective classes, as compared to 1 in the standard model. For large populations, the spectrum of fluctuations around the deterministic limit of the model can be computed analytically. The demographic stochasticity has the effect of transforming the decaying oscillations of the deterministic model into sustained oscillations in the stochastic formulation. We find that the amplification of these stochastic oscillations increases with L , as well as their coherence in frequency. For large values of L (of the order of 10 and greater), the height and position of the peak of the power spectra changes little and is described well by the model with fixed recovery period (L- >infinity) . In this limit we give a closed-form expression for the power spectrum of fluctuations of infective individuals. PMID- 19792167 TI - Fluctuation theorem for the flashing ratchet model of molecular motors. AB - Molecular motors convert chemical energy derived from the hydrolysis of adenosine triphosphate (ATP) into mechanical energy. A well-studied model of a molecular motor is the flashing ratchet model. We show that this model exhibits a fluctuation relation known as the Gallavotti-Cohen symmetry. Our study highlights the fact that the symmetry is present only if the chemical and mechanical degrees of freedom are both included in the description. PMID- 19792168 TI - Pacing-induced spatiotemporal dynamics can be exploited to improve reentry termination efficacy. AB - Some potentially fatal cardiac arrhythmias may be terminated by a series of premature stimuli. Monomorphic ventricular tachycardia, which may be modeled as an excitation wave traveling around in a ring, is one such arrhythmia. We investigated the mechanisms and requirements for termination of such reentry using an ionic cardiac ring model. Termination requires conduction block, which in turn is facilitated by spatial dispersion in repolarization and recovery time. When applying short series of two or three stimuli, we found that for conduction block to robustly occur, the magnitude of the spatial gradient in recovery time must exceed a critical value of 20 ms/cm. Importantly, the required spatial gradient can be induced in this homogeneous system by the dynamics of the stimulus-induced waves-we show analytically the necessary conditions. Finally, we introduce a type of pacing protocol, the "aggressive ramp," which increases the termination efficacy by exploiting such pacing-induced heterogeneities. This technique, which is straightforward to implement, may therefore have important clinical implications. PMID- 19792169 TI - Self-consistent analytic solution for the current and the access resistance in open ion channels. AB - A self-consistent analytic approach is introduced for the estimation of the access resistance and the current through an open ion channel for an arbitrary number of species. For an ion current flowing radially inward from infinity to the channel mouth, the Poisson-Boltzmann-Nernst-Planck equations are solved analytically in the bulk with spherical symmetry in three dimensions, by linearization. Within the channel, the Poisson-Nernst-Planck equation is solved analytically in a one-dimensional approximation. An iterative procedure is used to match the two solutions together at the channel mouth in a self-consistent way. It is shown that the current-voltage characteristics obtained are in good quantitative agreement with experimental measurements. PMID- 19792170 TI - Memristive model of amoeba learning. AB - Recently, it was shown that the amoebalike cell Physarum polycephalum when exposed to a pattern of periodic environmental changes learns and adapts its behavior in anticipation of the next stimulus to come. Here we show that such behavior can be mapped into the response of a simple electronic circuit consisting of a LC contour and a memory-resistor (a memristor) to a train of voltage pulses that mimic environment changes. We also identify a possible biological origin of the memristive behavior in the cell. These biological memory features are likely to occur in other unicellular as well as multicellular organisms, albeit in different forms. Therefore, the above memristive circuit model, which has learning properties, is useful to better understand the origins of primitive intelligence. PMID- 19792171 TI - Electron transfers in proteins: investigations with a modified through-bond coupling model. AB - By integrating the merits of previous models, a modified through-bond coupling (MTBC) model is proposed in this work and shows obvious improvement compared with previous models. With the MTBC model, the dominant electron coupling pathways in the polypeptide chains were identified, where the N-H bonds were found to be essential to the electron couplings. The local structures of peptides and proteins were finely characterized by the electron couplings and decay factors since they are structure sensitive. The neighboring carbonyl O-O distances are qualitatively correlated with the decay factors, and the deviations from the transconfigurations will weaken the coupling interactions. When the two amino acids being studied are not close in sequence, the couplings through hydrogen bonds are probably the main pathway because the electron transfers in this way save many steps, albeit the decay factor is less than that of per bond, consistent with the classical electron-tunneling model developed by Beratan [Science 252, 1285 (1991)]. It was found that the MTBC model can be effectively extended to study the electron transfers in complex biological systems with the combination of the fragment approach, which takes into account the contributions of key hydrogen bonds. PMID- 19792172 TI - Dynamics of populations and networks of neurons with voltage-activated and calcium-activated currents. AB - The profile of transmembrane-channel expression in neurons is class dependent and a crucial determinant of neuronal dynamics. Here, a generalization of the experimentally verified exponential integrate-and-fire model is introduced that includes biophysical, nonlinear gated conductance-based currents, and a spike shape. A Fokker-Planck-based method is developed that allows for the rapid numerical calculation of steady-state and linear-response properties for recurrent networks of neurons with gating-variable dynamics slower than that of the voltage. This limit includes many cases of biological interest, particularly under in vivo conditions of high synaptic conductance. The utility of the method is illustrated by applying it to two biophysically detailed models adapted from the literature: an entorhinal layer-II cortical neuron and a neuron featuring both calcium-activated and voltage-activated spike-frequency-adaptation currents. The framework generalizes to networks comprised of different neuronal classes and so will allow for the modeling of emergent states in neural tissue at significantly increased levels of biological detail. PMID- 19792173 TI - Cooperative molecular motors moving back and forth. AB - We use a two-state ratchet model to study the cooperative bidirectional motion of molecular motors on cytoskeletal tracks with randomly alternating polarities. Our model is based on a previously proposed model [Badoual, Proc. Natl. Acad. Sci. U.S.A. 99, 6696 (2002)] for collective motor dynamics and, in addition, takes into account the cooperativity effect arising from the elastic tension that develops in the cytoskeletal track due to the joint action of the walking motors. We show, both computationally and analytically, that this additional cooperativity effect leads to a dramatic reduction in the characteristic reversal time of the bidirectional motion, especially in systems with a large number of motors. We also find that bidirectional motion takes place only on (almost) apolar tracks, while on even slightly polar tracks the cooperative motion is unidirectional. We argue that the origin of these observations is the sensitive dependence of the cooperative dynamics on the difference between the number of motors typically working in and against the instantaneous direction of motion. PMID- 19792174 TI - Oscillatory Notch-pathway activity in a delay model of neuronal differentiation. AB - Lateral inhibition resulting from a double-negative feedback loop underlies the assignment of different fates to cells in many developmental processes. Previous studies have shown that the presence of time delays in models of lateral inhibition can result in significant oscillatory transients before patterned steady states are reached. We study the impact of local feedback loops in a model of lateral inhibition based on the Notch signaling pathway, elucidating the roles of intracellular and intercellular delays in controlling the overall system behavior. The model exhibits both in-phase and out-of-phase oscillatory modes and oscillation death. Interactions between oscillatory modes can generate complex behaviors such as intermittent oscillations. Our results provide a framework for exploring the recent observation of transient Notch-pathway oscillations during fate assignment in vertebrate neurogenesis. PMID- 19792176 TI - Model-based control of cardiac alternans on a ring. AB - Cardiac alternans, a beat-to-beat alternation of cardiac electrical dynamics, and ventricular tachycardia, generally associated with a spiral wave of electrical activity, have been identified as frequent precursors of the life-threatening spatiotemporally chaotic electrical state of ventricular fibrillation (VF). Schemes for the elimination of alternans and the stabilization of spiral waves through the injection of weak external currents have been proposed as methods to prevent VF but have not performed at the level required for clinical implementation. In this paper we propose a control method based on linear quadratic regulator (LQR) control. Unlike most previously proposed approaches, our method incorporates information from the underlying model to increase efficiency. We use a one-dimensional ringlike geometry, with a single control electrode, to compare the performance of our method with that of two other approaches, quasi-instantaneous suppression of unstable modes (QISUM) and time delay autosynchronization (TDAS). We find that QISUM fails to suppress alternans due to conduction block. Although both TDAS and LQR succeed in suppressing alternans, LQR is able to suppress the alternans faster and using a much weaker control current. Our results highlight the benefits of a model-based control approach despite its inherent complexity compared with nonmodel-based control such as TDAS. PMID- 19792175 TI - Effect of cholesterol on structural and mechanical properties of membranes depends on lipid chain saturation. AB - The effects of cholesterol on membrane bending modulus K(C), membrane thickness D(HH), the partial and apparent areas of cholesterol and lipid, and the order parameter S(xray) are shown to depend upon the number of saturated hydrocarbon chains in the lipid molecules. Particularly striking is the result that up to 40% cholesterol does not increase the bending modulus K(C) of membranes composed of phosphatidylcholine lipids with two cis monounsaturated chains, although it does have the expected stiffening effect on membranes composed of lipids with two saturated chains. The B fluctuational modulus in the smectic liquid crystal theory is obtained and used to discuss the interactions between bilayers. Our K(C) results motivate a theory of elastic moduli in the high cholesterol limit and they challenge the relevance of universality concepts. Although most of our results were obtained at 30 degrees C , additional data at other temperatures to allow consideration of a reduced temperature variable do not support universality for the effect of cholesterol on all lipid bilayers. If the concept of universality is to be valid, different numbers of saturated chains must be considered to create different universality classes. The above experimental results were obtained from analysis of x-ray scattering in the low angle and wide angle regions. PMID- 19792177 TI - Firing rate of noisy integrate-and-fire neurons with synaptic current dynamics. AB - We derive analytical formulas for the firing rate of integrate-and-fire neurons endowed with realistic synaptic dynamics. In particular, we include the possibility of multiple synaptic inputs as well as the effect of an absolute refractory period into the description. The latter affects the firing rate through its interaction with the synaptic dynamics. PMID- 19792178 TI - Effects of noise and variations on the duration of transient oscillations in unidirectionally coupled bistable ring networks. AB - We study effects of spatiotemporal noise and spatial variations on long-lasting transient oscillations in ring networks of unidirectionally coupled bistable elements (neurons), the duration of which increases exponentially with the number of neurons. On the one hand, spatiotemporal noise tends to sustain the transient oscillations. The duration of the oscillations occurring from fixed initial conditions changes nonmonotonically with noise strength and takes the maximum value at intermediate noise strength. Further, the duration of the oscillations is distributed in the form of the second power law and the mean duration increases with the number of neurons in the presence of an optimal noise. On the other hand, spatial variations degrade the exponential increases in the duration of the oscillations with the number of neurons. In the presence of fixed biases in the steady states of the neurons, there is a flat region in the distribution of the duration of the oscillations occurring under random initial conditions and an increase in the mean duration is almost linear with the number of neurons. Further, the duration of the oscillations in an ensemble of the networks with random biases drawing from an identical distribution is distributed in the form of the second power law and the ensemble mean increases in proportion to the five halves power of the number of neurons. PMID- 19792179 TI - Asymptotic nonequilibrium steady-state operators. AB - We present a method for the calculation of asymptotic operators for nonequilibrium steady-state quantum systems. The asymptotic steady-state operator is obtained by averaging the corresponding operator in Heisenberg representation over infinitely long time. Several examples are considered to demonstrate the utility of our method. The results obtained within our approach are compared to those obtained within the Schwinger-Keldysh nonequilibrium Green's functions. PMID- 19792180 TI - Multiplicative cascades and seismicity in natural time. AB - Natural time chi enables the distinction of two origins of self-similarity, i.e., the process memory and the process increments infinite variance. Employing multiplicative cascades in natural time, the most probable value of the variance kappa(1)(is identical to chi(2)-chi(2))is explicitly related with the parameter b of the Gutenberg-Richter law of randomly shuffled earthquake data. Moreover, the existence of temporal and magnitude correlations is studied in the original earthquake data. Magnitude correlations are larger for closer in time earthquakes, when the maximum interoccurrence time varies from half a day to 1 min. PMID- 19792181 TI - Fractional-time quantum dynamics. AB - Application of the fractional calculus to quantum processes is presented. In particular, the quantum dynamics is considered in the framework of the fractional time Schrodinger equation (SE), which differs from the standard SE by the fractional time derivative: partial differential/partial differentialt --> partial differential(alpha)/partial differentialt(alpha). It is shown that for alpha=1/2 the fractional SE is isospectral to a comb model. An analytical expression for the Green's functions of the systems are obtained. The semiclassical limit is discussed. PMID- 19792182 TI - Pattern switching and polarizability for colloids in optical-trap arrays. AB - We show that colloidal molecular crystal states interacting with a periodic substrate, such as an optical-trap array, and a rotating external field can undergo a rapid pattern switching in which the orientation of the crystal changes. In some cases, a martensiticlike symmetry switching occurs. It is also possible to create a polarized state where the colloids in each substrate minimum develop a director field which smoothly rotates with the external drive, similar to liquid-crystal behavior. These results open the possibility for creating different types of devices using photonic band-gap materials, and should be generalizable to a variety of other condensed matter systems with multiple particle trapping. PMID- 19792183 TI - Real-time detection of deoxyribonucleic acid bases via their negative differential conductance signature. AB - In this Brief Report, we present a method for the real-time detection of the bases of the deoxyribonucleic acid using their signatures in negative differential conductance measurements. The present methods of electronic detection of deoxyribonucleic acid bases are based on a statistical analysis because the electrical currents of the four bases are weak and do not differ significantly from one base to another. In contrast, we analyze a device that combines the accumulated knowledge in nanopore and scanning tunneling detection and which is able to provide very distinctive electronic signatures for the four bases. PMID- 19792184 TI - Phase of Ising spins on modular networks analogous to social polarization. AB - Coordination processes in complex systems can be related to the problem of collective ordering in networks, many of which have modular organization. Investigating the order-disorder transition for Ising spins on modular random networks, corresponding to consensus formation in society, we observe two distinct phases: (i) ordering within each module at a critical temperature followed by (ii) global ordering at a lower temperature. This indicates polarization of society into groups having contrary opinions can persist indefinitely even when mutual interactions between agents favor consensus. PMID- 19792185 TI - Localized pinning states in closed containers: Homoclinic snaking without bistability. AB - Binary mixtures with a negative separation ratio are known to exhibit time independent spatially localized convection when heated from below. Numerical continuation of such states in a closed two-dimensional container with experimental boundary conditions and parameter values reveals the presence of a pinning region in Rayleigh number with multiple stable localized states but no bistability between the conduction state and an independent container-filling state. An explanation for this unusual behavior is offered. PMID- 19792186 TI - Period fissioning and other instabilities of stressed elastic membranes. AB - We study the shapes of elastic membranes under the simultaneous exertion of tensile and compressive forces when the translational symmetry along the tension direction is broken. We predict a multitude of morphological phases in various regimes of a two-dimensional parameter space (in ,nu) that defines the relevant mechanical and geometrical conditions. These parameters are, respectively, the ratio between compression and tension, and the wavelength contrast along the tension direction. The predicted patterns emerge through new transition and instability mechanisms and include several types of irregular and smooth cascades composed of wrinkles and sharp folds. In particular, the hierarchical morphology predicted under high tension and large wavelength contrast (in< 1, nu> 1) , explains recent experimental observations on ultrathin membranes floating on liquid. PMID- 19792187 TI - Spatial chaos of traveling waves has a given velocity. AB - We study the complexity of stable waves in unidirectional bistable coupled map lattices as a test tube to spatial chaos of traveling patterns in open flows. Numerical calculations reveal that, grouping patterns into sets according to their velocity, at most one set of waves has positive topological entropy for fixed parameters. By using symbolic dynamics and shadowing, we analytically determine velocity-dependent parameter domains of existence of pattern families with positive entropy. These arguments provide a method to exhibit chaotic sets of stable waves with arbitrary velocity in extended systems. PMID- 19792188 TI - Scaling and statistical geometry in passive scalar turbulence. AB - We show that the statistics of a turbulent passive scalar at scales larger than the pumping may exhibit multiscaling due to a weaker mechanism than the presence of statistical conservation laws. We develop a general formalism to give explicit predictions for the large scale scaling exponents in the case of the Kraichnan model and discuss their geometric origin at small and large scale. PMID- 19792189 TI - Finite dissipation and intermittency in magnetohydrodynamics. AB - We present an analysis of data stemming from numerical simulations of decaying magnetohydrodynamic (MHD) turbulence up to grid resolution of 1536(3) points and up to Taylor Reynolds number of approximately 1200 . The initial conditions are such that the initial velocity and magnetic fields are helical and in equipartition, while their correlation is negligible. Analyzing the data at the peak of dissipation, we show that the dissipation in MHD seems to asymptote to a constant as the Reynolds number increases, thereby strengthening the possibility of fast reconnection events in the solar environment for very large Reynolds numbers. Furthermore, intermittency of MHD flows, as determined by the spectrum of anomalous exponents of structure functions of the velocity and the magnetic field, is stronger than that of fluids, confirming earlier results; however, we also find that there is a measurable difference between the exponents of the velocity and those of the magnetic field, reminiscent of recent solar wind observations. Finally, we discuss the spectral scaling laws that arise in this flow. PMID- 19792190 TI - Generation of terahertz radiation via an electromagnetically induced transparency at ion acoustic frequency region in laser-produced dense plasmas. AB - Electromagnetically induced transparency is a well-known quantum phenomena that electromagnetic wave controls the refractive index of medium. It enables us to create a passband for low-frequency electromagnetic wave in a dense plasma even if the plasma is opaque for the electromagnetic wave. This technique can be used to prove the ion acoustic wave because the ion acoustic frequency is lower than the plasma frequency. We have investigated a feasibility of electromagnetic radiation at THz region corresponding to the ion acoustic frequency from a dense plasma. We confirmed that the passband is created at about 7.5 THz corresponding to the ion acoustic frequency in the electron plasma density of 10(21) cm(-3) with a Ti:Sapphire laser with the wavelength of 800 nm and the laser intensity of 10(17) W/cm(2). The estimated radiation power is around 1 MW, which is expected to be useful for nonlinear THz science and applications. PMID- 19792191 TI - Nonholonomic double-bracket equations and the Gauss thermostat. AB - In this Rapid Communication we consider certain equations that arise from imposing a constant kinetic-energy constraint on a one-dimensional set of oscillators. This is a nonlinear nonholonomic constraint on these oscillators and the dynamics are consistent with Gauss's law of least constraint. Dynamics of this sort are of interest in nonequilibrium molecular dynamics. We show that under certain choices of external potential these equations give rise to a generalization of the so-called double-bracket equations which are of interest in studying gradient flows and integrable systems such as the Toda lattice. In the case of harmonic potentials the flow is described by a symmetric bracket and periodic solutions are obtained. PMID- 19792192 TI - Wave localization in strongly nonlinear Hertzian chains with mass defect. AB - We report observations of mechanical energy localization in a strongly nonlinear discrete lattice. The experimental setup we consider is a one-dimensional nonloaded horizontal chain of identical spheres interacting via the nonlinear Hertz potential which contains a mass defect. Our experiments show that the interaction of a solitary wave with a light intruder excites a nonlinear localized mode. In agreement with dimensional analysis, we find that the frequency of localized oscillations exceeds the incident wave frequency spectrum and nonlinearly depends on incident wave strength and on mass and size of the intruder. The absence of tensile stress between grains allows some gaps to open, which in turn induces a significant enhancement of the amplitude of oscillations. We performed numerical simulations that precisely describe our observations without any adjusting parameters. PMID- 19792193 TI - Accelerated algorithm for computing the motion of solid particles suspended in fluid. AB - A fast algorithm for computing the motion of solid particles suspended in fluid is presented. The motion of solid particles suspended in Stokes flow can be calculated without fully calculating the fluid motion. When the steady-state simulation is sufficient, this algorithm can greatly accelerate the simulation of solid particle suspension in Stokes flow. PMID- 19792194 TI - Self-similarity of waiting times in fracture systems. AB - Experimental and numerical results are presented for a fracture experiment carried out on a fiber-reinforced element under flexural loading, and a statistical analysis is performed for acoustic emission waiting-time distributions. By an optimization procedure, a recently proposed scaling law describing these distributions for different event magnitude scales is confirmed by both experimental and numerical data, thus reinforcing the idea that fracture of heterogeneous materials has scaling properties similar to those found for earthquakes. Analysis of the different scaling parameters obtained for experimental and numerical data leads us to formulate the hypothesis that the type of scaling function obtained depends on the level of correlation among fracture events in the system. PMID- 19792195 TI - Critical Boolean networks with scale-free in-degree distribution. AB - We investigate analytically and numerically the dynamical properties of critical Boolean networks with power-law in-degree distributions and for two choices of update functions. When the exponent of the in-degree distribution is larger than 3, we obtain results equivalent to those obtained for networks with fixed in degree, e.g., the number of the nonfrozen nodes scales as N(2/3) with the system size N. When the exponent of the distribution is between 2 and 3, the number of the nonfrozen nodes increases as N(x), with x being between 0 and 2/3 and depending on the exponent and on the cutoff of the in-degree distribution. These and ensuing results explain various findings obtained earlier by computer simulations. PMID- 19792196 TI - Node matching between complex networks. AB - Revealing corresponding identities of a dedicated individual in several different complex systems is a common task in many areas, and this task is transferred to a node matching problem among complex networks in this paper. A feasible node matching algorithm based on network structure is proposed. Through solving node matching problems on different types of networks by our algorithm, it is revealed that the structure of the networks under study may significantly influence the final matching results. For example, it is found that higher matching precision can be obtained on random networks with moderate density of links, and the results on small-world networks are always better than those on random or regular networks. Moreover, in scale-free networks, it seems that hub nodes play dominant roles, i.e., better matching results can be expected by selecting nodes with larger degrees as the revealed matched nodes. These findings will help us design more efficient node matching algorithm in the future. PMID- 19792197 TI - Information mobility in complex networks. AB - The concept of information mobility in complex networks is introduced on the basis of a stochastic process taking place in the network. The transition matrix for this process represents the probability that the information arising at a given node is transferred to a target one. We use the fractional powers of this transition matrix to investigate the stochastic process at fractional time intervals. The mobility coefficient is then introduced on the basis of the trace of these fractional powers of the stochastic matrix. The fractional time at which a network diffuses 50% of the information contained in its nodes (1/k(50)) is also introduced. We then show that the scale-free random networks display a better spread of information than the non-scale-free ones. We study 38 real-world networks and analyze their performance in spreading information from their nodes. We find that some real-world networks perform even better than the scale-free networks with the same average degree and we point out some of the structural parameters that make this possible. PMID- 19792198 TI - Cooperation in an evolutionary prisoner's dilemma on networks with degree-degree correlations. AB - We study the effects of degree-degree correlations on the success of cooperation in an evolutionary prisoner's dilemma played on a random network. When degree degree correlations are not present, the standardized variance of the network's degree distribution has been shown to be an accurate analytical measure of network heterogeneity that can be used to predict the success of cooperation. In this paper, we use a local-mechanism interpretation of standardized variance to give a generalization to graphs with degree-degree correlations. Two distinct mechanisms are shown to influence cooperation levels on these types of networks. The first is an intrinsic measurement of base-line heterogeneity coming from the network's degree distribution. The second is the increase in heterogeneity coming from the degree-degree correlations present in the network. A strong linear relationship is found between these two parameters and the average cooperation level in an evolutionary prisoner's dilemma on a network. PMID- 19792199 TI - Probabilistic framework for network partition. AB - Given a large and complex network, we would like to find the partition of this network into a small number of clusters. This question has been addressed in many different ways. In a previous paper, we proposed a deterministic framework for an optimal partition of a network as well as the associated algorithms. In this paper, we extend this framework to a probabilistic setting, in which each node has a certain probability of belonging to a certain cluster. Two classes of numerical algorithms for such a probabilistic network partition are presented and tested. Application to three representative examples is discussed. PMID- 19792200 TI - Delocalization transition for the Google matrix. AB - We study the localization properties of eigenvectors of the Google matrix, generated both from the world wide web and from the Albert-Barabasi model of networks. We establish the emergence of a delocalization phase for the PageRank vector when network parameters are changed. For networks with localized PageRank, eigenvalues of the matrix in the complex plane with a modulus above a certain threshold correspond to localized eigenfunctions while eigenvalues below this threshold are associated with delocalized relaxation modes. We argue that, for networks with delocalized PageRank, the efficiency of information retrieval by Google-type search is strongly affected since the PageRank values have no clear hierarchical structure in this case. PMID- 19792201 TI - Effects of strategy-migration direction and noise in the evolutionary spatial prisoner's dilemma. AB - Spatial games are crucial for understanding patterns of cooperation in nature (and to some extent society). They are known to be more sensitive to local symmetries than, e.g., spin models. This paper concerns the evolution of the prisoner's dilemma game on regular lattices with three different types of neighborhoods--the von Neumann, Moore, and kagome types. We investigate two kinds of dynamics for the players to update their strategies (that can be unconditional cooperator or defector). Depending on the payoff difference, an individual can adopt the strategy of a random neighbor [a voter-model-like dynamics (VMLD)] or impose its strategy on a random neighbor, i.e., invasion-process-like dynamics (IPLD). In particular, we focus on the effects of noise, in combination with the strategy dynamics, on the evolution of cooperation. We find that VMLD, compared to IPLD, better supports the spreading and sustaining of cooperation. We see that noise has nontrivial effects on the evolution of cooperation: maximum cooperation density can be realized either at a medium noise level, in the limit of zero noise or in both these regions. The temptation to defect and the local interaction structure determine the outcome. Especially, in the low noise limit, the local interaction plays a crucial role in determining the fate of cooperators. We elucidate these both by numerical simulations and mean-field cluster approximation methods. PMID- 19792202 TI - Effects of inhomogeneous partial absorption and the geometry of the boundary on population evolution of molecules diffusing in general porous media. AB - We consider aspects of the population dynamics, inside a bound domain, of diffusing agents carrying an attribute which is stochastically destroyed upon contact with the boundary. The normal mode analysis of the relevant Helmholtz equation under the partially absorbing, but uniform, boundary condition provides a starting framework in understanding detailed evolution dynamics of the attribute in the time domain. In particular, the boundary-localized depletion has been widely employed in practical applications that depend on geometry of various porous media such as rocks, cement, bones, and cheese. While direct relationship between the pore geometry and the diffusion-relaxation spectrum forms the basis for such applications and has been extensively studied, relatively less attention has been paid to the spatial variation in the boundary condition. In this work, we focus on the way the pore geometry and the inhomogeneous depletion strength of the boundary become intertwined and thus obscure the direct relationship between the spectrum and the geometry. It is often impossible to gauge experimentally the degree to which such interference occurs. We fill this gap by perturbatively incorporating classes of spatially varying boundary conditions and derive their consequences that are observable through numerical simulations or controlled experiments on glass bead packs and artificially fabricated porous media. We identify features of the spectrum that are most sensitive to the inhomogeneity, apply the method to the spherical pore with a simple hemispherical binary distribution of the depletion strength, and obtain bounds for the induced change in the slowest relaxation mode. PMID- 19792203 TI - Spiraling solitons: A continuum model for dynamical phyllotaxis of physical systems. AB - A protean topological soliton has recently been shown to emerge in systems of repulsive particles in cylindrical geometries, whose statics is described by the number-theoretical objects of phyllotaxis. Here, we present a minimal and local continuum model that can explain many of the features of the phyllotactic soliton, such as locked speed, screw shift, energy transport, and--for Wigner crystal on a nanotube--charge transport. The treatment is general and should apply to other spiraling systems. Unlike, e.g., sine-Gordon-like systems, our soliton can exist between nondegenerate structures and its dynamics extends to the domains it separates; we also predict pulses, both static and dynamic. Applications include charge transport in Wigner Crystals on nanotubes or A - to B -DNA transitions. PMID- 19792204 TI - Conservative model for synchronization problems in complex networks. AB - In this paper we study the scaling behavior of the interface fluctuations (roughness) for a discrete model with conservative noise on complex networks. Conservative noise is a noise which has no external flux of deposition on the surface and the whole process is due to the diffusion. It was found that in Euclidean lattices the roughness of the steady state W(s) does not depend on the system size. Here, we find that for scale-free networks of N nodes, characterized by a degree distribution P(k) approximately k(-lambda), W(s) is independent of N for any lambda. This behavior is very different than the one found by Pastore y Piontti [Phys. Rev. E 76, 046117 (2007)] for a discrete model with nonconservative noise, which implies an external flux, where W(s) approximately ln N for lambda<3 , and was explained by nonlinear terms in the analytical evolution equation for the interface [La Rocca, Phys. Rev. E 77, 046120 (2008)]. In this work we show that in these processes with conservative noise the nonlinear terms are not relevant to describe the scaling behavior of W(s). PMID- 19792205 TI - Local elasticity map and plasticity in a model Lennard-Jones glass. AB - In this work we calculate the local elastic moduli in a weakly polydispersed two dimensional Lennard-Jones glass undergoing a quasistatic shear deformation at zero temperature. The numerical method uses coarse-grained microscopic expressions for the strain, displacement, and stress fields. This method allows us to calculate the local elasticity tensor and to quantify the deviation from linear elasticity (local Hooke's law) at different coarse-graining scales. From the results a clear picture emerges of an amorphous material with strongly spatially heterogeneous elastic moduli that simultaneously satisfies Hooke's law at scales larger than a characteristic length scale of the order of five interatomic distances. At this scale, the glass appears as a composite material composed of a rigid scaffolding and of soft zones. Only recently calculated in nonhomogeneous materials, the local elastic structure plays a crucial role in the elastoplastic response of the amorphous material. For a small macroscopic shear strain, the structures associated with the nonaffine displacement field appear directly related to the spatial structure of the elastic moduli. Moreover, for a larger macroscopic shear strain we show that zones of low shear modulus concentrate most of the strain in the form of plastic rearrangements. The spatiotemporal evolution of this local elasticity map and its connection with long term dynamical heterogeneity as well as with the plasticity in the material is quantified. The possibility to use this local parameter as a predictor of subsequent local plastic activity is also discussed. PMID- 19792206 TI - Agent-based model for friendship in social networks. AB - A model is proposed to understand the structuring of social networks in a fixed setting such as, for example, inside a university. The friendship formation is based on the frequency of encounters and mutual interest. The model shows distinctive single-scale behavior and reproduces accurately the measurable experimental quantities such as clustering coefficients, degree distribution, degree correlation, and friendship distribution. The model produces self organized community structures and can be described as a network of densely interconnected networks. For the friendships, we find that the mutual interest is the dominant factor, which optimizes the network and that the number of encounters determines the statistically relevant distributions. PMID- 19792207 TI - Self-adjusting routing schemes for time-varying traffic in scale-free networks. AB - We consider the effects of time-varying packet generation rates in the performance of communication networks. The time variations could be a result of the patterns in human activities. As a model, we study the effects of a degree dependent packet generation rate that includes a sinusoidal term. Applying a modified traffic awareness protocol (TAP) previously proposed for static packet generation rates to the present situation leads to an altered value of the optimization parameter, when compared to that obtained in the static case. To enhance the performance and to cope with the time-varying effects better, we propose a class of self-adjusting traffic awareness protocols that makes use of instantaneous traffic information beyond that included in the modified TAP. Two special cases that make use of global and local information, respectively, are studied. Comparing results of our proposal schemes with the modified TAP, it is shown that the present self-adjusting schemes perform more effectively. PMID- 19792208 TI - Network growth for enhanced natural selection. AB - Natural selection and random drift are competing phenomena for explaining the evolution of populations. Combining a highly fit mutant with a population structure that improves the odds that the mutation spreads through the whole population tips the balance in favor of natural selection. The probability that the spread occurs, known as the fixation probability, depends heavily on how the population is structured. Certain topologies, albeit highly artificially contrived, have been shown to exist that favor fixation. We present a randomized mechanism for network growth that is loosely inspired in some of these topologies' key properties and demonstrate, through simulations, that it is capable of giving rise to structured populations for which the fixation probability significantly surpasses that of an unstructured population. This discovery provides important support to the notion that natural selection can be enhanced over random drift in naturally occurring population structures. PMID- 19792209 TI - Finite-time singularities in the dynamics of hyperinflation in an economy. AB - The dynamics of hyperinflation episodes is studied by applying a theoretical approach based on collective "adaptive inflation expectations" with a positive nonlinear feedback proposed in the literature. In such a description it is assumed that the growth rate of the logarithmic price, r(t), changes with a velocity obeying a power law which leads to a finite-time singularity at a critical time t(c). By revising that model we found that, indeed, there are two types of singular solutions for the logarithmic price, p(t) . One is given by the already reported form p(t) approximately (t(c)-t)(-alpha) (with alpha>0 ) and the other exhibits a logarithmic divergence, p(t) approximately ln[1/(t(c)-t)] . The singularity is a signature for an economic crash. In the present work we express p(t) explicitly in terms of the parameters introduced throughout the formulation avoiding the use of any combination of them defined in the original paper. This procedure allows to examine simultaneously the time series of r(t) and p(t) performing a linked error analysis of the determined parameters. For the first time this approach is applied for analyzing the very extreme historical hyperinflations occurred in Greece (1941-1944) and Yugoslavia (1991-1994). The case of Greece is compatible with a logarithmic singularity. The study is completed with an analysis of the hyperinflation spiral currently experienced in Zimbabwe. According to our results, an economic crash in this country is predicted for these days. The robustness of the results to changes of the initial time of the series and the differences with a linear feedback are discussed. PMID- 19792210 TI - Spectral characteristics of network redundancy. AB - Many real-world complex networks contain a significant amount of structural redundancy, in which multiple vertices play identical topological roles. Such redundancy arises naturally from the simple growth processes which form and shape many real-world systems. Since structurally redundant elements may be permuted without altering network structure, redundancy may be formally investigated by examining network automorphism (symmetry) groups. Here, we use a group-theoretic approach to give a complete description of spectral signatures of redundancy in undirected networks. In particular, we describe how a network's automorphism group may be used to directly associate specific eigenvalues and eigenvectors with specific network motifs. PMID- 19792211 TI - Human activity in the web. AB - The recent information technology revolution has enabled the analysis and processing of large-scale data sets describing human activities. The main source of data is represented by the web, where humans generally use to spend a relevant part of their day. Here, we study three large data sets containing the information about web activities of humans in different contexts. We study in details interevent and waiting-time statistics. In both cases, the number of subsequent operations which differs by tau units of time decays powerlike as tau increases. We use nonparametric statistical tests in order to estimate the significance level of reliability of global distributions to describe activity patterns of single users. Global interevent time probability distributions are not representative for the behavior of single users: the shape of single users' interevent distributions is strongly influenced by the total number of operations performed by the users and distributions of the total number of operations performed by users are heterogeneous. A universal behavior can be anyway found by suppressing the intrinsic dependence of the global probability distribution on the activity of the users. This suppression can be performed by simply dividing the interevent times with their average values. Differently, waiting-time probability distributions seem to be independent of the activity of users and global probability distributions are able to significantly represent the replying activity patterns of single users. PMID- 19792212 TI - Structural phase transition in evolving networks. AB - A network as a substrate for dynamic processes may have its own dynamics. We propose a model for networks which evolve together with diffusing particles through a coupled dynamics and investigate emerging structural property. The model consists of an undirected weighted network of fixed mean degree and randomly diffusing particles of fixed density. The weight w of an edge increases by the amount of traffics through its connecting nodes or decreases by a constant factor. Edges are removed with the probability P(rew)=1/(1+w) and replaced by new ones having w=0 at random locations. We find that the model exhibits a structural phase transition between the homogeneous phase characterized by an exponentially decaying degree distribution and the heterogeneous phase characterized by the presence of hubs. The hubs emerge as a consequence of a positive feedback between the particle and the edge dynamics. PMID- 19792213 TI - Constant-net-time headway as a key mechanism behind pedestrian flow dynamics. AB - We show that keeping a constant lower limit on the net-time headway is the key mechanism behind the dynamics of pedestrian streams. There is a large variety in flow and speed as functions of density for empirical data of pedestrian streams obtained from studies in different countries. The net-time headway, however, stays approximately constant over all these different data sets. By using this fact, we demonstrate how the underlying dynamics of pedestrian crowds, naturally follows from local interactions. This means that there is no need to come up with an arbitrary fit function (with arbitrary fit parameters) as has traditionally been done. Further, by using not only the average density values but the variance as well, we show how the recently reported stop-and-go waves [Helbing, Phys. Rev. E 75, 046109 (2007)] emerge when local density variations take values exceeding a certain maximum global (average) density, which makes pedestrians stop. PMID- 19792214 TI - Partner selections in public goods games with constant group size. AB - Most of previous studies concerning the public goods game assume either participation is unconditional or the number of actual participants in a competitive group changes over time. How the fixed group size, prescribed by social institutions, affects the evolution of cooperation is still unclear. We propose a model where individuals with heterogeneous social ties might well engage in differing numbers of public goods games, yet with each public goods game being constant size during the course of evolution. To do this, we assume that each focal individual unidirectionally selects a constant number of interaction partners from his immediate neighbors with probabilities proportional to the degrees or the reputations of these neighbors, corresponding to degree based partner selection or reputation-based partner selection, respectively. Because of the stochasticity the group formation is dynamical. In both selection regimes, monotonical dependence of the stationary density of cooperators on the group size was found, the latter over the whole range but the former over a restricted range of the renormalized enhancement factor. Moreover, the reputation based regime can substantially improve cooperation. To interpret these differences, the microscopic characteristics of individuals are probed. We later extend the degree-based partner selection to general cases where focal individuals have preferences toward their neighbors of varying social ties to form groups. As a comparison, we as well investigate the situation where individuals locating on the degree regular graphs choose their coplayers at random. Our results may give some insights into better understanding the widespread teamwork and cooperation in the real world. PMID- 19792215 TI - Feedback topology and XOR-dynamics in Boolean networks with varying input structure. AB - We analyze a model of fixed in-degree random Boolean networks in which the fraction of input-receiving nodes is controlled by the parameter gamma. We investigate analytically and numerically the dynamics of graphs under a parallel XOR updating scheme. This scheme is interesting because it is accessible analytically and its phenomenology is at the same time under control and as rich as the one of general Boolean networks. We give analytical formulas for the dynamics on general graphs, showing that with a XOR-type evolution rule, dynamic features are direct consequences of the topological feedback structure, in analogy with the role of relevant components in Kauffman networks. Considering graphs with fixed in-degree, we characterize analytically and numerically the feedback regions using graph decimation algorithms (Leaf Removal). With varying gamma , this graph ensemble shows a phase transition that separates a treelike graph region from one in which feedback components emerge. Networks near the transition point have feedback components made of disjoint loops, in which each node has exactly one incoming and one outgoing link. Using this fact, we provide analytical estimates of the maximum period starting from topological considerations. PMID- 19792216 TI - Spectral and dynamical properties in classes of sparse networks with mesoscopic inhomogeneities. AB - We study structure, eigenvalue spectra, and random-walk dynamics in a wide class of networks with subgraphs (modules) at mesoscopic scale. The networks are grown within the model with three parameters controlling the number of modules, their internal structure as scale-free and correlated subgraphs, and the topology of connecting network. Within the exhaustive spectral analysis for both the adjacency matrix and the normalized Laplacian matrix we identify the spectral properties, which characterize the mesoscopic structure of sparse cyclic graphs and trees. The minimally connected nodes, the clustering, and the average connectivity affect the central part of the spectrum. The number of distinct modules leads to an extra peak at the lower part of the Laplacian spectrum in cyclic graphs. Such a peak does not occur in the case of topologically distinct tree subgraphs connected on a tree whereas the associated eigenvectors remain localized on the subgraphs both in trees and cyclic graphs. We also find a characteristic pattern of periodic localization along the chains on the tree for the eigenvector components associated with the largest eigenvalue lambda(L)=2 of the Laplacian. Further differences between the cyclic modular graphs and trees are found by the statistics of random walks return times and hitting patterns at nodes on these graphs. The distribution of first-return times averaged over all nodes exhibits a stretched exponential tail with the exponent sigma approximately 1/3 for trees and sigma approximately 2/3 for cyclic graphs, which is independent of their mesoscopic and global structure. PMID- 19792217 TI - Predicting extreme avalanches in self-organized critical sandpiles. AB - In a finite-size Abelian sandpile model, extreme avalanches are repelling each other. Taking a time series of the avalanche size and using a decision variable derived from that, we predict the occurrence of a particularly large avalanche in the next time step. The larger the magnitude of these target avalanches, the better is their predictability. The predictability which is based on a finite size effect, is discussed as a function of the system size. PMID- 19792218 TI - Information cascades on degree-correlated random networks. AB - We investigate by numerical simulation a threshold model of social contagion on degree-correlated random networks. We show that the class of networks for which global information cascades occur generally expands as degree-degree correlations become increasingly positive. However, under certain conditions, large-scale information cascades can paradoxically occur when degree-degree correlations are sufficiently positive or negative, but not when correlations are relatively small. We also show that the relationship between the degree of the initially infected vertex and its ability to trigger large cascades is strongly affected by degree-degree correlations. PMID- 19792219 TI - Ferromagnetic Ising spin systems on the growing random tree. AB - We analyze the ferromagnetic Ising model on a scale-free tree; the growing random tree model with the linear attachment kernel A(k) = k + alpha . We derive an estimate of the divergent temperature T(s) below which the zero-field susceptibility of the system diverges. Our result shows that T(s) is related to alpha as tanh(J/T(s)) = alpha/[2(alpha+1)] , where J is the ferromagnetic interaction. An analysis of exactly solvable limit for the model and numerical calculation supports the validity of this estimate. PMID- 19792220 TI - Determining the heterogeneity in time of the dynamics within a slowly relaxing region of a supercooled liquid: Role of sharp relaxation events. AB - Supercooled liquids have been shown to be dynamically heterogeneous with different regions of the system presenting dynamics that vary from each other even by orders of magnitude. Computer simulations have confirmed such a picture by detecting that the mobile particles in model glass formers are not homogeneously distributed within the system but arranged in clusters. More recently, the dynamics of small systems has been characterized by demonstrating that their structural relaxation is not homogeneous in time, in the sense that it does not evolve gradually but it is signed by rapid bursts of mobility characterized by relative compact clusters of mobile particles. These events (which have been named d clusters) are fast and sparse and trigger the transitions the system experiences between metabasins (MB) of its potential energy surface. The MB residence times are much larger than the time scales of occurrence of the d clusters, and it has been suggested that the events that occur within them scarcely contribute to the structural relaxation of the system. Thus, the picture of glassy relaxation that emerges would indicate that at any time a supercooled liquid may present different spatial regions, each one characterized by different structural relaxation times. In turn, each of such regions would not relax smoothly or gradually but by means of sporadic sharp relaxation events. Here, we assess for a model glass former the relative relevance of the MB exploration events and of the d clusters both in small systems and within regions of large systems, to show that the structural relaxation at the region level is indeed extremely heterogeneous in time and utterly governed by the latter. PMID- 19792221 TI - Scaling theory for steady-state plastic flows in amorphous solids. AB - Strongly correlated amorphous solids are a class of glass formers whose interparticle potential admits an approximate inverse power-law form in a relevant range of interparticle distances. We study the steady-state plastic flow of such systems, first in the athermal quasistatic limit and second at finite temperatures and strain rates. In all cases we demonstrate the usefulness of scaling concepts to reduce the data to universal scaling functions where the scaling exponents are determined a priori from the interparticle potential. In particular we show that the steady plastic flow at finite temperatures with efficient heat extraction is uniquely characterized by two scaled variables; equivalently, the steady-state displays an equation of state that relates one scaled variable to the other two. We discuss the range of applicability of the scaling theory, and the connection to density scaling in supercooled liquid dynamics. We explain that the description of transient states calls for additional state variables whose identity is still far from obvious. PMID- 19792222 TI - Detecting network communities by propagating labels under constraints. AB - We investigate the recently proposed label-propagation algorithm (LPA) for identifying network communities. We reformulate the LPA as an equivalent optimization problem, giving an objective function whose maxima correspond to community solutions. By considering properties of the objective function, we identify conceptual and practical drawbacks of the label-propagation approach, most importantly the disparity between increasing the value of the objective function and improving the quality of communities found. To address the drawbacks, we modify the objective function in the optimization problem, producing a variety of algorithms that propagate labels subject to constraints; of particular interest is a variant that maximizes the modularity measure of community quality. Performance properties and implementation details of the proposed algorithms are discussed. Bipartite as well as unipartite networks are considered. PMID- 19792223 TI - Iterated tabu search for identifying community structure in complex networks. AB - This paper presents an iterated tabu search (denoted by ITS) algorithm for optimizing the modularity of community structure in complex networks. The proposed algorithm follows a general framework composed of two phases: basic optimization and postrefinement. When the basic optimization cannot improve the modularity any more, a postrefinement procedure is employed to further optimize the objective function with a global view. For both these two phases, iterated tabu search algorithm is employed to optimize the objective function. Computational results show the high effectiveness of the proposed ITS algorithm compared with six state-of-the-art algorithms in the literature. In particular, our ITS algorithm improves the previous best known modularity for several small and medium size networks. PMID- 19792224 TI - Improved risk estimation in multifractal records: Application to the value at risk in finance. AB - We suggest a risk estimation method for financial records that is based on the statistics of return intervals between events above/below a certain threshold Q and is particularly suited for multifractal records. The method is based on the knowledge of the probability W(Q)(t;Deltat) that within the next Deltat units of time at least one event above Q occurs, if the last event occurred t time units ago. We propose an analytical estimate of W(Q) and show explicitly that the proposed method is superior to the conventional precursory pattern recognition technique widely used in signal analysis, which requires considerable fine tuning and is difficult to implement. We also show that the estimation of the Value at Risk, which is a standard tool in finances, can be improved considerably by the method. PMID- 19792225 TI - Propagation of extremes in space. AB - The propagation of extreme events in space is analyzed for a class of dynamical systems giving rise to spatiotemporal chaos. It is shown that this process can be mapped into a generalized random walk, whereby the mean square displacement increases linearly in time and there is a nonvanishing probability for jumps beyond first neighbors. The relative roles of the local dynamics and of the spatial coupling are identified. PMID- 19792226 TI - Perturbation analysis of complete synchronization in networks of phase oscillators. AB - The behavior of weakly coupled self-sustained oscillators can often be well described by phase equations. Here we use the paradigm of Kuramoto phase oscillators which are coupled in a network to calculate first- and second-order corrections to the frequency of the fully synchronized state for nonidentical oscillators. The topology of the underlying coupling network is reflected in the eigenvalues and eigenvectors of the network Laplacian which influence the synchronization frequency in a particular way. They characterize the importance of nodes in a network and the relations between them. Expected values for the synchronization frequency are obtained for oscillators with quenched random frequencies on a class of scale-free random networks and for a Erdos-Renyi random network. We briefly discuss an application of the perturbation theory in the second order to network structural analysis. PMID- 19792227 TI - Dissipative system with asymmetric interaction and Hopf bifurcation. AB - A dissipative system with asymmetric interaction, as well as the optimal velocity model, generally shows a Hopf bifurcation concerned with the transition from homogeneous motion to the formation of nontrivial patterns. We reveal that the origin of Hopf bifurcation in macroscopic phenomena is strongly related to asymmetric interaction in a microscopic many-body system, using the continuum system derived from the original discrete system. PMID- 19792228 TI - Role of the effective Hilbert-space size of the reservoir for the decoherence process. AB - We show that an environment composed by N bosons coupled through cross-Kerr interaction to an oscillator of interest can be effective at destroying quantum coherences at short times and around the revival times even if N=1 . It is analytically shown for this model that the effective Hilbert-space size is a relevant parameter for decoherence process. Based on numerical results, we investigate the long time dynamics and the classical limit. Since we are dealing with a phase reservoir, the model does not describe dissipation. PMID- 19792229 TI - Emerging attractors and the transition from dissipative to conservative dynamics. AB - The topological structure of basin boundaries plays a fundamental role in the sensitivity to the final state in chaotic dynamical systems. Herewith we present a study on the dynamics of dissipative systems close to the Hamiltonian limit, emphasizing the increasing number of periodic attractors, and on the structural changes in their basin boundaries as the dissipation approaches zero. We show numerically that a power law with nontrivial exponent describes the growth of the total number of periodic attractors as the damping is decreased. We also establish that for small scales the dynamics is governed by effective dynamical invariants, whose measure depends not only on the region of the phase space but also on the scale under consideration. Therefore, our results show that the concept of effective invariants is also relevant for dissipative systems. PMID- 19792230 TI - Synchronization transitions on scale-free neuronal networks due to finite information transmission delays. AB - We investigate front propagation and synchronization transitions in dependence on the information transmission delay and coupling strength over scale-free neuronal networks with different average degrees and scaling exponents. As the underlying model of neuronal dynamics, we use the efficient Rulkov map with additive noise. We show that increasing the coupling strength enhances synchronization monotonously, whereas delay plays a more subtle role. In particular, we found that depending on the inherent oscillation frequency of individual neurons, regions of irregular and regular propagating excitatory fronts appear intermittently as the delay increases. These delay-induced synchronization transitions manifest as well-expressed minima in the measure for spatial synchrony, appearing at every multiple of the oscillation frequency. Larger coupling strengths or average degrees can broaden the region of regular propagating fronts by a given information transmission delay and further improve synchronization. These results are robust against variations in system size, intensity of additive noise, and the scaling exponent of the underlying scale free topology. We argue that fine-tuned information transmission delays are vital for assuring optimally synchronized excitatory fronts on complex neuronal networks and, indeed, they should be seen as important as the coupling strength or the overall density of interneuronal connections. We finally discuss some biological implications of the presented results. PMID- 19792231 TI - Electro-optic delay oscillator with nonlocal nonlinearity: Optical phase dynamics, chaos, and synchronization. AB - We demonstrate experimentally how nonlinear optical phase dynamics can be generated with an electro-optic delay oscillator. The presented architecture consists of a linear phase modulator, followed by a delay line, and a differential phase-shift keying demodulator (DPSK-d). The latter represents the nonlinear element of the oscillator effecting a nonlinear transformation. This nonlinearity is considered as nonlocal in time since it is ruled by an intrinsic differential delay, which is significantly greater than the typical phase variations. To study the effect of this specific nonlinearity, we characterize the dynamics in terms of the dependence of the relevant feedback gain parameter. Our results reveal the occurrence of regular GHz oscillations (approximately half of the DPSK-d free spectral range), as well as a pronounced broadband phase chaotic dynamics. Beyond this, the observed dynamical phenomena offer potential for applications in the field of microwave photonics and, in particular, for the realization of novel chaos communication systems. High quality and broadband phase-chaos synchronization is also reported with an emitter-receiver pair of the setup. PMID- 19792232 TI - Selection of flow-distributed oscillation and Turing patterns by boundary forcing in a linearly growing, oscillating medium. AB - We studied the response of a linearly growing domain of the oscillatory chemical chlorine dioxide-iodide-malonic acid (CDIMA) medium to periodic forcing at its growth boundary. The medium is Hopf-, as well as Turing-unstable and the system is convectively unstable. The results confirm numerical predictions that two distinct modes of pattern can be excited by controlling the driving frequency at the boundary, a flow-distributed-oscillation (FDO) mode of traveling waves at low values of the forcing frequency f , and a mode of stationary Turing patterns at high values of f . The wavelengths and phase velocities of the experimental patterns were compared quantitatively with results from dynamical simulations and with predictions from linear dispersion relations. The results for the FDO waves agreed well with these predictions, and obeyed the kinematic relations expected for phase waves with frequencies selected by the boundary driving frequency. Turing patterns were also generated within the predicted range of forcing frequencies, but these developed into two-dimensional structures which are not fully accounted for by the one-dimensional numerical and analytical models. The Turing patterns excited by boundary forcing persist when the forcing is removed, demonstrating the bistability of the unforced, constant size medium. Dynamical simulations at perturbation frequencies other than those of the experiments showed that in certain ranges of forcing frequency, FDO waves become unstable, breaking up into harmonic waves of different frequency and wavelength and phase velocity. PMID- 19792234 TI - Homoclinic snaking in bounded domains. AB - Homoclinic snaking is a term used to describe the back and forth oscillation of a branch of time-independent spatially localized states in a bistable spatially reversible system as the localized structure grows in length by repeatedly adding rolls on either side. On the real line this process continues forever. In finite domains snaking terminates once the domain is filled but the details of how this occurs depend critically on the choice of boundary conditions. With periodic boundary conditions the snaking branches terminate on a branch of spatially periodic states. However, with non-Neumann boundary conditions they turn continuously into a large amplitude filling state that replaces the periodic state. This behavior, shown here in detail for the Swift-Hohenberg equation, explains the phenomenon of "snaking without bistability," recently observed in simulations of binary fluid convection by Mercader et al. Phys. Rev. E 80, 025201 (2009). PMID- 19792233 TI - Harmonic resonant excitation of flow-distributed oscillation waves and Turing patterns driven at a growing boundary. AB - We perform numerical studies of a reaction-diffusion system that is both Turing and Hopf unstable, and that grows by addition at a moving boundary (which is equivalent by a Galilean transformation to a reaction-diffusion-advection system with a fixed boundary and a uniform flow). We model the conditions of a recent set of experiments which used a temporally varying illumination in the boundary region to control the formation of patterns in the bulk of the photosensitive medium. The frequency of the illumination variations can select patterns from among the competing instabilities of the medium. In the usual case, the waves that are excited have frequencies (as measured at a constant distance from the upstream boundary) matching the driving frequency. In contrast to the usual case, we find that both Turing patterns and flow-distributed oscillation waves can be excited by forcing at subharmonic multiples of the wave frequencies. The final waves (with frequencies at integer multiples of the driving frequency) are formed by a process in which transient wave fronts break up and reconnect. We find ratios of response to driving frequency as high as 10. PMID- 19792235 TI - Phase multistability and phase synchronization in an array of locally coupled period-doubling oscillators. AB - We consider phase multistability and phase synchronization phenomena in a chain of period-doubling oscillators. The synchronization in arrays of diffusively coupled self-sustained oscillators manifests itself as rotating wave regimes, which are characterized by equal amplitudes and phases in every site which are shifted by a constant value. The value of the phase shift is preserved while the shape of motion becomes more complex through a period-doubling cascade. The number of coexisting attractors increases drastically after the transition from period-one to period-two oscillations and then after every following period doubling bifurcation. In the chaotic region, we observe a number of phase synchronized modes with instantaneous phases locked in different values. The loss of phase synchronization with decreasing coupling is accompanied by intermittency between several synchronous regimes. PMID- 19792236 TI - Locking behavior of three coupled laser oscillators. AB - Single-frequency operation or locking in a lateral array of three laser oscillators is studied within the composite-cavity-mode approach. We compute the regions of stable locking, which have a nontrivial shape in the plane of coupling strength versus frequency detuning. The locking regions depend drastically on the amount of amplitude-phase coupling of the lasing field that is quantified by the alpha parameter. For small alpha, locking is possible for arbitrary coupling, but only if the middle laser has sufficient frequency detuning from the two outer lasers. In contrast, for larger alpha, locking is only possible for weak to moderate coupling, provided that all three lasers have similar frequencies. PMID- 19792237 TI - Level statistics of a pseudo-Hermitian Dicke model. AB - A non-Hermitian operator that is related to its adjoint through a similarity transformation is defined as a pseudo-Hermitian operator. We study the level statistics of a pseudo-Hermitian Dicke Hamiltonian that undergoes quantum phase transition (QPT). We find that the level-spacing distribution of this Hamiltonian near the integrable limit is close to Poisson distribution, while it is Wigner distribution for the ranges of the parameters for which the Hamiltonian is nonintegrable. We show that the assertion in the context of the standard Dicke model that QPT is a precursor to a change in the level statistics is not valid in general. PMID- 19792238 TI - Detection of the type of intermittency using characteristic patterns in recurrence plots. AB - One of the common routes to chaos is intermittency. Identification of the intermittency type is usually made using the properties of the probability distribution of laminar phases and of the average length of the laminar phases. Both have a statistical character and to obtain them a long time series has to be examined. Here, we present a recurrence plot method applicable to the analysis of short time series and through which the type of intermittency may be identified. The three types of intermittency introduced by Pomeau and Manneville and a chaos chaos intermittency induced by interior crisis were examined. The identification of the type of intermittency is equivalent to the identification of the bifurcation associated with it. Our result seems particularly interesting as our method allows the analysis of short time series. The effect of the measurement noise on the effectiveness of the method is also discussed. An application of the method to the detection of type I intermittency in measured heart rate variability data is discussed. PMID- 19792239 TI - Feedback-controlled dynamics in a two-dimensional array of active elements. AB - We investigate collective behaviors in a two-dimensional array of active elements controlled by time-delayed feedback, where elements are prepared by localizing the Belousov-Zhabotinsky reaction in a gel matrix. We demonstrate that both the spatial and temporal coherence can be effectively controlled by varying feedback parameters, such as the time delay and the gain. For a sufficiently high feedback gain, the fully synchronized state with low temporal coherence appears, which might be the state induced only by the delay feedback. Experimental results are approximately reproduced in a numerical simulation with a forced Oregonator reaction-diffusion model. PMID- 19792240 TI - Large excursions of action within the resonance of a degenerate Hamiltonian system with two degrees of freedom. AB - We investigate the width of the resonance zone in a degenerate Hamiltonian system with two degrees of freedom, in which the Hamiltonian lacks the quadratic term in the Taylor expansion. This leads to larger excursions of action in the phase space than the nondegenerate one, and corresponding resonance frequency widths would become narrower. However, in contrast to the nonautonomous Hamiltonian system with one and half degree of freedom, we find that the above case is not generic and only occurs at particular resonances. An example relevant to the interaction of resonances is considered. Analytic results are verified in numerical simulations. PMID- 19792241 TI - Reliable detection of directional couplings using rank statistics. AB - To detect directional couplings from time series various measures based on distances in reconstructed state spaces were introduced. These measures can, however, be biased by asymmetries in the dynamics' structure, noise color, or noise level, which are ubiquitous in experimental signals. Using theoretical reasoning and results from model systems we identify the various sources of bias and show that most of them can be eliminated by an appropriate normalization. We furthermore diminish the remaining biases by introducing a measure based on ranks of distances. This rank-based measure outperforms existing distance-based measures concerning both sensitivity and specificity for directional couplings. Therefore, our findings are relevant for a reliable detection of directional couplings from experimental signals. PMID- 19792242 TI - Mapping of two-polarization-mode dynamics in vertical-cavity surface-emitting lasers with optical injection. AB - We report theoretically on the interplay between polarization switching and bifurcations to nonlinear dynamics in a vertical-cavity surface-emitting laser (VCSEL) subject to orthogonal optical injection. Qualitatively different bifurcation scenarios leading to polarization switching are found and mapped out in the plane of the injection parameters, i.e., the frequency detuning vs injection strength plane. A Hopf bifurcation mechanism on the two-polarization mode solution determines the injection-locking boundaries and influences polarization switching induced by optical injection. We furthermore report on a torus bifurcation emerging from a two-linearly polarized (LP) mode time-periodic dynamics before polarization switching and injection locking appear. It corresponds to an interesting combination of relaxation oscillation dynamics in the x -LP mode together with wave mixing dynamics in the injected y -LP mode. In agreement with recent experiments, we unveil a period-doubling route to chaos that involves both VCSEL orthogonal LP modes. The corresponding region of chaotic dynamics coincides with abrupt changes in the polarization switching boundaries in the plane of the injection parameters. PMID- 19792243 TI - Role of surface roughness characterized by fractal geometry on laminar flow in microchannels. AB - A three-dimensional model of laminar flow in microchannels is numerically analyzed incorporating surface roughness effects as characterized by fractal geometry. The Weierstrass-Mandelbrot function is proposed to characterize the multiscale self-affine roughness. The effects of Reynolds number, relative roughness, and fractal dimension on laminar flow are all investigated and discussed. The results indicate that unlike flow in smooth microchannels, the Poiseuille number in rough microchannels increases linearly with the Reynolds number, Re, and is larger than what is typically observed in smooth channels. For these situations, the flow over surfaces with high relative roughness induces recirculation and flow separation, which play an important role in single-phase pressure drop. More specifically, surfaces with the larger fractal dimensions yield more frequent variations in the surface profile, which result in a significantly larger incremental pressure loss, even though at the same relative roughness. The accuracy of the predicted Poiseuille number as calculated by the present model is verified using experimental data available in the literature. PMID- 19792244 TI - Turbulent transport and dynamo in sheared magnetohydrodynamics turbulence with a nonuniform magnetic field. AB - We investigate three-dimensional magnetohydrodynamics turbulence in the presence of velocity and magnetic shear (i.e., with both a large-scale shear flow and a nonuniform magnetic field). By assuming a turbulence driven by an external forcing with both helical and nonhelical spectra, we investigate the combined effect of these two shears on turbulence intensity and turbulent transport represented by turbulent diffusivities (turbulent viscosity, alpha and beta effect) in Reynolds-averaged equations. We show that turbulent transport (turbulent viscosity and diffusivity) is quenched by a strong flow shear and a strong magnetic field. For a weak flow shear, we further show that the magnetic shear increases the turbulence intensity while decreasing the turbulent transport. In the presence of a strong flow shear, the effect of the magnetic shear is found to oppose the effect of flow shear (which reduces turbulence due to shear stabilization) by enhancing turbulence and transport, thereby weakening the strong quenching by flow shear stabilization. In the case of a strong magnetic field (compared to flow shear), magnetic shear increases turbulence intensity and quenches turbulent transport. PMID- 19792245 TI - Interfacial instabilities in periodically driven Hele-Shaw flows. AB - We consider flow in a Hele-Shaw cell for which the upper plate moves up and down, making the fluid-fluid interface be driven periodically. To study such a flow we employ a mode-coupling approach, which allows the analytical assessment of important aspects about the stability and morphology of the evolving interface. At the linear level, it is shown that both the amplitude and the frequency of the drive have a significant role in determining the ultimate number of fingers formed. The influence of these factors on the mechanisms of finger competition and finger tip behavior at the onset of nonlinear effects is also studied. PMID- 19792246 TI - Heat transfer mechanisms in bubbly Rayleigh-Benard convection. AB - The heat transfer mechanism in Rayleigh-Benard convection in a liquid with a mean temperature close to its boiling point is studied through numerical simulations with pointlike vapor bubbles, which are allowed to grow or shrink through evaporation and condensation and which act back on the flow both thermally and mechanically. It is shown that the effect of the bubbles is strongly dependent on the ratio of the sensible heat to the latent heat as embodied in the Jakob number Ja. For very small Ja the bubbles stabilize the flow by absorbing heat in the warmer regions and releasing it in the colder regions. With an increase in Ja, the added buoyancy due to the bubble growth destabilizes the flow with respect to single-phase convection and considerably increases the Nusselt number. PMID- 19792247 TI - Predicting the evolution of fast chemical reactions in chaotic flows. AB - We study the fast irreversible bimolecular reaction in a two-dimensional chaotic flow. The reactants are initially segregated and together fill the whole domain. Simulations show that the reactant concentration decays exponentially with rate lambda and then crosses over to the algebraic law of chemical kinetics in the final stage of the reaction. We estimate the crossover time from the reaction rate constant and the flow parameters. The exponential decay phase of the reaction can be described in terms of an equivalent passive scalar problem, allowing us to predict lambda using the theory of passive scalar advection. Depending on the relative length scale between the velocity and the concentration fields, lambda is either related to the distribution of the finite-time Lyapunov exponent of the flow or given in terms of an effective diffusivity which is independent of the small-scale stretching properties of the flow. For the former case, we suggest an optimal choice of flow parameters at which lambda is maximum. PMID- 19792248 TI - Mixing-induced aggregation and associated microstructures in the capillary flow. AB - With a device that uses microscopic imaging as the signal detection method for online laser light scattering of solutions driven to flow in a capillary tube, we have found that mixing of a solution with water and vice versa induce large numbers of aggregates in the free flow stream. The degrees of aggregation as measured from the total number of aggregates and the corresponding light scattering intensities are dependent on the species of the solution. This species dependence of the mixing aggregation in the capillary flow has the potential for the development of new protocols or even spectroscopic methods for the detection of solute molecules and the assessment of solution qualities. Furthermore, even with pure-distilled and de-ionized water in the steady-state capillary flow, there are still countable numbers of aggregates detectable in the free flow stream, although of extremely low concentration of an estimated value of no more than 10(-15) M . PMID- 19792249 TI - Deformation and breakup of high-viscosity droplets with symmetric microfluidic cross flows. AB - The dynamic response of highly viscous droplets to a sharp increase in the surrounding liquid velocity is experimentally investigated in a square microchannel junction. The local injection of the continuous phase from symmetric side channels onto a train of droplets produces a large velocity contrast between the front and the rear of droplets, yielding a broad range of time-dependent deformation and breakup. In particular, due to microscale confinement, the system displays a nonlinear behavior with the initial droplet size. Deformations, relaxation times, and fragmentation processes are examined as a function of flow parameters and fluids properties with emphasis on the formation of slender viscous structures such as spoon-shaped droplets, i.e., asymmetrical droplets. PMID- 19792250 TI - Three-sphere low-Reynolds-number swimmer near a wall. AB - We study the influence of a wall on the dynamics of a low-Reynolds-number three sphere swimmer. A far swimmer whose arm makes an angle theta with the horizon experiences the wall presence as an angle-dependent quadrupole force proportional to (a/L)(2)(L/z)(2)cos theta, where a, L, and z are the radius of spheres, the arm length, and the swimmer distance to the wall, respectively. The wall-induced translational velocity of swimmer is perpendicular to the arms. A far swimmer prefers to orient its arms parallel to the plate. This state is stable. Remarkably, the parallel state is unstable when the swimmer is close to the wall. In this regime, the velocity of swimmer decreases as (z/L)(2). Numerical solution of the equations of motion for arbitrary initial z/L and theta reveals four different phases of locomotion. PMID- 19792251 TI - Flow fields in soap films: Relating viscosity and film thickness. AB - We follow the diffusive motion of colloidal particles in soap films with varying h / d, where h is the thickness of the film and d is the diameter of the particles. The hydrodynamics of these films are determined by looking at the correlated motion of pairs of particles as a function of separation R. The Trapeznikov approximation [A. A. Trapeznikov, (Butterworths, London, 1957), p. 242] is used to model soap films as an effective two-dimensional (2D) fluid in contact with bulk air phases. The flow fields determined from correlated particle motions show excellent agreement with what is expected for the theory of 2D fluids for all our films where 0.6 < or = h / d < or = 14.3 , with the 2D shear viscosity matching that predicted by Trapeznikov. However, the parameters of these flow fields change markedly for thick films (h / d > 7 + or - 3) . Our results indicate that three-dimensional effects become important for these thicker films, despite the flow fields still having a 2D character. PMID- 19792252 TI - Impact of inlet channel geometry on microfluidic drop formation. AB - We study the impact of inlet channel geometry on microfluidic drop formation. We show that drop makers with T-junction style inlets form monodisperse emulsions at low and moderate capillary numbers and those with Flow-Focus style inlets do so at moderate and high capillary numbers. At low and moderate capillary number, drop formation is dominated by interfacial forces and mediated by the confinement of the microchannels; drop size as a function of flow-rate ratio follows a simple functional form based on a blocking-squeezing mechanism. We summarize the stability of the drop makers with different inlet channel geometry in the form of a phase diagram as a function of capillary number and flow-rate ratio. PMID- 19792253 TI - Coagulation and fragmentation dynamics of inertial particles. AB - Inertial particles suspended in many natural and industrial flows undergo coagulation upon collisions and fragmentation if their size becomes too large or if they experience large shear. Here we study this coagulation-fragmentation process in time-periodic incompressible flows. We find that this process approaches an asymptotic dynamical steady state where the average number of particles of each size is roughly constant. We compare the steady-state size distributions corresponding to two fragmentation mechanisms and for different flows and find that the steady state is mostly independent of the coagulation process. While collision rates determine the transient behavior, fragmentation determines the steady state. For example, for fragmentation due to shear, flows that have very different local particle concentrations can result in similar particle size distributions if the temporal or spatial variation in shear forces is similar. PMID- 19792254 TI - Spatiotemporal evolution of Poiseuille-Rayleigh-Benard flows in binary fluids with Soret effect under initial pulselike disturbances. AB - The spatiotemporal evolution of Poiseuille-Rayleigh-Benard flows in binary fluids with Soret effect is investigated by carrying out fully nonlinear two-dimensional numerical simulations initiated by a pulselike disturbance. The traveling wave packets for positive as well as negative separation factors psi are obtained numerically for ethanol-water-like mixtures (Prandtl number Pr=10 , Lewis number Le=0.01) and selected combinations of Rayleigh and Reynolds numbers at psi=0.01, 0.1 and psi=-0.1. The characteristics of the wave fronts and the transitions observed between absolute and convective instabilities when changing the parameters are compared with the results previously obtained by linear spatiotemporal stability analysis. The simulations are in very good agreement with the stability results, which confirms the validity of both approaches. Finally, in order to characterize the possible interaction between the two wave packets of the so-called downstream and upstream modes for psi<0, the spatiotemporal stability analysis is used to detect a boundary curve in the (Re, Ra) parameter region beyond which the two wave packets will never completely separate. Numerical simulations illustrate the different evolutions of the wave packets on both sides of this boundary. PMID- 19792255 TI - Symmetry breaking, mixing, instability, and low-frequency variability in a minimal Lorenz-like system. AB - Starting from the classical Saltzman two-dimensional convection equations, we derive via a severe spectral truncation a minimal 10 ODE system which includes the thermal effect of viscous dissipation. Neglecting this process leads to a dynamical system which includes a decoupled generalized Lorenz system. The consideration of this process breaks an important symmetry and couples the dynamics of fast and slow variables, with the ensuing modifications to the structural properties of the attractor and of the spectral features. When the relevant nondimensional number (Eckert number Ec) is different from zero, an additional time scale of O(Ec(-1)) is introduced in the system, as shown with standard multiscale analysis and made clear by several numerical evidences. Moreover, the system is ergodic and hyperbolic, the slow variables feature long term memory with 1/f(3/2) power spectra, and the fast variables feature amplitude modulation. Increasing the strength of the thermal-viscous feedback has a stabilizing effect, as both the metric entropy and the Kaplan-Yorke attractor dimension decrease monotonically with Ec. The analyzed system features very rich dynamics: it overcomes some of the limitations of the Lorenz system and might have prototypical value in relevant processes in complex systems dynamics, such as the interaction between slow and fast variables, the presence of long-term memory, and the associated extreme value statistics. This analysis shows how neglecting the coupling of slow and fast variables only on the basis of scale analysis can be catastrophic. In fact, this leads to spurious invariances that affect essential dynamical properties (ergodicity, hyperbolicity) and that cause the model losing ability in describing intrinsically multiscale processes. PMID- 19792256 TI - Thermomagnetic convection in a ferrofluid layer exposed to a time-periodic magnetic field. AB - We have investigated the influence of a time-periodic and spatially homogeneous magnetic field on the linear stability properties and on the nonlinear response of a ferrofluid layer heated from below and from above. A competition between stabilizing thermal and viscous diffusion and destabilizing buoyancy and Kelvin forces occurs. Floquet theory is used to determine the stability boundaries of the motionless conductive state for a harmonic and subharmonic response. Full numerical simulations with a finite difference method were made to obtain nonlinear convective states. The effect of low- and high-frequency modulation on the stability boundaries as well as on the nonlinear oscillations that may occur is investigated. PMID- 19792257 TI - Fingering and pressure distribution in lifting Hele-Shaw cells with grooves: A computer simulation study. AB - We report a computer simulation study of viscous fingering patterns in a lifting Hele-Shaw cell with grooves. Here circular or square grooves concentric to the plates are etched on the lower plate. Experiments show that the presence of such grooves affect formation of viscous fingers quite strongly. We report a simulated pressure map generated in such grooved cells, when the two plates are separated with a constant force and compare the patterns with experiments. Variation in the simulated patterns for different fluid viscosity and lifting force is also studied. PMID- 19792258 TI - Experimental investigation of Lagrangian structure functions in turbulence. AB - Lagrangian properties obtained from a particle tracking velocimetry experiment in a turbulent flow at intermediate Reynolds number are presented. Accurate sampling of particle trajectories is essential in order to obtain the Lagrangian structure functions and to measure intermittency at small temporal scales. The finiteness of the measurement volume can bias the results significantly. We present a robust way to overcome this obstacle. Despite no fully developed inertial range, we observe strong intermittency at the scale of dissipation. The multifractal model is only partially able to reproduce the results. PMID- 19792259 TI - Average temperature and Maxwellian iteration in multitemperature mixtures of fluids. AB - This paper treats the nonequilibrium processes in mixtures of fluids under the assumption that each constituent is characterized by its own velocity and temperature field. First we discuss the concept of the average temperature of mixture based upon considerations that the internal energy of the mixture is the same as in the case of a single-temperature mixture. As a consequence, it is shown that the entropy of the mixture reaches a local maximum in equilibrium. An illustrative example of homogeneous mixtures is given to support the theoretical considerations. Through the procedure of Maxwellian iteration a new constitutive equation for nonequilibrium temperatures of constituents is obtained in a classical limit, together with the Fick's law for the diffusion flux. These results obtained for n-species are in perfect agreement with a recent classical approach of thermodynamics of irreversible processes in multitemperature case due to Gouin and Ruggeri and generalize our previous papers concerning the case of a binary mixture. PMID- 19792260 TI - Liquid meniscus oscillation and drop ejection by ac voltage, pulsed dc voltage, and superimposing dc to ac voltages. AB - The electrohydrodynamic (EHD) spraying technique has been utilized in applications such as inkjet printing and mass spectrometry technologies. In this paper, the role of electrical potential signals in jetting and on the oscillation of the meniscus is evaluated. The jetting and the meniscus oscillation behavior are experimentally investigated under ac voltage, ac voltage superimposed on dc voltage, and pulsed dc voltage. Based on this in-depth study of the meniscus behavior under various signals, the optimal signal is implemented to an EHD inkjet head for drop-on-demand operation. For applied ac voltage and ac voltage superimposed on dc voltage, the jetting phenomenon is a dynamic process due to sequential opposite sign signals. The jetting occurs at the end of the oscillation cycle, where the meniscus oscillates upward and arrives at its highest position. PMID- 19792261 TI - Three-dimensional simulation of viscous-flow agglomerate sintering. AB - The viscous-flow sintering of different agglomerate particle morphologies is studied by three-dimensional computer simulations based on the concept of fractional volume of fluid. For a fundamental understanding of particle sintering characteristics, the neck growth kinetics in agglomerate chains and in doublets consisting of differently sized primary particles is investigated. Results show that different sintering contacts in agglomerates even during the first stages are not completely independent from each other, even though differences are small. The neck growth kinetics of differently sized primary particles is determined by the smaller one up to a size difference by a factor of approximately 2, whereas for larger size differences, the kinetics becomes faster. In particular, the agglomerate sintering kinetics is investigated for particle chains of different lengths and for different particle morphologies each having ten primary particles and nine initial sintering contacts. For agglomerate chains, the kinetics approximately can be normalized by using the radius of the fully coalesced sphere. In general, different agglomerate morphologies show equal kinetics during the first sintering stages, whereas during advanced stages, compact morphologies show significantly faster sintering progress than more open morphologies. Hence, the overall kinetics cannot be described by simply using constant morphology correction factors such as fractal dimension or mean coordination number which are used in common sintering models. However, for the first stages of viscous-flow agglomerate sintering, which are the most important for many particle processes, a sintering equation is presented. Although we use agglomerates consisting of spherical primary particles, our methodology can be applied to other aggregate geometries as well. PMID- 19792262 TI - Time-resolved fluorescence spectroscopy of two-photon laser-excited 8p, 9p, 5f, and 6f levels in neutral xenon. AB - Laser-induced fluorescence of two-photon excited 8p, 9p, J=0, 2 and 5f, 6f, J=2 levels in neutral xenon has been investigated in the pressure regime between 4 and 120 Pa. Radiative lifetimes and collisional deactivation rates have been deduced especially for the 5f[3/2](2), 5f[5/2](2), and 8p[1/2](0) levels using the Stern-Volmer approach. The spontaneous lifetimes for 5f[3/2](2), 5f[5/2](2), and 8p[1/2](0) levels are 94, 78, and 207 ns, respectively. These lifetimes have been calculated also by applying extended multiconfiguration Dirac-Fock wave functions and are found in agreement with experiment within 10-25 %. PMID- 19792263 TI - Discrete breathers in hexagonal dusty plasma lattices. AB - The occurrence of single-site or multisite localized vibrational modes, also called discrete breathers, in two-dimensional hexagonal dusty plasma lattices is investigated. The system is described by a Klein-Gordon hexagonal lattice characterized by a negative coupling parameter epsilon in account of its inverse dispersive behavior. A theoretical analysis is performed in order to establish the possibility of existence of single as well as three-site discrete breathers in such systems. The study is complemented by a numerical investigation based on experimentally provided potential forms. This investigation shows that a dusty plasma lattice can support single-site discrete breathers, while three-site in phase breathers could exist if specific conditions, about the intergrain interaction strength, would hold. On the other hand, out of phase and vortex three-site breathers cannot be supported since they are highly unstable. PMID- 19792264 TI - Electron-ion thermal equilibration after spherical shock collapse. AB - A comprehensive set of dual nuclear product observations provides a snapshot of imploding inertial confinement fusion capsules at the time of shock collapse, shortly before the final stages of compression. The collapse of strong convergent shocks at the center of spherical capsules filled with D(2) and (3)He gases induces D-D and D-(3)He nuclear production. Temporal and spectral diagnostics of products from both reactions are used to measure shock timing, temperature, and capsule areal density. The density and temperature inferred from these measurements are used to estimate the electron-ion thermal coupling and demonstrate a lower electron-ion relaxation rate for capsules with lower initial gas density. PMID- 19792265 TI - Optimized Kalpha x-ray flashes from femtosecond-laser-irradiated foils. AB - We investigate the generation of ultrashort Kalpha pulses from plasmas produced by intense femtosecond p-polarized laser pulses on Copper and Titanium targets. Particular attention is given to the interplay between the angle of incidence of the laser beam on the target and a controlled prepulse. It is observed experimentally that the Kalpha yield can be optimized for correspondingly different prepulse and plasma scale-length conditions. For steep electron-density gradients, maximum yields can be achieved at larger angles. For somewhat expanded plasmas expected in the case of laser pulses with a relatively poor contrast, the Kalpha yield can be enhanced by using a near-normal-incidence geometry. For a certain scale-length range (between 0.1 and 1 times a laser wavelength) the optimized yield is scale-length independent. Physically this situation arises because of the strong dependence of collisionless absorption mechanisms-in particular resonance absorption-on the angle of incidence and the plasma scale length, giving scope to optimize absorption and hence the Kalpha yield. This qualitative description is supported by calculations based on the classical resonance absorption mechanism and by particle-in-cell simulations. Finally, the latter simulations also show that even for initially steep gradients, a rapid profile expansion occurs at oblique angles in which ions are pulled back toward the laser by hot electrons circulating at the front of the target. The corresponding enhancement in Kalpha yield under these conditions seen in the present experiment represents strong evidence for this suprathermal shelf formation effect. PMID- 19792266 TI - Rogue waves and rational solutions of the nonlinear Schrodinger equation. AB - We present a method for finding the hierarchy of rational solutions of the self focusing nonlinear Schrodinger equation and present explicit forms for these solutions from first to fourth order. We also explain their relation to the highest amplitude part of a field that starts with a plane wave perturbed by random small amplitude radiation waves. Our work can elucidate the appearance of rogue waves in the deep ocean and can be applied to the observation of rogue light pulse waves in optical fibers. PMID- 19792267 TI - Diverging probability-density functions for flat-top solitary waves. AB - We investigate the statistics of flat-top solitary wave parameters in the presence of weak multiplicative dissipative disorder. We consider first propagation of solitary waves of the cubic-quintic nonlinear Schrodinger equation (CQNLSE) in the presence of disorder in the cubic nonlinear gain. We show by a perturbative analytic calculation and by Monte Carlo simulations that the probability-density function (PDF) of the amplitude eta exhibits loglognormal divergence near the maximum possible amplitude eta(m), a behavior that is similar to the one observed earlier for disorder in the linear gain [A. Peleg, Phys. Rev. E 72, 027203 (2005)]. We relate the loglognormal divergence of the amplitude PDF to the superexponential approach of eta to eta(m) in the corresponding deterministic model with linear/nonlinear gain. Furthermore, for solitary waves of the derivative CQNLSE with weak disorder in the linear gain both the amplitude and the group velocity beta become random. We therefore study analytically and by Monte Carlo simulations the PDF of the parameter p, where p = eta/(1 epsilon(s)beta/2) and epsilon(s) is the self-steepening coefficient. Our analytic calculations and numerical simulations show that the PDF of p is loglognormally divergent near the maximum p value. PMID- 19792268 TI - Parallel acoustic near-field microscope: A steel slab with a periodic array of slits. AB - We propose a practical acoustic near-field microscope, which is simply a steel slab with periodic array of subwavelength slits. The near field is transported by the coupling of the incident evanescent waves and the acoustic guided modes supported by the structured slab. The transmission coefficients of the structured slab as a function of the transverse wave vector are theoretically derived, and a theoretical model is employed to study the imaging of the proposed device. Numerical simulations are also performed to verify the theoretical results, which show that subwavelength imaging with good quality can indeed be realized. PMID- 19792269 TI - Subharmonic response of a single-degree-of-freedom nonlinear vibro-impact system to a narrow-band random excitation. AB - The subharmonic response of single-degree-of-freedom nonlinear vibro-impact oscillator with a one-sided barrier to narrow-band random excitation is investigated. The narrow-band random excitation used here is a filtered Gaussian white noise. The analysis is based on a special Zhuravlev transformation, which reduces the system to one without impacts, or velocity jumps, thereby permitting the applications of asymptotic averaging over the "fast" variables. The averaged stochastic equations are solved exactly by the method of moments for the mean square response amplitude for the case of linear system with zero offset. A perturbation-based moment closure scheme is proposed and the formula of the mean square amplitude is obtained approximately for the case of linear system with nonzero offset. The perturbation-based moment closure scheme is used once again to obtain the algebra equation of the mean-square amplitude of the response for the case of nonlinear system. The effects of damping, detuning, nonlinear intensity, bandwidth, and magnitudes of random excitations are analyzed. The theoretical analyses are verified by numerical results. Theoretical analyses and numerical simulations show that the peak amplitudes may be strongly reduced at large detunings or large nonlinear intensity. PMID- 19792270 TI - Simultaneous normal and parallel incidence planar left-handed metamaterial. AB - We investigate numerically the negative refraction of a simultaneous normal and parallel incidence planar left-handed metamaterial (LHM) in this paper. This LHM is comprised of fourfold C-shaped rings, which are printed on both sides of the substrates symmetrically, and it can exhibit left-handed properties with electromagnetic wave incident in three different directions. The retrieved result and the simulated result verify the left-handed properties of the fourfold C shaped metamaterial very well. Then the different electric responses of the normal and parallel incidence cases to the incident electromagnetic wave are discussed, and it is due to the different distribution of the induced currents in the metallic wires. PMID- 19792271 TI - Two-dimensional dissipative gap solitons. AB - We introduce a model which integrates the complex Ginzburg-Landau equation in two dimensions (2Ds) with the linear-cubic-quintic combination of loss and gain terms, self-defocusing nonlinearity, and a periodic potential. In this system, stable 2D dissipative gap solitons (DGSs) are constructed, both fundamental and vortical ones. The soliton families belong to the first finite band gap of the system's linear spectrum. The solutions are obtained in a numerical form and also by means of an analytical approximation, which combines the variational description of the shape of the fundamental and vortical solitons and the balance equation for their total power. The analytical results agree with numerical findings. The model may be implemented as a laser medium in a bulk self defocusing optical waveguide equipped with a transverse 2D grating, the predicted DGSs representing spatial solitons in this setting. PMID- 19792272 TI - Analytical calculation of axial optical force on a Rayleigh particle illuminated by Gaussian beams beyond the paraxial approximation. AB - We investigate the optical trapping of a Rayleigh particle by a linearly or radially polarized Gaussian beam. The Mie theory is applied to obtain a full solution, with the incident beam being described by the mixed dipole model, which is beyond the paraxial approximation. We then obtain approximate analytical expressions for the optical force, equilibrium position, and trap stiffness for a Rayleigh particle. At equilibrium, the displacement for the particle from the focus scales like a(3) (where a is the radius) for a transparent particle, owing to scattering, whereas for absorptive particles it scales like C+Da(2), owing to absorption. The trap stiffness is found to be proportional to a(3), in agreement with the recent experiment. The radially polarized beam is found to be superior to the linearly polarized beam in the Rayleigh regime in terms of its ability to trap. It is found that the larger the ratio of epsilon(r)/epsilon(i), the closer the equilibrium to the focus, and thus higher stability. PMID- 19792273 TI - Wobbling kinks in varphi(4) theory. AB - We present a uniform asymptotic expansion of the wobbling kink to any order in the amplitude of the wobbling mode. The long-range behavior of the radiation is described by matching the asymptotic expansions in the far field and near the core of the kink. The complex amplitude of the wobbling mode is shown to obey a simple ordinary differential equation with nonlinear damping. We confirm the t( 1/2)-decay law for the amplitude, which was previously obtained on the basis of energy considerations. PMID- 19792274 TI - Resonantly driven wobbling kinks. AB - The amplitude of oscillations of the freely wobbling kink in the varphi(4) theory decays due to the emission of second-harmonic radiation. We study the compensation of these radiation losses (as well as additional dissipative losses) by the resonant driving of the kink. We consider both direct and parametric driving at a range of resonance frequencies. In each case, we derive the amplitude equations which describe the evolution of the amplitude of the wobbling and the kink's velocity. These equations predict multistability and hysteretic transitions in the wobbling amplitude for each driving frequency--the conclusion verified by numerical simulations of the full partial differential equation. We show that the strongest parametric resonance occurs when the driving frequency equals the natural wobbling frequency and not double that value. For direct driving, the strongest resonance is at half the natural frequency, but there is also a weaker resonance when the driving frequency equals the natural wobbling frequency itself. We show that this resonance is accompanied by the translational motion of the kink. PMID- 19792275 TI - Hybrid lattice Boltzmann model for binary fluid mixtures. AB - A hybrid lattice Boltzmann method (LBM) for binary mixtures based on the free energy approach is proposed. Nonideal terms of the pressure tensor are included as a body force in the LBM kinetic equations, used to simulate the continuity and Navier-Stokes equations. The convection-diffusion equation is studied by finite difference methods. Differential operators are discretized in order to reduce the magnitude of spurious velocities. The algorithm has been shown to be stable and reproducing the correct equilibrium behavior in simple test configurations and to be Galilean invariant. Spurious velocities can be reduced by approximately an order of magnitude with respect to standard discretization procedure. PMID- 19792276 TI - Simple lattice Boltzmann subgrid-scale model for convectional flows with high Rayleigh numbers within an enclosed circular annular cavity. AB - Natural convection within an enclosed circular annular cavity formed by two concentric vertical cylinders is of fundamental interest and practical importance. Generally, the assumption of axisymmetric thermal flow is adopted for simulating such natural convections and the validity of the assumption of axisymmetric thermal flow is still held even for some turbulent convection. Usually the Rayleigh numbers (Ra) of realistic flows are very high. However, the work to design suitable and efficient lattice Boltzmann (LB) models on such flows is quite rare. To bridge the gap, in this paper a simple LB subgrid-scale (SGS) model, which is based on our recent work [S. Chen, J. Tolke, and M. Krafczyk, Phys. Rev. E 79, 016704 (2009); S. Chen, J. Tolke, S. Geller, and M. Krafczyk, Phys. Rev. E 78, 046703 (2008)], is proposed for simulating convectional flow with high Ra within an enclosed circular annular cavity. The key parameter for the SGS model can be quite easily and efficiently evaluated by the present model. The numerical experiments demonstrate that the present model works well for a large range of Ra and Prandtl number (Pr). Though in the present study a popularly used static Smagorinsky turbulence model is adopted to demonstrate how to develop a LB SGS model for simulating axisymmetric thermal flows with high Ra, other state-of-the-art turbulence models can be incorporated into the present model in the same way. In addition, the present model can be extended straightforwardly to simulate other axisymmetric convectional flows with high Ra, for example, turbulent convection with internal volumetric heat generation in a vertical cylinder, which is an important simplified representation of a nuclear reactor. PMID- 19792277 TI - Jensen-Feynman approach to the statistics of interacting electrons. AB - Faussurier [Phys. Rev. E 65, 016403 (2001)] proposed to use a variational principle relying on Jensen-Feynman (or Gibbs-Bogoliubov) inequality in order to optimize the accounting for two-particle interactions in the calculation of canonical partition functions. It consists of a decomposition into a reference electron system and a first-order correction. The procedure appears to be very efficient in order to evaluate the free energy and the orbital populations. In this work, we present numerical applications of the method and propose to extend it using a reference energy which includes the interaction between two electrons inside a given orbital. This is possible, thanks to our efficient recursion relation for the calculation of partition functions. We also show that a linear reference energy, however, is usually sufficient to achieve a good precision and that the most promising way to improve the approach of Faussurier is to apply Jensen's inequality to a more convenient convex function. PMID- 19792278 TI - Numerical solution of stochastic differential equations with Poisson and Levy white noise. AB - A fixed time step method is developed for integrating stochastic differential equations (SDE's) with Poisson white noise (PWN) and Levy white noise (LWN). The method for integrating SDE's with PWN has the same structure as that proposed by Kim [Phys. Rev. E 76, 011109 (2007)], but is established by using different arguments. The integration of SDE's with LWN is based on a representation of Levy processes by sums of scaled Brownian motions and compound Poisson processes. It is shown that the numerical solutions of SDE's with PWN and LWN converge weakly to the exact solutions of these equations, so that they can be used to estimate not only marginal properties but also distributions of functionals of the exact solutions. Numerical examples are used to demonstrate the applications and the accuracy of the proposed integration algorithms. PMID- 19792279 TI - Reconstruction algorithm for single-particle diffraction imaging experiments. AB - We introduce the EMC algorithm for reconstructing a particle's three-dimensional (3D) diffraction intensity from very many photon shot-noise limited two dimensional measurements, when the particle orientation in each measurement is unknown. The algorithm combines a maximization step (M) of the intensity's likelihood function, with expansion (E) and compression (C) steps that map the 3D intensity model to a redundant tomographic representation and back again. After a few iterations of the EMC update rule, the reconstructed intensity is given to the difference-map algorithm for reconstruction of the particle contrast. We demonstrate reconstructions with simulated data and investigate the effects of particle complexity, number of measurements, and the number of photons per measurement. The relatively transparent scaling behavior of our algorithm provides an estimate of the data processing resources required for future single particle imaging experiments. PMID- 19792280 TI - Lattice Boltzmann model for wave propagation. AB - A lattice Boltzmann model for two-dimensional wave equation is proposed by using the higher-order moment method. The higher-order moment method is based on the solution of a series of partial differential equations obtained by using multiscale technique and Chapman-Enskog expansion. In order to obtain the lattice Boltzmann model for the wave equation with higher-order accuracy of truncation errors, we removed the second-order dissipation term and the third-order dispersion term by employing the moments up to fourth order. The reversibility in time appears owing to the absence of the second-order dissipation term and the third-order dispersion term. As numerical examples, some classical examples, such as interference, diffraction, and wave passing through a convex lens, are simulated. The numerical results show that this model can be used to simulate wave propagation. PMID- 19792281 TI - Structuring and sampling complex conformation space: Weighted ensemble dynamics simulations. AB - Based on multiple simulation trajectories, which started from dispersively selected initial conformations, the weighted ensemble dynamics method is designed to robustly and systematically explore the hierarchical structure of complex conformational space through the spectral analysis of the variance-covariance matrix of trajectory-mapped vectors. The nondegenerate ground state of the matrix directly predicts the ergodicity of simulation data. The ground state could be adopted as statistical weights of trajectories to correctly reconstruct the equilibrium properties, even though each trajectory only explores part of the conformational space. Otherwise, the degree of degeneracy simply gives the number of metastable states of the system under the time scale of individual trajectory. Manipulation on the eigenvectors leads to the classification of trajectories into nontransition ones within the states and transition ones between them. The transition states may also be predicted without a priori knowledge of the system. We demonstrate the application of the general method both to the system with a one-dimensional glassy potential and with the one of alanine dipeptide in explicit solvent. PMID- 19792282 TI - Model of binary opinion dynamics: Coarsening and effect of disorder. AB - We propose a model of binary opinion in which the opinion of the individuals changes according to the state of their neighboring domains. If the neighboring domains have opposite opinions then the opinion of the domain with the larger size is followed. Starting from a random configuration, the system evolves to a homogeneous state. The dynamical evolution shows a scaling behavior with the persistence exponent theta approximately 0.235 and dynamic exponent z approximately 1.02 + or - 0.02. Introducing disorder through a parameter called rigidity coefficient rho (probability that people are completely rigid and never change their opinion), the transition to a heterogeneous society at rho=0(+) is obtained. Close to rho=0, the equilibrium values of the dynamic variables show power-law scaling behavior with rho. We also discuss the effect of having both quenched and annealed disorder in the system. PMID- 19792283 TI - Fiber bundle model with stick-slip dynamics. AB - We propose a generic model to describe the mechanical response and failure of systems which undergo a series of stick-slip events when subjected to an external load. We model the system as a bundle of fibers, where single fibers can gradually increase their relaxed length with a stick-slip mechanism activated by the increasing load. We determine the constitutive equation of the system and show by analytical calculations that on the macroscale a plastic response emerges followed by a hardening or softening regime. Releasing the load, an irreversible permanent deformation occurs which depends on the properties of sliding events. For quenched and annealed disorder of the failure thresholds the same qualitative behavior is found, however, in the annealed case the plastic regime is more pronounced. PMID- 19792284 TI - Generalized synchronization of complex networks. AB - We consider generalized synchronization of complex networks, which are unidirectionally coupled in the drive-response configuration. The drive network consists of linearly and diffusively coupled identical chaotic systems. By choosing suitable driving signals, we can construct the response network to generally synchronize the drive network in a predefined functional relationship. This extends both generalized synchronization of chaotic systems and synchronization inside a network. Theoretical analysis and numerical simulations fully verify our main results. PMID- 19792285 TI - Magnetization of a warm plasma by the nonstationary ponderomotive force of an electromagnetic wave. AB - It is shown that magnetic fields can be generated in a warm plasma by the nonstationary ponderomotive force of a large-amplitude electromagnetic wave. In the present Brief Report, we derive simple and explicit results that can be useful for understanding the origin of the magnetic fields that are produced in intense laser-plasma interaction experiments. PMID- 19792286 TI - Transverse angular momentum and geometric spin Hall effect of light. AB - We present a novel fundamental phenomenon occurring when a polarized beam of light is observed from a reference frame tilted with respect to the direction of propagation of the beam. This effect has a purely geometric nature and amounts to a polarization-dependent shift or split of the beam intensity distribution evaluated as the time-averaged flux of the Poynting vector across the plane of observation. We demonstrate that such a shift is unavoidable whenever the beam possesses a nonzero transverse angular momentum. This latter result has general validity and applies to arbitrary systems such as, e.g., electronic and atomic beams. PMID- 19792287 TI - Standard quantum limit for probing mechanical energy quantization. AB - We derive a standard quantum limit for probing mechanical energy quantization in a class of systems with mechanical modes parametrically coupled to external degrees of freedom. To resolve a single mechanical quantum, it requires a strong coupling regime-the decay rate of external degrees of freedom is smaller than the parametric coupling rate. In the case for cavity-assisted optomechanical systems, e.g., the one proposed by Thompson et al. [Nature (London) 452, 72 (2008)], zero point motion of the mechanical oscillator needs to be comparable to the linear dynamical range of the optical system which is characterized by the optical wavelength divided by the cavity finesse. PMID- 19792288 TI - Breakdown of thermalization in finite one-dimensional systems. AB - We use quantum quenches to study the dynamics and thermalization of hard core bosons in finite one-dimensional lattices. We perform exact diagonalizations and find that, far away from integrability, few-body observables thermalize. We then study the breakdown of thermalization as one approaches an integrable point. This is found to be a smooth process in which the predictions of standard statistical mechanics continuously worsen as the system moves toward integrability. We establish a direct connection between the presence or absence of thermalization and the validity or failure of the eigenstate thermalization hypothesis, respectively. PMID- 19792290 TI - Anomalous lack of decoherence of the macroscopic quantum superpositions based on phase-covariant quantum cloning. AB - We show that all macroscopic quantum superpositions (MQS) based on phase covariant quantum cloning are characterized by an anomalous high resilence to the decoherence processes. The analysis supports the results of recent MQS experiments and leads to conceive a useful conjecture regarding the realization of complex decoherence-free structures for quantum information, such as the quantum computer. PMID- 19792289 TI - Mixtures of Bose gases confined in a ring potential. AB - The rotational properties of a mixture of two distinguishable Bose gases that are confined in a ring potential provide novel physical effects that we demonstrate in this study. Persistent currents are shown to be stable for a range of the population imbalance between the two components at low angular momentum. At higher values of the angular momentum, even small admixtures of a second species of atoms make the persistent currents highly fragile. PMID- 19792292 TI - Einstein equations for generalized theories of gravity and the thermodynamic relation deltaQ=TdeltaS are equivalent. AB - We show that the equations of motion of generalized theories of gravity are equivalent to the thermodynamic relation deltaQ=TdeltaS. Our proof relies on extending previous arguments by using a more general definition of the Noether charge entropy. We have thus completed the implementation of Jacobson's proposal to express Einstein's equations as a thermodynamic equation of state. Additionally, we find that the Noether charge entropy obeys the second law of thermodynamics if the energy-momentum tensor obeys the null energy condition. Our results support the idea that gravitation on a macroscopic scale is a manifestation of the thermodynamics of the vacuum. PMID- 19792291 TI - Multipartite entanglement detection via structure factors. AB - We establish a relation between entanglement of a many-body system and its diffractive properties, where the link is given by structure factors. Based on these, we provide a general analytical construction of multiqubit entanglement witnesses. The proposed witnesses contain two-point correlations. They could be either measured in a scattering experiment or via local measurements, depending on the underlying physical system. For some explicit examples of witnesses we analyze the properties of the states that are detected by them. We further study the robustness of these witnesses with respect to noise. PMID- 19792293 TI - Ghost-free, finite, fourth-order D = 3 gravity. AB - Canonical analysis of a recently proposed linear + quadratic curvature gravity model in D = 3 establishes its pure, irreducibly fourth derivative, quadratic curvature limit as both ghost-free and power-counting UV finite, thereby maximally violating standard folklore. This limit is representative of a generic class whose kinetic terms are conformally invariant in any dimension, but it is unique in simultaneously avoiding the transverse-traceless graviton ghosts plaguing D > 3 quadratic actions as well as double pole propagators in its other variables. While the two-term model is also unitary, its additional mode's second derivative nature forfeits finiteness. PMID- 19792294 TI - Gravitational fixed points from perturbation theory. AB - The fixed point structure of the renormalization flow in higher derivative gravity is investigated in terms of the background covariant effective action using an operator cutoff that keeps track of powerlike divergences. Spectral positivity of the gauge fixed Hessian can be satisfied upon expansion in the asymptotically free higher derivative coupling. At one-loop order in this coupling strictly positive fixed points are found for the dimensionless Newton constant g(N) and the cosmological constant lambda, which are determined solely by the coefficients of the powerlike divergences. The renormalization flow is asymptotically safe with respect to this fixed point and settles on a lambda(g(N)) trajectory after O(10) units of the renormalization mass scale to accuracy 10(-7). PMID- 19792295 TI - Strong electroweak symmetry breaking and spin-0 resonances. AB - We argue that theories of the strong electroweak symmetry breaking sector necessarily contain new spin 0 states at the TeV scale in the tt and tb/bt channels, even if the third generation quarks are not composite at the TeV scale. These states couple sufficiently strongly to third generation quarks to have significant production at LHC via gg --> phi(0) or gb --> tphi(-). The existence of narrow resonances in QCD suggests that the strong electroweak breaking sector contains narrow resonances that decay to tt or tb/bt, with potentially significant branching fractions to 3 or more longitudinal W and Z bosons. These may give new "smoking gun" signals of strong electroweak symmetry breaking. PMID- 19792298 TI - Magnetic dipole moment of (57,59)Cu measured by in-gas-cell laser spectroscopy. AB - For the first time, in-gas-cell laser spectroscopy study of the (57,59,63,65)Cu isotopes has been performed using the 244.164 nm optical transition from the atomic ground state of copper. The nuclear magnetic dipole moments for (57,59,65)Cu relative to that of (63)Cu have been extracted. The new value for (57)Cu of mu((57)Cu) = +2.582(7)mu(N) is in strong disagreement with the previous literature value but in good agreement with recent theoretical and systematic predictions. PMID- 19792299 TI - Three-nucleon low-energy constants from the consistency of interactions and currents in chiral effective field theory. AB - The chiral low-energy constants c(D) and c(E) are constrained by means of accurate ab initio calculations of the A = 3 binding energies and, for the first time, of the triton beta decay. We demonstrate that these low-energy observables allow a robust determination of the two undetermined constants, a result of the surprising fact that the determination of c(D) depends weakly on the short-range correlations in the wave functions. These two- plus three-nucleon interactions, originating in chiral effective field theory and constrained by properties of the A = 2 system and the present determination of c(D) and c(E), are successful in predicting properties of the A = 3 and 4 systems. PMID- 19792300 TI - Cavity sideband cooling of a single trapped ion. AB - We report a demonstration and quantitative characterization of one-dimensional cavity cooling of a single trapped (88)Sr(+) ion in the resolved-sideband regime. We measure the spectrum of cavity transitions, the rates of cavity heating and cooling, and the steady-state cooling limit. The cavity cooling dynamics and cooling limit of 22.5(3) motional quanta, limited by the moderate coupling between the ion and the cavity, are consistent with a simple model [Phys. Rev. A 64, 033405 (2001)] without any free parameters, validating the rate equation model for cavity cooling. PMID- 19792301 TI - Attosecond control of electron dynamics in carbon monoxide. AB - Laser pulses with stable electric field waveforms establish the opportunity to achieve coherent control on attosecond time scales. We present experimental and theoretical results on the steering of electronic motion in a multielectron system. A very high degree of light-waveform control over the directional emission of C(+) and O(+) fragments from the dissociative ionization of CO was observed. Ab initio based model calculations reveal contributions to the control related to the ionization and laser-induced population transfer between excited electronic states of CO(+) during dissociation. PMID- 19792302 TI - Control of the electronic energy transfer pathway between two single fluorophores by dual pulse excitation. AB - We report on the control of the energy transfer pathway in individual donor acceptor dyads by proper timing of light pulses matching the donor and acceptor transition frequencies, respectively. Excitation of both chromophores at virtually the same time induces efficient singlet-singlet annihilation, whereby excitation energy effectively flows from the acceptor to the donor. The dual pulse excitation scheme implemented here allows for all-optical switching of the fluorescence intensity at the single-molecule level. The population of higher excited states at the donor site was found to significantly increase the photobleaching probability. PMID- 19792303 TI - Benchmark measurements of H(3)(+) nonlinear dynamics in intense ultrashort laser pulses. AB - The H(3)(+) ion is the simplest polyatomic molecule and is destined to play a central role in understanding such molecules in intense ultrashort laser pulses. We present the first measurements of the intense field dissociation and ionization of D(3)(+) using coincidence three-dimensional momentum imaging. Our results show features that are a consequence of this molecule's unique equilateral triangular geometry, providing a fundamentally new system for theoretical development. PMID- 19792304 TI - Buffer-gas cooled Bose-Einstein condensate. AB - We report the creation of a Bose-Einstein condensate using buffer-gas cooling, the first realization of Bose-Einstein condensation using a broadly general method which relies neither on laser cooling nor unique atom-surface properties. Metastable helium ((4)He*) is buffer-gas cooled, magnetically trapped, and evaporatively cooled to quantum degeneracy. 10(11) atoms are initially trapped, leading to Bose-Einstein condensation at a critical temperature of 5 microK and threshold atom number of 1.1 x 10(6). This method is applicable to a wide array of paramagnetic atoms and molecules, many of which are impractical to laser cool and impossible to surface cool. PMID- 19792306 TI - Effects of elliptical polarization on strong-field short-pulse double ionization. AB - We predict new end-of-pulse behavior in high-field atomic double ionization. Calculations of atomic electron trajectories in short intense laser pulses confirm our analysis of elliptical polarization. We exhibit a four-band structure in ion momentum distributions under various ellipticities, and predict that sequential and nonsequential double ionization can be cleanly distinguished under elliptical polarization. PMID- 19792305 TI - Suppressed dissociation of H(2)(+) vibrational states by reduced dipole coupling. AB - The suppression of H(2)(+) strong-field dissociation has intrigued experimentalists and theorists since the early days of laser-molecular science. We unravel a vibrational suppression effect due to weak dipole-matrix element coupling strengths of certain vibrational states, dependent on the laser frequency-a form of Cooper minima. This effect is demonstrated by our full dimensional calculations on H(2)(+) dissociation and persists for a broad range of laser conditions including both weak and strong-field dissociation. Using a crossed-beams coincidence, three-dimensional momentum-imaging technique, the vibrational suppression effect is clearly observed for H(2)(+) and HD(+) at 790 and 395 nm, in good agreement with our theory. PMID- 19792307 TI - Controlling two-electron threshold dynamics in double photoionization of lithium by initial-state preparation. AB - Double photoionization (DPI) and ionization-excitation (IE) of Li(2s) and Li(2p), state-prepared and aligned in a magneto-optical trap, were explored in a reaction microscope at the free-electron laser in Hamburg (FLASH). From 6 to 12 eV above threshold (homega = 85, 91 eV), total as well as differential DPI cross sections were observed to critically depend on the initial state and, in particular, on the alignment of the 2p orbital with respect to the VUV-light polarization, whereas no effect is seen for IE. The alignment sensitivity is traced back to dynamical electron correlation at threshold. PMID- 19792308 TI - Mechanical oscillation and cooling actuated by the optical gradient force. AB - In this work, we combine the large per-photon optical gradient force with the sensitive feedback of a high quality factor whispering-gallery microcavity. The cavity geometry, consisting of a pair of silica disks separated by a nanoscale gap, shows extremely strong dynamical backaction, powerful enough to excite coherent oscillations even under heavily damped conditions (mechanical Q approximately 4). In vacuum, the threshold for regenerative mechanical oscillation is lowered to an optical input power of only 270 nW, or roughly 1000 stored cavity photons, and efficient cooling of the mechanical motion is obtained with a temperature compression factor of nearly 14 dB with an input optical power of only 11 microW. PMID- 19792309 TI - Repulsive Casimir force in chiral metamaterials. AB - We demonstrate theoretically that one can obtain repulsive Casimir forces and stable nanolevitations by using chiral metamaterials. By extending the Lifshitz theory to treat chiral metamaterials, we find that a repulsive force and a minimum of the interaction energy possibly exist for strong chirality, under realistic frequency dependencies and correct limiting values (for zero and infinite frequencies) of the permittivity, permeability, and chiral coefficients. PMID- 19792310 TI - Conical third-harmonic generation in normally dispersive media. AB - It is shown, both theoretically and experimentally, that in normally dispersive media under tight-focusing conditions third harmonic is generated by six-wave mixing rather than via common third-order frequency tripling. Though far-field pattern of third-harmonic signal was an axially symmetric ring for a wide range of the material wave vector mismatch and laser beam focusing conditions, in some cases the generation of more complex beams has been found possible. Results of simulations of the proposed model qualitatively correspond well with experimental data for the calculated values of third- and fifth-order nonlinear susceptibilities of sodium. PMID- 19792296 TI - Search for a standard model Higgs boson in WH --> lvbb in pp collisions at square root s = 1.96 TeV. AB - We present a search for a standard model Higgs boson produced in association with a W boson using 2.7 fb(-1) of integrated luminosity of pp collision data taken at square root s = 1.96 TeV. Limits on the Higgs boson production rate are obtained for masses between 100 and 150 GeV/c(2). Through the use of multivariate techniques, the analysis achieves an observed (expected) 95% confidence level upper limit of 5.6 (4.8) times the theoretically expected production cross section for a standard model Higgs boson with a mass of 115 GeV/c(2). PMID- 19792311 TI - Photonic binding in silicon-colloid microcavities. AB - Photonic binding between two identical silicon-colloid-based microcavities is studied by using a generalized multipolar expansion. In contrast with previous works, we focus on low-order cavity modes that resemble low-energy electronic orbitals. For conservative light intensities, the interaction between cavity modes with moderate Q factors produces extremely large particle acceleration values. Optical forces dominate over van der Waals, gravity, and Brownian motion, and they show a binding-antibinding behavior in analogy to electronic binding. As these photonic forces are associated with relatively broad Mie mode resonances and they are not strongly influenced by sample absorption, our study opens a plausible avenue towards manipulation of high-refractive-index colloidal assemblies. PMID- 19792312 TI - Optical vortices from liquid crystal droplets. AB - We report on the generation of mono- and polychromatic optical phase singularities from micron-sized birefringent droplets. This is done experimentally by using liquid crystal droplets whose three dimensional architecture of the optical axis is controlled within the bulk by surfactant agents. Because of its microscopic size these optical vortex generators are optically trapped and manipulated at will, thus realizing a robust self-aligned micro-optical device for orbital angular momentum conversion. Experimental observations are supported by a simple model of optical spin-orbit coupling in uniaxial dielectrics that emphasizes the prominent role of the transverse optical anisotropy with respect to the beam propagation direction. PMID- 19792297 TI - Search for charged Higgs bosons in decays of top quarks in pp collisions at square root s = 1.96 TeV. AB - We report on the first direct search for charged Higgs bosons decaying into cs in tt events produced by pp collisions at square root s = 1.96 TeV. The search uses a data sample corresponding to an integrated luminosity of 2.2 fb(-1) collected by the CDF II detector at Fermilab and looks for a resonance in the invariant mass distribution of two jets in the lepton + jets sample of tt candidates. We observe no evidence of charged Higgs bosons in top quark decays. Hence, 95% upper limits on the top quark decay branching ratio are placed at B(t --> H(+)b)< 0.1 to 0.3 for charged Higgs boson masses of 60 to 150 GeV/c(2) assuming B(H(+) --> cs)=1.0. The upper limits on B(t --> H(+)b) are also used as model-independent limits on the decay branching ratio of top quarks to generic scalar charged bosons beyond the standard model. PMID- 19792313 TI - Spontaneous motion of cavity solitons induced by a delayed feedback. AB - We study the properties of 2D cavity solitons in a coherently driven optical resonator subjected to a delayed feedback. The delay is found to induce a spontaneous motion of a single cavity soliton that is stationary and stable otherwise. This behavior occurs when the product of the delay time and the feedback strength exceeds some critical value. We derive an analytical formula for the speed of a moving soliton. Numerical results are in good agreement with analytical predictions. PMID- 19792314 TI - Broadband electromagnetic cloaking of long cylindrical objects. AB - Electromagnetic cloaks are devices that make objects undetectable for probing with electromagnetic waves. The known realizations of transformational-optics cloaks require materials with exotic electromagnetic properties and offer only limited performance in narrow frequency bands. Here, we demonstrate a wideband and low-loss cloak whose operation is not based on the use of exotic electromagnetic materials, which are inevitably dispersive and lossy. Instead, we use a simple structure made of metal layers. In this Letter, we present an experimental demonstration of cloaking for microwaves and simulation results for cloaking in the visible range. PMID- 19792315 TI - Transverse photovoltage induced by circularly polarized light. AB - We discovered that when circularly polarized light is obliquely incident on a two dimensional metallic photonic crystal slab, electrical voltage is induced perpendicular to the incident plane. The sign of the signal is reversed by changing the sense of polarization or incident angle. The origin of this transverse photoinduced voltage is explained in terms of the force proportional to the light intensity induced by the asymmetry, which is brought about by the angular momentum of the incident light, along with the modification of local near surface electromagnetic fields in the slab and field enhancement due to surface plasmon resonance. PMID- 19792316 TI - Electrically excited inverse electron spin resonance in a split-ring metamaterial resonator. AB - Bianisotropic properties of the metamaterial built from split-ring resonators are utilized to excite electron-spin resonance in a gadolinium gallium garnet by the electric field of light. Surprisingly, the observed electron-spin resonance signal is seen as a maximum in the field-dependent transmittance, which indicates strong modifications of the metamaterial parameters in the coupled regime. In the geometry where both modes, electron-spin resonance and split-ring resonance, are active, the anticrossing regime can be observed. These effects can be explained using the classical model of two coupled oscillators and the bianisotropic properties of split-ring resonators. PMID- 19792317 TI - Acoustic diode: rectification of acoustic energy flux in one-dimensional systems. AB - We numerically demonstrate a simple one-dimensional model of an acoustic diode formed by coupling a superlattice with a strongly nonlinear medium. The first numerical observation is presented of a significant rectifying effect on the acoustic energy flux within particular ranges of frequencies. By studying the underlying rectifying mechanism and the parameter dependence of the rectifying efficiency, the effectiveness of the acoustic diode is proved despite its simplicity. We also briefly discuss possible schemes of the experimental realization of this model as well as devising more efficient models. PMID- 19792318 TI - Marangoni shocks in unobstructed soap-film flows. AB - It is widely thought that in steady, gravity-driven, unobstructed soap-film flows, the velocity increases monotonically downstream. Here we show experimentally that the velocity increases, peaks, drops abruptly, then lessens gradually downstream. We argue theoretically and verify experimentally that the abrupt drop in velocity corresponds to a Marangoni shock, a type of shock related to the elasticity of the film. Marangoni shocks induce locally intense turbulent fluctuations and may help elucidate the mechanisms that produce two-dimensional turbulence away from boundaries. PMID- 19792319 TI - Flow conductance of a single nanohole. AB - The mass flow conductance of single nanoholes with a diameter ranging from 75 to 100 nm was measured using mass spectrometry. For all nanoholes, a smooth crossover is observed between single-particle statistical flow (effusion) and the collective viscous flow emanating from the formation of a continuum. This crossover is shown to occur when the gas mean free path matches the size of the nanohole diameter. As a consequence of the pinhole geometry, the breakdown of the Poiseuille approximation is observed in the power-law temperature exponent of the measured conductance. PMID- 19792320 TI - Rayleigh-Taylor growth measurements in the acceleration phase of spherical implosions on OMEGA. AB - The Rayleigh-Taylor (RT) growth of 3D broadband nonuniformities was measured using x-ray radiography in spherical plastic shells accelerated by laser light at an intensity of approximately 2 x 10(14) W/cm(2). The 20- and 24-microm-thick spherical shells were imploded with 54 beams on the OMEGA laser system. The shells contained diagnostic openings for backlighter x rays used to image shell modulations. The measured shell trajectories and modulation RT growth were in fair agreement with 2D hydro simulations during the acceleration phase of the implosions with convergence ratios of up to approximately 2.2. Since the ignition designs rely on these simulations, improvements in the numerical codes will be implemented to achieve better agreement with experiments. PMID- 19792321 TI - Identification of a quasiseparatrix layer in a reconnecting laboratory magnetoplasma. AB - The concept of quasiseparatrix layers (QSLs) has emerged as a powerful tool to study the connectivity of magnetic field lines undergoing magnetic reconnection in solar flares. Although they have been used principally by the solar physics community until now, QSLs can be employed to shed light on all processes in which reconnection occurs. We present the first application of this theory to an experimental flux rope configuration. The three-dimensional data set acquired in this experiment makes the determination of the QSL possible. PMID- 19792322 TI - Nonequilibrium Alfvenic plasma jets associated with spheromak formation. AB - Nonequilibrium Alfvenic flows have been observed in plasma jets during the helicity injection stage of the Caltech spheromak experiment. Density and time of flight measurements of these jets show that the flows convect dense plasma (beta approximately 1) because of the axial gradient in the current channel profile. A simplified MHD theory is derived to model the flow. PMID- 19792323 TI - Formation of plasmoid chains in magnetic reconnection. AB - A detailed numerical study of magnetic reconnection in resistive MHD for very large, previously inaccessible, Lundquist numbers (10(4) 10(4). PMID- 19792324 TI - Nonlinear saturation of cyclotron maser instability associated with energetic ring-beam electrons. AB - We study the cyclotron maser instability (CMI) driven by an energetic ring-beam distribution by a particle simulation to explain possible generation mechanisms of intense radiation phenomena observed in space. The main objective is to understand the nonlinear processes that control saturation of the emission process. Our study reveals new issues that have been overlooked in past literature. It is found that electrostatic wave modes excited by the electron beam instability compete with the electromagnetic waves excited by the CMI. Nonlinear effects of these electrostatic modes tend to redistribute the energy of the energetic electrons and make the physics more complicated. The CMI can be much less effective in a realistic case than it is anticipated theoretically. PMID- 19792325 TI - Symmetry breaking in dense solid hydrogen: mechanisms for the transitions to phase II and phase III. AB - Spectroscopic data for the high-pressure phases of hydrogen together with the topology of the phase diagram provide new insight on the behavior of the material at megabar pressure. Structural mechanisms are proposed for the transitions to phases II and III. These mechanisms include a partially ordered structure (possibly incommensurate) and an ordered isotranslational structure for the two phases, respectively. The analysis supports the existence of an additional phase, isostructural to phase III, with boundary that meets to form a second triple point with phases I and III. PMID- 19792326 TI - Nonequilibrium Josephson oscillations in Bose-Einstein condensates without dissipation. AB - We perform a detailed quantum dynamical study of nonequilibrium Josephson oscillations between interacting Bose-Einstein condensates confined in a finite size double-well trap. We find that the Josephson junction can sustain multiple undamped Josephson oscillations up to a characteristic time scale tau(c) without quasipartcles being excited in the system. This may explain recent related experiments. Beyond a characteristic time scale tau(c) the dynamics of the junction is governed by fast, quasiparticle-assisted Josephson tunneling as well as Rabi oscillations between the discrete quasiparticle levels. We predict that an initially self-trapped state of the Bose-Einstein condensates will be destroyed by these fast dynamics. PMID- 19792327 TI - Composite fermion theory for bosonic quantum Hall states on lattices. AB - We study the ground states of the Bose-Hubbard model in a uniform magnetic field, motivated by the physics of cold atomic gases on lattices at high vortex density. Mapping the bosons to composite fermions (CF) leads to the prediction of quantum Hall fluids that have no counterpart in the continuum. We construct trial states for these phases and test numerically the predictions of the CF model. We establish the existence of strongly correlated phases beyond those in the continuum limit and provide evidence for a wider scope of the composite fermion approach beyond its application to the lowest Landau level. PMID- 19792328 TI - Stability and pairing in quasi-one-dimensional Bose-Fermi mixtures. AB - We consider a mixture of single-component bosonic and fermionic atoms in an array of coupled one-dimensional "tubes." For an attractive Bose-Fermi interaction, we show that the system exhibits phase separation instead of the usual collapse. Moreover, above a critical intertube hopping, all first-order instabilities disappear in both attractive and repulsive mixtures. The possibility of suppressing instabilities in this system suggests a route towards the realization of paired phases, including a superfluid of p-wave pairs unique to the coupled tube system, and quantum critical phenomena. PMID- 19792329 TI - Correlation between critical temperature and strength of small-scale bcc pillars. AB - Microcompression tests were performed on focused-ion-beam-machined micropillars of several body-centered-cubic metals (W, Mo, Ta, and Nb) at room temperature. The relationship between yield strength and pillar diameter as well as the deformation morphologies were found to correlate with a parameter specific for bcc metals, i.e., the critical temperature T(c). This finding sheds new light on the phenomenon of small-scale plasticity in largely unexplored non-fcc metals. PMID- 19792330 TI - Ice XV: a new thermodynamically stable phase of ice. AB - A new phase of ice, named ice XV, has been identified and its structure determined by neutron diffraction. Ice XV is the hydrogen-ordered counterpart of ice VI and is thermodynamically stable at temperatures below approximately 130 K in the 0.8 to 1.5 GPa pressure range. The regions of stability in the medium pressure range of the phase diagram have thus been finally mapped, with only hydrogen-ordered phases stable at 0 K. The ordered ice XV structure is antiferroelectric (P1), in clear disagreement with recent theoretical calculations predicting ferroelectric ordering (Cc). PMID- 19792331 TI - Relaxation of hole spins in quantum dots via two-phonon processes. AB - We investigate theoretically spin relaxation in heavy-hole quantum dots in low external magnetic fields. We demonstrate that two-phonon processes and spin-orbit interaction are experimentally relevant and provide an explanation for the recently observed saturation of the spin-relaxation rate in heavy-hole quantum dots with vanishing magnetic fields. We propose further experiments to identify the relevant spin-relaxation mechanisms in low magnetic fields. PMID- 19792332 TI - Nonlinear Hall effect as a signature of electronic phase separation in the semimetallic ferromagnet EuB(6). AB - This work reports a study of the nonlinear Hall effect (HE) in the semimetallic ferromagnet EuB(6). A distinct switch in its Hall resistivity slope is observed in the paramagnetic phase, which occurs at a single critical magnetization over a wide temperature range. The observation is interpreted as the point of percolation for entities of a more conducting and magnetically ordered phase in a less ordered background. With an increasing applied magnetic field, the conducting regions either increase in number or expand beyond the percolation limit, hence increasing the global conductivity and effective carrier density. An empirical two-component model provides excellent scaling and a quantitative fit to the HE data and may be applicable to other correlated electron systems. PMID- 19792333 TI - Electron-energy-loss spectra of plasmonic nanoparticles. AB - We investigate electron-energy-loss spectroscopy (EELS) on metallic nanoparticles, through simulations, and provide a comprehensive comparison between EELS and the photonic local density of states (LDOS). Most importantly, we show that there is no direct link between EELS and LDOS maps, and that EELS can even be blind to hot spots in the gap between coupled nanoparticles. Although intimately related, the two quantities provide complementary information. This finding is in marked contrast to recently reported results. PMID- 19792334 TI - Mapping donor electron wave function deformations at a sub-Bohr orbit resolution. AB - Quantum wave function engineering of dopant-based Si nanostructures reveals new physics in the solid state, and is expected to play a vital role in future nanoelectronics. Central to any fundamental understanding or application is the ability to accurately characterize the deformation of the electron wave functions in these atom-based structures through electric and magnetic field control. We present a method for mapping the subtle changes that occur in the electron wave function through the measurement of the hyperfine tensor probed by (29)Si impurities. We calculate Stark parameters for six shells around the donor. Our results show that detecting the donor electron wave function deformation is possible with resolution at the sub-Bohr radius level. PMID- 19792335 TI - Splitting of Majorana-fermion modes due to intervortex tunneling in a p(x) + ip(y) superconductor. AB - We consider a two-dimensional (p(x) + ip(y)) superconductor in the presence of multiple vortices, which support zero-energy Majorana-fermion states in their cores. Intervortex tunnelings of the Majorana fermions lift the topological state degeneracy. Using the Bogoliubov-de Gennes equation, we calculate splitting of the zero-energy modes due to these tunneling events. We also discuss superconducting fluctuations and, in particular, their effect on the energy splitting. PMID- 19792336 TI - Manipulation of the Majorana fermion, Andreev reflection, and Josephson current on topological insulators. AB - We study theoretically the transport properties of a normal metal (N)/ferromagnet insulator (FI)/superconductor (S) junction and a S/FI/S junction formed on the surface of a three-dimensional topological insulator, where the chiral Majorana mode exists at the FI/S interface. We find the chiral Majorana mode generated in N/FI/S and S/FI/S junctions is very sensitively controlled by the direction of the magnetization m in the FI region. In particular, the current-phase relation of the Josephson current in S/FI/S junctions has a phase shift of neither 0 nor pi that can be tuned continuously by the component of m perpendicular to the interface. PMID- 19792337 TI - Tuning ferroelectric polarization reversal by electric and magnetic fields in CuCrO(2). AB - The effects of electric and magnetic fields on magnetic and electric properties have been investigated for a triangular lattice antiferromagnet CuCrO(2) showing magnetically induced ferroelectric order. We demonstrate that ferroelectric polarization reversal can be finely tuned by using both magnetic and electric fields in the triangular lattice antiferromagnet. The observed magnetoelectric tunability can be attributed to small in-plane spin anisotropy and a resultant high degree of freedom for the direction of ferroelectric polarization, which is characteristic of a multiferroic triangular lattice antiferromagnet with out-of plane 120 degrees spin structure. PMID- 19792338 TI - Itinerant magnetic multipole moments of rank five as the hidden order in URu(2)Si(2). AB - A broken symmetry ground state without any magnetic moments has been calculated by means of the local-density approximation to density functional theory plus a local exchange term, the so-called LDA+U approach, for URu(2)Si(2). The solution is analyzed in terms of a multipole tensor expansion of the itinerant density matrix and is found to be a nontrivial magnetic multipole. Analysis and further calculations show that this type of multipole enters naturally in time reversal breaking in the presence of large effective spin-orbit coupling and coexists with magnetic moments for most magnetic actinides. PMID- 19792339 TI - Spin excitations of a Kondo-screened atom coupled to a second magnetic atom. AB - Screening the electron spin of a magnetic atom via spin coupling to conduction electrons results in a strong resonant peak in the density of states at the Fermi energy, the Kondo resonance. We show that magnetic coupling of a Kondo atom to another unscreened magnetic atom can split the Kondo resonance into two peaks. Inelastic spin excitation spectroscopy with scanning tunneling microscopy is used to probe the Kondo effect of a Co atom, supported on a thin insulating layer on a Cu substrate, that is weakly coupled to a nearby Fe atom to form an inhomogeneous dimer. The Kondo peak is split by interaction with the non-Kondo atom, but can be reconstituted with a magnetic field of suitable magnitude and direction. Quantitative modeling shows that this magnetic field results in a spin-level degeneracy in the dimer, which enables the Kondo effect to occur. PMID- 19792340 TI - Striped multiferroic phase in double-exchange model for quarter-doped manganites. AB - The phase diagram of quarter-hole-doped perovskite manganites is investigated using the double-exchange model. An exotic striped type-II multiferroic phase, where 25% of the nearest-neighbor spin couplings are orthogonal to each other, is found in the narrow-bandwidth region. Comparing with the spiral-spin ordering phase of undoped manganites, the multiferroic Curie temperature of the new phase is estimated to be approximately 4 times higher, while the ferroelectric polarization is similar in magnitude. Our study provides a path for noncollinear spin multiferroics based on electronic self-organization, different from the traditional approach based on superexchange frustration. PMID- 19792341 TI - Momentum dependence of orbital excitations in Mott-insulating titanates. AB - High-resolution resonant inelastic x-ray scattering has been used to determine the momentum dependence of orbital excitations in Mott-insulating LaTiO(3) and YTiO(3) over a wide range of the Brillouin zone. The data are compared to calculations in the framework of lattice-driven and superexchange-driven orbital ordering models. A superexchange model in which the experimentally observed modes are attributed to two-orbiton excitations yields the best description of the data. PMID- 19792342 TI - Direct measurement of the nonconservative force field generated by optical tweezers. AB - The force field of optical tweezers is commonly assumed to be conservative, neglecting the complex action of the scattering force. Using a novel method that extracts local forces from trajectories of an optically trapped particle, we measure the three-dimensional force field experienced by a Rayleigh particle with 10 nm spatial resolution and femtonewton precision in force. We find that the force field is nonconservative with the nonconservative component increasing radially away from the optical axis, in agreement with the Gaussian beam model of the optical trap. PMID- 19792343 TI - Logarithmic decay in single-particle relaxation of hydrated lysozyme powder. AB - We present the self-dynamics of protein amino acids of hydrated lysozyme powder around the physiological temperature by means of molecular dynamics simulations. The self-intermediate scattering functions of the amino acid residue center of mass display a logarithmic decay over 3 decades of time, from 2 ps to 2 ns, followed by an exponential alpha relaxation. This kind of slow dynamics resembles the relaxation scenario within the beta-relaxation time range predicted by mode coupling theory in the vicinity of higher-order singularities. These results suggest a strong analogy between the single-particle dynamics of the protein and the dynamics of colloidal, polymeric, and molecular glass-forming liquids. PMID- 19792344 TI - Fisher waves in the strong noise limit. AB - We investigate the effects of a strong number fluctuations on traveling waves in the Fisher-Kolmogorov reaction-diffusion system. Our findings are in stark contrast to the commonly used deterministic and weak-noise approximations. We compute the wave velocity in one and two spatial dimensions, for which we find a linear and a square-root dependence of the speed on the particle density. Instead of smooth sigmoidal wave profiles, we observe fronts composed of a few rugged kinks that diffuse, annihilate, and rarely branch; this dynamics leads to power law tails in the distribution of the front sizes. PMID- 19792345 TI - Dynamical reconnection and stability constraints on cortical network architecture. AB - Stability under dynamical changes to network connectivity is invoked alongside previous criteria to constrain brain network architecture. A new hierarchical network is introduced that satisfies all these constraints, unlike more commonly studied regular, random, and small-world networks. It is shown that hierarchical networks can simultaneously have high clustering, short path lengths, and low wiring costs, while being robustly stable under large scale reconnection of substructures. PMID- 19792346 TI - Experimental demonstration of Snell's law for shear zone refraction in granular materials. AB - We present experiments on slow shear flow in granular materials. Under appropriate conditions shear localizes in narrow shear zones. We demonstrate that when the shear zone crosses a material boundary, it refracts in accordance with Snell's law in optics-an effect first found in simulations [Phys. Rev. Lett. 98, 018301 (2007)]. The shear zone is the one that minimizes the dissipation rate upon shearing, i.e., a manifestation of the principle of least dissipation. We have prepared the materials as to form a granular lens. Shearing through the lens is shown to give a very broad shear zone, which corresponds to fulfilling Snell's law for a continuous range of paths through the cell. PMID- 19792347 TI - Electronic coherence provides a direct proof for energy-level crossing in photoexcited lutein and beta-carotene. AB - We investigate femtosecond transient absorption dynamics of lutein and beta carotene. Strong oscillations up to about 400 fs are observed, depending on excitation or detection wavelength and solvent. We propose electronic quantum beats as the origin of these oscillations. They provide direct proof for strong coupling of the 1B(u)(+) with another electronic "dark" state predicted by quantum chemical calculations to be the 1B(u)(-) state resulting in a crossing within a dynamic relaxation model. The overall dynamics can be described well by an optical Bloch equation approach. PMID- 19792348 TI - Emergent self-organized complex network topology out of stability constraints. AB - Although most networks in nature exhibit complex topologies, the origins of such complexity remain unclear. We propose a general evolutionary mechanism based on global stability. This mechanism is incorporated into a model of a growing network of interacting agents in which each new agent's membership in the network is determined by the agent's effect on the network's global stability. It is shown that out of this stability constraint complex topological properties emerge in a self-organized manner, offering an explanation for their observed ubiquity in biological networks. PMID- 19792349 TI - Skull flexure from blast waves: a mechanism for brain injury with implications for helmet design. AB - Traumatic brain injury (TBI) has become a signature injury of current military conflicts, with debilitating, costly, and long-lasting effects. Although mechanisms by which head impacts cause TBI have been well researched, the mechanisms by which blasts cause TBI are not understood. From numerical hydrodynamic simulations, we have discovered that nonlethal blasts can induce sufficient skull flexure to generate potentially damaging loads in the brain, even without a head impact. The possibility that this mechanism may contribute to TBI has implications for injury diagnosis and armor design. PMID- 19792350 TI - Comment on "Superconducting coherence peak in the electronic excitations of a single-layer Bi(2)Sr(1.6)La(0.4)CuO(6 + delta) cuprate superconductor". PMID- 19792352 TI - Dynamical properties of the one-dimensional spin-1/2 Bose-Hubbard model near a Mott-insulator to ferromagnetic-liquid transition. AB - We investigate the dynamics of the one-dimensional strongly repulsive spin-1/2 Bose-Hubbard model for filling nu nu(e) oscillations. A signal-blind analysis was performed using a data sample corresponding to 3.39x10(20) protons on target. The data are consistent with background prediction across the full range of neutrino energy reconstructed assuming quasielastic scattering, 2001s(2)2s(2) J=0 electric-dipole radiation of high-Z, beryllium-like ions, following the resonant electron capture into initially lithium-like ions, for which the Breit interaction strongly dominates the Coulomb repulsion and leads to a qualitative change in the expected x-ray emission pattern. The proposed measurements are feasible with present-day x-ray detectors and may serve a stringent test on relativistic corrections to the electron electron interaction in the presence of strong fields. PMID- 19792368 TI - Vanishing electronic energy loss of very slow light ions in insulators with large band gaps. AB - Electronic energy loss of light ions in nanometer films of materials with large band gaps has been studied for very low velocities. For LiF, a threshold velocity is observed at 0.1 a.u. (250 eV/u), below which the ions move without transferring energy to the electronic system. For KCl, a lower (extrapolated) threshold velocity is found, identical for H and He ions. For SiO2, no clear velocity threshold is observed for He particles. For protons and deuterons, electronic stopping is found to perfectly fulfill velocity scaling, as expected for binary ion-electron interaction. PMID- 19792369 TI - Decoherence and collisional frequency shifts of trapped bosons and fermions. AB - We perform exact calculations of collisional frequency shifts for several fermions or bosons using a singlet and triplet basis for pairs of particles. The "factor of 2 controversy" for bosons becomes clear-the factor is always 2. Decoherence is described by singlet states and they are unaffected by spatially uniform clock fields. Spatial variations are critical, especially for fermions which were previously thought to be immune to collision shifts. The spatial variations lead to decoherence and a novel frequency shift that is not proportional to the partial density of internal states. PMID- 19792370 TI - Towards quantum experiments with human eyes as detectors based on cloning via stimulated emission. AB - We show theoretically that a large Bell inequality violation can be obtained with human eyes as detectors, in a "micro-macro" experiment where one photon from an entangled pair is greatly amplified via stimulated emission. The violation is robust under photon loss. This leads to an apparent paradox, which we resolve by noting that the violation proves the existence of entanglement before the amplification. The same is true for the micro-macro experiments performed so far with conventional detectors. However, we also prove that there is genuine micro macro entanglement even for high loss. PMID- 19792371 TI - Proposal for pulsed on-demand sources of photonic cluster state strings. AB - We present a method to convert certain single photon sources into devices capable of emitting large strings of photonic cluster state in a controlled and pulsed "on-demand" manner. Such sources would greatly reduce the resources required to achieve linear optical quantum computation. Standard spin errors, such as dephasing, are shown to affect only 1 or 2 of the emitted photons at a time. This allows for the use of standard fault tolerance techniques, and shows that the photonic machine gun can be fired for arbitrarily long times. Using realistic parameters for current quantum dot sources, we conclude high entangled-photon emission rates are achievable, with Pauli-error rates per photon of less than 0.2%. For quantum dot sources, the method has the added advantage of alleviating the problematic issues of obtaining identical photons from independent, nonidentical quantum dots, and of exciton dephasing. PMID- 19792372 TI - Light well: a tunable free-electron light source on a chip. AB - The passage of a free-electron beam through a nanohole in a periodically layered metal-dielectric structure creates a new type of tunable, nanoscale radiation source--a "light well". In the reported demonstration, tunable light is generated at an intensity of approximately 200 W/cm(2) as electrons with energies in the 20 40 keV range are injected into gold-silica well structures with a lateral size of just a few hundred nanometers. PMID- 19792373 TI - Observation of a microscopic cascaded contribution to the fifth-order nonlinear susceptibility. AB - Typically, low-order nonlinearities are much stronger than high-order nonlinearities. In this Letter, we demonstrate a procedure by which strong high order nonlinearities can be synthesized out of low-order nonlinearities. Our procedure involves the use of the previously largely overlooked process of microscopic cascading, which results from local-field effects. We have performed an experiment that allows us to distinguish the influence of microscopic cascading from the more-well-known process of macroscopic cascading, and we find conditions under which microscopic cascading can be the dominant effect. The ability to create a large high-order nonlinear response could prove useful for applications in quantum-information science that require the detection of the simultaneous presence of N entangled photons. PMID- 19792374 TI - Observation of three-dimensional discrete-continuous x waves in photonic lattices. AB - We report on the generation of three-dimensional discrete X waves in a femtosecond laser-written waveguide array. Our measurements constitute the first experimental observation of temporally localized three-dimensional discrete continuous entities. The X waves spontaneously emerge from a single-site excitation due to the discrete diffraction of the lattice and the normally dispersive as well as cubically nonlinear properties of the fused silica used as host material. PMID- 19792375 TI - Synchronization of sound sources. AB - Sound generation and interaction are highly complex, nonlinear, and self organized. Nearly 150 years ago Rayleigh raised the following problem: two nearby organ pipes of different fundamental frequencies sound together almost inaudibly with identical pitch. This effect is now understood qualitatively by modern synchronization theory M. Abel et al. [J. Acoust. Soc. Am. 119, 2467 (2006)10.1121/1.2170441]. For a detailed investigation, we substituted one pipe by an electric speaker. We observe that even minute driving signals force the pipe to synchronization, thus yielding three decades of synchronization-the largest range ever measured to our knowledge. Furthermore, a mutual silencing of the pipe is found, which can be explained by self-organized oscillations, of use for novel methods of noise abatement. Finally, we develop a reconstruction method which yields a perfect quantitative match of experiment and theory. PMID- 19792376 TI - Coexistence of two singularities in dewetting flows: regularizing the corner tip. AB - Entrainment in wetting and dewetting flows often occurs through the formation of a corner with a very sharp tip. This corner singularity comes on top of the divergence of viscous stress near the contact line, which is only regularized at molecular scales. We investigate the fine structure of corners appearing at the rear of sliding drops. Experiments reveal a sudden decrease of tip radius, down to 20 microm, before entrainment occurs. We propose a lubrication model for this phenomenon, which compares well to experiments. Despite the disparity of length scales, it turns out that the tip size is set by the classical viscous singularity, for which we deduce a nanometric length from our macroscopic measurements. PMID- 19792377 TI - Burgers shock waves and sound in a 2D microfluidic droplets ensemble. AB - We investigate the collective motion of a two-dimensional disordered ensemble of droplets in a microfluidic channel far from equilibrium and at Reynolds number approximately 10(-4). The ensemble carries ultraslow shock waves and sound, propagating at approximately 100 microm s(-1) and superposed on diffusive droplets motion. These modes are induced by long-range hydrodynamic dipolar interactions between droplets, the result of the symmetry breaking flow. The modes obey the Burgers equation due to a local coupling between droplets velocity and number density. This stems from a singular effect of the channel sidewall boundaries upon summation of the hydrodynamic interaction in two dimensions. PMID- 19792378 TI - Effect of the laser wavelength on the saturated level of stimulated Brillouin scattering. AB - Equivalent stimulated Brillouin backscattering (SBS) saturation levels have been measured in the interaction with 0.527 and 0.351 microm laser beams demonstrating that the initial interaction wavelength is not influencing the final saturation levels. Experiments have been performed at the two wavelengths in similar interaction conditions obtained by preforming the plasma from a solid target with a creation beam converted at the same wavelength as the interaction beam. This produces an almost exponential density profile from vacuum to the critical density of the interaction beam in which large SBS gains are reached. PMID- 19792379 TI - Laboratory observations of self-excited dust acoustic shocks. AB - Repeated, self-excited dust acoustic shock waves (DASWs) have been observed in a dc glow discharge dusty plasma using high-speed video imaging. Two major observations are reported: (1) The self-steepening of a nonlinear dust acoustic wave (DAW) into a saw-tooth wave with sharp gradient in dust density, very similar to those found in numerical solutions of the fully nonlinear fluid equations for a nondispersive DAW [B. Eliasson and P. K. Shukla, Phys. Rev. E 69, 067401 (2004)], and (2) the collision and confluence of two DASWs. PMID- 19792380 TI - Collision dynamics and rung formation of non-Abelian vortices. AB - We investigate the collision dynamics of two non-Abelian vortices and find that, unlike Abelian vortices, they neither reconnect themselves nor pass through each other, but create a rung between them in a topologically stable manner. Our predictions are verified using the model of the cyclic phase of a spin-2 spinor Bose-Einstein condensate. PMID- 19792381 TI - Potassium under pressure: a pseudobinary ionic compound. AB - Experimentally, we have found that among the "complicated" phases of potassium at intermediate pressures is one which has the same space group as the double hexagonal-close-packed structure, although its atomic coordination is completely different. Calculations on this P6(3)/mmc (hP4) structure as a function of pressure show three isostructural transitions and three distinctive types of chemical bonding: free electron, ionic, and metallic. Interestingly, relationships between localized metallic structures and ionic compounds are found. PMID- 19792382 TI - Initial structure memory of pressure-induced changes in the phase-change memory alloy Ge2Sb2Te5. AB - We demonstrate that while the metastable face-centered cubic (fcc) phase of Ge2Sb2Te5 becomes amorphous under hydrostatic compression at about 15 GPa, the stable trigonal phase remains crystalline. Upon higher compression, a body centered cubic phase is obtained in both cases around 30 GPa. Upon decompression, the amorphous phase is retained for the starting fcc phase while the initial structure is recovered for the starting trigonal phase. We argue that the presence of vacancies and associated subsequent large atomic displacements lead to nanoscale phase separation and loss of initial structure memory in the fcc staring phase of Ge2Sb2Te5. PMID- 19792383 TI - Irreversible rearrangements, correlated domains, and local structure in aging glasses. AB - Bidisperse colloidal suspensions of temperature-sensitive microgel spheres were quenched from liquid to glass states by a rapid temperature drop, and then the glass was permitted to age. Irreversible rearrangements, events that dramatically change a particle's local environment, were observed to be closely related to dynamic heterogeneity. The rate of these irreversible events decreased during aging and the the number of particles required to move as part of these irreversible rearrangements increased. Thus, the slowing dynamics of aging were governed by growing, correlated domains of particles. Additionally, short-range order developed, and a spatial decay length scale associated with orientational order was found to grow during aging. PMID- 19792384 TI - Coarse-grained simulations of flow-induced nucleation in semicrystalline polymers. AB - We perform kinetic Monte Carlo simulations of flow-induced nucleation in polymer melts with an algorithm that is tractable even at low undercooling. The configuration of the noncrystallized chains under flow is computed with a recent nonlinear tube model. Our simulations predict both enhanced nucleation and the growth of shish-like elongated nuclei for sufficiently fast flows. The simulations predict several experimental phenomena and theoretically justify a previously empirical result for the flow-enhanced nucleation rate. The simulations are highly pertinent to both the fundamental understanding and process modeling of flow-induced crystallization in polymer melts. PMID- 19792385 TI - Direct observation of a surface induced disordering process in magnetic nanoparticles. AB - We present experimental evidence of surface induced disordering at magnetic FeCoPd nanoparticles during the L1(0)-A1 phase transition using high-resolution aberration-corrected electron microscopy and strain mapping. In situ electron diffraction studies show a narrow temperature range of fully ordered L1(0) structure. The order-disorder transition is size dependent and induces strong lattice deformation in outer part of the nanocrystals. The formation of unusually large strain of 20% is discussed in terms of core-shell structure formation with surface disordered layer and ordered core. PMID- 19792386 TI - Understanding the clean interface between covalent Si and ionic Al2O3. AB - The atomic and electronic structures of the (001)-Si/(001)-gamma-Al(2)O(3) heterointerface are investigated by first principles total energy calculations combined with a newly developed "modified basin-hopping" method. It is found that all interface Si atoms are fourfold coordinated due to the formation of Si-O and unexpected covalent Si-Al bonds in the new abrupt interface model. And the interface has perfect electronic properties in that the unpassivated interface has a large LDA band gap and no gap levels. These results show that it is possible to have clean semiconductor-oxide interfaces. PMID- 19792387 TI - Quantum fluctuations due to spinons, polarons, and stripes in the two-dimensional Hubbard model. AB - Quantum fluctuations (QF's) in the two-dimensional Hubbard model are visualized by superposition of optimized nonorthogonal Slater determinants. In the half filled system, QF's consist of rotational and translational motions of spinon antispinon pairs, while in the lightly doped systems (delta=0.96), those motions of polarons form the QF's. It is shown that an attractive interaction works between two polarons, in the framework of a projected Hartree-Fock picture. At about 10% doping, the ground state has a stripe structure and QF's due to deviations from the uniform stripe. The present method gives the ground state energies comparable or in some cases superior to the variational Monte Carlo method with a Gutzwiller projection parameter. PMID- 19792388 TI - Appearance of "fragile" Fermi liquids in finite-width Mott insulators sandwiched between metallic leads. AB - Using inhomogeneous dynamical mean-field theory, we show that the normal-metal proximity effect could force any finite number of Mott-insulating "barrier" planes sandwiched between semi-infinite metallic leads to become "fragile" Fermi liquids. They are fully Fermi-liquid-like at T=0, leading to a restoration of lattice periodicity at zero frequency, with a well-defined Fermi surface, and perfect (ballistic) conductivity. However, the Fermi-liquid character can rapidly disappear at finite omega, V, T, disorder, or magnetism, all of which restore the expected quantum tunneling regime, leading to fascinating possibilities for nonlinear response in devices. PMID- 19792389 TI - Field-induced carrier delocalization in the strain-induced mott insulating state of an organic superconductor. AB - We report the influence of the field effect on the dc resistance and Hall coefficient in the strain-induced Mott insulating state of an organic superconductor kappa-(BEDT-TTF)(2)Cu[N(CN)(2)]Br. Conductivity obeys the formula for an activated transport sigma(square)=sigma(0)exp(-W/k(B)T), where sigma(0) is a constant and W depends on the gate voltage. The gate-voltage dependence of the Hall coefficient shows that, unlike in conventional field-effect transistors, the effective mobility of dense hole carriers ( approximately 1.6x10(14) cm(-2)) is enhanced by a positive gate voltage. This implies that carrier doping involves delocalization of intrinsic carriers that were initially localized due to electron correlation. PMID- 19792390 TI - Searching for the fractional quantum Hall effect in graphite. AB - Measurements of basal plane longitudinal rho(b)(B) and Hall rho(H)(B) resistivities were performed on highly oriented pyrolytic graphite samples in a pulsed magnetic field up to B=50 T applied perpendicular to graphene planes, and temperatures 1.5 K30 T and for all studied samples, we observed a sign change in rho(H)(B) from electron- to holelike. For our best quality sample, the measurements revealed the enhancement in rho(b)(B) for B>34 T (T=1.8 K), presumably associated with the field-driven charge density wave or Wigner crystallization transition. In addition, well-defined plateaus in rho(H)(B) were detected in the ultraquantum limit revealing possible signatures of the fractional quantum Hall effect in graphite. PMID- 19792391 TI - Optical Hall conductivity in ordinary and graphene quantum Hall systems. AB - We reveal from numerical study that the optical Hall conductivity sigma(xy)(omega) has a characteristic feature even in the ac ( approximately THz) regime in that the Hall plateaus are retained both in the ordinary two dimensional electron gas and in graphene in the quantum Hall regime, although the plateau height is no longer quantized in ac. In graphene sigma(xy)(omega) reflects the unusual Landau level structure. The effect remains unexpectantly robust against the significant strength of disorder, which we attribute to an effect of localization. We predict the ac quantum Hall measurements are feasible through the Faraday rotation characterized by the fine-structure constant alpha. PMID- 19792392 TI - Gate tunable infrared phonon anomalies in bilayer graphene. AB - We observe a giant increase of the infrared intensity and a softening of the in plane antisymmetric phonon mode E(u) ( approximately 0.2 eV) in bilayer graphene as a function of the gate-induced doping. The phonon peak has a pronounced Fano like asymmetry. We suggest that the intensity growth and the softening originate from the coupling of the phonon mode to the narrow electronic transition between parallel bands of the same character, while the asymmetry is due to the interaction with the continuum of transitions between the lowest hole and electron bands. The growth of the peak can be interpreted as a "charged-phonon" effect observed previously in organic chain conductors and doped fullerenes, which can be tuned in graphene with the gate voltage. PMID- 19792393 TI - Complex inductance, excess noise, and surface magnetism in dc SQUIDs. AB - We have characterized the complex inductance of dc SQUIDs cooled to millikelvin temperatures. The SQUID inductance displays a rich, history-dependent structure as a function of temperature, with fluctuations of order 1 fH. At a fixed temperature, the SQUID inductance fluctuates with a 1/f power spectrum; the inductance noise is highly correlated with the conventional 1/f flux noise. The data are interpreted in terms of the reconfiguration of clusters of surface spins, with correlated fluctuations of effective magnetic moments and relaxation times. PMID- 19792394 TI - Crystal orientation and thickness dependence of the superconducting transition temperature of tetragonal FeSe1-x thin films. AB - Superconductivity was recently found in the tetragonal phase FeSe. A structural transformation from tetragonal to orthorhombic (or monoclinic, depending on point of view) was observed at low temperature, but was not accompanied by a magnetic ordering as commonly occurs in the parent compounds of FeAs-based superconductors. Here, we report the correlation between structural distortion and superconductivity in FeSe(1-x) thin films with different preferred growth orientations. The films with preferred growth along the c axis show a strong thickness dependent suppression of superconductivity and low temperature structural distortion. In contrast, both properties are less affected in the films with (101) preferred orientation. These results suggest that the low temperature structural distortion is closely associated with the superconductivity of this material. PMID- 19792395 TI - Theoretical demonstration of how the dispersion of magnetic excitations in cuprate compounds can be determined using resonant inelastic X-ray scattering. AB - We show that in resonant inelastic x-ray scattering (RIXS) at the copper L and M edge direct spin-flip scattering is in principle allowed. We demonstrate how this possibility can be exploited to probe the dispersion of magnetic excitations, for instance magnons, of cuprates such as the high T(c) superconductors. We compute the relevant local and momentum dependent magnetic scattering amplitudes, which we compare to the elastic and dd-excitation scattering intensities. For cuprates these theoretical results put RIXS as a technique on the same footing as neutron scattering. PMID- 19792396 TI - Ultrafast path for optical magnetization reversal via a strongly nonequilibrium state. AB - Using time-resolved single-shot pump-probe microscopy we unveil the mechanism and the time scale of all-optical magnetization reversal by a single circularly polarized 100 fs laser pulse. We demonstrate that the reversal has a linear character, i.e., does not involve precession but occurs via a strongly nonequilibrium state. Calculations show that the reversal time which can be achieved via this mechanism is within 10 ps for a 30 nm domain. Using two single subpicosecond laser pulses we demonstrate that for a 5 microm domain the magnetic information can be recorded and readout within 30 ps, which is the fastest "write read" event demonstrated for magnetic recording so far. PMID- 19792397 TI - Spin polarized electron transport near the Si/SiO2 interface. AB - Using long-distance lateral devices, spin transport near the interface of Si and its native oxide (SiO(2)) is studied by spin-valve measurements in an in-plane magnetic field and spin precession measurements in a perpendicular magnetic field at 60 K. As electrons are attracted to the interface by an electrostatic gate, we observe shorter average spin transit times and an increase in spin coherence, despite a reduction in total spin polarization. This behavior, which is in contrast with the expected exponential depolarization seen in bulk transport devices, is explained using a transform method to recover the empirical spin current transit-time distribution and a simple two-stage drift-diffusion model. We identify strong interface-induced spin depolarization (reducing the spin lifetime by over 2 orders of magnitude from its bulk transport value) as the consistent cause of these phenomena. PMID- 19792398 TI - Valence bond and von Neumann entanglement entropy in Heisenberg ladders. AB - We present a direct comparison of the recently proposed valence bond entanglement entropy and the von Neumann entanglement entropy on spin-1/2 Heisenberg systems using quantum Monte Carlo and density-matrix renormalization group simulations. For one-dimensional chains we show that the valence bond entropy can be either less or greater than the von Neumann entropy; hence, it cannot provide a bound on the latter. On ladder geometries, simulations with up to seven legs are sufficient to indicate that the von Neumann entropy in two dimensions obeys an area law, even though the valence bond entanglement entropy has a multiplicative logarithmic correction. PMID- 19792399 TI - Model of the influence of an external magnetic field on the gain of terahertz radiation from semiconductor superlattices. AB - We theoretically analyze the influence of magnetic field on small-signal absorption and gain in a superlattice. We predict a very large and tunable THz gain due to nonlinear cyclotron oscillations in crossed electric and magnetic fields. In contrast to Bloch gain, here the superlattice is in an electrically stable state. We also find that THz Bloch gain can be significantly enhanced with a perpendicular magnetic field. If the magnetic field is tilted with respect to the superlattice axis, the usually unstable Bloch gain profile becomes stable in the vicinity of Stark-cyclotron resonances. PMID- 19792400 TI - Room-temperature ionic liquids: excluded volume and ion polarizability effects in the electrical double-layer structure and capacitance. AB - We study structures of room-temperature ionic liquids at electrified interfaces and the corresponding electrical double-layer capacities using a self-consistent mean-field theory. Ionic liquids are modeled as segmented dendrimers and the effective dielectric constant is calculated from the local distribution of ions to accommodate the excluded volume and the local dielectric screening effects. The resulting camel-shaped capacitance curve is further analyzed in terms of the thickness of alternating layers and the polarization of ions at electrified interfaces. PMID- 19792401 TI - Role of particle shape on the stress propagation in granular packings. AB - We present an experimental and numerical study on the influence that particle aspect ratio has on the mechanical and structural properties of granular packings. For grains with maximal symmetry (squares), the stress propagation in the packing localizes forming chainlike forces analogous to the ones observed for spherical grains. This scenario can be understood in terms of stochastic models of aggregation and random multiplicative processes. As the grains elongate, the stress propagation is strongly affected. The interparticle normal force distribution tends toward a Gaussian, and, correspondingly, the force chains spread leading to a more uniform stress distribution reminiscent of the hydrostatic profiles known for standard liquids. PMID- 19792402 TI - Repressor lattice: feedback, commensurability, and dynamical frustration. AB - We construct a hexagonal lattice of repressing genes, such that each node represses three of the neighbors, and use it as a model for genetic regulation in spatially extended systems. Using symmetry arguments and stability analysis we argue that the repressor lattice can be in a nonfrustrated oscillating state with only three distinct phases. If the system size is not commensurate with three, oscillating solutions of several different phases are possible. As the strength of the interactions between the nodes increases, the system undergoes many transitions, breaking several symmetries. Eventually dynamical frustrated states appear, where the temporal evolution is chaotic, even though there are no built in frustrations. Applications of the repressor lattice to real biological systems are discussed. PMID- 19792403 TI - Flapping wing flight can save aerodynamic power compared to steady flight. AB - Flapping flight is more maneuverable than steady flight. It is debated whether this advantage is necessarily accompanied by a trade-off in the flight efficiency. Here we ask if any flapping motion exists that is aerodynamically more efficient than the optimal steady motion. We solve the Navier-Stokes equation governing the fluid dynamics around a 2D flapping wing, and determine the minimal aerodynamic power needed to support a specified weight. While most flapping wing motions are more costly than the optimal steady wing motion, we find that optimized flapping wing motions can save up to 27% of the aerodynamic power required by the optimal steady flight. We explain the cause of this energetic advantage. PMID- 19792405 TI - Jamming in sheared foams and emulsions, explained by critical instability of the films between neighboring bubbles and drops. AB - Foam and emulsion jamming at low shear rates is explained by considering the thinning dynamics of the transient films, formed between neighboring bubbles and drops. After thinning gradually to a critical thickness, these films undergo an instability transition, which leads to the formation of very thin "black films" providing strong adhesion between the dispersed particles. Analysis shows that such film thickness instability occurs only if the contact time between particles is sufficiently long-an explicit expression for the respective critical shear rate is derived and compared to experimental data. PMID- 19792404 TI - pH-triggered block copolymer micelle-to-micelle phase transition. AB - We present a first experimental observation and provide a theoretical interpretation of a pH-induced micelle-to-micelle phase transition in aqueous solutions of spherical block copolymer micelles with polybasic coronas. Dynamic light scattering, static light scattering, and atomic force microscopy confirm sharp changes in micellar hydrodynamic size and aggregation number occurring in a narrow pH range, DeltapH<0.1. In agreement with theory, zeta potential measurements indicated an abrupt change in ionization of polymer chains in the micellar corona at the transition pH. PMID- 19792406 TI - Minimal energy clusters of hard spheres with short range attractions. AB - We calculate the ground states of hard-sphere clusters, in which n identical hard spherical particles bind by isotropic short-ranged attraction. Combining graph theoretic enumeration with basic geometry, we analytically solve for clusters of n9 the degeneracy decreases due to the formation of structures with >3n-6 contacts. Interestingly, for n=10 and possibly at n=11 and n=12, the ground states of this system are subsets of hexagonal close-packed crystals. The ground states are not icosahedra at n=12 and n=13. We relate our results to the structure and thermodynamics of suspensions of colloidal particles with short-ranged attractions. PMID- 19792407 TI - Direct measurement of sub-Debye-length attraction between oppositely charged surfaces. AB - Using a surface force balance with fast video analysis, we have measured directly the attractive forces between oppositely charged solid surfaces (charge densities sigma(+), sigma(-)) across water over the entire range of interaction, in particular, at surface separations D below the Debye screening length lambda(S). At very low salt concentration we find a long-ranged attraction between the surfaces (onset ca. 100 nm), whose variation at D, which is important for interpreting the results of some dark matter detection experiments. The method is to evaluate quark-line disconnected correlations on the MILC lattice ensembles, which include the effects of dynamical light and strange quarks. After continuum and chiral extrapolations, the result is = 0.69(7)_{stat}(9)_{syst}, in the modified minimal subtraction scheme (2 GeV) regularization, or for the renormalization scheme invariant form, m_{s} partial differentialM_{N}/ partial differentialm_{s} = 59(6)(8) MeV. PMID- 19792426 TI - Smallest known Q value of any nuclear decay: the rare beta;{-} decay of ;{115}In(9/2;{+}) --> ;{115}Sn(3/2;{+}). AB - The ground-state-to-ground-state Q_{beta;{-}} value of ;{115}In was determined to 497.68(17) keV using a high-precision Penning trap facility at the University of Jyvaskyla, Finland. From this, a Q_{beta;{-}} value of 0.35(17) keV was obtained for the rare beta;{-} decay to the first excited state of ;{115}Sn at 497.334(22) keV. The partial half-life was determined to 4.1(6) x 10;{20} yr using ultra low background gamma-ray spectrometry in an underground laboratory. Theoretical modeling of this 2nd-forbidden unique beta;{-} transition was also undertaken and resulted in Q_{beta;{-}} = 57_{-12};{+19} eV using the measured half-life. The discrepancy between theory and experiment could be attributed to atomic effects enhanced by the low Q value. The present study implies that this transition has the lowest Q value of any known nuclear beta decay. PMID- 19792427 TI - Q value of ;{115}In --> ;{115}sn(3/2;{+}): the lowest known energy beta decay. AB - Using precision, cryogenic, Penning-trap mass spectrometry we have measured the atomic mass difference M[;{115}In]-M[;{115}Sn] to be 497.489(10) keV/c;{2}. Combined with the energy of the 3/2;{+} first excited state of ;{115}Sn [J. Blachot, Nuclear Data Sheets 104, 967 (2005)10.1016/j.nds.2005.03.003], the Q value of the ;{115}In(9/2;{+}) --> ;{115}Sn(3/2;{+}) beta decay is determined to be 155(24) eV. This confirms the inference of Cattadori [Nucl. Phys. A 748, 333 (2005)10.1016/j.nuclphysa.2004.10.025] that this small branching-ratio beta decay has the lowest-known Q value. We also report improved values of the individual atomic masses: M[;{115}In] = 114.903 878 774(16) u and M[;{115}Sn] = 114.903 344 697(17) u. PMID- 19792428 TI - Rydberg-state-enabled deceleration and trapping of cold molecules. AB - Hydrogen molecules in selected core-nonpenetrating Rydberg-Stark states have been decelerated from a mean initial velocity of 500 m/s to zero velocity in the laboratory frame and loaded into a three-dimensional electrostatic trap. Trapping times, measured by pulsed electric field ionization of the trapped molecules, are found to be limited by collisional processes. As Rydberg states can be deexcited to the absolute ground state, the method can be applied to generate cold samples of a wide range of species. PMID- 19792429 TI - Theoretical determination of characteristic x-ray lines and the copper K alpha spectrum. AB - Core excitations above the K edge result in K alpha characteristic x-ray emission. Understanding these spectra is crucial for high accuracies in investigations into QED, near-edge x-ray structure and advanced crystallography. We address unresolved quantitative discrepancies between experiment and theory for copper. These discrepancies arise from an incomplete treatment of electronic interactions. By finding solutions to relativistic multiconfigurational Dirac Fock equations accounting for correlation and exchange corrections, we obtain an accurate reproduction of the peak energies, excellent agreement of theory with experiment for the line shapes, good convergence between gauges, and account for the K alpha doublet ratio of 0.522 +/- 0.003ratio1. PMID- 19792430 TI - Resonance coalescence in molecular photodissociation. AB - We study theoretically the photodissociation dynamics of the H_{2};{+} molecular ion exposed to a linearly polarized laser light. It is shown that it is possible to choose a laser wavelength and intensity so as to produce a coalescence of two photodissociation vibronic resonance states. At such a coalescence point, also called an exceptional point, the photodissociative resonance wave function is self-orthogonal. This unique phenomenon which is presented here for light induced molecular dynamics enables us to transfer completely the nondissociated molecules from one vibronic state to another by varying adiabatically the laser frequency and intensity along a closed contour which encircles the exceptional point. PMID- 19792431 TI - Trapping and manipulation of isolated atoms using nanoscale plasmonic structures. AB - We propose and analyze a scheme to interface individual neutral atoms with nanoscale solid-state systems. The interface is enabled by optically trapping the atom via the strong near-field generated by a sharp metallic nanotip. We show that under realistic conditions, a neutral atom can be trapped with position uncertainties of just a few nanometers, and within tens of nanometers of other surfaces. Simultaneously, the guided surface plasmon modes of the nanotip allow the atom to be optically manipulated, or for fluorescence photons to be collected, with very high efficiency. Finally, we analyze the surface forces, heating and decoherence rates acting on the trapped atom. PMID- 19792432 TI - Molecular dissociative ionization and wave-packet dynamics studied using two color XUV and IR pump-probe spectroscopy. AB - We present a combined theoretical and experimental study of ultrafast wave-packet dynamics in the dissociative ionization of H_{2} molecules as a result of irradiation with an extreme-ultraviolet (XUV) pulse followed by an infrared (IR) pulse. In experiments where the duration of both the XUV and IR pulses are shorter than the vibrational period of H_{2};{+}, dephasing and rephasing of the vibrational wave packet that is formed in H_{2};{+} upon ionization of the neutral molecule by the XUV pulse is observed. In experiments where the duration of the IR pulse exceeds the vibrational period of H_{2};{+} (15 fs), a pronounced dependence of the H;{+} kinetic energy distribution on XUV-IR delay is observed that can be explained in terms of the adiabatic propagation of the H_{2};{+} wave packet on field-dressed potential energy curves. PMID- 19792433 TI - Quantum jumps and spin dynamics of interacting atoms in a strongly coupled atom cavity system. AB - We experimentally investigate the spin dynamics of one and two neutral atoms strongly coupled to a high finesse optical cavity. We observe quantum jumps between hyperfine ground states of a single atom. The interaction-induced normal mode splitting of the atom-cavity system is measured via the atomic excitation. Moreover, we observe the mutual influence of two atoms simultaneously coupled to the cavity mode. PMID- 19792434 TI - Quantum pumping with ultracold atoms on microchips: fermions versus bosons. AB - We present a design for simulating quantum pumping of electrons in a mesoscopic circuit with ultracold atoms in a micromagnetic chip trap. We calculate theoretical results for quantum pumping of both bosons and fermions, identifying differences and common features, including geometric behavior and resonance transmission. We analyze the feasibility of experiments with bosonic ;{87}Rb and fermionic ;{40}K atoms with an emphasis on reliable atomic current measurements. PMID- 19792435 TI - Two electrons on a hypersphere: a quasiexactly solvable model. AB - We show that the exact wave function for two electrons, interacting through a Coulomb potential but constrained to remain on the surface of a D-sphere (D >or= 1), is a polynomial in the interelectronic distance u for a countably infinite set of values of the radius R. A selection of these radii and the associated energies are reported for ground and excited states on the singlet and triplet manifolds. We conclude that the D = 3 model bears the greatest similarity to normal physical systems. PMID- 19792436 TI - Bloch oscillations in complex crystals with PT symmetry. AB - Bloch oscillations in complex lattices with PT symmetry are theoretically investigated with specific reference to optical Bloch oscillations in photonic lattices with gain or loss regions. Novel dynamical phenomena with no counterpart in ordinary lattices, such as nonreciprocal Bloch oscillations related to violation of the Friedel's law of Bragg scattering in complex potentials, are highlighted. PMID- 19792437 TI - Time-resolved up-conversion of entangled photon pairs. AB - In the process of spontaneous parametric down-conversion, photons from a pump field are converted to signal and idler photon pairs in a nonlinear crystal. The reversed process, or up-conversion of these pairs back to single photons in a second crystal, is also possible. Here, we present experimental measurements of the up-conversion rate with a controlled time delay introduced between the signal and idler photons. As a function of delay, this rate presents a full width at half maximum of 27.9 fs under our experimental conditions, and we further demonstrate that group delay dispersion of the photon pairs broadens this width. These observations are in close agreement with our calculations, thus demonstrating an ultrafast, nonclassical correlation between the signal and idler waves. PMID- 19792438 TI - Autoresonant dynamics of optical guided waves. AB - We study, theoretically and experimentally, autoresonant dynamics of optical waves in a spatially chirped nonlinear directional coupler. We show that adiabatic passage through a linear resonance in a weakly coupled light-wave system yields a sharp threshold transition to nonlinear phase locking and amplification to predetermined amplitudes. This constitutes the first observation of autoresonance phenomena in optics. PMID- 19792439 TI - Filamentation of femtosecond laser Airy beams in water. AB - We report experiments on the propagation of intense, femtosecond, self-bending Airy laser beams in water. The supercontinuum radiation generated along the curved beam path is angularly resolved in the far field. Spectral maps of this radiation reveal the changing character of the laser-pulse evolution on propagation. PMID- 19792440 TI - Spectrum of light in a quantum fluctuating periodic structure. AB - We address the general problem of the excitation spectrum for light coupled to scatterers having quantum fluctuating positions around the sites of a periodic lattice. In addition to providing an imaginary part to the spectrum, we show that these quantum fluctuations affect the real part of the spectrum, in a way that we determine analytically. Our predictions may be observed with ultracold atoms in an optical lattice, on a J = 0 --> J;{'} = 1 narrow atomic transition. As a side result, we resolve a controversy for the occurrence of a spectral gap in a fcc lattice. PMID- 19792441 TI - Asymmetric disconnection of an underwater air bubble: persistent neck vibrations evolve into a smooth contact. AB - The disconnection of an underwater bubble illustrates how slight initial asymmetries can prevent the formation of a finite-time singularity. Creating a singularity by focusing a finite amount of energy dynamically into a vanishingly small amount of material requires that the initial condition be perfectly symmetric. In reality, imperfections are always present. We show a slight azimuthal asymmetry in the initial shape of the bubble neck excites vibrations that persist over time. As a result, the focusing singularity is generically preempted by a smooth contact. PMID- 19792442 TI - Three periods of drying of a single square capillary tube. AB - The drying kinetics of a porous medium is classically described in three main periods, which depend on the interplay between the external and internal mass transfers during evaporation. The first period is described as essentially depending on the external mass transfer, whereas the third period is dominated by the internal mass transfer. The second period is a crossover period. We show experimentally that a similar drying kinetics can be obtained from a much simpler system owing to the effect of corner liquid films: a capillary tube of square cross section. PMID- 19792443 TI - Strong scattering of high power millimeter waves in tokamak plasmas with tearing modes. AB - In tokamak plasmas with a tearing mode, strong scattering of high power millimeter waves, as used for heating and noninductive current drive, is shown to occur. This new wave scattering phenomenon is shown to be related to the passage of the O point of a magnetic island through the high power heating beam. The density determines the detailed phasing of the scattered radiation relative to the O-point passage. The scattering power depends strongly nonlinearly on the heating beam power. PMID- 19792444 TI - Pressure-induced insulator-to-metal transition in TbBaCo_{2}O_{5.48}. AB - TbBaCo_{2}O_{5.48} has been studied by high-pressure synchrotron x-ray diffraction together with resistivity measurements as a function of temperature and pressure. It was found that under pressure a structural phase transition takes place corroborating with a sluggish insulator-to-metal transition. An onset of the metallic state was deduced from a gradual drop of resistivity at the range 3-10 GPa culminating into the change in sign of dR/dT, from negative to positive, at P >or= 10 GPa; at the same pressure range there is a change of lattice strain components calculated from the unit cell dimensions. The changes in structural and transport properties are very similar to those found on heating at ambient pressure implying a common mechanism. PMID- 19792445 TI - Wurtzite to rocksalt phase transformation of cadmium selenide nanocrystals via laser-induced shock waves: transition from single to multiple nucleation. AB - The behavior of CdSe nanocrystals shocked to stresses of 2-3.75 GPa has been studied. Above 3 GPa a near-complete disappearance of the first excitonic feature and broadening of the low-energy absorption edge were observed, consistent with a wurtzite to rocksalt structural transformation. The transformation pressure is reduced relative to hydrostatic compression in a diamond anvil cell, and the rate increases, attributed to shock induced shear stress along the reaction coordinate. The especially rapid rate observed for a 3.75 GPa shock suggests multiple nucleation events per particle. PMID- 19792446 TI - Superionic conduction in substoichiometric LiAl alloy: an ab initio study. AB - Based on the new ab initio molecular dynamics method by Kuhne et al. [Phys. Rev. Lett. 98, 066401 (2007)10.1103/PhysRevLett.98.066401], we studied the mechanism of superionic conduction in substoichiometric Li-poor Li_{1+x}Al alloys by performing simulations at different temperatures for an overall simulation time of about 1 ns. The dynamical simulations revealed the microscopic path for the diffusion of Li vacancies. The calculated activation energy (0.11 eV) and the prefactor (D_{0} = 6.9 x 10;{-4} cm;{2}/s) for Li diffusivity via a vacancy mediated mechanism are in good agreement with experimental NMR data. The calculation of the formation energies of different defects-Li and Al Frenkel pair and Li antisites-revealed that only Li;{+} vacancies and Li_{Al} antisites are present in the stability range of the Zintl phase -0.1 < x < 0.2. PMID- 19792447 TI - Thermal conductivity of MgO periclase from equilibrium first principles molecular dynamics. AB - A method is presented by which the lattice thermal conductivity can be computed from first principles using relatively small system sizes and simulation times. The method uses the relation for thermal conductivity of a kinetic gas, with phonon lifetimes and frequencies determined by combining equilibrium first principles molecular dynamics and first principles lattice dynamics. To illustrate the method, the lattice conductivity is computed for MgO periclase. For individual wave vectors and vibrational modes, phonon lifetimes in periclase are found to be inversely proportional to temperature, with optic modes shorter lived than acoustic modes, contributing only approximately 5% to the lattice conductivity. Computed thermal conductivity values show excellent agreement with experimental measurements, and suggest that the radiative contribution to thermal transport in periclase starts playing a role above approximately 1500 K. PMID- 19792448 TI - Atomic structure imaging beyond conventional resolution limits in the transmission electron microscope. AB - Transmission electron microscopy is an extremely powerful technique for direct characterization of local structure at the atomic scale. However, the resolution of this technique is fundamentally limited by the partial coherence of the electron beam. In this Letter we demonstrate a method that extends the ultimate resolution of the latest generation of aberration corrected transmission electron microscopes by 41% relative to that achievable using conventional axial imaging. Experimental results verify that a real space resolution of 78 pm has been achieved at 200 kV. PMID- 19792449 TI - Critical metal phase at the Anderson metal-insulator transition with Kondo impurities. AB - It is well known that magnetic impurities can change the symmetry class of disordered metallic systems by breaking spin and time-reversal symmetry. At low temperature, these symmetries can be restored by Kondo screening. It is also known that at the Anderson metal-insulator transition, wave functions develop multifractal fluctuations with power-law correlations. Here, we consider the interplay of these two effects. We show that multifractal correlations open local pseudogaps at the Fermi energy at some random positions in space. When dilute magnetic impurities are at these locations, Kondo screening is strongly suppressed. When the exchange coupling J is smaller than a certain value J;{*}, the metal-insulator transition point extends to a critical region in the disorder strength parameter and to a band of critical states. PMID- 19792450 TI - Density enhanced diffusion of dipolar excitons within a one-dimensional channel. AB - We experimentally investigate the lateral diffusion of dipolar excitons in coupled quantum wells in two (2D) and one (1D) dimensions. In 2D, the exciton expansion obeys nonlinear temporal dynamics due to the repulsive dipole pressure at a high exciton density, in accordance with recent reports. In contrast, the observed 1D expansion behaves linearly in time even at high exciton densities. The corresponding 1D diffusion coefficient exceeds the one in 2D by far and depends linearly on the exciton density. We attribute the findings to screening of quantum well disorder by the dipolar excitons. PMID- 19792451 TI - Slow relaxations and aging in the electron glass. AB - Glassy systems are ubiquitous in nature. They are characterized by slow relaxations to equilibrium without a typical time scale, aging, and memory effects. Understanding this has been a long-standing problem in physics. We study the aging of the electron glass, a system showing remarkable slow relaxations of the conductance. We find that the appropriate broad distribution of relaxation rates leads to a universal relaxation of the form log(1 + t_{w}/t) for the common aging protocol, where t_{w} is the length of time the perturbation driving the system out of equilibrium was on, and t the time of measurement. These results agree well with several experiments performed on different glassy systems, and examining different physical observables, for times ranging from seconds to several hours. The suggested theoretical framework appears to offer a paradigm for aging in a broad class of glassy materials. PMID- 19792452 TI - dc conductivity of an array of Josephson junctions in the insulating state. AB - We consider microscopically low-temperature transport in weakly disordered arrays of Josephson junctions in the Coulomb blockade regime. We demonstrate that at sufficiently low temperatures the main contribution to the dc conductivity comes from the motion of single-Cooper-pair excitations, scattered by irregularities in the array. Being proportional to the concentration of the excitations, the conductivity is exponentially small in temperature with the activation energy close to the charging energy of a Cooper pair on a superconductive island. Applying a diagrammatic approach to treat the disorder potential we calculate the Drude-like conductivity and obtain weak localization corrections. At sufficiently low temperatures or strong disorder the Anderson localization of Cooper pairs ensues. PMID- 19792453 TI - Magnetic-field-induced superconducting state in Zn nanowires driven in the normal state by an electric current. AB - Four-terminal resistance measurements have been carried out on Zn nanowires formed using electron-beam lithography. When driven resistive by current, these wires reenter the superconducting state upon application of small magnetic fields. The data are qualitatively different from those of previous experiments on superconducting nanowires, which revealed either negative magnetoresistance near T_{c} or high-magnetic-field-enhanced critical currents. PMID- 19792454 TI - Evidence for a nodal energy gap in the iron-pnictide superconductor LaFePO from penetration depth measurements by scanning SQUID susceptometry. AB - We measure changes in the penetration depth lambda of the T_{c} approximately 6 K superconductor LaFePO. In the process, scanning SQUID susceptometry is demonstrated as a technique for accurately measuring local temperature-dependent changes in lambda, ideal for studying early or difficult-to-grow materials. lambda is found to vary linearly with temperatures from 0.36 to approximately 2 K, with a slope of 143 +/- 15 A/K, suggesting line nodes in the superconducting order parameter. The linear dependence up to approximately T_{c}/3, similar to the cuprate superconductors, indicates well-developed nodes. PMID- 19792455 TI - Exchange bias driven by the Dzyaloshinskii-Moriya interaction and ferroelectric polarization at G-type antiferromagnetic perovskite interfaces. AB - Exchange bias is usually rationalized invoking spin pinning effects caused by uncompensated antiferromagnetic interfaces. However, for compensated antiferromagnets other extrinsic factors, such as interface roughness or spin canting, have to be considered to produce a small uncompensation. As an alternative, here we propose two (related) possible mechanisms, driven by the intrinsic Dzyaloshinskii-Moriya interaction and ferroelectric polarization, for the explanation of exchange bias effects in perovskites with compensated G-type antiferromagnetism. One of the mechanisms is only active when a multiferroic material is involved and it is controllable by electric fields. PMID- 19792456 TI - Magnetization reversal of nanoscale islands: how size and shape affect the arrhenius prefactor. AB - The thermal switching behavior of individual in-plane magnetized Fe/W(110) nanoislands is investigated by a combined study of variable-temperature spin polarized scanning tunneling microscopy and Monte Carlo simulations. Even for islands consisting of less than 100 atoms the magnetization reversal takes place via nucleation and propagation. The Arrhenius prefactor is found to strongly depend on the individual island size and shape, and based on the experimental results a simple model is developed to describe the magnetization reversal in terms of metastable states. Complementary Monte Carlo simulations confirm the model and provide new insight into the microscopic processes involved in magnetization reversal of smallest nanomagnets. PMID- 19792457 TI - Control of the strong light-matter interaction between an elongated In_{0.3}Ga_{0.7}As quantum dot and a micropillar cavity using external magnetic fields. AB - We have studied a strongly coupled quantum dot-micropillar cavity system subject to an external magnetic field. The large diamagnetic response of elongated In_{0.3}Ga_{0.7}As quantum dots is exploited to demonstrate magneto-optical resonance tuning in the strong coupling regime. Furthermore, the magnetic field provides an additional degree of freedom to in situ manipulate the coupling constant. A transition from strong coupling towards the critical coupling regime is attributed to a reduction of the quantum dot oscillator strength when the magnetic confinement becomes significant with regards to the exciton confinement above 3 T. PMID- 19792458 TI - Vortexlike topological defects in nematic colloids: chiral colloidal dimers and 2D crystals. AB - We show that chiral ordering of the underlying complex fluid strongly influences defect formation and colloidal interactions. Nonsingular defect loops with a topological charge -2 are observed, with a cross section identical to hyperbolic vortices in magnetic systems. These loops are binding spontaneously formed pairs of colloidal particles and dimers, which are chiral objects. Chiral dimer-dimer interaction weakly depends on the chirality of dimers and leads to the assembly of 2D nematic colloidal crystals of pure or "mixed" chirality, intercalated with a lattice of nonsingular vortexlike defects. PMID- 19792459 TI - Creep motion of an intruder within a granular glass close to jamming. AB - We experimentally study the dynamics of an intruder dragged at a constant force in a horizontally vibrated monolayer of grains. At moderate packing fractions, the intruder moves rapidly as soon as the force is applied. Above some threshold value it has an intermittent creep motion with strong fluctuations reminiscent of "crackling noise". These fluctuations are critical at the jamming transition varphi_{J} unveiled in a previous study. The transition separates a regime with local free volume rearrangements from a regime where the displacement field is strongly heterogeneous and resembles force chain patterns. PMID- 19792460 TI - Transition by intermittency in granular matter: from discontinuous avalanches to continuous flow. AB - We investigate, in the rotating drum configuration, the transition from the regime of discontinuous avalanches observed at low angular velocity to the regime of continuous flow observed at higher velocity. Instead of the hysteretic transition reported previously by Rajchenbach [Phys. Rev. Lett. 65, 2221 (1990)], with an apparent bistability of the two flow regimes in a range of drum velocities, we observe intermittency with spontaneous erratic switches from one regime to the other. Both scenarios of transition are recovered by a model dynamic equation for the avalanche flow with two sources of stochasticity: a Langevin noise during the avalanche flow and a distributed maximal stability angle at which avalanches start. PMID- 19792461 TI - Driven front propagation in 1D spatially periodic media. AB - We study front propagation in one-dimensional spatially periodic media. Based on an optical feedback with a spatially amplitude modulated beam, we set up a one dimensional forced experiment in a nematic liquid crystal cell. By changing the forcing parameters, the front exhibits a pinning effect and oscillatory motion, which are confirmed by numerical simulations for the average liquid crystal tilt angle. A spatially forced dissipative varphi;{4} model, derived at the onset of bistability, accounts qualitatively for the observed dynamics. PMID- 19792462 TI - Magnetic wire traps and programmable manipulation of biological cells. AB - We present a multiplex method, based on microscopic programmable magnetic traps in zigzag wires patterned on a platform, to simultaneously apply directed forces on multiple fluid-borne cells or biologically inert magnetic microparticles or nanoparticles. The gentle tunable forces do not produce damage and retain cell viability. The technique is demonstrated with T-lymphocyte cells remotely manipulated (by a joystick) along desired trajectories on a silicon surface with average speeds up to 20 microm/s. PMID- 19792463 TI - Quantized ionic conductance in nanopores. AB - Ionic transport in nanopores is a fundamentally and technologically important problem in view of its occurrence in biological processes and its impact on novel DNA sequencing applications. Using molecular dynamics simulations we show that ion transport may exhibit strong nonlinearities as a function of the pore radius reminiscent of the conductance quantization steps as a function of the transverse cross section of quantum point contacts. In the present case, however, conductance steps originate from the break up of the hydration layers that form around ions in aqueous solution. We discuss this phenomenon and the conditions under which it should be experimentally observable. PMID- 19792464 TI - Effects of jamming on nonequilibrium transport times in nanochannels. AB - Many biological channels perform highly selective transport without direct input of metabolic energy and without transitions from a "closed" to an "open" state during transport. Mechanisms of selectivity of such channels serve as an inspiration for creation of artificial nanomolecular sorting devices and biosensors. To elucidate the transport mechanisms, it is important to understand the transport on the single molecule level in the experimentally relevant regime when multiple particles are crowded in the channel. In this Letter we analyze the effects of interparticle crowding on the nonequilibrium transport times through a finite-length channel by means of analytical theory and computer simulations. PMID- 19792465 TI - Protein-protein interaction in purple membrane. AB - We present experimental evidence for a long-range protein-protein interaction in purple membrane (PM). The interprotein dynamics were quantified by measuring the spectrum of the acoustic phonons in the 2D bacteriorhodopsin (BR) protein lattice using inelastic neutron scattering. Phonon energies of about 1 meV were determined. The data are compared to an analytical model, and the effective spring constant for the interaction between neighboring protein trimers are determined to be k = 53 N/m. Additional, optical-like excitations at 0.45 meV were found and assigned to intraprotein dynamics between neighboring BR monomers. PMID- 19792467 TI - Universality of state-independent violation of correlation inequalities for noncontextual theories. AB - We show that the state-independent violation of inequalities for noncontextual hidden variable theories introduced in [Phys. Rev. Lett. 101, 210401 (2008)] is universal, i.e., occurs for any quantum mechanical system in which noncontextuality is meaningful. We describe a method to obtain state-independent violations for any system of dimension d> or =3. This universality proves that, according to quantum mechanics, there are no "classical" states. PMID- 19792468 TI - Noise-immune conjugate large-area atom interferometers. AB - We present a pair of simultaneous conjugate Ramsey-Borde atom interferometers using large (20variant Planck's over 2pik)-momentum transfer beam splitters, where variant Planck's over 2pik is the photon momentum. Simultaneous operation allows for common-mode rejection of vibrational noise. This allows us to surpass the enclosed space-time area of previous interferometers with a splitting of 20variant Planck's over 2pik by a factor of 2500. Using a splitting of 10variant Planck's over 2pik, we demonstrate a 3.4 ppb resolution in the measurement of the fine structure constant. Examples for applications in tests of fundamental laws of physics are given. PMID- 19792469 TI - Non-markovian quantum trajectories: an exact result. AB - We analyze the non-Markovian stochastic Schrodinger equation describing a particle subject to spontaneous collapses in space (in the language of collapse models), or subject to a continuous measurement of its position (in the language of continuous quantum measurement). For the first time, we give the explicit general solution for the free particle case (H=p(2)/2m) and discuss the main properties. We analyze the case of an exponential correlation function for the noise, giving a quantitative description of the dynamics and of its dependence on the correlation time. PMID- 19792470 TI - Optimal cloning and singlet monogamy. AB - The inability to produce two perfect copies of an unknown state is inherently linked with the inability to produce maximal entanglement between multiple spins. Despite this, there is no quantitative link between how much entanglement can be generated between spins, and how well an unknown state can be cloned. This situation is remedied by giving a set of sufficient conditions such that a Completely Positive map can be optimally implemented as a teleportation operation into a standard, reference, state. The case of arbitrary 1-->N asymmetric cloning of d-dimensional spins can then be solved exactly, yielding the concept of "singlet monogamy." The utility of this relation is demonstrated by calculating properties of Heisenberg systems, and contrasting them with the results from standard monogamy arguments. PMID- 19792471 TI - Quantum adiabatic computation with a constant gap is not useful in one dimension. AB - We show that it is possible to use a classical computer to efficiently simulate the adiabatic evolution of a quantum system in one dimension with a constant spectral gap, starting the adiabatic evolution from a known initial product state. The proof relies on a recently proven area law for such systems, implying the existence of a good matrix product representation of the ground state, combined with an appropriate algorithm to update the matrix product state as the Hamiltonian is changed. This implies that adiabatic evolution with such Hamiltonians is not useful for universal quantum computation. Therefore, adiabatic algorithms which are useful for universal quantum computation either require a spectral gap tending to zero or need to be implemented in more than one dimension (we leave open the question of the computational power of adiabatic simulation with a constant gap in more than one dimension). PMID- 19792472 TI - Quantum computation in correlation space and extremal entanglement. AB - Recently, a framework was established to systematically construct novel universal resource states for measurement-based quantum computation using techniques involving finitely correlated states. With these methods, universal states were found which are in certain ways much less entangled than the original cluster state model, and it was hence believed that with this approach, many of the extremal entanglement features of the cluster states could be relaxed. The new resources were constructed as "computationally universal" states-i.e., they allow one to efficiently reproduce the classical output of each quantum computation whereas the cluster states are universal in a stronger sense since they are "universal state preparators." Here, we show that the new resources are universal state preparators after all, and must therefore exhibit a whole class of extremal entanglement features, similar to the cluster states. PMID- 19792473 TI - Phase measurements of barrier crossings in a periodically modulated double-well potential. AB - We report on the experimental observation of the phase angle of a particle escaping over a periodically modulated potential barrier. Optical tweezers and back-focal plane position detection were used to record particle trajectories in the entire double-well potential. These measurements provide a sensitive test of theories proposed in the past decade of escape driven by random thermal noise from a periodically modulated potential. The observed phase shifts as a function of modulation frequency are consistent with those calculated using existing theories. PMID- 19792474 TI - Novel low-temperature behavior in classical many-particle systems. AB - We show that classical many-particle systems interacting with certain soft pair interactions in two dimensions exhibit novel low-temperature behaviors. Ground states span from disordered to crystalline. At some densities, a large fraction of normal-mode frequencies vanish. Lattice ground-state configurations have more vanishing frequencies than disordered ground states at the same density and exhibit vanishing shear moduli. For the melting transition from a crystal, the thermal expansion coefficient is negative. These unusual results are attributed to the topography of the energy landscape. PMID- 19792475 TI - Trajectory approach to two-state kinetics of single particles on sculpted energy landscapes. AB - We study the trajectories of a single colloidal particle as it hops between two energy wells which are sculpted using optical traps. Whereas the dynamical behaviors of such systems are often treated by master-equation methods that focus on particles as actors, we analyze them instead using a trajectory-based variational method called maximum caliber (MaxCal). We show that the MaxCal strategy accurately predicts the full dynamics that we observe in the experiments: From the observed averages, it predicts second and third moments and covariances, with no free parameters. The covariances are the dynamical equivalents of Maxwell-like equilibrium reciprocal relations and Onsager-like dynamical relations. PMID- 19792476 TI - Theory of inelastic electron tunneling from a localized spin in the impulsive approximation. AB - A simple expression for the conductance steps in inelastic electron tunneling from spin excitations in a single magnetic atom adsorbed on a nonmagnetic metal surface is derived. The inelastic coupling between the tunneling electron and the spin is via the exchange coupling and is treated in an impulsive approximation using the Tersoff-Hamann approximation for the tunneling between the tip and the sample. PMID- 19792477 TI - TeV gamma rays from Geminga and the origin of the GeV positron excess. AB - The Geminga pulsar has long been one of the most intriguing MeV-GeV gamma-ray point sources. We examine the implications of the recent Milagro gamma-ray Observatory detection of extended, multi-TeV gamma-ray emission from Geminga, finding that this reveals the existence of an ancient, powerful cosmic-ray accelerator that can plausibly account for the multi-GeV positron excess that has evaded explanation. We explore a number of testable predictions for gamma-ray and electron or positron experiments (up to approximately 100 TeV) that can confirm the first "direct" detection of a cosmic-ray source. PMID- 19792478 TI - Identifying nearby accelerators of ultrahigh energy cosmic rays using ultrahigh energy (and very high energy) photons. AB - Ultrahigh energy photons (UHE, E>10(19) eV) are inevitably produced during the propagation of approximately 10(20) eV protons in extragalactic space. Their short interaction lengths (<20 Mpc) at these energies, combined with the impressive sensitivity of the Pierre Auger Observatory detector to these particles, makes them an ideal probe of nearby ultrahigh energy cosmic ray (UHECR) sources. We here discuss the particular case of photons from a single nearby (within 30 Mpc) source in light of the possibility that such an object might be responsible for several of the UHECR events published by the Auger collaboration. We demonstrate that the photon signal accompanying a cluster of a few >6 x 10(19) eV UHECRs from such a source should be detectable by Auger in the near future. The detection of these photons would also be a signature of a light composition of the UHECRs from the nearby source. PMID- 19792480 TI - Origin of the positron excess in cosmic rays. AB - We show that the positron excess measured by the PAMELA experiment in the region between 10 and 100 GeV may well be a natural consequence of the standard scenario for the origin of Galactic cosmic rays. The "excess" arises because of positrons created as secondary products of hadronic interactions inside the sources, but the crucial physical ingredient which leads to a natural explanation of the positron flux is the fact that the secondary production takes place in the same region where cosmic rays are being accelerated. Therefore secondary positrons (and electrons) participate in the acceleration process and turn out to have a very flat spectrum, which is responsible, after propagation in the Galaxy, for the observed positron excess. This effect cannot be avoided though its strength depends on the values of the environmental parameters during the late stages of evolution of supernova remnants. PMID- 19792479 TI - New limits on the ultrahigh energy cosmic neutrino flux from the ANITA experiment. AB - We report initial results of the first flight of the Antarctic Impulsive Transient Antenna (ANITA-1) 2006-2007 Long Duration Balloon flight, which searched for evidence of a diffuse flux of cosmic neutrinos above energies of E(nu) approximately 3 x 10(18) eV. ANITA-1 flew for 35 days looking for radio impulses due to the Askaryan effect in neutrino-induced electromagnetic showers within the Antarctic ice sheets. We report here on our initial analysis, which was performed as a blind search of the data. No neutrino candidates are seen, with no detected physics background. We set model-independent limits based on this result. Upper limits derived from our analysis rule out the highest cosmogenic neutrino models. In a background horizontal-polarization channel, we also detect six events consistent with radio impulses from ultrahigh energy extensive air showers. PMID- 19792481 TI - Multiple spectral splits of supernova neutrinos. AB - Collective oscillations of supernova neutrinos swap the spectra f(nu(e))(E) and f(nu[over ](e))(E) with those of another flavor in certain energy intervals bounded by sharp spectral splits. This phenomenon is far more general than previously appreciated: typically one finds one or more swaps and accompanying splits in the nu and nu[over ] channels for both inverted and normal neutrino mass hierarchies. Depending on an instability condition, swaps develop around spectral crossings (energies where f(nu(e))=f(nu(x)), f(nu[over ](e))=f(nu[over ](x)) as well as E-->infinity where all fluxes vanish), and the widths of swaps are determined by the spectra and fluxes. Washout by multiangle decoherence varies across the spectrum and splits can survive as sharp spectral features. PMID- 19792482 TI - Size bias in galaxy surveys. AB - Only certain galaxies are included in surveys: those bright and large enough to be detectable as extended sources. Because gravitational lensing can make galaxies appear both brighter and larger, the presence of foreground inhomogeneities can scatter galaxies across not only magnitude cuts but also size cuts, changing the statistical properties of the resulting catalog. Here we explore this size bias and how it combines with magnification bias to affect galaxy statistics. We demonstrate that photometric galaxy samples from current and upcoming surveys can be even more affected by size bias than by magnification bias. PMID- 19792483 TI - Pseudoscalar perturbations and polarization of the cosmic microwave background. AB - We show that models of new particle physics containing massless pseudoscalar fields superweakly coupled to photons can be very efficiently probed with CMB polarization anisotropies. The stochastic pseudoscalar fluctuations generated during inflation provide a mechanism for converting E-mode polarization to B-mode during photon propagation from the surface of last scattering. The efficiency of this conversion process is controlled by the dimensionless ratio H/(2pif(a)), where H is the Hubble scale during inflation, and f(a)-1 is the strength of the pseudoscalar coupling to photons. The current observational limits on the B mode constrain this ratio to be less than 0.07, which in many models of inflation translates to a sensitivity to f(a) exceeding 10(14) GeV, which surpasses other tests. PMID- 19792484 TI - Central charge of supersymmetric 5D anti-de sitter space solutions of type IIB supergravity. AB - We show that generic supersymmetric 5D anti-de Sitter solutions of type IIB supergravity admit a canonical contact structure. This structure determines the central charge of the dual field theory and the conformal dimension of operators dual to supersymmetric wrapped D3-branes. Hence both quantities can be calculated using incomplete information about the solutions, allowing us to prove that they are rational numbers for solutions with a U(1) R symmetry, in agreement with field theory expectations. We also discuss related Duistermaat-Heckman integrals and localization formulas. PMID- 19792485 TI - Measuring a long-range dark matter force at the Large Hadron Collider. AB - A long-range "dark force" has recently been proposed to mediate the dark matter (DM) annihilation. If DM particles are copiously produced at the Large Hadron Collider, the light dark force mediator will also be produced through radiation. We demonstrate how and how precise we can utilize this fact to measure the coupling constant of the dark force. The light mediator's mass is measured for the "lepton jet" to which it decays. In addition, the mass of the DM particle is determined using the m(T2) technique. Knowing these quantities is critical for calculating the DM relic density. PMID- 19792486 TI - New precise measurement of the pion weak form factors in pi+-->e+ nugamma decay. AB - We have measured the pi+-->e+ nugamma branching ratio over a wide region of phase space, based on a total of 65 460 events acquired using the PIBETA detector. Minimum-chi2 fits to the measured (E(e+), E(gamma) energy distributions result in the weak form factor value of F(A)=0.0119(1) with a fixed value of F(V)=0.0259. An unconstrained fit yields F(V)=0.0258(17) and F(A)=0.0117(17). In addition, we have measured a=0.10(6) for the dependence of F(V) on q2, the e+ nu pair invariant mass squared, parametrized as F(V)(q2)=F(V)(0)(1+aq(2)). The branching ratio for the kinematic region E(gamma)>10 MeV and theta(e(+)gamma)>40 degrees is measured to be B(expt)=73.86(54)x10(-8). Earlier deviations we reported in the high-E(gamma)-low-E(e+) kinematic region are resolved without a tensor term. We also derive new values for the pion polarizability alpha(E)=2.78(10)x10(-4) fm3 and neutral pion lifetime tau(pi0)=(8.5+/-1.1)x10(-17) s. PMID- 19792488 TI - Collins function and the single transverse spin asymmetry. AB - We study the Collins mechanism for the single transverse spin asymmetry in the collinear factorization approach. The corresponding twist-three fragmentation function is identified. We show that the Collins function calculated in this approach is universal. We further examine its contribution to the single transverse spin asymmetry of semi-inclusive hadron production in deep inelastic scattering and demonstrate that the transverse momentum dependent and twist-three collinear approaches are consistent in the intermediate transverse momentum region where both apply. PMID- 19792489 TI - Beam-helicity asymmetries in double-pion photoproduction off the proton. AB - Beam-helicity asymmetries have been measured at the MAMI accelerator in Mainz in the three isospin channels gamma[over -->]p-->pi(+)pi(0)n, gamma[over -->]p- >pi(0)pi(0)p, and gamma[over -->]p-->pi(+)pi(-)p. The circularly polarized photons, produced from bremsstrahlung of longitudinally polarized electrons, were tagged with the Glasgow magnetic spectrometer. Charged pions and the decay photons of pi(0) mesons were detected in a 4pi electromagnetic calorimeter which combined the Crystal Ball detector with the TAPS detector. The precisely measured asymmetries are very sensitive to details of the production processes and are thus key observables in the modeling of the reaction dynamics. PMID- 19792490 TI - Deconfinement phase transition and the quark condensate. AB - We study the dual quark condensate as a signal for the confinement-deconfinement phase transition of QCD. This order parameter for center symmetry has been defined recently by Bilgici et al. within the framework of lattice QCD. In this work we determine the ordinary and the dual quark condensate with functional methods using a formulation of the Dyson-Schwinger equations for the quark propagator on a torus. The temperature dependence of these condensates serves to investigate the interplay between the chiral and deconfinement transitions of quenched QCD. PMID- 19792491 TI - Shear viscosity coefficient and relaxation time of causal dissipative hydrodynamics in QCD. AB - The shear viscosity coefficient and the corresponding relaxation time for causal dissipative hydrodynamics are calculated based on the microscopic formula proposed in T. Koide and T. Kodama [Phys. Rev. E 78, 051107 (2008)10.1103/PhysRevE.78.051107]. Here, the exact formula is transformed into a more compact form and applied to evaluate these transport coefficients in the chiral perturbation theory and perturbative QCD. It is shown that in the leading order calculation, the causal shear viscosity coefficient eta reduces to that of the ordinary Green-Kubo-Nakano formula, and the relaxation time tau(pi) is related to eta and pressure P by a simple relationship, tau(pi)=eta/P. PMID- 19792492 TI - Coherent contributions to isospin mixing in the mirror pair 67As and 67Se. AB - Isospin symmetry breaking has been investigated in mass A=67 mirror nuclei through the experimental determination of the E1 strengths of analog electromagnetic transitions. Lifetimes of excited states have been measured in (67)Se and (67)As with the centroid shift method. Through the comparison of the B(E1) strengths of the mirror 9/2(+)-->7/2(-) transitions, the isovector and the isoscalar components of the electromagnetic transition amplitude were extracted. The presence of a large isoscalar component provides evidence for coherent contributions to isospin mixing, probably involving the isovector giant monopole resonance. PMID- 19792493 TI - Three-dimensional momentum imaging of electron wave packet interference in few cycle laser pulses. AB - Using a reaction microscope, three-dimensional (3D) electron (and ion) momentum (P) spectra have been recorded for carrier-envelope-phase (CEP) stabilized few cycle ( approximately 5 fs), intense ( approximately 4 x 10(14) W/cm2) laser pulses (740 nm) impinging on He. Preferential emission of low-energy electrons (E(e)<15 eV) to either hemisphere is observed as a function of the CEP. Clear interference patterns emerge in P space at CEPs with maximum asymmetry, interpreted as attosecond interferences of rescattered and directly emitted electron wave packets by means of a simple model. PMID- 19792495 TI - Probing weakly bound molecules with nonresonant light. AB - We show that weakly bound molecules can be probed by "shaking" in a pulsed nonresonant laser field. The field introduces a centrifugal term which expels the highest vibrational level from the potential that binds it. Our numerical simulations applied to the Rb(2) and KRb Feshbach molecules indicate that shaking by feasible laser pulses can be used to accurately recover the square of the vibrational wave function and, by inversion, also the long-range part of the molecular potential. PMID- 19792494 TI - Metastable helium: a new determination of the longest atomic excited-state lifetime. AB - Exited atoms may relax to the ground state by radiative decay, a process which is usually very fast (of order nanoseconds). However, quantum-mechanical selection rules can prevent such rapid decay, in which case these "metastable" states can have lifetimes of order seconds or longer. In this Letter, we determine experimentally the lifetime of the longest-lived neutral atomic state-the first excited state of helium (the 2(3)S1 metastable state)-to the highest accuracy yet measured. We use laser cooling and magnetic trapping to isolate a cloud of metastable helium (He*) atoms from their surrounding environment, and measure the decay rate to the ground 1(1)S0 state via extreme ultraviolet (XUV) photon emission. This is the first measurement using a virtually unperturbed ensemble of isolated helium atoms, and yields a value of 7870(510) seconds, in excellent agreement with the predictions of quantum electrodynamic theory. PMID- 19792496 TI - Three-body dynamics in single ionization of atomic hydrogen by 75 keV proton impact. AB - Doubly differential cross sections for single ionization of atomic hydrogen by 75 keV proton impact have been measured and calculated as a function of the projectile scattering angle and energy loss. This pure three-body collision system represents a fundamental test case for the study of the reaction dynamics in few-body systems. A comparison between theory and experiment reveals that three-body dynamics is important at all scattering angles and that an accurate description of the role of the projectile-target-nucleus interaction remains a major challenge to theory. PMID- 19792497 TI - Indistinguishable photons from independent semiconductor nanostructures. AB - We demonstrate quantum interference between photons generated by the radiative decay processes of excitons that are bound to isolated fluorine donor impurities in ZnSe/ZnMgSe quantum-well nanostructures. The ability to generate single photons from these devices is confirmed by autocorrelation experiments, and the indistinguishability of photons emitted from two independent nanostructures is confirmed via a Hong-Ou-Mandel dip. These results indicate that donor impurities in appropriately engineered semiconductor structures can portray atomlike homogeneity and coherence properties, potentially enabling scalable technologies for future large-scale optical quantum computers and quantum communication networks. PMID- 19792487 TI - Measurement of semileptonic B decays into orbitally excited charmed mesons. AB - We present a study of B decays into semileptonic final states containing charged and neutral D1(2420) and D_{2};{*}(2460). The analysis is based on a data sample of 208 fb;{-1} collected at the Upsilon(4S) resonance with the BABAR detector at the PEP-II asymmetric-energy B factory at SLAC. With a simultaneous fit to four different decay chains, the semileptonic branching fractions are extracted from measurements of the mass difference Deltam=m(D;{**})-m(D) distributions. Product branching fractions are determined to be B(B;{+}- >D_{1};{0}l;{+}nu_{l})xB(D_{1};{0}-->D;{*+}pi;{-})=(2.97+/-0.17+/-0.17)x10;{-3}, B(B;{+}-->D_{2};{*0}l;{+}nu_{l})xB(D_{2};{*0}-->D;{(*)+}pi;{-})=(2.29+/-0.23+/ 0.21)x10;{-3}, B(B;{0}-->D_{1};{-}l;{+}nu_{l})xB(D_{1};{-}-->D;{*0}pi;{ })=(2.78+/-0.24+/-0.25)x10;{-3} and B(B;{0}-->D_{2};{*-}l;{+}nu_{l})xB(D_{2};{*-} ->D;{(*)0}pi;{-})=(1.77+/-0.26+/-0.11)x10;{-3}. In addition we measure the branching ratio Gamma(D_{2};{*}-->Dpi;{-})/Gamma(D_{2};{*}-->D;{(*)}pi;{ })=0.62+/-0.03+/-0.02. PMID- 19792498 TI - Vacuum Rabi splitting and strong-coupling dynamics for surface-plasmon polaritons and rhodamine 6G molecules. AB - We report on strong coupling between surface-plasmon polaritons (SPP) and Rhodamine 6G (R6G) molecules, with double vacuum Rabi splitting energies up to 230 and 110 meV. In addition, we demonstrate the emission of all three energy branches of the strongly coupled SPP-exciton hybrid system, revealing features of system dynamics that are not visible in conventional reflectometry. Finally, in analogy to tunable-Q microcavities, we show that the Rabi splitting can be controlled by adjusting the interaction time between waveguided SPPs and R6G deposited on top of the waveguide. The interaction time can be controlled with sub-fs precision by adjusting the length of the R6G area with standard lithography methods. PMID- 19792499 TI - Ultrahigh-Q tunable whispering-gallery-mode microresonator. AB - Typical microresonators exhibit a large frequency spacing between resonances and a limited tunability. This impedes their use in a large class of applications which require a resonance of the microresonator to coincide with a predetermined frequency. Here, we experimentally overcome this limitation with highly prolate shaped whispering-gallery-mode "bottle microresonators" fabricated from standard optical glass fibers. Our resonators combine an ultrahigh quality factor of 3.6 x 10(8), a small mode volume, and near-lossless fiber coupling, characteristic of whispering-gallery-mode resonators, with a simple and customizable mode structure enabling full tunability. PMID- 19792500 TI - Magneto-optical control of light collapse in bulk Kerr media. AB - The Cotton-Mouton (Voigt) and Faraday effects induce adjustable linear and circular birefringence in optical media with external magnetic fields. We consider these effects as a technique for magneto-optical control of the transmission of bimodal light beams through Kerr-nonlinear crystals. Numerical analysis suggests that a properly applied magnetic field may accelerate, delay, or arrest the collapse of (2+1)D beams. Experimentally, the magnetic collapse acceleration is demonstrated in a bulk yttrium iron garnet (YIG) crystal. PMID- 19792501 TI - Varying the effective refractive index to measure optical transport in random media. AB - We introduce a new approach for measuring both the effective medium and the transport properties of light propagation in heterogeneous media. Our method utilizes the conceptual equivalence of frequency variation with a change in the effective index of refraction. Experimentally, we measure intensity correlations via spectrally resolved refractive index tuning, controlling the latter via changes in the ambient pressure. Our experimental results perfectly match a generalized transport theory that incorporates the effective medium and predicts a precise value for the diffusion constant. Thus, we directly confirm the applicability of the effective medium concept in strongly scattering materials. PMID- 19792502 TI - Relativistic quantum scars. AB - The concentrations of wave functions about classical periodic orbits, or quantum scars, are a fundamental phenomenon in physics. An open question is whether scarring can occur in relativistic quantum systems. To address this question, we investigate confinements made of graphene whose classical dynamics are chaotic and find unequivocal evidence of relativistic quantum scars. The scarred states can lead to strong conductance fluctuations in the corresponding open quantum dots via the mechanism of resonant transmission. PMID- 19792503 TI - Localization of resonance eigenfunctions on quantum repellers. AB - We introduce a new phase space representation for open quantum systems. This is a very powerful tool to help advance in the study of the morphology of their eigenstates. We apply it to two different versions of a paradigmatic model, the baker map. This allows us to show that the long-lived resonances are strongly scarred along the shortest periodic orbits that belong to the classical repeller. Moreover, the shape of the short-lived eigenstates is also analyzed. Finally, we apply an antiunitary symmetry measure to the resonances that allows us to quantify their localization on the repeller. PMID- 19792504 TI - Random matrix ensembles associated with lax matrices. AB - A method to generate new classes of random matrix ensembles is proposed. Random matrices from these ensembles are Lax matrices of classically integrable systems with a certain distribution of momenta and coordinates. The existence of an integrable structure permits us to calculate the joint distribution of eigenvalues for these matrices analytically. Spectral statistics of these ensembles are quite unusual and in many cases give rigorously new examples of intermediate statistics. PMID- 19792505 TI - Soap films burst like flapping flags. AB - When punctured, a flat soap film bursts by opening a hole driven by liquid surface tension. The hole rim does not, however, remain smooth but soon develops indentations at the tip of which ligaments form, ultimately breaking and leaving the initially connex film into a mist of disjointed drops. We report on original observations showing that these indentations result from a flaglike instability between the film and the surrounding atmosphere inducing an oscillatory motion out of its plane. Just like a flag edge flaps in the wind, the film is successively accelerated on both sides perpendicularly to its plane, inducing film thickness modulations and centrifuging liquid ligaments that finally pinch off to form the observed spray. This effect exemplifies how the dynamics of fragile objects such as thin liquid films is sensitive to their embedding medium. PMID- 19792506 TI - Transition in localized pipe flow turbulence. AB - Direct numerical simulation of transitional pipe flow is carried out in a long computational domain in order to characterize the dynamics within the saddle region of phase space that separates laminar flow from turbulent intermittency. For Reynolds numbers ranging from Re=1800 to 2800, a shoot and bisection method is used to compute critical trajectories. The chaotic saddle or edge state approached by these trajectories is studied in detail. For Re< or =2000 the edge state and the corresponding intermittent puff are shown to share similar averaged global properties. For Re> or =2200, the puff length grows unboundedly whereas the edge state varies only little with Re. In this regime, transition is shown to proceed in two steps: first the energy grows to produce a localized turbulent patch, which then, during the second stage, spreads out to fill the pipe. PMID- 19792507 TI - Fully kinetic Fokker-Planck model of thermal smoothing in nonuniform laser-target interactions. AB - Using a fully kinetic 2D Fokker-Planck model, the generation and evolution of ion density perturbations from nonuniform laser deposition in a plasma slab have been studied. It is found that significant smoothing of the ion density perturbations from nonuniform optically smoothed single beam laser deposition can be achieved on hydrodynamic times scales over a range of scale sizes. In addition, it is observed that the Fokker-Planck model predicts more smoothing than the hydrodynamic Spitzer model. PMID- 19792508 TI - Radial spreading of drift-wave-zonal-flow turbulence via soliton formation. AB - The self-consistent spatiotemporal evolution of a drift-wave (DW) radial envelope and a zonal-flow (ZF) amplitude is investigated in a slab model. The stationary solution of the coupled partial differential equations in a simple limit yields the formation of DW-ZF soliton structures, which propagate radially with speed depending on the envelope peak amplitude. Additional interesting physics, e.g., the generation, destruction, collision, and reflection of solitons, as well as turbulence bursting can also be observed due to the effects of linear growth or damping, dissipation, equilibrium nonuniformities and soliton dynamics. The propagation of soliton causes significant radial spreading of DW turbulence and therefore can affect transport scaling with the system size by broadening of the turbulent region. The correspondence of the present analysis with the description of DW-ZF interactions in toroidal geometry is also discussed. PMID- 19792509 TI - Gyrokinetic simulations of turbulent transport in a ring dipole plasma. AB - Gyrokinetic flux-tube simulations of turbulent transport due to small-scale entropy modes are presented in a ring-dipole magnetic geometry relevant to the Columbia-MIT levitated dipole experiment (LDX) [J. Kesner, Plasma Phys. J. 23, 742 (1997)]. Far from the current ring, the dipolar magnetic field leads to strong parallel variations, while close to the ring the system becomes nearly uniform along circular magnetic field lines. The transport in these two limits are found to be quantitatively similar given an appropriate normalization based on the local out-board parameters. The transport increases strongly with the density gradient, and for small eta=L(n)/L(T)<<1, T(i) approximately T(e), and typical LDX parameters, can reach large levels. Consistent with linear theory, temperature gradients are stabilizing, and for T(i) approximately T(e) can completely cut off the transport when eta greater or similar to 0.6. PMID- 19792510 TI - Theory of filamentary plasma array formation in microwave breakdown at near atmospheric pressure. AB - Recently reported observations of filamentation during high power microwaves breakdown of near-atmospheric pressure gas are explained using a one-dimensional fluid model coupled to a theoretical wave-plasma model. This self-consistent treatment allows for time-dependent effects, plasma growth and diffusion, and partial absorption and reflection of waves. Simulation results, consistent with experiments, show the evolution of the plasma filaments spaced less than one quarter wavelength, the sequential discrete light emission propagating back toward the source, and the diffusion and decay of the plasma. The model allows examination of many features not easily obtained experimentally, including dependence on field strength and frequency, pressure, and gas composition, which influence the breakdown and emission properties, including the spacing and speed of propagation of the filaments. PMID- 19792511 TI - Depinning transition in the failure of inhomogeneous brittle materials. AB - The dynamics of cracks propagating in elastic inhomogeneous materials is investigated experimentally. The variations of the average crack velocity with the external driving force are measured for a brittle rock and shown to display two distinct regimes: an exponential law characteristic of subcritical propagation at a low driving force and a power law above a critical threshold. This behavior can be explained quantitatively by extending linear elastic fracture mechanics to disordered systems. In this description, the motion of a crack is analogous to the one of an elastic line driven in a random medium, and critical failure occurs when the external force is sufficiently large to depin the crack front from the heterogeneities of the material. PMID- 19792512 TI - Surface-decorated silicon nanowires: a route to high-ZT thermoelectrics. AB - Based on atomistic calculations of electron and phonon transport, we propose to use surface-decorated silicon nanowires for thermoelectric applications. Two examples of surface decorations are studied to illustrate the underlying ideas: nanotrees and alkyl functionalized silicon nanowires. For both systems we find (i) that the phonon conductance is significantly reduced compared to the electronic conductance leading to high thermoelectric figure of merit ZT, and (ii) for ultrathin wires, surface decoration leads to significantly better performance than surface disorder. PMID- 19792513 TI - Structural prediction and phase transformation mechanisms in calcium at high pressure. AB - High-pressure phase transformations of Ca are studied using the metadynamics method to explore the anharmonic free-energy surface, together with a genetic algorithm structural search method to identify lowest enthalpy structures. Disagreement between theory and experiment regarding the structure of Ca in the pressure range 32-119 GPa is partially resolved by the demonstration of different phase transition behavior at 300 K from that at low temperatures. A new lowest enthalpy I4(1)/amd structure is obtained with both methods with an estimated superconducting critical temperature in agreement with experiment. PMID- 19792514 TI - Hexatic and mesoscopic phases in a 2D quantum coulomb system. AB - We study the Wigner crystal melting in a two-dimensional quantum system of distinguishable particles interacting via the 1/r Coulomb potential. We use quantum Monte Carlo methods to calculate its phase diagram, locate the Wigner crystal region, and analyze its instabilities towards the liquid phase. We discuss the role of quantum effects in the critical behavior of the system, and compare our numerical results with the classical theory of melting, and the microemulsion theory of frustrated Coulomb systems. We find a Pomeranchuk effect much larger then in solid helium. In addition, we find that the exponent for the algebraic decay of the hexatic phase differs significantly from the Kosterilitz Thouless theory of melting. We search for the existence of mesoscopic phases and find evidence of metastable bubbles but no mesoscopic phase that is stable in equilibrium. PMID- 19792515 TI - Surface geometry of C(60) on Ag(111). AB - The geometry of adsorbed C(60) influences its collective properties. We report the first dynamical low-energy electron diffraction study to determine the geometry of a C(60) monolayer, Ag(111)-(2 square root of 3 x 2 square root of 3) 30 degrees -C(60), and related density functional theory calculations. The stable monolayer has C(60) molecules in vacancies that result from the displacement of surface atoms. C(60) bonds with hexagons down, with their mirror planes parallel to that of the substrate. The results indicate that vacancy structures are the rule rather than the exception for C(60) monolayers on close-packed metal surfaces. PMID- 19792516 TI - Compressive stress generation in sn thin films and the role of grain boundary diffusion. AB - Stress evolution in high mobility Sn thin films was measured during electrodeposition and electrochemical etching to understand the roles of grain boundary diffusion and surface conditions in controlling stress. During deposition, the stress reaches a steady-state compressive value that depends on the growth rate. When the deposition or etching conditions were changed abruptly, reversible transients were observed that depend on the film thickness. The results are interpreted in terms of a model based on diffusion of atoms into the grain boundary driven by the chemical potential at the surface. PMID- 19792517 TI - Accurate bulk properties from approximate many-body techniques. AB - For ab initio electronic structure calculations, the random-phase approximation to the correlation energy is supposed to be a suitable complement to the exact exchange energy. We show that lattice constants, atomization energies of solids, and adsorption energies on metal surfaces evaluated using this approximation are in very good agreement with experiment. Since the method is fairly efficient and handles ionic, metallic, and van der Waals bonded systems equally well, it is a very promising choice to improve upon density functional theory calculations, without resorting to more demanding diffusion Monte Carlo or quantum chemical methods. PMID- 19792518 TI - Ising versus XY anisotropy in frustrated R(2)Ti(2)O(7) compounds as "Seen" by Polarized Neutrons. AB - We studied the field induced magnetic order in R(2)Ti(2)O(7) pyrochlore compounds with either uniaxial (R=Ho, Tb) or planar (R=Er, Yb) anisotropy, by polarized neutron diffraction. The determination of the local susceptibility tensor {chi(parallel to),chi(perpendicular)} provides a universal description of the field induced structures in the paramagnetic phase (2-270 K), whatever the field value (1-7 T) and direction. Comparison of the thermal variations of chi(parallel to) and chi(perpendicular) with calculations using the rare earth crystal field shows that exchange and dipolar interactions must be taken into account. We determine the molecular field tensor in each case and show that it can be strongly anisotropic. PMID- 19792519 TI - Thermalization after an interaction quench in the Hubbard model. AB - We use nonequilibrium dynamical mean-field theory to study the time evolution of the fermionic Hubbard model after an interaction quench. Both in the weak coupling and in the strong-coupling regime the system is trapped in quasistationary states on intermediate time scales. These two regimes are separated by a sharp crossover at U(c)dyn=0.8 in units of the bandwidth, where fast thermalization occurs. Our results indicate a dynamical phase transition which should be observable in experiments on trapped fermionic atoms. PMID- 19792520 TI - Quasiparticle transformation during a metal-insulator transition in graphene. AB - Here we show, with simultaneous transport and photoemission measurements, that the graphene-terminated SiC(0001) surface undergoes a metal-insulator transition upon dosing with small amounts of atomic hydrogen. We find the room temperature resistance increases by about 4 orders of magnitude, a transition accompanied by anomalies in the momentum-resolved spectral function including a non-Fermi-liquid behavior and a breakdown of the quasiparticle picture. These effects are discussed in terms of a possible transition to a strongly (Anderson) localized ground state. PMID- 19792521 TI - Electron-spin beat susceptibility of excitons in semiconductor quantum wells. AB - Recent time-resolved differential transmission and Faraday rotation measurements of long-lived electron-spin coherence in quantum wells displayed intriguing parametric dependencies. For their understanding we formulate a microscopic theory of the optical response of a gas of optically incoherent excitons whose constituent electrons retain spin coherence, under a weak magnetic field applied in the quantum well's plane. We define a spin beat susceptibility and evaluate it in linear order of the exciton density. Our results explain the many-body physics underlying the basic features observed in the experimental measurements. PMID- 19792522 TI - Tailoring the interaction strength between gold particles and silica thin films via work function control. AB - The possibility to modify the adsorption properties of a porous silica/Mo(112) film by controlling its work function has been studied by a combined STM and density-functional theory approach. While the original film is inert towards metal adsorption, Au atoms and clusters can be stabilized on the surface after Li doping. The Li atoms penetrate the topmost silica layer and bind as Li+ cations at the metal-oxide interface, thereby reducing the oxide work function. This induces a charge transfer into Au adatoms, which in turn enables strong Au-silica interaction mediated by a polaronic distortion of the oxide lattice. PMID- 19792523 TI - Correlated coherent oscillations in coupled semiconductor charge qubits. AB - We study coherent dynamics of two spatially separated electrons in a coupled semiconductor double quantum dot (DQD). Coherent oscillations in one DQD are strongly influenced by electronic states of the other DQD, or the two electrons simultaneously tunnel in a correlated manner. The observed coherent oscillations are interpreted as various two-qubit operations. The results encourage searching quantum entanglement in electronic devices. PMID- 19792524 TI - Controlling polarization at insulating surfaces: quasiparticle calculations for molecules adsorbed on insulator films. AB - By means of quasiparticle-energy calculations in the G0W0 approach, we show for the prototypical insulator-semiconductor system NaCl/Ge(001) that polarization effects at the interfaces noticeably affect the excitation spectrum of molecules adsorbed on the surface of the NaCl films. The magnitude of the effect can be controlled by varying the thickness of the film, offering new opportunities for tuning electronic excitations in, e.g., molecular electronics or quantum transport. Polarization effects are visible even for the excitation spectrum of the NaCl films themselves, which has important implications for the interpretation of surface science experiments for the characterization of insulator surfaces. PMID- 19792525 TI - Hall effect and resistivity study of the magnetic transition, carrier content, and Fermi-Liquid Behavior in Ba(Fe(1-x) Co(x))(2)As(2). AB - The negative Hall constant R(H) measured all over the phase diagram of Ba(Fe(1-x) Co(x))(2)As(2) allows us to show that electron carriers always dominate the transport properties. The evolution of R(H) with x at low doping (x<2%) indicates that important band structure changes happen for x<2% prior to the emergence of superconductivity. For higher x, a change with T of the electron concentration is required to explain the low T variations of R(H), while the electron scattering rate displays the T(2) law expected for a Fermi liquid. The T=0 residual scattering is affected by Co disorder in the magnetic phase, but is rather dominated by incipient disorder in the paramagnetic state. PMID- 19792526 TI - Tetragonal-to-orthorhombic structural phase transition at 90 K in the superconductor Fe(1.01)Se. AB - In this Letter we show that superconducting Fe(1.01)Se undergoes a structural transition at 90 K from a tetragonal to an orthorhombic phase but that nonsuperconducting Fe(1.03)Se does not. High resolution electron microscopy at low temperatures further reveals an unexpected additional modulation of the crystal structure of the superconducting phase that involves displacements of the Fe atoms, and that the nonsuperconducting composition shows a different, complex nanometer-scale structural modulation. Finally, we show that magnetism is not the driving force for the phase transition in the superconducting phase. PMID- 19792527 TI - Spin polarization of half-quantum vortex in systems with equal spin pairing. AB - We present a variational analysis for a half-quantum vortex (HQV) in the equal spin-pairing superfluid state which, under suitable conditions, is believed to be realized in Sr(2)RuO(4) and (3)He-A. Our approach is based on a description of the HQV in terms of a BCS-like wave function with a spin-dependent boost. We predict a novel feature: the HQV, if stable, should be accompanied by a nonzero spin polarization. Such a spin polarization would exist in addition to the one induced by the Zeeman coupling to the external field and hence may serve as an indicator in experimental search for HQV. PMID- 19792528 TI - Fundamental thickness limit of itinerant ferromagnetic SrRuO(3) thin films. AB - We report on a fundamental thickness limit of the itinerant ferromagnetic oxide SrRuO(3) that might arise from the orbital-selective quantum confinement effects. Experimentally, SrRuO(3) films remain metallic even for a thickness of 2 unit cells (uc), but the Curie temperature T(C) starts to decrease at 4 uc and becomes zero at 2 uc. Using the Stoner model, we attributed the T(C) decrease to a decrease in the density of states (N(o)). Namely, in the thin film geometry, the hybridized Ru d(yz,zx) orbitals are terminated by top and bottom interfaces, resulting in quantum confinement and reduction of N(o). PMID- 19792529 TI - Switching a single spin on metal surfaces by a STM Tip: Ab Initio studies. AB - The exchange coupling between single 3d magnetic adatoms (Cr, Mn, Fe, and Co) adsorbed on a Cu(001) surface and a Cr STM tip is studied with ab initio calculations. We demonstrate that the spin direction of single adatoms can be controlled by varying the tip-substrate distance, and the sign of the exchange energy is determined by the competition of the direct and the indirect interactions between the tip and the adatom. Based on the spin-dependent transport calculations, we find a magnetoresistance of about 70% at short tip substrate distances. PMID- 19792530 TI - Spin-induced optical second harmonic generation in the centrosymmetric magnetic semiconductors EuTe and EuSe. AB - Spectroscopy of the centrosymmetric magnetic semiconductors EuTe and EuSe reveals spin-induced optical second harmonic generation (SHG) in the band gap vicinity at 2.1-2.4 eV. The magnetic field and temperature dependence demonstrates that the SHG arises from the bulk of the materials due to a novel type of nonlinear optical susceptibility caused by the magnetic dipole contribution combined with spontaneous or induced magnetization. This spin-induced susceptibility opens access to a wide class of centrosymmetric systems by harmonics generation spectroscopy. PMID- 19792531 TI - Control of the anomalous hall effect by doping in Eu(1-x)La(x)TiO(3) thin films. AB - The anomalous Hall effect (AHE) has been studied for epitaxial films of Eu(1 x)La(x)TiO(3), in which band filling can be controlled by doping x without undesired changes in magnetization. This system has a simple band structure near the conduction band bottom, which makes it possible to design the AHE. As expected, the anomalous Hall resistivity shows a nonmonotonic change as a function of the carrier density accompanied with the sign reversal around n=2.4 x 10(20) cm(-3). This opens a possibility to control the AHE by devising the material, structure, and doping level. PMID- 19792532 TI - Pressure induced critical behavior of ferromagnetic phase transition in Sm-Nd-Sr manganites. AB - We report on the hydrostatic pressure dependence of the order of ferromagnetic (FM) to paramagnetic (PM) phase transition in a (Sm(0.7)Nd(0.3))(0.52)Sr(0.48)MnO(3) single crystal. At ambient pressure, the system undergoes a first-order FM-PM phase transition at 146 K. The application of pressure increases the T(C), suppresses the hysteresis width, and thus makes the transition second order. We have analyzed the critical behavior associated with the second-order FM-PM transition in the presence of an external pressure (12.1 kbar) and obtained the critical exponents beta=0.358, gamma=1.297, and delta=4.536, which are close to those predicted for the three-dimensional Heisenberg system. Using these values of beta, gamma, and T(C) ( approximately 176 K), one can scale the magnetization data below and above T(C) following a single equation of state. PMID- 19792533 TI - Controlling the nonequilibrium interlayer exchange coupling in asymmetric magnetic tunnel junctions. AB - We predict an oscillatory bias behavior of the fieldlike spin torque, T(perpendicular), in magnetic tunnel junctions, which can be selectively controlled via the asymmetry in band filling between the ferromagnetic leads. This can lead to a linear or quadratic low-bias behavior, including tuning the bias-induced reversal of T(perpendicular). These findings reconcile the apparently contradictory experimental results recently reported in the literature. The underlying mechanism for the nonequilibrium interlayer exchange coupling (IEC) of noncollinear configurations is the interplay of four independent IEC for the majority- and minority-spin bands of the leads solely in the ferromagnetic configuration. PMID- 19792534 TI - Time-resolved formation of excitons and electron-hole droplets in si studied using terahertz spectroscopy. AB - We investigated the formation dynamics of excitons and electron-hole (e-h) droplets (EHDs) in Si by using broadband terahertz time-domain spectroscopy. The formation of indirect excitons in Si was studied by observing their 1S-2P transition. Changes in surface plasmon resonance of the EHDs showed a gradual condensation from homogeneous e-h plasma at e-h densities above the exciton-Mott transition. Excitonic correlations were shown to exist prior to EHD condensation even above the Mott density. PMID- 19792535 TI - Spatially resolved spectroscopic mapping of polarization reversal in polycrystalline ferroelectric films: crossing the resolution barrier. AB - The mesoscopic reversible and irreversible polarization dynamics in polycrystalline PZT thin film capacitors are studied using local spectroscopic mapping and macroscopic first-order reversal curve measurements. The transition from a regime of short range domain wall motion to the formation of mesoscopic clusters to complete switching is observed. The fractal dimension of the clusters is consistent with the random-bond disorder model. The combination of macroscopic and local measurements allows the characteristics length scales corresponding to the transition from Rayleigh to Preisach behaviors and onset of macroscopic averaging to be determined. PMID- 19792536 TI - Stochastic and spatial influences on drug-induced bifurcations in cardiac tissue culture. AB - The addition of a drug that specifically blocks a potassium channel in spontaneously beating aggregates of chick heart cells leads to complex bifurcations over time. A stochastic partial differential equation model based on discrete ionic currents recorded in these cells demonstrates that drug diffusion and noise can induce the coupled beats and bursting rhythms observed. These results provide further evidence that stochastic events at a subcellular level are needed to understand complex cardiac arrhythmias and play an important role in the onset of these arrhythmias. PMID- 19792537 TI - Hydrodynamics of cellular cortical flows and the formation of contractile rings. AB - We propose a mechanism for the formation of contractile rings and the apparition of a flow in the cortical layer of cells undergoing cytokinesis at the end of cell division or during the healing of a wound in the cortex of Xenopus eggs. We generalize the hydrodynamic active gel theory along the lines of thin shell theory of continuum elasticity to describe the cell cortex. As in liquid crystal physics, the flow couples to the orientation of the actin filaments. The cortical flow is driven by an increased density of myosin motors in the cortex, and orients the filaments to form the ring. PMID- 19792538 TI - Influence of complex exciton-phonon coupling on optical absorption and energy transfer of quantum aggregates. AB - We present a theory that efficiently describes the quantum dynamics of an electronic excitation that is coupled to a continuous, highly structured phonon environment. Based on a stochastic approach to non-Markovian open quantum systems, we develop a dynamical framework that allows us to handle realistic systems where a fully quantum treatment is desired yet the usual approximation schemes fail. The capability of the method is demonstrated by calculating spectra and energy transfer dynamics of mesoscopic molecular aggregates, elucidating the transition from fully coherent to incoherent transfer. PMID- 19792539 TI - Extracting renewable energy from a salinity difference using a capacitor. AB - Completely renewable energy can be produced by using water solutions of different salinity, like river water and sea water. Many different methods are already known, but development is still at prototype stage. Here I report a novel method, based on electric double-layer capacitor technology. Two porous electrodes, immersed in the salt solution, constitute a capacitor. It is first charged, then the salt solution is brought into contact with fresh water. The electrostatic energy increases as the salt concentration of the solution is reduced due to diffusion. This device can be used to turn sources of salinity difference into completely renewable sources of energy. An experimental demonstration is given, and performances and possible improvements are discussed. PMID- 19792540 TI - Random graphs with clustering. AB - We offer a solution to a long-standing problem in the theory of networks, the creation of a plausible, solvable model of a network that displays clustering or transitivity--the propensity for two neighbors of a network node also to be neighbors of one another. We show how standard random-graph models can be generalized to incorporate clustering and give exact solutions for various properties of the resulting networks, including sizes of network components, size of the giant component if there is one, position of the phase transition at which the giant component forms, and position of the phase transition for percolation on the network. PMID- 19792541 TI - Comment on "influence of the dzyaloshinskii-moriya exchange interaction on quantum phase interference of spins". PMID- 19792543 TI - Measurement of the short-range attractive force between Ge plates using a torsion balance. AB - We have measured the short-range attractive force between crystalline Ge plates, and found contributions from both the Casimir force and an electrical force possibly generated by surface patch potentials. Using a model of surface patch effects that generates an additional force due to a distance dependence of the apparent contact potential, the electrical force was parametrized using data at distances where the Casimir force is relatively small. Extrapolating this model, to provide a correction to the measured force at distances less than 5 microm, shows a residual force that is in agreement, within experimental uncertainty, with five models that have been used to calculate the Casimir force. PMID- 19792544 TI - Fragmented many-body ground states for scalar bosons in a single trap. AB - We investigate whether the many-body ground states of bosons in a generalized two mode model with localized inhomogeneous single-particle orbitals and anisotropic long-range interactions (e.g., dipole-dipole interactions) are coherent or fragmented. It is demonstrated that fragmentation can take place in a single trap for positive values of the interaction couplings, implying that the system is potentially stable. Furthermore, the degree of fragmentation is shown to be insensitive to small perturbations on the single-particle level. PMID- 19792545 TI - Heavy-light fermion mixtures at unitarity. AB - We investigate fermion pairing in the unitary regime for a mass ratio corresponding to a ;{6}Li-;{40}K mixture using quantum Monte Carlo methods. The ground-state energy and the average light- and heavy-particle excitation spectrum for the unpolarized superfluid state are nearly independent of the mass ratio. In the majority light system, the polarized superfluid is close to the energy of a phase separated mixture of nearly fully polarized normal and unpolarized superfluid. For a majority of heavy particles, we find an energy minimum for a normal state with a ratio of approximately 3ratio1 heavy to light particles. A slight increase in attraction to k_{F}a approximately 2.5 yields a ground state energy of nearly zero for this ratio. A cold unpolarized system in a harmonic trap at unitarity should phase separate into three regions, with a shell of unpolarized superfluid in the middle. PMID- 19792546 TI - Cosmic ray electrons and positrons from supernova explosions of massive stars. AB - We attribute the recently discovered cosmic ray electron and cosmic ray positron excess components and their cutoffs to the acceleration in the supernova shock in the polar cap of exploding Wolf-Rayet and red supergiant stars. Considering a spherical surface at some radius around such a star, the magnetic field is radial in the polar cap as opposed to most of 4pi (the full solid angle), where the magnetic field is nearly tangential. This difference yields a flatter spectrum, and also an enhanced positron injection for the cosmic rays accelerated in the polar cap. This reasoning naturally explains the observations. Precise spectral measurements will be the test, as this predicts a simple E;{-2} spectrum for the new components in the source, steepened to E;{-3} in observations with an E;{-4} cutoff. PMID- 19792547 TI - Scaling laws of turbulence and heating of fast solar wind: the role of density fluctuations. AB - Incompressible and isotropic magnetohydrodynamic turbulence in plasmas can be described by an exact relation for the energy flux through the scales. This Yaglom-like scaling law has been recently observed in the solar wind above the solar poles observed by the Ulysses spacecraft, where the turbulence is in an Alfvenic state. An analogous phenomenological scaling law, suitably modified to take into account compressible fluctuations, is observed more frequently in the same data set. Large-scale density fluctuations, despite their low amplitude, thus play a crucial role in the basic scaling properties of turbulence. The turbulent cascade rate in the compressive case can, moreover, supply the energy dissipation needed to account for the local heating of the nonadiabatic solar wind. PMID- 19792548 TI - Revising the predictions of inflation for the cosmic microwave background anisotropies. AB - We point out that, if quantum field renormalization is taken into account and the counterterms are evaluated at the Hubble-radius crossing time or few e-foldings after it, the predictions of slow-roll inflation for both the scalar and the tensorial power spectrum change significantly. This leads to a change in the consistency condition that relates the tensor-to-scalar amplitude ratio with spectral indices. A reexamination of the potentials varphi;{2} and varphi;{4} shows that both are compatible with five-year WMAP data. Only when the counterterms are evaluated at much larger times beyond the end of inflation does one recover the standard predictions. The alternative predictions presented here may soon come within the range of measurement of near-future experiments. PMID- 19792549 TI - Explanation of the central charge ratio 27/32 in four-dimensional renormalization group flows between superconformal theories. AB - We show that when a four-dimensional N = 2 superconformal field theory (SCFT) flows to an N = 1 SCFT via giving a mass to the adjoint chiral superfield in a vector multiplet with marginal coupling, the central charges a and c of the N = 2 theory are related to those of the N = 1 theory by a universal linear transformation as long as there are no accidental symmetries in the infrared. In the large N limit, this relationship implies that the central charges obey a_{IR}/a_{UV} = c_{IR}/c_{UV} = 27/32. This gives a physical explanation to many examples of this number found in the literature, and also suggests the existence of a flow between some theories not previously thought to be connected. PMID- 19792553 TI - Atmospheric, long baseline, and reactor neutrino data constraints on theta_{13}. AB - An atmospheric neutrino oscillation tool that uses full three-neutrino oscillation probabilities and a full three-neutrino treatment of the Mikheyev Smirnov-Wolfenstein effect, together with an analysis of the K2K, MINOS, and CHOOZ data, is used to examine the bounds on theta_{13}. The recent, more finely binned, Super-K atmospheric data are employed. For L/E_{nu} greater, similar 10;{4} km/GeV, we previously found significant linear in theta_{13} terms. This analysis finds theta_{13} bounded from above by the atmospheric data while bounded from below by CHOOZ. The origin of this result arises from data in the previously mentioned very long baseline region; here, matter effects conspire with terms linear in theta_{13} to produce asymmetric bounds on theta_{13}. Assuming CP conservation, we find theta_{13} = -0.07_{-0.11};{+0.18} (90% C.L.). PMID- 19792551 TI - Search for muon neutrino and antineutrino disappearance in MiniBooNE. AB - The MiniBooNE Collaboration reports a search for nu_{micro} and nu[over]_{micro} disappearance in the Deltam;{2} region of 0.5-40 eV;{2}. These measurements are important for constraining models with extra types of neutrinos, extra dimensions, and CPT violation. Fits to the shape of the nu_{micro} and nu[over]_{micro} energy spectra reveal no evidence for disappearance at the 90% confidence level (C.L.) in either mode. The test of nu[over]_{micro} disappearance probes a region below Deltam;{2} = 40 eV;{2} never explored before. PMID- 19792554 TI - Do gluons carry half of the nucleon momentum? AB - We examine the conventional picture that gluons carry about half of the nucleon momentum in the asymptotic limit. We show that this large fraction is due to an unsuitable definition of the gluon momentum in an interacting theory. If defined in a gauge-invariant and consistent way, the asymptotic gluon momentum fraction is computed to be only about one-fifth. This result suggests that the asymptotic limit of the nucleon spin structure should also be reexamined. A possible experimental test of our finding is discussed in terms of novel parton distribution functions. PMID- 19792555 TI - New features of shape coexistence in ;{152}Sm. AB - Excited states in ;{152}Sm have been investigated with the ;{152}Sm(n,n;{'}gamma) reaction. The lowest four negative-parity band structures have been characterized in detail with respect to their absolute decay properties. Specifically, a new K;{pi} = 0;{-} band has been assigned with its 1;{-} band head at 1681 keV. This newly observed band has a remarkable similarity in its E1 transition rates for decay to the first excited K;{pi} = 0;{+} band at 684 keV to the lowest K;{pi} = 0;{-} band and its decay to the ground-state band. Based on these decay properties, as well as energy considerations, this new band is assigned as a K;{pi} = 0;{-} octupole excitation based on the K;{pi} = 0_{2};{+} state. An emerging pattern of repeating excitations built on the 0_{2};{+} level similar to those built on the ground state may indicate that ;{152}Sm is a complex example of shape coexistence rather than a critical point nucleus. PMID- 19792556 TI - Time modulation of the K-shell electron capture decay rates of H-like heavy ions at GSI experiments. AB - According to experimental data at GSI, the rates of the number of daughter ions, produced by the nuclear K shell electron capture decays of the H-like heavy ions with one electron in the K shell, such as ;{140}Pr;{58+}, ;{142}Pm;{60+}, and ;{122}I;{52+}, are modulated in time with periods T_{EC} of the order of a few seconds, obeying an A scaling T_{EC} = A/20 s, where A is the mass number of the mother nuclei, and with amplitudes a_{d};{EC} approximately 0.21. We show that these data can be explained in terms of the interference of two massive neutrino mass eigenstates. The appearance of the interference term is due to overlap of massive neutrino mass eigenstate energies and of the wave functions of the daughter ions in two-body decay channels, caused by the energy and momentum uncertainties introduced by time differential detection of the daughter ions in GSI experiments. PMID- 19792557 TI - Solution of the center-of-mass problem in nuclear structure calculations. AB - The coupled-cluster wave function factorizes to a very good approximation into a product of an intrinsic wave function and a Gaussian for the center-of-mass coordinate. The width of the Gaussian is in general not identical to the oscillator length of the underlying single-particle basis. The quality of the separation can be verified by a simple procedure. PMID- 19792558 TI - Coherent rho;{0} photoproduction in bulk matter at high energies. AB - The momentum transfer Deltak required for a photon to scatter from a target and emerge as a rho;{0} decreases as the photon energy k rises. For k > 3 x 10;{14} eV, Deltak is small enough that the interaction cannot be localized to a single nucleus. At still higher energies, photons may coherently scatter elastically from bulk matter and emerge as a rho;{0}, in a manner akin to kaon regeneration. Constructive interference from the different nuclei coherently raises the cross section and the interaction probability rises linearly with energy. At energies above 10;{23} eV, coherent conversion is the dominant process; photons interact predominantly as rho;{0}. We compute the coherent scattering probabilities in slabs of lead, water, and rock, and discuss the implications of the increased hadronic interaction probabilities for photons on ultrahigh energy shower development. PMID- 19792559 TI - Spin-1/2 optical lattice clock. AB - We experimentally investigate an optical clock based on ;{171}Yb (I = 1/2) atoms confined in an optical lattice. We have evaluated all known frequency shifts to the clock transition, including a density-dependent collision shift, with a fractional uncertainty of 3.4 x 10;{-16}, limited principally by uncertainty in the blackbody radiation Stark shift. We measured the absolute clock transition frequency relative to the NIST-F1 Cs fountain clock and find the frequency to be 518 295 836 590 865.2(0.7) Hz. PMID- 19792560 TI - Probing electron correlation via attosecond xuv pulses in the two-photon double ionization of helium. AB - Recent experimental developments of high-intensity, short-pulse extreme ultraviolet light sources are enhancing our ability to study electron-electron correlations. We perform time-dependent calculations to investigate the so-called "sequential" regime (variant Planck's over 2piomega > 54.4 eV) in the two-photon double ionization of helium. We show that attosecond pulses allow us not only to probe but also to induce angular and energy correlations of the emitted electrons. The final momentum distribution reveals regions dominated by the Wannier ridge breakup scenario and by postcollision interaction. PMID- 19792550 TI - Search for next-to-minimal supersymmetric Higgs bosons in the h --> aa --> micromicromicromicro, micromicrotautau channels using pp[over] collisions at sqrt[s] = 1.96 TeV. AB - We report on a first search for production of the lightest neutral CP-even Higgs boson (h) in the next-to-minimal supersymmetric standard model, where h decays to a pair of neutral pseudoscalar Higgs bosons (a), using 4.2 fb;{-1} of data recorded with the D0 detector at Fermilab. The a bosons are required to either both decay to micro;{+}micro;{-} or one to micro;{+}micro;{-} and the other to tau;{+}tau;{-}. No significant signal is observed, and we set limits on its production as functions of M_{a} and M_{h}. PMID- 19792561 TI - Ultrafast nonradiative decay rates on metallic surfaces by comparing surface enhanced Raman and fluorescence signals of single molecules. AB - By the simultaneous observation of surface-enhanced Raman scattering and surface enhanced fluorescence signals from a single molecule, we can measure and quantify the modification of the total decay rate of emitters in very close proximity to metals, even down to adsorbed molecules. This modified decay rate is shown to be largely dominated by its nonradiative component, which would be extremely difficult to estimate with conventional approaches. The method provides an indirect measurement of ultrafast (approximately 25 fs) mechanisms, which would be impossible to gain with time-resolved spectroscopy of a single molecule. PMID- 19792562 TI - Nonlocal van der Waals density functional made simple. AB - We derive a nonlocal correlation functional that adequately describes van der Waals interactions not only in the asymptotic long-range regime but also at short range. Unlike its precursor, developed by Langreth, Lundqvist, and co-workers, the new functional has a simple analytic form, finite for all interelectron separations, well behaved in the slowly varying density limit, and generalized to spin-polarized systems. PMID- 19792563 TI - Strong coupling of a mechanical oscillator and a single atom. AB - We propose and analyze a setup to achieve strong coupling between a single trapped atom and a mechanical oscillator. The interaction between the motion of the atom and the mechanical oscillator is mediated by a quantized light field in a laser driven high-finesse cavity. In particular, we show that high fidelity transfer of quantum states between the atom and the mechanical oscillator is in reach for existing or near future experimental parameters. Our setup provides the basic toolbox from atomic physics for coherent manipulation, preparation, and measurement of micromechanical and nanomechanical oscillators. PMID- 19792564 TI - Nanowire quantum dots as an ideal source of entangled photon pairs. AB - We predict that heterostructure quantum wires and [111] grown quantum dots have a vanishing fine-structure splitting on the grounds of their symmetry, and are therefore ideal candidates to generate entangled photon pairs. We underpin this proposal by atomistic million-atom many-body pseudopotential calculations of realistic structures and find that the vanishing fine-structure splitting is robust against possible variations in morphology. PMID- 19792565 TI - Plasmon-induced enhancement of quantum interference near metallic nanostructures. AB - We show that the quantum interference between two spontaneous emission channels can be greatly enhanced when a three-level V-type atom is placed near plasmonic nanostructures such as metallic slabs, nanospheres, or periodic arrays of metal coated spheres. The spontaneous emission rate is calculated by a rigorous first principles electromagnetic Green's tensor technique. The enhancement of quantum interference is attributed to the strong dependence of the spontaneous emission rate on the orientation of an atomic dipole relative to the surface of the nanostructure at the excitation frequencies of surface plasmons. PMID- 19792566 TI - Focusing of second-harmonic signals with nonlinear metamaterial lenses: a biphotonic microscopy approach. AB - Recent research on second-harmonic generation in left-handed materials has shown a light localization mechanism that originates from an all-angle phase-matching condition between counterpropagating electromagnetic modes at fundamental and double frequencies. By combining these properties with negative refraction, we propose in this Letter an original approach to the design of a second-harmonic lens. Numerical simulations demonstrate that feasible metamaterials can be tailored to operate in the visible range of frequency. These nonlinear lenses open an attractive solution for the biphotonic microscopy technique by imaging passive biological structures. PMID- 19792567 TI - Surface spontaneous parametric down-conversion. AB - Surface spontaneous parametric down-conversion is predicted as a consequence of continuity requirements for electric- and magnetic-field amplitudes at a discontinuity of chi;{(2)} nonlinearity. A generalization of the usual two-photon spectral amplitude is suggested to describe this effect. Examples of nonlinear layered structures and periodically poled nonlinear crystals show that surface contributions to spontaneous down-conversion can be important. PMID- 19792568 TI - Disorder-induced multiple scattering in photonic-crystal waveguides. AB - In this Letter, we study slow-light transport in photonic-crystal waveguides in the presence of structural imperfections. In contrast with previous theoretical works that rely on perturbation theories, the present formalism takes into account multiple scattering and localization effects. It allows for a quantitative prediction of the main statistical transport coefficients, including averaged values as well as probability distributions. In particular, we evidence that, as the group velocity decreases, the attenuation probability distribution exhibits a rapid broadening that one should consider for designing slow-light devices. PMID- 19792569 TI - Induced violation of time-reversal invariance in the regime of weakly overlapping resonances. AB - We measure the complex scattering amplitudes of a flat microwave cavity (a "chaotic billiard"). Time-reversal (T) invariance is partially broken by a magnetized ferrite placed within the cavity. We extend the random-matrix approach to T violation in scattering, determine the parameters from some properties of the scattering amplitudes, and successfully predict others. Our work constitutes the most precise test of the random-matrix theoretical approach to T violation so far available. PMID- 19792552 TI - Search for a fermiophobic Higgs boson decaying into diphotons in pp[over] collisions at sqrt[s] = 1.96 TeV. AB - A search for a narrow diphoton mass resonance is presented based on data from 3.0 fb;{-1} of integrated luminosity from pp[over ] collisions at sqrt[s] = 1.96 TeV collected by the CDF experiment. No evidence of a resonance in the diphoton mass spectrum is observed, and upper limits are set on the cross section times branching fraction of the resonant state as a function of Higgs boson mass. The resulting limits exclude Higgs bosons with masses below 106 GeV/c;{2} at a 95% Bayesian credibility level for one fermiophobic benchmark model. PMID- 19792570 TI - Radial wave crystals: radially periodic structures from anisotropic metamaterials for engineering acoustic or electromagnetic waves. AB - We demonstrate that metamaterials with anisotropic properties can be used to develop a new class of periodic structures that has been named radial wave crystals. They can be sonic or photonic, and wave propagation along the radial directions is obtained through Bloch states like in usual sonic or photonic crystals. The band structure of the proposed structures can be tailored in a large amount to get exciting novel wave phenomena. For example, it is shown that acoustical cavities based on radial sonic crystals can be employed as passive devices for beam forming or dynamically orientated antennas for sound localization. PMID- 19792571 TI - Dissolution of a liquid microdroplet in a nonideal liquid-liquid mixture far from thermodynamic equilibrium. AB - A droplet placed in a liquid-liquid solution is expected to grow, or shrink, in time as approximately t;{1/2}. In this Letter, we report experimental evidence that when the composition in the interface is far from thermodynamic equilibrium due to the nonideality of the mixture, a droplet shrinks as approximately t. This scaling is due to the coupling between mass and momentum transfer known as Korteweg forces as a result of which the droplet self-propels around. The consequent hydrodynamic convection greatly enhances the mass transfer between the droplet and the bulk phase. Thus, the combined effect of nonideality and nonequilibrium modifies the dynamical behavior of the dissolving droplet. PMID- 19792572 TI - Phase randomization of three-wave interactions in capillary waves. AB - We present new experimental results on the transition from coherent-phase to random-phase three-wave interactions in capillary waves under parametric excitation. Above the excitation threshold, coherent wave harmonics spectrally broaden. An increase in the pumping amplitude increases spectral widths of wave harmonics and eventually causes a strong decrease in the degree of the three-wave phase coupling. The results point to the modulation instability of capillary waves, which leads to breaking of continuous waves into ensembles of short-lived wavelets or envelope solitons, as the reason for the phase randomization of three wave interactions. PMID- 19792573 TI - X-ray nanointerferometer based on si refractive bilenses. AB - We report a novel type of x-ray interferometer employing a bilens system consisting of two parallel compound refractive lenses, each of which creates a diffraction limited beam under coherent illumination. By closely overlapping such coherent beams, an interference field with a fringe spacing ranging from tens of nanometers to tens of micrometers is produced. In an experiment performed with 12 keV x rays, submicron fringes were observed by scanning and moire imaging of the test grid. The far field interference pattern was used to characterize the x-ray coherence. Our technique opens up new opportunities for studying natural and man made nanoscale materials. PMID- 19792574 TI - Cross-field motion of plasma blobs in an open magnetic field line configuration. AB - The radial propagation of blobs generated from plasma instabilities is investigated in an open magnetic field line configuration. Blob cross-field velocities and sizes are obtained from internal probe measurements using pattern recognition. By varying the ion mass, the normalized vertical blob scale a[over] is scanned from a[over] < 1 to a[over] > 1. An analytical expression for the blob velocity including cross-field ion polarization currents, parallel currents to the sheath, and ion-neutral collisions is derived and shows good quantitative agreement with the experimental data. In agreement with previous theoretical studies, this scaling shows that, for a[over] < 1, the blob velocity is limited by cross-field ion polarization currents, while for a[over] > 1 it is limited by parallel currents to the sheath. PMID- 19792575 TI - Interplay between gyrokinetic turbulence, flows, and collisions: perspectives on transport and poloidal rotation. AB - The impact of ion-ion collisions on confinement is investigated with the full-f and global gyrokinetic Gysela code through a series of nonlinear turbulence simulations for tokamak parameters. A twofold scan in the turbulence drive and in collisionality is performed, highlighting (i) a heat transport expressed in terms of critical quantities-threshold and exponent, (ii) a first evidence of turbulent generation of poloidal momentum, and (iii) the dominance of mean flow shear, mediated through the turbulent corrugation of the mean profiles, with regard to the oft-invoked zonal flow shear. PMID- 19792576 TI - Rotation drive and momentum transport with electron cyclotron heating in tokamak plasmas. AB - The role of electron cyclotron resonance heating (ECRH) on the toroidal rotation velocity profile has been investigated in the JT-60U tokamak device by separating the effects of the change in momentum transport, the intrinsic rotation by pressure gradient, and the intrinsic rotation by ECRH. It is found that ECRH increases the toroidal momentum diffusivity and the convection velocity. It is also found that ECRH drives the codirection (co) intrinsic rotation inside the EC deposition radius and the counterdirection (ctr) intrinsic rotation outside the EC deposition radius. This ctr rotation starts from the EC deposition radius and propagates to the edge region. PMID- 19792577 TI - Transition from collisional to kinetic regimes in large-scale reconnection layers. AB - Using fully kinetic simulations with a Fokker-Planck collision operator, it is demonstrated that Sweet-Parker reconnection layers are unstable to plasmoids (secondary islands) for Lundquist numbers beyond S greater, similar 1000. The instability is increasingly violent at higher Lundquist numbers, both in terms of the number of plasmoids produced and the super-Alfvenic growth rate. A dramatic enhancement in the reconnection rate is observed when the half-thickness of the current sheet between two plasmoids approaches the ion inertial length. During this transition to kinetic scales, the reconnection electric field rapidly exceeds the runaway limit, resulting in the formation of electron-scale current layers that are unstable to the continual formation of new plasmoids. PMID- 19792578 TI - Nonlinear collisional absorption of laser light in dense strongly coupled plasmas. AB - We present a new theoretical approach for collisional absorption of laser energy in dense plasmas which accommodates arbitrary frequencies and high intensities of the laser field by establishing a connection between laser absorption by inverse bremsstrahlung and the stopping power for ions. This relation is then applied to include strong correlations beyond the mean field approach. The results show excellent agreement with molecular dynamics simulations up to very high coupling strength. PMID- 19792579 TI - Signature of the Fulde-Ferrell-Larkin-Ovchinnikov phase in the collective modes of a trapped ultracold Fermi gas. AB - We study theoretically the collective modes of a two-component Fermi gas with attractive interactions in a quasi-one-dimensional harmonic trap. We focus on an imbalanced gas in the Fulde-Ferrell-Larkin-Ovchinnikov (FFLO) phase. Using a mean field theory, we study the response of the ground state to time-dependent potentials. For potentials with short wavelengths, we find dramatic signatures in the large-scale response of the gas which are characteristic of the FFLO phase. This response provides an effective way to detect the FFLO state in experiments. PMID- 19792580 TI - Rate-dependent avalanche size in athermally sheared amorphous solids. AB - We perform an extensive numerical study of avalanche behavior in a two dimensional Lennard-Jones glass at T = 0, sheared at finite strain rates gamma[over]. From the finite size analysis of stress fluctuations and of transverse diffusion we show that flip-flip correlations remain relevant at all realistic strain rates. We predict that, in steady flow, the avalanche size scales as gamma[over];{-1/d}, with d the space dimension. PMID- 19792581 TI - Temperature stabilized surface reconstructions at polar ZnO(0001). AB - The atomic structure of the polar ZnO(0001) surfaces in a dry and humid oxygen environment is studied combining diffraction experiments and density-functional theory. Our results indicate that for similar stoichiometries a large number of very different, but energetically almost degenerate reconstructions exist. Thus vibrational entropy, which could be safely neglected for most semiconductor surfaces becomes dominant, giving rise to a hitherto not reported strong dependence of surface phase diagrams on temperature. Based on this insight we are able to consistently describe and explain the experimentally observed surface structures on polar ZnO(0001) surfaces. PMID- 19792582 TI - High-pressure behavior of perovskite: FeTiO_{3} dissociation into (Fe_{1 delta},Ti_{delta})O and Fe_{1+delta}Ti_{2-delta}O_{5}. AB - The stability of perovskite-structured materials at high pressure and temperature is of fundamental interest in solid-state physics, chemistry, and the geosciences. As an alternative to decomposition into oxides or transformation of the CaIrO_{3} postperovskite structure, we observe in situ the breakdown of FeTiO_{3} perovskite into a (Fe_{1-delta},Ti_{delta})O + Fe_{1+delta}Ti_{2 delta}O_{5} assemblage beyond 53 GPa and 2000 K. The high-pressure high temperature phase of Fe_{1+delta}Ti_{2-delta}O_{5} with a new structure (space group C2/c) could be preserved on decompression to 9 GPa, and amorphizes under further pressure release. Our study demonstrates that perovskite-structured materials can undergo chemical changes and form complex oxides with new structures, rather than only transform to denser polymorphs or decompose to simple oxides. PMID- 19792583 TI - Thermodynamic origins of shear band formation and the universal scaling law of metallic glass strength. AB - We report a universal scaling law, tau_{y} = 3R(T_{g}-RT)/V, that uncovers an inherent relationship of the yield strength tau_{y} with the glass transition temperature T_{g} and molar volume V of metallic glasses. This equation is derived from fundamental thermodynamics and validated by various metallic glasses with well-defined yielding. The linearity between tau_{y} and T_{g} demonstrates the intrinsic correlation between yielding and glass-liquid transition, which contributes to the basic understanding of the strength and deformation of glassy alloys. PMID- 19792584 TI - Glissile dislocations with transient cores in silicon. AB - We report an unexpected characteristic of dislocation cores in silicon. Using first-principles calculations, we show that all of the stable core configurations for a nondissociated 60 degrees dislocation are sessile. The only glissile configuration, previously obtained by nucleation from surfaces, surprisingly corresponds to an unstable core. As a result, the 60 degrees dislocation motion is solely driven by stress, with no thermal activation. We predict that this original feature could be relevant in situations for which large stresses occur, such as mechanical deformation at room temperature. Our work also suggests that postmortem observations of stable dislocations could be misleading and that mobile unstable dislocation cores should be taken into account in theoretical investigations. PMID- 19792585 TI - Novel pressure-induced interactions in silane-hydrogen. AB - We report novel molecular compound formation from silane-hydrogen mixtures with intermolecular interactions unprecedented for hydrogen-rich solids. A complex H_{2} vibron spectrum with anticorrelated pressure-frequency dependencies and a striking H-D exchange below 10 GPa reveal strong and unusual attractive interactions between SiH_{4} and H_{2} and molecular bond destabilization at remarkably low pressure. The unique features of the observed SiH_{4}(H_{2})_{2} compound suggest a new range of accessible pressure-driven intermolecular interactions for hydrogen-bearing simple molecular systems and a new approach to perturb the hydrogen covalent bond. PMID- 19792586 TI - Semiclassical ground-state energies of many-electron systems. AB - A new semiclassical method is proposed to obtain accurate ground-state energies for many-electron systems. The method borrows its semiclassical character from Thomas-Fermi (TF) theory, but improves upon it by including exchange-correlation effects, at least approximately. We illustrate our method (correlated TF method) on simple models of 1D-interacting electrons, showing that it yields dramatic improvements over TF theory, particularly in the strongly correlated regime. PMID- 19792587 TI - Exciton condensation and charge fractionalization in a topological insulator film. AB - An odd number of gapless Dirac fermions is guaranteed to exist at a surface of a strong topological insulator. We show that in a thin-film geometry and under external bias, electron-hole pairs that reside in these surface states can condense to form a novel exotic quantum state which we propose to call "topological exciton condensate" (TEC). This TEC is similar in general terms to the exciton condensate recently argued to exist in a biased graphene bilayer, but with different topological properties. It exhibits a host of unusual properties including a stable zero mode and a fractional charge +/-e/2 carried by a singly quantized vortex in the TEC order parameter. PMID- 19792588 TI - Optical modulation of effective on-site coulomb energy for the Mott transition in an organic dimer insulator. AB - We report an optical modulation of the effective on-site Coulomb energy U on a dimer (U_{dimer}) for achieving the Mott insulator-to-metal transition in kappa (BEDT-TTF)_{2}Cu[N(CN)_{2}]Br, as investigated by pump-probe spectroscopy. A reduction of U_{dimer} is optically induced by molecule displacement in the dimer under intradimer excitation. The mechanism of this metallization differs greatly from the photodoping-type mechanism reported previously. In contrast, a faster transition via the photodoping mechanism is detected for interdimer excitation. A metallic-domain-wall oscillation originating from the modulation of U_{dimer} was also observed near the critical end point of the Mott transition line. PMID- 19792589 TI - Hopping modulation in a one-dimensional Fermi-Hubbard Hamiltonian. AB - We consider a strongly repulsive two-component Fermi gas in a one-dimensional optical lattice described in terms of a Hubbard Hamiltonian. We analyze the response of the system to a periodic modulation of the hopping amplitude in the presence of a large two-body interaction. By (essentially) the exact simulations of the time evolution, we find a nontrivial double occupancy frequency dependence. We show how the dependence relates to the spectral features of the system given by the Bethe ansatz. The discrete nature of the spectrum is clearly reflected in the double occupancy after a long enough modulation time. We also discuss the implications of the 1D results to experiments in higher dimensional systems. PMID- 19792590 TI - Analysis of the antiferromagnetic phase transitions of the 2D Kondo lattice. AB - We study the antiferromagnetic quantum phase transition of a 2D Kondo-Heisenberg square lattice using the nonlinear sigma model. A renormalization group analysis of the competing Kondo-RKKY interaction is carried out to one-loop order in the expansion, and a new quantum critical point (QCP) strongly affected by Kondo fluctuations is found. Near this QCP, the spin-wave velocity scales logarithmically, i.e., breakdown of hydrodynamic behavior, and the spin wave is logarithmically frozen out. The renormalization group results also allow us to propose a new phase diagram near the antiferromagnetic fixed point of this 2D Kondo lattice model. PMID- 19792591 TI - Sign inversion of magnetoresistance in space-charge limited organic devices. AB - In this Letter, we explain the puzzling sign change of organic magnetoresistance in space-charge limited devices by device physics. We prove analytically and numerically that in the case of bipolar conduction with an Ohmic majority carrier and an injection limited minority carrier contact, a decrease in minority carrier mobility may give rise to an increase in the device current. It is shown that when the magnetic field acts to decrease the mobility of both carriers, a sign change in the magnetoconductivity as a function of applied bias may result. This behavior is in agreement with experimental observations. PMID- 19792592 TI - Spin torque and waviness in magnetic multilayers: a bridge between Valet-Fert theory and quantum approaches. AB - We develop a simple theoretical framework for transport in magnetic multilayers, based on the Landauer-Buttiker scattering formalism and random matrix theory. A simple transformation allows one to go from the scattering point of view to theories expressed in terms of local currents and the electromagnetic potential. In particular, our theory can be mapped onto the well-established classical Valet Fert theory for collinear systems. For noncollinear systems, in the absence of spin-flip scattering, our theory can be mapped onto the generalized circuit theory. We apply our theory to the angular dependence of spin accumulation and spin torque in noncollinear spin valves. PMID- 19792593 TI - Microscopic description of a quantum Hall transition without landau levels. AB - By restricting the motion of a high-mobility 2D electron gas to a network of channels with smooth confinement, we were able to trace, both classically and quantum mechanically, the interplay of backscattering, and of the bending action of a weak magnetic field. Backscattering limits the mobility, while bending initiates quantization of the Hall conductivity. We demonstrate that, in restricted geometry, electron motion reduces to two Chalker-Coddington networks, with opposite directions of propagation along the links, which are weakly coupled by disorder. The interplay of backscattering and bending results in the quantum Hall transition in a nonquantizing magnetic field, which decreases with increasing mobility. This is in accord with the scenario of floating up delocalized states. PMID- 19792594 TI - Origins of distinctly different behaviors of Pd and Pt contacts on graphene. AB - Based on first-principles calculations, we propose an exchange-transfer mechanism to understand the distinctively different behaviors of Pd and Pt contacts on graphene. The feature of the mechanism is that the pi electrons on the graphene transferring to the Pd d_{xz} + d_{yz} orbital are largely compensated by the electrons from the Pd d_{z;{2}} orbital. This mechanism causes more interaction states and transmission channels between the Pd and graphene. Most importantly, the mechanism keeps enough pi electrons on the graphene. We show that a tensile strain in the Pd layer, necessary to match the graphene lattice, plays a key role in stimulating this exchange transfer when Pd covers on graphene, while a similar strain in the Pt layer does not cause such a mechanism. PMID- 19792595 TI - Threshold voltage and space charge in organic transistors. AB - We investigate rubrene single-crystal field-effect transistors, whose stability and reproducibility are sufficient to measure systematically the shift in threshold voltage as a function of channel length and source-drain voltage. The shift is due to space charge transferred from the contacts and can be modeled quantitatively without free fitting parameters, using Poisson's equation, and by assuming that the density of states in rubrene is that of a conventional inorganic semiconductor. Our results demonstrate the consistency, at the quantitative level, of a variety of recent experiments on rubrene crystals and show how the use of field-effect transistor measurements can enable the determination of microscopic parameters (e.g., the effective mass of charge carriers). PMID- 19792596 TI - Doping driven (pi, 0) nesting and magnetic properties of Fe_{1+x}Te superconductors. AB - To understand newly discovered superconductivity in Fe-based systems, we investigate the electronic structure and magnetic properties of Fe_{1+x}Te using first-principles density functional calculations. While the undoped FeTe has the same Fermi surface nested at (pi,pi) as in Fe arsenides, doping by approximately 0.5 electrons reveals a novel square-type Fermi surface showing a strong (pi,0) nesting and leading to a different magnetic structure. Our result strongly supports the same mechanism of superconductivity in chalcogenides as in the arsenides, reconciling theory with existing experiments. The calculated magnetic interactions are found to be critically dependent on doping and notably different from the arsenides. PMID- 19792597 TI - Specific-heat measurement of a residual superconducting state in the normal state of underdoped Bi_{2}Sr_{2-x}La_{x}CuO_{6+delta} cuprate superconductors. AB - We have measured the magnetic field and temperature dependence of specific heat on Bi_{2}Sr_{2-x}La_{x}CuO_{6+delta} single crystals in wide doping and temperature regions. The superconductivity related specific-heat coefficient gamma_{sc} and entropy S_{sc} are determined. It is found that gamma_{sc} has a humplike anomaly at T_{c} and behaves as a long tail which persists far into the normal state for the underdoped samples, but for the heavily overdoped samples the anomaly ends sharply just near T_{c}. Interestingly, we found that the entropy associated with superconductivity is roughly conserved when and only when the long tail part in the normal state is taken into account for the underdoped samples, indicating the residual superconductivity above T_{c}. PMID- 19792598 TI - Dependence of band-renormalization effects on the number of copper oxide layers in Tl-based copper oxide superconductors revealed by angle-resolved photoemission spectroscopy. AB - Here we report the first angle-resolved photoemission measurement on nearly optimally doped multilayer Tl-based superconducting cuprates (Tl-2212 and Tl 1223) and a comparison study to single-layer (Tl-2201) compound. A "kink" in the band dispersion is found in all three compounds but exhibits different momentum dependence for the single-layer and multilayer compounds, reminiscent to that of Bi-based cuprates. This layer number dependent renormalization effect strongly implies that the spin-resonance mode is unlikely to be responsible for the dramatic renormalization effect near the antinodal region. PMID- 19792599 TI - Revision of model parameters for kappa-type charge transfer salts: an ab initio study. AB - Intense experimental and theoretical studies have demonstrated that the anisotropic triangular lattice as realized in the kappa-(BEDT-TTF)2X family of organic charge transfer salts yields a complex phase diagram with magnetic, superconducting, Mott insulating, and even spin liquid phases. With extensive density functional theory calculations we refresh the link between many body theory and experiment by determining hopping parameters of the underlying Hubbard model. This leads us to revise the widely used semiempirical parameters in the direction of less frustrated, more anisotropic triangular lattices. The implications of these results on the systems' description are discussed. PMID- 19792600 TI - Circular dichroism in the angle-resolved photoemission spectrum of the high temperature Bi_{2}Sr_{2}CaCu_{2}O_{8+delta} superconductor: can these measurements be interpreted as evidence for time-reversal symmetry breaking? AB - We report first-principles computations of the angle-resolved photoemission response with circularly polarized light in Bi_{2}Sr_{2}CaCu_{2}O_{8+delta} for the purpose of delineating contributions to the circular dichroism resulting from distortions and modulations of the crystal lattice. Comparison with available experimental results shows that the measured circular dichroism from antinodal mirror planes is reproduced in quantitative detail in calculations employing the average orthorhombic crystal structure. We thus conclude that the existing angle resolved photoemission measurements can be understood essentially within the framework of the conventional picture, without the need to invoke unconventional mechanisms. PMID- 19792601 TI - Crossed Andreev reflection and charge imbalance in diffusive normal superconducting-normal structures. AB - We formulate a microscopic theory of nonlocal electron transport in three terminal diffusive normal-superconducting-normal (NSN) structures with arbitrary interface transmissions. At low energies epsilon, we predict strong enhancement of nonlocal spectral conductance g_{12} proportional, variant1/epsilon due to quantum interference of electrons in disordered N terminals. In contrast, nonlocal resistance R_{12} remains smooth at small epsilon and, furthermore, is found to depend neither on parameters of normal-superconducting interfaces nor on those of N terminals. At higher temperatures, R_{12} exhibits a peak caused by the trade-off between charge imbalance and Andreev reflection. Our results are in a good agreement with recent experimental observations and can be used for quantitative analysis of future experiments. PMID- 19792602 TI - Symmetry-induced giant vortex state in a superconducting Pb film with a fivefold Penrose array of magnetic pinning centers. AB - A direct visualization of the flux distribution in a Pb film covering a fivefold Penrose array of Co dots is obtained by mapping the local field distribution with a scanning Hall probe microscope. We demonstrate that stable vortex configurations can be found for fields H approximately 0.8H_{1}, H_{1}, and 1.6H_{1}, where H_{1} corresponds to one flux quantum per pinning site. The vortex pattern at 0.8H_{1} corresponds to one vacancy in one of the vertices of the thin tiles, whereas at 1.6H_{1} the vortex structure can be associated with one interstitial vortex inside each thick tile. Strikingly, for H = 1.6H_{1}, interstitial and pinned vortices arrange themselves in ringlike structures ("vortex corrals") which favor the formation of a giant vortex state at their center. PMID- 19792603 TI - Spin gap and resonance at the nesting wave vector in superconducting FeSe_{0.4}Te_{0.6}. AB - Neutron scattering is used to probe magnetic excitations in FeSe_{0.4}Te_{0.6} (T_{c} = 14 K). Low energy spin fluctuations are found with a characteristic wave vector (1/21/2L) that corresponds to Fermi surface nesting and differs from Q_{m} = (delta01/2) for magnetic ordering in Fe_{1+y}Te. A spin resonance with variant Planck's over 2piOmega_{0} = 6.51(4) meV approximately 5.3k_{B}T_{c} and variant Planck's over 2piGamma = 1.25(5) meV develops in the superconducting state from a normal state continuum. We show that the resonance is consistent with a bound state associated with s_{+/-} superconductivity and imperfect quasi-2D Fermi surface nesting. PMID- 19792604 TI - Measurement of conduction-electron polarization via the pairing resonance. AB - We show that the pairing resonance in the Pauli-limited normal state of ultrathin superconducting Al films provides a spin-resolved probe of conduction-electron polarization in thin magnetic films. A superconductor-insulator-ferromagnet tunneling junction is used to measure the density of states in supercritical parallel magnetic fields that are well beyond the Clogston-Chandresekhar limit, thus greatly extending the field range of the tunneling density of states technique. The applicability and limitations of using the pairing resonance as a spin probe are discussed. PMID- 19792605 TI - Superconductivity and field-induced magnetism in SrFe_{1.75}Co_{0.25}As_{2}. AB - Using muon-spin rotation, we studied the in-plane (lambda_{ab}) and the out of plane (lambda_{c}) magnetic field penetration depth in SrFe_{1.75}Co_{0.25}As_{2} (T_{c} approximately 13.3 K). The penetration depth anisotropy gamma_{lambda} = lambda_{c}/lambda_{ab} increases from gamma_{lambda} approximately 2.1 at T_{c} to 2.7 at 1.6 K. The mean internal field in the superconducting state increases with decreasing temperature, just opposite to the diamagnetic response seen in magnetization experiments. This unusual behavior suggests that the external field induces a magnetic order which is maintained throughout the whole sample volume. PMID- 19792606 TI - Engineering giant nonlinearities in quantum nanosystems. AB - We describe a method to engineer giant nonlinearities in, and probes to measure nonlinear observables of, mesoscopic quantum resonators. This involves tailoring the Hamiltonian of a simple auxiliary system perturbatively coupled to the resonator, and has the potential to engineer a wide range of nonlinearities to high accuracy. We give a number of explicit examples, including a readily realizable two-qubit auxiliary system that creates an x;{4} potential and a chi;{(3)} (Kerr) nonlinearity, valid to fifth order in the perturbative coupling. PMID- 19792607 TI - Dominant role of the epitaxial strain in the magnetism of core-shell Co/Au self organized nanodots. AB - Self-organized Co nanodots on a Au(111) surface have been surrounded by controlled Au rings that progressively cap the entire dots. The magnetic susceptibility of these dots has been measured in situ as a function of the Au coverage. The blocking temperature increases when the Co bilayer dots are surrounded by the first Au atomic layer and decreases with the subsequent capping. This result cannot be explained by interfacial anisotropy which is generally assumed to be the dominant term in the magnetic anisotropy of nanostructures. Using molecular dynamics simulations, we evidence that the large strain inside the Co clusters is the main driving force for the anisotropy changes during the Au encapsulation. PMID- 19792608 TI - Kondo lattice scenario in disordered semiconductor heterostructures. AB - We study nuclear relaxation in the presence of localized electrons in a two dimensional electron gas in a disordered delta-doped semiconductor heterostructure and show that this method can reliably probe their magnetic interactions and possible long-range order. In contrast, we argue that transport measurements, the commonly employed tool, may not sometimes distinguish between spatial disorder and long-range order. We illustrate the utility of using the nuclear relaxation method to detect long-range order by analyzing a recent proposal made on the basis of transport measurements, on the spontaneous formation of a two-dimensional Kondo lattice in a 2D electron gas in a heterostructure. PMID- 19792609 TI - Spin-lattice coupling, frustration, and magnetic order in multiferroic RMnO3. AB - We have performed high-resolution neutron diffraction and inelastic neutron scattering experiments in the frustrated multiferroic hexagonal compounds RMnO_{3} (R = Ho,Yb,Sc,Y), which provide evidence of a strong magnetoelastic coupling in the whole family. We can correlate the atomic positions, the type of magnetic structure, and the nature of the spin waves whatever the R ion and temperature. The key parameter is the position of the Mn ions in the unit cell with respect to a critical threshold of 1/3, which determines the sign of the coupling between Mn triangular planes. PMID- 19792610 TI - Magnetically hidden order of Kramers doublets in d;{1} systems: Sr2VO4. AB - We formulate and study an effective Hamiltonian for low-energy Kramers doublets of d;{1} ions on a square lattice. We find that the system exhibits a magnetically hidden order in which the expectation values of the local spin and orbital moments both vanish. The order parameter responsible for a time-reversal symmetry breaking has a composite nature and is a spin-orbital analog of a magnetic octupole. We argue that such a hidden order is realized in the layered perovskite Sr_{2}VO_{4}. PMID- 19792611 TI - Large modulations in the intensity of Raman-scattered light from pristine carbon nanotubes. AB - Large modulations of up to 2 orders of magnitude are observed in the Raman intensity of pristine, suspended, quasimetallic, single-walled carbon nanotubes in response to applied gate potentials. No change in the resonance condition is observed, and all Raman bands exhibit the same changes in intensity, regardless of phonon energy or laser excitation energy. The effect is not observed in semiconducting nanotubes. The electronic energy gaps correlate with the drop in the Raman intensity, and the recently observed Mott insulating behavior is suggested as a possible explanation for this effect. PMID- 19792612 TI - Origin of universal optical conductivity and optical stacking sequence identification in multilayer graphene. AB - We show that the origin of the universal optical conductivity in a normal N-layer graphene multilayer is an emergent chiral symmetry which guarantees that sigma(omega) = Nsigma_{uni} in both low and high-frequency limits. [sigma_{uni} = (pi/2)e;{2}/h]. We use this physics to relate intermediate frequency conductivity trends to qualitative characteristics of the multilayer stacking sequence. PMID- 19792613 TI - Landau-type order parameter equation for shear banding in granular Couette flow. AB - We show that a Landau-type "order-parameter" equation describes the onset of shear-band formation in granular plane Couette flow wherein the flow undergoes an ordering transition into alternate layers of dense and dilute regions of low and high shear rates, respectively, parallel to the flow direction. Even though the linear theory predicts the stability of the homogeneous shear solution in dilute flows, our analytical bifurcation theory suggests that there is a subcritical finite-amplitude instability that is likely to lead to shear-band formation in dilute flows, which is in agreement with previous numerical simulations. PMID- 19792614 TI - Extinction rate fragility in population dynamics. AB - Population extinction is of central interest for population dynamics. It may occur from a large rare fluctuation. We find that, in contrast to related large fluctuation effects like noise-induced interstate switching, quite generally extinction rates in multipopulation systems display fragility, where the height of the effective barrier to be overcome in the fluctuation depends on the system parameters nonanalytically. We show that one of the best-known models of epidemiology, the susceptible-infectious-susceptible model, is fragile to total population fluctuations. PMID- 19792615 TI - Steering chiral swimmers along noisy helical paths. AB - Chemotaxis along helical paths towards a target releasing a chemoattractant is found in sperm cells and many microorganisms. We discuss the stochastic differential geometry of the noisy helical swimming path of a chiral swimmer. A chiral swimmer equipped with a simple feedback system can navigate in a concentration gradient of chemoattractant. We derive an effective equation for the alignment of helical paths with a concentration gradient which is related to the alignment of a dipole in an external field and discuss the chemotaxis index. PMID- 19792616 TI - Thymic selection of T-cell receptors as an extreme value problem. AB - T lymphocytes (T cells) orchestrate adaptive immune responses upon activation. T cell activation requires sufficiently strong binding of T-cell receptors on their surface to short peptides (p) derived from foreign proteins, which are bound to major histocompatibility gene products (displayed on antigen-presenting cells). A diverse and self-tolerant T-cell repertoire is selected in the thymus. We map thymic selection processes to an extreme value problem and provide an analytic expression for the amino acid compositions of selected T-cell receptors (which enable its recognition functions). PMID- 19792617 TI - Analysis of genetic toggle switch systems encoded on plasmids. AB - Genetic switch systems with mutual repression of two transcription factors, encoded on plasmids, are studied using stochastic methods. The plasmid copy number is found to strongly affect the behavior of these systems. More specifically, the average time between spontaneous switching events quickly increases with the number of plasmids. It was shown before that for a single copy encoded on the chromosome, the exclusive switch is more stable than the general switch. Here we show that when the switch is encoded on a sufficiently large number of plasmids, the situation is reversed and the general switch is more stable than the exclusive switch. These predictions can be tested experimentally using methods of synthetic biology. PMID- 19792618 TI - Comment on "Excess of proton mean kinetic energy in supercooled water". PMID- 19792620 TI - Collective states of interacting anyons, edge states, and the nucleation of topological liquids. AB - Quantum mechanical systems, whose degrees of freedom are so-called su(2)k anyons, form a bridge between ordinary SU(2) quantum magnets (of arbitrary spin-S) and systems of interacting non-Abelian anyons. Anyonic spin-1/2 chains exhibit a topological protection mechanism that stabilizes their gapless ground states and which vanishes only in the limit (k-->infinity) of the ordinary spin-1/2 Heisenberg chain. For anyonic spin-1 chains the phase diagram closely mirrors the one of the biquadratic SU(2) spin-1 chain. Our results describe, at the same time, nucleation of different 2D topological quantum fluids within a "parent" non Abelian quantum Hall state, arising from a macroscopic occupation with localized, interacting anyons. The edge states between the "nucleated" and the parent liquids are neutral, and correspond precisely to the gapless modes of the anyonic chains. PMID- 19792621 TI - Lattice interferometer for laser-cooled atoms. AB - We demonstrate an atom interferometer in which atoms are laser cooled into a 1D optical lattice, suddenly released, and later subjected to a pulsed optical lattice. For short pulses, a simple analytical theory predicts the signal. We investigate both short and longer pulses where the analytical theory fails. Longer pulses yield higher precision and larger signals, and we observe a coherent signal at times that can differ significantly from the expected echo time. The interferometer has potential for precision measurements of variant Planck's/m(A), and can probe the dynamics of atoms in an optical lattice. PMID- 19792622 TI - Violation of smooth observable macroscopic realism in a harmonic oscillator. AB - We study the emergence of macrorealism in a harmonic oscillator subject to consecutive measurements of a squeezed action. We demonstrate a breakdown of dynamical realism in a wide parameter range that is maximized in a scaling limit of extreme squeezing, where it is based on measurements of smooth observables, implying that macroscopic realism is not valid in the harmonic oscillator. We propose an indirect experimental test of these predictions with entangled photons by demonstrating that local realism in a composite system implies dynamical realism in a subsystem. PMID- 19792623 TI - Stabilization of the p-wave superfluid state in an optical lattice. AB - It is hard to stabilize the p-wave superfluid state of cold atomic gas in free space due to inelastic collisional losses. We consider the p-wave Feshbach resonance in an optical lattice, and show that it is possible to have a stable p wave superfluid state where the multiatom collisional loss is suppressed through the quantum Zeno effect. We derive the effective Hamiltonian for this system, and calculate its phase diagram in a one-dimensional optical lattice. The results show rich phase transitions between the p-wave superfluid state and different types of insulator states induced either by interaction or by dissipation. PMID- 19792624 TI - Quantum teamwork for unconditional multiparty communication with Gaussian states. AB - We demonstrate the capability of continuous variable Gaussian states to communicate multipartite quantum information. A quantum teamwork protocol is presented according to which an arbitrary possibly entangled multimode state can be faithfully teleported between two teams each comprising many cooperative users. We prove that N-mode Gaussian weighted graph states exist for arbitrary N that enable unconditional quantum teamwork implementations for any arrangement of the teams. These perfect continuous variable maximally multipartite entangled resources are typical among pure Gaussian states and are unaffected by the entanglement frustration occurring in multiqubit states. PMID- 19792625 TI - Quantum computing with an electron spin ensemble. AB - We propose to encode a register of quantum bits in different collective electron spin wave excitations in a solid medium. Coupling to spins is enabled by locating them in the vicinity of a superconducting transmission line cavity, and making use of their strong collective coupling to the quantized radiation field. The transformation between different spin waves is achieved by applying gradient magnetic fields across the sample, while a Cooper pair box, resonant with the cavity field, may be used to carry out one- and two-qubit gate operations. PMID- 19792626 TI - Operational families of entanglement classes for symmetric N-qubit States. AB - We solve the entanglement classification under stochastic local operations and classical communication (SLOCC) for all multipartite symmetric states in the general N-qubit case. For this purpose, we introduce 2 parameters playing a crucial role, namely, the diversity degree and the degeneracy configuration of a symmetric state. Those parameters give rise to a simple method of identifying operational families of SLOCC entanglement classes of all symmetric N-qubit states, where the number of families grows as the partition function of the number of qubits. PMID- 19792627 TI - A strong converse for classical channel coding using entangled inputs. AB - A fully general strong converse for channel coding states that when the rate of sending classical information exceeds the capacity of a quantum channel, the probability of correctly decoding goes to zero exponentially in the number of channel uses, even when we allow code states which are entangled across several uses of the channel. Such a statement was previously only known for classical channels and the quantum identity channel. By relating the problem to the additivity of minimum output entropies, we show that a strong converse holds for a large class of channels, including all unital qubit channels, the d-dimensional depolarizing channel and the Werner-Holevo channel. This further justifies the interpretation of the classical capacity as a sharp threshold for information transmission. PMID- 19792628 TI - Dynamical collective calculation of supernova neutrino signals. AB - We present the first calculations with three flavors of collective and shock wave effects for neutrino propagation in core-collapse supernovae using hydrodynamical density profiles and the S matrix formalism. We explore the interplay between the neutrino-neutrino interaction and the effects of multiple resonances upon the time signal of positrons in supernova observatories. A specific signature is found for the inverted hierarchy and a large third neutrino mixing angle and we predict, in this case, a dearth of lower energy positrons in Cherenkov detectors midway through the neutrino signal and the simultaneous revelation of valuable information about the original fluxes. We show that this feature is also observable with current generation neutrino detectors at the level of several sigmas. PMID- 19792629 TI - Non-Gaussian curvature spikes from chaotic billiards in inflation preheating. AB - A new class of non-Gaussian curvature fluctuations zeta(pr)(x) identical with deltaN(chi(i)) arises from the postinflation preheating behavior of a noninflaton field chi(i). Its billiardlike chaotic dynamics imprints regular log-spaced narrow spikes in the number of preheating e-folds N(chi(i)). We perform highly accurate lattice simulations of supersymmetry-inspired quartic inflaton and coupling potentials in a separate-universe approximation to compute N(chi(i)) as a function of the (nearly homogeneous) initial condition chi(i). The superhorizon modes of chi(i)(x) result in positive spiky excursions in zeta(pr) and hence negative gravitational potential fluctuations added to the usual sign-independent inflaton-induced perturbations, observably manifested in large cosmic structures and as (polarized) temperature cosmic microwave background cold spots. PMID- 19792630 TI - Observation of a large atomic parity violation effect in ytterbium. AB - Atomic parity violation has been observed in the 6s(2 1)S(0)-->5d6s(3)D(1) 408-nm forbidden transition of ytterbium. The parity-violating amplitude is found to be 2 orders of magnitude larger than in cesium, where the most precise experiments to date have been performed. This is in accordance with theoretical predictions and constitutes the largest atomic parity-violating amplitude yet observed. This also opens the way to future measurements of neutron distributions and anapole moments by comparing parity-violating amplitudes for various isotopes and hyperfine components of the transition. PMID- 19792631 TI - Testing new indirect CP violation. AB - If new CP violating physics contributes to neutral meson mixing, but its contribution to CP violation in decay amplitudes is negligible, then there is a model independent relation between four (generally independent) observables related to the mixing: the mass splitting (x), the width splitting (y), the CP violation in mixing (1-|q/p|), and the CP violation in the interference of decays with and without mixing (phi). For the four neutral meson systems, this relation can be written in a simple approximate form: y tan phi approximately x(1-|q/p|). In the K system, all four observables have been measured and obey the relation to excellent accuracy. For the B(s) and D systems, new predictions are provided. The success or failure of these relations will probe the physics that is responsible for the CP violation. PMID- 19792633 TI - Electroproduction of the N*(1535) resonance at large momentum transfer. AB - We report on the first lattice calculation of light-cone distribution amplitudes of the N*(1535) resonance, which are used to calculate the transition form factors at large momentum transfers using light-cone sum rules. In the region Q2>2 GeV2, where the light-cone expansion is expected to converge, the results appear to be in good agreement with the experimental data. PMID- 19792634 TI - Probing the nucleon's transversity and the photon's distribution amplitude in lepton pair photoproduction. AB - We describe a new way to access the chiral-odd transversity parton distribution in the proton through the photoproduction of lepton pairs. The basic ingredient is the interference of the usual Bethe-Heitler or Drell-Yan amplitudes with the amplitude of a process, where the photon couples to quarks through its chiral-odd distribution amplitude, which is normalized to the magnetic susceptibility of the QCD vacuum. A promising phenomenology of single and double spin observables emerges from the unusual features of this amplitude. PMID- 19792635 TI - How many phases meet at the chiral critical point? AB - We explore the phase diagram of Nambu-Jona-Lasinio-type models near the chiral critical point allowing for phases with spatially inhomogeneous chiral condensates. In the chiral limit it turns out that the region in the mean-field phase diagram where those phases are energetically preferred very generically reaches out to the chiral critical point. The preferred inhomogeneous ground state in this vicinity possibly resembles a lattice of domain wall solitons. This raises the question of their relevance for the phase diagram of QCD. PMID- 19792636 TI - Universal decay law in charged-particle emission and exotic cluster radioactivity. AB - A linear universal decay formula is presented starting from the microscopic mechanism of the charged-particle emission. It relates the half-lives of monopole radioactive decays with the Q values of the outgoing particles as well as the masses and charges of the nuclei involved in the decay. This relation is found to be a generalization of the Geiger-Nuttall law in alpha radioactivity and explains well all known cluster decays. Predictions on the most likely emissions of various clusters are presented. PMID- 19792637 TI - New Measurement of the 60Fe Half-Life. AB - We have made a new determination of the half-life of the radioactive isotope 60Fe using high precision measurements of the number of 60Fe atoms and their activity in a sample containing over 10(15) 60Fe atoms. Our new value for the half-life of 60Fe is (2.62+/-0.04) x 10(6) yr, significantly above the previously reported value of (1.49+/-0.27) x 10(6) yr. Our new measurement for the lifetime of 60Fe has significant implications for interpretations of galactic nucleosynthesis, for determinations of formation time scales of solids in the early Solar System, and for the interpretation of live 60Fe measurements from supernova-ejecta deposits on Earth. PMID- 19792638 TI - Bimodal behavior of the heaviest fragment distribution in projectile fragmentation. AB - The charge distribution of the heaviest fragment detected in the decay of quasiprojectiles produced in intermediate energy heavy-ion collisions has been observed to be bimodal. This feature is expected as a generic signal of phase transition in nonextensive systems. In this Letter, we present new analyses of experimental data from Au on Au collisions at 60, 80, and 100 MeV/nucleon showing that bimodality is largely independent of the data selection procedure and of entrance channel effects. An estimate of the latent heat of the transition is extracted. PMID- 19792639 TI - Rotational sublevels of an ortho-hydrogen molecule encapsulated in an isotropic C60 cage. AB - From specific heat measurements in high quality H2@C60 samples performed over a broad temperature range, we obtain the smallest yet observed splitting of rotational energy sublevels of encapsulated single H2 molecules, 0.1-0.2 meV, in the nearly spherical potential well provided by highly isotropic C60 cages. Additionally, we find evidence of the quantized oscillation state of isolated H2 in the C60 cage. The minuscule splitting indicates that H2@C60 provides unprecedented opportunities to study free-molecule quantum dynamic properties. PMID- 19792640 TI - Method for measuring the dwell time of spin-polarized Rb atoms on coated pyrex glass surfaces using light shift. AB - We present a simple method for directly measuring the average dwell time of spin polarized Rb atoms on coated Pyrex glass surfaces. The method relies on the light shift of the Zeeman resonances of spin-polarized Rb atoms pumped and probed by evanescent waves, and does not depend on the microscopic details of surface interactions. We use a cell whose length is adjustable between 70 and 500 microm. The inverse of the difference between the frequency shifts caused by sigma+ and sigma- pump beams depends linearly on the cell length, from which we obtain the average dwell time tau(s). For a Pyrex glass cell coated with octadecyltrichlorosilane we find that tau(s)=0.53+/-0.03 mus at a cell wall temperature of 103 degrees C. The temperature dependence of tau(s) is fitted to tau(s)=tau[mean](0) exp(E(a)/kT), yielding a preexponential factor tau[mean](0)=2.2(-1.4)(+5.1) ns and an activation energy E(a)=0.19+/-0.03 eV. PMID- 19792641 TI - Three-body recombination of 6Li atoms with large negative scattering lengths. AB - The three-body recombination rate at threshold for distinguishable atoms with large negative pair scattering lengths is calculated in the zero-range approximation. The only parameters in this limit are the 3 scattering lengths and the Efimov parameter, which can be complex-valued. We provide semianalytic expressions for the cases of 2 or 3 equal scattering lengths, and we obtain numerical results for the general case of 3 different scattering lengths. Our general result is applied to the three lowest hyperfine states of 6Li atoms. Comparisons with recent experiments provide indications of loss features associated with Efimov trimers near the 3-atom threshold. PMID- 19792642 TI - Possible efimov trimer state in a three-hyperfine-component lithium-6 mixture. AB - We consider the Efimov trimer theory as a possible framework to explain recently observed losses by inelastic three-body collisions in a three-hyperfine-component ultracold mixture of lithium 6. Within this framework, these losses would arise chiefly from the existence of an Efimov trimer bound state below the continuum of free triplets of atoms, and the loss maxima (at certain values of an applied magnetic field) would correspond to zero-energy resonances where the trimer dissociates into three free atoms. Our results show that such a trimer state is indeed possible given the two-body scattering lengths in the three-component lithium mixture and gives rise to two zero-energy resonances. The locations of these resonances appear to be consistent with observed losses. PMID- 19792643 TI - Calorimetric observation of the melting of free water nanoparticles at cryogenic temperatures. AB - We present an experimental study of the thermodynamics of free, size-selected water cluster anions consisting of 48 and 118 molecules. The measured caloric curves of the clusters are bulklike at low temperatures but show a well-defined, particle-size specific transition at 93+/-3 K for (H2O)48- and 118+/-3 K for (H2O)118-. At the transition temperature the heat capacity strongly increases, which marks the onset of melting. PMID- 19792644 TI - Active exterior cloaking for the 2D Laplace and Helmholtz equations. AB - A new cloaking method is presented for 2D quasistatics and the 2D Helmholtz equation that we speculate extends to other linear wave equations. For 2D quasistatics it is proven how a single active exterior cloaking device can be used to shield an object from surrounding fields, yet produce very small scattered fields. The problem is reduced to finding a polynomial which is close to 1 in a disk and close to 0 in another disk, and such a polynomial is constructed. For the 2D Helmholtz equation it is numerically shown that three exterior cloaking devices placed around the object suffice to hide it. PMID- 19792645 TI - Wavelength scaling of high harmonic generation efficiency. AB - Using longer wavelength laser drivers for high harmonic generation is desirable because the highest extreme ultraviolet frequency scales as the square of the wavelength. Recent numerical studies predict that high harmonic efficiency falls dramatically with increasing wavelength, with a very unfavorable lambda(-(5-6)) scaling. We performed an experimental study of the high harmonic yield over a wavelength range of 800-1850 nm. A thin gas jet was employed to minimize phase matching effects, and the laser intensity and focal spot size were kept constant as the wavelength was changed. Ion yield was simultaneously measured so that the total number of emitting atoms was known. We found that the scaling at constant laser intensity is lambda(-6.3+/-1.1) in Xe and lambda(-6.5+/-1.1) in Kr over the wavelength range of 800-1850 nm, somewhat worse than the theoretical predictions. PMID- 19792646 TI - Event-related desynchronization in diffusively coupled oscillator models. AB - We seek an explanation for the neurophysiological phenomenon of event-related desynchronization (ERD) by using models of diffusively coupled nonlinear oscillators. We demonstrate that when the strength of the event is sufficient, ERD is found to emerge and the accomplishment of a behavioral or functional task is determined by the nature of the desynchronized state. We illustrate the phenomenon for the case of limit cycle and chaotic systems. We numerically demonstrate the occurrence of ERD and provide an analytical explanation. We also discuss possible applications of the observed phenomenon in real physical systems other than the brain. PMID- 19792632 TI - Search for resonant pair production of neutral long-lived particles decaying to bb in pp collisions at square root(S)=1.96 TeV. AB - We report on a first search for resonant pair production of neutral long-lived particles (NLLP) which each decay to a bb pair, using 3.6 fb(-1) of data recorded with the D0 detector at the Fermilab Tevatron collider. We search for pairs of displaced vertices in the tracking detector at radii in the range 1.6-20 cm from the beam axis. No significant excess is observed above background, and upper limits are set on the production rate in a hidden-valley benchmark model for a range of Higgs boson masses and NLLP masses and lifetimes. PMID- 19792647 TI - Formation of nanopillar arrays in ultrathin viscous films: the critical role of thermocapillary stresses. AB - Experiments by several groups during the past decade have shown that a molten polymer nanofilm subject to a large transverse thermal gradient undergoes spontaneous formation of periodic nanopillar arrays. The prevailing explanation is that coherent reflections of acoustic phonons within the film cause a periodic modulation of the radiation pressure which enhances pillar growth. By exploring a deformational instability of particular relevance to nanofilms, we demonstrate that thermocapillary forces play a crucial role in the formation process. Analytic and numerical predictions show good agreement with the pillar spacings obtained in experiment. Simulations of the interface equation further determine the rate of pillar growth of importance to technological applications. PMID- 19792648 TI - Turbulent transfer of energy by radiating pulses. AB - We propose a new mechanism for turbulent transport in systems which support radiating nonlinear solitary wave packets or pulses. The direct energy cascade is provided by adiabatically evolving pulses, whose widths and carrier wavelengths decrease. The inverse cascade is due to the excitation of radiation. The spectrum is steeper than the Kolmogorov-Zakharov spectrum of wave turbulence. PMID- 19792649 TI - Edge-localized-mode suppression through density-profile modification with lithium wall coatings in the National Spherical Torus Experiment. AB - Reduction or elimination of edge localized modes (ELMs) while maintaining high confinement is essential for future fusion devices, e.g., the ITER. An ELM-free regime was recently obtained in the National Spherical Torus Experiment, following lithium (Li) evaporation onto the plasma-facing components. Edge stability calculations indicate that the pre-Li discharges were unstable to low-n peeling or ballooning modes, while broader pressure profiles stabilized the post Li discharges. Normalized energy confinement increased by 50% post Li, with no sign of ELMs up to the global stability limit. PMID- 19792650 TI - Radiation-dominated relativistic current sheets. AB - Relativistic current sheets (RCSs) feature plasma instabilities considered as the potential key to magnetic energy dissipation in Poynting-flux-dominated plasma flows. Kinetic plasma simulations show that the physical nature of RCS evolution changes in the presence of radiation losses: In the ultrarelativistic regime (i.e., magnetization parameter sigma=10(4) defined as the ratio of magnetic to plasma rest frame energy density), the combined effect of nonlinear RCS dynamics and synchrotron emission introduces a temperature anisotropy triggering the growth of the relativistic tearing mode. In contrast to previous studies of the RCS with sigma approximately 1, the relativistic tearing mode then prevails over the drift kink mode. The ultrarelativistic RCS shows a typical life cycle from radiation-induced collapse towards a radiation-quiescent phase with topology analogous to that introduced by Sweet and Parker. PMID- 19792651 TI - Enhanced self-focusing of an ion beam pulse propagating through a background plasma along a solenoidal magnetic field. AB - It is shown that the application of a weak solenoidal magnetic field along the direction of ion beam propagation through a neutralizing background plasma can significantly enhance the beam self-focusing for the case where the beam radius is small compared to the collisionless electron skin depth. The enhanced focusing is provided by a strong radial self-electric field that is generated due to a local polarization of the magnetized plasma background by the moving ion beam. A positive charge of the ion beam pulse becomes overcompensated by the plasma electrons, which results in the radial focusing of the beam ions. The expression for the self-focusing force is derived analytically and compared with the results of numerical simulations. PMID- 19792652 TI - Localized turbulence suppression and increased flow shear near the q=2 surface during internal-transport-barrier formation. AB - Broadband turbulent fluctuations in the plasma density are transiently suppressed when low-order rational q surfaces first appear in negative central magnetic shear plasmas on the DIII-D tokamak, which can lead to the formation of internal transport barriers. Increased localized flow shear is simultaneously observed. It transiently exceeds the measured turbulence decorrelation rate, providing a mechanism to trigger the formation of the transport barrier. This increased flow shear and turbulence suppression propagates radially outward, following the q=2 surface. PMID- 19792653 TI - Rovibrational wave-packet dispersion during femtosecond laser filamentation in air. AB - An impulsive, femtosecond filament-based Raman technique producing high quality Raman spectra over a broad spectral range (1554.7-4155 cm(-1)) is presented. The temperature of gas phase molecules can be measured by temporally resolving the dispersion of impulsively excited vibrational wave packets. Application to laser induced filamentation in air reveals that the initial rovibrational temperature is 300 K for both N2 and O2. The temperature-dependent wave-packet dynamics are interpreted using an analytic anharmonic oscillator model. The wave packets reveal a 1/e dispersion time of 3.9 ps for N2 and 2.8 ps for O2. Pulse self compression of temporal features to 8 fs within the filament is directly measured by impulsive vibrational excitation of H2. PMID- 19792654 TI - Global scale-invariant dissipation in collisionless plasma turbulence. AB - A higher-order multiscale analysis of the dissipation range of collisionless plasma turbulence is presented using in situ high-frequency magnetic field measurements from the Cluster spacecraft in a stationary interval of fast ambient solar wind. The observations, spanning five decades in temporal scales, show a crossover from multifractal intermittent turbulence in the inertial range to non Gaussian monoscaling in the dissipation range. This presents a strong observational constraint on theories of dissipation mechanisms in turbulent collisionless plasmas. PMID- 19792655 TI - Nonequilibrium dynamics of weakly and strongly paired superconductors. AB - We study small oscillations of the order parameter in weakly and strongly paired superconductors driven slightly out of equilibrium, in the collisionless approximation. While it was known for quite some time that the amplitude of the oscillations in a weakly paired superconductor decays as t(-1/2), we show that in a superconductor sufficiently strongly paired so that its fermions form bound states usually referred to as molecules, these oscillations decay as t(-3/2). The transition between these two regimes happens when the chemical potential of the superconductor vanishes; thus, the behavior of the oscillations can be used to distinguish weakly and strongly paired superconductors. Finally, we interpret the result in the strongly paired superconductor as the probability of the molecular decay as a function of time. PMID- 19792656 TI - Solution of the phase problem in the theory of structure determination of crystals from x-ray diffraction experiments. AB - We present a solution to a long-standing basic problem encountered in the theory of structure determination of crystalline media from x-ray diffraction experiments; namely, the problem of determining phases of the diffracted beams. PMID- 19792657 TI - Atomic-scale heterogeneity of a multicomponent bulk metallic glass with excellent glass forming ability. AB - We report the atomic structure of a multicomponent Cu45Zr45Ag10 bulk metallic glass investigated by state-of-the-art experimental and computational techniques. In comparison with a binary Cu50Zr50 metallic glass, Zr-rich interpenetrating clusters centered by paired and stringed Ag atoms and Cu-rich icosahedra are widely observed in the ternary Cu45Zr45Ag10 alloy. The atomic-scale heterogeneity caused by chemical short- and medium-range order is found to play a key role in stabilizing the liquid phase and in improving the glass forming ability of the multicomponent alloy. PMID- 19792658 TI - Ab initio study of fluorine in silicon: large clusters and the dominant mobile defect. AB - We determine the dominant mobile fluorine defect in silicon by density-functional based simulations. Among the mobile defects FV2, FV, F, and FI, we find the extra fluorine atom (F) to dominate diffusion. In p-type silicon it is neutral and in n type silicon it is negatively charged. The calculated concentration of this defect is by a factor of at least 10(6) higher compared to the other mobile defects. During migration of both F0 and F- the fluorine atom moves from one bond centered configuration into a neighboring one. For the negatively, neutral, and positively charged mobile defects the relative mobility was determined by molecular dynamics simulations at a temperature of 1000 degrees C. Defect concentrations were derived from calculated cluster formation energies for a large number of clusters. PMID- 19792659 TI - Isolated true surface wave in a radiative band on a surface of a stressed auxetic. AB - We demonstrate that a surface resonance (pseudosurface wave) may transform into a true surface wave, i.e., acquire an infinite lifetime, at a single isolated point within a bulk band (radiative region) in a model of a stressed auxetic material. In contrast with the secluded supersonic elastic surface waves, the one found here does not belong to a dispersion line of true surface waves. Therefore we propose to call it an isolated true surface wave (ITSW). The ITSW manifests itself by a deltalike peak in the local density of states and by anomalies in reflection coefficients. The phenomenon may be useful in redirecting energy and/or information from the bulk to the surface in devices supporting guided acoustic waves. PMID- 19792660 TI - Unusual compression behavior of anatase TiO2 nanocrystals. AB - The size-dependent stiffness variations in nanocrystalline anatase, a leading material for applications in photovoltaics, photocatalysis, photoelectrochromics, sensors, and optical coatings, were determined using in situ synchrotron x-ray diffraction and Raman scattering. An unusual, abrupt change in the compression curve at approximately 10 GPa and subtle breaks in the pressure shifts of the intense E(g) Raman band at approximately 10 and approximately 15 GPa have been correlated with approximately 2 A-scale disordering of nanocrystalline anatase structure that fully amorphizes under high compression. PMID- 19792661 TI - New microscopic mechanism for secondary relaxation in glasses. AB - The dynamics of simple molecular systems showing glassy properties has been explored by dielectric spectroscopy and nuclear quadrupole resonance (NQR) on the halogenomethanes CBr2Cl2 and CBrCl3 in their low-temperature monoclinic phases. The dielectric spectra display features which correspond to alpha- and beta relaxation processes, commonly observed in canonical glass formers. NQR experiments, also performed in the ergodic monoclinic phase of CCl4, enable the determination of the microscopic mechanism underlying the beta dynamics in these simple model glasses: Molecules that are nonequivalent with respect to their molecular environment perform reorientational jumps at different time scales. Thus our findings reveal another mechanism that can give rise to typical beta relaxation behavior, raising some doubt about the existence of a universal explanation of this phenomenon. PMID- 19792662 TI - High island densities in pulsed laser deposition: causes and implications. AB - By studying metal growth on Pt(111), we determine the reasons for the high island densities observed in pulsed laser deposition (PLD) compared to conventional thermal deposition. For homoepitaxy by PLD with moderate energies ( < or approximately 100 eV) of the deposited ions, high island densities are caused by the high instantaneous flux of arriving particles. Additional nuclei are formed at high ion energies (> or approximately 200 eV) by adatoms created by the impinging ions. For heteroepitaxy, the island density is also increased by intermixing (deposited material implanted in the surface), creating an inhomogeneous potential energy surface for diffusing atoms. We discuss implications for layer-by-layer growth and sputter deposition. PMID- 19792663 TI - Bistability of nanoscaleAg islands on a Si(111)-(4 x 1)-in surface induced by anisotropic stress. AB - We demonstrate experimentally the existence of two stability regimes of Ag nanoislands grown on a Si(111)-(4 x 1)-In surface: a conventional regime at low temperature where only one island shape is stable, and an unconventional regime at room temperature (RT) where isotropic compact islands coexist with anisotropic elongated ones. First-principles calculations show the unusual bistability at RT arises from the fact that the Ag nanoislands are under anisotropic stress, supporting a recent theoretical prediction by Zandvliet and van Gastel [Phys. Rev. Lett. 99, 136103 (2007)10.1103/PhysRevLett.99.136103]. PMID- 19792664 TI - Atomic-scale structure and stability of the square root(31) x square root(31)R9 degrees surface of Al2O3(0001). AB - Through the interplay of noncontact atomic force microscopy studies and density functional theory calculations, an atomistic model for the Al2O3(0001)-square root(31) x square root(31)R9 degrees surface reconstruction is revealed. The surface is found to consist of an Al adlayer on the Al2O3 substrate, and the driving force for the formation of the reconstruction is related to a detailed balance between strain in the adlayer and the preference for Al atoms to be located on distinct substrate sites. PMID- 19792665 TI - Surface geometric and electronic structures of BaFe2As2(001). AB - BaFe2As2 exhibits properties that are characteristic of the parent compounds of the newly discovered iron (Fe)-based high-T(C) superconductors. By combining real space imaging of scanning tunneling microscopy and spectroscopy (STM+STS) with momentum-space quantitative low-energy electron diffraction (LEED), we have identified the surface plane of cleaved BaFe2As2 crystals as the As terminated Fe As layer-the plane where superconductivity occurs. LEED and STM+STS data on the BaFe2As2(001) surface indicate an ordered arsenic (As) terminated metallic surface without reconstruction or lattice distortion. It is surprising that STM images the different Fe-As orbitals associated with the orthorhombic structure, but not the As atoms in the surface plane. PMID- 19792666 TI - Fermi surface of SrFe2P2 determined by the de Haas-van Alphen effect. AB - We report measurements of the Fermi surface (FS) of the ternary iron-phosphide SrFe2P2 using the de Haas-van Alphen effect. The calculated FS of this compound is very similar to SrFe2As2, the parent compound of the high temperature superconductors. Our data show that the Fermi surface is composed of two electron and two hole sheets in agreement with band-structure calculations. Several of the sheets show strong c-axis warping emphasizing the importance of three dimensionality in the nonmagnetic state of the ternary pnictides. We find that the electron and hole pockets have a different topology, implying that this material does not satisfy a (pi, pi) nesting condition. PMID- 19792667 TI - Coherence and pairing in a doped Mott insulator: application to the cuprates. AB - The issues of single particle coherence and its interplay with singlet pairing are studied within the slave boson gauge theory of a doped Mott insulator. Prior work by one of us [T. Senthil, Phys. Rev. B 78, 045109 (2008)10.1103/PhysRevB.78.045109] showed that the coherence scale below which Landau quasiparticles emerge is parametrically lower than that identified in the slave boson mean field theory. Here we study the resulting new non-Fermi liquid intermediate temperature regime characterized by a single particle scattering rate that is linear in temperature (T). In the presence of a d-wave pair amplitude, this leads to a pseudogap state with T-dependent Fermi arcs near the nodal direction. Implications for understanding the cuprates are discussed. PMID- 19792668 TI - 3D imaging of the Fermi surface by thermal diffuse scattering. AB - We use thermal diffuse scattering of x rays to visualize the lens-shaped portions of the Fermi surface in metallic zinc. Our interpretation of the nature of the observed scattered intensity anomalies is supported by the incorporation of inelastic x-ray scattering measurements as well as ab initio calculations of the electronic structure and lattice dynamics. Our work demonstrates that thermal diffuse scattering complements well-established techniques and is a powerful tool in its own right for studying the shape of the Fermi surface through the associated electron-phonon coupling. PMID- 19792669 TI - Evolution of critical scaling behavior near a ferromagnetic quantum phase transition. AB - Magnetic critical scaling in URu(2-x)Re(x)Si(2) single crystals continuously evolves as the ferromagnetic critical temperature is tuned towards zero via chemical substitution. As the quantum phase transition is approached, the critical exponents gamma and (delta-1) decrease to zero in tandem with the critical temperature and ordered moment, while the exponent beta remains constant. This novel trend distinguishes URu(2-x)Re(x)Si(2) from stoichiometric quantum critical ferromagnets and appears to reflect an underlying competition between Kondo and ferromagnetic interactions. PMID- 19792670 TI - Transport properties of graphene in the high-current limit. AB - We present a detailed study of the high-current transport properties of graphene devices patterned in a four-point configuration. The current tends to saturate as the voltage across graphene is increased but never reaches the complete saturation as in metallic nanotubes. Measurements are compared to a model based on the Boltzmann equation, which includes electron-scattering processes due to charged and neutral impurities, and graphene optical phonons. The saturation is incomplete because of the competition between disorder and optical phonon scattering. PMID- 19792671 TI - Numerical analysis of quasiholes of the moore-read wave function. AB - We demonstrate numerically that non-Abelian quasihole (qh) excitations of the nu=5/2 fractional quantum Hall state have some of the key properties necessary to support quantum computation. We find that as the qh spacing is increased, the unitary transformation which describes winding two qh's around each other converges exponentially to its asymptotic limit and that the two orthogonal wave functions describing a system with four qh's become exponentially degenerate. We calculate the length scales for these two decays to be xi(U) approximately 2.7l(0) and xi(E) approximately 2.3l(0), respectively. Additionally, we determine which fusion channel is lower in energy when two qh's are brought close together. PMID- 19792672 TI - Charge 2e skyrmions in bilayer graphene. AB - Quantum Hall states that result from interaction induced lifting of the eightfold degeneracy of the zeroth Landau level in bilayer graphene are considered. We show that at even filling factors electric charge is injected into the system in the form of charge 2e Skyrmions. This is a rare example of binding of charges in a system with purely repulsive interactions. We calculate the Skyrmion energy and size as a function of the effective Zeeman interaction and discuss the signatures of the charge 2e Skyrmions in the scanning probe experiments. PMID- 19792673 TI - Non-Abelian anyons: when Ising meets Fibonacci. AB - We consider an interface between two non-Abelian quantum Hall states: the Moore Read state, supporting Ising anyons, and the k=2 non-Abelian spin-singlet state, supporting Fibonacci anyons. It is shown that the interface supports neutral excitations described by a (1+1)-dimensional conformal field theory with a central charge c=7/10. We discuss effects of the mismatch of the quantum statistical properties of the quasiholes between the two sides, as reflected by the interface theory. PMID- 19792674 TI - Two-particle nonlocal Aharonov-Bohm effect from two single-particle emitters. AB - We propose a mesoscopic circuit in the quantum Hall effect regime comprising two uncorrelated single-particle sources and two distant Mach-Zehnder interferometers with magnetic fluxes, which allows us in a controllable way to produce orbitally entangled electrons. Two-particle correlations appear as a consequence of erasing of which-path information due to collisions taking place at distant interferometers and in general at different times. The two-particle correlations manifest themselves as an Aharonov-Bohm effect in noise, while the current is insensitive to magnetic fluxes. In an appropriate time interval the concurrence reaches a maximum and a Bell inequality is violated. PMID- 19792675 TI - Effects of quasiparticle ambipolarity on the nernst effect in underdoped cuprate superconductors. AB - We consider the Nernst effect in the normal state of the underdoped cuprate superconductors, where recent quantum oscillation experiments have indicated the existence of Fermi surface pockets and quasiparticle ambipolarity in the excitation spectrum. Using an ambipolar d-density-wave model for the pseudogap, we predict a peak in the Nernst coefficient with decreasing temperature below the pseudogap temperature. The existence of the peak and its sign, which we predict to be the same as that due to mobile vortices in a superconductor, result from the dominance of the electron pocket at low temperatures, as has been observed in recent Hall experiments. PMID- 19792676 TI - Predicted high-temperature superconducting state in the hydrogen-dense transition metal hydride YH3 at 40 K and 17.7 GPa. AB - Metallization in pure hydrogen has been proposed to give rise to high-temperature superconductivity at pressures which still lie beyond the reach of contemporary experimental techniques. Hydrogen-dense materials offer an opportunity to study related phenomena at experimentally achievable pressures. Here we report the prediction of high-temperature superconductivity in yttrium hydride (YH3), with a T(c) of 40 K at 17.7 GPa, the lowest reported pressure for hydrogen-dense materials to date. Specifically, we find that the face-centered cubic structure of YH3 exhibits superconductivity of different origins in two pressure regions. The evolution of T(c) with pressure follows the corresponding change of s-d hybridization between H and Y, due to an enhancement of the electron-phonon coupling by a matching of the energy level from Y-H vibrations with the peak of the s electrons from the octahedrally coordinated hydrogen atoms. PMID- 19792677 TI - Andreev spectra and subgap bound states in multiband superconductors. AB - A theory of Andreev conductance is formulated for junctions involving normal metals (N) and multiband superconductors (S) and applied to the case of superconductors with nodeless extended s(+/-)-wave order parameter symmetry, as possibly realized in the recently discovered ferropnictides. We find qualitative differences from tunneling into s-wave or d-wave superconductors that may help to identify such a state. First, interband interference leads to a suppression of Andreev reflection in the case of a highly transparent N/S interface and to a current deficit in the tunneling regime. Second, surface bound states may appear, both at zero and at nonzero energies. PMID- 19792678 TI - Enhancement of pairing interaction and magnetic fluctuations toward a band insulator in an electron-doped Li(x)ZrNCl Superconductor. AB - The doping dependence of specific heat and magnetic susceptibility has been investigated for Li(x)ZrNCl superconductors derived from a band insulator. As the carrier concentration is decreased, the anisotropy of superconducting gap changes from highly anisotropic to almost isotropic. It was also found that, upon reducing carrier density, the superconducting coupling strength and the magnetic susceptibility are concomitantly enhanced in parallel with T(c), while the density of states at the Fermi level is kept almost constant. Theoretical calculations taking into account the on-site Coulomb interaction reproduced the experimental results, suggesting a possible pairing mediated by magnetic fluctuations, even in the doped band insulators. PMID- 19792679 TI - Combined electron resonance driven by an all-oscillating potential of patterned magnets. AB - A novel mechanism is proposed for the phenomenon of combined electron resonance. It is shown that the spatially localized microwave fields of an Fe stripe array mediate the intense electronic transitions involving the changes in both spin and orbital quantum numbers when the electron moves along a cyclotron orbit in a semiconductor (e.g., InGaAs-based) quantum well. This discovery bridges the fields of spintronics and quantum computing, paving the way for conceptually new hybrid devices based on ferromagnetic and semiconductor structured materials. PMID- 19792680 TI - One-dimensional magnetic fluctuations in the spin-2 triangular lattice alpha NaMnO2. AB - The S=2 anisotropic triangular lattice alpha-NaMnO2 is studied by neutron inelastic scattering. Antiferromagnetic order occurs at T< or =45 K with opening of a spin gap. The spectral weight of the magnetic dynamics above the gap (Delta approximately equal to 7.5 meV) has been analyzed by the single-mode approximation. Excellent agreement with the experiment is achieved when a dominant exchange interaction (|J|/k(B) approximately 73 K), along the monoclinic b axis and a sizable easy-axis magnetic anisotropy (|D|/k(B) approximately 3 K) are considered. Despite earlier suggestions for two-dimensional spin interactions, the dynamics illustrate strongly coupled antiferromagnetic S=2 chains and cancellation of the interchain exchange due to the lattice topology. alpha-NaMnO2 therefore represents a model system where the geometric frustration is resolved through the lowering of the dimensionality of the spin interactions. PMID- 19792681 TI - Neutron diffraction study on the multiple magnetization plateaus in TbB4 under pulsed high magnetic field. AB - We present the first application of pulsed high magnetic fields up to 30 T for neutron diffraction experiments. As the first study, field variations of a couple of magnetic Bragg reflections have successfully been measured in the frustrated antiferromagnet TbB4. The results show that the conventional models fail, and a model, which is a mixture of the XY- and the Ising-type moments, matches for the half-magnetization state. We deduce an interaction that stabilizes an orthogonal moment arrangement as an origin of the unusual magnetization plateaus. Our results demonstrate the powerfulness of the present pulsed magnetic fields neutron diffraction system. PMID- 19792682 TI - Magnetic-field-induced polarization flop in multiferroic TmMn2O5. AB - We discovered a reversible electric polarization flop from the a axis (P(a)) to the b axis (P(b)) in multiferroic TmMn2O5 below 5 K by applying a magnetic field of approximately 0.5 T along the c axis. This phenomenon is the first example of the rare-earth (R) compound RMn2O5. This magnetic-field-induced polarization flop corresponds to a magnetic phase transition from one incommensurate magnetic (ICM) P(a) phase to another ICM P(b) phase, which is equivalent to an ICM P(b) phase above 5 K under no magnetic field. The spin chirality in the bc plane, which was observed in the P(b) phase by polarized neutron diffraction, disappeared in the ICM P(a) phase. This indicates that the polarization in the ICM phases of TmMn2O5 was induced by an S(i) x S(j)-type interaction. PMID- 19792683 TI - Magnetic-order-induced crystal symmetry lowering in ACr2O4 ferrimagnetic spinels. AB - We demonstrate that the onset of complex spin orders in ACr2O4 spinels with magnetic and Jahn-Teller active A=Fe and Cu ions lowers the lattice symmetry. This is clearly indicated by the emergence of anisotropic lattice dynamics-i.e., by the pronounced phonon splittings-even when experiments probing static distortions fail. The crystal symmetry in the magnetic phase is reduced from tetragonal to orthorhombic for both compounds. The conical spin ordering in FeCr2O4 is also manifested in the hardening of the phonon frequencies. In contrast, the multiferroic CoCr2O4 with no orbital degrees of freedom shows tiny deviations from cubic structure even in its ground state. PMID- 19792684 TI - Near-field interaction between domain walls in adjacent Permalloy nanowires. AB - The magnetostatic interaction between two oppositely charged transverse domain walls (TDWs) in adjacent Permalloy nanowires is experimentally demonstrated. The dependence of the pinning strength on wire separation is investigated for distances between 13 and 125 nm. The results can be described fully by considering the distribution of magnetic charge within rigid, isolated TDWs. Alternative DW internal structure cannot reproduce this observed dependence. Modeling suggests the TDW internal structure is not appreciably disturbed, and remains rigid although the pinning strength is significant. PMID- 19792685 TI - Phase diagram and spin dynamics in volborthite with a distorted kagome lattice. AB - We report a (51)V-NMR study on a high-quality powder sample of volborthite Cu3V2O7(OH)2 . 2H2O, a spin-1/2 Heisenberg antiferromagnet on a distorted kagome lattice formed by isosceles triangles. In the magnetic fields below 4.5 T, a sharp peak in the nuclear spin-lattice relaxation rate 1/T(1) accompanied with line broadening revealed a magnetic transition near 1 K. The low temperature phase shows anomalies such as a Lorentzian line shape, a 1/T(1) proportional, variantT behavior indicating dense low-energy excitations, and a large spin-echo decay rate 1/T(2) pointing to unusually slow fluctuations. Another magnetic phase appears above 4.5 T with less anomalous spectral shape and dynamics. PMID- 19792686 TI - Magnetic dichroism from optically excited quantum well states. AB - We demonstrate magnetic dichroism from optically excited states in two-photon photoemission. Using ultrathin cobalt films grown on Cu(001), we observe unoccupied quantum well states which give rise to a sizable intensity change in photoemission under magnetization reversal. The simultaneous comparison of both circular and linear magnetic dichroism in the same system permits us to check fundamental symmetry requirements and allows us to explicitly elucidate the common origin of both effects. Based on our observations we argue that the observed effect is related to spin-orbit coupling in the intermediate quantum well states. PMID- 19792687 TI - Direct observation of charge order and an orbital glass state in multiferroic LuFe2O4. AB - Geometrical frustration of the Fe ions in LuFe2O4 leads to intricate charge and magnetic order and a strong magnetoelectric coupling. Using resonant x-ray diffraction at the Fe K edge, the anomalous scattering factors of both Fe sites are deduced from the (h/3 k/3 l/2) reflections. The chemical shift between the two types of Fe ions equals 4.0(1) eV corresponding to full charge separation into Fe2+ and Fe3+. The polarization and azimuthal angle dependence of the superlattice reflections demonstrate the absence of differences in anisotropic scattering revealing random orientations of the Fe2+ orbitals characteristic of an orbital glass state. PMID- 19792688 TI - Observation of a soft mode of elastic instability in liquid crystal elastomers. AB - In monodomain liquid crystal elastomers a symmetry-breaking locked-in anisotropy causes a semisoft elastic response characterized by a plateau in the stress strain curve. We show by dynamic light scattering performed as a function of deformation that the relaxation rate of the nematic director fluctuations decreases with strain to a very small value at the onset of the soft elastic response, revealing the existence of a dynamic soft mode. The results are in complete agreement with the theory of semisoft elasticity and allow us to determine all the constants of the model. PMID- 19792689 TI - Accumulation of microswimmers near a surface mediated by collision and rotational Brownian motion. AB - In this Letter we propose a kinematic model to explain how collisions with a surface and rotational Brownian motion give rise to accumulation of microswimmers near a surface. In this model, an elongated microswimmer invariably travels parallel to the surface after hitting it from an oblique angle. It then swims away from the surface, facilitated by rotational Brownian motion. Simulations based on this model reproduce the density distributions measured for the small bacteria E. coli and Caulobacter crescentus, as well as for the much larger bull spermatozoa swimming between two walls. PMID- 19792690 TI - Wake tracking and the detection of vortex rings by the canal lateral line of fish. AB - Research on the lateral line of fish has mainly focused on the detection of oscillating objects. Yet many fish are able to track vortex wakes that arise from other fish. It is not yet known what the sensory input from a wake looks like and how fish can extract relevant information from it. We present a mathematical model to determine how vortices stimulate the canal lateral line and verify it by neuronal recordings. We also show how the information about the orientation of a vortex ring is captured by the lateral-line sensors so as to enable fish to follow a vortex street. PMID- 19792691 TI - Directional locking and the role of irreversible interactions in deterministic hydrodynamics separations in microfluidic devices. AB - We performed macroscopic experiments on the motion of a sphere through an array of obstacles that highlight the deterministic nature of the lateral displacements that lead to particle separation in microfluidic systems. The motion of the spheres is irreversible and displays directional locking. The locking directions can be predicted with a single parameter that distinguishes between reversible and irreversible particle-obstacle collisions. These results stress the need to incorporate irreversible interactions to predict the movement of a non-Brownian sphere passing through a periodic array. PMID- 19792692 TI - Melting of iron under Earth's core conditions from diffusion Monte Carlo free energy calculations. AB - The temperature of Earth's core is a parameter of critical importance to model the thermal structure of Earth. Since the core is mainly made of iron, with a solid liquid boundary (the inner core boundary) at 1220 km from the center of the Earth, the melting temperature of iron at the pressure of the ICB provides constraints on the temperature of the core. These constraints are based either on extrapolations to ICB pressure of experimental measurements, or on theoretical calculations which employed various flavors of quantum mechanics, most notably density functional theory. Significant disagreement between estimates obtained with different methods calls for calculations based on more accurate techniques. Here we used quantum Monte Carlo techniques to compute the free energies of solid and liquid iron at ICB conditions. We obtained an iron melting temperature at 330 GPa of 6900+/-400 K. PMID- 19792693 TI - Comment on "Osmotic propulsion: the osmotic motor". PMID- 19792695 TI - Quantum solution to the arrow-of-time dilemma. AB - The arrow-of-time dilemma states that the laws of physics are invariant for time inversion, whereas the familiar phenomena we see everyday are not (i.e., entropy increases). I show that, within a quantum mechanical framework, all phenomena which leave a trail of information behind (and hence can be studied by physics) are those where entropy necessarily increases or remains constant. All phenomena where the entropy decreases must not leave any information of their having happened. This situation is completely indistinguishable from their not having happened at all. In the light of this observation, the second law of thermodynamics is reduced to a mere tautology: physics cannot study those processes where entropy has decreased, even if they were commonplace. PMID- 19792696 TI - Probing minicharged particles with tests of Coulomb's law. AB - Minicharged particles arise in many extensions of the standard model. Their contribution to the vacuum polarization modifies Coulomb's law via the Uehling potential. In this Letter, we argue that tests for electromagnetic fifth forces can therefore be a sensitive probe of minicharged particles. In the low mass range < or approximately equal to microeV existing constraints from Cavendish type experiments provide the best model-independent bounds on minicharged particles. PMID- 19792697 TI - Microscopic theory of the Andreev gap. AB - We present a microscopic theory of the Andreev gap, i.e., the phenomenon that the density of states (DOS) of normal chaotic cavities attached to superconductors displays a hard gap centered around the Fermi energy. Our approach is based on a solution of the quantum Eilenberger equation in the regime tD<EeV gamma rays can be more direct evidence of UHECRs than approximately PeV neutrinos and GeV-TeV gamma rays. We demonstrate that coincident detections of approximately 1-100 events can be expected by current and future UHECR detectors such as Auger and JEM-EUSO, and the detection probability can be higher than that of neutrinos for nearby transient sources at < or approximately equal to 50-100 Mpc. They may be useful for constraining the uncertain cosmic radio background as well as knowing the source properties and maximum energy of UHECRs. They can also give us more than 10(4) times stronger limits on the Lorentz-invariance violation than current constraints. PMID- 19792708 TI - High-energy antiprotons from old supernova remnants. AB - A recently proposed model explains the rise in energy of the positron fraction measured by the PAMELA satellite in terms of hadronic production of positrons in aged supernova remnants, and acceleration therein. Here we present a preliminary calculation of the antiproton flux produced by the same mechanism. While the model is consistent with present data, a rise of the antiproton to proton ratio is predicted at high energy, which strikingly distinguishes this scenario from other astrophysical explanations of the positron fraction (such as pulsars). We briefly discuss important implications for dark matter searches via antimatter. PMID- 19792709 TI - Testing astrophysical models for the PAMELA positron excess with cosmic ray nuclei. AB - The excess in the positron fraction measured by PAMELA has been interpreted as due to annihilation or decay of dark matter in the Galaxy. More prosaically it has been ascribed to direct production of positrons by nearby pulsars or due to pion production during diffusive shock acceleration of hadronic cosmic rays in nearby sources. We point out that measurements of secondary cosmic ray nuclei can discriminate between these possibilities. New data on the titanium-to-iron ratio support the hadronic source model above and enable a prediction for the boron-to carbon ratio at energies above 100 GeV. PMID- 19792710 TI - Ultraviolet behavior of N = 8 supergravity at four loops. AB - We describe the construction of the complete four-loop four-particle amplitude of N=8 supergravity. The amplitude is ultraviolet finite, not only in four dimensions, but in five dimensions as well. The observed extra cancellations provide additional nontrivial evidence that N=8 supergravity in four dimensions may be ultraviolet finite to all orders of perturbation theory. PMID- 19792711 TI - Peccei-Quinn mechanism in gravity and the nature of the Barbero-Immirzi parameter. AB - A general argument provides the motivation to consider the Barbero-Immirzi parameter as a field. The specific form of the geometrical effective action allows one to relate the value of the Barbero-Immirzi parameter to other quantum ambiguities through the analog of the Peccei-Quinn mechanism. PMID- 19792712 TI - Cosmic microwave background bispectrum from primordial magnetic fields on large angular scales. AB - Primordial magnetic fields lead to non-Gaussian signals in the cosmic microwave background (CMB) even at the lowest order, as magnetic stresses and the temperature anisotropy they induce depend quadratically on the magnetic field. In contrast, CMB non-Gaussianity due to inflationary scalar perturbations arises only as a higher-order effect. We propose a novel probe of stochastic primordial magnetic fields that exploits the characteristic CMB non-Gaussianity that they induce. We compute the CMB bispectrum (b(l1l2l3)) induced by such fields on large angular scales. We find a typical value of l1(l1 + 1)l3(l3 + 1)b(l1l2l3) approximately 10(-22), for magnetic fields of strength B0 approximately 3 nG and with a nearly scale invariant magnetic spectrum. Observational limits on the bispectrum allow us to set upper limits on B0 approximately 35 nG. PMID- 19792713 TI - Sketching the Bethe-Salpeter kernel. AB - An exact form is presented for the axial-vector Bethe-Salpeter equation, which is valid when the quark-gluon vertex is fully dressed. A Ward-Takahashi identity for the Bethe-Salpeter kernel is derived therefrom and solved for a class of dressed quark-gluon-vertex models. The solution provides a symmetry-preserving closed system of gap and vertex equations. The analysis can be extended to the vector equation. This enables a comparison between the responses of pseudoscalar and scalar meson masses to nonperturbatively dressing the quark-gluon vertex. The result indicates that dynamical chiral symmetry breaking enhances spin-orbit splitting in the meson spectrum. PMID- 19792714 TI - Test of Lorentz invariance with spin precession of ultracold neutrons. AB - A clock comparison experiment, analyzing the ratio of spin precession frequencies of stored ultracold neutrons and 199Hg atoms, is reported. No daily variation of this ratio could be found, from which is set an upper limit on the Lorentz invariance violating cosmic anisotropy field b perpendicular < 2 x 10(-20) eV (95% C.L.). This is the first limit for the free neutron. This result is also interpreted as a direct limit on the gravitational dipole moment of the neutron |gn| < 0.3 eV/c2 m from a spin-dependent interaction with the Sun. Analyzing the gravitational interaction with the Earth, based on previous data, yields a more stringent limit |gn| < 3 x 10(-4) eV/c2 m. PMID- 19792715 TI - Measurement of the ratio of the numu charged-current single-pion production to quasielastic scattering with a 0.8 GeV neutrino beam on mineral oil. AB - Using high statistics samples of charged-current numu interactions, the MiniBooNE [corrected] Collaboration reports a measurement of the single-charged-pion production to quasielastic cross section ratio on mineral oil (CH2), both with and without corrections for hadron reinteractions in the target nucleus. The result is provided as a function of neutrino energy in the range 0.4 GeVJ/psipi0(eta). AB - Light quark masses are important fundamental parameters of the standard model. The decays psi'-->J/psipi0(eta) were widely used in determining the light quark mass ratio m(u)/m(d). However, there is a large discrepancy between the resulting value of m(u)/m(d) and the one determined from the light pseudoscalar meson masses. Using the technique of nonrelativistic effective field theory, we show that intermediate charmed meson loops lead to a sizable contribution to the decays and hence make the psi'-->J/psipi0(eta) decays not suitable for a precise extraction of the light quark mass ratio. PMID- 19792721 TI - Neutron properties in the medium. AB - We demonstrate that for small values of momentum transfer Q2 the in-medium change of the GE/GM form factor ratio for a bound neutron is dominated by the change in the electric charge radius and predict within stated assumptions that the in medium ratio will increase relative to the free result. This effect will act to increase the predicted cross section for the neutron recoil polarization transfer process 4He(e-vector,e'n-vector)3He. This is in contrast with medium modification effects on the proton GE/GM form factor ratio, which act to decrease the predicted cross section for the 4He(e-vector,e'p-vector)3H reaction. Experiments to measure the in-medium neutron form factors are currently feasible in the range 0.1